u j 03 all-2.pdf 623vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran abbas basiri, mahmoudreza nasiri, mohammad hossein soltani urothelial carcinoma of the ureter in a patient with functional single kidney corresponding author: abbas basiri, md urology and nephrology research center, no. 103, 9th boustan st, pasdaran ave, 1666677951, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir answer to cpc brief history a hydroureteronephrosis. quiz patient has undergone laparoscopic distal right ureterectomy and ureteroneocystostomy using boari the 10th 624 | answer to cpc figure 1. low-grade papillary urothelial carcinoma of the distal ureter (pt1). figure 2. diethylenetriamine pentaacetic acid scan revealed acceptable anastomotic continuity without obstruction 2 month post-operatively. ieus 2019 dear friends and colleagues, on behalf of the iranian endourology and urolaparoscopy society, it is our pleasure and honor to invite you cordially to the 11th iranian endourology and urolaparoscopy society (ieus) congress to be held on dec 04-06, 2019. we have invited a remarkable number of the world-renowned urologists. with the support of guest speakers, many endourological societies and with the great help of iranian scientists, we are putting a unique scientific program for 11th ieus congress. all areas of minimally invasive procedures and new technologies in endourology and laparoscopy will be touched by state of the art lectures, debates, expert video sessions and more. hope the attractive scientific program, shall meet your expectations, and we will try our best to provide you the latest cutting edge science. thanks to all invited speakers and endourology societies. looking forward to seeing you and make sure you don’t miss out of this very likely event, and get a taste of the historically famous persian hospitality. pejman shadpour m.d congress president amir h kashi m.d general secretary ⅲ v08_no_3_final.pdf clinical pathology case 236 urology journal vol 8 no 3 summer 2011 an unusual presentation of an uncommon renal disease farzaneh sharifiaghdas, hossein kilani, seyed amin mirsadeghi urol j. 2011;8:236-8. www.uj.unrc.ir shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran corresponding author: farzaneh sharifiaghdas, md shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran tel/fax: +98 21 2258 8016 e-mail: fsharifiaghdas@yahoo.com case presentation a 59-year-old man presented with non-specific right flank pain two years earlier. ultrasonography and intravenous urography revealed right staghorn renal calculi. thereafter, he underwent right open nephrolithotomy and stonefree condition was confirmed by follow-up imaging. figure 1. intravenous pyelogram demonstrating no excretion on the right side. clinical pathology case 237urology journal vol 8 no 3 summer 2011 after 18 months, the patient presented with the same chief complaint. small size (10 mm) stone of the right side of the pelvis was diagnosed, which was treated with extracorporeal shockwave lithotripsy at one session. two weeks later, he developed chills, high fever, and severe flank pain. ultrasonography showed right pyonephrosis, which was drained as an outpatient surgery by placing untrasound-guided nephrostomy catheter. a large amount of pus was drained and the patient became symptom-free. intravenous urography revealed non-functional right kidney (figure 1), which was confirmed by diethylene triamine pentaacetic acid (dtpa) scan (split function of 11.6% and 88.4% for the right and left kidneys, respectively). right side ureteral obstruction was also demonstrated in dtpa scan (figure 2). with the suspicion of obstruction made by small particles of fragmented stones, ureteroscopy was performed, which was unremarkable. double-j stent was inserted and nephrostomy tube was removed 2 days later. the patient became symptomatic again after double-j stent insertion and experienced several episodes of urinary tract infection, following which double-j stent was removed. follow-up computed tomography scan showed severe right upper pole caliectasis and moderate right hydronephrosis with deformation of the pyelocalyceal system suspicious for xanthogranulomatous pyelonephritis (figure 3). due to frequent relapses of symptoms and signs, the patient underwent right simple nephrectomy. figure 2. poor perfusion and function of the right kidney in renal dtpa scan. clinical pathology case 238 urology journal vol 8 no 3 summer 2011 quiz do you agree with the approach chosen for the diagnosis or do you recommend other imaging studies or procedures? what do you think the final pathology report of the specimen might be? the answers will be discussed in the next issue of urology journal. figure 3. abdominal computed tomography scan with intravenous contrast suspicious for xanthogranulomatous pyelonephritis. notice 189urology journal vol 4 no 3 summer 2007 notice of inadvertent duplicate publication urol j. 2007;4:189. www.uj.unrc.ir the urology journal wishes to draw attention to a paper by nikoobakht and colleagues, “the relationship between lipid profile and erectile dysfunction,” which was published in volume 2, number 1 (winter 2005) of the journal, that is similar to an article by the same authors and same title, published in the international journal of impotence research 2005;17:523-6. this inadvertent duplicate publication has occurred as a result of misinterpretation of local journals and a different group of readers; in 2005, our journal was not being indexed in the international indexing systems and used to be considered as a local publication. moreover, many authors were not familiar with the regulations of acceptable secondary publication. in this case, the corresponding author was contacted and it was confirmed that this is a case of inadvertent duplicate publication and the mistake was a result of a misunderstanding of the regulations by authors. 1502 | epidermoid cyst of the urinary bladder: a rare case wenying wang, wencheng lv , ye tian keywords: epidermalcyst;diagnosis;urinarybladderdiseases;urothelium;pathology. introduction epidermoidcystoftheurinarybladderisaveryrarebenignlesion.tothebestofourknowledge,thiscasereportofanepidermoidcystlocatedintheurinarybladderisthefirstintheenglish-languageliterature. case report a31-year-oldmanwasadmittedtothehospitalforalesionoftheurinarybladderdiscovered onroutinephysicalexamination.hehadahistoryofsurgeryforaperianalabscess3years earlier.theurinarynuclearmatrixprotein22(nmp22),serumcancerantigen19-9(ca199)andcarcinoembryonicantigen(cea)levelswereinthenormalrange.ultrasonography (us)examinationshowedanavascularonion-ringpatternwithalternatinghyperechoicand hypoechoicrings.computedtomography(ct)scanrevealedacysticmassintherightwallof thebladderthathadadensityof15-30hounsfieldunit(hu)withoutenhancement(figure1). surgicalexplorationrevealeda3.0×3.2×2.5cmregularlyshapedmassarisingfromthedetrusormusclelayerofthebladder.themasswasexcisedcompletely.uponincisingofthemass, alargeamountofcheesykeratinizedmaterialwasfoundinthecavity.hematoxylinandeosin stainingofthespecimenrevealedatypicalepidermoidcystthatwaslinedwithstratifiedsquamousepithelium.nohair,sebaceousglandsorotherskinadnexawereseenwithinthecyst,nor werethereanyfindingssuggestiveofdysplasiaormalignancy(figure2).thepatientdidwell postoperatively,andnorecurrencewasnotedatthe18-monthfollow-up. discussion epidermoidcystislinedwithstratifiedsquamousepitheliumthatcontainsagranularlayerand isfilledwithkeratinousmaterialthatisofteninalaminatedarrangement.thesecystsarerare corresponding author: ye tian, md department of urology, beijing friendship hospital, capital medical university, 95 yong an road, xuanwu district, beijing, 100050, china. tel: +86 186 0116 6102 fax: +86 106 3139 043 e-mail: miniaowwy@yahoo.com.cn received july 2012 accepted january 2013 department of urology, beijing friendship hospital, capital medical university, 95 yong an road, xuanwu district, beijing,100050, china. case report case report 1503vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l epidermoid cyst of the urinary bladder | wang et al inchildrenbutarecommoninadults,theirmostfrequentlocationsaretheface,scalp,neck,andtrunk.epidermoidcysts arerarelyseeninsolidorgans.afewcasesofepidermoid cystslocatedatraresitessuchasthekidneyandureterhave been reported in the literature.(1,2)tothebestofourknowledge,epidermoidcystoftheurinarybladderhasnotbeen reportedpreviously. epidermoidcystsareusuallyasymptomatic,althoughsymptomsmayoccurwhenthecystsarelarge.theymaybecome infected,oruncommonly,theymayrupture,causingaforeignbodyreaction.symptomsofflankpain,dysuria,orgross hematuriaareabletohappeninpatientswithrenalepidermoidcysts.(1)resultsofroutinelaboratorytestsareusually normalandnotdiagnostic.keratinizedmaterialinaurine samplemaysuggestanepidermoidcystintheurinarytract.(2) epidermoidcysts,whicharetruecongenitalprimarymesothelialcysts,haveanepithelialormesothelialcelllining,and arethoughttobedevelopmentalinorigin.differenttheories havebeenpostulatedforthepresenceofepidermoidcystin extraordinarysitessuchaskidney,spleen,brain,andureter. inthekidney,itissuggestedthatthistypeofcystcouldoriginatefromtheembryonicremnantofwolffianducts.(2) in this patient,thecystmayhavearisenfromsurgicalimplantation ofepidermaltissuesecondarytoperianalabscesssurgery. on us, the classic appearance is typically alternating of avascularhyperechoicandhypoechoicrings,whichwasdescribedasanonion-ringpattern.onctscan,epidermoid cystsappearashomogenous,well-defined, roundoroval, low-enhancingornon-enhancing,hypodenselesions.cysts shouldnotdemonstrateanyenhancementaftertheadministrationofgadolinium. mostepidermoidcystsdon'tcauseproblemsorrequiretreatment,butiftheyareacosmeticconcern,oriftheyrupture or become infected, they usually are removed surgically. epidermoidcystsareusuallybenign,butthereisareported 1to3percentrateofmalignanttransformation.squamous cellcarcinomahasbeenobservedoriginatingfromsquamous epitheliumlocatedinthetestis,aswellasfromanintracranialepidermoidcyst.(3) although a lesion such as this has notbeendemonstratedintheurinarybladder,excisionofthis cystisthemostappropriatemanagement. althoughrare,epidermoidcystoftheurinarybladdershould beconsideredinthedifferentialdiagnosisofincidentallydiscoveredbladderlesions. conflict of interest none declared. references 1. dadali m, emir l, sunay m, ozer e, erol d. intrarenal epidermal cyst. kaohsiung j med sci. 2010:26:555-7. 2. ishizaki h, iida s, koga h, shimamatsu k, matsuoka k. epidermoid cyst of the ureter: a case report. int j urol. 2007;14:443-4. 3. chiu my, ho st. squamous cell carcinoma arising from an epidermal cyst. hong kong med j. 2007;13:482-4. figure 1. computed tomography scan revealed a cystic mass in the right wall of the bladder that had a density of 15-30 hounsfield unit without enhancement. figure 2. hematoxylin and eosin staining of the specimen revealed a typical epidermoid cyst that was lined with stratified squamous epithelium (40×10). v08_no_4_final_new.pdf pictorial urology 269urology journal vol 8 no 4 autumn 2011 myiasis with carcinoma in situ of the glans penis an unusual combination urol j. 2011;8:269. www.uj.unrc.ir a 70-year-old man belonging to low socioeconomic status, illiterate, and daily-wage laborer, presented with painful, foul-smelling ulcer on the glans penis. the patient was examined properly and investigated thoroughly. when the ulcer was cleaned, maggots started emerging from the ulcer. they were removed by applying turpentine oil on the ulcer. the ulcer did not heal despite regular wound dressing and appropriate antibiotic therapy. histopathology following incisional biopsy revealed the ulcer as carcinoma in situ of the glans penis. the patient refused regular follow-up and wanted definitive treatment. hence, partial penectomy was performed. penile myiasis is a rare entity, which occurs due to infestation by larvae or maggots of numerous species of flies.(1) penile carcinoma is gradually becoming uncommon following improvement of general living condition in the third world.(2) case reports of penile myiasis do exist in literature,(1) but the association of myiasis with carcinoma in situ of the glans penis is rare; single case report (from brazil) has been mentioned in the english literature.(3) we highlight this unusual association and report the first such finding from asia. vishwajeet singh, rahul janak sinha* department of urology, csmmu (formerly kgmu), lucknow, (u.p.), india *e-mail: rahuljanaksinha@rediffmail.com references 1. passos mr, ferreira dc, arze wn, silva jc, passos fd, curvelo ja. penile myiasis as a differential diagnosis for genital ulcer: a case report. braz j infect dis. 2008;12:155-7. 2. solsona e, algaba f, horenblas s, pizzocaro g, windahl t. eau guidelines on penile cancer. eur urol. 2004;46:1-8. 3. tavares aj, barros r, favorito la. urgent penectomy in a patient presenting with epidermoid carcinoma of the penis associated to myiasis. int braz j urol. 2007;33:521-2. case report a simplified management of transverse testicular ectopia in patients with persistent mullerian duct syndrome massimiliano silveri1*, antonio zaccara1, marco cappa2 1department of surgery, ospedale pediatrico bambino gesù, rome, italy. 2department of pediatric endocrinology, ospedale pediatrico bambino gesù, rome, italy. *correspondence: department of surgery , ospedale pediatrico bambino gesù, rome, italy. piazza sant’onofrio 4, 00100, rome italy. phone: 0039668593358. fax: 0039668593373. e mail: massimiliano.silveri@opbg.net. received october 2019 & accepted april 2020 persistent müllerian duct syndrome (pmds) in the majority of cases is discovered during surgery for inguinal hernia or cryptorchidism. a transverse testicular ectopia (tte) with cryptorchidism may be very rarely associated to pmds. assuming that müllerian remnants have a very low malignant degeneration potential if compared to the malignancy risk of an undescended and not relocated testis, we describe a simplified surgical technique of orchiopexy that avoids an extensive anatomical dissection, in this way minimizing the risk of losing the deferential blood supply to the testis. keywords: radical cystectomy; ileal conduit, cutaneous ureterostomy; orthotopic neobladder; appendix introduction persistent müllerian duct syndrome (pmds) is frequently discovered during surgery for inguinal hernia or cryptorchidism(1). in this disorder of sex development (dsd), the patients show müllerian remnants located at scrotal, inguinal or intraabdominal level. a transverse testicular ectopia (tte) with cryptorchidism may be rarely associated to pmds because of defect in regression of fetal müllerian structures and concomitant aberrant testicular descent(2). in these rare cases, a planned surgical approach is advisable confirming the opportunity to perform, as a first step, a laparoscopic diagnostic approach in all cases of unpalpable testis. we describe a simplified orchiopexy technique performed in one of these rare cases in order to prevent devascularisation or direct damage to the vas. urology journal/vol 18 no. 2/ march-april 2021/ pp. 237-239. [doi: 10.22037/uj.v0i0.5685] figure 1. ultrasound showing two separate gonadal structures both located in the right inguinal channel. figure 2. laparoscopy showing the anatomy at the level of the right internal inguinal ring, with a rudimentary uterus and a rudimentary tube interposed between the two testes. case report a 2-year-old boy came to our attention for a left impalpable testis. following a neonatal diagnosis of bilateral cryptorchidism, the baby underwent an ultrasound (us) at 6 months of age showing a right testis in the scrotum and an extremely reduced gonadal structure approximately at the level of the left inguinal ring. however, the evidence of two separate and palpable structures both located in the right inguinal channel (figure 1) alerted our intersex team about the possibility of an underlying dsd. a hcg test for the exploration of leydigian function was normal and karyotype resulted as male 46, xy. technique the child underwent a laparoscopy (figure 2) showing the two normal testes, both located proximally to the right inguinal ring, with a rudimentary uterus and rudimentary tubes interposed and a not clear anatomy of the left vas. the baby underwent an open procedure through a right inguinal incision (figure 3). separation of the vas from the remnants was not possible except, most likely, with its sacrifice. therefore, a simplified pull-through of the complete anatomical package with repositioning of the left testis through a partial violation in the septal scrotum, was successfully attempted (figure 4). at 3 years follow-up, both testes are correctly located in the scrotum with a progressive catch-up growth highlighted by clinical (twice a year) and us (once a year) controls. discussion this eased surgical approach, in this particular category of patients, can be achievable only with the assumption that müllerian remnants do not have any malignant degeneration potential(3). persistent müllerian duct syndrome (pmds) is a rare form of dsd in which a phenotypically normal male has müllerian structures that fail to regress. this embryological event is upregulated by a glycoprotein produced by sertoli cells and called müllerian inhibiting substance (mis) )(4). mutations in case report 413 figure 3. surgical view of the műllerian structures and both the gonads exteriorized through an inguinal incision. figure 4. repositioning of both testes in their respective anatomical sites obtained through a trans-scrotal approach. vol 18 no 2 march-april 2021 238 surgical management of tte in pmds-silveri et al. mis and mis receptor genes, mapped to chromosome 19 (mis) and chromosome 12 (mis type ii specific receptor) cause lack of mis secretion or lack of translocation to the surface membrane with inactivity of the mis receptor(5). despite many hypotheses on the relationship between pmds and tte(6,7), the simple anatomic close contiguity of the testis to the persistent műllerian ducts is believed to be the cause of cryptorchidism in pmds. there is a dualism in literature about whether or not to remove műllerian structures in order to prevent a potential malignant degeneration(3,8). recent description of gynaecological malignancies in retained műllerian structures(9) is estimated in 3-8%. the overall incidence of malignant transformation in pmds testes is similar to the rate in abdominal testes in otherwise normal men(9,10) (18%), in this way representing another argument in favour of early orchiopexy. starting from these assumptions, we successfully adopted the above-described approach(11) as the gold-standard management in these rare cases. in our opinion, as suggested by the normal pattern of our biopsied gonads, even the previously reported foreclosures about the fertility potential of pmds testes should be reconsidered assuming that the only real limit is probably cryptorchidism. a close and long term instrumental and clinical follow-up is mandatory above all for that concerning the risk of possible late onset gynaecological malignancies. references 1. picard jy, cate rl, racine c et al. the persistent műllerian duct syndrome: an update based upon a personal experience of 157 cases. sex dev. 2017; 11:109-125 2. wuerstle m, lesser t, hurwitz r et al. persistent műllerian duct syndrome and transverse testicular ectopia: embryology, presentation, and management. j ped surg. 2007;42:2116-2119 3. vandersteen dr, chaumeton ak, ireland k et al. surgical management of persistent műllerian duct syndrome. urology. 1997; 49:941-945 4. guerrier d, tran d, vanderwinden jm et al. the persistent műllerian duct syndrome: a molecular approach. j clin endocrinol metab. 1989;68:45-52 5. bartlett je, lee smy, mishina y et al. gubernacular development in műllerian inhibiting substance receptor-deficient mice. bju int. 2002;89:113-118 6. gauderer mw, grisoni er, stellato ta et al. transverse testicular ectopia. pediatr surg. 1982;17:1-2 7. asero l, meli r. the persistent műllerian duct syndrome with transverse testicular ectopia. a hypothesis on the role of műllerian inhibiting factor in the process of testicular migration. pediatr med chir. 1997;19:223-225 8. shinmura y, yokoi t, tsutsui y. a case of clear cell adenocarcinoma of the műllerian duct in persistent műllerian duct syndrome: the first reported case? arch pathol lab med. 2000;124:694-698 9. farikullah j, ehtisham s, nappo s, patel l, hemayake s. persistent műllerian duct syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the műllerina remnants. bju int 2012;110:e1084-9) 10. alpo bf, demiren z, gűragaḉ a et al. persistent műllerian duct syndrome with transverse testicular ectopia and seminoma. int urol nephrol 2014; 46:1557-62 11. naouar s, maazoun k, sahnoun l et al. transverse testicular ectopia: a three-case report and review of the literature. urology 2008;71:1070-73 case report 212case report 428 surgical management of tte in pmds-silveri et al. case report 239 1343vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l intra urethral intercourse: a report of two cases mahtab zargham, homayon abbasi, farshid alizadeh, mohamad hatef khorami, farhad tadayon, mohamad reza gharaati, mohamad hosein izadpanahi keywords: urethra; female; coitus; injuries. introduction urethral coitus is very rare and in the reported cases, it was mostly presented with urinary incontinence and infertility. septate vagina and other anomalies of hyme-neal orifice are predisposing factors at the time of initiation of sexual activity.(1) urethral intercourse in the female is very rare. when urethral coitus occurs, it is usually in association with rape or with vaginal atresia or other hymeneal anomalies. we present two cases of urethral coitus in presence and absence of a genital anomaly. case 1 a 21-year-old woman was presented with a history of sever urinary incontinence since marriage (1.5 years earlier). she sought medical help for severe dyspareunia, infertility and recurrent urinary tract infection (uti) and were simultaneously evaluated for probable diagnosis of infertility. she used sanitary pads to keep herself dry. examination revealed that she had a 2.2 cm urethral wall with a tear extending from the urethral meatus proximally to bladder neck distally (figure 1). normal ovaries, uterus and vagina were confirmed by both physical corresponding author: farhad tadayon, md e-mail: tadayon@mui.ac.ir received march 2012 accepted september 2012 department of urology, noor hospital, isfahan university of medical sciences, isfahan, iran. case report 1344 | case report examination and ultrasonography. cystoscopy was done under anesthesia during which the urethra and the bladder neck was found to be damaged. under general anesthesia and in lithotomy position, a 3.5 cm vertical inverted u incision was made just in the proximal extent of urethral laceration and vaginal wall dissection of the urethra and opening of bladder neck. the paravaginal flap was sutured (with 4-0 vicryl placating sutures) to the edge of the parallel distal incisions over the catheter to form the new urethra. the classic rectus fascial graft was passed around the urethra and reinforced with martius flap and epithelium of vaginal wall was approximated trough the entire of urethra (figure 2). the catheter was removed 10 days after operation. she was followed up for 2 years and remained continent. case 2 a 19-year-old woman presented with history of enuresis, frequency, recurrent uti and also very painful coitus (dyspareunia) and infertility after two years of marriage. she was evaluated earlier with intravenous urography and ultrasonography elsewhere, which were reported as normal. the patient was a young woman from a poor family living in a small village. she had prior gynecological and psychological consultation for her problems. the patient had undergone vaginal examination. it revealed a vertical vaginal septum. resection of vaginal septum was done through the vagina which was about 8 mm thick (figure 3). however, urethral damage was missed for 1 year latter when she referred to our clinic for management of urinary incontinence. vaginal examination and cystoscopy under anesthesia revealed an open bladder neck and laceration of entire length of the urethra (figures 3 and 4) which strongly suggested intra urethral coitus. in an operative setting under general anesthesia, the urethral repair was done with a paravaginal flap. first, the edge of the urethral laceration was freshened. then the paravaginal flap was sutured to the edge of the parallel distal incisions of the damaged urethra over the 10 french foley catheter to form the new urethra. as an antiincontinence surgery, rectus fascia graft was passed around the urethra to maximized urethral closure pressure (figure 5). the vaginal wall was approximated in the midline to cover the neourethra. discussion among the causes of stress urinary incontinence (sui) in women, trauma and urethral loss are extremely rare. the most important causes of urethral laceration and loss of sphincteric mechanism include the impacts associated with pelvic fractures, puerperal trauma and iatrogenic causes. figure 1. urethral wall with a tear extending from the urethral meatus proximally to bladder neck distally. figure 2. the neo-urethra had adequate length and caliber. 1345vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l intra urethral intercourse | tadayon et al (2,3) rare cases of urethral rupture was reported after rape or sexual disabuse,(4,5) but in our first case, despite the existence of a normal genital anatomy, the intercourse was intraurethrally done by the husband that there was no explicit justification for it. in the second patient, the vertical vaginal septum can be propounded as a limiting factor of vaginal space and the background for urethral rupture. to our knowledge, this is the first case of urethral intercourse associated with vertical vaginal septum. in particular, the occurrence of most of the cases of intercourse through urethra were related to mullerian anomalies.(1,6) the reported anomalies include mayerrokitansky syndrome,(7) microperforated hymen,(8) and transverse vaginal septum,(9) but also there is some reports of urethral coitus despite normal genital anatomy.(10-12) in all of these patients, in addition to dyspareunia and/or unsatisfied coitus, patient has also complained from sever urinary incontinence.(7,10) in our reported patients, urethroplasty with paravaginal flap and classic sling(10) were also done for repairing the patients urethra. their outcomes were successful for sui treatment and patients’ urinary symptoms were solved. teaching the correct way of intercourse to patients’ partner and correction of the patient anatomical impairment, should also be performed for dyspareunia treatment and should be followed up carefully. conflict of interest none declared. figure 3. vertical vaginal septum (partially excised with gynecologist) and patulous urethra. figure 4. urethral laceration involves the entire length of the urethra and sphincteric mechanism. balloon of foley catheter is exposed at the damaged bladder neck. references 1. rouzi aa. urethral sex in a woman with previously undiagnosed mayer-rokitansky-küster-hauser syndrome. clin exp obstet gynecol. 2013;40:452-3. figure 5. rectus fascia graft is passed around the urethra to maximizing urethral closure pressure. 1346 | case report 2. mundy ar, andrich de. urethral trauma. part ii: types of injury and their management. bju int. 2011;108:630-50. 3. tandon jk, saksena js. acquired megalourethra in a woman with normal vagina: a case report. j urol. 1983;130:567-8. 4. okeke li, aisuodionoe-shadrach o, ogbimi ai. female urethral and bladder neck injury after rape: an appraisal of the surgical management. int urogynecol j pelvic floor dysfunct. 2007;18:683-5. 5. pierce jt. a 14-year-old victim of sexual assault with an imperforate hymen and urethral meatus tear. j emerg nurs. 1999;25:153-4. 6. taneja pp, heera d, gulati sm, grover nk. urethral coitus in a case of vaginal agenesis. br j urol. 1973;45:451. 7. deniz n, perk h, serel t, kosar a, ozsoy mh, arslan m. urethral coitus and urinary incontinence in a case of mayer-rokitansky syndrome: an alternative surgical procedure. eur j obstet ynecol reprod biol. 2002;103:95-6. 8. di d, v, manci n, palaia i, bellati f, perniola g, panici pb. urethral coitus in a patient with a microperforate hymen. j minim invasive gynecol. 2008;15:642-3. 9. srinath n, misra dn. pregnancy in an untreated case of transverse vaginal septum with vesicovaginal fistula. int urogynecol j pelvic floor dysfunct. 2007;18:583-5. 10. ayan s, gokce g, kilicarslan h, kaya k, gultekin ey. an unusual cause of incontinence: urethral coitus. scand j urol nephrol. 2001;35:254. 11. borski aa, mittemeyer bt. urethral coitus--maximum urethral dilatation. j urol. 1971;105:400-2. 12. shukla vk, tripathi vn. urethral coitus. urology. 1982;19:542-3. v08_no_4_final_new.pdf case report 325urology journal vol 8 no 4 autumn 2011 is extracorporeal shockwave lithotripsy safe in patients with chronic bleeding tendency? seyed alaeddin asgari, majid kazemzadeh, afshin safaee asl, mandana mansour ghanaei urol j. 2011;8:325-7. www.uj.unrc.ir keywords: kidney calculi, extracorporeal shockwave lithotripsy, blood coagulation disorder, hemorrhage urology research center, guilan university of medical sciences, rasht, iran corresponding author: seyed alaeddin asgari, md urology research center, razi hospital, rasht, iran tel/fax: +98 131 552 5259 e-mail: s_a_asgari@gums.ac.ir received november 2009 accepted july 2010 introduction since 1980, the extracorporeal shockwave lithotripsy (swl) has become the gold standard option for treatment of renal and ureteral calculi. but swl is not without complication and has its own contraindications. of absolute contraindication for swl is bleeding tendency. here, we report a case with bleeding diathesis who underwent swl without bleeding tendency correction. case report a 40-year-old active stone former woman with a 7-year history of autoimmune hepatitis and cirrhosis was found to have multiple kidney and ureteral stones. laboratory examination revealed thrombocytopenia and coagulopathy (prolonged pt and ptt), which are contraindications for swl, but she had undergone two sessions of swl, previously. her physician was not aware of her bleeding tendency. both swls have been performed without any complications. this patient presented to our clinic with bilateral ureteral stones and obstructive uropathy. she was scheduled for ureteroscopy, but because of her thrombocytopenia and coagulopathy, the anesthesiologist refused to perform a spinal or general anesthesia. patient was insisting on undergoing swl without correction of coagulopathy and thrombocytopenia. after obtaining her consent, she underwent 5 swl sessions. her platelate count, pt, and ptt were 50 000 to 60 000 μl, 19 seconds, and 49 seconds, respectively. during the procedure, the physician was careful to focus on the kidney stones while paying close attention to not traumatize the surrounding tissue. discussion extracorporeal shockwave lithotripsy has its own complications in a small percentage of patients, even though serious complications are unusual.(1) since its introduction by chaussy and schmiedt in 1980, swl has been proven to be a safe, effective, noninvasive, and preferred method of treatment for patients with the upper tract urolithiasis.(2) although the risks of this procedure are relatively low, the risk for perirenal or intrarenal hemorrhage is well known.(3-5) routine post-swl imaging by computed tomography scan swl and chronic bleeding tendency—asgari et al 326 urology journal vol 8 no 4 autumn 2011 and magnetic resonance imaging has revealed perirenal or intrarenal hemorrhage in 20% to 25% of cases.(6-8) hence, in the setting of deranged bleeding parameters, swl has been considered to be an absolute contraindication. acute urinary tract infection, uncorrected bleeding disorders, pregnancy, sepsis, and uncorrected obstruction distal to the stone, all are considered absolute contraindications for swl. development of perirenal or intrarenal hemorrhage following swl is a frequent observation in those with normal bleeding parameters.(4) the incidence of clinically significant bleeding is less than 1%.(3-5) these reports taken together support the concept that swl is potentially risky in the setting of bleeding diathesis. on the contrary, there are reports of successful use of swl in known hemophilia after specific therapy with infusion of anti-hemophilic factor.(9,10) ruiz marcellan and colleagues have reported successful use of swl in 17 patients with coagulation disorders, after instituting hemotherapy for blood factor deficiencies.(11) data support the use of swl in selected patients with correctable bleeding diathesis, but all the subjects were managed with collaboration of the hematology department. depending on the nature of the disorder, we suggest the following guidelines for treatment: in patients with von willebrand disease, factor viii level of > 70%; in those with hemophilia a, the factor viii level 80% to 100%, in idiopathic thrombocytopenic purpura, a platelet count of 60 000 μl; and for oral anticoagulant, international normalized ratio < 1/5 should be safe. there is no overall or complete consensus about the appropriate management of bleeding tendency disorders and anticoagulation therapy for patients receiving long-term warfarin and/or antiplatelet drugs (lip, 2005; vamc, 2001). samiran and coworkers performed a total of 27 swl sessions in 7 patients, including 1) von willebrand disease; 2) idiopathic thrombocytopenic purpura and solitary right kidney; 3) mitral valve replacement on warfarin; 4) ischemic heart disease on aspirin; 5) cirrhosis and portal hypertension; and 6) hemophilia a. deficient coagulation factors were administered. two out of seven patients developed mild hematuria, which settled within 48 hours. none of them required blood transfusion. all, except 1 patient (case 3), were stone-free at one month. none of them required a secondary procedure. case 1 had post procedure magnetic resonance imaging, which did not show any collection or perinephric hematoma. other patients were observed clinically and did not undergo post procedure imaging. therefore, swl is a safe method of treatment of urolithiasis in patients with bleeding diathesis, provided that bleeding diathesis is corrected. these procedures should be undertaken in the setting of a tertiary care institution with hematological facilities.(12) tsuboi and associates reported two cases of idiopathic thrombocytopenic purpura in which ureteral stones were successfully extracted by transurethral ureterolithotripsy and swl after high-dose gamma-globulin therapy and platelet transfusion with no bleeding complications.(13) in literature, all of the swl procedures in patients who had contraindication for swl, such as pregnancy, have been performed inadvertently. but we were aware of it.(14) according to literature, in patients with bleeding tendency, swl should be performed after necessary corrections. our patients with coagulopathy did not develop bleeding following 5 swl sessions. conflict of interest none declared. references 1. jeon bh, jang jh, oh jh, et al. kidney rupture after extracorporeal shockwave lithotripsy: report of a case. j emerg med. 2009;37:13-4. 2. chaussy c, schmiedt e. extracorporeal shock wave lithotripsy (eswl) for kidney stones. an alternative to surgery? urol radiol. 1984;6:80-7. 3. drach gw, dretler s, fair w, et al. report of the united states cooperative study of extracorporeal shock wave lithotripsy. j urol. 1986;135:1127-33. 4. knapp pm, kulb tb, lingeman je, et al. extracorporeal shock wave lithotripsy-induced perirenal hematomas. j urol. 1988;139:700-3. 5. coptcoat mj, webb dr, kellett mj, et al. the complications of extracorporeal shockwave lithotripsy: management and prevention. br j urol. 1986;58:578-80. swl and chronic bleeding tendency—asgari et al 327urology journal vol 8 no 4 autumn 2011 6. rubin ji, arger ph, pollack hm, et al. kidney changes after extracorporeal shock wave lithotripsy: ct evaluation. radiology. 1987;162:21-4. 7. baumgartner br, dickey kw, ambrose ss, walton kn, nelson rc, bernardino me. kidney changes after extracorporeal shock wave lithotripsy: appearance on mr imaging. radiology. 1987;163:531-4. 8. kaude jv, williams cm, millner mr, scott kn, finlayson b. renal morphology and function immediately after extracorporeal shock-wave lithotripsy. ajr am j roentgenol. 1985;145:305-13. 9. partney kl, hollingsworth rl, jordan wr, beckham d, may cr. hemophilia and extracorporeal shock wave lithotripsy: a case report. j urol. 1987;138:393-4. 10. czaplicki m, jakubczyk t, judycki j, et al. eswl in hemophiliac patients. eur urol. 2000;38:302-5. 11. ruiz marcellan fj, mauri cunill a, cabre fabre p, et al. [extracorporeal shockwave lithotripsy in patients with coagulation disorders]. arch esp urol. 1992;45:135-7. 12. samiran a, devasia a, gnanaraj l, chacko k, kekre n, gopalakrishnan g. is shock wave lithotripsy safe in bleeding diathesis? indian j urol. 2006;22:122-4. 13. tsuboi t, fujita t, maru n, matsumoto k, iwamura m, baba s. transurethral ureterolithotripsy and extracorporeal shock wave lithotripsy in patients with idiopathic thrombocytopenic purpura. hinyokika kiyo. 2008;54:17-22. 14. asgari ma, safarinejad mr, hosseini sy, dadkhah f. extracorporeal shock wave lithotripsy of renal calculi during early pregnancy. bju int. 1999;84:615-7. urol_v03_no4_001_editorial.indd appendixes 264 urology journal vol 3 no 4 autumn 2006 benign prostatic hyperplasia amjadi m, madaen sk, pour-moazen h. uroflowmetry findings in patients with bladder outlet obstruction symptoms in standing and crouching positions, 49-53 shahrokh h, movahhed m, zargar shoshtari ma, orafa am, hekmat s. ethylenedicysteine versus diethylenetriamine pentaacetic acid as the carrier of technetium tc 99m in diuretic renography for patients with upper urinary tract obstruction, 97-102 zargar shoshtari ma, mirzazadeh m, banai m, jamshidi m, mehravaran k. radiofrequency-induced thermotherapy in benign prostatic hyperplasia, 44-48 endourology ahmadnia h, younesi rostami m, yarmohammadi aa, parizadeh smj, esmaeili m, movarekh m. percutaneous treatment of bladder calculi in children: 5 years experience, 20-22 feizzadeh b, doosti h, movarrekh m. distilled water as an irrigation fluid in percutaneous nephrolithotomy, 208-211 geavlete p, seyed aghamiri sa, multescu r. retrograde flexible ureteroscopic approach for pyelocaliceal calculi, 15-19 hosseini sj, kaviani a, jabbari m, mohammad hosseini m, haji-mohammadmehdi-arbab a, simaei nr. diagnostic application of flexible cystoscope in pelvic fracture urethral distraction defects, 204-207 mohammadzadeh rezaee ma. intravesical explosion during endoscopic transurethral resection of prostate, 108-109 moradi mr, moradi a. urethroplasty for long anterior urethral strictures: report of long-term results, 160-164 ziaee sam, basiri a, nadjafi-semnani m, zand s, iranpour a. extracorporeal shock wave lithotripsy and transureteral lithotripsy in the treatment of impacted lower ureteral calculi, 75-78 zomorrodi a, elahian ar, ghorbani n, tavoosi a. extracorporeal shock wave lithotripsy in prone and supine positions for patients with upper ureteral calculi, 130-133 subject index to volume 3 infectious diseases nikibakhsh aa, yekta z, mahmoodzadeh h, karamiyar m, fazel m. technetium tc 99m dimercaptosuccinic acid renal scintigraphy in diagnosis of urinary tract infections in children with negative culture, 139-144 pourmand g, pourmand mr, salem s, mehrsai ar, taheri mahmoudi m, nikoobakht mr, ebrahimi r, saraji a, moosavi s, saboury b. posttransplant infectious complications: a prospective study on 142 kidney allograft recipients, 23-31 zamanian a, mahjub h, mehralian a. skin diseases in kidney transplant recipients, 230-233 kidney transplantation mahdavi r, arab d, taghavi r, gholamrezaie hr, yazdani m, simforoosh n, tabibi a. en bloc kidney transplantation from pediatric cadaveric donors to adult recipients, 82-86 mehrsai ar, mousavi s, nikoobakht mr, khanlarpoor t, shekarpour l, pourmand g. improvement of erectile dysfunction after kidney transplantation: the role of the associated factors, 240-244 pourmand g, pourmand mr, salem s, mehrsai ar, taheri mahmoudi m, nikoobakht mr, ebrahimi r, saraji a, moosavi s, saboury b. posttransplant infectious complications: a prospective study on 142 kidney allograft recipients, 23-31 shahbazian h, dibaei a, barfi m. public attitudes toward cadaveric organ donation: a survey in ahwaz, 234-239 shahbazian h, mombini h, zand moghaddam a, jasemi m, hosseini ma, vaziri p. changes in plamsa concentrations of hypoxanthine and xanthine in renal vein as an index of delayed kidney allograft function, 225-239 zamanian a, mahjub h, mehralian a. skin diseases in kidney transplant recipients, 230-233 pediatric urology nikibakhsh aa, yekta z, mahmoodzadeh h, karamiyar m, fazel m. technetium tc 99m dimercaptosuccinic acid renal scintigraphy in subject index to volume 3 urology journal vol 3 no 4 autumn 2006 265 diagnosis of urinary tract infections in children with negative culture, 139-144 seyedzadeh ah, momtaz he, moradi mr, moradi a. pediatric cystine calculi in west of iran: a study of 22 cases, 134-138 shadpour p, shiehmorteza m. enuresis persisting into adulthood, 117-129 reconstructive surgery hosseini sj, rahmani mr, razzaghi mr, barghi mr, karami h, hosseini moghaddam smm. fournier gangrene: a series of 12 patients, 165-170 sexual dysfunction and infertility ahmadi asr badr y, madaen k, haj ebrahimi s, ehsan nejad ah, koushavar h. prevalence of infertility in tabriz in 2004, 87-91 khalili ma, aghaie-maybodi f, anvari m, talebi ar. sperm nuclear dna in ejaculates of fertile and infertile men: correlation with semen parameters, 154-159 mehrsai ar, mousavi s, nikoobakht mr, khanlarpoor t, shekarpour l, pourmand g. improvement of erectile dysfunction after kidney transplantation: the role of the associated factors, 240-244 omrani md, samadzadae s, bagheri m, attar k. y chromosome microdeletions in idiopathic infertile men from west azarbaijan, 38-43 sadeghi-nejad h, farrokhi f. the genetics of azoospermia: current knowledge, clinical implications and future directions. part i, 193-203 salsabili n, mehrsai ar, jalalizadeh b, pourmand g, jalaie s. correlation of sperm nuclear chromatin condensation staining method with semen parameters and sperm functional tests in patients with spinal cord injury, varicocele, and idiopathic infertility, 32-37 ziaee sam, ezzatnegad mr, nowroozi mr, jamshidian h, abdi hr, hosseini moghaddam smm. prediction of successful sperm retrieval in patients with nonobstructive azoospermia, 92-96 stone disease ahmadnia h, younesi rostami m, yarmohammadi aa, parizadeh smj, esmaeili m, movarekh m. percutaneous treatment of bladder calculi in children: 5 years experience, 20-22 feizzadeh b, doosti h, movarrekh m. distilled water as an irrigation fluid in percutaneous nephrolithotomy, 208-211 geavlete p, seyed aghamiri sa, multescu r. retrograde flexible ureteroscopic approach for pyelocaliceal calculi, 15-19 seyedzadeh ah, momtaz he, moradi mr, moradi a. pediatric cystine calculi in west of iran: a study of 22 cases, 134-138 ziaee sam, basiri a, nadjafi-semnani m, zand s, iranpour a. extracorporeal shock wave lithotripsy and transureteral lithotripsy in the treatment of impacted lower ureteral calculi, 75-78 zomorrodi a, elahian ar, ghorbani n, tavoosi a. extracorporeal shock wave lithotripsy in prone and supine positions for patients with upper ureteral calculi, 130-133 urological oncology aliasgari m, ghadian ar. coincidence of angiomyolipoma and pheochromocytoma, 61-64 ayati m, nikfallah ag, jabalameli p, najjaran tousi v, noroozi mr, jamshidian h. extensive surgical management for renal tumors with inferior vena cava thrombus, 212-215 barghi mr, rahmani mr, hosseini moghaddam smm, jahanbin m. immediate intravesical instillation of mitomycin c after transurethral resection of bladder tumor in patients with low-risk superficial transitional cell carcinoma of bladder, 220-224 basiri a, parvin m, simaei nr, hajimohammadmehdi-arbab a. the role of surgery for local recurrence of renal ewing’s sarcoma: a case report, 250-252 canda ae, kirkali z. current management of renal cell carcinoma and targeted therapy, 1-14 dadkhah f, hosseini sy, aliasgari m, lashay ar. urethral tumors: a report of 6 cases, 184-187 daneshmand s, quek ml. adrenal myelolipoma: diagnosis and management, 71-74 darabi mr, tayebi meibodi n, mahdavi r, arab d. p53 protein in serum and urine samples of patients with bladder transitional cell carcinoma and its overexpression in tumoral tissue, 216-219 mombini h, givi m, rashidi i. relationship between expression of p53 protein and tumor subtype and grade in renal cell carcinoma, 79-81 tabibi a, simforoosh n, parvin m, abadpour b, abdi hr, khafri s. prediction of prostatic involvement by transitional cell carcinoma of the bladder using subject index to volume 3 266 urology journal vol 3 no 4 autumn 2006 pathologic characteristics of the bladder tumor, 145-149 ziaee sam, moula sj, hosseini moghaddam smm, eskandar-shiri d. diagnosis of bladder cancer by urine survivin, an inhibitor of apoptosis: a preliminary report, 150-153 miscellaneous asgari sa, mokhtari gr, falahatkar s, mansourghanaei m, roshani a, zare ar, zamani m, khosropanah i, salehi m. diagnostic efficacy of creactive protein and erythrocyte sedimentation rate in patients with acute scrotum, 103-107 barghi mr, rahmani mr, haghighatkhah hr. angiography and segmental artery embolization in renal stab wound, 245-246 farrokhi f. duplicate publication: justifiable in a different language?, 191-192 kharrazi smh, rahmani mr, sakipour m, khoob s. polyorchidism: a case report and review of literature, 180-183 mousavi s, abdolrasoul mehrsai ar, mohammad reza nikoobakht mr, abedi ar, salem s, pourmand g. a giant congenital posterior urethral diverticulum associated with renal dysplasia, 247-249 rajaie esfahani m, momeni a. comparison of ultrasonography and intravenous urography in the diagnosis of hematuria causes, 54-60 salimi j, nikoobakht mr, khaji a. epidemiology of urogenital trauma: results of the iranian national trauma project, 171-174 yarmohammadi aa, mohamadzadeh rezaei ma, feizzadeh b, ahmadnia h. retrocaval ureter: a study of 13 cases, 175-179 appendixes 256 urology journal vol 4 no 4 autumn 2007 cellular and molecular urology sharifiaghdas f, hamzehiesfahani n, moghadasali r, ghaemimanesh f, baharvand h. human amniotic membrane as a suitable matrix for growth of mouse urothelial cells in comparison with human peritoneal and omentum membranes, 71 editorial and letter to editor barbarian a, karbakhsh m. re: varicocele in brothers of patients with varicocele, 187 khoshdel a. reply. re: varicocele in brothers of patients with varicocele, 187 safarinejad mr. editorial independence: surrounding controversies, 191 safarinejad mr. editorial policy: the right to international papers and contributors, 129 safarinejad mr. our journal indexed in medline/ pubmed, 61 endourology and laparoscopy basiri a, mehrabi s, kianian hr, javaherforooshzadeh a, kamranmanesh mr. blind puncture in comparison with fluoroscopic guidance in percutaneous nephrolithotomy: a randomized controlled trial, 79 basiri a, mohammad ali beigi f, abdi hr, mahmoudnejad n. laparoscopic reimplantation for single-system ectopic ureter, 174 darabi mahboub mr, ahanian a, zolfaghari m. percutaneous nephrolithotomy of kidney calculi in horseshoe kidney, 147 davoudi m, mousavi-bahar sh, farhanchi a. intrathecal meperidine for prevention of shivering during transurethral resection of prostate, 212 hakimi aa, feder m, ghavamian r. minimally invasive approaches to prostate cancer: a review of the current literature, 130 maghsoudi r, azaripour a. bladder perforation during laparoscopic donor nephrectomy, 123 mohseni mg, khazaeli mh, aghamir smk, biniaz f. changes in intrarenal resistive index following electromagnetic extracorporeal shock wave lithotripsy, 217 subject index to volume 4 nikoobakht mr, emamzadeh a, abedi ar, moradi k, mehrsai ar. transureteral lithotripsy versus extracorporeal shock wave lithotripsy in management of upper ureteral calculi: a comparative study, 207 nouri-mahdavi k, basiri a. fluoroscopy-guided percutaneous biopsy of kidney: an alternative to open or laparoscopic approaches, 251 sharifiaghdas f, mohammadali beigi f, abdi hr. laparoscopic removal of a migrated intrauterine device, 177 simforoosh n, basiri a, danesh ak, ziaee sam, sharifiaghdas f, tabibi a, abdi hr, farrokhi f. laparoscopic management of ureteral calculi: a report of 123 cases, 138 tavakkoli tabasi k, baghban haghighi m. ureteroscopic and extracorporeal shock wave lithotripsy for rather large renal pelvis calculi, 221 female urology aghamir smk, mohseni mg, arasteh s. intravesical bacillus calmette-guerin for treatment of refractory interstitial cystitis, 18 hazhir s. asymptomatic bacteriuria in pregnant women, 24 rajaie esfahani m, abdar ar. unusual migration of intrauterine device into bladder and calculus formation, 49 sharifiaghdas f, mohammadali beigi f, abdi hr. laparoscopic removal of a migrated intrauterine device, 177 yassaee f, moshiri f. pregnancy outcome in kidney transplant patients, 14 infectious diseases afgan f, mumtaz s, ather mh. preoperative diagnosis of xanthogranulomatous pyelonephritis, 169 alshyarba mh. metachronous emphysematous pyelonephritis and xanthogranulomatous pyelonephritis in the contralateral kidney: an extremely rare condition, 248 hazhir s. asymptomatic bacteriuria in pregnant women, 24 pashapour n, nikibahksh aa, golmohammadlou s. urinary tract infection in term neonates with subject index to volume 4 urology journal vol 4 no 4 autumn 2007 257 prolonged jaundice, 91 stamatiou kn, karakos c, karanasiou v, papadimitriou v, sofras f. syphilitic elephantiasis of penis and scrotum, 245 zargar-shoshtari ma, shadpour p, robat-moradi n, moslemi mk. hydatid cyst of urinary tract: 11 cases at a single center, 41 infertility ahmadnia h, ghanbari m, moradi mr, khajedalouee m. effect of cigarette smoke on spermatogenesis in rats, 159 dadfar mr. orchidopexy for retractile testes in infertile men: a prospective clinical study, 164 sadeghi-nejad h, farrokhi f. genetics of azoospermia: current knowledge, clinical implications, and future directions. part ii: y chromosome microdeletions, 192 kidney transplantation mahdavi-mazdeh m, heidary rouchi a, norouzi s, aghighi m, rajolani h, ahrabi s. renal replacement therapy in iran, 66 mojahedi mj, hekmat r, ahmadnia h. kidney transplantation in patients with alport syndrome, 234 nafar m, khatami f, kardavani b, farjad r, pourreza-gholi f, firoozan a. atherosclerosis after kidney transplantation: changes of intima-media thickness of carotids during early posttransplant period, 105 nikbin b, talebian f, mohyeddin m. chimerism: a new look, 1 pour-reza-gholi f, nafar m, simforoosh n, einollahi b, basiri a, firouzan a, alipour abedi b, farhangi s. is preemptive kidney transplantation preferred? updated study, 155 yassaee f, moshiri f. pregnancy outcome in kidney transplant patients, 14 oncology falahatkar s, mohammadzadeh a, nikpour s, khoshrang h, askari k. first reported case of adrenal neurofibroma in iran, 242 hakimi aa, feder m, ghavamian r. minimally invasive approaches to prostate cancer: a review of the current literature, 130 jalali nadoushan mr, taheri t, jouian n, zaeri f. overexpression of her-2/neu oncogene and transitional cell carcinoma of bladder, 151 jones l, reeves m, wingo s, babanoury a. malignant tumor in a horseshoe kidney, 46 kalantari mr, ahmadnia h. p53 overexpression in bladder urothelial neoplasms: new aspect of world health organization/international society of urological pathology classification, 230 mazdak h, gharaati mr. plexiform neurofibroma of penis, 52 mofid b, jalali nodushan mr, rakhsha a, zeinali l, mirzaei hr. relation between her-2 gene expression and gleason score in patients with prostate cancer, 101 pourmand g, ziaee aa, abedi ar, mehrsai ar, alavi ha, ahmadi a, saadati hr. role of pten gene in progression of prostate cancer, 95 tabibi a, parvin m, abdi hr, bashtar r, zamani n, abadpour b. correlation between size of renal cell carcinoma and its grade, stage, and histological subtype, 10 tufek i, akpınar h, sevinc c, alıcı b, kural ar. surgical treatment of retroperitoneal leiomyosarcoma with adjuvant radiotherapy, 180 yarmohammadi a, ahmadnia h, abolbashari m, molaei m. results of inadvertent administration of bacillus calmette-guerin for treatment of transitional cell carcinoma of bladder, 121 pediatric urology chiang dt, dewan pa. guide wire-assisted urethral dilation in pediatric urology: experience of a single surgeon, 226 pashapour n, nikibahksh aa, golmohammadlou s. urinary tract infection in term neonates with prolonged jaundice, 91 reconstructive surgery babaei ar, safarinejad mr. penile replantation, science or myth? a systematic review, 62 sexual dysfunction foroutan sk, rajabi mr. erectile dysfunction in men with angiographically documented coronary artery disease, 28 nikoobakht mr, motamedi m, orandi ah, meysamie ap, emamzadeh a. sexual dysfunction in epileptic men, 111 subject index to volume 4 258 urology journal vol 4 no 4 autumn 2007 stone diseases ahmadi asr badr y, hazhir s, hasanzadeh k. family history and age at the onset of upper urinary tract calculi, 142 basiri a, mehrabi s, kianian hr, javaherforooshzadeh a, kamranmanesh mr. blind puncture in comparison with fluoroscopic guidance in percutaneous nephrolithotomy: a randomized controlled trial, 79 darabi mahboub mr, ahanian a, zolfaghari m. percutaneous nephrolithotomy of kidney calculi in horseshoe kidney, 147 hadjzadeh mr, khoei ar, hadjzadeh z, parizady mr. ethanolic extract of nigella sativa l seeds on ethylene glycol-induced kidney calculi in rats, 86 mohseni mg, khazaeli mh, aghamir smk, biniaz f. changes in intrarenal resistive index following electromagnetic extracorporeal shock wave lithotripsy, 217 nikoobakht mr, emamzadeh a, abedi ar, moradi k, mehrsai ar. transureteral lithotripsy versus extracorporeal shock wave lithotripsy in management of upper ureteral calculi: a comparative study, 207 simforoosh n, basiri a, danesh ak, ziaee sam, sharifiaghdas f, tabibi a, abdi hr, farrokhi f. laparoscopic management of ureteral calculi: a report of 123 cases, 138 tavakkoli tabasi k, baghban haghighi m. ureteroscopic and extracorporeal shock wave lithotripsy for rather large renal pelvis calculi, 221 others ayatollahi h, darabi mr, mohammadian n, parizadeh mr, kianoosh t, khabbaz khoob m, kamalian f. ratios of free to total prostate-specific antigen and total prostate specific antigen to protein concentrations in saliva and serum of healthy men, 238 garg a, gokhale a, garg p, patil p. endovascular treatment of a delayed renal artery pseudoaneurysm following blunt abdominal trauma, 184 mahdavi r, khooei ar, asadi l. hygroma renalis: an extremely rare renal lesion, 118 manuchehri a. urology as a specialty in the history of contemporary medicine in iran, 125 mohammadali beigi f, mehrabi s, javaherforooshzadeh a. varicocele in brothers of patients with varicocele, 33 taghavi r, ariana k, arab d. diuresis renography for differentiation of upper urinary tract dilatation from obstruction: f+20 and f-15 methods, 36 history 125urology journal vol 4 no 2 spring 2007 urology as a specialty in the history of contemporary medicine in iran alaeddin manuchehri urol j. 2007;4:125-8. www.uj.unrc.ir former professor of urology, tehran university of medical sciences, tehran, iran urology journal is the only urological journal published in english in iran that is distributed internationally. it was deemed advisable to review the history of iranian urology in this journal. since the history of urology in iran is inseparably related to sina hospital, i tried to gather information on the foundation of the hospital to the time of its affiliation to tehran university. sina hospital sina hospital was founded by king nasereddin after his return from a trip to the european countries in 1914 and was named as governmental hospital (figure 1). moshiroddoleh, the chancellor in the realm of ghajar, and aligholi mirza etezadossaltaneh had a substantial role in the establishment of this hospital. between 1919 and 1940 some non-native physicians were the working in the governmental hospital: drs lout, culling, igberg, neligan (surgeon), scott (surgeon), wolf (surgeon), and forsecue (the english colonel in india). ali akbar khan nafisi nazemolatebba was of the first iranian physicians who were practicing at sina hospital. of the other pioneering physicians were dr mohammad khan kermanshahi (known as blaspheme doctor, since he had returned from the foreign countries), who used to performed the bladder calculus surgery via the perineum; dr abolghasem khan bahrami; dr mirza zeinol-abedin khan loghmanol-mamalek; dr mohsen loghman adham; and dr hossein khan motamed, one of the most famous and successful surgeons for 2 decades and the chief of the surgery department in razi hospital. since the islamic revolution in 1978, the dean of the hospital was dr seyed ali mir figure 1. left, sina hospital at its early years of activity. right, sina hospital in 2007. 126 urology journal vol 4 no 2 spring 2007 mozafari (anesthesiologist), and then, dr gholamreza pourmand, dr parviz jabal-ameli, and dr mehrsai, were the urologists appointed as the hospital dean from 1981 to 1989, respectively. since 2006, dr gholamreza pourmand (the director of urology research center) has had this position for the second time. before affiliation of sina hospital to tehran university, departments of internal medicine, surgery, urology, otolaryngology, dentistry, and dermatology had been set up, and thereafter, by transferring of some departments to the other university hospitals, departments of surgery and urology became more active, directing by professors yahya adl and saeed malek who had returned from paris. professor saeed malek had been one of the students of dr marion, professor of urology in paris. in 1945, during the period of my internship, the urology ward was a dependent part of the department of surgery of the hospital, consisting of a part of an old building with limited rooms for men and only one for women, a hall which was used for endoscopic procedures (cystoscopy and retrograde ureterography), and an operating room in the west part of the building with primitive instruments (sterilization of the instruments had been performed using the boiling water and primus, a conventional portable oven). the surgical procedures including bladder, ureteral, and kidney calculi removal, and emergency operations had been performed in a same place. a clinic with a poor hygienic condition was also located in the northwest of the hospital yard for patients with gonococcal infections and outpatient practice. in 1947, when i was a resident of urology, the chief of the department was dr saeed malek, and dr mehdi pezeshkan (graduated from paris), dr karim motamed (head of the clinic), and i were the physicians working at the urology department. gradually, we progressed owing to our interest and the load of the work (figure 2). also, the thought of a new building appropriate for to the circumstances of that time and our activities grew, and ultimately, it was built with the latest facilities available by the help of a royal social service. it has to be mentioned that the chief of the department was so interested in elevating and promoting the level of scientific and practical skills of the surgeons. gradually, the number of patients referred for urological problems increased. however, most of the urological operations were being performed by our surgeon colleagues, and therefore, we decided to make ourselves independent. in 1959, a notice was published and the specialty of urology attained independency: the primary pivot of the department of urology was formed in june 7, 1959. the iranian urological association was then registered founded in july 21, 1962. dr malek made several contacts with dr marion, in paris, and could officially introduce our association and register the iranian urologists in the international society of urology. by the kind notice hereby, the result of the exam for urology specialists affiliated to the iranian association of clinicians is announced: chief: dr saeed malek assistants: dr mehdi pezeshkan, dr yahya moaser, dr karim motamed, and dr alaeddin manouchehri secretary: dr seyed mahmoud jahromi treasurer: dr hassan abolmolouki consultant: dr biouk farvar [signature:] yahya adl, md president, iranian association of clinicians figure 2. right to left: drs biouk farvar, mehdi pezeshkan, alaeddin manuchehri, saeed malek, serouj karapetian, nasser ghods, rene couvelaire (paris), yahya moaser, karim motamed, hassan abolmolouki. urology journal vol 4 no 2 spring 2007 127 consideration of professor adl, the independent activities of the association were started and scientific meetings were held (figure 3). i became a member of the international society of urology in july 14, 1967, and participated in the 16th congress of the international society of urology in amsterdam in 1973. at this meeting, i made a lecture on prostate cancer in iran in french (figure 4). it should be stated that, especially during the past 2 decades, with the painstaking efforts of professor gholamreza pourmand and his colleagues, urology has been introduced countrywide and internationally by participating in the international conferences, raising the research field, and especially setting up kidney transplantation at sina hospital. they have had a great role in making this hospital one of the most import transplantation centers nationwide. a memory of the past the first congress of the iranian endourology and urolaparoscopy society was held in 2004, in which i attended with interest to see the progression of another new branch of urology in my country. this reminded me of the completion of my last 4 months figure 3. professors manuchehri, adl, and kiafar (left to right) in a meeting on emergency medicine at sina hospital. figure 4. professor manuchehri participated in the 16th congress of the international society of urology in amsterdam in 1973 and presented his paper. 128 urology journal vol 4 no 2 spring 2007 of internship in 1945 at the urology department of sina hospital. for the first time, i was acquainted with cystoscope, an instrument with which they could have improved many urological problems of the patients at that time. it was obvious that only the chief of the department and his assistant could ever work with it, and we were sometimes permitted to see the bladder lesions by that cystoscope while they were teaching us. after finishing internship and graduating from the medical school, i passed my period of compulsory military service in the army hospital no 2 in which the urology ward was established. the services i made there attracted the attention of the chief of the department. after the termination of the military service, the university of medical sciences announced the need for a urology resident. i registered for the exam and was admitted as the top student. in 1957, i was appointed as the assistant professor of sina hospital. regarding my history of interest and services, i progressed well enough to be noticed by drs malek and pezeshkan. they soon gave me permission to perform cystoscopy, retrograde ureterography, and small operations on my own (figure 5). the cystoscope we used at that time was firstly made between 1886 and 1900 by joseph leiter which is now kept in the national museum of the history of science and medicine in leiden. later, i purchased the complete set of instruments for the adults and the children, including cystoscope, ureteroscope, and set of transurethral resectoscope) personally which was used for many years. those instruments were working by 6-v lamps connected to the alternating current electricity by an adaptor. the other memory that congress made me remember was that in 1986, i attended the international congress of endourology in madrid, spain, and was acquainted with the new and modern endoscopic instruments (figure 6). now, in my final days of scientific activities that i can visit my friends at such meetings, i would like to recommend my dear young colleagues of mine who are interested in this field to benefit from such a great situation and invaluable professors to their best in order to become the source of services for our patients in future. figure 5. professor manuchehri started performing cystoscopy in 1940s. figure 6. in 1986, professor manuchehri participated in the international congress of endourology in madrid, spain. 1316 | laparoscopic nephrectomy and transdiaphragmatic resection of inferior solitary lung tumor: technique and feasibility of the approach qi zhang‚1zaiyuan ye‚2 feng liu‚1xiaolong qi‚2 yuelong zhang‚2 dahong zhang1 corresponding author: dahong zhang, md tel: +86 571 85893312 fax: +86 571 85893587 e-mail: urology@zju.edu.cn 1 department of urology‚zhejiang provincial people’s hospital‚hangzhou 310014‚zhejiang province‚china. 2 department of surgery‚zhejiang provincial people’s hospital‚hangzhou 310014‚zhejiang province‚china. point of technique keywords: laparoscopy; nephrectomy; diaphragm; lung neoplasms; treatment outcome. point of technique introduction about 20% to 30% of patients with renal cell carcinoma (rcc) have metastatic dis-ease at presentation.(1) in case of a solitary metastasis, resection of both lesions has demonstrated increased survival.(2) therefore, once detected, resection is always advised if resectable. traditionally, resection of solitary lung metastasis has been performed by way of standard lobectomy. recently, such tumors have also been removed thoracoscopically. (3) sometimes a laparoscopic approach is less invasive than thoracoscopy, if the patients have either pulmonary disease or coincident renal mass, which are indicated to require an operation. now pure laparoscopic techniques has also been used to treat coexisting pathologies.(4) we attempted to perform laparoscopic surgery to excise an inferior solitary lung tumor and concomitant renal mass. this surgical procedure is herein presented. case report a 39-year-old woman underwent a computed tomography (ct) scan which showed a left inferior solitary lung tumor and ipsilateral renal mass. the tumor was located in the posterior basal 1317vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l transdiaphragmatic resection of inferior solitary lung tumor | zhang et al segment of the left inferior lung lobe (figure 1a) and with an enhancing, inferior pole 4 cm incidentally detected left renal mass (figure 1b). meanwhile ct revealed no evidence of adenopathy and a normal contralateral kidney. further examinations such as positron emission tomography were taken but the remaining metastatic evaluation was negative. the scans were reviewed with our cardiothoracic surgery department, and preoperative diagnosis was left renal cell carcinoma and pulmonary solitary tumor. we thus planned a laparoscopic resection of the left inferior solitary lung tumors and a nephrectomy. surgical technique the lung tumorectomy was carried out first followed by nephrectomy. the patients was put in the lateral decubitus position under general anesthesia for both surgery. pneumoperitoneum was established first by a 5-mm trocar through a 10-mm incision, 2 cm on the left lateral side of the rectus abdominis muscle and 2 cm above the umbilicus. this was the camera port. next, when a 12-mmhg pneumoperitoneum established we placed a 10-mm trocar instead the camera port. in addition, a 10-mm port providing access to instruments held by the surgeon's right hand was placed subcostally in the left anterior axillary line. then, we placed a 5-mm port subcostally at 1cm below arcus costarum at left midclavicular line to provide access to the instruments held by the surgeon’s left hand. finally, we placed a 5-mm port subcostally in the left midaxillary line to provide access for the instruments that held by the first assistant (figure 2). the colon was medialized by peritoneal incision along the white line of toldt. the colon was shifted and then the left crus of the diaphragm was directly identified. we used laparoscopic ultrasound probe with a deflective linear headpiece for intraoperative localization of the lung tumor when the lung was completely collapsed. we dissected the diaphragmatic muscle along a radial incision using the ultracision-harmonic scalpel device (ultracision, ethicon endosurgery, cincinnati, oh, usa). we identified the mass (figure 3). the mass was mobilized and underwent laparoscopic wedge resection of the lung tumor using endo cut stapler (ethicon endo-surgery, llc guaynabo, puerto rico). the excised mass was extracted in an endobag for frozen section pathologic evaluation. no pleural injury occurred intraoperatively. the diaphragmatic muscle was sutured continuously with 2-0 polyglactin suture when the anesthesiologist repeatedly hyperinflated the lungs to expel all pleural co2. this step was performed blindly since pneumoperitoneum had been nearly evacuated. the basic principle is to over sew the diaphragmatic incision and evacuate the air out of the pleural space. thereafter, we performed a laparoscopic nephrectomy using the same ports. postoperatively, an abdominal drain was inserted. the total operation time was 135 minutes. it spent 90 and 45 minutes to perform the lung tumorectomy and nephrectomy, respectively. the total bleeding volume was 90 ml. no noticeable hemodynamics changes was found after surgery and finally no respiratory complications happened. postoperatively, a left-sided chest tube was placed prophylactifigure 1. a) computed tomography scan showing a lung tumor measuring 4.5 cm in diameter. the tumor was located in the posterior basal segment of the left inferior lung lobe (arrow heads). b) computed tomography scan showing an enhancing, inferior pole, 4 cm, incidentally detected, left renal mass (arrowheads). 1318 | cally. the tube was removed after 48 hours, when the chest radiograph revealed a well expanded lung. we removed the abdominal drain after 72 hours. on the 4th postoperative day the patient activity returned to normal. the final pathologic examination of the lung tumor found a necrotic granuloma that was negative for malignancy. the pathologic findings of the renal mass was renal cell carcinoma, clear cell type, extending into the perinephric tissues but not beyond gerota’s fascia. all surgical margins were negative. discussion the most common treatment for patients who present with renal cell carcinoma with a solitary metastasis is surgical excision of both lesions. in the past patients with several concomitant pathologic findings requiring surgery that belong to different surgical specialties are commonly treated in separate time.(5) concomitant laparoscopy with other surgical procedures to treat coexisting pathologies is not a novel strategy, and its benefits for the patients, which are mainly the avoiding of repeat anesthesia, reducing surgery-related stress, less pain, and shorter hospital stay.(5) there has been one report in the literature on the surgical management of lung tumors using video-assisted thoracic surgery (vats) and concomitant nephrectomy.(2) the preoperative ct scan was jointly reviewed by the surgeon and the radiologist to determine whether the tumor could be excised using laparoscopic staple wedge resection techniques. we attempted to perform laparoscopic surgery in the excision of this inferior solitary lung tumor because of the anatomic location, the familiarity of the approach, the need to carry out a nephrectomy simultaneously, and also to avoid the morbidity normally associated with a thoracic approach. the suitable mobilization of the adjacent structures to ensure good visualization allows successful resection of such lesions intraoperatively. by the use of a 30° angled telescope we get an excellent view to access this space, laparoscopically. it was easy of access to reach the tumor using this procedure after dissecting the left crus of the diaphragm. a meticulous dissection from the diaphragm, pleura, and thoracic cavity tissue could thus be successfully performed. the absorption of co2 from pleural space basically can be ignored because the anesthesiologist can expel all pleural co2 by repeatedly hyperinflating. laparoscopic stapler appeared both safe and expedient during wedge pulmonary resection. in addition, the diaphragm was easily sutured. no pleural injury occurred and we inserted a chest drain for safe. the less destructive character of the thoracoscopic (vats) approach is associated with less deformity of the thorax than an open lobectomy, but the former is associated with an increased anesthetic morbidity compared with a laparoscopic approach.(6) some patients also have pneumonic disease and/or abdominal disease, which is thus an indication for operation. the laparoscopic transdiaphragmatic technique is a novel minimally invasive procedure considered to be advantageous for such patients. meanwhile, careful assessment of the resected margin and follow-up are mandatory. otherwise, several limits should be mentioned. the transabdominal transdiaphragmatic approach appears unlikely to afford adequate visualization for evaluation of the entire chest. point of technique figure 2. port sites. a) the camera port; b) the surgeon's right hand; c) the surgeon’s left hand; d) the first assistant’s hand. 1319vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l figure 3. intraoperative view of the left inferior solitary lung tumor. transdiaphragmatic resection of inferior solitary lung tumor | zhang et al intraoperative bleeding may become predicament when working in the thoracic cavity from inside the abdominal cavity. meanwhile, surgical instruments need to be further improved so this technique could be used in the future, and patients need to be carefully selected. it is a feasible procedure with an acceptable risk of complications. actually, they may justify the use of laparoscopic techniques as an alternative approach in the management of thoracic surgery in the future. further randomized trials are needed to follow up the long-term survival rates of laparoscopic excision in such cases. conflict of interest none declared. references 1. tosco l, van poppel h, frea b, gregoraci g, joniau s. survival and impact of clinical prognostic factors in surgically treated metastatic renal cell carcinoma. eur urol. 2013;63:646-52. 2. nelson ba, sprunger jk, ninan m, herrell sd. simultaneous thoracoscopic wedge resection of a solitary lung nodule and laparoscopic partial nephrectomy for a renal mass. urology. 2004;64:377-8. 3. celik m, halezeroglu s, senol c, et al. video-assisted thoracoscopic surgery: experience with 341 cases. eur j cardiothorac surg. 1998;14:113-6. 4. deng dy, meng mv, grossfeld gd, stoller ml. simultaneous laparoscopic management of 3 urological malignancies. j urol. 2002;167:2125-6. 5. tsivian a, konstantinovsky a, tsivian m, et al. concomitant laparoscopic renal surgery and cholecystectomy: outcomes and technical considerations. j endourol. 2009;23:1839-42. 6. chowbey pk, vashistha a, khullar r, et al. laparoscopic excision of a lower posterior mediastinal paraspinal mass: technique and feasibility of the laparoscopic approach. surg laparosc endosc percutan tech. 2002;12:378-81. 1457vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l comparison of different autogenous graft materials for reconstruction of large segment vas deferens defect: experimental study in rat serdar nasir,1 sedat soyupek,2 selman altuntas,3 ersoy konas,1 emir charles roach,1 alper özorak,2 sema bircan4 correspondence author: serdar nasir, md ahmet rasim sokak 31/11 cankaya, ankara, turkey. tel: +90 312 305 1762 fax: +90 312 309 0445 e-mail: snasir@hacettepe.edu. tr;snasir72@gmail.com received november 2012 accepted june 2013 1 department of plastic and reconstructive surgery, hacettepe university, school of medicine, ankara, turkey. 2 department of urology, süleyman demirel university, school of medicine, isparta, turkey. 3 department of plastic and reconstructive surgery, süleyman demirel university, school of medicine, isparta, turkey. 4 department of pathology, süleyman demirel university, school of medicine, isparta, turkey. purpose:vasectomyisoneofthemostcommonurologicaloperationsperformed,andprovidespermanentcontraception.manyvasectomizedmenultimatelyseekvasectomyreversal becauseofunforeseenchangesinlifestyle.vasovasostomyhasvaryingratesofsuccess.in thisstudy,weutilizevasdeferens(vd),artery,andveingraftstoreconstruct30%and50% defectsofthetotalvasdeferenslength. materials and methods:fortytwomalewistarratsweredividedintothreegroupsasvd graft,carotidarteryandexternaljugularveintransplantations.eachgroupwasequallydivided into2differentsubgroupsaccordingtothelengthoftransplantmaterialas1.0cm(n=7)and 1.5cm(n=7).toevaluatewhetherthesematerialsmaybeusedforlongsegmentvasdeferens reconstruction,thepatencyrate,partialortotalgraftocclusion,andhistologicexaminationof allspecimenswereexamined. results:nopatencywasfoundinanyofthegraftsandmanyofthemsuffereddestructive changesinanatomicstructure.spermgranulomasweredeterminedaroundthetesticularside anastomosisduetoaccumulatedsemenfluidwhichwasinourbelief,aresultofaperistaltic zonecausedbythegrafts conclusion:whenthepoorresultsobtainedinourstudyareputintoperspective,vasoepididymostomyistheonlytreatmentmethodtodateforreconstructionoflargesegmentvas deferensdefects. keywords:vasdeferens;vasovasostomy;rats;vasectomy;transplantation;graftsurvival; animals. sexual dysfunction and infertility 1458 | sexual dysfunction and infertility introduction thesafestandmostcost-effectivetreatmentoptionforthereversalofthevasectomiesremainsmicro-surgical reconstruction, which also allows natural conception.(1)thesuccessrateofthisproceduredepends onamyriadoffactors,includingtheperformingsurgeon’s skill,presenceofantispermantibodies,highintravasaland epididymalpressurethatdevelopsaftervasectomy,andthe obstructionintervalbetweenthevasectomyandreversal. (2,3)technicalfailureofhumanvasdeferens(vd)reconstructionmainlyoccursseveralweekstomonthsaftersurgery,usuallyasaresultofstrictureoftheanastomosis.the narrowingandobliterationofthelumentakesplacedueto granulomaformationatthesiteofanastomosis,andtraction onordevascularizationofthevdwall,whicheventually leadstospermleakageafterthereversal.prostheticstents havebeenusedtosimplifytheprocedureandpreventthis spermleakage.autodilatingstentshavebeenputforthasa possiblesolutionforpreventingthesecondarystrictureof theanastomosis.also,bypreventingspermextravasation, there is less perivasal inflammation, reducing secondary strictureatthesiteoftheanastomosis.(4,5) waldandcolleaguesevaluatedabiodegradablegraftforreconstructionofratvasadeferentiawithlongobstructedor missing segments with or without some medical therapy. they found that potential role for biodegradable grafts in thereconstructionofvdwithlongobstructedsegments.(4,6) rothmanandcolleagues(7)carriedoutarandomizedclinical trialcomparingtheusual2-layermicrosurgicalvasectomyreversalagainstaprocedureusingthenewstent.asinteresting result,theyfoundthatthemicroscopicvasovasostomy(vv) resultsingreaterpregnancyratesthanvvusingtheabsorbablestent.theydidnotrecommendabsorbablestentdueto poormeasuredpatencyratioandspermmotility(8) were preferredforreconstructionofvasectomy.(7) ontheotherhand,largesectionsofthevdmaybeaffected aftersomesurgicaloperationssuchasherniarepair,hydrocelectomy,orcomplicationsofvasectomy.inthemajorityof suchcases,thelengthofvasdefectsrendersdirectvasovaso anastomosiseitherimpossibleortoorisky,duetoincreased tensionintheanastomosisarea.toovercomethisobstacle, extra anatomical (sub- and suprapubic) vas rerouting was performedtoallowshorteningofthenecessaryvaslength foranastomosing.thistechniquehasbeenestablishedtobe oneofthemosttechnicallychallengingtypeofsurgeryofthe malereproductivesystem.anotherinterestingpossibilityfor resolutionofavasdefectmightbetheuseofavasculartransplant. theaimofthisstudypresentedwastodetermineexperimentallyifavasdefectcouldberepairedeitherbyvastransplantationorbytransplantationofanarteryandveingraft.anotherobjectivewastodeterminecriticalmaximumlengththat canbetransplantedwhilestillachievingacceptablepatency forspermtransport. material and methods inourexperimentalsetting,weusedmaleadultinbredwistar rats,weighing250-300g,mean270g.femalesofthesame figure 1. view of scrotal contents of rat. keys: t, testis; e, epididymis; vd, vas deferens. figure 2. completed anastomosis of vas deferens autograft. keys: ts, testicular side anastomosis; as, abdominal side anastomosis. 1459vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l vas deferens reconstruction | nasir et al raceandstandardswereusedasvasculardonorsintheexperiment.thestudywasconductedinaccordancewiththe guidelinesforanimalcareandresearchoftheuniversity. theanimalswerekeptinaroomwithstandardenvironmentalconditionsandfedadlibidum.themalerats(n=42)were dividedintothreegroupsasvdgraft,carotidarteryandexternaljugularveintransplantations.eachgroupwasequally dividedinto2differentsubgroupsaccordingtothelengthof transplantmaterialas1.0cm(n=7)and1.5cm(n=7). operative technique operationstookplaceunderketamine(90mg/kg)andxylazine(10mg/kg)anesthesia.supplementarydosesweregiven asnecessary.asurgicaloperationmicroscope(m651surgicalmicroscope;leica,sweden),standardmicrovascularinstruments,and8-0nylonsuturewith75µmneedlewereused. thesurgicalprocedureandpostoperativeobservationswere performedbytheleadingauthor. theleftsidewaspreferredfortheexperimentalgroups.an abdominalmidlineincisionwasusedtoexplorethevdfollowedbytheopeningoftheinternalspermaticfasciaandthe vd,whichwaslyingloosenexttothefuniculus,whichwas easilyexposedleavingthescrotalcontentsinsitu.twodifferentlengthsofvdsegment(1.0cmand1.5cm)wereresected tocreatedefectsinvdandthesesegmentsrepresented30% and50%ofthetotalvdlengthrespectively.thesedefects were reconstructed using vd, carotid artery and external figure 3. (a) view of resected vas deferens segment (1.5 cm) with similar length of the arterial graft (1.5 cm). arterial graft is seen shortly compared to vas deferens defect due to elastic shrinkage of vessel wall. (b) completed vas deferensarterial graft anastomoses. table . results of anastomosis condition in all groups. variables autotransplantation groups artery graft groups vein graft groups total testicular site anastomosis 1 cm 1.5 cm 1 cm 1.5 cm 1 cm 1.5 cm -----normal 2/7 1/7 2/7 0/7 0/7 0/7 5/42 partial stenosis 2/7 3/7 1/7 2/7 1/7 1/7 10/42 occluded 3/7 3/7 4/7 5/7 6/7 6/7 27/42 abdominal site anastomosis 1 cm 1.5 cm 1 cm 1.5 cm 1 cm 1.5 cm -----normal 1/7 0/7 1/7 1/7 0/7 0/7 3/42 partial stenosis 2/7 3/7 1/7 4/7 0/7 0/7 10/42 occluded 4/7 4/7 5/7 2/7 7/7 7/7 29/42 1460 | sexual dysfunction and infertility jugularveingraftsandgraftsusedforreconstructionwerethe samelengthastheresectedvassegment. autotransplantation group (n =14) inthisgroup,resectedsegmentofvdwereanastomosedin thesameplace.anastomoseswereperformedbyapplying4 stitchesandonlyseromuscularsuturewasplacedusing8-0 non-absorbablenylon.thefirsttwosutureswereplacedat oppositeends180degreesapartpreciselyaligningmucosaof twoendsofvd.onesuturewasplacedbetweenthesestitchesoneachofthefrontandbackwall. artery and vein groups carotidarteryandexternaljugularveingraftswereharvested thesamelength(1.0cmand1.5cm)asthevasdefectfrom thefemalewistarrats.fortheanastomosisofvdwithartery andveingrafts,thesameoperativetechniquedescribedasabove wasusedwithexceptionthatonlyfull-thicknesssutureswere appliedthroughthevascularwall.theskinwasclosedwith4-0 silksuturesineveryrataftertheapplicationpftheprocedure. final examination fourweekspostoperativelytheratswereeuthanized.occurrenceofspermgranulomas(9)wasrecorded.theabdominal endof thevdafterbothanastomosiszones inallgroups weretransectedandtheintraluminalfluidwasmicroscopicallyexaminedforfunctionalpatencywiththeoccurrenceof spermat400×magnification.thevdsweretransecteddistalfromtheanastomosesandfunctionalpatencycheckedby smearexaminationtoseethepresenceofspermatthedistal portion.thetransplantedsegmentwasthenincisedlongitudinallyinordertoexploreifthereareanyocclusionsorpartial stenosis.equalsegmentsofthevd,arteryandveingrafts withtheanastomosesincludedwereexcised.forthecontrol specimen,ductusdeferensfromonemaleanimal,carotidarteryandexternaljugularveinfromonefemaleanimalwere harvested.allspecimenswerefixedinneutralbuffered4% formalinandparaffinembeddedforfurtherslicing.multiple tissuesegmentsofeachspecimenweretakenfromanastomosisareaandproximalanddistaltotheanastomosis.all sampleswerecutat4µmthicknessandslideswerestained withhematoxylinandeosin.allthesampleswereexamined bythesamepathologist. figure 4. sperm granulomas in the vein graft. this collection populated neighbor areas of testicular side anastomosis while abdominal side anastomosis did not occupied this structure. figure 6. (a) control artery tissue (hematoxylin and eosin × 40), (b) vascular wall was fragmented in artery graft, and mix inflammatory cells and also suture material (arrow) were seen (hematoxylin and eosin × 200). 1461vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l results autotransplantation group anatomical patency was not preserved in any of the segments.inthe1cm-longgraftgroup,normal,partialstenosis, andocclusionwereobservedas2/7,2/7and3/7intesticularside(ts)anastomosis,and1/7,2/7and4/7inabdominal side(as)anastomosis,respectively.inthe1.5cmlonggraft group,normal,partialstenosis,andocclusionwereobserved as1/7,3/7,and3/7intsanastomosis,and0/7,3/7,and4/7 inasanastomosisrespectively.spermgranulomas(sg)occurredinall14segmentsandtheyweresituated12/14and 2/14tsandasanastomoses,respectively. artery graft group anatomicalpatencywasnotobservedinanyofthesegments. inthe1cm-longgraftgroup,normal,partialstenosis,andocclusionwereobservedas2/7,1/7and4/7intsanastomosis, and1/7,1/7and5/7inasanastomosis,respectively.inthe 1.5cmlonggraftgroup,normal,partialstenosis,andocclusion0/7,2/7,and5/7wereobservedasintsanastomosis, and1/7,4/7,and2/7inasanastomosis,respectively.sgoccurredinall12segmentsandtheyweresituated11/12and 1/14tsandasanastomoses,respectively. vein graft group anatomicalpatencywasnotrecordedinanyofthesegments. inthe1cm-longgraftgroup,normal,partialstenosis,andocclusionwereobservedas0/7,1/7and6/7intsanastomosis, figure 5. (a) control vas deferens (hematoxylin and eosin × 40), (b) the lumen was obliterated and the thickness of muscle layer was reduced, and subepithelial area was expanded by fibrous tissue growing and inflammatory cells in the vas deferens graft (hematoxylin and eosin × 100). figure 7. (a) control vein tissue (hematoxylin and eosin × 100), (b) necrotic debris and semen material filled the vein lumen and covered the inner surface, and also inflammatory cells were seen in the vascular wall and the lumen of graft (hematoxylin and eosin × 100). vas deferens reconstruction | nasir et al 1462 | sexual dysfunction and infertility and0/7,0/7and7/7inasanastomosis,respectively.inthe 1.5cmlonggraftgroup,normal,partialstenosisandocclusionwereobservedas0/7,1/7,and6/7intsanastomosis, and0/7,0/7,and7/7inasanastomosis,respectively.sgoccurredinall12segmentsandtheyweresituated12/12and 0/12stsandasanastomoses,respectively. intraluminal fluid examination no motile sperm were found in intraluminal fluid microscopically.onlynecroticcellsanddebriswereobservedupon smearexamination. histological examination vd grafts themusclelayerofthegraftwasreduced,tobetween10 and35%oftheoriginalthicknessinmostofthecases.for somecasesespeciallyin thelongergrafts, thewholewall wasreplacedbyfibroustissue.atrophicepitheliallayerwas observedwithintactepitheliuminshortgraftswhilelonger graftshadonlyremnantsofanatrophicepithelium. artery grafts thethicknessofthemuscularlayerwasslightlyormoderatelyreduced.inflammatorychangeswerepresent,especially withmassivesg.intimallayerwasdestroyedanddetached frombasallayerandprotrudedintothevascularlumen. vein grafts thewholewallsofveingraftswereinvadedbyinflammatorycells.thelumensofmanyveingraftswereoccludedby pannus-liketissue,whichisgranulationandfibroustissues. intimallayerwasnotfoundinmanygraftsanditwasdetachedfrombasallayerintothelumen. discussion therearealotoftechniquesdescribedforthereversalofvasectomiesandthereconstructionofdefectsinthevasdeferencearea.itwasreportedthatone-layervvandtwo-layer vvseemtobeequalwithregardtovasalpatency.(9)furthermorewepreferredonelayervvasourmicrosurgicalskills withourclinicalcases.webelievedthatonelayerapproximationofvasalendsiseasier,quickerandsafercompareto twolayertechnique. however,inlargedefects,whenthevvisnotpossibledueto technicalreasons,hollowstructuressuchasvesselsmightcome upasanideaforgrafting.however,sincethereiscontractility presentinvd,especiallyduetoparasympatheticstimulation,(8) itisextremelyhardtodemonstratethatcontractilitywithgraft materials.inhuman,thevdepididymisandefferentductshas proximodistalincreaseinthemusclelayer,andalsothethicknessofthemusclelayerisgreaterthananystructureinhuman body,comparedtoitslumen.vdanddistalepididymispropel thespermwiththeirrhythmiccontractions,andifthisperistalsisisdisrupted,aspermgranulomamightoccur. itwasreportedthirtyyearsagothatmicrosurgicalvvtechniqueforvasectomyreversalhasresultedinsignificantlyimprovedoutcomescomparedtooldertechniques.(10) patency rates after microsurgicalvv using non-absorbable sutures havereached99%.thesemencanpassthroughtheanastomosiszoneaswellasanaperistalticsegmentinanastomosis zoneshortlyaftervv.theobstructiveintervalaftervasectomyisasignificantdeterminantofthepatencyandpregnancyrates.whichcanbeexemplifiedbythepatencyand pregnancyratesdecreased88%and53%between3-8years aftervasectomy.(11)thosepoorresultsmayberelatedtolong segmentfibrosisinvdfollowingalongtermintervalafter vasectomy.shandlingandjanikfoundthatsimplyclamping thevasofratscouldproducemuscledisruptionandfibrosis. (12)thethickmusclelayerscaneasilygetdamagedwithan insultminorthanvasectomywhichtriggersfibrosis.inflammationandfibrosisworseningthewholescenariobycausing moreextensivedamagewithvasectomy.(13)theproblemassociatedwithvasectomyoriatrogenicinjurytothevdincludealongobstructiveinterval,unpredictablelengthofocclusion,injurytothetesticularbloodsupplyandthesefactors maycauselongsegmentinjuriestovd.(14)vasoepididymosfigure 8. normal seminiferous tubules were seen at the lower area, but some tubules at the upper side (arrows) were degenerated and filled with necrotic and cellular debris (hematoxylin and eosin × 100). 1463vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l tomymaybeperformedtoresolvelargevddefects.(15)but advancedmicrosurgicaltechniquesarenecessaryandithasa lowerpregnancyandpatencyratecomparedtoavv.(16)also, prostheticstentsarenotlongenoughtouseformicrosurgicalvvreconstructionofvddefect.althoughexperimental vdauto-transplantationisnotapplicableforclinicaloperations,carringerevaluatedvdandvasculargraftstorepair largevddefectinrats.(17)however,lowpatencyrateswere reportedforthesegraftsandthisresultwasexplainedwith poorgraftviabilityandabsentneuralinnervations.carringer postulated that graft neovascularization occurred from the marginsofthetransplantandtheoutcomedependedonthe “bridgingphenomenon”.thisphenomenon,toelaborate,is thegrowthofvesselsanastomosingwiththevesselsofthe transplant.(17) thetotallengthofratvdis3-3.5cm.inourstudy,weaimed tocreatevddefectsat30%and50%ofthetotallength,making1and1.5cmsegmentresectionsfromvdrespectively. afterthedefectswerecreated,weexaminedtheresultscomparingvariousgraftswhichhaddifferentmusclelayerthicknesses.wefoundnopatencyineitherauto-transplantationor vasculargraftsgroups.however,ratesofveingraftocclusion werehighercomparedtoitsarterygroups.wehypothesized thatthisresultwasduetothethickwallofthearterygraft preventinglumenfromcollapsing,thuscreatinglowergraft occlusion, although they still yielded poor total patency outcomes.wehavesomedifferencesfromcarringer’sneovascularization hypothesis.(17)mainneovascularizationmechanismofallgraftsisprovidedbysproutingnewvesselsfrom donorsiteorformationofanastomosesbetweengraftand hostvessels.graft’snutrition isdependentonplasmadiffusionuntilnewvesselsform.itisknownthatthintissues gainenoughneovascularizationprovidinggraftnutritionina shortertimethanthicktissues.(18) although we did not conductdetailedexaminationsinordertodeterminethedifferenceofneovascularizationquality,allgroupsdisplayedthe samehistologicalviewsofnewvesselssproutingunderlight microscopicstudy.arteryandveingraftswhichhavethin wallsmaycausemechanicalobstructionintheirlumenasa resultofcollapseandkinking.mechanicalblockageinvites inflammationandfibroustissuegrowingintoluminalspace asaresult,permanentlumenobstruction.wehaveobserved intraluminalfibroustissueinsomehistologicalsectionsduringlightmicroscopicstudy.inouropinion,themainproblemoflowerpatencyrateswererelatedtolongvddefects whichcreateaperistalticzonesduringsementransport.althoughthereisnoevidenceofvdcontractionexceptduring theejaculationperiod,thickmuscleandmucosallayerofvd maypropelsemenduringasexualperiodaswell. conclusion weconcludedthatveinandvdgraftsarenotusefulforlong segmentdefectreconstructionswhichare30-50%ofthevd lengthinrats.wethinkthatanymaterialusedforlargevd defectreconstructionmusthaveperistalticmovementinordertopushthesemenforward.furthermore,weconcluded thatthereisnoautogenicorprostheticmaterialhasthisspecialfunctiontoperformsementransportation.forthisreason, vasoepididymostomyseemstobeonlyindisputablesolution forlongsegmentvdreconstruction. conflict of interest none declared. vas deferens reconstruction | nasir et al references 1. pavlovich cp, schlegel pn. fertility options after vasectomy: a cost-effectiveness analysis. fertil steril. 1997;67:133-41. 2. silber sj. microscopic vasectomy reversal. fertil steril. 1977;28:1191-202. 3. belker am, thomas aj jr, fuchs ef, konnak jw, sharlip id. results of 1,469 microsurgical vasectomy reversals by the vasovasostomy study group. j urol. 1991;145:505-11. 4. simons cm, de young br, griffith ts, et al. early microrecanalization of vas deferens following biodegradable graft implantation in bilaterally vasectomized rats. asian j androl. 2009;11:373-8. 5. holoch pa, mallapragada sk, ariza ca, griffith ts, deyoung br, wald m. micro-recanalization in a biodegradable graft for reconstruction of the vas deferens is enhanced by sildenafil citrate. asian j androl. 2010;12:814-8. 6. rosevear hm, krishnamachari y, ariza ca, et al. effect of combined locally delivered growth factors and systemic sildenafil citrate on microrecanalization in biodegradable conduit for vas deferens reconstruction. urology. 2012;79:967 e1-4. 7. rothman i, berger re, cummings p, jessen j, muller ch, chapman w. randomized clinical trial of an absorbable stent for vasectomy reversal. j urol. 1997;157:1697-700. 8. elzanaty s, dohle gr. vasovasostomy and predictors of vasal patency: a systematic review. scand j urol nephrol. 2012;46:241-6. 1464 | 9. cipriani r, contedini f, santoli m, et al. abdominal wall transplantation with microsurgical technique. am j transplant. 2007;7:1304-7. 10. owen er. microsurgical vasovasostomy: a reliable vasectomy reversal. j urol. 2002;167(2 pt 2):1205. 11. o'brien bm, macleod am, hayhurst jw, morrison wa. successful transfer of a large island flap from the groin to the foot by microvascular anastomoses. plast reconstr surg. 1973;52:271-8. 12. shandling b, janik js. the vulnerability of the vas deferens. j pediatr surg. 1981;16:461-4. 13. bowins b. vasectomy: the cruelest cut of all. west conshohocken: infinity publishing; 2006. 14. sheynkin yr, hendin bn, schlegel pn, goldstein m. microsurgical repair of iatrogenic injury to the vas deferens. j urol. 1998;159:139-41. 15. kramer wc, meacham rb. vasal reconstruction above the internal inguinal ring: what are the options? j androl. 2006;27:481-2. 16. wei fc, jain v, celik n, chen hc, chuang dc, lin ch. have we found an ideal soft-tissue flap? an experience with 672 anterolateral thigh flaps. plast reconstr surg. 2002;109:221926. 17. carringer m, pedersen j, schnürer lb. experimental vas replacement by either vas or a vascular graft. scand j urol nephrol. 1995;29:97-102. 18. kimura n, satoh k, hosaka y. microdissected thin perforator flaps: 46 cases. plast reconstr surg. 2003;112:1875-85. sexual dysfunction and infertility uj 35 summer.pdf 562 | learning curve for retroperitoneoscopic renal pedicle lymphatic disconnection for intractable chyluria a single surgeon’s experience long wang,1 zhenyu ou,1 hequn chen,1 zhenzhen cao,2 zhengyan tang,1 xiang chen,1 xiongbing zu,1 longfei liu,1 lin qi1 long wang and zhenyu ou contributed equally to this work. purpose: to evaluate the surgical experience and outcomes of retroperitoneoscopic renal pedicle materials and methods: to document the learning curve for the procedure. results: in the operation time (p = .000) and the blood loss (p did not differ in terms of demographic data, peri-operative complications, gastrointestinal recovery time, extubation time, or hospitalization duration. conclusion: reproducible procedure. this study of the learning curve of a single surgeon suggests that competence at performing rrpld is reached after approximately 20 cases. keywords: corresponding author: lin qi, md; phd department of urology, xiangya hospital, central south university, no.87 xiangya road, changsha, hunan 410008, china tel: +86 138 7315 1645 fax: +86 731 8432 7242 e-mail: xyurology@gmail. com received september 2011 accepted april 2012 1department of urology, xiangya hospital, central south university, changsha, china 2department of gynecologic oncology, hunan provincial tumor hospital, changsha, china laparoscopic urology laparoscopic urology 563vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l introduction hyluria is the passage of chyle into the urine urinary tract and the lymphatic system. the most common cause of chyluria is a parasitic infection, especially wuchereria bancrofti. other non-parasitic causes, such as neoplasia, lymphatic malformation, abdominal trauma, or tuberculosis, are occasionally seen.(1)although chyluria quently seen in asian countries. some patients can obtain satisfactory curative effects through conservative measures, including dietary managetervention.(2) (3) the plications, and rapid postoperative recovery, has been utilized more and more as the alternative surgical technique for chyluria. curve, and the learning curve for each procedure can be (4-6) the learning curve for retroperitoneoscopic renal pedicle lymphatic disconnection (rrpld) has not been reported of the learning curve on peri-operative outcomes in 40 connumber of cases needed to achieve reasonable results using a laparoscopic approach to perform renal pedicle lymphatic disconnection. materials and methods the surgeon has been trained primarily in open surgery, and has had some advanced laparoscopic training during fela fatty meal revealed chyluria from the left ureter in 24, the age, gender, involvement site (left or right), body mass inplications, gastrointestinal recovery time, extubation time, and the last port closure. surgical procedure all the patients received general anesthesia, and routine latth costal itoneum ventrally and separate the space. the creation of a introduced 2 cm above the iliac crest. another 5-mm and lary line under the 12th rib and the initial lumbotomy inci2 nally close to the psoas magnum muscle. after removing the adipose capsule carefully, the surrounding fat tissues on pletely bare after adequately stripping the circumambient fatty and connective tissues containing lymphatic vessels disconnected using ultrasonic scissors or ligated by titanilearning curve for retroperitoneoscopic surgery | wang et al 564 | rant arteries. to prevent tension on the renal vessels and iliac crest into the retroperitoneum. learning curve for surgery operation time, blood loss, and other peri-operative pabecause surgical times reached a plateau around the 20th patient. statistical analysis independent samples t test, mann-whitney u test, or pearp value less than .05. results formed laparoscopically by a beginner surgeon (conversion of illness in the left or right sides. b c figure 1. (a) disconnection of lymphatic vessels around the ureter (arrow); (b) disconnection of lymphatic vessels around the renal artery (arrow); (c) disconnection of lymphatic vessels around the renal vein (arrow). laparoscopic urology 565vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l learning curve for retroperitoneoscopic surgery | wang et al the 20th last 20 (90.5 versus 69.0 minutes, p = .000). the median 37.0 ml, p = .006). 1), 2 inadvertent minor rupture of the inferior vena cava, gastrointestinal recovery, extubation, and hospitalization the operations. the urine chyle test became negative in all no gross chyluria reappeared in all the patients. discussion (1) not responding to conservative measures requires surgical (7) with the advent and the subsequent popularity of laparosco(3) described retroperitoneoscopic lymphatic management of several clinical trials demonstrated that rrpld has many advantages over open surgery, including minimal invasion, less blood loss, shorter postoperative hospital stay, and rapid recovery.(9-11) the standard of care for intractable chyluria in many institutions. the present study demonstrated that rrpld is a reproducible, safe technique requiring a short learning curve to achieve satisfying results in terms of operation duration number of cases required for a surgeon to perform a parfigure 2. operation time according to surgeon’s experience. o p er at io n ti m e (m in ) surgeon experience table 1. clinical characteristics of the analyzed patients. variables group 1 (cases 1 to 20) group 2 (cases 21 to 40) p age, y 50.3 ± 12.7 47.4 ± 9.7 .416 body mass index, kg/m2 17.8 ± 2.1 18.5 ± 1.6 .242 women/men 7/13 7/13 .000 left/right side 13/7 13/9* .694 *2 patients with bilateral chyluria table 2. correlation of surgeon’s experience with clinical outcomes. groups operation time, min blood loss, ml gastrointestinal recovery time, hr extubation time, hr hospitalization time, day overall complications, n (%) group 1 90.5 (82.0 to 102.5) 55.0 (42.5 to 72.5) 24.0 (14.3 to 39.0) 28.2 (15.3 to 36.0) 4.0 (3.1 to 5.3) 3 (15.0) group 2 69.0 (64.0 to 76.0) 37.0 (29.0 to 50.0) 29.5 (17.3 to 39.3) 31.5 (17.5 to 32.0) 4.5 (2.8 to 5.0) 2 ( 9.1) all cases 77.5 (69.0 to 89.0) 46.5 (35.0 to 67.0) 28.0 (15.0 to 38.5) 29.0 (16.5 to 33.5) 4.3 (3.2 to 5.1) 5 (11.9) p .000 .006 .735 .815 .513 .656 566 | ticular procedure to stabilize operation times and achieve acceptable outcomes.(12) erated by a single beginner surgeon and divided them into 2 groups according to the change tendency of operation time. therefore, potential statistic errors arising from different laparoscopists, centers, criteria, and surgical procedures ing operation duration, complication rates, and blood loss duration and the blood loss range from 65 to 120 minutes able to delineate a learning curve of approximately 20 cases overall complication analysis is another important parameter in estimating the safety of a surgical procedure during erature are quite variable, ranging from 0% to 50% (table age in their series(13) despite the fact that a higher incidence had been reported in their previous research.(14) seven published series reported that complications, including inferior vena cava injury, clipping of an auxiliary artery, and postoperative hematuria, occurred in a small number of patients in their series.(9-11,13-16) similarly, the complications of the experience of rrpld even in the early stages of the learning curve. the present study demonstrated that gastrointestinal recovery and extubation and hospitalization times did ence, suggesting that these parameters might not be suitable measures for assessing accredited laparoscopic surgeons. ate number for a beginner surgeon to complete the learning curve. these can be interpreted and explained in several second, the experience acquired from other retroperitoneoscopic surgeries, such as radical nephrectomy and live dotable 3. retroperitoneoscopic renal pedicle lymphatic disconnection: literature overview first author (ref number) men /women mean age, y mean operation time, min mean blood loss, ml mean hospitalization, day major complications (n) complication rate, % hemal(14) 0/2 26.5 120 80 2.5 lymphatic leak (1) 50% hemal(13) 6/3 36.5 111 95 2.6 lymphatic leak (1); clipping of post segmental artery branch (1) 22.2% zhang(9) 3/4 49 65.0 29.3 4.7 postoperative hematuria (1) 14.3% jiang(15) 4/2 42 95 85 7.2 clipping of auxiliary artery branch (1) 16.7% zhang(10) 26/15 46.2 66.6 25 3.7 inferior vena cava injury (1) 2.4% lan(11) 7/2 49 77 46 6 none 0% xia(16) 31/47 56 92 55 6.8 inferior vena cava injury (1), clipping of an auxiliary artery (1) 2.6% present series 14/26 50 80.9 50.0 4.5 inferior vena cava injury (2), clipping of an auxiliary artery (1), lymphatic leak (2) 11.9% laparoscopic urology 567vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l facilitates better execution of rrpld. third, pre-operative of surgical videos for technical tips and pitfalls helped our team to improve step by step. the main limitation of this study is that the learning curve small sample size of 40 patients, limiting the generalizabillearning curve varies depending on initial training and prespread, as there is increasing information available in the literature, educational videos, and symposiums. moreover, (17) surgeons and maybe the duration for prospective mentorship by an experienced surgeon to optimize results. conclusion retroperitoneoscopic renal pedicle lymphatic disconnecthis procedure. during the learning curve period, excellent results in terms of operation time and blood loss can be outcome. conflict of interest none declared 4. tekkis pp, senagore aj, delaney cp, fazio vw. evaluation of the learning curve in laparoscopic colorectal surgery: comparison of right-sided and left-sided resections. ann surg. 2005;242:83-91. 5. neo el, zingg u, devitt pg, jamieson gg, watson di. learning curve for laparoscopic repair of very large hiatal hernia. surg endosc. 2011;25:1775-82. 6. ahlberg g, kruuna o, leijonmarck ce, et al. is the learning curve for laparoscopic fundoplication determined by the teacher or the pupil? am j surg. 2005;189:184-9. 7. punekar sv, kelkar ar, prem ar, deshmukh hl, gavande pm. surgical disconnection of lymphorenal communication for chyluria: a 15-year experience. br j urol. 1997;80:858-63. 8. gomella lg, shenot p, abdel-meguid ta. extraperitoneal laparoscopic nephrolysis for the treatment of chyluria. br j urol. 1998;81:320-1. 9. zhang x, ye zq, chen z, et al. comparison of open surgery versus retroperitoneoscopic approach to chyluria. j urol. 2003;169:991-3. 10. zhang x, zhu qg, ma x, et al. renal pedicle lymphatic disconnection for chyluria via retroperitoneoscopy and open surgery: report of 53 cases with followup. j urol. 2005;174:1828-31. 11. lan wh, jin fs, wang lf, zhu fq. a comparison of retroperitoneoscopic and open surgical renal pedicle lymphatic disconnection for the treatment of serious filarial chyluria. chin med j (engl). 2007;120:932-4. 12. herrell sd, smith ja, jr. robotic-assisted laparoscopic prostatectomy: what is the learning curve? urology. 2005;66:105-7. 13. hemal ak, gupta np. retroperitoneoscopic lymphatic management of intractable chyluria. j urol. 2002;167:2473-6. 14. hemal ak, kumar m, wadhwa sn. retroperitoneoscopic nephrolympholysis and ureterolysis for management of intractable filarial chyluria. j endourol. 1999;13:507-11. 15. jiang j, zhu f, jin f, jiang q, wang l. retroperitoneoscopic renal pedicle lymphatic disconnection for chyluria. chin med j (engl). 2003;116:1746-8. 16. xia gw, ding q, yu j, xu k, zhang yf. retroperitoneoscopic renal pedical lymphatic disconnection in the treatment of chyluria. chin med j (engl). 2008;121:1478-80. 17. rosser jc, jr., lynch pj, cuddihy l, gentile da, klonsky j, merrell r. the impact of video games on training surgeons in the 21st century. arch surg. 2007;142:181-6; discusssion 6. references 1. sharma s, hemal ak. chyluria-an overview. int j nephrol urol. 2009;1:14-26. 2. kumar r, hemal ak. retroperitoneal renal laparoscopy. int urol nephrol. 2012;44:81-9. 3. chiu aw, chen mt, chang ls. laparoscopic nephrolysis for chyluria: case report of long-term success. j endourol. 1995;9:319-22. learning curve for retroperitoneoscopic surgery | wang et al urological oncology 230 urology journal vol 4 no 4 autumn 2007 p53 overexpression in bladder urothelial neoplasms new aspect of world health organization/international society of urological pathology classification mahmoudreza kalantari,1 hassan ahmadnia2 introduction: the aim of this study was to investigate the probable differences in p53 expression between papillary urothelial neoplasm of low malignant potential (punlmp) and varying grades of transitional cell carcinoma (tcc) of the bladder. materials and methods: ten biopsy specimens of the patients with punlmp, 20 of the patients with papillary low-grade tcc, 20 of those with invasive high-grade tcc, and 10 of healthy individuals were stained for p53 protein by immunohitochemical methods. histological grading was performed according to the world health organization/international society of urological pathology consensus classification of urothelial neoplasms of the urinary bladder. results: nuclear p53 protein in invasive high-grade tcc was slightly more frequent than that in noninvasive low-grade papillary tcc (p = .35). ten percent of specimens with punlmp had nuclear p53 accumulation, while in low-grade and high-grade tccs, 75% and 85% of the specimens were positive for p53 protein accumulation (p < .001). expression of p53 was nil in all normal transitional epithelium specimens. conclusion: overexpression of p53 in papillary low-grade tcc and invasive high-grade tcc, while lacking of expression in punlmp indicates that mutations of p53 gene are not usually associated with the development of urothelial neoplasms and they may play a crucial role only in progression of punlmp to low-grade tcc. urol j. 2007;4:230-3. www.uj.unrc.ir keywords: tumor suppressor protein p53, bladder, transitional cell carcinoma, immunohistochemistry 1department of pathology, ghaem hospital, mashhad university of medical sciences, mashhad, iran 2department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran corresponding author: mohmoudreza kalantari, md department of pathology, ghaem hospital, mashhad, iran tel: +98 915 513 9060 e-mail: dr_m_kalantari@yahoo.com received february 2007 accepted august 2007 introduction mutations in p53 gene are the most common genetic abnormality in human cancers.(1) p53 acts as a tumor suppressor gene and the major functional activities of the p53 protein are cell-cycle regulation and initiation of apoptosis in response to dna damage.(2,3) wild-type p53 protein has a short half-life; however, the protein encoded by mutated p53 remains active for a long period. therefore, mutation of p53 gene results in p53 protein accumulation in cells’ nuclei. this accumulation is detectable with immunohistochemical methods and correlates with p53 gene mutation.(4) mutated p53 gene is a common genetic abnormality in transitional cell carcinoma (tcc) of the bladder.(3) previous studies have depicted that overexpression of p53 occurs in higher stages and grades of tcc.(3,4) in this study, we investigated whether there are immunohistochemical differences in the p53 expression between papillary urothelial neoplasm p53 overexpression in bladder neoplasms—kalantari and ahmadnia urology journal vol 4 no 4 autumn 2007 231 of low malignant potential (punlmp), varying grades of papillary noninvasive tcc, and invasive tcc. materials and methods biopsy specimens of 10 patients with punlmp, 20 with papillary low-grade tcc, 20 with invasive highgrade tcc, and 10 with normal transitional mucosa and no cystoscopic and microscopic pathologic findings were selected. histological grading was performed according to the world health organization/international society of urological pathology (who/isup) consensus classification of urothelial neoplasms of the urinary bladder.(5) immunohistochemical staining for p53 was performed on formalin-fixed, paraffin-embedded sections using avidin-biotin technique (dako, carpinteria, california, usa). samples of the bladder carcinoma with known p53 mutations and documented accumulations of p53 protein by immunohistochemical analysis were used as positive controls. nonepithelial cells (lymphocytes, stromal cells, and endothelial cells), used as internal negative controls, demonstrated no immunoreactivity. only nuclear localization of immunoreactivity was evaluated. samples demonstrating at least 10% nuclear reactivity were considered to be positive for p53 (have a mutation in p53 gene; figure).(4) the immunohistochemical analysis was performed blindly to the tumor grade and stage. the chi-square test was used to evaluate the association of p53 protein accumulation in the nuclei of the urothelial cells with pathologic stage and histological grade of tcc. a p value less than .05 was considered significant. results analysis of 50 tumoral and 10 normal transitional epithelium specimens revealed that nuclear p53 protein was identified more frequently in invasive high-grade tcc in comparison with noninvasive low-grade papillary tcc, but this association was not statistically significant (p = .35). in contrast, the difference of nuclear p53 accumulation between punlmp and low and high grade tcc (invasive or noninvasive) was statistically significant (p < .001; table). actually, about 90% of punlmp specimens were p53-negative. expression of p53 was nil in all normal transitional epithelium specimens. specimen number of specimens p53 positive normal urothelium 10 0 punlmp 10 1 (10) papillary low-grade tcc 20 15 (75) invasive high-grade tcc 20 17 (85) nuclear p53 immunoreactivity in normal and neoplastic urothelial specimens* *values in parentheses are percents. punlmp indicates papillary urothelial neoplasm of low malignant potential and tcc, transitional cell carcinoma. immunohistochemical staging for p53 protein reactivity. left, there is no nuclear reactivity in a specimen diagnosed with papillary urothelial neoplasm of low malignant potential (× 100). right, moderate to severe nuclear reactivity in about 80% of tumoral cells in a specimen with high-grade invasive transitional cell carcinoma (× 100). p53 overexpression in bladder neoplasms—kalantari and ahmadnia 232 urology journal vol 4 no 4 autumn 2007 discussion in spite of short half-life of wild-type p53 protein, the half-life of a mutated p53 product is long.(6) this characteristic results in accumulation of the mutated p53 product, and thus, detection of p53 protein in the nuclei of cells by immunohistochemical methods. however, in 15% to 20% of tumors, despite of p53 gene mutation, its product does not accumulate in the nucleus.(4) on the other hand, in a proportion of tumors, despite the nuclear accumulation of p53 protein, there is no mutation in p53 gene.(3) in the first condition, some p53 gene mutations (such as point mutations) may result in lack of or severe decrease in p53 protein synthesis, and in the second condition, it has been shown that some cellular oncogenic products, such as mouse double minute 2 (mdm2), which bind to and inactivate wild-type p53 protein, result in a long half-life of p53 protein. in fact, recent studies have revealed that overexpression of mdm2 leads to overexpression of p53, without any detectable p53 mutation.(7,8) in early stages of bladder cancer, deletion of chromosome 9 may be the only genetic abnormality, suggesting an initial role in development of the urothelial cancer.(9-12) deletion in chromosome 9 is thought to be associated with loss of genes that have a tumor suppression role.(13-15) carcinomas with only chromosome 9 aberration do not show progression. however, addition of other genetic abnormalities such as p53 defects may indicate potential for progression. comparative studies on the molecular genetics of ta urothelial carcinomas and nonpapillary flat urothelial carcinoma in situ, which is a full-thickness proliferation of malignant urothelial cells confined to the epithelium, have revealed that these tumors are probably derived from a distinctly different genetic pathway.(16-18) whereas, the earliest genetic aberration in papillary tcc may involve chromosome 9 deletion, nonpapillary flat urothelial carcinoma in situ is characterized by abnormalities of the p53 genes. simon and colleagues, using comparative genomic hybridization, showed that low-grade noninvasive papillary neoplasms (ta) are not associated with major genomic aberrations, except for chromosome 9 losses.(19) these authors also showed that there is clearly a higher number of genetic alterations in t1 than in ta tumors. most of all, a much higher degree of genetic instability is suggested in t1 than in ta tumors.(19) papillary low-grade tcc and punlmp present the first step of tumor development. although the only difference between these tumors is the presence or absence of mild anaplasia and dysplasia, there may be other differences which are not apparent on histological evaluation alone. in our study, a significant genetic difference (p53 overexpression) was found between punlmp and papillary lowgrade tcc; only 10% of punlmps were p53 positive, suggesting that p53 mutation does not play a role in development of transitional tumors. conversely, 75% of the papillary low-grade tcc tumors revealed p53 overexpression that shows a crucial role for p53 mutation in further tumor progression from punlmp to low-grade tcc. moreover, multiple genomic alterations may be needed for transformation of papillary tcc (ta) to invasive forms, but p53 mutation is most probably not such an alteration, since there was no significant statistical difference between low-grade papillary tcc and high-grade invasive tcc in nuclear p53 protein accumulation. however, our data were on a very small sample size. the significant differences we observed between the stages of tumor progression encourage us to perform future research to confirm these findings. conclusion our findings of p53 overexpression in papillary lowgrade tcc and invasive high-grade tcc together with lack of its expression in punlmp support the notion that mutation of p53 gene might be unrelated to the development of urothelial neoplasm. whereas, we can speculate that mutation of this gene may play a crucial role in further progression of punlmp to low-grade tcc. in our opinion, recent changes in urothelial neoplasm classification from triple-staging systems to who/isup are in agreement with our findings. thus, this study shows the importance of who/isup classification in renaming of grade 1 tcc to punlmp. conflict of interest none declared. p53 overexpression in bladder neoplasms—kalantari and ahmadnia urology journal vol 4 no 4 autumn 2007 233 references 1. hollstein m, sidransky d, vogelstein b, harris cc. p53 mutations in human cancers. science. 1991;253:4953. 2. lane dp. cancer. p53, guardian of the genome. nature. 1992;358:15-6. 3. esrig d, elmajian d, groshen s, et al. accumulation of nuclear p53 and tumor progression in bladder cancer. n engl j med. 1994;331:1259-64. 4. esrig d, spruck ch 3rd, nichols pw, et al. p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. am j pathol. 1993;143:1389-97. 5. epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998;22:1435-48. 6. finlay ca, hinds pw, tan th, eliyahu d, oren m, levine aj. activating mutations for transformation by p53 produce a gene product that forms an hsc70p53 complex with an altered half-life. mol cell biol. 1988;8:531-9. 7. oliner jd, kinzler kw, meltzer ps, george dl, vogelstein b. amplification of a gene encoding a p53-associated protein in human sarcomas. nature. 1992;358:80-3. 8. cordon-cardo c, latres e, drobnjak m, et al. molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. cancer res. 1994;54:7949. 9. takahashi t, habuchi t, kakehi y, et al. clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. cancer res. 1998;58:5835-41. 10. spruck ch 3rd, ohneseit pf, gonzalez-zulueta m, et al. two molecular pathways to transitional cell carcinoma of the bladder. cancer res. 1994;54:784-8. 11. fearon er, feinberg ap, hamilton sh, vogelstein b. loss of genes on the short arm of chromosome 11 in bladder cancer. nature. 1985;318:377-80. 12. gonzalez-zulueta m, ruppert jm, tokino k, et al. microsatellite instability in bladder cancer. cancer res. 1993;53:5620-3. 13. miyao n, tsai yc, lerner sp, et al. role of chromosome 9 in human bladder cancer. cancer res. 1993;53:4066-70. 14. ruppert jm, tokino k, sidransky d. evidence for two bladder cancer suppressor loci on human chromosome 9. cancer res. 1993;53:5093-5. 15. orlow i, lianes p, lacombe l, dalbagni g, reuter ve, cordon-cardo c. chromosome 9 allelic losses and microsatellite alterations in human bladder tumors. cancer res. 1994;54:2848-51. 16. al hamdan n, al zahrani a, koriech o, bazarbashi s, ajarim d. cancer incidence report, saudi arabia 1994-1996. ministry of health national cancer registry. may 1999. 17. droller mj. bladder cancer: state-of-the-art care. ca cancer j clin. 1998;48:269-84. 18. reznikoff ca, belair cd, yeager tr, et al. a molecular genetic model of human bladder cancer pathogenesis. semin oncol. 1996;23:571-84. 19. simon r, burger h, brinkschmidt c, bocker w, hertle l, terpe hj. chromosomal aberrations associated with invasion in papillary superficial bladder cancer. j pathol. 1998;185:345-51. 1095vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l the effect of urethral catheter size on meatal stenosis formation in children undergoing tubularized incised plate urethroplasty suleyman cuneyt karakus,1 naim koku,1 mehmet ergun parmaksiz,1 idris ertaskin,1 huseyin kilincaslan,2 hasan deliaga,3 corresponding author: huseyin kilincaslan, md department of pediatric surgery, faculty of medicine, adnan menderes bulvari, bezmialem vakif university, 34093 fatih, i̇stanbul, turkey tel: +90 505 939 7834 fax: +90 212 534 6970 e-mail: hkilincaslan@yahoo.com.tr received october 2012 accepted march 2013 1 department of pediatric surgery, gaziantep children hospital, gaziantep, turkey 2 department of pediatric surgery, faculty of medicine, bezmialem vakif university, istanbul, turkey 3 department of pediatric surgery, servergazi state hospital, denizli, turkey pediatric urology purpose: meatal stenosis is still a common problem in tubularized incised plate urethroplasty. in this study, we aimed to seek for a relationship between the size of urethral catheter and meatal stenosis formation in children undergoing tubularized incised plate urethroplasty. materials and methods: we retrospectively reviewed 83 children who underwent tubularized incised plate urethroplasty for hypospadias. the whole group was classified into the groups a and b based on the catheter size. one group (group a) consisted of 44 patients (mean age, 4.82 ± 3.83 years) with tubularized neourethra over a 6 fr catheter, while the other group (group b) included 39 patients (mean age, 5.19 ± 3.83 years) with tubularized neourethra over a 8 fr catheter. results: there were no significant differences between the groups according to their age, location of urethral meatus, dehiscence and urethrocutaneous fistula formation. meatal stenosis formation in group b was markedly higher than that in group a. number of meatal dilatation was higher in group b compared to group a. conclusion: we suggest that the tubularization of urethral plate over a small-sized (6 fr) catheter, regardless of the age of the patients, prevents meatal stenosis by reducing foreign body reaction and pressure injury and by hindering secondary healing. keywords: hypospadias; child; urethra; treatment outcome; urologic surgical procedures; urethral stricture. 1096 | introduction tubularized incised plate (tip) urethroplasty has become the most commonly used method in pa-tients with distal and mid-shaft hypospadias in recent years. although there have been modified techniques described in order to reduce meatal stenosis, it is still a common problem in tip urethroplasty.(1-3) however, the size of the urethral catheter may be a factor to prevent meatal stenosis. to the best of our knowledge, it is the first reported study that seeks for a relationship between the size of urethral catheter and meatal stenosis formation in children undergoing tip urethroplasty. material and methods we retrospectively reviewed 83 children who underwent tip urethroplasty for hypospadias performed by the first author between may 2008 and march 2011 at gaziantep children hospital, turkey. the whole group was classified into the groups a and b based on the catheter size. one group (group a) consisted of 44 patients (mean age, 4.82 ± 3.83 years, range 1-16 years) with tubularized neourethra over a 6 french (fr) catheter, while the other group (group b) included 39 patients (mean age, 5.19 ± 3.83 years, range 1-13 years) with tubularized neourethra over a 8 fr catheter. glanular hypospadias and secondary repair were excluded from this study. under general anesthesia, formal tip urethroplasty operation was performed as briefly described in the following parts; a stay suture was placed through the glans for traction. afterwards, the penis was degloved and two parallel incisions were made on the glans to form the glanular wings. one midline deep incision was carried out in the urethral plate as described by snodgrass.(4) finally, the plate measured at least 13 mm in width. at first, incised urethral plate was tubularized over a 8 fr catheter with 6-0 polyglactin suture and these patients were classified into group b. afterwards, tubularization was made over a 6 fr catheter in order to decrease meatal stenosis in group a. neomeatus was given a slit-like shape in order to avoid stenosis. mobilized divergent corpus spongiosum was approximated in the midline to cover neourethra. the glans wings were reapproximated with no tension and the skin was closed. the catheters were removed 7 days after surgery. children in both groups were evaluated for 1 year (every fortnight for 1 month and then once a month and also whenever a specific problem appeared) in the postoperative period. diagnosis of meatal stenosis was made according to the history given by parents (difficulty in urination, narrow and high flow of urinary stream, pain during urination, and the need to sit or stand back from the toilet bowl to urinate), inspection of meatus (circular, small and narrowed shape) and calibration of meatus. under local anesthesia, urethral sounding was performed on the postoperative 15th day, 1st, 3rd and 6-month and 1st year. the caliber of the meatus smaller than the normal minimal size for a given age group was regarded as meatal stenosis.(5) under general anesthesia, dilatation was performed when meatal stenosis was determined. twenty eight (63.6%) of the patients in group a and 23 (59.0%) of the patients in group b were not yet potty trained. so, we were not able to performed uroflowmetry in these patients and we did not use uroflowmetry as a diagnostic tool. data collected included age, the location of hypospadias, dehiscence, urethrocutaneous fistula formation, urethral meatal stenosis formation and number of meatal dilatation in each patient. the statistical analyses were made using the statistical package for the social science (spss inc, chicago, illinois, usa) version 11.5. the results were expressed as mean ± standard deviation (sd). mann-whitney u and t tests were used for the statistical analysis. p < .05 was accepted as statistically significant. results patients’ characteristics and results are summarized in table. there were no significant differences between the groups according to their age (p = .489). in group a, the location of hypospadias was distal penile in 34 patients (77.3%) and mid-shaft in 10 (22.7%). in group b, it was distal penile in 29 patients (74.4%) and mid-shaft in 10 (25.6%). there pediatric urology 1097vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l the effect of urethral catheter size in tipu | karakus et al were no significant differences between the groups according to the location of urethral meatus (p = .758). in group a, urethrocutaneous fistula occurred in 2 (4.5%) of the patients and 3 (7.7%) of the patients in group b. there were no significant differences between the groups according to the urethrocutaneous fistula formation (p = .550). there was no dehiscence in either group. urethral meatal stenosis occurred in 1 (2.3%) of the patients in group a and 6 (15.4%) of the patients in group b. meatal stenosis formation in group b was markedly higher than that in group a (p = .033). all the meatal stenosis were resolved after dilatation program at the end of the first year. the mean of meatal dilatation number was 0.046 ± 0.30 in group a and 0.44 ± 1.07 in group b, it was higher in group b compared to group a (p = .030). discussion tip urethroplasty, as described by snodgrass in 1994, is the method of choice for treating distal and mid-shaft hypospadias.(4) the success rate has been reported to be 88 to 100%. (6,7) the meatal stenosis formation rate has been reported between 1% and 17% after tip urethroplasty.(3,4,8) in tip urethroplasty, some modifications such as the intactness of the anticipated dorsal lip of the neomeatus and creating a generous wide elliptical external meatus were reported in order to reduce the risk of fistula and meatal stenosis. (1,3,9) another possible reason for meatal stenosis may be the tension of glans wings approximation. it is generally acknowledged that distal urethroplasty must not be considered a separate procedure from glansoplasty. the size of the catheter determines the likelihood for meatal stenosis as it increases the tension exerted for glans approximation. although uroflowmetry is a simple and non-invasive way of evaluating the dynamics of micturition, the calibration of the meatus, the history given by parents and the physical examination of the meatus were sufficient in the diagnosis of meatal stenosis.(10) in our study, there were no significant differences between the groups in terms of their ages. the urethral meatus corresponds generally with age. since the urethral meatus is the narrowest part of urethra in boys, the catheter size in hypospadias repair should be chosen according to the width of the narrowest part of urethra for a given age group. yang et al calibrated the size of the urethral meatus by sounding and reported that the normal minimal size of the urethral meatus is 10 fr in 88 uncircumcised boys aged 0-14 years. (5) since the catheters used in both groups were smaller than 10 fr, the selection of catheter size was made regardless of the age of the patients. inflammation, the first phase of the wound healing, is often accompanied by local interstitial fluid accumulation expressed as edema.(11) also, re-epithelialization begins in 24 hours after surgery. neourethra covers 8 fr catheter more tightly than 6 fr. therefore, using a 6 fr catheter could provide an adequate area for edema and an adherence of both raw sides of the wound. increased need for regular dilatation after tubularization of incised urethral plate over a 8 fr catheter can be explained by edema that caused a pressure injury on the urethral mea and by hindered re-epithelialization. the critical period of healing after the tip urethroplasty is the first few weeks and using a large-sized catheter can separate both raw sides of incised plate resulting in secondary healing. in secondary healing, centripetally directed contraction reduces the area of the wound. over time, meatal stenosis occurs. delayed wound healing resulting from a foreign-body reaction to biomaterials have also been reported. besides, biotable. summary of patients’ characteristics and results. group a group b number of patients 44 39 mean age, years 4.82 ± 3.83 5.19 ± 3.83 location of hypospadias, n (%) distal mid-shaft 34 (77.3) 10 (22.7) 29 (74.4) 10 (25.6) urethrocutaneous fistula, n (%) 2 (4.5) 3 (7.7) dehiscence, n (%) 0 (0) 0 (0) urethral meatal stenosis, n (%) 1 (2.3) 6 (15.4) number of meatal dilatation 0.046 ± 0.30 0.44 ± 1.07 1098 | 8. el-kassaby aw, al-kandari am, elzayat t, shokeir aa. modified tubularized incised plate urethroplasty for hypospadias repair: a long-term results of 764 patients. urology. 2008;71:611-5. 9. lorenzo a, snodgrass w. regular dilatation is unnecessary after tubularized incised plate hypospadias repair. bju int. 2002;89:94-7. 10. bazmamoun h, ghorbanpour m, mousavi-bahar sh. lubrication of circumcision site for prevention of meatal stenosis in children younger than 2 years old. urol j. 2008;5:233-6. 11. stamatas gn, southall m, kollias n. in vivo monitoring of cutaneous edema using spectral imaging in the visible and near infrared. j invest dermatol. 2006;126:1753-60. 12. orenstein sb, saberski er, klueh u, kreutzer dl, novitsky yw. effects of mast cell modulation on early host response to implanted synthetic meshes. hernia. 2010;14:511-6. 13. weyhe d, hoffmann p, belyaev o, et al. the role of tgf-beta1 as a determinant of foreign body reaction to alloplastic materials in rat fibroblast cultures: comparison of different commercially available polypropylene meshes for hernia repair. regul pept. 2007;138:10-4. 14. ritch cr, murphy am, woldu sl, reiley ea, hensle tw. overnight urethral stenting after tubularized incised plate urethroplasty for distal hypospadias. pediatr surg int. 2010;26:639-42. materials increased early inflammation and fibrosis.(12,13) ritch and colleagues reported no meatal stenosis in 49 patients who underwent tip urethroplasty with an overnight urethral stenting technique.(14) it can be the result of limited foreign-body reaction. using a large-sized catheter leads to a foreign body reaction more often than a biomaterial does, and it can bring about increased early inflammation, edema and fibrosis resulting in meatal stenosis. conclusion we recommend the tubularization of urethral plate over a small-sized (6 fr) catheter. also, following the tubularization over a large-sized catheter, it can be altered by a smallsized one. using a small-sized catheter, regardless of the age of the patients, prevents meatal stenosis by reducing foreign body reaction and pressure injury and by hindering secondary healing. conflict of interest none declared. references 1. jayanthi vr. the modified snodgrass hypospadias repair: reducing the risk of fistula and meatal stenosis. j urol. 2003;170:1603-5. 2. elbakry a. regular dilatation is unnecessary after tubularized incised-plate hypospadias repair. bju int. 2002;90:4734. 3. stehr m, lehner m, schuster t, heinrich m, dietz hg. tubularized incised plate (tip) urethroplasty (snodgrass) in primary hypospadias repair. eur j pediatr surg. 2005;15:420-4. 4. snodgrass w. tubularized incised plate urethroplasty for distal hypospadias. j urol. 1994;151:464-5. 5. yang ss, hsieh ch, chen yt, chen sc. normal size of the urethral meatus in uncircumcised boys. j urol roc. 2001;12:202. 6. chen sc, yang ss, hsieh ch, chen yt. tubularized incised plate urethroplasty for proximal hypospadias. bju int. 2000;86:1050-3. 7. yang ss, chen yt, hsieh ch, chen sc. preservation of the thin distal urethra in hypospadias repair. j urol. 2000;164:151-3. pediatric urology urological oncology 94 urology journal vol 5 no 2 spring 2008 separate submission of standard lymphadenectomy in 6 packets versus en bloc lymphadenectomy in bladder cancer m hammad ather, zaheer alam, anila jamshaid, khurram m siddiqui, m nasir sulaiman introduction: our aim was to evaluate detection of nodal metastasis during radical cystectomy with standard pelvic lymph node dissection versus en bloc lymphadenectomy for the treatment of bladder cancer. materials and methods: hospital records of a total of 77 patients with radical cystectomy and either standard pelvic lymph node dissection or en bloc lymphadenectomy were reviewed. nodal dissection specimens during standard lymphadenectomy were sent for pathology examination in 6 separate containers marked as external iliac, internal iliac, and obturator groups from both sides. en bloc dissection specimens were sent in 2 containers marked as the right and the left pelvic nodes. clinical and pathological findings of these two groups were compared in terms of the number of dissected lymph nodes, number of nodes with metastasis, lymph node density, and clinical outcomes. results: there were 34 patients with standard lymph node dissection and 43 with en bloc lymphadenectomy (anterior pelvic exenteration). age, sex, duration of the disease, number of transurethral resections prior to cystectomy, pathological grade at cystectomy, and stage of the primary tumor were comparable in the two groups of patients. the median numbers of nodes removed per patient were 15.5 (range, 4 to 48) and 7.0 (range, 1 to 24) in those with standard and en bloc lymphadenectomy, respectively (p < .001). nodal involvement was detected in 10 (29.4%) and 9 (20.9%) patients, respectively (p = .43). conclusion: although nodal involvement was not significantly different between the two groups, standard lymphadenectomy submitted in 6 different containers significantly improved the nodal yield over en bloc resection. obturator nodes were the most commonly involved nodes in our study. urol j. 2008;5:94-8. www.uj.unrc.ir keywords: urinary bladder neoplasms, cystectomy, lymph node excision department of surgery, aga khan university, karachi, pakistan corresponding author: m hammad ather, md po box 3500, stadium road, karachi 74800, pakistan tel: +92 21 486 4778 fax: +92 21 493 4294 e-mail: hammad.ather@aku.edu received december 2007 accepted april 2008 introduction transitional cell carcinoma (tcc) of the bladder originates from the mucosa, invades the lamina propria, and involves the muscularis propria, perivesical fat, and pelvic structures with increasing incidence of lymph node involvement during progression.(1) on cystectomy, 14% to 28 % of the patients show evidence of lymph node metastasis.(2) radical cystectomy (rc) is the standard management of high-grade and muscle-invasive bladder tumors. bilateral pelvic lymphadenectomy is now an standard versus en bloc lymphadenectomy in bladder cancer—ather et al urology journal vol 5 no 2 spring 2008 95 essential part of rc. a combination of these two provides excellent local control and long-term survival rate for most of the patients with tumors in stage pt2 or higher.(3,4) thus, accurate staging is decisive in terms of choosing the treatment option and reducing local recurrence. preoperative imaging modalities may miss microscopic nodal metastasis in up to 70% of the patients.(5) lymph node involvement is associated with increased risk of local recurrence and disease progression with survival rates varying from 20% to 40% in patients with and without lymph node metastasis, respectively.(6,7) the practice of lymphadenectomy is not standardized. it has been shown that the number of nodes retrieved could vary from 0 to 53 per patient.(8) recent studies suggest that both the number of nodes removed and the method of submission of lymph node specimens affect the treatment outcome.(3, 9-11) some recent papers have also indicated that the lymph node specimens separately retrieved and submitted for pathology have a greater number of nodes compared to en bloc resection.(9-11) studies have shown that the incidence of positive lymph nodes increased with higher stage, higher pathological grade, and greater number of transurethral resections prior to rc.(10-12) in the present study, we sought to identify if there was a difference in the number of nodes retrieved between separately retrieved and submitted pathologic specimens and specimens from en bloc resection. materials and methods hospital records of all patients with tcc of the bladder treated by rc or anterior pelvic exenteration (ape) at our institution between 1995 and 2007 were retrospectively studied. during this period, 95 patients had undergone rc or ape for primary bladder cancer. we excluded 18 patients because their lymph nodes could not been evaluated. the hospital was not a referral center for oncological surgery. there are 3 trained oncological urologists and all types of urinary diversions including orthotopic bladder replacements are performed. of 77 patients, 34 (44.2%) had undergone standard lymphadenectomy (group 1; lymph nodes submitted in 6 separate nodal packets) and 43 (55.8%) had undergone en bloc dissection (group 2). the extent and operative field in the two groups were similar. the field of standard lymph node dissection extends caudally, up to the lacunar ligament; cranially, to the angle of marcille; laterally, to the genitofemoral nerve; and medially, up to the obturator nerve. nodal dissection specimens during standard lymphadenectomy had been sent for pathology examination in 6 separate containers marked as external iliac, internal iliac, and obturator groups from both sides. en bloc dissection specimens had been sent in 2 containers marked as the right and the left pelvic nodes. the patients in the two surgical groups were compared in terms of the number of dissected lymph nodes, number of nodes with metastasis, lymph node density, and other clinical outcomes. lymph node density was defined as the ratio of positive nodes for metastasis to the total number of nodes examined. operative mortality was defined as death within 30 days after the procedure. data were analyzed using the spss software (statistical package for the social sciences, version 15.0, spss inc, chicago, ill, usa). continuous variables were compared between the groups using the independent sample t test or the mann whitney u test. the chisquare test and the fischer exact test were used to compare categorical and dichotomous variables. a p value less than .05 was considered significant. results of 77 patients with tcc of the bladder, 67 (87.0%) were men and 10 (13.0%) were women. the two groups were comparable in terms of age, sex, primary tumor stage, grade of the tumor, duration of the disease, and number of transurethral resections (table 1). the median number of nodes removed per patient were 15.5 (range, 4 to 48) in group 1 and 7 (range, 1 to 24) in group 2 (p < .001). there were 10 patients (29.2%) and 9 patients (20.9%) with involved nodes in groups 1 and 2, respectively (p = .43). the obturator lymph nodes were the most commonly involved nodes followed by internal and external iliac node groups in patients standard versus en bloc lymphadenectomy in bladder cancer—ather et al 96 urology journal vol 5 no 2 spring 2008 of group 1 (figure). lymph node density was significantly higher in the patients of group 1 than those of group 2 (p < .001; table 2). early complications, including lymphocele, were noted in 7 patients (20.6%) in group 1 and 4 (9.3%) in group 2; however, none of the patient required surgical intervention. no other complication or peri-operative death was attributed directly to the lymph node dissection in neither of the groups (table 2). discussion lymph node metastasis is detected in 14% to 28% of the patients undergoing pelvic lymphadenectomy during rc for bladder cancer.(2) it is associated with an increased risk of local recurrence, regional disease progression, and overall poorer outcome. extended standard lymphadenectomy is important for accurate surgical treatment characteristics standard lymphadenectomy(group 1) en bloc cystectomy (group 2) p number of patients 34 (44.2) 43 (55.8) mean age, y 56.5 ± 13.3 64.0 ± 12.4 .51 sex male 28 (82.4) 39 (90.7) female 6 (17.6) 4 (9.3) .32 duration of disease, d† 76.0 ± 946.8 147.0 ± 927.0 .97 tumor stage t0 3 (8.8) 4 (9.3) t1 1 (2.9) 2 (4.7) t2 16 (47.1) 23 (53.5) t3 9 (26.5) 6 (14) t4 5 (14.7) 8 (18.6) .74 tumor grade 1 0 1 (2.3) 2 5 (14.7) 12 (27.9) 3 29 (85.3) 30 (69.8) .19 number of resections 1.0 ± 1.0 1.0 ± 1.1 .90 table 1. demographic and clinical profile of patients with bladder cancer who underwent either radical cystectomy and standard lamyphadenectomy or en bloc cystectomy* *values in parentheses are percents. †duration of disease was defined as the time from diagnosis to cystectomy. location of 46 metastatic nodes in 34 patients with anatomical dissection (standard lymphadenectomy). iil indicates internal iliac lymph node; eil, external iliac lymph node; and ol, obturator lymph node. surgical treatment characteristics standard lymphadenectomy(group 1) en bloc cystectomy (group 2) p median number of removed nodes 15.5 7 < .001 patients with involved lymph nodes 10 (29.4) 9 (20.9) .43 median lymph node density, % 23.5 11.0 < .001 operative mortality 1 (2.9) 1 (2.3) .70 patients with early complications 7 (20.6) 4 (9.3) .16 table 2. outcomes of standard lamyphadenectomy and en bloc cystectomy standard versus en bloc lymphadenectomy in bladder cancer—ather et al urology journal vol 5 no 2 spring 2008 97 staging and provides direct survival benefit.(2) recent evidence has shown that node involvement is a significant and independent prognostic factor.(3-5) a growing body of evidence suggests that an extended lymph node dissection may provide prognostic information and therapeutic benefits for patients with or without lymph node involvement undergoing rc for tcc. boundaries of the lymphadenectomy are still a subject of controversy. abol-enein and colleagues reported that extended lymphadenectomy up to the origin of the inferior mesenteric vessels showed 37% and 60% bilateral and unilateral node involvement, respectively.(13) dissection of only internal iliac nodes will miss 85% of positive nodes, whereas dissection of the internal and external iliac and obturator nodes will pick two-thirds of the nodes. dissection up the aortic bifurcation picks four-fifth of the nodes.(13) guidelines for the treatment of muscle-invasive bladder cancer by the european association of urology recommend limited pelvic node dissection, consisting of removal of the tissue in the obturator fossa in patients undergoing surgery with a curative intent.(14) several authors have noted an improved 5-year survival rate with extensive pelvic lymph node dissection in the patients with node-involved bladder cancer.(5,15) herr and colleagues studied the number of nodes removed and its effect on the outcome of the patient after rc.(3) they found that a minimum of 9 nodes was needed to be examined to accurately assess nodal involvement. they also found that survival improved in both patients with and without node involvement as the number of the removed nodes increased. they also evaluated the impact of submitting nodes en bloc or as separate packages and suggested that submitting nodes as separate packages not only is easier, but also optimizes the evaluation and number of the lymph nodes retrieved.(3) some studies indicate that lymphadenectomy in combination with rc can cure a small fraction of node-positive patients.(9) conclusion we found that the number of the nodes retrieved per specimen increases significantly if dissection and submission of the nodes is done in the anatomically defined areas rather than en bloc submission. conflict of interest none declared. acknowledgement we would like to thank dr syed iqbal azam, assistant professor, coordinator, statistical consulting services, community health sciences, aga khan university. references 1. ather mh, fatima s, sinanoglu o. extent of lymphadenectomy in radical cystectomy for bladder cancer. world j surg oncol. 2005;3:43. 2. vieweg j, gschwend je, herr hw, fair wr. pelvic lymph node dissection can be curative in patients with node positive bladder cancer. j urol. 1999;161:44954. 3. herr hw, bochner bh, dalbagni g, donat sm, reuter ve, bajorin df. impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. j urol. 2002;167:1295-8. 4. steven k, poulsen al. radical cystectomy and extended pelvic lymphadenectomy: survival of patients with lymph node metastasis above the bifurcation of the common iliac vessels treated with surgery only. j urol. 2007;178:1218-23. 5. ghoneim ma, el-mekresh mm, el-baz ma, el-attar ia, ashamallah a. radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. j urol. 1997;158:393-9. 6. frazier ha, robertson je, dodge rk, paulson df. the value of pathologic factors in predicting cancerspecific survival among patients treated with radical cystectomy for transitional cell carcinoma of the bladder and prostate. cancer. 1993;71:3993-4001. 7. leissner j, hohenfellner r, thüroff jw, wolf hk. lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. bju int. 2000;85:817-23. 8. koppie tm, vickers aj, vora k, dalbagni g, bochner bh. standardization of pelvic lymphadenectomy performed at radical cystectomy: can we establish a minimum number of lymph nodes that should be removed? cancer. 2006;107:2368-74. 9. bochner bh, herr hw, reuter ve. impact of separate versus en bloc pelvic lymph node dissection on the number of lymph nodes retrieved in cystectomy specimens. j urol. 2001;166:2295-6. 10. stein jp, penson df, cai j, et al. radical cystectomy with extended lymphadenectomy: evaluating separate package versus en bloc submission for node positive bladder cancer. j urol. 2007;177:876-81. standard versus en bloc lymphadenectomy in bladder cancer—ather et al 98 urology journal vol 5 no 2 spring 2008 11. honma i, masumori n, sato e, et al. removal of more lymph nodes may provide better outcome, as well as more accurate pathologic findings, in patients with bladder cancer--analysis of role of pelvic lymph node dissection. urology. 2006;68:543-8. 12. wiesner c, pfitzenmaier j, faldum a, gillitzer r, melchior sw, thüroff jw. lymph node metastases in non-muscle invasive bladder cancer are correlated with the number of transurethral resections and tumour upstaging at radical cystectomy. bju int. 2005;95:301-5. 13. abol-enein h, el-baz m, abd el-hameed ma, abdellatif m, ghoneim ma. lymph node involvement in patients with bladder cancer treated with radical cystectomy: a patho-anatomical study--a single center experience. j urol. 2004;172:1818-21. 14. van der meijden ap, sylvester r, oosterlinck w, et al; for the eau working party on non muscle invasive bladder cancer. eau guidelines on the diagnosis and treatment of urothelial carcinoma in situ. eur urol. 2005;48:363-71. 15. poulsen al, horn t, steven k. radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. j urol. 1998;160:2015-9. u j spring 2012.pdf 514 | reconstructive surgery tubularized incised plate urethroplasty using buccal mucosa graft for repair of penile hypospadias kamyar tavakkoli tabassi,1 toktam mohammadi rana2 purpose: to describe the results of penile hypospadias repair using the snodgrass second layer. materials and methods: underwent hypospadias repair using the snodgrass method and bmg as the urepatients were followed up, and outcomes and complications were recorded. results: the following minor complications, not requiring additional intervention, were infection; and 1 had meatal stenosis postoperatively. only one patient required additional surgical intervention resulting in a success rate of 95%. no urethrocutaneconclusion: fortifying a combination of bmg and snodgrass method with double keywords: urethra, hypospadias, mouth mucosa, reconstructive surgical procedures, treatment outcome corresponding author: kamyar tavakkoli tabassi, md department of urology, imamreza hospital, mashhad, iran tel: +98 511 854 3031 fax: +98 511 859 1057 e-mail: kamiartt@yahoo. com received february 2011 accepted may 2011 1mashhad center for reconstructive urology, mashhad, iran 2mashhad university of medical sciences, mashhad, iran reconstructive surgery 515vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l introduction hypospadias is a common congenital mal-formation of the genitourinary system affecting one in 300 male newborns. various surgical procedures have been employed for the urethral reconstruction in hypospadias. the goals of repair is to achieve straight penis, normal position of the urethral meatus on the glans, adoptimal sexual function during adulthood. throplasty is the most common technique used for correction of distal hypospadias and the method of choice for treatment of many types of hypospadias. compared to other techniques, tip has lower complication rate and one-stage surgical repair can be accomplished. usually preputial and penile skins are used for urethral reconstruchypospadias or after circumcision. consequently, alternative reconstructive option, has gained popularity in these cases. in spite of improvement in these techniques, uricommon and serious complication of tip, followed by urethral stenosis. in this study, we evalvascularized tissue, in addition to tip with bmg for the repair of hypospadias and their positional materials and methods parents of each patient were informed about the details of surgical procedure and potential outcomes and complications. furthermore, they were asked if they would consent for the results of the surgery to be reported in medical literature withconsent was obtained. the study design has been approved by mashhad center for reconstructive urology. patients we performed a pilot prospective cohort study all the patients underwent a buckle mucosal graft ond layer of repair. we scheduled follow-up vis3 months thereafter. to ensure completeness of follow-ups, patients were called if they failed to show up for a follow-up visit. during each visit, we evaluated patients for the development of wound infection, penile torsion, urethrocutanecomplications. procedure was considered a success if subjects did not develop any complications or had minor complications that could be corrected with simple procedures, such as meatotomy or meatal dilataas a case that needed another surgery for repair. surgical technique under general anesthesia, after placing stay suture, following the method of incised plate urethroplasty, a midline incision was made. thereafter, based on the anatomy of the individual penis, this incision was either widened or deepened to create a suitable bed for the graft. to prevent exurethroplasty with buccal mucosa graft | tavakkoli tabassi and mohammadi rana 516 | cessive bleeding, we delayed the extension of the incision into the glans penis until the buccal graft harvest was obtained. the buccal mucosa graft was harvested with a width of 10 to 15 mm and a length matching with the length of penile incision. subsequently, the buccal graft was placed monocryl sutures. thereafter, the incision was extended into the glans penis and the graft was extended onto this area to prevent later meatal stenosis formation. two parallel incisions were made on the ventral skin of the penis and urethral tubularization was completed in two layers using incision completely degloving the skin. then, the rotated towards the ventral surface of the penis and sutured on each other onto the neourethra controlled for any tension on either side and adjusted our sutures to prevent penile torsion. when pre-existing penile torsion due to previous surgeries was detected, we would adjust the tension on pressure dressing was applied. finally, patient’s duce a slight pressure keeping the graft on its bed. th postoperative day. patients were discharged 5 to 6 days after the procedure. urethral catheters were removed 7 to 10 days after the surgery. statistical analysis the data were analyzed using spss software (the statistical package for the social sciences, verused fisher’s exact test to compare the prevalence of independent variables of interest between those who were successful and those who failed. p values less than results table outlines the characteristics of the patients. overall success rate was 95%. complication-free failure with a need to repeat operation occurred in one subject resulted in a failure rate of 5%. in correction because the degree of chordee was meatal stenosis, but responded to repeated urethral dilatations. two subjects developed infection; one responded to antibiotic therapy and one did not, resulting in failure of the repair. this was the only failure and was planned for delayed surzero. the location of hypospadias, proximal, mid-shaft, development of complications (p subjects had distal penile hypospadias, of whom 6 patients suffered from mid-shaft and proximal developed complications, respectively. subjects with a history of previously failed opreconstructive surgery 517vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l urethroplasty with buccal mucosa graft | tavakkoli tabassi and mohammadi rana figure 1. (a) penile hypospadias before operation. (b) buccal mucosa graft was fixed on incised urethral plate. (c) two parallel incisions were made on the ventral skin of the penis. (d) urethral tubularization was completed in two layers. (e) the dartos flap was incised longitudinally in the middle dividing it into two. (f) each of these flaps were rotated towards the ventral surface of the penis and sutured on each other onto the neourethra. (g) dorsal view of the penis before the skin closure. (h) the penis after operation. 518 | p tions in 10 patients with history of previous failed surgery included meatal stenosis in one, chordee in one, and infection in one subject. from complications after the repair surgery. and the development of complications (p reconstructive surgery figure 2. (a) penile torsion before operation. (b) making midline incision. (c) fixing buccal mucosa graft to underlying tissues. (d) two parallel incisions were made on the ventral skin of the penis. (e) urethral tubularization was completed in two layers. (f) the dorsal darthe operation. 519vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l ment of complications (p we were able to eliminate penile torsion in 3 patients who had a pre-existing penile torsion as a result of previous surgical interventions. the discomfort at the buccal donor site was mild in all of our subjects in the 1st nd postoperative days, nd postoperative day. there were no aesthetic or functional complications at the oral donor site during our follow-up period. discussion in this study, we demonstrated high success rate and low complication rate with the combination of snodgrass method and bmg and used double spective of patients’ age, location of hypospadias, history of previously failed surgery, and presence or absence of the prepuce. widespread acceptance and has become the treatment of choice for many types of hypospadias. tubularized incised plate is relatively simple, has a low complication rate, and attains superior cosmetic and functional results. the superiority of tip is the result of the incision that widens the urethral plate in order to create a tension-free neourethra. nique have resulted in reduced risk of complications. however, in other studies, especially in patients with history of previous surgery, higher urethroplasty with buccal mucosa graft | tavakkoli tabassi and mohammadi rana patients’ characteristics. patient no. age, y types of hypospadias previous operations follow-up, month complications 1 11 proximal penile yes 9 2 15 distal penile yes 9 3 3 mid penile no 9 chordee 4 4 proximal penile yes 9 5 7 distal penile yes 6 chordee 6 11 mid penile no 6 infection 7 9 mid penile no 6 3 proximal penile no 6 9 4 distal penile yes 6 10 2 mid penile no 6 11 distal penile no 6 infection 12 5 mid penile yes 6 13 2 mid penile no 6 14 6 mid penile yes 3 15 9 proximal penile yes 3 meatal stenosis 16 12 distal penile yes 3 17 2 mid penile no 3 7 distal penile no 3 19 3 distal penile no 3 20 proximal penile yes 3 21 7 proximal penile yes 3 520 | reported. buccal mucosa graft has several advantages over other grafts; hence, it has become the graft of choice in hypospadias repair. the tissue is tough and resilient, which allows for manipulation, the process of harvesting is simple and does not create a visible donor site scar, and it is compatible with the wet environment of the urethra. matoma formation, and lifting the graft from the bed as the result of shear forces can be decreased by quilting of bmg well onto its bed. snodgrass and elmore reported a two-stage operation, in which dorsal bmg replaced the plate or scarred skin. using this method, they demonstrated improved vascularization and an initial graft healing rate of 88%, with the overall success rate of 65%. we used snodgrass method and corpus cavernosum, which resulted in low complication rate both at the area of graft removal and outcome of the repair. the most common complication in hypospadias la. several surgical techniques have been used to ameliorate the rate of this complication. retik and neourethra. yerkes and colleagues used the yto-v procedure to wrap the corpus spongiosum and reinforce the neourethra. shanberg and associates used a laterally-based de-epithelialized vious repair failure. however, these methods may result in other complications. rotated asymmay cause rotation in the penis. spongial tissue has limited application in mid-shaft hypospadias. sozubir and snodgrass used dorsal dartos pedirotated it to the ventral side with a button whole maneuver, formation, with less risk of rotation. mustafa and coworkers reported the advantages of dou in our study, we divided dartos to two parts, as mustarotated laterally and symmetrically to cover the neourethra; hence, reduced the risk of the penile rotation. furthermore, by adjusting the tension of nile rotations as well. by creating double barrier, la. in comparison, mustafa and associates reporthowever, not in subjects who underwent primary reconstruction. in our study, we believe in the use of bmg conas a decreased rate of meatal stenosis because we extended the bmg to the glans. this in return allowed us to avoid creation of high pressure voidformation. ously reported by hosseini and colleagues. ye and associates combined tip with bmg in 53 patients. the outcome was especially acceptable in patients with prior failed hypospadias repair. the overall complication rate, after an average folture formation. additional use of double dorsal dartos as a second layer to cover the neourethra la formation in our study. on the other hand, it could be argued that the lower complication rate reconstructive surgery 521vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l mustafa m, wadie bs, abol-enein h. standard snodgrass the neourethra with dorsal dartos flap is the therapy of first 9. yerkes eb, adams mc, miller da, pope jct, rink rc, brock jw, 3rd. y-to-i wrap: use of the distal spongiosum for hypospa10. holland aj, smith gh. effect of the depth and width of the urethral plate on tubularized incised plate urethroplasty. j 11. preputial free graft to extend the indications of snodgrass 12. hayes mc, malone ps. the use of a dorsal buccal mucosal graft with urethral plate incision (snodgrass) for hypospadias 13. kolon tf, gonzales et, jr. the dorsal inlay graft for hypospa14. asopa hs, garg m, singhal gg, singh l, asopa j, nischal a. dorsal free graft urethroplasty for urethral stricture by ventral 15. snodgrass w, elmore j. initial experience with staged buccal graft (bracka) hypospadias reoperations. j urol. 16. retik ab, borer jg. primary and reoperative hypospadias re91. 17. shanberg am, sanderson k, duel b. re-operative hypospadias repair using the snodgrass incised plate urethroplasty. sozubir s, snodgrass w. a new algorithm for primary hypospadias repair based on tip urethroplasty. j pediatr surg. 19. mustafa m, wadie bs, abol-enein h. dorsal dartos flap in snodgrass hypospadias repair: how to use it? urol int. 20. hosseini j, kaviani a, mohammadhosseini m, rezaei a, rezaei i, javanmard b. fistula repair after hypospadias surgery using 21. hensle tw, kearney mc, bingham jb. buccal mucosa grafts for hypospadias surgery: long-term results. j urol. in our study may be due to the shorter duration of follow-up period. however, usually, the majority after the operation. furthermore, 5 out of the 8 reported complications in ye’s series occurred when the surgeon was in learning curve period, which may improve as the surgical technique is mastered. our study is not without limitations. first, the follow-up period is short. second, we compared our complex method with other techniques. conclusion is an acceptable technique for the urethral reconstruction in penile hypospadias. further studies conflict of interest none declared. references 1. duckett jw. hpospadias. in: walsh ab, retik ed, vaughan j, eds. compbell's urology. vol 2. 7 ed. philadelphia: wb saun2. snodgrass w. tubularized, incised plate urethroplasty for 3. snodgrass w, koyle m, manzoni g, hurwitz r, caldamone a, ehrlich r. tubularized incised plate hypospadias repair for 4. dessanti a, iannuccelli m, ginesu g, feo c. reconstruction of hypospadias and epispadias with buccal mucosa free graft as primary surgery: more than 10 years of experience. j urol. 5. snodgrass w, koyle m, manzoni g, hurwitz r, caldamone a, ehrlich r. tubularized incised plate hypospadias repair: 6. snodgrass wt, lorenzo a. tubularized incised-plate urethro7. ye wj, ping p, liu yd, li z, huang yr. single stage dorsal inlay buccal mucosal graft with tubularized incised urethral plate urethroplasty with buccal mucosa graft | tavakkoli tabassi and mohammadi rana 405vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l the role of hypothyroidism in male infertility and erectile dysfunction mohammad reza nikoobakht,1 mehdi aloosh,1,2 nafiseh nikoobakht,1 abdolrasoul mehrsay,1 farzad biniaz,3 mohammad amin karjalian1 purpose: to evaluate the effect of hypothyroidism on erectile function and sperm parameters. materials and methods: this study was conducted on 24 patients with hypothyroidism and 66 normal individuals. serum levels of hormones, including thyroid stimulating hormone (tsh), thyroxin (t4), follicle-stimulating hormone (fsh), luteinizing hormone (lh), prolactin (prl), and testosterone, were measured and semen analysis was done in all the participants. erectile function was evaluated using international index of erectile function (iief-5) questionnaire. results: the mean iief-5 total score was 11.75 [95% confidence interval (ci): 9.70 to 13.79) and 20.81 (95% ci: 20.02 to 21.6) for hypothyroid group and normal subjects, respectively (p = .005). furthermore, serum concentrations of prl and seminal parameters were significantly different between two groups (p < .001). conclusion: hypothyroidism adversely affects erectile function and sperm parameters, including sperm count, morphology, and motility. in patients with sperm abnormalities and erectile dysfunction, measurement of thyroid hormones is recommended. keywords: hypothyroidism, infertility, erectile dysfunction, semen corresponding author: mohammad reza nikoobakht, md sina hospital, emam khomeini st, tehran, iran tel/fax: +98 21 6671 6546 e-mail: nikoobakht_r@ live.com received december 2010 accepted may 2011 1 urology research center, sina hospital, tehran university of medical sciences, tehran, iran 2 research development center of sina hospital, tehran university of medical sciences, tehran, iran 3 department of radiology, sina hospital, tehran university of medical sciences, tehran, iran sexual dysfunction and infertility 406 | sexual dysfunction and infertility introduction hyper and hypothyroidism are the main thyroid diseases with adverse effects on male reproductive system. short-term hypothyroidism has no significant effect on male reproduction in adults, while severe, prolonged hypothyroidism may impair the reproductive function.(1) although the effects of the thyroid dysfunction on female gonadal function have been clearly established, its impact on male reproductive function remains controversial.(2,3) thyroid hormone disorders cause some sexual dysfunctions that normalizing the thyroid hormone levels can reverse them.(4) el-sakka and colleagues reported that low serum testosterone (15%), hyperprolactinemia (13.7%), and hypothyroidism (3.1%) are the most frequent endocrine abnormalities seen in patients with sexual dysfunction. they also reported a significant association between sexual dysfunction and endocrine imbalance.(5) furthermore, hypothyroidism has an adverse effect on human spermatogenesis; as griboff showed that morphology is significantly affected and motility may be less affected.(6) on the other hand, histological abnormalities in all testicular biopsies have been reported.(7,8) the aim of this study was to evaluate erectile functions, serum levels of hormones, and sperm parameters in male patients with hypothyroidism and normal subjects. we hypothesized that hypothyroid state has an adverse effect on the erectile function and sperm parameters in men. materials and methods between january 2009 and june 2010, 24 consecutive hypothyroid patients (group a), who were referred to the outpatient endocrine clinic of sina hospital, affiliated to tehran university of medical sciences, were enrolled in this study. the inclusion criteria were as follows: age range of 20 to 70 years, not being investigated or treated for sexual dysfunction before the onset of thyroid symptoms, and being married for more than 1 year. patients with diabetes mellitus, cardiovascular diseases, including history of myocardial infarction, coronary angioplasty, or coronary artery bypass grafting, or urological diseases were excluded from the study. group a, with the mean age of 43.1 ± 11.6 years (range, 20 to 63 years), were complaining from clinical symptoms of hypothyroidism. they had documented hypothyroidism. the control group, group b, consisted of 66 healthy normal hospital staff, with the mean age of 41.5 ± 69.0 years (range, 21 to 69 years). all participants provided written informed consent and the study was approved by the medical ethics committee of tehran university of medical sciences. serum levels of free thyroxin (ft4), thyroid stimulating hormone (tsh), free testosterone, prolactin (prl), follicle-stimulating hormone (fsh), and luteinizing hormone (lh) were measured using immunoassay commercial kits in both groups. the normal reference ranges for thyroid hormones were as follows: tsh, 0.3 to 5.0 iu/ml and t4, 4.5 to 12.5 g/dl. erectile dysfunction was evaluated using international index of erectile function (iief-5) questionnaire.(9) this is a 5-item version of the 15-item iief questionnaire for diagnosing the presence and severity of erectile dysfunction (ed). these items focus on erectile function and intercourse satisfaction. possible scores for the iief-5 range from 5 to 25. this questionnaire was translated into persian language and its validity and reliability have been tested previously in our center. semen analyses were done according to the world health organization guidelines.(10) semen was obtained by masturbation after 3 to 7 days of sexual abstinence. semen sample was collected into a sterile container, using no lubricant jelly. reference limits of semen parameters are as follows: total sperm number, 39 million per ejaculate (range, 407vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l hypothyroidism, infertility, and sexual dysfunction | nikoobakht et al 33 to 46); sperm concentration, 15 million per ml (range, 2 to 16); vitality, 58% live (range, 55% to 63%); progressive motility, 32% (31% to 34%); total (progressive + nonprogressive) motility, 40% (range, 38% to 42%); and morphologically normal forms, 4.0% (range, 3.0% to 4.0%).(10) statistical analysis each variable, including age, serum levels of hormones, sperm parameters, and iief-5 scores, was assessed using a univariate analysis by independent sample t test, mann-whitney u test, and pearson correlation, where appropriate. the kolmogorov–smirnov test was used to check if iief5 scores had a normal distribution. variables that were significantly related to hypothyroidism (p < .05) were assessed in a multivariate analysis with a logistical regression procedure and forward stepwise selection. the dependent variable was coded as zero for absence and one for the presence of hypothyroidism. results while age was not significantly different between the two groups (p = .465), a significant difference was found in iief-5 scores (p < .001). serum prl level, sperm count, sperm motility, and morphology were significantly different between two groups (p = .001, p < .001, p < .001, and p < .001, respectively; table 1). multivariate analysis showed that hypothyroidism affected the morphology of the sperm more than other parameters (or = 75.3; table 2). in the hypothyroid group, tsh and ft4 were 15.02 ± 3.30 iu/ml and 2.91 ± 1.40 g/dl, respectively. there was no correlation between serum tsh levels and severity of ed (iief-5), serum testosterone levels, and sperm parameters (table 3). discussion the effects of thyroid hormone alterations on the reproductive system have been studied extensively in animals, which showed that abnormal thyroid function resulted in decreased fertility and table 1. characteristics, hormonal, and seminal parameters of participants hypothyroid group normal group 95% confidence intervalmean ± sd mean ± sd p participants, n 24 66 age, y 43.1± 11.6 41.5 ± 69 .45 -4.09 to 7.19 iief-5 score 11.75 ± 4.84 20.81 ± 3.21 .005 -10.82 to -7.31 fsh, mu/ml 8.70 ± 4.17 7.51 ± 7.37 .342 -1.29 to 3.67 lh, mu/ml 7.40 ± 3.70 6.58 ± 2.62 .327 -0.85 to 2.49 free testosterone, pg/ml 5.40 ± 2.27 17.73 ± 98.09 .311 -36.45 to 11.80 prolactin, ng/ml 359.41 ± 77.57 290.13 ± 96.86 .001 29.48 to 109.08 sperm count, million/ml 28.04 ± 25.72 72.98 ± 42.72 .000 -59.82 to -30.05 sperm motility, % 30.08 ± 18.53 67.39 ± 12.20 .000 -45.61 to -29.00 sperm morphology, % 35.12 ± 13.87 65.10 ± 11.28 .000 -36.38 to -23.57 sd indicates standard deviation; iief-5, international index of erectile function questionnaire; fsh, follicle-stimulating hormone; and lh, luteinizing hormone. table 2. multivariate analysis of iief-5 and sperm parameters. variables r p odds ratio iief-5 -93.953 .989 0.000 sperm count 1.079 .991 2.942 sperm motility .502 .992 1.652 sperm morphology 4.322 .985 75.307 iief-5 indicates international index of erectile function questionnaire. 408 | impaired sexual activity.(11,12) in animals, if hypothyroidism occurs soon after birth, delay in sexual maturation will be observed.(13) in male pax8-/ mice with congenital hypothyroidism, the efferent ducts and epididymis are either absent or the efferent ducts lumen are reduced, which leads to impaired testicular drainage and absence of spermatozoa.(14) moreover, in male rats with transient gestational onset hypothyroidism, post-testicular sperm maturation is impaired in the epididymis. in these cases, androgen bioavailability, its receptor expression, and function are subnormal; however, there are no lower serum levels of androgen.(15) in the current study, patients with hypothyroidism had significantly higher level of serum prl and lower iief-5 score, which means more erectile problems. serum levels of fsh, lh, and free testosterone were not significantly different. in hypothyroid subjects, high levels of prl may affect sexual drive and result in ed.(16,17) on the other hand, hypothyroidism in women decreases serum level of sex hormone-binding globulin (shbg) and increases the prl secretion by affecting the ovarian function. thyroxin administration can improve fertility and reverses hormonal abnormalities.(18,19) in addition, primary hypothyroidism causes decreased serum levels of shbg and total testosterone. it has been shown that thyroid hormone administration to men with hypothyroidism increases both shbg and total serum testosterone. (20) we did not observe significant difference in serum testosterone, lh, and fsh levels between two groups. it may be due to subnormal bioavailable androgen and abnormal receptor expression and function, as shown in the animal studies or small sample size of study.(15) not all of the patients with thyroid diseases do experience sexual dysfunction. moreover, all of the patients with hyper or hypothyroidism reaching euthyroid state do not recover from sexual dysfunction. these observations show that sexual dysfunctions are almost always multifactorial (physical and psychological factors).(4) in the current study, there are some potential confounders, such as body mass index, smoking habits, etiology of hypothyroidism, abstinent time for semen analysis, season, and time of the day that sampling happened. they may affect serum levels of hormones and sperm parameters. in addition, only a single sample of semen and blood were collected in a small group of patients. therefore, it is needed to conduct studies with higher degree of evidence, such as cohort studies, on larger number of participants to clarify the effects of hypothyroidism on male reproductive system. conclusion hypothyroidism adversely affects erectile function and semen quality in men. further large scale studies are needed to replicate our results. acknowledgements we thank research development center of sina hospital for its support. conflict of interest none declared. references 1. krassas ge, pontikides n. male reproductive function in relation with thyroid alterations. best pract res clin endocrinol metab. 2004;18:183-95. table 3. correlation analysis of tsh levels in the hypothyroid group variables r p free testosterone -0.182 .396 iief-5 0.088 .681 sperm count -0.154 .472 sperm motility -0.135 .529 sperm morphology 0.098 .650 *correlation is significant at the 0.05 level (2-tailed). tsh indicates thyroid stimulating hormone; and iief-5 international index of erectile function questionnaire. sexual dysfunction and infertility 409vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l 2. krassas ge. thyroid disease and female reproduction. fertil steril. 2000;74:1063-70. 3. mcdermott mt. thyroid disease and reproductive health. thyroid. 2004;14 suppl 1:s1-3. 4. carani c, isidori am, granata a, et al. multicenter study on the prevalence of sexual symptoms in male hypoand hyperthyroid patients. j clin endocrinol metab. 2005;90:64729. 5. el-sakka ai, hassoba hm, sayed hm, tayeb ka. pattern of endocrinal changes in patients with sexual dysfunction. j sex med. 2005;2:551-8. 6. griboff si. semen analysis in myxedema. fertil steril. 1962;13:436-43. 7. de la balze fa, arrillaga f, mancini re, janches m, davidson ow, gurtman ai. male hypogonadism in hypothyroidism: a study of six cases. j clin endocrinol metab. 1962;22:212-22. 8. wortsman j, rosner w, dufau ml. abnormal testicular function in men with primary hypothyroidism. am j med. 1987;82:207-12. 9. rosen rc, cappelleri jc, smith md, lipsky j, pena bm. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 1999;11:319-26. 10. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. hum reprod update. 2010;16:231-45. 11. krassas ge. the male and female reproductive system in thyrotoxicosis in: werner sc, ingbar sh, braverman le, utiger rd, eds. werner and ingbar’s the thyroid—a fundamental and clinical text. 9 ed. philadelphia: lippincott williams & wilkins; 2005:621-8. 12. johnson ca. thyroid issues in reproduction. clin tech small anim pract. 2002;17:129-32. 13. jannini ea, crescenzi a, rucci n, et al. ontogenetic pattern of thyroid hormone receptor expression in the human testis. j clin endocrinol metab. 2000;85:3453-7. 14. wistuba j, mittag j, luetjens cm, et al. male congenital hypothyroid pax8-/mice are infertile despite adequate treatment with thyroid hormone. j endocrinol. 2007;192:99-109. 15. anbalagan j, sashi am, vengatesh g, stanley ja, neelamohan r, aruldhas mm. mechanism underlying transient gestational-onset hypothyroidism-induced impairment of posttesticular sperm maturation in adult rats. fertil steril. 2010;93:2491-7. 16. corona g, mannucci e, petrone l, et al. psycho-biological correlates of hypoactive sexual desire in patients with erectile dysfunction. int j impot res. 2004;16:275-81. 17. cohen lm, greenberg db, murray gb. neuropsychiatric presentation of men with pituitary tumors (the 'four a's'). psychosomatics. 1984;25:925-8. 18. poppe k, velkeniers b, glinoer d. the role of thyroid autoimmunity in fertility and pregnancy. nat clin pract endocrinol metab. 2008;4:394-405. 19. trokoudes km, skordis n, picolos mk. infertility and thyroid disorders. curr opin obstet gynecol. 2006;18:446-51. 20. cavaliere h, abelin n, medeiros-neto g. serum levels of total testosterone and sex hormone binding globulin in hypothyroid patients and normal subjects treated with incremental doses of l-t4 or l-t3. j androl. 1988;9:215-9. hypothyroidism, infertility, and sexual dysfunction | nikoobakht et al pediatric urology utility of urine interleukines in children with vesicoureteral reflux and renal parenchymal damage azar nickavar1, baranak safaeian2*, ehsan valavi3, homa davoodi2 purpose: vesicoureteral reflux (vur) is the most common risk factor of urinary tract infection in children. currently, diagnosis of vur depends on invasive imaging studies, with a high radiologic burden. therefore, different biomarkers have been introduced for the evaluation of these patients. the objective of this study was to identify alteration of urinary interleukins (ils) excretion in children with primary vur and renal parenchymal damage, for further clinical application. materials and methods: urinary concentrations of il-1α, il-1β, il-6, and il-8 were evaluated in 34 children with vur (cases) and 36 without vur (control), during 2018-2019. urinary concentrations of il-1, il-1, il-6 and il-8 were measured, using polyclonal antibody elisa kit, and standardized to urine creatinine (cr). patients with infectious or inflammatory disorders, urolithiasis, immune deficiency, acute or chronic kidney disease, and secondary vur were excluded from the study. results: mean age of cases (36.00 ± 27.66) had no significant difference with the control (32.86±29.31) group (p=0.44). the majority of patients had moderate vur (58.8%), followed by severe (35.3%) and mild (5.9%) grades. urinary concentration of all ils/cr were significantly higher in patients with vur, compared with those without vur. there was no significant correlation between urine ils/cr with age, gender, serum electrolytes, urine specific gravity, renal ultrasound, laterality or severity of vur, and dmsa renal scan. all urine ils/cr had acceptable sensitivity and accuracy for workup of children with primary vur. conclusion: urine il-1α, il-1β, il-6 and il-8/cr were sensitive and accurate additionary screening biomarkers in children with primary vur. keywords: vesicoureteral reflux; interleukin; cytokine; renal damage introduction vesicoureteral reflux (vur) accounts for 30–50% of urinary tract infections (uti) in children. about 8.5–18% of chronic kidney disease occurs secondary to vur in pediatrics. therefore, early diagnosis and appropriate management of vur might prevent its longterm complications, such as hypertension, proteinuria, and decreased renal function(1). nowadays, identification of vur depends on invasive and expensive imaging modalities, with high radiologic exposure. meanwhile, recently introduced noninvasive biomarkers such as urine interleukins (ils) have been suggested as alternative diagnostic approaches in patients with vur and their high risk siblings (2,3). cytokines are small soluble proteins, and regulate both humoral and cellular immunity(4). il-1α, il-6, and il-8 are proinflammatory cytokines, which stimulate peripheral neutrophilia, chemokine secretion, and scar formation in different tissues(5-7). lymphocyte and plasma cell infiltration is responsible for increased urinary il excretion in patients with vur or reflux associated nephropathy(7). although inflammatory processes and immune system dysfunction have been suggested in the pathogenesis of renal parenchymal damage (rpd), however, a correlation between vur and urinary cytokines excretion remains controversial(7,8). the purpose of this study was to identify alteration of urinary ils excretion in children with primary vur and rpd. materials and methods this is a cross sectional multicentric case-control study on children admitted to 3 pediatric nephrology clinics during 2018-2019. it was approved by the institutional ethics committee (ethical code; ir.goums. rec.1396.02), and informed consent was obtained from legal guardians. children with a history of recurrent utis, urosepsis, uti with abnormal ultrasound, atypical uti, and asymmetrical kidneys who had a definite cystography and 99mtc-dmsa scintigraphy were included in this study. all of them were in healthy condition with normal body mass index at the time of the study. totally, 70 children (35 females, 35 males) were evaluated. of them, 34 had vur (case group) and 36 did not 1department of pediatric nephrology, iran university medical sciences, tehran, iran. 2neonatal and children’s health research center, golestan university of medical sciences, gorgan, iran. 3chronic renal failure research center, ahvaz jundishapur university of medical sciences, ahvaz, iran. *correspondence: baranak safaeian and homa davoodi, neonatal and children’s health research center, golestan university of medical sciences, gorgan, iran. tel: 0098-2122226127. email: baranak54@yahoo.com. received january 2020 & accepted july 2020 urology journal/vol 18 no. 2/ march-april 2021/ pp. 199-202. [doi: 10.22037/uj.v16i7.5957] have vur (control group). conventional cystography (vcug) or radioisotopic cystography (direct rnc) was done under prophylactic antibiotic treatment in all patients. 99mtc-dmsa renal scan was performed in patients with documented vur or other inclusion criteria 9. patients with a history of uti in the preceding 3 months, inflammatory disorders, active infections, ongoing antibiotic treatment, secondary vur, neurogenic bladder, obstructive uropathy, urolithiasis, immune deficiency, malnutrition, obesity, hypertension, and chronic kidney disease were excluded from the study. based on imaging studies, vur was classified as mild (i, ii), moderate (iii), and severe (iv, v) grades. the highest grade was taken in to consideration in patients with bilateral vur. parenchymal damage was defined as decreased cortical uptake or renal outline defect in 99mtc-dmsa scintigraphy. a spot morning urine sample was obtained from all individuals and frozen at _80°_ c within 3 hours of collection. urinary level of cytokines was measured using polyclonal antibody elisa kit. to avoid dilutional effects, urinary ils were expressed as the ratio of cytokine-to-urine creatinine (cr) excretion (pg/mg). statistical analysis was performed using spss ver. 24.0 and 15.4 med calc. values are presented as mean±sd. student’s t test, nonparametric mann-whitney test, and chi2 were used for comparison of variables between two groups. correlations between urine ils with other variables were determined, using the spearman’s, mann-whitney, and kruskal walis tests. a receiver operating characteristic (roc) curve was constructed to determine the cutoff values of each cytokine with the best sensitivity, specificity, and accuracy. p values < 0.05 considered to be statistically significant. results a total of 34 children with vur (m/f=1), and 36 without vur (m/f=1) were enrolled in this study. vur was bilateral in 21 (61.8%) patients. two patients (1 unilateral, 1 bilateral) had mild vur, followed by 20 with moderate (7 unilateral, 13 bilateral) and 12 with severe (5 unilateral, 7 bilateral) grades. laboratory findings including renal function, serum electrolytes, serum bicarbonate, and urine specific gravity had no significant difference between the two groups. renal ultrasound and 99mtc-dmsa renal scan were normal in the majority of patients, with no significant difference between the two groups (table 1). mean urinary concentration of all ils/cr were significantly higher in children with vur, compared with those without vur (table 2). none of the urine ils had a significant correlation with quantitative (age, sodium, potassium, bicarbonate, urine sg) and qualitative (gender, ultrasound, vur laterality, vur grade) variables, except for a direct correlation between urine il-1β/cr (p = 0.033) and il-6/ cr (p = 0.037) with dmsa renal parenchymal damage. however, multivariate analysis showed no association between dmsa scan, unilateral or bilateral vur, and severity of vur with urine ils/cr excretion (table 3). the optimal cutoff values of urine ils/cr with the highest sensitivity, specificity, and accuracy are shown in table 4 and figure 1. accordingly, all ils/cr had acceptable sensitivity and accuracy for the workup of children with vur. discussion increased urinary cytokine excretion occurs secondary to tubular damage and interstitial fibrosis in patients with reflux associated nephropathy(3,7). therefore, measurement of urine ils has been suggested for early identification of vur, prior to the development of rpd and its serious complications(4,10). this study was performed to identify alteration of urine ils excretion in children with primary vur and rpd. il-6 is a proinflammatory cytokine which is produced by endothelial and mesangial cells, fibroblasts, activated t cells and b cells, macrophages, and destructive renal tubular cells. urinary concentration of il-6 might reflect intrarenal production of this cytokine(7,10). it has a central role in t cell and b cell differentiation, mesangial cell proliferation, and promotion of tubulointerstitial damage. urine il-6 has been considered a noninvasive urine interleukins and vur-nickavar et al. table 1. comparison of qualitative and quantitative variables in children with and without vur. variables vur (mean±sd) no vur (mean±sd) p-value age (m) 36.00 ± 27.66 32.86 ± 29.31 0.444 gender (m/f) 17(50%)/17(50%) 18(50%)18((50%) 1 serum na 138.36 ± 6.40 137.22 ± 5.16 0.412 serum k 4.17 ± 0.55 4.28 ± 0.48 0.172 serum cr 0.51 ± 0.10 0.54 ± 0.09 0.278 serum hco3 21.37 ± 2.45 21.46 ± 2.47 0.752 urine sg 1014.12 ± 3.85 1013.67 ± 4.36 0.762 ultrasound (n/h) 22(64.7%)/12(35.3%) 23(63.9%)/13(36.11%) 0.943 dmsa renal scan (n/d/s) 17(50%)/10(29.4%)/7(20.6%) 27(75%)/6(16.7%)/3(8.3%) 0.09 abbreviations: m: month, m:male, f: female, na: sodium, k: potassium, cr: creatinine, hco3: bicarbonate, sg: specific gravity, n: normal, h: hydronephrosis, d: decreased cortical uptake, s: scar variables vur (mean±sd) no vur (mean±sd) p-value il1α/cr 5.88 ± 7.62 3.52 ± 10.28 < 0.001 il1β/cr 343.44 ± 462.37 72.66 ± 193.24 < 0.001 il6/cr 8.19 ± 11.01 1.90 ± 7.32 < 0.001 il8/cr 14.94 ± 21.78 0.8 ± 1.51 < 0.001 table 2. comparison of urine ils/cr in children with and without vur. vol 18 no 2 march-april 2021 200 biomarker for monitoring the progression of rpd in patients with reflux associated nephropathy(4,6,10). urine il-6/cr was higher in our children with vur, with acceptable sensitivity and accuracy. similarly, krzemier et al showed increased urine il-6/cr in 8/33 children, aged 1-24 months with first time febrile uti and mildmoderate vur(8). in addition, gokce found increased urine il-6/cr in a study on 114 patients in 4 groups with or without vur and rpd(7). however, urine il-6 level was below the lower detection limit with no clinical importance in haraoka et al. study on 17 renal units with vur (2 mild, 12 moderate and 3 high grade)(11). fernández et al. found no significant difference of urine il-6/cr excretion in a case control study on 40 children with documented vur(12). urine il-6 had no significant correlation with rpd in multivariate analysis and seems to be an unreliable biomarker for the prediction of rpd in our study. similarly, renata et al. found no correlation between urine il-6 concentration and renal scarring, and urine il-6 was not higher in those who developed renal scar than those without scar(13). however, urine il-6 was higher in children with severe renal damage than those without renal scar in wang et al study on 66 patients aged 10-18 years with a history of antireflux surgery(10) il-8 is a major proinflammatory chemokine, which is produced by mesangial and destructive renal tubular epithelial cells in patients with rpd,(7) and consider a useful biomarker for localization and determination of the severity of urinary tract inflammation. it has an important role in neutrophil chemoattraction and il-6 secretion(13). increased urinary il-8 concentration has been reported in patients with urinary tract infection, vur, and congenital kidney urinary tract abnormalities (cakut). it has been suggested a sensitive and nonspecific screening test for diagnosis of vur and rpd in the previous studies(3,7). urine il-8/cr level was higher in our children with vur, compared with the control group. urine il-8/ cr>0.6 pg/ml was a sensitive, specific, and accurate biomarker for evaluation of vur in our patients. therefore, we suggested evaluation of urine il-8 as a valuable test for prediction of vur. similarly, urine il-8 was a noninvasive diagnostic biomarker of isolated vur in some of the previous studies, which suggested mild inflammatory process in these patients, and independent to the severity of vur(3,11,12,14). galanakis et al. performed a study on 59 infants in 3 groups (24 with vur, 14 with a history of uti and no vur and 21 with a history of impaired renal function), and recommended screening of vur in patients with increased urine il-8 excretion(2). urine il-8 was higher in patients with vur and rpd or isolated renal scar in the other studies, which suggested urine il-8 as a predictive biomarker of rpd with a direct correlation to the severity of renal damage(7,11,13). however, we showed no correlation between urine il-8 excretion and dmsa uptake defect in our patients. il-1 is the first line cytokine of antigen recognition and anti-inflammatory function, which has been considered for prediction of late renal scar in children with acute pyelonephritis(5). both urine il-1α/cr and il-1β/cr were significantly higher in our children with vur, irrespective to its severity, with acceptable sensitivity and accuracy for the prediction of vur. therefore, alteration of urine il-1α and il-1β were valuable biomarkers for the prediction of vur in our patients. in addition, urine il-1α/cr or il-1β/cr had no significant correlation with renal damage in multivariate analysis. sheu et al. in a study on 69 children, aged 1-121 months, found no alteration of urine il-1β excretion in patients with vur, but lower level in those with renal cortical scarring, and suggested protective effect of urine il-1β against renal scarring during the active phase of acute pyelonephritis(5). we found no significant correlation between urine ils with age, gender, serum electrolytes, renal function, laterality or severity of vur, and imaging studies (ultrasound, dmsa scan) in our patients. similarly, age and gender had no significant effect on urine il-1, il-6, and il-8 excretion in the previous studies(5,7). we concluded that urine il-1α/cr, il-1β/cr, il-6/cr, and il-8/cr were sensitive and accurate noninvasive additionary biomarkers in children with primary vur. in addition, none of these ils had significant value for the prediction of renal damage in these patients. the major limitation of this study was the low number of patients with rpd, which needs further studies for accurate diagnosis. meanwhile, multiple collections of urine ils over years might benefit the prediction of late renal scar in these patients. in addition, future studies with a larger patient population are recommended to confirm the potential application of these biomarkers in suspected patients to primary vur, especially those with negative imaging studies, and siblings of an index case. further studies dmsa scan severity of vur uunilateral or bilateral vur variables regression coefficient pv regression coefficient pv regression coefficient p-value il1α/cr -0.430 0.793 -.229 0.923 1.219 0.654 il1β/cr -14.309 0.886 -52.854 0.717 -61.644 0.710 il6/cr -0.538 0.822 -.597 0.894 1.012 0.798 il8/cr -1.351 0.788 -1.414 0.839 1.859 0.815 table 3. multivariate analysis of urine ils/cr excretion (regression model). variables cut point sensitivity specificity auc ci (95%) se p-value il1α/cr >0.83 78.79 69.44 0.744 0.625-0.842 0.0617 < 0.001 il1β/cr >12.38 97 63.90 0.854 0.749-0.928 0.0456 < 0.001 il6/cr >0.49 90.91 72.22 0.875 0.773-0.942 0.0428 < 0.001 il8/cr >0.6 97 77.80 0.929 0.841-0.977 0.0440 < 0.001 table 4. sensitivity, specificity and accuracy of different urine ils/cr in patients with vur. urine interleukins and vur-nickavar et al. pediatric urology 201 are recommended for differentiation of primary vur from secondary suspected patients with controversial results. conflict of interest none declared by the authors. references 1. nickavar a, valavi e, safaeian b, moosavian m.validity of urine neutrophile gelatinaseassociated lipocalin in children with primary vesicoureteral reflux. int urol nephrol. 2020;52:599-602. 2. galanakis e, bitsori m, dimitriou h, giannakopoulou c, karkavitsas ns, kalmanti m. urine interleukin-8 as a marker of vesicoureteral reflux in infants. pediatrics. 2006; 117: e863-7. 3. bitsori m, karatzi m, dimitriou h, christakou e, savvidou a, galanakis e. urine il-8 concentrations in infectious and non-infectious urinary tract conditions. pediatr nephrol. 2011; 26: 2003-7. 4. ninan gk, jutley rs, eremin o. urinary cytokines as markers of reflux nephropathy. j urol. 1999; 162:1739-42. 5. sheu jn, chen mc, cheng sl, lee ic, chen sm, tsay gj. urine interleukin-1beta in children with acute pyelonephritis and renal scarring. nephrology (carlton). 2007; 12: 487-93. 6. tramma d, hatzistylianou m, gerasimou g, lafazanis v. interleukin-6 and interleukin-8 levels in the urine of children with renal scarring. pediatr nephrol. 2012; 27: 1525-30. 7. gokce i, alpay h, biyikli n, unluguzel g, dede f, topuzoglu a. urinary levels of interleukin-6 and interleukin 8 in patients with vesicoureteral reflux and renalparenchymal scar. pediatr nephrol. 2010; 25: 905-12. 8. krzemień g, roszkowska-blaim m, kostro i et al . urinary levels of interleukin-6 and interleukin-8 in children with urinary tractinfections to age 2. med sci monit. 2004; 10: cr593-7. 9. nickavar a, safaeian b, valavi e, moradpour f. validity of neutrophil gelatinase associated lipocaline as a biomarker for diagnosis of children with acute pyelonephritis. urology j. 2016; 13: 2860-3. 10. wang j, konda r, sato h, sakai k, ito s, orikasa s. clinical significance of urinary interleukin-6 in children with reflux nephropathy. j urol. 2001; 165: 210-4. 11. haraoka m, senoh k, ogata n, furukawa m, matsumoto t, kumazawa j. elevated interleukin-8 levels in the urine of children with renal scarring and/or vesicoureteral reflux. j urol. 1996; 155: 678-80. 12. fernández córdoba ms, gonzálvez piñera j, juncos tobarra ma et al. utility of urine levels of interleukins in the diagnosis of vesicoureteral reflux: a case-control study in children. cir pediatr. 2012; 25: 46-52. 13. renata y, jassar h, katz r, hochberg a, nir rr, klein-kremer a. urinary concentration of cytokines in children with acute pyelonephritis. eur j pediatr. 2013; 172: 769-74. 14. merrikhi ar, keivanfar m, gheissari a, mousavinasab f. urine interlukein-8 as a diagnostic test for vesicoureteral reflux in children. j pak med assoc. 2012; 20-12; 62 (3 suppl 2): s52-4. figure 1. roc analysis demonstrated an overall accuracy of different ils /cr for diagnosis of vur. urine interleukins and vur-nickavar et al. vol 18 no 2 march-april 2021 202 urological oncology evaluation of three-dimensional printing-assisted laparoscopic cryoablation of small renal tumors: a preliminary report cao jian, zhu shuai, ye mingji, liu kan, liu zhizhong, han weiqing, xie yu* purpose: this study aimed to explore the security and feasibility of three-dimensional (3d) printing technology-assisted laparoscopic cryoablation to treat small renal tumors. patients and methods: four patients recruited from our hospital from april 2016 to august 2017 underwent 3d printing technology-assisted laparoscopic cryoablation. three-dimensional reconstruction technology was used to mimic cryoablation treatment before operations to determine the number of needles needed for the operation and the depth and angle required for needle insertion into the tumor to preserve nephron integrity. ct scans were used to assess the treatment’s efficacy after operation during regular follow-up. results: the operation was performed successfully in all cases and all patients recovered without major complications. the operation times ranged from 106 to 118 minutes and blood loss ranged from 50 to 100 ml. the follow-up times were between 8-16 months and the mean time was 13.3 months. follow-up surveys were conducted regularly based on a standard outpatient protocol. results showed no abnormal reinforcing signals in cryoablation treated areas. conclusion: 3d printing technology-assisted laparoscopic cryoablation is a feasible method for the treatment of renal tumors and may be a way to better preserve nephrons, especially in elderly patients and/or those with comorbidities. keywords: laparoscopy; cryoablation; renal cell carcinoma; three-dimentional-printing introduction kidney cancer is a globally common malignancy of the genitourinary system. according to cancer statistics from china from 2015, kidney cancer is the third most common malignant tumor of the urinary system in males, and it is the sixth in women.(1) due to the increase of personal health awareness, regular physical examinations have gradually become routine, therefore the rate of small kidney tumor detection has concurrently increased. however, only about 30% of kidney cancer is diagnosed by the presence of typical symptoms; due to this new methods of treatment for small renal cancer have recently emerged, such as active surveillance, laparoscopic or robot-assisted partial nephrectomy, and high-intensity focused ultrasound radiofrequency ablation and cryoablation, and have been gradually accepted by doctors and patients.(2,3) high-intensity focused ultrasound radiofrequency cryoablation has been used in particular. rapidly progressing 3d printing technology is based on computer graphic data and overlays specific materials to make the desired end products, which can vary greatly in size and shape. this technology has been applied in clinical practice for things such as medical model design and the manufacturing of medical equipment. in particular, 3d printing has especially been applied in department of urology, the affiliated cancer hospital of xiangya school of medicine, central south university and hunan cancer hospital, changsha, 410006, china. *correspondence: department of urology, the affiliated cancer hospital of xiangya school of medicine, central south university and hunan cancer hospital, changsha, 410006, china. tel: +86-135-7484-1178. fax number:+86-0731-88651900. e-mail: 9789691@qq.com. received september 2019 & accepted january 2020 assisting various surgical operations through the printing of specific auxiliary models for operations, replacements, and surgical instruments.(4,5) cryoablation therapy works using the immediate damage seen with cryogenic freezing in conjunction with delayed damage caused by microcirculation disorder, changing the inside and outside environment of tumor cells and inducing cell death or apoptosis. these mechanisms can help to achieve effective tumor treatment. there has been much research conducted to examine the use of this cryoablation technique in the treatment of renal tumors, and findings have confirmed this method's security and approved associated oncologic outcomes. (6-8) cryoablation is mainly conducted by percutaneous puncture via computed tomography (ct), magnetic resonance imaging (mri), or ultrasound guidance, or directly under laparoscopy. this procedure heavily relies on doctors’ experiences to decide how many needles are needed and the depth and angle required for insertion into the tumor. as a result, it is difficult to precisely freeze the tumor according to the variations in tumor shape. using too many needles may increase complications and injure healthy tissues; on the other hand too few needles can hinder the effectiveness of cancer therapy. in this study, we explored the use of 3d printing technology to assist preoperative planning and intraoperative cryoablation therapy, achieve precise urology journal/vol 18 no. 2/ march-april 2021/ pp. 171-175. [doi: 10.22037/uj.v0i0.5541] vol 18 no 2 march-april 2021 172 freezing of tumors, and preserve the maximum number of normal renal units, so as to benefit the patients. patients and methods study population this study included four cases, including two male and two female patients, aged 50 to 75 years old. one patient had only one kidney due to the resection of renal cancer on the other kidney. in the four patients, one tumor was located in the upper lobe, one tumor was located in the renal hilum, and the remaining two were located in the lower lobes. tumor diameters ranged from 3.8 to 2.4 cm. one patient had a history of five cycles of chemotherapy for pelvic mucinous adenocarcinoma. in another patient, severe hydronephrosis was detected in the other kidney due to kidney stones. one patient suffered from high blood pressure and a contralateral renal cyst. urinary system ct scans with additional enhancement and 3d reconstruction were conducted on all patients before operations, in order to assess the malignancy of the renal tumor. renal biopsy and pathological diagnosis confirmed all tumors were renal clear cell carcinoma. pathological diagnoses for two cases were confirmed by pre-operative biopsy and the remaining two by biopsy during laparoscopy before cryoablation. instruments and equipment the 3d printing technology adopts the medical image control system (materialise mimics 18.0) software and uses a hs402p 3d printer with fs3200pa nylon powder printing material. the american hydrogen helix figure 1: 3d printing assisted cryoablation therapy: a: renal ct scan data was extracted to develop 3d reconstruction of the kidney, and then a cryoablation procedure was simulated to figure out the number of needles needed and the angle and depth required for insertion into the tumor to find the optimal plan. b: the kidney model was created through 3d printing technology to guide intraoperative manipulation. figure 2: laparoscopic renal tumor cryoablation: a: needles were inserted into the tumor under laparoscopy according to the scheme predetermined with the help of 3d printing technology before surgery. b. an ice ball was formed that reached more than one centimeter beyond the tumor’s edge during cryoablation therapy. a new choice for nephron sparing surgery-cao et al. knife system (cryocare surgical system) was used for cryoablation treatment. 3d printing technology medical imaging control system software used data of renal ct scans to reconstruct the kidney, including the tumor, in 3d, then mimicked the punctures of the cryoablation therapy according to the size and location of the tumor. in the simulation, we aimed to calculate the number of needles needed and the best angle and depth for insertion into the tumor in order to find the best scheme. the best scheme is defined as the technique that uses the least amount of needles to completely freeze the tumor, as shown in figure 1a. a 3d model of a kidney was utilized to guide intraoperative surgical operations, as shown in figure 1b. laparoscopic renal tumor cryoablation the four cases underwent laparoscopic surgery via a retroperitoneal approach with the guidance of a preoperative auxiliary model recreated by 3d printing technology. we chose laparoscopic guidance over percutaneous access via ultrasound guidance during cryoablation because we had direct vision, and this technique could improve the accuracy of positioning and reduce side pain. furthermore, some studies had shown that percutaneous renal cryoablation had higher rates of surgical failure and higher recurrence rates than laparoscopic cryoablation.(9-11) the renal tumor cryoablation procedure was conducted according to the preoperative simulation optimization scheme with the guidance of the preoperative auxiliary model recreated using 3d printing technology (figure 2a). a hydrogen helium knife system (cryocare surgical system) was used in cryoablation therapy. needles were inserted into the tumor under laparoscopy according to the scheme determined using 3d printing technology before the operation, and the tumor was subjected to a quick freeze for 10 minutes, making an ice ball that reached more than one centimeter beyond the tumor’s edge. the tumor was thawed after 10 minutes; after a total of two cycles of freezing and thawing, the needles were slowly removed (figure 2b). great attention was paid to respiratory movements during the whole operation process to avoid probe offset and intraoperative bleeding. evaluation of oncologic outcomes follow-up was conducted routinely during outpatient. patients had to do renal enhancing ct scans, chest radiographs, abdominal ultrasonography, and routine laboratory tests; if any problem was found, further investigation was done. treatment effectiveness was assessed through renal enhancing ct scans to check for abnormal enhancing signals in the frozen areas of the kidney. postoperative serum creatinine levels were also monitored. the present study was approved by the ethics committee of hunan cancer hospital and was performed in accordance with the declaration of helsinki. informed consent was obtained from all patients. results figure 3: typical images of the effect of cryoablation therapy in the same patient: a: significant uneven enhancement was seen in the center of the right renal before surgery. b: postoperative renal ct examination showed no obvious enhancement in the frozen region after one month, and large necrotic tumor tissue was seen. c: there was no obvious enhancement in the operational area after six months, but necrotic tumor tissue decreased. d: 12 months after surgery, there was almost no necrotic tissue in the treated area, and no obvious abnormal enhancement was observed, indicating the efficacy of tumor therapy. tumor area and frozen area were marked with red arrow. a new choice for nephron sparing surgery-cao et al. urological oncology 173 vol 18 no 2 march-april 2021 174 clinical outcomes operation times ranged from 106 to 118 minutes. intraoperative blood loss ranged from 50 to 100 ml. preoperative serum creatinine ranged from 70.7 to 80.1 umol/l. the serum creatinine one week after surgery was between 68.5 and 84.4 umol/l. patient characteristics and surgical indicators were shown in table 1. follow-up follow-up time was between 8 to 16 months, with an average time of 13.3 months. renal enhancing ct scans were conducted routinely after surgery, and no obvious tumor signals were found in the frozen areas of all patient cases; the typical images of one of the patients are shown in figure 3. postoperative serum creatinine levels were stable (table 2) and no obvious distant metastases were detected. discussion the main use of 3d printing technology in the clinical field is printing out specific anatomical models to assist surgical operations.(5) in clinical applications to urology, 3d printing technology is applied to assist partial nephrectomies,(12) adrenal partial resections,(13) percutaneous nephrolithotomies,(14) prostate needle biopsies,(15) and more. in partial nephrectomies, the auxiliary kidney model printed out via a 3d printer could accurately display the size and location of the tumor, the infiltrating depth of the tumor, and the anatomic relationship between renal artery, renal vein, and collecting system. this information gained from the kidney model can facilitate preoperative surgical planning and intraoperative guidance, which could reduce intraoperative complications and improve success rate and precision of surgery.(12,16) the application of laparoscopic cryoablation in the treatment of renal tumors is well established, can achieve great efficacy in cancer treatment, and also has an advantage in protecting renal function. in 2010, guazzoni et al. performed a study that included 44 cases of renal cell carcinoma patients who underwent laparoscopic cryoablation and found that the tumor specific survival rate was 100% and overall survival rate was 93.2% through the average follow-up of 5 years.(17) tsivian and tanagho et al. monitored the renal function of patients who underwent laparoscopic cryoablation therapy and found no significant change in patients’ renal function. (18,19) cryoablation has its own advantages, like easy implementation, no intraoperative thermal ischemia damage, and no need for incision and suture of renal parenchyma, which can better preserve renal function. this method is significant to patients with kidney deficiency and poor general conditions who need to retain maximum renal function. laparoscopic partial nephrectomies are the most widely used operation in nephron sparing surgery with a highly satisfactory efficacy. this technique requires high proficiency on the surgeons part to block the renal blood supply, resect the tumor, and suture the rest of renal parenchyma during the operation. laparoscopic cryoablation, on the other hand, is simpler than a laparoscopic partial nephrectomy and causes less damage to the kidney. european urology guidelines recommend cryoablation for elderly and/or comorbid patients with small renal masses. a number of studies have compared oncological outcomes and operational parameters a new choice for nephron sparing surgery-cao et al. between these two methods, but there are no consistent conclusions. a systematic review and meta-analysis showed that, compared to a laparoscopic partial nephrectomy, laparoscopic cryoablation could better protect renal function and reduce complications, but the local recurrence rate (or = 13.03) and distant metastasis rate (or = 9.05) was significantly higher than that of a laparoscopic partial nephrectomy.(20) on the other hand, the author also pointed out that patients selected for laparoscopic cryoablation had poorer general conditions and were older than those receiving a laparoscopic partial nephrectomy, and the isolated kidney rate was higher in the laparoscopic cryoablation group as well. therefore, surgeons have to be very careful and choose the most beneficial method for the patient based on the individual conditions of each patient. for elderly patients and those with serious complications, cryoablation is the preferred choice. here we integrated 3d printing technology with laparoscopic cryoablation, which can further promote the advantages of cryoablation and provide better protection of renal function. this study aimed to explore the feasibility of using 3d printing technology-assisted laparoscopic cryoablation to precisely preserve normal renal tissue. although these two technologies are applied in treatment separately, this is the first time that we combined these two techniques to treat renal tumors. the combination of these two technologies integrated their individual advantages, making nephron sparing more accurate. the following is a summarization of the advantages of 3d printing-assisted laparoscopic cryoablation. first, before operations, cryoablation therapy can be mimicked on the computer through 3d reconstruction to figure out the point of insertion and the depth and angle of needles needed to design the optimal cryoablation scheme. next, 3d printing technology can provide a kidney model that can be used to communicate with patients, which could increase the patients’ understanding of renal anatomy and the surgical operation, thus increasing the patients’ trust in their surgeons. the model can also provide intraoperative guidance, improving the success rate of the operation, shortening operation time, and reducing intraoperative haemorrhage and other complications. under laparoscopic guidance, the tumor was fully exposed, side damage was reduced, and there was sufficient vision to do an accurate renal tumor puncture. during the operation, surgeons could refer to the 3d printing model of patients’ kidneys and easily confirm puncture point and depth. the most important advantage is that the optimal cryoablation therapy scheme can effectively preserve renal units and reduce injury to normal renal tissue. therefore, we think that the combination of 3d printing technology and laparoscopic cryoablation, which are already widely applied in renal tumor treatment separately, could better preserve patients’ renal function and is worth further application in clinical. however, this study, which only included four cases, is a preliminary exploration of this method. additional studies using larger sample sizes and prospective randomized trials are needed to prove the feasibility and effectiveness of this method. conclusions our study suggested that it is feasible and safe to use 3d printing technology-assisted laparoscopic cryoablation to treat small renal tumors, which is a new technique for nephron sparing surgery, especially for elderly and/ or comorbid patients. further prospective studies with larger sample sizes should be conducted to confirm this technique. acknowledgements we thank all the patients participated in this study. we thank the funding provided by hunan province's seventh batch of science and technology development plan(key research projects)(2018sk2120). conflict of interest the authors report no conflict of interest. references 1. chen w, zheng r, baade, pd, et al. cancer statistics in china,2015. ca cancer j clin. 2016; 66:115-132. 2. ha s, zlomke h, cost n, wilson s. the past, present, and future in management of small renal masses. j oncol. 2015;2015:364807. 3. umberto c, francesco m. renal cancer. lancet. 2016;387: 894-906. 4. tack p, victor j, gemmel p, annemans l. 3d-printing techniques in a medical setting: a systematic literature review. biomed eng online. 2016;15:115. 5. hoang d, perrault d, stevanovic m, ghiassi a. surgical applications of three-dimensional printing: a review of the current literature & how to get started. ann transl med. 2016; 4:1-19. 6. zagoria rj, hawkins ad, clark pe, et al. percutaneous ct guided radiofrequency ablation of renal neoplasm: factors influencing success. am j roentgenol. 2009;193:16861690. 7. aron m, kamoi k, remer e, berger a, desai m, gill i. laparoscopic renal cryoablation: 8 years, single surgeon outcomes. j urol. 2010;183:889-895. 8. haber gp, lee mc, crouzet s, kamoi k, gill is. tumor in solitary kidney: laparoscopic partial nephrectomy vs laparoscopic cryoabaltion. bju int. 2010;109:118-124. 9. mues ac, okhunov z, haramis g, et al. comparison of percutaneous and laparoscopic renal cryoablation for small ( <3.0 cm) renal masses. j endourol. 2010;24:1097-1100. 10. crouzet s, goel rk, haber gp, et al. laparoscopic versus percutaneous renal cryoablation. j endourol. 2009;23:10701071. 11. strom kh, derweesh i, stroup sp, et al. second prize: recurrence rates after percutaneous and laparoscopic renal cryoablation of small renal masses: does the approach make a difference? j endourol. 2011;25:371-375. 12. zhang y, ge hw, li nc, et al. evaluation of threedimensional printing for laparoscopic partial nephrectomy of renal tumors: a preliminary report. world j urol. 2016;34:533-537. 13. srougi v, rocha ba, tanno fy, et al. the use of three-dimensional printers for partial adrenalectomy: estimating the resection limits. urology. 2016;90:217-220. 14. atalay ha, canat hl, ülker v, alkan i, özkuvanci ü, altunrende f. impact of personalized three-dimensional -3dprinted pelvicalyceal system models on patient information in percutaneous nephrolithotripsy surgery: a pilot study. int braz j urol. 2017;43:470-475. 15. wang y, gao x, yang q, et al. threedimensional printing technique assisted cognitive fusion in targeted prostate biopsy. asian j urol. 2015;2:214-219. 16. fan g, li j, li m, et al. three-dimensional physical model-assisted planning and navigation for laparoscopic partial nephrectomy in patients with endophytic renal tumors. sci rep. 2018;8:582. 17. guazzoni g, cestari a, buffi n, et al. oncologic results of laparoscopic renal cryoablation for clinicl t1a tumours: 8 years of experience in a single institution. urology. 2010;76:624-630. 18. tsivian m, caso j, kimura m, polascik tj. renal function outcomes after laparoscopic renal cryoablation. j endourol. 2011;25:12871291 . 19. tanagho ys, roytman tm, bhayani sb, et al. laparoscopic cryoablation on renal masses: single-center long-term experience. urology. 2012;80:307-314. 20. klatte t, shariat sf, remzi m. systematic review and meta-analysis of perioperative and oncologic outcomes of laparroscopic cryoabalstion verse laparoscopic partial nephrectomy for the treatment of small renal tumours. j urol. 2014;191:1209-1217. a new choice for nephron sparing surgery-cao et al. urological oncology 175 v08_no_3_final.pdf review 171urology journal vol 8 no 3 summer 2011 endourologic procedures for benign prostatic hyperplasia review of indications and outcomes ravi kacker,1 stephen b. williams1,2 purpose: to discern the positive and negative attributes of the various treatment modalities for benign prostatic hyperplasia. materials and methods: a comprehensive literature review is presented for endoscopic treatment of the bladder outlet obstruction with an emphasis on current randomized controlled trials available comparing these treatment modalities. results: transurethral resection of the prostate remains the gold standard when assessing alternative treatment options available for benign prostatic hyperplasia. holmium laser enucleation of the prostate demonstrates equivalent efficacy with a more favorable risk profile. photoselective vaporization, transurethral needle ablation, and transurethral microwave therapy have demonstrated safety and short-term efficacy; however, data on long-term efficacy are currently lacking. conclusion: the current endoscopic methods may offer favorable safety and efficacy for the treatment of the bladder outlet obstruction. however, further research is needed to establish long-term efficacy for many of the currently available treatment options. urol j. 2011;8:171-6. www.uj.unrc.ir keywords: benign prostatic hyperplasia, minimally invasive, treatment outcome, prostatectomy 1department of urology, brigham and women’s hospital, harvard medical school, boston, massachusetts 2associated urologists of orange county, santa ana, california corresponding author: stephen b. williams, md 75 francis street, boston, 20015, massachusetts tel: +617 732 6325 fax: +617 566 3475 e-mail: williams@ocurology.com received april 2011 accepted july 2011 introduction the management of benign prostatic hyperplasia (bph) has become more diverse during recent years with introduction of various novel pharmaceuticals and minimally invasive techniques. the goal for surgical management of bph is to reduce the bulk of the prostatic tissue causing the bladder outlet obstruction and lower urinary tract symptoms (luts). the gold standard treatments include open prostatectomy and transurethral resection of the prostate (turp). open prostatectomy is an invasive surgical procedure with associated morbidity requiring extended lengths of hospitalization. traditional turp is the gold standard regarding minimally invasive treatments; however, up to 20% of patients have significant complications with 10% to 15% requiring a second procedure within ten years.(1) with increasing concern regarding the soaring rise of health care costs with mediocre results, minimally invasive therapies for the management of bph will become ever increasingly important regarding cost effectiveness. the use of minimally invasive therapies for bph has been driven to a great degree by changes in medicare reimbursement during the past endourologic procedures for benign prostatic hyperplasia—kacker and williams 172 urology journal vol 8 no 3 summer 2011 few years as they are now considered to be office procedures.(2) however, the perceived efficacy and long-term durability of these therapies remain to be proven. our aim was to review the literature on minimally invasive endoscopic treatment options for bph focusing on patient selection and treatment outcomes for each modality. materials and methods pubmed and medline searches were conducted in december 2010 using the search terms of “laser prostatectomy, photoselective vaporization, transurethral microwave therapy, transurethral needle ablation” alone and combined with the phrase “randomized controlled trial (rct).” all the abstracts were reviewed for relevance and all rcts were reviewed in full. studies other than rcts were reviewed when there were no rcts on the topic, or when multiple abstracts with a lower level of evidence produced contradictory results to a single rct. results endourologic procedures for bph histological changes of bph are nearly universal with advanced age, and an estimated quarter of men will have undergone surgical treatment for luts secondary to bph by the age 80.(3) transurethral resection of the prostate and open prostatectomy are well-established gold standard treatments for luts secondary to bph with excellent long-term results.(4) despite the wellestablished efficacy of turp, complications approach 20%(5) and in recent decades, multiple minimally invasive techniques have been developed with the goal of similar long-term outcomes with a lower rate of complications. herein, we review promising new minimally invasive surgical treatment options available for the management of the bladder outlet obstruction secondary to bph. photoselective vaporization prostatectomy photoselective vaporization prostatectomy (pvp) utilizes a 532-nm wavelength laser to rapidly vaporize the prostate tissue through selective absorption of hemoglobin.(6) the laser is commercially available as the greenlight laser (american medical systems, minnetonka, minnesota, usa) at 80 w (potassium titanyl phosphate [ktp]) and 120 w (lithium borate [lbo]), which allows creation of a turp-like defect using saline irrigation. a major advantage of pvp is coagulation during tissue vaporization that allows use of the technique for patients on anticoagulation therapy, including aspirin, coumadin, and clopidogrel.(7) multiple studies have demonstrated safety and short-term efficacy for pvp for most patients with bph, including those with acute urinary retention.(8) short-term improvements in urodynamic parameters, including urethral opening pressure and detrusor pressure at maximum flow (pdet at qmax) have been reported.(9) however, some studies have shown high retreatment rates in the short-term, and there is insufficient long-term efficacy data.(10) efficacy and adverse outcomes may be influenced by the surgical technique, and the extent of adenoma removal may vary. the international greenlight users group published recommendations on the surgical technique in 2008 in order to establish guidelines for the use of pvp and maximize results.(11) two randomized controlled trials were identified comparing subjective and objective outcomes for pvp with the ktp laser versus turp. at 1-year follow-up, bouchier-hayes and colleagues found no difference in the decrease in the international prostate symptom score (ipss) or post void residual (pvr) between pvp and turp, with advantages in the pvp group having no transfusions, with shorter catheter duration and hospital stay.(12) horasanli and associates studied patients with the prostates larger than 70 gram with a 6-month follow-up period, and demonstrated lower ipss scores (6.4 versus 13.1), qmax (20.7 versus 13.3 cc/s), and pvr (22.9 versus 78.9 cc) with a high retreatment rate in the pvp group (7 of 39 patients).(13) these different results are in contrast to prior studies, including a prospective, single-center study by pfitzenmaier and coworkers, which did not find a difference in flow rate for patients irrespective of the prostate size.(14) endourologic procedures for benign prostatic hyperplasia—kacker and williams 173urology journal vol 8 no 3 summer 2011 no reports of catastrophic complications were observed in this review. postoperative irritative voiding symptoms, including urge incontinence, are commonly reported with a rate up to 25.7% and may require anti-inflammatory or analgesic medication.(4) urethral stricture has been reported, but may be related to improper technique, and the bladder neck contracture occurs at low rates.(4) there are few reports of sexual side effects from pvp with significant improvement in international index of erectile function scores.(9) however, retrograde ejaculation was reported in over 50% of patients in the trial by horasanli and colleagues, which may be due to turp-like complete removal of the adenoma.(13) transurethral needle ablation transurethral needle ablation (tuna) utilizes low-level radiofrequency energy (460 khz) to induce necrosis of hyperplastic tissue under local anesthesia on an outpatient basis. it was first used in 1993 and radiofrequency generators and disposable ablation catheters are currently commercially available through medtronic (medtronic, minneapolis, minnesota). multiple comparative and non-comparative studies have evaluated exclusion criterion, safety, and efficacy of tuna for bph. overall, tuna appears to be suitable for most of the patients with bph and offers a low complication rate and short-term efficacy.(15) a prospective, multicenter trial of 65 and 54 patients randomized to tuna and turp, respectively, demonstrated equivalent improvement in subjective parameters, including ipss and quality-of-life scores, sustained over a 5-year follow-up period despite less improvement in objective parameters, including pvr and qmax, and a re-treatment rate of 14% for patients undergoing tuna.(16) a recent meta-analysis of 35 studies showed an improvement of 41% to 61% in subjective parameters with a trend towards decreased subjective urinary improvement after 3 years. there was a maximum improvement of 35% in objective urodynamic parameters.(15) the most frequent adverse effect of tuna is hematuria, which is mild or transitory in most cases in the non-comparative studies pooled in the meta-analysis by bouza and colleagues. (15) transient urinary retention is common, but rarely sustained, and routine postoperative catheterization is at the discretion of the surgeon. the procedure is well-tolerated under local anesthesia with conscious sedation with few reports of severe pain leading to termination of the procedure.(17) sexual side effects are uncommon in the meta-analysis with no retrograde ejaculation, stricture, and a 3% rate of new erectile dysfunction.(15) few studies have reported on the selection of ideal candidates for tuna. while one study found poor improvement in objective parameters for the prostates over 50 grams,(18) this finding has not been confirmed in other studies. the metaanalysis by bouza and associates demonstrated a 70% spontaneous voiding rate for patients undergoing tuna for acute or chronic urinary retention.(15) transurethral microwave therapy thermotherapy for the treatment of bph has evolved since the 1980s culminating in specialized available transurethral catheters that use microwave therapy to induce stromal necrosis by achieving temperatures of 45° to 60° c. multiple transurethral microwave therapy (tumt) catheter models are available and most, but not all, employ urethral cooling mechanisms that, in theory, protect the urethra, bladder neck, and striated sphincter while allowing for maximum thermal damage to hypertrophic tissue and minimizing the time of therapy.(2) clinical improvement of luts after tumt is due to decreased prostatic volume, and also possibly, smooth muscle tone.(19) transurethral microwave therapy can be accomplished in the outpatient setting. contraindications to tumt include implanted pacemakers, defibrillators, metallic pelvic or hip implants, and the prostate or bladder cancer. traditionally, patients with the prostate over 100 grams or less than 30 grams as well as subjects endourologic procedures for benign prostatic hyperplasia—kacker and williams 174 urology journal vol 8 no 3 summer 2011 with ‘ball-valve’ median lobe enlargement are not candidates for tumt.(2) while some early reports showed limited efficacy for tumt in the setting of chronic urinary retention, an 80% catheterfree rate is reported for 24 patients with chronic urinary retention using the coretherm tumt system (prostalund, lund, sweden).(20) a review by walmsley and kaplan demonstrated short-term improvement in tumt with decrease in ipss of between 3 and 12.8 points and an improvement in qmax of 12.6 to 17.8 cc/s. (2) earlier tumt systems have shown inferior short-term outcomes compared to turp,(21) and a more recent meta-analysis confirmed these findings for more advanced high energy tumt systems.(22) however, a multicenter rct showed no difference in outcomes with a 5-year followup period for turp and the coretherm device, with a 10% retreatment rate in the tumt group versus 4.3% in the turp group.(23) these longterm results may be subject to bias as only 66% of patients completed five years of follow-up. while most series have shown a favorable side effect profile compared to turp, particularly in terms of a lower rate of erectile dysfunction and retrograde ejaculation,(24) postoperative transient dysuria has been reported in up to 50% of patients. additionally, in december 2000, the food and drug administration warned against severe complications, such as penile necrosis and fistula;(25) however, these are very rare in reported series and may represent improper use of the device.(2) holmium laser enucleation of the prostate the holmium: yttrium-aluminum-garnet (ho:yag) 2010 nm wavelength laser is absorbed by water and produces precise vaporization of the prostate tissue with a depth of penetration of 0.4 mm and simultaneous coagulation.(26) application of this laser to bph was initially in the form of tissue ablation, but holmium enucleation of the prostate (holep) became possible with advent of mechanical morcellators to retrieve the prostate fragments. complete enucleation, including apical tissue, is possible even for the prostates up to 300 grams.(27) multiple randomized and non-randomized prospective trials have shown equivalent or even superior short and long-term results with holep over turp.(28) kuntz and associates randomized patients with the prostate larger than 100 grams to either open prostatectomy or holep with 74 patients completing five-year follow-up. outcomes were equivalent for both groups in terms of ipss score, qmax, and pvr with a low rate of re-operation for stricture or bladder neck contracture in both groups (5% versus 6.7%). holmium enucleation of the prostate was a day surgery procedure for most of the patients.(27) similarly, a case series by larner and coworkers over 200 patients showed a transfusion rate of zero with over 90% of patients discharged without a catheter on either postoperative day zero or one.(29) shah and colleagues published a single surgeon experience with 280 patients, 4.3% of whom needed to be converted to turp due to malfunction of the laser or morcellation device and 3.9% sustained superficial bladder injury from the morcellator. there was a trend to more complications and conversions early in the series illustrating the high technical learning curve. capsular perforation might occur in some patients, but did not change the management.(30) fluid absorption does occur in up to 26% of patients, but normal saline irrigation is used and there are no reports of tur syndrome after holep.(31) overall, low rates of minor re-operations (0 to 5.4%) for stricture or bladder neck contracture have been reported.(4) holmium enucleation of the prostate is an endoscopic treatment for the bladder outlet obstruction that is compared favorably with turp and open prostatectomy in terms of safety and efficacy. however, its adoption may be limited by a high technical learning curve and the presence of a small number of experts in the field. conclusion minimally invasive and endoscopic methods may offer high success rates with minimal complications, often in an ambulatory setting, for the treatment of the bladder outlet obstruction endourologic procedures for benign prostatic hyperplasia—kacker and williams 175urology journal vol 8 no 3 summer 2011 secondary to bph. certain therapies, such as holep, have shown equivalent long-term results to turp. other treatment options, such as pvp, tumt, and tuna, have shown acceptable short-term results; however, long-term efficacy is lacking. more robust long-term results may soon become available through the national institute of health sponsored minimally invasive surgical therapies trial. conflict of interest none declared. references 1. mebust wk, holtgrewe hl, cockett at, peters pc. transurethral prostatectomy: immediate and postoperative complications. a cooperative study of 13 participating institutions evaluating 3,885 patients. 1989. j urol. 2002;167:999-1003; discussion 4. 2. walmsley k, kaplan sa. transurethral microwave thermotherapy for benign prostate hyperplasia: separating truth from marketing hype. j urol. 2004;172:1249-55. 3. barry mj. medical outcomes research and benign prostatic hyperplasia. prostate suppl. 1990;3:61-74. 4. reich o, gratzke c, bachmann a, et al. morbidity, mortality and early outcome of transurethral resection of the prostate: a prospective multicenter evaluation of 10,654 patients. j urol. 2008;180:246-9. 5. borboroglu pg, kane cj, ward jf, roberts jl, sands jp. immediate and postoperative complications of transurethral prostatectomy in the 1990s. j urol. 1999;162:1307-10. 6. lee r, gonzalez rr, te ae. the evolution of photoselective vaporization prostatectomy (pvp): advancing the surgical treatment of benign prostatic hyperplasia. world j urol. 2006;24:405-9. 7. ruszat r, wyler s, forster t, et al. safety and effectiveness of photoselective vaporization of the prostate (pvp) in patients on ongoing oral anticoagulation. eur urol. 2007;51:1031-8; discussion 8-41. 8. fu wj, gao jp, hong bf, yang y, cai w, zhang l. photoselective laser vaporization prostatectomy for acute urinary retention in china. j endourol. 2008;22:539-43. 9. hamann mf, naumann cm, seif c, van der horst c, junemann kp, braun pm. functional outcome following photoselective vaporisation of the prostate (pvp): urodynamic findings within 12 months followup. eur urol. 2008;54:902-7. 10. naspro r, bachmann a, gilling p, et al. a review of the recent evidence (2006-2008) for 532-nm photoselective laser vaporisation and holmium laser enucleation of the prostate. eur urol. 2009;55: 1345-57. 11. malek rs. greenlight (tm) hps laser therapy for bph: clinical outcomes and surgical recommendations from the international greenlight user (iglu) group. eururol supp 2008;7:361-2. 12. bouchier-hayes dm, anderson p, van appledorn s, bugeja p, costello aj. ktp laser versus transurethral resection: early results of a randomized trial. j endourol. 2006;20:580-5. 13. horasanli k, silay ms, altay b, tanriverdi o, sarica k, miroglu c. photoselective potassium titanyl phosphate (ktp) laser vaporization versus transurethral resection of the prostate for prostates larger than 70 ml: a short-term prospective randomized trial. urology. 2008;71:247-51. 14. pfitzenmaier j, gilfrich c, pritsch m, et al. vaporization of prostates of > or =80 ml using a potassium-titanylphosphate laser: midterm-results and comparison with prostates of <80 ml. bju int. 2008;102:322-7. 15. bouza c, lopez t, magro a, navalpotro l, amate jm. systematic review and meta-analysis of transurethral needle ablation in symptomatic benign prostatic hyperplasia. bmc urol. 2006;6:14. 16. hill b, belville w, bruskewitz r, et al. transurethral needle ablation versus transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia: 5-year results of a prospective, randomized, multicenter clinical trial. j urol. 2004;171:2336-40. 17. kahn sa, alphonse p, tewari a, narayan p. an open study on the efficacy and safety of transurethral needle ablation of the prostate in treating symptomatic benign prostatic hyperplasia: the university of florida experience. j urol. 1998;160:1695-700. 18. schulman cc, zlotta ar. transurethral needle ablation of the prostate for treatment of benign prostatic hyperplasia: early clinical experience. urology. 1995;45:28-33. 19. corvin s, boesch s, maneschg c, radmayr c, bartsch g, klocker h. effect of heat exposure on viability and contractility of cultured prostatic stromal cells. eur urol. 2000;37:499-504. 20. schelin s. microwave thermotherapy in patients with benign prostatic hyperplasia and chronic urinary retention. eur urol. 2001;39:400-4. 21. hoffman rm, monga m, elliot sp, macdonald r, wilt tj. microwave thermotherapy for benign prostatic hyperplasia. cochrane database syst rev. 2007cd004135. 22. kaye jd, smith ad, badlani gh, lee br, ost mc. high-energy transurethral thermotherapy with coretherm approaches transurethral prostate resection in outcome efficacy: a meta-analysis. j endourol. 2008;22:713-8. 23. mattiasson a, wagrell l, schelin s, et al. five-year follow-up of feedback microwave thermotherapy versus turp for clinical bph: a prospective randomized multicenter study. urology. 2007;69:91-6; discussion 6-7. 24. arai y, aoki y, okubo k, et al. impact of interventional therapy for benign prostatic hyperplasia on quality of endourologic procedures for benign prostatic hyperplasia—kacker and williams 176 urology journal vol 8 no 3 summer 2011 life and sexual function: a prospective study. j urol. 2000;164:1206-11. 25. food us. drug administration, microwave therapy warning. jama. 2002;284:2711. 26. lerner lb, tyson md. holmium laser applications of the prostate. urol clin north am. 2009;36:485-95, vi. 27. kuntz rm, lehrich k, ahyai sa. holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-year followup results of a randomised clinical trial. eur urol. 2008;53:160-6. 28. tooher r, sutherland p, costello a, gilling p, rees g, maddern g. a systematic review of holmium laser prostatectomy for benign prostatic hyperplasia. j urol. 2004;171:1773-81. 29. larner tr, agarwal d, costello aj. day-case holmium laser enucleation of the prostate for gland volumes of < 60 ml: early experience. bju int. 2003;91:61-4. 30. shah hn, mahajan ap, hegde ss, bansal mb. perioperative complications of holmium laser enucleation of the prostate: experience in the first 280 patients, and a review of literature. bju int. 2007;100:94-101. 31. shah hn, kausik v, hegde s, shah jn, bansal mb. evaluation of fluid absorption during holmium laser enucleation of prostate by breath ethanol technique. j urol. 2006;175:537-40. u j 03 all-2.pdf 625vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l extracorporeal shockwave lithotripsy needed for fragmentation of stones depend upon their size swl. depending on the size, density, and position of your urinary stone, your doctor may recommend alternative treatment methods. large stones are not good candidates for swl. sometimes, your doctor may prefer to perform swl the produced pain is severe and needs analgesic prescription. sions or auxiliary treatment modalities. sometimes, smaller success of swl for stone fragmentation of ureteral stones ureteral stones. accelerate stone passage. patients are also instructed to void through a stone screen in order to obtain stone fragments avoid at least 7 to 10 days prior to swl. these medications the prescribing doctor to get their approval. extracorporeal see page 549 for full-text article. what’s up in urology journal, summer 2012? urology for people urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. scientific committe abbas basiri mehrdad mohammadi-sichani akbar nouralizadeh mohammad-hadi radfar ali tabibi mohammad najafi-semnani alireza lashay mohamad-reza nikoobakht amir hossein kashi mohammad-hossein soltani anahita ansari mohammad soleimani behnam shakiba nasser simforoosh farzaneh sharifiaghdas pejman shadpour hamidreza akbari gilani robab maghsoudi heshmatollah soufi-majidpour saman farshid amir-hossein kashi ali tabibi pejman shadpour mahdi arab amin zakeri tila farahani mahtaj hashemi yavar ansari peyman hamekhani hamidreza mohammad-hosseini shabnam golshan farzaneh soleimani maryam hosseini mohsen moshtagh leyla lack amin azizpour mahmoudreza razeghian mahmoud matin akbar mohammadzadeh saeid fallah samaneh rajbandi executive committe kaveh mehravaran seyed amir-mohsen ziaee ⅳ masoud etemadian seyed habibollah mousavi-bahar 11th congress of the iranian endourology and urolaparoscopy society, 2019 abolfazl hosseini. m.d. sweden ahmet yaser muslumanoglu.m.d. turkey sajjad rahnama'i. m.d, phd germany/netherlands emrah yuruk. m.d. turkey shabir almousawi. m.d. kuwait pradeep sharma. m.d. india shivalingaiah mare gowda. m.d. india ahmad shamsodini takhtei.m.d. qatar ali-reza amini-sharifi. m.d. usa international faculty ⅴ 11th congress of the iranian endourology and urolaparoscopy society, 2019 zamari noori. m.d. afghanistanabdul majid rana. m.d. pakistan ⅵ v08_no_4_final_new.pdf pictorial urology 270 urology journal vol 8 no 4 autumn 2011 renal osteodystrophy secondary to congenital bilateral ureteropelvic junction obstruction urol j. 2011;8:270-00. www.uj.unrc.ir a 4-year-old girl presented with progressive distension of the abdomen and bowing of the legs (genu valgum) since birth. she was anemic, with a blood pressure of 180/110 mmhg. the serum level of creatinine was 1.7 mg/dl. she had hypocalcemia, and elevated serum level of phosphorous and parathyroid hormones. ultrasonography revealed bilateral grossly hydronephrotic kidneys with thinned out parenchyma. intravenous urography showed impaired renal function with stasis of contrast media and non-visualization of the ureters. a diagnosis of bilateral congenital ureteropelvic junction obstruction with renal osteodystrophy was made. her blood pressure was controlled with two antihypertensive agents and she was started on calcium and vitamin d supplements along with phosphate binders. bilateral percutaneous nephrostomies were placed with a hope to improve her renal function. however, her serum level of creatinine failed to improve. she underwent a dismembered anderson and hynes pyeloplasty along with reduction of the massively dilated pelvis on the right side. as the ureter was found to be atretic on the left side, a pyelocystoplasty was performed. at discharge, her serum level of creatinine remained stable at 1.7 mg/dl. her parents were educated regarding the various options available for renal replacement therapy, including pediatric renal transplantation. congenital anomalies of the kidneys and urinary tract are a major cause of chronic and end-stage renal failure in children.(1) “renal osteodystrophy” describes the skeletal complications seen in end-stage renal disease and results from a multifactorial disorder of the bone remodeling.(2) thampi john nirmal,* nitin s kekre department of urology, christian medical college, vellore, india *e-mail: nirmaltj@gmail.com references 1. kemper mj, muller-wiefel de. renal function in congenital anomalies of the kidney and urinary tract. curr opin urol. 2001;11:571-5. 2. barzel us. renal osteodystrophy. n engl j med. 1995;333:1428. laparoscopic and robotic urology a comparison of robot-assisted laparoscopic ureteral reimplantation and conventional laparoscopic ureteral reimplantation for the management of benign distal ureteral stricture yucong zhang1,2#, wei ouyang 1#, hao xu1, yang luan1, jun yang1, yuchao lu1, jia hu1, zheng liu1, xiao yu1, wei guan1, zhiquan hu1, shaogang wang1**, zhangqun ye1, heng li 1* purpose: to describe our experience and analyze the outcomes of robot-assisted laparoscopic ureteral reimplantation (ralur) and conventional laparoscopic ureteral reimplantation (lur) in treating benign distal ureteral stricture (dus). material and methods: patients who underwent ralur or lur for dus were retrospectively analyzed. all surgeries were performed by transperitoneal approach in a refluxing manner. baseline characteristics, history of previous abdominal surgery, operative profile and follow-up data were collected and analyzed. results: among 68 patients with dus, 62 were diagnosed with unilateral dus, including 28 patients underwent ralur. the mean operative time of the ralur group was 2.44 ± .45 hours, while the mean operative time of the lur group was 3.09 ± .74 hours (p < .001). the average suturing time of lur (39.59 ± 3.78 min) is about 2 times that of ralur (20.04 ± 3.5 min) (p < .001). the success rate of the ralur group and the lur group were 89.3% and 82.4% respectively (p = .494). in multiple linear regression model, the modality of surgery was the only variable that influences operative time (beta = -.964, p < .001), suturing time (beta = -1.899, p < .001) and hemoglobin decline (beta = -.611, p = .020). conclusion: basically, the postoperative outcomes are similar but robotic surgery offers a quicker surgery and anastomosis. keywords: anastomosis; laparoscopy; robotic surgical procedures; ureteral obstruction. introduction the ureteral stricture, which can occur anywhere on the ureter, can result in hydronephrosis, chronic pain or even permanent renal damage. according to the etiology, location and length of stricture, there are various treatment modalities. for the benign distal ureteral stricture (dus), ureteral reimplantation is considered to be the gold standard treatment modality. after more than half a century of application, the safety and effectiveness of open ureteral reimplantation(our) have been recognized by most urologists with long term success rate up to 97% at 45 months(1). the laparoscopy, as a minimally invasive surgery, was first reported for ureteral reimplantation in 4 mini-pigs with bilateral vesicoureteral reflux in 1993(2). it provided advantages over open surgery with more rapid recovery, shorter hospitalization time and better cosmetic appearance(3). after that, the robotic surgical system dramatically improves laparoscopy by providing finer movement and 1department of urology, tongji hospital of tongji medical college, huazhong university of science and technology, 1095 jiefang avenue, qiaokou, wuhan, hubei, china. 430030 2department of geriatrics, tongji hospital of tongji medical college, huazhong university of science and technology, 1095 jiefang avenue, qiaokou, wuhan, hubei, china. 430030. *correspondence: department of urology, tongji hospital of tongji medical college, huazhong university of science and technology, 430030, china. tel: +86-27-836-63454, fax: +86-27-836-63454, e-mail: lihengtjmu@163.com. ** department of urology, tongji hospital of tongji medical college, huazhong university of science and technology, 430030, china. tel: +86-27-836-63454, fax: +86-27-836-63454, e-mail: sgwangtjm@163.com. # yucong zhang and wei ouyang contributed equally to this work. received july 2019 & accepted february 2020 easier intracorporeal suturing. several studies have compared our with conventional laparoscopic ureteral reimplantation(lur) or robot-assisted laparoscopic ureteral reimplantation(ralur)(4-6). our study intends to compare ralur with lur by describing our experience of ralur and lur for the treatment of dus. materials and methods a retrospective study was conducted for patients with dus who underwent lur or ralur from january 2014, a year before our hospital was equipped with an operating robot, intuitive surgical davinci s/si system®, to december 2018. there was no sampling for this study. the decision for an ralur or lur was based on the surgical referral pattern to our hospital rather than specific inclusion or exclusion criteria. the ralur and lur were carried out by two different surgeons, but both with experience of more than a thousand laparoscopic surgeries. all surgeries were urology journal/vol 17 no. 3/ may-june 2020/ pp. 252-256. [doi: 10.22037/uj.v0i0.5478] performed by transperitoneal approach in a refluxing manner. before induction of general anesthesia, a foley catheter was placed. then the patient was placed in a supine position with the head slightly lower than feet. four trocars (one 12mm optic trocar, one 12mm trocar and on 8 mm trocar for working arms and one 8 mm conventional laparoscopic trocar) were placed for ralur. four trocars (one 12 mm optic trocar, one 12 mm and two 5 mm working trocars) were also placed for lur. the end of ureter was ligated first. at the junction of dilation and stricture, the distal ureter was transected. after that, about 200ml normal saline was injected into bladder through foley catheter. the bladder was incised about 1 cm at the lateral dome. the ureter was pulled about 1 cm into the bladder. both ends of a double-j tube were inserted into the ureter and bladder respectively. the ureter was then anastomosed to the full thickness bladder wall in a continuous suture pattern with 4-0 absorbable sutures. the absence of leakage of urine was confirmed by injection of normal saline into bladder. at the end of the procedure, a tube was placed for the drainage of abdominal cavity. antibiotics were used to help prevent urinary tract infection perioperatively. the drain tube was removed if the output remains minimal, about 3 to 5 days after surgery. the foley catheter was left in place for about 10 to 14 days. the double-j tube was removed 2-3 months after discharge under cystoscopy in the outpatient department. all patients were suggested to have ultrasonography and renal function test every six months in the first two years and then annually. the patients’ characteristics, including gender, age, body mass index (bmi), dus characteristics, abdominal surgical history, details of the operative profile, complications, and post-operative hospitalization time were collected. and follow-up information was also collected by phone. statistical analysis was performed by the spss 22.0. continuous variables were presented as mean and standard deviation and compared by using fisher's exact test. the categorical variables were presented as absolute value and percentages and compared by using rank-sum test. in a multiple linear regression model, we added a mixture of age, gender, bmi, laterality and the modality of surgery to assess the combined effect of those parameters on the outcomes of patients receiving unilateral reimplantation, including operative time, suturing time and hemoglobin (hb) decline. the continuous variables in the models were standardized. f-test was applied for testing all coefficients of variables included in the model. meanwhile, each coefficient of variable was tested by t-test. for all statistical tests, if p-value was less than .05, then the difference was considered to be significant. results there were 68 patients who underwent lur or ralur. six of them were diagnosed with bilateral dus and received bilateral reimplantation. sixty-two pa ralur lur p-value gender (male/female) (9/19) (13/21) .790 age (yrs.) 47.29 ± 12.13 47.53 ± 12.06 .972 bmi (kg/m2) 23.71 ± 3.37 23.18 ± 2.93 .876 laterality (left/right) (17/11) (14/20) .202 gynecologic surgeries myomectomy 1 1 hysterectomy 3 1 adnexectomy 1 3 urologic surgeries ureterotomy 0 2 cystolithotomy 1 1 previous ureteral reimplantation 3 1 table 1. baseline characteristics of patients with unilateral dus. abbreviatons:dus: distal ureteral stricture; ralur: robot-assisted laparoscopic ureteral reimplantation; lur: laparoscopic ureteral reimplantation; bmi: body mass index. ralur lur p-value operative time (hours) 2.44 ± .45 3.09 ± .74 < .001 suturing time(min) 20.04 ± 3.50 39.59 ± 3.78 < .001 hb decline(g/l) 8.18 ± 5.30 12.10 ± 5.94 .010 post-operative hospitalization time (day) 5.54 ± 1.04 5.74 ± 1.78 .912 follow-up time (months) 27.47 ± 15.37 28.08 ± 16.33 .926 success rate 89.3% (25/28) 82.4% (28/34) .494 complications grade ⅱ 7.1% (2/28) 11.8% (4/34) .681 abbreviations: dus: distal ureteral stricture; ralur: robot-assisted laparoscopic ureteral reimplantation; lur: laparoscopic ureteral reimplantation; hb: hemoglobin. table 2. detail operative profile and follow-up data of patients with unilateral dus. laparoscopic ureteral reimplantation-zhang et al. vol 17 no 03 may-june 2020 253 laparoscopic and repotic urology 254 tients who received unilateral reimplantation were included in statistical analysis. all patients presented with decreased renal function, pain or hydronephrosis confirmed by ultrasonography. these 62 patients were divided into two groups according to the operation modality. among these patients, 34 patients were managed with conventional lur, and 28 patients were managed with ralur. table 1 shows the baseline characteristics of patients who underwent unilateral ureteral reimplantation. both groups were comparable in baseline characteristics including age, gender, bmi and laterality. the characteristics of patients who received bilateral ureteral reimplantation were showed in supplementary table 1. nine patients in each group have received abdominal surgery before. in 14 patients, dus appeared after their previous abdominal surgeries. among these surgeries, ten were gynecologic surgeries, including myomectomy, hysterectomy and adnexectomy, eight were urologic surgeries, including ureterotomy and cystolithotomy for urolithiasis. from the previous surgery to symptoms occurred, the time ranged from 1 month to 13 years. in addition, four patients also experienced recurrent dus after their first ureteral reimplantation. table 2 shows the detail operative profile and follow-up data of patients who underwent unilateral ureteral reimplantation. the differences of operative time, suturing time and hb decline between two group are significant. in the ralur group, the operative time of 7 (25.0%) patients was less than or equal to 2 hours, and no one had operative time more than or equal to 4 hours. however, in the lur group, five (14.7%) patients had operative time more than four hours. a patient who received lur experienced much longer operative time, about 8 hours, than others but similar suturing time due to extensive peripelvic fibrous tissue and scar formation. fortunately, this patient discharged at the 5th day after surgery without apparent complication. none of these patients needed blood transfusion after operation. according to clavien classification of surgical complications, three patients in the ralur group and four patients in the lur group had grade ii complication. three patients in the ralur group and two patients in the lur group had a fever after surgery, with body temperature over 38℃. two patients in the lur group were hospitalized for more than 10 days due to hypoproteinemia. one patient in the lur group experienced urinary leakage, leading to an extension of hospital stay. three patients in the ralur group and 7 patients in the lur group had a double-j stent placed or balloon dilatation because of recurrent dus. the ureteral reimplantation of these patients were considered to be failed. all of them didn’t receive secondary ureteral reimplantation. therefore, the success rates of the ralur group and the lur group were 89.3% and 82.4% respectively. the results of multiple linear regression for the outcomes of patients who underwent unilateral ureteral reimplantation are shown in table 3. the ralur leads to shorter operative time, shorter suturing time and less hb decline, compared with lur. in addition, gender, age, bmi and laterality were not influence factors for those outcomes. discussion the iatrogenic injury of the ureter accounts for about 2–10% of all ureteral defects(7). some injuries occur during difficult ureteroscopic manipulations or ureterotomy, such as those in 3 patients in our study(7). some injuries may also occur during gynecologic procedures, which was reported as the leading cause of iatrogenic dus(8), such as those in 9 patients in our study. since the 1960s, our has been the standard treatment modality for the benign dus that was not suitable for endoscopic repair. however, the success rate of endoscopic repair was reported as only 52.6%(9), and the our can achieve satisfactory long-term results with success rates over 90%(1,10,11). though much satisfactory has gained in our, lur provides some additional advantages such as less intraoperative blood loss and postoperative pain, and more rapid recovery(12). the first lur was introduced in 1994 in pediatric patients with vesicoureteral reflux(13). in the same year, lur was performed in a 74-year-old man without postoperative intravenous pain medication(14). a retrospective study compared 10 our with 10 lur and demonstrated significant advantages for lur in terms of lower estimated blood loss, postoperative analgesic requirement, and shorter hospitalization time(5). the tamponade effect of the pneumoperitoneum may lessen bleeding from venous plexus. furthermore, combined with laparoscopic magnification, less bleeding significantly improves visualization for precise dissection and reconstruction(15). though feasibility has been repeatedly demonstrated, a large number of studies on lur highlight the challenging nature, especially difficulties about intracorporeal suturing of the ureter. sufficient experience with laparoscopy and intracorporeal suturing remains necessary, which leads to the limitation of promotion of lur. in recent decades, the presence of robotic platform makes the laparoscopic surgery easier dramatically, particularly reduces the difficulty in intracorporeal suturing by providing 3-dimensional(3d) visualization, precision in instrument movement and six degrees of laparoscopic ureteral reimplantation-zhang et al. table 3. the results of multiple linear regression for the outcomes of patients with unilateral dus. gender age bmi laterality modality surgery beta 95%ci p beta 95%ci p beta 95%ci p beta 95%ci p beta 95%ci p operative -.004 -.489, .988 -.036 -.283, .769 .089 -.163, .481 .061 -.419, .799 -.964 -1.443, <.001 time(hours) .482 .211 .341 .541 -.486 suturing .024 -.165, .802 -.054 -.149, .268 .026 -.071, .592 -.115 -.301, .222 -1.899 -2.085, <.001 time(minutes) .212 .042 .124 .071 -1.713 hemoglobin .102 -.419, .696 -.023 -.288, .861 -.074 -.344, .586 .218 -.296, .399 -.611 -1.124, .021 decline(g/l) .623 .242 .196 .733 -.097 abbreviation: bmi: body mass index. vol 17 no 03 may-june 2020 255 freedom. it can also help alleviate perceived difficulties associated with conventional laparoscopy(4). similar to other study(16), compared to conventional laparoscopic approach, robot-assisted laparoscopic approach decreases the difficulty in suturing and shortens surgical time obviously. in our study, the operative time and suturing time were influenced by the modality of surgery. also, a patient in the lur group had a history of hysterectomy and abdominopelvic radiation therapy. the resultant extensive scaring and adhesions may result in difficulties in trocar placement, exposure and dissection of distal ureter, and extension of the laparoscopic operative times. however, this factor didn’t lead to an obvious increase in blood loss. some studies(17,18) found less estimated blood loss in the lur group, compared with the ralur group, while other studies(16) showed an opposing result. it may be influenced by the experience of the surgeon in laparoscopic and robotic techniques. in our study, we found a statistically significant difference in terms of estimated blood loss in favor of ralur. however, the absolute blood loss difference was about 4g/l hemoglobin, which meant about only 160ml blood loss difference, and the hemoglobin decline might be influenced by the intravenous infusion. although the p is less than 0.05 and the difference is statistically significant, the clinical difference was not that meaningful. similar to the study reported by baldie et al.(18), the difference of post-operative hospitalization time between lur and ralur group were not significant in our study. the key to the success of ureter reimplantation is to achieve a well vascularized, watertight and tension-free anastomosis(15). due to the ischemia or excessive tension during ureteral bladder anastomosis, the most commonly postoperative complications are urinary leakage and recurrent distal ureter stricture(1,10,19,20). in our study, all of the ralur and lur were performed by a refluxing modality. no urinary leakage was observed in these patients. in order to avoid reflux and associated potential infection of upper urinary tract, some urologists are more inclined to perform non-refluxing anastomosis. unfortunately, there remain some problems in non-refluxing manner. one of the traditional anti-reflux managements is submucosal tunnel ureteroneocystostomy(21). it requires an additional ureteral length, usually about 2 to 3 cm, to accommodate tunneling. however, such length is not always available in some patients. on the other hand, the necessary ureteral length for a tunneled anastomosis may not ensure adequate tissue vascularity, and thus decrease ureteral viability. in addition, tunneled technique is still a challenging point in the laparoscopic approach and leads to more complex intracorporeal suturing and longer operative time. another anti-reflux modality is nipple technique. though compared with submucosal tunnel reimplantation, the nipple technique is much easier and less time-consuming, some urologists still tried to modify this manner by extracorporeal tailoring. however, this may result in an inappropriate traction of ureter and elevation of the risk of ischemic damage to the distal ureter. compared with anti-refluxing manner, the suturing in reflux anastomosis is much easier. in our study, the mean suturing time of lur was 39 minutes, and even 20 minutes in ralur. in addition, reflux anastomosis may also avoid ureteral angulation or torsion which is of paramount importance for the success of reimplantation. nevertheless, due to the possible postoperative reflux, a potential disadvantage of this anastomosis is the tendency toward recurrent pyelonephritis and deterioration in renal function. fortunately, similar to other studies(22,23), no one experienced complications associated to reflux such as pyelonephritis during their follow-up time in our study. further support for refluxing anastomoses in this setting may also be extrapolated from the transplant literature, in which fewer cases of ureteral obstruction have been observed among renal transplants with extravesical vs politano-leadbetter ureteroneocystostomy24). although this reflux anastomosis can reduce the chance of recurrence of postoperative stricture in some sense, six patients experienced recurrent strictures during follow-up time and required balloon dilatation or insertion of double-j tube, which may be caused by high-tension anastomosis. therefore, even in a high-volume center with experience of thousands of laparoscopic urological surgeries, like us, ralur or lur remains a challenging surgery. because of the retrospective and observational nature and limited amount of cases of this study, selection bias may exist. due to insufficient sample size of patients who underwent bilateral ureteral reimplantation, statistical analysis didn't make for the data of these patients. the characteristics of these 6 patients received bilateral ureteral reimplantation were described and summarized in the supplementary table 1. the selection of lur or ralur in our hospital is mainly based on economic conditions of patients, which may also affect post-discharge care and review. in addition, lur and ralur were carried out by different surgeons, thus the difference in surgeon experience may also lead to bias. we also didn’t investigate whether the additional cost for the robot is reasonable or worthy for the patients. besides, all ureteral reimplantation in our study was performed in a refluxing manner, while anti-refluxing manner also plays an important role in this surgery. conclusions basically, the postoperative outcomes are similar but robotic surgery offer a quicker surgery and anastomosis. further high-quality clinical studies, such as randomized clinical trial, are needed to confirm the superior of ralur. reflux anastomosis, which requires easy suture, can also achieve high success rate. the differences between lur and ralur in anti-reflux anastomosis also need to be compared in the future. disclosure of interest the authors declared that they have no conflicts of interest to this work. references 1. h. riedmiller, e. becht, l. hertle, g. jacobi, r. hohenfellner. psoas-hitch ureteroneocystostomy: experience with 181 cases. eur urol. 1984;10:145-50. 2. a. atala, l. r. kavoussi, d. s. goldstein, a. b. retik, c. a. peters. laparoscopic correction of vesicoureteral reflux. j urol. 1993;150:74851. 3. d. campobasso, r. gaston, j. l. hoepffner, c. mugnier, t. piechaud. long-term results of laparoscopic lich-gregoir technique for laparoscopic ureteral reimplantation-zhang et al. laparoscopic ureteral reimplantation-zhang et al. ureteral reimplantation: saint augustin clinic experience. int j urol. 2017;24:559-560. 4. s. i. kozinn, d. canes, a. sorcini, a. moinzadeh. robotic versus open distal ureteral reconstruction and reimplantation for benign stricture disease. j endourol. 2012;26:147-51. 5. j. j. rassweiler, a. s. gozen, t. erdogru, m. sugiono, d. teber. ureteral reimplantation for management of ureteral strictures: a retrospective comparison of laparoscopic and open techniques. eur urol. 2007;51:512-22; discussion 522-3. 6. v. t. packiam, a. j. cohen, c. u. nottingham, j. j. pariser, s. f. faris, g. t. bales. open vs minimally invasive adult ureteral reimplantation: analysis of 30-day outcomes in the national surgical quality improvement program (nsqip) database. urology. 2016;94:123-8. 7. fx jr keeley, m. bibbo, d. h. bagley. ureteroscopic treatment and surveillance of upper urinary tract transitional cell carcinoma. j urol. 1997;157:1560-5. 8. a. ostrzenski, b. radolinski, k. m. ostrzenska. a review of laparoscopic ureteral injury in pelvic surgery. obstet gynecol surv. 2003;58:794-9. 9. c. m. lin, t. h. tsai, t. c. lin,et al. holmium: yttrium-aluminum-garnet laser endoureterotomy for benign ureteral strictures: a single-centre experience. acta chir belg. 2009;109:746-50. 10. c. g. stief, u. jonas, k. u. petry,et al. ureteric reconstruction. bju int. 2003;91:138-42. 11. s. wenske, c. a. olsson, m. c. benson. outcomes of distal ureteral reconstruction through reimplantation with psoas hitch, boari flap, or ureteroneocystostomy for benign or malignant ureteral obstruction or injury. urology. 2013;82:231-6. 12. j. h. kaouk, i. s. gill. laparoscopic reconstructive urology. j urol. 2003;170:10708. 13. r. m. ehrlich, a. gershman, g. fuchs. laparoscopic vesicoureteroplasty in children: initial case reports. urology. 1994;43:255-61. 14. p. k. reddy, r. m. evans. laparoscopic ureteroneocystostomy. j urol. 1994;152:20579. 15. c. a. seideman, c. huckabay, k. d. smith,et al. laparoscopic ureteral reimplantation: technique and outcomes. j urol. 2009;181:1742-6. 16. r. schiavina, s. zaramella, f. chessa,et al. laparoscopic and robotic ureteral stenosis repair: a multi-institutional experience with a long-term follow-up. j robot surg. 2016;10:323-330. 17. s. m. lucas, c. p. sundaram, js. jr. wolf, et al. factors that impact the outcome of minimally invasive pyeloplasty: results of the multi-institutional laparoscopic and robotic pyeloplasty collaborative group. j urol. 2012;187(2):522-7 18. k. baldie, j. angell, k. ogan, n. hood, j. g. pattaras. robotic management of benign mid and distal ureteral strictures and comparison with laparoscopic approaches at a single institution. urol. 2012; 80(3):596-601. 19. m. c. benson, k. s. ring, c. a. olsson. ureteral reconstruction and bypass: experience with ileal interposition, the boari flap-psoas hitch and renal autotransplantation. j urol. 1990;143:20-3. 20. m. ahn, k. r. loughlin. psoas hitch ureteral reimplantation in adults--analysis of a modified technique and timing of repair. urology. 2001;58:184-7. 21. p. a. androulakakis, a. a. stefanidis, d. k. karamanolakis, v. moutzouris, g. koussidis. the long-term outcome of bilateral cohen ureteric reimplantation under a common submucosal tunnel. bju int. 2003;91:853-5. 22. c. wiesner, j. w. thuroff. techniques for uretero-intestinal reimplantation. curr opin urol. 2004;14:351-5. 22. o. engel, m. rink, m. fisch. management of iatrogenic ureteral injury and techniques for ureteral reconstruction. curr opin urol. 2015;25:331-5. 24. j. b. thrasher, d. r. temple, e. k. spees. extravesical versus leadbetter-politano ureteroneocystostomy: a comparison of urological complications in 320 renal transplants. j urol. 1990;144:1105-9. laparoscopic and repotic urology 256 endourology and stone disease 79urology journal vol 4 no 2 spring 2007 blind puncture in comparison with fluoroscopic guidance in percutaneous nephrolithotomy a randomized controlled trial abbas basiri,1 sadrollah mehrabi,2 hamidreza kianian,1 ahmad javaherforooshzadeh,1 mohammad reza kamranmanesh3 introduction: our aim was to evaluate blind puncture in percutaneous nephrolithotomy (pcnl) for decreasing the risk of radiation. materials and methods: one hundred candidates for pcnl were randomly assigned into 2 groups. blind access was performed for the patients in group 1 and the standard access using fluoroscopy for those in group 2. in group 1, displacement of the targeted calyx in the prone position was estimated by fluoroscopy comparing to the image on intravenous urography. puncture of the calyx was attempted 3 cm to 4 cm below the marked site of the targeted calyx with a 30° angle. if the access to the collecting system was felt and urine came out, the site of puncture would be controlled by fluoroscopy. if the access failed, we would repeat puncturing up to 5 times. results: the mean time to access was 6.6 ± 2.1 minutes and 5.5 ± 1.7 minutes in groups 1 and 2, respectively (p = .008). the mean time of radiation exposure was 0.95 ± 0.44 minutes in group 2. a successful puncture to the targeted calyx was achieved in 50% and 90% of the patients in groups 1 and 2, respectively (p < .001) and a successful calculus removal in 62% and 100% of the patients in groups 1 and 2 (p < .001). conclusion: although about half of the patients benefited from blind access in our study, this technique can not be solely relied on, and fluoroscopy or ultrasonography should be available for prevention of complications. urol j. 2007;4:79-85. www.uj.unrc.ir keywords: percutaneous nephrolithotomy, blind puncture, fluoroscopy 1urology and nephrology research center & department of urology, shaheed labbafinejad medical center, shaheed beheshti medical university, tehran, iran 2department of urology, yasuj university of medical sciences, yasuj, iran 3department of anesthesiology, shaheed labbafinejad medical center, shaheed beheshti medical university, tehran, iran corresponding author: sadrollah mehrabi, md department of urology, shaheed beheshti hospital, yasuj, iran tel: +98 741 222 1813 e-mail: mehrabi390@yahoo.com received december 2006 accepted march 2007 introduction percutaneous nephrolithotomy (pcnl) is the treatment of choice for kidney calculi greater than 2 centimeters in diameter and for cases of failed shock wave lithotripsy such as those with cystine calculi.(1) the routine approach for accessing the pyelocaliceal system is the placement of a ureteral catheter, injection of contrast media or air, and puncturing the caliceal system using fluoroscopy. other methods of the caliceal access are ultrasonography-guided method using intravenous contrast injection and computed tomography-guided (ct-guided) methods, especially if there is an abnormal caliceal anatomy.(2-5) there are few studies reporting blind access for drainage of the obstructed kidneys in emergency cases or when catheter placement for retrograde injection of a contrast medium for pcnl is not possible; the results have been acceptable and indicative of a safe technique in a hydronephrotic kidney.(6) given the negative impact blind puncture versus fluoroscopic guidance in percutaneous nephrolithotomy—basiri et al 80 urology journal vol 4 no 2 spring 2007 of radiation on the patient and the surgical team during pcnl, seeking for techniques not dependent on x-ray such as ultrasonography are encouraged.(7) the blind technique can be a favorable alternative that needs to be more investigated. our objective in the present study was to compare the efficacy of blind access to puncture the pyelocaliceal system with fluoroscopy-guided access in patients who underwent pcnl. materials and methods in a randomized controlled trial between june 2005 and june 2006, we performed pcnl in 100 patients using either fluoroscopy-guided or blind access methods. patients older than 15 years with a kidney or proximal ureteral calculus and without active infection, abnormal pyelocaliceal anatomy, or coagulopathy were included. they were evaluated by history taking, physical examination, blood chemistry and kidney function tests, urinalysis, and urine culture to rule out kidney dysfunction, urinary tract infection, and coagulation disorders. intravenous urography (ivu) was performed in all patients and the size and location of the calculi, the anatomy of upper urinary system, the degree of hydronephrosis, and the targeted calyx for insertion of a chiba needle were determined. after providing informed consent, the eligible patients were randomly assigned into 2 groups. using fluoroscopy, we had designed a pilot study on 20 patients and estimated the displacement of the kidney and the inferior calyx in the prone position in relation to the ivu images. the average displacement of the kidney was 1.8 cm to the cephalad direction. accordingly, in the patients of group 1, the place of the calyx was marked on the patient’s back 1.8 cm cephalad to what was seen on the ivu. then, the access was attempted by a chiba needle, 3 cm to 4 cm lower than the targeted calyx with a direction consistent with the infundibulopelvic angle of the respective calyx. the needle was inserted into the kidney with an angle of 30° to 40° to the patient’s vertical axis of the body. if access to the collecting system was felt, the chiba’s mandarin was removed; we would be assured of the correct entrance to the caliceal system if urine came out spontaneously or by aspiration. a contrast medium or air was injected through the ureteral catheter after drainage of the urine to control the appropriateness of the position of access to the calculus by the fluoroscope. if proper access from the targeted calyx or another calyx was achieved to perform pcnl, a guide wire was inserted and the next steps were done according to the standard methods under the guidance of fluoroscopy. in case of no urine drainage, puncturing was repeated for a maximum of 5 times and if it failed, the proper access was done under fluoroscopic guidance. patients in group 2 underwent pcnl using fluoroscopic guidance. under general anesthesia, a ureteral catheter was placed by cystoscopy while the patient was secured in the lithotomy position. then, the access to the collecting system was achieved under the guidance of fluoroscopy by injection of a contrast medium with an 18-f chiba needle in the prone position. tract dilation and a classic pcnl were done afterwards. for editorial comment see p 83 the collected data, comprising demographic characteristics, degree of hydronephrosis, time to access (from the start of puncturing to complete dilation), time of radiation exposure, number of puncturing attempts, site of access to the system, abnormal bleeding, visceral or pulmonary complications, and hemoglobin decrease were compared between the 2 groups. the student t test was used for normally distributed continuous variables and the chi-square test was used to compare proportional variables. continuous variables were presented as mean ± standard deviation and a p value less than .05 was considered significant. results fifty patients were studied in each group. all of the patients in both groups completed the study. there were no differences in the patients’ demographic and clinical characteristics between groups 1 and 2 (table 1). a successful puncture to the targeted calyx was achieved in 25 (50%) and 45 patients (90%) in groups 1 and 2, respectively (p < .001). in the remaining failed cases, access was achieved to a calyx through which pcnl was possible, resulting in a successful calculus removal in a total of 31 patients (62%) in group 1 compared to that in 100% of the patients blind puncture versus fluoroscopic guidance in percutaneous nephrolithotomy—basiri et al urology journal vol 4 no 2 spring 2007 81 in group 2 (p < .001). the site of inappropriate puncture was renal pelvis in 12%, out of the collecting system in 14%, and calyxes not appropriate for pcnl in 12% of the patients in group 1. also in this group, the rate of successful access to the targeted calyx was 50% and 77.8% in the patients with mild to moderate and severe hydronephrosis, respectively. table 2 demonstrates the details of the treatments in each group. the mean time to access was about 1 minute longer in group 1 (p = .008). the mean time of radiation exposure was 0.50 ± 0.19 minutes in group 1 and 0.95 ± 0.44 minutes in group 2 (p = .001). intraoperative or postoperative complications such as visceral injury and unusual bleeding did not occur in any of the patients. the mean hemoglobin decrease during the 24 postoperative hours was 1.9 ± 0.1 g/dl in group 1 and 1.7 ± 0.2 g/dl in group 2 (p = .30). discussion percutaneous access to the pyelocaliceal system is the first measure in most percutaneous treatments such as pcnl, endopyelotomy, and the upper urinary tract drainage in obstructive uropathies. this can be achieved by insertion of a ureteral catheter for instillation of contrast medium under the guidance of fluoroscopy, ultrasonography, or ct scan.(7-9) however, a blind access may be required in cases such as obstruction or stricture of the ureter, abnormal anatomy of the ureteral orifice, or when the required equipment for the standard approach is not available. furthermore, the known complications of radiation exposure for the surgical team in long-term have emerged lowering the duration of exposure in endourological procedures.(10) chien and bellman have used blind access in 26 patients with hydronephrosis in which an urgent drainage of hydronephrosis was required and placing a ureteral catheter was not possible.(6) they had a table 1. demographic and clinical characteristics in patients with blind puncture (group 1) and fluoroscopy-guided (group 2) percutaneous nephroloithotomy* characteristics group 1 group 2 p no of patients 50 50 mean age, y 43.2 ± 12.3 41.6 ± 13.7 .55 sex men 34 (68) 31 (62) women 16 (32) 19 (38) .67 involved kidney left 30 (60) 28 (56) right 20 (40) 22 (44) .60 mean body mass index, kg/m2 25.4 ± 3.4 24.6 ± 4.0 .20 hydronephrosis mild 13 (26) 16 (32) moderate 19 (38) 21 (42) severe 18 (36) 13 (26) .54 *mean values are demonstrated as mean ± standard deviation. values in parentheses are percents. tables 2. treatment details in patients with blind puncture (group 1) and fluoroscopy-guided (group 2) percutaneous nephrolithotomy* characteristics group 1 group 2 p targeted calyxes upper 0 1 (2) middle 9 (18) 9 (18) lower 41 (82) 40 (80) .60 successful puncture to targeted calyx 25 (50) 45 (90) < .001 successful calculus removal 31 (62) 50 (100) < .001 mean puncturing attempts 3.5 ± 2.3 3.0 ± 1.8 .19 time to access, min 6.6 ± 2.1 5.5 ± 1.7 .008 *mean values are demonstrated as mean ± standard deviation. values in parentheses are percents. blind puncture versus fluoroscopic guidance in percutaneous nephrolithotomy—basiri et al 82 urology journal vol 4 no 2 spring 2007 98% success rate, but in 14 attempts, the access to the system for introduction of the nephrostomy tube or drainage was not appropriate on ultrasonography and led to repeat puncturing. in 75% of the cases, direct access to the renal pelvis was achieved. in 1 patient, blind access failed and it was done under the guide of ultrasonography. a mean of 2.5 puncturing attempts per patient was required and no significant complication was seen. in this study, the main objective of access to the system was drainage of hydronephrosis, recovery of the obstruction, and insertion of the nephrostomy catheter. thus, a precise selection of the targeted calyx was not required. moreover, in this study, the degree of hydronephrosis which could affect the successful entrance into the system had not been analyzed; however, guided access to a proper calyx is a requisite in pcnls in which direct access to the calculus is needed. most radiologists prefer insertion of nephrostomy tube under the guidance of ultrasonography and local anesthesia. in 2 other studies, it has been shown that percutaneous nephrostomy under the guidance of ultrasonography has a 98.5% success rate. the authors have concluded that pcnl could be done this way without the need of inserting ureteral catheter for contrast medium injection.(11,12) mcdougall and colleagues have described blind access method in percutaneous approach in which the insertion of a 22-f chiba needle with a 90° angle, 1 cm to 1.5 cm lateral to l1 vertebra, is done for antegrade procedures or contrast medium injection for the following percutaneous procedures.(13) in our study, no complications of the initial access to the system such as abnormal bleeding, visceral injuries, and pulmonary complications were seen in neither of the groups. however, the overall rate of access to the collecting system (86%) and entrance into the targeted calyx (50%) were lower than those in the studies by chien and bellman (98%) and by gupta and colleagues (98.5%).(6,11) this could be proportionally due to the lower degree of hydronephrosis in our patients and the need for a precise approach to a particular calyx in pcnl. a proper selection of the access position and the angle of introduction are crucial for preventing vascular and visceral injuries. the higher success rate in the patients with severe hydronephrosis compared to those with mild to moderate hydronephrosis (77.7% versus 50%) indicates that the blind approach can be a successful method in such patients. the number of puncturing attempts was not different between the 2 groups of our patients, and the time of radiation exposure was 0.95 ± 0.44 minutes in group 2. considering that a urologist is exposed to 1100 mrem of radiation every hour during pcnl and that a 5000-mrem radiation is the upper limit of the annual exposure, the excessive exposure in using fluoroscopic guidance compared to blind approach is not very higher than the upper limit and the clinical value of this radiation exposure is trivial.(10) nonetheless, techniques with lower radiation doses are always preferred. although blind access is successful for percutaneous nephrostomy and pcnl in severe hydronephrosis, it does not eliminate the need for imaging methods such as ultrasonography or fluoroscopy, and pcnl with safer techniques such as ultrasonography seems to be warranted for the surgical team. conclusion blind approach for access to the system in pcnl, especially in severely hydronephrotic kidneys, is a potential alternative for experienced surgeons for reducing radiation exposure. however, it is reasonable to guide access using fluoroscopy or ultrasonography to avoid complications related to inappropriate puncturing site and for a significant proportion of patients in whom the access will fail. conflict of interest none declared. references 1. kader ak, finelli a, honey rj. nephroureterostomydrained percutaneous nephrolithotomy: modification combining safety with decreased morbidity. j endourol. 2004;18:29-32. 2. montanari e, serrago m, esposito n, et al. ultrasoundfluoroscopy guided access to the intrarenal excretory system. ann urol (paris). 1999;33:168-81. 3. delavierre d, fournier g, mangin p. [percutaneous drainage nephrostomy guided by ultrasound. apropos of 80 adult cases. j urol (paris)]. 1989;95:319-29. french. 4. patel u, hussain ff. percutaneous nephrostomy of nondilated renal collecting systems with fluoroscopic guidance: technique and results. radiology. 2004;233:226-33. blind puncture versus fluoroscopic guidance in percutaneous nephrolithotomy—basiri et al urology journal vol 4 no 2 spring 2007 83 5. matlaga br, shah od, zagoria rj, dyer rb, streem sb, assimos dg. computerized tomography guided access for percutaneous nephrostolithotomy. urol. 2003;170:45-7. 6. chien gw, bellman gc. blind percutaneous renal access. j endourol. 2002;16:93-6. 7. inglis ja, tolley da, law j. radiation safety during percutaneous nephrolithotomy. br j urol. 1989;63:591-3. 8. roth m. [experiences with sonographically guided percutaneous nephrostomy]. z urol nephrol. 1986;79:147-54. german. 9. lee wj. advances in percutaneous nephrostomy. yonsei med j. 1990;31:285-300. 10. rao pn, faulkner k, sweeney jk, asbury dl, sambrook p, blacklock nj. radiation dose to patient and staff during percutaneous nephrostolithotomy. br j urol. 1987;59:508-12. 11. gupta s, gulati m, uday shankar k, rungta u, suri s. percutaneous nephrostomy with real-time sonographic guidance. acta radiol. 1997;38:454-7. 12. vansonnenberg e, casola g, talner lb, wittich gr, varney rr, d’agostino hb. symptomatic renal obstruction or urosepsis during pregnancy: treatment by sonographically guided percutaneous nephrostomy. ajr am j roentgenol. 1992;158:91-4. 13. mcdougall em, liatsikos en, dinlenc cz, smith ad. percutaneous approaches to the upper urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3320-45. editorial comment there is no doubt that using fluoroscopy for a successful access to the kidney is essential. while learning percutaneous nephrolithotomy (pcnl), it is wise to use only fluoroscopy, and with the increasing experience of the endourologist, the time to access will be minimized. nonetheless, concerns about radiation exposure to the surgeon and the surgical team in long-term remain. radiation hazards can be either stochastic or nonstochastic, the former of which is not dose dependent and may cause dna damage and lead to cancers development at any time. thus, it is reasonable to minimize the use of the x-ray in practice. in many cases such as hydronephrotic systems and staghorn calculi, we can easily use the landmark made by intravenous urography and enter the pyelocaliceal system. according to my experience in more than 700 pcnls by fluoroscopic guidance, i concluded that in such cases with pelvic or upper ureteral calculi, we can have access to the kidney from the lumbar notch and the success rate with blind approach is 100%, as we reported recently.(1) i would like to express my congratulations to the authors to start blind approach and also point out some ideas: first, nonhydronephrotic systems, single calculi in the pelvis, and collecting systems with a narrow infundibulum or small pelvis are good cases for blind access, but in the present study, the authors have attempted this method regardless of these criteria. second, to confirm the access, especially in nonhydronephrotic systems, we have to induce hydronephrosis with injection of water via the ureteral catheter simultaneously with trying access; otherwise, aspiration per se cannot be a good indicator of successful access. third, the authors have not mentioned if the access was attempted by a single skilled surgeon or not. i believe that trying this approach without the experience of at least 300 to 400 fluoroscopy-guided pcnl can lower the success rate. and fourth, in hydronephrotic systems with large pelvis and infundibulum, the calculi can be removed by the nephroscope maneuver if the access is successful. however, in case of a narrow infundibulum, access should be achieved by the targeted calculus that necessitates the use of fluoroscopy. hossein karami department of urology, shohada-e-tajrish hospital, shaheed beheshti medical university, tehran, iran reference 1. karami h, arbab ah, hosseini sj, razzaghi mr, simaei nr. impacted upper-ureteral calculi >1 cm: blind access and totally tubeless percutaneous antegrade removal or retrograde approach? j endourol. 2006;20:616-9. editorial comment blind access to the pyelocaliceal system with a background of the radiographic and ultrasonographic findings is used daily in many centers around the world. it was first reported by chien and bellman in 2002.(1) they utilized this technique for cases in which intravenous or retrograde injection of contrast medium was not possible. they recommended to inject the contrast medium through the same needle from which urine is drained or find another location if needed (in 40% of cases).(1) for the first time, we reported blind access to blind puncture versus fluoroscopic guidance in percutaneous nephrolithotomy—basiri et al 84 urology journal vol 4 no 2 spring 2007 the system and its dilation for pcnl in persian literature, with 87% success rate in 62 cases of kidney calculus.(2) thereafter, karami and colleagues published their study in 2006, comparing blind access with ureteroscopy for pcnl of impacted calculi. they had only 3 failures that led to the use of fluoroscopy and changing the place of nephroscope. in the present article, basiri and colleagues have designed an interesting randomized trial for this comparison and, as anticipated, they observed a suboptimal success rate. accordingly, they suggested blind access only in particular selected occasions. none of the above studies have focused on the intraoperative or postoperative surgical complications and the follow-ups were all short. it is noteworthy that removal of the calculi is not the only goal, and preservation of the kidney tissue is a crucial aim. various instruments and techniques such as fluoroscopy, ultrasonography, computed tomography, and robots has been introduced to approach these objectives altogether.(3-5) michel and colleagues have recently reported the complications of more than 1000 pcnls, and by reviewing the published papers, have suggested a series of measures to reduce or prevent complications: preoperative radiologic or ultrasonographic assessment, a proper puncturing through a proper calyx, guide of an imaging modality while entering the system, atraumatic dilation by fluoroscopic monitoring, and using the minimum angle for the rigid nephroscope.(6) overall, along with emphasis on the safe technique for the surgical team, we should be concerned with the safety of patient and the kidney. although blind puncture of the pyelocaliceal system with complete obstruction shows the surgeon’s skill, it is suggested that antegrade contrast medium injection be done after puncturing and drainage of urine. the next steps after making sure of the needle’s place would be preferred to be taken under fluoroscopic or ultrasonographic guidance. seyed habibollah mousavi-bahar department of urology, ekbatan hospital, hamedan university of medical sciences, hamedan, iran references 1. chien gw, bellman gc. blind percutaneous renal access. j endourol. 2002;16:93-6. 2. mousavi-bahar sh, minaei ma. [results of pcnl for renal and upper ureteral stones without fluoroscopy]. sci j hamadan univ med sci. 2003;10:35-8. persian 3. osman m, wendt-nordahl g, heger k, michel ms, alken p, knoll t. percutaneous nephrolithotomy with ultrasonography-guided renal access: experience from over 300 cases. bju int. 2005;96:875-8. 4. matlaga br, shah od, zagoria rj, dyer rb, streem sb, assimos dg. computerized tomography guided access for percutaneous nephrostolithotomy. urol. 2003;170:45-7. 5. su lm, stoianovici d, jarrett tw, et al. robotic percutaneous access to the kidney: comparison with standard manual access. j endourol. 2002;16:471-5. 6. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899906. reply by author we acknowledge the valuable comments by our honorable colleagues on our paper. hereby, we would like to explain some points about our study: 1. it should be noted that in our patients, only the puncture of the pyelocaliceal system was considered, by not the access, because the safety of blind access has not been confirmed by enough evidence yet. regarding the ethic considerations and our concern to preserve the renal parenchyma and to prevent from long-term complications, we preferred to restrict blind approach to puncturing, and if it failed after 5 attempts or the location was not appropriate, we switched to the classic approach by fluoroscopic guidance. 2. since only blind puncture was tried and fluoroscopy was used to change the puncture site, if needed, there was no reason for long-term follow-up and assessment of late complications; we tried the classic site of entering the pyelocaliceal system regardless of the puncturing technique. 3. we designed a randomized trial, so we could not use selection criteria for the patients recruiting in the blind group; otherwise, we could not reach our aim to compare these techniques in similar groups. on the other hand, there is no documented guideline for the inclusion criteria to be used in blind access; the published studied on this issue are still limited. 4. we have used injection of solution through the blind puncture versus fluoroscopic guidance in percutaneous nephrolithotomy—basiri et al urology journal vol 4 no 2 spring 2007 85 catheter, too. the suggested method of water injection and induction of hydronephrosis can be helpful only to find out whether the chiba needle is in the pyelocaliceal system, but not to confirm its placement in an appropriate site. our main goal was to achieve puncturing from a proper site. likewise, contact collide of the needle to the calculus indicates reaching the calculus, but it is not predictive of an appropriate pathway for stone removal. furthermore, it does not determine whether the needle is in a hypovascular area and far from the pelvis or the ureteropelvic junction. 5. blind puncture was done by 2 endourology fellows who did the fluoroscopy-guided procedures, too. it should be noted that blind puncture in our study was done systematically according to the identified landmark; hence, interoperative variation does not have a significant role. whereas, techniques that are highly dependent on the surgeon’s skills and do not have a distinct method cannot be evaluated in a study and do not have external validity. 6. even in dilated systems in which nephrostomy drainage is done, stone removal may not be possible through the same tract and access with the help of fluoroscopic or ultrasonographic guidance is required. this is indicative of blind access failure and unsuccessful stone removal with minimal complications. we should bear it in mind that entering the kidney is not the ultimate goal and a safe access should be achieved. 7. although avoiding radiation is wise, it has been documented that the exposure of the surgical team is within the safe range, (1,2) and given the 20-year worldwide experience in pcnl, there is no reported case of malignancy among the surgeons and personnel involved with this treatment modality. the highest dose of radiation is received by the patient while pcnl. if a urologist performs 150 pcnls per year, he/she receives a radiation dose of 2.4 msv, while even when the contribution from other diagnostic and interventional radiologic procedures in urology is added, the total effective dose equivalent hardly exceeds 5 msv or 10% of the allowed radiation.(3) in another study, it was shown that 50 pcnls per year is equivalent to a maximum 2% of the allowed yearly radiation.(4) 8. finally, to achieve a safe access to the caliceal system and the optimum avoidance of radiation, it is recommended that safer techniques with a proper visualization of the kidney anatomy while puncturing, such as ultrasonography-guided access, be used. abbas basiri, hamidreza kianian department of urology, shaheed labbafinejad medical center, shaheed beheshti medical university, tehran, iran references 1. lowe fc, auster m, beck tj, chang r, marshall ff. monitoring radiation exposure to medical personnel during percutaneous nephrolithotomy. urology. 1986;28:221-6. 2. kumari g, kumar p, wadhwa p, aron m, gupta np, dogra pn. radiation exposure to the patient and operating room personnel during percutaneous nephrolithotomy. int urol nephrol. 2006;38:207-10. 3. geterud k, larsson a, mattsson s. radiation dose to patients and personnel during fluoroscopy at percutaneous renal stone extraction. acta radiol. 1989;30:201-5. 4. hellawell go, mutch sj, thevendran g, wells e, morgan rj. radiation exposure and the urologist: what are the risks? j urol. 2005;174:948-52 pediatric urology microorganisms and antibiotic profile of the subpreputial space in uncircumcised boys selamettin demir1*, cennet ragbetli2, nazim abdulkadir kankilic1, abdullah yildiz1, alper bitkin1 purpose: this study investigates the frequency of isolated microorganisms and the antimicrobial resistant pattern of inner foreskin and smegma in prepubertal children. materials and methods: this comparative cross-sectional study was conducted between march and november 2019, where 132 prepubertal boys, who were scheduled to receive religious circumcisions at our outpatient clinic, were examined. the patients were divided into the following groups based on the presence of smegma in their subpreputial space: group i (with smegma, n=58) and group ii (without smegma, n=74). sterile stuart transport swabs (advanced diagnostic research, mediko kimya, turkey) were taken from the smegma or the subpreputial space (glans surface and inner foreskin) using aseptic techniques and then the swab samples were immediately transported by sterile stuart transportation for microscopy, culture identification, and antibiographic resistance testing by conventional test methods and automated systems (vitek ii, biomerieux, france) to the microbiological laboratory of our hospital. results: 48 bacteria isolated from 39 boys in group i comprised 28 gram-positive species (58.3%) and 20 gram-negative species (41.7%). the most commonly isolated gram-negative bacterium was proteus mirabilis (45%) while most positive was staphylococcus hominis (42.9%). in group ii, 68 boys had 103 bacterial isolates in the glans comprising 81 gram-positive species (78.6%) and 22 gram-negative species (21.4%). the most commonly isolated gram-negative bacterium was proteus mirabilis (42.9%) while the most positive were enterococcus faecalis (40.7%) and s. hominis (42.9%) conclusion: the subpreputial space of uncircumcised boys is colonized by various types of uropathogens resistant to multidrug drugs. smegma does not pose additional risks to microbiological colonization in children. keywords: child; circumcision; foreskin; microbiology; smegma introduction circumcision—the routine removal of the fore-skin—is the world’s oldest and most controversial surgery(1) and has been done for nearly half a century(2,3). in 1971, the american academy of pediatrics (aap) opposed routine circumcision stating that it is not a valid medical procedure(4). it’s importance was reaffirmed in 1975 and later approved by the american college of gynecology and obstetrics(4). nevertheless, subsequent studies have shown that of the 0.78% of infants diagnosed with urinary tract infections (utis) in their first year of life, 95% are uncircumcised(5). furthermore, only 0.47% of female babies and 0.21% of circumcised male babies in contrast to the 4.12% of uncircumcised male babies develop utis(5). thus, uncircumcised babies are 20 times more likely to get utis in their first year than circumcised babies(4). the common causative organisms of utis in children stem colonisation and ascending infection from intestinal flora. additionally, in uncircumcised boys, the 1department of urology, the ministry of health, university of health sciences, van education and research hospital, van 65000, turkey. 2department of microbiology, the ministry of health, university of healthsciences, van education and researchhospital, van 65000, turkey. *correspondence: department of urology, the ministry of health, university of health sciences, van education and research hospital, van 65000, turkey. tel: +90 505 798 79 25, fax: +90(432) 212 1954, e-mail: drselami1978@hotmail.com. received february 2020 & accepted september 2020 preputial space is also a potential reservoir for microbial agents as uropathogenic bacteria can easily colonize unretractable foreskin, which is important in the pathogenesis of utis(4-7). further, periurethral colonization is another important factor in the development of utis(8). escherichia coli is the most common pathogen in utis amongst boys and girls(9). it is worth noting that although e. coli with fimbria (most common type 1 and p-fimbriae) can be attached to the inner mucosal surface of the foreskin, it does not adhere to the outer surface of the foreskin(10). meanwhile, smegma is the accumulation of desquamated epithelial cells, collected between the glans penis and the foreskin. it is cheese-like fat with a mixture of prostate gland and seminal vesicles secretion and mucin released from the urethral glands. smegma moistens and lubricates the cavity between the glans and the prepuce, which is known as the subpreputial space(11–13). however, several studies have shown organisms can colonize the subpreputial space cavity(13-15). however, whether smegma is a risk factor for utis is still an unanswered urology journal/vol 17 no. 6/ november-december 2020/ pp. 614-619. [doi: 10.22037/uj.v16i7.6030] question, but knowledge regarding local antimicrobial resistance is essential in terms of guiding empirical antibiotic usage in the treatment of uti in children. this article is to examine the frequency of isolated microorganisms and the antimicrobial resistance patterns of subpreputial flora through studying the smegma samples and swabs taken from the closed subpreputial space of asymptomatic, uncircumcised boys. materials and methods study population this comparative cross-sectional study was conducted at our hospital between march and november 2019 and approved by the ethics committee of the ministry of health, university of health sciences, van education and research hospital van, turkey (approval number: 2018–9). all patients involved in this study offered written informed consent. the 132 boys enrolled in the study were split into two groups: group i (with smegma) and group ii (glans swabs without smegma) based on the presence of smegma in their closed subpreputial space between the inner prepuce skin and the glans surface. inclusion and exclusion criteria to avoid confounding the results, we excluded patients with utis, including cases of balanoposthitis, phimosis, and past uti histories14, and those who had recently taken antimicrobial or immunosuppressive drugs. procedures after surgical draping in the operating room, the prepuce was aseptically retracted to expose the glans. with the patients in group i, the smegma was obtained within the exposed subpreputial space. with the patients in group ii, who did not have smegma, the subpreputial space was swabbed. in group i, the smegma was removed by means of sterile surgical forceps and mixed in normal saline during circumcision. this mixture was kept in a sterile tube for smegma culture. in group ii, a sterile stuart transferring swab was taken from the mucosal surface of the foreskin and the glans within the subpreputial space. evaluations the swabs were then directly sent to our hospital’s microbiology of internal foreskin and smegma-demir et al. table 1. the characteristics of patients, and the type and number of uropathogens isolated from the groups. variablesa group i (n = 58) group ii (n = 74) p-value age (month) 35.0 ± 22.0 33.0 ± 23.5 .856 the number of patients with bacterial isolation (n) 39 (39/58, 67.2%) 68 (68/74, 91.9%) < 0.001 the number of patients with single bacterial isolation (n) 30 (30/39, 76.9%) 35 (35/68, 51.5%) .009 the number of patients with mixed bacterial isolation (n) 9 (9/39, 23.1%) 33 (33/68, 48.5%) .001 the number of patients with no bacterial isolation (n) 19 (19/58, 32.8%) 6 (6/74, 8.1%) < 0.001 total number of bacteria isolated (n) 48 (48/151, 31.8%) 103 (103/151, 68.2%) <0.001 gram (+) bacteria number (n) 28 (58.3%) 81 (78.6%) .016 gram (-) bacteria number (n) 20 (41.7%) 22 (21.4%) .016 the most frequently isolated gram (+) bacterium staphylococcus enterococcus faecalis hominis (12/28, 42.9%) (34/81, 42%) the most frequently isolated gram (-) bacterium proteus mirabilis proteus mirabilis (9/20, 45%) (9/22, 40.9%) group i, with smegma; group ii, without smegma (glans swap) a: fisher’s exact test and chi-square test (p < 0.05) variablesa group i (n = 58) group ii (n = 74) p-value total number of bacteria isolated (n) 48 (31.8%) 103 (68.2%) <0.001 gram (+) bacteria (n) 28 (58.3%) 81 (78.6%) .016 enterococcus faecalis 10 (35.7%) 34 (42.0%) .720 staphylococcus hominis 12 (42.9%) 27 (33.3%) .498 staphylococcus haemolyticus 0 (0%) 6 (7.4%) .335 staphylococcus epidermidis 1 (3.6%) 5 (6.2%) .515 staphylococcus warneri 2 (7.1%) 2 (2.5%) .272 staphylococcus aureus 2 (7.1%) 2 (2.5%) .272 streptococcus pneumoniae 0 (0%) 1 (1.2%) .743 granulicatella adiacens 0 (0%) 1 (1.2%) .743 micrococcus spp 1 (3.6%) 2 (2.5%) .594 kocuria rosea 0 (0%) 1 (1.2%) .743 gram (-) bacteria (n) 20 (41.7%) 22 (21.4%) .016 proteus mirabilis 9 (45%) 9 (40.9%) .789 pseudomonas florescens 0 (0%) 1 (4.5%) .524 escherichia coli 5 (25%) 6 (27 %) .864 enterobacter aerogenes 1 (5%) 2 (9%) .537 morganella morgani 1 (5%) 2 (9%) .537 klebsiella oxytoca 0 (0%) 1 (4.5%) .524 klebsiella pneumoniae 2 (10%) 0 (0%) .221 proteus hauseri 0 (0%) 1 (4.5%) .524 providencia rettgeri 1 (5%) 0 (0%) .476 citrobacter farmeri 1 (5%) 0 (0%) .476 group i, with smegma; group ii, without smegma (glans swap) a: fisher’s exact test and chi-square test (p < 0.05) table 2. type and number of uropathogens isolated from groups. pediatric urology 615 vol 17 no 06 november-december 2020 616 microbiology laboratory for microscopy, culture identification, and antimicrobial sensitivity testing. first, the swabs were inoculated aseptically onto blood agar, chocolate agar, and emb agar using a sterile plastic wire loop. all incubations were kept at 37 °c for 24 hours for the aerobic culture. next, the bacteria were isolated, identified, and confirmed by standard bacteriological techniques and antimicrobial sensitivity tests (ast) using the vitec ii system (biomérieux, inc., durham, nc) by eucast mic breakpoints. it was not prepared a direct smear to gram stain. after the surgery, the patients underwent a routine follow-up scheduled for six months later. statistical analysis statistical analysis was performed using ibm spss statistics ver. 22.0 (ibm co., armonk, ny, usa) with a fisher’s exact test and a chi-square test. a p-value < 0.05 was considered statistically significant. results the 132 children ranged from six months to 7 years 4 months in age (mean age: 34 ± 22.7 months). they were divided into two groups: the age of the children in group i ranged from 1 years to 6 years 11 months (mean age: 35.0 ± 22.0 months) while the age of the children in group ii ranged from six months to 7 years 4 months (mean age: 33.0 ± 23.5 months) (p =.856). smegma samples were obtained from 58 patients (group i). in 39 of them, 48 organisms were isolated; 30 samples had a single organism isolated (76.9%), 9 had mixed growths isolated (23.1%), and 19 had no organisms isolated (32.8%). further, 28 gram-positive (58.3%) and 20 gram-negative (41.7%) bacteria found. the most commonly isolated gram-negative bacterium was proteus mirabilis (9/20, 45%), while the most positive was staphylococcus hominis (12/28, 42.9%) (tables1 and 2). subpreputial space swabs were taken from 74 patients (group ii) out of which, 35 (51.5%) had a single organism isolated, 33 had mixed growths isolated (48.5%), and six had no bacteria isolated (8.1%); 103 bacterial uropathogens were isolated from 68 boys. these uropathogens were made up of 22 gram-negative isolates (21.4%) and 81 gram-positive isolates (78.6%). the most commonly isolated gram-negative uropathogen was proteus mirabilis (9/22, 40.9%) while the most positive was enterococcus faecalis (34/81, 42%) (table 1 and table 2). meanwhile, among the total isolates obtained from group i and group ii, the most commonly isolated gram-negative bacterium was proteus mirabilis (18/42, 42.9%) while the most positive were enterococcus faecalis (44/109, 40.7%) and s. hominis (39/109, 42.9%) (table 2). however, most of the bacterial isolates were multi-drug resistant (61.8%) testing by conventional test methods and automated systems (vitek ii, biomerieux, france) (table 3 and table 4). it is important to note that none of the patients have any post-operative complications, such as surgical site infections (ssi) or utis. discussion a variety of organisms can colonize the subpreputial space and its smegma(13-15). in some cases, this colonization can be the initial step in the development of a uti(8). moreover, studies have shown that uncircumcised infants have a higher rate of urinary tract infections in the first few months of life as compared to circumcised infants. in this context, ginsburg and mccracken first noted that 95% of male infants with utis were uncircumcised(5). later, in extensive retrospective cohort studies of u.s. army dependents, wiswell et al. documented that uncircumcised children have 10 to 20 times greater risk of utis in the first few months of life as compared to circumcised children(5). thus, it can be seen that non-circumcision is a highly significant risk factor in the development of utis in infants up to 12 months of age and affects infants regardless of race and socioeconomic status(9). further, the risk of utis appears to be particularly reltable 3. gram (+) bacterial isolates and result of resistance test to the antimicrobial agents (%)by conventional test methods and automated systems (bacteria number and acronym for antibiotic names) bacteria number (n) tec amp ci̇p lzd dap va tgc tmp/sxt e da dap te fos fa fox gn f lev ri̇f mox p e.faecalis (44) 7.1 0 2.3 0 7.1 7.1 0 100 s.hominis (39) 0 0 0 0 0 86.2 13.7 0 0 72.4 75.8 6.8 0 s.haemolyticus (6) 100 100 100 0 0 100 100 100 100 100 100 100 0 s.epidermidis (6) 0 100 0 40 100 0 0 s. warneri (4) 0 0 0 0 0 0 100 0 100 100 0 0 s aureus (4) 25 25 0 25 0 25 s.pneumoniae (1) 0 100 0 0 0 0 0 0 0 0 100 0 100 0 g. adiacens(1) 0 100 0 0 100 100 100 100 100 100 100 notes: among gram-positive bacteria, kocuria rosea and micrococcus spp: since they are considered flora component, antibiotic sensitivity testing is not performed (see table 2) abbreviations: tec: teicoplanin, am: ampicillin, ci̇p: ciprofloxasin, lzd: linezolid, dap:daptomycin, va:vancomycin, tgc:tigecycline, tmp/sxt:trimethoprim/ sulfamethoxazole, e:erithromycine, da:clindamycin, dap: daptomycine te: tetracycline, fos: fosfomycin, fa:phucydic acid, fox:cefoxitin, gn: gentamycin, f:nitrofurantoin, lev:levofloxasin, ri̇f: riphampin, mox:moksifloxasin, p:penisilin. microbiology of internal foreskin and smegma-demir et al. evant during the first six months of a child’s life when there is an increased amount of uropathogenic bacteria colonizing the prepuce. in other words, the periurethral colonization of uncircumcised children seems to be an important first step for ascending uti seems to decrease and resolve itself by the time the child is around the age of five(8). thus, in general, circumcision has many health benefits, including a decreased risk of utis as it reduces the rate of uti development in the first six months of a child’s life almost tenfold(16,17). on the other hand, the build-up of necrotic debris under the prepuce is a common occurrence in uncircumcised children, unless the prepuce is regularly retracted and the area cleaned. this debris is popularly known as “smegma”—a word of greek origin that means “soap” or “salve”. at first, smegma was thought to be produced by ectopic subpreputial sebaceous glands near the frenulum, called the tyson’s glands, which were never found(13). however, in actuality, smegma is a subpreputial collection of desquamated epithelial debris mixed with mucin and secretions. it has a composition that includes fat (about 27%) and protein (about 13%) and largely functions to moisten and lubricate the subpreputial space(12,13). it also contains cathepsin b, lysozymes, chymotrypsin, neutrophil elastase, and cytokines, which may play an important role in the immune mechanism(11,18). fleiss et al. supported this idea by suggesting that the oligosaccharides in breast milk are excreted when a child urinates, thereby preventing e. coli from adhering to the urinary tract and inner lining of the prepuce(11). further, lysozyme, which originates from the prostate and seminal vesicles, destroys bacterial cell walls and inhibits or destroys candida species(19). despite these findings, the role of smegma in pediatric utis has not yet been completely understood. in a study from nigeria(19), bacterial isolates were found in smegma swabs from 52 boys ranging from 7 days to 11 years in age; 34 boys had single bacteria isolated (65.4%), 8 had mixed growths isolated (15.4%), and 10 had no isolated bacteria (19.2%). the most commonly isolated gram-positive bacterium was staphylococcus epidermidis (44.8%) and s. aureus (41.4%), while the most negative was e. coli (90.5%). the study suggested that the differences found in the organisms relative to other studies may be ascribed to local variations and socio-economic differences due to variations in climate and diet. similar to this study’s findings, most of the bacterial isolates were found to be multi-drug resistant by conventional test methods and automated systems. in a study from turkey, smegma swabs were taken from 100 prepubertal, healthy boys ranging from two months to nine years(20). the 72 isolates consisted of 54 gram-positive bacteria (75.0%), 17 gram-negative bacteria (23.6%), and one candida isolate (1.4%). the most commonly isolated gram-negative bacterium was e. coli (41.2%), while most positive was enterococcus sp. (57.4%). however, most of the bacterial isolates were found to be drug-sensitive. meanwhile, when treating utis, higher antibiotic resistance rates were frequently determined with regards to ampicillin, nitrofurantoin, and gentamycin. in a study from korea, patients were classified into two groups: group s (with smegma, n=20) and groupc (without smegma, n=20)(5). in group s, 12 boys had 22 bacterial isolates in the glans. the commonly isolated bacteria were e. coli (27.3%), e. avium (22.7%), and e. faecalis (18.2%). in group c, 13 boys had 21 bacterial isolates in the glans. the most commonly isolated bacterial uropathogens were e. faecalis (6/21, 28.6%), e.avium (2/21, 9.5%), and e.raffinosus (2/21, 9.5%). however, e. coli was isolated in just one patient from group c. most of the organisms isolated were sensitive to common antimicrobial agents in clinical practices, except ampicillin for gram-negative isolates and erythtable 4. gram (-) bacterial isolates and result of resistance test to the antimicrobial agents (%) by conventional test methods and automated systems (bacteria number and acronym for antibiotic names) bacteria cxm fox am caz cro fep etp mem ak gn ci̇p tgc co tmp/sxt f fos pip tpz azt ne tob lev ipm cf ax number (n) p mirabilis (18) 0 0 0 0 0 0 0 0 0 28.5 100 100 71.4 100 0 pflurescens (1) 0 0 0 0 0 0 0 0 0 0 0 0 ecoli (11) 0 0 14.2 0 0 0 0 0 0 0 0 0 14.2 0 0 14.2 14.2 e aerogenes (3) 100 100 100 100 100 0 0 0 0 0 0 100 0 0 100 100 100 m morgani (3) 0 0 0 0 0 0 0 100 100 0 0 0 0 0 0 0 0 33.3 k oxytoca (1) 0 0 0 0 0 0 0 0 0 0 100 100 0 0 100 0 k pneumoniae 100 0 100 100 100 0 0 0 0 0 0 0 0 0 100 100 (2) p hauseri (1) 100 100 100 0 100 0 0 0 0 0 0 100 100 0 0 100 100 providencia 100 0 100 100 100 100 0 0 0 0 0 100 100 0 rettgeri (1) citrobacter 100 0 100 0 100 0 0 0 0 0 0 0 0 0 0 100 0 farmeri (1) abbreviations: cxm: cefuroxime, fox:cefoksitin, am: ampicillin, caz: ceftazidime, cro: ceftriaxone, fep: cefepime, etp:ertapenem, mem: meropenem, ak: amikasin, gn: gentamycin, ci̇p: ciprofloxasin, tgc:tigecycline, co: colistin, tmp/sxt:trimethoprim/ sulfamethoxazole, f:nitrofurantoin, fos: fosfomycin, pip: piperasilin, tpz: piperasilin/ tazobactam, azt:azetroenam, ne: netilmisin, tob: tobramisin, lev:levofloxasin, ipm: imipenem, cf: cefazolin, ax: amoxicillin. microbiology of internal foreskin and smegma-demir et al. pediatric urology 617 vol 17 no 06 november-december 2020 618 romycin, penicillin-g, and tetracycline for gram-positive isolates. moreover, over half (61.3%) of the organisms isolated were multi-drug resistant. to the best of our knowledge, this study surveyed the largest number of patients when comparing smegma and glans swab culture. the number of patients with bacterial isolation, total bacteria, gram (+) and gram (-) bacteria isolated in group ii were significantly higher than group i, respectively. (p = .001, p = .001, p = .016, p = .016). we demonstrated that smegma does not pose additional risk in microbiological colonization. among all the isolates obtained from groups i and ii, the most commonly isolated gram-negative bacterium was proteus mirabilis (18/42, 42.9%), while positive was enterococcus faecalis (44/109, 40.7%) and s. hominis (39/109, 42.9%) (table2). most of the organisms isolated were sensitive to commonly used antimicrobial agents, except ampicillin, cefazolin, and amoxicillin in gram-negative isolates, and erythromycin and fosfomycin in gram-positive isolates. further, most of the bacterial isolates were multi-drug resistant (61.8%) (table 3 and table 4). in a study by chung et al., 20% of patients had no microorganisms(5). in our study, 18.9% (25/132) of our patients did not have microorganisms and were found to be compatible with the literature (table 1). antibiotic resistance differs according to geographic locations and is directly proportional to the use and misuse of antibiotics. understanding the effect of drug resistance is crucial because of its deep effect on the treatment of infections. recently, these multi-drug resistant organisms have become a serious threat to regions around the world, including turkey, and require treatment using reserve drugs. in this context, the high detection rates of multi-drug resistance in smegma and glans swabs is an interesting dimension to this study. the variety of organisms in the smegma of boys, which are multi-drug resistant, may be linked to an increased virulence in these organisms(21,22). thus, it is imperative that these organisms be examined and characterized before any surgical reconstruction involving the prepuce, such as hypospadias repair, as it may contribute to poor wound outcomes. although the diagnosis of utis in young children requires a semiquantitative culture of urine to be obtained by suprapubic aspiration or urethral catheterization(22,23), a subpreputial swab in uncircumcised boys may aid in the diagnostical process, given that periurethral colonization is an important prelude to ascending infections through the urethra(8). despite the discovery of a variety of organisms in the subpreputial space of boys, none of the patients studied were detected with uti symptoms or postoperative uti complications. this supports the fact that colonization does not always lead to infection. conclusions the preputial space of the children we examined were colonized by various multi-drug resistant organisms including gram positive and gram negative organisms by standard bacteriological techniques and antimicrobial sensitivity tests (ast) using the vitec ii system (biomérieux, inc., durham, nc) by eucast mic breakpoints. the researchers believe that because the microbiology of smegma is similar to that of the preputial space, it did not present any additional risk to microbiological colonization in the children in this study. conflict of onterest all of the 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koca o, ozgü i, zorlu f. effect of preputial type on bacterial colonization and wound healing in boys undergoing circumcision. korean j urol. 2012;53(6):431-4. 9. abara eo. prepuce health and childhood circumcision: choices in canada. can urol assoc j. 2017;11:55-62. 10. dubrovsky as, foster bj, jednak r, mok e, mcgillivray d. visibility of the urethral meatus and risk of urinary tract infections in uncircumcised boys. cmaj. 2012;184(15):796-803. 11. fleiss pm, hodges fm, van howe rs. immunological functionsof the human prepuce. sex transm infect. 1998;74:364-7. 12. van howe rs, hodges fm. the carcinogenicity of smegma: debunking a myth. j eur acad dermatol venereol. 2006;20:104654. 13. palinrungi ma, kholis k, syahrir s, syarif, faruk m. multiple preputial stones: a case report and literature review. int j surg case rep. 2020;70:87-92. 14. cold cj, taylor jr. the prepuce. bju int. 1999;83:34-44. 15. sonnex c, croucher pe, dockerty wg. balanoposthitis associatedwith the presence of subpreputial"smegma stones".genitourin microbiology of internal foreskin and smegma-demir et al. med. 1997;73:567. 16. verit a, zeyrek fy, mordeniz c, ciftci h, savas m. status ofhigh-risk oncogenic human papillomavirus subtypes harboredin the prepuce of prepubertal boys. urology. 2012;80:423-6. 17. schoen ej, colby cj, ray gt. newborn circumcision decreasesincidence and costs of urinary tract infections during the firstyear of life. pediatrics. 2000;105:789-93. 18. agartan ca, kaya da, ozturk ce, gulcan a. is aerobic preputialflora age dependent? jpn j infect dis. 2005;58:276. 19. anyanwu lj, kashibu e, edwin cp, mohammad am. microbiologyof smegma in boys in kano, nigeria. j surg res. 2012;173:21-5. 20. balci m, tuncel a, baran i, guzel o, keten t, aksu n, et al.high-risk oncogenic human papilloma virus infection of theforeskin and microbiology of smegma in prepubertal boys. urology. 2015;86:368-72. 21. ghigo jm. natural conjugative plasmids induce bacterial biofilm development. nature. 2001;412:442. 22. maclennan c, swingler g, craig j. urinary tract infections in infants and children in developing countries in the context of imci. discussion papers on child health 2005. who/ fch/cah/05.11.availableat:whqlibdoc.who. int/hq/2005/who_fch_cah_05.11.pdf. accessed march 18, 2011. 23. american academy of pediatrics, committee on quality improvement, subcommittee on urinary tract infection. practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. paediatrics. 1999;103:843. microbiology of internal foreskin and smegma-demir et al. pediatric urology 619 v08_no_4_final_new.pdf case report 328 urology journal vol 8 no 4 autumn 2011 concealed male epispadias a rare form of penile epispadias presenting as phimosis alireza sina,1 farshid alizadeh2 urol j. 2011;8:328-9. www.uj.unrc.ir keywords: male, phimosis, foreskin, epispadias 1alborz faculty of medicine, bahonar hospital, karaj, iran 2isfahan urology and renal transplantation research center, alzahra hospital, isfahan university of medical sciences, isfahan, iran corresponding author: farshid alizadeh, md no. 8, farhad alley, daneshgah ave., isfahan, iran tel: +9133179509 fax: +311235 0532 e-mail: f_alizadeh@med.mui.ac.ir received december 2009 accepted april 2010 introduction isolated epispadias is a rare congenital urologic abnormality with an incidence of around 1 in every 120 000 births.(1) prepuce is usually absent dorsally and hangs as a tag of redundant tissue on the ventral aspect of the penis. it is extremely rare to see an epispadiac penis with complete prepuce, with less than 10 cases being reported in the literature.(1-7) we add another case and briefly discuss about the diagnosis, embryogenesis, and management of this anomaly. case report a 2-month-old male infant presenting with concealed penis and asymptomatic urinary infection was referred to us (figure 1). on physical examination, the glans penis was not felt very well because of the small penile size. urine culture was positive for escherichia coli. ultrasonography of the urinary tract was normal, but voiding cystourethrography was postponed until after phimosis release. after general anesthesia, a dorsal slit was done to release the glans, but unexpectedly, we encountered a penile epispadias, which included nearly the whole penile length, 17 mm (figure 2). urethroplasty and glanuloplasty by urethral plate tubularization and repair of dorsal chordee with medial rotation and suturing of the corpora cavernosa were performed and an 8f urethral catheter was fixed into the bladder for 1 week. the cosmetic result was excellent (figure 3). figure 1. patient presenting with phimosis. figure 2. penile epispadias discovered after dorsal slit. concealed male epispadias—sina and alizadeh 329urology journal vol 8 no 4 autumn 2011 discussion the first case of epispadias associated with phimosis was reported by raghavaiah,(6) which was a case of balanic epispadias. he stated that if the defect does not reach the coronal sulcus, the preputial development can take place normally. but later, other authors reported cases of penile epispadias with complete prepuce and phimosis.(1,4) considering the rarity of this anomaly, the correct diagnosis could not be made before attempted circumcision. however, some findings on the physical examination can make the examiner suspicious of the presence of this very unusual variant of epispadias. the glans penis is broad-based and has been stated to be tent-like or spade-like.(1,3) when one palpates the glans, the gap between the two corpora cavernosa can be felt, and the preputial opening is diverted dorsally. dorsal chordee sometimes exists. the raphe penis is totally absent on the glans. it ends near the base of the glans and may assume a horizontal direction,(5) but this kind of abnormality of raphe is not always seen, as it was the case in our patient. embryologically, the development of the prepuce begins from the 8th week of gestation from the low preputial folds that appear on both sides of the penile shaft. they first join dorsally and when the development of the glandular urethra is completed, they join ventrally as well. active growth of the mesenchyme between the preputial fold and the glandular lamella transports the fold distally until it covers the glans totally.(8) if these folds appear proximal to the urethral defect, they can cover the defective urethra as well as the glans. some believe that the preputial development in this type of epispadias is not completely normal. deviation of the preputial opening towards the dorsal aspect of the penis, absence of frenulum line on the glans, and horizontal termination of the raphe phallus close to the glans are the results of this abnormality.(7) mccahill and colleagues proposed that “the developing prepuce beside the dorsal urethral defect is partially diverted over the defect, causing a skewed median raphe”.(1) careful physical examination is mandatory in any patient that presents with concealed penis or phimosis. simple circumcision is not indicated in these patients and attempt should be made to close the defective urethra as well as correct the chordee if present. conflict of interest none declared. references 1. mccahill pd, leonard mp, jeffs rd. epispadias with phimosis: an unusual variant of the concealed penis. urology. 1995;45:158-60. 2. bhattacharya v, sinha jk, tripathi fm. a rare case of epispadias with normal prepuce. plast reconstr surg. 1982;70:372-4. 3. kang jg, yoon jh, yoon jb. penile epispadias: a case report. korean j urol. 1985;26:387-91. 4. krishna a, iyer pu. epispadias with complete nonretractile prepuce. indian pediatr. 1989;26:1055-6. 5. merlob p, mor n, reisner sh. epispadias with complete prepuce and phimosis in a neonate. clin pediatr (phila). 1987;26:43-5. 6. raghavaiah nv. epispadias associated with phimosis. j urol. 1976;116:671-2. 7. sarin y, sinha a. concealed epispadias. indian j urol. 2001;17:183-4. 8. baskin ls. basic science of the genitalia. in: kelalis pp, docimo sg, king lr, canning da, belman ab, khoury ak, eds. the kelalis-king-belman textbook of clinical pediatric urology. london: informa health care; 2007:1122. figure 3. the final result after surgical repair. 1011vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l lower moiety pelvi ureteric junction obstruction leading to acute renal failure in an ectopic fused kidney priyadarshi ranjan, ranjana singh, aneesh srivastava keywords: ureteral obstruction; etiology; surgery; kidney abnormalities; acute renal failure introduction uretero-pelvic junction obstruction (upjo) has many etiologies and remains a rare cause of renal failure. we present a rare case of fused kidney causing pelvi-ureteric junction obstruction and acute renal failure. case report a 37 years old man presented to the emergency department with oliguric renal failure. at presentation his serum creatinine was 12 mg/dl and he was in septicemia. he had passed only 250 ml of urine in the past 24 hours. abdominal sonography revealed right fused renal mass with hydronephrosis of both the upper and the lower moieties. an abdominal computed tomography (ct) scan revealed grossly destroyed parenchyma of the lower moiety with preserved parenchyma but gross hydronephrosis of the upper moiety (figure 1). after stabilization bilateral percutaneous nephrostomies were placed in both the moieties. the upper moiety drained around 3 liters per day, while the lower moiety did not show urine produccorresponding author: priyadarshi ranjan, md consulatant urologist and cheif kidney transplant surgeon, fortis hospital, mohali, punjab, india. tel: +91 800 440 0008 email: priydarshiranjan@sify.com received june 2011 accepted september 2011 case report 1012 | tion. subsequent nephrostograms revealed pelvi ureteric junction (puj) obstruction in the lower moiety with normal drainage of the upper moiety. a review ct and magnetic resonance imaging (mri) revealed the cause of obstruction of the lower moiety at the level of the puj which subsequently lead to the concomitant obstruction of the upper moiety (figure 2). in view of negligible renal function of the lower moiety, lower polar heminephrectomy was done. (1,2) the upper moiety compression was relieved and did not require any intervention. the patient had uneventful recovery with normal renal function at discharge. conflict of interest none declared. figure 1. ct scan and mri demonstrating the grossly hydronephrotic parenchyma of the lower pole due to puj obstruction. the upper polar ureter emerging laterally marked with arrow can be seen getting compressed due to the compression by the lower moiety. figure 2. a triphasic ct reconstruction demonstrating both the upper and lower moiety nephrostomies and the normal ureter of the upper moiety marked with an arrow. case report references 1. ulchaker j, ross j, alexander f, kay r. the spectrum of ureteropelvic junction obstructions occurring in duplicated collecting systems. j pediatr surg. 1996;3:1221-4. 2. horst m, smith gh. pelvi-ureteric junction obstruction in duplex kidneys. bju int. 2008;101:1580-4. case report 200 urology journal vol 5 no 3 summer 2008 high-grade vesicoureteral reflux in pfeiffer syndrome abolhassan seyedzadeh, farshid kompani, ebrahim esmailie, sara samadzadeh, bohaire farshchi urol j. 2008;5:200-2. www.uj.unrc.ir keywords: pfeiffer syndrome, cleft lip, cleft palate, craniosynostoses, vesicoureteral reflux urology-nephrology research center, kermanshah university of medical sciences, kermanshah, iran corresponding author: abolhassan seyedzadeh, md emam reza hospital, zakaria blvd, kremanshah, iran tel: +98 918 131 2529 e-mail: asayedzadeh@kums.ac.ir received november 2007 accepted march 2008 introduction in 1964, pfeiffer described an acrocephalosyndactyly syndrome consisting of bicoronal craniosynostosis, midface hypoplasia, broad thumbs, broad big toes, and partial and variable soft-tissue syndactyly of the hands and feet.(1) autosomal dominant inheritance with complete penetrance is the main characteristic despite variable expressivity related to the presence or absence of syndactyly and its degree of severity. based on the severity of the phenotype, cohen proposed a classification of pfeiffer syndrome into 3 clinical subtypes.(2) we report, a case of pfeiffer syndrome type 2 with high-grade bilateral vesicoureteral reflux (vur), and discuss the importance of surveillance for urogenital problems in patients with this syndrome. case report a 4-month-old male infant was admitted to our hospital because of fever since 3 days earlier and generalized tonic-clonic seizure. he was a product of term normal vaginal delivery. he had 3 normal siblings. there was a history of abortion at the third month of gestation in the first maternal pregnancy. the parents had a normal phenotype and were not consanguineous. the mother was 34 years and the father was 36 years old. the child had failure to thrive with a birth weight of 3.8 kg. his present weight was 4.5 kg. developmental delay was also noticed. on physical examination, the patient had a cloverleaf skull, cleft palate, cleft lip, flat nasal bridge, broad toes, and low-set ears. proptosis and some degree of strabismus were also noticed (figure 1). on cardiac examination, a grade 2/6 systolic murmur was auscultated at the pulmonary area. mild valvular pulmonary stenosis was documented by echocardiography. skull radiography showed acrocephaly and the prominence of temporal bones (cloverleaf skull). computed tomography of the skull and brain showed bicoronal craniosynostosis and enlargement of lateral ventricles suggestive of moderate hydrocephalus. electroencephalography showed paroxysmal discharge. according to the abovementioned findings, diagnosis of pfeiffer syndrome was made clinically. ultrasonography of the urogenital vesicoureteral reflux in pfeiffer syndrome—seyedzadeh et al urology journal vol 5 no 3 summer 2008 201 system revealed intermittent dilatation in the pyelocaliceal system and also bilateral ureteral dilatation. the findings were suggestive of vur. a grade 4 bilateral vur was documented by voiding cystourethrography (figure 2). subsequently, dimercaptosuccinic acid renal scintigraphy showed bilateral cortical scars with moderate cortical loss in the right and severe cortical loss in the left side. blood urea and serum creatinine were 32 mg/dl and 0.6 mg/dl, respectively. during the course of hospitalization, urinary tract infection was documented by an active urinalysis and a positive urine culture for pathogen microorganisms. discussion the exact incidence of pfeiffer syndrome is unknown, but is expected to be 1 in every 100 000 births in the western population. approximately, 60 cases had been reported in the literature,(3) and it is even rarer in the asian population, with few cases reported in japan and korea.(4,5) pfeiffer syndrome is known to be caused by mutations in exon iiia or exon iiic of the fibroblast growth factor receptor 1 or 2 gene.(6,7) therefore, the disease is genetically heterogeneous. in pfeiffer syndrome type 1, fresh mutations or autosomal dominance are the genetic disorders. in types 2 and 3, inheritance is sporadic. pfeiffer syndrome type 1, which is named “classic,” involves individuals with mild manifestations including brachycephaly, midface hypoplasia, and toe abnormalities. this type is associated with normal intelligence and generally good outcome. pfeiffer syndrome type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, developmental delay, and neurologic complications. type 3 of this syndrome is similar to type 2, but without a cloverleaf skull. it should be noted that clinical overlap between the three types may occur.(2) our patient had clinical manifestations in favor of pfeiffer syndrome type 2 in addition to high-grade bilateral vur. cloverleaf skull is a characteristic feature of pfeiffer syndrome type 2, which is often associated with hydrocephalus due to aqueductal stenosis. patients with pfeiffer syndrome type 2 may have variable degrees of abnormalities in their hands and feet, including elbow ankylosis, short broad thumbs, and big toes which are deviated away from other digits.(5,8,9) they may have other congenital anomalies of the upper airway, cleft palate, cleft lip, choanal atresia, fused vertebrae, imperforate anus, hydrocephalus, figure 1. the patient had a cloverleaf skull, cleft palate, cleft lip, flat nasal bridge, low-set ears, proptosis, and some degree of strabismus. figure 2. voiding cystourethrography showed grade 4 bilateral vesicoureteral reflux. vesicoureteral reflux in pfeiffer syndrome—seyedzadeh et al 202 urology journal vol 5 no 3 summer 2008 and arnold-chiari malformation.(5) there have been occasional reports of hydronephrosis (without any obvious etiology) and pelvic kidney as abnormalities of the urogenital system accompanying pfeiffer syndrome.(2,3) however, to our knowledge, the association of pfeiffer syndrome and vur has not been reported to date. this shows the importance of investigation for urogenital abnormalities not described yet such as vur, especially when presenting with urinary tract infection. conflict of interest none declared. references 1. pfeiffer ra. [dominant hereditary acrocephalosyndactylia.]. z kinderheilkd. 1964;90:301-20. german. 2. cohen mm, jr. pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. am j med genet. 1993;45:300-7. 3. plomp as, hamel bc, cobben jm, et al. pfeiffer syndrome type 2: further delineation and review of the literature. am j med genet. 1998;75:245-51. 4. nagase t, nagase m, hirose s, ohmori k. japanese sisters with pfeiffer syndrome and achondroplasia: a mutation analysis. j craniofac surg. 1998;9:477-80. 5. park ms, yoo je, chung j, yoon sh. a case of pfeiffer syndrome. j korean med sci. 2006;21:374-8. 6. muenke m, schell u, hehr a, et al. a common mutation in the fibroblast growth factor receptor 1 gene in pfeiffer syndrome. nat genet. 1994;8:269-74. 7. teebi as, kennedy s, chun k, ray pn. severe and mild phenotypes in pfeiffer syndrome with splice acceptor mutations in exon iiic of fgfr2. am j med genet. 2002;107:43-7. 8. oyamada mk, ferreira hs, hoff m. pfeiffer syndrome type 2--case report. sao paulo med j. 2003;121:176-9. 9. wilkie ao, patey sj, kan sh, van den ouweland am, hamel bc. fgfs, their receptors, and human limb malformations: clinical and molecular correlations. am j med genet. 2002;112:266-78. urology journal vol 4 no 1 winter 2007 49 case report unusual migration of intrauterine device into bladder and calculus formation mohammad rajaie esfahani,1 ahmadreza abdar 2 urol j (tehran). 2007;4:49-51. www.uj.unrc.ir keywords: bladder calculus, foreign body, intrauterine device, bladder perforation 1department of urology, kashani hospital, shahrekord university of medical sciences, shahrekord, iran 2department of urology, fatimazahra hospital, nadjafabad, iran corresponding author: mohammad rajaie esfahani, md department of urology, kashani hospital, shahrekord, iran tel: +98 913 382 0669 e-mail: dr_mrajaei@yahoo.com received april 2006 accepted october 2006 introduction foreign bodies in the bladder can result in recurrent urinary tract infection (uti), hematuria, calculus formation, and pelvic pain.(1) instruments used for surgical and endoscopic procedures or masturbation may migrate into the bladder. intrauterine device (iud) is a safe and cost-effective means of contraception.(2) however, since its application, many complications including dysmenorrhea, hypermenorrhea, pelvic infections, pregnancy, spontaneous abortion, uterine rupture, and migration into the neighboring organs have been reported.(3,4) migration of the iud into the bladder has been rarely reported in the literature. we report a case of iud migration into the bladder and calculus formation. case report a 28-year-old woman with a history of 4 deliveries presented to our urology clinic of fatima-zahra hospital in najafabad, iran, with dysuria, frequency, hematuria, and disseminated pelvic pain especially during the menstruation period since 4 years earlier. she had a history of cystocele and rectocele repairs, and experienced recurrent uti after the surgery without fever and chills not sufficiently responding to antibiotic therapy. intrauterine device had been inserted 8 years earlier. four years after the insertion of the iud, the string of the device had not been detected by the gynecologist and it was assumed that the iud had been exploded spontaneously. thereafter, oral contraceptive had been started. on physical examination, tenderness was noted in the suprapubic area and with movements of the cervix and the anterior wall of the vagina. urinalysis was indicative of pyuria and hematuria, and urine culture was positive for escherichia coli. on ultrasonography, a large bladder calculus and severe inflammation of the bladder mucosa were reported. the bladder calculus was also detected by abdominal radiography and an iud was seen in the pelvis, as well (figure 1). cystoscopy was performed twice and revealed local inflammation and severe swelling in the left side of the bladder, but the bladder calculus was not seen beyond the inflammation. the patient refused computed tomography; therefore, a second ultrasonography was done and the iud was seen in an abnormal position adjacent to the calculus. according to the findings of the abdominal radiography and ultrasonography, suprapubic cystolithotomy was performed. a 2cm bladder calculus was detected in the upper left side of the bladder. an iud which was stuck to the calculus was also removed intact (figure 2), but it resulted in a rupture migration of intrauterine device and calculus formation—rajaie esfahani and abdar 50 urology journal vol 4 no 1 winter 2007 migration of intrauterine device and calculus formation—rajaie esfahani and abdar urology journal vol 4 no 1 winter 2007 51 in the bladder wall. the rupture was internally repaired in 2 layers by catgut sutures. a urethral catheter was fixed for 2 weeks. the patient had an uneventful postoperative period without any special complication. discussion intrauterine device is an accepted worldwide contraceptive instrument. however, a very small proportion of sexually active women in the united state use the iud because of the fear of its complications.(5) its complications include uti, spontaneous abortion, and uterine rupture.(6) migration of the iud into the neighboring organs or the abdominal cavity is a rare complication. in a review of 165 cases, the omentum, rectosigmoid, peritoneum, bladder, appendix, small bowel, adnexa, and iliac vein were the location of migrated iud, in 45, 44, 41, 23, 8, 2, 1, and 1 patients, respectively.(7) these patients generally present with the chief complaint of not finding the device string. they may be asymptomatic or have abdominal and pelvic signs and symptoms, based on the severity of the problem and location of the iud. copper iuds result in abundant inflammatory reaction and adhesion.(8) uterine rupture has been reported with a frequency of 1:350 to 1:2500 in women with iud.(9) factors raising suspicion of uterine rupture include insertion of the device by inexperienced persons, inappropriate position of the iud, susceptible uterine wall due to multiparity, and a recent abortion or pregnancy.(10) all iuds are radio-opaque; therefore, plane abdominal radiography may be used for detection of the iud as well as ultrasonography and ct scan. transvaginal ultrasonography provides the best view for locating the iud, but it restricts the space for its simultaneous removal.(8) magnetic resonance imaging is not contraindicated in copper iuds.(8) even if the iud migration is asymptomatic, it should be removed for prevention from the complications such as pelvic abscess, bladder or intestinal rupture, and adhesion. migration of the iud into the bladder and formation of a secondary calculus is an uncommon complication.(11) only 31 cases of complete or incomplete migration of iud into the bladder and calculus formation have been reported in the literature by 2006.(11,12) although the process of iud migration into the bladder is gradual and accompanies with complications such as cystitis, hematuria, and pelvic pain, most of the perforations occur at the time of insertion.(5-13) in summary, the iud should be correctly inserted by an experienced person. a proper selection of patient and a thorough history and physical figure 1. plain abdominal radiography revealed a large calculus in the bladder and an intrauterine device. figure 2. a 2-cm calculus adhered to an intrauterine device was removed by suprapubic cystolithotomy. migration of intrauterine device and calculus formation—rajaie esfahani and abdar 50 urology journal vol 4 no 1 winter 2007 migration of intrauterine device and calculus formation—rajaie esfahani and abdar urology journal vol 4 no 1 winter 2007 51 examination is crucial. if uterine rupture is suspected, ultrasonography should be performed to determine the probable location of the rupture. women should be informed of the potential complications and be suggested to check the device string regularly. if the string is not found, abdominal radiography is required even in asymptomatic patients. in women with iud who presents with lower urinary tract symptoms, migration of the iud into the bladder, although very uncommon, should not be neglected. conflict of interest none declared. references 1. tan lb, chiang cp, huang ch, chou yh, wang cj. [foreign body in the urinary bladder]. gaoxiong yi xue ke xue za zhi. 1993;9:604-9. chinese. 2. cheng d. the intrauterine device: still misunderstood after all these years. south med j. 2000;93:859-64. 3. yalcin v, demirkesen o, alici b, onol b, solok v. an unusual presentation of a foreign body in the urinary bladder: a migrant intrauterine device. urol int. 1998;61:240-2. 4. sehgal a, gupta b, malhotra s. intravesical migration of copper-t. int j gynaecol obstet. 2000;68:265-6. 5. stubblefield pg. family planning. in: berek js, editor. novak’s gynecology. 13th ed. philadelphia: lippincott williams & wilkins; 2002. p. 231-93. 6. dietrick dd, issa mm, kabalin jn, bassett jb. intravesical migration of intrauterine device. j urol. 1992;147:132-4. 7. kassab b, audra p. [the migrating intrauterine device. case report and review of the literature]. contracept fertil sex. 1999;27:696-700. french. 8. speroff l, fritz ma. intrauterine contraception. the iud. in: speroff l, fritz ma, editors. clinical gynecologic endocrinology and infertility. 17th ed. philadelphia: lippincott williams & wilkins; 2005. p. 975-95. 9. ohana e, sheiner e, leron e, mazor m. appendix perforation by an intrauterine contraceptive device. eur j obstet gynecol reprod biol. 2000;88:129-31. 10. junceda avello e, gonzalez torga l, lasheras villanueva j, de quiros a gb. uterine perforation and vesical migration of an intrauterine device. case observation. acta ginecol (madr). 1977;30:79-86. 11. demirci d, ekmekcioglu o, demirtas a, gulmez i. big bladder stones around an intravesical migrated intrauterine device. int urol nephrol. 2003;35:495-6. 12. gonzalvo perez v, lopez garcia lm, aznar serra g, et al. [uterine perforation and vesical migration of intrauterine device]. actas urol esp. 2001;25:458-61. spanish. 13. woods m, wise hm jr. an unusual cause of cystolithiasis: a migrant intrauterine device. j urol. 1980;124:720-1. robotic & laparoscopic urology robot-assisted laparoscopic pyeloplasty in adults: a comparison analysis of primary versus redo pyeloplasty in a single center najib isse dirie1,4, mahad a ahmed3, mohamed abdulkadir mohamed2, zongbiao zhang*1, shaogang wang*1 purpose: approximately 10% of all primary pyeloplasties will require at least one secondary intervention. our aim was to analyze whether secondary repair will pose additional challenges during robotic pyeloplasty compared with the primary pyeloplasty. material and methods: 114 patients who underwent robot-assisted laparoscopic pyeloplasty (ralp) between february 2015 and august 2018 were retrospectively reviewed. patients were divided into; primary and secondary repair. the demographics, intraoperative parameters, postoperative parameters, and success rate of these two groups were collected and compared. primary ralp data were further stratified into those who previously underwent ipsilateral endourological surgeries (ies) at the obstruction site and those who did not, to evaluate the effect of ies has on the outcome of ralp. success was defined as symptomatic and radiological relief. results: of the 114 patients, five complicated cases (three horseshoe kidneys, one duplicated system, and one retrocaval ureter) were excluded from the comparison. the remaining 96 primary and 13 secondary repairs were compared. intraoperative and postoperative parameters showed no significant difference between the two groups. the results of 99 patients (87 vs. 12 in primary vs. secondary, respectively) were available after 27.5 months mean follow-up. the overall success was 92%, 8 patients failed (5 vs. 3 in primary vs. secondary, respectively) and required further surgical interventions. conclusion: though surgically challenging with increased recurrence rates according to the literature we reviewed. however, our data failed to show any significant difference between the primary and redo ralp perhaps due to the smaller size in the redo ralp group. keywords: primary pyeloplasty; secondary pyeloplasty; robot-assisted laparoscopy; comparison; outcomes introduction open pyeloplasty has been the gold standard treat-ment for the management of ureteropelvic junction obstruction (upjo) for more than a century with an excellent success rate of up to 100%(1). nevertheless, reports indicate that approximately 11.4% of post-pyeloplasty patients will require at least one redo procedure, and within one year in up to 87% (2). unlike primary pyeloplasty, the redo approach is particularly challenging due to the disrupted anatomical planes, decreased vascularity to the ureteropelvic junction (upj) area, and scar tissue around the previously repaired site. several minimally invasive techniques such as balloon dilatations, retrograde or antegrade endopyelotomy, conventional laparoscopy, and lately robotic approach have been reported in the literature to replace open repair in redo pyeloplasty for their lower morbidity. 1department of urology, tongji hospital, tongji medical college of hust, wuhan 430030, p.r. china. 2department of cardiac surgery, tongji hospital, tongji medical college of hust, wuhan 430030, p.r. china. 3internal medicine department, beaumont health dearborn, dearborn, michigan, usa 4urology department, dr.sumait hospital, faculty of medicine and health science, simad university, mogadishu ,somalia. *corespondence: department of urology, tongji hospital, tongji medical college, huazhong university of science and technology, liberalization ave, no. 1095, wuhan 430030, p.r. china. tel: 86-2783663460; tel & fax: +86-27-83663460, e-mail: sgwangtjm@163.com and zzb070@126.com received april 2019 & accepted december 2019 nevertheless, techniques such as endopyelotomy have shown significantly lower success rates than open redo pyeloplasty(3). in the last 2 decades, robot-assisted laparoscopic approach has gained significant attention. compared with traditional laparoscopy, da vinci® robotic system (intuitive surgical, inc., sunnyvale, ca) provides a better hand instrument and vision which has tremendously improved the speed of intracorporeal suturing in all laparoscopic reconstructive surgeries. for the above advantages, many centers, including ours, have utilized da vinci® robotic system when dealing with failed pyeloplasty for its excellent image quality and better fine dissections which is very vital for this technically demanding procedure. in the literature, we found numerous studies addressing the novelty, operational safety, efficacy, and success of the robotic pyeloplasty, some studies compared with urology journal/vol 18 no. 1/ january-february 2021/ pp. 45-50. [doi: 10.22037/uj.v16i7.5257] traditional laparoscopy, and open technique. however, only a few reports have compared primary with redo pyeloplasty in the robotic setting. therefore, we aimed to evaluate the surgical and clinical outcomes of robotic redo pyeloplasty compared to primary pyeloplasty. materials and methods from february 2015 to august 2018, 114 consecutive patients underwent robot-assisted laparoscopic pyeloplasty (ralp) at tongji hospital, urology department using da vinci si robotic system for upjo management. during preoperative imaging work-up, a multislice computed tomography (ct) scan, intravenous urography, magnetic resonance urography (mru) or retrograde urography were utilized to localize and evaluate the extent and the degree of the obstruction. diuretic 99mtc-mercaptoacetyltriglycine (mag3) renography examination was performed if an ipsilateral renal parenchymal loss is suspected. once the diagnosis was established, a complete preoperative work-up containing; detailed history, physical examination, renal function test, blood chemistry, urinalysis, coagulation primary vs. redo robotic pyeloplasty in adults-isse dirie et al. endourology and stones diseases 130 study, and blood screening study was conducted. an informed consent document was obtained from each patient before any surgery was carried out. our institution’s ethical committee approval was obtained to conduct this retrospective review. after that, we collected the data and divided patients into two groups; primary ralp and secondary ralp (after open or laparoscopic primary pyeloplasty has failed). the surgical and clinical outcomes of these two groups were compared and analyzed. preoperative parameters such as; age, sex, body mass index (bmi), symptoms, obstruction side, history of prior surgery, type of previous intervention, and associated conditions were recorded. intraoperative, and postoperative parameters such as; american society of anesthesiologists (asa) score, estimated blood loss (ebl), operative time, complication rates, length of hospital stays (los), double j (d-j) removal time, follow-up period, and recurrence rates between the groups were also collected and analyzed. in the primary ralp group, some patients had a history of ipsilateral endourological surgery (ies) such as percutaneous nephrolithotomy (pcnl), uretertable 1. patient demographics (primary vs. secondary ralp) demographicsa overall n (%) primary pyeloplasty secondary pyeloplasty p-value no. of patients 109 96 13 sex, n (%) male 74 (67.9) 65 (67.7) 9 (69.2) .999 female 35 (32.1) 31 (32.3) 4 (30.8) age, years; median (range) 29 (10 -70) 33 (10 70) 25 (18 51) .156 bmi, kg/m2; mean ± sd 22.6 ± 3.4 22.8 ± 3.3 21.7 ± 4.0 .273 asa score, n (%) i 32 (29.3) 28 (29.2) 4 (30.8) ii 73 (67) 64 (66.7) 9 (69.2) .999 iii 4 (3.7) 4 (4.1) 0 presented symptom, n (%) flank pain 31 (28.4) 30 (31.3) 1 (7.7) .104 asymptomatic hydronephrosis 32 (29.4) 29 (30.2) 3 (23.1) .752 abdominal pain 20 (18.4) 17 (17.7) 3 (23.1) .703 others 26 (23.8) 20 (20.8) 6 (46.1) .076 obstruction side, n (%) left 58 (53.2) 49 (51.0) 9 (69.2) .217 right 51 (46.8) 47 (49.0) 4 (30.8) history of ipsilateral urolithiasis, n (%) yes 33 (30.3) 30 (31.2) 3 (23.1) .751 no 76 (69.7) 66 (68.8) 10 (76.9) crossing vessel, n (%) 8 (7.3) 7 (7.3) 1 (7.7) .999 abbreviations: ralp, robot-assisted laparoscopic pyeloplasty; bmi, body mass index; asa, american association of anesthesiologists; sd, standard deviation. a categorical and continuous (except bmi parameter) data were compared using fisher’s exact test and man-whitney u test, respectively. table 2. intra and postoperative outcomes (primary vs. secondary ralp) parametersa overall primary pyeloplasty secondary pyeloplasty p-value no. of patients 109 96 13 operative timeb (min); median (range) 0 (0 – 300) 0 (0 – 300) 100 (0 – 300) .104 ebl (ml); median (range) 141 (47 – 375) 137 (47 – 375) 148 (79 – 308) .340 complications, n (%) clavien ii 16 (14.68) 14 (14.58) 2 (15.38) .995 clavien iii 8 (7.34) 7 (7.29) 1 (7.69) los (days); median (range) 6 (3 – 14) 6 (3 – 14) 6 (3 – 14) .872 stent removal time (weeks); median (range) 8 (4 – 10) 8 (4 – 10) 8 (4 – 10) .636 follow-up periodc (months); median (range) 25 (6 – 57) 25.5 (6 – 57) 25 (15 – 56) .807 recurrence rateb, n (%) 8 (8.1) 5 (5.7) 3 (25) .054 abbreviations: ralp, robot-assisted laparoscopic pyeloplasty; ebl, estimated blood loss; los, length of hospital stays; ga, general anesthesia. b one subject’s data was unavailable; c contains 99 cases (87 vs. 12) since 10 cases were lost in the follow-up. a categorical and continuous data were compared using fisher’s exact test and man-whitney u test, respectively. robotic and laparoscopic urology 46 vol 18 no 1 january-february 2021 20 oscopic laser lithotripsy (url), and endopyelotomy at the obstruction site for stone or upjo treatment. we compared patients with ies history to those who did not undergo any prior ipsilateral surgery at obstruction site to evaluate the effect of ies on the outcome of ralp. during the follow-up, ctu or mru was used as the first choice in the postoperative imaging review. however, some patients chose ultrasound imaging for its convenience, lower price, and absence of radiation. the first examination was conducted one month after the double j stent removal, and then every six months. success was defined as symptomatic and radiological relief; symptomatic relief is accounted according to patients subjectively reporting that their pain has subsided and they are no longer using any pain medication. radiological success is achieved if the hydronephrotic state is not severed compared to before the surgery, and no apparent radiological evidence of any obstruction seen at the operated site. statistical analysis we have used version 16 of the software of statistical package for the social sciences (spss) to compare our data. fisher’s exact test was performed in all categorical data for the group comparison (except obstruction side in table 1 for which we performed a pearson’s chisquared test). for the continuous data, since data was not normally distributed, we performed a man-whitney u test to compare the groups, and the results are presented as median and range (except the bmi for which we performed a student t test and the results are shown as mean and ± sd). p < 0.05 was considered to be statistically significant. results of 114 patients, seventy-percent were symptomatic while the rest presented with asymptomatic hydronephrosis. transperitoneal approach with dismembered pyeloplasty was performed in all operations using da vinci® si robotic system under two experienced surgeons (each surgeon performed >1500 robotic procedures). the primary pyeloplasty group comprised of 101 subjects while the secondary pyeloplasty group contained 13 patients. of the 101 primary pyeloplasty patients, five anatomically complicated cases (three horseshoe kidneys, one duplicated system, and one retrocaval ureter) were excluded from the comparison analysis since these conditions could have extra surgical challenges and have a tendency to alter the results. the remaining 96 vs. 13 patients of primary vs. secondary ralp, respectively, were compared. table 1 shows the overall demographic data of the two groups. intraoperative and postoperative parameters are shown in table 2. the previous failed interventions of the secondary ralp group were five open pyeloplasties and eight conventional laparoscopic pyeloplasties, and the meantime from their primary surgery was 5.6 years (range, five months to 20 years). the surgical details of our approach have been previously well described by other investigators(4). a double j ureter stent was placed before the completion of each anastomosis (figure 1). no patient required conversion to an open approach. in the comparison analysis, none of the intraoperative and postoperative parameters we compared showed significant between the two groups. the primary ralp group contained two sets of patients; 32 patients who had prior ipsilateral upj surgeries (the list of their previous surgeries is shown in table 3), and 64 patients who did not have any previous ipsilateral surgery. 30 patients (two patients with a history of open lithotomy were excluded from this subgroup comparison) who previously underwent ies were compared with the 64 patients who did not receive prior ipsilateral surgery to evaluate the effect of ies on ralp outcome. the analysis results showed no significant difference between the two subgroups (table 4). we encountered one case of antegrade double j insertion failure in the primary ralp group, which required intraoperative use of a retrograde ureteroscope for stent placement. six patients required postoperative cystoscopic stent pulling into the bladder to prevent further stent migration. the ureter stent was challenging to be removed under cystoscope in one case, which required the use of ureteroscopy under general anesthesia. ten patients were lost to follow-up; for this reason, the results of the remaining 87 vs. 12 cases in primary vs. secondary ralp, respectively, were used when comparing the follow-up period and success rates. finally, table 3. list of previous ipsilateral surgeries procedure no. of patients mean time from previous intervention, year (range) ureteroscopic laser lithotripsy (url) 19 2.7 (6 month – 13 years) percutaneous nephrolithotomy (pcnl) 6 1.2 (1 month 3 year) both pcnl and url 3 6 (2 10 years) endopyelotomy 2 0.3 (3 month 4 month) open lithotomy 2 8 (7 – 9 years) parametera no previous endourological surgery previous endourological surgery p-value no. of patients 64 30 bmi, kg/m2; mean ± sd 22.2 ± 3.1 24 ± 3.6 .014 operative time (min); median (range) 140 (47 – 375) 137 (80 – 295) .984 ebl (ml); median (range) 10 (0 – 300) 0 (0 – 300) .136 los (days); median (range) 6 (3 – 14) 6 (4 – 14) .726 stent removal time (weeks); median (range) 8 (4 – 10) 8 (4 – 10) .544 follow-up (months); median (range) 26 (7 – 57) 25 (6 – 53) .917 recurrence rate, n (%) 4 (6.9) 1 (3.7) .999 abbreviations: ralp, robot-assisted laparoscopic pyeloplasty; ebl, estimated blood loss; los, length of hospital stays. a categorical and continuous (except bmi parameter) data were compared using fisher’s exact test and man-whitney u test, respectively. table 4. effect of previous ipsilateral endourological surgeries on outcome of ralp primary vs. redo robotic pyeloplasty in adults-isse dirie et al. vol 18 no 1 january-february 2021 47 in table 5, we have summarized previously published articles comparing primary vs. secondary ralp. discusion minimally invasive techniques and open approach for primary pyeloplasty are abundant in the literature, unlike redo pyeloplasty studies, which are very limited. one explanation could be the rarity of persistent and recurrent upjo due to the high success rates of the primary pyeloplasty, particularly when an open technique is utilized in the primary setting. several causes that may lead to the failure of the primary pyeloplasty have been suggested including; formation of periureteric fibrosis due to urine extravasation after pelviureteral anastomotic failure, thermal damage to the ureteral blood supply, and missed lower pole crossing vessel during the initial surgery(5). furthermore, the dissection and repair of failed pyeloplasty’s are technically very challenging, due to abdominal adhesions and periureteric fibrosis. techniques such as; placement of ureter stents, balloon dilations, and endopyelotomy are among the least invasive procedures for the management of upjo. some of the techniques were associated with superior surgical and clinical outcomes compared with others when dealing with recurrent upjo. for instance, abdel-karim et al. reported higher ebl and pain score, and prolonged operative time and los in open redo pyeloplasty (orp) compared with laparoscopic redo pyeloplasty (lrp)(5). similarly, a meta-analysis study comprising 88 lrp vs. 153 orp has shown significantly reduced los in the table 5. summary of published articles comparing primary vs. redo ralp author (year) no. of participants age (year) sex (m/f) crossing vessel (n) operative time (min) ebl (ml) primary/redo primary/redo primary/redo primary/redo primary/redo primary/redo atug (10) (2006) 37/7 32.8/37.8 (20/24)/ (2/5) 16/2 219.4/279.8 49.5/52.5 mufarrij (26) (2008) 117/23 38.2/40 (52/65)/ (14/5) 62/15 217.2/215.9 57.5/68.3 sivaraman (27) (2012) 147/21 37.8/36.0 (82/65)/ (12/9) 63/12 125.9/190.4 42.9/86.2 niver (28)(2012) 97/20 39.4/41.8 (41/56)/ (9/11) 64/16 218.7/217.9 62.8/98.8 thom (11) (2012) 46/9 41a 23/32a na 192/205 90/125 baek (9) (2018) 55/10 5.1/8.2 (40/15)/ (9/1) na/na 143.2/187.7 na/na current study 96/13 35.4/27.5 (65/31)/ (9/4) 7/1 150.2/170.5 40.5/85.4 author (year) complication rate conversion rate los (days) follow-up (months) successb rate (%) primary/redo primary/redo primary/redo primary/redo primary/redo atug (10)(2006) 0/0 0/0 1.1/1.2 13.5/10.7 100/100 mufarrij (26)(2008) 0/0 0/0 2.1/2.1 30.1/24.1 96.6/91.3 sivaraman (27) (2012)8/3 0/0 1.4/1.7 39a 97.6% a niver (28) (2012) 15/3 0/0 2.5/2.8 21.9/26 96.6/95 thom (11) (2012) 1a 1a na 16a 98/78 baek (9) (2018) 0/1 0/0 1.4/1.2 10.5/13.6 98.2/100 current study 21/3 0/0 6.3/6.6 27.4/28.1 94.3/75 abbreviations: bold data: indicates significance difference between the groups”; na; not available; a: only overall results were reported; b: success means “not requiring further intervention”; note: the results in the table are expressed as “mean values”. figure 1. robot-assisted laparoscopic dismembered pyeloplasty (ralp) a)urography image (contrast media is injected percutaneously and retrogradely). b)mru scan showing severe left kidney hydronephrosis due to upjo c)ct scan taken 1 year after left side ralp d)robotic dissection at the upj area e)performing robotic dismembered pyeloplasty f)d-j stent placement before pelviureteral anastomosis completion primary vs. redo robotic pyeloplasty in adults-isse dirie et al. robotic and laparoscopic urology 48 lrp with no significant difference in the success rate, although the operative time was shorter in the orp(6). furthermore, endopyelotomy technique as a secondary intervention has also shown to decrease the los compared with orp(7). however, the success rates were significantly higher in lrp compared with endopyelotomy, 87.5% vs. 74%, respectively(8). recognizing the increased challenge when doing subsequent reconstructive surgeries, we expected a significant rise in surgical time, complication rates, and ebl in redo pyeloplasty. nevertheless, our analysis failed to show any significant difference in terms of operative time, ebl, complication rates, and recurrence. unlike ours, baek et al.(9) and atug et al.(10) found significantly longer operative time, console time, and dissecting time in the secondary ralp group when compared with primary ralp. thom et al.(11) have also significantly increased ebl in the redo robotic pyeloplasty compared with primary ralp. similarly, a newly published meta-analysis study by dirie et al.(12) (containing; 613 vs. 107 patients in primary vs. redo ralp, respectively) found significantly increased operative time, ebl, and recurrence in redo robotic pyeloplasty compared with primary ralp. on the other hand, the literature concerning previous abdominal surgeries (pas) and their impact on the subsequent abdominal surgeries are conflicting; some reported that pas has no adverse effect on secondary operations(13) while others reported the opposite. two recent studies; one laparoscopic radical cystectomy and one robot-assisted laparoscopic partial nephrectomy have found a higher ebl in those patients who had previous major abdominal surgery compared to those who did not(14,15). conventional laparoscopy in redo pyeloplasty has shown poor outcomes when compared with laparoscopic primary pyeloplasty. nishi et al. found an increased operative time, ebl, and complication rates in lrp when compared with secondary laparoscopic pyeloplasty(16). additionally, the longer learning curve and the technical challenges related to mastering intracorporeal suturing skills made conventional laparoscopy less popular approach than robotics in reconstructive urology. however, we should acknowledge the newly emerged technologies in traditional laparoscopy such as 3d laparoscopic cameras and robotized laparoscopic needle drivers; these technologies have demonstrated improved surgical outcomes in reconstructive surgeries (17,18). improvements in conventional laparoscopy could be appreciated considering the higher cost required to purchase and maintain robotic machines, especially for those medical centers with smaller budgets. robot-assisted laparoscopy has been the cornerstone surgical modality for reconstructive urology including ralp surgery since its birth in the early 2000s. robot-assisted laparoscopy has an excellent surgical and clinical record in both adults and children in the primary pyeloplasty. autorino and colleagues(19) presented the largest review study to date in which they have critically analyzed a large data concerning robotic and laparoscopic pyeloplasty. of the 841 ralp adult cases reviewed in the study, the operative time ranged between 105-335minutes with only three conversions while reintervention and success rates were 1.8-13.1% and 81-100%, respectively. compared with the conventional laparoscopy, significantly shorter operative time, suturing time, and los were found in ralp(20). similarly, another study linked ralp with significantly improved obstruction, pain, and fewer secondary intervention needed(21). furthermore, hemal et al. reported 10 cases of redo ralp with a 100% success rate after 7.4 months of mean follow-up (22). despite the growing popularity and the outstanding results with robotic surgeries, the high direct and indirect costs to purchase and maintain it makes robotic surgeries economically less competitive than open approach(23). besides the technique utilized, one should keep in mind that there are other factors such as the surgeon’s experience, the preoperative severity of hydronephrosis, and renal function which can influence the surgical and clinical outcomes after pyeloplasty repair. for instance, some studies associated poor preoperative renal function and severe hydronephrosis with increased failure rates after the surgery(24,25). there are some limitations in our study that must be addressed such as; the retrospective nature, lack of long-term follow-up since failure can be seen even after many years later, lack of urographic imaging in all cases in the follow-up, and the small sample size of our cohort. conclusions according to the existing literature and our current study, robot-assisted laparoscopic pyeloplasty is an excellent surgical approach in primary pyeloplasty. furthermore, our data failed to show any significant difference in terms of surgical and clinical outcomes between primary and redo pyeloplasty, perhaps the smaller data in our redo pyeloplasty. however, one must be aware the increased surgical challenges and the higher recurrence after surgery in the redo pyeloplasty according to the other similar literature we reviewed including recently published meta-analysis study. acknowledgement authors are grateful to dr. magdalena f. dennis and jama yasin farah for correcting the language. special thanks to mr. wilhellmuss mauka and mr. olotu frank for providing advices about statistics. conflict on interest authors declare that there is no conflict of interest to disclose. references 1. bansal p, gupta a, mongha r, narayan s, das rk, bera m, et al. laparoscopic versus open pyeloplasty: comparison of two surgical approachesa single centre experience of three years. indian j surg. 2011;73:264-7. 2. dy gw, hsi rs, holt sk, lendvay ts, gore jl, harper jd. national trends in secondary procedures following 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urol. 2012;187:522-7. 22. hemal ak, mishra s, mukharjee s, suryavanshi m. robot assisted laparoscopic pyeloplasty in patients of ureteropelvic junction obstruction with previously failed open surgical repair. int j urol. 2008;15:7446. 23. rowe ck, pierce mw, tecci kc, houck cs, mandell j, retik ab, et al. a comparative direct cost analysis of pediatric urologic robotassisted laparoscopic surgery versus open surgery: could robot-assisted surgery be less expensive? j endourol. 2012;26:871-7. 24. patel t, kellner cp, katsumi h, gupta m. efficacy of endopyelotomy in patients with secondary ureteropelvic junction obstruction. j endourol. 2011;25:587-91. 25. grimsby gm, jacobs ma, gargollo pc. success of laparoscopic robot-assisted approaches to ureteropelvic junction obstruction based on preoperative renal function. journal of endourology. 2015;29:874-7. 26. mufarrij pw, woods m, shah od, palese ma, berger ad, thomas r, et al. robotic dismembered pyeloplasty: a 6-year, multi-institutional experience. j urol. 2008;180:1391-6. 27. sivaraman a, leveillee rj, patel mb, chauhan s, bracho je, 2nd, moore cr, et al. robot-assisted laparoscopic dismembered pyeloplasty for ureteropelvic junction obstruction: a multi-institutional experience. urology. 2012;79:351-5. 28. niver be, agalliu i, bareket r, mufarrij p, shah o, stifelman md. analysis of roboticassisted laparoscopic pyleloplasty for primary versus secondary repair in 119 consecutive cases. urology. 2012;79:689-94. primary vs. redo robotic pyeloplasty in adults-isse dirie et al. robotic and laparoscopic urology 50 urol_v03_no4_001_editorial.indd case report 245urology journal vol 3 no 4 autumn 2006 angiography and segmental artery embolization in renal stab wound mohammadreza barghi, mohammadreza rahmani, hamidreza haghighatkhah urol j (tehran). 2006;4:245-6. www.uj.unrc.ir keywords: angiography, therapeutic embolization, stab wounds department of urology, shohada-etajish hospital, shaheed beheshti university of medical sciences, tehran, iran corresponding author: mohammadreza barghi, md department of urology, shohada-etajrish hospital tajrish sq, tehran, iran tel: +98 912 384 8723 e-mail: urorahmanireza@yahoo.com received october 2005 accepted july 2006 introduction delayed or secondary renal bleeding may occur in up to 25% of cases with grade 3 and grade 4 injuries to the kidney, especially in stab wounds, when they are managed conservatively. the average interval between the injury and the onset of secondary hemorrhage is approximately 12 days (range, 2 to 36 days) and is most often due to an arteriovenous fistula (avf) or pseudoaneurysm.(1) an initial management of bed rest and hydration is performed routinely. in case of persistent bleeding, definite diagnosis is usually made by angiography, and selective embolization can be performed within the same angiography session as a definite treatment. open exploration and partial or total nephrectomy are rarely required.(1,2) we report a case of delayed renal bleeding following stab wound which was treated successfully by angioembolization. case report a 17-year-old man was referred to our clinic with intermittent gross hematuria. he had a history of the right flank stab wound about 2 weeks earlier. his vital signs were stable. the patient was admitted and observed for 6 days, and hematuria persisted within this period. abdominal ct scan revealed subcapsular hematoma in the lower pole of the right kidney and a parenchymal laceration greater than 1 cm, without the rupture of the collecting system or urinary extravasation, which suggested a grade 3 injury. on renal angiography, bleeding was detected from the segmental renal artery of the lower pole (pseudoaneurysm) of the right kidney (figure 1). embolization was then performed promptly using a 5-f cobra-ii catheter (cordis, miami, fl, usa) and a 0.018-inch soft platinum microcoil (cook, bloomington, in, usa) as the embolizing agent (figure 2). hematuria ceased completely and the patient was discharged two days thereafter. figure 1. angiography was indicative of a bleeding segmental renal artery (pseudoaneurysm). segmental artery embolization in renal stab wound—barghi et al 246 urology journal vol 3 no 4 autumn 2006 discussion delayed or secondary hemorrhage is a common complication of the deep lacerations of the renal cortex and medulla, especially in stab wounds.(1) it is most often a result of an avf or pseudoaneurysm.(2) when the laceration of a large segmental branch of the renal artery exists, bleeding from the lacerated vessel is stopped temporarily due to the tamponade effect of the hematoma. with resolution of the hematoma, the artery rebleeds into the resultant cavity and forms a pseudoaneurysm. when the hematoma resulted from the laceration of a large branch of the renal artery and a large nearby vein is resolved, the arterial branch rebleeds and will be drained into the lacerated vein. this leads to the formation of an avf. in case of penetrating trauma, a connection often exists between the collecting system and the resolving hematoma cavity; thus, bleeding from the avf or pseudoaneurysm drains directly into the pyelocaliceal system and a very rapid blood loss may occur.(3) therapeutic embolization for treatment of the injuries to the renal artery branch was first described in 1973 by bookstein and goldstein who successfully treated the hemorrhage following renal biopsy.(4) ulfacker and colleagues reported successful selective embolization in 14 out of 17 patients (82%) with renovascular lesions induced by penetrating injury in 10 and blunt trauma in 7.(5) fisher and coworkers treated renal artery branch lesions by embolization in 15 patients (8 of them were injured in street knifings) and achieved hemostasis in all.(6) kantor and colleagues performed renal embolization for arterial bleeding in 20 patients (13 of whom had penetrating injuries) and successfully controlled hemorrhage in 19 (95%).(7) in addition, using angioembolization, we can lower the risk of total renal loss in comparison with that in surgical exploration of the kidney.(8)in conclusion, these reports demonstrate successful selective renal artery embolization for managing secondary hemorrhage in stable patients after penetrating renal trauma. conflict of interest none declared. references 1. heyns cf, de klerk dp, de kock ml. stab wounds associated with hematuria--a review of 67 cases. j urol. 1983;130:228-31. 2. heyns cf, van vollenhoven p. selective surgical management of renal stab wounds. br j urol. 1992;69: 351-7. 3. heyns cf. renal trauma: indications for imaging and surgical exploration. bju int. 2004;93:1165-70. 4. bookstein jj, goldstein hm. successful management of postbiopsy arteriovenous fistula with selective arterial embolization. radiology. 1973;109:535-6. 5. uflacker r, paolini rm, lima s. management of traumatic hematuria by selective renal artery embolization. j urol. 1984;132:662-7. 6. fisher rg, ben-menachem y, whigham c. stab wounds of the renal artery branches: angiographic diagnosis and treatment by embolization. ajr am j roentgenol. 1989;152:1231-5. 7. kantor a, sclafani sj, scalea t, duncan ao, atweh n, glanz s. the role of interventional radiology in the management of genitourinary trauma. urol clin north am. 1989;16:255-65. 8. blankenship jc, gavant ml, cox ce, chauhan rd, gingrich jr. importance of delayed imaging for blunt renal trauma. world j surg. 2001;25:1561-4. figure 2. angiography after the successful embolization. review prevalence of infertility in iran: a systematic review and meta-analysis marzieh saei ghare naz1, giti ozgoli2*, koroush sayehmiri3 purpose: in the present study, a systematic review and meta-analysis was conducted to determine the prevalence of infertility in iran. materials and methods: a search of studies was performed in june 2019 on scopus, pubmed, web of science (wos), scientific information database (sid), magiran, irandoc and google scholar using keywords related to infertility. the search for articles was limited to those published over the past 20 years in persian and english languages. in this research, only population-based studies were included. results: the results of the analysis showed that the overall prevalence of infertility was 7.88%, 95% ci: 5.6110.51. the prevalence of primary and secondary infertility after sensitivity analyses was 3.09%, 95% ci: 2.274.02 and 2.18%, 95% ci: 1.56-2.89, respectively. the slope of meta-regression line showed that the prevalence of primary (p = .7) and secondary infertility (p = .4) is rising with a slow slope in iran. conclusion: it is emphasized that the results of this study are related to the areas where investigations have been conducted and that there is high heterogeneity in findings. given that information is not available in all parts of iran, a population-based study or the design and implementation of further research is suggested. keywords: infertility; iran; prevalence; meta-analysis introduction globally, infertility is a prevalent problem among couples that affects over 186000000 people worldwide, and most of its social burden is on women(1,2). infertility is defined as the lack of pregnancy after twelve months of unprotected sex(3). in a number of developing countries, as well as in iran, childbearing is a social value for married women (4). therefore, couples who experience this critical condition are at risk of depression, anxiety, low self-esteem, dissatisfaction(5,6), and reduced quality of life(7), not to mention a further significant economic burden for the couple and the society(8). various studies have proposed several infertility risk factors including alcohol consumption, chronic diseases, overweight, smoking(9), exposure to environmental toxins, coping with stress(10), consumption of fried foods(12), and higher age of marriage(12). the evidence shows that 21-22% of iranian women suffer from lifetime primary infertility(13), while different infertility rates have been reported in various parts of the world. a study in canada shows 11.5-15.7% prevalence of infertility(14). in another study in china on women of fertility age, infertility rate has been reported at 25% (15) while studies on the incidence rate of infertility in nigeria and britain have reported it at 15.7% and 12.5%, respectively(16,17). in a meta-analysis study in iran examining the pub1student research committee, reproductive endocrinology research center,research institute for endocrine sciences, shahid beheshti university of medical sciences,tehran,iran. 2department of midwifery and reproductive health, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. 3faculty of health, department of biostatistics, ilam university of medical sciences, ilam, iran. *correspondence: department of midwifery and reproductive health, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. tel/ fax: +98 21 88202512, e-mail: g.ozgoli@gmail.com. received september 2019 & accepted december march 2020 lished studies of 2001-2011, the primary and secondary infertility rates have been reported as 5.2 and 3.2%, respectively. it has been reported that infertility has an incremental trend in iran(18) and a meta-analysis study has shown that approximately 10% of the world’s population suffers from infertility(19). direkvand moghadam (2015) et al. conducted a meta-analysis study about the trend of infertility in iran, in which the search for articles was carried on up to 2011(20). another systematic review and meta-analysis was performed on epidemiology and etiology of infertility in iran in 25 recent years until 2012(21). these studies include a large number of investigations about infertility in iran. in this research, we aimed to include the population-based studies. since meta-analysis is a quantitative, formal, and epidemiological research design used for the systematic evaluation of previous studies to reach a conclusion about a collection of research works,(23) it has been used in the current investigation to determine the prevalence of infertility in iran based on population based studies. materials and methods search strategy and data sources this study is related to a project in shahid beheshti university of medical sciences. the prisma checklist was used a search of articles for the study was conurology journal/vol 17 no. 4/ july-august 2020/ pp. 338-345. [doi: 10.22037/uj.v0i0.5610 ] ducted in june 2019 by two independent investigators and the disagreement between the investigators was resolved by consensus. the authors limited the electronic search of papers to the last 20 years, which was done across the databases of scopus, pubmed, web of science (wos), scientific information database (sid), magiran, irandoc and google scholar. the search for articles was limited to persian and english languages over 2000-2019. also, a manual search was conducted among the references included in the articles. the search process and study selection was performed by two independent reviewers and any disagreement between the reviewers was solved by a third person. search strategy the study used the following keywords: infertility, sub hypofertility, reduced fertility, sterility, prevalence, iran, which were combined with ‘or’ and ‘and’ operators. inclusion and exclusion criteria inclusion criteria for the research were as follows: cross-sectional population-based or community based studies, married life >1 year and mentioned prevalence of primary (not becoming pregnant about one year after unprotected intercourse based on the who standard), or secondary (couples who were pregnant at least once before), or lifetime infertility or primary lifetime infertility (couple had experienced primary infertility in their life). studies such as review, letter to editor, case report, case control, case series as well as those with irrelevant results were excluded. data extraction the main outcome in this study is the prevalence of overall, primary and secondary infertility. in this research, two researchers participated in data extraction table 1. summary of studies reviewed in this study. author/ location population infertility rate quality assessment year/ current life secondary overall urban rural references primary time selection comparability outcome primary afroughi kohgiluyeh 2284 couples, 249 152 97 ***** * ** (2019)(49) va boyer aged upper (10.9%) (10%) (12.7%) ahmad than 15 yr mirzaei yazd 2611 women 81 75 135 ***** * *** (2018)(50) aged 20-49 yr (2.6%) (2.1%) (4.73%) rostami golestan, 888 women 57(6.4%) 238 69 ***** * ** hormozgan gazvin, 18-45 yr. (21.1%) (7.8%) dovom kermanshah, (2014) (51) hosseini esfahan, 2296 women 72(3.2%) 599 40 ***** * ** (2012)(52) hormozgan, 18-49 yr. (26.1%) (1.7%) kermanshah, golestan esmaeilzadeh babol 1140 women 47(4.3%) 132 20 ***** * ** (2012) (53) 20-45 yr. (12.2%) (1.9%) akhondi national 17187 women 3472 ***** * ** (2013) (54) aged 20-40 (20.2%) kazemijaliseh tehran 1067 women 185 ***** * *** (2015) (55) 18-45 yr (17.3%) aflatoonian yazd 5200 couples 170 107 277 144 133 ***** * ** (2009) (56) 18-65yr (3.48%) (2.04%) (5.52%) (6.8%) (5.3%) esmaelzadeh mazandaran 2953 couples 16(4%) 351 38 389 14.4% 12.3% **** * * mogadam (57) (11.9%) (1.3%) (13.2%) badr tabriz 2623 couples 54 34 88 ***** * ** (2006) (58) whose wives (2.05%) (1.30%) (3.35%) were at their reproductive age vahidi national 10783 women 368 2685 ***** * ** (2009) (59) 19-49yr. (3.4%) (25.2%) safarinejad national 11441 women 526 389 915 ***** * ** (2006) (60) 15-50 yr. (4.6%) (3.4%) (8%) nojomi tehran 1174 women 18 98 43 141 ***** * ** (2002) (61) 40-50 yr. (1.5%) (8.3%) (3.7%) (12%) shafi babol 1081 women 46 168 **** * * (2016) (62) 20-45 yr. (4.25%) (15.5%) prevalence of infertility in iransaei, ghare naz et al. vol 17 no 04 july-august 2020 339 phases. after the article search, a preliminary assessment of the title or abstract of all articles was done and those that had reported the prevalence of total, primary, primary lifetime or secondary infertility were included in the next level of assessment. in the next stage, the researchers extracted a list of required information, including the prevalence of infertility, the place and time of the study, and the causes of infertility. the two researchers were provided a checklist of information required for systematic evaluation, including the name of the researcher, title of the article, year and place of the study, sample number and collection method, study type, measurement tool, infertility, the overall prevalence of infertility, as well as the primary and secondary prevalence of infertility. in overall all items related to picos such as participants, comparisons, outcomes, and study design were extracted. risk of bias and quality assessment a valid and reliable tool, namely newcastle-ottawa quality assessment scale adapted for cross sectional studies, was used for quality assessment of the relevant studies. according to this tool, studies with a score of five stars or more were included into the current study. furthermore, this scale examined the methodology of the studies such as representativeness of the sample, sample size, non-respondents, ascertainment of the exposure comparability, assessment of the outcome, statistical test measurement criteria(23). table 1 shows the results of bias risk and quality assessment. statistical analysis effect size in this study was the prevalence of infertility, the variance of which (with 95% confidence interval) was calculated using the binomial distribution. the effect size of individual studies is calculated by weighting each one of them by its inverse variance, and a confidence interval (ci) is thus obtained(24). each study was weighted inversely proportional to its variance. to calculate the variance of each research, a binomial distribution was used. the q statistics and i2 index with α significance level of <10% were used to investigate heterogeneity. in this research, the random-effects model is considered when there is heterogeneity among the studies (i2> 50%)(25). the authors used the begg's and egger's test to check publication bias(26). in our investigation, metaprop command in stata was used to stabilize the variances(27). meta-regression, sensitivity analysis and sub group analysis were employed to evaluate the potential source of heterogeneity and possible source of bias. for unmeasured confounding factors, the sensitivity analyses were used for estimation of the true effect of sizes(28) and stata software (version 11.2) was our tool for data analysis. results this research was based on the prisma (preferred reporting items for systematic reviews and meta-analyses) checklist. in this study, 14 population-based studies were entered into the final analysis phase (table 1). the number of participants in this study was 62728 and figure 1 shows the process of article selection. we used sensitivity analysis for obtaining reliable results and in order to ensure the stability of the results the sensitivity analysis have been used. the results of the analysis showed that the overall prevalence of infertility in seven studies was 7.88%, 95% ci: 5.61-10.51%, q = 323.63, p < .001. the current primary infertility prevalence rate in 12 studies was 4%, 95% ci: 1.4-7.85%, but after sensitivity analyses, the primary infertility prevalence rate in 11 studies was 3.09%, 95% ci: 2.27-4.02%, q = 245.14, p < .001. the secondary infertility prevalence rate in nine studies was 2.59%, 95% ci 1.82-3.49%, but after sensitivity analyreview 340 sub group analyze primary prevalence overall prevalence secondary prevalence no prevalence i2 p no prevalence i2 p no prevalence i2 p of studies (95% ci) of studies (95% ci) of studies (95% ci) time course 2000-2010 5 2.39 97.72 < 0.001 2 7.6 0 < 0.001 4 3.15 95.29 < 0.001 (1.38-3.66) (6.88-8.36) (1.48-5.42) 2010-2019 6 4.04 80.67 < 0.001 5 7.93 98.51 < 0.001 5 2.22 95.36 < 0.001 (3.08-5.12) (5.12-11.28) (1.36-3.29) location urban 3 9(4.9-14.18) 98.51 < 0.001 rural 3 6.92 98.7 < 0.001 (3.16-11.97) table 2.the result of subgroup analysis. figure 1. flowchart of article selection. prevalence of infertility in iransaei, ghare naz et al. ses, the secondary infertility prevalence rate in 8 studies was 2.18%, 95% ci: 1.56-2.89%, q = 150.92, p < .001. also, the primary lifetime prevalence in eight studies was 13.96% 95% ci: 7.94-21.34%, q = 1329.38, p < .001. figures 2-4 shows the prevalence of overall infertility, current primary infertility, and secondary infertility. according to the results of begg's test (p = .484) and egger's test (p = .466), there was no publication biases in this study, and because of heterogeneity, the random effect model was used (figure 5). subgroup analysis and meta-regression: in this study meta-regression, investigating the association between prevalence of current primary, overall and secondary infertility was investigated based on publication date of studies (figure 6). the positive slope of meta-regression line showed that the prevalence of primary (p = .7) and secondary infertility (p = .4) in iran was rising with a slow slope based on year and that the overall prevalence had a downward trend (p = .7), which was not significant. table 2 shows the result of subgroup analysis. our study showed that over the period of (2000-2010) to (2010-2019), the prevalence of current primary infertility increased from 2.39% to 4.04%, the overall prevalence slowly increased from 7.6 % to 7.93%, and secondary prevalence decreased from 3.15% to 2.22%. the prevalence of infertility in urban areas in the three reported studies was 9%, 95% ci: 4.9%-14.18%, q = 134.58, p < .001 and in rural areas, it was 6.92%, 95% ci: 3.16-11.97%, q = 154.27, p < .001. discussion this review study on 62728 persons in iran indicated that the overall prevalence of infertility was 7.88%, the current primary and secondary infertility prevalence was 3.09% and 2.18%, respectively and the lifetime primary infertility was 13.96%. for accurate estimation of infertility, we measured the figure 2. prevalence of overall infertility by researcher, year, prevalence and 95% confidence interval in iran. each line segment indicates a confidence interval of 95%. the diamond mark shows the in all regions. figure 3. prevalence of current primary infertility by researcher, year, prevalence and 95% confidence interval in iran. each line segment indicates a confidence interval of 95%.the diamond mark shows the in all regions. prevalence of infertility in iransaei-ghare naz et al. vol 17 no 04 july-august 2020 341 prevalence of infertility only based on population-based studies. there is little difference between our findings and previous studies. estimation of the prevalence of infertility is confronted with several practical difficulties(29) and there is inconsistency between infertility definitions in different studies(29). parsanezhad et al. conducted a systematic review and metaanalysis on epidemiology and etiology of infertility in iran over the recent 25 years until 2012, the results of which showed that the average rate of infertility in iran is 10.9% (21). in a systematic review study in 2013 wherein the trend of infertility prevalence in iran was reported from nine investigations, the prevalence of overall infertility was reported as 13.2%, average primary infertility was 5.2%, and secondary infertility was 3.2% (30). compared with the two previous reviews, our research included 14 studies. it seems that diverse study populations and newly published studies in the past six years result in different findings in this research. in different regions of world, studies report different prevalence rates. in an investigation in saudi arabia, the overall prevalence of infertility was 18.93% (31). zhang et al reported an incremental trend of infertility in beijing (32). in a study in colombo, the prevalence rate of primary infertility was 40.5 among 1000 women in their reproductive age, and the prevalence of secondary infertility was 160 among 1000 women at the same age (33). in another research in india, the primary infertility prevalence rate was 12.6% (34). a study in a gambian population showed the prevalence rate of infertility as 14.3%, of which 33.9% had primary infertility and 59.1% had secondary infertility (35). the result of our study showed that in the time course of 2000 to 2019, the prevalence of current primary infertility increased from 2.39% to 4.04%, the overall review 342 figure 4. prevalence of secondary infertility by researcher, year, prevalence and 95% confidence interval in iran, each line segment is indicative of a confidence interval of 95%. the diamond mark shows all the regions. figure 5. funnel plot for checking publication bias figure 6. meta-regression diagram: investigating association between prevalence of current primary (a) overall (b) and secondary (c) infertility, based on publication year of studies. prevalence of infertility in iransaei-ghare naz et al. prevalence slowly increased from 7.6 % to 7.93%, and secondary prevalence decreased from 3.15% to 2.22%. in a 2007 study, it has been reported that approximately 72.4 million infertile people exist globally, of which 40.5 million people were in search of treatment(36). but according to the global estimation of infertility in 195 countries, the infertility and disability-adjusted life years related to the infertility had an increasing trend from 1990 to 2017(37). a study in africa has reported that despite the reduced prevalence of primary infertility, the prevalence of secondary infertility is on the rise(38). an investigation in turkey has shown that the prevalence trend of infertility has declined from 19932013(39). global trends in infertility showed that the level of primary infertility was decreased in south asia from 1990 to 2010(40). the best age for marriage of iranian women is 20-27, which has the lowest prevalence rate of infertility(13). social change in communities, increased marriage age and delayed pregnancy in today’s couples play an important role in infertility(41). factors such as the marriage age, environmental pollution, smoking and alcohol consumption, and lifestyle are involved in infertility(42). therefore, change of lifestyle, control of chronic diseases, as well as fast and timely treatment of sexually transmitted diseases can increase the chance of fertility in women(43). also, training strategies to increase awareness of couples in the field of reproductive health can be effective in the prevention of infertility(44). our finding showed that the prevalence of infertility in urban areas in three reported studies was 9%, 95% ci: 4.9%-14.18% and in rural areas of the three reported studies, it was 6.92%, 95% ci: 3.16-11.97%. according to evidence, urban fertility starts to drop earlier than rural fertility in developing countries, and it seems that rural‐to‐urban migration and higher rate of childbearing among them tends can lead this decreasing trend(45). cultural and socio-economic factors, health care performance, and environmental factors can have an effect on the prevalence of infertility in each region(46). prevalence and types of etiology of infertility are different in each geographic location(47). there is limited information about the prevalence of infertility in developing countries(49). some evidence suggests that the social, economic, and psychological burden of infertility might be higher among infertile men and women in developing countries(49). a reason for relatively high rate of infertility in iran is that it is too late for many of these women to become pregnant. also, statistics in urban and rural areas are changing due to the dominant culture of the region. one of the weak points of this study was its high heterogeneity. another limitation of the study was that there were no relevant researches from different parts of the country that may affect the prevalence rate of infertility in iran, which precludes the generalization of our finding to all regions of iran. the strength of our study is that only population-based studies were included in it. conclusions it is emphasized that the results of this study are related to the areas where studies have been conducted. given that information is not available in all parts of iran, a population-based investigation or the design and implementation of further studies are suggested. acknowledgement this study is related to a project from shahid beheshti university of medical sciences, tehran, iran. we also appreciate the “research & technology chancellor” in shahid beheshti university of medical sciences for 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and territories, 1990–2017: results from a global burden of disease study, 2017. aging (albany ny). 2019;11:10952. 38. larsen u. primary and secondary infertility in sub-saharan africa. int j epidemiol. 2000;29:285-91. 39. sarac m, koc i. prevalence and risk factors of infertility in turkey: evidence from demographic and health surveys, 1993–2013. j biosoc sci. 2018;50:472-90. 40. mascarenhas mn, flaxman sr, boerma t, vanderpoel s, stevens ga. national, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. plos med. 2012;9:e1001356. 41. brugo-olmedo s, chillik c, kopelman s. definition and causes of infertility. reprod biomed online. 2001;2:173-85. 42. macaluso m, wright-schnapp tj, chandra a, et al. a public health focus on infertility prevention, detection, and management. fertil steril. 2010;93:16. e1-. e0. 43. direkvand-moghadam a, delpisheh a, khosravi a. epidemiology of female review 344 prevalence of infertility in 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primary infertility in iran in 2010. iran j public health. 2013;42:1398. 55. kazemijaliseh h, tehrani fr, behboudigandevani s, hosseinpanah f, khalili d, azizi f. the prevalence and causes of primary infertility in iran: a population-based study. glob j health sci.2015;7:226. 56. aflatoonian a, seyedhassani sm, tabibnejad n. the epidemiological and etiological aspects of infertility in yazd province of iran. int j reprod biomed. 2009;7:117-22. 57. mogadam ae, karimpur a, talebpur amiri prevalence of infertility in iransaei-ghare naz et al. f, taringo f. the prevalence of infertility in central mazandaran in 2000. j mazandaran univ med sci . 2000;10:12-8. 58. badr yaa, madaen k, ebrahimi sh, nejad ahe, koushavar h. prevalence of infertility in tabriz in 2004. urol j. 2009;3:87-91. 59. vahidi s, ardalan a, mohammad k. prevalence of primary infertility in the islamic republic of iran in 2004-2005. asia pac j public health. 2009;21:287-93. 60. safarinejad mr. infertility among couples in a population‐based study in iran: prevalence and associated risk factors. int j androl. 2008;31:303-14. 61. nojomi m, ashrafi m, koohpayehzadeh j. study of couples infertility in the west of tehran, in the year of 2000. razi journal of medical sciences. 2002;8:633-9. 62. shafi h, agajani delavar m, esmaeilzadeh s. comparing the prevalence of infertility in urban and rural areas in babol. j mazandaran univ med sci. 2016;25:335-9. vol 17 no 04 july-august 2020 345 1157vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l acute infection of a documented seminal vesicle cyst via hematogenous seeding william c. palmer,1 neal c. patel,2 johnathan r. renew,3 mellena d. bridges,4 fernando f. stancampiano5 keywords: seminal vesicles; cysts; genital diseases; complications; microbiology; abscess. introduction genital abnormalities have been reported in up to 12 percent of men with unilat-eral renal agenesis.(1) there have also been reports of neurofibromatosis patients manifesting ipsilateral renal agenesis.(2) abnormal development of the mesonephric duct between the fourth and thirteenth week of embryonic life seems to be the origin of such cysts, which can have a variable clinical presentation.(3) the presence of seminal vesicle cysts in patients with renal agenesis is well documented.(4,5) approximately 68 percent of all seminal vesicle cysts are associated with renal agenesis.(1) here we report a 26-year old patient with neurofibromatosis type 1, unilateral renal agenesis, and a known seminal vesicle cyst who presented to the emergency department with bacteremia caused by an infected dual lumen hemodialysis catheter. case report a 26-year old caucasian male with a history of neurofibromatosis type 1 and left renal agenesis was admitted to the hospital because of perineal pain and fever. twelve days earlier, he had been found to have methicillin-sensitive staphylococcus aureus (mssa) bacteremia, which was treated with intravenous antibiotics (vancomycin, piperacillin-tazobactam, and nafcillin) and dual-lumen hemodialysis catheter removal. simultaneous blood cultures obtained from the new dialysis catheter and periphery at the time of admission were negative and a computed tomography (ct) without contrast of the abdomen and pelvis revealed the acute expancorresponding author: william palmer, md 4500 san pablo road south, jacksonville, fl usa tel: +1 904 953 2000 fax: +1 904 953 0655 email: palmer.william@mayo.edu received october 2011 accepted october 2011 1 division of gastroenterology, mayo clinic, jacksonville, fl usa 2 division of gastroenterology, mayo clinic, arizona, usa 3 division of anesthesiology, mayo clinic, jacksonville, fl usa 4 division of radiology, mayo clinic, jacksonville, fl usa 5 division of internal medicine, mayo clinic, jacksonville, fl usa case report 1158 | sion of a left seminal vesicle cyst with a displaced bladder (figure 1). the first documented visualization of the 6 × 5 × 9 cm cyst by ct scan had been 17 months earlier. failed foley catheter placement by the urology team and the need for more definite evaluation of anatomy prompted further imaging. a magnetic resonance image (mri) without contrast demonstrated an 11.5 × 9 × 3.4 cm cystic mass compressing the bladder anteriorly, which was consistent with a large infected left seminal vesicle cyst (figure 2). percutaneous drainage of the cyst yielded 720 ml of dark fluid at the time of placement, and another 400 ml over the next several days via an indwelling drain. culture of the fluid showed methicillin-sensitive staphylococcus aureus with the same sensitivity pattern as the positive blood culture that was performed during the previous hospitalization. the drain was removed and the patient was discharged on vancomycin. blood cultures drawn two weeks later remained negative but the patient required transurethral unroofing of the cyst due to recurrence of the abscess. discussion patients with seminal vesicle cysts can present with dysuria, epididymitis, prostatitis, or simply vague pain complaints of the lower abdomen, perineum, scrotum or lower back.(6) however, patients with small cysts found incidentally often require no intervention.(7) there has been at least one case report of a chronic seminal vesicle cyst infections in which pain was not present, with the only symptoms being urinary frequency and nocturia.(6) imaging techniques depend on presentation and clinical intuition. however, all have limitations. vesiculography calls for general anesthesia and radiation exposure, along with needle insertion through the scrotal sac and vas deferens.(8) transrectal ultrasound is invasive and limited by low resolution and soft-tissue contrast.(7) mri can provide more information regarding tissue density and characteristics than any of the other imaging modality. this is key in determining whether the fluid inside the cyst is thin, proteinaceous, or hemorrhagic. however, mri has its own drawbacks. it is more expensive than ct, and the administration of gadolinium may be contraindicated in renal patients due to the risk of nephrogenic systemic fibrosis.(9) this case suggests that, the threshold to use mri to assess the cyst for infection should be low. in low risk patients with a recent abdominal image that can be used for comparison, a contrast-assisted ct scan is reasonable to assess cyst anatomy. however, in light of the need for very accurate soft tissue differentiation in diagnosing an infected figure 1. non-contrasted ct on the day of admission showed a large fluid filled structure, thought to be bladder. figure 2. mri without contrast showing infection of a giant seminal vesicle cyst. case report 1159vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l seminal vesicle cyst infection | palmer et al seminal vesicular cyst, high clinical suspicion for infection should steer clinical management toward a non-contrasted mri in order to make both the diagnosis and the appropriate therapeutic decisions. conflict of interest none declared. references 1. case records of the massachusetts general hospital. weekly clinicopathological exercises. n engl j med. 1980;302:124651. 2. demierre mf, gerstein w. segmental neurofibromatosis with ipsilateral renal agenesis. int j dermatol. 1996;35:445-7. 3. gallmetzer j, gozzi c, dolif r, salsa a. seminal vesicle cyst (and ejaculatory duct cyst) with ipsilateral renal agenesis. report of five cases and review of literature. minerva urol nefrol. 1999;51:27-31. 4. denes ft, montellato ni, lopes rn, barbosa filho cm, cabral ad. seminal vesicle cyst and ipsilateral renal agenesis. urology. 1986;28:313-315 5. rappe bj, meuleman ej, debruyne fm. seminal vesicle cyst with ipsilateral renal agenesis. urol int. 1993;50:54-6. 6. chen tw, yang zg, li y, zhou p, qian ll, zhang sf. chronic infection of seminal vesicle cyst as depicted on mr imaging. korean j radiol. 2008;9 suppl:s73-6. 7. carter ss, shinohara k, lipshultz li. transrectal ultrasonography in disorder of the seminal vesicles and ejaculatory ducts. urol clin north am. 1989;16:773-90. 8. dunnick nr, ford k, osborne d, carson cc 3rd, paulson df. seminal vesiculography: limited value in vesiculitis. urology. 1982;20:454-457 9. centers for disease control and prevention (cdc). nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents--st. louis, missouri, 2002-2006. mmwr morb mortal wkly rep. 2007;56:137-41. 1648 | recruiting testicular torsion introduces an azoospermic mouse model for spermatogonial stem cell transplantation saeid azizollahi,1 reza aflatoonian,2 mohammad ali sedigi-gilani,3,4 mohammad asghari jafarabadi,5 babak behnam,6,7 gholamabbas azizollahi,8 morteza koruji1,6 corresponding author: morteza koruji, phd department of anatomical sciences, iran university of medical sciences, hemmat highway, p.o. box 14155-5983, tehran, iran. tell and fax: +98 21 886 22689 e-mail: koruji@iums.ac.ir received january 2013 accepted june 2013 1 department of anatomical sciences, division of reproductive biology, school of medicine, iran university of medical sciences, tehran, iran. 2 department of endocrinology and female infertility at reproductive biomedicine research center, royan institute for reproductive biomedicine, the academic center for education, culture and research, tehran, iran. 3 department of urology, school of medicine, tehran university of medical sciences, tehran, iran. 4 department of andrology, reproductive biomedicine research center, royan institute for reproductive biomedicine, the academic center for education, culture and research, tehran, iran. 5 tabriz health services management research center, department of statistics and epidemiology, faculty of health, tabriz university of medical sciences, tabriz, iran. 6 cellular and molecular research center, iran university of medical sciences, tehran, iran. 7 department of medical genetics and molecular biology, school of medicine, iran university of medical sciences, tehran, iran. 8 physiology research center, kerman university of medical sciences, kerman, iran. sexual dysfunction and infertility sexual dysfunction and infertility purpose: to investigate the long-term effect of testicular torsion on sperm parameters and testis structure in order to introduce a novel mice azoospermic model for spermatogonial stem cell transplantation. materials and methods: unilateral testicular torsion was created. the animals were divided into two groups each containing 15 mice. they underwent 2 and 4 hours of unilateral testicular ischemia, respectively. all animals in this experiment were aged matched. the experimental (n = 5) groups were studied 2, 4 and 10 weeks after testicular ischemia reperfusion. moreover, the left testes and epididymis were removed for sperm analysis and for weight and histopathological evaluation. finally isolated spermatogonial stem cells were transplanted in the testes that underwent 2 hours of ischemia reperfusion, two weeks post-surgery. results: all the investigated parameters demonstrated a sharp decline at 2, 4 and 10 weeks after testicular torsion, whereas 2-hour ischemia was found to be less injurious in testicular tissue structure. two months after xenotransplantation, the transplanted cells were localized in the basal of the seminiferous tubules of the recipient ischemic testes. conclusion: torsion can cause permanent azoospermia in mouse. also testicular torsion 2 weeks after the 2 hours ischemia reperfusion may prove useful for recipient preparation for sscs transplantation in mouse. keywords: adult stem cells; transplantation; animals; fertility preservation; mice; testis; spermatogonia; reperfusion injury; blood supply. 1649vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l testicular torsion as candidate model for sscs transplantation | azizollahi et al introduction spermatogonial stem cells (sscs) transplantation is prov-en to be an efficient technique for studying sertoli cells and germ cells interactions via the model preparation. this promising technology can also provide transgenic animals. (1) in addition, ssc transplantation has been widely used to investigate the spermatogenesis recovery in various species.(2-4) the first critical step in successful transplantation is preparation of the recipient testes.(5) hence, depletion of internal germ cells with minimal damage to the local spermatogenic microenvironment and stem cell niches are requisite.(5) on the other hand, the sscs fate is controlled by factors associated with stem cell niche, which reside near the basement membrane of seminiferous tubules in the vicinity of sertoli cells. however, an assessment of stem cell niche alterations remains difficult in order to evaluate the present sscs recipient model, so the only way in which stem cell activity and microenvironment can be determined is via a transplantation assay.(6) different methods have been suggested to deplete testicular germ cells from immature and adult animals(5,7) including treatment with cytotoxic agents. these may consist of busulfan(8) or radiation(9), induction of cryptorchidism(10), hyperor hypothermia(11) and vitamin a deficiency.(12) most of these approaches can effectively deplete the majority of ssc, however damaging side effects and prolonged duration of treatment are the main disadvantages of these methods.(13) testicular torsion is a urological emergency disorder in which one testicle gets twisted in the scrotum, subsequently cutting off its blood supply. an affected testicle tends toward ischemia and reproductive system dysfunction.(14) although the germ cell apoptosis was reported following testicular torsion, long term histopathologic changes of the testes following the torsion have not been studied yet.(15) long-term investigation of testicular torsion effects on sperm parameters and testis structure and also assessment of stem cell niche alterations were the main aims of the present study. it is believed that the present model is a proper tool in ssc transplantation for treating testicular torsion complications and for performing further medical researches on infertility and spermatogenesis. materials and methods animal preparation and spermatic cord torsion a total of 70 male nmri mice at 6-8 weeks of age were purchased from razi vaccine and serum research institute (karaj, iran). animals were divided into two groups each containing 15 mice. in the first and second groups, animals underwent two and four hours of unilateral testicular ischemia (via a 720˚ torsion in a counterclockwise direction, fixed to the scrotum with a 6-0 nylon suture passing through the tunica albuginea and dartos,(16) respectively. after proper time of ischemia, the suture was removed and the left testis was untwisted and replaced in the scrotum and the incision was closed. control (n = 15) and sham (n = 15) animals were matched to the ages of the experimental groups. sham surgeries involved a midline scrotal incision and physical manipulation of the testis before placing it back into the scrotum. the mice (n = 5) were sacrificed by cervical dislocation 2, 4 and 10 weeks after testicular ischemia reperfusion. the left testes and epididymis were removed for sperm analysis and for weight and histopathological evaluation. the mice were fed with standard commercial laboratory chow [(pellet form), javeneh khorasan co., mashhad, iran], water and housed under standard laboratory conditions (12 h light: 12 h dark at 22 ± 2˚c) during the experimental period. all animal experiments were aged matched and approved by the animal ethics committee at tehran university of medical sciences. all operations were performed under sterile condition with the subject under 100 mg/kg of ketamine hydrochloride (rotexmedica, trittau, germany) and 10 mg/kg xylazine (alfasan, holland) anesthesia (single intraperitoneally). histopathologic evaluation the testes of mice were removed, weighed and fixed in a bouin’s mixture, embedded in paraffin, sectioned at 5 µm thicknesses and finally stained with hematoxylin and eosin (h&e). one hundred seminiferous tubules that were round or nearly round for each testis were assessed randomly. the mean seminiferous tubule diameter and epithelium height was measured in each testes using image j (version 1.240; national institutes of health, usa). the seminiferous tubules were graded according to the johnsen score system in which seminiferous tubules in each section are evaluated systematically and each is given a score.(17) sperm quality parameters left cauda epididymis and vas deferens were isolated and placed in 1 ml of phosphate buffered saline (pbs) (ph = 7.4), prior to be minced using sharp scissors. the spermatozoa were allowed to swim out for 15 min in an atmosphere of 5% co2 at 37˚c, for the purpose of sperm quality and motility analyzed under light microscope (olympus, type ch2, 400 × magni 1650 | sexual dysfunction and infertility fications) the sperm suspensions were counted using neubauer counting chamber (thoma, assistant sondheim/rhon, germany) for determination of sperm concentration and expressed as ×106/ml. eosin b (0.5% in saline) was used to determine the percentage of viable sperm (sperm with red head was counted as dead sperm). sscs isolation and culture bilateral testes from ten neonate 3-6-day-old nmri mice were gathered for ssc isolation. testis cells were obtained by two-step enzymatic digestion and used for culture utilizing the method previously described with some modifications. (18) in brief, minced testis pieces were suspended in dmem containing collagenase and trypsin 1 mg/ml each (both from gibco, paisley, scotland, uk), as well as hyaluronidase type ii 1 mg/ml (sigma) and incubated at 37˚c for 15 min with shaking and a little pipetting. after removal of interstitial cells by 3 washes in dulbecco's modified eagle's medium (dmem), seminiferous cord fragments were incubated in dmem after adding fresh enzymes for 30-45 min as described above. cells were separated from the remaining tubule fragments by centrifugation at 300g (1200 rpm) for 5 min. after filtration through sterile mesh (41-μm opening, 5-6 cm2), the cells were pelleted and subjected to differential plating to eliminate the somatic cells (myoid and sertoli cells).(19,20) the obtained cells were cultured at 37°c and 5% co2, in a humidified atmosphere in the presence of 2.5% fetal bovine serum (fbs) and glial cell line-derived neurotrophic factor (gdnf) 10 ng/ml for two weeks. transplantation procedure and assay the spermatogonial-cell-derived colonies were labeled with dii (invitrogen, carlsbad, ca, usa) based on manufacturer’s protocol and transplanted into the seminiferous tubules of the recipient mice that had undergone two hours of left testicular ischemia 2 weeks after reperfusion via rete testis. the recipient mice (n = 10) were anesthetized as described. approximately, 105 cultured sscs in 10 μl dmem were then injected into the seminiferous tubules in affected testis of each recipient mouse. transplantation was performed by retrograde injection through the efferent ducts,(21) with some modifications. seminiferous tubules were tracked and visualized by adding trypan blue in the germ cell injection media. the existence and proliferation of injected cells were evaluated 10 weeks post transplantation under fluorescent microscope (olympus, type ch2, 400 × magnification). statistical analysis variables were presented as means (±sd) and the normal distribution of data was evaluated and then confirmed by kolmogorov–smirnov test. to assess the effect of interventions, figure 1. figure 1. comparison of seminiferous tubule deterioration in different groups of our study following torsion. normal seminiferous tubules are seen in control (a), sham (b) and treated groups during long time. effects of 2-hour ischemia after 2 weeks (c), 4 weeks (d) and 10 weeks (e), also injurious and irreversible effects of a 4-hour testicular torsion was observed at 2 weeks (f), 4 weeks (g) and 10 weeks (h) post-surgery (bar = 200 µm). figure 2. cell labeling of spermatogonial stem cell and transplantation. (a) cluster of spermatogonial stem cells, (b) labeled cell with dii, (c) the transplanted spermatogonial cells, (d) colonization and proliferation of labeled injected cells, (e) unstained seminiferous tubule, and (f) section of testis 10 weeks after testicular torsion under ultraviolet light without any obvious signals (bar = 50 µm). 1651vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l time and possible interaction of these effects, mixed model analysis was applied by choosing diagonal covariance structure based on minimum akaike information criterion (aic). for post hoc tests two series of analyses were performed. to investigate the effect of intervention and comparing groups in various time points before and after intervention, analysis of variance (anova) and covariance (ancova) were used, respectively. in post-intervention group, an adjustment for baseline measurements followed by sidak post hoc test in most cases was performed (the false positive rate was controlled and remained on 0.05 level). to compare time points in each group, mixed model analysis was used by choosing diagonal covariance structure followed by sidak post hoc test in significant cases. all analyses were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0 at a .05 significance level. results sperm analysis following testicular torsion based on the sperm analysis parameters in sham and control animals no considerable discrepancy was identified throughout 10 weeks of evaluations. however, a significant reduction in epididymal sperm count was perceived 2 weeks following testicular ischemia reperfusion and vanished 4 weeks after treatment compared to sham and control groups (p = .001 and p = .015, respectively). whereas no significant difference was observed for 2 and 4 hours treated animals. also different values obtained during 2, 4 and 10 weeks of our assessment were not significant (table 1). there is a significant decline in sperm motility 2 and 4 hours after testicular torsion, and two weeks post-surgery (p = .001 and p = .009, respectively). however, no significant difference was found between experiment mice including 2, 4 and 10 weeks post-surgery as well as 2 and 4 hours of ischemia (table 1). furthermore, sperm viability reduction was observed in both groups that underwent 2 and 4 hours of ischemia, 2, 4 and 10 weeks after surgery (p = .001, p = .05, p = .033, respectively). neither there was any significant difference of testicular torsion as candidate model for sscs transplantation | azizollahi et al table 1. spermatogenesis evaluation during different time after surgery by assessment of johnsen score, mean epididymis sperm count, percentage of sperm motility, percentage of viable sperm.* duration groups 2 weeks 4 weeks 10 weeks control 9.34 ± 0.46 9.36 ± 0.47 9.08 ± 0.51 johnsen score sham 9.20 ± 0.87 9.10 ± 0.55 9.24 ± 0.61 torsion 2 hours 2.60 ± 0.12a 1.52 ± 0.63a, c 2.46 ± 0.82a torsion 4 hours 1.36 ± 0.29a, b 1.20 ± 0.12 a 0.00 ± 0.00a, b, c, d control 6.12 ± 0.92 6.30 ± 0.84 5.96 ± 0.79 sperm count sham 5.98 ± 0.94 6.48 ± 1.39 6.00 ± 0.91 ( mean±sd) ×106 torsion 2 hours 0.19 ± 0.16a 0.00±0.00a 0.01 ± 0.01a torsion 4 hours 0.01 ± 0.01a 0.00 ±0.00a 0.00 ± 0.00a control 60.60 ± 7.44 61.00 ± 6.36 60.00 ± 7.11 sperm motility sham 61.20 ± 14.08 63.00 ± 12.0 60.60 ± 13.43 (%) torsion 2 hours 1.80 ± 1.92a 0.00 ± 0.00a 0.60 ± 0.89a torsion 4 hours 0.00 ± 0.00 a 0.00 ± 0.00a 0.00 ± 0.00a control 67.00 ± 7.21 65.00 ±7.18 65.20 ± 7.05 sperm viability sham 71.40 ± 7.40 70.20 ± 7.12 72.00 ± 4.12 (%) torsion 2 hours 3.00 ± 2.12a 0.0 ± 0.00a 1.80 ± 2.49a torsion 4 hours 0.60 ± 0.89 a 0.00 ± 0.0a 0.00 ± 0.0a * the results of five separate experiments were used for all groups. the values are the mean ± sd at different times. a significant difference versus control and sham in the same column (p ≤ .05). b significant difference versus torsion 2 hours in the same column (p < .05, based on tukey post hoc test). c significant difference versus 2 weeks in the same row (p ≤ .05). d significant difference versus 4 weeks in the same row (p < .05, based on sidak post hoc test). 1652 | the ischemia duration effect on the sperm viability (table 1). histopathological observations figure 1 illustrates testes sections from animals used in this study (control, sham and experimental groups) under a light microscopy. testis sections of control and sham animals showed a normal seminiferous tubule contour and morphology (figures 1 a and b). the epithelium of all seminiferous tubules in the treated groups was severely disrupted and most of tubules depleted 2 weeks post operation. in some tubules only the basement membrane was observed. however the 4 hours testicular ischemia showed a more serious and irreversible effect and the sclerotic seminiferous tubules were observed 10 weeks after the 4 hours ischemia and reperfusion (figure 1). despite the reversible effects of 2-hour ischemia on testicular tissue, damaging effects and persistent spermatogenesis arrest was observed up to 10 weeks post operation based on histopathological observation. assessment of morphological changes reduction in left testis weight was remarkable compared to that of sham and control groups (p ≤ .05) 2 weeks after reperfusion of testicular torsion; however, testicular weight value was not correlated with the duration of ischemia (table 2). as shown in table 2, the tubule diameter was lesser significantly in 4-hour than 2-hour ischemia during 2, 4 and 10 weeks after surgery (p = .001). however in 4-hour-ischemia group, tubule diameter reached its minimum after 10 weeks (table 2). similar results were also obtained for thickness of the seminiferous germinal epithelium, with this exception that the significant reduction in epithelial thickness was observed in 2-hour group, two weeks after ischemia. furthermore a non-significant increase in thickness of seminiferous epithelium and regeneration of seminiferous epithelium was observed for 2 hours group, 10 weeks following ischemia (table 2). johnsen score assessment following torsion, the mean johnsen score was dramatically declined at different time intervals during the study in comparison to sham and control groups (p = .005). seminiferous tubule score for 4-hour testicular ischemia was significantly lower than that of 2-hour ischemia, two weeks following operation and it reached a score of zero, 10 weeks after ischemia (p = .001). based on johnsen scoring, most seminiferous tubules were depleted 2 weeks following ischemia and it persists for 10 weeks after ischemia-reperfusion (table1). spermatogonial stem cell culture and transplantation the clusters appeared in 2-3 days after primary culture. when these clusters were enzymatically dispersed and re-plated, their ssc contents could start new clusters during 2 weeks of culture (figure 2). cell labeling with dii was performed sexual dysfunction and infertility table 2. histopathologic evaluation of testicular tissue by weight, seminiferous tubule diameter and seminiferous epithelium diameter.* groups 2 weeks 4 weeks 10 weeks testicular weight (gr) control 0.134 ± 0.011 0.130 ± 0.019 0.124 ± 0.011 sham 0.123 ± 0.008 0.118 ± 0.013 0.119 ± 0.009 torsion 2 hours 0.078 ± 0.007a 0.064 ± 0.012a 0.068 ± 0.015a torsion 4 hours 0.073 ± 0.012a 0.063 ± 0.013a 0.066 ± 0.024a seminiferous tubule control 200.00 ± 5.34 198.60 ± 4.13 201.18 ± 4.12 sham 199.28 ± 4.01 198.48 ± 2.55 198.82 ± 1.17 torsion 2 hours 143.24 ± 9.17 a 148.00 ± 16.44 a 136.46 ± 8.87a torsion 4 hours 126.92 ± 5.66a, b 126.40 ± 3.39 a, b 109.76 ± 3.16 a,b,c seminiferous epithelium control 58.84 ± 12.19 63.34 ± 11.51 62.22 ± 11.28 sham 48.06 ± 8.03 47.82 ± 9.86 50.56 ±7.40 torsion 2 hours 18.94 ± 1.07a 10.04 ± 1.38 a, c 16.52 ± 6.77a torsion 4 hours 5.10 ± 3.28a, b 6.28 ± 1.62a 2.62 ± 1.12a b, d * the results of five separate experiments were used for all groups. the values are the mean ± sd at different times. a significant difference versus control and sham in the same column (p ≤ .05). b significant difference versus torsion 2 hours in the same column (p < .05, based on tukey post hoc test). c significant difference versus 2 weeks in the same row (p ≤ .05). d significant difference versus 4 weeks in the same row (p < .05, based on sidak post hoc test). 1653vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l before transplantation. two months after transplantation, florescent labeled spermatogonial stem cell considered as transplanted cells. the labeled cells were localized in the basal compartment of seminiferous tubules of the recipient testes. two months after stem cell transplantation, colonization and proliferation of transplanted cells were found (figure 2). discussion the results from this study showed that testicular torsion have extensive changes in mouse testis structure and epididymal sperms parameters upon 2 and 4 testicular ischemia reperfusions and the effects were irreversible up to 10 weeks. preparation of sscs transplantation in mouse case of testicular torsion 2 weeks after 2 hours ischemia reperfusion may also prove useful and applicable. for preparation of the recipient testes in a successful transplantation, maximal depletion of endogenous germ cells with minimal defect to the local spermatogenic niche and microenvironment, are required.(22) busulfan has been used to prepare transplantation recipients in a divers species, including mouse,(23) rat,(24) monkey,(25) and pig.(26) in other species, busulfan treated animal has not been well prepared for ssc transplantation. in rats, offspring have been obtained via germ cell transplantation in busulfan-treated recipients.(27,28) however, the efficiency of transplantation is poor due to dramatic disturb of the testicular ssc niche by busulfan. testicular niche disturbance prevents transplanted sscs differentiation and proliferation.(29) busulfan administration can produce systemic toxicity and even lethality due to severe bone marrow depression.(26) the side effects of busulfan treatment limit the efficiency of ssc transplantation. radiation is another method for recipient preparation, but the calcification of seminiferous tubules induced by irradiation, and this can impair the migration of transplanted cells.(7) a less harmful and more effective recipient model for ssc transplantation is desirable. testicular ischemia is the main consequence of testicular torsion, from both clinical and experimental points of view.(30) since a severe disruption of seminiferous epithelium is observed during testes reperfusion just after torsion, the injury must occur either during the ischemia or upon reperfusion. our data showed a remarkable decrease in epididymal sperm concentration following 2 and, 4 hours ischemia two weeks after surgery and reached zero 4 weeks post-intervention. discrepancies in sperm count at 2nd, 4th and 10th week of our evaluation were non-significant. on the other hand, ipsilateral azoospermia occurred in epididymis of affected testis 2 weeks following reperfusion and persisted up to 10 weeks. some long term studies have already been published on evaluating the absence of sperm in seminiferous tubule in histopathological observations following testicular torsion.(31,32) however, this study is the first to assess and evaluate sperm concentration following spermatic cord torsion, so far. data revealed an intensive decline in sperm motility and viability due to testicular torsion 2 weeks after ischemia and remained the same until the 10th week. deterioration of testes structure does not seem to be the main cause of sperm parameters in testicular torsion 2 weeks post-surgery. the main stimulant components in pathophysiology of testicular torsion involve the generation of reactive oxygen species (ros) after restoration of blood following the ischemia.(33) it has been demonstrated that ros increased in the areas of ischemia and reperfusion, and is responsible for ischemia-reperfusion injury that has received little attention in the testis.(34,35) spermatozoa are highly sensitive to oxidative stress, particularly to lipid peroxidation due to their high content of polyunsaturated fatty acids in the plasma membrane. a damaging role of ros on ejaculated sperm was also clarified by a large number of studies.(36) therefore, based on these results, the main cause of the poor sperm quality could be an increased ros production. as mentioned, the implication of testicular torsion on epididymal sperm parameters has not already been identified. in general to be fertile, approximately 50% of the seminiferous tubules of a mouse must contain complete spermatogenesis.(37) histopathological observations indicated that all the treated groups in this study are considered infertile, but after 4 hours of testicular torsion, a serious and irreversible injury was perceived. histopathological reports of the previous studies were in agreement with our results.(31,32) thus, it is not reasonable to assume a correlation for the ssc transplantation with sclerotic changes after 4 hours of testicular torsion due to disruption of seminiferous tubular structure deviation in the ssc niche and severe tubular ectasia. depletion of seminiferous tubules was shown by the testicular weight loss following testicular torsion. moreover, similar results were perceived in other studies investigating the experimental torsion in the sham and control groups of animals. these studies demonstrated no effect on ipsilateral testis weight at several time points after torsion repair. whereas, increasing the time of torsion to 1, 2, and 4 hours, caused a pro testicular torsion as candidate model for sscs transplantation | azizollahi et al 1654 | gressive loss in testis weight, after 30 days from torsion repair and leaded to an almost total loss of spermatogenesis at both the 30th and 60th day.(30,38) seminiferous tubular diameter indicates the function of testis in spermatogenesis,(39) thus in our study significant reduction in spermatogenesis was detected following testicular ischemia. however, the amount of reduction depends on the duration of ischemia.(40) although spermatogenesis defects by measuring seminiferous tubules epithelium and testicular tissue destruction following torsion was reported by several studies, the lack of accurate data on tissue structure is one of the drawbacks of these reports.(31,32,38) the johnsen score describes a new and rapid method for registration of spermatogenesis in testes. pathognomonic score counts that lead to immediate diagnosis at a glance, were obtained in many instances. an obvious correlation has been found between sperm count and testicular biopsy scoring for the first time to correlate endocrine conditions with the functional state of the testicular tissue.(17) the result of johnsen score estimation was consistent with the other findings of our study. intensive, irreversible injury was observed in damaged testis by 4-hour (but not by 2-hour) testicular ischemia. in addition, azoospermic mice were invented 2-week post 2-hour testicular torsion, so scc was transplanted 2-week after the 2-hour testicular ischemia. there are several applications for spermatogonial stem cell transplantation beyond basic researches.(41) obtaining and storage of spermatogonial stem cells in special occasions including cancer treatment that may lead to infertility is beneficial. so providing cells from affected individuals for restoring fertility could be transplanted back into the patient, or at emergency situations that unilateral orchiectomy is indicated, a testicular biopsy would provide the spermatogonial stem cells for cryopreservation, storage, and transplantation.(41,42) standpoint of basic research, due to no specific biochemical or morphological markers for spermatogonial stem cells has not yet been determined. therefore, the only assay for the presence of spermatogonial stem cells in a cell suspension is the spermatogonial stem cell transplantation technique.(5,7) ssc transplantation has been examined in various azoospermic animal models.(2,4,37,43) conclusion in conclusion, the present study explains detailed information on the effects of testicular torsion on the testicular and epididymal parameters. torsion can cause permanent azoospermia in mouse which is irreversible until 10 weeks. also testicular torsion might be useful in recipient preparation for sscs transplantation in mouse, which might in turn lead to a novel treatment for infertility and other consequences of testicular torsion, clinically. acknowledgements authors would like to appreciate contribution and administrative support of professor mt joghataei. this study was funded by a grant from iran university of medical sciences, (number: 90-04-30-14879) and all experiments have been performed at cellular and molecular research center, iran university of medical sciences, tehran, iran. conflict of interest none declared. references 1. honaramooz a, yang y. recent advances in application of male germ cell transplantation in farm animals. vet med int. 2010;2011. 2. honaramooz a, behboodi e, blash s, megee so, dobrinski i. germ cell transplantation in goats. mol reprod dev. 2003;64:422-8. 3. izadyar f, den ouden k, stout ta, et al. autologous and homologous transplantation of bovine spermatogonial stem cells. reproduction. 2003;126:765-74. 4. koruji m, movahedin m, mowla sj, gourabi h, pour-beiranvand s, jabbari arfaee a. autologous transplantation of adult mice spermatogonial stem cells into gamma irradiated testes. cell j. 2012;14: 82-9. 5. brinster cj, ryu by, avarbock mr, karagenc l, brinster rl, orwig ke. restoration of fertility by germ cell transplantation requires effective recipient preparation. biol reprod. 2003;69:412-20. 6. mclean dj. spermatogonial stem cell transplantation, testicular function, and restoration of male fertility in 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2003;69:412-20. 23. ogawa t, ohmura m, yumura y, sawada h, kubota y. expansion of murine spermatogonial stem cells through serial transplantation. biol reprod. 2003;68:316-22. 24. zhang z, renfree mb, short rv. successful intra-and interspecific male germ cell transplantation in the rat. biol reprod. 2003;68:961-7. 25. hermann bp, sukhwani m, lin cc, et al. characterization, cryopreservation, and ablation of spermatogonial stem cells in adult rhesus macaques. stem cells. 2007;25:2330-8. 26. honaramooz a, behboodi e, hausler cl, et al. depletion of endogenous germ cells in male pigs and goats in preparation for germ cell transplantation. j androl. 2005;26:698-705. 27. ryu by, orwig ke, oatley jm, et al. efficient generation of transgenic rats through the male germline using lentiviral transduction and transplantation of spermatogonial stem cells. j androl. 2007;28:353-60. 28. hamra fk, gatlin j, chapman km, et al. production of transgenic rats by lentiviral transduction of male 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effects of co‐administration of dopamine and vitamin c on ischaemia‐reperfusion injury after experimental testicular torsion‐detorsion in rats. andrologia. 2011;43:100-5. 36. agarwal a, said tm. oxidative stress, dna damage and apoptosis in male infertility: a clinical approach. bju int. 2005;95:503-7. 37. honaramooz a, megee so, dobrinski i. germ cell transplantation in pigs. biol reprod. 2002;66:21-8. 38. turner t. on unilateral testicular and epididymal torsion: no effect on the contralateral testis. j urol. 1987;138:1285-90. 39. russell l, ettlin r, sinha hikim a, clegg e. mammalian spermatogenesis. histological and histopathological evaluation of the testis. clearwater, fl; cache river press; 1990. p. 1-40. 40. hernández‐franyutti a, uribe mc. seasonal spermatogenic cycle and morphology of germ cells in the viviparous lizard mabuya brachypoda (squamata, scincidae). j morphol. 2012;273:1199-213. 41. kubota h, brinster rl. technology insight: in vitro culture of spermatogonial stem cells and their potential therapeutic uses. nat clin pract endocrinol metab. 2006;2:99-108. 42. brinster rl. male germline stem cells: from mice to men. science. 2007;316:404-5. 43. oatley jm, reeves jj, mclean dj. biological activity of cryopreserved bovine spermatogonial stem cells during in vitro culture. biol reprod. 2004;71:942-7. uj 35 summer.pdf 626 | retraction note published online: winter 2011 erratum to: urol j. 2011 winter; 8(1):1-11. review. pmid: 21404194 this article has been retracted due to plagiarism. the online version of the original article can be found at: http://www.urologyjournal.org/index.php/uj/article/viewfile/923/523 el mehdi tazi, ismail essadi, mohamed fadl tazi, youness ahellal, hind m’rabti, hassan errihani erratum: advanced treatments in non-clear renal cell carcinoma el mehdi tazi* department of medical oncology, national institute of oncology, rabat, morocco tel: +21 266 847 9120 fax: +21 253 767 2580 e-mail: moulay.elmehdi@ yahoo.fr urol j. 2011 winter;8(1):1-11. retraction note urological oncology minimal residual disease defines the risk and time to biochemical failure in patients with pt2 and pt3a prostate cancer treated with radical prostatectomy: an observational prospective study nigel p murray1,2* , socrates aedo1, cynthia fuentealba2, eduardo reyes3,4, anibal salazar2, marco antonio lopez 5, simona minzer 6, shenda orrego5, eghon guzman5. purpose: to compare gleason score (gs), pathological stage, minimal residual disease (mrd) and outcome after prostatectomy radical for prostate cancer. patients and methods: 290/357 men with gs 6 or 7 and pt2 or pt3a disease treated with radical prostatectomy participated. blood and bone marrow were obtained one month after surgery. circulating prostate cells (cpcs) were detected using differential gel centrifugation and immunocytochemistry with anti psa, micro-metastasis weas detected using immunocytochemistry with anti-psa. biochemical failure free survival (bffs) and restricted mean survival times (rmst) were calculated according to gs and stage. mrd was classified as negative, patients only positive for micro-metastasis and patients positive for cpcs; bffs and rmst were calculated according to mrd sub-type. results: gs7 (hr 3.03) and pt3a (hr 3.68) cancers were associated with a higher failure rate, shorter time to failure and associated with cpc positive mrd (p < 0.001), while g6 and pt2 with mrd negative disease (p<0.001). men with cpc (+) mrd were at high risk of early treatment failure; 15% bffs at 10 years, rmst 3.0 years. men positive for only micro-metastasis were at risk of late failure, 50% bffs at 10 years, rmst 8.0 years compared with mrd negative patients; 80% bffs at 10 years, rmst 9.0 years. conclusion: the sub-type of mrd identifies gleason 6 pt2 patients with a poor prognosis and gleason 7 pt3a patients with a good prognosis and could be used to classify men according to personal risk characteristics for the use of adjuvant treatment. keywords: biochemical failure; circulating prostate cells; micro-metastasis; minimal residual disease; prostate cancer introduction after radical prostatectomy for prostate cancer, bi-ochemical failure occurs in 15-40% of patients, and is associated with the surgical gleason score and pathological stage. extra prostatic extension (epe) of the tumour is an adverse prognostic risk factor, defining pt2 from pt3a disease(1) and therefore between organ confined and specimen confined disease. it has been suggested that pt3a patients should be classified into focal capsular penetration and non-focal penetration as biochemical failure free survivals are different(2,3); however, all cases of epe are classified as pt3a disease in the american joint committee on cancer, seventh edition staging manual(4). in both pt2 (organ confined) and pt3a margin negative (specimen confined) all the tumor has been removed at surgery, however there is a difference in prognosis. the simplest explication would be an erroneous pathological classification, which may explain some cases but 1faculty of medicine, university finis terrae, santiago, 7501015, chile. 2urology service, hospital de carabineros, santiago 7770199, chile 3faculty of medicine, university diego portales, santiago, 8370179, chile 4urology service, hospital dipreca, santiago, 7601003, chile 5faculty of medicine, university mayor, santiago, 7510041, chile 6faculty of medicine, university de los andes, santiago, chile. *correspondence: faculty of medicine, university finis terrae, santiago, 7501015, chile. email: nigelpetermurray@gmail.com. received february 2019 & accepted september 2019 not the majority(5). the second possibility is that cancer have disseminated beyond the prostate and thus outside the surgical field at the time of operation. the residual tumor cells that remain after local or systemic therapy in patients with no signs of clinical disease is termed minimal residual disease (mrd). the presence of mrd will depend on the characteristics of the primary tumor and the ability of cancer cells to disseminate, implant and survive in distant tissues. two types of mrd have been described(6), in patients with circulating prostate cells or tumor cells (cpcs) detected in the blood there is an increased frequency of early treatment failure(7,8). whereas in patients with tumor cells detected only in bone marrow samples there is an association with late failure(7,9). we present a prospective, observational long-term follow up study of the effect of the sub-types of mrd on the outcome of radical prostatectomy monotherapy in urology journal/vol 17 no. 3/ may-june 2020/ pp. 262-270. [doi: 10.22037/uj.v0i0.5174] men with gleason 6 and 7 and pt2 and pt3 margin negative prostate cancer. a small group of men with epe and positive surgical margins who did not undergo adjuvant therapy was used as a control group with adverse prognostic features. patients and methods study population a single center, prospective observational study of men who underwent radical prostatectomy as mono-therapy for prostate cancer between 2000 and 2008, and the acquisition of follow up data was concluded in december 2017. pre-treatment psa and age at surgery were registered; the pathological study of the surgical piece was performed by dedicated genitourinary pathologists according to the gleason system (pre-2005) and the pathological stage was defined according to the partin criteria(10). extra-capsular extension was defined as a specimen with cancer cells in contact with the prostatic capsule and classified as positive or negative, sub-division into focal and non-focal capsular penetration was not used. positive surgical margins were defined as one with cancer cells in contact with the inked surface of the specimen. patients were classified as pt2 (organ confined), pt3a negative surgical margins (specimen confined) and pt3a positive margin. all men had a nadir psa post-surgery of < 0.01ng/ml. exclusion criteria: previous treatment or consideration for treatment with androgen blockade or radiotherapy; infiltration of the seminal vesicles and/or regional lymph nodes with cancer or a positive bone scan; men with gleason 8 and 9 cancer. serial total psa levels were monitored three monthly for the first year and six monthly thereafter. biochemical failure was defined as a serum psa > 0.2ng/ml on two separate occasions. the biochemical failure free survival time was defined as the time from surgery to the time of a post-surgery psa of > 0.20ng/ml or to the time of the last follow up. mrd detection was independently evaluated with the evaluators being blinded to the clinical details. procedures a) detection of secondary circulating prostate cells: one-month post-surgery an 8ml venous blood sample was taken and mononuclear cells were obtained by differential centrifugation using histopaque 1,077 (sigma-aldrich, usa). the cells were used to make slides (silanized, dako, usa), air dried for 24 hours and fixed in a solution of 70% ethanol, 5% formaldehyde, and 25% phosphate buffered saline (pbs) ph 7.4. immunocytochemistry: cpcs were detected using a table 1. clinical and pathological findings according pathological stage. variable pt2 pt3a margin negative pt3a margin positive p-value (two tail) n=192 n=78 n=20 age, years 65.0 ± 8.2 66.2 ± 9.0 67.0 ± 8.8 03708a mean ± sd psa, ng/ml 5.21; 1.68 6.37; 5.07 6.66; 6.59 < 0.001a median; iqr gleason score 25 (13%) 39 (50%) 12 (60%) < 0.001b greater than 6 n (%) biochemical failure 49 (26%) 53 (68%) 17 (85%) < 0.001b n (%) abbreviations: iqr= interquartile range; psa= serum total prostate specific antigen; a kruskal-wallis test; b pearson's chi-squared test. figure 1. circulating tumour cell and leukocyte. minimal residual disease in prostate cancer-murray et al. vol 17 no 03 may-june 2020 263 monoclonal antibody directed against psa, clone 28a4 (novocastro laboratory, uk), and identified using an alkaline phosphatase-anti alkaline phosphatase based system (lsab2, dako, usa), with new fuchsin as the chromogen. samples positive for psa staining cells were incubated with anti-cd45 clone 2b11 + pd7/26 (dako, usa) and cells identified with a peroxidase based system (lsab2,dako, usa) with dab (3,3 diaminobenzidine tetrahydrochloride) as the chromogen. a cpc was defined as expressing psa but not cd45 and a leukocyte as expressing cd45 but not psa (figure 1) (11) . a test was considered positive when at least 1 cell/8ml of blood was detected. b) bone marrow biopsy: it has been reported that prostate tumor cells detected in bone marrow aspirates are phenotypically different than those prostate cells detected in bone marrow biopsies and may not represent “true” micro-metastasis but rather cells circulating within the bone marrow(12). for this reason, bone marrow biopsy “touch preps” were used as the sample to test for micro-metastasis. patients were sedated with intravenous midazolam and a bone marrow biopsy, using local anesthetic, was taken from the posterior superior iliac crest one month after surgery. four ”touch preps” using salinized slides (dako, usa) were prepared and processed as described for cpcs, a micro-metastasis was defined as cells staining positive for psa and negative for cd45. evaluations: patients were divided into three groups: pt2, pt3a (margin negative), pt3a (margin positive) and further subdivided into; group a negative for both cpcs and micro-metastasis patients (without evidence of mrd); group b cpc negative, micro-metastasis positive; group c cpc positive with or without bone marrow micro-metastasis detected. study end point: the primary study end point was the presence of biochemical failure and secondary end point mean time to failure after primary treatment. statistical analysis the analysis was performed using the program stata (stata/se 15.0 for windows, copyright 1985-2017 statacorp llc). descriptive statistics were used to describe the results. the variables pt2, pt3a margin negative and pt3a margin positive) were compared for age, total serum psa, pathological gleason score and mrd (group a, b and c). the kruskal–wallis test was used to test whether samples originate from the same distribution. a p value < .05 was taken to signify statistical significance and all tests were two tailed(13). for the whole cohort, a nonparametric survival analysis (13) was performed to establish the survival proportion of kaplanmeier (km) and restricted mean survival time (rmst) for the biochemical failure during the ten-year follow-up period(14). the rmst establishes the expecturological oncology 264 minimal residual disease in prostate cancer-murray et al. table 2. survival proportion and restricted mean survival time (rmst) at 10 years for biochemical failure observed from use curves kaplan-meier, on 290 men treated by radical prostatectomy for prostate cancer. variable survival proportion kaplan-meier % (95% ci) rmst kaplan-meier a years (95% ci) pt2 gleason score 6 72.0 9.2 n=192 n=167 (62.5 to 79.6) (8.9 to 9.5) gleason score 7 26.1 6.5 n=25 (5.2 to 54.4) (5.1 to 8.0) pt3a gleason score 6 28.1 6.7 group margin n=39 (10.6 to 48.7) (5.7 to 7.8) negative n=78 gleason score 7 12.1b 4.0 n=39 (3.5 to 26.2) (3.2 to 4.9) pt3a gleason score 6 18.8 c 3.7 margin n=8 (1.1 to 53.5) (2.9 to 4.4) positive n=20 gleason score 7 16.7 d 2.8 n=12 (2.7 to 41.3) (2.1 to 3.5) abbreviations: %=percentage; ci= confidence interval; a the rmst is the area under the kaplan-meier survival curve, determined by the numerical integration; b at 9.08 years last time not censored observed; c at 5.08 years last time not censored observed; d at 4.33 years last time not censored characteristic pt2 pt3a margin negative pt3a margin positive p-value two tail n=192 n=78 n=20 cpc (-) and mm (-) 114 (60%) 22 (28%) 3 (15%) < 0.001a n (%) cpc (-) and mm (+) 39 (20%) 11 (14%) 4 (20%) .487 n (%) cpc (+) n (%) 39 (20%) 45 (58%) 13 (65%) < 0.001a abbreviations: cpc, circulating prostate or tumor cells; mm, micro-metastasis a pearson's chi-square test with marascuilo procedure for post hoc analysis pt2 versus pt3a margin negative and pt2 versus pt3a margin positive. table 3. minimal residual disease according to pathological stage: classification criteria observed survival predicted rmst predicted predicted survival rmst hr stage mrd gleason score kaplan-meier fpm kaplan-meier a fpm years % (95% ci) % (95% ci) years (95% ci) (95% ci) (95% ci) pt2 n=192 cpc 6 97.8 90.5 9.9 9.7 negative / n=108 (91.3-99.5) (82.1-95.0) 1 mm (9.7-10.0) (9.5-9.9) negative 7 100 b 82.4 5.6 j 9.5 n=6 (65.1-91.7) 1.9 (9.1-9.9) (1.2-3.0) cpc 6 64.1 72.1 9.4 9.2 negative / n=31 (38.7-81.2) (57.5-82.5) 3.3 mm positive (9.0-9.8) (8.7-9.6) (1.4-7.4) 7 75.0 53.2 9.8 8.5 n=8 (12.8-96.1) (29.4-72.2) 6.3 (9.6-10.1) (7.6-8.3) (2.5-15.8) cpc 6 16.6 24.1 positive n=28 (5.3-33.3) (12.0-38.5) 7.0 6.3 9.5 (6.0-7.9) (5.5-7.2) (3.7-24.7) 7 9.01 c 6.4 2.7 4.7 n=11 (0.5-33.3) (0.9-20.0) 18.4 (1.9 to 3.5) (3.5-5.9) (6.5-52.1) pt3a margin cpc 6 88.9 d 81.2 8.5 9.4 negative negative / n=13 (43.30-98.4) (63.4-90.0) 2.1 n=78 mm negative (7.5 to 9.6) (9.0-9.9) (1.3-3.3) 7 45.7 66.9 6.8 9.0 n=9 (6.9-79.5) (41.2-83.3) 4.0 (4.2 to 9.4) (8.3-9.7) (2.4-6.6) cpc 6 33.3 50.7 8.6 8.4 negative / n=11 (7.8-62.3) (27.7-70.0) 6.8 mm positive (7.7-9.5) (7.5-9.2) (2.7-17.2) 7 not observed 26.9 not observed 7.3 n=0 (8.6-49.6) 13.1 (5.2-33.2) (6.1-8.5) cpc 6 10.0 5.2 3.9 4.5 positive n=15 (0.8-33.5) (0.9-15.5) 19.8 (2.5-5.3) (3.5-5.6) (7.2-54.5) 7 5.0 0.3 3.4 n=30 (0.5-18.9) (0.1-2.3) 38.2 3.1 (2.6 to 4.2) (2.6-3.7) pt3a (13.8-105.5) margin cpc 6 not determined 67.0 not determined 9.0 positive negative / n=1 (36.9-85.1) 4.0 (8.2-9.8) n=20 mm negative (2.1-7.6) cpc 7 50.0 e 46.1 2.6 8.2 negative / n=2 (0,6 to 91.0) (14.1-73.4) 7.7 mm negative (2.0 to 3.3) (6.9-9.5) (3.9-15.2) cpc 6 100% f 27.1 5.8 j 7.3 negative / n=2 (5.8-55.0) 13.0 mm positive (4.7-36.2) (5.9-8.8) 7 50%g 8.0 3.5 6.0 n=2 (0,6-91.0) (0.4-31.7) 25.2 (2.2-4.7) (4.3-7.7) (9-70.6) cpc 6 20.00 h 0.3 3.1 3.1 positive n=5 (0,8-58.2) (0.1-5.1) 38.1 (2.3-4.0) (2.2-4.1) (12.5-115.7) 7 12.5 0.1 2.6 2.3 n=8 (0.7-42.3) (0-0.3) 73.5 (1.7-3.5) (1.8-2.8) (24.0-226.0) table 4. survival proportion and restricted mean survival time (rmst) at 10 years for biochemical failure observed (kaplan-meier) and predicted (flexible parameter model) according to the following classification criteria: a) epe, b) mrd and c) gleason score greater than 6; on 290 men treated by radical prostatectomy for prostate cancer abbreviations: mrd, minimal residual disease, cpc, circulating prostate cells;, mm, micro-metastasis, %,percentage; ci, confidence interval; fpm, flexible parameter model. a the rmst is the area under the kaplan-meier survival curve, determined by the numerical integration; b at time 5.58 years not observed events; c 5.76 years last time not censored observed; d at 9.08 years last time not censored observed; e at 2.17 years last time not censored observed; f at time 5.08 years not observed events; g at 4.33 years last time not censored observed; h 3.41 years last time not censored observed; i3.33 years last time not censored observed; j confidence interval not determined, there are no patients with biochemical failure. fpm=flexible parameter model; hr=hazard ratio minimal residual disease in prostate cancer-murray et al. vol 17 no 03 may-june 2020 265 ed time from surgery to biochemical failure during the total observation period(15). patients were classified according: a) pathological stage), b) mrd sub-type, and c) gleason score > 6 and the km and rmst determined, and the results compared using the log-rank test. a flexible parametric survival model (fp model) was used to predict the survival proportion, rmst and the hazard ratio as there was no compliance with the proportional risk assumption (cox model)(16). the discrimination of a prognostic model reflects its ability to distinguish between patient outcomes, for which the harrell’s c discrimination index was used(17). from the fp model for biochemical failure to ten years, the rmst, hazard ratio and survival proportion were established according to the following classification criteria a) pathological stage, b) mrd and c) gleason score > 6. ethical considerations: the study was approved by the local ethics committee and in complete agreement with the declaration of helsinki. all patients provided written informed consent. results 357 men underwent radical prostatectomy; 67 fulfilled exclusion criteria leaving 295 men in the study group. the median follow up time was 6.7 years (iqr: 5.9 years; range 1-15 years). the mean age was 65 ± 8.5 years and a median psa of 6.9 ng/ml (iqr 2.8). table 1 shows the findings according to pathological stage of the patients. the serum psa at the time of diagnosis, frequency of gleason score 7 and frequency of biochemical failure were significantly higher with increasing pathological stage. kaplan-meier survival (km) curves and rmst time to biochemical failure according to pathological stage and gleason score: the km proportion for biochemical failure free survival at ten years of follow-up for the whole cohort was 7.6 years (95% ci: 7.2 to 8.0 years). the biochemical failure free survival and time to failure significantly decreased with increasing pathological stage and a higher gleason score (p < 0.01 log rank test) (figure 3). compared to baseline risk of failure (gleason 6 pt2), univariate hazard ratios (hrs) were: gleason score 7 hr 3.03 (ic: 1.99 -4.60; p < 0.01), pt3a margin negative hr 3.68 (95% ic: 2.37-5.71; p < 0.01) and pt3a margin positive hr 7.63 (95% ic: 4.0314.44; p < 0.01). multi-variate hr were gleason score 7 2.12 (95% ci: 1.76-2.57), pt3a margin negative 2.31 (95% ci: 1.94-2.79) and pt3a margin positive 5.32 (95% ci: 4.16-8.73) respectively. there was agreement between the predicted survival (according to the final model of cox) versus observed survival (model kaplan-meier) (figure 3) with a harrell’s c discrimination index of 0.77 (95% ic: 0.74 to 0.81), considered as a good fit. in summary, the results are consistent with the known risk factors for treatment failure, higher gleason score and pathological stage (organ confined and specifigure 2. bone marrow sample positive and negative for psa expressing micro-metastasis. figure 3. comparing predicted (cox final model) versus observed survival (kaplan-meier survival) by gleason score 7 and pathological stage, pt2, pt3a margin negative and pt3a margin positive for biochemical failure free progression at 10 years on 290 subjects treated with radical prostatectomy for prostate cancer minimal residual disease in prostate cancer-murray et al. urological oncology 266 vol 17 no 03 may-june 2020 267 men-confined cancer) and represents a typical prostate cancer population. kaplan-meier survival curves and rmst time to biochemical failure according to pathological stage and gleason score and minimal residual disease: for each pathological stage the minimal residual disease was assessed, (table 2), as may be predicted, mrd negative patients were significantly more frequently found in patients with pt2 disease, those with cpc positive mrd were significantly more frequently found in pt3a disease. however, the frequency of cpc negative mrd was not significantly associated with pathological stage. classifying the patients according to mrd subtype, and where the number of patients permits this analysis, the presence of cpcs signified a significantly poorer biochemical failure free survival and shorter time to failure, and associated with increasing gleason score and pathological stage. however, patients mrd negative, independent of pathological stage had better biochemical failure free survival and longer time to treatment failure, even those patients with pt3a margin positive (table 3). patients with micro-metastasis positive mrd (group b) had a different pattern of failure, although with a lower biochemical failure free survival the time to failure was significantly longer than those patients cpc (+). those patients mrd micro-metastasis positive have a four to five years of excellent prognosis but afterwards there is increasing late failure, in other words the risk of failure was not constant with time. (figure 4). the non-parametric comparison of survival by groups: a) pathological stage, b) mrd and c) gleason score 7 showed differences with statistical significance (p value < 0.01 for log-rank test). for the whole cohort, the kaplan-meier survival curves for the three mrd subgroups were not parallel, which differed from the two survival curves based on gleason score and pathological stage alone. testing for a cohort interaction between gleason score, pathological stage and mrd category showed a significant difference (p < 0.05), which implies that the risk of biochemical failure is not constant, and changes with time. the flexible parametric survival model using the following coefficients of variables: a) pt3a margin negative: 0.73 (p-value: 0.003), b) pt3a margin positive:1.39 (p-value < 0.0001) c) cpc negative/micro-metastasis positive: 1.18 ( p-value: 0.005), d) cpc positive: 3.16 (p-value < 0.0001) and e) gleason score 7: 0.66 (p-value: 0.003). this fp final model considered subjects with: pt2, cpc: negative/micro-metastasis negative and gleason score 6 as the group basal. there was agreement when comparing the predicted fp model with the observed survival (kaplan-meier survival) with a harrell’s c discrimination index of 0.91 showing an excellent fit between observed and predicted models. (figure 4). the predicted survival proportions, rmsts and hazard ratios (group basal: subjects with: pt2, mrd negative and gleason score 6) for the fp final model according to pathological stage, mrd and gleason score are shown in table 3. as can be seen the hr when using gleason score and pathological stage alone; hr gleason 7 3.03, pt3a margin negative 3.68 and pt3a margin positive gives a very different risk classification. as can be seen from table 3 patients with pt3a margin negative g6 tumours have a better-predicted outcome than pt2 gleason 6 patients with only bone marrow micro-metastasis. similarly, patients with pt3a margin negative g7 tumours and negative for mrd had a better-predicted outcome than pt2 gleason 6 patients with cpcs detected. sub-classifying the patients using mrd, gleason score and pathological stage suggests that not all gleason 6 or 7 and not all pt2 and pt3a cancers have the same risk of treatment failure. discussion classification of patients following radical prostatectomy according to the risk of treatment failure is important in the management of prostate cancer. the identification of patients who may or may not benefit from adjuvant therapy, such as radiotherapy or androgen deprivation therapy is essential. that gleason 7 tumors or those patients with higher pathological stage cancers had a higher risk of treatment failure, as seen in this study is not surprising. the study has its limitations; it was started in 2000 and we maintained the old gleason 7 score rather than 3 + 4 and 4 +3(18) accepting that some patients classified as gleason 7 would be classified as gleason 3 + 4 and that some gleason 7 would be gleason 4 +3. secondly, the small number of patients in some of the subgroups limits the number figure 4. kaplan meier survival curves according to minimal residual disease. abbreviations: cpc, circulating prostate cells, mm, micro-metastasis, ci, confidence interval. minimal residual disease in prostate cancer-murray et al. of conclusions, and this can be seen in the form of the wide confidence intervals. however, the fact that statistical significant differences were detected implies real differences between patient populations. a multi-centre study with a much larger number of patients would overcome this limitation and essential before establishing concrete conclusions. the few patients with pt3a margin positive cancer were included as a bad prognosis group; only 20/82 (24%) of pt3a margin positive patients did not undergo adjuvant treatment, this group of patients were treated between 2000 and 2004. in the recruitment stage patients with pt3a margin negative disease were observed after radical prostatectomy; studies published covering this era, reported acceptable cancer control and radiation therapy did not impact the appearance of metastasis or survival although it did delay time to biochemical failure and improve local control(19). psa could be considered as a marker for minimal residual disease; post radical prostatectomy a level of over 0.2ng/ml is used to define treatment failure and to consider additional treatment. at these levels the patient normally does not have clinical symptoms, however the psa level does not determine whether there is local or systemic residual disease. in this context, cpcs do not differentiate between local and systemic disease, whereas micro-metastasis in the bone marrow represent systemic disease. the use of bone marrow biopsies to evaluate the presence of micro-metastasis is more invasive than the use of blood tests. however, a three-year annual survey reported only 0.07% of patients reported side effects(20) and significantly less than those occurring after prostate biopsy(21). cpc detection is method dependent; methods using anti-epcam (epithelial cell adhesion molecule) such as cellsearch® detected cpcs in only 25% of men with localized cancer and failed to distinguish between healthy controls and men with prostate cancer(22). in contrast, using an anti-ber-4 and telomerase based method; cpcs were detected in 80% of men with localized prostate cancer(23). similarly using a size-based filtration method, cpcs were detected in 34% of men compared with only 18.6% using the cellsearch system24( ). we used a simple differential gel centrifugation method to enrich cpcs and standard immunocytochemistry to detect them; the limitation of this method is the lack of external validation. this method used to detect cpcs has been internally validated at our centre, we acknowledge that there is variability in inter and intra observer evaluation, however used as a positive/negative test the results show a clinical utility the key points of the results of this study are the following: a) stratifying patients according to the subtypes of mrd goes beyond gleason score and pathological stage. although for the three types of mrd the outcome of gleason 7 patients is worse than gleason 6 patients, and similarly patients with pt3a margin negative cancer worse than those with pt2 cancer, not all gleason 6, 7 and pt2 and pt3a behave in a similar fashion. this implies that the worse prognosis for gleason 7 and pt3a patients in general is due to a higher frequency of mrd cpc positive patients. independent of the subtype of mrd, gleason 7 patients had a worse prognosis and shorter time to treatment failure. the implication is that gleason 7 cancer cells are inherently more aggressive than gleason 6 tumour cells. however independent of the mechanism of tumour dissemination, there is a subgroup of gleason 7 patients mrd negative with an excellent prognosis. more recently, a 30 gene mrna expression signature improved predictions of indolent and lethal outcome of men with gleason 7 prostate cancer, independent of whether the gleason score was 3 + 4 or 4 + 3, for both types there were indolent and lethal variants(25). the differing sub-types of mrd represent different biological potentials of cancer cells and may help to differentiate between indolent and lethal forms of cancer, even in patients with the same gleason score and pathological stage. morphological analysis of the cancer does not assess the biological potential of the tumour. b) the time kinetics of treatment failure differs between gleason 6 and gleason 7 tumours. in gleason 7 the risk of early failure is significantly higher than in gleason 6 cancer. however, by ten years post prostatectomy the risk of future failure had decreased to be the same as mrd negative patients. in contrast with gleason 6 cancer there was a constant failure risk. this suggests that the biological characteristics and behaviour of gleason 6 and 7 tumour cells are different. this pattern has been reported previously, patients with adverse pathological findings at surgery, gleason score ≥ 7, higher pre-surgery psa levels had a high initial risk of failure which rapidly decreased to almost zero, while those with low gleason scores and t2 disease had fairly constant progression rates for up to ten years(26). patients cpc positive had a significantly higher biochemical failure rate and shorter time to failure suggesting a more aggressive form of mrd. although this simple system of mrd classification allows risk stratification of prostate cancer patients, the future molecular characterisation of these tumour cells may allow for individualized treatments that are more effective, potentially reveal targets to prevent relapse and avoid overtreatment of patients with indolent mrd. there is a clinical need to delineate the patients with indolent mrd as they present a different biological and thus clinical process, which may require different treatment strategies. conclusions within the limitations of the study, the results suggest that the differences in treatment failure between gleason 6 and gleason 7 and pt2 and pt3a cancer patients can be explained by the phenotypic characters of the tumour cells, which give rise to differing patterns of mrd and in the different clinical patterns of relapse. patients mrd negative or an “indolent” pattern may thus avoid overtreatment whereas those with cpc positive disease and a high risk of early relapse may benefit from early adjuvant treatment. this would need to be confirmed with larger scale randomized long-term trials. acknowledgements the authors wish to thank mrs ana maria palazuelos for her help in redacting the manuscript. the study was supported by a hospital de carabineros de chile research grant. conflict of interest dr murray reports having received consultancy fees from viatar ctc solutions. minimal residual disease in prostate cancer-murray et al. urological oncology 268 vol 17 no 03 may-june 2020 269 references 1. mottet n, bellmunt j, bolla m, et al. eauestro-siog guidelines on prostate cancer. part 1: screening, diagnosis and local treatment with curative intent. eur urol 2017: 71: 618629 2. maubon t, branger n, bastide c, et al. impact of the extent of extraprostatic extension 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radical prostatectomy for clinically localized prostate cancdr. urol 1997; 50: 93-99 minimal residual disease in prostate cancer-murray et al. urological oncology 270 v08_no_2_final.pdf urological oncology 120 urology journal vol 8 no 2 spring 2011 is positron emission tomography reliable to predict post-chemotherapy retroperitoneal lymph node involvement in advanced germ cell tumors of the testis? ziya akbulut, abdullah erdem canda, ali fuat atmaca, alper caglayan, erem asil, mevlana derya balbay purpose: to evaluate if 18 fluorodeoxyglucose positron emission tomography (18fdg-pet) scan could identify post-chemotherapy retroperitoneal lymph node (rpln) involvement in advanced germ cell tumors of the testis. materials and methods: between january 2005 and january 2009, 16 patients with advanced germ cell tumors of the testis underwent rpln dissection (rplnd) following chemotherapy. before rplnd, abdominal computed tomography (ct), magnetic resonance imaging (mri), and 18fdg-pet were performed in all the patients. findings on 18fdg-pet were compared with pathological evaluation of the removed lymphatic tissue. results: both abdominal ct and mri demonstrated retroperitoneal masses in all the patients following chemotherapy. although pet did not demonstrate any activity in 8 patients, tumor was detected histopathologically. in 1 patient, 18fdg-pet demonstrated activity; however, no tumor was detected on pathology. of the remaining 7 patients, 18fdg-pet findings were concordant with the histopathological findings. no activity was detected in 2 patients with no tumors whereas all 5 patients harboring viable tumor cells showed positive 18fdg-pet activity. in our study, sensitivity and specificity of 18fdg-pet in detecting rpln involvement were detected to be 39% and 67%, respectively. conclusion: 18fdg-pet imaging does not seem to be a reliable method in detecting rpln involvement in advanced germ cell tumors of the testis following chemotherapy. therefore, we neither recommend routine use of 18fdg-pet scanning nor decide the treatment work-up by solely relying on the 18fdg-pet findings in this patient group. urol j. 2011;8:120-6. www.uj.unrc.ir keywords: testicular neoplasms, lymph nodes, positron-emission tomography, sensitivity and specificity 1st urology clinic, ankara ataturk training and research hospital, ankara, turkey corresponding author: abdullah erdem canda, md 1st urology clinic, ankara ataturk training and research hospital, 06800, ankara, turkey tel: + 90 532 261 1105 fax: + 90 312 291 2715 e-mail: erdemcanda@yahoo.com received march 2010 accepted august 2010 introduction chemotherapy is a treatment modality for patients with or without retroperitoneal lymph node (rpln) involvement after radical orhiectomy.(1) those patients with a residual retroperitoneal mass after chemotherapy are subject to retroperitoneal lymph node dissection (rplnd). since it is impossible to determine whether these lymph nodes harbor viable tumor cells postoperatively. even tumor markers are within normal limits. conventional radiographic evaluations, including computed tomography (ct) or use of pet in advanced testis tumors—akbulut et al 121urology journal vol 8 no 2 spring 2011 magnetic resonance imaging (mri) fall short to identify viable tumor cells in such situations. positron emission tomography with the use of 18 fluorodeoxyglucose (18fdg-pet) has been developed to identify viable tumor cells depending on the presumed metabolic activity in viable tissues. it has been so far shown that this holds true for several different tumors, including breast cancer, malignant melanoma, and colorectal cancer.(2-4) the purpose of present study is to investigate if 18fdg uptake on pet scans after chemotherapy is an efficient way of identifying viable tumor cells in patients with testicular tumors who received chemotherapy and underwent rplnd for their residual retroperitoneal masses. materials and methods between january 2005 and january 2010, we performed rplnd on 16 patients with advanced germ cell tumors of the testis following chemotherapy. before rplnd, abdominal ct, mri, and 18fdg-pet were performed in all the patients. tumor markers, including alphafetoprotein, beta subunit of human chorionic gonadotropin, and lactate dehydrogenase were all within normal limits in all the patients before performing rplnd. patients’ characteristics are summarized in table 1. we retrospectively evaluated if 18fdg uptake on pet scans after chemotherapy is an efficient way of identifying viable tumor cells in patients with testicular tumors who received chemotherapy and underwent rplnd for their residual retroperitoneal masses. 18fdg-pet scan was performed on full-ring pet and pet-ct cameras. the assessment included scanning of an image quality phantom, establishment of image reconstruction parameters, and assessment of local quality control procedures. following 6-hour fasting, 350 to 400 mbq 18fdg was administered and a non–attenuation-corrected “halfbody” scan was performed. the emission scan was carried out to initiate 1 hour following injection. an attenuation-corrected local view was obtained over an approximately 20-cm field of view from the celiac lymph nodes (lns) to the iliac lns. reconstruction of the images was performed due to the ordered subset expectation maximization algorithm. all pet scans were reviewed and reported by the department of nuclear medicine. in case of increased 18fdg uptake detection compared to the normal surrounding tissue, the 18fdg-pet scan was considered as positive regarding metastatic disease.(5) advanced germ cell testis tumor is regarded as presence of systemic disease, including the retroperitoneum detected by radiological imaging modalities, such as ct, mri, and pet. according to american joint committee on cancer staging system, advanced germ cell testis tumors are regarded as stage iic and stage iii for advanced seminoma and stage iib and higher stages for advanced nonseminomatous germ cell tumors (nsgct).(6) at our department, in compliance with the advancements in technique of rplnd, we have adopted modification of surgical templates and used modified template for rplnd. in our technique, we strictly adhere to the surgical techniques and through a midline abdominal incision, we thoroughly remove all the interaortocaval and ipsilateral lns between the level of renal vessels and bifurcation of the common iliac artery. we minimize the contralateral dissection, particularly below the inferior mesenteric artery. on the left side, the following lns are dissected: left iliac, pre-aortic, para-aortic, and interaortocaval nodes. on the right side, right iliac, paracaval, interaortocaval, pre-aortic, and para-aortic lns are dissected.(6) results the mean patients’ age was 29 ± 7 years (range, 23 to 46 years). the pathological findings were mixed germ cell tumor (n = 11), embryonal carcinoma (n = 2), teratoma (n = 2), endodermal sinus tumor (n = 1), and seminoma (n = 1). the chemotherapeutic regimens were as below: bleomycin (b), etoposide (e) and cisplatinum (p): bep (4 cycles, n = 13), bep (3 cycles, n = 1), bep (2 cycles, n = 1), and bep (4 cycles) + ep (2 cycles) (n = 1). use of pet in advanced testis tumors—akbulut et al 122 urology journal vol 8 no 2 spring 2011 pa tie nt n um be r pa tie nt s ag e te st is tm si te te st is tu m or p at ho lo gy c t & m r i f in di ng s m ax im um r pl n si ze o n c t & m r i 18 fd g p et fi nd in gs pr eop er at iv e ch em ot he ra py o pe ra tiv e fin di ng s r pl n d pa th ol og y fa ls e (-) g ro up (n = 8 ) 1 34 le ft e m br yo na l c ar ci no m a, in tra tu bu la r ge rm c el l n eo pl as ia le ft pa ra -a or tic , l ef t r en al hi la r m as se s 6. 0 × 3. 0 × 3. 0 cm n o ac tiv ity b e p (4 c yc le s) in te ra or ta ca va l a nd p ar aao rti c m as se s m at ur e cy st ic te ra to m a 2 35 r ig ht m ix ed g er m c el l t m (s em in om a, yo lk s ac tm , i m m at ur e te ra to m a) p ar aao rti c, p er ic av al , l ef t pa ra ili ac m as se s 5. 0 cm n o ac tiv ity b e p (4 c yc le s) in te r a or ta -c av al a nd p ar aca va l m as se s m at ur e cy st ic te ra to m a 3 28 le ft te ra to m a le ft pa ra -a or tic , p re -a or tic , le ft re na l h ila r m as se s 4. 5 × 3. 8 × 3. 2 cm n o ac tiv ity b e p (4 c yc le s) le ft re na l h ila r m as s m at ur e cy st ic te ra to m a 4 29 le ft m ix ed g er m c el l t m (e m br yo na l ca rc in om a, c ho rio ca rc in om a, y ol k sa c tm , s em in om a) le ft re na l h ila r, pa ra -a or tic m as se s 3. 0 × 5. 0 cm n o ac tiv ity b e p (4 c yc le s) in te r a or ta -c av al , p ar aao rti c, re na l hi la r m as se s m et as ta tic te ra to m a an d yo lk sa c tm 5 23 le ft e m br yo na l c ar ci no m a, m at ur e te ra to ca rc in om a le ft pa ra -a or tic , r en al h ila r m as se s 2. 0 cm n o ac tiv ity b e p (4 c yc le s) le ft pa ra -a or tic , i nt er ao rta -c av al , an d re na l h ila r 2 × 2 c m m as s im m at ur e te ra to m a 6 24 r ig ht m ix ed g er m c el l t m (e m br yo na l ca rc in om a, y ol k sa c tm ) le ft pa ra -a or tic m as s 2. 5 cm n o ac tiv ity b e p (4 c yc le s) in te ra or ta -c av al a nd ri gh t e xt er na l ili ac m as se s m at ur e te ra to m a 7 33 le ft e m br yo na l c ar ci no m a le ft re na l h ila r, le ft ili ac m as se s 5. 0 × 5. 0 cm n o ac tiv ity b e p (4 c yc le s) a nd e p (2 c yc le s) le ft re na l h ila r a nd in te ra or ta -c av al m as se s m at ur e cy st ic te ra to m a 8 23 r ig ht e m br yo na l c ar ci no m a r ig ht p ar aao rti c m as s 9. 0 cm n o ac tiv ity b e p (4 c yc le s) p ar ac av al 1 0 × 5 cm m as s te ra to ca rc in om a fa ls e (+ ) g ro up (n = 1 ) 1 25 r ig ht m ix ed g er m c el l t m (e m br yo na l ca rc in om a, y ol k sa c tm , t er at om a) p ar aao rti c m as s 6. 8 × 6. 5 cm p ar aao rti c m as s ac tiv ity b e p (4 c yc le s) in te ra or ta -c av al an d pa ra ca va l m as se s tm n ec ro si s c on co rd an t g ro up (n = 7 ) 1 26 le ft m ix ed g er m c el l t m p ar aao rti c m as se s 1. 8 cm p ar aao rti c m as s ac tiv ity b e p (4 c yc le s) in te ra or ta -c av al , p re ca va l, pa ra ao rti c, le ft an d pa ra -c av al m as se s im m at ur e te ra to m a 2 25 r ig ht s em in om a p ar aao rti c m as s 3. 0 × 1. 0 cm r ig ht c om m on il ia c an d ex te rn al il ia c ac tiv ity b e p (4 c yc le s) 4 cm m as s ne xt to ri gh t c om m on ili ac v ei n s em in om a 3 46 r ig ht im m at ur e te ra to m a p ar aao rti c, re tro -c av al m as se s 8. 0 × 6. 0 cm p ar aao rti c, re tro -c av al a nd in te ra or ta -c av al a ct iv ity b e p (3 c yc le s) p ar aao rti c, in te ra or ta -c av al , p ar aca va l m ax im um 1 2 cm m as se s m at ur e cy st ic te ra to m a 4 29 le ft e nd od er m al s in us tm le ft re na l h ila r m as s 10 × 7 × 8 c m a ct iv ity o n le ft ps oa s m us cl e at l 3 le ve l b e p (4 c yc le s) p ar aao rti c 8 × 6 cm m as s m et as ta tic fi nd in gs s ec on da ry to c he m ot hr ap y 5 36 le ft te ra to m a, y ol k sa c tm le ft re na l h ila r m as s 3. 8 × 4. 0 cm le ft pa ra -a or tic m as s ac tiv ity an d m as s ac tiv ity b et w ee n rig ht m ed ia st in um a nd li ve r b e p (4 cy cl es ) m as se s lo ca te d on le ft pa ra ao rta ca va l s up er io r t o in fe rio r m es en te ric a rte ry yo lk s ac tm 6 41 le ft e m br yo na l c ar ci no m a, s em in om a le ft pa ra -a or tic m as s 2. 8 × 3. 0 × 2. 4 cm n o ac tiv ity b e p (4 c yc le s) in te ra or ta -c av al , l ef t p ar aao rti c m as se s ly m ph oc ys t 7 29 le ft m ix ed g er m c el l t m (e m br yo na l ca rc in om a, im m at ur e te ra to m a) p ar aao rti c an d pa ra -c av al ly m ph n od es 2. 0 × 1. 6 cm n o ac tiv ity b e p (2 c yc le s) in te ra or ta -c av al , l ef t p ar aao rti c m as se s s in us h is tio cy to si s an d re ac tiv e ly m ph oi d hy pe rp la si a ta bl e 1. c ha ra ct er is tic s of p at ie nt s w ho u nd er w en tr p ln d fo r te st is tu m or a nd c om pa ris on o f t he ir ab do m in al c t, m r i, an d p e t fin di ng s w ith r p ln d p at ho lo gi es * *c t in di ca te s co m pu te d to m og ra ph y; m r i, m ag ne tic r es on an ce im ag in g; 1 8f d g -p e t, 1 8f lu or od eo xy gl uc os e po si tr on e m is si on to m og ra ph y; r p ln d : r et ro pe rit on ea l l ym ph n od e di ss ec tio n; tm , tu m or ;r p ln , r et ro pe rit on ea l l ym ph n od e; b e p : b le om yc in , e to po si de , c is pl at in um ; a nd e p, e to po si de , c is pl at in iu m . use of pet in advanced testis tumors—akbulut et al 123urology journal vol 8 no 2 spring 2011 both abdominal ct and mri demonstrated retroperitoneal masses in all the patients following chemotherapy. mean retroperitoneal mass size detected on ct or mri was 4.9 ± 2.6 cm (range, 1.8 to 10 cm). characteristics of ct, mri, and 18fdg-pet scans are demonstrated in table 1 with histopathological findings. of 16 patients, pet was not able to detect residual tumor in the rplnd specimen following chemotherapy in 8 (50%) patients (false negative group). positron emission tomography was able to correctly detect residual tumor in the rplnd specimen in 7 (43.8%) patients (concordant group) (table 1). in the remaining 1 (6.2%) patient, although pet detected activity, necrosis was demonstrated pathologically following rplnd (false positive group) (table 1). other patients’ parameters are summarized in table 1. sensitivity, specificity, positive predictive value (ppv), and negative predictive value (npv) of 18fdg-pet in detecting rpln involvement were 39%, 67%, 83%, and 20%, respectively (table 2). pathological findings detected following chemotherapy and rplnd included mature cystic teratoma (n = 5), metastatic teratoma and yolk sac tumor (n = 1), immature teratoma (n = 2), mature teratoma (n = 1), teratocarcinoma (n = 1), seminoma (n = 1), metastatic findings secondary to chemotherapy (endodermal sinus tumor) (n = 1), yolk sac tumor (n = 1), tumor necrosis (n = 1), lymphocysts (n = 1), and sinus histiocytosis and reactive lymphoid hyperplasia (n = 1). including 16 patients in our study, ct and mri demonstrated mass lesion(s) in the retroperitoneal area. following rplnd, tumor was detected histopathologically in all, but 3 patients. necrosis, lymphocyst, and lymphoid hyperplasia were detected in these 3 patients (table 1). discussion in the recent years, pet has very commonly been used in oncologic urology. positron emission tomography provides images of physiologic and metabolic processes by using positron emitters. the metabolic pet tracer that is most commonly used in oncology scans is 18fdg. increased cellular proliferation in malignant tumors leads to increased fdg use.(7) positron emission tomography scan gives functional information of the tissues; however, its ability to localize lesions is poor.(8) on the other hand, ct is superior in giving anatomical details of the lesions. therefore, these imaging modalities are combined as 18fdg-pet scan in order to obtain both anatomical and functional tissue images in clinical practice.(8) 18fdg-pet scan has been suggested to be superior to standard imaging modalities in detection of disease extent in a number of tumors;(2-4) however, it is increasingly being used in evaluation of metastatic testis tumors. currently, limited number of publications exist in the literature regarding testis tumors (seminomatous versus nonseminomatous) and the use of pet. our study included patients who all underwent rplnd following chemotherapy with normal serum tumor markers; and they were mostly patients with nonseminomatous germ cell testis tumors (table 1). in our series of 16 patients, pet was not able to detect residual tumor in the rplnd specimens following chemotherapy in 8 patients (table 1). the impact of chemotherapy on the use of 18fdg by the tumor tissues in patients with testis tumor is not clear, which might affect pet findings and warrant further research. current guidelines suggest post-chemotherapy rplnd in advanced seminomas with residual retroperitoneal masses if pet scan performed 6 to 8 weeks after chemotherapy is positive and also in nsgcts for all residual radiographic lesions with negative or plateauing markers.(9) sensitivity, specificity, ppv, and npv of 18fdg-pet in our study, sensitivity, specificity, ppv, and npv of 18fdg-pet in detecting rpln involvement were 39%, 67%, 83%, and 20%, presence of live tumor cells in the rplnd specimens 18fdg-pet (+) (n) 18fdg-pet (-) (n) live tumor cells (+) 5 8 live tumor cells (-) 1 2 table 2. demonstration of 18fdg-pet results related to presence of live tumor cells in the rplnd specimens.* *18fdg-pet indicates 18 fluorodeoxyglucose positron emission tomography; and rplnd, retroperitoneal lymph node dissection. use of pet in advanced testis tumors—akbulut et al 124 urology journal vol 8 no 2 spring 2011 respectively. in a study on 46 patients with stage i nsgct who did not receive chemotherapy, 18fdg-pet detected 70% of subjects who subsequently relapsed with metastatic disease. the sensitivity, specificity, and accuracy of pet were 70%, 100%, and 93%, respectively.(10) cremerius and colleagues obtained similar results comparing 18fdg-pet and rplnd findings in 12 patients with testis tumors.(11) de santis and associates evaluated the clinical value of 18fdg-pet as a predictor of viable tumor in post-chemotherapy seminoma residuals (n = 19). the specificity, sensitivity, ppv, and npv of 18fdg-pet were 100%, 80%, 100%, and 96%, respectively.(12) lower sensitivity, specificity, ppv, and npv of 18fdg-pet detected in our series compared to the literature might be due to the effect of previous chemotherapy administered to our patients. pet and seminomatous testis tumors 18fdg-pet was suggested as a predictor of viable residual tumor in post-chemotherapy seminoma residuals.(12) in that study, all the patients with residual lesions > 3 cm (n = 19) 3cm were correctly predicted by 18fdg-pet.(12) becherer and coworkers reported no false positive results whereas they had 3 false negative pet scans in a series of 56 patients with advanced seminomas.(13) in our series, we had 1 patient with pure seminoma in which 18fdg-pet correctly detected rpln involvement. we had additional 3 patients with mixed germ cell testis tumors having seminomatous components. of these 3 patients, 18fdg-pet findings were false negative in 2 patients whereas they were concordant with the rplnd pathology in only 1 patient. further studies with larger number of patients are needed in order to find out if 18fdg-pet could correctly detect rpln involvement following chemotherapy in patients with advanced seminomas. pet and nonseminomatous testis tumors nonseminomatous germ cell tumors are reported to avidly take up 18fdg.(5) in a study on 46 patients with stage i nsgct, 18fdg-pet detected 70% who subsequently relapsed with metastatic disease.(10) in a multicenter study on patients with clinical stage i nsgct, it was concluded that although pet identified some patients with disease not detected by ct scan, the relapse rate among pet-negative patients remained high suggesting that 18fdgpet scanning does not seem to be sensitive enough in identification of patients at low risk of relapse.(5) on the other hand, in a study by hain and colleagues evaluating 31 patients with testis tumor, 18fdg-pet scan identified metastatic disease in 10 and was negative in 16 patients. there were no false positives, but 5 false negatives. they concluded that 18fdg-pet is capable of detecting metastatic disease at diagnosis that has not been identified by other imaging modalities.(14) the german multicenter positron emission tomography study group evaluated the accuracy of 18fdg-pet for prediction of pathology compared with ct scan and serum tumor markers in a series of 121 patients with stage iic or iii nsgct scheduled for secondary resection after cisplatin-based chemotherapy. prediction of tumor viability with 18fdg-pet was accurate in 56% of the patients and sensitivity and specificity of 18fdg-pet were 70% and 48%, respectively. they concluded that 18fdg-pet is unable to give a clear additional clinical benefit to the standard diagnostic procedures, ct scan and serum tumor markers, in prediction of tumor viability in residual masses.(15) impact of rpln size on 18fdg-pet findings in our study, the smallest tumor size was 2 cm both in the false positive and false negative groups. additionally, we had 3 patients with a 3-cm or less rpln and 18fdg-pet correctly identified histopathologic findings in rplnd materials. on the other hand, 18fdg-pet was not able to identify correctly the histopathologic findings in rplnd specimens in 2 patients with mixed germ cell tumors, including seminoma components both having 5-cm rpln. some authors suggested tumor size as a parameter in detecting viable tumor in 18fdgpet,(16,17) whereas others did not find such a use of pet in advanced testis tumors—akbulut et al 125urology journal vol 8 no 2 spring 2011 relationship.(18,19) it was reported that lesions particularly smaller than 1 cm in size can not be detected by 18fdg-pet.(19) according to our results, we do not believe either rpln size or tumor type affects the tumor detection reliability of 18fdg-pet. pitfalls and limitations related to 18fdg-pet pitfalls could be summarized as follows: 1) the problem of accurate image alignment; 2) misregistration errors; 3) artefactual mislocalization errors; 4) misplacement and mislocation of the lesions; 5) inflammatory and granulomatous tissues also show extensive fdg uptake; 6) lesions < 1 cm in size can not be detected; and 7) mature teratoma is indistinguishable from normal and necrotic tissue.(8,19,20) these pitfalls are explained to occur due to the possibility of misregistration of the ct and pet images and movement artifacts occurring due to respiration effects.(8,19) therefore, these scans have been suggested to be reviewed by experienced experts.(8) in order to sort out these problems, respiration-averaged ct matching pet images, respiratory gating of the pet acquisition in improving misregistration issues, and using more detector rows in the scanner are currently being used.(8,21,22) teratoma and 18fdg-pet findings in our series, most of the rplnd pathologies were teratoma (mature or immature) in the false negative group and pet was able to correctly detect only 2 patients with teratoma following rplnd. in the literature, it was reported that fdg uptake was very low in teratomas and pet failed to detect or distinguish mature teratoma from necrosis or fibrosis because both accumulate very little or no fdg.(19,23,24) conclusion in conclusion, ct and mri are frequently used in detection of rpln and masses in advanced testis tumors; however, controversial reports exist regarding the use of 18fdg-pet scan in this setting. although the number of patients in our study is limited, our results demonstrated that 18fdg-pet imaging does not seem to be a sufficiently sensitive method in detecting rpln involvement in advanced germ cell tumors of the testis following chemotherapy. decision making solely relying on 18fdg-pet scan findings could easily lead to overtreatment or vice versa, particularly in this patient group. therefore, pathologic evaluation of the surgically removed masses seems to be the most reliable method in final diagnosis, which would guide the final treatment approach. conflict of interest none declared. references 1. spiess pe, brown ga, liu p, et al. recurrence pattern and proposed surveillance protocol following postchemotherapy retroperitoneal lymph node dissection. j urol. 2007;177:131-8. 2. utech ci, young cs, winter pf. prospective evaluation of fluorine-18 fluorodeoxyclucose positron emission tomography in breast cancer for staging of the axilla related to surgery and immunocytochemistry. eur j nucl med. 1996;23:1588-93. 3. boni r, boni ra, steinert h, et al. staging of metastatic melanoma by whole-body positron emission tomography using 2-fluorine-18-fluoro-2deoxy-d-glucose. br j dermatol. 1995;132:556-62. 4. delbeke d, vitola jv, sandler mp, et al. staging recurrent metastatic colorectal carcinoma with pet. j nucl med. 1997;38:1196-201. 5. huddart ra, o’doherty mj, padhani a, et al. 18fluorodeoxyglucose positron emission tomography in the prediction of relapse in patients with high-risk, clinical stage i nonseminomatous germ cell tumors: preliminary report of mrc trial te22--the ncri testis tumour clinical study group. j clin oncol. 2007;25:3090-5. 6. sheinfeld j, bartsch g, bosl gj. surgery of testicular tumors. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. philadelphia: saunders elsevier; 2007:936-58. 7. bouchelouche k, oehr p. positron emission tomography and positron emission tomography/ computerized tomography of urological malignancies: an update review. j urol. 2008;179:34-45. 8. wang j, cook g, frank j, et al. case report: pet/ct, a cautionary tale. bmc cancer. 2007;7:147. 9. heidenreich a, thuer d, polyakov s. postchemotherapy retroperitoneal lymph node dissection in advanced germ cell tumours of the testis. eur urol. 2008;53:260-72. 10. lassen u, daugaard g, eigtved a, hojgaard l, damgaard k, rorth m. whole-body fdg-pet in patients with stage i non-seminomatous germ cell use of pet in advanced testis tumors—akbulut et al 126 urology journal vol 8 no 2 spring 2011 tumours. eur j nucl med mol imaging. 2003;30:396402. 11. cremerius u, wildberger je, borchers h, et al. does positron emission tomography using 18-fluoro-2deoxyglucose improve clinical staging of testicular cancer?--results of a study in 50 patients. urology. 1999;54:900-4. 12. de santis m, becherer a, bokemeyer c, et al. 2-18fluoro-deoxy-d-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric sempet trial. j clin oncol. 2004;22:1034-9. 13. becherer a, de santis m, karanikas g, et al. fdg pet is superior to ct in the prediction of viable tumour in post-chemotherapy seminoma residuals. eur j radiol. 2005;54:284-8. 14. hain sf, o’doherty mj, timothy ar, leslie md, partridge se, huddart ra. fluorodeoxyglucose pet in the initial staging of germ cell tumours. eur j nucl med. 2000;27:590-4. 15. de santis m, bokemeyer c, becherer a, et al. predictive impact of 2-18fluoro-2-deoxy-dglucose positron emission tomography for residual postchemotherapy masses in patients with bulky seminoma. j clin oncol. 2001;19:3740-4. 16. oechsle k, hartmann m, brenner w, et al. [18f] fluorodeoxyglucose positron emission tomography in nonseminomatous germ cell tumors after chemotherapy: the german multicenter positron emission tomography study group. j clin oncol. 2008;26:5930-5. 17. puc hs, heelan r, mazumdar m, et al. management of residual mass in advanced seminoma: results and recommendations from the memorial sloan-kettering cancer center. j clin oncol. 1996;14:454-60. 18. schultz sm, einhorn lh, conces dj, jr., williams sd, loehrer pj. management of postchemotherapy residual mass in patients with advanced seminoma: indiana university experience. j clin oncol. 1989;7:1497-503. 19. de santis m, pont j. the role of positron emission tomography in germ cell cancer. world j urol. 2004;22:41-6. 20. cook gj, wegner ea, fogelman i. pitfalls and artifacts in 18fdg pet and pet/ct oncologic imaging. semin nucl med. 2004;34:122-33. 21. pan t, mawlawi o, nehmeh sa, et al. attenuation correction of pet images with respiration-averaged ct images in pet/ct. j nucl med. 2005;46:1481-7. 22. beyer t, rosenbaum s, veit p, et al. respiration artifacts in whole-body (18)f-fdg pet/ct studies with combined pet/ct tomographs employing spiral ct technology with 1 to 16 detector rows. eur j nucl med mol imaging. 2005;32:1429-39. 23. albers p, bender h, yilmaz h, schoeneich g, biersack hj, mueller sc. positron emission tomography in the clinical staging of patients with stage i and ii testicular germ cell tumors. urology. 1999;53:808-11. 24. spermon jr, de geus-oei lf, kiemeney la, witjes ja, oyen wj. the role of (18)fluoro-2-deoxyglucose positron emission tomography in initial staging and re-staging after chemotherapy for testicular germ cell tumours. bju int. 2002;89:549-56. u j spring 2012.pdf 522 | urology and nephrology research center, hamedan university of medical sciences, hamedan, iran seyed habibollah mousavi-bahar, ali ahanian, babak borzouei needle manipulation for removing inaccessible stones in parallel calices during percutaneous nephrolithotomy corresponding author: seyed habibollah mousavi-bahar, md department of urology, shahid beheshti hospital, eram blvd, hamedan, iran tel: +98 918 111 3612 fax: +98 811 838 1035 e-mail: shmbahar@ umsha.ac.ir received february 2011 accepted january 2012 point of technique keywords: kidney calculi, kidney calices, percutaneous nephrolithotomy, manipulation introduction pstones in patients who are not candidate for extracorporeal shockwave possible to access all the stones via a single-tract. in these cases, multiple access tracts may be required to increase stone-free rate, which obviously increase the risk of complications and morbidity. other procedures have also been infundibular tilt, angular access pcnl, and swl, as an adjuvant procedure. here, we describe a new technique for displacing the stone from an inaccessible calyx of the kidney to an accessible area by the single pre-existing tract, called “needle manipulation”. case report in two neighborhood calices or staghorn calculi that occupied calices without hydronephrosis and acute angle between calices were included in the study. exclusion criteria were non-opaque calculi, long length of infundibulum, large size of residual stone, acute angle of infundibulum, and smooth surface of calculus. forty-eight patients were enrolled in the study, including 33 men and 15 women, point of technique 523vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l needle manipulation during pcnl | mousavi-bahar et al rotation. the procedure was done by one surgeon technique stent, like other routine procedures. by contrast material injection through the ureteral stent, the the largest stone burden. we selected the calyx with maximum access to stone burden. after tract dilatation and amplatz sheath insertion, accessiif stones could not be accessed in other calices, especially parallel calices, we inserted the needle into the kidney at the site of inaccessible stone unto touch and push the stone using the needle to displace it into or near an accessible area, such as if manipulation fails to displace the stone, we can pass a guidewire through the same needle and create a new tract to remove the stone. needle manipulation may cause minimal hemorrhage, which results among more than 1500 pcnls, we used needle discussion skolarikos and papatsoris have described that residual stone fragments can occur in up to 8% of patients who undergo pcnl. when left untreated, approximately half of them will develop a stonerelated complication in the future, and more than half of these patients will ultimately require another surgical intervention. sometimes it is impossible to access all the stones by a single-tract during pcnl, which may be due to scattered stone fragments, complex stones, or a large staghorn calculus. furthermore, an accessible stone may migrate into an inaccessible calyx during surgery. saline irrigation of the kidney is one of the easiest maneuvers to displace such stones, but it may not be always successful. moreover, creating another tract can lead to increased morbidity. in some studies, multiple-tract pcnl was accomcreatinine and reduction in creatinine clearance postoperatively. furthermore, hospitalization was prolonged, but hemorrhage was not different from single-tract pcnl. in the “angular percutaneous renal access” that was described by liatsikos and colleagues, the skin incision was single, but it was used for multiple nephrostomy tracts. the cosmetic results were better than multiple-tract pcnl, but the transfuguidewire-assisted infundibular tilt technique has ( displaced stone is grasped, fragmented, and removed. 524 | also been described, but its utility is limited to subjects with moderate to severe dilatation of the pyelocaliceal system, in which the parenchymal wall between the two adjacent calices is thin and permits tilting of stone bearing calyx and opening its infundibulum. this technique is not useful in patients with no or mild hydronephrosis. adjuvant swl can lead to complications, such as residual stone fragments, infection, and adverse effects on adjacent tissues, including urinary, gastrointestinal, cardiovascular, genital, and reproductive systems. flexible nephroscopy during the primary operation or as a second-look procedure can increase the stone-free rate and decrease the need to multiple-tract creation, but the instruments are very expensive and are not available in all communities. our technique does not need additional tract creation and has no additional risk for the patient. its limitation is seemed in patients with narrow infundibulum that does not permit stone or instrument passage. there is also increase in radiation time, but using a needle holder can decrease radiation exposure of the surgeon’s hand. however, needle manipulation is not useful for stones in the anterior calices. we made second tract for important residuals and left small residuals, and followed them by medication or swl if needle manipulation was not helpful. conflict of interest none declared. references 1. loss during percutaneous nephrolithotomy: prospective 2. akman t, sari e, binbay m, et al. comparison of outcomes after percutaneous nephrolithotomy of staghorn calculi in those with single and multiple accesses. j endourol. 3. skolarikos a, papatsoris ag. diagnosis and management of postpercutaneous nephrolithotomy residual stone frag4. ahlawat r, dalela d. intra-operative percutaneous caliceal irrigation--a technique for clearing caliceal residue during 5. hegarty nj, desai mm. percutaneous nephrolithotomy requiring multiple tracts: comparison of morbidity with sin6. handa rk, evan ap, willis lr, et al. renal functional effects of multiple-tract percutaneous access. j endourol. 7. liatsikos en, kapoor r, lee b, jabbour m, barbalias g, smith ad. "angular percutaneous renal access". multiple tracts through a single incision for staghorn calculous treatment dalela d, sankhwar sn, goel a, bhandari m, goel t. guidewire assisted infundibular tilt—gait: solving problems of accessibility during pcnl in hydronephrotic kidneys j env 19/6. 9. m. guidewire-assisted infundibular tilt: a technique for access into another calix during percutaneous nephrolithoto10. skolarikos a, alivizatos g, de la rosette j. extracorporeal shock wave lithotripsy 25 years later: complications and 11. beaghler ma, poon mw, dushinski jw, lingeman je. expanding role of flexible nephroscopy in the upper urinary 12. williams sk, leveillee rj. a single percutaneous access and flexible nephroscopy is the best treatment for a full stag13. raman jd, bagrodia a, bensalah k, pearle ms, lotan y. residual fragments after percutaneous nephrolithotomy: cost comparison of immediate second look flexible nephroscopoint of technique v08_no_3_final.pdf pictorial urology 177urology journal vol 8 no 3 summer 2011 ureteral obstruction and stent thrombosis after endovascular treatment of iliac artery aneurysm a 36-year-old man presented with asymptomatic ureteral obstruction incidentally discovered in a routine health examination. his only past surgical history included an endovascular stenting of a right inflammatory common iliac artery aneurysm 12 years earlier. however, the patient did not take anticoagulant therapy regularly due to noncompliance. magnetic resonance imaging revealed a normal left kidney and grade iii hydronephrosis of both segments of the right duplex kidney with a bifid ureter joining further distal to the kidney. retrograde pyelography showed obstruction of the right ureter at the level of crossing with the right common iliac artery (rcia) with the stent in situ. computed tomography scan demonstrated a totally thrombosed rcia and peri-arterial fibrosis, causing proximal ureteral dilatation and hydronephrosis. the patient underwent a right nephroureterectomy for nonfunctioning duplex kidney. the completely thrombosed stent was removed in the same session. the collateral circulation to the lower limb was sufficient to maintain normal motor function and viability of the leg. premature anticoagulant therapy discontinuation was identified as predictors of thrombotic events. to the best of our knowledge, this is the first report of ureteral obstruction and stent thrombosis following endovascular stenting of rcia. with the increasing frequency of endovascular treatment of the iliac artery aneurysm, we must become aware of potential complications associated with these procedures.(1,2) long wang, lin qi, zhengyan tang* department of urology, xiangya hospital, central south university, china *e-mail: xyurology@yahoo.com.cn references 1. metcalfe mj, hanna ms, gill s, burfitt nj, mitchell aw, franklin ij. hydronephrosis after embolization of internal iliac artery aneurysms. j vasc interv radiol. 2010;21:571-3. 2. ozturk mh, eyuboglu i, pulathan z, dinc h. spontaneous thrombosis of a saccular iliac artery aneurysm induced by overlapping self-expandable bare metallic stents. diagn interv radiol. 2010;16:308-11. urol j. 2011;8:177. www.uj.unrc.ir female urology 24 urology journal vol 4 no 1 winter 2007 bacteriuria in pregnant women—hazhir urology journal vol 4 no 1 winter 2007 25 asymptomatic bacteriuria in pregnant women samad hazhir introduction: the aim of this study was to evaluate the frequency of bacteriuria in pregnant women referred to the medical centers of tabriz, iran, for prenatal care. materials and methods: a total of 1100 healthy pregnant women who were referred to 50 medical centers in tabriz for a regular prenatal care were evaluated for bacteriuria. results: the frequency of asymptomatic bacteriuria was 6.1%. maternal age was lower in the women with a positive urine culture (p = .02). asymptomatic bacteriuria had no relationship with gestational age, parity, level of education, and body mass index. conclusion: we found a relatively high rate of bacteriuria in our cohort of asymptomatic pregnant subjects, especially the younger ones. for prevention from the complications of the asymptomatic bacteriuria in pregnant women, such as pyelonephritis, hypertension, preeclampsia, low birth weight, prematurity, septicemia, and even maternal and neonatal death, it is recommended to perform urine culture as a routine evaluation during the pregnancy. urol j (tehran). 2007;4:24-7. www.uj.unrc.ir keywords: bacteriuria, pregnancy, urine culture urology department, sina hospital, tabriz university of medical sciences, tabriz, iran corresponding author: samad hazhir, md no 2, zhan ln, shariati st, vali-easr district, tabriz, iran tel: +98 914 115 7380 e-mail: samadhazhir@yahoo.com received december 2005 accepted november 2006 introduction special attention to the pregnant women is one of the most important points in health care. one of the problems in pregnancy is urinary tract infection (uti).(1,2) the prevalence of asymptomatic uti has been reported to be 2% to 11% in pregnant women (6% to 8% in average).(3-7) neglecting the treatment of uti in pregnant women may result in some health and economic problems. due to the increase in sex hormones and the anatomic and physiologic changes during pregnancy, bladder and kidney infection is more likely and may result in hypertension, preeclampsia, low birth weight, prematurity, septicemia, and maternal death.(2,4,5,8,9) it has been estimated that the costs of screening and treatment of asymptomatic bacteriuria and pyelonephritis during the pregnancy are about us$ 1605 and us$ 2864, respectively, in the united states.(4) in our country, no precise information exists about the prevalence of asymptomatic bacteriuria in pregnancy and the its treatment costs. we designed this study to evaluate the prevalence of bacteriuria in pregnant women referring to the medical centers of tabriz, iran. materials and methods we designed a cross-sectional study to evaluate asymptomatic bacteriuria in pregnant women. according to the results in the previous studies on asymptomatic bacteriuria in pregnant women, a sample size of 1100 subjects was considered adequate and a total of 50 family programming and pregnancy control female urology 24 urology journal vol 4 no 1 winter 2007 bacteriuria in pregnant women—hazhir urology journal vol 4 no 1 winter 2007 25 centers in tabriz were selected for this study.(7,10-12) the study population and the sample size of each center were determined according to the proportion of the patients referring to each center. women at any gestational age who presented for a regular prenatal care were included and those with a history of urinary tract symptoms (dysuria, frequency, and urgency, etc), pregnancy-induced diabetes mellitus or hypertension, antibiotic administration within the previous 7 days, and active regional bleeding were excluded. the doctors and midwives in all of the 50 centers were instructed in the method of the study. they were asked to record the required information of the pregnant women and to introduce all of those without any urinary symptoms to the reference laboratory of tabriz university of medical sciences. to perform urinalysis, the midstream urine samples were taken in the lithotomy position after cleaning the vestibule of the vagina. women with more than 105 bacteria in each milliliter of urine were considered as the patients with bacteriuria.(13) urine culture was carried out for this group of women to confirm the diagnosis. patients’ demographics including age, bmi, level of education, gestational age, and parity, as well as the laboratory results, were recorded. data were evaluated by the chi-square test and t test, as appropriate. a p value less than .05 was considered significant.. results a total of 1100 pregnant women in tabriz participated in this study. the prevalence of asymptomatic bacteriuria was 6.1%. the prevalence rates in relation to the clinical and demographic characteristics of the patients are illustrated in table. the maternal age was significantly lower in the subjects with asymptomatic bacteriuria (p = .02). asymptomatic bacteriuria did not have any significant relation with the trimester of the pregnancy (p = .53), parity (p = .84), the level of education (p = .52), and the bmi (p = .17). the mean bmi was 26.4 kg/m2 and 26.6 kg/m2 in the women with and without bacteriuria, respectively. discussion most of the anatomic and physiologic changes in pregnancy influence the urinary tract and can result in urologic diseases and changes in kidney function which are serious threats for both the mother and the fetus. asymptomatic bacteriuria must be treated during the pregnancy in order to prevent complications such as pyelonephritis, premature labor, hypertension, preeclampsia, and septicemia.(14) in a study by uncu, 270 pregnant women were evaluated and the prevalence of asymptomatic bacteriuria was reported to be 9.3%.(11) in a study performed in turkey, 110 pregnant women were evaluated and the prevalence of asymptomatic bacteriuria was reported to be 8.1%, being more prevalent in the third trimester which is in contrast with our findings.(12) also, in their study, the prevalence of bacteriuria was higher in women older than 25 years, while in our study, it was more prevalent in younger women. in another study, 268 women were evaluated and the need for disease detection and prevention from the pyelonephritis was emphasized.(15) mcisaac and colleagues evaluated the urine cultures obtained from pregnant women before 20 weeks’ gestation and at 28 weeks’ and 36 weeks’ gestation. prevalence of asymptomatic bacteriuria in pregnant women characteristic positive urine culture (%) total number pregnancy trimester first 13 (6.7) 194 second 32 (6.8) 473 third 22 (5.1) 432 age, y < 20 22 (9.9) 223 20 to 30 33 (4.7) 704 > 30 12 (6.9) 173 parity 1 18 (5.8) 313 2 32 (6.8) 469 3 13 (6.0) 216 > 3 4 (3.9) 102 bmi, kg/m2 < 20 3 (6.1) 49 20 to 25 30 (7.9) 382 > 25 33 (5.0) 662 education illiterate 2 (2.6) 76 primary education 21 (7.1) 296 secondary education 18 (6.1) 296 high school degree 25 (6.5) 387 higher education 1 (2.3) 43 total 67 (6.1) 1100 bacteriuria in pregnant women—hazhir 26 urology journal vol 4 no 1 winter 2007 bacteriuria in pregnant women—hazhir urology journal vol 4 no 1 winter 2007 27 they found that a single urine culture before 20 weeks’ gestation missed more than one-half the asymptomatic bacteriuria cases and recommended culture in each trimester to identify most cases.(7) we observed a consistent risk of bacteriuria in all 3 trimesters of the pregnancy, warranting screening program over the whole conception period. other studies have also emphasized the necessity of screening and treatment of bacteriuria during the pregnancy period in order to prevent its dangerous complications.(1,16-19) studies show that urine culture is the gold standard method of diagnosis for this disease.(3,10) it is shown that urine dipstick testing for nitrites, urinalysis, and enzymatic urine screening tests can poorly detect all the culture positive bacteriuria cases in pregnant women.(3,10,20) kutlay and colleagues(3) evaluated 406 pregnant women admitted for an initial obstetric examination during the first trimester. they performed clean-catch urine culture, microscopic urinalysis and dipstick urine tests and found that the sensitivity and specificity of microscopic urinalysis were below 75% and those for dipstick testing were about 35%. we could detect a comparable rate of bacteriuria with the findings of other studies by clean-catch urine culture. one of the most important points of our study was the large sample size in comparison with the previous studies and evaluation of other variables including the mothers’ age and its relation with the trimesters of pregnancy.(3,7,10-12,15,21) additionally, in our study, variables including bmi, parity, and level of education were evaluated for the first time. conclusion bacteriuria was present in about 6.1% of the pregnant women in this study. a most sensitive test for its detection is urine culture with clean-catch sampling from the midstream urine. regarding the frequency of asymptomatic bacteriuria in pregnant women younger than 20 years, it is recommended to perform urine culture as a part of the routine examinations of the pregnant women, and provide them with complete information about the complications of pregnancy at younger ages. conflict of interest none declared. references 1. mittal p, wing da. urinary tract infections in pregnancy. clin perinatol. 2005;32:749-64. 2. saidi a, delaporte v, lechevallier e. [urological problems encountered during pregnancy]. prog urol. 2005;15:1-5. french. 3. kutlay s, kutlay b, karaahmetoglu o, ak c, erkaya s. prevalence, detection and treatment of asymptomatic bacteriuria in a turkish obstetric population. j reprod med. 2003;48:627-30. 4. delzell je jr, lefevre ml. urinary tract infections during pregnancy. am fam physician. 2000;61:71321. 5. abyad a. screening for asymptomatic bacteriuria in pregnancy: urinalysis vs urine culture. j fam pract. 1991;33:471-4. 6. christensen b. which antibiotics are appropriate for treating bacteriuria in pregnancy? j antimicrob chemother. 2000;46:29-34. 7. mcisaac w, carroll jc, biringer a, et al. screening for asymptomatic bacteriuria in pregnancy. j obstet gynaecol can. 2005;27:20-4. 8. klein ll, gibbs rs. use of microbial cultures and antibiotics in the prevention of infection-associated preterm birth. am j obstet gynecol. 2004;190:1493502. 9. grio r, porpiglia m, vetro e, et al. asymptomatic bacteriuria in pregnancy: a diagnostic and therapeutic approach. panminerva med. 1994;36:195-7. 10. teppa rj, roberts jm. the uriscreen test to detect significant asymptomatic bacteriuria during pregnancy. j soc gynecol investig. 2005;12:50-3. 11. uncu y, uncu g, esmer a, bilgel n. should asymptomatic bacteriuria be screened in pregnancy? clin exp obstet gynecol. 2002;29:281-5. 12. tugrul s, oral o, kumru p, kose d, alkan a, yildirim g. evaluation and importance of asymptomatic bacteriuria in pregnancy. clin exp obstet gynecol. 2005;32:237-40. 13. gerber gs, brendler cb. evaluation of the urologic patient: history, physical examination, and urinalysis. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 109. 14. raz r. asymptomatic bacteriuria. clinical significance and management. int j antimicrob agents. 2003;22: 45-7. 15. bookallil m, chalmers e, andrew b. challenges in preventing pyelonephritis in pregnant women in indigenous communities. rural remote health. 2005;5:395. 16. le j, briggs gg, mckeown a, bustillo g. urinary tract infections during pregnancy. ann pharmacother. 2004;38:1692-701. 17. varma r, gupta jk, james dk, kilby md. do screening-preventative interventions in asymptomatic pregnancies reduce the risk of preterm delivery--a critical appraisal of the literature. eur j obstet gynecol bacteriuria in pregnant women—hazhir 26 urology journal vol 4 no 1 winter 2007 bacteriuria in pregnant women—hazhir urology journal vol 4 no 1 winter 2007 27 reprod biol. 2006;127:145-59. 18. sheffield js, cunningham fg. urinary tract infection in women. obstet gynecol. 2005;106:1085-92. 19. caputo s, ciardo a. [asymptomatic bacteriuria in pregnancy]. clin ter. 2001;152:315-8. italian. 20. bachman jw, heise rh, naessens jm, timmerman mg. a study of various tests to detect asymptomatic urinary tract infections in an obstetric population. jama. 1993;270:1971-4. 21. lumbiganon p, chongsomchai c, chumworathayee b, thinkhamrop j. reagent strip testing is not sensitive for the screening of asymptomatic bacteriuria in pregnant women. j med assoc thai. 2002;85:922-7. endourology and stone disease 142 urology journal vol 4 no 3 summer 2007 family history and age at the onset of upper urinary tract calculi yadollah ahmadi asr badr, samad hazhir, kamaleddin hasanzadeh introduction: the aim of this study was to evaluate the effect of family history on the age of urinary calculus formation and its relation with characteristics of the calculi and patients. materials and methods: in a cross-sectional study in tabriz, a total of 210 patients with upper urinary tract calculi were evaluated. their demographics and clinical characteristics and detailed information on their family history were recorded. results: of the patients, 28.6% had a positive family history for urinary calculi. siblings were the majority of the affected family members (71.1%). the rate of a positive family history was slightly higher in women than in men (30.0% versus 28.1%; p = .20). the mean age at the disease onset of the men with and without a positive family history was 37.2 years versus 39.3 years, respectively (p = .20). such a difference was not detected in the female patients, either (p = .63). in general, the calculi were more detected on the left renal unit, but more prevalent on the right side in patients with a positive family history (p = .008). no relation was found between the number and size of the calculi and the family history. conclusion: about one-third of the patients with urinary calculi had a positive family history too. men with affected family members are slightly more susceptible to the disease at younger ages. there might be differences in the side of the calculi and family members with a history of disease that warrants further studies. urol j. 2007;4:142-6. www.uj.unrc.ir keywords: urinary calculi, family history, age, inheritance department of urology, sina hospital, tabriz university of medical sciences, tabriz, iran corresponding author: yadollah ahmadi asr badr, md department of urology, sina hospital, tabriz, iran tel: +98 411 541 2101 fax: +98 411 541 2151 e-mail: yadollahahmadi@yahoo.com received september 2006 accepted may 2007 introduction urinary calculi are more prevalent between 20 and 40 years of age and men are affected 3 times more than women.(1) age is one of the factors evaluated in association with the risk of calculus formation. in a prospective study on patients with urinary calculus in italy, the authors found that patients who had 2 or more calculi during the follow-up were younger at the onset of the disease than those who had only 1 calculus or no recurrence.(1) having a positive family history of urinary calculus and its effect on different factors is another important issue in this condition. it has been shown that a positive family history is more common in patients with calculi than healthy individuals.(2,3) among patients with a positive family history, the prevalence rate of the disease reaches 25%.(4) also, recurrence of the calculi is more common in these patients and occurs faster.(2) although could be related to the genetic factors, patients’ relatives may be at risk of common environmental factors participating in calculi formation.(2,5) the cause (either genetic or environmental) put the family in a higher risk of calculus formation. we designed a study to evaluate the relationship between family history and age of calculi onset—ahmadi asr badr et al urology journal vol 4 no 3 summer 2007 143 upper urinary tract calculi and family history of urinary calculi and sex of the patients. materials and methods in a cross-sectional study performed between november 2003 and may 2003, we evaluated 210 patients. they had presented to the urology clinic of imam and sina hospitals in tabriz, iran, and were between 25 and 55 years old. the cause of referral was a diagnosed upper urinary tract calculus or flank pain that was found to be due to upper urinary tract calculi in our diagnostic evaluation. patients with systemic disorders and those who were receiving medical therapy were excluded. informed consent was obtained from all eligible patients. demographic and clinical characteristics of the patients including sex, age, occupation, place of living during the last 10 years, previous episodes of urinary calculi, the age at the onset of the first discovered calculus, and documented history of calculi in the patients or their first-degree relatives (father, mother, sister, and brother) were recorded. to confirm the collected data, a second interview was planned for the patients who were not sure of their information. characteristics of the calculi including location, number, and size were recorded according to the results of ultrasonography and plain abdominal radiography. if there was more than 1 calculus, the largest one was evaluated. the patients were categorized based on the family history of urinary calculus. for evaluating the differences between the two groups in age and calculus size, the independent sample t test was used. the chi-square and mann-whitney tests were used for the evaluation of the relation of the patients’ sex, location of the calculi, and number of the calculi with the family history. continuous variables were shown as mean ± standard deviation and the 95% confidence interval was calculated. a p value less than .05 was considered significant. results of 210 patients, 60 (28.6%) had a positive family history for urinary calculus formation. thirteen patients (21.7%) had the history in more than one person in their family. the affected family members were 30 brothers (39.5%), 24 sisters (31.6%), 14 fathers (18.4%), and 8 mothers (10.5%). therefore, a positive family history was more detected in patients’ siblings. the mean age and sex distribution of the patients are shown in table 1. the age range of the patients at the onset of urinary calculus disease was 7 to 54 years and 15 to 55 in those with and without a positive family history, respectively. although not statistically significant, the age at the onset of the disease was 2 years less in the men with a positive family history than the men without a family history. no significant relation was detected between the sex of the patients and the family history of urinary calculi (p = .20). values characteristics all patients positive family history negative family history p number of patients 210 60 (28.6) 150 (71.4) male-female ratio 3.2:1 3:1 3:1 .20 men number of patients 160 45 (28.1) 115 (71.9) mean age (95%ci), y 40.9 ± 8.7 40.6 ± 8.5 (38.1 to 43.1) 41.0 ± 8.8 (39.4 to 42.6) .89 mean age at disease onset (95%ci), y 38.7 ± 9.5 37.2 ± 9.3 (34.5 to 39.9) 39.3 ± 9.6 (37.6 to 41.1) .20 women number of patients 50 15 (30.0) 35 (70.0) mean age (95%ci), y 39.2 ± 8.9 38.2 ± 8.9 (33.7 to 42.7) 39.5 ± 9.1 (36.4 to 42.5) .63 mean age at disease onset (95%ci), y 36.8 ± 10.9 36.8 ± 11.0 (31.6 to 41.9) 36.7 ± 11.0 (33.1 to 40.4) .99 single calculi number of patients 132 41 (31.1) 91 (68.9) mean age at disease onset (95%ci), y 39.0 ± 10.3 36.3 ± 9.3 (33.5 to 39.2) 39.3 ± 9.8 (37.3 to 41.3) .10 multiple calculi number of patients 78 19 (24.4) 59 (75.6) mean age at disease onset (95%ci), y 38.5 ± 9.7 38.6 ± 10.5 (33.9 to 43.3) 37.8 ± 10.3 (35.2 to 40.5) .77 table 1. age and sex distribution of patients with and without a positive family history of urinary calculi* *values in parentheses are percents unless otherwise indicated. ci indicates confidence interval. family history and age of calculi onset—ahmadi asr badr et al 144 urology journal vol 4 no 3 summer 2007 the most common site for calculus formation was the left kidney, while in the patients with a positive family history of urinary calculi, it was the right kidney (table 2). the side of the involved renal unit was mostly right in the patients with a positive family history (p = .008); however, there was no relation between the bilaterality of the calculi and family history. the number of the calculi was between 1 and 6 in our patients, and 9 patients (4.3%) had undetermined number of the calculi which had been reported to be a complex of calculi on ultrasonography. there was no relation between the family history and the number or the maximum size of the calculi. the mean number of the calculi was 1.6 ± 0.9 and 1.6 ± 1.2 in the patients with and without a positive family history, respectively (p = .90). the mean maximum size of the calculi was 12.0 ± 4.5 mm and 13.3 ± 5.6 mm, respectively (p = .08). discussion kidney calculus is the third common disease of the urinary system in both men and women, and both genetic and environmental factors influence its development and characteristics.(6) due to the high prevalence of the calculi in different regions, it has always been an important issue. the prevalence of urinary calculi has been reported to be 5.7% in tehran, iran.(7) due to the diversity of environmental factors, the prevalence of kidney calculus is different in different countries. for example, in greece, the prevalence of kidney calculus reaches 15%.(6) many studies have been performed evaluating the relationships between the history of calculus formation and recurrence or between the patients’ sex and the characteristics of the calculi.(1,8) the results of our study were in accordance with other studies. however, it should be mentioned that our study was performed in the patients referring to general university hospitals and this may cause the evaluation of the patients in only one socioeconomic class. in a study performed in tehran, iran, the prevalence of urinary calculi was different in the east and south of the city in comparison with the north and west.(7) a family history of urinary calculus was reported in 34.7% of women and 31% of men with the disease in paris.(9) in our study, it was 30% and 28.1%, respectively, showing a greater likelihood of a positive family history in women. the reason behind such a difference warrants further research. it has also been suggested that this prevalence is influenced by the recurrence rate of the calculi.(8) in the study done in paris, calculi had been diagnosed about 5 years earlier in men with a positive family history.(9) this figure is in accordance with our results; age at the onset of calculi was 2 years less in the men with a positive family history than the men without a family history, but in the women, such an age difference was not observed. kodama and ohno reported that the prevalence rate of urinary calculi is higher in the brothers and fathers of the patients.(10) also, in a study by ljunghall and associates, calculus was more prevalent in the fathers than the mothers of the patients.(8) it has also been shown that the history of calculi is more prevalent in the parents and siblings of the patients with calculi than that in general population, but such a difference is not seen in the spouses, suggesting the predominance of genetic rather than environmental factors.(11) in the present study, brothers and sisters of the patients were the majority of the family members with a history of urinary calculi, and in agreement with other studies, calculi were less prevalent in the mothers of our patients. these differences may be affected by the geographical, social, and racial factors, as well. in our study, the patients with a positive family patients calculus location all positive family history negative family history right kidney 72 (34.3) 27 (45.0) 45 (30.0) right ureter 19 (9.0) 8 (13.3) 11 (7.3) left kidney 84 (40.0) 17 (28.3) 67 (44.7) left ureter 16 (7.7) 4 (6.7) 12 (8.0) bilateral 19 (9.0) 4 (6.7) 15 (10.0) table 2. location of urinary calculi* *values in parentheses are percents. family history and age of calculi onset—ahmadi asr badr et al urology journal vol 4 no 3 summer 2007 145 history had a tendency to have the calculi in the right kidney which might be an accidental finding as it has not been reported in the previous studies; however, it needs more evaluations for the probable causes. we did not find a relation between the positive family history and the number of the calculi; the paris study supports our result.(9) concerning the type of the calculi, ljunghall and coworkers showed that the family history was not related to the level of the calcium and uric acid excretion in urine, which is in contrast to the study of marya and colleagues that showed the higher prevalence of hypercalciuria in patients who had first-degree relatives with a history of calculi in comparison with their spouses. it can be concluded that genetics is a factor more important than the environment.(8,12) more studies in this regard are warranted to come to a clear conclusion finally, in our study there was no significant relation between the calculus size and family history. in our search, we found no article on this issue. we did not evaluate the recurrence of urinary calculi; however, most of the studies have a consensus of conclusion on the effect of family history on the recurrence of the disease.(1,2,10,12) conclusion the age of the first diagnosis of urinary calculus is slightly less in men with a positive family history than those without a family history. the patients’ relatives are recommended to pay attention to the consumption of the calculus-forming foods. more studies are needed to evaluate the risk of calculus formation and its characteristics and complications in the patients’ family members. conflict of interest none declared. references 1. trinchieri a, ostini f, nespoli r, rovera f, montanari e, zanetti g. a prospective study of recurrence rate and risk factors for recurrence after a first renal stone. j urol. 1999;162:27-30. 2. ljunghall s, hedstrand h. epidemiology of renal stones in a middle-aged male population. acta med scand. 1975;197:439-45. 3. curhan gc, willett wc, rimm eb, stampfer mj. family history and risk of kidney stones. j am soc nephrol. 1997;8:1568-73. 4. menon m, resnick mi. urinary lithiasis: etiology, diagnosis, and medical management. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3289-92. 5. kodama h, ohno y. [analytical epidemiology of urolithiasis] hinyokika kiyo. 1989;35:935-47. japanese. 6. stamatiou kn, karanasiou vi, lacroix re, et al. prevalence of urolithiasis in rural thebes, greece. rural remote health. 2006;6:610. 7. safarinejad mr. adult urolithiasis in a populationbased study in iran: prevalence, incidence, and associated risk factors. urol res. 2007;35:73-82. 8. ljunghall s, danielson bg, fellstrom b, holmgren k, johansson g, wikstrom b. family history of renal stones in recurrent stone patients. br j urol. 1985;57:370-4. 9. ulmann a, clavel j, destree d, dubois c, mombet a, brisset jm. [natural history of renal calcium lithiasis. data obtained from a cohort of 667 patients. presse med]. 1991;20:499-502. french. 10. kodama h, ohno y. [descriptive epidemiology of urolithiasis. hinyokika kiyo]. 1989;35:923-34. japanese. 11. ishikawa y, konya e, yamate t, et al. [influence of genetic factors on family history of upper urinary stones]. hinyokika kiyo. 1995;41:349-53. japanese. 12. marya rk, dadoo rc, sharma nk. genetic predisposition to renal stone disease in the first-degree relatives of stone-formers. urol int. 1981;36:245-7. editorial comment a lack of difference versus a lack of power: do we have enough soldiers to liberate the castle? ahmadi asr badr and colleagues conducted a crosssectional study to evaluate the impact of family history on the age of onset and other characteristics of urolithiasis. while the study was based on an interesting question, the authors could not find any significant impact of family history on the age at the onset of the disease, neither in men nor in women. nevertheless, they discussed the difference both in the text and in the conclusion. although a nonsignificant result is not conclusive, it seems that this statistical failure in the present study is mainly due to a lack of power rather than a lack of real difference. for instance, given the number of individuals and the mean and standard deviation for the age of onset (table 1 of the paper), the power of the t test for detecting a significant difference is family history and age of calculi onset—ahmadi asr badr et al 146 urology journal vol 4 no 3 summer 2007 only 26% in men and 5% in women! the same is also true for the other characteristics. in particular for the single calculi, it seems that increasing the sample size would reach to a significant difference (the current power is 38% for this group). patients’ recruitment from a public hospital may be a source of selection bias, as discussed by the authors; however, a systematic difference in family history of calculus between the public and private hospitals is unlikely. therefore, it is not a major issue in this study. abbas basiri,1 ali khoshdel2 1editor, urology journal 2department of clinical epidemiology, artesh university of medical sciences, tehran, iran march-april 2019 best reviewer of the issue – zohreh nazmara zohreh nazmara march 2019 zohreh nazmara has already completed her ph.d. degree in anatomical science at iums (iran university of medical science), tehran, iran, however she has collaborated with her supervisors as an advisor in their team in the fertility health field. she has published some papers and books in international accredited journals. she received two research award from asc (addiction science congress) and ezama (esmaeil zamanian addiction medicine award), which is the most prestigious award in addiction medicine in iran. i have published a paper in urology journal, thus it was an interesting time when i was selected to review in this journal. being a reviewer can raise our scientific insight as a researcher and help us to have dynamic thinking. fortunately, as an iranian researcher, i understand the present research situation and i try to focus on positive points of papers. kidney transplantation 178 urology journal vol 5 no 3 summer 2008 patient and graft survival of kidney allograft recipients with minimal hepatitis c virus infection a case-control study heshmatollah shahbazian,1 eskandar hajiani,2 ali ehsanpour1 introduction: the impact of pretransplant hepatitis c virus (hcv) infection on the outcome of kidney transplantation is controversial. this study was designed to determine the impact of pretransplant minimal hcv infection on the patient and graft survival at a single center in southwest of iran. materials and methods: we designed a historical cohort study on 337 kidney transplant recipients and selected 35 patients with hcv infection and a histological activity index score less than 4 (minimal hcv infection). a group of kidney recipients with negative anti-hcv antibody were compared with the anti-hcv-positive patients in terms of acute allograft rejection, graft loss, mortality, causes of death, and patient and graft survival. the controls were matched for age, sex, donor source, pretransplant dialysis duration, and panel reactive antibodies test. all of the participants had a follow-up period of at least 5 years. results: there were no significant differences in terms of early and late acute allograft rejection episodes between the groups. although patient and graft survival rates were lower in hcv-positive patients at 2 and 5 years, the differences between the two groups were not significant. the main causes of death among patients with and without hcv infection were sepsis and cardiovascular events, respectively. conclusion: our findings suggest that pretransplant minimal hcv infection had no detrimental effect on the short-term patient and graft survival. however, we suggest that kidney transplant recipients with minimal hcv infection be monitored for severe systemic bacterial infections. urol j. 2008;5:178-83. www.uj.unrc.ir keywords: kidney transplantation, hepatitis c, graft rejections, survival analysis 1diabetes research center and division of nephrology, department of internal medicine, golestan hospital, ahwaz jundishapur university of medical sciences, ahwaz, iran 2division of gastroenterology and hepatology, department of internal medicine, golestan hospital, ahwaz jundishapur university of medical sciences, ahwaz, iran corresponding author: heshmatollah shahbazian, md department of internal medicine, golestan hospital, ahwaz jundishapur university of medical sciences, ahwaz, po box 89, iran tel: +98 611 338 6258 fax: +98 611 334 3964 e-mail: shahbazian_he@yahoo.com received may 2007 accepted april 2008 introduction hepatitis c virus (hcv) is a common pathogen that causes chronic hepatitis in patients with end-stage renal disease. the effect of hcv infection on patient survival after kidney transplantation has been a subject of debate, with some but not all studies finding an increased risk of death among patients with a positive anti-hcv antibody before transplantation.(1-5) notwithstanding the outstanding amount of research worldwide, to the best of our knowledge, there has been limited information on the prognosis of hcv-infected patients who received kidney transplantation in iran.(2,6) the prevalence of hcv infection among patients undergoing hemodialysis in our community is still high, especially in the southwest of iran.(7) determination of the severity of hepatitis in patients undergoing kidney transplantation is not a hepatitis c and kidney allograft outcome—shahbazian et al urology journal vol 5 no 3 summer 2008 179 routine procedure in transplant centers. however, it seems that pretransplant liver biopsy in hcvinfected patients may increase the accuracy of the staging of liver disease and improve patient selection for kidney transplantation. our aim was to compare the outcomes of the patient and the kidney allograft between kidney transplant recipients with and without hcv infection. materials and methods we designed a historical cohort study to evaluate the posttransplant impact of chronic hcv infection on the patients who received a kidney transplant at ahwaz jundishapur university’s transplantation centers. the research ethics committee of the university approved the study protocol. a total of 337 patients had received a kidney allograft between may 1997 and december 2001. we selected patients with hcv infection and a histological activity index (hai) score(8) less than 4 (minimal hcv infection) and a matched group of kidney recipients with negative antihcv antibody. all of the patients had routinely been tested for anti-hcv antibody before transplantation using the 2nd or 3rd generation of enzyme-linked immunosorbent assay. serum hcv rna was also assayed with a combined reverse transcript polymerase chain reaction assay (amplicor hcv test; roche diagnostic system inc, branchburg, new jersey, usa) with a detection sensitivity of 10 to 100 copies per milliliter. the hcvinfected patients had been further evaluated by liver biopsy for severity of liver disease before transplantation. patients with an hai score of 4 or higher were excluded from our study. we also excluded those with a positive hepatitis b virus (hbv) surface antigen, because hepatitis b infection may affect the clinical course of hcv infection. of note, none of our patients was coinfected by the human immunodeficiency virus. the control group was selected from among kidney recipients with negative hcv and hbv tests. stratified randomization was used to select a group matched for age, sex, donor source, pretransplant dialysis duration, and panel reactive antibodies test with the patients with minimal hcv infection. all of the patients had received their allografts from a living (related or unrelated) donor. immunosuppressive therapy comprised cyclosporine (initiation dose of 3.5 mg/ kg/d), prednisolone (5 mg/d to 10 mg/d), and azathioprine (100 mg/d) or mycophenolate mofetil (2 g/d). episodes of acute allograft rejection were treated by methylprednisolone, 1 g/d, intravenously for 3 days. physical examination and biochemical tests including serum hcv rna level and liver function tests were performed every other month. transplantation outcomes were reviewed at the 1st, 2nd, and 5th years of the posttransplant follow-up period, and data on death, cause of mortality, chronic allograft nephropathy, and graft loss were collected. survival time was defined as the time between the date of transplantation and death, the most recent followup date, or the end of the study period. graft failure was defined as return to dialysis after transplantation and did not include death with a functioning graft (death-censored analysis). acute rejection was determined according to clinical diagnosis or pathological evidence. the collected data were coded in microsoft access 2000 database software (microsoft corp, redmond, washington, usa) and statistical analyses were done by the spss software (statistical package for the social sciences, version 11.0, spss inc, chicago, ill, usa). the fisher exact test, chi-square test, mann whitney u test, and student t test were used to make univariate comparisons. the kaplan–meier method and log rank test were used for patient and graft survival analyses. continuous variables were demonstrated as mean ± standard deviation or median, where appropriate. the criterion for statistical significance was a p value less than .05. results patients thirty five kidney recipients with a positive antihcv antibody or a positive hcv rna were selected. they had minimal liver involvement and a negative hbv surface antigen. there were 9 seropositive patients for hcv, 7 of whom hepatitis c and kidney allograft outcome—shahbazian et al 180 urology journal vol 5 no 3 summer 2008 with an hai score higher than 4 and 2 with a positive hbv surface antigen, all of whom were excluded. all of the patients had a minimum follow-up period of 5 years, and none of them were lost to follow up in either group. the control group consisted of a matched group of 35 kidney recipients without any positive tests for hcv or hbv. there were no significant differences between the patients and the control group of kidney recipients in terms of age, sex, etiology of kidney disease, duration of follow-up, and duration of hemodialysis, or donor source. the main demographic and clinical features of the transplant patients are shown in table 1. graft outcome during the follow-up period, 7 patients (20.0%) in the anti-hcv-positive group and 5 (14.3%) in the control group experienced acute allograft rejection within the first posttransplant year (p = .38). there were 2 cases of acute rejection during the second posttransplant year, both of which were among the anti-hcv-positive recipients (p = .25). the kidney allograft survival rates were comparable; the 1-, 2-, and 5-year graft survival rates in the anti-hcv-positive patients were 94%, 74%, and 60%, respectively. in the anti-hcvnegative transplant recipients, these rates were 94%, 83%, and 74%, respectively (p = .92, p = .35, and p = .65, respectively). the mean graft survivals were 47.8 ± 3.3 months and 51.7 ± 3.0 months for the kidney recipients in the anti-hcv-negative and anti-hcv-positive groups, respectively (p = .21; figure 1). after the fifth year of follow-up, 6 anti-hcvpositive patients (17.1%) and 4 anti-hcv-negative patients (11.4%) were on dialysis. the remaining kidney recipients showed stable kidney function with normal or nearly normal serum creatinine levels. patient outcome there was no clinical or laboratory evidence of decompensation of liver disease in the anti-hcvpositive group. ten patients (28.6%) in the antihcv-positive group and 5 (14.3%) in the antihcv-negative group died during the follow-up period (p = .12). sepsis was the prominent cause of death in the patients of the anti-hcv-positive group. in contrast, this complication was not frequent in the kidney recipients of the control group; however, the differences between the two groups in causes of death were not significant (table 2). the 1-, 2-, and 5-year patient survival rates in the anti-hcv-positive patients were 97%, 84%, and 68%, respectively. in the anti-hcv-negative transplant recipients, these rates were 97%, 87%, and 84%, respectively (p = .19, p = .34, and p = .75, respectively). the mean patient survival rates were 52.6 ± 2.7 months and 55.7 ± 2.2 characteristics hcv positive hcv negative number of patients 35 35 mean age, y 38.0 ± 8.4 37.4 ± 7.6 sex male 21 (60.0) 20 (57.1) female 14 (40.0) 15 (42.9) donor source living related 8 (22.9) 9 (25.7) living unrelated 27 (77.1) 26 (74.3) duration of dialysis, y 2.2 ± 1.2 2.2 ± 1.1 median follow-up, y 7.2 7.4 median pra, % 20 20 table 1. characteristics of kidney transplant recipients with positive anti-hepatitis c virus antibody and a matched group of kidney recipients *values in parentheses are percents. hcv indicates hepatitis c virus and pra, panel reactive antibody. figure 1. graft survival rates for kidney transplant recipients with and without positive anti-hepatitis c virus (hcv) antibody. hepatitis c and kidney allograft outcome—shahbazian et al urology journal vol 5 no 3 summer 2008 181 months for the kidney recipients in the antihcv-negative and anti-hcv-positive groups, respectively (p = .54; figure 2). discussion the impact of hcv infection on survival figures after kidney transplantation remains controversial.(3-6,9-14) it has been demonstrated that hepatic failure plays an important role as the cause of death in patients surviving more than 5 posttransplant years.(15) however, some reports have indicated similar patient and graft survival in hcv-positive and hcv-negative kidney recipients.(3,14) results of our study demonstrate that the patient and graft survival were comparable between hcv-positive and hcv-negative patients at the first year of transplantation, and although the 2and 5-year survival rates were lower in hcv-positive than in hcv-negative patients, there were no significant differences between the two groups. also, there were no significant differences in the frequency of early or delayed acute allograft rejection between the two groups. ozdemir and associates found a higher graft failure rate due to chronic rejection in hcvpositive than in hcv-negative transplant recipients (68.0% versus 47.8%; p = .001).(13) however, our data showed that although the antihcv-positive recipients had a higher rate of graft loss, there was no significant difference between the two groups. sabet and colleagues published a study from iran,(6) in which they demonstrated that graft loss was seen in 5% of the hcv-positive and none of the hcv-negative patients.(6) the 2-year graft survival was lower in both hcvpositive and hcv-negative patients in our study compared with that in sabet and coworkers’ study. hestin and colleagues(14) demonstrated that 1and 5-year graft survival rates were comparable in the recipients with and without a seropositive hcv. interestingly, they found that hcv infection was associated with proteinuria, a factor that had worsened graft survival independently. according to a study on a large group of 73 707 recipients, meier-kriesche and coworkers found that while graft survival was worse, patient survival of hcv-positive recipients was slightly superior to that of hcv-negative patients. in this study, cardiovascular-related death was less frequent, while gastrointestinal-related and infection-related deaths were more frequent in the hcv-positive patients.(3) our study showed no significant difference in mortality rate between the two groups, and the major causes of death were similar to this study. contrary to meier-kriesche and colleagues’ study, a report by gentil and associates was indicative of that graft survival was significantly lower in hcvpositive transplant recipients. their study was on a cohort of 335 cadaveric allograft recipients who received a 4-drug immunosuppressive regimen. in this study, the comparison results revealed significant difference between the patients with and without hcv infection. their 1-, 5-, and 10-year patient survival rates were 96%, 87%, and 72%, respectively.(4) results of this study are different to ours, but it should cause of death hcv positive (%) hcv negative (%) cardiovascular events 2 (5.7) 3 (8.6) sepsis 6 (17.1)* 1 (2.9) gastrointestinal bleeding 1 (2.9) 0 sudden death 1 (2.9) 0 unknown 0 1 (2.9) table 2. main causes of death in kidney transplant recipients with and without positive anti-hepatitis c virus (hcv) antibody *p value was .053 for sepsis (fisher exact test). figure 2. patient survival rates for kidney transplant recipients with and without positive anti-hepatitis c virus (hcv) antibody. hepatitis c and kidney allograft outcome—shahbazian et al 182 urology journal vol 5 no 3 summer 2008 be noted that all of our patients received their allografts from living donors and were on a triple-drug immunosuppressive regimen. data from one large study on 33 479 kidney allograft recipients showed a significantly higher risk of mortality in hcv-positive patients (adjusted hazard ratio, 1.23; 95% confidence interval, 1.01 to 1.49; p = .04).(5) however, seropositivity was associated with african-american race, male gender, cadaveric donor source, increased duration of pretransplant dialysis, previous transplant, recipient age, etc. patients with hcv infection are more likely to have longer dialysis duration and they are usually older than other patients at transplantation. thus, a lower patient survival rate might be related to these factors rather than hcv infection. such a bias was noted by gentil and colleagues, as well(4); their group of seropositive patients had longer dialysis duration and more frequent blood transfusions. our matched group of hcv-negative kidney recipients did not have such differences with the hcv-positive patients. meier-kriesche and colleagues reported that acute rejection within the first 6 months after allograft transplantation was significantly more frequent in hcv-positive compared with hcv-negative recipients.(3) ozdemir and colleagues noted that there was no significant difference between hcv-positive and hcv-negative patients in early acute graft function, but late acute rejections was significantly more frequent in hcv-positive recipients.(13) in contrast, corell and coworkers demonstrated a significantly lower rate of acute rejection in 118 hcv-positive recipients (28%) compared with 229 hcv-negative recipients (40%). they suggested that it could be explained by the reduction of t-helper cells and altered t-cell proliferative responses to mitogens in hcv-positive recipients.(16) although our study showed a higher rate of early and late acute rejections in hcv-positive patients, the difference was not significant. controversy exists regarding the short-term and long-term impact of hcv infection on the outcome of kidney allograft transplantation and an exact conclusion could not be made from the published papers. differences in the results of these studies may be due to differences in immunosuppressive regimens, study design, diagnostic method of hcv infection, variation in hcv genotypes, duration of pretransplant dialysis, and age of allograft recipients. although in most of these studies long-term survival rates are lower in hcv-positive graft recipients comparing with hcv-negative recipients, regarding the similar short-term graft and patient survival and comparable long-term survival rates—as reported by the present study, renal transplantation remains the best choice for patients with end-stage renal disease and hcv infection with regard to the lower survival rate of hcv-positive patients on maintenance dialysis.(10) conclusion our data suggest that minimal hcv infection per se has no adverse effect on short-term and long-term graft and patient survival, and hcv antibody-positive recipients do not have an increased risk of death after transplantation compared with hcv-negative recipients. since sepsis was slightly more frequent as the cause of death in hcv-positive patients, we suggest that kidney transplant recipients with minimal hcv infection be monitored for severe systemic bacterial infections. these conclusions were based on the comparison of two matched groups. however, a larger sample size is required to further confirm the results. conflict of interest none declared. references 1. legendre c, garrigue v, le bihan c, et al. harmful long-term impact of hepatitis c virus infection in kidney transplant recipients. transplantation. 1998;65:667-70. 2. einollahi b, hajarizadeh b, bakhtiari s, et al. pretransplant hepatitis c virus infection and its effect on the post-transplant course of living renal allograft recipients. j gastroenterol hepatol. 2003;18:836-40. 3. meier-kriesche hu, ojo ao, hanson ja, kaplan b. hepatitis c antibody status and outcomes in renal transplant recipients. transplantation. 2001;72:241-4. 4. gentil ma, rocha jl, rodriguez-algarra g, et al. impaired kidney transplant survival in patients with antibodies to hepatitis c virus. nephrol dial transplant. 1999;14:2455-60. hepatitis c and kidney allograft outcome—shahbazian et al urology journal vol 5 no 3 summer 2008 183 5. batty ds, jr., swanson sj, kirk ad, ko cw, agodoa ly, abbott kc. hepatitis c virus seropositivity at the time of renal transplantation in the united states: associated factors and patient survival. am j transplant. 2001;1:179-84. 6. sabet s, hakemi m, nadjafi i, ganji mr, argani h, broumand b. impact of hepatitis c virus infection on short-term outcome in renal transplantation: a singlecenter study. transplant proc. 2003;35:2699-700. 7. makvandi m, mombini h, latifi m, borhanpovr kh. prevalence of positive anti-hcv antibody in hemdialysis patients. med j ahwaz med univ. 2001;29:1-5. 8. knodell rg, ishak kg, black wc, et al. formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. hepatology. 1981;1:431-5. 9. sezer s, ozdemir fn, akcay a, arat z, boyacioglu s, haberal m. renal transplantation offers a better survival in hcv-infected esrd patients. clin transplant. 2004;18:619-23. 10. knoll ga, tankersley mr, lee jy, julian ba, curtis jj. the impact of renal transplantation on survival in hepatitis c-positive end-stage renal disease patients. am j kidney dis. 1997;29:608-14. 11. pereira bj. hepatitis c in organ transplantation: its significance and influence on transplantation policies. curr opin nephrol hypertens. 1993;2:912-22. 12. roth d, zucker k, cirocco r, et al. a prospective study of hepatitis c virus infection in renal allograft recipients. transplantation. 1996;61:886-9. 13. ozdemir fn, micozkadioglu h, sezer s, et al. hcv antibody positivity significantly affects renal allograft survival. transplant proc. 2003;35:2701-2. 14. hestin d, guillemin f, castin n, le faou a, champigneulles j, kessler m. pretransplant hepatitis c virus infection: a predictor of proteinuria after renal transplantation. transplantation. 1998;65:741-4. 15. weir mr, kirkman rl, strom tb, tilney nl. liver disease in recipients of long-functioning renal allografts. kidney int. 1985;28:839-44. 16. corell a, morales jm, mandrono a, et al. immunosuppression induced by hepatitis c virus infection reduces acute renal-transplant rejection. lancet. 1995;346:1497-8. chronic kidney disease in iran: first report of the national registry in children and adolescences neamatollah ataei1*, abbas madani1, seyed taher esfahani1, hasan otoukesh2, nakysa hooman2, rozita hoseini2, mojtaba fazel3, ali derakhshan4, alaleh gheissari5, hadi sorkhi6, arash abbasi1, daryoosh fahimi7, fatemeh ghane sharbaf8, fakhrossadat mortazavi9, behnaz falakaflaki10, ahmad ali nikibakhsh11, simin sadeghi bojd12, seyyed mohammad taghi hosseini tabatabaei12, kambiz ghasemi13, ali ahmadzadeh14, parsa yousefichaijan15, afshin safaei asl16, baranak safaeian17, salman khazaei18, leila hejazipour1, abolhassan seyed zadeh19, and fatemeh ataei1,20 purpose: knowing the epidemiological aspects of chronic kidney disease (ckd) in children is crucial for early recognition, identification of reversible causes, and prognosis. here, we report the epidemiological characteristics of childhood ckd in iran. materials and methods: this cross-sectional study was conducted during 1991 2009. the data were collected using the information in the iranian pediatric registry of chronic kidney disease (iprckd) core dataset. results: a total of 1247 children were registered. the mean age of the children at registration was 0.69 ± 4.72 years (range, 0.25 –18 years), 7.79 ± 3.18 years for hemodialysis (hd), 4.24 ± 1.86 years for continuous ambulatory peritoneal dialysis (capd), and 3.4±1.95 years for the children who underwent the renal transplantation (rt) (p < .001). the mean year of follow-up was 7.19 ± 4.65 years. the mean annual incidence of ckd 2–5 stages was 3.34 per million age-related population (pmarp). the mean prevalence of ckd 2–5 stages was 21.95 (pmarp). the cumulative 1-, 5-, and 10-year patients' survival rates were 98.3%, 90.7%, and 84.8%, respectively. the etiology of the ckd included the congenital anomalies of the kidney and urinary tract (cakut) (40.01%), glomerulopathy (19.00%), unknown cause (18.28%), and cystic/hereditary/congenital disease (11.14%). conclusion: the incidence and prevalence rate of pediatric ckd in iran is relatively lower than those reported in europe and other similar studies. cakut was the main cause of the ckd. appropriate management of cakut including early urological intervention is required to preserve the renal function. herein, the long-term survival rate was higher among the children with ckd than the literature. keywords: chronic kidney disease; children; epidemiology; etiology; end-stage renal disease; iran introduction chronic kidney disease (ckd) is a condition char-acterized by a gradual loss of renal function. it can 1pediatric chronic kidney disease research center, department of pediatric nephrology, children’s medical center, tehran. university of medical sciences, tehran, iran. 2ali-asghar children’s hospital, iran university of medical sciences, tehran, iran. 3imam khomeini hospital complex, tehran university of medical sciences, tehran, iran. 4shiraz nephro-urology research center, shiraz university of medical sciences, shiraz, iran. 5al-zahra hospital, isfahan university of medical sciences, isfahan, iran. 6non-communicable pediatric diseases research center, department of pediatric nephrology, amirkola children hospital, babol university of medical sciences, babol, iran. 7bahrami children's hospital, tehran university of medical sciences, tehran, iran. 8sheikh children’s hospital, mashhad university of medical sciences, mashhad, iran. 9department of pediatrics, tabriz university of medical sciences tabriz, iran. 10mousavi hospital, zanjan university of medical sciences, zanjan, iran. 11urmia university of medical sciences, urmia, iran. 12department of pediatrics, zahedan university of medical sciences, zahedan, iran. 13department of pediatrics nephrology, hormozgan university of medical sciences, bandar abbas, iran. 14abozar hospital, ahvaz jondishapour university of medical sciences, ahvaz, iran. 15amirkabir hospital, arak university of medical sciences, arak, iran. 16department of pediatrics, guilan university of medical sciences, guilan, iran. 17taleghani pediatric hospital, golestan university of medical sciences, gorgan, iran. 18research center for health sciences, hamadan university of medical sciences, hamadan, iran. 19razi hospital, kermanshah university of medical sciences, kermanshah, iran. 20department of nuclear medicine, valiasr hospital, zanjan university of medical sciences, zanjan, iran. *correspondence: pediatric chronic kidney disease research center, department of pediatric nephrology, children’s medical center, tehran university of medical sciences, tehran, iran. tel : +98 21 66929234, e-mail: ataiinem@tums.ac.ir. received november 2019 & accepted august 2020 be progressive and may ultimately lead to the irreversible nephron loss and scarring(1). extensive research has focused on the epidemiology of ckd in the adult population(2,3). in contrast, there is limited knowledge about urology journal/vol 18 no. 1/ january-february 2021/ pp. 122-130. [doi: 10.22037/uj.v16i7.5759] unclassified the epidemiology of ckd in the pediatric population(4). understanding the epidemiology of ckd in children is crucial for early detection and precise diagnosis, as well as identification of preventable causes of progression, prognosis, and treatment decisions including treatment of reversible causes. etiology, the progression of the disease, and treatment modality in the children with ckd are different from those observed in the adult patients(5,6). in children, ckd not only may progress to end-stage renal disease (esrd) but also influences on the longitudinal bone growth through alterations in the nutrition and mineral metabolism(7). it can also negatively influence the life quality of the patients and family members (8,9). despite few recent studies on the epidemiological and clinical features of the pediatric ckd(10), there is insufficient knowledge about the risk factors leading to disease progression in the children(11). there is much less information available on the epidemiological and clinical manifestations of the iranian children with ckd because of the lack of a central reporting registry(12,13). therefore, in 1991, the iranian pediatric nephrology working group established the iranian pediatric registry of chronic kidney disease (iprckd) aimed at providing a comprehensive national data warehouse for studying various aspects of ckd in the pediatric population. thus, the present study is conducted to report the basic epidemiological information for analysis of the iprckd activity in which 1247 patients with ckd were registered from january 1991 to december 2009. patients and methods study design, setting, and sampling the data were collected using the iprckd core dataset including name, date of birth, gender, primary renal diagnosis and associated diseases, residence, height, serum creatinine (cr), treatment modality, changes in the therapy, death and its cause at the time of registration. the inclusion criteria of the study were: (1) estimated creatinine clearance (ecci) of ≤ 75 ml/min/1.73m2 body surface area according to the schwartz’s formula (14,15,16) for at least 3 months and (2) having less than 19 years of age at the time of registration. there were 31 large and small provinces, at the time of registration in iran, all of which were covered by 19 pediatric nephrology centers. in other words, all the centers in iran were potentially involved in the care of children and adolescents with ckd, accounting for a total population base of 21.3 million children, and a general population of 75 million inhabitants(17) was considered to report the index cases. herein, the children with ckd were not evaluated in each province separately. on the other hand, some provinces lacked the pediatric nephrology center(s) thus; their patients referred to neighboring or non-adjacent provinces with pediatric nephrology center(s) for follow-up treatment. all the 19 pediatric nephrology centers were asked to voluntarily register the characteristics of their children with ckd in the questionnaire. there was mandatory request to register ckd patients in this database. the children with ckd were detected using a standardized registration form containing a predefined list of diagnoses classified into eight groups: congenital anomalies of the kidney and urinary tract (cakut) in the forms of hypodysplasia ± reflux nephropathy and obstructive uropathy, glomerular diseases, cystic/hereditary/congenital diseases, vascular nephropathies, neoplasia/tumors, other renal disorders, miscellaneous causes, and unknown causes. after developing a software program at the following website: “http://www.tums.ac.ir” entitled “http://iprcrf. tums.ac.ir” and including identification code for regional principal investigators (pediatric nephrologists), they were asked to record their own patient’s data electronically in the questionnaires and send them via e-mail to the executive director. this phase of the registry has been completed with the participation of nearly 120 pediatric nephrologists working in 19 pediatric nephrology centers in the country. all pediatric nephrologists followed a single protocol and, considering the comprehensiveness of the registration system that covered the whole country, as well as the full justification of pediatric nephrologist, the validity, and reliability of the results can be confirmed. the data set used and analyzed during the study is available from the corresponding author upon request. in this phase of registry (first phase), we did not invite primary care physician or pediatrician to register and participate in sharing ckd patients. however, we intended to include primary care physicians in the upcoming second phase of registry. the incidence was calculated using the number of newly detected cases in each year, while the point prevalence rate included all the living children followed in the registry on 31 december 2009. both incidence and prevalence were expressed as per million age-related population (pmarp). hypertension was defined as the blood pressure above the 95th percentile with respect to age, gender, and height as reported in the task force percentile reference(18). the children were categorized into the patients with ckd stages 2–5 according to the classification described by the clinical practice guidelines of the national kidney foundation’s kidney disease outcomes quality initiative (kdoqi guidelines)(19). stages 2 4 were considered as preterminal chronic ckd in iran-ataei et al. table 1. distribution of the children with respect to different stages of ckd in the studied patients ckd stage study no (% ) period ckd 2 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 0 0 2(5.8) 2(8) 2(5.2) 1(2) 2(2.8) 3(4.5) 5(6.3) 2(2.5) 1(1.35) 3(3.75) 2(2.35) 2 (2.2) 1(1.35) 4(4.4) 2(2.3) 3(4.3) 4(6.1) ckd 3 0 0 1(2.9) 1(4) 1(2.6) 1(2) 6(8.3) 6(9) 7(8.8) 7(8.8) 2(2.7) 7(8.75) 6(7) 9(9.8) 9(9.7) 6(6.5) 14(15.9) 2(2.9) 9(13.6) ckd 4 1(3) 1(3.6) 2(5.8) 2(8) 2(5.2) 8(16.3) 4(5.6) 10(14.9) 12(15) 17(21.2) 7(9.5) 7(8.75) 10(11.75) 13(14.1) 12(12.9) 19(20.4) 17(19.3) 17(22.5) 15(27.7) ckd 5 32(97) 27(96.4) 29(85.3) 20(80) 33(86.8) 39(79.6) 60(83.3) 48(71.6) 56(70) 54(67.5) 64(86.5) 63(78.75) 67(78.8) 68(76.1) 71(81.7) 64(68.8) 55(62.5) 48(68.6) 38(57.6) total 33 28 34 25 38 49 72 67 80 80 74 80 85 92 93 93 88 70 66 vol 18 no 1 january-february 2021 123 renal failure, while ckd stage 5 esrd was defined as either having a glomerular filtration rate (gfr) of <15 ml/min/1.73m2 or being candidate for renal replacement therapy (rrt) through dialysis or transplantation. for the children less than two years of age, the percentage of loss of renal function in each stage of the kdoqi guidelines was extrapolated considering the reference values of gfr in the children under than two years old(19). the gfr was assessed according to the schwartz’s formula(14,15,16). the estimated glomerular filtration rate (egfr) in all the children with ckd was calculated based on the schwartz's formula modified for the children (cystatin c-based gfr estimating equation) using the fixed numbers of 48 and 38 for boys and girls, respectively according to the following equation(16). creatinine was determined by the jaffe method in all the centers. descriptive statistics including the frequency tables, charts, and percentages were used for presenting the categorical variables. the patient’s survival was analyzed using the kaplan– meier method. the risk for progression to esrd was assessed using the multiple cox proportional hazards regression. p-value of ≤ .05 was considered as statistically significant. statistical analyses were performed using the stata software, version 12 (stata corp, college station, tx, usa). table 2. primary causes of ckd in all the registered patients groups of diseases no % n % obstructive 190 15.23 posterior urethral valve 73 5.85 anterior urethral valve 1 0.08 cakut bilateral ureteral stenosis 5 0.4 ureteropelvic junction stenosis 22 1.76 ureterovesical junction stenosis 9 0.72 other obstructive malformation 9 0.72 prune belly syndrome 2 0.16 neurogenic bladder 69 5.53 hypodysplasia 79 6.33 renal aplasia / hypo/dysplasia 79 6.33 interstitial nephritis 14 1.12 reflux nephropathy/ 230 18.44 reflux nephropathy 105 8.42 pyelonephritis pyelonephritis 26 2.08 vur with associated neurogenic bladder 60 4.81 vur without associated neurogenic bladder 25 2 glomerulopathies 237 19.00 focal segmental glomerulosclerosis 82 6.57 gn with advanced diffuse sclerosis 4 0.32 focal segmental proliferative gn 2 0.16 post infectious gn 21 1.68 crescentic gn 38 3.04 membranous gn 3 0.24 membranoproliferative gn type1 20 1.6 membranoproliferative gn type2 4 0.32 nonclassified gn 9 0.72 idiopathic nephrotic syndrome 20 1.6 sle nephritis 28 2.24 henoch-schonlein nephritis 5 0.4 other systemic immunologic disease 1 0.08 cystic / hereditary /congenital diseases 159 12.72 juvenile nephronophthisis 25 2 infantile polycystic kidney disease 29 2.32 adult-type polycystic kidney disease 1 0.08 undetermined polycystic kidney 7 0.56 medullary cystic disease 6 0.48 primary hyperoxaluria 3 0.24 laurence moon biedl syndrome 10 0.8 congentital nephrotic syndrome 22 1.76 alport syndrome 21 1.68 cystinosis 34 2.72 cystinuria 1 0.08 vascular nephropathies 47 3.76 hemolytic uremic syndrome 40 3.2 sepsis-induced renal ischemia 4 0.32 polyarteritis nodosa 2 0.16 renal artery stenosis 1 0.08 neoplasia / tumors 6 0.48 wagner syndrome 1 0.08 wilms' tumor 4 0.32 others 1 0.08 other renal disorders 24 1.92 sickle cell nephropathy 1 0.08 diabetic glomerulonephritis 6 0.48 nephropathy + mental retardation 6 0.48 fanconi syndrome 10 0.8 acute tubolar necrosis 1 0.08 miscellaneous conditions 47 3.76 nephrolithiasis 25 2 hyperoxaluria 11 0.88 others 11 0.88 unknown 228 18.28 228 18.28 total 1247 100 ckd in iran-ataei et al. unclassified 124 results general characteristics of the subjects totally, 1247 children were registered (662 boys, 585 girls, male/female ratio of 1.1) from january 1991 to december 2009. the mean age of the patients at the time of registration was 7.69 ± 4.72 years (range, 0.318). the mean follow-up duration was 7.19 ± 4.65 years. concerning the gender of the patients, mean age of the patients at the time of registration was (6.27 ± 3.78) and (6.53 ± 3.82) years for boys and girls, respectively (p = 0.22). the mean annual incidence and prevalence of ckd 2–5 stages was 3.34 (pmarp) and 21.95 (pmarp), respectively. the mean annual incidence of ckd 2–4 and ckd 5 stages was 0.83 (pmarp) (range, 0.06-1.57) and 2.53 (range, 1.11-3.62), respectively. the mean annual prevalence of ckd 2–4 and ckd 5 stages was 2.98 (pmarp) (range, 0.06-7.14) and 18.98 (range, 1.78-45.86), respectively. ckd classification at the time of registration, 41(3.28%) children were in ckd stage 2, 94 (7.54%) in ckd stage 3, 176 (14.11%) in ckd stage 4, and 936 (75.06%) were in ckd stage 5. a high proportion (75.06%) of the patients was diagnosed with ckd stage 5 at the first visit. during the study period, the number of the patients with ckd stage 5 decreased from (97%) in 1991 to (57.6%) in 2009. at the same time, the frequencies of ckd in the early stages increased over the years. table 1 shows the distribution of the children with respect to ckd stage during the whole registration period. incidence and prevalence the annual incidence of ckd was equal to 1.43 (pmarp) in 1991. it decreased to 1.21(pmarp) in 1992, while gradually increased to 4.03 (pmarp) in 2006, thereafter the incidence decreased to 2.86 (pmarp) (mean 2.84; range, 1.08-4.03). the prevalence rate had an increasing trend in this period so that, it reached from 1.43 (pmarp) in 1991 to 48.10 (pmarp) in 2009 (mean 19.41; range, 1.43-48.10) (figure 1). causes of ckd the etiology of ckd included the cakut in 499 cases (40.01%) [hypodysplasia ± reflux nephropathy in 309 cases (24.77%) ,and obstructive uropathy in 190 cases (15.23%)], glomerulopathy in 237 cases (19.00%), unknown cause in 228 cases (18.28%), cystic/hereditary/ congenital diseases in 139 cases (11.14%), miscellaneous conditions in 47 cases (3.76%), vascular nephropathies in 47 cases (3.76%), other renal disorders in 44 cases (3.52%) ,and neoplasia /tumors in 6 cases (0.48%) as shown in (figure 2). table 2 shows the primary causes of ckd in all the registered children. a significant decreasing trend was observed in the cases with unknownetiology from 33% in 1991 to 13.6% in 2009 (p for trend=.01). renal replacement therapy out of 1247 registered children, 310 (24.86%) of them were on the conservative treatment (188 boys, 122 girls mean age: 6.53 ± 4.77 years (range, 0.24-17.8), 537 (43.06%) of them had esrd who were on the chronic hemodialysis (hd), ( 281boys and 256 girls; mean age: 8.85 ± 4.26 years (range, 0.24-17), 182 (14.6%) of them were on the continuous ambulatory peritoneal dialysis (capd) (98 boys, 84 girls mean age: 4.27 ± 4.41 years (range, 0.5-16.4), and 218 (17.48%) of them underwent the renal transplantation (rt) (104 boys,114 girls mean age: 9.41 ± 4.13 years (range, 1-15.2). the death occurred in 138 patients (11.06%), mainly due to the cardiovascular and infectious complications. hd was the most commonly used modality of rrt. among 218 children who underwent the rt, 48 patients (22.01%) lost their first grafts. the majority (73.17%) of the transplanted children received their graft from the deceased donors. according to the results of kaplan-meier analysis, the 1-, 5 and 10-year patients' survival rates were obtained as 98.3%, 90.7%, and 84.8%, respectively (table 3). as shown in figure 3, (a) the survival rate was lower in the boys than girls, there were no significant gender differences (hr= 1.14, p = 0.42) and (b) patients with esrd had lower survival rate compared to those affected with other stages of ckd, but the difference was not statistically significant between the two groups (hr = 1.28, p = 0.26). mean age of the patients at the time of death was 6.71 ± 4.52 years (range, 0.25-15). the percentage of death in the studied patients ranged from 20.43% in 2005 to 4.55% in 2009. discussion currently, ckd is a public health issue due to the rapid rising trend of its prevalence (20). to the best of our knowledge, this study is the first cross-sectional, nationwide report on the epidemiologic characteristics and etiology of the iranian children and adolescents with ckd. due to the asymptomatic nature of ckd, especially in the earlier stages, there are no accurate epidemiological data on the pediatric patients. according to the annual report by the european renal association – european dialysis and transplant association (era-edta) registry in 2007, the overall ckd prevalence in the usa adult population was equal to 11% (stage 1, 3.3%; stage 2, 3.0%; stage 3, 4.3%; stage 4, table 3. patients' survival for all the registered children with ckd (1991-2009) using the life table survival time (year) total event censored survival probability se 95%ci 1 1247 21 1 0.983 0.004 0.97, 0.989 2 1225 25 68 0.962 0.005 0.95, 0.97 3 1132 18 120 0.946 0.007 0.93, 0.958 4 994 17 107 0.929 0.008 0.91, 0.94 5 870 19 110 0.907 0.009 0.89, 0.92 6 741 8 106 0.897 0.01 0.88, 0.91 7 627 12 114 0.878 0.011 0.84, 0.89 8 501 5 50 0.869 0.011 0.84, 0.88 9 444 3 4 0.863 0.012 0.82, 0.87 10 437 7 60 0.848 0.013 0.82, 0.87 ckd in iran-ataei et al. vol 18 no 1 january-february 2021 125 unclassified 126 0.2%, and stage 5, 0.2%)(21). the prevalence rate for the early stages of ckd was about 50 times higher than that of advanced stages. unfortunately, there is no comparable information regarding the ckd in a pediatric population, especially for early-stages of the disease. in the present study, the prevalence of ckd stages 2-5 was lower than that reported in the studies conducted in italy(10) and serbia(22). the prevalence rate of ckd stage 5 decreased over the study period. in the same period, an increase occurred in the frequency of the early stages of ckd (table1) attributing to the routine antenatal ultrasound screening, early detection of renal and urinary tract anomalies, early urological interventions, and treatment. the mean incidence and prevalence rate of ckd among the iranian children was relatively lower compared to those reported from the european countries, such as serbia( 22), italy(10), as well as chile(23) and nigeria(24) (figure 4). however, it is difficult to make a direct comparison regarding the incidence and prevalence of ckd in different pediatric populations due to the methodological differences in the case definitions and disease classifications both within and between the countries. it has been reported that, pediatric patients with esrd account for a very small proportion of the total esrd population(21). there are considerable variations in the incidence and prevalence of esrd in the pediatric poptable 4. etiology of ckd in iran compared to other similar studies registry naprtcs[6] italy[10] belgium[29] iran anzdata[34] espn/erauk [36] japan [32] [reference] edta [37] inclusion criteria ckd(egfr <75) ckd(egfr <75) ckd(egfr <60) ckd(egfr <75) esrd ( rrt ) esrd ( rrt) esrd (rrt) esrd (rrt) age ( years) 0-20 0-19 0-19 0-19 0-19 0-15 0-15 0-19 period 1994 2007 1990 2000 2001-2005 1991-2009 2003-2008 2008 2004-2008 1998 study sample size 7,037 1,197 143 1247 369 499 428 582 cakut 3,361 (48%) 689 (58.0%) 84 (59%) 499 (40%) 127 (34%) 182 (36.0%) 184(43% ) 208 (36%) hypodyspalasia± 1,907(27% ) 516(43.1%) 66 (46.1% ) 309 (24.7%) 95 (25.7%) 135(31.5%) 198 (34%) etiology reflux nephropathy obstructive uropathy 1,454(20.6%) 173 (14.4%) 18 (12.6% ) 190 (15.2% ) 32 (8.7%) 49(11.4%) 10 (1.7%) glomerulopathies 993 (14%) 55 (5%) 10 (7% ) 237 (19.0%) 108 (29%) 76 (15%) 78(18% ) 130 (22% ) hus 141 (2.0%) 43 (4%) 9 ( 6% ) 40 (3.2%) 9 (2.0%) 29 (6%) 13 (2%) hereditary nephropathies 717 (10%) 186 (15%) 27 (19% ) 21 (1.7%) 112 (22%) 69 (12%) congenital ns 75 (1%) 13 (1%) 5 (3.5%) 22 (1.8%) 7 (1.9%) 15(3.5%) 34 (5.8%) metabolic disease 5 (3.5%) 17 (3.4%) 18(4.2% ) cystinosis 104 (1.5%) 22 (1.8%) 2 (1.4%) 34 (2.7%) 4 (1%) 2 (0.3%) cystic kidney disease 368 (5.2%) 101 (8.4%) 13 ( 9% ) 43 (3.4%) 25 (6.7%) 59 (11.8%) 49(11.4%) 35 (6%) ischemic renal failure 158 (2%) 49 (4%) 3 (2% ) 4 (0.3%) 8 (2%) 11 (2%) 11(1.9%) miscellaneous conditions 1,485 (21.1%) 122 (10.2%) 10 ( 7% ) 47 (3.8%) 65 (17.6%) 52 (10.4%) 19(4.4%) 83 (14.3%) missing / unknown 182 (2.6%) 40 (3.3%) 228 (18.3%) 16 (4.3%) 37 (7.4%) 65 (15.2%) 34 (5.8%) abbreviations: ckd, chronic kidney disease; esrd, end-stage renal disease; rrt, renal replacement therapy; egfr, estimated glomerular filtration rate (ml/min/1.73 m2); cakut, congenital anomalies of the kidney and urinary tract; ns, nephrotic syndrome; hus, hemolytic uremic syndrome; naprtcs, north american pediatric renal trials and collaborative studies; anzdata, australia and new zealand dialysis and transplant registry; espn/era-edta registry, european registry for children on renal replacement therapy figure 1. incidence and prevalence rate of ckd during the study period ckd in iran-ataei et al. ulation across the regions of the world. in the present study, the mean annual incidence and prevalence rates of esrd for children were equal to 2.53 and 18.98 (pmarp), respectively. the results of the study showed that the annual incidence of childhood ckd in iran increased from 1.21 (pmarp) in 1992 to 4.46 (pmarp) in 2006, while at the end of three years of study, the trend became downward. this increasing trend has been also observed in the usa from 1980 to 2008(25), as well as european countries during the 1980s(26) while, australia and new zealand have experienced a constant trend regarding the incidence of childhood ckd during the past 25 years (27). consistent with our findings, the above-mentioned studies have also reported an increasing trend for the prevalence of childhood ckd attributing to the improved survival rate of the patients. the annual incidence of rrt including the chronic hd, capd, and rt was less in the iranian children 2.53 (pmarp) than that of other pediatric studies conducted in the countries such as serbia 5.7 (pmarp)(22), netherlands 5.8 (pmarp) (28), belgium 6.2 (pmarp)(29), and turkey10.9 (pmarp) (30). the true proportion of ckd is expected to be higher than the value observed in the present study, as it is usually asymptomatic in its earliest stages and is often not diagnosed, and therefore, is not reported. our results revealed a higher frequency of ckd in the boys than the girls (m/f=1.13), which is in accordance with other pediatric studies worldwide (24,29). the highest reported incidence rate for esrd in the children belonged to the usa, new zealand, and austria by 14.8, 13.6, and 12.4 per million populations, respectively(31) while, the lowest rate was reported in japan(32). in our study, the prevalence of ckd stage 5 was similar to the report from sweden(33) but lower than that of other european countries, australia, and the united states(10,22,31, 34,35) (figure 4). cakut is the most common cause of esrd in the figure 2. primary causes of ckd stages 2–5 in the iranian children figure 3. (a) estimated patient’s survival in the studied children with respect to the gender. (b) estimated patient’s survival in the studied children with respect to the ckd stage. ckd in iran-ataei et al. vol 18 no 1 january-february 2021 127 unclassified 128 pediatric patients undergoing the rrt(9,10,23). in this study, cakut and glomerulopathies were leading causes of ckd in 40.01% and 19.00% of cases, respectively, which is consistent with the results reported by the anzdata(34), uk(36) and japanese registry(32), but hereditary nephropathies were the second cause of ckd in the espn/era-edta(37), italian(10), and belgian registry(29) (table 4). higher frequency of cakut including renal hypodysplasia as well as obstructive uropathy in the males can justify more frequency of ckd in the boys than the girls(9). hd was the first modality used for rrt in the majority of children with esrd. the etiology of ckd remained unknown in 18.3% of the patients similar to the studies by safouh et al., (20.6%)(38) and lewis et al., (15.2%)(36) mostly due to late manifestation with small smooth kidneys, where tissue sampling (biopsy) would be of little or no benefit to the patients highlighting the need for further investigations in this regard to save many lives. in our study, more than 75% of the children were in the advanced stage of ckd at the time of presentation. poor manifestation of ckd symptoms, delay in diagnosis, and late referral to the pediatric nephrologist makes it difficult to detect the ckd in early stages. since 1976, the pediatric ckd registries revealed the reduction of unknown cause of etiology from 39% to 1.8% in the recent years (10,22,39,40). however, the etiology of ckd is still unknown in 20 27% of the adult patients attributing to the multiple factors in the adults(41). the mortality rate of 11.06% in the population under study was similar to that reported in the study by mcdonald and craig(42). among them, one patient died in the pre-terminal phase due to primary disease or serious coexisting morbidity; 81(15.08%) patients died during treatment with the figure 4. incidence and prevalence rate of childhood ckd in different countries hd; 54(29.67%) patients died during capd treatment, and 2 patients died after rt (1 died due to the cerebrovascular accident, the other died due to the sepsis). in our study, cardiovascular events (50%) and infections (11.11%) were the main causes of death as reported by other studies(43). rt is associated with higher patients' survival rates, improving quality of life, and fewer public health costs compared to relying on the dialysis(44). the 10–year patients' survival (84.8%) observed in our study is comparable to that reported in the studies by mcdonald and craig (79%)(42), peco-antic et al., (75%) (22) and anzdata registry (79%)(34). on the other hand, these results are consistent with the findings reported in the studies by mitsnefes et al.,(45) and neild (41). the improving trend in the survival rates among the patients in the present study is more likely to be related to rt rather than dialysis. all the pediatric nephrologists followed a single protocol thus, the validity and reliability of the results can be confirmed considering the comprehensiveness of the registration system that covered the whole country, as well as the full justification by the pediatric nephrologists. there were a number of limitations in this study. firstly, the retrospective nature of the study and the lack of screening programs to identify the children with ckd in the early stages of the disease secondly, incomplete or missing data within the medical records and finally, inter-laboratory variation in the calibration of serum cr assay, which might have led to some variability, especially for estimating the gfr were among the limitations of this study. despite these limitations, this study provided a comprehensive data source on the childhood ckd in iran that can be used for healthcare planning and as a basis for further researches. conclusions the iprckd provided valuable information about the epidemiological characteristics of the pediatric ckd in iran. the incidence and prevalence rate of childhood ckd in iran was found to be relatively lower than those reported from european countries and other similar studies. most children had non-glomerular disease and cakut was the main cause of ckd similar to the studies reported from the european countries. however, the etiology of ckd was unknown in a significant number of children (18.3%) highlighting the need for further investigation on the etiologic factors associated with the progression of ckd. the long-term survival rate among the children with ckd in the present study was higher than the similar studies. acknowledgement the authors would like to thank professor farahnak asadi for his thoughtful comments. we also thank the staff of pediatric nephrology, dialysis, and transplant centers in all parts of the country for their kind cooperation, as well as the patients and their families who contributed to this study. conflict of interest the authors declare no conflict of interest. ckd in iran-ataei et al. references 1. greenbaum la, warady ba, furth sl. current advances in chronic kidney disease in children: growth, cardiovascular, and neurocognitive risk factors. semin nephrol. 2009; 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33:169-79. 8. kiliś-pstrusińska k, medyńska a, chmielewska ib, grenda r, kluska-jóźwiak a, leszczyńska b, et al. perception of healthrelated quality of life in children with chronic kidney disease by the patients and their caregivers: multicentre national study results. qual life res. 2013; 22:2889-97. 9. warady ba, chadha w. chronic kidney disease in children: the global perspective. pediatr nephrol. 2007; 22: 1999–2009. 10. ardissino g, dacco v, testa s, bonaudo r, claris-appiani a, taioli e, et al. italkid project epidemiology of chronic renal failure in children: data from the italkid project. pediatrics. 2003; 111:e382–e87. 11. staples ao, greenbaum la, smith jm, gipson ds, filler g, warady ba, et al. association between clinical risk factors and progression of chronic kidney disease in children. clin j am soc nephrol. 2010; 5:2172-79. 12. madani k, otoukesh h, rastegar a, van why s. chronic renal failure in iranian children. pediatr nephrol. 2001; 16:140-44. 13. gheissari a, kelishadi r, roomizadeh p, abedini a, haghjooy-javanmard s, abtahi sh, et al. chronic kidney disease stages 3-5 in iranian children: need for a school-based screening strategy: the caspian-iii study. int j prev med. 2013; 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39: s1– s2 66 (suppl1). 20. hallan si, coresh j, astor bc, asberg a, powe nr, romundstad s, et al. international comparison of the relationship of chronic kidney disease prevalence and esrd risk. j am soc nephrol. 2006; 17:2275-84. 21. stel vs, kramer a, zoccali c, jager, kj. the 2007 era-edta registry annual report—a precis. ndt plus. 2009; 2: 514–21. 22. peco-antic a, bogdanovic r, paripovic d, paripovic a, kocev n, golubovic e, et al. epidemiology of chronic kidney disease in children in serbia. nephrol dial transplant. 2011; 27:1978-84. 23. lagomarsimo e, valenzuela a, cavagnaro f, solar e. chronic renal failure in pediatrics 1996. pediatr nephrol. 1999; 13:288-91. 24. anochie i, eke f. chronic renal failure in children: a report from port harcourt, nigeria (1985–2000). pediatr nephrol. 2003; 18:69295. 25. the united states renal data system. usrds 2010. annual data report: atlas of chronic kidney disease and end-stage renal disease in the united states. national institutes of health, national institute of diabetes and digestive and kidney diseases: bethesda, md, 2010. 26. van der heijden bj, van dijk pc, verrier-jones k, jager kj, briggs jd. renal replacement therapy in children: data from 12 registries in europe. pediatr nephrol.2004; 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17: 456–61. 33. esbjörner e, berg u, hansson s. epidemiology of chronic renal failure in children: a report from sweden 1986-1994. swedish pediatric nephrology association. pediatr nephrol. 1997; 11:438-42. 34. mctaggart s, mcdonald s, henning p, dent h. paediatric report. anzdata registry report 2009, australia and new zealand dialysis and transplant registry. adelaide, south australia. 35. fivush ba, jabs k, neu am, sullivan ek, feld l, kohaut e, et al. chronic renal insufficiency in children and adolescents: the 1996 annual report of naprtcs. north american pediatric renal transplant cooperative study. pediatr nephrol.1998; 12:328–37. 36. lewis ma, shaw j, sinha md, adalat s, hussain f, castledine c, et al. uk renal registry 12th annual report (december 2009): chapter 14: demography of the uk pediatric renal replacement therapy population in 2008. nephron clin pract. 2010;115:c279– c88. 37. espn/era-edta registry. espn/eraedta registry annual report 2008. 2010. http://www.espn-reg.org. 38. safouh h, fadel f, essam r, salah a, bekhet a. causes of chronic kidney disease in egyptian children. saudi j kidney dis transpl. 2015; 26:806-09. 39. scharer k, chantler c, brunner fp, gurland hj, jacobs c, selwood nh, et al. combined report on regular dialysis and transplantation of children in europe, 1975. proc eur dial transplant assoc.1976; 13:59–103. 40. smith jm, martz k, blydt-hansen td. pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: a report of the north american pediatric renal trials and collaborative studies. pediatr transplant. 2013; 17:149-57. 41. neild gh. what do we know about chronic renal failure in young adults? primary renal disease. pediatr nephrol. 2009; 24: 1913–19. 42. mcdonald sp, craig jc. australian and new zealand paediatric nephrology association. long-term survival of children with end-stage renal disease. n engl j med. 2004; 350:2654– 62. 43. chesnaye nc, schaefer f, groothoff jw, bonthuis m, reusz g , heaf jg , et al. mortality risk in european children with endstage renal disease on dialysis. kidney int. 2016; 89:1355-62. 44. wolfe ra, ashby vb, milford el, ojo ao, ettenger re, agodoa ly, et al. comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. n engl j med. 1999; 341:1725-30. 45. mitsnefes mm , laskin bl, dahhou m, zhang x, foster bj. mortality risk among children initially treated with dialysis for end-stage kidney disease, 1990-2010. jama. 2013; 309:1921-29. ckd in iran-ataei et al. unclassified 130 pediatric urology suprapubic percutaneous assisted cystoscopic excision of posterior urethral fibroepithelial polyps in pediatric patients esra ozcakir*1, mete kaya1 purpose: the aim of this study was to evaluate pediatric posterior urethral fibroepithelial polyps, their diagnosis and endoscopic treatments with suprapubic assisted transurethral polyp excision which is described by us. materials and methods: we reviewed the charts of patients (n=6) who underwent suprapubic percutaneous assisted cystoscopic excision for posterior urethral fibroepithelial polyp from 2014 to 2019. their data were retrospectively reviewed in terms of clinical features, diagnostic methods, endoscopic approaches, and postoperative results. results: the 6 patients, the mean age of 3 years (4 months-6 years), with a solitary polyp of posterior urethra diagnosed and removed by suprapubic percutaneous assisted cystoscopic excision in five years. the most common complaint was urinary tract infection (n:3). the urethral polyps were diagnosed by ultrasound and cystoscopy. there was no intraoperative or postoperative complication except for one patient with bleeding from the trocar site. all of the specimens after histopathology examinations showed fibroepithelial polyps and no recurrence was seen. conclusion: posterior urethral polyps may cause obstructive effect in the urinary tract. the treatment should be performed with the least possible invasive method without injuring urethral wall. we believe that suprapubic percutaneous assisted cystoscopic resection, described by us is an easy, reliable and effective method for treatment procedure of posterior fibroepithelial urethral polyps. keywords: solitary urethral polyp; children; endoscopic resection; cystoscopy; voiding cystourethrography introduction isolated polyps can emerge and develop in any area of the urinary tract. the sources of their origination are mostly the ureter and renal pelvis, as well as the posterior urethra in rare cases(1). the posterior urethral fibroepithelial polyp (pufp) is known as a rare and usually benign lesion emerging from the verumontanum or posterior urethral mesodermal tissue(1-4). polyps usually provoke a variety of explicit symptoms such as recurrent urinary tract infection (uti), urinary retention, and lower urinary tract symptoms among pediatric patients(1). to diagnose pufp, ultrasound (us), voiding cystourethrogram (vcug), and cystourethroscopy are used(3). the treatment approaches of pufp include open cystostomy and transurethral resection or fulguration of the polyp by cystoscopy(3). the current study involves the six pediatric patients who underwent pufp excision with suprapubic percutaneous assisted transurethral excision (spate) endoscopically. in the present study, we aim to reflect on the experience of clinical appearance for pufps and treatment method by spate. materials and methods this retrospective study is based on the evaluation of the data of patients diagnosed with pufp who were treated in the pediatric surgery department of university of health sciences, bursa medical faculty between january 2014 and june 2019. the required data for the 1university of health sciences, bursa medical faculty, department of pediatric surgery, bursa 16100, turkey. *correspondence: university of health sciences, bursa medical faculty, department of pediatric surgery, bursa 16100, turkey. phone: +90(224) 2955000. e-mail: dresramermer@hotmail.com. received october 2019 & accepted june 2020 analyses were obtained from the electronic database of the institution. the clinical characteristics, diagnostic methods, endoscopic approaches, surgical techniques, as well as postoperative results, were recorded for the cases with urethral polyp (table 1). the data revealed that the endoscopically polyp excision by spate method was applied to all patients by the same surgeon over the previous five years. written informed consent was obtained from each parent before the procedure. this method is visually illustrated in figure 1. since the cystoscopic approach is now a routinely practiced surgery for evaluation of various urinary diseases, we did not seek approval from the ethics committee because our method did not pose an additional risk for patients and is a modification of previous methods. all tissue samples were examined histopathologically. operative procedure spate: a smooth, mobile, pedunculated polyp developing within posterior urethra was identified via cystoscopy (figure 2). during a cystoscopic operation, a 2 mm laparoscopic grasper was placed into the patient's filled bladder transvesically through a sharped-edged suprapubic bladder catheter's trocar. mannitol solution was used for intermittent or continuous irrigation to get a brighter cystoscopic view. a laparoscopic instrument was utilized to hold polyp as tightly as possible. stabilization of polyp secured total resection with ensuring a safe distance to the base of the bladder mucosa. in urology journal/vol 18 no. 1/ january-february 2021/ pp. 86-91. [doi: 10.22037/uj.v16i7.5688] vol 18 no 1 january-february 2021 87 the meantime, a transurethral excision was performed easily by using the electrocautery resectoscope for the lesion's complete removal (figure 3). the removed polyp was retrieved by transurethral basket catheter. samples taken during the operation were examined histopathologically. results the pediatric population included five boys and one girl aged between four months and six years (the mean age of 3). of these, three patients (50%) had recurrent uti with fever, vomiting, hematuria, and abdominal pain. two patients had voiding issue with acute urinary retention and intermittent micturition resulting from polyp obstacle. the last boy presented with extra-urinary symptoms and had an incidentally detected urethral polyp by us. in addition, patients had concomitant urinary diseases such as vesicoureteral reflux, urinary collecting system duplication, and hydronephrosis. the patients' characteristics and the diseases accompanied by pufp were presented in table 1. diagnostic modalities for the pufp were as followed: in two cases the polypoid mass image was clearly identified by us (figure 4), in three cases the polyp was detected by cystoscopy during vesico ureteral reflux (vur) treatment, and for the last one, the vcug revealed a polyp as a filling defect in the posterior urethra (figure 5). all polyps, solitary and sizes were ranging from 5×8 mm to 9×20 mm emerged in the posterior urethra, and all of the polyps were removed successfully by spate. the urethral catheters were removed within 36 hours, following the surgical intervention. the extra surgical intervention included sub ureteric injection for three patients with vur and ureteroneocystostomy in one patient who also has right-sided duplicated collecting system with vur. further, the clinical course of the patient with bilateral hydronephrosis was improved remarkably after spate procedure without extra intervention. except for bleeding that stops spontaneously in the trocar line, no intraoperative or postoperative complications were observed. the mean duration of hospitalization was 3,4 days. histopathologic examinations revealed fibroepithelial polyps in all patients (figures 6-7). the patients were continued to be monitored for a period of one year. they were followed up with the urinary us and urine analyses every month. afterward, all patients were evaluated by vcug at the first 6th months and control cystoscopies at the first year. there were good cosmetic outcomes for all and no complications or recurrence was observed throughout this follow up period. discussion in childhood, pufps are rare lesions originating in the lower urinary tract, yet they are considered to be a benign fibrous tumour(3,4). regarding the current literature, the reported epidemiologic age of patients diagnosed with pufp ranges from first months to 80 years, whereas 82% of all cases usually occur in patients younger than 20 years and manifest themselves in the first decade(5-7). as claimed by kimchhe and downs, the average age of manifestation is between 8.25 and 9.7 years, yet our series of clinical studies represented the mean age of 3 years(6,7). additionally, boys are known to have a higher risk of developing pufp than girls; for all that, the literature and clinical data related to female patients are quite limited(3,8-10). alike, in our series, male patients were the majority. the etiology of pufp still remains unclear, and it is suggested that the pathology has congenital origins. in the literature, experts on pufp propose certain concepts on the etiology of pufps, including the developmental failure in the invagination process of submucous glandular material of the prostate gland's inner zone, an abnormal protrusion of the urethral wall or epithelial changes secondary to the maternal estrogen(7,11,12). besides, infectious, obstructive and traumatic causes have been theoretically considered as the physiological triggers of this disease(7,13). from the clinical viewpoint, pufps are accompanied with explicit symptoms due to intermittent or acute obstruction of the bladder outlet, such as hesitancy, diminpercutaneous assisted cystoscopic excision of posterior urethral polyps -ozcakir et al. table 1: patient’s demographic data (ad: accompanied disease, aur: acute urinary retention, bh: bilateral hydronephrosis, unc: ureteroneocystostomy, uti: urinary tract infection, r: right side, spate: suprapubic percutaneous assisted transurethral excision, vcug:voiding cystouretrography, vur: vesicoureteral reflux). patient no age gender symptoms diagnose size ad treatment 1 4 month m uti cystoscopy 10x10mm r grade iii vur spate 2 6 years m us 20x9 mm spate 3 4 years m intermittent us 10x10 mm r grade iii vur spate micturition aur 4 5 years f uti cystoscopy 15x10 mm r grade iii vur spate r duplex system unc 5 10 month m uti vcug 15x10 mm bh spate 6 2 years m intermittent cystoscopy 12x10 mm bilateral grade iii vur spate figure 1. spate is illustrated ished urinary stream, incomplete emptying, and urinary retention. hematuria and dysuria are other common symptoms associated with urinary tract infections(1,8). the clinical triad, including intermittent urinary retention, hematuria, and lower urinary tract symptoms, indicates highly probable and noticeable signs of urethral polyps in children(1,8). by reviewing the outcomes of 48 cases, kearney et al. found obstruction (48%) to be the most common presenting symptom followed by hematuria (27%) and retention (25%)(14). however, pufps could also be asymptomatic depending on sizes and location of polyp. de castro et al. reported on a series of 17 cases where patients had been treated throughout a 16-year period. in fact, 14 out of 17 cases were symptomatic, and three were identified and diagnosed incidentally(8). in our series, the mostly observed presentation was reccurrent uti (n:3), urinary retention with intermittent voiding (n:2), and the last one was asymptomatic. the diagnosis of pufp is typically based on clinical findings, imaging modalities (us, vcug) and cystoscopic evaluation(3,4,7). while us tends to show polyps as an echogenic foci projecting into the lumen, vcug reveals them as a polypoid filling defect, prolapsing through an external sphincter into the bulbous urethra. intravenous urography is rarely applied because of radiation levels. although us and vcug are efficient diagnostic imaging, cystourethroscopy is utilised as a confirmatory strategy(3). cystoscopic evaluation is the most specific examination for identifying polyps. additionally, because of the overlap in clinical presentation and radiological findings, diagnosis of polyp becomes a diagnostic challenge to distinguish a fibroepithelial polyp from a blood clot, radiolucent calculi or neoplasm. cystoscopic evaluation; reveals the existence of polyps precisely and contributes to the excision of them simultaneously. in addition, to overcome the overlap, ct and urine cytology could be helpful for the diagnosis of calculi and malignancy(11,13). cystoscopy remains to be the most effective examination method, while the macroscopic appearance of the polyp being diagnosed in the majority of cases represents solid, mobile, smooth and pedunculated fibrous tumours that originate from the vicinity of the verumontanum and lie along the surface figure 2. intraoperative cystoscopic view figure 3. the cystoscopic view presented that the using of electrocautery resectoscope for the complete removal of the lesion. percutaneous assisted cystoscopic excision of posterior urethral polyps -ozcakir et al. pediatric urology 88 vol 18 no 1 january-february 2021 89 of the posterior urethra(1,3). in our series, all polyps were observed on the posterior urethral wall by cystoscopy and confirmed by the histopathological examination. with reference to the current literature, a polyp can be accessed and removed by transurethral excision or open cystostomy(3,15-17). in 1985, bruijnes et al. emphasized the importance of the general suprapubic approach through open cystostomy for the purpose of resecting polyps; in the meantime, it was mentioned that smaller lesions could be resected transurethrally(17). in addition, schafer reported on three cases with intravesical obstruction in 1989: two polyps were excised by open cystotomy, and the last one was treated transurethrally(18). de castro managed 17 cases of pufp’s endoscopically without complications or relapses(8). nowadays, open cystostomy is rarely required and can be applied mostly for removing large lesions. common urethral polyps are usually removed transurethrally by the endoscopic resection electrocautery, cold knife or laser(1,2,6,7,11). in the present series, patients were successfully treated by spate procedure with the electrocautery for pufp’s endoscopic resection. in addition, we relied on the transvesically suprapubic approach without conducting open surgery. figure 4. us examination demonstrates that an irregular mass, arises from the bladder neck and extended into the bladder. figure 5. vcug image demonstrate that polypoid filling defect on bladder neck. figure 6. histopathologic examination shows polypoid lesion with papillary fronds lined by transitional urothelium and associated submucosal fibrous stroma exhibiting mild chronic inflammation (hematoxylin and eosin x 40). figure 7. histopathologic appearance with large magnification of polyp presents enriched stroma with various component, such as vascular formations with angiomatous features, smooth muscular fibers, pseudoglandular structures and inflammatory infiltrates (hematoxylin and eosin x 200). percutaneous assisted cystoscopic excision of posterior urethral polyps -ozcakir et al. it is important to note that to detect the original base of the polyp for the successful endoscopic treatment is significant. although it is stated that the urethral approach can be easily performed in adults, it may not be able to reach the root of polyp cause of large peduncle that leads to the obstacle in childhood. reaching the root of polyp might be complicated in some cases due to the obstacles that arise from the folding of the lesion's pedunculated body. moreover, during cystoscopy, hypermobile pedunculated polyp might glide in and out of the bladder neck due to the endoscopic fluid flow. the use of a percutaneous dissector for the proper holding simplifies the identification of the polyp's root and helps to differentiate the urethral wall from the polyp itself during the resectoscopic excision. thus, a full excision is secured under a direct vision without residual tissue. to the best of our knowledge, this is the first clinical series of children undergoing successful suprapubic assisted, transurethral polyp excision in terms of percutaneous treatment of pufps. a diagnosis of urethral polyps must be distinguished from inflammatory and neoplastic lesions located within the urethra. this usually includes non-opaque stones, a foreign body, posterior urethral valves, cowper's duct cyst, ectopic urethral insertion, urethral diverticulum and/or hypertrophy of the verumontanum(14). these lesions provoke outlet obstructions of different degrees, and thus they require the differential diagnosis to identify a posterior urethral polyp(19). it is crucial to keep in mind that without accurate tissue diagnosis, the invasive open surgery management may cause a negative impact on the clinical follow-up, such as subsequent fibrosis or urethral strictures, thus requiring and leading to a second surgical operation(14). as the cystoscopy becomes the gold standard for diagnosis, treatment has to be performed with the least possible invasive method to avoid precedents for injuring the urethral wall. in terms of spate, the proper holding of polyp guarantees a stretched appearance on the pedicle that allows the resectoscope to commit a complete excision without damaging the surrounding tissue. the spate procedure ensures reliable outcomes from conducting an operation with direct observation of the process. in this sense, it is easier to perform as compared to other invasive strategies. in addition, this methodology requires no new or extra tools for spate, since all shaped-edged suprapubic bladder catheter's trocars are suitable and sufficient for use. in the case of children, polyps emerging from the verumontanum are congenital in origins(1,3,5,7,11,12). the verumontanum is viewed as a landmark for the exit of the mesonephric duct. kuppusami and moors conducted a histological analysis of the verumontanum to find that it incorporates smooth muscle and small glands; in all cases, it was lined by transitional cell epithelium(12). histopathologically, pufps are characterised by a fibrous core covered by transitional epithelium. the edematous stroma becomes the most variable element which is often filled with various components, such as vascular formations with angiomatous properties, smooth muscular fibres, nerves, glands, pseudoglandular structures, and inflammatory infiltrates(5,8,12,13). also, in our experience, the histopathological examination confirmed the clinical diagnosis of fibroepithelial urethral polyps in all cases. there have not been reports on the malignant transformation of pufp to date. nevertheless, the possibility of recurrence because of the incompletely removed polypoid lesion has been mentioned(20). thus, we recommend that close follow-up, even if the risk of recurrence is low. several urethral polyps have been associated with other congenital urinary tract anomalies(7,14,19). for example, de castro reported that 50% of the patients with urethral polyps had a urinary pathology of different nature, especially vur(8). kimche and lask reported about 50 cases with a similar clinical picture; dilatation of the upper collecting system was identified in 10 patients (20%), while vur was diagnosed in four (8%) patients(6). additionally, bladder diverticulum was present in four patients (8%). in the series of 18 patients reported by akbarzadeh et al., six patients had vur (33%), and five patients had dysfunctional voiding findings (27%)(19). in our series, the associated diseases involved duplicated urinary system in one patient and vur in four patients (66,6%). drawbacks in our study concerning spate include the limited number of cases, a low degree of control over cystoscopic evaluation and the shortage of long-term uroflowmetry results after the procedure. however, our initial observations presume that the spate procedure is easy to perform, which makes it also efficient for complete excision without residue. conclusions pufp is a rare pathology in children, whereas cystoscopy remains the gold standard for diagnosing the disease. despite the status of a benign lesion, urethral polyps may cause obstructive effect in the urinary tract. pufp resection by endoscopic methods should be considered a complete treatment in the majority of patients. the current research review has revealed that transurethral resection is the best treatment choice, while spate is the most reliable strategy for ensuring complete excision. acknowledgements we would like to thank duncan t. wilcox, the chief of pediatric urology at colorado university, children's hospital colorado, for kindly reviewing our manuscript. conflict of interest the authors declare that they have no competing interests. references 1. gleason pe, kramer sa. genitourinary polyps in children. urology. 1994;44:106–9. 2. carrión lp, domínguez hc, serrano da, et al. congenital fibroepithelial polyps of the urethra. cir pediatr. 2010;23(1):7-9. 3. jain p, shah h, parelkar sv, et al. posterior urethral polyps and review of literature. indian j urol. 2007;23(2):206-207. 4. williams tr, wagner bj, corse wr, et al. fibroepithelial polyps of the urinary tract. abdominal imaging. 2002;27(2):217-21. 5. peterson ro. urethral polyp. in: petersen ro, sesterhenn ia, davis cj ,editors. urologic pathology. philadelphia: jb lipp. complete percutaneous assisted cystoscopic excision of posterior urethral polyps -ozcakir et al. pediatric urology 90 vol 18 no 1 january-february 2021 91 second edition;1992. p. 404. 6. kimche d, lask d. congenital polyp of the prostatic urethra. j urol. 1982;127(1):134. 7. downs ra. congenital polyps of the prostatic urethra. a review of the literature and report of two cases. br j urol. 1970 feb;42(1):76-85. 8. de castro r, campobasso p, belloli g, et al. solitary polyp of posterior urethra in children: report on seventeen cases. eur j pediatr surg. 1993;3(2):92-6. 9. klee lw, rink rc, gleason pe, et al. urethral polyp presenting as interlabial mass in young girls. urology. 1993;41(2):132-3. 10. yamashita t, masuda h, yano m, et al. female urethral fibroepithelial polyp with stricture. j urol. 2004;171(1):357. 11. walsh ik, keane pf, herron b. benign urethral polyps. br j urol. 1993;72(6):937-8. 12. kuppusami k, moors de. fibrous polyp of the verumontanum. can j surg. 1968;11(3):38891. 13. demircan m, ceran c, karaman a, et al. urethral polyps in children: a review of the literature and report of two cases. int j urol. 2006;13(6):841-3. 14. kearney gp, lebowitz rl, retik ab. obstructing polyps of the posterior urethra in boys: embryology and management. j urol. 1979;122(6):802-4. 15. eziyi ak, helmy te, sarhan om, et al. management of male urethral polyps in children: experience with four cases. afr j paediatr surg. 2009;6(1):49-51. 16. murshidi ms, akl k. a case of urinary bladder benign polyp treated successfully by resection in a child. ann saudi med. 2007;27(1):52. 17. bruijnes e, de wall jg, scholtmeijer rj, et al. congenital polyp of the prostatic urethra in childhood. report of 3 cases and review of literature. urol int. 1985;40(5):287-91. 18. schäfer j, porkolab l, pinter a. congenital urethral polyps. a rare cause of obstructive uropathy in childhood. urologe a. 1989;28(2):80-3. 19. akbarzadeh a, khorramirouz r, kajbafzadeh am. congenital urethral polyps in children: report of 18 patients and review of literature. j pediatr surg. 2014;49(5):835-9. 20. tsuzuki t, epstein ji. fibroepithelial polyp of the lower urinary tract in adults. am j surg pathol. 2005;29(4):460-6. percutaneous assisted cystoscopic excision of posterior urethral polyps -ozcakir et al. kidney transplantation 105urology journal vol 4 no 2 spring 2007 atherosclerosis after kidney transplantation: changes of intima-media thickness of carotids during early posttransplant period mohsen nafar,1 fatemeh khatami,1 babak kardavani,1 reza farjad,2 fatemeh pour-reza-gholi,1 ahmad firoozan1 introduction: the aim of this study was to evaluate atherosclerotic changes in the carotid artery following kidney transplantation. materials and methods: twenty-six nonsmoker kidney allograft recipients who did not have cardiovascular disease or diabetes mellitus were enrolled in the study. the carotid intima-media thickness (imt) was measured at 12 points using b-mode ultrasonography. the mean of the measured values was considered as the patient’s imt. we followed the patients and changes in the carotid imt were evaluated every 2 months up to the 6th posttransplant month. results: the mean age of the patients at transplantation was 41.5 ± 11.1 years. the mean baseline imt was 0.84 ± 0.22 mm. during the follow-up period it reached 0.85 ± 0.22 mm, 0.87 ± 0.23 mm (p = .01), and 0.88 ± 0.24 mm (p = .002) after 2, 4, and 6 months, respectively. the imt measures significantly correlated with the age and body mass index. using the imt cutoff points of 0.75 mm for stroke and 0.82 mm for mi, we found that 57.7% and 68% of the patients were at the risk of stroke at baseline and 6 months after transplantation (p < .001). also, 46.2 % of the patients were at the risk of mi at baseline that rose to 53.8% at the end of the study (p < .001). conclusion: atherosclerosis is an early event after kidney transplantation even in asymptomatic patients and those without major risk factors such as cardiovascular disease, diabetes mellitus, and smoking. early diagnosis and treatment of atherosclerosis is of utmost importance. urol j. 2007;4:105-10. www.uj.unrc.ir keywords: kidney transplantation, atherosclerosis, cardiovascular diseases, carotid artery, intima-media thickness 1department of nephrology, shaheed labbafinejad medical center, shaheed beheshti medical university, tehran, iran 2department of radiology, shaheed labbafinejad medical center, shaheed beheshti medical university, tehran, iran corresponding author: mohsen nafar, md department of transplantation, shaheed labbafinejad medical center, pasdaran, tehran 16666, iran tel: +98 21 2258 0333 fax: +98 21 2258 0333 e-mail: nafar@sbmu.ac.ir received january 2007 accepted april 2007 introduction cardiovascular diseases (cvds) are the most prevalent causes of morbidity and mortality after kidney transplantation.(1) it is estimated that cvds are responsible for 40% to 55% of all deaths after kidney transplantation, the majority of which being atherosclerosis and coronary artery disease (cad).(2) the high prevalence of such diseases is the result of a combination of traditional and transplantation-specific risk factors.(2,3) like the healthy individuals, many kidney-transplanted patients remain asymptomatic until the heart disease occurs. therefore, early diagnosis and management of atherosclerosis in these patients is of utmost importance.(4) while procedures like coronary angiography have good sensitivity and specificity for detecting the atherosclerotic lesions, their complexity, expense, and high rate atherosclerosis and kidney transplantation—nafar et al 106 urology journal vol 4 no 2 spring 2007 of complications make them an inappropriate measure for screening and monitoring the progress of atherosclerotic lesions. findings about the mirror atherosclerotic changes in the carotid artery along with the process of general atherosclerosis by the high resolution b-mode ultrasound scan have made this noninvasive method a good measure for assessment of asymptomatic atherosclerosis both in general population and end-stage renal disease (esrd) patients.(5-7) ultrasonographic measurement of the intima-media thickness (imt) in the carotid arteries is used as an indicator of coronary atherosclerosis in these populations.(5) this method has a good reproducibility index with acceptable interobserver and intra-observer variabilities.(8,9) there is also a close relation between the morphology of the carotid artery wall and development of cad.(10,11) in the general population, the risks of the first myocardial infarction (mi) and stroke increase with the imts greater than 0.82 mm and 0.75 mm, respectively.(12) it is also found that a progression rate of 0.034 millimeters per year or more in the carotid imt significantly increases the risk of future cardiovascular events.(12) despite a handful of studies that have evaluated the risk of cad and atherosclerosis by measurement of the carotid imt in general population and in esrd patients, there is a lack of evidence on the progression of atherosclerosis after kidney transplantation.(13-16) information on the course of atherosclerosis after kidney transplantation would be helpful for development of policies for early detection and proper management of cvd and prevention of its life-threatening consequences. the aim of this study was to evaluate atherosclerosis by measurement of the carotid imt at the time of kidney transplantation and during the first 6 months after the transplantation period. materials and methods patients and setting between june 2005 and march 2006, we recruited 26 consecutive kidney allograft recipients in a longitudinal study at shaheed labbafinejad medical center. candidates for kidney transplantation who consented to participate in the study were enrolled. the inclusion criteria were an age between 25 and 65 years of age, negative history of cvd (such as mi, coronary bypass surgery, congestive heart disease, etc), stroke, diabetes mellitus (dm), or cigarette smoking and no participation in other clinical studies on evaluation of cardiac diseases. on the other hand, the patients who had one of the followings during the course of the study were excluded: unstable condition of the transplanted kidney (serum creatinine > 3 mg/dl and/or blood urea nitrogen > 50 mg/dl), cyclosporine a intoxication according to the recommended values by international consensus statement,(17) a new onset of any severe disease (such as mi, stroke, dm), and administration of antihyperlipidemic agents. the ethics committee of shaheed beheshti medical university on human research approved the study and all the participants signed a written consent before enrollment into the study. all patients received kidney transplant from a living donor and were under triple immunosuppressive regimen consisting of cyclosporine microemulsion (neoral, novartis), mycophenolate mofetil (cellcept, roche), and prednisolone. before kidney transplantation, demographic and anthropometric indices (age, sex, height, and weight), past medical history, history of hemodialysis, and disease duration were recorded. after transplantation, we followed each patient every 2 months for a total period of 6 months and the carotid imt, as well as other routine posttransplantation evaluations, was examined. intima-media thickness measurement we used longitudinal b-mode doppler ultrasonography (eub-565, hitachi medical, tokyo, japan) for evaluation of 12 carotid segments (the near and far walls of the left and right common carotid arteries, carotid bifurcation, and internal carotid artery) in the supine position. for measurement of the carotid imt, we first identified the carotid arteries by a transverse scan. then, by a 90° rotation of the probe angle, 2 parallel lines of the lumen–intima interface and the media–adventitia interface were generated. the distance between these 2 lines was determined as the index of the carotid imt. the maximum carotid thickness was considered as the imt value for each specific site. we calculated the mean of these 12 imt values as the carotid imt for atherosclerosis and kidney transplantation—nafar et al urology journal vol 4 no 2 spring 2007 107 each patient. all of the examinations were carried out by a single trained ultrasonographist. statistical analyses we used relative frequencies for qualitative variables and mean ± sd for quantitative variables. differences between groups were tested using the wilcoxon signed rank test, pearson correlation coefficient test, and the chi-square test, as appropriate. for evaluating the correlation of the imt with other variables, we used the pearson correlation coefficient. the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa) was used for statistical analyses. a p value of less than .05 was considered significant. results there were 20 men (76.9%) and 6 women (23.1 %) with a mean age of 41.5 ± 11.1 year (range, 25 to 62 years) in our study. the mean duration of esrd was 4.0 ± 2.7 years. eight patients (30.8%) had no history of dialysis, while 10 (38.5%) had been receiving hemodialysis for less than 1 year and 8 (30.8%) for more than 1 year. the mean body mass index (bmi) was 23.0 ± 3.8 kg/m2. four patients (15.4%) were underweight (bmi ≤ 20), 10 (38.5%) had a desirable weight (bmi, 20 to 24.9), 11 (42.3%) were overweight (bmi, 25 to 29.9), and 1 (3.8%) was obese (bmi, 30 to 39.9). during the study period, 1 patient developed ischemic heart disease and was therefore excluded from the study. the remaining 25 patients completed the study. the mean baseline imt was 0.84 ± 0.22 mm. after two months posttransplantation, it increased to 0.85 ± 0.22 mm which was not significantly higher than the baseline value. this increasing trend continued during the 4th and 6th months and showed a significant increase compared to the baseline imt (0.87 ± 0.23 mm; p = .01 and 0.88 ± 0.24 mm; p = .002, respectively; figure 1). the median imt changes from baseline value after six months of follow-up was 0.02 mm (first quartile, 0.01 mm; third quartile 0.05 mm). the patients’ age and bmi showed a significant direct correlation with the imt at different time intervals. this relationship was not observed with the disease duration (table). in addition, there were not any differences in the imt values of the patients with regard to their hemodialysis history and gender. using the cutoff points for the carotid imt value defined by previous studies for patients at the risk of mi (imt > 0.82 mm), stroke (imt > 0.75 mm), and cardiovascular problems in general (imt change > 0.034 mm/y), we determined the patients at risk for such events.(12) at baseline, 57.7% of the patients had imts greater than 0.75 mm that put them at the risk of stroke. this number reached to 68% six months after the transplantation (p < .001). also, 46.2% of the patients were at the risk of mi at baseline that figure 1. the intima-media thickness (imt) changes during the 6 posttransplant months. *p < .05 †p < .01 correlation of imt at different times with clinical and demographic factors in kidney allograft recipients* imt factors baseline after 2 months after 4 months after 6 months age 0.59† 0.63† 0.64† 0.63† bmi 0.34 0.43 ‡ 0.46‡ 0.45‡ esrd duration 0.37 0.35 0.30 0.29 *values are correlation coefficients determined by the pearson correlation test. imt indicates intima media thickness; bmi, body mass index; and esrd, end-stage renal disease. †p < .01 ‡p < .05 atherosclerosis and kidney transplantation—nafar et al 108 urology journal vol 4 no 2 spring 2007 rose to 53.8 % at the end of the study (p < .001). in the case of imt changes, 72% of the patients had imt changes more than 0.02 mm in the period of 6 months. categorizing patients based on the age (figure 2) and bmi (figure 3) showed that the older patients or those with a higher bmi were at a higher risk of developing mi, stroke, or cvd. discussion our findings showed that the carotid imt increased over a short time in kidney transplant recipients. the increase rate was so high and in the 4th posttransplant month, it reached a level significantly higher than the baseline. finding that 6 months after transplantation, 68% of the patients are at the risk of stroke and 54% are at the risk of developing mi confirms the results of previous studies about the high prevalence of cvd in kidney allograft recipients.(1,3) in other studies, jogestrand and colleagues and suwelack and colleagues evaluated the characteristics of the carotid artery after kidney transplantation. they found that during a shorttime period after kidney transplantation, the carotid atherosclerosis markers are significantly increased compared to those of the healthy individuals.(18,19) figure 3. distribution of the patients at the risk of stroke (imt > 0.75 mm), mi (imt > 0.82 mm), and cardiovascular problems in general (imt change > 0.03 mm/y) based on the bmi categories. imt indicates intima-media thickness and bmi, body mass index. figure 2. distribution of the patients at the risk of stroke (imt > 0.75 mm), mi (imt > 0.82 mm), and cardiovascular problems in general (imt change > 0.03 mm/y) based on the age groups. imt indicates intima-media thickness. atherosclerosis and kidney transplantation—nafar et al urology journal vol 4 no 2 spring 2007 109 several studies have evaluated the cause of such a great prevalence of cvd after kidney transplantation. by improving the uremic state, platelet activity, endothelial dysfunction, and microinflammation after kidney transplantation, it is expected that the rate of cardiovascular events be decreased.(20-22) however, a combination of traditional risk factors such as smoking, hypertension, dm, physical inactivity, and anemia along with transplantationspecific risk factors like immunosuppressive drugs (especially cyclosporine a) and new-onset dm seem to overcome the beneficial effects of kidney transplantation on cardiovascular risk factors.(23-25) there are some kinds of controversies over the role of bmi in kidney allograft recipents’ survival. johnson and associates reported that there was no difference in the short-term and long-term patient and graft survival rates between the obese and nonobese patients.(26) this is while some more studies have reported decreased patient and graft survivals mainly due to cvd.(27,28) our findings about the correlation of higher carotid imt values and high relative frequency of patients at the risk of stroke and mi with bmi supports the findings of other studies about the harmful effects of increased bmi both in general population and kidney transplanted patients. age was another factor which was related to the carotid imt in our series, in line with the findings of other studies about the progression of atherosclerosis and cardiovascular events in normal population, esrd patients, and kidney transplanted patients.(29-31) other studies have found that longer duration of dialysis and male gender are related to increased carotid imt(32-34); however, our results failed to show any association of gender or duration of the previous dialysis with the progression of atherosclerosis in the carotids. we believe that the small sample size of our study is the main cause of such differences. it is not clear whether the transplantation per se or other comorbid conditions are the cause of such progress in atherosclerosis. the complexity of the situation makes it difficult to isolate a single cause. further studies with longer follow-up periods are required to pinpoint on the issue. the value of our study lies in the use of a valid and powerful tool—carotid imt measurement—for evaluation of atherosclerotic changes in kidney transplanted patients. by excluding the patients with a history of cvd, dm, and smoking, we were able to assess the progression of atherosclerosis in the absence of these major confounders. all the participants except one finished the study and it adds to the power of our work. one weakness of our study is the small sample size. future studies with longer duration and larger sample sizes focusing on the effect of treatment modalities on atherosclerosis markers would be of great usefulness. conclusion we observed that atherosclerosis is an early event after kidney transplantation. special attention should be paid to the older patients and those with cvd risk factors such as a high bmi. early treatment and preventive measures could be useful in increasing the patient and graft survivals. conflict of interest none declared. references 1. lindholm a, albrechtsen d, frodin l, tufveson g, persson nh, lundgren g. ischemic heart disease-major cause of death and graft loss after renal transplantation in scandinavia. transplantation. 1995;60:451-7. 2. raine ae, margreiter r, brunner fp, et al. report on management of renal failure in europe, xxii, 1991. nephrol dial transplant. 1992;7:7-35. 3. kasiske bl. epidemiology of cardiovascular disease after renal transplantation. transplantation. 2001;72: s5-8. 4. massy za, drueke tb, kreis h. carotid atherosclerosis in renal transplant recipients. transplantation. 2000;69:457. 5. craven te, ryu je, espeland ma, et al. evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis. a casecontrol study. circulation. 1990;82:1230-42. 6. ekart r, hojs r, hojs-fabjan t, balon bp. predictive value of carotid intima media thickness in hemodialysis patients. artif organs. 2005;29:615-9. 7. salonen r, seppanen k, rauramaa r, salonen jt. prevalence of carotid atherosclerosis and serum cholesterol levels in eastern finland. arteriosclerosis. 1988;8:788-92. 8. smilde tj, wollersheim h, van langen h, stalenhoef af. reproducibility of ultrasonographic measurements of different carotid and femoral artery segments in healthy subjects and in patients with increased intimamedia thickness. clin sci (lond). 1997;93:317-24. 9. kanters sd, algra a, van leeuwen ms, banga jd. reproducibility of in vivo carotid intimaatherosclerosis and kidney transplantation—nafar et al 110 urology journal vol 4 no 2 spring 2007 media thickness measurements: a review. stroke. 1997;28:665-71. 10. salonen jt, salonen r. ultrasonographically assessed carotid morphology and the risk of coronary heart disease. arterioscler thromb. 1991;11:1245-9 11. norris jw, zhu cz, bornstein nm, chambers br. vascular risks of asymptomatic carotid stenosis. stroke. 1991;22:1485-90. 12. aminbakhsh a, mancini gb. carotid intimamedia thickness measurements: what defines an abnormality? a systematic review. clin invest med. 1999;22:149-57. 13. fabris f, zanocchi m, bo m, et al. carotid plaque, aging, and risk factors. a study of 457 subjects. stroke. 1994;25:1133-40. 14. blankenhorn dh, selzer rh, crawford dw, et al. beneficial effects of colestipol-niacin therapy on the common carotid artery. twoand four-year reduction of intima-media thickness measured by ultrasound. circulation. 1993;88:20-8. 15. benedetto fa, mallamaci f, tripepi g, zoccali c. prognostic value of ultrasonographic measurement of carotid intima media thickness in dialysis patients. j am soc nephrol. 2001;12:2458-64. 16. nishizawa y, shoji t, maekawa k, et al. intima-media thickness of carotid artery predicts cardiovascular mortality in hemodialysis patients. am j kidney dis. 2003;41:s76-9. 17. levy g, thervet e, lake j, uchida k; consensus on neoral c(2): expert review in transplantation (concert) group. patient management by neoral c(2) monitoring: an international consensus statement. transplantation. 2002;73:s12-8. 18. jogestrand t, fehrman-ekholm i, angelin b, berglund l, gabel h. increased prevalence of atherosclerotic wall changes in patients with hyperlipidaemia after renal transplantation. j intern med. 1996;239:177-80. 19. suwelack b, witta j, hausberg m, muller s, rahn kh, barenbrock m. studies on structural changes of the carotid arteries and the heart in asymptomatic renal transplant recipients. nephrol dial transplant. 1999;14:160-5. 20. da silva cd, brunini tm, reis pf, et al. effects of nutritional status on the l-arginine-nitric oxide pathway in platelets from hemodialysis patients. kidney int. 2005;68:2173-9. 21. diaz-buxo ja, woods hf. protecting the endothelium: a new focus for management of chronic kidney disease. hemodial int. 2006;10:42-8. 22. brunini tm, da silva cd, siqueira ma, moss mb, santos sf, mendes-ribeiro ac. uremia, atherothrombosis and malnutrition: the role of larginine-nitric oxide pathway. cardiovasc hematol disord drug targets. 2006;6:133-40. 23. malyszko j, malyszko js, takada a, mysliwiec m. effects of immunosuppressive drugs on platelet aggregation in vitro. ann transplant. 2002;7:55-68. 24. morris st, mcmurray jj, rodger rs, farmer r, jardine ag. endothelial dysfunction in renal transplant recipients maintained on cyclosporine. kidney int. 2000;57:1100-6. 25. marchetti p. new-onset diabetes after transplantation. j heart lung transplant. 2004;23:s194-201. 26. johnson dw, isbel nm, brown am, et al. the effect of obesity on renal transplant outcomes. transplantation. 2002;74:675-81. 27. el-agroudy ae, wafa ew, gheith oe, shehab el-dein ab, ghoneim ma. weight gain after renal transplantation is a risk factor for patient and graft outcome. transplantation. 2004;77:1381-5. 28. guida b, trio r, nastasi a, et al. body composition and cardiovascular risk factors in pretransplant hemodialysis patients. clin nutr. 2004;23:363-72. 29. holaj r, spacil j, petrasek j, malik j, haas t, aschermann m. intima-media thickness of the common carotid artery is the significant predictor of angiographically proven coronary artery disease. can j cardiol. 2003;19:670-6. 30. diaz jm, sainz z, guirado ll, et al. risk factors for cardiovascular disease after renal transplantation. transplant proc. 2003;35:1722-4. 31. aker s, ivens k, grabensee b, heering p. cardiovascular risk factors and diseases after renal transplantation. int urol nephrol. 1998;30:777-88. 32. kablak-ziembicka a, przewlocki t, tracz w, pieniazek p, musialek p, sokolowski a. gender differences in carotid intima-media thickness in patients with suspected coronary artery disease. am j cardiol. 2005;96:1217-22. 33. kronenberg f, kathrein h, konig p, et al. apolipoprotein(a) phenotypes predict the risk for carotid atherosclerosis in patients with end-stage renal disease. arterioscler thromb. 1994;14:1405-11. 34. pascazio l, bianco f, giorgini a, galli g, curri g, panzetta g. echo color doppler imaging of carotid vessels in hemodialysis patients: evidence of high levels of atherosclerotic lesions. am j kidney dis. 1996;28:713-20. urol_v03_no4_001_editorial.indd urological oncology 220 urology journal vol 3 no 4 autumn 2006 immediate intravesical instillation of mitomycin c after transurethral resection of bladder tumor in patients with low-risk superficial transitional cell carcinoma of bladder mohammad reza barghi,1 mohammad reza rahmani,1 seyed mohammad mehdi hosseini moghaddam,2 mehrnoosh jahanbin2 introduction: the aim of this study was to evaluate the effect of immediate intravesical instillation of mitomycin c after transurethral resection of bladder tumor (turbt) in patients with low-risk superficial transitional cell carcinoma (tcc). materials and methods: a total of 43 patients with low-risk superficial bladder cancer were randomly assigned into two groups after the surgery; 22 patients in group 1 were treated by immediate instillation of mitomycin c after turbt, and 21 patients in group 2 received placebo. the two groups were compared using urine cytology and cystoscopy during the 24 postoperative months. results: recurrence within the first 3 months was reported in none of the patients in group 1 and 5 in group 2 (p = .02). of these, 4 had recurrence of tumor in the primary site. at 12 and 24 months, there were 1 patient (4.5%) in group 1 and 8 (38.1%) in group 2 with recurrence (p = .007). we had no patients with multifocal recurrence in group 1, but 3 (14.2%) in group 2. nine-month tumor-free survival rate was 95% in group 1. three-, 6-, 9-, and 12-month tumor-free survival rates in group 2 were 76%, 71%, 66%, and 62%, respectively (p = .007). none of the patients in group 1 and 3 in group 2 (14.3%) experienced some degrees of tumor progression (p = .06). conclusions: immediate instillation of mitomycin c after turbt seems to be effective in the recurrence reduction and increase of recurrence-free interval at least in short term. urol j (tehran). 2006;4:220-4. www.uj.unrc.ir keywords: bladder cancer, transitional cell carcinoma, drug instillation, mitomycin, transurethral resection 1department of urology, shohada-etajrish hospital, shaheed beheshti university of medical sciences, tehran, iran 2urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: syed mohammad mehdi hosseini moghaddam, md urology and nephrology research center no 44, 9th boustan, pasdaran ave, tehran 1666679951, iran tel: +98 21 22567222 fax: +98 21 22567282 e-mail: h_sasan@hotmail.com introduction although intravesical chemotherapy postpones the recurrence of transitional cell carcinoma (tcc), receiving it by the patients with a single low-risk tumor is a matter of debate.(1) multiple noncomparative studies have demonstrated the favorable outcomes of the immediate treatment by instillation of mitomycin c after transurethral resection of bladder tumor (turbt) in cases of tcc.(14) we conducted this placebocontrolled, triple-blind, randomized controlled trial to evaluate the effect of immediate mitomycin c instillation following turbt on early recurrence rate of tcc. materials and methods between december 2003 and december 2005, we conducted a placebo-controlled, triple-blind, randomized clinical trial in shohadamitomycin c after transurethral resection of bladder tumor—barghi et al urology journal vol 3 no 4 autumn 2006 221 e-tajrish hospital. we enrolled 56 patients with superficial transitional cell carcinoma. the study was approved by the ethical committee of the urology and nephrology research center, affiliated to shaheed beheshti university of medical sciences. written informed contest was obtained from all patients. patients with primary or papillary tumors, single tumors of 3 cm or less in size, and low-grade superficial tumors (ta g1, ta g2, and t1 g1) were included. individuals with muscle-invasive or grade 3 tumors or in situ bladder carcinoma on the pathological examination, nontransitional cell carcinoma, invasion to the prostate and the upper urinary tract, and a history of previous turbt or intravesical chemotherapy were excluded. using balanced randomization method, we randomly assigned the patients into 2 groups(5); group 1, with 22 patients who received a single dose of mitomycin c, 30 mg, diluted in 30 ml of distilled water(3) and group 2, with 21 patients who received placebo (distilled water) and were served as controls. after emptying the bladder, mitomycin c and the placebo were instilled intravesically 6 to 24 hours after turbt. the instillation was retained for 2 hours by catheter clamping and then the bladder was irrigated using normal saline.(6) side effects of mitomycin c such as cystitis, allergic reactions, hematuria, fever, erythema, skin rash, incontinence, chills, nausea and vomiting, fatigue, weakness, and muscle pain were recorded. the two groups were compared using urinary cytology and cystoscopy at 3, 6, 9, 12, 18, and 24 postoperative months. the time of the onset, location, size, stage, and grade of the recurrent tumors were determined. we compared the two groups by chi-square test and unpaired t test. disease-free interval was calculated using kaplanmeier method and the distribution was compared by breslow test. values were considered statistically significant at p < .05. results one patient with in situ carcinoma and 2 with a highgrade tumor (g3) were excluded from group 1. also, 3 patients in this group did not complete the study. in group 2, there were 2 patients with high-grade tumor, 2 with muscle invasion (stage t2), and 3 with incomplete follow-up who were excluded. a total of 22 patients in group 1 (subjects) and 21 in group 2 (controls) were evaluated. table 1 demonstrates the patients’ demographic and clinical characteristics. table 2 shows the recurrence and tumor progression table 1. patients’ demographic and clinical characteristics* *values in parentheses are percents unless otherwise indicated. characteristics group 1 mitomycin c group 2 placebo all p number of patients 22 21 43 … mean age, y (range) 55.9 ± 13.3 (35 to 82) 53.6 ± 17.9 (22 to 83) 54.8 ± 15.6 (22 to 83) .6 male/female 17/5 17/4 34/9 .7 mean tumor size, cm (range) 1.80 ± 0.77 (0.5 to 3) 1.90 ± 0.80 (0.5 to 3) 1.89 ± 0.80 (0.5 to 3) .94 pathological stage* pta 16 (72.7) 15 (71.4) 31 (72.1) .92 pt1 6 (27.7) 6 (28.6) 12 (54.4) .92 g1 20 (90.9) 19 (90.5) 39 (90.7) .96 g2 2 (9.1) 2 (9.5) 4 (9.3) .96 mean follow-up, mo (range) 16.7 (9 to 24) 14.7 (9 to 24) 15.7 (9 to 24) .2 table 2. recurrence and progression* *values in parentheses are percents. recurrence and progression group 1 group 2 p time of recurrence 3 0 5 (23.8) .02 6 0 6 (28.5) .007 9 1 (4.5) 7 (33.3) .02 12 1 (4.5) 8 (38.1) .007 18 1 (4.5) 8 (38.1) .007 24 1 (4.5) 8 (38.1) .007 progression 0 3 (14.3) .06 mitomycin c after transurethral resection of bladder tumor—barghi et al 222 urology journal vol 3 no 4 autumn 2006 rates in the two groups. recurrence within the first 3 months was not reported in the patients of group 1, while in group 2, there were 5 patients who experienced recurrence. of these, 4 had recurrence of tumor in the primary site. in addition, in group 1, only 1 patient (4.5%) had recurrence during the first 12 months compared to 8 (38.1%) in group 2 (p = .007). table 3 shows the clinical and pathological variables in the patients with recurrence in both groups. we had no patients with multifocal recurrence in group 1, but 3 (14.2%) in group 2. nine-month tumor-free survival rate was 95% in group 1. three-, 6-, 9-, and 12-month tumor-free survival rates in group 2 were 76%, 71%, 66%, and 62%, respectively. survival analysis using breslow test showed a significant difference between the two groups (p = .007). no patient in group 1 and 3 in group 2 (14.3%) experienced some degrees of tumor progression (p = .06). the patients in group 1 had a significantly longer recurrence-free interval in comparison with those in group 2. figure shows comparison of the two groups regarding the recurrence-free survival analysis and table 4 shows the side effects of mitomycin c versus placebo in the two groups. discussion to date, multiple clinical trials have focused on the efficacy of single immediate instillation of chemotherapeutic agents for the treatment of bladder tcc after turbt. some studies have been conducted to evaluate the effect of thiotepa, adriamycin, epodyl, and epirubicin.(7-10) although they provided new evidence of chemotherapy after turbt, none of the trials were a randomized study. zincke and colleagues showed the advantage of thiotepa and doxorubicin instillation at the time of transurethral surgery of bladder cancer.(11) although their report had an acceptable randomized doubleblind design, patients with carcinoma in situ were also enrolled and some patients received additional instillations before the recurrence. a disadvantage of this study was the administration of 2 agents in one arm. in 1985, a study on 417 patients with newly diagnosed superficial bladder tumors (ta/t1) compared the instillation of thiotepa at the time of primary treatment and its instillation with a 3month interval. this study showed that neither of these regimens produced sufficient improvement.(12) thereafter, trials on other chemotherapeutics were reported. oosterlinck and associates, in a randomized multicenter trial on 431 patients with primary or recurrent ta or t1 stages of the bladder comparison of the two groups regarding tumor recurrence-free survival. table 4. side effects of mitomycin c* *none of the side effects were seen in the control group. values in parentheses are percents. side effects group 1 local bladder symptoms dysuria 2 (9.0) frequency 1 (4.5) pain/cramps/urgency 2 (9.0) bacterial cystitis 4 (18.1) hematuria 4 (18.1) systemic symptoms myalgia 1 (4.5) fever and chills 1 (4.5) nausea and vomiting 1 (4.5) total 10 (45.5) table 3. clinical and pathological characteristics of recurrence cases within 1 year* *values in parentheses are percents. characteristics group 1 group 2 number of patients 1 8 number of the multiple tumors 1 (4.5) 3 (14.2) pathological stage pta 1 (4.5) 4 (19.0) pt1 0 4 (19.0) pt2 0 0 g1 0 7 (33.3) g2 1 (4.5) 1 (4.7) g3 0 0 mitomycin c after transurethral resection of bladder tumor—barghi et al urology journal vol 3 no 4 autumn 2006 223 tumor, demonstrated that immediate instillation of epirubicin after tumor resection decreased the recurrence rate up to 53%.(13) the main disadvantage of their trial was enrollment of the cases with recurrent tumors. in addition, the control group received water instead of the placebo. in our study, we had no recurrence in our study group. in group 2, 4 out of 5 patients with recurrence within 3 months after the intervention had their tumors in the primary site. this finding provides a support for the hypothesis of oosterlinck and colleagues who suggested that the recurrences in the original location might be due to tumor cell implantation. other studies on epirubicin were surprising. aliel-dein and colleagues performed a randomized controlled trial on 168 patients and showed that immediate instillation of a single-dose epirubicin is as effective as delayed maintenance therapy (epirubicin 1 to 2 weeks after turbt, 8 weeks later, and monthly up to 1 year, thereafter).(14) in a randomized control trial on 131 patients with superficial bladder cancer, solsona and coworkers found a positive effect of a single immediate mitomycin c instillation.(3) they did not use placebo in their control group and enrolled cases with recurrent tumors in their study. in our study, we observed only 1 patient (4.5%) with recurrence during the first 12 months compared to 8 (38.1%) in the control group. therefore, follow-up cystoscopies at 3, 6, and 9 postoperative months could have been limited and substituted with noninvasive procedures like ultrasonography and cytology in cases who received mitomycin c. tolley and colleagues carried out a multicenter randomized control trial on 452 patients with newly diagnosed superficial bladder cancer and showed the positive but nonsignificant benefits of mitomycin c.(4) although this study included a large number of cases, they enrolled patients at low, medium, and high risk for the subsequent recurrences. some researchers conducted other studies for evaluating the effects of other chemotherapeutics. two clinical trials showed the positive effects of epirubicin and doxorubicin.(15,16) rajala and colleagues(15) showed a sustained decrease in the recurrence of bladder cancer after a single perioperative instillation of epirubicin and ineffectiveness of interferon-α for this purpose. for patients in the control group, transurethral resection alone was performed and the cases with grades 1 to 3 of the bladder cancer were included. okamura and associates performed a randomized study comparing 6 and 17 instillations of doxorubicin in patients with single superficial bladder cancer.(16) subjects with new or recurrent tumors were enrolled in that study. in our study, we had no patients with multifocal recurrence in the subjects group but 3 (14.2%) in the controls. this finding shows that mitomycin c may decrease the transition from low-risk state to high-risk condition and alleviate the necessity of the therapy with bacillus calmette-guerin. the main disadvantages of all the abovementioned studies were no administration of placebo in the control groups and enrollment of the cases with recurrent tumors that might enter some confounding variables in the study due to the effects of the previous treatment modalities. to our best knowledge, all of the mentioned clinical trials provided a high level of evidence demonstrating the benefit of immediate instillation of mitomycin c after turbt. using placebo in our protocol and a method of balanced randomization protect our findings from potential confounders. since we enrolled cases with newly diagnosed primary bladder tumors of stage ta/t1 in protocol, our findings seem to be free of effects resulting from previous treatment modalities. we acknowledge the limited number of patients in our study and a relatively high proportion of excluded cases. however, according to our results and previous evidence mentioned above, immediate instillation of mitomycin c within 6 to 24 hours following turbt seems to be effective and decreases the short-term recurrence rate while prolongs recurrence-free interval. in addition, as our study and previous reports showed, this treatment provides prevention from tumor progression. a new protocol introduced by 2 pioneers, nieder and soloway, demonstrated that after the diagnosis of low-grade bladder tumors (ta/t1), treatment schedule should include turbt and mitomycin c. they recommend therapy by bacillus calmetteguerin be added to this protocol for high-grade tumors.(17) mitomycin c after transurethral resection of bladder tumor—barghi et al 224 urology journal vol 3 no 4 autumn 2006 conclusion our results demonstrate the superiority of mitomycin c versus placebo in the prophylaxis of the recurrence in primary low-risk superficial bladder tcc following turbt. consequently, we strongly recommend instillation of mitomycin c in the first 24 hours after the tumor resection. conflict of interest drs seyed mohammad mehdi hosseini moghaddam and mehrnoosh jahanbin are the full-time researchers of the urology and nephrology research center, the sponsor of the study. funding support this study was financially supported by the urology and nephrology research center affiliated with shaheed beheshti university of medical sciences. references 1. sylvester rj, oosterlinck w, van der meijden ap. a single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage ta t1 bladder cancer: a metaanalysis of published results of randomized clinical trials. j urol. 2004;171:2186-90. 2. bohle a, jocham d, bock pr. intravesical bacillus calmette-guerin versus mitomycin c for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. j urol. 2003;169: 90-5. 3. solsona e, iborra i, ricos jv, monros jl, casanova j, dumont r. effectiveness of a single immediate mitomycin c instillation in patients with low risk superficial bladder cancer: short and long-term follow up. j urol. 1999;161:1120-3. 4. tolley da, parmar mk, grigor km, et al. the effect of intravesical mitomycin c on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of follow up. urol. 1996;155:1233-8. 5. peto r, pike mc, armitage p, et al. design and analysis of randomized clinical trials requiring prolonged observation of each patient. i. introduction and design. br j cancer. 1976;34:585-612. 6. au jl, badalament ra, wientjes mg, et al. international mitomycin c consortium. methods to improve efficacy of intravesical mitomycin c: results of a randomized phase iii trial. j natl cancer inst. 2001;93:597-604. 7. burnand kg, boyd pj, mayo me, shuttleworth ke, lloyd-davies rw. single dose intravesical thiotepa as an adjuvant to cystodiathermy in the treatment of transitional cell bladder carcinoma. br j urol. 1976;48: 55-9. 8. abrams ph, choa rg, gaches cg, ashken mh, green na. a controlled trial of single dose intravesical adriamycin in superficial bladder tumours. br j urol. 1981;53:585-7. 9. kurth kh , maksimovic pa , hop wcj , schröder fh, bakker nj. single-dose intravesical epodyl after tur of ta tcc bladder carcinoma. world j urol. 1983;1: 89-93. 10. selvaggi fp, de micheli p, pamparana f, sacchetti g. epirubicina endovesicale nella profilassi delle recidive dei tumori superficiali della vesica. studio multicentrico, randomizzato. acta urol ital. 1990;1:331. 11. zincke h, utz dc, taylor wf, myers rp, leary fj. influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized, double-blind, controlled trial. j urol. 1983;129:505-9. 12. [no authors listed]. the effect of intravesical thiotepa on the recurrence rate of newly diagnosed superficial bladder cancer. an mrc study. mrc working party on urological cancer. br j urol. 1985;57:680-5. 13. oosterlinck w, kurth kh, schroder f, bultinck j, hammond b, sylvester r. a prospective european organization for research and treatment of cancer genitourinary group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage ta, t1 papillary carcinoma of the bladder. j urol. 1993;149: 749-52. 14. ali-el-dein b, nabeeh a, el-baz m, shamaa s, ashamallah a. single-dose versus multiple instillations of epirubicin as prophylaxis for recurrence after transurethral resection of pta and pt1 transitional-cell bladder tumours: a prospective, randomized controlled study. br j urol. 1997;79:731-5. 15. rajala p, kaasinen e, raitanen m, liukkonen t, rintala e; finnbladder group. perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter study--finnbladder iii longterm results. urol. 2002;168:981-5. 16. okamura k, ono y, kinukawa t, et al. randomized study of single early instillation of (2”r)-4’-otetrahydropyranyl-doxorubicin for a single superficial bladder carcinoma. cancer. 2002;94:2363-8. 17. nieder am, soloway ms. eliminate the term “superficial” bladder cancer. j urol. 2006;175:417-8. v08_no_4_final_new.pdf case report 330 urology journal vol 8 no 4 autumn 2011 prostatic cyst causing severe infravesical obstruction in a young patient bayram dogan, abdullah erdem canda, ziya akbulut, ali fuat atmaca, engin duran, mevlana derya balbay urol j. 2011;8:330-2. www.uj.unrc.ir keywords: prostate, cysts, prostatic diseases, urinary retention 1st urology clinic, ankara atatürk training & research hospital, ankara, turkey corresponding author: abdullah erdem canda, md 1st urology clinic, ankara atatürk training & research hospital, ankara, 06800, turkey tel: +90 532 261 1105 fax: +90 312 291 2715 e-mail: erdemcanda@yahoo.com received december 2009 accepted february 2010 introduction prostatic cysts are rare entities, usually asymptomatic, and detected incidentally during transrectal or abdominal ultrasonography. mostly, they originate from the posterior area of the prostate, such as the mullerian ducts and utricle, as an embryological remnant.(1) symptomatic prostatic cysts usually present with recurrent urinary tract infections, chronic pelvic pain syndrome, infertility, or ejaculatory pain in addition to low semen volume, hematospermia, and painful testes.(2) very few cases have been reported in the english literature (pubmed/medline) related with symptomatic prostatic cysts. herein, we report a prostatic cyst causing severe infravesical obstruction in a young patient, discuss its symptoms, diagnostic work-up, and management. case report a 25-year-old young healthy man presented to our outpatient clinic with infravesical obstructive symptoms lasted for 1 year. he did not have any history of previous urethral catheterization or urinary tract infection. physical examination of the genitalia and external urethral meatus were normal. digital rectal examination revealed a normal prostate. urine microscopy was normal and culture was negative. international prostate symptom score (ipss) was 22 and quality of life (qol) score was 6. uroflowmetry showed a peak flow rate (qmax) of 5 ml/sec with 265 ml urine volume (figure 1). abdominal ultrasonography showed a prostate of 22 ml and a 9.3 × 4.4 mm anechoic cyst located on the anterior surface of it bulging into the bladder (figure 2). the urethra and prostatic lobes appeared normal on cystourethroscopy with increased bladder trabeculations. a 10 × 5 mm prostatic cyst originating from the left prostatic lobe obstructed the bladder neck (figure 3). transurethral resection (tur) of the cyst was performed (figure 3), which revealed benign prostatic tissues following histopathological evaluation. on the 1st-month follow-up, he did not have any infravesical obstructive or lower urinary tract symptoms (luts). uroflowmetry demonstrated a qmax of 11 ml/ sec with 428 ml of voided urine volume. his ipss was 9 and qol was 6. discussion prostatic cysts have been reported to exist in 5% of men with luts.(2) obstructive prostatic cyst—dogan et al 331urology journal vol 8 no 4 autumn 2011 cysts located in the midline of the prostate are mullerian duct or utricular cysts.(3) mullerian duct cysts may extend over the base of the prostate forming an obvious projection into the bladder.(4) on the other hand, the ejaculatory ducts could open into the lateral wall of the utricular cysts; therefore, sperm could be found in the cavity.(5) anterior location of the prostatic cyst is very rare. prostatic cysts are commonly located on the posterior surface of the prostate, which might suggest that these cysts could be originated from the prostatic capsule.(6) figure 1. pre-operative uroflowmetry of the patient showing an obstructive pattern, peak flow rate of 5 ml/sec, and voided urine volume of 265 ml. figure 2. appearance of the prostatic cyst on abdominal ultrasonography. figure 3. cystoscopic appearance of the cyst. obstructive prostatic cyst—dogan et al 332 urology journal vol 8 no 4 autumn 2011 symptoms related to prostatic cysts have been reported to be of irritative and/or obstructive luts, decreased ejaculate volume, painful ejaculation, and infertility.(6) a medially located prostatic cyst was suggested to present with prostatitis-like symptoms.(2) in most studies, no relationship between prostatic cysts and serum level of prostate-specific antigen was reported.(7) our patient had only infravesical obstructive symptoms with obstructive uroflowmetry findings (figure 1). diagnosis can be made through medical history, physical examination, urine analysis, transrectal ultrasonography, uroflowmetry, ultrasonography, cystoscopy, computed tomography scan, and magnetic resonance imaging.(7-9) we used most of these diagnostic work-up in our patient. treatment of prostatic cysts include tur, endoscopic marsupialization, endoscopic urethrotomy and incision, transrectal ultrasoundguided drainage, and open surgery.(7) although anterior prostatic cysts are commonly nonobstructive,(1) our patient presented mainly with obstructive symptoms. therefore, we performed only tur of the cyst and on the 1st-month of follow-up, our patient did not have any obstructive luts. retrograde ejaculation might occur following tur of the prostate; however, aspiration of the cyst would be a less invasive procedure and would lessen the risk of retrograde ejaculation.(10) since we performed resection of the prostatic cyst only, our patient did not experience any retrograde ejaculation postoperatively. particularly in young patients, transrectal ultrasound-guided aspiration of the cyst might also be performed when possible. in conclusion, symptomatic prostatic cysts are rarely seen lesions and patients might present to the urology departments with infravesical obstructive symptoms. therefore, we should consider prostatic cysts particularly in young men with obstructive luts. management of the cyst with tur seems to be a minimally invasive approach with successful and satisfactory outcomes. conflict of interest none declared. references 1. ishikawa m, okabe h, oya t, et al. midline prostatic cysts in healthy men: incidence and transabdominal sonographic findings. ajr am j roentgenol. 2003;181:1669-72. 2. dik p, lock tm, schrier bp, zeijlemakerby, boon ta. transurethral marsupialization of a medial prostatic cyst in patients with prostatitis-like symptoms. j urol. 1996;155:1301-4. 3. anding r, steinbach f, bernhardt tm, allhoff ep. treatment of large prostatic cyst with retropubic insertion of a fat tissue flap. j urol. 2000;164:454-5. 4. barzilai m, ginesin y. a mullerian prostatic cyst protruding into the base of the urinary bladder. urol int. 1998;60:194-6. 5. kim ed, onel e, honig sc, lipschultz li. the prevalence of cystic abnormalities of the prostate involving the ejaculatory ducts as detected by transrectal ultrasound. int urol nephrol. 1997;29: 647-52. 6. issa mm, kalish j, petros ja. clinical features and management of anterior intraurethral prostatic cyst. urology. 1999;54:923. 7. terris mk. transrectal ultrasound guided drainage of prostatic cysts. j urol. 1997;158:179-80. 8. jarow jp. diagnosis and management of ejaculatory duct obstruction. tech urol. 1996;2:79-85. 9. yildirim i, kibar y, sumer f, bedir s, deveci s, peker af. intraurethral prostatic cyst: a rare cause of infravesical obstruction. int urol nephrol. 2003;35: 355-6. 10. rassweiler j, teber d, kuntz r, hofmann r. complications of transurethral resection of the prostate (turp)--incidence, management, and prevention. eur urol. 2006;50:969-79; discussion 80. urol_v03_no4_001_editorial.indd notice 262 urology journal vol 3 no 4 autumn 2006 notice of inadvertent duplicate publication the urology journal wishes to draw attention to a paper by pourmand and colleagues, “posttransplant infectious complications: a prospective study on 142 kidney allograft recipients,” which was published in volume 3, number 1 (winter 2006) of the journal, that is for the most part similar to an article by the same authors, entitled “post-transplant infectious complications in iranian kidney recipients: a prospective study on 142 patients”, published in the journal of school of public health and institute of public health research 2006;4: 2 (persian). the corresponding author was contacted and it was confirmed that this is a case of inadvertent duplicate publication and the mistake was a result of a misunderstanding of the regulations by authors. the two journals were unaware of the other publication. it should be noted that the urology journal’s policy is not to consider any manuscript published or under consideration in another journal regardless of the language. secondary publication would be accepted only when the editors of the two journals are informed and agree due to a reasonable aim. urol j (tehran). 2006;4:262. www.uj.unrc.ir 568 | association of serum ykl-40 level with tumor burden and metastatic stage of prostate cancer enver özdemir,1 tarık çiçek,1 mehmet onur kaya2 purpose: to investigate the relationship between serum level of ykl-40 and gleason score, grade and stage of the disease, and for the first time, with tumor burden in patients with prostate cancer (pca). materials and methods: serum levels of ykl-40 and prostate-specific antigen were measured in 34 men (mean age: 66 years) with newly diagnosed and untreated pca, in 34 men (mean age: 65 years) with biopsy proven benign prostatic hyperplasia, and in 29 healthy young men (mean age: 24 years). results: serum ykl-40 concentration in men with pca and benign prostatic hyperplasia, and in controls were 165.67 ± 107.84 ng/ml, 137.38 ± 82.04 ng/ml, and 69.69 ± 18.46 ng/ml, respectively. serum level of ykl-40 was correlated with tumor burden in 30.4% of the patients with pca (p = .04). a cut-off serum ykl-40 value of 92.696 ng/ml produced 70.6% sensitivity and 93.1% specificity. elevated serum level of ykl-40 was strongly associated only with metastatic stage of the pca. no association was observed between elevated level of ykl-40 and gleason score groups or gleason grade. conclusion: our results suggest that elevated serum level of ykl-40 may be a useful indicator of tumor burden and metastatic stage of pca. further studies are warranted to better elucidate the meaning of ykl-40 in tumor burden and invasiveness. keywords: prostatic neoplasms, tumor marker, tumor burden, prostate-specific antigen corresponding author: enver özdemir, md; phd department of urology, faculty of medicine, fırat university, 23199, elazığ, turkey tel: +90 532 463 7370 fax: +90 424 238 8096 e-mail: drenver@ enverozdemir.com received august 2010 accepted may 2011 1department of urology, fırat university hospital, elazığ, turkey 2department of statistics, fırat university, elazığ, turkey urological oncology urological oncology 569vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l serum level of ykl-40 in prostate cancer | özdemir et al introduction ykl-40 (chitinase-3-like-1), also called human cartilage glycoprotein-39 (hc gp-39), is a mem-ber of family 18 glycosyl hydrolases and plays a significant role in cancer cell proliferation, survival, and invasiveness, and has a regulating role in cell-matrix interactions and in the production of the altered extracellular matrix surrounding the cancer cells.(1) previous studies have reported elevated serum levels of ykl-40 in patients with primary and metastatic carcinoma of the breast,(2) colorectal,(3) ovary,(4) lung,(5) and prostate.(6) the relationship of elevated serum level of ykl-40 with the prostate cancer (pca) is not yet fully established; however, possible association of ykl-40 elevation with only high gleason score was suggested.(6) elevated serum level of ykl-40 in patients with pca, especially re-elevation after androgen resistance stage of the disease, was reportedly associated with short survival, and serum ykl-40 concentration was independent of other prognostic factors.(7) a number of prognostic factors, including prostate-specific antigen (psa), gleason grade and score, and the stage of disease, have been suggested as predictors of the outcome of primary treatment and prognosis of pca.(8) serum psa concentrations significantly affect treatment modalities in man with pca. nonetheless, over-diagnosis and as a result over-treatment of occult cancer have occurred significantly. prostate-specific antigen test suffers from both limited sensitivity and specificity. furthermore, the significance of psa declines in later stages of the disease.(9) identification of additional and/or better biomarkers is of utmost importance to better predict clinical behavior of pca and define the need for additional therapies. several new biomarkers have shown promise, and are still being evaluated in studies to investigate the role of these markers in the early detection, staging, and prognosis of pca. in this prospective study, we investigated the association of serum level of ykl-40 with serum level of psa, gleason grade and score, and pathologic stage in newly diagnosed and untreated patients with pca, and compared to that of the patients with benign prostatic hyperplasia (bph) and healthy controls. moreover, for the first time, the correlation of serum level of ykl-40 with tumor percentile in the pathologic specimens was also investigated. materials and methods patients blood samples were obtained from 34 men with newly diagnosed and untreated pca, 34 men with bph, and 29 healthy volunteers from june 1, 2008 to december 31, 2009. mean age of the patients with pca and bph was 66 years (range, 54 to 82 years) and 65 years (range, 38 to 79 years), respectively, and that of healthy controls was 24 years (range, 23 to 25 years). pretreatment serum level of psa, stage, gleason grade, gleason score, and percent tumor burden were recorded. according to the stage, patients with pca were divided as localized (t1a-t2b), local-advanced (t3a-t4), and metastatic (tx, n+, m+). staging was based on histological and/or clinical parameters, such as digital rectal examination, plain x-ray, and radio-isotopic bone imaging and tomography. according to gleason score, they were divided into low (2 – 4), medium [5 – (3 + 4)], and high [(4 + 3) – 10]. the research protocol was approved by the medical ethics committee. informed consents were obtained from all the patients. patients under medications with possibility to influence serum ykl-40 and psa levels, such as 5α-reductase inhibitors, luteinizing hormone-releasing hormone analogs, androgen receptor inhibitors, and testosterone replacement, were excluded. procedure and evaluations the biopsy was performed using transrectal ultrasound guidance in patients with abnormal digital rectal examination with even psa values within normal range or above 4 ng/ml. for prophylaxis of postprocedural sepsis, patients were given 500 mg ciprofloxacin twice daily starting 12 hours before and following five days. twelve-quadrant transrectal ultrasound-guided prostate biopsies were performed under local anesthesia at department of radiology using an ultrasound probe (bk medical, herlev, denmark; 2101 falcon; 7.5 mhz). pro-mag biopsy gun and 18 gauge 20-cm needle were preferred. blood samples were collected after pathological confirmation of the diagnosis, and left on the clot, and serum was 570 | separated by centrifugation at 3000 rpm for 10 minutes (heraeus biofuge stratos; kendo laboratory products, osterodegermany). all serum samples were stored at -80 ˚c until examination. serum samples were melted and ykl-40 concentrations were determined by microvue ykl-40 eia kit (quidel corporation: 10165 mckellar court, san diego, ca 92121 usa), and by manual enzyme-linked immunosorbent assay using washer and reader (washer–elx, reader-elx bio-tek, usa). serum levels of psa were determined by using chemiluminescent immunometric assay kit working on immulite 2000 hormone autoanalyzer (siemens healthcare diagnostics inc. flanders, nj, 07836, usa). statistical analysis the statistical analysis was performed using medcalc® version 10.1.6.0. all values were expressed as mean ± standard deviation. non-parametric kruskal-wallis test was used for multiple comparisons, non-parametric mann-whitney u test for analyzing the differences among groupings, and pearson correlation coefficient test for the relationships of parametric data. receiver operator characteristic (roc) curves were plotted for relevant parameters. statistically significance was set at p < .05 level. results the number, age, and serum levels of psa and ykl-40 of the patients with pca and bph, and those of healthy controls are summarized in table. serum levels of ykl-40 of controls, patients with bph, and those with pca were 69.69 ± 18.46 ng/ml, 137.38 ± 82.04 ng/ml, and 165.67 ± 107.84 ng/ml, respectively. as shown in figure 1, multiple comparison of serum levels of ykl-40 in patients with localized (t1a-t2b; n = 20), local-advanced (t3a-t4; n = 5), and metastatic (tx, n+, m+; n = 9) stage pca and that of patients with bph yielded significant difference (kruskal-wallis test, p < .0001). there was a significant difference for the serum levels of ykl-40 between the bph and metastatic stage in patients with pca in mann-whitney u test (p = .02). serum levels of ykl-40 also differed significantly between the patients with localized stage and metastatic stage pca (p = .01), but not between localized and local-advanced, and between local advanced and metastatic stage of pca. comparisons of serum levels of ykl-40 between the patients with bph and those with urological oncology figure 1. box-and-whisker plots for serum levels of ykl-40. the box represents the 25th and 75th percentiles and the median is shown by a horizontal line. the multiple comparison by kruskalwallis test is significant (p < .001). clinicopathological profiles of the patients.£ characteristics 1localized pca (t1a-t2b) (n = 20) 2local advanced pca (t3a-t4) (n = 5) 3metastatic pca (ptx, n+, m+) (n = 9) 4bph (n = 34) 5controls (n = 29) p* mean age (range), y 64 (54 to 75) 70 (61 to 75) 70 (60 to 82) 65 (38 to 79) 24 (23 to 25) < .0001 psa (mean ± sd), ng/ml 1174 ± 8.01 28.80 ± 12.10 314.38 ± 388.56 11.52 ± 10.75 0.42 ± 0.27 < .0001 serum ykl (mean ± sd), ng/ml 126.45 ± 92.48 175.11 ± 89.71 247.57 ± 110.39 137.38 ± 82.04 69.69 ± 18.46 < .0001 £pca indicates prostate cancer; bph, benign prostatic hyperplasia; psa, prostate-specific antigen; and sd, standard deviation. *non-parametric kruskal-wallis test, post-hoc analysis among groupings yielded significant differences for serum ykl-40 levels (p < .05) between (1) and (2,3,5), between (2) and (1,5), between (3) and (1,5), between (4) and (5), and between (5) and (1,2,3,4). 571vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l localized or local-advanced stage pca did not show any significant difference. serum levels of ykl-40 were strongly higher in patients with pca than that of subjects with bph (p < .001). in patients with bph, serum levels of psa and ykl-40 were not correlated (p = .31). as expected, serum levels of psa and ykl-40 in the patients with pca were significantly correlated (p = .02). we evaluated the %tumor volume in the pathologic specimen and compared it with serum levels of ykl-40 and psa. while there was no correlation between %tumor volume and serum levels of psa, there was a correlation of 30.4% between serum levels of ykl-40 and %tumor burden in the specimen (p = .04) as shown in figure 2. while there was no significant difference between gleason grade (1 – 5) and serum levels of ykl-40 in patients with pca, gleason grading was strongly associated with serum levels of psa (p = .009). accordingly, gleason score groupings as low (2 – 4), medium [5 – (3 + 4)], and high [(4 + 3) – 10] were also not associated with serum levels of ykl-40. while the association of gleason score groupings with serum levels of psa was strong (p = .006). furthermore, both gleason grade and gleason scoring groups were strongly associated with %tumor burden in the specimens (p < .001). the roc curve for serum levels of ykl-40 in 34 patients with pca and in 29 healthy controls is shown in figure 3. receiver operator characteristic analysis suggested that a serum ykl-40 level cut-off value of 92.696 may have predictive value (area under curve: 0.774; sensitivity: 70.6%; specificity: 93.1%) for pca (p < .0001; 95% confidence interval: 0.651 to 0.870). initial therapy was radical prostatectomy in 22 (64.7%) patients, and pathologic stage was localized in 20 and local advanced in 2 patients. three patients with clinically local advanced stage disease and 9 patients with metastatic stage disease underwent medical castration. none of our patients were treated with radiotherapy. discussion serum ykl-40 elevations observed in patients with pca and its correlation with tumor burden suggest a possible role of ykl-40 as a marker in pca. the present study is the first report showing the relationships of elevated serum level of ykl-40 with %tumor volume in the pathological specimen. we found a significant correlation of 30.4% between serum levels of ykl-40 and %tumor burden in the pathologic specimen, contrasting to no correlation of %tumor volume with serum levels of psa in our patients with pca. partin and colserum level of ykl-40 in prostate cancer | özdemir et al figure 2. correlation of % tumor burden in the pathologic specimen with serum levels of ykl-40 in patients with prostate cancer. pearson’s correlation = 0.304; p = .04 (1-tailed). figure 3. receiver operation characteristic curve of serum level of ykl-40 in patients with prostate cancer and in controls. the area under the curve is 0.774. 100 specificity ykl 40 0 20 40 60 80 100 100 80 60 40 20 0 se n si ti vi ty 572 | leagues evaluated usefulness of psa in pre-operative staging of pca, and reported that serum level of psa is not reflecting the tumor burden.(9) they suggested two reasons for this; the first one is unpredictable contribution of bph region within the gland and the other one is decreased production of psa by higher grade lesions as tumor volume increases. furthermore, our finding of strong association of serum ykl-40 elevations solely with metastatic stage of the patients with pca suggests that increased serum level of ykl-40 may be a marker of increased tumor burden and metastasis in patients with pca. our results also confirmed the previous finding of significantly elevated serum levels of ykl-40 in patients with pca at the initial diagnosis than that of patients with histological bph.(6) on the other hand, we found no association of elevated serum levels of ykl-40 with medium, low, and high gleason score groups and also gleason grades by using nonparametric multivariate analysis, contrasting to the findings of previous researchers.(9) furthermore, we found strong differences among these groupings for the serum levels of psa. brasso and associates measured serum level of ykl-40 in patients with metastatic pca and compared with that of normal controls.(10) they found meaningful serum ykl-40 elevations in 43% of the patients with metastatic pca. therefore, they suggested that elevated serum level of ykl-40 may be an independent prognostic factor for short survival in patients with metastatic pca. johansen and coworkers administered total androgen blockade or parenteral estrogen therapy for 6 months to the patients with metastatic pca and reported meaningful decrease in the serum level of ykl-40.(7) moreover, they suggested the restart of increase in the serum level of ykl-40 in patients with androgen insensitive metastatic pca as an important prognostic factor for deaths within the following seven months. although decreased serum level of ykl-40 after radical prostatectomy was reported,(6) it did not decrease to the normal values. this finding clarifies that ykl-40 protein production is continued by surrounding structures without evidence of cancer remnants. defining a proper cut-off value for markers is crucial for better detection of cancer. despite small sample numbers in our study, roc curve was generated. with a cut-off serum ykl40 value of 92.696, a predictive 70.6% sensitivity and 93.1% specificity were produced for pca (p < .001). future large scale studies are being awaited for better predicting the diagnostic value of serum ykl-40 in patients with pca. immunohistochemical tissue expression of ykl-40 in solid tumors has not been published yet.(6) interesting data are expected with future studies analyzing the tissue expression level of ykl-40. the ages of the healthy volunteers were preferentially selected less than 30 years, just before the start of the development of bph nodules, in our study as previous research.(6) ideal similar-age control group without histological evidence of bph is almost impossible. all of our patients with histological bph and primary pca were not on any medication and had no clinical signs or symptoms of other diseases, such as other cancers or joints, liver, metabolic, and hormonal diseases. controls had no clinical signs or symptoms of illnesses or hormonal disturbances. ykl-40 was first discovered as a 40 kda protein secreted by the mg63 human osteosarcoma cell line.(11) ykl-40 gene is located on chromosome 1. structurally, it is related to mammalian chitinase-like proteins; however, lacking their characteristic enzymatic activity. elevated levels of ykl-40 have been reported in a wide variety of diseases, such as inflammatory bowel disease, cirrhosis, rheumatoid arthritis, bacterial sepsis, and malignancies.(12-16) along with cancer cells, macrophages and neutrophils have been demonstrated to secrete ykl-40. immunohistochemical reactivity of ykl-40 is cytoplasmic. ykl-40 protein is possibly associated with such processes in malignancy as cell differentiation and proliferation, inhibition of apoptosis, angiogenesis, and remodeling of extracellular matrix.(1) cancer development and invasion are closely related with the interaction of surrounding structures. stromal tissues surrounding cancer have quite a lot of unique characteristics resembling granulation tissue developed around inflammation and tissue healing processes. tumor associated macrophages and leucocytes within this granulation tissue secrete growth factors, angiogenesis stimulating factors, cytokines, and tissue destruction enzymes, such as metalloproteinases.(12) elevated urological oncology 573vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l serum levels of ykl-40 in cancerous patients may play some roles in all of these processes. the relationship of elevated serum levels of ykl-40 with cancer cell proliferation, invasion, and development of metastasis is extensively investigated in several cancer types, including pca.(6) furthermore, ykl-40 is regarded as a potential target in the design of anticancer therapy. potential methods for inhibition of ykl-40 activity include inhibition of ykl-40 production, development of specific molecules or antibodies against ykl-40 and its receptors, and inhibition of signal transporting cascade.(1) one potential limitation of our study is the relatively small number of subjects. conclusion elevated serum level of ykl-40 may be a useful indicator of tumor burden and advanced stage pca. ykl-40 is neither organnor cancer-specific. meaningful serum ykl-40 elevations have been reported consistently only in advanced stage cancer, and indicates poor prognosis in different types of cancer. more studies are required to further clarify ykl40 as a biomarker; our findings highlight the importance of ykl as a marker in pca. conflict of interest none declared. references 1. johansen js, jensen bv, roslind a, nielsen d, price pa. serum ykl-40, a new prognostic biomarker in cancer patients? cancer epidemiol biomarkers prev. 2006;15:194202. 2. kim sh, das k, noreen s, coffman f, hameed m. prognostic implications of immunohistochemically detected ykl-40 expression in breast cancer. world j surg oncol. 2007;5:17. 3. cintin c, johansen js, christensen ij, price pa, sorensen s, nielsen hj. high serum ykl-40 level after surgery for colorectal carcinoma is related to short survival. cancer. 2002;95:267-74. 4. dehn h, hogdall ev, johansen js, et al. plasma ykl-40, as a prognostic tumor marker in recurrent ovarian cancer. acta obstet gynecol scand. 2003;82:287-93. serum level of ykl-40 in prostate cancer | özdemir et al 5. johansen js, drivsholm l, price pa, christensen ij. high serum ykl-40 level in patients with small cell lung cancer is related to early death. lung cancer. 2004;46:333-40. 6. kucur m, isman fk, balci c, et al. serum ykl-40 levels and chitotriosidase activity as potential biomarkers in primary prostate cancer and benign prostatic hyperplasia. urol oncol. 2008;26:47-52. 7. johansen js, brasso k, iversen p, et al. changes of biochemical markers of bone turnover and ykl-40 following hormonal treatment for metastatic prostate cancer are related to survival. clin cancer res. 2007;13:3244-9. 8. steuber t, o'brien mf, lilja h. serum markers for prostate cancer: a rational approach to the literature. eur urol. 2008;54:31-40. 9. partin aw, carter hb, chan dw, et al. prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. j urol. 1990;143:747-52. 10. brasso k, christensen ij, johansen js, et al. prognostic value of pinp, bone alkaline phosphatase, ctx-i, and ykl-40 in patients with metastatic prostate carcinoma. prostate. 2006;66:503-13. 11. johansen js, williamson mk, rice js, price pa. identification of proteins secreted by human osteoblastic cells in culture. j bone miner res. 1992;7:501-12. 12. rathcke cn, vestergaard h. ykl-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis. inflamm res. 2006;55:221-7. 13. johansen js, jensen hs, price pa. a new biochemical marker for joint injury. analysis of ykl-40 in serum and synovial fluid. br j rheumatol. 1993;32:949-55. 14. johansen js, krabbe ks, moller k, pedersen bk. circulating ykl-40 levels during human endotoxaemia. clin exp immunol. 2005;140:343-8. 15. johansen js. studies on serum ykl-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer. dan med bull. 2006;53:172-209. 16. de ceuninck f, gaufillier s, bonnaud a, sabatini m, lesur c, pastoureau p. ykl-40 (cartilage gp-39) induces proliferative events in cultured chondrocytes and synoviocytes and increases glycosaminoglycan synthesis in chondrocytes. biochem biophys res commun. 2001;285:926-31. urological oncology 95urology journal vol 4 no 2 spring 2007 role of pten gene in progression of prostate cancer gholamreza pourmand,1 abed-ali ziaee,2 amir reza abedi,1 abdolrasoul mehrsai,1 hossein afshin alavi,3 ali ahmadi,1 hamid reza saadati2 introduction: the aim of this study was to clarify the role of pten gene in progression of prostate cancer. materials and methods: a total of 51 formalin-fixed paraffin-embedded specimens of prostate cancer were analyzed for pten mutations. tissue microdissection and polymerase chain reaction/single-strand conformation polymorphism methods were used. clinical and pathologic data of the patients were reviewed with regard to pten mutation. results: the gleason score (gs) was less than 7 in 29 (56.8%), 7 in 11 (21.6%), and greater than 7 in 11 (21.6%). tumor stage was iia, iib, iic, and iv in 14 (27.4%), 4 (7.8%), 21 (41.2%), and 12 (23.6%) patients, respectively. eleven of 12 stage iv tumors had metastases at the time of presentation. six of 51 cases (11.6%) showed mutation in pten which had involved exones 1, 2, and 5. two of these cases had localized and the others had advanced prostate cancer. one case of the tumors with pten mutation had a gs of 7 and 5 had gss greater than 7. patients with a positive mutation of pten had a significantly greater gs (p < .001), lower survival rate (p = .001), higher tendency to metastasis (p = .002), and higher prostate-specific antigen (p = .03). cox proportional hazard model showed that only gs was significantly correlated with mortality (p = .03). conclusion: patients with prostate cancer who had pten mutation had also a significantly greater gs, poorer prognosis, and higher rate of metastasis. however, this mutation cannot predict the prognosis and the gs is a more precise factor. urol j. 2007;4:95-100. www.uj.unrc.ir keywords: prostatic neoplasms, pten, mutations, gleason score, prostate-specific antigen, iran 1urology research center, tehran university of medical sciences, tehran, iran 2institute of biophysics and biochemistry, university of tehran, tehran, iran 3department of pathology, day hospital, tehran, iran corresponding author: gholamreza pourmand, md urology research center, sina hospital, hasanabad sq, tehran, iran tel: +98 21 6671 7447 fax: +98 21 6671 7447 e-mail: gh_pourmand@yahoo.com received september 2006 accepted april 2007 introduction prostate adenocarcinoma is one of the most commonly diagnosed malignancies affecting the men in both the united states and europe.(1) the prognostic factors in patients with prostate cancer who undergo radical prostatectomy are pathological stage and gleason score (gs).(2) prostate cancer is a heterogeneous disease and identifying factors associated with a poor outcome at the time of radical prostatectomy is challenging.(2) the molecular mechanisms of prostate carcinogenesis are unknown. pten/ mmac1 is a tumor suppressor gene located on 10q23.(3,4) pten that encodes a dual-specificity phosphatase is a tumor suppressor gene whose inactivation has been associated with many different types of cancers including glioma, melanoma, and carcinoma of the endometrium, kidney, breast, lung, upper respiratory tract, and prostate.(5) the tumor suppressor activity of pten is thought to be primarily due to its ability to dephosphorylate phosphoproteins pten and prostate cancer—pourmand et al 96 urology journal vol 4 no 2 spring 2007 or phospholipids and negatively regulate the activity of the phosphatidylinositol 3-kinase pathway. it is shown that expression of pten can inhibit cell cycle progression, induce a g1 arrest, inhibit cell migration, and induce cell cycle arrest and apoptosis.(6-8) loss of pten activity as a tumor suppressor gene enhances cell proliferation and tumor angiogenesis and decreases apoptosis.(9) mutations in pten have often been detected in metastases of prostate cancer; however, lower rates of mutations have been found in localized tumors (0 to 20% in different studies).(2) the rate of pten mutations in prostate cancer has not been adequately studied in asia. one study based on 32 chinese men with prostate cancer showed a 16% rate of pten mutations.(5) we analyzed prostate cancers of 51 iranian patients to scrutinize the role of pten mutations in tumor progression. materials and methods tumor specimens this study was performed in accordance with the declaration of helsinki and subsequent revisions and approved by ethics committee at tehran university of medical sciences. we used 51 paraffinembedded prostate cancer specimens archived in the departments of pathology of day and sina hospitals between 1997 and 2005. twelve specimens were of patients who had undergone transurethral resection and the remaining had been obtained by radical prostatectomy. the prostatectomy procedures had been performed by 3 surgeons over a period of 8 years. all specimens were collected from the archived paraffin blocks used for routine diagnosis of cancer. follow-up data were available for all of the cases in the database with a mean patient follow-up period of 48 months. the initial values of prostate-specific antigen (psa) and gs were recorded. for every case, a representative paraffin block was selected that contained both tumor and benign prostate tissue. dna extraction formalin-fixed paraffin samples were cut into 10-μm sections. the sections were pulverized under liquid nitrogen condition using microdismembrator (b braun melsungen ag, melsungen, germany). of each sample, 0.1 g of pulverized tissue powder was resuspended in 1 ml of xylene and left for 15 minutes at 55°c. the suspension was then centrifuged at 14 000 g for 5 minutes. the pellet was suspended in 0.1 ml of xylene and processed as above for the second time. the resulted sediment was mixed with 100% ethanol and processed with xylene lysis buffer (tris, sodium dodecyl sulfate, ethylenediamine tetraacetic acid [edta]). a lysis buffer containing 300 μg/ml of proteinase-k was added to the pellet, mixed and incubated at 55°c for an overnight period. the dna was extracted following the use of phenol-chloroform procedure, then dissolved in te buffer (tris-hcl and edta) and stored at 4°c. polymerase chain reaction analysis for polymerase chain reaction (pcr) application (genius, boehringer-mannheim, indianapolis, usa), increasing concentrations of extracted dna of each specimen was tested to find out the optimum dose that resulted in good amplicon product. each primer pair of the selected exons was used for mutation detection of pten/mmac1 following the pcr for the single-strand conformation polymorphism (pcrsscp). the pcr protocol was carried out as outlined in table 1, and primers used for each pten exon were as follows: pten 1f 5’-agtcgctgcaaccatcca pten 1r 5’-gatatttgcaagcatacaaa pten 2f 5’-gtttgattgccatatttcag pten 2r 5’-ggcttagaaatcttttctaaatg pten 5f 5’-gcaacatttctaaagttacctacttg pten 5r 5’-catatcattacaccagttcg table 1. polymerase chain reaction protocol denaturation annealing extension exon temperature, °c times temperature, °c times temperature, °c times pten exon 1 95 40 60 45 72 60 pten exon 2 95 30 60 45 72 60 pten exon 5 95 40 56 60 72 60 pten exon 8 95 40 58 45 72 60 pten and prostate cancer—pourmand et al urology journal vol 4 no 2 spring 2007 97 pten 8f 5’-cattataaagattcaggcaatg pten 8r 5’-gacagtaagatacagtctatc any shift in the pattern of single-strand migration in the gel electrophoresis was considered as mutated exon. the pcr product was mixed with an sscp denaturating buffer (98% foramide, 20 mm edta, 0.05% xylene cynol, 0.05% bromophenol blue, 0.05 m naoh) and heated at 98°c for 8 minutes. the heated mixture was subsequently loaded on polyacrylamide gel and electrophoresed at 250 v for 6 to 8 hours at room temperature. the electrophoresed gel was processed, stained, and developed using silver staining method. statistical analyses the t test and mann-whitney u test were used to compare the psa and gs between the patients with and without pten mutation, respectively. the chi-square test was used to evaluate metastasis in the patients with and without pten mutation. to analyze survival of the patients and the prognostic variables, kaplan-meier method, log-rank test, and cox proportional hazards regression model were used. data analyses were performed by the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). a value of p less than .05 was considered significant. results fifty-one formalin-fixed paraffin-embedded prostate cancer specimens of the patients were used in this study. radical prostatectomy had been performed in 39 localized prostate cancers and transurethral resection of prostate plus adjuvant therapy in 12 advanced cancer cases. the mean age of the patients was 69.1 ± 7.9 years (range, 57 to 82 years). of the patients, 29 (56.8%), 11 (21.6%), and 11 (21.6%) had gss less than 7, equal to 7, and greater than 7, respectively. twenty-eight of 39 localized prostate cancers (71.8%) had gss of less than 7, while 9 out of 12 advanced prostate cancers (75.0%) had gss greater than 7. preoperative serum psa level was less than 4 ng/ml in 9 patients with localized prostate cancer (23.1%), greater than 10 ng/ml in 3 (7.7%), and between 4 ng/ml and 10 ng/ml in 27 (69.2%). in advanced cancer cases, all of the patients had a preoperative psa level greater than 10 ng/ml. there was a correlation between the psa level and the gs (p = .001; figure 1). eleven of 12 advanced prostate cancers had metastases at the time of presentation. the prostate cancer stage was iia in 14 patients with radical prostatectomy (35.9%), iib in 4 (10.3%), and iic in 21 (53.8%). the pcr-sscp analyses of the specimens revealed band shifts in 6 tumors (2 in exon 1, 1 in exon 2, and 3 in exon 5) which indicated the existence of possible sequence alterations within these sites. two of these cases had localized and the others had advanced prostate cancer. one case of the tumors with pten mutation had a gs of 7 and 5 had gss greater than 7 (table 2). all of the tumors with a positive mutation of pten and advanced prostate cancer were associated with metastasis, whereas 1 of the tumors with a positive mutation and localized prostate cancer was metastatic. during the follow-up, table 2. frequency of pten gene mutation in different gleason score categories pten gleason score negative positive total < 7 29 (100.0) 0 29 7 10 (90.9) 1 (9.1) 11 > 7 6 (54.6) 5 (45.4) 11 total 45 (88.2) 6 (11.8) 51 figure 1. the correlation of preoperative serum psa level with gleason score. pten and prostate cancer—pourmand et al 98 urology journal vol 4 no 2 spring 2007 5 of 6 patients with pten mutation had died as a result of metastases. patients with a positive mutation of pten had a significantly greater gs (p < .001), lower survival rate (p = .001; figure 2), and higher tendency to metastasis (p = .002). the mean psa value was 21.42 ± 14.60 ng/ml in the mutation-positive patients and 11.25 ± 12.93 ng/ml in the mutationnegative ones (p = .03; figure 3). cox proportional hazard model was used and the variables including age, gs, pten mutation, and psa value entered in the model (table 3). only gs was significantly correlated with mortality (p = .03; figure 4). discussion prostate cancer is the most common form of malignancy in men in the western countries and is the second most common cause of cancer deaths in the united states.(1) quantitative and structural genetic alterations can cause the development and progression of prostate cancer. detection of these genes will be a key role for improving the treatment of prostate cancer. the frequency of pten inactivation coincide with the progression of prostate cancer.(1) the pten tumor suppressor gene is frequently inactivated in human tumors including glioma, melanoma, and carcinoma of the endometrium, kidney, breast, lung, upper respiratory tract, and prostate.(10) our finding of pten mutations in 6 of 51 prostate cancer specimens, 5 of which being high grade, confirms that pten is a major gene in progression of prostate cancers. the frequency of pten mutation in prostate cancer differs between studies published to date, most probably because of differences in tumors’ grade and stage in the study populations. in one study of 37 tumors with 20 (54.1%) high-grade and 17 (45.9%) low-grade tumors, 5 cases had pten mutations, 4 of which were high-grade tumors.(11) in another study of 45 prostate cancers that were mainly low grade (67%), no pten mutations were found.(12) in a study on 32 cases of prostate cancer (70% with a gs of 8 to 10), pten mutations were detected in 5 (15.6%).(5) summarizing 5 studies on pten in prostate cancer, 51 of 192 high-grade tumors (26.6%) showed figure 2. patients with positive mutation had worse prognoses. figure 4. high grade tumors have worse prognosis. figure 3. the frequency of pten gene mutation in each preoperative psa level category. 0 5 10 15 20 25 30 < 4 4 to 10 > 10 psa, ng/m l n um be r o f p at ie nt s pten negative pten positive pten and prostate cancer—pourmand et al urology journal vol 4 no 2 spring 2007 99 mutations in the pten, while only 3 of 95 low-grade cases (3.2%) showed mutations (table 4).(2,5,11-13) we found pten mutations in 6 of 51 (11.8%) iranian patients; five of the 6 cases with mutations were high-grade tumors and the patients died as a result of metastasis. these studies indicate that pten mutations occur more often in tumors with greater gss. orikasa and associates examined 45 primary prostate cancer specimens. loss of heterozygosity at the pten locus was observed in 2 out of 18 tumors (11.1%). however, no mutations were observed in any of the primary prostate cancers. these data propose that mutation of the pten gene does not play an important role in prostate carcinogenesis of japanese patients.(12) in another study, the pten appeared to be the most commonly mutated gene in metastases of prostate cancer occurring in at least 1 metastatic site in 12 of 19 (63%) patients with multiple metastases.(14) mutations of pten in localized prostate cancers have been detected at lower rates (2.5% to 5%).(15-17) these results show a role for the pten in the progression of prostate cancer. in our study, the variables which showed correlation with mortality in univariate analyses (psa and pten), did not correlate with mortality in multivariate analysis. only gs was significantly correlated with mortality (p = .03). conclusion patients with prostate cancer who had pten mutation had also a significantly greater gs, poorer prognosis, and higher rate of metastasis. the increase in the gs was associated with pten gene mutation and increase in the mortality. the same condition exists about the psa value. as a result, in multivariate analysis, only gs was significantly correlated with mortality. conflict of interest none declared. references 1. deocampo nd, huang h, tindall dj. the role of pten in the progression and survival of prostate cancer. minerva endocrinol. 2003;28:145-53. 2. mcmenamin me, soung p, perera s, kaplan i, loda m, sellers wr. loss of pten expression in paraffinembedded primary prostate cancer correlates with high gleason score and advanced stage. cancer res. 1999;59:4291-6. 3. gray ic, phillips sm, lee sj, neoptolemos jp, weissenbach j, spurr nk. loss of the chromosomal region 10q23-25 in prostate cancer. cancer res. 1995;55:4800-3. 4. arps s, rodewald a, schmalenberger b, carl p, bressel m, kastendieck h. cytogenetic survey of 32 cancers of the prostate. cancer genet cytogenet. 1993;66:93-9. 5. dong jt, li cl, sipe tw, frierson hf jr. mutations of pten/mmac1 in primary prostate cancers from chinese patients. clin cancer res. 2001;7:304-8. 6. furnari fb, huang hj, cavenee wk. the phosphoinositol phosphatase activity of pten mediates a serum-sensitive g1 growth arrest in glioma cells. cancer res. 1998;58:5002-8. 7. davies ma, koul d, dhesi h, et al. regulation of akt/pkb activity, cellular growth, and apoptosis in prostate carcinoma cells by mmac/pten. cancer res. 1999;59:2551-6. table 3. cox regression hazard model for survival of patients with prostate cancer variable hazard ratio standard error z p 95% confidence interval age 1.068 0.048 1.46 0.14 0.977 1.167 psa 1.007 0.026 0.27 0.79 0.956 1.060 gs 2.347 0.915 2.19 0.03 1.092 5.041 pten 1.699 1.698 0.53 0.60 0.239 12.051 table 4. summary of 5 studies on pten mutations and gleason scores in prostate cancer patients high-grade tumor low-grade tumor authors total pten mutation total pten mutation total pten mutation mcmenamin and colleagues(2) 109 17 (15.6) 79 17 (21.5) 30 0 dong and colleagues(5) 38 7 (18.4) 27 6 (22.2) 12 1 (8.3) gray and colleagues(11) 37 5 (13.5) 20 4 (20.0) 17 1 (5.9) orikasa and colleagues(12) 45 0 15 0 30 0 leube and colleagues(13) 57 22 (38.6) 51 21 (41.1) 6 1 (16.7) pten and prostate cancer—pourmand et al 100 urology journal vol 4 no 2 spring 2007 8. persad s, attwell s, gray v, et al. inhibition of integrin-linked kinase (ilk) suppresses activation of protein kinase b/akt and induces cell cycle arrest and apoptosis of pten-mutant prostate cancer cells. proc natl acad sci u s a. 2000;97:3207-12. 9. backman sa, ghazarian d, so k, et al. early onset of neoplasia in the prostate and skin of mice with tissuespecific deletion of pten. proc natl acad sci u s a. 2004;101:1725-30. 10. cooney ka, tsou hc, petty em, et al. absence of pten germ-line mutations in men with a potential inherited predisposition to prostate cancer. clin cancer res. 1999;5:1387-91. 11. gray ic, stewart lm, phillips sm, et al. mutation and expression analysis of the putative prostate tumoursuppressor gene pten. br j cancer. 1998;78:1296300. 12. orikasa k, fukushige s, hoshi s, et al. infrequent genetic alterations of the pten gene in japanese patients with sporadic prostate cancer. j hum genet. 1998;43:228-30. 13. leube b, drechsler m, muhlmann k, et al. refined mapping of allele loss at chromosome 10q23-26 in prostate cancer. prostate. 2002;50:135-44. 14. suzuki h, freije d, nusskern dr, et al. interfocal heterogeneity of pten/mmac1 gene alterations in multiple metastatic prostate cancer tissues. cancer res. 1998;58:204-9. 15. facher ea, law jc. pten and prostate cancer. j med genet. 1998;35:790. 16. dong jt, sipe tw, hyytinen er, et al. pten/mmac1 is infrequently mutated in pt2 and pt3 carcinomas of the prostate. oncogene. 1998;17:1979-82. 17. pesche s, latil a, muzeau f, et al. pten/mmac1/ tep1 involvement in primary prostate cancers. oncogene. 1998;16:2879-83. 1160 | treatment of juxtaglomerular cell tumor of the kidney by retroperitoneal laparoscopic partial nephrectomy zhi chen,1 zheng-yan tang,1 hai-tao liu,2 xiang chen1 keywords: kidney neoplasms; laparoscopy; juxtaglomerular apparatus; renin; laparoscopy; retroperitoneal space. introduction juxtaglomerular cell tumor (jct) of the kidney, first described by robertson and col-leagues in 1967,(1) is a rare cause of serve hypertension. because the tumor is small, mainly occurs in children and young adults, and has benign nature, nephron-sparing surgery is particularly recommended.(2) here we present for the first time a case of jct in a 29-year old woman who underwent retroperitoneal laparoscopic partial nephrectomy. case report a 29-year old woman presented with a history of headache, polyuria, nocturia, and blurred vision. her blood pressure was 190/120 mmhg and had hypokalemia (2.9 mmol/l). blood urea and creatinine and 24-hour urinary vanillyl mandelic acid (vma) levels were all normal. ultrasonography revealed a hypoechoic 2 × 3 cm mass in the left kidney. contrast-enhanced computed tomography (ct) of the abdomen documented a 2 × 3cm hypo enhancing, solitary, well-circumscribed mass lesion in the anterior aspect of the middle pole of the left kidney (figure 1). serum levels of plasma renin activity (pra) and aldosterone (ald) were high in supine and upright position (pra 7.3 µg/l/h vs. 8.9 µg/l/h and ald 258.1 pmol/l vs. 443.7 pmol/l, respectively). renal venous sampling for renin assay was performed. the ratio of left kidney to right kidney was 1.7. considering the small peripheral lesion, retroperitoneal laparoscopic partial nephrectomy was performed. the operative time was 145 min and the warm ischemic time was 29 min. the estimated blood loss was 80 ml. the hospital corresponding author: xiang chen, md department of urology, xiangya hospital, central south university, no. 87 xiangya road, changsha, 410008, china tel: +86 0138 7480 8998 fax: +86 731 8432 7354 e-mail: cxiang1007@126.com received october 2011 accepted april 2012 1 department of urology, xiangya hospital, central south university, hunan province, china. 2 department of urology, second affiliated hospital, hunan university of traditional chinese medicine, hunan province, china. case report case report 1161vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l juxtaglomerular cell tumor of the kidney | chen et al stay was 3 days. no intraoperative and postoperative complication occurred. the preand postoperative serum creatinine levels were 1.38 mg/dl and 1.45 mg/dl, respectively. the pathological findings confirmed the diagnosis of a jct (figure 2). her blood pressure returned to normal without medical treatment postoperatively. hypokalemia has also resolved. she was alive without evidence of recurrence 25 months after surgery. discussion the definitive treatment for jct is surgical excision.(3) to our knowledge, no case of jct of the kidney treated by retroperitoneal laparoscopic partial nephrectomy has been reported to date. the retroperitoneal approach for jct of kidney offers various obvious advantages. it provides a direct and rapid approach to kidney and renal hilum, allows the renal artery to be dissected directly without the retraction of the vein, there is closer proximity to the conventional open approach, provides the advantage of easier management of post-operative complication such as urine leakage or bleeding, and offers an alternative to the patients with previous transperitoneal surgery. furthermore, our previously extensive experience with many retroperitoneal laparoscopic procedures also contributed to the choice of the retroperitoneal approach for jct.(4) in conclusion, this case suggested that retroperitoneal laparoscopic partial nephrectomy is a safe and feasible procedure for jct of the kidney. acknowledgment zhi chen and zheng-yan tang contributed equally to this work. conflict of interest none declared. references 1. robertson pw, klidjian a, harding lk, walters g, lee mr, robb-smith ah. hypertension due to a renin-secreting renal tumour. am j med. 1967;43:963-76. 2. mete uk, niranjan j, kusum j, rajesh ls, goswami ak, sharma sk. reninoma treated with nephron-sparing surgery. urology. 2003;61:1259-59. 3. feliciotti f, campagnacci r, perretta s, et al. laparoscopic resection of a juxtaglomerular cell tumor of the right kidney. surg endosc. 2002;16:539. 4. chen z, chen x, luo yc, he y, li nn, wu zh. retroperitoneoscopic decortication of symptomatic peripelvic renal cysts: chinese experience. urology. urology. 2011;78:803-7. figure 1. contrast-enhanced computed tomography scan shows a 2 × 3cm hypo enhancing, solitary, well circumscribed mass lesion in the anterior aspect of the middle pole of the left kidney. figure 2. the pathological examination shows that the tumor cells consist of clusters of polygonal cells, with a moderate amount of eosinophilic cytoplasm and centrally located nuclei. there is a prominent vessels under light microscope. (hematoxylin eosin × 400). v08_no_3_final.pdf pictorial urology 178 urology journal vol 8 no 3 summer 2011 giant vulval filariasis an uncommon problem in endemic region a 40-year-old woman presented with complaint of mass in her genitalia associated with dragging pain and difficulty in coitus and walking for the past five years. on examination, two nontender irreducible well-defined bosselated vulval masses were detected, right and left measuring 45 × 38 cm and 22 × 20 cm in size, respectively. there were multiple nodular swellings on the outer surface of each mass. on laboratory investigation, hemoglobin 11 g/dl, leukocyte count 6400 cells/mm3, and absolute eosinophil count 200 were observed. serum level of anti-filarial ige found significantly raised. pre-operatively, 2-week therapy of diethylcarbamazine was started. excision of both right and left masses weighing 15 and 8 kg, respectively, was done with vulvoplasty. the postoperative period was uneventful. on histopathlogical examination, stratified squamous epithelium with hyperkeratosis was seen. underlying stroma showed dermal fibrosis and collagenization with mixed inflammatory infiltrate suggestive of chronic inflammatory pathology. wuchereria bancrofti commonly affects the lower limb and genitalia than the arms and breasts.(1) however, the genitalia is rarely affected with brugia malayi infection.(2) patients with lymphedema are treated with a combination of limb elevation, compression garment, and compression pump therapy, and surgery, if necessary.(3) surgical treatment helps reduce the weight of the affected organ, minimize inflammatory attacks, improve cosmesis, and reduce the risk of secondary angiosarcoma.(4) sudheer rathi, abhishek jain,* rajesh sharma department of surgery, llrm medical college, meerut, u.p, india *e-mail: jain2k2@yahoo.com references 1. tayel sel s, sharapy ael d, el shazly am, shahat sa, zaalouk t, al sayed my. clinical, parasitological and social studies on wuchereria bancrofti in egypt. j egypt soc parasitol. 2011;41:179-97. 2. bernhard p, makunde rw, magnussen p, lemnge mm. genital manifestations and reproductive health in female residents of a wuchereria bancrofti-endemic area in tanzania. trans r soc trop med hyg. 2000;94:409-12. 3. pipinos ii, baxter tb. the lymphatics. in: townsend cm, beauchamp rd, evers bm, mattox kl, eds. sabiston textbook of surgery. 18 ed. philadelphia: saunders elsevier; 2008:2023-5. 4. miller ta, wyatt le, rudkin gh. staged skin and subcutaneous excision for lymphedema: a favorable report of long-term results. plast reconstr surg. 1998;102:1486-98; discussion 99-501. urol j. 2011;8:178. www.uj.unrc.ir u j spring 2012.pdf 445vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l purpose: to compare and evaluate the mostly used methods of urinary stone analysis. materials and methods: we searched pubmed and google scholar for “urolithiasis, nephrolithiasis, renal stone, and kidney stone” combined with “stone analysis, spectroscopy, x-ray diffraction, chemical analysis, mass spectrometry, and laserinduced breakdown spectroscopy, review article, and quality control assessment.” results: sis techniques and their quality control trials. seven articles were not in english language; hence, were omitted from this review. the remaining 17 articles and their related references were studied thoroughly. there are various chemical and physical techniques available for urinary stone analysis. the correct stone analysis has to identify not only all stone components, but also the molecular structure and crystalline forms of them with the exact quantitative determination of each component. conclusion: the knowledge of urinary stone composition is important for understanding pathophysiology, choice of treatment modality, and prevention of realthough there are many techniques available for identifying the urinary stone composition and structure, no single method can provide all the requiring information. therefore, a combination of structural and morphological tests is needed for this purpose. keywords: kidney calculi, chemical analysis, spectroscopy, x-ray diffraction 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2department of clinical biochemistry, faculty of medical sciences, tarbiat modares university, tehran, iran abbas basiri,1 maryam taheri,1 fatemeh taheri2 review what is the state of the stone analysis techniques in urolithiasis? corresponding author: maryam taheri, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., 1666677951, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: taheri233@yahoo. com received april 2012 accepted april 2012 446 | review introduction the incidence of nephrolithiasis has consid-erably increased throughout the world in the last twenty years. the treatment of urinary stone can be painful, stone removal often requires surgery, and renal failure occurs in about 3% of patients. furthermore, the recurrence rates reach 50% within 5 years if a proper management, stone analysis, and follow-up are not applied. the most frequent component of urinary calculi is calcium, which is the major constituent of nearly 75% of stones. urinary stone is mostly composed of calcium oxalate about 60%, mixed calcium oxamately 10%, struvite (magnesium ammonium 1%. the purposes of stone analysis are qualitative differentiation of all stone components and their semiquantitative determination. the aim of this review is to compare the principles and practical application of various chemical and physical techniques used for urinary stone analysis. materials and methods according to our search on pubmed and google scholar for “urolithiasis, nephrolithiasis, renal stone, and kidney stone” combined with “stone analysis, spectroscopy, x-ray diffraction, chemical analysis, mass spectrometry, and laser-induced breakdown spectroscopy, review article, and quality control assessment.” results ciples of stone analysis techniques and their quality control trials. seven articles were not in english language; hence, were omitted from this review. the remaining 17 articles and their related references were studied thoroughly. currently, the following methods are available for stone analysis: wet chemical analysis, thermogravimetry, optic polarizing microscopy, scanning electron microscopy, and different methods of these methods and then, compare their accuracy and practical application according to our literature review. wet chemical analysis although wet chemical technique is the most widely used approach for stone analysis in routine laboratories, it can only identify the presence of individual ions and radicals without differentiatmixtures. an external quality assurance scheme showed relatively poor performance of qualitative and semi-quantitative wet chemical tests, including commercial kits. however, its performance can improve by using quantitative wet chemical approach, in which the same routine quantitative chemical analysis methods for blood and urine are used for a suitably prepared solution of the stone. thermogravimetry since the 1970s, thermogravimetric analysis (tg ing kidney stones. thermogravimetry is a viable, fast, and simple technique based on continuous recording of both the temperature and weight loss of the material during a progressive temperature increase to 1000 ºc in an oxygen atmosphere. transformation, the starting and ending temperature of transformation, the amount of change in weight, and enthalpy, the nature of the substance and the magnitude of this change indicates the proportion. optic polarizing microscopy the base of this technique is the interaction of polarized light with crystals of stones. after the stone is fractured and the material is removed from various points of it, it can be assessed under the polarizing microscope using a drop of the appropriate refractive index liquid. parameters which iden447vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l tify the stone minerals include the color, refraction of light, and double refraction. scanning electron microscopy (sem) scanning electron microscopy is a precise technique for the study of morphology of urinary calculi. this technique is non-destructive and reveals details about stones 1 to 5 nm in size, without nents. furthermore, it can produce very high-resolution images of a sample surface. spectroscopy spectroscopy is the study of the interaction between matter and radiated energy. spectroscopy are summarized in table 1. here the principles and practical application of mostly used methods of spectroscopy will be presented. infrared (ir) spectroscopy however, it has become as a popular reliable method for in-vitro quantitative stone analysis in the last decade. id, and versatile method, which uses ir radiation in order to cause atomic vibrations, consequently, ention bands in the ir spectrum of stone samples. two different ir spectroscopy approaches are common: the direct ir transmission, in which, the stone material is mixed with potassium bromide and compressed to form a disc, which is used for the analysis. therefore, stone material cannot be recovered for further supporting analysis, such as wet chemical tests. but in non-destructive approach, such as photo-acoustic detection, recovery of the sample is possible. a more recent technique in ir spectroscopy is the furstone analysis techniques in urolithiasis | basiri et al table 1. classification of the spectroscopy techniques. 1. type of radiated energy electromagnetic radiation classified by the wavelength region of the spectrum and includes microwave, terahertz, infrared, near infrared, visible and ultraviolet, x-ray, and gamma spectroscopy. particles electrons and neutrons can also be a source of radiative energy acoustic spectroscopy involves radiated pressure waves 2. nature of the interaction absorption emission elastic scattering and reflection spectroscopy determines how incident radiation is reflected or scattered by a material, such as x-xay diffraction impedance spectroscopy inelastic scattering raman scattering coherent or resonance spectroscopy nuclear magnetic resonance (nmr) spectroscopy 3. type of material atoms atomic absorption spectroscopy (aas) atomic emission spectroscopy (aes) flame emission spectroscopy inductively coupled plasma atomic emission spectroscopy x-ray spectroscopy x-ray fluorescence (xrf) molecules infrared and raman spectroscopy crystals nuclei nmr spectroscopy 448 | thermore, sample preparation for this technique is very easy, as it does not require mixing the sample with an ir inactive material, such as potassium bromide, prior to analysis. x-ray powder diffraction (xrd) x-ray powder diffraction uses monochromatic x-rays for identifying the constituents of a renal stone based on the unique diffraction patterns produced by a crystalline material. crystal moieties of in particular patterns. elementary distribution analysis (edax) to obtain the percentage of composition of all stone nary light microscopy or sem alone. elementary sem results and also evaluate the percentage of the different elements present in a sample. discussion nephrolithiasis is a recurrent condition with considerable morbidity. while in symptomatic stone episodes the appropriate treatment is necessary, prophylactic workup to prevent recurrences is also of great importance, which is possible by a complete metabolic workup and a suitable stone analysis. the chemical composition of urinary calculi was th century, when important chemical components of urinary calculi, chemical analysis of urinary calculi was presented as an established routine. izing microscopy as an analytical tool for identiby refractive index measurements. the ability lyze small amounts of stones, and the rapidity of polarizing microscopy are the advantages of this technique over chemical analysis. silva and colleagues studied a sample of 50 stones retrieved from patients in brazil in order to compare the chemical with morphological kidney stone composition analysis. they found that unlike morphological analysis, chemical analysis can only detects calcium and oxalate separately without differentiating the crystalline types. identifying the crystalline form is very useful for planning therapy, eg, with hypercalciuria while calcium oxalate monoaluria. therefore, they offered using both types of analysis routinely for a better understanding of the mechanisms involved in lithogenesis. jhaumeer-laulloo and subratty employed wet chemical tests and ir spectroscopy techniques to ings revealed that the chemical analysis method clinical errors. they also showed that the spectroscopic methods were applicable for smaller amount of sample and were able to identify the different constituents of the renal stones. singh analyzed urinary stones of 50 patients by mine urinary stone composition. he also mentioned that using computerized ir spectrophotometer and large reference library enable us to determine exact quantitative stone composition, and this method should be extended to all urolithiasis centers. while estepa and coworkers depicted the poscause of library incompleteness and also considerable differences between the spectra of natural and synthetic compounds. for example, they observed that the spectrum of human whewellite shows a peak at 1315 cm–1 while the peak is at 1319 cm–1 for the synthetic one. on the other hand, a peak at review 449vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l 1319 cm–1 in human stone samples corresponds to a mixture of whewellite and weddellite in 50/50 proportions. weddellite may occur using the search procedure if synthetic whewellite is included as a reference in libraries. stones and supported its ability to produce fast and quantitative results. however, limitations of tga require relatively large amount of material for optimal resolution and non-recovery of sample. furthermore, similarity in ignition temperatures and rates of disintegration of some closely related compounds, such as purines, may make the identicalcium pyrophosphate display very little weight change on heating, tga cannot convincingly identify them from each other. since 1970s, physico-chemical techniques have been increasingly employed for urinary stone analysis, which resulted in discovering numerous crystalline elements in urinary stones. many clinical laboratories employed x-ray diffraction and ir spectroscopy as reference techniques for stone analysis. thereafter, a lot of studies were designed to compare the quality of these methods in addition to quality control surveys that were conducted for improving the standards of them, some of which are presented as follows. rebentisch presented the result of six external tive and various qualitative analytical techniques during 1983 and 1988. he used both standard of quality and the mean deviation as two determining parameters for ranking the methods, which were from the best performance to worst in the following order: x-ray diffraction, ir spectroscopy, ul according to these results, rebentisch offered that x-ray diffraction and ir spectroscopy methods give comparable and highly acceptable analytical for the analysis of urinary calculi. the fourth international ring test for checking the quality of methods for urinary calculus analysis, conducted by rebentisch and colleagues in 1988, demonstrated that the method of xrd is clearly superior to ir spectroscopy. also in external quality assessment of analysis of urinary calculi, which was commenced in 1991, they suggested that the use of chemical methods should be discontinued because of laboratories. hesse and associates designed a twice-yearly ring trials quality control survey to examine the quality of urinary stone analysis based on synthetic products in averagely 100 laboratories since 1980. the methods employed for these analyses were based on chemical analysis, ir spectroscopy, and x-ray carried out using chemical methods for more than of ir spectroscopy progressively increased to 79%. the number of specialized laboratories which used x-ray diffraction was constantly about 5% to 9%. additionally, these ring trials revealed that error rates for ir spectroscopy and x-ray diffraction were only limited to individual substances, whereas for the chemical methods very high proportion of errors occurred with both the pure substances majority of laboratories stopped using chemical analysis, which is now considered to be obsolete. kasidas and associates analyzed the results of external quality assurance for urinary stone analysis stone analysis techniques in urolithiasis | basiri et al 450 | 55% to 65% accuracy versus ir with 85% to 90% correct analyses. another study in china confraction for qualitative and quantitative analysis of urinary stones. mon techniques based on the reviewed studies are in addition to the most common techniques that were mentioned above, there are other techniques which may have in-vivo application in practice lecular structure or several unexpected trace elements mainly in the nuclear region of the stones. meanwhile, often these techniques are not useful in routine laboratory for being costly and requiring special expertise or sample preparation. kim and colleagues analyzed 86 consecutive urinary stones by x-ray analysis and compared the diffraction, ir spectrometry, and chemical analysis. this study indicated that the sensitivity of xray analysis was several times more than other three methods, especially in detection of apatite. this study also offered x-ray analysis as a particularly suitable method for detection of rare inorganic components of urinary stones, such as silica and gypsum. batchelar and coworkers revealed that the x-ray coherent scatter analysis is a novel technique for intact stone analysis using monoenergetic x-ray from the standard diagnostic x-ray equipment. because the coherent scatter properties is related to the molecular structure of the scattering media of each of the stone components, com, cystine, magnesium ammonium phosphate, and calcium phosphate showed a distinct coherent scatter pattern, which matches that of a pure chemical sample. wignall and associates suggested that coherent xray scatter would be useful in future studies of the ability of commercial laboratories because it can visualize even small struvite regions in stones. siritapetawee and pattanasiriwisawa used x-ray xrpd for analyzing 15 human urinary stones. comparing the result of xanes spectra of unknown compounds from human kidney stones with the diffractogram data of the xrpd, it was shown that these two techniques agreed well with each other, while xanes required a smaller amount of each sample than xrpd for analysis. in 1995, the use of nonenhanced computed tomoghas become the standard diagnostic tool for evaluation of patients with renal colic. due to the ment, several groups were interested in comparing attenuation and stone composition in vitro. studies involving the use of single-energy ct technology have shown that some information about stone composition may be gained, enabling differentiation between uric acid and calcium stones on the basis of their different attenuations, with lower atstones. to the considerable overlap of attenuation values, dual-energy ct by low and high-energy scanning is capable to differentiate various materials with similar electron densities, but different photon absorption. therefore, it may not only contribute acterization of stones in the urinary tract, which could be useful in surgical or medical treatment decisions. hidas and coworkers used dual-energy ct to pre-operatively assess the composition of sults with postoperative in-vitro x-ray diffraction analysis. they found that dual-energy ct was able to characterize the kidney stone composition with review 451vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l tify struvite stones which had attenuation ratios could not be assessed reliably. by combination of x-ray attenuation values and morphological appearance, micro ct can identify especially for apatite. furthermore, detection of the following 6 minerals, uric acid, com, cod, cystine, struvite, and hydroxy apatite, in pure or heterogeneous urinary stones is possible without having overlapped ranges of micro attenuation values. however, the study by krambeck and als with lower x-ray attenuation, such as struvite, is not always possible as a minor inclusion in particular mineral. in addition, its use in routine laboratory has not been exploited because it costs 10 times more than ft-ir. a simple, rapid, and remote technique, which percation of the major and trace elements present in the calculus. in this technique, a pulsed laser beam is focused on the surface of the sample in order to produce high-density plasma that excites various atomic elements and elemental transitions in the focal volume. singh and associates performed libs to estimate the quantitative elemental constituents distributed in different parts of the kidney stones obtained directly from 5 patients by surgery, and compared the results with that of inductively both libs spectra and icp-ms analysis showed that the major constituent of the kidney stones was calcium. laser ablation inductively coupled plasma mass for the study of biological and geological samples, which uses a focused laser beam issued to mobilize sample material as droplets or vapor from the sample surface. thereafter, the material is transported to the plasma often by argon as a carrier gas. the plasma causes the material to be ionized and moved through to the mass spectrometer, which selectively detects ions at a given mass-tocharge ratio. kontoyannis and colleagues analyzed mineral components of a urinary stone forming layers with the use of three spectroscopic methods: raman troscopy could analyze the various mineral layers in the kidney stones by focusing the laser beam at the desired layer, whereas application of ft-ir produced overlapping broad bands and xrd could not analyze the mineral components of the various layers of small stones precisely since the material in the study by cytron and associates, analysis of chemical composition of the stones and their concentrations were determined by analysis of the ir spectroscopy. the urine samples were collectbe applied as an alternative method for complete and quick metabolic evaluation of patients without sample preparation. according to the studies described above, there are many different methods available for urinary stone analysis, but the fact is that no single method formation about the structure and composition of the stones. therefore, a combination of these techniques is advised. fazil marickar and coworkers revealed that the combination of optical microscopy and ir spectroscopy of core, cross section, and surface of calculi is an accurate and reliable components while being highly cost-effective. uldall showed that combination of x-ray diffraction or ir spectrometry and wet chemistry may be suitable as reference methodology. stone analysis techniques in urolithiasis | basiri et al 452 | in the literature, other combinations of methods, such as tga with x-ray diffraction by konjiki and colleagues, and tg with ft-ir spectroscopy by materazzi and associates, have been mentioned. also, fazil marickar and coworkers analyzed 10 mixed stones using ft-ir spectroscopy and semedax combination in order to get a thorough understanding of mixed stone morphology, and concluded that although ft-ir analysis is more modern, less time-consuming, and more precise, combination of sem-edax will give a clear indication of the structure of the stone on the surface all stone elements. more importantly, the study by schubert revealed that useful results of any of these methods are obtained when different areas of the calculus are analyzed separately. conclusion in this review, we observed that although wet chemical analysis technique of urinary stone is the traditional gold standard, it has been replaced with more accurate spectroscopy techniques, such as ft-ir, xrd, ct scan, etc. also we believe that our current results provide compelling evidence to support the notion that in addition to applying combination techniques, analysis of different parts of stone separately is of utmost importance. conflict of interest none declared. table 2. comparison of the stone analysis techniques. test advantages disadvantages chemical analysis rather than a specific compound, eg, unable to distinguish between the two commonly occurring calcium stones (monohydrate/dihydrate) polarization microscopy ponents in the stone* of uric acid, purine derivates, and calcium phosphates infrared spectroscopy reflection technique ing search–match functions nents or noncrystalline substances, eg, purines, proteins, or fat and drug metabolites may affect the infrared spectroscopy spectrum quality bands may affect its reliability eg, whewellite in weddellite or reverse, or urates and uric acid dihydrate in uric acid their absorption band, such as carbonate in struvite stones or cystine in whewellite or uric acid stone x-ray diffraction nents is possible thermogravimetry scanning electron microscopy altering their spatial orientation and specific morphology * whereas kasidas and colleagues in another study showed that the polarization microscopy cannot identify small amounts of crystalline material in mixtures. review 453vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l stone analysis techniques in urolithiasis | basiri et al references 1. stamatelou kk, francis me, jones ca, nyberg lm, curhan gc. time trends in reported prevalence of kidney stones in 2. kasidas gp, samuell ct, weir tb. renal stone analysis: why 3. estepa l, daudon m. contribution of fourier transform infrared 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[the application of x-ray diffraction in the study of urinary stones]. guang pu xue yu guang pu fen xi. 31. fazil marickar ym, lekshmi pr, varma l, koshy p. problem in analyzing cystine stones using ftir spectroscopy. urol res. 32. kim km, alpaugh hb, johnson fb. x-ray microanalysis of urinary stones, a comparison with other methods. scan 33. batchelar dl, chun ss, wollin ta, et al. predicting urinary stone composition using x-ray coherent scatter: a novel technique with potential clinical applications. j urol. 34. wignall gr, cunningham ia, denstedt jd. coherent scatter computed tomography for structural and compositional stone analysis: a prospective comparison with infrared 35. siritapetawee j, pattanasiriwisawa w. an attempt at kidney stone analysis with the application of synchrotron radia36. gerber gs, brendler cb. evaluation of the urologic patient: history, physical examination, and urinalysis. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. 10 ed. philadelphia: saunders 37. hidas g, eliahou r, duvdevani m, et al. determination of renal stone composition with dual-energy ct: in vivo analysis and comparison with x-ray diffraction. radiology. bellin mf, renard-penna r, conort p, et al. helical ct evaluation of the chemical composition of urinary tract calculi with a discriminant analysis of ct-attenuation values and 39. gottlieb rh, la tc, erturk en, et al. ct in detecting urinary tract calculi: influence on patient imaging and clinical 40. mostafavi mr, ernst rd, saltzman b. accurate determination of chemical composition of urinary calculi by spiral 41. zarse ca, mcateer ja, sommer aj, et al. nondestructive analysis of urinary calculi using micro computed tomogra42. matlaga br, williams jcj, evan ap. calcium oxalate stones are frequently found attached to randall’s plaque. in: evan ap, lingeman je, williams jcj, eds. renal stone disease. proceedings of the first international urolithiasis research symposium. review 43. pramanik r, asplin jr, jackson me, williams jc, jr. protein content of human apatite and brushite kidney stones: significant correlation with morphologic measures. urol 44. williams jc, jr., zarse ca, jackson me, witzmann fa, mcateer ja. variability of protein content in calcium oxalate 45. miller nl, gillen dl, williams jc, jr., et al. a formal test of the hypothesis that idiopathic calcium oxalate stones grow 46. zarse ca, mcateer ja, sommer aj, et al. nondestructive analysis of urinary calculi using micro computed tomogra47. abdel-halim re, abdel-halim mr. a review of urinary stone krambeck ae, khan nf, jackson me, lingeman je, mcateer ja, williams jc, jr. inaccurate reporting of mineral composition by commercial stone analysis laboratories: implications for infection and metabolic stones. j urol. 49. singh vk, rai ak, rai pk, jindal pk. cross-sectional study of kidney stones by laser-induced breakdown spectroscopy. 50. lobinski r, moulin c, ortega r. imaging and speciation of trace elements in biological environment. biochimie. 51. austin c, hare d, rozelle al, robinson wh, grimm r, doble p. elemental bio-imaging of calcium phosphate crystal deposits in knee samples from arthritic patients. metallomics. 52. kontoyannis c, bouropoulos n, koutsoukos p. urinary stone layer analysis of mineral components by raman spectroscopy, ir spectroscopy, and x-ray powder diffraction: a 53. cytron s, kravchick s, sela ba, et al. fiberoptic infrared spectroscopy: a novel tool for the analysis of urine and 54. fazil marickar ym, lekshmi pr, varma l, koshy p. edax 55. 56. 57. materazzi s, curini r, d'ascenzo g, magri a. tg-ftir coupled analysis applied to the studies in urolithiasis: characterization endourology and stone disease role of sexual intercourse after shockwave lithotripsy for distal ureteral stones: a randomized controlled trial wenfeng li1, yuansheng mao1*, chao lu1, yufei gu1, bao hua1, weixin pan1 purpose: to explore whether sexual intercourse is beneficial to the clinical outcome of swl for ureteral calculi of 7-15 mm in the distal ureter. materials and methods: between march 2016 and january 2017, 225 patents with a stone (7-15 mm) in distal ureter were randomly divided into three groups after swl: group 1 was asked to have sexual intercourse at least three times a week, group 2 was administered tamsulosin 0.4 mg/d and group 3 was received standard therapy alone and served as the controls. stone free rate, time to stone expulsion, pain score at admission, number of hospital visits for pain and steinstrasse were recorded in 2 weeks. results: 70 patients in group 1, 71 patients in group 2 and 68 patients in group 3 were enrolled to the study. at the end of the first week and the second week, the stone free rates for group 1 (68.6%, 80.0%) and group 2 (69.0%, 81.7%) were approximately the same, but were significantly higher than group 3 (50.0%, 63.2%) (p = .031, p = .022). the vas scores of groups 1 and 2 were slightly higher than those of group 3 (p = .233). the number of patients in group 3 who visited the emergency room for pain was significantly higher than in the other two groups (p = .015). at the end of the second week, the incidence of steinstrasse in groups 1 and 2 was significantly lower (2.9%, 2.8% vs 11.8%) (p = .034). conclusion: at least three sexual intercourses per week after swl can effectively improve the stone free rate, reduce the formation of steinstrasse and relieve renal colic. it provides a choice for urologists in the swl treatment of lower ureteral calculi. keywords: shockwave lithotripsy; sexual intercourse; tamsulosin; ureteral stone; pain introduction ureteral calculi are one of the most common diseas-es of the urinary system(1). the treatment of ureteral stones includes conservative treatment, medical expulsive therapy (met), shock wave lithotripsy (swl), ureteroscopy (urs), and other invasive and non-invasive methods (2). since the 1980s, swl has gradually become one of the preferred treatment methods for ureteral stones. management of residual fragment after swl is still a major concern as it may eventually cause pain and require reintervention. elimination of residual fragments depends on various parameters, such as stone size, number, location in the urinary tract, patient’s anatomy, and ureteral peristaltic capability(3-6). medical expulsive therapy for urolithiasis has gained increasing attention in the last decade. various agents have been investigated including calcium channel blockers, alpha-adrenergic antagonists, corticosteroids and phosphodiesterase type 5 inhibitors (pde5i)(7-12). the goal of medical therapy is to enhance stone expulsion with a parallel decrease in the associated pain after swl. recent studies found that sexual intercourse can effectively promote the expulsion of lower ureteral stones (13-15). however, whether it is also effective for the expulsion of stones after swl for lower ureteral calculi 1department of urology, the ninth people's hospital affiliated to shanghai jiao tong university, shanghai 200011, china *correspondence: department of urology, the ninth people's hospital affiliated to shanghai jiao tong university , shanghai, china. tel: +86 21 56691101. e-mail: lichen0612@163.com. received june 2019 & accepted december 2019 has not been reported. therefore, we designed a randomized, prospective study to explore whether sexual intercourse is beneficial to the clinical outcome of swl for ureteral calculi of 7-15 mm in the distal ureter. patients and methods study population this prospective, randomized, controlled study included 225 male patients presented to our institution with renal colic in the period between march 2016 and january 2017. patients were enrolled in the study by research nurse after a routine preoperative evaluation. inclusion criteria were presence of distal ureteric or intramural stone from 7 to 15 mm in diameter detected by plain x-ray film and low-dose noncontrast enhanced computed tomography (ncct) scan for radiolucent stones. their age ranged from 21 to 50 years. exclusion criteria were patients with abnormal kidney anatomy and function, body weight over 100 kg, previous administration of drugs that may induce stones, history of urologic surgery, hydronephrosis higher than level 1, coagulation dysfunction, urinary system infection, tamsulosin allergy, serum creatinine greater than 2 mg/dl, multiple ureteral calculi, fever, or hypotension, as well as pain that was difficult to control by analgesics, bladder ureteral urology journal/vol 17 no. 2/ march-april 2020/ pp. 134-138. [doi: 10.22037/uj.v0i0.5400] vol 17 no 02 march-april 2020 135 reflux, neurogenic bladder, or erectile dysfunction. the nature of the study was explained to each patient and informed consent was obtained. the protocol of this study was approved by the institutional ethics committee of the ninth people's hospital affiliated to shanghai jiao tong university (no.192). patients’ enrollment algorithm has been illustrated in figure 1. a complete medical history along with anthropometric parameters was routinely collected. body mass index (bmi) was calculated as weight in kilograms divided by height in meters squared (kg/m2). blood samples were taken and tested for blood count and serum creatinine. urinalysis and urine culture were also performed before swl. in patients with negative urine culture, no antibiotics was administered before swl. stone number, size, location and hounsfield unit (hu) were assessed preoperatively by means of a low-dose ncct scan, the accurate imaging modality to define stone size and location. study design this study was a prospective single center, parallel-group randomized clinical trial with balanced randomization [1:1:1] by using block randomization method. sample size was calculated based on the assumption of an increase in the stone-free rate from 50% to 75% per person in both treatment arms(16). to detect such a difference with 80% power using a two-tailed test at 5% significance level, it was estimated that 58 evaluable patients per group were needed. to consider possible dropout, 75 patients per group were planned (www. dsssresearch.com). block randomization was used to allocate subjects into three equally sized groups. eligible patients were randomly assigned to one of the three groups according to a computer-based block randomization list generated by the sealed envelope. the block sizes were six. procedures all patients underwent swl within 24 hours after diagnosis. a standard swl treatment of 3,000 shocks/ session transabdominal at a prone position was planned in each patient under adequate sedation and analgesia. all swl procedures were performed by a single urologist who was blinded to the group allocation. however, the stone was observed to have completely fragmented during the procedure in some patients, and the swl treatment was terminated earlier. the procedure was performed at a frequency of 90 shocks per minute, by gradually increasing the therapeutic power from 15 kv to 20 kv during the first 500 shocks, using the dornier hm3 lithotripter (dornier medtech, germany) after swl, it was recommended that all patients take fluids and produce more than 2000 ml of urine per day. in addition, for patients in group 1 (the sexual intercourse group), it was recommended they have sexual intercourse at least three times per week. the patients in group 2 (the tamsulosin group) received 0.4 mg tamsulosin daily. the patients in group 3 received standard therapy (take enough fluids alone) and served as the controls. the patients in groups 2 and 3 were asked to avoid sexual intercourse and masturbation for two weeks. no patients taking pde5 inhibitors for any reason which includes on demand consumption in a normal person in any group. the trial will be terminated immediately if the patient has special symptoms such as fever, unrelieved pain, renal function impairment, et al. the patient will be provided with appropriate treatment by the specialist. evaluations the primary outcome was the difference among intervention groups with respect to the stone free rates at the end of the first week and the second week after swl. all patients underwent a low-dose ncct scan by a senior radiologist blinded to the group of the study objectives and protocols at that time. patients were considered stone free if residual stones were ≤ 3 mm. even though a few patients passed fragments of stone during the treatment period, ncct was still performed in all the patients to confirm complete clearance of stones. the secondary outcomes were the differences among intervention groups with respect to pain score at admission, number of hospital visits for pain and steinstrasse in 2 weeks after swl. after swl, patients were informed regarding how to complete a visual analogue scale (vas) (0: no pain, 1–4: mild, 5–6: moderate, and 7–10: severe) and provided with one paper copy, so that they could mark the intensity of pain when the most pain happening in 2 weeks. if the pain was not relieved, further treatment was given in the emergency room of the hospital, and the number of patients in such a situation was recorded for each group. steinstrasse is a well-recognized complication of swl and defined as the presence of more than one ipsilateral ureteral stone simultaneously(17). statistical analysis statistical analysis was performed using spss 12.0 software. kolmogorov-smirnov test was used to verify the normality of the distribution of continuous variables. evaluation of data distribution showed a non-normal distribution of the study data set. differences between groups of patients in medians for quantitative variables and differences in distributions for categorical variables were tested with kruskal–wallis test and x2 test respectively. a value of 5% was considered as threshold for significance. sexual intercourse after swl for distal ureteral stones -li et al. table 1. demographic and clinical characteristics of patients. group1: sexual intercourse(n=70) group2: tamsulosin(n=71) group3: control(n=68) pvalues age, year; mean ± sd a 35.1 ± 8.3 35.3 ± 8.1 34.1 ± 8.4 0.668 bmi, kg/m2; mean ± sd a 24.2 ± 15.8 23.9 ± 8.9 24.0 ± 8.8 0.813 mean hu, hu; mean ± sd a 828.2 ± 349.7 880.9 ± 357.2 834.8 ± 362.0 0.633 left sided stone, n (%) b 28 (40.0) 39 (54.9) 32 (47.1) 0.206 stone diameter, mm; mean ± sd a 11.1 ± 2.4 10.6 ± 1.9 11. 9 ± 2.3 0.306 abbreviations: bmi, body mass index; hu, hounsfield unit. a non-normal distribution variables were compared by kruskal–wallis test b categorical variables were compared by x2 test endourology and stones diseases 136 results of 225 patients, 209 met the inclusion criteria, which were randomly assigned into 3 groups. there was a dropout of 5 patients in groups 1, 1 in group 2, and 4 patients in group 3 for wrong contact. in addition, 3 patients in group 2 and 3 patients in group 3 were excluded from the study due to having sexual intercourse and masturbating more than once weekly. no patients withdrew from the study for other reasons, such as emergency surgery or patient request. no statistically significant differences were observed regarding patient’s age, bmi, stone size laterality, and mean hounsfield units. patient’s demographic characteristics has been outlines in table 1. at the end of week 1, the stones free rate was 48 (68.6%) of the 70 patients in the sexual intercourse group, 49 (69.0%) of the 71 patients in the tamsulosin group, and 34 (50.0%) of the 68 patients in the control group. group 1 and group 2 showed a significantly higher stone free rate compared with group 3 (p = .031, and .022, respectively). group 2 had a slightly higher stone free rate than group 1 but was not statistically significant (p = .955). at the end of the second week of the study, similar results were observed (p = .022). additionally, the vas scores of groups 1 and 2 were slightly higher than those of group 3, but there was not a significant difference among the three groups (p = .233). however, the number of patients in group 3 who visited the emergency room due to severe acute pain was significantly higher than in the other two groups (p = .015). at the end of the second week, the incidence of steinstrasse in groups 1 and 2 was significantly lower (p = .034) (table 2). discussion due to its characteristics of a high success rate, no anesthesia needed, and outpatient treatment, swl is becoming a non-invasive important method for the treatment of ureteral calculi since its introduction in the 1980s (18). however, compared with ureteroscopic lithotomy, swl still requires expulsion of the stone fragments from the long ureter after the operation. therefore, there remain a series of postoperative complications, including renal colic, steinstrasse formation, bladder irritation, and urinary tract infection (19). the size of the stones, comminution degree of the stones, and patency of the ureter are important factors affecting the success rate of stone expulsion. the expulsion of stones may cause ureteral smooth muscle spasms, mucosal edema and pain which may hinder expulsion. local inflammation and even infection caused by stones may further aggravate the ureteral smooth muscle spasms and mucosal edema (20-22). therefore, the proper conservative treatment after swl to relieve ureteral smooth muscle spasms, reduce mucosal edema, and relieve pain will be conducive to reducing the occurrence of complications and increasing the success rate of stone expulsion. to increase the stone free rate after swl, many scholars have conducted research in regard to changing the ureteral factors affecting stone expulsion. the use of α-receptor blocking agents, calcium antagonists, and steroid hormones after swl can effectively increase the stone free rate(7,8). our results are in agreement with those of previous scholars. in our study, the stone clearance rate was significantly higher in the tamsulosin group compared with the control group, at 81.7% and 63.2%, respectively (p = .029). renal blood flow (rbf) and glomerular filtration rate improvement also can facilitate stone passage except for ameliorating ureteral factors. ziaee et al. found that the percent of stone-free patients was higher in the group of patients who slept ipsilaterally relative to the kidney stone compared with patients who slept on the contralateral side by increasing rbf(23). however, this study did not collect patients sleep position data after swl. the smooth muscle of the distal ureter and uretero-vesical junction is regulated by the autonomic nervous system, including noradrenergic, cholinergic, and non-adrenergic non-cholinergic nerves. neurotransmitter nitric oxide (no), released by male penis erections, regulates table 2. therapeutic effect and pain after eswl in each group. group1: sexual intercourse(n=70) group2: tamsulosin(n=71) group3: control(n=68) p values(1-2-3, 1-2, 1-3, 2-3 ) sfr after 1 weeks, free/failure(%)a 48/22 (68.6%) 49/22(69.0%) 34/34(50%) 0.031 0.955 0.026 0.022 sfr after 2 weeks, free/failure(%)a 56/14(80.0%) 58/13(81.7%) 43/25(63.2) 0.022 0.799 0.029 0.015 vas; mean ± sd b 5.76±1.74 5.58±1.69 6.04±1.40 0.233 0.510 0.299 0.091 need for relieve pain emergency yes/no(%)a 6/64(8.6%) 4/66(5.7%) 14/54(19.1%) 0.015 0.512 0.045 0.009 steinstrasse yes/no(%)a 2/68(2.9%) 2/69(2.8%) 8/60(11.8%) 0.034 0.989 0.044 0.041 abbreviations: vas, visual analogue scale. a categorical variables were compared by x2 test b non-normal distribution variables were compared by kruskal–wallis test sexual intercourse after swl for distal ureteral stones -li et al. vol 17 no 02 march-april 2020 137 peristalsis and tension in the distal ureter(24). many studies have shown that the nitric oxide/guanosine monophosphate (no/cgmp) pathway in human and rat ureteral tissue plays a significant role in ureteral tension regulation(12). in males, sexual activity releases a large amount of no from the nerve endings to act on the lower part of the ureter, which can reduce the tension of the ureteral wall, enhance the urine transport capacity, and accordingly increase the pressure above the stone while weakening ureteral peristalsis and reducing the distal resistance of the stone, thereby forming a powerful pressure gradient to promote stone expulsion. the study by doluoglu and abdel-kader found that having sexual intercourse three or four times per week can significantly increase the rate of stone expulsion in the lower ureter and shorten the expulsion time(13,14). in a prospective, randomized controlled study, bayraktar et al. used tamsulosin and sexual intercourse as interventions to treat patients with lower ureteral stones (5-10 mm), and the results showed that both tamsulosin and sexual intercourse could increase the expulsion rate of distal ureteral stones of 5-10 mm in size. having sexual intercourse at least three times per week had the same effect as oral tamsulosin, which is inferred to be related to increasing no levels during erection(15). in this study, sexual intercourse was used as an adjuvant treatment option after swl for ureteral calculi for the first time, and whether it could prevent the formation of steinstrasse was explored. the results showed that the stone free rate of the sexual intercourse group in the first and the second week after swl (68.6% and 80.0%, respectively) was higher than that of the control group (50.0% and 63.2%; p = .026 and p = .029, respectively). the formation rate of steinstrasse in the sexual intercourse group (2.9%) was also much lower than that in the control group (11.8%; p = .044). the results of the sexual intercourse group were similar to those of the tamsulosin group, indicating that sexual intercourse could effectively increase the rate of stone expulsion after swl and prevent the formation of steinstrasse. after swl for ureteral calculi, expulsion of the stone debris from the ureter often causes severe pain. in our study, the average vas pain scores of the sexual intercourse group and the tamsulosin group (5.76 ± 1.74 and 5.58 ± 1.69, respectively) were slightly lower than that of the control group (6.04 ± 1.40; p = .233). although there was no significant difference between them, the number of patients in the control group who received pain relief treatment in the emergency room was significantly greater than in the sexual intercourse and tamsulosin groups (p = .015), and the number of such patients in the sexual intercourse group and the tamsulosin group was similar (p = .512). it suggests that the stone fragments have more chance to discharge after severe pain in the sexual intercourse group and the tamsulosin group than the control group. patients in the control group can only visited the emergency room due to severe persistent pain caused by the stone fragment. but no such measurement was performed in this study. further studies may be useful to focus on this issue. one study confirmed that the use of α-receptor blocking agents can relieve the patient's pain by selectively acting on the α-1d receptors in the lower ureter, reduce the frequency of colic attacks, and reduce the pain score, thus reducing the need for analgesics(25). in our study, post-swl sexual intercourse could also effectively relieve pain and achieve the same effect as oral tamsulosin. recent studies showed that sexual intercourse can significantly reduce the frequency of renal colic and analgesic demand in patients with lower ureteral calculi, which is considered to be related to the elevated level of endogenous no(13,14). suresh et al. found that pde5i, such as tadalafil, can reduce the onset of ureteral colic and the required amount of analgesia through the no/cgmp pathway, thereby improving the patient's painful experience in the treatment of ureteral calculi (26). therefore, the analgesic effect of sexual intercourse after swl may also be related to the elevated no level during erection. however, the most important limitation of our study is the lack of double-blind design and the intercourse treatment standardization include the frequency, body position, intensity and duration of sexual intercourse. the effects of sexual intercourse, masturbation, relaxations on the smooth muscles of the lower ureter still should be examined in the future. whether or not moderate sexual intercourse is equally effective in female patients, patients with upper urinary stones in other sites after swl, or patients undergoing ureteroscopic holmium laser lithotripsy will also be our future research direction. conclusions in summary, having sexual intercourse more than three times per week after swl can effectively improve the stone free rate, shorten the stone expulsion time, reduce the formation of steinstrasse, and relieve renal colic. to some extent, it makes up for the shortcomings of a single swl treatment and provides a choice for urologists in the swl treatment of lower ureteral calculi. conflict of interest the authors report no conflict of interest. references 1. shoag j, tasian ge, goldfarb ds, eisner bh. the new epidemiology of nephrolithiasis. adv chronic kidney dis. 2015; 22: 273-8. 2. ludwig ww, matlaga br. urinary stone disease: diagnosis, medical therapy, and surgical management. med clin north am. 2018; 102: 265-77. 3. choo ms, han jh, kim jk, et al. the transgluteal approach to shockwave lithotripsy to treat distal ureter stones: a prospective, randomized, and multicenter study. world j urol. 2018; 36:1299-1306 4. ozgor f, tosun m, kayali y, 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role of nitric oxide and hydrogen sulfide in urinary tract function. basic clin pharmacol toxicol. 2016; 119 suppl 3: 34-41. 25. li m, wang z, yang j, et al. adjunctive medical therapy with α-blocker after extracorporeal shock wave lithotripsy of renal and ureteral stones: a meta-analysis. plos one. 2015; 10: e0122497. 26. suresh kg, vikash s, himanshu p, et al. comparative efficacy of tamsulosin versus tadalafil as medical expulsive therapy for distal ureteric stones. urol ann. 2018; 10: 82–6. sexual intercourse after swl for distal ureteral stones -li et al. first day wednesday, december 04, 2019 time program speaker-panel member chairman / moderator 13:00-14:00 prayer time-launch 14:00-15:00 live surgeries or telesurgery with nasser simforoosh.m.d. mohammadreza ebadzadeh, m.d. conversation akbar nouralizadeh, m.d. afashar zomorodi, m.d. daryush irani, m.d. 15:00-17:00 oral presentation [hall a] vahid najaran, m.d. mohammad masoud nikkar, m.d. arash ardestanizadeh, m.d. mousa asadi, m.d. anahita ansari, m.d. 15:00-17:00 video presentation [hall b] davood arab, m.d. sepehr hamedanchi, m.d. amir abbas shahdoust, m.d. javid samadi, m.d. hormoz karami, m.d. 19:00-21:00 dinner at the invitation of homa tehran hotel homa hotel: no 2, laleh alley, medissa raya darman (kmt) sadaf hall vanak sq, tehran 08:30-09:30 panel: pcnl masoud etemadian, m.d. -tips and tricks hossein karami.m.d. (shohada hosp.) -mini-pcnl: my experience -the guinness staghorn siavash falahatkar, m.d. -miniaturization in pcnl: does it pradeep kumar sharma , m.d. (india) make any sense? -residual stones after pcnl:how to manage saeed zand, m.d. 09:30-10:00 panel: akbar nouralizadeh, m.d. mohammadreza nikoobakht, m.d. laparoscopic partial nephrectomy seyed hossein hosseini sharifi, m.d. for benign and malignant lesions hamidreza nasseh, m.d. 10:20:11:05 opening ceremony welcome message from president of congress welcome message form ieus welcome, chanceller of iran university of medical sciences(iums) 11:20-11:45 engineering session pejman shadpour, m.d. majid ali asgari, m.d. “health system engineering” mini-teasers mohammad mehdi sepehri, m.d. hamid shafie, m.d. alborz salavatipour 11:45-12:45 panel: heshmatolah soufi-majidpour, m.d. seyed amir mohsen ziaee, m.d. handling complications of endourology mohammad hossein nourbala, m.d. seyed habibolah mousavibahar, m.d. mohammad hatef khorrami, m.d. 10:00-10:20 b r e a k 08-08:15 update wce 2019 robab maghsoudi, m.d. ali taghizadeh-afshari, m.d. majid jasemi-zargani, m.d. alireza tadayon, m.d. 08:15-08:30 the evolution of robotic surgery alireza amin-sharifi. m.d. ali taghizadeh-afshari, m.d. (skype lecture) cleveland clinic(us) majid jasemi-zargani, m.d. alireza tadayon, m.d. 11:05-11:20 the future of neuromodulation in urology sajjad rahnama'i, m.d; phd nasser simforoosh, m.d. (skype lecture) (germany/netherlands) majid ali asgari, m.d. hamid shafie, m.d. 12:45-13:00 robot assisted lap. totally abolfazl hosseini(sweden) abbas basiri, m.d. intra corporal neobladder mohammad yazdani kachouei, m.d. after radical cystectomy (skype lecture) navid masoumi, m.d. ⅷ second day thursday, december 05, 2019 time program speaker-panel member chairman / moderator 08:00-08:15 yesterday in brief seyed arsalan aslani, m.d. 08:15-08:30 robotic radical prostatectomy emrah yuruk, m.d. (turkey) hossein shahrokh, m.d. mohammad ali zargar, m.d. erfan amini, m.d. 08:30-08:55 debate: hamid pakmanesh, m.d. mohammad najafi-semnani, m.d. retroperitoneal vs transperitoneal laparoscopy (retroperitoneal ) amir hossein kashi, m.d. (transperitoneal) 08:55-09:25 panel: mohsen amjadi, m.d. reza kaffashe-nayeri, m.d. update on mis for bph sadrollah mehrabi-sisakht, m.d. (prostate lift/vaporization/ holep) mohammad hossein soltani, m.d. 09:40-10:10 b r e a k 10:10-10:55 panel: medical management of stone hasan ahmadnia, m.d. role of non endourological m shivalingaiah, m.d. (india) management in urinary tract stones medical management of pediatric stones pejman shadpour, m.d. iranian peculiarities on urolithiasis abbas basiri, m.d. 10:55-11:20 rirs: single use vs. permanent kaveh mehravaran, m.d. seyed kazem aghamir, m.d. 12:00-12:45 general assembly 11:20-11:45 position in pcnl: does it matter? abdul majid rana, m.d.(pakistan) mohammad hadi radfar, m.d. hossein karami, m.d. siavash falahatkar, m.d. pradeep kumar sharma, m.d. 11:45-12:00 what is new in non-muscle invasive ahmet yaser muslumanoglu, m.d. hassan jamshidian, m.d. bladder cancer? (turkey) mohsen ayati, m.d. mohammadreza nowroozi, m.d. ali razi, m.d. 12:45-13:00 mini perc zamari noori, m.d. (afghanistan) seyed hasan inanloo, m.d. diniyar khazaeli, m.d. farid dadkhah, m.d. 13:00-14:00 prayer time-launch 14:00-15:15 challenging case discussions with the professors nasser simforoosh, m.d. heshmatollah soufi-majidpour, m.d. abbas basiri, m.d. pejman shadpour, m.d. seyed habibolah mousavibahar, m.d. pradeep kumar sharma , m.d. (india) m shivalingaiah, m.d. (india) 15:15-16:15 live surgeries or telesurgery with conversation masoud etemadian, m.d. seyed jalil hosseini, m.d. pejman shadpour, m.d. babak javanmard, m.d. kaveh mehravaran, m.d. hayat mombeini, m.d. nima narimani, m.d. alaeddin asgari, m.d. 16:15-17:30 oral/video presentation (hall a) amir reza abedi, m.d. (hall b) saman farshid, m.d. mahmoud reza nasiri, m.d. hassan hooshyar, m.d. arash ardestanizadeh, m.d. 19:00-21:00 dinner at the invitation of arman tandorost espinas hotel tehran province, tehran, farah abad, no, valiasr square, keshavarz blvd, no. 126 09:25-09:40 laparoscopic adrenalectomy : update nasser simforoosh, m.d. ali taghizadeh-afshari, m.d. hossein karami, m.d.(kerman) reza sarhangnejad, , m.d. ⅸ third day friday, december 06, 2019 time program speaker-panel member chairman / moderator 08:00-08:15 yesterday in brief iman ghenaat, m.d. 08:15-08:45 young endourologists session behnam shakiba, m.d. mehdi zeynali, m.d. amir afyouni, m.d. hamidreza akbari gilani, m.d. mojtaba ameli, m.d. 09:55-10:20 debate: nasser shakhs-salim, m.d. (laparoscopy) alireza farshi, m.d. salvage for failed upjo laparoscopy alireza lashei, m.d. (endoscopy) versus endoscopy 10:20-10:45 debate: mohammad javad soleimani, m.d. (swl) koosha kamali , m.d. the 2 cm pediatric stone swl vs pcnl seyed mehdi hosseini, m.d.(pcnl) 10:45-11:15 b r e a k 11:15-11:45 panel: sakineh hajebrahimi, m.d. farzaneh sharifi-aghdas, m.d. sui and pop maryam emami, m.d. nastaran mahmoudnejad, m.d. 11:45-12:00 lecture of iua abdolmohammad kajbafzadeh, m.d. mohammad yazdani kachouei, m.d. (iranian urological association): esmaeil azimi, m.d. minimally invasive surgery for pediatric urology ardalan ozand, m.d. 12:00-12:30 panel: mojtaba ameli, m.d. mehrdad mohammadi sichani, m.d. laparoscopic hernia operations: ali ahanian, m.d. endourologists’ experiences kiarash attar, m.d. 12:30-12:45 authentic happiness hossein sheikholeslami 12:45-13:00 take home message 08:45-09:10 debate: dinyar khazaeli. m.d. (perc) mohammad soleimani, m.d. focal therapy for utuc flex esmaeil mousapour, m.d. (urs) urs vs perc resection 09:35-09:55 panel: laser mohammad reza razzaghi, m.d. -ho yag and thullium update ali tabibi, m.d. on technique and setting lecture -laser lithotripsy tips and tricks mohammad asl-zare, m.d 09:10-09:35 debate: seyed yousef hosseini, m.d. (monopolar) mohammad sedehi, m.d. bipolar versus monopolar turp saeed zand. m.d. (bipolar) ⅸ 11th congress of the iranian endourology and urolaparoscopy society, 2019 oral and video presentations 11th congress of the iranian endourology and urolaparoscopy society, 2019 video presentation first day: wednesday, december 04, 2019-hall b laparoscopic anatrophic nephrolithotomy mohammad aslzare, amir abbas asadpour, alireza akhavan rezayat, abdolhay etesami rare presentation of h-type ectopic ureter in a single system managed by laparoscopic nephroureterectomy pejman shadpour, asghar alizadeh, kaveh mehravaran, m mehdi atarod, farshad gouran, roozbeh roohinezhad laparoscopic right side donor nephrectomy with inadvertent clipping of renal artery branch and its management nasser simforoosh, mohammad najafi-semnani, saman farshid, hamid-reza akbari gilani¹, iman ganaat laparoscopic pyeloplasty in a boy with upjo secondary to high grade reflux farzaneh sharifi aghdas, saman farshid ,hamid akabri gilani laparoscopic ureteric reimplantation of a single system ectopic ureter in a girl alireza golshan bilateral laparoscopic ureteral reimplantation in a patient with endometriosis: a case presentation robab maghsoudi, ameneh sadat haghgoo, saeed esmaeil soufian, mehran moghimian laparoscopic ureteropyelolithotomy in pediatric age mohammad-hossein soltani, mohsen varyani, hamid-reza akbari gilani laparoscopic pyelolithotomy in 11 month old infant mohammad-hossein soltani, saman farshid, hamid-reza akbari gilani* laparoscopic partial nephrectomy with zero ischemia time mohammad-hossein soltani, mohsen varyani, hamid-reza akbari gilani, sa aslani laparoscopic radical nephrectomy and pelvic cyst removal farzaneh sharifi aghdas, mohsen varyani, z bartani, hamid-reza akbari gilani laparoscopic rplnd abbas basiri, saman farshid, hamid-reza akbari gilani, iman ghanaat is it possible to do laparascopic live donor nephrectomy in presence of left inferior vena cava nasser simforoosh, iman ghanaat, hamidreza akbari gilani feasibility of laparascopic resection of renal capsular endometriosis ⅹ 1 2 3 4 5 6 7 8 9 10 11 12 13 11th congress of the iranian endourology and urolaparoscopy society, 2019 abbas basiri , iman ghanaat, hamidreza akbari gilani endoscopic management of large ureteral tumor: a video presentation akbar nooralizade, seyed arsalan aslani laparoscopic management of ureteral stricture in kidney transplant, a video presentation nasser simforoosh, seyed arsalan aslani antegrade ureteroscopy in patient with history of illeal loop diversion and distal ureteral stenosis kaveh mehravaran , massoud etemadian, pejman shadpour, mayhar fasihi , ahmadreza rafati, asgharalizadeh, said pakdel , mohamad mehdi atarod , farshad gooran, roozbeh roohinezhad lower calyce stone with calyceal stenosis treated with retrograde intera renal surgery ( rirs). kaveh mehravaran, massoud etemadian, pejman shadpour, mayhar fasihi, ahmadreza rafati, asghar alizadeh, said pakdel , mohamad mehdi atarod, farshad gooran, roozbeh roohinezhad partial nephrectomy with two-layer reconstruction of resection bed: iranian adoption alternative (video) amir h kashi, hamid-reza akbari gilani, arsalan aslani oral presentation first day: wednesday, december 04, 2019hall a a 5 years missed nelatone tube as a stent ureter which has been inserted post peylonphrotomy afshar zomorrodi minimal invasive pcnl(mpcnl) in patients under age of 18 mohammad mehdi hosseini, alaa altofeyli, ali eslahi,reza haghpanah, mitra basratnia comparison of the monoplanar and biplanar renal access in percutaneous nephrolithotomy:a single center experience dariush irani,mohammad mehdi hosseini, reza haghpanah,kian omidbakhsh a randomized, crossover, pilot study of carvedilol and terazosin on urinary symptoms of patients with hypertension and benign prostate hyperplasia alireza farshi, nooriyeh dalirakbari, afshar zomorrodi, mohammad khalili comparison of presence of detrusor muscle in pathology report between monopolar conventional turbt and en-bloc turbt koosha kamali, pejman shadpour, ehsan zolfi, nasrollah abian a posteriori dietary patterns are associated with urinary risk factors of nephrolithiasis: findings from a ⅺ 14 15 16 17 18 20 22 23 24 25 26 11th congress of the iranian endourology and urolaparoscopy society, 2019 cross-sectional study on iranian men niloofarsadat maddahi, khadijeh mirzaei, seyed mohammad kazem aghamir, seyed saeed modaresi, mir saeed yekaninejad comparison of tubeless intercostal percutaneous nephrolithotomy with its standard method seyed habibollah mousavi-bahar, shahryar amirhasani¹, mehdi shahmirzaei efficacy of ureteral stent in children with distal ureteral stones treated by adult type semi-rigid ureteroscope seyed mohammadreza rabani, seyedeh maryam rabani retrograde intrarenal surgery for management of nephrolithiasis: outcomes of fellows in training kaveh mehravaran, massoud etemadian, pejman shadpour, mayhar fasihi, ahmadreza rafati, asghar alizadeh, said pakdel , mohamad mehdi atarod ,farshad gooran, roozbeh roohinezhad case report of endourologic management of basket entrapment pejman shadpour, kaveh mehravaran, masoud etemadian, roozbeh roohinezhad, farshad gouran, m mehdi atarod endoscopic management for uretero-ileal anastomotic obstruction in ileal loop diversion: a case series pejman shadpour, kaveh mehravaran, masoud etemadian, kiarash attar, roozbeh roohinezhad, farshad gouran, mehdi atarod laparoscopic pyeloplasty and pyelolithotomy in a case with history of midline laparotomy for ipsilateral bowel cancer surgery and chemoradiation pejman shadpour, m mehdi atarod, kaveh mehravaran, masoud etemadian farshad gouran, roozbeh roohinezhad comparison of ultra-rapid and rapid dilation techniques for access in percutaneous nephrolithotomy sasan mehrabi, alidad kiani, behzad mohammad soori results and complicatins of tubeless ultra-mini pcnl in children mohammad mehdi hosseini, ali eslahi, reza haghpanah, ali mirzakhanlouei comparison efficacy of peganum harmala seeds on improving pain and passage of 6 to 10 mm stones of kidney and ureter sadrollah mehrabi, nahid shakeri renal pelvic trauma management after percutaneous nephrolithotomy which one is recommended: nephrostomy or dabble j stent? robab maghsoudi, mohammad kolbadinezhad, masoud etemadian, amir h kashi, kaveh mehravaran, nasrollah abian, vahid fakhar necrotizing fasciitis after pcnl: a case report robab maghsoudi1, asaad moradi, behnam shakiba, saeed esmaeil soufian early detection and endoscopic management of post cesarean section ureterovaginal fistula seyed mohammadreza rabani, seyedeh maryam rabani the safety of continued low dose aspirin therapy during complete supine percutaneous nephrolithotomy ⅻ 27 28 29 30 31 32 33 34 35 36 37 38 11th congress of the iranian endourology and urolaparoscopy society, 2019 (cspcnl) siavash falahatkar, samaneh esmaeili, nadia rastjou herfeh, ehsan kazemnezhad, reza falahatkar, masoumeh yeganeh, alireza jafari comparison of the effect of pregabalin, solifenacin and the adminitration of combination of them on symptoms related to ureteral double-j stent insertion (usrs) following ureteroscopy and transureteral lithotripsy in patients with ureteral stone siavash falahatkar, mohammadreza beigzade, gholamreza mokhtari, ehsan kazamnazhad, samaneh esmaeili the efficacy of bimanual abdomino-flank compression in control of postoperative bleeding in percutaneous nephrolithotomy robab maghsoudi, masoud etemadian, amir h kashi, nasrollah abian, mehran moghimian comparison of the effect of tamsulosin, tadalafil and placebo in stone expulsion of patients with distal ureteral stones siavash falahatkar, ardalan akhavan, ehsan kazamnazhad, samaneh esmaeili evaluation of applicable protocols to radiation dose reduction during percutaneous nephrolithotomy hadi radfar, amir hossein kashi, saman farshid factors affecting fluoroscopic screening time and radiation dose during percutaneous nephrolithotomy hamidreza nasseh, siavash falahatkar, keivan gholamjani moghaddam second day; thursday, december 05, 2019 hall a pneumatic lithotripsy versus laser lithotripsy for ureteral stones amir reza abedi, mohammad reza razzaghi, farzad allameh, fereshte aliakbari, morteza fallahkarkan, arash ranjbar incidence and underlying factors for occurrence of post-intervention new contralateral reflux in patients undergoing unilateral antireflux surgery pejman shadpour, maryam emami, nasrollah abian, delaram beirami our novel scoring system for triage in management of intrarenal vascular complications of percutaneous nephrolithotomy: presenting the popvesl score pejman shadpour, robab maghsoudi, masoud etemadian, nasser yousefzadeh, nasrollah abian prospective trial comparing fluoroscopic guidance and combined fluoroscopic and ultrasonographic guidance in percutaneous nephrolithotomy in term of safety, efficacy, perioperative facors and total x-ray dosage seyed hossein hosseini sharifi, ali tabibi, vahid najjaran tousi, flora khaledi, parham rabiee, abbas basiri determining the impact of preoperative asa score on pcnl results sepehr hamedanchi, shahryar sane, melina eqbal efficacy of nigella sativa seeds and tamsulosin on improving pain and passage of 4 to 10 mm stones of kidney and ⅻⅰ 40 41 42 43 44 45 46 47 48 49 39 11th congress of the iranian endourology and urolaparoscopy society, 2019 ureter sadrollah mehrabi, nahid shakeri challenges in laparascopic pyeloplasty of ureteropelvic junction obstruction in intrarenal renal pelvis amir-hossein kashi, iman ghanaat, saman farshid the necessity of ureterolysis during laparoscopic excision of deep infiltrating endometriosis lesions roya padmehr, khadijeh shadjoo, atefeh googin,abolfaz ghodgani comparative study of nitroglycerin and magnesium sulfate effect on endoscopic surgical outcome of ureteral stones salman soltani, mahmoud tavakkoli laparoscopic adrenal sparing surgery in management of adrenal tumors nasser simforoosh, seyed arsalan aslani, mehdi dadpour investigating eswl success rate in the treatment of renal and ureteral stones in children mohammad javad soleimani, hossein shahrokh, vahid vahedi soraki, vahid fakhar laparoscopic pyelolithotomy for management of renal stones: 15 years of experience in a pioneering referral center amir h kashi, akbar nouralizadeh, arsalan aslani, milad bonakdar hashemmi, nasser simforoosh, abbas basiri, seyed amir mohsen ziaee, ali tabibi, mohammad hadi radfar, mohammad hossein soltani, reza valipour second day; thursday, december 05, 2019 hall b head to head comparison of clinical and radiological success rate of endoscopic vs open anti-reflux surgery pejman shadpour, nasrollah abian, maryam emami, delaram beirami re-operation after endoscopic or open antireflux surgery, can it be foreseen? pejman shadpour, nasrollah abian, maryam emami, delaram beirami clinical outcomes of the simultaneous bilateral percutaneous nephrolithotomy (pcnl) in patients with kidney stones: a prospective cohort study mohammad reza darabi, salman soltani, alireza akhavan rezayat, mahmoud tavakkoli laparoscopic donor nephrectomy is a safe surgical approach in healthy obese kidney donor; ten-year single-center experience, retrospective study nasser simforoosh, mohsen variani, seyed arsalan aslani evaluation and comparison of metabolic disorders between patients with unilateral and bilateral staghorn renal stones mehrdad mohammadi sichani, amir jafarpisheh, alireza ghoreifi ⅺⅴ 51 52 53 54 55 56 57 58 59 60 61 50 11th congress of the iranian endourology and urolaparoscopy society, 2019 functional results and recurrence after laparoscopic partial adrenalectomy versus total adrenalectomy nasser simforoosh, mohammad-hossein soltan, hamid-reza shemshaki, m bonakdar hashemi, mehdi dadpoor ultrasound guided percutaneous access to kidney for percutaneous nephrolithotomy in patients with retrorenal colon amir h kashi; iman ghanaat the effects of intravenous mannitol in reducing acute kidney injury following percutaneous nephrolithotomy kaveh mehravaran, masood etemadian, pejman shadpour, mohammadmehdi atarod, nasrollah abian, farshad gouran, roozbeh roohinezhad role of flexible ureteroscopy in diagnosis of the cause of chronic unilateral essential hematuria asghar alizadeh, m. r. mokhtari, kaveh mehravaran, pejman shadpour our experience in transperitoneal laparoscopic pyelolithotomy for large renal pelvic stones hamid pakmanesh, rayka sharifian amiri, sohrab mohammadsalehi 15 years experience with laparoscopic adrenalectomy at hsheminejad kidney center(hkc) pejman shadpour, kaveh mehravaran, masoud etemadian ,farshad gouran ,m mehdi atarod , ruzbeh rouhinezhad epidemiology of escherichia coli st131 as an emerged high-risk clone in patients with urinary tract infections in western asia: a systematic review and meta-analysis alireza jafari, siavash falahatkar, kourosh delpasand, hoda sabati, hadi sedigh ebrahim-saraie ⅹⅴ 62 63 64 65 67 68 69 u j spring 2012.pdf 525vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l penile mondor’s disease long-term functional follow-up rafael boscolo-berto,1 daniela i. raduazzo2 keywords: penile diseases, orchiopexy, erectile dysfunction, thrombosis introduction penile mondor’s disease is a rare and underdiagnosed entity involving the mondor’s disease complicating a bilateral orchidopexy for funiculus subtorsions episodes, with the longest andrological follow-up reported in literature. as this is a very common and worldwide spread surgical operation, urologists must be aware of this clinical condition. case report a 19-year-old caucasian man presented with a rope-like induration on the dorsal surface of the penis. he had an unremarkable previous medical and surgical history with exception for a prior bilateral orchidopexy performed few days earlier on the basis of repeated funiculus sub-torsions episodes. he never experienced a sexually transmitted disease. the patient complained of a local discomfort worsening during erections. he negated sexual intercourse and other sexual activity during the preceding months. physical examination revealed a palpable and visible cord-like induration on the dorsal surface of the penile shaft, without evidence of infection, masses comprising coagulative screening was normal. a penile pulsed color doppler ultrasonography signals. we advised the patient to abstain from sexual intercourse until a complete regres50 mg twice/day, for two weeks. corresponding author: rafael boscolo-berto, md department of oncological and surgical sciences, urology clinic, university of padova, via giustiniani, 2–35100, padova, italy tel: +39 339 113 1099 fax: +39 049 821 2721 e-mail: boscolorafael@ tiscali.it received january 2010 accepted february 2010 1department of oncological and surgical sciences, urology clinic, university of padua, italy 2department of clinical and experimental medicine, university of padua, italy case report 526 | case report the clinical picture self-resolved in about a month evaluation, the patient came back to our department for an episodic urinary infection, successfully treated with antibiotics. during the revaluation, the physical examination was completely normal. furthermore, the patient reported the absence of any clinical relapse and a full preservation of erections discussion the penile mondor’s disease is an infrequent vein, a self-limiting pathology presenting as consequence of vigorous sexual intercourse, use of sexual vacuum-devices, local injection of illegal substances, pelvic neoplasms, distended bladder, local or remote infections, penile trauma, thrombophilia, or inguinal hernia repair. in this report, we describe the onset of a penile mondor’s disease after bilateral orchidopexy. the penile mondor’s disease generally self-resolves vein recanalization is described within 9 weeks. in literature, other conservative approaches are suggested, including a local dressing with a heparin ointment, while use of antibiotics and anticoagulant drugs is not recommended as treatment. only in case of unimproved conditions and persistent discomfort, a thrombectomy or a vein is performed. in our patient, a supportive care was instituted, consisting of temporary abstinence from sexual intercourse and the short-term administration of ment was fully effective and no anatomical or year follow-up. ported case of penile mondor’s disease complicating a bilateral orchidopexy. indeed, a previous paper reported the onset of such a condition as consequence of an inguinal hernia repair, which occurred after a week from the intervention. in our patient, the time-to-onset and recovery was the same, but the previous surgical intervention implied a lowinguinal incision without an inguinal channel violation. therefore, we hypothesize a possible role of inguinal incision that can be exin the subcutaneous district, on an external plane with respect to the scarpa’s fascia, and converge into the right and left external pudendal veins at nous vein at the groin. hence, the local venous surgical incision at that level, leading to a consequent thrombotic event. leaving out the uncertain pathogenesis not yet clarour longest follow-up existing in literature. conflict of interest none declared. references 1. helm jd, jr., hodge ig. thrombophlebitis of a dorsal vein of 2. kumar b, narang t, radotra bd, gupta s. mondor's disease of 3. han hy, chung dj, kim kw, hwang cm. pulsed and color doppler sonographic findings of penile mondor's disease. 4. boscolo-berto r, iafrate m, casarrubea g, ficarra v. magnetic resonance angiography findings of penile mondor's dis5. al-mwalad m, loertzer h, wicht a, fornara p. subcutaneous penile vein thrombosis (penile mondor's disease): patho6. kutlay j, genc v, ensari c. penile mondor's disease. hernia. 7. ganem jp, kennelly mj. ruptured mondor's disease of the urological oncology influences of different operative methods on the recurrence rate of non-muscle-invasive bladder cancer shoubin li#1, yi jia#1, chunhong yu2, helong xiao1, liuxiong guo1, fuzhen sun1, dong wei1, panying zhang1, jingpo li1,j unjiang liu*1 purpose: to compare the influence of three operative approaches [transurethral en bloc resection of bladder tumor by pin-shaped electrode (pin-erbt), transurethral resection of bladder tumor (turbt), and transurethral holmium laser resection of bladder tumor (holrbt)] on the recurrence rate of non-muscle-invasive bladder cancer (nmibc) with low dimensions (i.e. diameter below 3 cm). materials and methods: a retrospective analysis was conducted for a total of 115 patients affected by solitary nmibc, with a diameter < 3 cm, who were submitted to operation between march 2013 to may 2017. the patients were divided according to the operative method applied (pin-erbt, turbt, and holrbt groups, respectively). the 2-year recurrence rate was compared among the three groups, and multivariate cox hazard model analysis was applied to analyze the influencing factor(s) for postoperative recurrence. results: the 2-year recurrence rate was 10.0% in erbt, 38.5% in turbt and 40.0% in holrbt group, with a significant difference (p = 0.014). according to the cox hazard model analysis, age (hr = 1.058, 95% ci: 1.019~1.098, p = 0.003), operative method (hr = 2.974,6.508, 95% ci: 0.862~10.255,1.657~25.566, p = 0.023), smoking (hr=2.399, 95% ci: 1.147~5.017, p = 0.020), and pathological grade (hr = 2.012,95% ci: 1.279~3.165, p = 0.002) were risk factors for postoperative recurrence of bladder cancer. conclusion: pin-erbt can prominently decrease the postoperative recurrence rate of solitary nmibc with a diameter < 3 cm. keywords: erbt; pin-shaped electrode; nmibc; recurrence; turbt; holrbt introduction bladder cancer (bc) is considered one of the com-mon malignant tumors of the urinary system. bc can be classified as non-muscle-invasive bladder cancer (nmibc) and muscle-invasive bladder cancer (mibc). transurethral resection of bladder tumor (turbt) is the most typical treatment for this pathological condition. still, turbt has certain disadvantages, such as dissemination and seeding as well as incomplete resection due to fragmentation of tumor tissues, which can potentially lead to a higher postoperative recurrence rate. maurice and colleagues have shown that the postoperative recurrence rate of turbt can be as high as 30-50%(1) as a novel operative methodology, en bloc resection of bladder tumor by pin-shaped electrode (pin-erbt) can entirely promote the resection of the bladder tumor utilizing the distinctive features of a pinshaped electrode, which possesses advantages such as clear layer, precise cleavage and accurate pathological stage after operation. transurethral holmium laser resection of bladder tumor (holrbt) is another new procedure that enables a gradual or entire excision of the bladder tumor by laser-based energy.(2) therefore, here we investigated the impact of these three operative methods on the postoperative recurrence rate of bc. for this, their recurrence rates were 1department of urology, hebei general hospital, , shijiazhuang, hebei, china 2department of medical checkup centre, hebei general hospital,, shijiazhuang, hebei, china. # equal contributors and first authors *correspondence: department of urology, hebei general hospital, , shijiazhuang, hebei china, 050051, china tel: +86 0311 85988751, e-mail: liujunjiang67@163.com received february 2020 & accepted october 2020 retrospectively reviewed, and cox hazard model analysis was performed to analyze the risk factors linked to the recurrence of solitary nmibc, at the dimension of less than 3 cm. patients and methods study population a total of 115 nmibc patients who were treated with transurethral surgery for the first time in our hospital, between march 2013 and may 2017, were selected. inclusion and exclusion criteria inclusion criteria: ① primary, solitary, and ta stage bladder tumor with a maximum diameter less than 3cm. ② treated by one of the three transurethral surgeries; ③ recieved 1 year of standardized bladder perfusion treatment after operation, and regular reexamination of cystoscopy. ④ the surgeons had experience of turbt over 10 years. exclusion criteria: ①recurrent bladder tumor. ②benign or non-urothelial tumor pathological diagnosis. ③ tumors which were multiple or with a diameter greater than or equal to 3cm; ④ patients with other tumors. the operation was performed by 3 senior consultants with rich experience in turbt. surgical technique the enrolled patients were divided into 3 groups acurology journal/vol 18 no. 4/ july-august 2021/ pp. 411-416. [doi: 10.22037/uj.v16i7.5965] cording to the operative methods, namely pin-erbt (n = 30), turbt (n = 65) and holrbt (n = 20) groups. based on the who 2004 classification(3), tumors were classified into grade i (papillary urothelial neoplasm of low malignant potential), ii (low-grade urothelial carcinoma) and iii (high-grade urothelial carcinoma). the baseline data of the patients are shown in table 1. their diagnosis was confirmed by ultrasonography, ct plain scan, and contrast-enhanced scan of the urinary system, as well as cystoscopy and tissue biopsy. the local ethics committee approved the use of patient data, and consent was obtained from all patients involved. pin-erbt group a tissue range of ~1 cm away from the basilar part of the tumor was initially marked with the pin-shaped electrode. mucous, submucosa, and superficial muscular layers were then cut open and gradually separated towards the basilar part of the bladder tumor, along with the superficial muscular layer, using the electrode. thereafter, the whole tumor and basilar parts were fully dissociated and the supply vessels of the tumor were concomitantly coagulated. isolated tumor tissues were further washed out using an irrigator or taken out with a retrieval basket. turbt group the operation range was labeled at ~1 cm away from the tumor area using a looped electrode. subsequently, both tumor and peripheral mucosa were electrically resected from the crown of the tumor to the superficial muscular layer of the bladder. the resected tissues were then washed out using an irrigator. holrbt group an optical fiber (diameter =550 μm, laser energy =1.02.0 j, frequency =15-20 hz) was selected for a circular cutting of the muscular layer, along the periphery, at 1 cm away from the basilar region of the tumor. cutting was done towards the tumor root until the intact tumor was excised. this procedure was performed under a direct light source. tumor tissues were further washed out using an irrigator. alternatively, tumors were removed using a retrieval basket. after each operative procedure, patients were given persistent bladder washout and postoperative indwelling of urethral catheter. thereafter, intravesical instillation of pirarubicin or gemcitabine was performed. patients were reexamined by cystoscopy once every 3 months after the operation, when the time to recurrence was eventually recorded. each patient was followed up to 2 years or recurrence. the median follow-up duration in each group was 24 months. statistical analysis spss 21.0 was adopted for statistical data analysis. data measurements were expressed as mean ± standard deviation ( ± s). independent sample’s t-test was used for comparison between two groups. alternatively, oneway analysis of variance was performed for comparison among multiple groups. categorical and count data were presented as n (%). the comparison of unordered categorical data between groups was subjected to χ2 test, while the comparison of ordered categorical data between two groups was examined by mann-whitney u test kruskal-wallis h test was utilized for comparison among multiple groups. the cumulative recurrence rate at each time point was compared, among different operative approaches, using the kaplan-meier method. cox hazard model analysis was applied to screen the risk factors for tumor recurrence. statistical significance was defined by p < 0.05. results clinical features of selected nmibc patients are presented in table 1. comparison of surgery information among distinct patient groups as indicated in table 2, no significant differences were observed in regard to sex, age, diabetes mellitus, and smoking among the patient groups. the differences in the lesion size, pathological grade, and bladder lesion position were not statistically significant when comparing each group of patients. also, we observed that the operation time was longer in pin-erbt group than that in turbt and holrbt groups. this difference was statistically significant (p = 0.007). according to the results of χ2 test, however, no statistically significant differences among the groups were observed in the type of anesthesia used (p = 0.888) and the category of perfused drug (p = 0.991). comparison of recurrence rate in patients from distinct groups the pin-erbt group had a remarkably lower recurrence rate than turbt and holrbt groups after 24 months of operation (p = 0.014) (table 3). analysis of risk factors for recurrence in distinct patient groups based on the results of univariate analysis, the recurrence was not correlated with the perfused drug (p = 0.544) and lesion position (p = 0.723). nevertheless, the recurrence rate had associations with factors including sex (p = 0.024), age (p ＜0.001), smoking (p ＜0.001), pathological grade (p ＜0.001), type of antable 1. statistics of clinical features among the bc patient population.re results clinical feature statistical result sex male 93 (80.9) female 22 (19.1) age (years old) 64.46±11.91 (33.0-88.0) lesion size (cm) 1.86±0.73 (0.2-3.0) type of anesthesia general anesthesia 74 (64.3) spinal anesthesia 41 (35.7) operation time (hrs) 1.53±0.31 (0.8-3.0) pathological grade papillary urothelial neoplasms 43 (37.4) of low malignant potential low-grade urothelial carcinoma 37 (32.2) high-grade urothelial carcinoma 35 (30.4) perfused drug pirarubicin 103 (89.6) gemcitabine 12 (10.4) diabetes mellitus 20 (17.4) smoking 35 (30.4) recurrence rate at 12 months 11 (9.6) recurrence rate at 24 months 36 (31.3) operative method pin-erbt 30 (26.1) turbt 65 (56.5) holrbt 20 (17.4) lesion position lateral wall 72 (62.6) neck 8 (7.0) anterior wall 25 (21.7) trigone 10 (8.7) operation techniques and recurrence in nmibc-li et al. vol 18 no 4 july-august 2021 412 urological oncology 413 esthesia (p =0.018) and operative method (p = 0.044) (table 4). in the multivariate cox hazard model analysis, the recurrence was taken as the dependent variable, the follow-up time was taken as the time variable, and the indexes with statistical significance in the univariate analysis, including gender, age, anesthesia mode, pathological level, smoking, operation mode were regarded as independent variables. the assignment of each variable is shown in table 4. the results indicated that age (p = 0.003), operative method (p = 0.023), smoking (p = 0.020) and pathological grade (p = 0.002) were the risk factors for the recurrence among the patients. comparison of cumulative recurrence rate among groups the 24-month cumulative recurrence rates in the turbt and holrbt groups were similarly higher than that in the pin-erbt group, and this difference was statistically significant (p = 0.021) (figure 1). discussion bladder cancer is a relatively high incidence rate of cancer. accurate diagnosis requires cystoscopy and pathological diagnosis. special types of bladder tumors, such as bladder small cell carcinoma, are difficult to diagnose and need to be confirmed by immunohistochemistry(4).turbt is a commonly used operative method for bladder cancer. still, 36-51% of the turbt-derived specimens lack muscular layer tissues(5), limiting the determination of the pathological stage(13). besides, the table 2. description of biopsy needle tip cultures and blood cultures of febrile patients pin-erbt n=30 turbt n=65 holrbt n=20 pvalue sex male 24 (80.0) 55 (84.6) 14 (70.0) 0.344 female 6 (20.0) 10 (15.4) 6 (30.0) age; mean ± sd, year 63.23 ± 10.39 66.23 ± 11.86 60.55±13.51 0.141 diabetes 4 (13.3) 14 (21.5) 2 (10.0) 0.390 smoking 9 (30.0) 20 (30.8) 6 (30.0) 0.996 lesion size (cm) mean ± sd, 1.94±0.64 1.88 ± 0.75 1.66 ± 0.76 0.374 pathological grade (%)a i 13 (43.3) 21 (32.3) 9 (45.0) 0.680 ii 9 (30.0) 24 (36.9) 4 (20.0) iii 8 (26.7) 20 (30.8) 7 (35.0) lesion position(%) lateral wall 23 (76.7) 38 (58.5) 11 (55.0) 0.555 neck 1 (3.3) 5 (7.7) 2 (10.0) anterior wall 4 (13.3) 17 (26.2) 4 (20.0) trigone 2 (6.7) 5 (7.7) 3 (15.0) operation time (h) 1.68 ± 0.32 1.49 ± 0.27b 1.44 ± 0.34 0.007 type of anesthesia (%) general anesthesia 20 (66.7) 42 (64.6) 12 (60.0) 0.888 spinal anesthesia 10 (33.3) 23 (35.4) 8 (40.0) perfused drug (%) pirarubicin 27 (90.0) 58 (89.2) 18 (90.0) 0.991 gemcitabine 3 (10.0) 7 (10.8) 2 (10.0) note a: i: papillary urothelial neoplasm of low malignant potential, ii: low-grade urothelial carcinoma, iii: high-grade urothelial carcinoma. noteb: bp < 0.05 vs. pin-erbt group. figure 1. comparison of cumulative recurrence rate at 24 months after operation among groups. operation techniques and recurrence in nmibc-li et al. tumor residual rate along the basilar region can be up to 30-44% after turbt(6). second transurethral resection may remove the tumor more thoroughly, but there are also controversies. some scholars think that in patients with single, small t1 and/or high-grade tumors, secondary turbt is not closely related to tumor residual and disease deterioration(7). at the same time, the incidence of obturator reflex in turbt is high, and there is a risk of bladder perforation(8). it has been denoted that, in the turbt group,~70% of specimens contain muscular layer tissues, while entire tumor specimens containing muscular layer tissues can be obtained in both holrbt and erbt groups(9). the cauterization of the tumor tissues by turbt can alter the tissue morphology, so that intact specimens containing a muscular layer cannot be acquired. some studies have indicated that tumor staging can be clinically underestimated up to 49% of the patients(10). engilbertsson and colleagues(11) have identified the conditions of tumor cells in the circulating blood of 16 patients before and during turbt. in this case, tumor cells could be observed in 7 patients, from which 6 (86%) had a much higher number of tumor cells during operation, suggesting that tumor cells may enter the circulation system during turbt, therefore increasing the risk of tumor metastasis and tumor recurrence. the recurrence rate of bc is typically high, but related data can vary in the current literature. for instance, hurle and colleagues have reported that the recurrence rate of bc is 15% by a 2-year follow-up after en bloc resection by pin-shaped electrode(12). based on laser en bloc resection, muto and colleagues have found a recurrence rate of ~14.5% at 16 months after postoperative follow-up(13). liu and colleagues also compared the postoperative recurrence rate between patients who were submitted to laser en bloc resection (n = 64) versus traditional turbt (n = 56)(14). according to their results, the recurrence rates were 10.9%, 19.5% and 31.3% after 1, 2, and 3 years of en bloc resection, versus 10.7%, 22.9%, and 33.9%, after traditional electro resection, respectively. still, no significant differences were detected between the two groups. in terms of the risk factors related to the recurrence of bc, rink and colleagues revealed that an active smoking history was an independent risk factor for recurrence after bc surgery in males(15). lu and colleagues found that the recurrence rate was positively correlated with the pathological grade of the tumor(16). moreover, koumpan and colleagues have shown that patients undergoing combined spinal-epidural analgesia have a lower recurrence rate than those undergoing general anesthesia(17). in this case, it appears that the volatile anesthetics used during general anesthesia may stimulate the production of hypoxia-inducible factor 1 (hif-1), thus activating the proliferation of tumor cells. in this study, we did not find that the choice of intravesical instillation drugs is related to tumor recurrence, and the relevant literature also shows that the difference between the choice of pirarubicin and gemcitabine is not a risk factor for tumor recurrence, but the incidence of bladder irritation symptoms after gemcitabine selection is slightly lower than that of pirarubicin(18) . in the present study, the recurrence rate in the pin-erbt group after 2 years of operation was markedly lower than in the turbt and holrbt groups, which is consistent with some previous studies(19,20). intriguingly, chen’(21) s reports have shown similar postoperative recurrence rates on both erbt and holrbt but, in the present study, the holrbt group exhibited a distinctly higher long-term (2-year) recurrence rate than the table 3. comparison of recurrence rate among patients receiving different operative methods. group n recurrence rate at 24 months pin-erbt 30 3 (10.0) turbt 65 25 (38.5)a holrbt 20 8 (40.0)a χ2 8.583 p 0.014 note: ap < 0.05 vs. pin-erbt group. un-adjusted effect size (univariate) adjusted effect size (multivariate) factor waldχ2 p hr(95% ci) variable waldχ2 p hr(95% ci) recurrence yes =1, no = 0 gender 5.107 0.024 2.228(1.112~4.464) male=1, female=2 0.006 0.937 1.031(0.486~2.189) age 12.382 0.000 1.064(1.028~1.101) numerical type 8.864 0.003 1.058(1.019~1.098) lesion size 0.118 0.731 0.922(0.580~1.465) anesthesia method 5.598 0.018 2.206(1.145~4.248) spinal anesthesia =1, 0.778 0.378 1.404(0.661~2.98) general anesthesia =2 operation time 0.962 0.327 0.562(0.178~1.778) pathological gradea 15.259 0.000 2.417(1.552~3.764) grade i =1, grade ii =2, 9.152 0.002 2.012(1.279~3.165) grade iii =3 perfused drug 0.367 0.544 0.694(0.213~2.262) diabetes 0.515 0.473 0.708(0.275~1.820) smoking 8.508 0.004 2.648(1.376~5.095) yes=1, no=0 5.407 0.02 2.399(1.147~5.017) operative method pin-erbt 6.227 0.044 1 pin-shaped electrode =1 7.533 0.023 1 turbt 5.828 0.016 4.375(1.320~14.499) electric resection =2 2.977 0.084 2.974(0.862~10.255) holrbt 5.381 0.020 4.816(1.276~18.173) holmium laser =3 7.199 0.007 6.508(1.657~25.566) lesion position lateral wall 1.326 0.723 neck 0.353 0.552 1.445(0.429~4.868) anterior wall 1.128 0.288 1.509(0.706~3.225) trigone 0.001 0.976 1.019(0.303~3.430) notea: i: papillary urothelial neoplasm of low malignant potential, ii: low-grade urothelial carcinoma, iii: high-grade urothelial carcinoma. table 4. univariate cox analysis and multivariate cox regression analysis results. operation techniques and recurrence in nmibc-li et al. vol 18 no 4 july-august 2021 414 urological oncology 415 pin-erbt group. there are some possible explanations for this kind of contradicting results. first, the holmium laser may simultaneously cleave and vaporize properties, so it cannot clearly recognize anatomical layers when compared with the pin-shaped electrode. second, the holmium laser does not generally achieve a satisfactory resection effect on tumors located in sharp angles, such as the bladder dome and the anterior bladder wall, due to the straight optical fibers. third, it is difficult to control the depth of cutting promoted by the holmium laser, which can easily cause bladder perforation(22). according to the results of multivariate cox hazard model regression analysis, clinical features including age, operative method, smoking and pathological grade were the risk factors for the recurrence of bc. the operative method served as an influencing factor with statistical significance, indicating that operative factors can affect the recurrence rate, besides the biological characteristics of the tumor. the pin-shaped electrode is typically slim in shape and able to flexibly rotated and to bluntly dissect, allowing a precise cleavage of the tissue. therefore, it can accurately resect tumors at distinct sites of the bladder by means of 360° rotation of endoscopic sheath. some advantages can be highlighted for this kind of operation: (i) tumors can be cut and isolated along the muscular layer, so the resection is more precise and the exact pathological stage can be defined; (ii) labeling of the cutting range before cleavage as well as partial blockage of blood supply can decrease the probability of metastasis and recurrence induced by blood-borne dissemination; (iii) specimens can be removed entirely, reducing the implantation and recurrence rates of bc. in contrast, pin-erbt also has a few limitations. this technique, for instance, is not suitable for extensive nmibc tumors. indeed, in the case of tumors larger than 3 cm in diameter, the resected specimens cannot be removed completely. therefore, some in-depth optimization for en bloc resection of larger tumors(i.e. diameter less than 3 cm) will be further required. compared with turbt and holrbt, pin-erbt is characterized by fewer complications, higher efficiency, thorough tumor enucleation, lower recurrence rate, and easier handling. as such, this operative method is worthy of clinical popularization and application. nevertheless, there were some limitations in this study. firstly, the sample size for this research was small, so the elaboration of more long-term, large-sample and multi-center prospective studies will be needed to confirm our data. secondly, only the patients with solitary tumors with a diameter over 3 cm were analyzed, so the operative efficacy using multiple ranges of large tumors should be further verified. acknowledgements the authors would like to express their gratitude to editsprings (https://www.editsprings.com/) for the expert linguistic services provided. yi-jia espeically wishes to thank xi-lin,whose long term company have given he powerful spiritual support over the past times. conflict of interest the authors report no conflict of interest. references 1. maurice mj, vricella gj, maclennan g, buehner p, ponsky le. endoscopic snare resection of bladder tumors: evaluation of an alternative technique for bladder tumor resection. j. endourol. 2012;26:614-7. 2. bai y, liu l, yuan h, et al. safety and efficacy of transurethral laser therapy for bladder cancer: a systematic review and metaanalysis. world j. surg. oncol. 2014;12:301. 3. lopez-beltran a, montironi r. non-invasive urothelial neoplasms: according to the most recent who classification. eur. urol. 2004;46:170-6. 4. nayeri rk, sadri m, shahrokh h, et al. small cell carcinoma of bladder; still a diagnostic and therapeutic challenge: seven years of experience and follow-up in a referral center. urol j. 2020. 5. dutta sc, smith ja, shappell sb, coffey cs, chang ss, cookson ms. clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. j. urol. 2001;166:490-3. 6. suer e, hamidi n, gokce mi, et al. significance of second transurethral resection on patient outcomes in muscle-invasive bladder cancer patients treated with bladderpreserving multimodal therapy. world j. urol. 2016;34:847-51. 7. ayati m, amini e, damavand rs, et al. second transurethral resection of bladder tumor: is it necessary in all t1 and/or highgrade tumors? urol j. 2019;16:152-6. 8. dagli r, dadali m, emir l, bagbanci s, ates h. comparison of classic and inguinal obturator nerve blocks applied for preventing adductor muscle contractions in bladder tumor surgeries: a prospective randomized trial. urol j. 2019;16:62-6. 9. chen j, zhao y, wang s, et al. green‐ light laser en bloc resection for primary non‐muscle‐invasive bladder tumor versus transurethral electroresection: a prospective, nonrandomized two‐center trial with 36‐month follow‐up. lasers surg. med. 2016;48:859-65. 10. brauers a, buettner r, jakse g. second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? j. urol. 2001;165:808-10. 11. engilbertsson h, aaltonen ke, björnsson s, et al. transurethral bladder tumor resection can cause seeding of cancer cells into the bloodstream. j. urol. 2015;193:53-7. 12. hurle r, lazzeri m, colombo p, buffi n, guazzoni g. “en bloc” resection of nmibc: a prospective single centre study. urology. 2016;90. 13. muto g, collura d, giacobbe a, d'urso l, castelli e. thulium:yttrium-aluminum– garnet laser for en bloc resection of bladder cancer: clinical and histopathologic advantages. urology. 2014;83. 14. liu h, wu j, xue s, et al. comparison of the safety and efficacy of conventional monopolar and 2-micron laser transurethral resection in the management of multiple nonmuscleinvasive bladder cancer. j. int. med. res. operation techniques and recurrence in nmibc-li et al. 2013;41:984-92. 15. rink m, furberg h, zabor ec, et al. impact of smoking and smoking cessation on oncologic outcomes in primary non–muscle-invasive bladder cancer. eur. urol. 2013;63:724-32. 16. ðug h, jagodić s, ahmetović-ðug j, selimović z, sulejmanović a. predicting recurrence of non-muscle-invasive bladder cancer after transurethral resection. medicinski glasnik. 2016;13. 17. koumpan y, jaeger m, mizubuti gb, et al. spinal anesthesia is associated with lower recurrence rates after resection of nonmuscle invasive bladder cancer. j. urol. 2018;199:940-6. 18. yang h, li jy, tan w, wang j. clinical study of bladder infusion with different drugs to prevent postoperative recurrence of bladder tumor patients. pla journal of medicine. 2016. 19. sureka sk, agarwal v, agnihotri s, kapoor r, srivastava a, mandhani a. is en-bloc transurethral resection of bladder tumor for non-muscle invasive bladder carcinoma better than conventional technique in terms of recurrence and progression?: a prospective study. indian journal of urology: iju: journal of the urological society of india. 2014;30:144. 20. zhong c, guo s, tang y, xia s. clinical observation on 2 micron laser for nonmuscle-invasive bladder tumor treatment: single-center experience. world j. urol.. 2010;28:157-61. 21. chen sy ff, du y,du ld. comparison of efficacy and safety of transurethral pin-shaped electrode en bloc resection of bladder tumor and transurethral holmium laser resection of bladder tumor for non muscle invasive bladder cancer. journal of china capital medical university. 2014;v.39:138-42. 22. greskovich iii fj, von eschenbach ac. bladder perforation resulting from the use of the neodymium: yag laser. lasers surg. med. 1991;11:5-7. operation techniques and recurrence in nmibc-li et al. vol 18 no 4 july-august 2021 416 endourology and stone disease 86 urology journal vol 4 no 2 spring 2007 ethanolic extract of nigella sativa l seeds on ethylene glycol-induced kidney calculi in rats mousa-al-reza hadjzadeh,1 alireza khoei,2 zahra hadjzadeh,1 mohammadreza parizady3 introduction: the aim of this study was to investigate the effects of the ethanolic extract of nigella sativa l (ns) seeds on kidney calculi in rats. materials and methods: thirty-two wistar rats were randomly divided into 4 groups: group a received tap drinking water for 30 days (intact control). groups b, c, and d received 1% ethylen glycol for induction of calcium oxalate calculus formation. as the preventive, and treatment subjects, rats in groups c and d received ethanolic extract of ns, 250 mg/kg, in drinking water since day 0 and day 14, respectively. urine was collected on days 0, 7, 14, and 30 of the study period. after 30 days, the kidneys were removed and prepared for histologic evaluation of calcium oxalate deposits. urine calcium oxalate concentrations were determined by atomic absorption. results: the number of caox deposits was significantly greater in group b (p = .001). calcium oxalate concentrations in the urine on days 14 and 30 increased significantly in group b and were higher than those in group c (p = .006 and p = .002, respectively). urine oxalate concentration in group d decreased on day 30 and was lower than that in group b (p = .04). conclusion: treatment of rats with ethanolic extract of ns reduced the number of calcium oxalate deposits in a group of rats that received ethanolic extract of ns. the ns could also lower the urine concentration of calcium oxalate. we suggest further studies on the therapeutic and preventive effects of the ns on kidney calculus formation in human. urol j. 2007;4:86-90. www.uj.unrc.ir keywords: nigella sativa, kidney calculus, ethylene glycol, calcium oxalate, rat 1department of physiology, ghaem hospital, mashhad university of medical sciences, mashhad, iran 2department of pathology, imam reza hospital, mashhad university of medical sciences, mashhad, iran 3department of biochemistry medical school, mashhad university of medical sciences, mashhad, iran corresponding author: mousa-al-reza. hadjzadeh, md, phd department of physiology, ghaem hospital, mashhad university of medical sciences, mashhad, iran tel: +98 511 844 0350 fax: +98 511 844 0350 e-mail: ms-hajzadeh@mums.ac.ir received february 2007 accepted may 2007 introduction urinary calculi are the third prevalent disorder in the urinary system.(1) approximately, 80% of these calculi are composed of calcium oxalate (caox) and calcium phosphate.(2,3) urinary calculi may cause obstruction, hydronephrosis, infection, and hemorrhage in the urinary tract system. surgical operation, lithotripsy, and local calculus disruption using high-power laser are widely used to remove the calculi. however, these procedures are highly cost-effective and may cause severe complications. spontaneous passage of calculus is accompanied by severe renal colic which is not relieved by conventional analgesics, and therefore, narcotics are drugs of choice in many cases. the seeds of nigella sativa l (ns) or black seeds, a member of the family of ranunculaceae, are used in traditional medicine all over the world. black seeds have been reported to be analgesic, anti-inflammatory, anticonvulsant, antidiabetic, anticancer, and antioxidant and have been proposed to lower serum levels of cholesterol and triglycerides, nigella sativa seeds and kidney calculus in rats—hadjzadeh et al urology journal vol 4 no 2 spring 2007 87 balance enzyme activities, increase glutathione in the kidney, and reconstruct kidney tissue after nephrotoxicity.(4-12) black seeds with honey have been mentioned to disintegrate the calculi in the kidney and bladder to small pieces and remove them.(13,14) however, there is no evidence for this traditional therapeutic usage. therefore, we decided to investigate the effect of ethanolic extract of ns seeds on calcium oxalate calculi in a rat model. materials and methods the animal procedure was conducted in conformity with institutional guidelines and national laws, and the study was approved by mashhad university of medical sciences. thirty-two male wistar rats weighed 200 ± 10 g were housed at 25 ± 2°c on a standard diet and tap water. they were randomly divided into 4 groups and treated according to the experimental protocol for 30 days. rats in group a received tap drinking water and served as the intact control group. groups b, c, and d were considered as ethylene glycole control, preventive, and treatment groups and received 1% ethylene glycol (merck, darmstadt, germany) in drinking water for 30 days.(15-17) groups c and d were also treated with 250 mg/kg body weight of ethanolic extract of ns since the first and the 14th day through the end of the experiment, respectively. the ns seeds were purchased from a local herb store in mashhad, iran. they were powdered and dried. then, 100 g of the prepared powder was mixed with a sufficient volume of 96% ethanol and extracted with a soxhlet apparatus for 16 to 18 hours. after removing the solvent in vacuum, the extract was dried in an oven with the temperature of 50°c to 60°c. the dried extract weighed 33.3 g, and therefore, it was 33.3%. the extract was then kept in a refrigerator and was added daily to the drinking water of the rats. ethanolic extract was dissolved in water by adding a few drops of toin 80. the 24-hour urine samples were collected on days 0, 7, 14, and 30, while each rat was kept in a metabolic cage. urine oxalate was measured by atomic absorption.(18) each sample was prepared and the yielding color was read by spectroscopy at 422.7 nm wave length. at the end of the experiment (day 31), all rats were killed by guillotine. the kidneys were removed, weighed, and kept in formalin for histological processing. fivemicrometer sections of both kidneys were prepared for each rat and slides were stained with hematoxylineosin. the slides were examined under light microscope and caox deposits were determined. aggregations of caox deposits (tubules containing caox deposits) were counted in 10 microscopic fields and expressed as mean ± standard error for each group. data were analyzed by nonparametric kruskal-wallis test and mann-whitney u test. p values of less than .05 were considered significant. results the table outlines the urine levels of oxalate on the follow-up days in each group of rats. at the baseline there were no differences between the 4 groups in unrine oxalate levels. in comparison with the rats in other groups, those in group b (ethylene glycole controls) had a significantly higher urine oxalate concentration on days 14 (p = .003) and 30 (p = .005). urine oxalate level in group b was higher compared to group c (preventive group) on days 14 (p = .006) and 30 (p = .002), while no significant difference was found between groups c and a on these days. urine oxalate in the rats of group d (treatment group) was significantly lower than that in group b on day 30 (p = .04). no caox deposits or other abnormalities were found in the nephron segments of group a (figure 1). changes of urine oxalate concentration in rats* urine oxalate concentration, mg/dl days group a (control) group b (ethylene glycol) group c (treatment) group d (preventive) 0 6.27 1.13 4.93 1.17 7.68 0.63 7.17 0.51 7 8.76 0.60 9.31 0.96 7.31 1.11 8.63 0.5 14 8.88 0.44 13.47 0.50 9.39 1.25 12.68 1.23 30 8.43 1.00 15.57 1.26 8.10 0.70 10.64 1.20 *data are expressed as mean ± standard error. nigella sativa seeds and kidney calculus in rats—hadjzadeh et al 88 urology journal vol 4 no 2 spring 2007 on the other hand, many caox deposits were found in the proximal tubules, loops of henle, distal tubules, collecting ducts, and even calyxes in group b (figures 2 to 5). deposits were composed of 3 to 4 large polygonal crystals in different segments of the renal tubules. the number of caox deposits in 10 microscopic fields in the kidney specimens of group b was 55.05 ± 9.88 which was significantly higher than that in group a (p = .001; figure 6). in group c, the number of deposits was 19.75 ± 7.40 which was significantly lower than that in group b (p = .02; figure 6). calcium oxalate crystals in different parts of the renal tubules in the group c were clearly smaller in comparison with group b. in group d, oxalate crystals were deposited both at small and large sizes in the nephron segments. the number of oxalate deposits in this group was calculated to be 24.14 ± 9.08 which was 56% smaller when compared with group b; however, the difference was insignificant (p = .07; figure 6). at the end of the study, the weight of the kidneys was greater in group b compared with group a, but the difference was not significant. no significant differences were found between ethanolic extracttreated rats and those in group b. figure 1. normal medullary and papillary tubules are shown in a rat’s kidney (hematoxylin-eosin, × 200). figure 2. multiple tubular calculi (arrows) in an ethylene glycoltreated rat (hematoxylin-eosin, × 400). figure 3. tubular calculi (arrow) with secondary tubular dilatation (hematoxylin-eosin, × 200). figure 4. calcium oxalate crystals (arrow) in a renal tubule (hematoxylin-eosin, × 1000). figure 5. secondary renal tubular dilatation with epithelial damage (arrow) and leukocyte reaction producing granular and leukocyte cast (hematoxylin-eosin, × 400). nigella sativa seeds and kidney calculus in rats—hadjzadeh et al urology journal vol 4 no 2 spring 2007 89 discussion our data demonstrated that ethanolic extract of ns seeds had a preventive effect on caox calculus formation in the kidney of rats. the ethanolic extract also decreased the number of caox calculi in the treated group by 57%, and therefore, demonstrates a therapeutic effect, albeit trivial, on the disruption of caox calculi formed in the kidney due to ethylene glycol consumption (figure 6). the ns (black seeds) extract with the dose of 250 mg/kg had a significant preventive effect on the formation of caox kidney calculus (figure 6). to our best knowledge, this is the first report on the effect of ethanolic extract of the ns on the prevention and treatment of caox kidney calculus. since the crude extract was used in this study, discussing about the exact mechanisms involved in the effect of the black seeds on caox calculi. calcium oxalate crystals and high oxalate levels in nephrons can produce damages in the epithelial cells, and consequently, the cells may produce some products, as well as free radicals, inducing heterogenous crystal nucleation and cause aggregation of crystals.(19) black seeds have glycoside flavonoids such as kaempferol, quercetin, and quercetin-3. phytochemical analysis of black seeds of khorasan province has demonstrated that the seeds contain tanin, flavonoids, and alkaloids which also constitute a portion of the ethanolic extract of the seeds.(20-23) several studies have reported that flavonoides—especially qurecetin and kaempferol— have anti-inflammatory and antioxidant effects.(22-25) it can be speculated that of the role of the ns ethanolic extract in preventing formation of caox calculi and disruption of them, as seen in the present study, is in part due to the anti-inflammatory and antioxidant effects of the different compounds of the black seeds. these compounds may interfere with the process of epithelial cell damage induced by crystals or may exert inhibitory effect on inflammation.(26) aglichon and glyceride flavonoles which are present in black seeds have strong antioxidant and scavenging effects; thus, it may be suggested that the preventive and disruptive effects of black seeds on caox calculi are attributed to these mechanisms.(24) it has been reported that caox calculi such as struvite calculi may have a bacterial origin such as nanobacteria.(27) black seeds also have antibacterial effects and therefore, may be effective in this mechanism of caox calculus formation.(28) the weight of the kidneys increased in the group of rats which received only ethylene glycol (group b); this may be due to water retention or inflammation of the epithelium of nephrons. the ethanolic extract was not able to decrease significantly the weight of kidneys in experimental groups (c and d), which in part may be due to the very short period of treatment. conclusion we could find that the ethanolic extract of ns seeds with a dose of 250 mg/kg significantly decreased the number and size of caox deposits in different parts of the renal tubules and also prevented damages to the tubules and calyxes. it also seems that the preventive effect of ethanolic extract is more effective than its treatment effect. black seeds are commonly used in folk medicine; therefore, it may be suggested that ethanolic extract or other products of the ns seeds be used for prevention and perhaps treatment of caox calculi in human. further studies on larger animal models and on human are warranted to draw final conclusions. acknowledgement this study was supported by a grant from the council of research, mashhad university of medical sciences. figure 6. the number of calcium oxalate crystal deposits (per 10 microscopic fields) in the kidneys of the rats at the end of the experiment. data are expressed as mean ± standard error. the kruskal-wallis test demonstrated a significant difference between the 4 groups (p = .001). 0 10 20 30 40 50 60 70 group a group b group c group d rats n um be r of c al ci um o xa la te d ep os its nigella sativa seeds and kidney calculus in rats—hadjzadeh et al 90 urology journal vol 4 no 2 spring 2007 conflict of interest none declared. references 1. stoller ml, bolton dm. urinary stone diseases. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 15 th ed. ohio: mcgraw-hill; 2004. p. 291321. 2. menon m, resnick mi. urinary lithiasis: etiology, diagnosis, and medical management. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3229-305. 3. coe fl, evan a, worcester e. kidney stone disease. j clin invest. 2005;115:2598-608. 4. al-ghamdi ms. the anti-inflammatory, analgesic and antipyretic activity of nigella sativa. j ethnopharmacol. 2001;76:45-8. 5. hosseinzadeh h, parvardeh s. anticonvulsant effects of thymoquinone, the major constituent of nigella sativa seeds, in mice. phytomedicine. 2004;11:56-64. 6. hosseinzadeh h, parvardeh s, nassiri-asl m, mansouri mt. intracerebroventricular administration of thymoquinone, the major constituent of nigella sativa seeds, suppresses epileptic seizures in rats. med sci monit. 2005;11:br106-10. 7. burits m, bucar f. antioxidant activity of nigella sativa essential oil. phytother res. 2000;14:323-8. 8. sattar a, zaman latif ms, tayyib m. estimation of serum lipids in albino rats fed on atherogenic supplemented palm oil diet and nigella sativa. j rawal med coll. 2002;6:48-51. 9. badary oa, abdel-naim ab, abdel-wahab mh, hamada fm. the influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats. toxicology. 2000;143:219-26. 10. el-dakhakhny m, mady n, lembert n, ammon hp. the hypoglycemic effect of nigella sativa oil is mediated by extrapancreatic actions. planta med. 2002;68:465-6. 11. mojab f. nigella sativa. in: ghasemei dehkordy n, editor. iranian herbal pharmacopia. tehran: council of food & drugs, ministry of health and medical education; 2002. p. 466-70. 12. khan n, sharma s, sultana s. nigella sativa (black cumin) ameliorates potassium bromate-induced early events of carcinogenesis: diminution of oxidative stress. hum exp toxicol. 2003;22:193-203. 13. mir heidar h. nigella sativa. in: mir heidar h, editor. encyclopedia of medicinal plants of iran. 6th ed. tehran: islamic culture press; 2004. p. 211-4. 14. aqili khorasani mh. nigella sativa. in: aqili khorasani mh, editor. makhzan-al-advah. tehran: islamic publishing and educational organization; 1992. p. 556-8. 15. christina aj, packia lakshmi m, nagarajan m, kurian s. modulatory effect of cyclea peltata lam. on stone formation induced by ethylene glycol treatment in rats. methods find exp clin pharmacol. 2002;24:77-9. 16. sakly r, chaouch a, el hani a, najjar mf. effects of intraperitoneally administered vitamin e and selenium on calcium oxalate renal stone formation: experimental study in rat. ann urol (paris). 2003;37:47-50. 17. fan j, chandhoke ps, grampsas sa. role of sex hormones in experimental calcium oxalate nephrolithiasis. j am soc nephrol. 1999;10:s376-80. 18. sriboonlue p, suwantrai s, prasongwatana v. an indirect method for urinary oxalate estimation. clin chim acta. 1998;273:59-68. 19. khan sr, thamilselvan s. nephrolithiasis: a consequence of renal epithelial cell exposure to oxalate and calcium oxalate crystals. mol urol. 2000;4:305-12. 20. merfort i, wray v, barakat hh, hussein sam, nawwar mam, willuhn g. flavonol triglycosides from seeds of nigella sativa. phytochemistry. 1997;46:359-363. 21. bazzaz bsf, haririzadeh g, imami sa, rashed mh. survey of iranian plants for alkaloids, flavonoids, saponins, and tannins [khorasan province]. pharmaceutical biology (formerly international journal of pharmacognosy). 1997;35:17-30. 22. ahmed ms, el tanbouly nd, islam wt, sleem aa, el senousy as. antiinflammatory flavonoids from opuntia dillenii (ker-gawl) haw. flowers growing in egypt. phytother res. 2005;19:807-9. 23. xu j, li x, zhang p, li zl, wang y. antiinflammatory constituents from the roots of smilax bockii warb. arch pharm res. 2005;28:395-9. 24. comalada m, ballester i, bailon e, et al. inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship. biochem pharmacol. 2006;72:1010-21. 25. nair mp, mahajan s, reynolds jl, et al. the flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the nf-kappa beta system. clin vaccine immunol. 2006;13:319-28. 26. el-dakhakhny m, madi nj, lembert n, ammon hp. nigella sativa oil, nigellone and derived thymoquinone inhibit synthesis of 5-lipoxygenase products in polymorphonuclear leukocytes from rats. j ethnopharmacol. 2002;81:161-4. 27. kramer g, klingler hc, steiner ge. role of bacteria in the development of kidney stones. curr opin urol. 2000;10:35-8. 28. hanafy ms, hatem me. studies on the antimicrobial activity of nigella sativa seed (black cumin). j ethnopharmacol. 1991;34:275-8. special feature 10 urology journal vol 7 no 1 winter 2010 spontaneous resolution of severe hemorrhagic intrarenal pseudoaneurysm after percutaneous nephrolithotomy abbas basiri, vahid najjaran toussi, mehrdad mohammadi sichani, arash ardestani zadeh urol j. 2010;7:10-1. www.uj.unrc.ir keywords: percutaneous nephrosotomy, false aneurysm, angiography, spontaneous remission urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran corresponding author: arash ardestani zadeh, md no 103, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: ardestani_a@yahoo.com received january 2010 accepted february 2010 introduction percutaneous renal procedures have become an established approach for diagnosis and treatment of a number of renal pathologic lesions. hemorrhage and vascular lesions are the most serious complications. the reported incidence of postoperative hemorrhage requiring selective angio-embolization for bleeding control is 1.2%.(1) delayed bleeding after percutaneous procedures is almost always secondary to pseudoaneurysms or arteriovenous fistulas.(2) we report a case of pseudoaneurysm following percutaneous nephrolithotomy (pcnl) that caused recurrent episodes of severe hematuria after the operation, requiring embolization, but it resolved spontaneously. case report a 44-year-old diabetic man presented with a recurrent left renal colic. ultrasonography and computed tomography (ct) without contrast showed a 2-cm calculus in the left renal pelvis with moderate hydronephrosis and a 1-cm calculus in the lower calyx of the right kidney without hydronephrosis. the patient had chronic kidney disease and his serum creatinine was 1.8 mg/dl. extracorporeal shock wave lithotripsy failed to fragment the left pelvic calculus, and therefore, the patient underwent pcnl in the prone position. the procedure was uneventful and the patient was discharged on the 3rd postoperative day. fourteen days after the procedure, he was re-admitted due to severe gross hematuria. bleeding and coagulation parameters were within the reference ranges pre-operatively. the patient was resuscitated with intravenous fluids and blood transfusions. hematuria ceased with conservative management. patient underwent angio-ct, which revealed pseudoaneurysm arising from the lower polar segmental artery (figure 1). since the episodes of gross hematuria recurred several times during the conservative management, it was decided to perform angiographic embolization. eighteen days after angio-ct, angiography was done for embolization, but it did not show further opacification of the pseudoaneurysm (figure 2). therefore, the embolization was not performed. three days after angiography, the patient was discharged from the hospital, and during 1 year follow-up, he did not have any episodes of gross hematuria. pseudoaneurysm after percutaneous nephrolithotomy—basiri et al 11urology journal vol 7 no 1 winter 2010 discussion blood loss is common during percutaneous procedures of the kidney. in the majority of patients, bleeding improves with conservative management. however, some lesions like pseudoaneurysm could be persistent, requiring specific treatment. pseudoaneurysm is usually assessed by renal angiography,(3,4) providing the possibility of diagnosis and treatment at the same time. clinical diagnosis can also be done through noninvasive methods such as angio-ct or doppler ultrasonography. in this case, angioct was utilized for diagnosis, which revealed a perfect image of pseudoaneurysm. angio-ct helps planning endovascular treatment thanks to the excellent quality of images. selective renal embolization is currently considered as the most appropriate technique in the treatment of renovascular complications with a success rate greater than 80% and a low complication rate.(4) in contrast to surgery, the endovascular management helps saving the kidney in many patients. spontaneous resolution, as seen in our patient, could be one of the natural outcomes of an intrarenal pseudoaneurysm. the mechanism is probably spontaneous thrombosis and occlusion of the pseudoaneurysm. this suggests that a conservative management could be an option for managing intrarenal pseudoaneurysm. these patients must be followed with serial color doppler ultrasonography to look for any changes in the size and internal flow of the pseudoaneurysm. spontaneous resolution of pseudoaneurysm after blunt abdominal trauma or stab wound has been reported by other authors, but to our knowledge, there is not any report of radiologically confirmed intrarenal pseudoaneurysm with massive hematuria disappeared spontaneously after pcnl. it seems that although patients with persistent gross hematuria due to intrarenal pseudoaneurysms after pcnl are candidates for intervention, there are some cases of intrarenal pseudoaneurysm that may be resolved spontaneously with conservative management. these patients must be carefully followed up clinically and radiologically with serial color doppler ultrasonography. conflict of interest none declared. references 1. richstone l, reggio e, ost mc, et al. first prize (tie): hemorrhage following percutaneous renal surgery: characterization of angiographic findings. j endourol. 2008;22:1129-35. 2. gupta m, ost mc, shah jb, mcdougall em, smith ad. percutaneous management of the upper urinary tract. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1526-63. 3. jain r, kumar s, phadke rv, baijal ss, gujral rb. intra-arterial embolization of lumbar artery pseudoaneurysm following percutaneous nephrolithotomy. australas radiol. 2001;45:383-6. 4. soyer p, desgrippes a, vallee jn, rymer r. intrarenal pseudoaneurysm after percutaneous nephrostolithotomy: endovascular treatment with n-butyl-2-cyanoacrylate. eur radiol. 2000;10:1358. figure 1. left, angio-ct demonstrates the pseudoaneurysm (arrow) in the lower pole of the left kidney. right, 3-d reconstruction following angio-ct shows the pseudoaneurysm (arrow) arising from the lower polar segmental artery. figure 2. angiography done 18 days after angio-ct shows no pseudoaneurysm. kidney transplantation 234 urology journal vol 4 no 4 autumn 2007 kidney transplantation in patients with alport syndrome mohammad javad mojahedi,1 reza hekmat,1 hassan ahmadnia2 introduction: the aim of this study was to evaluate the results of kidney transplantation in patients with alport syndrome. materials and methods: a total of 15 patients with alport syndrome underwent kidney transplantation and the result of their transplantation was compared with the results in patients without alport syndrome. rejection episodes and the presence of antiglomerular basement membrane (anti-gbm) nephritis were assessed in these patients. results: fifteen patients with alport syndrome were compared with a control group including 212 kidney allograft recipients. one patient with alport syndrome (6.7%) and 30 controls (14.2%) experienced delayed graft function. renal artery thrombosis was reported in 1 patient (6.7%) with alport syndrome and 10 (4.7%) in the control group, which led to nephrectomy in all cases. acute rejection was confirmed in 2 patients (13.3%) by kidney biopsy and classic treatment yielded relative response. however, they lost their grafts 35 and 44 months after the transplantation. on pathologic examination, no specific finding of anti-gbm nephritis was found. in the control group, 43 cases of acute rejection (20.3%) were reported and 12 patients (5.7%) returned to dialysis. the 1-, 3-, and 5-year graft survival rates were 100%, 92%, and 84% in the patients with alport syndrome, which was not different from those in the control group (p = .53). conclusion: in spite of the risk of anti-gbm nephritis in the patients with alport syndrome, it seems that kidney transplantation can yield favorable results and anti-gbm nephritis is not a common etiology of rejection. urol j. 2007;4:234-7. www.uj.unrc.ir keywords: hereditary nephritis, kidney transplantation, antiglomerular basement membrane antibody 1division of nephrology, department of internal medicine, ghaem hospital, mashhad university of medical sciences, mashhad, iran 2department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran corresponding author: mohammad javad mojahedi, md department of medicine, ghaem hospital, mashhad, iran tel: +98 511 726 6007 fax: +98 511 841 7404 e-mail: mjm_1ir@yahoo.com received august 2006 accepted june 2007 introduction alport syndrome is a hereditary kidney disease that manifests by glomerular damage, loss of hearing, and visual defects.(1) kidney damage results in chronic kidney failure and emerges the need for dialysis or transplantation.(2) anti-glomerular basement membrane (gbm) antibody is a cause of immunologic complications in this syndrome and forms as a result of mutations that lead to defects in the α chain of collagen type iv in the gbm.(3,4) less than 10% of transplant patients with alport syndrome experience anti-gbm nephritis.(5,6) the immune system of the recipient encounters the gbm antigens after transplantation and produces antibodies against them, resulting in anti-gbm nephritis and allograft failure.(1,4) two cases of anti-gbm nephritis were reported by shah and colleagues in 1988.(7) since then, several researchers have investigated the clinical outcome of transplantation in these patients.(8) they have proposed that the incidence of nephritis following transplantation is less than predicted, kidney allograft recipients with alport syndrome—mojahedi et al urology journal vol 4 no 4 autumn 2007 235 but immunosuppression may have a role in triggering anti-gbm reaction. we decided to perform this study to determine the results of kidney transplantation in patients with alport syndrome and compare them with kidney allograft recipients without this syndrome. materials and methods in a prospective study between 1994 and 2003, we evaluated 15 patients with alport syndrome (case group) undergoing transplantation at our center and compared their outcomes with the results in our kidney recipients without alport syndrome. diagnosis of alport syndrome was made regarding the criteria proposed by gubler and colleagues(9) that included hematuria with or without proteinuria, hypertension, and chronic kidney failure with one of the characteristics below: proved impairment of the kidney, progress to kidney failure in at least one of the relatives, sensory-neural hearing loss in the patients or their kinsmen, and visual impairment. those patients who underwent nephrectomy due to the complications within the first month of transplantation were excluded. after transplantation, diuresis and the decrease in serum creatinine and blood urea nitrogen was monitored and diagnostic evaluations were performed in case of kidney dysfunction. all patients received cyclosporine with the initial dose of 9 mg/kg on the first day and 6 mg/kg/d, afterwards. azathioprine was administered with the dose of 3 mg/kg/d in the first month and 1.5 mg/kg/d to 2 mg/kg/d, afterwards. instead of azathioprine, some patients received mycophenolate mofetil with the dose of 2 g/d. in addition, pulse of methyl prednisolone succinate was started on with the dose of 10 mg/kg to 15 mg/kg for the first 3 days, and then, prednisolone with the dose of 1 mg/kg was administered, which was slowly tapered. the survival rate of the kidney allografts and the patients were determined using the kaplan-meier method and the log-rank test. a p value less than .05 was considered significant. results during the study period, 352 kidney transplantations were done at our center, of which 15 were in patients (4.3%; 14 men and 1 woman) had alport syndrome (table). they all received their transplants from living unrelated donors for the first time and all were negative for hepatitis b antigen and hepatitis c antibody. therefore, in the control group, we included all of the kidney recipients with the same characteristics. the control group included 212 patients, 123 (58%) of whom were men and 89 (42%) were women. the mean age of the patients was 31.0 ± 7.4 years (range, 20 to 42 years) and 32.5 ± 7.9 years (range, 20 to 42 years) in the case and control patients age sex underlying disease diuresis after transplant creatinine on the 3rd posttransplat day arterial thrombosis acute rejection graft loss followup, mo outcome 1 24 m … early 1.7 n n n 54 fair 2 26 m … early 1.5 n n n 72 fair 3 28 m … early 1.4 n n n 30 fair 4 20 m htn little 6.7 p n p 1 nephrectomy 5 21 f … early 1.7 n n n 76 fair 6 29 m … delayed 4.9 n n n 93 fair 7 39 m … early 1.6 n p p 35 nonfunctional 8 42 m … early 1.3 n n n 112 fair 9 22 m vur early 1.7 n p p 44 nonfunctional 10 31 m … early 1.6 n n n 64 fair 11 37 m … early 1.5 n n n 102 fair 12 41 m … early 1.4 n n n 96 fair 13 35 m … early 1.5 n n n 65 fair 14 38 m … early 1.6 n n n 29 fair 15 32 m … early 1.4 n n n 30 fair demographic and clinical data of transplanted patients with alport syndrome* *m indicates male; f, female; htn, hypertension; vur, vesicoureteral reflux; n, negative; and p, positive. ellipses indicate no finding. kidney allograft recipients with alport syndrome—mojahedi et al 236 urology journal vol 4 no 4 autumn 2007 groups, respectively. in the control group, causes of kidney failure included glomerulonephritis (34.0%), hypertension (30.7%), diabetes mellitus (11.3%), unknown causes (9.9%), vesicoureteral reflux (8.0%), polycystic kidney (4.2%), and obstructive uropathies (1.9%). of 15 patients with alport syndrome, 13 (86.7%) had early diuresis after transplantation and serum creatinine level decreased to 1.7 mg/dl or less within 3 days after the transplantation. one patient (6.7%) experienced delayed graft function (serum creatinine decreased to 1.7 mg/dl or less within 10 days). early and delayed graft functions were seen in 180 patients (84.9%) and 30 patients (14.2%) of the control group, respectively. renal artery thrombosis confirmed by angiography or color doppler ultrasonography was reported in 1 patient (6.7%) with alport syndrome and 10 (4.7%) in the control group, which led to nephrectomy. the patients underwent a total evaluation 1 and 6 months after the transplantation and every 6 months, afterwards. they were followed up for a mean period of 60.2 ± 32.1 months and 64.1 ± 38.4 months in the case and control groups, respectively. two patients in the case group (13.3%) experienced increased levels of urea and creatinine. both patients were men (22 years and 39 years). acute rejection was confirmed by kidney biopsy and classic treatment yielded relative response. however, they lost their grafts 35 and 44 months after the transplantation. on pathologic examination, no specific finding of anti-gbm nephritis was found. the rest of the patients with alport syndrome did not experience any dysfunction in the transplanted kidney during the follow-up period. no mortality was reported in the case group. in the control group, 43 cases of acute rejection (20.3%) were reported and 12 patients (5.7%) returned to dialysis (4 within the first, 4 within the second, and 4 within the third posttransplant year), 5 of whom died during the follow-up period. also, 14 deaths happened in the patients with functioning allografts which were due to car accident and myocardial infarction. the 1-, 3-, and 5-year graft survival rates were 100%, 92%, and 84% in the case group and 98%, 94%, and 90% in the control group (p = .53). patient survival rates at 1, 3, and 5 years were 100% in the case group and 96%, 91%, and 90% in the control group, respectively (p = .22) discussion genetic mutations in the α chain of collagen type iv in the gbm results in the x-linked or autosomal recessive alport syndrome.(10) lack of one or more normal antigens in the α chain results in an increased possibility of anti-gbm nephritis. until 1983, more than 100 cases of kidney transplantation in alport patients had been reported,(6) in less than 10% of whom, anti-gbm nephritis occurred.(5) men with deafness and kidney failure before 30 years of age are more susceptible to anti-gbm nephritis.(11) anti-gbm nephritis occurs within the first year of transplantation or it may last longer to become evident.(1) those patients with antibodies against the membrane are more susceptible to crescent glomerulonephritis and graft loss. treatment with plasmapheresis and cyclosphosphamide are valuable in these patients.(1) surprisingly, anti-gbm nephritis occurs in few of the patients who receive a kidney allograft. this can be best described by the effect of immunosuppressive therapy to prevent acute rejection which results in less anti-gbm antibody formation, as well.(6,12,13) also, the col4a5 gene plays a very important role and patients with mutation in this gene are at a high risk of developing nephritis.(14-17) it was shown that 54% of the patients with alport syndrome and anti-gbm nephritis had deletions in col4a5, while this mutation exists only in 16% of the alport syndrome population. less severe defects do not impair expression of the vital parts in the α-5 chain in the gbm and the antigens will not induce antibody formation. in a study by shah and colleagues, 2 cases of anti-gbm nephritis were reported 5 months and 18 months after the transplantation. byrne and associates reported it in 41 patients with alport syndrome and believed that the occurrence of antigbm nephritis in patients with alport syndrome was less than the predicted value.(8) in our study, no case of nephritis was seen and graft survival was similar in the patients of the case and control groups, which argues the results of other studies.(8) we had limitations in our study including the lostto-follow-up cases, few numbers of the patients, and lack of genetic evaluations. more studies with genetic considerations before the operation, evaluation of the presence of antibody against gbm in the serum kidney allograft recipients with alport syndrome—mojahedi et al urology journal vol 4 no 4 autumn 2007 237 of the patients, and evaluation of the number of the patients with anti-gbm antibody progressing to antigbm nephritis are warranted. conclusion despite the risk of anti-gbm nephritis, we found that in patients with alport syndrome, kidney transplantation is the method of choice for the treatment of chronic kidney failure, and the risk of graft loss due to anti-gbm antibodies is not a major concern. conflict of interest none declared. references 1. kashtan ce, michael af. alport syndrome. kidney int. 1996;50:1445-63. 2. o>neill wm jr, atkin cl, bloomer ha. hereditary nephritis: a re-examination of its clinical and genetic features. ann intern med. 1978;88:176-82. 3. hudson bg, kalluri r, gunwar s, et al. the pathogenesis of alport syndrome involves type iv collagen molecules containing the alpha 3(iv) chain: evidence from anti-gbm nephritis after renal transplantation. kidney int. 1992;42:179-87. 4. mccoy rc, johnson hk, stone wj, wilson cb. absence of nephritogenic gbm antigen(s) in some patients with hereditary nephritis. kidney int. 1982;21:642-52. 5. milliner ds, pierides am, holley ke. renal transplantation in alport>s syndrome: anti-glomerular basement membrane glomerulonephritis in the allograft. mayo clin proc. 1982;57:35-43. 6. jeraj k, kim y, vernier rl, fish aj, michael af. absence of goodpasture>s antigen in male patients with familial nephritis. am j kidney dis. 1983;2:626-9. 7. shah b, first mr, mendoza nc, clyne dh, alexander jw, weiss ma. alport>s syndrome: risk of glomerulonephritis induced by anti-glomerularbasement-membrane antibody after renal transplantation. nephron. 1988;50:34-8. 8. byrne mc, budisavljevic mn, fan z, self se, ploth dw. renal transplant in patients with alport>s syndrome. am j kidney dis. 2002;39:769-75. 9. gubler m, levy m, broyer m, et al. alport>s syndrome. a report of 58 cases and a review of the literature. am j med. 1981;70:493-505. 10. kashtan ce. alport syndrome. an inherited disorder of renal, ocular, and cochlear basement membranes. medicine (baltimore). 1999;78:338-60. 11. yoshikawa n, white rh, cameron ah. familial hematuria; clinico-pathological correlations. clin nephrol. 1982;17:172-82. 12. jenis eh, valeski je, calcagno pl. variability of anti-gbm binding in hereditary nephritis. clin nephrol. 1981;15:111-4. 13. wilson cb, dixon fj. anti-glomerular basement membrane antibody-induced glomerulonephritis. kidney int. 1973;3:74-89. 14. tryggvason k, zhou j, hostikka sl, shows tb. molecular genetics of alport syndrome. kidney int. 1993;43:38-44. 15. heiskari n, zhang x, zhou j, et al. identification of 17 mutations in ten exons in the col4a5 collagen gene, but no mutations found in four exons in col4a6: a study of 250 patients with hematuria and suspected of having alport syndrome. j am soc nephrol. 1996;7:702-9. 16. kashtan ce, butkowski rj, kleppel mm, first mr, michael af. posttransplant anti-glomerular basement membrane nephritis in related males with alport syndrome. j lab clin med. 1990;116:508-15. 17. ding j, zhou j, tryggvason k, kashtan ce. col4a5 deletions in three patients with alport syndrome and posttransplant antiglomerular basement membrane nephritis. j am soc nephrol. 1994;5:161-8. fall 2012 08.pdf 685vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l validity and reliability of the international consultation on incontinence questionnaire-urinary incontinence short form and its correlation with urodynamic findings sakineh hajebrahimi,1 davoud nourizadeh,2 roghayeh hamedani,2 mohammad zakaria pezeshki3 purpose: to validate the persian version of the international consultation on incontinence questionnaire-urinary incontinence short form (iciq-ui sf) as a standard questionnaire for assessment of urinary incontinence (ui). materials and methods: after translation and back translation of the questionnaire, the harmothe psychometric aspects of the questionnaire, such as reliability and construct validity, were asresults: mean age of the participants was 46.30 ± 13.14 years (range, 16 to 72 years). based urgency urinary incontinence was 35%, 34.1%, and 30.9%, respectively. cronbach’s alpha coconclusion: persian version of iciq-ui sf is a simple, valid, and reliable method for evaluation parameters. keywords: urinary incontinence, validation studies, questionnaires, translating, diagnosis corresponding author: davoud nourizadeh, md department of urology, imam reza hospital; faculty of medicine, tabriz university of medical sciences, tabriz, iran tel: +98 411 335 7328 fax: +98 411 335 7328 e-mail: davoudnourizadeh @yahoo.com received april 2011 accepted january 2012 1department of urology, iranian center for evidence-based medicine, faculty of medicine, tabriz university of medical sciences, tabriz, iran 2department of urology, imam reza hospital, faculty of medicine, tabriz university of medical sciences, tabriz, iran 3department of community medicine, iranian center for evidence-based medicine, faculty of medicine, tabriz university of medical sciences, tabriz, iran female urology 686 | ???female urology introduction u rinary incontinence (ui) is a major health problem worldwide, with a 5% to 72% prevalence rate, depending on the study.(1) age, vaginal delivery, obesity, menopause, smoking, chronic cough, constipation, and previous pelvic surgery are among its primary risk factors.(1,2) appropriate diagnosis and assessment of ui is crucial for its treatment. to cure or improve the sympto growing interest in clinical evaluation with subjective methods. various different questionnaires have been used to assess and diagnose ui, each with advantages and disadvantages. few diseases-related quality of life (qol) questionnaires have been developed for clinical practice, and most are too long and unclear. the international consultation on incontinence questionnaire-urinary incontinence short form (iciq-ui sf) consists of 6 questions developed by the international consultation on incontinence. the original version is in english and has been translated into 26 other languages, including spanish,(3) chinese,(4) turkish,(5) arabic,(6) portuguese,(7) japanese,(8) and taiwanese.(9) a valid and reliable questionnaire may prevent the need for unnecessary ui studies.(10) in prior reports, the iciq-ui sf has been translated and validated for initial diagnosis, management, and patient’s follow-up.(11-15) it can be used as a self-administrated questionnaire or can be administered by the physician.(14) the iciq-ui sf has not yet been translated into persian; therefore, its reliability and validity have not been assessed in iran, which has a ui prevalence of 23.5%.(2) urodynamic studies are performed to investigate the function of the consuming, and invasive. a less complicated method for determining this urodynamic information would therefore for this cross-sectional study, the iciq-ui sf was translated into persian according to the iciq and reliability proand the results were compared with the clinical urodynamic to translate the iciq-ui sf into persian with appropriate cultural adaptations, validate it for clinical and research practices in persian-speaking countries, and evaluate its correlation with urodynamic studies. materials and methods from 123 consecutive patients with ui referred to the female urology clinic at tabriz university of medical sciences from may 2008 to june 2009. a written informed consent was obtained from each participant. the patients younger than 16 years. the original iciq-ui sf was translated into persian by 2 pert. the english and persian versions were reviewed by 2 physicians who were aware of the research aims. the persian translation was then back-translated into english unaware of the research objectives of this study. after the grammatical corrections, the persian version was evaluated by a committee of 5 bilingual health workers. to observe the appropriate translation methodology, the back-translation of the questionnaire was sent to the ici advisory board for review in england. this was to ensure that the content of the translation remained consistent with the original version. a pilot test was conducted on 28 patients with pretested ui using the persian translated iciq-ui sf to assess reliability and validity. the questionnaire was read to the patient and tent validity, the patient responses were analyzed based on previously validated results from the pre-translated original iciq-ui sf. concurrent validity, a core criterion of this study, was investigated by cross-validating the results of the iciq-ui sf with the urodynamic results. because urodynamic studies are considered to have high validity, they were used here as a criterion standard, making it possible to assessment. the purpose of this study was not to assess the diagnostic value of the iciq-ui sf. for this reason, sensiconcurrent validity. the questionnaire was administered at 687vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l correlation between iciq-ui sf and urodynamic findings | hajebrahimi et al 2 separate times with an interval of 1 week to ensure lack of recall-induced agreement. according to the results of the pilot study, some of the patients did not understand question 4 regarding qol. we attributed this to cultural reasons. therefore, we made a second pretest to improve the cultural implications of this question. the results of the pilot and main studies were separately anacalculated to assess the reliability of the questions, and the were calculated to determine the test-retest value. to evaluate the correlation between the results of the questionnaire and p the construct validity was evaluated by comparison of the persian version of the iciq-ui sf with the urodynamic studies. validity of the persian iciq-ui sf was determined by its ability to distinguish between different types of ui, to assess the predictive ability of the questionnaire, true positives, false positives, true negatives, false negatives, voiding cystometry and valsalva leak point pressure, was performed using a laborie delphis b urodynamic system, with the patient in a sitting position according to international continence society standards. results one hundred and twenty-three women with some degree of ui in the previous 4 weeks were enrolled in this study. the mean patients’ age was 46.30 ± 13.14 years (range, 16 to 72 years). more than 68% of the participants had low levels of literacy. the mean questionnaire scores of the patients are shown in table 1. according to the iciq-ui sf, 43 (35.0%) patients had mui, 42 (34.1%) had sui, and 38 (30.9%) had uui. based on the urodynamic and stress test results, 6 (4.9%) patients had mui, 38 (30.9%) had sui, and 63 (51.2%) had patients, including 9 (7.3%) with underactive detrusor, 2 (1.6%) with acontractile detrusor, and 2 (1.6%) with bladder outlet obstruction. three (2.4%) subjects had normal urodynamics study. patients who had more severe symplevel of reliability of this questionnaire in determining ui. tial questionnaire and the translated version was 0.70. the between the questionnaire and the urodynamic study. the ed in table 2. discussion the persian version of the iciq-ui sf demonstrated good ing effects were observed, suggesting that it enabled discrimination among an adequate range of ui conditions. as tended to score higher than those with less severe symptoms. the persian version showed good internal consistency and test-retest reliability, suggesting that it can be efthe construct validity was analyzed by measuring the corurodynamic study. there was generally a moderate association between the two approaches. this was not entirely study (p < .01). the questionnaire measured an mui with a sensitivity of table 1. average questionnaire scores. number of question mean score standard deviation 1st 3.52 1.27 2nd 3.9 1.81 3rd 7.85 2.35 total score 16.6 4.07 688 | women with ui may adapt their lifestyles to avoid situacriterion standard. patients with low levels of literacy had problems understanding the qol scale in the pilot study. for this reason, we changed the number scale for these patients to a visual scale, but the results were not completely satisfactory and the iciq-ui sf has been translated into more than 26 languages and is used worldwide as a common instrument for assessing the symptoms and qol of patients with ui.(11) questionnaire in persian-speaking countries. using this method, the outcomes of studies on ui conducted worldiciq-ui sf consists of only 3 scored questions and is therefore not time-consuming for the patient. the simplicity of this method renders it especially useful for clinical practice, where time and resources are limited. however, because a short questionnaire cannot always provide detailed information about symptoms and qol,(12,13) other assessment measures may be necessary. conclusion the persian version of the iciq-ui sf is a reliable and valid tool for the assessment of patients with ui. acknowledgements this study was conducted by grant of urology research team and research vice chancellor of tabriz university of medical sciences. their great help is appreciated. conflict of interest none declared. table 2. comparison of questionnaire results with urodynamics study.* type of incontinence sensitivity (95% ci) specificity (95% ci) mui 0.84 (0.653 to 0.936) 0.78 (0.689 to 0.85) uui 0.525(0.402 to 0.645) 0.953 (0.871 to 0.984) sui 0.636 (0.466 to 0.778) 0.826 (0.736 to 0.89) *ci indicates confidence interval; mui, mixed urinary incontinence; uui, urgency urinary incontinence; sui, stress urinary incontinence. female urology references 1. nitti vw. the prevalence of urinary incontinence. rev urol. 2001;3 suppl 1:s2-6. 2. hajebrahimi s, madaen sk. prevalence of urinary incontinence in tabrizian women. iranian j urol. 2001;61-4. 3. espuna pons m, rebollo alvarez p, puig clota m. [validation of the spanish version of the international consultation on incontinence questionnaire-short form. a questionnaire for assessing the urinary incontinence]. med clin (barc). 2004;122:288-92. 4. huang l, zhang sw, wu sl, ma l, deng xh. the chinese version of iciq: a useful tool in clinical practice and research on urinary incontinence. neurourol urodyn. 2008;27:522-4. 5. cetinel b, ozkan b, can g. the validation study of iciq-sf turkish version. turkish j urol. 2004;30:332–8. 6. hashim h, avery k, mourad ms, chamssuddin a, ghoniem g, abrams p. the arabic iciq-ui sf: an alternative language version of the english iciq-ui sf. neurourol urodyn. 2006;25:277-82. 7. tamanini jt, dambros m, d'ancona ca, palma pc, rodrigues netto n, jr. [validation of the "international consultation on incontinence questionnaire -short form" (iciq-sf) for portuguese]. rev saude publica. 2004;38:438-44. 8. gotoh m, homma y, funahashi y, matsukawa y, kato m. psychometric validation of the japanese version of the international consultation on incontinence questionnaireshort form. int j urol. 2009;16:303-6. 9. chang sr, chen kh, chang tc, lin hh. a taiwanese version of the international consultation on incontinence questionnaire--urinary incontinence short form for pregnant women: instrument validation. j clin nurs. 2011;20:714-22. 689vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l correlation between iciq-ui sf and urodynamic findings | hajebrahimi et al 10. avery k, donovan j, peters tj, shaw c, gotoh m, abrams p. iciq: a brief and robust measure for evaluating the symptoms and impact of urinary incontinence. neurourol urodyn. 2004;23:322-30. 11. espuna-pons m, dilla t, castro d, carbonell c, casariego j, puig-clota m. analysis of the value of the iciq-ui sf questionnaire and stress test in the differential diagnosis of the type of urinary incontinence. neurourol urodyn. 2007;26:836-41. 12. seckiner i, yesilli c, mungan na, aykanat a, akduman b. correlations between the iciq-sf score and urodynamic findings. neurourol urodyn. 2007;26:492-4. 13. tamanini jt, dambros m, d'ancona ca, palma pc, rodrigues-netto n, jr. responsiveness to the portuguese version of the international consultation on incontinence questionnaire-short form (iciq-sf) after stress urinary incontinence surgery. int braz j urol. 2005;31:482-9; discussion 90. 14. klovning a, avery k, sandvik h, hunskaar s. comparison of two questionnaires for assessing the severity of urinary incontinence: the iciq-ui sf versus the incontinence severity index. neurourol urodyn. 2009;28:411-5. 15. kieres p, rokita w, stanislawska m, rechberger t, galezia m. [the diagnostic value of chosen questionnaires (udi 6sf, gaudenz, mesa, iciq-sf and king's health questionnaire) in diagnosis of different types of women's urinary incontinence]. ginekol pol. 2008;79:338-41. 690 | iciq ui sf female urology | | | | ………… | | kidney transplantation effect of visceral, subcutaneous and retroperitoneal adipose tissue on renal function after living donor nephrectomy: a retrospective analysis of 69 cases murat ferhat ferhatoglu1*, eray atli2, alp gurkan1 purpose: recent studies reported that the presence of metabolic syndrome is closely correlated with impaired kidney function after living donor nephrectomy. since the measurement of body mass index cannot differentiate the amount of body adipose tissue from total body weight, body mass index is not a reliable parameter for determining metabolic syndrome. in the present study, we investigated the correlation between body adipose tissue and kidney function recovery following living donor nephrectomy. materials and methods: the patients who underwent living kidney donor nephrectomy consequently from july 2016 through december 2017 were enrolled in the study. we preoperatively measured the visceral (vadt), retroperitoneal (rpadt), and subcutaneous (scadt) adipose tissue volume by a computed tomography scan. body mass index, adipose tissue measurements, and postoperative estimated glomerular filtration rate (egfr) were evaluated. results: the decrease between preoperative egfr, and the first day, the first month and the sixth month egfr after surgery were statistically significant (p = .001; p = .001; p = .001, respectively). the negative correlation between vadt/scadt measurements and changes in egfr at the first and the sixth postoperative month compared to preoperative egfr were statistically significant (p = .049; p = .041, respectively). additionally, rpadt measurements and changes in egfr at the first and the sixth postoperative month compared to preoperative egfr (decreasing as rpadt value increased) were statistically significant (p = .035; p = .026, respectively). conclusion: according to a preoperative computed tomography scan, vadt, rpadt, and vadt-to-sadt ratio can predict impaired kidney function recovery. furthermore, rpadt measurement is a new variable to predict the impaired kidney function after living donor nephrectomy. keywords: adipose tissue; donor nephrectomy; kidney; metabolic syndrome; retroperitoneal; visceral introduction being a kidney donor increases the risk of renal impairment and the possibility of being a chronic kidney disease patient in the future.(1,2) recent studies showed that the presence of metabolic syndrome is an independent risk factor for the development of chronic kidney disease.(1,3-6) metabolic syndrome has two main components, increased body mass index (bmi) (obesity) and increased blood pressure (hypertension). we think the selection of a living kidney donor is a crucial process. many studies or guidelines have tried to present the best criteria for the selection of the living kidney donors.(7-9) however, none of these studies or guidelines may fully guarantee the safety of the living donor in perioperative or postoperative period. the calculation of bmi gives no idea about the distribution of abdominal adipose tissue or visceral obesity, which have been linked to the risk of microalbuminuria and chronic kidney disease.(1,3,10,11) for this reason, the current living donor selection criteria should be modified. in the present study, we aimed to assess the distribution of abdominal adipose tissue and recovery of kid1department of general surgery, istanbul okan university, faculty of medicine, tuzla istanbul 34759, turkey. 2department of radiodiagnostics, istanbul okan university, faculty of medicine, tuzla istanbul 34759, turkey. *correspondence: department of general surgery, istanbul okan university, faculty of medicine, tuzla istanbul 34959, turkey tel: +905553214793, fax: +902164449863, e-mail: ferhatferhatoglu@yahoo.co.uk received september 2019 & accepted december 2019 ney function after living kidney donor nephrectomy. also, this study may show the importance of preoperative evaluation of adipose tissue potentially may lead to getting better outcomes in living donors after donor nephrectomy procedure. materials and methods selection of donor candidates all of the kidney donor candidates had detailed blood and urine tests and renal computed tomography (ct) angiography. candidates who were found to be healthy were considered as kidney donors. patients with comorbid disease and alcohol and cigarette dependence were not considered as living kidney donor candidates in the institution where the present study was conducted. inclusion criteria: the patients who underwent living kidney donor nephrectomy consequently from july 2016 through december 2017 at istanbul okan university hospital and research center were enrolled in this observational cohort study. exclusion criteria: the patients who had computed tomography angiography at another institution, who did urology journal/vol 17 no. 4/ july-august 2020/ pp. 379-385. [doi: 10.22037/uj.v0i0.5558 ] not want to participate in the study protocol, and who had a follow-up period of less than six months were excluded from the study (figure 1). surgical procedure the same two surgeons performed all surgical procedures by using the video-assisted mini-incision technique, which was described and standardized by choi kh et al.(12) evaluation of the individuals: we evaluated routine blood tests, renal ct angiography for all individuals. after laparoscopic kidney donor nephrectomy, routine blood tests were performed until the patients were discharged. since choi et al. stated that the time when the renal functions were stabilized in kidney donor patients was six months after surgery, we followed our patients for six-months.(13) we calculated their estimated glomerular filtration rate (grf) (calculated by using modification of diet in renal disease formula, gfr (ml/min/1.73 m2) = 175 × (scr)-1.154 × (age)-0.203 × (0.742 if female) × (1.212 if african american))(14) preoperatively, first, and the sixth month of the nephrectomy. body mass index (bmi) was calculated according to the formula: the bodyweight/ height in meters squared. patients with bmi ≥ 30kg/m2 were defined as obese.(15) the body surface area was calculated according to the formula described by mosteller.(16) radiologic evaluation total intraabdominal and subcutaneous (scadt) adipose tissue were measured at the level of the umbilicus using ct axial slice (optima ct 660, general electric medical systems, milwaukee, wisconsin, usa) (figure 2). total intraabdominal adipose tissue was divided into two part including retroperitoneal adipose tissue (rpadt) and visceral adipose tissue (vadt) (total intraabdominal adipose tissue= vadt + rpadt). after the margin of the intraabdominal cavity and subcutaneous soft tissue were delineated on the ct slice, the volumes of total intraabdominal and scadt were calculated by a single radiologist (10-year experienced) using ct software (ge aw 4.7 work station, volume and threshold tools, general electric medical systems, milwaukee, wisconsin, usa). this software electronically defines adipose tissue volume by setting the attenuation values for a region of interest within a range of -50 to -250 hounsfield. rpadt was calculated in the same way margining border of the retroperitoneal area. the vadt was calculated by subtracting the rpadt value from total intraabdominal adipose tissue. ethical approval: all procedures performed in studies involving human participants were following the helsinki declaration and its later amendments or comparable ethical standards. the study protocol was also reviewed and approved by the ethics committee of istanbul okan university, istanbul (no: 104, date: march 13, 2019). all individuals gave written informed consent statistical analysis ncss (number cruncher statistical system) 2007 (kaysville, utah, usa) was used for statistical analysis. descriptive statistical methods (mean, standard deviation, median, frequency, percentage, minimum, maximum) were used to evaluate the study data. the suitability of the quantitative data for normal distribution was tested with the shapiro-wilk test and graphical analysis. the kruskal-wallis test was used for comparison of more than two groups of quantitative variables those were not normally distributed. bonferroni corrected paired evaluations were used for intra-group comparisons of quantitative variables showing normal distribution, repeated measures analysis of variance, and paired comparisons. wilcoxon signed-ranks test was used for intra-group comparisons of quantitative variables that were not normally distributed. spearman correlation analysis was used to evaluate the relationships between quantitative variables (table 1).(17) statistical significance was accepted as p < .05. results twenty-seven caucasian male, thirty-two caucasian kidney transplantation 380 table 1. spearman correlation coefficient interpretation guideline r description of strength 0.00 — 0.19 very weak 0.20 — 0.39 weak 0.40 — 0.59 moderate 0.60 — 0.79 strong 0.80 — 1.00 very strong table 2. patients characteristics and adipose volume measurements age (year) min-max (median) 20-71 (44) mean ± sd 44.09 ± 13.54 gender female 32 (54.2%) male 27 (45.8%) bmi (kg/m2) min-max (median) 18.6-40.23 (28.2) mean ± sd 28.30 ± 4.44 bsa (m2) min-max (median) 1.33-2.28 (1.85) mean ± sd 1.86±0.19 hospitalization time (day) min-max (median) 2-9 (3) mean ± sd 3.61 ± 1.39 scadt (cm3) min-max (median) 4.58-190.03 (35.98) mean ± sd 54.13 ± 47.42 vadt (cm3) min-max (median) 376.89-10368.71 (2923.85) mean ± sd 2846.84 ± 1694.85 rpadt (cm3) min-max (median) 39.49-4690.36 (1028.25) mean ± sd 1200.21 ± 879.44 vadt/scadt min-max (median) 5.79-312.77 (71.41) mean ± sd 84.99 ± 70.13 *bmi: body mass index, bsa: body surface area, scadt: subcutaneous adipose tissue, vadt: visceral adipose tissue, rpadt: retroperitoneal adipose tissue, padt: peritoneal adipose tissue effect of adipose tissue on kidney function after donor nephrectomyferhatoglu et al. female, included to study with a mean age was 44.09 ± 13.54, and follow-up time was six-months. table 2 shows patient characteristics and adipose volume measurements. the relationship between preoperative egfr and the first day, first month and sixth month egfr decrement (23.07 ± 23.2 ml/min/m2, 36.67 ± 14.69 ml/min/m2, 31.71 ± 13.66 ml/min/m2) were statistically significant (p = .001; p = .001; p = .001, respectively; bonferroni test, p <.01) (figure 3). bmi, vadt and scadt measurements had a statistically significant correlation with each other (p = .035, pearson correlation, p <.05). relationship between changes in egfr and adipose tissue measurements was demonstrated on table 3. the negative correlation between vadt/scadt measurements and changes in egfr at the first and the sixth postoperative month compared to preoperative egfr (decreasing as vadt/ scadt value increased) were statistically significant (r = -0.256; p = .049 and r = -0.267; p = .041, respectively). additionally, rpadt measurements and changes in egfr at the first and the sixth postoperative month compared to preoperative egfr (egfr decreases as rpadt value increase) were statistically significant (r = -0.232; p = .035 and r = -0.205; p = .026, respectively). also, there is a positive correlation between changes in egrf at the sixth postoperative month in patients with bmi ≥ 30 kg/m2 (r = 0.275; p = .035). however, no correlation was observed between egfr changes and bmi in patients with bmi < 30 kg/m2. discussion we investigated the accuracy of evaluating the fat composition of the kidney donor to predict delayed kidney function, and find out that rpadt, vadt, and vadtto-scadt ratio are significantly associated with an impaired kidney function of the donor patient. it is well known that metabolic syndrome and its components, obesity, hyperglycemia, and hypertriglyceridemia are closely correlated with impaired kidney function.(18,19) also, many studies demonstrated that the presence of obesity is linked to impaired postoperative kidney function in kidney donors.(1,3,18,19) studies from the usa and sweeden (the framingham offspring effect of adipose tissue on kidney function after donor nephrectomyferhatoglu et al. table 3. evaluation of the relationship between changes in egfr and bmi and adipose tissue preoperative-1st day preoperative-1st month preoperative-6th month donor bmi (kg/m2) ≥ 30 (obese) (n=29) r 0.023 0.038 -0.275 p .860 -775 .035* <30 (non-obese) (n=40) r 0.157 0.023 0.038 p .235 .860 .775 scadt r 0.267 0.034 0.189 p .041* .797 .152 vadt r 0.097 -0.301 -0.428 p .465 .021* .036* rpadt r 0.122 -0.232 -0.205 p .359 .035* .026* vadt/scadt r -0.099 -0.256 -0.467 p .457 .049* .041* d r = spearman’s correlation coefficient *p < 0.05 **p < 0.01 egfr: estimated glomerular filtration rate. bmi: body mass index. scadt: subcutaneous adipose tissue. vadt: visceral adipose tissue. rpadt: retroperitoneal adipose tissue. figure 1. scheme of the present study vol 17 no 04 july-august 2020 381 cohort and the hypertension detection and follow-up program) have revealed that higher bmi is linked with impaired kidney function.(20-22) locke et al. also showed that obesity was independently associated with an increased risk for esrd in living kidney donors.(23) bmi can be easily calculated, and it has been generally used as a reliable anthropometric index of obesity.(24) however, bmi is not a reliable anthropometric measure due to changes in body fluid distribution in patients candidate for kidney transplantation. moreover, generally accepted bmi norms for determining obesity do not reflect the degree of visceral obesity.(25,26) additionally, whether visceral obesity quantitatively measured by vadt, scadt, rpadt, and vadt-to-scadt quotient before the surgery estimate results in living kidney donor have not been well researched. numerous studies prove that vadt has various endocrine, metabolic, and inflammatory roles.(27-30) many hypotheses have been proposed to explain this enigma of vadt and metabolic syndrome. the bloodstream of peritoneal and retroperitoneal fatty tissue differs from each other. one idea is that the veins of peritoneal fatty tissue drain into the portal venous system. this drainage may cause an increase in free fatty acid levels in the liver, which may lead to insulin resistance, high triglyceride concentrations, and low hdl cholesterol concentrations.(31,32) also, naya et al. demonstrated the increased proinflammatory effect of visceral fat accumulation.(26) cornier ma et al. showed the role of elevated free fatty acid levels in the portal system, and the endocrine role of adipokines in metabolic syndrome.(33) we think, vadt analysis (r = -0.428; p = .036, moderate correlation at sixth month egfr change, spearman correlation analysis) might be a more reliable and precise parameter to predict a metabolic syndrome component and the possibility of incoming chronic kidney disease following donor nephrectomy than bmi (r = -0.275; p = .035; weak correlation at sixth month egfr change, spearkidney transplantation 382 figure 2. a. demonstration of scadt, vadt, rpadt*; b. vadt; c. rpadt; d. scadt *scadt: subcutaneous adipose tissue, vadt: visceral adipose tissue, rpadt: retroperitoneal adipose tissue figure 3. estimated glomerular filtration rate in preoperative and postoperative period (calculated by using modification of diet in renal disease formula, gfr (ml/min/1.73 m2) = 175 × (scr)-1.154 × (age)-0.203 × (0.742 if female) × (1.212 if african american)); po d: postoperative day, po m: postoperative month effect of adipose tissue on kidney function after donor nephrectomyferhatoglu et al. man correlation analysis), which is affected by different determinants, including adipose tissue, muscles, bones, body water, and other organs. lee et al. showed the importance of visceral and subcutaneous adipose tissue in estimating forthcoming kidney disease in kidney donors.(1) like the study of lee et al., we found a negative correlation between egfr and vadt/scadt ratio (r = -0.467; p = .041; moderate correlation at sixth-month egfr change, spearman correlation analysis). previous studies proved that the vadtto-scadt ratio is an indicator of visceral obesity.(34) several studies demonstrated negative outcomes of elevated vadt-to-scadt ratio.(1,3,35,36) ghigliotti et al. showed the different cytokine synthesis profile of vadt and scadt, and proposed that, although the vadt has more tendency to produce proinflammatory cytokines such as tnf and il-6, scadt has more tendency to produce anti-inflammatory cytokines.(37) we think defining the imbalance between visceral and subcutaneous adipose tissue and the probability of excessive inflammation, which is a known factor for impaired kidney functions, may ease to estimate fort coming delayed kidney function of the donor patient. retroperitoneal fat is similar to peritoneal fat, which is associated with metabolic syndrome, and related to inflammation, hypertension, and obesity.(26) another interesting finding of our study demonstrated that the amount of rpadt was correlated with the decrease in egfr after donor nephrectomy (r = -0,205; p = .026, the weak correlation at sixth-month egfr change, spearman correlation analysis). unlike the visceral venous system, the venous system of the retroperitoneal fatty tissue drains into kidney veins or caval venous systems, which leads to a "fatty kidney" which is associated with hypertension. also, this adipose tissue consists of an increased amount of brown adipose tissue, which has a known interaction with obesity and metabolic syndrome ergo possible cause of delayed kidney function.(38) even it has impressive outcomes, this study should be considered in light of several limitations. first, retrospective, single-institution conducted nature, and the limited number of individuals are the main limitations of the present study. second, the possibility of sampling bias exists in terms of patient inclusion in the study group, because six patients (6%) were excluded from the study protocol, only because they had not undergone preoperative radiological evaluation at another institution. therefore, there was likely to selection bias in the study. we think performing this research in the prospective form with longer follow-up time would improve the reliability and quality of the study. moreover, overlooking the comorbidities may be the third limitation of the present study. however, living kidney donors are not drawn from the general population, and they are healthy at baseline. also, living donors are very carefully screened in preoperative evaluation, and the impact of obesity might be different in these healthier individuals. conclusions evaluation of visceral adiposity before donor nephrectomy procedure closely involved with postoperative impaired kidney function in living kidney donors. to improve outcomes of kidney donor after surgery, it is essential to clarify the enigma between visceral adiposity and kidney functions. also, obesity definition, which is determined only by bmi calculation neglects visceral adiposity. therefore, the diagnostic criteria for obesity, and accordingly, diagnostic criteria for the metabolic syndrome, should be updated to include visceral adiposity. conflict of interest no conflict of interest of financial ties was declared by the authors. references 1. lee hh, kang sk, yoon ye, et al. impact of the ration of visceral to subcutaneous adipose tissue in donor nephrectomy patients. transplant proc. 2017;49:940–3. doi: 10.1016/j.transproceed.2017.03.039 2. muzaale ad, massie ab, wang mc, et al. risk of end-stage renal disease following live kidney donation. jama 2014;311:579–86. doi: 10.1001/jama.2013.285141 3. hori s, miyake m, morizawa y, et al. impact of preoperative abdominal visceral adipose tissue area and nutritional 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lentine kl, vella j. evaluation of the living kidney donor candidate. in brennan dj (ed.) uptodate. retrieved august 1, 2019, from https://www.uptodate.com/contents/ evaluation of-the-living-kidney-donorcandidate 10. bae s, massie ab, luo x, et al. changes in discard rate after the introduction of the kidney donor profile index (kdpi). am j transplant. 2016;16:2202–7. doi: 10.1111/ ajt.13769 11. masajtis-zagajewska a, muras k, nowicki m. effects of a structured physical activity effect of adipose tissue on kidney function after donor nephrectomyferhatoglu et al. vol 17 no 04 july-august 2020 383 program on habitual physical activity and body composition in patients with chronic kidney disease and in kidney transplant recipients. exp clin transplant. 2019;17:155– 64. doi: 10.6002/ect.2017.0305 12. choi kh, yang sc, lee sr, et al. standardized videoassisted retroperitoneal minilaparotomy surgery for 615 living donor nephrectomies. transpl int 2011;24:973–83. doi: 10.1111/j.1432-2277.2011.01295.x 13. choi kh, yang sc, joo dj, et al. clinical assessment of renal function stabilization after living donor nephrectomy. transplant proc. 2012;44:2906–9. doi: 10.1016/j. transproceed.2012.05.086 14. u.s. department of health and human services, national institute of diabetes and digestive and kidney diseases. https:// www.niddk.nih.gov/health-information/ communication-programs/nkdep/laboratorye v a l u a t i o n / g l o m e r u l a r f i l t r a t i o n r a t e / estimating#the-mdrd-equation 15. mocarski m, tian y, smolarz gb, mcana j, crawford a. use of international classification of diseases, ninth revision codes for obesity: trends in the united states from an electronic health record-derived database. popul health manag. 2018;21:22230. doi: 10.1089/pop.2017.0092 16. mosteller rd. simplified calculation of bodysurface area. n engl j med. 1987;317:1098. 17. evans, jd. straightforward statistics for the behavioral sciences. pacific grove, ca: brooks/cole publishing; 1996. 18. ohashi y, thomas g, nurko s, et al. association of metabolic syndrome with kidney function and histology in living kidney donors. am j transplant. 2013;13:2342–51. doi: 10.1111/ajt.12369 19. yoon ye, choi kh, lee ks, et al. impact of metabolic syndrome on postdonation renal function in living kidney donors. transplant proc. 2015;47:290–4. doi: 10.1016/j. transproceed.2014.10.051 20. ejerblad e, fored cm, lindblad p, et al. obesity and risk for chronic renal failure. j am soc nephrol. 2006;17:1695–702. 21. fox cs, larson mg, leip ep, et al. predictors of new-onset kidney disease in a communitybased population. jama. 2004;291:844–50. 22. kramer h, luke a, bidani a, et al. obesity and prevalent and incident ckd: the hypertension detection and follow-up program. am j kidney dis. 2005;46:587–94. 23. locke je, reed rd, massie a, et al. (2017). obesity increases the risk of end-stage renal disease among living kidney donors. kidney international. 2017;91:699–703. doi:10.1016/j.kint.2016.10.014 24. ersoz f, erbil y, sari s, et al. predictive value of retroperitoneal fat area measurement for detecting metabolic syndrome in patients undergoing adrenalectomy. world j surg. 2011;35:986–94. doi: 10.1007/s00268-0111012-z 25. kim s, cho b, lee h, et al. distribution of abdominal visceral and subcutaneous adipose tissue and metabolic syndrome in a korean population. diabetes care 2011;34:504–6. doi: 10.2337/dc10-1364 26. hung cs, lee jk, yang cy, et al. measurement of visceral fat: should we include retroperitoneal fat. plos one 2014;9:112355. doi: 10.1371/journal. pone.0112355 27. cejkova s, kubatova h, thieme f, et al. the effect of cytokines produced by human adipose tissue on monocyte adhesion to the endothelium. cell adh migr. 2019;13:293– 302. doi:10.1080/19336918.2019.1644856 28. jurrissen tj, grunewald zi, woodford ml, et al. overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise. am j physiol endocrinol metab. 2019 jul 16. doi: 10.1152/ajpendo.00178.2019 [epub ahead of print] 29. eder p, adler m, dobrowolska a, kamhiehmilz j, witowski j. the role of adipose tissue in the pathogenesis and therapeutic outcomes of inflammatory bowel disease. cells. 2019;8:628. doi: 10.3390/cells8060628 30. naya y, zenbutsu s, araki k, et al. influence of visceral obesity on oncologic outcome in patients with renal cell carcinoma. urol int 2010;85:30–6. doi: 10.1159/000318988 31. yoshii h, lam tk, gupta n, et al. effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux. am j physiol endocrinol metab. 2006;290:1089– 97. doi: 10.1152/ajpendo.00306.2005 32. kabir m, catalano kj, ananthnarayan s, et al. molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance. am j physiol endocrinol metab. 2005;288:454–61. doi: 10.1152/ajpendo.00203.2004 33. cornier ma, despres jp, davis n, et al. assessing adiposity: a scientific statement from the american heart association. circulation 2011;124:1996–2019. doi: 10.1161/cir.0b013e318233bc6a 34. hamaguchi y, kaido t, okumura s, et al. impact of skeletal muscle mass index, intramuscular adipose tissue content, and visceral to subcutaneous adipose tissue area ratio on early mortality of living donor liver transplantation. transplantation. 2017;101:565–74. doi: 10.1097/ tp.0000000000001587 35. schlecht i, fischer b, behrens g, leitzmann mf. relations of visceral and abdominal kidney transplantation 384 effect of adipose tissue on kidney function after donor nephrectomyferhatoglu et al. subcutaneous adipose tissue, body mass index, and waist circumference to serum concentrations of parameters of chronic inflammation. obes facts. 2016;9:144–57. doi: 10.1159/000443691 36. delgado c, chertow gm, kaysen ga, et al. associations of body mass index and body fat with markers of inflammation and nutrition among patients receiving hemodialysis. am j kidney dis. 2017;70:817–25. doi: 10.1053/j.ajkd.2017.06.028 37. ghigliotti g, barisione c, garibaldi s, et al. adipose tissue immune response: novel triggers and consequences for chronic inflammatory conditions. inflammation. 2014;37:1337–53. doi: 10.1007/s10753-0149914-1 38. villarroya f, cereijo r, gavalda-navarro a, villarroya j, giralt m. inflammation of brown/ beige adipose tissues in obesity and metabolic disease. j int med. 2018;284: 492–504. doi: 10.1111/joim.12803 effect of adipose tissue on kidney function after donor nephrectomyferhatoglu et al. vol 17 no 04 july-august 2020 385 v08_no_3_final.pdf case report 239urology journal vol 8 no 3 summer 2011 prostatic carcinoma shrunk after intraprostatic injection of botulinum toxin konstantinos vezdrevanis urol j. 2011;8:239-41. www.uj.unrc.ir keywords: prostatic neoplasm, botulinum toxins, injections, adenocarcinoma, disease progression university of ioannina, greece corresponding author: konstantinos vezdrevanis, md 23 kyprou st., gr-46100, igoumenitsa, greece tel: +30 266 502 9090 fax: +30 266 502 9091 e-mail: kvezdrevanis@yahoo.com received september 2009 accepted october 2009 introduction i present a patient with metastatic prostate cancer (pca), who had an intraprostatic injection of botulinum toxin in order to relieve his prostatic obstruction. one month later, the ultrasonographic appearance of the primary prostatic tumor was improved dramatically. case report a 68-year-old man presented with metastatic pca three years earlier with initial serum level of prostate-specific antigen (psa) 521 ng/ml, gleason score 4 + 4 = 8, and extensive bone disease. he underwent castration-refractory one year after the primary diagnosis and he was till recently progressing slowly under castration plus dexamethasone and lanreotide. i performed a transperineal intraprostatic injection of botulinum toxin type a (bt-a) with a dosage of 1000 units of dysport™/ ipsen diluted in 0.5% adrenaline solution of water for injection, in a single injection directly between the two apparent hypoechoic areas under transrectal ultrasound (trus) guidance, in a total volume of 7 cm3, in order to relieve his ongoing prostatic obstruction. (1-9) in the trus performed just before the bt-a injection, there were apparent two hypoechoic oval areas at the peripheral zone of the left lateral prostatic lobe, reflecting the digital finding of the left lobe hardness, sized 26 ×14 mm and 16 × 9 mm, respectively. the lesions were obviously infiltrating far outside the prostatic capsule (figure 1). twenty-eight days later, the hardness of the left lobe was much lessened; however, the whole gland was found digitally much smaller. transrectal ultrasonography revealed only one hypoechoic area located inside the gland measuring 10 × 8 mm (figure 2). the total prostate volume dropped from figure 1. two hypoechoic oval areas at the peripheral zone of the left lateral prostatic lobe (just before bt-a injection). botulinum toxin in prostate carcinoma—vezdrevanis 240 urology journal vol 8 no 3 summer 2011 48.8 to 34.3 cm3 (30% reduction), ie, much less than the primary tumors’ size reduction. the serum level of psa continued rising from 92 to 131 ng/ml, with an almost stable doubling time of about two months. his serum level of alkaline phosphatase (alp) rose from 77 to 87 units (normal value < 136 units). the stamey mears test was negative for prostatitis or other urinary tract infection. post-void residual urine volume dropped from 122 to 88 cm3 while qmax rose from 5 to 9 ml/min. immediately after bt-a injection, alfuzosin with a dosage of 10 mg/day was discontinued, and the patient received a two-week circle of capecitabine with an average dosage of 1.5 gr/ day (1 gr/m2/day). the initial dosage of 2 gr/day had to be reduced twice during the circle due to neurotoxicity and severe fatigue. finasteride with a dosage of 10 mg/day was added to his treatment. two months after the bt-a treatment, the trus of the prostate revealed no hypoechoic lesion. the serum level of psa decreased to 101 ng/ml, and then alp continued rising, but less quickly, from 87 to 94 ng/ml. in the meantime, the patient received one more circle of capecitabine. four months after the bt-a injection and progressive deterioration of the systemic disease, the patient turned paraplegic, due to pressure to the spinal cord by spinal metastases. he had been irradiated and became better initially, but died thirteen months after the bt-a injection. his death was due to repeated ileus probably due to symphyses caused by the irradiation treatment. no ascites, no bowel or hepatic tumor, and no pulmonary metastasis were seen. he only had a surgical history of cholecystectomy. due to his general condition, he underwent the evaluation of the prostate under trus only once again, five months after the bt-a injection, with absence of hypoechoic lesions and normal digital findings. however, eight months after the bt-a injection and after the progression of the spinal cord involvement, the prostate turned digitally again malignant (psa = 240 ng/ml, alp = 101 units). discussion i do not believe that the shrinking of the primary tumors was due to the action of capecitabine or finasteride, but of course, nobody can deny that their combination may be helpful. possible synergy of castration, dexamethasone, and lanreotide should be taken into account as well. to the best of our knowledge, this is the first reported bt-a injection in a patient with the pca. since long ago, there was evidence of possible action of bt-a against pca, including the presence of muscarinic, specifically m3, receptors in lncap cells(10) and in natural human prostatic carcinomas.(11) recently, it was reported that bt-a inhibits the growth of lncap cells in vitro and in vivo, as xenografts in nude mice. (12) my findings of the primary prostate tumors being clinically dissolved after local bt-a injection and being effective for at least 5 months (no more than 8 months), with the proviso of a heavy cancerous burden and a very aggressive cancer, supports the former preclinical data and should be investigated further. unfortunately, ideal candidates to study the clear effect of bt-a injection on the local prostate cancer are only patients with well-documented local disease, suitable for watchful waiting, with prostatic obstruction refractory to medical treatment, and unwilling to undergo transurethral resection of the prostate; and these patients are not so many. maybe a clinical trial of the patients with the prostate cancer having local irradiation with two types of bt-a and non-bt-a injection could help as well. figure 2. transrectal ultrasonography shows only one hypoechoic area located inside the gland (one month after bt-a injection). botulinum toxin in prostate carcinoma—vezdrevanis 241urology journal vol 8 no 3 summer 2011 conflict of interest none declared. references 1. maria g, brisinda g, civello im, bentivoglio ar, sganga g, albanese a. relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebocontrolled study. urology. 2003;62:259-64; discussion 64-5. 2. kuo hc. prostate botulinum a toxin injection--an alternative treatment for benign prostatic obstruction in poor surgical candidates. urology. 2005;65:670-4. 3. chuang yc, tu ch, huang cc, et al. intraprostatic injection of botulinum toxin type-a relieves bladder outlet obstruction in human and induces prostate apoptosis in dogs. bmc urol. 2006;6:12. 4. chuang yc, chiang ph, yoshimura n, de miguel f, chancellor mb. sustained beneficial effects of intraprostatic botulinum toxin type a on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia. bju int. 2006;98:1033-7; discussion 337. 5. silva j, silva c, saraiva l, et al. intraprostatic botulinum toxin type a injection in patients unfit for surgery presenting with refractory urinary retention and benign prostatic enlargement. effect on prostate volume and micturition resumption. eur urol. 2008;53:153-9. 6. brisinda g, cadeddu f, vanella s, mazzeo p, marniga g, maria g. relief by botulinum toxin of lower urinary tract symptoms owing to benign prostatic hyperplasia: early and long-term results. urology. 2009;73:90-4. 7. brawer mk, loeb s, partin aw, et al. best of the 2009 aua annual meeting: highlights from the 2009 annual meeting of the american urological association, april 25-30, 2009, chicago, il. rev urol. 2009;11:82-107. 8. roehrborn cg, crawford ed, donnell r, et al. the utility of ultrasound derived prostate parameters in predicting clinical response in men treated with botulinum neurotoxin type a (bont-a) for benign prostatic hyperplasia (bph). j urol. 2009;181:650-. 9. crawford ed, donnell r, hirst k, mist study group. 12 week results of a phase ii trial of 100 and 300 units of botulinum neurotoxin type a for the management of benign prostatic hyperplasia (bph). j urol suppl. 2009;181:649–50. 10. rayford w, noble mj, austenfeld ma, weigel j, mebust wk, shah gv. muscarinic cholinergic receptors promote growth of human prostate cancer cells. prostate. 1997;30:160-6. 11. song w, yuan m, zhao s. variation of m3 muscarinic receptor expression in different prostate tissues and its significance. saudi med j. 2009;30:1010-6. 12. karsenty g, rocha j, chevalier s, et al. botulinum toxin type a inhibits the growth of lncap human prostate cancer cells in vitro and in vivo. prostate. 2009;69:1143-50. 1331vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l multiple surgeries due to pneumaturia, cystolithiasis and neurogenic bladder in a case with munchausen syndrome necmettin penbegul,1 yasar bozkurt,1 kadir yildirim,1 ahmet ali sancaktutar,1 haluk soylemez,1 murat atar,1 yasin bez2 keywords: urinary bladder fistula; pathology; urinary bladder calculi; munchausen syndrome; complications. introduction pneumaturia is the passage of gas in the urine, and it usually suggests a fistula between the urinary tract and the bowel. this occurs most commonly in the bladder or urethra, but it may also be seen in the urethra or renal pelvis.(1) the most common causes are carcinoma of the sigmoid colon, diverticulitis, regional enteritis (crohn’s disease), and trauma. (2) congenital anomalies account for most urethroenteric fistulas. certain bacteria, by the process of fermentation, may liberate gas on rare occasions. rarely, however, do patients with diabetes mellitus have gas-forming infections.(1) munchausen syndrome (mhs) is a chronic psychiatric disorder in which patients consciously simulate or self-inflict symptoms of an illness in repeated attempts to gain hospital admission. patients suffering from mhs successfully obtain repeated invasive diagnostic management by the permanent presentation of various symptoms, especially in the surgical branches of medicine. in urology, the “hemorrhagic type,” the “abdominal type,” and the “neurological type” are predominant.(3) in this study, we report a 16-year-old female who presented with pneumaturia and who had undergone multiple surgeries for these symptoms, which were consciously generated by the patient. hint points until the diagnosis of mhs in this patient are discussed. case report a 16-year-old female was admitted to our urology clinic and had suffered pneumaturia for two days prior to her admission. her recent medical history revealed the swallowing of a hooked needle 10 days before her admission that was defecated out with her stool. she had also suffered gross hematuria for the previous two days that resolved spontaneously. the patient had corresponding author: necmettin penbegul, md department of urology, dicle university school of medicine 21280, diyarbakir, turkey. tel: +90 412 248 8001 fax: +90 412 248 8440 e-mail: penbegul@yahoo.com received december 2011 accepted march 2012 1 department of urology, dicle university, faculty of medicine, diyarbakır, turkey. 2 department of psychiatry, dicle university, faculty of medicine, diyarbakır, turkey. case report 1332 | case report an operation of right percutaneous nephrolithotomy (pnl) two years ago because of a right renal stone. afterwards, for unknown reasons, she developed a glob vesicle. then urodynamic evaluation was performed with the preliminary diagnosis of neurogenic bladder. but obviously there was not any evidence consistent with neurogenic bladder. patient’s complaint (glob vesicle) continued and consequently she was advised to use clean intermittent catheterization. she had used this catheterization for the previous year, during which the catheter broke three times in her bladder. a cystoscopy and the removal of the catheter were performed under local anesthesia. during her physical examination, only mild abdominal distension was observed. then, a transurethral catheter was applied. five minutes after its application, the urine bag became distended (figure 1). none of the laboratory tests, intravenous pyelography, abdominopelvic computed tomography scan, pelvic magnetic resonance imaging, retrograde urethrocystography, or urethrocystoscopy revealed any morphological or functional abnormalities. after extensive laboratory analyses, the only abnormality found was on ultrasonography scan, which suggested grade 1 hydronephrosis of the right renal collecting system due to a previous surgery. however, the cause of pneumaturia was not clearly identified. then, she was consulted about general surgery. a colonoscopy could not be administered because of the patient’s incongruity. then, she underwent a diagnostic laparotomy that showed no evidence of fistula tract. a per operative urologic evaluation showed a clear urinary tract. after the operation, figure 1.distended urine bag after applying a transurethral catheter. figure 3. bladder calculus in the plain radiograph. figure 2. distended urine bag after the nephrostomy catheter was pulled out and fixed under the dermis. 1333vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l pneumaturia in a case with munchausen’s syndrome | penbegul et al the patient was followed up in our clinic about 10 days. however, her pneumaturia had continued with the additional symptom of post-operative right flank pain. a right nephrostomy catheter was applied to the patient because of her right hydronephrosis. two days after the nephrostomy catheter application, free air started to fill the nephrostomy catheter. diagnostic ureterorenoscopy was applied and no pathology was observed. at this stage, suspicions were raised regarding the possible factitious nature of her problem. the nephrostomy catheter was pulled out and fixed under the dermis. with this procedure, the treating physicians wanted the patient to think that the catheter was in her kidney. in this way, they could observe any air in her catheter, which, in fact, was located under her dermis. when free air was still observed in the catheter (figure 2), the clinicians concluded that the patient might have a psychiatric disorder. after a detailed psychiatric examination and observations, the patient was diagnosed with mhs. then, we learned that she spent a long time unsupervised in the toilet where was puffing up her urine bag. after her psychiatric treatment, she recovered from her pneumaturia and neurogenic bladder symptoms. however, six months later, this same patient applied to our clinic complaining of difficulty in micturition. the ultrasonography showed one 8 mm piece of bladder calculus (figure 3). this piece was removed during a cystoscopy. it was observed that the shapes of the bladder calculus were well-rounded so it could not be a real calculus. for this reason and her previous mhs diagnosis, the patient was again referred to the psychiatry clinic. discussion to our knowledge, this is the first case in the literature of a patient admitted with pneumaturia due to mhs, a rare disorder in which patient presents with factitious disorders and a self-destructive urge to undergo invasive procedures. this syndrome should be kept in mind, especially for the patients who repeatedly undergo surgeries. these patients can also put a large strain on the urologists’ time and may cause increased costs for the healthcare system due to their selfgenerated symptoms.(4) reich and colleagues describe patients who present with renal colic and an intravenous contrast allergy and have an increased probability of a factitious disorder. in their article, 10 of 12 patients (83%) were men and most of the patients were likely to leave against medical advice.(4) so these patients usually left one hospital and went to another hospital. however, recent case reports showed that most of these factitious patients are female and most of them averaged above 25 years of age. all of these patients underwent extensive investigations, and some of them underwent invasive procedures, such as a kidney biopsy, a ureteroscopy, a nephroscopy, multiple blood transfusions, and a nephrectomy.(5-11) mhs patients are usually admitted to a urology clinic by complaining of recurrent renal colic, recurrent urinary tract infections, hematuria, or bladder lithiasis. these patients are usually likable and extremely convincing. possible diagnoses should be ruled out with extensive tests and invasive interventions and then the real diagnosis, namely mhs, can be reached at the end of the procedures. our patient was clearly suffering from pneumaturia and initially we did not suspect factitious pneumaturia. however, we eventually concluded that she had a factitious disorder (mhs), which clinicians should keep in their mind when the symptoms are recurrent and unexplainable with well-known medical examinations and investigations. conclusion mhs is a rare chronic psychiatric disorder that can be seen in urology practice, but patients consciously simulate or selfinflicted symptoms of illnesses in repeated attempts to gain hospital admission. psychiatric help is usually rejected, and treatment is frequently unsuccessful. urologists should be aware of these patients and avoid the administration of unnecessary tests that may impose a great burden on the healthcare system. conflict of interest none declared. 1334 | case report references 1. mcaninch jw. symptoms of disorders of the genitourinary tract. in: tanagho ea, mcaninch jw, editors. smith’s general urology. san francisco: the mcgraw hill company; 2008. p. 30-8. 2. weiss rm. urine transport, storage, and emptying. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. philadelphia: saunders elsevier; 2007. p. 81-110. 3. heimbach d, bruhl p. munchhausen's syndrome in urology. int urol nephrol. 1995;27:539-45. 4. reich jd, hanno pm. factitious renal colic. urology. 1997;50:858-62. 5. fukuhara s, kawamura n, kakuta y, imazu t, hara t, yamaguchi s. case of self mutilation of urethra in a munchausen's syndrome patient. hinyokika kiyo. 2007;53:829-31. 6. chettouh-harrache d, amar a, taleb s, bouhacina n, auberthie r. factitious lithiasis: case report from western algeria. sante. 2004;14:257-60. 7. el khader k, el mamoun m, koutani a, ibn attya a, hachimi m, lakrissa a. unusual case of munchausen's syndrome: factitious vesical lithiasis. acta urol belg. 1998; 66:33-5. 8. cai t, pazzagli a, gavazzi a, bartoletti r. recurrent renal colic in young people: abdominal munchausen syndrome-a diagnosis not to forget. arch ital urol androl. 2008;80:39-41. 9. chew bh, pace kt, honey rj. munchausen syndrome presenting as gross hematuria in two women. urology. 2002;59:601. 10. schmidt f, strutz f, quellhorst e, muller ga. nephrectomy and solitary kidney biopsy in a patient with munchausen's syndrome. nephrol dial transplant. 1996;11:890-2. 11. ifudu o, kolasinski sl, friedman ea. brief report: kidney-related munchausen's syndrome. n engl j med. 1992;327:388-9. v08_no_2_final.pdf sexual dysfunction and infertility 127urology journal vol 8 no 2 spring 2011 general health and quality of life in patients with sexual dysfunctions mohammad reza naeinian, mohammad reza shaeiri, fahimeh sadat hosseini purpose: to study the general health and quality of life in patients with sexual dysfunctions. materials and methods: one hundred and thirty-seven patients with diagnosis of a known sexual dysfunction (sd) were studied. a healthy group of 111 individuals matched for sex, education, and marital status were also selected as a control group. both groups completed two rquestionnaires: general health questionnaire-28 (ghq-28) and personal wellbeing index– adult (pwi-a). to analyze data, descriptive methods as well as student t test for independent groups were used. results: the mean scores for individuals suffering from sd were more than the control group in total ghq scale and all its subscales. the mean scores in total pwi-a scale and most of its subscales for individuals suffering from sd were lower than the control group. since the obtained t values (4.16 to 5.22) for all the comparisons done between the mean scores in ghq for the two groups were higher than t value in the ‘t table’ for df = 206 at = 0.01 (2.58), differences obtained were significant. since obtained t values (-2.03 to 4.65) for total quality of life and health, achievements, personal relationship, safety, and feeling part of community dimensions were higher than t value in the ‘t table’ for df = 206 at = 0.05 and = 0.01 (1.96 and 2.58, respectively), differences obtained except for standard of living and future security were significant. conclusion: somatic, social, and mental measures for people having sexual dysfunctions (patient group) were lower than the control group. urol j. 2011;8:127-31. www.uj.unrc.ir keywords: quality of life, sexual dysfunctions, health status, health surveys department of psychology, faculty of arts and humanity, shahed university, tehran, iran corresponding author: mohammad reza naeinian, phd department of psychology, faculty of arts and humanity, shahed university, khalij-e-fars high way, tehran, iran tel: + 98 912 770 2588 fax: + 98 21 5121 2418 e-mail: mnainian@yahoo.com received may 2010 accepted october 2010 introduction sexual problems are common in most of the populations and depending on cultural norms‚ they surface intermittently in the family practice setting.(1) sexual dysfunction (sd) is an issue of growing interest. in a populationbased study in iran, of 2626 women interviewed, 31.5% (759) reported sd. the prevalence increased with age from 26% in women aged between 20 and 39 years to 39% in those >50 years (tested for trend p < .001).(2) in another populationbased study in iran, to explore the prevalence of and risk factors for erectile dysfunction (ed), a total of 2674 men aged between 20 and 70 years were interviewed.(3) of the men interviewed, 18.8% (460) reported ed. the prevalence increased with age, from 6% in men aged between 20 to 39 years to 47% in those >60 years (tested for trend p < .001). research examining the occurrence quality of life and sexual dysfunction—naeinian et al 128 urology journal vol 8 no 2 spring 2011 of sexual problems in nonclinical populations tends to be restricted to highly selected populations,(4) such as healthy women in an outpatient gynecological clinic‚(5) normal married couples‚(6) young married couples with children‚(7) and middle-aged men(8) and women with sexual dysfunction‚(9) with sample size of 38 to 439 subjects. a review of 23 “community samples” reported a frequency of 4% to 10% for difficulty in achieving orgasm in both men and women‚ 4% to 9% for erectile problems in men‚ and 36% to 38% for premature ejaculation in men.(7) similarly, a large-scale international collaboration of multidisciplinary experts reported that 40% to 45% of adult women and 20% to 30% of adult men suffer from at least one form of sd. the following prevalence rates were also reported in women: low levels of sexual interest in 17% to 55%, lubrication difficulties in about 8% to 15%, orgasmic dysfunction in 25%, and vaginismus in approximately 6%. the prevalence of ed was reported to be 1% to 9% in men younger than 40 years, which rapidly increased with age to 20% to 40% in men in the age range of 60 to 69 years.(10) it is difficult to obtain an accurate estimate of the prevalence of sd from the international literature because of the discrepancies existing in definitions and tools used in different studies. only somatic dysfunctions are well-defined‚ while predominantly psychologically conditioned dysfunctions appear under a multiplicity of labels in various investigations. there is clinical evidence that sexual problems have a multifactorial etiology, including organic, social, and psychological components.(11) the impact of certain pathologies, such as depression and diabetes mellitus, on sexual function is wellknown.(12,13) in men, ed is associated with age and is more prevalent in patients suffering from other medical problems.(14) sexual dysfunctions often coexist with other problems‚ such as depression‚ lack of self-esteem‚ unsuccessful relationships‚ or just inadequate sexual experience. nevertheless‚ very little is known about the relationship between sexual problems and the quality of life.(15) materials and methods target populations were all the people referring to family health clinic in tehran, with the complaint of a sexual problem. one hundred and thirty-seven patients without a history of other psychiatric disorders were selected for the study by consecutive sampling. they confirmed experiencing a sd through clinical interview by a psychologist, a psychiatrist, or a urologist on the basis of diagnostic and statistical manual, 4th edition, text revision (dsm-iv-rt). one hundred and eleven normal individuals were selected from general population as a control group matched for sex, education, and marital status without having history of sexual problems, to make comparisons possible. to measure the study outcomes, following instruments were used: 1) clinical interview on the basis of dsm-iv-tr; 2) general health questionnaire-28 (ghq-28) developed originally by goldberg(16) and translated into persian by taqhavi.(17) taqhavi reported good psychometric measures (reliability and validity) for the test in iranian population; 3) personal wellbeing index-adult (pwi-a), developed by cummins,(18) is claimed to measure quality of life for adults. its psychometric properties were confirmed in original articles. naeinian and colleagues found good psychometric reliability and validity for this tool in iranian population.(19) both patient and control groups, who met inclusion criteria for the present study, were individually given the above-mentioned tools initially before starting the treatment. results the patient group consisted of 95 (69.30%) men and 42 (30.70%) women, with the mean age of 49.01(± 12.62) years, while in the control group, 75 (67%) of the participants were men and 36 (32.40%) were women, with the mean age of 40.86 (± 12.92) years. single and married participants in the patient group were 14 (10.20%) and 123 (89.80%), and in the control group were 9 (8.10%) and 102 (91.90%), respectively. frequency distribution and percentages of common sexual problems among respondents quality of life and sexual dysfunction—naeinian et al 129urology journal vol 8 no 2 spring 2011 are shown in table 1. results show that the most common sexual problems were rapid ejaculation in men (27%), reduced sexual desire (21.90%) and vaginismus (15.30%) in women, and performance anxiety (6.6%) and premature erection in men (6.6%). descriptive measures, such as mean scores, standard deviations, maximum and minimum scores in ghq-28 for patients and controls are given in table 2. data show that the mean scores for individuals suffering from sd (patient group) were more than the control group in total ghq scale and all its subscales. as table 3 shows, the mean scores in total pwi-a scale and most of its subscales for individuals suffering from sd (patient group) were lower than the control group. on the basis of data depicted in table 4, since obtained t values (4.16 to 5.22) for all the comparisons done between the mean scores for the two groups were higher than t value in the ‘t table’ for df = 206 at = 0.01 (2.58), differences obtained were significant. therefore, general health measures in all studied dimensions were lower in patients suffering from sd in comparison with the control group. according to table 5, since obtained t values (-2.03 to 4.65) for total quality of life and health, achievements, personal relationship, safety, and feeling part of community dimensions were higher than t value in the ‘t table’ for df = 206 at = 0.05 and = 0.01 (1.96 and 2.58, respectively), differences obtained except for standard of living and future security were significant. therefore, total quality of life measure as well as quality of life measure in studied dimensions were lower in patients suffering from sd in comparison with the control group. discussion the most prevalent sexual problems in the studied sample were primary ejaculation, low libido, erection problems, and vaginismus, which were consistent with findings in previous studies.(7,10) it must be mentioned that apart from cultural and geographical factors in different countries, a proportion of general population in each country suffers from sd, of whom only a limited number seek help. results in this study also showed that somatic, social, and psychological measures of people dimensions group statistics mean standard deviation minimum maximum n somatic dimension patient 7.54 4.15 1 19 97 control 5.36 3.42 0 15 111 anxiety and sleepless patient 7.57 4.34 0 20 97 control 5.23 3.54 0 18 111 social dysfunction patient 8.26 2.59 1 19 97 control 6.70 2.55 0 16 111 depression patient 5.04 5.17 0 21 97 control 2.49 3.24 0 18 111 total ghq score patient 28.41 13.65 8 77 97 control 19.78 10.15 1 67 111 table 2. descriptive data in general health dimensions as measured by ghq-28* *ghq-28 indicates general health questionnaire-28. diagnosis frequency percentage (%) masturbation 4 2.90 reduced desire 30 21.90 vaginismus 21 15.30 rapid ejaculation 37 27.00 homosexuality 2 1.50 performance anxiety 9 6.60 pain during intercourse 1 0.70 lack of orgasm 4 2.90 transvestitism 1 0.70 premature erection 9 6.60 lack of pleasure 4 2.90 frigidity 1 0.70 sexual aversion 2 1.50 more than one complaint 11 8.10 unknown 1 0.70 total 137 100.00 table 1. frequency distribution and percentage of sexual problems quality of life and sexual dysfunction—naeinian et al 130 urology journal vol 8 no 2 spring 2011 dimensions group statistics mean difference standard error difference df t p somatic dimension patient 2.18 0.53 206 4.16 .000 control anxiety and sleeplessness patient 2.34 0.55 206 4.28 .000 control social dysfunction patient 1.56 0.36 206 4.38 .000 control depression patient 2.60 0.59 206 4.32 .000 control total ghq* score patient 8.63 1.69 206 5.22 .000 control table 4. comparison between patients and controls’ mean scores in general health dimensions on the basis of student t test for independent groups. *ghq-28 indicates general health questionnaire-28. dimensions group statistics mean difference standard error difference df t p standard of living patient -0.49 0.29 246 -1.70 .09 control health patient -1.42 0.30 246 -4.65 .000 control achievements patient -0.89 0.31 246 -2.96 .003 control personal relationships patient -0.89 0.27 246 -3.32 .001 control safety patient -0.66 0.32 246 -2.03 .04 control feeling part of your community patient -0.66 0.30 246 -2.16 .03 control future security patient -0.17 0.34 246 -0.51 .61 control total qol score patient -5.18 1.64 246 -3.16 .002 control *qol indicates quality of life. table 5. comparison between patients and controls’ mean scores in qol dimensions on the basis of student t test for independent groups* dimensions group statistics mean standard deviation minimum maximum n standard of living patient 6 2.13 0 10 137 control 4.49 2.42 0 10 111 health patient 5.98 2.46 0 10 137 control 7.40 2.29 0 10 111 achievements patient 5.93 2.15 0 10 137 control 6.82 2.60 0 10 111 personal relationships patient 6.60 2.17 0 10 137 control 7.49 1.99 1 10 111 safety patient 6.65 2.57 0 10 137 control 7.31 2.48 0 10 111 feeling part of your community patient 6.19 2.38 0 10 137 control 6.85 2.36 0 10 111 future security patient 5.85 2.42 0 10 137 control 6.02 2.93 0 10 111 total qol score patient 43.19 12.69 0 69 137 control 48.37 13.02 3 70 111 table 3. descriptive data in qol dimensions as measured by pwi-a* *qol indicates quality of life; and pwi-a, personal wellbeing index-adult. quality of life and sexual dysfunction—naeinian et al 131urology journal vol 8 no 2 spring 2011 having sd were lower in comparison with general population. depressive symptoms have been reported in individuals with sd in earlier studies.(15) findings in the present study while confirm such previous results, also suggest that adverse effects of sexual problems go more beyond depression. this study also showed that quality of life for people having sd was lower than the control group. this finding is in accordance with the results observed in other countries.(15,20) conclusion we concluded that low general health and quality of life in people with sexual dysfunction cannot be attributed to sexual problems. conflict of interest none declared. references 1. shahar e, lederer j, herz mj. the use of a selfreport questionnaire to assess the frequency of sexual dysfunction in family practice clinics. fam pract. 1991;8:206-12. 2. safarinejad mr. female sexual dysfunction in a population-based study in iran: prevalence and associated risk factors. int j impot res. 2006;18: 382-95. 3. safarinejad mr. prevalence and risk factors for erectile dysfunction in a population-based study in iran. int j impot res. 2003;15:246-52. 4. fog e, køster a, larsen gk, garde og inge lunde k. female sexuality in various danish general population age-cohorts. nordisk sexologi. 1994. 5. rosen rc, taylor jf, leiblum sr, bachmann ga. prevalence of sexual dysfunction in women: results of a survey study of 329 women in an outpatient gynecological clinic. j sex marital ther. 1993;19: 171-88. 6. frank e, anderson c, rubinstein d. frequency of sexual dysfunction in “normal” couples. n engl j med. 1978;299:111-5. 7. nettelbladt p, uddenberg n. sexual dysfunction and sexual satisfaction in 58 married swedish men. j psychosom res. 1979;23:141-7. 8. solstad k, hertoft p. frequency of sexual problems and sexual dysfunction in middle-aged danish men. arch sex behav. 1993;22:51-8. 9. osborn m, hawton k, gath d. sexual dysfunction among middle aged women in the community. br med j (clin res ed). 1988;296:959-62. 10. lewis rw, fugl-meyer ks, bosch r, et al. epidemiology/risk factors of sexual dysfunction. j sex med. 2004;1:35-9. 11. dunn km, croft pr, hackett gi. association of sexual problems with social, psychological, and physical problems in men and women: a cross sectional population survey. j epidemiol community health. 1999;53:144-8. 12. souetre e, achard f. [impact of therapeutics on sex. value of measurements of quality of life]. therapie. 1993;48:461-4. 13. schiel r, muller ua. prevalence of sexual disorders in a selection-free diabetic population (jevin). diabetes res clin pract. 1999;44:115-21. 14. benet ae, melman a. the epidemiology of erectile dysfunction. urol clin north am. 1995;22:699-709. 15. ventegodt s. sex and the quality of life in denmark. arch sex behav. 1998;27:295-307. 16. goldberg dp. the detection of psychiatric illness by questionnaire. maudsley monograph no 21: london: oxford university press; 1972. 17. taghavi sm. to study reliability and validity for general health questionnaire-28 (ghq-28). j psychol. 2001;5:381-98. 18. cummins ra, eckersley r, lo sk, okerstrom e. australian unity wellbeing index survey 10. australian centre for quality of life, deakin university, melbourne, report. 2004;10. 19. naeinian mr, babapour j, shaeiri mr, rostami r. the effect of neurofeedback training on the decrement of generalized anxiety disorder (gad) symptoms and patients, quality of life. j psychol, university of tabriz. 2009;5:175-202. 20. lau jt, kim jh, tsui hy. prevalence of male and female sexual problems, perceptions related to sex and association with quality of life in a chinese population: a population-based study. int j impot res. 2005;17:494-505. urological oncology incidence, gleason score and ethnicity pattern of prostate cancer in the multi-ethnicity country of iran during 2008-2010 abbas basiri1, babak eshrati1, ali zarehoroki1 shabnam golshan1, nasser shakhssalim1, alireza koshdel1, nastaran khalili1, amir h kashi1* purpose: to investigate the geographical incidence, and grade of prostate cancer in iran during 2008-2010 and evaluate its relationship with ethnicity. materials and methods: data was extracted from the nationwide iranian cancer registry system during 20082010. pathologies and grade was extracted from scanned reports of patients’ pathologies by a urologist. results: the average 3-year age standardized incidence rate of prostate cancer during the study period was 11.52 per 100000 males. the age standardized incidence rates for persian, arab, turkish and turkmen, lor, kurd and baluch ethnicities were 13.5, 9.3, 7.9, 7.9, 7.2 and 2.1 per 100000, respectively. poisson regression analysis revealed a statistically significant difference in incidence of prostate cancer in baluch ethnicity (p = 0.028) and a near significant difference for incidence of prostate cancer in turk-turkmen and kurd ethnicity (p = 0.067 and p = 0.082) in comparison with persian ethnicity. the median gleason score distribution of prostate cancer was not concordant to the age standardized incidence rates. 97% of all pathologies were adenocarcinoma of the prostate followed by malignant carcinoma (1.9%), and transitional cell carcinoma (1.1%). conclusion: the incidence of prostate cancer was different between baluch and fars ethnicities in iran. the lowest asr of pca was observed in baluch ethnicity, however the possibility of underreporting due to less access in baluch ethnicity cannot be ruled out. the gleason distribution pattern was not concordant to the incidence distribution of prostate cancer. keywords: epidemiology; iran; prostate cancer; gleason score; incidence introduction prostate cancer (pca) is the second most common cancer in the world(1) and in iran has been reported as the second most common cancer among men. epidemiologic studies have revealed that the incidence of pca is different in different ethnicities and/or races.(2) the incidence of pca is lower in iran and asia relative to europe and the united states.(3) iran is a large country in the middle east hosting more than 80/000/000 people. the location of iran in the past had been pivotal for transfer from east to west as part of the silk road. this strategic location had rendered this country a place for conquering in the past. iran has been occupied by greeks, arabs, mongols and turks over the past two millennia. as a result, the ethnical distribution of iran includes azeri (turkish and turkmen) ethnicity in the north west who have close ethnical relationship with turks of turkey and central asia, arabs in south west who have close ethnical relationship with arabs of the persian gulf, kurds in west with close ethnical relationship with kurds of iraq and turkey, baluchs in south east with close ethnical relationship with baluchs of pakistan, and persian ethnicity in north and central parts which constitutes the major predominant ethnicity in iran (figure 1).(4) few reports have previously evaluated the association urology and nephrology research center (unrc), shahid beheshti university of medical sciences (sbmu), tehran, iran. *correspondence: urology and nephrology research center (unrc), shahid beheshti university of medical sciences (sbmu), tehran, iran. tel: +98-22594204; email: ahkashi@gmail.com received september 2019 & accepted may 2020 of ethnicity with pca incidence;(5) however these comparisons were not flawless due to different quality of reporting systems and modernization between the middle east and central asian countries. the comparison of the incidence of pca in iran with ethnicity has not been reported before. neither the nationwide grade of cancer has been reported earlier. in this study, we report the 3-year incidence of pca and its gleason score in iran from 2008-2010 and investigate the relation of this incidence with ethnicity and geography. materials and methods data was gathered from the iranian cancer registry regarding all incident cases of pca from 2008-2010 including data regarding the residence location of patients. scanned reports of pathologies were investigated by experienced personal and urology residents to extract pathologic specifications of cancers including gleason score. the iranian cancer registry is an office in the ministry of health and medical education and collects all data of pathologic specimens from pathology laboratories, outpatient clinics and treatment centers. data were checked to remove duplicate cases. in order to adjust the incidence estimates by age (age standardized rates or asrs), we directly standardized urology journal/vol 17 no. 5/ november-december 2020/ pp. 602-606. [doi: 10.22037/uj.v0i0.5618] the crude incidences of pca by the standard who suggested population. for each province of iran, we estimated asr based on its population. the population of each year of each province was estimated based on 2011 and 2006 consensuses by geometric method. we estimated the population of each province for each age group of males separately. we used the following equation for population estimation of each year: pt = p0 (1+ r)t these estimates provided the denominators necessary for asr estimates. for each year we estimated asrs separately then we estimated the weighted average of the three years of 2008-2010 based on the total male population of each year. in order to assess the clustering of prostate incidence in the country, we estimated moran i index and its related p value. we considered p values less than 0.05 as statistically significant. the statistical package for social sciences (spss version 25), excel (2016) and arcgis (10.2) was used for statistical and spatial analysis of data. results according the results of the cancer registration data in 3 years of 2008-2010 the average asr of prostatic cancer in iran was 11.52 per 100000 males (95% confidence interval: 11.12-11.93 per 100000 males). figure 2 represents the average 3-year asr of pca in iran based on different provinces. dark colors of map represent higher average 3-year asrs. as illustrated, the highest asr is observed in the capital province of tehran illustrated by dark red. after tehran, high asrs are observed in central provinces of the country (mostly of persian ethnicity) and the lowest asr is estimated from a province located near pakistan border which is the sistan & balouchestan province hosting baluch ethnicity. the differences between the asrs of pca in different provinces is statistically significant (p < 0.05 corrected for multiple comparisons). the ethnicity map of iran including the settlement of different ethnicities (kurdish, turkish and turkmen, persian, arabs, and baluchs) has been depicted in figure 1. the asr, of pca in the aforementioned ethnicities in iran were 13.5 for persians, 9.3 for arabs, 7.9 for turks and turkmen, 7.9 for lors, 7.2 for kurds and 2.1 for baluchs.(figure 3) considering the persian ethnicity which is the major dominant ethnicity in iran as the reference category, the difference is pca incidence for the baluch ethnicity was statistically significant relative to persian ethnicity (p = 0.028) and also a trend to statistically significance was observed between incidence rates of pca in turk&turkmen and kurd ethnicities relative to the persian ethnicity (table 1). figure 3 represents the median gleason score of pca in different provinces. gleason score was not available in the iranian cancer registry and was manually extracted from scanned reports of patients’ pathologies. gleason score data was available only for 11% of the total population of patients. interestingly, the pattern of median gleason score distribution does not conform to the pattern of pca incidence. the pathologies of pca included: adenocarcinoma 96.6%, malignant carcinoma 1.9 %, transitional cell carcinoma 1.1%, sarcoma 0.1%, lymphoma 0.1%, and other categories 0.2%, based on icd-o (3rd edition) classification. the 3-year incidence of pca based on age groups have been presented in figure 4. no significant clustering of pca asr was detected according to the spatial analysis (p-value > 0.05). discussion the findings of this study represent a higher incidence of pca in the capital and more industrialised states in iran during 2008-2010. furthermore, the incidence of prostate cancer was higher in persian ethnicity, moderate in turkish, lors, kurdish, arab ethnicities, and lowest in baluchs (p-value for baluch versus persian ethnicity: p = 0.028) to our best knowledge, this is the first study to provide the relationship of pca incidence with ethnicity in the middle east/central asian ethnicities within a single country. the incidence of pca has been lower in asian and african countries in comparison with europe and the us.(3) the asr of prostate cancer has been reported 174 in 2007 and after a substantial decrease consequent to the recommendation of the united states preventive services task force against psa screening was still at 114 in 2012.(6,7) the incidence of prostate cancer in europe was estimated 96 in 2012.(8) in the globocan report, the lowest worldwide rate of regional prostate cancer asr was for south-central asia with an asr of 4.1 and the highest for australia/new zealand with an asr of 104 in 2008 illustrating wide worldwide differences in pca incidence.(9) in the 2010 globocan report, the world asr of prostate cancer has increased form 27.9 of the 2008 report to 31.1 in 2012.(8) iran has been included in the central-south asia with an average asr of 4.5 in the 2012 report consisting the lowest regional reported asr of pca in the world. the average regional asr of pca for western asian countries which includes western neighboring countries of iran (turkey, azerbaijan, armanestan, iraq, kuwait, and saudi arabia) was 28 in this report highlighting a great regional difference. a steady increase in the incidence has been reported in many developing countries in the past decades.(10-12) recent studies in the us however present a recent decrease in the incidence of prostate cancer in the past decade after recommendations against psa screening as described earlier.(6) prostate cancer and ethnicity-basiri et al. table 1. poisson regression comparing the incidence rate of prostate cancer in different ethnic groups (persian ethnicity was considered as the comparison group) ethnicity irr 95% confidence interval p-value kurd 0.69 0.46 1.05 0.082 turk&turkmen 0.72 0.51 1.02 0.067 arab 0.87 0.52 1.44 0.584 lor 0.87 0.57 1.33 0.534 baluch 0.22 0.06 0.85 0.028 constant 9.73 8.23 11.50 urological oncology 603 vol 17 no 06 november-december 2020 604 the incidence of pca in iran has been constantly increasing: the average asr of pca was reported 5.1 during 1996-2000,(1) which increased to 5.4 in 2003 and 12.6 in 2009 (12) which represents more than 100% increase during a decade. the reasons for such in dramatic increase has been attributed to better reporting systems, modernized diet, and lifestyle, and more frequent use of psa screening.(12,13) the gleason distribution of pca depicted in figure 3 favors the theory of better reporting systems as still in less developed provinces with the lowest incidence of pca, high mean gleason scores were observed which implies under-reporting or less access to health facilities in these areas. limited previous publications from iran have reported the incidence of pca in different provinces and all such publications have reported the incidence of pca in a limited number of provinces or have focused on the age distribution of incident pca without analyzing the geographical distribution of pca in iran. the importance of such investigation lies in ethnical diversities in iran that as depicted in figure 1 which enables the investigation of the influence of ethnicity of pca incidence adjusted for development and reporting system quality. moore and colleagues reported the geographical distribution of pca in central asia.(5) despite marked observed differences in the incidence of pca, they concluded that a crude comparison of asr is not flawless regarding the quality of cancer registries and different levels of modfigure 1. ethnical distribution within iran. figure 2. the 3-year average asr of prostate cancer in different provinces of iran during 2008 – 2010. figure 3. the average 3-year asr of prostate cancer in different ethnicities within iran. figure 4. distribution of prostate cancer gleason score within iran. prostate cancer and ethnicity-basiri et al. ernization within these countries. in the current study, we compared asrs of pca in different ethnicities within one country with a single cancer registry system and with less diversity in modernization within its states. the lowest observed asr was in baluch ethnicity who settle in a southeast province of iran and have close ethnical origins with baluchs of pakistan. this observation becomes interesting when we note that the incidence of kidney and bladder cancer in baluch ethnicity is one of the lowest asrs in iran (data in press). the asr incidence of pca in pakistan during 1998-2002 was reported 10.1 by bhurgri et al.(14) nevertheless, one of the reasons which may underlie such an observation can be the access level of different regions to health facilities as people in remote provinces may have less access to health facilities. we could not find studies focusing on the access level of different provinces within iran to diagnostic and surgical facilities regarding cancer, however, one recent study in iran aiming to study access inequality in cardiovascular services failed to reveal statistically significant differences in the provision of ccu beds in different regions of iran(15). the average 3-year asr of pca in decreasing order were observed in persian ethnicity, then in arab ethnicity, then in lor and turk ethnicity, then in kord ethnicity, and at last the lowest asr was observed in baluch ethnicity respectively. in contrast, the statistics presented by moore et al. revealed a higher incidence of pca in turkey, azerbaijan, and armanestan (mainly including turk&turkmen ethnicity) relative to iran.(5) the primary objective of this research was to investigate whether there are any differences in pca incidence across iranian ethnicities which are located in different geographical locations within iran. the reason for the observed differences was beyond the scope of the current study. one can attribute the observed differences to differences in geographical climate, dietary patterns, and quality of life within investigated ethnicities. contemporary studies on quality of life and food security of iranian provinces during the study period fail to reveal mapping of pca incidence with quality of life or food security within iranian provinces.(16,17) the next noticeable observation is the pattern of median gleason score distribution in this study. to our best knowledge, no prior nationwide study has investigated gleason score of pca in iran. figure 3 illustrates that the lowest median gleason score was observed in kerman province which is one of the provinces with relatively high asr of pca. the political map of gleason score reveals that the median gleason score in most iranian provinces in 7. isolated provinces with a median gleason score of 6 include kohkiluye and buyerahmad, gazvin, qom, golestan, gilan, and ardebil. provinces with a median gleason score of 8-9 (highest median gleason score) were mazandaran, zanjan, and east azerbayejan. as indicated previously there is no obvious concordance between asr of pca in reported provinces and median gleason score of cancers in these provinces. around 97% of all pathologies were adenocarcinoma of the prostate. this observation has also been reported from other neighboring countries as more than 90% of pathologies in studies from saudi arabia and pakistan were adenocarcinoma.(18,19) the trend of adenocarcinoma relative frequency with time was reported negative in iran (decreasing relative frequency of adenocarcinoma type relative to all pca frequencies each year) by pakzad et al.(13) during 2003-2008. in the current study, a statistically significant decrease was observed from 97.0% in 2008 and 97.6 in 2009 to 95.5% in 2010. in considering the results of the current study the following limitations should be taken into consideration: the data of the current study is based on the iranian cancer registry system during the years 2008-2010. any weakness in the iranian cancer registry system including inequality of access to health care across different provinces can affect the results and conclusions of this study. also, the grade of cancer according to icd-0 is different from the commonly used gleason score used in prostate cancer. we manually extracted the gleason score from scanned copies of patients' pathological reports. however, the number of patients with a total gleason score report was only 11% of the total patients population. conclusions in conclusion, the results of this study reveal a higher incidence of pca in iran in modernized provinces in persian ethnicity and lower in baluch ethnicity. the median gleason score pattern is not concordant with the pca incidence pattern and in the states with lowest incidences of pca, a moderate to high median gleason score was observed. the most prevalent pathology was adenocarcinoma in 97% of cases. the age distinction pattern is similar to neighboring countries and different from european countries and the us. conflicts of interest the authors declare no conflict of interest. acknowledgments this study was supported by urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. references 1. sadjadi a, nooraie m, ghorbani a, alimohammadian m, zahedi m-j, darvishmoghadam s, et al. the incidence of prostate cancer in iran: results of a population-based cancer registry. arch iran med. 2007;10:4815. 2. sandblom g, varenhorst e. incidence rate and management of prostate carcinoma. biomed pharmacother. 2001;55:135-43. 3. nakata s, ohtake n, kubota y, imai k, yamanaka h, ito y, et al. incidence of urogenital cancers in gunma prefecture, japan: a 10‐year summary. int j urol. 1998;5:364-9. 4. rashidvash v. iranian people: iranian ethnic groups. int j humanit soc sci. 2013;3:216-26. 5. moore ma, eser s, igisinov n, igisinov s, mohagheghi ma, mousavi-jarrahi a, et al. cancer epidemiology and control in northwestern and central asia past, present and future. asian pac j cancer prev. 2010;11 suppl 2:17-32. 6. herget ka, patel dp, hanson ha, sweeney c, lowrance wt. recent decline in prostate cancer incidence in the united states, by age, stage, and gleason score. cancer med j. prostate cancer and ethnicity-basiri et al. urological oncology 605 2016;5(1):136-41. 7. howlader n. seer cancer statistics review, 1975-2008. http://seer cancer gov/ csr/1975_2008/. 2011. 8. ferlay j, steliarova-foucher e, lortettieulent j, rosso s, coebergh jw, comber h, et al. cancer incidence and mortality patterns in europe: estimates for 40 countries in 2012. eur j cancer : 2013;49:1374-403. 9. center mm, jemal a, lortet-tieulent j, ward e, ferlay j, brawley o, et al. international variation in prostate cancer incidence and mortality rates. eur urol. 2012;61: 1079-92. 10. ahmadi m, ranjbaran h, amiri mm, nozari j, mirzajani mr, azadbakht m, et al. epidemiologic and socioeconomic status of bladder cancer in mazandaran province, northern iran. asian pac j cancer prev. 2012;13:5053-6. 11. akbari me, hosseini sj, rezaee a, hosseini mm, rezaee i, sheikhvatan m. incidence of genitourinary cancers in the islamic republic of iran: a survey in 2005. asian pac j cancer prev. 2008;9:549-52. 12. basiri a, shakhssalim n, jalaly ny, miri hh, partovipour e, panahi mh. difference in the incidences of the most prevalent urologic cancers from 2003 to 2009 in iran. asian pac j cancer prev. 2014;15:1459-63. 13. pakzad r, rafiemanesh h, ghoncheh m, sarmad a, salehiniya h, hosseini s, et al. prostate cancer in iran: trends in incidence and morphological and epidemiological characteristics. asian pac j cancer prev. 2016;17:839-43. 14. bhurgri y, kayani n, pervez s, ahmed r, tahir i, afif m, et al. incidence and trends of prostate cancer in karachi south. asian pac j cancer prev. 2009;10:45-8. 15. meskarpour-amiri m, dopeykar n, ameryoun a, mehrabi tavana a. assessment inequality in access to public cardiovascular health services in iran. medical journal of the islamic republic of iran. 2016;30:420. 16. a bklm. ranking the quality of life in iran provinces. social welfare quarterly. 2010;10(37):95-112. 17. f kfs. national system for monitoring food security and nutrition situation in iran and development of the first map of food security in the country. tehran: department of community nutrition, ministry of health and medical education; 2012. 18. albasri a, el-siddig a, hussainy a, mahrous m, alhosaini aa, alhujaily a. histopathologic characterization of prostate diseases in madinah, saudi arabia. asian pac j cancer prev. 2014;15:4175-9. 19. arshad h, ahmad z. overview of benign and malignant prostatic disease in pakistani patients: a clinical and histopathological perspective. asian pac j cancer prev. 2013;14:3005-10. prostate cancer and ethnicity-basiri et al. vol 17 no 06 november-december 2020 606 v08_no_4_final_new.pdf endourology and stone disease 271urology journal vol 8 no 4 autumn 2011 percutaneous nephrolithotomy complications in 671 consecutive patients a single-center experience seyed habibollah mousavi-bahar,1 sasan mehrabi,1 mohammad kazem moslemi2 purpose: to evaluate major and minor complications of percutaneous nephrolithotomy (pcnl) and their management in our consecutive cases. materials and methods: we reviewed medical records of 671 patients who had undergone pcnl in our center from march 2000 to march 2006. the demographic data, stone parameters, pcnl complications, and stone-free rate were evaluated. multiple parameters were evaluated for their association with pcnl complications using chi-square test. results: complications occurred in 203 (30.3%) patients; renal parenchymal injury in 103 (15.4%), peri-operative bleeding in 42 (6.3%), late bleeding in 6 (0.9%), renal collecting ducts injury in 35 (5.2%), fever in 7 (1.0%), colon perforation in 2 (0.3%), major vessels injury in 3 (0.4%), pneumothorax in 3 (0.4%), and hemothorax in 2 (0.3%) subjects. mortality occurred in 1 patient with colon perforation (0.15%). conclusion: percutaneous nephrolithotomy has low complication rate in experienced hands. urol j. 2011;8:271-6. www.uj.unrc.ir keywords: complications, percutaneous nephrolithotomy, urogenital system, kidney calculi, hemorrhage 1department of urology, shahid beheshti hospital, school of medicine, hamadan university of medical sciences, hamadan, iran 2department of urology, kamkar hospital, school of medicine, qom university of medical sciences, qom, iran corresponding author: mohammad kazem moslemi, md department of urology, kamkar hospital, school of medicine, qom university of medical sciences, qom, iran tel: +98 912 252 1646 fax: +98 251 783 6646 e-mail: mkmoslemi@gmail.com received march 2011 accepted june 2011 introduction percutaneous nephrolithotomy (pcnl) was defined as a surgical treatment for removal of the renal stones in the 1970s.(1,2) today, this procedure should be the first option for the treatment of single large or multiple renal stones and those in the inferior calyx.(3) percutaneous stone removal was suggested as the first line treatment option for the management of staghorn calculi by the american urological association nephrolithiasis clinical guidelines panel.(4) furthermore, pcnl has been advised for the treatment of large, hard, or infected stones, obstructive stones, and extracorporeal shock wave lithotripsy (swl) failure.(5) although percutaneous renal surgery is less invasive than an open procedure, complications may occur. percutaneous nephrolithotomy is a successful, less invasive surgery (> 90%) at the cost of greater complications (> 10%).(6,7) there are some complications that may be predictable or unpredictable, such as hemorrhage, collecting system injuries, contiguous organ injuries, intra-operative technical complications, hypothermia, fluid overload, sepsis, stricture formation, nephrocutaneous fistula, renal loss, and death.(6,8) in this study, we evaluated the incidence and types of complications, with special attention to bleeding and adjacent organ injuries. pcnl complications—mousavi-bahar et al 272 urology journal vol 8 no 4 autumn 2011 materials and methods in this study, the data from all the patients who had undergone pcnl in ekbatan hospital in hamadan, iran, between 2000 and 2006, were reviewed retrospectively. the ethics committee of hamadan university of medical sciences approved the study. serum levels of electrolytes, creatinine, and hemoglobin were recorded and intravenous urography data were evaluated. a single endourologist had performed all of the pcnls. the necessary data were collected from the patients’ medical records and analyzed with spss software (the statistical package for the social sciences, version 16.0, spss inc, chicago, illinois, usa) using chi-square test. p values less than .05 were considered statistically significant. technique of pcnl single-stage pcnl was performed in all the patients as the standard procedure. the kidney was punctured under fluoroscopy guidance as standard. depending on the existence of hydronephrosis, the working tract was dilated using alken dilators or one-shot technique.(9,10) nephroscopy was done with rigid nephroscope. pneumatic/ultrasonic devices (swiss lithoclast master, ems, nyon, sz) were used for lithotripsy using a standard nephroscope (26 f). for removal of stone fragments, suction irrigation device and/or grasping forceps were used. stone fragments were retrieved with 3-pronged grasping forceps. fluoroscopy and contrast nephrography were done to evaluate the stone-free status at the end of the operation. the number and type of access depended on the size of the treated stones (staghorn stone versus single pelvic stone) and localization (upper or lower pole). postoperative care at the end of the procedure, a 22 or 24 f foley catheter was used as a nephrostomy tube. an antegrade nephrography was carried out 24 to 48 hours after the procedure. the tube was removed if no extravasation or retained calculi were present. on the first postoperative day, all the patients had complete blood count postoperative kidneys, ureters, and bladder (kub) x-ray was routinely done in all the subjects. symptoms and kubs were used to evaluate the complications and stone remnants, respectively. results the study consisted of 671 patients, including 417 (62.0%) men and 254 (38.0%) women, with the mean age of 40.7 years (range, 1 to 87 years). the mean duration of the operation was 45 minutes (range, 35 to 125 minutes) and the mean postoperative hospital stay was 36 hours (range, 1 to 3 days). the right and left kidneys were affected in 370 (55.0%) and 301 (45.0%) patients, respectively. there was no pcnl for the solitary kidneys, kidney anomalies, chronic renal failure, or synchronous bilateral stones. no open conversion occurred in the patients. complications occurred in 203 (30.3%) patients; peri-operative bleeding in 42 (6.3%), late bleeding in 6 (0.9%), fever with no signs of urosepsis in 7 (1.0%), renal collecting ducts injury in 35 (5.2%), renal parenchymal injury in 103 (15.4%), colon perforation in 2 (0.3%), major vessels injury in 3 (0.4%), pneumothorax in 3 (0.4%), and hemothorax in 2 (0.3%) patients. mortality occurred in 1 patient with colon perforation (0.1%). hemorrhage was considered a major complication when it was severe enough to terminate the operation or caused blurred vision at the time of working and/or blood transfusion was needed. pre-operative and operative characteristics in relation to complications of pcnl are demonstrated in table 1. as table 1 shows, there was no difference in pcnl complications regarding the kidney site (right versus left), severity of hydronephrosis, stone size, history of previous procedures, and the tract number (p = .593, p = .861, p = .938, p = .265, and p = .073, respectively). a significant difference was only reported in pcnl complications regarding stone and tract locations (p = .030 and p = .001). there was no significant association between complications and age (p = .643). complete stone-free rate was reported in 617 pcnl complications—mousavi-bahar et al 273urology journal vol 8 no 4 autumn 2011 (92.0%) patients while in the remaining 54 (8.0%) subjects, it was partial, which denotes presence of stone remnants less than 5 mm or insignificant remnants. re pcnl and swl was needed in 34 (5.0%) and 20 (3.0%) patients, respectively. the failure rate was zero. discussion stone burden is a major factor determining the morbidity of the pcnl.(11) however, it is important to note that having a safe and effective percutaneous access is essential in performing an uneventful and successful pcnl.(12,13) according to the literature, the total complication rate of pcnl was found 83%.(14-19) the complications of pcnl are divided into the major and minor categories. the minor complications include pain (49%), fever (30%), urinary tract infection (11%), and renal colic (4%). the two major complications of pcnl are septicemia (4.1%) and severe hemorrhage requiring blood transfusion (2.7%).(20) although open stone surgery is needed for some specific renal stones,(21) no open conversion occurred in our patients. in a study by lee and colleagues on 500 patients who underwent pcnl, the most common complication was bleeding, with a 12% transfusion rate.(22) renal hemorrhage is the most worrisome and frequent complication of pcnl, which has been often addressed.(23) however, severe bleeding leading to complications, such as hypovolemic shock or renal failure, may occur in less than 3% of patients.(24-26) severe hemorrhage may occur at the time of needle passage, dilation of the tract, or during nephrostomy creation.(19,27,28) the two key factors determining the transfusion rate are large stone burden and use of multiple access tracts.(11) in our study, the incidence was 0.6%, much smaller than previously reported studies.(29,30) although a blood transfusion rate of 5% to 18% was reported in the literature,(14-19,23,24,31,32) our intra-operative transfusion rate was zero and postoperative transfusion rate occurred in 4 (0.6%) patients. in the study by turna and associates on 193 pcnls, the transfusion rate was reported as high as 23.8%.(6) the probability of vascular lesions increases when the nephrostomy tract passes close to the renal hilus or goes directly posteriorly to it. the high pressure system of a lacerated artery will leak into the lower pressure system of a vein or parenchyma leading to arteriovenous fistula or pseudoaneurysm formation, respectively. doing the initial puncture with bull’s-eye technique or creation of a postero-lateral puncture may decrease the chance of injury.(23,29,33) our puncture procedure was with the bull’s-eye technique. excessive bleeding during pcnl can be managed by some maneuvers, like placement of a larger nephrostomy tube, nephrostomy tube clamping, hydration, and balloon tamponade. the bleeding is mainly venous in origin and is controllable with above maneuvers.(34) in our study, only 1 (0.15%) patient needed angiographic embolization of the bleeding renal artery, two weeks after pcnl. whereas kessaris and colleagues reported 0.8% of their subjects needed angioembolization due to intractable bleeding.(29) most of our intraoperative bleeding was controlled conservatively. occurrence of vascular lesions depends mainly on the total number of punctures. it would be variable complication p stone location, n (%) .030 upper calyx, n = 68 (10.13%) n = 19 (28.0%) middle calyx, n = 11 (1.6%) n = 5 (45.5%) lower calyx, n = 93 (13.8%) n = 32 (34.4%) pelvic, n = 499 (74.4%) n = 147 (29.5%) stone size (cm), n (%) .938 < 2, n = 118 (17.6%) n = 33 (28.0%) > 2, n = 404 (60.0%) n = 125 (31.0%) staghorn stone, n = 149 (22.2%) n = 45 (30.0%) hydronephrosis severity, n (%) .861 mild, n = 439 (65.4%) n = 127 (29.0%) moderate, n = 212 (31.6%) n = 72 (34.0%) severe, n = 20 (3.0%) n = 4 (20.0%) history of open stone surgery, n (%) .265yes, n = 25 (3.7%) n = 6 (24.0%) no, n = 646 (96.3%) n = 197 (30.5%) tract number, n (%) .073one, n = 590 (88.0%) n = 177 (30.0%) two, n = 81 (12.0%) n = 26 (32.0%) tract location, n (%) .001supracostal, n = 199 (29.6%) n = 64 (32.2%) infracostal, n = 472 (70.4%) n = 139 (29.5%) table 1. significant pre-operative and operative characteristics in relation to complications in percutaneous nephrolithotomy. pcnl complications—mousavi-bahar et al 274 urology journal vol 8 no 4 autumn 2011 logical that with decreasing the total number of punctures, the risk of damage to the renal vasculature would be decreased.(28,29) the rates of major complications were 0.9% to 4.7% for septicemia and 0.6% to 1.4% for renal hemorrhage needing intervention.(14-19,23,24,31,32,35-40) the total rates of access-related pleural and colonic complications were 2.3% to 3.1% and 0.2% to 0.8%, respectively. the risk of injury to the pleura and lung increases (10%) if the puncture is above the 12th rib.(10) if puncture is through the pleura, a chest tube has to be inserted for prevention of hydrothorax or hemothorax. rate of pleural injury in our study was 0.7% (5 subjects, 2 hemothorax and 3 hydrothorax), which only occurred with the supracostal access and were all controlled with chest tube insertion. several risk factors contribute to the colonic injury during pcnl, such as left-sided procedure, an extremely lateral percutaneous nephrostomy tract, horseshoe kidney, advanced patient’s age, distended colon, an associated colon obstruction, a hypermobile kidney, a retrorenal colon, and extreme thin patients.(11,38) perforation of the colon can be seen in less than 1% of subjects.(40) furthermore, the urologist should be very careful if the patient has had a history of gastrointestinal surgery, which increases the potential risk of the duodenal or colon injury.(38) after reviewing a series of 200 patients on abdominal computed tomography (ct) scan, the rate of posterolaterally or retrorenally positioned colon has been reported in 1% of the general population.(41) however, the low incidence of this complication does not justify the routine use of ct scan.(11) only a selected group of patients, including those with ectopic kidney, a retrorenal colon, any form of splenomegaly, and hepatomegaly require ct-guided percutaneous access to perform pcnl.(11,42) in the case of extraperitoneal colon perforation, the gastrointestinal tract must be separated from the urinary system.(10) we had two cases of colon perforation; in the first one, the perforation was diagnosed intra-operatively and was managed with laparotomy and primary repair of the intraperitoneal colon injury. the second patient was a 50-year-old thin woman, in whom pcnl was done for removal of a 2.5-cm left renal pelvic stone. the procedure was successful and she was discharged on the 2nd postoperative day uneventfully. she was readmitted on the 7th postoperative day with peritonitis and laparotomy was done for creation of a colostomy. she died after 3 days with sepsis. septicemia can be seen as a result of infection introduction via the access tract to the kidney or working with the infected stones. following pcnl, fever is significantly higher and more frequent in patients with infected urinary stones than in those with sterile stones.(10,43) therefore, prophylactic antibiotics and drainage of a pyonephrotic kidney is mandatory prior to pcnl.(10) antibiotics can be applied as single-dose or short-course prophylaxis with no significant differences between these two regimes in the occurrence of postoperative infections.(24,44) the total time of procedure and the amount of irrigation fluid are major risk factors for occurrence of postoperative fever.(10,35) it is important to preserve low pressure in the collecting system and keep the duration of surgery to minimum (< 90 minutes).(10) our mean operation time was 45 minutes. perforation of the collecting system is the common reason for fluid extravasation and its systemic absorption.(10) we used an open flow system with normal saline as irrigant. following pcnl and in the case of severe perforation of the collecting system, urine extravasation may occur. postoperative symptoms are flank pain or persistent infection. for the percutaneous drainage of the urinoma and as a temporizing measure of the collecting system injury, nephrostomy catheters or double-j stent insertion may become necessary.(10) we did not have any case of urinoma or persistent urine leakage. in a patient with history of open stone surgery, pcnl is time-consuming and may lead to use of auxiliary procedures, probably due to presence of scar tissue and some anatomic changes in the operated kidney.(45) in our study, there was no difference in complication rate between the patients with open stone surgery and without it, which is compatible with other studies.(45,46) pcnl complications—mousavi-bahar et al 275urology journal vol 8 no 4 autumn 2011 an overview of pcnl complications in the literature and their comparison with our study are demonstrated in table 2. conclusion based on our findings, the pcnl complications 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complications—mousavi-bahar et al 276 urology journal vol 8 no 4 autumn 2011 wave lithotripsy and percutaneous nephrolithotomy. eur urol. 1998;33:396-400. 21. moslemi mk, safari a. a huge left staghorn kidney, a case report of inevitable open surgery: a case report. cases j. 2009;2:8234. 22. lee wj, smith ad, cubelli v, vernace fm. percutaneous nephrolithotomy: analysis of 500 consecutive cases. urol radiol. 1986;8:61-6. 23. srivastava a, singh kj, suri a, et al. vascular complications after percutaneous nephrolithotomy: are there any predictive factors? urology. 2005;66:38-40. 24. gallucci m, fortunato p, schettini m, vincenzoni a. management of hemorrhage after percutaneous renal surgery. j endourol. 1998;12:509-12. 25. carson cc, brown mw, weinerth jl. vascular complications of percutaneous renal surgery. j endourol. 1987;1:181-7. 26. osman m, wendt nordahl g, heger k, michel ms, alken p, knoll t. percutaneous nephrolithotomy with ultrasonography guided renal access: experience from over 300 cases. bju int. 2005;96:875-8. 27. roth ra, beckmann cf. complications of extracorporeal shock-wave lithotripsy and percutaneous nephrolithotomy. urol clin north am. 1988;15:155-66. 28. patterson de, segura jw, leroy aj, benson rc, jr., may g. the etiology and treatment of delayed bleeding following percutaneous lithotripsy. j urol. 1985;133:447-51. 29. kessaris dn, bellman gc, pardalidis np, smith ag. management of hemorrhage after percutaneous renal surgery. j urol. 1995;153:604-8. 30. martin x, murat fj, feitosa lc, et al. severe bleeding after nephrolithotomy: results of hyperselective embolization. eur urol. 2000;37:136-9. 31. patel rd, newland c, rees y. major complications after percutaneous nephrostomy-lessons from a department audit. clin radiol. 2004;59:766-9. 32. preminger gm, assimos dg, lingeman je, nakada sy, pearle ms, wolf js, jr. chapter 1: aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005;173:19912000. 33. sacha k, szewczyk w, bar k. massive haemorrhage presenting as a complication after percutaneous nephrolithotomy (pcnl). int urol nephrol. 1996;28:315-8. 34. galek l, darewicz b, werel t, darewicz j. haemorrhagic complications of percutaneous lithotripsy: original methods of treatment. int urol nephrol. 2000;32:231-3. 35. dogan hs, sahin a, cetinkaya y, akdogan b, ozden e, kendi s. antibiotic prophylaxis in percutaneous nephrolithotomy: prospective study in 81 patients. j endourol. 2002;16:649-53. 36. aron m, yadav r, goel r, et al. multi-tract percutaneous nephrolithotomy for large complete staghorn calculi. urol int. 2005;75:327-32. 37. vorrakitpokatorn p, permtongchuchai k, raksamani eo, phettongkam a. perioperative complications and risk factors of percutaneous nephrolithotomy. j med assoc thai. 2006;89:826-33. 38. el-nahas ar, shokeir aa, el-assmy am, et al. colonic perforation during percutaneous nephrolithotomy: study of risk factors. urology. 2006;67:937-41. 39. gerspach jm, bellman gc, stoller ml, fugelso p. conservative management of colon injury following percutaneous renal surgery. urology. 1997;49:831-6. 40. vallancien g, capdeville r, veillon b, charton m, brisset jm. colonic perforation during percutaneous nephrolithotomy. j urol. 1985;134:1185-7. 41. sherman jl, hopper kd, greene aj, johns tt. the retrorenal colon on computed tomography: a normal variant. j comput assist tomogr. 1985;9:339-41. 42. matlaga br, shah od, zagoria rj, dyer rb, streem sb, assimos dg. computerized tomography guided access for percutaneous nephrostolithotomy. j urol. 2003;170:45-7. 43. takeuchi h, ueda m, nonomura m, et al. [fever attack in percutaneous nephrolithotomy and transurethral ureterolithotripsy]. hinyokika kiyo. 1987;33:1357-63. 44. moslemi mk, movahed sm, heidari a, saghafi h, abedinzadeh m. comparative evaluation of prophylactic single-dose intravenous antibiotic with postoperative antibiotics in elective urologic surgery. ther clin risk manag. 2010;6:551-6. 45. margel d, lifshitz da, kugel v, dorfmann d, lask d, livne pm. percutaneous nephrolithotomy in patients who previously underwent open nephrolithotomy. j endourol. 2005;19:1161-4. 46. sofikerim m, demirci d, gulmez i, karacagil m. does previous open nephrolithotomy affect the outcome of percutaneous nephrolithotomy? j endourol. 2007;21:401-3. 1063vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l 1department of urology, g.hatzikosta general hospital, 450 01, ioannina, greece. nikolaos grivas1, ioannis tsimaris1, aikaterini makatsori1, konstantinos hastazeris1, vasillios kafarakis1 and nikolaos e. stavropoulos1 the effectiveness of otis urethrotomy combined with six weeks urethral dilations until 40 fr in the treatment of bladder outlet obstruction in women: a prospective study corresponding author: grivas nikolaos, md, phd department of urology, g. hatzikosta general hospital, makriyianni avenue 45001, ioannina, perfecture of epirus, greece. tel: +302 651 080 408 fax: +302 651 080 546 e-mail: ngrivas@cc.uoi.gr received june 2012 accepted february 2013 purpose: to evaluate the effectiveness of otis urethrotomy combined with six weekly urethral dilations until 40 french (fr) in the treatment of women with urodynamic diagnosis of bladder outlet obstruction (boo). materials and methods: women diagnosed with lower urinary tract symptoms underwent urodynamic evaluation. severity of symptoms and quality of life were assessed with international prostate symptom score (ipss) and quality of life (qol) questionnaires. bladder outlet obstruction was defined as the presence of two or more of the following: maximum flow rate (qmax) < 12 ml/s, detrusor pressure at maximum flow (pdetqmax) > 50 cmh2o and urethral resistance factor (urf) greater than 0.2. ten out of 25 women diagnosed with boo met the criteria. all women underwent otis urethrotomy to 40 f and six-week urethral dilations until 40 f. after six months all patients underwent free uroflowmetry. moreover post voiding residual (pvr), ipss-qol were recorded. results: six months post-operatively there was a significant improvement in all parameters: ipss = 13.5 vs. 22.5 (p = .001), qol = 3 vs. 5 (p = .001), voided volume = 312 ml vs. 216 ml (p = .055), qmax = 27.5 ml/s vs. 12 ml/s (p = .001), and pvr = 27.5 ml vs. 170 ml (p = .005). five women had close follow up during an average of 82 months. they maintained improved qol (p < .005) and low pvr (p < .002). all other parameters lost their statistical significance. conclusion: the described therapeutical modality seems to improve all clinical and urodynamic parameters in women with evidence of boo not related to detrusor sphincter dyssynergia or obvious functional and anatomical pathology. keywords: urinary bladder neck obstruction; female; urodynamics; quality of life; urination disorders. female urology 1064 | introduction the overall incidence of bladder outlet obstruction (boo) among women presenting with lower urinary tract symptoms (luts) is estimated between 1% and 30%. this great range in incidence could be attributed to the different definitions given for women with boo which mainly refer to patients symptoms, pressure-flow studies,(1,2) imaging results(3) or combination methods.(4) causes of boo in women could be divided into anatomic (pelvic organ prolapse, uterine fibroids, previous stress urinary incontinence surgery, urethral strictures, atrophic vaginitis, urethral diverticula, primary bladder neck obstruction) and functional (detrusor sphincter dyssynergia, dysfunctional voiding, fowler syndrome). literature suggests that treatment of these women could be the anatomical reconstruction of bladder neck, urethral dilations, otis urethrotomy and intermittent selfcatheterizations.(5) aim of this study is to investigate the therapeutic efficacy of otis urethrotomy combined with 6-week urethral dilations until 40 fr in women with urodynamic evidence of boo correlated with coordinated relaxation of the urethral sphincter in emg during voiding while no obvious anatomical or functional obstacle exists. materials and methods this is a prospective study with an enrollment period from october 2001 to october 2006. candidates to enter this study were women with luts due to boo. medical history and voiding diary were recorded, while all patients filled ipss and qol questionnaires. clinical assessment included gynecological and neurological examination. patients with suspected neurological disease were referred for further investigation to a neurologist. all women were submitted to uroflowmetry and pvr measurement. urodynamic study was accomplished according to the instructions of the international continence society.(6) adhesive skin surface electrodes on the perineum were used to record electromyography of the urethral sphincter, while the patient was in the sitting position. the rate of administration of normal saline was 50 ml/min unless voiding diary showed evidence of small bladder capacity or detrusor overactivity appeared during the examination. in the last two cases the filling rate was reduced to 30 ml/min. we used the diagnostic algorithm of massey and abrams(5) to assess boo in women. obstruction was defined as the coexistence of at least two of the following criteria: a) maximum urine flow during pressure-flow study (qmax) < 12 ml/s, b) detrusor pressure at maximum flow (pdetqmax) > 50 cmh2o and c) abrams-griffiths urethral resistance factor (urf) > 0.2. urf is calculated from the equation urf = pdetqmax/ qmax2. the above algorithm helps to avoid overdiagnosis of boo in women.(7) women excluded from the study were those suffering from neurogenic bladder, pelvic organ prolapse, patients with a history of previous dilatations and pelvic or stress incontinence surgery, those with a large increase in intraabdominal pressure during voiding (intraabdominal pressure increase > 20 cmh2o ), patients with detrusor-sphincter dyssynergia or poor relaxation of pelvic floor muscles. those who met the inclusion criteria, i.e. those with boo and coordinated relaxation of the urethral sphincter in electromyography (emg), were submitted to otis urethrotomy and 6-week urethral dilations until 40 fr. the procedure was as follows: under general anesthesia cystoscopy was performed using a 18 fr cystoscopy sheath. subsequently an otis urethrotome was placed in the urethra, while the bladder was filled with 250 ml 0.9% nacl. otis urethrotomy to 40 fr was performed along the 12 hour of the urethra. at the end of the procedure a 18 fr foley catheter was placed. next morning catheter was removed and after hospital discharge all women underwent 6-week urethral dilations until 40 fr. six months after surgery follow up included uroflowmetry, post void residual measurement and ipss and qol questionnaires assessment. data analysis was made with wilcoxon t test and chi-square test. a p value of < .05 was considered statistically significant. results ten women fulfilled the entry criteria of the study. the average age was 65.7 years (54-80 years). during cystoscopy the majority of women (90%) were found to have bladder trabeculae. the cystoscope entry was difficult in three women. no patient was diagnosed with urethral stricture. ipss parameters before and after surgery are shown in table 1. patients had severe preoperatively voiding and storage symptoms, with a median ipss value of 21.5. after otis urethrotomy and 6-week urethral dilations there was statistically signififemale urology 1065vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l cant improvement in total ipss, straining, urgency and urine flow (p = .000; p = .000; p = .004; and p = .000, respectively). table 2 presents preoperatively data along with results at 6 months postoperatively and in august 2011. median preoperative maximum detrusor pressure was 68 cmh2o. all parameters, i.e. urinary flow, post voiding residual, urine volume, ipss score and qol were significantly improved 6 months after surgery (p =.001; p = .005; p = .055; p = .001; and p < .0001, respectively). no woman had stress incontinence post-operatively. in august 2011 only 5 women accepted reevaluation but all of them refused to undergo urodynamic testing. the median post-operative interval period was 82 (55-107) months. data from table 2 show that the improvement of quality of life and pvr are maintained, both at statistically significant levels (p < .005 and p < .002, respectively) compared with preoperative values. discussion bladder outlet obstruction in women is a diagnostic challenge because there is no agreed definition.(8) recently its existence as a clinical entity is increasingly confirmed as shown by the number of articles published concerning diagnostic algorithms(5,7) or cut-off definition points.(9-12) the reproducibility of pressure flow studies seems to be very good in the literature. nomograms have been described to assess a possible obstruction, but some studies show no correlation between the severity of symptoms of boo and results on the main nomogram (nomogram of blaivas).(13) we used the diagnostic algorithm of mossey and abrams for the diagnosis of boo in women presenting with lower urinary tract symptoms.(5) it was considered the best diagnostic method among the models proposed during the entry year of the study, i.e. 2001. the inclusion of more parameters, i.e. qmax, pdetqmax and urf ensured greater diagnostic accuracy. in 2006 akinwala and colleagues(7) compared all the suggested methods of boo diagnosis and concluded that mossey and abrams method probably results in underdiagnosis. in 2000 groutz and colleagues(14) was the first who tried to apply men self-assessment questionnaires in women with symptoms suggesting boo. this study included a group of patients with specific urodynamic characteristics i.e. women who had coordinated urethral sphincter relaxation in emg during voiding and boo with no obvious anatomical or functional obstacle. the results were excellent at 6 months but in the long term only the improvements in qol and pvr were maintained. it is interesting that qmax appeared to be slightly worse in long term. however this result does not limit the efficacy of our method, since pvr and qol are considered to be the most important treatment parameters. the main limitation of this trial was a lack of control group. effectiveness of otis urethrotomy in women | grivas et al table 1. ipss parameters and total ipss score preoperatively and 6 months after surgery. ipss before surgery six months post-operatively p voiding 2 (0–3) 1 (0–2) .132 frequency 3 (1–5) 3 (2–3) .342 intermittency 3 (0–5) 2 (1–3) .095 urgency 4 (2–4) 3 (2–3) .004 weak stream 4 (4–5) 1 (0–2) .000 straining 4 (3–5) 1 (0–2) .000 nocturia total score 3 (1–3) 21.5 (17–28) 2 (1–3) 11 (10–15) .343 .000 key: ipss, international prostate symptom score. table 2. urodynamic and clinical findings preoperatively at 6 months and 82 months post-operatively. preoperatively six months post-operatively 82 (55-107) months post-operatively ipss 21.5 ( 1728) 11 ( 10-15 ), p = .001 22 (18-28), p = .442 qol 5 ( 5-6) 3 (3-4), p < .0001 4, (p < .005) voiding volume, ml 216 ( 157-762) 312 (205-768), p =. 055 315.8 (92-1038 ), p = .124 qmax, ml/s 12 (6-15) 27.5 (11.6-53), p = .001 10.3 ( 6-12.4), p = .645 p detqmax , cmh 2 o 68 (40-87) na na pvr, ml 170 (35-610) 27.5 (0-30), p = .005 42 (15-80) p < .002 urf 0.44 (0.22-0.52) na na key: ipss, international prostate symptom score; qol, quality of life; qmax, maximum flow rate; p detqmax , detrusor pressure at maximum flow rate; pvr, post voiding residual; urf, urethral resistance factor. 1066 | another drawback of this study is that the imaging evaluation didn’t include voiding cystourethrography. we didn’t proceed to this diagnostic method because it would not help to the differential diagnosis. it could only help to determine the exact location of the obstacle which in any case would have the same therapeutic approach. moreover it is well defined that no correlation exists between urethral diameter and urodynamic diagnosis of boo unless it is ≤ 10 fr.(15) no woman needed urethral dilations for the placement of 18 fr cystoscope. otis urethrotomy probably results in: temporary partial paralysis of the external sphincter in patients with detrusor–sphincter dyssynergia,(16) bladder neck or urethral stricture,(17) and urethral denervation due to dilatation.(18) other studies present otis urethrotomy as an empirical treatment because there are no data which record its effectiveness objectively.(19) otis urethrotomy has been applied to treat recurrent bladder infections(20) and urethral syndrome(21) but no therapeutic effectiveness was proved. urethral overdistension to treat symptoms of lower urinary tract in women showed well short term results.(22) conclusions our study showed very good short term results when we combined otis urethrotomy with 6-week urethral dilations. surgery resulted in statistically significant reduction in ipss score, improved qol, increased qmax, reduced post voiding residual and increased voided volume. the improvement in quality of life and residual volume seems to be maintained in long term. acknowledgments this work was attributed to the urology department, g. hatzikosta general hospital, ioannina, greece. conflict of interest none declared. references 1. lemack ge, zimmern pe. pressure flow analysis may aid in identifying woman with outflow obstruction. j urol. 2000;163:1823-8. 2. chassagne s, bernier pa, haab f, roehrborn cg, reish jl, zimmern pe. proposed cutoff values to define bladder outlet obstruction in woman. urology. 1998;51:408-11. 3. nitti vw, tu lm, gitlin j. diagnosing bladder outlet obstruction in woman. j urol. 1999;161:1535-40. 4. grouts a, blaivas jg, chaikin dc. bladder outlet obstruction in woman: definition and characteristics. neurourol urodyn. 2000;19:21320. 5. massay ja, abrams ph. obstructed voiding in the female. br j urol. 1988;61:36-9. 6. 4th international consultation on incontinence, paris: 5-8 july 2008; p. 417-21. 7. akikwala tv, fleischman n, nitti vw. comparison of diagnostic criteria for female bladder outlet obstruction. j urol. 2006;176:209397. 8. griffiths d, hofner k, van mastrigt r. standardization of terminology of lower urinary tract function: pressure-flow studies of voiding, urethral resistance, and urethral obstruction. international continence society subcommittee on standardization of terminology of pressure-flow studies. neurourol urodyn. 1997;16:1-18. 9. chassange s, bernier pa, haab f. proposed cutoff values to define bladder outlet obstruction in women. urology. 1998;51:408-11. 10. lemack ge, zimmern pe. pressure flow analysis may aid in identifying women with outflow obstruction. j urol. 2000;163:18:23-8. 11. defreitas ga, zimmern pe, lemack ge. refining diagnosis of anatomic female bladder outlet obstruction: comparison of pressure flow study parameters in clinically obstructed women with those of normal controls. urology. 2004;64:675-81. 12. nitti vw, tu lm, gitlin j. diagnosing bladder outlet obstruction in women. j urol. 1998;161:1535-40. 13. deffieux x, thubert t, amarenco g. contribution of investigations to the diagnosis of bladder outlet obstruction in women. prog urol. 2012;22:628-35. 14. groutz a, blaivas jg, fait g. the significance of the american urological association symptom index score in the evaluation of women with bladder outlet obstruction. j urol. 2000;163:207-211. 15. tanagho ea, mccurry e. pressure and flow rate as related to lumen caliber and entrance configuration. j urol. 1971;105:583-85. 16. seddon jm, bruce aw. cystourethritis. urology. 1978;11:1-10. 17. smith pj. the management of the urethral syndrome. br j hosp med. 1979;22:578-87. 18. farrar dj. an evaluation of otis urethrotomy in female patients with recurrent urinary tract infections. a review after 6 years. br j urol. 1980;52:68-74. 19. choa rg, abrams ph, pynsent pb, ashken mh. a controlled trial of otis urethrotomy. br j urol. 1983;55:694-7. 20. netto nr, pimenta da silva r. treatment of recurrent cystitis in woman by internal urethrotomy or antimicrobial agents. int urol and nephrol. 1980;12:211-15. 21. choa rg, abrams ph, pynsent pb. a controlled trial of otis urethrotomy. br j urol. 1983;55:694-7. 22. eastwood dm, goldma m, farrar dj. urethral overdilatation in females with lower urinary tract symptoms. j r soc med. 1984;77:63942. female urology v08_no_3_final.pdf pictorial urology 178 urology journal vol 8 no 3 summer 2011 giant vulval filariasis an uncommon problem in endemic region a 40-year-old woman presented with complaint of mass in her genitalia associated with dragging pain and difficulty in coitus and walking for the past five years. on examination, two nontender irreducible well-defined bosselated vulval masses were detected, right and left measuring 45 × 38 cm and 22 × 20 cm in size, respectively. there were multiple nodular swellings on the outer surface of each mass. on laboratory investigation, hemoglobin 11 g/dl, leukocyte count 6400 cells/mm3, and absolute eosinophil count 200 were observed. serum level of anti-filarial ige found significantly raised. pre-operatively, 2-week therapy of diethylcarbamazine was started. excision of both right and left masses weighing 15 and 8 kg, respectively, was done with vulvoplasty. the postoperative period was uneventful. on histopathlogical examination, stratified squamous epithelium with hyperkeratosis was seen. underlying stroma showed dermal fibrosis and collagenization with mixed inflammatory infiltrate suggestive of chronic inflammatory pathology. wuchereria bancrofti commonly affects the lower limb and genitalia than the arms and breasts.(1) however, the genitalia is rarely affected with brugia malayi infection.(2) patients with lymphedema are treated with a combination of limb elevation, compression garment, and compression pump therapy, and surgery, if necessary.(3) surgical treatment helps reduce the weight of the affected organ, minimize inflammatory attacks, improve cosmesis, and reduce the risk of secondary angiosarcoma.(4) sudheer rathi, abhishek jain,* rajesh sharma department of surgery, llrm medical college, meerut, u.p, india *e-mail: jain2k2@yahoo.com references 1. tayel sel s, sharapy ael d, el shazly am, shahat sa, zaalouk t, al sayed my. clinical, parasitological and social studies on wuchereria bancrofti in egypt. j egypt soc parasitol. 2011;41:179-97. 2. bernhard p, makunde rw, magnussen p, lemnge mm. genital manifestations and reproductive health in female residents of a wuchereria bancrofti-endemic area in tanzania. trans r soc trop med hyg. 2000;94:409-12. 3. pipinos ii, baxter tb. the lymphatics. in: townsend cm, beauchamp rd, evers bm, mattox kl, eds. sabiston textbook of surgery. 18 ed. philadelphia: saunders elsevier; 2008:2023-5. 4. miller ta, wyatt le, rudkin gh. staged skin and subcutaneous excision for lymphedema: a favorable report of long-term results. plast reconstr surg. 1998;102:1486-98; discussion 99-501. urol j. 2011;8:178. www.uj.unrc.ir v08_no_4_final_new.pdf case report 333urology journal vol 8 no 4 autumn 2011 hydronephrosis secondary to sliding inguinal hernia containing the ureter walid atef massoud, pascal eschwege, pascal hajj, ayman awad, lahbib aoubid iaaza, joseph chabenne, yacine hammoudi, stéphane droupy, gérard benoit urol j. 2011;8:333-4. www.uj.unrc.ir keywords: hydronephrosis, hernia, ureter, etiology, complications department of urology, chu de bicêtre, le kremlin-bicêtre, france corresponding author: walid atef massoud, md chu de bicêtre, department of urology, 78, rue du général leclerc, 94275 le kremlin, bicêtre, france tel: +33 699 114 939 fax: +33 145 212 047 e-mail: walidmassoud@yahoo.fr received january 2010 accepted april 2010 introduction herniation of the ureter occurs infrequently in a sliding inguinal hernia. significant herniation may cause ureteral obstruction leading to hydronephrosis.(1,2) case report a 62-year-old man presented with the left flank pain. physical examination revealed a left reducible inguinal hernia. ultrasonography showed a mild left ureterohydronephrosis. computed tomography scan demonstrated a loop of the left ureter in the inguinal hernia sac (figures 1 and 2). at operation, a large indirect sliding inguinal hernia was found. the ureter was dissected free of the sac, then reduced, and herniorrhaphy was done. convalescence was uneventful and follow-up ultrasonography showed resolving of the left hydronephrosis. discussion scrotal herniation of the ureter is an extremely rare and often misdiagnosed condition with figure 1. computed tomography scan showing left ureterohydronephrosis and looping of the ureter into the inguinal hernia. hydronephrosis due to hernia—massoud et al 334 urology journal vol 8 no 4 autumn 2011 possible serious surgical complications. it is often determined during inguinal hernias surgery or sometimes fortuitously.(1) most reported cases have occurred in obese men during the 5th and 6th decades of life.(2,3) however, there may be another factor, such as the existence of a redundant ureter, which is located over the spermatic cord.(4) two anatomical variations of ureteral hernia have been reported. almost in 80% of cases, the ureter slides beside the peritoneal sac (paraperitoneal type), which frequently contains other sliding organs, usually the colon. the other is characterized by the absence of a peritoneal sac; the herniated ureter is hidden within the retroperitoneal fat (extraperitoneal type).(2,4) herniation of the ureter may cause ureteral obstruction leading to hydronephrosis. surgeons must be aware of this condition in order to carefully preserve ureteral integrity and avoid ureteral injury during hernia repair. conflict of interest none declared. references 1. ilgan s, ozguven m, emer mo, karacalioglu ao. massive inguinoscrotal herniation of the bladder with ureter: incidental demonstration on bone scan. ann nucl med. 2007;21:371-3. 2. akpinar e, turkbey b, ozcan o, akdogan b, karcaaltincaba m, ozen h. bilateral scrotal extraperitoneal herniation of ureters: computed tomography urographic findings and review of the literature. j comput assist tomogr. 2005;29:790-2. 3. bertolaccini l, giacomelli g, bozzo re, gastaldi l, moroni m. inguino-scrotal hernia of a double district ureter: case report and literature review. hernia. 2005;9:291-3. 4. sanchez as, tebar jc, martin ms, et al. obstructive uropathy secondary to ureteral herniation in a pediatric en bloc renal graft. am j transplant. 2005;5:2074-7. figure 2. 3d abdominal and pelvic computed tomography scan. 1347vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l milroy’s disease associated with scrotal lymphangioma circumscriptum filiz cebeci,1 levent verim,2 nahide onsun,3 adnan somay4 keywords: milroy’s disease; lymphatic abnormalities; pathology; lymphangioma circumscriptum; scrotum; child. introduction milroy’s disease (md) is characterized by peripheral edema of the lower extremities at birth or in early childhood which is due to complete aplasia of dermal lymphat-ics. diagnosis of md can be made easily by imaging the lymphatic channels with radionuclide lymphoscintigraphy or dynamic magnetic resonance lymphangiography. lymphangioma circumscriptum (lc) is also a benign disorder of lymphatic vascular channels and considered to be a circumscribed developmental disease of lymphatic tissues in the dermis which is characterized by lymphatic cisterns in the subcutaneous tissue and communicate with dilated dermal lymphatics. lc is generally localized at any anatomic site of human body but more frequently affect the chest, axillary folds, shoulders, neck, buccal mucosa, proximal limbs and rarely hips, groins, and genital area. the pathognomonic appearance of lc is multiple translucent or hemorrhagic vesicular lesions with clear leakage. association of md with lc is very rare.(1) case report a 13-year-old boy presented with one year history of multiple vesicles with oozing serous fluid on his enlarged scrotum (figure 1). on physical examination; mild lymphedema of the lower limbs were found. there were multiple, translucent and slightly pinkish papules on the skin of scrotum which were 2 mm to 4 mm in size. his parents emphasized that swelling of left lower limb has been present ever since birth, and at first, only dorsal aspect of his left foot was edematous then the edema has been progressed to upside of his left leg (figure 2). biopsy corresponding author: levent verim, md sircasaray sokak yenigun appartmen 4-3, kavacik-beykoz, istanbul, turkey. tel: +90 54 251 14155 fax: +90 21 6465 6057 e-mail: leventverim@hotmail.com 1 department of dermatology, haydarpasa numune training and research hospital, istanbul, turkey. 2 department of urology, haydarpasa numune training and research hospital, istanbul, turkey. 3 department of dermatology, bezmialem university, medical faculty, istanbul, turkey. 4 department of pathology, fatih sultan mehmet training and research hospital, istanbul, turkey. case report 1348 | case report of papular lesions exhibited papillated epidermal hyperplasia secondary to lymphedema and dilated characteristic of lymphangiectasia which was filled with eosinophilic proteineous substance [lc disease] (figure 3). the patient was searched for etiology of edema of lower extremities. the hematological and biochemical parameters of the patient, urinalysis and urological examination were within normal limits. there was no abnormality in abdominal ultrasonography, and venousarterial color doppler ultrasonography of both lower limbs and testicles. but lymphoscintigraphy of lower limbs was confirmed the delaying and extremely impairment of lymphatic flow. so, this patient was diagnosed as md in the light of his medical history and in the evidence of lymphoscintigraphy. at last, we diagnosed that this case was consistent with md associated with lc and we treated the scrotal infection with appropriate antibiotic therapy. scrotal edema was regressed and tenderness was vanished. conservative treatment without surgical approach was preferred because of mild symptoms of the patient. discussion lymphatic vascular insufficiency is a widespread problem in the adult population, but rare in the childhood. the lymphatic vessels mediate immune responses in inflammatory disease, whereas dysfunction of the lymphatic drainage leads to lymphedema and infection. primary lymphedema is a hereditary condition arising from an abnormality of lymphatic development whereas secondary lymphedema is caused by an extrinsic process; e.g. surgery, radiotherapy, trauma or infection like tuberculosis, filariasis and etc. which damages a previously normal lymphatic system. the primary lymphedema is more common than secondary lymphedema, 97% and 3%, respectively in the pediatric age group. the pediatric primary lymphedema usually involves the lower limbs and genitalia, 91.7% and 4.3%, respectively. boys are typically affected at birth, and girls most often present during adolescence.(2) in one study; prevalence of congenital primary lymphedema under twenty-years of age was reported to be 1-15/100000.(3) william milroy was first published a case with hereditary lymphedema in the year 1892.(4) md is characterized by peripheral edema of lower extremities and mostly dorsal aspect of feet at birth or in early childhood which is due to the complete aplasia of dermal lymphatics. md is an inherited autosomal dominant lymphedema caused by mutation in the gene for vascular endothelial growth factor receptor-3 [vegfr-3, also known as fms-related tyrosine kinase 4 (flt4)]. vegfr-3 is necessary for the development and functioning of the initial lymphatic system, but we could not have a chance for genetic molecular investigation neither the patient nor his family.(5,6,7) md is mostly a life-long disease but does not affect longevity. but md is chronic condition with negative effects on physical, social and emotional level.(8) figure 2. edema has been progressed to upside of left leg. figure 1. multiple vesicles with oozing serous fluid on scrotum. 1349vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l milroy’s disease associated wıth scrotal lymphangioma | cebeci et al lymphangiomas are rare and benign proliferations of the lymphatic system. circumscriptum form (or capillary form), cavernous form, and cystic form are the three types of congenital lymphangiomas. lc may be acquired due to injury of lymphatics after inflammations, trauma, infection etc. lc is most common type of lymphangiomas involving skin and subcutaneous tissue. lc is caused by an abnormality of the dermal lymphatics, and lymphedema of skin occurs as a result of lymphostasis. the dilated cutaneous lymphatics are associated with large muscular-coated lymphatic channels deep within the subcutaneous tissue without general lymphatic communication. lc commonly appears at upper part of the body, but rarely in the hips, groins and genital area. lc is characterized by persistent clusters of thin-walled translucent vesicles. these vesicles are varying size, though commonly 2 mm to 4 mm diameter, bright, pinkish hue and usually asymptomatic. but scrotal lc lesions can be bleed into the cysts spontaneously and this hemorrhage causes acute painful swelling of scrotum and mimics acute scrotum of childhood. genital lc sometimes presents as verrucous papules that mimicking warts especially in adult patients, although very rare in childhood. the diagnosis of lc is usually made by means of biopsy. hemangioma, melanoma, lymphangiectasia, lymphangiosarcoma, maculopapular herpetic rash, and carcinoma telengiacteticum all should be thought in the differential diagnosis of lc. treatment of patients with md and lc is primarily directed against the prevention of references 1. makhoul ir, sujoy p, ghanem n, bronsthein m. prenatal diagnosis of milroy's primary congenital lymphedema. prena diagn. 2002;22: 823-6. 2. schookcc, mulliken jb, fishman sj, grant fd, zurakowski f, greene ak. primary lymphedema; clinical features and management in 138 pediatric patients. plast reconstr surg. 2011;127:2419-31. 3. smeltzer dm, stickler gb, shirger a. primary lymphedema in children and adolescents: a follow-up study and review. pediatrics. 1985;76: 206-18. 4. milroy wf. a undescribed variety of hereditary oedema. new york med j. 1892;56:505-8. 5. mellor rh, hubert ce, stanton aw, et al. lymphatic dysfunction, not aplasia, underlies milroy disease. microcirculation. 2010;17:281-96. 6. kitsiou-tzeli s, vrettou c, leze e, makrythanasis p, kanavakis e, willems p. milroy's primary congenital lymphedema in a male infant and review of the literature. in vivo. 2010;24:309-14. 7. brice g, child ah, evans a, et al. milroy disease and the vegfr-3 mutation phenotype. j med genet. 2005;42:98-102. 8. symvoulakis ek, anyfantakis di, lionis c. primary lower limb lymphedema: a focus on its functional, social and emotional impact. int j med sci. 2010;7:353-7. 9. kokcam i. lymphangioma circumscriptum of the penis: a case report. acta dermatovenerol alp panonica adriat. 2007;16:81-2. 10. aksakal b, oztas p, oztas mo. lymphangioma circumscriptum associated with milroy’s disease. ejves extra. 2003;5:26-7. infection. elevation of extremities and elastic bandages application diminish the lymphedema of md. but there is no definitive medication or prevention of md. lc disease is primarily treated with adequate surgical excision of affected region. the co2 laser, electrocautery, cryotherapy and sclerosants can also be effective in lc treatment.(9) here in, we presented a md associated with lc disease as the second child case in current medical literature.(10) md should be kept in mind when lc disease was diagnosed in child’s genital area associated with lymphedema of lower limbs. this case is important for dermatologists, pediatricians, cardiovascular surgeons and urologists because of a thorough diagnosis of the lymphedema and for treating the complications of md and lc. differentiating the mimicking diseases and avoiding the mistreatment as a consequence of misdiagnosis of the lymphedema will be possible in the child patient with the light of this rare case report. conflict of interest none declared. figure 3. pathologic examination demonstrates papillated epidermal hyperplasia and lymphangiectasia which has been filled with eosinophilic proteineous substance. miscellaneous 51urology journal vol 7 no 1 winter 2010 a modified technique of simple suprapubic prostatectomy no bladder drainage and no bladder neck or hemostatic sutures mohammad kazem moslemi, mehdi abedin zadeh introduction: open prostatectomy is the conventional surgical treatment of benign prostatic hyperplasia. the major early complication of this procedure is bleeding. we introduce a technique of prostatectomy in order to prevent significant bleeding, reduce morbidity, and shorten convalescence and hospital stay periods. materials and methods: we enrolled 202 consecutive patients diagnosed with benign prostatic hyperplasia who were candidates for open prostatectomy. the operation was performed by one surgeon within 6 years using a modified technique of simple suprapubic prostatectomy (no bladder drainage and no bladder neck suture). clot retention episodes, hemoglobin decrease, urethral catheterization time, and hospital stay were evaluated postoperatively. the patients were followed up for 1 to 2 years. results: the mean operative time was 18 minutes (range, 14 to 28 minutes) with an estimated mean intra-operative blood loss of 120 ml. the mean hospital stay was 3 days (range, 2 to 4 days). the median urethral catheterization time was 5 days. no intra-operative complication or mortality was noted. return to baseline urinary function and subjective continence at 3 months were 100% and 99%, respectively. only in 1 patient (0.4%), bladder neck contracture was detected 3 months after the operation. conclusion: transurethral prostate resection has been introduced as the surgical treatment of choice in patients with benign prostatic hyperplasia. however, open prostatectomy still has a place. suprapubic prostatectomy with no bladder drainage and no bladder neck suture appeared to be successful in decreasing convalescence and hospitalization times, with no significant complication, major blood loss, or bladder neck contracture. urol j. 2010;7:51-5. www.uj.unrc.ir keywords: prostatic hyperplasia, prostatectomy methods, surgical blood loss, urinary bladder neck obstruction department of urology, kamkar hospital, qom university of medical sciences, qom, iran corresponding author: mohammad kazem moslemi, md urology division, kamkar hospital, qom university of medical sciences, qom, iran tel: +98 251 783 2820 e-mail: moslemi@muq.ac.ir received may 2009 accepted september 2009 introduction clinical benign prostatic hyperplasia (bph) is a highly prevalent disease. by the age of 60 years, nearly 60% of the cohort of the baltimore longitudinal study of aging had some degree of clinical bph.(1) minimally invasive procedures for bladder outlet obstruction secondary to bph have been developed, such as visual laser ablation, transurethral electrovaporization, transurethral needle ablation, transurethral microwave thermotherapy, interstitial laser coagulation, and transurethral incision of the prostate.(2-6) these techniques are associated with low morbidity and short-term catheterization. however, they are usually reserved for men with moderate symptom simple suprapubic prostatectomy—moslemi and abedin zadeh 52 urology journal vol 7 no 1 winter 2010 severity and a small to medium prostate. traditionally, transurethral resection of the prostate (turp) and open prostatectomy are used in patients with acute urinary retention, persistent or recurrent urinary tract infections (utis), severe hemorrhage from the prostate, bladder calculi, high international prostate symptom score (ipss) unresponsive to medical therapy, and renal insufficiency as a result of chronic bladder outlet obstruction. open prostatectomy offers the advantages of a lower re-treatment rate and more complete removal of the prostate adenoma under direct vision, while it avoids the risk of additional hyponatremia (turp syndrome). (7) it can be performed by the retropubic or suprapubic approach. the standard suprapubic approach consists of enucleating the hyperplastic adenoma through an extraperitoneal incision of the anterior bladder wall. finally, a urethral catheter and cystostomy are fixed. however, there is a certain risk of postoperative morbidity associated with this surgical technique, including hemorrhage, clot retention, incontinence, urethral or bladder neck stricture, and uti. (8) in this study, suprapubic prostatectomy was done without cystostomy insertion but with a silicone 3-way foley catheter, which led to decreased hospitalization, cystostomy site leakage, morbidity, and cost. materials and methods patients the study was a single-center trial done at kamkar hospital, qom university of medical sciences, from april 2003 to december 2008. during the study period, 310 consecutive men with symptomatic bph presented to our outpatient urology clinic with significant symptoms of bladder outlet obstruction secondary to bph. twenty-two patients were not good candidates for surgery due to underlying conditions, such as congestive heart failure or ischemic heart disease. the other patients were scheduled for surgery (turp or open prostatectomy) after full cadrdiovascular, coagulation, and routine biochemichal laboratory evaluations. before the evaluation, 276 patients (89.9%) had received some medical therapy of bph, like α-blockers (terazosin, 2 mg/d to 4 mg/d) and/or 5 α-reductase inhibitor (finastride, 5 mg/d). one hundred and two patients (33.3%) complained of diabetes mellitus that were under treatment with oral hypoglycemic agents or insulin therapy. in all of the patients, cystourethroscopy was performed to rule out urethral stricture or bladder malignancy. by means of this procedure and prostate ultrasonography, the patients were selected for turp or open prostatectomy on the basis of their prostate volumes. in rough estimate, if prostate volume was greater than 60 g to70 g, open prostatectomy was selected. digital rectal examination, routine laboratory data, serum level of prostate-specific antigen (psa), and urinary system ultrasonography were performed in all of the patients. if digital rectal examination findings or psa values were abnormal, transrectal prostate biopsy would be performed; 34 patients (11.0%) underwent biopsy, in 2 of whom prostate carcinoma was detected. the remaining 32 patients were scheduled for open prostatectomy. overall, 84 men were scheduled for turp and excluded from the study, and the 202 remaining were scheduled for open prostatectomy. surgical technique after preparation and drape and under spinal anesthesia, 183 patients (90.5%) underwent open prostatectomy with pfannensteil incision and the remaining 19 (9.5%) were operated on through a low midline incision. after incising the lower median abdominal wall, fascia, and muscles, the anterior bladder wall was opened vertically and prostate lobes were enucleated conventionally. the prostate fossa was packed with a gauze sponge for less than 1 minute, and then, a 22-f or 24-f 3-way silicone foley catheter was introduced transurethrally and was fixed. the foley ballon was filled with 40 ml to 60 ml of distilled water. the bladder wall was closed with 0-0 chromic catgut suture. a mild traction was inserted on the foley, and a suprapubic tubular drain was fixed. the abdominal wall layers were repaired subsequently. at the end, normal saline irrigation of the bladder via the 3-way foley catheter was simple suprapubic prostatectomy—moslemi and abedin zadeh 53urology journal vol 7 no 1 winter 2010 begun, and the traction on the catheter was released. the tubular drain was removed 48 hours after the operation. the foley catheter was removed after 5 days. the patients were followed-up for 1 to 2 years. the follow-up protocol was multiple visits as listed below: 3 months, 6 months, and 1 year after the operation, and then yearly. the evaluation during the follow-up period was done by ultrasonography of the kidneys and bladder, and a questionnaire about lower urinary tract symptoms, and in suspected cases urethroscopy for evaluation of urethral situations. results a total of 202 patients underwent open prostatectomy using the modified approach. indications of admission in this group was a high ipss in spite of medical therapy in 106 patients (52.5%) with a mean ipss of 19.5, recurrent acute urinary retention in 35 (17.3%), bladder calculus in 28 (13.8%), recurrent uti in 17 (8.4%), and bilateral hydroureteronephrosis in 16 (8.0%). characteristics of the patients are listed in the table. the mean intra-operative blood loss, estimated by measuring of collected blood in the suction bottle and blood quantity of sponge gauzes, was 120 ml. continuous isotonic saline irrigation performed for the first 24 hours, and thereafter if needed. no foley traction insertion was needed during hospital stay. in 5 patients (2.4%) clot retention episodes were detected 4 to 12 hours after the operation, all of which were treated with forceful irrigation and evacuation of clots. cystoscopic management of continuous bleeding or open reexploration was not needed in any of the cases. the mean duration of hospital stay was 3 days (range, 2 to 4 days). hemoglobin level at discharge was 1.8 g/ dl on average lower than that at admission. complete blood count was checked 6 hours after the surgery, and then daily, in addition to serum creatinine. in 29 patients (14.3%), serum hemoglobin was lower than 10 g/dl during hospital stay, and transfusion of packed cell was done (2 units in 21 and 3 units in 8). the foley catheter was removed on the 5th to 6th day after the operation (median 5 days; range, 5 to 8 days). in 3 patients (1.4%), recatheterization was needed for another 3 to 5 days due to retention or rebleeding. pathology report in all of the patients was in favor of bph, except 6 patients that were found to have incidental prostate adenocarcinoma. in 1 patient, persistent vesicocutaneous fistula was detected 2 weeks after removal of the foley catheter. this patient was recatheterized, and fistula was cured after 2 weeks. postoperative epididymoorchitis was noted in 8 patients (3.9%), 1 to 3 weeks after the operation, all of which were treated by appropriate oral antibiotics. bladder neck contracture was detected in 1 patient (0.4%) after 3 months. retrograde ejaculation occurred in 160 patients (72.9%). the mean residual urine volume decreased from 126 ml pre-operatively to 10 ml 3 months after the operation. significant decrease in the ipss occurred after the operation (the mean ipss decreased from 19.5 to 1.5, after 3 months). of the 202 patients, 174 (86.1%) were visited at the end of the 1st year after the operation and 102 (50.5%) were visited at the 2nd year. no new situations like regrowth of the prostate tissue, urethral stricture, or bladder neck contracture was noted. one death due to urosepsis occurred 3 months after the operation. variable value mean age, y 69.7 (54 to 87) mean body mass index, kg/m2 25.8 (19 to 31) body weight, kg 79.4 (58 to 92) mean enucleated prostate volume 83 (50 to 156) mean intra-operative blood loss, ml 120 (90 to 200) irrigation fluid volume, l 35 to 40 mean hemoglobin, g/dl baseline 13.3 (10.4 to 15.4) at discharge 11.5 (9.3 to 13.5) median hospital stay, d 3 (2 to 4) median follow-up, y 2 (1 to 2) complications unilateral epididymioorchitis 8 (3.9) urethral recatheterization 3 (1.4) bladder neck contracture 1 (0.4) vesicocutaneous fistula 1 (0.4) patients’ characteristics and operation outcomes* *values in parentheses are ranges for continuous variables and percents for dichotomous variables. simple suprapubic prostatectomy—moslemi and abedin zadeh 54 urology journal vol 7 no 1 winter 2010 discussion open prostatectomy (suprapubic or retropubic) and turp are the conventional surgical options for the treatment of bph. open prostatectomy is the treatment of choice for large glands (80 ml to 100 ml), cases associated with complications such as large bladder calculus, or in cases in which resection of the bladder diverticula is indicated.(9) open simple suprapubic prostatectomy is occasionally performed for symptomatic and large-volume bph. similar to the traditional open in the supine position, skin and the underlying layers are opened (low midline or pfannensteil incision). the bladder is opened vertically; an electrocautery is used to create a circular incision in the bladder mucosa distal to the trigone. using a pair of metzenbaum scissors, the plane between the prostatic adenoma and prostatic capsule is developed at the 6 o’clock position. after enucleation of the prostate lobes, a 0-0 chromic suture is used to place 2 figure-of-eight stitches to advance the bladder mucosa into the prostatic fossa at the 5 o’clock and 7 o’clock positions at the prostatovesical junction to ensure control of the main arterial blood supply to the prostate. after introducing a urethral catheter, a malecot suprapubic tube is placed into the dome of the bladder and secured with a chromic stitch.(9) we did not use such previously mentioned methods, and did not face any additional complication. urinary extravasation can also be of concern in the immediate postoperative period; this most likely results from an incomplete closure of the cystostomy site in suprapubic prostatectomy. (9) we did not have such a problem due to the absence of cystostomy tube in our technique. retrograde ejaculation occurs in approximately 80% to 90% of patients following surgery.(9) the rate of this adverse effect was similar in our study. also, approximately 2% to 5% of patients develop a bladder neck contracture 6 to 12 weeks after an open prostatectomy.(10) we had such an adverse effect in only less than 0.5% of our patients. luttwak and coworkers studied the results of open prostatectomy on the 98 men. the mean operative time was 62 minutes, and 56.6% of the patients received 1 to 4 units of packed cell. bladder neck constriction and urethral strictures occurred in 4.1% and 3% of cases, respectively.(11) the rate of our blood transfusion was 14.3%, bladder neck contracture was 0.4%, and no urethral stricture was noted. the total complication rate in tubaro and associates’ study on the 32 patients was 31.3%.(12) this rate in our study was 6.4%. in the study of takle and coworkers on 66 patients,(13) the mean operative time was 88 minutes, blood loss during the operation was 917 ml, 50% of the pateints needed blood transfusion during hospital stay, and 9% needed surgical re-intervention during the first 30 days. the time to removal of the postoperative catheter was 7.2 days and postoperative hospital stay lasted for 8.4 days. whereas, median hospital stay of our patients was 3 days and catheterization time was 5 days. wound infection was the most common complication (35%) following open prostatectomy in kiptoon and colleague’s study.(14) zargooshi reported a transfusion rate of 3.3% in 3000 cases, and the acute myocardial infection rate was 0.5%. (15) long-term complications including bladder neck contraction, urethral stricture, and meatal stenosis, occurred in 5.2% of cases were reported by another team.(16) urethral complications rate of our series was 0.4%. the most common reported nonurologic adverse effects included deep vein thrombosis, pulmonary embolus, myocardial infarction, and a cerebral vascular event. the incidence of any one of these complications is less than 1%. we did not have any of these complications. for reducing bleeding, some other methods are used such as bladder neck hemostasis at 5 o’clock and 7 o’clock positions or using some local vasoconstrictors like ornithine-8 vasopressin. we believe that our method requires further case-control studies and it should be applied in a larger population to be evaluated more comprehensively. conclusion transvesical prostatectomy proved to be successful, with a low rate of complications. its success had a durable effect and a corrective procedure was rarely necessary. our method of cystostomy-free open prostatectomy is a good way of decreasing hospital stay, complications, simple suprapubic prostatectomy—moslemi and abedin zadeh 55urology journal vol 7 no 1 winter 2010 and costs in patients with bph, with faster recovery and much shorter catheterization time. no added risk or complications were detected in our series. this approach can be considered in the list of possible treatment modalities to discuss with patients with an enlarged prostate. conflict of interest none declared. references 1. arrighi hm, metter ej, guess ha, fozzard jl. natural history of benign prostatic hyperplasia and risk of prostatectomy. the baltimore longitudinal study of aging. urology. 1991;38:4-8. 2. cowles rs, 3rd, kabalin jn, childs s, et al. a prospective randomized comparison of transurethral resection to visual laser ablation of the prostate for the treatment of benign prostatic hyperplasia. urology. 1995;46:155-60. 3. engelstein d, livne pm, cohen m, servadio c. type ii ureteral triplication associated with ectopic ureter. urology. 1996;48:786-8. 4. schulman cc, zlotta ar, rasor js, hourriez l, noel jc, edwards sd. transurethral needle ablation (tuna): safety, feasibility, and tolerance of a new office procedure for treatment of benign prostatic hyperplasia. eur urol. 1993;24:415-23. 5. ogden cw, reddy p, johnson h, ramsay jw, carter ss. sham versus transurethral microwave thermotherapy in patients with symptoms of benign prostatic bladder outflow obstruction. lancet. 1993;341:14-7. 6. muschter r, hofstetter a. technique and results of interstitial laser coagulation. world j urol. 1995;13:109-14. 7. mebust wk, holtgrewe hl, cockett at, peters pc. transurethral prostatectomy: immediate and postoperative complications. a cooperative study of 13 participating institutions evaluating 3,885 patients. j urol. 1989;141:243-7. 8. djaladat h, mehrsai a, saraji a, moosavi s, djaladat y, pourmand g. suprapubic prostatectomy with a novel catheter. j urol. 2006;175:2083-6. 9. han m,partin aw. retropubic and suprapubic open prostatectomy. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2850-52. 10. varkarakis i, kyriakakis z, delis a, protogerou v, deliveliotis c. long-term results of open transvesical prostatectomy from a contemporary series of patients. urology. 2004;64:306-10. 11. luttwak z, lask d, abarbanel j, manes a, paz a, mukamel e. transvesical prostatectomy in elderly patients. j urol. 1997;157:2210-1. 12. tubaro a, carter s, hind a, vicentini c, miano l. a prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. j urol. 2001;166:172-6. 13. takle m, hjelle k, beisland c. [transvesical prostatectomy]. tidsskr nor laegeforen. 2007;127:435-7. 14. kiptoon dk, magoha ga, owillah fa. early postoperative outcomes of patients undergoing prostatectomy for benign prostatic hyperplasia at kenyatta national hospital, nairobi. east afr med j. 2007;84:s40-4. 15. zargooshi j. open prostatectomy for benign prostate hyperplasia: short-term outcome in 3000 consecutive patients. prostate cancer prostatic dis. 2007;10: 374-7. 16. varkarakis i, kyriakakis z, delis a, protogerou v, deliveliotis c. long-term results of open transvesical prostatectomy from a contemporary series of patients. urology. 2004;64:306-10. 1494 | brief communication discontinuation of the tyrosine kinase inhibitor sunitinib in patients with metastatic renal cell carcinoma: a case series thomas neuhaus,1 joachim luyken,1 sebastian stier2 corresponding author: thomas neuhaus, md st. vincenz-krankenhaus, auf dem schafsberg, 65549 limburg, germany. tel: +49 6431 2924331 fax: +49 6431 2924346 e-mail: t.neuhaus@st-vincenz.de received october 2012 accepted july 2013 1 st. vincenz-hospital, limburg, germany. 2 private practice for hematology and oncology, brühl, germany. brief communication purpose:tyrosinekinaseinhibitors(tki)playapivotalroleinthemoderntreatmentof patientswithmetastaticrenalcellcarcinoma(mrcc).dependingonthecourseandthe response,thetargetedtherapymaylastforyears.thusthequestionarises,ifasuccessful treatmentleadingtoacompleteresponseoratleastastablediseaseafterapartialremission, maybediscontinued. materials and methods:herewepresent3patientswithmrcctreatedwithsunitinibforat leastoneyear,resultinginapartialresponse,followedbyastablediseaseforseveralyears.in thesepatients,thetreatmentwasinterruptedfordifferentmedicalreasons. results:afteraperiodof20,33and34months,respectively,themetastasesoftherenalcell cancershowednosignsofprogression,neitherclinicallynorincomputedtomographyscans, butthesideeffectsoftkiorthemedicalproblemleadingtotreatmentinterruptionresolved inallpatientswithinafewweeks. conclusion:thediscontinuationofthetreatmentformrccwithtkiseemstobepossible,eveninthosepatientswithapartialresponseonly,butnocompleteremissionhasbeen achievedbefore. keywords:carcinoma,renalcell;kidneyneoplasms;proteinkinaseinhibitors;drugtherapy; treatmentoutcome;antineoplasticagents;neoplasmmetastasis. 1495vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l discontinuation of sunitinib in metastatic rcc | neuhaus et al introduction atthetimeofdiagnosis,20%ofallpatientswithrenalcellcarcinoma(rcc)present inameta-staticstage,resultinginamediansurvivalof16 monthsonlyandafive-yearsurvivalrateoflessthan10%. (1)thispoorprognosiswasmainlycausedbythelowefficacyoftheformertreatmentofchoice,amixtureofinterferonandinterleukin.(2) recentlyithasbeenshownthattheuseofmultitargeted tyrosinekinaseinhibitors(tki)likesunitinibmayleadto asufficienttumorcontrolinpatientswithmetastaticrenal cell carcinoma (mrcc).the pathophysiological base of theirefficacyliesinthevonhippel-lindauhypoxia-induciblefactorandvascularendothelialgrowthfactor(vegf) axisthatplaysacentralroleinthedevelopmentofrcc andwhichmembersworkasthetargetoftki.(3) in detail, sunitinib is an orally administered tki, that influences negatively the receptor families of vegf and plateletderivedgrowthfactor(pdgf)aswellasfms-liketyrosinekinase-3receptor(flt-3)andstemcellfactorreceptor (c-kit).sunitinibshowsrespondratesof40%inpatients withmrcc,anditincreasestheoverallsurvivalratesto morethan2yearsandtheprogressionfreesurvival(pfs) to about one year.(4)althoughincertainpatientssevereside effectslikehypertension,leukopeniaordiarrheamayoccur. (5)sunitinibbecameoneofthestandardmedicationforthe first-linetreatmentofpatientswithmrcc. becauseofitsefficacy,thetumorremissionreachedbysunitinib orothertkimaylastforyears.thusthequestionarises,ifthe medication,forexampleduetoseriousanddisturbingtreatmentassociatedcomplications,butalsobecauseofitshighcosts,can bestopped,atleastincaseofacompleteremission. herewepresent3mrcc-patientswithastablediseaseafterpartialresponseachievedbysunitinib,inwhomtreatmentwasstoppedforcertainreasons.duringafollow-upof 22,34and33months,respectively,nosignsofsignificant tumorgrowthcouldbefoundneitherclinicallynorinthe radiologicalscansperformed;forthisthediscontinuation willbeprolonged.toourknowledgethisisthefirstreport aboutasuccessfulinterruptionoftki-therapyinpatients withpersistingevidenceofmetastases. materials and methods case 1 patient1isa78-year-oldwoman,whounderwentaleft-sidednephrectomyduetoalocalizedrccin1990(thehistory ofthethreepatientspresentedhereissummarizedintable).atthistime,nofiliaeweredescribed.about18years later,inmay2008,amasswasfoundintherightbreast, andsurprisingly,thehistologicalexaminationofthebiopsy revealedthediagnosisofametastasisofthercc.afterwards,acompletestagingwasperformed,andfurthermetastasesinvolvingthepancreasandbothsidesofthelung weredetected.becausethefiliaewereclinicallyinapparent andthepatientpresentedinaverygoodcondition,justthe conductionofcontrols3monthslaterwasrecommended. since herein a tumor progression of approximately 30% wasfoundinseptember2008,wedecidedtostartatreatmentwithsunitinibbyusingtheregulardose(50mg/day, administeredorallyfor4weeks,followedbya2-weekrestingperiod).duetodifferentsideeffectslikemucositis,obstipation,headacheandweaknessthedosagewasreduced to37.5mg/dayforsixcycles.thefirstcontrols,performed after3and6months,revealedpartialresponseseach,while inthefollowingcomputedtomography(ct)scansastable diseasewasfound.inoctober2009,i.e.about13months aftertherapystarted,thepatientdevelopedarterialhypertension,probablyasasideeffectofsunitinib.althoughthe dosesofsunitinibwasreducedagain to25mg/daynow andacombinationofatleast6differentantihypertensive agentswereused,theelevationofbloodpressurepersistedandbecamesymptomatic.thusindecember2009,15 monthsaftertheintakeofsunitinibstarted,wedecidedto stopthis treatment.withinafewweeks, thebloodpressureimprovedandtheantihypertensivemedicationcould bereduced.aboutfourmonthsaftertheuseofsunitinib hadbeenstopped,afirstctscanwasperformedshowing nosignsoftumorgrowth.inaddition,thepatientpointed outtofeelmuchbetteraftertreatmentwithtkiendedand thusweagreedtocontinuetheobservationalprocedure.in anotherctscan,performedafteroneyearwithouttki,the metastasisinthebreastevenbecamesmallerspontaneously.meanwhilethetherapywithsunitinibwasstoppedfor33 1496 | months,however,themetastaseskeptstablewithoutsigns ofprogression(figure,aandd). case 2 patient2isan87-year-oldwomaninaverygoodcondition withabiologicalageofaround70years.in1996sheunderwentleftsidednephrectomy.twelveyearslater,injune 2008,metastasesinbothsidesofthelungandinthesoft tissueoftherightshoulderweredetected.afterconfirming thediagnosisofmrccbytakingabiopsy,thelesionin theareaoftherightshoulderwastreatedforpainreliefby radiotherapytillaugust2008.thereafter,inoctober2008, anotherctscanwasperformed,showingagrowth-rateof thepulmonaryfiliaeofabout20-30%;thusasystemictherapy was initiated by using sunitinib at the regular schedule anddosagesimilartothepatient1.threeweeksaftertreatmentstarted,disturbingsideeffectslikeepistaxis,painin differentjointsandgeneralweaknessappeared,leadingto aninterruptionofthetreatment.within2weeks,thecomplaintsvanishedandthetreatmentcouldbecontinued,but byusingsunitinibinareduceddosageof25mg/day.herewiththetreatmentwastoleratedverywell,andradiologicalcontrolsperformedbyconventionalx-raysofthelung every3months,revealedpartialresponseseach.atlastthe pulmonarylesionsnearlydisappeared.however,fromjuly 2009,thepatientsdevelopedanulcuscrurisduetovenous insufficiency.althoughprofessionalsupportbyavascular surgeon and a nurse specialized in wound care was used, the lesiondidnotimprove;onthecontrary,recurrentsuperinfectionresultedinrepeatingantibiotictherapies.therefore thepatientaskedforabreakofthesunitinibadministration, andthetreatmentwasstoppedaftera15monthsperiodin october2009.thecontrolswerecontinuedevery3to6 months,butevenafter34monthswithouttkinonewfilia appearedandnoprogressionoftheknownmetastaseswas found,thus,stillastablediseaseexists(figure,bande). case 3 inpatient3,a60-year-oldwoman,aleftsidednephrectomy wasperformedinaugust2005.innovember2007thepatientdevelopedagreatmetastasiswithasizeof10.7-6.8 cm,includingtherightpelvisandthesurroundingsofttissue.sinceanoperativeapproachwasnotpossible,radiotherapywasperformedfromdecember2007tofebruary 2008(62gy).actscaninmarch2008showedareduction ofthevascularperfusion,butthesizeofthefiliaremained stable.weperformedactscancheck12weekslater,in whichthetumorpresentedwithlittlesignsofgrowth(1015%)andincreasingvascularperfusion.therefore,werecommendedtostartantineoplastictreatmentwithsunitinib intheregularschedule.however,duetohepaticsideeffects (jaundice,elevationofliverenzymes)thedosagehadtobe reducedstepwiseto25mg/day,usedsinceoctober2008. inamagneticresonancetomographyofthepelvisregion, performedinjanuary2009,thetumorsizewasstable,but themagneticresonanceimaging(mri)conductedduring the following months, showed changing distributions of contrastenhancementweredescribed,andforthisweasfigure. computed tomography scans (a-d) and magnetic resonance imaging (e,f ) show the exemplary course of metastases in three patients suffering from renal cell cancer. the scans at the left side were performed directly before the treatment with a tki was stopped, the scans at the right side 32 (b), 33 (d) and 20 (f ) months later. brief communication 1497vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l sumedthatthemalignanttissuewasstillvital.frommarch 2010thecreatininevalueofthepatientincreasedslowly, butcontinuously.inaddition,inautumn2010,thepatient developedunspecific,butdisturbingsymptomsliketirednessandweakness,occurringwhiletakingsunitinib,and for this the patient asked to stoptki-treatment after 30 monthsindecember2010.again,mriswereperformed regularlythroughoutthefollowing21months,butneither thesizenorthecontrastdistributionwithinthemetastasis alteredthusfar(figure,candf). discussion thedevelopmentoftkisledtoafundamentalchangein treatmentproceduresofpatientswithmrcc,notonlywith regardtothegoodtoleranceoftheseagents,butmainlybecauseoftheirefficacy.whilethemediansurvivalachieved by using cytokines did not exceed 10 months, tki like sunitiniborsorafenibmayatleastdoublethisperiod.(3,6) however,asaresultoftheprolongedsurvival,numerous oftheaffectedpatientsmayneedtotakeatkiforseveral years,andthereforequestionsforexampleconcerningthe safetyorthehighcostsofitslong-termusearise.apossible answer and approach would be the controlled discontinuationoftreatment,butsurprisingly,besideaveryfewreports describingflareupsandrapidangiogenesisonset,whilethe useoftkiwereinterrupted,(7-9)there are only two studies dealing with this subject. the first study that systematically analyzed the outcome ofdiscontinuingtki-treatmentinpatientswithmrccis published by johannsen and colleagues.(10) the authors described36patientswithcompleteremission(cr)orno evidenceofdiseaseaftertherapyformrcc,inwhomthe treatment,mainlyconsistingofsunitinib,wasstopped.afteramediantimeof7months,thecarcinomarecurredin about65%ofthepatients,butabout30%ofthepatients remainedtumor-free.inaddition,albigesandcolleagues(11) describedthefollow-upof36patientswithmrcc,aftera crbyusingatki(againmainlysunitinib)wasachieved. while8ofthemcontinuedtreatment,28patientsstopped takingtki.ofthesepatients61%werestilldiseasefree withamedianfollow-upof8.5months;thispercentageis superiortothatfoundbyjohannsenandcolleagues.(10) bycomparingtheseresultswithourlimiteddata,somedifferencesbecomeobvious.atfirst,thetreatmentperiodin ourpatients took12,15and30monthswithanaverage of19months,whiletheaveragetreatmentdurationofthe patients described in the studies by johannsen and albiges was7.5and12.5months,respectively.(10,11)secondly,the medianfollow-upofthepatientsmentionedinthesestudieswas12and8.5months,respectively,butthesemedians consistedofaverywiderange(3to31monthsand0.3to 39.1months,respectively).inopposite, thecurrentaveragedurationofprogressionfreesurvivalinourpatientsis 28months,howeverthese3patientswerestilldisease-free. discontinuation of sunitinib in metastatic rcc | neuhaus et al table . epidemiological data of the patients presented. variables patient 1 patient 2 patient 3 sex female female female current age (years) 78 87 60 date of first diagnosis 02/1990 06/1996 08/2005 initial treatment nephrectomy nephrectomy nephrectomy date metastases were diagnosed 06/2008 06/2008 11/2007 systemic treatment before tki no no no local treatment no radiotherapy, for analgetic reason radiotherapy, for analgetic reason date tki-treatment started 09/2008 10/2008 05/2008 kind of tki sunitinib sunitinib sunitinib duration of tki-treatment (months) 15 12 30 reason for stopping tki hypertension superinfection, ulcus cruris weakness, elevated creatinine progression-free survival (months) * 33 34 22 key: tki, tyrosine kinase inhibitor. * still ongoing. 1498 | finally, themaindifferencebetweenbothcollectivesaffectstheoutcome.sincefromtheresultsofjohannsenand colleagues(10)arecommendationforinterruptingthetreatmentwithtkicannotbededuced,ourdataaswellasthe resultsfoundbyalbigesandcolleagues(11) rather support suchanapproach,especiallybecause,likejohannsenand colleaguespointout,mostofthepatientsrespondtoatki ifitisre-administeredincaseofaprogression. since,accordingtothedatadescribedabove,35to61%of theirpatientsremainedtobetumor-free,theauthorstried toidentifyfactorsprobablyinfluencingthepatient´soutcome.however,neitherthelengthoftreatmentbeforethe breaknortheriskprofilenorthedifferentsubstancesused, correlatewiththefurthercourseofthepatients,buttheauthorsrightlyrefertothesmallnumberofpatientsincluded inthestudies,whichhampersreachingasignificantresult. regardingourpatientsitisremarkablethatin2ofthemthe rccrelapsedafteradisease-freeperiodofmorethan10 years,andallpatientsachievedundertherapyastablediseaseforalongerperiod.thusitcouldbeassumedthatthe tumorspresentedhereshowareducedactivity,butthehistologicalanalysisofthemetastasesrevealedtypicalgrowth ratesof20to30%.however,possiblyinthosepatients,in whomdiseaseisstableforalongertime,eitherbeforeor undertreatment,theuseoftkimaybestoppedespecially formedicalreasons,butfurtherstudiesareurgentlyneeded forproofingthisthesis. conclusion wepresent3patientssufferingfrommrcc,inwhomthe treatmentwiththetkisunitinibhadtobestoppedbecause ofcertainmedicalreasons.surprisinglyinallpatientsthe tumordidnotrelapsetodate,resultingcurrentlyinaprogressionfreesurvivalofatleasttwoyears.whilethereare 2smallstudieswith72patientsinall,thatdealwiththe interruptionoftki-treatmentafterachievingacr,thesuccessful discontinuation of sunitinib in patients, in whom justapartialresponsebutnocrhasbeenachievedbefore, isdescribedhereforthefirsttime. acknowledgements we thank dr. hess, radiology department st. vincenzhospitalinlimburg(germany),dr.wever,radiological practiceinlimburg(germany)anddr.steinhardt,radiologicalpracticeinmontabaur(germany)forprovidingthe ct-scans. conflict of interest none declared. brief communication references 1. motzer rj, mazumdar m, bacik j, berg w, amsterdam a, ferrara j. survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. j clin oncol. 1999;17:2530-40. 2. mcdermott df. update on the application of interleukin-2 in the treatment of renal cell carcinoma. clin cancer res. 2007;15:716s20s. 3. cho ic, chung j. current status of targeted therapy for advanced renal cell carcinoma. korean j urol. 2012;53:217-28. 4. porta c, szczylik c, escudier b. combination or sequencing strategies to improve the outcome of metastatic renal cell carcinoma patients: a critical review. crit rev oncol hematol. 2012;82:323-37. 5. kollmannsberger c, soulieres d, wong r, scalera a, gaspo r, bjarnason g. sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects. can urol assoc j. 2007;1(2 suppl):s41-54. 6. dorff tb, goldkorn a, quinn di. targeted therapy in renal cancer. ther adv med oncol. 2009;1:183-205. 7. desar im, mulder sf, stillebroer ab, et al. the reverse side of the victory: flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. a report of three cases. acta oncol. 2009;48:927-31. 8. wolter p, beuselinck b, pans s, schöffski p. flare-up: an often unreported phenomenon nevertheless familiar to oncologists prescribing tyrosine kinase inhibitors. acta oncol. 2009;48:621-4. 9. griffioen aw, mans l, de graaf a, et al. rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients. clin cancer res. 2012;18:1-11. 10. johannsen m, staehler m, ohlmann ch, et al. outcome of treatment discontinuation in patients with metastatic renal cell carcinoma and no evidence of disease following targeted therapy with or without metastasectomy. ann oncol. 2011;22:657-63. 11. albiges l, oudard s, negrier s, et al. complete remission with tyrosine kinase inhibitors in renal cell carcinoma. j clin oncol. 2012;30:482-7. unclassified tamsulosin and sodium diclofenac as an effective therapy to reduce pain after ureteral stent removal: a prospective, double blinded randomized placebo controlled trial exsa hadibrata1, ahmad farishal2, zulfikar ali3, r danarto4 purpose: this study was conducted to determine the effects of tamsulosin and diclofenac sodium use on patients' pain perception after ureteral stents removal. materials and methods: this study was a randomized control trial with double-blinded design. eighty patients who underwent ureteral stent removal surgery at kardinah hospital during january to march 2017 were divided into four groups. the following medications were administered for two days, (a) placebo tid, or (b) diclofenac sodium 50 mg bid, or (c) tamsulosin 0.2 mg sid, or (d) combination of tamsulosin and diclofenac sodium. analgesic effects were assessed with the visual analog scale (vas). relationships among variables were assessed using one-way anova and post hoc tests. results: the surgical procedure for ureteral stent removal consisted of 48 (60%) male and 32 (40%) female. the average age of group a, b, c, and d were 51.0, 51.9, 47.6, and 47.3 years, and the average stent dwell time was 6.3 weeks. vas values of the entire experimental group were lower than the control group on the first day until the second day after the stent removal (p < 0.05). in the experimental group, there was no difference between group b and c (p > 0.05). group d showed better analgesic effects than group b and c (p <0.05). no severe side effects were observed. conclusion: the result shows that combination therapy of diclofenac sodium and tamsulosin is better in reducing the pain after ureteral stent removal compared to the admission of a single placebo, tamsulosin, or diclofenac sodium therapy. keywords: tamsulosin; diclofenac sodium; pain; stent removal introduction ureteral stents are now commonly used by urolo-gists, but the usage of ureteral stents often causes significant morbidity for patients. some patients experience pain and urinary disorders during stent use.(1) several studies have been conducted to determine the complications after stent removal. as many as 64% of patients undergoing stent removal reported complaints, including pain, hematuria, frequency, urgency, or fever, with pain as the most common one.(2) thirty-two percent of patients reported delayed severe pain after they had their ureteral stent removed, and 9% visited the intensive care unit.(3) pain management in transurethral postoperative patients is an issue of concern. in general, postoperative regional and local anesthesia have both the advantages and disadvantages for patient morbidity.(4) therefore, those type of anesthesia is replaced by oral and topical analgesics such as opioids, sedatives and non-steroidal anti-inflammatory drugs (nsaids) for irritation and pain management of postoperative urological endoscopy.(5) non-steroidal anti-inflammatory drugs (nsaids) 1department of urology, faculty of medicine universitas lampung/ abdul moeloek general hospital, lampung, indonesia. 2medical doctor departmet of urology, faculty of medicine universitas lampung, lampung, indonesia. 3department of surgery, kardinah hospital, tegal, central java, indonesia. yogyakarta, indonesia. 4department of surgery, faculty of medicine universitas gadjah mada/dr sardjito general hospital. *correspondence: department of urology, faculty of medicine universitas lampung/ abdul moeloek general hospital, lampung, indonesia. e mail: exsa.hadibrata@gmail.com. received february 2019 & accepted december 2019 are commonly used drugs that have antipyretic and analgesic effects. this drug works in alleviating the postoperative pain by preventing the production and release of prostaglandins.(6) diclofenac sodium is one of the recommended types of nsaids for postoperative urological endoscopy patients.(7) research on pain perception after stent removal is very limited in number. in a previous study, it was mentioned that the administration of a single dose of the non-steroidal anti-inflammatory drug (nsaid) prevented severe pain after the removal of a ureteral stent.(8) other studies stated that the combination of silodosin and diclofenac sodium was effective in reducing pain after ureteral stent removal. (9) the combination of tamsulosin and propiverine also decreased irritative voiding symptoms, suprapubic pain and improved the quality of life of the patients with dj stent.(10-11) tamsulosin is an α1 selective blocker drug. alpha 1 receptors distributed in the prostate, bladder, and ureter. the use of tamsulosin can cause a decrease in ureteral contractions, as well as reduce irritation in the trigone area. this is a mechanism for reducing pain in pain caused by ureteric stents in the use of tamsuurology journal/vol 18 no. 1/ january-february 2021/ pp. 111-116. [doi: 10.22037/uj.v0i0.5190] losin.(12-14) the study examined the patient's complaints, and visual analog score (vas) score after removal of dj stents. this study was conducted to determine the effect of tamsulosin and diclofenac sodium use on pain perception of patients after ureteral stent removal methods study design this study was a prospective, randomized, double-blind, placebo-controlled trial. the number of samples is determined based on comparative numerical analysis. the study compared the analgesic effects following endoscopic removal ureteral stent surgery. pain perception was assessed from the first day until the second day following surgery. analgesic drugs were administered for two days following surgery. the analgesic effects were assessed using the visual analog scale (vas). all patients above 17 years and below 55 years undergoing unilateral ureteral stenting following renal and ureteric stone surgery were included. no history was presented of psychotic mental illness, organic psychiatric conditions, and other mental illnesses, severe pain-induced illnesses and malignancy. patients with open surgery conversion, history of peptic ulcer disease, liver impairment, chronic renal failure, coronary artery disease, bleeding diathesis, asthma, urinary tract infections (uti), chronic painful conditions like arthritis, pregnancy, allergy to medications, significant lower urinary tract symptoms (luts) and use of alpha-blockers and residual calculus were excluded. patients with complications during stent removal like hematuria and mucosal injury were also excluded. the study was initiated after obtaining the approval of the institutional ethics committee at kardinah hospital. ref: 071/001/2017. interventions the patients who underwent endoscopic surgery removal ureteral stent at urology health center kardinah hospital, tegal from january 2017 to april 2017 unclassified 112 table 1. patient characteristic variable overall (a) placebo (b) diclofenac (c) tamsulosin (d) combination age (year), mean (sd) 49.6 (11.7) 51.0 (13.1) 51.9 (10.6) 47.6 (11.4) 47.3 (11.8) stent insitu duration (week), mean (sd) 6.3 (2.8) 6.0 (2.4) 66 (30) 5.5 (2.5) 6.9 (3.1) gender, n (%) • male 48 (60) 9 (45) 11 (55) 13 (65) 13 (65) • female 32 (40) 11 (55) 9 (45) 7 (35) 7 (35) stent location, n (%) • right 44 (55) 14 (70) 10 (50) 11 (55) 9 (45) • left 36 (45%) 6 (30) 10 (50) 9 (45) 11 (55) diagnose, n (%) • renal stone 26 (32,5) 6 (30) 6 (30) 8 (40) 8 (40) • ureteral stone 54 (67,5) 14 (70) 14 (70) 12 (60) 12 (60) previous operation, n (%) • endourology 43 (53,8) 11 (55) 9 (45) 10 (50) 10 (50) • open surgery 37 (46,3) 9 (45) 11 (55) 10 (50) 10 (50) vas score after removal stent, n (%) • < 3 39 (48,7) 1 (5) 13 (65) 9 (45) 16 (80) • 3-5 38 (47,5) 18 (90) 7 (35) 9 (45) 4 (20) • >5 3 (3,7) 1 (5) 0(0) 2 (10) 0 (0) complication • colic pain 3 (3,7) 2 (10) 1 (5) 0 (0) 0 (0) • hematuria 4 (5) 2 (10) 1 (5) 1 (5) 0 (0) • frequency and urgency 4 (5) 4 (20) 0 (0) 0 (0) 0 (0) • no complication 69 (86,2) 12 (60) 18 (90) 19 (95) 20 (100) figure 1. flowchart of randomized control trial study design tamsulosin & diclofenac in reducing stent pain-hadibrata et al. were included. the experimental groups (b, c, and d) consisted of 20 patients in each group, and the control group also (a) consisted of 20 patients. in control group a, patients were administered vitamin tablet containing folic acid tid for two days. in group b, patients were administered diclofenac sodium 50 mg twice a day for two days. in group c, 0.2 mg of tamsulosin was applied once a day for two days. group d was administered combination diclofenac 50 mg twice a day and tamsulosin 0,2 mg once a day for two days. all medications were placed in a numbered envelope as per the computer-generated model. all patients received a single dose of levofloxacin 500 mg before stent removal as per our department protocol. all patients and investigators were blinded to the medicine identity and randomization design until the end of the study. visual analog score (vas) was taken on a scale from zero to ten, zero meaning no pain to 10, meaning excruciating pain. the surgeon removing the stent was also blinded about the grouping. stent removal was performed under local anesthesia using 2 % xylocaine jelly under vision with 15 fr cystoscope. the stent used in this study was a double j stent with a diameter of 5 fr and a length of 26 cm. all patients were contacted after 24 h and 48 h. vas score, additional medications requirement, and site of pain, and any other relevant parameters were recorded. statistical analysis age, gender, week of ureteral stenting, stent location (right or left), diagnosis, previous surgery, patient satisfaction, adverse events, patient complaints, and vas scale for each patient were recorded. statistical analysis of data that is normal and homogeneously distributed then followed by a one way anova parametric test. however, if it does not meet the requirements for a parametric test, then a non-parametric test, namely kruskal-wallis, followed by the mann whitney posthoc analysis to see the differences between treatment groups was employed. a p-value of less than 0.05 was considered to be statistically significant results in this research, 80 patients who met the inclusion criteria were divided into four study groups. the average age of the entire sample was 49.6 years involving 48 male patients and 32 female patients. primary data analysis included the length of stents dwell times, stent placement, diagnosis, types of operation, vas score < 3, 3-5, >5 and complication after up dj stent were recorded the entire groups. characteristics of the patients are tabulated in table 1. in the four groups, the vas score was analyzed after stent removal. the assessment was performed at 24 hours and 48 hours post-operation. at 24 hours after stent removal, the mean vas scores in the placebo group were 4.0; diclofenac sodium group was 2.4, tamsulosin group was 2.6, and the combination group was 1.8. furthermore, at 48 hours after stent removal measurement, the mean vas score in the placebo group was 2.5, the diclofenac sodium group was 1.0, the tamsulosin group was 1.1, and combination group was 0.5 (table 2). in the post hoc analysis, there was a significant difference in the vas score of the combination therapy group compared to the entire group (table 3; p < 0.05). discussion pain management is currently a significant issue among urologists. unrelieved pain can be a major medical tamsulosin & diclofenac in reducing stent pain-hadibrata et al. table 2. vas mean score before-after removal stent condition placebo na diclofenac tamsulosin combination pre-op 0,9 0,7 0,95 1,1 post op day 1 4 2,45 2,65 1,85 post op day 2 2,4 1 1,15 0,55 figure 2. pain scale graphic vol 18 no 1 january-february 2021 113 unclassified 114 problem. in the late 1990s, pain management in the transurethral surgical procedures was established. (6,11) however, many urologists did not understand yet how to address the post-operative acute pain problems in patients undergoing endoscopic surgery. the primary goal of endoscopic post-operative pain management is to overcome the pain with minimal side effects of drugs.(11,15) the use of a ureteral stent is significantly associated with the pain and discomfort experienced by the patient.(1) in patients with a history of double-j insertion, the perception of catheter-related bladder discomfort (crbd) is less in comparison with patients without such a history.(22) as many as 80% of patients reported experiencing pain due to stent.(1) in another study, 64% of patients who underwent ureteral stent removal reported complaints, including pain, hematuria, frequency, urgency or fever, and the major complaint was pain.(2) several studies have been conducted to reduce the pain and discomfort caused by ureteral stent use by using alpha-blocker, anti-cholinergic, and phosphodiesterase inhibitor as well as the design, material and dimension of the stent. (10,16-19) almost all the existing literature focus on the morbidity of the ureteral stent when the stent is in situ. frequently, the urologists have patients with colic-like pain after ureteral stent removal, requiring additional analgesic and hospitalization for severe pain cases. previous studies reported that as many as 32% of patients complained about the delayed severe pain after ureteral stent removal, and 9% returned to the intensive care unit to be treated.(3) in this study, pain assessment was performed using vas score at 24 hours and 48 hours after ureteral stent removal. the administration of diclofenac sodium, tamsulosin, and the combination of both significantly reduced pain after stent removal compared to placebo (p < 0.001). this result lasted up to 24 hours and 48 hours after the operation. pain during ureteral stent removal is due to the activation of the nociceptor. friction between the stent and ureteral mucosa irritates the ureteric smooth muscle, trigonal irritation, and induces pressure changes in the pelvicocalices system.(9) tamsulosin is a selective α1 blocker drug. alpha 1 receptors are distributed in the prostate, vesica urinaria, and ureter. the use of tamsulosin may cause a decrease in ureteral contraction as well as reducing irritation in the trigonum area. it is a pain-reducing mechanism for the pain caused by ureteral stent.(18-20) diclofenac sodium is one recommended type of nsaids for post-operative urological endoscopy patients, and it is a standard drug in renal colic. (7) cox inhibitors and non-selective cox inhibitors, significantly reduce ureteral contraction in the human and porcine ureter.(20) in addition, the use of diclofenac sodium drugs can reduce renal blood flow resulting in analgesic and anti-inflammatory effects.(21) there was no significant difference in vas score between the diclofenac sodium group and the tamsulosin group (p > 0.05). in the diclofenac group, the mean vas score was lower than that of tamsulosin. at 24 hours post-operative, vas score of the diclofenac sodium group was 2.4 and 2.6 in the tamsulosin group. at 48 hours post-operative, vas score of the diclofenac sodium group was 1.0 and 1.1 in the tamsulosin group. these results were consistent with the previous studies which stated that there was no significant difference in vas score in the diclofenac sodium group and alpha-blocker silodosin.9 the incidence of pain with vas score of ≥ 3≤ 5 was the most prevalent in the placebo group (90%). in the diclofenac sodium group and tamsulosin group, the score was 35% and 55% respectively. while in the combination group, the incidence of pain with a vas score of ≥ 3≤ 5 was 20%, and vas score > 5 was 0%. these results suggest that the occurrence of severe pain can be prevented by providing a combination of diclofenac sodium and tamsulosin. in this study, the admission of combination therapy was better in reducing the vas score of 24 hours and table 3. post hoc analysis p value vas score day 1 day 2 combination placebo 0.000 0.000 tamsulosin 0.039 0.039 diclofenac 0.234 0.020 tamsulosin placebo 0.000 0.000 diclofenac 1.000 0.951 diclofenac placebo 0.000 0.000 characteristic our study gangkak et al., 20169 irfansyah et al., 201610 tadros et al., 20128 study design prospective, double prospective, double blinded prospective, single blinded prospective, double blinded blinded randomized randomized control trial study randomized control trial study randomized control trial study control trial study regiment diclofenac sodium diclofenac sodium and silodosin tamsulosin and propiverine hcl rofecoxib and tamsulosin total sample 80 240 30 22 vas measure 24 hours dan 48 24 hours post surgery while stent insitu and 24 hours 24 hours post surgery hours post surgery post surgery conclusiom combination therapy of combination therapy of diclofenac tamsulosin is better compared to rofecoxib single therapy prior diclofenac sodium and sodium and silodosin did not differ propiverine hcl in reducing pain, to stent release prevents severe tamsulosin is better in significantly compared to the but propiverine hcl is better at pain post-release of ureteral reducing the pain after admission of singe silodosin and increasing qol and decreasing stent ureteral stent removal sodium diclofenac therapy ipss score compared to the admission of single placebo, tamsulosin, and diclofenac sodium therapy table 4. comparison of research results 8,9,10 tamsulosin & diclofenac in reducing stent pain-hadibrata et al. 48 hours postoperatively, compared with other groups (p < 0.05). we did not find any significant side effects on the combination therapy of diclofenac sodium and tamsulosin. the most common side effect of the administration of diclofenac sodium was gastrointestinal symptoms. in this study, we did not find any significant gastrointestinal complaints and urinary complaints (colic pain, hematuria, and frequency-urgency) in the use of drug combinations sodium diclofenac 50 mg twice daily and tamsulosin 0.2 mg once daily for two days. when compared to previous studies, this study did not only evaluate the 24 hours post-operative pain scores, but it continued the evaluation until 48 hours postoperation.(9) the results of combination therapy remained better in reducing the 48 hours post-operative pain of the vas score. results and conclusions in this study, compared with other researches, is presented in table 4. this study, nevertheless, has some disadvantages. first, in this study, the numbers of randomized samples are few, and the population of this study are limited to a district hospital in central java only. future researches are expected to develop the types of therapy and surgery techniques that can significantly reduce the pain after ureteral removal. conclusions our study showed that the combination therapy between diclofenac sodium and tamsulosin is better in reducing pain after ureteral removal than placebo, tamsulosin, and diclofenac sodium admission. conflict of interest the authors reported no potential conflict of interest. references 1. joshi hb, stainthorpe a, macdonagh rp, keeley fx, timoney ag, barry mj. indwelling ureteral stents: evaluation of symptoms, quality of life and utility. j urol 2003; 169:1065-9. 2. theckumparampil n, elsamra se, carons a, salami ss, leavitt d, kavoussi a, et al. symptoms after removal of ureteral stents. j endourol 2015; 29:246-52. 3. loh-doyle jc, low rk, monga m, nguyen mm. patient experiences and preferences with ureteral stent removal. j endourol 2015; 29:35-40. 4. tyritzis si, stravodimos kg, vasileiou i, fotopoulou g, koritsiadis g, migdalis v, et al. spinal versus general anaesthesia in postoperative pain management during transurethral procedures. isrn urol 2011; 895874:1-6. 5. liu j, zang yj. comparative study between three analgesic agents for the pain management during extracorporeal shock wave lithotripsy. urol j 2013; 10:942-5. 6. kara c, resorlu b, cicekbilek i, unsal a. analgesic efficacy and safety of nonsteroidal anti-inflammatory drugs after transurethral resection of prostate. int braz j urol 2010; 36;49-54. 7. borda ap, sonnek fc, fontetne v, papaioannou eg. guidelines on pain management & palliative care. european association of urology 2014; 28-33. 8. tadros nn, bland l, legg e, olyaei a, conlin mj. a single dose of a non-steroidal antiinflammatory drug (nsaid) prevents severe pain after ureteric stent removal: a prospective, randomised, double-blind, placebo-controlled trial. bju int 2012; 111:101-5. 9. gangkak g, teli rd, yadav ss, tomar v, priyadarshi s, aggarwal sp. a single oral dose of silodosin an d diclofenac sodium is effective in reducing pain after ureteric stent removal: a prospective, randomized, double blind placebo controlled study. springerplus 2016; 5:23. 10. irfansyah. effect of alpha blocker and anti cholinergic on ureteral stent related symptoms : a single-blind randomized clinical trial. [tesis]. universitas gadjah mada. 2016. 11. yuri p, ali z, rasyid n, birowo p. effect of ppemidic acid, phenazopyridine hcl, and sodium diclofenac on pain perception following endoscopic urological surgery: double-blinde randomized-controlled trial. acta medica indones 2016; 48:184-92. 12. beddingfield r, pedro rn, hinck b, kreidberg c, feia k, monga m. alfuzosin to relieve ureteral stent discomfort: a prospective, randomized, placebo controlled study. j urol 2009; 181:170-6. 13. itoh y, kojima y, yasui t, tozawa k, sasaki s, kohri k. examination of alpha 1 adrenoceptor subtypes in the human ureter. int j urol 2007; 14:749-53. 14. michel mc, vrydag w. alpha1-, alpha2and beta-adrenoceptors in the urinary bladder, urethra and prostate. br j pharmacol 2006; 147(suppl 2):88-119. 15. yesil s, polat f, ozturk u dede o, imamoglu m, bozkirli. effect of different analgesic on pain relief durung extracorporeal shock wave litotripsi. hippokratia 2014; 18:107-9. 16. damiano r, autorino r, de sio m, giacobbe a, palumbo im, d'armiento m. effect of tamsulosin in preventing ureteral stent-related morbidity: a prospective study. j endourol 2008; 22:651-6. 17. deliveliotis c, chrisofos m, gougousis e, papatsoris a, dellis a, varkarakis im. is there a role for alpha1-blockers in treating double-j stent-related symptoms. urology 2006; 67:359. 18. dellis a, joshi hb, timoney ag, keeley fx. relief of stent related symptoms: review of engineering and pharmacological solutions. j urol 2010; 184:1267-72. 19. gupta m, patel t, xavier k, maruffo f, lehman d, walsh r, et al. prospective randomized evaluation of periureteral botulinum toxin type a injection for ureteral stent pain reduction. j urol 2010; 183:598602. 20. nakada sy, jerde tj, bjorling de, saban r. selective cyclooxygense-2 inhibitors reduce ureteral contraction in vitro: a better alternative for renal colic? j urol 2000; 163:607-12. tamsulosin & diclofenac in reducing stent pain-hadibrata et al. vol 18 no 1 january-february 2021 115 21. chaignat v, danuser h, stoffel mh, z’brun s, studer ue, mevissen m. effects of a non-selective cox inhibitor and selective cox-2 inhibitors on contractility of human and porcine ureters in vitro and in vivo. br j pharmacol 2008; 154:1297-307. 22. maghsoudi r, niaki sf, etemadian m, kashi ah, shadpour p, shirani a, et al. comparing the efficacy of tolterodine and gabapentin versus placebo in catheter related bladder discomfort after percutaneous nephrolithotomy: a randomized clinical trial. j endourology 2018; 32:168-174. tamsulosin & diclofenac in reducing stent pain-hadibrata et al. unclassified 116 1289vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l success rate and patients' satisfaction following intradetrusor dysport injection in patients with detrusor overactivity: a comparative study of idiopathic and neurogenic types of detrusor overactivity saeed shakeri,1 reza mohammadian,1 alireza aminsharifi,1 ali ariafar,1 jalal vaghedashti,1 maryam yazdani,2 mahnza yadollahi,3 vahid emadmarvasti,1 amir baharikhoob1 purpose: to evaluate the efficacy of intradetrusor dysport (a type of botulinum toxin type a) injection in patients with idiopathic or neurogenic detrusor overactivity, who were refractory to antimuscarinic drugs, and to compare the efficacy of dysport injection in both groups. materials and methods: twelve patients with neurogenic detrusor overactivity (ndo) and 18 patients with idiopathic detrusor overactivity (ido) participated in this study. all the patients received intravesical injection of 500 units of dysport. they were followed up for 3 months after injection with maximum cystometric capacity, maximum detrusor filling pressure, and number of catheterization or pad usage. results: after 3 months, the mean maximum cystometric capacity increased from 109.36 ± 24.11 ml to 266.81 ± 97.18 ml (p = .000) in the ndo group and from 192.24 ± 36.21 ml to 272.61 ± 63.37 ml (p = .000) in the ido group. the mean maximum detrusor filling pressure decreased from 48.14 ± 26.51 cmh2o to 28.91 ± 9.01 cmh2o (p = .005) in the ndo group and from 39.22 ± 9.92 cmh2o to 29.64 ± 10.14 cmh2o (p = .003) in the ido group. conclusion: intradetrusor dysport injection improved urodynamic parameters and quality of life (qol) in both groups significantly. we did not find significant difference in qol or urodynamic parameters between both groups. keywords: botulinum toxins, type a; administratin and dosage; urinary bladder, overactive; drug therapy; adverse effects. corresponding author: reza mohammadian, md department of urology, faghihi hospital, shiraz university of medical sciences, shiraz, iran. tel: +98 917 713 7302 e-mail: reza_mohammadian@ yahoo.com received november 2012 accepted june 2013 1 urology and nephrology research center, shiraz university of medical sciences, shiraz, iran. 2 department of obstetrics and gynecology, shiraz university of medical sciences, shiraz, iran. 3 trauma research center, shiraz university of medical sciences, shiraz, iran. miscellaneous 1290 | introduction overactive bladder (oab) is a clinical syndrome characterized by urgency with or without urge in-continence, frequency, and nocturia(1) with a prevalence of 11.8% worldwide.(2) oab has a significant effect on the quality of life in men and women suffering from this syndrome.(3-5) detrusor overactivity (do) is one of the main causes of oab and is classified into idiopathic do (ido) and neurogenic do (ndo) according to the international continence society classification.(6) oral antimuscarinic agents are the first line treatment modality for patients with do; however, its usage has been limited due to the adverse effects such as dry mouth or headache and their decreased efficacy in long term period as the result of up-regulation phenomenon.(7) more invasive procedures such as bladder augmentation and urinary diversion pose a significant risk of morbidity and complications to the patient.(8) botulinum toxin type a (btx-a) which is produced by clostridium botulinum, a gram positive bacteria, inhibits the release of acetylcholine at the neuromuscular junction and subsequently paralyses the muscle. the effects of btx-a on parasympathetic nervous system was first investigated in the 1920s by dickson and colleagues.(9) although several studies also revealed the efficacy of intradetrusor injection of btx-a in the treatment of both types of do which were intractable to antimuscarinic therapy,(10,11) the data comparing the efficacy of intradetrusor injection of btx-a in patients suffering either ido or ndo are lacking.(12,13) in this study, we evaluated the efficacy of intradetrusor injection of dysport ((reloxin/bont-a, ipsen biopharm ltd., wrexham, uk) in patients with ido and ndo, and the resulting improvement in the quality of life (qol) in both groups. materials and methods study design our prospective cohort study was conducted from september 2010 to december 2011. patients with symptoms of oab and urodynamically proven ido or ndo who were refractory to oral antimuscarinic medication for at least 3 months or those who had discontinued medical therapy due to drug side effects participated in this experimental study. being refractory to antimuscarinic treatment was defined as no effect of antimuscarinic drugs available in iran, i.e. oxybutynin hydrochloride (iran darou co., tehran-iran), and detrusitol (pharmacia & upjohn spa, milan, italy) during a trial for at least 3 months. patients with history of previous bladder surgery or botox injection, an active urinary tract infection, any anatomical anomaly of the urinary system, urinary stone or urinary tract tumors and any medical disorder such as diabetes mellitus or multiple sclerosis were excluded from the study. besides, all female patients were examined by a gynecologist to rule out genital infection or pelvic organ prolapse or relaxation which may induce voiding dysfunction. pretreatment evaluations all the patients gave their written informed consent and were divided into ido and ndo groups. the patients were asked to chart a 3 days voiding diary mentioning the number of voids and episodes of urge incontinence per day. in patients with spinal cord injury and associated ndo, the numbers of urethral catheterization, and pad count per day were measured. urodynamic study was performed in both groups according to international continence society’s recommendations,(14) measuring parameters such as maximum cystometric capacity (mcc), maximum detrusor pressure on filling cystometry (mdp), and post void residual (pvr) urine volume in the ido group during urodynamic study or by bladder ultrasonography. qol was assessed by the incontinence impact questionnaire short form 7 (iiq-7). oral ciprofloxacin 500 mg (razak laboratories, tehran, iran) was administered twice daily one day before operation prophylactically in adult patients and cefexime (zakaria pharm. co., tabriziran) 8 mg/kg/day in children. patients on antiplatelet drugs were asked to stop their medication 7 days before the operation. injection technique the procedure was performed in an outpatient manner under general anesthesia in dorsal lithotomy position with some modifications in those patients with chronic spinal cord injury and limitation of hip joint motion. after cleaning and draping, 20 ml lidocaine gel 2% (sina darou, tehran-iran) was applied intraurethrally. dysport was administered with an 11.5 french (f) wolf rigid pediatric nephroscope (richard wolf gmbh, germany). for each adult patient, 1 vial of dysport (500 units) was administered, and the dosage for children was 20 units/kg. each vial was diluted with 20 ml of sterile normal saline solution before injection. the minimiscellaneous 1291vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l mally invasive technique involved 20 injections at 25 units/ml per injection site into the lateral and posterior walls of the bladder while sparing the trigonal area. then, the bladder was drained from irrigation solution and checked for any bleeding site. all patients had an indwelling urethral catheter which was removed 24 hour after the operation. the patients were observed for 2 hours after recovery from general anesthesia and then discharged with a 5 day prescription of ciprofloxacin 500 mg twice daily. followup the patients were followed up 1 week after the injection to evaluate early post-operative complications or complaints. in the 12th week after operation, urodynamic study was performed to measure mcc and mdp. pvr urine volume was measured during urodynamic study or by bladder ultrasonography in ido group. the participants of both groups were also asked to chart the 3 days voiding diary and qol was reassessed by the iiq-7. statistical analysis descriptive data were evaluated by epidemiological parameters such as prevalence, mean, and standard deviation. normality of quantitative variables (iiq-7, clinical and urodynamic parameters) was assessed using kolmogorov-smirnov test. to compare normal variables between (within) ido and ndo groups paired t test and for non-normal mann-whitney u (wilcoxon test) were used. to compare categorical variables (sex, effect of drugs and adverse reactions) between groups chi-square test was used. p < .05 values was considered as statistically significant. results demographic data of the 38 initially recruited patients, 8 were excluded from the study considering the exclusion criteria mentioned in the study design. a total of 30 patients (15 males, 15 females) remained in the study who were divided into ido (18 patients) and ndo (12 patients) groups. the mean age of the participants in the ido and ndo groups were 58.03 ± 17.16 years and 43.99 ± 15.21 years, respectively which were comparable. the age range of the patients was 18 to 74 years. in the ido group, 14 patients (77.77%) were female, and 4 (22.23%) were males. in the ndo group, 1 patient (8.33%) was female, and 11 (91.67%) were males. the mean duration of antimuscarinic consumption was 18.6 ± 14.5 months (4 to 60 months). the drugs were not effective in 14 (77.77%) patients in the ido group, and in 11 (91.66%) patients of the ndo group. adverse reactions as the causes of medical treatment cessation were 27.77% (5 patients) and 16.66% (2 patients) in the ido and ndo groups, respectively. post-operation complications in the ido group, one (5.55%) case of urinary tract infection was detected who was treated with a course of oral antimicrobial agent according to the result of urine culture. another patient (5.55%) developed pelvic pain one week after injection which resolved spontaneously in 3 days. in the ndo group, one patient (8.33%) developed a severe febrile urinary tract infection 3 days after injection that was successfully treated with intravenous antibiotics. none of the participants experienced acute urinary retention or significant pvr urine (in the ido group who void themselves), generalized muscle weakness, or significant gross hematuria. urodynamic parameters intradetrusor dysport injection in detrusor overactivity | shakeri et al table 1. comparison of clinical and urodynamic parameters before and after treatment in ido patients. variables before injection after injection p mean mcc, ml (n = 18) (n = 18) < .001 mean maximum detrusor pressure, cmh 2 o 192.24 ± 36.21 272.61 ± 63.37 .003 mean frequency 39.22 ± 9.92 29.64 ± 10.14 < .001 mean fdv 18.13 ± 3.45 13.3 ± 3.74 < .001 mean iiq7 60.87 ± 16.71 101.33 ± 45.15 < .001 key: ido, idiopathic detrusor overactivity; mcc, maximum cystometric capacity; fdv, mean first desire to void; iiq7, incontinence impact questionnaire short form 7. 1292 | the urodynamic parameters are shown in tables 1 and 2. twelve weeks after dysport treatment, the urodynamic study revealed a significant decrease in the mean mdp and a significant increase in mcc in both groups. although the mean mcc was significantly different between the two groups before injection (p = .000), the changes in post-injection mean mcc did not differ significantly between the two groups (p = .700) (figure 1). although mean mdp before and after dysport injection decreased significantly in each group, it did not differ significantly between the ido and ndo groups (p = .200 and .800, respectively) (figure 2). the mean pvr was significantly increased in ido patients after dysport injection from 31 ml to 82.2 ml (p = 0.021). mean first desire to void (fdv) was significantly increased in ido patients following the treatment from 60.87 ± 16.71 ml to 101.33 ± 45.15 ml (p = .000) 3-day voiding diary the results were analyzed as a mean of 3 days before treatment and 12 weeks after treatment. in the ido group before the treatment, 6 patients (33.33%) complained of frequency and 13 of them (72.22%) complained of both frequency and urgency with urge incontinence. the mean frequency rate and mean pad count decreased significantly after treatment in the ido and ndo patients, respectively (p < .001 and p = .001, respectively) (tables 1 and 2). quality of life quality of life, as assessed using the iiq-7, improved in both groups at 12 weeks when comparing the mean iiq-7 score after the treatment (16.22 ± 1.03) with the mean iiq-7 score before treatment (21.64 ± 0.48), (p = .000). according to the iiq-7, 10 patients (33.33%) did not respond to the treatment, and 20 (66.66%) patients responded to the treatment. of the non-responders, 7 patients (48.88%) were in the ido group and 3 patients (25%) were in the ndo group; however, the difference between 2 groups was not statistically significant (p = .400) satisfaction rate when all patients asked about their satisfaction following the treatments, 76.91% of ndo patients and 57.93% of ido patients were satisfied with dysport treatment. satisfaction rate did not differ significantly between the two groups (p = .600). discussion oab is a prevalent condition that affects millions of people in the world.(15) oab symptoms including frequency and urgency, with or without urge incontinence significantly worsen the patient’s qol. most patients and practitioners are seeking a therapeutic method which offers appropriate and durable treatment responses in addition to minimal adverse side effects. btx relaxes the detrusor muscle by inhibiting the release of acetylcholine at the neuromuscular junction. there are seven distinct serotypes of btx (a, b, c, d, e, f, g) but only two of them, btx-a and b, are available for clinical use. several studies have shown the highly beneficial effect of intradetrusor injection of btx-a in the treatment of do.(10,11,16,17) btx-b has more side effects and a shorter duration of action compared with btx-a; however, the data on btx-b for the treatment of do and incontinence are limited(18) and it is too early to determine whether it will have similar results to those with btx-a. it has been proposed that btx-a reduces the level of the nerve growth factor in the suburothelium and urine; a factor which can be responsible for induction of inflammatory processes or bladder overactivity.(19) botox and dysport are the available products of table 2. comparison of clinical and urodynamic parameters before and after treatment in ndo patients. before injection after injection p mean mcc (n = 12) (n = 12) < .001 mean maximum detrusor pressure, cmh 2 o 109.36 ± 24.11 266.81 ± 97.18 .005 mean pad usage 48.14 ± 26.51 28.91 ± 9.01 .001 mean iiq7 6.16 ± 0.86 4.75 ± 1.11 < .001 key: ndo, neurogenic detrusor overactivity; mcc, maximum cystometric capacity; iiq7, incontinence impact questionnaire short form 7. miscellaneous 1293vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l btx-a which are now being used and it is suggested that each unit of botox is equivalent to 3.5 to 5 units of dysport. (20) to date according to published studies 100 to 400 units of botox and 500 to 1000 units of dysport have been used; comparison of the results of these studies shows relatively similar subjective and objective outcomes.(21) in our study, intradetrusor injection of 500 units of dysport had a significant therapeutic effect on both ido and ndo patients who were refractory to oral antimuscarinic medications. in each group, a significant increase in mcc and a significant decrease in mdp were observed following treatment with dysport. comparing the urinary frequency rate before and after the treatment in ido patients revealed a significant decrease after the treatment. the mean pad count in ndo patients who used pads within the intervals of urethral catheterizations was significantly decreased after dysport injection. in ido patients fdv was significantly increased following the treatment which is probably due to both increase in cystometric capacity and decrease in urgency. according to the iiq-7, the patients’ qols were significantly improved in both groups following the treatment and in almost all patients; changes in the urodynamic parameters were concomitant with the improvement in patients’ qols and symptoms. considering the mentioned results, our study confirmed the results of previous studies regarding the beneficial effects of intradetrusor injection of dysport in patients with do. a systematic review of the role of botox and dysport in the management of lower urinary tract disease was conducted by mangera and colleagues.(22) they found a high level of evidence for the use of botox in children and adults with ndo or ido, but only level 1 evidence for dysport in adults with ndo. they also concluded that the effective dose of botox or dysport was different when managing ido or ndo patients. similar results were found in another systematic review done by chancellor and colleagues.(23) however we used dysport in both ido and ndo adult patients with the same dosage and found significant improvements in urodynamic parameters, lower urinary tract symptoms and qol in both groups. our results regarding the effectiveness of dysport in treating both ndo and ido patients were similar to the chancellor and colleagues review.(23) while most of the surveys recommend about two fold dose of dysport to treat patients with ndo than ido, we managed both groups with the same dose. we should keep in mind that we used 500 units of dysport for both groups which might be more than what is necessary for treating ido patients. although the efficacy of btx-a injection in the treatment of do has been proved in different studies, the number of studies comparing the effects of btx-a injection in the two subdivisions of do, i.e. ndo and ido, are lacking. popat and colleagues followed 24 patients with ndo and 31 patients with ido 4 weeks and 16 weeks after botox injection and found no significant differences regarding improvement in clinical and urodynamical parameters figure 1. comparison of mean maximum cystometric capacity before and after treatment in each group. key: ndo, neurogenic detrusor overactivity; ido, idiopathic detrusor overactivity. figure 2. comparison of mean maximum detrusor pressure before and after treatment in each group. key: ndo, neurogenic detrusor overactivity; ido, idiopathic detrusor overactivity. intradetrusor dysport injection in detrusor overactivity | shakeri et al 1294 | between the mentioned groups.(12) kalsi and colleagues compared the qol following intradetrusor botox injections in ido and ndo patients and found a similar percent improvement in qol score for both ndo and ido groups at 4 and 16 weeks.(13) evaluating the patients’ satisfaction rates following the treatment in our study revealed that the patients with ndo were more satisfied with their treatment than those with ido (76.91% vs. 57.93%). although this finding was not statistically significant (p = .600). there are several factors which could be explain the achievement of such results. first, the mean age of the patients with ndo was less than that of ido patients (43.99 years vs. 58.03 years) which might be an explanation for a better satisfaction rate. likewise, in a study held by brian and colleagues evaluating the predictors of response to intradetrusor btx-a injection in patients with ido, it was found that younger patients with incontinence were more likely to respond.(24) the second point that should be taken into account is that the patients with ndo in our study had a higher mean mdp and a lesser mean mcc before treatment as compared to the patients with ido (39.1 cmh2o vs. 47.4 cmh2o) and (101.3 ml vs. 197.4 ml). it seems that these more abnormal urodynamic parameters in ndo groups responded better to dysport injection, causing more satisfactory results. similarly, sahai and colleagues in their survey found that poor responders to btx-a injection had significantly higher mdp during do;(25) however, a confounding factor in their study was that patients participating in that study continued antimuscarinic consumption even after btx-a injection. with respect to the urodynamic parameters in our study, although the improvements in mean mdp and mean mcc in each group were statistically significant, comparing both groups changes did not differ significantly. voiding dysfunction and especially urinary retention can be one of the complications after btx-a injection which is due to the muscle paralysis caused by this substance. in a study by stephen jeffery and colleagues a high incidence of voiding dysfunction was reported following injection of 500 units of dysport in ido patients which 36% of them required catheterization in 6 weeks and 36 months after injection.(26) the incidence of retention following dysport injection was 19% in the study held by popat and colleagues.(12) in our study, the mean pvr urine was significantly increased in ido patients after dysport injection from 31 ml to 82.2 ml; however, we did not notice any episodes of urinary retention in our ido group following the treatment and all the ido patients voided successfully. transient muscle weakness is another complication after dysport injection mentioned in some studies,(26,27,28) but this complication also was not detected in our patients. according to these results, although intradetrusor injection of dysport was an effective treatment modality for both groups, we did not find any priority for dysport injection between ndo and ido patients. our study is not without limitations. although neurogenic and idiopathic detrusor overactivity can cause the same clinical symptoms, their pathophysiology and severity of symptoms are different which make the comparison of both groups difficult. in our study the gender and severity of symptoms in both groups were not statistically comparable which can cause a selection bias while comparing both groups. we are also aware that some insignificant findings in our results can be due to small sample which resulted in low study power. conclusion considering our results and also previous studies, there is no doubt about the valuable effects of btx-a and especially dysport in our study in alleviating the signs and symptoms of patients suffering from do by improving their urodynamic parameters; however, more studies are needed to compare the effects of btx-a in ndo and ido patients. acknowledgement the authors would like to thank dr. abdolreza haghpanah, for his support, time and consideration. conflict of interest none declared. references 1. brubaker linda. urgency: the cornerstone symptom of overactive bladder. urology. 2004;64(suppl 6a):12-16. 2. irwin de, milsom i, hanskaar s, et al. population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the epic study. eur urol. 2006;50:1306-14. 3. aslan g, köseoğlu h, sadik o, gimen s, cihan a, esen a. sexual function in women with urinary incontinence. int j impot res. 2005;17:248-51. miscellaneous 1295vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l 17. schurch b, de sèze m, denys p, et al. botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. j urol. 2005;174:196-200. 18. ghei m, maraj bh, miller r, et al. effects of botulinum toxin b on refractory detrusor overactivity: a randomized, double-blind, placebo controlled, crossover trial. j urol. 2005;174:1873-7. 19. liu ht, chancellor mb, kuo h. urinary nerve growth factor levels are elevated in patients with detrusor overactivity and decreased in responders to detrusor botulinum toxin-a injection. eur urol. 2009;56:700-7. 20. grosse j, kramer g, tong tqt, stohrer m, jakse g. efficacy, dosage and safety of dysport english botulinum toxin a in severe neurogenic detrusor overactivity. eur urol. 2005; suppl. 4:abst #405. 21. rapp de, lucioni a, bales gt. botulinum toxin injection: a review of injection principles and protocols. int braz j urol. 2007;33:132-41. 22. magnera a, andesson ke, apostolidis a, et al. contemporary management of lower urinary tract disease with botulinum toxin a: a systematic review of botox (onabotulinumtoxina) and dysport (abobotulinumtoxina). eur urol. 2011;60:784-95. 23. chancellor mb, elovic e, esquenazi a, et al. evidence-based review and assessment of butolinum neurotoxin for the treatment of urologic conditions. toxicon. 2013;67:129-40. 24. cohen bl, caruso dj, kanagarajah p, gousse ae. predictors of response to intradetrusor botulinum toxin-a injections in patients with idiopathic overactive bladder. adv urol. 2009:328364. 25. sahai a, khan ms, le gall n, dasgupta p; gkt botulinum study group. urodynamic assessment of poor responders after botulinum toxin-a treatment for overactive bladder. urology. 2008;71:455-9. 26. jeffery s, fynes m, lee f, wang k, williams l, morley r. efficacy and complications of intradetrusor injection with botulinum toxin a in patients with refractory idiopathic detrusor overactivity. bju int. 2007;100:1302-6. 27. ruffion a, capelle o, paparel p, leriche b, leriche a, grise p. what is the optimum dose of type a botulinum toxin for treating neurogenic bladder overactivity? bju int. 2006;97:1030-4. 28. grosse j, kramer g, stohrer m. success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. eur urol. 2005;47:653-9. 4. kim yh, seo jt, yoon h. the effect of overactive bladder syndrome on the sexual quality of life in korean young and middle aged women. int j impo res. 2005;17:158-63. 5. liberman jn, hunt tl, stewart wf, et al. health-related quality of life among adults with symptoms of overactive bladder: results from a us community-based survey. urology. 2001;57:1044-50. 6. sand pk, dmochowski r. analysis of the standardisation of terminology of lower urinary tract dysfunction: report from the standardisation sub-committee of the international continence society. neurourol urodynam. 2002;21:167-78. 7. andersson ke. antimuscarinics for treatment of over active bladder. lancet neurol. 2004;3:46-53. 8. flood hd, malhotra sj, o'connell he, ritchey mj, bloom da, mcguire ej. long term results and complications using augmentation cystoplasty and reconstruction urology. neurourol urodyn. 1995;14:297-309. 9. dickson ec, shevky r. studies on manner in which the toxin of clostridium botulinum acts upon the body. the effect upon the autonomic nervous system. j exp med. 1923;37:711-31. 10. sahai a, shamim khan m, dasgupta p. efficacy of botulinium toxina for treating idiopathic detrusor overactivity: results from a single center, randomized, double blind, placebo controlled trial. j urol. 2007;177:2231-36. 11. patki ps, hamid r, arumugam k, shah pj, craggs m. botulinum toxin-type a in the treatment of drug resistant neurogenic detrusor overactivity secondary to traumatic spinal cord injury. bju int. 2006;98:77-82. 12. popat r, apostolidis a, kalsi v, gonzales g, fowler cj, dasgupta p. a comparison between the response of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity to the first intradetrusor injection of botulinum-a toxin. j urol. 2005;174: 984-9. 13. kalsi v, apostolidis a, popat r, gonzales g, fowler cj, dasgupta p. quality of life changes in patients with neurogenic versus idiopathic detrusor overactivity after intradetrusor injection of butolinum neurotoxin type a and correlations with lower urinary tract symptoms and urodynamic changes. eur urol. 2006;49:528-35. 14. schäfer w, abrams p, liao l, et al. good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies. neurourol urodyn. 2002;21:261-74. 15. milsom i, abrams p, cardozo l, roberts rg, thüroff j, wein aj. how widespread are the symptoms of an overactive bladder and how are they managed? a population-based prevalence study. bju int. 2001;87:760-6. 16. patel ak, patterson jm, chapple cr. botulinum toxin injections for neurogenic and idiopathic detrusor overactivity: a critical analysis of results. eur urol. 2006;50:684-710. intradetrusor dysport injection in detrusor overactivity | shakeri et al unclassified levofloxacin: is it still suitable as an empirically used antibiotic during the perioperative period of flexible ureteroscopic lithotripsy? a single-center experience with 754 patients ping ao1, ling shu2, zhenxing zhang1, dong zhuo1*, zhongqin wei3 purpose: to determine the empirical usage of antibiotics and analyze the pathogen spectrum during the perioperative period of flexible ureteroscopic lithotripsy (fursl) with a focus on levofloxacin. materials and methods: this retrospective analysis included 754 patients who underwent fursl successfully in our hospital from january 2015 to july 2019. all patients were sent for urine cultures and prescribed antibiotics during the perioperative period. patients with negative preoperative urine cultures were divided into levofloxacin (lvxg) and non-levofloxacin groups (nlvxg) based on the empirical use of antibiotics. operative time, the length of postoperative hospital stays and total hospital stays, total hospitalization costs, postoperative fever rate, and removal rate of stones were compared. patients with positive urine cultures were analyzed for pathogen distribution and antibiotic resistance. results: in the empirical use of antibiotics among 541 cases with negative urine cultures, the prescription rate of levofloxacin was 68.95%. compared to that in nlvxg, lvxg had a lower cost of antibiotics but a higher postoperative fever rate and a longer hospital stay. there were no significant differences in operative time, the total hospitalization costs, and the removal rate of stones between the two groups. the top two common pathogens were escherichia coli (36.11%) and enterococcus faecalis (24.07%), with resistance rates of 74.36% and 71.15% to levofloxacin, respectively. conclusion: levofloxacin might be no longer suitable as the first-line choice of clinical experience when performing fursl in some centers. keywords: flexible ureteroscopic lithotripsy; levofloxacin; urine culture introduction flexible ureteroscopic lithotripsy (fursl) has been widely performed for the removal of kidney stones in several chinese regional hospitals in recent years. the prevalence of kidney stones is about 5.88% in china and is higher in the south.(1) however, increasing cases of perioperative urinary tract infection (uti) and even sepsis have been reported.(2,3) asian urologists tend to prescribe antibiotics to reduce the risk of uti during ureteroscopic lithotripsy, even in patients with negative preoperative urine cultures.(4) the appropriate use of antibiotics is a common concern of doctors and patients. levofloxacin is a quinolone antibiotic commonly used in urology owing to its efficacy and low price. recently, we observed that sometimes the anti-infective effect of levofloxacin was not satisfactory. studies have demonstrated typical pathogens with increased resistance to levofloxacin.(5-8) to date, there are few studies regarding the use of levofloxacin in the perioperative period of fursl and the use of empirical antibiotics in ureteroscopic lithotripsy.(9) in this study, we aimed to evaluate whether levofloxacin is still suitable as an empirically used antibiotic during the perioperative period of fursl. we conducted a case-control 1department of urology, the first affiliated hospital of wannan medical college, wuhu 241001, china. 2department of operating room, the first affiliated hospital of wannan medical college, wuhu 241001, china. 3department of urology, the second affiliated hospital of nanjing medical university, nanjing 210011, china. *correspondence: dong zhuo, department of urology, the first affiliated hospital of wannan medical college, no. 2, zheshan west road, jinghu district, wuhu, 241001, china. tel: +86-13705535953, e-mail: whzhuo2008@sina.com. received february 2020 & accepted october 2020 study to evaluate the pathogenic distribution in urine culture and analyze antibiotic resistance, which provided a reference for the rational usage of antibiotics. materials and methods after obtaining approval from the institutional review board (no. wk2017f01), we conducted a retrospective study on patients with a high incidence of stones who underwent fursl successfully between january 2015 and july 2019, at the urology department of the first affiliated hospital of wannan medical college in southern china. in all patients, the diagnosis of upper urinary calculi was confirmed using ultrasound, plain radiography, a computed tomography scan, and intravenous pyelography. surgical indications for fursl were determined by analyzing the imaging data and clinical conditions, and a preoperative double-j stent was indwelt for 14 weeks. in all patients, a routine preoperative urinalysis and urine culture were performed the morning before surgery, and re-examined based on the clinical condition after surgery. patients with negative urine cultures were empirically treated using antibiotics during the perioperative period of fursl to prevent uti. empirical urology journal/vol 18 no. 4/ july-august 2021/ pp. 445-451. [doi: 10.22037/uj.v16i7.6033] vol 18 no 4 july-august 2021 446 antibiotics, which we refer to as the antibiotics chosen by surgeons based on clinical experience when the pathogen test results were unknown or negative, were prescribed with a course of intravenous treatment that lasted 30-60 minutes preoperatively to 24-48 hours postoperatively in patients without risk factors for infection. correspondingly, the course of antibiotics in patients with risk factors for infection (long history of lithiasis, severe hydronephrosis, chronic kidney disease, and diabetes mellitus) was prolonged from 24-48 hours preoperatively to 48-72 hours postoperatively. based on the antibiotic regimen used, patients were divided into two groups, namely: levofloxacin group (lvxg) and non-levofloxacin group (nlvxg). levofloxacin hydrochloride injection (yangtze river pharmaceutical group, china) was usually used in lvxg at a dosage of 0.2 g twice daily. perioperative characteristics and postoperative clinical outcomes, including patient gender, age, the side, location, size, and history of urinary stones were recorded. additionally, conditions such as severe hydronephrosis, chronic kidney disease, diabetes mellitus, operative time, postoperative and total hospital stay, the total cost of hospitalization, postoperative fever rate and removal rate of stones were recorded for each group. operative time was defined as the time from ureteroscopy insertion to the placement of the ureteral stent. axillary temperature above 38℃ was considered as postoperative fever, which indicated the diagnostic criteria of systemic inflammatory response syndrome. the definition of complete removal of stones by surgery was when no residual stones were observed in the kidney or if stone fragments less than 4mm were revealed upon imaging studies one month later. the clinical outcomes of fursl were compared between the two groups to evaluate the intervention effect of empirically used antibiotics focusing on levofloxacin. pathogen distribution and their antibiotic sensitivities were obtained in patients with positive urine cultures. urine samples from those patients were tested again after they were administered anti-infective treatment using sensitive antibiotics; fursl was carried out when a negative culture report was obtained or when the leukocytes in their urine decreased. endoscopic surgery apparatus and accessory tools such as modular flexible ureteroscope (polydiagnost, germany), fiberoptic flexible ureteroscope (storz, germany), digital flexible ureteroscope (olympus, japan), rigid ureteroscope (wolf, germany), holmium laser (lumenis, usa), ureteral access sheath (cook, usa) and nitinol stone baskets (cook, usa) were used when required. in most cases, the procedure of fursl was as follows: patients were general anesthesia in the lithotomy position. the double-j stent, placed preoperatively, was removed using ureteroscopy (8/9.8f), and the ureteroscope was drawn out leaving a retrograde safety guidewire. subsequently, a flexible ureteroscope was inserted after the ureteral access sheath (12/14f) had been placed under the guidance of wire. while locating the kidney stones, a 200μm holmium laser fiber was prepared for fragmenting calculi using appropriate parameters (1.0j, 20hz). larger fragments were taken out using a nitinol stone basket and subjected to analysis using infrared spectroscopy table 1. empirical use of antibiotics with negative urine cultures during perioperative period. antibiotics cases (n) prescription rate (%) levofloxacin 373 68.95 cefoxitin sodium 79 14.60 cefotaxime sodium 27 5.00 piperacillin-sulbactam 19 3.51 cefotaxime 22 4.07 sulbacillin sodium 6 1.11 clindamycin 3 0.55 piperacillin-tazobactam 6 1.11 ceftriaxone sodium 3 0.55 etimicin sulfate 3 0.55 total 541 100.00 parameters total lvxg nlvxg p patients, n 541 373 168 gender, n(%) 0.297 male 371 (68.6) 261 (70.0) 110 (65.5) female 170(31.4) 112 (30.0) 58 (34.5) age in years, mean ± sd 49.57 ± 11.27 49.01 ± 10.68 50.82 ± 12.41 0.085 stone side, n(%) 0.687 left 256 (47.3) 181 (48.5) 75 (44.6) right 256 (47.3) 173 (46.4) 83 (49.4) bilateral 29 (5.4) 19(5.1) 10 (6.0) stone location, n(%) 0.211 kidey 477 (88.2) 335 (89.8) 142 (84.5) upper ureteral 25 (4.6) 15 (4.0) 10 (6.0) kidney and upper ureteral 39 (7.2) 23 (6.2) 16 (9.5) stone size, mm, mean ± sd 18.87 ± 3.74 18.94 ± 3.79 18.69 ± 3.64 0.467 history of urinary stone, n(%) 0.493 positive 208 (38.4) 147 (39.4) 61 (36.3) negative 333 (61.6) 226 (60.6) 107 (63.7) severe hydronephrosis, n(%) 0.832 positive 18 (3.3) 12 (3.2) 6 (3.6) negative 523 (96.7) 361(96.8) 162 (96.4) chronic kidney disease, n(%) 0.494 positive 30 (5.5) 19 (5.1) 11 (6.5) negative 511 (94.5) 354(94.9) 157 (93.5) diabetes mellitus, n(%) 0.894 positive 47 (8.7) 32 (8.6) 15 (8.9) negative 494 (91.3) 341(91.4) 153 (91.1) lvxg = levofloxacin group; nlvxg = non-levofloxacin group; n = number of patients; sd = standard deviation. table 2. preoperative characteristics of patients with negative urine cultures. levofloxacin during the perioperation of furslao et al. to evaluate the calculi composition. lastly, 5f double-j stent and 16f catheter were retained. the research was approved by the research ethics committee of the first affiliated hospital of wannan medical college. informed consents were obtained from the participants. the leader of the first affiliated hospital of wannan medical college and the ethics committees made an agreement on this research and approved this consent procedure. statistical package for social sciences for windows version 22.0 was used for comparing the perioperative characteristics and postoperative clinical outcomes between the two groups using the independent sample t-test and chi-squared test with two-sided p < 0.05 being regarded as statistically significant. multivariate logistic regression analysis was performed to confirm the role of risk factors of postoperative fever in patients with negative preoperative urine cultures. furthermore, the pathogen spectrum determined from positive urine cultures and resistance rates of antibiotics were listed and analyzed. results during the perioperative period of fursl, 541 patients with negative urine cultures were prescribed antibiotics, including quinolones, β-lactams, and lincosamides which were concerned mainly with the use of levofloxacin and cephalosporins. the empirical utilization rate of levofloxacin was as high as 68.95% (373/541) (table 1). the preoperative characteristics of all patients with negative urine cultures are described in table 2. no significant differences in the characteristics between the characteristics of lvxg and nlvxg are seen, which indicates good comparability. table 3 demonstrates that nlvxg has similar postoperative clinical outcomes compared to that of lvxg in terms of operative time, the total cost of hospitalization, and the removal rate of stones. on the other hand, lvxg has a lower cost of antibiotics (53.83 ± 10.17 vs 68.28 ± 13.81 usd, p = 0.000) but a higher postoperative fever rate (9.4% vs 4.2%, p = 0.036), longer postoperative hospital stay (2.74 ± 1.36 vs 2.38 ± 1.62, p = 0.007), and total hospital stay (8.51 ± 3.25 vs 7.83 ± 2.68, p = 0.011) compared to that in nlvxg. perioperative urine culture was positive in 213 patients, including 80 males (37.56%) and 133 females (62.44%). a total of 216 positive isolates were detected, which comprised 115 types of gram-negative bacteria, 82 types of gram-positive bacteria, and 19 variants of fungi. the most common pathogen isolated was escherichia coli (36.11%) followed by enterococcus faecalis (24.07%) (table 4). after investigating the drug sensitivity test reports of pathogens to antibiotics, it was found that the common gram-negative bacteria that are sensitive to cefoperazone sulbactam, piperacillin-tazobactam, cefotetan, amikacin, imipenem etc., had high resistance to ampicillin, cefazolin, ceftriaxone, levofloxacin and aztreonam (table 5). similarly, the typical parameters total lvxg nlvxg p patients, n 541 373 168 operative time, min, mean ± sd 90.49 ± 37.66 89. 42 ± 36.23 92.85 ± 40.68 0.328 postoperative hospital stay, d, mean ± sd 2.63 ± 1.45 2.74 ± 1.36 2.38 ± 1.62 0.007 total hospital stay, d, mean ± sd 8.30 ± 3.01 8.51 ± 3.25 7.83 ± 2.68 0.011 total cost of antibiotics, usd, mean ± sd 58.32 ± 13.23 53.83 ± 10.17 68.28 ± 13.81 0.000 total cost of hospitalization, usd, mean ± sd 2704 ± 522.3 2692 ± 508.5 2731 ± 552.1 0.415 postoperative fever, n(%) 0.036 positive 42 (7.8) 35 (9.4) 7 (4.2) negative 499 (92.2) 338 (90.6) 161 (95.8) stone removal, n(%) 0.521 complete 412 (76.2) 287 (76.9) 125 (74.4) incomplete 129 (23.8) 86 (23.1) 43 (25.6) table 3. postoperative clinical outcomes in lvxg versus nlvxg. lvxg = levofloxacin group; nlvxg = non-levofloxacin group; n = number of patients; sd = standard deviation; usd = united states dollar (converted from cny at the exchange rate on october 22, 2019). isolated pathogens isolates (n) constituent ratio (%) gram-negative 115 53.24 escherichia coli 78 36.11 proteus mirabilis 18 8.33 klebsiella pneumoniae 9 4.17 pseudomonas aeruginosa 3 1.39 acinetobacter junii 3 1.39 serratia marcescens 2 0.93 aeromonas hydrophila 2 0.93 gram-positive 82 37.96 enterococcus faecalis 52 24.07 staphylococcus epidermidis 12 5.56 streptococcus agalactiae 9 4.17 staphylococcus haemolyticus 6 2.78 staphylococcus saprophyticus 1 0.46 staphylococcus aureus 2 0.93 fungus 19 8.80 candida albicans 11 5.09 candida glabrata 8 3.70 table 4. distribution and constituent ratio of pathogens in urine cultures during perioperative period. levofloxacin during the perioperation of furslao et al. unclassified 447 vol 18 no 4 july-august 2021 448 gram-positive bacteria, that are sensitive to vancomycin, linezolid, furantoin etc., had high resistance to tetracycline, clindamycin, erythromycin, gentamycin and levofloxacin (table 6). remarkably, our study showed high resistance rate for levofloxacin for e. coli, proteus mirabilis and klebsiella pneumoniae with values of 74.36%, 61.11% and 66.67% respectively, while the corresponding values were determined to be 71.15%, 83.33%, and 66.67% for e. faecalis, staphylococcus epidermidis and streptococcus agalactiae. in the multivariate logistic regression analysis, the use of levofloxacin, moderate to severe hydronephrosis, and history of diabetes were independent risk factors for postoperative fever in preoperative urine culture-negative patients (p < 0.05) (table 7). discussion it is well known that the treatment of large upper urinary tract stones, especially kidney stones, relied on open surgery in the past. currently, minimally invasive percutaneous nephrolithotripsy (pcnl) and fursl are the primary choices.(10,11) clinical studies have confirmed that fursl is effective in treating renal calculi that are around 2 cm in size.(12-15) in such cases, fursl is more popular than pcnl as the former involves less trauma, is a safer procedure and is associated with faster patient recovery(16). however, there are still some serious complications in the perioperative period of fursl, such as postoperative uti, urosepsis, and even septic shock. these could be caused by factors such as preoperative uti, obstruction due to renal calculi, high intrarenal pressure, kidney injury, pathogens invading the blood after lithotripsy, and prolonged surgical duration.(8,17,18) despite generally attaching importance to the fursl procedure, knowledge regarding the prevention of infection and selection of antibiotics during the perioperative period of fursl is limited. routine urine cultures during the perioperative period are of great value to prevent uti and help select suitable antibiotics.(19) in our institution, urine culture and drug susceptibility testing should be performed at least once before fursl. surgery can only be carried out if the urine culture is negative. studies have shown that positive urine cultures, hydronephrosis, large stones, infectious stones, high renal pressure, and diabetes are risk factors for postoperative infection of the upper urinary tract in patients who have undergone endoscopy. (20,21) however, preoperative urine cultures may not accurately reflect the infection status of patients with renal obstruction and those in whom the double-j stent is not appropriately placed in the renal pelvis.(21) in such patients, pyelouria or core fragments of the stone can be used for culture and antibiotic susceptibility tests. furthermore, a postoperative urine culture should also be repeated to prevent changes in pathogens. calculi generally obstruct the urinary tract, which may antibiotics escherichia coli (n = 78) proteus mirabilis (n = 18) klebsiella pneumoniae (n = 9) isolates (n) resistance rate (%) isolates (n) resistance rate (%) isolates (n) resistance rate (%) ampicillin 66 84.62 13 72.22 9 100.00 ampicillin-sulbactam 55 70.51 7 38.89 7 77.78 cefoperazone-sulbactam 0 0.00 0 0.00 0 0.00 piperacillin-tazobactam 6 7.69 0 0.00 0 0.00 ciprofloxacin 61 78.21 7 38.89 7 77.78 levofloxacin 58 74.36 11 61.11 6 66.67 cefazolin 66 84.62 7 38.89 4 44.44 cefotaxime 6 7.69 0 0.00 0 0.00 ceftazidime 49 62.82 4 22.22 4 44.44 cefatriaxone 64 82.05 3 16.67 3 33.33 cefepime 52 66.67 3 16.67 0 0.00 compound sulfamethoxazole 38 48.72 13 72.22 7 77.78 tobramycin 26 33.33 4 22.22 0 0.00 aztreonam 55 70.51 4 22.22 0 0.00 gentamicin 32 41.03 10 55.56 0 0.00 amikacin 14 17.95 0 0.00 0 0.00 nitrofurantoin 6 7.69 17 94.44 4 44.44 imipenem 3 3.85 3 16.67 0 0.00 table 5. resistance rates of common gram-negative pathogens to antibiotics antibiotics enterococcus faecalis (n = 52) staphylococcus epidermidis (n = 12) streptococcus agalactiae (n = 9) isolates (n) resistance rate (%) isolates(n) resistance rate (%) isolates (n) resistance rate (%) ampicillin 3 5.77 10 83.33 0 0.00 clindamycin 35 67.31 11 91.67 8 88.89 ciprofloxacin 12 23.08 11 91.67 6 66.67 erythromycin 29 55.77 11 91.67 7 77.78 gentamicin 23 44.23 1 8.33 6 66.67 tetracycline 38 73.08 5 41.67 5 55.56 vancomycin 0 0.00 0 0.00 0 0.00 levofloxacin 37 71.15 10 83.33 6 66.67 penicillin 6 11.54 11 91.67 1 11.11 linezolid 0 0.00 0 0.00 0 0.00 moxifloxacin 12 23.08 10 83.33 5 55.56 nitrofurantoin 0 0.00 0 0.00 0 0.00 tegafycline 0 0.00 0 0.00 0 55.56 table 6. resistance rates of common gram-positive pathogens to antibiotics. levofloxacin during the perioperation of furslao et al. result in bacteriuria or infection following lithotripsy. studies have shown that prophylactic antibiotics can reduce the incidence of bacteriuria after ureteroscopic lithotripsy, but can not reduce the risk of postoperative uti.(22-24) a reduction in the incidence of bacteriuria should reduce the risk of infection; however, the actual situation may be complicated and depend on several factors, including damage to the ureteral wall during the procedure, location of the stone, and pressure of the irrigation fluid, which may increase the chances of postoperative infection in the urinary tract. most urologists recommend the use of prophylactic antibiotics before ureteroscopic lithotripsy.(24) the use of the ureteroscope, especially during lithotripsy, causes varying degrees of ureteral-wall injury. the extent of damage depends on the clinical experience of the surgeon. generally, complicated renal calculi treated using ureteroscopic lithotripsy pose higher risks of infection. therefore, even if urine cultures are negative in patients who have been indicated lithotripsy, empirical antibiotic treatment is still necessary.(25) in this study, 541 patients with negative urine cultures were empirically prescribed antibiotics to prevent uti. the commonly prescribed antibiotics in our department are levofloxacin and cephalosporins. compared to nlvxg, patients in lvxg had similar clinical outcomes, such as operative time, the total cost of hospitalization, and complete stone removal rate, but lower total cost of antibiotics, higher postoperative fever rate, and longer hospitalization. although levofloxacin is inexpensive and a frequently prescribed drug in china, our study shows that levofloxacin use did not significantly reduce the total cost incurred by patients, but rather increased postoperative fever rate and prolonged the hospital stay, leading to increased costs. this may be related to the false-negative results of urine cultures and levofloxacin resistance, both of which resulted in an unsatisfactory anti-infective effect. to a certain extent, our study reveals that there is no obvious value or advantage in prescribing levofloxacin empirically during the perioperative period of fursl. after analyzing the pathogen spectrum and drug-susceptibility results from positive cultures, we found that e. coli (36.11%) and e. faecalis (24.07%) were the top two bacteria that were highly resistant to levofloxacin. (7,8,26) the most accepted method to determine an antibiotic regimen is to select appropriate and sensitive anti-infective agents based on culture results. however, since laboratory reports are obtained relatively late, the norm is to first prescribe antibiotics empirically and then titrate the regimen based on laboratory findings and patient condition. prolonged delays and waiting for culture results may adversely affect the efficacy of drug therapy, especially in patients with high-risk of utis; therefore, it is particularly essential to choose suitable antibiotics during the perioperative period. the rate of levofloxacin resistance in bacteria was more than 60% and as high as 74.36% in the case of e. coli in our investigation, which suggested that this antibiotic was table 7. multivariate analysis of fever after fursl in patients with preoperative urine culture negative cases p value or 95%ci use of levofloxacin < 0.001 8.901 2.633～30.095 moderate to severe hydronephrosis 0.001 7.381 2.305～23.632 operative time (≥60min) 0.342 0.561 0.170～1.851 history of diabetes(yes) 0.015 4.437 1.338～14.714 not efficacious and, therefore, unsuitable for empirical use. our clinical study reveals the experiential rate of levofloxacin to be 68.95%, which is inappropriate. on the other hand, if high-grade antibiotics such as ceftriaxone, imipenem, and vancomycin are used directly to achieve anti-infective effect when culture studies are not indicated, patients are treated by supposed safe medication with the suspicion of abusing antibiotics which may lead to more resistant pathogens and even super-bacteria in the long run. the increasing insensitivity of ceftriaxone to pathogens for uti treatment is a problem that has been faced in recent years.(27,28) based on the data from our study, we believe that the empirical utilization of levofloxacin should be reduced in the perioperative period of fursl. in line with our analysis, antibiotics, such as cefotetan, piperacillin-tazobactam, and amikacin, or similar drugs (cefoxitin, piperacillin sulbactam, etimicin,etc.) , with low resistance to common bacteria may be used instead of levofloxacin. eventually, these antibiotics can be adjusted based on the results of drug-susceptibility tests. in addition, easy-to-use tools, for instance, “excel” spreadsheets for monitoring and standardizing the management of antibiotics and, summarizing the pathogens spectra and antibiotic sensitivity, thereby reducing the irrational use of antibiotics in clinical work.(29) in the long run, such measures may not only improve the safety and effectiveness of the procedure, but also accelerate the postoperative rehabilitation of patients therefore, this would be in accordance with the concept of enhanced recovery after surgery.(30) our study had some limitations. in addition to the limitations of the retrospective study itself, several surgeons were involved in performing fursl. at times, the choice of antibiotic inevitably depended on the surgeon’s preference or the clinical knowledge of antibiotic-resistance profiles of microorganisms, which may have resulted in different surgical outcomes. in this single-center investigation, fursl procedures were performed by qualified senior endoscopic specialists of our department, and we believe that this difference may have had minimal impact on standardized fursl. owing to the increase in surgical steps and associated costs, we did not consider urine from the renal pelvis or the core part of the stone for pathogen cultures. however, it has been reported that the discordance between the results of urine and stone cultures carries a high risk of postoperative systemic inflammatory response syndrome.(21,31) therefore, this study needs further improvement and our future work will be directed toward a multicenter prospective cohort study to obtain more convincing data that could serve as a powerful reference for the rational use of antibiotics during the perioperative period of fursl. conclusions this study determined that levofloxacin, which is familiar to surgeons, was used empirically in the perioplevofloxacin during the perioperation of furslao et al. unclassified 449 vol 18 no 4 july-august 2021 450 erative period of fursl and often used excessively. despite it being inexpensive, levofloxacin was found to be unsatisfactory in clinical practice and displayed an inordinate resistance rate. when fursl is performed in areas with a high incidence of urinary calculi, levofloxacin might no longer be suitable as an empirically used antibiotic in our center; therefore, a decrease in the use of levofloxacin and using alternative sensitive antibiotics based on the findings from urine culture is recommended. conflict of interest none declared. references 1. zeng g, mai z, xia s, et al. prevalence of kidney stones in china: an ultrasonography based cross-sectional study. bju int. 2017;120:109-16. 2. komori m, izaki h, daizumoto k, et al. complications of flexible ureteroscopic treatment for renal and ureteral calculi during the learning curve. urol int. 2015;95:26-32. 3. xu k, ding j, shi b, wu y, huang y. flexible ureteroscopic holmium laser lithotripsy with polyscope for senile patients with renal calculi. exp ther med. 2018;16:1723-8. 4. carlos ec, youssef rf, kaplan ag, et al. antibiotic utilization before endourological surgery for urolithiasis: endourological society survey results. j endourol. 2018;32:978-85. 5. jang wh, yoo dh, park sw. prevalence of and risk factors for levofloxacin-resistant e. coli isolated from outpatients with urinary tract infection. korean j urol. 2011;52:5549. 6. wu yh, chen pl, hung yp, ko wc. risk factors and clinical impact of levofloxacin or cefazolin nonsusceptibility or esbl production among uropathogens in adults with community-onset urinary tract infections. j microbiol immunol infect. 2014;47:197-203. 7. wu hh, liu hy, lin yc, hsueh pr, lee yj. correlation between levofloxacin consumption and the incidence of nosocomial infections due to fluoroquinolone-resistant escherichia coli. j microbiol immunol infect. 2016;49:424-9. 8. senocak c, ozcan c, sahin t, et al. risk factors of infectious complications after flexible uretero-renoscopy with laser lithotripsy. urol j. 2018;15:158-63. 9. deng t, liu b, duan x, et al. antibiotic prophylaxis in ureteroscopic lithotripsy: a systematic review and meta-analysis of comparative studies. bju int. 2018;122:2939. 10. taguchi k, cho sy, ng ac, et al. the urological association of asia clinical guideline for urinary stone disease. int j urol. 2019;26:688-709. 11. zetumer s, wiener s, bayne db, et al. the impact of stone multiplicity on surgical decisions for patients with large stone burden: results from resku. j endourol. 2019;33:742-9. 12. hyams es, monga m, pearle ms, et al. a prospective, multi-institutional study of flexible ureteroscopy for proximal ureteral stones smaller than 2 cm. j urol. 2015;193:1659. 13. pieras e, tubau v, brugarolas x, ferrutxe j, piza p. comparative analysis between percutaneous nephrolithotomy and flexible ureteroscopy in kidney stones of 2-3cm. actas urol esp. 2017;41:194-9. 14. zhu z, cui y, zeng f, li y, chen z, hequn c. comparison of suctioning and traditional ureteral access sheath during flexible ureteroscopy in the treatment of renal stones. world j urol. 2019;37:921-9. 15. el-nahas ar, almousawi s, alqattan y, alqadri im, al-shaiji tf, al-terki a. dusting versus fragmentation for renal stones during flexible ureteroscopy. arab j urol. 2019;17:138-42. 16. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015 ;67:125-137. 17. berardinelli f, de francesco p, marchioni m, et al. infective complications after retrograde intrarenal surgery: a new standardized classification system. int urol nephrol. 2016;48:1757-62. 18. chen y, liao b, feng s, et al. comparison of safety and efficacy in preventing postoperative infectious complications of a 14/16f ureteral access sheath with a 12/14f ureteral access sheath in flexible ureteroscopic lithotripsy. j endourol. 2018;32:923-7. 19. hu h, lu y, he d, et al. comparison of minimally invasive percutaneous nephrolithotomy and flexible ureteroscopy for the treatment of intermediate proximal ureteral and renal stones in the elderly. urolithiasis. 2016;44:427-34. 20. koras o, bozkurt ih, yonguc t, et al. risk factors for postoperative infectious complications following percutaneous nephrolithotomy: a prospective clinical study. urolithiasis. 2015;43:55-60. 21. singh p, yadav s, singh a, et al. systemic inflammatory response syndrome following percutaneous nephrolithotomy: assessment of risk factors and their impact on patient outcomes. urol int. 2016;96:207-11. 22. deng t, liu b, duan x, et al. antibiotic prophylaxis in ureteroscopic lithotripsy: a systematic review and meta-analysis of comparative studies. bju int. 2018;122:2939. 23. whitehurst l, jones p, somani bk. mortality from kidney stone disease (ksd) as reported in the literature over the last two decades: a systematic review. world j urol. 2019;37:75976. 24. lo cw, yang ss, hsieh ch, chang sj. effectiveness of prophylactic antibiotics against post-ureteroscopic lithotripsy levofloxacin during the perioperation of furslao et al. infections: systematic review and metaanalysis. surg infect (larchmt). 2015;16:41520. 25. wang ss, ratliff pd, judd wr. retrospective review of ceftriaxone versus levofloxacin for treatment of e. coli urinary tract infections. int j clin pharm. 2018;40:143-9. 26. lin ha, yang ys, wang jx, et al. comparison of the effectiveness and antibiotic cost among ceftriaxone, ertapenem, and levofloxacin in treatment of community-acquired complicated urinary tract infections. j microbiol immunol infect. 2016;49:237-42. 27. ramos lazaro j, smithson a, jove vidal n, batida vila mt. clinical predictors of ceftriaxone resistance in microorganisms causing febrile urinary tract infections in men. emergencias. 2018;30:21-7. 28. chua kyl, stewardson aj. individual and community predictors of urinary ceftriaxoneresistant escherichia coli isolates, victoria, australia. antimicrob resist infect control. 2019;8:36. 29. miglis c, rhodes nj, avedissian sn, et al. a simple microsoft excel method to predict antibiotic outbreaks and underutilization. infect control hosp epidemiol. 2017;38:8602. 30. saidian a, nix jw. enhanced recovery after surgery: urology. surg clin north am. 2018;98:1265-74. 31. nevo a, mano r, shoshani o, kriderman g, schreter e, lifshitz d. stone culture in patients undergoing percutaneous nephrolithotomy: a practical point of view. can j urol. 2018;25:9238-44. levofloxacin during the perioperation of furslao et al. unclassified 451 kidney transplantation the frequency and risk factors of delayed graft function in living donor kidney transplantation and its clinical impact on graft and patient survival in part of middle east mohsen nafar1,2, pedram ahmadpoor1,2, torki al otaibi3, fahad e alotaibe4,5 , meteb m albugami 4,5, wael habhab6, ali abdulmajid dyab allawi7, nooshin dalili1,2*, denis glotz8 purpose: delayed graft function (dgf) is a form of acute renal failure which results in increased post-transplantation allograft immunogenicity and risk of rejection episodes in addition to decreased long-term survival. its incidence and risk factors have been extensively studied, especially after deceased donation. however until now, only few data has been published on dgf in living donor kidney transplant recipients. the present study was performed to investigate the frequency and risk factors of dgf among livingkidney transplant recipients. material and methods: in this retrospective study, 500 living kidney transplant recipients recruited and data collected from hospital registries in three countries (iran, kingdom of saudi arabia (ksa) , and kuwait ). results: incidence of dgf revealed to be %95) %2.3 ci: %3.6-%0.9). dgf group showed significant older age for the recipients and in “without dgf” group, there were more females, and lower weight for the recipients. it was found that patients with dgf had longer pre transplant dialysis duration, cold ischemic and anastomosis time during surgery . conclusion: dgf after living-donor kidney transplantation is a multifactorial complication which donor, recipient, and technical factors would lead toward. consideration and optimization of these risk factors may drive through better long-term patient and graft outcomes in living kidney transplant recipients. keywords: living kidney transplantation; delayed graft function; allograft rejection; slow graft function introduction there are many different descriptions for delayed graft function in litreture as defined by: dialysis requirements within one week after transplantation, urine output less than 1200 ml during first day after transplantation, serum creatinine decrease less than 10% during 48 hours after transplantation, creatinine greater than 2.5 mg/dl at ten days after transplantation , creatinine clearance less than 10 ml/min/1.73m2 during 24 hours after transplantation or creatinine did not decrease less than preoperative value(1-6). what we have used as the definition of dgf is requirement for dialysis within the first week after surgery. regarding diversity in definition, the incidence of dgf varries widely among different studies. according to published literature, the incidence of dgf in living donor kidney recipients varies 1division of nephrology, department of internal medicine, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2chronic kidney disease research center (ckdrc), department of nephrology, labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. 3transplant nephrology department, hamed al-essa organ transplant center, kuwait. 4multi-organ transplant center, king fahad specialist hospital, dammam, saudi arabia. 5department of internal medicine, college of medicine, university of dammam, dammam, saudi arabia. 6department of medicine, king faisal specialist hospital and research centre, jeddah, saudi arabia. 7frcp london,baghdad college of medicine,university of baghdad. 8hopital saint louis, paris, university paris-diderot and inserm u1160, paris, france. *correspondence: assistant prof. of nephrology, division of nephrology, department of internal medicine, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran ,chronic kidney disease research center (ckdrc), department of nephrology, labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran tel:00989122404331 e-mail: nooshindalili4@gmail.com. drn.dalili@sbmu.ac.ir received april 2019 & accepted september 2019 from 1.6% up to 18.3% (3-7) depending on the different studies. whatever the definition is , the occurrence of delayed graft function , has been shown to be a strong risk factor for reduced renal allograft survival(4). factors related to the donor and the recipient can contribute to this condition(5-6). although many studies published on predictive factors of dgf after cadaveric kidney transplantation , related factors in living donor kidney recipients are still unclear. as dgf has significant impacts on living donor kidney transplantation outcome, identification of dgf risk factors is critical to improve prognosis in this population. in the present study we aimed to evaluate incidence and related risk factors of dgf after living donor kidney transplant recipients in three different countries of middle east. urology journal/vol 17 no. 1/ january-february 2020/ pp. 55-60. [doi: 10.22037/uj.v0i0.5263] materials and methods study population no formal sample size calculation was performed, the sample size has not been determined in terms of statistical power, but rather in terms of precision (95% confidence interval) associated to event rate estimation. according to the number of kidney transplantation in each participating site, it was estimated that 500 living donor kidney transplantations are done over 8-10 months. accordingly and in order to have 3 years post transplant follow up information, all living donor kidney transplantations through oct 2009 oct 2011 who met the inclusion criteria were enrolled. 500 patients, from 3 centers in 3 countries were recruitted. distribution of subjects by country was as following :iran (n = 300), kuwait (n = 100) and ksa (n = 100) (figure 1). as it was a retrospective registry with no access or possibility to recall patients, obtaining informed consent from patients was waived up to the local regulatory processes. approvals were obtained from each site to access patients’ records and collect their data. patient selection and evaluation inclusion criteria was: living donor kidney recipients with complete history prior transplantation and 3 years post transplantation data, including those who died during the observation period. exclusion criteria was kidney recipients younger than 18 years. this was a retrospective observational study conducted in three centers, using pre-existing data of local hospital registries in iran, ksa and kuwait including living donor kidney transplantation with recipient’s history before the transplant up to 3 years post surgery. utilized data for this study was collected based on routine clinical practice of medical practitioners across the participating countries. this study did not impose any additional procedures, assessments or changes to routine management of patients. specific collecting forms were designed for gathering the following data: the recipients and donors characteristics prior to transplantation, time on dialysis(months), the number of previous transplantations, panel reactive antibody (pra) after transplantation if available, frequency of dgf, cold and warm ischemic times, immunosuppressive regimens (induction, if any used), adverse events, acute and chronic biopsy proven graft rejections, graft survival and patient survival at 1, 2 and 3 years follow-up. as a potential important contributor in dgf is timing of introduction of clacineurin inhibitors (cni) , we tried to choose centers with similar immunosuppression protocols post transplantation. based on this concept cni was initiated according to same protocol in involved centers when the serum creatinine decreases to ≤ 4 mg/dl or to ≤ 50% of pre-operation value whichever is lower, or within 72 hours after surgery. cnis dose should be maximized within 24 h of the last dose of atg. cyclosporine (neoral®) initiated at 6 mg/ kg orally divided to two times per day; or tacrolimus (prograf®) 0.15 mg/kg orally divided to two times per day. primary endpoint was to assess percentage of recipients experiencing dgf among living donor kidney transplantation. dgf defined as need of dialysis within the first days after transplantation in living donor kidney transplantation recipients. secondary endpoints were : demonstrating demographic data of donors and recipients , primary causes of end-stage renal disease, pre-transplant time on dialysis, ischemic time , immunological status , pra( panel reactive antibody) if it was done, status of hla matching if available, type of immunosuppressive regimens (induction if used), post transplantation complications, acute and chronic biopsy proven graft rejection, graft and patient survival at 1, 2 table 1. the eligible patients’ records flow throughout study categorized by involved countries and percentage of patients experiencing dgf in living donor kidney transplantation recipients dgf status iran (n=297) ksa (n=83) kuwait (n=100) overall (n=480) count % count % count % count % dgf 6 2% 3 3.6% 2 2% 11 2.3% lower 95% ci 0.4% -0.5% -0.8% 0.9% upper 95% ci 3.6% 7.7% 4.8% 3.6% no dgf 291 98% 80 96.4% 98 98% 469 97.7% total 297 100 83 100% 100 100% 480 100% esrd suspected causes with dgf (n=11) without dgf (n=469) p value overall (n=480) count % count % count % unknown 5 45.5% 184 39.2% 0.759** 189 39.4% known* 6 54.5% 285 60.8% 291 60.6% • diabetes mellitus 5 45.5% 73 15.6% 0.021** 78 16.3% • hypertension 2 18.2% 172 36.7% 0.342** 174 36.3% • glomerular disease 0 0% 17 3.6% 1** 17 3.5% • adpkd 0 0% 9 1.9% 1** 9 1.9% • failure of previous transplant 0 0% 2 0.4% 1** 2 0.4% • urological disorders 0 0% 13 2.8% 1** 13 2.7% • other causes 0 0% 24 5.1% 1** 24 5% esrd duration mean ±sd mean ±sd p value mean ±sd duration (years) 2.01 ±1.86 1.44 ±1.88 0.106*** 1.46 ±1.88 *fisher s exact test to compare the percentage between the study groups (with dgf and without dgf). **mann-whitney u to compare between the study groups (with dgf and without dgf). ***one patient may has one or two suspected causes for esrd. table 2. comparison between primary cause of end-stage renal disease in two groups delayed graft function in living kidney transplantation-nafar et al. kidney transplantation 56 vol 17 no 01 january-february 2020 57 and 3 years post transplantation depending on follow-up time and slow graft function (sgf) incidence defined as creatinine reduction ratio (crr) between time 0 of transplantation and day 7 post-transplantation of <70%. data was summarized using frequency and percentages for categorical parameters with its 2-sided 95% confidence interval (ci) and mean, median, standard deviation, range and 95% ci for continuous parameters. all statistical tests performed using two-tailed tests at a 5% level of significance. for comparison between patients who experienced dgf and those without dgf regarding all secondary endpoints the appropriate statistical tests for comparison were used according to type of compared parameters (e.g. chi square tests for categorical data and student ttest for continuous parameters). using binary logistic regression analysis, the potential risk factors for occurrence of dgf in living donor transplantations were tested. graft and patient survival at 1, 2 and 3 years depending on follow-up time was evaluated using kaplan-meier survival method or wilcoxon test at 5% level of significance. when a greater event rate was seen early in the trial rather than toward the end of the trial, the generalized wilcoxon rank-sum test seemed to be more appropriate test. results the total enrolled patients included in the study sites consisted of 500 patients while the eligible patients consisted of 480 patients. detailed study population, reasons for exclusion and countries distribution are shown in (figure 1). overall, dgf found in 11 recipients (2.3%; 95% ci: 0.9%-3.6%) (table 1) .slow graft function (sgf) defined by creatinine reduction ratio (crr) between time 0 of transplantation and day 7 post-transplantation of < 70% was also calculated and data analysis showed that the overall incidence of sgf in this study was 10.6%. the mean ± sd age of all 480 eligible patients was 42.9 ±13.7 years. the youngest patient was 18 while the oldest patient was 83 years old. the mean ± sd age of the 11 patients with dgf was 44.45 ±12.72 years. out of the 480 eligible patients; 314 (65.4%) were men and 166 (34.6%) were women. out of the 11patients with dgf, eight were men and three (27.3%) were women. the two most common causes of esrd were hypertension (36.3%) and diabetes mellitus (16.3%). among diabetic cases, 45.5% had experienced dgf with significant statistical difference (p = 0.021) (table 2). among the 11 patients with dgf, five (45.45%) patients had other comorbidities. hypertension (36.4%) was the main comorbidity found in patients with dgf and without dgf (32.8%). the mean ± sd duration for dialysis before transplantation for the 11 patients who had developed dgf was 26.36 ± 26 months, while for the 434 patients who had not developed dgf it was 15.39 ± 20.60 months. taking into consideration that a patient could have more than one pre-transplant immunizing event type, it was found that 99 (20.63%) patients had history of blood or blood product transfusion, 17 (3.54%) were pregnant and only four (0.83%) had high panel reactive antibody (pra). 399 (83.3%) patients have done pra level test mostly at transplantation time. out of the 11 patients who have experienced dgf, 9 (81.82%) patients have done pra test. taking into account that patient could have more than one pra method, collected data showed that pra in dgf patients was determined mainly by cytotoxicity (66.67%), followed by solid phase assays in 33.33% and flow cytometry in 11.11%. all of the 11 patients who have experienced dgf showed negative cytotoxicity white blood cell cross match results. collected data showed that among the patients who have experienced dgf, two (18.18%) patients had hla-a1 mismatching, two (18.18%) patients had hla-b2 mismatching followed by one (9.1%) patient who had hla-a2 mismatching, one (9.1%) patient had hla-b1 mismatching, one (9.1%) patient had hladr1 mismatching and one (9.1%) patient had hladr2 mismatching. regarding donor specific antibody (dsa); among patients with dgf, it was found that 72.73% were dsa-negative, while results for 27.27% were unknown. among donor population overall, the mean ± sd age of all 480 donors was 29.41 ±5.6 years. out of the 480 donors; 404 (84.2%) were men and 76 (15.8%) were women. the mean bmi ±sd of the donors was 25.43 ± 4.17 kg/m2. regarding the 11 patients who have developed dgf, only three (27.27%) patients received a graft from genetically related donors. complete classification regarding the type of living donation is summarized in table 3. regarding the ischemia time, for the 11 patients with dgf, the data was missing for eight patients regarding to cold ischemia time but for the remaining three patients whose data were available, the mean ± sd duration for preservation in cold temperature was 101 ± 72 min. it was found that the mean table 3. type of living transplant type of living transplant with dgf without dgf overall count % count % count % genetically related 3 27.2% 107 22.8% 110 22.9% unrelated 8 72.7% 362 77.2% 370 77.08% total 11 100% 469 100% 480 100% patient death with functioning graft with dgf (n=11) without dgf (n=469) p value overall (n=480) count % count % count % yes 0 0% 12 2.6% 1* 12 2.5% no 11 100% 457 97.4% 468 97.5% *fisher s exact test to compare the percentage between the study groups (with dgf and without dgf) table 4. patient survival at 1,2 and 3 years post-transplant followup delayed graft function in living kidney transplantation-nafar et al. ± sd cold ischemia time for harvested kidney preservation was significantly longer (p = 0.013) in patients with dgf than in patients without dgf (25 ±7.9 min). cold ischemia time (cit) was defined as the duration between the beginning of cold storage and reperfusion of the graft. regarding warm ischemia time in patients with dgf, the data was missing for six cases but in remaining five patients whose data were available there was insignificant difference (p = 0.138) in the warm time preservation between patients with dgf (21.8 ± 22 min) and patients without dgf (18.8 ± 12.1 min). the vascular anastomosis duration was significantly longer (p = 0.013) among patients with dgf (49 ±18 min) than in patients without dgf (31.5 ± 6.9 min) . out of the eligible population (n = 480), the number of patients who have not received induction therapies was 274 (57.08%) patients. out of the 11 patients who have developed dgf, data showed that seven (63.64%) patients have received induction therapies. the most common type of induction therapy administered was basiliximab followed by rabbit anti-human thymocyte immunoglobulin. during the first week of post-transplantation phase, 18.18% patients with dgf have experienced surgical complications from which 9.1% fulfilled sepsis criteria and 9.1% experienced other surgical complications. among patients without dgf 2.13% have experienced surgical complications meanwhile hemorrhage was the most common one (1.5%) followed by sepsis. hence, it is shown that the percentage of early surgical complications was significantly lower (p = 0.028) among patients who had not developed dgf (2.13%) than patient who had developed dgf (18.18%). post-transplant early medical complications in recipients were found in 19.1% out of the total eligible population (n = 480) while the percentage of early complications was again significantly lower within the first week post transplantation (p = 0.002) among patients who had not developed dgf (18.1%) than patient who had developed dgf (63.6%). safety results revealed that the percentage of patients who experienced post transplant complications was significantly lower (p < 0.001) in patients without dgf than patients with dgf. the most frequently reported among these adverse events from the total enrolled population was renal tubular necrosis as it had occurred in 10.2% of patients and transplant rejection in 9.4% of patients, followed by thrombocytopenia in 6% , urinary tract infection in 2.6% , cytomegalovirus positive test in 1.8% and graft loss in 1.4% of patients. as it was a retrospective study missing data about the rate and pathologic details of rejections limit concluding significant result however biopsy proven graft rejection had been reported in 60 (12.5%) of patients from the total eligible population. the rejection was considered early (occur figure1. patient disposition figure 2. graft survival delayed graft function in living kidney transplantation-nafar et al. kidney transplantation 58 vol 17 no 01 january-february 2020 59 within less than 6 months) in 44 (75% ) cases while it defines as late ( after 6 months post transplantation) in 24.1%. overall, there was no statistical significant difference between both groups (with or without dgf) regarding the graft rejection frequency proven by biopsy (p=0.636). there was statistically significant higher rate (p<0.001) of graft loss among patients with dgf (27.3%) than patients without dgf (0.9%) throughout 3 years of follow-up. the 3 years graft survival rate among patients with dgf was 72.7% while among patients without dgf was 99.1%. thus, the graft survival was significantly shorter (p < 0.001) among patients with dgf (2.26 years) than patients without dgf (4.02 years). (figure 2) during three years follow-up it was found that, 12(2.5%) patients had died. there was statistically insignificant difference (p = 1) regarding patient survival among patients with dgf (100%) and without dgf (97.4%) throughout these 3 years follow-up post transplantation. (table 4) discussion incidence of dgf varies a lot according to previous literature with different mentioned risk factors including female donor (6), low donor weight (6), high recipient / donor weight ratio(5-6), donor age(8), warm ischemia time (8), hla mismatch(3), female recipient(3) and non-related donor(3). in one published study(4) conducted between 1994 and 2010 in iran, dgf complicated 67/385 transplant recipients (17.4%). dgf is not a minor event. indeed, patients experiencing dgf are more at risk of rejection which can be considered as the main drawback of kidney transplantation and long term graft survival is significantly impacted in patients experiencing both dgf and rejection(6). in a study published by kwon (5) evaluating effect of dgf on graft survival in living donor kidney transplantation, the rate of acute rejection in patients experiencing dgf was 70.6%(6), the 5-year graft survival rate was significantly lower in patients with acute rejection episode complicated by dgf than in patients who experienced acute rejection without dgf (61% vs. 74% respectively, p < 0.002). moreover, in a retrospective cohort study reported by narayanan (7) in 645 patients with first living kidney transplantation over 12 years the cumulative probability of biopsy-proven acute rejection (bpar) was higher in dgf patients. the 1-, 3-, and 5-year probabilities of bpar were 16.0% (95% confidence interval (ci): 11.8, 21.3), 21.8% (95% ci: 16.8, 27.9), and 22.6% (95% ci: 17.5, 28.9) in the dgf group and 10.1% (95% ci: 7.6, 13.5), 12.4% (95% ci: 9.5, 16.1), and 15.7% (95% ci: 12.2, 20.1) in the non-dgf group, respectively (p = 0.01). in our study as the primary end point 2.3% experienced dgf (n = 11) which can be logical due to short ischemic time in living–donated recipients accompanied by younger and healthier donors. comparing the demographic data of both recepients and donors this can be shown that, in the cases that had experienced dgf , recipients were significantly older (44.5 ± 12.7 years). as request for kidney transplants outweighs the reserve pool, some transplantation centers have consumed ‘extended criteria kidneys’ particularly those from older donors(9) which are associated with inferior recipient outcomes including reduced short-term and long-term glomerular filtration rate and reduced overall graft survival(10-11). according to a previous experience in iran conducted on 3716 transplanted cases, donor age was the only statistically significant predictor of graft survival rate.(12) on the other hand, older recipients are also at an increased risk of death with functioning graft independent of donor age(12-13). the total effect of age matching seems to be little, but as an individualized approach there appears to be benefits. this study confirmed that recipient’s diabetes appeared as one of the important risk factors for poor initial graft function. we believe that this is more than a simple incidental finding and an underlying relationship may exist as diabetes potentiates ischemia/reperfusion injury thus increases the need for early post transplant dialysis. while expressing the role of long-term diabetes remains challenging, controlling hyperglycemia at the time of transplant is entirely achievable. evaluating the effect of tight versus poor glucose control in both donors and recipients to determine the effect of glucose control at the time of organ procurement and at the time of reperfusion of the transplanted kidney would be the next step to clarify the impact of diabetes on delayed graft function after living kidney transplantation. the mean duration of dialysis pre-transplantation for the patients with dgf was clinically but not statistically longer in dgf group (p = 0.055). these data ascertained that waiting time on dialysis before kidney transplantation is a risk factor for graft dysfunction independent of donor factors(14). because pre-transplantation dialysis duration is increasing as a result of the widening gap between the increase in the demand for organs and the increase in organ donations, importance of preemptive transplantation should be taken into account more than the last decade. prolonged vascular anastomosis duration is another risk factor for dgf. according to the united network for organ sharing registry (unos) data, the effect of cold ischemic time continues for years, beyond an average level of about 20 h. (15) according to this study longer cold ischemic and vascular anastomosis time can prone the recipients to develop dgf. more than half of our eligible population did not received induction therapy (57.1%). the mechanism of thymoglubulin as an induction therapy in reducing ischemia-reperfusion injury (iri) known to be mainly the result of direct blocking the cell-to-cell interactions and decreasing the degree of leukocyte rolling and adhering along capillary endothelium.(16) furthermore, thymo reduces the number of peripheral lymphocytes from the circulating pool by inducing t-cell depletion through complement-related lysis or activation associated apoptosis (17). lopez et al. showed that the therapeutic effect of thymo is not only due to t-cell depletion, but also due to generation of regulatory t-cell(18). hence using thymoglobulin as pre transplantation induction would minimize the ischemia reperfusion injury in the grafted organ and subsequently preventing dgf. this study evaluated the very important topic of delayed graft function among recipients of living donor kidney transplants . however , the small sample size limits meaningful subgroup analysis . meanwhile this retrospective study was mainly based on collecting data from existing local hospital registries facing with incompleted medical records and missing data . pathological details about the type of rejections were missing data as well which disable us to pulling out any significant results regarding the differences between rejection in dgf and nondgf groups. delayed graft function in living kidney transplantation-nafar et al. conclusions a number of recipient and donor variables have been identified as dgf risk factors for patients with deceased donor grafts , still, predictive factors associated with dgf following living donor kidney transplantation, remain unknown. the aim of this study was to explore these predictors. it was a, retrospective study on dgf incidence and risk factors among living donor kidney transplant recipients in three countries of middle east including; iran, ksa and kuwait. incidence of dgf revealed to be 2.3% (95% ci: 0.9%-3.6%) of the 480 eligible enrolled cases .the comparisons between recipients and donors among dgf group showed significant older age for the recipients than donors. in the “without dgf” group, there were significant, more females, and lower weight for the recipients. it was found that patients with dgf had longer pre transplant dialysis duration, cold ischemic and anastomosis time during surgery. dgf after living-donor kidney transplantation is a multifactorial complication which donor, recipient, and technical factors would lead toward. consideration and optimization of these risk factors may lead to better long-term patient and graft outcomes in living kidney transplant recipients. acknowledgements we express our gratitude to all the transplantation ward staff for their support and cooperation in completing this study. conflict of interest this publication received research support from sanofi medical funding . all authors disclose no conflict of interest that may have a direct bearing on the subject matter or content of this article. references 1. perico n, cattaneo d, sayegh mh, remuzzi g. delayed graft function in kidney transplantation. the lancet. 2004; 364 181427. 2. salamzadeh j, sahraee z, nafar m, parvin m. delayed graft function (dgf) after living donor kidney transplantation: a study of possible explanatory factors. ann transplant. 2012; 17 : 69-76 . 3. park hs, hong ya, kim hg. delayed graft function in living-donor renal transplantation: 10-year experience. transplant proc. 2012; 44 :43-6. 4. ghadiani mh, peyrovi s, mousavinasab. delayed graft function, allograft and patient survival in kidney transplantation. arab j nephroltranspl .2012; 5: 19-24. 5. kwon oj, ha mk, kwak jy. the impact of delayed graft function on graft survival in linving donor transplantation. transplant proc .2003; 35: 92-3 . 6. senel fm, karakayali h, moray g. delayed graft function: predictive factors and impact on outcome in living-related kidney transplantations. ren fail .1998 ; 20 : 589-95. 7. narayanan r, cardella cj, cattran dc. delayed graft function and the risk of death with graft function in living donor kidney transplant recipients. am j kidney dis .2010 ;56: 961-70. 8. sharma ak, tolani sl, rathi gl. evaluation of factors causing delayed graft function in live related donor renal transplantation. saudi j kidney dis transpl. 2010 ;21: 242-5. 9. campbell s, mcdonald s, livingston b. transplant waiting list. australia and new zealand dialysis and transplant registry. 2007; 1: 1-7. 10. hawley c, kearsley j, campbell s . estimated donor glomerular filtration rate is the most important donor characteristic predicting graft function in recipients of kidneys from live donors. transpl int .2007; 20: 64–72 . 11. issa n, stephany b, fatica r et al. donor factors influencing graft outcomes in live donor kidney transplantation. transplantation .2007; 83: 593–599 . 12. simforoosh n, basiri a, tabibi a, javanmard b, kashi ah, soltani mh, obeid k .living unrelated versus related kidney transplantation: a 25-year experience with 3716 cases. urol j. 2016 ; 13: 2546-51. 13. lim w, chang s, coates p, mcdonald s. parental donors in live-donor kidney transplantation associated with increased rejection rates and reduced glomerular filtration rates. transplantation .2007; 84: 972–980 . 14. ceckaj.the unos renal transplant registry. clintranspl.2001;1:21 . 15. wong g .waiting time between failare of fisrt graft and second kidney transplant and graft and patient survival. transplantation .2016 ;100: 1767-75. 16. salahudeen ak, haider n, may w. cold ischemia and the reduced long-term survival of cadaveric renal allografts. kidney int .2004;65: 713-8. 17. michallet mc, preville x, flacher m, fournel s, genestier l, revillard jp. functional antibodies to leukocyte adhesion molecules in antithymocyte globulins. transplantation .2003; 75: 657–62. 18. mohsen nafar, nooshin dalili.the appropriate dose of thymoglobulin induction therapy in kidney transplantation. clinical transplantation . 2017; 6: 1-8. 19. lopez m, clarkson mr, albin m, sayegh mh, najafian n. a novel mechanism of action for anti-thymocyte globulin: induction of cd4+cd25+foxp3+ regulatory t cells. j am soc nephrol .2006;17: 2844-53. delayed graft function in living kidney transplantation-nafar et al. kidney transplantation 60 1126 | miscellaneous a non-invasive method to evaluate the efficacy of human myoblast in botulinum-a toxin induced stress urinary incontinence model in rats balaji bandyopadhyay, anirban thakur, viral dave, chandra viswanathan, deepa ghosh corresponding author: deepa ghosh, phd tissue engineering group, regenerative medicine, reliance life sciences pvt. ltd., dalc campus, 282–ttc area of midc, thane belapur road, rabale, navi mumbai 400701, india. tel: +11 91 22 67678436 fax: +91 22 3911 8099 e-mail: deepa_ghosh@relbio.com received july 2012 accepted december 2012 tissue engineering group, regenerative medicine, reliance life sciences pvt. ltd., dalc campus, navi mumbai 400701, india miscellaneous purpose: to develop a simple non-invasive method to assess the efficacy of a cell based therapy for treating stress urinary incontinence (sui). materials and methods: in this study, skeletal myoblasts were used as candidate therapy to reverse sui. the sui model was created in rats using periurethral injection of botulinum-a toxin injection. two weeks later, the rats were administered saline and the level of continence in each botulinum-a toxin treated and control animals was assessed by the extent of voiding using metabolic cages. to determine the efficacy of myoblasts to reverse sui, botulinum-a toxin treated incontinent rats were injected with either cultured human skeletal myoblasts or with buffered saline (sham control). two weeks post implantation, the extent of continence was evaluated as mentioned above. results: the difference in void volume between botulinum-a toxin -treated and control rats were significant. histological analysis of the urethra showed remarkable atrophy of the muscular layer. a significant reversal (p = .025) in the volume of voiding was observed in cell-implanted rats as compared to sham injected rats. histological analysis of the urethra implanted with myoblasts showed recovery of the atrophied muscular layer in comparison to sham control. immunofluorescence analysis of the cell injected tissues confirmed the presence of human myoblasts in the regenerated area. conclusion: this simplified method of in vivo testing can serve as a tool to test the efficacy of new therapies for treating sui. keywords: muscle; botulinum toxins, type a; urinary incontinence; stress; urethra; rat; disease model. 1127vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction it has been reported that more than 200 million people are afflicted with urinary incontinence (ui) worldwide(1) and nearly half of them have symptoms of stress urinary incontinence (sui). sui severely impacts quality of life and its etiology is considered to be multifactorial. current therapies for sui do not treat the underlying causes and often involve the introduction of foreign materials such as silicone particles, carbon beads and bovine collagen.(2) however, the efficacy of such treatment declines with time, and repeated injections are required.(3) other disadvantages of these include periurethral abscess, chronic inflammation and obstruction of the lower urinary tract, severe voiding dysfunction, and pulmonary embolism.(4) treatment of sui with conventional surgical sling procedure sometimes results in postoperative voiding difficulty with a limited cure rate due to intrinsic sphincter deficiency.(5) the potential of cells such as skeletal muscle derived myoblasts and stem cells like adipose tissue-derived stem cells (adsc) and bone marrow derived mesenchymal stem cells to reverse sui have been studied extensively.(6,7) although none of the existing animal models completely simulate the human situation, nonetheless, animal models are widely used to understand the pathophysiology of sui and enable preclinical testing of potential treatments.(8) several sui animal models such as nerve injury,(9,10) urethral cauterization,(11) pubourethral ligament injury, urethrolysis,(12) and botulinum-a toxin induced chemical denervation(13) models have been developed to understand different aspects of urinary continence mechanism. in sui, unintentional urine leakage occurs as a result of a behavioral condition. since animals cannot indicate their intent, the assessment of sui in animal models therefore involves functional surrogates of urethral resistance to leakage.(14) methods such as urethral closure pressure testing, sneeze testing and leak point pressure (lpp) testing etc are some of the methods that are used for assessing sui in animal models.(15) cannon and colleagues had demonstrated the formation of new skeletal muscle fiber following an injection of skeletal muscle cells (myoblasts) in the urethra.(16) autografting of muscle precursor cells in a murine model of urethral sphincter injury has also been reported.(17) the results demonstrated that this procedure may accelerate sphincter muscle repair by producing a significant increase in the diameter and number of myofibers, suggesting that these cells could serve as a potential therapeutic approach to treat urethral sphincter insufficiency. the aim of our present study was to develop a simplified noninvasive method to test the efficacy of treatment for sui. using cultured human myoblasts as a candidate, we have tested its efficacy in a botulinum-a toxin induced sui animal model. in this study, cultured human myoblasts were injected periurethrally and efficacy of the implanted cells to reverse sui was analyzed following intraperitoneal administration of saline. the volume of urine voided was compared in rats injected with and without cells. histological tests were performed to check the morphology of the urethra and immunohistochemical analysis was done to confirm the presence of the implanted cells. materials and methods materials myoblast culture media (skgm-2 bullet kit) was purchased from lonza, usa. the dulbecco's modified eagle's medium (dmem) and all other cell culture reagents were purchased from sigma, usa. plastic ware for cell culture was obtained from nunc, usa. calcium phosphate transfection kit was purchased from promega, usa, and antibodies (desmin and myosin 1a-heavy chain) were from abcam, usa. the cdna of the gfp constructed into the lentiviral vector prlsindeco, was a kind gift from dr. wei li (department of dermatology, university of southern california, usa). animals wistar rats were bred in-house. all animals were handled in accordance with the cpcsea guidelines for the welfare of laboratory animals practices laid down by the government of india. the study was approved by the institutional animal ethical committee (iaec). myoblasts isolation, culture and characterization skeletal muscle biopsies were collected from patients undergoing elective surgery after receiving informed consent method to evaluate sui | bandyopadhyay et al 1128 | and approval from an independent institutional ethics committee. biopsy samples were transported to the lab and were processed under aseptic condition. briefly, the biopsies were rinsed in hanks buffered saline solution (hbss) and their surface was decontaminated by immersing in povidoneiodine (win medicare, india) for 1-2 min. the tissues were further incubated for 20 min serially in 10×, 5× and 1× concentration of ampicillin-amphotericin-streptomycin (aas) solution (gibco). the tissues were chopped into small pieces and digested in a solution containing a mixture of 1.2 units of dispase and 4 mg/ml of collagenase iv (1:1), for 30 min at 37ºc with intermittent shaking. the resulting tissue suspension was passed through 70µm strainer (becton dickinson, usa) and centrifuged for 5 min at 1200 rpm. the cell pellet was then re-suspended in myoblast growth media (skgm2 bullet kit from lonza, usa) supplemented with 10% fetal bovine serum (lonza, usa) and plated in tissue culture dishes and incubated at 37ºc in a humidified atmosphere containing 5% co2. to obtain an enriched myoblast population, the unattached cells in the dishes were transferred after 48 h to collagen-i (sigma) coated plates (100 ng/ml). media was changed every third day in the coated dishes till the cells reached 70-80% confluency. the cultured myoblasts were purified by macs® separation (millteny biotec, usa) using anti-human desmin antibody. the identity of the isolated cells was further confirmed by staining with the above desmin antibody. differentiation of the purified myoblasts to myotubes was induced by culturing highly confluent myoblasts (> 80% confluency) in differentiation media containing dmem and 2% horse serum (lonza, usa) for two weeks. myoblasts were identified by standard immunofluorescence method. briefly, cells were fixed with cold acetone for 20 min followed by incubation with monoclonal anti-human desmin antibody (1:50). positive cells were identified by counterstaining with fitc-conjugated anti-mouse antibody (1:500) (bd bioscience, usa). differentiated myoblasts were identified after incubation with monoclonal myosin heavy chain (mhc) antibody (1:100), followed by alexa-fluor-568 conjugated secondary antibody. total cells in each field were identified by 4'6 -diamidino2-phenylindole (dapi) (sigma) staining and visualized using fluorescence microscope (observer.z1.carl zeiss, germany) transduction of gfp into myoblasts using lentiviral vector the lentivirus-derived vector prrlsinhcmv was inserted with egfp cdna using ecorv. this construct was used to co-transfect 293t cells together with packaging vectors pcmvδr8.2 and vsvg. typical viral titers were 1-7 × 106 transduction units/ml as measured by previously described method.(18) the cell infection efficiency was 66% (data not included) as monitored by the percentage of cells positive for gfp expression using facs analysis [facs calibur (e3851), (beckton dickenson)]. creation of sui model in rats the sui model was created in rats by using the method described by takahashi and colleagues.(13) briefly, twelve rats aged between 4-6 weeks were anesthetized with ketamine (80 mg/kg) and xylazine (40 mg/kg) intraperitoneally. physiological saline containing botulinum-a toxin (allergan, india), (7u/100 µl) was injected periurethrally at the mid urethra, which was located at the level of the symphysis pubis. three rats were similarly injected with only saline (control). the rats were kept in individual cages and had free access to water and food. incontinence testing two weeks after the botulinum toxin treatment, 10 ml of normal saline solution warmed to 37ºc was injected intraperitoneally into each rat and the animals were housed individually in metabolic cages (tecniplast, italy). bladder function was assessed by measuring urine output at the end of 15 minutes after saline injection. saline was injected thrice in each animal at an interval of 30 minutes, and the average volume voided by each animal was calculated. table. volume of urine voided by control and treated rats in metabolic cages. treatment group no. of animals volume of urine voided (ml) saline control 3 0.9 ± 0.2 botulinum a toxin 12 4.4 ± 0.5 sham control 3 4.5 ± 0.6 myoblasts treated 6 1.3 ± 0.4 miscellaneous 1129vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l periurethral implantation of labeled cells to study the efficacy of implanted myoblasts on sui, the incontinent rats created as mentioned earlier were immunosuppressed with cyclosporine a (5mg/kg of body weight) starting 2 days prior to the implantation of cells till the end of the study.(19) six rats were injected with gfp positive myoblasts (8 × 106 cells) suspended in hbss on either side of urethra, and three animals were similarly injected with hbss buffer alone(sham control). after two weeks, the continence test was repeated in the sham control and cell injected test animals. the animals were euthanized and the urethra was excised for histological and immunohistological analysis. histological analysis for histological analysis, the excised mid-urethra was fixed in 10% buffered formalin, and embedded in paraffin blocks and sectioned into 5-μm thick slices. these were de-paraffinized and hydrated with water. sequential sections were stained with hematoxylin and eosin or masson trichrome according to the manufacturer’s protocol (sigma-aldrich, usa). figure 1. phase contrast images of myoblasts (a) and (c) myotubes. fluorescence images of myoblasts stained with antidesmin antibody (b) and myotubes stained with antimhc-1a antibody (d). scale bar represents 50 µm. figure 3. representative sections of rat urethra stained with hemotoxylin eosin (top lane) and masson’s trichrome stain (bottom lane). scale bar represent 100 µm. figure 2. diagrammatic representation of the experimental design. method to evaluate sui | bandyopadhyay et al 1130 | the effect of treatment on the muscular layer of the urethra was evaluated using light microscopy and photographed. the mean thickness of the four regions of external urethral sphincter (eus) comprising striated muscles, near the two diagonal lines was evaluated in detail in each rat using zen software (carl zeiss, oberkochen, germany). to prevent variations in masson’s trichrome staining, all samples were stained simultaneously. images from the entire sections were acquired under light microscope (observer. z1, carl zeiss, oberkochen, germany). following masson’s trichrome staining of the sections, cells in blood vessels, smooth muscle layer and rhabdosphincter layer, stained red while collagens stained blue. the multiple images were analyzed using the software zen (carl zeiss, oberkochen, germany) which automatically distinguished regions stained with different colors and measured the area of muscle and collagen to yield muscle/collagen ratio. immunohistochemical analysis of myoblasts formalin-fixed, paraffin-embedded tissues were sectioned at 5 µm thickness. these sections were deparaffinized and rehydrated. antigen retrieval was performed by heating the deparaffinized sections in citrate buffer in a microwave for 35 seconds followed by cooling at room temperature for 20 min. the sections were further incubated in 1% bovine serum albumin (bsa) in pbs for 1 hr at room temperature followed by incubation with mouse anti-desmin monoclonal antibody, (abcam biotech, usa) at 4ºc overnight. desmin positive cells were detected by counter staining with alexa-fluor-568 secondary antibody (molecular probes, invitrogen, oregon, usa). total cells in the sections were visualized by staining with dapi. green and red fluorescent cells were visualized under a fluorescence microscope (observer. z1, carl zeiss, oberkochen, germany). statistical analysis histological data are reported as mean (median). microsoft excel was used for statistical analysis. mann whitney u test was used to determine the significance of difference in voiding as well as morphometric data seen between rats implanted with human myoblasts and control. statistical significance was determined at p values < 0.05. results cultured myoblasts characterization human myoblasts were highly enriched following macs® separation. under phase contrast microscope, cultured myoblasts are spindle shaped (figure 1a) and expressed myoblast specific desmin (1b). in presence of low serum, the cultured myoblasts differentiated to form multi-nucleated myotubes (figure 1c) that expressed myosin heavy chain (mhc-1a). evaluation of continence figure 4. ratio of muscle/collagen in the urethral wall of treated and untreated rats. *p = .002 and **p < .001. figure 5. fluorescence images of human myoblast implanted rat urethral wall. a. gfp positive human myoblasts are identified as green cells. b. the same section counter stained with anti-human desmin antibody and counter stained with alexa-fluor-568 secondary antibody. positive cells are visualized as red cells. total cells in the field are identified after staining with dapi. miscellaneous 1131vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l a pilot study using 2.5, 5, 7 and 10 u of botulinum-a toxin was conducted in wistar rats to identify the effective concentration of botulinum-a toxin needed to cause chemical denervation of the urethra. based on the results of the pilot study, 7 u was identified as the optimal dose required for inducing incontinence. a diagrammatic representation of the experimental design is shown in figure 2. as shown in table, a significant increase in the volume of micturition was observed in all animals injected with botulinum-a toxin as compared to control (p = .009). the effect of myoblast implantation/hbss injection (sham control) in the above sui induced rats was assessed using the same procedure as mentioned earlier. a significant difference was observed in the volume of urine voided between sham and myoblasts injected animals (p = .025). 84% of rats injected with myoblasts regained continence within two weeks as compared to 0% in hbss injected animals. histological analysis histological examination of the urethra stained with hemotoxylin and eosin revealed a typical morphology in saline injected control rats (figure 3a). the tissue showed several layers, starting with the epithelial layer (filled arrow) then the underlying lamina propria consisting of a layer of smooth muscle cells and the external urethral sphincter (eus) made of a thick layer of striated muscle (open arrow). mid-urethral cross-sections showed striated and smooth muscle fibers circumferentially around the urethra. the mean thickness of the four regions of striated muscle, near the two diagonal lines was evaluated in each rat. the morphological images revealed that the striated muscles significantly atrophied at 2 weeks after botulinum-a toxin administration (figure 3b). the thickness of eus was 82.4 (80) µm at two weeks in botulinum-a toxin injected urethra as compared to 172.3 (162) µm in control rats (p < .0001). following myoblast implantation, the thickness of the muscle layers increased to 192.7 (205) µm as compared to sham injected control which was 91.3 (94) µm (p < .0001). the distribution of muscle to collagen in the eus area of massons’s trichrome stained sections was captured as a ratio using the zen1-observer software. four to six random areas in each section were analyzed under 200× magnification. as shown in figure 4, the ratio of muscle to collagen content in botulinum toxin injected rats reduced to 1.03 (1.0) as compared to saline injected control rats 2.1 (1.9), p = .002. sham control group presented a muscle/collagen distribution similar to the botulinum toxin injected urethral wall 0.94 (0.8), p = .1. following myoblasts implantation, however the muscle content significantly increased as compared to sham control 1.85 (1.85), p < .0001. figure-3 (e-h) shows representative masson´s trichrome stained sections at different time points. presence of gfp positive cells in the paraffin sections of urethra of rats implanted with human myoblasts indicated the presence of implanted myoblasts in the urethra (5a). the same section on counter staining with human desmin antibody confirmed the presence of human cells (5b). the gfp positive cells had formed myotubes and were seen to be aligned along the rhabdosphincter. significance was observed between saline and botulinum-a toxin injected (p = .009) and sham control and myoblast treated (p = .025) discussion clinical treatments for sui include conservative techniques, pharmacologic therapy, and surgical procedures. in the clinical condition, sophisticated urodynamics and other related tests are performed for diagnosis and treatment. to test the efficacy of new surgical techniques or pharmacologic targets it is still necessary to use animal models of sui. the existing techniques to evaluate efficacy of a therapy in sui animal models are labor intensive and require specialized instruments. besides, existing animal testing methods require anesthesia to immobilize the animal in addition to invasive and non-survival studies. the main purpose of the present study was to develop a simplified noninvasive method to evaluate the efficacy of a therapy such as myoblast therapy in a sui model. takahashi and colleagues had earlier demonstrated that periurethral injection of botulinum-a toxin induced chemical denervation lead to a significant decrease in lpp, and remarkable shrinkage of the smooth muscle layer and striated sphincter.(13) as compared to pudendal nerve transection(20) and electrocauterization(21,22) methods used to impair urethral sphincter, botulinum-a toxin induced urethral muscle sphincter impairment does not involve an abdominal incimethod to evaluate sui | bandyopadhyay et al 1132 | sion. we had chosen this noninvasive model to create sui. while 10 u botulinum-a toxin was used in takashi’s study, our preliminary studies indicated 7 u was optimal for sui creation. this could be attributed to the difference in the animal strain being used in the study. in the incontinence model developed by lin and colleagues using vaginal balloon dilation method, only 46% of animals were deemed incontinent after the procedure(26) whereas with botulinum toxin induced sui model 100% of animals became incontinent. disadvantage of both models is the spontaneous restoration of continence with time. to determine urethral resistance in animal models of sui, several methods mimicking a variety of clinical urodynamic tests have been developed. one of the most widely used methods to evaluate urethral resistance in rats is lpp.(13,21,24,25,27) in these animal models, the intravesicular pressure is evaluated by urethral or suprapubic catheter. however, since lpp evaluation in rats can trigger micturition and urethral catheter may increase the urethral resistance, a well-trained investigator is required to eliminate confounding variables. our method of evaluation which is also based on urethral resistance to leakage does not involve the use of a catheter and overcomes some of these challenges facing lpp test. several studies have shown that direct injection of muscle derived cells improve urethral sphincter contraction and contribute to continence in animal models of sui.(23, 24) periurethral injection of muscle derived cells improved the lpp in a denervated female rat model of sui,(20) and in rats that showed intrinsic sphincter deficiency following radical prostatectomy.(11) using human myoblasts as a candidate we have demonstrated the efficacy of periurethrally implanted muscle cells by analyzing the urine output following cell implantation. our results corroborate with lpp data observed in other similar studies.(21,24,25,27) kim and colleagues demonstrated the feasibility of using muscle derived human cells in nude denervated rat sui model.(25) a decrease in lpp from control levels was observed in the sham group following denervation of urethra. as compared to the sham group, the group reported restoration of lpp in the rats injected with muscle derived cells. using a botulinum toxin induced sui rat model, we similarly observed a significant increase in micturition in botulinum toxin injected rats as compared to control group (p < .05). this increased micturition could be a result of decreased lpp. the authors’ observation correlates with our data wherein the recovery of continence was observed following myoblast implantation when compared to sham group (p < .05). the reversal of incontinence observed in our study could be attributed to the presence of implanted cells as confirmed by positive staining with human muscle specific desmin antibody. while the implanted cells might have contributed directly to the formation of the skeletal muscle, its paracrine effect on resident stem cells to stimulate new muscle formation cannot be ignored. some of the structural changes observed in the intrinsic structure of the urethra affected with sui was observed in our histological analysis.(28,29) our data demonstrated that urethral dysfunction induced by botulinum toxin was accompanied by decreased muscle content and/or increase in connective tissue deposition which was reversed following myoblast implantation. conclusion the simplified non-invasive technique that was employed in this study to assess continence can be used as a screening method to check for efficacy of potential candidates for sui treatment. acknowledgements we acknowledge the encouragement and support of reliance life sciences pvt. ltd to carry out the research work (www. rellife.com). we thank dr. harinarayana rao, dr. akash shinde and other members of lars and tissue engineering group for their support. conflict of interest none declared. references 1. wagner th, hu tw. economic costs of urinary incontinence. int urogynecol j. 1998;9:127-8. 2. chapple cr, wein aj, brubaker l, et al. stress incontinence injection therapy: what is best for our patients? eur urol. 2005;48:552-65. miscellaneous 1133vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l method to evaluate sui | bandyopadhyay et al 3. corcos j, fournier c. periurethral collagen injection for the treatment of female stress urinary incontinence: 4-year follow-up results. urology. 1999;54:815-8. 4. strasser h, tiefenthaler m, steinlechner m, eder i, bartsch g, konwalinka g. age dependent apoptosis and loss of rhabdosphincter cells. j urol. 2000;164:1781-85. 5. haab f, zimmern pe, leach ge. female stress urinary incontinence due to intrinsic sphincteric deficiency: recognition and management. j urol. 1996;156:3-17. 6. 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kefer jc, liu g, daneshgari f. pubo-urethral ligament injury causes long-term stress urinary incontinence in female rats: an animal model of the integral theory. j urol. 2009;181:397400. 13. takahashi s, chen q, ogushi t, et al. periurethral injection of sustained release basic fibroblast growth factor improves sphincteric contractility of the rat urethra denervated by botulinum-a toxin. j urol. 2006;176:819-23. 14. rodriguez lv, chen s, jack gs, de af, lee kw, zhang r. new objective measures to quantify stress urinary incontinence in a novel durable animal model of intrinsic sphincter deficiency. am j physiol regul integr comp physiol. 2005;288:r1332-8. 15. jiang hh, damaser ms. animal models of stress urinary incontinence. handb exp pharmacol. 2011;202:45-67. 16. cannon tw, lee jy, somogyi g, et al. improved sphincter contractility after allogenic muscle-derived progenitor cell injection into the denervated rat urethra. urology. 2003;62:958-63. 17. yiou r, dreyfus p, chopin dk, abbou cc, lefaucheur jp. muscle precursor cell auto-grafting in a murine model of urethral sphincter injury. bju int. 2002;89:298-302. 18. bandyopadhyay b, fan j, guan s, li y, chen m, woodley dt. a traffic control role for tgfβ3: orchestrating dermal and epidermal cell motility during wound healing. j cell biol. 2006;172:1093-105. 19. ye l, haider kh, tan rs, et al. transplantation of nanoparticle transfected skeletal myoblasts overexpressing vascular endothelial growth factor – 165 for cardiac repair. circulation. 2007;116:i113-20. 20. lee jy, cannon tw, pruchnic r, fraser mo, huard j, chancellor mb. the effects of periurethral muscle derived stem cell injection on leak point pressure in rat model of stress urinary incontinence. int urogynecol j pelvic floor dysfunct. 2003;14:31-7. 21. chermansky cj, tarin t, kwon dd, et al. intraurethral muscle derived cell injections increase leak point pressure in a rat model of intrinsic sphincter deficiency. urology. 2004;63:780-85. 22. cannon tw, lee jy, somogyi g, et al. improved sphincter contractility after allogenic muscle-derived progenitor cell injection into the denervated rat urethra. urology. 2003;62:958-63. 23. lin cs, lue tf stem cell therapy for stress urinary incontinence: a critical review. stem cells dev. 2012;10;21:834-43. 23. lin cs, lue tf. stem cell therapy for stress urinary incontinence: a critical review. stem cells dev. 2012;21:834-43. 24. kamo i, hashimoto t. involvement of reflex urethral closure mechanisms in urethral resistance under momentary stress condition induced by electrical stimulation of rat abdomen. am j physiol renal physiol. 2007;293:f920-6. 25. kim yt, kim dk, jankowski rj, et al. human muscle-derived cell injection in a rat model of stress urinary incontinence. muscle nerve. 2007;36:391-3. 26. lin as, carrier s, morgan dm, lue tf. effect of simulated birth trauma on the urinary continence mechanism in the rat. urology. 1998;52:143-151. 27. xu y, song yf, lin zx. transplantation of muscle-derived stem cells plus biodegradable fibrin glue restores the urethral sphincter in a pudendal nerve-transected rat model. braz j med biol res. 2010;43:1076-83. 1134 | 28. skaff m, pinto ers, leite krm, almeida fg. development of a rabbit’s urethral sphincter deficiency animal model for anatomical-functional evaluation. int braz j urol. 2012;38:1724 29. kwon d, kim y, pruchnic r, et al. periurethral cellular injection: comparison of muscle-derived progenitor cells and fibroblasts with regard to efficacy and tissue contractility in an animal model of stress urinary incontinence. urology. 2006:68:449-454. miscellaneous endourology and stone disease 22 urology journal vol 7 no 1 winter 2010 results and complications of spinal anesthesia in percutaneous nephrolithotomy sadrollah mehrabi, kambiz karimzadeh shirazi introduction: percutaneous nephrolithotomy (pcnl) is the treatment of choice for large kidney calculi, staghorn calculi, and calculi that are multiple or resistant to shock wave lithotripsy. in many centers, pcnl is performed under general anesthesia. however, complications under spinal anesthesia can be less frequent. we evaluated the impact of spinal anesthesia on intraoperative and postoperative outcome in patients undergoing pcnl. materials and methods: the intra-operative and postoperative anesthetic and surgical outcomes were evaluated in 160 consecutive patients who underwent pcnl under spinal anesthesia in the prone position. results: the mean age of the patients was 40.0 ±14.3 years, and the mean operative time was 95.0 ± 37.8 minutes. the mean calculus size was 34.2 ± 9.8 mm. ten patients had staghorn calculi (mean size, 4.2 ± 1.1 cm; mean operative time, 140 ± 40 minutes). return of sensory and motor activity took 140.0 ± 19.7 minutes and 121.0 ± 23.8 minutes, respectively. during the first part of anesthesia, 18 patients developed hypotension, which was controlled by ephedrine, 10 mg, intravenously. ten patients (6.3%) needed blood transfusion and 6 complained of mild to moderate headache, dizziness, and mild low back pain for 2 to 4 days after the operation, which improved with analgesics and bed rest. seventy percent of the patients had complete clearance of calculus or no significant residual calculi larger than 5 mm on follow-up ultrasonography. conclusion: spinal anesthesia is safe and effective for performing pcnl and is a good alternative for general anesthesia in adult patients. urol j. 2010;7:22-5. www.uj.unrc.ir keywords: percutaneous nephrolithomy, spinal anesthesia, complications department of urology, shahid beheshti medical center, yasuj university of medical sciences, yasuj, iran corresponding author: sadrollah mehrabi sisakht, md department of urology, shahid beheshti medical center, yasuj, iran tel: +98 917 3414331 fax: +98 741 2226517 e-mail: mehrabi390@yahoo.com received february 2009 accepted december 2009 introduction percutaneous nephrolithotomy (pcnl) is now a popular method for removal of kidney and ureteral calculi and the treatment of choice for kidney calculi greater than 2 cm to 3 cm in diameter, multiple kidney calculi, staghorn calculi, and cases of failed shock wave lithotripsy (such as those with calcium oxalate monohydrate and cystine calculi).(1,2) anesthesia for pcnl can be general or regional. regional anesthesia has the advantage of general anesthesia in the abdomen and extremities and avoidance of anaphylaxis due to the use of multiple drugs.(1,3) spinal anesthesia has been proven to reduce the anesthesiologist charge on patients undergoing lower abdominal and limb surgery.(4) complications of general anesthesia such as pulmonary (athlectasia), vascular, and neurologic disorders (brachial nerve injury or spinal cord injury), especially during change of the position are more likely than spinal anesthesia in percutaneous nephrolithotomy—mehrabi and karimzadeh shirazi 23urology journal vol 7 no 1 winter 2010 of spinal anesthesia.(2) there are limited studies regarding the efficacy of regional anesthesia in pcnl. therefore, the aim of this study was to evaluate the intra-operative and postoperative outcomes in patients undergoing spinal anesthesia during pcnl. materials and methods we reviewed a series of 160 pcnls for treatment of urinary calculi in patients older than 16 years old who underwent spinal anesthesia between december 2006 and july 2008. the ethics committee of yasuj university approved the study. the patients’ pre-operative characteristics were recorded. the hemodynamic and anesthetic variables were recorded before, during, and after the operation. spinal anesthesia was induced with bupivacaine, 15 mg, and fentanyl, 25 µg, injected intrathecally at the l3-l4 interspaces, and the head of the bed was tilted down for 5 to 10 minutes, while checking the level of anesthesia. the patients underwent cystoscopy and a ureteral catheter was placed under direct vision whilst in the lithotomy position. conscious sedation during pcnl was obtained with intravenous diazepam, 2.5 mg, or midazolam, 1 mg to 1.5 mg. replacement of the sedative drug was then performed to maintain adequate anxyolisis and parallel protective airway reflexes during the surgery. following the induction of spinal anesthesia, the patients were helped to be rotated to the prone position in order to obtain the best position for percutaneous access to the affected renal system. percutaneous nephrolithotomy was done under the guide of fluoroscopy with 1-shot technique by an amplatz dilator, holding a 28-f to 30-f amplatz sheath, and the use of a 24-f nephroscope according to the standard methods of access. for kidney elevation in the prone position, only a small gelatinous bolster or a rolled towel was held under the flank of the patient. severity of pain during the operation and 1 hour after return of sensory blockage was checked by visual analogue scale (vas), and the results and complications were recorded. all of the patients received 10 mg of metoclopramide, 2 mg to 4 mg of dexamethasone, and prophylactic antibiotics. they were advised to have complete bed rest for at least 12 hours, postoperatively. on the first postoperative day, presence of any complications and postoperative pain were checked. on the 2nd postoperative day, the nephrostomy tube was clumped for at least 3 hours in case there was not any obstructive calculus in the pelvis or the ureter on plain abdominal radiography. if there was no fever, urinary leak, or flank pain, the nephrostomy tube would be removed and the patient would be discharged from the hospital. for 1 week, if the patient had any problem including headache, backache, lower limb pain, and weakness, or cardiopulmonary impairment, they were referred to the emergency room and standard treatment was started on. two weeks after the operation, all of the patients underwent an ultrasonography for evaluation of the efficacy of operation and detection of any residual calculi. results the mean age of the patients was 35.0 ± 12.7 years. seventy-five percent of the patients (n = 120) were men. the mean operative time, from the beginning of anesthesia to termination of the operation, was 110 ± 40 minutes. the mean calculus size was 3.2 ± 1.6 cm. twelve patients had staghorn calculi with a mean calculus size of 4.1 ± 1.3 cm, and the operative time was 138 ± 45 minutes in this group. the mean time for return of sensory and motor activity was 140.0 ± 19.7 minutes and 121.0 ± 23.8 minutes, respectively. in all of the patients, pcnl was successful. in 8 patients (5.0%), supracostal access was required, which was tolerated well without pulmonary complications. according to the vas, 1 patient (0.6%) had moderate to severe pain and 8 patients (5.0%) had mild pain during the operation. one of the patients with a staghorn calculus complained of local pain in the site of the operation after 130 minutes, which was controlled by 1 ml (50 µg) of fentanyl and ketamine. major intra-operative or postoperative spinal anesthesia in percutaneous nephrolithotomy—mehrabi and karimzadeh shirazi 24 urology journal vol 7 no 1 winter 2010 complications such as visceral, vascular, and neurologic injury or unusual bleeding did not occur in any of the patients. eighteen patients developed hypotension 3 to 10 minutes after the regional anesthesia that was controlled by injecting 10 mg of ephedrine intravenously. the mean hemoglobin decrease during the 24 postoperative hours was 2.1 ± 0.4 g/dl. eight patients (5.0%) required transfusion of 1 to 2 units of packed cell. six patients younger than 30 years old complained from moderate postsubarachnoid puncture headache and dizziness and also mild low back pain, 3 to 7 days after the operation, all of which improved by bed rest and conventional analgesics such as acetaminophen and nonsteriod anti-inflammatory drugs (table). on the follow-up ultrasonography, 115 patients (71.8%) had complete clearance of their calculus or no significant residual calculi larger than 5 mm. in the 12 patients with staghorn calculi, complete clearance of calculus was 66.6%, and 4 patients had residual calculi larger than 10 mm. discussion percutaneous nephrolithotripsy is used for the fragmentation and removal of large or multiple calculi from the renal pelvis and renal caliceal systems.(1) it has been shown that pcnl under assisted local anesthesia is safe and effective in selected patients.(5) general anesthesia can be a challenge in some situations such as pcnl for staghorn calculi, because of the possibility of fluid absorption and electrolyte imbalance. therefore, regional anesthesia may be a good alternative. (6) maintaining a good postoperative quality of life may be achieved in most patients regardless of the anesthesiologic technique used. however, anesthesia can influence the early postoperative recovery of patients, and because the aim of all urologists is to discharge the patient from the hospital in a safe condition as early as possible, the choice of anesthesia matters.(7) in this study, we assessed the impact of spinal anesthesia on the most critical intra-operative and postoperative parameters during pcnl. acute anemia due to blood loss or dilution is a potential complication of pcnl that needs transfusion of blood products.(8) stoller and coworkers showed that the incidence of blood transfusion in uncomplicated single puncture pcnl reached 14%, with an average decrease of 2.8 g/dl in hemoglobin concentration.(9) recently, the same investigators reported a lower decrease in hemoglobin levels after pcnl with a transfusion rate of 7%.(10) several studies have also shown that spinal anesthesia results in less intra-operative bleeding compared with general anesthesia.(11-13) although the reported rate of transfusion during pcnl is about 5% to 12%, in our series, only 6.3% of the patients required blood transfusion. overall, these data confirmed that spinal anesthesia is safe and comparable in terms of intra-operative bleeding during pcnl. salonia and colleagues(14) evaluated the impact of general anesthesia versus spinal anesthesia on intra-operative and postoperative outcome in patients undergoing radical retropubic prostatectomy. they found that spinal anesthesia allowed good muscle relaxation and a successful surgical outcome in these patients. moreover, spinal anesthesia resulted in less intra-operative blood loss, less postoperative pain, and a faster postoperative recovery than general anesthesia. also, despite a small amount of mild and transient side effects, spinal anesthesia was associated with significantly reduced blood loss, allowing a good hemodynamic and respiratory safety profile both intra-operatively and preoperatively.(14) although we did not have a control group of general anesthesia and we did not require muscle relaxation for pcnl, the patients tolerated the operation and were satisfied with it. the exception was 1 patient who had a staghorn calculus and developed local pain during the operation. in a study by maurer and coworkers,(15) blood loss, operative time, and complications were compared in 606 patients undergoing primary minor complications* patient (%) blood loss requiring transfusion 10 (6.3) hypotension 18 (11.3) local peri-operative pain 1 (0.6) headache 6 (3.8) complications of percutaneous nephrolithotomy with spinal anesthesia among 160 patients *there were no major complications. spinal anesthesia in percutaneous nephrolithotomy—mehrabi and karimzadeh shirazi 25urology journal vol 7 no 1 winter 2010 unilateral total hip arthroplasty with either spinal anesthesia or general anesthesia. the patients were followed for 2 years after the surgery. compared with general anesthesia, spinal anesthesia resulted in a mean reduction of 12% in the operative time, 25% in estimated intra-operative blood loss, 38% in the rate of operative blood loss, and 50% in intra-operative transfusion requirements. compared with patients receiving general anesthesia, those receiving spinal anesthesia had higher hemoglobin levels on postoperative days 1 and 2 and a 20% lower total transfusion requirement. spinal anesthesia appeared superior to general anesthesia for this procedure. in one study by plaja and colleagues for comparing duration of spinal block by prilocaine or bupivacaine in transurethral resections, the mean duration of sensory and motor blockade were 145.83 ± 35.81 minutes and 133.16 ± 42.21 minutes, respectively.(16) we used fentanyl with bupivacaine for spinal anesthesia, and our results were similar to the above-cited study in returning of sensory and motor blockade. spinal anesthesia is easy to perform and allows the operation to be performed under the best possible conditions. conclusion our data showed that spinal anesthesia combined with sedation could be an attractive method of anesthesia for pcnl with trivial pain and blood loss and without major complications. thus, it will be a good alternative for performing pcnl in adult patients. future research is needed to evaluate the impact of spinal anesthesia versus general anesthesia on intra-operative and postoperative outcome in patients undergoing pcnl. conflict of interest none declared. references 1. wong my. evolving technique of percutaneous nephrolithotomy in a developing country: singapore general hospital experience. j endourol. 1998;12:397-401. 2. basiri a, mehrabi s, kianian h, javaherforooshzadeh a. blind puncture in comparison with fluoroscopic guidance in percutaneous nephrolithotomy: a randomized controlled trial. urol j. 2007;4:79-83. 3. singh i, kumar a, kumar p. “ambulatory pcnl” (tubeless pcnl under regional anesthesia) -a preliminary report of 10 cases. int urol nephrol. 2005;37:35-7. 4. montamat sc, cusack bj, vestal re. management of drug therapy in the elderly. n engl j med. 1989;321:303-9. 5. aravantinos e, karatzas a, gravas s, tzortzis v, melekos m. feasibility of percutaneous nephrolithotomy under assisted local anaesthesia: a prospective study on selected patients with upper urinary tract obstruction. eur urol. 2007;51:224-7. 6. corbel l, guille f, cipolla b, staerman f, leveque jm, lobel b. [percutaneous surgery for lithiasis: results and perspectives. apropos of 390 operations]. prog urol. 1993;3:658-65. french. 7. rozentsveig v, neulander ez, roussabrov e, et al. anesthetic considerations during percutaneous nephrolithotomy. j clin anesth. 2007;19:351-5. 8. kukreja ra, desai mr, sabnis rb, patel sh. fluid absorption during percutaneous nephrolithotomy: does it matter? j endourol. 2002;16:221-4. 9. stoller ml, wolf js, jr., st lezin ma. estimated blood loss and transfusion rates associated with percutaneous nephrolithotomy. j urol. 1994;152: 1977-81. 10. stoller ml, lee kl, schwartz bf, viele mk. autologous blood use in percutaneous nephrolithotomy. urology. 1999;54:444-9. 11. shir y, raja sn, frank sm, brendler cb. intraoperative blood loss during radical retropubic prostatectomy: epidural versus general anesthesia. urology. 1995;45:993-9. 12. faas cl, acosta fj, campbell md, o’hagan ce, newton se, zagalaniczny k. the effects of spinal anesthesia vs epidural anesthesia on 3 potential postoperative complications: pain, urinary retention, and mobility following inguinal herniorrhaphy. aana j. 2002;70:441-7. 13. davis fm, mcdermott e, hickton c, et al. influence of spinal and general anaesthesia on haemostasis during total hip arthroplasty. br j anaesth. 1987;59:561-71. 14. salonia a, suardi n, crescenti a, colombo r, rigatti p, montorsi f. general versus spinal anesthesia with different forms of sedation in patients undergoing radical retropubic prostatectomy: results of a prospective, randomized study. int j urol. 2006;13:1185-90. 15. maurer sg, chen al, hiebert r, pereira gc, di cesare pe. comparison of outcomes of using spinal versus general anesthesia in total hip arthroplasty. am j orthop (belle mead nj). 2007;36:e101-6. 16. plaja i, arxer a, metje m, et al. [comparative study between 5% prilocaine and 2% mepivacaine by the subarachnoid route in transurethral resections]. rev esp anestesiol reanim. 2000;47:194-7. spanish. u j 02 spring 2012 all 008without adv.pdf 527vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l keywords: ureter, embryology, vena cava, ureteral neoplasms introduction t the clinical and surgical implications. case report a 75-year-old man presented to the emergency ward with recurrent macroscopic hematuria and irritative voiding symptoms. in our diagnostic process, urinalysis, urine cytology, intravenous urography, and cystoscopy were employed. a tumor in the bladder and another one in the distal ureter were diagnosed. transurethral resection of the bladder tumor was initially performed and the pathology was subsequently performed for tumor staging, which incidentally revealed a left the urologic history of the patient started 5 years earlier when an urothelial pt1 grade iib tumor of the bladder was diagnosed. the treatment included transurecal instillations. the upper urinary tract had been examined that time with ultradiomidis kozyrakis,1 ioannis prombonas,1 vasilios kyrikos,1 alkiviadis grigorakis,1 georgios pliotas,2 dimitrios malovrouvas1 left retrocaval ureter associated with urothelial malignancy presentation of a rare case corresponding author: diomidis kozyrakis, md sofokli venizelou 77 st., halandri, 15232, athens, greece tel: +30 210 681 9942 fax: +30 210 681 1795 e-mail: dkozirakis@yahoo. gr. received april 2010 accepted october 2010 case report 1department of urology, “evagelismos” general hospital of athens, athens, greece 2department of urology, western attica hospital, athens, greece 528 | left nephroureterectomy and radical cystoprostatectomy were performed for the treatment of his urothelial malignancy. the nephroureterectomy was a laborious procedure, and accidently, an opening to the ivc was made, which was immeradical cystoprostatectomy was uncomplicated. the frozen section of the right ureteral margin was positive for urothelial malignancy and right distal ureterectomy with ileal loop diversion was performed. the postoperative recovery was uneventful. one and a half year after the operation, no signs of tumor recurrence, distant metastasis, or renal dysdiscussion in cases of a retrocaval ureter, the subcardinal vein generates the ivc, which results in a course of the ureter dorsally to this vein. the term preureteral for the vascular origin of the abnormality to be emphasized. if the subcardinal vein persists at encountered. reviewing the international literature, only 6 cases have been reported so far. recurrent abdominal pain, lumbar pain, hydronephrosis, and nephrolithiasis are the presenting symptoms of lpuvc. traditionally, the combination of retrograde urography with cavography can identify the puvc. the spiral computed tomography can substantially contribute towards the correct diagnosis. should the use of intravenous radiopaque agents is contraindicated, magnetic resonance imaging can be performed instead. the left ivc and puvc may be misdiagnosed as a retroperitoneal lymphadenopathy or a primary tumor of the retroperitoneal space. they also pose a threat for vascular or tissue damage during operations to the retroperitoneum, particularly when they are associated with situs inversus. the left renal vein has a brief course, which does not cross the aorta and subsequently, in cases of nephrectomy, living renal donor surgery, and reno-vascular dissected from the surrounding tissues. the treatment of puvc is ureterotomy and relocation of the ureter anteriorly to the ivc. this operation is usually an open surgical procedure, but nowadays it can be performed laparoscopifigure 1. computed tomography of the abdomen with administration of contrast agent. a left inferior vena cava (asterisk) and a retrocaval course of the left ureter (arrow) can be diagnosed. figure 2. abnormal course of the left ureter, dorsally to the left inferior vena cava. the proximal ureter is grasped with a forceps. the big black arrow shows the inferior vena cava, while the small black one indicates the course of the ureter dorsally to the vein. the opening on the inferior vena cava was corrected (white arrow). case report 529vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l cally. apart from hematuria, no other symptoms were described by our patient. considering that his initial showed normal renal units and collecting systems bilaterally, it is estimated that the urothelial malignancy and not the lpuvc generated a clinical evident obstruction of the left urinary tract. to the best puvc is associated with urothelial malignancy. despite the pre-operative diagnosis, the left ivc and the abnormal ureteral course obscured the retroperitoneal structures. in our patient, an opening to the ivc was made. the surgeon must have a high index of suspicion and attention, and must be extremely meticulous during renal and ureteral dissection for any damage to the retroperitoneal organs to be avoided and a source of intra-operative complications to be prevented. conflict of interest none declared. left retrocaval ureter associated with urothelial malignancy | kozyrakis et al references 1. bass je, redwine md, kramer la, huynh pt, harris jh, jr. spectrum of congenital anomalies of the inferior vena cava: cross-sectional imaging findings. radiographics. 2. hyams bb, schneiderman c, mayman ab. retrocaval ureter. 3. pais vm, strandhoy jw, assimos dg. pathophysiology of urinary tract obstruction. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 4. rubinstein i, cavalcanti ag, canalini af, freitas ma, accioly pm. left retrocaval ureter associated with inferior vena 5. pierro ja, soleimanpour m, bory jl. left retrocaval ureter associated with left inferior vena cava. ajr am j roent6. brooks re, jr. left retrocaval ureter associated with situs 7. ishitoya s, arai y, waki k, 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f, 155 farjad r, see nafar m, 105 farrokhi f, see sadeghi-nejad h, 192 farrokhi f, see simforoosh n, 138 feder m, see hakimi aa, 130 firoozan a, see nafar m, 105 firouzan a, see pour-reza-gholi f, 155 foroutan sk, rajabi mr. erectile dysfunction in men with angiographically documented coronary artery disease, 28 g garg a, gokhale a, garg p, patil p. endovascular treatment of a delayed renal artery pseudoaneurysm following blunt abdominal trauma, 184 garg p, see garg a, 180 ghaemimanesh f, see sharifiaghdas f, 71 ghanbari m, see ahmadnia h, 159 gharaati mr, see gharaati mr, 52 ghavamian r, see hakimi aa, 130 gokhale a, see garg a, 180 golmohammadlou s, see pashapour n, 91 h hadjzadeh mr, khoei ar, hadjzadeh z, parizady mr. ethanolic extract of nigella sativa l seeds on ethylene glycol-induced kidney calculi in rats, 86 hadjzadeh z, see hadjzadeh mr, 86 hakimi aa, feder m, ghavamian r. minimally invasive approaches to prostate cancer: a review of the current literature, 130 hamzehiesfahani n, see sharifiaghdas f, 71 hasanzadeh k, see ahmadi asr badr y, 142 hazhir s. asymptomatic bacteriuria in pregnant women, 24 hazhir s, see ahmadi asr badr y, 142 heidary rouchi a, see mahdavi-mazdeh m, 66 hekmat r, see mojahedi mj, 234 j jalali nadoushan mr, taheri t, jouian n, zaeri f. overexpression of her-2/neu oncogene and transitional cell carcinoma of bladder, 151 jalali nodushan mr, see mofid b, 101 javaherforooshzadeh a, see basiri a, 79 javaherforooshzadeh a, see mohammad beigi f, 33 jones l, reeves m, wingo s, babanoury a. malignant tumor in a horseshoe kidney, 46 jouian n, see jalali nadoushan mr, 151 k kalantari mr, ahmadnia h. p53 overexpression in bladder urothelial neoplasms: new aspect of world health organization/international society of urological pathology classification, 230 kamalian f, see ayatollahi h, 238 kamranmanesh mr, see basiri a, 79 karakos c, see stamatiou kn, 245 karanasiou v, see stamatiou kn, 245 karbakhsh m, see barbarian a, 187 kardavani b, see nafar m, 105 khabbaz khoob m, see ayatollahi h, 238 khaje-dalouee m, see ahmadnia h, 159 khatami f, see nafar m, 105 khazaeli mh, see mohseni mg, 217 khoei ar, see hadjzadeh mr, 86 khooei ar, see mahdavi r, 118 khoshdel a. reply. re: varicocele in brothers of patients with varicocele, 187 khoshrang h, see falahatkar s, 242 kianian hr, see basiri a, 79 kianoosh t, see ayatollahi h, 238 kural ar, see tufek i, 180 author index to volume 4 urology journal vol 4 no 4 autumn 2007 261 m maghsoudi r, azaripour a. bladder perforation during laparoscopic donor nephrectomy, 123 mahdavi r, khooei ar, asadi l. hygroma renalis: an extremely rare renal lesion, 118 mahdavi-mazdeh m, heidary rouchi a, norouzi s, aghighi m, rajolani h, ahrabi s. renal replacement therapy in iran, 66 manuchehri a. urology as a specialty in the history of contemporary medicine in iran, 125 mazdak h, gharaati mr. plexiform neurofibroma of penis, 52 mehrabi s, see basiri a, 79 mehrabi s, see mohammad beigi f, 33 mehrsai ar, see nikoobakht mr, 207 mehrsai ar, see pourmand g, 95 meysamie ap, see nikoobakht mr, 111 mirzaei hr, see mofid b, 101 mofid b, jalali nodushan mr, rakhsha a, zeinali l, mirzaei hr. relation between her-2 gene expression and gleason score in patients with prostate cancer, 101 moghadasali r, see sharifiaghdas f, 71 mohammadali beigi f, mehrabi s, javaherforooshzadeh a. varicocele in brothers of patients with varicocele, 33 mohammadali beigi f, basiri a, 174 mohammadali beigi f, see sharifiaghdas f, 177 mohammadian n, see ayatollahi h, 238 mohammadzadeh a, see falahatkar s, 242 mohseni mg, khazaeli mh, aghamir smk, biniaz f. changes in intrarenal resistive index following electromagnetic extracorporeal shock wave lithotripsy, 217 mohseni mg, see aghamir smk, 18 mohyeddin m, see nikbin b, 1 mojahedi mj, hekmat r, ahmadnia h. kidney transplantation in patients with alport syndrome, 234 molaei m, see yarmohammadi a, 121 moradi k, see nikoobakht mr, 207 moradi mr, see ahmadnia h, 159 moshiri f, see yassaee f, 14 moslemi mk, see zargar-shoshtari ma, 41 motamedi m, see nikoobakht mr, 111 mousavi-bahar sh, see davoudi m, 212 mumtaz s, see afgan f, 169 n nafar m, khatami f, kardavani b, farjad r, pourreza-gholi f, firoozan a. atherosclerosis after kidney transplantation: changes of intima-media thickness of carotids during early posttransplant period, 105 nafar m, see pour-reza-gholi f, 155 nikbin b, talebian f, mohyeddin m. chimerism: a new look, 1 nikibahksh aa, see pashapour n, 91 nikoobakht mr, emamzadeh a, abedi ar, moradi k, mehrsai ar. transureteral lithotripsy versus extracorporeal shock wave lithotripsy in management of upper ureteral calculi: a comparative study, 207 nikoobakht mr, motamedi m, orandi ah, meysamie ap, emamzadeh a. sexual dysfunction in epileptic men, 111 nikpour s, see falahatkar s, 242 norouzi s, see mahdavi-mazdeh m, 66 nouri-mahdavi k, basiri a. fluoroscopy-guided percutaneous biopsy of kidney: an alternative to open or laparoscopic approaches, 251 o orandi ah, see nikoobakht mr, 111 p papadimitriou v, see stamatiou kn, 245 parizadeh mr, see ayatollahi h, 238 parizady mr, see hadjzadeh mr, 86 parvin m, see tabibi a, 10 pashapour n, nikibahksh aa, golmohammadlou s. urinary tract infection in term neonates with prolonged jaundice, 91 patil p, see garg a, 180 pourmand g, ziaee aa, abedi ar, mehrsai ar, alavi ha, ahmadi a, saadati hr. role of pten gene in progression of prostate cancer, 95 pour-reza-gholi f, nafar m, simforoosh n, einollahi b, basiri a, firouzan a, alipour abedi b, farhangi s. is preemptive kidney transplantation preferred? updated study, 155 pour-reza-gholi f, see nafar m, 105 author index to volume 4 262 urology journal vol 4 no 4 autumn 2007 r rajabi mr, see foroutan sk, 28 rajaie esfahani m, abdar ar. unusual migration of intrauterine device into bladder and calculus formation, 49 rajolani h, see mahdavi-mazdeh m, 66 rakhsha a, see mofid b, 101 reeves m, see jones l, 46 robat-moradi n, see zargar-shoshtari ma, 41 s saadati hr, see pourmand g, 95 sadeghi-nejad h, farrokhi f. genetics of azoospermia: current knowledge, clinical implications, and future directions. part ii: y chromosome microdeletions, 192 safarinejad mr. editorial independence: surrounding controversies, 191 safarinejad mr. editorial policy: the right to international papers and contributors, 129 safarinejad mr. our journal indexed in medline/ pubmed, 61 safarinejad mr, see babaei ar, 62 sevinc c, see tufek i, 180 shadpour p, see zargar-shoshtari ma, 41 sharifiaghdas f, hamzehiesfahani n, moghadasali r, ghaemimanesh f, baharvand h. human amniotic membrane as a suitable matrix for growth of mouse urothelial cells in comparison with human peritoneal and omentum membranes, 71 sharifiaghdas f, mohammadali beigi f, abdi hr. laparoscopic removal of a migrated intrauterine device, 177 sharifiaghdas f, see simforoosh n, 138 simforoosh n, basiri a, danesh ak, ziaee sam, sharifiaghdas f, tabibi a, abdi hr, farrokhi f. laparoscopic management of ureteral calculi: a report of 123 cases, 138 simforoosh n, see pour-reza-gholi f, 155 sofras f, see stamatiou kn, 245 stamatiou kn, karakos c, karanasiou v, papadimitriou v, sofras f. syphilitic elephantiasis of penis and scrotum, 245 t tabibi a, parvin m, abdi hr, bashtar r, zamani n, abadpour b. correlation between size of renal cell carcinoma and its grade, stage, and histological subtype, 10 tabibi a, see simforoosh n, 138 taghavi r, ariana k, arab d. diuresis renography for differentiation of upper urinary tract dilatation from obstruction: f+20 and f-15 methods, 36 taheri t, see jalali nadoushan mr, 151 talebian f, see nikbin b, 1 tavakkoli tabasi k, baghban haghighi m. ureteroscopic and extracorporeal shock wave lithotripsy for rather large renal pelvis calculi, 221 tufek i, akpınar h, sevinc c, alıcı b, kural ar. surgical treatment of retroperitoneal leiomyosarcoma with adjuvant radiotherapy, 180 w wingo s, see jones l, 46 y yarmohammadi a, ahmadnia h, abolbashari m, molaei m. results of inadvertent administration of bacillus calmette-guerin for treatment of transitional cell carcinoma of bladder, 121 yassaee f, moshiri f. pregnancy outcome in kidney transplant patients, 14 z zaeri f, see jalali nadoushan mr, 151 zamani n, see tabibi a, 10 zargar-shoshtari ma, shadpour p, robat-moradi n, moslemi mk. hydatid cyst of urinary tract: 11 cases at a single center, 41 zeinali l, see mofid b, 101 ziaee aa, see pourmand g, 95 ziaee sam, see simforoosh n, 138 zolfaghari m, see darabi mahboub mr, 147 uj 35 summer.pdf 574 | urological oncology a plausible anti-apoptotic role of up-regulated oct4b1 in bladder tumors jamshid asadzadeh,1 malek hossein asadi,2 nasser shakhssalim,3 mahmoud-reza rafiee,4 hamid reza kalhor,5 mahmoud tavallaei,6 seyed javad mowla1 purpose: to investigate and compare the expression of oct4b1 tumor bladder tissues. materials and methods: we investigated the expression of oct4b1 in 30 tumor and nontumor surgical specimens of the bladder, using the taqman real-time polymerase chain reacof the variant. results: oct4b1 expression, but p < .002). moreover, the up-regulation of oct4b1 (p < .05). we have also employed the rna interference strategy to evaluate the functional role of oct4b1 in a bladder cancer cell line, 5637. suppression of oct4b1 caused some conclusion: oct4b1 or progression of the bladder cancer. additionally, oct4b1 keywords: cancer stem cells, urinary bladder neoplasms, apoptosis, neoplasm invasiveness, prognosis corresponding author: seyed javad mowla, phd department of molecular genetics, faculty of biological sciences, tarbiat modares university, tehran, iran tel: +98 21 8288 3464 fax: +98 21 8288 4717 e-mail: sjmowla@modares.ac.ir received june 2011 accepted january 2012 1 department of molecular genetics, faculty of biological sciences, tarbiat modares university, tehran, iran 2 department of biotechnology, research institute of environmental sciences, international center for science, high technology & environmental sciences, kerman, iran 3 urology and nephrology research center , shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 4 nanomedicine and tissue engineering center, shahid beheshti university of medical sciences, tehran, iran 5 omics research center, golestan university of medical sciences, gorgan, iran 6 human genetics research center, baqiyatallah medical sciences university, tehran, iran urological oncology 575vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l up-regulation of oct4b1 in bladder cancer | asadzadeh et al introduction bladder cancer is the 9 th most common malignancy and the 2nd most common tumor of the genitourith most numerous cause of cancer death.(1,2) potential, tumorigenesis, resistance to therapy, etc. similar based on this hypothesis, this highly tumorigenic subset of (3-7) octamer binding protein 4 (oct4 oct3, pou5f1, and otf3 oct4 exrespectively).(9) oct4 cancer stem cells.(10,11) subsequently, other research groups have reported oct4 overexpression in the bladder, gastric, prostate, and colorectal cancers.(12-16) based on its main role oct4 expression in cancer has been regarded as a possible route (17) ectopic expression of oct4 has an anti-differentiation effect on the differentiated host cells. moreover, it has been reblasts resulted in complete reprogramming of the host cells oct4 turned out to be one of the essential players.(19-22) oct4a), human oct4 gene variants, designated as oct4b(10) and oct4b1.(23) oct4b oct4b cannot maintain the self(9,10) our previous reports revealed that oct4b1 is expressed in pleuripotent and nonpleuripotent cells,(23) (24) and plays a potential role as an anti-apoptotic factor in gastric adenocarcinoma.(15) although oct4b1 expression has been studied in gastric and colorectal cancers.(15,16) about its expression and function in other tumors, including bladder cancer. pression of oct4b1 in a series of bladder cancer samples and further examined its function in a bladder cancer cell line using rna interference (rnai) technology. materials and methods clinical specimens normal tissues as control. the bladder, and all had a tumoric counterpart in the tumor prior to participation. rna extraction and real-time polymerase chain reaction (pcr) 576 | negative control. oct4b1 oct4 b1 variant: gapdh: gapdh mrna oct4b1 normalized to gapdh expression value in each sample. all using serial dilutions of an embryonic carcinoma cell line, or triplicate. state and grade of the tumors. cell culture 2 2. rnai oct4b1 urological oncology clinicopathological characteristics of the patients with bladder cancer. characteristic n % histological type tcc 30 100 tumor grade high 13 43.34 low 17 56.66 tumor stage ta 4 13.34 pt1 19 63.34 pt2/pt2a 6 20 pt4 1 3.34 gender male 28 6.67 female 2 93.34 577vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l oct4b1 oct4b1-sirna2 target sequence: aag agg tgg taa quence of oct4b1, to discriminate it from other variants of oct4. 4 cells 2 incubator. cell cycle analysis enediaminetetraacetic acid to yield single cell suspensions. optimization of rt-pcr reactions and reverse primers and the probe for oct4b1 other oct4 variants and pseudogenes. to determine the rerelative expression of oct4b1 gapdh tranprobable sampling errors. results elevated expression of oct4b1 in bladder tumors we have detected the expression of oct4b1 stronger in the tumor samples, compared to their non-tumor oct4b1 in bladder tumor samples (p the samples (0.39; p < .01). oct4b1 oct4b1 high-grade tumors (p oct4b1 expression level and the grade of the tumors (0.31; p < .05). cell cycle alterations following oct4b1 knock-down in 5637 cells against octb1 three days after the transfection. the level of oct4b1 exsirnas against oct4b1 up-regulation of oct4b1 in bladder cancer | asadzadeh et al 578 | oct4b1 tion (p < .05) in the percentage of the cells in the sub-g1 of cells in g1 phase of oct4b1 suppressed group declined discussion initiation and progression is one of the most important aims (3-7) sev(12-16,25-27) oct4, is the most notable oct4 oct4 expression in some cancers, cancer cell lines, and adult stem cells.(11-16) appeared to be controversial, and there is a need to discrimiurological oncology figure 2. (a) cells treated with oct4b1-sirna, compared to the ones treated with ir-sirna, demonstrated a dramatic suppression in oct4b1 expression as determined by real-time pcr. gapdh was used as an internal control. (b and c) effect of oct4b1 knock-down on cell cycle distribution in 5637 cell line. cb figure 1. (a) comparison of the relative expression level of the oct4b1 between tumor and non-tumor samples. each triangle represents the mean expression level of a single specimen, obtained by averaging values from two to three independent experimental replicates. (b) comparison of relative expression of oct4b1 between 13 high-grade and 17 low-grade tumor samples, as determined by real-time pcr. 579vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l nate the expression of oct4 variants in different types of cancers. oct4 variants, oct4a and oct4b the oct4 gene coined oct4b1.(23) this variant is primarily expressed in undifferentiated cells, and might contrib(15,23,24) expression and function in different cancers. to gain more insight on the role of the oct4 of oct4b1 desired mrna transcript for oct4b1. our results revealed that oct4b1 cantly elevated in tumor samples compared to that of nontumor samples. oct4b1 expressed at higher levels in the high-grade tumors compared oct4b1 expression also existed in most of the non-tumor samples, ie, the expresas oct4 in adult stem cells,(11,15,27) oct4b1 is expressed at a basic level in normal tissue of the bladder as a result of existing adult stem cells. secondly, several lines of evidence exist in supporting a clonal expansion of multifocal carcinomas, suggesting derivation of these tumors from a primary transformed progenitor cell. therefore, it can at other luminal surfaces of the urinary tract could be reoct4b1 parts of the bladder. elevated expression of oct4b1 in high-grade tumors is quite of differentiation.(23) vious data on gastric cancer,(15) this novel variant may play an anti-differentiation role as the tumor grade is related to the degree of differentiation. according to the grading system, the degree of differentiation of a given tumor has an inverse relationship to its grade, ie, the higher the grade of tumor, the (31) (15) suppression of oct4b1 of cells in the sub-g1 fraction, suggesting that oct4b1 plays conclusion altogether, our data revealed that oct4b1 in the bladder cancer and the variant seemed to have a role in tumorigenesis process, probably as an anti-apoptotic factor. therefore, oct4b1 can be considered as a novel tumor tional oct4b1 of oct4b1 and its 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b, et al. biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. j cell biochem. 2006;99:1285-97. 28. denzinger s, mohren k, knuechel r, et al. improved clonality analysis of multifocal bladder tumors by combination of histopathologic organ mapping, loss of heterozygosity, fluorescence in situ hybridization, and p53 analyses. hum pathol. 2006;37:143-51. 29. sidransky d, frost p, von eschenbach a, oyasu r, preisinger ac, vogelstein b. clonal origin bladder cancer. n engl j med. 1992;326:737-40. 30. junker k, wolf m, schubert j. molecular clonal analysis of recurrent bladder cancer. oncol rep. 2005;14:319-23. 31. engers r. reproducibility and reliability of tumor grading in urological neoplasms. world j urol. 2007;25:595-605. urological oncology 3. pardal r, clarke mf, morrison sj. applying the principles of stem-cell biology to cancer. nat rev cancer. 2003;3:895902. 4. al-hajj m, clarke mf. self-renewal and solid tumor stem cells. oncogene. 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mh, chang cc, kiupel m, webster jd, olson lk, trosko je. oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. carcinogenesis. 2005;26:495-502. 12. atlasi y, mowla sj, ziaee sa, bahrami ar. oct-4, an embryonic stem cell marker, is highly expressed in bladder cancer. int j cancer. 2007;120:1598-602. 13. chen z, xu wr, qian h, et al. oct4, a novel marker for human gastric cancer. j surg oncol. 2009;99:414-9. 14. sotomayor p, godoy a, smith gj, huss wj. oct4a is expressed by a subpopulation of prostate neuroendocrine cells. prostate. 2009;69:401-10. 15. asadi mh, mowla sj, fathi f, aleyasin a, asadzadeh j, atlasi y. oct4b1, a novel spliced variant of oct4, is highly expressed in gastric cancer and acts as an antiapoptotic factor. int j cancer. 2011;128:2645-52. 16. gazouli m, roubelakis mg, theodoropoulos ge, et al. oct4 spliced variant oct4b1 is expressed in human colorectal cancer. mol carcinog. 2012;51:165-73. 17. gidekel s, pizov g, bergman y, pikarsky e. oct-3/4 is a dose-dependent oncogenic fate determinant. cancer cell. 2003;4:361-70. 1296 | comparison of intravesical application of chondroitin sulphate and colchicine in rat protamine/lipopolysaccharide induced cystitis model orhun sinanoglu,1 isin dogan ekici,2 sinan ekici1 purpose: to investigate beneficial effect of the readily available colchicine through its intravesical application on protamine/lipopolysaccharide induced interstitial cystitis model in rat and to compare its efficacy to the chondroitin sulphate available for clinical use. materials and methods: twenty-four wistar female rats were assigned to control (c), interstitial cystitis (ic), chondroitin sulphate (cs) and colchicine (col) groups. ic, cs and col groups received protamine sulphate and lipopolysaccharide (ps/lps) instillation. testing agents cs and col were administered a day after ps/lps inoculation into the bladders. rats in group c received saline solution. cs and col groups received 1 ml cs (0.2%) and 1 ml col (0.05 mg/ml). the treatment agents were left in bladders for one hour’s duration. animals were sacrificed 5 days after the inoculation and the bladder tissues were examined histologically to evaluate the amount of extravasated leucocytes, mast cell concentration (by counting total number of cells per 10 high power field (hpf; 1 hpf = ×400 magnification) as well as interstitial tissue edema for each bladder. results: intravesical application of cs reduced significantly the leucocyte and mast cell infiltration as well as interstitial edema compared to group c . the level of reduction in leucocyte and mast cell infiltration in col group was comparable to that of cs, although the interstitial edema was not resolved. conclusion: intravesical administration of col decreased leucocyte and mast cell infiltration to the same extent of cs in ps/lps induced bladder inflammation in rat. col may be an alternative to other treatment modalities for painful bladder conditions such as ic. keywords: cystitis; disease models; animal; rats; chondroitin sulfates; therapeutic use. correspondence author: orhun sinanoglu, md maltepe üniversitesi tıp fakültesi üroloji anabilim dalı, feyzullah caddesi, no: 39, pk:34843 maltepe, i̇stanbul, turkey. tel: +90 533 658 6922 e-mail: orhundr@hotmail.com received december 2012 accepted june 2013 1 department of urology, maltepe university school of medicine, istanbul, turkey. 2 department of pathology, yeditepe university school of medicine, istanbul, turkey. miscellaneous miscellaneous 1297vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l introduction interstitial cystitis (ic) is a chronic debilitating disease of the urinary bladder affecting the individuals, 90% of those being in female gender.(1) it is characterized by painful bladder symptoms, presented with urinary frequency, urgency, and nocturia. most of the patients have recurrences and requires additional therapies. beside oral medicines such as pentosan polysulphate, intravesical instillation of hyaluronic acid and chondroitin sulphate (cs) are currently used in the ic treatment. alteration of urothelial glycosaminoglycan (gag) layer leading to cause increased bladder permeability is the supposed pathogenetic mechanism, and the symptom relief in ic patients has been reported from intravesically gag solutions, including cs.(2) the proposed mechanism of this beneficial gag therapy is restoration of the gag layer. (3) however, the pathogenetic mechanism suggesting the disruption of gag barrier is controversial as increasing number of studies suggest the presence of both common inflammatory state with abundance of activated mast cells in ic.(4,5) some analgesic and anti-inflammatory agents against ic has been used intravesically in parallel to these reports, and the search of effective and definitive therapy still continues.(6,7) to investigate ic pathophysiology different models of bladder inflammation have been studied in experimental animals whereby ic was induced by intravesical administration of an irritant or immune stimulant, systemic and environmentally induced inflammation.(8) the appearance of bladder inflammation, including edema, inflammatory cell infiltration, epithelial damage, fibrosis, venous congestion, and hemorrhage are common to all these previous ic models. in a model, bladder damage was induced in rats by injecting hydrochloric acid in saline solution through the cannula into the bladder, whereas several other models used only protamine sulfate (ps) to initiate bladder inflammation.(9,10) furthermore, the combined intravesical instillation of ps and lipopolysaccharide (lps) has been reported to induce ic rat model.(11) colchicine (col) is a tricyclic alkaloid. it has analgesic and anti-inflammatory effects through inhibition of granulocyte migration into the inflamed area inhibiting mitotic activity and affecting cells with high turnover. thus, it inhibits various leukocyte functions and depresses their action at the site of the inflammation.(12) its application in the inflammatory bladder condition has not been yet reported. in this study, we compared the intravesical col with the well known cs against ps/lps induced ic rat model to investigate its potential effect. materials and methods the maltepe university institutional animal care and experimental use committee approved the protocol of this study. twenty-four wistar female rats weighing 175-200 gr were assigned into four groups of 6 animals each [control (c), interstitial cystitis (ic), chondroitin sulphate (cs) and colchicine (col) groups]. all groups received intramuscular ketamine (50 mg/kg) and xylasine 4 mg/kg for anesthesia. a sterile 24 gauge angiocath was inserted into the bladder through the urethral opening and all treatment agents were administered with 2 ml syringe. saline solution of 1 ml was instilled into the urinary bladder of group c waiting 75 minutes. ic, cs and col groups received ps (sigma-aldrich, chemie gmbh, munich, germany) 10 mg/ml in the urinary bladder waiting 30 minutes followed by 2 mg/ml lps (sigma-aldrich, chemie gmbh, munich, germany) instillation waiting additional 45 minutes. for treatment purpose, a day after the ps/ lps inoculation, rats in c and ic groups s received 1 ml saline solution, and rats in cs and col groups received 1 ml cs (gepan instill farmatek, istanbul, turkey) and 1 ml 0.05 mg/ml col (sigma-aldrich, 0.5 mg colchicine powder solved in 10 ml sterile h2o solution) through 24 gauge angiocath intravesically, respectively. treatment agents were left in the bladder in 1 hr of duration. animals were sacrificed with high dose anesthesia 5 days later and their bladders were removed and stored in 10% formalin solution. the samples were blindly reviewed by a pathologist. the specimens were cut by a longitudinal section and both two pieces of a bladder specimen were processed for routine histopathological examination. formalin fixed specimens were embedded in paraffin and 3 micrometer thick sections from each paraffin block were stained with hematoxylin and eosin (h&e) and in order to the detect mast cells with toluidine blue (tb; bio-optica, milan, italy) respectively. severity of inflammation was examined by using optical microscope (olympus bx51 , tokyo, japan) in each section according to 4 criteria including; leukocyte infiltration (by colchicine vs. chondroitin sulphate against interstitial cystitis in rat | sinanoglu et al 1298 | counting extravasated leukocyte number per 10 high power field (hpf; 1 hpf = × 400 magnification]), edema (0 = no edema, 1 = mild edema; an increase of less than twice the width of submucosa, 2 = severe edema; an increase of more than twice the width of submucosa), mast cell infiltration (by counting total number of mast cells per 10 hpf (table and figures 1 and 2). all values are expressed as the mean ± sd and statistical significance was determined using kruskal wallis and mann whitney u tests. p < .05 was considered as statistically significance. results mean leucocyte count per 10 hpf in c, ic, cs and col groups were 3.67 ± 3.14, 59.17 ± 37.29, 14.0 ± 18.6 and 17.3±21.74, respectively (table). intravesical administration of cs and col reduced significantly leucocyte count (p = .007) (figures 1 and 2). mean mast cell count per 10 hpf in c, ic, cs and col groups were 21.67 ± 5.01, 40.17 ± 6.43, 24.50 ± 9.5 and 22.83 ± 13.36, respectively (table). intravesical application of cs and col reduced significantly mast cell infiltration (p = .027) (figures 1 and 2). the bladder tissue edema was negative in c and cs groups whereas positive in ic and col groups. the level of reduction in leucocyte and mast cell infiltration in col group was to the same extent of cs group (p = .335 and p = .517 respectively), although the interstitial edema was not resolved. discussion ic in generally is a painful disease with its devastating symptoms. its exact causes and pathogenesis remain to be identified. several animal models have been developed to investigate ic. most of the models were based on the hypothesis that an initial insult to the bladder is due to a permeability change in its gag lining, leading noxious urinary solutes to penetrate the underlying epithelium and smooth muscle, in turn resulting in inflammatory reactions.(13) although, among the current therapies intravesical cs and hyaluronic acid have been suggested to restore the gag layer, the protective role of gag layer against noxious urinary solutes and whether instillation of such agents into the bladder restores the damaged mucosal barrier is controversial.(14) using chamber experiments showed that gag contributes little or nothing to mammalian urothelial barrier function.(15) besides, many other treatment alternatives are tried due to unsatisfying results with gag replenishing agents, among these antihistamines act on mast cell involvement and intravesical dimethyl sulphoxide was proven to reduce bladder inflammation and figure 1. normal urothelial mucosa in control group (a). inflammatory reaction composed of mainly lymphocytic aggregate in protamin and lipopolisacharide induced interstitial cystitis (b) which was reduced following intravesical application of chondroitin sulphate (c) and colchicine (d). h & e × 200 magnification; 1cm = 63.2 micrometer. figure 2. normal urothelial mucosa in control group with limited number of mast cells (a). inflammatory reaction composed of mainly lymphocytes accompanied with numerous mast cells in protamin and lipopolisacharide induced interstitial cystitis (b) which was reduced following intravesical application of chondroitin sulphate (c) and colchicine (d). toluidine blue × 400 magnification; 1 cm = 31.6 micrometer. miscellaneous 1299vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l stabilize mast cells.(16) in an in-vitro bladder ic model, a reduction of tumor necrosis factor alpha (tnf-α) induced interleukin 6 release after treatment with hyaluronic acid and cs was observed which indicated that their anti-inflammatory action played the predominant role in the treatment of ic.(17) this opinion led us to evaluate the supposed beneficial effect of col, an old and cheap molecule which is underestimated among a wide variety of available anti-inflammatory drugs, and to compare its effect on bladder inflammation to that of cs. since it inhibits various leukocyte functions and depresses the action of the leukocytes and of the fibroblasts at the site of the inflammation, it is commonly used in chronic diseases such as familial mediterranean fever, primary biliary cirrhosis, alkaline esophagitis, psoriasis, behçet's disease, aphthous stomatitis, chronic urticaria unresponsive to antihistamine. its anti-inflammatory effect has been linked to its disruption of microtubules in neutrophils thereby inhibiting their migration with chemotactic factors. furthermore, col was also shown to alter the distribution of adhesion molecules on the surface of both neutrophils and endothelial cells, leading to the inhibition of interaction between endothelial cells and leucocytes interfering with their transmigration.(18) the evidence suggested that the anti-inflammatory effect of col was through various pathways.(19) the previous studies reported that the suppression of enzymes such as caspase-1, endothelial nitric oxide synthase 3 or other mediators of chemotaxis led to inflammatory restraint following col administration. (18) the data presented in our study showed that intravesical col instillation reduced both leucocyte and mast cell counts in a rat model of bladder inflammation in a comparable level to that of cs. however, the bladder tissue edema in ic did not disappear in col group in contrast to cs group which might be due to col’s inability to restore bladder gag layer unlike cs. in parallel to previous reports suggesting that the agents used for painful bladder conditions reduced either inflammation or mast cell activity, our findings can be helpful in addressing the problems associated with chronic inflammation in the human bladder. there are limitations of our study; first, the present model is not identical to chronic human ic as it induces a short-term acute inflammation in the bladder and, the confirmation of ic in rat bladder remains within histological evaluation without comparison of urinary frequency in treatment groups due to lack of metabolic cages; second, although ketamine was reported to induce cystitis itself in some cases, it is known that this was encountered especially among ketamine abusers. additionally, the bladder tissues in group c did not show evidence of cystitis in the present study.(20) lastly, different concentrations of col may be further investigated as no previous data is available in the literature for its intravesical instillation. conclusion in conclusion, with the exclusion of edema, intravesical administration of col decreased leucocyte and mast cell infiltration to the same extent of cs in ps/lps induced ic. this potential action may be useful on bladder inflammation and should be further investigated. conflict of interest none declared. references 1. hanno pm. diagnosis of interstitial cystitis. urol clin north am. 1994:21:63-66. 2. parsons cl, lilly jd, stein p. epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). j urol. 1991;145:732-5. 3. nickel jc, ergerdie b, downey, j et al. a real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis. bju int. 2009;103:56-60. 4. theoharides tc, kempuraj d, sant gr. mast cell involvement in interstitial cystitis: a review of human and experimental evidence. urology. 2001;57(6 suppl 1):47-55. 5. tyagi p, hsieh vc, yoshimura n, kaufman j, chancellor mb. instillation of liposomes vs dimethyl sulphoxide or pentosan polysulphate for reducing bladder hyperactivity. bju int. 2009;104:1689-92. 6. soler r, bruschini h, truzzi jc, et al. urinary glycosaminoglycans excretion and the effect of dimethyl sulfoxide in an experimental model of non-bacterial cystitis. int braz j urol. 2008;34:503-11. 7. theoharides tc. treatment approaches for painful bladder syndrome/interstitial cystitis. drugs. 2007;67:215-35. 8. westropp jl, buffington ca. in vivo models of interstitial cystitis. j urol. 2002;167:694-702 9. hauser pj, buethe da, califano j, sofinowski tm, culkin dj, hurst re. restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. j urol. 2009;182:2477-82. colchicine vs. chondroitin sulphate against interstitial cystitis in rat | sinanoglu et al 1300 | 10. fraser mo, chuang yc, lavelle jp, yoshimura n, de groat wc, chancellor mb. a reliable, nondestructive animal model for interstitial cystitis: intravesical low-dose protamine sulfate combined with physiological concentrations of potassium chloride. urology. 2001;57(6 suppl 1):112. 11. jordan jl, henderson s, elson cm, et al. use of a sulfated chitosan derivative to reduce bladder inflammation in the rat. urology. 2007;70:1014-8. 12. dainese l, cappai a, biglioli p. recurrent pericardial effusion after cardiac surgery: the use of colchicine after recalcitrant conventional therapy. j cardiothorac surg. 2011;6:96. 13. kitta t, tanaka h, mitsui t, moriya k, nonomura k. type 4 phosphodiesterase inhibitor suppresses experimental bladder inflammation. bju int. 2008;102:1472-6. 14. ratner v. interstitial cystitis: patients, researchers, caregivers; putting the pieces together. supplement of interstitial cystitis association. rockland, maryland, 2004. p. 1-8. obtained from http://www. ichelp.org. 15. tzan cj, berg j, lewis sa. effect of protamine sulfate on the permeability properties of the mammalian urinary bladder. j membr biol. 1993; 133: 227-42 16. metts j. interstitial cystitis: urgency and frequency syndrome. am fam physician. 2001;64:1199-1206. 17. schulz a, vestweber am, dressler d. anti-inflammatory action of a hyaluronic acid-chondroitin sulfate preparation in an in vitro bladder model. aktuelle urol. 2009;40:109-12. 18. ben-chetrit e, bergmann s, sood r. mechanism of the anti-inflammatory effect of colchicine in rheumatic diseases: a possible new outlook through microarray analysis. rheumatology (oxford) 2006;45:274-82. 19. cronstein bn, molad y, reibman j, balakhane e, levin ri, weissmann g. colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. j clin invest. 1995;96:9941002. 20. nomiya a, nishimatsu h, homma y. interstitial cystitis symptoms associated with ketamine abuse: the first japanese case. int j urol. 2011;18:735. miscellaneous v08_no_3_final.pdf case report 242 urology journal vol 8 no 3 summer 2011 vesical hirudiniasis a rare case report biswajit datta,1 amrendra n sarkar,2 mriganka kumar ghosh2 urol j. 2011;8:242-3. www.uj.unrc.ir keywords: leeches, hematuria, urinary bladder 1department of urology, north bengal medical college, sushruta nagar, darjeeling, 734012, west bengal, india 2department of surgery, north bengal medical college, sushruta nagar, darjeeling, 734012, west bengal, india corresponding author: biswajit datta, ms, mch department of urology, north bengal medical college, sushruta nagar, darjeeling, 734012, west bengal, india tel: +91 0353 258 5607 fax: +91 0353 254 4944 e-mail:docbiswa@gmail.com received october 2009 accepted november 2009 introduction hirudiniasis, which is rare with unusual symptoms, is caused by accidental introduction of leeches through natural orifices. leech is an invertebrate having a tendency to enter the body through natural orifices. a few studies have reported internal hirudiniasis found in the nasal cavity, pharynx, larynx, tonsils, rectum, and urinary bladder. (1-5) vesical hirudiniasis can be considered as an unusual cause of profuse hematuria. we present one case of vesical hirudiniasis causing hematuria.(6) case report a 16-year-old boy presented with a history of sudden pain in the lower abdomen and hematuria after returning from farming in a waterlogged paddy field. on clinical examination, there was tenderness in the suprapubic area. he was hemodynamically stable. ultrasonography revealed a tubular, 8.5 cm long nonshadowing structure with highly echogenic wall and less echogenic center on the left posterior wall of the urinary bladder. cystourethroscopy under general anesthesia showed the urinary bladder cavity containing blood clot, which was evacuated. one large tubular reddish structure suggestive of leech was found on the posterior wall of the urinary bladder with oozing from the bladder wall. we tried to remove the leech cystoscopically with an endoscopic forceps, but we were unsuccessful. thereafter, the patient was catheterized with foley catheter and 50 ml normal saline was instilled inside the bladder through the catheter, which was then clamped for 3 hours. the catheter was then removed and we waited for 24 hours expecting expulsion of the leech per urethra.(5) but the leech did not come out per urethra and hematuria persisted. therefore, suprapubic cystostomy was performed. on entering the leech is being taken out of the urinary bladder. vesical hirudiniasis—datta et al 243urology journal vol 8 no 3 summer 2011 bladder cavity, the swollen dead leech about 10.5 cm long was found to be lying against the posterior bladder wall with active bleeding from the bladder wall, where the leech was fixed to. the leech was removed, the bleeding site was cauterized, and the bladder and then the abdomen were closed in layers (figure). postoperative recovery was uneventful. discussion the leech is a blood sucking worm belonging to the class hirudinea of the phylum annelida. leeches are commonly found in the waterlands of temperate and tropical countries. they can swim or crawl by looping movements entering the human body, like the urinary bladder, through natural orifices, like the urethra. leech usually sucks blood from the body surface and releases anticoagulant at the site of bite, which is responsible for prolonged bleeding.(6) very few cases of vesical hirudiniasis have been reported in literature, all from asian countries. alam and colleagues have reported the largest series of 43 subjects from bangladesh. all of their patients were treated with intravesical instillation of normal saline followed by spontaneous expulsion of dead leeches per urethra.(5) but in our subject, leech did not come out per urethra after intravesical saline treatment; hence, it was removed by suprapubic cystostomy. conflict of interest none declared. references 1. gupta sc. nasal hirudiniasis in kumaon hills, india. trop geogr med. 1980;32:303-5. 2. raj sm, radzi m, tee mh. severe rectal bleeding due to leech bite. am j gastroenterol. 2000;95:1607. 3. mohammad y, rostum m, dubaybo ba. laryngeal hirudiniasis: an unusual cause of airway obstruction and hemoptysis. pediatr pulmonol. 2002;33:224-6. 4. paul ak, islam n. vesical hirudiniasis: an unusual cause of bleeding from the urethra. j ultrasound med. 2005;24:1731-3. 5. alam s, das choudhary mk, islam k. leech in urinary bladder causing hematuria. j pediatr urol. 2008;4: 70-3. 6. deka pm, rajeev tp. unusual cause of hematuria. urol int. 2001;66:41-2. 1147vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l multi-detector computed tomography angiography of a ruptured giant renal angiomyolipoma with pseudoaneurysm and associated saccular dilatation of left renal artery umesh c. parashari, sachin khanduri, samarjit bhadury, gaurav singh keywords: angiomyolipoma; tomography; x-ray computed; rupture; embolism; laparoscopy; magnetic resonance imaging. introduction angiomyolipoma (aml) is a neoplastic lesion consisting of mature blood vessels, smooth muscle cells and fat tissue. its most common site is kidney. the common complication is rupture with intrarenal or peri lesional hemorrhage depending on size of the tumor. the treatment depends on the size and clinical features of the tumor, usually being embolization. case report a 55-year old female presented with history of acute abdominal pain, localized to the left flank following a minor trauma after a fall. lab investigations revealed low hemoglobin count and hematuria. on ultrasonography, a heterogenous mass measuring approximately 15 × 20 × 13 cm in the left renal area arising from the upper and mid pole region being visible. a provisional diagnosis of renal mass with possible hemorrhage was made. on contrast enhanced computed tomography (ct) scan there was evidence of a large exophytic heterogeneous mass measuring approximately 13.2 × 10.8 × 19.0 cm having predominantly fat attenuation (figure 1). mass lesion is in anterolateral cortex of upper and middle pole of left kidney displacing and compressing residual renal parenchyma posteromedially and lower pole anteromedially. ct angiography was done in the same setting. on angiography dilated tortuous left renal artery was seen with mild dilation of its branches supplying the mass lesion. there was evidence of a large lobulated vascular sac like lesion of approximate size corresponding author: umesh chandra parashari, md department radio diagnosis, era’s lucknow medical college, lucknow, india tel: +94 150 88926 e-mail: id-drumesh.rd@gmail.com received june 2011 accepted september 2011 department radio diagnosis, era’s lucknow medical college, lucknow, india case report 1148 | case report 7.4 × 4.8 × 7.0 cm in center of the lesion which showed homogenous filling in arterial phase and persistent filling in portal venous phase. multiple small saccular dilatations of renal artery branches were also seen (figure 2). a diagnosis of large aml on left side with multiple saccular aneurysmal dilatations of branches of left renal artery was made. patient was immediately taken for surgery and a partial nephrectomy was performed along with embolization of the pseudoaneurysm. the operated tumor tissue was sent for histopathology which confirmed our diagnosis of aml. discussion there are two types of aml: classic renal aml containing smooth muscle, vascular, and fat tissue, and very rarely infiltrating perirenal tissue; and a second type of aml containing a large fourth component, perivascular epithelioid cells, making it more aggressive.(1,2,3) aml either occur in isolation or as multiple lesions associated with tuberous sclerosis in 20% of cases.(4) the amls are caused by mutations in either the tuberous sclerosis complex (tsc1) or tsc2 genes, which govern cell growth and proliferation.(5) the classic symptoms includes flank pain, a palpable tender mass or signs of internal bleeding caused by intracapsular or retroperitoneal hemorrhage.(1,6) few present with shock following hemorrhage due to rupture of blood vessels. wünderlich's syndrome, a spontaneous retroperitoneal hemorrhage of non-traumatic origin occurs in up to 50% of patients with tumors less than 40 mm.(6) abdominal ct figure 1. axial on contrast enhanced computed tomography (1a and 1b) and coronal reformation (1c) showing a large exophytic heterogeneous left renal mass having predominantly fat attenuation (open white arrow) arising anterolateral cortex of upper and middle pole of left kidney with a thick rim of hyperdense hematoma (white arrow head). a large lobulated vascular sac like lesion is seen in the center of the mass (thick white arrow). volume rendered coronal image (1d) during angiography phase showing dilated tortuous left renal artery (thin white arrow) with a large lobulated pseudoaneurysm in center of the mass (thick white arrow). 1149vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l giant renal angiomyolipoma | parashari et al scanning is the diagnostic tool of choice to diagnose and differentiate between various causes of a renal mass, and assess the size of the aml and the extent of hemorrhage. (1,3) fat density within a non-calcified renal mass remains the most important diagnostic finding of aml. on magnetic resonance imaging (mri) sequences the tumor appears hyperintense on t1 weighted and t2 weighted sequences due to presence of fat. recent advances in ct and mr angiography may improve the detection of aneurysm formation in these tumors.(7,8) various treatment modalities available for aml depend upon its size. embolization and partial or total nephrectomy are usually done. larger lesions require treatment such as surgical excision or embolization. medium sized lesions need monitoring and follow up.(9) embolization is the preferred therapy and appears to be the most successful nephron sparing procedure or to reduce the size or to stop bleeding during acute situations. life threatening complications can be avoided if diagnostic tests and therapeutic interventions are readily available. conflict of interest none declared. references 1. bissler jj, kingswood jc. renal angiomyolipomata. kidney int. 2004;66:924-34. 2. oesterling je, fishman ek, goldman sm, marshall ff. the management of renal angiomyolipoma. j urol. 1986;135:1121-4. figure 2. computed tomography angiography mip (maximum intensity projection) image shows dilated tortuous left renal artery (thin white arrow) and a large intra lesion pseudoaneurysm on left side (thick white arrow). 1150 | 3. pruijm m t, falke t h, peltenburg h g. [retroperitoneal bleeding caused by renal angiomyolipoma] ned tijdschr geneeskd. 2003;147:1696-9. 4. casper ka, donelly lf, chen b, bissler jj. tuberous sclerosis complex: renal imaging findings. radiology. 2002;225:4516. 5. bissler jj, henske ep. renal manifestations of tuberous sclerosis complex. in: tuberous sclerosis complex: from genes to therapeutics. in: kwiatkowski dj, thiele ea, whittemore v, editors. weinheim, germany: wiley-blackwell; 2010. p. 321-325. 6. albi g, del campo l, tagarro d. wunderlich's syndrome: causes, diagnosis and radiological management. clin radiol. 2002;57:840-5. 7. joarder r, gedroyc wm. magnetic resonance angiography: the state of the art. eur radiol. 2001;11:446-453. 8. hayashi h, kawamata h, ishio m, kumazaki t. multiple renal artery aneurysms diagnosed by three-dimensional ct angiography. clin imaging. 2000;24:221-23. 9. dickinson m, ruckle h, beaghler m, hadley hr. renal angiomyolipoma: optimal treatment based on size and symptoms. clin nephrol. 1998;49:281-6. case report 347vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l purpose: to review different aspects of the bladder involvement in behcet’s disease as a rare complication. materials and methods: we searched pubmed, ovid, and google scholar for behcet’s and neuro-behcet’s disease and neurogenic and neuropathic bladder, bladder involvement, voiding dysfunction, and urologic manifestations. fourteen full-texts and one abstract were retrieved. results: most involved patients are young to middle-aged men. both bladder filling and emptying problems can be seen, with the storage symptoms being the most common finding. sphincter function could be normal, dyssynergic, or deficient. the most common urodynamic finding is detrusor overactivity. in cystoscopic examination, ulcers or nodules due to vasculitis can be seen, which along with neurologic causes give rise to the voiding symptoms. the rate of cancers does not increase in behcet’s disease. surgery and chemotherapy are tolerated well. however, radiotherapy may be associated with increased complication rates. conclusion: treatment plan should be tailored according to the specific type of the bladder involvement. periodic re-evaluation is required because of the changing nature of the bladder behavior. keywords: behcet syndrome, urinary bladder, complications, neurogenic, etiology isfahan urology and renal transplantation research center (iurc), alzahra hospital, isfahan university of medical sciences, isfahan, iran farshid alizadeh, mohammad hatef khorrami, mohammad hossein izadpanahi, kia nourimahdavi, mehrdad mohammadi sichani review bladder involvement in behcet’s disease corresponding author: mohammad hatef khorrami, md no. 33, olfat alley, apadana dovom st, isfahan, iran tel: +98 913 113 9043 fax: +98 311 235 0532 e-mail: khorami@med. mui.ac.ir. received december 2011 accepted december 2011 348 | review introduction behcet’s disease (bd) is a systemic vas-culitis with an unknown etiology, which affects the small and large vessels in both arterial and venous systems.(1) the hallmark of this disease is recurrent oral aphtae(2) that when accompanies with at least two of the followings, bd is suggested: recurrent genital ulcer, skin lesions, eye lesions, and a positive pathergy test.(3) in the international criteria for behcet’s disease (icbd), vascular manifestations have also been added to increase the sensitivity of the diagnosis. (4) this disease may involve cardiovascular, central and peripheral nervous, musculoskeletal, respiratory, and gastrointestinal systems as well.(5) turkey and other countries along the ancient silk road have the highest prevalence of bd.(6) in these countries, males and females are affected almost equally, usually in their 3rd to 5th decades of life.(7) aside from genital ulcers, other urological problems are encountered infrequently, usually in the form of epididymitis and sterile urethritis.(8) even rarer is the bladder involvement that has been addressed in a few case reports and case series. in this article, we aim to review different aspects of the bladder involvement in bd. materials and methods in september 2011, we performed a detailed internet search on pubmed, ovid, and google scholar, looking for articles relating behcet’s and neurobehcet’s disease and neurogenic or neuropathic bladder, bladder involvement, voiding dysfunction, and urologic manifestations. checking the search results and their references, we retrieved 14 full-text articles and one abstract. one of the articles was in japanese, which was translated. most of the articles were case reports or small case series that underscores the rarity of the bladder involvement in bd. results most involved patients are young to middle-aged men.(2,9-17) the most common symptoms are storage symptoms,(2,9-11,13,14,16) and sometimes urge incontinence.(9,10,12-14) however, emptying symptoms(2,11,12,14,16) and urinary retention(11,16) may also occur. sphincter function can be normal. however, detrusor sphincter dyssynergia(9,12,16) or sphincter deficiency(2) may also be seen. meatal ulceration,(14) sterile urethritis,(8) or cystitis(18) can give rise to dysuria. gross hematuria is very rare.(2,15) bladder cancer has been reported either sporadically(19) or after cyclophosphamide therapy.(20) other rare sequelae of bd are urethrovaginal and vesicovaginal fistulas.(14) as in other causes of neuropathic bladder dysfunction, hydroureteronephrosis could ensue in bd as a consequence of increased intravesical pressure or severe bladder wall trabeculation.(2) when urodynamic study is performed, following findings may be observed: detrusor overactivity either alone(2,9,12-14,16) or with impaired contractility,(2,11,16) decreased bladder compliance(2,14) or capacity,(9,10) bladder hypersensitivity,(9,10,12) hypo or acontractility alone,(11,14,16) and increased postvoid residual urine,(9,12) with the detrusor overactivity being the most common. in cystoscopic examination of the bladder, selfhealing ulcers(2,14) or mass lesions that may resemble the bladder tumor have been reported. the pathologic examination of the mass shows vascular thrombosis, perivascular inflammatory exudates, and severe mucosal ulceration in one report(15) while in the other, it was reported as an indurated hypervascular lesion.(2) discussion neurologic involvement (neuro-behcet’s disease) has been reported in 5% to 10% of patients with bd,(7) of whom 5% manifest voiding symptoms. (17) cetinel and colleagues estimated the incidence 349vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l bladder manifestation of behcet’s disease | alizadeh et al of the bladder involvement to be 0.07%.(2) central nervous system involvement in bd is progressive in 85% of the patients and has an intermittent nature in the remaining 15%. it usually affects the brain stem and may resemble central nervous system infection, stroke, or multiple sclerosis.(911) therefore, one reason for high prevalence of frequency and urgency in bd patients with lower urinary tract symptoms could be involvement of the pontine micturition center by a vasculitis process.(10) direct involvement of the bladder, however, is possible in the form of ulceration and nodules(2,14,15) or recurrent cystitis.(18) storage symptoms in these patients, as a result, could be due to neuro-behcet’s disease, direct bladder wall involvement, or their combination.(14) in a study, cetinel and associates compared a group of male patients with bd with a control group and found that irritative voiding symptoms, but not obstructive ones, were more prevalent in bd group.(14) one should keep in mind that the pattern of the bladder involvement can change during time. porru and coworkers reported a case whose bladder’s behavior changed from areflexia to instability with impaired contractility.(11) neurologic symptoms usually become manifested five to six years after the beginning of nonneurologic manifestations. nevertheless, they can occur concurrently or even prior to other symptoms.(21) in the cetinel’s study, the bladder involvement became evident 1 to 10 years after the onset of neuro-behcet’s disease. however, in one patient, it preceded neurological involvement. urodynamic abnormalities can be present even in patients without neurologic involvement.(2) treatment of the bladder dysfunction is individualized for each patient according to their urodynamic and imaging findings. emptying failure is usually managed by clean intermittent catheterization while storage problems have been treated by anticholinergics; however, sometimes augmentation cystoplasty becomes mandatory. patients with bd have hyperreactivity of the skin and other tissues to minor trauma (pathergy). despite this hyperreactivity, cystoscopy, bladder biopsy, and even ileocystoplasty or radical cystoprostatectomy have been done in them without complication.(2,19) association of bd and malignancies is rare.(22) some believe that the incidence of malignancies does not increase in bd.(19) increased toxicity of chemotherapy has not been reported in bd. however, radiotherapy can have such late adverse effects as ureteral stricture or skin break-down.(22,23) conclusion bladder involvement in bd can be neuropathic and/or due to vasculitis in the bladder wall. different types of voiding dysfunction due to sphincter and bladder dysfunction, either in filling or emptying phases can occur. conflict of interest none declared. references 1. yazici y, yurdakul s, yazici h. behcet's syndrome. curr rheumatol rep. 2010;12:429-35. 2. cetinel b, akpinar h, tufek i, uygun n, solok v, yazici h. bladder involvement in behcet's syndrome. j urol. 1999;161:52-6. 3. international study group for behcet's disease. criteria for diagnosis of behcet's disease. lancet. 1990;335:1078-80. 4. davatchi f. diagnosis/classification criteria for behcet's disease. patholog res int. 2012;2012:607921. 5. davatchi f, shahram f, chams-davatchi c, et al. behcet's disease in iran: analysis of 6500 cases. int j rheum dis. 2010;13:367-73. 6. yurdakul s, hamuryudan v, yazici h. behcet syndrome. curr opin rheumatol. 2004;16:38-42. 7. davatchi f, shahram f, chams-davatchi c, et al. behcet's disease: from east to west. clin rheumatol. 2010;29:823-33. 350 | 8. kirkali z, yigitbasi o, sasmaz r. urological aspects of behcet's disease. br j urol. 1991;67:638-9. 9. erdogru t, kocak t, serdaroglu p, kadioglu a, tellaloglu s. evaluation and therapeutic approaches of voiding and erectile dysfunction in neurological behcet's syndrome. j urol. 1999;162:147-53. 10. karandreas n, tsivgoulis g, zambelis t, et al. urinary frequency in a case of neuro-behcet disease involving the brainstem clinical, electrophysiological and urodynamic features. clin neurol neurosurg. 2007;109:806-10. 11. porru d, pau ac, scarpa rm, zanolla l, cao a, usai e. behcet's disease and the neuropathic bladder: urodynamic features: case report and a literature review. spinal cord. 1996;34:305-7. 12. sakakibara r, hattori t, boku k, uchiyama t, yamanishi t. micturitional disturbance in neuro-behcet's syndrome. auton neurosci. 2000;83:86-9. 13. theodorou c, floratos d, hatzinicolaou p, vaiopoulos g. neurogenic bladder dysfunction due to behcet's disease. int j urol. 1999;6:423-5. 14. cetinel b, obek c, solok v, yaycioglu o, yazici h. urologic screening for men with behcet's syndrome. urology. 1998;52:863-5. 15. carswell gf. a case of behcet's disease involving the bladder. br j urol. 1976;48:199-202. 16. nakagawa h, namima t, aizawa m, uchi k, orikasa s. [three cases of neurogenic bladder due to neuro-bechet disease]. nihon hinyokika gakkai zasshi. 1994;85:1399-402. 17. iida s, taniguchi n, nishihara m, miyata m, kaneko s, yachiku s. [a case of neurogenic bladder due to neurobehcet disease]. hinyokika kiyo. 2000;46:727-9. 18. sarica k, suzer o, gurler a, baltaci s, ozdiler e, dincel c. urological evaluation of behcet patients and the effect of colchicine on fertility. eur urol. 1995;27:39-42. 19. baltaci s, gogus c, karamursel t, tulunay o. invasive bladder carcinoma in a patient with behcet's disease. int j urol. 2003;10:669-71. 20. celik i, altundag k, erman m, baltali e. cyclophosphamideassociated carcinoma of the urinary bladder in behcet's disease. nephron. 1999;81:239. 21. akman-demir g, serdaroglu p, tasci b. clinical patterns of neurological involvement in behcet's disease: evaluation of 200 patients. the neuro-behcet study group. brain. 1999;122 ( pt 11):2171-82. 22. cengiz m, altundag mk, zorlu af, gullu ih, ozyar e, atahan il. malignancy in behcet's disease: a report of 13 cases and a review of the literature. clin rheumatol. 2001;20:239-44. 23. meyer j, wahidi m, shofer s, evans j, crawford j, kelsey cr. formation of a bronchoesophageal fistula following concurrent radiation and chemotherapy for lung cancer in the setting of behcet's disease. j thorac oncol. 2008;3:1361-2. review pdf-1215.pdf 410 | cellular and molecular urology purpose: to investigate the feasibility and safety of using biocompatmaterials and methods: plasma-treated electrospun unseeded mats and the second and third ones after 4 months, and then, the graft was examined macroscopically with subsequent morphological and histochemical evaluation. results: mat was very low. all three implantation models showed the same light microscopic morphology, immunohistochemistry, and scanning electron vorable clinical results. conclusion: could be a suitable material for the bladder tissue engineering; however, it deserves further investigations. keywords: urinary bladder, tissue engineering, biocompatible materials, polymers nasser shakhssalim,1 mohammad mehdi dehghan,2 reza moghadasali,3 mohammad hossein soltani,4 iman shabani,5 masoud soleimani6 bladder tissue engineering using biocompatible nanofibrous electrospun constructs feasibility and safety investigation corresponding author: masoud soleimani, phd unrc, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: msoleimani94@yahoo.com received november 2011 accepted december 2011 1urology and nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti university of medical sciences (sbmu), tehran, iran 2unrc, department of clinical sciences, faculty of veterinary medicine, university of tehran, tehran, iran 3unrc, sbmu, department of stem cells, royan institute, tehran, iran 4unrc, shahid labbafinejad medical center, sbmu, tehran, iran 5unrc, nanotechnology and tissue engineering department, stem cell technology research center, tehran, iran 6unrc ,tarbiat modares university, school of medical science, hematology department and stem cell technology research center, tehran, iran cellular and molecular urology 411vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l introduction bladder is a unique organ in possessing includes three layers, namely mucosa, submocusa, and detrusor muscle. detrusor consists of smooth muscle cells that have capability communication with sympathic, parasympathic, and somatic nerves make the bladder a challenging organ to be substituted. the bladder is susceptible to a variety of possible abnormalities, other tissue damages or losses, tion, highlight the need for tissue reconstruction. bladder reconstruction is done using a segment of the gastrointestinal tract as an alternative matrix for the bladder augmentation or replacement. (1) reconstruction of the bladder with autologous non-urologic tissues does not provide the entire function. furthermore, there are some important complications that limit the use of these natural matrices, such as metabolic abnormalities, perforation, malignancy, and infection.(2) to overcome the problems related to the using of the intestinal segments for the urinary tract reconstruction, many efforts have been made using several biological and synthetic materials, such as the de-epithelialized intestinal segments, seromuscular intestinal segments, dura mater, peritoneum, and fascia, which have resulted in varying degrees of tissue reconstruction.(3) the use of naturally-derived agents, including lyophilized dura and submocusa of porcine small intestine and placenta could result in contraction for an unknown period of time.(4) recently, attention has been turned toward auto-augmentation and ureterocystoplasty. autoaugmentation has had disappointing outcomes in long-term follow-up and ureterocystoplasty requires severely dilated ureters. de-epithelialization of the bowel segment may lead to growth of mucosal layer; however, shrinkage of graft and re-epithelialization of afore-mentioned bowel segment are the main limitations.(5) proper native bladder tissue and the distrust in the existence of healthy tissue in the involved bladder reconstruction using native tissue. previously, biological synthetic materials, such as construction, but they had no favorable outcomes. the main reason for their failure was body reaction to the foreign agents.(6,7) permanent synthetic mechanical problems. recently, some investigators have focused their attention on tissue engineering and using biocompatible synthetic materials for soft tissue substitution. there are two forms of the bladder tissue the isolated and cultured primary cells are seeded on natural or synthetic scaffold and then transplanted into the host, and subsequently the graft regeneration and maturation could be continued in vivo. the second form is cell independent and the acellular matrix or biodegradable, biocompatible scaffolding is transplanted into the host. this acellular matrix is used as a mechanical support generation. acellular collagen matrix has many growth factors expected to promote tissue regeneration,(8) but according to literature, this matrix, seeded or unseeded, has not improved tissue regeneration. atala and colleagues produced an effective bladder tissue by using cell implantabladder tissue engineering | shakhssalim et al 412 | tion on collagen/polyglycolic acid scaffold. they achieved notable results in compliance, leak point pressure, cellular structure, and phenotypical characteristics in some later cellular transplantation on synthetic scaffold.(11) synthetic polymers due to their reproducibility in synthesis, also having appropriate mechanical properties, are the best candidates for matrix synthesis. furthermore, it is possible to process the application of synthetic/polyglactin composite may lead to chronic infection, foreign body reaction, implant shrinkage, and rejection of the implant.(12,13) therefore, it is important to investigate the body response to the implanted synthetic unseeded scaffold to check the suitability of using synthetic scaffold for the regeneration of the tissue of interest. previously, rohman and associates reported that cells may show preferential growth on materials displaying mechanical properties that most closely represent those of the derived tissue.(14) strate. we also evaluated the graft morphologically and immunohistochemically after implantation in dogs. materials and methods three adult intact female mongrel dogs weighing used in this study. the dogs were determined to be healthy based on the results of physical examination and complete blood count. animals outdoor system during the experiment period. they were fed by a balanced commercial dry maintenance diet (friskies, purina, marne-la-vallee, france) once a day, and water was offered ad libitum. the experimental protocol was approved the netherlands) (2 mg/kg) intramuscularly. this was followed by induction of general anesthesia kg), and maintained by the same drugs. the urinary bladder was approached through a caudal midline abdominal incision, and linear cystotomies of the bladder dome were done. augmentation cystoplasty was performed with the to the third dog. a single layer of continuous inused for the anastomosis. the omentum was then placed over the graft and secured to the bladder glycolic acid material before the abdominal incisions were routinely closed in three layers (figure 1). all dogs received teramadol for 3 days and an antibiotic for 14 days. a urethral foley catheter urine leakage and relieve tension on the suture line. all the animals underwent abdominal ultrastenography to evaluate urine leakage on the 3rd cellular and molecular urology 413vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l and 7th postoperative days, then monthly aftergen, and serum level of creatinine were tested twice a week for two weeks, and then monthly after the operation. the second and third ones 4 months later. the graft was investigated macroscopically and then evaluated for light and electronic microscopic morphology as well as immunohistochemistry characteristics. fabrication and preparation of pcll and scaffolds were prepared by double jet electrospinning method, as described by khademhosseini and colleagues and matthews and associates.(15,16) and n, n-dimethylformamide (dmf) were purchased from sigma (st. louis, mo, usa). these materials were used as received without any furin chloroform at room temperature and dmf was added to the chloroform just before the electrospinning process. many studies have shown that dmf helps during the electrospinning and the (17,18) experiments were conducted at chloroform to dmf ratio of tained at 12 wt%. polylactic acid was dissolved at a concentration of 4 wt% in a solvent mixture of chloroform and dmf. a variable voltage power supply was used for to stock each of the prepared solutions. the electrospinning setup utilized in this study consisted of three syringes, a ground electrode (stainless steel drum, with outer diameters of 3 and 5 mm, syringe nozzle through pe extension tubing. the needle tip could move in restricted distance along the direction of the deposition area; thus, gave the capability of having a uniform mat. a voltto the solution and the jet emerging from the needle to the drum collector. the collecting surface consisted of a cylindrical stainless steel collector 1 minute, while for in-vitro assessment, in-vitro the scaffold was produced in about 2 hours. the samples were then washed 3 or 4 times in sterhydrophilicity, oxygen plasma treatment was performed. the bare materials were exposed to oxygen plasma at 13.6 mhz for 5 minutes using a figure 1. a single layer of continuous interlocking sutures with 4-0 polyglycolic acid was used for the anastomosis of pcl/plla to the bladder of the third dog. bladder tissue engineering | shakhssalim et al 414 | diener electronic plasma device. scanning electron microscopy (sem) observation morphology was ob-© tescan, served with scanning electron usa) after sputter coating with platinum. the diameter and the distribution of the diameter were measured using image analyzing software. nonwoven fabric samples with proliferated cells phosphate-buffered saline (pbs). after rinsing and dehydrating in sequentially increasing ethasputter coating with platinum. anterior bladder wall incision was made, and the cutting margin was sewn to the square patch of for immunostaining, the samples were washed these cells were permeabilized and blocked in tively. thereafter, the samples were incubated tibodies used in this study were desmin (santa sc-15367), and alpha-smooth muscle actin (sigma, a5228). at the end of the incubation time, pus, japan). furthermore, for histological examination, the specimens were washed twice with through a series of graded alcohol solutions and ness. the sections were attached to poly-l lysine for 12 hours, dewaxed in xylene, and stained with hematoxylin and eosin. hours at room temperature, and then, dehydrated through a series of graded alcohol solutions. once dried, the samples were mounted on aluminum stubs, sputter-coated with gold-palladium (aupd), and viewed by using sem (tescan veresults as demonstrated, this polymer had high interaction with cells. hematoxylin and eosin staindles and urothelial layer were formed. macroscopic view of the graft site in the bladder cellular and molecular urology 415vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l low-up period upto 4 months for the second dog. hematoxylin and eosin staining of harvested implantation, showed proper muscle and urothe(figures 2a and 2b). again encrustation was observed in intraluminal view of the bladder (figure immunohistochemical, and sem results, macroscopic view of the bladder in the later case after 4 months revealed normal mucosal appearance, and encrustation could not be detected (figures 3a and 3b). therefore, it seems that in our excal results. discussion the introduction of alternative tissue regeneration technique by using unseeded synthetic polymers has caused enormous controversy. pattison and colleagues demonstrated that the possible etiology of limitations of this experience, including infection, toxicity, and biocompatibility problems, was related to the micron size of these polymers; thus, these particles could not regenerate the new tissue from the surrounded native cells.(19) study by vance and associates demonstrated that figure 2a. hematoxylin and eosin staining of the harvested graft site of the second dog after 4 months of pcl implantation. figure 2c. encrustation was observed in intraluminal view of the bladder after implantation of pcl. figure 2b. the immunohistochemical appearance of the harvested graft site of the second dog after 4 months of pcl implantation. bladder tissue engineering | shakhssalim et al 416 | yglycolic acid (plga) polymers prepared with cells growth; ymers to nano dimensions gained more attention. completely different cellular response. thapa and coworkers presented the in-vitro study that revealed the enhancement of proliferation and adhesion of the bladder smooth muscle cells on nano-structural they showed that cell growth increases over the extended periods of 1, 3, and 5 days after using those nano-structural polymers.(21) another in-vitro study revealed that cellular adhesion on nano-dimenicantly in comparison with traditional micron size polymers.(22) pattison and colleagues produced a nano-rough surface of three dimensional plga in the laboratory environment successfully, and then, cellular growth, adhesion, and protein production improved with these particles in comparison to the micron polymers. they recommended that using nano-rough surface of three dimensional plga scaffolds may be a proper medium for regeneration of the bladder wall cells in in-vivo environment.(23) harrington and associates reported their in-vitro experience of implantation of multipotent stem cells on nano-dimensional structure(24) and the other similar studies explored the interesting aspects of using these polymers with two different approaches, including bottom-up (self-assembling cells)(25) and top-down (differentiation was solely controlled by nanotexture size).(26) allogenic matrix with seeded cells used in the canine model brought about more noticeable results than the acellular matrix(27) figure 3a. hematoxylin and eosin staining of the harvested graft site of the third dog after 4 months of pcl/plla implantation. cellular and molecular urology 417vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l improvement of regeneration of the bladder wall cells was observed on scaffold with seeded cells functional capacity).(28) domingos and coworkers revealed that the latex biomembrane as a biocompatible agent can be used in a rabbit model for the bladder augmentation successfully and this material promoted epithelium and muscle regeneration with proper clinical and histological outcomes. the transitional epithelium continuity of the host bladder tissue on the patch area and the wellorganized muscle layers were detected on the 9th day.(29) the other study demonstrated successful bladder wall grafting in 16 rats. two months after grafting, proper epithelialization and growth of smooth muscle cells were detected. mensions in our canine model (an in-vivo study) as a bioavailable substrate layer in reconstruction of the bladder and regeneration of the epithelium and smooth muscle cells. further efforts are required in future to evaluate the results of cellular seeding on this nano scaffolds that may revolutionize the bladder tissue engineering. conclusion all three implantation models showed the same plla model has come up with desirable clinical results. folds in nano dimensions in a big animal model for the bladder tissue engineering. however, further studies by using other nanopolymers may advance the results of tissue engineering in organ reconstruction in the future. figure 3b. macroscopic view of the bladder after 4 months showed normal mucosal appearance, and encrustation was not detected. bladder tissue engineering | shakhssalim et al 418 | conflict of interest none declared. references 1. scriven sd, trejdosiewicz lk, thomas df, southgate j. urothelial cell transplantation using biodegradable synthetic scaffolds. j mater sci mater med. 2001;12:991-6. 2. kropp bp, eppley bl, prevel cd, et al. experimental assessment of small intestinal submucosa as a bladder wall substitute. urology. 1995;46:396-400. 3. campodonico f, benelli r, michelazzi a, ognio e, toncini c, maffezzini m. bladder cell culture on small intestinal submucosa as bioscaffold: experimental study on engineered urothelial grafts. eur urol. 2004;46:531-7. 4. kelami a. lyophilized human dura as a bladder wall substitute: experimental and clinical results. j urol. 1971;105:51822. 5. atala a. this month in investigative urology: commentary on the replacement of urologic associated mucosa. j urol. 1996;156:338-9. 6. kudish hg. the use of polyvinyl sponge for experimental cystoplasty. j urol. 1957;78:232-5. 7. kelami a, dustmann ho, ludtke-handjery a, carcamo v, herlld g. experimental investigations of bladder regeneration using teflon-felt as a bladder wall substitute. j urol. 1970;104:693-8. 8. chun sy, lim gj, kwon tg, et al. identification and characterization of bioactive factors in bladder submucosa matrix. biomaterials. 2007;28:4251-6. 9. zhang y. bladder reconstruction by tissue engineering-with or without cells? j urol. 2008;180:10-1. 10. zhang y, frimberger d, cheng ey, lin hk, kropp bp. challenges in a larger bladder replacement with cell-seeded and unseeded small intestinal submucosa grafts in a subtotal cystectomy model. bju int. 2006;98:1100-5. 11. atala a, bauer sb, soker s, yoo jj, retik ab. tissue-engineered autologous bladders for patients needing cystoplasty. lancet. 2006;367:1241-6. 12. danielsson c, ruault s, basset-dardare a, frey p. modified collagen fleece, a scaffold for transplantation of human bladder smooth muscle cells. biomaterials. 2006;27:1054-60. 13. aragona f, d'urso l, scremin e, salmaso r, glazel gp. polytetrafluoroethylene giant granuloma and adenopathy: long-term complications following subureteral polytetrafluoroethylene injection for the treatment of vesicoureteral reflux in children. j urol. 1997;158:1539-42. 14. rohman g, pettit jj, isaure f, cameron nr, southgate j. influence of the physical properties of two-dimensional polyester substrates on the growth of normal human urothelial and urinary smooth muscle cells in vitro. biomaterials. 2007;28:2264-74. 15. khademhosseini a, ling y, karp jm, langer r. micro-and nanoscale control of cellular environment for tissue engineering. in: mirkin ca, niemeyer cm, eds. nanobiotechnology ii. weinheim: wiley-vch; 2007:347-57. 16. matthews ja, wnek ge, simpson dg, bowlin gl. electrospinning of collagen nanofibers. biomacromolecules. 2002;3:232-8. 17. lee k, kim h, khil m, ra y, lee d. characterization of nanostructured poly (ε-caprolactone) nonwoven mats via electrospinning. polymer. 2003;44:1287-94. 18. hsu cm, shivkumar s. n, n-dimethylformamide additions to the solution for the electrospinning of poly (ε‐caprolactone) nanofibers. macromol materials eng. 2004;289:33440. 19. pattison m, webster tj, leslie j, kaefer m, haberstroh km. evaluating the in vitro and in vivo efficacy of nano-structured polymers for bladder tissue replacement applications. macromol biosci. 2007;7:690-700. 20. vance rj, miller dc, thapa a, haberstroh km, webster tj. decreased fibroblast cell density on chemically degraded polylactic-co-glycolic acid, polyurethane, and polycaprolactone. biomaterials. 2004;25:2095-103. 21. thapa a, miller dc, webster tj, haberstroh km. nano-structured polymers enhance bladder smooth muscle cell function. biomaterials. 2003;24:2915-26. 22. thapa a, webster tj, haberstroh km. polymers with nanodimensional surface features enhance bladder smooth muscle cell adhesion. j biomed mater res a. 2003;67:137483. 23. pattison ma, wurster s, webster tj, haberstroh km. threedimensional, nano-structured plga scaffolds for bladder tissue replacement applications. biomaterials. 2005;26:2491500. 24. harrington da, sharma ak, erickson ba, cheng ey. bladder tissue engineering through nanotechnology. world j urol. 2008;26:315-22. cellular and molecular urology 419vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l 25. gelain f, bottai d, vescovi a, zhang s. designer self-assembling peptide nanofiber scaffolds for adult mouse neural stem cell 3-dimensional cultures. plos one. 2006;1:e119. 26. dalby mj, gadegaard n, tare r, et al. the control of human mesenchymal cell differentiation using nanoscale symmetry and disorder. nat mater. 2007;6:997-1003. 27. yoo jj, meng j, oberpenning f, atala a. bladder augmentation using allogenic bladder submucosa seeded with cells. urology. 1998;51:221-5. 28. atala a. tissue engineering and cell therapy: perspectives for urology. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. 9 ed. philadelphia: saunders; 2007:562-3. 29. domingos al, tucci s, jr., garcia sb, de bessa j, jr., cologna aj, martins ac. use of a latex biomembrane for bladder augmentation in a rabbit model: biocompatibility, clinical and histological outcomes. int braz j urol. 2009;35:217-24; author reply 25-6. 30. yu ds, lee cf, chen hi, chang sy. bladder wall grafting in rats using salt-modified and collagen-coated polycaprolactone scaffolds: preliminary report. int j urol. 2007;14:939-44. bladder tissue engineering | shakhssalim et al laparoscopic and robotic urology feasibility and safety of clipless and sutureless laparoscopic adrenalectomy: a 7-year single center experience nasser simforoosh1*, behnam shakiba2, mehdi dadpour1, seyyed erfan mortazavi1, hamid reza hamedibazaz1, mahdyar mahdavi1 purpose: laparoscopic adrenalectomy (lad) is considered the gold standard surgical method for resecting adrenal tumors. to date, only few small studies have investigated the safety of clipless laparoscopic adrenalectomy in which the adrenal vessels were controlled by the ligasure system or bipolar coagulation. the aim of the present study was to evaluate the safety and feasibility of sutureless and clipless laparoscopic adrenalectomy operations performed in our center. materials and methods: all patients with functional adrenal tumors, nonfunctional adrenal tumors larger than 5 cm and secondary adrenal metastases from the kidneys, lungs or breasts who had underwent an lad procedure between 2012 to 2019 were included in our study. in all of the cases, complete coagulation of adrenal veins was achieved through bipolar cautery and no vascular staplers, clips or other energy sources were used for controlling the adrenal vessels whatsoever. outcomes of interest included operation time, length of hospital stay, changes of serum hemoglobin level, and occurrence of major complications. results: of a total 251 patients, unilateral right and left-side adrenalectomy was performed in 168 and 67 cases, respectively, and 16 cases had underwent bilateral adrenal resection. the mean age (sd) of patients was 40.7 (13.6) years old at the time of operation and the mean size (sd) of the adrenal lesions was 5.2 (3.1) cm as measured by the greatest diameter. histological examination showed that the most common pathology of the resected adrenal glands was pheochromocytoma (n=78). none of the laparoscopic operations required a conversion to open surgery. also, major bleeding or other serious complications did not occur in any of the cases either intraoperatively or postoperatively. conclusion: clipless and sutureless laparoscopic adrenalectomy seems to be feasible and safe for removing adrenal tumors. moreover, bipolar cautery is associated with an acceptable outcome for vessel closure. keywords: laparascopic adrenalectomy; clipless; sutureless; laparoscopy; adrenal tumors, adrenalectomy introduction adrenalectomy is the treatment of choice for most of the malignant and benign tumors of the adrenal. gagner and his colleagues performed the very first successful laparoscopic adrenalectomy (lad) surgery in 1992 (1). subsequently, lad became the gold standard surgical technique for removing adrenal tumors of up to 8-11 cm at many specialized medical centers worldwide(2). in the recent years, many attempts have been made to improve the technical aspects of this procedure and also to reduce the surgical morbidities associated with it. to date, only a few small sample-sized studies have reported the safety of clipless laparoscopic adrenalectomy in which the adrenal vessels were closed by the ligasure system and bipolar coagulation(3,4). in this study, we report our experience with 267 cases of clipless and sutureless transperitoneal laparoscopic adrenalectomy in terms of safety and surgical outcomes. 1urology and nephrology research center, shahid labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. 2department of urology, firoozgar hospital, iran university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center, shahid labbafinejad hospital, tehran, iran. email: n.simforoosh@gmail.com, simforoosh@iurtc.org.ir. received july 2019 & accepted august 2019 materials and methods in this retrospective study, we evaluated the efficacy and safety of 267 clipless and sutureless transperitoneal lad operations performed in 251 patients from january 2012 to march 2019. all patients with functional adrenal tumors, nonfunctional adrenal tumors larger than 5 cm and secondary adrenal metastases from the kidneys, lungs or breasts were selected for this procedure. unilateral right-side and left-side adrenalectomy was performed in 168 and 67 patients, respectively, and 16 patients had undergone bilateral resection. selected patients underwent physical examination along with metabolic and hormonal assessment. imaging studies including computed tomography scan (ctscan) or magnetic resonance imaging (mri) were used based on each patient’s specific clinical status. patients with pheochromocytoma were admitted at least one week prior to surgery for adequate alpha blockade with oral phenoxybenzamine. all cases underwent lad via a transperitoneal approach. the operation was performed under general anesthesia with patients placed urology journal/vol 17 no. 2/ march-april 2020/ pp. 143-145. [doi: 10.22037/uj.v0i0.5493] in a lateral decubitus position. for camera insertion, a port was introduced through the umbilicus by applying hasson technique. after creating a pneumoperitoneum, three 5 mm trocars were inserted under direct vision. for right-side adrenalectomy, another 5 mm trocar was used to retract the liver. adrenal veins were coagulated by bipolar cautery and then divided. no vascular staplers, clips, or any other energy sources were used for the closure of adrenal vessels. the details of the surgery technique have been explained previously(5). adrenal glands were separated from the surrounding tissue by scissors and bipolar cautery and finally, considering the size of the tumor, specimens were retrieved from the abdominal cavity by using the endobag through the umbilical and lower quadrant port sites. the outcomes of interest were duration of operation, length of hospital stay, changes in hemoglobin level, and occurrence of major complications. this study was approved by the ethics committee of urology and nephrology research center (unrc), shahid beheshti university of medical sciences, and was conducted in accordance with the helsinki declaration. results two hundred and sixty-seven clipless lad procedures were performed in our institute on 251 patients (91 male) during the study period. of the total 251 patients, 168 had a mass in the right adrenal, 67 in the left, and 16 had bilateral adrenal involvement. the patients’ mean age (sd) was 40.7 (13.6) years old. the mean greatest diameter (sd) of adrenal lesions was 5.2 (3.1) cm, ranging from 1-13 cm. the mean overall operation time from trocar insertion was 103 minutes (range: 65-142 minutes) with the operation time not being statistically different across the leftand right-side cases. the mean duration (sd) of hospital stay was 2.2 (0.7) days (range: 1-5 days). conversion into open surgery was not necessary in any of the patients and no intraoperative complications such as major bleeding were observed. the mean (sd) pre and post-operative hemoglobin levels were 12.9 (1.3) and 12.6 (0.6), respectively. also, there was no significant correlation between tumor size and decrease of serum hemoglobin concentration (p-value > .05). as presented in table 1, histopathological evaluation showed that the most common etiology of the adrenal lesions was pheochromocytoma (n=78). discussion previous studies have proposed that laparoscopic adrenalectomy is associated with less post-operative pain and discomfort, minimal surgery-related blood loss, shorter operation and recovery time, and more appealing cosmetic results in comparison to open surgery(5,6). considering these advantages, laparoscopic adrenalectomy has become the standard therapy for treating adrenal masses (3,7). in the previous decade, many attempts of modifying surgical techniques and laparoscopic instruments have been made to facilitate this surgical procedure and improve its results. with conventional lad, one of the main concerns is the precise dissection, isolation, and control of adrenal veins with hemo-lok clips. this procedure is associated with multiple risks such as the avulsion of short adrenal fragile veins, spontaneous clips displacement, troublesome bleeding, and possible need for conversion into open surgery(4,5). on the other hand, previous studies have suggested that conventional laparoscopic bipolar electrocoagulation is safe and effective for controlling lesser gastric, mesoappendix, and uterine vessels and also the cystic artery during laparoscopic removal of the respective organs (8-10). based on the result of these studies, several urologists have tried to perform clipless and sutureless laparoscopy for the removal of adrenal glands. chueh and his colleagues reported their experience of performing clipless laparoscopic adrenalectomy with needlescopic instruments in 12 cases. they found that clipless laparoscopic adrenalectomy with needlescopic instruments is feasible for most benign adrenal tumors(11). surgit et al. evaluated the use of the ligasure vessel closure system during laparoscopic adrenalectomy in 32 patients. they concluded that the ligasure device system seems to be safe and effective for vessel closure during laparoscopic adrenalectomy(4). we have previously reported 13 clipless laparoscopic adrenalectomy surgeries carried out in our center which was limited to pediatric patients(5). the results of our previous study showed that this approach is likely to have an acceptable outcome if performed by an expert surgeon. in the present study we reported our 7-year experience of performing clipless transperitoneal laparoscopic adrenalectomy for benign and malignant adrenal masses in a relatively large sample population. we applied the conventional bipolar cautery as the vessel-sealing system in all of our cases. no conversion to open surgery was needed during any laparoscopic operation. furthermore, there were no cases of troublesome bleeding during lad which showed the effectiveness of conventional bipolar cautery in maintaining hemostasis. the results of the present study were notable in some aspects: firstly, to the best of our knowledge, no similar study has evaluated the feasibility and safety of clipless sutureless lad with such a large sample size so far. second, despite the controversies existing about the maximum size of the adrenal lesions being operable by a laparoscopic approach, we included all cases regardless of their tumor size. the maximum size of an adrenal mass in our series of cases was 13 centimeclipless and sutureless laparoscopic adrenalectomy-simforoosh et al. table 1. etiology of the adrenal lesions after histopathological examination (n=267) pathology of adrenal tumor total number (%) left-side (n) right-side (n) pheochromocytoma 78 (29.2%) 30 48 conn’s adenoma (hyperaldosteronism) 45 (16.8%) 11 34 adrenocortical hyperplasia 44 (16.5%) 11 33 non-functional adenoma 37 (13.8%) 8 29 myelolipoma 20 (7.4%) 8 12 cushing 17 (6%) 4 13 adrenocortical carcinoma 7 (2.6%) 3 4 other (cyct, metastasis, etc.) 19 (7.1%) 8 11 laparoscopic and repotic urology 144 vol 17 no 02 march-april 2020 145 ters. furthermore, our study demonstrated that conventional bipolar cautery besides being safe and effective for controlling the adrenal vessels, is associated with diminished costs compared to hem-o-lok and ligasure. previous studies have shown that bipolar cautery and ligasure are both safe for using around the adrenal gland in pheochromocytoma and the present study confirmed their results(4,5,11). also, in this study, the frequency of right adrenalectomy and pheochromocytoma was higher compared to other literature reports. a possible reason is that our hospital is a referral center for urologic diseases. as to any other study, this study was also associated with few limitations. this was a retrospective case series study and as such all methodological disadvantages of a retrospective study should be considered before interpretation of the findings. also, all tumors were removed laparoscopically using the transperitoneal approach which is the preferred approach in our institute for lad in lateral position. theoretically, controlling the adrenal vessels during retroperitoneal approach is similar to transperitoneal lad, but our findings cannot completely support the safety of clipless and sutureless retroperitoneal adrenalectomy. in conclusion, clipless and sutureless transperitoneal laparoscopic adrenalectomy is a safe and effective approach for adrenal mass resection. in addition to the benefits of conventional lad, clipless laparoscopic adrenalectomy further simplifies this procedure and reduces the operation time and also the associated costs. conflict of interest the authors declare no conflicts of interest. references 1. gagner m, lacroix a, bolte ejtnejom. laparoscopic adrenalectomy in cushing's syndrome and pheochromocytoma. 1992;327. 2. ramacciato g, nigri g, di santo v, et al. [minimally invasive adrenalectomy: transperitoneal vs. retroperitoneal approach]. chir ital. 2008;60:15-22. 3. misra mc, aggarwal s, guleria s, seenu v, bhalla ap. clipless and sutureless laparoscopic surgery for adrenal and extraadrenal tumors. jsls. 2008;12:252-5. 4. surgit o. clipless and sutureless laparoscopic adrenalectomy carried out with the ligasure device in 32 patients. surg laparosc endosc percutan tech. 2010;20:109-13. 5. simforoosh n, ahanian a, mirsadeghi a, lashay a, hosseini sharifi sh, soltani mh. clipless laparoscopic adrenalectomy in children and young patients: a single center experience with 12 cases. urol j. 2014;11:1228-31. 6. haveran la, novitsky yw, czerniach dr, kaban gk, kelly jj, litwin de. benefits of laparoscopic adrenalectomy: a 10-year single institution experience. surg laparosc endosc percutan tech. 2006;16:217-21. 7. matsuda t. laparoscopic adrenalectomy: the 'gold standard' when performed appropriately. bju int. 2017;119:2-3. 8. song j, cho sj, park cs, kim sh, ku ps, lee ma. two uterine arterial management methods in laparoscopic hysterectomy. j obstet gynaecol res. 1998;24:145-51. 9. underwood ra, dunnegan dl, soper nj. prospective, randomized trial of bipolar electrosurgery vs ultrasonic coagulation for division of short gastric vessels during laparoscopic nissen fundoplication. surg endosc. 1999;13:763-8. 10. mckernan jb, stuto a, champion jk. new application of bipolar coagulation in laparoscopic surgery. surg laparosc endosc. 1996;6:335-40. 11. chueh sc, chen j, chen sc, liao ch, lai mk. clipless laparoscopic adrenalectomy with needlescopic instruments. j urol. 2002;167:39-42; discussion -3. clipless and sutureless laparoscopic adrenalectomy-simforoosh et al. pediatric urology introduction ureteropelvic junction obstruction (upjo) is a com-mon disease in pediatric urology. most cases are diagnosed and treated in infancy(1). the standard procedure is dismembered pyeloplasty, which varies from an open approach to various minimally invasive approaches. however, which approach is more advantageous remains controversial, especially for infants(2,3). gatti et al. recommended that the approach to repair may best be based on the family’s preference for incision aesthetics and the surgeon’s comfort with the approach, rather than more classically objective outcome measures(4). despite the increasing popularity of laparoscopy and robotics in the current era, open surgery remains an important option. we have performed dismembered pyeloplasty via a mini flank incision (less than 3 cm in length) for infants with upjo since 2015. to evaluate its safety and efficacy, we present our experience using a retrospective study that compared the results of pyeloplasty via a mini flank incision to a laparoscopic procedure in children younger than 3 years of age. patients and methods study population from january 2015 to january 2018, 85 unilateral pyeloplasties were performed in infants with upjo. data open surgery in the era of minimally invasive surgery: pyeloplasty via a mini flank incision in the treatment of infants with ureteropelvic junction obstruction xiaodong liu1,2, xinghuan wang1* purpose: to evaluate the clinical effects of open pyeloplasty via a mini flank incision in the treatment of infants with ureteropelvic junction obstruction (upjo). materials and methods: we retrospectively analyzed 85 cases of infants with upjo in our hospital from jan. 2015 to jan. 2018. the cases were divided into two groups according to the procedure: open pyeloplasty (n=45) and laparoscopic pyeloplasty (n=40). after 12~24 months of follow-up, the clinical effects of the two groups were compared. results: there was no significant difference in age between the two groups (p = .1). the operation time, postoperative fasting time and the indwelling time of the perirenal drainage tube in the open group were shorter than those in the laparoscopic group (68.0 ± 15.3 minutes versus 79.6 ± 18.8, p = .002; 5 ± 1 hours versus 14 ± 8.2 hours, p =.001; 2.8 ± 0.8 days versus 3.7 ± 1.3 days, p = .001, respectively), and there was no significant difference in the volume of intraoperative bleeding (2.1±0.9 versus 2.2±0.6, p=.55). the number of recurrences and complications in both groups were 0 versus 2 (p = .22) and 5 versus 7 (p = .40), respectively. conclusion: open pyeloplasty via a mini flank incision has the advantages of being minimally invasive, safe, effective, and easy to master, and it requires a short operation time. it is a reasonable option for the treatment of infants with upjo despite this era of minimally invasive surgery. keywords: ureteropelvic junction obstruction; pyeloplasty; minimally invasive; infant 1department of urology, zhongnan hospital of wuhan university, wuhan, china. 2department of urology, shenzhen children's hospital, shenzhen, china. *correspondence: department of urology, zhongnan hospital of wuhan university, wuhan,china. tel:+86 027-67812888. fax:+86 027-67812892. email: wangxinghuan@whu.edu.cn. received june 2019 & accepted december 2019 from the clinical history, physical examination, blood investigations, and imaging studies, including ultrasonography, intravenous pyelography (ivp) or magnetic resonance urography (mru) and diuretic renography, were gathered. patients with abnormal cardio-pulmonary function and urinary calculi were excluded from the study. the nature of the study was explained to each patient, and informed consent was obtained. the ethics committee of shenzhen children's hospital approved the protocol of this study. indications for surgical intervention included impaired split renal function (< 40%), a decrease in split renal function of >10% in subsequent studies, poor drainage function after the administration of furosemide, increased anteroposterior diameter on us, and grade iii and iv dilatation, as defined by the society for fetal urology(5). study design this study was a retrospective collection of data from a single center, nonrandomized study performed in a children's hospital in shenzhen, china. the sample size was calculated according to a non-inferiority test analysis. considering type i error of 0.05 and type ii error of 0.1, 40 samples were needed for each arm. the children were divided into two groups: the open pyeloplasty (op) group (n = 45), in which the procedure was performed via a small flank incision; and the laparoscopic pyeloplasty (lp) group (n = 40). in the op group, 39 urology journal/vol 17 no. 2/ march-april 2020/ pp. 169-172. [doi: 10.22037/uj.v0i0.5405] patients were male, and 6 patients were female, and the age ranged from 1 month to 3 years. in the lp group, 33 patients were male, and 7 patients were female, and the ages ranged from 2 months to 3 years. the qualifications of the two groups of surgeons were equal and comparable. surgical technique open pyeloplasty (op) under general anesthesia, the lateral decubitus position (figure 1) was used, and a lumbar subcostal muscle splitting incision was made with an incision length of less than 3 cm. the abdominal muscles were separated with the help of retractors, and the surgeon opened the perirenal fat sac. the surgeon identified and hooked the ureteropelvic junction (upj) using right angle vascular forceps and performed the standardized open technique described by hynes and anderson after proper freeing of the upj. the anastomosis was performed using a 6-0 vicryl (polyglactin 910) continuous suture, and an antegrade dj stent (3f/4f) was placed in all cases. a perirenal drainage tube was placed routinely. the incision was closed using medical glue (figure 2). laparoscopic pyeloplasty (lp) the conventional three-hole laparoscopic anderson-hynes procedure was performed (figure 3~4). the application of anesthesia and dj stent were same the op group. outcome assessment the fasting time was determined according to abdominal distension, vomiting and intestinal peristalsis. the perirenal drainage tube was removed when the output was less than 10 ml for 2 days. the catheter was kept for 3 days, and the dj stent was removed via cystoscopy 4 weeks after surgery. the operation time, intraoperative bleeding volume, postoperative fasting time, indwelling time of perirenal drainage tube and complications were counted. the children were followed for more than 12 months. ultrasound and urine routine analysis were performed 3, 6, and 12 months after surgery. during the follow-up period, the following conditions were diagnosed as recurrence: (1) progressively aggravated hydronephrosis; (2) progressive reduction in the split function of the affected kidney; and (3) symptomatic hydronephrosis (recurrent urinary tract infection or hematuria). statistical analysis was performed using spss software (statistical package for the social sciences, v. 26.0; spss inc, chicago, il, usa) . the independent t-test was used for numerical variables, and the chi squared or fisher’s exact tests was for qualitative variables. results the demographic and perioperative findings are summarized in tables 1 and 2, respectively. the operative time, postoperative fasting time and indwelling time of the perirenal drainage tube in the op group were shorter than those in the lp group (68.0 ± 15.3 minutes versus 79.6± 18.8, p = .002; 5 ± 1 hours versus 14 ± 8.2 hours, p =.001; 2.8 ± 0.8 days versus 3.7 ± 1.3 days, p = .001). there was no significant difference in the volume of intraoperative bleeding between the two groups (2.1 ± 0.9 ml versus 2.2 ± 0.6 ml, p = .55). postoperative complications are summarized in table 3. the success rates of the op and lp groups were 100% and 95%, respectively. the number of recurrence and complications in both groups were 0 versus 2 (p = .22) and 5 versus 7 (p = .40). all parents were satisfied with the appearance of the wound. urinary leakage in both groups was improved with prolonged catheterization, and febrile (defined as prolonged body temperature > 38.5°c for > 24 h) urinary tract infection was managed successfully using intravenous antibiotic therapy. a 2-year-old boy in the lp group presented an abdominal internal hernia on reoperative exploration after failure of conservative treatment for postoperative ileus. table 1. demographic data of the patients in op and lp groups. characteristicsa op lp p value male 39(86.7) 33(82.5) 0.6 left 31(68.9) 28(70) 0.9 age (mo) 7.5 ± 10.2 10.8 ± 9.9 0.1 adata are presented as the means ± sd or number (percent) characteristicsa op lp p value operative time (min) 68.0 ± 15.3 79.6± 18.8 0.002 intraoperative bleeding volume (ml) 2.1 ± 0.9 2.2 ± 0.6 0.55 postoperative fasting time (h) 5 ± 1 14 ± 8.2 0.001 indwelling time of perirenal 2.8 ± 0.8 3.7 ± 1.3 0.001 drainage tube (d) adata are presented as the means ± sd or number (percent) adata are presented as the means±sd or number (percent) table 2. perioperative findings of the patients in op and lp groups. table 3. postoperative complications of the patients in op and lp groups. characteristicsa op lp p value recurrence (n) 0(0) 2(5) 0.22 urinary leakage (n) 2(4.4) 2(5) 1.00 febrile urinary tract infection (n) 3(6.7) 4(10) 0.87 ileus (n) 0(0) 1(2.5) 0.47 figure 1. surgical position. pyeloplasty via a mini flank incision-liu et al. pediatric urology 170 vol 17 no 02 march-april 2020 171 discussion since peters et al. reported laparoscopic pyeloplasty in children for the first time in 1995(6), lp gained the advantages of decreased length of hospital stay, better cosmetic appearance, less postoperative pain and early recovery after more than 20 years of development(7,8,9). the number of robotic-assisted laparoscopic pyeloplasty (ralp) procedures is increasing annually. notably, lp and ralp had success rates equal to those of op (10), even in infants and newborns(1,11). pyeloplasty in children has entered a minimally invasive era similar to adults(9,12). however, lp has a steep learning curve(13), and ralp is expensive(14). therefore, op remains a main option for many pediatric urologists, especially in infants and young children. colaco et al.(14) used a retrospective cross-sectional analysis of the national surgical quality improvement program pediatrics database and reached the following conclusions: minimally invasive renal and ureteral pediatric surgery offered no improvement in 30-day complications, and it required longer operative times. therefore, op remains competitive in the minimally invasive era because it achieves better results with improved surgical technique. we performed op via a small flank incision for infants with upjo. the success rates of the op and lp groups were 100% and 95%, respectively, which is consistent with the literature reports(10). the results showed that both methods were safe and effective, but the op had the following advantages.(1) op required less surgical time for surgeons who are equally qualified and skilled. because the upj can be cut out and anastomosed outside of the incision, the procedure is more convenient and easier than under laparoscopy, especially for the process of anastomosis. therefore, the operation takes less time.(2) fasting time was decreased after op. eating sooner after the operation reduces fluid infusion and helps placate infants. lp has a certain effect on gastrointestinal function due to the intraperitoneal surgery and the continuous use of high-pressure pneumoperitoneum. however, the surgery in op is performed outside of the peritoneum, with little disruption to the gastrointestinal tract, and the children may eat soon after anesthesia and resuscitation.(3) the perirenal drainage tube may be removed earlier following op than following lp. because blunt dissection of muscles into the posterior abdominal cavity causes a minor disturbance to the surrounding tissues of the kidney, and magnifying glasses and microsurgical instruments are used to make the anastomosis more precise, the amount of urine leakage from the anastomotic site after the operation is less. therefore, the drainage tube may be removed earlier. (4) the present study showed that there were fewer complications after op. cutting and anastomosis of the renal pelvis occur under direct vision, and the surgery is more accurate. combined with superior suture suspension skill, op effectively avoids ureteral torsion and tissue injury caused by surgical instruments and protects the anastomotic site blood supply. therefore, the anastomotic site is unobstructed as much as possible. although there was no significant difference, this finding may be related to the sample size, and further research is needed to confirm this result.(5) the use of intradermic suture and glue application resulted in a wound appearance that was approximately equal to laparoscopic surgery from the perspective of the parents. (6) the learning curve of op was shorter. according to our experience, it is easier to learn and master the op via the small flank incision, and the longer learning duration and steep learning curve remain the main limiting factors of lp, especially for young children. although op has a certain advantage with the use of a small flank incision, it is not applicable in all children with upjo. according to the experience of the authors, the abdominal wall muscles are relatively loose in infants, the perirenal fascia and fat sac are relatively weak, the degree of freedom of the kidney is large, and the operative field may be conveniently exposed via the small incision. because older children do not have the figure 2. wound appearance (open surgery) figure 3. position of trocars figure 4. wound appearance (laparoscopic surgery) pyeloplasty via a mini flank incision-liu et al. physiological characteristics described above, it is more difficult to complete the procedure using a small incision. for some special cases, such as a long stricture of the ureter, intrarenal pyelopelvic and horseshoe kidney with upjo, it is difficult to expose the surgical field using a small incision, and the surgical outcome is difficult to guarantee. these conditions should be regarded as contraindications. the optimal surgical approach should be based on the preoperative imaging results. there are some limitations of our study.(1) it was a retrospective, nonrandomized study, and the decision of surgical approach may be related to the preference of parents or surgeons, which may lead to a certain bias. (2) the sample size was not sufficiently large, and more cases may lead to more reasonable conclusions.(3) postoperative pain and cosmetic results were not evaluated. (4) a multicenter research approach would improve future results. conclusions our data suggest that op via a mini flank incision has the advantages of being minimally invasive, safe, effective, and easy to master, and it requires a short operation time. op remains a reasonable option for the treatment of infants with upjo in this era of minimally invasive surgery. acknowledgments this study was approved in shenzhen children's hospital, as a research project. the authors thank the team of dr. jianguo wen (team no. szsm201612013) and appreciate his support for the preparation of this manuscript. conflict of interest the authors report no conflicts of interest. references 1. kafka iz, kocherov s, jaber j, chertin b. pediatric robotic-assisted laparoscopic pyeloplasty (ralp): does weight matter? pediatr surg int. 2019;35:391-6. 2. eau guidelines.copenhagen, c. radmayr.2018;p.60. 3. cundy tp, harling l, hughes-hallett a, et al. meta-analysis of robot-assisted vs conventional laparoscopic and open pyeloplasty in children. bju int. 2014;114:582-94. 4. gatti jm, amstutz sp, bowlin pr, stephany ha, murphy jp. laparoscopic vs open pyeloplasty in children: results of a randomized, prospective, controlled trial. j urol. 2017;197:792-7. 5. fernbach sk, maizels m, conway jj. ultrasound grading of hydronephrosis: introduction to the system used by the society for fetal urology. pediatr radiol. 1993;23:478-80. 6. peters ca, schlussel rn, retik ab. pediatric laparoscopic dismembered pyeloplasty. j urol.1995;153:1962-5. 7. reddy mn, nerli rb. the laparoscopic pyeloplasty: is there a role in the age of robotics? urol clin north am. 2015;42:43-52. 8. tasian ge, casale p. the robotic-assisted laparoscopic pyeloplasty: gateway to advanced reconstruction. urol clin north am. 2015;42:89-97. 9. pelit es, ciftci h, kati b,et al.minilaparoscopic pyeloplasty in adults: functional and cosmetic results.urol j.2018;15:339-43. 10. huang y, wu y, shan w, zeng l, huang l. an updated meta-analysis of laparoscopic versus open pyeloplasty for ureteropelvic junction obstruction in children. int j clin exp med. 2015;8:4922-31. 11. kutikov a, resnick m, casale p. laparoscopic pyeloplasty in the infant younger than 6 months--is it technically possible? j urol. 2006;175:1477-9; discussion 9. 12. autorino r, eden c, el-ghoneimi a, et al. robot-assisted and laparoscopic repair of ureteropelvic junction obstruction: a systematic review and meta-analysis. eur urol. 2014;65:430-52. 13. singh o, gupta ss, arvind nk. laparoscopic pyeloplasty: an analysis of first 100 cases and important lessons learned. int urol nephrol. 2011;43:85-90. 14. colaco m, hester a, visser w, rasper a, terlecki r. relative to open surgery, minimally-invasive renal and ureteral pediatric surgery offers no improvement in 30-day complications, yet requires longer operative time: data from the national surgical quality improvement program pediatrics. investig clin urol. 2018;59:200-5. pyeloplasty via a mini flank incision-liu et al. pediatric urology 172 v08_no_4_final_new.pdf urology for people 335urology journal vol 8 no 4 autumn 2011 what’s up in urology journal, autumn 2011? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2011;8:335. www.uj.unrc.ir epispadias epispadias is a rare congenital defect of the penis, in which the urethra ends in an opening on the upper aspect of the penis. however, it is possible for the urethra to be open along the entire length of the penis. the problem can also include the urethra, bladder, and large intestine. the prevalence of epispadias is 1 in 117 000 newborn boys and 1 in 484 000 newborn girls. the condition is usually diagnosed at birth or shortly thereafter. in females, the mons pubis is often deficient; the clitoris is bifid with divergent labia superiorly. the goals of surgical procedures are to correct the curvature, reconstruct the missing portion of the urethra, and restore the normal aspect of the external genitalia. surgical repair is usually successful at achieving continence. see page 328 for full-text article varicocele varicocele is a dilatation of the veins within the scrotum, the loose bag of the skin that holds man’s testicles. a varicocele is similar to a varicose vein that can occur in the leg. it is a fairly common condition, affecting 15% of men overall and 40% of men with known infertility. varicoceles occur most often in the left testicle. the varicocele occurs when the valves within the veins along the spermatic cord do not work properly. varicoceles develop slowly and may not have any symptoms. symptoms can include enlarged, twisted veins in the scrotum, painless testicle lump, scrotal swelling, or bulge within the scrotum, and infertility. the sudden appearance of a varicocele in an older man may be caused by a kidney tumor, which can block blood flow to a vein. treatment is by varicocelectomy, the surgical correction of a varicocele, which is performed on an outpatient basis. see page 298 for full-text article 1335vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l mesh hood fascial closure in renal allograft compartment syndrome in pediatric transplantation sajni i. khemchandani keywords: child; kidney transplantation; surgical mesh; herniorrhaphy; fascia. introduction donor recipient organ size disparity remains a major obstacle in pediatric renal trans-plantation. successful closure of the anterior abdominal wall in children following renal transplantation of adult organs may present as a challenging dilemma to transplant surgeons.(1) renal allograft compartment syndrome (racs) is an under-appreciated and poorly described surgical complication of renal transplantation.(2) it occurs when a tight fascial closure compresses the graft in its limited retroperitoneal space leading to graft ischemia and resultant early renal allograft dysfunction.(2,3) early renal allograft dysfunction may be caused by a number of technical factors including thrombosis, kinking of vessels, and a page kidney situation in which allograft is compressed within a shallow false pelvis and limited retroperitoneal space.(4) the successful treatment requires a high index of suspicion, prompt recognition and early surgical decompression. to facilitate closure of the abdominal wall in these cases, a tension free technique using a polypropylene mesh is described. mesh hood fascial closure (mhfc) was performed in two children, primarily to prevent graft loss due to racs, and secondarily to treat this complication and avert incisional hernia. case 1 a 13 years old male child weighing 23 kg received living related renal donor graft from father weighing 64 kg at our institute. vascular anastomosis was done using right common iliac vessels. brisk diuresis was established on release of clamps. stented ureteric reimplantation was done by lich's method.the wound closure was done by approximating all muscles with interrupted absorbable sutures. but because of large kidney; fascial closure was under excessive correspondence author: sajni i, khemchandani, md 401, sudarshan flats, 13, shantinagar society, usmanpura, ahmedabad380 013, gujarat, india. tel: +91 9426 520 112 fax: +91 79 2764 0095 e-mail: dr_sajni@rediffmail.com received december 2011 accepted april 2012 institute of kidney diseases and research center, dr hl trivedi its, civil hospital campus, ahmedabad, gujarat, india. case report 1336 | tension leading to compression of the graft and anuria. the wound was reopened; kidney was soft and hypo-perfused with diminished renal artery pulsations. we tried to reposition it in optimal position within iliac fossa to avoid kinking of renal artery, but again on fascial closure child developed anuria. hence wound closure was carried out using a large ellipsoid of polypropylene mesh which was draped loosely and without tension over the graft. the mesh was attached to edges of external oblique aponeurosis using continuous 1-0 polypropylene sutures, closed suction drain was placed in the retroperitoneal space lateral to the kidney. skin closure was then completed. although child had acute tubular necrosis in immediate postoperative period, graft function was established and he was discharged with serum creatinine of 0.8 mg/dl. at six months follow up, serum creatinine was stable. case 2 this 9 years old female child, weighing 26 kg with end stage renal disease (esrd) underwent live related donor transplantation from mother, weighing 62 kg. vascular anastomosis was done using proximal external iliac vessels. brisk diuresis occurred on release of clamps, stented ureteric reimplantation was done by lich's method. since wound closure was under excessive tension, releasing incision over rectus sheath was kept and wound was closed. on third post operative day, child developed graft dysfunction function and severe edema of right lower limb. doppler ultrasound showed increased resistive index (ri) and decreased flow in renal, external iliac and femoral veins. hence the child was re-explored and renal graft was found to be dusky, soft with decreased turgidity. the repositioning and release of pressure over the graft lead to return of color and turgidity. hence, the wound was closed by approximation of subcutaneous tissue and skin only, the external oblique sheath and muscles were left open. postoperative color-doppler study showed normalization of the flow and ri with restoration of renal function. on 12th postoperative day, j-j stent was removed and fascial closure was done by loosely suturing polypropylene mesh to the external oblique aponeurosis edges with continuous 1-0 polypropylene suture to avoid racs and incisional hernia (figure).the skin closure was done without using subcutaneous drain. the child was discharged with serum creatinine of 0.58 mg/dl without any wound infection. serum creatinine was 0.8 mg/ dl at six months of follow up. discussion racs is an under-reported and poorly described surgical complication of renal transplantation.(2) early renal allograft dysfunction may be caused by a number of technical factors including thrombosis, kinking of vessels, and a page kidney situation in which allograft is compressed within a shallow false pelvis and limited retroperitoneal space. it occurs when a tight fascial closure compresses the graft in its limited retroperitoneal space leading to possible compartment syndrome and graft ischemia and resultant early renal allograft dysfunction.(2,3,4) the renal allograft experiences further potential insult after wound closure: ureteral kinking and obstruction, vascular kinking and obstruction. it should be suspected when patient displays rapid deterioration of graft function after good initial function.(5) the causes of racs are otherwise poorly described, although the implantation of a relatively large renal allograft into a limited retroperitoneal space, especially in a pediatric recipient may represent a classical scenario and may be contributing factor to the higher rates of vascular thrombosis in pediatric transplantation.(4) patients at risk for racs may include recipients with significant weight discrepancy in relation to their donors. in beasley and colleagues series mean recipient weight was 17% less figure . wound closure using polypropylene mesh. case report 1337vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l fascial closure in pediatric transplantation | khemchandani than donor’s weight, in our patients recipient’s weight was 60% less than donor’s weight. racs may be prevented by positioning the allograft deeper into the abdominal cavity by choosing vessels proximal to the external iliac vessels for anastomosis. in our first child although common iliac vessels were used for anastomosis, we were not able to close the wound, hence polypropylene mesh was used for wound closure. treatment options for post-transplantation racs include: 1. intraperitoneal reallocation of graft and wound closure. 2. subcutaneous placement of graft with delayed secondary repair of hernia. 3. creation of a relaxing incision of the external and internal oblique fascia. 4. mesh closure: a: the porcine dermal collagen graft, b: the mesh hood fascial closure using polypropylene mesh as described by beasley and colleagues and nguan and colleagues.(2,4) 5. wound closure using vicryl mesh. in our second patient, although relaxing incision of external and internal oblique fascia was kept, child still developed racs in post-operative period. probably the compression over the graft was exacerbated in postoperative period by edema leading to precipitation of racs. hence urgent fasciotomy was done and graft was placed subcutaneously as suggested by ball and colleagues.(3) once allograft function established, secondary mhfc was done to prevent incisional hernia.(5) the surgical view states that the implantation of permanent synthetic material such as polypropylene mesh in the setting of genitourinary system may predispose to the development of wound infection.(3) in our experience, the use of polypropylene mesh in wound closure allowed proper placement of the allograft in the retroperitoneal space, avoiding excessive compression of kidney as in racs. we also think that this tension-free surgical technique should be primary application if fascial closure is under considerable tension to avoid racs and incisional hernia. we conclude that mesh hood fascial closure can be safely performed after size mismatched kidney transplantation to prevent or treat racs. it is easy to perform, is associated with minimal morbidity and does not preclude doppler/ ultrasound evaluation of the graft. conflict of interest none declared. references 1. richards sk, lear pa huskissan l, saleen ma, morgan jd. porcine dermal collagen graft in pediatric renal transplantation. pediatr transplant. 2005;9:627-9 2. beasley k a, mcalister vc, luke ppw. mesh hood fascial closure in renal allograft compartment syndrome. transplant proc. 2003;35:2418-9. 3. ball cg, kirkpatrick aw, yilmaz s, monroy m, nicolaou s, salazar a. renal allograft compartment syndrome an underappreciated post-operative complication. am j surg. 2006;191:619-24. 4. nguan cyc, beasley ka. mcalister vc, luke ppw. treatment of renal transplant complications with a mesh hood fascial closure technique. am j surg. 2007;193:119-21. 5. maione c, gambino g, di bona a, et al. ptfe mesh in renal allograft compartment syndrome. transplant proc. 2006;38:1049-50. letter re: the effect of aerobic training on serum levels of adiponectin, hypothalamic-pituitary-gonadal axis and sperm quality in diabetic rats nicola zampieri this is an intersting manuscript about the role of adiponectin and hormones and their relationship with fertility potential. those working with infertility, have always to remember that abnormal semen analysis could be associated with many systemic diseases. diabetes mellitus, obesity and hypogonadism are often associated with abnormal semen analysis; it is well known that after bariatric procedures there is an improvement in semen quality and also after hormones therapy in those cases of hypogonadisms. what is less known is about the recovery of spermatogenesis in diabetes mellitus patients but this study can explain how and when. in clinical practice all these diseases can be associated with each-other and for this reason all these patients should have weight control and should have a good sport activity. if bariatric surgery can reduces diabetes mellitus, hypertentyion and hypogonadism (abnormal hormonal axis – fsh,lh and tt), aerobic training can improve semen quality through the adiponectin action for all these patients.(1-2) tt action is related to the adipose tissue, and testicular volume has a relationship with spermatogenesis and fertility potential. probably in clinical practice these patients have lower testicular volume respect to controls(3). sport activity can improve hormonal function, with lower adipose tissue percentage higher adiponectin levels and higher tt with improvement in semen quality. an interesting key point is to verify in humans if there is also in these patients a correlation between spermatogenesis and testicular volume especially after weight control. references 1. engin-ustun y, yılmaz n, akgun n, aktulay a, tuzluoğlu ad, bakırarar b.body mass index effects kruger's criteria in infertile men. int j fertil steril. 2018;11:258-62. 2. aly jm, polotsky aj.paternal diet and obesity: effects on reproduction. semin reprod med. 2017;35:313-7. 3. liu y, ding z.obesity, a serious etiologic factor for male subfertility in modern society.reproduction. 2017;154:r123-r131 pediatric surgical unit woman and child hospital azienda ospedaliera universitaria itegrata, piazzale a.stefani n.1, 37134 verona, italy. e-mail: dr.zampieri@libero.it urology journal/vol 17 no. 2/ march-april 2020/ pp. 215-215. [doi: 10.22037/uj.v0i0.5265] point of technique 56 urology journal vol 7 no 1 winter 2010 a novel idea of using digital camera for laparoscopy training in urology devendra s pawar, santosh k singh, shobha benjwal, indu kumari urol j. 2010;7:56-8. www.uj.unrc.ir keywords: equipment design, laparoscopy, educational models, urologic surgical procedures department of urology, pt. bd sharma university of health sciences, rohtak, haryana, india corresponding author: devendra singh pawar, mbbs, ms (gen surg), mch (urol) 8-l; model town, rohtak, india, pin code: 124001 tel: +91 931 536 0943 e-mail: pawar.devendra@rediffmail.com received may 2009 accepted october 2009 introduction learning laparoscopic skills is difficult in the current era of fast developing laparoscopic urology. there are many commercially available good-quality laparoscopy trainers, but their prohibitive costs have limited their use in developing countries. to answer this problem, we conceptualized a home-made economical digital camera coupled with a laparoscopy trainer. digital camera has also been used in endourology for documenting interesting findings.(1-3) technique to test the compatibility of portable digital camera in figure 1. digital camera coupled with a trainer box. figure 2. inside view, displaying kidney model and laparoscopic instruments. laparoscopic urology setting, we first constructed a plywood board box of 16 × 12 × 9 inch in size, which had a space for attaching a digital camera (figure 1). a conventional small tube light was fitted in the corner in a concealed manner. then holes were made on the top of the box at appropriate places for passage of laparoscopic instruments (figure 2). we used a digital camera (nikon coolpix 3200, tokyo, japan) which has digital and optical zoom and continuous autofocusing facility and tv monitor display (figure 3). the camera uses rechargeable nickel cadmium a-a size batteries which usually last an hour. using this trainer with tv monitor, basic laparoscopic skills like holding suture needle while lying free on the internal organ surface, transferring needle from digital camera for laparoscopy training—pawar et al 57urology journal vol 7 no 1 winter 2010 one hand instrument to other holding sutures, passing needle through soft objects, applying square knot, doing blunt dissection, etc, were performed. artificial kidney, pelvis, and ureter could be kept inside the box, and laparoscopic pyeloplasty and nephrectomy could be practiced (figure 2). one could also zoom in and out the point of interest for which no assistant was required. results the quality of performing procedures and their perception on the tv screen was just like real laparoscopy via the applied digital camera in the laparoscopy trainer. it tremendously increased perception of depth and hand-eye coordination. in the view of colleagues who tested the instrument, learning laparoscopic skill was just like or even better with this innovation than other expensive comparable trainers. it did not require costlier laparoscope and camera and could be easily constructed and practiced at home by a beginner during their idle time. the camera could also record the procedure, which could be reproduced. discussion learning laparoscopic skills is essential for a budding urologist in the present era of minimally invasive surgery and increasing applications of laparoscopy in urology. since laparoscopic urology is still in its developing phase, younger urologists are not provided much time in learning basic skills in live conditions. to overcome this, various laparoscopy trainers are available, both expensive and economical.(3) some good-quality laparoscopy trainers are so expensive that they can be owned only by an institution. we designed a training module which was economical and easy to built and carry. revolution in electronic goods has made pocketsize high-resolution digital camera available at affordable price. we utilized nikon (3.2 mega pixel) with optical zoom, autofocus connected to a tv monitor display facility. with the help of camera, procedures performed inside the box can be seen in a 2-dimensional way on the monitor, and with practice, perception of depth can be improved significantly. we also experienced that the regular practice with this laparoscopy trainer significantly reduces ones learning time. one can also zoom in and out the point of interest and no assistant is required for this purpose. other laparoscopy trainers which utilize closed-circuit camera do not have the autofocus zoom facility. (4,5) whereas the use of laparoscope requires an assistant and it is expensive. in conclusion, this digital camera coupled with laparoscopy trainer is a good simulator of laparoscopy. its ability of projection on tv screen and autofocus facility eliminates the need of an expensive laparoscope and single 3-chip cameras for training, and an assistant is also not required for zooming in and out the tip of laparoscopic instruments. overall, we feel that this novel idea for learning laparoscopic skills will help new urologists arriving in this field. figure 3. laparoscopy trainer coupled with a tv monitor. digital camera for laparoscopy training—pawar et al 58 urology journal vol 7 no 1 winter 2010 acknowledgements the authors are highly thankful to professor tc sadasukhi, head, department of urology, sms medical college, in jaipur, for taking keen interest and helping us out in every way to complete this project and dr shaleen who has helped us a lot for solving out many technical problems. conflict of interest none declared. references 1. truzzi jc, bruschini h, simonetti r, andreoni c, ortiz v, srougi m. a simple way to take pictures during endoscopic procedures. j urol. 2004;171:327-8. 2. bruno d, delvecchio fc, preminger gm. digital still image recording during video endoscopy. j endourol. 1999;13:353-6. 3. kuo rl, delvecchio fc, preminger gm. use of a digital camera in the urologic setting. urology. 1999;53:613-6. 4. ramalingan m, senthil k, selvarajan k. simple innovative ideas in laparoscopic training methodology. indian j urol. 2004;26:86. 5. sanjay ja. handmade endotrainer: role in learning laparoscopy technique. indian j urol. 2004;20:85. v08_no_2_final.pdf reconstructive surgery 132 urology journal vol 8 no 2 spring 2011 triamcinolone injection following internal urethrotomy for treatment of urethral stricture kamyar tavakkoli tabassi,1 aliasghar yarmohamadi,2 shabnam mohammadi3 purpose: to investigate the success rate of internal urethrotomy when combined with corticosteroid injection in urethral scar tissue for treatment of urethral stricture. materials and methods: we performed a double-blind, randomized, placebo-controlled study on 70 patients with urethral stricture, who underwent internal urethrotomy from june 2003 to july 2008. patients were randomized into 2 groups; the experimental group (34 patients) who received triamcinolone acetonide injection and the control group (36 patients) that received an injection of sterile water after internal urethrotomy. postoperative results were compared between two groups. results: in the experimental group, 1 (2.94%), 3 (8.82%), and 2 (5.8%) patients developed infection, bleeding, and extravasation, respectively, and recurrence was noted in 12 patients. in the control group, infection, bleeding, and extravasation occurred in 2 (5.55%), 3 (8.33%), and 2 (5.55%) patients, respectively, and stricture recurred in 15 patients. there were no significant differences in stricture location as well as its etiology between the two groups (p = .672 and p = .936, respectively). complication and recurrence rates in experimental group were lower than the control group, but the difference was not statistically significant (p = .847 and p = .584, respectively). however, time to recurrence decreased significantly in experimental group (8.08 ± 5.55 versus 3.6 ± 1.59 months) (p < .05). in our study, we did not find any complications that could be attributed to the triamcinolone acetonide injections. conclusion: it seems that steroid injection after internal urethrotomy is a safe method, which may delay the recurrence of urethral stricture. urol j. 2011;8:132-6. www.uj.unrc.ir keywords: urethra, urethral stricture, triamcinolone acetonide, recurrence, retreatment 1mashhad center for reconstructive urology, department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran 2mashhad university of medical sciences, mashhad, iran 3department of anatomy and cell biology, school of medicine, mashhad university of medical sciences, mashhad, iran corresponding author: kamyar tavakkoli tabassi, md department of urology, imam reza hospital, mashhad, iran tel: +98 915 311 6149 fax: +98 511 859 1057 e-mail: kamiartt@yahoo.com received december 2009 accepted may 2010 introduction urethral strictures can occur due to trauma, infection, ischemia, inflammation, or unknown causes. as a result, scar tissue forms in the epithelium, which leads to decrease in caliber of the urethral lumen. stricture can develop in any part of the urethra from the prostatic urethra to the meatus.(1) different techniques have been described for treatment of urethral strictures, depending on the stricture length, location, and depth of scar. internal urethrotomy is a worthwhile method for treating urethral strictures which are less than 1.5 cm in length. however, high recurrence rates have been reported with this technique.(2) triamicinolone and internal urethrotomy—tavakkoli tabassi et al 133urology journal vol 8 no 2 spring 2011 several adjuvant interventions have been proposed to minimize the recurrence rate of urethral strictures after internal urethrotomy.(1) local corticosteroid injection (triamcinolone) after urethrotomy was proposed by hebert for the first time.(3) corticosteroids decrease the scar formation by reducing collagen and glycosaminoglycans synthesis and expression of inflammatory mediators.(4) hebert’s study was followed by sachse (5) and gaches and colleagues,(6) who reported favorable results with corticosteroid injection. abourachid and associates recommended intralesional steroid injection as a means to reduce the recurrence rate of urethral stricture.(7) in this study, we investigated the results of triamcinolone acetonide injection on the recurrence rate of the stricture following internal urethrotomy. in addition, we longitudinally looked at the interval between urethrotomy and the recurrence of urethral stricture. materials and methods we performed a double-blind, randomized, placebo-controlled study on patients with urethral stricture who presented to our clinic from june 2003 to july 2008. one hundred and seven patients with the mean age of 42.18 ± 17.7 years were studied for eligibility. patients with previous urethroplsty, urethral manipulation (urethrotomy or urethral dilatation), urethral strictures longer than 1.5 cm, neurogenic bladder, urinary tract infection, history of systemic or immune disease, and use of corticosteroids were excluded from the study. of recruited patients, 70 met our inclusion criteria and were randomized into 2 groups: the experimental group (34 patients), who received triamcinolone acetonide injection and the control group (36 patients), who received an injection of sterile water after internal urethrotomy (figure 1). the operating surgical team was blinded to the figure 1. patients selection triamicinolone and internal urethrotomy—tavakkoli tabassi et al 134 urology journal vol 8 no 2 spring 2011 intervention. the length of the urethral stricture was 0.5 to 15 mm. the stricture length was measured by both pre-operative urethrogram and endoscopic evaluation. the location of stricture was bulbar in 43 (61.42%), penile in 20 (28.57%), and both sites in 7 (10%) patients. the mean follow-up was 8.68 ± 5.36 months (range, 6 to 24 months). failure was defined as a need for repeat of surgical intervention during the followup period. recorded complications were wound infections, bleeding, and extravasation. surgical technique pre-operative evaluation consisted of physical examination, history taking, retrograde urethrography, and cytoscopy. furthermore, patients received a single dose of a first-generation cephalosporin half an hour before the surgery. first, by using a cold knife, multiple incisions were made through stricture sites at various positions endoscopically. in this manner, only fibrous tissue was cut and normal healthy urethra was remained intact. the incisions were continued until a 20 f urethral catheter could pass through the stricture site into the bladder. subsequently, 5 cc of the study solution was injected into the fibrotic tissue of the stricture site in four quadrants (figure 2). thereafter, an 18 f foley catheter was inserted and left in place for 3 to 5 days. after removal of the catheter, patients were followed up for 6 to 24 months for development of any complications. followup visits included history taking, questions about urinary symptoms as well as retrograde urethrography and cystoscopy if indicated. follow-ups were scheduled every 3 months and when patients had any complaints. statistical analysis data were analyzed using spss software (the statistical package for the social sciences, version 14.0, spss inc., chicago, illinois, usa). chisquare and student t test were used to compare two groups. non-normal distributed data were analyzed using mann-whitney u test. results complications occurred in 13 patients: infections in 3 (4.28%), bleeding in 6 (8.57%), and extravasation in 4 patients (5.71%). twentyseven patients had recurrent stricture formation, and the mean time to recurrence was 6.37 ± 4.86 months. in the group who received triamcinolone acetonide injection, we observed infection in 1 (2.94%), bleeding in 3 (8.82%), and extravasation in 2 (5.8%) patients, and recurrence in 12 patients. in the control group, we observed infection in 2 (5.55%), bleeding in 3 (8.33%), and extravasation in 2 (5.55%) patients, and recurrence in 15 patients. there were no significant differences regarding stricture location and etiology of strictures between the two groups (p = .672 and p = .936, respectively). complication rate in experimental group was lower than the control group, but the difference was not statistically significant (p = .847). recurrence rate was lower in the experimental group, but the difference did not reach statistical significance (35.3% versus 41.7%) (p = .584). however, time to recurrence decreased significantly in experimental group compared to placebo group (8.08 ± 5.55 versus 3.6 ± 1.59 months) (p < .05) (table). there was not any complication which could be attributed to the triamcinolone acetonide injections. discussion internal urethrotomy has been suggested as a procedure of choice for correction of the urethral strictures shorter than 1.5 cm; however, recurrence of strictures has been remained as its major drawback.(2) holm-nielsen and colleagues reported recurrence rates ranging from 50% to figure 2. sites of transurethral injections triamicinolone and internal urethrotomy—tavakkoli tabassi et al 135urology journal vol 8 no 2 spring 2011 75% during a 2-year follow-up period.(8) in our study, the overall recurrence rate was 38.6%, and the recurrence rate in the control group was 41.7%, which is consistent with the findings of holm-nielsen and colleagues. the reason for lower recurrence rates may be due to shorter duration of follow-up in our study. several adjuvant therapies, including brachytherapy,(9) injection of captopril,(10) mitomycin c, and steroids(11) have been proposed to minimize the recurrence rate of urethral strictures after internal urethrotomy. intraurethral brachytherapy with iridium-192 has been used after internal urethrotomy with early success. initial dose of 1000 to 1500 centigray was followed with daily irradiation for 3 days. of 17 patients, 6 developed complications during 20-month follow-up.(9) this study was followed by shin and colleagues who used rhenium-188mercaptoacetyltriglycine (188re-mag3)-filled balloon dilation in five patients. only one of their subjects did not develop stricture during followup period.(12) however, further studies are needed to confirm advantage of brachtherapy for the treatment of stricture. shirazi and associates used captopril gel after internal urethrotomy with good results, but the heterogeneity of patients makes interpretation of their results difficult.(10) because of its anticollagen property, mitomycin c has been used to decrease the recurrence rates after internal urethrotomy.(11) results showed that only 10% of patients had recurrence at 6 months. however, long-term results are not available. korhonen and colleagues reported transurethral injection of steroid for treatment of urethral strictures. of 38 patients, 21 underwent internal urethrotomy while 17 received triamcinolone injection after internal urethrotomy. urethrotomy was done at 12 o’clock position and catheter was removed one day after the surgery. in their study, some patients had strictures longer than 2 cm. recurrence rate was 61% in patients who underwent internal urethrotomy and 71% in those who received triamcinolone. it should be noted that strictures in the first group were tighter than the latter one.(13) hardec and coworkers reported that steroid injection decreased recurrence rate form 19.4% to 4.3%.(14) in a recent randomized, placebo-controlled trial, hosseini and colleagues administered triamcinolone in 70 patients on the clean summary of results characteristics experimental group(n = 34) control group (n = 36) p stricture location bulbar 64.70 58.33 .672* penile 23.52 33.33 both 11.76 8.33 stricture causes 38.23 38.23 .936* trauma 17.64 17.64 catheter 11.76 20.58 infection 5.88 5.88 unknown 26.47 23.52 complications infection 2.94 5.55 .847* bleeding 8.82 8.33 extravasation 5.8 5.55 none 82.44 80.57 recurrence rate 12 15 .584* time to recurrence (month) 8.08 3.6 < .05# mean age (y) 42.38 42.00 .929† mean follow-up (month) 9.55 7.86 .097# stricture length (cm) 0.80.7 ± 1.40 0.83.97 ± 1.38 > .05 comparison of experimental and placebo groups *chi-square test † t test # mann-whitney u test triamicinolone and internal urethrotomy—tavakkoli tabassi et al 136 urology journal vol 8 no 2 spring 2011 intermittent catheterization after internal urethrotomy. they put their patients on a urethral catheterization program and triamcinolone was used for lubrication. thirty patients used triamcinolone injections (experimental group) and 34 patients used waterbased jelly injections (control group). recurrence rate in experimental and control groups were 30% and 44%, respectively.(15) our results were similar to this study; however, in our study, the difference between recurrence rates was not statistically significant. considering that we did not use clean intermittent catheterization, the similarity of the results in these two studies suggests that triamcinolone injection during internal urethrotomy combined with a urethral catheterization program may decrease the recurrence rate significantly. in our study, we measured both the recurrence rate and the time to recurrence. our results showed that triamcinolone injection significantly delays the time to recurrence of urethral strictures after internal urethrotomy. conclusion steroid injection into the urethral fibrous tissue is a safe and effective adjuvant therapy after internal urethrotomy. although we could not demonstrate a decrease in recurrence rate of stricture formation, we were able to postpone the recurrence of urethral stricture after internal urethrotomy. conflict of interest none declared. references 1. latini jm. minimally invasive treatment of urethral strictures in men. current bladder dysfunction reports. 2008;3:111-6. 2. naude am, heyns cf. what is the place of internal urethrotomy in the treatment of urethral stricture disease? nat clin pract urol. 2005;2:538-45. 3. hebert pw. the treatment of urethral stricture: transurethral injection of triamcinolone. j urol. 1972;108:745-7. 4. koc e, arca e, surucu b, kurumlu z. an open, randomized, controlled, comparative study of the combined effect of intralesional triamcinolone acetonide and onion extract gel and intralesional triamcinolone acetonide alone in the treatment of hypertrophic scars and keloids. dermatol surg. 2008;34:1507-14. 5. sachse h. die sichturethrotomie mit scharfem schnitt. indikation-technik-ergebnisse. urologe a. 1978;17:177. 6. gaches cg, ashken mh, dunn m, hammonds jc, jenkins il, smith pj. the role of selective internal urethrotomy in the management of urethral stricture: a multi-centre evaluation. br j urol. 1979;51:579-83. 7. abourachid h, louis d, goudot b, dahmani f, hakami f, daher n. [internal urethrotomy in the treatment of stenosis of the urethra. late results and a review of the literature]. j urol (paris). 1989;95:477-80. 8. holm-nielsen a, schultz a, moller-pedersen v. direct vision internal urethrotomy:a critical review of 365 operations. br j urol. 1984;365:308–12. 9. sun yh, xu cl, gao x, et al. intraurethral brachytherapy for prevention of recurrent urethral stricture after internal urethrotomy or transurethral resection of scar. j endourol. 2001;15:859-61. 10. shirazi m, khezri a, samani sm, monabbati a, kojoori j, hassanpour a. effect of intraurethral captopril gel on the recurrence of urethral stricture after direct vision internal urethrotomy: phase ii clinical trial. int j urol. 2007;14:203-8. 11. mazdak h, meshki i, ghassami f. effect of mitomycin c on anterior urethral stricture recurrence after internal urethrotomy. eur urol. 2007;51:1089-92; discussion 92. 12. shin jh, song hy, moon dh, oh sj, kim th, lim jo. rhenium-188 mercaptoacetyltriglycine-filled balloon dilation in the treatment of recurrent urethral strictures: initial experience with five patients. j vasc interv radiol. 2006;17:1471-7. 13. korhonen p, talja m, ruutu m, alfthan o. intralesional corticosteroid injections in combination with internal urethrotomy in the treatment of urethral strictures. int urol nephrol. 1990;22:263-9. 14. hradec e, jarolim l, petrik r. optical internal urethrotomy for strictures of the male urethra. effect of local steroid injection. eur urol. 1981;7:165-8. 15. hosseini j, kaviani a, golshan ar. clean intermittent catheterization with triamcinolone ointment following internal urethrotomy. urol j. 2008;5:265-8. 1013vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l emergency laparoscopic orchiectomy for intra-abdominal testicular torsion a case report hossein karami,1 mohammad yaghoobi,1 amin hasanzadeh hadad1 introduction undescended testis (udt) occurs in 1-4% of full-term neonates and in up to 45% of preterm neonates.1 despite increased susceptibility of torsion in undescended tes-tes, this is a rare condition and a high clinical suspicion is needed to diagnose this emergency. ultrasound and other imaging modalities are not absolutely reliable for evaluation of torsion in udt. in this case report we used laparoscopy to diagnose torsion in the patient with udt and find a cure. case report the patient was an eighteen-year-old male, a known case of left abdominal udt, who was admitted to emergency service with left lower abdominal pain. the pain had started suddenly seventeen hours before arrival to hospital. the pain was sustained, localized in the left lower quadrant of abdomen, without radiation to other areas. the patient had nausea and vomiting. there was no change in the color of the abdominal skin and no visible mass in the pain area. vital signs were normal and no fever was detected. in deep palpation, there was moderate tenderness without rebound at the left lower quadrant of abdomen. digital rectal examination was normal and there was no evidence of gasterointestinal bleeding. cell blood count revealed no leukocytosis and there was no pyuria or microscopic hematuria in the urine analysis. plane and upward abdominal x-rays did not show any positive findings for gasterointestinal probcorresponding author: hossein karami, md urology and nephrology research center (unrc), shohadae-tajrish medical center, shahid beheshti university of medical sciences, tehran, iran tel: +98 21 22567222 fax: +98 21 22567282 email: karami_hosein@yahoo. com received november 2012 accepted may 2013 1urology and nephrology research center (unrc), shohadae-tajrish medical center, shahid beheshti university of medical sciences, tehran, iran case report 1014 | lems. ultrasound evaluation of abdomen revealed an intraabdominal testis in the left side, close to the internal inguinal ring. arterial blood flow which was suggestive of torsion of the intra-abdominal testis was not detected in the organ. after primary preparation, the patient underwent laparoscopy and an intra-abdominal testis appeared posterior to the internal inguinal ring with gangrenous appearance (figures 1, 2). laparoscopic orchiectomy was conducted. the pathology report confirmed our primary diagnosis and indicated necrotic testicular tissue. discussion there is a greater risk of testicular malignancy and infertility for udt.(1-2) intra-abdominal testes are more susceptible to malignancy than inguinal udts.(3) torsion occurs more commonly in the udts and it has been mentioned to be even up to 13 times higher than normal testes in some studies.(4-5) malignancy is common in those udts manifested with torsion. torsion of udt was described by delasiauve in 1840 , curling in 1857, and ormond in 1923.(6) undescended testes are susceptible to torsion perhaps by mechanism of abnormal contractions of cremaster and the greater relative broadness of testis than its mesentery,(7,8) but the mechanism of torsion has not been clearly defined yet. laparoscopy is the golden standard method for the diagnosis and treatment of intra-abdominal testis. it is wise to use laparoscopy to diagnose torsion in emergency situations. according to this idea, we used laparoscopy for such purpose in this case. as far as we are aware, there are two reports of using laparoscopy for this purpose up to now.(9,10) however, before using laparoscopy, we should rule out other surgical causes of abdominal pain such as acute peritonitis. by laparoscopy, we can get a direct surgical view and better vision of the intraabdominal pathology, and additionally, if the testis is viable, therapeutic management will be a possibility by performing laparoscopic orchiopexy. prophylactic orchiopexy of testis in the contralateral side is controversial though recommended in some articles. unfortunately, the majority of cases of torsion in intra-abdominal testis are diagnosed when the golden time for saving testis has passed and such patients usually undergo orchiectomy because of nonviable testis. teaching the warning signs of torsion to the patients and their parents, will help with early diagnosis and pave the way to save at risk testicle. conflict of interest none declared. case report references 1. hack ww, sijstermans k, van der voort-doedens lm, meijer rw, heij ha, delemarre-van de waal ha, et al. [undescended testis: current views and advice for treatment]. ned tijdschr geneeskd 2008;152:246-52. 2. schneck fx. bellinger mf. abnormalities of the testis and scrotum and their surgical management. in: patrick c. walsh, alan b. retik, e. darracott vaughan, alan j. wein, editors; campbell’s urology 8th edition. philadelphia: saunders; 2002. p. 2353-2394. figure 1. gangrenous feature of intraabdominal testis figure 2. the gangrenous intraabdominal testis and spermatic chord 1015vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l laparoscopic orchiectomy for intra | abdominal testicular torsion-karami et al 3. jost a. embryonic sexual differentiation (morphology, physiology, abnormalities). in: jones jw jr, scott ww, editors; hermaphroditism genital abnormalities and related endocrine disorders 2nd edition. baltimore: williams and wilkins; 1971. p. 16-64. 4. ein sh. torsion of an undescended intraabdominal benign testicular teratoma. j pediatr surg 1987;22:799-801. 5. johnson jh. the undescended testis. arch dis child. 1965;40:113-122.. 6. ormond jk. torsion of an intra-abdominal testis. ann surg 1927;85:280-3. 7. johnson jh. abnormalities of the scrotum and the testes. in: williams di, editor; paediatric urology 2nd edition. london: butterworth scientific; 1982. p. 451-465. 8. candocia fj, sack-solomon k. an infant with testicular torsion in the inguinal canal. pediatr radiol 2003;33:722-4. 9. lee kf, tang yc, leong ht. emergency laparoscopic orchidectomy for torsion of intra-abdominal testis: a case report. j r coll surg edinb 2001;46:110-2. 10. porpiglia f, destefanis p, fiori c, tarabuzzi r, fontana d. laparoscopic diagnosis and management of acute intraabdominal testicular torsion. j urol 2001;166:600-1. endourology and stone disease 138 urology journal vol 4 no 3 summer 2007 laparoscopic management of ureteral calculi a report of 123 cases nasser simforoosh, abbas basiri, abdolkarim danesh, seyed amir mohsen ziaee, farzaneh sharifiaghdas, ali tabibi, hamidreza abdi, farhat farrokhi introduction: our aim was to evaluate the efficacy and safety of laparoscopic surgery for the management of ureteral calculi. materials and methods: we performed 123 laparoscopic calculus removal in 103 men and 31 women. indications for the procedure were extracorporeal shockwave lithotripsy or transureteral lithotomy failure and large calculus. the mean age of the patients was 39.6 ± 13.8 years. the calculi were between 1 and 5.6 cm and located in the upper, middle, and lower ureter in 90 (73.2%), 20 (16.3%), and 13 (10.5%) patients, respectively. ureteral stent was used in 52 (42.3%) patients. we used 3 ports for camera and instruments. intraperitoneal approach was used in 104 (84.6%) and extraperitoneal in 19 (15.4%). results: the mean operative time was 143.2 ± 60.5 minutes. one hundred and nineteen patients (96.7%) became stone free. minor complications occurred in 14 (11.4%) patients. conversion to open surgery was required in 1 patient due to migration of the calculus to the peritoneum after removal from the ureter. intra-abdominal hematoma led to reoperation 1 day after the surgery in 1 patient. operative time was different significantly between extraperitoneal and intraperitoneal approaches (171.3 ± 91.3 minutes and 137.3 ± 52.2 minutes, respectively; p = .02). conclusion: our results confirm the efficacy and safety of laparoscopic removal of ureteral calculi in selected groups of patients, taking the advantage of this minimally invasive procedure such as better cosmetic results and patient’s satisfaction. urol j. 2007;4:138-40. www.uj.unrc.ir keywords: urinary calculi, ureter, laparoscopy, nephrolithotomy department of urology, shaheed labbafinejad medical university and urology and nephrology research center, shaheed beheshti medical university, tehran, iran corresponding author: nasser simforoosh, md department of urology, shaheed labbafinejad medical center, 9th boustan, pasdaran, tehran 1666679951 iran tel: +98 21 2258 8016 fax: +98 21 2258 8016 e-mail: simforoosh@iurtc.org.ir received april 2007 accepted july 2007 introduction urolithiasis is a very common disease with its management drastically changed over the recent years.(1) open surgery for the treatment of urinary calculi is almost abandoned today, but still may be indicated in some cases with failure of firstline treatment modalities or cases with some specific characteristics of the calculus (size, composition, or location).(2) most upper or middle ureteral calculi are treated with extracorporeal shockwave lithotripsy (swl), percutaneous nephrolithotomy (pcnl), or ureteroscopy.(2-5) recently, laparoscopic approach has gained footage as another minimally invasive alternative in patients with ureteral calculi. to date, limited numbers of studies have reported laparoscopic removal of the ureteral calculi. there are a few articles on large, hard, and impacted ureteral calculi, all of which with acceptable outcomes.(1,2) in the current study, we review our experience in laparoscopic removal of the ureteral calculi. to the best of running title urology journal vol 4 no 3 summer 2007 139 our knowledge, with 123 cases of ureteral calculi, our series is the largest of its kind. materials and methods we performed a total of 123 laparoscopic surgical operations on patients with ureteral calculi from september 1999 to april 2006. the patients had ureteral calculi larger than 1.5 cm or those with failed transureteral lithotripsy (tul) or swl. all of the calculi were radio-opaque and diagnosed by plain abdominal radiography of the kidneys, ureters, and bladder (kub). ultrasonography and intravenous urography (ivu) had also been performed in all of the patients (figure). the demographic and clinical characteristics of the patients are demonstrated in the table. patients with upper and middle ureteral calculi were secured in the flank position and those with lower ureteral calculi were secured in the supine position. routinely, 3 ports were used for introduction of the instruments, and laparoscopic operation was performed intraperitoneally in 104 (84.6%) patients and extraperitoneally in 19 (15.4%), according to the personal preference of the surgeon. also, based on the surgeon’s preference, ureteral stent was placed in 52 patients (42.3%). we reviewed the hospital and follow-up records of the patients and evaluated their surgical data and complications. statistical analysis was done to compare the 2 groups with intraoperitoneal and extraperitoneal approaches using the t test (for normally distributed continuous variables), chi-square test, and fisher exact test, where appropriate. a p value less than .05 was considered significant. results the mean operative time was 143.2 ± 60.5 minutes. oral intake was started 22.39 ± 13.60 hours, postoperatively. the mean hospital stay was 5.86 ± 3.51 days. double-j stent was removed cystoscopically in all patients except for 1, in whom percutaneous removal was done. on the first postoperative day, 119 (96.7%) patients were stone free. surgical complications occurred in 14 (11.4%) patients and conversion to open surgery was required in 1 (0.8%) due to migration of the calculus to the peritoneum after removal from the ureter. re-operation was carried out in 1 patient (0.8%) with intra-abdominal hematoma and hemoglobin decrease, 2 days postoperatively. abdominal wall hematoma was detected in 1 patient (0.8%). there were 3 cases characteristics values number of patients 123 mean age (range), y 39.6 ± 13.8 (3 to 75) sex male 102 (82.9) female 21 (17.1) calculus location upper ureter 90 (73.2) middle ureter 20 (16.3) lower ureter 13 (10.5) side of calculus right 70 (56.9) left 53 (43.1) mean calculus size (range), cm 1.75 ± 0.6 (1 to 5.6) demographic and clinical characteristics of patients with laparoscopic urinary calculus removal* *values in parentheses are percents unless otherwise indicated. intravenous urography in a patient with a right upper ureteral calculus. top, urography before laparoscopic calculus removal. bottom, urography after laparoscopic calculus removal. running title 140 urology journal vol 4 no 3 summer 2007 (2.4%) of urinoma, all responded to double-j stent insertion. acute tubular necrosis and cholecystitis were seen in 1 patient (0.8%) on the second postoperative day, which were resolved conservatively. hemoglobin decrease requiring blood transfusion was reported in 4 patients (3.3%), but intra-operative transfusion was not needed in any of the patients. hydrocele developed in 1 patient (0.8%). of the 4 patients with failed treatment, 1 underwent tul and 3 underwent swl, all of which were successful. one patient experienced gastrointestinal bleeding that was treated conservatively. pyelonephritis was seen 2 weeks after the operation in 1 patient (0.8%) who was re-hospitalized and treated. ileus was seen in 20 patients (16.3%) and 59 (48.0%) had significant leakage that required dressing more than once. five patients with significant leakage were treated by double-j stent insertion. ureteral stricture was reported in 4 patients. one of them underwent retrograde ureteroscopy and then open surgical repair. the other 3 patients were treated successfully by double-j stent placed for about 1 month. the mean operative times for intraperitoneal and extraperitoneal approaches were 137.3 ± 52.2 minutes and 171.3 ± 91.3 minutes, respectively (p = .02). minor urine leakage was seen in 47 (45.2%) of the patients with intraperitoneal and in 12 (63.2%) with extraperitoneal surgical methods (p = .11). also, there was no difference between the 2 surgical methods regarding ileus; 18 (17.3%) versus 2 (10.5%), respectively (p = .48). finally, 4 cases of ureteral stricture were seen in the patients, all with intraperitoneal surgical approach (3.8% versus zero; p = .52). discussion wickham was the first who introduced extraperitoneal ureterolithotomy in 1979,(6) and in early 90’s, raboy and colleagues were the first to perform intraperitoneal laparoscopic ureterolithotomy.(7) the panel on ureteral stones clinical guideline of the american urological association(4) suggested that the treatment of choice, even for calculi greater than 1 cm, should be shockwave lithotripsy, ureteroscopy, or percutaneous removal. the panel also suggested that open surgery might be appropriate in complicated cases and as a salvage therapy. however, laparoscopic ureterolithotomy was not proposed, since ample evidence were not available in the literature until then.(4) reportedly, laparoscopic ureterolithotomy is usually done either intraperitoneally or extraperitoneally. the main disadvantage of extraperitoneal laparoscopy is the small surgical field which needs to be expanded to create a viable working area.(1) nonetheless, goel and hemal reported that retroperitoneoscopy was an acceptable option for removal of large upper and middle ureteral calculi with a reasonable operative time (mean, 108.8 minutes).(8) demirci and colleagues reported 21 cases of laparoscopic removal of the ureteral calculi in 2004.(1) all of their patients had upper or middle ureteral calculi which were operated extraperitoneally. the median operative time was 105 minutes and 5 patients had leakage requiring dj stent insertion. they also observed 2 cases of pneumoscrotum and 1 wound infection. the average hospital stay was 6 days. hemal and associates(9) performed laparoscopic surgery on 31 upper ureteral calculi with extraperitoneal approach. they reported a mean operative time of 67 minutes and a mean hospital stay of 2.4 days. only 2 patients required dj stent placement. vallee and coworkers achieved a mean operative time of 80 minutes and hospitalization of 3.86 days in 18 patients with extraperitoneal approach (n = 15) and intraperitoneal (n = 3).(10) the calculi in their patients were intradiverticular in 1, inferior caliceal in 1, and ureteral in 16. one case of urinoma and 15 dj stent placements were reported. finally, nouira and colleagues performed extraperitoneal lithotomy for 6 upper ureteral calculi within 160 minutes in average. no major complication occurred in their series.(11) we demonstrate a large series of laparoscopic management of the ureteral calculi with a lower rate of conversion to open surgery in comparison with that in other studies.(1) we achieved a mean operative time of 143.2 ± 60.5 minutes that seems relatively long, but we considered the operative period from anesthesia to sending the patient to recovery room. thus, the time spent for set up of laparoscopic instruments was a part of the operative time. furthermore, the operations were performed in an academic center along with a surgical team under training. this time was shorter in intraperitoneal operations, mostly due to our greater experience in running title urology journal vol 4 no 3 summer 2007 141 this approach. overall, 84.6% of our surgeries were intraperitoneal. complication rate was not significant, consistent with other series reported.(1,8-11) conclusion our findings confirm the efficacy and safety of laparoscopic management of ureteral calculi, having the advantages of this minimally invasive procedure such as the better cosmetic results and patient’s satisfaction. we also demonstrated that intraperitoneal laparoscopic surgery was a rapid and easy method with a low learning curve and a low complication rate. conflict of interest none declared. references 1. demirci d, gulmez i, ekmekcioglu o, karacagil m. retroperitoneoscopic ureterolithotomy for the treatment of ureteral calculi. urol int. 2004;73:234-7. 2. marberger m, hofbauer j, turk c, hobarth k, albrecht w. management of ureteric stones. eur urol. 1994;25:265-72. 3. wickham je. treatment of urinary tract stones. bmj. 1993 nov 27;307:1414-7. 4. segura jw, preminger gm, assimos dg, et al. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. the american urological association. j urol. 1997;158:1915-21. 5. erhard m, salwen j, bagley dh. ureteroscopic removal of mid and proximal ureteral calculi. j urol. 1996;155:38-42. 6. wickham jea. the surgical treatment of renal lithiasis. in: wickham jea, editor. urinary calculus disease. new york: churchill livingstone; 1979. p. 145-98. 7. raboy a, ferzli gs, ioffreda r, albert ps. laparoscopic ureterolithotomy. urology. 1992;39:2235. 8. goel a, hemal ak. upper and mid-ureteric stones: a prospective unrandomized comparison of retroperitoneoscopic and open ureterolithotomy. bju int. 2001;88:679-82. 9. hemal ak, goel a, goel r. minimally invasive retroperitoneoscopic ureterolithotomy. j urol. 2003;169:480-2. 10. vallee v, emeriau d, faramarzi-roques d, ballanger p. [laparoscopy in the management of upper urinary tract stones based on a series of 18 cases]. prog urol. 2005;15:226-30. french 11. nouira y, kallel y, binous my, dahmoul h, horchani a. laparoscopic retroperitoneal ureterolithotomy: initial experience and review of literature. j endourol. 2004;18:557-61. endourology and stone disease feasibility of percutaneous nephrolithotomy in positive urine culture: a single center retrospective study ivan gorgotsky1*, dmitry shkarupa1,2, andrey shkarupa1, nadezhda yarova1, denis suchkov1 purpose: to determine the efficacy and safety of pcnl in patients with positive urine culture without an any other risk factors prior to surgery, and to define an optimal pre-operative antibiotic regimen for these patients. materials and methods: the study included 269 consecutive pcnl cases. these cases were divided into 2 groups according pre-operative urine culture results: sterile (group 1, n=166) and positive (group 2, n=103). patients with risk factors linked to infection complications were excluded from study. all patients underwent pcnl in the prone position. in group 1, the antibiotic regimen included parenteral injection 30 minutes prior to operation and for 3 days after surgery. group 2 was given antibiotics 24 hours before pcnl as well as 30 minutes before pcnl and then for 3 days following surgery. on the first day after the operation low dose ct and common blood count were performed on all patients to determine residuals, hematomas, blood loss, and inflammatory markers. results: mean age, stone size, failed eswl, and prior nephrostomy tube insertion were higher in group 2. although rate of pre-stented patients was equal in groups. no significant differences were observed between group 1 and 2 in regard to operative time (74,3 ± 26,9 vs 70,2 ± 26,5 min, p = .52), length of stay (3,9 ± 1,2 vs 3,8 ± 1,6 days, p = .24), sirs (6,0% vs 7,8% patients, p = .07), and leukocyte levels exceeding 10*10*9 (77 (46,4%) vs 49 (47,6%) p =.11). moreover, there was no sepsis or hemotransfusion in either group. stone-free rates were also similar (78,9% vs 77,7%, p = .35). conclusion: 24-hours continuous antibiotic administration before the operation (paying respect to specific resistance bacterial features) can be considered as alternative to 1-week treatment and allow to perform pcnl with sufficient safety in selected patients. infected urine is not an independent risk factor of post-operative infections complications after pcnl in low risk patients with kidney stones. keywords: lithotripsy; nephrolithiasis; nephrostomy; pcnl; sirs; stent; urine culture introduction percutaneous nephrolithotomy (pcnl) is the most efficient treatment for large staghorn calculi(1,2). furthermore, pcnl has spread widely in the past decade in developing countries because of its cost-efficacy compare to flexible ureteroscopy(3). according to recent data, post-pcnl inflammatory complications occur between 10,8 and 43% of patients, with sepsis occurring in 0,3%-9,3% of patients postoperatively(4,5). in an effort to avoid these complications, current aua and eau guidelines do not recommend the surgical management of kidney stones when the patient has a positive urine culture(4,6,7). upper urinary tract drainage (jj-stent or nephrostomy tube) and antibacterial therapy are recommended in such cases with subsequent pcnl(4,6,7). there is little guidance, however, in regard to the proper duration of antibacterial treatment. recent publications have indicated a 7-day preoperative treatment with ciprofloxacin or nitrofurantoin is sufficient, but more data needs to be obtained(8,9). furthermore, obtaining a sterile urine culture is not always possible prior to pcnl. in fact, several circumstances indicate pcnl could be performed in patients 1urology department, clinic of high medical techonologies n.a. n.i. pirogov, saint-petersburg state university, saint-petersburg, russia 2urology department, north-west state medical university n.a. i.i. mechnikov, saint-petersburg, russia. *correspondence: department of urology, saint-petersburg state university clinic, 190103 russian federation, saint-petersburg, fontanka embankment, 154. phone: +79602696343. e-mail: casextra@yandex.ru. received september 2019 2019 & accepted january 2020 with positive urine cultures(2,10). reasons for this approach may be: patients living in rural, outlying areas with an insufficient level of medical care, a previously unsuccessful antibacterial treatment, or an intolerance of jj-stents or nephrostomy tubes. we have not found special guidelines to assist in treating these kinds of patients. thus, in this study we sought to determine the efficacy and safety of pcnl in patients with positive urine culture without a signs of significant urinary tract infection (uti) prior to surgery, and to define an optimal pre-operative antibiotic regimen for these patients. materials and methods study population two hundred and fifty-four patients were enrolled in this study. data from 428 consecutive pcnls performed on these 388 patients was retrospectively reviewed from a prospectively maintained electronic hospital database. the study was approved by the medical ethics committee of saint-petersburg state university. patients underwent pcnl at department of urology of saint-petersburg university clinic between march 2013 and april 2018. 159 cases performed to 134 patients urology journal/vol 17 no. 6/ november-december 2020/ pp. 587-591. [doi: 10.22037/uj.v0i0.5561] with defined risk factors, that can lead to inflammatory complications, such as staghorn stones, hydronephrosis, upper urinary tract abnormalities, kidney insufficiency, a solitary kidney, any kind of immunodeficiency, diabetes mellitus, morbid obesity and after any kind of urinary diversion were excluded from study. the rest of 269 pcnls performed on 254 patients that considered to be low-risk patients were divided into two groups: group 1 (n=166, 61,7%) with sterile urine, and group 2 (n=103, 38,3%) with positive urine culture. all of these patients were non-obstructive and without significant uti or fever. the stones and associated renal anatomy were evaluated with contrast computer tomography images. in subjects with bilateral pcnl procedures, each kidney was considered separately with respect to residual fragments, re-interventions, and complications. standard preoperative investigation (laboratory tests, ecg, etc.) were normal in all patients. specimens for bacteriologic evaluation were derived from midstream urine samples or from a nephrostomy tube. urine culture performed within a month before the operation in each particular patient. informed consent was obtained from all individual participants included in the study. major indications for nephrostomy tube and stent insertions were renal colic and/or uti manifestation caused by obstructive calculi. stone size (larger dimension), density and a detailed history including past renal surgery (especially failed eswl), nephrostomy/stent insertion and duration, and uti were obtained for all patients (table 1). surgical technique all pcnl were performed by three expert surgeons. after induction of general endotracheal anesthesia, an 6f ureteral catheter or stent was placed using a cystoscope in the lithotomy position. the patient was then turned prone. percutaneous access was performed by surgeon using an 18-gauge needle under ultrasound and fluoroscopic guidance. following successful puncture, an ultra stiff hydrophilic guidewire was inserted to the collecting system and the tract was dilated using an amplatz dilator until a 20or 30-fr amplatz sheath could be placed. nephroscopy was conducted under low pressure and stones were disintegrated using ultrasound, pneumatic, or laser lithotripsy. the stone fragments were removed with forceps. in some cases, when residual fragments were suspected, we performed a final inspection of the kidney with a fiber-optic flexible cystoscope. a 12-fr nephrostomy tube was placed at the end of each procedure. antibacterial prophylaxis for patients with sterile urine consisted of a single-dose intravenous broad-spectrum antibiotic (cephalosporinum 3rd generation, or fluoroquinolone) when the patient was anesthetized prior to the procedure, and was continued for 3 days postoperatively. for patients with positive urine cultures, antibiotics based on the sensitivity profile of the bacteria were continuously provided for one day before the surgery, at the time of anesthesia induction, and continued for 3 days postoperatively. all antibiotics were given continuously in a standard dosage considering patient’s age and renal function according to local treatment protocols. outcome assessment our primary outcomes were sirs rate, leucocytes level on common blood count and length of stay. secondary outcomes included stone-free rate, operative time, post-operative haematoma, and average hemoglobin drop level (difference between preand postoperative level on 1 day). a complete blood count and low-dose ct were performed in all the patients on post-operative day one. patients were considered stone free if residual stones were ≤ 4 mm. statistical analysis was performed using an independent sample t-test, and a chi-square test. statistical significance was set at a p-value of <0,05. we performed all statistical analyses using the spss statistical software package (version 15.0 for windows, spss, inc). pcnl in positive urine culture – gorgotsky et al. table 1. basic characteristics of pcnl patients. parameter group 1 (n=166) group 2 (n=103) p-value 1 age, years 49.5 ± 12.7 55.3±14.1 .63 male/female 91/76 42/61 < 0.01 2 right/left 71/96 53/50 .03 3 stone size in lager dimension, mm 17.0 ± 7.1 21.3 ± 13.4 .02 4 stone density, hu 1191.2 ± 385.2 1130.9 ± 443.5 .07 7 previously inserted stent 41 (24.7%) 26 (25.2%) .06 8 previously inserted nephrostomy 6 (3.6%) 26 (25.2%) < 0.01 10 failed eswl 33 (19.9%) 30 (29.1%) < 0.01 parameter group 1 (n=166) group 2 (n=103) p-value 1 operative time, min 74.3 ± 26.9 70.2 ± 26.5 .52 2 access size 20 ch 48 (28.9%) 31 (30.1%) .62 30ch 118 (71.1%) 72 (69.9%) .47 4 sirs on 1-2 postoperative day 10 (6.0%) 9 (8.7%) .07 5 average hemoglobin drop level (difference between preand postoperative 11.2 ± 5.3 12.8 ± 6.7 .17 level on 1 day), g/l. 6 leukocytes level in cbc exceeding 77 (46.4%) 49 (47.6%) .41 10*109 on 1 post-operation day 7 postoperative hematoma (≥100 ml) 4 (2.4%) 2 (1.9%) .09 8 length of stay (days) 3.9 ± 1.2 3.8 ± 1.6 .67 9 stone-free rate (no or less than 4 mm residuals) 131 (78.9%) 80 (77.7%) .35 table 2. intraand postoperative parameters, complications and results of treatment. vol 17 no 06 november-december 2020 588 results mean patient age, stone size, stone density, previously inserted stent, nephrostomy and stent duration time, and failed eswl rates were similar in groups, although left-side disease and male gender was more common in group 1. furthermore, group 2 had a higher prevalence of patients with previously established nephrostomy tracts when compared to group 1 (25,2% vs 3,6%, respectively; p < .01). the enterobacteriaceae and enterococci bacteria accounted for about half of all detected pathogens in group 2. klebsiella and proteus accounted for 10% each. the rest of the results were presented by pseudomonas, staphylococci and streptococci. mixed flora was observed in 5 (5%) patients of the second group. multi-resistant bacteria were noticed in 13 (12,6%) patients. reserve antibiotic such as carbapenems, vancomycin etc. were used for treatment according sensitivity range. no patients with super-resistant bacteria were observed in our study. we found no significant difference in the operative time, the sizes of accesses and the length of hospital stay between the two groups. intraand post-operative bleeding did not require any interventions, and no hemotransfusion was needed in either group. comparative intraand postoperative results shown in table 2. there was also no statistical difference for infection-related complications between the two groups. clinical and laboratory data correlated with these data: systemic inflammatory response syndrome (sirs) rates and leukocyte level on postoperative day one were similar in both groups. of note: patients with fever were included in sirs group as fever is element of this syndrome. there was no sepsis (as a life-threatening complication, required intensive care) following any pcnl in either group, and stone-free rates were similar between groups. postoperative complications according to modified clavien score are shown in table 3. no grade iiib-v complications were noticed. two patients from group 1 and one patient from group 2 required second-look flexible nephroscopy under local anesthesia for 5-8 mm residual stones. no severe complications grade iiib-v were noted in both groups. discussion there is overwhelming clinical experience and expert consensus that a preoperative urine culture should be obtained and confirmed to be sterile prior to pcnl; therefore in patients with positive urine culture, antibiotic treatment prior to pcnl is recommended(7). according to several studies, a positive preoperative urine culture has been associated with increased infectious risk(2,10,11). according to eau and aua guidelines, obtaining a negative urine culture is one of the requirements for pcnl alongside the insertion of any type of drainage tube in the case of obstruction followed by subsequent antimicrobial therapy and a secondary pcnl session at a later date even if there were no clinical signs of active infection(4,6). in non-complicated patients in the absence of obvious infection there is a variety of options as there is no defined standard for preoperative antibiotic regimen(12,13,14). from the other hand, several authors(15,16) suggested that performing surgery even in presence of hydronephrosis and cloudy urine can, in fact, be safe. concerning the staged procedure, sharma et al(17) noticed a higher risk of infection complications in patients with previously inserted nephrostomy tubes: the cause of such complications possibly being a bacterial biofilm on the surface of the tube. we have similar results in our study: there were more patients with nephrostomy in positive urine culture group comparing with sterile urine group – 35 (20,1%) vs 16 (6,3%) respectively. however, in our study previously placed ureteral stents were not found to increase the bacterial stone burden, concluding this option seems to be safer if staged treatment is needed. many studies dedicated to duration of antimicrobial prophylaxis in patients with sterile urine(18,19,20), but there are no guidelines how to reach this condition preoperatively. two studies evaluated the role of 1-week preoperatively-administered antibiotics for the prevention of sepsis/sirs. it was reported that 1 week of ciprofloxacin prophylaxis before pcnl significantly reduced the risk for urosepsis(8). the second study investigated the impact of prophylaxis with nitrofurantoin for a week before pcnl and found a significantly lower rate of endotoxemia (17.5 vs 41.9%) and sirs (19 vs 49%) in the nitrofurantoin group(9). these studies indicate that a 7-day pre-pcnl course of antibiotics may play an important role in the prevention of infective complications in patients at a higher risk for the development of urosepsis and included patients with very large renal calculi and/or hydronephrosis with a higher risk for urosepsis. keeping in mind growing bacterial resistance and toxic effect of ciprofloxacin and overuse of other antibiotics, more opportune approaches are needed(21). our study promotes alternative tactic to long-term antibiotic course. some studies indicated that the majority of the stones, including non-infected stones such as oxalate stones, contain bacteria and bacterial toxins that are mediators of sirs and sepsis(22,23). despite careful pre-operative preparation, serious systemic infection can be difficult to predict. the source of the infection is almost always the stone itself, but this is impossible to predict pre-operatively with certainty, although in many cases there will be a high index of suspicion(24). the main reasons for the development of uti after pcnl include the release of bacteria from the surgical manipulation, fragmentation of calculi, and the introduction of bacteria through the nephrostomy tract, which traverses through table 3. postoperative complications in groups according to modified clavien score. group 1 (n=166) group 2 (n=103) p value none 142 (85.5%) 83 (80.6%) .83 grade i 14 (8.4%) 12 (11.7%) .09 grade ii 9 (5.4%) 7 (6.7%) .86 grade iiia 2 (0.7%) 1 (1.0%) .96 pcnl in positive urine culture – gorgotsky et al. endourology and stones diseases 589 skin, retroperitoneum, and renal tissues(24). after stone disruption during eswl, the square of the stone is increased, possibly leading to the escape of bacteria and endotoxins from the inside of the stone. probably this could cause a previously negative urine culture to become positive(25). indeed, we noticed such a trend in our study: there was a higher prevalence of post-eswl patients in group 2 compared to group 1 – 51 (29,3%) vs 40 (15,7%) respectively. in majority of the patients of both group ultrasonic lithotripsy used for stone fragmentation, as we believe that suction effect of the probe during the procedure can eliminate some portion of planktonic bacteria. although radfar et al(26) reported no significal difference of success rates and complications between ultrasonic or pneumatic lithotripsy. some authors consider the contrast and density of the stone as an additional predictor of sfr and possible complications after pcnl(27). of course, this method of evaluation can also be used to assess the likely infectious nature of the stone, which may lead to changes in the therapy both in patients with sterile or infected urine culture. several studies investigated the significance of leukocytosis, sirs and readmission rate following pcnl and any association with postoperative infection(28,29). nearly half of the patients in both studies had a leukocytosis and met the criteria for sirs. in contrast to our study, there was no association between leukocytosis and urine culture. of note, negative bladder urine culture does not exclude the presence of bacteria in stones or in urine within the renal pelvis: it was found that in patients with negative bladder cultures, about one-third had infected pelvic urine and half had positive stone cultures(30). obviously proper source of infection cannot be directly established at preoperative examination both in patients with sterile and infected urine. conclusions 24-hours continuous antibiotic administration before the operation (paying respect to specific resistance bacterial features) can be considered as alternative to 1-week treatment and allow to perform pcnl with sufficient safety in selected patients (without risk factors, that can lead to inflammatory complications, such as staghorn stones, hydronephrosis, upper urinary tract abnormalities, kidney insufficiency, a solitary kidney, any kind of immunodeficiency, diabetes mellitus, morbid obesity and after any kind of urinary diversion). infected urine is not an independent risk factor of post-operative infections complications after pcnl in low risk patients with kidney stones. conflict of interest the authors report no conflict of interest. references 1. jayram g, matlaga br. contemporary practice patterns associated with percutaneous nephrolithotomy among certifying urologists. j endourol. 2014;28:1304-1307. 2. gutierrez j, smith a, geavlete p, et al. urinary tract infections and post-operative fever in percutaneous nephrolithotomy. world j urol. 2013;31:1135–1140. 3. patel sr, nakada sy. the modern history and evolution of percutaneous nephrolithotomy. j endourol. 2015;29:153-157. 4. c. türk, a. neisius, a. petrik, et al. eau guidelines on urolithiasis 2019. available from: http://uroweb.org/guideline/urolithiasis/ 5. moses r, agarwal d, raffin e, et al. post pcnl sirs is not associated with unplanned readmission. urology. 2017;100: 33-37. 6. assimos d, krambeck a, miller nl et al. surgical management of stones: american urological association/endourological society guideline. j. urol. 2016;196:11531160. 7. daniel a. wollin, adrian d. joyce, mantu gupta, et al. antibiotic use and the prevention and management of infectious complications in stone disease. world j urol. 2017;35:13691379. 8. mariappan p, smith g, moussa sa, et al. one week of ciprofloxacin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study. bju int. 2006;98:1075– 1079. 9. bag s, kumar s, taneja n, et al. one week of nitrofurantoin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study. urology. 2011;77:45–49. 10. skolarikos a, de la rosette j. prevention and treatment of complications following percutaneous nephrolithotomy. curr opin urol. 2008;18:229–234. 11. gonen m, turan h, ozturk b, et al. factors affecting fever following percutaneous nephrolithotomy: a prospective clinical study. j endourol. 2008;22:2135–2138 12. lai ws, assimos d. the role of antibiotic prophylaxis in percutaneous nephrolithotomy. rev. urol. 2016;18:10–4. 13. joseph km li, jeremy yc teoh, chi-fai ng. updates in endourological management of urolithiasis. int j urol. 2018;25:1-12. 14. ibrahim a, wollin d, preminger g, et al. technique of percutaneous nephrolithotomy. j endourol. 2018;32, suppl 1. 15. etemadian m, haghighi r, madianeay a, et al. delayed versus same-day percutaneous nephrolithotomy in patients with aspirated cloudy urine. urol j. 2008;5:28-33. 16. hosseini mm, basiri a, moghaddam h. percutaneous nephrolithotomy of patients with staghorn stone and incidental purulent fluid suggestive of infection. j endourol. 2007; 21:1429-1432. 17. sharma k, narayan s, goel a, et al. factors predicting infectious complications following percutaneous nephrolithotomy urology annals. 2016;8:434-438. 18. dogan hs, sahin a, cetinkaya y, et al. antibiotic prophylaxis in percutaneous nephrolithotomy: prospective study in 81 patients. j endourol. 2002;16:649–653. 19. gravas s, montanari e, geavlete p, et al. postoperative infection rates in low pcnl in positive urine culture – gorgotsky et al. vol 17 no 06 november-december 2020 590 risk patients undergoing percutaneous nephrolithotomy with and without antibiotic prophylaxis: a matched case control study. j urol. 2012;188:843–847. 20. demirtas a, yildirim ye, sofikerim m, et al. comparison of infection and urosepsis rates of ciprofloxacin and ceftriaxone prophylaxis before percutaneous nephrolithotomy: a prospective and randomized study. sci world j. 2012;9:1-6. 21. bonkat g, wagenlehner f. in the line of fire: should urologists stop prescribing fluoroquinolones as default? eur urol. 2018; available at: https://doi.org/10.1016/j. eururo.2018.10.057 22. fowler je jr. bacteriology of branched renal calculi and accompanying urinary tract infection. j urol. 1984;131:213–215. 23. mcaleer i, kaplan gw, bradley js. endotoxin content in the renal calculi. j urol. 2003;169:1813–1814. 24. mariappan p, tolley d. endoscopic stone surgery: minimizing the risk of post-operative sepsis. curr op urol. 2005;15:101–105. 25. li l, shen z, wang h, fu s, cheng g. investigation of infection risk and the value of urine endotoxin during eswl. chin med j (engl). 2001;114:510-513. 26. radfar mh, basiri a, nouralizadeh a, et al. comparing the efficacy and safety of ultrasonic versus pneumatic lithotripsy in percutaneous nephrolithotomy: a randomized clinical trial. eur urol focus; 2017;3:82-88. 27. maghsoudi r, etemadian m, kashi ah, et al. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016;13:2899-2902. 28. moses ra, agarwal d, raffin ep, et al. postpercutaneous nephrolithotomy systemic inflammatory response syndrome is not associated with unplanned readmission. urology. 2017;100:33–37. 29. bozkurt ih, aydogdu o, yonguc t, et al. predictive value of leukocytosis for infectious complications after percutaneous nephrolithotomy. urology. 2015;86:25-29. 30. korets r, graversen ja, kates m, et al. post-percutaneous nephrolithotomy systemic inflammatory response: a prospective analysis of preoperative urine, renal pelvic urine and stone cultures. j urol. 2011;186:1899–1903. pcnl in positive urine culture – gorgotsky et al. endourology and stones diseases 591 urol_v03_no4_001_editorial.indd review article 193urology journal vol 3 no 4 autumn 2006 genetics of azoospermia: current knowledge, clinical implications, and future directions part i hossein sadeghi-nejad,1 farhat farrokhi2 introduction: we reviewed the most recent advances in the genetics of male infertility focusing on karyotypic abnormalities, obstructive azoospermia, and idiopathic hypogonadotropic hypogonadism. materials and methods: to update our previous review, we searched the literature using pubmed and skimmed articles published from january 1998 to november 2006. there were 52, 30, and 41 relevant articles to our subject on karyotypic abnormalities, obstructive azoospermia, and idiopathic hypogonadotropic hypogonadism. the full texts of these articles and their bibliographic information were reviewed and a total of 93 were used to contribute this review. results: the frequency of sperm aneulpoidy in karyotypic abnormalities such as 47,xxy and 47,xyy is higher than that in the healthy individuals, but transmission of the abnormalities to the offspring is rare and the outcomes of assisted reproductive techniques are encouraging. mutations in the cystic fibrosis gene are detectable in up to 80% of men with congenital bilateral absence of the vas deferens. however, there is a considerable diversity among different populations and the role of other potential causes is not ruled out yet. autosomal and x-linked genetic aberrations in men with idiopathic hypogonadotropic hypogonadism are now well known. as hormone replacement therapy can provide the chance of fathering in these patients, the risk of mutations’ transmission, especially the autosomal dominant ones, is high. conclusion: in the recent decade, a parallel progress has been made in the genetics of men with azoospermia and the treatment modalities for these patients. assisted reproductive techniques can help most of the patients, but there are several genetic abnormalities that must be considered before decision making for treatment of their infertility. urol j (tehran). 2006;4:193-203. www.uj.unrc.ir keywords: male infertility, azoospermia, genetic diseases, kallmann syndrome, chromosome aberrations, klinefelter syndrome 1department of urology, hackensack university medical center and umdnj new jersey medical school, hackensack, nj and section of urology, va new jersey health care system, east orange, new jersey, usa 2urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: farhat farrokhi, md no 44, 9th boustan, pasdaran, tehran, iran tel & fax: +98 21 2259 4204 e-mail: farrokhi@unrc.ir introduction genetic aberrations account for a significant proportion of malefactor infertility. these abnormalities cover a wide spectrum including chromosome number and structure, the y chromosome and azoospermia factor, the hypothalamic-pituitary gonadal axis, the morphogenesis of the internal ductal system, sperm function, and other nonspecific disorders with variable effects on the reproductive axis.(1) with the advent of intracytoplasmic sperm injection (icsi) for the treatment of severe male factor infertility, an understanding of the genetic etiology of a patient-specific disorder is critical for proper counseling and decision-making. in the recent genetics of azoospermia—sadeghi-nejad and farrokhi 194 urology journal vol 3 no 4 autumn 2006 decade, a significant number of reports have been published on icsi in men with specified genetic aberrations with encouraging outcomes. to provide the newest knowledge, we reviewed the literature published in the recent 9 years and updated our previous paper published in 1997.(2) this 2-part article will review the most recent advances pertaining to some of the main genetic etiologies of syndromes resulting in azoospermia. the first part (in this issue) encompasses karyotypic abnormalities, obstructive azoospermia, and idiopathic hypogonadotropic hypogonadism. the next part will cover the other topics including y chromosome microdeletion. karyotypic abnormalities karyotypic analysis of the azoospermic or severely oligozoospermic men may reveal genetic abnormalities that warrant concern. up to 14% of patients in this population may have abnormalities of chromosome number or structure.(3-5) in a cytogenetic study of 694 infertile men, van assche and colleagues found that infertile men were eight times more likely than fertile men to harbor some kinds of chromosome abnormalities.(3) karyotypic abnormalities are either structural or numerical found in sex or autosomal chromosomes. less than 10% of the major chromosome anomalies in this group involve the autosomes.(6) the most common chromosome abnormalities in infertile male subjects are klinefelter syndrome (numerical sex chromosome disorder) and y chromosome microdeletions (structural, not detected by karyotype analyses). klinefelter syndrome the most common cytological anomaly in azoospermic men is 47,xxy (klinefelter syndrome), representing 82.5% of the total number of sex chromosome abnormalities.(7) klinefelter syndrome is found in approximately 1 in 500 to 1 in 1000 live births in boys.(6,8) it is found in 3% of infertile men,(8) 3.5% to 14% of azoospermic men,(6,9) and in 1% of couples referring for icsi.(9) both maternal and paternal origins are described for klinefelter syndrome. the incidence of 47,xxy increases with maternal age and is due to nondisjunction in either the meiotic division of the oocytes/spermatocytes or cleavage division of an early embryo. paternal age may increase the percent of xy aueuploid sperm and subsequently the risk of fathering boys with klinefelter syndrome.(10) arnedo and colleagues showed that sperm aneuploidy was more frequent in the fathers’ sperm of klinefelter patients with paternal origin.(11) in this group, the age of the fathers correlated with xy sperm frequency. the prototypical klinefelter male presents with spermatogenic and androgenic failure. however, there is great variability and many affected individuals have normal virilization and are diagnosed by karyotype analysis for infertility.(12) eighty-five percent of klinefelter men have a pure 47,xxy karyotype while 15% are mosaics (46,xy/47,xxy).(8) almost all 47,xxy men are azoospermic while mosaic patients may have the capacity for a minimal amount of spermatogenesis. successful sperm retrieval procedures are reported in 16% to 49% of nonmosaic klinefelter men,(13-16) and this rate is higher in mosaic patients.(17) contradictory results have been reported on predictor factors of successful testicular sperm extraction (tese) in klinefelter patients.(14) larger testicular volume, higher serum levels of testosterone, and younger age are suggested as the predictors of successful sperm recovery,(18,19) but most authors have found no predictive parameters.(16,17,20) yamamoto and colleagues suggested that men who exhibit both 46,xy and 47,xxy spermatogonia in their sminiferous tubule have a greater probability of testicular foci of spermatozoa than men who exhibit only 47,xxy spermatogonia type in their seminiferous tubules. they also suggested that men with a higher degree of sertoli cell secretory dysfunction have a poor prognosis for having testicular foci of spermatozoa.(13) high fertilization rates have been reported with icsi in mosaic klinefelter cases,(21-23) and to date, 46 healthy children have been the result of icsi from nonmosaic klinfelter men.(14,24,25) however, several cases of abortion and 1 offspring with klinefelter syndrome were reported.(14,23,24) thus, concerns remain about the risk of producing offspring with chromosome aneuploidies. since only about half of the embryos with 47,xxy karyotype have the chance of survival to birth,(26) abortions in couples with klinefelter syndrome can be due to the transmission of the disease. furthermore, it is shown that the frequency of other genetic defects in klinefelter genetics of azoospermia—sadeghi-nejad and farrokhi urology journal vol 3 no 4 autumn 2006 195 syndrome, such as y chromosome microdeletions, is high.(27) thus, other genetic infertility factors should not be neglected.(27) autosomal and gonosomal aneuploidies in the spermatozoa of 47,xxy men are more frequent than in healthy men,(9,28) and mosaic patients have a comparable frequency of sex chromosome abnormalities with mosaics in their extracted sperm cells.(14) nonetheless, the percentage of 47,xxy karyotype in the peripheral lymphocytes of these men do not predict the percentage of hyperhaploidy in sperm cells.(14,22) hyperploid sperm cells are seen in 0.9% to 7.5% of the patients.(14) this suggests two possibilities. the first is that the supernumerary x chromosome is lost during spermatogenesis and does not enter meiosis such that all spermatozoa are either 23,x or 23,y. the second possibility is of low level gonadal mosaicism where a markedly reduced population of 46,xy spermatogonia are actually the direct precursors of the few whole spermatozoa present in those selected patients. however, the proportion of xy and xx spermatozoa in 47,xxy patients are not consistent with the expected proportions that can be derived from a segregation of abnormal cells during meiosis.(29) in a prospective analysis of meiosis, blanco and associates found that the abnormal cells are unable to enter meiosis in 47,xxy males.(29) they speculated that the higher proportion of aneuploid spermatozoa than that found in healthy males is a result of nondisjunctional events induced by an abnormal testicular environment (eg, elevated follicle-stimulating hormone). however, as concluded in previous studies, the presence of 47,xxy germ cells and their completion of spermatogenesis process cannot be rejected.(29) overall, assisted reproductive techniques (arts) are recommended for klinefelter patients, but professional genetic counseling including the options of prenatal diagnosis and preimplantation genetic diagnosis must be offered.(14) early detection of klinefelter patients and cryopreservation of their sperm may be of help, since a depletion in spermatogenesis occurs with age.(15,30) however, wikstrom and colleagues demonstrated that in adolescent boys with klinefelter syndrome, the older ones did not have testicular germ cells while their hormonal profile was still normal and testicular volume was increasing. thus, early puberty may not be the unique opportunity to preserve the sperm these patients for their future fathering potential.(31) finally, okada and colleague showed that serum testosterone concentrations decline after conventional or microdissection tese, requiring potential androgen replacement therapy.(32) however, in another report of microsurgical testis sperm extraction with cryopreservation, damani and colleagues found no alteration of testosterone levels.(33) a large scale study of the impact of tese on testicular function in azoospermic men documented relative reversibility of changes in long term follow-up. specifically, although there was an initial drop in serum testosterone levels to 80% of pre-tese levels at 3 to 6 months after surgery, the levels rose to 95% after 18 months.(34) regarding the declining trend of testosterone levels in men with klinefelter syndrome, it seems that even a slight alteration caused by tese can influence the treatment of these patients and should not be neglected. other numerical abnormalities of numerical autosomal anomalies, only trisomy 21 may allow survival into puberty, but all of the patients are azoospermic.(26) numerical sex chromosome abnormalities other than 47,xxy may be found including 47,xyy and 45,x/46,xy. the 45,x/ 46,xy mosaism is a rare entity and most infertile males of this type are low-level mosaics (less than 10% abnormal cells).(9) recently, successful icsi and delivery of a healthy female was reported from an infertile man with 46,xx/46,xy karyotype.(35) a 47,xyy sex chromosome constitution is the second most common chromosome anomaly causing infertility, after klinefelter syndrome.(36) men with an extra y chromosome are mostly fertile, but azoospermia may be seen in some cases. sperm aneuploidy has been reported in 0.11% to 10% of the spermatozoa of 47,xyy males.(37) autosomal chromosome abnormalities are also seen in the spermatozoa of these patients (such as disomic 18 spermatozoa).(37) the 24,xy spermatozoa are specially increased(37); thus, 47,xxy progeny production can be more frequent, with a 50% probability of survival to birth, explaining the contribution of 47,xyy men to recurrent abortion.(26) genetics of azoospermia—sadeghi-nejad and farrokhi 196 urology journal vol 3 no 4 autumn 2006 there is increasing evidence that, although an elimination mechanism reduces the number of 47,xyy germ cells in humans, a variable number of them can become viable spermatozoa.(29) rives and colleagues showed the presence of the extra y chromosome in more then 50% of primary spermatocytes in a nonmosaic 47,xyy infertile patient and concluded that a high rate of germ cell degeneration must be responsible for spermatogenesis impairment and the low rate of aneuploid spermatozoa.(36) structural abnormalities the y chromosome-specific structural irregularities that may be detected upon cytological analysis include pericentric inversion of the y, dicentric y, ring y, and truncated y.(3) the x-autosome and y-autosome translocations in men are usually associated with azoospermia, but successful icsi and birth of healthy offspring have been reported.(9) the xx male syndrome is another rare type of structural chromosome abnormality seen in 0.9% of azoospermic men.(9) two mechanisms are proposed: translocation of a fragment containing the sex determining region (sry) on y chromosome to the x chromosome, and a mutation in an x region necessary for inhibition of an autosomal testis determining gene.(6) autosomal chromosome abnormalities are usually structural (rather than numeric) in infertile males.(7) these include reciprocal and robertsonian translocations, inversions, insertions, and ring chromosomes. in the oligozoospermic population, autosomal anomalies, especially robertsonian and reciprocal translocations, are more frequent than sex chromosome abnormalities.(3,9) robertsonian translocations are found in about 0.1% of newborns.(26) they are mostly fusions between chromosomes 13 and 14.(38) a robertsonian translocation between two of the same chromosome, for example a t(13q;13q) homozygote, would produce only disomy 13 or nullisomy 13 spermatozoa. in such cases, icsi would not be an option.(38) variable rates of unbalanced spermatozoa is seen in structural reorganization carriers.(26) reciprocal translocations, for example, are associated with repeated pregnancy losses and varying degrees of unbalanced sperm.(39) finally, autosomal inversions are 8-fold more frequent in infertile men than in normal population. particularly, inversions in chromosome 9 are associated with azoospermia and severe oligospermia.(6) obstructive azoospermia congenital bilateral absence of vas deferens congenital bilateral absence of the vas deferens (cbavd) is found in 6% of obstructive azoospermia cases and in 1% to 2% of all infertile men.(40) mutations in the cystic fibrosis transmembrane conductance regulator gene (cftr) are responsible for cbavd and cystic fibrosis (cf). the cftr is a protein (chloride selective ion channel regulated by camp) encoded by the cftr gene.(41,42) located on chromosome 7 (7q31.2), the cftr gene is 250 kb in length and contains 230 000 base pairs and 27 exons. more than 1000 different mutations and 200 polymorphisms have been identified in this large gene.(43) of these, approximately 50% to 80% are ∆f508, a three-base pair deletion in exon 10.(40) although there is no absolute genotypephenotype correlation, some general principles do apply. when the patient possesses two severe aberrations in cftr, eg, homozygous for ∆f508, clinical cystic fibrosis is recognized which is the most common autosomal recessive disease among the caucasian population. over 95% of all cf males are infertile due to obstructive azoospermia. if two mild mutations are inherited, congenital absence of the vas deferens (cavd), epididymal obstruction, or bilateral ejaculatory duct obstruction, namely the genital forms of cf, may be the only clinical manifestation.(40,43) the ultimate phenotypic expression depends upon the level of functionally normal cftr present. in cases of ∆f508 homozygosity, there is little, if any, cftr that is functionally adequate and the diseased respiratory, pancreatic, and reproductive ductal systems all reflect this. in other cases of severe/mild, mild/mild, sever/-, or mild/mutations, a relatively mild set of cftr anomalies, pulmonary and pancreatic function may be entirely normal while vasal aplasia persists as the only recognizable consequence. it appears that anatomical vasal deficiency is the most subtle expression of cftr protein dysfunction. approximately 60% to 80% of men afflicted with genetics of azoospermia—sadeghi-nejad and farrokhi urology journal vol 3 no 4 autumn 2006 197 cbavd will have at least one easily detectable, standard, cftr mutation.(44-46) among the iranian cbavd men, 80% harbor a mutation or variant.(47) the ∆f508 (32% to 82%) and r117h (~30%) are the 2 most common gene mutations in cbavd patients.(43,48-50) up to 30% of the mutations will be compound heterozygotes.(51) of the simple heterozygotes, in whom only one cf mutation exists, up to 40% may harbor the 5t variant on the opposite allele. in intron 8, there is a poly-t tract that is variably comprised of 5, 7, or 9 thymidine bases. splicing efficiency is optimal with a 9t sequence, but markedly reduced in the 5t variant. exon 9 bears the brunt of this inefficiency, its mrna sequence being lost from the final message in a significant percentage when a 5t series is present.(52,53) therefore, while some qualitatively normal cftr protein still results from a 5t allele, the ultimate amount is quite low. the combination of mutation/5t allele variant leads to a quantitative deficiency in functional cftr, a level too low for proper male reproductive ductal morphogenesis. overall, the 5t variant is seen in 12% to 27% of cftr alleles from cbavd patients.(43) in a study on 106 iranian patients by radpour and colleague, the combination of the 5t allele in one copy of the cftr gene with a cf mutation in the other copy was the most common cause of cbavd.(47) recently a 3t allele in the cftr gene was found associated with cbavd.(54) in a considerable proportion of cbavd patients (20% to 40%), cftr mutations are not found.(40,47) some authors suggested that the etiology of the cbavd in this group is secondary to causes other than an abnormal cf gene.(46,55) on the other hand, the standard screening tests for cftr mutations may not recognize all abnormalities,(56) because of the wide-ranging allelic heterogeneity.(47) variable mutations reported from different countries emphasizes the necessity of designing populationspecific panels.(47,57,58) however, the most extensive mutation analyses can detect aberration in nearly 82% of cbavds, reserving the other potential etiologies for further investigation.(51) wang and colleagues used a panel of 100 cftr mutations analysis and could increase the percentage of mutation-positive cbavd patients only up to 67%.(51) the presence of subclinical cf symptoms such as elevated sweat chloride concentrations, polyps, rhinosinositis, bronchitis, and sinusitis in cbavd men supports the concept of incomplete forms of cf.(59,60) defining lower values for the upper limit of normal sweat chloride concentrations, the diagnosis of some cbavd cases can be changed into cf.(59) josserand and colleagues reported sweat chloride values and cftr aberrations in 50 patients with cbavd. a mutated allele was more frequent in the group of elevated sweat chloride concentrations (> 60 mmol/l, 47%; 40 to 59 mmol/l, 41%; and < 40 mmol/l, 35%). there were 10 patients with no mutation/5t variant in whom the sweat chloride concentration was less than 60 mmol/ l. the 5t variant was not associated with sweat concentration.(59) dumur and colleagues found a high frequency of cftr mutations in the group with high sweat chloride values.(61) a second group of patients with equivocal sweat chloride values had a high frequency of the 5t variant with or without the ∆f508 mutation. no abnormalities of the cf gene could be detected in a third group of patients who had low chloride values and other congenital abnormalities of the urogenital tract. with specific attention to the pulmonary function, colin and colleagues evaluated the clinical status of 18 patients with cbavd.(62) they found cftr mutations in 58% of the cbavd patients with 26% being ∆f508 mutations. all patients had normal pulmonary function tests (except one with asthma) and normal general anthropomorphic and physical examinations. the authors concluded that patients with cbavd without any other clinical features of cf should not be considered to have a mild form of cf, because the two diagnoses, although constituting different ends of a spectrum, have completely separate clinical and prognostic characteristics. concerning the reproductive characteristics, there is no genotype-phenotype consonance. mennicke and coworkers found that abnormally low semen ph, normal fsh, normal testicular volume, and azoospermia are predictive of cftr mutations.(43) but, the sensitivity for the combination of these factors was low. most patients with cbavd have completely normal spermatogenesis and a small subgroup have impaired spermatogenesis.(49) the underlying cause can be the cftr gene mutations, other genetic/nongenetic conditions, and the impact of chronic obstruction.(63) genetics of azoospermia—sadeghi-nejad and farrokhi 198 urology journal vol 3 no 4 autumn 2006 van der ven and coworkers tested the interesting hypothesis that the cftr gene might be responsible for reduced sperm quality in otherwise healthy men with no evidence of cbavd.(64) they found at least 1 mutation in 14.3% of healthy azoospermic men and a significantly higher frequency of mutations in their sample of infertile males (17.5%) than that expected in a random sample of the population (p = .001), suggesting that the cftr protein may have a role in the normal processes of spermatogenesis. furthermore, the frequency of 5t allelic variant was reported to be similar in obstructive azoospermic men and the general population, but higher in nonobstructive azoospermic patients.(40) nonetheless, meng and colleagues found no higher frequency of 5t allele in those with impaired spermatogenesis. they found other abnormalities (y deletions and varicocele) in this group of patients. thus, they concluded that impaired spermatogenesis in cbavd may be mostly related to other causes than cftr mutations.(63) a proportion of patients with cavd may suffer from concomitant urogenital abnormalities, mainly unilateral renal aplaisa. in addition, cryptorchidism, dysplastic seminal vesicles, and inguinal hernia are reported.(60,65) however, the association of cftr muatations with these urinary tract abnormalities is controversial. the rate of urinary tract abnormalities in cbavd is about 10%, mostly seen in the group without cftr gene aberrations.(46,66) the physical separation of renal/ureteral system and the ipsilateral vas deferens, seminal vesicle, and distal epididymis occurs at the week 7 of gestation. the cftr protein impacts the latter part in cbavd males with normal renal system. thus, it seems to act after this separation and cannot be the mere etiology of cbavd with renal agenesis. mccallum and coworkers evaluated 17 cbavd men with urinary tract abnormalities and 97 isolated cbavd men. no differences in physical examination, laboratory assay, and ultrasonographic assessment were detected. but, cftr mutations were found in 19% and 100% of the 2 groups, respectively. this emphasizes the possible role of a mesonephric duct gene anomaly rather than the cftr mutations.(66) in line with the above hypothesis, males with a unilateral form of cavd have a lower frequency of cftr mutations and higher frequency renal agenesis.(60) however, casals and colleagues found cftr mutations in one-third of cavd patients with renal agenesis using an extensive genetic analysis.(60) a multifunctional or polygenic point of view may explain the coexistence of cavd and renal anomalies.(60) thanks to advances in art, men with cavd can enjoy parenting their own children. josserand and colleagues reported 8 successful pregnancies by icsi and birth of 10 healthy children among 28 cbavd who attempted icsi.(59) mccallum and coworkers reported 10 fetuses conceived by icsi, but one had bilateral renal agenesis, emerging prenatal ultrasonography.(66) because of a high frequency of cftr gene carriers in the general population and the high frequency of ∆f508, a severe mutation, both in cbavd men and general population, the probability of the birth of an offspring with cf is high. thus, careful counseling before ivf or icsi is recommended.(48) stuppia and associates studied cftr mutations in 1195 couples counseling for ivf in italy. a total of 11% had mutations or 5t allele. among 16 cbavd males, 62.5% had only a 5t allele and 37.5% were heterozygote (5t variant/mutation).(50) since the prevalence of cftr mutations was not higher than those in the general population, they concluded that it is sufficient to analyze only one partner (preferably the infertile) and perform screening in the second one only when a mutation or 5t allele is found in the first one.(50) however, the wide spectrum of mutations may lead to a false-negative result in the routine screening tests done for one partner. thus, testing both partners to increase the possibility of case finding can be rational. hypogonadotropic hypogonadism and kallmann syndrome idiopathic hypogonadotropic hypogonadism (ihh) and anosmia are the most prominent clinical features of kallmann syndrome. this syndrome has an incidence of 1:10 000 to 1:60 000.(67) some of the genetic defects described for kallmann syndrome are also associated with normosmic ihh. consequently, the current idea that kallmann syndrome and ihh are two distinct entities is disputed.(68,69) there are families with individuals having cases of typical kallmann syndrome, normosmic ihh, and isolated anosmia, corresponding to a heterogeneity with different phenotypes.(70) genetics of azoospermia—sadeghi-nejad and farrokhi urology journal vol 3 no 4 autumn 2006 199 about 30% to 60% of men with ihh have anosmia.(67,71) delayed puberty is a usual presentation.(72) other clinical features include renal agenesis (seen in x-linked kallmann syndrome), pes cavus, cerebellar ataxia, microphallus, cryptorchidism, high-arched palate, color blindness, hearing loss, midline craniofacial abnormalities, and bimanual synkinesia (mostly x-linked).(71-75) magnetic resonance imaging (mri), as well as karyotype analysis, measurement of sexual hormones, and gonadotropin releasing hormone (gnrh) stimulation test is useful for diagnosis. on mri, absence of olfactory bulbs and hypoplasia or absence of olfactory sulci are usually observed, but hypoplasia of the anterior pituitary may not be present in all cases.(76) thus, mri may not be able to differentiate kallmann syndrome from the normosmic form of gnrh deficiency.(77) most patients with kallmann syndrome present as sporadic cases.(73) the disease may also be inherited in an autosomal dominant (64%), autosomal recessive (25%), or x-linked fashion (11%).(78) autosomal genes account for the majority of familial and sporadic kallmann syndrome cases.(67) x-linked kallmann syndrome kal1 is the gene responsible for the x-linked form of kallmann syndrome and has been localized to xp22.3.(79) mutations or deletions in kal1 are seen in 10% to 14% of all kallmann syndrome cases,(73,80) mostly seen in familial ones.(67,73) the gnrh-synthesizing neurons normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway.(81) cariboni and colleagues demonstrated the direct action of anosmin-1 on the migratory activity of gnrh-synthesizing neurons. anosmin-1 (namely, kal protein) is encoded by kal1.(82) there is a lack of genotype-phenotype correlation in kal1-positive patients.(67) there are patients who have normal gonadal function.(83,84) for instance, kal1 mutations were reported in 3 brothers, 2 with kallmann syndrome and 1 with isolated partial anosmia.(85) on the other hand, sato and coworkers found 2 cases of normosmia and asymptomatic borderline olfactory function. however, hypoplastic olfactory bulbs on mri were observed.(68) different phenotypes have been found even in monozygotic twins with kallmann syndrome and a same mutation of the kal1 gene.(86) these indicate a spectrum of clinical manifestations in mutation-positive patients and emphasize the role of putative modifier genes and/or epigenetic factors in the expressivity of the x-linked kallmann syndrome.(87) to explain the discrepancy between the degrees of anosmia and hypogonadism, de roux found another mutation in gln66x, responsible for complete inactivation of the kal1 gene.(85) autosomal dominant kallmann syndrome the autosomal dominant (ad) form of kallmann syndrome is more frequent than x-linked and most familial cases are inherited in an autosomal fashion.(67) dode and colleagues described for the first time loss-of-function mutations in fibroblast growth factor receptor 1 gene (fgfr1) on 8p12 which were responsible for the ad form of kallmann syndrome.(75) this gene is required for initial olfactory bulb evagination and its mutation accounts for 8% to 10% of all kallmann syndrome cases.(67,80,88) it is shown that fgfr1 mutations can cause both kallmann syndrome and normosmic ihh.(69,74) of the associated anomalies, cleft palate and dental agenesis are only seen in fgfr1 mutated cases.(73,81,85) pitteloud and colleagues reported a case of kallmann syndrome with mutation in fgfr1 who had spontaneous recovery after discontinuation of testosterone therapy. they suggested that despite the disruption of the olfactory bulbs, gnrh neuronal migratory defects in fgfr1 mutations are not always complete and milder cases of ad forms of kallmann syndrome may bee seen.(72) autosomal recessive kallmann syndrome genes responsible for autosomal recessive (ar) inheritance have only been reported in normosmic ihh. in 1997, de roux and colleagues reported gonadotropin releasing hormone receptor gene (gnrhr) mutation in a man with the ar form of ihh and his sister.(89) further investigation demonstrated this mutation in 1.6% of ihh men,(71) 40% of ar forms of ihh, and 16% of sporadic ihh.(90) de roux and colleagues also identified a mutation in gpr54 as an ar form of isolated ihh.(91) the phenotypes resulting from mutations in gnrhr and gpr54 are similar and do not have genetics of azoospermia—sadeghi-nejad and farrokhi 200 urology journal vol 3 no 4 autumn 2006 a significant diversity. gpr54 seems to be involved in regulating hypothalamic gnrh secretion, but an effect at the pituitary level is not discounted. these 2 genes may act in concert to regulate the gonadotropic axis, thereby also regulating the onset of puberty.(85) treatment and paternity patients with kallmann syndrome and ihh can benefit from hormonal therapy. life-long physiological doses of gonadotropins or pulsatile gnrh is required to achieve and maintain sexual maturity. spontaneous recovery after discontinuation of testosterone therapy was also reported.(72) the size of the testes might be a predictor of response to hcg/hmg administration and production of sperm.(92) however, the testes may remain of infantile volume despite hormone replacement therapy. ferro and associates transferred one testis to the contralateral hemiscrotum and placed a testicular prosthesis instead to normalize the appearance of the genital area while presenting testicular function.(93) treatment of kallmann syndrome can directly induce fertility. thus, patients with kallmann syndrome, especially those with ad genetic defects, are at the risk of transmission of mutations to their next generation. nevertheless, there are few reported cases in this regard. sato and colleagues showed transmission of fgfr1 mutation in 3 patients who received gonadotropin therapy to their offspring. they concluded that transmission of kallmann syndrome, especially the ad forms, to the next generation may occur following 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olfactory bulb morphogenesis. development. 2003;130:1101–11. 89. de roux n, young j, misrahi m, et al. a family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. n engl j med. 1997;337:1597-601. 90. beranova m, oliveira lm, bedecarrats gy, et al. prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. j clin endocrinol metab. 2001;86: 1580-8. 91. de roux n, genin e, carel jc, matsuda f, chaussain jl, milgrom e. hypogonadotropic hypogonadism due to loss of function of the kiss1-derived peptide receptor gpr54. proc natl acad sci u s a. 2003;100: 10972-6. 92. miyagawa y, tsujimura a, matsumiya k, et al. outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers: a 30-year retrospective study. j urol. 2005;173:2072-5. 93. ferro f, borrelli p, lucchetti mc. a surgical method to preserve testicular function and restore cosmetic appearance in hypogonadal men. j urol. 2004;171: 2368-70. u j spring 2012.pdf 530 | case report keywords: urinary bladder, adenocarcinoma of lung, neoplasm metastasis, immunohistochemistry introduction primary adenocarcinomas of the urinary bladder, including urachal carci-epithelial malignancies. however, secondary involvement of the bladder by metastatic spread or direct extension from adenocarcinomas arising in other organs can also occur. the morphological and histopathological similarities can sometimes blur the distinctions between primary and secondary lesions, especially in biopsy specimens. for determining primary sites of metastatic adenocarcinoma. thyroid transcription factor 1 is expressed in most primary and metastatic sites of the lung adenocarcinomas. by contrast, expressions of ttf-1 in adenocarcinomas other than lung adenocarcinomas and their metastatic sites are rare. primary bladder adenocarcinomas expressing ttf-1 have not been reported. enocarcinoma origin of distant sources of metastases, where the primary adenocarcinomas can arise. however, to the best of our knowledge, differentiation between the bladder and lung adenocarcinomas using this panel has not been reported so far. case report hiroshi shirakawa,1 norihide kozakai,1 2 hitoshi sugiura,3 satoshi hara1 urinary bladder metastasis originating from lung adenocarcinoma a case definitively diagnosed by immunohistochemistry corresponding author: hiroshi shirakawa, md department of urology, school of medicine, keio university, 35 shinanomachi, shinjyuku-ku, tokyo, 160-8582, japan tel: +81 333 531 211 fax: +81 332 251 985 e-mail: hiroshi_srkw@ a8.keio.jp received may 2010 accepted june 2010 1department of urology, kawasaki municipal hospital, kanagawa, japan 2department of general thoracic surgery, kawasaki municipal hospital, kanagawa, japan 3department of pathology, kawasaki municipal hospital, kanagawa, japan case report 531vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l secondary bladder adenocarcinoma | shirakawa et al showed a mixed subtype adenocarcinoma staged as ia, pt1n0m0. subsequently, his disease relapsed locally and metastasized to hilar lymph nodes. he was administered induction chemotherapy consisting of carboplatin and docetaxel, followed by gemcitabine and vinorelbine, and the ment of urology for assessment of gross hematuria. mm in diameter that was suspected to be the cause of the patient’s urinary symptoms. a vesicolithotripsy was subsequently performed. during the operation, a 3-mm diameter papillary tumor on the right lateral wall of the bladder was incidentally cold cup biopsy of the bladder tumor. the tumor was histopathologically diagnosed as an adenocarcinoma located beneath the intact urothelial epithelium without the bladder muscle invasion. immunohistochemical examination demonstrated tumor cells positive for ttf-1 and of the clinical history and the identical immunohistochemical expression pattern in the lung and bladder adenocarcinomas, the bladder tumor was diagnosed as a metastasis of the lung adenocarcinoma. after the cold cup biopsy, no recurrence of the bladder tumor was detected by ultrasonography. however, the primary lung cancer progressed, biopsy. discussion lung cancer is the most frequently occurring form of cancer in the world, and lung adenocarcinoma is the most common cell type representing approximately 50% of all lung cancer cases. whereas lung cancer is a common form of cancer, bladder metastasis from the lung cancer, particularly from lung adenocarcinoma, is uncommon. in a computed tomography-based study examlung cancer, no urinary tract metastases were detected. tients with distant metastases of lung cancer, only tected, in which the cell type was unknown. in cancer (four, squamous cell carcinomas; one, adhowever, lung adenocarcinoma-originated tumor and the process for diagnosis was not mentioned in this study. in individual case reports, only one spanish article has described bladder metastasis of lung adenocarcinoma. in the absence of immunohistochemistry, a pathological differential diagnosis of primary or secsimilar features of primary lung and secondary bladder adenocarcinomas complicate the ability figure 1. computed tomography scan of the chest performed prior to lobectomy revealed a primary lung adenocarcinoma with a cross section of 20 × 12 mm in the upper lobe of the right lung (arrow). 532 | to differentiate between these two lesion types, especially in biopsy specimens. in the present case, clinical history and immunohistochemical the diagnosis of bladder metastasis originating from the previous lung adenocarcinoma. the intact urothelial epithelium overlying the bladder tumor, which suggests that a tumor is a secondary lesion, also contributed to the differential diagnosis. in the present case, lung adenocarcinoma had already relapsed and the distinctive diagnosis of the bladder tumor of the pulmonary origin regrettably did not affect subsequence survival. however, considering the high prevalence of lung adenocarcinomas and the knowledge that bladder mary bladder epithelial malignancies, urologists and thoracic surgeons will potentially encounter patients with both bladder adenocarcinomas and likely localized lung adenocarcinomas. for such patients, differential diagnoses for determining whether the bladder adenocarcinoma is primary or metastatic are essential to treat them optimally. therefore, the immunohistochemical panel of able method for distinguishing between primary and secondary bladder adenocarcinomas, is cliniconflict of interest none declared. figure 2. gross appearance of the urinary bladder tumor during the cold cup biopsy. figure 3. histopathological findings. (a, b) primary lung adenocarcinoma. immunohistochemically positive for thyroid b: ttf-1, ×100). (c, d) metastatic site in the urinary bladder. the adenocarcinoma is visible under an intact urothelial epithelium with hematoxylin and eosin staining. (c: hematoxylin and case report references 1. thomas dg, ward am, williams jl. a study of 52 cases of 2. bates aw, baithun si. secondary neoplasms of the bladder are histological mimics of nontransitional cell primary tu3. lau sk, luthringer dj, eisen rn. thyroid transcription factor-1: a review. appl immunohistochem mol morphol. 4. oien ka. pathologic evaluation of unknown primary cancer. 5. ginsberg ms, grewal rk, heelan rt. lung cancer. radiol clin 6. metastases from newly diagnosed non-small cell lung can7. martin-marquina aspiunza a, diez-caballero alonso f, rodriguez-rubio cortadellas fi, et al. [bladder metastasis of 351vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l department of radiodiagnosis, pgimer and dr rml hospital, new delhi, india *e-mail: smitadhingra@yahoo.co.in a 46-year-old man presented with right scrotal swelling and bilateral dull pain since 4 months ear-lier. on physical examination, there was firm enlargement of the right testis and epididymis with hydrocele. left testis was hard in consistency with lack of testicular sensation. bilateral inguinal lymph nodes were enlarged. scrotal ultrasonography revealed few hypoechoic nodules involving the right testis and epididymis, and heterogeneous echopattern of the left testis and epididymis. sagittal t1-weighted magnetic resonance imaging revealed mildly hyperintense nodular lesions in the right testis and epididymis. on axial t2-weighted images, the lesions were hypointense to the testicular parenchyma with markedly low-signal intensity of the entire left testis. mild right hydrocele was also evident. post contrast t1-weighted coronal image showed peripheral rim enhancement of the lesions and bilateral inguinal lymphadenopathy. fine needle aspiration was consistent with tuberculosis, showing caseous necrosis and epithelioid cell granulomas. urinary system evaluation was normal. the patient was started on antitubercular therapy and has been kept on ultrasonographic follow-up. tubercular involvement of the scrotum is rare (7%) and usually occurs via retrograde spread from the urinary tract.(1) ultrasonographic appearance can be non-specific. magnetic resonance imaging, with its wide field of view, multiplanar capabilities, and superior soft tissue contrast, helps in accurate localization and characterization of scrotal lesions.(2) as in this patient, iso to hyperintense signal on t1-weighted image, typical low t2 signal intensity (due to chronic inflammation, fibrosis, and calcification), and peripheral rim-like contrast enhancement helped to make a diagnosis of tubercular etiology. smita manchanda,* bharat bhushan sharma, sushil kumar tuberculous epididymo-orchitis mri appearance references 1. michaelides m, sotiriadis c, konstantinou d, pervana s, tsitouridis i. tuberculous orchitis us and mri findings. correlation with histopathological findings. hippokratia. 2010;14:297-9. 2. tsili ac, tsampoulas c, giannakis d, et al. case report. tuberculous epididymo-orchitis: mri findings. br j radiol. 2008;81:e166-9. pictorial urology kidney transplantation investigating risk factors for the development of bk virus infection in kidney transplant recipients in guilan province during 2007-2015 masoud khosravi1, mahlagha dadras2, ali monfared3, siamak granmaieh4, mohammad shenagari rashti5, soheil soltanipour6, gholamreza mokhtari7* purpose: polyomavirus nephropathy has been recognized as an important cause of silent loss of kidney transplant function in up to 50% of kidney recipients (1). the present study aimed to evaluate the risk factors associated with bk virus infection in kidney transplant recipients. materials and methods: clinical information, urinary decoy cells, and blood polymerase chain reaction (pcr) tests were collected for polyomavirus infection in 223 kidney transplant recipients undergoing surgery at razi hospital at guilan university of medical sciences between 2007 and 2015. kidney biopsies were performed in patients with bkpyvdnaemia more than 10,000 copies/ml or increased plasma creatinine. results: among 223 patients, 116 (52%) were male. the mean age of participants was 49.57±13.48 years. out of 223 participants, 41 (18.4%) had decoy cells in their urine, and 182 (81.6%) did not, 15 of whom (6.7%) had viral genome in their blood. only 3 patients out of 10 had bk virus nephropathy in their kidney biopsy. among risk factors, it was found that post-transplant duration (p < 0.001) and the use of anti-thymocyte globulin (p = 0.001) were the most significant risk factors for finding decoy cells in patients’ urine. conclusion: post-transplant time, particularly the first 6 months, was found as the most important risk factor for the reactivation of polyomavirus infection in our patients because of strong immunosuppression and use of anti-thymocyte globulin (for prophylaxis or rejection treatment). it is concluded that kidney transplant recipients should be monitored episodically after transplantation. keywords: bk virus; decoy cells; polyomavirus infection; renal transplantation; risk factors. introduction bk polyomavirus (bkpyv) is a non-enveloped doublestranded dna virus that is a member of polyoma subgroup of papova viruses, which includes jc virus and sv40(2,3). infection with bk virus is common in the general population, with an estimate of seropositivity in adults by 80%90%(4,5). after resolution of primary infection, bk virus remains latent in several locations throughout the body, most notably within the genitourinary system(6). 1associate professor of nephrology, urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran. e-mail: drmasoudkhosravi@gmail.com. 2urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran. e-mail: mahlagha.dadras@yahoo.com. 3urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran. e-mail: drmonfared2009@gmail.com. 4pathologist, worked in private lab, all urine sample were examined by him. rip. 5associate professor of medical virology, department of medical microbiology rip, school of medicine, guilan university of medical sciences rasht, iran e-mail: shenagari@gmail.com 6associate professor of community medicine, gi cancer screening and prevention research center, department of community medicine, school of medicine, guilan university of medical sciences, rasht, iran. e-mail: ssoltanipour@yahoo.com 7associate professor of urology, urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran. e-mail: gh.mokhtari@yahoo.com. *correspondence: kidney transplant department, razi hospital, sardar jangal street, rasht, iran. pc: 4144895655. tel: 00981333537500; fax: 00981332111728. e-mail: gh.mokhtari@yahoo.com. received january 2020 & accepted august 2020 during immunosuppression, the virus may become reactivated and begin to replicate(3,7,8). after the introduction of potent immunosuppressive medications in the late 1990s, bk virus viruria was reported in up to half of renal allograft recipients in the first few months(9,10), but only 10%-15% of patients developed viremia(6). progression of viremia is thought to be a prerequisite for the development of bk virus nephropathy (bkvn)(5); about 3%-5% of allografts were being lost due to bkvn(11). transplant kidney biopsy remains the gold standard for diagnosing bkvn(12). urology journal/vol 17 no. 6/ november-december 2020/ pp. 620-625. [doi: 10.22037/uj.v16i7.5972] there is no definite treatment for bk virus (bkv) infection including: bkv nephropathy(11,12). studies that look for risk factors responsible for bkvn have shown inconclusive results(11). to identify risk factors for bkpyv, we examined the patients who received kidney transplants during 2007-2015. materials and methods patients and sample size this is a descriptive, retrospective, cross-sectional single center study. among 250 adult kidney transplant (kidney tx) patients, 223 patients who had undergone surgery in the university hospital (razi hospital, guilan university of medical sciences, rasht, iran) from october 2007 to september 2015, have been enrolled in this study. all the patients provided written informed consent before study entry. study design the purpose of this study was to evaluate the impact of age, gender, blood group, body mass index (bmi), length of time of kidney tx, level of serum creatinine (scr), and glomerular filtration rate (gfr) (measured by mdrd equation) during detection of decoy cells, length of time on hemodialysis (hd) before kidney tx, etiology of end stage renal disease (esrd), duration of having a stent after kidney transplant, type of immunosuppressive drugs used for induction and maintenance therapy, hepatitis b and c, cytomegalovirus (cmv) infection association, diabetes mellitus (dm) involvement before kidney tx, rejection prophylaxis by methyl prednisolone (mp) pulse and anti-thymocyte globulin (atg), maintenance immunosuppressive therapy by cyclosporine, tacrolimus, mycophenolate mofetil, and sirolimus, as the risk factors associated with the advent of polyomavirus infection in kidney tx recipients . procedures all the patients received mp pulse (500-1000mg/ day, for 1-3days) and atg (1mg kg/ day, for 7 days, cumulative dose:350400 mg) as induction therapy in operating room and after surgery. maintenance immunosuppressive drugs included prednisolone (5-7.5 mg/day with breakfast), cyclosporine (trough level 100-150ng/ml), tacrolimus (trough level 5-8 ng/ml), sirolimus (trough level 6-10ng/ ml), and mycophenolate mofetil (10002000 mg/day before meal). all kidney transplant recipients received living-unrelated kidney donation. inclusion and exclusion criteria inclusion criteria were those who had done their kidney transplantation surgery in our center and those who had a gfr more than 20 ml/min. also, those who had a kidney tx for less than 3 months and those with graft loss due to other etiologies were excluded from the study. evaluations evaluation began with finding decoy cells (even one cell) in urine every month at first six months post-transplant and then every other months, [urine cytology smears stained using papanicolaou method were evaluated for the presence of cells with intranuclear viral inclusions (decoy cells, which were counted (number per 10 high-power fields)]. the viral load of bkjc virus dna rtpcr (sensitivity for detection of bkjc virus genome is 2 copy/μl) was measured in blood and urine in case of an increase in plasma creatinine level (>25% baseline) or if decoy cell was seen more than 2 times in the urine cytology. all laboratory tests were performed in one laboratory. if the scr were normal, the dose of immunosuppressive drugs would be reduced, and the patient would be followed regularly. however, if scr were increased or if plasma bkv (bk virus) dna pcr exceeded more than 10,000 copies/ml respectively, whichever happens alone or together (13, 14), a kidney tx biopsy would be considered. due to high costs of both bk-jc virus dna rt-pcr measurement and kidney biopsy, some patients did not accept to do such tests because their insurance did not cover the expenses. statistical analysis all collected data were analyzed via spss software version18. according to the type of variables, descriptive statistics, mean, and standard deviation (sd) were used. since distribution of bmi values based on klomogorovsmirnova and shapiro-wilktests in both kidney tx groups followed a normal distribution in terms of the status of decoy cells in the urine (positive or negative), therefore, the independent ttest was used to compare the mean of bmi in the two groups. since the duration of the transplant variable and the values of gfr in both groups do not follow the normal distribution, therefore, the nonparametric u mann whitney test was used to compare the mean transplantation time. parameters would be considered significant if pvalue were < .005. results 223 kidney tx adult recipients had undergone kidney tx surgery from october 2007 to september 2015. 116 recipients (52%) were male, and 107(48%) were female. the youngest and oldest recipient were 17 and 79-years-old. decoy cells were found in 41(18.3%) recipients; 15 patients (6.7%) had viral genome in their blood. the mean post transplantation time was 7 months for those with the decoy cells in the urine and an average of 12 months for those without any decoy cells, showing a significant difference between the two groups using mann whitney u test (p < .001). there was no significant relationship between the age, sex, blood groups and etiology of esrd with bkv infection in kidney tx recipients. kolmogorov-smirnova test for the distribution of bmi showed that in both groups of patients with or without decoy cells in urine [(26.45 ± 4.02) (27.11 ± 5.02) respectively], bmi followed the normal distribution. comparing bmi in both groups of patients by two independent t test showed no meaningful differences between them. there was no significant relationship between rejection and initiation of dialysis in transplant patients with finding decoy cell in urine. there was no significant statistical difference in the average and sd of plasma creatinine (1.38 ± 0.65 mg/dl), and gfr with (61.09 ± 20.97 ml/min) or without (59.86 ± 24.85 ml/min) decoy cells in urine. comparing dialysis duration before transplantation in patients with or without decoy cells in urine [(12.88 ± 11.99months), (16.91 ± 18.75months) respectively] by mann-whitney u test showed no significant differences. fisher’s exact test showed no meaningful relationship between positive urine decoy cells and infection by hepatitis b and c, cmv infections and dm. chi-square test showed no relationship between positive urine bk virus in kidney transplant recipients-khosravi et al. kidney transplantation 621 vol 17 no 06 november-december 2020 622 decoy cells and corticosteroid pulse induction (1 or 3 grams) during kidney tx. fisher’s-exact test showed a meaningful relationship between positive urine decoy cells and thymoglobulin injection (95% ci: 1.88-22.79, or = 6.55, p =.001, table 1). there was no association between the type of immunosuppressive drug regimen (tacrolimus, cyclosporine, mycophenolate mofetil, and sirolimus) and positive decoy cells in urine (fisher’s exact test p = .337). in almost all the patients, ureteral stent was removed after nearly one month, and no ureteral stricture was found. although nearly all the recipients and donors were hla mismatched, this was not statistically significant for emerging of decoy cells in urine. recipients and donors were all negative for finding “decoy cells” in urine before kidney transplant. urinalysis in the patients with decoy cells in their urine was interestingly normal. cold ischemic time was less than 1 hour. cmv serostatus in all donors and recipients were positive just for igg. discussion the human bk polyomavirus is associated with two significant complications in transplant recipients: polyoma virus associated nephropathy (pyvan) in 1-10% of kidney transplant recipients and polyomavirus-associated hemorrhagic cystitis (pyvhc) in 5-15% of hematopoietic stem cell transplant (hsct) patients(15-17). although jc virus (jcv) inhabits in the uroepithelium (18) and during the periods of immunosuppression may be reactivated(19), it rarely causes nephropathy(20). after kidney transplantation, the state of immunosuppression bkv replication starts and progresses through detectable stages: viruria, viremia and then nephropathy(21). in reviewing the articles for screening bkv infection after kidney transplantation, different methods for finding bkv are provided by articles, the choice of which depends on the policy of the kidney transplant department and economic issues. these tests vary from finding decoy cells in the urine (sensitivity 100%specificity 45%. (2,22), to measure the bk viral load in the urine and bloo (10,11,12,23, 24). however, measuring bk viral load has a higher value (sensitivity 100%specificity 66-90%) depending on viral load more than 10,000 copies/ml in blood.(22, 25). accordingly, it is chosen to find decoy cells in urine as screening test in our study, because it is less expensive and insurance covers it. figure 1 shows “decoy cell” taken in the lab. among 223 participants in this study, 41 (18.3%) had decoy cells in their urine, 15 of whom (6.7%) had viral genome in their blood, virus counts was more than 104 copies/ml. only 10 patients agreed to have a kidney biopsy, of whom only 3 reported bkv nephropathy. although a negative kidney biopsy due to focal nature of involvement cannot rule out bkvn with 100% certainty, according to literature, diagnosis may be missed in one third of biopsies(2). vera and colleagures showed positive pcr in 75% of urine and 33% in plasma of kidney tx patients (26). study by bohl et al. showed viral genome in the urine of 44% of patients(21). in our study, the incidence of bkv in men and women was 5.2% and 10.3% respectively, in addition the incidence of jc virus in men was 10.3%, and in women was 6.5%, and the incidence of finding bk and jc virus together in urine in men and women was 1.7%, and 2.8% respectively. in our study, there was no statistically-significant relationship between sex, bk and jc virus. in a retrospective study of 880 kidney transplant patients by prince et al., male sex was reported as the main risk factor for the virus(27). this finding is in contrast to our findings. in our study, the average age of patients was 49.57±13.48 years. there was no relationship between age and decoy cells in urine of our patients. nevo et al. showed similar finding(28). ramos and colleagues found that age is associated with finding bkjc virus in renal transplant recipients(29). these differences are not statistically significant. average scr in our patients with decoy cells in their urine was 1.38 ± 0.65 mg/dl, no significant increases were found in plasma creatinine. in our study, the incidence of cmv (igg positive and igm negative) was 97.6 % in those patients with decoy cells in their urine, but it was 6% in patients without decoy cells in their urine. in a study by theodoropoulos in 2012, the incidence of cmv in bk virus negative patients was 8.5%, but in those with viruria, viremia, and those with bkvn, it was 12.4, 21.3, and 32.3%, respectively(30). these differences in findings may be related to the level of immunosuppression, type of immunosuppressive drugs, and race. in our study, the average bmi was 26.4 ± 4 in patients with positive urine decoy cells was and 27.1±5 in those with negative urine decoy cells. this calculation showed no statistically meaningful relations between bmi and urine decoy cells. in some studies, bmi was considered as a risk factor. perez showed that bmi more than 25 must be considered as a risk factor(31). obesity may predispose to infection through creation of a pro-inflammatory state with blunting of the immune response at both the humoral and cellular levels, as well as generalized tissue hypoperfusion leading to decreased tissue oxygen tension(31). increased weight may also cause inconsistencies of immunosuppressant drug table 1. frequency of finding decoy cells in urine by immunosuppressive drugs drug regimen urine decoy cells n (%) no urine decoy cells n (%) total p-value mycophenolate mofetil + tacrolimus 1 (0.4%) 18 (8.1%) 19(8.5%) 0.337 mycophenolate mofetil + cyclosporine 30 (13.5%) 122 (54.7%) 152 (68.2%) mycophenolate mofetil + sirolimus 7 (3.1%) 14 (6.3%) 21 (9.4%) mycophenolate mofetil 0 3 (1.3%) 3 (1.3%) sirolimus 0 5 (2.2%) 5 (2.2%) cyclosporine 3 (1.3%) 18 (8.1%) 21 (9.4%) tacrolimus 0 2 (0.9 %) 2 (0.9%) total 41 (18.4%) 182 (81.6%) 223 (100%) thymoglobulin therapy + 27 (90%) 70 (57.9%) 97 (64.2%) 0.001 3 (10%) 51 (42.1%) 54 (35.8%) bk virus in kidney transplant recipients-khosravi et al. levels and longer operation time, resulting in prolonged graft ischemia and delayed graft function(31). there was no association between kidney tx recipient’s blood group and bkv infection. all our patients were abo compatible, googling for it showed no results except for blood group incompatibility. no significant relationship was found between hepatitis c, b, and bk viruria. dheir demonstrated positive relationship between bk virus nephropathy and hepatitis b virus positivity(32). hepatitis b virus positivity was related to dialysis care and duration. the relationship between immunosuppressive drugs (cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, and antithymocyte globulin) used for our patients and urine decoy cells showed statistically significance relationship between anti-thymocyte globulin use and positive urine decoy cells 95% ci: 1.88-22.79, or = 6.55, p =.001 (table 1) those patients who received anti-thymocyte globulin showed decoy cells in their urine 6.5 times more than other patients. this finding was consistent with a study by oliver prince(27). bernnan showed a positive relationship between viruria and tacrolimus (in 46% of 200 renal transplant recipients), but only 13% in those who received cyclosporine, (p .005)(9). the differences between our study and bernnan’s is related to drug protocol (e.g., drug dose, genetic, and anti-thymocyte globulin) which was used for all of our patients as induction therapy and rejection treatment. average post-transplant duration in the patients with decoy cells in their urine was 10.90 ± 5.62 months. in the group with positive urine decoy cells, it was calculated as 7 months, and in the group with negative urine decoy cell it was 12 months, which was statistically significant (p < .001). this result means that regarding intense immunosuppression during first months post kidney transplantation, most decrease in immunity would be happen at that time and can result in reactivation of latent virus. in study by saundh, different patterns of reactivation were observed: bk viruria was detected after 3-6 months, and jc viruria was observed as early as 5 days post-transplantation(33). the difference in our study and saundh was related to drug protocol. in our study, 9 out of 223 patients had dm, 3 of whom (7.3%) had positive urine decoy cells, which was not statistically significant. this was consistent with lopez finding(34). dm was considered as a recipient risk factor for developing bkvn(1). there was no relationship between kidney tx rejection and polyomavirus infection in our study, because only 4 patients had acute rejection, one of whom was jc positive. in his study, christopher showed no relationship between transplant rejection and polyomavirus infection(35). in our study, average gfr in patients with positive, and negative decoy cells was 61.09 ± 20.97, 59.86 ± 24.58 ml/min respectively, that was not statistically significant. haung also showed similar findings(36). it means that we do not have severe nephropathy to deteriorate gfr. in our study, average duration on dialysis before kidney tx for patients with positive and negative urine decoy cells was 12.88 ± 11.99 and 16.91 ± 18.75 months, respectively, which is not statistically significant. girmaneva et al, found that unlike the control group, patients with viruria >10 7 were treated longer by dialysis and had impaired graft function one-year post transplantation.(p < .05)(37). hemodialysis was considered as an immunosuppressed state(38). ureteral stent was removed 3 to 4 weeks post transplantation, and was not statistically significant in the presence of the virus in the urine. however, jamboti reported that ureteric stent could be associated with increased risk of bk viremia(1). this may be related to ureteric stenosis and urinary stagnation. conclusions polyomavirus infection is a serious threat for the life of transplanted kidney. it could occur at any time post transplantation and cause an increase in plasma creatinine level silently. also, it may lead to irreversible tubulointerstitial changes in transplanted kidney and then loss of the graft (21). there is no definite treatment for bkv nephropathy(25,39). our study found that the first few months post kidney tx and the use of anti-thymocyte globulin were considered as serious risk factors for polyomavirus infection. conflict of interest the authors: masoud khosravi, mahlagha dadras, ali monfared, siamak granmaieh, mohammad shenagari rashti, soheil soltanipour, gholamreza mokhtari, declared that they have no conflicts of interest with respect to the research and authorship of this publication. references 1. jamboti js. bk virus nephropathy in renal transplant recipients. nephrology. 2016;21(8):647-54. 2. barreto p, almeida m, dias l, vieira p, pedroso s, martins ls, et al. bk virus nephropathy in kidney transplantation: a literature review following a clinical case. portuguese journal of nephrology & hypertension. 2016;30(4):259-68. figure 1. decoy cells in urine (photo taken in our lab) bk virus in kidney transplant recipients-khosravi et al. kidney transplantation 623 vol 17 no 06 november-december 2020 624 3. christiadi d, karpe km, walters gd. interventions for bk virus infection in kidney transplant recipients. cochrane database of systematic reviews. 2019(5). 4. stolt a, sasnauskas k, koskela p, lehtinen m, dillner j. seroepidemiology of the human polyomaviruses. journal of general virology. 2003;84(6):1499-504. 5. hirsch hh, knowles w, dickenmann m, passweg j, klimkait t, mihatsch mj, et al. prospective study of polyomavirus type bk replication and nephropathy in renal-transplant recipients. new england journal of medicine. 2002;347(7):488-96. 6. wiseman ac. polyomavirus nephropathy: a current perspective and clinical considerations. american journal of kidney diseases. 2009;54(1):131-42. 7. hirsch hh, steiger j. polyomavirus bk. the lancet infectious diseases. 2003;3(10):61123. 8. boubenider s, hiesse c, marchand s, hafi a, kriaa f, charpentier b. post-transplantation polyomavirus infections. journal of nephrology. 1999;12(1):24-9. 9. brennan dc, agha i, bohl dl, schnitzler ma, hardinger kl, lockwood m, et al. incidence of bk with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. american journal of transplantation. 2005;5(3):582-94. 10. bressollette‐bodin c, coste‐burel m, hourmant m, sebille v, andre‐garnier e, imbert‐marcille b. a prospective longitudinal study of bk virus infection in 104 renal transplant recipients. american journal of transplantation. 2005;5(8):1926-33. 11. pai d, mann d, malik a, hoover d, fyfe b, mann r, editors. risk factors for the development of bk virus nephropathy in renal transplant recipients. transplantation proceedings; 2015: elsevier. 12. sawinski d, goral s. bk virus infection: an update on diagnosis and treatment. nephrology dialysis transplantation. 2015;30(2):209-17. 13. hirsch hh, randhawa ps, practice aidco. bk polyomavirus in solid organ transplantation—guidelines from the american society of transplantation infectious diseases community of practice. clinical transplantation. 2019;33(9):e13528. 14. sawinski d, trofe-clark j. bk virus nephropathy. clinical journal of the american society of nephrology. 2018;13(12):1893-6. 15. hirsch h, randhawa p, practice aidco. bk polyomavirus in solid organ transplantation. american journal of transplantation. 2013;13(s4):179-88. 16. ramos e, drachenberg c, portocarrero m, wali r, klassen d, fink j, et al. bk virus nephropathy diagnosis and treatment: experience at the university of maryland renal transplant program. clinical transplants. 2002:143-53. 17. lee yj, glezerman i, jakubowski a, papanicolaou g, editors. bk polyoma virus nephropathy in hematopoietic cell transplant recipients with renal dysfunction. open forum infectious diseases; 2017: oxford university press. 18. boldorini r, veggiani c, barco d, monga g. kidney and urinary tract polyomavirus infection and distribution: molecular biology investigation of 10 consecutive autopsies. archives of pathology & laboratory medicine. 2005;129(1):69-73. 19. randhawa p, uhrmacher j, pasculle w, vats a, shapiro r, eghtsead b, et al. a comparative study of bk and jc virus infections in organ transplant recipients. journal of medical virology. 2005;77(2):238-43. 20. wen mc, wang cl, wang m, cheng ch, wu mj, chen ch, et al. association of jc virus with tubulointerstitial nephritis in a renal allograft recipient. journal of medical virology. 2004;72(4):675-8. 21. bohl dl, brennan dc. bk virus nephropathy and kidney transplantation. clinical journal of the american society of nephrology. 2007;2(supplement 1):s36-s46. 22. elfadawy n, yamada m, sarabu n. management of bk polyomavirus infection in kidney and kidney-pancreas transplant recipients: a review article. infectious disease clinics. 2018;32(3):599-613. 23. muhsin sa, wojciechowski d. bk virus in transplant recipients: current perspectives. transplant research and risk management. 2019;11:47. 24. scadden jr, sharif a, skordilis k, borrows r. polyoma virus nephropathy in kidney transplantation. world journal of transplantation. 2017;7(6):329. 25. sharma r, zachariah m. bk virus nephropathy: prevalence, impact and management strategies. international journal of nephrology and renovascular disease. 2020;13:187. 26. vera-sempere f, rubio l, moreno-baylach m, garcıa a, prieto m, camañas a, et al., editors. polymerase chain reaction detection of bk virus and monitoring of bk nephropathy in renal transplant recipients at the university hospital la fe. transplantation proceedings; 2005: elsevier. 27. prince o, savic s, dickenmann m, steiger j, bubendorf l, mihatsch mj. risk factors for polyoma virus nephropathy. nephrology dialysis transplantation. 2009;24(3):102433. 28. nevo s, swan v, enger c, wojno k, bitton r, shabooti m, et al. acute bleeding after bone marrow transplantation (bmt)—incidence and effect on survival. a quantitative bk virus in kidney transplant recipients-khosravi et al. analysis in 1,402 patients. blood. 1998 feb 15;91(4):1469-77. 29. ramos e, drachenberg cb, papadimitriou jc, hamze o, fink jc, klassen dk, et al. clinical course of polyoma virus nephropathy in 67 renal transplant patients. j am soc nephrol. 2002 aug;13(8):2145-51. 30. theodoropoulos n, wang e, penugonda s, ladner d, stosor v, leventhal j, et al. bk virus replication and nephropathy after alemtuzumab‐induced kidney transplantation. am j transplant. 2013 jan;13(1):197-206. 31. pérez‐torres d, bertrán‐pasarell j, santiago‐ delpín e, gonzález‐ramos m, medina‐ mangual s, morales‐otero l, et al. factors and outcome in bk virus nephropathy in a hispanic kidney transplant population. transpl infect dis. 2010 feb;12(1):16-22. 32. dheir h, sahin s, uyar m, gurkan a, turunc v, kacar s, et al., editors. intensive polyoma virus nephropathy treatment as a preferable approach for graft surveillance. transplantation proceedings; 2011: elsevier. 33. saundh bk, tibble s, baker r, sasnauskas k, harris m, hale a. different patterns of bk and jc polyomavirus reactivation following renal transplantation. journal of clinical pathology. 2010;63(8):714-8. 34. lopez v, gutierrez c, sola e, garcia i, burgos d, cabello m, et al., editors. does jc polyomavirus cause nephropathy in renal transplant patients? transplantation proceedings; 2010: elsevier. 35. buehrig ck, lager dj, stegall md, kreps ma, kremers wk, gloor jm, et al. influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirusassociated nephropathy. kidney international. 2003;64(2):665-73. 36. huang g, zhang l, liang x, qiu j, deng r, li j, et al., editors. risk factors for bk virus infection and bk virus– associated nephropathy under the impact of intensive monitoring and preemptive immunosuppression reduction. transplantation proceedings; 2014: elsevier. 37. girmanova e, brabcova i, bandur s, hribova p, skibova j, viklicky o. a prospective longitudinal study of bk virus infection in 120 czech renal transplant recipients. j med virol. 2011 aug;83(8):1395-400. 38. lisowska ka, pindel m, pietruczuk k, kuźmiuk-glembin i, storoniak h, dębskaślizień a, et al. the influence of a single hemodialysis procedure on human t lymphocytes. scientific reports. 2019;9(1):19. 39. lamarche c, orio j, collette s, senécal l, hébert m-j, renoult é, et al. bk polyomavirus and the transplanted kidney: immunopathology and therapeutic approaches. transplantation. 2016;100(11):2276. bk virus in kidney transplant recipients-khosravi et al. kidney transplantation 625 fall 2012 08.pdf 691vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l association of g/a polymorphism, rs266882, in arei region of the prostate-specific antigen gene with prostate cancer risk and clinicopathological features mohammad samzadeh,1 mandana hasanzad,2 seyed hamid jamaldini,3 ali akbar haghdoost,4 mahdi afshari,4 seyed amir mohsen ziaee1 purpose: phism with clinicopathologic characteristics of the disease and prostate cancer (pca) risk. materials and methods: 111 subjects with benign prostatic hyperplasia (bph), were recruited in this study. genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism method. results: compared to ag genotype (adjusted odds ratio = 2.4; p = .03). the percentages of g alleles of polymorphisms in patients with pca were more than that in ones with bph (odds ratio = 1.2; p = .7). conclusion: the gg genotype of psa 158a/g polymorphism is a predisposing factor for pca. but no association was observed between alleles and grade, stage, or age of diagnosis. similarly, the rs266882 polymorphism was not associated with psa plasma levels. keywords: polymorphism corresponding author: seyed amir mohsen ziaee, md urology and nephrology research center, no. 103, 9th boustan st, pasdaran ave, 1666677951, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: samziaee@hot mail.com received december 2011 accepted may 2012 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2tehran medical branch, islamic azad university, tehran, iran 3genetics research center, university of social welfare and rehabilitation sciences, tehran, iran 4research center for modeling of health, kerman university of medical sciences, kerman, iran cellular and molecular urology 692 | introduction p rostate malignancy, the second most common cancer in men, accounts for 32% of all types of cancer and is the 4th most frequent cancer in the world. although the main etiological cause of the disease is still unclear, it is known to be a multifactorial disease with a genetic component.(1) dase 3, is a serine protease that is part of the kallikrein superfamily, mainly produced by prostate cells.(2) it has widely been used as a diagnostic marker of the prostate cancer (pca) since the early 1990s. serum level of psa increases with benign prostatic conditions, but a higher surge of it is seen with pca and that is why it is the most commonly used clinical biomarker for pca diagnosis and follow-up. early detection through serum testing for psa and improved procedures for surgical intervention and radiation however, there is still no effective cure for men with advanced disease. therefore, much research has been dedicated to identifying prognostic markers that distinguish indolent versus aggressive forms of pca.(3) recent technological advances have allowed investigators to interrogate thousands of single nucleotide polymorgenetic markers associated with risk of developing this liferation of the prostate gland are not well-known, but the gene for psa has been the focus of several studies.(3) the psa gene is mapped on chromosome 19 (19q13.4).(4) androgens. production of psa is mediated through binding of the androgen receptor (ar) to androgen response elements (are) in the promoter region of the psa gene. (4) after binding of androgen to the ar, a cascade of cellular events happens, which causes the movement of ar to the nucleus, where it binds to ares in the promoters of target genes to initiate psa gene transcription. at least region.(5) the one nearest to the transcription start site is referred to as arei. several polymorphisms have been reported which can in(6) a recent study mentioned using this snp as a predictive marker.(7) the psa gene contains a polymorphism, substitution of a guanine (g) by an adenine (a), locating 158 bases upstream of the transcription site, which have transcriptional control role related to serum levels of psa.(3,6,8-10) with regard to the role of psa g158a snp, a number of surveys have been focused on the association between this snp, serum level of psa, and pca susceptibility in different populations. since the psa test in screening patients who had to undergo prostate biopsy encounters many challenges, using the psa 158 a/g polymorphism genotypes combined with the result of serum psa is a method for decreasing unnecessary biopsies. this study investigated any relation between psa 158 g/a polymorphism and risk of pca, tumor stage and grade, and patients with pca. materials and methods this case-control study consisted of 206 subjects, including 95 patients with pca and 111 controls with benign prostatic hyperplasia (bph), who were recruited from department of iran, between february 2010 and april 2011. the present study was approved by the urology and nephrology research center review board (www.unrc.ir) aftehran, iran. after a written informed consent was obtained from each participant, a structured questionnaire was completed to gather information on potential risk factors, inst-degree relatives, blood group, and total and free psa level. blood samples were taken using sample tubes containing tion was performed according to the standard protocol.(11) c. open laparoscopic or radical prostatectomy was used to determine the tumor grade and stage and perineural and vascular invasion. tumor stage and grade are determined according to 1997 tnm guideline(12) and gleason grading cellular and molecular urology 693vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l rs266882 polymorphism on prostate cancer risk | samzadeh et al system, from 1 (most differentiated) to 5 (least differentiated), respectively. control groups with bph had the following criteria in order to rule out the false diagnosis of pca: 1) either serum psa < 4.0 ng/ml or negative pathological report of the prostate biopsy with serum psa > 4.0 ng/ml; 2) normal digital malignancy in resected prostatic tissues from open surgiof pca in control group, consuming any psa decreasing medication, hormone therapy, orchiectomy, and non-adenocarcinoma of the prostate. polymerase chain reaction-restriction fragment length polymorphism analysis polymerase chain reaction (pcr) was performed using 20 pmol of forward primer (5'-ttg tat gaa gaa tcg ggg atc gt-3') and reverse primer (5'tcc ccc agg agc cct ata aaa-3') in a 50-μl reaction volume containing 2 mm mgcl 2 . the pcr program was 94 °c for 10 min followed by 35 cycles at 94 °c for 1 min, 59 °c for 1 for 10 min. after pcr, a restriction fragment length polymorphism (rflp) method was used with nhei restriction enzyme (roche), then, separated on a 2% agarose gel. the three genotypes were determined according to their size: aa (300 bp), ag (150, 300 bp), and gg (150 bp) (figure 1). by direct sequencing of several pcr samples with each genotype (figure 2). statistical analyses data analysis was performed by stata (v.11) software. chi-square test and student’s t test were used for evaluating the association between categorical variables and mean values of variables, respectively. serum levels of psa were estimate the effect of polymorphisms on serum total psa. multivariable logistic regression models were used to determine odds ratio (or) for categorical dependent variables adjusting for potential confounders, such as age, family history of cancer, and grade and stage of tumor. results were p value was less than .05. using the ps power and sample size calculations software, version 3.0, january 2009 (http://biostat.mc.vanderbilt. edu/powersamplesize) (william d. dupont and walton d. plummer, 2009), our sample size in different subgroups .05) to detect an or of 2.4. results subjects’ characteristics the average ± standard deviation age of the patients was 67 ± 8.7 years (range, 47 to 89 years). total psa levels were serum total psa was 467 ng/dl more than that in patients with bph (p < .001). in this group, the percentage of posithat in patients with bph (17.4% versus 1%; p < .001). in overall, the education level of patients with pca was sigp < .001; table 1) among patients, 31% had poorly differentiated tumors diagnosis (tnm stage iii and iv) (table 2). psa and risk of pca having considered the ag genotype as the reference group between psa polymorphisms, patients with gg genotype had 1.2-fold greater risk of developing high-grade (gleason p = .7). the or between gg and aa genotypes and stages of pca was 0.75 and 0.78, respectively, indicating that these polymorphisms had a protective effect on the high level of disease stages compared to ag genotype as the reference group. but the adjusted or was slightly more than null value (table 3). results showed that there was not a statistical association between polymorphisms and vascular or perineural invasion. the mean age in those who had different polymorphisms indicated that patients with gg and aa genotypes had higher mean ages compared to the reference group (ag genotype). it means that patients with these polymorphisms could get the pca at higher ages compared to those without this polymorphism. in other words, it can be said that poly694 | reducing the onset and also the time of diagnosis of pca. the mean total psa in those who had gg and aa genotypes was around 1.2 and 0.2 ng/dl more than that in those with ag genotype (p = .9 and p = .2, respectively); adjusting for other factors did not change this difference considerably (table 3). psa genotypes and pca and control groups for any of the psa are-i genotypes. however, some kinds of polymorphisms, like gg genotype, had more frequencies in patients with pca (32%) than in bph group (22.6%). the or between gg polymorphism and ag polymorphism (reference) was 1.76. having adjusted for potential confounders, such as age and stage and grade of tumor, this gap became more prominent and stap = .03); it means 2.4-fold greater risk of developing pca in patients with gg genocellular and molecular urology figure 1. representative screening for the prostate-specific antigen genotypes. left to right: line 1: gg, line 2: gg, line 3: ag, line 4: ag, line 5: aa, and line 6: aa figure 2. a sample of sequencing result for confirming prostate-specific antigen genotyping. arrow is the position of rs266882. 695vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l rs266882 polymorphism on prostate cancer risk | samzadeh et al was observed between aa genotype and pca (table 4). the allele frequency of psa gene patients with pca had a greater percentage of g alleles than the control bph ones; however, it was not statistically sigment of pca was 1.22, which means 1.2-fold greater risk of developing pca compared to a allele, but that was not table 2. frequency of different stages and grades of prostate cancer in the study population. grade and stage number percent grade gleason < 7 gleason > 7 58 70.65 26 29.35 tnm stage i and ii iii and iv 63 78.16 17 21.84 table 1. comparison of main variables in patients with prostate cancer and benign prostatic hyperplasia.* variables cancer benign prostatic hyperplasia p number percent number percent smoking never stop currently 63 67.7 88 83 .02911 11.8 9 8.5 19 20.4 9 8.5 drug history (finasteride) 14 14.7 55 49.5 < .001 marital status 91 97.8 104 98 .89 family history of prostate cancer 16 17.4 1 1 < .001 > 40 year’s son (> 2 sons) 0 0 6 15.4 < .001 education illiterate primary diploma academic 15 16.3 32 31.7 < .001 36 39 4 53.5 23 25 11 10.9 18 19.6 4 4 blood group o a b ab 32 36.8 31 36 .78 39 45 34 39.5 15 17.2 20 23.3 1 1.1 1 1.2 other disease none cvd hlp breast cancer dm 75 78.9 102 92 .76 14 14.7 7 6.3 2 2.1 0 0 1 1.1 0 0 3 3.2 2 1.8 abnormal psa ratio 45 50.6 14 17.9 < .001 mean (sd) mean (sd) total psa 474.4 (4299) 7.3 (7.11) < .001 age 63.2 (7.34) 70.3 (8.53) < .001 body mass index* 25 (3.11) 25.2 (3.50) .67 *cvd indicates cardiovascular disease; hlp, hyperlipidemia; dm, diabetes mellitus; psa, prostate-specific antigen; and sd, standard deviation. 696 | discussion in previous studies, it was demonstrated that psa gene homozygous for the g allele is associated with higher serum psa concentration and some other tumors(3,6,13-15) whereas the homozygous for the a allele is associated with a higher level of total psa in men with or without pca.(9,10) in a case-control analysis of 500 caucasian cases and 676 conand total and free psa plasma levels.(16) in the present study, the total psa levels in those who had gg genotypes cellular and molecular urology table 3. relationship between arei (psa-158 g/a) genotype and prostate cancer stage and grade, total psa level, perineural and vascular invasion of cancer, and age at diagnosis.* gg genotypeag genotypeaa genotypeoverall pprostate cancer 0.9 (based on chi-square)stage 21 (33)22 (35)20 (32) stages 1and 2, n (%) 5 (29)7 (41)5 (29) stages 3 and 4, n (%) 0.75 ( .7) 1.04 ( .9) 1 1 0.78 ( .7) 1.04 ( .9) or (p) crude adjusted 0.9 (based on fisher’s exact test)grade 18 (31)22 (37.9)18 (31) gleason < 7, n (%) 9 (34.6)9 (34.6)8 (30.7) gleason ≥ 7, n (%) 1.2 ( .7) 1.80 ( .3) 1 1 1.08 ( .9) 1.51 ( .5) or (p) crude adjusted 0.4 (based on fisher’s exact test)vascular invasion 20 (31)24 (37)20 (31) negative, n (%) 0 (0)3 (75)1 (25) positive, n (%) 1 1 0.4 ( .4) 0.6 ( .7) or (p) crude adjusted 0.5 (based on fisher’s exact test)perineural invasion 3 (37)4 (50)1(12) negative, n (%) 19 (27)26 (37.7)24 (34.8) positive, n (%) 0.97 ( .9) 1.2 ( .8) 1 1 3.7 ( .2) 5.8 ( .15) or (p) crude adjusted 0.7 (based on anova test)age of diagnosis 497758 number 66.9 (7.9)66.8 (9)67.9 (8.9) mean age (sd) 3.3 ( .09) 3.9 ( .05) 0 0 0.9 ( .6) 1.9 ( .3) mean difference (p) crude adjusted 0.6total psa level 456346 number 15.7 (24)13 (17)12 (15.6) mean psa (sd) 1.2 ( .9) 1.06 ( .9) 0 0 0.2 ( .2) 0.2 ( .2) mean difference crude adjusted *or indicates odds ratio; sd, standard deviation; and psa, prostate-specific antigen. 697vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l rs266882 polymorphism on prostate cancer risk | samzadeh et al was 1.2 ng/dl more than that in those who had a/g, but like turkish and japanese population, it was not statistically (17) there are two different reports on the association of this snp with serum psa level in japanese population. one showed association between higher psa level and gg genotypes and the other showed no association between -158 g/a polymorphism and the serum psa level.(18,19) a functional study has indicated that the psa -158 g/a polymorphism has no functional effect on the activity of the psa promoter in vitro and in vivo,(20) which supports it has been proposed that rs266882 polymorphism is associated with disease stage or grade.(6,9,21-26) the gg genotype in taiwanese is associated with larger tumor volume and higher pathological stage.(14) a large case-control study of caucasian-australians (821 patients and 734 controls) stage iii to iv tumors,(15) whereas a larger case-control study on a white american population found that the gg genotype is associated with the lower stage of the disease. (22) tween rs266882 and high grade or advanced stage of the disease. the gg genotype was associated with a 1.2-fold pca (or = 1.2; p = .7). another study which investigated the association of rs266882 snp with pca risk found that this snp was not associated with cancer grade.(27) several investigators have studied the relation of the rs266882 polymorphism with pca susceptibility. an initial case-control study of non-hispanic white men (57 patients and 156 controls) reported a positive association of homozygous variant gg genotype of rs266882 with a three-fold risk of advanced cancer suggesting that the psa promoter activity under the control of allelic variation is an androgen-dependent event.(28) subsequent studies on this polymorphism also reported increased risk of pca with the g allele in taiwan (122 patients and 84 controls),(14) scotland (97 patients and 144 controls),(24) and turkey (49 patients and 47 controls). in a larger sibling-based casecontrol study on a predominantly white american population, the association between pca susceptibility and the g (22) a case-control study on patients with turkish origin re(29) another study in 2008 found that the gg genotype carriers have a higher risk of developing pca than those with the ag and aa genotypes. (30) ciation between the a allele and increased risk of pca.(10,23) similarly, a larger study of australian caucasian men (209 patients and 223 controls) found a three-fold risk of pca with the aa allele.(25) table 4. genotype and allele frequency and odds ratio between different polymorphisms in patients with prostate cancer and benign prostatic hyperplasia.£ polymorphism cancer, no (%) benign prostatic hyperplasia, no (%) overall p* 95%ci odds ratio (p) crude adjusted psa polymorphism ag gg aa polymorphism allele g a .27 33 (38) 50 (47) 1 1 28 (32.2) 24 (22.6) 1.76 ( .1) 2.4 ( .03) 26 (29.9) 32 (30.2) 1.23 ( .5) 1.54 ( .3) .389 (51) 98 (46.2) 85 (49) 114 (53.8) *based on chi-square test. £ci indicates confidence interval; and psa, prostate-specific antigen. 698 | cantly increased the risk of cancer more than 2-fold compared to ag genotype (adjusted or = 2.4; p = .03), which is in line with several studies.(18,31,32) the percentages of g alleles of polymorphisms in patients with pca were more than that in those with bph. however, we found a 70% increased risk of pca with gg polymorphism. in patients with pca, allele frequency of the psa polymorphism at position -158 (a 0.49, g 0.51) was similar to african american men (a 0.52, g 0.48), non-hispanic white men (a 0.48, g 0.52), and hispanic white men (a 0.37, g 0.63),(9) and different from turkish (a 0.63, g 0.36) and japanese men (a 0.22 g 0.78). polymorphisms provided such inconsistent results cannot be fully understood, but some factors, such as ethnicity, life-style, and/or gene–gene, and gene–environment interby studies with larger number of advanced cases. conclusion genotype of psa polymorphism and pca risk compared to ag genotype. but no association was observed between alleles and grade, stage, or age of diagnosis. similarly, the rs266882 polymorphism was not associated with psa plasma levels and cancer risk. the difference in results for psa arei polymorphisms between studies may be minimized using larger study groups. acknowledgements this work was supported by grant no. 415/87 from the ated to shahid beheshti university of medical sciences, tehran, iran. we thank all those who collaborated with us in this survey. conflict of interest none declared. references 1. bostwick dg, burke hb, djakiew d, et al. human prostate cancer risk factors. cancer. 2004;101:2371-490. 2. yousef gm, chang a, scorilas a, diamandis ep. genomic organization of the human kallikrein gene family on chromosome 19q13.3-q13.4. biochem biophys res commun. 2000;276:125-33. 3. xu j, meyers da, sterling da, et al. association studies of serum prostate-specific antigen levels and the genetic polymorphisms at the androgen receptor and prostatespecific antigen genes. cancer epidemiol biomarkers prev. 2002;11:664-9. 4. kim j, coetzee ga. prostate specific antigen gene regulation by androgen receptor. j cell biochem. 2004;93:233-41. 5. schuur er, henderson ga, kmetec la, miller jd, lamparski hg, henderson dr. prostate-specific antigen expression is regulated by an upstream enhancer. j biol chem. 1996;271:7043-51. 6. schatzl g, marberger m, remzi m, et al. polymorphism in are-i region of prostate-specific antigen gene associated with low serum testosterone level and high-grade prostate cancer. urology. 2005;65:1141-5. 7. thompson i, leach rj, pollock bh, naylor sl. prostate cancer and prostate-specific antigen: the more we know, the less we understand. j natl cancer inst. 2003;95:1027-8. 8. rao a, cramer sd. identification of a polymorphism in the are 1 region of the psa promotor. proc am assoc cancer res. 1999;40:65. 9. xue wm, coetzee ga, ross rk, et al. genetic determinants of serum prostate-specific antigen levels in healthy men from a multiethnic cohort. cancer epidemiol biomarkers prev. 2001;10:575-9. 10. medeiros r, morais a, vasconcelos a, et al. linkage between polymorphisms in the prostate specific antigen are1 gene region, prostate cancer risk, and circulating tumor cells. prostate. 2002;53:88-94. 11. miller sa, dykes dd, polesky hf. a simple salting out procedure for extracting dna from human nucleated cells. nucleic acids res. 1988;16:1215. 12. international union against cancer. urological tumours: prostate. in: hermanek p, sobin lh, eds. tnm classification of malignant tumors. 4 ed. berlin: springer-verlag; 1992:141–4. cellular and molecular urology 699vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l rs266882 polymorphism on prostate cancer risk | samzadeh et al 13. bharaj b, scorilas a, diamandis ep, et al. breast cancer prognostic significance of a single nucleotide polymorphism in the proximal androgen response element of the prostate specific antigen gene promoter. breast cancer res treat. 2000;61:111-9. 14. chiang ch, chen kk, chang ls, hong cj. the impact of polymorphism on prostate specific antigen gene on the risk, tumor volume and pathological stage of prostate cancer. j urol. 2004;171:1529-32. 15. severi g, hayes vm, neufing p, et al. variants in the prostate-specific antigen (psa) gene and prostate cancer risk, survival, and circulating psa. cancer epidemiol biomarkers prev. 2006;15:1142-7. 16. jesser c, mucci l, farmer d, et al. effects of g/a polymorphism, rs266882, in the androgen response element 1 of the psa gene on prostate cancer risk, survival and circulating psa levels. br j cancer. 2008;99:1743-7. 17. kalay e, ergen a, narter f, et al. are-i polymorphism on psa gene in prostate cancer patients of a turkish population. anticancer res. 2009;29:1395-8. 18. wang lz, sato k, tsuchiya n, et al. polymorphisms in prostate-specific antigen (psa) gene, risk of prostate cancer, and serum psa levels in japanese population. cancer lett. 2003;202:53-9. 19. shibahara t, onishi t, franco oe, et al. a g/a polymorphism in the androgen response element 1 of prostate-specific antigen gene correlates with the response to androgen deprivation therapy in japanese population. anticancer res. 2006;26:3365-71. 20. rao a, chang bl, hawkins g, et al. analysis of g/a polymorphism in the androgen response element i of the psa gene and its interactions with the androgen receptor polymorphisms. urology. 2003;61:864-9. 21. penney kl, schumacher fr, kraft p, et al. association of klk3 (psa) genetic variants with prostate cancer risk and psa levels. carcinogenesis. 2011;32:853-9. 22. cicek ms, liu x, casey g, witte js. role of androgen metabolism genes cyp1b1, psa/klk3, and cyp11alpha in prostate cancer risk and aggressiveness. cancer epidemiol biomarkers prev. 2005;14:2173-7. 23. gsur a, preyer m, haidinger g, et al. polymorphic cag repeats in the androgen receptor gene, prostate-specific antigen polymorphism and prostate cancer risk. carcinogenesis. 2002;23:1647-51. 24. binnie mc, alexander fe, heald c, habib fk. polymorphic forms of prostate specific antigen and their interaction with androgen receptor trinucleotide repeats in prostate cancer. prostate. 2005;63:309-15. 25. lai j, kedda ma, hinze k, et al. psa/klk3 arei promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility. carcinogenesis. 2007;28:1032-9. 26. xu j, isaacs sd, sun j, et al. association of prostate cancer risk variants with clinicopathologic characteristics of the disease. clin cancer res. 2008;14:5819-24. 27. cramer sd, sun j, zheng sl, xu j, peehl dm. association of prostate-specific antigen promoter genotype with clinical and histopathologic features of prostate cancer. cancer epidemiol biomarkers prev. 2008;17:2451-7. 28. xue w, irvine ra, yu mc, ross rk, coetzee ga, ingles sa. susceptibility to prostate cancer: interaction between genotypes at the androgen receptor and prostate-specific antigen loci. cancer res. 2000;60:839-41. 29. gunes s, bagci h, sarikaya s, bilen cy, kara n. prostatespecific antigen and 17-hydroxylase polymorphic genotypes in patients with prostate cancer and benign prostatic hyperplasia. dna cell biol. 2007;26:873-8. 30. dos santos rm, de jesus cm, filho jc, trindade jc, de camargo jl, rainho ca. psa and androgen-related gene (ar, cyp17, and cyp19) polymorphisms and the risk of adenocarcinoma at prostate biopsy. dna cell biol. 2008;27:17. 31. salinas ca, austin ma, ostrander eo, stanford jl. polymorphisms in the androgen receptor and the prostatespecific antigen genes and prostate cancer risk. prostate. 2005;65:58-65. 32. mononen n, seppala eh, duggal p, et al. profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors. cancer res. 2006;66:743-7. v08_no_3_final.pdf case report 244 urology journal vol 8 no 3 summer 2011 monophasic primary renal synovial sarcoma accompanied with a hemorrhagic cyst takeshi nishida,1 teruo inamoto,1 hiroshi uehara,1 naokazu ibuki,1 kohei koyama,1 kazumasa komura,1 yutaka fujisue,1 yoshitake kurisu,2 motomu tsuji,2 haruhito azuma,1 yoji katsuoka1 urol j. 2011;8:244-7. www.uj.unrc.ir keywords: synovial sarcoma, kidney neoplasms, cysts, diagnosis 1department of urology, osaka medical college, osaka, japan 2department of pathology, osaka medical college, osaka, japan corresponding author: teruo inamoto, md, phd department of urology, osaka medical college, takatsuki, osaka 569-8686, japan tel: +81 726 831 221 fax: +81726 846 546 e-mail: tinamoto@poh.osaka-med.ac.jp introduction synovial sarcoma is a soft tissue sarcoma with uncertain histogenesis, which is most prevalent in young adolescents. primary synovial sarcoma rarely originates from the renal parenchyma. when this entity occurs, origin of this unusual tumor type has been the subject of discussion in the literature, with a suggestion that some previously reported cases might be more correctly described as renal cell carcinoma with sarcomatoid dedifferentiation. renal synovial sarcoma (rss) and sarcomatoid renal cell carcinoma may be hard to be distinguished only on histopathologic and immunohistochemical examination, but these tumors contain distinctly different sets of chromosomal abnormalities.(1) renal synovial sarcoma produces three types of fusion gene formed in part by ss18 (syt) from chromosome 18 and by ssx1, ssx2 or, rarely, ssx4 from the x chromosome.(1) the syt-ssx fusions do not seem to occur in other tumor types. of 45 cases reported as rss previously, only 29 are available, whose diagnosis was validated by fluorescence in situ hybridization (fish) or reverse transcription polymerase chain reaction, which demonstrated sytssx translocation, a characteristic chromosomal abnormality for synovial sarcoma. hence, proper molecular analysis, in addition to conventional immunohistochemical analysis, should be undertaken to establish a proper diagnosis.(2) we present a case of primary rss validated by fish analysis. case report a 63-year-old woman presented with dysuria and gross hematuria. she had been diagnosed and treated for a presumed hypertension. laboratory study was within normal limit. cystoscopy revealed bleeding from the right ureter. ultrasonography showed a complex renal mass of 5 cm in the greatest dimension. axial contrast-enhanced computed tomography scan demonstrated a 5-cm complex cystic mass that contained mildly thickened septation, along with a slightly contrast-enhancing region (figure 1). no calcification or tumor capsule was observed. on magnetic resonance imaging, the solid components of the tumor showed slightly high signal intensity as the renal medulla on t1-weighted and slightly low signal intensity in t2-weighted primary renal synovial sarcoma—nishida et al 245urology journal vol 8 no 3 summer 2011 images (figure 2). on coronal images using t1weighted fat-saturated technique, the tumor was present on the upper pole of the kidney with pre-operative diagnosis of renal cell carcinoma, stage ct1cn0cm0, the patient underwent a radical nephrectomy. macroscopically, the lateral side of the upper pole of the kidney has been replaced by a multiloculated cystic mass accompanied with a solid component. a massive hematoma, formed by intra-operative bleeding, was seen between the kidney and extra-renal connective tissue (figure 3). on histological examination, spindle cells with dark-staining nuclei and indistinct cytoplasm proliferated densely in the solid component. spindle cells were arranged in bundle, fascicular, or storiform pattern (figure 4). immunohistochemical studies revealed that vimentin was positive for both spindle cells of the solid component and epithelial cells lining cysts. cd99, cd56, bcl2, and focal cytoplasmic staining for c-kit were positive in spindle cells, but negative in epithelial cells. pancytokeratin, cytokeratin-7, cd10, and beta-2 microglobulin were positive in epithelial cells, but negative in spindle cells. given these findings, the cysts were thought figure 1. computed tomography scan showing a right renal tumor (2.5 × 1.5 cm) with multilocular hemorrhagic cysts. enhanced solid component is seen between the cysts on contrast-enhancement. figure 2. on magnetic resonance imaging, cysts in the tumor are shown as low intensity, figure 3. formalin-fixed kidney demonstrating an ill-defined, pale, 2-cm medullary mass with central necrosis (arrow). primary renal synovial sarcoma—nishida et al 246 urology journal vol 8 no 3 summer 2011 to be entrapped dilated renal tubules, but not an epithelial component of biphasic synovial sarcoma; hence, monophasic synovial sarcoma was suspected. result of the fish analysis using a break-apart style probe was consistent with synovial sarcoma (figure 4). after 1-year followup period, this patient is still free of recurrence. discussion primary rss is a rare tumor first described in 1999 and further elaborated upon by two separate studies in 2000.(3) this rare tumor is distinct from other more common forms of sarcoma originating in the kidney. it is difficult for a pathologist to differentiate between synovial sarcoma and congenital mesoblastic nephroma, adults wilms tumor, or clear cell sarcoma of the kidney due to similarities in histological appearance and the absence of specific immunohistochemical markers.(4) no clinical or imaging characteristics can indicate the diagnosis. the clinical symptoms most frequently observed, including abdominal pain and hematuria, do not differ from those present in other malignant renal tumors. the main histologic subtypes of rss are biphasic synovial sarcoma, monophasic spindle synovial sarcoma, and monophasic epithelial synovial sarcoma.(5) when a tumor with epithelial and stromal components is diagnosed as synovial sarcoma in the kidney, the characteristic of epithelial cells should be determined. if the epithelial cells are entrapped renal tubules, the tumor is defined as monophasic synovial sarcoma. (5) if the cells are neoplastic, it is defined as biphasic synovial sarcoma. in the present patient, the epithelial cells are identified as entrapped renal tubules by the following results. epithelial cells indicated positive immunostaining for cd10, beta-2 microglobulin, and antibodies to renal tubules, and negative for n-cam and bcl-2, antibodies often positive in synovial sarcomas. (4,5) therefore, the diagnosis of monophasic synovial sarcoma was established. furthermore, a morphologic transition from epithelial cells to spindle cells, often seen in biphasic synovial sarcomas, was not observed in the present subject. the translocation t(x;18)(p11.2;q11.2) is specific for synovial sarcoma regardless of location or type and grade of differentiation.(5,6) the translocation results in the fusion of the 5’ part of the ss18 gene and the 3’ part of ssx1, ssx2, ssx4 gene, or rarely the splice variant ssx4v.(5,6) polymerase chain reaction testing has greatly aided in confirming the diagnosis of rss by detecting the syt-ssx fusion gene that results from the translocation of the syt gene on chromosome 18 with the ssx gene on the x chromosome.(5,6) a variety of diagnostic methods exist to detect translocation, including cytogenetic analysis, reverse transcription polymerase chain reaction, and fish. various fish methods have been described to allow the visualization of structural chromosomal abnormalities in archival figure 4. results of some fluorescence in situ hybridization experiments: ssx1 in red, ssx2 in violet. (a) distribution of signals in a tetraploid nucleus of the present case carrying a fusion gene. (b) control distribution pattern shown in merged image in yellow. primary renal synovial sarcoma—nishida et al 247urology journal vol 8 no 3 summer 2011 tissue. dual-color break-apart probe fish assays employ probes that flank the translocation breakpoint and are separated by the translocation event, and have been optimized for use on paraffin-embedded tissues. complementary to conventional histopathologic and immunohistochemical analysis, in characterizing the status of the ssx and syt genes, fish study is important in the differential diagnosis when dealing with a renal tumor with epithelial and stromal components. conflict of interest none declared. references 1. tornkvist m, wejde j, ahlen j, brodin b, larsson o. a novel case of synovial sarcoma of the kidney: impact of ss18/ssx analysis of renal hemangiopericytomalike tumors. diagn mol pathol. 2004;13:47-51. 2. chen pc, chang yh, yen cc, pan cc, chiang h. primary renal synovial sarcoma with inferior vena cava and right atrium invasion. int j urol. 2003;10:657-60. 3. perlmutter ae, saunders se, zaslau s, chang ww, farivar-mohseni h. primary synovial sarcoma of the kidney. int j urol. 2005;12:760-2. 4. shao l, hill da, perlman ej. expression of wt-1, bcl-2, and cd34 by primary renal spindle cell tumors in children. pediatr dev pathol. 2004;7:577-82. 5. chen s, bhuiya t, liatsikos en, alexianu md, weiss gh, kahn lb. primary synovial sarcoma of the kidney: a case report with literature review. int j surg pathol. 2001;9:335-9. 6. argani p, faria pa, epstein ji, et al. primary renal synovial sarcoma: molecular and morphologic delineation of an entity previously included among embryonal sarcomas of the kidney. am j surg pathol. 2000;24:1087-96. v08_no_4_final_new.pdf endourology and stone disease 277urology journal vol 8 no 4 autumn 2011 evaluating percutaneous nephrolithotomyinduced kidney damage by measuring urinary farzaneh sharifiaghdas, amir hossein kashi, ramin eshratkhah purpose: to assess percutaneous nephrolithotomy (pcnl)-induced kidney tubular damage and the associated factors. materials and methods: one hundred and eight patients who have undergone pcnl from may 2007 to october 2007 were recruited in this study. urinary level of 2-microglobulin (u 2mg) was measured on the day before the operation as well as on the 1st and 7th post pcnl days. percutaneous nephrolithotomy was performed using standard method. patients’ demographic and peri-operative data were collected to evaluate factors influencing renal injury. results: median urinary levels of 2-microglobulin on pre-operative, 1st, and 7th postoperative days were 0.2 mg/dl (range, 0.1 to 82), 0.4 mg/ dl (range, 0.2 to 97), and 0.2 mg/dl (range, 0.2 to 114), respectively. high levels of u 2mg (> 2.3 mg/dl) were observed in 10 (9%), 20 (19%), and 10 (9%) patients pre-operatively and on the 1st and 7th postoperative days, respectively. in multivariable analysis, u 2mg on the 1st postoperative day was associated with pre-operative serum creatinine level (p < .001) and diabetes mellitus (p = .05), while u 2mg on the 7th day after the operation was associated with pre-operative serum creatinine level (p = .01), diabetes mellitus (p = .01), and pcnl time (p = .02). conclusion: percutaneous nephrolithotomy does not cause kidney tubular injury beyond one week. in patients with pre-operative high serum creatinine concentration, diabetes mellitus, and/or long operation time, the likelihood of the kidney damage is higher than others. urol j. 2011;8:277-82. www.uj.unrc.ir keywords: percutaneous nephrolithotomy, beta 2-microglobulin, acute kidney injury urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran corresponding author: farzaneh sharifiaghdas, md department of urology, shahid labbafinejad medical center, 9th boustan st., pasdaran ave., 16666-94516, tehran, iran tel/fax: +98 21 2258 8016 e-mail: fsharifiaghdas@yahoo.com received march 2011 accepted august 2011 introduction different methods have been used to assess percutaneous nephrolithotomy (pcnl)induced renal injury, including measurement of serum level of creatinine, creatinine clearance,(1,2) and nuclear scans, such as diethylenetriamine pentaacetic acid (dtpa), dimercaptosuccinic acid (dmsa), and mercaptuacetyltriglycine (mag-3). (3-7) these markers demonstrate the changes in glomerular function of the kidneys after the pcnl, on which little work has been done, to the best of our knowledge. previous studies have shown that -2 microglobulin is a more sensitive marker of renal tubular injury in comparison with serum creatinine level. therefore, its measurement has been advocated kidney damage with pcnl—sharifiaghdas et al 278 urology journal vol 8 no 4 autumn 2011 as an early marker of tubular injury.(8-12) furthermore, unlike nuclear scans, concentrations of urinary -2 microglobulin (u 2mg) are not influenced by urinary obstruction.(13) this study was aimed to assess pcnl-induced renal tubular injury by measuring u 2mg. materials and methods this study was carried out on 108 patients with nephrolithiasis who underwent pcnl in labbafinejad medical center in tehran, iran, from may 2007 to october 2007. the reasons for pcnl were as follows: obstructive kidney stones > 2 cm, failed extracorporeal shock wave lithotripsy (swl), kidney stones with distal stenosis, and stones > 1 cm in proximal ureter and failed swl. percutaneous nephrolithotomy was done using standard method. urinary -2 microglobulin was measured preoperatively and on the 1st and 7th postoperative days by an immunoassaykit (mininephtm; the binding site ltd., birmingham, uk). the u 2mg samples on the 1st and 7th postoperative days were collected from the nephrostomy catheter and the voided urine sample, respectively. the normal reference range of u 2mg according to the manufacturer instructions is 0.3 to 2.3 mg/dl. therefore, u 2mg values higher than 2.3 mg/dl were considered abnormal. patients’ demographic, laboratory, and peri-operative data were collected to identify factors correlated with u 2mg changes on postoperative days. statistical analysis the gathered data were analyzed using spss software (the statistical package for the social sciences, version 16.0, spss inc., chicago, illinois, usa). two separate analyses were planned: at first, changes in concentrations of u 2mg on the 1st and 7th postoperative days were compared with pre-operative values. the associations of u 2mg changes with independent categorical and qualitative variables were investigated by mann-whitney u test and spearman correlation coefficient, respectively. the independent variables included age, gender, stone size, hypertension, ischemic heart disease and diabetes mellitus as well as pre-operative hydronephrosis, regional renal cortical atrophy, creatinine level, operation duration, and access numbers. thereafter, significant variables were entered into two analysis of covariance models with dependent variables defined as u 2mg values on days 1 and 7 after the operation. pre-operative u 2mg was used as a covariate to remove its effect. the second analysis was restricted to patients with normal pre-operative serum creatinine level (group n). the associations of high postoperative u 2mg with independent variables were assessed by chi-square or fisher’s exact tests, as appropriate. to obtain odds ratios for significant variables in group n, a logistic regression was used. results patients’ characteristics and peri-operative data are summarized in table 1. stone location was the renal pelvis in 27 (25.0%), lower calyx in 18 (16.6%), lower calyx and pelvis in 18 (16.6%), multiple calyces in 12 (11.1%), upper calyx in 3 (2.7%), staghorn in 22 (20.3%), middle calyx in 3 (2.7%), diverticulum in 2 (1.8%), and proximal ureter in 3 (2.7%) patients. mild, moderate, and severe obstructive hydronephrosis due to the kidney stones were present on pre-operative intravenous pyelography in 18 (16.6%), 59 (54.6%), and 13 (12.0%) patients, respectively. high u 2mg on the pre-operative day, 1st, and 7th postoperative days was found in 10 (9%), 20 (19%), and 10 (9%) patients, respectively. the 20 patients with high u 2mg on the 1st postoperative day included 10 patients with high and 10 with normal pre-operative u 2mg. all these patients had normal u 2mg on the 7th postoperative day, except one patient. in bivariable analysis, u 2mg changes on the 1st day after the operation were associated with access numbers and operation time while on the 7th day, they were correlated with hydronephrosis severity, cortical atrophy, and pre-operative serum creatinine level (table 2). in analysis of covariance, pre-operative serum creatinine level kidney damage with pcnl—sharifiaghdas et al 279urology journal vol 8 no 4 autumn 2011 and diabetes mellitus were statistically significant predictors of u 2mg on the 1st postoperative day (p < .001 and p = .05, respectively), while pre-operative serum creatinine level (p = .01), presence of diabetes mellitus (p =.01), and operation duration (p = .02) were significant predictors of the u 2mg on the 7th postoperative day (table 2). group n included 98 patients with normal pre-operative serum creatinine level. all of these patients had normal pre-operative u 2mg. ten (10%) patients in group n developed high u 2mg on the 1st day while only 1 patient had increased u 2mg levels on the 7th postoperative day. therefore, we did not perform statistical analysis for factors contributing to increased u 2mg on the 7th postoperative day. the factors contributing to high u 2mg on day 1 after the operation in this subgroup of patients with normal pre-operative u 2mg were analyzed (table 3). injury in this subgroup of patients was correlated with operation time and access numbers. on day 1, u 2mg levels significantly increased as operation time exceeded 40 minutes. stone size was neither associated with pre-operative u 2mg nor operation characteristic age (y), mean ± sd 44 ± 15 gender (male/female), n/n 74/34 stone size (mm), mean ± sd 2.6 ± 0.6 pre-operative creatinine (mg/dl), median (range) 1.0 (0.1 to 3.6) pre-operative hemoglobin (g/dl), mean ± sd 14.0 ± 1.3 pre (range) 0.2 (0.12 to 82) history of stone intervention, n (%) swl 37 (34) pcnl 4 (4) open surgery 12 (11) multiple 12 (11) hypertension, n (%) 19 (18) diabetes, n (%) 5 (5) ischemic heart disease, n (%) 7 (7) access numbers, n (%) one 91 (84) two 17 (16) postoperative creatinine (mg/dl), median (range) 1.1 (0.5 to 4.1) hemoglobin drop (g/dl), median (range) 0.8 (0 to 6.1) operation duration (min), median (range) 40 (20 to 120) hospital stay (d), median (range) 4 (1 to 10) (range) 0.4 (0.2 to 97) (range) 0.2 (0.2 to 114) table 1. patients’ characteristics and peri-operative data swl, extracorporeal shock wave lithotripsy; and pcnl, percutaneous nephrolithotomy. variables number /dl day 1 day 7 pre-operative creatinine, mg/dl 98 0.20 (0.20 to 0.23) 0.34 (0.20 to 1.07)† 0.20 (0.20 to 0.21)*† > 1.5 10 13.5 (5.4 to 27.7) 12.5 (6.9 to 62.5)† 14.3 (6.7 to 58.5)*† pre-operative hydronephrosis moderate to severe 72 0.20 (0.20 to 0.29) 0.50 (0.20 to 2.30) 0.20 (0.20 to 0.50)* none to mild 36 0.21 (0.20 to 0.29) 0.37 (0.20 to 1.09) 0.20 (0.20 to 0.20)* cortex thickness normal 53 0.20 (0.20 to 0.27) 0.23 (0.20 to 1.07) 0.20 (0.20 to 0.20)* decreased 55 0.20 (0.20 to 0.40) 0.53 (0.20 to 3.40) 0.20 (0.20 to 0.70)* operation duration, min 20 to 40 57 0.20 (0.20 to 0.27) 0.20 (0.20 to 0.89)* 0.20 (0.20 to 0.22)† 40 to 120 51 0.20 (0.20 to 0.40) 0.86 (0.20 to 6.00)* 0.20 (0.20 to 0.56)† access numbers one 91 0.20 (0.20 to 0.30) 0.34 (0.20 to 1.35)* 0.20 (0.20 to 0.36) two 17 0.20 (0.20 to 0.23) 0.90 (0.28 to 6.15)* 0.20 (0.20 to 0.49) diabetes mellitus yes 5 0.70 (0.20 to 10.90) 2.20 (1.55 to 12.00)† 0.30 (0.20 to 11.50)† no 103 0.20 (0.20 to 0.28) 0.36 (0.20 to 1.40)† 0.20 (0.20 to 0.36)† table 2. demographic and operative factors statistically significant in bivariable analysis between two subgroups of the factor under variables column (p < .05) †statistically significant difference column in the analysis of covariance (p < .05) kidney damage with pcnl—sharifiaghdas et al 280 urology journal vol 8 no 4 autumn 2011 tubular injury in group n. the odds ratios (95% confidence interval) predicting the possibility of high postoperative u 2mg for pre-operative creatinine, pre-operative u 2mg, operation duration, and access numbers were 0.00 (0 to 0.64), 35.80 (1.11 to 11200), 1.07 (1.01 to 1.12), and 18.50 (2.7 to 120.3), respectively. discussion early studies of pcnl that induced injury to the kidneys in animal models reported 1.5± 0.5% anatomic scar with no or minimal longterm functional changes.(2) later human studies showed that this procedure does not result in impaired renal function.(1-3,5-7,14) however, there is the possibility of renal tubular injury after pcnl, but few studies have addressed this issue. understanding the presence and importance of the kidney tubular injury during pcnl can provide further injury through medications or interventions like early re-pcnl. many studies have shown that u 2mg increases in renal tubular injury as an early marker;(8,12) therefore, it has been suggested as a screening tool for diagnosis of such injuries.(10) urinary -2 microglobulin has also been used to measure the kidney tubular injury after swl.(15-17) an important point in using u 2mg as a renal injury assessment tool is its simple, non-invasive measurement, and the convenient serial tracking of its levels.(18) several human studies reported elevation of u 2mg in some conditions, such as obstructive pediatric and fetal uropathies, pediatric reflux disease,(19) heavy metal poisoning,(20,21) kidney trauma,(22) and spinal cord injuries.(23) one human study after pcnl reported increased levels of u 2mg that returned to normal level before one month.(24) the results of this study suggest that preoperative serum creatinine level plays a valuable predictive role in estimating pcnl-induced renal injury as pre-operative serum creatinine levels were correlated with postoperative changes of u 2mg on days 1 and 7. urinary levels of -2 microglobulin remained elevated and usually increased relative to their pre-operative values on the 7th day after the operation. high pre-operative serum creatinine level indicates prior kidney injury due to a chronic inflammatory process initiated by a renal stone.(25) these patients experienced further tubular injury during pcnl and its magnitude judged by u 2mg was higher than patients with normal pre-operative serum creatinine level. characteristic 1 st n = 88 1st day high n = 10 p gender, n (%) nsmale 60 (88) 8 (12) female 28 (93) 2 (7) stone size, cm, n (%) ns27 (90) 3 (10) > 2 61 (90) 7 (10) pre-operative hydronephrosis, n (%) nsnone to mild 33 (92) 3 (8) moderate to severe 55 (89) 7 (11) pre-operative kidney cortex, n (%) nsthin 41 (89) 5 (11) normal 47 (90) 5 (10) operation duration, min, n (%) < .001 20 to 50 66 (99) 1 (1) 51 to 80 20 (74) 7 (26) 81 to 120 2 (50) 2 (50) access numbers, n (%) < .0011 78 (96) 3 (4) 2 10 (59) 7 (41) table 3. st postoperative day ns indicates non-significant. kidney damage with pcnl—sharifiaghdas et al 281urology journal vol 8 no 4 autumn 2011 in addition to pre-operative serum creatinine level, operation time was also associated with u 2mg changes on day 7. operation time may result in more renal injury by factors, such as more prolonged litholapaxy, or indirectly through more complicated operations that prolong both operation duration and renal injuries. in bivariable analysis, access numbers (one or two) were related to u 2mg changes on the 1st day, but not the 7th day. the same relationship was observed in group n. this finding has been previously reported by eshghi and colleagues.(4) in their study on the kidney effects of pcnl measured by nuclear scans several weeks after the operation, no difference was noticed in cases of more than one nephrostomy tract creation compared with one tract creation. increased access numbers can result in transient kidney injury that may be recovered soon. stone size was not a statistically significant predictor of postoperative u 2mg. we think that part of this observation is related to the narrow window of variability in the size of renal stones in this study, 95% of stones were 2 to 3.5 cm. therefore, other factors, including stone composition, location, and caliceal anatomy could play more substantial roles in operation duration and tubular induced injury than stone size. conclusion the findings of this study support the risk of renal tubular injury during pcnl, but shows that this injury may reverse before the 7th postoperative day in most patients. there is a subset of patients with high pre-operative serum creatinine level, presence of diabetes mellitus, or long operation time, in whom pcnl could result in a more prolonged injury. conflict of interest none declared. references 1. webb dr, fitzpatrick jm. percutaneous nephrolithotripsy: a functional and morphological study. j urol. 1985;134:587-91. 2. wilson wt, husmann da, morris js, miller gl, alexander m, preminger gm. a comparison of the bioeffects of four different modes of stone therapy on renal function and morphology. j urol. 1993;150: 1267-70. 3. balbay md, varoglu e, devrim h, et al. quantitative evaluation of renal parenchymal mass with 99mtechnetium dimercapto-succinic acid scintigraphy after nephrolithotomy. j urol. 1997;157:1226-8. 4. eshghi m, schiff rg, smith ad. renal effects of percutaneous stone removal. urology. 1989;33:120-4. 5. kawamura j, itoh h, okada y, et al. preoperative and postoperative cortical function of the kidney with staghorn calculi assessed by 99mtechnetiumdimercaptosuccinic acid renal scintigraphy. j urol. 1983;130:430-3. 6. morey af, nitahara ks, mcaninch jw. modified anatrophic nephrolithotomy for management of staghorn calculi: is renal function preserved? j urol. 1999;162:670-3. 7. schiff rg, lee wj, eshghi m, moskowitz gw, levy lm, smith ad. morphologic and functional changes in the kidney after percutaneous nephrosto-lithotomy. ajr am j roentgenol. 1986;147:283-6. 8. chen jy, lee yl, liu cb. urinary beta 2-microglobulin and n-acetyl-beta-d-glucosaminidase (nag) as early markers of renal tubular dysfunction in sick neonates. j formos med assoc. 1991;90:132-7. 9. chiaramonte c, cigna rm, cataliotti f. [microproteinuria as a marker of renal damage in children]. minerva urol nefrol. 2002;54:237-42. 10. grillenberger a, weninger m, lubec g. determination of urinary low molecular weight proteins for the diagnosis of tubular damage. padiatr padol. 1987;22:229-34. 11. nishida m, kawakatsu h, komatsu h, et al. values for urinary beta 2-microglobulin and n-acetyl-betad-glucosaminidase in normal healthy infants. acta paediatr jpn. 1998;40:424-6. 12. piscator m. early detection of tubular dysfunction. kidney int suppl. 1991;34:s15-7. 13. hall pw, 3rd, ricanati es, vacca cv, chung-park m. renal metabolism of beta 2-microglobulin. experimental animal studies. vox sang. 1980;38: 343-7. 14. chatham jr, dykes te, kennon wg, schwartz bf. effect of percutaneous nephrolithotomy on differential renal function as measured by mercaptoacetyl triglycine nuclear renography. urology. 2002;59:522-5; discussion 5-6. 15. rutz-danielczak a, pupek-musialik d, raszeja-wanic b. effects of extracorporeal shock wave lithotripsy on renal function in patients with kidney stone disease. nephron. 1998;79:162-6. 16. sen s, erdem y, oymak o, et al. effect of extracorporeal shock wave lithotripsy on glomerular and tubular functions. int urol nephrol. 1996;28: 309-13. 17. uozumi j, ueda t, naito s, et al. clinical significance of urinary enzymes and beta 2-microglobulin following kidney damage with pcnl—sharifiaghdas et al 282 urology journal vol 8 no 4 autumn 2011 eswl. int urol nephrol. 1994;26:605-9. 18. portman rj, kissane jm, robson am. use of beta 2 microglobulin to diagnose tubulo-interstitial renal lesions in children. kidney int. 1986;30:91-8. 19. assadi fk. urinary beta 2-microglobulin as a marker for vesicoureteral reflux. pediatr nephrol. 1996;10:642-4. 20. peng sz, zhang cs, hu y, et al. [monitoring indexes for early renal injury in the workers exposed to mercury]. zhonghua lao dong wei sheng zhi ye bing za zhi. 2004;22:122-4. 21. tian l, zhao c, li j, lu x. [changes on certain biochemical indexes for renal injury in workers exposed to lead]. wei sheng yan jiu. 2004;33:343-4. 22. yokota j, sakamoto t, uenishi m, et al. [renal tubular impairment in traumatized patients]. nihon geka gakkai zasshi. 1986;87:1391-7. 23. saito m, kondo a, gotoh m, et al. [serum beta 2-microglobulin in spinal cord injury patients-its efficacy as a screening test of renal function]. hinyokika kiyo. 1987;33:1618-22. 24. yajima i, nishimura t, yoshida k, et al. [influences of percutaneous nephrolithotomy on renal function, an observation using the nag-index and beta 2-microglobulin as indices]. hinyokika kiyo. 1987;33:662-8. 25. pupek-musialik d. [usefulness of determining beta-2-microglobulin in serum and urine in patients with metabolically active kidney calculi and healthy individuals]. pol tyg lek. 1993;48:464-6. 1429vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l department of urology, namik kemal university, tekirdag, turkey. cenk m. yazici, cagri dogan can non-urological doctors play a role in early prostate cancer detection? corresponding author: cenk m. yazici, department of urology, namik kemal university, tekirdag, 59100, turkey. tel: +90 506 855 2687 fax: +90 282 262 4625 e-mail: drcenkyazici@yahoo. com received august 2012 accepted february 2013 purpose:toevaluatetheawarenessofnon-urologicaldoctorsfortheirroleinevaluatingprostate cancer(pca)inscientificmannerwhichmaybeapossibleprobabilityforlatediagnosisofpca. materials and methods:atotalof936non-urologicalspecialistsworkingin1universityand 4educationandresearchhospitalwhowereabletoevaluatemalepatientsover50yearsofage wereincludedtothesurvey.afacetofacequestionnairehadbeenadministeredtoallparticipants. results:atotalof92(9.8%)participantswereevaluatingprostate-specificantigen(psa)level toalltheirelderlymalepatientswhile404(43.2%)participantshadnevermadethisevaluation. amongtheparticipantswhowereevaluatingpsa,nonewasperforminganinformeddecision makingconsultandeventheydidnothaveanyideaaboutthemeaningofthisstrategy.about thecriteriaforurologicalconsultation,56(6%)reportedthattheyconsultalltheirelderlymale patients,whereas880(94%)answeredthattheyperformconsultationiftheirpatientshassought helpforanyurologicalsymptom. conclusion: urologistsmustremindthenon-urologicalspecialiststhattheirapproachestopca evaluationmaychangemortalityratesofthisdiseaseandgivethemproperinformationaboutthe scientificevaluationofpca.thismayhelpustodecreasethemortalityratesofpca. keywords:prostate-specificantigen;earlydetectionofcancer;prostaticneoplasms;physicians; familypractice. urological oncology 1430 | introduction prostatecancer(pca)isthemostimportantcancerofmalepopulation.itwasreportedtobethe4thmostcommoncancerintheworldandmostfrequentsolid tumorineurope.(1)whiletheincidenceoforganconfined pcahasincreased,theincidenceofinvasiveormetastatic pca decreased in the last 2 decades. despite this decrease incidenceof invasiveness,cancerspecificmortalityrates of pca did not decline with the same proportion.(2) pca hasstillbeentheleadingcauseofnewcancercasesand thesecondleadingcauseofcancerdeathsamongmalesin unitedstates.(3)theinventionofprostatespecificantigen (psa)wasacornerstonefordiagnosisofpca.(4)asitgave theopportunityforearlydetectionofpca,ithadbeenwidely acceptedallaroundtheworld.severalscreeningprograms hadbeendefinedtoprovideearlydetectionofpca.butthis programsalsocausedargumentsaboutover-diagnosisand over-treatmentsforpatientswithincidentalpca.twomajor trialsevaluatingtheeffectofscreeningpcareporteddifferent results.whileeuropeanrandomizedstudyofscreeningfor prostatecancer(erspc)studyreportedabeneficialeffect ofscreeningonmortalityrates,prostate,lung,colorectal andovarian(plco)studyfailedtodocumentthisrelation. (5,6)whether,screeninghasscientificmannerornot,psahas stillbeenthemostreliableandfavorabletumormarkerfordiagnosisofpcaanditisrecommendedtoperformpsaevaluationtomalepatientsover50yearsofageafteradecision makingconsult.(7)anydelayinperformingpsatoelderly patientsmaycausethediseaseprogresstoincurablestages. inmostdevelopedcountries,generalpractitioners(gps)and familydoctorsarethemainphysiciansthathavefirstcontact withthemajorityofpatients.theirviewforpcaevaluationis thoughttobeveryimportantsoseveralstudiesinvestigated this issue.(8,9)but,therearealsosomecountriesthatother specialistsmaybetheprimarydoctorofpatients.so,those non-urologicalspecialistsmaybethefirstdoctorsthathave theopportunity tocontactwithpatientsandevaluatepca. accordingtoourknowledge,thereisnostudydefiningthe viewofnon-urologicalspecialistinevaluationofpca.inthis study,weaimedtoevaluatetheawarenessofnon-urological doctorsfortheevaluationofpcaintheirdailyworklife. materials and methods atotalof936non-urologicalspecialistsworkingin1universityand4educationandresearchhospital,whowereable toevaluatemalepatientsover50yearsofagewereincluded tothesurvey.specialtiesthatdonotgetcontactwithelderly malepatients, likepediatrician,pediatricsurgeon,radiologistandobstetricsandgynecologistwereexcludedfromthe survey.allotherspecialtieswereincludedtothestudy.the numbersofparticipantsaccordingtotheirspecialtieswere shownintable.alloftheparticipantswereactivelyworkingatoutpatientclinicsoftheirspecialties.afterthepermissionoflocalethiccommittee,afacetofacequestionnaire includingawrittenconsenthadbeenadministeredtoallparticipants.thequestionnairewascomposedof4parts(appendix);1)questionsaboutthedemographiccharacteristics ofparticipants,2)questionsabouttheparticipants’approach forthediagnosisofpcaintheirdailyworklifesuchaspsa evaluation and rectal examination, 3) questions about the generalknowledgeofparticipantsaboutthenormalvalues oftotalpsa,and4)questionsabouttheparticipants’preferencesforurologicalconsultationsandfamilyhistory.asthis wasaquestionnairestudy,resultsweregiveninpercentages withoutaneedofanystatisticalanalysis. results allofthedoctorswereagreedtoparticipateinthestudy. among the participants, 536 (57.3%) were male and 400 (42.7%)werefemale.theparticipantswereevaluating92± 32malepatientsover50yearsofageinonemonth.when weaskedthefrequencyofpsaevaluation,404(43.2%)participantstoldthattheyneverevaluatethismarkerfortheir elderlypatients.amongtherestoftheparticipants,only92 (9.8%)informedthattheyroutinelyevaluatepsafortheir patientsover50yearsofage.atotalof312(33.3%)participantsdeclaredthattheywereanalyzingthismarkeratless thanhalfoftheirpatientswhereas128(13.7%)wereanalyzingatmorethanhalfoftheirelderlypatients(figure,a). therewasafemalepredominance(73.9%)atthegroupwho wereevaluatingpsaattheirwholeelderlypatientsandmale predominance(77.2%)atthegroupwhowereneverevaluatingpsa.amongtheparticipantswhowereevaluatingpsa, nonewasperforminganinformeddecisionmakingconsult fortheevaluationofpcaandeventheydidnothaveanyidea aboutthemeaningofthisstrategy. tothequestionrelatedtoabnormalvalueoftotalpsa,36 (1.7%)participantsansweredthattheyconsideritasabnormalifpsa>1ng/dl,168(17.9%)ifpsa>2.5ng/dl,396 urological oncology 1431vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l non-urological doctors and prostate cancer detectıon | yazici et al (42.4%)ifpsa>4ng/dl,144(15.4%)ifpsa>10ng/dl and84(9%)ifpsa>20ng/dl.atotalof128(13.6%)participantsreportedthattheyhavenoideaaboutthenormal valuesoftotalpsa(figure,b).concerningthephysicalexamination,816(87.2%)participantsreportedthattheydonot dodigitalrectalexamination(dre)ontheirroutinephysical examinationwhereas120(12.8%)toldthattheydoitroutinely.amongtheparticipantswhoperformdre,64were generalsurgeonand56wereinternist.whenweaskedthe reasonofnon-performingdre,680(83.3%)repliedthatit wasuselessfortheirspecialty. whenweaskedtheparticipantsabouttheircriteriaforconsultingtheirelderlymalepatientswithurologist,56(6.0%)reportedthattheyconsultalltheirelderlymalepatients,whereas880 (94.0%)answeredthattheyseekconsultationiftheirpatients hastalkedaboutanyurologicalsymptom.inordertoestimate theeffectofthelowerurinarytractsymptomsonpsaevaluation,weasked“doesthepresenceoflowerurinarytractsymptomschangeyourdecisionabouttheevaluationoftotalpsa”? amongtheparticipantswhoneverevaluatepsa,396(98%) told that it does not change their decision. aswethoughtthattheevaluationofpcamaynotbetheresponsibilityofnon-urologicaldoctors,wetriedtodemonstratetheapproachofparticipantstopcaintheirdailylife andaskedquestionsabouttheirfathers.atotalof52(5.5%) participants’fathersweredeadatthetimeofstudyand3of themhadahistoryofpca.oneoftheparticipant’sfathers was dead because of end-organ failure due to metastatic pca.whenwecheckedtheapproachoftheseparticipants, whohadafamilyhistoryofpca,wefoundthattheyallwere consultingtheirelderlymalepatientstourologists.among therestoftheparticipants,828(93.6%)hadafatherover 50yearsofage.whenweaskedthemiftheyperformedany psaevaluationtotheirfathers,244(29.5%)repliedthatthey hadneverperformedpsaevaluationwhereas396(47.8%) hadthisevaluationinevery4or5yearsand188(22.7%)had thisevaluationannually(figure,c). discussion pcahasstillbeenanimportantcauseofcancerrelateddeaths amongthemalepatients.althoughtheincidenceoforgan confinedpcahadincreasedinthelast2decades,diseasespecificmortalityratesdidnotdecreasewiththesimilarproportion.therearestillplentyofpatientswhohadbeendiagnosed atinvasiveormetastaticstageandlosetheirchancefordefinitivetreatment.(2)so,earlydiagnosisofpcaisveryimportanttodecreasethecancerrelatedmortalityrates.although therehavebeendebatesaboutthesensitivityandspecificity ofpsaforpcascreening,ithasstillbeenthemostreliable andusefultumormarkerfordiagnosisofpca.(5,6) when it is combinedwithdigitalrectalexamination,itssensitivityand specificityfordiagnosingpcaincreases.(10) afterthepublicationof2majorrandomizedtrials(erspc andplcotrials),screeningprotocolsforpcabecameacontroversialissue.(5,6)generalideaformedaboutthissubject istoperformpsaevaluationwiththedecisionofpatients after an informed decision making consult. on the other hand,thereislittleevidenceabouthowtoorganizeservices toachievethebestinformeddecision.indevelopedcountries withawell-accomplishedhealthpolicy,generalpractitioners andfamilydoctorsaretheprimarydoctorsthatgetcontact withalargeproportionofthepopulationandcouldplayan importantroleininformeddecisionmakingconsult,butthere arealsosomecountriesthatnon-urologicalspecialistsother thangpsandfamilydoctorscouldbethemaindoctorthat getfirstcontactwithpatients.so,theycouldassumearolein preventiveeffortofpca.forthisreason,non-urologicaldoctorsmustbeawareofoneofthemostimportantcancertype ofelderlymalepatientsandunderstandtheirpossiblerolein figure. the ratios of general answers to the questionnaire. 1432 | thecampaignagainstthiscancer. therearesomestudiesevaluatingtheviewofgpsandfamilydoctorstopcaevaluationandscreening.meliaandcolleaguesreportedthatannualpsatestingratioamonggpsin englandwas6%insymptomaticand2%inasymptomatic elderly male patients.(11) on the other hand, hudson and colleagues reported much higher ratios (77%) of evaluatingpsaamongamericangps.(3)thesetwostudiesfrom differentcountrieswithdifferentresultsreportedthesimilarconclusionthatinformeddecisionmakinghasyettobe incorporatedasaroutinepartofprimarycarepractice.we alsoagreewiththisconclusionandwethinkthat,notonly gpsandfamilydoctorstakeroleininformeddecisionmaking consult about pca, non-urological specialist may also haveroleinthisissue.forthisreason,evaluatingtheviewof non-urologicalspecialisttopcamaybeimportantforstrategyplanningagainstthismortaldisease.accordingtoour knowledgethisisthefirststudyinliteratureevaluatingthe viewofnon-urologicalspecialisttoevaluationofpca. inourstudy,only9.8%ofnon-urologicalspecialistsreported thattheydopsaevaluationtoalloftheirelderlymalepatients,whereas43%ofparticipantsreportedthattheynever performthisevaluation.besidethis,94%ofparticipantsdeclaredthattheydon’tseekanyurologicalconsultationfor theirelderlymalepatientsunlesspatientshavetalkedabout theirurologicalsymptoms.asnoneofourparticipantswas talkingabouttherisksofpcatotheirelderlypatients,they werenottakinganyroleininformeddecisionmakingconsult forpcaevaluation.evenifwethinkthatthesepatientsdo nothaveanyurologicalsymptomanddidnotvisitanurologist,thesedoctorswillbetheonlyopportunityforpatients forearlydetectionofpca.theirapproachtothesepatients maycauseadelayindiagnosisofpcaandmayletthedisease progress to an incurable stage. digitalrectalexaminationisonepartofthemainurologicalexamination.inabout18%ofpatientswithpcacanbe detectedbyanabnormaldre,irrespectiveofpsalevel.(12) forthisreason,dreisveryimportantfordiagnosisofpca. urologistsarenottheonlyspecialiststhatperformdrein theirdailypractice.generalsurgeonsandinternalmedicine doctoralsoperformdrenormallyintheirdailypractice. accordingtoourstudy,nearly80%ofinternalmedicinedoctorsand35%ofgeneralsurgeonswerenotperformingdre. besidethis,87%ofspecialistsinourstudypopulationwere notperformingdre.indeed,dreisnotaroutineexaminationforsomespecialties,buttobeawareoftheimportance ofthisexaminationmayhelptoguidethepatientforbasic pcascreening.urologistsmayprovidethisbyclosecontact withtheircolleaguesinformingthemabouttheimportance ofdre. nearlyallparticipantstoldthat,evaluationofpcawasnot theresponsibilityofnon-urologicaldoctors.thismaybean explanationforthemnottoevaluatepsafortheirelderly patients.ontheotherhand,nearly70%ofourparticipants reportedthattheyperformedpsaevaluationfortheirfathers. thisdatashowsthatourparticipantsweremostlyawareof theimportanceofpca,buttheydonotpayattentiontothis subjectintheirdailyworklife.urologistsmustbeawareof thisfactandencouragethenon-urologicaldoctorsfordecisionmakingconsultforpcadiagnosisorconsultingtheirelderlypatientstourologistsforevaluationofpca. inordertoaccomplishthispurposewemustexplainthenonurologicaldoctorsthat,theymayhaveopportunitytoseeelderlymalepatientsthathadneverbeenseenbyanurologist. table. the number of participants according to specialties. specialty number specialty number emergency medicine 12 family medicine 44 neurosurgery 24 internal medicine 240 dermatology 36 physical rehabilitation 28 general surgery 92 ophthalmology 92 cardiology 64 otolaryngology 96 neurology 76 plastic surgery 32 psychiatry 32 orthopedics 28 cardiovascular surgery 20 thoracic surgery 20 total number 936 urological oncology 1433vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l soanon-urologicalspecialistmaybetheonlydoctorthatis abletoreachandevaluatethosepatientsandthesevisitsmay beveryimportanttoeliminatethedoctorrelateddelayon thediagnosisofpca.forthispurpose,non-urologicaldoctorsmustbeawareofoneofthemostcommoncancertype ofelderlymalepatientsandunderstandtheirpossiblerolefor earlydetectionofpca.thisrolecanbeachievedbyasimple psadeterminationafterabriefinformeddecisionmaking consultatpatientswhodidnothaveanyurologicalevaluation. thereweresomelimitationsinpresentstudy.firstofall, thiswasaquestionnairebasedstudyperformedtoalimited numberofnon-urologicaldoctorsandmaynotbeenough togeneralizetoallnon-urologicaldoctors.besidethis,we werenotabletoreachpastmedicalrecordstoconfirmthe ratesofpsaevaluationofparticipants.wealsodidnothave anyideaaboutthenumberofpatientswhowereevaluatedby non-urologicaldoctorsbuthadnotevaluatedbyurologists. sowecannotidentifythepossiblepcariskofelderlypatients whowereseenbynon-urologicalpatients.ourstudywasdesignedonatheorythatnon-urologicaldoctorsdonotevaluateandinformtheirelderlypatientsaboutpca.thisstudy mayshowtherelationbutmaynotbeenoughtoprovethis theoryandmorecomprehensivestudiesareneeded.another issueaboutthissubjectis;weevaluatedthenon-urological doctorswhoworkinteachingoruniversityhospitals.these findingsmaynotreflecttherealpracticeinperipheralhealth units,butthereisanotherfactthatpcamortalityratesdidnot decrease although the diagnosis rates increased by the last 2decades.thisshowsthatthereisstillaprobleminearly detectionofpca. conclusion asaconclusion,campaignsagainstimportantdiseasesneed ateamworkincludingdoctors,healthpersonalsandmedia. wemustrememberthatnon-urologicaldoctorsarethemembersoftheteamagainstpca.wemustremindthemthattheir approachestopcaevaluationmaychangemortalityratesof thisdiseaseandgivethemproperinformationaboutthescientificevaluationofpca.thismayhelpustodecreasethe mortalityratesofpca. conflict of interest none declared. non-urological doctors and prostate cancer detectıon | yazici et al references 1. boyle p, ferlay c. cancer incidence and mortality in europe 2004. ann oncol. 2005;16:481-8. 2. quinn m, babb p. patterns and trends in prostate cancer incidence, survival, prevalence and mortality. part i: international comparisons. br j urol int. 2002;90:162-73. 3. hudson sv, ohman-strickland p, ferrante jm, lu-yao g, orzano aj, crabtree bf. prostate-specific antigen testing among the elderly in community-based family medicine practices. j am board fam med. 2009;22:257-65. 4. stamey ta, yang n, hay ar, mcneal je, freiha fs, redwine e. prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. n engl j med. 1987;317:909-16. 5. andriole gl, crawford ed, grubb rl et al. plco project team. mortality results from a randomized prostate-cancer screening trial. n engl j med. 2009;360:1797. 6. schröder fh, hugosson j, roobol mj, et al. erspc investigators. screening and prostate-cancer mortality in a randomized european study. n engl j med. 2009;360:1320-8. 7. de la rosette j, alivizatos g, madersbacher s, et al. eau guidelines on benign prostatic hyperplasia 2006. p. 13-14. 8. melia j, moss s. survey of the rate of psa testing in general practice. br j cancer. 2001;85:656-7. 9. williams n, hughes lj, turner el, et al. prostate-specific antigen testing rates remain low in uk general practice: a cross-sectional study in six english cities. bju int. 2011;108:1402-8. 10. catalona wj, richie jp, ahmann fr, et al. comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. j urol. 1994;151:1283-90. 11. melia j, moss s, johns l. contributors in the participating laboratories. rates of prostate-specific antigen testing in general practice in england and wales in asymptomatic and symptomatic patients: a cross-sectional study. bju int. 2004;94:51-6. 12. richie jp, catalona wj, ahmann fr, et al. effect of patient age on early detection of prostate cancer with serum prostate-specific antigen and digital rectal examination. urology. 1993;42:365-74. 1434 | appendix. questionnaire for evaluation of the view of non-urological doctors to prostate cancer. gender: female□ male□ specialty: 1.howmanymalepatientsover50yearsofagedoyouevaluateinamonthperiodatyouroutpatientclinic? 2.howfrequentdoyouevaluatetotalpsalevelofyourpatientsover50yearsofage? a.none(idonotevaluatetotalpsa) b.<50%patients c.50%patients d. all patients 3.doyouhaveanyideaaboutinformeddecisionmakingfor psascreening? a.yes(pleasespecifywhatdoesitmeanforyou)? b. no, i did not hear about it. 4.ifyouareevaluatingtotalpsa,doyougiveanyinformationaboutprostatecancerandpossiblerisksofscreening totalpsa? a.yes,iinformallmypatients. b.yes,iinformsomeofmypatients. c.no,idonotgiveanyinformation. 5.(fortheparticipantwhoreplied“none”tothefirstquestion).does thepresenceof lowerurinary tractsymptoms changeyourdecisionforevaluatingtotalpsalevel? a.yes b. no 6.whichtotalpsaleveldoyouconsidertobeabnormaland consulttoanurologist? a.psa>1ng/dl b.psa>2.5ng/dl c.psa>4ng/dl d.psa>10ng/dl e.psa>20ng/dl f.idonothaveanyidea. 7.doyouperformdigitalrectalexaminationtoyourmale patientsover50yearsofageinyourdailypractice? a.yesiperformthisexaminationroutinely. b.sometimes(pleasespecify). c.no,ineverperformthisexamination. 8.ifyoudonotperformdigitalrectalexamination,would youpleasespecifythereason? 9.doyouconsiderseekingaurologicalconsultationforyour malepatientsover50yearsofage? a.yes,iconsultallmalepatientsover50yearsofage. b.iconsultmalepatientsover50yearsofageinsomeconsiderations(pleasespecify). c.no,ineverconsultmalepatientsover50yearsofage. 10.whatistheageofyourfather?(ifyourfatherisdead pleasenotethereason). 11.didyouperformtotalpsaevaluationtoyourfather? a.no,ididnotmaketotalpsaevaluationtomyfather. b.yes,idototalpsaevaluationeveryyear. c.yes,idototalpsaevaluationinevery_______years. thankyouforyourkindparticipation. urological oncology sexual dysfunction and infertility 28 urology journal vol 4 no 1 winter 2007 erectile dysfunction and coronary artery disease—foroutan et al urology journal vol 4 no 1 winter 2007 29 erectile dysfunction in men with angiographically documented coronary artery disease seyed kazem foroutan,1 mohammadreza rajabi2 introduction: we evaluated erectile function of men with coronary artery disease (cad) and the relation between the degree of erectile dysfunction (ed) and the extent of coronary artery stenosis on cardiac angiography. materials and methods: nondiabetic men with cad documented by angiography were evaluated for ed. erectile function was assessed by a 5-item version of the international index of erectile dysfunction, the sexual health inventory for men (shim). results: of 401 men, 186 (46.4%) had ed (shim score, 21 or less). men with ed were more likely to have more than 1 stenotic cardiac vessel (p < .001). the mean shim score was 20.9 ± 7.6, 12.9 ± 9.2, and 14.3 ± 9.1 for men with 1-, 2, and 3-vessel disease, respectively (p < .001). multivariate analysis showed that only the shim score had a relationship with the number of involved vessels (p < .001); the shim score was lower and ed was more frequent in men with more than 1 vessel involvement. forty-one patients (19.1%) without ed and 45 (24.2%) with ed had a positive history of myocardial infarction (p = .21). symptoms of ed had appeared prior to cad detection in 78 out of 189 patients (41.9%) with a mean time interval of about 23 months (range, 10 to 36 months). conclusion: our finding showed that the prevalence of ed is relatively high in patients with cad, and has a relationship with the extent of cad. furthermore, ed may occur before cad with an average interval of 2 years. urol j (tehran). 2007;4:28-32. www.uj.unrc.ir keywords: erectile dysfunction, coronary artery disease, vascular diseases, myocardial infarction, cardiac catheterization 1department of urology, mostafa khomeini hospital, shahed university, tehran, iran 2department of cardiology, mostafa khomeini hospital, shahed university, tehran, iran corresponding author: seyed kazem foroutan, md address: department of urology, mostafa khomeini hospital, shahed university, tehran, iran tel: +98 21 8896 3122 fax: +98 21 8896 3122 e-mail: skf356@ yahoo.com received october 2005 accepted february 2006 introduction erectile dysfunction (ed) is a common medical problem affecting approximately 15% of men each year.(1) it is strongly related to both physical and psychological health status. some major risk factors are diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking, all of which are the risk factors of coronary artery disease (cad), too.(2) despite its increasing prevalence among older men, ed is rarely due to age-related hypogonadism, and a vascular disorder is present in the majority of the patients.(3) the association between vascular disease and ed has been recognized and well documented.(2-5) indeed, alternation in the vascular hemodynamics (either arterial insufficiency or venoocclusive dysfunction) is believed to be the most common cause of organic ed.(1) therefore, ed can be a manifestation of a vascular disease that affects penile arteries and also other vessels such as coronary arteries.(3) this explains the higher incidence of ed among patients with vascular diseases such as mi, cerebrovascular accident, peripheral vascular disease, and hypertension compared to the general population. recent studies have sexual dysfunction and infertility 28 urology journal vol 4 no 1 winter 2007 erectile dysfunction and coronary artery disease—foroutan et al urology journal vol 4 no 1 winter 2007 29 shown that ed is present in 42% to 75% of men with cad.(2,4,6) it is speculated that ed manifests prior to cad and consequently, it can be an index of subclinical cad.(7) it has been shown that a considerable number of men with ed have a silent cad,(4) and the degree of ed has a relationship with the severity of cad.(5,8) however, since ed is a common disease among middle-aged men, it is not rational to always intensively investigate cad in these patients or to consider them as high risk for cad, yet. further evidence is required to correlate ed and its degree with different stages of cad. in this study, we evaluated ed in men with angiographically documented cad and investigated the extension of coronary artery involvement in relation to the degree of ed. materials and methods in a cross-sectional study performed between june 2004 and april 2006, we evaluated men who were referred for angiography to shaheed mostafa khomeini and shaheed rajaei hospitals in tehran. all men with cad confirmed by angiography were enrolled. significant cad was defined as at least 50% reduction of the luminal diameter of any of the coronary arteries or their major branches.(4) the enrolled patients were interviewed and underwent physical examination. laboratory study for hormonal profile was done in case of decreased libido or testicular atrophy. men with hormonal, anatomic, neurogenic, or psychologic ed were excluded from this study. other exclusion criteria were age of less than 40 years, inactive sexual function, ejection fraction less than 40%, valvular heart disease, myocardial infarction (mi) within the past 2 weeks, history of trauma to the pelvis, perineum, genitalia, or spinal cord, history of colorectal surgery, radical prostatectomy, or orchidectomy, urinary incontinence, diabetes mellitus, chronic kidney disease, constant administration of drugs that impact erectile function (antihypertensive, antiandrogen, estrogens, digitals, alcohol, narcotic), and history of pelvic radiotherapy. a written informed consent was signed by all eligible patients. this study was approved by the ethics committee of shahed university. erectile function was assessed by a 5-item version of the international index of erectile dysfunction (iief), the sexual health inventory for men (shim).(9) according to the shim scores patients were diagnosed with mild (score, 17 to 21), mild to moderate (11 to 16), moderate (8 to 10), and severe (7 or less) ed. shim in detail available from: http://www.uj.unrc.ir see the electronic version of article in addition, the patients’ sociodemographic and clinical data were collected including age, weight, height, education, cigarette smoking, history of unstable angina and mi, hyperlipidemia, and duration of ed and cardiac symptoms. comparisons between the groups were done by chisquare, student t, and one-way anova tests, where appropriate. correlations were assessed by pearson and spearmen correlation tests. the binary logistic regression analysis was used to evaluate the relation of ed and classical risk factors of cad with the extent of coronary artery stenosis. a value for p less than .05 was considered significant. results the clinical and demographic characteristics of the patients are shown in table 1. of 401 men aged between 40 and 84 years, 186 (46.4%) had ed (shim score, 21 or less). the frequency of ed was higher in heavy smokers (p = .002), older patients (p = .01), and those with hyperlipidemia (p = .03). however, the shim score correlated only with age (r = .15; p = .002). table 2 demonstrates the degree of ed based on shim scores in relation to the angiography results. men with ed were more likely to have more than 1 stenotic vessel and the number of involved coronary arteries correlated with the shim score (r = .31; p < .001). the mean shim score was 20.9 ± 7.6, 12.9 ± 9.2, and 14.3 ± 9.1 for men with 1-, 2-, and 3-vessel disease, respectively (p < .001; figure 1). other than ed, the level of education (r = .10; p = .047) and cigarette smoking (r = .12; p = .02) were associated with the number of the stenotic vessels. using binary logistic regression, only the shim score was associated with the number of involved vessels; the shim score was lower in men with more than 1 vessel involvement (p < .001). concerning ed erectile dysfunction and coronary artery disease—foroutan et al 30 urology journal vol 4 no 1 winter 2007 erectile dysfunction and coronary artery disease—foroutan et al urology journal vol 4 no 1 winter 2007 31 (shim score, 21 or less), the same association was present (p < .001); however, the shim score was not associated with the number of involved vessels when only men with ed were considered (p = .10). furthermore, 41 patients (19.1%) without ed and 45 (24.2%) with ed had a positive history of mi (p = .21). symptoms of ed had appeared prior to cad detection in 78 out of 189 patients (41.9%) with a mean time interval of about 23 months (range, 10 to 36 months). however, there was no significant relationship between length of time interval from ed to cad onset and the number of involved vessels. discussion in the present study, we evaluated men with established cad confirmed by angiography and found ed in nearly half of them. this rate is significantly higher than that in the general male population in iran. safarinejad has studied 2674 iranian men aged 20 to 70 years and found that 18.8% of men interviewed reported ed.(10) using the 5-item version of iief (shim), the degree of ed *values are means ± standard deviations, or otherwise, numbers (percents). ed indicates erectile dysfunction and cad, coronary artery disease. table 1. clinical and sociodemographic characterizations of men with cad* characteristics values mean age, y 53.3 ± 10.7 mean weight, kg 74.3 ± 12.8 mean height, cm 168.9 ± 7.2 mean bmi, kg/m2 26.0 ± 4.1 education level illiterate 59 (14.7) under high school degree 273 (68.1) high school degree 32 (8.0) bachelor�s degree 25 (6.2) higher degrees 12 (2.9) cigarette smoking, pack-y 0 208 (51.9) < 10 47 (11.7) 10 to 20 41 (10.2) > 20 105 (26.2) hyperlipidemia positive 63 (34.1) negative 122 (65.9) cad history myocardial infarction 86 (21.4) unstable angina 315 (78.6) mean duration of cad, mon 17.2 ± 29.7 mean ejection fraction, % 54.8 ± 7.38 stenotic coronary vessels 1 166 (41.4) 2 120 (29.9) 3 115 (28.7) mean shim score 16.6 ± 9.3 ed degree no ed 215 (53.6) mild 6 (1.5) mild to moderate 15 (3.7) moderate 36 (9.0) severe 129 (32.2) mean duration of ed, mon 23.6 ± 33.7 table 2. degree of ed based on shim scores in relation to angiography results* *values in parentheses are percents. ed indicates erectile dysfunction and shim, sexual health inventory for men. number of coronary arteries with stenosis ed 1 2 3 no 127 (76.5) 42 (35.0) 46 (40.0) mild 4 (2.4) 2 (1.7) 0 mild to moderate 2 (2.2) 2 (1.7) 11 (9.6) moderate 8 (4.8) 14 (11.7) 14 (12.2) severe 25 (15.1) 60 (50.0) 44 (38.3) the shim scores in men with 1, 2, and 3 vessels involved with coronary artery disease. shim indicates sexual health inventory for men. erectile dysfunction and coronary artery disease—foroutan et al 30 urology journal vol 4 no 1 winter 2007 erectile dysfunction and coronary artery disease—foroutan et al urology journal vol 4 no 1 winter 2007 31 was determined in our patients, which was associated with the number of stenotic vessels according to angiography. however, this finding was diminished when only men with ed were considered. the final analysis was indicative of 2vessel or 3-vessel disease in men with ed. the link between ed and cad has now been well established.(2,3,10) it was shown that in the iranian male population, history of diabetes, hypertension, smoking, peripheral vascular disorders, hypercholesterolemia, and coronary artery disease (odds ratio, 1.61; 95% confidence interval, 1.21 to 2.85) were significantly associated with ed.(10) in a prospective study by vlachopoulos and colleagues, of 50 men with organic ed, 12 had a positive noninvasive test for cad and 1 developed mi. they performed cardiac angiography in 10 that showed coronary vessel involvement in 9 of them.(4) the degree of ed was studied by solomon and colleagues.(8) they found that the iief score of men with angiographically confirmed cad correlated with their atherosclerotic disease burden. in a study on 40 patients who underwent coronary angiography, a statistically significant correlation was found between erectile function and the number of involved coronary vessels. patients with 1-vessel disease had a more effective erection with fewer difficulties in achieving an erection than men with 2-vessel or 3-vessel disease.(5) however, in another study on 300 patients, the clinical and angiographic characteristics were not different in regard to erectile function.(6) although men with ed had a more extensive cad (multivessel disease), our study failed to depict a correlation between the degree of ed and the clinical severity of cad. patients in our study were those with an established heart disease. besides, ed was mostly severe in our cases (129 out of 186). accordingly, it can be assumed that patients with milder forms of ed might have had asymptomatic or mild cad and did not need to undergo angiography. thus, our findings do not necessarily oppose the hypothesis of a linear correlation between ed and cad degrees. most investigators suggest that patients with ed should undergo further cardiovascular evaluation to detect asymptomatic cad.(2,4) however, montrosi and colleagues dispute this approach as ed is a very common disease and a systematic cardiologic screening would not be cost effective.(3) thus, ed may not be a valuable predictor of ischemic heart disease. whereas, the presence of ed, as our data supported, can be indicative a more extensive cad in patients with symptomatic cardiac disease, warranting invasive studies such cardiac angiography. recently, a hypothesis of “artery size” is proposed by montsori and colleagues,(7) suggesting a temporal relationship of ed and cad. they consider these two disorders as two different aspects of a same disease. in the presence of a series of risk factors, a vascular disease affects the endothelium of the arteries. since the coronary arteries are larger vessels than the penile ones, they better tolerate the resultant stenosis and thus, ed develops prior to cad. in contrast, more than half of the patients in this series mentioned the onset of ed to be simultaneous or after the start of cad manifestations. in line with our study, solomon and colleagues found that 58% of men with established ischemic heart disease had experiences ed before the diagnosis of cad.(8) there might be other factors that influence different vessels separately. the artery size theory comes mostly from retrospective data and needs to be tested in a large-scale prospective study evaluating ed and cad. an interesting finding in our study was that despite the association of erectile function with the extent of coronary artery stenosis, the frequency of previous mi was not higher in men with ed than those without ed. this is in agreement with the studies that demonstrated nearly 70% of mis occur in cases with uncritical coronary stenosis (less than 50%).(11) coronary artery disease causes a clinical spectrum including silent ischemia, chronic angina pectoris, mi, ischemic cardiomyopathy, and sudden cardiac death. although the same pathophysiology plays a role in ed and cad, not all the manifestations of cad are in association with ed. this emphasizes the role of other mechanisms other than the obstruction of the coronary vessels involved in progression of clinical cad that can make it different from ed. some limitations in our study need to be addressed. anatomical and functional evaluation of penile circulation through ultrasonography evaluation and dynamic doppler test were not systematically carried out in this patient population. coronary angiography was considered as the gold standard technique to erectile dysfunction and coronary artery disease—foroutan et al 32 urology journal vol 4 no 1 winter 2007 detect cad. however, this technique detects only changes in the artery lumen and not the true plaque volume extension. thus, in patients with uniform lumen artery reduction, small vessel disease, or plaque with positive remodeling change, angiography results will be normal despite a significant atherosclerotic burden. coronary intravascular ultrasonography represents a more appropriate technique for cad even at early stages. the important goal of this study was to explore the association between cad and ed; therefore, factors such as ejection fraction and heart failure, or diabetes mellitus, that influence sexual function and perfect erection on many ways, were excluded. conclusion the key findings of this study were as follows: first, ed rate significantly differs among the patients with established cad according to coronary clinical presentation and atherosclerosis burden. second, the ed severity, but not ed prevalence is related to the extent of cad. third, the ed symptoms come prior to cad symptoms in about half of the patients with ed. acknowledgement we would like to appreciate drs a panahi, m hashemizadeh, and f zaeri’s kind collaboration. conflict of interest none declared. references 1. johannes cb, araujo ab, feldman ha, derby ca, kleinman kp, mckinlay jb. incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the massachusetts male aging study. j urol. 2000;163:460-3. 2. borgquist r, gudmundsson p, winter r, nilsson p, willenheimer r. erectile dysfunction in healthy subjects predicts reduced coronary flow velocity reserve. int j cardiol. 2006;112:166-70. 3. montorsi p, ravagnani pm, galli s, et al. association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient. eur urol. 2006;50:721-31. 4. vlachopoulos c, rokkas k, ioakeimidis n, et al. prevalence of asymptomatic coronary artery disease in men with vasculogenic erectile dysfunction: a prospective angiographic study. eur urol. 2005;48: 996-1002. 5. greenstein a, chen j, miller h, matzkin h, villa y, braf z. does severity of ischemic coronary disease correlate with erectile function? int j impot res. 1997;9:123-6. 6. montorsi f, briganti a, salonia a, et al. erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. eur urol. 2003;44:360-4. 7. montorsi p, montorsi f, schulman cc. is erectile dysfunction the “tip of the iceberg” of a systemic vascular disorder? eur urol. 2003;44:352-4. 8. solomon h, man jw, wierzbicki as, jackson g. relation of erectile dysfunction to angiographic coronary artery disease. am j cardiol. 2003;91:230-1. 9. rosen rc, cappelleri jc, smith md, lipsky j, pena bm. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 1999;11:319-26. 10. safarinejad mr. prevalence and risk factors for erectile dysfunction in a population-based study in iran. int j impot res. 2003;15:246-52. 11. welt fg, simon di. atherosclerosis and plaque rupture. catheter cardiovasc interv. 2001;53:56-63. errata 190 urology journal vol 4 no 3 summer 2007 errata urol j. 2007;4:190. www.uj.unrc.ir in volume 4, number 2 of the urology journal, the following errors occurred: on page 67, the first line of the second column, reached a record of 23 should have read reached 26.5. on page 70, in the end of reference 16, in press 2002 should have read in press 2006. on page 95, the name of an author was inadvertently omitted; sepehr salem is the fourth author of the paper entitled “role of pten gene in progression of prostate cancer” with the affiliation of urology research center, tehran university of medical sciences, tehran, iran. on page 101, affiliation of the second author, mohammadreza jalali nadushan, is department of pathology, school of medicine, shahed university, tehran, iran. on page 121, the name of the second author, hassan ahmadinia should have read hassan ahmadnia. we regret the above errors. urological oncology 151urology journal vol 4 no 3 summer 2007 overexpression of her-2/neu oncogene and transitional cell carcinoma of bladder mohammad reza jalali nadoushan,1 touraj taheri,2 neda jouian,1 farid zaeri3 introduction: the aim of this study was to evaluate the relationship between her-2/neu oncogene expression and grade of transitional cell carcinoma (tcc) of the bladder. materials and methods: in this cross-sectional study, 75 formalin-fixed paraffin-embedded specimens of primary tcc of the bladder were stained with a monoclonal antibody against her-2/neu oncoprotein. another section was stained by hematoxylin-eosin and the tumor grade was determined according to the world health organization/international society of urological pathologists criteria. results: tumor specimens belonged to 49 men (65.3%) and 26 women (34.7%) with a mean age of 56.3 ± 9.1 years (range, 39 to 80 years). the tumor grades were 1, 2, and 3 in 14 (18.7%), 35 (46.7%), and 26 (34.7%) specimens, respectively. a total of 28 (37.3%) patients were positive for overexpression of her-2/neu. there were 1 case of her-2/neu-positive (7.1%) with a grade 1 tumor, 10 (28.6%) with grade 2, and 17 (65.4%) with grade 3; a significant relationship between her-2/neu overexpression and grade of the bladder tcc tumors was found (p = .002). conclusion: expression of her-2/neu oncogene has a direct relationship with the grade of the bladder tcc. further studies with longer follow-up period and a larger sample size can determine the probable role of her-2/neu expression as a prognostic factor in the tcc of bladder. urol j. 2007;4:151-4. www.uj.unrc.ir keywords: bladder, transitional cell carcinoma, grade, her-2/neu, oncogene 1department of pathology, school of medicine, shahed university, tehran, iran 2department of pathology, apadana hospital, tehran, iran 3department of social medicine, school of medicine, shahed university, tehran, iran corresponding author: mohammad reza jalali nadoushan, md school of medicine, shahed university, shaheed abdollahzadeh st, keshavarz blvd, tehran, iran tel: +98 912 132 8320 e-mail: jalalinadooshan@yahoo.com received march 2007 accepted june 2007 introduction it is estimated that 67 160 new cases of transitional cell carcinoma (tcc) of the bladder and 13 750 deaths will occur in 2007 in the united states due to this disease. for local tumors and distant metastases, the 5-year survival rates are 48% and 6%, respectively.(1) life expectancy will increase in patients with tcc if a correct and early diagnosis is made. several factors involve in determination of prognosis and selection of the treatment. a known independent factor is the grade of the tumor.(1,2) other factors such as growth rate, patient’s age, and tumor aggressiveness are also important.(3) however, they may be inadequate in determination of the prognosis and therefore, other factors such as oncoproteins can be helpful.(4) molecular predictors of cancer behavior are not currently available for bladder tcc and would be valuable to categorize patients accurately. her-2/neu (c-erb b2) is an oncogene encoding a type 1 tyrosine kinase growth factor receptor. latif and colleagues reported that polysomy 17, gene amplification, and her2/neu overexpression are associated with a poor prognosis in patients with bladder tcc.(4) overexpression of her-2/neu has been associated with some different types of human her-2/neu and transitional cell carcinoma—jalali nadoushan et al 152 urology journal vol 4 no 3 summer 2007 cancers.(5,6) in the present study, we evaluated the expression of this gene in bladder tcc and its relationship with tumor grade. materials and methods we evaluated the available tissue blocks of 75 patients with bladder tcc who had referred to mostafa khomeini hospital between 2001 and 2004. threemicrometer thick sections were prepared from paraffin-embedded tissue blocks and stained by hematoxylin-eosin method. tumor grade was then determined using the world health organization/ international society of urological pathologists criteria by a single pathologist blinded to the records of the patients.(7) a manual avidine-biotin-peroxidase complex procedure was used in the immunohistochemical analysis (dakocytomation, copenhagen, denmark); another section from each block was used for evaluation of her-2/neu oncoprotein. for this purpose, the sections were deparaffinized and processed as follows: the specimens were first placed in oven at 50°c to 60°c for 30 minutes, and then, were rinsed in 100% xylol, 100%, 85%, and 75% ethanol, water, 10% phosphate-buffered saline (pbs), 1:9 h2o2/ethanol solution (for 10 minutes), and 10% pbs. the specimens were then placed in sodium nitrate buffer (ph = 8.0) and autoclave for 10 minutes in 120°c and pressure of 1.2 atmosphere. afterwards, they were rinsed in 10% pbs again. two drops of serum blocking solution was then added, and after 10 minutes, the slides were covered by 2 drops of her-2/neu primary antibody for 30 to 60 minutes and rinsed in 10% pbs. two drops of biotinylated antibody were added on the slides and after 10 minutes, rinsed in 10% pbs. then, 2 drops of enzyme conjugate was added and after 10 minutes, rinsed in 10% pbs. thereafter, 100 lambda ready dab chromogen was added and remained for 50 minutes and then the slides were rinsed in 10% pbs. two drops of hematoxylin was added for contrast making for 1 to 3 minutes and rinsed in water and pbs for 30 seconds, dehydrated in 75%, 85%, and 100% alcohol, and then 100% xylol for clearing. the cover was slipped and coded. the slides were then evaluated under standard light microscope with × 40 magnification and the positive cases for overexpression of her-2/neu were determined. the membrane staining intensity and pattern were considered for scoring according to the food and drug administration approved criteria(8): zero, no staining or membrane staining observed in less than 10% of the tumor cells; 1+, partial membrane staining in more than 10% of the tumor cells and membrane staining not circumferential; 2+, circumferential weak to moderate staining observed in more than 10% of the tumor cells; 3+, strong circumferential membrane staining observed in more than 10% of the tumor cells. areas that were poorly preserved, crushed, cauterized, folded, or retracted were specifically avoided. scores of 2+ and 3+ were considered positive. data were analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa) and the chi-square was used to compare dichotomous variables between tumor grade groups. results of the patients, 49 (65.3%) were men and 26 (34.7%) were women. the mean age of the patients was 56.3 ± 9.1 years (range, 39 to 80 years). the tumors were grade 1, 2, and 3 in 14 (18.7%), 35 (46.7%), and 26 (34.7%) cases, respectively. a total of 28 (37.3%) patients were positive for overexpression of her2/neu oncogene. high histologic grades of the ttc tumors were associated with increased expression of her-2/neu. there were 1 case of her-2/neu-positive (7.1%) with a grade 1 tumor, 10 (28.6%) with grade 2, and 17 (65.4%) with grade 3 (p = .002). discussion according to our findings, higher grade of the tcc of the bladder is accompanied by her-2/neu overexpression. in the study by latif and colleagues, her-2/neu and muscle invasiveness were evaluated in 25 patients with tcc. no significant relation was detected in the expression of this protooncogene and grade of the tumors; however, the percentage of positive cells for her-2/neu was greater in invasive tumors suggesting anti-her-2/neu treatment in invasive cases.(4) our sample size was greater, but their method was more sensitive since they used fluorescence in situ hybridization for her-2/neu and transitional cell carcinoma—jalali nadoushan et al urology journal vol 4 no 3 summer 2007 153 immunohistochemistry. in another study performed on a total of 106 patients, it was revealed that higher grade and stage of the tcc tumor correlated with more her-2/neu overexpression.(6) in the latter study, stage of the tumors and her-2/neu expression were both finally considered as 2 independent factors for disease-free survival. they also studied p53 and mdm2 overexpressions, but the correlation between these 2 markers and tcc grade and stage were not significant. these results agree with the results of mellon and colleagues and coombs and colleagues(9,10); however, their results cannot be compared to ours due to different degrees of involvement. one relevant study by lipponen and associates on 91 patients with bladder tcc showed 11 patients (12%) to be her-2/neu-positive and in 4% of them, the expression was graded as moderate or severe.(11) the expression of her-2/neu was significantly related to the tumor grade according to the world health organization/international society of urological pathologists criteria, whereas no significant difference was detected in its expression between the superficial and invasive or papillary and nonpapillary tcc tumors. in conclusion, they found out that moderate and severe overexpression of her-2/ neu oncoprotein in tcc seemed to be related to a more aggressive behavior of the tumor, while low expression of this oncoprotein had no predictive value.(11) although that study had some differences in the method of cellular evaluation, it was similar in other ways to ours. tetu and coworkers studied low malignant potential papillary tcc tumors and found out that her-2/neu expression was unremarkable in superficial bladder cancer which is compatible with our results.(12) coogan and colleagues’ study on 54 selected paraffin blocks revealed her-2/neu overexpression in 26% of the tcc cases; moreover, there were similarities between their results and ours in term of differences in overexpression and grade of malignancy. the difference in her-2/neu overexpression rate between these 2 studies can be due to the small volume and selected nature of coogan and colleagues’ study sample.(13) in another study, 36% of cases were positive for her-2/neu using the immunohistochemistry method precisely similar to our study and might confirm our results.(14) conclusion since most previous studies have shown a relationship between the tumor grade and expression of her-2/neu oncoprotein, as we did in the present study, this gene can be used in determination of the prognosis of bladder tcc. finally, comprehensive research with longer follow-up period and larger sample sizes are needed for further elucidation of the role of the oncogenes. conflict of interest none declared. references 1. american cancer society [http://www.cancerplanmn. org/]. minnesota caner facts and figures 2006. atlanta. available from: http://www.cancerplanmn.org/sites/ 528d17b0-2c73-45c9-894d-872fc0beac4e/uploads/ mn_facts_and_figures_2006_2.pdf 2. messing em. urothelial tumors of the urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 2732-73. 3. carroll pr. urothelial carcinoma: cancers of the bladder, ureter, and renal pelvis. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 15th ed. philadelphia: mcgraw hill; 2000. p. 355-77. 4. ramzi c, vinay k, stanley l r. urinary bladder. in: ramzi c, vinay k, stanley c, editors. robbins pathologic basis of disease. philadelphia: wb saunders; 2000. p. 994-1004. 5. latif z, watters ad, dunn i, grigor k, underwood ma, bartlett jm. her2/neu gene amplification and protein overexpression in g3 pt2 transitional cell carcinoma of the bladder: a role for anti-her2 therapy? eur j cancer. 2004;40:56-63. 6. korkolopoulou p, christodoulou p, kapralos p, et al. the role of p53, mdm2 and c-erb b-2 oncoproteins, epidermal growth factor receptor and proliferation markers in the prognosis of urinary bladder cancer. pathol res pract. 1997;193:767-75. 7. epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998;22:1435-48. 8. lara pn jr, meyers fj, gray cr, et al. her-2/neu is overexpressed infrequently in patients with prostate carcinoma. results from the california cancer consortium screening trial. cancer. 2002;94:2584-9. 9. mellon jk, lunec j, wright c, horne ch, kelly p, neal de. c-erbb-2 in bladder cancer: molecular biology, correlation with epidermal growth factor receptors and prognostic value. j urol. 1996;155:321-6. 10. coombs lm, pigott da, sweeney e, et al. her-2/neu and transitional cell carcinoma—jalali nadoushan et al 154 urology journal vol 4 no 3 summer 2007 amplification and over-expression of c-erbb-2 in transitional cell carcinoma of the urinary bladder. br j cancer. 1991;63:601-8. 11. lipponen p, eskelinen m. expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbb-2, p53) expression and long-term prognosis. br j cancer. 1994;69:1120-5. 12. tetu b, fradet y, allard p, veilleux c, roberge n, bernard p. prevalence and clinical significance of her/2neu, p53 and rb expression in primary superficial bladder cancer. j urol. 1996;155:1784-8. 13. coogan cl, estrada cr, kapur s, bloom kj. her2/neu protein overexpression and gene amplification in human transitional cell carcinoma of the bladder. urology. 2004;63:786-90. 14. wood dp jr, wartinger dd, reuter v, cordoncardo c, fair wr, chaganti rs. dna, rna and immunohistochemical characterization of the her2/neu oncogene in transitional cell carcinoma of the bladder. j urol. 1991;146:1398-401. pdf-962.pdf 420 | miscellaneous a new anatomical and surgical landmark in internal abdominal oblique muscle fat triangle kazem madaen,1 behrooz niknafs2 purpose: to determine the anatomical landmark within the internal oblique muscle. materials and methods: ratomy. results: there was a fat line at anterior superior iliac spine level to access the underlying layers and then to the abdominal cavity. conclusion: a fat triangle within the internal oblique muscle provides a suitable region of surgical incision at the lower part of the abdominal wall. keywords: abdominal muscles, abdominal wall, adult, diagnosis corresponding author: behrooz niknafs, anatomical phd department of anatomical sciences, school of medical sciences, tabriz university of medical sciences, tabriz, iran tel: +98 411 386 2062 fax: +98 411 334 2086 e-mail: niknafsbeh@yahoo.com received april 2011 accepted august 2011 1 department of urology, faculty of medicine, tabriz university of medical sciences, tabriz, iran 2 department of anatomical sciences, faculty of medicine, tabriz university of medical sciences, tabriz, iran miscellaneous 421vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l landmark in internal oblique muscle | madaen and niknafs introduction nternal oblique muscle is one of the abdominal layers, which is located deep to the external oblique muscle, and leads to intra-abdominal cavity. the internal oblique muscle must be incised to approach the abdominal cavity either through intra-peritoneal or retro-peritoneal spaces. repair of the abdominal wall is important after a put little or no emphasis on a landmark or a particular region for incision through the internal oblique muscle.(1-4) the incision must be made the nerves and vessels. the aim of this study was to determine the anatomical landmark within the internal oblique mussite is an easy way to go underneath the abdominal layers and can be used in different surgical applications. this landmark can be used in the repairs and incisions of the internal oblique muscle with little damage. materials and methods the abdominal wall was exposed by dissection verse or para-umbilical incisions were made on 1/4 of the lower anterior abdominal wall at the nal oblique aponeurosis were incised on the line cle was dissected easily through the fat triangle. deep to the fat triangle, the transverse abdominis and other layers were incised to approach abdominal cavity. the margins of the fat triangle were ligated after completing the surgery. the surgical dissection exposed the underlying internal oblique muscle, which was precisely studied. results within the internal oblique muscle, a fat line was ing layers and then to the abdominal cavity. the border of the rectus abdominis sheath in a triangle shape. the base of the fat triangle was located adjacent to the lateral border of the sheath. the fat triangle was observed on both the left and right sides of the subjects. the width and size of the fat triangle were more prominent in obese patients than the thin ones. furthermore, no blood vessels and nerves were discussion internal oblique muscle as a new landmark. this triangle can be recognized by bony landmark at out any severe damage to the abdominal wall. to the best of our knowledge, the fat triangle as anatomical or surgical landmark has not been addressed previously. this anatomical landmark has attracted more attention from surgeons than figure 1. anterior abdominal wall showing the external surface of internal oblique muscles. the fat triangle is seen at the anterior superior iliac spine level. 422 | miscellaneous anatomists. according to insertion point of the muscle, the internal oblique muscle can be divided into three parts; cranial, middle, and caudal parts. the cranial part is inserted into the inferior border of the last three ribs. the middle part continues transversally and medially to become aponeurotic, and then reach the linea alba. the caudal part ends on inguinal ligament.(5) was constructed by a space between the caudal and middle parts of the internal oblique muscle, nal oblique muscle. there are three requirements for proper abdominal incision: 1) accessibility; 2) extensibility; and 3) security. the incision should be long and wide enough for a good exposure.(6) this fat triangle has enough length and provides safe dissection plan. furthermore, surgeons must take care to than transect them.(6) this splitting can be done abdominal wall consists of eight layers, below the cal preparations and repairs. the fat triangle as a critical guidance might prevent the damage to the layers.(2) since the fat triangle was devoid of any nerves and blood vessels, it was supposed to be an appropriate region to cut the muscle and get to the deep layers without any damage to the nerves. for instance, the iliohypogastric nerve innervates caudal part of the internal oblique muscle except cremasteric part.(3) surgical care must be taken not to sever the nerve as this causes motor paralysis in the segments of the abdominal muscle that they innervate, and subsequently weakness in the abdominal wall. therefore, manipulating the fat triangle was safe to sever the probable nerves. conclusion we concluded that the fat triangle within the internal oblique muscle as a landmark provides a good region of surgical incision at lower part of ing, and no vessels and nerves injury. furthermore, the surgical approach is easy through the internal oblique muscle. conflict of interest none declared. references 1. healy jc, borley nr. aboman and pelvis in: standring s, ed. gray’s anatomy: the anatomical basis of clinical practice. 39 ed. london: eleseveir inc; 2005:1108-9. 2. ramasastry ss, futrell jw. surgical anatomy of the internal oblique muscle: a practical approach. am surg. 1987;53:27881. 3. yang d, morris sf, geddes cr, tang m. neurovascular territories of the external and internal oblique muscles. plast reconstr surg. 2003;112:1591-5. 4. mahadevan v. anatomy of the anterior abdominal wall and groin. surgery (oxford). 2006;24:221-3. 5. platzer w. locomotor system in: kahle w, leonhardt h, platzer w, eds. color atlas and textbook of human anatomy. vol 1. 3 ed. new york: thieme; 1986:86-7. 6. skandalakis je, skandalakis pn, skandalakis lj. surgical anatomy and technique: a pocket manual. 2 ed: springer verlag; 2000:156-63. figure 2. schematic illustration of the position of the fat triangle. io indicates internal oblique muscle; and ta, transversus abdominis. review article urology journal vol 4 no 1 winter 2007 1 chimerism a new look behrouz nikbin, fatemeh talebian, mandana mohyeddin introduction: microchimerism has become a familiar term in the past few years. many groups all over the globe, specializing in a diverse array of basic and medical sciences, have turned their attention to microchimerism, its possible role in disease or repair, and its mechanism of action in the host body. we reviewed the current knowledge about this novel term. materials and methods: we search the pubmed, using all the derivatives of chimera. all papers and their bibliographic information published by december 2005 were reviewed and 61 were selected. results: microchimerism is the presence of foreign or nonhost cells in a body. these are cells that live, differentiate, and persist in the host body by definition. these cells can enter the host body in a variety of manners. the most familiar aspect is microchimerism resulting from organ transplant. for many years now scientists have been debating over the interpretation of this phenomenon. we know that donor cell engraftment in the recipient body is a sign of transplantation success. what this means is that the body has developed tolerance toward the foreign organ and created a chimer. conclusion: how long this chimeric state will last, whether these cells will induce or be induced to create a chronic complication in the long run, or will these genetically distinct cell types live peacefully in one body to the end of the host’s life are the essence of the ongoing discussion and what probes researchers to continue their search. urol j (tehran). 2007;4:1-9. www.uj.unrc.ir keywords: chimerism, stem cell, immune system, transplantation immunogenetic research center, department of immunology, tehran university of medical sciences, tehran, iran corresponding author: behrouz nikbin, phd department of immunology, tehran university of medical sciences, tehran, iran. po box: 14155-3673 tehran tel: +98 21 6443 2465 e-mail: dnik@ams.ac.ir introduction as a general rule, nothing is perfect. the human immune system is no exception. a mechanism causing immunity under normal conditions may induce tolerance at some points due to an environmental trigger or it might go over the line and break out into a systemic autoimmunity. therefore, we are almost always dealing with a two-sided blade and the best we can do is to balance the knife and keep everything safe. many times, nature takes on the role of protection and we might never know it. for some decades now, we know there is fetomaternal trafficking across the placenta. this fact has been immensely helpful for prenatal diagnosis.(1) but, if these cells enter the maternal body, are they destroyed or do they stay intact? do they engraft into the mother’s body? will they differentiate? we know the answers to these questions now. the cells that enter the maternal body are not necessarily destroyed. a proportion of them is very likely to stay alive. some researchers believe fetal cell survival is directly proportionate to fetomaternal compatibility.(2) they argue that if chimerism—nikbin et al 2 urology journal vol 4 no 1 winter 2007 chimerism—nikbin et al urology journal vol 4 no 1 winter 2007 3 fetus hla is vastly different from the maternal one, these cells will be recognized as foreign elements and destroyed by the maternal immune cells. if the hla is identical, these cells survive and will give no cause for concern. however, if the hla is not identical but compatible enough for the maternal body to accept, they will enter the circulation and populate the host body. in such cases, it might be a matter of time before they attack the body and show their dark side. we must keep in mind that tolerance toward fetal cells or any foreign cell is more likely during the months of pregnancy, because the body is under an immunosuppressed condition to tolerate the fetal graft living within its womb. thus, it would be ideal if a cell is going to engraft and if the body is going to become tolerant to a non-self-genetic make-up under natural circumstances. functional studies in this respect are very limited, but these foreign cells have been detected in many tissues including the thyroid gland,(3) the cardiomyocytes,(4) and the peripheral blood.(5) therefore, we know they disperse. recent animal studies show such dispersion, as well.(6) no mechanism has been defined for this scattering, but a fair amount is reported to populate the lymph nodes. these cells are called chimeric cells. in cases of organ transplantation, the amount of the donor’s chimeric cells is great and what results in is chimerism. in the case of pregnancy, blood transfusion or other possible means, as this amount is very little, it is referred to as microchimerism. root of the word chimera in greek mythology, there is a fabled creature possessing the strength and body parts of many animals (figure). what is special about chimera is its being almost indestructible. such a creature is able to compensate for some of its shortcomings, because it not only possesses its own strength, but also has the added strength of another. that was the idea when it entered medical terminology; an experimental animal or a human that accepts another genetic make-up, tolerates it and becomes its permanent host. where the two-sidedness of the blade comes into play is that chimera—in other words, chimeric cells—might not always be favorable. of course, it is not very plausible to think of microchimerism as an unfavorable event overall, as it is the work of nature. another reason we could use as encouraging evidence is its role in transplantation success.(7) this is applicable both to solid organ and bone marrow and stem cell transplantation. for many decades, scientists have been debating over the interpretation of this phenomenon. we know that donor cell engraftment in the recipient’s body is a sign of transplantation success.(8) the main concerns are duration this chimeric state will last, whether these cells will induce or be induced to create a chronic complication in the long run, and whether these 2 genetically distinct cell types live peacefully in one body to the end of the host’s life. where does story of chimerism begin? the story of chimerism begins with a hypothesis put forth some years earlier.(9) the underlying general idea was that autoimmune disease occurs more frequently in women. many women develop symptoms in their 30s or later. this is an age in which hormone changes have passed, old age complications have not taken effect, and most women have children. bearing children leads to development of microchimerism. some autoimmune diseases resemble, in form and presentation, chronic graft versus host disease (gvhd). the chronic gvhd is a disease developing in recipients of bone marrow transplantation.(10) it has come to be looked upon as an autoimmune (or allo-autoimmune) disease. thus, microchimerism could be a cause of autoimmune development. the chimera of arezzo is a bronze statue found in arezzo, italy, in 1553 (archeological museum in firenze). chimera is a mythic three-headed monster. chimerism—nikbin et al 2 urology journal vol 4 no 1 winter 2007 chimerism—nikbin et al urology journal vol 4 no 1 winter 2007 3 how prevalent is chimeric state after pregnancy? microchimerism is so prevalent, in fact, that we now know it to be a natural phenomenon. thus, we may conclude that the detection of microchimerism per se is not a signal for health or disease or a risk of any kind, at least none that we know of at this time. nelson, who originally presented the hypothesis of chimerism being a possible risk for autoimmune disease, published an article in which male microchimerism was detected in mothers with no history of male pregnancy and went on to conclude that it might be induced by other means, some that we are not even aware of.(11) it might even transfer across generations or transfer to a fetus from a previous pregnancy, or a twin. this comes as no surprise knowing that placental transfer is two sided and the fetus is just as likely to become microchimeric by receiving cells from the mother. therefore, we might in fact carry cells from our ancestors and never become aware of them. women could donate them to their children, and never realize the diversity of genetic combinations they possess and turn over to their babies. microchimerism is a state induced by acceptance of a foreign cell into a body. this is done artificially by transplantation and naturally through pregnancy, blood transfusion, etc. these cells populate many organs and are not confined to the path they must take. hypothetically, these cells should be undifferentiated cells if they are able to roam about and home to various organs. these cells have been reported to express an antigen appropriate to the organ they reside in. following this line of reasoning, articles have been published recently stating these cells to be stem cells.(12) these cells are named pregnancy-associated progenitor cells.(13) they could therefore be considered a more youthful source of stem cells, perhaps a gift, a token of gratitude given to the maternal host by the fetal donor. what role could stem cells play in a body? the stem cells could function as a fountain of youth. they have the potential to differentiate into many different cell types. they are called upon to repair damaged tissue and differentiate into the cell type that the microenvironment they enter dictates to them. one of the reasons people become more susceptible in their old ages is because their repair potential decreases. one explanation is that the stem cell pool deteriorates with age. it might be interesting to note that women have longer lives in general. an intriguing study would be delving into the relationship between pregnancy and aging of women. could this novel source enrich their stem cell pool and give them better chances of damage repair? could these new refugee soldiers be fortifying the body that accepts them? could this be the work of nature? will we reach new conclusions if we look at these microchimeric cells in a positive light and not the potential damage they might be imposing? we must not forget that nature always has two sides to tell about the same story, so we are not denying the possibility that these cells could turn pathologic under certain conditions. what we mean to emphasize here though is the idea that a phenomenon recognized to be natural, and a cell population mostly composed of stem cells could more reasonably be a helpful source and their populating an organ is an outcome of a pathologic condition driving them to the site rather than them being the primary trigger to start a diseased condition. in 1957 and 1959, microchimerism was reported in twins.(14,15) liegeois and colleagues showed these cells to have “a stable state of low-ratio proliferation” in the body of successful allogenic bone marrow transplant recipients.(16) later, gaillard and colleagues made this statement: “fetal cells are able to survive and multiply in the hematopoietic organs of the pregnant mouse.(17)” thus, pregnancy seems to bring about a physiological microchimerism. meanwhile, in the field of transplantation, a new idea was proposed; induction of chimerism before transplantation could lead to better tolerance.(18) starzl and associates(19) reported systemic microchimerism after successful liver transplant and suggested immunosuppression in transplant recipients to promote the microchimeric state. however, negative reports were given where rejection was noted after long-term grafting in recipients who had developed microchimerism,(20,21) while positive speculations surfaced time and again.(22) some groups were more skeptic about its role,(23) saying that the low frequency observed and the insignificance of hla match with induction of microchimerism chimerism—nikbin et al 4 urology journal vol 4 no 1 winter 2007 chimerism—nikbin et al urology journal vol 4 no 1 winter 2007 5 raises “doubts about a major role of chimerism in development of long-lasting specific tolerance following kidney allografting.” some considered the evidence pointing toward the “apparent dichotomous role of donor cell chimerism in the processes of organ rejection and acceptance.(24)” reports in the same range were given regarding other transplantations, like that of the heart and the lung.(20) but, studies denying the presence of microchimerism persisted as well.(25) this inconsistency can be attributed to the different methods used and variations in test set up conditions. from the onset of the 21st century, medical literature is peppered with experiments, opinions, and successful or hopeful signs of positive effect of microchimerism on graft acceptance, whether from solid organ or bone marrow transplants.(26,27) trauma-induced microchimerism (through blood transfusion) has also been studied.(28,29) here again, we see microchimerism associated with a diseased condition. mircochimerism has been looked at the other way, too. it has been reported in diseases of the neonate such as severe combined immunodeficiency and erythema toxicum neonatorum.(30) chimeric cells have been sited decades later in the offspring blood and organs.(31) other studies have looked at juvenile idiopathic inflammatory myopathies,(32( juvenile systemic scleroderma,(33) rheumatoid disorders,(34) biliary atresia,(35) neonatal lupus syndromecongenital heart block,(36) and dermatosis,(37) where microchimerism and its effect are directed toward the child. there is much discrepancy in the results obtained. none show a definite correlation between microchimerism and the onset of disease. some groups believe the level of hla compatibility has a relationship with the persistence of microchimerism, and thus, is a contributing factor to this possible cause or risk factor in autoimmune disease induction.(2,38) conversely, others challenge the idea of hla subtypes being a risk factor of this kind.(39) animal models of fetomaternal microchimerism have been studied sporadically.(40-42) animal studies put this phenomenon in a positive and hopeful light. almost all of them show acceptance of fetal cells and successful engraftment not only in hematopoietic tissues, but also in different organs. these studies have entertained the idea and strengthened the notion of these microchimeric stem cells harbored in the body having repair potentials yet unappreciated and undiscovered. since 2000, a different view has been presented. conclusions start to point to the fact that many other means for microchimeric induction are possible that do not relate to pregnancy at all, and the idea that this is a natural phenomenon and much more common than expected took momentum. here, the new information shadowed the strength of an argument in favor of microchimerism having a determining role in bringing about an autoor allo-autoimmune state. studies started to look at the pattern of microchimerism, questioning whether they get around to different organs in humans as well and found fetal cells homing to multiple organs. they postulated their preferential sequestration to the spleen, site of immune cells. here, we see evidence of thought lines turning toward fetal progenitor cells being a source of help to the mother in as much as saying “the presence of these male cells may also be a result of disease, possibly through the migration of terminally differentiated and/or progenitor cells to areas of tissue damage.(43)” some start to mention “that immunoablation followed by stem cell rescue could be of potential therapeutic benefit.(33)” looking at it clearly, we see that it is exactly what is naturally happening in the body. the pregnant mother is being conditioned to an immunoablation state, or an immunosuppressed state, so it can tolerate and accept the graft or fetus. then the stem cells, new, unused, and full of potential enter this conditioned host or recipient, home to different organs, and stay there until called upon. when we are copying the act of nature for the benefit of human kind, offering this as a possible therapeutic solution to hopeless disease states, why not possible that nature’s purpose for this act is beneficial as well? in a case review, johnson and colleagues reported a study on a woman who had suffered from systemic lupus erythematous.(44) in their search for fetal cells they found male cells “in every histologically abnormal tissue type that was examined,” while the normal tissue lacked these cells or at least detectable concentration of them. they did not give a definite verdict on the role of these microchimeric cells in the respective tissues. but, with the facts that are now accumulated, could we say, these fetal cells that had chimerism—nikbin et al 4 urology journal vol 4 no 1 winter 2007 chimerism—nikbin et al urology journal vol 4 no 1 winter 2007 5 entered the body as stem cells years ago were called upon and summoned to the sites of inflammation and disease when the body needed their aid and played their part in helping heal and repair the organ? could that be the reason they are found there? could that explain why normal tissue lacked them, meaning normal tissue was not in any hazard, and this novel source of stem cells was not needed nor summoned to those sites? imaizumi and colleagues performed a study on experimental autoimmune thyroiditis in mice.(45) when they isolated the thyroids and examined the green florescent (microchimeric) cells, they found them to be immune cells such as t cell and dendritic cells. we must ask ourselves, if these were the “enemy”? would they stay in the body so long? we are speaking about fully competent hosts. it seems unlikely they have come to combat the host, but could they be here to aid it? it seems that the host’s body is the only “house” they have had since they were “new born” stem cells with no previous memory to hold onto. in a study done on thyroid specimens, microchimeric cells were found in the diseased tissue of many patients, but no detectable population was observed in healthy individuals. they do point to the microchimeric cells as having been stem cells.(46) microchimerism has been implicated repeatedly in hyporesponsiveness of the fetal/maternal immune system towards the fetal allograft and in the longevity of organ transplants.(47) some have taken a more favorable look at this phenomenon in the wake of its seeming helpfulness in haploidentical graft acceptance.(48) what we would like to add to this view is this: there is a possibility that microchimerism is a favorable event. this phenomenon may indeed cover and stop many diseased and potentially unfavorable conditions taking form in the maternal body before they present themselves. we can test the hypothesis the other way around, saying that any diseases that present were stronger than the combined effort of the body’s defense system and microchimeric fetal stem cells could combat. a study on sjogren’s syndrome detected microchimeric cells in the salivary gland and the inflammatory sites, but not in the peripheral blood.(5) the more common view taken in light of this evidence is that because microchimeric cells are more frequent at the site of lesion, they are a destructive force vitalizing the inflammation and promoting disease, possibly even leading to autoimmunity. but, from the same exact evidence, another conclusion could be drawn: when these accepted cells, circulating the body like any other host cell, come to be found more at the site of disease—keeping in mind their greater vigor, younger life, and stem cell origin—they could be the extra help come to the site because of the sos signals sent by that area to recruit repair forces. they are not as concentrated in other areas because their help is not required there. here, we can refer to another phenomenon in scientific history which might prove to be relevant in the near future. when lesions were first studied, the infiltrating cells were hypothesized to be the destructive force. the reason was their abundance in the inflamed sites. later, the theory reversed. the cells in the infiltrates turned out to be immune cells, the essential components in the immune reaction. by 2000, the idea that these placenta-crossing fetal cells have stem cell potentials had become a familiar speculation, although not studied very deeply. then, investigators demonstrated a new intriguing result. they found a rare population of mesenchymal stem cells in the maternal body, mesenchymal stem cells that are with fetal markers.(49) they did go on to say they are a rare population and they are not detected postnatally. however, they speculated this could be due to their engraftment in the maternal tissues early on. this is an idea worth looking into. we know much about mesenchymal stem cells these days.(50) worth noting is their immunosuppressive or immunomodulatory potential, their lack of mhc class ii antigens, etc. besides, a study on posttransplantation engraftment points to the presence of mesenchymal stem cells in the peripheral blood after allogenic transplantation and shows their ability to engraft in the bone marrow.(51) another study focused on engraftment potential of amnion and chorionic cells from the fetus.(52) the intriguing conclusion is that these cells had mesenchymal stem cell-like profiles that “did not induce allogeneic nor xenogeneic lymphocyte proliferation responses and were able to actively suppress lymphocyte responsiveness.” such cells are suggested for “an advantageous source of progenitor cells with potential applications in a variety of cell therapy and transplantation procedures.” if we can use such cells, chimerism—nikbin et al 6 urology journal vol 4 no 1 winter 2007 chimerism—nikbin et al urology journal vol 4 no 1 winter 2007 7 or at least investigate the possibility of using cells with such potential for the improvement of human health, what is to say nature has not been doing this all along? when fetal mesenchymal stem cells are engrafting in the maternal body without rejection, a natural allogenic transplantation is in fact taking place. autoimmune or autoimmune-like diseases after bone marrow transplantation have been noted several times.(53) as we mentioned before, gvhd is not looked upon as an autoimmune disease per se. this issue, though not proving the matter of microchimerism being capable or responsible for any disease induction, holds the issue in a certain interesting light inviting investigation in this field to actively pursue its course. taking the view of fetal cells entering maternal circulation as stem cells, a study was performed on organ specimens that showed favorable results to this end.(54) namely, xy+ cells were detected in the epithelial, hematopoietic, and hepatic cells, bearing respective markers (cytokeratin, cd45, heppar-1, respectively). like mentioned earlier, these stem cells entering the body are suggested to be mesenchymal stem cells.(55) these cells enter the maternal circulation in the first trimester of pregnancy and rapidly engraft to the marrow where they reside and possibly differentiate at a later time. this is interesting because the rare population of mesenchymal stem cells is noted for differentiating into all tissue lineages. it is exciting to think we may be able to develop targeted therapies if we understand the mechanism underlying this phenomenon. the conditions under which the semi-allogenic fetus is tolerated and the modifications the maternal body undergoes for this purpose to be accomplished, plus the function of microchimeric cells, and where, when, and for what purpose they enter the circulation or act as active cells (whether that means immune cells or organ specific cells) are areas that must be actively pursued to arrive at these answers. to examine how natural and widespread microchimerism really is a study was performed on healthy populations very recently, examining the presence of y chromosome in the liver, the kidney, and the heart of healthy individuals.(56) results showed that these organs have a fair chance of presenting chimeric cells obtained from different sources at various stages of their lives. khosrotehrani and coworkers launched a study on the natural history of microchimerism and pregnancy on an inbred group of mice.(57) they detected a widespread engraftment of fetomaternal cells in the tissues, with an emphasis on lymphoid tissues. their study gives a favorable outlook to the matter of microchimerism in a body and invite investigations into the possibilities that this issue may offer. tan and colleagues found these fetal cells in maternal brain, opening up an avenue of new ideas and untested possibilities for brain repair without extensive manipulation.(58) some studies have focused on multiple sclerosis (ms) and the possible role microchimerism could play in its onset or persistence. it has been stated in various studies that relapse and disease severity decreases during pregnancy in ms patients.(59,60) confavreux and colleagues(61) demonstrated that “the decrease in the relapse rate during pregnancy [in ms patients] was more marked than any therapeutic effect reported to date.” one more place to consider the usefulness of understanding the natural phenomenon of microchimerism is concerning its relationship with mesenchymal stem cells. as mentioned above, the earliest fetal cells noted to enter the maternal body are found in the first trimester and they engraft to various organs with alacrity. much of this population has been characterized as fetal mesenchymal stem cells. these cells are noted for their immunosuppressive potential. these cells could be a factor in the improvement seen in the disease condition of pregnant women. true, this matter has been attributed to hormonal changes and t-cell shift from a type 1 helper t cell profile to a type 2 helper t cell; however, with the new emerging evidence, mesenchymal stem cells could well be a plausible addition to the array of factors cooperating in this systemic network to establish the suppressed state a pregnant woman experiences. after all, we know that no isolated factor creates a condition. when we performed the tests in our ms patients, our results gave no significant indication of a relationship between microchimerism and ms induction.(62) the frequencies of microchimerism in the patients and controls were not significantly different. we did, however, observe that among the subjects who were positive for microchimerism, the patients displayed a significantly higher titer. we can conclude that first, the presence of cells in the peripheral blood can be chimerism—nikbin et al 6 urology journal vol 4 no 1 winter 2007 chimerism—nikbin et al urology journal vol 4 no 1 winter 2007 7 a sign of migration, and thus, higher quantity means greater need in a different place. these fetal cells are migrating in higher numbers in patients exhibiting microchimerism. therefore, they may be recruiting to a site of inflammation, injury, etc. second, ms is a chronic autoimmune disease. consequently, the factors triggering this disease must have been in the degenerated microenvironment long before symptoms occur. these microchimeric cells are moving in that direction after the onset and outbreak. conclusion considering the plethora of information in scientific literature and their links upon probing, fetal microchimerism can be said to be a nondestructive component of the maternal body. their natural engraftment (successful allogenic transplantation) into maternal tissue, their stem cell features (fountain of youth for the maternal body), and their presence in healthy individuals (almost as frequently as patients) seems to be ample support for their harmless nature. on the other hand, their higher quantity in the detected population was almost exclusively disease related; thus, a more focused study is to be designed to evaluate the reason behind this higher titer. a plausible suggestion is that they are a sign of disease severity or a signal for inflammation. immune cells do not circulate the peripheral blood in high titers under normal circumstances. the immune network must somehow be involved in a combat and need recruitments to a specific site for these cells to enter the peripheral blood in large numbers. this could mean that microchimeric levels in the peripheral blood are different if measured at various time periods. this issue was pointed out in a study by tajik and associates(63) where they demonstrated variations in microchimerism detection over a 30-month period follow-up on kidney transplant patients, saying: “among the microchimeric recipients, none were positive on all posttransplant analyses. interestingly, nonmicrochimeric cases were negative throughout the study.” they offered no explanation for this observation. today, we may have the information to offer a possible interpretation. under immune active circumstances, immune cells and stem cells will migrate to the concerned site. the microchimeric cells, whether as immune cells or stem cells, could be part of the recruitments. thus, in such cases microchimerism should be higher. however, to draw a definite conclusion, functional studies are warranted. these are only speculations worth investigation. conflict of interest none declared. references 1. bianchi dw, zickwolf gk, weil gj, sylvester s, demaria ma. male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. proc natl acad sci u s a. 1996;93:705-8. 2. lambert nc, evans pc, hashizumi tl, et al. cutting edge: persistent fetal microchimerism in t lymphocytes is associated with hla-dqa1*0501: implications in autoimmunity. j immunol. 2000;164: 5545-8. 3. klintschar m, schwaiger p, mannweiler s, regauer s, kleiber m. evidence of fetal microchimerism in hashimoto‘s thyroiditis. j clin endocrinol metab. 2001;86:2494-8. 4. ansari aa, fett jd, carraway re, mayne ae, onlamoon n, sundstrom jb. autoimmune mechanisms as the basis for human peripartum cardiomyopathy. clin rev allergy immunol. 2002;23: 301-24. 5. kuroki m, okayama a, nakamura s, et al. detection of maternal-fetal microchimerism in the inflammatory lesions of patients with sjogren’s syndrome. ann rheum dis. 2002;61:1041-6. 6. wang y, iwatani h, ito t, et al. fetal cells in mother rats contribute to the remodeling of liver and kidney after injury. biochem biophys res commun. 2004;325: 961-7. 7. bettens f, tiercy jm, campanile n, et al. microchimerism after 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25. garnier jl, daoud s, favre-victoire i, et al. absence of microchimerism in long-term tolerant living-donor kidney graft recipients. transplant proc. 1996;28:2834. 26. ochiai n, shimazaki c, fuchida s, et al. successful non-t cell-depleted hla haplo-identical three-loci mismatched hematopoietic stem cell transplantation from mother to son based on the feto-maternal microchimerism in chronic myelogenous leukemia. bone marrow transplant. 2002;30:793-6. 27. shimazaki c, ochiai n, uchida r, okano a, fuchida s, ashihara e, inaba t, fujita n, maruya e, nakagawa m. non-t-cell-depleted hla haploidentical stem cell transplantation in advanced hematologic malignancies based on the feto-maternal michrochimerism. blood. 2003;101:3334-6. 28. lee th, paglieroni t, ohto h, holland pv, busch mp. survival of donor leukocyte subpopulations in immunocompetent transfusion recipients: frequent long-term microchimerism in severe trauma patients. blood. 1999;93:3127-39. 29. lee th, paglieroni t, utter gh, et al. high-level longterm white blood cell microchimerism after transfusion of leukoreduced blood components to patients resuscitated after severe traumatic injury. transfusion. 2005;45:1280-90. 30. srivatsa b, srivatsa s, johnson kl, bianchi dw. maternal cell microchimerism in newborn tissues. j pediatr. 2003;142:31-5. 31. maloney s, smith a, furst de, et al. microchimerism of maternal origin persists into adult life. j clin invest. 1999;104:41-7. 32. selva-o’callaghan a, boeckh-behrens tm, baladaprades e, solans-laque r, vilardell-tarres m. fetal microchimerism and inflammatory myopathies. lancet. 2001;357:887. 33. martini a. juvenile systemic scleroderma. curr rheumatol rep. 2001;3:387-90. 34. reed am. microchimerism in children with rheumatic disorders: what does it mean? curr rheumatol rep. 2003;5:458-62. 35. suskind dl, rosenthal p, heyman mb, et al. maternal microchimerism in the livers of patients with biliary atresia. bmc gastroenterol. 2004;4:14. 36. stevens am, hermes hm, lambert nc, nelson jl, meroni pl, cimaz r. maternal and sibling microchimerism in twins and triplets discordant for neonatal lupus syndrome-congenital heart block. rheumatology (oxford). 2005;44:187-91. 37. vabres p, bonneau d. childhood dermatosis due to microchimerism. dermatology. 2005;211:388-9. 38. lambert nc, erickson td, yan z, et al. quantification of maternal microchimerism by hla-specific realtime polymerase chain reaction: studies of healthy women and women with scleroderma. arthritis rheum. 2004;50:906-14. 39. artlett cm, o’hanlon tp, lopez am, song yw, miller fw, rider lg. hla-dqa1 is not an apparent risk factor for microchimerism in patients with various autoimmune diseases and in healthy individuals. arthritis rheum. 2003;48:2567-72. 40. collins gd, chrest fj, alder wh. maternal cell traffic in allogenic embryos. j reprod immunol. 1980;2:16372. 41. jimenez df, tarantal af. quantitative analysis of male fetal dna in maternal serum of gravid rhesus monkeys (macaca mulatta). pediatr res. 2003;53:18-23. 42. kaplan j, land s. influence of maternal-fetal histocompatibility and mhc zygosity on maternal microchimerism. j immunol. 2005;174:7123-8. 43. johnson kl, nelson jl, furst de, et al. fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis. arthritis rheum. 2001;44: 1848-54. 44. johnson kl, mcalindon te, mulcahy e, bianchi dw. microchimerism in a female patient with systemic lupus erythematosus. arthritis rheum. 2001;44:210711. chimerism—nikbin et al 8 urology journal vol 4 no 1 winter 2007 chimerism—nikbin et al urology journal vol 4 no 1 winter 2007 9 45. imaizumi m, pritsker a, unger p, davies tf. intrathyroidal fetal microchimerism in pregnancy and postpartum. endocrinology. 2002;143:247-53. 46. srivatsa b, srivatsa s, johnson kl, samura o, lee sl, bianchi dw. microchimerism of presumed fetal origin in thyroid specimens from women: a casecontrol study. lancet. 2001;358:2034-8. 47. ichinohe t, teshima t, matsuoka k, maruya e, saji h. fetal-maternal microchimerism: impact on hematopoietic stem cell transplantation. curr opin immunol. 2005;17:546-52. 48. ichinohe t, maruya e, saji h. long-term feto-maternal microchimerism: nature‘s hidden clue for alternative donor hematopoietic cell transplantation? int j hematol. 2002;76:229-37. 49. o’donoghue k, choolani m, chan j, et al. identification of fetal mesenchymal stem cells in maternal blood: implications for non-invasive prenatal diagnosis. mol hum reprod. 2003;9:497-502. 50. mohyeddin bonab m, alimoghaddam k, talebian f, ghaffari sh, ghavamzadeh a, nikbin b. in search of mesenchymal stem cells: bone marrow, cord blood or peripheral blood. int j hematol oncol bone marrow transplant. 2005;2:17-22. 51. villaron em, almeida j, lopez-holgado n, et al. mesenchymal stem cells are present in peripheral blood and can engraft after allogeneic hematopoietic stem cell transplantation. haematologica. 2004;89: 1421-7. 52. bailo m, soncini m, vertua e, et al. engraftment potential of human amnion and chorion cells derived from term placenta. transplantation. 2004;78:1439-48. 53. tivol e, komorowski r, drobyski wr. emergent autoimmunity in graft-versus-host disease. blood. 2005;105:4885-91. 54. khosrotehrani k, johnson kl, cha dh, salomon rn, bianchi dw. transfer of fetal cells with multilineage potential to maternal tissue. jama. 2004;292:75-80. 55. o’donoghue k, chan j, de la fuente j, et al. microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. lancet. 2004;364:179-82. 56. koopmans m, kremer hovinga ic, baelde hj, et al. chimerism in kidneys, livers and hearts of normal women: implications for transplantation studies. am j transplant. 2005;5:1495-502. 57. khosrotehrani k, johnson kl, guegan s, stroh h, bianchi dw. natural history of fetal cell microchimerism during and following murine pregnancy. j reprod immunol. 2005;66:1-12. 58. tan xw, liao h, sun l, okabe m, xiao zc, dawe gs. fetal microchimerism in the maternal mouse brain: a novel population of fetal progenitor or stem cells able to cross the blood-brain barrier? stem cells. 2005;23: 1443-52. 59. hutchinson m. pregnancy in multiple sclerosis. j neurol neurosurg psychiatry. 1993;56:1043-5. 60. abramsky o. pregnancy and multiple sclerosis. ann neurol. 1994;36 suppl:s38-41. 61. confavreux c, hutchinson m, hours mm, cortinovistourniaire p, moreau t. rate of pregnancy-related relapse in multiple sclerosis. pregnancy in multiple sclerosis group. n engl j med. 1998;339:285-91. 62. talebian f, amirzargar a, ghaffari sh, khosravi f, lotfi j, nikbin b. association of microchimerism and multiple sclerosis patients [abstract]. j neurol sci. 2005;238 suppl 1: s251. 63. tajik n, singal d, pourmand g, et al. prospective study of microchimerism in renal allograft recipients: association between hla-dr matching, microchimerism and acute rejection. clin transplant. 2001;15:192-8. 1557vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l department of urology, isfahan urology and renal transplantation research center, alzahra hospital, isfahan university of medical sciences, isfahan, iran. mohammadhatef khorrami, mazaher hadi, mehrdad mohammadi sichani, kia nourimahdavi, mohammad yazdani, farshid alizadeh, mohammad-hosein izadpanahi, farhad tadayyon percutaneous nephrolithotomy success rate and complications in patients with previous open stone surgery corresponding author: mehrdad mohammadi sichani, md department of urology, isfahan urology and renal transplantation research center, alzahra hospital, isfahan university of medical sciences, isfahan, iran tel: +98 311 624 9031 fax: +98 311 669 2174 e-mail: m_mohammadi@med. mui.ac.ir received october 2012 accepted april 2014 purpose: to determine the effect of previous single or multiple open stone surgeries on percutaneous nephrolithotomy (pcnl) results and complications. materials and methods: we reviewed medical records of 1422 patients who had been undergone pcnl in our institute between 1998 and 2011 by the same surgeon. patients were divided into 3 groups. the first group included patients with no history of previous ipsilateral open stone surgery (n = 711). patients in second group had been undergone only one open stone surgery before pcnl (n = 405) and patients with more than one previous open stone surgery were placed in third group (n = 306). we compared operation duration, stone free rate (sfr), number of attempts to access the collecting system and intraoperative and postoperative complications between 3 groups. results: there were no differences in sex, body mass index, stone burden and laterality between 3 groups. operation time was significantly shorter in the first group (p = .000) while there was no statistically significant differences in operation duration between second and third groups (p > .973). the number of attempts to enter the collecting system was significantly lower in the first group in comparison to other two groups (p = .00). we didn’t find significant differences between 3 groups in hospital stay, sfr, intraoperative and postoperative complications. conclusion: our findings demonstrated that pcnl can be performed in patients with one or more open stone surgery history successfully without further complications. keywords: kidney calculi; surgery; nephrostomy; percutaneous; treatment outcome; lithotripsy; retrospective studies. endourology and stone disease 1558 | introduction percutaneous nephrolithotomy (pcnl) was de-scribed by fernstrom and johannson in 1976.(1) im-provements in pcnl technology and instruments after its invention have made it the most useful surgical treatment to large kidney stones.(2) recently european association of urology (eau) has considered pcnl as the first surgical option for large, multiple or inferior calyx kidney stones.(3) open stone surgery has been replaced by pcnl because of its cost effectiveness, lower morbidity, shorter operative time and lower post-operative complications.(4,5) some patients with the history of open stone surgery need pcnl because of renal stone recurrences.(6,7) open stone surgery cause scar tissue and anatomical modifications in kidney that may affect later pcnl. some studies have reported that previous open stone surgery can increase pcnl failure rate(8) while others show that previous open stone surgery does not affect pcnl outcome.(9,10) the aim of our study is to compare pcnl efficiency and complications in patients with and without the history of open stone surgery. materials and methods we reviewed records of all pcnl procedures (1422 procedures) that had been performed in alzahra hospital from 1998 till 2011 by the same surgeon. patients categorized into 3 groups based on previous open stone surgery. group 1 included patients with no history of open renal stone surgery on the ipsilateral kidney (n = 711). patients who had been undergone only one previous open stone surgery classified as second group (n = 405). the third group consisted of patients with more than one open surgical history (n = 306). patients with body mass index (bmi) ≥ 30, patients with abnormal renal anatomy such as ectopic or horse shoe kidneys and a stone burden of more than 700 mm2 were excluded from the study. the renal functions tests, serum electrolytes, hemoglobin, hematocrit, coagulation tests and urine culture were assessed before and daily after operation in all patients. if urine culture was positive, appropriate antibiotic prescribed for at least 2 weeks before undergoing pcnl. intravenous urography was our preferred imaging modality and computed tomography (ct) scan was performed in patients with history of open surgery. patients with retrorenal colon in ct scan were candidate for open stone surgery. one patient had incisional hernia due to previous open renal surgery, so he excluded from the study because of the risk of intestine perforation during pcnl. after general anesthesia, a 5 or 6 french (f) ureteral catheter was inserted and fixed to a foley catheter. patients were then turned into a prone position with special care for the pressure points. the desired calyx was punctured under fluoroscopic guidance and a guide wire was inserted. tract dilation was performed by serial metallic dilators. after amplatz sheath insertion, nephroscopy was performed and stones were fragmented by a pneumatic lithotripter (litho crack, sp. swissgermany) and removed. normal saline was used for continuous irrigation. if there was a more than 2 cm residual stone that could not be accessed from the first tract, a second access was established. residual stones of less than 2 cm in diameter were scheduled for extracorporeal shock wave lithotripsy (swl). no swl was performed during first few days after surgery. foley and ureteral catheter were removed 24 h after operation. nephrostomy tube was clamped 48 h after operation and removed after 24 h if there was no urine leakage, pain or fever. seven days after surgery plain radiography and abdominal ultrasonography or ct scan (for radiolucent stones) were performed to determine the residual stones. then we compared them to modalities were done before surgery to evaluate the stone free rate (sfr). patients’ age, sex, bmi, stone burden, laterality, operative duration, length of hospital stay, number of attempts before successful entry into collecting system, sfr and complications rate were compared between three groups. statistical analysis was performed with statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0 using the chi-square and anova tests. a p value < .05 was considered as significant. results table 1 illustrates patients’ demographic and renal stones characteristics. patients’ mean age in group 3 was significantly higher (50.4 ± 14.5, p = .001) in comparison to other two groups. there were no statistically significant differences in patients’ sex, mean bmi, stone laterality and mean stone endourology and stone disease 1559vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l pcnl in patients with previous open surgery | khorrami et al burden between 3 groups. all patients had pelvis stone; 80, 82 and 83% of patients had concurrent lower or middle calyceal stones in first, second and third groups respectively (p = .87). upper calyceal stone were detected in 15% of group 1, 13% of group 2 and 14% of patients in group 3 (p = .9). mean stone burden was the same in all groups. it was 4.76 ± 1.39 mm in group 1, 4.92 ± 1.34 mm in group 2 and 4.83 ± 1.38 mm in group 3 (p = .301). mean operation duration was 116 ± 24, 128 ± 14 and 128 ± 14 minutes in groups 1, 2 and 3, respectively (p = .00). the mean hospital stay between 3 groups was not statistically different (p = .962) (table 2). we also didn’t observe any significant differences between three groups in sfr (p = .75). mean number of attempts to access collecting system was significantly lower in the first group (1.5 ± 0.9 vs. 2.5 ± 0.5 and 2.3 ± 0.4 in groups 2 and 3 respectively) (p = .00). one hundred eighty three patients (12.8%) in group 1, 61 patients (15%) in group 2 and 22 (16.1%) patients in group 3 required a second access tract for additional stone removal (p = .5). as listed in table 3 there were no differences between 3 groups regarding intraoperative and postoperative complications. seventy one patients (5%) in group 1, 11 (5.4%) in group 2 and 8 (5.8%) in group 3 received blood transfusion during or after procedures (p = .7). postoperative fever developed in 170 patients (23.9%) in group 1, 91 (22.4%) in group 2 and 72 (23.5%) in group 3 (p = .9). auxiliary procedures such a second look pcnl and swl were performed in 9.7, 10.2 and 11% of patients in groups 1, 2 and 3, respectively (p = .9). delayed hematuria (more than 14 days after surgery) was seen in 16 patients in group 1, 3 in group 2 and 1 in group 3. one of 16 patients in group 1 required arteriography and angioembolization of an arteriovenous fistula. all other cases were managed conservatively. colon perforation was occurred in 2 patients (both in group 1) that managed conservatively. table 1. demographic and clinical characteristics of study groups. variables no. (%) mean (sd) p p** male/female group 1 1052/370 (74) ----group 2 150/55 (73) .669a group 3 98/38 (72) right/left side group 1 892/520 (62.7) ----group 2 121/84 (59) .370a group 3 87/49 (64) age (years) group 1‡# 42.5 ± 12.25 .000# group 2‡* --45.7 ± 17.27 .000b .003* group 3# * 50.4 ± 14.5 .003‡ body mass index (kg/m2) group 1 27.44 ± 2.5 -- group 2 --27.50 ± 2.6 .88b group 3 267.9 ± 1.7 stone burden (cm) group 1 4.76 ± 1.39 --group 2 --4.92 ± 1.34 .301b group 3 4.83 ± 1.38 a: chi-square test; b: one-way anova test. ** p value between study groups. 1560 | discussion our findings showed that previous open stone surgery doesn’t affect subsequent pcnl results and complications. conversely some studies demonstrated that anatomical changes that happen after open stone surgery such as infundibulum stenosis, perinephric fibrosis, bowel displacement and incisional hernia may decrease pcnl success rate and increase its complications.(11,12) same as our study a number of studies showed that pcnl can perform successfully without higher risk of complications in patients with a history pf open surgery history.(12-14) the number of patients in our study is not comparable to others. we reviewed pcnl records of 1422 patients which was extremely higher than sample size in similar studies. on the other hand we didn’t find any study which compared patients with single and multiple stone surgery history with ones without such a history separately as we did. based on our findings history of single or multiple ipsilateral open renal stone surgeries does not aftable 2. percutaneous nephrolithotomy results and complications in study groups. variables no. (%) mean (sd) ci 95% p p** hospital stay (day) -- group 1 3.93 ± 1.47 group 2 3.90 ± 1.47 .962a group 3 3.92 ± 1.45 operation time (min) group 1 # * 116 ± 24 114-117 .000# group 2 #‡ --128 ± 14 126-130 .000a .000* group 3 ‡* 128 ± 14 125-130 .973‡ access attempts (n) group 1 ‡# 2.5 ± 0.9 .00# group 2 ‡* --1.5 ± 0.5 .00a .122* group 3 # * 1.3 ± 0.4 .00‡ transfusion rate, no. (%) group 1 #‡ 71 (5) group 2 ‡* 11(5.4 ) .7b --group 3 *# 8 (5.8) auxiliary procedures, no. (%) ---- group 1 138 (9.7) group 2 21 (10.2) group 3 15 (11) .9 fever, no. (%) group 1 341 (24) ------ group 2 46 (22.5) .9b group 3 31 (23.7) secondary tract, no. (%) group 1 183 (12.8) group 2 61 (15.0) ----.5b -- group 3 22 (16.1) stone free rate (%) group 1 90.60 ± 5.96 --.75a group 2 90.45 ± 5.92 -- group 3 89.63 ± 5.91 a: one-way anova test; b: chi-square test. ** p value between groups. endourology and stone disease 1561vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l fect pcnl success rate. the mean operation time in the present study was significantly higher in groups with single or multiple previous stone surgeries in compare to first group while there was not any difference between patients categorized in second and third group. two other studies also have expressed that operative time is longer in patients with a history of open nephrolithotomy.(12,13) factors that may cause prolonged pcnl in patients after open surgery are difficulties in tract dilation in scarred collecting system and perinephric spaces, difficulties in stone fragments removal by grasping forceps and rigid nephroscopy in scarred kidneys and cautious fixation of kidney in the retroperitoneum. the rate of auxiliary procedures like second-look pcnl or swl was the same in all groups. some other studies have reported the same result.(7,10,13,14) only two studies have reported different results about auxiliary procedures need. (12,15) margel and colleagues compared pncl efficiency and morbidity in patients with previous nephrolithotomy with primary patients.(12) based on their findings secondary procedures was higher in patients with nephrolithotomy history. gupta and colleagues also found that relook pcnl is higher in patients with previous open surgery (18.2% vs. 7.8%).(15) the mean number of attempts to enter the collecting system was significantly lower in group 1. similar to our results margel found that access attempts is higher in patients with open surgery history.(12) we didn’t find any other study which had reported significant differences between two groups in access attempts. probably this difference is because of distorted calyceal anatomy due to previous open surgeries and subsequent scarring. same as other studies our study showed that there are no differences between primary patients and patients with open surgery history in sfr and hospitalization time.(7,10,14) we also didn’t find any differences in pcnl complications including fever and transfusion rate between three groups. in small group of patients, distortion of pyelocalyceal system due to previous surgery or recurrent stone formation may decrease stone free rate.(11,12) performing intravenous urography or ct-urography may helpful to identify such circumstances before operation. although our findings have demonstrated that pcnl can be performed successfully in patients with one or more open stone surgery history without further complications, some important items should be considered. each endourologist encounters some cases with difficult rod insertion and tract dilation. sometimes balloon or one shot dilation must be replaced by tract dilation with metallic dilators. it seems that perinephric fibrosis has an essential role in such cases. perinephric scar tissue formation depends on some factors including long standing calculus pyelonephritis, previous surgery complications (prolonged urine leakage), previous surgery type (nephrolithotomy, pyeloplasty, pyelolithotomy and etc) and severity of endogenous patients' reaction to operation. urinary tract infection usually leads wide adhesion resulted from serious inflammatory reaction around renal parenchyma. it has been shown that tract dilation is especially difficult in patients with cystinuria. it may be related to parenchymal fibrosis in such patients.(16) it seems that in this conditions stone free rate and complications may be different. so it is so important to consider above mentioned situations before pcnl of previous operated kidneys and prepare yourselves to encounter such difficult conditions. so it is so useful to review previous surgery files, search about post operation infections and urine leakage, determine previous surgery type and get sure about metallic dilators accessibility in operating room. a complete imaging evaluation is also necessary to collect more information about such challenging cases. some authors prefer a supracostal approach(11) while a lower calyceal puncture preferred by others.(9) scarring after open nephrolithotomy is usually subcostal so the best approach which helps to avoid colonic injury is supracostal.(17) a surgeon should avoid scar tissue when select the access site, but scar tissue alone is not an indication for upper-pole access as advocated by margel and associates.(12) the calyx that provides access to maximum stone burden is chosen as a primary calyx of entry regardless of its relation to scar tissue or ribs. conclusion based on our findings it doesn’t seem that previous open surgical procedures affect pcnl efficiency. pcnl complications are also the same in patients with or without the history of open stone surgery. conflict of interest none declared. pcnl in patients with previous open surgery | khorrami et al 1562 | references 1. fernström i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. preminger gm, assimos dg, lingeman je, nakada sy, pearle ms, wolf js. chapter1: aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005;173:1991-2000. 3. turk c, knoll t, petrik a, et al. guidelines on urolithiasis. chapter 6.4: selection of procedure for active removal of kidney stones. presented at: 26th european association of urology congress; march18–22, 2011; vienna, austria. 4. al-kohlany km, shokeir aa, mosbah a, et al. a treatment of complete staghorn stones: a prospective randomized comparison of open surgery versus percutaneous nephrolithotomy. j urol. 2005;173:469-73. 5. chandhoke ps .cost-effectiveness of different treatment options for staghorn calculi. j urol. 1996;156:1567-71. 6. trinchieri a1, ostini f, nespoli r, rovera f, montanari e, zanetti g. a prospective study of recurrence after a first renal stone. j urol. 1999;162:27-30. 7. lojanapiwat b. previous open nephrolithotomy: does it affect percutaneous nephrolithotomy techniques and outcome? j endourol. 2006; 0:17-20. 8. jones dj, russell gl, kellett mj, wickham je. the changing practice of percutaneous stone s urgery: review of 1000 cases 1981–1988. br j urol 1990;66:1–5. 9. basiri a, karrami h, moghaddam sm, shadpour p. percutaneous nephrolithotomy in patients with or without a history of open nephrolithotomy. j endourol. 2003;17:213-6. yucesan s, dindar h, olcay i, et al. prevalence of congenital abnormalities in turkish school children. eur j epidemiol. 1993;9:373-80. 10. sofikerim m, demirci d, gulmez i, karacagil m. does previous open nephrolithotomy affect the outcome of percutaneous nephrolithotomy? j endourol. 2007;21:401-3. 11. shah h n, mahajan a p, hegde s s, bansal m. tubeless percutaneous nephrolithotomy in patients with previous ipsilateral open renal surgery: a feasibility study with review of literature. j endourol. 2008;22:19-24. 12. margel d, lifshitz da, kugel v, dorfmann d, lask d, livne pm. percutaneous nephrolithotomy in patients who previously underwent open nephrolithotomy. j endourol. 2005;19:1161-4. 13. tugcu v, ernis su f, kalfazade n, sahin s, ozbay b, tasci ai: percutaneous nephrolithotomy (pcnl) in patients with previous open stone surgery. int urol nephrol. 2008:40:881-4. 14. kurtulus fo, fazlioglu a, tandugdu z, aydin m, karaca s, cek m. percutaneous nephrolithotomy: primary patients versus patients with history of open renal surgery. j endourol. 2008;20:2671-5. 15. gupta np, mishra s, nayyar r, seth a, anand a. comparative analysis of percutaneous nephrolithotomy in patients with and without a history of open stone surgery: single center experience. j endourol. 2009;23:913-6. 16. el-nahas ar, shokeir aa, el-assmy am, et al. colonic perforation during percutaneous nephrolithotomy: study of risk factors. urology. 2006;67:937-41. 17. ap evan, fl coe, je lingeman, et al. renal crystal deposits and histopathology in patients with cystine stones. kidney int. 2006;69:222735. endourology and stone disease 581vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l e-cadherin expression as a prognostic factor in transitional cell carcinoma of the bladder after transurethral resection mohammad hatef khorrami, mazaher hadi, mohammad reza gharaati, mohammad hossein izadpanahi, amir javid, mahtab zargham purpose: to analyze the role of negative versus positive immunoexpression of e-cadherin in recurrence rate of low-grade bladder tumors. materials and methods: a total of 180 patients with unifocal, superficial, low-grade, papillary transitional cell carcinoma of the bladder were included in this study. the e-cadherin expression was evaluated using e-cadherin antibody. the patients were followed up for 36 months. thereafter, recurrence rate of the tumor was compared between e-cadherin positive and negative groups. results: of 180 low-grade carcinomas, e-cadherin immunoexpression was negative in 101 (56%) and positive in 79 (44%) patients. the recurrence rate in negative and positive groups was 65.6% and 37.9%, respectively. negative in comparison with positive e-cadherin expression was associated with more disease recurrence (p = .045). conclusion: there is an association between decreased e-cadherin immunoexpression and tumor recurrence in low-grade and non-muscle invasive transitional cell carcinoma of the bladder. keywords: urinary bladder neoplasm, transitional cell carcinoma, cadherins, recurrence corresponding author: mazaher hadi, md department of urology, alzahra hospital, soffeh st., isfahan, iran tel: +98 311 785 1597 fax: +98 311 628 5555 e-mail: mazaherhadi2009@gmail.com received may 2011 accepted september 2011 department of urology, alzahra hospital, isfahan university of medical sciences, isfahan, iran urological oncology 582 | introduction recurrence is common in all patients with non–muscle-invasive urothelial cancer after tran-surethral resection (tur). this risk is more prominent in patients with high-grade tumors. intravesical chemotherapy or immunotherapy can be used to prevent recurrence in these subjects.(1) factors other than grade, such as e-cadherin (e-cd) expression, have been proposed as a prognostic factor. the cadherins are a group of membrane glycoprotein and the mediators of cell to cell adhesion. e-cadherin, which is an epithelial-specific cadherin, plays a major role in the selective adhesion of cells in epithelial tissue and is necessary for the maintenance of normal epithelial cells integrity.(1) loss of e-cd expression causes separation of the cells from cohesive epithelial tissues and leads to undifferentiation and invasiveness in a group of solid tumors, showing the important role of e-cd as a suppressor for malignant cells invasion and metastasis.(2,3) several studies have demonstrated that decreased expression of e-cd, as determined by immunohistochemistry, is associated with high grade and advanced stage in transitional cell carcinoma (tcc) of the bladder.(4-10) the aim of this study was to assess the role of e-cd expression in initial specimen of low-grade tcc in identifying patients at risk for disease recurrence. materials and methods of 256 patients with an initial diagnosis of bladder tumors who had undergone transurethral resection of bladder tumor (turbt), 191 subjects were identified as low-grade tumors using who/isup classification system. their specimens were sent for immunohistochemistry assay of e-cd by link streptavidin-biotin method. mouse monoclonal antibodies to human e-cd were purchased from dako laboratories inc., denmark. of 191 patients, 11 (4 in positive and 7 in negative groups) missed the complete follow-up period and were excluded from the study. one hundred and eighty formalin-fixed, paraffin-embedded tcc samples were obtained from patients. individual tumor sections of 4 to 5 mm were deparaffinized and heated in a 10 mol/l citric acid monophosphate buffer (ph = 6.0) for 30 minutes in a 1.35-kw microwave oven at high power. immunohistochemical staining was performed with biotinylated secondary antibodies for 10 minutes at room temperature. slides were washed thoroughly with phosphate buffered saline again. diaminobenzidine chromogen 1 was added for 5 minutes at 25 ºc. after being stained with hematoxylin, tissues were dried out and watched under optical microscope. a pathologist counted the cells and compared them with a normal sample. normal and increased cell counts were considered as positive and decreased ones as figure 1. decreased e-cadherin immunoexpression. figure 2. increased e-cadherin immunoexpression. figure 3. normal e-cadherin immunoexpression. urological oncology 583vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l e-cadherin immunoexpression in tcc | khorrami et al negative immunoexpression (figures 1 to 3). cystoscopic follow-up was performed every 3 months for the first year and every 6 months for the second year. if the tumor recurrence occurred during the follow-up period, turbt was performed and immediate instillations of 40 mg intravesical mitomycin c were done. the patients were followed up for at least 20 months. median follow-up period of patients was 26 months. at the end of the follow-up period, 180 patients remained in the study and were evaluated. the recurrence rates were compared between patients with negative and positive e-cd immunoexpression, with kaplan-meier recurrence survival analysis using spss software (the statistical package for the social sciences, version 16.0, spss inc, chicago, illinois, usa). results of 180 low-grade bladder carcinomas, negative and positive e-cd immunoexpression were reported in 101 (56%) and 79(44%) patients, respectively. one hundred and fifty-one patients were men, 81 in negative and 70 in positive e-cd groups. the median age was 64 and 66.5 years in negative and positive e-cd groups, respectively. the median follow-up period was 26 months (range, 20 to 36 months); 26.7 ± 6.3 months in negative and 26.08 ± 6.6 months in positive immunoexpression groups (p = .522). overall recurrence rate was 53.3%. recurrence was detected in 65 (65.6%) patients in negative and in 30 (37.9%) subjects in positive group. negative e-cd expression was significantly associated with disease recurrence (p = .021). test positive and negative predictive values were 38.0% and 35.6%, respectively. of 65 patients in negative e-cd group who recurred in 2-year follow-up, 15 had high-grade tumor in re-tur and underwent intravesical immunotherapy. in 5 patients, there was muscle invasion in the specimen and radical cystectomy was recommended. in positive e-cd group, 9 patients with high-grade tumor were reported in the follow-up period. radical cystectomy was carried out in 2 patients in this group (table). e-cadherin negative group had more progression in this study; however, it was not statistically significant. discussion patients with bladder tcc prone to recurrence and progression are candidate for more comprehensive treatments, such as intravesical immunotherapy or chemotherapy. the most important cellular marker of unfavorable prognosis is tumor grade. other parameters include tumor stage, presence of carcinoma in situ, tumor appearance, etc.(1) e-cadherin plays a critical role in maintaining intercellular junctions in epithelial tissues. in general, adhesion between normal epithelial cells is strong and stable. for malignant cells to separate from each other, invade, and metastasize from their native tissue, cell-to-cell associations have to be destroyed.(11,12) immunohistochemical studies have revealed that loss of e-cd expression in a tissue is often associated with increased biological aggressiveness, such as high degree of invasiveness, more metastatic disease, poor histological differentiation, and a lower survival rate in patients with oral,(13) breast,(14) hepatocellular,(15) bladder,(16) prostate,(17) renal,(18) pancreatic,(19) esophageal,(20) thyroid,(21) head and neck,(22) and gastric carcinomas.(23) in this study, we evaluated the immunohistochemical expression of e-cd in formalin-fixed, paraffin-embedded tissue specimens in primary low-grade bladder tumors. although the prognostic value of e-cd in bladder tumor needs to be confirmed in a larger number of patients, our comparison of findings between positive versus negative ecadherin immunoexpression groups. parameters e-cadherin negative e-cadherin positive p recurrence rate, n(%) 65 (65.6%) 30 (37.9%) .045 progression rate, n(%) 15 (14.8%) 9 (11.3%) ns male/female 81/20 70/9 ns tumor size, cm 3 to 4 2.5 to 3.5 ns mean recurrence time, month 15 22 .035 mean age, y 64 66.5 ns high-grade recurrence, n 15 9 ns radical cystectomy, n 5 2 ns ns indicates non-significant. 584 | results indicate that the immunohistochemical assessment of e-cd into negative versus positive expression in lowgrade bladder carcinomas may be valuable to predict the recurrence. this information can be used to stratify patients for therapeutic strategies. conclusion this study demonstrates that there is an association between e-cd immunoexpression and bladder tumor recurrence rate. further studies with larger sample sizes are needed to confirm our results. conflict of interest none declared. references 1. jones js, campbell sc. non–muscle invasive bladder cancer (ta, t1, and cis). in: wein a, kavoussi l, novick a, partin a, peters c, eds. campbell-walsh urology. vol 3. new york: saunders elsevier; 2007:2447-68. 2. frixen uh, behrens j, sachs m, et al. e-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. j cell biol. 1991;113:173-85. 3. vleminckx k, vakaet l, jr., mareel m, fiers w, van roy f. genetic manipulation of e-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. cell. 1991;66:107-19. 4. bringuier pp, umbas r, schaafsma he, karthaus hf, debruyne fm, schalken ja. decreased e-cadherin immunoreactivity correlates with poor survival in patients with bladder tumors. cancer res. 1993;53:3241-5. 5. lipponen pk, eskelinen mj. reduced expression of e-cadherin is related to invasive disease and frequent recurrence in bladder cancer. j cancer res clin oncol. 1995;121:303-8. 6. syrigos kn, krausz t, waxman j, et al. e-cadherin expression in bladder cancer using formalin-fixed, paraffin-embedded tissues: correlation with histopathological grade, tumour stage and survival. int j cancer. 1995;64:367-70. 7. wakatsuki s, watanabe r, saito k, et al. loss of human ecadherin (ecd) correlated with invasiveness of transitional cell cancer in the renal pelvis, ureter and urinary bladder. cancer lett. 1996;103:11-7. 8. fujisawa m, miyazaki j, takechi y, arakawa s, kamidono s. the significance of e-cadherin in transitional-cell carcinoma of the human urinary bladder. world j urol. 1996;14 suppl 1:s12-5. 9. shimazui t, schalken ja, giroldi la, et al. prognostic value of cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120cas) in bladder tumors. cancer res. 1996;56:4154-8. 10. byrne r, chakraborty s, brown r. an immunohistochemical study of e-cadherin in transitional cell carcinoma and carcinoma in situ in frozen and paraffin sections. j urol. 1996;155:614a. 11. takeichi m. cadherin cell adhesion receptors as a morphogenetic regulator. science. 1991;251:1451-5. 12. rodriguez-boulan e, nelson wj. morphogenesis of the polarized epithelial cell phenotype. science. 1989;245:718-25. 13. bankfalvi a, krassort m, buchwalow ib, vegh a, felszeghy e, piffko j. gains and losses of adhesion molecules (cd44, ecadherin, and beta-catenin) during oral carcinogenesis and tumour progression. j pathol. 2002;198:343-51. 14. yoshida r, kimura n, harada y, ohuchi n. the loss of e-cadherin, alphaand beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer. int j oncol. 2001;18:513-20. 15. endo k, ueda t, ueyama j, ohta t, terada t. immunoreactive e-cadherin, alpha-catenin, beta-catenin, and gammacatenin proteins in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, and patients' survival. hum pathol. 2000;31:558-65. 16. garcia del muro x, torregrosa a, muņoz j, et al. prognostic value of the expression of e-cadherin and [beta]-catenin in bladder cancer. eur j cancer. 2000;36:357-62. 17. richmond pj, karayiannakis aj, nagafuchi a, kaisary av, pignatelli m. aberrant e-cadherin and alpha-catenin expression in prostate cancer: correlation with patient survival. cancer res. 1997;57:3189-93. 18. katagiri a, watanabe r, tomita y. e-cadherin expression in renal cell cancer and its significance in metastasis and survival. br j cancer. 1995;71:376-9. 19. pignatelli m, ansari tw, gunter p, et al. loss of membranous e-cadherin expression in pancreatic cancer: correlation with lymph node metastasis, high grade, and advanced stage. j pathol. 1994;174:243-8. 20. krishnadath kk, tilanus hw, van blankenstein m, et al. reduced expression of the cadherin-catenin complex in oesophageal adenocarcinoma correlates with poor prognosis. j pathol. 1997;182:331-8. urological oncology 585vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l 21. von wasielewski r, rhein a, werner m, et al. immunohistochemical detection of e-cadherin in differentiated thyroid carcinomas correlates with clinical outcome. cancer res. 1997;57:2501-7. 22. mattijssen v, peters hm, schalkwijk l, et al. e-cadherin expression in head and neck squamous-cell carcinoma is associated with clinical outcome. int j cancer. 1993;55:580-5. 23. gabbert he, mueller w, schneiders a, et al. prognostic value of e-cadherin expression in 413 gastric carcinomas. int j cancer. 1996;69:184-9. e-cadherin immunoexpression in tcc | khorrami et al female urology trans-obturator approach and the native tissue in the treatment of high stage prolapse of the anterior vaginal wall: midterm results of a new surgical technique farzaneh sharifiaghdas* purpose: pelvic organ prolapse is a common condition as a consequence of the pelvic floor support weakness. this study evaluated the clinical results of treating the high stage prolapse of the anterior vaginal wall using a trans-obturator approach and the native vaginal wall tissue. methods: this was a prospective analysis of 94 patients with anterior vaginal wall prolapse stage ≥ ⅲ. they underwent surgery with the trans-obturator approach using the native vaginal wall tissue. the objective primary outcome was evaluated according to the pelvic organ prolapse staging system (pop-q). the subjective primary outcome was evaluated with pelvic floor distress inventory (pfdi-20) and pelvic floor impact questionnaire (pfiq-7) questionnaires. the secondary outcomes were post-surgery complications. results: totally, 85 of 94 patients were followed up for a mean of 38.2 ± 4 months. the objective anatomical success rate was 90.58%. pdfi-20 and pfiq-7 scores had improved (p = 0.001). the complications were minor (g1) according to the clavien-dindo classification (8.2 %). at one year follow up 3 out of 8 patients with clinical sui underwent transvaginal repair with the poly propylene mini sling mesh. conclusion: the midterm results of the surgical repair of the high stage anterior vaginal wall prolapse are promising with a new surgical technique by trans-obturator approach and native vaginal wall as the supportive layer keywords: high stage; anterior vaginal wall prolapse; trans obturator introduction pelvic organ prolapse (pop) affects one third of the middle-aged and elderly women(1). its incidence is rising due to the increase of population age in many countries(2). according to the population-based studies, the life-time risk of surgical intervention for pop is 1119%(1). the anterior vaginal wall prolapse (cystocele) is the most common type of pop(2). different surgical approaches have been introduced via the abdominal or vaginal cavity to treat pop. anterior colporrhaphy was the procedure of choice in the treatment of cystocele with 80% to 100% success rates(3). other native tissue repair options include: abdominal or paravaginal repair, which was supported by white in 1912 with 67% to 100% success rates(4). however, the high failure rate of anterior colporrhaphy at long term and major complications of the paravaginal repair were the key factors to popularize mesh-augmented repairs (5,6). although non-absorbable synthetic materials such as polypropylene mesh offer improved results, however there are associated with increased morbidity which has raised health related concerns(7,8). in this prospective study, we report the midterm clinical results of repairing the high stage prolapse of the anterior vaginal wall with a new surgical technique using native tissue and trans-obturator approach to avoid the urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology nephrology research center, no. 103, 9th boostan street, pasdaran avenue, tehran, iran. postal code: 1666663111 tel: +98 21 22567222. fax: +98 21 22567282. mobile: +98 9124339099. email: f.sharifiaghdas@gmail.com. received september 2019 & accepted may 2020 adverse effects of trans vaginal synthetic non-absorbable mesh products. materials and methods in the past decade, use of mesh products has been limited in our medical center, especially because its costs were not totally covered by the healthcare insurances of our country. from june 2013 to february 2017, 94 patients who complained of sensing a lump in their vaginal cavity and prolapse of the anterior vaginal wall (cystocele) stage ≥ ⅲ were treated in our center. their data is used in this prospective study. the evaluations before surgery included: medical history, physical examination according to the pelvic organ prolapse staging system (pop-q)(9), urinary ultrasound imaging (to determine the amount of post-void residual urine), urine analysis and culture, complete blood count and serum electrolyte levels. patients with an associated bothersome lower urinary tract symptom underwent the conventional urodynamic study with pop reduction by gentle vaginal packing. the severity of pop and its impact on quality of life was evaluated with the pelvic floor distress inventory (pfdi-20) and pelvic floor impact questionnaire (pfiq-7)(10). all participants were informed about the type and steps of the procedure. they were referred to the anesthesiolurology journal/vol 18 no. 1/ january-february 2021/ pp. 97-102. [doi: 10.22037/uj.v0i0.5619] ogy and cardiology departments to evaluate the overall risk of surgery and get permission for the operation. they all signed an informed consent before undergoing the surgery. the inclusion criterion was having a cystocele stage iii iv (point ba ≥ +1)(9). the exclusion criteria were having: 1) a history or evidence of urogenital malignancies, 2) history of pelvic radiotherapy, 3) uncontrolled diabetes mellitus, 4) history of anterior compartment surgery with mesh products, vaginal vault or uterine prolapse (point c ≥ +1)(9) (such cases were scheduled for a simultaneous apical and anterior vaginal wall repair via transvaginal sacrospinous fixation with polypropylene mesh). in case of any active vaginal or urinary tract infection, the patient was treated promptly and then scheduled for a surgery after it. all surgeries were done by one surgeon (the author) at one hospital. the local ethics committee of our center approved the study protocol. all investigations were carried out according to the principles of the declaration of helsinki. the procedure was done under general or spinal anesthesia. preoperative antibiotic prophylaxis was administered to all patients. the patients were placed in the exaggerated lithotomy position and an indwelling 16-f urethral catheter was inserted and left in place. the surgical procedure the anterior vaginal wall epithelium and its underlying connective tissue were incised longitudinally from the cervix or vaginal cuff to 1 cm cephalad to the bladder neck. dissection was carried out widely up to the pubic rami in both sides (figure 1). the stab skin incisions were created unilaterally (according to the right dominant hand of the surgeon, left side of the patient). the distal stab skin incision was made at the level of clitoris, the proximal stab skin incision was 2 cm lateral and 3 cm inferior to the distal one. the obturator fossa was entered only at one side (left side) with the aid of helical needles and out-in approach (figure 2). the most proximal and distal points of the dissected right half of the vaginal wall mucosa and sub-mucosa (contralateral to the left stab skin incisions) were sutured by two separate 1-0 vicryl at the cephalad and caudal parts. the free ends of the vicryl material were passed into the open hole of helical needle and brought out through the proximal and distal stab skin incisions by a reverse rotation of the helical needle (figure 3). by putting gentle traction on the vicryl arms, the dissected right half of the vaginal wall mucosa and sub-mucosa covered all the space underneath the bladder base, pushing it to a higher level as much as possible. to create a reliable anchoring point for the vicryl sutures, the third stab skin incision was made halfway of the first two (figure 4). the final knots were made by tying the free ends of both vicryl sutures (figure 5). to obtain a symmetric position of the bladder base, the remaining dissected half of the vaginal wall (usually the left side) was brought to the opposite side of the vaginal cavity (right side) and sutured to the former half which was beneath in an overlying manner by 0-2 vicryl sutures in a separate order. urethra and bladder neck were checked and readjusted for inadvertent overcorrection. vaginal packing and the urethral catheter were left in place for 12 hours. the patients were advised to to avoid vaginal intercourse during the first 3 months post operation. the patients were examined at the first week, one, three and six months after the surgery and every six months thereafter. the pfdi-20 and pfiq-7 were completed again at the second year after surgery and an independent physician re-examined the patients. the primary end points were objective anatomical success (ant. vaginal wall prolapse ≤ stage 1) (ba ≤ -1) and subjective improvement in bothersome symptoms (change in the scores of the pfdi-20 and pfiq-7 questionnaires). the secondary end points were post-operative adverse effects. the local ethics committee of the urology and nephrology research center of shahid beheshti university of medical sciences approved the study protocol. all investigations were carried out according to the principles of the declaration of helsinki. all patients had signed an informed consent before undergoing the surgery. statistical analysis the data were analyzed with the statistical package for social sciences (spss) software version 19. numeric data were expressed as mean ± standard deviation and categorical data were reported as number and percentage. after doing the normality test, the paired t-test or wilcoxon were used for comparing the data before and after surgery. p value less than 0.05 was considered significant. results a number of 94 patients underwent surgical repair of the anterior vaginal wall prolapse by the above-mentioned technique in our center. nine of them were extable 1. demographic data of patients parameter value age ,years old mean(range) 63.7 (46-77) parity mean(range) 4.1 (1-9) body mass index (kg/m2) mean(range) 27.09 (21-34) menopause mean (%) 78 (91.7%) prior hysterectomy mean (%) 27 (31.76%) prior ant vaginal wall prolapse repair mean (%) 38 (44.70%) prior anti-incontinence surgery mean (%) 21 (24.70%) questionnaire before surgery 2 years follow up paired difference p-value pfdi20 42.3 ± 6.6 8.3 ± 6.4 33.1 ±7.7 < 0.001 pfiq7 popiq 76.6 ± 6.9 21.9 ± 11.1 51.3 ± 12.1 < 0.001 uiq 80.1 ± 11.9 22.8 ± 11.6 52.2 ± 16.9 < 0.001 craiq 20.5 ± 11.6 10.9 ± 9.6 9.3 ± 7.1 < 0.001 sum score 172 ± 25.4 53.9 ± 24.6 116 ± 25.9 < 0.001 abbreviations: pfdi-20, pelvic floor distress inventory; pfiq-7, pelvic floor impact questionnaire short form; popiq, pelvic organ prolapse impact questionnaire; uiq, urinary impact questionnaire; craiq, colorectalanal impact questionnaire. table 2. quality of life assessment at two years follow up time. values are presented as mean ± standard deviation. transobturator native tissue for prolapse-sharifiaghdas female urology 98 vol 18 no 1 january-february 2021 99 cluded from the final analysis because they had not cooperated until the end of follow-up. their short-term follow-up was good until three months after surgery. so, the data of 85 patients were analyzed (table 1). mean age was 63.7 ( range 4677 ) years. the patients’ most common symptoms and signs before surgery were as following: sensation of a lump in the vagina (93.2%). obstructive urinary symptoms (68.3%), urinary urge incontinence (62.7%), clinical stress urinary incontinence (9.41%), occult stress urinary incontinence (17.64%) and recurrent urinary tract infections (25.5%). anterior vaginal wall prolapse was at stage iv in 28% of the patients. there were no major intraoperative complications such as massive bleeding according to clavien-dindo classification. the mean of surgery time was 45 ± 10 minutes .the duration of hospital stay was 26±5 hours. the mean of follow up time was 38.2 ± 4 months (range of 25 to 57 months). the anatomical success rate was 90.58% (77 out of 85). the pfdi20 and pfiq7 scores improvement were 42.3 ± 6.6 to 8.3 ± 6.4 and 172. ± 25.4 to 53.9±24.6 respectively, after the surgery which were statistically significant (p < 0.001) (table 2). totally, 9.3% of the patients complained of pelvic and thigh pain which resolved gradually until one month after the surgery. 6.5% complained of mild induration of stab skin incision over the place of vicryl knot which resolved one month after surgery. 4.6% of the patients who refused sexual abstinence through vaginal cavity during the first 3 months post –operative, complained of de novo mild dyspareunia which did not interfere seriously with their sexual life. the rate of urinary urge incontinence decreased to 21% post-operation. (p = 005). seven (8.2%) patients complained of de novo frequency and urgency which resolved after two months. at one year follow up, 3 out of 8 patients with pre-op clinical and bothersome sui requested surgical treatment and underwent trans vaginal repair with mini-sling polypropylene mesh tape. the vaginal mucosa over the mid-urethra was longitudinally incised for 1 cm and the mini-tape was positioned and secured in the surgical plane. the procedure was fast and uneventful, as the incisional site was far enough from the previous surgical scars. sui was mild in another 7 cases ( including 2 with de novo sui) , managed by pelvic floor physiotherapy and regular kegel exercise with no request from the patients` side for invasive treatment. discussion many surgical techniques have been introduced to correct high stage anterior vaginal wall prolapse. in 2015 we reported our results with trans-obturator four arm polypropylene mesh in the treatment of high stage anterior vaginal wall prolapse. in that group of patients, we did not trim the excess vaginal wall tissue and covered the polypropylene mesh with over sewn bilayer vaginal wall tissue to decrease the rate of post-operative vaginal mesh extrusion. there was no complication regarding the over sewn vaginal tissues which became the basis of the present study(11). the high failure rate of anterior colporrhaphy and major complications with the paravaginal repair were the key factors to popularize mesh-augmented repairs(12,13). parker placed the marlex mesh in the vaginal cavity during the surgical treatment of rectocele for the first time in 1993(14). reviews in the cochrane database regarding the surgifigure 1. the anterior vaginal wall longitudinally incised from the vaginal apex up to the bladder neck. figure 2. the distal stab skin is incised and the helical needle is passed through the obturator space entering the vaginal cavity with an out-in maneuver. the distal point of the right half of dissected vaginal wall is sutured by vicryl. transobturator native tissue for prolapse-sharifiaghdas cal management of pop in women revealed that the risk of anterior vaginal wall prolapse recurrence is reduced by placing polypropylene mesh(15). however, there are specific complications (pain, vaginal extrusion, shrinkage of mesh, dyspareunia) related to mesh repairs as well as longer surgery time(16). barski stated that use of light-weight mesh results in fewer complications after surgery(17). in the past decades, vaginal wall flap was introduced as a suspensory tissue. raz et al proposed vaginal wall as figure 6. the anchoring knot has been made by suturing the vicryl materials to each other. the anterior vaginal wall prolapse has been repaired. figure 5. the third stab skin incision is made half way the proximal and distal stab skin incisions. the free ends of both vicryl suture material are passed sub cutaneously and brought out from the middle stab skin incision. figure 4. both free ends of the vicryl sutures have been passed through the obturator fossa and brought from the skin. transobturator native tissue for prolapse-sharifiaghdas figure 3.the proximal stab skin incision is made and the proximal point of the vaginal wall flap is sutured by vicryl. female urology 100 vol 18 no 1 january-february 2021 101 four corner bladder and urethral suspension in the treatment of stress urinary incontinence and moderate cystocele(18). ferrari and frigerio created a triangular vaginal patch sling for the stress-related urinary incontinence and hypermobile urethra. they covered the intact vaginal mucosa patch by the remaining vaginal wall without adverse events related to buried intact vaginal wall mucosa(19). in 2001, cosson et al reported 93% success rate for an autologous vaginal patch measuring 6-8 cm in length and 4 cm in width suspended from the tendinous arcus of the pelvic fascia(20). there has been no longer follow up reported by the authors. nevertheless, the use of non-absorbable mesh kits is controversial based on fda safety communications (21) in a prospective randomized controlled trial, minasian et al reported two years follow-up results of an anterior colporrhaphy plus a polyglactin mesh (vaginal approach) compared to a paravaginal defect repair (abdominal approach). women with symptomatic anterior vaginal wall prolapse were enrolled in both groups. the results were 32% and 40% objective failure rates for their vaginal and abdominal groups, respectively. subjective failure rates were lower and similar in both groups(22). balzarro et al. showed the long term (more than five years) results of 109 patients retrospectively. their patients were allocated to the three groups of anterior colporrhaphy alone, anterior colporrhaphy reinforced by porcine xenograft and, transvaginal anterior repair with polypropylene mesh(23). they concluded that using mesh and xenograft does not significantly improve objective and subjective outcomes. instead prosthetic device led to higher rates of complications. in a systematic review about the surgical treatment of anterior compartment vaginal prolapse, durnea et al concluded that clinical trials often neglect to report important safety outcomes(24). some recent reports are in favor of native tissue repair. lavelle et al reported an institution’s outcomes for native tissue repair with a mean follow up of 5.8 years. there was 7.4% rate of recurrent isolated anterior compartment prolapse, but only 3.3% of them required a second procedure(25). in a review article on suture-based repairs for anterior compartment vaginal prolapse, amin and lee conclude that native tissue repair is the most common procedure, whether done solely or concomitantly with other prolapse surgeries. it is safe for women and has symptom relief(26). in our study, subjective and objective success rates of using native vaginal wall tissue have shown to be promising at midterm follow-up with more than 90% objective response. the surgery time was short and there were no major complications according to the clavien-dindo classification. among 23 patients with sui,8 suffered from clinical sui. concomitant pop and sui surgical repair is not the policy of our medical center, nor it is an obligation and depends on the physician-patient preferences and agreements .three out of 8 patients with pre-op clinical sui underwent correction of sui by transvaginal approach and mini sling synthetic tapes. the other 7 cases (including 2 with de-novo sui) were managed non-invasively which emphasizes in step by step management in this special group of patients, as overall 22 (including 2 with de-novo mild sui) escaped from an additional intervention. despite medical advice to avoid vaginal intercourse during the first 3 months post-operation, some refused and complained of dyspareunia , however the symptom was mild and temporary and there was no sexual dysfunction related to native tissue that limited sexual intimacy at midterm, perhaps as there has been no foreign material in the place. according to our knowledge, this is the first clinical report of a new surgical technique by trans-obturator approach with a native vaginal wall tissue as a supportive layer to repair high stage prolapse of the anterior vaginal wall. some of the limitations of this study were the small number of patients, and lack of long term follow-up. conclusions the midterm clinical results of a new surgical technique with trans-obturator approach and native vaginal wall tissue as a supportive layer is promising in the treatment of high stage prolapse of anterior vaginal wall. the complications are minor and insignificant. however, long-term data in multi-centered studies with large number of patients is needed to confirm the efficacy of this new surgical approach. conflict of interest the author declares that she has no conflict of interest. references 1. samuelsson ec, victor fa, tibblin g, svärdsudd kf. signs of genital prolapse in a swedish population of women 20 to 59 years of age and possible related factors. am j obstet gynecol. 1999;180:299-305. 2. moore rd, beyer rd, jacoby k, freedman sj, mccammon ka, gambla mt. prospective multicenter trial assessing type i, polypropylene mesh placed via transobturator route for the treatment of anterior vaginal prolapse with 2-year follow-up. int urogynecol j. 2010;21:545-52. 3. smith fj, holman caj, moorin re, tsokos n. lifetime risk of undergoing surgery for pelvic organ prolapse. obstet gynecol. 2010;116:1096-100. 4. white gr. an anatomical operation for the cure of cystocele. transactions of the american association of obstetricians and gynecologists for the year... 1912;24:323. 5. olsen al, smith vj, bergstrom jo, colling jc, clark al. epidemiology of surgically managed pelvic-organ prolapse and urinary incontinence. obstet gynecol. 1997;89:501-6. 6. rane a, iyer j, kannan k, corstiaans a. prospective study of the perigee™ system for treatment of cystocele–our five‐year experience. aust n z j obstet gynaecol. 2012;52:28-33. 7. handel ln, frenkl tl, kim yh. results of cystocele repair: a comparison of traditional anterior colporrhaphy, polypropylene mesh and porcine dermis. j urol. 2007;178:153-6; discussion 6. 8. porges rf, smilen sw. long-term analysis of the surgical management of pelvic support defects. am j obstet gynecol. 1994;171:151826; discussion 26-8. transobturator native tissue for prolapse-sharifiaghdas 9. bump rc, mattiasson a, bø k, et al. the standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. am j obstet gynecol. 1996;175:10-7. 10. lemack ge, anger jt. urinary incontinence and pelvic prolapse: epidemiology and pathophysiology. campbell-walsh urology. 2016;11:1743-60. 11. sharifiaghdas f, daneshpajooh a, mirzaei m. simultaneous treatment of anterior vaginal wall prolapse and stress urinary incontinence by using transobturator four arms polypropylene mesh. korean j urol. 2015;56:811-6. 12. young sb, daman jj, bony lg. vaginal paravaginal repair: one-year outcomes. am j obstet gynecol. 2001;185:1360-6; discussion 6-7. 13. mallipeddi pk, steele ac, kohli n, karram mm. anatomic and functional outcome of vaginal paravaginal repair in the correction of anterior vaginal wall prolapse. int urogynecol j pelvic floor dysfunct. 2001;12:83-8. 14. parker mc, phillips rk. repair of rectocoele using marlex mesh. ann r coll surg engl. 1993;75:193-4. 15. maher c, feiner b, baessler k, adams ej, hagen s, glazener cm. surgical management of pelvic organ prolapse in women. cochrane database syst rev. 2010cd004014. 16. maher c, feiner b, baessler k, christmannschmid c, haya n, brown j. surgery for women with anterior compartment prolapse. cochrane database syst rev. 2016;11:cd004014. 17. barski d, otto t, gerullis h. systematic review and classification of complications after anterior, posterior, apical, and total vaginal mesh implantation for prolapse repair. surg technol int. 2014;24:217-24. 18. raz s, klutke cg, golomb j. four-corner bladder and urethral suspension for moderate cystocele. j urol. 1989;142:712-5. 19. ferrari a, frigerio l. the triangular vaginal patch sling for stress urinary incontinence and hypermobile urethra. am j obstet gynecol. 1997;177:1426-31. 20. cosson m, collinet p, occelli b, narducci f, crepin g. the vaginal patch plastron for vaginal cure of cystocele. preliminary results for 47 patients. eur j obstet gynecol reprod biol. 2001;95:73-80. 21. shah hn, badlani gh. mesh complications in female pelvic floor reconstructive surgery and their management: a systematic review. indian j urol. 2012;28:129-53. 22. minassian va, parekh m, poplawsky d, gorman j, litzy l. randomized controlled trial comparing two procedures for anterior vaginal wall prolapse. neurourol urodyn. 2014;33:72-7. 23. balzarro m, rubilotta e, porcaro ab, et al. long-term follow-up of anterior vaginal repair: a comparison among colporrhaphy, colporrhaphy with reinforcement by xenograft, and mesh. neurourol urodyn. 2018;37:27883. 24. durnea cm, pergialiotis v, duffy jm, bergstrom l, elfituri a, doumouchtsis sk. a systematic review of outcome and outcome-measure reporting in randomised trials evaluating surgical interventions for anterior-compartment vaginal prolapse: a call to action to develop a core outcome set. i int urogynecol j. 2018;29:1727-45. 25. lavelle rs, christie al, alhalabi f, zimmern pe. risk of prolapse recurrence after native tissue anterior vaginal suspension procedure with intermediate to long-term followup. the j urol. 2016;195:1014-20. 26. amin k, lee u. surgery for anterior compartment vaginal prolapse: suture-based repair. urol clin north am. 2019;46:61-70. transobturator native tissue for prolapse-sharifiaghdas female urology 102 case reports 174 urology journal vol 4 no 3 summer 2007 laparoscopic reimplantation for single-system ectopic ureter abbas basiri,1 faramarz mohammad ali beigi,2 hamidreza abdi,1 nastaran mahmoudnejad1 urol j. 2007;4:174-6. www.uj.unrc.ir keywords: urogenital abnormalities, ectopic ureter, laparoscopy, reimplantation 1department of urology, shaheed labbafinejad medical center and urology and nephrology research center, shaheed beheshti medical university, tehran, iran 2department of urology, shahrekord university of medical sciences, shahrekord, iran corresponding author: abbas basiri, md urology and nephrology research center, 9th boustan, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax : +98 21 2256 7282 e-mail: basiri@unrc.ir received october 2006 accepted may 2007 introduction ureteral anomalies, ectopic ureter being one of them, are of the most important urogenital abnormalities because they directly affect kidney function.(1) several techniques have been used for treatment of ectopic ureter. the goal of obstruction relief can be achieved by either ureteropyelostomy or common sheath ureteral reimplantation for a duplicated system, or reimplantation for a single system.(1) heminephrectomy and ureteropyelostomy are well described elsewhere, but several technical points deserve emphasis.(1) laparoscopic procedures putatively offer reduced morbidity due to less postoperative pain, earlier return of gastrointestinal function, earlier discharge, and a quicker return to work. to our knowledge laparoscopic reimplantation for ectopic ureter has not been reported, yet. we performed laparoscopic ureteral reimplantation on a 29-year-old man with ectopic ureter. case report a 29-year-old man was referred with dysuria, frequency, postvoid dribbling, and left flank pain. urinalysis and urine culture showed urinary tract infection (uti). after the treatment of uti, ultrasonography revealed severe left kidney hydroureteronephrosis and partial reduction in parenchymal thickness of the left kidney. a single system was also confirmed on intravenous urography (figure 1). figure 1. left, preoperative intravenous urography revealed hydroureteronephrosis of the left kidney with reflux of the contrast medium into the vas deferens. middle, significant reduction of hydroureteronephrosis and ureteral diameter was revealed by intravenous urography postoperatively. right, postoperative voiding cystourethrography showed no vesicoureteral reflux. v indicates vas deferens and u, ureter. laparoscopic reimplantation for ectopic ureter—basiri et al urology journal vol 4 no 3 summer 2007 175 on technetium tc 99m dimercaptosuccinic acid scan, function of the left kidney was acceptable. diagnostic cystourethroscopy was performed. the bladder and the right ureteral orifice were normal, but on the left side, the ureteral orifice was not seen in its normal position in the trigone. after a more careful evaluation, the left ureteral orifice was seen in the prostatic urethra about 3 mm above the verumontanum (figure 2). retrograde ureteral catheterization was then performed which confirmed the same findings (a single urinary tract system). no other abnormality was seen. the place of the ectopic ureter was confirmed to be in the posterior urethra. reflux into the vas deferens and seminal vesicle was observed during voiding cystourethrography. the patient underwent intraperitoneal ureteral reimplantation with the diagnosis of left ectopic ureter. the patient was secured in the left flank position. one port was inserted through the umbilicus for the camera (10 mm), another was inserted through the left lateral rectus muscle at the level of the umbilicus (5 mm), and the last port was inserted through the midline suprapubic space 6 cm below the umbilicus for the instruments (5 mm). first, the terminal colon was mobilized and the distal part of the ureter was released, clamped, and cut, 2 cm below the vas deferens (figure 3). regarding the dilatation of the ureter, ureteral spatulation was not necessary. catheterization was performed using a 10-f stent (figure 4). to perform extravesical lich-gregoir ureterovesical anastomosis, the bladder tunnel was created using a hook cautery with the semifull bladder in the lateral and anterior aspects. on the distal part, mucosa of the bladder was opened, ureter-bladder anastomosis was performed separately with vicryl 4-0, and a catheter was placed. the operative time was 150 minutes and no complication occurred intraoperatively or postoperatively. oral feeding was started the day after the operation and 5 days later, the patient was discharged. one month postoperatively, the stent was removed and 6 months later, intravenous urography and voiding cystourethrography revealed no obstruction or reflux (figure 1). discussion the prevalence of ectopic ureter is not well determined. campbell reported 10 cases among 19046 autopsies in children.(2) ectopic ureters appear figure 2. ectopic orifice of the ureter is shown in the posterior urethra above the verumontanum. figure 3. the ureter was released behind the bladder below the left vas deferens. v indicates vas deferens; u, ureter; and b, bladder. figure 4. the ureter was cut and a ureteral stent was inserted for anastomosis to the bladder. s indicates stent; u, ureter; and b, bladder. laparoscopic reimplantation for ectopic ureter—basiri et al 176 urology journal vol 4 no 3 summer 2007 2 to 12 times more frequently in women.(1) of all ectopic ureteral orifices, 80% are associated with a duplicated collecting system. in women, more than 80% of the collecting systems are duplicated, but in men, most ectopic ureters drain single systems.(3) in men, the most prevalent site of ectopic ureter is the posterior urethra (47%).(2) patients with ectopic ureters draining into the posterior urethra often suffer from urgency and frequency and may have severe obstruction. another prevalent complication is uti. drainage into the genital tract involves the seminal vesicles 3 times more frequent than the ejaculatory duct and the vas deferens together.(4,5) most of the ectopic ureters including the upper pole ureters and single systems are accompanied by the least functional kidneys; therefore, upper pole nephrectomy or nephrectomy for single collecting systems is indicated.(1) kidney function is one of the most important factors in selection of the treatment choice. in some patients, especially with single systems, kidney preservation is important. in such patients, ureteropyelostomy and common sheath reimplantation (in double systems) or solitary reimplantation (in single systems) is helpful in the treatment of obstruction. laparoscopic techniques have been performed in nephrectomy or heminephrectomy of nonfunctional kidneys; however, laparoscopic reimplantation has not been reported in single systems so far. modified lichgregoir technique has been successfully used for laparoscopic ureteral reimplantation in the treatment of vesicoureteral reflux.(6) ureteral reimplantation has also been reported in the treatment of ureterovaginal fistula.(6) we performed laparoscopic reimplantation of the ectopic ureter which is, to our knowledge, the first report worldwide. laparoscopic techniques are accompanied by less morbidity due to less pain, earlier return of gastrointestinal function, earlier discharge of the hospital and return to work, adequate view during the surgery, excellent cosmetic results, and minimal abdominal incision. these are of the most important reasons for choosing laparoscopic approach in the treatment of these patients. since this is the first report of laparoscopic reimplantation of an ectopic ureter, undoubtedly long-term follow-up and study of more cases are needed to consider it as the procedure of choice for surgical reimplantation of ectopic ureter. conflict of interest none declared. references 1. richard n, schlussel rn, retik ab. ectopic ureter, ureterocele and other anomalies of the ureter. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 2007-2013. 2. campbell mf. anomalies of the ureter. in: campbell mf, harrison jh, editors. urology. 3rd ed. philadelphia: wb saunders; 1970. p. 1512. 3. schulman cc. the single ectopic ureter. eur urol. 1976;2:64-9. 4. sullivan m, halpert l, hodges cv. extravesical ureteral ectopia. urology. 1978;11:577-80. 5. squadrito jf, rifkin md, mulholland sg. ureteral ectopia presenting as epididymitis and infertility. urology. 1987;30:67-9. 6. ramalingam m, senthil k, venkatesh v. laparoscopic repair of ureterovaginal fistula: successful outcome by laparoscopic ureteral reimplantation. j endourol. 2005;19:1174-6. case report mesothelioma in situ of the spermatic cord arising from a patent processus vaginalis: a case report yasuyuki kobayashi1*, yumiko yasuhara2, hiroki arai1, masahito honda1, masataka hiramatsu3, sho goya3 mesothelioma is an aggressive tumor originating from mesothelial cells. mesothelioma of the spermatic cord is a very rare disease, and the most common presentation of this disease is that of aggressive mesothelioma with no description of mesothelioma in situ. we report an extremely rare case of mesothelioma in situ of the spermatic cord arising from a patent processus vaginalis. to our best knowledge, this is the first report of this finding. the identification of a patent processus vaginalis and investigation of single-layered atypical mesothelial cells led to the final diagnosis. keywords: atypical mesothelial cells; mesothelioma in situ; radical orchiectomy; spermatic cord tumor introduction mesothelioma is an aggressive tumor originating from mesothelial cells (1). mesothelioma of the spermatic cord is a rare disease, with only 9 cases reported in detail in the english literature and none describing mesothelioma in situ (2-10). we report an extremely rare case mesothelioma in situ of the spermatic cord arising from a patent processus vaginalis. case report an 82-year-old man complaining of a gradually enlarging swollen mass in his right inguinal area for the past three months was referred to our hospital. the right spermatic cord mass was hard, smooth, and immobile. chest and abdominal computed tomography showed right spermatic cord swelling and no other significant findings (figure 1). we diagnosed the patient as having right spermatic cord tumor, for which he underwent right radical orchiectomy. a spermatic cord tumor was found adhering to the surrounding tissue, and no obvious residual tumor existed intraoperatively. macroscopically, the spermatic cord was enlarged at 7.0 × 4.0 cm and had a smooth and capsulated surface. the cut surface was creamy white, solid, thickened and poorly circumscribed (figures 2a, b). microscopically, the tumor was a mixture of tubulopapillary, trabecular, and solid structures (figures 2c, d). immunohistochemically, the tumor cells were positive for calretinin, wilms’ tumor 1, podoplanin, glucose transporter type 1 (glut-1) and epithelial membrane antigen (ema), negative for carcinoembryonic antigen, moc-31 and ber-ep4, and showed loss of brca1-associated protein (bap1). we diagnosed the spermatic cord tumor as epithelial mesothelioma. interestingly, a patent processus vaginalis was found lined by a single layer of mesothelial cells from the proximal end to the tunica vaginalis (figure 3a). a single layer of atypical mesothelial cells with enlarged nuclei lined the ipsilateral side of the mesothelioma and flattened normal mesothelial cells lined the cavity on the opposite figure 1. abdominal ct showing the right spermatic cord swelling. urology journal/vol 17 no. 6/ november-december 2020/ pp. 671-673. [doi: 10.22037/uj.v16i7.5421 departments of urology, 2diagnostic pathology, and 3respiratory medicine, kinki central hospital of mutual aid association of public school teachers, itami, hyogo, japan. *correspondence: department of urology, kinki central hospital of mutual aid association of public school teachers, 3-1 kurumazuka, itami, hyogo 664-8533, japan phone: +81-72-781-3712; fax: +81-72-779-1567. e-mail: ya_su_koba@yahoo.co.jp. received june 2019 & accepted december 2019 vol 17 no 06 november-december 2020 112 side (figure 3b). immunohistochemically, the atypical mesothelial cells were positive for glut-1 and ema, negative for desmin, and showed loss of bap1, whereas the normal mesothelial cells showed an opposite pattern (figures 3c-d), indicating that the single-layered atypical mesothelial cells were mesothelioma in situ. finally, we diagnosed mesothelioma in situ of the spermatic cord arising from a patent processus vaginalis. a second surgery and adjuvant therapy were not performed because there was no obvious tumor elsewhere. he was alive without signs of disease at 2 years after surgery. discussion mesothelioma of the spermatic cord is a rare entity; only 9 cases have been reported so far in the english case report 413 mesothelioma of the spermatic cord-kobayashi et al. figure 2. (a) macroscopic findings of the spermatic cord. the spermatic cord was enlarged (arrowheads). (b) the cut surface showed a solid and thickened spermatic cord (arrowheads) and no involvement of the testis and tunica vaginalis (arrows). (c) epithelioid mesothelioma with a papillary pattern of growth. (d) epithelioid mesothelioma with trabecular and solid patterns of growth. (c-d): hematoxylin and eosin stain. figure 3. (a) cross-sections of the specimen of the right spermatic cord. (a) mesothelioma of the spermatic cord (red line), (b) patent processus vaginalis (yellow line) and (c) vas deferens (green point). patent processus vaginalis stained with hematoxylin and eosin (b), desmin (c) and bap-1 (d). (b-d) mesothelioma is present on the right side of the images. cells on the right lining are mesothelioma in situ (arrowhead). cells on the left lining are normal mesothelial cells (arrow). ※ = patent processus vaginalis. vol 17 no 06 november-december 2020 672 literature (table 1) (2-10). the patients most commonly presented with an inguinal mass, and all 9 patients underwent surgery. histological findings showed no descriptions of mesothelioma in situ. mesothelioma arising from the peritoneum may have invaded the spermatic cord in cases 4 and 6. our patient being alive without signs of disease at 2 years after surgery excluded the possibility of a peritoneal origin. bap1 expression is detected by immunohistochemistry, which is useful for distinguishing benign and malignant mesothelial proliferations(11). bap1 expression is detected in the nuclei of benign mesothelial cells, whereas bap1 loss is detected in the nuclei of mesothelioma cells (12). recently, churg et al. reported two cases of mesothelioma in situ. they proposed that mesothelioma in situ be defined as well-confirmed in situ lesions and be related to genomic events such as bap1 loss(13). the single-layered atypical mesothelial cells in our patient were an in situ lesion and showed loss of bap1. thus, they were diagnosed as mesothelioma in situ of the spermatic cord arising from a patent processus vaginalis. references 1. gemba k, fujimoto n, kato k, et al. national survey of malignant mesothelioma and asbestos exposure in japan. cancer sci. 2012; 103:483-90. 2. kozlowski h, zoltowska a. mesothelioma of spermatic cord. neoplasma. 1968; 15:97-100. 3. arlen m, grabstald h, whitmore wf jr. malignant tumors of the spermatic cord. cancer. 1969; 23:525-32. 4. pizzolato p, lamberty j. mesothelioma of spermatic cord: electron microscopic and histochemical characteristics of its mucopolysaccharides. urology. 1976; 8:4038. 5. leiber c, katzenwadel a, popken g, kersten a, schultze-seemann w. tumour of the spermatic cord: an unusual primary manifestation of an epithelial mesothelioma of the peritoneum with patent processus vaginalis. bju int. 2000; 86:142-3. 6. torbati pm, parvin m, ziaee sa. malignant mesothelioma of the spermatic cord: case report and review of the literature. urol j. 2005; 2:115-7. 7. park yj, kong hj, jang hc, shin hs, oh hk, park js. malignant mesothelioma of the spermatic cord. korean j urol. 2011; 52:2259. 8. meng x, guzzo tj, bing z. malignant mesotheliomas in spermatic cords: reports of two cases and a brief review of literature. rare tumors. 2013; 26:5:e4. 9. d'antonio a, mastella f, colucci a, silvestre g. malignant mesothelioma of spermatic cord in an elderly man with a history of asbestos exposure. urology. 2016; 87:e1-3. 10. ahmed z, singh s, mangal a, mittal a. primary malignant mesothelioma of the spermatic cord. bmj case rep. 2016; pii: bcr2016214602. 11. kinoshita y, hida t, hamasaki m, et al. a combination of mtap and bap1 immunohistochemistry in pleural effusion cytology for the diagnosis of mesothelioma. cancer cytopathol. 2018; 126:54-63. 12. wu d, hiroshima k, yusa t, et al. usefulness of p16/cdkn2a fluorescence in situ hybridization and bap1 immunohistochemistry for the diagnosis of biphasic mesothelioma. ann diagn pathol. 2017; 26:31-7. 13. churg a, hwang h, tan l, et al. malignant mesothelioma in situ. histopathology. 2018; 72:1033-8. case report 212case report 428case report 673 mesothelioma of the spermatic cord-kobayashi et al. case age asbestos side symptom tumor operation histologic postoperative follow-up ref (y) exposure metastasis type recurrence 1 63 na lt mass in the na na biphasic na na 2 inguinal region 2 40 na lt high near groin external ro, rald na no ned 18 y 3 iliac lymph node 3 57 na rt inguinal hernia no sr epithelioid local at 12 m dod 42 m 4 periaortic, iliac lymph nodes at 34 m 4 46 no rt mass in the no ra biphasic na dod 8 m 5 inguinal region 5 52 na rt scrotal enlargement no ra epithelioid local at 9 m awd 30 m 6 iliac lymph nodes at 30 m 6 65 yes lt mass in the inguinal no ra biphasic local, peritoneal dod 6 m 7 region at 3 m 7 45 no lt mass in the inguinal no sr epithelioid no ned 6 m 8 region 8 80 yes rt mass in the inguinal no ra biphasic no ned 12 m 9 region 9 45 no rt swelling in the no ra biphasic na na 10 inguinal region our 82 no rt swelling in the no ra epithelioid no ned 2 y case inguinal region table 1. clinical and pathologic features of primary mesothelioma. abbreviations: na, not available; lt, left; rt, right; ro, radical orchiectomy; rald, retroperitoneal and para-aortic lymph node dissection; sr, spermatic cord resection; ned, no evidence of disease; dod, dead of disease; awd, alive with disease; y, years; m, months; ref, reference. clinical pathology case 59urology journal vol 7 no 1 winter 2010 biochemical failure after treatment of testis tumor abbas basiri, mohammad hadi radfar urol j. 2010;7:59-60. www.uj.unrc.ir urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran corresponding author: abbas basiri, md urology and nephrology research center, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir case presentation a 37-year-old man was admitted with a hard large mass in the right testis in 1992. serum levels of β-human chorionic gonadotropin and α-fetoprotein (α-fp) were 280 iu/ml and 0.5 iu/ml, respectively. after right inguinal orchidectomy, pathologic examination result was reported as teratoma with choriocarcinoma without involvement of the spermatic cord. the patient was followed up with laboratory tests and computed tomography (ct). in 1994, ct revealed a lymph node in the right iliac fossa. since tumor markers were within reference ranges, lymphadenectomy was not performed. in 2001, following a rise in β-human chorionic gonadotropin and α-fp levels, ct results of the patient was normal except for the right iliac fossa lymphadenopathy (figure 1). the patient underwent retroperitoneal lymph node dissection. although the lymph node was adhered to the iliac vessels and the bladder, it was completely removed. pathology examination revealed the lymph node contained metastatic adenocarcinoma confirmed by immunohistochemistry. para-aortic lymph nodes did not contain any tumoral tissue. postoperative chemotherapy was administered using 4 courses of bleomycin, etoposide, and cisplatin regimen. tumor markers dropped into the normal range after chemotherapy. follow-up studies including upper gastrointestinal tract endoscopy, colonoscopy, total body bone scan, and ct did not show any abnormality. in 2002, about 7 months after the last course of chemotherapy, serum α-fp levels rose again. chemotherapy was performed using 4 courses of vinblastin, ifosfamide, and cisplatin. again, ct scan and bone scan were normal. in 2003, nearly 6 months after the last course of chemotherapy, α-fp level rose again. high-dose chemotherapy (carboplatin, etoposide, and ifosfamide) and autologous bone marrow transplantation were figure 1. computed tomography in 2001 revealed lymphadenopathy in the right iliac fossa. l indicates lymph node, and b, bladder. clinical pathology case 60 urology journal vol 7 no 1 winter 2010 performed. however, α-fp levels increased to 550 iu/ml in 2004. computed tomography, bone scan, and positron emission tomography revealed no evidence of metastasis. since all other tests were normal, the patient was treated with 3 courses of capecitabine. serum level of α-fp did not change; therefore, 3 courses of paclitaxel were administered. serum α-fp level increased to 2250 iu/ml, while imaging studies were normal. in december 2004, ct showed a lymphadenopathy in the right iliac fossa (figure 2). lymphadenectomy was undertaken and pathology assessment revealed germ cell tumor in 8 of 12 removed lymph nodes. two months later, serum level of α-fp decreased to 157 iu/ml. however, in 2005, serum α-fp level again rose to 450 iu/ml. computed tomography and other imaging studies were normal. quiz what could be the possible source of afp raise? what is your suggestion as the next step of diagnosis and treatment? the answers will be discussed in the next issue of urology journal. figure 2. computed tomography in 2004 showed lymphadenopathy in the right iliac fossa. miscellaneous 238 urology journal vol 4 no 4 autumn 2007 ratios of free to total prostate-specific antigen and total prostate-specific antigen to protein concentrations in saliva and serum of healthy men hossein ayatollahi,1 mohammad reza darabi mahboub,2 nema mohammadian,3 mohammad reza parizadeh,1 tayyebeh kianoosh,1 mahdi khabbaz khoob,4 fahimeh kamalian4 introduction: we evaluated the ratio of free to total prostate-specific antigen (psa) and psa to protein concentrations in saliva and serum of healthy men. materials and methods: concentrations of protein, free psa, and total psa in serum and saliva were measured in 30 healthy men aged 42 to 73 years, and their ratios were compared between the two fluids. results: there was a significant direct correlation between serum free-total psa ratios of serum and saliva (p = .04) and between total psa-protein ratios of serum and saliva (p = .02). also, there were significant correlations between total and free psa levels in saliva (p = .05) and between those in serum (p < .001). significant inverse and direct correlations were detected between the body mass index and serum values of total psa-protein (p = .04) and free-total psa (p = .01), respectively. conclusion: we can use saliva sample instead of serum sample for estimation of free-total psa and total psa-protein levels in men without prostate diseases. there is, however, a pressing need for much additional research in this area before the true clinical value of saliva as a diagnostic fluid can be determined. urol j. 2007;4:238-41. www.uj.unrc.ir keywords: saliva, serum, prostatespecific antigen 1department of biochemistry and nutrition, mashhad university of medical sciences, mashhad, iran 2department of urology, mashhad university of medical sciences, mashhad, iran 3department of pathology, mashhad university of medical sciences, mashhad, iran 4mashhad university of medical sciences, mashhad, iran corresponding author: hossein ayatollahi, md assistant professor of pathology department of biochemistry and nutrition mashhad university of medical sciences mashhad, iran tel: +98 511 801 2423 fax: +98 511 841 2578 e-mail: ayatollahih@mums.ac.ir received june 2007 accepted october 2007 introduction saliva has been considered as a diagnostic medium during the past 15 years. thanks to the current developments in technology, the use of saliva as a diagnostic fluid is now possible in practice. for example, the ability of measuring a wide spectrum of molecular components in saliva and comparing them with serum has made it possible to study chemicals and immunologic markers.(1) the major advantages of using saliva instead of blood are its ease of access and noninvasive collection method.(1-4) one of the markers that can be measured in saliva is prostatespecific antigen (psa). given its high specificity, psa is known as a useful tumor marker for prostate cancer.(5) it is a 33-kd glycoprotein secreted by the prostate.(6) values of the total psa, free psa, and psa-alpha-1antichymotrypsin (psa-act) are independent prognostic factors of survival in patients with prostate cancer.(6) however, several reports have described elevation in serum psa levels in a variety of nonprostatic malignancies.(7) moreover, it has recently become widely accepted that psa is also present in many nonprostatic sources, casting doubts about the specificity of its tissues expression.(8) prostate-specific antigen in saliva and serum—ayatollahi et al urology journal vol 4 no 4 autumn 2007 239 immunoreactivity for psa in salivary gland neoplasms has also been reported.(9) in addition, a consistently positive reaction for psa and prostate acid phosphatase, independent of sex, in the ductal cells of normal salivary glands has been demonstrated using monoclonal antibody assay.(10) it can be concluded that psa might also be secreted by salivary glands, and therefore, it is important to assess extraprostatic sources of psa to avoid errors in diagnosis and management.(11) to emphasize this issue, it should be noted that psa has also been found in human endometrium and amniotic fluid albeit its significance is unclear.(12,13) based on these findings, we evaluated free and total psa levels and the free-total ratio of psa in the fasting saliva and serum of the healthy men. also, we investigated the ratios of serum total psa to serum protein and salivary total psa to salivary protein in healthy individuals using radioimmunoassay technology. materials and methods serum and saliva concentrations of free and total psa were measured in 30 men aged between 42 and 73 years who presented for routine checkup. all of the participants underwent physical examination, chest radiography, electrocardiography, routine biochemical analyses of blood, urine analysis, and urine culture, and they had no evidence of any diseases. all of them were confirmed to have a normal prostate by digital rectal exam and ultrasonographic evaluations performed 1 month earlier in their prostate examination. the participants were informed of the purpose of the study and provided written consent. the study was approved by the medical ethics committee of mashhad university of medical sciences. one month after recruitment of the volunteers, we obtained serum and saliva samples after 12 hours of fasting between 8 am and 9 am. each participant rinsed his mouth with water for 5 minutes and then 5 ml of saliva was collected. samples of blood and saliva were centrifuged at 2000 g for 10 minutes. bubbles in the samples were removed prior to analysis. free and total psa concentrations in serum and saliva samples were measured on the same day at our laboratory with radioimmunoassay technique (kavoshyar, tehran, iran). interassay and intraassay coefficients of variation for serum total psa were 5.6% and 4.1%, respectively. the psa levels were shown as ng/ml and the lowest measurable concentration that could be distinguished was 0.01 ng/ml for free psa and 0.02 ng/ml for total psa. the precision of measurement method for total psa in saliva was determined according to the following protocol: 10 samples of saliva were assayed in 2 replicates at 2 separate times per day for 20 days and interassay and intra-assay coefficients of variation were 6.2% and 6.5%, respectively. serum and saliva protein levels were measured by biuret method (boehringer mannheim gmbh, diagnostica, germany) using technicon ra-1000 auto-analyzer and pyrogallol red method (chem enzyme, iran) using spectrophotometric assay, respectively. data analyses were done using the paired sample t test to investigate the differences in serum and saliva psa levels and pearson correlation test to evaluate correlations. a p value less than .05 was considered significant. results the free and total psa values in serum and saliva samples are shown in the table. there was a significant difference between serum and saliva total psa levels (0.75 ± 0.46 ng/ml versus 0.11 ± 0.06 ng/ml; p = .03). also, such a difference was noted between serum and saliva free psa levels (0.16 ± 0.10 ng/ml versus 0.03 ± 0.02 ng/ml; p = .04). no correlation was found between serum and salivary parameter mean (range) age, y 56.6 ± 9.1 (42 to 73) body mass index, kg/m2 25.70 ± 4.62 (19.7 to 41.4) total psa, ng/ml serum 0.75 ± 0.46 (0.4 to 2.5) salivary 0.11 ± 0.06 (0.05 to 0.30) free psa, ng/ml serum 0.16 ± 0.10 (0.02 to 0.50) salivary 0.03 ± 0.02 (0.01 to 0.10) protein, g/dl serum 6.90 ± 0.35 (6.20 to 7.70) salivary 0.08 ± 0.01 (0.06 to 0.11) demographic data and values of prostate-specific antigen (psa) and protein in serum and saliva of healthy men prostate-specific antigen in saliva and serum—ayatollahi et al 240 urology journal vol 4 no 4 autumn 2007 levels of the total or free psa in the participants. not surprisingly, there is a direct correlation between total psa and free psa levels in saliva, and also between total psa and free psa levels in serum (r = 0.45, p = .04 and r = 0.56, p < .001, respectively). furthermore, a significant correlation was found between free-total psa ratios in serum and saliva (r = 0.26, p = .04) and also between serum total psa-protein ratios in serum and salivary (r = 0.30, p = .02). finally, body mass index (bmi) inversely correlated with serum total psa-protein ratio (r = -0.38, p = .04) and serum free-total psa (r = 0.45, p = .01). discussion prostate-specific antigen, a single-chain 33-kd glycoprotein serine protease, is widely used as a clinical marker of prostate cancer.(6) the gene responsible for its expression is a member of the human kallikrein (hk) gene family on the long arm of chromosome 19. serum psa exists in different molecular forms and mainly binds to antitrypsin and α-2macroglobulin in a smaller proportion. approximately, 10% to 30% of total psa is not bound to protein and is called free psa.(5) although the function of psa in the salivary glands is not clear, it can be involved in regulating insulinlike growth factor binding protein and insulin-like growth factors. also, it may play a role in proteolysis or digestion-related function.(10) the concentration of salivary psa is very low (less than 0.03 ng/ml to 0.34 ng/ml).(12,14) in a study by mannello and colleagues on a group of 40 female volunteers, half of whom were taking contraceptives, the group taking the contraceptive exhibited a higher concentration of psa in saliva (mean, 0.099 ± 0.016 ng/ml; range, 0.04 ng/ml to 0.34 ng/ml). in the control group, the mean value was 0.048 ± 0.007 ng/ ml (range, 0.02 ng/ml to 0.15 ng/ml). however, psa concentration in serum did not differ between the two groups.(14) aksoy and associates determined changes in the psa concentration in serum and saliva over the menstrual cycle. the highest values were found on day 9 (follicular phase) and day 14 (midcycle) with values of 0.024 ± 0.011 ng/ml and 0.029 ± 0.013 ng/ml, respectively. no cases of psa concentration higher than 0.06 ng/ml was found in this study.(8) a study by breul and coworkers did not show the low psa concentration in saliva.(15) in their study, extremely high concentrations of psa were found in the saliva of 165 patients (20 women, 39 patients with benign prostatic hyperplasia, 24 with localized prostate carcinoma, 17 with metastasizing prostate carcinoma, 14 with a history of transurethral manipulation, and 51 with other urological diseases) with the values ranging between 129 ng/ml and 688 ng/ml. these values did not correlate with the serum concentrations, and so far, we cannot explain what caused these high values. it may be due to the hybritech assay showing a cross-reactivity with another protein in saliva. however, it is felt that these high values are somehow doubtful. in our study, we selected the healthy men, just for evaluation of correlations between free and total psa levels and free-total psa ratio between serum and saliva in their normal ranges as a pilot study. although a positive correlation was found between serum and saliva psa in one study,(8) turan and colleagues found that there was neither a correlation between serum and salivary psa levels nor between the patient's age and level of psa in saliva.(11) in our study, there was a significant difference between serum psa and salivary psa, or beween their free portion in the fluids. we also found that there was no correlation between serum and salivary total psa or free psa in healthy men, but a significant correlation was found in the ratio of free to total psa between serum and saliva. in order to eliminate the effect of protein concentrations in serum and saliva, we used the total psa-protein ratio in these two fluids. to our best knowledge, our experience is the first report in the literature that includes the ratio of psa to protein concentration in saliva. a significant correlation was found between serum total psa-protein and salivary total psa-protein ratios (p = .02). it can be concluded that free-total psa or total psa-protein ratios in saliva may be used to predict the same ratios in serum of healthy people, but due to another significant inverse correlation found between bmi and serum total psa-protein ratio and a positive correlation between bmi and serum free-total ratio, the discussed correlation between free-total psa ratios in serum and saliva should be analyzed with attention to bmi. prostate-specific antigen in saliva and serum—ayatollahi et al urology journal vol 4 no 4 autumn 2007 241 conclusion we concluded that fasting salivary ratio of free to total psa levels detected by radioimmunoassay technology may be useful for predicting the same ratio in serum of healthy men. also, there was a significant correlation between serum total psaprotein ratios in saliva and serum of men with a normal prostate. further studies are needed to draw final conclusion. conflict of interest none declared. references 1. slavkin hc. toward molecularly based diagnostics for the oral cavity. j am dent assoc. 1998;129:1138-43. 2. ferguson db. current diagnostic uses of saliva. j dent res. 1987;66:420-4. 3. mandel id. a contemporary view of salivary research. crit rev oral biol med. 1993;4:599-604. 4. malamud d. saliva as a diagnostic fluid. bmj. 1992;305:207-8. 5. lee p, pincus mr, mcpherson ra. diagnosis and management of cancer using serologic tumor markers. in: mcpherson ra, pincus mr, editors. henry’s clinical diagnosis and management by laboratory methods. 21st ed. philadelphia: saunders-elsevier; 2007. p. 1362-3. 6. chan dw, booth ra, diamandis ep. tumor markers. in: burtis ca, ashwood er, bruns de, editors. tietz textbook of clinical chemistry and molecular diagnostics. 4th ed. philadelphia: saunders-elsevier; 2006. p. 757-61. 7. wilbur dc, krenzer k, bonfiglio ta. prostate specific antigen (psa) staining in carcinomas of non-prostatic origin. am j clin pathol. 1987; 88:530. 8. aksoy h, akcay f, umudum z, yildirim ak, memisogullari r. changes of psa concentrations in serum and saliva of healthy women during the menstrual cycle. ann clin lab sci. 2002;32:31-6. 9. van krieken jh. prostate marker immunoreactivity in salivary gland neoplasms. a rare pitfall in immunohistochemistry. am j surg pathol. 1993;17:410-4. 10. elgamal aa, ectors nl, sunardhi-widyaputra s, van poppel hp, van damme bj, baert lv. detection of prostate specific antigen in pancreas and salivary glands: a potential impact on prostate cancer overestimation. j urol. 1996;156:464-8. 11. turan t, demir s, aybek h, atahan o, tuncay ol, aybek z. free and total prostate-specific antigen levels in saliva and the comparison with serum levels in men. eur urol. 2000;38:550-4. 12. lovgren j, valtonen-andre c, marsal k, lilja h, lundwall a. measurement of prostate-specific antigen and human glandular kallikrein 2 in different body fluids. j androl. 1999;20:348-55. 13. streckfus cf, bigler lr. saliva as a diagnostic fluid. oral dis. 2002;8:69-76. 14. mannello f, bianchi g, gazzanelli g. immunoreactivity of prostate-specific antigen in plasma and saliva of healthy women. clin chem. 1996;42:1110-1. 15. breul j, pickl u, hartung r. prostate-specific antigen in urine and saliva. j urol. 1993;149:302a. sexual dysfunction and infertility 111urology journal vol 4 no 2 spring 2007 sexual dysfunction in epileptic men mohammadreza nikoobakht, mahmood motamedi, amirhossein orandi, alipasha meysamie, ala emamzadeh introduction: the aim of this study was to evaluate the frequency of sexual dysfunction among epileptic patients. materials and methods: eighty married men between 22 and 50 years with a confirmed diagnosis of epilepsy were enrolled in this study. patients with other neurological diseases, hypertension, cardiovascular diseases, diabetes mellitus, underlying urogenital diseases, and impaired general health status were excluded. furthermore, those with mental health problems were identified by the standardized general health questionnaire-28 and were excluded. demographic and clinical characteristics of the disease were evaluated, and sexual function was assessed by the self-administered questionnaire of the international index of erectile function-15 (iief-15). results: of 80 patients, 34 (42.5%) had erectile dysfunction. there were no differences between the patients in the 3 age groups (> 30 years, 30 to 40 years, and > 40 years) in the iief scores. type of seizure had a significant correlation with erectile function score (p = .008). none of the iief domains scores were different between the patients with controlled epilepsy and those with uncontrolled epilepsy during the previous 6 months. however, frequency of epileptic seizures (before treatment) correlated with the scores for erectile function (r = 0.31; p = .005), orgasmic function (r = 0.23; p = .04), and sexual desire (r = 0.24; p = .03). conclusion: it seems that the main aspects of sexual activity such as erectile function, orgasmic function, and sexual desire are frequently impaired in epileptic patients. our findings were also indicative of a higher risk of sexual dysfunction in patients with partial seizures. urol j. 2007;4:111-7. www.uj.unrc.ir keywords: nervous system diseases, epilepsy, sexual activity, erectile dysfunction, partial epilepsy department of urology, sina hospital, tehran university of medical sciences, tehran, iran corresponding author: mohammadreza nikoobakht, md department of urology, sina hospital, hassanabad sq, tehran 1995345432, iran e-mail: nikoobakht_m@hotmail.com tel:+98 21 6671 7447 fax: +98 21 6671 7447 received november 2006 accepted march 2007 introduction sexual function can be altered in patients with different types of neurological disorders, especially those with an underlying undiagnosed neurological disease. impaired sexual activity affects the quality of life which is a very important indicator of the patient’s health status. thus, it is no longer acceptable to ignore such very important aspects of life.(1) about 40 million people are affected with epilepsy and seizure worldwide,(2) and numerous symptoms of sexual dysfunction can be seen in epileptic patients. the figures vary in different studies but are generally higher than those observed in the general population. many men with epilepsy suffer from loss of sexual desire, reduced sexual activity, and inhibited sexual arousal.(3-5) they also have organic sexual problems including lack of spontaneous morning penile tumescence, anorgasmia, and erectile dysfunction (ed).(5) in epileptic women, decreased sexual arousal, vaginismus, and dyspareunia are reported.(6) epileptic patients, especially men, have a lower marriage sexual dysfunction and epilepsy—nikoobakht et al 112 urology journal vol 4 no 2 spring 2007 rate compared to the general population, and married women have fewer children than expected.(4) moreover, it should be noticed that anticonvulsant drugs, especially the older types such as phenytoin, phenobarbital, primidone, carbamazepine, and sodium valproate may lead to hormonal changes (increased levels of estradiol and decreased levels of free testosterone in men), as well as decreased sexual desire and performance in both sexes.(7,8) on the other hand, sexual activity can provoke a seizure attack through hyperventilation and triggering the genital sensory cortical area. sexual phenomena may be a part of an epileptic seizure (eg, motor symptoms such as erection, lubrication, ejaculation, orgasm, pelvic sexual movements, or compulsive masturbation). finally, epileptic patients may display changes in their sexual behavior.(9-13) in this study, we evaluated the frequency of sexual dysfunction among epileptic men in iran and determined factors that affected their sexual function. materials and methods one hundred married men diagnosed with epilepsy were recruited in this study. the patients provided informed consent and the study was approved by the local ethics committee. they had no history of psychiatric diseases, diabetes mellitus, hypertension, hypothyroidism, hyperthyroidism, evident urogenital diseases, and other known neurological disorders. their clinical data on epilepsy were collected and controlled epilepsy was defined as no seizure episodes during the previous 6 months. for evaluating the patients’ sexual function, we used standardized self-administered questionnaire of the international index of erectile function-15 (iief-15) that addresses the relevant domains of male sexual function (appendix).(14) the iief-15 is scored on a likert scale with greater total numbers indicating better sexual function. the questions are divided into 5 sexual function domains: erectile function (questions 1 to 5 and 15; score, 1 to 30), sexual satisfaction (questions 6, 7, and 8; score, 0 to 15), orgasmic function (questions 9 and 10; score, 0 to 10), sexual desire (questions 11 and 12; score, 2 to 10), and overall satisfaction (questions 13 and 14; score, 2 to 10). scores greater than 25 for erectile function were classified as normal.(15) the patients were asked for having premature ejaculation in a separate subjective question. for assessment of mental health as a confounding factor, we used another standardized questionnaire named general health questionnaire-28 (ghq28).(16) this questionnaire contains 4 groups of 7 questions that evaluate the symptoms of depression, social function, psychosomatic disorders, anxiety, and sleep disorders. according to the ghq28, 20 patients had impaired health status and therefore, were excluded from the data analyses. statistical analyses were performed using the spss software (statistical package for the social sciences, version 11.0, spss inc, chicago, ill, usa). for 1sample comparison of any type of impairment in different aspects of the sexual function, we used the 95% confidence intervals. for comparison of qualitative variables, we used the chi-square test and the fisher exact test. patients in different age groups were compared for the iief scores by the kruskal-wallis test. a p value of less than .05 was considered significant. results demographic and clinical characteristics of the patients are depicted in table 1. the iief scores for each dimension of sexual function are outlined in table 2; there were no differences between the patients in the 3 age groups (> 30 years, 30 to 40 table 1. demographic and clinical characteristics of patients* characteristics patients mean age, y 34.2 ± 7.6 (22 to 50) mean duration of epilepsy, y 14.2 ± 8.7 (2 to 42) seizure type simple partial 3 (3.8) complex partial 13 (16.3) complex partial with secondary generalization 24 (30.0) generalized tonic-clonic 25 (31.2) absence 1 (1.2) myoclonic 13 (16.3) tonic 1 (1.2) frequency of seizures daily 3 (3.8) weekly 13 (16.2) 2 per month 3 (3.8) monthly 6 (7.5) 6 per year 6 (7.5) 4 per year 7 (8.7) 3 per year 5 (6.3) 2 per year 3 (3.8) 1 per year 9 (11.2) irregular 25 (31.2) controlled epilepsy 57 (71.3) *values in parentheses are percents, unless otherwise indicated. sexual dysfunction and epilepsy—nikoobakht et al urology journal vol 4 no 2 spring 2007 113 years, and > 40 years) in the iief scores. also, duration of epilepsy was not associated with the iief scores. figure 1 depicts the percentages of the patients with ed for each type of epilepsy. of 80 epileptic patients with a normal health status (according to the ghq28), 34 (42.5%; 95% confidence interval [ci], 31.7 to 53.3) had ed. type of seizure had a significant correlation with erectile function score (p = .008; figure 1). carbamazepine, sodium valproate, and phenytoin were the most common medications used for the treatment of our patients (figure 2), and epileptic table 2. iief scores in epileptic patients* patients’ age groups iief-15 all patients < 30 (n = 30) 30 to 40 (n = 32) > 40 (n = 18) p† erectile function (1 to 30) 23.3 ± 7.4 (1 to 30) 23.6 ± 7.0 23.7 ± 6.7 21.8 ± 9.4 .86 orgasmic satisfaction (0 to 10) 7.7 ± 2.9 (0 to 10) 7.5 ± 2.8 7.9 ± 2.6 7.7 ± 3.7 .60 intercourse satisfaction (0 to 15) 9.6 ± 3.8 (0 to 15) 9.8 ± 3.7 9.9 ± 3.2 8.6 ± 4.8 .81 sexual desire (2 to 10) 7.4 ± 2.2 (2 to 10) 7.3 ± 2.2 7.8 ± 1.7 6.9 ± 2.9 .86 overall satisfaction (2 to 10) 7.6 ± 2.3 (2 to 10) 7.1 ± 2.5 8.0 ± 1.8 7.5 ± 2.6 .48 *values are demonstrated as mean ± standard deviation. iief indicates international index of erectile function. †kruskal-wallis test. figure 2. types of medications prescribed for the patients with epilepsy. 0 5 10 15 20 25 30 35 40 45 50 ethosuximide primidone clonazepam topiramate phenobarbital lamotigine phenytoin sodium valproate carbamazepine anticonvulsant drugs p er ce nt o f p at ie nt s figure 1. frequency of erectile dysfunction in patients with different types of epilepsy. cpsg indicates complex partial with secondary generalization. 0 5 10 15 20 25 30 sim ple partial com plex partial cpsg generalized tonic-clonic abs ence myoclonic tonic type of epilepsy n um be r of p at ie nt s patients without ed patients with ed sexual dysfunction and epilepsy—nikoobakht et al 114 urology journal vol 4 no 2 spring 2007 seizures were controlled in 57 patients (71.3%). the relationship between the medications used for control of the seizure and each domain of sexual function is demonstrated in table 3. none of the iief domains scores were different between the patients with controlled epilepsy and those with uncontrolled epilepsy. however, frequency of epileptic seizures (before treatment) correlated with the scores for erectile function (r = 0.31; p = .005), orgasmic function (r = 0.23; p = .04), and sexual desire (r = 0.24; p = .03). nine patients (11.3%) reported premature ejaculation during the previous month and there was no correlation between premature ejaculation and seizure type, frequency of epileptic seizures, control of the disease, and the medication used. also, no correlation was found between the age or duration of epilepsy and any domains of the iief-15. discussion the mean age of our patients showed that they were in their sexually active ages, and therefore, their disease could directly affect their quality of life. although the frequencies of generalized and partial seizures were equal, generalized tonic-clonic seizure was the most common type of seizure in our patients. our study revealed a correlation between the partial seizures and ed similar to the literature.(17) inability to maintain erection, ejaculatory dysfunction, decreased sexual satisfaction, reduced sexual fantasies, and reduced orgasmic capacity are reported in patients with some types of epilepsy.(17,18) the prevalence of ed in our patients was 42.5% which is in accordance with the results of the massachusetts male aging study that was performed on men between 40 and 70 years and showed that 52% of responders had some degrees of ed.(19) however, in another study performed by the national health and social life survey (nhsls) on general population (age range, 18 to 59 years), it was demonstrated that 10.4% of men had mentioned inability to achieve and maintain erection.(20) in iran, safarinejad has studied 2674 iranian men aged 20 to 70 years and found that 18.8% of men interviewed reported ed.(21) although the method of detecting ed might have a significant role in the discrepancies of its rate in general population, we can assume that the condition resulted from epilepsy might have caused an increased rate ta bl e 3. d ru gs u se d fo r t re at m en t o f e pi le pt ic p at ie nt s an d t he ir r el at io n w ith s ex ua l f un ct io n d om ai ns * c ar ba m az ep in e s od iu m v al pr oa te p he ny to in la m ot ri gi ne p he no ba rb ita l c lo na ze pa m s ex ua l d om ai ns ye s (n = 3 7) n o (n = 4 3) ye s (n = 3 2) n o (n = 4 8) ye s (n = 1 5) n o (n = 6 5) ye s (n = 8 ) n o (n = 7 2) ye s (n = 6 ) n o (n = 7 4) ye s (n = 3 ) n o (n = 7 7) e re ct ile d ys fu nc tio n (n = 3 4) 13 ( 35 .1 ) 21 ( 48 .8 ) 14 ( 43 .8 ) 20 ( 41 .7 ) 11 ( 73 .3 )† 23 ( 35 .4 )† 3 (3 7. 5) 31 ( 43 .1 ) 2 (3 3. 3) 32 ( 43 .2 ) 1 (3 3. 3) 33 ( 42 .9 ) in te rc ou rs e di ss at is fa ct io n (n = 3 5) 17 ( 45 .9 ) 18 ( 41 .9 ) 13 ( 40 .6 ) 22 ( 45 .8 ) 8 (5 3. 3) 27 ( 41 .5 ) 1 (1 2. 5) 34 ( 47 .2 ) 4 (6 6. 7) 31 ( 41 .9 ) 1 (3 3. 3) 34 ( 44 .2 ) o rg as m ic d ys fu nc tio n (n = 1 6) 8 ( 21 .6 ) 8 ( 18 .6 ) 7 ( 21 .9 ) 9 ( 18 .8 ) 5 (3 3. 3) 11 ( 16 .9 ) 0 16 ( 22 .2 ) 2 (3 3. 3) 14 ( 18 .9 ) 3 (1 00 .0 )‡ 13 ( 16 .9 )‡ s ex ua l d es ire im pa irm en t (n = 23 ) 12 ( 32 .4 ) 11 ( 25 .6 ) 8 ( 25 .0 ) 15 ( 31 .3 ) 7 (4 6. 7) 16 ( 24 .6 ) 0 23 ( 31 .7 ) 2 (3 3. 3) 21 ( 28 .4 ) 1 (3 3. 3) 22 ( 28 .6 ) o ve ra ll di ss at is fa ct io n (n = 2 4) 11 ( 29 .7 ) 13 ( 30 .2 ) 1 1 (3 4. 4) 13 ( 27 .1 ) 7 (4 6. 7) 17 ( 26 .2 ) 0 24 ( 33 .3 ) 2 (3 3. 3) 22 ( 29 .7 ) 1 (3 3. 3) 23 ( 23 .9 ) p re m at ur e ej ac ul at io n (n = 9 ) 6 ( 16 .2 ) 3 ( 7. 0) 2 ( 6. 3) 7 ( 14 .6 ) 2 (1 3. 3) 7 ( 10 .8 ) 0 9 (1 2. 5) 2 (3 3. 3) 7 (9 .5 ) 0 9 ( 11 .7 ) *v al ue s in p ar en th es es a re p er ce nt s in r el at io n to th e nu m be rs o f p at ie nt s w ho r ec ei ve /d o no t r ec ei ve th e dr ug . †p = .0 07 ( ch i-s qu ar e te st ) ‡p = .0 07 ( f is he r ex ac t t es t) sexual dysfunction and epilepsy—nikoobakht et al urology journal vol 4 no 2 spring 2007 115 of ed in our patients. we found that ed was not associated with age in our epileptic patients, and this can be an indicator of epilepsy being an additional factor other than age that influences erectile function. impairment in other domains of sexual activity like the overall satisfaction of sexual activity and intercourse satisfaction was higher in our study in comparison with the findings of the nhsls study in which 8.1% of the respondents had no pleasure for doing sexual activity.(20) sexual desire was impaired in 28.8% of our patients, but in the nhsls study, only 15.8% had impaired libido during the previous year. premature ejaculation was the only aspect of the male sexual function that was as frequent or even less common in our series in comparison to its prevalence in the general population of men. in the nhsls study, for instance, 28.5% of men between 18 and 59 years had reported premature ejaculation.(20) the differences between our patients and general population in the nhsls study cannot be explained by age differences between the two studies because in our study, age of our patients did not have any correlation with any aspect of sexual dysfunction; however, it seems that with growing older, the process of aging and arteriosclerosis affects erectile function. the relationship between the frequency of epileptic seizures in our study and sexual desire may show that the preoccupation of repeating seizure attacks may interfere with the sexual desire and activity; this idea may be protected by the relationship found between the disease control and sexual desire in our patients. although in our study duration of the disease had no significant correlation with sexual dysfunction, it seems that in long-term, depression due to a chronic problem may affect sexual function, especially sexual desire and the overall satisfaction. on the other hand, a relationship was found between the control of the disease and the overall satisfaction. therefore, it seems that mental status and stability in mind may have had an important role in sexual satisfaction of our patients. carbamazepine, sodium valproate, and phenytoin were the most common medications used for the treatment of our patients. although there might be adverse effects on every aspect of sexual activity by medications, only phenytoin and clonazepam showed effects on erectile and orgasmic functions. overall, the effects of medical treatment in epilepsy can be important in the management of patients’ sexuality.(7,8) conclusion our findings indicate that sexual dysfunction, especially ed, is a frequent problem in epileptic patients. reduction of the frequency of epileptic seizures is of great importance in improving the quality of life and sexual health in epileptic patients. it may be useful for the patients to be assessed and managed via a complete protocol for sexual disturbances during the seizure management. patient education and management with a team consisting of a urologist, a psychiatrist, and a neurologist may be useful for improving the quality of life in epileptic patients. conflict of interest none declared. financial support this study was supported by the urology research center of tehran university of medical sciences. appendix international index of erectile function questionnaire over the past four weeks: 1. how often were you able to get an erection during sexual activity? (0) no sexual activity (1) almost never/never (2) a few times (much less than half the time) (3) sometimes (about half the time) (4) most times (much more than half the time) (5) almost always/always 2. when you had erections with sexual stimulation, how often were your erections hard enough for penetration? (0) no sexual activity (1) almost never/never (2) a few times (much less than half the time) (3) sometimes (about half the time) (4) most times (much more than half the time) (5) almost always/always sexual dysfunction and epilepsy—nikoobakht et al 116 urology journal vol 4 no 2 spring 2007 3. when you attempted sexual intercourse, how often were you able to penetrate (enter) your partner? (0) did not attempt intercourse (1) almost never/never (2) a few times (much less than half the time) (3) sometimes (about half the time) (4) most times (much more than half the time) (5) almost always/always 4. during intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? (0) did not attempt intercourse (1) almost never/never (2) a few times (much less than half the time) (3) sometimes (about half the time) (4) most times (much more than half the time) (5) almost always/always 5. during sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? (0) did not attempt intercourse (1) extremely difficult (2) very difficult (3) difficult (4) slightly difficult (5) not difficult 6. how many times have you attempted sexual intercourse? (0) no attempts (1) one to two attempts (2) three to four attmepts (3) five to six attempts (4) seven to ten attempts (5) eleven or more attempts 7. when you attempted sexual intercourse, how often was it satisfactory for you? (0) did not attempt intercourse (1) almost never/never (2) a few times (much less than half the time) (3) sometimes (about half the time) (4) most times (much more than half the time) (5) almost always/always 8. how much have you enjoyed sexual intercourse? (0) no intercourse (1) no enjoyment (2) not very enjoyable (3) fairly enjoyable (4) highy enjoyable (5) very highly enjoyable 9. when you had sexual stimulation or intercourse, how often did you ejaculate? (0) no sexual stimulation/intercourse (1) almost never/never (2) a few times (much less than half the time) (3) sometimes (about half the time) (4) most times (much more than half the time) (5) almost always/always 10. when you had sexual stimulation or intercourse, how often did you have the feeling of orgasm or climax? (0) no sexual stimulation/intercourse (1) almost never/never (2) a few times (much less than half the time) (3) sometimes (about half the time) (4) most times (much more than half the time) (5) almost always/always 11. how often have you felt sexual desire? (1) almost never/never (2) a few times (much less than half the time) (3) sometimes (about half the time) (4) most times (much more than half the time) (5) almost always/always 12. how would you rate your sexual desire? (1) very low/none at all (2) low (3) moderate (4) high (5) very high 13. how satisfied have you been with your overall sex life? (1) very dissatisfied (2) moderately dissatisfied (3) about equally satisfied and dissatisfied (4) moderately satisfied (5) very satisfied 14. how satisfied have you been with your sexual relationship with your partner? sexual dysfunction and epilepsy—nikoobakht et al urology journal vol 4 no 2 spring 2007 117 (1) very dissatisfied (2) moderately dissatisfied (3) about equally satisfied and dissatisfied (4) moderately satisfied (5) very satisfied 15. how would you rate your confidence that you could get and keep an erection? (1) very low (2) low (3) moderate (4) high (5) very high references 1. lundberg po, ertekin c, ghezzi a, swash m, vodusek d; european federation of neurological societies task force on neurosexology. neurosexology: guidelines for neurologists. eur j neurol. 2001;8 suppl 3:2-24. 2. fisher rs, van emde boas w, blume w, et al. epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ilae) and the international bureau for epilepsy (ibe). epilepsia. 2005;46:470-2. 3. saunders m, rawson m. sexuality in male epileptics. j neurol sci. 1970;10:577-83. 4. dansky lv, andermann e, andermann f. marriage and fertility in epileptic patients. epilepsia. 1980;21:261-71. 5. guldner gt, morrell mj. nocturnal penile tumescence and rigidity evaluation in men with epilepsy. epilepsia. 1996;37:1211-4. 6. demerdash a, shaalan m, midani a, kamel f, bahri m. sexual behavior of a sample of females with epilepsy. epilepsia. 1991;32:82-5. 7. isojarvi ji, repo m, pakarinen aj, lukkarinen o, myllyla vv. carbamazepine, phenytoin, sex hormones, and sexual function in men with epilepsy. epilepsia. 1995;36:366-70. 8. duncan s, blacklaw j, beastall gh, brodie mj. antiepileptic drug therapy and sexual function in men with epilepsy. epilepsia. 1999;40:197-204. 9. blumer d, walker ae. sexual behavior in temporal lobe epilepsy. a study of the effects of temporal lobectomy on sexual behavior. arch neurol. 1967;16:37-43. 10. herzog ag, seibel mm, schomer dl, vaitukaitis jl, geschwind n. reproductive endocrine disorders in men with partial seizures of temporal lobe origin. arch neurol. 1986;43:347-50. 11. jensen p, jensen sb, sorensen ps, et al. sexual dysfunction in male and female patients with epilepsy: a study of 86 outpatients. arch sex behav. 1990;19:114. 12. fenwick pb, mercer s, grant r, et al. nocturnal penile tumescence and serum testosterone levels. arch sex behav. 1986;15:13-21. 13. jensen p, jensen sb, sorensen ps, et al. sexual dysfunction in male and female patients with epilepsy: a study of 86 outpatients. arch sex behav. 1990;19:114. 14. rosen rc, cappelleri jc, gendrano n 3rd. the international index of erectile function (iief): a stateof-the-science review. int j impot res. 2002;14:22644. 15. cappelleri jc, rosen rc, smith md. some developments on the international index of erectile function (iief). drug inf j. 1999;33:179-90. 16. goldberg dp, gater r, sartorius n, et al. the validity of two versions of the ghq in the who study of mental illness in general health care. psychol med. 1997;27:191-7. 17. taylor dc. sexual behavior and temporal lobe epilepsy. arch neurol. 1969;21:510-6. 18. shukla gd, srivastava on, katiyar bc. sexual disturbances in temporal lobe epilepsy: a controlled study. br j psychiatry. 1979;134:288-92. 19. feldman ha, goldstein i, hatzichristou dg, krane rj, mckinlay jb. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994;151:54-61. 20. laumann eo, paik a, rosen rc. the epidemiology of erectile dysfunction: results from the national health and social life survey. int j impot res. 1999;11 suppl 1:s60-4. 21. safarinejad mr. prevalence and risk factors for erectile dysfunction in a population-based study in iran. int j impot res. 2003;15:246-52. risk factors associated with chronic kidney disease in infants with posterior urethral valve: a single center study of 110 patients managed by valve ablation and bladder neck incision hossein amirzargar1, elaheh shahab2, seyyedmohammad ghahestani1, pooya hekmati1, hamid arshadi1* purpose: concurrent valve ablation and bladder neck incision is suggested as an effective and safe treatment approach in posterior urethral valve children with prominent bladder neck. we evaluated chronic kidney disease risk factors in these children. materials and methods: we retrospectively reviewed medical records of children with posterior urethral valve and included those younger than 18 years old who underwent valve ablation and bladder neck incision at our institution. we recorded patient demographics, presenting symp-toms, laboratory and radiographic data. our primary outcome was chronic kidney disease de-fined as stage 3 chronic kidney disease or higher. renal outcome risk factors such as preoperative vesicoureteral reflux and serum creatinine, age at diagnosis, adjuvant urinary diversion were ana-lyzed. results: a total of 110 patients met our inclusion criteria. the median age at diagnosis was 10.4 months (range 14 days to 12 years). prenatal diagnosis in 72.7% was the most common presenta-tion. mean follow-up duration was 3 years and 12 (10.9%) patients progressed to chronic kidney disease. preoperative serum creatinine greater than 1 mg/dl was the only factor associated with progression to chronic kidney disease. conclusion: in our group of children with posterior urethral valve ablation and bladder neck in-cision, initial creatinine value of greater than 1 mg/dl is more probably associated with renal im-pairment while; vesicoureteral reflux, age at diagnosis, presenting symptoms, and adjuvant uri-nary diversion were not significant prognostic factors. further randomized controlled evaluations are required to analyze the effects of concurrent valve ablation and bladder neck incision on renal outcome. keywords: creatinine; kidney failure, chronic; renal insufficiency, chronic; urethra; urethral obstruction introduction puv (posterior urethral valve) is the most sig-nificant congenital cause of lower urinary tract ob-struction in male children leading to progressive renal damage and end-stage renal disease in a proportion of them.(1-3) although valve ablation is the treatment of choice for relieving obstruction in puv patients, the risk of chronic kidney disease (ckd) remains notable even after ablating the valves.(4) we have performed endoscopic valve ablation and bladder neck incision (bni) from 1996 for puv patients with prominent bladder neck. bni is considered beneficial in boys with bladder neck obstruction and the combination with valve ablation in puv patients with prominent blad-der neck is suggested as being safe and effective.(5-7) regarding the promising results of concurrent valve ablation and bni, it has become our premier surgical option in puv management;(8,9) but the prognostic significance of factors determining renal outcome in puv patients undergoing the combination surgery is unclear 1division of pediatric urology, pediatric center of excellence, tehran university of medical sciences, no 62, dr. gharib’s street, keshavarz blvd, po box: 1419733151, tehran, iran. 2department of surgery, kosar general hospital, semnan university of medical sciences, go-lestan blvd, po box: 3519899558, semnan, iran. *correspondence: division of pediatric urology, pediatric center of excellence, tehran university of medical sci-ences, no 62, dr. gharib’s street, keshavarz blvd, po box: 1419733151, tehran, iran. tel: +98 21 61472017, fax: +98 21 66565500. e-mail: drhamidarshadi@yahoo.com. received march 2020 & accepted september 2020 and few studies are addressing the aforementioned issue. therefore, we tried to identify ckd risk factors in puv patients who underwent valve ablation with bni at our center. materials and methods study population children who underwent surgical ablation of puv with bni at our pediatric center of excel-lence, tehran, iran from 2007 to 2017 were evaluated retrospectively. inclusion and exclusion criteria in this study, we included children younger than 18 years old who underwent posterior urethral valve ablation with bni at our institution over a period of 10 years. exclusion criteria were incomplete data, previous surgical intervention, and less than two years of follow-up. procedures we performed urethral catheter drainage followed by endoscopic valve ablation with bni in all children as pediatric urology urology journal/vol 18 no. 4/ july-august 2021/ pp. 429-433. [doi: 10.22037/uj.v16i7.6038] vol 18 no 4 july-august 2021 138 the initial treatment management, while high urinary diversion (cutaneous ureterosto-my or pyelostomy) was done if renal function or hydronephrosis did not improve after 48 hours of lower drainage or urosepsis secondary to pyonephrosis occurred. urethral valves were fulgurated using bugbee electrodes with an appropriate cystoscope. incision of bladder neck was done at 6 o’clock position by cutting current, just proximal to verumonta-num and not deep into the adventitia. cutaneous vesicostomy is not our advocated procedure for urinary drainage in puv patients. evaluations after institutional review board approval, medical records including demographics, age at diag-nosis, prenatal findings (oligohydramnios, urinary system abnormalities), the evidence of vesicoureteral reflux (vur), urinary ascites, laboratory data before and after relief of obstruction like serum creatinine(cr), glomerular filtration rate (gfr), urinalysis, urine culture and type of surgical intervention were gathered. in all included patients, puv diagnosis was made using voiding cystourethrogram (vcug) and confirmed via cystoscopy, and vur was graded from ⅰ to ⅴ according to the standard classification on vcug. serum cr at diagnosis and last follow-up were recorded. regarding the diversity of age at diag-nosis of involved patients and different range of normal values for each age group, we catego-rized serum cr at diagnosis as ≤ one mg/dl or more. our primary outcome was ckd. patients were classified into two groups; with or without ckd at the last follow-up. ckd was defined as stage 3 ckd (gfr less than 60 ml/minute/1.73 m² by schwartz formula for children less than 18 years old and by the modification of diet in renal disease study equation in adults)(10) or higher according to king disease outcome quality initiative guidelines. the data for the calculation of gfr at diagnosis was not accessible for many of our patients. patients not willing to continue follow-up visits after two years were not excluded from the study but their last data sufficient for gfr calculation were included. statistical analysis statistical analysis was carried out by spss statistics for windows, version 13.0 (spss inc., chicago, il, usa) version 13. numerical variables were reported as mean, standard deviation, and range. the chi-square and fisher exact tests were used to analyze the association between categorical variables and student’s t-test was used for comparison of means between groups. a p-value of less than .05 is considered statistically significant. results a total of 110 patients fulfilled our inclusion criteria. the mean age at diagnosis was 14.7 ± 26.13 months (range from 14 days to 12 years) which 75.5% (83 patients) were within one-year-old and 24.5% (27 patients) were older. the range of follow-up period was 2-8 years (mean 3 years). the clinical presentation was prenatal diagnosis in 80 (72.7%), febrile urinary tract infection in 10 (9.1%), voiding disturbances or urinary incontinence in 24(20.9%), and one patient was diag-nosed during evaluation for renal failure. ckd was detected in 12 (10.9%) of patients at the last follow-up. 6 patients (5.45%) aggravated into end-stage renal disease of which 4 (3.63%) died due to uremic complications. univariate analysis of the risk factors for ckd in the two groups is listed in table 1. 92 patients (83.6%) were treated only with endoscopic valve ablation and bni while high urinary diversion as ureterostomy or pyelostomy was required additionally in 13 (11.8%) and 5 (4.5%) patients, respectively. although not statistically significant but upper tract urinary diversion was more necessary in ckd group, 3 of 12 patients (16.7 %) compared to 15 of 98 patients (83.3 %) in non-ckd group (p = .25). we considered the age at diagnosis as the date of surgical relief of puv; since we performed valve ablation with bni not so far after diagnosis. ckd developed in 7 (8.4%) of patients diagnosed within one-year-old age and in 5 (18.5%) of those diagnosed later; which is statistically insignificant (p = .15). the mean serum cr at diagnosis was 1.09 ± 1.8 (.3-14) mg/dl and at last follow-up was .65 ± .44 (.3-3) mg/dl. elevated initial serum cr greater than one mg/dl was seen in 22.7% of cases and it was more significant in the ckd group (p = .001). 84 (76.3%) of patients had vur at diagnosis which was bilateral in 60 patients (54.5%), right sided in 10 (9.1%), and left sided in 14 patients (12.7%). chronic kidney disease and puvs amirzargar et al. variables ckd(n = 12) non-ckd(n = 98) p-valueª age at diagnosis ≤ 1year, n( % ) 7 (58.3%) 76 (77.5%) ns age at diagnosis, month; mean ± sd(range) 24.3 ± 32.6 (1-96) 13.5 ± 25 (0.5-144) ns uti, n( % ) 2 (16.7%) 8 (8.2%) ns vur, n( % ) 10 (83.3%) 74 (75.5%) ns cr at diagnosis > 1mg/dl, n( % ) 9 (75%) 16 (16.3%) <0.05 cr at diagnosis, mg/dl; mean ± sd(range) 1.88 ± 0.92 (0.5-2.8) 0.99 ± 1.85 (0.3-14) ns cr at last followup, mg/dl; mean ± sd(range) 1.75 ± 0.65 (0.6-3) 0.52 ± 0.11 (0.3-1.1) <0.05 valve ablation with bni, n( % ) 9 (75%) 83 (84.7%) ns upper tract diversion, n( % ) 3 (25%) 15 (15.3%) ns bilateral vur, n( % ) 8 (80%) 52 (70.3%) ns vurd syndromeᵇ, n( % ) 0 (0%) 19 (19.4%) ns table 1. comparison of patients’ characteristics at diagnosis and last follow up. abbreviations: bni: bladder neck incision; ckd: chronic kidney disease; cr: creatinine; ns: non significant; uti: urinary tract infection; vur: vesicoureteral reflux; vurd: vesicoureteral reflux dysplasia ª: p-value < 0.05 is significant. ᵇ: unilateral massive vur into a dysplastic kidney. vol 18 no 4 july-august 2021 430 the presence of vur (p = .77) or its laterality (p = .48) was not associated with an increased risk of ckd in our study. vur improved after valve ablation and bni spontaneously in most of our patients and anti-reflux surgery was rarely required. discussion despite improvements in the medical and surgical treatment of puv, it remains one of the main causes of ckd in children.(3) the incidence of ckd was 10.9% in our study. although numerous studies have been conducted addressing prognostic factors affecting puv management outcome, there is still controversy regarding which factors determine the renal out-come. application of bni simultaneously with valve ablation has been proposed as an effective treat-ment modality that may reduce bladder dysfunction and consequently renal damage.(8,9) we conducted a retrospective and non-randomized study to help clarify the significance of vari-ous factors on long-term renal outcome in our group of patients on whom we have performed en-doscopic valve ablation with bni. vesicostomy is not our choice for urinary diversion in puv patients as we believe that effective bladder drainage is obtained by proper valve ablation and catheterization.(11) in the severe dis-tended ureter, relief of bladder obstruction may not be able to drain the upper urinary system suf-ficiently due to failed peristalsis and coaptation, therefore cutaneous pyeloureterostomy seems more efficient.(11) proponents of high urinary diversion believe that temporary pyeloureterostomy doesn’t interfere with bladder function in long term as well as improving the renal function by adequate drainage of the pyelocaliceal system.(12-14) high urinary diversion was done in 16.3% of our patients in case of pyonephrosis or when hy-dronephrosis or renal failure did not improve after 48 hours of bladder drainage. there is conflicting data regarding urinary diversion in puv patients.(13,14) some authors believe that renal function is independent from the kind of treatment modality chosen for patients as they emphasize on the role of congenital renal dysplasia which makes these patients prone to pro-gressive renal failure.(15-17) in our study, ckd occurred in 9 (9.8%) patients treated simply with valve ablation and bni which was not significantly different from 3 patients (16.7%) with upper urinary diversion. our findings are similar to previous studies suggesting that long-term renal function is affected by other factors like severity of disease at initial presentation other than the kind of therapy start-ed for the patient.(17,18) however, to help clarify the role of urinary diversion in renal protection of patients with puv, larger randomized-controlled studies comparing different treatment modali-ties are necessary. age at diagnosis has been suggested to influence renal outcome in puv patients.(19,20) 72.7% of our patients were diagnosed prenatally. some authors claim that prenatal diagnosis may improve the renal prognosis due to earlier relief of obstruction and slowing the renal damage process.(21) on contrary, others have concluded that diagnosis at an older age may be an indicator of a milder and more benign form of disease which caused later presentation. (17,22) 75% of our patients were diagnosed within one year of age. our analysis of age at diagnosis and final renal outcome did not show any difference between patients diagnosed before and after one year of age. our study is similar to earlier ones.(17,22) serum cr level at diagnosis has been mentioned as the most significant prognostic indicator in puv patients. (23-25) in our study, ckd occurred in 3.5% of patients when serum cr at diagnosis was ≤ 1 mg/dl and the frequency increased to 36% when initial serum cr was above 1 mg/dl which the difference was statistically significant (p = .001). our results, similar to previous studies, indicate that higher initial serum cr levels determine a poorer renal outcome.(23,25-27) the retrospective method of our study limited us in gathering data necessary for other important clinical factors in renal prognosis such as serum cr level at oneyear age, nadir cr after a time of bladder decompression, bladder function status and etc. in our study, 84 patients (76.3%) had vur on their initial vcug of which 27 patients (32.1%) showed complete resolution after surgical relief of obstruction. our data is similar to other studies showing a prevalence of 50-70% for puv patients with vur at the time of diagnosis(28) and a resolution of up to 50% for vur after surgical correction.(29) we did not find any correlation between the presence of vur (either bilateral or unilateral) and final renal outcome (p = .77). otherwise, ckd developed in 8.3% of patients with unilateral vur compared to 13.3% of patients with bilateral vur, which the difference was not statisti-cally significant (p = .48). though our study confirms the results of most prior ones,(26,30) but some authors believe that bi-lateral vur implies a poorer renal outcome(4,25) and unilateral severe vur protecting contrala-teral kidney by its pop-off mechanism is a good prognostic factor.(17) in our study, ckd did not develop in cases with vesicoureteral reflux dysplasia syndrome (uni-lateral massive vur into a dysplastic kidney) and in 13.2% of patients with other patterns of vur at diagnosis; but the difference was not statistically significant (p = .12). conclusions our findings are consistent with the emerging significance of initial serum cr and gfr values in the final renal outcome of puv patients undergoing valve ablation with bni. further prospective studies are necessary to clarify the prognostic significance of different renal risk factors. conflict of interest none declared by the auhtors. references 1. hebenstreit d, csaicsich d, hebenstreit k, muller-sacherer t berlakovich g, springer a. long-term outcome of pediatric renal transplantation in boys with posterior urethral valves. j pediatr surg. 2018; 53:2256-60. 2. uthup s, binitha r, geetha s, hema r, kailas l. a follow-up study of children with posterior pediatric urology 431 chronic kidney disease and puvs amirzargar et al. urethral valve. indian j nephrol. 2010; 20: 725. 3. vasconcelos ma, acs es, gomes ir, carvalho ra, pinheiro sv, colosimo ea, et al. a clinical predictive model of chronic kidney disease in children with posterior urethral valves. pediatr nephrol. 2019; 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152: 698-701. 22. kibar y, ashley ra, roth cc, frimberger d, kropp bp. timing of posterior urethral valve diagnosis and its impact on clinical outcome. j pediatr urol. 2011; 7:538-42. 23. sarhan o, el-dahshan k, sarhan m. prognostic value of serum creatinine levels in chil-dren with posterior urethral valves treated by primary valve ablation. j pediatr urol. 2010; 6: 11-4. 24. ansari ms, gulia a, srivastava a, kapoor r. risk factors for progression to endstage renal disease in children with posterior urethral valves. j pediatr urol. 2010; 6: 261-4. 25. otukesh h, sharifiaghdas f, hoseini r, fereshtehnejad sm, rabiee n, kiaiee mf, et al. long-term upper and lower urinary tract functions in children with posterior urethral valves. j pediatr urol. 2010; 6: 143-7. 26. nickavar a, otoukesh h, sotoudeh k. validation of initial serum creatinine as a predic-tive factor for development of end stage renal disease in posterior urethral valves. ind j pediatr. 2008; 75:695-7. 27. nimako b, lazarus j, dewan p, nourse p, gajjar p. are early prognostic indicators reliable in posterior urethral valves management? african j urol.2018; 24:243-7. 28. lopez pereira p, martinez urrutina mj, espinosa l, lobato r, navarro m, jaureguizar e. bladder dysfunction as a prognostic factor in patients with posterior urethral valves. bju int. 2002; 90:308-11. 29. puri p, kumar r. endoscopic correction of vesicoureteric reflux secondary to posterior urethral valves. j urol. 1996; 156; 680-682. noninvasive stent removal in pediatric ureteroneocystostomyissi vol 18 no 4 july-august 2021 432 30. sarhan om, el-ghoneimi aa, helmy te, dawaba ms, ghali am, ibrahiem el-hi. posterior urethral valves: multivariate analysis of factors affecting the final renal outcome. j urol. 2011; 185: 2491-5. noninvasive stent removal in pediatric ureteroneocystostomyissi pediatric urology 433 unclassified role of p-erk1/2 in benign prostatic hyperplasia during hyperinsulinemia yong-zhi li1, ben-kang shi2, jing-yu li3, xing-wang zhu1, jia liu1, yi-li liu1* purpose: using a rat model of hyperinsulinemia, the present study investigated the role of p-erk1/2 in benign prostatic hyperplasia (bph). materials and methods: forty male sprague-dawley rats were randomly selected and assigned to four groups: high fat diet (hfd)+bph (n=10), hfd (n=10), bph (n=10), and control (n=10) groups. hyperinsulinemia was induced by hfd feeding, while bph was induced using testosterone propionate. plasma glucose, plasma insulin and bodyweight were examined weekly. immunohistochemistry (ihc) and western blot analysis were used to analyze the expression of erk1/2 and p-erk1/2 in rat prostates. results: plasma glucose and plasma insulin levels were significantly greater in the hfd+bph and hfd groups, when compared to the other two groups (p < 0.05). prostate weights were significantly greater in the hfd+bph, hfd and bph groups, than in the control group (p < 0.05). ihc and western blot analysis revealed that p-erk1/2 expression was greater in the hfd+bph group than in the other three groups (p < 0.05). conclusion: androgens plus a hyperinsulinemic condition induced by hfd can result in prostatic cell hyperplasia, and this mechanism may be correlated to the upregulation of p-erk1/2. further investigations of this possibility are required. keywords: p-erk1/2; hyperinsulinemia; bph; androgen; erk1/2 introduction benign prostatic hyperplasia (bph), which is caused by the nonmalignant-anomalous growth of the prostate gland, is the most common benign disease in elderly men and is characterized by augmented cell proliferation and/or contractility of the gland(1). there are multiple causes for bph, and its development and differentiation are affected by genetic, nutritional, and hormonal factors(2-4). recent studies have demonstrated that several other factors play a role in bph development, including inflammatory mediators, oxidative stress, and ischemia. however, there is no consensus as to which is the most important(5-8). a parallel increase in the incidence of type-2 diabetes mellitus and bph has been reported(9). the study conducted by qu et al. revealed that prostate volume (pv) is correlated with diabetes in elderly bph patients(10). the study conducted by ozden et al. demonstrated that the transition zone and pv have a positive relationship with serum insulin, suggesting that hyperinsulinemia is a general pathogenic factor for bph(11). both experimental and clinical reports have shown an association between insulin resistance and bph(12-14). there are two major insulin signal transduction pathways: (1) the insulin receptor substrate/phosphatidylinositol 3-kinase (irs/pi-3 kinase) pathway, which 1department of urology, the fourth affiliated hospital of china medical university, shenyang, liaoning province, 110032 china. 2department of urology, qilu hospital of shandong university, jinan, shandong province, 250012 china. 3first department of urology, central hospital of dandong, dandong, liaoning province, 118010 china. *correspondence; department of urology, the fourth hospital of china medical university, no.4 chongshan east road, huanggu district, shenyang 110032, china. tel: +86 18900913055. fax: +86 024 62043486. e-mail: liuyy_771@163.com. received october 2019 & accepted july 2020 is correlated to the intake and metabolism of blood sugar; (2) the raf/mitogen-activated protein kinase (mek)/extracellular-signal-regulated kinase (erk) (raf/mek/erk) pathway, which has profound effects on cellular proliferation. both the raf/mek/erk and irs/pi-3 kinase pathways control cellular proliferation and/or differentiation(13). however, it is the irs/pi-3 kinase pathway that is inhibited during hyperinsulinemic conditions(15). thus, it was hypothesized that during hyperinsulinemic conditions, cellular proliferation and/ or differentiation is a result of mek/erk activation. erk, containing erk1 and erk2, is a member of the family of mitogen-activated protein kinases (mapk), which has a wide distribution, and contributes to a number of physiological processes, including the regulation of cellular proliferation, differentiation and apoptosis. phosphorylation by erk (p-erk) results in the translocation of several transcription factors to the nucleus (e.g. ap-1, elk-1 and sap), which promote cellular proliferation. it has now been established that hyperinsulinemia may be due to activation of the signaling pathway belonging to p-erk1/2, which is a member of the family of mapk(16). the aim of the present study was to assess the role of erk signaling during hyperinsulinemic conditions. therefore, this trial was conducted to evaluate the role of p-erk1/2 in the cause of prostatic hypertrophy. urology journal/vol 18 no. 2/ march-april 2021/ pp. 225-229. [doi: 10.22037/uj.v16i7.5694] materials and methods animals all experiments were performed in accordance with the guiding principle of the institutional animal ethics committee, and approved by the animal care committee of china medical university. male specific pathogen-free (spf) sprague-dawley (sd) rats (nine weeks, 190 ± 10 g) were purchased from the experimental animal center of china medical university. the animals were kept in our in-house colony with automatic daynight control (12/12 hours), and allowed free access to food and water. these animals were acclimated for one week prior to the start of the experiments. chemicals and dose administration testosterone propionate (tp, 25 mg/ml) was obtained from shanghai general pharmaceutical co., ltd. (batch 081004). anti-erk1/2, anti-p-erk1/2 and igg were purchased from santa cruz biotechnology inc. (ca, usa). experimental design hyperinsulinemia was induced by hfd feeding for 8 weeks, while bph was induced by tp injection for 4 weeks. sd rats were randomly selected and assigned to four groups (each group contain 10 rats): high fat diet (hfd)+bph, hfd, bph, and control groups. rats were tested for blood sugar and blood insulin levels each week. four weeks after the start of the experiment, rats in the hfd+bph and bph groups were given subcutaneous injection of testosterone (20 mg/kg; wako chemicals, tokyo, japan) each week for four weeks. rats in the hfd and control groups were given the same volume of olive oil (20 mg/kg). eight weeks later, one rat, which was randomly chosen from each group, was sacrificed for confirmation of bph. in total, 40 sd rats were used in the present study. all the animals were sacrificed by cervical dislocation. diet for the induction of experimental hyperinsulinemia in the present study, high fat diet (hfd) is special feed for animals. hfd comprised of 5.3 kcal g−1, 17% carbohydrate, 25% protein and 58% kcal of fat for a period of eight weeks(17). immunohistochemistry immunohistochemistry was performed on 4-μm-thick sections after deparaffinization. microwave antigen retrieval was performed in citrate buffer, ph 6.0, for 10 minute, prior to peroxide quenching with 3% h2o2 in phosphate buffered saline (pbs, ph 7.4) for 10 minutes. then, the sections were washed in water and pre-blocked with normal goat or rabbit serum (santa cruz biotechnology inc.) for 10 minutes. for the primary antibody reaction, the slides were incubated with anti-p-erk 1/2 hcv (santa cruz, ca, usa) (diluted at 1:100) overnight at 4°c. then, the sections were incubated with biotinylated secondary antibodies (1:1,000) for one hour. after washing with pbs, streptavidin-horseradish peroxidase was applied. finally, the sections were rinsed with pbs and developed using diaminobenzidine tetrahydrochloride substrate for 10 minutes. at least three random fields for each section were examined at 100× magnification. a fiber image analysis instrument (metamorph/dp10/bx51, beijing, china) was used to determine the integrated optical density (iod) of p-erk1/2 and erk1/2. next, 10-40 fields per group were examined at 400× magnification. the analysis was performed by two individuals who were blinded to the analyzed groups. the results were presented as mean ± standard error of the mean (sem) for two separate observations(18). western blot analysis western blot was performed, as previously described role of p-erk1/2 in hyperinsulinemiali et al. figure 1. showed the he expression and p-erk1/2 expression in the four groups. figure 1a shows the microscopic prostate gland cavity was bigger in the hfd+bph and bph groups than in the hfd and control groups. for these groups, adenomatosis was significant, stratified epithelium appeared and was disarranged, and interstitial fibrous tissue and smooth muscle tissue increased, when compared to the hfd and control groups. the microscopic prostate tissue in the hfd group had none of those characteristics, except for the irregular glandular cavity. figure 1b show the p-erk1/2 expression in the cytoplasm of prostate tissues. a greater expression was identified in the hfd+bph group, when compared to the other three groups. the hfd group and bph group had detectable p-erk1/2 expression levels, while the control group did not. vol 18 no 2 march-april 2021 226 unclassified 227 (16). briefly, the membranes were incubated overnight at 4°c with the primary antibody against either mek1/2 (1:400, cell signaling technology, beverly, ma, usa), or p-mek1/2 (1:400, cell signaling). the signals were detected using an enhanced chemiluminescence kit (amersham, buckinghamshire, uk). β-actin (1:1,000, santa cruz biotechnology) was used as the loading control. three independent experiments were performed for each animal. statistical methods data are expressed as the mean ± standard deviation (sd). the significance of differences among groups for the quantitative index was determined using one-way anova, followed by a post hoc lsd test. the hepatic histopathologic evaluation was performed using the mann-whitney u test. the statistical analysis was conducted using spss 19.0 software, and a p < 0.05 was considered statistically significant. results general results as shown in table 1, the hfd+bph and hfd groups had greater plasma glucose and plasma insulin levels, suggesting that hyperinsulinemia has been established (p < 0.05). bodyweight in the hfd+bph and hfd groups were significantly greater than that in the bph and control groups (all p < 0.05). prostate weights were greater in the hfd+bph, hfd and bph groups than those in the control group (p < 0.05). prostate weights were greater in the bph group than those in the control group, but the difference was not statistically significant. however, as for prostatic index, hfd does not increase prostate mass with (0.705 versus 0.778) or without bph (0.638 versus 0.657). hence, under this experimental model hfd influence was not so direct. immunohistochemistry figure 1a demonstrates that microscopic prostate gland cavities were bigger in the hfd+bph and bph groups than in the hfd and control groups. for these groups, adenomatosis was significant, stratified epithelium appeared and was disarranged, and interstitial fibrous tissue and smooth muscle tissue increased, when compared to the hfd and control groups. the microscopic prostate tissues in the hfd group had none of these characteristics, except for irregular glandular cavities. figure 1b shows the p-erk1/2 expression in the cytoplasm of prostate tissues. a greater expression was identified in the hfd+bph group than in the other three groups. the hfd and bph groups had detectable p-erk1/2 expression, while the control group did not. western blot analysis as shown in figures 2c and 2d, the expression of erk1/2 was strongest in the hfd+bph group. however, the difference among the four groups was not statistically significant. furthermore, p-erk1/2 expression differed among groups, with the strongest expression observed in the hfd+bph group, which was significantly different from the other three groups (all, p < 0.01; figures 2a and 2b). furthermore, the expression of p-erk1/2 was statistically greater in the hfd group than in the control group (p < 0.01). discussion benign prostatic hyperplasia is a very complex phenomenon that includes structural and functional development, and this phenomenon is mainly administered by androgens, estrogen and mesenchymal-epithelial figure 2. western-blot expression of (c, d) erk1/2 and (a, b) p-erk1/2 in the four groups. as shown in figure 2 (c, d), the expression of erk1/2 was strongest in the hfd+bph group. however, the differences among the four groups were not statistically significant. as shown in figure 2 (a, b), the p-erk1/2 expression differed among groups, with the strongest expression observed for the hfd+bph group, which was significantly different from the other three groups (all, p < 0.01). the expression of p-erk in the hfd group was statistically greater than in the control group (p < 0.01). role of p-erk1/2 in hyperinsulinemiali et al. interactions(19). it has been reported that hyperinsulinemia, secondary to insulin resistance (ir), is an independent risk factor for bph development(20,21). prostatic vascular lesions can also be induced by atherosclerosis, which could lead to heavier prostate tissue due to ischemia, and contribute to the development of bph(22). ozden et al.(11) found that both transition zone and prostate volumes were positively correlated to serum insulin levels, which suggests that hyperinsulinemia may be a general pathogenic factor for bph. in the present study, a model of rat hyperinsulinemia was successfully established, and it was found that hfd feeding could significantly increased body weight. moreover, it was found that testosterone produced greater prostate weight gain, when compared with hfd feeding. this result demonstrates the importance of androgens in bph. however, combination of testosterone injections with hfd did not increase prostatic index compared with bph group, while hfd without testosterone injections did not cause prostate enlargement versus control group. hence hfd alone does not influence prostatic index. it has been considered that mek1 binds erk1/2, and phosphorylates either a tyrosine or threonine residue of erk1/2, and subsequently, mek1 dissociates. monophosphorylated erk1/2 is again bound by activated mek-1 and double phosphorylated. activated in this fashion, erk phosphorylates p90 rsk, which translocates to the nucleus and phosphorylates transcription factor elk-1. the regulation of the raf/mek/ erk signaling cascade is central to the control of cellular proliferation and differentiation(23-27). in the present study, it was found that the expression of p-erk1/2 significantly increased in the hfd+bph group, when compared with the control group. vikram et al.(12-14) found significantly increased levels of p-erk in the prostate of hyperinsulinemic rats, suggesting the involvement of mek/erk. it was established that the hfd and bph groups do not have significant differences between themselves in the expression of p-erk1/2 and erk1/2, but with a combination of fat diet and testosterone, the expression of these factors significantly increases in hfd+bph group, especially perk1/2. therefore, we can assume that the effect of testosterone on the prostate mass is significantly enhanced in the presence of a fat diet and the resulting hyperinsulinemia. in the absence of testosterone, hyperinsulinemia does not significantly affect the mass of bph in this model. diabetes mellitus (dm) patients typically have heavier prostates than non-dm patients. srinivasan et al. reported in 2004 that patients with dm had more prostate volume and greater international prognostic scoring system (ipss) scores(28). in the present study, it was found that prostate weight and expression of p-erk1/2 was statistically higher in the hfd+bph group, when compared to that in the other three groups. on the base of these data, we can assume that the hyperinsulinemia rises p-erk1/2 expression in the bph model induced with testosterone. this result suggests the role for hfd and androgens in bph. further investigation of this possibility is required. the current study suffers from the following limitations: first, this study lacked specific data on ventral and dorsolateral prostate. second, the quality of the western blot data was limited. conclusions in conclusion, androgens plus a hyperinsulinemic condition induced by hfd can result in prostatic cell hyperplasia, and the mechanism may be correlated to the upregulation of p-erk1/2. further investigations of this possibility are required. acknowledgement this study was funded by department of education in liaoning province (201202251). we are particularly grateful to all the people who have given us help on our article. conflict of interest the authors report no conflict of interest. references 1. li sh, yang qf, zuo py, liu yw, liao yh, liu cy. prostate volume growth rate changes over time: results from men 18 to 92 years old in a longitudinal community-based study. j huazhong univ sci technolog med sci. 2016; 36: 796-800. 2. zeng xt, su xj, li s, weng h, liu tz, wang xh. association between srd5a2 rs523349 and rs9282858 polymorphisms and risk of benign prostatic hyperplasia: a metaanalysis. front physiol. 2017; 12: 688. 3. robinson d, garmo h, holmberg l, stattin p. 5-α reductase inhibitors, benign prostatic hyperplasia and risk of male breast cancer. cancer causes control. 2015; 26: 1289-97. 4. schauer ig, rowley dr.the functional role of reactive stroma in benign prostatic hyperplasia. differentiation. 2011; 82: 20010. 5. paola lucia minciullo, antonino inferrera, michele navarra, gioacchino calapai, carlo magno, sebastiano gangemi. oxidative stress in benign prostatic hyperplasia: a systematic table 1. effect of high-fat diet-feeding and testosterone on the body weight and biochemical parameters groups body weight (g) prostatic wet weight (mg) prostatic index (mg/g) plasma glucose (mg/dl) plasma insulin (ng/ml) control 312.34 ± 3.5 205.32 ± 5.4 0.657 ± 0.02 96.60 ± 2.7 0.70 ± 0.3 hfd 369.51 ± 4.8* 235.82 ± 6.5& 0.638 ± 0.02* 127.63 ± 3.5*& p = 0.023 p = 0.024 p = 0.014 p = 0.021, p = 0.032 2.41 ± 0.3*& p = 0.024, p = 0.030 bph 324.81 ± 4.2 252.60 ± 7.8& 0.778 ± 0.03& 97.40 ± 2.6 0.84 ± 0.2 p = 0.035 p = 0.016 hfd+bph 376.53 ± 5.6* 265.42 ± 8.5*& 0.705 ± 0.03* 125.33 ± 3.2*& 2.30 ± 0.2*& p = 0.031 p = 0.026, p = 0.023 p = 0.042 p = 0.015, p = 0.031 p = 0.024, p = 0.035 *p < 0.05, compared with bph; & p < 0.05, compared with control group role of p-erk1/2 in hyperinsulinemiali et al. vol 18 no 2 march-april 2021 228 unclassified 229 review. urol int. 2015; 94: 249-54. 6. bostanci y, kazzazi a, momtahen s, laze j, djavan b. 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reversal of glucose intolerance by pioglitazone in high fat diet-fed rats. methods find exp clin pharmacol. 2004; 26: 327-33. role of p-erk1/2 in hyperinsulinemiali et al. urol_v03_no4_001_editorial.indd case report 247urology journal vol 3 no 4 autumn 2006 a giant congenital posterior urethral diverticulum associated with renal dysplasia shahram mousavi, abdolrasoul mehrsai, mohammadreza nikoobakht, amir reza abedi, sepehr salem, gholamreza pourmand urol j (tehran). 2006;4:247-9. www.uj.unrc.ir keywords: congenital, urethra, diverticulum, mullerian ducts, renal dysplasia urology research center, sina hospital, tehran university of medical sciences, tehran, iran corresponding author: shahram mousavi, md urology research center, sina hospital, hasan-abad sq, tehran, iran tel: +98 21 6671 7447 fax: +98 21 6671 7447 e-mail: shahram_moosavi1353@yahoo.com received january 2006 accepted july 2006 introduction there is a paucity of information about congenital posterior urethral diverticulum (pud). in the english literature, only 3 cases have been reported.(1-3) we report a unique case of pud in association with renal dysplasia. case report a 19-year-old man with a history of recurrent urinary tract infection (uti) due to escherichia coli, chronic urinary obstructive symptoms, and incomplete bladder emptying since childhood presented to sina hospital. the patient did not mention any history of the urethral trauma, instrumentation, or surgical intervention. physical examination revealed a massive bladder distention up to the umbilicus. examination of the external genitalia was unremarkable. serum creatinine level was 1.3 mg/dl and other biochemistry results were within the reference ranges. in the evaluations performed by ultrasonography and renal scintigraphy, the right kidney was absent and the left one showed compensatory hypertrophy. a large bladder and a large mass in the left side of the pelvis with multiple hyperechoic masses were seen. on ct scan, there was a large cystic mass beginning from the lower pole of the right kidney extending into the pelvis (figure 1). there was another cystic mass, posterior to the first one, which was at a lower level in the pelvis. the left kidney was normal with significant ureteral dilatation. voiding cystourethrography (vcug) showed a giant diverticulum, communicated with the urethra, shifting the bladder to the right side. also, left vesicoureteral reflux was noted (figure 2). on urethrocystoscopy, an orifice was seen adjacent to the verumontanum. the ureteroscope was advanced into a capacious pouch full of debris. its volume was approximately 500 milliliters. there was a long prostatic urethra (approximately 4 cm) and an elevated bladder neck. a huge moderately trabeculated bladder with a fully developed trigone was observed. although the left ureteral orifice was figure 1. a slice from the abdominopelvic ct scan. b indicates the bladder; d, diverticulum; and u, the ureter. congenital posterior urethral diverticulum—mousavi et al 248 urology journal vol 3 no 4 autumn 2006 prominent, our effort to find the right ureteral orifice was not successful. posterior urethral valve (puv) was not detected in our evaluation. a foley catheter was inserted into the diverticulum. the large diverticulum was dissected from the surrounding tissues and the urinary bladder through a lower midline incision; its communication with the posterior part of the urethra was identified and the diverticulum was resected completely (figures 3 and 4). the right kidney was absent. the right ureter was dissected completely. reduction cystoplasty was also performed. foley catheters were placed into the bladder and the perivesical space. the pathologic evaluation of the tip of the resected ureter indicated features of a dysplastic kidney. the wall of the diverticulum consisted of the muscle cells and squamous epithelium. after the catheter removal, the patient experienced a transient period of stress incontinence which was spontaneously relieved after 2 months. vesicoureteral reflux disappeared on the follow-up vcug. on retrograde urethrography, there was no stricture. no episode of uti was reported during the 6 months’ follow-up. the only complication reported was meatal stenosis that was corrected by meatotomy. during the follow-up period, serum creatinine levels were within the normal range with an average of 1.2 mg/dl (range, 0.9 mg/dl to 1.7 mg/dl). discussion urethral diverticulum is an epithelium-lined pouch that is formed because of either distention figure 3. retrograde urethrography. left, preoperative image. right, postoperative image. figure 2. lateral view of the bladder, the diverticulum, and the left ureter. b indicates the bladder; d, diverticulum; and u, the ureter. congenital posterior urethral diverticulum—mousavi et al urology journal vol 3 no 4 autumn 2006 249 of a segment of the urethra or the attachment of a structure to the urethra by a narrow neck (ie, a mullerian remnant).(4) this condition, especially in men, is extremely rare and may be congenital or acquired. an acquired diverticulum usually forms due to infection, urethral stricture, and/or trauma.(5) majority of the cases with pud are of the mullerian origin. the remainders are formed as a result of an aborted urethral duplication. the mullerian remnants may be prostatic utricles or mullerian duct cysts.(1) prostatic utricles do not usually require any treatment, unless they become very large causing recurrent utis or other complications.(4) mullerian duct cysts are cystic dilatations in the remnants of the distal ends of the fused mullerian ducts. they rarely communicate with the urethra. if they are connected to the urethra, they usually enter the midline of verumontanum.(1) esposito and colleagues reported a giant congenital pud in a 4-year-old boy with an enlarged utricle.(2) the 41-year-old patient described by plank and scholen was a case of congenital pud simulating mullerian duct cyst.(3) these authors concluded that the detected cases of pud were not of mullerian origin in neither of the articles mentioned. similar to ng’s report,(1) all features of our case including its midline location, well developed external genitalia, and the absence of communication with genital tract imply that this is a mullerian duct cyst. the method of treatment depends on the size of the diverticulum and the degree of the obstruction. small and asymptomatic lesions may just be followed up.(6) excision of the symptomatic lesions is often a surgical challenge. there are different approaches for the symptomatic lesions. classically, they are excised through suprapubic, retorovesical, or transvesical approaches(7,8); however, while some authors have used this approach with an acceptable success rate, others have shown a lower rate of complete excision in their cases.(9) a posterior approach has been advocated for the better maintenance of the erectile response.(10) perineal approach affords more direct access for diverticula originating at the level of the urogenital diaphragm.(3) our case is unique due to the existence of both renal dysplasia and congenital pud. conflict of interest none declared. references 1. ng wt. congenital posterior urethral diverticulum. aust n z j surg. 1996;66:717-9. 2. esposito g, savanelli a, tenore a, tamburrini o, palescandolo p, di tuoro a. congenital giant diverticulum of the posterior urethra in a 4-year-old boy. z kinderchir. 1986;41:244-5. 3. plank le, schoen wa jr. congenital prostatic urethral diverticulum simulating mullerian duct cyst. j urol. 1960;84:144-6. 4. jordan gh, schlossberg sm. surgery of the penis and urethra. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3903-4. 5. laungani rg, angermeier kw, montague dk. giant urethral diverticulum in an adult male: a complication of the artificial urinary sphincter. j urol. 2003;170: 1307-8. 6. mohan v, gupta sk, cherian j, tripathi vn, sharma bb. urethral diverticulum in male subjects: report of 5 cases. j urol. 1980;123:592-4. 7. smith ja jr, middleton rg. surgical approach to large mullerian duct cysts. urology. 1979;14:44-6. 8. monfort g. transvesical approach to utricular cysts. j pediatr surg. 1982;17:406-9. 9. schuhrke td, kaplan gw. prostatic utricle cysts (mullerian duct cysts). j urol. 1978;119:765-7. 10. wesson mb. cysts of the prostate and urethra. j urol. 1925;13:605-29. figure 4. postoperative voiding cyctourethrography demonstrated no remained diverticula. u j spring 2012.pdf 533vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l keywords: urachus, urachal adenocarcinoma, urinary bladder neoplasms introduction urachal adenocarcinoma is a very rare type of all the bladder neoplasms, typically arises in the remnant of the allantoic stalk. its annual incidence is estimated to be 1 in 5 million individuals and the majority of patients are in the 5th and 6th decades of life with presenting symptoms of mucusuria, hematuria, irritative voiding symptoms, and palpable suprapubic mass. urachal adenocarcinomas typically involves the wall of the bladder and may exhibit ulceration of the overlying urothelium. we here report a case with a huge dimensions of urachal adenocarcinoma without involvement of the bladder wall. case report examination revealed a midline infra-umbilical mass. ultrasonographic evaluations showed that it was not consistent with an obstructed bladder. computed tomography and magnetic resonance imaging demonstrated lower abdominal wall ate it as a malignancy. there was only an irregularity at the dome of the bladder without a sign of involvement. the patient underwent partial cystectomy with resection of the urachus, posterior rectus fascia, and overlying peritoneum. the tumor measured 9 × 6.5 × 5 cm with a weight of 77 g. a bilateral pelvic lymph node dissection was performed. frozen section of the bladder margin was negative. enis rauf coskuner,1 burak ozkan,2 veli yalcin2 urachal adenocarcinoma big dimensions without involvement of the bladder wall corresponding author: enis rauf coskuner, md school of medicine, acibadem university; department of urology, acibadem bakirkoy hospital, halit ziya usakligil cad. no: 1, 34140 bakirkoy, istanbul, turkey tel: +90 542 421 55 50 e-mail: enisraufcoskuner@ hotmail.com received may 2010 accepted december 2010 1school of medicine, acibadem university; department of urology, acibadem bakirkoy hospital, istanbul, turkey 2department of urology, acibadem bakirkoy hospital, istanbul, turkey case report 534 | the duration of catheterization and hospital stay were 5 days. there were no intra-or postoperative teric type urachal adenocarcinoma with abundant computed tomography and bone scan was negative for distant metastases. after evaluation in our department of oncology, we did not need any chemotherapy or radiation. the patient remains free from the disease after a discussion the natural disease course of urachal adenocarcinoma is hampered by the paucity of reported cases. urachal adenocarcinomas typically involve the bladder wall and exhibit any kind of deformation of the mucosal layer. their size ranges from a small mass to a bulky tumor. the clinicopathologic criteria for diagnosing urachal adenocarcinoma are tumor location in the bladder wall, demarcation line between tumor and surface epithelium, and exclusion of a primary adenocarcinoma in another location with secondary bladder involvement. in one recent report of 130 patients with urachal masses, two predictors for malignancy were found; age over 55 years and presence of hematween partial cystectomy and radical cystectomy. surgical margins and tumor grade were independent predictors of mortality. urachal adenocarcinomas’ response to radiotherapy and chemotherapy is modest and the only effective therapeutic approach is surgical eradication. its poor prognosis is duo to late presentation of symptoms leading to advanced stage at diagnosis, a propensity of early local invasion, and distal metastasis. our case is a rare one of a big, enteric type urachal adenocarcinoma, with abundant mucin formation, but without the bladder wall involvement. we could not see enough data about the dimensions of urachal adenocarcinomas and their behaviors. tuis another subject to examine for large serial ones. conflict of interest none declared. figure 1. magnetic resonance imaging showing a supravesical mass. figure 2. microscopic view of the urachal adenocarcinoma. case report 535vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l urachal adenocarcinoma | coskuner et al references 1. cho sy, moon kc, park jh, kwak c, kim hh, ku jh. outcomes of korean patients with clinically localized urachal or nonurachal adenocarcinoma of the bladder. urol oncol. 2011. 2. hong sh, kim jc, hwang tk. laparoscopic partial cystectomy with en bloc resection of the urachus for urachal ad3. johnson de, hodge gb, abdul-karim fw, ayala ag. urachal 4. grignon dj, ro jy, ayala ag, johnson de, ordonez ng. primary adenocarcinoma of the urinary bladder. a clinico5. ashley ra, inman ba, sebo tj, et al. urachal carcinoma: clinicopathologic features and long-term outcomes of an ag6. siefker-radtke ao, gee j, shen y, et al. multimodality management of urachal carcinoma: the m. d. anderson cancer v08_no_2_final.pdf miscellaneous 137urology journal vol 8 no 2 spring 2011 the lunar cycle effects of full moon on renal colic hojjat molaee govarchin ghalae,1 samad zare,2 maryam choopanloo,3 roya rahimian4 purpose: to evaluate renal colic frequency in different seasons and around full moon. materials and methods: a total of 1481 patients with renal colic were studied retrospectively addressing days of a month both in solar and lunar calendar. results: the mean age of the patients was 57 ± 13 years. total admissions in summer was 613; of which 288 (41%), 199 (39%), and 126 (43%) were in years 2002, 2003, and 2004, respectively. the highest frequencies in solar calendar were on days 2 (56), 20 (63), and 27 (59) and the lowest were on days 6 (36), 22 (38), 26 (34), and 31 (31). we did not find any statistically significant association according to solar calendar (p = .3). in lunar calendar, most of the admissions were on day 15 (69) and the lowest rates were on days 1 (25) and 30 (26), which was statistically significant (p = .04). conclusion: renal colic frequency is not correlated with solar calendar, but its highest frequency in lunar calendar is in the middle of the month period. although we found a correlation between full moon effect and renal tide, but this is a new window for further studies. urol j. 2011;8:137-40. www.uj.unrc.ir keywords: nephrolithiasis, renal colic, moon 1department of urology, shohadae-tajrish hospital, tehran, iran 2shahid sadoughi university of medical sciences, yazd, iran 3ghamare bani hashem hospital, khoy, iran 4department of chemistry, yazd university, yazd, iran corresponding author: samad zare, md trauma research center, shahid rahnemoon hospital, yazd, iran tel: +98 351 822 4000 fax: +98 351 822 4100 e-mail: drzare@ssu.ac.ir received may 2009 accepted november 2009 introduction human and animals physiology and behavior are subject to seasonal, lunar, and circadian rhythms. although the seasonal and circadian rhythms have been fairly welldescribed, little is known about the effects of the lunar cycle.(1) it has been shown that hospital and emergency unit admissions are correlated with the moon phases.(2) an increased incidence of acute coronary events(3) as well as intracranial aneurysm rupture and subarachnoid hemorrhage have been reported on new moon days.(4) in a review on patients admitted for seizure occurrence to an emergency unit, a significant clustering of seizures was observed around the full-moon period, supporting the ancient belief of periodic increased seizure frequency during full-moon days.(5) roman and colleagues suggested an increase in the number of admissions due to gastrointestinal hemorrhage during the full moon, especially in men experiencing variceal hemorrhage.(6) a seasonal variation in the onset of appendicitis was also reported.(7) takemura and associates suggested the direct influence of moonlight intensity on serum level of melatonin produced by pineal glands as well.(8) recently, a circadian variability has been reported for the occurrence of renal colic, with a pattern characterized by a morning peak, independent of gender and effects of full moon on renal colic—molaee govarchin ghalae et al 138 urology journal vol 8 no 2 spring 2011 presence of the kidney stones. most, if not all, renal functions, including glomerular filtration rate, urine production, and renal excretion of solutes, exhibit temporal changes leading to an increased night-time concentration of urine, which could act as a predisposing factor for the morning occurrence of renal colic attacks.(9) in an epidemiological study of urinary stone colic, days of decreasing air pressure and high temperature were frequently associated with renal colic.(10) high incidence of renal colic signifies study in this field, but to the best of our knowledge, no survey has been performed on the association of full moon and renal colic. renal colic admissions in periodic rhythms evoked us to study such association. materials and methods this retrospective study evaluated a total of 1481 patients, 903 (61%) men and 578 (41%) women, with renal colic who were admitted to the emergency ward of ghamare bani hashem hospital, the only renal colic care center in khoy, iran, from june 2002 to december 2004. diagnosis was made on the basis of past history, physical examination, and imaging modalities, including kidney, urinary, and bladder x-ray, ultrasonography, or intravenous urograpgy, as needed. subjects were divided into days of a month in solar calendar from june 21, 2002 (beginning of persian summer) to december 20, 2004 (end of persian autumn). thereafter, these dates were divided into days of a month in lunar calendar beginning in arabic spring 1423 (2002) ending in arabic winter 1425 (2004). then figures were designed upon relative frequencies. two different statistical methods were utilized: chisquare goodness of fit test and partial fourier series. conventional statistical analysis was performed using student’s t test for unpaired data. p values less than .05 were considered statistically significant. results the mean age of the patients was 57 ± 13 years. figure 1 illustrates gathered data according to the frequency of renal colic admissions in different seasons. total admissions in summer was 613; 288 (41%), 199 (39%), and 126 (43%) in years 2002, 2003, and 2004, respectively (figure 1). the highest frequencies in solar calendar were on days 2 (56), 20 (63), and 27 (59) and the lowest were on days 6 (36), 22 (38), 26 (34), and 31 (31) (figure 2). no statistically significant association figure 1. frequency of renal colic admissions in different seasons. figure 2. renal colic admissions according to solar calendar effects of full moon on renal colic—molaee govarchin ghalae et al 139urology journal vol 8 no 2 spring 2011 was found according to solar calendar (p = .3). as figure 3 shows, most of the admissions were on day 15 (69) and the lowest rates were on days 1 (25) and 30 (26), which was statistically significant (p = .04). discussion our study shows that the highest rate of admissions occurs in summer because of sweating and volume contraction and the lowest rate is seen in spring. in the study by perez and colleagues, the incidence was also significantly high in summer and low in autumn.(10) in our study, the persian (solar) calendar has no association with lunar cycles. due to loss of any effect of full moon on solar months, we did not expect regular arrangement in incidence. based on our findings, the highest and lowest levels of renal colic admissions were around full moon (days 14 to 17) and the extreme days of lunar month, respectively. this may be explained by full moon effect on tide of seas. water accounts for 60% of body weight and also 60% of our planet contains water. therefore, if the moon can change the weather and cause tides, why can not it affect our renal beaches? a belief that challenges stiff criticizers. due to independent nature of renal colic manifestations from psychological situations, we can not relate clinical symptoms to “full moon madness”. therefore, this study opens a new window toward other aspects and invites scientists to enter discussion and begin surveys on moon effect to distinguish science from superstition. although the exact mechanism of the moon influence on humans and animals awaits further exploration, knowledge of this kind of biorhythm may be helpful in police surveillance, medical practice, and investigations involving laboratory animals. conclusion a variety of studies have paid attention to the association between full moon effect and popular beliefs. although herein seems that episodes of renal colic can be correlated with full moon effect, but more studies with greater number of subjects are needed for propagation of this idea. acknowledgements we thank mr. esmaeel azimee for his help in statistical analysis. conflict of interest none declared. references 1. zimecki m. the lunar cycle: effects on human and animal behavior and physiology. postepy hig med dosw (online). 2006;60:1-7. 2. zargar m, khaji a, kaviani a, karbakhsh m, yunesian figure 3. renal colic admissions according to lunar calendar effects of full moon on renal colic—molaee govarchin ghalae et al 140 urology journal vol 8 no 2 spring 2011 m, abdollahi m. the full moon and admission to emergency rooms. indian j med sci. 2004;58:191-5. 3. oomman a, ramachandran p, shanmugapriya, subramanian p, nagaraj bm. a novel trigger for acute coronary syndromes: the effect of lunar cycles on the incidence and in-hospital prognosis of acute coronary syndromes--a 3-year retrospective study. j indian med assoc. 2003;101:227-8. 4. ali y, rahme r, matar n, et al. impact of the lunar cycle on the incidence of intracranial aneurysm rupture: myth or reality? clin neurol neurosurg. 2008;110:462-5. 5. polychronopoulos p, argyriou aa, sirrou v, et al. lunar phases and seizure occurrence: just an ancient legend? neurology. 2006;66:1442-3. 6. roman em, soriano g, fuentes m, galvez ml, fernandez c. the influence of the full moon on the number of admissions related to gastrointestinal bleeding. int j nurs pract. 2004;10:292-6. 7. gallerani m, boari b, anania g, cavallesco g, manfredini r. seasonal variation in onset of acute appendicitis. clin ter. 2006;157:123-7. 8. takemura a, ueda s, hiyakawa n, nikaido y. a direct influence of moonlight intensity on changes in melatonin production by cultured pineal glands of the golden rabbitfish, siganus guttatus. j pineal res. 2006;40:236-41. 9. boari b, manfredini r. [circadian rhythm and renal colic]. recenti prog med. 2003;94:191-3. 10. perez ja, palmes mde l, ferrer jf, urdangarain oo, nunez ab. renal colic at emergency departments. epidemiologic, diagnostic and etiopathogenic study. arch esp urol. 2010;63:173-87. urol_v03_no4_001_editorial.indd endourology and stone disease 204 urology journal vol 3 no 4 autumn 2006 diagnostic application of flexible cystoscope in pelvic fracture urethral distraction defects seyed jalil hosseini, ali kaviani, mohammad jabbari, mojtaba mohammad hosseini, amir haji-mohammadmehdi-arbab, navid reza simaei introduction: the aim of this study was to evaluate the diagnostic value of antegrade flexible cystoscopy in pelvic fracture urethral distraction defects (pfudd). materials and methods: between 1999 and 2004, a total of 111 patients with pfudd were evaluated by antegrade flexible cystoscopy. the flexible cystoscope was introduced into the posterior urethra and the area was evaluated for any probable fistula, false passages, or displacement of the posterior urethra. for preventing misalignment, flexible cystoscope was also used during the urethroplasty to open the posterior urethra at its exact distal point. results: posterior urethra ended distal to the external sphincter in 16 patients (14.4%). five (4.5%) and 9 (8.1%) patients had severe displacement of the posterior end of the urethra and bladder neck false passage, respectively. prostatic urethrorectal fistula was detected in 1 patient. another 1 patient had bladder rhabdomyoma. conclusion: flexible cystoscopy is a valuable procedure in the evaluation of the bladder, the bladder neck, and the posterior urethra in patients with urethral distraction defects and complements voiding cystography before the surgery. it is also helpful for showing the exact distal point of the proximal urethra during urethroplasty in cases with displaced posterior urethra. urol j (tehran). 2006;4:204-7. www.uj.unrc.ir keywords: urogenital trauma, urethral stricture, cystoscopy reproductive health research center, shohada-e-tajrish hospital, shaheed beheshti university of medical sciences, tehran, iran corresponding author: seyed jalil hosseini, md shohada-e-tajrish hospital, tajrish sq, tehran, iran tel: +98 21 8852 6900 fax: +98 21 8852 6901 e-mail: sjhosseinee@yahoo.com received june 2006 accepted august 2006 introduction pelvic fracture urethral distraction defects (pfudds) accompany 10% of the pelvic fractures. the most frequent point of distraction is at the level of the junction of the membranous and bulbospongiosus parts of the urethra.(1,2) defining the precise anatomy of the distraction defect is important in repairing any subsequent stricture. contrast studies are the first-choice methods for evaluation of the distraction defect. the conventional methods include simultaneous voiding cystourethrography (vcug) and dynamic retrograde urethrography (rug). when the proximal urethra is not visualized, antegrade flexible cystoscopy is used for assessment of the bladder neck and the posterior urethra.(1,2) however, the knowledge of flexible cystoscopy usage for routine evaluation of the urethral distractions are limited. we examined diagnostic flexible cystoscopy in the evaluation of the bladder, the bladder neck, and the posterior urethra in cases suspected of urethral distraction. during our 10-year experience of urethroplasty, we found many patients with pfudd in whom the proximal urethra was displaced from its normal position due to the severity flexible cystoscope in reconstructive urology—hosseini et al urology journal vol 3 no 4 autumn 2006 205 of the trauma. also, we observed some cases of misalignment of the posterior urethra in previously operated patients (figure 1). thus, we used flexible cystoscope as the guiding tool for finding the exact distal point of the proximal urethra during urethroplasty. materials and methods we performed a retrospective study on patients with pfudd and complete obliteration of the urethral ends in shohada-e-tajrish hospital. these patients underwent diagnostic antegrade flexible cystoscopy under a light sedation after an average of 6 months following the trauma. all patients had indwelling suprapubic catheter. the diagnostic procedure was fully instructed to the patients and informed consent was obtained. we routinely performed simultaneous vcug and rug as well as antegrade flexible cystoscopy in all patients. the flexible cystoscope was introduced through a mature suprapubic tract easily and often without any need for further dilatation or use of the amplatz sheath. the bladder and the bladder neck were initially inspected for any possible calculus, tumor, or fistula. then, the flexible cystoscope was introduced into the posterior urethra and the area was evaluated for any probable fistula, false passages, or deviation of the posterior urethra. we used the verumontanum as a landmark that determined the 6 o’clock position of the posterior urethra. therefore, we were able to determine any displacement of the urethral ends to the right, left, up, or down. in cases with severe displacement toward rectum or the lower limit of the pubic bone, we repeated antegrade flexible cystoscopy toward the proximal urethral end during perineal dissection urethroplasty to make sure that the posterior urethra would be opened exactly at its end (figures 2 and 3). in such cases, we perineally introduced a tiny needle at the proposed figure 3. flexible cystoscope light. figure 1. urethral misalignment after urethroplasty. figure 2. the bulbar and membranous parts of the urethra are dissected and the obliterated urethra is ready to be cut out of the fibrotic site. flexible cystoscope in reconstructive urology—hosseini et al 206 urology journal vol 3 no 4 autumn 2006 site of the proximal urethral opening and checked it endoscopically to make sure that it has entered the urethra exactly at its end. in some cases with severe displacement, we adjusted the site of the needle once or twice before opening the proximal urethra (figures 4 and 5). results a total of 111 patients underwent diagnostic flexible cystoscopy. the mean age of the patients was 32.1 years (range, 10 to 72 years). the posterior urethra ended distal to the external sphincter in 16 patients (14.4%). five patients (4.5%) had severe displacement of the posterior urethral end toward the rectum or the lower limit of the pubic bone. prostatic urethrorectal fistula, bladder rhabdomyoma (determined by biopsy), and bladder neck false passage were reported in 11 patients (9.9%). the standard vcug did not show the abovementioned information except for urethrorectal fistula in 1 patient and bladder neck false passage in 3. details of the cystoscopic findings are listed in the table. discussion evaluation of the pfudd has traditionally been performed by vcug and rug. magnetic resonance imaging (mri) is a valuable technique for defining the length of prostatomembranous defect and distorted pelvic anatomy.(3-5) however, the digital subtraction details of the urethra are not obtainable by mri.(1) in addition, it is costly and unfamiliar to the urologist.(6) three-dimensional spiral computed tomography/ cysto-urethrography (ctcug) has been used for determining the location of the distraction and the length of the misalignment of the urethral ends.(6,7) although ctcug does not require an experienced operator and is simpler than conventional radiology, it is relatively expensive and not available at all centers. some investigators have proposed ultrasonography, which is especially useful in anterior urethral stricture disease.(3) antegrade flexible cystoscopy is suggested to assess the bladder neck and the posterior urethra in cases whose proximal urethra is not visualized on cystography.(1) lewis and mccullough performed this diagnostic procedure on 2 patients in 1985.(2) cystoscopic findings in patients with pelvic fracture urethral distraction defects cystoscopic findings patients (%) end of the proximal urethra distal to external sphincter 16 (15.0) distal to verumontanum 95 (85.0) deviation of posterior urethral end anterior 2 (1.8) posterior 1 (0.9) left 2 (1.8) right 0 total 5 (4.5) false passage posterior urethra 6 (5.4) bladder neck 3 (2.7) figure 4. needle insertion to the proximal urethral end with the help of flexible cystoscopy. figure 5. adjustment of the needle to the proximal urethral end with the help of flexible cystoscopy. flexible cystoscope in reconstructive urology—hosseini et al urology journal vol 3 no 4 autumn 2006 207 kielb and colleagues reported their experience with initial flexible cystourethroscopic evaluation of the suspected urethral injury due to blunt trauma in 10 patients. they concluded that primary flexible cystourethroscopy with placement of a urethral catheter streamlines evaluation of the traumatic posterior urethral injury.(8) we routinely performed vcug, rug, and diagnostic antegrade flexible cystoscopy in all patients with pfudd who had complete separation of the urethral ends. this diagnostic procedure is easy-doing and adds only 4 to 5 minutes to the total operative time. it helps us have better understanding of the bladder and its pathologic disease before the operation. it completes standard voiding cystography in the diagnosis of bladder neck false passages which are mainly caused by previous manipulations and is also valuable in the evaluation of proximal urethral length and fistula especially when proximal urethra is not visualized on voiding cystography. it is also valuable in determination of the severe proximal deviation of the urethral end and helps us do an exact and undervision opening of the posterior urethra in cases with severe displacement of the posterior urethral end. conclusion flexible cystoscopy is a valuable procedure for evaluating the bladder, the bladder neck, and the posterior urethra in cases of pfudd and complements the results of vcug before the surgery. conflict of interest none declared. references 1. jordan gh, schlossberg sm. surgery of the penis and urethra. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3886-954. 2. lewis rm, mccullough dl. use of the flexible fiberoptic nephroscope in the preoperative evaluation and delayed repair of traumatic urethral strictures. j urol. 1985;133:1036-7. 3. gallentine ml, morey af. imaging of the male urethra for stricture disease. urol clin north am. 2002;29:36172. 4. pavlica p, barozzi l, menchi i. imaging of male urethra. eur radiol. 2003;13:1583-96. 5. dixon cm, hricak h, mcaninch jw. magnetic resonance imaging of traumatic posterior urethral defects and pelvic crush injuries. j urol. 1992;148: 1162-5. 6. el-kassaby aw, osman t, abdel-aal a, sadek m, nayef n. dynamic three-dimensional spiral computed tomographic cysto-urethrography: a novel technique for evaluating post-traumatic posterior urethral defects. bju int. 2003;92:993-6. 7. chou cp, huang js, wu mt, et al. ct voiding urethrography and virtual urethroscopy: preliminary study with 16-mdct. ajr am j roentgenol. 2005;184: 1882-8. 8. kielb sj, voeltz zl, wolf js. evaluation and management of traumatic posterior urethral disruption with flexible cystourethroscopy. j trauma. 2001;50: 36-40. v08_no_3_final.pdf case report 248 urology journal vol 8 no 3 summer 2011 pleomorphic hyalinizing angiectatic tumor of the scrotum apostolos p labanaris,1 vahudin zugor,1 jorn h witt,1 2 urol j. 2011;8:248-50. www.uj.unrc.ir keywords: scrotum, neoplasms, diagnosis, hyaline, soft tissue neoplasms 1department of urology and pediatric urology, prostate center northwest, st. antonius medical center, gronau, germany 2department of urology, martha maria medical center, nurnberg, germany corresponding author: apostolos p labanaris, md, phd department of urology and pediatric urology, prostate center northwest, st. antonius medical center, gronau, germany tel: +49 256 2915 2100 fax: +49 256 2915 2105 e-mail: labanaris@web.de received november 2009 accepted january 2010 introduction the pleomorphic hyalinizing angiectatic tumor (phat), first described by smith and colleagues,(1) is a rare mesenchymal tumor with intermediate malignant potential. this unique tumor occurs principally in the superficial soft tissues of the distal extremities, and features ectatic, fibrincontaining vessels with prominent circumferential hyalinization, spindled and pleomorphic stromal cells with intranuclear inclusions, and a variable inflammatory component.(2) although the number of reported cases is limited and there is disagreement regarding the line of cellular differentiation, the pathologic features of phat have been well-delineated.(3) the purpose of this report is to present the case of phat encountered within the scrotal sac and add this rare tumor to the differential diagnosis of the scrotal swelling. case report a 68-year-old man was referred to our department for evaluation of a right scrotal mass that had been enlarging slowly for several years causing mild discomfort. bimanual examination of the scrotum confirmed the presence of a painless nontender mass of the right hemiscrotum inseparable from the right testicle. the left hemiscrotum and testicle were unremarkable and with no evidence of disease. scrotal ultrasonography revealed a homogeneous echo-poor mass of the right hemiscrotum involving the testicle, measuring approximately 180 mm × 150 mm and consistent with the ultrasonographic appearance of a testicular tumor. computed tomography of the pelvis exhibited an inhomogeneous mass with calcifications, suggesting an enhancing soft tissue component, measuring approximately 160 mm × 150 mm and not involving the right testicle (figure 1). there was no evidence of metastatic disease or lymphadenopathy on imagings. tumor markers, including alphafetoprotein, lactate dehydrogenase, and beta-human chorionic gonadotropin assays, were all within normal limits. the clinic, ultrasonographic, and radiographic appearances were suspected to be malignant, but were not proved conclusively. therefore, a surgical exploration was performed. peri-operative distinguishment between the scrotal mass and the testicle was impossible. subsequently, a right inguinal radical orchiectomy with high ligation of the spermatic cord was performed. on pathological examination, the angiectatic tumor of the scrotum —labanaris et al 249urology journal vol 8 no 3 summer 2011 excised mass lacked sufficient surrounding tissue to thoroughly examine the presence of positive or negative surgical margins. gross findings revealed a well-circumscribed 160 mm × 150 mm × 120 mm nonencapsulated mass, with cystic components and diffusely infiltrative borders, and maroon in color. microscopic examination exhibited a moderately cellular lesion with a lobular pattern demarcated toward the periphery by a thin pseudocapsule featuring infiltrative margins and was characterized by the presence of alternating vascular and cellular areas. the most prominent feature was the various sized thin-walled ectatic hyalinized blood vessels (figure 2). the tumor cells consisted of a mixture of spindled and rounded pleomorphic cells that were arranged in sheets without obvious differentiation, had a distinct cytoplasmic border, and were eosinophilic, with some intranuclear inclusions or cytoplasmic hemosiderin deposits. immunohistochemically, the neoplastic cells were strongly positive for vimentin and cd34 and negative for s-100 protein, cd31, desmin, smooth muscle actin, and cytokeratin. the right testicle was unremarkable and with no evidence of disease. the patient has been currently followed up for 1 year and there is no evidence of clinic or radiographic recurrences so far. discussion the differential diagnosis of scrotal swelling includes tumor, epididymitis, epididymo-orchitis, epididymal cyst, testicular torsion, and less commonly, hernia, hydrocele, spermatocele, varicocele, hematoma, and hamatocele. to the best of our knowledge, this report presents a rare tumor entity that has never been before documented as a primary scrotal lesion. pleomorphic hyalinizing angiectatic tumor is a rare soft tissue neoplasm that occurs mainly in the 4th to 7th decades, with a slight female preponderance.(2) approximately, 80 cases have been reported to date.(4) in most of the cases, patients had the mass for more than 1 year before operation.(5) the main location of occurrence is the lower limb; however, other anatomic sites have been reported, such as the trunk, upper extremities, inguinal triangle, buttock, oral cavity, and mesorectal soft tissue.(6,7) although most of the patients are cured with local excision and no metastases have been reported so far, a high rate of local recurrences (33% to 50%), sometimes necessitating amputation for local control, has been observed.(1) grossly, phats are well-circumscribed, but unencapsulated lesions with a lobulated growth pattern and measure up to 20 cm in diameter. (4) histologically, they are of low to moderate cellularity, with a combination of sheets of spindled and pleomorphic cells associated with figure 1. computed tomography of an inhomogeneous mass with calcifications, suggesting an enhancing soft tissue component, measuring approximately 160 mm × 150 mm and not involving the right testicle. figure 2. thin-walled ectatic blood vessels with red blood cells in the vascular lumen (hematoxylin and eosin, original magnification ×100). angiectatic tumor of the scrotum —labanaris et al 250 urology journal vol 8 no 3 summer 2011 an ectatic, partially hyalinized vasculature. the variously sized dilated blood vessels are scattered and clustered, and their walls are lined by amorphic eosinophilic material. immunohistochemically, the tumor cells show positive staining for vimentin in almost all cases, with variable cd34 and cd99 positivity.(4) other antigens, such as s-100 protein, actin, desmin, cytokeratin, and cd31, are generally negative.(3) the differential diagnosis of phat includes malignant fibrous histiocytoma, schwannoma, solitary fibrous tumor, myofibroblastoma, spindle cell metaplastic carcinoma, and kaposi sarcoma.(8) with the increasing use of ultrasonography and computed tomography, other examples of scrotal phat are expected to be discovered. awareness of the possibility that phat may occur in the scrotum should be kept in the differential diagnosis of scrotal swelling. the recognition of this rare tumor entity could avoid unnecessary radical surgery. conflict of interest none declared. references 1. smith mef, fisher c, weiss sw. pleomorphic hyalinizing angiectatic tumor of soft parts: a low-grade neoplasm resembling neurilemoma. am j surg pathol. 1996;20:21-9. 2. folpe al, weiss sw. pleomorphic hyalinizing angiectatic tumor: analysis of 41 cases supporting evolution from a distinctive precursor lesion. am j surg pathol. 2004;28:1417-25. 3. weiss sw. pleomorphic hyalinizing angiectatic tumour of soft parts. in: fletcher cdm, unni kk, mertens f, eds. world health organization classification of tumours: pathology and genetics of tumours of soft tissue and bone. lyon, france: iarc press; 2002:191. 4. tallarigo f, squillaci s, putrino i, zizzi n, bisceglia m. pleomorphic hyalinizing angiectatic tumor of the male breast: a heretofore unreported occurrence. pathol res pract. 2009;205:69-73. 5. matsumoto k, yamamoto t. pleomorphic hyalinizing angiectatic tumor of soft parts: a case report and literature review. pathol int. 2002;52:664-8. 6. ide f, shimoyama t, horie n. pleomorphic hyalinizing angiectactic tumor of the buccal mucosa. j oral pathol med. 2004;33:451-3. 7. iascone c, sadighi a, ruperto m, paliotta a, borrini f, mingazzini p. pleomorphic hyalinizing angiectatic tumour of the mesorectal soft tissue. a case report and review of the literatre. chir ital. 2008;60:159-63. 8. ke q, erbolat, zhang hy, et al. clinicopathologic features of pleomorphic hyalinizing angiectatic tumor of soft parts. chin med j (engl). 2007;120:876-81. 1499vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l non invasive management of refractory hemorrhage after renal surgery with factor viia: report of 3 cases wadah ceifo,1 adel al tawheed,2 aischa fakeir3 corresponding author: wadah ceifo, md departments of surgery, urology unit, al-jahra hospital, ministry of health, p.o. box: 40206, al-jahra, kuwait. tel: +965 9739 0065 fax: +965 4570 858 e-mail: wceifo@yahoo.de received june 2012 accepted january 2013 departments of surgery and urology1,2 and hematology units,3 al jahra hospital, alqasr, al-jahra, kuwait. case report keywords:bloodloss;surgical;prevention;control;urologicsurgicalprocedures,adverseeffects;intraoperativecomplications;kidney;surgery. iintroduction recombinantactivatedfactorvii(rfviia)isavitamink-dependentglycoproteinconsistingof406aminoacidresidues(molecularweight50kdalton).(1) it is struc-turallysimilar tohumanplasma-derivedfactorviia.(2)overthelastfewyears, rfviiahasbeenused“off-label”inpatientswithuncontrolledbleedingduetoocculthemostaticabnormalitycausedbytraumaand/ormassivebloodloss,(3,4) thrombocytopenia, plateletdysfunctionorliverdysfunctionandmanyothersituationscharacterizedbycritical bleeding.(5)wepresentourexperienceofthesuccessfuluseofrfviiatotreatlifethreateninghemorrhagein3patientswhohadrefractoryhemorrhagefollowingsurgicalprocedures onthekidney. case report threepreviouslyhealthymales,withoutpre-existingcoagulopathy,presentedwithstaghorn calculus(n=2)andalargerenalpelviccalculus(n=1).twopatientsweresubjectedtoper1500 | cutaneousnephrolithotomy(pcnl)andonehadopenpyelolithotomy.inonecaseduringpcnl,therewaspneumohemothoraxandretroperitonealbleedinguptoday5after the procedure. in the other case of pcnl, uncontrollable hemorrhageoccurredonday13followingremovalofpcnl tube.profusebleedingstartedonday5inthepatientwithpyelolithotomy.all3patientswereinitiallymanagedbyblood transfusions. when hemorrhage persisted despite blood transfusionsandthepatientsbecamehemodynamicallyunstable,intravenousrfviiawasgivenatadoseof60-90µg/ kg.theclinicalcharacteristicsandtreatmentresponseofall the3casesareshownintable1.bloodproductsusageand changeincoagulationprofilebeforeand24hoursafteradministrationofrfviiaissummarizedintable2. discussion thetissuefactorisexposedandformsacomplexwith rfviiafollowinginjurytothevesselwall.(6)thiscomplex activatesfactorxwhichleadstoconversionofprothrombin tothrombin,andactivationofplatelets,greatlyenhanced thrombin generation, and activation of thrombin activated fibrinolysis inhibitor (tafi).(6) rfviia isused to treat patientswithhemophiliaaandb,(7)alsoforthetreatment oflifethreateninghemorrhageinthesettingofcoagulopathy disorders,(8,9)bluntandpenetratingtraumaandsurgical bleeding.(10)rfviia,canminimizebloodlossandneed forbloodtransfusionpriortoretropubicprostatectomy(11) or in patients on platelet aggregation inhibitors, prior to renal transplantation.(12,13) asshownontable1,ourstudydemonstratedtheeffectivenessofintravenous(iv)administrationofrfviiainlateonsetbleedingafterrenalsurgery.inall3cases,hemorrhage subsidedafterrfviiaadministration.itispossibleforbleeding to occur again in a patient that has shown response to initialadministrationof rfviia. from our thirdpatient, it wouldappearthatfutureresponsestoivadministrationof rfviiacanbeexpectedwithrepeateddosing.table2shows thepossiblemechanismofactionofivrfviiausage.inall 3patientsthehemoglobinremainedstableandtherewasan improvementinprothrombintime(pt),partialthromboplastintime(ptt)andinternationalnormalizedratio(inr)after ivrfviiaadministration.angiographywithembolizationof anybleedingvesselsisthestandardmethodofdealingwith significanthemorrhagefromthekidneyafterrenalsurgery. (13)however,insomecases,thebleedingvesselsmaybedifficulttoidentify.whatismore,whenbleedingisfromother sourceslikelumbarvesselsandetc.,asanadjuvantpriorto embolization,ivadministrationofrfviiaisworthatrial. theadvantageofivrfviiaadministrationoverangiographyandembolismisthat,itdoesnotrequireanyexpertise toadministeranditiseasierandquickertousethanangioembolization.furthermore,inpatientsinextremis,ivrfviia canbeusedeasily.noneofourpatientsexperiencedanyfurtherepisodesofbleedingafterameanfollowupofabout6 months.similarly,therewasnolossofrenalfunctionfrom theaffectedkidneys.whenthereisanyclinicalorlaboratory signsofpresenceofthrombosis,(14)therfviiadosageshould bereducedorstopped,dependingonthepatient’ssymptoms. conclusion thisstudyrevealedthatadministrationofrfviiaisapromisingtreatmentoptionforpatientsundergoingrenalsurgery table 1. clinical and imaging features of the series. case age, years/sex primary diagnosis coagulopathy dosage (µg/kg) clinical efficacy* complications death 1 43/male partial right stage horn stone no 90 yes none no 2 39/male right renal pelvic stone no 60 yes none no 3 51/male left lower calyceal stone no 60a yes none no key: rfviia, recombinant activated factor vii. a multiple doses administered. * defined as marked reduction or cessation of post-operative hemorrhage. case report 1501vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l management of refractory hemorrhage after renal surgery | ceifo et al complicatedwithlife-threateninghemorrhage.itseemstobe botheffectiveandsafe.however,furtherresearchisrequired toextendtheapprovalofthisproductinurologicprocedures whileassessingpotentialcomplications. conflict of interest none declared. table 2. study parameters in patients who received four rfviia replacement therapies before and 24 hours after treatment. case prbc (u) ffp (u) platelets (u) hb pt ptt inr prbc (u) ffp (u) platelets (u) hb pt ptt inr 1 3 0 0 8.8 11.6 34.4 0.0913 0 0 0 10.1 10.2 28.7 0.0767 2 2 0 0 9.6 11.0 35.1 0.0912 0 0 0 10.6 10.7 27.8 0.0765 3a 2 0 0 9.2 11.2 34.3 0.0911 0 0 0 10.1 10.3 27.8 0.0870 3b 2 0 0 9.1 11.7 34.2 0.0913 0 0 0 10.2 10.1 27.7 0.0760 keys: rfviia, recombinant activated factor vii; prbc, packed red blood cells; ffp, fresh frozen plasma; u, units; hb, hemoglobin; pt, prothrombin time; ptt, partial thromboplastin time; inr, international normalized ratio. hb in g/dl. a, first administration of rfviia in case 3. b, second administration of rfviia in case 3. references 1. hedner u. recombinant coagulation factor viia: from the concept to clinical application in haemophilia treatment in 2000. semin thromb hemost. 2000;26:363-6. 2. lisman t, mosnier lo, lambert t, et al. inhibition of fibrinolysis by recombinant factor viia in plasma from patients with severe hemophilia a. blood. 2002;99:175-9. 3. lisman t, de groot pg. mechanism of action of recombinant factor viia. j thromb haemost. 2003;1:1138-9. 4. gabriel da, li x, monroe dm 3rd, roberts hr. recombinant human factor viia (rfviia) can activate factor fix on activated platelets. j thromb haemost. 2004;2:1816-22. 5. lisman t, adelmeijer j, cauwenberghs s, van pampus cm, heemskerk jwm, de groot pg. recombinant factor viia enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count. j thromb haemost. 2005;3:742-51. 6. abshire t, kenet g. recombinant factor viia: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor viii or ix inhibitors. j thromb haemost. 2004;2:899909. 7. shapiro ad, gilchrist gs, hoots wk, copper ha, gastineau da. prospective, randomised trial of two doses of rfviia (novoseven) in haemophilia patients with inhibitors undergoing surgery. thromb haemost. 1998;80:773-8. 8. ghorashian s, hunt bj. “off-license” use of recombinant activated factor vii. blood rev. 2004;18:245-59. 9. levi m, peters m, buller hr. efficacy and safety of recombinant factor viia for treatment of severe bleeding: a systematic review. crit care med. 2005;33:883-90. 10. moscardo f, perez f, de la rubia j, et al. successful treatment of severe intra-abdominal bleeding associated with disseminated intravascular coagulation using recombinant activated factor vii. br j haematol. 2001;113:174-6. 11. friederich pw, henny cp, messelink ej, et al. effect of recombinant activated factor vii on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. lancet. 2003;361:201-5. 12. hagen l, jens s, paolo f. recombinant factor viia reduces bleeding risk in patients on platelet aggregation inhibitors immediately prior to renal transplantation. urol int. 2007;78:135-9. 13. kevin r loughlin. complications of urologic surgery and practice; diagnosis, prevention and management. new york, informa healthcare; 2007, p. 69-72,320-322. 14. roberts hr. clinical experience with activated factor vii: focus on safety aspects. blood coagul fibrinolysis. 1998;9 suppl 1:s115-8. pediatric urology concealed penis after circumcision: is it beneficial in lowering uropathogenic colonization in penile skin and preventing recurrence of febrile urinary tract infections? mete özkıdık,¹* onur telli,² nurullah hamidi,³ uygar bağcı,4 adil hüseyinov,4 aytac kayış,4 anar ibrahimov,4 tarkan soygür,5 berk burgu5 purpose: to discuss whether concealed penis after circumcision lowers perimeatal urethral and glanular sulcus uropathogenic bacterial colonization in healthy boys with no urinary tract problems and prevents attacks of febrile urinary tract infections in non-healthy boys with defined urinary tract abnormalities. materials and methods: this case-control study was conducted in ibn-i sina hospital and retrospectively collected data of 471 boys were analyzed. all patients were scanned for any urinary tract abnormality and those with any defined abnormalities were classified as non-healthy group. (123 patients) non-healthy patients were divided into two subgroups as concealed (n:31) and non-concealed (n:92) penis after circumcision. healthy patients with no urinary problems were divided into three groups as circumcised without concealed penis (n:144), with concealed penis after circumcision (n:104) and uncircumcised control group (n:100). bacterial cultures were obtained from both periurethral meatal and glanular sulcus areas by adhering strictly to the rules of obtaining bacterial culture to avoid false-positive or negative culture results. also only uropathogenic bacterias were evaluated, irrelevant results were excluded. results: mean age was similar in healthy population. comparison of three groups showed that there was a significant difference in both cultures.(p = .026 for periurethral meatal region, p = .039 for glanular sulcus region) in post hoc analysis, non-concealed group had a lower rate of culture positivity in both areas compared to other groups. mean age was also similar in non-healthy population. mean follow-up period was 18.2 months. patients with concealed penis after circumcision had a significantly higher number of febrile uti attacks (20 attacks in 8 patients vs 7 attacks in 5 patients) compared to non-concealed group. (p = .019) all febrile uti attacks except one in this group occurred below the age of 12 months. a total of 10 patients in both healthy and non-healthy groups had postoperative hemorrhage after circumcision and only 1 patient had a wound infection. conclusion: concealed penis after circumcision does not lower perimeatal urethral and glanular sulcus uropathogenic bacterial colonization in healthy patients and does not protect unhealthy patients from febrile urinary tract infection attacks. if circumcision is planned, concealed penis should be avoided and also parents should be informed about the possible risks due to concealed penis before the procedure, particularly in patients with urinary tract abnormalities. keywords: circumcision; colonization; glans; urethral; urinary tract infection introduction circumcision is the surgical excision of the pre-puce. it has been performed as a surgical procedure since ancient times. males were circumcised inspired by religious beliefs or social traditions over years, particularly in muslim and jewish populations. many boys in united states undergo circumcision in their first year of life.(1) in contrast to these examples, in uk and european countries circumcision is not performed routinely for every boy, but only for boys whose parents prefer or doctors recommend. scandinavian culture is known to be more strict about the preservation of the foreskin, and as a result nordic countries have the lowest rate 1 asistant professor of urology, department of urology, school of medicine, biruni university, istanbul. 2 professor of urology, department of urology, school of medicine, marmara university, istanbul. *correspondence: department of urology, school of medicine, biruni university, özel medicine hospital, hoca ahmet yesevi cad. no:149 güneşli, bagcılar, istanbul tel: +90 0532 7919430. fax: +90 0212 4963658. e-mail:akyuzosman@hotmail.com, kamilcam@hotmail.com. received february 2019 & accepted august 2019 of circumcision in the westernized societies. though there are different approaches to circumcision in distinct populations, contributions of circumcision to improve public health have been proved in recent years by several studies including large samples.(²) boys who have no anatomical or functional urinary tract problems and no urogenital diseases such as recurrent balanoposthitis, balanitis xerotica obliterans (bxo), paraphimosis or phimosis generally do not need circumcision along life. the main benefit of circumcision which has been shown in many studies from different centers is that it lowers bacterial colonization in penile skin.(³) in a prospective randomized study including 197 patients, gücük a et al. urology journal/vol 17 no. 2/ march-april 2020/ pp. 164-168. [doi: 10.22037/uj.v0i0.5192] evaluated the effect of circumcision on periurethral pathogenic bacterial flora.(4) the study concluded that circumcision significantly decreases the pathogenic bacterial colonization and combined with antibiotic prophylaxis, circumcision prevents recurrent and febrile utis. this effect of circumcision is particularly beneficial for patients with urinary tract abnormalities, such as posterior urethral valve (puv), vesicoureteral reflux (vur), ureteropelvic junction (upj) obstruction or obstructive megaureter. although this colonization causes no significant problems in healthy patients, patients with anatomical or functional urinary problems would have recurrent febrile urinary tract infections (utis) due to the increased rate of uropathogenic bacterial colonization in penile skin.(5) kose et al. investigated the effect of circumcision on frequency of utis in 134 boys with antenatal hydronephrosis.(6) the results showed that the pre-circumcision uti frequency (2.97 ± 1.14/year) was significantly higher than the post-circumcision (0.25 ± 0.67/year) period. (p < .05) concealed penis is a relatively new definition in the urologic literature. it refers to a redundant skin after circumcision and causes the glans seem like “ concealed”. the main cause for concern in these patients is the possibility of inadequate reduction of bacterial colonization in penile skin, particularly in glanular sulcus region, because of the redundant skin covering glanular sulcus as in uncircumcised males. studies comparing circumcised and uncircumcised healthy boys for uropathogenic bacterial colonization rates declare that non-circumcised boys have higher colonization rates.(7) however, we do not have sufficient data about patients who have concealed penis after circumcision. in this study, we aimed to investigate whether concealed penis is effective to lower the uropathogenic bacterial colonization in penile skin of healthy children or to prevent recurrent febrile uti attacks in boys with urinary tract abnormalities. materials and methods our research was a case-control study and conducted in ibn-i sina hospital in ankara university faculty of medicine with a retrospective design. the data of 471 boys who referred to our pediatric urology clinic between march 2010 and september 2014 was collected and evaluated. study population there were two different populations in our study as healthy and non-healthy boys which referred to patients with no urinary tract problems and defined urinary tract abnormalities respectively. scanning process for any urinary tract malformation was performed in our clinic. all members of non-healthy group had a follow-up schedule on a patient specific basis. healthy patients were classified into three groups. group 1 consisted of 144 (41.3 %) circumcised boys without concealed penis whereas group 2 included 104 (29.8 %) boys with a concealed penis after circumcision and group 3 (control group) consisted of 100 (28.7%) uncircumcised boys without phimosis. in addition, records of 123 unhealthy circumcised boys with a diagnosed urinary abnormality such as vur, puv, upj obstruction, obstructive megaureter, neurogenic bladder related to spina bifida were retrospectively analyzed to evaluate the post circumcision frequency of febrile uti attacks in concealed and non-concealed groups. 31 of these patients (25%) had concealed penis after circumcision. inclusion and exclusion criteria the participants had no phimosis and history of recurrent balanoposthitis. (2 times or more in total) patients with serious complications after circumcision such as meatal stenosis or urethral fistula, patients with post circumcision scarring, patients who were uncircumcised or had concealed penis after circumcision and perform regular cleaning of glans penis, unhealthy patients who lack their follow-up were excluded to avoid any possible bias. inclusion-exclusion assessment was done by one physician. procedures we accepted patients who had penile skin covering 1/3 or more of the glans after circumcision as concealed. a swab was swept circumferentially once around the periurethral meatus and glanular sulcus regions. afterwards, bacterial cultures were obtained from both of the areas, by adhering strictly to the rules of obtaining bacterial culture to avoid false positive or negative culture results, for detection of table 1. positive uropathogenic bacterial culture rates in three groups. healthy population with no group 1 circumcised boys group 2 concealed penis group 3 uncircumcised total p value analysis of urinary tract abnormalities without concealed penis after circumcision three groups mean age (years) 6.12 ± 0.7 6.15 ± 0.6 6.36 ± 0.8 6.2 ± 0.7 .15 number of patients 144 (41.3 %) 104 (29.8 %) 100 (28.7 %) 348 .048 percentage of positive 29.6 % 62.6 % 68.9 % 50.7 % .026 uropathogenic culture in periurethral meatal area percentage of positive 43.8 % 69.2 % 77.4 % 61.0 % .039 uropathogenic culture in glanular sulcus percentage of positive 45.2 % 73.4 % 82.9 % 64.4 % .032 uropathogenic culture in any area p value for periurethral group 2 p = .008 group 1 p = .008 group 1 p = .004 meatal culture group 3 p = .004 group 3 p = .11 group 2 p = .11 p value for glanular group 2 p = .011 group 1 p = .011 group 1 p = .009 sulcus culture group 3 p = .009 group 3 p = .097 group 2 p = .097 p value for any culture group 2 p = .009 group 1 p = .009 group 1 p = .007 group 3 p = .007 group 3 p = .081 group 2 p = .081 p values refer to anova analysis, p values refer to post hoc analysis. bonferroni test was used for post hoc analysis. concealed penis after circumcision-özkıdık et al. vol 17 no 02 march-april 2020 165 uropathogenic bacteria. positive bacterial cultures were consulted to a bacteriologist and results which would be irrelevant were not assessed and only uropathogenic colonies were evaluated. evaluations our primary end point in healthy population was rates of uropathogenic bacterial colonization in periurethral meatal or glanular sulcus areas. total culture positivity in both areas for uropathogenic bacteria was calculated for each group of healthy population. non-healthy population was evaluated separately and the primary end point was the reduction in number of febrile uti attacks. concealed and non-concealed groups were compared for total number of febrile uti attacks in 18 months’ follow-up. statistical analysis we used spss 22.0 for statistical analysis.(8) in healthy population, anova analysis was done to compare three groups whether uropathogenic bacterial colonization rates were different. bonferroni test was used for post hoc analysis. to minimize error in the test, we used α/3 instead of α. in non-healthy population, student t test was used to compare concealed and non-concealed groups for number of febrile uti attacks. a p value of < .05 was accepted for statistical significance. results general characteristics of healthy population in the study were summarized in table 1. mean age was similar in three groups. non-concealed group had a higher number of participants than others. as three groups were compared for uropathogenic bacterial colonization rates, the difference was significant in both areas. (periurethral meatal region p = 0.026 and glanular sulcus region p = 0.039) in post hoc analysis, culture positivity rate of non-concealed group were significantly lower than concealed and uncircumcised groups.(table 1) however, there was no significant difference between concealed and uncircumcised groups.(table 1) most patients with a positive uropathogenic bacterial culture in the periurethral meatal region had also positive cultures in the glanular sulcus region, except a few participants who had only positive culture in the glanular sulcus region. as culture positivity in any area were compared with anova analysis for three groups, there was a significant difference as expected. (p = .032) in post hoc analysis, non-concealed group had significantly lower rates of colonization than others. (table 1) general characteristics for unhealthy population were summarized in table 2. mean age was similar in both groups and the mean follow up period was 18.2 months. non-concealed group had a higher number of patients compared to concealed. 8 patients had 20 febrile uti attacks in concealed penis group whereas 5 patients had 7 febrile uti attacks in non-concealed penis group. (table 2) the difference between recorded number of febrile utis was significant. (p = .019) there was no significant difference in number of patients having febrile uti attacks after circumcision between two groups. all febrile uti attacks except one in the non-healthy population occurred below the age of 12 months. 6 (0.01%) patients had postoperative hemorrhage in the healthy group and 4 (0.03%) in the nonhealthy group after circumcision. in management of hemorrhage, wrapping the wound with a sterile gauze was successful in 9 of these patients. only in 1 patient, it required intervention and detailed laboratory examination revealed deficiency of factor 7. after the replacement of factor 7, no persistant hemorrhage was observed. wound infection was only seen in 1 patient in the non-healthy group that was managed with appropriate antibiotic therapy and did not cause a scar or recurrent infection in penis. no other complication due to circumcision was seen in both groups. discussion circumcision is still a conflicting surgical experience though it is widely performed in many countries of the world. current literature declares that it is not necessary for every boy but recommended particularly for those who have recurrent balanoposthitis or uti attacks due to defined anatomical or functional urinary tract abnormalities.(9) most authors agree on circumcision if the benefits outweigh the risks.(10) however, it is not always easy to select right patients to undergo circumcision as each patient with a defined urinary tract abnormality may not have uti attacks or it is not certain how many times of balanoposthitis require circumcision. as expected in every surgical procedure, circumcision have also complications both in the short and long term. early complications of circumcision defined in the literature are hemorrhage, wound infection, retention of urine, meatal ulceration, glans necrosis and penil amputation whereas long term complications are urethral fistula and meatal stenosis.(11-13) hemorrhage is the most common complication of circumcision. during the intervention, surgeon may face with problematic bleeding, use of cautery would be beneficial to control it. in addition, anesthetic agents may have an effect on surgical site hemorrhage in circumcision. karasu et al. conducted a study including 100 patients compediatric urology 166 table 2. number of febrile uti attacks in two groups. non-healthy population with urinary tract abnormalities concealed penis after circumcision non-concealed penis after circumcision total p value mean age (months) 28 ± 3.38 25.3 ± 3.0 26 ± 3.1 .076 number of patients 31 (25 %) 92 (75 %) 123 .041 number of febrile uti attacks 20 7 27 .019 number of patients who had febrile uti after circumcision 8 5 13 .069 abbreviations: uti, urinary tract infection. p values refer to student t test concealed penis after circumcision-özkıdık et al. paring ketamine+midazolam to sevoflurane+propofol in terms of surgical site hemorrhage in circumcision.(14) they found that the intraoperative bleeding scores were significantly higher in ketamine+midazolam group. wrapping the wound with a sterile gauze circumferentially around the sutured area after circumcision helps to avoid postoperative bleeding. the dressing should be removed approximately after 24 hours, after making sure that there is no bleeding or oozing. gently washing the wound for 5-7 days helps prevent postoperative wound infections. management of severe complications due to circumcision is generally complicated and patients should be referred to tertiary centers for advanced treatments. another issue under debate about circumcision is the appropriate age for the procedure. each age period in which the surgery has planned has its own advantages and disadvantages. neonatal circumcision has a shorter time of recovery but with the higher risk of meatal ulceration and stenosis.(15) males in phallic period tend to be affected adversely in psychological way due to undergoing a surgery associated with their sex organ. school aged boys may need sedation anesthesia in addition to dorsal penile nerve block during the procedure.(16) boys in peripubertal period may have tearing of sutures before healing is complete due to intermittant nocturnal erections. physician should consider both risks and benefits for each patient and then inform parents about the procedure. therefore, favorable age for circumcision would be different for each individual. the definition of concealed penis is not clear in the literature. although authors agree on that concealed penis is the appearance of redundant skin covering glans in circumcised males, there is no consensus on exactly how much of the glans should be covered by redundant skin to regard it as concealed penis. the ideas of authors vary, some declare that if glanular sulcus is not visible after circumcision, it should be classified as concealed penis. however, some declare that if external meatal opening and most part of glans are clearly visible after circumcision, it should be classified as non-concealed penis. the point which should be considered here is that the distance between external meatal opening and glanular closure line has a direct correlation with age.(17) therefore, glanular sulcus would be visible in some patients after puberty when penis reaches its ultimate length even it is not visible after circumcision. in our study, we adopted a reasonable approach and accepted patients whose penile skin covered 1/3 or more of the glans after circumcision as concealed. however, we admit this as a limitation of our study because there is no widely accepted definition of concealed penis in the literature. most authors agree on that concealed penis would not be regarded as a complication of circumcision, such as other complications mentioned above. defining it as a surgical error seems to be more accurate. because, healthy patients with no defined urinary tract abnormalities who have concealed penis after circumcision generally do not have balanoposthitis or utis in their whole life despite the higher rates of bacterial colonization in their penile skin. even, some patients may do regular cleaning of glans penis by the help of their parents as a preventive measure to decrease penile skin bacterial colonization. some uncircumcised patients would also get this benefit. however; in unhealthy patients with recurrent urinary tract infections due to poor hygiene of the glans, a second intervention for removal of the redundant skin in concealed penis should be considered. we did not include patients who do regular cleaning of glans penis in our study to avoid any possible bias. our study yielded the result that penile skin bacterial colonization rates are significantly higher both in uncircumcised and concealed penis than in circumcised penis. so we should keep in mind concealed penis as a surgical error limiting benefits of circumcision. circumcision has a protective effect on penis through the reduction of uropathogenic bacterial colonization in penile skin. however, concealed penis with its redundant skin covering glans serves as a base for uropathogenic bacterial colonization. this causes an argument about the proved benefit of circumcision. in our study; we also compared uropathogenic bacterial colonization rates of uncircumcised and concealed with each other, and found no significant difference between them in both periurethral meatal and glanular sulcus cultures. results obtained from the unhealthy group also verified our results reported for healthy group, as concealed had significantly higher number of febrile urinary tract infections. we think there is a direct correlation between the increased uropathogenic bacterial colonization in penis and recurrent febrile uti attacks. as a limitation of our study, bacterial colonization rates and febrile uti attacks were evaluated in different populations. in addition, we could not report the results of positive cultures in details including which uropathogenic bacteria was detected in glanular sulcus or periurethral meatal area. all data in the study were collected retrospectively so this data lacked in our study. we also believe that our sample size would not be adequately large as to provide definitive results. these limitations would diminish the validity of the study results. however, we avoided a possible bias with the exclusion of post-circumcision scars and serious complications such as urethral fistula, meatal stenosis or ulceration. we should exactly state that concealed penis after circumcision causes lack of penile hygiene. our results supported our hypothesis and also were similar with the current literature. we found a significantly lower rate of penile uropathogenic bacterial colonization in circumcised patients without concealed penis. in post hoc analysis, there was no significant difference between concealed and uncircumcised group. this result showed us that concealed penis significantly diminishes benefits of circumcision. in addition, febrile uti attacks were significantly higher in patients with concealed penis compared to non-concealed in the non-healthy population. our study objective was to highlight these points. to our knowledge, this is the first study assessing patients with concealed penis for the risk of uropathogenic bacterial colonization in penile skin and recurrent febrile uti attacks. as we balance advantages of our study against its limitations, we realize that our results would concealed penis after circumcision-özkıdık et al. vol 17 no 02 march-april 2020 167 contribute to the current literature. however, randomized prospective clinical trials including larger samples should be conducted to provide definitive results about concealed penis after circumcision. conclusions as a conclusion, we declare that concealed penis after circumcision does not lower uropathogenic bacterial colonization in penile skin, also it is not protective for recurrent febrile uti attacks. if circumcision is planned, concealed penis should be avoided. in addition, parents should be informed about the risks of concealed penis before the procedure. in concealed penis after circumcision, a second intervention should be discussed for the removal of redundant skin unless the patient has a normal hygiene of the glans. conflict of interest the authors declare that they have no conflict of interest in connection with this article. references 1. el bcheraoui c, zhang x, cooper cs, rose ce, kilmarx ph, chen rt. rates of adverse events associated with male circumcision in u.s. medical settings, 2001 to 2010. jama pediatr. 2014;168:625-34. 2. tewary k, narchi h. recurrent urinary tract infections in children: preventive interventions other than prophylactic antibiotics. world j methodol. 2015;26:139. 3. bader m, mccarthy l. what is the efficacy of circumcision in boys with complex urinary tract abnormalities? pediatr nephrol. 2013;28:2267-72. 4. gücük a, burgu b, gökçe i̇, mermerkaya m, soygür t. do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with vur? j pediatr urol. 2013;6:1131-6. 5. wiswell te, miller gm, gelston hm jr, jones sk, clemmings af. effect of circumcision status on periurethral bacterial flora during the first year of life. j pediatr. 1988;113:442-6. 6. kose e, yavascan o, turan o, et al. the effect of circumcision on the frequency of urinary tract infection, growth and nutrition status in infants with antenatal hydronephrosis. ren fail. 2013;35:1365-9. 7. hellerstein s. urinary tract infections in children: why they occur and how to prevent them. am fam physician. 1998;57:2440-6, 2452-4. 8. icr. ibm spss statistics for windows, version 22.0. armonk, ny: ibm corp. 2013 9. na af, tanny sp, hutson jm. circumcision: is it worth it for 21st-century australian boys? j paediatr child health. 2015;51:5803. 10. earp bd. do the benefits of male circumcision outweigh the risks? a critique of the proposed cdc guidelines. front pediatr. 2015;3:18. 11. gold g, young s, o'brien m, babl fe. complications following circumcision: presentations to the emergency department. j paediatr child health. 2015;51:1158-63. 12. odoyo-june e, feldblum pj, fischer s, et al. unexpected complications following adult medical male circumcision using the prepex device. urol int. 2016;96:18893. 13. tuncer aa, deger m. incidence of complications following thermocauteryassisted circumcisions. urol j. 2018;15:35964. 14. karasu d, yilmaz c, ozgunay se, karaduman i, ozer d, kaya m. effects of different anesthetic agents on surgical site hemorrhage during circumcision. urol j. 2018;15:21-6. 15. sorokan st, finlay jc, jefferies al, canadian paediatric society, fetus and newborn committee, infectious diseases and immunization committee. newborn male circumcision. paediatr child health. 2015;20:311-20. 16. tutuncu ac, kendigelen p, ashyyeralyeva g, et al. pudendal nerve block versus penile nerve block in children undergoing circumcision. urol j. 2018;15:109-15. 17. abbas to, ali m. urethral meatus and glanular closure line: normal biometrics and clinical significance. urol j. 2018;15:277-9 pediatric urology 168 concealed penis after circumcision-özkıdık et al. u j spring 2012.pdf 455vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l department of urology, monash medical center, victoria, australia *e-mail: yktay2@gmail.com we report a rare case of an ectopically placed ureteral stent, which was acceptable and functional. obstructing 8 × 15-mm proximal right-sided ureteral calculus. there were also multiple nonobstructing renal calculi on the left side. an antegrade ureteral stent was placed to relieve his infected and obstructed right kidney. during stent placement, the interventional radiologist was unable to keep the distal end of the ureteral stent coiled in the ileal conduit. unintentionally, the distal end of the guidewire was fed into the contralateral ureter. this resulted in the ureteral stent being placed across both renal collecting systems via the ileal conduit. the inadvertent placement of the ureteral stent into both ureters is rare; that the patient had a bricker anastomosis, which makes it even less likely. subsequent nephrostogram demonstrated bilateral patent ureters. once the sepsis resolved, the patient underwent a right percutaneous nephrolithotomy. during this procedure, the ectopic ureteral stent was also removed. an elective left percutaneous nephrolithotomy was performed to clear his left renal calculi. urinary tract infection and lower urinary tract reconstruction are associated with a higher incidence and recurrence rates of urolithiasis. surgical options for the ureteral calculi include ureteroscopic lithotripsy, pyeloscopic lithotripsy, percutaneous nephrolithotomy, and extracorporeal shockwave lithotripsy. it is disobstructing the urinary system via an ileal conduit, a nephrostomy and antegrade ureteral stent should be placed without delay. this provides control of the urinary tract and an opportunity to plan the most apyeng kwang tay,* dan spernat, john stuckey, sree appu when is an ectopically placed ureteral stent acceptable? references 1. 2. 3. goumas-kartalas i, montanari e. percutaneous nephrolithotomy in patients with spinal depictorial urology urological oncology 99urology journal vol 5 no 2 spring 2008 overexpression of bmi1, a polycomb group repressor protein, in bladder tumors a preliminary report afsaneh malekzadeh shafaroudi,1 seyed javad mowla,1 seyed amir-mohsen ziaee,2 ahmad-reza bahrami,3 yaser atlasi,1 mahshid malakootian1 introduction: a polycomb group repressor protein named bmi1 represses the genes that induce cellular senescence and cell death, and it can contribute to cancer when improperly expressed. we aimed to evaluate expression of bmi1 gene in bladder tumors. materials and methods: tissue specimens containing bladder tumor were evaluated and compared with intact tissues from tumor margins and normal bladders. there were 40 tumor specimens of patients with transitional cell carcinoma of the bladder, 20 tumor-free tissues taken from the margin of the tumors, and 8 specimens from patients without tumor. specific primers for bmi1 and b2m (as an internal control) were used for reverse transcript polymerase chain reaction technique. the production and distribution of bmi1 protein was also examined by western blotting and immunohistochemistry techniques. results: polymerase chain reaction generated a 683-bp product, corresponding to the expected size of bmi1 amplified region. the identity of the amplified fragment was then confirmed by direct dna sequencing. the mean of expression of bmi1 detected in tumor tissues was significantly higher than that in intact tissues, and there was also a significant association between the mean of gene expression and the stage of malignancy (p < .001). the expression of bmi1 at protein level was further confirmed by western blotting and immunohistochemistry. conclusion: bmi1 is a potent repressor of retinoblastoma and p53 pathways, and hence, elucidating its role in tumorigenesis is very important. we reported for the first time the expression of bmi1 and its correlation with incidence and progress of bladder tumors. urol j. 2008;5:99-105. www.uj.unrc.ir keywords: bladder neoplasms, tumor markers, bmi1, gene expression 1department of genetics, faculty of basic science, tarbiat modares university, tehran, iran 2urology and nephrology research center and shahid labbafinejad medical center, shahid beheshti university (mc), tehran, iran 3institute of biotechnology, ferdowsi university of mashhad, mashhad, iran corresponding author: seyed javad mowla, phd department of genetics, faculty of basic sciences, tarbiat modares university, po box: 1411-175 tehran, iran tel: +98 21 8288 3464 fax: +98 21 8288 3463 e-mail: sjmowla@modares.ac.ir received december 2007 accepted march 2008 introduction our understanding of the tumor biology has improved measures to prevent progression of superficial tumors to advanced and metastatic disease.(1) in bladder cancer for instance, we know that genetic alterations may occur at early stages and that they are retained in the recurrent tumors. consequently, information on changes in the cell-cycle regulatory genes at early diagnosis may be useful for predicting tumor progression and recurrence. today, cancer studies are focused on the identification of molecular markers that would predict which superficial bladder tumors will progress to invasive forms. however, our knowledge of predictive markers has not reached their reliable usage in practice.(1) the human bmi1 is located on bmi1 in bladder tumors—malekzadeh shafaroudi et al 100 urology journal vol 5 no 2 spring 2008 chromosome 10p13, a region known to be involved in translocations in various leukemias and rearrangements in malignant t-cell lymphomas.(2-4) it is responsible for expression of bmi1 protein, a member of the polycomb group (pcg) proteins which form multiprotein complexes that function as transcriptional repressors.(5) bmi1 was first identified as an oncogene that cooperates with c-myc in the generation of mouse pre-b-cell lymphomas.(6,7) the oncogenic activity of bmi1 may be linked to its another fundamental function; several recent reports showed that bmi1 is essential for the self-renewal of both hematopoietic and neuronal stem cells, as well as cancer stem cells.(8-11) this function of bmi1 depends on its ability to repress the ink4a/arf locus. along with a role of bmi1 in stem-cell biology, bmi1 expression in the bone marrow is strong in undifferentiated precursor cells, but it gradually declines in the course of differentiation.(12) the bmi1 gene is amplified in certain mantle-cell lymphomas and is overexpressed in a subset of non-small-cell lung cancer and colorectal carcinomas.(13-15) moreover, it plays a role in the development of human breast cancer and increases in metastatic prostate cancer.(16-19) despite many studies on the potential involvement of bmi1 in the oncogenesis of various lymphomas and leukemias, little is known about its role in the pathogenesis of solid tumors, including urothelial carcinomas. to our knowledge, the only available report is that of glinsky and colleagues who employed a genomics approach to identify an 11-gene, including bmi1, signature that consistently displays a stem-cellresembling expression profile in distant metastatic lesions of different cancers, including prostate and bladder cancers.(20) to investigate the potential involvement of bmi1 in human bladder cancer, we examined the expression of bmi1 in the bladder specimens with and without malignant lesions. materials and methods human clinical specimens fresh tissue biopsies were obtained from patients who were referred to shahid labbafinejad medical center. the tissues were immediately snap-frozen in liquid nitrogen and categorized into 3 groups: 40 tumor specimens prepared by transurethral resection from patients with transitional cell carcinoma of the bladder (table), 20 tumor-free tissues taken from the margin of tumors (cystoscopically normal appearance), and 8 specimens from patients with no symptoms and signs of bladder cancer who had undergone surgical treatment for benign prostatic hyperplasia. histopathological parameters were evaluated according to the grading and tnm system for stage classification of the world health organization. the experimental design was approved by the ethics committees of tarbiat modares university and the urology and nephrology research center of shahid beheshti university (mc). the patients’ written informed consents were obtained prior to participation. rna extraction total rna was isolated from frozen tissues using the rnx plus solution (cinnagen, tehran, iran) according to the manufacturer’s instructions. the quality of rna was evaluated by gel electrophoresis, and the concentration of rna was measured by optical density at 260 nm. semiquantitative polymerase chain reaction two micrograms of the total rna was used for cdna synthesis using random hexamer primer (fermentas, vilnius, lithuania) and revertaid mmulv reverse transcriptase (fermentas, vilnius, lithuania) in a 20 μl reaction according characteristics values patients number 40 mean age, y 65.4 ± 11.1 age range, y 33 to 84 sex male 36 (90.0) female 4 (10.0) stage ta 7 (17.5) t1 24 (60.0 t2 9 (22.5) grade low 25 (62.5) high 15 (37.5) characteristics of patients with bladder cancer* *values in parentheses are percents. bmi1 in bladder tumors—malekzadeh shafaroudi et al urology journal vol 5 no 2 spring 2008 101 to the manufacturer’s instructions. reverse transcription polymerase chain reaction (pcr) primers were designed using previously described human bmi1 and β2-microglobulin (b2m) sequences (genbank accession numbers: nm_005180 and nm_004048, respectively). the appropriate pcr primers were designed using genrunner software (version 3.02; hastings software, new york, usa) as follows: bmi1f: 5’-gag ggt act tca ttg atg cca c-3’ bmi1r: 5’-cca gtt ctc cag cat ttg tca g-3’ b2mf: 5’-cta ctc tct ctt tct ggc ctg-3’ b2mr: 5’-gac aag tct gaa tgc tcc ac-3’ polymerase chain reaction amplifications were performed using 2 μl of cdna with 1 u of taq polymerase (cinnagen, tehran, iran), 1.5 mm of mgcl2, 200 μm of dntps, and 0.4 μm of each primer in a 25-μl pcr reaction. the pcr cycling conditions were as follows: initial denaturation at 94 °c for 4 minutes and following 38 (bmi1) or 32 (b2m) cycles of 94°c for 30 seconds, 59°c (for both bmi1 and b2m) for 40 seconds, 72°c for 45 seconds, with a final extension at 72°c for 10 minutes. the primers amplified 683-bp and 191-bp fragments for bmi1 and b2m cdna, respectively. the pcr products were separated on a 1% agarose gel, stained with ethidium bromide, and visualized under the ultraviolet light. the intensity of bands was determined using uvitec software (uvitec, cambridge, uk). the identity of pcr products was confirmed by direct dna sequencing (millegen, toulouse, france). western blotting frozen tissue samples were homogenized and lysed in modified ripa buffer (tris-hcl, 50 mm, ph 7.4; nacl, 150 mm; phenylmethylsulfonyl fluoride, 1 mm; ethylenediamine tetra-acetic acid, 1 mm; triton x-100, 1%; sodium deoxycholate, 1%; sodium dodecyl sulfate, 0.1%; trypsin inhibitor, 10 μg/ml). the concentration of proteins in cell lysates was quantified by means of bradford assay, and 20 μg of total protein was loaded in each lane. samples were electrophoresed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (12.5%) and blotted for 2 hours onto hyband-p polyvinylidene difluoride membrane (amersham biosciences europe gmbh, freiburg, germany). membranes were then blocked for 2 hours in ecl advance blocking solution (amersham biosciences, piscataway, new jersey, usa), according to the manufacturer’s instructions. blots were incubated with the anti-bmi1 antibody for 3 hours and anti-β-actin antibody for 1 hour, and then with the secondary antibodies for 1 hour in room temperature, before being visualized by ecl advance western blotting detection kit (amersham biosciences, piscataway, new jersey, usa). anti-bmi1 antibody (mouse monoclonal antibody to bmi1 (ab14389) and anti-β-actin antibody (prosci, poway, california, usa) were used at dilutions 1:1000, and horse raddish peroxidase-conjugated antimouse igg a4416 (dako, glostrup, denmark) and horseradish peroxidase-conjugated antirabbit igg (sigma, st louis, missouri, usa) were used at 1:42000 dilution. all antibodies were diluted in ecl advance blocking solution (amersham biosciences, piscataway, new jersey, usa), according to the manufacturer’s instructions. immunohistochemistry formalin-fixed paraffin-embedded tissue sections (5 μm) were deparaffinized with xylene, rehydrated in descending concentrations of ethanol, and boiled for 15 minutes in citrate buffer (10 mm, ph 6.0). endogenous peroxidase activity was suppressed with 3% hydrogen peroxidase for 20 minutes. slides were serum blocked and incubated with mouse monoclonal antibody to bmi1 (ab14389, 1:200 dilution) for 2 hours at room temperature followed by staining with secondary horse raddish peroxidaseconjugated antimouse antibody (a4416, 1:200 dilution). in negative controls, all the conditions were kept the same, except that the first antibody was eliminated. statistical analyses all experiments were replicated 2 or 3 times, and the results were analyzed by performing analysis of variance test to determine the relative intensity of bmi1 expression among different biopsy groups. also, the least significant difference test bmi1 in bladder tumors—malekzadeh shafaroudi et al 102 urology journal vol 5 no 2 spring 2008 was used to study the differences between pairs of tumor stages. the spss software (statistical package for the social sciences, version 15.0, spss inc, chicago, illinois, usa) was used for statistical analyses. results expression of bmi1 we collected a total number of 68 specimens of tumoral tissue, margin of tumor, and apparently normal bladder tissue. to make sure of using the same amount of rna for each pcr reaction, b2m gene expression was employed as an internal control. for each sample, the reverse transcript pcr reaction was carried out for both b2m and bmi1 genes, in separate tubes and under similar conditions (except for the number of cycles). furthermore, in each reaction, a tube with no cdna was used as a negative control. we determined the relative expression of bmi1 in 40 tumors, 20 tumor margins from the same patients, and 8 apparently normal tissue samples of the bladder. an expected 191-bp pcr product corresponding to amplified b2m segment was visualized in all of the examined samples (figure 1). the designed primers for bmi1 amplified an expected 683-bp segment in most of the samples. the accuracy of the amplified products was further confirmed by dna sequencing. we detected the expression of bmi1 in 21 of 40 (52.5%) examined tumoral specimens of the bladder. the expression was also detected in 5 of 20 (25.0%) tumor margin specimens, as well as in 2 of 8 (25.0%) apparently normal specimens. however, the intensity of expression was much higher in tumoral tissues compared to the other ones (figure 1). because we have used a semiquantitative reverse transcript pcr approach, a densitometric evaluation and comparison of the relative expression of bmi1/b2m between different tissue samples was feasible. the intensity of bmi1 expression was significantly higher in neoplastic tissues compared to the specimens with no neoplastic changes (p = .004; figure 2). then, we examined the potential correlation between bmi1 expression and the clinicopathological features (eg, tumor grade and stage) of the patients. despite the fact that the expression level of bmi1 in high-grade tumors was more than that of the low-grade ones, the difference was not significant (figure 2). furthermore, the intensity of bmi1 expression was significantly lower in stage ta malignant tumors compared to that in tumors with higher stages of t1 or t2 (p = .03; figure 2). expression of bmi1 at protein level we employed western blotting and immunohistochemical techniques to confirm the expression of bmi1 protein in bladder tumors and also to determine its tissue distribution and subcellular localization. the western blot data showed a single band of ~45 kda in tumor specimens, corresponding to the expected size of the protein (figure 3). we also used the embryonic carcinoma cell line, ntera2 (nt2), as a negative control. based on our reverse transcript pcr results, there was no expression of bmi1 in the cell line (data not shown). as it is evident in figure 3, there was no signal relevant to bmi1 protein expression in the cells. to determine the tissue distribution and figure 1. reverse transcript polymerase chain reaction analysis of the expression of bmi1 and b2m (as an internal control) in the bladder tissues obtained from tumors (t) and the margin of tumors (m) from the same patients (numbers). bmi1 in bladder tumors—malekzadeh shafaroudi et al urology journal vol 5 no 2 spring 2008 103 subcellular localization of bmi1 in bladder tumors, formalin-fixed paraffin-embedded blocks were collected from archival collections of shahid labbafinejad medical center and 5-μm tissue sections prepared from the samples. the immunohistochemical data revealed that the bmi1 protein is primarily localized in the nuclei of the tumor cells (figure 4). to asses the specificity of the antibody, a negative control slide was accompanied each immunohistochemical processing (figure 4). similar conditions were used for both positive and negative slides, except for the omission of the first antibody in the negative slides. discussion the cell cycle is a complex process in which many molecules are involved. among these molecules, inhibitors of cyclin-dependent kinase p16ink4a and p14arf (coded from cdkn2a locus) correlates inversely with the markers of eukaryotic cell proliferation prb and p53, respectively.(21) the unique genomic structure and compact organization of these genes, which have common reading frames, may be essential for maintaining a balanced rb and p53 pathway function.(22) in terms of cancer, the ink4a/arf locus which is negatively regulated by bmi1 is also a frequent target for mutations, deletions, and epigenetic silencing in a wide spectrum of human tumors.(23-25) this raises the possibility that transcriptional regulators of the locus may also be involved in cancer progression. in line with this prediction, it has recently been shown that figure 2. relative (b2m-normalized) intensities of bmi1 expression (mean + standard error). top, tumoral and intact bladder tissues. middle, low-grade and high-grade bladder tumors. bottom, different stages of bladder tumors. relative band intensities for bmi1 for each sample were quantitated by densitometry, normalized to b2m expression. statistical analysis revealed that the expression of bmi1 is significantly higher in tumor specimens compared to that in normal tissues and also in stage t1 and t2 compared to ta (p < .001). figure 3. western blot analysis of bmi1 protein expression in the bladder tissues. total proteins were isolated from nt2 cell line (that showed no expression in reverse transcript polymerase chain reaction) and 2 representative tumor (t1 and t2) bladder biopsies. the experiments confirmed the expression of an approximately 45 kda form of bmi1 protein in the bladder tissues. the expression of β-actin was used as a loading control. bmi1 in bladder tumors—malekzadeh shafaroudi et al 104 urology journal vol 5 no 2 spring 2008 bmi1 is amplified in some hematologic disorders, such as mantle-cell and non-hodgkin lymphomas, and is also overexpressed in solid tumors such as non-small-cell lung cancer, medulloblastoma, colorectal cancer, breast cancer, and prostate cancer.(13-19) in this study, the suitability of the bmi1 gene expression was evaluated as a potential molecular marker in diagnosis and molecular classification of bladder tumors. bmi1 is a transcriptional repressor that involves in many cellular mechanisms including tumorigenesis. despite several reports demonstrating overexpression of bmi1 in a series of cancers,(13-19) to date, there is no evidence on potential involvement and causative role of bmi1 in bladder cancer. the main goal of this study was to determine and compare the relative expression of bmi1 gene in neoplastic tissue versus intact tissue of bladder cancer and its potential involvement in induction and progression of bladder cancer. our data revealed a differential expression of bmi1 in tumoral tissues versus apparently normal tissues and tumor margins of bladder cancer. furthermore, the data suggests that bmi1 may play a role in bladder tumor progression rather than initiating the process of tumorigenesis. based on our data, the expression of the gene is not a good indicator for early detection of bladder tumors (eg, at ta stage). however, it could be employed to distinguish ta lesions, which are papillary in nature and limited to the mucosa from t1 lesions, which invade the submucosa or the lamina propria, and hence, are more aggressive.(26) despite overexpression of bmi1 in high-grade tumors compared to the low-grade ones, the difference was not statistically significant in our series. this is probably due to the small size of the patients’ population. the data is also in accordance with our previous report on the expression of oct4 in bladder cancer,(27) where we found no significant correlation between the expression level of oct4 and the grade of the tumors. conclusion the present study suggests that alteration of the bmi1 might play a role in the development and progression of bladder cancer. furthermore, the current study provides some novel data that further elucidate the complex biology of bladder tumor cells and could potentially be used in diagnosis, prognosis, and treatment of bladder cancer. in summary our data has revealed for the first time that (1) the relative expression of bmi1 in tumor tissues is much higher than the nontumor samples (~5 times more), and (2) there is a statistically significant correlation between the level of bmi1 expression and the stage of the bladder tumors. accordingly, the relative amount of bmi1 expression in stage ta is significantly lower than that in stages t1 and t2. in other words, the bmi1 overexpression is not a primary event in the genetics of bladder cancer, and probably, the gene is involved in the progression of the tumor. this finding is in accordance with previous reports showing a gain and amplification of 10 p (the bmi1 locus) in stages t1 and t2, but not in stage ta of bladder cancer.(16) figure 4. representative immunohistochemical data of bmi1 protein expression in formalin-fixed, paraffin-embedded sections of tumor tissues. bladder sections were deparaffinized and subsequently incubated with bmi1 antibody and avidinhorse-radish peroxidase before being visualized with diaminobenzidine. top, bmi1 expression was primarily localized in the nuclei (in brown color, white arrows) of the cells. bottom, the negative control, sections from the same specimen was identically processed, except for the omission of the first bmi1 antibody. bmi1 in bladder tumors—malekzadeh shafaroudi et al urology journal vol 5 no 2 spring 2008 105 conflict of interest none declared. acknowledgement we are grateful to ms nasim hatefi for her valuable help and assistance. this work was financially supported by a research grant from iranian stem cell network. all the samples were provided by shahid labbafinejad medical center and the experiments were performed in tarbiat modares university. references 1. hussain sa, james nd. molecular markers in bladder cancer. semin radiat oncol. 2005;15:3-9. 2. alkema mj, wiegant j, raap ak, berns a, van lohuizen m. characterization and chromosomal localization of the human proto-oncogene bmi-1. hum mol genet. 1993;2:1597-603. 3. pui ch, raimondi sc, murphy sb, et al. an analysis of leukemic cell chromosomal features in infants. blood. 1987;69:1289-93. 4. berger r, baranger l, bernheim a, valensi f, flandrin g. cytogenetics of t-cell malignant lymphoma. report of 17 cases and review of the chromosomal breakpoints. cancer genet cytogenet. 1988;36:12330. 5. orlando v. polycomb, epigenomes, and control of cell identity. cell. 2003;112:599-606. 6. haupt y, alexander ws, barri g, klinken sp, adams jm. novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in e mu-myc transgenic mice. cell. 1991;65:753-63. 7. van lohuizen m, frasch m, wientjens e, berns a. sequence similarity between the mammalian bmi-1 proto-oncogene and the drosophila regulatory genes psc and su(z)2. nature. 1991;353:353-5. 8. molofsky av, pardal r, iwashita t, park ik, clarke mf, morrison sj. bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. nature. 2003;425:962-7. 9. lessard j, sauvageau g. bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. nature. 2003;423:255-60. 10. park ik, qian d, kiel m, et al. bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. nature. 2003;423:3011. valklingbeek me, bruggeman sw, van lohuizen m. stem cells and cancer; the polycomb connection. cell. 2004;118:409-18. 12. lessard j, baban s, sauvageau g. stage-specific expression of polycomb group genes in human bone marrow cells. blood. 1998;91:1216-24. 13. bea s, tort f, pinyol m, et al. bmi-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. cancer res. 2001;61:2409-12. 14. vonlanthen s, heighway j, altermatt hj, et al. the bmi-1 oncoprotein is differentially expressed in nonsmall cell lung cancer and correlates with ink4a-arf locus expression. br j cancer. 2001;84:1372-6. 15. kim jh, yoon sy, kim cn, et al. the bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16ink4a/ p14arf proteins. cancer lett. 2004;203:217-24. 16. dimri gp, martinez jl, jacobs jj, et al. the bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. cancer res. 2002;62:4736-45. 17. kim jh, yoon sy, jeong sh, et al. overexpression of bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. breast. 2004;13:383-8. 18. berezovska op, glinskii ab, yang z, li xm, hoffman rm, glinsky gv. essential role for activation of the polycomb group (pcg) protein chromatin silencing pathway in metastatic prostate cancer. cell cycle. 2006;5:1886-901. 19. van leenders gj, dukers d, hessels d, et al. polycomb-group oncogenes ezh2, bmi1, and ring1 are overexpressed in prostate cancer with adverse pathologic and clinical features. eur urol. 2007;52:455-63. 20. glinsky gv, berezovska o, glinskii ab. microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. j clin invest. 2005;115:1503-21. 21. dai cy, furth ee, mick r, et al. p16(ink4a) expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation. gastroenterology. 2000;119:929-42. 22. kawada y, nakamura m, ishida e, et al. aberrations of the p14(arf) and p16(ink4a) genes in renal cell carcinomas. jpn j cancer res. 2001;92:1293-9. 23. jacobs jj, scheijen b, voncken jw, kieboom k, berns a, van lohuizen m. bmi-1 collaborates with c-myc in tumorigenesis by inhibiting c-myc-induced apoptosis via ink4a/arf. genes dev. 1999;13:267890. 24. jacobs jj, kieboom k, marino s, depinho ra, van lohuizen m. the oncogene and polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. nature. 1999;397:164-8. 25. lowe sw, sherr cj. tumor suppression by ink4aarf: progress and puzzles. curr opin genet dev. 2003;13:77-83. 26. knowles ma. molecular subtypes of bladder cancer: jekyll and hyde or chalk and cheese? carcinogenesis. 2006;27:361-73. 27. atlasi y, mowla sj, ziaee sa, bahrami ar. oct-4, an embryonic stem cell marker, is highly expressed in bladder cancer. int j cancer. 2007;120:1598-602. pictorial aorto-caval fistula mimicking clinical signs of renal colic zbyněk tüdös1, filip čtvrtlík1*, františek hruška2, milan král2 keywords: urolithiasis; renal colic; aortic rupture; aorto-caval fistula; non-enhanced computed tomography; angiography 1department of radiology, faculty of medicine and dentistry, palacky university and university hospital, olomouc, czech republic 2department of urology, faculty of medicine and dentistry, palacky university and university hospital, olomouc, czech republic *correspondennce: department of radiology, university hospital, i. p. pavlova 6, olomouc, 77900, czech republic email: filip.ctvrtlik@fnol.cz. received july 2017 & accepetd februaty 2018 a 71-year-old male came to the emergency room complaining of weakness, nausea and pain in the left flank and groin irradiating into his left hemiscrotum. clinical examination revealed arterial hypotensis and tachycardia. because of the patient’s history of urolithiasis in the past, left renal colic was suspected and non-enhanced computed tomography (ct) was requested. the ct scan confirmed nephrolithiasis, but the crucial finding was an aneurysm of the abdominal aorta measuring 95 mm in diameter. furthermore, the dorsal wall of the aorta was in direct contact with the spine, creating a “draped aorta sign” (figure 1a). there were hyperdense bands along the aorta, the psoas muscles and the gerota’s fascia corresponding to retroperitoneal hematoma (figure 2b)(1). the ct finding was immediately reviewed and ct angiography was promptly performed to evaluate the suspected acute aortic rupture. contrast-enhanced angiography confirmed an aortic rupture with fistula to the inferior vena figure 1. non-enhanced computed tomography initially performed to confirm suspected left renal colic. a) displays abdominal aorta aneurysm and the disappearance of fat plane between the aorta and the spine and the merging of the contours of the two structures, thus creating a “draped aorta sign” (arrows), which is considered a sign of impending aortic rupture. b) displays hyperdense bands along the aorta, the psoas muscles and the gerota’s fascia (arrows), corresponding to retroperitoneal hematoma as a sign of acute aortic rupture. figure 2. contrast-enhanced ct angiography performed to evaluate the extent of the suspected aortic rupture. images in a) the axial and b) the coronal plane offer direct evidence of aortic rupture with 5-mm-wide fistula to the inferior vena cava (arrows). urology journal/vol 17 no. 1/ january-february 2020/ pp. 107-108. [doi: 10.22037/uj.v0i0.5633] cava (figure 2), and the lumen of the vein was homogenously enhanced in arterial phase (figure 3). the patient underwent urgent surgery with partial resection of the aneurysm and implantation of an aorto-iliac bypass graft. this case illustrates the broad and tricky differential diagnosis of renal colic and also the diagnostic capabilities of non-enhanced ct. acknowledgments “supported by palacky university grant iga_ l f _ 2 0 1 8 _ 0 0 2 ” . references 1. cerna m, kocher m, thomas rp. acute aorta, overview of acute ct findings and endovascular treatment options. biomed pap med fac univ palacky olomouc czechoslov. 2017;161:14-23. figure 3. volume rendering reconstruction of ct angiography. contrast filling of the inferior vena cava in arterial phase is clearly seen. aorto-caval fistula with renal colic-tudos et al. pictorial 108 v08_no_3_final_last.pdf endourology and stone disease 185urology journal vol 8 no 3 summer 2011 evaluation of urinary stones ex vivo with microcomputed tomography preliminary results of an investigational technique emre huri,1,2 l an atar,2 can on ermi anoglu,1 olga ara an,1 ha an hamdi eli ,2 r un erso 3 purpose: to evaluate the ultrastructural features of the urinary stones removed with endoscopic stone surgery, using micro computed tomography (micro-ct). materials and methods: patients who had endoscopic surgery for renal or ureteral stones removal were included in this study. after surgery, the stones were classified into three groups and investigated with skyscan 1174 micro-ct. group i underwent percutaneous nephrolithotomy (pnl) with ultrasonic lithotripsy; group ii had ureteroscopic stone surgery (uss) with pneumatic lithotripsy; and group iii (the control group) had stone removal with uss or pnl without lithotripsy. stone homogeneity, voids, and the internal structure of the stones were evaluated. chi-square test was used to evaluate the difference statistically. p values less than .05 were considered statistically significant. results: a total of 24 “calcium oxalate monohydrate” stones from 24 patients were scanned with micro-ct. stones treated with ultrasonic lithotripsy (group i) were more fragile, fragmented, and cracked than those treated with the pneumatic lithotripsy (group ii; p = .01). stones in group ii were more homogeneous and smooth than those in group i and resembled those of the control group (p = .02). homogeneous, non-fragile stones and heterogeneous, fragile calculi were seen in all groups. conclusion: the stone fragility could be confirmed by micro-ct investigation. ultrasonic lithotripters increase the stone fragility, which is demonstrated with increased heterogeneity by micro-ct. urol j. 2011;8:185-90. www.uj.unrc.ir keywords: urinary calculi, microct scan, radiographic image interpretation, calcium oxalate 1second urology clinic, ministry of health, ankara training and research hospital, ankara, turkey 2department of anatomy, medical school, hacettepe university, ankara, turkey 3department of geological engineering, hacettepe university, ankara, turkey corresponding author: emre huri, md, febu associate professor of urology department of second urology clinic, ankara training and research hospital; department of anatomy, medical school, hacettepe university, ankara, turkey tel: +90 312 595 3720 e-mail: dremrehuri@yahoo.com received july 2010 accepted april 2011 introduction the treatment of choice for large renal and proximal ureteral stones (> 2 cm) is usually percutaneous nephrolithotomy (pnl). ureteroscopic stone surgery (uss) is also applied for ureteral stones larger than 1 cm.(1) in these operations, stone removal is generally achieved following breaking of stones. to accomplish this, laser, ultrasonic, and pneumatic lithotripters are used according to the availability of surgical equipment. after surgery, clinical laboratory assessment of the urinary stones is typically conducted. laboratory assessment is geared to identify stones by their primary mineral content, using methods destructive to the stones. knowing the mineral composition of a patient’s stones micro-ct of urinary stones—huri et al 186 urology journal vol 8 no 3 summer 2011 has obvious value in determining a treatment plan. it has long been appreciated that there is variability in stone fragility to shock waves in lithotripsy, and that stones of a given mineral type do not all break in the same way.(2) apart from mineral composition, we have limited information regarding the postoperative stone analysis that determines the stone structure. the purpose of this study was to use microcomputed tomography (micro-ct) as a potential method for observing ultrastructural characteristics of stones removed by pnl and uss. therefore, the effects of ultrasonic or pneumatic lithotripters on the stone structure will be evaluated. materials and methods study design patients with renal or ureteral stone diagnosis that were recommended one of the endoscopic stone surgery techniques were included in this study. the patients who had previous urinary stone history, previous stone therapy, urinary tract infection, or active hematuria were excluded from the study. disease-specific history, physical and urogenital examinations, and pre-operative blood and urine tests were performed in all the patients. the urinary system was evaluated by ultrasonography, intravenous pyelography, and stone sequence spiral ct without contrast when necessary. renal stones were treated with pnl using the ultrasonic lithotripsy, and ureteral stones were treated with uss using the pneumatic lithotripsy. the ems swiss lithoclast® master device (a.k.a. swiss lithoclast ultra, natick, us) was used for ultrasonic and pneumatic lithotripsy. simultaneous application of ultrasonic and pneumatic lithotripsy was not performed. the number and location of the stones were recorded. the stone removal technique was standardized for each group. the grouping was done with respect to lithotripsy technique. the power of ultrasonic lithotripsy and frequency of pneumatic lithotripsy were standardized in each group. ultrasonic or pneumatic probes were touched on the stone surface up to achieving the stone fragmentation in each group. the complete stone fragmentation by lithotripters was defined as destruction of the stone up to 2 to 3 mm. after removal of the stones, the stones were divided into three groups and investigated by micro-ct: group i, pnl and ultrasonic lithotripsy; group ii, uss and pneumatic lithotripsy; group iii (control group), uss or pnl without lithotripsy. after operations, the mineral composition was analyzed by micro-ct, following the stone mineral analysis for each stone. calcium oxalate monohydrate stones were just included to provide homogeneous groups. therefore, the homogeneous stone composition was provided to compare the effect of each lithotripsy technique. the other types of mineral compositions were excluded from the study. chi-square test was used to evaluate the difference statistically (p < .05). investigation technique all samples were scanned using a desktop x-ray microfocus ct scanner (skyscan 1174, skyscan, aartselaar, belgium) at hacettepe university, faculty of medicine, department of anatomy (figure 1). micro-ct scanning technique was applied to the stones extracorporeally. scanning time was 60 to 120 minutes. the scanning procedure was completed using 50 kv x-ray tube voltages, 800 μa anode current. there were 120 panoramic .tiff images with 3 degree rotation step, resulting in a pixel size of 10 to 18 μm. these digital data were further elaborated by a figure 1. x-ray microfocus ct scanner (skyscan 1174, skyscan, aartselaar, belgium). micro-ct of urinary stones—huri et al 187urology journal vol 8 no 3 summer 2011 reconstruction software (nrecon) for attenuation measurement and 3d model creative software (ctan) for surface rendering. skyscan 1174 has a spatial resolution of 6 to 30 μm (voxel size). the images were averaged over 3 to 4 frames. the terminology of the results were criticized in accordance with the study by zarse and colleagues.(2) the evaluated parameters with micro-ct were presence or absence of homogeneity, heterogeneity, fragility, and internal voids in ultrastructural body of stones. homogeneous pattern was accepted as a smooth type, which could be broken difficult, while heterogeneous pattern was accepted as a rough type that could be broken easily. therefore, heterogeneity was accepted as a predictor of fragility. results there were a total of 24 “calcium oxalate monohydrate” stones from 24 patients scanned with micro-ct. the mean age of the patients for groups i, ii, and iii was 55, 48, and 44 years, respectively. the stone number in each group was 8. mean stone volume was 22, 9, and 4 mm for groups i, ii and iii, respectively. each stone was completely fragmented before removal from the collecting system. the analyzed stone volume was similar in each group. six renal stones were in the lower, 3 in the middle, and 2 in the upper calyceal system. of ureteral stones, 5 were in the upper, 4 in the middle, and 4 in the lower ureter. in ultrasonic lithotripsy, sudden fragmentation of stones was seen during surgery while in pneumatic lithotripsy, stepwise split of stones was seen. we observed that heterogeneity might be a predictor of stone fragility because of apatite crystals and radiolucent voids, and it facilitated stone comminution. the number of heterogeneous stones was significantly higher in group i than group ii (p = .02). therefore, the stones treated with ultrasonic lithotripsy (group i) might be more fragile, fragmented, and cracked than those treated with pneumatic lithotripsy (group ii; p = .01). stones treated by pneumatic lithotripters were more homogeneous and smooth than those in group i, while they were similar to control group (p = .02). ctan software showed homogeneous and visible voids in stones (figure 2) and heterogeneous and rough calculi (figure 3). discussion recently, treatment of urinary stones with minimally invasive technology, including extracorporeal shock wave lithotripsy and ureteroscopic and percutaneous procedures, has been gaining popularity. for renal stones larger than 1 cm, intracorporeal lithotripsy using ultrasonic and pneumatic lithotripters is performed.(3) ultrasonic lithotripsy through a rigid scope is used for large renal stones. it has been shown that ultrasonic lithotripsy is preferred by urologists when using rigid scopes because of figure 2. homogeneous pattern (a) and visible voids (b) in stone piece: ctan software. micro-ct of urinary stones—huri et al 188 urology journal vol 8 no 3 summer 2011 its high fragmentation rate and 94% postoperative stone-free rate.(4) however, pneumatic lithotripsy yields the minimum amount of urothelial injury, and is considered amongst most competent forms of intracorporeal fragmentation.(3) in our clinic, we generally prefer to use the ultrasonic lithotripter during the pnl and pneumatic lithotripter during uss. therefore, procedure selection was done according to our clinical application. many studies have been performed regarding the efficacy of intracorporeal lithotripsy during urinary stone surgery. gurbuz and colleagues demonstrated that pneumatic lithotripsy was highly effective in the treatment of impacted ureteral stones.(5) zhu and associates compared the efficacy and safety of pnl with different intracorporeal lithotripters for proximal ureteral stones in patients with severe hydronephrosis. they demonstrated superior outcomes with shorter operation time using the swiss lithoclast master (dual modality of ultrasonic and pneumatic lithotripsy) compared with pneumatic lithotripsy.(6) lowe and knudsen also demonstrated that dual-modality lithotripters offered superior efficiency compared to separate ultrasonic and pneumatic lithotripters.(7) during our research in pubmed, we did not find any articles regarding the evaluation of the ultrastructural effect of lithotripters on the urinary stones with micro-ct. micro-ct produces high resolution in vitro imaging of the urinary tract calculi for nondestructive stone analysis. fine resolution together with the 2d and 3d reconstruction capabilities of micro-ct produces diagnostic studies with outstanding images of surface and internal stone structure. (2) mineral deposition pattern presents the type of stone with non-overlapping ranges of attenuation value, while the regions of potential structural weakness, such as voids, demonstrate the ultrastructural physical features inside the stone. (2) the use of micro-ct for determination of mineral composition of stones is an important step toward the use of helical ct to provide similar analysis and help the urologist evaluate appropriate treatment options.(8) we standardized the mineral composition among the groups; therefore, the evaluation was just focused on the stone structures. today, micro-ct could be just used in extracorporeal fashion after the operation. hence, this feature limits the effectiveness preoperatively. however, according to the aim of our study, pre-operative application of micro-ct is not necessary. in our study, we determined the difference in stone fragility among groups which had the same mineral composition. the degree of stone fragility triggered by intracorporeal lithotripsy was significantly greater using ultrasonic rather than pneumatic lithotripsy, as detected by micro-ct. bhatta and colleagues reported that cystine stones with a “rough” morphology (having large, blocky crystals on their surface) broke more easily with shock waves than those with “smooth” morphology (smaller crystals on the surface). (9) it has been stated that the roughness of the figure 3. heterogeneous (a) and rough (b) stone pieces: ctan software. micro-ct of urinary stones—huri et al 189urology journal vol 8 no 3 summer 2011 surface cannot be evaluated at diagnosis. (10) kim and associates showed that rough cystine stones possess void regions within them that make them distinctive by helical ct.(11) consistent with the literature, we confirmed increased stone fragility in group i, with highly relevant radiolucent void and heterogeneous rough surface on micro-ct. in pre-operative evaluation with helical ct, to obtain accurate attenuation measurements, narrow slice widths must be used, and bone view should be used to show minor components and apparent homogeneity.(8) however, parallel to this knowledge, we increased the scanning period up to 2 hours to examine detailed ultrastructural features of the stones with micro-ct. zarse and coworkers demonstrated that calcium oxalate monohydrate stones that showed visibly heterogeneous structure on ct were more fragile to shock waves than calcium oxalate monohydrate stones that appeared to be homogeneous in their structure.(1) irregularities in the structure of the stone could act as sites for focusing of shock waves energy;(12) hence, the stone might break easily. in our study, the criteria of stone fragility related with homogeneity or heterogeneity was based on these parameters, which were in accordance with the literature. up to now, the effect of shock waves on urinary stones was studied in vitro or in vivo by micro-ct or helical ct. to the best of our knowledge, this is the first report regarding ultrastructural analysis of stones applied to evaluate the use of ultrasonic or pneumatic lithotripsy in endoscopic stone surgery. micro-ct yields excellent high resolution analysis of the stone structure. it is a relatively fast method, taking approximately 1 to 2 hours for a complete 6 to 12 μm slice scan of a urinary stone that is 1 cm in diameter.(2) furthermore, micro-ct allows nondestructive mapping of the internal and surface structure of urinary stones and permits identification of mineral composition based on x-ray attenuation values. six common stone minerals were found to occupy non-overlapping ranges of attenuation value, allowing identification of mineral types using micro-ct alone.(2) the main target in urinary stone surgery is to break and remove the stone from the urinary system. the variability in stone fragility may be related to the differences in stone structure.(13,14) to support this hypothesis, leger and colleagues reported that stones that were highly organized in their crystalline structure broke more easily than those that were less organized.(15) additionally, williams and coworkers hypothesized that the presence of voids and/or apatite regions could correlate with altered matrix protein content on micro-ct evaluation.(16) we detected apatite crystal significantly higher in group i, which may be related with increased fragility. the stone size could not be optimized for this study. in our clinical practice, we used the ultrasonic power for high volume stones during pnl and pneumatic lithotripsy in ureteroscopic surgery. the optimized stone may give standard results comparing these two techniques. this study seems to be the first basic research regarding the use of micro-ct in the urinary stones which were removed by endoscopic stone surgery. the clinical pre-operative application of micro-ct is not possible; however, two types of lithotripters were considered with micro-ct regarding their effects on the stone structure basically. we observed that ultrasonic lithotripters increase the stone fragility. however, further randomized controlled studies are required to evaluate exact effect of lithotripters on the stones located in each part of the urinary tract. conclusion intracorporeal lithotripsy is a very important tool to deal with urinary stones during endoscopic stone surgery. micro-ct is a simple, easy, and feasible method to evaluate stone structure. ultrasonic lithotripsy might be a predictor of stone fragility, as can be proven by heterogeneity; however, the stones which are destroyed by pneumatic lithotripsy have a homogeneous and smooth surface. our future goal is to verify the micro-ct findings of the stones surface and internal structure with the material analysis probe of scanning electron microscope. conflict of interest none declared. micro-ct of urinary stones—huri et al 190 urology journal vol 8 no 3 summer 2011 references 1. zarse ca, hameed ta, jackson me, et al. ct visible internal stone structure, but not hounsfield unit value, of calcium oxalate monohydrate (com) calculi predicts lithotripsy fragility in vitro. urol res. 2007;35:201-6. 2. zarse ca, mcateer ja, sommer aj, et al. nondestructive analysis of urinary calculi using micro computed tomography. bmc urol. 2004;4:15. 3. hanson k. minimally invasive and surgical management of urinary stones. urol nurs. 2005;25:458-65. 4. leveillee rj, lobik l. intracorporeal lithotripsy: which modality is best? curr opin urol. 2003;13:249-53. 5. gurbuz zg, gonen m, fazlioglu a, akbulut h. ureteroscopy and pneumatic lithotripsy, followed by extracorporeal shock wave lithotripsy for the treatment of distal ureteral stones. int j urol. 2002;9:441-4. 6. zhu z, xi q, wang s, et al. percutaneous nephrolithotomy for proximal ureteral calculi with severe hydronephrosis: assessment of different lithotriptors. j endourol. 2010;24:201-5. 7. lowe g, knudsen be. ultrasonic, pneumatic and combination intracorporeal lithotripsy for percutaneous nephrolithotomy. j endourol. 2009;23:1663-8. 8. zarse ca, mcateer ja, tann m, et al. helical computed tomography accurately reports urinary stone composition using attenuation values: in vitro verification using high-resolution micro-computed tomography calibrated to fourier transform infrared microspectroscopy. urology. 2004;63:828-33. 9. bhatta km, prien el, jr., dretler sp. cystine calculi-rough and smooth: a new clinical distinction. j urol. 1989;142:937-40. 10. kim sc, burns ek, lingeman je, paterson rf, mcateer ja, williams jc, jr. cystine calculi: correlation of ct-visible structure, ct number, and stone morphology with fragmentation by shock wave lithotripsy. urol res. 2007;35:319-24. 11. kim sc, hatt ek, lingeman je, nadler rb, mcateer ja, williams jc, jr. cystine: helical computerized tomography characterization of rough and smooth calculi in vitro. j urol. 2005;174:1468-70; discussion 70-1. 12. cleveland ro, tello js. effect of the diameter and the sound speed of a kidney stone on the acoustic field induced by shock waves. acoustics research letters online. 2004;5:37-43. 13. dretler sp. stone fragility--a new therapeutic distinction. j urol. 1988;139:1124-7. 14. dretler sp, polykoff g. calcium oxalate stone morphology: fine tuning our therapeutic distinctions. j urol. 1996;155:828-33. 15. leger p, daudon m, magnier m. [in vitro test of piezoelectric lithotripsy with ultrasound detection using an edap lt 01 lithotripser]. j urol (paris). 1990;96:353-64. 16. williams jc, jr., zarse ca, jackson me, witzmann fa, mcateer ja. variability of protein content in calcium oxalate monohydrate stones. j endourol. 2006;20:560-4. fall 2012 08.pdf 700 | adult male circumcision performed with plastic clamp technique in turkey results and long-term effects on sexual function ferda m. senel,1 mustafa demirelli,2 fatih misirlioglu,3 tezcan sezgin4 purpose: to evaluate the long-term results of adult circumcisions performed by plastic clamp materials and methods: a total of 186 adult males with the mean age of 21.2 ± 2.8 years who presented to our clinic for circumcision between february 2007 and january 2010 were included in the study. safety and acceptability of circumcision with plastic clamp technique as well as its (range, 12 to 52 months). results: the mean duration of circumcision and removal of the clamp were 3.1 ± 1.1 minutes and 16 ± 7 seconds, respectively. the total complication rate was 2.15%. wound dehiscence (1.07%), infection (0.54%), and bleeding (0.54%) were the encountered complications. complete wound healing was observed at a mean of 25.5 ± 4.6 days. we did not encounter any penile deformity or tion improved following circumcision. conclusion: circumcision performed by plastic clamp technique in adult males had a low early functions. we suggest the utilization of this technique as an easy and a safe way of circumcising adult males. keywords: corresponding author: ferda m. senel, md department of pediatric urology, dr.sami ulus women’s and children’s hospital, ornek mahallesi, babur caddesi, no.44, altindag, ankara, turkey tel: +90 312 305 6418 fax: +90 312 3170353 e-mail: mfsenel@yahoo. com.tr received september 2011 accepted february 2012 1department of pediatric urology, dr.sami ulus women’s and children’s hospital, ankara, turkey 2elif circumcision clinic, ankara, turkey 3department of anesthesiology, dr.sami ulus women’s and children’s hospital, ankara, turkey 4department of urology, bitlis government hospital, bitlis, turkey miscellaneous miscellaneous 701vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l circumcision with plastic clamp | senel et al introduction m ale circumcision is the oldest surgical procedure with a history of at least 15000 years and has been described in ancient egyptian papyri dating 4000 bc.(1) currently, it is estimated that one out of three males worldwide is circumcised.(2) circumcision is mainly performed for religious reasons in our country to every muslim male at an average age of 7 years.(3) at some rural areas of turkey, children may not have the opportunity to get circumcised until their adulthood due to low socio-economic status as well as the lack of adequate number of health professionals. adults are usually circumcised during the military service or local mass circumcision campaigns. in the current study, the results of male circumcision performed by a medical team utilizing plastic clamp technique in our country were analyzed, and the early and late comfunction were investigated. materials and methods subjects a total of 186 adult males with the mean age of 21.2 ± 2.8 years who presented to our clinic for circumcision between february 2007 and january 2010 were included in the study. males with history of bleeding disorder, severe allergy, and genital anomalies, such as hypospadias, microfrom each participant. a questionnaire, including patients’ characteristics, such as age, marital status, education level, and the city they live, ual function (table 1). additionally, a pain scale chart and a questionnaire regarding the daily activities and satisfaction from the procedure were asked to be completed by the circumcised males. the advisability of the procedure to uncircumcised males was accepted as the main criteria for overall satisfaction from the circumcision. males were called for weekly follow-up visits for 6 weeks postoperatively in order to observe the status of wound healing. all of the 186 circumcised males were invited for a followup visit between january and march 2011 to investigate the penis, and skin bridge between the glans and the penile shaft. furthermore, males were asked to complete a questechnique all the males were circumcised with the plastic clamp technique using alisklamp, which consists of an inner tube and an outer ring in various sizes (figure 1). initially, the an appropriate size of inner plastic tube was placed. the retracted foreskin was then pulled over the inner tube, and the second outer plastic ring was placed over the foreskin and locked. the foreskin which was squeezed between the a to c). the apparatus was safely removed without any complication after a mean of 5 ± 1.1 days following the circumcision. the mean duration of circumcision procedure and removal of the clamp were 3.1 ± 1.1 minutes and 16 ± 7 seconds, respectively. analysis the analysis of the early complications, such as bleeding, wound infection, and wound dehiscence was performed on 186 males. of the 186 circumcised males, 142 (76.3%) came to the late follow-up visit in 2011, and the remainfigure 1. alisklamp consists of an inner tube which is placed over the glans penis and an outer ring placed over the tube. depending on circumference of the glans, clamp sizes vary between 20 to 34. 702 | miscellaneous fore, the analysis of late complications and assessment of (4) the bmsfi scores obtained before and after circumcision were compared by paired t cepted as p < .05. results the total complication rate was 2.15%. wound dehiscence, the most common complication, which occurred in two (1.07%) men. bleeding was encountered in one (0.54%) and wound infection in one (0.54%) man. complete wound and total appearance of the incision line, was achieved at a mean of 25.5 ± 4.6 days (figure 3). of the 186 men, 86% reported little or no disruption of sleep at the night of circumcision. after 7 days following circumcision, there was no disruption of the sleep reported by any of the men, and normal daily activities with no disruption were achieved at a rate of 99.5%. of the 186 men, 181 (97.63%) stated that they would recommend plastic clamp method to the uncircumcised men. the mean follow-up period was 30.4 months (range, 12 to figure 2. a) foreskin is retracted completely to expose the glans, and an appropriate size of inner plastic tube is placed. following the placement of the inner tube, retracted foreskin is pulled over the inner tube; b) second outer plastic ring is placed over the foreskin and locked; c) adequate amount of the foreskin is squeezed between the inner tube and the outer ring, then excised with a surgical blade. a b c figure 3. complete wound healing is defined as disappearance of the crusts and total appearance of the incision line. 703vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l circumcision with plastic clamp | senel et al 52 months) for the 142 men who came to the visit in january 2011 (table 1). during the follow-up period, there was a slight difference in the marital status. of the 142 men, 14 (18.3%) were married at the time of circumcision. during the follow-up period, 3 were devorced and 15 got married. the number of married men was 26 (24.6%) at the end of the study (table 1). among the 142 men, we did not encounter any penile deformity or any long-term complications, such as urinary and ejaculatory functions adversely. it was observed that long-term post-circumcision bmsfi scores for erection, problem assessment, and overall satisfaction rates were sigdiscussion the popularity of adult male circumcision has remarkably increased following a study conducted in africa, which (5) following this report, various studies mainly held in africa were conducted to assess the safety of adult male circumcision. complication rate as high as 35.2% was reported in a study where circumcisions were performed by traditional practitioners utilizing the conventional dissecting technique. (6) in another study performed in africa where all circumcisions were performed by general practitioners at their reported among hiv-negative and hiv-positive males.(7) in our previously reported study, we have also obtained a complication rate of 10.4% in those who were circumcised by conventional dorsal slit technique.(3) these data show that the conventional surgical technique carries high risk of practitioners. results of the current study show that the overall complication rate is reduced to 2.15% when a plastic clamp technique is utilized. furthermore, we did not encounter any penile deformity or any long-term complications with this technique. plastic clamp method is shown to simplify the circumcision, shorten its duration, and reduce the complication rate by eliminating the need for suturing and dressing. easy application and short duration are very important advantages, especially if large number of men are planned to be circumcised. bleeding and infection are considered as uncommon complications of the plastic clamp technique while they are sigto a rate of 5%.(3) in the current study, bleeding occurred table 2. brief male sexual function inventory scores of 142 men before and after circumcision. parameters before after p sexual drive 7.2 ± 0.8 7.4 ± 0.6 .2 erection 9.5 ± 0.7 10.3 ± 0.4 .01 ejaculation 6.9 ± 0.8 7.1 ± 0.5 .45 problem assessment 10.1 ± 0.4 11.5 ± 0.8 .02 overall satisfaction 3.1 ± 0.2 3.9 ± 0.6 .01 table 1. background characteristics and follow-up periods of 142 men included in the late follow-up survey. variable n % age, y 18 to 20 69 (48.6) 21 to 23 46 (32.4) ≥ 24 27 (19) mean 21.2 education level primary school 28 (19.7) high school 82 (57.8) university 32 (22.5) marital status married 26 (18.3) non-married 116 (81.7) location ankara 114 (80.3) outside the city 28 (19.7) follow-up period, mo 1 to 24 35 (24.6) 25 to 36 47 (33.1) 37 to 48 49 (34.5) > 48 11 (7.8) mean 30.4 704 | miscellaneous in one man within 24 hours following the removal of the clamp, which was conservatively managed. infection after circumcision is an important concern, especially if performed outside the hospital, reaching to a rate of 10%.(8) infection rate was found to be 2.7% in a study where 700 men were circumcised during a 5-day period by a medical team utilizing conventional method.(9) in our study, the infection rate was 0.54%, which is remarkably lower than the previously reported rates. the low bleeding and infection rates observed after plastic clamp technique make this technique a safe procedure for circumcising large number of adult males. plastic clamp technique appears to have remarkably lower complication rates compared to other minimally-invasive circumcision devices. among the similar devices, commonly used plastibell apparatus is not removed and is let to fall off spontaneously. the mean fall-off duration is 8.7 days among infants whereas after 12 months age, the fall-off period goes up to 13.4 days.(10) due to this reason, plastibell is generally not recommended above the age of one year. the most commonly observed complication with the plastic clamp technique observed in our study was wound dehiscence which occurred at a rate of 1.07%. however, this is remarkably less then the reported rate of wound dehiscence, which was 3% among the 534 adult males circumcised by using another minimally-invasive device consisting of two concentric plastic rings.(11) in the current study, the distance of wound edges was less than 4 mm and no bleeding was tion. the lower incidence of wound dehiscence observed in our study can be contributed to the anatomically adjusted design of the clamp. the inner plastic tube is well-adjusted to the curve of the penile glans; thus, leaving more skin and mucosa on the ventral part, which reduced the tension on the skin during erection. a similar minimally-invasive circumcision apparatus consisting of an inner tube and an outer ring has also been reported to enable circumcisions safely and easily.(12) however, high risk of adverse events related to use of this apparatus has been reported, and a strong caution against the use of this method on young adults has been suggested.(13) in our study, normal daily activities were achieved at a rate of 89% even on the 1st post-circumcision day. our data show that the alisklamp technique seems to be a safe alternative to other current minimally-invasive circumcision devices. results of our study showed that circumcision did not sulted in improvement in erection, problem assessment, and overall satisfaction. in a study which investigated the was mailed to 123 men and responses were received from only 43.(14) the authors concluded that adult circumcision sensitivity. on the other hand, a prospective study comparing bmsfi scores before and after circumcision concluded function.(15) in a recent study that assessed the pudental evoked potentials in adults before and at least 12 weeks after the circumcision, it was concluded that the circumcision evoked potentials latency.(16) the ejaculatory latency time in a study performed on 42 adults.(17) in our previous study and quality of erection as well as status of libido, erectile function was intact in all adults following circumcision.(18) the mean follow-up period was short (10 days) and none of the patients initiated intercourse within this period. were assesed seperately in a prospective design. furthermore, current study included larger number of men and considerably longer follow-up period compared to our preregarding erection, problem assessment, and overall satisfaction in the current study. the lower socio-cultural level of the men, which caused from follow-up could be limitations of our study. nevertheless, our study still seems to bear one of the largest sample size among studies investigating the long-term effects of 705vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l circumcision with plastic clamp | senel et al conclusion circumcision with plastic clamp technique did not adverseimprovement in erectile function and overall satisfaction. the ease of application, low early complication rates, abscence of long-term complications, and high satisfaction ratio make the alisklamp technique an acceptable, safe, and important alternative for adult male circumcision, especially for the regions where large number of males are planned to be circumcised. conflict of interest none declared. references 1. bhattacharjee pk. male circumcision: an overview. afr j paediatr surg. 2008;5:32-6. 2. who/unaids. neonatal and child male circumcision: a global review; isbn 978 92 9 3. senel fm, demirelli m, oztek s. minimally invasive circumcision with a novel plastic clamp technique: a review of 7,500 cases. pediatr surg int. 2010;26:739-45. 4. o'leary mp, fowler fj, lenderking wr, et al. a brief male sexual function inventory for urology. urology. 1995;46:697-706. 5. bailey rc, moses s, parker cb, et al. male circumcision for hiv prevention in young men in kisumu, kenya: a randomised controlled trial. lancet. 2007;369:643-56. 6. bailey rc, egesah o, rosenberg s. male circumcision for hiv prevention: a prospective study of complications in clinical and traditional settings in bungoma, kenya. bull world health organ. 2008;86:669-77. 7. auvert b, taljaard d, lagarde e, sobngwi-tambekou j, sitta r, puren a. randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs 1265 trial. plos med. 2005;2:e298. 8. williams n, kapila l. complications of circumcision. br j surg. 1993;80:1231-6. 9. ozdemir e. significantly increased complication risks with mass circumcisions. br j urol. 1997;80:136-9. 10. samad a, khanzada tw, kumar b. plastibell circumcision: a minor surgical procedure of major importance. j pediatr urol. 2010;6:28-31. 11. peng yf, cheng y, wang gy, et al. clinical application of a new device for minimally invasive circumcision. asian j androl. 2008;10:447-54. 12. schmitz rf, abu bakar mh, omar zh, kamalanathan s, schulpen tw, van der werken c. results of group-circumcision of muslim boys in malaysia with a new type of disposable clamp. trop doct. 2001;31:152-4. 13. lagarde e, taljaard d, puren a, auvert b. high rate of adverse events following circumcision of young male adults with the tara klamp technique: a randomised trial in south africa. s afr med j. 2009;99:163-9. 14. fink ks, carson cc, devellis rf. adult circumcision outcomes study: effect on erectile function, penile sensitivity, sexual activity and satisfaction. j urol. 2002;167:2113-6. 15. collins s, upshaw j, rutchik s, ohannessian c, ortenberg j, albertsen p. effects of circumcision on male sexual function: debunking a myth? j urol. 2002;167:2111-2. 16. senol mg, sen b, karademir k, sen h, saracoglu m. the effect of male circumcision on pudendal evoked potentials and sexual satisfaction. acta neurol belg. 2008;108:90-3. 17. senkul t, iser ic, sen b, karademir k, saracoglu f, erden d. circumcision in adults: effect on sexual function. urology. 2004;63:155-8. 18. senel fm, demirelli m, pekcan h. mass circumcision with a novel plastic clamp technique. urology. 2011;78:174-9. uj 35 summer.pdf 586 | female urology ultrasound estimated bladder weight in asymptomatic adult females ghadeer al-shaikh, hazem al-mandeel purpose: and interobserver reproducibility of this method. materials and methods: from hospital staff and patients attending the gynecological clinic over a period of six months. all results: der volume. conclusion: females yields reproducible measurements and can be used as a reference for future understanddisorders. keywords: corresponding author: ghadeer al-shaikh, mbbs; frcsc college of medicine (box #12), p.o. box 231214, king saud university, riyadh, 11321, saudi arabia tel: +966 146 9339 fax: +966 1467 9557 e-mail: ghadeer-alshaikh@ hotmail.com received january 2012 accepted may 2012 departments of obstetrics and gynecology, college of medicine, king saud university, riyadh, saudi arabia female urology 587vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l ultrasound estimated bladder weight | al-shaikh and al-mandeel introduction lurinary incontinence or voiding disorders, af(1) vestigations to obtain a diagnosis and initiate treatment. generally invasive, time-consuming, and inconvenient to most patients, and may cause urinary tract infection.(2) (3,4) (5) (6) recently, the bladderscan has been developed. the device uses three-dimensional (3-d) ultrasound as opposed to the 2-d ultrasound origidevice calculates the surface area of the bladder rather than assuming the bladder as a sphere. a study on the validity and reproducibility of the device measurement using manual measurement by 2-d ultrasound and con(7) limits its use in everyday practice. therefore, calculated and colleagues found that 3-d ultrasound estimation of (7) an advolumes; thereby, avoiding unnecessary catheterization (7) bright and assorespectively. several studies have used ultrasonography to assess (3,5,9,10) the intra-observer and interobserver reproducibility of materials and methods after institutional ethical approval to conduct the study tients attending the gynecological clinic in king khalid validated instrument commonly used in urogynecology estimation.(11,12) exclusion criteria include the presence ing pregnant, and declining to have the test. an informed ticipation. 588 | wa) at a bladder capacity of 150 to 400 ml as per deto the bladder direction. thereafter, the bladder region is delineated precisely to calculate the actual surface area s), t p) uss t p(7) intra-observer and interobserver reproducibility of the the probe is placed approximately 3 cm superior to the symphysis pubis. the scanner automatically detects misalignment of the probe and directs the user to the optimal out as appropriate (median, mean, frequency, and percentages). the reproducibility analysis consisted of interobserver agreement and intra-observer consistency assumed some reliability; 0.21 to 0.40 fair; 0.41 to 0.60 reliability.(13) results 2 (table 1). of particihad a previous cesarean section, and none had undergone p < .001). (p (table 2; p discussion sess the state of bladder hypertrophy secondary to outlet obstruction and detrusor overactivity, as an alternative method to invasive, expensive, and time-consuming urotable 1. association between specific sample characteristics and ultrasonic evaluation of the bladder weight. characteristics mean (± standard deviation) range r p age, y 37.5 (11.1) 18 to 65 0.02 .26 height, cm 155.6 (6) 143 to 175 0.05 .36 weight, kg 66.7 (14.5) 32 to 106 0.09 .06 body mass index, kg/m2 27.5 (5.6) 13 to 42 0.19 .10 female urology 589vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l tests for bladder outlet obstruction, the authors concluded that bwt is a promising measurement that has the potential to replace urodynamic evaluation.(14) as a clinical tool becomes limited in everyday practice. kojima and colleagues attempted to resolve this problem sessing bladder function beside urodynamic parameters. (5,9) healthy asymptomatic population. such normative data (6) viation: 4.9) and mean bwt is 1.62 mm (standard deviation: 0.34). the use of a portable automated ultrasound highly to moderately reproducible values both in the intra-observer and interobserver measurements. (15) the results of this study can be a base for understanding table 2. reliability of bladderscan bvm 9500 for ultrasonic evaluation of the bladder weight and bladder wall thickness measurements. ultrasound estimated bladder weight bladder wall thickness mean (sd), g range intra-observer correlation coefficient interobserver correlation coefficient mean (sd), mm range intra-observer correlation coefficient interobserver correlation coefficient operator 1 trial 1 32.05 (4.86) 22 to 45 0.8 0.81 1.61 (0.35) 1 to 3 0.47 0.6 trial 2 32.20 (4.75) 21 to 43 1.61 (0.31) 1 to 3 operator 2 trial 3 32.0 (4.78) 22 to 48 0.79 1.62 (0.37) 1 to 3 0.55 trial 4 32.66 (4.91) 21 to 43 1.63 (0.33) 1 to 2 sd indicates standard deviation. ultrasound estimated bladder weight | al-shaikh and al-mandeel figure 2. the bland-altman plot of the interobserver reproducibility for bladder wall thickness. figure 1. the bland-altman plot of the interobserver reproducibility for ultrasonic evaluation of the bladder weight. d iff er en ce in e bw b y tw o op er at or s (1 st o b se rv at io n ) d iff er en ce in w t b y tw o op er at or s (1 st o b se rv at io n ) 590 | pecially that the measurement techniques for bladder (6) therefore, automated method for large residuals secondary to chronic retention. attention to the predictive diagnostic performance of the conclusion ble of evaluating bladder hypertrophy in female patients acknowledgements tion; rosalia mahmoud for helping us in collecting the ting the manuscript based on publication requirements statistical analysis. conflict of interest none declared. references 1. hunskaar s, arnold ep, burgio k, diokno ac, herzog ar, mallett vt. epidemiology and natural history of urinary incontinence. int urogynecol j pelvic floor dysfunct. 2000;11:301-19. 2. klingler hc, madersbacher s, djavan b, schatzl g, marberger m, schmidbauer cp. morbidity of the evaluation of the lower urinary tract with transurethral multichannel pressure-flow studies. j urol. 1998;159:191-4. 3. kojima m, inui e, ochiai a, naya y, ukimura o, watanabe h. noninvasive quantitative estimation of infravesical obstruction using ultrasonic measurement of bladder weight. j urol. 1997;157:476-9. 4. khullar v, cardozo ld, salvatore s, hill s. ultrasound: a noninvasive screening test for detrusor instability. br j obstet gynaecol. 1996;103:904-8. 5. kojima m, inui e, ochiai a, naya y, ukimura o, watanabe h. ultrasonic estimation of bladder weight as a measure of bladder hypertrophy in men with infravesical obstruction: a preliminary report. urology. 1996;47:942-7. 6. bright e, oelke m, tubaro a, abrams p. ultrasound estimated bladder weight and measurement of bladder wall thickness--useful noninvasive methods for assessing the lower urinary tract? j urol. 2010;184:1847-54. 7. chalana v, dudycha s, yuk jt, mcmorrow g. automatic measurement of ultrasound-estimated bladder weight (uebw) from three-dimensional ultrasound. rev urol. 2005;7 suppl 6:s22-8. 8. bright e, pearcy r, abrams p. automatic evaluation of ultrasonography-estimated bladder weight and bladder wall thickness in community-dwelling men with presumably normal bladder function. bju int. 2012;109:1044-9. 9. naya y, kojima m, honjyo h, ochiai a, ukimura o, watanabe h. intraobserver and interobserver variance in the measurement of ultrasound-estimated bladder weight. ultrasound med biol. 1998;24:771-3. 10. kojima m, inui e, ochial a, ukimura o, watanabe h. possible use of ultrasonically-estimated bladder weight in patients with neurogenic bladder dysfunction. neurourol urodyn. 1996;15:641-9. 11. ross s, soroka d, karahalios a, glazener cm, hay-smith ej, drutz hp. incontinence-specific quality of life measures used in trials of treatments for female urinary incontinence: a systematic review. int urogynecol j pelvic floor dysfunct. 2006;17:272-85. female urology 591vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l 12. altaweel w, seyam r, mokhtar a, kumar p, hanash k. arabic validation of the short form of urogenital distress inventory (udi-6) questionnaire. neurourol urodyn. 2009;28:330-4. 13. shrout pe, fleiss jl. intraclass correlations: uses in assessing rater reliability. psychol bull. 1979;86:420-8. 14. belal m, abrams p. noninvasive methods of diagnosing bladder outlet obstruction in men. part 1: nonurodynamic approach. j urol. 2006;176:22-8. 15. morris v, steventon n, hazbun s, wagg a. a cross-sectional study of ultrasound estimated bladder weight in a sample of men and women without lower urinary tract symptoms. neurourol urodyn. 2009;28:995-7. ultrasound estimated bladder weight | al-shaikh and al-mandeel fall 2012 09 resized.pdf 629vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l purpose: to provide key evidence-based strategies to improve outcomes of radiofrequency ablation and limit recurrences of small renal tumors. materials and methods: the literature was searched via ovidsp medline from 1997 to current using mesh terms. all levels of evidence and types of reports were reviewed. results: we comprehensively reviewed technical issues, mechanisms, imaging criteria, ablarates, and follow-up strategies. conclusion: the technique is safe and effective. tumors < 2.5 cm are statistically most likely to remain disease-free. anterior tumors are contraindicated. strict follow-up is needed to detect failures, most of which occur within 3 months and can be easily salvaged with repeat radiofrequency ablation. homogeneous enhancement within 1 month is not necessarily a failure, and tends to disappear after 4 to 6 weeks. multi-disciplinary meetings must occur to discuss each case prior to treatment. keywords: percutaneous, radiofrequency ablation, renal cell carcinoma, computed tomography 1division of urology & robotics, mcgill university health centre, canada 2montreal general hospital, montreal qc, canada 3jewish general hospital, montreal qc, canada 4royal australasian college of surgeons & urological society of australia and new zealand, australia 5westmead private hospital, westmead, australia richard l haddad,1,2,3,4 manish i patel,4 philip vladica,5 wassim kassouf,1,2 frank bladou,1,3 maurice anidjar1,3 review percutaneous radiofrequency ablation of small renal tumors using ct-guidance a review and its current role corresponding author: richard l haddad, md division of urology, mcgill university health centre, 687 pine avenue, west s6.88, montreal quebec, canada h3a 1a1 tel: +1 514 561 2803 e-mail: rlhad01@gmail.com received july 2012 accepted august 2012 630 | review introduction small renal tumors (srt) are increasingly detected as abdominal imaging, such as computed tomography (ct) and ultrasonography (us). an enhancing srt may be either benign or malignant. the patient and physician have many treatment options available, including active surveillance, open or minimally-invasive surgery, or ablative techniques, such as radiofrequency ablation (rfa) and cryoablation (ca). percutaneous rfa plays a role in clinical t1a renal cell carcinoma (rcc) in bidity, and in those with hereditary multiple rcc syndromes or those with a high risk of chronic kidney disease in whom nephron-sparing surgery (nss) is favored. renal cell carcinoma comprises 2% to 3% of human adult cancers, with an incidence that has risen from 7.4 to 17.6 per 100 000 from 1975 to 2006 in the united states, corresponding to a mean annual increase in incidence of 3%.(1) there are 50 000 new cases of rcc per year in the united states.(2) as is the case with other urological malignancies, the treatment of a srt suspected of being rcc depends on stage, grade, and patient’s factors. the metastatic potential of srt rises with increasing tumor size from 1.2% of 2 to 3 cm rcc metastasizing to 3.9% of 3 to 4 cm rcc metastasizing.(3,4) the histological grade although biopsy can help, it may lead to false-negative reof 499 nephrectomies over 15 years and discovered that fuhrman grade 3 rcc and the papillary rcc subtype were increasingly seen over time,(5) and that benign tumors were sible treatment modality for a srt.(6) the treatment options for a clinical stage t1a rcc depend on patient choice after the treatment options have been discussed.(7) surgical is the gold standard for a healthy patient who is keen on intervention. oncological outcomes have been shown to be equivalent comparing radical nephrectomy versus partial surgery (nss).(8,9) also relies on a strict imaging follow-up protocol involving either ct, us, or magnetic resonance imaging (mri). may complicate such an approach. radiofrequency ablation major surgery, or when nss is preferable, as in hereditary or multiple rcc syndromes, chronic kidney disease, and a solitary kidney. the percutaneous technique is minimally invasive and can be performed as an outpatient procedure. computed tomography guidance allows for accurate tumor localization and immediate assessment of tumor response to treatment, and level 4 evidence case series of percutaneous-rfa have reported complete ablation rates of above 90% at 3 to 27 months follow-up.(10-17) in a survey of trends of the treatment of srt in academic american centers using ablative technology, 55% used rfa while 79% used ca.(18) materials and methods a literature search was performed using ovidsp medline from 1997 to current, using the keywords of “radiofrequency ablation, percutaneous, computed tomography-guided, relevancy to percutaneous ct-guided rfa of renal tumors to include review articles, any available level 1 to 4 evidence series, reports of technique, and morbidity. cryoablause of rfa in open or minimally-invasive surgery. oncorfa procedure technique a combined urology and interventional radiology approach is required to decide on appropriate cases. coagulation protion is used for the most part, otherwise general anesthesia positioning. the patient position depends on tumor location and the relationship of adjacent viscera to the kidney. immediately preceding rfa. the electrode is inserted 631vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l along the same tract, and the tract ablated at the completion of the procedure to reduce the risk of seeding.(15) the diameter of the probe tines is matched to the diameter of the tumor. therefore, the probe tines cover an additional 5 to 10 mm margin of renal tissue beyond the circumferential marthe probe’s position and accounts for motion. the number of probe tines that are deployed depends on the diameter or size of the lesion. deploying more tines allows for increased coverage and enhanced ablative effect. dependent upon the tumor size and density and the number of probe tines being used, the impedance and temperature settings can be adjusted by the operator. larger lesions may require overlapping or repeated rfa sessions to achieve a complete ablative response. an immediate post-rfa ct scan is performed to assess addure-related complications. after an observation period of 4 hours, the patient is discharged. the follow-up ct scan protocol is 6 weeks, then at 3, 6, 12, and 18 months, and then annually.(11) mechanism of tumor destruction radiofrequency ablation produces thermal injury on tumor cells. the thermal energy produces ionic agitation and frictional heating. a minimum critical temperature of 48 to 50 ºc is required for cellular damage. temperatures reaching 80 to 100 ºc produce irreversible protein denaturation, cell membrane damage, and coagulation necrosis.(19) the ion.(20) radiofrequency delivers a high frequency (460 to 500 khz) alternating current into the tumor via the electrode (also called a tine), delivered from a power generator (250 w).(21,22) the energy is transferred via electrodes that cm tip. the tumor core is vaporized at temperatures nearing 100 ºc, whereas the surrounding concentric zones of tumor are ablated by convective heating. one single electrode will generally ablate a tumor less than 3 cm in diameter; however, this depends upon the variability in tissue density. larger and denser tumors require overlapping ablations with repositioning of the electrode tines and longer treatment sessions. radiofrequency is limited by tissue charring and carbonization, which increases impedance to the rfa current.(19,23) technical considerations there are different types of rfa energy delivery systems. (21) the ‘impedance based’ system delivers energy based on a predetermined level of tissue impedance. the problem with this method is that even if a preset level of impedance is reached, this may not correlate with what is needed to reach adequate levels of tissue coagulative necrosis, and treatment may fail. the ‘heat based’ system delivers energy based on a preset temperature level. usually the temperature is set to 70 to 100 ºc for a duration of 5 to 12 minutes. the problem with this method is that the temperature at the tip of the electrode may be higher than the actual temperature within the tumor tissue, again accounting for treatment failure. this reiterates the importance of the post-treatment ct scan to assess tissue destruction and then the long-term follow-up imaging to rule out tumor recurrence. electrode tips can be either ‘wet’ or ‘dry’. a wet electrode tip is one which is cooled by infusing a saline solution into the peri-tumor tissue before and during the rfa session. (21,23) this decreases tissue resistance and allows for larger tumors to be treated. the problem with a wet electrode technique is that it may cause ct imaging artifact and compromise the accuracy of the immediate post-rfa ct scan. a dry electrode is more prone to cause peri-electrode charring that increases resistance, which in turn limits the energy transfer from the central tumor zone to the peripheral zone. another consideration is the protection of adjacent viscera during treatment, including the colon, spleen, duodenum, inferior vena cava, ureter, body wall muscle, pancreas, and pleura. one reported technique is the instillation of water or 5% away from the treatment zone.(24-27) a separate puncture is made between the tumor and the viscera, and the solution is instilled into the peri-nephric space. renal ct-guided rfa | haddad et al 632 | review at 1 atmosphere pressure) within the peri-nephric space to push the at risk structure aside.(28) the urinary collecting system is also at risk of thermal damage, which may lead to urinoma, ureteral perforation, or stricture. ing up the ureter into the collecting system via a retrograde ureteral catheter has been described.(28,29) ml per minute is suggested. ct-guidance computed tomography guidance is the preferred method ing renal tumors of 100% and 90%, respectively.(30) a pretreatment ct scan is performed to assess tumor size and location and the surrounding viscera, and to plan the path of electrode insertion. intermittent ‘real-time’ ct can be performed to assess tumor response, seen on ct imaging as change. computed tomography gives accurate information about electrode position and movement during treatment. computed tomography may however be contraindicated in certain populations, such as young women, pregnancy, and iodinated contrast allergy. here there is a role for us or mri. ultrasonography may not be as accurate as ct because gas bubbles, which form during rfa, appear hyperechoic and distort the us image. magnetic resonance imaging with gadolinium is well-suited for rfa because it ic planes. in addition, the t2-weighted acquisition times of 2 seconds allows for real-time monitoring of rfa.(19,31) furthermore, mri provides an accurate account of ablative success, seen as a signal loss in t2-weighted images. magnetic resonance imaging can be used during pregnancy and iodinated contrast allergy. defining complete ablative success success. in the immediate term, success is divided into techrecurrence-free survival (rfs). immediate technical success requires (i) ‘impedance roll-off’, which suggests that an adequate level of tissue ablation has taken place during treatment, and (ii) immediate ct evidence of tissue change, including ct evidence of loss of tissue density, tumor vacuolation, and cavitation.(32,33) at the earliest follow-up ct, at the 6 week mark, there should be no appreciable contrast enhancement of the treated tumor, which is no increase in hu density greater than 10 hu between the non-contrast and contrast scans.(14,34) there should also be no enlargement of the tumor bed or rfa treatment zone at long-term follow-up (after several months).(10,11) earlier than 4 to 6 weeks, there may be posttreatment effect visualized on a contrast-enhanced ct that may be confused with failure. these changes eventually disappear and should not be evident at a 1-month scan.(35) furthermore, another study has shown that the post ablation beds of srt < 3 cm can show a slight increase in volume on however, this eventually scars down and the post ablation bed becomes smaller at long-term follow-up.(36) ment of the tumor using the 10 hu cut-off and/or enlargement of the tumor bed after rfa treatment beyond the 1 month point. it is not infrequent that a repeat treatment session is required after the 1 month mark, within the followup period, generally for persistent contrast enhancement, and this should be considered a failed rfa treatment. it is possible to visualize scar tissue within the treatment bed on follow-up scans, which is not to be confused with true treatment failure. scar tissue will have a differing hu density than surrounding renal tissue; however, it should not (19) in the ablation zone immediately after the rfa session (day 0), and compared this to ct scans 1 and 6 months posttreatment. at day 0, 78% of tumors (28 of 36) showed a ment (> 10 hu) within the ablation zone.(35) however, at contrast enhancement. this means that early enhancement (< 1 month) post-rfa will eventually disappear at follow633vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l up (usually after 1 month), and does not mean rfa has failed. post-rfa biopsy of the ablation zone, as a method of conappear like there is cancer still present. however, when a are in fact dead.(37) in summary, the interventional radiologist and urologist need to follow the post-ablation bed months post-rfa. there are predictable imaging patterns that guide the interpretation of successful rfa. indications and contraindications for rfa indications can be divided into patient’s and tumor’s factors.(13,18,22,32) it is important to choose a suitably sized and cessful rfa session. this is particularly relevant when a urology unit begins to offer rfa to patients, and undergoes id neoplasm, without cystic component; and 4) favorable peri-renal anatomy. it has been shown that size > 3 cm is prognostic of recurrence.(38,39) this suggests that especially during the learning phase, the urologist and radiologist should choose smaller 2 patients who recurred had tumor sizes of 3.2 cm and 4 cm (40) rfa for cystic rcc (total of 9 patients). however, it is generally felt that a cystic rcc does not respond to rfa well tive thermal energy transfer from the central to peripheral zone of the tumor.(41) unfavorable tumor’s factors therefore include: 1) size > 2.5 cm; 2) anterior location; 3) endophytic; 4) close to the collecting system; and 5) cystic rcc. the patient’s factors that make rfa a preferred treatment kidney disease, or solitary kidney; and 3) multiple rcc syndrome, or high risk of developing rcc in the future. the patient’s factors that preclude rfa include a coagulation disorder, gross obesity (precluding electrode placement), or noncompliance with follow-up protocol. oncological efficacy several series, as listed in table, have shown an overall recurrence-free rate of > 90%, at median follow-up periods greater than 24 months.(17,38,41-43) radiofrequency ablation has become a popular treatment alternative in elderly or comorbid patients. such a patient cohort may not tolerate a partial nephrectomy, and particularly may not tolerate the morbidity of a partial nephrectomy. the rfa series listed in table are ct-guided renal rfa series. radiofrequency ablation can also be used via a laparoscopic technique. in one large series of 208 patients receiving either percutaneous or laparoscopic rfa, the percutaneous approach was used for posterior or laterally positioned tumors, whereas tumors located anteriorly or medially, or in rfa.(17) it is not uncommon for certain tumors to recur either early on in follow-up (within 3 to 6 months) or later (after 24 months). recurrence occurrs in less than 10% of the time. recurrence is dealt with differently, either by additional rfa sessions, with success, or by radical nephrectomy or partial nephrectomy in other cases. most rfa recurrences can be salvaged by repeat rfa, and this is one advantage of rfa over ca. tumor size and location have been shown to be independent predictors of success.(13,38,49) anterior tumors are in bad locations and tend to recur, and are linked to a higher rate of adjacent organ damage.(51) tumors smaller than 2.5 cm are relation (p = .001) between higher 3 and 5-year disease-free survival and tumor size < 3 cm. their difference in 5-year disease-free survival rates for tumors that were < 3 cm compared to > 3 cm was 91% and 79%, respectively.(52) for tumors > 3 cm, the recurrence rate was 20%. peripheral tumors are surrounded by peri-nephric fat, which renal ct-guided rfa | haddad et al 634 | is insulating and tends to enhance the coagulative effects of rfa current. central tumors suffer from a ‘heat-sink’ effect. this is when the rfa energy is dispersed because of ing system. vessels and the collecting system do not have the same insulating properties as fat, and rfa heat energy is lost to these structures. furthermore, it has been suggested that benign lesions, such as oncocytoma, may have better from less heat-sink effect.(53) most patients require one rfa session; however, a minority requires an additional rfa session to salvage early failures. (38) the indication is for those tumors with persistent enhancement after 4 to 6 weeks. the treatment times within one rfa session depends on tumor size, with larger lesions requiring several overlapping rfa sessions in order to completely cover the entire tumor area. possible to determine, and at times the biopsy is inconclusive. certain authors use biopsy only if they are uncertain of static lesion to the kidney.(41) of viable cancer cells within the ablation zone at one year post-rfa by performing a biopsy of the tumor bed using an 18-gauge tru-cut needle, with 4 passes into each tumor. (43) cases. one author reported on rfa of 9 patients with cystic rcc, either bosniak iii or iv lesions, with 100% rfs at 8 months median follow-up.(45) in general, cystic rcc is seen as a contraindication to rfa. one earlier series described a mean age of 39 years, wherein 21 patients with either von hippel-lindau or hereditary papillary rcc were treated with rfa.(16) one study compared either laparoscopic or percutaneous rfa with either open or laparoscopic partial nephrectomy for clinical t1a review oncological results of percutaneous ct-guided renal rfa series.* first author year n size (mean), cm age (mean), y fu (mean), mon rfs, % pre-rfa biopsy nitta(44) 2012 22 2.4 73 18 85 na kim(41) 2011 49 2.4 58.6 31.7 94 13/49 tracy(17) 2010 172 2.4 64 27 97 172/172 ferakis(38) 2010 31 3.9 61 61 90 na hiraoka(39) 2009 40 2.4 73 16 85 34/40 levinson(42) 2008 31 2.1 71.7 61.6 90 31/31 park(45) 2008 9 2.5 50 8 100 na raman(43) 2008 19 2.3 62 27 100 19/19 watkins(10) 2007 11 3.5 74 8 82 8/11 sabharwal(11) 2006 11 1.95 72 11 78 11/11 hegarty(46) 2006 72 2.5 67 12 100 72/72 arzola(33) 2006 23 2.7 74 24 90 23/23 park(47) 2006 46 2.4 63.5 25 96.8 41/46 ahrar(48) 2005 29 3.5 65 10 96 29/29 matsumoto(34) 2005 63 2.5 62 19 98 63/63 gervais(49) 2005 85 3.2 70 27 90 85/85 mayo-smith(15) 2003 32 2.6 76 9 81 18/32 pavlovich(16) 2002 21 2.4 39 2 79 na mcgovern(50) 1999 1 3.5 84 3 100 1/1 zlotta(6) 1997 3 2 to 5 na na na 3/3 *ct indicates computed tomography, rfa, radio frequency ablation; fu, follow-up; and na, not available. 635vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l rcc. of 40 rfa and 37 partial nephrectomy, there were local recurrences in 2 rfa and 1 partial nephrectomy (mean follow-up of 30 and 47 months, respectively).(54) there is reproducible level 4 evidence (table) that rfa is effective in rendering the patient disease-free. ongoing reporting of longer term outcomes is required to monitor a durable rfs. radiofrequency ablation is also safe with minimal morbidity. morbidity reported morbidity rates are between 0 to 11%.(17,39,41,46,49) there is no standardized reporting of morbidity among series. however, morbidity can be divided into major that requires intervention and minor, which resolves with concal complications should be used to standardize morbidity reporting.(55) it is conceivable that any structure adjacent to the rfa zone may be injured. mortality is very rare; however, it has been reported.(56) the cause of death is aspiration pneumonia post procedure. any form of adverse cardiorespiratory or cerebrovascular outcome is possible, especially since the patient cohort is elderly and comorbid. the more frequent minor complications include hematoma (peri-nephric or retroperitoneal) not requiring transfusion (5%), hematoma requiring transfusion (1%), neuromuscu(< 2%), and wound infection.(57,58) other more problematic complications include urinoma (< 1%), ureteral stricture (< 1%), thermal injury to the duodenum (< 1%), reno-duodesplenic or liver injury, pancreatic injury, hilar vascular injury or dissection, and colonic or bowel perforation (all < 1%).(59) and appendicular perforation are reported. post-procedure pneumonia can occur. also delayed ureteropelvic junction obstruction is seen. chronic pain or paresthesia at the skin site or in the distribution of the genitofemoral nerve is seen. skin tract metastasis has been reported.(15) damage to a segmental arterial branch can cause segmental renal infarction.(60) with these morbidities in mind, the operative morbidity is higher after partial nephrectomy, ranging from 14% to 26%.(60) recommendations an option for treating an srt. its role is in comorbid papost-rfa ct imaging follow-up protocol is required to identify recurrences, most of which can be salvaged with repeat rfa. risk factors for recurrence include tumor size > 2.5 cm and anterior tumors. ideal tumors are < 2.5 cm, evidence, we rely on series which report long-term diseasefree survival rates. curve of units, which begin to offer renal rfa. strong collaboration between the urologist and interventional radiologist through a multi-disciplinary meeting is mandatory to discuss each case and decide whether the tumor meets suitability selection criteria. this will help reduce morbidity conflict of interest none declared. references 1. chow wh, devesa ss, warren jl, fraumeni jf, jr. rising incidence of renal cell cancer in the united states. jama. 1999;281:1628-31. 2. nepple k, strope s. 961 population-based analysis of the rising incidence of renal cancer: evaluation of age-specific trends (1975-2006). j urol. 2011;185:e387-e. 3. chawla sn, crispen pl, hanlon al, greenberg re, chen dy, uzzo rg. the natural history of observed enhancing renal masses: meta-analysis and review of the world literature. j urol. 2006;175:425-31. 4. frank i, blute ml, cheville jc, lohse cm, weaver al, zincke h. solid renal tumors: an analysis of pathological features related to tumor size. j urol. 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percutaneous ctguided radiofrequency ablation of renal neoplasms: factors influencing success. ajr am j roentgenol. 2004;183:201-7. 33. arzola j, baughman sm, hernandez j, bishoff jt. computed tomography-guided, resistance-based, percutaneous radiofrequency ablation of renal malignancies under conscious sedation at two years of follow-up. urology. 2006;68:983-7. 34. matsumoto ed, johnson db, ogan k, et al. short-term efficacy of temperature-based radiofrequency ablation of small renal tumors. urology. 2005;65:877-81. 35. javadi s, ahrar ju, ninan e, gupta s, matin sf, ahrar k. characterization of contrast enhancement in the ablation zone immediately after radiofrequency ablation of renal tumors. j vasc interv radiol. 2010;21:690-5. 36. davenport ms, caoili em, cohan rh, et al. mri and ct characteristics of successfully ablated renal masses: imaging surveillance after radiofrequency ablation. ajr am j roentgenol. 2009;192:1571-8. 37. marcovich r, aldana jp, morgenstern n, jacobson ai, smith ad, lee br. optimal lesion assessment following acute radio frequency ablation of porcine kidney: cellular viability or histopathology? j urol. 2003;170:1370-4. 38. ferakis n, bouropoulos c, granitsas t, mylona s, poulias i. long-term results after computed-tomography-guided percutaneous radiofrequency ablation for small renal tumors. j endourol. 2010;24:1909-13. 39. hiraoka k, kawauchi a, nakamura t, soh j, mikami k, miki t. radiofrequency ablation for renal tumors: our experience. int j urol. 2009;16:869-73. 40. watanabe f, kawasaki t, hotaka y, et al. radiofrequency ablation for the treatment of renal cell carcinoma: initial experience. radiat med. 2008;26:1-5. 41. kim jh, kim th, kim sd, lee ks, sung gt. radiofrequency ablation of renal tumors: our experience. korean j urol. 2011;52:531-7. 42. levinson aw, su lm, agarwal d, et al. long-term oncological and overall outcomes of percutaneous radio frequency ablation in high risk surgical patients with a solitary small renal mass. j urol. 2008;180:499-504; discussion. 43. raman jd, stern jm, zeltser i, kabbani w, cadeddu ja. absence of viable renal carcinoma in biopsies performed more than 1 year following radio frequency ablation confirms reliability of axial imaging. j urol. 2008;179:2142-5. 44. nitta y, tanaka t, morimoto k, et al. intermediate oncological outcomes of percutaneous radiofrequency ablation for small renal tumors: initial experience. anticancer res. 2012;32:6158. 45. park bk, kim ck, lee hm. image-guided radiofrequency ablation of bosniak category iii or iv cystic renal tumors: initial clinical experience. eur radiol. 2008;18:1519-25. 46. hegarty nj, gill is, desai mm, remer em, o'malley cm, kaouk jh. probe-ablative nephron-sparing surgery: cryoablation versus radiofrequency ablation. urology. 2006;68:7-13. 47. park s, anderson jk, matsumoto ed, lotan y, josephs s, cadeddu ja. radiofrequency ablation of renal tumors: intermediate-term results. j endourol. 2006;20:569-73. 48. ahrar k, matin 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and follow-up protocol. urology. 2012;79:827-30. 54. stern jm, svatek r, park s, et al. intermediate comparison of partial nephrectomy and radiofrequency ablation for clinical t1a renal tumours. bju int. 2007;100:287-90. 55. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 56. varkarakis im, allaf me, inagaki t, et al. percutaneous radio frequency ablation of renal masses: results at a 2-year mean followup. j urol. 2005;174:456-60; discussion 60. 57. kimura m, baba s, polascik tj. minimally invasive surgery using ablative modalities for the localized renal mass. int j urol. 2010;17:215-27. 638 | 58. igor pinkhasov g, raman jd. management and prevention of renal ablative therapy complications. world j urol. 2010;28:559-64. 59. weizer az, raj gv, o'connell m, robertson cn, nelson rc, polascik tj. complications after percutaneous radiofrequency ablation of renal tumors. urology. 2005;66:1176-80. 60. park bk, kim ck, lim hk. renal infarction resulting from segmental arterial injury during radiofrequency ablation of renal tumor in patient with a single kidney. urology. 2009;73:442 e9-11. review editorial comment covid-19, urologists and hospitals amir h kashi *correspondence: urology and nephrology research center (unrc); shahid labbafinejad medical center; shahid beheshti university of medical sciences (sbmu), tehran, iran. email: ahkashi@gmail.com. nowroozi et al. have presented a letter expressing concerns over the current strategy adopted by many countries including iran to manage the covid-19 outbreak(1). we have also faced a similar scenario in our center which is a referral urology center in iran. according to the policy of the ministry of health and medical education, all elective operations have been cancelled and all hospitals have been ordered to admit patients suspected for covid-19 infection(2). consequently, for over a month in our center, most hospital beds have been assigned to covid-19 patients including most intensive care unit beds. the outlook, in case the control of outbreak spread is not successful or does not happen in near future, includes exhaustion of medical staff and shortage of intensive care beds leading to increased direct mortality of the coivd-19 disease and indirect mortality and morbidity due to shortage of available beds for providing medical care to other illnesses including urology treatments. guidelines have been prepared for postponing elective operations in the era of covid-19 infection(3) however, elective operations cannot be postponed for long. on the other hand, we have observed occasional cases of covid-19 infection in patients admitted for urgent urological operations like fornier gangarene who did not reveal symptoms of covid-19 infection at presentation which presents the possibility of acquiring infection during hospitalization that complicates the scenario further. hospitals have been declared the most important location for covid-19 infection transmission as 45% of covid-19 infections were assumed to originate from hospitals(4). therefore, keeping patients hospitalized in wards other than covid-19 wards and caring for not contracting the covid-19 infection is of paramount importance. yet, despite vast research into the covid-19 infection in the recent months, some aspects of transmission through bodily fluids have not been elucidated especially in the field of urology. the possibility of viral shedding in urine and its course and the possibility of infection transmission through this route which was suggested earlier for sars infection(5) remains unanswered for covid-19(6). also, there are raising concerns in infertility laboratories working on semen samples and in some assisted reproductive techniques on the possibility of infection transmission through semen or sperm donation which should be further investigated. another interesting observation in covid-19 pandemic is humanitarian cooperations taken place. iran which has a high number of infected patients has received medical aids from many countries including qatar, russia, china, france, uk and germany; however the country’s drug supply and medical facilities (including diagnostic kits for covid-19) were in shortage even before the outbreak due to imposed sanctions by the us government and a universal intention to lift these inhuman sanctions is needed to avoid further suffering for iranian patients in this crisis(7). references 1. nowroozi a, amini e. urology practice in the time of covid-19. urol j. 24 march 2020 [epub ahead of print]. 2. [no authorlisted]. all iranian hospitals ready to admit coronavirus patients. irna, 2020. 3. [no authorlisted]. https://www.auanet.org/covid-19-info-center. accessed 23/3/2020. 4. [no author listed]. https://khabarfarsi.com/u/83070214. accessed 23/3/2020 [article in persian] 5. niedrig m, patel p, el wahed aa, schädler r, yactayo s. find the right sample: a study on the versatility of diagnosis of emerging viruses. bmc saliva and urine samples for the infectious diseases. 2018;18:707. 6. world health organization. laboratory testing for coronavirus disease (covid-19) in suspected human cases: interim guidance. 19 march 2020, world health organization. 7. takian a, raoofi a, kazempour-ardebili s. covid-19 battle during the toughest sanctions against iran. lancet. 2020. urology journal/vol 17 no. 3/ may-june 2020/ pp. 327-327. [doi: 10.22037/uj.v0i0.6064] pediatric urology 91urology journal vol 4 no 2 spring 2007 urinary tract infection in term neonates with prolonged jaundice nader pashapour,1 ahmad ali nikibahksh,1 sariyeh golmohammadlou2 introduction: the aim of this study was to evaluate the frequency of urinary tract infection (uti) in neonates with prolonged jaundice. materials and methods: newborn infants with jaundice lasted more than 2 weeks were included in this study. patients who had other signs or symptoms were excluded. workup of prolonged hyperbilirubinemia was performed, including direct coomb’s test, blood group of the neonate and the mother, complete blood count, blood smear, glucose-6-phosphate dehydrogenase (g6pd), reticulocyte count, serum level of bilirubin (unconjugated and conjugated), thyroid function tests (serum thyroxine [t4] and thyroid-stimulating hormone), urinalysis, and suprapubic urine culture. pediatric nephrologists carried out further investigation including kidney function tests, renal ultrasonography, voiding cystourethrography, and technetium tc 99m dimercaptosuccinic acid renal scintigraphy for patients with a positive urine culture for microorganisms. results: of 100 neonates who were evaluated, 43 were boys and 57 were girls. all of the neonates were breastfed. six suffered from uti (4 boys and 2 girls). reflux was detected on voiding cystourethrography in 1 and cortical defect in the kidney on renal scan in 2 boys. conclusion: in our region, with a high rate of breastfeeding, uti remains as an important cause of prolonged jaundice. despite the high rate of urogenital system abnormality accompanied by neonatal uti, there was not a significant difference between the signs and symptoms of jaundice in patients with and without uti. performing urine cultures should be considered as a routine procedure in the evaluation of every infant with prolonged jaundice. urol j. 2007;4:91-4. www.uj.unrc.ir keywords: neonatal jaundice, urinary tract infection, newborn infant, breast feeding 1department of pediatrics, imam hospital, urmia university of medical sciences, urmia, iran 2department of mother and child health, urmia university of medical sciences, urmia, iran corresponding author: nader pashapour, md department of pediatrics, imam hospital, urmia university of medical science, urmia, iran tel: +98 914 141 5300 fax: +98 441 278 0801 e-mail: npashapor@yahoo.com received february 2007 accepted may 2007 introduction renal scarring, hypertension, and even kidney failure can be prevented by early diagnosis and treatment of urinary tract infection (uti).(1) symptoms and signs of uti in infants are nonspecific and hyperbilirubinemia is commonly the main clinical feature at presentation that may be the only manifestation of uti.(2) prolonged jaundice is more common in breastfed infants than artificiallyfed infants. studies performed in developed countries focusing on nonbreastfed infants have suggested that prolonged jaundice should aggressively be investigated in artificially-fed infants.(3) the majority of researchers have considered asian ethnicity as a risk factor and showed that the peak serum levels of bilirubin in full-term asian and americanindian neonates were twice more than that in white and black populations.(4) all of the mentioned causes may distract physicians from diagnosing urinary tract infection in neonates with jaundice—pashapour et al 92 urology journal vol 4 no 2 spring 2007 uti as an important cause of prolonged jaundice. complete clinical assessment is needed in all cases of prolonged jaundice; however, the indications and extent of investigation remain unclear.(5) this study was conducted to evaluate the frequency of uti and to determine the importance of performing uti workup in neonates with prolonged jaundice in an area with a high rate of breastfeeding. materials and methods we conducted this cross-sectional descriptive study from april 2005 to march 2006 on 107 newborn infants older than 2 weeks with visible yellow skin or eye color who were otherwise clinically well. they had been admitted to the newborn nursery of imam hospital for evaluation of prolonged jaundice. the research council of urmia university of medical sciences approved the study design and written informed consent was obtained from the infants’ parents. demographic and clinical features including age, weight, sex, gestational age, status of feeding, and postnatal events were recorded. premature neonates, those previously treated for jaundice, and those with uncooperative parents were excluded. for editorial comment see p 94 workup of prolonged hyperbilirubinemia was performed, including direct coomb’s test, blood group of the infant and the mother, complete blood count, blood smear, glucose-6-phosphate dehydrogenase (g6pd), reticulocyte count, serum level of bilirubin (unconjugated and conjugated), thyroid function tests (serum thyroxine [t4] and thyroid-stimulating hormone), urinalysis, and suprapubic urine culture. pediatric nephrologists carried out further investigation including kidney function tests, renal ultrasonography, voiding cystourethrography (vcug), and technetium tc 99m dimercaptosuccinic acid (99mtc-dmsa) renal scintigraphy in the patients with a positive urine culture for microorganisms. prolonged jaundice was defined as jaundice lasting for more than 14 days in full-term infants. the cause of jaundice was diagnosed in each case and proper treatment and follow-up were performed. the collected data were analyzed and presented in 2 conditions: first, in all patients, and second, in 2 groups according to the diagnosis of uti. data were analyzed with the spss software (statistical package for the social sciences, version 10.5, spss inc, chicago, ill, usa) using the chi-square test and mann-whitney u test, as appropriate. results of quantitative variables were presented as mean ± standard deviation and 95% confidence interval. results seven neonates were excluded due to the unwillingness of their parents to continue the study. a total of 43 boys and 57 girls were studied (table). all male infants were uncircumcised. according to the records of the family members, jaundice had been started during the first week of life. test results revealed that none of the infants had direct hyperbilirubinemia; also, it was shown that breastfeeding, fetomaternal incompatibility in rh and blood group, and congenital hypothyroidism were of the most important causes of hyperbilirubinemia. six patients suffered from uti, 4 of whom were boys. the isolated microorganisms were escherichia coli in 3 patients, klebsiella pneumonia in 2, and proteus in 1. the mean age at admission was 23.0 ± 5.9 days and 27.3 ± 10.8 days in the patients with and without uti, respectively (p = .52). the mean body weight was 3.80 ± 0.46 kg and 3.93 ± 0.67 kg, respectively (p = .33). the mean serum level of total bilirubin was 10.36 ± 1.60 mg/dl and 10.37 ± 1.95 mg/dl in the patients with and without uti, respectively (p = .99; table). kidney function tests were within clinical and demographic data of neonates with prolonged jaundice at admission* factors all patients patients with uti patients without uti sex male 57 4 41 female 43 2 53 mean age, d 27.1 ± 10.6 (24.97 to 29.19) 23.0 ± 5.9 (16.80 to 29.10) 27.3 ± 10.8 (25.10 to 29.50) mean serum bilirubin, mg/dl 10.37 ± 1.90 (9.92 to 10.49) 10.36 ± 1.60 (9.25 to 11.48) 10.37 ± 1.95 (9.97 to 10.77) mean body weight, kg 3.92 ± 0.66 (3.70 to 4.05) 3.80 ± 0.46 (3.30 to 4.29) 3.93 ± 0.67 (3.79 to 4.07) *values in parentheses are percents for sex proportions and 95% confidence interval for means. urinary tract infection in neonates with jaundice—pashapour et al urology journal vol 4 no 2 spring 2007 93 reference ranges in all of the patients. in the neonates with uti, bilateral reduced absorption of isotope was detected in renal parenchyma of 1 boy on the 99mtcdsma scan. unilateral reflux of grade 3 to 4 was confirmed in another boy by the vcug. discussion in the present study, uti was detected in 6% of the jaundiced infants. isolated microorganisms in this study included escherichia coli, klebsiella pneumonia, and proteus mirabilis that are among the common causes of uti in neonatal period. the rate of uti in our series is in accordance with the results of a study by garcia and nager.(6) also, similar to our results, falcao and colleagues reported that escherichia coli was the most common isolated microorganism in newborns’ uti.(7) the incidence of neonatal uti varies from 0.1% to 1% in the general population of healthy newborns,(8) while it was 6 times higher in this study. to our best knowledge, this is the first research in this region with a high rate of neonatal breastfeeding. also, it should be noted that previous studies have confirmed the protective effect of newborn circumcision against uti during infancy.(9) in our series, circumcised infant were not included and the high rate of jaundice might be interpretable by this situation, too. a study in tehran revealed that jaundice was due to breastfeeding and congenital hypothyroidism in 76.6% and 10% of the cases, respectively, and these two were the main causes of hyperbilirubinemia followed by torch infections, g6pd deficiency, and cephalohematoma.(10) in agreement with our results, in a study by hannam and colleagues, 2 out of 9 patients were found to have uti; therefore, they recommended urine culture for investigation of prolonged jaundice.(11) in another study, it was revealed that of 127 infants with prolonged jaundice, 125 were breastfed.(12) it is suggested that the incidence of prolonged jaundice in full-term breastfed infants is higher (9.2% at 28 days).(3) it is well known that the incidence of uti in boys is higher than in girls within the first year of the life.(13,14) four out of 6 patients diagnosed with uti in this study were males. age, weight, and serum total bilirubin level of patients with and without uti were not different. in this study, all newborns were breastfed similar to another study conducted in iran.(15) it is shown that newborn infants with uti present with unconjugated hyperbilirubinemia in the early stages but conjugated hyperbilirubinemia after 6 week.(16) although garcia and nager reported that patients with an elevated conjugated bilirubin fraction were more likely to have uti,(6) none of our patients had an increased direct bilirubin level. although performing renal ultrasonography, vcug, and 99mtc-dmsa scan are recommended after the first uti, controversies continue about complications and results of these tests.(17) in this study, ultrasonography did not show any significant pathologic finding in uti cases. the results of 99mtcdsma scan were abnormal in 1 male infant with uti and vcug revealed grade 3 to 4 reflux in another male case. it has been proved that the presence of vesicoureteral reflux is significantly related to younger age at the time of uti presentation.(12) in contrast to these results, a search conducted in turkey revealed a high rate of abnormality in the urogenital system of newborn infants with uti.(18) conclusion in our region, with a high rate of breastfeeding, uti remains as an important cause of prolonged jaundice. despite the high rate of urogenital system abnormality accompanied by neonatal uti, there was not a significant difference between the signs and symptoms of jaundice in patients with and without uti. performing urine cultures should be considered as a routine test in the evaluation of every infant with prolonged jaundice. acknowledgement the authors would like to thank drs davoud omrani, amir heydari, and zahra yekta and members of the research council of urmia university of medical sciences for supporting this study. conflict of interest none declared. financial support this study was approved and financially supported by the research council of urmia university of medical sciences. urinary tract infection in neonates with jaundice—pashapour et al 94 urology journal vol 4 no 2 spring 2007 references 1. struthers s, scanlon j, parker k, goddard j, hallett r. parental reporting of smelly urine and urinary tract infection. arch dis child. 2003;88:250-2. 2. morven se. postnatal bacterial infections. in: avery gb, fletcher ma, macdonald mg, editors. neonatalogy: pathophysiology and management of the newborn. 5th ed. philadelphia: lippincott williams & wilkins; 1999. p. 934. 3. kuschel c. assessment of prolonged and late-onset jaundice. newborn services clinical guidelines. auckland district health board. available from: http://www.adhb.co.nz/newborn/guidelines/gi/ prolongedandlatejaundice.htm 4. huang mj, kua ke, teng hc, tang ks, weng hw, huang cs. risk factors for severe hyperbilirubinemia in neonates. pediatr res. 2004;56:682-9. 5. ratnavel n, ives nk. investigation of prolonged neonatal jaundice. curr pediatr. 2005;15:85-91. 6. garcia fj, nager al. jaundice as an early diagnostic sign of urinary tract infection in infancy. pediatrics. 2002;109:846-51. 7. falcao mc, leone cr, d'andrea ra, berardi r, ono na, vaz fa. urinary tract infection in full-term newborn infants: risk factor analysis. rev hosp clin fac med sao paulo. 2000;55:9-16. 8. briton l, satlion lm, edelman cm. hyperbilirubinemia. in: fanaroff aa, martin rj, editors. neonatal-prenatal medicine. 7th ed. london: mosby; 2002. p. 730. 9. schoen ej, colby cj, ray gt. newborn circumcision decreases incidence and costs of urinary tract infections during the first year of life. pediatrics. 2000;105:789-93. 10. milani sm. study of newborn with pathologic hyperbilirubinemia after 5 days of birth in children medical center hospital. tehran univ med j. 2007;59:30-36. 11. hannam s, mcdonnell m, rennie jm. investigation of prolonged neonatal jaundice. acta paediatr. 2000;89:694-7. 12. crofts dj, michel vj, rigby as, tanner ms, hall dm, bonham jr. assessment of stool colour in community management of prolonged jaundice in infancy. acta paediatr. 1999;88:969-74. 13. vilanova juanola jm, canos molinos j, rosell arnold e, figueras aloy j, comas masmitja ll, jimenez gonzalez r. [urinary tract infection in the newborn infant]. an esp pediatr. 1989 aug;31(2):105-9. spanish. 14. cleper r, krause i, eisenstein b, davidovits m. prevalence of vesicoureteral reflux in neonatal urinary tract infection. clin pediatr (phila). 2004;43:619-25. 15. hajian-tilaki ko. factors associated with the pattern of breastfeeding in the north of iran. ann hum biol. 2005;32:702-13. 16. lee hc, fang sb, yeung cy, tsai jd. urinary tract infections in infants: comparison between those with conjugated vs unconjugated hyperbilirubinaemia. ann trop paediatr. 2005;25:277-82. 17. cascio s, chertin b, yoneda a, rolle u, kelleher j, puri p. acute renal damage in infants after first urinary tract infection. pediatr nephrol. 2002;17:503-5. 18. bilgen h, ozek e, unver t, biyikli n, alpay h, cebeci d. urinary tract infection and hyperbilirubinemia. turk j pediatr. 2006;48:51-5. editorial comment i read this article with interest and would like to thank the authors for their excellent study. the cause-and-effect relation of uti and jaundice is still a matter of debate. we can also speculate that uti might be a concurrent disease along with jaundice in newborn infants. a meta-analysis of the studies published on infants with uti showed that 12% of 255 neonates with uti had jaundice, which is a very small proportion.(1) seyed alaeddin asgari department of urology, razi hospital, gilan university of medical sciences, rasht, iran reference 1. pohl hg, rushton hg. urinary tract infections in children. in: docimo sg, canning da, khoury ae, editors. the kilalis-king-belman textbook of clinical pediatric urology. 5th ed. informa healthcare; 2007. p. 122. reply by author we acknowledge the comment by dr asgari and the fact that the cause-and-effect between uti and jaundice is not clear yet. as we mentioned in the introduction of this paper, symptoms and signs of uti in infants are nonspecific and hyperbilirubinemia (without its common etiologies) is usually the only manifestation when uti is diagnosed. such a concurrent development of uti and jaundice of unknown cause has been reported in many studies (references 1, 6, and 16) and we believe that our result shows a relation, though not clearly. nader pashapour department of pediatrics, imam hospital, urmia university of medical sciences, urmia, iran v08_no_4_final_new.pdf laparoscopic urology 283urology journal vol 8 no 4 autumn 2011 “latex glove” laparoscopic pyeloplasty model a novel method for simulated training syed johar raza, kashifuddin q soomroo, mohammad hammad ather purpose: to present a ‘latex glove’ laparoscopic pyeloplasty (lpp) training model and determine its construct validity for its effective use in resident training. materials and methods: the ‘latex glove’ model was used to perform lpp by five operators with variable level of experience, ranging from an experienced (> 20 independent lpps) to minimal operative experience (year 5 medical student). the palm of the glove was considered the renal pelvis with finger of the glove as the proximal ureter. a knot at the junction of the two was considered as ureteropelvic junction obstruction. a basic lap trainer was used to simulate the lpp. operation time was noted in minutes and quality of continuous suturing was determined for each operator, using a previously described nonvalidated scoring system by a blinded reviewer. results: the operation time varied from 47 to 160 minutes for the most to the least experienced operator, and the difference was statistically significant (p = .043), while the quality of suturing score ranged from 1 to 6 for the most to the least experienced operator, respectively (p = .038). the operation time and quality of suturing were negatively correlated with the level of experience (-0.962 and -0.987, respectively), which were statistically significant (p = .009 and p = .002, respectively). conclusion: this novel training model has proven its validity, as a costeffective and readily available option for lpp training. urol j. 2011;8:283-6. www.uj.unrc.ir keywords: laparoscopy, urologic surgical procedures, reconstructive surgical procedures, ureteral obstruction, hydronephrosis aga khan university, karachi, pakistan corresponding author: mohammad hammad ather, md, fcps (urology), febu department of surgery, aga khan university, p o box 3500, stadium road, karachi 74800, pakistan tel: +92 213 486 4778 fax: +92 213 493 4294 e-mail: hammad.ather@aku.edu received january 2011 accepted october 2011 introduction introduction of minimally invasive methods has revolutionized not only surgery in general, but also the abdominal and pelvic urological procedures. pyeloplasty is one such procedure, for which minimally invasive approach is gaining popularity, especially laparoscopic pyeloplasty, as its results are comparable with the open technique.(1) however, the problems associated with long learning curve and complexity of the reconstruction make it difficult in not only readily adopting, but also in training of the residents for this procedure. these problems are overcome with the use of various simulators or models to improve resident training.(2) due to the high costs and lack of availability of sophisticated simulators, it becomes difficult for trainees in less developed countries to develop their skills. on the other hand, animal-based models are otherwise associated with ethical and cost issues.(3) for a simulation to be valid, it has to be close to reality, correlate with the performance in a real case, and “latex glove” laparoscopic pyeloplasty model—raza et al 284 urology journal vol 8 no 4 autumn 2011 be able to discriminate between individuals with different degrees of experience. it is important to validate a model or simulator before it could be incorporated into urology residency training program. mcdougall described various types of validity and emphasized the need for validation before its use.(4) construct validity is one such type, in which a simulator is able to differentiate between experienced and beginner operators; thus, proving its ability to improve skills of novice to expert levels. in the current study, we present a lpp training model, made out of a simple latex glove, which is readily available and affordable for use by all urological trainees. we also determined its construct validity for its effective use in resident training. materials and methods we used an ordinary latex glove and placed it in the laparoscopic training box. the knot in the finger simulated the ureteropelvic junction obstruction and palm of the glove as dilated renal pelvis (figure 1). an anderson-hynes dismembered pyeloplasty was laparoscopically performed, using continuous suturing technique. initially, the glove is suspended in the simulator box. using normal laparoscopic scissors, the “strictured” part of the ureteropelvic junction is cut and anastomosis is made between the cut part of the “ureter” (finger of the glove) with the remaining “pelvis” (palm of the glove). the first knot is placed at the edge and continuous suturing is performed in the anterior and posterior layers, placing a final knot in the end, following completion of the two layers. to determine the construct validity of the model, the procedure was performed by five operators. the operators were divided from the most experienced, with more than 20 lpps to the least experienced, with no experience of laparoscopic procedure, having basic knowledge of suturing and knot tying skills (table). total duration of procedure in minutes and quality of suturing score were recorded for each operator, by a blinded mentor using a standardized nonvalidated form described by laguna and colleague.(5) the recorded parameters were; distance between the sutures (< 2 mm, < 2 mm in one suture, and > 2 mm in more than one suture), tissue tear (no, once, and more than once), quality of knot tying (good, bad, and not applicable), and lesion of the posterior wall (no or inclusion). statistical analysis was done using spss software (the statistical package for the social sciences, version 16.0, spss inc, chicago, illinois, usa). one-way anova was used to detect differences in suturing time among the operators. according to this method, higher the score, poorer was the quality of suturing. to further confirm the figure 1. “latex glove” laparoscopic pyeloplasty model operators (level of experience) operator 1 (> 20 lpp) operator 2 (> 100 endo ) operator 3 (> 20 lap cc ) operator 4 (> 20 endo ) operator 5 (ms) p duration of procedure, min 47 74 92 142 160 .043 quality of suturing score 1 2 3 6 6 .038 study variables lpp indicates laparoscopic pyeloplasties; endo, endourological procedures; lap cc, laparoscopic cholecystectomies; and ms, medical student minimal hands on operative experience. “latex glove” laparoscopic pyeloplasty model—raza et al 285urology journal vol 8 no 4 autumn 2011 influence of level of experience on the operation time and quality of suturing score, we determined the pearson correlation coefficient too. results forty-seven minutes for duration of procedure was recorded for the most experienced operator, which increased to 160 minutes, with decreasing level of experience, for the least experienced operator (figure 2). similarly, the quality of suturing score increased from 1 to 6 for the most to the least experienced operator, respectively (table). the differences in time and quality of suturing score were statistically significant (p = .043 and p = .038, respectively). on determination of pearson correlation coefficient, the duration of procedure and quality of suturing score were negatively correlated with the level of experience (-0.962 and -0.987, respectively) with statistical significance (p = .009 and p = .001, respectively). discussion since introduction in 1993 by schuessler and his colleagues,(6) lpp proved its success in terms of better outcomes comparable to open technique in the operative management of ureteropelvic junction obstruction.(1) however, the laparoscopic technique, which comprises of major reconstruction and intracorporeal suturing, has been reported to be related with steeper learning curve,(7) which poses difficulty in ‘on patient’ resident training; hence, emphasizing the importance of dry and wet laboratories, before reaching the operating table for the trainees. construct validity is one of the most valuable and mandatory assessments, as it can differentiate the experienced from the inexperienced surgeon based on the performance score. content validity is the assessment of the appropriateness of the simulator as a teaching modality, and involves formal evaluation by experts’ knowledge about the device. before a surgical simulator can be used to assess competency, it must be vigorously and objectively evaluated to determine both its scientific reliability and validity. benefits of simulation have been proven in laparoscopic training,(8) and various models of both live and dead animals have been reported in literature for lpp training.(9-12) these models have also been validated in studies; however, no inanimate model has been reported in literature to our knowledge. apart from the type or availability of the models, an important factor of validity stands a significant ground, before considering a simulation as a valid learning tool for residents. mcdougall described four types of validities, namely face, content, construct, and criterion validity.(4) others reported models using chicken skin, chicken crop, and live porcine model; all determined construct type a validity, which assesses the ability of a simulation in improving the performance of an inexperienced operator over time.(9-11) in the live porcine model by teber and colleagues, the authors determined the validity of a specific suturing technique of pyeloplasty and then performed the same in a real time scenario on a patient; thus, determining its predictive validity.(12) in this ‘latex glove’ model, we determined the construct validity type b, which enables the simulator or model to distinguish between an experienced and inexperienced individual, who later improves on his skills or operative timings by repeated practice, demonstrating the construct type a validity. similar type of validity has been reported in another animal model, for simulation of vesicourethral anastomosis in radical prostatectomy by laguna and associates.(5) although ramachandran used the chicken crop model, which could be considered as a cheap and figure 2. graphical presentation of time taken to complete task by operators with variable levels of experience “latex glove” laparoscopic pyeloplasty model—raza et al 286 urology journal vol 8 no 4 autumn 2011 readily available alternate, the study was unable to give a statistical significance to type a construct validity.(10) we particularly determined this model because of its cost-effectiveness and ready availability, and proved its construct validity as well. in future, we would like to determine the concurrent validity of this model, by comparing it with a standard simulation, ie, chicken skin or crop model, to improve its novelty and acceptability for development of lpp skills of the residents in training in this part of the world. conclusion this ‘latex glove’ pyeloplasty model has proven its construct validity as a simulator for laparoscopic skills development. we believe that its validity will further improve its novelty as a cost-effective and readily available option for lpp training. acknowledgements dr syed raziuddin biyabani, fcps, febu dr khurram siddiqui, frcs, febu dr shahrukh effandi, mrcs dr mohammad hashim hanif, mbbs dr ghulam murtaza sheikh, mbbs, mrcs conflict of interest none declared. references 1. calvert rc, morsy mm, zelhof b, rhodes m, burgess na. comparison of laparoscopic and open pyeloplasty in 100 patients with pelvi-ureteric junction obstruction. surg endosc. 2008;22:411-4. 2. clevin l, grantcharov tp. does box model training improve surgical dexterity and economy of movement during virtual reality laparoscopy? a randomised trial. acta obstet gynecol scand. 2008;87:99-103. 3. steffens k, koob e, hong g. training in basic microsurgical techniques without experiments involving animals. arch orthop trauma surg. 1992;111:198-203. 4. mcdougall em. validation of surgical simulators. j endourol. 2007;21:244-7. 5. laguna mp, arce-alcazar a, mochtar ca, van velthoven r, peltier a, de la rosette jj. construct validity of the chicken model in the simulation of laparoscopic radical prostatectomy suture. j endourol. 2006;20:69-73. 6. schuessler ww, grune mt, tecuanhuey lv, preminger gm. laparoscopic dismembered pyeloplasty. j urol. 1993;150:1795-9. 7. parsons jk, varkarakis i, rha kh, jarrett tw, pinto pa, kavoussi lr. complications of abdominal urologic laparoscopy: longitudinal five-year analysis. urology. 2004;63:27-32. 8. fried gm, feldman ls, vassiliou mc, et al. proving the value of simulation in laparoscopic surgery. ann surg. 2004;240:518-25; discussion 25-8. 9. ooi j, lawrentschuk n, murphy dl. training model for open or laparoscopic pyeloplasty. j endourol. 2006;20:149-52. 10. fu b, zhang x, lang b, et al. new model for training in laparoscopic dismembered ureteropyeloplasty. j endourol. 2007;21:1381-5. 11. ramachandran a, kurien a, patil p, et al. a novel training model for laparoscopic pyeloplasty using chicken crop. j endourol. 2008;22:725-8. 12. teber d, guven s, yaycioglu o, et al. single-knot running suture anastomosis (one-knot pyeloplasty) for laparoscopic dismembered pyeloplasty: training model on a porcine bladder and clinical results. int urol nephrol. 2010;42:609-14. u j spring 2012.pdf 536 | kidney stone in children there is a wide mistaken belief that only adults develop urinary stones. on the contrary, kidney stones can also occur in children. kidney stones develop when a collection of minerals or other materials form a small “stone.” the stone can cause severe pain, obstruction if it is not diagnosed and treated promptly. the incident of a kidney stone in a child is a relatively rare event. in countries where plants are the main source of protein in the diet, for example the middle east, india, southeast asia, and eastern europe, the prevalence of the kidney stone is higher in children and rises. in china recently, some children who used milk contaminated with melamine (a toxic material illegally added to watered-down milk to increase the protein kidney stone in united states is also rising. the increase in the united states is attributed to some factors, including a food additive that is both legal and ubiquitous: salt. the initial sign in an infant may be a crying and devastated baby, and the presentation may be mistaken for colic. limiting salt in the diet and drinking plenty of water are the best ways to prevent the most common types of the kidney stones or slow their growth. see page 465 for full-text article. what is varicocele? tion of the scrotal vein, the loose bag of the skin that holds the testicles. they are rather common, affecting 15% of men overall and cocele occurs most often in the left testis. varicocele usually becomes obvious during adolescence and is rarely reported to arise in older men. the sudden appearance of a varicocele in an older man may be caused by a kidney tumor, which can block varicocele is generally made on physical ity of the varicocele is graded i through iii. having a varicocele is thought to increase the chance of being infertile, but most men with a varicocele are not infertile. most men who have a varicocele have no symptoms. others may have the following signs and symptoms: pain in the testis, feeling of heaviness in one or both testes, infertility, larged vein. treatment is by surgery. see page 505 for full-text article. urology for people what’s up in urology journal, spring 2012? urology for people urology for people is a section in the urology journal for providing people with a summary of what is important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. 1135vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l step-by-step illustrated endoscopic extraperitoneal radical prostatectomy (eerp): tips and tricks to trifecta outcomes leonardo o. reis,1,2 eduardo s. starling,2 antonio c. l. pompeo,2 rodolfo b. dos reis,3 lucas nogueira,4 eliney f. faria,5 gustavo f. carvalhal,6 marcos tobias-machado2 introduction laparoscopic prostatectomy has become a widely accepted and applied surgical method of localized prostate cancer treatment. the pearls of critical anatomical and technical features to optimal oncological and functional outcomes on radical prostatectomy are illustrated. several aspects with respect to that must be recognized in the early phases of training to optimize trifecta outcomes: disease recurrence free, urinary continence and sexual functions preservation. technique a-surgical steps of retrograde technique 1. patient is positioned in horizontal dorsal decubitus, with y-shaped abduction of lower limbs on the table. 2. display of the surgical team. the surgeon operates on the left side; the camera is positioned at the upper end of the table, and the assistant stand at the patient's right side. during suture, for improved comfort, the surgeon and the camera switch places. 3. umbilical incision measuring 1.5 cm up to the retzius space. 4. creation of extra-peritoneal space through digital dissection and modified balloon dilator (handicraft). 5. hasson trocar (10 mm) through the umbilical incision for the 0-grade optics. 6. making of pneumo-retroperitonium with co2 tension of 15 mmhg; 7. introduction of another 4 working trocars (2 para-rectal external measuring 10 mm, and 2 in iliac fosse measuring 5 mm) under direct view, in an arciform shape, taking care in order to avoid peritoneal lesion (figure 1). 8. exercises of pre-prostatic fat with monopolar cautery for proper identification of prostate, bladder and pubo-prostatic ligaments. corresponding author: leonardo oliveira reis, md, msc, phd faculty of medical sciences, university of campinas, unicamp rua: tessália vieira de camargo, 126 cidade universitária "zeferino vaz" campinas spcep: 13083-887, brazil. tel/fax: +55 019 352 17481 e-mail: reisleo@unicamp.br; reisleo.l@gmail.com received november 2011 accepted april 2012 1 urologic oncology division, department of urology, university of campinas, unicamp, são paulo, brazil and faculty of medicine (urology) center for life sciences pontifical catholic university of campinas puc-campinas, brazil. 2 urologic oncology and laparoscopy section, department of urology, abc school of medicine, são paulo, brazil. 3 urologic division, department of surgery, ribeirão preto medical school, sao paulo university (usp), brazil. 4 federal university of minas gerais ufmg, brazil. 5 barretos cancer hospital, pio xii foundation, barretos, brazil. 6 catholic university, rio grande do sul, brazil. point of technique 1136 | 9. bilateral opening of endo-pelvic fascia with scissors, following previous contra-lateral traction of the prostate. 10. identification and sectioning of pubo-prostatic ligaments. 11. vascular control of dorsal vein complex of the penis with a x-stitch using 2-0 polyglactine suture with circle taper (ct)-1 needle, and control of the retrograde blood flow with harmonic or bipolar scalpel, or polymer clip (hem-olok). applying the clip makes the subsequent identification of the bladder neck easier for reconstruction, a surgical step that is often arduous when we choose to preserve the bladder neck 12. apical dissection with preservation of the sphincter apparatus. 13. sectioning of the dorsal vein complex of the penis with electrocautery or harmonic scalpel, until the urethra is viewed. 14. opening of the urethral anterior wall with scissors. section is performed after perfectly identifying the limits of the prostate apex and urethra, thus avoiding positive margins. point of technique figure 1. the sites for trocar placement. figure 2. the bladder neck is opening. preservation is desired, but in case of suspicious invasion, a resection with free margins must be performed. figure 3. opening posterior denonvilliers fascia with identification of prostate. no energy dissection between prostate capsule and prostatic visceral fascia in medial to lateral direction. figure 4. the prostatic pedicles are identified and clipped with hem-o-lok near to prostate. 1137vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l 15. the catheter balloon is filled with 20 ml of distilled water. the foley catheter is externally pulled for subsequent knot application with 0-cotton suture including drainage and balloon routes. 16. cutting the catheter close to the previously applied knot. 17. removing of the remaining stump of the foley catheter, through endoscopic view in the extra peritoneal space. 18. posterior dissection of the urethra and recto-urethral muscle following cranial traction of the catheter by the assistant. 19. blunt retro prostatic dissection up to the most proximal point as feasible. 20. identification and opening of the posterior layer of the denonvilliers fascia. at this time it is possible to identify the pre-rectal fat. the neurovascular bundle lies laterally and under the fascia, which makes nervous preservation easier during ligation of the prostatic pedicle, which is performed by posterior access. 21. sectioning of the bladder neck, with preservation of muscular fibers whenever possible. the dissection is started with harmonic or bipolar scalpel and upon reaching the urethral mucosa; it is sectioned with scissors. 22. identification and opening of the anterior layer of denonvilliers fascia, posterior to the prostate with visualization of vasa deferentia. 23. identification and sectioning of vasa deferentia with harmonic or monopolar scalpel. 24. superior traction of the vasa deferentia by the assistant in order to release the seminal vesicles. at this time, we preferred to use harmonic or bipolar scalpel in order to avoid dissipation of thermal energy that could damage the nervi erigentes. 25. the assistant performs the lateral and superior traction of previously mobilized (released) prostate, enabling the clear identification of the prostatic pedicles and the prostate capsular limits. the control of the prostatic pedicles is performed with harmonic or bipolar scalpel. alternatively polymer clips (hem-o-lok) can be used. 26. exercise and entrapment of the specimen that is located in right iliac fossa. 27. vesicourethral anastomosis is initiated with the patient in trendelemburg position in order to improve the visualization of the urethra. the surgeon works with the pararectal 10-mm trocars at the upper end of the table. we perform a continuous 3-0 polyglecaprone (monocryl) suture with small half (sh) circle needle. we use two 13-cm sutures, one colorless and the other one violet, externally tied by the distal end. a modified van velthoven suture(1) begins at 4 o'clock position in the bladder directed inwards and each of the sutures rises toward 8 o'clock position, where a single internal knot is made. 28. drainage with penrose though one of the 5-mm ports. figure 5. vertical opening of anterior aspect of prostatic visceral fascia from puboprostatic ligament to bladder neck. athermal retrograde blunt and sharp dissection of neurovascular bundle between capsule and prostatic visceral fascia. a: apical view, b: proximal view. illustrated endoscopic extraperitoneal radical prostatectomy | reis et al 1138 | 29. removal of the specimen by enlargement of the umbilical port and closure of the incisions. b-surgical steps of antegrade technique the theoretical advantage of this technique is to perform the division of dorsal venous plexus in the last step of surgery. in this way, less bleeding occurs in the initial steps of dissection. the same surgical steps are performed to access the extra-peritoneal cavity. actually we open the endopelvic fascia only if intra-fascial dissection was not elected and control the venous plexus as the same manner exposed on retrograde technique. we tie the knot but we do not section the plexus, and at that moment we start a dissection from the bladder neck to the prostate apex. 1. after santorini’s plexus knot, the back bleeding suture was placed on the anterior surface of the prostate. traction is placed in this knot to push the prostate and the bladder through the sixth trocar. beniquet can aid to find the transition between the bladder and prostate. at this moment we open the bladder neck with harmonic scalpel (figure 2). 2. the foley catheter is grasped to perform the posterior bladder neck dissection. 3. after opening the posterior layer of detrusor muscle, vasa deferentia are identified, dissected free and divided. diagonal contra-lateral traction was performed to better expose the homo-lateral seminal vesicle. here there is always a small artery and a careful dissection is encouraged. vessels near to the vascular bundle are controlled athermically with clips. the dissection of the seminal vesicles is performed. 4. after dissection the seminal vesicle is retracted anteriorly, the denonvilliers fascia is opened behind the prostate to identify the peri-rectal fatty and the bundles are dissected gently without any thermo source (figure 3). 5. hem-o-lok clips are used to control the pedicles (figure 4). at this moment we decide about the level of preservafigure 6. apical dissection taking care to achieve a good urethral length preventing positive margins and lesion of neurovascular bundle. figure 7. retroprostatic dissection near to prostate to maintain posterior fibers of urinary sphincter attached to urethra. a: schematic view, b: endoscopic view. point of technique 1139vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l illustrated endoscopic extraperitoneal radical prostatectomy | reis et al tion of neurovascular bundle (intrafacial, interfascial or extrafascial). the limits between the prostate and the pedicle can be perfectly seen. in selected and favorable patients in whom preservation is possible we perform the most recent refinement of the endoscopic extra-peritoneal radical prostatectomy the intra-fascial nerve sparing. as part of the intrafascial technique, the dissection plane is directly on the prostatic capsule, freeing the prostate laterally from its thin surrounding fascia that contains small vessels and nerves. the technique enables pubo-prostatic ligament preservation, leaving intact endopelvic fascia, peri-prostatic fascia, and neurovascular bundles. based on anatomic relationships between investing prostatic fascial layers and the neurovascular bundle, emphasis is placed on division of the apical prostatic urethra between the anterolateral endopelvic fascia and denonvilliers fascia (intrafascial dissection) in avoidance of the apical nerves (figure 5a). it maintains veil of aphrodite and open the visceral fascia anteriorly just in the moment of pedicle ligation. vertical incision in the fused distal portion of denonvilliers fascia is necessary to make this dissection atraumatic regarding the adjacent para-prostatic neurovascular bundle (figure 5b). 6a beniquet is important to complete lateral dissection of the prostate. it can push the prostate down to secure a good separation between the apical bundle and the prostate (figure 6). 7at this moment apical dissection is performed. it is extremely important step because most of the positive margin comes from the apex. an excellent visualization permit a better preservation of fibers from urinary sphincter maintaining the urethral stamp attached to pubo-prostatic ligament without jeopardize apical margin. the dorsal venous complex is divided with a best length of urethra (figure 7a and 7b); the urethra and recto-urethralis is divided and the specimen freed from final adhesions (figure 8). 8pathological specimen is removed in a bag. 9running vesico-urethral anastomosis is done similar to previous description. technique standardization and the recognition of pearls of critical anatomical and technical features are fundamental to optimal oncological and functional outcomes on radical prostatectomy named trifecta: disease recurrence free, urinary continence and sexual functions preservation. furthermore, it must be recognized in the early phases of training.(2) conflict of interest none declared. references 1. van velthoven rf, ahlering te, peltier a, skarecky dw, clayman rv. technique for laparoscopic running urethrovesical anastomosis: the single knot method. urology. 2003;61:699702. 2. starling es, reis lo, vaz juliano r, et al. extraperitoneal endoscopic radical prostatectomy: how steep is the learning curve? overheads on the personal evolution technique in 5-years experience. actas urol esp. 2010;34:598-602. figure 8. aspects of neurovascular bundles after the infra-vesical nerve sparing technique. case reports 242 urology journal vol 4 no 4 autumn 2007 first reported case of adrenal neurofibroma from iran siavash falahatkar,1 ali mohammadzadeh,2 sara nikpour,1 hossein khoshrang,2 korosh askari3 urol j. 2007;4:242-4. www.uj.unrc.ir keywords: neurofibroma, adrenal tumor, pheochromocytoma, laparoscopy 1department of urology, urology research center, razi hospital, rasht, iran 2department of anesthesiology, razi hospital, rasht, iran 3department of pathology, razi hospital, rasht, iran corresponding author: siavash falahatkar, md department of urology, razi hospital, rasht, iran tel: +98 131 323 2050 fax: +98 131 323 2050 e-mail: falahatkar_s@yahoo.com received february 2007 accepted august 2007 introduction there is a broad spectrum of neurogenic tumors involving the abdominal organs. these tumors can be classified as those originating from the ganglion cells (ganglioneuroblastoma, ganglioneuroma, neuroblastoma), paraganglionic system (pheochromocytoma, paraganglioma), and nerve sheaths (neurilemmoma, malignant nerve sheath tumor, neurofibroma, and neurofibromatosis). abdominal neurogenic tumors are mostly located in the retroperitoneum, especially in the paraspinal areas and adrenal glands.(1) adrenal neurofibroma is a rare benign tumor which has not been considered in the text books of urology, yet.(2) we report a case of this tumor diagnosed in an iranian woman presented with discomfort in her right flank. case report our patient was a 24-year-old woman who presented with the chief complaint of discomfort in her right flank. she did not have any history of hypertension or other specific diseases. her blood pressure was 120/80 mmhg and the pulse rate was 80 per minute. on ultrasonography, a 5-cm mass was discovered in the retroperitoneoum and near the upper pole of the right kidney which had shifted the renal vein anteriorly. computed tomography (ct) revealed a 4.6 × 3.9-cm mass in the right adrenal gland with significant enhancement and central hypodensity (figures 1 and 2). figure 1. a tumor in the right adrenal gland is seen. the renal vein is shifted anteriorly. figure 2. a tumor in the right adrenal gland is detected with central hypodensity. adrenal neurofibroma—falahatkar et al urology journal vol 4 no 4 autumn 2007 243 on laboratory examinations the mass was nonfunctional; 24-hour urine levels of vanillylmandelic acid, metanephrine, normetanephrine, and free urine cortisol were 4.3 μg (reference range, 0.5 μg to 12 μg), 91 μg (reference range, 25 μg to 312 μg), 390 μg (reference range, 35 μg to 445 μg), and 51 mg (reference range, 10 mg to 136 mg), respectively. the patient underwent laparoscopic right adrenalectomy. after medialization of the colon, the right adrenal tumor was seen. dissection was performed from the upper renal pole to the medial side. the tumor was adhered to the renal vein; therefore, the vein was firstly released and then, the tumor was completely removed. the patient was discharged 72 hours postoperatively without any complication and was visited 2, 4, and 12 weeks after the operation. no complication was reported during the follow-up period. pathologic examination revealed neurofibroma (figure 3). discussion neurofibromatosis is a rare systemic disease and urinary tract involvement is even more uncommon. bladder is the organ in the urinary tract which is most frequently involved. the type of involvement is generally diffused infiltration and sometimes, it is manifested as a solitary tumor. final diagnosis is made by pathologic and immunohistochemical examination.(3) abdominal neurogenic tumors are most commonly located in the retroperitoneum, especially in the paraspinal areas and adrenal glands.(1) there are few case reports of retroperitoneal neurofibroma in the literature.(4-6) casey found a large firm painless palpable mass without neurological deficits in a 29-year-old man which was reported to be neurofibroma in pathological evaluation.(5) also, aoki and colleagues reported a case of solitary retroperitoneal neurofibroma in a 70-year-old woman.(6) all abdominal neurogenic tumors except neuroblastomas and ganglioneuroblastomas are seen in adult patients. abdominal neurogenic tumors commonly manifest as well-defined and lobulated masses on radiological images.(1) neurofibromas may show themselves as solitary tumors or a component of neurofibromatosis. neurilemmomas and neurofibromas originate from the nerve sheaths; however, each has a special histologic appearance and may occur in different clinical settings. malignant degeneration often happens to these tumors, particularly in the cases of neurofibromatosis. on ct scan, these tumors have a homogeneous and smooth appearance with definite outlines. they often contain many cystic spaces with different sizes that are due to myxoid degeneration as seen in our patient (figure 2).(7) medullary necrosis seen on the patient’s ct scan may also be due to myxoid degeneration. in addition, the well-defined neurofibromas arising from nerves traversing the mesentery or retroperitoneal space may be completely extensive. differentiating these lesions from adenopathy may be quite difficult.(7) laparoscopic adrenalectomy is now the gold standard method for the treatment of adrenal tumors except for huge pheochromocytomas or invasive malignant tumors. the shorter convalescence with laparoscopic approach compared with open adrenalectomy has been accepted from the very beginning. less blood loss, less pain, and better cosmetic results are the advantages of this method.(8) laparoscopic resection of large adrenal tumors such as ganglioneuroma needs experience in open and advanced laparoscopic surgery. it seems that neurofibromas have not the potential for bleeding and can be dissected and separated from the surrounding tissues easily. to our best knowledge, this is the first case of adrenal neurofibroma in iran. figure 3. the section reveals a benign neurogenic neoplasm composed of spindle-shaped cells with wavy nuclei and scanty cytoplasm among the collagen bundles (hematoxylin-eosin, × 40). on serial sections, no ganglion cells are detected. staining by s100 and vimentin was positive and by neuron-specific enolase was focally positive. specimens stained by cd34, collagen iv, desmin, bcl 2, hmb45, and cd99 were negative. adrenal neurofibroma—falahatkar et al 244 urology journal vol 4 no 4 autumn 2007 conflict of interest none declared. references 1. rha se, byun jy, jung se, chun hj, lee hg, lee jm. neurogenic tumors in the abdomen: tumor types and imaging characteristics. radiographics. 2003;23:29-43. 2. winke ja, lack ee. the adrenal gland. in: silverberg sg, de lellis ra, frable wj, li volsi va, wick mr, editors. silverberg>s principles and practice of surgical pathology and cytopathology. 4th ed. philadelphia: churchill livingstone; 2005. p. 2169-209. 3. cabrera castillo pm, alonso y gregorio s, cansino alcaide jr, aguilera basan a, de la peña barthel jj. [bladder neurofibroma: case report and bibliographic review]. arch esp urol. 2006;59:899-901. spanish. 4. nozomu t, kenshi s, kenji s, hiroji o, masayoshi y. solitary retroperitoneal neurofibroma with a cystic lesion: a case report. jap j of clinical urol. 2001;55:567-70. 5. casey at. neurological pictures. massage of a giant retroperitoneal neurofibroma. j neurol neurosurg psychiatry. 2006;77:814. 6. aoki m, nakano m, sen s, ohta n, suzuki k, fujita k. a case of solitary retroperitoneal neurofibroma hinyokika kiyo (hinyokika kiyo). 1998;44:273-6. 7. zografos gn, markou a, ageli c, et al. laparoscopic surgery for adrenal tumors. a retrospective analysis. hormones (athens). 2006;5:52-6. 8. nakagawa k, murai m. laparoscopic adrenalectomy: current status with a review of japanese literature. biomed pharmacother. 2002;56:107s-112s. kidney transplantation 173urology journal vol 5 no 3 summer 2008 influence of hypernatremia and polyuria of braindead donors before organ procurement on kidney allograft function seyed mohammad kazemeyni,1 fatemah esfahani2 introduction: polyuria and hypernatremia are common problems during the pretransplant care of brain-dead donors. they have not only important role in hemodynamic stability, but also may influence organ transplantation outcomes. the influence of donor hypernatremia in liver transplantation was reported. this study aimed to determine these effects on kidney allograft. materials and methods: we retrospectively studied on 57 transplanted kidney allografts from cadaveric donors. the effects of the urine output volume and serum level of sodium of the donors were on the recipients’ serum creatinine levels 1 week after transplantation and at the last follow-up visit were assessed. results: of the donors, 58% had polyuria and 45% had hypernatremia. the median pretransplant urine output of the donors was 130 ml/h (range, 35 ml/h to 450 ml/h), and their mean serum sodium level was 152.0 ± 13.0 meq/l. serum creatinine concentrations in the recipients at the 1st posttransplant week correlated significantly with the recipients’ age (r = 0.355, p = .02) and the donors’ urine output volume (r = 0.329, p = .04). the serum creatinine measured in the last follow-up visit significantly correlated only with the donors’ serum sodium levels (r = 0.316, p = .02) and the donors’ age (r = 0.306, p = .02). multivariate regression analysis showed that the donors’ serum levels of sodium and potassium were the predictors of the last measured serum creatinine level. conclusion: polyuria and hypernatremia in brain-dead donors are frequent. elevated serum level of sodium and polyuria in the donor can have adverse effects on kidney allograft function. urol j. 2008;5:173-7. www.uj.unrc.ir keywords: kidney transplantation, brain death, tissue and organ procurement, hypernatremia, polyuria, creatinine 1department of urology, shariati hospital, tehran university of medical sciences, tehran, iran 2department of research and development, shariati hospital, tehran university of medical sciences, tehran, iran corresponding author: seyed mohammad kazemeyni, md department of urology, shariati hospital, kargar st, tehran, iran tel: +98 21 2284 2405 e-mail: mkazemeyni@tums.ac.ir received march 2008 accepted july 2008 introduction during the period before organ retrieval for cadaveric transplantation, polyuria and hypernatremia are two common findings that can compromise hemodynamic stability of the organs. these may be due to diabetes insipidus; central diabetes insipidus is present in 30% to 90% of the brain-dead donors,(1,2) resulting from insufficient blood levels of antidiurethic hormone from the posterior pituitary gland. other causes of polyuria are hyperglycemia and administration of mannitol and diuretic drugs. polyuria may lead to severe metabolic and hemodynamic disturbances during procurement. in this situation, substitution with common electrolyte solutions hypernatremia and polyuria of brain-dead donors—kazemeyni and esfahani 174 urology journal vol 5 no 3 summer 2008 will induce disturbances of water and electrolyte balance (edema, hyperosmolarity, hypernatremia, and hypokalemia) with deterioration of cell membrane and organ function.(2,3) the influence of elevated serum sodium levels of the donor on early postoperative graft function has been reported in human liver transplantation.(4-6) however, there is a lack of knowledge on these effects on kidney transplant outcome. in the present study, we assessed the effect of elevated urine volume and hypernatremia on kidney transplantation outcomes. materials and methods we reviewed our records of the kidney allograft recipients from the brain-dead donors. the allografts were retrieved between june 2005 and december 2007 in the organ procurement unit of shariati hospital in tehran, iran. during this period, a total of 141 organs were harvested from 46 brain-dead donors. eighty-four of these organs were kidneys, half of which were transplanted at the same hospital and another half were transferred to other centers of transplantation sharing in the iranian network for transplant organ procurement. we could collect the complete data of 69 kidney allograft recipients and analyzed 55 of those with functioning kidneys after transplantation in this retrospective study. all of the kidney allograft recipients were on prednisolone, cyclosporine, and mycophenolate mofetil for immunosuppressive therapy. according to our protocol, management and maintenance of the donor was started since the initial brain death identification and continued for at least 24 hours. this time is necessary for re-evaluation of brain death and reconfirmation of the diagnosis by a group of specialists with legal authorization. during this period, if polyuria or diabetes insipidus was evident, volume substitution was preferably done with hypotonic solutions, ie, 2.5% glucose with 0.45% sodium chloride. fluid substitution was controlled by continuous measurement of arterial blood pressure, central venous pressure, and hourly determination of urine output. once urine output exceeded 300 ml/h or 4 ml/kg/h, desmopressin (1 μg to 4 μg, every 8 to 12 hours) was administered.(3,7,8) data on polyuria (urine output of 125 ml/h or greater during the average 3 hours before organ retrieval) and hypernatremia (serum sodium level higher than 155 meq/l) were collected and the donors were grouped accordingly (normal serum sodium level versus hypernatremia). serum creatinine levels of the recipients and other characteristics of the donors and the recipients were compared between these groups. serum creatinine levels at the end of the first posttransplant week and the latest follow-up visit were considered in this study. statistical analyses were performed using the spss software (statistical package for the social sciences, version 15.0, spss inc, chicago, ill, usa). data distribution was tested with the 1-sample kolmogorov-smirnov test. the recipients’ serum creatinine levels, donors’ urine volume, and donors’ age were nonparametric variables. correlations of quantitative variables were analyzed by spearman rho correlation or pearson correlation tests, where appropriate. differences between the groups were assessed by the mann-whitney u test and t test. a p value less than .05 was considered significant. results a total of 55 kidney allograft recipients from 44 brain-dead donors were evaluated in this study. the median age of the donors was 25 years (range, 10 to 60 years). two-thirds of them were men. the main causes of brain death were head trauma (70.5%), cardiac arrest, and intracranial hemorrhage. the time interval from the initial diagnosis of brain death to the retrieval of the organs was approximately 24 hours, and almost all transplantations were performed within 6 hours thereafter. of the donors, 58% had polyuria and 45% had hypernatremia. the median pretransplant urine output of the donors was 130 ml/h (range, 35 ml/h to 450 ml/h). at the terminal phase, the donors had a mean serum creatinine of 1.25 ± 0.4 mg/dl, serum sodium of 152.0 ± 13.0 meq/l, and serum potassium of 3.7 ± 0.7 meq/l. hypernatremia and polyuria of brain-dead donors—kazemeyni and esfahani urology journal vol 5 no 3 summer 2008 175 the mean age of the 55 recipients was 41.0 ± 14.0 years. their median serum creatinine after 1 week of transplantation was 1.8 mg/dl (range, 0.8 mg/dl to 9.0 mg/dl). they were followed up for a median of 20 months (range, 2 to 36 months), and the median value of the last measured serum creatinine level was 1.4 mg/dl (range, 0.9 mg/dl to 5.0 mg/dl). these early and last serum creatinine values significantly correlated with each other (r = 0.311, p = .04). of note, all except 3 patients had a follow-up period of at least 6 months, and excluding the 3 patients with shorter follow-ups did not alter the results of analyses. serum level of creatinine after 1 week significantly correlated with the recipients’ age (r = 0.355, p = .02) and the donors’ urine output volume (r = 0.329, p = .04). the linear correlation between the donors’ urine output volume and the recipients’ serum creatinine level after 1week of transplantation was more prominent in the group of recipients who had a donor with polyuria (r = 0.486, p = .02; figure 1). comparison of this finding with that in the group with normal urine output was difficult, because the high and low urine outputs could influence kidney function and make categorizations impractical. polyuria was not associated with the last measured serum creatinine level of the recipients. the last measured serum creatinine significantly correlated only with the donors’ serum sodium levels (r = 0.316, p = .02; figure 2) and the donors’ age (r = 0.306, p = .02). multivariate regression analysis showed that the donors’ serum levels of sodium and potassium were the predictors of the last measured serum creatinine level (p = .03). the table outlines the differences between the two groups of kidney allograft recipients with and without hypernatremia. figure 1. correlation of the urine output volume of brain-dead donors with serum creatinine levels of their recipients 1 week after transplantation. figure 2. correlation of the serum sodium level of brain-dead donors with the last measured serum creatinine of the recipients during the follow-up period. serum sodium of donor characteristics ≤ 155 meq/l > 155 meq/l p donors mean age, y 28.1 ± 11.8 28.2 ± 14.0 .71 median urine volume, ml 130 (40 to 350) 170 (35 to 450) .43 mean serum creatinine, mg/dl 1.20 ± 0.40 1.27 ± 0.38 .45 mean serum potassium, meq/l 4.04 ± 0.54 3.45 ± 0.67 .002 recipients median serum creatinine after 1 week, mg/dl 1.8 (0.8 to 6.0) 1.9 (0.9 to 9.0) .59 median latest serum creatinine, mg/dl 1.3 (0.9 to 2.1) 1.6 (0.8 to 5.0) .02 characteristics of donors and recipients in two groups with different pretransplant serum sodium levels of donors* *values are presented as mean ± standard deviation or median (range). hypernatremia and polyuria of brain-dead donors—kazemeyni and esfahani 176 urology journal vol 5 no 3 summer 2008 discussion the most important goal of the care of brain dead potential organ donors is to stabilize their hemodynamic status. the management period of brain-dead donors takes at least 24 hours in our center to confirm brain death and prepare for organ retrieval. to control the hemodynamic status, serum sodium level and urine output should be monitored. almost half of the donors in our series had polyuria (urine output greater than 125 ml/h) and hypernatremia. these findings are consistent with the results of other studies.(1,2) polyuria and hypernatremia could be induced by central diabetic insipidus resulting from insufficient blood levels of antidiurethic hormone from the posterior pituitary gland of brain-dead patients.(2) polyuria causes hypovolemia and impairment of the balance in electrolytes that contributes to decrease blood pressure and result in cardiovascular problem.(9) therefore, it is necessary to evaluate urine output and serum electrolytes every 2 to 4 hours.(1) these parameters are not only important for donor maintenance and preventing cardiac arrest, but also are necessary for adequate tissue perfusion and preservation of organ viability. as we found in this study, hypernatremia and polyuria may influence kidney allograft function. hypernatremia correlated to the serum creatinine levels of the recipients recorded in their last follow-up visits. we categorized the recipients with donors who had serum sodium levels lower and upper than 155 meq/l and found that the serum creatinine levels of those with lower sodium concentrations in their donors were significantly lower (p = .02). although we could not consider all the factors that might have impacted the recipients’ kidney function, the influence of donors’ serum levels of sodium was a noticeable finding that should be further studied. similar results have been reported only in liver transplant recipients.(4-6) figueras and colleagues reported that hypernatremia in the donors led to a higher frequency of liver allograft loss.(6) it was explained that high serum sodium concentrations in the donor might promote the accumulation of idiogenic osmoles within the liver allograft cells. the subsequent transplantation of these livers into recipients with relatively normal sodium levels may promote intracellular water accumulation, cell lysis, and death during recirculation.(4,5) in this study, polyuria also correlated with increased recipient’s serum creatinine level early after transplantation. however, polyuria did not have such an effect in the long term. of course, this may depend on other factors such as hypovolemia or hypernatremia in the donor. the urine output categorization and analysis of the complications of polyuria is not easy, since both oliguria and polyuria in the brain-dead donor may influence the kidney transplantation outcome, and there is no definite cutoff point for urine output in the brain-dead subjects. some guidelines for donor management recommended keeping urine output around 100 ml/h.(3) they suggest that treatment of diabetic insipidus be started if urine output exceeds 300 ml/h.(3) larger randomized studies are necessary to define the potentially harmful range of urine output in brain-dead donors in the context of kidney transplantation. conclusion the rate of polyuria and hypernatremia in braindead donors are high and the elevated serum sodium level and polyuria might be risk factors of kidney allograft dysfunction. as the results of this study showed, donor hypernatremia may influence the recipient’s serum creatinine in the long term. acknowledgment we would like to thank dr al heidary, dr a afzali, and ms a darvish for their help in collecting the data. conflict of interest none declared. references 1. ramos hc, lopez r. critical care management of the brain-dead organ donor. curr opin organ transplant. 2002;7:70-5. 2. hirschl mm, matzner mp, huber wo, et al. effect of desmopressin substitution during organ procurement hypernatremia and polyuria of brain-dead donors—kazemeyni and esfahani urology journal vol 5 no 3 summer 2008 177 on early renal allograft function. nephrol dial transplant. 1996;11:173-6. 3. shah v, bhosale g. organ donor problems and their management. indian j crit care med. 2006;10:29-34. 4. totsuka e, dodson f, urakami a, et al. influence of high donor serum sodium levels on early postoperative graft function in human liver transplantation: effect of correction of donor hypernatremia. liver transpl surg. 1999;5:421-8. 5. kutsogiannis dj, pagliarello g, doig c, ross h, shemie sd. medical management to optimize donor organ potential: review of the literature. can j anaesth. 2006;53:820-30. 6. figueras j, busquets j, grande l, et al. the deleterious effect of donor high plasma sodium and extended preservation in liver transplantation. a multivariate analysis. transplantation. 1996;61:410-3. 7. marshall vc. renal preservation. in: morris pj, editor. kidney transplantation, principles and practice. 5th ed. philadelphia: wb saunders; 2001. p. 113-34. 8. wood ke, becker bn, mccartney jg, d’alessandro am, coursin db. care of the potential organ donor. n engl j med. 2004;351:2730-9. 9. bos em, leuvenink hg, van goor h, ploeg rj. kidney grafts from brain dead donors: inferior quality or opportunity for improvement? kidney int. 2007;72:797-805. pdf-1002.pdf 423vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l pediatric sutureless circumcision without using skin closure adhesives a new technique for poor setting seyyed alaeddin asgari,1 mandana mansur ghanaie,1 siavash falahatkar,1 hassan niroomand,1 elham iran-pour,2 mohammad reza safarinejad2 keywords: penis, circumcision, sutures, hemorrhage, child introduction ircumcision is one of the most common procedures performed worldwide. neonatal circumcision is mostly done due to social, cultural, personal, and religious reasons.(1) cised.(2,3) world health organization has introduced medical male circumcision as a human (4) nevertheless, inadequate funding and concerns about the safety of the surgical procedure, as well as diverse tance to circumcision. many various methods can be used for circumcision, but the two commonly used are the sleeve technique and use of the plastibell® device. with the sleeve technique, the skin edges are approximated by interrupted stitches using non-absorbable suture materials. the main disadvantage of this method is unsatisfactory cosmesis.(5,6) on the other hand, proximal migration of the plastibell® ring, due to use of an inappropriate size, may occur causing serious penile injury.(7) for the skin closure in sleeve technique, the long chain derivatives of cyanoacrtoxicity and good bonding strength.(6,8) corresponding author: mohammad reza safarinejad, md p.o. box 19395-1849, tehran, iran tel: +98 21 2245 4499 fax: +98 21 2245 6845 e-mail: mersa_mum@ hotmail.com received may 2011 accepted november 2011 1 urology research center, guilan university of medical sciences, rasht, iran 2 private practice of urology and andrology, tehran, iran point of technique 424 | point of technique available in every community. furthermore, cost usd for each patient. technique of sutureless circumcision, compared to the standard closure using interrupted sutures, has ter postoperative appearance, parental satisfaction, diminished operative time.(6,9-11) to promote large population-based circumcision syndrome, an easy, safe, cost-effective, and cosmetically acceptable technique can be helpful. to the best of our knowledge, there have been no reports of pediatric sutureless circumcision without auxiliary measure for the skin closure. case report children were circumcised by the same surgeon. the indication for circumcision was ritual causes and none of our subjects had phimosis or other conditions, such as urinary tract infection or repetitive balanoposthitis. the study was approved by the medical ethics ences and all the parents of the children involved signed an informed consent allowing their child to participate. technique seventy-one surgeries were performed under general anesthesia, due to parental preference, and 55 children underwent local anesthesia with dorforeskin was completely retracted, freeing the adhesions from the glans. thereafter, the skin was marked circumferentially with a surgical pen to afford a suitable tissue apposition. mosquito forceps were applied to the tip of the foreskin ventrally and dorsally, and the foreskin was protracted. a straight figure 2. the foreskin is incised below the forceps using a scalpel blade through the skin and dartos fascia to the inner mucosa. figure 1. a straight forceps has been applied over the marked line above the glans. figure 3. a dorsal slit is made through both layers of the prepuce back to the incision line of the skin. 425vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l sutureless circumcision | asgari et al forceps was applied over the marked line above glans was not caught within the forceps. the foreskin was incised below the forceps using a scalpel blade through the skin and dartos fascia to the inner mucosa (figure 2). thereafter, a dorsal slit was made through both layers of the prepuce back to the incision line of the skin, and inner mucosa was trimmed with scissors, leaving an adequate mucosal cuff (figure 3). electric cauterization. furthermore, meticulous hemostasis was secured with electric cauterization or sels if necessary. particular attention was paid to provide complete hemostasis at the frenulum. the incision was then cleansed, and the skin edges were aligned by upward moving of the penile shaft skin from its usual place below the incision to appose the distal mucosal collar. the edges of incision were not closed with sutures, and tissue–glue was not applied (figure 4). no dressing was used. vent the raw and sensitive tissue from sticking to clothing. to prevent the repair from adhering to the glans or penile shaft skin, antibiotic ointment was applied to the wound for 1 week. parents whose boys were still in diapers were instructed to leave the penis exposed at convenient times. the children were allowed to bathe after 72 hours as their usual habit after discharge from the hospital. the duration of the circumcision was recorded by the circulating nurse, since the penile block or foreskin retraction until the covering was done. after the operation, the children were sent home with a prescription of acetaminophen every 6 hours on the day of the surgery and on the following days only if necessary. parents were told to return to the hospital at any time if anything unusual occurred. and at 12 months after the surgery. the following parameters were addressed: wound infection, dehiscence, hemorrhage, and cosmetic appearance. all parents completed a non-validated satisfaction survey (appendix). data were expressed as mean ± standard deviation. results the mean age of the children was 36 ± 11 months (range, 4 months to 6 years). the mean operating figure 4. the edges of incision have not been closed with sutures, and tissue–glue has not been applied. figure 5. six-month post-operative result. 426 | dren, after excision of the prepuce, the skin edges (penile shaft skin and distal mucosal collar) were not apposed spontaneously without traction, and a standard sutured repair was carried out. one-hundred and nine (91.6%) parents were “very ance and with the operation being carried out as a dehiscence at ventral aspect 2 to 3 days after surtory to both patients and surgeons. other complications included minor postoperative bleeding in 8 (6.7%) subjects, which were managed by compressive dressing, and meatal stenosis in 4 (3.4%), which might be due to extensive diathermy used near the frenulum. hematoma or bleeding requiring additional intervention did not and abnormal scarring did not happen in any children, and nearly all the subjects had very good or excellent cosmetic results. figure 5 shows postoperative condition after 6 months. parents of 111 (93.3%) children wanted their next son undergo this operation as well. discussion quently performed operations with some potential complications. many surgeons use interrupted chromic or plain catgut sutures to appose the skin edges reapproximation has demonstrated acceptable cosmetic results.(6,12,13) advantages of tissue glue versus sutures for circumcision were compared in 152 boys.(9) glue was reported a superior cosmetic result following tissue glue approximation, which did not reach statisticircumcision with tissue glue approximation, there were two postoperative complications of wound dehiscence.(9) the authors concluded that the sutureless circumcision technique should be reserved for boys under the age of 12 years due to the increased risk of wound dehiscence following penile erection. underwent circumcision with tissue glue and 46 boys underwent circumcision with suturing; the age range of the patients was 1 to 11 years. the cosmetic results of the two groups were comparable. furthermore, the incidence of bleeding and infection was similar.(12) dian length of surgery with tissue glue application was longer than conventional suturing; however, this has not been reported in other studies. most recent systematic literature review, lane and associates concluded that sutureless circumcision the standard closure technique, using interrupted sutures.(11) including bleeding, infection, dehiscence of the wound, meatal stenosis, cosmetic failure due to abnormal scarring, penile injury, such as glanular necrosis and glans and penis amputation, and ure(14-16) bleeding can occur at a variety of points during circumcision and typically happens at the frenulum as apposed to the preputial excision line. this complication can be reduced by adequate hemostasis during surgery using bipolar electrocautery and suture ligature. the reported rate of bleeding as the early complication of circumcision was between (17) ported acute bleeding after circumcision in 24% of their patients.(18) however, wiswell and colleagues point of technique 427vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l reported excessive bleeding in 3 out of 478 boys who underwent circumcision beyond the neonatal period.(19) with this technique, meticulous hemostasis has outmost importance, because bleeding can be worrisome for parents and the child may require re-operation. to avoid the bleeding, we bleeding occurred in 8 (6.7 %) patients within few hours after the operation and all of them were managed by compressive dressing. tissue adhesives have some complications, escircumcisions using tissue glue, meticulous skin edges apposition is important, since insertion of tissue glue into the skin edges can slow the healing process and may result in a foreign body reaction. tissue glue can be challenging and may result in unwanted adherence of the incision to the glans or penile shaft.(6) releasing, it is mandatory to take away any forceps prior to polymerization of tissue adhesives. using tissue glue in children with hidden penis, even partial, can lead to unwanted complications.(6) elmore and associates recommended that tissue glue should not be used by those who depend on sutures to manage unsatisfactory skin edge apposition or for hemostasis.(6) recent data stating that circumcision confers sigraised considerable interest in the procedure.(21,22) veloped countries, mainly in sub-saharan africa, where usually medical resources are very limited and the parents have to pay for circumcision. chromic suture costs about 7 usd. furthermore, longer operating time is required for wound clothe mean time taken for circumcision was about 7 minutes. elmore and colleagues reported that of 7 minutes per case.(6) therefore, it represents a operating time might reduce the circumcision cost. therefore, cost-effectiveness, time savings, and acceptable results make this method very suitable in some communities. naire to accurately evaluate parental satisfaction with circumcision results. however, the results from non-validated postoperative questionnaire used in the present study indicated very good or excellent parents’ satisfaction. was being performed by traditional method without suturing to appose the skin edges. nowadays, in our country, there are millions of middle-aged men who have been circumcised with the abovementioned traditional method with very good or excellent cosmetic results. this was the rational for performing the present study. to the best of our knowledge, sutureless circumcision without using tissue glue has not been reported previously. sutureless circumcision without wound closure appears to be a reliable, cost-effective, and safe method of circumcision that sigprovides very good or excellent cosmetic results and can be recommended for some communities. conflict of interest none declared. references 1. schoen ej. the status of circumcision of newborns. n engl j med. 1990;322:1308-12. 2. elder js. circumcision—are you with us or against us? j urol. 2006;176:1911. 3. nelson cp, dunn r, wan j, wei jt. the increasing incidence of newborn circumcision: data from the nationwide inpatient sample. j urol. 2005;173:978-81. sutureless circumcision | asgari et al 428 | 20. edmonson mb. foreign body reactions to dermabond. am j emerg med. 2001;19:240-1. 21. bailey rc, moses s, parker cb, et al. male circumcision for hiv prevention in young men in kisumu, kenya: a randomised controlled trial. lancet. 2007;369:643-56. 22. auvert b, taljaard d, lagarde e, sobngwi-tambekou j, sitta r, puren a. randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs 1265 trial. plos med. 2005;2:e298. 4. who/unaids technical consultation on male circumcision and hiv prevention: research implications for policy and programming. mar, pp. 6–8. available at: http://data.unaids. org/pub/report/2007/mc_recommendations_en.pdf. 5. petratos pb, rucker gb, soslow ra, felsen d, poppas dp. evaluation of octylcyanoacrylate for wound repair of clinical circumcision and human skin incisional healing in a nude rat model. j urol. 2002;167:677-9. 6. elmore jm, smith ea, kirsch aj. sutureless circumcision using 2-octyl cyanoacrylate (dermabond): appraisal after 18-month experience. urology. 2007;70:803-6. 7. bode co, ikhisemojie s, ademuyiwa ao. penile injuries from proximal migration of the plastibell circumcision ring. j pediatr urol. 2010;6:23-7. 8. kamer fm, joseph jh. histoacryl. its use in aesthetic facial plastic surgery. arch otolaryngol head neck surg. 1989;115:193-7. 9. subramaniam r, jacobsen as. sutureless circumcision: a prospective randomised controlled study. pediatr surg int. 2004;20:783-5. 10. arunachalam p, king pa, orford j. a prospective comparison of tissue glue versus sutures for circumcision. pediatr surg int. 2003;19:18-9. 11. lane v, vajda p, subramaniam r. paediatric sutureless circumcision: a systematic literature review. pediatr surg int. 2010;26:141-4. 12. cheng w, saing h. a prospective randomized study of wound approximation with tissue glue in circumcision in children. j paediatr child health. 1997;33:515-6. 13. zafar f, thompson jn, pati j, kiely ea, abel pd. sutureless circumcision. br j surg. 1993;80:859. 14. harrison nw, eshleman jl, ngugi pm. ethical issues in the developing world. br j urol. 1995;76 suppl 2:93-6. 15. ceylan k, burhan k, yilmaz y, can s, kus a, mustafa g. severe complications of circumcision: an analysis of 48 cases. j pediatr urol. 2007;3:32-5. 16. johnson pv. childhood circumcision. surgery. 2008;26:31416. 17. american academy of pediatrics, task force on circumcision. circumcision policy statement pediatrics 1999;103:686-93. 18. ben chaim j, livne pm, binyamini j, hardak b, ben-meir d, mor y. complications of circumcision in israel: a one year multicenter survey. isr med assoc j. 2005;7:368-70. 19. wiswell te, tencer hl, welch ca, chamberlain jl. circumcision in children beyond the neonatal period. pediatrics. 1993;92:791-3. point of technique appendix non-validated parents’ questionnaire used at follow-up evaluation 12 months postoperatively. 1. are you pleased with the results of the circumcision/surgery? very satisfied moderately satisfied satisfied dissatisfied very dissatisfied 2. how would you evaluate this technique? excellent very good good fair negative 3. would you like your next son undergo this operation? yes no endourology and stone disease febuxostat promoted dissolution of radiolucent nephrolithiasis in patients with hyperuricemia mao yunhua1, zhang hao1, li ke1, huang wentao1, li xiaokang1, situ jie1* purpose: this study aimed to investigate the efficacy and safety of febuxostat in patients with radiolucent nephrolithiasis. materials and methods: from march 2016 to june 2018, data of 96 patients with radiolucent nephrolithiasis and hyperuricemia who referred to the third affiliated hospital of sun yat-sen university were retrospectively analyzed. these patients were divided into allopurinol 300mg/d (control), febuxostat 40mg/d (f40) and 80mg/d (f80) groups respectively. all patients took potassium citrate as a combination treatment and had been followed up for at least 6 months. before treatment and on after 1st, 3rd and 6th month, complete blood count, serum uric acid (sua), hepatic and renal function as well as ultrasound were carried out. arthritic and gastrointestinal symptoms were also monitored. computed tomography was performed before treatment and 6 months after medication. results: compared with allopurinol group, f40 group showed no difference in urate-lowering effect, while f80 had the best effect across all the visits (p<0.01). at 6th month, 25(83.3%) cases of f80 group achieved sua<6mg/ dl, which was better than allopurinol group (18 cases, 58.1%) and f40 group (17 cases, 58.6%). in the dissolution effect of radiolucent calculi, f80 had the best effect, followed by f40 and then allopurinol (p<0.05). no statistical difference was observed in adverse events among three groups. conclusion: febuxostat significantly decreased sua, promoted radiolucent stone dissolution and reduced the total stone number, whereas it did not increase the adverse events. keywords: nephrolithiasis; hyperuricemia; febuxostat; allopurinol introduction uric acid (ua) is the end chemical product of pu-rine degradation in human. since approximately 2/3 of uric acid passes out in urine, hyperuricemia usually cause high concentration of ua in the urine, which is called hyperuricosuria. when urine is supersaturated with undissolved ua, ua stones which are radiolucent form subsequently. studies also demonstrated that hyperuricosuria promotes not only the ua stones but also the calcium oxalate stones(1-3). it was reported that up to 10-15% of urinary stones and most of the radiolucent stones are ua stones(4-6). thus, lowering the serum ua (sua) is an important intervention for nephrolithiasis treatment. the two main approaches to lowering sua are promoting the excretion and inhibiting the production(6,7). drugs promoting ua excretion, such as benzbromarone, usually exacerbate ua stones, for which reason they are contraindicated for patients with hyperuricemia and nephrolithiasis. xanthine oxidase inhibitors, such as allopurinol and febuxostat, remarkably decrease hyperuricemia and hyperuricosuria and are beneficial in the treatment of ua stones(8). although the efficacy of febuxostat has been examined in primary gout, there are still no reports concerning the efficacy and safety of febuxostat as well as its advantages over allopurinol in radiolucent nephrolithiasis(9). herein, this study predepartment of urology, the 3rd affiliated hospital of sun yat-sen university, guangzhou, china. *correspondence: department of urology, the third affiliated hospital of sun yat-sen university, no.600, tianhe road, guangzhou, china, 510630. phone: +86-20-85252660. fax: +86-20-85252678. email: situjie_sysu@126.com. received september 2019 & accepted february 2020 sents results about the efficacy and safety of febuxostat in radiolucent nephrolithiasis based on single-center retrospective study. patients and methods study population this single-center retrospective study was approved by the institutional ethics committee of 3rd affiliated hospital of sun yat-sen university. all patients had signed informed consents for using related information. from march 2016 to june 2018, patients with nephrolithiasis who were referred to the 3rd affiliated hospital of sun yat-sen university were screened. patients with radio-lucent nephrolithiasis and hyperuricemia which was defined as serum uric acid (sua) greater than 8mg/ dl were further selected based on inclusion and exclusion criteria for final analysis. the inclusion criteria are:1)18-70 years old, sua>8m/ dl, bmi<30kg/m2;2) ultrasound and ctu confirmed renal stones<2.5cm, stones were radiolucent in kub, absence of ureteral or bladder stones or hydronephrosis or other congenital abnormalities; 3) serum creatine<130umol/l; 4) receiving single urate-lowering drug (allopurinol or febuxostat) and administration with potassium citrate as a combination treatment. based on their medication, the selected patients were divided into three groups of allopurinol 300mg/d (100mg tid, conurology journal/vol 18 no. 1/ january-february 2021/ pp. 34-39. [doi: 10.22037/uj.v0i0.5564] vol 18 no 1 january-february 2021 35 trol group), febuxostat 40mg/d (40mg qd, f40 group) and 80mg/d (40mg bid, f80 group). patients were excluded when their baseline data met exclusion criteria. exclusion criteria were:1) secondary hyperuricemia; 2) under gout attack or frequent gout attacks;3) liver dysfunction, ast/alt>2 upper normal limit;4) white blood cells<4.0×109/l, hemoglobin<100 mg/dl, platelets< 100×109/l;5) receiving other urate-lowering agents or receiving ;2 kinds of urate-lowering agents; 6) using glucocorticoids, immunoimpressive agents, thiazine diuretics or other drugs that interfere with sua; 7) a history of alcohol or drug abuse; 8) other severe or progressive diseases including cancer, heart diseases and chronic or severe infection, gastrointestinal, endocrine, pulmonary, cardiac, neurological, or cerebral diseases. 9) pregnant or breastfeeding woman. data extraction and evaluations regularly, patients with hyperuricemia who referred to our clinics were advised to drink enough water and maintain urine volume excessing 2000ml per day. low purine intake was also recommended. the day before treatment and the day at 1,3,6 months after treatment, blood routine test, sua, liver/kidney functions were determined. ultrasound was performed on the day before treatment and the day at 1, 3, 6 months after treatment, while computed tomography (ctu) was performed on febuxostat in radiolucent nephrolithiasis-yunhua et al. table 1. baseline data of selected patients allopurinol 300mg/d febuxostat 40mg/d febuxostat 80mg/d p patients number, n 34 30 32 age,median (range),years 45(23-69) 47(26-74) 48(25-76) 0.365a gender,n(%) male 18(52.9) 14(46.7) 17(53.1) 0.903b female 16(47.1) 16(53.3) 15(46.9) bmi, kg/m2 23.3 ± 3.12 22.5±2.89 23.50±3.07 0.542c gouty tophi,n(%) 5(16.1) 3(10.0) 4(12.5) 0.718d baseline ua, median(range), mg/dl 9.72(8.1-13.6) 9.83(8.1-13.8) 9.92(8.1-14.2) 0.487 ast, mean±sd, u/l 25.56 ± 5.17 26.91 ± 4.88 24.77 ± 5.02 0.762 alt, mean±sd, u/l 22.34 ± 5.34 24.98 ± 4.67 23.68 ± 4.89 0.469 cr, mean±sd, umol/l 65.12 ± 9.24 68.34 ± 8.55 69.38 ± 10.12 0.387 a, cruskal-wallis test. b, χ2 test. c, anova test. d, fisher exact test. abbreviations: bmi: body max index. ua: uric acid. ast: aspartate transaminase. alt: alanine aminotransferase. cr: creatine. figure 1. flowchart of patients through the study. aes, adverse events. the day before treatment and the day at 6 months after treatment. hypersensitivity, gastrointestinal and cardiac symptoms, arthralgia, and gout flares were recorded. patients who did not have complete data were excluded, but those who discontinued medication due to severe adverse events still remained in adverse events analysis so as not to underestimate the incidence of adverse events. end points: 1) the change in sua; 2) stones changes, including the maximum diameter and stone numbers; 3) adverse events. patients whose maximum stone diameter decreased by >50% or the numbers of stones with diameter>5mm decreased were regarded as significantly effective cases. statistical analysis category variables were presented as frequencies or percent, statistical differences between groups were analyzed with χ2 test or fisher exact test. continuous variables were presented as mean ± standard deviation (sd) or s median (range), statistical differences among three groups were analyzed using kruskal-wallis test or anova test, and statistical differences between two groups were performed using students’t test or mann– whitney u test. pairwise comparisons were performed to analyze the changes of sua levels, stones diameters, and numbers in each group before and after treatment. two tailed p < 0.05 indicated statistical significance. results patients’ characteristics in this study, a total of 96 patients were selected for final analysis, including 34, 30 and 32 cases for allopurinol group, f40 group and f80 group respectively. however, there were 3,1 and 2 patients who didn’t complete medication for at least 6 months due to severe adverse events (figure 1). therefore, these patients were not included in the final efficacy analysis of serum uric acid (sua) changes and stones changes, but still remained in adverse events analysis so as not to underestimate the incidence of adverse events. for all the eligible patients, the median (range) of age was 46 (23-76) years old, the median (range) sua level was 9.87 (8.1-14.2) mg/dl, and gouty tophi were found in 12 patients. baseline data for each group were shown in table 1. serum uric acid (sua) change there were 31, 29 and 30 cases for allopurinol group, f40 group and f80 group respectively in the efficacy analysis of sua change. the baseline median (range) sua were 9.72(8.1-13.6), 9.83(8.1-13.8), and 9.92(8.114.2) mg/dl for allopurinol, f40 and f80 group respectively, with no statistical differences among groups. after treatment, sua decline velocities were similar in allopurinol group and f40 group, whereas sua dropped the fastest across the time (figure 2). at the 1st month after treatment, the average decline of sua were 2.42 ± 0.34, 2.58 ± 0.46 and 3.18 ± 0.52 mg/dl. at the 3rd month, the average decline of sua were 3.96 ± 0.94, 4.11± 0.89 and 4.89 ± 1.32 mg/dl. at the 6th month, patients with sua<6mg/dl were 25 (83.3%) in f80 group, which was much better than allopurinol group (18 cases, 58.1%, p < 0.01) and f40 group (17 cases, 58.6%, p < 0.01). since all the patients were medicated with potassium citrate as the combination therapy and the urine ph is effective for examining the effects of citrate, we compared the urinary parameters at baseline and 6 months after treatment. results of 24-hour urine collections are reported in table 2. although urine was remarkably alkalized by potassium citrate in each group (p < 0.001), there were no significant differences among three groups in ph at baseline or at the 6th month (p = 0.659 and 0.987). this means that the differences of treatment effects were mainly caused by urate-lowering drugs. stone changes there were 31, 29 and 30 cases for allopurinol group, f40 group and f80 group respectively in the efficacy analysis of stones changes. the maximum diameter and the total number of the stones were used to evaluate the table 2. changes in urinary parameters for one-day urine collection measurements parameters allopurinol(n=23) febuxostat 40mg/d(n=25) febuxostat 80mg/d(n=23) pb ph baseline 5.93 (0.54) 5.83 (0.53) 5.78 (0.64) 0.659 month 6 6.86 (0.48) 6.98-0.2 (0.49) 6.92 (0.65) 0.987 pa < 0.001 < 0.001 < 0.001 potasium(meq/d) baseline 85.0 (18.1) 82.3 (17.1) 84.2 (25.4) 0.708 month 6 97.6 (18.8) 96.4 (23.9) 93.3 (29.7) 0.823 pa 0.005 0.023 0.003 sodium(meq/d) baseline 231.1(45.6) 244.7 (35.4) 261.1(45.1) 0.06 month 6 190.1(53.6) 192.4 (43.7) 201.9 (45.5) 0.672 pa 0.009 < 0.001 0.001 citrate(mg/d) baseline 558.1(143.8) 578.6 (132.2) 595.9 (122.3) 0.631 month 6 628.5(127.3) 621.6 (112.3) 628.4 (109.0) 0.972 pa 0.115 0.019 0.039 calcium(mg/d) baseline 231.0 (61.9) 281.4 (60.5) 259.0 (34.3) 0.008 month 6 227.1(44.7) 250.3 (67.2) 272.4 (27.3) 0.012 pa 0.684 0.101 0.068 uric acid(mg/d) baseline 946.8 (208.2) 932.2 (203.3) 954.2 (180.0) 0.923 month 6 535.5 (108.6) 526.2 (130.9) 440.3 (112.0) 0.012 pa < 0.001 < 0.001 < 0.001 a, the differences at baseline and at month 6 in each group were compared using pairwise t test. b, the differences among groups at the same timepoint were compared using one-way anova test. febuxostat in radiolucent nephrolithiasis-yunhua et al. endourology and stones diseases 36 vol 18 no 1 january-february 2021 37 stone burden. at the 6th month, the reduced maximum diameters were 5.1 mm (39.8%), 5.3mm (40.1%) and 7.6mm (56.7%) for allopurinol group, f40 and f80 groups respectively. there were 16(51.6%), 17(58.6%) and 22(73.3%) patients whose stones became smaller by more than 50%. changes of the maximum diameter of stones showed no difference between the allopurinol group and the f40 group (p = 0.11). among the three groups, f80 reduced the stone size the most significantly (p < 0.05). regarding the stone number, there were 61, 58 and 64 stones in the allopurinol group, f40 and f80 groups respectively. after 6 months of treatment, there were 16 (26.2%), 14 (24.1%), and 31 (48.4%) stones being reduced, indicating f80 had the best reduction rate, followed by f40 and then the allopurinol group (table 3). when significantly effective cases were defined as patients whose maximum stone diameter decreased by >50% or the stone number with diameter>5mm decreased, there were 18 (58.1%), 19 (65.5%) and 24 (80.0%%) cases with significant efficacy for each group (table 2). therefore, patients medicated with febuxostat 40mg twice daily had the best treatment efficacy in stone dissolution. adverse events (aes) in order to avoid underestimating the incidence of adverse events (aes), those patients discontinued medication due to severe aes and progressive symptoms still remained in aes analysis. data on aes were summarized in table 4. among 96 patients, 32 (33.3%) patients experienced a total of 63 aes. there were 24, 17, 22 events in allopurinol, f40 and f80 groups, respectively. there were 12/34 (35.3%), 9/30(30.0%) and 11/32(34.4%) patients of each group who experienced at least one ae (p = 0.927), suggesting the incidence of aes in patients were similar among the three groups. only 3 subjects in the allopurinol group discontinued medication, including 2 cases of hypersensitivity and 1 case of repeated gout attack, which required hospitalization. in the f40 group, 1 case of hypersensitivity stopped medications. two patients discontinued medications in the f80 group, with 1 case of hypersensitivity and 1 case of abnormal myoenzymes that was suspected of myocardiopathy. among all the aes, liver dysfunction was the most common, but all recovered to normal liver function within 2 – 4 weeks and were able to switch to other urate-lowering agents (table 4). patients medicated with febuxostat 80mg/d experienced similar aes with patients who medicated with febuxostat 40mg/d, indicating increasing febuxostat to 80mg/d could achieve better urate-lowering effect but did not increase aes incidence. discussion approximately 2/3 of uric acid is excreted through urine. hyperuricemia results in elevated uric acid in urine, which is called hyperuricosuria. when the uric acid becomes saturated, it forms crystals thus uric acid stones reside in renal pelvis(10). uric acid stones are radiolucent in the x-ray. allopurinol and febuxostat, as two classic urate-lowering drugs, inhibit xanthine oxidase to reduce serum uric acid, which results in lower uric acid excretion in urine(11). since allopurinol has a purine-like backbone, it affects enzymatic activity related to purine and pyrimidine metabolism and could table 3. stone changes after treatment allopurinol 300mg/d febuxostat 40mg/d febuxostat 80mg/d patients included in analysis, n 31 29 30 stone size, mm baseline mean(sd) 12.8 (6.3) 13.2 (5.8) 13.4 (7.1) median(range) 12 (6-24) 13 (6-26) 13.1(6-29) at 6 mon mean(sd) 7.7 (5.5) 7.9 (5.9) 5.8 (4.3) a,b median(range) 7 (3-21) 8 (3-20) 5.8 (3-19) a,b stone numbers baseline, n 61 58 64 mean(sd) 2.0 (0.4) 2.0 (0.5) 2.1 (0.7) median 2 (1-4) 2 (1-5) 3 (1-5) at 6 mon, n 45 44 33 a,b mean(sd) 1.5 (0.3) 1.5 (0.5) 1.1(0.3) a,b median 1(0-5) 1(0-5) 1(0.4) dissolved stones, n(%) 16 (26.2) 14 (24.1) 31(48.4)a,b a, p < 0.05 when compared with allopurinol group. b, p < 0.05 when compared with group of febuxostat 40mg/d. allopurinol 300mg/d, n=34 febuxostat 40mg/d, n=30 febuxostat 80mg/d, n=32 liver dysfunction 7 8 9 nonobstrunctive renal dysfunction 1 1 1 abnormal complete blood count 2 2 1 hyperlipidemia 1 3 6 abnormal myoenzymes 0 1 2 hypersensitivity 7 1 1 gastrointestinal symptoms 6 1 2 total aes, n 24 17 22 patients with aes, n (%) 12(35.3) 9(30) 11(34.4) abbreviation: aes, adverse events table 4. adverse events in the three groups febuxostat in radiolucent nephrolithiasis-yunhua et al. be reincorporated into nucleotides, thus reducing its urate-lowering effect and increasing adverse events. however, febuxostat has a different configuration from purine, which gives it a better inhibitory effect and specificity(12). it selectively occupies the access channel to the molybdenum-pterin active site of the enzyme. furthermore, febuxostat is primarily metabolized in the liver, and renal elimination plays a minor role in febuxostat pharmacokinetics. although reports have clarified the efficacy of allopurinol in nephrolithiasis(13,14), the efficacy and safety of febuxostat especially in radiolucent stones remains unclear(9). this study is a single-center retrospective study aiming to compare the efficacy and safety of allopurinol and febuxostat in radiolucent nephrolithiasis. the results demonstrated that febuxostat 40mg/d achieved a similar urate-lowering effect with allopurinol 300mg/d. moreover, febuxostat 80mg/d had a better treatment effect than allopurinol and febuxostat 40mg/d while the incidences of adverse events were similar. our study suggests that febuxostat is an effective and safe urate-lowering agent for radiolucent nephrolithiasis. it has been reported that hyperuricosuria contributes not only uric acid nephrolithiasis but also calcium oxalate stones, both of which comprise about 90% of nephrolithiasis(15,16). therefore, urate-lowering agents may promote the dissolution of a large part of urinary stones. a randomized multicenter clinical trial by david s. goldfarb et al. demonstrated that febuxostat 80mg/d or allopurinol 300mg/d promoted dissolution of calcium oxalate stones, and that both agents had similar treatment effects(4). our results revealed that febuxostat 80mg/d was better for radiolucent stones dissolution. several reasons explain why febuxostat promoted stone dissolution in our study. on one hand, febuxostat inhibited uric acid production, thus lowering uric acid concentration in the urine and preventing uric acid crystal formation in the renal pelvis. on the other hand, a combination therapy of potassium citrate increased urine ph, which increased the solubility of uric acid. based on these results, we proposed that lowering uric acid might be helpful for the dissolution of calcium oxalate stones or radiolucent stones. balancing the drug effect and adverse events is of top priority in practice. our results showed that when increasing drug dose from 40mg/ to 80mg/d, febuxostat significantly reduced serum uric acid in a shorter time, but its adverse events were similar to allopurinol 300mg/d. although studies suggested that increment of allopurinol dose correlated with improved urate-lowering effect, the adverse events would also increase proportionally(17). to date, 300mg/d of allopurinol is most regarded as a safe dose, further dose increment was not recommended because the risks are over the merits(18). as for febuxostat 80mg/d, it did not cause more adverse events while achieving a better treatment effect, suggesting febuxostat had a bigger dose window(19). it should be noted that liver dysfunction was the most common adverse event in our study, which could be explained by that febuxostat is metabolized by oxidation and glucuronidation in the liver. recently, studies reported that febuxostat could cause higher mortality in patients with gout and cardiovascular diseases(20,21). in our study, 1 case of suspected cardiomyopathy was observed in patients medicated with febuxostat 80mg/d. therefore, cardiovascular adverse events should be strictly monitored when using high dose of febuxostat. there were several limitations of this study. firstly, the sample size was relatively small for a common disease like nephrolithiasis. since it was a single-centered retrospective study, bias was inevitably introduced to some extent, but results were statistically significant figure 2. changes of serum uric acid levels after treatment. febuxostat in radiolucent nephrolithiasis-yunhua et al. endourology and stones diseases 38 and efficient to draw a conclusion. secondly, the follow up period of 6 months was relatively short. dissolution of large stones needs a long time, and therefore the clearance rate of large stones couldn’t be evaluated. in this study, we defined effective cases as patients whose maximum stone diameter decreased by >50% or the numbers of stones with diameter>5mm reduced, which would help in treatment efficacy evaluation. theoretically, the pure uric acid stones could be dissolved and passed to achieve total clearance at last. we will continue to follow up these patients and evaluate the longterm treatment of febuxostat. finally, only one kind of urine-alkalized agent potassium citrate was used in this study. in practice, urine alkalization directly affects the treatment effect, thus urate-lowering agents are usually combined with urine-alkalized agents to improve the excretion. we didn’t compare which urine-alkalized agent would be better in combination with febuxostat. conclusions this single-center retrospective study compared the treatment efficacy and safety of allopurinol 300mg/d, febuxostat 40mg/d, and febuxostat 80mg/d in radiolucent nephrolithiasis. our results demonstrated that compared with allopurinol, febuxostat achieved much better efficacy while keeping a similar incidence of adverse events. febuxostat in combination with urine-alkalized agents is better recommended in the treatment of radiolucent stones. acknowledgement this work was financially supported by science and technology planning & social development project of guangdong province of china (2017a020215027). conflict of interest the authors report no conflict of interest. references 1. coe fl, kavalach ag. hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. n engl j med. 1974; 291:1344-50. 2. spivacow fr, del valle ee, lores e, et al. kidney stones: composition, frequency and relation to metabolic diagnosis. medicina (b aires). 2016; 76:343-8. 3. moe ow, xu lhr. hyperuricosuric calcium urolithiasis. j nephrol. 2018. 31:189-96. 4. goldfarb ds, macdonald pa, gunawardhana l, et al. randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones. clin j am soc nephrol. 2013; 8:1960-1967. 5. trinchieri a, montanari e. prevalence of renal uric acid stones in the adult. urolithiasis. 2017; 45:553-62. 6. ma q, fang l, su r, et al. uric acid stones, clinical manifestations and therapeutic considerations. postgrad med j. 2018; 94:45862. 7. heilberg ip. treatment of patients with uric acid stones. urolithiasis. 2016; 44:57-63. 8. soskind r, abazia dt, bridgeman mb. updates on the treatment of gout, including a review of updated treatment guidelines and use of small molecule therapies for difficultto-treat gout and gout flares. expert opin pharmacother. 2017; 18:1115-25. 9. cicerello e. uric acid nephrolithiasis: an update. urologia. 2018; 85:93-8. 10. capasso g, jaeger p, robertson wg, et al. uric acid and the kidney: urate transport, stone disease and progressive renal failure. curr pharm des. 2005; 11:4153-59. 11. zhou q, su j, zhou t, et al. a study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in chinese gout patients: a retrospective cohort study. int j clin pharmacol ther. 2017; 55:163-8. 12. takano y, hase-aoki k, horiuchi h, et al. selectivity of febuxostat, a novel nonpurine inhibitor of xanthine oxidase/xanthine dehydrogenase. life sci 2005; 76:1835-47. 13. ettinger b, tang a, citron jt, et al. randomized trial of allopurinol in the prevention of calcium oxalate calculi. n engl j med. 1986; 315:1386-9. 14. arowojolu o, goldfarb ds. treatment of calcium nephrolithiasis in the patient with hyperuricosuria. j nephrol. 2014; 27:601-5. 15. rizvi sah, hussain m, askari sh, et al. surgical outcomes of percutaneous nephrolithotomy in 3402 patients and results of stone analysis in 1559 patients. bju int. 2017; 120:702-9. 16. mandel ns, mandel ic, kolbach-mandel am. accurate stone analysis: the impact on disease diagnosis and treatment. urolithiasis. 2017; 45:3-9. 17. dalbeth n, stamp l: allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. semin dial. 2007;20:391-5. 18. chao j, terkeltaub r. a critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. curr rheumatol rep. 2009; 11:135-40. 19. jordan a, gresser u. side effects and interactions of the xanthine oxidase inhibitor febuxostat. pharmaceuticals (basel). 2018; 11: pii: e51. 20. white wb, saag kg, becker ma, et al. cardiovascular safety of febuxostat or allopurinol in patients with gout. n engl j med. 2018; 378:1200-10. 21. zhang m, solomon dh, desai rj, et al. assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol. circulation. 2018; 138:1116-26. febuxostat in radiolucent nephrolithiasis-yunhua et al. vol 18 no 1 january-february 2021 39 urol_v03_no4_001_editorial.indd case report 250 urology journal vol 3 no 4 autumn 2006 the role of surgery for local recurrence of renal ewing’s sarcoma a case report abbas basiri, mahmoud parvin, navid eza simaei, amir haji-mohammadmehdi-arbab urol j (tehran). 2006;4:250-2. www.uj.unrc.ir keywords: bladder stones, percutaneous cystolithotripsy, children urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: abbas basiri, md no 44, 9th boustan, pasdaran tehran 1666679951, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir received june 2006 accepted september 2006 introduction primitive neuroectodermal tumor (pnet) is a rare malignancy mainly developed in the central nervous system and soft tissues of the children; however, primary occurrence of this tumor in the kidney has been recently reported.(1,2) histological diagnosis of such cases is challenging. we report a case with recurrence of left renal pnet that was treated successfully by mere tumor resection. case report in february 2003, a 22-year-old man presented to our center with the chief complaint of gross hematuria and pain in the left flank. medical history and physical examination were unremarkable. except for a microscopic hematuria, all laboratory tests had normal results. ultrasonography revealed a 145 × 106-mm heterogeneous mass in the upper pole of the left kidney without the evidence of the metastatic disease. the findings were confirmed by ct scan with mild enhancement after contrast injection (figure 1a). no tumoral tissue was detected in the inferior vena cava and the renal veins by magnetic resonance imaging. chest radiography was also normal. figure 1. diagnostic and follow-up ct scans. a, primary renal tumor. b, local recurrence. c, last follow-up. surgery in local recurrence of renal ewing’s sarcoma—basiri et al urology journal vol 3 no 4 autumn 2006 251 with the probable diagnosis of primary left kidney tumor, radical nephrectomy was performed. histopathological assessment demonstrated uniform, small, round cells compatible with a stage ii blastemal-type wilms tumor. the surgical margins were free of tumor. the patient underwent chemotherapy afterwards. but due to its complications, he refused to continue the treatment after 3 courses of chemotherapy. he was only followed with biochemistry, chest radiography, and abdominal and pelvic ct scan every 3 months. at the 12th postoperative month, ct scan revealed a 40 × 50-mm mass with central calcification in the left renal fossa (figure 1b). since chemotherapy was refused by the patient, resection of the mass was performed. it was excised with a margin of the psoas muscle and the colon mesentery to which it was adhered (figure 2a). pathologic findings were identical to the primary kidney tumors such as a small round-cell sarcoma with extensive necrosis. although all margins were tumor-free, immunohistochemical assessment of the specimen was performed due to the rosette formation (figure 2b). the patient had a periodic acid-schiff staining as focal fine granular cytoplasmic depositions. on immunohistochemistry, the neoplastic cells showed cytoplasmic staining of synaptophysin and cell membrane staining for microneme protein 2, but no reactivity was noted for desmin, actin, terminal deoxynucleotidyl transferase, and wilms tumor suppressor (wt1). we additionally performed fluorescence in situ hybridization analysis which showed a split signal with dna probes against the ews gene, indicating ews rearrangement. overall, histology and immunohistochemistry studies confirmed the diagnosis of ewing’s sarcoma (figure 2c). the tumor was qualified as a renal pnet. again, the patient refused further chemotherapy and he remained disease-free (within 16 months of followup after the recurrence). on the last follow-up visit, ct scan of the abdomen and pelvis was negative for metastatic disease or local recurrence (figure 1c) and the patient was in a good general condition. discussion primitive neuroectodermal tumor should be differentiated from other small round cell tumors of the kidney including lymphoma, small cell carcinoma, renal carcinoid tumor, neuroblastoma, rhabdomyosarcoma, blastema-predominant wilms tumor, synovial sarcoma, and desmoplastic round cell tumor.(3) figure 2. a, excised recurrent tumor. b, sheets of small cells with rosette formation (hematoxylin-eosin, × 400). c, the cell membrane staining of mic2 in the neoplastic cells (× 400) surgery in local recurrence of renal ewing’s sarcoma—basiri et al 252 urology journal vol 3 no 4 autumn 2006 renal pnet was first reported by mor and colleagues.(4) thereafter, a large number of renal ewing’s sarcoma/primitive neuroectodermal tumor (es/pnet) cases have been reported in the literature.(1,2,5,6) most of the reported cases have been found among the young adults (average age, 28 years) with a slight male predominance (male-female ratio, 1.5 to 1).(6) radiotherapy or chemotherapy is not effective and the prognosis is poor in most cases with a reported 5-year survival rate of 45% to 55%.(7) current chemotherapy protocols used in the treatment of the children with es/pnet is composed of induction and consolidation cycles with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide.(6) further investigation of these regimens in patients with renal es/pnet is warranted to determine their precise impact on the survival. these tumors have a great tendency to develop metastases and subsequently a poorer prognosis is expected.(2,5,6) although there is a report of spontaneous regression of pulmonary metastasis following nephrectomy,(8) most patients die within an average duration of 16 months despite chemotherapy.(6) to our best knowledge, this is the first report in which mere resection of the recurrent tumor in the kidney could yield at least 16 months of being free of tumor or metastasis. thus, re-exploration and removal of the recurrent tumor in cases of renal pnet may have a decisive role in the treatment of local recurrences of renal ewing’s sarcoma. conflict of interest none declared. references 1. kuroda m, urano m, abe m, et al. primary primitive neuroectodermal tumor of the kidney. pathol int. 2000;50:967-72. 2. thomas jc, sebek ba, krishnamurthi v. primitive neuroectodermal tumor of the kidney with inferior vena cava and atrial tumor thrombus. j urol. 2002;168: 1486-7. 3. parham dm, roloson gj, feely m, green dm, bridge ja, beckwith jb. primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the national wilms’ tumor study group pathology center. am j surg pathol. 2001;25:133-46. 4. mor y, nass d, raviv g, neumann y, nativ o, goldwasser b. malignant peripheral primitive neuroectodermal tumor (pnet) of the kidney. med pediatr oncol. 1994;23:437-40. 5. karnes rj, gettman mt, anderson pm, lager dj, blute ml. primitive neuroectodermal tumor (extraskeletal ewing’s sarcoma) of the kidney with vena caval tumor thrombus. j urol. 2000;164:772. 6. jimenez re, folpe al, lapham rl, et al. primary ewing’s sarcoma/primitive neuroectodermal tumor of the kidney: a clinicopathologic and immunohistochemical analysis of 11 cases. 2002;26: 320-7. 7. casella r, moch h, rochlitz c, et al. metastatic primitive neuroectodermal tumor of the kidney in adults. eur urol. 2001;39:613-7. 8. wada y, yamaguchi t, kuwahara t, sugiyama y, kikukawa h, ueda s. primitive neuroectodermal tumour of the kidney with spontaneous regression of pulmonary metastases after nephrectomy. bju int. 2003;91:121-2. 1211vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l 1 department of urology, baskent university, konya, turkey. 2 department of anesthesiology, baskent university, konya, turkey. murat gonen,1 betul basaran2 tubeless percutaneous nephrolithotomy: spinal versus general anesthesia corresponding author: murat gonen, md hoca cihan mahallesi, saray caddesi, no. 1, selcuklu, konya, turkey. tel: +90 332 2570606 fax: +90 332 2570637 e-mail: murat.gonen4@ gmail.com received october 2012 accepted march 2013 purpose: tubeless percutaneous nephrolithotomy (pcnl) with double-j stenting is a good option for large kidney calculi without increasing blood loss. in many centers tubeless pcnl is performed under general anesthesia. in the present study we evaluated the impact of spinal anesthesia in patients undergoing tubeless pcnl. material and methods: between february 2011 and february 2012, forty six patients with kidney calculi were treated with tubeless pcnl. of these patients 26 were treated under spinal anesthesia (group 1) and remaining 20 were treated under general anesthesia (group 2). groups were compared according to patient demographics, stone size, access number, operative time, presence of supracostal access, analgesic requirement, length of hospital stay, and complications. results: there were not any statistically significant differences between groups in terms of patient demographics, mean stone size, mean access number, operative time, presence of supracostal access, and length of hospital stay. however, the analgesic requirement was significantly less in group 1 (53 ± 39 mg vs. 111 ± 46 mg, intravenous tramadol in groups 1 and 2, respectively p < .001). conclusion: tubeless pcnl under spinal anesthesia is a good alternative for general anesthesia in adult patients. spinal anesthesia decreases analgesic requirement in patients that were performed tubeless pcnl compared to general anesthesia. keywords: kidney calculi; surgery; nephrostomy, percutaneous; adverse effects; anesthesia. endourology and stone disease 1212 | introduction percutaneous nephrolithotomy (pcnl) is the standart treatment modality of large upper tract urinary stones. european urology guidelines on urolithiasis recommended pcnl as a first line treatment modality for renal stones over 300 mm².(1) pcnl is a highly effective method with over 90% success rate. further modification of pcnl such as the tubeless method decreased the morbidity, but in the meantime maintained its efficacy.(2) anesthesia for pcnl can either be general or regional. recently, pcnl performed under regional anesthesia was reported confer some advantages over general anesthesia, such as lower dose requirement of analgesic drugs.(3-6) however, there is limited number of studies regarding the applicability and feasibility of spinal anesthesia in patients undergoing tubeless pcnl. in the present study, we evaluated the impact of spinal anesthesia in patients undergoing tubeless pcnl. materials and methods we reviewed the records of 46 consecutive patients with renal calculi who had undergone tubeless pcnl by the same surgeon at our institution between february 2011 and december 2011. twenty-six of these patients were treated under spinal anesthesia (group 1) and remaining 20 were treated under general anesthesia (group 2). in our routine clinical practice, we perform pcnl operations under spinal anesthesia with tubeless technique. we perform general anesthesia to patients who are not willing to be treated under spinal anesthesia and when the expected operation time is more than 2.5 hours. pcnl procedures were performed in patients with sterile urine cultures. in all patients cefazolin 1g was administered intravenously for antibiotic prophylaxis. preoperatively noncontrast computerized tomography, serum creatinine, hemoglobin, protrombin time and chest radiography were obtained from all patients. the pcnl procedure was begun with insertion of ureteral catheter under cystoscopic guidance in supine lithotomy position. percutaneous access was achieved in prone position under the guidance of c-arm fluoroscopic examination using an 18-gauge access needle. after insertion of the guide-wire, the tract was dilated to 30 french (f) using amplatz dilators and 30f amplatz sheath was placed. additional tracts were created when indicated. nephroscopy was performed with rigid 26f nephroscope. stone disintegration was performed using a pneumatic lithotripter. stone fragments were extracted with forceps. nephroscopic views and fluoroscopic guidance were used to determine the stone-free status. after achieving stone-free status a double-j stent was placed antegradly under fluoroscopic guidance. nephrostomy tube was not used. operative time was calculated from the beginning of cystoscopy to the end of wound closures. the length of hospitalization was calculated from the day of operation until day of discharge. stone size was calculated using two measurements (i.e., largest width and length) obtained from kidney ureter bladder (kub) x-ray. lactated ringer solution 20 mg/kg was administered 30 minutes before the operation to prevent hypotension in the spinal anesthesia group. midline or paramedian approach for spinal anesthesia was utilized. whitacre 25 gauge needles were used. after successful dural puncture at the level of l2-l3 interspace, 8-15 mg of heavy bupivacaine was injected according to height of the patient in lateral decubitus position. subsequently, the sensory and motor blocks were assessed. pinprick testing was used to evaluate the level of anesthesia, which was performed using a sterile needle that did not need to pierce the skin. patients were asked to compare the testing at the anesthetized part of the body with the non-anaesthetized part of the body such as arm. the decision was made according to perceived the difference by the patient. thirty minutes before the operation general anesthesia group were premadicated with 2 mg intravenous midazolam. moreover, induction was performed using 2 mg/kg propofol, 1 mg/kg fentanyl and 0.6 mg/kg rocuronyum bromide. the 1.2 minimum alveolar concentration isoflurane with 40% oxygen air mixtures were used for maintenance. for the management of postoperative pain tramadol was given intravenously. the kub x-ray and hemoglobin measurements were obtained from all of the patients on the first postoperative day. chest radiography was obtained only from the patients with supracostal access. postoperatively, at 1 month, non-contrast computerized tomography was performed to all of the patients to determine the stone-free status. our criterion for blood transfusion was postoperative hemoglobin level less than 10 g/dl with accompanying hemodynamic instability. the double-j stents were removed 2 weeks after the surgery as an outpatient procedure that was performed under local anesthesia. endourology and stone disease 1213vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l the patient characteristics were shown in table 1. the two groups were compared with regard to access number, stone size, presence or absence of supracostal access, operative time, analgesic requirement, length of hospital stay, blood transfusion, and the observed complications. for stastical analysis mann-whitney u test was used and p values less than .05 were considered significant. results no differences were observed between the groups regarding age, gender, stone size, the duration of operation, blood transfusion rate, presence of supracostal access, number of access, and hospitalization time. complete stone clearance was achieved in all patients intraoperatively by nephroscopic and fluoroscopic guidance. stone clearance was also demonstrated with kub x-ray on the first postoperative. however, noncontrast computerized tomography showed residual stones in one patient in group 1 and in one patient in group 2. the difference was not stastically significant. all residual stones were 4 mm or less in maximum diameter and no auxilliary procedures were performed. the analgesic requirement was significantly lower in spinal anesthesia group (p < .001). no major complications were observed intraoperatively related to spinal anesthesia. postoperatively, one patient complained headache lasted up to 5 days, which was controlled by nonsteroidal anti-inflammatory drugs. the results are also shown in table 2. discussion pcnl is the procedure of choice for the treatment of large renal and upper tract urinary calculi. several new techniques and modifications such as mini-pcnl, tubeless pcnl and pcnl under regional anesthesia have been reported to decrease morbidity, analgesic requirement and length of hospitalization.(2-6) tubeless pcnl was first introduced by bellman and colleagues in l997.(²) since then numerous studies have been reported regarding the safety and efficacy of the tubeless pcnl. recently, wang and colleagues(7) and shen and colleagues(8) summarized the results of tubeless pcnls and standard pcnls in their meta-analyses.(7,8) they reported that postoperative analgesic requirement and length of hospitalization were less in tubeless pcnl.(7,8) anesthesia for pcnl can either be general or regional. general anesthesia (ga) has some disadvantages compared to regional anesthesia, which are increased incidence of anaphylaxis due to multiple drug usage and problems associated with endotracheal tube during positioning of patient from lithotomy to prone.(9) in the english literature, the preferred method of regional anesthesia for pcnl is combined spinal-epidural anesthesia (csea). in our institute, we prefer mostly spinal anesthesia (sa) rather than csea for pcnl operations due to lower cost of sa. recently, kuzgunbay and colleagues(3) reported their experience of standard pcnl under csea versus ga in a prospective non-randomized study and they reported that complications and hospitalization times (2.7 ± 0.7 days for csea and 2.8 ± 0.7 days for ga) between groups were similar. and they concluded that pcnl under csea was effective and safe as pcnl under ga. the major limitation of their study was that postoperative analgesic requirements were not compared between groups.(3) karacalar and colleagues(4) compared the results of 90 patients who underwent pcnl under ga with 86 patients under csea in a prospective randomized study. they concluded that the csea group had greater patient satisfaction with less postoperative pain scores and with less analgesic requireanesthesia in tubeless pcnl | gonen et al table 1. patient characteristics. variables group 1 (n = 26) group 2 (n = 20) p age (years) (range) 45.6 ± 13.6 (21-79) 40.8 ± 12.9 (18-64) .395 sex (male/female) 18/8 13/7 .414 stone size (mm²) (range) 558.6 ± 297.2 (250-1600) 630.7 ± 486.2 (250-2000) .227 stone side (right/left) 17/9 14/6 .771 1214 | ment (119.9 ± 63.5 mg intravenous tramadol in csea group and 262.5 ± 76.9 mg intravenous tramadol in ga group, p < .001). vomiting, itching, hypotension, and bradycardia were not different between the groups. the drawback of their study was hospitalization times that were not studied.(4) mehrabi and shirazi reported the results of sa in 160 patients undergoing standard pcnl, and they concluded that sa was a good alternative method for adult patients undergoing pcnl.(9) in their study they did not report major complications related to sa. the major drawback of their study is that it is not a controlled study.(9) recently, singh and colleagues(10) reported their experience with tubeless pcnl under sa on 10 patients. to best of our knowledge, their study is the only one in english literature and they concluded that sa plus tubeless pcnl synergism shortens length of hospitalization to an average of 40 hours without analgesic requirement.(10) the limitations of their study were that it was not a randomized controlled study, had strict inclusion criteria, and a small sample size.(10) recently, singh and colleagues(5) compared the standard pcnls under ga versus csea in a prospective randomized study. the study consisted of 32 patients in each group. and they found that the mean visual analog scale (vas) (4.63 ± 0.87 in csea and 6.56 ± 1.44 in ga group, p < .0001) and analgesic use (100.0 ± 10.0 mg in csea and 158.6 ± 22.84 mg in ga, intravenous tramadol, p < .0001) was less in csea group. in this study length of hospitalization ( 4.0 ± 0.9 days in csea and 4.56 ± 1.0 days in ga, p = .02) was also significantly less in csea group.(5) lojanapiwat and colleagues(6) reported the results of standard pcnls under csea and ga in a randomized prospective study. mean vas at the first post-operative hour was 3.12 in csea group and 6.88 in ga group (p < .001). they concluded that, in csea group patients required fewer analgesics. the major limitation of their study was that mean amounts of analgesic requirements were not clearly given. in the study of lojanapiwat and colleagues(6) hospitalization times between groups were not stastically different (5.04 ± 1.85 days in csea group and 5.46 ± 2.08 days in ga group, p = .456). limitations of the present study are the small patient number and it is not prospective. however, this is perhaps the first study in english literature which compares the tubeless pcnl under sa versus tubeless pcnl under ga. our results showed that sa did not influence hospitalization time in patients underwent tubeless pcnl (1.04 ± 0.2 vs. 1.06 ± 0.2 days, p = .678). however, patients in sa group required less analgesics than patients in ga group, with a mean of 53.8 ± 39.8 mg intravenous tramadol. this amount is nearly the lowest analgesic requirement in english literature for patients undergoing pcnl under regional anesthesia.(3-6) conclusion our limited experience demonstrated that the combined use of tubeless technique and sa in adult patients undergoing endourology and stone disease table 2. outcomes variables in both study groups. variables group 1 (n = 26) group 2 (n = 20) p duration of operation (minutes)(range) 72.4 ± 22.2 (30-130) 81.9 ± 40.3 (35-160) .109 access number (range) 1.4 (1-5) 1.6 (1-4) .452 presence of supracostal access (%) 6 (23.07) 4 (20.0) .909 bleeding requiring transfusion (%) 1 (3.8) 1 (5.0) .792 length of hospitalization (days) (range) 1.04 ± 0.2 (1-2) 1.06 ± 0.2 (1-2) .678 mean analgesic requirement (tramadol iv) (mg) (range) 53.8 ± 39.8 (0-200) 111.5 ± 46.3 (50-200) < .001 stone-free rate (%) 25/26 (96.2) 19/20 (95.0) .892 1215vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l references 1. tiselius hg, alken p, buck j, et al. guideline on urolithiasis. eur urol. 2001;40:362-71. 2. bellman gc, davidoff r, candela j, gerspach j, kurtz s, stout l. tubeless percutaneous renal surgery. j urol. 1997:157:1578-1582. 3. kuzgunbay b, turunc t, akin s, ergenoglu p, aribogan a, ozkardes h. percutaneous nephrolithotomy under general versus combined spinal-epidural anesthesia. j endourol. 2009;23:1835-8. 4. karacalar s, bilen cy, sarihasan b, sarikaya s. spinal-epidural anesthesia versus general anesthesia in the management of percutaneous nephrolithotomy. j endourol. 2009;23:1591-7. 5. singh v, sinha rj, sankhwar sn, malik a. a prospective randomized study comparing percutaneous nephrolithotomy under combined spinal-epidural anesthesia with percutaneous nephrolithotomy under general anesthesia. urol int. 2011;87:293-8. 6. lojanapiwat b, nisoog c, tangpaitoon t. efficacy and safety of percutaneous nephrolithotomy (pcnl): a prospective and randomized study comparing regional epidural anesthesia with general anesthesia. int braz j urol. 2012;38:504511. 7. shen p, liu y, wang j. nephrostomy tube-free versus nephrostomy tube for renal drainage after percutaneous nephrolithotomy: a systematic review and meta-analysis. urol int. 2012;88:298-306. 8. zhong q, zheng c, mo j, piao y, zhou y, jiang q. tubeless versus standard percutaneous nephrolithotomy: a metaanalysis. bju int. 2012;109:918-924. 9. mehrabi s, karimzadeh shirazi k. results and complications of spinal anesthesia in percutaneous nephrolithotomy. urol j. 2010;7:22-5. 10. singh i, kumar a, kumar p. “ambulatory pcnl” (tubeless pcnl under regional anesthesia) a preliminary report of 10 cases. int urol nephrol. 2005;37:35-7. pcnl decreases analgesic requirement. conflict of interest none declared. anesthesia in tubeless pcnl | gonen et al 988 | unwanted intra-operative penile erection during pediatric hypospadiasis repair comparison of propofol and halothane hamid reza abbasi,1 seyed soheil ben razavi,2 mohammad reza hajiesmaeili,3 shekoufeh behdad,1 mohammad mehdi ghiamat,4 ahmad eghbali5 purpose: to compare the erectile effect of propofol and halothane on unwanted intraoperative penile erection (uiope) during pediatric hypospadiasis repair. materials and methods: one hundred and seventeen boys who were in the age range of 6 months to 6 years and referred for hypospadiasis repair to our referral teaching hospital were included in this randomized clinical trial. patients were randomly assigned to one of the two study groups before anesthesia induction. anesthesia was maintained with a continuous intravenous infusion of propofol and inhalational halothane in the propofol (p) and halothane (h) groups, respectively. data regarding the patients’ age, weight, preand intra-operative chordee, uiope, anesthesia time, surgery time, hematoma formation, and wound infection were collected. the chi-square and fisher’s exact tests were used for comparison. results: no statistically significant differences were noted regarding age, weight, and pre and intra-operative chordee between the two groups. the incidence of uiope (10.34% versus 57.63%; p = .000), anesthesia time (174.15 ± 15.02 versus 181.26 ± 15.19; p = .012), and surgery time (162.34 ± 12.99 versus 167.69 ± 13.90; p = .034) were significantly lower in group p compared with group h. conclusion: the use of propofol during hypospadiasis surgical repair is more safe and effective than halothane in preventing uiope and reducing surgery and anesthesia time. keywords: anesthesia, propofol, halothane, child, penile erection corresponding author: mohammad reza hajiesmaeili, md department of anesthesiology and critical care medicine, parsian hospital, school of medicine, tehran university of medical sciences, tehran, iran tel: 02164352326 fax: 02164352326 e-mail: mr-hajiesmaeili@razi.tums.ac.ir 1department of anesthesiology, shahid sadoughi hospital, school of medicine, shahid sadoughi university of medical sciences, yazd, iran 2department of pediatric surgery, shahid sadoughi hospital, school of medicine, shahid sadoughi university of medical sciences, yazd, iran 3department of anesthesiology and critical care medicine, parsian hospital, school of medicine, tehran university of medical sciences, tehran, iran 4department of anesthesiology, loghman hospital, school of medicine, shahid beheshti university of medical sciences, tehran, iran 5department of anesthesiology, mofid hospital, school of medicine, shahid beheshti university of medical sciences, tehran, iran pediatric urology pediatric urology 989vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l introduction hypospadiasis repair is a relatively common pedi-atric urological procedure. in which, correction of the chordee is an important step.(1) if chordee is not diagnosed by history taking and physical exam in the pre-operative visit, drug-induced artificial erection or via saline injection into the corpora cavernosa is done at the beginning of surgical repair.(1) thereafter, any erection during surgery is unwanted and very troublesome to perform the procedure.(2,3) unwanted intra-operative penile erection (uiope) is mostly idiopathic; however, it may be caused by anesthesia.(2,3) penile engorgement can occur because of blood pooling and vascular resistance changes during general or neuroaxial anesthesia.(4,5) although the effects of anesthetic medications and methods have been widely studied on the female genitalia, especially on the uterine blood flow, its specific effects on the male genitalia and uiope have not been completely discussed.(6) to the best of our knowledge, only two studies have reported penile erection during remifentanil anesthesia in children(7) and uiope and its management.(3) due to different mechanisms of anesthetic drugs and methods, it seems that these drugs have different effects on uiope. general anesthesia with volatile or total intravenous anesthesia (tiva) has been commonly used for hypospadiasis surgery. in our current clinical practice, we used propofol or halothane for the maintenance of pediatric anesthesia. this clinical trial was designed to compare the erectile effects of propofol and halothane during pediatric hypospadiasis repair. materials and methods patients and study design one hundred and seventeen boys in the age range of 6 months to 6 years, who had referred for surgical hypospadiasis repair and had american society of anesthesiologist (asa) physical status class i, were enrolled in this randomized clinical trial. prior to the study, the approval of the university’s ethics committee and the institutional review board of the tertiary referral teaching hospital, shahid sadoughi university of medical sciences, yazd, iran, was obtained. patients with airway abnormalities and adverse reactions to the study drugs were excluded. the study was designed as a randomized, investigator-blinded study. only the anesthesiologist was aware of the study groups. all medications were administered by the attending pediatric anesthesiologist, who was familiar with the medications and the protocol. anesthesia and study drugs from march 2006 to january 2009, all patients received a standardized anesthetic protocol with fentanyl 2 µg/kg iv and midazolam 0.05 mg/kg for premedication. after preoxygenation by face mask and o2 100%, anesthesia was induced with thiopental 4 mg/kg and atracurium 0.5 mg/kg. tracheal intubation was performed after 3 minutes. the patients were randomly assigned to one of the two study groups using a sealed envelope technique before anesthesia induction. anesthesia was maintained with a continuous intravenous infusion of propofol 100 μg/kg/min and inhalational 0.5 to 1 mac halothane in the propofol (p) and halothane (h) groups, respectively. both groups received nitrous oxide (n2o) 50% + o2 50% during the maintenance of anesthesia. intravenous ringer was the standard fluid management for intra-operative fluid maintenance and the replacement of fluid deficits in patients with insufficient oral fluid intake. the following drugs were used in the study: thiopental (sandoz gmbh, kundl, austria), propofol emulsion (fresenius kabi austria gmbh, austria), fentanyl, midazolam, and atracurium (glaxo wellcome s.p.a parma, italy). monitoring was done using standard anesthesia monitors. in the pre-operative visit, chordee was diagnosed by manual compression in the perineum and penile shaft. after the induction of anesthesia and before the beginning of anesthesia maintenance, classic artificial erection was induced by injecting saline into the corpora cavernosa. unwanted intra-operative penile erection, which was defined as increase in size without hardness (grade 1 of the erectile hardness grading scale [ehgs]) during urethral reconstruction was recorded by the surgeon (9). all surgical procedures were performed by an attending pediatric surgeon. finally, halothane and propofol were discontinued and the effect of atracurium was reversed by the administration of neostigmine 60 μg/kg and atropine 20 μg/kg. data regarding the patients’ age, weight, preand intra-operunwanted intra-operative penile erection | abbasi et al 990 | ative chordee, uiope, anesthesia time (time from induction of anesthesia to endotracheal extubation), surgery time (time from beginning of surgery to the end of bleeding control), hematoma formation, and wound infection were recorded by the pediatric surgeon. statistical analysis the sample size for each group was calculated to be 57 (power = 90%, type 1 error = 5%, and significant difference = 25% for uiope). chi-square and fisher’s exact tests were used to analyze data related to occurrence and frequency of preand intra-operative chordee and uiope during surgery in both groups. p values less than .05 were considered statistically significant. continuous data, including age, weight, anesthesia time, and surgery time were analyzed using independent sample fisher’s exact t test, and expressed as mean ± standard deviation. all statistical analyses were done by spss software (the statistical package for the social sciences, version 16.0, spss inc, chicago, illinois, usa). results of 117 patients, 58 (50.43%) were assigned to group p and 59 (49.57%) to group h. the patients’ characteristics (table 1) and their intraand postoperative data (table 2) were compared. the patients’ characteristics and preand intra-operative chordee of both groups were well-matched. the type of hypospadiasis and kind of operation were similar in the studied groups (table 1). six patients in group p and 34 in group h had uiope during surgery (10.34% versus 57.63%, p = .000). anesthesia (174.15 ± 15.02 versus 181.26 ± 15.19, p = .012) and surgery (162.34 ± 12.99 versus 167.69 ± 13.90, p = .034) times were significantly lower in group p compared with group h (table 2). if the patients were divided in two groups according to the incidence of uiope, the differences between surgery and anesthesia times would be statistically significant (p = .000 and p = .000, respectively). the risk difference between the two groups and the number needed to treat (nnt) were 47.29% and 2.11, respectively. hematoma formation and wound infection were not found in the patients of the two groups. discussion unwanted intra-operative penile erection during penile surgery is a challenge for the surgeon. penile engorgement and concurrent complications, such as excessive bleeding and surgical trauma leading to delayed surgery, complicate penile surgery.(2,3) we found that general anesthesia with propofol infusion may be more effective in decreasing the incidence of uiope, anesthesia time, and surgery time during hypospadiasis repair as well as postoperative nausea and vomiting compared with halothane. based on the nnt (2.11) and number needed to harm (0) in uiope, this study shows that the use of propofol during hypospadiasis surgical repair can be more safe than volatile anesthetics. studies on the effects of halothane on the female genitalia, especially on the uterine blood flow, show that halothane can increase uterine blood flow and bleeding during surgical procedures, such as cesarean section. thus, it has been recommended to decrease halothane concentration after delivery.(6) during anesthesia, the autonomic nervous system is depressed. therefore, sympathetically-mediated vasoconstriction may subside and vascular engorgement may occur requiring deeper levels of anesthesia to prevent uiope. volatile anesthetics increase uterine,(6) nasal sinuses,(4,5) and cerebral blood flows.(8) penile blood flow is probably increased by changing penile vascular resistance with or without decreasing outflow drainage and increasing penile blood pediatric urology table 1. comparison of patients’ characteristics between the studied groups. variables group p (n = 58) group h (n = 59) p age (mean ± sd), mo weight (mean ± sd), kg pre-operative chordee, n (%) intra-operative chordee, n (%) type of hypospadiasis (operation) distal third (mathieu) glandular (magpi) coronal (magpi) mid shaft (snod gross) proximal type (snod gross or tip) redo operation (snod gross or tip) 37.90 ± 21.78 18.85 ± 7.63 40 (68.97%) 41 (70.69%) 7 4 3 5 4 35 37.05 ± 21.88 18.09 ± 7.00 39 (66.10%) 42 (71.19%) 7 4 4 5 3 36 .834 .575 .740 .952 .973 .980 .714 .977 .680 .941 sd indicates standard deviation; magpi, meatal advancement with glandoplasty and increment; and tip, transverse incised plate. 991vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l unwanted intra-operative penile erection | abbasi et al volume; hence, penile engorgement and uiope could occur. in an anesthetized patient, effect of tactile stimulation could suppress, except in early stages and light anesthesia. neuroaxial and general anesthesia with volatile agent or tiva may induce vasodilatation and pooling of blood in the venous sinuses of the penis. therefore, penile engorgement during anesthesia is not uncommon.(2,3) inhalational anesthetics, such as halothane, are widely used in pediatric patients. various volatile anesthetics have different effects on the circulation of different organs. their effects on the uterine,(6) cardiovascular,(9,10) nasal sinuses,(4,5) and brain(8) circulation have been studied. halothane decreases vascular resistance in the uterus leading to increased uterine blood flow and blood volume.(6) the vasodilatation induced by anesthetics in the heart and brain is mediated by oxygen free radicals participation,(11) edrf/cgmp-mediated vascular smooth muscle relaxation,(12) potassium channel blockade,(10) and adenosine triphosphate–sensitive. the main methods to prevent uiope include use of deeper levels of anesthesia with a simultaneous induction of hypotension by sodium nitroprusside, dorsal nerve block paralysis, corporeal aspiration with or without shunting procedures, and ketamine, phenylephrine, epinephrine, amylnitrate, terbutaline, noradrenaline, metaraminol, and epinephrine administration.(13-15) several studies have suggested that propofol reduces the incidence of postoperative nausea and vomiting and results in shorter emergence times.(15,16) currently, propofol tiva is more expensive than anesthesia with inhalational halothane and n2o. considering the costs of treating postoperative nausea and vomiting and the costs of increased recovery room stay after inhalational anesthesia, tiva could be cost-effective.(16,17) considering a reduction in anesthesia time, surgery time, complication of surgery, and probably, bleeding, use of propofol can cover its higher cost in comparison with inhalational anesthesia. we did not observe any of the above-mentioned complications during the surgery. however, this could be because of the small volume of bleeding. therefore, this variable was not measured because. conclusion according to our findings, the use of propofol during hypospadiasis surgical repair is more safe and effective than halothane in preventing uiope and reducing surgery and anesthesia time. however, further studies are suggested to compare the effects of other anesthetic drugs and methods to find the safest one. conflict of interest none declared. acknowledgements the authors would like to thank z.h. khan, md, professor of anesthesiology, department of anesthesiology, school of medicine, tehran university of medical sciences, tehran, iran. references 1. kogan ba. intraoperative pharmacological erection as an aid to pediatric hypospadias repair. j urol. 2000 ;164:2058-61. 2. baltogiannis dm, charalabopoulos ak, giannakopoulos xk, giannakis dj, sofikitis nv, charalabopoulos ka. penile erection during transurethral surgery. j androl. 2006;27:376-80. 3. rao th, zaman w, jain rk. intraoperative penile erection. arch esp urol. 2000;53:953-6. 4. beule ag, wilhelmi f, kuhnel ts, hansen e, lackner kj, hosemann w. propofol versus sevoflurane: bleeding in endoscopic sinus surgery. otolaryngol head neck surg. 2007;136:45-50. 5. sivaci r, yilmaz md, balci c, erincler t, unlu h. comparison of propofol and sevoflurane anesthesia by means of blood loss during endoscopic sinus surgery. saudi med j. 2004 ;25:1995-8. table 2. comparison of propofol and halothane during hypospadiasis surgery. group p (n = 58) group h (n = 59) p uiope, n (%) surgery time (mean ± sd), min anesthesia time (mean ± sd), min hematoma formation, n wound infection, n 6 (10.34%) 162.34 ± 12.99 174.15 ± 15.02 0 0 34 (57.63%) 167.69 ± 13.90 181.26 ± 15.19 0 0 .000 .034 .012 ns ns uiope indicates unwanted intra-operative penile erection; sd, standard deviation; and ns, not significant. 992 | 6. birnbach d, browne i. anesthesia for obstetrics. in: miller r, eriksson llf, editors. miller’s anesthesia. 7th ed: churchill livingstone elsevier; 2010. p. 2203-41. 7. bakan m, elicevik m, bozkurt p, kaya g. penile erection during remifentanil anesthesia in children. paediatr anaesth. 2006 ;16:1294-5. 8. monkhoff m, schwarz u, gerber a, fanconi s, banziger o. the effects of sevoflurane and halothane anesthesia on cerebral blood flow velocity in children. anesth analg. 2001 ;92:891-6. 9. cason ba, shubayev i, hickey rf. blockade of adenosine triphosphate-sensitive potassium channels eliminates isoflurane-induced coronary artery vasodilation. anesthesiology. 1994 ;81:1245-55; discussion 27a-28a. 10. larach dr, schuler hg. potassium channel blockade and halothane vasodilation in conducting and resistance coronary arteries. j pharmacol exp ther. 1993;267:72-81. 11. yoshida k, okabe e. selective impairment of endothelium-dependent relaxation by sevoflurane: oxygen free radicals participation. anesthesiology. 1992;76:440-7. 12. hart jl, jing m, bina s, freas w, van dyke ra, muldoon sm. effects of halothane on edrf/cgmp-mediated vascular smooth muscle relaxations. anesthesiology. 1993 ;79:323-31. 13. pertek jp, coissard a, artis m. [management of intraoperative erection by penile block]. ann fr anesth reanim. 1995;14:352-5. 14. staerman f, nouri m, coeurdacier p, cipolla b, guille f, lobel b. treatment of the intraoperative penile erection with intracavernous phenylephrine. j urol. 1995;153:1478-81. 15. sundien e, kolmert t. ephedrine: a possible alternative for treatment of penile erection in connection with transurethral resection of prostatic or bladder tumors. j urol. 1987;138:411. 17. sneyd jr, carr a, byrom wd, bilski aj. a meta-analysis of nausea and vomiting following maintenance of anaesthesia with propofol or inhalational agents. eur j anaesthesiol. 1998;15:433-45. 17. visser k, hassink ea, bonsel gj, moen j, kalkman cj. randomized controlled trial of total intravenous anesthesia with propofol versus inhalation anesthesia with isoflurane-nitrous oxide: postoperative nausea with vomiting and economic analysis. anesthesiology. 2001;95:616-26. pediatric urology u j spring 2012.pdf 456 | pictorial urology endourology and stone services, barts and the london nhs trust, london, uk *e-mail: junaido@aol.com a -went an abdominal computed tomography showing atresia of the infra-hepatic segment of the inferior vena cava malformations are thought to occur embryologically or secondary to a thrombotic event, and are present in 0.3% to 0.5% of healthy individuals, but are often associated with severe congenital heart diseases, asplenia, or polysplenia syndromes. there remains some controversy over whether an absent or partially absent ivc is a true embryonic anomaly or occurs as a result of peri-natal ivc thrombosis. the ivc has a complex embryogenesis, but is fundamentally formed from the anastomoses of three parallel longitudinal paired embryonic veins; posterior cardinal, subcardinal, and supracardinal veins. pelvic varicosities occur where there is hemodynamic disruption in the ivc, iliac, or left renal veins. in pelvic varicosities. bladder varices are a rare, but important cause of hematuria and should be considered in the differential diagnoses of an otherwise asymptomatic patient presenting in this way. chandran tanabalan , athanasios g papatsoris, junaid masood* absent inferior vena cava with resulting bladder varices a rare cause of frank hematuria references 1. kondo y, koizumi j, nishibe m, muto a, dardik a, nishibe t. deep venous thrombosis caused 2. bass je, redwine md, kramer la, huynh pt, harris jh, jr. spectrum of congenital anomalies of 3. ramanathan t, hughes tm, richardson aj. perinatal inferior vena cava thrombosis and abpictorial urology review 1urology journal vol 7 no 1 winter 2010 current management of advanced and metastatic renal cell carcinoma m hammad ather,1 nehal masood,2 tahmeena siddiqui3 introduction: unresectable renal cell carcinoma (rcc) is a technically incurable condition. historically, rcc is resistant to chemotherapy and radiotherapy. cytokine therapy was until recently considered the mainstay of treatment. however, responses are modest. improvement in the understanding of the biology of rcc, particularly the hereditary types, is providing the basis for novel therapeutic targets. our aim was to review the clinical utility of various systemic agents and surgery in the management of advanced rcc and suggest practice guidelines in the light of current literature. materials and methods: evidence was collected by review of current literature, guidelines of the american and european associations and the national comprehensive cancer network. results: treatment of advanced rcc has recently undergone a major change with the development of targeted agents and potent angiogenesis inhibitors. small-molecule multikinase inhibitors that target vascular endothelial growth factor receptors have a favorable toxicity profile and can prolong time to progression and preserve quality of life when used in newly diagnosed or previously treated patients; bevacizumab enhances the response rate and prolongs disease control when added to interferon-α. temsirolimus, a mammalian target of rapamycin inhibitor, prolongs the survival duration of patients with poor-risk disease. all currently available agents have variable toxicity profile and they, at best, improve survival by a few months. surgery still has a significant role in the management of stage iv rcc. conclusion: supportive care and surgery remain the mainstay of treatment even in the management of advanced and metastatic rcc. systemic therapeutic agents are showing promising results. urol j. 2010;7:1-9. www.uj.unrc.ir keywords: renal cell carcinoma, neoplasm metastasis, cytokines, vascular endothelial growth factor receptors 1department of surgery, aga khan university, karachi, pakistan 2department of medicine, aga khan university, karachi, pakistan 3department of biochemistry, karachi university, karachi, pakistan corresponding author: m hammad ather, fcps (urol), febu department of surgery, po box: 3500 stadium road, karachi 74800 fax: +92 21 493 4294/2095 tel: +92 21 486 4778 e-mail: hammad.ather@aku.edu introduction the current estimate of renal cancer incidence is about 200 000 cases, making it the 3rd most common urogenital cancer worldwide.(1) in the united states, an estimated 51 190 patients were diagnosed with renal cell carcinoma (rcc) in 2007, and 12 890 would die of the disease. (1) renal cell carcinoma comprises a histologically diverse group of solid tumors, together making up about 3% of all adult neoplasms. (1) about one-third of patients have metastatic disease at presentation, a median survival of 7 to 11 months, and a 5-year survival of 10%. its incidence has been increasing, a phenomenon for which wider use of imaging procedures alone cannot account.(2) renal cell carcinoma, if detected early, is potentially curable by advanced and metastatic renal cell carcinoma—ather et al 2 urology journal vol 7 no 1 winter 2010 surgery; however, about one-third present with metastases and one-third of organ-confined cancers treated by nephrectomy develop metastases during the follow-up.(3) if surgical extirpation alone for all tumor deposits is not possible, tumor nephrectomy remains a palliative therapy, considered for symptomatic control and as part of multimodality treatment (eg, in conjunction with immunotherapy or experimental therapies). metastatic rcc is a difficult disease to manage, as it is resistant to chemotherapy and radiotherapy. patients with metastatic disease have a median survival time of less than 12 months. however, survival can be quite variable, depending on several prognostic factors, including performance status; lactate dehydrogenase (ldh), hemoglobin, and calcium levels; and the absence of prior nephrectomy.(4) recent advances in immunotherapy protocols, development of targeted therapy with smallmolecule kinase signal transduction inhibitors, vascular endothelial antibodies, and combination treatment modalities have shown promising trends. rising incidence, improved imaging and other diagnostic procedures, and emerging role of multimodality therapeutic concepts justify the need for evidence-based guidelines for treatment of rcc. particularly, the challenging aspect is the management of locally advanced and metastatic rcc. in the current review, we have tried to define patient selection, efficacy, and safety of some of the newer agents in the light of best evidence in the current literature. pathogenic pathway renal cell carcinoma exists in 4 distinct histological subtypes. these include clear cell, papillary, chromophobe, and collecting duct tumors. the majority of cases (75%) are clear-cell rcc. these are characteristically associated with loss of function of the von hippel-lindau (vhl) gene. latif and associates(5) reported in a study of 221 vhl kindred a linkage analysis to identify the vhl gene on the short arm of chromosome 3p. the vhl gene product forms a complex with elongin c and b, which further binds to cul-2. this results in upregulation of the α-fragment of hypoxia inducible factor (hif) subunits, hif1 and hif-2.(6) the hif activation results in upregulation of hif target genes, such as vascular endothelial growth factor (vegf), transforming growth factor, hepatocyte growth factor receptor (met), stromal cell-derived factor-1, and others. (7) the hif plays an important role in rcc oncogenesis, but besides hif deregulation, there are many other mechanisms and hif alone is probably not sufficient to cause oncogenesis.(8) a different histological subtype of rcc, ie, papillary type, is not associated with vhl gene at 3p, but with met proto-oncogene at chromosome 7q31. the met gene encodes a cell membrane receptor specific for hepatocyte growth factor. studies have indicated that hepatocyte growth factor stimulation leads to mitogenesis, cellular migration, and morphogenesis.(9) prognostic indicators renal cell carcinoma is a heterogeneous disease that is recognized based on differences in morphology, genetic alterations, and clinical behavior. in view of variable biological behavior and poor results of most therapies for advanced and metastatic rcc, it is important to have a universally acceptable prognostic model. currently, some pathological factors are not covered by the tnm classification. the nonpathological factors such as performance status, thrombocytosis, and neutrophilia are also important. the predictors of short survival include serum ldh levels higher than 1.5 times upper limit of normal, low hemoglobin levels, corrected serum calcium levels higher than 10 mg/dl (2.5 mmol/l), a time interval of less than 1 year from original diagnosis to the start of systemic therapy, the karnofsky performance score of 70 or lower, and 2 or more sites of organ metastases.(10) angiogenesis is a critical step in the growth, invasive progression, and metastatic spread of solid tumors. recently, minardi and coworkers(11) assessed the importance of tumor necrosis, microvessel density, vascular endothelial growth factor (vegf), and hif-1α immunohistochemical expression in a large series of clear-cell rccs treated with radical nephrectomy and assessed the prognostic value of their expression in terms advanced and metastatic renal cell carcinoma—ather et al 3urology journal vol 7 no 1 winter 2010 of patient survival in long-term follow-up. they noted that tumor necrosis, microvascular invasion and renal capsular infiltration are more likely to occur in higher stages and grades of rcc; cytoplasmic hif-1α is highly expressed in highgrade rcc. survival is dependent upon tumor stage and grade, the presence of vascular invasion and capsular infiltration, and tumor necrosis. microvessel density also resulted as being an important prognostic factor. generally, vegf and hif-1α correlate with prognosis in highstage tumors and vegf is the most important independent prognostic factor for cancer-specific death. the histological and immunohistochemical parameters considered here can influence disease recurrence and survival in rcc. treatment role of surgery in management of advanced and metastatic renal cell carcinoma surgery has a significant role in the overall management of advanced rcc (figure). regional lymph node involvement on imaging may be reactive or hyperplastic only; therefore, surgical resection and pathological evaluation become important. in a recent report, margulis and coworkers(12) noted that true pathologic involvement of adjacent organs by rcc cannot be predicted from pre-operative or intraoperative parameters. a significant proportion of patients clinically suspected of having t4 rcc are downstaged and benefit from aggressive surgical resection with en bloc removal of the involved organs. moshrafa and associates(13) demonstrated that radical nephrectomy in the setting of metastatic rcc has a low morbidity and acceptable recovery in these patients with advanced primary tumors and poorer performance status. patients with primary renal tumor and isolated metastatic site or with isolated metastatic recurrence benefit from surgical extirpation.(14) complete resection of either synchronous or metachronous solitary metastases from rcc is justified and can contribute to a long-term survival in this selected group of patients. nephrectomy in patients with advanced rcc prior to the introduction of effective systemic therapy was a palliative procedure without significant improvement in overall survival. with the introduction of immunotherapy, and more recently, molecularly targeted therapy, nephrectomy has shown to improve survival when performed before interferon (ifn) therapy in a selected group of patients. there is, however, lack of high level of evidence as to whether to remove the primary tumor prior to the targeted therapy or following it up. the initiation of a phase 3 study should be considered to compare the survival of patients treated by nephrectomy plus targeted therapy with the survival of patients treated by targeted therapy alone, with nephrectomy reserved for clinical indications, in order to answer these questions. until evidence management algorithm of locally advanced and metastatic renal cancer (stage iv). *the national comprehensive cancer network practice guidelines for kidney cancer. 2008. available from: http://www.nccn.org advanced and metastatic renal cell carcinoma—ather et al 4 urology journal vol 7 no 1 winter 2010 from such a study becomes available to guide physicians, and without evidence to the contrary, cytoreductive nephrectomy should be considered, as it has shown a survival benefit, and should be used in appropriately selected patients with metastatic rcc receiving postsurgical systemic therapies.(15) the southwest oncology group trial on 8949 patients and the european organization for the research and treatment of cancer trial on 30 947 are two remarkable studies on the issue.(16-18) using an identical treatment protocol (designed by the former group), these trials provide the best information to date regarding the use of cytoreductive nephrectomy. both trials demonstrated significantly longer overall survival in the groups randomized to nephrectomy before immunotherapy, and this benefit persisted across all study stratifications, including performance status, site of metastasis, and measurable versus nonmeasurable disease. immunotherapy for metastatic renal cell carcinoma renal cell carcinoma evokes immune response that occasionally results in spontaneous tumor regression.(19) spontaneous regression of metastatic rcc is a rare but well-documented event, most often involving pulmonary metastases; however, its incidence is about 0.1%. (23) over the past several decades, in order to duplicate, an accentuated response of various immunomodulations have been attempted. these include specific and nonspecific stimulation of the immune system. most of these therapies have shown antitumor activity; however, the most consistent results have been observed only with interleukin-2 (il-2) and with ifn-α. these agents target various inherent immune defects in rcc. particularly important are the qualitative and quantitative defects in dendritic cell function in rcc,(20) which result in inherent immune deficiency and tumor progression. renal cell carcinoma also alters body’s antitumor immunity by altering the t-cell function in cytokine production by t helper cells.(21) interferon-α trials. interferon-α is a glycoprotein produced in response to viral infections and foreign antigens. the postulated mechanisms of action in rcc include immunomodulation, antiproliferative, and anti-angiogenic activities. interferon-α is produced by macrophages and lymphocytes and induces several biological effects including immunomodulation, antiproliferation, and enhanced expression of cell surface antigens. in phase 2 studies, recombinant ifnα is reported to induce response to treatment of rcc in up to 29% of cases.(22) in a randomized controlled trial by the medical research council renal cancer collaboration,(23) 335 patients were randomized into two groups to receive either ifn-α or medroxyprogesterone. in this intention-to-treat analysis, there was a significant advantage in overall survival for patients treated with ifn-α (p = .02). the median survival was 2.5 months more in this group. in another trial, 160 patients were randomized to receive a chemotherapeutic agent, vinblastine, or ifn-α versus vinblastine alone.(24) the authors noted a significant overall survival advantage of 7 months (p = .005) in the ifn-α arm. there was also a significant difference in the overall response rate (16.5% versus 2.4%; p = .003), complete response rate (8.9% versus 1.2%), and median time to disease progression (3 months versus 2 months; p < .001), all favoring ifn-α. coppin and colleagues(25) performed a meta-analysis of 53 randomized controlled trials with over 6000 patients treated over a decade between 1995 and 2004. they noted that compared to control patients, those who received ifn-α had a 3.8 months of median improvement in survival (p = .007). interestingly, ifn-α, in spite of being one of the most commonly used agents until recently and often adopted as the control arm in comparative trials with new drugs, has never been approved in the united states for treatment of rcc. interleukin-2 trials. interleukin-2, a glycoprotein, produced in response to infections, is important in identifying self and foreign antigens. the antitumor action of il-2 is not completely understood; however, it is postulated to have direct killing action by activated t cells and natural killer cells.(26) various modes of delivery for il-2, including intravenous and subcutaneous, have also been advanced and metastatic renal cell carcinoma—ather et al 5urology journal vol 7 no 1 winter 2010 studied, attempting to maximize efficacy and decrease the significant toxicities that can be associated with high-dose il-2 therapy. the importance of dose intensity of il-2 for patients with metastatic rcc was clarified in a national institutes of health trial that randomized patients to receive high-dose il-2 (156 patients) or a dose that was 10 times lower (150 patients). there was a significantly higher response rate with high-dose il-2 than with low-dose intravenous il-2 (21% versus 13%), but no overall survival difference, and a higher morbidity, as anticipated.(27) this was confirmed in a multi-institutional phase 3 trial involving 192 patients with metastatic rcc randomized to receive intravenous high-dose il-2 or subcutaneous low-dose il-2 plus ifn-α. the response rate was significantly greater in patients treated with high-dose il-2 (23.2% versus 9.9%). while there was no significant difference in overall survival (17 months versus 13 months), 7% of the patients were reported alive and disease free after 3 years of follow-up in the high-dose il-2 arm versus none in the control arm. as expected, there were more grade 3 and 4 toxicities in the high-dose il-2 arm, although treatment-related mortality was rare.(28) the authors concluded that high-dose il-2 was an acceptable therapy for patients with little or no comorbidities and excellent performance status, for whom the possibility of long-term complete response is worth the complexity, risk, and acute toxicity of the treatment. how to best sequence or combine il-2 with newer drugs is unknown. overall, in most reported series, toxicity is worse with il-2-based therapy than with nonil-2 therapy; however, most studies described il-2 regimens as moderately to well tolerated by most patients.(22) specific to il-2, hypotension, cardiac toxicity, diarrhea, and fatigue increased when compared with ifn-α or other treatment arms. none of the trials studied in the metaanalysis by hotte and colleagues(29) reported toxic deaths or quality-of-life changes. it is, however, important to understand that il-2-based regimens are associated with significant toxicity, and the magnitude of this toxicity may be underestimated in clinical trials because of patient selection factors. specialized centers have the expertise to manage and minimize the impact of these toxicities. in a meta-analysis of trials on il-2 versus nonil-2,(29) hotte and colleagues noted that the response rates were higher in patients receiving il-2-based regimens (range, 6.5% to 39%), compared with non-il-2 controls (zero to 20%). all 6 trials that they included in their analysis reported mortality data, and when the 6 trials were pooled in a meta-analysis, mortality at 1 year was not significantly different between il2-based regimens and non-il-2 regimens. hotte and colleagues(29) concluded that non-high-dose il-2 containing regimens do not provide superior treatment efficacy over non-il-2-based regimens, with added toxicity, and therefore, should not be used as standard treatment for patients with unresectable or metastatic rcc. rosenberg(30) showed that il-2 is the only systemic treatment currently available that is capable of curing patients with metastatic rcc, albeit in smaller number of patients with unmaintained complete response. multikinase inhibitors deregulation of hif is an important aspect of rcc development. thus, agents that affect hif target genes, especially those encoding vegf and vegf receptors, may be particularly useful. small-molecule kinase inhibitors that have more than one target (multikinase inhibitors) like sorafenib and sunitinib malate are being currently evaluated in many clinical trials. these agents have potent activities against specific kinases; however, the true biologic targets responsible for tumor regression are not precisely known. the ability of solid tumors to invade and develop metastasis depends on angiogenesis. targeted therapies, like multikinase inhibitors and antiangiogenic antibodies, reduce tumor vascularity and induce tumor necrosis before a change in tumor size or volume is observed.(31) standard response end points based on unidimensional and bidimensional measurements, such as the response evaluation criteria in solid tumors or the world health organization criteria, originally designed to evaluate cytotoxic drugs, do not accurately reflect changes in tumor volume, and therefore, often fail to accurately register advanced and metastatic renal cell carcinoma—ather et al 6 urology journal vol 7 no 1 winter 2010 responses to targeted agents, which are typically cytostatics.(32) imaging techniques that provide morphologic and functional perfusion data, such as doppler ultrasonography with contrast agent injection,(23) may be combined with standard criteria to better assess the efficacy of targeted agents. sunitinib. sunitinib malate is an orally administered inhibitor of a number of tyrosine kinases, including vegf receptor and the platelet-derived growth factor receptor,(33) which are known to play a significant role in the pathogenesis of rcc through their involvement with the vhl gene. a recently published phase 3 randomized trial(34) reported the superior efficacy of sunitinib malate over ifn for patients with locally advanced unresectable or metastatic rcc who had had no previous systemic therapy. these results were based on the pooled analysis of 2 phase 2 studies of sunitinib for patients who had undergone previous cytokine therapy and had a response rate of 42%.(35) in a phase 3 study,(36) using ifn as a control for advanced rcc, 750 patients with clear cell histology without prior systemic therapy were randomized to receive either sunitinib or ifn. none of the patients had complete response, partial responses were observed for 31% of patients treated with sunitinib and 6% of those treated with ifn. the median progressionfree survival was 11 months for patients in the sunitinib arm and 4 months for those in the ifn arm (hazards ratio, 0.42; 95% confidence interval, 0.33 to 0.52). all differences were highly significant. subgroup analyses suggested that patients with various risk factors seemed to have similar benefits with sunitinib. when divided into good-, intermediate-, or poor-risk categories according to the motzer criteria, patients in all the three categories that received sunitinib fared better than those who received ifn.(25) although few patients were categorized in the poor-risk group (23 patients in the sunitinib group and 25 in the ifn group), the trend was toward improvement in median progression-free survival (4 months versus 1 month, respectively; hazards ratio, 0.53; 95% confidence interval, 0.23 to 1.23). health-related quality of life measured in this study was better in the sunitinib group than in the ifn group (p < .001). the results of this large phase 3 trial convincingly demonstrated that sunitinib was significantly better than ifn for previously untreated patients with advanced rcc and should be considered the new standard of care for first-line treatment of this disease. diarrhea and fatigue were the most commonly reported treatment-related adverse events of sunitinib, and other adverse events included stomatitis, hand-foot syndrome (characterized by painful lesions on the palms and soles), and hypertension.(37) neutropenia was reported, but there were no reports of associated fever or sepsis. (35) elevated serum concentrations of lipase were not associated with clinical signs or symptoms of pancreatitis.(37) sorafenib. sorafenib is an orally administered multikinase inhibitor that targets raf kinase and receptor tyrosine kinases, including vegf receptor-2 and platelet-derived growth factor receptor-β.(36) sorafenib’s antitumor activity is by targeting the tumor or tumor endothelium to inhibit proliferation and angiogenesis.(38,39) in phase 2/3 trials, sorafenib significantly prolonged progression-free survival versus placebo and showed good tolerability in advanced rcc patients.(37) based on these phase 2/3 rcc trial findings, sorafenib was approved recently for the treatment of advanced rcc. sorafenib may be acting through inhibition of angiogenesis in rcc, but the precise mechanism of action by which sorafenib exerts its clinical effects, and the etiologic role of the raf/mek/erk pathway, is undergoing further investigation in this tumor type. in the treatment approaches in renal cancer global evaluation trial, 903 previously treated patients with metastatic clear-cell rcc of low or intermediate risk, according to the memorial sloan-kettering cancer center classification,(39) were randomized to receive sorafenib or placebo. the median progression-free survival times were 5.5 months in the sorafenib group and 2.8 months in the placebo group, and the objective response rates were 10% in the sorafenib arm and 2% in the placebo arm. although the difference in survival favoring sorafenib was not significant, it may have advanced and metastatic renal cell carcinoma—ather et al 7urology journal vol 7 no 1 winter 2010 been because of early crossover allowed shortly after an interim analysis showed a difference in progression-free survival. discontinuation of treatment because of side effects occurred in 10% of patients receiving sorafenib, and 13% required dose reductions because of toxicity. the most important side effects were diarrhea (43%), hypertension (17%), skin rash (40%), and handfoot syndrome (30%).(40) unlike the results for sunitinib, results for sorafenib do not justify its use as adjuvant in patients at high risk of recurrence following nephrectomy. potential patients should be referred to centers participating in such trials. anti-angiogenic therapy in metastatic renal cell carcinoma the majority of rccs have upregulation of the hif and the resultant upregulation of target gene vegf. bevacizumab is a humanized recombinant anti-vegf antibody that binds all types of vegf-a isoforms.(41) bevacizumab was tested in a phase 2 trial of 116 patients with metastatic clear-cell rcc who were randomized to receive placebo or low-dose (3 mg/kg) or high-dose (10 mg/kg) bevacizumab, given every 2 weeks. there was a 10% objective partial response rate, which was confined to the high-dose arm. compared with placebo, there was also a significantly longer time to disease progression (4.8 months versus 2.5 months).(42) most recently, a phase 3 trial involving 641 patients with metastatic clear-cell rcc compared ifn-α combined with either bevacizumab or placebo. when compared with placebo, bevacizumab resulted in a significantly longer progression-free survival (10.2 months versus 5.4 months) and higher objective tumor response rate (30.6% versus 12.4%). in an interim analysis, there was no significant survival advantage. common toxicities seen in this and previous trials were hypertension, proteinuria, and a tendency to bleeding and thrombotic events.(43) conclusion the grade of recommendation for the abovementioned treatment option is listed in the table. surgery still plays a significant role in the management of advanced and metastatic rcc. in a selected group of patients, resection of the primary tumor along with complete resection of solitary or limited metastases can lead to long-term disease-free or relapse-free survival. nephrectomy before immunotherapy has been shown in phase 3 trials to result in a survival benefit in patients with good performance status and limited burden of disease, although the overall improvement in survival is modest. in patients with nonresectable disease or those with residual disease following maximal surgical extirpation, the systemic therapy with immunological agents and targeted therapy remain a viable option. recent reports have indicated encouraging results with these agents. sorafenib, sunitinib and temsirolimus have all been shown to significantly alter the natural history of advanced rcc, and many more agents are currently being evaluated. trials evaluating combinations of these agents are currently underway or planned, and the optimal sequence of use of these agents is also being evaluated. however, much more evidence is necessary before the utility of these novel inhibitors of angiogenesis is established in providing the ultimate clinical benefit to patients diagnosed with rcc. in a recently reported phase intervention grade of recommendation tumor nephrectomy + interferon-α* a metastasectomy (synchronous and metachronous)*† b radiotherapy b chemotherapy (5-fluorouracil) + immunotherapy b immunotherapy (control arm in trials, interferon-α + interleukin-2 for clear-cell histology) a tyrosine kinase inhibitors (sorafenib as 2nd line, sunitinib as 1st line*, temsirolimus 1st line‡) a grade of evidence in the management of metastatic renal cell carcinoma *good performance status. †surgically resectable, metastasectomy in patients with residual disease should be performed in patients with resectable lesion previously responding to immunotherapy. this option has been recommended for osseous and brain lesions. ‡poor-risk patients. advanced and metastatic renal cell carcinoma—ather et al 8 urology journal vol 7 no 1 winter 2010 3, randomized, double-blind, placebo-controlled trial by motzer and colleagues(44) the role of everolimus in patients with metastatic rcc was assessed. they noted that treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies. the available agents for advanced rcc are toxic but can prolong life for a couple of months. conflict of interest none declared. references 1. jemal a, siegel r, ward e, et al. cancer statistics, 2008. ca cancer j clin. 2008;58:71-96. 2. eble jn. international agency for research on cancer. world health organization, editors. pathology and genetics of tumours of the urinary system and male. genital organs. lyon: iarc press; 2004. 3. janzen nk, kim hl, figlin ra, belldegrun as. surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. urol clin north am. 2003;30:843-52. 4. citterio g, bertuzzi a, tresoldi m, et al. prognostic factors for survival in metastatic renal cell carcinoma: retrospective analysis from 109 consecutive patients. eur urol. 1997;31(3):286-91. 5. latif f, tory k, gnarra j, et al. 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long term follow-up. int j immunopathol pharmacol. 2008;21:447-55. 12. margulis v, sanchez-ortiz rf, tamboli p, cohen dd, swanson da, wood cg. renal cell carcinoma clinically involving adjacent organs: experience with aggressive surgical management. cancer. 2007;109:2025-30. 13. mosharafa a, koch m, shalhav a, et al. nephrectomy for metastatic renal cell carcinoma: indiana university experience. urology. 2003;62:636-40. 14. thyavihally yb, mahantshetty u, chamarajanagar rs, raibhattanavar sg, tongaonkar hb. management of renal cell carcinoma with solitary metastasis. world j surg oncol. 2005;3:48. 15. pantuck aj, belldegrun as, figlin ra. cytoreductive nephrectomy for metastatic renal cell carcinoma: is it still imperative in the era of targeted therapy? clin cancer res. 2007;13:693s-6s. 16. flanigan rc, salmon se, blumenstein ba, et al. nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. n engl j med. 2001;345:1655-9. 17. mickisch gh, garin a, van poppel h, de prijck l, sylvester r. radical nephrectomy plus interferon-alfabased immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. lancet. 2001;358:966-70. 18. flanigan rc, mickisch g, sylvester r, tangen c, van poppel h, crawford ed. cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. j urol. 2004;171:1071-6. 19. snow rm, schellhammer pf. spontaneous regression of metastatic renal cell carcinoma. urology. 1982;20:177-81. 20. troy aj, summers kl, davidson pj, atkinson ch, hart dn. minimal recruitment and activation of dendritic cells within renal cell carcinoma. clin cancer res. 1998;4:585-93. 21. rayman p, wesa ak, richmond al, et al. effect of renal cell carcinomas on the development of type 1 t-cell responses. clin cancer res. 2004;10:6360s-6s. 22. quesada jr. role of interferons in the therapy of metastatic renal cell carcinoma. urology. 1989;34:803; discussion 7-96. 23. [no authorlisted]. interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. medical research council renal cancer collaborators. lancet. 1999;353:14-7. 24. pyrhonen s, salminen e, ruutu m, et al. prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. j clin oncol. 1999;17:2859-67. 25. coppin c, porzsolt f, awa a, kumpf j, coldman a, wilt t. immunotherapy for advanced renal cell cancer. cochrane database syst rev. 2005cd001425. 26. mule jj, yang jc, afreniere rl, shu sy, rosenberg sa. identification of cellular mechanisms operational in vivo during the regression of established pulmonary metastases by the systemic administration of high-dose recombinant interleukin 2. j immunol. 1987;139:285-94. 27. yang jc, sherry rm, steinberg sm, et al. randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. j clin oncol. 2003;21:3127-32. advanced and metastatic renal cell carcinoma—ather et al 9urology journal vol 7 no 1 winter 2010 28. mcdermott df, regan mm, clark ji, et al. randomized phase iii trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. j clin oncol. 2005;23:133-41. 29. hotte s, waldron t, canil c, winquist e. interleukin-2 in the treatment of unresectable or metastatic renal cell cancer: a systematic review and practice guideline. can urol assoc j. 2007;1:27-38. 30. rosenberg sa. interleukin 2 for patients with renal cancer. nat clin pract oncol. 2007;4:497. 31. lassau n, lamuraglia m, leclere j, rouffiac v. [functional and early evaluation of treatments in oncology: interest of ultrasonographic contrast agents]. j radiol. 2004;85:704-12. 32. lamuraglia m, escudier b, chami l, et al. to predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced doppler ultrasound. eur j cancer. 2006;42:2472-9. 33. abrams tj, lee lb, murray lj, pryer nk, cherrington jm. su11248 inhibits kit and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. mol cancer ther. 2003;2:471-8. 34. motzer rj, hutson te, tomczak p, et al. sunitinib versus interferon alfa in metastatic renal-cell carcinoma. n engl j med. 2007;356:115-24. 35. motzer rj, rini bi, bukowski rm, et al. sunitinib in patients with metastatic renal cell carcinoma. jama. 2006;295:2516-24. 36. wilhelm sm, carter c, tang l, et al. bay 43-9006 exhibits broad spectrum oral antitumor activity and targets the raf/mek/erk pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. cancer res. 2004;64:7099-109. 37. escudier b, szczylik c, eisen t, et al. randomized phase iii trial of the raf kinase and vegfr inhibitor sorafenib (bay 43-9006) in patients with advanced renal cell carcinoma (rcc). j clin oncol. 2005;23:lba4510. 38. chang ys, adnane j, trail pa, et al. sorafenib (bay 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in rcc xenograft models. cancer chemother pharmacol. 2007;59:561-74. 39. motzer rj, bacik j, schwartz lh, et al. prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. j clin oncol. 2004;22:454-63. 40. escudier b, eisen t, stadler wm, et al. sorafenib in advanced clear-cell renal-cell carcinoma. n engl j med. 2007;356:125-34. 41. presta lg, chen h, o’connor sj, et al. humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. cancer res. 1997;57:4593-9. 42. yang jc, haworth l, sherry rm, et al. a randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. n engl j med. 2003;349:427-34. 43. escudier b, pluzanska a, koralewski p, et al. bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, doubleblind phase iii trial. lancet. 2007;370:2103-11. 44. motzer rj, escudier b, oudard s, et al. efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase iii trial. lancet. 2008;372:449-56. reconstructive surgery 111urology journal vol 5 no 2 spring 2008 transanal repair of rectourethral and rectovaginal fistulas ali razi, seyed reza yahyazadeh, mohammad ali sedighi gilani, seyed mohammad kazemeyni introduction: we evaluated the efficacy and safety of repair of the rectourethral and rectovaginal fistulas with transanal approach using the latzko technique. materials and methods: we repaired 8 fistulas with transanal approach. fistulas were rectourethral in 5 patients, and in the only woman of the series, they were rectovaginal and vesicovaginal. in 3 patients, the fistulas had been diagnosed following prostatectomy, urethral stricture repair, and colonic resection and radiotherapy due to rectosigmoid cancer in 3, 2, and 1 patients, respectively. complying with latzko technique, the fistula orifice was exposed and a fusiform incision was made with the orifice in its center. the mucosa lying between the incision and the orifice was excised in the direction of the incision to the orifice, leaving the fistula edges to meet. then, the edges were closed, followed by closure of the muscular layers above it. finally, the edges of the rectal mucosa were closed results: two patients had 2 fistulas and 4 had 1 fistula who were all managed by transanal approach. during a median follow-up period of 44 months, no serious complication was noted, except for recurrence of deep vein thrombosis in 1 patient with a positive history for this complication. hospitalization period was 1 to 7 days. conclusion: it seems that transanal repair is a simple and effective technique with minimal complication rate in the treatment of rectourethral fistulas. regardless of the etiology, this method can be used as the preferred therapeutic technique. further studies are necessary to confirm our findings. urol j. 2008;5:111-4. www.uj.unrc.ir keywords: rectal fistula, urethra, surgery, transanal approach department of urology, shariati hospital, tehran university of medical sciences, tehran, iran corresponding author: ali razi, md department of urology, shariati hospital, north karegar st, tehran, iran tel: +98 912 159 0209 fax: +98 21 8802 6010 e-mail: reza_mehr@yahoo.com received november 2007 accepted march 2008 introduction rectourethral and rectovaginal fistulas, connections between the gastrointestinal and genitourinary systems, are very unpleasant complications. patients present with recurrent urinary tract infections and passing mixed urine and stool in most of the cases. repair of these fistulas by perineal or abdominal methods is difficult and needs extensive dissections and interposition of the omentum, fatty tissue, or muscles. obviously, these difficult operations are accompanied by a high rate of complications and low success rate.(1,2) conversely, transanal repair is an easier approach with easier access, shorter operative time, and lower complication rate. however, it has not been reported very often in the literature.(3,4) the present study bears evidence to the feasibility and safety of the transanal technique of repair in transanal repair of rectourethral and rectovaginal fistulas—razi et al 112 urology journal vol 5 no 2 spring 2008 addition to its high success rate. our aim was to determine the efficacy, simplicity, and safety of latzko transanal approach for the treatment of rectovaginal and rectourethral fistulas. materials and methods between 1999 and 2006, we had 6 patients with 8 fistulas who were treated by latzko technique. the patients’ characteristics are listed in the table. patient 1 was referred to our center with colostomy and cystostomy. on urethroscopy and proctoscopy, 1 fistula was noted 1.5 cm in diameter 5 cm from the anal verge and another fistula, 2 cm above the first one, draining to the bulbar urethra and bladder trigone, respectively. patient 2 had cystostomy with apparent fecaluria. on rectal examination, a rectourethral fistula 1.5 cm in diameter was discovered in the anterior rectal wall, 4 cm from the anal verge. in patient 3, cystostomy and colostomy had been done. on urethroscopy, a huge fistula (3 cm in diameter) was noted in the floor of the prostatic fossa, which was also visible through proctoscopy, 6 cm from the anal verge. in patient 3, urethroscopy revealed a fistula at the proximal bulb (1.5 cm in diameter). it was 4 cm from the anal verge on proctoscopy. in patient 4, who was a woman, 1 fistula was seen in the bladder trigone on cystoscopy, draining into the vagina, and on proctoscopy, a rectovaginal fistula (2 cm in diameter) was evident, 5 cm from the anal verge. finally, in patient 6, a fistula, 2 cm in diameter, was seen, located 5 cm from the anal verge. two of the patients (patients 1 and 3) had been referred with colostomy, and for the remaining 4, we performed double-barrel colostomies 2 weeks before the reconstructive surgery. mechanical bowel preparation was employed with irrigation through the distal part of colostomy tube until the day of surgery. chemical bowel preparation was performed with 4 oral doses of erythromycin and metronidazole the day before the operation. all these patients were treated by latzko transanal technique.(4) the patient was placed in the exaggerated lithotomy position. afterwards, anal speculum was applied and the fistula orifice was exposed. around the tract, a fusiform incision was made with the orifice in its center (figure). the mucosa lying between the incision patient age, y sex fistula history 1 27 male 2 rectourethral fistulas at the floor of bulbar urethra tractor accident injury extensive pelvic fracture 2 7 male 1 rectourethral fistula to bulbar urethra failed operation for urethral stricture 3 66 male 1 rectourethral fistula to prostatic urethra prostatectomy 4 74 male 1 rectourethral fistula vigorous urethral dilatation 5 72 female 2 vesicovaginal and rectovaginal fistulas colectomy and adjuvant radiotherapy 6 70 male 1 rectourethral fistula prostatectomy characteristics of patients with fistulas repair of the rectourethral and rectovaginal fistulas by the latzko method. transanal repair of rectourethral and rectovaginal fistulas—razi et al urology journal vol 5 no 2 spring 2008 113 and the orifice was excised in the direction of the incision to the orifice, leaving the fistula edges to meet. the edges were closed by vicryl 3-0 sutures, followed by closure of the muscular layers above it. finally, the edges of the rectal mucosa were closed (figure). in patient 2, an appropriate speculum for his age was not accessible. therefore, a long nasal speculum was used that created a satisfactory exposure. the colostomies were closed in all of the patients 4 to 6 weeks after the operation. the patients were followed for a median of 44 months (11 to 94 months), and urinary and fecal continence, fecaluria, and pneumaturia were assessed regularly. continence was defined as the absence of any need to use sanitary pads or diapers. results all the fistulas were successfully repaired in all of the patients after a median follow-up period of 44 months (11 to 94 months). none of the patients reported any episodes of urinary leakage, fecaluria, or pneumaturia. anal continence was also preserved for all of the patients. the median hospitalization period was 3 days (range, 1 to 7 days). except for deep vein thrombosis, which occurred in the 4th patient who had a history of deep vein thrombosis too, no other major complication occurred. discussion rectourethral fistulas are not common, but occasionally occur during surgical interventions for the management of prostate diseases or urethral reconstructions. they do not usually heal spontaneously and often need surgical intervention. various techniques have been used for the treatment of this complication including abdominal, perineal, and sometimes, mixed approaches. few cases of transanal approaches (latzko technique) have been reported, the results of which are in accordance with ours.(3,4) hata and colleagues reported successful treatment of rectourethral fistula in a single case,(3) and noldus and coworkers repaired 7 fistulas of this kind in 6 patients.(4) they found transanal approach safe and effective. mason method has been suggested by some authors, while some have proposed a series of modifications to this method.(5,6) some authors believe that when the rectal end of the fistula is closed, there is no need to close its vesicourethral end.(1,7-9) this has been substantiated in our small series. garofalo and colleagues published their 20-year experience on rectal advancement flap and claimed a 100% success rate.(10) dreznik and associates also used rectal flap in 3 of their patients with satisfactory results.(11) visser and colleagues advocated transperineal method for the repair of rectourethral fistula. others have used methods that are more aggressive.(12,13) kraske method is one of the discussed methods, which follows 3 basic principles: complete separation of the urethra from the rectum, prevention from urethral injury, and sparing urinary and stool continence.(14) it is believed that these fistulas are complicated and very difficult to repair.(1) the major point is that the first attempt to repair these fistulas is the best and subsequent attempts are not usually successful. therefore, the first surgeon trying to repair must have the necessary expertise, should not incur further problems or complicate the situation, and should make the best decision on the treatment approach. al-ali and colleagues reported their 30-year experience using different methods and concluded that flap advancement method with anterior approach was the best choice.(8) in some reports, abdominoperineal approach with omentoplasty has been strongly emphasized.(9) in addition to all these treatment option, this small series of transanal method bears evidence to the simplicity and safety of this technique in addition to its high success rate. conclusion due to the high success rate, ease of the operation, and relatively low complication rates, we suggest that the patients with rectovaginal and rectourethral fistulas, irrelevant of the etiology (iatrogenic, traumatic, or malignancy) can be treated by transanal method as a primary procedure. other methods such as transabdominal and perineal approaches might be better for failed surgeries. in spite of the small transanal repair of rectourethral and rectovaginal fistulas—razi et al 114 urology journal vol 5 no 2 spring 2008 current series, the very low failure rate seems promising. conflict of interest none declared. references 1. bukowski tp, chakrabarty a, powell ij, frontera r, perlmutter ad, montie je. acquired rectourethral fistula: methods of repair. j urol. 1995;153:730-3. 2. angioli r, penalver m, muzii l, et al. guidelines of how to manage vesicovaginal fistula. crit rev oncol hematol. 2003;48:295-304. 3. hata f, yasoshima t, kitagawa s, et al. transanal repair of rectourethral fistula after a radical retropubic prostatectomy: report of a case. surg today. 2002;32:170-3. 4. noldus j, fernandez s, huland h. rectourinary fistula repair using the latzko technique. j urol. 1999;161:1518-20. 5. culp os, calhoon hw. a variety of rectourethral fistula. experiences with 20 cases. j urol. 1964;91:560–571. 6. renschler td, middleton rg. 30 years of experience with york-mason repair of recto-urinary fistulas. j urol. 2003;170:1222-5. 7. cherr gs, hall c, pineau bc, waters gs. rectourethral fistula and massive rectal bleeding from iodine-125 prostate brachytherapy: a case report. am surg. 2001;67:131-4. 8. al-ali m, kashmoula d, saoud ij. experience with 30 posttraumatic rectourethral fistulas: presentation of posterior transsphincteric anterior rectal wall advancement. j urol. 1997;158:421-4. 9. trippitelli a, barbagli g, lenzi r, fiorelli c, masini gc. surgical treatment of rectourethral fistulae. eur urol. 1985;11:388-91. 10. garofalo te, delaney cp, jones sm, remzi fh, fazio vw. rectal advancement flap repair of rectourethral fistula: a 20-year experience. dis colon rectum. 2003;46:762-9. 11. dreznik z, alper d, vishne th, ramadan e. rectal flap advancement--a simple and effective approach for the treatment of rectourethral fistula. colorectal dis. 2003;5:53-5. 12. visser bc, mcaninch jw, welton ml. rectourethral fistulae: the perineal approach. j am coll surg. 2002;195:138-43. 13. tiptaft rc, motson rw, costello aj, paris am, blandy jp. fistulae involving rectum and urethra: the place of parks’s operations. br j urol. 1983;55:711-5. 14. wiseman ne, decter a. the kraske approach to the repair of recurrent rectourethral fistula. j pediatr surg. 1982;17:342-6. 1258 | efficacy and safety of potassium–titanyl-phosphate laser vaporization for clinically non-muscle invasive bladder cancer dongrong yang, boxin xue, yachen zang, xiaolong liu, jin zhu, yibin zhou, yuxi shan purpose: although transurethral resection of the bladder tumor (turbt) is still regarded as the gold standard for the treatment of clinical non-muscle invasive bladder cancer, alternative surgical options remain investigating. our aim was to evaluate the efficacy and safety of potassium– titanyl-phosphate (ktp) laser for the treatment of primary, clinically non-muscle invasive bladder cancer compared with standard transurethral resection of bladder tumor. materials and methods: the data of primary non-muscle invasive bladder cancer patients treated by either ktp laser vaporization (pvb group) or turbt were analyzed retrospectively. the preoperative conditions and intraoperative complications such as obturator nerve reflex and bladder perforation and postoperative characteristics such as catheterization time and tumor recurrence were compared. results: the patients’ demographics and tumor characteristics in the two groups were comparable. pvb was superior to turbt in terms of intraoperative complications such as obturator nerve reflex (p = .0289), postoperative bladder irrigation (p = .038) and postoperative catheterization time (p < .0001). recurrence rate after pvb was also lower than that after turbt. conclusion: our results indicated that pvb is a feasible, safe and effective alternative surgical approach for the management of primary, clinically non-muscle invasive bladder cancer, especially for those with lifetime oral taken anticoagulation medicine, with fewer perioperative complications and lower recurrence. keywords: urinary bladder neoplasms; laser therapy; neoplasm invasiveness; neoplasm recurrence; surgery. corresponding author: yuxi shan, md department of urology, the second affiliated hospital of soochow university, suzhou, 215004, china. tel: +86 512 6778 4136 fax: +86 512 6778 4136 e-mail: shanyx1002@aliyun.com received august 2012 accepted april 2013 department of urology, the second affiliated hospital of soochow university, suzhou, 215004, china. urological oncology urological oncology 1259vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l introduction bladder cancer is the most common cancer in geni-tourinary system. in usa, an estimated 73510 new cases of bladder cancer and 14,880 bladder cancer related deaths are expected to occur in 2012.(1) most newly diagnosed bladder cancers (75%) are non–muscle invasive bladder cancer (nmibc),(2) and can be treated by transurethral resection of the bladder tumor (turbt). but when the lesions were located in the lateral bladder wall or near ureter orifice and treated by turbt, complications, such as bleeding, bladder perforation and obturator nerve reflex (onr) even hydronephrosis would occur.(3) on the other hand, some bladder cancer patients are using coumarin derivatives and platelet aggregation inhibitors because of cardiac and cerebrovascular events, interruption of long-term anticoagulation in these patients creates a paradox situation in which competing risks of thrombosis and hemorrhage must be managed. therefore, alternative surgical options such as laser resection have advantages for the treatment of such cases. until now, holmium and thulium laser resection of bladder tumor are the most frequent used surgery for the treatment of nmibc and provide satisfactory outcomes.(4,5,6) however, whether it is suit for those with anticoagulation medicine is not reported. potassium-titanyl-phosphate (ktp) laser is 532 nm laser which was transformed from 1064 nm neodymium-doped yttrium aluminum garnet (nd:yag) laser by potassiumtitanylphosphate crystine. in 1995, malek and colleagues introduced the 80 w ktp laser for photoselective vaporization of prostate (pvp) and subsequently reported its results 5 years after surgery.(7,8) nowadays, this method has become an alternative choice for those who suffer from lower urinary tract symptoms (luts) secondary to benign prostatic hyperplasia and need surgical intervention,(9,10) especially pvp is more benefit for those with oral anticoagulation medications, because anticoagulation medications withdrawal would have posed a considerable risk for thromboembolic events.(11) however, the efficacy and safety of ktp laser used for the treatment of nmibc, especially when the lesion is located in the lateral wall of the bladder or near the ureter orifice, for those using oral anticoagulation medications, is still remain further investigation. in the present preliminary study, we evaluated the efficiency and safety of the ktp laser for bladder tumor resection via a continuous cystoscope for the treatment of nmibc, and we called it as photoselective vaporization of bladder cancer (pvb), and the results compared with conventional turbt in terms of intra-operative complications, postoperative characteristics and efficacy as determined by the tumor recurrence. materials and methods study population from august 2004 to december 2010, bladder cancer patients treated with either turbt or pvb at the author's institution were retrospectively analyzed. the inclusion criteria for this investigation must meet the following standards: primary, not the recurrent bladder cancer, the diameter of the tumor was less than 4 cm with no upper urinary tract tumor, the pathological result was non-muscle invasive bladder cancer with no carcinoma in situ (cis). the detail history of all patients has been obtained preoperatively. ultrasonography, intravenous urography, computerized tomography, and cystoscopy have been routinely performed to exclude upper urinary tract tumors, to determine the location, number, and volume of the tumor and to evaluate the clinical stage of tumor preoperatively. random bladder biopsies before the operation were obtained to diagnose pathological characterization of bladder cancer and to detect cis. in order to try to avoid missing high-grade tumor, we routinely biopsied at least three lesion in the bulking mass for pathological diagnosis. all patients chose the surgical strategy with written informed consent. and all the operations were performed by three expertise (y shan, d yang, and b xue) with standard procedure to get a comparable result. surgical procedure for the pvp group patients were under general or continuous epidural anesthesia and positioned in a routine lithotomic position. the equipment involved in the pvb procedure was described elsewhere.(9) continuous flow laser cystoscope was inserted into the bladder cavity via a video system and the bladder cavity was examined to verify the previous cystoscopic examination results. the laser fiber was inserted through the working channel of the continuous cystoscope. the power is set at 60 w – 80 w for laser vaporization and 50 1260 | urological oncology w – 60 w for laser coagulation. at the beginning of the surgical procedure, a circular coagulation blockage mark about 1.5 cm away from the tumor edge was made around the lesion. the resection procedure was somewhat different according to the characterization of the lesion. if the tumor was papillary with a long tip and a small volume, the tip was vaporized first to resect the body of the tumor. then the basement of the lesion was vaporized gradually until the underlying detrusor muscle layer was visible. if the tumor was sessile or had a bigger volume, the vaporization was begun from the surface of the lesion till the muscle layer was seen. during the procedure, three or four specimens from endoscopically “normal” appearing areas from the bottom and the margin of the tumor were biopsied via the working channel of the cystoscope for pathological examination to verify whether there was any tumor residual so as to determine the finally clinical stage of the cancer. after the exposure of deeper detrusor muscle, careful vaporization of the underlying muscle and surrounding mucosa that marked at the beginning of the operation was performed. then the floating tissues in the bladder cavity were retrieved by using an elik’s evacuator. after verifying the lack of perforation or hemorrhage, a catheter was inserted and indwelled as demand. the turbt was performed using an acmi 25.6 french (f) continuous flow resectoscope with loop electrode (richard wolf gmbh, knittlingen, germany) and a cutting and coagulation power set at 160 w and 80 w respectively. a traditional piece-by-piece resection to the muscle layer was performed.(4) three or four loci of the basement of the resection zone was biopsied as that was done in pvb group for pathological examination. the surrounded bladder mucosa about 1.5 cm away from the tumor base was also electrocauterized. after the operation, a catheter was inserted and indwelled as did in pvb group. postoperative followup the postoperative management included bladder irrigation when bleeding is obvious, and the urethral catheter was removed when the urine became clear. the intravesical instillation regimen was epirubicin, started within 24 hours after surgery for the first time, thereafter 40 mg weekly for 8 weeks, followed by monthly maintenance up to 1 year post-operatively. all the patients were followed up in the outpatient clinical at regular intervals. patients were required to do ultrasonography and cystoscopy every 3 months after the surgery, for which we adhere the 2011 guideline of the chinese urologic association for non-muscle invasive bladder cancer. the data regarding operation time, complication such as obturator nerve reflex, bladder perforation and catheterization time, the recurrences or recurrence location were recorded. statistical analysis continuous data were summarized using the mean ± sd and compared by non-parametric t test. categorical variables were compared using the chi-square test or fisher’s exact test. the statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0 was used for statistical analysis. p < .05 was considered as statistical significance. results from august 2004 to december 2010, a total of 287 patients were diagnosed as bladder cancer and treated either by turbt or by pvb at the author's institution. only 60 patients met study criteria and were enrolled in this investigation. the data of 60 patients and tumor characteristics in the pvp and turbt groups were comparable for sex, age, tumor multiplicity, tumor size and grade. p values regarding all listed variables were > .05 (table 1). but 6 patients with lifetime oral taken aspirin or warfarin because of cardiac and cerebrovascular problems were enrolled in the pvb group, and during the operation the medications did not discontinued. table 2 lists the intraand postoperative characteristics of pvb vs turbt. the number of lateral lesion in the pvb group and turbt group were 22 and 17, respectively. however no onr and bladder perforation occurred in the pvb group. on the contrary, 3 of 17 patients in the turbt group had onrs (0/22 vs. 3/17, p = .0289, fisher’s exact test), which have statistical significance. although of patients in turbt group, 2 had bladder perforation, but with no statistical significance (0/28 vs. 2/32, p = .18, chi-square test). the proportion of patients needed postoperative bladder irrigation in the pvb group was also lower than that in the turbt group (1/28 vs. 7/32, chi-square test, p = .038). the pvb group was associated with a shorter operative time 1261vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l laser vaporization for non-muscle invasive bladder cancer | shan et al and postoperative catheter drainage period as compared with turbt group (p < .0001, non-parametric t test). no blood transfusion were needed in both groups. all patients were followed for 20 to 64 months after surgery (the mean follow up were 38.5 months in turbt group and 38 months in pvb group). among patients involved in this study, an 83 years old patient with multiple lesions was recurred in new site 6 months after the pvb surgery and treated by pvb again. this patient had coronary artery stent with lifetime aspirin taken. no other recurrence was found in pvb group in the following period. but 3 cases had cancer recurrence in the turbt group, among which 2 recurrences were found at another site in the bladder wall and retreated by turbt. discussion the primary approach to the management of non–muscle invasive bladder cancer (nmibc) is turbt followed by intravesical therapy with either chemotherapeutic agents or bacillus calmette-guerin (bcg). currently, the european association of urology (eau), the first international consultation on bladder tumors (ficbt), the national comprehensive cancer network (nccn), and the american urological association (aua) guidelines still recommend turbt as the gold standard for the initial diagnosis and treatment of nmibc.(12) however, the intraand postoperative complication and the ultimate efficacy of turbt largely depend on the appropriate resection techniques, the experience of individual surgeons and the pathological characterization of nmibc.(3,4,13-15) for example, relatively shallow depth resection can cause an incomplete initial resection, such patient also need re-turbt,(13,16) on the other hand, deeper resection would lead to higher risk of bladder perforation and severe bleeding, especially when the lesion was located in the lateral bladder wall and was resected by turbt. in such cases, obturator nerve would ultimately be stimulated by the current flow, the obturator spasm and leg jerk would occur and bladder perforation sometimes occurred. when the lesion’s location was less than 2 cm away from the ureter orifice and were treated with turbt, ureteral stricture and scarring of the ureteral orifices could occurred and potentially lead to ureteral obstruction and hydronephrosis,(6) and in such situation, the lesion were often resected by open surgery. the use of lasers such as holmium:yag and thulium for treating bladder cancer especially non-invasive bladder cancer have been confirmed to be safe and minimally invasive and the success rate is at least as good as those of standard turbt.(4,5) but the holmium:yag laser was usually produced by pulse mode. during the surgical procedure, it is not so easy to control obviously bleeding because the fiber was easily to move away from the wanted location. the 80 w potassium–titanyl-phosphate (ktp) laser was first reported in 2003 in a pilot study for the treatment of bph with good outcome and minimal morbidity.(7) nowadays it was proved to be an efficacy and safety alternation for the treatment of benign prostatic hyperplasia (bph), especially for those patients on anticoagulation therapy, including aspirin, coumadin, and clopidogrel, that is not suitable for routine methods such as turp or tvp.(10) table 1. patient demographics and tumor characteristics.* variables pvb turbt sex, no 28 32 male 22 25 female 6 7 age, mean ± sd 45.3 ± 8.3 42.5 ± 9.2 tumor multiplicity single 22 24 multiple 6 8 tumor size, cm ≤ 3 24 26 3-4 4 6 location lateral 22 17 other 6 15 t stage ta 8 7 t1 20 25 grade 1 15 16 2 10 10 3 3 6 key: turbt, transurethral resection of the bladder tumor; pvp, ktp laser vaporization. *in the pvp and turbt groups, sex, age, tumor multiplicity, tumor size and grade were comparable, p > .05. 1262 | urological oncology in the author’s department, ktp laser was initially used for the treatment of bph in august 2004. we thought that ktp laser was produced by green light ktp laser system (laserscope) without any current flow going through the human body, if it was used for the treatment of nmibc that located in the lateral wall, might not occurred. in our pilot study when we first used it for the resection of the lateral bladder wall lesion, no onrs were observed. because of the laser beam has a forward deflection of 70° and a divergence angle of 15°, for those tumors located in special site such as in the dome that cannot so easily be resected by routine turbt technical, the pvb can performed successfully. thirdly, the unique 532 nm wavelength that the laser operates at is highly absorbed by hemoglobin and minimally absorbed by water, which limits the optical penetration depth of the ktp laser to 0.8 mm.(7,9) the heat remaining in the tissue induces a coagulation zone of only 1~2 mm thickness. so in pvb group, bladder perforation was not happened and serious bleeding needed bladder irrigation was not so common as compared with that in turbt group. these advantages made it more suitable for the treatment of the lesion located in the lateral bladder wall and near the ureter orifice to prevent onrs and potential hydronephrosis secondly to ureteral stricture which can be caused by turbt.(6) finally, for those bladder cancer patients with anti-coagulation therapy, pvb is superior to turbt, because no perioperative discontinuation in drug administration needed. in order to prevent or delay tumor recurrence, transurethral resection followed by intravesical therapy is considered as standard treatment strategy for nmibc, the majority intravesical medicine used are bcg or chemotherapeutic drugs such as thiotepa, mitomycin c, doxorubicin (adriamycin), pirarubicin and epirubicin.(12) but the strategy used for the treatment of nmibc sometimes varies according to the eau, ficbt, nccn and aua guideline.(13) for example, for low risk nmibc, a single immediate postoperative instillation of chemotherapeutic agents after turbt is recommend enough, but for intermediate and high risk of nmibc, bcg (rather than other chemotherapeutic medicine) is recommended as the most useful medicine. since bcg is not commercial provided in our nation, and there are still 40– 80% of tumors recurrence in spite of complete resection,(17) we performed an intravesical instillation with epirubicin within 24 hours plus one year maintenance postoperatively. the follow up results indicated that the recurrence number in pvb group is also less than that in turbt group. the major drawback of pvb is the lack of tissue for histological examination because all the tumor was vaporized by ktp laser unless we do biopsy pre-operation and intro-operation. in order to determine the infiltrate depth, we routinely table 2. intraand postoperative characteristics of pvp group vs. turbt group. variables pvb turbt p number 28 32 operation time (min) 22 ± 8.3 27 ± 7.8 .019 complications, no obturator nerve reflex 0 4 .028 bladder perforation 0 2 ns postoperative bladder irrigation, no 1 7 .038 catheterization time (days) 3.24 ± 1.2 5.73 ± 0.9 .0001 recurrence, no 1 3 ns key: turbt, transurethral resection of the bladder tumor; pvp, ktp laser vaporization, ns, not significant. 1263vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l references 1. american cancer society, cancer facts & figures 2012. atlanta: american cancer society; 2012. 2. sobin dh, wittekind ch. tnm classification of malignant tumors. 6th edn. newyork, wiley-liss; 2002. p. 199-202. 3. xishuang s, deyong y, xiangyu c, et al. comparing the safety and efficiency of conventional monopolar, plasmakinetic, and holmium laser transurethral resection of primary non-muscle invasive bladder cancer. j endourol. 2010:24:69-73. 4. zhu y, jiang x, zhang j, chen w, shi b, xu z. safety and efficacy of holmium laser resection for primary nonmuscle-invasive bladder cancer versus transurethral electro-resection: single-center experience. urology. 2008;72:608-12. 5. kramer mw, bach t, wolters m, et al. current evidence for transurethral laser therapy of non-muscle invasive bladder cancer. world j urol. 2011;29:433-42. 6. gao x, ren s, xu c, sun y. thulium laser resection via a flexible cystoscope for recurrent non-muscle-invasive bladder cancer: initial clinical experience. bju int. 2008;102:1115-8. 7. hai ma, malek rs. photoselective vaporization of the prostate: initial experience with a new 80 w ktp laser for the treatment of benign prostatic hyperplasia. j endourol. 2003;17:93-6. 8. malek rs, kuntzman rs, barrett dm. photoselective potassium-titanyl-phosphate laser vaporization of the benign obstructive prostate: observations on long-term outcomes. j urol. 2005;174:1344-8. 9. gómez sancha f, bachmann a, choi bb, tabatabaei s, muir gh. photoselective vaporization of the prostate (greenlight pv): lessons learnt after 3500 procedures. prostate cancer prostatic dis. 2007;10:316-22. 10. gravas s, bachmann a, reich o, roehrborn cg, gilling pj, de la rosette j. critical review of lasers in benign prostatic hyperplasia (bph). bju int. 2011;107:1030-43. 11. ruszat r, wyler s, forster t, et al. safety and effectiveness of photoselective vaporization of the prostate (pvp) in patients on ongoing oral anticoagulation. eur urol. 2007;51:1031-8. 12. witjes ja, hendrichsen k. intravesical pharmacotherapy for nonmuscle-invasive bladder cancer: a critical analysis of currently available drugs, treatment schedules, and long-term results. eur urol. 2008;53:45-52. 13. brausi m, witjes ja, lamm d, et al. a review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the international bladder cancer group. j urol. 2011;186:2158-67. 14. furuse h, ozono s. transurethral resection of the bladder tumour (turbt) for non-muscle invasive bladder cancer: basic skills. int j urol. 2010;17:698-9. 15. richterstetter m, wullich b, amann k, et al. the value of extended transurethral resection bladder tumour (turbt) in the treatment of bladder cancer. bju int. 2012;110:e76-9. 16. yucel m, hatipoglu nk, atakanli c, et al. is repeat transurethral resection effective and necessary in patients with t1 bladder carcinoma? urol int. 2010;85:276-80. 17. saika t, tsushima t, nasu y, et al. two instillations of epirubicin as prophylaxis for recurrence after transurethral resection of ta and t1 transitional cell bladder cancer: a prospective, randomized controlled study. world j urol. 2010;28:413-8. laser vaporization for non-muscle invasive bladder cancer | shan et al get biopsy sample before the operation, and when vaporized layer was reached the muscle, we did biopsy from the muscle layer beneath the vaporized lesion via the working channel of the continuous cystoscope. if no residual cancer was found in this layer, we defined it as nmibc. conclusion in conclusion, pvb via continuous cystoscopy is a safe and effective treatment for nmibc. it is a promising treatment option due to the precise incision, lower complication rate and excellent hemostasis. long-term prospective randomized studies will be needed to confirm these promising preliminary results. conflict of interest none declared. 1504 | ampullary tumor caused by metastatic renal cell carcinoma and literature review wang haidong, wang jianwei, li guizhong, liu ning, he feng, man libo abstract:wepresentacaseofa50-year-oldmanwithametastasistotheampullaofvaterthat ledtothediscoveryofrenalcellcarcinomas.themanwasreferredtousbecauseofjaundice. computedtomography(ct)scanoftheabdomenshowedirregularmassesintherightkidney. magneticresonanceimaging(mri)revealeddilatationofthebileduct.thepatientunderwent rightnephrectomyandpancreatoduodenectomy.postoperativehistopathologicexaminationrevealedclearcellcarcinomainboththerenalandampullarylesions.aftera5-yearfollow-up, thepatientwasalivewithnoevidenceofrecurrentdisease. keywords:ampullaryneoplasm,renalcellcarcinoma,metastasis introduction renalcellcarcinomasaccountfor3-4%ofallcancersandhaveapredilectiontometastasizetorarelocations.theampullaryregionisn’tausualsiteofmetastaticmalignancy.theampullaofvatermetastaticlesionfromrenalcellcarcinomais anextremelyrareoccurrence.thisisthefirstcasethatmetastatictumorofampullaofvater wasdisclosedbeforerenalcellcarcinoma.theobjectiveofthiscasereportistopresentthe unusualclinicalcaseandassesstheroleofsurgicalmanagement. corresponding author: man libo, md beijing jishuitan hospital, beijing 100035, china. tel: +86 010 58398240 e-mail: doctorwhd@163.com received august 2012 accepted march 2013 beijing jishuitan hospital, beijing 100035, china. case report case report 1505vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l ampullary tumor caused by metastatic rcc | haidong et al case report herewereportanunusualclinicalcaseofa50-year-oldman withmetastasisfromrenalcellcarcinomatotheampullaof vater.thepatientwashospitalizedwithaone-monthhistoryof fever,malaise,fatigue,andjaundice.thepatientsufferedfrom diarrheasometimesandlost2kilogramsinrecentfewmonths. onadmission,thepatientwaspaleandanemic.thehemoglobinwas88g/l.stoolwaspositiveforoccultblood.results ofpertinentlaboratorystudiesonadmissionshowed:serum glutamic-oxaloacetic transaminase(got), 146 iu/l; glutamicpyruvictransaminase(gpt),324iu/l;totalbilirubin(tbil), 41μmol/l;carcinoembryonicantigen(cea),5.6ng/ml.mri discloseddilatationofbileduct(figure1).ultrasonicsound showedthatthereisalowecho-leveltumorinrightkidney.a ctscanconfirmedthattheirregularlyshapedtumorwassituatedintheupperpartofrightkidney(figures2and3). thetentativepreoperativediagnosiswassynchronousprimarycancersofthekidneyandtheampullaofvater.the patientunderwentopenrightradicalnephrectomyandstandardpancreatoduodenectomy.thepostoperativecoursewas uneventful.therenallesionwas432cm,andmicroscopy wasconsistentwithclear-cellcarcinoma(figure4).thefinal pathologicaldiagnosisoftheampullarylesionswasmetastaticclearcellcarcinomaofthekidney(figure5).alllymph nodesandthemarginsofresectionofthecommonbileduct, pancreas,duodenum,jejunum,andureterwerenegativefor tumor.thepatientsreceivedsystemictherapy(ifn-α-2b)aftertheradicalnephrectomy.follow-upstudies,includingct scanoftheabdomen,chestradiography,andlaboratorystudies,weredone.fiveyearslater,thepatientwasalivewithout evidenceofrecurrentdisease. discussion in2010kidneycanceraccountedfor4%and3%ofallnewly diagnosedmalignanciesinmenandwomen,respectively.from 80%to85%ofkidneycancersarerenalcellcarcinomas. (1) thetumoriscommonlylargeatpresentationandsymptoms maynotoccuruntilrelativelylateinthedisease.(2) at the timeofdiagnosis,20-30%ofpatientspresentwithmetastatic figure 1. mri showing dilatation of bile duct. figure 2. ct scan showing a mass in the right kidney figure 3. ct scan showing that the tumor was situated in the upper part of right kidney 1506 | case report disease,40-50%ofrenalcellcarcinomaspatientsdevelop metastaticdiseaseeventuallyand20-30% patients relapse distantlyafterradicalnephrectomy.(3)kidneycancerisone ofthemostdeadlyurologicaltumors.the5-yearsurvival rateforallstagesisapproximately69.5%.(4)ifdetectedearly, renalcellcarcinomascanbetreatedsurgically,and5-year survivalratesapproaching85%canbeachievedforpatients withorgan-confineddisease(stagest1,t2,andn0).(1)the prognosis of metastatic renal cell carcinomas is generally poor;mediansurvivalis10monthsandfive-yearsurvivalis lessthan5%.(5)untilrecently,veryfewsystemictherapeutic optionsexistedforlocallyadvancedormetastaticrenalcell carcinomapatients.immunotherapywithifn-αcanbeconsideredatreatmentoptiontomodestlyimprovesurvivaland disease control in patients.(6)ourpatienthassurvivedfor5 yearsaftersurgerywiththetreatmentofifn-α-2b.thepatientwasadmittedevery3monthsforroutineexaminations, andthereisnoevidenceofrecurrent. renalcellcarcinomarepresentsapotentiallylethalcancerthat hasapropensityformetastaticspread.themostfrequentsites ofmetastasisarethelung,lymphnodes,liver,boneandadrenal glands.(7)metastasisofrenalcellcarcinomatopancreatic andgallbladderisrare.ampullaofvatermetastasisfromrenal cellcarcinomaisextremelyrare,andveryfewcaseshavebeen reported in literatures.the epidemiology, clinical presentation,andtreatmentofampullaofvatermetastasesfromrenal cellcarcinomaarelessknown.theefficiencyofsurgeryin themanagementofthesepatientshasnotbeenclearlydefined. accordingtodocument(8)andourexperience,onethingisfor sure,thatistherelativelygoodprognosis. thesymptomsofpatientpresentedhereisindistinguishable fromthoseofprimarycanceroftheampullaofvater.onlya fewpatientswithrenalcellcarcinomacangetearlydiagnosis,whichresultsinahighproportionofpatientswithmetastases.(9)inrecentyears,thewidespreadapplicationofctand ultrasonographyforotherindicationshasledtotheincreased detectionofrenalcellcarcinomaasanincidentalfinding.tumorsfoundincidentallyaretypicallysmallerthanthosethat producesymptoms,andaremorelikelytoberesectedfor cure.(10)inourpatient,therenaltumorwasalsofoundincidentallythroughctandultrasonography,andthetumorwas notlarge.thekidneyandtumorwasremovedcompletely andsmoothly,whichleadstolongsurvivalofthepatient. conclusion renalcellcarcinomarepresentsapotentiallylethalcancerassociatedwithaggressivebehavior.thepatternofmetastases fromrenalcellcarcinomatotheampullaofvaterisrare,and radicalnephrectomyandstandardpancreatoduodenectomy canbeatherapyofchoice.theprognosisisrelativelygood. figure 4. histopathologic appearance of renal cell carcinoma (hematoxylin and eosin stain, ×40) figure 5. histopathological view of the ampullary tumor (hematoxylin and eosin stain, ×40) 1507vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l references 1. jemal a, siegel r, xu j, ward e. cancer statistics, 2010. ca cancer j clin. 2010;60:277-300. 2. furniss d, harnden p, ali n, royston p, eisen t, oliver rt, hancock bw. national cancer research institute renal clinical studies group. prognostic factors for renal cell carcinoma. cancer treat rev. 2008;34:407-26. 3. bukowski rm. prognostic factors for survival in metastatic renal cell carcinoma: update 2008. cancer. 2009;115:2273-81. 4. tan hj, hafez ks, ye z, wei jt, miller dc. postoperative complications and long-term survival among patients treated surgically for renal cell carcinoma. j urol. 2012;187:60-6. 5. clement jm, mcdermott df. the high-dose aldesleukin (il-2) "select" trial: a trial designed to prospectively validate predictive models of response to high-dose il-2 treatment in patients with metastatic renal cell carcinoma. clin genitourin cancer. 2009;7:e7-9 6. canil c, hotte s, mayhew la, waldron ts, winquist e. interferon-alfa in the treatment of patients with inoperable locally advanced or metastatic renal cell carcinoma: a systematic review. can urol assoc j. 2010;4:201-8. 7. takeda t, shibuya t, osada t, et al. metastatic renal cell carcinoma diagnosed by capsule endoscopy and double balloon endoscopy. med sci monit. 2011;17:cs15-7. 8. janzen rm, ramj as, flint jd, scudamore ch, yoshida em. obscure gastrointestinal bleeding from an ampullary tumour in a patient with a remote history of renal cell carcinoma: a diagnostic conundrum. can j gastroenterol. 1998;12:75-8. 9. frantzi m, metzger j, banks re, et al. discovery and validation of urinary biomarkers for detection of renal cell carcinoma. j proteomics. 2014;98:44-58. 10. sugimoto k, shimizu n, oki t, et al. clinical outcome of incidentally discovered small renal cell carcinoma after delayed surgery. cancer manag res. 2013;5:85-9. ampullary tumor caused by metastatic rcc | haidong et al urol_v03_no4_001_editorial.indd appendixes 263urology journal vol 3 no 4 autumn 2006 acknowledgement reviewers in volume 3 the editorial team of the urology journal would like to acknowledge a depth of gratitude to the following colleagues who have done us the great favor of peer reviewing of the submitted manuscripts over the past year: seyed kazem aghamir seyed abdollah aghamiri hassan ahmadnia hamed akhavizadegan majid ali-asgari alireza amin-sharifi violet amir-jalali mohsen amjadi hamid arshadi seyed alaeddin asgari mohsen ayati mohammad reza barghi aboulfazl bohlouli farid dadkhah abdolkarim danesh mohammad reza darabi homan djaladat masoumeh fallahian latif gachkar parivash ghavamian mirsaeed ghazizadeh hamidreza gholamrezaie sakineh hadj-ebrahimi abdolmajid hajebi kalantar hormozi mahmoud kabiri-esfahani alireza kheradmand abdolaziz khezri seyed kazem madaen robab maghsoudi reza mahdavi reza malek-hosseini hamid mazdak darab mehraban sadrollah mehrabi abdolrasoul mehrsai faramarz mohammadali beygi mahmoud reza moradi esmail mousapour mohammad nadjafi-semnani mohsen nafar abdollah nasehi mohammadreza nikoobakht naser niroomanesh fatemeh pour-reza-gholi mohamdreza rafiee mohamad rakhshan effat razeghi ali razi mahamdreza razzaghi mohamad sedighi-ghilani heshmatolla shahbazian hossein shahrokh saeed shahrokhi saeed shakeri naser shakhssalim ali shamsa mostafa sharifian hamid shayani-nasab ali tabibi alireza tadayyon mahmoud tavakkoli saeed zand mohammadali zargar shoshtari 352 | pictorial urology department of urology, aintree university hospital, lower lane, liverpool, l9 7al, united kingdom *e-mail: nilbury@oceanfree.net a 57-year-old man presented with a 6-month history of suprapubic pain, abdominal distension, ano-rexia, and altered bowel habit. he had no urological symptoms. physical examination revealed a distended abdomen with shifting dullness and a benign prostate. routine hematology, biochemistry, and serum tumor markers were within normal limits. computed tomography of his abdomen revealed bilateral simple renal cysts with the largest measuring 28 × 14 × 16 cm. he underwent bilateral renal cyst aspiration whereby 6 liters of fluid were removed with negative cytology. the patient reported rapid weight loss of 4 kg and restoration of appetite within days. subsequent ultrasonography after 4 months revealed partial reaccumulation of the cysts, but the patient remained asymptomatic. unilateral renal cysts measuring 15 cm have been reported to cause anorexia, intermittent diarrhea, and intestinal obstruction, and when aspirated, have contained 1.5 liters of fluid.(1) giant renal cysts presenting simply with progressive abdominal distension can lead to a misdiagnosis, such as obesity, which reverses following open decortication.(2) laparoscopic decortication for renal cysts up to 25 cm remains technically challenging.(3) massive renal cysts may present with gastrointestinal symptoms, which resolve promptly following decompression. michael st john floyd jr,* rahul mistry, andrew david baird bilateral giant renal cysts masquerading as malignant ascites references 1. vos b, laureys m. [giant renal cyst as cause of colic obstruction]. rev med brux. 2009;30:107-9. 2. brown ja, segura jw, blute ml. a giant left renal cyst presenting as obesity: a unique presentation. arch esp urol. 1998;51:105-7. 3. mingoli a, brachini g, binda b, carocci v, tiddi c, modini c. laparoscopic transperitoneal decortication of a giant peripelvic renal cyst. j laparoendosc adv surg tech a. 2008;18:845-7. pictorial urology v08_no_3_final.pdf case report 251urology journal vol 8 no 3 summer 2011 arteriovenous hemangioma of the urinary bladder following intravesical treatment urol j. 2011;8:251-3. www.uj.unrc.ir urinary bladder neoplasms, hemangioma, antineoplastic agents department of urology, kocaeli university, kocaeli, turkey corresponding author: levend özkan, md department of urology, medical faculty, kocaeli university tel: +90 262 303 8592 e-mail: lozkan@kocaeli.edu.tr received november 2009 accepted february 2010 introduction hemangioma of the urinary bladder is a very rare benign tumor believed to have congenital origin; however, it can present at any age, being relatively more common in adulthood.(1) to the best of our knowledge, few cases of the urinary bladder hemangioma have been documented.(1) we report a case of a vesical arteriovenous hemangioma in a patient with a history of transurethral resection of the bladder tumor (tur-bt) and intravesical installation of bacillus calmette-guerin (bcg). case report a 66-year-old man was hospitalized with painless macroscopic hematuria. he had a history of tur-bt two years earlier. he also received intravesical bcg induction therapy after developing a recurrence with high grade stage t1 tumor after 1 year. no recurrence was reported after bcg treatment. physical examination showed no abnormal findings. he had no voiding difficulty or pain. initial blood work-up was also normal; however, urinalysis showed 40 to 50 red blood cells and 2 to 4 white blood cells per high power field. cystoscopy was planned to rule out recurrent bladder tumor and 1 cm × 0.8 cm, reddish, exophytic mass with a partial necrotic surface was detected above the left ureteral orifice. the scarred area due to the former resection was noted on the right side. transurethral resection of the mass and coagulation was performed using 26f resectoscope without complication. histological examination revealed arteriovenous hemangioma without any evidence of malignancy (figure). detailed physical examination was repeated to confirm that there was no other visible hemangioma in the body. hematuria ceased after resection and there was no recurrence during histological examination shows arteriovenous hemangioma without any evidence of malignancy. 252 urology journal vol 8 no 3 summer 2011 the 18-month follow-up period. discussion hemangioma is histologically classified as cavernous, capillary, or arteriovenous, and the cavernous type is the most common one. (2) several case reports showed a wide age distribution, but the majority is middle-aged.(1,3) the urinary bladder is an uncommon location for hemangioma.(1-3) the largest series of the bladder hemangioma was published by cheng and colleagues. they reported 19 subjects during a 66-year period. the mean age of the patients was 58 years and male to female ratio was 3.7:1. the mean tumor size was 1.1 cm (range, 0.2 to 3 cm) and only 2 patients had a tumor with the muscle wall involvement.(1) hendry and vinnicombe reviewed 32 patients younger than 20 years old that had been reported up to 1971. only 22 patients had bladder hemangioma that was proven histologically. in most of the subjects, hemangioma involved the muscular layer of the bladder; especially if the tumor was large.(4) angiosarcoma and kaposi sarcoma should be considered in the differential diagnosis of the bladder hemangioma, which exhibit less cytologic atypia.(2) multiple bladder hemangiomas may be associated with klippelweber syndrome.(5) the most common presenting symptom of a bladder hemangioma is gross hematuria, which rarely causes hemodynamic complications, and may be accompanied by voiding symptoms or abdominal pain. endoscopic view of hemangioma is nonspecific. only 16% of the cases are suspected clinically before histological diagnose. (1) usually, the tumor is a small (< 3 cm), sessile, and blue mass.(2) transurethral biopsy with fulguration provides diagnose and treatment.(1,3) laser treatment was also reported successful.(5) for larger tumors, partial or total cystectomy may be required. (1) in our patient, the lesion was thought to be a recurrent bladder tumor and was resected transurethrally. macroscopic hematuria disappeared after surgery and there was no recurrent bleeding or mass during the follow-up period. to our knowledge, there is no published report on the association between intravesical bcg immunotherapy and the bladder hemangioma. bacillus calmette-guerin treatment is known to cause chronic inflammation and granulomas.(6) recent studies depict a close relationship between inflammation and vascular endothelial growth factor production,(7,8) which plays an important role in the pathological change of hemangiomas by promoting endothelial cell proliferation and angiogenesis.(9) in light of these data, we think that bcg therapy and consequent increase of vascular endothelial growth factor might be the predisposing factors for formation of the bladder hemangioma in this patient. to the best of our knowledge, this is the first report on the bladder hemangioma proved to develop after intravesical treatment, tur-bt and bcg. this case suggests, but does not prove, an association between intravesical bcg immunotherapy and the bladder hemangioma. further studies are needed to clarify this association. conflict of interest none declared. references 1. cheng l, nascimento ag, neumann rm, et al. hemangioma of the urinary bladder. cancer. 1999;86:498-504. 2. cheng l. urologic surgical pathology. in: bostwick dg, cheng l, eds. neoplasms of the urinnary bladder. 2 ed: mosby; 2008:259-352 3. tavora f, montgomery e, epstein ji. a series of vascular tumors and tumorlike lesions of the bladder. am j surg pathol. 2008;32:1213-9. 4. hendry wf, vinnicombe j. haemangioma of bladder in children and young adults. br j urol. 1971;43: 309-16. 5. kato m, chiba y, sakai k, orikasa s. endoscopic neodymium:yttrium aluminium garnet (nd:yag) laser irradiation of a bladder hemangioma associated with klippel-weber syndrome. int j urol. 2000;7:145-8. 6. koya mp, simon ma, soloway ms. complications of intravesical therapy for urothelial cancer of the 253urology journal vol 8 no 3 summer 2011 bladder. j urol. 2006;175:2004-10. 7. saban mr, backer jm, backer mv, et al. vegf receptors and neuropilins are expressed in the urothelial and neuronal cells in normal mouse urinary bladder and are upregulated in inflammation. am j physiol renal physiol. 2008;295:f60-72. 8. halin c, tobler ne, vigl b, brown lf, detmar m. vegf-a produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. blood. 2007;110:3158-67. 9. shan s, shan g, zhang d. treatment of hemangioma by transfection of antisense vegf gene. j huazhong univ sci technolog med sci. 2009;29:335-9. v08_no_2_final.pdf miscellaneous 141urology journal vol 8 no 2 spring 2011 ligature versus transvenous endovenorrhaphy for closure of side-to-side arteriovenous fistula created for hemodialysis jalaladin khoshnevis, mohammad reza sobhiyeh, niki tadayon, hojat molaee govarchin ghalae, mohammad reza kalantar motamedi purpose: to report a novel technique for arteriovenous fistula (avf) closure in side-to-side fistulas. materials and methods: one hundred and sixty-two patients with sideto-side avfs, who were candidates for avf closure, were randomly divided into two groups: group a (84 patients) who underwent avf ligature and group b (78 patients) who underwent avf closure using transvenous endovenorrhaphy technique. both procedures were conducted by the same surgical team. the patients were followed up for 6 months. results: of 124 patients with proximal avfs, 65 (52%) subjects underwent ligation and 59 (42%) transvenous endovenorrhaphy. of 38 patients with distal avfs, half underwent ligation and for the remainder, transvenous endovenorrhaphy was done. failure of avf closure was detected in 28 (17%) patients; 25 (89.28%) were in group a and 3 (10.71%) were in group b. all of these recurrences were successfully treated by transvenous endovenorrhaphy technique. conclusion: we claim that significant lower failure rate of transvenous endovenorrhaphy makes it the technique of choice, especially for side-to-side avfs. urol j. 2011;8:141-4. www.uj.unrc.ir keywords: arteriovenous fistula, hemodialysis, treatment outcome, prospective studies department of general and vascular surgery, shohada-e-tajrish hospital, tehran, iran corresponding author: mohamad reza sobhiyeh, md department of general and vascular surgery, shohada-e-tajrish hospital, tehran, iran tel: +98 21 227 180 0112 fax: +98 21 2272 1144 e-mail: mreza_sobhiyeh@yahoo.com received october 2009 accepted march 2010 introduction revolutionary changes in management of end-stage renal disease have led to increase in the need for hemodialysis during the last two decades. it is estimated that its incidence is rising at a rate of 2% to 4% annually.(1) vascular access is essential for chronic hemodialysis and persists as a surgical challenge. more than 60% of all the patients with endstage renal disease, who require chronic hemodialysis, are accessed through a native arteriovenous fistula (avf) or bridge fistula made by polytetrafluorethylene graft (arteriovenous graft).(1) native avf provides the best possible vascular access. compared with the prosthetic bridge graft, avf is more durable and has better long-term patency and fewer complications, including a lower incidence of infection and vascular steal syndrome.(2) patients who are candidate for avf creation, must be evaluated pre-operatively and selected meticulously to prevent serious complications. superficial or deep venous stenosis or thrombosis can result in venous hypertension,(3) endovenorrhaphy for arteriovenous fistula closure—khoshnevis et al 142 urology journal vol 8 no 2 spring 2011 and missed arterial insufficiency may lead to steal syndrome with critical limb ischemia necessitating avf closure.(4,6) incorrect technique of puncture may cause pseudoaneurysms and possibly lifethreatening bleeding.(7,8) some patients with successful renal transplantation may prefer to have the avf being closed without developing any complications.(9) different techniques have been introduced for avf closure. the most popular one is ligation of fistula’s tract or ligation of proximal and venous part, including side-to-side avf.(10) despite tedious dissection and difficult arterial and venous control, serious complications, such as pseudoaneurysm and venous aneurysms formation may occur.(11) materials and methods between october 2002 and september 2008, 168 patients with side-to-side avfs, who were candidates for avf closure due to complication or successful kidney transplantation, regardless of age, gender, and underlying disease, were randomly divided into two groups: group a had ligation and group b underwent fistula closure using transvenous endovenorrhaphy technique. both procedures were performed by the same surgical team. the patients were followed (up to 6 months) by another team which were blinded to the surgical technique. thrill palpation or bruit auscultation in the site after avf closure was considered as the closure failure. results were assessed on the 1st postoperative day and monthly thereafter. six patients missed follow-ups; therefore, they were excluded from the study. the data of the remaining 162 patients were analyzed using spss software (the statistical package for the social sciences, version 9.0, spss inc. chicago, illinois, usa) by chi-square method. surgical techniques because of the general medical condition of these patients, every effort was made to use local anesthesia. therefore, lidocaine 2% was injected with the dosage of 5 to 10 ml at the site of the maximum thrill palpation. technique of ligation: arteriovenous fistula was exposed through an incision slightly longer than the previous incision scar. dissection was continued to expose four limbs of the avf. a loop of silk-0 was encircled around the venous limbs and avf tract, and was ligated. hence, the thrill would no longer be palpable (figure). technique of transvenous endovenorrhaphy: maximum thrill palpation site was marked. thereafter, a tourniquet was applied on the arm. a bloodless field was provided by smarch band (elastic band) around the limb and inflating the tourniquet, which was set on 250 to 300 mmhg pressure. after removing the smarch band, an incision was made exactly on the premarked area, which corresponds to the previous incision scar. without creating skin flaps and exposing limbs, venotomy was performed. four ostia, two belonging to the arterial source of avf and the other two belonging to the vein side, became evident. the ostia of avf (connection) were obliterated with prolene 5-0 suture. thereafter, the ventomy was repaired by the same suture (figure). to prevent superficial thrombophlebitis, elastic bandage was applied for one week. results the participants consisted of 90 (55.5%) men and 72 (44.4%) women, with the mean age of 52 years. techniques for arteriovenous fistulas closure. endovenorrhaphy for arteriovenous fistula closure—khoshnevis et al 143urology journal vol 8 no 2 spring 2011 one hundred and twenty-four (76.5%) avfs have been created in the antecubital fossa (side-to-side brachiocephalic or side-to-side brachiobasilic type) and remaining 38 (23.4%) were at the wrist or snuffbox region (side-to-side brachiocephalic type). indications for avf closure are demonstrated in table. in patients with proximal avfs, fistula closure was done using ligation and transvenous endovenorrhaphy, in 65 and 59 patients, respectively. of 38 patients with distal avfs, half underwent ligation and the other half had transvenous endovenorrhaphy. avf closure failed in 28 patients; 25 (89.28%) were in group a (17 in antecubital and 8 at the wrist) and 3 (10.71%) were in group b (1 in antecubital and 2 at the wrist). the rate of closure failure was 15.4% and 1.8% in ligature and transvenous endovenorrhaphy groups, respectively (p = .000). the rate of closure failure was 11.1% in the proximal (antecubital) avf group and 23.3% in the distal (snuff box) and wrist group. these recurrences were detected from first postoperative day up to 6 months with the mean of 43-day interval. the mean age of patients with fistula recurrence was 50.5 years. all of these recurrences were successfully treated by transvenous endovenorrhaphy technique. in 15 (53.5%) subjects, there was a painful palpable mass in addition to the presence of bruit. discussion there are complications cited for permanent hemodialysis access, including refractory heart failure and dialysis shunt-associated steal syndrome (dass).(12,13) in addition to steal phenomenon (stage i), which can be treated conservatively, there are three stages of dass following autogenous hemodialysis access that require surgical intervention (stage ii, no acral lesions; stage iii, small acral lesions; and stage iv, extended acral lesions).(14) correction of symptomatic vascular steal distal to an avf requires either fistula ligation or banding, which can be done using substances such as amplatzer vascular plug type ii (avp ii). it is a self-expandable nitinol wire-mesh device.(15) ligation carries the obvious disadvantage of destruction of a functioning angioaccess, whereas banding procedures have been plagued by the complexity of many of the reported techniques and the difficulty of balancing fistula flow with distal perfusion.(16) there is no consensus about the best technique for avf closure. however, ligation technique has been used traditionally. considering personal technical skills, ligation may provide acceptable results, but our study showed that it is associated with high failure rate. dissection in scar tissue may damage artery or vein, and lead to pseudoaneurysm formation. scared tissue has less elasticity and may be cut when silk-1 is going to be tied. accordingly, there is some resistance to closure due to its inherent rigidity and gradual opening by each arterial pulse. additionally, the arterial pulse is intensified due to chronic artery hyperfunctioning and hypertrophy. this may also underline the pseudoaneurysm formation. therefore, failure may occur, which can be diagnosed clinically by thrill palpation, bruit auscultation, or pulstile mass.(5,17,18) in our experience, transvenous endovenorrhaphy was associated with significantly less failure rate than ligature technique (p = .000). this technique also has the advantage of less operation time, minimal bleeding, and simplicity. conclusion our results indicated that transvenous endovenorraphy is a versatile technique with lower failure rate, especially for closure of side-toside avfs. conflict of interest none declared. indication number percentage avf hypertension 117 72.22 venous aneurysm 20 12.34 steal syndrome 18 11.12 kidney transplantation 7 4.32 totally 162 100 indications for avf closure endovenorrhaphy for arteriovenous fistula closure—khoshnevis et al 144 urology journal vol 8 no 2 spring 2011 references 1. lin ph, bush rl, nguyen l, guerrero ma, chen c, lumsden ab. anastomotic strategies to improve hemodialysis access patency--a review. vasc endovascular surg. 2005;39:135-42. 2. kreidy r, ghabril r. arteriovenous fistula for chronic hemodialysis in children. j med liban. 2000;48: 288-93. 3. elsharawy ma, moghazy km. impact of pre-operative venography on the planning and outcome of vascular access for hemodialysis patients. j vasc access. 2006;7:123-8. 4. salahi h, fazelzadeh a, mehdizadeh a, razmkon a, malek-hosseini sa. complications of arteriovenous fistula in dialysis patients. transplant proc. 2006;38:1261-4. 5. sessa c, pecher m, maurizi-balzan j, et al. critical hand ischemia after angioaccess surgery: diagnosis and treatment. ann vasc surg. 2000;14:583-93. 6. morsy ah, kulbaski m, chen c, isiklar h, lumsden ab. incidence and characteristics of patients with hand ischemia after a hemodialysis access procedure. j surg res. 1998;74:8-10. 7. karabay o, yetkin u, silistreli e, uskent h, onol h, acikel u. surgical management of giant aneurysms complicating arteriovenous fistulae. j int med res. 2004;32:214-7. 8. franco g. [technique and results of duplex-doppler for non-stenosing complications of vascular access for chronic hemodialysis: ischemia, steal, high flow rate, aneurysm]. j mal vasc. 2003;28:9200-5. 9. manca o, pisano gl, carta p, et al. the management of hemodialysis arteriovenous fistulas in well functioning renal transplanted patients: many doubts, few certainties. j vasc access. 2005;6:182-6. 10. vasiutkov v, evstifeev lk, nemtsov av. [surgical treatment of arteriovenous fistulas and aneurysms]. vestn khir im i i grek. 1984;132:86-8. 11. quilala ep, bryant mf, gray sw, skandalakis je. radical ligation in two cases of arteriovenous fistula. j med assoc ga. 1971;60:112-5. 12. thermann f, ukkat j, wollert u, dralle h, brauckhoff m. dialysis shunt-associated steal syndrome (dass) following brachial accesses: the value of fistula banding under blood flow control. langenbecks arch surg. 2007;392:731-7. 13. kurita n, mise n, tanaka s, et al. arteriovenous access closure in hemodialysis patients with refractory heart failure: a single center experience. ther apher dial. 2011;15:195-202. 14. thermann f, wollert u, dralle h, brauckhoff m. dialysis shunt-associated steal syndrome with autogenous hemodialysis accesses: proposal for a new classification based on clinical results. world j surg. 2008;32:2309-15. 15. powell s, narlawar r, odetoyinbo t, et al. early experience with the amplatzer vascular plug ii for occlusive purposes in arteriovenous hemodialysis access. cardiovasc intervent radiol. 2010;33:150-6. 16. rivers sp, scher la, veith fj. correction of steal syndrome secondary to hemodialysis access fistulas: a simplified quantitative technique. surgery. 1992;112:593-7. 17. melliere d, hassen-khodja r, cormier jm, le bas p, mikati a, ronsse h. proximal arterial dilatation developing after surgical closure of long-standing posttraumatic arteriovenous fistula. ann vasc surg. 1997;11:391-6. 18. berardinelli l. the endless history of vascular access: a surgeon’s perspective. j vasc access. 2006;7: 103-11. 960 | urological oncology 1department of urology and 2department of pathology, kanto rosai hospital, kawasaki, japan takumi takeuchi,1 koichi sakazume,2 akiko tonooka,2 masayoshi zaitsu,1 yuta takeshima,1 koji mikami,1 toshimasa uekusa2 cytosolic hmgb1 expression in human renal clear cell cancer indicates higher pathological t classifications and tumor grades corresponding author: takumi takeuchi, md 1-1 kizukisumiyoshi-cho, nakahara-ku, kawasaki, japan. 211-8510 tele: +81 444 11 3131 fax: +81 444 33 3150 e mail: takeuchit@abelia.ocn. ne.jp purpose: high mobility group box (hmgb) proteins are nuclear nonhistone chromosomal proteins that bend dna, bind preferentially to distorted dna structures, and promote the assembly of site-specific dna binding proteins. recent reports indicate that hmgb1 functions as a proinflammatory cytokine. here, we studied expressions of hmgb1 and hmgb2 in human renal cancer. material and methods: immunohistological expressions of hmgb1 and hmgb2 were assessed in 39 surgically resected human renal cancer specimens. results: hmgb1 was expressed in the nucleus in 37 out of 39 (94.9%) renal clear cell cancers, while its expression in the cytosol was noted in 19 cases (48.7%). cytosolic hmgb1 is expressed more frequently in cancers beyond the pt1b classification than in those at the pt1a classification. higher tumor grades (≥ g2) were also significantly linked with the cytosolic expression of hmgb1. hmgb2 was expressed in the nucleus in 35 of 39 (89.7%) renal clear cell cancers, while its expression in the cytosol was observed in only 7 case (17.9%). linkage between cytosolic expression of hmgb2 and t classifications was weakly observed, while that between nuclear expression and t classifications was not. conclusion: hmgb1 expressed in the cytoplasm may be an effective marker indicating higher t classifications and tumor grades. keywords: kidney neoplasms; gene expression; hmgb1 protein; genetics; neoplasm invasiveness urological oncology 961vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l hmgb and renal cancer | takeuchi et al introduction high mobility group box (hmgb) proteins are nuclear nonhistone chromosomal proteins which bend dna, bind preferentially to distorted dna structures, and promote the assembly of site-specific dna binding proteins leading to the regulation of gene transcription.(1) hmgb1 consists of 215 amino acids and is markedly conserved among species.(2) hmgb1, as well as hmgb2 and hmgb3 of the same family, is structurally composed of a bipolar structure of two l-shaped homologous dna-binding sequences termed box a and box b, and a highly negatively charged c terminus.(3) each of the two conserved hmg box domains forms three alpha-helices that fold into a sequence-nonspecific dna-binding module recognizing the dna minor groove. hmgb1 has been regarded as a ubiquitous nuclear protein with an architectural function, although hmgb2 and hmgb3 expressions are relatively restricted. however, recent reports indicate that hmgb1 expression can be outside of the nucleus, and so it is not a housekeeping protein but has a dual function,(4) a cytokine in addition to a nuclear protein. in certain cell types, extranuclear and extracellular hmgb1 as a potent proinflammatory cytokine plays important roles in inflammation, cell migration, and tumor proliferation/invasion.(5,6) although hmgb1 was first believed to be released by necrotic cells, not by apoptotic cells,(7) its release from cells can occur during the course of apoptosis and autophagy as well as necrosis with the release process varying with the cell type.(8,9) the receptor for advanced glycation end products (rage), toll-like receptor-2 (tlr-2), and toll-like receptor-4 (tlr-4) are known as receptors of hmgb1.(10) the autocrine loop consisting of hmgb1 and rage modulates the maturation of human plasmacytoid dendritic cells.(11) extracellular hmgb1 is an inflammation mediator and a danger signal.(12) the release of hmgb1 by necrotic cells as well as activated macrophages or monocytes triggers inflammation, and hmgb1-negative necrotic cells have a markedly reduced ability to promote inflammation.(7) the hmgb1 b box domain induces dendritic cell maturation and th1 cell polarization, enhancing immune reactions.(13) on the contrary, kusume and associates reported that hmgb1 produced by colon cancer cells disturbed anti-cancer immunity in the host by suppressing nodal dendritic cells.(14) the increased expression of hmgb1, particularly in conjunction with rage, has been reported for several different tumors, including colon cancer,(14) breast cancer,(15) melanoma,(16) prostate cancer,(17,18) and gastrointestinal stromal tumors,(19) often indicating invasiveness, metastasis, and a poor prognosis.(20,21) lung cancer is an exception where the loss of hmgb1-rage-mediated regulation is associated with increased aggressiveness of tumor behavior.(22) on the contrary, a role for hmgb1 in the error-free repair of dna lesions is indicated with its absence leading to increased mutagenesis, decreased cell survival, and altered chromatin reorganization after dna damage.(23) hmgb2 has not been reported to come out of the nuclus or cells differently from hmgb1. ubiquitous expressions of hmgb1 and hmgb2 have the potential to regulate the transcriptional activity of different members of the p53 family in cell-specific and promotor-specific manners in vivo.(24) both hmgb1 and hmgb2 are sensors of dna damage inducing a p53-mediated dna damage response, abrogation of which increased chemoresistance in some cancer cell lines.(25) renal cancer can be cured only by surgical excision, i.e. radical or partial nephrectomy. radiotherapy and conventional chemotherapy are basically ineffective. immunotherapy by administrating interferon-a and/or interleukin-2 has been used for a long time for the treatment of metastatic or unresectable renal cancer with a limited response rate of less than 20%. now, molecular targeting drugs such as sunitinib, sorafenib, everolimus, and temsilolimus are replacing immunotherapy. here, we have studied histological expressions of hmgb1 and hmgb2 in surgically resected human renal cancer specimens, and compared them with the clinicopathologic features. hmgb1 expression localized in the cytopasm of renal clear cell cancer was correlated with poor pathological characteristics. material and methods ethics statement this study was conducted in accordance with the helsinki declaration after approval by the ethical committee of kanto rosai hospital. the committee approved the use of the oral consent documented in the chart for each patient, as the study 962 | was retrospective and non-randomized. oral informed consent was obtained from all participants involved in the study. written consent was not obtained based on the judgment of the ethical committee. the process of obtaining oral consent was documented in the individual electronic chart used in kanto rosai hospital, and the ethical committee approved this consent procedure. study design consecutive thirty-nine patients with pathologically confirmed renal clear cell carcinoma in kanto rosai hospital between january, 2009 and august, 2012 were enrolled in this study. paraffin-embedded sections of specimens of renal cancers excised by radical or partial nephrectomy were histochemically stained with anti-human mouse monoclonal hmgb1 antibody (abcam, ab80246) or anti-human mouse monoclonal hmgb2 antibody (abgent, at2387a) as primary antibodies essentially following the manufacturers’ instructions. expressions of hmgb1/2 were determined by a single pathologist (at). basically, expressions of hmgb1/2 in more than 30% tumor cells on sections were judged as positive. statistical analyses hmgb1/2 expressions in different pathological t classifications and tumor grades (the fuhrman grading system) were statistically analyzed using the two-tailed fisher’s exact test. results patient and tumor profiles are presented in table 1. representative microphotographs of nuclear and cytosolic hmgb1 expression are shown in figure 1, while those of hmgb2 are in figure 2. in the present study, hmgb1 was expressed in the nucleus in 37 out of 39 (94.9%) renal clear cell cancers, while its expression in the cytosol was noted in 19 out of 39 cases (48.7%). as shown in table 2, nuclear hmgb1 is expressed in all pt1a renal cancers and almost all renal cancers whose pt classifications are above pt1b. on the contrary, cytosolic hmgb1 is expressed more frequently in cancers with classifications above pt1b than in those at the pt1a classification (table 3). in addition, higher tumor grades (≥ g2) were significantly linked with cytosolic expression of hmgb1 (table 3), but not with its nuclear expression (table 2). hmgb2 was expressed in the nucleus in 35 of 39 (89.7%) renal clear cell cancers, while its expression in the cytosol (figure 2) was only noted in 7 cases (17.9%). linkage between cytosolic expression of hmgb2 and t classifications urological oncology table 1. patient and tumor profiles. diagnostic index values age at renal surgery, years median 63 (34-81) sex male 28 female 11 tumor grades g1 12 g2 18 g3 8 g4 1 pt classifications pt1a 22 pt1b 10 pt2 3 pt3a 1 pt3b 3 metastasis at renal surgery m0 36 m1 3 metastasis after renal surgery 2 mri indicates magnetic resonance imaging; and ci, confidence interval. table 2. nuclear hmgb expression classified by pt classification and tumor grade. hmgb1hmgb1+ hmgb2hmgb2+ pt1a 0 22 1 21 ≥ pt1b 2 15 3 14 p = .1835 p = .2998 g1 0 12 2 10 ≥ g2 2 25 2 25 p = 1.0000 p = .5733 p values by the two-tailed fisher’s exact test. 963vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l was weakly observed (tables 3), while that between nuclear expression and t classifications was not (table 2). linkage between cytosolic/nuclear expression of hmgb2 and tumor grades was not observed (tables 2 and 3). discussion hmgb1/2 expression in renal cancer has not previously been reported. in the present study, renal clear cell cancer basically expressed hmgb1 as a nuclear protein at any tumor stage and grade. thus, nuclear hmgb1 may be engaged in the regular intranuclear functioning of hmgb, such as the assembly of proteins, gene transcription, and dna repair. as tumor stages and grades progress, hmgb1 is expressed not only in the nucleus but also the cytosol. this may indicate that hmgb1 released from cancer cells functions as a proinflammatory cytokine in renal cancers of higher stages and grades. otherwise, hmgb1 released from them may suppress antitumor immunity, leading to more invasiveness, metastasis, and a poorer prognosis. in most of the previous reports showing overexpression of hmgb1 in cancers, localization of hmgb1 in cancer cells was not necessarily described clearly,(14-18) as the experiments were done utilizing proteins or mrnas extracted from materials. a report by kostova and associates(20) uniquely revealed the localization of hmgb1 in cancer tissues by immunohistochemistry, in which ductal breast, colorectal, and hepatocellular cancer all exhibited perinuclear localization of hmgb1 in moderately differentiated carcinomas, while they showed whole nuclear localization in less differentiated ones. additionally, gastrointestinal stromal tumors with kit mutation were reported to show nuclear and cytoplasmic expression of hmgb1, but those without kit mutation did not express hmgb1 at all.(19) our study may be the first to show that the cytoplasmic expression of hmgb1 in cancer cells is clearly linked with the poorer pathological characteristics as t classifications and tumor grades. actually, two cases where distant metastasis occurred after radical nephrectomy as well as a case with multiple lung metastases at nephrectomy were all hmgb1-positive in the cytoplasm of cancer cells in nephrectomy specimens. in the present study, hmgb2 expression in renal clear cell cancer was mainly in the nucleus and less frequently in the cytosol. it has not been definitely reported that hmgb2 is expressed extranuclearly and secreted extracellularly, but table 3. cytosolic hmgb expression classified by pt classification and tumor grade. hmgb1hmgb1+ hmgb2hmgb2+ pt1a 17 5 21 1 ≥ pt1b 3 14 11 6 p = .0003 p = .0301 g1 10 2 11 1 ≥ g2 10 17 21 6 p = .0138 p = .4026 p values by the two-tailedfisher’s exact test. figure 1. representative hmgb1 staining in renal clear cell cancer. top: nuclear staining +, cytoplasmic staining -, bottom: nuclear staining -, cytoplasmic staining +. bar=50 µm. hmgb and renal cancer | takeuchi et al 964 | urological oncology figure 2. representative hmgb2 staining in renal clear cell cancer. top: nuclear staining +, cytoplasmic staining -, middle: nuclear staining -, cytoplasmic staining -, bottom: nuclear staining -, cytoplasmic staining +. bar=50 µm. references 1. thomas jo, travers aa. hmg1 and 2, and related 'architectural' dna-binding proteins. trends biochem sci. 2001;26:167-4. 2. andersson u, erlandsson-harris h, yang h, tracey kj. hmgb1 as a dna-binding cytokine. j leukoc biol. 2001; 72:1084-91. 3. pasheva e, sarov m, bidjekov k, et al. in vitro acetylation of hmgb1 and -2 proteins by cbp: the role of the acidic tail. biochemistry. 2004;43:2935-40. 4. muller s, ronfani l, bianchi me. regulated expression and subcellular localization of hmgb1, a chromatin protein with a cytokine function. j intern med. 2004; 255: 332-43. 5. taguchi a, blood dc, del toro g, et al. blockade of rage-amphoterin signalling suppresses tumour growth and metastases. nature. 2000;405:354-60. 6. wang h, bloom o, zhang m, et al. hmg-1 as a late mediator of endotoxin lethality in mice. science. 1999;285:248-51. 7. scaffidi p, misteli t, bianchi me. release of chromatin protein hmgb1 by necrotic cells triggers inflammation. nature. 2002;418:191-5. 8. bell cw, jiang w, reich cf 3rd, pisetsky ds. the extracellular release of hmgb1 during apoptotic cell death. am j physiol cell physiol. 2006; 291: c1318-25. 9. thorburn j, horita h, redzic j, hansen k, frankel ae, thorburn a. autophagy regulates selective hmgb1 release in tumor cells that are destined to die. cell death differ. 2009;16:175-83. 10. jaulmes a, thierry s, janvier b, raymondjean m, maréchal v. activation of spla2-iia and pge2 production by high mobility group protein b1 in vascular smooth muscle cells sensitized by il-1beta. faseb j. 2006;20: 1727-9. hmgb2 is clearly localized in the cytoplasm of renal cancer cells on occasion, as shown in figure 2. thus, it can be hypothesized that hmgb2 is also secreted from cells and functions as a cytokine as hmgb1. there was actually weak linkage between cytosolic expression of hmgb2 and t classifications similarly with hmgb1. a role of hmgb2 in cancer biology needs to be further investigated. conclusion hmgb1 expressed in the cytoplasm may be an effective marker indicating higher t classifications and tumor grades. conflict of interest none declared. 965vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l 11. dumitriu ie, baruah p, bianchi me, manfredi aa, rovere-querini p. requirement of hmgb1 and rage for the maturation of human plasmacytoid dendritic cells. eur j immunol. 2005;35:2184-90. 12. erlandsson-harris h, andersson u. mini-review: the nuclear protein hmgb1 as a proinflammatory mediator. eur j immunol. 2004;34:1503-12. 13. messmer d, yang h, telusma g, et al. high mobility group box protein 1: an endogenous signal for dendritic cell maturation and th1 polarization. j immunol. 2004;173:307-13. 14. kusume a, sasahira t, luo y, et al. suppression of dendritic cells by hmgb1 is associated with lymph node metastasis of human colon cancer. pathobiology. 2009;76:155-62. 15. brezniceanu ml, völp k, bösser s, et al. hmgb1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma. faseb j. 2003;17:1295-7. 16. poser i, golob m, buettner r, bosserhoff ak. upregulation of hmg1 leads to melanoma inhibitory activity expression in malignant melanoma cells and contributes to their malignancy phenotype. mol cell biol. 2003;23:2991-8. 17. kuniyasu h, chihara y, kondo h, ohmori h, ukai r. amphoterin induction in prostatic stromal cells by androgen deprivation is associated with metastatic prostate cancer. oncol rep. 2003;10:1863-8. 18. gnanasekar m, thirugnanam s, ramaswamy k. short hairpin rna (shrna) constructs targeting high mobility group box-1 (hmgb1) expression leads to inhibition of prostate cancer cell survival and apoptosis. int j oncol. 2009;34:425-31. 19. choi yr, kim h, kang hj, et al. overexpression of high mobility group box 1 in gastrointestinal stromal tumors with kit mutation. cancer res. 2003; 63: 2188-93. 20. kostova n, zlateva s, ugrinova i, pasheva e. the expression of hmgb1 protein and its receptor rage in human malignant tumors. mol cell biochem. 2010;337:251-8. 21. ellerman je, brown ck, de vera m, et al. masquerader: high mobility group box-1 and cancer. clin cancer res. 2007; 13: 2836-48. 22. bartling b, hofmann hs, weigle b, silber re, simm a. downregulation of the receptor for advanced glycation end-products (rage) supports non-small cell lung carcinoma. carcinogenesis. 2005;26:293-301. 23. lange ss, mitchell dl, vasquez km. high mobility group protein b1 enhances dna repair and chromatin modification after dna damage. proc natl acad sci u s a. 2008;105:10320-5. 24. stros m, ozaki t, bacikova a, kageyama h, nakagawara a. hmgb1 and hmgb2 cell-specifically down-regulate the p53and p73-dependent sequence-specific transactivation from the human bax gene promoter. j biol chem. 2002;277:7157-64. 25. krynetskaia nf, phadke ms, jadhav sh, krynetskiy ey. chromatin-associated proteins hmgb1/2 and pdia3 trigger cellular response to chemotherapy-induced dna damage. mol cancer ther. 2009;8:864-72. hmgb and renal cancer | takeuchi et al modified lich-gregoir ureteral reimplantation for the treatment of unilateral primary vesicoureteral reflux in pediatric patients: a comparative analysis with medium-term outcomes yavuz güler1, akif erbin2*, gokhun ozmerdiven3 purpose: to present the medium-term results for the modified lich-gregoir (lg) reimplantation technique in the treatment of unilateral primary vesicoureteral reflux (vur) by comparing patients under and over 12 months of age. materials and methods: data for patients who underwent modified lg surgery between january 2006 and december 2018 were retrospectively reviewed from the hospital data-recording system and patients under the age of 18 years were included in the study. after exclusion criteria, 55 patients in total were included in advanced analysis. the patients were grouped as ≤12 months and >12 months. demographic characteristics, operative, and postoperative follow-up data were comparatively analyzed. results: the mean±sd (range) of age was 10.4 ± 2.8 (6-12) and 41.4 ± 18.5 (13-96) months in the ≤12 months and >12 months groups, respectively. mean operation time and hospitalization time were not significant between the groups. mean follow-up times were 39.5 ± 14.1 and 38.4 ± 13.2 months, in the ≤12 months and >12 months groups, respectively. there was no difference in terms of complications between the groups and all of the complications in both groups were in grade 1 category according to the modified clavien complication classification. one (6.6%) patient in the ≤12 months group and 3 (7.5%) patients in the >12 months group had late (>30 days) febrile uti, but none of them had a recurrence of vur. febrile infection did not recur during the follow-up period in these patients. while recurrent vur was not seen in any patient in the ≤12 months group (success: 100%), it was observed in 2 (5%) patients in the >12 months group (success rate: 95%) (p = 0.38). conclusion: the open lg ureteral reimplantation technique is an effective procedure for the treatment of unilateral primary vur in children both under 12 months and over 12 months of age with minor morbidity. keywords: extracapsular extension; localized prostate cancer; partin table; psa; psad; radical prostatectomy introduction vesicoureteral reflux (vur) is an anatomical and/or functional disorder with potentially serious consequences, such as pyelonephritis, renal scarring, hypertension, and end-stage renal disease. the main management goal is the preservation of kidney function by preventing renal scar formation and recurrent urinary tract infections (utis) (1). surgical treatment of vur includes endoscopic injection therapy, open, laparoscopic, and robot-assisted laparoscopic reimplantation. although endoscopic injection therapy remains stable over time (>10 years), it has lower success rates especially in patients with high-grade reflux(2,3). laparoscopic and robotic-assisted laparoscopic techniques are more invasive than endoscopic injection therapy and their advantages over open surgery are still debated. therefore, at present, laparoscopic and robotic-assisted laparoscopic approaches cannot be recommended as routine procedures(4). in clinical practice, reimplantation surgeries in the pediatric population are usually performed with open techniques. to date, various intravesical (cohen, politano-leadbet1department of urology, private safa hospital, istanbul, turkey. 2department of urology, haseki traning and research hospital, istanbul, turkey. 3department of urology, istanbul aydin university medical faculty, istanbul, turkey. *correspondence: department of urology, haseki traning and research hospital, istanbul, turkey, phone: +90 506 543 1062, fax: +90 212 529 4400, e-mail: akiferbin@hotmail.com. received november 2019 & accepted august 2020 ter and glenn-anderson, gil-vernet) and extravesical (lich-gregoir) techniques were described. although each method has specific advantages and complications, all of them share the same basic principle of lengthening the intramural part of the ureter and present very high and similar success rates for the treatment of unilateral primary vur(4). among these procedures, the most popular one is the cohen cross trigonal re-implantation technique. the main concern with this procedure is the difficulty of accessing the ureters endoscopically if needed(5). the lich-gregoir (lg) technique is superior to the cohen technique in terms of hospital stay and operative time. moreover, it avoids the necessity of urethral and ureteral stenting, which may increase the comfort of patients postoperatively(6). follow-up data associated with this advantageous technique is limited. in this context, we present the medium-term results of the modified lg technique for the treatment of unilateral primary vur by comparing patients aged under and over 12 months. pediatric urology urology journal/vol 18 no. 2/ march-april 2021/ pp. 194-198. [doi: 10.22037/uj.v16i7.5784] materials and methods study design in order to conduct the present study, ‘data usage approval’ was obtained from the authorized hospital management (private safa hospital, date: 22.10.2019). parents or legal guardians of the patients gave written and verbal informed consent for inclusion in the study and to undergo the procedures described. the study was conducted in accordance with the ethical guidelines of the declaration of helsinki and its amendments. data for patients who underwent modified lg surgery between january 2006 and december 2018 were retrospectively reviewed from the hospital data-recording system and patients under the age of 18 years were included in the study. of these, patients with urinary anomalies (ureterocele, duplex system or ectopic ureter), patients who underwent bilateral lg operation, patients with neurogenic bladder, or bowel bladder dysfunction, and patients with incomplete medical records were excluded from the study. after exclusion criteria, 55 patients in total were included in advanced analysis. the patients were grouped as ≤12 months (n=15) and >12 months (n=40). demographic characteristics, operative, and postoperative follow-up data were comparatively analyzed between the groups. all patients were evaluated with routine voiding diary, urinary ultrasonography (usg) and voiding cystourethrogram (vsug). vesicoureteral reflux was classified by radiologic evaluation on vcug into five grades (grade ireflux into the ureter; grade ii reflux into the renal pelvis, without any dilation of the calyces; grade iiireflux to the renal pelvis with mild dilation of the renal pelvis; grade ivreflux to the renal pelvis with greater dilation of the renal pelvis; grade vreflux to the renal pelvis with ureteral and pelvic dilation) as defined by the international reflux study in children(7). complications were classified according to the modified clavien-dindo classification(8). success was defined as the absence of documented febrile uti and the absence of recurrence of vur on vcug. preoperative assessment the basic indication for children under 12 months was frequent febrile breakthrough utis in spite of continuous antibiotic prophylaxis and circumcision. surgery indications for children over 12 months included progressive reflux, persistent high-grade reflux (grades iv/v), recurrent utis despite medical treatment and/ or endoscopic injection therapy, deterioration of renal function, new scar development, and non-compliance with medical treatment. informed consent was obtained from each patient’s parents prior to the procedure. the patient assessment included medical history, physical examination, complete blood count, coagulation tests, serum biochemical analysis, urinalysis, urine culture, urinary ultrasonography (usg), and vcug. patients were screened for voiding dysfunction or neurogenic bladder with medical history and physical examination. if indicated, patients underwent urodynamic evaluation. renal scarring was evaluated with a dimercapto-succinic acid (dmsa) scan on initial presentation. surgical antibiotic prophylaxis was administered with second-generation cephalosporin. operation technique following general anesthesia, a gibson incision was made. the lateral subperitoneal space was opened and the iliac vessels were exposed. bladder mobilization was achieved by ligation and cutting of the lateral umbilical ligament which crosses the ureter. the ureter was liberated from the iliac vessels towards its entry into the bladder. the future course of the ureter along the posterior bladder wall was chosen and labeled at a distance of 3-5 cm, according to the diameter of the ureter (5:1 ratio). the detrusor was incised in the anterolateral direction until the bladder mucosal protrusion was observed uniformly, creating the new submucosal tunnel. after the ureter was placed in the new submucosal tunnel, the seromuscular layer was closed over it using interrupted 4‐0/5‐0 synthetic absorbable sutures. at the end of the procedure, the bladder was emptied by direct needle puncture. there was neither instrumentation nor catheter insertion into the urethra during the operation. routine urethral catheters were inserted in patients with mucosal perforation during dissection. all patients were operated by a single surgeon. postoperative follow-up the placement of the bladder catheter was only inditable 1. demographic data and patient characteristics. parameters ≤12 months (n=15) >12 months (n=40) p age, month (mean ± sd) 10.4 ± 2.8 41.4 ± 18.5 < 0.001 sex n,(%) 0.84 male 6 (40%) 18 (45%) female 9 (60%) 22 (55%) weight kg (mean ± sd) 8.9 ± 2.3 21.4 ± 6.5 < 0.001 prenatal diagnosis n, (%) 11 (73.3%) 10 (25%) < 0.001 reflux side n, (%) 0.87 right 6 (40%) 17 (42.5%) left 9 (60%) 23 (57.5%) reflux grade n, (%) < 0.001 grade 3 2 (13.3%) 30 (75%) grade 4 7 (46.6%) 6 (15%) grade 5 6 (40%) 4 (10%) hn n, (%) 0.029 grade 0 7 (17.5%) grade 1-2 2 (13.3%) 10 (25%) grade 3 10 (66.6%) 19 (47.5%) grade 4 3 (20%) 4 (10%) history of endoscopic injection n, (%) 2 (13.3%) 7 (17.5%) 0.72 abbreviations: sd: standard deviation;vur: vesicoureteral reflux; hn: hydronephrosis unilateral vur in pediatric-guler et al. pediatric urology 195 vol 18 no 2 march-april 2021 196 cated in those cases who developed globe vesicale. postoperative routine follow-up protocol included urinary usg and vcug at 3 months and urinary usg and dmsa in the first year. if persistent or contralateral reflux was discovered, follow-up vcug was performed after 6 months of surveillance. repeat vcug or dmsa was also requested in case of febrile urinary infection. antibiotic prophylaxis was terminated with the correction of vesicoureteral reflux confirmed by a single normal vcug. statistical analysis statistical comparison of the groups used the spss 22.0 (ibm, ny, usa) program. quantitative data are expressed as mean ± standard deviation and categorical data are expressed with frequency (n) and percentages (%). the kolmogorov-smirnov test was used to determine whether the variables were distributed normally or not. the independent t-test was used to compare the means of two independent groups. mann–whitney u test was used to compare the continuous variables. the statistical significance threshold was accepted as p < 0.05 for all analyses. results table 1 presents demographic data and patient characteristics. the mean±sd (range) of age were 10.4 ± 2.8 (6-12) and 41.4 ± 18.5 (13-96) months in the groups under and over 12 months, respectively. there were significant differences between the groups with regard to weight, prenatal diagnosis, reflux grade, and hn. all patients received antibiotic prophylaxis. however, all patients in the ≤12 months group and 37.5% of >12 months group had recurrent utis. there was history of unsuccessful endoscopic injection in 13.3% of the ≤12 months group and 17.5% of the >12 months group. table 2 presents operative and postoperative data. mean operation time and hospitalization time were not significant between the groups. in 26.6% of the ≤12 months group and 22.5% of the >12 months group, mucosal perforation was observed during dissection and the mucosa was closed as a separate layer in a simple continuous appositional pattern. only these patients had urethral catheterization. mean catheterization time was 3.0 days for both groups. none of the patients had postoperative globe vesicale. there was no difference in terms of complications between the groups and all of the complications in both groups were in grade 1 category according to the modified clavien complication classification. one (6.6%) patient in the ≤12 months group and 3 (7.5%) patients in the >12 months group had late (>30 days) febrile uti, but none of them had a recurrence of vur. febrile infection did not recur during the follow-up period in these patients. during the follow-up period, while recurrence vur was not observed in any patient in the ≤12 months group (success: 100%), it was encountered in 2 (5%) patients in the >12 months group (success rate: 95%). however, this difference was not statistically significant. discussion ureteral reimplantation can be performed with open, laparoscopic, and robot-assisted laparoscopic methods in children(9,10). at present, laparoscopic and robotic approaches cannot be recommended as routine procedures and open surgical techniques still remain the gold standard with good long-term results(4,11,12). open ureteral reimplantation can be performed with intravesical (cohen transtrigonal, politano-leadbetter, glenn-anderson gill-vernet and paquin), and extravesical (lich‐ unilateral vur in pediatric-guler et al. table 2. operative outcomes and postoperative follow-up data. parameters ≤12 months (n=15) >12 months (n=40) p operation time, min (mean ± sd) 57.4 ± 11.2 60.4 ± 14.5 0.37 perioperative mucosal perforation, n, (%) 4 (26.67%) 9 (22.5%) 0.75 hospitalization time, day (mean ± sd) 2.9 ± 0.4 3.1 ± 0.5 0.22 postoperative urinary retention, n, (%) 0 0 urethral catheter time, day (mean ± sd) 3 3 complications, n, (%), (modified clavien classification) 6 (40%) 17 (42.5%) 0.87 spasm pain due to catheter (grade 1) 3 (20%) 9 (22.5%) 0.36 macroscopic hematuria (grade 1) 2 (13.33%) 3 (7.5%) 0.51 febrile uti (grade 1) 1 (6.67%) 3 (7.5%) 0.91 wound infection (grade 1) 0 2 (5%) 0.38 follow-up time, months (mean ± sd) 39.5 ± 14.1 38.4 ± 13.2 0.42 recurrent reflux, n, (%) 0 2 (5%) 0.38 postoperative hn, n, (%) grade 1 3 (20%) 7 (17.5%) 0.90 grade 2 1 (6.67%) 3 (7.5%) uti: urinary tract infection figure 1. stages of the modified lg operation. complete division of the detrusor muscle to the epithelium cutting in an anterolateral direction 3–5 cm from the ureter (a,b,c,). placing the ureter in the groove in contact with the bladder epithelium (d,e) and loose closure of the muscle over the ureter with interrupted 4‐0/5‐0 synthetic absorbable sutures (f). gregoir) methods. although the cohen cross-trigonal ureteral reimplantation is a commonly used technique in children due to the long-term reliable results and broad applicability, it has some disadvantages such as catheter requirements, bladder spasm pain, hematuria, clot retention and need for longer hospitalization. the lich‐gregoir extravesical ureteral reimplantation technique causes less morbidity and there is no need for long-term urethral catheterization except in cases where the integrity of the bladder mucosa is impaired during dissection(13,14). the technique was described by lich and gregoir in 1961 and 1964, respectively(15,16). in the following years, various modifications of the technique were reported(17). the lg technique has a very high success rate like intravesical methods and the learning curve is shorter. in our series, the success rate was 100% for children under 12 months in the mid-term follow-up in accordance with the literature. despite high success rates, the main concerns with lg are urinary retention and possible onset of postoperative voiding dysfunction, which in some cases requires catheterization for several weeks especially in cases with bilateral reimplantation. several series reported bladder voiding dysfunction with an incidence ranging from 3 to 20% in different series(18,19). this is thought to be caused by neurovascular bundle (nvb) injury during ureter and bladder dissection. neuropraxia can be reduced with greater knowledge of the topography of the main neural elements, located 1.5-2 cm superior/dorsal to the bladder trigone and medial/dorsal to the ureter(20). we did not detect any voiding dysfunction or urinary retention during midterm follow-up. this is probably due to unilateral vur in our patients and careful and minimal dissection at the level of the ureterovesical junction. in addition to voiding dysfunction and urinary retention, the lg technique has the risk of ureteric obstruction and periosteal formation of a bladder diverticulum and is not suitable for all kinds of reflux; for example, in cases of obstructed megaureter. the majority of failed antireflux procedures are the result of inadequate patient selection, or incomplete diagnostic work-up prior to surgery and failure of surgical techniques. in case of failure of reflux surgery, firstly, unspecified previous bladder and/or bowel dysfunctions should be considered. in our series, one of our 2 patients with recurrent reflux from the >12 months group had unstable bladder which we subsequently diagnosed. anticholinergic therapy completely relieved recurrent reflux. in the other patient, the ureter was very large and recurrence reflux spontaneously regressed at 1 year. urinary tract infections are more common after failed reflux surgeries. postoperative febrile uti may be an indicator of reflux recurrence or ureteral obstruction. we did not detect reflux in vcug of 4 patients in total with febrile uti. so, we considered that febrile utis in our patients were caused by temporary ureteral obstruction. if there is an increase in hn degree without reflux in the postoperative follow-up, ureteral obstruction should be suspected. in this case, drainage should be planned with dj stent or nephrostomy. if there is no improvement with drainage, redo-ureteroneocystostomy (unc) should be done. in our patients, obstruction was temporary and no patient required drainage or redo-unc. guney reported that redo-unc was required in 8.2% of cases after unc and that age, sex, laterality of vur, vur grade, existence of primary or secondary vur, relative renal function on renal scintigraphy, unc technique, subureteric injection procedure, and ureteral tapering were not risk factors for redo-unc (21). our study showed that complication rates were similar in the ≤12 months group when compared with the >12 months group. although complication rates were relatively high in both groups, all of these were minor complications that did not require intervention. in addition, the highest complication in both groups was urethral catheter-related pain. our study has several limitations. the most important limitation is its retrospective nature. other potential limitations are that it included a single-center and relatively small number of patients. larger studies with long-term results are needed to clarify the value of the lg technique, and especially durability in patients under 12 months. conclusions the open lg ureteral reimplantation technique is an effective procedure for the treatment of unilateral primary vur in children both under 12 months and over 12 months with satisfactory medium-term outcomes. although complication rates are relatively high, all of the complications are minor complications. the primary cause of failure is previous bladder and bowel dysfunction. therefore, preoperative bladder and bowel dysfunction should be evaluated carefully. conflict of interest the authors have no conflicts of interest to declare. references 1. murugapoopathy v, christine mccusker c, gupta ir. the pathogenesis and management of renal scarring in children with vesicoureteric reflux and pyelonephritis. pediatr nephrol. 2019. doi: 10.1007/s00467-018-4187-9 [epub ahead of print]. 2. harper l, paillet p, minvielle t, dobremez e, lefevre y, bouali o, et al. long-term (>10 years) results after endoscopic injection therapy for vesicoureteral reflux. j laparoendosc adv surg tech a. 2018;28:1408-1411. 3. alizadeh f, omidi i, haghdani s, hatef khorrami m, izadpanahi mh, mohammadi sichani m. a comparison between dextranomer/ hyaluronic acid and polyacrylate polyalcohol copolymer as bulking agents for treating primary vesicoureteral reflux. urol j. 2019;16:174-179. 4. radmayr c, bogaert g, dogan hs, kočvara r, nijman jm, stein r, et al. european urology guidelines, paediatric urology. 2019. uroweb. org/guideline/paediatric-urology 5. carrillo arroyo i, fuentes carretero s, gómez fraile a, morante valverde r, tordable ojeda c, cabezalí barbancho d. technical challenges of endoscopic treatment for vesicoureteral reflux after cohen reimplantation.actas urol esp. 2019;43:384-388. 6. silay ms, turan t, kayalı y, basibuyuk i, gunaydin b, caskurlu t, et al. comparison of intravesical (cohen) and extravesical (lich-gregoir) ureteroneocystostomy in the unilateral vur in pediatric-guler et al. pediatric urology 197 vol 18 no 2 march-april 2021 198 treatment of unilateral primary vesicoureteric reflux in children. j pediatr urol. 2018;14:65. e1-65.e4. 7. lebowitz rl, olbing h, parkkulainen kv, smellie jm, tamminen-möbius te. international system of radiographic grading of vesicoureteric reflux. pediatric radiology. 1985;15:105–109. 8. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.ann surg 2004;240:205-13. 9. soulier v, scalabre al, lopez m, li cy, thach s, vermersch s, et al. laparoscopic vesico-ureteral reimplantation with lichgregoir approach in children: medium term results of 159 renal units in 117 children. world j urol. 2017;35:1791-1798. 10. esposito c, masieri l, steyaert h, escolino m, cerchione r, la manna a, et al. robotassisted extravesical ureteral reimplantation (revur) for unilateral vesico-ureteral reflux in children: results of a multicentric international survey. world j urol. 2018;36:481-488. 11. deng, t., liu b, luo l, duan x, cai c, zhao zet al. robot-assisted laparoscopic versus open ureteral reimplantation for pediatric vesicoureteral reflux: a systematic review and meta-analysis. world j urol, 2018;36: 819. 12. ravindra sahadev, katelyn spencer, arun k. srinivasan, christopher j. long and aseem ravindra shukla. the robot-assisted extravesical anti-reflux surgery: how we overcame the learning curve. front. pediatr 2019;7:93. 13. sriram k, babu r.extravesical (modified gregoir lich) versus intravesical (cohen's) ureteric reimplantation for vesicoureteral reflux in children: a single center experience. indian j urol. 2016 ;32:306-309. 14. fadil iturralde jl, marani j, contardi jc, damiani hj. vesicoureteral antireflux surgery with lich-gregoir technique without vesical drainage: long-term results. actas urol esp. 2019;43:439-444. 15. lich r, howerton lw, davis la. ureteral refux, its signifcance and correction. south med j 1962;55:633–635 16. gregoir w. the surgical treatment of congenital vesicoureteral refux. acta chir belg 1964;63:431–439 17. zaontz mr, maizels m, sugar ec, firlit cf.detrusorrhaphy: extravesical ureteral advancement to correct vesicoureteral reflux in children. j urol. 1987;138:947-49 18. fung lc, mc lorie ga, jain u, khoury ae, churchill bm. voiding efficiency after ureteral reimplantation: a comparison of extravesical and intravesical techniques. j urol. 1995;153:1972–75. 19. david s, kelly c, poppas dp. nerve-sparing extravesical repair of bilateral vesico-ureteral reflux. description of technique and evaluation of urinary retention. j urol. 2004;172:1617– 20. 20. leissner j, allhoff w, wolff w, feja c, höckel m, black p, et al. . the pelvic plexus and antireflux surgery: topographical findings and clinical consequences. j urol. 2001;165:1652–55. 21. guney d, tiryaki th. the prevalence of redo-ureteroneocystostomy and associated risk factors in pediatric vesicoureteral reflux patients treated with ureteroneocystostomy. urol j. 2019;16:72-77. unilateral vur in pediatric-guler et al. 1007vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l laparoscopy assisted ‘u’ configuration bilateral ileal ureter in pelvic lipomatosis with bilateral ureteric obstruction manickam ramalingam,1 kallappan senthil,2 anandan murugesan,1 mizar ganapathy pai,2 keywords: laparoscopy; carcinoma, transitional cell; ureter; ileum; treatment outcome introduction pelvic lipomatosis is a benign proliferation of adipose tissue predominantly in the pelvic retroperitoneum. involvement of the bladder and ureter may cause bilateral hydroureteronephrosis and low capacity bladder.(1) we present the case report of a patient with pelvic lipomatosis causing bilateral hydroureteronephrosis with low capacity bladder managed by laparoscopy assisted ‘u’ configuration bilateral ileal ureter. case report a 45 year old gentleman presented with lower abdominal pain with mild voiding and storage lower urinary tract symptoms for a year. clinical examination revealed mild lower abdominal distension and the prostate was felt a bit higher level in the pelvis. serum creatinine was 1.6 mg/dl. micturating cystourethrogram showed a tear shaped, low capacity (100 ml) bladder with irregular contour (figure 1). computed tomography confirmed the diagnosis of pelvic lipomatosis and bilateral hydroureteronephrosis with obstruction below the level of pelvic brim (figure 2). there was no bowel or blood vessel involvement. tc99m-dtpa (diethylene triamine pentacaetic acid) renogram showed bilateral reduced cortical function with delayed transit time, and prolonged t1/t2 (figure 2). urodynamic evaluation revealed small corresponding author: manickam ramalingam, md associate professor, department of urology, psg institute of medical sciences and research, psg hospitals, peelamedu, coimbatore-641004, india tel: +91 422 224 1138 e mail: uroram@yahoo.com received june 2011 accepted december 2011 1 associate professor, department of urology, psg institute of medical sciences and research, psg hospitals, peelamedu, coimbatore-641004, india 2 consultant urologist, urology clinic, avinashi road, coimbatore, india case report 1008 | capacity, poor compliance bladder (figure 2). cystoscopy revealed excessive bullous edema around the bladder base involving the trigone. biopsy of the bullous lesion showed chronic nonspecific cystitis. under general anesthesia, patient in supine position, laparoscopy was done with 5 ports (one 10 mm supraumbilical port, two 5 mm ports in pararectus area and 1 port in each flank) (figure 3). laparoscopy revealed abundant fatty tissue in the pelvis completely surrounding the bladder, and hence only the bladder dome could be dissected. the right and left colon were mobilized by incising the line of toldt and the ureters were dissected bilaterally (figure 4). through a 5 cm subumbilical incision, 30 cm distal ileal segment was isolated and prepared with povidone iodine. ileo-ileal continuity was restored extracorporeally. segment internalized, abdomen closed and laparoscopy continued. the ends of the ileal loop were anastomosed with the proximal ureter on each side keeping the ileal segment in a ‘u’ shaped configuration (figure 4). transverse cystotomy was done on the dome of the bladder (figure 5). the dependent portion of the loop opposing the cystotomy was detubularised and ileo-cystostomy completed using 3-0 polyglactin interrupted sutures (figure 5). as the bladder was completely encased in the inflammatory tissue it was case report figure 1. ct image showing the perivesical pelvic lipomatosis and cystogram showing ‘tear drop’ bladder figure 2. pre operative and post operative o ‘reilly curves and urodynamic studies figure 3. port positions (with incision for ileum retrieval) and post-operative radiological image of ureter and bladder figure 4. right and left ureter mobilization and uretero ileal anastomosis 1009vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l laparoscopy assisted bilateral ileal ureter | ramalingam et al possible to dissect only the dome of the bladder. hence a satisfactory augmentation of the bladder was not possible. suprapubic catheter and tube drain were placed and port sites closed. surgery lasted 360 minutes with 350 ml blood loss. the patient needed opioid analgesics for one day and subsequently the pain control was satisfactory with simple non-steroidal anti-inflammatory drugs. post operatively, patient developed transient azotemia which was managed conservatively. drain was removed on the day 6 and patient discharged on day 10. supra pubic catheter was removed on day 14. follow up cystogram was done on 21st day to detect any extravasation. urethral foley catheter was removed on the 21st day. serum creatinine was 1.2 mg/dl. electrolytes were normal. isotope renogram showed stabilized renal function with improved drainage on the left side (figure 2). postoperative urodynamic study revealed improved compliance (figure 2). he voids 6-7 times a day, around 100-200 per void, between mandatory self-intermittent catheterization twice a day. residual urine was around 100 ml. ten months after surgery patient remains asymptomatic. discussion management of pelvic lipomatosis ideally should involve excision of adipose tissue.(1) but, loss of tissue planes with organ and vessel infiltration precludes complete excision and ileal conduit is the preferred management for ureteric obstruction.(1) ileal replacement of ureter is done for long ureteric replacements, when the serum creatinine is less than 2 mg/dl. in this patient bilateral ureteric obstruction was also associated with small capacity bladder. hence, the dependent portion of the ‘u’ configuration was designed to be used for bladder augmentation and the proximal and distal limbs for relief of ureteric obstruction.(2) ‘u’ configuration of ileal ureter was used since it was technically easier. such configurations have been described earlier.(2-5) bladder outflow obstruction could not be corrected since the lipomatous tissue around the bladder neck and urethra were not amenable to removal. hence he is being managed currently by self-intermittent catheterization. laparoscopic unilateral ileal ureter has been reported previously.(6,7) to our knowledge this is the first report of laparoscopy assisted bilateral ileal replacement of ureter and ileal augmentation for pelvic lipomatosis. laparoscopy is associated with lesser post-operative pain and hospital stay. the prolonged hospital stay in our patient was due to transient post-operative azotemia. conclusion in bilateral ureteric obstruction associated with low compliance bladder laparoscopy assisted bilateral ileal ureter replacement using a ‘u’ configuration ileal loop for concomitant augmentation cystoplasty is a viable procedure. conflict of interest none declared. references 1. frederick a gulmi, diane felsen, darracott vaughan. pathophysiology of urinary tract obstruction. in: patrick c. walsh , alan b. retik, e. darracott vaughan, alan j. wein, editors; campbell’s urology 8th edition. philadelphia: saunders; 2002. p. 419-422. 2. michael e mitchell, richard c rink, mark c adams. augmentation cystoplasty, implantation of artificial urinary sphincter in men and women and reconstruction of the dysfunctional urinary tract. in: patrick c. walsh , alan b. retik, thomas a. stamey, e darracott vaughan, editors; campbell’s urology, 6th edition, philadelphia: saunders; 1992. p. 2635-6. 3. crassweller po. bilateral primary carcinoma of the ureter with use of ileal graft for ureteral replacement: case report. br j urol. br j urol. 1958;30:152-60. figure 5. cystotomy at the dome of the bladder and ileovesical anastomosis 1010 | case report 4. verduyckt fj, heesakkers jp, debruyne fm. long-term results of ileum interposition for ureteral obstruction. eur urol. 2002;42:181-7. 5. ghoneim ma, shoukry i. the use of ileum for correction of advanced or complicated bilharzial lesions of the urinary tract. int urol nephrol. 1972;4:25-33. 6. ramalingam m, senthil k, pai mg. modified technique of laparoscopy-assisted surgeries (transportal). j endourol. 2008;22:2681-5. 7. nagesh kamat, p. khanderwal, m. ramalingam laparoscopically assisted ileal ureter. in: m ramalingam, vipul r. patel, editors; operative atlas of laparoscopic reconstructive urology, london: springer; 2008 p. 471-82. miscellaneous urology journal vol 4 no 1 winter 2007 33 varicocele in brothers of patients with varicocele faramarz mohammadali beigi,1 sadrollah mehrabi,2 ahmad javaherforooshzadeh3 introduction: the aim of this study was to evaluate varicocele patients’ brothers to determine whether they are at a higher risk of varicocele than the general population of men. materials and methods: a total of 56 patients with varicocele and their 131 brothers (> 16 years old) were evaluated. the brothers had no complaints of infertility, pain, or cosmetic problems. they were all examined for varicocele. one hundred and fifty men who referred for employment medical examinations were considered as the control group. results: of the subjects, 39 (69.6%) had grade iii varicocele. sixty (45.8%) of the brothers had varicocele. the grade of varicocele was iii in 16 (26.7%) brothers. in the control group, varicocele was present in 15 (10%) which was grade iii in 5 (33.3%). the frequency of varicocele was 4.5-fold greater in the brothers of the patients than the controls (p < .001). also, the frequency of grade iii varicocele was significantly more than grades i and ii in the patients in comparison with their brothers and controls with varicocele (p < .001). there was no significant difference in the grades between the controls and the patients’ brothers (p = .31). the frequency of bilateral varicocele was not statistically different between the three groups (p = .14). conclusion: our findings showed that a significant increase is seen in the prevalence of varicocele in the patients’ brothers compared to men in the general population, warranting evaluation of the first-degree relatives of men who present with varicocele. urol j (tehran). 2007;4:33-5. www.uj.unrc.ir keywords: varicocele, inheritance patterns, infertility 1department of urology, shahr-ekord university of medical sciences, shahr-e-kord, iran 2department of urology, yasouj university of medical sciences, yasouj, iran 3department of urology, shaheed beheshti university of medical sciences, tehran, iran corresponding author: sadrollah mehrabi, md department of urology,shaheed labbafinejad medical center, pasdaran, tehran 1666679951, iran tel: +98 917 341 4331 fax: +98 21 2258 8016 e-mail: mehrabi390@yahoo.com received july 2006 accepted november 2006 introduction varicocele is the most common surgically correctable disorder in infertile men and may result in impaired sperm motility, sperm morphology, and sperm count.(1) upward drainage of the gonadal veins into the renal vein that has a horizontal position, pressure of the superior mesenteric artery on the renal vein, and insufficiency of the venous valves have been proposed as the causes of varicocele; but, there is no documented hereditary pattern for the disease.(2) findings such as damage to the dna in the sperm of patients with varicocele and genetic causes of infertility, warrants the evaluation of the disease inheritance pattern.(3-5) the prevalence of varicocele has been reported to be 15% in the adolescence and 20% to 40% in infertile men.(6,7) infertility results from the harmful effects of varicocele on spermatogenesis and growth of testes.(8) surgical repair of varicocele can improve the impairment of sperm parameters in about 70% and infertility in 40% to 50% of patients.(9) early diagnosis of varicocele is very important for preventing the progression of testis atrophy.(7) varicocele can be easily varicocele in brothers of patients—mohammadali beigi et al 34 urology journal vol 4 no 1 winter 2007 varicocele in brothers of patients—mohammadali beigi et al urology journal vol 4 no 1 winter 2007 35 diagnosed and its consequences can be prevented; however, no precise information is available about its risk factors and inheritance pattern to determine the high risk men or asymptomatic cases. in this study, we examined brothers of patients with varicocele. materials and methods in a case-control study between september 2003 and september 2004, patients who presented with varicocele to the clinic of kashani hospital in shahre-kord, iran, were recruited into the study. their chief complaints were infertility, testis pain, and cosmetic problems. the patients were instructed and asked to refer their brothers to be examined. of 95 consecutive patients, 56 could refer with their 131 brothers. inform consent was obtained from all of the patients and their brothers. the exclusion criteria for the brothers were age of less than 16 years, infertility, testis pain, anatomic disorders in the genitalia, history of trauma to the testes, and history of diagnosed varicocele in their family members. physical examinations were preformed by a single physician and the grade of varicocele and presence of bilateral varicoceles were determined. meanwhile, 150 consecutive healthy people referred for employment medical examinations without a history of subfertility were considered as the control group and were examined for varicocele. varicocele was graded according to the standard classification: grade i, palpable only with the valsalva maneuver; grade ii, palpable without the valsalva maneuver in the standing position; and grade iii, easily visualized without the valsalva maneuver. statistical analyses were done using the chi-square test by the spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa). results the mean age of the subjects was 21.8 ± 8.1 years (range, 16 to 48 years). varicocele was grade iii in 39 (69.6%). the brothers included 131 men with a mean age of 20.0 ± 8.9 years (range, 16 to 46 years). sixty (45.8%) of these men had varicocele. the grade of varicocele was iii in 16 (26.7%) brothers. the control group included 150 healthy people with a mean age of 19.2 ± 5.6 years (range, 17 to 42 years). varicocele was present in 15 (10%) and was grade iii in 5 (33.3%). table shows the frequencies of varicocele and its clinical characteristics in the three groups. the frequency of varicocele was 4.5-fold greater in the brothers of the patients than the controls (p < .001). also, the frequency of grade iii varicocele was significantly more than grades i and ii in the patients in comparison with their brothers and controls with varicocele (p < .001); however, there was no difference in the grades between the controls and the patients’ brothers (p = .31). the frequency of bilateral varicocele was not statistically different between the three groups (p = .14). discussion given the results of the previous studies on the etiology and incidence of varicocele in general population, our findings indicated that the frequency of varicocele increases significantly in the first-degree relatives of the patients especially in their brothers. the literature lacks ample investigation to conclude a hereditary basis for varicocele. although several genetic roles have been identified in the infertility of the men, varicocele has not been separately studied.(10) ziv and colleagues found no relation between hla and the varicocele; however, other genetic and environmental factors could not be excluded.(11) there are limited information about the high frequency of y chromosome microdeletion in infertile men with varicocele, but their association is still controversial.(4,12) in a similar case-control study to ours, performed by raman and associates, a total of 44 patients with 62 available male first-degree family members were compared with 263 men who had referred for vasectomy reversal. it was shown that 56.6% of the first-degree family members (especially their brothers varicocele characteristics in patients, their brothers, and controls* *values in parentheses are percents. characteristics patients brothers controls number 56 131 150 varicocele 56 (100.0) 60 (45.8) 15 (10.0) bilateral varicocele 10 (17.9) 20 (33.3) 5 (33.3) varicocele grades i 8 (14.3) 20 (33.3) 2 (13.3) ii 9 (16.1) 24 (40.0) 8 (53.3) iii 39 (69.6) 16 (26.7) 5 (33.3) varicocele in brothers of patients—mohammadali beigi et al 34 urology journal vol 4 no 1 winter 2007 varicocele in brothers of patients—mohammadali beigi et al urology journal vol 4 no 1 winter 2007 35 [74%]) had varicocele in the clinical examinations which showed a significant difference with the control group (6.8%; p < .001).(13) in their study, no association of varicocele grade or its bilaterality was found with the possibility of varicocele occurrence in the family members of the patients. the control group in the study of raman and colleagues included fertile people who might be different from the general population. this explains the greater difference between the first-degree relatives and controls in their study compared to ours (8-fold versus 4.5-fold). in our study, the prevalence of varicocele was reported to be 45.8% and 10% in the patients’ brothers and the controls which showed a familial background in the occurrence of the disease (p < .001). our findings suggest that evaluation of the genetic factors and the people with more than one patient in their families can be helpful. the frequency of grade iii varicocele was significantly higher than grades i and ii in the patients compared with their brothers and controls with varicocele (p < .001); however, there was no difference in the grades between the controls and the patients’ brothers (p = .31), which showed no relationship between the severity of the disease and the possibility of its detection in the patients’ brothers. the frequency of bilateral varicocele was not statistically different between the three groups (p = .14). also, no clinically significant difference was found between the brothers and controls regarding the bilaterality which was in accordance with the study of raman and colleagues that failed to show a relationship between the bilaterality and the chance of varicocele in the first-degree relatives of the patients. in our study, only the patients’ brothers were evaluated and therefore, no genetic relation could be considered in the occurrence of varicocele. evaluation of other male relatives and genetic and environmental factors are needed. also, studies on larger samples of varicocele patients and their family members are needed to evaluate the relation between the grade of varicocele and the possibility of its detection in other people of the family and determining the clinical importance of the disease in family members. conclusion due to the importance of varicocele in the men’s infertility and its easy diagnosis and treatment subject to on-time diagnosis, evaluation of the patients’ brothers is recommended. conflict of interest none declared. references 1. haans lc, laven js, mali wp, te velde er, wensing cj. testis volumes, semen quality, and hormonal patterns in adolescents with and without a varicocele. fertil steril. 1991;56:731-6. 2. sigman m, jarow jp. male infertility. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 2123-4. 3. saleh ra, agarwal a, sharma rk, said tm, sikka sc, thomas aj jr. evaluation of nuclear dna damage in spermatozoa from infertile men with varicocele. fertil steril. 2003;80:1431-6. 4. song nh, wu hf, zhang w, et al. screening for y chromosome microdeletions in idiopathic and nonidiopathic infertile men with varicocele and cryptorchidism. chin med j (engl). 2005;118:1462-7. 5. dada r, gupta np, kucheria k. cytogenetic and molecular analysis of male infertility: y chromosome deletion during nonobstructive azoospermia and severe oligozoospermia. cell biochem biophys. 2006;44:171-7. 6. massad ca, kogan ba. the adolescent varicocele. in: gonzales et, roth d, editors. common problems in pediatric urology. st louis: mosby-year book; 1991. p. 341-2. 7. steeno o, knops j, declerck l, adimoelja a, van de voorde h. prevention of fertility disorders by detection and treatment of varicocele at school and college age. andrologia. 1976;8:47-53. 8. salisz ja, kass ej, steinert bw. the significance of elevated scrotal temperature in an adolescent with a varicocele. in: zorgnioti aw, editor. temperature and environmental effects on the testis. new york: plenum press; 1991. p. 245-51. 9. yamamoto m, hibi h, katsuno s, miyake k. effects of varicocelectomy on testis volume and semen parameters in adolescents: a randomized prospective study. nagoya j med sci. 1995;58:127-32. 10. shah k, sivapalan g, gibbons n, tempest h, griffin dk. the genetic basis of infertility. reproduction. 2003;126:13-25. 11. ziv y, livne pm, siegenreich e, zamir r, servadio c. familial varicocele. panminerva med. 1992;34:38-9. 12. acar h, kilinc m, yurdakul t, guven s. lack of significant association between chromosome y microdeletion and varicocele in turkish patients. genet couns. 2006;17:69-71. 13. raman jd, walmsley k, goldstein m. inheritance of varicoceles. urology. 2005;65:1186-9. pdf-cpc.pdf 429vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l urothelial carcinoma of the ureter in a patient with functional single kidney farzaneh sharifiaghdas, mohammad hossein soltani, mahmoudreza nasiri case presentation a56-year-old man with a past history of left radical nephrectomy for clear cell months ago without any other accompanying symptoms. physical examination was normal. the results of routine lab tests, including complete blood count and serum biochemistry, were within normal limits, except a serum creatinine level of 1.9 mg/dl. dominopelvic computed tomography scan without intravenous contrast injection (figures (figure 3). on cystoureteroscopy, a vegetative space occupying lesion was seen in the distal segment urine sample was obtained for cytology; and then cold cup biopsy was taken from the lesion. the result for cytology was positive for atypical cell, and pathologic examination showed low-grade transitional cell carcinoma. quiz the answers will be discussed in the next issue of urology journal. corresponding author: farzaneh sharifi aghdas, md department of urology, shahid labbafinejad medical center, 9th boustan st., pasdaran ave., 1666694516, tehran, iran tel/fax: +98 21 2258 8016 e-mail: fsharifiaghdas@ yahoo.com urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran figures 1 and 2. computed tomography scan without contrast injection revealed hydroureteronephrosis in the right side. figure 3. retrograde pyelography revealed filling defect in the distal part of the ureter. cilinical pathology case 1151vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l ureteropelvic junction rupture-an unusual presentation of distal ureteric calculus pradeep m. kulkarni, rajiv p. mukha, nitin s. kekre keywords: kidney pelvis; rupture; ureteral obstruction; ureteral calculi; ureter injuries. introduction obstructing ureteric calculus causing perinephric collection, contained by the gero-ta’s fascia, is seen secondary to forniceal rupture. here we present a case of distal ureteric 4 mm calculus in otherwise normal kidney in elderly male, presenting clinically as acute appendicitis, secondary to ureteropelvic junction (upj) rupture and urinoma outside the gerota’s fascia, in the paranephric space, extending down to right iliac fossa. case report a 52-year old gentleman, non-diabetic, presented with a 3 day history of right iliac fossa pain and vomiting. clinical examination was suggestive of localized peritonitis. urine microscopy showed pyuria and hematuria. he had leucocyte count of 13 600/µl and his serum creatinine was 1.7 mg/dl. a working diagnosis of acute appendicitis was made. upon preliminary imaging, the kidney ureter bladder (kub) x-ray showed faint 4 mm radioopaque shadow in the right hemipelvis (figure 1). the ultrasonography revealed a right mild hydroureteronephrosis (figure 2a) with a right retroperitoneal perinephric collection up to the right iliac fossa (figure 2b). the opposite side kidney and bladder were normal. computed tomography (ct) scan of the abdomen pelvis showed a 4 mm calculus in the right distal ureter with mild hydroureteronephrosis (figure 3a), ipsilateral perinephric stranding and extravasation of the contrast medium at the level of upj seen in delayed films (figures 3b and 4). collection was medial to and behind the renal pelvis in the paranephric space corresponding author: pradeep m kulkarni, md departments of urology and radiodiagnosis, christian medical college vellore, tamil nadu, india. e-mail: drpradeepmk@gmail.com received july 2011 accepted april 2012 departments of urology and radiodiagnosis, christian medical college vellore, tamil nadu, india case report 1152 | of retroperitoneum, anterior to right psoas muscle and was found trickling down behind the ascending colon down to right iliac fossa. there was no contrast medium seen in perinephric space. discussion reported cases of traumatic rupture of the kidney or ureter usually reflect an underlying renal pathologic condition. the most common underlying causes are hydronephrosis and congenital ureteropelvic junction obstruction (upjo). (1) it also might occur when the upper third of the ureter is fixed in its position by an ectopic vessel or scars because of previous trauma.(2) spontaneous rupture of the renal pelvis has also been reported.(3-5) traumatic rupture of the renal figure 1. faint 4 mm radiopaque shadow in right hemipelvis. figure 2. mild dilatation of pyelocalyceal system upper ureter noted on the right side (a). collection is noted in right lower abdomen and iliac fossa, appendix is not visualized (b). figure 3. non-enhanced computed tomography (ct) scan shows a 4 mm radiopaque density in right hemipelvis (a). in enhanced ct scan, delayed films demonstrate contrast material leak in ureteropelvic junction (upj) region extending outside gerota’s fascia into the paranephric space (b). case report 1153vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l pelvis usually occurs in the region of ureteropelvic junction (upj), in pediatric patients and more often on the right side.(2,3) diagnosis is often difficult because gastrointestinal symptoms may prevail and there are often no urinary symptoms at all.(4) ultrasonography could be used as a simple screening tool but is often not accurate enough.(6,7) in stable patients, contrast-enhanced ct should be performed to define an exact extent of the lesion and to provide detailed information about associated intra-abdominal or retroperitoneal injuries.(6,7) ureteric obstruction resulting in urine leak is commonly due to forniceal rupture where contrast medium is seen collected in perinephric space contained by gerota’s fascia. the above-mentioned case situation was unusual in the presentation of distal ureteric calculus with upj rupture in a normal kidney. conflict of interest none declared. upj rupture due to ureteral stone | kulkarni et al references 1. mcaleer im, kaplan gw, losasso be. congenital urinary tract anomalies in pediatric renal trauma patients. j urol. 2002;168:1808-10. 2. hopkins tb, klein la. disruption of the renal pelvis by blunt trauma. j trauma. 1975;15:250-4. 3. presti jc, carroll pr, mcaninch jw. ureteral and renal pelvic injuries from external trauma: diagnosis and management. j trauma. 1989;29:370-4. 4. ashebu sd, elshebiny yh, dahniya mh. spontaneous rupture of renal pelvis. australas radiol. 2000;44:125-7. 5. viville c, biechler m, cinqualbre j. closed traumatic ruptures of normal upper urinary tract. j urol (paris). 1983;89:533-9. 6. nguyen mm, das s. pediatric renal trauma. urology. 2002;59:762-7. 7. wessel lm, scholz s, jester i, et al. management of kidney injuries in children with blunt abdominal trauma. j pediatr surg. 2000;35:1326-30. figure 4. maximum intensity projection images, in sagittal section, better delineates the site of contrast medium leak outside gerota’s fascia. single percutaneous tract combined with flexible nephroscopy in the management of kidney stones 2-4 cm: better options of treatment protocols xiaobo zhang1,2,3, jie gu1,2, xiong chen1,2, yuanqing dai2, mingquan chen1, sheng hu1, zhenyu liu1, dongjie li1,2* purpose: to investigate the safety and efficacy of single percutaneous tract combined with flexible nephroscopy in the management of 2-4 cm renal calculi. materials and methods: we retrospectively analysed the treatment data of patients with 2-4 cm renal calculi from june 2010 to june 2017. the data included 217 cases of percutaneous nephrolithotomy (pnl), 441 cases of retrograde intrarenal surgery (rirs) and 217 cases of single-access percutaneous nephrolithotomy combined with flexible nephroscopy (pncfn). the collected data were analyzed. results: a total of 875 cases were studied, with an average age of 42.35 ± 10.29 years. group pncfn showed the highest stone-free rates (sfrs)(73.7 vs 66.7 vs 80.2, p = .00), best patient satisfaction (89.84 vs 87.23 vs 92.29, p = .00). the length of stay was shorter in the rirs group relative to the other two groups (5.22 vs 5.65 vs 3.72, p = .00). haemoglobin decrease (> 10 g/l) was higher in group pnl than that in group rirs and group pncfn (p = .012). hospitalization fees (rmb) were increased in group pncfn compared with that in group pnl and group rirs (34563.45 vs 21334.69 vs 33343.16, p = .000). treatment protocols of pnl decreased from 17.51% to 9.22%, those for rirs from 5.22% to 17.69%, peaking at 2012, pncfn from 8.29% to 15.67% showed a rapid growth trend. conclusion: the percutaneous nephrolithotomy combined with flexible nephroscopy treatment on renal calculi of 2-4 cm was associated with higher stone-free rates and better patient satisfaction than rirs and pnl. keywords: flexible nephroscopy; percutaneous nephrolithotomy; retrograde intrarenal surgery; stone free rate; patient satisfaction introduction renal calculi larger than two cm are known for their complexity of clearance, high risk in operation, and high rate of residuals and relapse. percutaneous nephrolithotomy (pnl) had been recommended as the firstchoice treatment for renal calculi larger than 2 cm(1). the advantages of pnl included higher efficiency and lower rates of residual stones(2). however, single-access pnl cannot effectively deal with parallel calices calculi; multiple-tract pnl in one session is effective while it caused more surgical trauma(3-5). many researchers have explored rirs to remove kidney stones 2 cm, reducing operation trauma and shortening length of stay. as rirs has a lower efficiency than pnl, it takes 1.2 to 1.7 more times of operation and leading to higher expenses to the patients(6), the one stage sfr was reported in 72.2% and even lower. residual stones are related to future stone events and concomitant surgery. flexible nephroscopy is able to reach more calyces and inspect them for residual fragments, it may reduce the use of the fluoroscopy and detection of the residual stones to 1xiangya international medical center, department of geriatrics, xiangya hospital, central south university, changsha, p. r. china, 410008. 2national clinical research center for geriatric disorders, central south university changsha, p. r. china, 410008. 3urolithiasis institute of central south university, changsha, p. r. china, 410008. *correspondence: department of geriatrics, xiangya international medical center, xiangya hospital, central south university, changsha, p. r. china, 410008. tel: +86 0731 89753054, e-mail: jerry1375@126.com. received june 2019 & accepted december 2019 improve the efficacy and reduce the morbidity of the procedure(7,8). in current research, with the emergence of new instrument flexible nephroscopy, single-access pncfn was used to deal with the 2-4 cm renal calculi. this method was expected to have higher calculi removal efficiency, lower risks in operation and a lower rate of residuals. so far, the study of the comparison among pcnl, rirs and pncfn in the management of kidney stones 2-4 cm at the same time is lacking. hence, we compared our clinical experiences and previous clinical cases, where rirs and pnl were adopted for 2-4 cm renal calculi removal for better reference when selecting treatment protocols. materials and methods clinical data our study was based on the clinical cases of 2-4 cm renal calculus treatment in our hospital from june 2010 to june 2017. the calculi sizes were measured through ct examination (single calculus 2-4 cm or multiple stones urology journal/vol 18 no. 1/ january-february 2021/ pp. 28-33. [doi: 10.22037/uj.v0i0.5427] endourology and stone disease vol 18 no 1 january-february 2021 20 2-4 cm combined). the participants were divided into 3 groups according to treatment methodology, including 217 cases of pnl, 441 cases of rirs and 217 cases of single-channel pncfn. all patients were informed about the procedures, and the surgical choice was made by the patient with counselling from the surgeon. all patients received appropriate preoperative antibiotic. the operation time was recorded from insertion of the endoscope to the completion of stent placement. all protocols in the present investigation were reviewed and approved by the ethical review committee of the xiangya hospital, central south university of china. an independent third-party survey center participated in the accurate reporting of patient satisfaction after surgery. all surgeries were completed by the same doctor. we recorded and analyzed patients' general information such as age, gender, the size of the calculi and bmi. the operation time, variation of haemoglobin, the sfrs, complications and length of stay were collected. the length of stay was recorded from admission to discharge. the inclusion criteria were applicable to all three surgical procedures: 1. age 20-80 years; 2. renal calculi 2~4 cm; 3. serious heart and lung diseases were excluded; 4. systemic haemorrhagic disease was excluded; 5. the ipsilateral gfr was more than 10 ml/min; 6. if both sides met the requirements, bilateral treatment was not included in the study; if staging treatment was performed, the first side of the clinical data was included in the study. operation protocol for the group pnl, operations were performed on patients under general anaesthesia in lithotomy position. a 4 fr retrograde ureteral catheter was inserted into the surgical side of the ureter with a ureteroscope. then the position was changed to prone. with the guidance of colour doppler ultrasound, the puncture point was located at the 11th-12th intercostal between the posterior axillary line and scapular line. the puncture was made through the fornix of calices, and then the tract was dilated to 20 fr with a balloon or coaxial dilators. a nephrostomy sheath was advanced over the balloon the management of kidney stones 2-4 cm -zhang et al. table 1. the detailed general patient information. pcnl rirs pncfn p value cases, n 217 441 217 n/a age, years 42.35 ± 11.20 42.62 ± 9.63 41.44 ± 10.36 0.379 bmi (kg/m2) 24.60 ± 3.40 24.99 ± 3.54 24.35 ± 3.37 0.069 gender (m/f) 100/117 220/221 107/110 0.647 stone burden (mm) 34.21 ± 4.81 34.57 ± 3.32 34.53 ± 2.86 0.470 stone location, n(%) 0.000 upper pole 20(9.22) 34(7.71) 18(8.29) middle pole 37(17.05) 113(25.62) 33(15.21) lower pole 74(34.10) 108(24.49) 84(38.71) renal pelvis 53(24.42) 131(29.70) 41(18.89) multiple stones 33(15.20) 55(12.47) 41(18.89) hydronephrosis, n(%) 0.327 no 58(26.73) 103(23.36) 49(22.58) mild 77(35.48) 140(31.75) 87(40.10) moderate 61(28.11) 152(34.47) 62(28.57) severe 21(9.68) 46(10.43) 19(8.76) urine leukocyte positive, n (%) 51 (23.50) 93 (21.09) 47 (21.66) 0.778 urine erythrocyte positive, n (%) 24 (11.06) 42 (9.52) 28 (12.9) 0.414 abnormal serum creatinine, n (%) 18 (8.29) 42 (9.52) 24 (11.06) 0.618 measurement data between groups were expressed as the mean ± sd (¯x ± s) one-way analysis of variance was used to compare the variables in different groups. counting data were shown as the number and/or percentage (%), using the chi-square test (χ2). p < 0.05 illustrates statistical significance. figure 1. changes in treatment protocols vol 18 no 1 january-february 2021 29 and the nephroscope or ureteroscope was placed along the sheath; when the calculi were detected, they were removed with a holmium laser (2.0-2.5 j, 20-25 hz, 550 μm). a routine postoperative indwelling ureteral stent was placed on the operative side. for the group rirs, the operations were performed on patients under general anaesthesia and in the lithotomy position. a 8.0-9.5 fr ureteroscopy was used to check the surgical side of the ureter up to the pelvis, and a smooth guidewire (0.89 mm, 150 cm, cook® medical, america) was placed. along the guidewire, a ureteral access sheath (12 fr cook® medical) was installed, then an olympus flexible ureteroscope was used. every calyx was examined via the flexible ureteroscope, and the calculi were removed with a holmium laser (0.81.0 j, 20 hz, 200 μm). larger stone fragments were removed using a 1.7 fr n gagetm nitinol basket (cook® medical, bloomington america). upon finishing the operation, each calyx was examined again. when the flexible ureteroscope was removed, the whole ureter was checked at the same time, while a routine postoperative indwelling ureteral stent was placed on the operative side. for the group pncfn a 20 fr tunnel was established in the same way as for group pnl. calculi were removed with a holmium laser (2.0-2.5 j, 20-25 hz, 550 μm) after the insertion of a nephroscope or ureteroscope. note that the angle change was avoided in the access to reduce the risk of laceration of calices’ necks. when calculi were difficult to reach, flexible nephroscopy with a holmium laser (0.8-1.0 j, 20 hz, 200 μm) was used to enter the calices through the 20 fr tunnel and remove the calculi. upon finishing the operation, each calyx, the pelvis and ureteropelvic junction was examined. and a routine postoperative indwelling ureteral stent was placed on the operative side. collected data consisted of patient age, gender, the size of the calculi and bmi. information about the operation time, variation of haemoglobin, sfrs, complications and length of stay were collected. after 4 weeks, if the non-contrast ct examination indicated no residual calculi or if the residual calculi were less than 4 mm and the patients showed no related symptoms, calculi removal was effectively performed. the ureteral stent was maintained for 4 weeks. an independent third party (hualun consulting co., ltd. hunan) was responsible for the satisfaction survey, which was conducted by telephone one month after discharge. patient satisfaction is a subjective quantitative score of the medical service. this questionnaire includes six main parts and 15 detailed indicators (figure 2). statistical analysis the statistical analysis was conducted using spss software, version 19.0. measurement data between groups were expressed as the mean ± sd ( ¯x ± s), one-way analysis of variance was used to compare the variables in different groups. counting data were shown as the number and/or percentage (%), using the chi-square test (χ2) to compare the variables in different groups. p < 0.05 illustrates statistical significance. results a total of 875 cases was studied, with an average age of 42.25 ± 10.35 years. the general information of the patients in each group is shown in table 1. among different groups, features such as age, bmi, maximum table 2. comparison of the perioperative related data. pcnl rirs pncfn p value stone-free n (%) 160(73.7) 294(66.7) 174(80.2) 0.000 operation time (min) 104.35 ± 40.65 129.17 ± 41.91 131.88 ± 45.63 0.000 bleeding (ml) 60.65 ± 40.42 23.86 ± 18.09 54.17 ± 31.81 0.000 conversion to open surgery n (%) 4(1.8) 2(0.5) 3(1.4) 0.211 length of stay (d) 5.65 ± 0.74 3.72 ± 1.24 5.22 ± 0.88 0.000 blood transfusion n (%) 6(2.8) 1(0.2) 4(1.8) 0.188 complications n (%) 21(9.7) 30(6.8) 11(5.1) 0.165 unplanned re-operation n (%) 5(2.3) 4(1) 2(0.9) 0.280 haemoglobin decrease (>10 g/l), n (%) 26 26 24 0.012 (12.0) (5.9) (11.1) fees (rmb) 21334.69 ± 3006.73 33343.16 ± 3639.04 34563.45 ± 5198.03 0.000 satisfaction score 89.84 ± 4.37 87.23 ± 5.99 92.29 ± 3.88 0.000 measurement data between groups were expressed as the mean ± sd (¯x ± s). one-way analysis of variance was used to compare the variables in different groups. counting data were shown as the number and/or percentage (%), using the chi-square test (χ2). p < 0.05 illustrates statistical significance. pcnl vs rirs pcnl vs pncfn rirs vs pncfn one-stage stone-free 0.065 0.111 0.000 operation time 0.000 0.000 0.000 bleeding 0.000 0.056 0.000 conversion to open surgery 0.078 0.703 0.181 length of stay 0.000 0.006 0.000 blood transfusion 0.099 0.801 0.142 complications 0.586 0.350 0.685 unplanned re-operation 0.147 0.253 0.985 hemoglobin decrease >10 g/l 0.014 0.880 0.021 hospitalization fees 0.000 0.000 0.001 patient satisfaction(discharged for one month) 0.000 0.000 0.000 one-way analysis of variance was used to compare the measurement variables in different groups. chi-square test (χ2) was used to compare the counting variables in different groups. p < 0.05 illustrates statistical significance. table 3. comparison of the perioperative data between every two groups. the management of kidney stones 2-4 cm -zhang et al. endourology and stones diseases 30 vol 18 no 1 january-february 2021 20 diameter of calculus, gender proportion, hydronephrosis, rate of urine leukocyte positive, rate of urine erythrocyte positive, and the proportion of abnormal serum creatinine showed no significant differences. the stone locations of lower pole and multiple stones in group pncfn was higher than that in groups pnl and rirs (38.71 vs 34.10 vs 24.49%, 18.89 vs 15.20 vs 12.47%). renal pelvis stones frequency in group pnl, rirs, pncfn were 24.42, 29.70, 18.89% respectively. the perioperative-associated parameters of different groups are shown in table 2. group pncfn had higher sfrs (80.2%, p = .00), better patient satisfaction (score 92.29, p = .00), but a longer operation time (131.88 min, p = .01). the length of stay in group pncfn was shorter than that in group pnl (multiple-tract was performed for 102 (47.0%) cases in the pnl group) but longer than that in group rirs (average 5.22 vs 5.65 vs 3.72 d, p < .001). haemoglobin decrease (> 10 g/l) was higher in group pnl than those in groups rirs and pncfn (p = .012). increased hospitalization fees (rmb) was observed in group pncfn compared to groups pnl and rirs (average 34563.45 vs 21334.69 vs 33343.16 rmb, p < .001). the reason for conversion to open surgery in group pcnl was that 2 patients were morbidly obese; 1 case of renal parenchymal laceration by multi-channel; and 1 case of anatomical abnormalities (renal neck stenosis). 1 case of ureteral avulsion injury and 1 case of intraoperative ureteral perforation necessitated conversion in the group rirs. 1 case of skeletal malformation and 2 case of ureteropelvic junction obstruction in group pncfn resulted in conversion. the rate of conversion to open surgery, ratio of blood transfusion, incidence of complications and rate of unplanned reoperation displayed no statistically significant differences. the comparisons of the perioperative data between every two groups are shown in table 3. compared to group pnl, group pncfn demonstrated a shorter length of stay (p = .006) and a higher patient satisfaction (p < .001), but a longer duration of operation (p < .001) and a higher hospitalization fees (p < 0.001). when comparing groups rirs and pncfn, group pncfn showed higher sfrs (p < .001) and patient satisfaction rates (p < .001), but greater bleeding (p < .001), longer length of stay (p < .001), and higher haemoglobin decrease (p < .001). the treatment protocols for 2-4 cm renal calculi are shown in figure 1. the choice of pnl decreased smoothly (17.51% to 9.22%), and rirs showed a rapid growth trend (5.22% to 17.69%, peaking at 2012). pncfn continued to increase steadily (8.29% to 15.67%). discussion guidelines recommend pnl as the first-choice treatment for renal calculi larger than 2 cm(9). however, parallel calices calculi with the treatment of single-track pnl was difficult. multiple-access pnl increased complications, such as haemorrhage.(10-12) the advantages of rirs include utilizing the inherent cavity of the human body, low trauma, fast recovery, and better curative effect(13). it can significantly reduce the incidence of surgical trauma and complications and shorten the average days of hospitalization(14). in our study, the average length of stay was 3.72d (rirs). however, due to the limitation of lithotripsy efficiency, rirs for renal calculi larger than 2 cm needs to be performed in stages, and the sfr is low. xiaokun zhao et al, reported a 92.0% sfr after 3 procedures for rirs with holmium laser lithotripsy (mean stone burden of 24.5 mm)(15). in our study, the one-stage sfr was 66.7% (rirs). moreover, the success rate of rirs was largely dependent on the angle between the funnel and the pelvis (infundibulopelvic angle, ipa). petrisor et al. found that when the ipa was between 30 and 90 degrees, the success rate of rirs was 74.3%, and when the ipa was less than 30 degrees, the success rate of flexible ureteroscopic lithotripsy became 0% (6). the eau and aua guidelines recommendation is that routine stenting is not necessary before rirs. however, pre-stenting facilitates rirs management of stones, improves the sfr, and reduces complications. in our study, if ureteral access is not possible, insertion of a 6 fr double-j stent 4 weeks before the second attempt offers an alternative to dilation. over the last 10 years, living standards and the econfigure 2. patient satisfaction the management of kidney stones 2-4 cm -zhang et al. vol 18 no 1 january-february 2021 31 omy improved, causing people to be more engaged health and healthcare consumers which lead to a rapid growth of less invasive rirs (figure 1). however, there remain several controversial issues in the application of flexible ureteroscopy, such as operation indication, operative skills, and cost efficiency. we focus on the hot issues that puzzle clinicians most, and hope our study will be able to help some urologists in clinical practice. our hospital did not introduce mini-percutaneous nephrolithotomy, super-mini percutaneous nephrolithotomy, or chinese minimally invasive percutaneous nephrolithotomy, which have improved smaller tracts and are less invasive(16-18). the use of flexible nephroscopy during pnl was known for its higher sfrs, fewer interventions and minimal bleeding(19). improvements in design and novel surgical instruments, such as flexible nephroscope and the introduction of the holmium: yag laser, increased the sfrs for pnl(20-22). williams et al. observed a high sfr and low morbidity rate with staghorn stones following single-access pnl and flexible nephroscopy(23). our results showed that there was an 80.2% (174/217) one-stage sfr for pncfn versus 66.7% (294/441) for rirs (p < .001), indicating that pncfn was an effective treatment protocol that provided more efficacy in patients with 2-4 cm renal calculi. bleeding is a major and troublesome complication of pnl. the volume of blood loss is associated with the number of access points, stone size, and duration of surgery 5,24. in our present study, the mean duration was slightly longer in group pncfn than that in group pnl (131.88 versus 104.35, p = .001) as shown in table 2, whereas the mean bleeding was 54.17 (pncfn) versus 60.65 ml (pnl), which showed no statistically significant differences (p = .056). this result may have been due to the lower number of interventions that were associated with flexible nephroscopy, or the use of a smaller diameter instrument that could reach stones that were inaccessible via rigid nephroscopy (with minimal damage to renal parenchyma)19. our puncture was made through the fornix of calices. the fornix of the papilla is the preferred site for a puncture to the collecting system(25). the principle behind this approach relies on the anatomical distribution of the blood vessels within the kidney, it is associated with less haemorrhagic risk (26,27). the patient satisfaction survey was relevant and meaningful, and assessed patient satisfaction using an independent, third-party survey center to eliminate observer bias(28,29). although it is a comprehensive data, there are many influencing factors, however it can reflect the satisfaction to some extent. in our study, the mean score of patient satisfaction was the highest in group pncfn 92.29, as represented in table 2, which was higher than 89.84 (pnl) and 87.23 (rirs), and this result may have been due to the high one-stage sfr (73.7% vs 80.2%), less bleeding (54.17 vs 60.65ml), less complications (11(5.1%) vs 21(9.7%) and the decreased length of stay (5.22 vs 5.65) compared to pnl, although more instruments were used and the expenses were slightly higher than those for pnl. another crucial factor was that there were no multi-channel cases in group pncfn. to our knowledge, our study is the first to report the comparison among pnl, rirs and pncfn. there are no assessments of the three protocols based on patient satisfaction by independent investigators. the complications were low in the three groups, and it showed no statistically significant differences, which may be due to a small sample size. to clarify whether the two were correlated, larger sample sizes are needed to evaluate the long-term outcome of our study. retrospective design is a drawback of our study, we do agree that prospective and randomized design is needed in the future studies. when multiple treatment protocols compete in the clinical setting, decisions of the optimal treatment option in an individual patient are mainly dependent on medical factors, including procedural efficacy, success rate and safety. from a broader perspective, these decisions reflect comprehensive factors including the above mentioned factors, as well as doctor`s preference, cost-effectiveness, medical care status, and insurance authorization. therefore, identifying the changing trends in the numbers or rates of certain treatments is meaningful and may provide a comprehensive assessment of the treatment of kidney stones 2-4 cm that can be used in clinical management. in our study, a single access percutaneous nephrolithotomy combined with flexible nephroscopy was used, which gave full play to the advantages of flexible and rigid nephroscopy. salient advantages of our pncfn include one-stage stonefree rate of 80%, length of stay shortened to 5.22 days and improved patient satisfaction. in addition, the cost of the pncfn was marginally higher than that of the rirs, which is also in favour of the promotion of the pncfn surgery in the primary hospitals. as far as we know, our study is the first to report the comparison among pnl, rirs, and pncfn at the same time. there are no assessments of the three protocols based on patient satisfaction by independent investigators in one study. our study had certain limitations. there may be a choice bias in this study. fortunately, the study has a large sample size so that this bias is effectively reduced, and table 1 shows no significant difference in the baseline data of each group. conclusions the percutaneous nephrolithotomy combined with flexible nephroscopy treatment on renal calculi of 2-4 cm was associated with higher stone-free rates and better patient satisfaction than rirs and pnl. acknowledgements we thank mingquan chen for editorial assistance with our manuscript funding the project was supported by the china graduate contest on smart-city technology and creative design (grant no.2018jspy108). conflict of interest all authors declare that they have no conflict of interest or financial ties to disclose. references 1. türk c, skolarikos a, neisius a et al. eau guidelines on urolithiasis 2019. eau guidelines office, arnhem, the netherlands. https://uroweb.org/guideline/urolithiasis/. the management of kidney stones 2-4 cm -zhang et al. vol 18 no 1 january-february 2021 23endourology and stones diseases 32 2019 2. saad ksm, youssif me, hamdy sain et al. percutaneous nephrolithotomy (pcnl) versus retrograde intra-renal surgery (rirs) in treatment of large renal stones (>2cm) in pediatric patients: a randomized controlled trial. j urol 2015;194:1716-1720 3. akman t, sari e, binbay m et al. comparison of outcomes after percutaneous nephrolithotomy of staghorn calculi in those with single and multiple accesses. j endourol. 2010;24(6):955-60 4. akman t, binbay m, sari e et al. factors affecting bleeding during percutaneous nephrolithotomy: single surgeon experience. j endourol. 2011;25:327-33 5. chen j, zhou x, chen z et al. multiple tracts percutaneous nephrolithotomy assisted by lithoclast master in one session for staghorn calculi: report of 117 cases. urolithiasis. 2014;42:165-9 6. geavlete p, multescu r, geavlete b. influence of pyelocaliceal anatomy on the success of flexible ureteroscopic approach. j endourol. 2008;22:2235-9 7. gokce mi, gulpinar o, ibis a et al. retrograde vs. antegrade fl exible nephroscopy for detection of residual fragments following pnl: a prospective study with computerized tomography control. int braz j urol. 2019;45:581-587 8. sfoungaristos s, mykoniatis i, katafigiotis i et al. single lower calyceal percutaneous tract combined with flexible nephroscopy: a valuable treatment paradigm for staghorn stones. can urol assoc j. 2018;12:e21-e24 9. assimos d, krambeck a, miller nl et al. surgical management of stones: american urological association/endourological society guideline, part ii. j urol. 2016;196:1161-9 10. el-nahas a, shokeir a, el-assmy a et al. 882 post percutaneous nephrolithotomy extensive hemorrhage: a study of risk factors. j urology. 2007;177:576 11. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899 12. bucuras v, gopalakrishnam g, jr wj et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: nephrolithotomy in 189 patients with solitary kidneys. j endourol. 2011;25:11-7 13. akman t, binbay m, ozgor f et al. comparison of percutaneous nephrolithotomy and retrograde flexible nephrolithotripsy for the management of 2–4cm stones: a matchedpair analysis. eur urol suppl. 2011;10:1384– 1389 14. chen x, li d, dai y et al. retrograde intrarenal surgery in the management of symptomatic calyceal diverticular stones: a single center experience. urolithiasis. 2015;43:557-562 15. huang z, fu f, zhong z et al. flexible ureteroscopy and laser lithotripsy for bilateral multiple intrarenal stones: is this a valuable choice? urology. 2012;80:800-804 16. zeng g, zhu w, liu y et al. the new generation super-mini percutaneous nephrolithotomy (smp) system: a step-by-step guide. bju int. 2017; 17. zhu w, li j, yuan j et al. a prospective and randomised trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini-percutaneous nephrolithotomy. bju int. 2016;119 18. huang z, fu f, zhong z et al. chinese minimally invasive percutaneous nephrolithotomy for intrarenal stones in patients with solitary kidney: a singlecenter experience. plos one. 2012;7:e40577 19. gucuk a, kemahli e, uyeturk u et al. routine flexible nephroscopy for percutaneous nephrolithotomy for renal stones with low density: a prospective, randomized study. j urol. 2013;190:144-8 20. albala dm, assimos dg, clayman rv et al. lower pole i: a prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for lower pole nephrolithiasis-initial results. j urol. 2001;166:2072-80 21. wong c, leveillee rj. single upper-pole percutaneous access for treatment of > or = 5-cm complex branched staghorn calculi: is shockwave lithotripsy necessary? j endourol. 2002;16:477-81 22. gao x, zeng g, chen h et al. a novel ureterorenoscope for the treatment of upper urinary tract stones: initial experience from a prospective multicentre study. j endourol. 2015;29 23. williams sk, leveillee rj. management of staghorn calculus: single puncture with judicious use of the flexible nephroscope. curr opin urol. 2008;18:224-8 24. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016;13:2899-2902 25. basiri a, kashi ah, zeinali m et al. ultrasound guided access during percutaneous nephrolithotomy: entering desired calyx with appropriate entry site and angle. int braz j urol. 2016;42:160-1167 26. miller nl, matlaga br, lingeman je. techniques for fluoroscopic percutaneous renal access. j urology. 2007;178: 15-23 27. sampaio fj. renal anatomy. endourologic considerations. urol clin n am. 2000;27:585607 28. nunley rm, nam d, berend kr et al. new total knee arthroplasty designs: do young patients notice? clinical orthopaedics and related research®. 2015;473:101-108 29. nam d, nunley rm, berend me et al. residual symptoms and function in young, active hip arthroplasty patients: comparable to normative controls? j arthroplasty. 2016;31:1492-7 the management of kidney stones 2-4 cm -zhang et al. vol 18 no 1 january-february 2021 33 1162 | horseshoe kidney with complete unilateral duplication of ureter and pelvicalyceal systema case report vipin tyagi, tanveer iqbal dar, abdul rouf khawaja, sudhir chadha keywords: abnormalities; kidney; humans; urogenital abnormalities; ureter. introduction horseshoe kidney is the most common fusion abnormality in the kidney and oc-curs in 1 per 400 people with the male female ratio of 2:1.(1) duplication of renal collecting system is the most common upper tract anomaly with an incidence of 0.5-0.8%.(2) unilateral duplication is six times more frequent than bilateral duplication, with equal incidence on right and left sides.(3) however duplicated system in a horseshoe kidney is very rare. most patients with horseshoe kidney are asymptomatic, up to 80% have hydronephrosis, about 20% develop renal calculi and 1/3-1/2 of cases have another associated anomaly.(2) the aim of this report is to highlight its rarity and technical difficulties in its management. case report a 30 years male patient presented to our department with history of left flank pain since last few months. base line investigations revealed serum creatinine of 1.05 mg/dl, hemoglobin 13.5 g/dl and urine routine-microscopy showed pus cells 15-20/hpf. on evaluation he was found to have horseshoe kidney with bilateral pelvic calculi. ultrasonography showed left small kidney (7 × 5 × 3 cm) with large pelvic calculus, gross hydronephrosis and thinned out cortex. intravenous urography showed no contrast uptake on left side and normally functioning right kidney with right complete duplex system and bilateral renal calculi (figure). dtpa scan showed left nonfunctioning kidney and normally functioning right kidney. cystoscopy corresponding author: tanveer iqbal, md department of urology and kidney transplant surgery, sir ganga ram hospital, new delhi, 110060, india. tel: +11 4225 1235 e mail; drtanveerdar@gmail.com received october 2011 accepted february 2012 department of urology, sir ganga ram hospital, new delhi, 110060, india, case report case report 1163vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l horseshoe kidney with complete collecting system duplication | tyagi et al showed two ureteric orifices on right side and only one on left side. he was subjected to right pcnl, complete stone clearance was achieved. after one month left heminephrectomy was performed through a left flank sub costal incision. findings of single ureter with three arteries and two veins were noted on left side during open retroperitoneal nephrectomy. left kidney was hydronephrotic with very thin cortex and its ureter was crossing in front of the isthmus. isthmus was divided at a line where thinned out cortex ended and normal cortex was evident. he recovered well and was discharged on 5th post-operative day. histopathological study of the kidney showed features of chronic pyelonephritis. he is following our outpatient department since then (two months) and is doing well. discussion horseshoe kidneys may be a result of teratogenic factors, which may also be responsible for the known increase in the incidence of related congenital anomalies and nephroblastoma.(4) christoffersen and colleagues stated that combination of horseshoe kidneys with bilateral ureteral duplication is a very rare entity. only two cases have been reported till now. (2,5) he described a case of partial hydronephrosis, bilateral duplication of the pelvis and ureter with horseshoe kidney. (5) similarly kuzel and colleagues described a horseshoe kidney with bilateral double pelvis system and double ureters.(6) kevin and colleagues reported a horseshoe kidney with bilateral partial duplex pelvicalyceal system and ureter in a cadaver during its anatomical dissection. he concluded that intravenous urography (ivu) is the main radiological investigation method to diagnose this anomaly.(7) we report a case of unilateral complete duplex system in a horse shoe kidney. we reviewed literature by searching in google and pub med database, using “horseshoe kidney with unilateral completely duplicated system” as key words and found no such case reported till date. khong and colleagues reported a 9-month-old boy who had a horseshoe kidney, associated with bilateral single system ectopic ureters. the right ureteric orifice was located near the midline of a deformed trigone while the grossly dilated left ureter inserted into the posterior urethra.(8) pode and colleagues reported a case of unilateral triplication of the collecting system in a horseshoe kidney.(9) clinicians should be conscious of complete duplex systems in horseshoe kidneys which is very rare and may pose a diagnostic and interventional challenge. conflict of interest none declared. figure. x ray of kub region showing right side horseshoe kidney with complete duplication of ureter and pelvis. left renal radio opaque shadow (stone) is seen with no contrast uptake. references 1. glodny b, petersen j, hofmann kj, et al. kidney fusion anomalies revisited: clinical and radiological analysis of 209 cases of crossed fused ectopia and horseshoe kidney. bju int. 2009;103:224-35. 2. keskin s, erdogan n, kurt a, tan s, ipek a. bilateral partial ureteral duplication with double collecting system in horseshoe kidney. adv med sci. 2009;54:302-304. 1164 | 3. schlussel rn, retik ab. ectopic ureter, ureterocele, and other anomalies of the ureter. chapter 58. in: walsh pc (ed). campbell’s urology, 8th edn. philadelphia: saunders; 2002. p. 2007-52. 4. hohenfellner m, schultz-lampel d, lampel a, steinbach f, cramer bm, thuroff jw. tumor in the horseshoe kidney: clinical implications and review of embryogenesis. j urol.1992;147:1098-102. 5. christoffersen j, iversen hg. partial hydronephrosis in a patient with horseshoe kidney and bilateral duplication of the pelvis and ureter. scand j urol nephrol. 1976;10:91-93. 6. kuzel m, makarewicz j, musial s, sarzynska m. case of horseshoe kidney with bilateral double pelvis system and double ureters (in polish). pediatr pol. 1979;54:407-9. 7. kevin w. ongeti, julius ogeng’o, hassan saidi. a horseshoe kidney with partial duplex systems. ijav. 2011;4:55-56. 8. khong pl, peh wc, mya gh, chan kl, saing h. horseshoe kidney with bilateral single system ectopic ureters. aust n z j surg. 1996;66:773-6. 9. pode d, shapiro a, lebensart p. unilateral triplication of the collecting system in a horseshoe kidney. j urol. 1983;130:533-4. case report v08_no_4_final_new.pdf pediatric oncology 287urology journal vol 8 no 4 autumn 2011 management and follow-up of pediatric asymptomatic testicular microlithiasis are we doing it well? massimiliano silveri,1 francesca bassani,1 mauro colajacomo,2 cinzia orazi,2 ottavio adorisio1 purpose: to define timing and methods for a balanced follow-up of testicular microlithiasis (tm) in pediatric age. materials and methods: we retrospectively reviewed medical records of 21 pediatric asymptomatic patients (42 testicular units) diagnosed with tm and without associated risk factors. microliths were found bilaterally on ultrasonography in all the patients. distribution of microliths (focal or diffuse) inside the parenchyma was evaluated as well as its eventual variation over time. every six months, each patient underwent clinical and ultrasonography evaluation, as well as serum chemistry markers ( -fetoprotein and -human chorionic gonadotropin) measurement to detect potential malignancy. in the interval between the follow-ups, parents and/or patients themselves were asked to control eventual enlargement of the gonads or scrotal swelling. testicular biopsy was not performed in any of our subjects. results: of 21 patients, 6 had unilateral undescended testis, 4 varicocele, and 1 patent processus vaginalis with scrotal swelling while 10 patients did not show associated anomalies. the distribution pattern of microliths on ultrasonography remained unchanged in all follow-ups in every patient, showing a predominance of diffuse pattern in the undescended testis series. tumor markers remained within normal limits. in no subject, we observed a shift toward a malignant condition. conclusion: in the pediatric population with an incidentally diagnosed tm and without any associated risk factor, a slight follow-up is suggested, consisting of clinical evaluation every 6 months, without any justifiable recommendation to perform a testis biopsy and a measurement of serum tumor markers. urol j. 2011;8:287-90. www.uj.unrc.ir keywords: testis, testicular diseases, testicular neoplasms, child, lithiasis 1department of pediatric surgery, bambino gesù children hospital, palidoro (rome), italy 2department of imaging and radiodiagnostic, bambino gesù children hospital, palidoro (rome), italy corresponding author: massimiliano silveri, md department of pediatric surgery, bambino gesù children hospital, via torre di palidoro 00050, palidoro (rome), italy tel: +39 06 6859 3316 fax: +39 06 6859 3373 e-mail: massimiliano.silveri@gmail. com received april 2011 accepted august 2011 introduction testicular microlithiasis (tm) is a relatively rare clinical entity characterized by the existence of microliths located in the seminiferous tubules and composed of hydroxyapatite.(1) a relatively large number of benign and malignant conditions, such as testicular torsion or atrophy, cryptorchidism, gonadal dysgenesis, varicocele, klinefelter syndrome, and male pseudohermaphroditism are strictly related to microlithiasis.(2,3) giving complete information about clinical implications of tm to parents, the opportunity of a clinical and instrumental endless pediatric asymptomatic testicular microlithiasis—silveri et al 288 urology journal vol 8 no 4 autumn 2011 follow-up is experienced as a “sword of damocle” for the whole life-time. we studied asymptomatic pediatric patients with tm to verify risks and benefits of a closed, aggressive instrumental and clinical follow-up since an early age opposite to an individualized and balanced one according to well-known riskfactors. materials and methods data from 21 patients who suffered from an incidentally discovered tm were retrospectively reviewed. they were all observed at our institution since january 2002. microliths were found bilaterally in all the patients (42 testicular units). all of them underwent ultrasonography performed with high frequency (10 to 17 mhz) linear transducers. distribution of microliths (focal or diffuse) inside the parenchyma was evaluated as well as its eventual variation over time. every six months, each patient underwent a clinical and ultrasonographyevaluation as well as serum chemistry markers ( -fetoprotein and -human chorionic gonadotropin) determination to detect potential malignancy. in the interval time between the follow-ups, parents and/or patients themselves were asked to control, throughout regular examination or self-examination, eventual enlargement of the gonads or scrotal swelling. a testicular biopsy was not performed in any of our subjects according to recommendations for asymptomatic and apparently healthy patients.(4) results mean age of the patients and the mean followup duration were 10.5 years (range, 8 months to 18 years) and 41.2 months, respectively. as table shows, of 21 patients, 6 had unilateral undescended testis, 4 varicocele, and 1 patent processus vaginalis with scrotal swelling while 10 patients (two of them twins) did not show associated anomalies. the younger patient was an 8-month-old boy with a left undescended testis and an underlying bilateral partially diffuse microlithiasis (figure 1). all the patients who resulted as normal were referred to us after they underwent a scrotal ultrasonography to detect an adolescent patient age at diagnosis right testis left testis tumor markers ultrasonographic distribution pattern associated pathology 1 8 mos yes yes nl diffuse undescended testis 2 9 yrs yes yes nl diffuse undescended testis 3 18 yrs yes yes nl focal varicocele 4 4 yrs yes yes nl focal hydrocele 5 11 yrs yes yes nl focal 6 11 yrs yes yes nl focal 7 8 yrs yes yes nl diffuse undescended testis 8 17 yrs yes yes nl focal 9 9 yrs yes yes nl focal varicocele 10 16 yrs yes yes nl focal 11 15 yrs yes yes nl diffuse 12 10 yrs yes yes nl focal 13 11 yrs yes yes nl focal 14 13 yrs yes yes nl focal 15 11 yrs yes yes nl focal varicocele 16 13 yrs yes yes nl diffuse varicocele 17 15 yrs yes yes nl diffuse undescended testis 18 17 yrs yes yes nl focal 19 2 yrs yes yes nl diffuse undescended testis 20 12 mos yes yes nl focal undescended testis 21 9 yrs yes yes nl focal twenty-one pediatric patients with testicular microlithiasis mos indicates months; yrs, years; and nl, normal. pediatric asymptomatic testicular microlithiasis—silveri et al 289urology journal vol 8 no 4 autumn 2011 varicocele. two of them were monozygotic twins with a focal distribution pattern of microliths (figure 2). the distribution pattern of microliths on ultrasonography remained unchanged in all the serial follow-ups in every patient, showing a predominance of diffuse pattern in the undescended testis series (n. 1, 2, 7, 17, and 19 of our series). tumor markers determination performed in all the patients, which were within normal limits. in no subject, we observed a shift toward a malignant condition. discussion the first description of tm and ultrasonography dates back to 1965(5) and 1987,(6) respectively. the first report of a pediatric case dates back to 1970.(7) nowadays, state of the art of the literature on the argument tends toward a clear separation between incidentally discovered tm in a healthy patient and microliths accompanying a testicular tumor or found in a testis that suffered from a torsion and/or a hemorrhagic infarction.(4,8) furthermore, grading of tm as observed on ultrasonography seems to have no effect on the prevalence of associated malignancy.(9) a prevalent category of patients, in our opinion needing a high level of suspicion, includes those children with underlying pathologies, such as disorders of sex development, wt1 gene mutation related syndromes,(10) mccune–albright,(11) and klinefelter syndrome.(12) however, the most common pediatric patient observed having a tm is that who underwent an ultrasonography examination for an associated cryptorchidism or varicocele. we believe that undescended testis and the varicocele itself may not be considered as a risk factor even if they are associated with tm. subfertility related to varicocele and eventual hormonal therapies may, nevertheless, be judicious in a patient with tm. associated risk factors determine the intensity of long-term follow-up period. in a land of reports that associate tm from lentigines(13) to mediastinal germ cell tumor,(14) experts on the field are still debating if tm is a benign or a premalignant condition.(15-18) obviously, not all the patients with a diagnosed tm are at risk for testicular cancer development, but association with already known risk factors, such as hypogonadism, intersexual conditions, wt1 gene-related syndromes, and familial history of testicular germ cell tumors (tgct), renders it a really worrisome entity. how to organize and plan a balanced follow-up since an early age in order to ensure a proper protection from malignancy is a challenging matter. there are not updated data suggesting that testicular tumors may arise in a pediatric population with an incidentally discovered tm. furthermore, suggestions to perform a biopsy in a pediatric patient with the testis with microliths without any other risk factors, above all in a bilateral condition, seem really questionable. as a matter of fact, in a recently published report, figure 1. an 8-month-old boy with a left undescended testis and an underlying bilateral partially diffuse microlithiasis. figure 2. focal distribution pattern of microliths. pediatric asymptomatic testicular microlithiasis—silveri et al 290 urology journal vol 8 no 4 autumn 2011 two high-risk groups were identified fitting the decision to perform a biopsy: patients with unilateral tgct and patients with extragonadal tgct. (19) adult patients with tm based on the scrotal ultrasonography might be possibly considered for biopsy when additional scrotal anomalies and/or infertility are present. measurement of serum tumor markers, even at an interval time of 6 months, has not proven to be a useful and justifiable method to ensure a safe surveillance, and this is also why the onset of a tgct may require a less time than the interval to develop and grow. a review of the literature on the incidence of testicular malignancy in pediatric patients revealed few case reports and two relevant case series with a definitive prevalence of 4.2% among asymptomatic boys.(7,8,20-23) conclusion in a pediatric population with asymptomatic and incidentally discovered tm and without an association with well-known risk factors, a conservative approach is recommended. in this selected category of patients with tm, testicular biopsy and measurement of serum markers are not recommended. conflict of interest none declared. references 1. de jong bw, de gouveia brazao ca, stoop h, et al. raman spectroscopic analysis identifies testicular microlithiasis as intratubular hydroxyapatite. j urol. 2004;171:92-6. 2. miller rl, wissman r, white s, ragosin r. testicular microlithiasis: a benign condition with a malignant association. j clin ultrasound. 1996;24:197-202. 3. derogee m, bevers rf, prins hj, jonges tg, elbers fh, boon ta. testicular microlithiasis, a premalignant condition: prevalence, histopathologic findings, and relation to testicular tumor. urology. 2001;57:1133-7. 4. tan mh, eng c. testicular microlithiasis: recent advances in understanding and management. nat rev urol. 2011;8:153-63. 5. bieger rc, passarge e, mcadams aj. testicular intratubular bodies. j clin endocrinol metab. 1965;25:1340-6. 6. doherty fj, mullins tl, sant gr, drinkwater ma, ucci aa, jr. testicular microlithiasis. a unique sonographic appearance. j ultrasound med. 1987;6:389-92. 7. priebe cj, jr., garret r. testicular calcification in a 4-year-old boy. pediatrics. 1970;46:785-8. 8. furness pd, 3rd, husmann da, brock jw, 3rd, et al. multi-institutional study of testicular microlithiasis in childhood: a benign or premalignant condition? j urol. 1998;160:1151-4; discussion 78. 9. sanli o, kadioglu a, atar m, acar o, nane i. grading of classical testicular microlithiasis has no effect on the prevalence of associated testicular tumors. urol int. 2008;80:310-6. 10. zugor v, zenker m, schrott km, schott ge. [frasier syndrome: a rare syndrome with wt1 gene mutation in pediatric urology]. aktuelle urol. 2006;37:64-6. 11. wasniewska m, matarazzo p, weber g, et al. clinical presentation of mccune-albright syndrome in males. j pediatr endocrinol metab. 2006;19 suppl 2:619-22. 12. aizenstein ri, hibbeln jf, sagireddy b, wilbur ac, o’neil hk. klinefelter’s syndrome associated with testicular microlithiasis and mediastinal germ-cell neoplasm. j clin ultrasound. 1997;25:508-10. 13. leman j, brush jp, tidman mj. multiple lentigines and testicular microlithiasis. clin exp dermatol. 2000;25:655-6. 14. howard rg, roebuck dj, metreweli c. the association of mediastinal germ cell tumour and testicular microlithiasis. pediatr radiol. 1998;28:998. 15. bach am, hann le, hadar o, et al. testicular microlithiasis: what is its association with testicular cancer? radiology. 2001;220:70-5. 16. bach am, hann le, shi w, et al. is there an increased incidence of contralateral testicular cancer in patients with intratesticular microlithiasis? ajr am j roentgenol. 2003;180:497-500. 17. dagash h, mackinnon ea. testicular microlithiasis: what does it mean clinically? bju int. 2007;99:157-60. 18. costabile ra. how worrisome is testicular microlithiasis? curr opin urol. 2007;17:419-23. 19. dieckmann kp, kulejewski m, heinemann v, loy v. testicular biopsy for early cancer detection-objectives, technique and controversies. int j androl. 2011;34:e7-13. 20. goede j, hack ww, van der voort-doedens lm, pierik fh, looijenga lh, sijstermans k. testicular microlithiasis in boys and young men with congenital or acquired undescended (ascending) testis. j urol. 2010;183:1539-43. 21. van casteren nj, looijenga lh, dohle gr. testicular microlithiasis and carcinoma in situ overview and proposed clinical guideline. int j androl. 2009;32: 279-87. 22. drut r, drut rm. testicular microlithiasis: histologic and immunohistochemical findings in 11 pediatric cases. pediatr dev pathol. 2002;5:544-50. 23. chiang lw, yap tl, asiri mm, phaik ong cc, low y, jacobsen as. implications of incidental finding of testicular microlithiasis in paediatric patients. j pediatr urol. 2011. review safety of surgery in benign prostatic hyperplasia patients on antiplatelet or anticoagulant therapy: a systematic review and meta-analysis xiongfa liang1,2,*, weizhou wu1,2,*, yapeng huang1,2, shike zhang1,2, jian huang1,2, tao zeng1,2, fangling zhong1,2, yongchang lai1,2, xiaolu duan1,2, chao cai1,2, alberto gurioli3, tuo deng1,2, wenqi wu#1,2 purpose: the management strategies of anticoagulant (ac) or antiplatelet (ap) therapy in the preoperative period of benign prostatic hyperplasia (bph) is still controversial. therefore, a meta-analysis to systematically evaluate the surgical safety for bph patients on ac or ap therapy was performed. materials and methods: the protocol for the review is available on prospero (crd42018105800). a literature search was performed by using medline, web of science, pubmed, cochrane library, and embase. summarized odds ratios (or), mean difference (md) and 95% confidence intervals (ci) were used to assess the difference in outcomes. results: we identified 13 trials with a total of 3767 patients. an intragroup significant difference was found in bleeding complications and blood transfusions when undergoing transurethral resection of the prostate (turp). for laser surgery, the intragroup significant difference was found in the result of blood transfusion. bridging therapy would not cause a higher risk of bleeding complications and blood transfusion during the perioperative period. besides, no difference existed in operation time, catheterization time, hospitalization, and thromboembolic events. conclusion: patients with bph on perioperative ac/ap therapy would have a risk of postoperative hemorrhage after turp or laser treatments. to reduce the risk of hemorrhage, bridging therapy could be a good choice. keyword: transurethral resection of prostate (turp); laser treatment; benign prostatic hyperplasia (bph); anticoagulant; antiplatelet introduction benign prostatic hyperplasia (bph) is a disease common in men over 50 years of age. up to 50% of men in their sixth decade suffer from bph, and the corresponding rate was increased with age(1) the men troubled by lower urinary tract symptoms need drug treatment or surgical intervention. for pharmacological treatment, α1-adrenoceptor antagonists like tamsulosin can effectively improve lower urinary tract symptoms. (2) nevertheless, α1-adrenoceptor antagonist cannot prevent the occurrence of urinary retention or the need for surgery. transurethral resection of the prostate (turp) has been the gold standard for the surgical management of bph in recent decades. however, morbidity followed with turp is still concerned, especially bleeding requiring blood transfusion and late postoperative bleeding.(3) with an aging population and a high incidence of cardiovascular disease, the number of patients requiring anticoagulant (ac) or antiplatelet (ap) therapy is steadily growing.(4) with an increasing elderly population requiring surgical procedures for bph treatment and long-term use of anticoagulants, the management strategies of ac/ap therapy in the preoperative period remain controversial. some surgeons prefer to discontinue ac/ap therapy and replaced low molecular weight heparin (lmwh) in advance of surgery, whereas others continue ac/ap therapy perioperatively. recently, a number of laser techniques have emerged as alternatives to turp including the holmium yttrium aluminum garnet neodymium (ho:yag), thulium laser, and potassium titanyl phosphate (ktp, also known as the greenlight), offering new options for patients with bph. these laser surgeries present the advantage of hemostasis comparing with turp and have been an effective tool for bph.(5-8) all types of lasers are considered suitable and safe for patients taking anticoagulants in the recommendation of european association of urology (eau) guidelines for the treatment of bph. furthermore, eau guidelines on the surgical treatment of bph nominated that 532-nm laser vaporization should be considered in patients receiving anticoagulant medication or for those with a high cardiovascular risk.(9) however, the eau guidelines did not mention whether preoperative anticoagulant therapy should be urology journal/vol 18 no. 2/ march-april 2021/ pp. 151-158. [doi: 0.22037/uj.v16i7.5974] 1department of urology, minimally invasive surgery center, the first affiliated hospital of guangzhou medical university, china. 2guangdong key laboratory of urology, guangzhou, guangdong, china. 3department of urology, turin university of studies, italy. *correspondence: department of urology, minimally invasive surgery center, the first affiliated hospital of guangzhou medical university, guangdong key laboratory of urology, guangzhou, guangdong, china. kangda road. haizhu district, guangzhou, guangdong, china, 510230. email: wwqwml@163.com. * these authors contributed equally to this work. received february 2020 & accepted july 2020 vol 18 no 2 march-april 2021 138 withdrawn regardless of whether traditional turp or advanced laser technology is selected. similarly, the national institute for health and care excellence (nice) guidelines did not specify the perioperative management of patients under ac/ap therapy.(10) therefore, we performed this meta-analysis based on the current evidence to assess the safety of surgery in bph patients on ac/ap therapy. our goal was to derive an evidence-based recommendation for clinical practice. materials and methods literature search the present meta-analysis was performed in accordance with the preferred reporting item for systematic reviews and meta-analysis (prisma) guidelines. the protocol for the review was available on prospero (crd42018105800; https://www.crd.york.ac.uk/prospero/). the studies were identified by a literature search of medline, web of science, pubmed, cochrane library and embase database articles published up to july 2019. separate searches were completed using the following search terms: benign prostatic hyperplasia, bph, transurethral resection of the prostate, turp, holmium laser enucleation of the prostate, holep, photoselective vaporization of the prostate, pvp, thulium vaporesection of the prostate, thuvarp, laser therapy, anticoagulants, antiplatelet, aspirin, warfarin, coumadin and clopidogrel. the detailed retrieval strategy was listed in s1 file. in addition, a manual search was also performed in the references from the included studies and databases like embase. no temporal, regional, publication status, or language restrictions were applied. inclusion and exclusion criteria literature searching, study examinations, data extractions, study quality assessment and statistical analyses were conducted by two authors (jh and yh) independently. disagreement was resolved through consultation with the third author (tz). eligibility criteria for the included studies were defined base on the picos principles: (1) participants (p): patients having a series of symptoms of urinary obstruction, with clinical and laboratory evidence suggesting enlarged prostate and necessitating surgical treatment. (2) interventions (i) and comparisons (c): exploring the safety of surgery in bph patients on ac/ap therapy compared with the patients who do not need ac/ap therapy. (3) outcomes (o): including at least one of the predefined outcome measurements. (4) study design (s): randomized controlled trials (rcts), case-control studies or cohort studies with relative data could be used directly or indirectly. in contrast, studies were excluded if the inclusion criteria were not met or the relevant data could not be extracted in the appropriate format and obtaining the data from the authors. additionally, studies as conference proceedings, reviews, case reports, abstracts, and unpublished studies were excluded from this study. procedures patients on ac/ap therapy during the surgery for bph constituted ac/ap group, and patients who do not need ac/ap therapy formed the control group. the following variables from each study were recorded independently by two reviewers: first author name; publication year; study period; research design type; ac/ ap type; total number of patients enrolled; psa (prostate-specific antigen level); ipss (international prostate symptom score); maximum urinary flow; prostate volume; weight of resected tissue; and age of patients. in addition, the following outcome measures were extracted: operative time, bleeding complications, thromboembolic events, blood transfusion, length of hospital stay, and catheterization time. bleeding complication is a combined concept described in the included studies. several studies directly defined bleeding complication as an extended period of bladder irrigation (3 or more days postoperatively), clot retention or persistent hematuria necessitating recatheterization.(11-13) while two only record incidents of persistent hematuria,(14,15) and the other one record incidents of extended period of bladder irrigation.(16) thromboembolic events, as included studies described, was defined as pulmonary embolism, deep venous thrombosis, acute coronary syndromes, and cerebrovascular events like stroke.(12, 1719) outcome of bleeding complication and blood transfusion, assessing the degree of hemorrhage, were the key parameters evaluating the safety of the surgery for bph patients with ac/ap therapy. discrepancies were resolved through consultation with the third author. safety of bph surgery under anticoagulants-liang et al. table 1. characteristics and quality evaluation of including studies. study country study period design no. of patients age comparability study quality ac/ap control ac/ap control ala-opas et al. 1995 finland may. 1993 to feb. 1994 cct 40 42 69 (53-85) 75 (64-86) ①④⑥ 4 (nos) dotan et al. 2002 america nov. 1997 to feb. 2001 cct 20 20 n/a n/a ①③④⑤ 6 (nos) nielsen et al. 2000 denmark 1996 to 1998 rct 26 27 70 (66-74) 69 (65-76) ①②③④⑤⑥ 3 (jadad) descazeaud et al. 2011france jan. 2007 to dec. 2008 cct 55 406 75 ± 14.14 71 ± 14.14 ②③④⑤⑥ 6 (nos) taylor et al. 2011 australia jan. 2008 to jun. 2009 cct 7 91 69 ± 6.37 71 ± 8.56 ①④ 6 (nos) ong et al. 2015 australia jan. 2011 to dec. 2013 cct 32 166 n/a n/a ①④⑤⑥ 6 (nos) tyson et al. 2009 england may. 2002 to sep. 2007 cct 25 37 69.4 ± 7.2 65.2 ± 8.7 ①③⑤ 5 (nos) tayeb et al. 2016 america 1999 to 2014 cct 30 1558 n/a n/a ②③④⑤ 7 (nos) ruszat et al. 2006 switzerland sep. 2002 to jan. 2006 cct 71 92 72 ± 9 68 ± 9 ②③⑤ 7 (nos) knapp et al. 2017 australia jul. 2010 to dec. 2016 cct 59 272 74.9 ± 10.3 67.6 ± 9 ①②③⑤ 6 (nos) piotrowicz et al. 2017 poland 2009 to 2012 cct 65 44 68.3 ± 6.63 66.9 ± 6.5 ②③⑤ 6 (nos) eken et al. 2018 turkey nov. 2012 to oct. 2016 cct 59 174 74.8±9.1 69.2±5.5 ① 5 (nos) meskawi et al. 2018 canada 2011 to 2016 cct 87 274 70±7.48 66±9.62 ①②③④ 7 (nos) ①bleeding complications ②operation time ③catheterization time ④blood transfusion ⑤hospitalization ⑥thromboembolic events. rct: randomized controlled trials, cct: case control trials, ac: anticoagulant, ap: antiplatelet, n/a: not available, nos: newcastle– ottawa scale, jadad: jadad scale. values are presented as mean ± standard deviation or mean ( range). vol 18 no 2 march-april 2021 152 vol 18 no 1 january-february 2021 evaluations the quality of the randomized controlled trials (rct) included in this systematic review was assessed independently by two reviewers by using the jadad scale score,(20) which ranges from 0 to 5 points; a higher score indicates a better quality of the research. the jadad score evaluates studies based upon their randomization, blinding, and descriptions of participant withdrawals and dropouts. a study with a jadad score of 3 points or more was considered to be a relatively high-quality study. the newcastle-ottawa scale (nos) was used to assess the quality of case-control trials included in this meta-analysis.(21) the review scores range from 0 to 9 points for each trial. scores between 0 and 4 implied a low-quality study, while those between 5 and 9 implied a high-quality study. discrepancies were resolved through consultation with the third author. statistical analysis odds ratios (or) were used for binary outcomes with 95% confidence intervals (ci), and mean difference (md) or standardized mean difference was used for continuous variables with 95% ci. pooled estimates were calculated using a fixed-effects model(22) if no heterogeneity was presented; otherwise, a random-effects model(23) was used. the overall effect was determined by the z-effect, and p < .05 was considered to be statistically significant. the cochrane x2-test and inconsistency (i2) were used to assess the heterogeneity among studies.(24,25) p < .1 indicated the presence of heterogeneity, and i2 < 50% indicated that the level of heterogeneity was acceptable. sensitivity analysis was performed using a single item removal method. the funnel plot was used to assess the publication bias. all tests were performed using review manager software (revman 5.3, cochrane collaboration, oxford, english). results study characteristics the search protocol and its results are shown in figure 1. the initial search identified 383 potentially relevant studies. additionally, 33 studies were available by manual search with references. then 181 duplicates were detected and excluded by noteexpress. after screening of studies titles and abstract, 39 potentially relevant studies needed further assessment for eligibility. among them, 9 studies were excluded for no control study surgery prostate weight of preoperative preoperative preoperative maximum ac/ap perioperative type volume (ml) resected tissue (g) psa (ng/ml) ipss urinary flow (ml/s) type management ac/ap control ac/ap control ac/ap control ac/ap control ac/ap control of ac/ap therapy alaturp n/a n/a 30 (7-70) 28 (5-80) n/a n/a n/a n/a 9 (4.2-19) 9.6 (4.6-16.8) ac ac continued opas et al. 1995 dotan turp n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a type of ac/ ac/ap withdrawal + lmwh et al. 2002 ap was not counted separately nielsen turp n/a n/a 37 (27-64) 30 (16-50) n/a n/a n/a n/a n/a n/a ap ap continued et al. 2000 descazturp 58.5 49 30.5 21.7 3.8 4.6 17.6 20.5 5.8 8.3 ac ac withdrawal + lmwh eaud et al. 2011 taylor turp n/a n/a 17 25 n/a n/a n/a n/a n/a n/a ap ap continued et al. 2011 ong turp n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a ap ap continued et al. 2015 tyson holep 50.3 ± 16.7 49.9 ± 20.6 n/a n/a 3.9 (2.2) 4.4 (3.9) 16.5 (8.7) 23.5 (6.7) n/a n/a ac ac continued et al. 2009 tayeb holep n/a n/a 55.5 68 5.5 5.2 n/a n/a n/a n/a ap ap continued et al. 2016 (1-206) (0.2-532.2) ruszat pvp 58 ± 31 71 ± 39 n/a n/a 3.4 (2.7) 4.6 (4.2) n/a n/a n/a n/a ap ap continued et al. 2006 knapp pvp 90.8 ± 58.7 79.1 ± 47 n/a n/a 5.6 (6.2) 6.2 (8.0) 17.8 (6.9) 20(7.1) n/a n/a ac ac continued et al. 2017 piotropvp 66.3 ± 6.63 66.9 ± 6.5 n/a n/a 2.55 (1.25) 2.68 (1.42) 24.7 (4.58) 25.19 (4.11) 9.78 (2.99) 9.42 (2.73) type of ac/ap withdrawal + lmwh wicz et al. 2017 ac/ap was not counted separately eken pvp 61.5 ± 20.7 54.8 ± 16.9 n/a n/a 3.3 (2.8) 3 (2.4) 22.5 (7.6) 21.6 (5.3) 7.9 (2.2) 8.3 (3.1) type of ac/ap withdrawal + lmwh et al. 2018 ac/ap was not counted separately meskapvp 71 ± 29.63 76 ± 29.63 n/a n/a 3.8 7.6 n/a n/a n/a n/a ap ap continued wi et al. 2018 ac: anticoagulant, ap: antiplatelet, psa: prostate-specific antigen level, ipss: international prostate symptom score, holep: holmium laser enucleation of the prostate, turp: transurethral resection of the prostate, pvp: photoselective vaporization of the prostate, lmwh: low molecular weight heparin, n/a: not available, values are presented as mean ± standard deviation or mean ( range). table 2. perioperative parameters of each selected studies. safety of bph surgery under anticoagulants-liang et al. review 12 review 153 group; 8 studies were excluded for irrelevant topics; 3 studies were excluded for failure to extract the primary data assessing the safety of surgery; and 6 for being reviews. at the end, 13 eligible studies(11-19, 26-29) including 3767 patients (564 on ac/ap and 3203 control) were included in the subsequent meta-analysis according to our predefined selection criteria. the 13 studies included one rct and twelve case-control trials. no prospective cohort study that met the inclusion criteria was found (table 1). the methodological quality of the included non-randomized studies was mostly granted a score between 5 and 7, while the rct got 3 points on the jadad scale. ac agent reported included coumadin and pradaxa, and ap agent reported included aspirin, clopidogrel, ticlopidine and dipyridamole. of bph patients on ac/ ap, seven included studies evaluated the surgical safety of perioperative ap therapy, and three included studies evaluated the surgical safety of perioperative ac therapy. three included studies did not record the use of ac and ap agent separately when assessing the safety of surgery. ac/ap therapy was continued during the perioperative period in nine studies, while ac/ap therapy was withdrawn and replaced with low molecular weight heparin in four studies (table 2). preoperative measurement of prostate size and the weight of the resected prostate during operation of each study were summarized in table 2. five studies reported weight of resected tissue, and seven studies reported preoperative measurement of prostate volume rather than weight of resected tissue. one study reported both preoperative measurement of prostate volume and weight of resected tissue. preoperative psa, ipss, and maximum urinary flow in each study were also described in table 2. bleeding complications figure 2a presents the comparison of the cases of bleeding complications between the ac/ap group and the control group. as the heterogeneity was low among these studies (p = .17, i2 = 31%), a fixed-effects model was applied for meta-analysis and showed that perioperative ac/ap therapy would lead to a higher risk of bleeding complications compared with the control group (95% ci: 1.32–4.13, or = 2.33, p = .004) (figure 2a). the funnel plot showed no publication bias (figure s1a). subgroup analysis was conducted on account of surgical type, ac/ap type, and management of ac/ ap therapy. the subgroup meta-analysis result showed that patients in turp treatment for bph would have a higher risk of bleeding complication in ac/ap group (or = 2.58, p = .005, table s1). however, for laser surgical treatment for bph, including holmium laser enucleation of the prostate (holep) and photoselective vaporization of the prostate (pvp), the risk of bleeding complications in the ac/ap group was similar to the control group (or = 1.70, p = .36, table s1). the subgroup meta-analysis result also showed that perioperative ap therapy would increase the risk of bleeding complication (or = 2.65, p =.004, table s1), while no significant difference between patients on perioperative ac therapy and controls (or = 0.91, p = .92, table s1). besides, the analysis indicated no significance between ac/ap patients bridged with lmwh and controls (or = 2.58, p = 0.24, table s1). continuing ac/ ap therapy during surgery could led to increased risk of bleeding complication (or = 2.29, p = .008, table s1). blood transfusion eight studies were included in the forest plot of blood transfusion. as no heterogeneity existed among these studies (p = .89, i2 = 0%, figure 2b), a fixed effects model was applied for meta-analysis. the pooled result showed that perioperative ac/ap therapy would lead to a higher risk of blood transfusion compared with the control group (or = 2.86, 95% ci: 1.50–5.45, p = figure 1. meta-analysis flowchart. safety of bph surgery under anticoagulants-liang et al. vol 18 no 2 march-april 2021 154 .001, figure 2b). the funnel plot did not show obvious publication bias (figure s1b). the subgroup analysis showed that both the patients undergoing laser surgical treatment and turp need more blood transfusions (or = 2.53, p = .01; or = 5.47, p = .01, respectively, table s2). of ac/ap type, the subgroup analysis presented the transfusion rate of patients under ac therapy was similar to that of the control group (or = 3.79, p = .13, table s2), whereas the transfusion rate of patients under ap therapy was higher than the control group (or = 2.76, p = .004, table s2). of perioperative administration of ac/ap therapy, the method that preoperative ac/ap therapy replaced with lmwh would not cause a higher risk of blood transfusion in bph patients during the perioperative period (or = 2.81, p = .12, table s2). the patients who continued ac/ap therapy during perioperative period had a higher risk of blood transfusion compared with the control group (or = 2.76, p = .004, table s2). operation time seven studies were included in the forest plot of operation time. the pooled result showed no significant difference between the ac/ap group and control group (md = -4.18 min, 95% ci: -10.13–1.76, p = .17, figure 2c). the random effect model was applied because there was evidence of significant heterogeneity (p = .0001, i2 = 79%). the sensitivity analysis showed that heterogeneity originated from the studies of tayeb et al(27) and meskawi et al(29), probably due to the different size of resected prostate tissue (table 2). the funnel plot showed no publication bias (figure s1c). the subgroup analysis results based on surgical type, ac/ ap type and management of ac/ap therapy all showed that no significant difference between the ac/ap group and control group, which were consistent with overall outcome (table s3). catheterization time nine studies reported the catheterization time after surgery. random effect was applied for analysis with significant heterogeneity (p < .00001, i2 = 95%). the pooled results showed that no significant difference between the ac/ap group and control group (md = 0.26 day, 95% ci: -0.06–0.58, p = .11, figure 3a). the sensitivity analysis suggested that heterogeneity being mainly from the study of dotan et al(16). limited sample size from the study of dotan et al, causing potential bias, may be the reason of the heterogeneity. after removal of study of dotan et al, the pooled results still showed no significant difference between the ac/ap group and control group with mild heterogeneity (md = 0.08 day, 95% ci: -0.08–0.25, p = .33, i2 = 35%). the subgroup analysis results account of surgical type, ac/ap type and management of ac/ap therapy was figure 2. forest plots and meta-analysis. (a) bleeding complications, (b) blood transfusion, (c) operation time. safety of bph surgery under anticoagulants-liang et al. review 155 also conducted. the funnel plot did not show obvious publication bias (figure s1d). the subgroup analysis revealed that patients on perioperative ap therapy would have a longer catheterization time (md = 0.18 day, 95% ci: 0.11–0.24, p < 0.00001, table s4), while perioperative ac therapy would not prolong the catheterization time (md = 0.46 day, 95% ci: -0.16–0.24, p < 0.00001, table 4). meanwhile, the subgroup analysis of surgical type or management of ac/ap therapy showed that no significant difference between the ac/ ap group and control group, which were consistent with overall outcome (table s4). hospitalization nine studies reported the hospitalization time. the pooled meta-analysis result using a random effects model because of existence of significant heterogeneity among these studies (p < 0.00001, i2 = 97%) showed no significant difference between the ac/ap group and control group (md = 0.71 day, 95% ci: -0.04–1.45, p = .06, figure 3b). the sensitivity analysis showed that heterogeneity mainly originated from the study of dotan et al and descazeaud et al(16,17). the sample size, study design, geographical area, and individual differences of patients were all likely responsible for the heterogeneity. the heterogeneity decreased substantially after remove the study of dotan et al and descazeaud et al (md = 0.13 day, 95% ci: -0.07–0.34, p = .20, i2 = 30%). the funnel plot did not show obvious publication bias (figure s1e). the subgroup analysis results based on the surgical type and ac/ap type showed that no significant difference between the ac/ap group and the control group, which were consistent with the overall outcome (table s5). of perioperative management of ac/ap therapy, our subgroup analysis indicated that the patients who continued ac/ap therapy during perioperative period had longer hospitalization time compared with the control group (md = 0.25, p = .04, table s5), whereas the method that preoperative ac/ ap therapy replaced with lmwh would not prolong hospitalization time (md = 1.60, p = .08, table s5). thromboembolic events four studies were included in the forest plot of thromboembolic events. all included studies were on turp treatment group. a fix effects model was applied for analysis as no heterogeneity exist (p = .88, i2 = 0%, figure 3c). the pooled results revealed that no significant difference between ac/ap group and control (or = 2.42 , 95% ci: 0.69–8.51, p = .17, figure 3c). the funnel plot did not give any indication of publication bias (figure s1f). the subgroup results of ac/ap type and management of ac/ap therapy was also conducted. the results both showed that no significant difference figure 3. forest plots and meta-analysis. (a) catheterization time, (b) hospitalization, (c) thromboembolic events. safety of bph surgery under anticoagulants-liang et al. vol 18 no 2 march-april 2021 156 between the ac/ap group and control group, which were consistent with overall outcome (table s6). discussion turp has been widely used for the treatment of bph. however, the morbidity of patients after turp is considerably high due to intraoperative and postoperative bleeding and electrolyte disorder. due to the ac/ap therapy for atrial fibrillation, recurrent thromboembolic disease, or prosthetic heart valves, the risk of bleeding complications associated with surgery is higher in bph patients;(30) however, discontinuation of ac/ap therapy before surgery may predispose patients to thromboembolism caused by the release of tissue thromboplastins. (31) various laser treatment options have been developed for bph surgery for these patients on ac/ap therapy in recent years, such as pvp, ho:yag. these laser therapies seem to minimize bleeding during surgery.(32-35) particularly in patients receiving ac/ap therapy, these laser treatments seem to have a favorable safety profile.(33,35,36) both eau guidelines and nice guidelines recommend that laser treatment can be safely applied in patients who have an increased risk of bleeding. however, regarding the perioperative management of ac/ap therapy, the guidelines did not mention whether there is a need to discontinue or replace to lmwh. (9,10) consequently, some surgeons discontinued ac/ap therapy and replaced lmwh in advance of surgery, whereas others continued ac/ap therapy perioperatively. recently, zheng and his colleagues conducted a meta-analysis to assess the efficacy and safety of pvp on high-risk patients including patients on anticoagulation.(37) however, their analysis did not conduct subgroup analysis for people on ac/ap therapy, and the management of perioperative ac/ap therapy still remained unsettled. therefore, our meta-analysis, which synthesized all available evidence including turp and other laser surgeries, should offer an objective verdict. a series of subgroup analyses based on surgical type, ac/ap type, and management of ac/ap therapy were conducted. the present meta-analysis studied the safety profile of the surgery for bph patients with ac/ap therapy. the incidence of bleeding complications and blood transfusions can represent a key parameter when evaluating the safety of the surgery for bph patients with ac/ ap therapy. our subgroup analysis indicated that ac/ ap therapy would have a higher risk of blood transfusion and bleeding complications when receiving turp treatment for bph. for the patients receiving laser surgical treatment for bph, our result presented that continuing perioperative ac/ap therapy would increase blood transfusions, but would not have effects on the incidence of bleeding complications. although the excellent hemostasis of laser surgery,(38,39) the laser treatment might still carry a risk of bleeding on patients receiving ac/ap therapy. besides, the subgroup meta-analysis result of bleeding complication, blood transfusion, and catheterization time on ac/ap type showed that the patients under perioperative ap therapy had a higher risk of postoperative bleeding than those who did not need anticoagulant or antiplatelet agent, which was in line with previous studies.(13,17) however, the subgroup analysis results indicated that perioperative ac therapy would not affect postoperative bleeding. the reason is probably because of limited sample size. notably, ac therapy subgroup analysis showed all postoperative bleeding was related to laser treatment. for perioperative ac/ap management, the commonly used procedure in current practice included bridging treatment with lmwh and continued therapy. one of the main concerns about bridging treatment is that it might increase the risk of thromboembolic events. to settle this dilemma, the subgroup analysis of perioperative ac/ap management was also conducted. according to our result, the patients bridging with lmwh would not increase the incidence of bleeding complications, blood transfusion, and prolong hospitalization time, indicating that bridging treatment could effectively reduce the risk of severe hemorrhage requiring blood transfusion. furtherly, our meta-analysis proved that the bridging treatment before surgery had no effect on thromboembolic events, which was consistent with the previous researches. chakravarti et al.(40) managed anticoagulation for 11 patients undergoing turp by stopping warfarin and bridging with heparin preoperatively. they observed only one blood transfusion, but mild bleeding occurred in 27% of the patients. descazeaud et al.(41) also concluded that replacement by lmwh preoperatively is preferable for bph patients under ac/ap therapy. among the studies for operation time and catheterization time, the synthesis of meta-analysis revealed a same effect between groups. these results suggest that application of ac/ap therapy during perioperative period would not affect the quality of surgery. there are several limitations to our present study. first, most of the studies were case-control trials except for one rct, which may cause potential bias in our results. in addition, because the use of anticoagulant and antiplatelet drugs in the included studies is not recorded in detail, comparison among antiplatelet drugs or anticoagulant drugs failed to be conducted. comparison of different doses of ac/ap therapy failed to be performed, either. all included studies did not mention the threshold of transfusion, and the definition of bleeding complication varied among included studies, posing potential bias on the pooled results. in addition, although random-effect model was applied to some parameters with high heterogeneity, there might be some influence on the efficiency of our meta-analysis. conclusions this meta-analysis has demonstrated that patients on perioperative ac/ap therapy would have a higher risk of hemorrhage in turp for the treatment of bph. even for laser treatments, perioperative ac/ap therapy also have a risk of postoperative hemorrhage. to reduce the incidence of hemorrhage requiring transfusion, bridging treatment with lmwh could be a good choice. due to the inherent limitations of the included studies, further large cohorts prospective, multi-center, and rcts should be conducted to confirm our findings. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/18 acknowledgement this work was supported by the national natural scisafety of bph surgery under anticoagulants-liang et al. review 157 vol 18 no 2 march-april 2021 158 ence foundation of china (no.81402430, 81602541). conflict of interest no conflict of interest exits in this study. references 1. berry s j, coffey d s, walsh p c, ewing ll. the development of human benign prostatic hyperplasia with age[j]. j urol. 1984,132(3):474-479. 2. kim bs, kim th, kim kh, et al. patientreported goal achievement after treating male benign prostatic hyperplasia with alpha-adrenergic antagonist: a 12-week prospective multicenter study. urol j. 2019;16(4):386-391. 3. reich o, gratzke c, bachmann a, et al. morbidity, mortality and early outcome of transurethral resection of the prostate: a prospective multicenter evaluation of 10,654 patients.[j]. j urol. 2008,180(1):246-249. 4. mozaffarian d, benjamin e j, go a s, et al. 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[j]. j endourol. 2005,19(10):1196-1198. 34. costello a j, bowsher w g, bolton d m, braslis k g, burt j. laser ablation of the prostate in patients with benign prostatic hypertrophy.[j]. br j urol. 1992,69(6):603608. 35. van melick h h, van venrooij g e, boon t a. laser prostatectomy in patients on anticoagulant therapy or with bleeding disorders.[j]. j urol. 2003,170(5):1851-1855. 36. bolton d m, costello a j. management of benign prostatic hyperplasia by transurethral laser ablation in patients treated with warfarin anticoagulation.[j]. j urol. 1994,151(1):7981. 37. zheng x, qiu y, qiu s, et al. photoselective vaporization has comparative efficacy and safety among high-risk benign prostate hyperplasia patients on or off systematic anticoagulation: a meta-analysis[j]. world j urol, 2019,37(7):1377-1387. 38. berger j, robert g, descazeaud a. laser treatment of benign prostatic hyperplasia in patients on oral anticoagulant therapy.[j]. current urology reports. 2010,11(4):236241. 39. melick h h e v, venrooij g e p m, boon t a. laser prostatectomy in patients on anticoagulant therapy or with bleeding disorders[j]. j urol. 2003,170(5):1851-1855. 40. chakravarti a, macdermott s. transurethral resection of the prostate in the anticoagulated patient[j]. br j urol. 1998,81(4):520-522. 41. descazeaud a, robert g, azzousi a r, et al. laser treatment of benign prostatic hyperplasia in patients on oral anticoagulant therapy: a review[j]. bju int. 2009,103(9):1162-1165. safety of bph surgery under anticoagulants-liang et al. review 159 editorial 61urology journal vol 4 no 2 spring 2007 our journal indexed in medline/pubmed urol j. 2007;4:61. www.uj.unrc.ir i am delighted to announce that in march 2007, the urology journal was selected by the national library of medicine (nlm) to be indexed in medline/ pubmed, the world’s most heavily used set of databases for health and medical professions. this encouraged the journal to open up to new topics, in turn garnering a broader audience of readers and contributors. let’s hope we will find ourselves going the same route. all articles will be indexed from volume 4, issue 1, and the previous issues will be also included in the pubmed. thanks to the contributions of our authors and readers over 3 years of publication, the urology journal has proven that it has something to offer. the pubmed has become the primary information nexus for biomedical science and indexing of the urology journal will greatly enhance the visibility of our authors’ work. acceptance in this prominent database speaks not only to the importance of the field, but also to the incredibly high quality of the articles and features published to date. i would personally like to thank the journal’s chairman, professor simforoosh, for his encouragement, and the outstanding editorial board for their continuing support, and look forward to continuing the progress of this journal. we greatly appreciate our executive editor, dr farrokhi; the help he provided was invaluable. urology journal is published quarterly in print format and offers review articles, original research, case reports, point of techniques, experimental research, and a variety of added-value content. rigorous peer review and rapid publication ensure that only the best quality and pertinent research is published in a timely manner. access to the urology journal is also currently available based on the open access policy; thus, we will be able to deliver the full text articles to readers directly from the pubmed page. the editorial board, composed of highly cited researchers from all over the world, elicits high quality scientific works of broad interest. now the urology journal is going to become among the premier forum for a fast growing community of specialists to address the important challenges and advances that are now occurring in urological research and molecular medicine. now, we are going to apply for inclusion in the isi database. our mission is to disseminate the most meritorious scientific research produced in the field of urology and the related sciences. to have readers, a new publication must prove that it has something to offer. it has to be taken seriously. because of the increase in high quality research conducted in the field and the better exposure of the urology journal to the scientific community via medline, the journal is able to attract better quality papers that are potentially more worthy of citation. therefore, we feel that, if indexed by isi, the urology journal would make an important and strategic contribution to the urology literature. there is no doubt that indexing in the isi database would provide our journal much greater visibility. our aim is to build a high-quality, comprehensive, and balanced reference resource that can be used to prepare teaching aids and research presentations, as well as to inform residents, scientists, and clinicians. the editorial board of the urology journal is proud to be among the pioneers of successful and sustainable peer-reviewed journals and again thanks everybody who has contributed to this success, most of all our authors, our peer-reviewers and our readers, who continue to give us useful feedback. let us hear from you. what do we do right? and where could we do better? our ability to measure the extent to which we satisfy our readers will be the ultimate determinant of our sustainability. mohammad reza safarinejad associate editor, urology journal fall 2012 08.pdf 706 | inferior distraction of the kidney to aid upper pole and supracostal punctures during supine percutaneous renal access anuj goyal, kumar mukerjee, theocharis karaolides, christian bach, athanasios papatsoris, junaid masood keywords: nephrostomy, percutaneous, kidney, drainage introduction p nal calculi. percutaneous renal access is also often used for management of ureteropelvic tumors. to achieve the optimal result, it is important to gain intra-renal access through an approand upjo, supracostal access, and in others, upper pole access may be needed to achieve the best and a subcostal approach is used to reduce the risk of intrathoracic complications.(1,2) better knowledge of pleural and diaphragmatic anatomy and further development in surgical techniques have reduced the risk of intrathoracic complications,(3) but published series report rates of intrathoracic complications varying between 3.1% and 12.5% in those undergoing supracostal percutaneous access. these series further report that the rate of intrathoracic complications is sigth rib compared to a supra-12th puncture.(1-8) there access (32%) versus those having subcostal access (5%).(9) the supra-12th th rib access is both transthoracic and transpleural.(8) pulmonary complications may arise after supracostal puncture due to the anatomic relationship of the upper pole of the kidney with the diaphragm and the pleura. corresponding author: junaid masood, mbbs; msc; frcs 3 taleworth close, ashtead, surrey, kt21 2pu, uk tel: +44 781 518 3605 e-mail: junaido@aol.com received january 2012 accepted may 2012 endourology and stone services, barts and the london nhs trust, london, uk point of technique point of technique 707vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l the right kidney is usually lower than the left kidney and the posterior surface of the right kidney is crossed by the 12th rib, whereas the left kidney is usually crossed by the 11th and the 12th ribs. the upper pole of the kidney is usually medial and posteriorly placed compared to the lower pole, which is the 10th th rib at the level of l1 vertebra. the lung is located at the 10th thoracic vertebral level posteriorly with the lowermost part lying above the 11th rib at the 10th intercostal space,(10) and may move caudally as much as 2 vertebral bodies during inspiration whilst in the prone position.(11) upper pole lies above the 12th tion, when using a supracostal approach, the pleura may be traversed on the right in about 29% of cases and on the left in 14% of cases.(12) the diaphragm arises from the tip of the 10th to 12th ribs posteriorly and as high as the 7th rib anteriorly.(5) it appears clear from the above anatomic description that supracostal punctures will usually traverse the diaphragm, and many of these punctures will also pierce the pleura. endourologists have employed a variety of techniques to reduce the incidence of complications during supracostal puncture. some suggest to keep the puncture site as medial as possible, close to the lateral border of the erector spinae to 35 degrees to avoid injury to the spleen, liver, and colon. (13) others recommend that the puncture should ideally be over the lateral half of the rib,(14) avoiding the lower rib margin in order not to puncture the intercostals vessels. with the roperitoneum and diaphragm with the needle to prevent any potential injury to the lung, whilst the needle is passed into the renal collecting system through the parenchyma during full inspiration to enable full downward displacement of the kidney.(15) the amplatz sheath should be placed well in to the collecting system and a well-draining nephrostomy tube should be placed in the end to minimize the leakage of urine into the pleural space.(16) some go further and advocate a subcostal entry even for the upper pole calculi.(17) however, this often very oblique course has its own potential complications and limitations. the acute entry angle makes the use of rigid instruments to risk of trauma during manipulation of the rigid instruments. the risk of injuring the peri-infundibular vessels would also be increased in this position. one important point to consider during supracostal puncture is the kidney movement during respiration. the kidneys tend to move in a tilted sagittal and coronal plane.(18) one study almost 40 mm.(18) from the prior discussion, it would appear that access above the 12th rib is relatively safe, but access above the 11th rib should be avoided if possible due to increased risk of complications.(2) some have stated that supra-10th rib puncture should always be avoided.(2) even those who say that supracostal renal punctures are effective and safe, with low and acceptable complications, state that these should be attempted in selected cases and with caution.(14,19,20) with these thoughts in mind, we have started using a technique to inferiorly distract the kidney prior to a potentially high supracostal percutaneous puncture in order to reduce the risk of pleural and chest complications. this “inferior distraction” of the kidney lowers the percutaneous access point, and is a valuable technique useful in all supracostal, but especially upper pole punctures. case report we report a technique used to inferiorly distract the kidney logical procedures, such as percutaneous nephrolithotomy, in order to lower the entry point into the kidney. this has the potential to reduce intrathoracic complications during supracostal renal access whilst allowing the surgeon to place an in our last 10 upper pole punctures without any increased morbidity whilst lowering the percutaneous puncture site by an average of 3.2 cm. technique this technique is suitable during supine pcnl, including any pole calculi, where a lower pole puncture alone would not be enough to achieve clearance (figure 1), or in high-lying kidneys and in those where direct access to the upj is required inferior kidney distraction during supine pcnl | goyal et al 708 | point of technique and where the ideal puncture is likely to be supra-10th rib or supra-11th has been carried out (figure 2), we introduce a hydrophilic system and manipulate it down the ureter (figure 3) and into the bladder, where it can be grasped with forceps introduced figure 1. an initial retrogradely placed guidewire in the collecting system to help carry out filling of the kidney prior to the anterograde lower pole puncture. an access needle is marking the upper pole calculus. figure 2. a retrograde study confirming an upper pole stone. note the long and relatively narrow upper pole calyceal neck. figure 3. note the lower pole inferior distraction wire introduced anterogradely. comparing the position of the upper pole stone in relation to the adjacent vertebral bodies with figure 2 (both images in full inspiration with the c-arm of the image intensifier in the same position) clearly shows the inferior distraction of the kidney. figure 4. the long thick arrow point shows the location of the upper pole stone in inspiration before the inferior distraction wire is placed. the short thin arrow shows the location of the stone in inspiration after the inferior distraction wire is placed. 709vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l inferior kidney distraction during supine pcnl | goyal et al through-and-through wire. each end of this wire is then put under tension by gentle caudal traction either by an assistant both ends using standard mosquito clips (we would like to stress the importance of gentle traction) and this serves two purposes. firstly, it stops the respiratory-related movement of the kidney, which makes the puncture technically easier and safer in a lower position than would otherwise be possible. as has been mentioned in some studies, respiratoryrelated kidney movement may be up to 40 mm. secondly, it enables further caudal distraction of the kidney, which also helps lower the ideal puncture site and therefore, reduces the risk of pleural injury as has been alluded to in the literature earlier. with this inferior renal distraction wire in place and under gentle tension, a further percutaneous puncture into the standard. results we have carried out this technique safely and without any increased morbidity for our last 10 upper pole punctures with the percutaneous puncture site being on average 3.2 cm lower (in full inspiration) after the inferior distraction wire has been placed and put under gentle tension (figure 4). this downward displacement of the kidney is evident when one compares the placement of the upper pole stone (marked with access needle) in relation to the vertebrae in figures 3 and 4. in 6 cases, a potential supra-10th rib puncture was made into a supra-11th puncture and in 4, a supra-11th puncture turned in to a supra-12th puncture. in all cases, the upper pole puncture renal pelvis subsequently was straightforward with relatively complications. clearance of stones was achieved in all 10 cases after successful upper pole punctures. discussion the literature is clear in stating that supracostal percutaneous renal punctures carry a higher risk of pulmonary and intrathoracic complications.(15) this risk appears to progressively increase with higher punctures positions. the evidence suggests that supra-11th rib punctures carry a higher risk than supra-12th punctures.(1-8) some state that supra-10th rib punctures should be avoided altogether.(2) rior renal distraction in order to more safely carry out upper pole puncture.(21) sible in the complete supine position using this technique.(21) however, the puncture site was subcostal meaning that the tract is likely to be angled, which means that manipulation of instruments and entry into the renal pelvis and upj would be when a supracostal puncture is deemed necessary, any technique that would help achieve an ideal access in the line of whilst lowering the access site, would be potentially very useful. our technique of placing a “through-and-through” lower pole wire under gentle caudal traction at both ends helps lower the entry point into the kidney (mean of 3.2 cm in our cases) and hence, has the potential to reduce intra-thoracic complications whilst still potentially allowing the surgeon to we have found this a safe and effective technique with no increased morbidity and we would like to highlight its use during supracostal punctures to lower the access point. it is particularly useful for upper pole punctures where supra-11th or even supra-10th access may otherwise often be needed to achieve good or ideal access. not only it lowers the kidney and hence makes the access potentially safer, it also stops the kidney moving during respiration and hence, makes the puncture easier as this would normally require coordination with the anesthetist for controlling breathing. conflict of interest none declared. references 1. gupta r, kumar a, kapoor r, srivastava a, mandhani a. prospective evaluation of safety and efficacy of the supracostal approach for percutaneous nephrolithotomy. bju int. 2002;90:809-13. 2. shaban a, kodera a, el ghoneimy mn, orban tz, mursi k, hegazy a. safety and efficacy of supracostal access in percutaneous renal surgery. j endourol. 2008;22:29-34. 710 | 3. kekre ns, gopalakrishnan gg, gupta gg, abraham bn, sharma e. supracostal approach in percutaneous nephrolithotomy: experience with 102 cases. j endourol. 2001;15:789-91. 4. young at, hunter dw, castaneda-zuniga wr, et al. percutaneous extraction of urinary calculi: use of the intercostal approach. radiology. 1985;154:633-8. 5. forsyth mj, fuchs ef. the supracostal approach for percutaneous nephrostolithotomy. j urol. 1987;137:197-8. 6. narasimham dl, jacobsson b, vijayan p, bhuyan bc, nyman u, holmquist b. percutaneous nephrolithotomy through an intercostal approach. acta radiol. 1991;32:162-5. 7. lashley db, fuchs ef. urologist-acquired renal access for percutaneous renal surgery. urology. 1998;51:927-31. 8. munver r, delvecchio fc, newman ge, preminger gm. critical analysis of supracostal access for percutaneous renal surgery. j urol. 2001;166:1242-6. 9. radecka e, brehmer m, holmgren k, magnusson a. complications associated with percutaneous nephrolithotripsy: supraversus subcostal access. a retrospective study. acta radiol. 2003;44:447-51. 10. sampaio fjb. surgical anatomy of the kidney in the prone, oblique, and supine positions. in: smith ad, preminger g, badlani gh, kavoussi lr, eds. smith's textbook of endourology. vol 1. 3 ed: wiley-blackwell; 2012:61-94. 11. golijanin d, katz r, verstandig a, sasson t, landau eh, meretyk s. the supracostal percutaneous nephrostomy for treatment of staghorn and complex kidney stones. j endourol. 1998;12:403-5. 12. hopper kd, yakes wf. the posterior intercostal approach for percutaneous renal procedures: risk of puncturing the lung, spleen, and liver as determined by ct. ajr am j roentgenol. 1990;154:115-7. 13. lingeman je. staghorn stones: the continued challenge. aua update series. 1993;12:146-51. 14. yadav r, gupta np, gamanagatti s, yadav p, kumar r, seith a. supra-twelfth supracostal access: when and where to puncture? j endourol. 2008;22:1209-12. 15. lojanapiwat b, prasopsuk s. upper-pole access for percutaneous nephrolithotomy: comparison of supracostal and infracostal approaches. j endourol. 2006;20:491-4. 16. amplatz k, lange ph. percutaneous nephrolithotomy: special puncture techniques. atlas of endourology. chicago: year book medical publishers; 1986:149-56. 17. rehman j, chughtai b, schulsinger d, adler h, khan sa, samadi d. a percutaneous subcostal approach for intercostal stones. j endourol. 2008;22:497-502. 18. schwartz lh, richaud j, buffat l, touboul e, schlienger m. kidney mobility during respiration. radiother oncol. 1994;32:84-6. 19. mousavi-bahar sh, mehrabi s, moslemi mk. the safety and efficacy of pcnl with supracostal approach in the treatment of renal stones. int urol nephrol. 2011;43:983-7. 20. yadav r, aron m, gupta np, hemal ak, seth a, kolla sb. safety of supracostal punctures for percutaneous renal surgery. int j urol. 2006;13:1267-70. 21. falahatkar s, enshaei a, afsharimoghaddam a, emadi sa, allahkhah aa. complete supine percutaneous nephrolithotomy with lung inflation avoids the need for a supracostal puncture. j endourol. 2010;24:213-8. point of technique fall 2012 09 resized.pdf 639vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l departments of urology1 and radiology2, michael heal unit, leighton hospital, mid cheshire hospital nhs foundation trust, crewe, uk *e-mail: nilbury@oceanfree.net a45-year-old man presented with sciatica. magnetic resonance imaging (mri) of his lumbosacral spine revealed an gram benign prostate noted. vealed an absent right kidney, dilated right ureter and seminal vesicle, and a normal left renal tract (figure 1). t1 and t2-weighted mri with gadolinium again demonstrated right renal agenesis, a dilated, non-obstructed right ureter containing proteinaceous material with no vesical connection, and a dilated right seminal vesicle (figures 2 and 3). cystic dilatation of the right seminal vesicle associated with right renal agenesis and a prostatic utricle cyst has been described in a patient presenting with lower tract symptoms.(1) incidental detection of seminal vesicle cysts, renal agenesis, and ectopic ureter has been documented in asymptomatic patients presenting for prostatic biopsy.(2) laparoscopic removal of cystic seminal vesicles and an aplastic renal moiety with associated ectopic megaureter has been described.(3) michael st john floyd jr,1* john scally,2 paul patrick irwin1 incidental detection of a unilateral dilated blind-ending ureter, renal agenesis, and a dilated seminal vesicle references 1. oh-oka h, fujisawa m, okada h, arakawa s, kamidono s. male genital malformations associated with right renal agenesis. urology. 2003;61:1260. 2. roberts sg, garcia mediero jm, segura jw, rivas ja, garcia alonso j. incidental pelvic mass identified during ultrasound-guided transrectal needle biopsy of the prostate. arch esp urol. 2002;55:466-8. 3. hoschke b, may m, seehafer m, helke c. [outlet of a megaureter with aplastic kidney into a seminal vesicle cyst. case report of laparoscopic intervention]. urologe a. 2003;42:1092-6. pictorial urology figure 1 figure 2 figure 3 uj 35 summer.pdf 592 | evaluation of inguinoscrotal pathologies among adolescents with special emphasis on association between varicocele and body mass index cengizhan yigitler,1 hakan yanardag,2 emir silit,3 ahmet sahin alpay4 purpose: to investigate the prevalence of inguinoscrotal pathologies among a stable population in materials and methods: results: p = .0001) and varicocele than the older group (p p p = .0001), but p tion regarding the somatometric features. conclusion: keywords: varicocele, body mass index, epidemiology, prevalence, inguinal hernia corresponding author: cengizhan yigitler, md gülhane military medical academy, department of surgery, haydarpasa training hospital, usküdar, istanbul, turkey e-mail: cyigitler@hotmail. com tel/fax: +90 216 348 7880 received june 2011 accepted september 2011 1gülhane military medical academy, department of surgery, haydarpasa training hospital, usküdar, istanbul, turkey 2department of urology, balikesir military hospital, balikesir, turkey 3department of radiology, bozok university, yozgat, turkey 4 department of infectious diseases, izmir military hospital, izmir, turkey miscellaneous miscellaneous 593vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l introduction m -ity and sexual dysfunction become problematic in young treated only in highly selected cases, correction of almost all inguinoscrotal abnormalities during childhood aims avoiding potential infertility or restoration and maintenance of reproductive activity. ported to be as high as 15% to 20% in general population.(1) ters.(2-9) candidates coming from all regions of our country after prevalence of these pathologies among adolescent populamaterials and methods ized database records obtained from applications for junior gust 2002 through august 2009. elected after a matricula2). after a 12-hour overnight fasting, their blood and urine (internal medicine specialist, general surgeon, chest disear, nose, and throat specialist, neurologist, psychiatrist, dist) examined all the applicants. during the procedure, geon and urologist examined and recorded together all disof any suspicion or doubt on diagnosis, ultrasonography, not made. an incision scar from a previous inguinoscrotal treated. in a health council consisted of ten specialists in order to nal hernia, undescended testis, and varicocele. thereafter, percentages and prevalence of detected inguinoscrotal discomparison of continuous variables, such as age, height, 594 | pendent samples t test, and multivariate logistic regression p results sided atrophic testis in one patient, hypospadias in one, leftand bilateral inguinal hernia in one patient. inguinal hernia and one (0.20%) bilateral inguinal hernia table 1. examination results of 12581 subjects with detailed diagnoses and laterality of inguinoscrotal diseases. health status no. (%) healthy candidates 7754 (61.63) patients affected with other diseases 3403 (27.05) patients with inguinoscrotal diseases 1424 (11.32 %) right-side left-side bilateral overall (%) varicocele 743 (5.91) 1 729 13 750 (5.96)* + atrophic testis 1 (0.01) 1 + hypospadias 1 (0.01) 1 + left hydrocele 2 (0.01) 2 + inguinal hernia 3 (0.02) 2 1 overall number of patients with varicocele (%) 750 (100) 1 (0.1) 735 (98) 14 (1.9) inguinal hernia 481 (3.82)† 269 202 14 485(3.85)‡ + undescended testis 1 (0.01) 1 undescended testis 95 (0.76) 40 33 22 96 (0.76)§ atrophic testis 34 (0.27) 14 18 2 35 (0.28)** hypospadias 34 (0.27) 35 (0.28)†† hydrocele 20 (0.16) 13 9 22 (0.17)‡‡ epididymal cyst 6 (0.05) 1 5 6 (0.05) penile curvature 1 (0.01) 1 (0.01) mea stenosis 2 (0.01) 2 (0.02) * 1 with atrophic testis, 1 with hypospadias, 2 with hydrocele, and 3 with inguinal hernia. 81 cases underwent varicocelectomy , † of those, 428 (88.9%) have had hernia surgery. ‡ 3 with varicocele, and 1 with undescended testis § 1 with inguinal hernia ** 1 with varicocele †† 1 with varicocele ‡‡ 2 with varicocele miscellaneous 595vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l prevalence of inguinoscrotal pathologies among adolescents | yigitler et al 2 (range, 15.25 2 p = .0001). tients (202; 5.61%) (p older subjects (p = .036; table 2). p (p p = .22). 2 2) (p = .001). 2 table 2. comparison of bmi, isp, and varicocele by age category.* characteristics patients aged 16 to 18 years (n = 8775) patients aged 19 to 23 years (n = 3806) p bmi, kg/m2 21.35 ± 1.72 21.62 ± 1.85 t = 7.97 .0001 patients with isp, n (%) 1019 (11.61) 405 (10.64) x2 = 2.49 .114patients without isp 7756 3401 varicocele, n (%) 548 (6.60) 202 (5.61) x2 = 4.19 .041subjects without isp 7756 3401 varicocele, n (%) 548 (6.25) 202 (5.31) x2 = 4.39 .036all other subjects 8227 3604 *bmi indicates body mass index; and isp, inguinoscrotal pathology. table 3. comparison of subjects’ physical characteristics by presence of isp and varicocele.* patients’ characteristics age, y height, cm weight, kg bmi, kg/m2 overall (n = 12581) 18.17 ± 0.95 174.74 ± 4.60 65.21 ± 4.95 21.43 ± 1.77 isp (+) (n = 1424) 18.13 ± 0.98 175.34 ± 4.77 65.49 ± 6.31 21.29 ± 1.77 isp (-) (n = 11157) 18.18 ± 0.95 174.95 ± 4.82 65.71 ± 6.38 21.45 ± 1.76 t = 1.565; p = .118 t = 2.852; p = .004 t = 1.229; p = .22 t = 3.314; p = .001 varicocele (+) (n = 750) 18.10 ± 0.99 175.77 ± 4.86 65.29 ± 6.24 21.13 ± 1.74 varicocele (-) (n = 11831) 18.17 ± 0.95 174.95 ± 4.82 65.71 ± 6.38 21.46 ± 1.77 t = 2.028; p = .04 t = 4.504; p = .0001 t = 1.752; p = .08 t = 5.014; p = .0001 *bmi indicates body mass index; and isp, inguinoscrotal pathology. 596 | 2 than varicocele or not (p = .05 for age; p = .0001 for height, and p p the adjusted varicocele-physical characteristics odd ratios revealed similar pattern to the crude descriptive analyses. cocele (table 4). discussion chological affection. these conditions, if left untreated or not treated properly, may lead to further complications and have negative impact on physical, psychological, and socioeconomic status of the patient himself, his family, and among a stable population in adolescent and young adult age group. ly scholar and military screenings, has been estimated in a (2,10,11) cele.(2) namely regrouped for a recruitment tool. the exact etiology of varicocele has yet to be determined. incompetent venous valves in the internal spermatic veins, longer course and perpendicular insertion of left internal spermatic vein to the left renal vein, and increased intraluminal pressure of the latter due to possible compression of are the popular arguments for the anatomic pathogenesis and left-side predominance of the varicocele.(12-14) “nuttion due to compression of the duodenum in regard to narteric artery. tion of varicocele around the spermatic cord at physical examination, and thus, varicocele can be highly diagnosed (2,3) (3) (4) did not consider investigating the grading of varicocele. we table 4. associations between varicocele and somatometric characteristics by logistic regression analysis.* b p exp (b) 95% confidence interval for exp (b) height 0.034 .000 1.034 1.019 to 1.049 weight -0.011 .080 0.990 0.978 to 1.001 age -0.084 .040 0.919 0.848 to 0.996 *hosmer-lemeshow goodness-of-fit test of equations p > .05 miscellaneous 597vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l prevalence of inguinoscrotal pathologies among adolescents | yigitler et al been used for detection of varicocele in this study. as in other studies.(2,3,5,6) applicants (p phenomenon or simply theory on easier detection. overm2 haps because of the longer course of left spermatic vein and increased hydrostatic pressure in a greater height.(6,7) study. nielsen and associates, in a study exploring the reerectile dysfunction.(2) development of varicocele. while varicocele is hardly ever that the incidence of varicocele increased by about 10% for (15) the higher the age, the higher the prevalence of varicocele. local studies from our country reported similar results 0.15% to 3.22% among primary school and adolescent students(11,16) and as high as 10.6% in 19 to 20-year-old population.(17) kumanov and colleagues demonstrated the close (6) age. period. mostly seen in men, inguinal hernia is the protrusion of a neum through the inguinal canal. therefore, it is usually the 10:1.(19,20) dren(21,22) and 3.2% among males of 20 to 22 years of age. (23) conducted on people in military service. surgeon at later period of adolescence rather than a pediatric play a role in the development of this difference. our country.(21) (24) right(25) 598 | conclusion (1) compromising his life style or not, and the prevalence of (2) varicocele, in front of all congenital male adolescent group; and (3) the prevalence of varicocele needed to detect thoroughly the relationship of varicocele and environmental conditions. acknowledgements proof reading. conflict of interest none declared. references 1. jarow jp. effects of varicocele on male fertility. hum reprod update. 2001;7:59-64. 2. nielsen me, zderic s, freedland sj, jarow jp. insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. urology. 2006;68:392-6. 3. chen ss, huang wj. differences in biochemical markers and body mass index between patients with and without varicocele. j chin med assoc. 2010;73:194-8. 4. al-ali bm, marszalek m, shamloul r, pummer k, trummer h. clinical parameters and semen analysis in 716 austrian patients with varicocele. urology. 2010;75:1069-73. 5. tsao cw, hsu cy, chou yc, et al. the relationship between varicoceles and obesity in a young adult population. int j androl. 2009;32:385-90. 6. kumanov p, robeva rn, tomova a. adolescent varicocele: who is at risk? pediatrics. 2008;121:e53-7. 7. delaney dp, carr mc, kolon tf, snyder hm, 3rd, zderic sa. the physical characteristics of young males with varicocele. bju int. 2004;94:624-6. 8. kilic s, aksoy y, sincer i, oguz f, erdil n, yetkin e. cardiovascular evaluation of young patients with varicocele. fertil steril. 2007;88:369-73. 9. kumanov p, deepinder f, robeva r, tomova a, li j, agarwal a. relationship of adolescent gynecomastia with varicocele and somatometric parameters: a cross-sectional study in 6200 healthy boys. j adolesc health. 2007;41:126-31. 10. hauser r, paz g, botchan a, yogev l, yavetz h. varicocele: effect on sperm functions. hum reprod update. 2001;7:4825. 11. adayener c, ates f, soydan h, turk l, senkul t, baykal k. the rates of external genital organ diseases in adolescent boys aged 13-15 years in turkey. turkish j urol. 2010;36:155-9. 12. pryor jl, howards ss. varicocele. urol clin north am. 1987;14:499-513. 13. graif m, hauser r, hirshebein a, botchan a, kessler a, yabetz h. varicocele and the testicular-renal venous route: hemodynamic doppler sonographic investigation. j ultrasound med. 2000;19:627-31. 14. fretz pc, sandlow ji. varicocele: current concepts in pathophysiology, diagnosis, and treatment. urol clin north am. 2002;29:921-37. 15. levinger u, gornish m, gat y, bachar gn. is varicocele prevalence increasing with age? andrologia. 2007;39:77-80. 16. kayikci ma, cam k, akman ry. [the ratio of external genital anomalies in male children attending primary school in duzce]. turkish j urol. 2005;31:79-81. 17. sahin c. [urogenital system anomalies among the military candidates in tokat and misconceptions about these anomalies]. turkish j urol. 2001;27:456-8. 18. baek m, park sw, moon kh, et al. nationwide survey to evaluate the prevalence of varicoceles in south korean middle school boys: a population based study. int j urol. 2011;18:55-60. 19. ruhl ce, everhart je. risk factors for inguinal hernia among adults in the us population. am j epidemiol. 2007;165:1154-61. miscellaneous 599vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l prevalence of inguinoscrotal pathologies among adolescents | yigitler et al 20. yegane ra, kheirollahi ar, bashashati m, rezaei n, tarrahi mj, khoshdel ja. the prevalence of penoscrotal abnormalities and inguinal hernia in elementary-school boys in the west of iran. int j urol. 2005;12:479-83. 21. yucesan s, dindar h, olcay i, et al. prevalence of congenital abnormalities in turkish school children. eur j epidemiol. 1993;9:373-80. 22. koltuksuz u, mutuş m, yakıncı c, et al. congenital inguinal pathologies in malatya school age children. j turgut ozal tip merkezi. 1999;6:9-12. 23. akin ml, karakaya m, batkin a, nogay a. prevalence of inguinal hernia in otherwise healthy males of 20 to 22 years of age. j r army med corps. 1997;143:101-2. 24. john radcliffe hospital cryptorchidism study group: cryptorchidism: a prospective study of 7,500 consecutive male births, 1984–1988. arch dis child. 1992;67:892-9. 25. kumanov p, tomova a, robeva r, hubaveshki s. prevalence of cryptorchidism among bulgarian boys. j clin res pediatr endocrinol. 2008;1:72-9. v08_no_3_final.pdf urology for people 254 urology journal vol 8 no 3 summer 2011 what’s up in urology journal, summer 2011? urol j. 2011;8:254. www.uj.unrc.ir kidney stones kidney stones, one of the most painful diseases, have beset humans for centuries. unfortunately, kidney stones are one of the most common diseases of the urinary tract. each year, people make almost 3 million visits to health care providers and more than half a million people go to emergency rooms for kidney stone problems. kidney stones are a common cause of blood in the urine (hematuria) and often severe pain in the abdomen, flank, or groin. anyone may develop a kidney stone, but people with certain diseases and conditions or those who are taking certain medications are more susceptible to its development. when the stone sits in the kidney, it rarely causes symptoms, but when it falls into the ureter, it blocks urine follow. as the kidney produces urine, pressure builds up behind the stone and causes the kidney to swell. this pressure is what causes the pain of a kidney stone (renal colic), but it also helps push the stone along the course of the ureter downward. when the stone enters the urinary bladder, the obstruction in the ureter is relieved and the symptoms of a kidney stone are resolved. see page 185 for full-text article bladder cancer the inside of the bladder is covered with a urine-proof lining, called the urothelium, which prevents urine being absorbed back into the body. the cells of this lining are called transitional cells or urothelial cells. men get bladder cancer much more commonly than women. the most common type of the bladder cancer, urothelial carcinoma, is very strongly associated with cigarette smoking. about 50% of all the bladder cancers in men and 30% in women may be caused by cigarette smoking. the longer and heavier the exposure, the greater are the chances of developing bladder cancer. the most common symptoms of the bladder cancer are as follows: blood in the urine (hematuria), pain or burning during urination without evidence of urinary tract infection, and change in the bladder habits. having these symptoms does not necessarily mean you have bladder cancer. if you have any of these symptoms, you should see your health-care provider right away. see page 203 for full-text article urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. 1356 | sudden decline in semen volume due to seminal vesicle fistula in a patient with crohn’s disease: a case report yasushi yumura,1,2 kazumi noguchi,1 masatoshi moriyama,2 akira iwasaki3 keywords: seminal vesicles; fistula; etiology; crohn's disease; complications. introduction seminal vesicle fistula (svf) is an uncommon condition. many cases of seminal vesicle fistula are related to bowel lesions. we report a very rare case of svf associated with a perianal abscess that developed in a crohn’s disease patient complaining of decline in semen volume. case report a 34-year-old man with a history of crohn’s disease was referred to our department in july 2007 complaining of a decrease in ejaculated semen volume and pneumaturia for the past 2 months. he had previously undergone two perineal abscess drainage procedures (seton’s method) in 2000 and 2007 due to perianal and ischiorectal abscesses arising from crohn’s disease. his erectile function was normal. physical examination revealed induration of the tail of the left epididymis. he was afebrile. testicular size, measured with an orchidometer, was normal bilaterally (14 ml). the prostate could not be examined because of anal stricture and a penrose drain that was indwelling from the perineum to a perianal abscess. on ejaculation, watery fluid was discharged from the perineal drain. we did not examine whether spermatozoa existed in the fluid discharged from the perineal drain. semen analysis revealed very low semen volume (0.3 ml and 0.7 ml) and azoospermia. serum sex hormones levels including follicle-stimulating hormone, luteinizing hormone and testosterone were within normal limits. cystogram and cystoscopy revealed no abnormalities. magnetic resonance imaging (mri) before the second perineal drainage showed bilateral contracted seminal vesicles and a high-incorresponding author: yasushi yumura, md department of urology, yokohama city university, medical center, yokohama, japan. tel: +81 45 261 5656 fax: +81 45 253 1962 e-mail: yumura@yokohama-cu.ac.jp received august 2012 accepted march 2013 1 department of urology, yokohama city university, medical center, yokohama, japan. 2 department of urology, yokohama municipal citizen’s hospital, yokohama, japan. 3 department of urology, yokohama minato red cross hospital, yokohama, japan. case report case report 1357vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l decline in semen volume due to seminal vesicle fistula | yumura et al tensity cystic lesion that was located posterior to the seminal vesicle, and we suspected this was an abscess (figure 1a). mri after the second drainage failed to show seminal vesicle (figure 1b). vasography showed bilateral obstruction at the level of the ejaculatory duct. left seminal vesicle was not visualized. leakage of contrast from the right seminal vesicle to the perineal drain via the posterior lesion of the urinary bladder was demonstrated (figure 2). subsequently, he underwent colostomy because the perianal and ischiorectal abscess had not improved. seminal tract reconstruction was not performed because of the operation difficulties expected with severe perivesical adhesion. after the surgery, the abscess gradually healed and semen volume increased to 1.0 ml. we found sperm (64.0×106/ml) in his ejaculate 16 months after the operation. discussion in this case, the causes of azoospermia and sudden decline in semen volume were obstruction of the ejaculatory duct and leakage of seminal vesicle fluid to an abscess. we speculated that the abscess that had been drained unsuccessfully extended to the periand rearprostatic and vesical lesions and led to seminal vesicle destruction and seminal tract obstruction. because of seminal vesicle destruction, we speculated that the right seminal vesicle was connected to the abscess and seminal vesicle fluid was discharged through the seton drain. we considered that the colostomy led to reduction of the abscess and repair of the seminal tract. svf is a very rare disease. to our knowledge, approximately 20 cases have been reported to date. the most common causes of fistulae are diverticulitis,(1) colorectal cancer (2-4) and crohn’s disease.(2,5) other causes include trauma,(6) radiotherapy, infectious cyst (7) and unknown causes.(8) almost all reported cases had fistula that connected the seminal vesicle with the colon or rectum.(1,3-8) to our knowledge, cases of a fistula connected to a perianal abscess are very uncommon. many seminal vesicle fistulas present with symptoms relating to febrile genitourinary tract infection or lower urinary tract symptom, such as pollakiuria or dysuria. this svf patient had a unique clinical course. there has been no report concerning svf with a chief complaint of sudden decline in semen volume and obstruction of the ejaculatory duct, as in our patient. crohn’s disease may cause fistula in the extra-intestinal tract, including refractory perianal abscesses. carlin and colleagues also reported a case of svf related crohn’s disease.(2) in their case, seminal vesicle communicated with perineum area and the patient had recurrent white discharge from the perineal fistula. it was not reported that the patient had a complaint of decline in semen volume. computed tomography is usually used for the diagnosis of svf. vesiculography,(5, 8) contrast enema (1,2,4) and fistulogfigure 1. a) magnetic resonance imaging (mri) before perineal drainage showed bilateral contracted seminal vesicles and a highintensity cystic lesion that was located posterior to the seminal vesicle, and we suspected this was an abscess (white arrow). b) mri after drainage did not show seminal vesicle. 1358 | case report raphy have also been used. in general, vesiculography mri of the seminal vesicle are alternative diagnostic tests for low ejaculate volume. in our case, these examinations were useful for diagnosis of svf and scrutiny around the seminal vesicle. the reported treatment modalities for svf are conservative treatment,(2,5,8) surgical drainage (transurethral unroofing,(9) transperinael approach,(7) percutaneous approach (4,6) and laparotomy and excision of the culprit lesion. (1) when excision of the culprit lesion is difficult, colostomy is a valuable tool for treatment. in our patient, the abscess gradually healed, the semen volume increased and spermatozoa appeared in ejaculate after the surgery. conflict of interest none declared. figure 2. vesiculography showed bilateral obstruction at the level of the ejaculatory duct. left seminal vesicle was not shown and leakage of contrast from the right seminal vesicle to the perineal drain via the posterior lesion of the urinary bladder was demonstrated. references 1. laspina m, facklis k, posalski i, fleshner p. coloseminal vesicle fistula: report of a case and review of the literature. dis colon rectum. 2006;49:1791-3. 2. carlin j, nicholson da, scott na. two cases of seminal vesicle fistula. clin radiol. 1999;54:309-11. 3. goldman sm, fishman ek, gatewood om, jones b, siegelman ss. ct in the diagnosis of enterovesical fistulae. ajr am j roentgenol. 1985;144:1229-33. 4. kollmorgen ta, kollmorgen cf, lieber mm, wolff bg. seminal vesicle fistula following abdominoperineal resection for recurrent adenocarcinoma of the rectum. a case report. dis colon rectum. 1994;37:1325-7. 5. hamidinia a. recto-ejaculatory duct fistula: an unusual complication of crohn's disease. j urol. 1984;131:123-4. 6. maeda h, arai y, aoki y, okubo k, okada t. successful treatment of a persistent cutaneous fistula to the seminal tract: imaging with three-dimensional computed tomography. br j urol. 1998;82:595-6. 7. hammad ft. seminal vesicle cyst. scand j urol nephrol. 2006;40:426-8. 8. izumi k, takase y, kobayashi t, tokunaga s, namiki m. seminal vesicle-rectal fistula with preceding right acute epididymitis. urol int. 2007;78:367-9. 9. frye k, loughlin k. successful transurethral drainage of bilateral seminal vesicle abscesses. j urol. 1988;139:1323-4. review the prevalence of nocturnal enuresis among iranian children: a systematic review and meta-analysis masoud mohammadi*, aliakbar vaisi-raygani, rostam jalali, akram ghobadi, nader salari purpose: nocturnal enuresis is one of the most common diseases in children, which can affect their mental health. the aim of the present study is to determine the prevalence of nocturnal enuresis in iranian children through systematic review and meta-analysis. materials and methods: the present study was conducted through systematic review and meta-analysis of studies during march 2000july 2018. articled related to the subject were reviewed by searching the medline (pubmed), scopus, sciencedirect, sid, magiran, barakat, and google scholar databases where the heterogeneity of studies was investigated using i2 index. the data analysis was then carried out using comprehensive meta-analysis software. results: 15 articles with a sample size of 16614 individuals aged 3 to 18 years entered the meta-analysis process. the overall prevalence of nocturnal enuresis in children of iran was 10.2% (95% ci: 7-14.8%). the highest and lowest prevalence of nocturnal enuresis was seen in children living in tehran 28.5% (95% ci: 16.1% -45.4) and tabriz 1.8% (95% ci: 1.2-2.8%), respectively. the findings of the present study revealed that the prevalence of nocturnal enuresis in children decreases with enlargement of the sample size. in addition, the prevalence of nocturnal enuresis grows with an increase in the years of research, which is statistically significant (p < 0.05). conclusion: considering the high prevalence of nocturnal enuresis in the current study, health policy makers need to raise the awareness of families by taking efficient and effective policies. keywords: nocturnal enuresis; prevalence; children; iran; meta-analysis introduction children are the architects of the society’s future, so their physical and mental health status is important and their disorders and diseases should be taken care of seriously(1). children who are neglected physically and psychologically today and have no access to adequate health and education will be individuals with physical and mental disabilities in the future(2). nocturnal enuresis is one of the most commonly reported diseases in children following allergic diseases. this disorder is known as involuntary passage of urine during sleep (3), as well as frequent and unintentional passage of urine in the clothes or bed in children who should have gained control over their bladder considering their age. it is also known in case of absence of certain physical abnormalities(4). the majority of children gain regular daytime urine control by age of 3 to 4, so 5 years old is considered as the best age for the diagnosis and screening of the nocturnal enuresis(5). nocturnal enuresis diagnosis is proved when involuntary urination occurs in clothes or bed at least twice a week for three consecutive months, or the bedwetting manifests itself as a clinically important concern in the child's life(6). nocturnal enuresis occurs among 3-15% of 6-year-old children at least one night in a month, and reaches 4 to 16% in 12-year-old children(7). mental health problems department of nursing, school of nursing and midwifery, kermanshah university of medical sciences, kermanshah, iran. *correspondence: department of nursing, school of nursing and midwifery, kermanshah university of medical sciences, kermanshah, iran. tel: +989189057962. e-mail: masoud.mohammadi1989@yahoo.com. received february 2019 & accepted august 2019 in children with nocturnal enuresis are 2 to 6 times more prevalent than those of the total population of the world (8). nocturnal enuresis can cause severe mental stress for families and discomfort for children and adolescents. parents often feel anxious and angry and may blame, punish, and humiliate children due to lack of awareness of this disorder. they may also create serious mental injuries for children(8,9). diagnostic and therapeutic measures, as well as awareness raising plans in families, require access to comprehensive information and statistics on the prevalence of nocturnal enuresis in children. studies in iran have reported different rates of nocturnal enuresis. in a study in sanandaj in 2001, the prevalence of nocturnal enuresis was 8.8% (10), 14.3% in ahwaz in 2013(11), and 11.9% in birjand in 2005(12), indicating the inconsistency and uncertainty of the nocturnal enuresis among iranian children. there are still unclear statistics at the national level. the aim of the present study is to determine the overall prevalence of nocturnal enuresis in iranian children by systematic review and meta-analysis. the results of this study can be useful in conducting interventional studies as well as making health policies. materials and methods this study was a systematic review and meta-analysis urology journal/vol 16 no. 5/ september-october 2019/ pp. 427-432. [doi: 10.22037/uj.v0i0.5194] and has been the result of findings extracted from the previous studies on the prevalence of nocturnal enuresis in iranian children. it includes articles published in domestic and foreign journals, and searches carried out in sid, magiran, barakat knowledge network system, medline (pubmed), sciencedirect, scopus, and google scholar during march 2000 to july 2018. search strategy the search process was carried out in the above websites using the keywords of ‘nocturnal enuresis’, ‘children’, and their equivalent english words and possible combinations. with regard to the persian databases, the search was carried out using farsi keywords of (nocturnal enuresis), (children) while their equivalent english keywords were used in the english key words of nocturnal enuresis, children. in addition, both farsi and english words were searched in the google scholar search engine and the (and) and (or) operators were combined in order to provide more comprehensive access to all articles. specifically, or operators were applied to check the common names for a disorder (children or preschool), (nocturnal enuresis or nighttime urinary incontinence). and word was used in the keywords by matching words in the mesh browser. criteria for selecting and evaluating articles first, all articles were collected using selected keywords and a list of abstracts was then prepared after the search process. after hiding the articles’ specifications, including the magazine name and the author's name, the full text of the articles was provided to the reviewers. each article was read by two reviewers (mm and avr) independently. if the article was rejected, the reason should have been mentioned. in case of any disagreement between the two reviewers (mm and avr), the article was judged by a third reviewer (rj). the inclusion criteria were persian and english articles taken from cross-sectional studies on the prevalence of nocturnal enuresis in iranian children in age group of 4-15 years. in order to evaluate the articles obtained in this study, the prisma checklist was used. other studies, including review, case-control, cohort, and interventional studies were excluded from the list of articles. in this study, searching keywords in google and reviewing related websites were done to examine gray literature, which is the general name for non-formally published scholarly or substantive information. duplicate publication and multiple publications from the same population would be removed using citation management, software endnote (version x7, for windows, thomson reuters). quality assessment for quality assessment of cross-sectional studies, the strobe checklist was used. this checklist contains 22 sections, 18 of which are general and practical for all observational studies, including cohort, case study, and cross-sectional studies. on the other hand, four sections are specific, depending on the type of study as well as various aspects of the methodology including objectives of the study, determining the appropriate sample size, type of study (cross sectional, case-control and cohort), sampling method, research population, data collection method, variables definition and sample study method, data collection tools, objectives of the study, statistical test, and study results. accordingly, the maximum quality score of 32 was considered, while papers with a score of less than 14 were considered to have low quality, and thus excluded from the study. statistical analysis in each study, the prevalence of nocturnal enuresis in children was obtained. the heterogeneity of studies was also assessed using the i2 index. overall, the heterotable 1. specifications of studies included in the study row author (reference) publication year area participants' age sample size prevalence 1 ghotbi (11) 2001 sanandaj 9.3±9 681 8.8 2 zargar (12) 2013 ahwaz 5-6 807 14.3 3 khazaei (13) 2005 birjand 5.5-6.5 455 11.9 4 haghbin (14) 2003 yasuj and gachsaran 7 2846 3.6 5 mohammadpour (15) 2012 gonabad 8.6±1.05 250 6.8 6 emamghoraishi (16) 2004 jahrom 6-11 1000 16.5 7 hakim (17) 2015 ahwaz 8.6±1.8 200 32 8 naderian (18) 2000 tehran 4-12 35 28.5 9 shafipour (19) 2014 rasht 7-11 768 7.2 10 ranjbar (20) 2003 tabriz 5-16 1092 1.8 11 hashem (21) 2013 urmia 7-11 918 18.7 12 safarinejad (22) 2013 tehran 5-18 7562 6.8 figure 1. the flowchart for the stages of including the studies in the systematic review and meta-analysis (prisma 2009) prevalence of nocturnal enuresis in iranian children-mohammadi et al. review 428 vol 16 no 04 september-october 2019 429 geneity was classified into three categories including i2 value of < 25% (low heterogeneity), 25-75 % (moderate heterogeneity), and >75% (high heterogeneity) (10). the data were analyzed using the comprehensive meta-analysis (biostat, englewood, nj, usa version 3). the probability of publication bias in results was measured using the funnel plot, the egger test, and the significance level of 0.05 along with begg and mazumdar's rank correlation and the significance level of 0.1. in addition, the meta-regression test was used in two factors of the sample size and research year to investigate the effects of the potential factors affecting the heterogeneity of the studies. results search output according to the review made on the prevalence of nocturnal enuresis among iranian children and included articles published in domestic and foreign journals, along with the searches made, 383 articles were obtained from the first search, which was ultimately evaluated based on prisma 2009 (figure 1). finally, in the final review, relevant articles were introduced into the meta-analysis, in which 12 relevant articles were included, as reported in table 1. this table presents the researcher’s name, the article title, the year, and place of the study, sample size, the frequency, and prevalence of nocturnal enuresis in children in the studies(11-22). heterogeneity and publication bias the heterogeneity of the studies was evaluated using the i2 test, was 97%, showing a high heterogeneity in the studies. therefore, the random effects model was used to combine the results of the studies. the publication bias of the results was analyzed by a funnel plot and egger test (figure 2) at the significance level of 0.05. it indicated that the publication bias was not statistically significant (p = 0.573). also, considering the high sample size examined in the study, the publication bias was also investigated based on the begg and mazumdar's rank correlation test at the significance level of 0.1, which was not statistically significant (p = 0.921). the total sample size of the study was 16614 participants aged 3 to 18 years. the overall prevalence of nocturnal enuresis in iranian children based on meta-analysis was 10.2% (95% ci: 7-14.8%). the maximum and minimum prevalence of nocturnal enuresis was seen in children living in tehran 28.5% (95% ci: 16.1% -45.4) (18) and tabriz 1.8% (95% ci: 1.2-2.8%),(20) respectively (figure 3). in this figure, the prevalence of nocturnal enuresis in children is shown based on the random effects model, where the black square indicates the prevalence rate and the length of the line segment, on which the square shows 95% ci of each study. the diamond sign reveals the prevalence rate of nocturnal enuresis in all studies at the national level. sensitivity analysis a sensitivity analysis was performed to ensure the stability of results, where after removing each study, the results did not change (figure 4). meta-regression in order to investigate the effects of factors potentially affecting heterogeneity in the prevalence of nocturnal enuresis in children, a meta-regression was used for two factors of sample size and year of study (table 2). based on figure 2, the prevalence of nocturnal enuretable 2. effect of effective factors on heterogeneity (meta-regression) point estimate standard error lower limit upper limit p value sample size slope -0.0001 0.00001 -0.0001 -0.00009 0.000 intercept -1.87 0.04 -1.93 -1.76 0.000 years slope 0.08 0.007 0.06 0.09 0.000 intercept -163.4 14.4 -191.73 -135.11 0.000 figure 2. funnel plot for results of prevalence of nocturnal enuresis in iranian children figure 3. overall prevalence of nocturnal enuresis in children based on random effects model prevalence of nocturnal enuresis in iranian children-mohammadi et al. sis diminishes in children with increasing sample size, which is statically significant (p < 0.05). it was also found that the prevalence of nocturnal enuresis rose in children with an increase in the number of years, which was statistically significant (p < 0.05) (table 2). discussion nocturnal enuresis is one of the most common problems in children, which needs to be treated through counseling and effective measures(23) due to its mental and psychological impacts on the child and the subsequent problems for the family. previous studies have stated that nocturnal enuresis is a multifactorial disorder and cases such as impaired cerebral cortex maturation, rapid eye movement sleep behavior disorder (rbd), disturbed circadian rhythm of adh secretion, genetic disorders, psychiatric disorders, and kidney problems can contribute to its development(24,25). many reports have concluded that since the disease prevalence decreases automatically by 14% with increasing age of the child, the delayed development of the nervous system is one of its major etiologies. other factors such as the socioeconomic status of the family, previous history of urinary tract infection, family history, parental education, and mental status can also contribute to the prevalence of nocturnal enuresis(26,27). ismail et al.(28) reported, in their study in egypt, that there are other risk factors for this disorder such as positive family history, deep sleep, low socioeconomic levels, and child punishment. nocturnal enuresis can also follow a family pattern and can usually affect several members in one family(26). studies have suggested that the nocturnal enuresis in homozygous twins is more common than in heterozygous twins. in the current study and a survey on 16614 children aged 3-18 years, the overall prevalence of nocturnal enuresis in iranian children was reported to be 10.2% based on a meta-analysis. studies in the middle east and asian countries have reported different prevalence rates as follows: turkey, 16.2% (29), saudi arabia 15% (30), taiwan 10% (31), korea 9.2% (32), india 11.1% (33), china 4.3%(34), australia 18.9%(35). the same studies in european and african countries reported the following prevalence rates: italy 3% (36), burkina faso (13%)(37), egypt 10.1% (28), and nigeria 23.2% (38). differences can be attributed to cultural and geographical differences in studies. in most studies, the prevalence of nocturnal enuresis has been greater in boys than in girls(39). for example, the results of a study in spain showed a boy-girl ratio 5:1(40). the results of a study in saudi arabia(30) also revealed a higher prevalence of nocturnal enuresis in boys; researchers justified it by stating that girls usually reach every step of bladder control faster than boys do, which is due to the early development of bladder control in girls(41). further studies reported the same prevalence rates for nocturnal enuresis in both genders(42). however, another study, which reported higher prevalence rates for nocturnal enuresis in girls, attributed such results to the higher risk of urinary tract infections (utis) in this gender (43). nocturnal enuresis can be considered as a problem with associated individual, family, social, and emotional dimensions. considering that this disorder is one of the children's behavioral disorders and various factors are involved in it, the following measures should be considered: increasing family’s level of awareness through counseling, adopting health measures as well as appropriate policies to assess the mental health of children, evaluating physical and mental abilities in measurement bases before entering school for early diagnosis and treatment, providing guidance to parents and mental health services in schools and establishing psychological counseling centers, and familiarizing parents with the mental health issues of children in order to adequately identify and deal with children's mental disorders(13). the ultimate goal is to prevent social-functional consequences in children and enhance their self-confidence and promote their physical and mental health status by treating their disorder. the most important limitation of the present study was the lack of access to the full texts article of some of the old articles and the omission of some of these articles due to their low quality in evaluating the quality of the articles reviewed. conclusions considering the high prevalence of nocturnal enuresis in the current study, it is imperative that health-policy makers take effective and effective measures to raise family awareness, and ensure early diagnosis and treatment. acknowledgements the authors thank the faculty members of the faculty of nursing and midwifery, kermanshah university of medical sciences. conflict of interest there are no conflicts of interest to be disclosed. references 1. branca f, piwoz e, schultink w, sullivan lm. nutrition and health in women, children, and adolescent girls. bmj. 2015; 351:h4173. 2. liu h, fang h, zhao z. urban-rural disparities of child health and nutritional status in china from 1989 to 2006. econ hum biol. 2013; 11:294-309. 3. oge o,kocak i, gemalmaz h. enuresis, point prevalence and associated factors among turkish children turkey pediatric figure 4. results of sensitivity analysis prevalence of nocturnal enuresis in iranian children-mohammadi et al. review 430 vol 16 no 04 september-october 2019 431 2001 ,43:38-43 4. behrman er, kliegman mr, jenson bh. nelson textbook of pediatrics. 18thed. philadelphia: saunders; 2007: 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22. safarinejad mr. prevalence of nocturnal enuresis, risk factors, associated familial factors and urinary pathology among school children in iran. j pediatr urol. 2007; 3:44352. 23. mckenna ph, herdon a. voiding dysfunction associated with incontinence, vesicoureteral reflux and urinary tract infection. curr opin urol. 2003; 10: 599-606. 24. ozden c, ozdal ol, altinova s, oguzulgen i,urgancioglu g, memis a. prevalence and associated factors of enuresis in turkish children.int br a z j ur ol. 2007; 33: 216-22. 25. nuhoglu b, ayyildiz a, fidan v, cebeci o,kosar u, germiyanoglu c. do children withprimary nocturnal enuresis have a retarded boneage? a cross-sectional study. int j ur ol. 2006; 13:109-10 26. stephen b, sulkes. develop mental and behavioral pediatrics. behrman kliegman .essential of pediatrics. third ed. 1998. saunders philadelphia.p:33-34 27. gumus b, virgin n.lekil m. at all prevalence of nocturnal enuresis and accompanying factors in children aged 7-11 years in turkey . 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nocturnal urinary control , nocturnal enuresis and behavior problem in chinese children aged 6 through 16 years. j.am acad. child adolesc psychiatry 2000; 34:1557-64 35. bower ef, more kh. shepherd rb,et al. the epidemiology of children enuresis in australia, br j urol 1996:78:602-6. 36. chozza ml, bernardinelli l, caione p, del gado r, ferrara p, giorgi pl, montomoli c, rottoli a, vertucci p. an italian epidemiological multi centre study of nocturnal enuresis. br j urol. 1998; 81:86-9. 37. ouédraogo a, kere m, ouédraogo tl, jesu f. epidemiology of enuresis in children and adolescents aged 5-16 years in ouagadougou (burkina faso). arch pediatr. 1997; 4:947-51. 38. paul ni, alikor e, anochie ic. factors associated with enuresis among primary school children in port harcourt. niger j paediatr. 2013;40:370-4 39. ghahramani m, basiri moghadam m, ghahramani aa. nocturnal enuresis and impact on growth. iran j pediatr 2008; 18: 167-170 40. clavero arévalo m, toro trallero j. enuresis and encopresis: their relationship. an esp pediatr. 1993; 39:320-4. 41. fritz, g. rockney, b.w. practice parameter for the assessment and treatment of children and adolescents with enuresis. j.am. acad. child adolesc psychiatry. 2004; 43, 1540-50. 42. sengler j, minaire p. epidemiology and psycho-social consequences of urinary incontinence. rev prat. 1995; 45:281-5. prevalence of nocturnal enuresis in iranian children-mohammadi et al. review 432 urological oncology comparison of the efficacy of local anesthesia methods and caudal regional anesthesia in prostate biopsy applied under transrectal ultrasonography: a randomized controlled study sahin pasali1, cuneyt ozden1, yalcin kizilkan1*, suleyman camgoz2, semih baskan2, samet senel1, doruk demirel1, cevdet serkan gokkaya1 purpose: to evaluate the efficacy of caudal regional anesthesia and local anesthesia methods in prostate biopsy applied under transrectal ultrasonography. matherials and methods: this prospective study included a total of 160 patients randomly separated into 4 equal groups as intrarectal local anesthesia (irla), periprostatic local anesthesia (ppla), combined local anesthesia (irla+ppla), and caudal regional anesthesia (cra). the patients were evaluated using the pain scores on a visual analog scale. results: the pain score during anesthesia induction was significantly higher in the cra group than in the irla and irla+ppla groups (p < 0.001). the pain score during entry of the probe to the rectum and movement was significantly lower in the cra group than the irla groups (p = 0.014). the pain score on penetration of the needle to the prostate and at 30 mins after the biopsy was significantly higher in the irla group (p < 0.001). at 2 hours after the biopsy, the pain score in the cra group was significantly lower than irla groups (p = 0.015). conclusion: the ppla alone can be applied more quickly than cra, causes less pain during the application, and has similar efficacy in reducing pain during and after the prostate biopsy procedure. keywords: caudal regional anesthesia; pain; prostate biopsy; prostate cancer; periprostatic local anesthesia. introduction prostate cancer is the second most common can-cer in males and the fifth most frequent cause of male cancer-related deaths(1). a definitive diagnosis of prostate cancer is determined with prostate biopsy taken under transrectal ultrasonography (trus) guidance(2). most trus prostate biopsies are performed under local anesthesia and approximately 20% of these procedures create negative effects of physical pain, stress and anxiety(3). there is a need for repeated biopsies in approximately 21-28% of clinically important cancers(4). in addition, patients under the active observation protocol require repeated biopsies. minimizing pain during the biopsy procedure increases patient compliance with the follow-up protocol(5). research is currently ongoing for the most appropriate form of anesthesia to reduce the pain during trus prostate biopsy. previous studies have shown that patients feel pain at two stages during prostate biopsy: the entry and movement of the trus probe inside the rectum, and during penetration of the biopsy needle to the prostate(6). some studies have reported that periprostatic local anesthesia (ppla) causes no pain during entry and movement of the trus probe (7, 8). previous studies have demonstrated that caudal 1ankara numune training and research hospital, department of urology, ankara, turkey. 2ankara numune training and research hospital, department of anesthesiology, ankara, turkey. *correspondence: ankara şehir hastanesi, üniversiteler mahallesi, bilkent caddesi no:1, çankaya, ankara, 06490 turkey. phone no: +905327231998. e mail: yalcinkizilkan@yahoo.com received august 2019 & accepted december 2019 regional anesthesia (cra) reduces pain both during entry and movement of the trus probe, and during penetration of the biopsy needle(9,10). however, to our knowledge, there is no study in literature that has compared cra with the all other most frequently used anesthesia methods for prostate biopsy. the aim of this study was to compare and evaluate the efficacy of cra and the local anesthesia methods of intrarectal local anesthesia (irla), ppla and irla+ppla in prostate biopsy applied under trus. materials and methods this prospective randomised controlled study was carried out in the ankara numune training and research hospital, department of urology, ankara, turkey in 2017-2018. the study protocol was approved by the institutional review board of ankara numune training and research hospital (1569/2017) and was performed in accordance with the ethical standards laid down in the 1964 declaration of helsinki. informed consent was obtained from all the patients. patients were excluded from the study if they had any evident coagulopathy, immunosuppression, prostatitis, neurological disease, previous prostate biopsy, inflammatory intestinal disease, rectal maligurology journal/vol 17 no. 6/ november-december 2020/ pp. 597-601. [doi: 10.22037/uj.v16i7.5503] vol 17 no 06 november-december 2020 112 nancy, anorectal disease, and allergy to local anesthetic. all patients were evaluated with medical history, international prostate symptom score (ipss), physical examination, dre, full blood count, blood biochemistry, urine analysis and serum psa. the height and weight of all patients were measured and their body mass index (bmi) was calculated. indication for prostate biopsy were suspicion of malignancy in dre and/or serum psa value > 4ng/ml. the patients included in the study were randomly separated into 4 anesthesia groups using the sealed envelope randomization method. group 1 patients were applied with 10 ml 2% lidocaine gel for irla. group 2 patients were administered 5 ml 1% lidocaine hcl to the area defined as the vascular nerve bundle in the posterolateral of the prostate, using a 22g 25cm chiba needle under trus. group 3 patients were administered 10 ml irla then ppla induction was applied 10 mins later. the prostate biopsy was applied 10 minutes after local anesthesia to these patients in group 1-3. for patients in group 4, first a vascular route was opened and 3 ml/kg/hour ringer lactate solution infusion was started. the patients were monitored and vital signs were followed. the patients were placed in the left lateral decubitus, knee-chest position, then the sacral horns and sacral hiatus were identified. after aseptic cleaning of the region where the needle was to enter, the same anesthesia specialist in all cases applied local anesthesia with 2ml 2% prilocaine. entering the skin at a 45˚ angle with a 22g 9cm spinal needle, the sacrococcygeal ligament was pierced and when it was felt that a space was entered, the needle was brought to a position of 20˚ to the skin and was advanced 5-6cm into the epidural space. when it was confirmed that no cerebral spinal fluid or blood had appeared with aspiration, a 20 ml solution containing 20mg/ml 2% 15ml lidocaine and 5ml 0.9% isotonic nacl was injected in 2 doses at a 2-minutes interval. the effect of the cra was evaluated with the cold test. motor block status was evaluated bilaterally with the bromage scale (0= no block, 1=hip cannot be brought into flexion, 2=hip and knee cannot be brought into flexion, 3= hip, knee and ankle cannot be brought into flexion). the prostate biopsy was performed 15 minutes after cra. all the prostate biopsy procedures were performed by the same urology specialist using a hitachi eub-400 ultrasonography device (hitachi, tokyo, japan) with a 6.5 mhz biplane transrectal probe and an 18g 25cm biopsy needle. before the procedure, the prostate volume was calculated using the ellipsoid formula. at least a 12-core systematic prostate biopsy was taken from all patients. all of the patients used ciprofloxadifferent anesthesia methods in prostate biopsy-pasali et al. endourology and stones diseases 130 cin (1000 mg bid) from the day before the trus biopsy (5 days) for prophylactic antibiotic treatment. after insertion of the trus probe, the biopsy procedure was completed and the duration of biopsy was recorded as the time until removal of the probe. the durations of applying ppla and cra induction were recorded. during ppla and cra induction, on entry of the trus probe to the rectum and during movement, during penetration of the needle to the prostate, and at 30 mins, 2 hours and 1 day following the biopsy, the pain scores using a visual analog scale (0= no pain10= intolerable pain) were recorded by a nurse blinded to the type of anesthesia. statistical analysis data obtained in the study were analysed statistically using statistical package for social sciences (spss) version 22.0 software (spss inc. chicago, il, usa). in the group comparisons, the chi-square test was used for determination of prostate cancer, the kruskal-wallis test for numerical variables not showing normal distribution, and the one-way anova test for variables showing normal distribution. a value of p < 0.05 was accepted as statistically significant. in the post hoc comparison of variables which were significant in the kruskal-wallis test, the mann whitney u-test with bonferroni correction was used. results trus biopsy was performed to the 203 patients in our clinic between october 2017 and october 2018 and 43 of these patients stated that they did not want to be included in the study, and the study continued with the remaining 160 patients. fourty patients were randomly included to the each group the patients included in the study were determined with a mean age of 63.04 ± 7.47 years, bmi 26.8±4.5 kg/m2 and mean number of biopsy cores 12.9 ± 2.4. median values of serum psa, ipss and prostate volume were 7.37 ng/dl (range 2.7– 2035), ipss 10 (range 0–35) and prostate volume 57.7 ml (range 18.6-174.03), respectively. no statistically significant difference was determined between the groups in respect of mean age, bmi, serum psa value, ipss, prostate volume and number of biopsy cores (table 1). urine analysis was performed to 156 patients; 113 were normal, 17 patients had microscopic hematuria, 15 patients had leukocyturia and microscopic hematuria + leukocyturia. dre was performed 157 patients; 78 patients had normal prostate examination, 79 had pathologies (nodule, asymmetry etc.). full blood count and blood biochemistry were normal for all patients. table 1.characteristics of study population irla ppla irla + ppla cra p* age (years) 64.32 ± 7.97 62.82±7.31 63.67 ± 7.57 62.35 ± 6.99 0.41* bmi (kg/m2) 27.8 ± 2.5 28.8 ± 6.6 25.9 ± 4.1 26.07 ± 3.3 0.1* psa (ng/ml) 97.60 ± 343.67 14.29 ± 31.06 42.56 ± 203 19.01 ± 33.15 0.28** ipss 12.82 ± 10.05 12.75 ± 8.4 12.22 ± 9.43 13.27 ± 9.24 0.73** prostate volume (ml) 64.39 ± 26.32 64.29 ± 24.23 64.54 ± 26.47 66.41 ± 33.13 0.98** number of biopsy cores 13.07 ± 3.07 12.85 ± 2.23 13.20 ± 2.82 12.50 ± 1.03 0.83** abbreviations: bmi: body mass index; ipss: international prostate symptom score; psa: prostate spesific antigene; irla: intrarectal local anesthesia; ppla: periprostatic local anesthesia, cra : caudal regional anesthesia * one-way anova test ** kruskal wallis test vol 17 no 06 november-december 2020 598 the mean pain scores during anesthesia induction were statistically significantly higher in the cra group (p < 0.001). no statistically significant difference was determined between the ppla and irla+ppla groups (table 2). the mean pain scores during entry of the trus probe and movement were lowest in the cra group, but a statistically significant difference was only determined between the irla group and the cra group (p < 0.001) (table 2). the mean pain scores during penetration of the needle to the prostate were statistically significantly higher in the irla group than the other groups (p < 0.001) (table 2). the mean pain scores at 30 mins after biopsy were statistically significantly higher in the irla group than other anesthesia methods (p < 0.001). in the pain scores at 2 hours after the biopsy, a statistically significant difference was only determined between the irla group and the cra group (p = 0.002). at 1 day after the biopsy, no statistically significant difference was determined between the groups in respect of the mean pain scores (table 2). the mean anesthesia induction time before prostate biopsy was determined to be significantly longer in the cra group than in the ppla and irla+ppla groups (7.38 ± 2.9 mins, 3.93 ± 1.7 mins, 4.25 ± 1.5 mins, respectively, p < 0.001). the mean duration of the prostate biopsy procedure was 7.93 ± 2.9 minutes in all the patients and no statistically significant difference was observed between all 4 groups (irla: 7.46 ± 2.9 mins, ppla: 8.10 ± 2.7 mins, irla+ppla: 8.03 ± 2.8 mins, cra: 8.15 ± 3.2 mins, p = 0.47). in the cra patients, motor block was determined as bromage 0 in 80%, bromage 1 in 10%, bromage 2 in 2.5%, and bromage 3 in 7.5%. prostate cancer was determined in 31.3% of patients following the prostate biopsy. no statistically significant difference was determined between the groups in respect of the rates of cancer determination with the biopsy (p = 0.57). following the prostate biopsy, hematuria was observed within the first 48 hours in 51.9% of patients, hematuria lasting longer than 48 hours in 37.5%, rectal bleeding within the first 48 hours in 55%, rectal bleeding lasting longer than 48 hours in 7.5%, hematospermia in 35.3%, urinary system infection in 6.9%, and inability to urinate in 6.8%. no statistically significant difference was determined between the groups in respect of these complications (p = 0.12, p = 0.17, p = 0.1, p = 0.86, p = 0.6, p = 0.15, and p = 0.58, respectively). early and late complications according to clavien classification were summarised at tables 3 and 4. the trus biopsy confirmed the presence of prostate cancer in 12 (30%), 9 (22.5%), 13 (32.5%) and 13 (32.5%) patients of group 1,2,3,4, respectively. the trus biopsy results of 14 patients were reported as atypical small acinar proliferation, therefore, a second biopsy was performed. discussion although prostate biopsy is an effective diagnostic method for prostate cancer, approximately 65%90% of patients feel pain or discomfort during the procedure(11). it has been determined that pain can be affected by the patient age, prostate volume, serum psa level, prior application of lavage, a history of biopsy, the prostate section taken in the biopsy and the number of cores taken(12). in the current study, no significant difference was determined between the groups in respect of patient age, prostate volume, psa level, or the number of cores taken in the biopsy. based on the high drug absorption capability of rectal mucosa, irla was the first method researched in the reduction of pain related to prostate biopsy(10). however, the effect of irla on pain related to prostate biopsy continues to be a subject of debate. in a meta-analysis by yan et al., irla was reported to decrease pain scores endourology and stones diseases 354 table 2. the groups in respect of the pain scores irla ppla irla + ppla cra p* during anesthesia induction 2.02 ± 2.00 2.57 ± 1.66 5.15 ± 2.25 < 0.001a during entry and movement of probe to the rectum 3.25 ± 2.19 2.42 ± 1.67 2.65 ± 2.35 1.85±2.21 0.014b during penetration of the needle to the prostate 5.80 ± 2.61 2.45 ± 1.96 2.52 ± 1.90 2.17 ± 2.81 < 0.001c 30 minutes after the biopsy 3.05 ± 1.63 1.62 ± 1.51 1.45 ± 1.28 1.40 ± 1.75 < 0.001d 2 hours after the biopsy 2.07 ± 1.54 1.75 ± 1.61 1.37 ± 1.21 1.05 ± 1.23 0.015e 1 day after the biopsy 1.30 ± 1.30 0.87 ± 1.20 0.82 ± 0.95 0.82 ± 1.25 0.197 abbreviations: irla: intrarectal local anesthesia; ppla: periprostatic local anesthesia, cra : caudal regional anesthesia * kruskal wallis test a ppla vs cra , irla + ppla vs kra(p < 0.001, bonferroni corrected mann-whitney test results) b,e irla vs cra (p < 0.001 ve p = 0.002, respectively. bonferroni corrected mann-whitney test results) c,d irla vs ppla, irla vs irla + ppla, irla vs cra (p < 0.001, bonferroni corrected mann-whitney test results) different anesthesia methods in prostate biopsy-pasali et al. irla ppla irla + ppla cra no complications 4 (10%) 8 (20%) 8 (20%) 7 (17.5%) clavien 1 34 (85%) 32 (80%) 28 (70%) 26 (65%) clavien 2 2 (5%) 0 3 (7.5%) 5 (12.5%) clavien 3a 0 0 1 (2.5%) 2 (5%) table 3. early complications of prostate biopsy. abbreviations: irla: intrarectal local anesthesia; ppla: periprostatic local anesthesia, cra : caudal regional anesthesia kruskal wallis test was used. all p values were higher than 0.05 urological oncology 599 but no significant difference was determined between irla and the placebo and non-anesthetized groups(13). in another meta-analysis, yang et al. reported that pain during local anesthesia induction and during entry of the trus probe was decreased with irla. however, the reduction in prostate biopsy-related pain of ppla was reported to be superior to irla(14). the results obtained in the current study showed that irla was less effective than ppla and cra in the reduction of prostate biopsy-related pain, and irla applied before ppla did not provide any additional benefit to ppla in the reduction of pain in local anesthesia induction or during entry of the trus probe to the rectum and during movement. ppla has been determined to reduce pain during needle penetration to the prostate, but doesn’t have an effect on pain created by the trus probe(7,8). however, several studies have reported that the epidural anesthesia method of cra reduces pain during trus probe entry and movement and during penetration of the needle to the prostate, by blocking the sacrococcygeal nerves which innervate the whole perineum(9,10). to date, there have been 5 prospective studies that have evaluated the effect of cra on pain during prostate biopsy. the first of these reported that ppla was superior to cra in reducing pain during prostate biopsy. however, it was also stated that when anatomic variations and the anatomic capacity of the sacral canal were taken into consideration, the dose of 10 ml 1% lidocaine used for cra may not be sufficient(15). the second study reported that the pain scores of the cra group were determined to be significantly lower than those without cra, but the anesthesia methods used in the group without cra were not described in detail(16). in the third study, it was reported that compared to irla, cra significantly reduced pain during placement of the trus probe, in probe maneuvers and when taking the biopsy cores(10). in the fourth study the pain score of the cra group was determined to be at a significantly high level during anesthesia induction compared to the ppla group, significantly lower during entry and movement of the trus probe, and during needle penetration there was no difference. moreover, at 30 minutes and 1 day after the biopsy, no difference was determined between the pain scores of the two groups(9). in the fifth study the pain scores of the irla+cra group were determined to be significantly higher during anesthesia induction, and significantly lower during trus probe entry compared to the scores of the irla+ppla group. during needle penetration there was no difference between the groups. in the sub analyses, the pain scores of patients with bmi ≥ 25 kg/m2 in the irla+cra group were significantly higher than the irla+ppla group during anesthesia induction and needle penetration, but there were no difference during trus probe entry. this could be attributed to insufficient anesthesia due to the difficulty of identifying bony landmarks in obese patients(17). in recent years, kim et al. published meta-analysis which included 47 rct and showed that there are many options for pain control during trus biopsy, however, pelvic plexus block + irla, ppla + ipla, pelvic plexus block, ppla + irla, and ppla methods are potentially more acceptable options. (18). the limitations of performing cra are anesthetist dependent procedure and not cost-effective. in our study, the duration of anesthesia induction was longer and the pain level during anesthesia induction was higher in the cra group compared to the other two local anesthesia groups applied with ppla. the application of irla before ppla did not significantly reduce pain during anesthesia induction, trus probe entry and movement and prostate needle penetration. unlike previous studies, no significant difference was determined between the groups administered cra, ppla alone and irla+ppla in respect of the pain scores during probe entry and movement, during prostate needle penetration and at 30 minutes, 2 hours and 1 day after the biopsy. the current study has some limitations including the lack of placebo group and not performing power analyses prior to the study. conclusions the results of this study demonstrated that the administration of irla before ppla had no effect on pain related to the anesthesia induction or the biopsy procedure. the application of ppla alone can be applied more rapidly than cra, causes less pain while administering anesthesia, has a similar effect on reducing pain during and after the biopsy procedure, does not require an anesthesia specialist and does not require monitoring of the patients during and after anesthesia. therefore it can be considered an ideal anesthesia method in routine urology practice. references 1. ferlay j, soerjomataram i, dikshit r, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer. 2015;136:e359-86. 2. mottet n, bellmunt j, bolla m, et al. eauestro-siog guidelines on prostate cancer. part 1: screening, diagnosis, and local different anesthesia methods in prostate biopsy-pasali et al. irla ppla irla + ppla cra no complications 32 (80%) 35 (87.5%) 29 (72.5%) 33 (82.5%) clavien 1 5 (12.5%) 4 (10%) 8 (20%) 5 (12.5%) clavien 2 1 (2.5%) 0 3 (7.5%) 1 (2.5%) clavien 3a 0 1 (2.5%) 0 1 (2.5%) clavien 3b 1 (2.5%) 0 0 0 clavien 4a 1 (2.5%) 0 0 0 abbreviations: irla: intrarectal local anesthesia; ppla: periprostatic local anesthesia, cra : caudal regional anesthesia kruskal wallis test was used. all p values were higher than 0.05 table 4. late complications of prostate biopsy vol 17 no 06 november-december 2020 600 treatment with curative intent. eur urol. 2017;71:618-629. 3. packiam vt, nottingham cu, cohen aj, eggener se, gerber gs. no effect of music on anxiety and pain during transrectal prostate biopsies: a randomized trial. urology. 2018;117:31-35. 4. litwin ms, tan hj. the diagnosis and treatment of prostate cancer: a review. jama. 2017;317:2532-2542. 5. zargar h, marshall d, siva g, king q. topical diltiazem before transrectal ultrasonographyguided biopsy of the prostate: a randomized controlled trial. anz j surg. 2015;85:430-2. 6. valdez-flores ra, campos-salcedo jg, torres-gomez jj, et al. prospective comparison among three intrarectal anesthetic treatments combined with periprostatic nerve block during transrectal ultrasonographyguided prostate biopsy. world j urol. 2018;36:193-199. 7. gurbuz c, canat l, bayram g, gokhan a, samet g, caskurlu t. visual pain score during transrectal ultrasound-guided prostate biopsy using no anesthesia or three different types of local anaesthetic application. scand j urol nephrol. 2010;44:212-6. 8. otunctemur a, dursun m, besiroglu h, et al. the effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy. arch ital urol androl. 2013;85:69-72. 9. wang n, fu y, ma h, wang j, gao y. advantages of caudal block over intrarectal local anesthesia plus periprostatic nerve block for transrectal ultrasound guided prostate biopsy. pak j med sci. 2016;32:978-82. 10. cesur m, yapanoglu t, erdem af, ozbey i, alici ha, aksoy y. caudal analgesiafor prostate biopsy. acta anaesthesiol scand. 2010;54:557-61. 11. li m, wang z, li h, et al. local anesthesia for transrectal ultrasound-guided biopsy of the prostate: a meta-analysis. sci rep. 2017;7:40421. 12. nazir b. pain during transrectal ultrasoundguided prostate biopsy and the role of periprostatic nerve block: what radiologists should know. korean j radiol. 2014;15:54353. 13. yan p, wang xy, huang w, zhang y. local anesthesia for pain control during transrectal ultrasound-guided prostate biopsy: a systematic review and meta-analysis. j pain res. 2016 11;9:787-796. 14. yang y, liu z, wei q, et al. the efficiency and safety of intrarectal topical anesthesia for transrectal ultrasound-guided prostate biopsy: a systematic review and metaanalysis. urol int. 2017;99:373-383. 15. horinaga m, nakashima j, nakanoma t. efficacy compared between caudal block and periprostatic local anesthesia for transrectal ultrasound-guided prostate needle biopsy. urology. 2006;68:348-51. 16. ikuerowo so, popoola aa, olapade-olaopa eo, et al. caudal block anesthesia for transrectal prostate biopsy. int urol nephrol. 2010;42:19-22. 17. urabe f, kimura t, shimomura t, et al. prospective comparison of the efficacy of caudal versus periprostatic nerve block, both with intrarectal local anesthesia, during transrectal ultrasonography-guided prostatic needle biopsy. scand j urol. 2017;51:245250. 18. kim dk, lee jy, jung jh, et al. what is the most effective local anesthesia for transrectal ultrasonography-guided biopsy of the prostate? a systematic review and network meta-analysis of 47 randomized clinical trials. sci rep. 2019 mar 20;9:4901. different anesthesia methods in prostate biopsy-pasali et al. urological oncology 601 pdf-mini.pdf 353vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l keywords: nephrectomy, laparoscopy, tissue donors introduction rdonor nephrectomy (ldn)(1,2) and now it is performed in the most major transplant centers for donor nephrectomy. further attempts are made to make this minimally invasive technique more acceptable for donors by introducing transumbilical and pfannenstiel laparoendoscopic single site surgery (less) nephrectomy.(3,4) not only more cosmetic comparing to standard laparoscopy (sl), but also more ergonomic and user-friendly than less technique. technique lateral to the umbilicus and were used for grasping and scissoring, respectively. nenstiel incision, which would be used for the kidney extraction (figure 1). this trocar was used for suctioning, traction, and bipolar coagulation for the adrenal and lumbar veins during nephrectomy. vascular clips for controlling the renal pedicle were also introduced through this trocar. laparoscopic nephrectomy was shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran nasser simforoosh, mohammad hossein soltani, ali ahanian rapid communication mini-laparoscopic donor nephrectomy a novel technique corresponding author: nasser simforoosh, md department of urology, shahid labbafinejad medical center, 9th boustan st., pasdaran ave., tehran, iran tel/fax: +98 21 2258 8016 e-mail: simforoosh@iurtc. org.ir website: www. iurtc.org.ir received january 2012 accepted january 2012 354 | rapid communication performed as we reported in detail previously.(1) the colon was mobilized medially and the splenorenal ligament was divided. the left ureter together with the gonadal vein was freed from surrounding tissues while preserving peri-ureteral tissue. the renal vein was dissected distal to the gonadal vein by bipolar coagulation and division of the lumbar veins and adrenal vein (figure 2). renal artery was exposed after the lumbar veins were divided. the rest of the kidney was dissected free from surrounding tissues as we do in ldn. a transverse incision was made lateral to suprapubic trocar and the rectus muscles were separated from each other without opening the peritoneum. the renal artery and vein and the ureter were clipped through suprapubic trocar using hem-o-lok clip applier and titanium clip applier. the renal artery and vein and the ureter were divided and the kidney was hand extracted. results mini-laparoscopic donor nephrectomy (mldn) was successfully performed in a 27-year-old male donor using 3-mm instrument. his body mass index was 18.5 kg/m². operation time was 135 minutes with a warm ischemia of 5 minutes. pain score was zero at discharge and the patient left hospital in 36 hours (less than 2 days). no peri-operative complications occurred. harvested kidney started diuresis immediately post transplant and nadir sediscussion laparoscopic donor nephrectomy has encouraged donors for the kidney donation. randomized and large retrospective studies have shown that ldn has similar graft outcome in recipients while has less morbidity in donors.(1,5) recently, ldn has become the standard of care for donor nephrectomy in the most major transplant centers around the world. several attempts have been made to make ldn sumbilical and pfannenstiel less, have been introduced in this regard. gill and colleagues reported (e-notes) in 4 patients.(3) kurien and associates compared sl donor nephrectomy versus transumbilical less in a randomized comparative study graft function, shorter hospital stay, and longer warm ischemia time (p figure 2. renal vein was freed from surrounding tissues using mini-laparoscopic scissors. figure 1. two 3.5-mm trocars were placed above and lateral to the umbilicus and a 10-mm trocar with 5 mm reducer was fixed through the fascia from a 5-cm pfannenstiel incision, which would be used for the kidney extraction. 355vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l mini-laparoscopic donor nephrectomy | simforoosh et al that less donor nephrectomy is challenging even for expert sl surgeons.(6) andonian and their colleagues performed less pfannenstiel donor nephrectomy in 6 patients with acceptable results and median warm ischemia time of 5 minutes.(4) thereafter, they compared the initial 6 less donor nephrectomies with 6 cases matched sl in the other study. final results were similar in both groups and the only advantage of less in comparison with sl was better cosmetic appearance.(7) both of these techniques have some limitations: laparoendoscopic single site surgery technique is not ergonomic, requires new training and experassistants. another limitation is the lack of triangulation and rolls over of the instruments both inside and outside the peritoneal cavity, which makes the afore-mentioned techniques, the surgeons have routinely used in sl techniques, which adds to the cost of procedure in addition to deep learning curve for using these unfamiliar instruments. novitsky and colleagues revealed that mini-laparoscopic cholecystectomy is concomitant with less pain and shorter hospital stay and recovery time comparing to sl.(8) hence, surgeons perform the procedure more comfortably and no new videoscope is needed while achieving excellent cosmetic results. likewise, working instruments are regular pediatric and adult instruments already used in sl operating rooms. mini incision in this approach requires no suturing conclusion mini-laparoscopic donor nephrectomy offers the nor nephrectomy while being more ergonomic and more comfortable for laparoscopic surgeons doing ldn. randomized clinical trials are needed to compare mldn and sldn. conflict of interest none declared. references 1. simforoosh n, basiri a, tabibi a, shakhssalim n, hosseini moghaddam sm. comparison of laparoscopic and open donor nephrectomy: a randomized controlled trial. bju int. 2005;95:851-5. 2. dols lf, ijzermans jn, wentink n, et al. long-term follow-up of a randomized trial comparing laparoscopic and miniincision open live donor nephrectomy. am j transplant. 2010;10:2481-7. 3. gill is, canes d, aron m, et al. single port transumbilical (e-notes) donor nephrectomy. j urol. 2008;180:637-41; discussion 41. 4. andonian s, herati as, atalla ma, rais-bahrami s, richstone l, kavoussi lr. laparoendoscopic single-site pfannenstiel donor nephrectomy. urology. 2010;75:9-12. 5. jacobs sc, cho e, foster c, liao p, bartlett st. laparoscopic donor nephrectomy: the university of maryland 6-year experience. j urol. 2004;171:47-51. 6. kurien a, rajapurkar s, sinha l, et al. first prize: standard laparoscopic donor nephrectomy versus laparoendoscopic single-site donor nephrectomy: a randomized comparative study. j endourol. 2011;25:365-70. 7. andonian s, rais-bahrami s, atalla ma, herati as, richstone l, kavoussi lr. laparoendoscopic single-site pfannenstiel versus standard laparoscopic donor nephrectomy. j endourol. 2010;24:429-32. 8. novitsky yw, kercher kw, czerniach dr, et al. advantages of mini-laparoscopic vs conventional laparoscopic cholecystectomy: results of a prospective randomized trial. arch surg. 2005;140:1178-83. urol_v03_no4_001_editorial.indd urological survey 253urology journal vol 3 no 4 autumn 2006 urology in the iranian biomedical journals etiology of end-stage renal disease in dialysis patient in gilan province khosravi m, ghaheryfar m, monfared a department of nephrology, razi hospital, gilan university of medical sciences, rasht, iran background: the etiology of end stage renal disease (esrd) in every community differs according to genetic, nutrition, and public health status. esrd, the terminal stage of chronic renal failure, needs replacement therapy otherwise could lead to death. the aim of the study is to determine the relative frequency of esrd etiology in hemodialysis patients of gilan province. methods: this descriptive study was performed on 407 patients who were being hemodialysis in all hemodialysis centers of the gilan province from september 2002 to september 2003. the original data was collected from the medical records of patients. results: the most prevalent causes were: hypertension 35.4%; unknown etiology 16.2%; diabetes melitus 13.8%, glomerulopathies 9.6%, urologic causes 9.1%, cystic kidney diseases 7.6%; other causes 5.9%; congenital 2.5%. conclusion: in our study hypertension was the first etiology of esrd, followed by unknown causes, however nephrology textbooks indicate diabetes melitus as the primary and hypertension as the secondary etiology of esrd. tehran univ med j. 2006;64:54-60. a study of the risk factors for posttransplant erythrocytosis at sina and baghiat-allah hospital razaghi e, kaboli ar, lesan-pezeshki m, pash-meysami a, khatami mr department of nephrology, sina hospital, tehran university of medical sciences, tehran, iran background: post-transplant erythrocytosis (pte) is characterized by persistent hematocrit level above 51% that develops in 10-20% of kidney recipients, mostly 2 years after kidney transplantation. pte is self limited in 25% of the patients but can be persistent in other patients with an increased susceptibility for thrombosis. the purpose of this study was to identify the risk factors for development of pte in our center. methods: we selected 45 patients who were transplanted at least 3 months before selection (minimum time required for detection of pte) and were referred to the kidney transplantation clinic during 5 years (1998-2003) as the case group. at the same time, we considered 2 patients without erythrocytosis as control for each patient in the case group among kidney transplant recipients who were referred to the same clinic during 5 years (1998-2003). in total we had selected 135 patients, 45 patients with erythrocytosis as the case group and 90 patients without erythrocytosis as the control group. patients who were affected by high hematocrit before transplantation (hc > 51%), overt pulmonary disorder, and polycytemia vera were excluded from this study. we collected basic information by using old charts and complementary information was added through phone conversations and urol j (tehran). 2006;4:253-7. www.uj.unrc.ir urology in the iranian biomedical journals 254 urology journal vol 3 no 4 autumn 2006 physical examination in the clinic. all the information was entered in the digital questionnaire and was analyzed by the spss statistical package. results: there was no significant difference between the case and control group for age, history of hypertension, diabetes, pretransplant hematocrit, pretransplant transfusions, and function of graft and source of kidney. a significantly higher proportion of pte patients were male, also the case group had a significantly higher frequency for personal history of polycystic kidney disease, glomerulonephritis and higher frequency of azathioprine, prednisolone and cyclosporine regimen. conclusion: pte is an important complication of kidney transplantation that can be fatal. there are multiple risk factors that should be addressed to prevent this complication. tehran univ med j. 2006;64:61-8. the etiologies and outcome of esrd in children medical center from 1988 to 2003 madani a, shakiba m, ataei n, esfahani st, mohseni p department of pediatric nephrology, children’s medical center, tehran university of medical sciences, tehran, iran background: chronic renal failure defines as progressive and irreversible dysfunction of kidneys that could eventually terminated to end stage renal disease (gfr < 10% nl). because of therapeutic problem and high mortality and morbidity and its implication quality of life, esrd is one of the important dilemma of pediatric medicine. methods and materials: in our study 216 patients evaluated. results: male to female ratio was 1.1. the peak of the presenting age of esrd was 10 years old (8-12 y). congenital urological malformation (30%), glomerulopathies (20%), hereditary nephropathies (14.3%), multisystem diseases (7%) and nephrolithiasis (6.2%) are the most common etiologies of esrd. vur in 21% and congenital obstructive disease in 8.5% are the etiology of esrd. in patients with age 5 years old and lesser common causes of esrd are congenital urologic malformation and glomerulopathies. in other age groups, urologic malformation is the most a common cause of esrd. in etiologic assessment of 2 separate 7 years’ intervals, 1988-93 and 1996-2003, there was not any significant changes in frequency of etiologies but frequency of congenital obstructive uropathy decreased from 10% to 5.7%. total amount of vur (vur ± neuropathic bladder) did not change, but frequency of primary reflux nephropathy decreased from 14.2% to 8%. in this study, in 145 patients, hemodialysis continued and 28 cases had unsuccessful renal transplant (13.8%). a total of 7.4% of patients had successful renal replacement therapy (rrt) and mortality rate was 7.4%. conclusion: based on that the most common cause of esrd in all ages in congenital urologic malformations, early diagnosis and appropriate management of these cases are effective in decreasing incidence of esrd and with respect to few cases of renal transplant and unsuccessful results in 65% of rrt, the approach to this problem should be revised. j tehran fac med. 2005;1:67-1. urology in the iranian biomedical journals urology journal vol 3 no 4 autumn 2006 255 survey of cutaneous complications after renal transplantation in emam reza and qaem hospitals, mashhad yazdan panah mj, ebrahimi rad m, mojahedi mj departments of dermatology and internal medicine, mashhad university of medical sciences, mashhad, iran background and objective: renal transplantation is an appropriate treatment for end stage renal disease and helps prolongation of patients’ survival with better quality, but immunosuppressive drugs that are used for inhibition of rejection after transplantation may cause some adverse effects in other organs such as the skin. apparently, early recognition of those side effects and their appropriate management can reduce morbidity and mortality. this study was designed to study cutaneous complication in renal transplantation recipients. materials and methods: in this descriptive study, cutaneous side effects in one hundred kidney transplant patients who admitted to transplantation clinics of qaem and emam reza hospital of mashhad during a six-month period (april to september 2003) were studied. results: sixty-five patients were males and 35 cases were female. the mean age was 36 years (sd=14). totally, cutaneous manifestations were observed in 88% of patients. in an descending order they included hypertrichosis, cushingoid appearance, gingival hyperplasia, steroid acne, common warts, herpes simplex infection, superficial fungal infection, candidiasis, actinic keratosis, porokeratosis, lymphoma, stria, telangiectasia and sebaceous hyperplasia. conclusion: early recognition of these complications and appropriate treatment of them can reduce probable mortality and morbidity. iran j derm. 2005;32:281-6. skin lesions after renal transplantation in shiraz university of medical sciences salmanpoor r, mirnezami, m department of dermatology, shiraz university of medical sciences, shiraz, iran background and objective: renal transplantation may be considered as the only effective long term therapy for chronic renal failure. better surgical techniques and recent advances in immunosuppressive therapy allows patients to survive for many years. however, cutaneous lesions (cosmetic, infectious, precancerous and neoplastic) can be a significant problem for this group of patients. this study was performed to determine the frequency of skin lesions in renal transplant recipients (rtr) in shiraz university of medical sciences in 2003, 2004. materials and methods: this descriptive study was done on rtr operated in transplantation center, namazi hospital in shiraz. they had a complete dermatologic history taken and received a thorough dermatologic examination in the department of dermatology at faghihi hospital. results: from july 2003 to october 2004 two hundred (130 males and 70 females) patients with a mean age of 39 years were studied. hypertrichosis was the most commonly observed dermatologic condition which was observed in 191 cases. the most common skin infection was wart presented in 101 cases. eight patients had non-melanoma skin cancer. urology in the iranian biomedical journals 256 urology journal vol 3 no 4 autumn 2006 conclusion: awareness of rtrs and their medical personnel about cutaneous complications of renal transplantation as well as early referral of these patients to dermatologists to treat their lesions can improve their quality of life and survival. iran j derm. 2005;32:276-80. extracorporeal shock wave lithotripsy for treatment of renal stones in children younesi rostami m, rezaei mehr b background and purpose: children with urinary stone disease for longer period of time are at risk of stone recurrence. in two-thirds of the cases medical intervention is mandatory and minimally invasive therapy is advised. the purpose of this research was to evaluate the efficacy and complications of eswl in these children. materials and methods: in this study 30 patients with renal stones were recruited. patients with ureteral and bladder stones were excluded. imaging study for diagnosis of renal stones were sonography (23 patients) kidney-ureter-bladder (3 patients) and intravenous pyelography (ivp) (4 patients). all patients were evaluated for pt, ptt and medical history of coagulophaty. twenty five patients had renal stones lesser than 20 mm and patients had stones greater than 20 mm. patients treated with 1200-2200 shocks (mean 1500) and 1618 kv. all patients were evaluated with sonography 2 weeks, 4 weeks and 12 weeks after treatment. in patients with renal stones greater than 2 cm a double j stent inserted before eswl. results: stones were from 9 to 26 mm in size (mean 13 mm). 25 patients became stone free (83.3%) after on course of eswl. in one patient (3.3%) three courses and in 4 patients (13.3%) 2 courses of eswl necessitated for removing of stones. 2 cases (6.6%) complicated with steinstrasse one of whom was managed with conservative therapy and in the other tul was done. conclusion: extracorporeal shock wave lithotripsy is effective in the treatment of renal stones in children. in patients with stones greater than 2 cm additional course of eswl may be necessary. we recommend that in patients with stones greater than 2 cm insertion of a double j stent can reduce occurrence of steinstrasse. complication of eswl in children is very low and no significant morbidity occurs with eswl j mazandaran univ med sci. 2005;46:77-81. a study on the rate, type and clinical features of urolithiasis in children younger than 15 years with symptomatic urinary tract infection ahmad zadeh a, jamshidi moghaddam z objective: marked variation exists in the incidence of urolithiasis in children worldwide. urolihiasis may be declared by the passage of stone, but is more commonly revealed during the investigation of a child for urinary tract infection (uti). the aim of this study was to determine the rate of renal calculi in patients with symptomatic uti. methods: over an eight months’ period, 196 children (aged two months to 15 years) admitted with symptomatic uti were evaluated for renal calculi by plain abdominal x-ray and ultrasonography. urology in the iranian biomedical journals urology journal vol 3 no 4 autumn 2006 257 results: the results showed that 15 (7.6%) had urolithiasis, which was more common in boys. fever and dysuria were the commonest clinical features in 80% of cases. the implicated organisms isolated in both uti and urolithiasis were as follows: e coli (67%), klebseilla (26%) and proteus (7%). obstructive hydronephrosis was detected in 40% of cases leading to surgical intervention. the sites of stones were as follow: upper urinary (67%), bladder (20%), and urethra (13%). stone analysis was done in 12 cases revealing calcium oxalate in 8 (53%), cysine in 2 (13%), struvite and uric acid 1 (6.7%) in each. in 80% of patients, the stones were multiple and 66.6% were bilateral. in 50% of cases, the underlying disorders were identified. two cases had distal renal tubular acidosis, two brothers had cystinuria and one child had a staghorn struvite. on admission, 40% of our cases had an obstruction and 27% of them had arf who on discharge had better renal function following treatment with anti-microbial drugs. conclusion: these findings suggest that early diagnosis and management of renal stones in children with uti is necessary to prevent the development of renal failure sci med j ahwaz univ med sci. 2005;45:155-62. sensitivity and specificity of urinary bladder cancer antigen for diagnosis of bladder tumor; a comparative study with urinary cytology radkhah k, nowroozi mr, jabalameli p department of urology, imam khomeini general hospital, school of medicine, tehran university of medical sciences, tehran, iran cystoscopy and urinary cytology are currently the basis for diagnosis and follow-up of bladder tumors. research to find a sensitive and specific tumor marker for diagnosis of bladder tumor is actively underway, however, due to low sensitivity and high cost of cytology. this cross-sectional study was performed in 65 patients to evaluate whether urinary bladder cancer (ubc) antigen level can predict the presence of active bladder tumor. in patients with inactive tumor, ubc antigen level was determined in addition to standard cystoscopy and cytology for follow-up. patients with active tumor were subjected to standard treatment and ubc antigen level determination. ubc antigen levels were measured by elisa, using monoclonal antibodies specific for ubc antigen. as a control group, ubc antigen level was also determined in 65 persons who had been referred for urinalysis for other reasons. ubc antigen level more than 1 µg/l which was regarded as positive was found in 49.4% of the patients. in control group, 96.9% had ubc antigen < 1µg/l. mean ubc antigen level in patients was 3.77 µg/l while it was 0.508 µg/l in controls (p < 0.001). sensitivity of ubc antigen was 53.3% and its specificity was 40%. sensitivity and specificity of urinary cytology was 17.3% and 88.2%, respectively. this difference was statistically significant (p < 0.001). ubc antigen is more sensitive than urinary cytology, although cytology still retains its priority in specificity. it is not yet recommended to replace ubc antigen for cytology due to its low specificity and not favorable sensitivity. acta med iran. 2005;43:169-72. case report 61urology journal vol 7 no 1 winter 2010 bilateral perirenal subcapsular fluid collection a rare presentation of renal parenchymal disease majid aliasgari, shahnaz atabak, alireza lashay, erfan amini, ali shahabi urol j. 2010;7:61-2. www.uj.unrc.ir keywords: nephrotic syndrome, membranoproliferative glomerulonephritis, urologic surgical procedures department of urology, shahid modarres hospital, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran corresponding author: erfan amini, md department of urology, shahid modarress hospital, sa’adatabad, tehran, iran tel. +98 21 2207 4087 e-mail: amini.erfan@gmail.com received february 2009 accepted august 2009 introduction perirenal fluid accumulation (floating kidney) is an unusual presentation of nephrotic syndrome. in this condition, the renal parenchyma is compressed and kidney function is impaired. we present a 27-year-old woman with membranoproliferative glomerulonephritis (mpgn) and massive bilateral perirenal fluid accumulation. case report a 27-year-old woman presented with abdominal pain and a huge mass in the right upper quadrant. the patient had a history of hypertension and proteinuria during pregnancy. at presentation, the patient was hypertensive, and abdominal examination revealed a huge mass in the right side with extension to the midline and pelvic cavity. the patient had a serum creatinine level of 1.3 mg/dl, serum protein level of 5.5 g/dl, and serum albumin level of 2.7 g/ dl. proteinuria of 4 g/d was noted on 24-hour urinalysis. abdominopelvic ultrasonography revealed extensive perirenal fluid collection, which was more intense on the right side. increased cortical echogenisity and decreased corticomedullary differentiation was also noted on ultrasonography. renal subcapsular accumulation of homogenous fluid was noted on abdominopelvic computed tomography, which was more prominent on the right side, causing gross medial displacement of the right kidney. both kidneys secreted normally with no evidence of hydronephrosis (figure). the right perirenal collection was drained percutaneously. the drained fluid was a transudate containing 1.2 g/ dl of protein. despite sufficient gross medial displacement of the right kidney due to massive fluid accumulation. both kidneys secreted normally. bilateral perirenal fluid collection—aliasgari 62 urology journal vol 7 no 1 winter 2010 drainage, re-accumulation of fluid was seen on ultrasonography 10 days later. eventually, surgery was performed to fenestrate gerota’s fascia and drain the perirenal fluid into the peritoneal cavity. kidney biopsy was performed simultaneously. a combination of conventional light microscopy and immune fluorescence study revealed type 2 mpgn. a thorough investigation was performed before initiation of the treatment. viral markers and immunologic evaluations (including antinuclear antibody, complements, etc) revealed no abnormality, and treatment began with prednisolone and mycophenolate mofetil. proteinuria remained unchanged after the treatment; therefore, she received intravenous methylprednisolone pulse therapy. although proteinuria remained unresponsiveness to different treatment attempts, abdominal pain was relieved, and blood pressure was controlled within preferable limits. despite the occurrence of mild ascites, no right perirenal fluid reaccumulation was observed on ultrasonography 6 months later, and the left perirenal fluid remained unchanged. discussion perirenal fluid accumulation may occur as a rare presentation of nephrotic syndrome. sodium and fluid retention can lead to fluid transudation into the perirenal space. distension of the renal capsule and gerota’s fascia due to massive fluid accumulation may cause pain. in addition, arterial hypertension secondary to renal ischemia and activation of renin-angiotensin-aldosterone system may occur. similar findings have been noted in patients with subcapsular bleeding (“page kidney”).(1) although the first step in the treatment of such patients is nonsurgical, surgery is an appropriate option for refractory cases. yalcin and colleagues described a patient with focal segmental glomerulosclerosis and nephrotic syndrome associated with massive perirenal fluid accumulation that was successfully managed with corticosteroid and cyclophosphamide. (2) koppelstaetter and associates performed laparoscopic fenestration of gerota’s fascia into the peritoneal cavity in a patient with focal segmental glomerulosclerosis and refractory perirenal fluid accumulation.(3) another therapeutic approach is instillation of povidone iodine into the renal capsule, which has been proposed by orofino and coworkers.(4) the underlying parenchymal disorder in our patient was type 2 mpgn, in which medical treatment may be less effective. despite receiving different therapies, proteinuria in this patient remained unchanged during a 6-month followup, but fenestration of gerota’s fascia into the peritoneal cavity improved the pain and hypertension significantly, and postoperative follow-up revealed no recurrence of perirenal fluid accumulation. conflict of interest none declared. references 1. mccune tr, stone wj, breyer ja. page kidney: case report and review of the literature. am j kidney dis. 1991;18:593-9. 2. yalcin au, akcar n, can c, kasapoglu e, sahin g. an unusual presentation for nephrotic syndrome. bilateral perirenal subcapsular fluid collection. nephron. 2002;92:244-5. 3. koppelstaetter c, peschel r, glodny b, riegler p, passler w, lhotta k. fenestration of the gerota’s fascia as symptomatic treatment of floating kidneys. am j kidney dis. 2007;50:1020-2. 4. orofino l, herrero ja, quereda c, et al. perirenal subcapsular fluid collection in a patient with membranous nephropathy and renal vein thrombosis. j urol. 1986;136:1287-9. v08_no_3_final_last.pdf endourology and stone disease 191urology journal vol 8 no 3 summer 2011 prone position in percutaneous nephrolithotomy and postoperative visual loss mahvash agah,1 mahshid ghasemi,2 fatemeh roodneshin,3 badiozaman radpay,3 siamak moradian4 purpose: to study the simultaneous effects of prone position and anesthesia on intraocular pressure (iop) and the time impact on post anesthesia visual loss development in percutaneous nephrolithotomy (pcnl). materials and methods: twenty patients who were candidates for pcnl were recruited in this study. intraocular pressure was measured in five occasions: 1. base line; 2. ten minutes after anesthesia (supine-i); 3. ten minutes after position change to prone (prone-i); 4. at the end of the operation (prone-ii); and 5. ten minutes after position change to supine (supine-ii). the data were analyzed by spss software using repeated measures anova and paired t test. results: the participants consisted of 17 (85%) men and 3 (15%) women, with the mean age of 44 years. the duration of the prone position was 79.75 ± 22.73 minutes. intraocular pressure changed significantly in five positions (p = .000). it was lower in supine-i than baseline, higher in prone-i than base line and supine-i, lower in supine-ii than prone-ii, and highest in prone-ii (p = .000). there was a linear relationship between iop and prone position duration (r = 0.67; p = .001). conclusion: intraocular pressure dropped significantly after anesthesia and increased in prone position. there was a linear relationship between iop rise and the prone position duration, doubled within two hours. therefore, in pcnl carried out in prone position, it is recommended to observe safety measures and necessary precautions for iop rise and possible post anesthesia visual loss, particularly in glaucoma. urol j. 2011;8:191-6. www.uj.unrc.ir keywords: intraocular pressure, percutaneous nephrolithotomy, prone position, vision acuity 1anesthesiology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences,tehran, iran 2taleghani medical center, shahid beheshti university of medical sciences, tehran, iran 3urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 4shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran corresponding author: fatemeh roodneshin, md urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran tel/fax: +98 21 2254 9029 e-mail: dr_roodneshin_f2007@yahoo.com received december 2010 accepted march 2011 introduction of peri-operative complications, post anesthesia visual loss (pvl) is one of the most important ones reported in numerous articles. (1-6) post anesthesia visual loss is an unfortunate, horrifying, and rare complication that is among the legal complaints.(7) it has been mostly reported in spinal surgeries and the prone position.(3) several factors, including hypotension, anemia, and the pressure on the eyes may lead to pvl.(2) however, some researchers have suggested that hemorrhage, changes in blood pressure, hematocrit level alterations, and the volume of fluid replacement during the operation might not be contributory factors in development of pvl.(7) reduction prone position and visual loss—agah et al 192 urology journal vol 8 no 3 summer 2011 in eye’s perfusion, the volume of blood loss, and the replacement fluids have been mentioned as the most common factors that lead to pvl. ischemic optic neuropathy (ion), in which either the anterior (aion) or the posterior (pion) section of the nerve is involved, is the most common cause of pvl.(6) ho and colleagues studied the ion after the spinal cord surgeries in prone position and reported that mostly the external part of the nerve was affected by ischemia and was frequently bilateral (40% for aion and 47% for pion).(8) unfortunately, nowadays, the routine check of the optic nerve blood flow is not carried out.(7) the anterior and posterior sections of the nerve are supplied separately by the posterior branches of the ciliary artery and perforating arteries, respectively. over 20% of normal populations have abnormal autoregulation that is undetectable clinically.(9) blood vessels are compressible easily at the posterior section of the optic nerve and with the alteration in the eye perfusion pressure, some patients become susceptible to ion,(10,11) and atherosclerosis worsens the situation.(11) in normal patients, reduction in the eye perfusion in the range of autoregulation is tolerable, but in the existence of atherosclerosis, there is a possibility of blood flow reduction in the nerve,(12) and patients with vascular impairment are at higher risk of developing ion.(10,11) optic nerve is sensitive to acute bleeding; nonetheless, acute hemodilution is not precarious and therefore there is no need to extra blood.(6,7) hemodilution and hypotension are routine in open heart surgery, but pvl is rare.(7) generally, pvl is not caused by direct pressure on the eye globe, but the main factor is the effect of hemodynamic alterations on ocular perfusion pressure (opp) that is the result of subtracting the intraocular pressure (iop) from mean arterial pressure (map); opp = map – iop.(13) yet in ocular perfusion, the attention has been focused more on holding map normal or high, and iop has been left relatively unnoticed, since even if map is steady, a high iop prevents a proper opp. hypotension also decreases iop, which in turn reduces opp.(14) in a study on the effect of position on iop in awake patients, the pressure raised from 13.5 mmhg in supine position to 20 mmhg in the prone position.(15) prone position causes an increase in the peritoneal pressure with subsequent increase in iop, peak inspiratory pressure (pip), and central vein pressure. in the patients not suffering from glaucoma, the peritoneal pressure during the laparoscopic surgery did not yield increased iop in the lithotomy position,(16) but iop increased in glaucomatous rabbits.(17) intraocular pressure showed an increase in the anesthetized patients and the awake volunteers in the supine position with low head placement (trendelenburg). the mechanism is the rise in the episcleral venous pressure.(9) furthermore, general anesthesia reduces iop.(18) the rise in paco2 could increase iop during the general anesthesia in the supine position,(19) but paco2 does not change substantially during general anesthesia.(20) in a study, the rises of paco2 and end-tidal carbon dioxide concentration (etco2) in the prone position were reported.(21) the balance between the prone position and general anesthesia plays an important role in opp. percutaneous nephrolithotomy (pcnl) is relatively a new technique and the treatment of choice for removing stones in the kidney, proximal ureter, inferior pole of the kidney, or infundibulopelvic and the stones accompanied by the evidence of obstruction. this operation usually results in low blood loss and the overall need for blood transfusion is less than 10%.(22) to carry out this operation, there is mostly a need to general anesthesia. although pcnl is usually completed in prone position, performing it in the supine and flank positions is still under debate.(23-26) the aim of this study was to investigate the simultaneous effects of anesthesia and prone position on iop during pcnl and the risk of developing pvl. materials and methods this study was a non-controlled, nonrandomized, and non-blinded (pre post quasiexperimental design) clinical trial that was carried out on 20 patients candidate for pcnl. all of them were in american society of anesthesiologists (asa) class i to iii. the written prone position and visual loss—agah et al 193urology journal vol 8 no 3 summer 2011 informed consents were obtained from each participant. patients with a history of either eye disease or eye surgery were excluded from the study. the demographic and clinical data were collected using a questionnaire. all the patients had hematocrits above 30% and the duration of patients’ fasting was 8 hours. first, electrocariography monitors, non-invasive sphygmomanometer, pulse oximetry, and nerve stimulator were connected to the patient. both eyes were anesthetized by 0.5% tetracaine. before prescription of any premedication, the pressures of both eyes were measured in supine position by tono-pen xl hand-held applanation tonometer (baseline). the mean of 4 measurements with the right standard deviation of less than 5% was acceptable that otherwise the measurement was repeated. anesthesia protocol was the same for all the patients and achieved as follows: premedication with xylocaine 1.5 mg/kg and fentanyl 1 to 2 μg/ kg. induction with nesdonal 3 to 5 mg/kg and atracurium 0.5 mg/kg and the continuation of the anesthesia by fentanyl 1 to 2 μg/kg/h infusion, halothane 0.5% to 0.6%, and n2o 50%. mean arterial pressure was regulated at the range of 20% of wakefulness and ventilation on the basis of etco2 30 to 35 mmhg. in order to maintain the intravascular volume during the operation, in addition to the precise compensation of the hemorrhage, 5 ml/kg normal saline was prescribed for each patient. any subject with the hemorrhage of greater than 1000 cc was excluded from the study. by controlling train of four, the timing for intubation and the re-prescription of the muscle relaxants were determined that in the case of the existence of more than one twitch, muscle relaxant (0.1 mg/kg) was repeated. particularly, at the time of the position change, patient was sustained flaccid and in deep anesthesia. the iop was measured in the following stages: 1. awakeness and in supine position (baseline) 2. ten minutes after induction and in supine position (supine-i) 3. ten minutes into acquiring prone position (prone-i) 4. at the end of the operation in prone position (prone-ii) 5. ten minutes into acquiring supine position (supine-ii) before the reverse injection and the change in depth of anesthesia simultaneously, in the above-mentioned stages, pip, end-tidal halothane (et hal), etco2, pulse rate, saturation of peripheral oxygen (spo2), and map were measured as well. the xl hand-held tonometer was calibrated after each use. the change of position was carried out by the same team, considering all necessary precautions gently for all the patients. applying pressure on the eyes was avoided during the prone position and a gelatinous head ring was placed under the patient’s head without any contact with the eyes. the method of operation was unchanged. the surgeon, surgical equipment, the evaluators, and persons who collected the data were the same for all the patients. the patients were questioned concerning the visual acuity or any other visual disturbances in both eyes in the recovery room. pre and postoperative hematocrit level as well as urine output and blood loss were measured. the data were analyzed by spss software (the statistical package for the social sciences, version 11.0, spss inc., chicago, illinois, usa) using repeated measures anova and paired t test. p values less than .05 were considered significant. results the participants consisted of 17 (85%) men and 3 (15%) women, with the mean age of 44 years. the duration of the prone position was 79.75 ± 22.73 minutes. no significant differences were observed regarding pip, etco2, map, spo2, and et hal in the five stages. since the statistical differences were unavailable between the right-eye and the left-eye iops, we considered the left-eye iop in our calculations. the measured iop ranged between 12 and 40 mmhg and it was observed that iop changed prone position and visual loss—agah et al 194 urology journal vol 8 no 3 summer 2011 significantly in the five positions (p = .000). the iop in supine i (12.5 ± 0.5 mmhg) was lower than the baseline (15.42 ± 0.9 mmhg) (p = .000). the intraocular pressure in prone i (25.5 ± 1.5 mmhg) was higher than supine i and the baseline (p = .000). the iop in prone ii (38.9 ± 0.9 mmhg) was higher than all previous measurements (p = .000). the iop in supine ii (13.7 ± 0.4 mmhg) was lower than prone ii (p = 0.000) (table and figure). there was a linear relationship between the iop and duration of the prone position (r = 0.67; p = 0.001) that the iop rose as the time elapsed. discussion to the best of our knowledge, this study is the first one on the iop in pcnl and the effect of the duration of the prone position on the anesthetized patients. in this study, anesthesia reduced the iop, which is in line with other studies showing that administration of anesthetic drugs, such as nesdonal and atracurium, resulted in reduction of the iop.(27) the other finding is that the position change to prone leads to alteration of the iop in a way that not only it compensates the reducing effects of the anesthetic drugs in 10 minutes, but also exceeds the baseline. the effects of the prone position have also been demonstrated in a study by lam and douthwaite, in which the iop raised within 8 minutes after the change of position to prone.(15) they carried out the trial on awake volunteers. our study showed that the increasing effect of the prone position on iop is stronger than the reducing effects of general anesthesia on iop. the most accurate method of measuring iop over the time is its continuous and invasive measurement. this type of recording iop has been reported in two groups of patients by implanting a probe into the anterior chamber of the eye for 96 hours.(28) however, we utilized tono-pen xl similar to the study by lam and douthwaite.(15) the accuracy of this device in comparison with the invasive method of probe implantation has been demonstrated by setogawa and kawai.(29) rises in paco2 and etco2 have been reported in the prone position.(21) since the rise of the paco2 could increase the iop,(21) we kept paco2 unchanged from the beginning to the end of the anesthesia in order to abolish its interfering effects. a number of researchers induced a rise in the iop by increasing the acute fluid administration. (25) in our study, we compensated not only the fluid loss, but also the patients received 5cc/ kg/h of fluid. the point that the intravascular volume change is capable of changing the iop requires prospective studies.(27) nonetheless, we maintained the fluid balance and the intravascular volume in a steady state in order to prevent the possible effects of the intravascular volume. unlike the study by pillunat and colleagues, 95% confidence interval for meanstd. errorstd. deviationmean (range), mm/hgn 15.01 to 15.83.1963.877715.42 (14.00 to 17.00)20base line 12.31 to 12.78.1141.510412.55 (12.00 to 13.00)20supine i 24.83 to 26.26.34391.538125.55 (20.00 to 28.00)20prone i 38.50 to 39.39.2112.944538.95 (37.00 to 40.00)20prone ii 13.54 to 13.959.934e-02.444313.75 (13.00 to 14.00)20supine ii 19.20 to 23.201.007010.069621.24 (12.00 to 40.00)100total patients’ mean intraocular pressures in five occasions 50 40 30 20 10 95 % c on fid en ce in te rv al o f i nt ra oc ul ar p re ss ur e groups n 20 20 20 20 20 base line supine i prone i prone ii supine ii patients’ mean intraocular pressures in five positions in percutaneous nephrolithotomy prone position and visual loss—agah et al 195urology journal vol 8 no 3 summer 2011 our patients were in a position completely in parallel to the horizontal surface, and therefore, the effects of increase or decrease in episcleral intravenous pressure due to the trendelenburg position could not be measured in our study.(9) fortunately, we did not observe any visual loss after anesthesia, but the first reported case of pvl after pcnl in the labbafinejad medical center was a 75-year-old man with the history of diabetes mellitus, hyperlipidemia, and mild anemia. the patient had painless pvl in both eyes limited to light perception immediately after the operation. in ophthalmologic examination, the optic disc was pink without swelling and visual fields were severely affected; however, neuroimaging was normal. the visual fields and acuity improved dramatically in a matter of three months, but optic disc turned slightly pale and this was the first report of pion after pcnl.(30) according to the report by roth and barach, there is a possibility of pvl in the prone position, with hypotension, anemia, and direct pressure to the eyeball as risk factors.(7) in our study, we have avoided all the three mentioned factors and the fact that whether or not it is the reason for no visual loss after anesthesia is not assessable with this number of patients and it requires further studies. on the other hand, it does not seem that acute hemodilution is precarious. since hemodilution occurs frequently in open heart surgery, but visual loss usually occurs after the spinal surgeries in prone position.(22) in a study on 20 anesthetized patients in spinal surgery in prone position, hunt and coworkers reported the rise in the iop. nevertheless, the duration of the operation, age, and body mass index have been mentioned as non-contributory factors.(31) according to the report of ho and colleagues in assessing the reasons for ion duration, the prone position has been lengthy in all the subjects with the average of 450 minutes, which points to the time factor in the development of ion in prone position. (8) also the reduction of opp, intra-operative bleeding, anemia or hemodilution, and the infusion of large amounts of intravascular fluids are among the aggravating factors in ion.(8) in healthy volunteers, iop increases with the acute rise in the fluid load,(25) and dehydration due to physical exercise reduces iop.(32) the reduction in osmolarity during dialysis also increases iop. (33) prospective studies are required in order to demonstrate the relationship between the fluid balance and iop in prone position.(27) in a comprehensive literature review on visual loss after non-ocular surgeries, it has been reported that risk of decrease in visual acuity and visual ability rises in case of preexisting diseases, such as hypertension, diabetes mellitus, sickle cell anemia, renal failure, gastrointestinal ulcer, narrow-angle glaucoma, vascular occlusive disease, cardiac disease, arteriosclerosis, polycythemia vera, and collagen vascular disorders. furthermore, the precipitating factors for ion include prolonged hypotension, anemia, surgery, trauma, gastrointestinal bleeding, hemorrhage, shock, prone position, direct pressure on the globe, and long operation time.(34) in our study, the effect of the duration of the prone position on the rise of iop was significant and other factors were ruled out. all the patients had the blood pressures of above 120 mmhg during the operation. by maintaining other conditions unchanged, it was tried to study the effect of the duration of the prone position on iop in pcnl. after doubling the iop from the normal level,(35) the risk of damage to the optic nerve starts, and according to our study the iop was doubled and reached up to 40 mmhg after two hours. conclusion since in pcnl the rise of iop in the prone position has a linear relationship with time and doubles within two hours, it is recommended that in the prone position surgeries, special attention has to be focused on the iop. prospective larger studies on the iop with different setting are needed to confirm our results. conflict of interest none declared. references 1. stoelting rk. apsf survey results identify safety issues priorities. anesthesia patient safety fouodation prone position and visual loss—agah et al 196 urology journal vol 8 no 3 summer 2011 newslett. 1999;14:6-7. 2. brown rh, schauble jf, miller nr. anemia and hypotension as contributors to perioperative loss of vision. anesthesiology. 1994;80:222-6. 3. cheng ma, sigurdson w, tempelhoff r, lauryssen c. visual loss after spine surgery: a survey. neurosurgery. 2000;46:625-30; discussion 30-1. 4. myers ma, hamilton sr, bogosian aj, smith ch, wagner ta. visual loss as a complication of spine surgery. a review of 37 cases. spine (phila pa 1976). 1997;22:1325-9. 5. stevens wr, glazer pa, kelley sd, lietman tm, bradford ds. ophthalmic complications after spinal surgery. spine (phila pa 1976). 1997;22:1319-24. 6. williams el, hart wm, jr., tempelhoff r. postoperative ischemic optic neuropathy. anesth analg. 1995;80:1018-29. 7. roth s, barach p. postoperative visual loss: still no answers--yet. anesthesiology. 2001;95:575-7. 8. ho vt, newman nj, song s, ksiazek s, roth s. ischemic optic neuropathy following spine surgery. j neurosurg anesthesiol. 2005;17:38-44. 9. pillunat le, anderson dr, knighton rw, joos km, feuer wj. autoregulation of human optic nerve head circulation in response to increased intraocular pressure. exp eye res. 1997;64:737-44. 10. hayreh ss. posterior ischemic optic neuropathy. ophthalmologica. 1981;182:29-41. 11. isayama y, hiramatsu k, asakura s, takahashi t. posterior ischemic optic neuropathy. i. blood supply of the optic nerve. ophthalmologica. 1983;186:197-203. 12. hayreh ss, bill a, sperber go. effects of high intraocular pressure on the glucose metabolism in the retina and optic nerve in old atherosclerotic monkeys. graefes arch clin exp ophthalmol. 1994;232:745-52. 13. hayreh ss. anterior ischemic optic neuropathy. clin neurosci. 1997;4:251-63. 14. tsamparlakis j, casey ta, howell w, edridge a. dependence of intraocular pressure on induced hypotension and posture during surgical anaesthesia. trans ophthalmol soc u k. 1980;100:521-6. 15. lam ak, douthwaite wa. does the change of anterior chamber depth or/and episcleral venous pressure cause intraocular pressure change in postural variation? optom vis sci. 1997;74:664-7. 16. lentschener c, benhamou d, niessen f, mercier fj, fernandez h. intra-ocular pressure changes during gynaecological laparoscopy. anaesthesia. 1996;51:1106-8. 17. lentschener c, leveque jp, mazoit jx, benhamou d. the effect of pneumoperitoneum on intraocular pressure in rabbits with alpha-chymotrypsin-induced glaucoma. anesth analg. 1998;86:1283-8. 18. murphy df. anesthesia and intraocular pressure. anesth analg. 1985;64:520-30. 19. hvidberg a, kessing sv, fernandes a. effect of changes in pco2 and body positions on intraocular pressure during general anaesthesia. acta ophthalmol (copenh). 1981;59:465-75. 20. pelosi p, croci m, calappi e, et al. the prone positioning during general anesthesia minimally affects respiratory mechanics while improving functional residual capacity and increasing oxygen tension. anesth analg. 1995;80:955-60. 21. wahba rw, tessler mj, kardash kj. carbon dioxide tensions during anesthesia in the prone position. anesth analg. 1998;86:668-9. 22. thueroff jw, gillitzer r. percutaneous endourology and ureterorenoscopy. in: tanagho ea, mcaninch jw, eds. smith’s general urology. 17 ed. new york: mcgraw-hill; 2008:114-34. 23. liu l, zheng s, xu y, wei q. systematic review and meta-analysis of percutaneous nephrolithotomy for patients in the supine versus prone position. j endourol. 2010;24:1941-6. 24. wu p, wang l, wang k. supine versus prone position in percutaneous nephrolithotomy for kidney calculi: a meta-analysis. int urol nephrol. 2011;43:67-77. 25. miano r, scoffone c, de nunzio c, et al. position: prone or supine is the issue of percutaneous nephrolithotomy. j endourol. 2010;24:931-8. 26. karami h, rezaei a, mohammadhosseini m, javanmard b, mazloomfard m, lotfi b. ultrasonography-guided percutaneous nephrolithotomy in the flank position versus fluoroscopy-guided percutaneous nephrolithotomy in the prone position: a comparative study. j endourol. 2010;24:1357-61. 27. cheng ma, todorov a, tempelhoff r, mchugh t, crowder cm, lauryssen c. the effect of prone positioning on intraocular pressure in anesthetized patients. anesthesiology. 2001;95:1351-5. 28. hoh h, schwanengel m. [continuous intraocular pressure measurement over several days with the codman microsensor--a case report]. klin monbl augenheilkd. 1999;215:186-96. 29. setogawa a, kawai. measurement of intraocular pressure by both invasive and noninvasive techniques in rabbits exposed to head-down tilt. jpn j physiol. 1998;48:25-31. 30. pakravan m, kiavash v, moradian s. posterior ischemic optic neuropathy following percutaneous nephrolithotomy. jovr. 2008;2:76-80. 31. hunt k, bajekal r, calder i, meacher r, eliahoo j, acheson jf. changes in intraocular pressure in anesthetized prone patients. j neurosurg anesthesiol. 2004;16:287-90. 32. martin b, harris a, hammel t, malinovsky v. mechanism of exercise-induced ocular hypotension. invest ophthalmol vis sci. 1999;40:1011. 33. tawara a. [intraocular pressure during hemodialysis]. j uoeh. 2000;22:33-43. 34. rupp-montpetit k, moody ml. visual loss as a complication of nonophthalmologic surgery: a review of the literature. aana j. 2004;72:285-92. 35. salmon jf. glaucoma. in: riordan-eva p, ed. vaughan and asbury’s general ophthalmology. 17 ed. new york: lange medical books/mcgraw-hill; 2008:212-28. endourology and stone disease comparison of safety and efficiency of general, spinal and epidural anesthesia methods used for the endoscopic surgical treatment of ureteral stones: which one is better to access the ureter and reach the stone? unal oztekin1*, mehmet caniklioglu1, fatih atac2, cigdem unal kantekin3, abdullah gurel1, levent isikay1. purpose: the aim of this study is to evaluate the effects of anesthesia methods on the success of urethral access and stone access achievement in endoscopic treatment of urolithiasis. materials and methods: in this prospective randomized study, 105 patients who underwent primary ureterorenoscopy (urs) procedure for ureteral stones were evaluated. the patients were randomized into three groups by permuted block randomization according to the applied anesthesia method: general anesthesia (ga): 33 patients, spinal anesthesia (sa): 31 patients, and epidural anesthesia (ea): 31 patients. ten patients, whose ureteral access was not successful, were dropped out. the success of the three anesthesia methods on the success of the ureter access and its effects on surgical outcomes were compared. results: there was no statistically significant difference among the three groups in terms of the demographic values and preoperative features except the american society of anesthesiologists (asa) status. dilatation and the access time to stone were statistically significantly longer in sa and ea group compared to the ga group. there was no statistically significant difference among the groups in terms of operation, lithotripsy time, stone-free rate (sfr), and complication rates. the visual analog scale (vas) scores in the 8th and 24th hours were statistically significantly higher in the ga group. conclusion: in patients who decided to undergo primary ureterorenoscopy procedure, it can be suggested to treat with ga to provide a better relaxation of the ureter if there are no contraindications. keywords: anesthesia methods; endoscopy; epidural anesthesia; spinal anesthesia; ureteral stone; ureterorenoscopy introduction ureterorenoscopy (urs) has been a routine surgi-cal procedure since 1980(1). the success rate has increased, and the indications have expanded with the use of advanced technology and modern equipment(2). it is widely used as a minimally invasive method in the endoscopic treatment of urinary stone disease, which is a common problem. the stone disease may show a prevalence of 20% due to geographic, climatic, ethnic, dietary, and genetic factors(3). patient selection, proper use of surgical instruments, and the appropriate technique increase the reliability and success. ureteral access is one of the critical steps in urs. the success of ureteral access and the process of reaching the stone depend on the axial force in the orifice(4). in primary surgery, the ureteral access may not always be possible, and ureteral injury secondary to excessive force may happen(5). there are several studies for more successful surgical results by increasing ureteral access achievement in the literature. among them, methods that improve the ureteral access achievement have been stated, such as; ureteral balloon dilatation, preoperative stent implantation with passive dilatation, and preoperative alpha-blocker 1yozgat bozok unıversity, faculty of medicine, department of urology, yozgat, turkey 2kırıkkale university, faculty of medicine, department of urology, kırıkkale, turkey 3yozgat bozok university, faculty of medicine, department of anesthesiology, yozgat, turkey *correspondence: yozgat bozok unıversity, faculty of medicine, department of urology, yozgat, turkey phone: +90 5303478578 fax: + 90 354 2127060. e-mail: dr_unal@hotmail.com. received october 2019 & accepted february 2020 usage. there are various advantages and disadvantages of these methods. active balloon dilatation is an option, but the risks such as ureteral edema, postoperative discomfort or secondary stenosis cannot be excluded(6). this is one of the challenging topics in urology to avoid these risks and increase the success of ureteral access. there is no study in the literature evaluating the effect of anesthesia type on this stage of ureteroscopy. as mentioned in the european association of urology (eau) guidelines, although most procedures are performed under general anesthesia (ga), however local or spinal anesthesia (sa) can be the other options. intravenous sedation can also be suggested in female patients with distal ureteral stones(7). however, there are not enough studies in the literature showing the effects of anesthetic methods on ureteral access and surgical success. the applied anesthesia method may affect the manipulation in ureteral access and influence ureteral entrance and surgical success. the aim of this study is to evaluate the effects of anesthesia methods on the surgical results of spinal, epidural, and general anesthesia procedures and the success of urethral access and stone access achievement. urology journal/vol 17 no. 3/ may-june 2020/ pp. 237-242. [doi: 10.22037/uj.v0i0.5638] materials and methods after the approval of the local ethics committee (2018kaek-189_2018.01.25_03), the study was designed prospectively. the informed consent form was obtained from all patients, and an assessment was made by the helsinki declaration. between february 2018 and february 2019, 105 patients whom urs was planned due to the ureteral stones in our clinic were included in the study. patients older than 18 years of age, who underwent primary surgery, were included in the study. patients who had chronic pain treatment, double j stent, previous surgery, previous minimal invasive procedures, neurogenic disease, urethral and ureteric stenosis, kidney anomaly, multiple stones, contraindications for regional anesthesia (ra) and whose ureteral access was unsuccessful or anesthesia method was changed preoperatively were excluded. also, patients with an american society of anesthesiologists (asa) score of ≥ grade 3 were excluded from the study. asa classification system is defined as: asa grade 1: a normal healthy patient, asa grade 2: a patient with mild systemic disease, asa grade 3: a patient with severe systemic disease, asa grade 4: a patient with severe systemic disease that is a consistent with threat to life and asa grade 5: a moribund patient who is not expected to survive without the operation(8). at the end of the study, the patients whose ureteral access was not successful were dropped out because the duration could not be calculated, and the data of 95 patients were evaluated. among the dropped outpatients, 4 of them were in spinal anesthesia (sa) group, 4 of them were in epidural anesthesia (ea), and two patients were in the ga group. the patients were randomized into three groups according to the applied anesthesia method: ga: 33 patients (group 1), sa: 31 patients (group 2), and ea: 31 patients (group 3). all patients were evaluated by direct urinary tract x-ray, urinary system ultrasonography (usg), and computed tomography (ct) by the stone protocol. proximal, middle, and distal ureteral stones were included in the study. preoperative, intraoperative, and postoperative data including age, gender, body mass index (bmi), stone size (longest diameter measured by computed tomography), volume, preoperative creatinine level, asa status, stone side, localization, opacity, co-morbid diseases, were recorded. duration of dilatation (the duration starting from the urethral meatus access with ureteroscopy, under the guidance of the guidelines, until the orifice entry) and access to stone (the duration from the start of the orifice entry until the stone is seen), the period of stone crushing and operation (the duration from the beginning of the urethral meatus access to the end of the double j stent placement operation), rates of intraoperative and postoperative complications, visual analog scale (vas) score in 8th and 24th hour and stone-free rates (sfr) were recorded. the patients were administered with intravenous 3rd generation cephalosporin prophylactically 30 minutes before the operation. patients who had germs in the urine culture were operated after the treatment with an appropriate antibiotic for the culture. informed consent was obtained from all patients. anesthesia method all patients underwent anesthesia with the same anesthesiologist. vascular access was established to the patients by using a 20 g intravenous cannula in the preparation room for the operation. the patients were monitored, and systolic arterial pressure (sap), dicomparison of anesthesia methods in endoscopy-oztekin et al. general anesthesia (n=33) spinal anestesia (n=31) epidural anesthesia (n=31) p age (±sd) 40.82 ± 10.63 44.39 ± 16.44 49.03 ± 15.51 .078 gender (n,%) 61 male 25 (75.8%) 22 (71.0%) 20 (64.5%) . female 8 (24.2%) 9 (29.0%) 11 (35.5%) bmi (±sd) 27.07 ± 5.18 26.47 ± 3.99 29.97 ± 6.97 .20 stone size (mm)(±sd) 10.93 ± 4.3 10.25 ± 3.57 10.90 ± 2.72 .52 stone volume (±sd) 483.85 ± 463.06 354.72 ± 396.27 348.50 ± 232.66 .309 preoperative cre (mg/dl)(±sd) 0.85 ± 0.20 1.0 ± 0.30 0.92 ± 0.27 .19 asa (n,%) .018 asa 1 20 (60.6%) 15 (48.4%) 8 (25.8%) asa 2 13 (39.4%) 16 (51.6%) 23 (74.2%) stone side (n,%) .69 right 19 (57.6%) 15 (48.4%) 15 (48.4%) left 14 (42.4%) 16 (51.6%) 16 (51.6%) stone location (n,%) .965 upper 10 (30.3%) 10 (32.2%) 11 (35.4%) mid 14 (42.4%) 11 (35.4%) 12 (38.7%) lower 9 (27.2%) 10 (32.2%) 8 (25.8%) stone opacity(n,%) .52 opaque 24 (72.7%) 20 (64.5%) 26 (83.9%) semiopaque 1 (3%) 1 (3.2%) 0 (0%) non-opaque 8 (24.2%) 10 (32.3%) 5 (16.1%) co-morbidity (n,%) .53 absent 30 (90.9%) 29 (93.5) 26 (83.9%) present 3 (9.1%) 2 (6.5%) 5 (16.1%) hydronephrosis (n,%) . 681 absence 4 (12.1%) 4 (12.9%) 2 (6.4%) grade1 3 (9.1%) 5 (16.1%) 4 (12.9%) grade 2 23 (69.7) 20 (64.5%) 24 (77.4%) grade 3 3 (9.1%) 2 (6.4%) 2 (6.4%) table 1. the demographic values and preoperative features abbreviations: bmi, body mass index; asa, american society of anesthesiologists; sd, standart deviation; mm, milimeter. endourology and stones diseases 238 astolic arterial pressure (dap), mean arterial pressure (map), heart rate (hr), and oxygen saturation (spo 2 ) measurements were performed noninvasively and recorded. group 1: the patients undergoing ga were preoperatively oxygenized with 100% oxygen for 3-5 minutes after monitoring. in the induction of anesthesia, 2 mcg / kg fentanyl, 2-3 mg / kg propofol and 0.5 mg / kg rocuronium were administered. endotracheal intubation was performed after muscle relaxation was provided. in the cases, controlled ventilation was provided by adjusting the tidal volume as 8-10 ml/kg and the respiratory frequency as 10-12 min. maintenance of anesthesia was provided with 50% o 2 and 50% n 2 o in 1% mac sevoflurane. group 2: patients undergoing sa were preoperatively hydrated with a balanced electrolyte solution (500 ml) half an hour before the operation. after the patient, taken to the operating room was monitored, skin cleaning was performed in the sitting position, and 25 g or 26 g spinal needle was used through l3-4 or l4-5 range; the spinal range was entered with midline approach technique. after the clear csf flow was observed, 0.5% hyperbaric bupivacaine3 ml (5 mg/ml) was administered slowly. sensory block levels of the patients were evaluated with the pinprick test. the surgical procedure was initiated when the level t8-t6 reached the area of the dermatome. group 3: after regular monitoring in the ea group, skin cleaning was performed in the sitting position, t11 to t12 range was entered with 18 g toughy needle, the epidural range was found by negative pressure method, and the epidural catheter was placed. after applying 3 ml of prilocaine (citanest® 2% 20 mg) as a test dose, 1.5 ml of prilocaine was added for each segment. when the sensory block was provided at the t6 level, the surgery started. urs technique all procedures were performed by two experienced surgeons. after anesthesia, a ureteral 0.038-inch hydrophilic guidewire was inserted in the modified dorsal lithotomy position, and dilatation was achieved by entering the ureter with 9.5 f ureterorenoscope (karl storz®, tuttlingen, germany). after the stone was seen, a probe compatible with 200 μm of holmium laser (quanta system®, litho 30w, milan-italy) was used. lithotripsy was performed with a frequency of 8-15 hz and power of 1.2-3.0 joules. after the stones were completely fragmented, the process was terminated. after the procedure, jj stent was placed in all patients. in the postoperative first day, the place of the stent and the status of the fragmented stones on x-ray and non-opaque stones were evaluated by usg imaging. the pain levels of all patients were assessed with vas in the 8th and 24th hours. four weeks later, the patients were called for control, the stent was withdrawn, and the ct was performed without contrast. the absence of stones in the ct image and patients with a stone size of ≤3mm were considered as stone-free. intraoperative and postoperative complications were recorded, and intraoperative complications were classified according to satava complication classification, and postoperative complications were classified according to the modified clavian classification system (9,10). at the end of this study, the success of the three anesthesia methods on the success of the ureter access and its effects on surgical outcomes were compared. kolmogorov-smirnov and shapiro-wilk tests are conducted for the assessment of normal distributions in our sample group. differences in the categoric parameters between the three groups were calculated using the chi-square test. pearson exact test was performed for all categorical parameters. for numerical parameters, kruskal-wallis analysis was performed except age, and preoperative haemoglobin, which were assessed using one-way anova analysis because of their distributions were normal. p < .05 was considered statistically significant. the three groups were compared with regard to ureteral orifice dilatation time, time to reach to stone, total surgery time, vas scores in 8th and 24th hours of operation, sfr (the rates given in the table belongs to the patients without any stone) and both intraoperative and postoperative complication rates (the rates given in the table belongs to the patients with any complications). in the case of p-value was smaller than .05, pairwise comparisons were performed to find the parameter that was responsible for the difference. general anesthesia (n=33) spinal anestesia (n=31) epidural anesthesia (n=31) p dilatation time (sec)(mean±sd) 80.45 ± 52.96 156.45 ± 66.20 176.29 ± 90.42 < .001 time to reach to stone (sec)(mean±sd) 105.54 ± 34.13 151.61 ± 98.46 181.93 ± 115.33 .003 operation time (min)(mean±sd) 37.08 ± 14.8 30.42 ± 12.4 36.94 ± 20.59 .156 litotrpsy time (min) 12.25 ± 6.05 11.53 ± 9.92 15.19 ± 14.9 .35 vas score 8th hour(sd) 4.06 ± 1.98 2.35 ± 2.04 2.48 ± 1.78 .001 24th hour(sd) 2.55 ± 1.54 1.00 ± 1.18 1.39 ± 1.58 < .001 stone free rates (n,%)* 29 (87.9%) 28 (90.3%) 27 (87.1%) .918 complication rate (n,%)** intraoperative 3 (9.1%) 7 (22.6%) 9 (29.0%) .125 postoperative 5 (15.2%) 7 (22.6%) 4 (12.9%) .566 satava grade 1 3 (9.1%) 7(22.6%) 9 (29.0%) .125 clavian .566 grade 1 1 (3.0%) 5 (16.1%) 4 (12.9%) grade 2 3 (9.1%) 2 (6.5%) 0 (0.0%) grade (iva/ivb) 1 (3.0%) 0 (0.0%) 0 (0.0%) table 2. intraoperative and postoperative comparison of the outcomes abbreviations: sd, standart deviation; sec, second; min, minute. comparison of anesthesia methods in endoscopy-oztekin et al. vol 17 no 03 may-june 2020 239 results ninety-five patients who were enrolled and met the study criteria were included in the study. there was no statistically significant difference among three groups in terms of age, bmi, stone size, volume, preoperative creatinine level, stone side, localization, opacities, concomitant comorbidities, hydronephrosis levels, and preoperative hemoglobin levels except asa status. (table 1). dilatation and stone access durations were significantly different among the groups. in the ga group, the duration was shorter than sa and ea groups. there was no statistically significant difference among the groups in terms of operation, lithotripsy time, sfr, and complication rates. a statistically significant difference was found between the 8th and 24th hour when vas scores were compared (p <.05). vas score was higher in the ga group. (table 2) in the binary comparisons which were made to determine which group causes the differences, it was found that the differences, in terms of the dilatation, duration to reach the stone, 8th, and 24th-hour vas scores, were derived from the group ga. the pain score was higher in the ga group (table 3). discussion the endoscopic stone treatment is used in the treatment of urinary system stones. these methods can be used in anomalous kidney stones and secondary kidney stones. (11) urs is a minimally invasive method that urologists use safely and efficiently. it is often used in the treatment of urinary tract stones. moreover, in the diagnosis of abnormal lesions reported in imaging methods (intravenous pyelography, magnetic resonance, ct, etc.), it can be applied in ureteral stricture, diagnosis, and treatment to investigate the source in positive urine culture and cytology(12-14). in the urs procedure, anesthesiologists prefer ra methods to avoid complications due to ga and to provide patient turnover and postoperative care easiness in the operating room. in contrast, surgeons prefer the ga method mostly to avoid ureteral trauma by providing more controlled case management (15). in the literature, it has been emphasized that the urs procedure can be performed safely with anesthesia methods such as intravenous sedation, sacral block, local anesthesia, and spinal anesthesia(15-20). access to ureteral orifice and access to stone is one of the important stages of the urs procedure. at this stage, the applied force and manipulations may cause complications and decrease ureteral access and surgical success. in the distal part of the ureter, the ι-adrenergic receptors are at higher densities than the middle and proximal regions(21). the presence of more intense adrenergic receptors in the distal ureters in patients who have had ra may lead to inadequate relaxation and excessive manipulation. in a study measuring the force exerted during primary urethral entry and ureteral access sheath placement in patients undergoing retrograde intrarenal surgery procedure under ga, the control group and the group had given α-blocker before the operation were compared. in the group using ι-blocker, it has been concluded that the ureteral access force is significantly lower. smaller diameter access or pre-stenting has been proposed to avoid ureteral damage by reducing this insertion force(5). parikh et al. have stated that extra anesthesic drug administration during ureteral catheterization has been required in 5 patients, in a study comparing segmental ea and ga in patients undergoing percutaneous nephrolithotomy (pcnl). it has been emphasized that ea does not block proprioception, which may cause discomfort to patients despite adequate sensory blockage. furthermore, in these patients, propofol and the complementary ga are required, and the segmental ga is not sufficient.(23,24) basiri et al. conducted that sa did not provide enough analgesia for the patient in a limited frequency of pcnl operations. in our study, we evaluated the success of the ureteral entry in terms of dilatation and the access time to stone. these durations were statistically significantly longer in sa and ea group compared to the ga group, suggesting that sufficient ureteral relaxation could not be achieved in ra and more manipulation was required, in the ga group, this duration was short, suggesting better ureteral relaxation. kizilay et al. analyzed 638 patients with proximal ureteral stones by dividing them into two groups as urs under sa and ga. although there was no difference between the groups in terms of operation time and complication rates, sfr was found to be better in the sa group (p = .041). however, in this study, stone density and area have been found significantly lower in the sa group. also, the push-back ratio has been found significantly higher in the sa group, and it has been thought that ureteric stones may be more mobile if adequate relaxation is not provided as much as it is expected in ga.(16) conversely, according to the results of our study, we think that ureteral relaxation is better under ga. shaikh et al. have compared sa and ga methods in their series of 60 diseases urs. no difference has been found between the two groups in terms of sfr and complications. although the stone size was significantly smaller in the ga group, the operation time was lower in the sa group(19). in our study, there was no statistically significant difference between the groups in terms of stone size, density, and location, operation time, and sfr. pain after urs is a common postoperative complication.(24,25) there are studies showing that ra methods are advantageous in terms of postoperative pain in urs and other surgical procedures.(19,22,26) in our study, when the vas scores in 8th and 24th hours were compared, they were higher in the ga group. in the spinal and epitablo 3. p values for each group comparisons after pairwise comparisons. general vs. spinal general vs. epidural spinal vs. epidural dilatation time < .001 < .001 .69 time to reach the stone .054 .003 .61 8th hour vas score .004 .004 .99 24th hour vas score < .001 .013 .62 abbreviations: vas, visual analog scale. comparison of anesthesia methods in endoscopy-oztekin et al. endourology and stones diseases 240 dural anesthesia groups, the provided pre-emptive analgesia may also lead to a lower vas score(27). this result is seen as important data for postoperative comfort in the urs procedure under ra. in general, studies conducted in the literature showed no effect of anesthesia methods on complications in terms of urs and other surgical procedures.(15,16,19,20,28,29) the overall complication rate is 9-25% after urs. most complications are minor complications that do not require additional treatment(7). in our study, sepsis developed in one patient in the ga group. minor complications were recorded as infection, mucosal injury, hematuria without blood transfusion necessity, although they were lower in the ga group, there was no statistically significant difference between the groups. in addition, there was a significant difference in asa scores between the groups in our study. in the literature, it is reported that major complications were increased by 58% and minor complications were increased by 49% for patients with asa > grade 3.(30) therefore we included asa i and ii patients who did not have a serious systemic disease in order to standardize the data and not to affect the results of our study. we planned this study based on the observation that the urs procedure we performed under ra required more manipulation, especially during the ureteral entrance and the access to the stone. although this is not a ureteral pressure measurement study, shorter entry time in the ga group suggests that ureteral relaxation might be better in the ga group. in surgeries performed under ga, muscle relaxant agents may contribute to ureteral relaxation. conclusions ra methods may be preferred to reduce the risk of complications related to ga and for the postoperative low pain score. however, under the ga, the primary urs procedure provides a better relaxation of the ureter, allowing the surgeon to enter the ureter in a shorter time with less manipulation and to reach the stone more easily. therefore, in patients who are planned with primary urs procedure due to the stone, it can be suggested to treat with ga if there are no contraindications. conflict of interest the authors report no conflict of interest. references 1. taylor al, oakley n, das s, et al. day-case ureteroscopy: an observational study. bju int. 2002;89:181-5. 2. cheung mc, lee f, leung yl, et al. outpatient ureteroscopy: predictive factors for postoperative events. urology 2001;58:914-8. 3. trinchieri a. epidemiological trends in urolithiasis: impact on our health care systems. urol res. 2006;34:151-6. 4. monga m1, gawlik a, durfee w. systematic evaluation of ureteral access sheaths. urology 2004;63:834-6. 5. koo kc, yoon jh, park nc, et al. the impact of preoperative α-adrenergic antagonists on ureteral access sheath insertion force and the upper limit of force required to avoid ureteral mucosal injury: a randomized controlled study. j urol. 2018;199:1622-30. 6. cetti rj, biers s, keoghane sr. the difficult ureter: what is the incidence of pre-stenting? ann r coll surg engl. 2011;93:31-3. 7. türk, c., neisius, a., petrik, a. et al., eau guidelines on urolithiasis 2018, in european association of urology guidelines. 2018 edition. 2018, the european association of urology guidelines office: arnhem, the netherlands. 8. sweitzer bj. preoperative preparation and intraoperative management. in: pardo jr. mc, miller rd, editors. basics of anesthesia. philadelphia: elsevier; 2011. p. 165-88 9. satava rm. identification and reduction of surgical error using simulation. minim invasive ther allied technol. 2005;14:25761. 10. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205–13. 11. kartal i, cakıcı mç, selmi v, sarı s, özdemir h, ersoy h. retrograde intrarenal surgery and percutaneous nephrolithotomy for the treatment of stones in horseshoe kidney; what are the advantages and disadvantages compared to each other? cent european j urol. 2019;72:156-62. 12. johnson gb, grasso m. exaggerated primary endoscope deflection: initial clinical experience with prototype flexible ureteroscopes. bju int. 2004;93:109-14. 13. grasso m. ureteropyeloscopic treatment of ureteral and intrarenal calculi. urol clin north am. 2000;27:623-31. 14. razdan s, johannes j, cox m, et al. current practice patterns in urologic management of upper-tract transitional-cell carcinoma. j endourol. 2005;19:366-71. 15. kızılay f, i̇rer b, şen v, et al. effect of the anesthetic method on the outcomes of ureteroscopy for proximal ureteral stones: a multi-center study of the society of urological surgery aegean study group. j urol surg. 2018;5:170-5 16. kroczak tj, kaler ks, patel p, et al. ureteroscopy with conscious sedation for distal ureteric calculi: 10-year experience. can urol assoc j. 2016 jan-feb;10(1-2):e12-6. 17. zhu h, xiao x, chen x, et al. ureteroscopic treatment of urological calculi under sacral block anesthesia. urol res. 2012;40:361-3. 18. miroglu c, saporta l. transurethral ureteroscopy: is local anesthesia with intravenous sedation sufficiently effective and safe? eur urol. 1997;31:36-9. comparison of anesthesia methods in endoscopy-oztekin et al. vol 17 no 03 may-june 2020 241 endourology and stones diseases 242 19. shaikh ah, khalid se, zaidi sz. ureteroscopy under spinal versus general anaesthesia: morbidity and stone clearance. j coll physicians surg pak. 2008;18:168-71. 20. park hk, paick sh, oh sj, et al. ureteroscopic lithotripsy under local anesthesia: analysis of the effectiveness and patient tolerability. eur urol. 2004;45:670-3. 21. park hk, choi ey, jeong bc, et al. localizations and expressions of alpha-1a, alpha-1b and alpha-1d adrenoceptors in human ureter. urol res. 2007;35:325-9. 22. parikh da, patkar ga, ganvir ms, et al. is segmental epidural anaesthesia an optimal technique for patients undergoing percutaneous nephrolithotomy? indian j anaesth. 2017;61:308-14. 23. wuethrich py, kessler tm, panicker jn, et al. detrusor activity is impaired during thoracic epidural analgesia after open renal surgery. anesthesiology. 2010;112:1345–9. 24. cheung mc, lee f, leung yl, et al. outpatient ureteroscopy: predictive factors for postoperative events. urology 2001;58:914-8. 25. schuster tg, hollenbeck bk, faerber gj, et al. complications of ureteroscopy: analysis of predictive factors. j urol. 2001;166:538-40. 26. tangpaitoon t, nisoog c, lojanapiwat b. efficacy and safety of percutaneous nephrolithotomy (pcnl): a prospective and randomized study comparing regional epidural anesthesia with general anesthesia. int braz j urol. 2012;38:504-11. 27. pu c, wang j, tang y, et al. the efficacy and safety of percutaneous nephrolithotomy under general versus regional anesthesia: a systematic review and meta-analysis. urolithiasis 2015;43:455-66. 28. zeng g, zhao z, yang f, et al. retrograde intrarenal surgery with combined spinalepidural vs general anesthesia: a prospective randomized controlled trial. j endourol. 2015;29:401-5. 29. singh v, sinha rj, sankhwar sn, et al. a prospective randomized study comparing percutaneous nephrolithotomy under combined spinal-epidural anesthesia with percutaneous nephrolithotomy under general anesthesia. urol int. 2011;87:293–8 30. belmont jr pj, goodman gp, waterman br, bader jo, schoenfeld aj. thirty-day postoperative complications and mortality following total knee arthroplasty: incidence and risk factors among a national sample of 15, 321 patients. j bone joint surg am 2014;96:20–6. comparison of anesthesia methods in endoscopy-oztekin et al. urological oncology 26 urology journal vol 7 no 1 winter 2010 clinical relevance of her-2/neu overexpression in patients with testicular nonseminomatous germ cell tumor mohammad reza ghavamnasiri,1 hamid saeedi saedi,1 soodabeh shahid sales,1 kamran ghafarzadegan2 introduction: recent scientific attention has focused on the role of growth factors in the progression of cancer. her-2/neu is an epidermal growth factor receptor that is demonstrated to have correlation with poor prognosis of many cancers. this study evaluated the overexpression of her-2/neu protein and its clinical importance in nonseminomatous germ cell tumors of the testis. materials and methods: testis specimens of 54 patients with testicular nonseminomatous germ cell tumors, referred to omid hospital from 2001 to 2007, were re-evaluated and the patients’ records were reviewed. patients’ age, tumor subtype, tumor stage, tumor markers, therapeutic response, and disease-free survival were assessed and the specimens were evaluated for the degree of her-2/neu expression using an immunohistochemistry method. results: immunohistochemical staining was performed for 54 specimens. overexpression of her-2/neu was seen in 33.3% of the patients with nonseminomatous germ cell tumors, especially in those with teratocarcinoma subtype compared to those with mixed germ cell tumors or embryonal cell carcinoma. however, her-2/neu overexpression did not show any correlation with tumor stage, therapeutic response, disease-free survival, age, β-human chorionic gonadotropin, or α-fetoprotein. conclusion: we observed overexpression of her-2/neu receptor in teratocarcinoma subtype of germ cell tumor. we suggest further studies to evaluate the clinical importance of this finding. urol j. 2010;7:26-9. www.uj.unrc.ir keywords: germ cell and embryonal neoplasms, neoplasm proteins, prognosis, tumor markers 1department of radiation oncology, mashhad university of medical sciences, mashhad, iran 2department of pathology, mashhad university of medical sciences, mashhad, iran corresponding author: soodabeh shahidsales, md cancer research center, omid hospital, koohsangi st, mashhad, iran tel: +98 915 316 0721 fax: +98 511 846 1518 e-mail: soodabehshahidsales@gmail.com received may 2009 accepted august 2009 introduction recent scientific attention has focused on the role of growth factors in the progression of cancer. her-2/neu is an epidermal growth factor receptor (egfr)—encoded by the erbb2 gene (formerly named her-2/ neu)—that is overexpressed on the cell surface of approximately 25% to 30% of breast cancers.(1) this expression correlates with a relatively poor prognosis for patients with breast cancer; it is associated with a shorter diseasefree survival and overall survival. (2) her-2/neu has proved to be a useful therapeutic target in many cancers. treatment of patients with her-2/neu-amplified tumors with trastuzumab, a monoclonal antibody, results in a better clinical response rate.(3) overexpression of her-2/neu has been reported in her-2/neu overexpression in germ cell tumor—ghavamnasiri et al 27urology journal vol 7 no 1 winter 2010 many epithelial malignancies, including cancers of the lung, prostate, bladder, pancreas, and esophagus, as well as sarcoma.(4-13) however, there is no evidence so far that her-2/neu expression is of prognostic relevance in these malignancies. the potential role of her-2/neu in germ cell tumors (gcts) is unknown. some recent studies have tested these tumors immunohistochemically with monoclonal anti-her-2/neu antibody. (14) the objective of our study was to determine the clinical importance of her-2/neu protein overexpression in gcts. materials and methods we studied 54 patients with documented testicular nonseminomatous gct referred to omid hospital between 2001 and 2007. pathology specimens were collected and the patients’ records were reviewed. patients’ age, tumor subtype, tumor stage, therapeutic response, tumor markers, and disease-free survival were assessed and the specimens were evaluated for the degree of her-2/neu expression by immunohistochemistry methods (herceptest kit, dako, carpinteria, california, usa), according to the manufacturer’s instructions. a pathologist who was unaware of tumor type evaluated all immunohistochemistry specimens. the staining intensity was scored from 0 to 3+ using the breast cancer her-2/neu scoring system,(1) with 2+ or 3+ staining considered positive for protein overexpression. patients with and without her-2/neu overexpression were compared in terms of tumor characteristics, outcome, and tumor markers using the t test and the chi-square test, where appropriate. continuous variables were shown as mean ± standard deviation. p values less than .05 were considered significant. results immunohistochemical staining was performed in 54 testis specimens of patients with documented nonseminomatous gct. results of the test are shown in table 1. her-2/neu overexpression was reported in 18 specimens (33.3%). a positive overexpression was more prominent in cases of teratocarcinoma, but stage of the tumor and the response to treatment were not linked with her-2 /neu expression (table 2). the frequency of her-2/neu overexpression in tumor subtypes of different stages is demonstrated in table 3. her-2 /neu overexpression was associated with a lower level of lactate dehydrogenase (p = .006), but it was not linked with the other tumor markers (table 4). her-2/neu expression patient (%) negative 15 (27.8) 1+ 21 (38.9) 2+ 15 (27.8) 3+ 3 (5.6) table 1. her-2/neu expression in patients with nonseminomatous germ cell tumor of testis her-2/neu overexpression tumor stage no yes embryonal cell i 1 0 ii 8 0 iii 3 1 teratocarcinoma i 1 3 ii 2 1 iii 0 2 mixed tumor i 8 4 ii 8 6 iii 4 2 table 3. relation of her-2/neu overexpression with stage of tumor subtype in patients with nonseminomatous germ cell tumor of testis her-2/neu overexpression variable no yes p tumor subtype embryonal cell 12 (92.3) 1 (7.7) teratocarcinoma 3 (33.3) 6 (66.7) mixed tumor 21 (65.6) 11 (34.4) .02 tumor stage i 11 (61.1) 7 (38.9) ii 19 (76.0) 6 (24.0) iii 6 (54.5) 5 (45.5) .38 response to treatment cure 21 (63.6) 12 (36.4) recurrence 8 (72.7) 3 (27.3) .72 *values in parentheses are percents. table 2. relation of her-2/neu overexpression with tumor characteristics and outcome of treatment in patients with nonseminomatous germ cell tumor of testis* her-2/neu overexpression in germ cell tumor—ghavamnasiri et al 28 urology journal vol 7 no 1 winter 2010 follow-up duration ranged from 2 to 91 months. the mean disease-free survival time was not significantly different between the patients with and without her-2/neu overexpression (table 4). discussion the recent availability of targeted therapy with tyrosine kinase inhibitors, particularly with agents directed against egfr, offers new hope for effective and better tolerated therapy for human neoplasms. we designed a preliminary study evaluating the expression of her-2/neu among nonseminomatous gcts. the expression of egfr has been previously evaluated in primary gcts. shuin and associates reported the expression of egfr at the transcriptional level in 2 of 3 immature teratomas, but no expression could be demonstrated in 15 seminomas and 6 embryonal carcinomas.(15) moroni and colleagues evaluated the expression of egfr by immunohistochemistry in a series of 24 testicular tumors. the expression of egfr appeared to be restricted to the β-human chorionic gonadotropin (β-hcg)positive component (choriocarcinoma) in 16 of 18 primary nonseminomatous gcts. in contrast, 1 leydig cell tumor, 5 seminomas, and β-hcg-negative components of gcts did not express egfr.(16) recently, kollmannsberger and coworkers evaluated the expression of egfr by immunohistochemistry in a series of 22 patients with platinum-resistant gcts and 12 patients with chemosensitive gcts. they reported that the presence of egfr was restricted to trophoblastic giant cells and the syncytiotrophoblastic elements of 4 nonseminomas, including 1 pure choriocarcinoma, and to a secondary non-germcell malignancy arising from a transformed teratoma. there were no differences in the pattern of egfr expression between platinumresistant and platinum-sensitive patients.(17) in the present study, we found overexpression of her-2/neu in 33.3% of the patients with nonseminomatous gcts, especially in those with teratocarcinoma subtype. our experience with agents targeting egfr did not show any correlation between tumor stage or therapeutic response and the degree of expression of her-2/ neu. the mean disease-free survival, age, β-hcg, and α-fetoprotein were almost similar between the two groups of patients with and without her-2/ neu overexpression. in our study and several other previous investigations, the overexpression of her-2/neu in teratocarcinoma was more frequently observed compared to mixed gcts or embryonal cell carcinoma. mandoky and colleagues also studied clinical relevance of her-2 /neu expression in germ cell testicular tumors in 2004, and they reported that teratomatous and choriocarcinoma components showed significantly higher her-2/neu expression compared to other histological subtypes of gcts.(18) mandoky and colleagues also studied expression of her-2/neu in testicular tumors in 2003 and showed that overexpression of her-2/ neu was restricted to the more differentiated histotypes.(19) in our cohort, there was no significant correlation between expression of her-2/neu and β-hcg, α-fetoprotein, patient survival, or age. however, some investigators such as soule and colleagues who studied her-2/neu expression in gcts have reported that overexpression of the her-2/ neu protein in gcts is of prognostic or therapeutic relevance.(20) mandoky and colleagues also reported that her-2/neu overexpression was associated with an adverse clinical outcome and had a prognostic role in testicular gcts.(18) some her-2/neu overexpression parameter no yes p disease-free, mo 20.77 ± 32.09 24.94 ± 22.28 .58 age, y 28.47 ± 9.21 25.83 ± 11.90 .37 β-human chorionic gonadotropin, mu/ml 1505.49 ± 7672.56 240.35 ± 373.76 .49 α-fetoprotein, ng/ml 184.37 ± 341.88 441.38 ± 1268.53 .26 lactate dehydrogenase, u/l 658.77 ± 999.80 253.44 ± 633.26 .006 table 4. disease-free survival time, age, and tumor markers in patients with and without her-2/neu overexpression her-2/neu overexpression in germ cell tumor—ghavamnasiri et al 29urology journal vol 7 no 1 winter 2010 other studies showed the correlation between her-2/neu overexpression and histological subtype (teratocarcinoma), but they could not demonstrate the exact clinical importance of this finding. the reason might be the small sample volume that would limit further interpretations about clinical factors.(14) thus, we suggest further investigations with more cases and with prolonged follow-up to evaluate clinical role of her-2/neu expression in predicting disease course and treatment outcome. we suggest studies especially focused on teratocarcinoma with overexpression of her-2/neu receptor in order to find a practical and clinical predictor factor for treatment planning. conclusion we observed overexpression of her-2/neu receptor in teratocarcinoma subtype of gct. we suggest further studies to evaluate the clinical importance of this finding. conflict of interest none declared. references 1. slamon dj, clark gm, wong sg, et al. human breast cancer: correlation of relapse and survival with amplification of the her-2/neu oncogene. science. 1987;235:177-82. 2. slamon dj, godolphin w, jones la. studies of the her-2/neu proto-oncogene in human breast and ovarian cancer. science. 1989;244:707-12. 3. vogel cl, cobleigh m, tripathy d. superior outcomes with herceptin (trastuzumab) (h) in fluorescence in situ hybridization (fish)-selected patients. am soc clin oncol. 2001;20:86. 4. laptalo l, lara pn jr, lau dh, et al. her-2/neu screening in advanced non-small cell lung cancer (nsclc): a california cancer consortium trial of trastuzumab and docetaxel. am soc clin oncol. 2001;20:335a. 5. gray cr, lara pn, jr, gandara d, et al. her-2/ neu screening in hormone refractory prostate cancer (hrpc): a california cancer consortium trial of trastuzumab and docetaxel. am soc clin oncol. 2001;20:181a. 6. reese dm, small ej, et al. her-2 expression in androgen-independent prostate cancer. am soc clin oncol. 2000;19:347a. 7. jimenez re, grignon dj, vaishampayan u, et al. analysis of her-2/neu overexpression in primary and metastatic transitional cell carcinoma of the bladder. am soc clin oncol. 2000;19:329a. 8. estrada cr, coogan cl, kapur s, et al. her-2/neu receptor protein over-expression in grade i, ii and iii bladder transitional cell carcinoma. am soc clin oncol. 2001;20:199a. 9. safran h. her-2/neu overexpression in pancreatic adenocarcinoma. am soc clin oncol. 2000;19:317a. 10. safran h, ramanathan r, schwartz j, et al. herceptin and gemcitabine for metastatic pancreatic cancers that overexpress her-2/neu. am soc clin oncol. 2001;20:130a. 11. steinhoff m, tantravahi u, king t, et al. her-2/ neu overexpression in adenocarcinoma of the distal esophagus. am soc clin oncol. 2001;20:150b. 12. tsai jy, aviv h, benevenia j, et al. prognostic factors in osteosarcoma—role of her-2/neu and p53: an immunohistochemical (ihc) and fluorescence in situ hybridization (fish) analysis. am soc clin oncol. 2001;20:295b. 13. oliveira am, medeiros f, okuno sh, et al. her-2/neu protein overexpression is a rare event in adult soft tissue sarcomas. am soc clin oncol. 2001;20:294b. 14. henley j, einhorn l. c-erb-2 (her-2/neu) overexpression in recurrent germ cell tumors. am soc clin oncol. 1999;18:341a. 15. shuin t, misaki h, kubota y, et al. differential expression of protooncogenes in human germ-cell tumors of the testis. cancer. 1994;73:1721-7. 16. moroni m, veronese s, schiavo r, et al. epidermal growth factor receptor expression and activation in nonseminomatous germ-cell tumors. clin cancer res. 2001;7:2770-5. 17. kollmannsberger c, mayer f, pressler h, et al. absence of c-kit and members of the epidermal growth factor receptor family in refractory germ-cell cancer. cancer. 2002;95:301-8. 18. mándoky l, géczi l, bodrogi i, tóth j, csuka o, kásler m. clinical relevance of her-2/neu expression in germ-cell testicular tumors. anticancer res. 2004;24:2219-24. 19. mandoky l, geczi l, bodrogi i, toth j, bak m. expression of her-2/neu in testicular tumors. anticancer res. 2003;23:3447-51. 20. soule s, baldridge l, kirkpatrick k, et al. her-2/ neu expression in germ cell tumours. j clin pathol. 2002;55:656-8. u j spring 2012.pdf 457vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l 2nd department of urology, sisli etfal training and research hospital, istanbul, turkey orhan tanriverdi, mesrur selcuk silay, mustafa kadihasanoglu, mustafa aydin, muammer kendirci, cengiz miroglu revisiting the predictive factors for intra-operative complications of rigid ureteroscopy a 15-year experience corresponding author: mesrur selcuk silay, md sisli etfal egitim ve arastirma hastanesi, 2. uroloji klinigi, 34360, istanbul, turkey tel: +90 212 231 2209 fax: +90 212 233 9876 e-mail: selcuksilay@gmail. com received august 2011 accepted october 2011 endourology and stone disease purpose: to revise the predictive factors for intra-operative complications of rigid ureteroscopy in the treatment of ureteral calculi. materials and methods: consecutive patients who had undergone 1660 ureteroscopy procedures were retrospectively reviewed. after exclusion of the cases for diagnostic purposes, diseases other than ureteral calculi, and repeated ureteroscopy procedures, 1189 patients were left as the study population. those patients were then divided into two groups based regarding patients’ age and gender, stone surface area, lateralization and localization of the stone, impaction of the stone, type of the ureteroscope, necessity of ureteral effect of leaving the fragmented stones in situ small enough to pass spontaneously results: surface area, lateralization, and type of lithotripter used were comparable between the groups, but impacted stones and the stones located at the upper ureters were asless complication has been observed in cases where we performed break’n’leave. furthermore, multivariate analysis revealed that stone impaction and failure to adhere to the “break’n’leave” principle were the independent predictors of occurring of the complications. conclusion: ureteroscopy is safe and effective in the treatment of ureteral calculi. careful attention for the patients having a potential for occurrence of the complications and selection of the techniques are of importance for reducing untoward events. keywords: ureteroscopy, complications, retrospective studies, ureteral calculi, lithotripsy 458 | endourology and stone disease introduction technical advances in the design of uretero-scopes have encouraged urologists for the for the treatment of ureteral calculi or for some diagnostic approaches. continuously, evolving ious baskets and stents, and improvements in the ability of stone fragmentation have broadened the indications of urs and upgraded this procedure location of the collecting system of the urinary tract. the competitions among urs, extracorporerenal surgery, and percutaneous nephrolithotomy subject of numerous publications in the last decade, maintaining the debate among urologists. unfortunately, surgical misadventures may still occur, some of which have lasting consequences. the nature of the ureteroscopic complications is well-known, but the predictive factors are still a question that has yet to be clearly elucidated. careful attention to the selection of the instruments and techniques are of importance for reducing untoward events related to ureteroscopic procedures. furthermore, the ultimate technologies are still not available in the majority of the urological centers in developing countries that make rigid or semirigid urs the best cost-effective option for the urologists. frankly, patients having a potential for occurrence of the complications should be welldiscriminated and addressed to different treatment modalities, such as swl, pnl, laparoscopy, or multimodal approaches. our aim is to report the predictive factors related to the occurrence of intraoperative complications during urs procedures in the treatment of ureteral calculi. materials and methods 1660 urs procedures were retrospectively analyzed. after exclusion of the cases for diagnostic purposes, diseases other than ureteral calculi, and repeated urs procedures, 1189 patients were left as the study population. analysis was focused on intra-operative complications and possible predictive factors. the study population was divided into two groups based on the presence of the complications: complication– complications were mucosal injury, mucosal eversion, ureteral perforation, ureteral avulsion, hematuria, and rupture of the basket catheter inside such as push-back of the stone towards the kidney were included in the analysis of the risk factors for the complications, they were primarily dea complication of the procedure. mucosal injury without the perforation of the ureter. the presence of visible periureteral fatty tissue and/or contrast extravasation was considered as evidence of complete ureteral perforation. hematuria was usually minor and occurred in most of the patients, but was only considered as a complication when caused a mination of the procedure. comparative parameters were as follows: patients’ age and gender, stone surface area, lateralization and localization of the stone, impaction of the stone, type of the ureteroscope, necessity of ing and after the procedure. furthermore, pushback of the stone and adhering to the break’n’leave policy were also evaluated for whether they have an impact on occurring of the complications. stones located below the pelvic brim were called as distal or lower and above the pelvic brim were called as proximal or upper. break’n’leave policy 459vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l intra-operative complications of ureteroscopy | tanriverdi et al was named by our department previously. stone plete ureteral obstruction on excretory urography, causing obstructive anuria, or present at the same site for more than 3 months, or documented to be impacted in the operative details. hospital charts, operative notes, and available videos of urs procedures were reviewed in order to determine the stone-free status with the detailed evaluation of radiographic images. dimension of stones were calculated from the radiographic images pre-operatively. treatment sucas stone-free status after multimodal intervention in 3 months. stone-free status was determined either by direct visualization of the involved ureter or by radiographic follow-up imaging. if possible, extracted calculi were sent for analysis and additional medical therapy was provided for recurrent urolithiasis. patients with positive urine cultures were treated according to the culture results at least for 3 days prior to the procedure. antibiotic prophylaxis (third-generation on the day of surgery. after obtaining signed informed consent, urs was performed under regional or general anesthesia. the patients were placed in the lithotomy position on an endoscopy table allowing the use of the procedure, patient’s characteristics, availability, and individual surgeon preference. to minimize heat loss during the operation, 0.9% nacl warmed to 37°c was used as an irrigant. routine cystoscopy and ureteral dilation were not used and the safety guidewire was inserted under direct vision. the ureteroscope was passed along der video monitoring. a 0.035/0.038-inch standcontrolled hydrodilation was used to traverse the intramural ureter. an electrohydraulic lithotripter was used in the lithotripter for the remaining cases. a tempoin some patients to avoid ureteral damage or in whom were considered for swl treatment. the decision of stenting was made according to the duration of the procedure and the degree of visible ureteral trauma at the end of the procedure. complications were treated with stents, percutaneous nephrostomy, or open surgical repair according to the severity or patient’s condition. complications or comorbidity demanded prolonged hospitalization. in patients in whom urs was not possible due to inability to advance the ureteroscope into the ureter, a ureteric stent was placed and urs was performed a few days later univariate analyses, including chi-square and student’s t test, were performed to detect any tic regression analysis was used to determine the predictive factors affecting intra-operative complications. the values were provided as mean p value of less than results 13.89 years, respectively, p cal difference was found regarding the male-to460 | p the groups were comparable regarding the p 87.05 mm², respectively, p tion of the ureteral stones was found to be a significant predictor in occurring of the complications in the univariate analysis (p the type of the ureteroscope used did not exhibit any impact on the complication rates (p of the intra-operative complications, 51 out of 57 of a dj catheter, whereas remaining 6 procedures required open surgery. the reasons for open surgical approach in these cases were ureteral perfothe stone-free rate after a single ureteroscopic 86.30%. the push-back of the ureteral stone toprocedures and was mostly encountered in the rected to swl for further treatment. furthermore, the inability in advancing the ureteroscope in the ary procedures, including re-urs, swl, pnl, and open surgery, the overall stone-free rate was pneumatic lithotripsy was the most commonly of the patients who had stones, the break’n’leave (p tions in univariate analysis. another predictor in the univariate analysis was the impaction of the 5.60%, respectively, p formed in only 16 out of 1189 urss when the ureteroscope could not be advanced. there was p dures to facilitate the advance of the ureteroscope, hand-held irrigation pump was enough for ureteral access in the rest of the cases. there was groups with regards to the rate of using an access catheter (p in multivariate stepwise logistic regression analysis, the independent predictive factors associated the impaction of the stone was found to be the independent factor for increased complication rates. furthermore, deeming the stones small enough to be the other predictor decreasing the complication rates. discussion table 1. classification of complications. intra-operative complications n (%) 30 (52.6) hematuria 9 (15.7) ureteral perforation ureteral avulsion 2 (3.5) mucosal eversion 1 (1.7) rupture of the basket catheter 2 (3.5) total number 57 (100) endourology and stone disease 461vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l studies. with the auxiliary procedures. in univariate analysis, upper location of the stones, stone impaction, and disrespect to the break’n’leave policy were complication rates. presence of stone impaction and the break’n’leave policy remained independent predictors at multivariate analyses. th century, with the development of small diameter endoscopes and a widely accepted modality in the treatment of ureteral calculi. therefore, urs has been a safworldwide experience. however, complications may still occur and the predictive factors should be clearly elucidated to understand the nature of the complications. in this study, mucosal injury was the most frewhich was treated with stent placement and resolved with no further consequences. parallel to our results, mucosal injury was the most common intra-operative complication over other compliries. ureteral perforation was second most common complication in our group. of 13 ureteral perforations, while 11 were treated with dj surgery due to guidewire slippage and failed dj placement. stone extraction and repair of the damaged segment of the ureter were successfully surgery was required due to the rupture of the tip of the basket catheter inside the ureter, which were both successfully managed with open surgery. the most tragic complication, however, was the complete ureteral avulsion in two cases. one of them had multiple ureteral stones in the proximal ureter and the other one had proximally located stone with acute kinkings in the mid-ureter. the proximally located stones were fragmented successfully, but with the unbalanced downward table 2. univariate analysis of risk factors for occurring of the complications. categorical factor group 1 (n = 57) group 2 (n = 1132) p age (mean ± sd)*, y .363 gender (male), % 63.20 64.50 stone surface area (mean ± sd), mm² .757 lateralization, % right 43.90 46.10 .744 upper 47.40 31.70 .047 type of ureteroscope (wolf ), % 66.70 73.20 .537 ureteral access catheter, % 63.20 47.00 .109 postoperative ureteral catheter, % 56.10 45.30 .263 stone impaction, % 17.50 5.60 .0001 balloon dilation of the ureteral orifice, % 1.75 1.32 push-back, % 7.01 .650 break’n’leave, % 19.30 .0001 *sd indicates standard deviation. intra-operative complications of ureteroscopy | tanriverdi et al 462 | traction of the ureteroscope, the whole ureter came out in both cases. primary anastomosis was tried initially, but after a period of follow-up with the ancillary procedures, including ileal neoureter placement, unfortunately both cases had undergone nephrectomy. in a comprehensive review of endoscopic ureteral injuries, complete ureteral avulsion has been reported in 17 out of 5117 furthermore, nephrectomy has also been reported as one of the most worrisome complications of urs in other published series. another technical factor to consider is the success rate of the procedures. the reported overall stonefree rate of urs for ureteral stones is remarkably high ranging between 85% and 100%. our data demonstrated comparable results with the literature, ranging from 86.3% with initial urs taking the main goal of ureteroscopic lithotripsy as rendering the patient stone-free without any complication either during or after urs into acgroups according to the presence of complications. both groups were statistically evaluated for outcome. the complications was stone location. the stones located in the upper portion of the ureters were tended to be complicated. although some restone location and complication, in those studies, the number of the procedures was either low, or statistical evaluation was not possible for the independent prediction. however, some other reports showed that proximal location of the stone was the predictor for complications using multivariate analyses. which are also supported by the published series, as for the initial treatment, it would be wiser to refer the patients with proximally located stones to swl treatment. after multivariate analysis of all factors, two independent predictors of complications have been impaction. the edema at the impaction site may easily result in false route and mucosal injury. as outlined by some researchers, the risk for perforation might be increased in impacted stones. we teral perforations had impacted stones in the ureter. el-nahas and coworkers also found that stone impaction was the independent predictor for the unfavorable results similar to our series. finally, adhering to the break’n’leave policy was found to be the other predictor for decreasing the complication rates. the idea for break’n’leave is that if the left fragments of the stone are small procedure should be terminated without any other maneuvers. the effort of continuing the fragmencant fragments down may cause damage to the ureter and prolong the procedure. we found that in the procedures in which break’n’leave were table 3. multivariate analysis of risk factors for occurring of the complications. independent factor b* exp (b)° 95% confidence interval p stone impaction -2.164 0.115 0.036 to 0.365 .0001 disrespect to break’n’leave 1.959 .01 localization (upper) 0.055 0.003 to 0.925 .692 ° relative risk endourology and stone disease 463vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l not performed, the patient has almost seven times higher risk of having a complication. to the best this factor statistically as a possible predictor of complications. some limitations of our study must be taken into long-term follow-up period. this is because our center is a referral for many hospitals in our region and thus many patients were followed up elsewhere after the procedure. therefore, the main focus of our study was the prediction of intra-operative complications. another drawback of our study might be the lack of the use of a laser energy source, which may decrease the rate of push-back ratios, particularly for the proximally located stones. although laser lithotripsy with limited complications, because of its high cost it may not be available in many urology departments like ours. recently, we were equipped with laser system and due to limited number of cases, these patients have not been included into the present study. conclusion ureteroscopy is a safe and highly effective procedure for the treatment of ureteral calculi. complications are rare and generally can be managed with the placement of a ureteral catheter or with minimally-invasive treatments. stones located cantly increased complication rates. furthermore, multivariate analysis revealed that stone impaction and failure to adhere to the “break’n’leave” principle were the independent predictors of occurring of the complications. frankly, careful attention for the patients having a potential for occurrence of the complications and selection of the techniques are of importance for reducing untoward events. conflict of interest none declared. references 1. shock wave lithotripsy or ureteroscopy for the management of proximal ureteral calculi: an old discussion revis2. extracorporeal shock wave lithotripsy and transureteral lithotripsy in the treatment of impacted lower ureteral 3. geavlete p, seyed aghamiri sa, multescu r. retrograde flexible ureteroscopic approach for pyelocaliceal calculi. 4. abdelrahim af, abdelmaguid a, abuzeid h, amin m, mousa el s, abdelrahim f. rigid ureteroscopy for ureteral stones: factors associated with intraoperative adverse 5. geavlete p, georgescu d, nita g, mirciulescu v, cauni v. complications of 2735 retrograde semirigid ureteroscopy procedures: a single-center experience. j endourol. 6. miroglu c, horasanli k, tanriverdi o, altay b, gumus e. operative failure during ureteroscopic pneumatic lithotripsy: 51. 7. fuganti pe, pires s, branco r, porto j. predictive factors for intraoperative complications in semirigid ureteroscopy: analysis of 1235 ballistic ureterolithotripsies. urology. aridogan ia, zeren s, bayazit y, soyupak b, doran s. complications of pneumatic ureterolithotripsy in the early 9. anagnostou t, tolley d. management of ureteric stones. eur 10. ather mh, paryani j, memon a, sulaiman mn. a 10-year experience of managing ureteric calculi: changing trends towards endourological intervention--is there a role for 11. mcaninch jw, ed. traumatic and reconstructive urology. intra-operative complications of ureteroscopy | tanriverdi et al 464 | 12. el-nahas ar, el-tabey na, eraky i, et al. semirigid ureteroscopy for ureteral stones: a multivariate analysis of unfavora13. harmon wj, sershon pd, blute ml, patterson de, segura jw. ureteroscopy: current practice and long-term compli14. hollenbeck bk, schuster tg, faerber gj, wolf js, jr. comparison of outcomes of ureteroscopy for ureteral calculi located above and below the pelvic brim. urology. 15. sozen s, kupeli b, tunc l, et al. management of ureteral stones with pneumatic lithotripsy: report of 500 patients. j endourology and stone disease best reviewer of november-december 2019 kyungtae ko kyungtae ko november 2019 kyungtae ko, md, phd is an assistant professor of urology at hallym university, kandong sacred heart hospital, seoul, korea. dr. ko earned a medical degree from hallym university, chuncheon, korea in 2005, then, he earned phd degree from seoul national university, seoul, korea with “prognostic significance of ki-67 in non-muscle invasive bladder cancer patients: systematic review and meta-analysis”. from april 2009 to april 2012, he worked army surgeon at department of urology, chairman, daegu army hospital. his main concerns are lithiasis and minimal invasive surgery such like miniaturized pcnl, laparoscopic surgery. he is known to be good at ultra-miniperc (ump) and metabolic workup in korea. he has been serving as a member of korean society of endourology and robotics, the society of endourology and yes (young endoluminal society). he has published many papers in sci(e) journals. he wrote several guidelines about lithiasis and he is the author of chapters for bladder cancer, elsevier. careful and fair-minded evaluation of scientific articles is an important scholarly contribution and a gratifying duty in academics. peer review is a vital process for any journal and enables publication of innovative research that meets the highest standards of quality. "dr. ko was chosen as the best reviewer(s) of the issue by the editorial board of the urology journal for his valuable and timely review of manuscript" endourology and stone disease laparoscopic pyelolithotomy for the management of large renal stones with intrarenal pelvis anatomy nasser simforoosh1, mohammad hadi radfar1*, reza valipour2, mehdi dadpour1, amir h kashi1* purpose: the role of laparoscopic pyelolithotomy (lpl) in the management of renal stones is evolving. one of the challenges in lpl for renal stones is patients with intrarenal pelvis. here we present our experience with laparoscopic pyelolithotomy for the management of renal stones with intrarenal pelvis anatomy. materials and methods: patients candidate for laparoscopic pyelolithotomy from february 2014 to march 2015 were included. intrarenal pelvis was defined as > 50% of the renal pelvis area contained inside renal parenchyma. laparoscopic pyelolithotomy was done by transperitoneal approach. residual stones were checked by computed tomography and/or intravenous pyelography and ultrasonography 6 weeks after the operation. results: 28 patients were included in this study. the mean±sd of patients’ age was 45.8±12.5 years. 19 patients (68%) were male. stone locations were pelvis, multiple, and staghorn in 22, 3, and 3 patients respectively. the mean±sd of operation duration was 160±48 minutes. residual stones were observed in 3 patients with multiple (n=2) or staghorn (n=1) stones. urinary leak was observed in 3 patients and was managed conservatively in 2 patients. in one patient ureteral stent was inserted by cystoscopy. no conversion to open surgery or re-operation occurred. conclusion: laparoscopic pyelolithotomy is a feasible operation for patients with renal stones and intrarenal pelvis in centers with adequate experience in laparoscopy. however, the success of lpl decreases in patients with multiple stones and intrarenal pelvis. keywords: intrarenal; kidney anatomy; laparoscopy; urolithiasis introduction the management of renal stones has dramatically changed after the 1980's. with the introduction of shock wave lithotripsy and minimally invasive interventions (e.g. ureteroscopy, percutaneous nephrolithototmy (pcnl), and laparoscopy) the role of open stone surgery is now limited to < 5% of the cases.(1-3) currently, pcnl is the gold standard treatment modality for the management of large renal stones.(4,5) complications related to pcnl include bleeding, premature termination, sepsis, adjacent organ injury, and hydro or pneumothorax, especially for very large and complex stones.(6,7) therefore the management of very large and complex stones is still a challenge for many urologists. (2) laparoscopic pyelolithotomy (lpl) was first described by gaur et. al. more than 2 decades ago.(8) there have been some descriptive and comparative studies reporting the results of lpl or comparing its results with pcnl.(1,9-15) some recent studies have reported satisfactory or even better overall results and/or complications with lpl in comparison with pcnl.(4,12,16,17) nevertheless, the total cases reported by lpl are still limited and are mostly from non-randomized studies. currently, the indications for lpl in the management of renal stones 1urology and nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti, university of medical sciences (sbmu), tehran, iran. 2azad university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti university of medical sciences (sbmu), tehran, iran. email: ahkashi@gmail.com received september 2019 & accepted march 2020 have not been clearly defined.(9,12) the majority of reported lpls include patients with an extrarenal pelvis.(2,4,15) lpl for patients with an intrarenal pelvis is challenging due to surgical difficulty releasing enough surface of renal pelvis to remove the stone en bloc. here we report our experience with lpl for renal stones with intrarenal pelvis anatomy. materials and methods from february 2014 to march 2015 patients who were candidate for stone surgery with solitary renal stones and/or a limited number of stones in renal calices were included in the study. in our department, pcnl is routinely provided to patients with renal stones with an average of 900-1000 pcnls each year. lpl is also provided based on surgeons' and patients’ preferences to some patients and at the time of the study was performed in an average of 50-60 operations each year. preoperative evaluation included clinical history taking, physical examination, urine analysis and culture, serum creatinine, electrolytes and hemoglobin, intravenous pyelography (ivp) or computerized tomography (ct) scan, and renal ultrasonography. renal pelvic anatomy was reviewed on preoperative imaging (ct and/or ivp). intrarenal pelvis was defined by a novel urology journal/vol 18 no. 1/ january-february 2021/ pp. 40-44. [doi: 10.22037/uj.v0i0.5576] vol 18 no 1 january-february 2021 41 method proposed by tomaszewski et al.(18,19) (figure 1) briefly, a line was drawn connecting two polar lines of renal pelvis border with renal parenchyma (dots a and b in figure 1) on excretory phases cross imaging and the percentage of renal pelvic area (by linear dimensions) contained inside the volume of renal parenchyma was calculated. intrarenal pelvis was defined when > 50% of renal pelvic area was contained inside renal parenchyma. (figure 1) data was gathered prospectively. prophylactic antibiotics were administered on the day of surgery before the operation. lpl was performed as described before(2,3) and is summarized below: after general anesthesia, the patient was positioned in the modified lateral decubitus with minimal fiexion. a 12-mm camera port was inserted in the umbilicus by open access. three 5-mm working ports were inserted under direct vision in the midline,10 cm above the umbilicus, in the midclavicular line parallel to the umbilicus, and below the umbilicus lateral to the rectus muscle. the white line of toldt was incised, and the colon was medially reflected. the pelvis and ureter were identified, the renal pedicle was exposed, and then the renal pelvis was freed from surrounding peripelvic fat up to the junction of pelvis with renal parenchyma.(figure 2) a transverse pyelotomy incision was made away from ureteropelvic junction to prevent ureteropelvic junction stenosis by electrocautery or cold scissors. this incision was made on the renal pelvis as much needed to extract the stone(s) cautiously to prevent excessive pelvis tearing. the tip of the pelvic stone was freed from the ureteropelvic junction, and then the stone was extracted with a curve grasper and/or babcock grasper. the pelvic incision was extended as needed to allow removal of the branches of staghorn stones or large stones if needed. additional stones were removed if present using graspers and direct vision of the pelvicalyceal system by laparoscope and the pyelocalyceal system was washed out with normal saline. a double pigtail ureteral stent was inserted, and the edge of the incision line on the renal pelvis was re-approximated using 4-0 vicryl (ethicon, inc., johnson & johnson,somerville, nj) suture according to the running fashion or by few interrupted sutures when continuous suturing was felt difficult. the stones were extracted from the abdominal cavity using a surgical glove or an endobag. a drain was fixed in the peritoneal cavity near the operative laparoscopy for intrarenal pelvis stones-simforoosh et al. figure 1. preoperative (left) and postoperative (right) intravenous pyelography of a patient with intrarenal pelvic stone operated by laparoscopic pyelolithotomy. points a (upper border) and b (lower border) show the junction of pelvis with renal parenchyma in cross imaging and the line drawn illustrates that the most part of pelvis is intarenal (more than 50% of pelvis surface in cross imaging is intrarenal) variable age, years; mean±sd 45.8±12.5 gender, male; n(%) 19(68) side, left; n(%) 15(54) stone size, mm; mean±sd 26.1±9.9 stone location; n pelvis, multiple, staghorn 22,3,3 history of stone surgery; n nil, swl,pcnl,oss 19,6,1,2 table 1. patients' characteristics. variable mean ± sd creatinine before operation, mg/dl 1.15 ± 0.44 creatinine 1st postop day, mg/dl 1.26 ± 0.43 hb before operation, mg/dl 14.2 ± 1.9 hb 1st postop day, mg/dl 13.2 ± 2.1 operation duration, minutes 160 ± 48 hospitalization days; mean (range) 5.8(3-14) clavien-dindo grade of complications; n(%) grade ii 4 (14) grade iii 1 (4) table 2. operations' characteristics and postoperative complications field and was subsequently removed 3-6 days after the operation. the foley catheter was retained for 3-5 days. the ureteral stent was removed 4-6 weeks after the surgery. the assessment of residual stones was performed by using plain abdominal radiography one day after the operation and intravenous pyelography and/or non-contrast computed tomography six weeks after the operation (figure 1). this latter intravenous pyelography and/ or computed tomography were employed to assess the structure and function of renal pelvicalyceal anatomy after the operation. patients were consulted regarding alternative treatment strategies for their renal stones and informed consent was obtained. results 28 patients were enrolled from feb 2014 to mar 2015. patients’ demographic and operative characteristics have been outlined in tables 1 and 2. preoperative and postoperative intravenous pyelography of one patient has been presented in figure 1. intraoperative ureteral catheter was not inserted in 6 patients. our routine protocol was the insertion of ureteral catheter and omission of its insertion in these 6 cases was technical difficulty of ureteral catheter insertion in these cases due to intrarenal pelvis and the narrow window for passage of the distal end of the ureteral catheter from renal pelvis opening to the upper ureter. out of these 6 patients, in one patient, postoperative urinary leak was observed. this patient was a 46-year-old man with a previous history of open stone surgery and shock wave lithotripsy. he had a staghorn 45 mm stone with multiple stones in lower calices. ureteral catheter was inserted on the 7th postoperative day due to continued leakage. urinary leak subsided after ureteral catheter insertion. he also experienced fever from the 3rd postoperative day that was managed conservatively by intravenous antibiotics. fever subsided on the 11th postoperative day. urinary leak was observed in 3 patients. in one patient, intraoperative ureteral catheter was not inserted which was commented on above. in the other two patients, an intraoperative ureteral catheter had been inserted. one patient was a 34-year-old man with a pelvis stone in a horseshoe kidney. urinary leak subsided after 13 days with conservative management. in another patient with a 44 mm stone in the right pelvis, urinary leak lasted 8 days and subsided on the 9th postoperative day. postoperative fever was observed in 5 patients. three patients were patients with a postoperative urinary leak. fever in all these 5 patients was managed by intravenous antibiotics and in patients without urinary leak by intravenous fluids. residual stones were observed in 3 patients with staghorn (n=1) or multiple stones(n=2). discussion laparoscopic pyelolithotomy has been introduced more than 2 decades ago. nevertheless, it has not been popularized among many urologists due to its long learning curve together with an already established pcnl technique.(12) currently, lpl is employed for the management of large, hard, impacted renal stones; as a salvage procedure after failed swl or endourology; renal and anatomical abnormalities; and before embarking to open surgery.(2,9,12) yet it is believed that the indications for lpl have not been sharply defined.(9,12) many urologists believe that lpl should be used for patients with extrarenal pelvis. the technical difficulties associated with suturing of intrarenal pelvis and fear of postoperative urinary leak have caused many authors to exclude cases with intrarenal pelvis from the series of lpl.(15) despite these difficulties and technical challenges, promising results in comparison of pcnl and lpl has been recently published highlighting the feasibility of lpl and reporting better stone free rate, hemoglobin drop, and complications with lpl(4,20,21) we have previously reported our experience of laparoscopic pyelolithotomy in the management of staghorn renal stones(2) and bilateral renal and ureteral surgeries(22). figure 2. preoperative pyelography of a patient with intrarenal pelvis (left side: a) together with intraoperative picture of the pelvis (right side: b) after removing peripelvic fat and exposing surface of renal pelvis and the major calices of upper, middle and lower poles. (ur = ureter, p = pelvis, l=lower calyx, m = middle calyx, u = upper calyx) laparoscopy for intrarenal pelvis stones-simforoosh et al. endourology and stones diseases 42 vol 18 no 1 january-february 2021 43 in this series, we reported 28 patients with intrarenal pelvis as defined by tomaszewski et al. who were operated by lpl(18). this series included 3 patients with staghorn renal stones and 3 patients with multiple stones in pelvicaliceal system. urinary leakage was observed in 3 cases (11%). in two patients, urinary leak was managed conservatively. in the third patient in whom the operation was completed without insertion of ureteral catheter, we inserted a ureteral stent (double pigtail) by cystoscopy and urinary leak resolved after ureteral catheter placement. no difference was observed in the frequency of urinary leak between patients with intraoperative ureteral catheter insertion and patients without it, however, the frequency of patients was few to detect a reasonable difference. we excluded the insertion of a ureteral stent in patients in whom it was technically difficult because of narrow window and acute entry angle for ureteral stent in some patients as described previously but we recommend the insertion of a ureteral catheter as the standard procedure if possible during laparoscopy and if not possible through cystoscopy at the end of operation after turning position of the patient to lithotomy to obviate the possibility of urinary leakage until further confirmation of the safety of excluding ureteral catheter insertion in difficult cases in large scale studies. residual stones were observed in 3 patients with staghorn or multiple stones in calices which were difficult to extract by laparoscopy. in such cases, there is the possibility of residual stones by other conventional minimally invasive surgical approaches (pcnl or endourology). pcnl stone free rate for staghorn stones in croes global study was 57%; however, there is not head to head comparative study between the two approaches(23). the stone free rate for multiple/staghorn stones in this study is 50%. (3 out of 6 patients) we did not use flexible instruments (nephroscopy or ureteroscope) during laparoscopy in such cases due to its unavailability in our center in the time of the study, however, we recommend to use flexible nephroscope or ureteroscope to increase stone free status in cases of multiple stones and / or solitary stones in calyces in addition to pelvis stone. the following tips will help in lpl for stones in intrarenal pelvis: • it is advisable to dissect the renal pelvis from surrounding fat and tissues to the border of renal parenchyma and by elevating the parenchymal border even to expose the proximal parts of the major calices. this maneuver will help in extracting large stones or stones with a branch in a major calyx. • in a few cases in whom urinary leak develops after the operation and does not respond to conservative measures, a ureteral catheter can be inserted by cystoscopy. • if the anterior surface of the renal pelvis cannot be approached because of aberrant vessels, the kidney can be turned medially and the posterior pelvis surface can be approached. this series is limited in number, however, paves the way for management of renal stones for a subgroup of patients with renal stones in whom the lpl is technically difficult and challenging. it is very important to consult with the patient about the alternative options in this group of patients as lpl is technically challenging and may be associated with relatively higher complications compared to patients with extrarenal pelvis. another limitation of this study is the absence of long term follow-up in patients. conclusions we think that laparoscopic pyelolithotomy is a feasible option for renal stones with intrarenal pelvis if adequate laparoscopy experience is available and the patient is willing to undergo laparoscopy given alternative choices. however, in cases with multiple stones associated with intrarenal pelvis anatomy the stone free rate will decrease. conflict of interest the 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percutaneous nephrolithotomy for larger stones? minimally invasive therapy & allied technologies. 2001;10:105-9. 11. goel a, hemal ak. evaluation of role of retroperitoneoscopic pyelolithotomy and its comparison with percutaneous nephrolithotripsy. int urol nephrol. 2003;35:73-6. 12. haggag ym, morsy g, badr mm, al emam ab, farid m, etafy m. comparative study of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in the management of large renal pelvic stones. can urol assoc j. 2013;7:e171-5. 13. meria p, milcent s, desgrandchamps f, mongiat-artus p, duclos jm, teillac p. management of pelvic stones larger than 20 mm: laparoscopic transperitoneal pyelolithotomy or percutaneous nephrolithotomy? urol int. 2005;75:322-6. 14. nambirajan t, jeschke s, albqami n, abukora f, leeb k, janetschek g. role of laparoscopy in management of renal stones: singlecenter experience and review of literature. j endourol. 2005;19:353-9. 15. tefekli a, tepeler a, akman t, et al. the comparison of laparoscopic pyelolithotomy and percutaneous nephrolithotomy in the treatment of solitary large renal pelvic stones. urol res. 2012;40:549-55. 16. li s, liu tz, wang xh, et al. randomized controlled trial comparing retroperitoneal laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for the treatment of large renal pelvic calculi: a pilot study. j endourol. 2014;28:946-50. 17. wang x, li s, liu t, guo y, yang z. laparoscopic pyelolithotomy compared to percutaneous nephrolithotomy as surgical management for large renal pelvic calculi: a meta-analysis. j urol. 2013;190:888-93. 18. tomaszewski jj, cung b, smaldone mc, et al. renal pelvic anatomy is associated with incidence, grade, and need for intervention for urine leak following partial nephrectomy. eur urol. 2014;66:949-55. 19. tomaszewski jj, smaldone mc, cung b, et al. internal validation of the renal pelvic score: a novel marker of renal pelvic anatomy that predicts urine leak after partial nephrectomy. urology. 2014;84:351-7. 20. bai y, tang y, deng l, et al. management of large renal stones: laparoscopic pyelolithotomy versus percutaneous nephrolithotomy. bmc urol. 2017;17:75. 21. xiao y, li q, huang c, wang p, zhang j, fu w. perioperative and long-term results of retroperitoneal laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for staghorn calculi: a single-center randomized controlled trial. world j urol. 2019;37:14417. 22. nouralizadeh a, kashi ah, valipour r, nasiri kopaee mr, zeinali m, sarhangnejad r. bilateral laparoscopic stone surgery for renal stonesa case series. urol j. 2017;14:5043-6. 23. desai m, de lisa a, turna b, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: staghorn versus nonstaghorn stones. j endourol. 2011;25:1263-8. laparoscopy for intrarenal pelvis stones-simforoosh et al. endourology and stones diseases 44 urol_v03_no4_001_editorial.indd kidney transplantation 225urology journal vol 3 no 4 autumn 2006 changes in plamsa concentrations of hypoxanthine and xanthine in renal vein as an index of delayed kidney allograft function heshmatollah shahbazian, hayat mombini, ahmad zand moghaddam, majid jasemi, mohammad ali hosseini, payam vaziri introduction: the aim of this study was to evaluate the plasma levels of hypoxanthine (hx) and xanthine in the renal vein blood samples for prediction of delayed graft function (dgf). materials and methods: two blood samples were taken from 47 kidney recipients, intraoperatively. the first sample was obtained from a peripheral vein before vascular anastomosis and the second from the allograft renal vein, 15 minutes after the anastomosis. purine metabolites including xanthine and hx were measured and their associations with operative time, anastomosis time, frequency of clamping, urine output, and dgf were evaluated. results: the mean levels of xanthine and hx were 0.12 ± 0.10 mg/l and 0.37 ± 0.17 mg/l in the first plasma samples, respectively. thirty patients (63%) had no significant changes in neither of their purine metabolite levels and 17 (37%) had higher levels of hx, but not xanthine, in their second samples. only anastomosis time had a significant relation with the level of the metabolites (p = .04). three patients (10%) with no changes in the metabolites and 5 (29.4%) with higher hx levels had dgf (p = .12). the anastomosis time and frequency of vascular clamping were higher and the urine output after the anastomosis was lower in the patients with dgf. conclusion: cold ischemia in kidney transplantation causes a mild increase in the hx concentration indicative of short-term ischemia effects on the cell metabolism. but it cannot predict dgf. anastomosis time, frequency of clamping, and urine output after the anastomosis are more sensitive indices. urol j (tehran). 2006;4:225-9. www.uj.unrc.ir keywords: purines, xantine, hypoxanthine, kidney transplantation, delayed graft function department of kidney transplantation, golestan hospital, jondishapour university of medical sciences, ahwaz, iran corresponding author: heshmatollah shahbazian, md department of kidney transplant golestan hospital ahwaz, iran tel: +98 916 111 4595 fax: +98 611 338 6257 e-mail: heshmatolahs@yahoo.com received june 2006 accepted august 2006 introduction delayed graft function (dgf) is one of the earliest complications after kidney transplantation and is generally defined as the need for dialysis within the first posttransplant week.(1) its incidence vary from 5% in living-donor transplantation to 25% in cadaveric transplantation.(2) delayed graft function can result in acute rejection within the early stages after transplantation impacting the long-term graft survival.(1) thus, it is of utmost importance to find effective prevention and treatment measures and to introduce a sensitive and noninvasive method for its differentiation from other complications, especially acute rejection. although in some studies dgf has not shown any relation with increased duration of cold ischemia, its natural process and lower incidence hypoxanthine and xanthine and delayed kidney allograft function—shahbazian et al 226 urology journal vol 3 no 4 autumn 2006 in transplantation from living donors (with shorter ischemia time) depict the role of ischemia and the similarity between the mechanism of dgf and acute tubular necrosis.(1) the main index of tissue ischemia is the cellular adenosine triphosphate reduction which can intervene the function of the na/k pump of the cell and disrupt the intracellular electrolyte balance and cellular ph resulting in lysosomal activation, cell death, and kidney failure.(1-3) another theory for dgf is free radical formation due to reperfusion.(1) according to this theory, mediator metabolites of adenosine triphosphate, such as hypoxanthine (hx), may result in cell damage during the ischemia period. its oxidation to xanthine during the reperfusion period can also damage the cell by free radical formation.(4) measurement of the hx and xanthine levels following ischemia and reperfusion has been performed in animal models. also, it has been studied in human models following myocardial infarction and in neonates following intrauterine hypoxic states.(5-7) we designed this study to evaluate the changes in the plasma levels of hx and xanthine in the blood samples from the renal vein following vascular anastomosis as a factor indicating dgf. materials and methods in this cohort study, we evaluated the kidney recipients from living donors in golestan hospital of ahwaz between march 2004 and september 2005. the study was approved by the ethics committee of ahwaz university of medical sciences. living donor nephrectomy was performed according to the standard method. the harvested kidney was put into a receiver containing frozen sterile saline and a preservation solution with the temperature of 0˚c to 4˚c was introduced into the kidney through an arterial cannula. the solution was injected within 20 minutes (50 ml/min). the ingredients of the preservation solution are mentioned in table 1. after cooling, kidney transplantation was carried out. when the anastomosis was made, furosemide (3 mg/kg to 5 mg/kg), manitol (0.5 mg/kg), and normal saline (3 l to 4 l) were administered intravenously. three blood samples were taken from each patient. these samples included sample 1, obtained from a peripheral vein before the anastomosis for evaluating the baseline level of the metabolites; sample 2, obtained from the allograft renal vein 15 minutes after the anastomosis; and sample 3, obtained from a peripheral vein 15 minutes after the anastomosis. the blood samples were centrifuged and the plasma was mixed with an equal volume of 10% trichloroacetic acid. the resultant solution was again centrifuged and the supernatant liquid was used for injection into the high-performance liquid chromatography (hplc) system to measure the plasma levels of xanthine and hx. to provide the appropriate conditions for hplc, the ambulatory phase, the column (eurosphere 100 c18, knauer, berlin, germany), the detector (uv/visable, cecil instruments, cambridge, uk), sample injection, data analysis, and producing standard curves were tested and adjusted according to the instructions.(8-10) according to the changes in the plasma levels of the purine metabolites (sample 2 in comparison with sample 1), the patients were divided into two groups: group 1, without and group 2, with increase in the metabolite levels. the criteria for selecting the patients of group 2 were (1) an increase in the plasma level of hx greater than 11 µmol/l (> 1.5 mg/l) or in the plasma level of xanthine greater than 2.7 µmol/l (> 0.38 mg/l) when the initial levels were normal, (2) a 3-fold increase in the plasma level of hx or xanthine, and (3) any increase in each metabolite to the levels greater than the accepted laboratory biases when the initial levels were higher than the normal range.(7,11) a necessary condition for attributing this increase to the graft was the higher level of the metabolites’ concentrations in sample 2 compared to sample 3. if the levels of purine metabolites were higher in sample 3, the patient would be excluded because that increment could be indicative of the decreased perfusion and ischemia in other tissues (eg, due to the decrease in the systemic blood pressure or severe bleeding). none of the patients met this criterion and thus, none of them was excluded. table 1. ingredients of preservation solution ingredient value ringer lactate solution verapamil glucose 50% heparin lidocaine 2% bicarbonate 1 l 20 mg 10 ml 5000 u 5 ml 20 meq hypoxanthine and xanthine and delayed kidney allograft function—shahbazian et al urology journal vol 3 no 4 autumn 2006 227 the patients were followed up for 10 to 14 days postoperatively and any episode of dgf was recorded. delayed graft function was defined as one of the following conditions: (1) need for dialysis within the first week after the operation,(4) (2) serum creatinine level of 2.5 mg/dl or more and the peak activity time of more than 6.5 minutes on renal isotope scan performed on day 5,(2) and (3) less than 10% decrement in the serum level of creatinine within the first 24 hours after the transplantation.(12) during the follow-up period, monitoring of the fluid intake and output and daily laboratory tests including blood urea nitrogen, and serum creatinine levels were performed. also, ultrasonography, doppler ultrasonography, and renal scintigraphy were used to rule out other causes of the kidney allograft dysfunction (eg, acute tubular necrosis). percutaneous needle biopsy was performed in patients if diagnosis could not be made by noninvasive methods. other variables including age of the donor and the recipient, sex of the recipient, anastomosis time (the time period between the removal of the kidney from the cooling solution and removal of the vascular clamps), operative time, frequency of clamping, and urine output after the anastomosis were recorded. the collected data were analyzed by fisher exact test and chi-square test, for comparison of categorical variables; mann-whitney test, for comparison of nonparametric continuous variables; and wilcoxon rank sum test, for evaluation of alterations in hx and xanthine levels. the spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa) was used and p values less than .05 were considered significant. results forty-seven patients were enrolled in this study, of whom 30 (63%) were men and 17 (37%) were women. the mean age of the patients was 34.8 ± 7.1 years (range, 16 to 62 years). the mean levels of xanthine and hx were 0.12 ± 0.10 mg/l and 0.37 ± 0.17 mg/l in sample 1, respectively. thirty patients (63.8%) had no significant changes in their purine metabolite levels (group 1) and 17 (36.2%) had higher levels in their second samples (group 2). table 2 demonstrates the mean changes in the level of the metabolites in each group. in group 1, no significant difference was seen in the level of hx and xanthine. in group 2, the significant change was attributed to the level of hx (p < .001), but, xanthine was not increased significantly (p = .13). evaluation of other variables showed that only anastomosis time had a significant relation with the level of the metabolites (35.0 ± 7.3 minutes in group 1 versus 40.0 ± 7.9 minutes in group 2; p = .04). three patients (10%) in group 1 and 5 (29.4%) in group 2 had dgf (p = .12). the anastomosis time and frequency of vascular clamping were higher and the urine output after the anastomosis was lower in patients with dgf (table 3). table 2. concentrations of purine metabolites in plasma samples from peripheral vein before anastomosis (sample 1) and from allograft renal vein 15 minutes after anastomosis (sample 2)* *values are means ± standard deviations. hx indicates hypoxanthine. purine metabolites sample 1 sample 2 p group 1 xanthine 0.12 ± 0.14 0.20 ± 0.12 .14 hx 0.37 ± 0.35 0.63 ± 0.51 .24 group 2 xanthine 0.11 ± 0.60 0.30 ± 0.07 .13 hx 0.36 ± 0.89 1.69 ± 1.22 < .001 table 3. factors influencing graft function within the first week of transplantation* *values in parentheses are percents. factors dgf (n = 8) no dgf (n = 39) p anastomosis time, min 42.0 ± 6.9 33.0 ± 7.2 .002 clamping > 1 time 6 (75) 6 (15.4) .002 urine output < 200 ml at 1st day 4 (50) 4 (10.3) .02 hypoxanthine and xanthine and delayed kidney allograft function—shahbazian et al 228 urology journal vol 3 no 4 autumn 2006 discussion the present study shows that any changes in the level of the purine metabolites following kidney transplantation are associated with the duration of the anastomosis and subsequently warm ischemia. several studies have shown the relation between high amounts of xanthine and hx in the plasma following ischemia. poulsen and colleagues designed a study to evaluate the effects of oxygen 100% in cardiopulmonary resuscitation of newborn pigs and showed an increase in the plasma level of hx, xanthine, and uric acid following generalized warm ischemia.(11) saugstad and aasen noticed that warm ischemia resulted in a significant increase in the level of hx.(13) van wylen and associates showed that brain ischemia and anoxia caused a 30-fold increase in the plasma level of hx and xanthine of cerebrospinal fluid in mice.(14) the level of xanthine did not significantly increase after ischemia in our study. this could be due to one of these reasons; first, the abovementioned studies have been performed in animal models. it can be speculated that the mechanism of purine metabolism is not similar in human beings and animals and the response may be different in humans. second, it is possible that the pattern of xanthine increment does not follow a linear pattern in relation to the duration of ischemia. third, our study was performed on cooled grafts. this may decrease the cellular metabolism rate while none of the previous studies has been performed on models with cold ischemia. fourth, in the abovementioned studies, the periods of the tissue ischemia were significantly higher than those in our study. fifth, reverse metabolic pathways may have been activated, metabolizing the hx formed in the peripheral parts. eklund and colleagues evaluated the level of hx in the transitional tissue of rats’ kidneys following warm ischemia and reperfusion using microdialysis method. they measured the hx level in two different groups of the rats with the warm ischemia duration of 20 and 40 minutes. in this study, although hx increased significantly during the 20-minute ischemia period, it became normal after reperfusion.(5) the 20-minute period in this study is approximately similar to the time of sampling from the renal vein in our study. ischemic damage and reperfusion have been accepted as two important etiologies of dgf in kidney transplants. in a study performed on 3365 patients between 1990 and 1998, sola and associates showed that dgf had a significant relation with ischemia.(15) in another study performed by ojo and colleagues on 37 216 cadaveric kidney transplants, it was shown that the increase in the duration of the ischemia had the strongest relation with dgf and by each 6-hour increase in the duration of the cold ischemia, the risk of this complication increased up to 23%.(16) in 2002, mota and colleagues evaluated the risk factors and their effects on dgf.(17) a significant relation was found between the duration of the ischemia and dgf. abreu and coworkers evaluated the predisposing factors of the dgf in 100 patients. they showed that the most important risk factors were the age of the recipient, donor–recipient relation, and the duration of cold ischemia.(18) in a study on liver transplantation, net and colleagues divided 30 rats into 2 groups. one group underwent 10 minutes of warm ischemia and this time was about 40 minutes in the other group. all rats underwent reperfusion, afterwards. it was shown that a significant association existed between the tissue xanthine level and ischemia period, dgf, and graft survival. they suggested that the xanthine level of the tissue might be an appropriate indicator for the prediction of the graft survival.(19) in our study, no significant relation was found between the hx level of the blood and dgf. although the hx increment was significantly associated with the increase in the anastomosis time, both these variables have been mildly increased, which can be a sign of transient ischemia, especially because no change was seen in the xanthine levels of the 2 groups. we showed that among many risk factors affecting the dgf, anastomosis time, ischemia, and frequency of clamping had the essential role. the deleterious effects of frequent vascular clamping on the kidney parenchyma during the surgeries involving the vascular parts is well known.(20) thus, it seems that the factor resulting in dgf in our study is not the mild ischemia and increased hx level, but it is due to the manipulations on the tissues and vasculature, accumulation of the inflammatory cells, and free radical formation because of the frequent clamping and damage to the parenchyma of the kidney. hypoxanthine and xanthine and delayed kidney allograft function—shahbazian et al urology journal vol 3 no 4 autumn 2006 229 conclusion during the phase of cold ischemia of the transplantation (with live donor) a mild increase in the level of hx is seen which can be due to the short-time ischemic defects on the cell metabolism. thus, it can not be a good predictor of dgf. our findings depicted that anastomosis time, frequency of clamping, and vascular manipulations were better indices for the prediction of this delay in the function of the transplanted kidney. references 1. knechtle sj, pirsch jd. early course of patient with a kidney transplant. in: morris pj, editor. kidney transplantation, principles and practice. 5th ed. philadelphia: wb saunders; 2001. p. 207-15. 2. marshall vc. renal preservation. in: morris pj, editor. kidney transplantation, principles and practice. 5th ed. philadelphia: wb saunders; 2001. p. 113-34. 3. goldfarb da, nally jv, schreiber mj jr. etiology, pathogenesis, and management of renal failure. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 272-86. 4. barry jm. renal transplantation. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 345-73. 5. eklund t, wahlberg j, ungerstedt u, hillered l. interstitial lactate, inosine and hypoxanthine in rat kidney during normothermic ischaemia and recirculation. acta physiol scand. 1991;143:279-86. 6. kock r, delvoux b, sigmund m, greiling h. a comparative study of the concentrations of hypoxanthine, xanthine, uric acid and allantoin in the peripheral blood of normals and patients with acute myocardial infarction and other ischaemic diseases. eur j clin chem clin biochem. 1994;32:837-42. 7. saugstad od. hypoxanthine as a measurement of hypoxia. pediatr res. 1975;9:158-61. 8. czauderna m, kowalczyk j. simultaneous measurement of allantoin, uric acid, xanthine and hypoxanthine in blood by high-performance liquid chromatography. j chromatogr b biomed sci appl. 1997;704:89-98. 9. czauderna m, kowalczyk j. quantification of allantoin, uric acid, xanthine and hypoxanthine in ovine urine by high-performance liquid chromatography and photodiode array detection. j chromatogr b biomed sci appl. 2000;744:129-38. 10. liu z, li t, wang e. simultaneous determination of guanine, uric acid, hypoxanthine and xanthine in human plasma by reversed-phase high-performance liquid chromatography with amperometric detection. analyst. 1995;120:2181-4. 11. poulsen jp, oyasaeter s, saugstad od. hypoxanthine, xanthine, and uric acid in newborn pigs during hypoxemia followed by resuscitation with room air or 100% oxygen. crit care med. 1993;21:1058-65. 12. bhandari. s, eisinger d, eris j. early postoperative urine flow predicts delyed graft function irrespective of diuretic use. the journal of applied research. 2004:4: 173-179. 13. saugstad od, aasen ao. plasma hypoxanthine concentrations in pigs. a prognostic aid in hypoxia. eur surg res. 1980;12:123-9. 14. van wylen dg, park ts, rubio r, berne rm. increases in cerebral interstitial fluid adenosine concentration during hypoxia, local potassium infusion, and ischemia. j cereb blood flow metab. 1986;6:522-8. 15. sola r, alarcon a, jimenez c, osuna a. the influence of delayed graft function. nephrol dial transplant. 2004;19:32-7. 16. ojo ao, wolfe ra, held pj, port fk, schmouder rl. delayed graft function: risk factors and implications for renal allograft survival. transplantation. 1997;63:968-74. 17. mota a, freitas l, macario f, bastos c, figueiredo a. risk factors for acute tubular necrosis in 744 cadaver renal transplantations. int braz j urol. 2002;28: 93-101. 18. abreu sc, goldfarb da, derweesh i, et al. factors related to delayed graft function after laparoscopic live donor nephrectomy. j urol. 2004;171:52-7. 19. net m, valero r, almenara r, et al. hepatic xanthine levels as viability predictor of livers procured from nonheart-beating donor pigs. transplantation. 2001;71: 1232-7. 20. novick ac. surgary of the kidney. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3570-4. 1478 | miscellaneous changes in bacterial species and antibiotic sensitivity in intensive care unit: acquired urinary tract infection during 10 years interval (2001-2011 ) byung il yoon,1 hyo sin kim,2 sung dae kim,3 kang jun cho,2 sun wook kim,4 u-syn ha,4 yong-hyun cho,4 dong wan sohn4 corresponding author: department of urology, yeouido st. mary’s hospital, college of medicine, the catholic university of korea, seoul, korea. tel: +82 2 3779 1038 fax: +82 2 761 1626 e-mail address: uroking@naver.com received september, 2012 accepted december, 2013 1 department of urology, international st. mary’s hospital, incheon, korea. 2 department of urology, bucheon st. mary’s hospital, college of medicine, the catholic university of korea, bucheon, korea. 3 department of urology, school of medicine, jeju national university, jeju, korea. 4 department of urology, yeouido st. mary’s hospital, college of medicine, the catholic university of korea, seoul, korea. miscellaneous purpose:patientsintheintensivecareunit(icu)areusuallyatgreaterriskforacquiringurinarytractinfections(utis).fewstudieshavefocusedonutisspecificallyacquiredwithin theicu.westudiedthechangeinbacterialspeciescausingutisinicuadmittedpatients in 2001 and 2011. materials and methods:wereviewedthemedicalrecordsofatotalof2,890icupatients whohadundergoneurineculturein2001and2011attheyeouidoandbucheonst.mary’s hospitals.changesincausativeorganismsandtheirantibioticsensitivitybetweentheyears 2001 and 2011 were analyzed. results:escherichiacoli(e.coli)wasthemostcommonorganisminicu-acquiredutisin 2001and2011inourstudy.thepathogensthatsignificantlyincreasedin2011comparedto 2001werepseudomonas,andklebsiellaspecies(p<.05).in2011gram-negativeorganisms showedrelativelyhighersensitivitiestoamikacin,imipenem,andtazocin(72.0%,77.5%and 76.1%,respectively),whereastheyshowedrelativelylowersensitivitiestothird-generation cephalosporinsandciprofloxacin(55.2%and45.0%,respectively).in2011gram-positive organismsshowedhighsensitivitiestoteicoplaninandvancomycin(91.1%and87.9%,respectively),whereastheyshowedlowsensitivitiestoampicillinandciprofloxacin(24.1% and25.5%,respectively).theantibioticresistancerateofpseudomonasspecieswasnearly doublesthatofe.coli. conclusion:infectionscausedbypseudomonasandklebsiellaspecieswerefoundtohave increasedsignificantlyin2011.pseudomonasspecieshadasignificantlylowersusceptibility toantibioticsensitivitythanotheridentifiedorganisms. keywords:bacterialinfections;drugresistance;intensivecareunits;microbialsensitivity tests;retrospectivestudies. 1479vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l bacterial species and antibiotic sensitivity in icu | yoon et al introduction patients admitted to intensive care unit (icu) arepronetovariousinfectionsi.e.lung,urinarytract,skin,oralmucosalandetc.ahugenumberofinfectionsaredevice-associatedhealth-care-associatedinfection (da-hai),ornosocomialinfections.(1)asisknowntoall, duetothespecificityofpathogensandhighdrugresistance, nosocomialinfectionisoftendifficulttocontrol,andassociateswithpooroutcome.(2) urinarytractinfections(utis)areoneofthemostcommon typesofnosocomialinfectionsencounteredintheinpatient settingsincludingicu.amongstpatientsadmittedtoicu, studieshaverevealedtheincidenceofnosocomialutisto rangefrom9%to29%.(3,4)theriskofpatientsacquiringa utisinanicuisapproximately2.5-foldhigherthanthatof patientsinageneralhospitalward.complicatednosocomial utismayleadtourosepsis,andincreasepatientmorbidity andmortality.(5) theprimarycausefornosocomialutisiscatheterizationof theurinarysystem.sincemosticupatientsaremonitored withregardtotheamountofintakeandoutputbythefoley catheter,theyareeasilyexposedtotheriskofinfectiondue toitsindwellingcharacteristic.todate,manystudieshave beenconductedtoexaminethecausativebacteriaforutis amongoutpatientsandhospitalizedpatients.however,few studieshavefocusedonuticausativeorganismsortheirsensitivitytoantibioticsinicupatients.inuticases,empirical antibiotics should be used until the bacterial culture is confirmed;therefore,itisessentialtoexaminetheantibiogram ofthecausativeorganism.sensitivitytoantibioticsmayvary dependingonthehospitalandtheregion.particularlyforpatientsintheicu,causativebacteriaforutismaybedifferent fromthoseisolatedfromtheregularoutpatientandgeneral wardpatients.specifically,inicupatientsthesensitivityto antibioticsmaybelowercomparedtootherpatients. basedonthisinformation,wecomparativelyanalyzedthe majorcausativebacteriaofutisandinvestigateddisparityin thesensitivitytoantibioticsbetweenisolatesfrom2001and 2011intheicusoftwomedicalinstitutions. materials and methods a retrospective analysis was performed on urine cultures performedin2001and2011inicupatientsintwohospitals.fouricusincludedinthisstudy:surgicalicu(25bed), medical icu (24 bed), neurosurgical icu (20 beds) and cardiacicu(16beds).wedefinedicuacquiredutiwhen urinecultureispositive[urineculturewithabacterialcount >100,000colony-formingunits(cfu)/ml]within48hours orlaterafteradmissioninicu.(6)weexcludedthepatients whoshowedapositiveurineculturewithin30daystominimizetheduplicationoftestresultssuchasreinfectionsoffirst uti.themedicalrecordsofpatientswerereviewedtomake a differential diagnosis between asymptomatic bacteriuria anduti.dysuriaandfeveratthetimeofurineculturetestingwereconsideredassymptomaticofuti.asymptomatic bacteriuriawasexcludedfromthestudy. urinecollectionwasconductedaccordingtothefollowing methods.thetipofthecatheterwascleanedusingaboric sponge, and then the urine was collected using a sterilized syringefrompatientswithanindwellingcatheter.fromthe patientswithoutindwellingcatheters,themiddleurinewas collectedaftercleaningoftheurethralmeatusandtheperinealregionusingaboricsponge.ifself-voidingwasimpossible,urinesampleswereobtainedbycatheterization.the midstreamurinewascollectedfrompediatricpatientswith theabilityofvoidingcontrol.inothercases,urinesamples wereobtainedbycatheterization.bacterialidentificationwas conductedwiththeuseofatbkits(biomérieux,mumbai, india).speciesidentificationforyeastwasdoneonvitek 2compactsystem(biomérieux,mumbai,india)asperthe manufacturers’instruction.antimicrobialsusceptibilitytests wereperformedusingthekirby-bauermethod.theprotocolofthestudywasapprovedbyacentralethicalcommittee (catholicmedicalcenter,thecatholicuniversityofkorea collegeofmedicine,seoul,korea,no.hirb-00145_2-002) andbytherespectivelocalethicalcommittees. statistical analysis sigmastatforwindows(systatinc.,chicago,il,usa)was usedforstatisticalanalysis.tomakeacomparisonoftherate ofbacterialculturebetweenthetwoyears,afisher'sexact testwasperformed.ap value<.05wasconsideredstatisticallysignificant. results thenumberoficupatientswhounderwenturineculture testingwas1,007in2001and1,883in2011,foratotalof 2,890icupatientswhounderwenturineculturetesting.of thesepatients,208in2001and256in2011metstudycriteria and enrolled into the study. 1480 | miscellaneous themaletofemaleratiowas93:129in2001and107:120 in 2011 (p =.689).themeanageswere57.4±21.7yearsin 2001and60.7±24.4yearsin2011(p =.854).inbothyears, themostcommonbacterialstrainisolatedfromutipatients wase.coli(table1).in2001,thecausativebacterialspeciesthatwereculturedincludede.coli(24.5%),enterococcus(15.5%),pseudomonas(10.5%),staphylococcus(8.2%), coagulase negative staphylococcus (cns) (7.2%) and klebsiella(4.2%).in2011,thecausativebacteriathatwere cultured included e. coli (23.1%), pseudomonas (19.0%), enterococcus (17.2%), klebsiella (10.1%), cns (4.2%), andstaphylococcus(4.2%).foryeastspecies,candidaand trichosporonspecieswereidentified.otherbacterialstrains included,enterobacter,serratia,stenotrophomonas,streptococcus,myroides,proteus,providencia,morganella,citrobacter,acinetobacterandalcaligenes.overall, theproportionofgram-negativebacteriawas35.0%in2001and50.1% in 2011 (p<.05)andtheproportionofgram-positivebacteriawas30.9%in2001and39.6%in2011(p=.748).the proportionofyeastwas13.7%in2001and15.5%in2011. theproportionofpseudomonasandklebsiellasignificantly increasedfrom2001to2011(p<.05).despitealackofstatisticalsignificance,theproportionofenterococcusincreased from15.5%to17.2%andstaphylococcusaureusdecreased from8.2%to4.2%in2011comparedto2001. ineachbacterialstrain,antibioticsensitivitywasanalyzed (table2).ampicillinshowedlowsensitivitytogram-negative bacteria(24.5%in2001and23.4%in2011).ceftazidime,a third-generationcephalosporin,showedrelativelyhighsensitivitytogram-negativebacteria(33.0%in2001and62.0% in2011).oftheaminoglycosidesingram-negativebacteria, amikacin(70.2%in2001and72.0%in2011)showedhigh sensitivityascomparedtogentamicin(60.1%in2001and 57.2%in2011)ortobramycin(54.5%in2001and60.1%in 2011).quinolonessuchasciprofloxacinshowedrelatively low sensitivity (50.1% in 2001 and 55.2% in 2011) comparedtotheaminoglycosidesingram-negativebacteria.in addition,thebactrim(sulfamethoxazoleandtrimethoprim) showedalowdegreeofantibioticsensitivityat30.2%and 40.1%,respectively. inameticulousreviewofthedata,escherichiacoli(e.coli) hadalowerdegreeofantibacterialsensitivitytoampicillin in2001andin2011,butithadarelativelyhigherdegreeof antibacterialsensitivitytothethird-generationcephalosporin ceftazidimein2001andin2011.inthecaseofaminoglycosides,amikacinshowedaveryhighantibacterialsensitivity. ciprofloxacinhadarelativelyhigherdegreeofantibacterial sensitivityin2001andin2011.klebsiellahadaverylow degreeofantibacterialsensitivitytoampicillinin2001andin 2011.pseudomonaswasfoundtohavealmostnosensitivity tocefotaximeandthenshowedarelativelylowerdegreeof antibacterialsensitivitytoceftazidime,theaminoglycosides, andquinoloneatarateof30-40%.inparticular,therewasa lowdegreeofantibacterialsensitivitytoimipenematarateof 45%in2011(table3). accordingtotheresultsobtainedfor2011,enterococcushad alowerdegreeofantibacterialsensitivitytoampicillinand ciprofloxacinbuthadahigherdegreeofantibacterialsensitivitytotetracycline,teicoplanin,andvancomycin.staphylococcushadahigherdegreeofantibacterialsensitivityto table 1. species distribution of urine isolates from patients with urinary tract infections. organisms 2001 (%) 2011 (%) p escherichia coli 24.5 23.1 .475 enterococcus 15.5 17.2 .308 yeast 13.7 15.5 .530 coagulase negative staphylococcus 7.2 4.2 .176 pseudomonas 10.5 19.0 .003 klebsiella 4.2 10.1 .04 staphylococcus aureus 8.2 4.2 .054 others* 16.2 6.7 .005 totals 100.0 100.0 ----* enterobacter, serratia, stenotrophomonas, streptococcus, myroides, proteus, providencia, morganella, citrobacter, acinetobacter and alcaligenes genera. 1481vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l teicoplaninandvancomycinin2001andin2011.someantibioticswerenotconsideredfordrugsensitivitytestingand thushadnoavailableresults.inthetesteddrugs,sensitivity wasshowntochangewithtime(table4). discussion themajorfindingsofourstudywereasfollows;e.coliwas themostcommonorganisminicu-acquiredutisbothin 2001and2011;pseudomonas,andklebsiellaspeciessignificantlyincreasedin2011comparedto2001andinfections withpseudomonas,theantibioticsresistancerateswerehigherthanthatofotherbacterialstrains.utiisoneofthemost commoninfectiousdiseases,onlysecondtorespiratoryinfectionsinclinicalpracticeofinternalmedicine.despitetherapidlyupdatedtreatmentmodalitiesforuti,somepatientswith refractoryutisandcomplicatedutisaredifficulttotreat.(7) anosocomialutiisoneofthemostcommontypesofinfectionsandaccountsforthehighestincidenceoftotalnosocomialinfections.accordingtoasurveythatwasconductedto examinediseasestatusin1996,theincidenceofutisconstituted30.3%oftotalnosocomialinfectioncases.(8) accordingtoclinicalguidelinesproposedbytheeuropeanassociationofurology(eau)in2006,casesinwhichautiwas acquiredinahospitalsettingwereestablishedasoneofthe indicatorsassociatedwithcomplexutis(9) because patients whohavebeenhospitalizedweretypicallyolderinageand hadcomplicatingchronicdiseasessuchasdiabetesmellitus orhypertension.inaddition,theyhadahigherfrequencyof exposuretootherinfectiousdiseases.thesecharacteristics aremoreprevalentlyseeninicupatientsinparticular. mostcasesoficu-acquiredutisoccurastheresultofsinglebacterialstraininfections.complex-typeinfectionsdueto morethantwobacterialstrainshavebeenreportedtooccurat anincidencerateof5-12%.(5,10) in the current study the incidenceofcomplex-typeinfectionswasapproximately18%, mostof themweredue tocontaminationduring theurine sampling procedure.according to studies about infectious diseasesoccurringinanicusettinginnorthamericaand europe,e.coli,pseudomonas,andenterococcusarethemost commonbacterialstrainsincasesoficuinfections.(11)candidaspecieshavebeenreportedtobepresentatamaximal frequencyof1/3oftotalcasesoficuinfections.(12) in the currentstudy,bacterialculturesshowedanorderofincidence ofe.coli(23.1%),pseudomonas(19.0%)andenterococcus (17.2%)in2011.yeastsincludingcandidaweredetectedat arateof15.5%.incomparisonwiththeresultsthatwereobtainedin2001,e.colishowednogreatdifference.enterococcusshowedadetectionrateof15.5-17.2%despitealackof statisticalsignificance.inparticular,pseudomonasinfections greatlyincreasedfrom10.5to19.0%andklebsiellaalsoincreasedfrom4.2to10.1%.theseresultswereinagreement withthelatestkoreanreportsthatidentifiedthemajorcausativebacteriaforutisinkorea.theincidenceofinfections duetogram-positivebacteriawasgreatlyincreased.withregardtogram-negativebacterialinfections,theincidenceof infectionsduetoe.colidecreased,andinfectionsduetoother gram-negativebacteriasuchaspseudomonas,klebsiella,and enterobacterincreased.(13,14) table 2. antibiotic sensitivities for gram-stained pathogens in 2001 versus 2011. variables antibiotic susceptibility (%) year ac cl cz ct gm ak tm cf lf ip bt tz gram (-) 2001 24.5 51.8 33.0 60.1 70.2 54.5 50.1 55.8 90.8 30.2 70.2 2011 23.4 45.5 62.0 44.0 57.2 72.0 60.1 55.2 82.1 77.5 40.1 76.1 p .982 .731 < .05 .684 .963 .741 .891 <0.05 < .05 .061 .794 antibiotic susceptibility (%) year em gm tc ac cl tp vm cf gram (+) 2001 24.5 24.1 60.1 9.2 20.4 85.4 85.7 39.5 2011 27.1 10.2 54.2 24.1 19.1 91.1 87.9 25.5 p .891 < .05 .641 < .05 .941 .791 .912 < .05 keys: ac = ampicillin, cl = cephalothin, cz = ceftazidime, ct = cefotaxime, gm = gentamicin, ak = amikacin, tm = tobramycin, cf = ciprofloxacin, lf = levofloxacin, ip = imipenem, bt = bactrim, tz = tazocin, em = erythromycin, tc = tetracycline, tp = teicoplanin and vm = vancomycin. bacterial species and antibiotic sensitivity in icu | yoon et al 1482 | miscellaneous inregardtoantibioticsensitivity,theemergenceofbacterial resistanttoantibioticshasgreatlyincreasedsincethe1990s. koandcolleagues(13)reportedthatampicillinhadantibacterialsensitivityingram-negativebacteriaatarateof15.6% in1994and11.6%in1998.withciprofloxacin,antibacterial sensitivityhasbeenreportedtobe87.8%and78.8%inthose sameyears.ryuandcolleagues(15)reportedthatthesensitivityofgram-negativebacteriatociprofloxacindecreasedfrom 53.9%in2000to42.6%in2005.inthecurrentstudy,sensitivitytociprofloxacinwassimilarlyshownadecreaseata rateof50.1%in2001and55.2%in2011.thesensitivityto ampicillinandbactrimwasshowntobe23.4%and40.1%, respectively.theseresultsindicatethatampicillinandbactrimshouldnotbefurtherusedastheprimarytreatmentfor icupatientswithutis.itisalsoassumedthatspecialattentionshouldbepaidtotheuseofquinolones.in2005,ryuand colleagues(15) reportedthat thesensitivitytopenicillinand ampicillin was 40%, and sensitivity to the first-generation cephalosporinwas16%ingram-positivemicroorganisms.in thecurrentstudy,gram-positivebacterialsensitivitytoampicillin, the first-generation cephalosporin, quinolone, and erythromycinallshowedasensitivityrateof10-20%in2011. theserateswereoveralllowerthanthoseinthereportmade by ryu and colleagues.(15)thismightbebecauseonlyicu patientswereenrolledintherelevantstudies. ananalysisofsensitivitywasperformedforeachbacterial strain.in2011,e.colihadsensitivitytoampicillin,ciprofloxacin,andthethird-generationcephalosporinatarateof 32.1%,63.8%and76-78%,respectively.oftheaminoglycosides,amikacinhadahigherdegreeofantibacterialsensitivityascomparedtogentamicinortobramycin.however,antibioticsensitivityforpseudomonaswasshowntobe30-45%. itwasfoundthatpseudomonashaveantibioticresistanceapproximatelytwotimeshigherthane.coli.inparticular,the sensitivityofe.coliorklebsiellatoimipenemandtazocin wasfoundtobeatmost40-55%.accordingtoryuandcolleagues(15)thesensitivityofpseudomonastoceftazidime,cefotaxime,ofloxacinandimipenemabruptlyincreasedin2005 ascomparedto2000.theseresultsmakeitdifficulttoselect empiricalantibioticsinicupatientswithcatheterization. intheuticasesthataroseintheicu,themostimportant riskfactorwascatheterizationoftheurinarysystem.richards and colleagues(16)reportedthatmorethan95%oftotalicuacquirednosocomialuticaseswereassociatedwithcatheterization. recent reports showed that catheter-associated utiinicuisalsoverycommon,onlysecondarytoventilator-associatedpneumoniabothindevelopinganddeveloped countries.(2,17) thisstudyhadseverallimitations.firstly,theresultswere basedonasinglegroupofpatientsfromtwohospitals.therefore,thefindingmaynotberepresentativeofallicupatients inourcountryhospitals.thesamplesizewassmall,observationalnatureofthisstudymayalsohaveaffectedthefindings ofthisstudy.thesmallsamplesizemightalsoexplainwhy theresultsofourantibacterialtestingwerenotinagreement withpreviousreports.second, thepatients types,duration oficustay,changesofdevices,trendsofsimplifiedacute physiologyscoreii (sapsii),antibioticsusageduration, table 3. antibiotic sensitivities for gram-stained pathogens in 2001 versus 2011. variables antibiotic susceptibility (%) year ac cl cz ct gm ak tm cf lf ip bt tz gram (-) 2001 24.5 51.8 33.0 60.1 70.2 54.5 50.1 55.8 90.8 30.2 70.2 2011 23.4 45.5 62.0 44.0 57.2 72.0 60.1 55.2 82.1 77.5 40.1 76.1 p .982 .731 < .05 .684 .963 .741 .891 < .05 < .05 .0 .794 antibiotic susceptibility (%) year em gm tc ac cl tp vm cf gram (+) 2001 24.5 24.1 60.1 9.2 20.4 85.4 85.7 39.5 2011 27.1 10.2 54.2 24.1 19.1 91.1 87.9 25.5 p .891 < .05 .641 < .05 .941 .791 .912 < .05 keys: ac = ampicillin, cl = cephalothin, cz = ceftazidime, ct = cefotaxime, gm = gentamicin, ak = amikacin, tm = tobramycin, cf = ciprofloxacin, lf = levofloxacin, ip = imipenem, bt = bactrim, tz = tazocin, em = erythromycin, tc = tetracycline, tp = teicoplanin and vm = vancomycin. 1483vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l references 1. edwards jr, peterson kd, mu y, et al. national healthcare safety network (nhsn) report: data summary for 2006 through 2008, issued december 2009. am j infect control. 2009;37:783-805. 2. dudeck ma, horan tc, peterson kd, et al. national healthcare safety network (nhsn) report, data summary for 2010, deviceassociated module. am j infect control. 2011;39:798-816. 3. moreno ca, rosenthal vd, olarte n, et al. device-associated infection rate and mortality in intensive care units of 9 colombian hospitals: findings of the international nosocomial infection control consortium. infect control hosp epidemiol. 2006;27:349-56. 4. rosenthal vd, maki dg, salomao r, et al. device-associated nosocomial infections in 55 intensive care units of 8 developing countries. ann intern med. 2006;145:582-91. 5. laupland kb, bagshaw sm, gregson db, kirkpatrick aw, ross t, church dl. intensive care unit-acquired urinary tract infections in a regional critical care system. crit care. 2005;9:r60-5. 6. garner js, jarvis wr, emori tg, horan tc, hughes jm. cdc definitions for nosocomial infections, 1988. am j infect control. 1988;16:128-40. 7. di filippo a, casini a, de gaudio ar. infection prevention in the intensive care unit: review of the recent literature on the management of invasive devices. scand j infect dis. 2011;43:243-50. 8. kim jm, park es, jeong js, et al. multicenter surveillance study for nosocomial infections in major hospitals in korea. nosocomial infection surveillance committee of the korean society for nosocomial infection control. am j infect control. 2000;28:454-8. 9. naber k, bishop m, bjerklund-johansen t, et al. eau guidelines on the management of urinary and male genital tract infections. eau working group on urinary and male genital tract infections. in: european association of urology guidelines, 2006 ed. arnhem: drukkerij gelderland; 2006. p. 1-126. trendsofantibioticsconsumptionandetc.during10years mayhavechanged.butweoverlookedthesefactorsandthis canbeselectionbiasforourresult.third,wethinkthatshort termtrends(e.g.3-5yearsinvestigations)oforganismsand antibioticsensitivitywouldbemorereliableandinteresting. fourth,theabsencedataaboutextendedspectrumofbetalactamase(esbl)isanotherlimitationsofpresentstudy.the esblisthehotissuesinutirelatedpartfromthe3-5years before. our study was comparing the periods of 10 years before(2001).sowecouldnotcollecttheaccuratedataof esblinthatperiod. futurestudiesshouldinvolvemoreicuswithmanyinstitutions;treatmentregimensandcomparisonsofantibioticresistancepatternsbetweenicusandgeneralwardsandacross institutionsshouldalsobecarriedouttofurtherevaluatepatientswithicu-acquiredutiinkorea. conclusion themostcommonbacteriaresponsiblefortheoccurrenceof utisintheicuincludee.coli,pseudomonas,klebsiella, andenterococcus.inparticular,pseudomonasandklebsiella infectionsweregreatlyincreasedin2011comparedto2001. incasesofpseudomonasinfection,thesensitivitytoantibioticswasapproximatelytwotimeslowerthaninothertypes ofgram-negativebacterialstrains.thissignifiesthatattentionshouldbepaidtoselectingoptimalempiricalantibiotics. hence,furthermulti-centerstudiesarerequiredtoexamine theantibacterialsensitivityofbacteriacausingutisinthe icusetting. conflict of interest none declared. table 4. antibiotic sensitivities for gram-positive organisms in 2001 versus 2011. variables antibiotic susceptibility (%) year ac cl cz ct gm ak tm cf lf ip bt tz gram (-) 2001 24.5 51.8 33.0 60.1 70.2 54.5 50.1 55.8 90.8 30.2 70.2 2011 23.4 45.5 62.0 44.0 57.2 72.0 60.1 55.2 82.1 77.5 40.1 76.1 p .982 .731 < .05 .684 .963 .741 .891 < .05 < .05 .061 .794 antibiotic susceptibility (%) year em gm tc ac cl tp vm cf gram (+) 2001 24.5 24.1 60.1 9.2 20.4 85.4 85.7 39.5 2011 27.1 10.2 54.2 24.1 19.1 91.1 87.9 25.5 p .891 < .05 .641 < .05 .941 .791 .912 < .05 keys: ac = ampicillin, cl = cephalothin, cz = ceftazidime, ct = cefotaxime, gm = gentamicin, ak = amikacin, tm = tobramycin, cf = ciprofloxacin, lf = levofloxacin, ip = imipenem, bt = bactrim, tz = tazocin, em = erythromycin, tc = tetracycline, tp = teicoplanin and vm = vancomycin. bacterial species and antibiotic sensitivity in icu | yoon et al 1484 | 10. tissot e, limat s, cornette c, capellier g. risk factors for catheterassociated bacteriuria in a medical intensive care unit. eur j clin microbiol infect dis. 2001;20:260-2. 11. gaynes r, edwards jr, national nosocomial infections surveillance s. overview of nosocomial infections caused by gram-negative bacilli. clin infect dis. 2005;41:848-54. 12. alvarez-lerma f, nolla-salas j, leon c, et al. candiduria in critically ill patients admitted to intensive care medical units. intensive care med. 2003;29:1069-76. 13. ko hs, choi dy, han yt. a study of the changes of antibiotic sensitivity to the causative organisms of urinary tract infection for recent 5 years. korean j urol. 1999;40:809-16. 14. ko yh, oh js, cho dy, bea jh, koh sk. changes of causative organisms and antimicrobial sensitivity of urinary tract infection between 1979 and 2001. korean j urol. 2003;44:342-50. 15. ryu kh, kim mk, jeong yb. a recent study on the antimicrobial sensitivity of the organisms that cause urinary tract infection. korean j urol. 2007;48:638-45. 16. richards mj, edwards jr, culver dh, gaynes rp. nosocomial infections in combined medical-surgical intensive care units in the united states. infect control hosp epidemiol. 2000;21:510-5. 17. tao l, hu b, rosenthal vd, gao x, he l. device-associated infection rates in 398 intensive care units in shanghai, china: international nosocomial infection control consortium (inicc) findings. int j infect dis. 2011;15:e774-80. miscellaneous 1067vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l references 1. lemack ge, zimmern pe. pressure flow analysis may aid in identifying woman with outflow obstruction. j urol. 2000;163:1823-8. 2. chassagne s, bernier pa, haab f, roehrborn cg, reish jl, zimmern pe. proposed cutoff values to define bladder outlet obstruction in woman. urology. 1998;51:408-11. 3. nitti vw, tu lm, gitlin j. diagnosing bladder outlet obstruction in woman. j urol. 1999;161:1535-40. 4. grouts a, blaivas jg, chaikin dc. bladder outlet obstruction in woman: definition and characteristics. neurourol urodyn. 2000;19:21320. 5. massay ja, abrams ph. obstructed voiding in the female. br j urol. 1988;61:36-9. 6. 4th international consultation on incontinence, paris: 5-8 july 2008; p. 417-21. 7. akikwala tv, fleischman n, nitti vw. comparison of diagnostic criteria for female bladder outlet obstruction. j urol. 2006;176:209397. 8. griffiths d, hofner k, van mastrigt r. standardization of terminology of lower urinary tract function: pressure-flow studies of voiding, urethral resistance, and urethral obstruction. international continence society subcommittee on standardization of terminology of pressure-flow studies. neurourol urodyn. 1997;16:1-18. 9. chassange s, bernier pa, haab f. proposed cutoff values to define bladder outlet obstruction in women. urology. 1998;51:408-11. 10. lemack ge, zimmern pe. pressure flow analysis may aid in identifying women with outflow obstruction. j urol. 2000;163:18:23-8. 11. defreitas ga, zimmern pe, lemack ge. refining diagnosis of anatomic female bladder outlet obstruction: comparison of pressure flow study parameters in clinically obstructed women with those of normal controls. urology. 2004;64:675-81. 12. nitti vw, tu lm, gitlin j. diagnosing bladder outlet obstruction in women. j urol. 1998;161:1535-40. 13. deffieux x, thubert t, amarenco g. contribution of investigations to the diagnosis of bladder outlet obstruction in women. prog urol. 2012;22:628-35. 14. groutz a, blaivas jg, fait g. the significance of the american urological association symptom index score in the evaluation of women with bladder outlet obstruction. j urol. 2000;163:207-211. 15. tanagho ea, mccurry e. pressure and flow rate as related to lumen caliber and entrance configuration. j urol. 1971;105:583-85. 16. seddon jm, bruce aw. cystourethritis. urology. 1978;11:1-10. 17. smith pj. the management of the urethral syndrome. br j hosp med. 1979;22:578-87. 18. farrar dj. an evaluation of otis urethrotomy in female patients with recurrent urinary tract infections. a review after 6 years. br j urol. 1980;52:68-74. 19. choa rg, abrams ph, pynsent pb, ashken mh. a controlled trial of otis urethrotomy. br j urol. 1983;55:694-7. 20. netto nr, pimenta da silva r. treatment of recurrent cystitis in woman by internal urethrotomy or antimicrobial agents. int urol and nephrol. 1980;12:211-15. 21. choa rg, abrams ph, pynsent pb. a controlled trial of otis urethrotomy. br j urol. 1983;55:694-7. 22. eastwood dm, goldma m, farrar dj. urethral overdilatation in females with lower urinary tract symptoms. j r soc med. 1984;77:63942. prostatic fluid free insulin-like growth factor-1 in relation to benign prostatic hyperplasia: a controlled study cavit ceylan,1 ahmet serel,1 omer gokhan doluoglu,2 abdullah armağan,3 selcen yüksel4 purpose: insulin-like growth factors (igfs) have potent mitogenic and antiapoptotic effects on prostate tissue, whereas free igf-1 is responsible for its metabolic effects but its role in benign prostatic hyperplasia (bph) is unclear. material and methods: plasma and prostatic fluid levels of free igf-i were determined from the fasting bloods of 35 bph cases admitted for treatment and 35 randomly selected population controls. results: prostatic fluid free igf-1 concentrations did not differed significantly between two groups (p = .23). there was also no statistical difference in serum free igf-1 levels between these groups. there was also no correlation between prostatic fluid free igf-1 and serum prostate specific antigen (psa) levels and prostate volume. when compared with control group, mean ipss scores and prostate volumes of bph group were significantly high, while mean maximum measured flow rate (qmax) and international prostate symptom score (ipss) and quality of life (qol) scores were significantly low (p < .05). conclusion: our study shows that free igf-i is not associated with bph risk. further investigation is needed to elucidate the role of the free igf-1 in bph. keywords: prostatic hyperplasia; insulin-like growth factor; risk; humans; signal transduction. corresponding author: omer gokhan doluoglu, md clinic of urology, konya numune hospital, nalcaci/konya, turkey tel fax: +90 533 215 7809 e-mail: drdoluoglu@yahoo.com received november 2011 accepted november 2012 13 rd clinic of urology, türkiye yüksek ihtisas training and research hospital, ankara, turkey 2clinic of urology, konya numune hospital, konya, turkey 3department of urology, süleyman demirel university, school of medicine, isparta, turkey 4department of biostatistics, faculty of medicine, university of ankara, ankara, turkey cellular and molecular urology 1068 | cellular and molecular urology introduction it has been suggested that insulin-like growth factor-1 (igf-1) play a role in maintaining the replication of pro-static epithelial cells, and inhibits apoptosis.(1,2) in the circulation, 99% of igf-1 is found in binding complexes.(3) however, a small, but important proportion (< 5%) of igf-1 (free igf-1) is not associated with igf binding proteins(4-7) reported that free igf-1 represented the biologically active fraction of igf-1. insulin-like growth factor i (igf-i) is the peptide functioning as both endocrine hormones and tissue growth factors.(8) the role of the igf axis in benign prostatic hyperplasia (bph) is suggested by studies showing that expression of igf1 receptor is not only higher in periurethral than in intermediate and subcapsular regions of bph tissue(9) but also higher in bph cells than in normal or cancer cells.(10) in addition, in a recent study, men with bph and increased levels of igf-i and growth hormone (gh) due to acromegaly regained normal prostate volumes when they achieved gh/igf-i control.(11) since this growth factor act primarily through autocrine and paracrine processes, circulating levels are not likely to serve as useful biomarkers. prostatic fluid (pf) produced by prostatic epithelium provides a reliable reflection of the metabolic status of the prostate, and can be obtained repeatedly from most men by transrectal massage.(12) prostatic fluid provides a unique medium for noninvasive evaluation of critical growth and differentiation signals in the prostatic microenvironment. thus we investigated the patients with bph to determine in quantity of biologically active free igf-1 in pf and to compare it in patients with bph and in control patients with no bph. material and methods a total of 35 patients, who have been admitted to our outpatient clinic between may-2008 and may-2009 with lower urinary tract symptoms (luts) and considered to be bph, were included to our study (group-a). patients with diabetes mellitus, prostate cancer, neurologic disease, previous operation due to infravesical obstruction and patients using drugs which affect lower urinary system functions were excluded from study. the control group (group-b) was consisted of patients who were admitted to our outpatient clinic with some other urological problems (urolithiasis, hydrocele, etc.) except luts. all patients were selected prospectively. for all patients, after giving detailed information, written approvals were obtained. detailed histories were taken from all the patients. the patients with diabetes, a prostate operation history and endocrinologic pathology (acromegaly, growth hormone deficiency, etc.) which can influence igf-1 level were not included in the study. luts of each patient were scored by international prostate symptom score (ipss). all patients were performed rectal examination and biochemical, hematological and urine analysis. also serum total and free-psa levels were determined. psa levels above 4.0 ng/ml were considered as “high’’. all patients were evaluated with transrectal ultrasonography (trus) to detect prostatic volume and to perform prostatic needle biopsy, if necessary. as to calculate prostatic volume, ellipsoid formula was used (ellipsoid formula: transverse diameter × anteroposterior diameter × cephalocaudal diameter × 0.52). expressed prostatic fluid samples, following digital massage of the prostate, obtained from 35 patients with bph (group a) and an equal number of male controls were examined microscopically for cellular elements, sperm, and seminal vesicle globules. two pf samples of at least 30 µl each were obtained on separate visits within 7 days. uncontaminated pf samples were immediately placed in a refrigerator freezer and transported on ice to a –20 oc freezer within 4 hr. the mean prostatic fluid volume was approximately 64 µl. prostatic fluid was diluted in a saline-tris-bsa buffer (1/10, v/v) as provided in the kit for free igf-1 (diagnostic systems laboratories inc, free igf-1 dsl-9400, webster, texas, usa). free igf-1 level in pf was measured in duplicated direct assay immunoradiometric (irma) method which was described by miles and colleagues.(13) the irma is a non-competitive assay in which the analytic to be measured is “sandwiched” between two antibodies. the first antibody is immobilized to the inside walls of the tubes. the other antibody is radiolabelled for detection. for the direct assay, the diluted sample was added directly to the assay tube. unbound and readily dissociable igf-1 was then captured by the antibody coating, the remaining sample was washed away, and the igf-1 bound to the tube was then detected 1069vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l using a radiolabelled antibody directed to a second epitope. the absolute sensitivity of the assay used were 0.1 ng/ml for free igf-1 and the usual amounts used for assay were 5 µl of prostatic fluid. serum free igf-1 immunoradioactivity was also measured by using duplicated irma method. the results were expressed as ng/ml. data were analyzed by using the statistical package for social sciences (spss). pearson correlation analysis and student’s t test were used for statistical assessment and considered significant at p < .05. results the mean age of patients with bph was 69.9 ± 1.18 standard error of measurement (sem) and was 62.7 ± 2.41 sem years in those without. the mean total psa value in patients with bph were significantly higher in those without bph but free igf-1 levels in pf and serum free igf-1 contents were similar in both groups (table 1). when compared with control group, mean ipss scores and prostate volumes of bph group were significantly high, while mean qmax, ipss, and qol scores were significantly low (p < .05) (table 2). the mean prostatic fluid free igf-1 level was not correlated with serum psa level (r = 0.11, p = .4). the mean prostate volume was also not correlated with free igf-1 level (r = 0.15, p = .15). discussion peptide growth factors such as igf-1 and igf-2 appear to be potent signaling factors for modulating the growth and differentiation of prostate cells and the growth of normal and malignant prostate cells in culture is dependent on the presence of igf-1 and 2.(14) they are usually bound to an igf-binding proteins which are found abundantly in prostate cells.(1,14) there are two types of receptors for the igfs and the majority of the mitogenic effects of the igfs appear to be mediated via the type 1 igf receptor.(1,15) igf-1 receptors are very sensitive to stimulation by igfs.(16) involvement of the igf axis in bph etiology is biologically plausible. prostate cells express igfs, insulin-like growth factor binding proteins (igfbps), and the type i igf receptor,(17) and prostate cell growth is stimulated by igfs and inhibited by igfbps.(16,18-20) furthermore, men with acromegaly induced gh/igf-i hypersecretion have enlarged prostates, and among acromegalic men with bph, prostate size and igf-i levels were shown to return to normal after treatment.(11) a recent epidemiologic study among scandinavian men revealed a nonsignificant upward trend in bph risk associated with increasing circulating igf-i (p trend¼ .10). (21) however, a study in greek men found no association of igf-i levels with bph.(22) all these studies were concerned with the plasma levels of igf-1. in this population-based study done in turkey, the prostatic fluid levels of free igf-1, which is biologically active form of igf-1, were not associated with a significantly increased risk of bph.(12) the prostatic levels of igf-1 are better indicator than the plasma levels. they reflect the intraprostatic statement of igf-1. it has been also showed that many different factors e.g. smoking, during waking hours, fasting, can alter circulating concentrations of igf-1.(23,24,25) thus, it is possible that circulating levels of igf-1 may be influenced by various factors. in our study, we determined free igf-1 levels in the prostatic fluid table 1. age, free igf-1 and psa levels in distinguishing patients with benign prostatic hyperplasia (group a) from those without (group b). variable* group a (n = 35) group b (n = 35) p age (years) 69.9 ± 1.18 62.7 ± 2.41 .12 serum free igf-1 (nmol/l) 33.8 ± 2.6 31.4 ± 2.6 .21 prostatic fluid free igf-1(µg/l) 1.43 ± 0.02 1.38 ± 0.02 .23 serum psa (ng/ml) 3.8 ± 0.23 1.74 ± 0.14 .71 key: igf, insulin-like growth factor; psa, prostate specific antigen; * variables are presented as mean ± standard error of measurement. table 2. the statistical correlation between qol, ipss, peak urine flow rate, and prostate volume through trus, in group a and group b. variable* group a (n = 35) group b (n = 35) p prostate volume (ml) 44 ± 2.4 22 ± 1.6 .034 maximum flow (ml/s) 13.0 ± 4.6 20.0 ± 5.4 .041 ipss total 20.0 ± 1.7 12.6 ± 4.3 .041 ipss qol 1.5 ± 0.7 3.2 ± 0.4 .024 key: qol, quality of life; ipss, international prostate symptom score; trus, transrectal ultrasonography. * variables are presented as mean ± standard error of measurement. free igf-1 in bph | ceylan et al 1070 | which is responsible for the biological function of the igf-1. the prostatic fluid levels of free igf-1 were not significantly associated with increased risk of bph. this is the first report showing the expression of free igf-1 in prostatic fluids of bph patients. however, larger prospective studies are needed to confirm our findings for free igf-1 and bph risk. conclusion our results showed that free igf-1 can be accurately measured in prostatic fluid by radio immunoassay. its levels were detectable in serum and pf samples. the mean prostate volume was not correlated with free igf-1 level. the findings currently reveal the prostatic fluid level of this marker is not differed in patients with bph in comparison to non-bph individuals. the mean prostate volume was not correlated with free igf-1 level. conflict of interest none declared. references 1. byrne rl, leung h, neal de. peptide growth factors in the prostate as mediators of stromal epithelial interaction. br j urol. 1996;77:62733. 2. baserga r,resnicoff m, d’ambrosio c, valenitis b. the role of the igf1 receptor in apoptosis. vitam horm. 1997;53:65-98. 3. hirscberg r. insulin-like growth factor in the kidney. miner electrolyte metab. 1996;22:128-32. 4. bereket a, lang ch, blethen sl, kaskel fj, stewart c, wilson ta. growth hormone treatment in growth retarded children with end stage renal failure: effect on free/dissociable igf-i levels. j pediatr endocrinol metab. 1997;10:197-202. 5. juul a, holm k, kastrup kw, pedersen sa, et al. free insulin-like growth factor i serum levels in 1430 healthy children and adults, and its diagnostic value in patients suspected of growth hormone deficiency. j clin endocrinol metab. 1997;82:2497-502. 6. zapf j, hauri c, waldvogel m, froesch er. acute metabolic effects and half-lives of intravenously administered insulin like growth factors i and ii in normal and hypophysectomized rats. j clin invest. 1986;77:1768-75. 7. guler hp, zapf j, froesch er. short-term metabolic effects of recombinant human insulin-like growth factor i in healthy adults. n engl j med. 1987;16:137-40. 8. grimberg a, cohen p. role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. j cell physiol. 2000;183:1-9. 9. monti s, di silverio f, iraci r, et al. regional variations of insulin-like growth factor i (igf-i), igf-ii, and receptor type i in benign prostatic hyperplasia tissue and their correlation with intraprostatic androgens. j clin endocrinol metab. 2001;86:1700-06. 10. cohen p, peehl dm, baker b, liu f, hintz rl, rosenfeld rg. insulinlike growth factor axis abnormalities in prostatic stromal cells from patients with benign prostatic hyperplasia. j clin endocrinol metab. 1994;79:1410–15. 11. colao a, marzullo p, spiezia s, et al. effect of two years of growth hormone and insulin-like growth factor-i suppression on prostate diseases in acromegalic patients. j clin endocrinol metab. 2000;85:3754-61. 12. perk h, serel ta, delibaş n, sütçü r. prostatic fluid-free insulin-like growth factor-1 in relation to prostate cancer. bju int. 2001;88:9469. 13. miles lem, lipschitz da, bieber cp, cook jd. measurement of serum ferritin by a 2-site immunoradiometric assay. analyt biochem. 1974;61:209-24. 14. grant es, ross mb, ballard s, naylor a, habib fk. the insulin-like growth factor type i receptor stimulates growth and suppresses apoptosis in prostatic stromal cells. j clin endocrinol metab. 1998;83:3252-7. 15. shimasaki s, ling n. identification and molecular characterisation of insulin-like growth factor binding proteins. prog growth factor res. 1991;3:243-66. 16. cohen p, peehl dm, lamson g, rosenfeld rg. insulin-like growth factors, igf receptors and igf binding proteins in primary culture of prostate epithelial cells. j clin endocrinol metab. 1991;73:401-7. 17. yu h, rohan t. role of the insulin-like growth factor family in cancer development and progression. j natl cancer inst. 2000;92:1472-89. 18. torring n, vinter-jensen l, pedersen sb, sorensen fb, flyvbjerg a, nexo e. systemic administration of insulin-like growth factor i (igfi) causes growth of the rat prostate. j urol. 1997;158:222-27. 19. rajah r, valentinis b, cohen p. insulin-like growth factor (igf) binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53and igf-independent mechanism. j biol chem. 1997;272:12181-8. 20. monti s, di silverio f, lanzara s, et al. insulin-like growth factor-i and -ii in human benign prostatic hyperplasia: relationship with binding proteins 2 and 3 and androgens. steroids. 1998; 63:362–66. 21. stattin p, kaaks r, riboli e, ferrari p, dechaud h, hallmans g. circulating insulin-like growth factor-i and benign prostatic hyperplasia: a prospective study. scand j urol nephrol. 2001;35:122-26. 22. mantzoros cs, tzonou a, signorello lb, stampfer m, trichopoulos d, adami ho. insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. br j cancer. 1997;76:1115-18. 23. juul a, bang p, hertel nt. serum insulin-like growth factor-1 in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. j clin endocrinol metab. 1994;78:744-52. cellular and molecular urology 1071vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l free igf-1 in bph | ceylan et al 24. juul a, main k, blum wf, lindholm j, ranke mb, skakkebaek ne. the ratio between serum levels of insulin-like growth factor (igf)-1 and the igf binding proteins (igfbp-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients. clin endocrinol. 1994;41:85-93. 25. goodman-gruen d, barrett-conor e. epidemiology of insulin-like growth factor-1 in elderly men and women. the rancho bernardo study. am j epidemiol. 1997;145:970-6. case reports 245urology journal vol 4 no 4 autumn 2007 syphilitic elephantiasis of penis and scrotum konstantinos n stamatiou,1 christos karakos,1 vasilissa karanasiou,1 vaios papadimitriou,2 frank sofras3 urol j. 2007;4:245-7. www.uj.unrc.ir keywords: sexually transmitted diseases, syphilis, elephantiasis 1department of urology, general hospital of thebes, university of crete school of medicine, thebes, greece 2department of urology, university of crete school of medicine, heracleion, greece 3department of urology, university of crete school of medicine, crete, greece corresponding author: stamatiou konstantinos, md 4 salepoula st, 18536 piraeus, greece tel: +30 210 452 6651 fax: +30 210 429 6987 e-mail: stamatiouk@gmail.com received march 2007 accepted august 2007 introduction syphilis is normally manifested 2 weeks after sexual exposure with the characteristic painless penile sore. the infection rapidly progresses to the secondary stage unless adequate treatment is administered. the secondary stage is characterized by the appearance of rashes in which the infection overwhelms the body. systematic symptoms such as fever, swollen lymph nodes, sore throat, patchy hair loss, headache, weight loss, muscle ache, and fatigue may also appear.(1) if left untreated, secondary stage progresses to the tertiary stage. syphilis has often been called “the great imitator” because many of its signs and symptoms are indistinguishable from those of other diseases.(2) many people infected with syphilis do not have any symptoms for years. in addition, the long incubation period of the disease (between 10 and 90 days) makes the diagnostic process difficult. although enlargement of inguinal lymph nodes is often detected, coexistent penoscrotal elephantiasis is rather rare.(3) we present a man with penoscrotal elephantiasis and mild enlargement of the inguinal lymph nodes. case report a 15-year-old male romanian immigrant presented with fever (38.5°c), acute penoscrotal edema, arthralgia, and malaise in the absence of symptoms and signs of lower urinary tract infection. clinical examination revealed few brown spots in the inguinal folds. elephantiasis of the scrotum was present with the smooth and soft overlying skin, while both testes were normal (figure 1). the penis was solidified and twisted. although there was no obvious inguinal lymphadenopathy, figure 1. penoscrotal elephantiasis is shown at the day of presentation. syphilitic elephantiasis of penis and scrotum—stamatiou et al 246 urology journal vol 4 no 4 autumn 2007 the inguinal lymph nodes were palpable and slightly painful. digital rectal examination of the prostate was normal. examination of the penis revealed a single genital ulcer. the patient reported an unprotected sexual contact 1 month earlier, but he denied any history of preceding urethritis. there was no history of bladder outlet obstruction and rectal discharge. laboratory investigations revealed an elevation of white blood cell count (14.5 × 109/l, granulocytes 81%) and a mild eosinophilia (4.8%). other laboratory results were as follows: blood hemoglobin, 12.5 g/dl; hematocrit, 37.5%; and red blood cell count, 4.26 × 109/l). total serum protein, albumin-globulin ratio, and blood glucose were also normal. chest radiography and abdominal ultrasonography did not reveal any abnormality. the patient was seronegative for human immunodeficiency virus. the repeated midnight peripheral blood smears, after provocation by a 100mg tablet of diethyl carbamazine, were negative for microfilariae. the venereal disease research laboratory and the fluorescent treponemal antibody absorption tests were both positive. darkfield microscopic examination of chancre smear was performed in order to confirm the diagnosis of syphilis. after confirming the diagnosis, intramuscular benzathine penicillin g, 1 liter of intravenous fluid per day, paracetamol with the intramuscular dose of 1g, and oral serratiopeptidase were administered. all symptoms disappeared within 3 days (figure 2). discussion although it has been nearly a quarter of a century since the incidence of syphilis is dramatically reduced (accounting now for less than 2.5 per 100 000 people), syphilis still remains a diagnostic challenge.(4) of the three stages of the disease recognized, the primary stage of syphilis, marked by the appearance of a single or multiple chancres in the genital region can occur silently. indeed, chancres are usually small and painless, and they heal without treatment.(5) in contrast, the secondary stage is manifested with both systematic symptoms and development of the rashes.(1) the characteristic rash of secondary syphilis may appear as rough, red, or reddish brown spots.(6) these rashes usually appear on the palmar or plantar regions as the chancre is healing. however, in many cases, the characteristic sores are unrecognized, while rashes appear several weeks after the chancre has healed. rarely, rashes with a different appearance may occur on other parts of the body, independently to the presence of typical rashes of secondary syphilis. sometimes rashes associated with secondary syphilis are so faint that they are not noticed and in some cases there are no rashes at all. on the other hand, systematic symptoms could be misdiagnosed in the absence of evident cutaneous lesions. indeed, many of the signs and symptoms of syphilis are indistinguishable from those of other diseases.(2) penoscrotal elephantiasis is a very rare manifestation of syphilis, which probably appears as a result of the enlargement of the lymph nodes and lymphatic flow obstruction caused by the infection of the genitalia.(3) although the incidence of syphilis has been dramatically declined, physicians, especially younger ones, should be familiarized with this important sexually transmitted disease. in conclusion, syphilis should be considered in the differential diagnosis of the patients with systematic symptoms accompanied with penoscrotal elephantiasis and a painless genital ulcer. conflict of interest none declared. references 1. krause w. [syphilis]. urologe a. 2006;45:1494-500. german. 2. arfan-ul-bari, mehmood t, khan b, malik n, malik kz, figure 2. penoscrotal elephantiasis 3 days after treatment is shown. syphilitic elephantiasis of penis and scrotum—stamatiou et al urology journal vol 4 no 4 autumn 2007 247 sukhera am. secondary syphilis presenting as vertigo. j coll physicians surg pak. 2006;16:727-8. 3. elsahy ni. syphilitic elephantiasis of the penis and scrotum. plast reconstr surg. 1976;57:601-3. 4. groseclose sl, brathwaite ws, hall pa, et al; centers for disease control and prevention. summary of notifiable diseases--united states, 2002. mmwr morb mortal wkly rep. 2004;51:1-84. 5. janier m, dupin n, gerhardt p, schmutz jl, timsit fj, verraes-derancourt s; section mst de la sfd. [early syphilis]. ann dermatol venereol. 2006;133:2s192s23. french. 6. lautenschlager s. cutaneous manifestations of syphilis: recognition and management. am j clin dermatol. 2006;7:291-304. v08_no_2_final.pdf miscellaneous 145urology journal vol 8 no 2 spring 2011 double ureter and duplex system a cadaver and radiological study prakash,1 thimmiah rajini,1 jayanthi venkatiah,1 ajay kumar bhardwaj,2 deepak kumar singh,3 gajendra singh4 purpose: to study the prevalence of duplex system and double ureter in cadavers and intravenous pyelograms in indian population. materials and methods: fifty cadavers were dissected and 50 intravenous pyelograms were examined on both (right and left) sides for the presence of duplex system and double ureter. results: one male cadaver aged 43 years showed complete double ureter and duplex system on the right side and incomplete double ureter and duplex system on the left side. another male cadaver aged 56 years showed incomplete double ureter and duplex system only on the right side. an intravenous pyelogram of a 43-year-old man showed incomplete double ureter along with duplex system on the right side. conclusion: developmental anomalies of the kidney, ureter, and urinary bladder should be kept in mind and promptly detected before the manifestations of aforementioned complications increase the morbidity of the affected individuals. urol j. 2011;8:145-8. www.uj.unrc.ir keywords: ureter, cadaver, anatomy, dissection 1department of anatomy, vydehi institute of medical sciences and research center, whitefield, bangalore, karnataka, india 2department of ophthalmology, katihar medical college, katihar, bihar, india 3department of biophysics, santosh medical college, ghaziabad, up, india 4department of anatomy, institute of medical sciences, banaras hindu university, varanasi u.p., india corresponding author: prakash, md department of anatomy, vydehi institute of medical sciences and research center, whitefield, bangalore, karnataka, india, 560066 tel: +91 948 022 9670 e-mail: prakashrinku@rediffmail.com received march 2010 accepted january 2011 introduction underlying embryological basis can be explained as development of two ureteral buds separately from a single mesonephric duct give rise to a duplex kidney with complete ureteral duplication. on the other hand, bifurcation of a single ureteral bud proximal to the ampulla (distal dilated part) gives rise to a duplex kidney with a bifid pelvis or ureter.(1) double ureter, with the prevalence of 0.1% to 3%,(2,3) has been reported by various authors.(1,4-8) duplex system is explained as the kidney with two pyelocaliceal systems, which may have either single or bifid ureter (partial duplication) or double ureter draining separately into the urinary bladder (complete duplication), with a single renal parenchyma that is drained by two pyelocaliceal systems.(9) double ureter and duplex system reported in the literature time and again have potential for future complications, such as the collecting system obstruction, lithiasis, ureterocele, and vesicoureteral reflux.(10-16) hence, their early detection may be helpful in better management and increased survival rates. lee and colleagues through three-dimensional reconstructed computed tomography urography demonstrated that duplicated ureters on the right side joined at the upper proximal part of the double ureter and duplex system—prakash et el 146 urology journal vol 8 no 2 spring 2011 ureter and duplicated ureters on the left side put together just above the ureterovesical junction.(17) sun and associates presented one case of blindending bifid ureter originating from the middle third of the ureter.(18) reported ureteral duplication with coexistent uterine myoma and colon adenocarcinoma in a young woman.(19) a case of double ureter and renal pelvis associated with double superior vena cava has been reported earlier.(3) sufficient information is lacking regarding study of duplex system and double ureter in indian population. cadaver study is important and relevant even in modern era of imaging techniques. hence, present study was performed to study the prevalence of duplex system and double ureter in cadavers and intravenous pyelograms in indian population. materials and methods properly embalmed and formalin-fixed cadavers were selected for the present study. fifty cadavers, 38 men and 12 women, with the age range of 19 to 74 years, were dissected in the abdomen region. skin incision was followed by fascia (superficial and deep) and muscles to expose the kidney, ureter, and urinary bladder. each cadaver was examined on both (right and left) sides for the presence of duplex system and double ureter. fifty intravenous pyelograms (29 men and 21 women, in the age range of 16 to 65 years) collected from the radio-diagnosis department of our institute were studied for presence of double ureter and duplex system. results double ureter and duplex system were seen in a male cadaver aged 43 years (figure 1). on the right side of the cadaver, the ureter draining the upper pole opened in the urinary bladder inferior and medial to the opening of the ureter draining the lower pole of the kidney. on the contrary, incomplete double ureter (y-shaped), which joined in the middle of the duplex system was present on the left side of the aforementioned cadaver. the y-shaped incomplete ureter on the left side was opening through a single opening on figures 2 and 3. incomplete double ureter (y-shaped) in a male cadaver, which joined in the middle of the duplex system only on the right side. rk, indicates right kidney; ivc, inferior vena cava; ao, abdominal aorta; du, double ureter; and ru, right ureter. figure 1. double ureter and duplex system are seen in a male cadaver. rk, indicates right kidney; lk, left kidney; ivc, inferior vena cava; ao, abdominal aorta; du, double ureter; lu, left ureter, ru, right ureter; and ub, urinary bladder. double ureter and duplex system—prakash et el 147urology journal vol 8 no 2 spring 2011 the posterior surface of the urinary bladder. another male cadaver aged 56 years showed incomplete double ureter (y-shaped), which joined in the middle of the duplex system only on the right side (figures 2 and 3). in the remaining 48 cadavers, single ureter and collecting system were present on both the right and left sides. an intravenous pyelogram of a 43-year-old man showed incomplete double ureter along with duplex system on the right side (figure 4). discussion ureteral bud develops as an outgrowth from the mesonephric duct and ascends with increase in vertical length till it fuses with metanephric blastoma, which gives rise to future adult ureter and kidney.(1) sun and colleagues suggested that if two ureteral buds form and one fails to contact with the metanephrogenic blastema, the blindending bifid ureter with double ureteral orifices presents.(18) according to dähnert, the prevalence of partial duplication of the ureter is three times more than complete duplication of the ureters as found on urograms.(2) of 50 studied intravenous pyelograms in our study, incomplete duplication was observed on the right side of one subject. on the other hand, of 50 cadavers in our study, complete duplication of the ureter was observed on the right side of one cadaver. furthermore, partial duplication was observed on the right side of one cadaver and left side of another one. dähnert reported that occurrence of complete duplication in first-degree relatives of a patient with complete duplication of the ureters is sixty times more likely.(2) reported that ureteral duplication may be genetically determined by an autosomal dominant trait with incomplete penetrance.(19) on the contrary, bruno and colleagues opined that ureteropelvic obstruction is more common when a duplex kidney exists and can be inherited as an autosomal dominant pattern.(20) in approximately 85% of subjects with complete double ureters, according to weigert-meyer rule, the orifices of the ureters draining the upper pole open inferior and medial to the orifice draining the lower pole of the kidney. the same finding was observed in our study. in a duplex kidney drained by double ureter, the lower pole system is dominant in majority of the individuals; and hence the lower moiety is more frequently affected in pelvic-ureteric junction obstruction as compared to the upper moiety.(8) a duplex kidney with ureterocele can be associated with vesicoureteral reflux in the lower pole of the duplex system.(21) ureteropelvic junction obstruction can be associated with anomalies of the renal system.(22) vesicoureteral obstruction reflux involving the lower pole in a duplex system usually results from maldevelopment of the valve mechanisms. on the other hand, stenosis of the upper pole ureteral orifice results in hydronephrosis involving the upper pole of the duplex system. mahajan and associates suggested that a duplex renal system associated with massive dilatation of the upper pole moiety may result from either vesicoureteral reflux or error in development.(23) figure 4. an intravenous pyelogram of a 43-year-old man with incomplete double ureter along with duplex system on the right side. rk, indicates right kidney; du, double ureter; and ru, right ureter. double ureter and duplex system—prakash et el 148 urology journal vol 8 no 2 spring 2011 conclusion developmental anomalies of the kidney, ureter, and urinary bladder should be kept in mind and promptly detected before the manifestations of aforementioned complications increase the morbidity of the affected individuals. conflict of interest none declared. references 1. dalla palma l, bazzocchi m, cressa c, tommasini g. radiological anatomy of the kidney revisited. br j radiol. 1990;63:680-90. 2. dähnert w. radiology review manual. 6 ed. philadelphia: lipincott williams wilkins; 2007. 3. tohno s, azuma c, tohno y, et al. a case of double renal pelves and ureters associated with double superior venae cavae. j nara med assoc. 2008183-7. 4. braga lh, moriya k, el-hout y, farhat wa. ureteral duplication with lower pole ureteropelvic junction obstruction: laparoscopic pyeloureterostomy as alternative to open approach in children. urology. 2009;73:374-6; discussion 6. 5. ochoa urdangarain o, hermida perez ja, montes de oca jo, miranda rosales f, rivero garcia c. [complete triple ureter. case report]. arch esp urol. 2006;59:284-7. 6. dominici a, travaglini f, maleci m, di cello v, rizzo m. giant stone in a complete duplex ureter with ureterocele. a case report. urol int. 2003;71:336-7. 7. lackgren g, wahlin n, skoldenberg e, neveus t, stenberg a. endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid copolymer is effective in either double ureters or a small kidney. j urol. 2003;170:1551-5; discussion 5. 8. horst m, smith gh. pelvi-ureteric junction obstruction in duplex kidneys. bju int. 2008;101:1580-4. 9. glassberg ki, braren v, duckett jw, et al. suggested terminology for duplex systems, ectopic ureters and ureteroceles. j urol. 1984;132:1153-4. 10. chacko jk, koyle ma, mingin gc, furness pd, 3rd. ipsilateral ureteroureterostomy in the surgical management of the severely dilated ureter in ureteral duplication. j urol. 2007;178:1689-92. 11. chertin b, mohanan n, farkas a, puri p. endoscopic treatment of vesicoureteral reflux associated with ureterocele. j urol. 2007;178:1594-7. 12. lebowitz rl, avni fe. misleading appearances in pediatric uroradiology. pediatr radiol. 1980;10:15-31. 13. morgan cl, grossman h, trought ws, oddson ta. ultrasonic diagnosis of obstructed renal duplication and ureterocele. south med j. 1980;73:1016-9. 14. avni fe, nicaise n, hall m, et al. the role of mr imaging for the assessment of complicated duplex kidneys in children: preliminary report. pediatr radiol. 2001;31:215-23. 15. wu f, snow b, taylor a, jr. potential pitfall of dmsa scintigraphy in patients with ureteral duplication. j nucl med. 1986;27:1154-6. 16. raman ss, pojchamarnwiputh s, muangsomboon k, schulam pg, gritsch ha, lu ds. surgically relevant normal and variant renal parenchymal and vascular anatomy in preoperative 16-mdct evaluation of potential laparoscopic renal donors. ajr am j roentgenol. 2007;188:105-14. 17. lee s, kim w, kang kp, et al. bilateral incomplete double ureters. nephrol dial transplant. 2007;22:2720-1. 18. sun mh, kung kl, tsai hm, lin ym. blindending bifid ureter and its embryological correlation: a case report. chin j radiol. 2002;27:263-6. coexistent uterine myoma, colon adenocarcinoma 20. bruno d, delvecchio fc, preminger gm. successful management of lower-pole moiety ureteropelvic junction obstruction in a partially duplicated collecting system using minimally invasive retrograde endoscopic techniques. j endourol. 2000;14:727-30. 21. calisti a, oriolo l, pisera a, perrotta ml, miele v. [ureterocele associated to duplex system: an individualized approach to endoscopic incision]. minerva pediatr. 2002;54:449-53. 22. modi p, goel r, rizvi sj. case report: laparoscopic pyeloplasty for ureteropelvic junction obstruction of lower moiety in duplex system. j endourol. 2007;21:1037-40. 23. mahajan nn, sahay s, kale a, nasre m. unilateral upper-pole giant hydroureter in a duplex renal system: an incidental finding in cesarean section. arch gynecol obstet. 2008;278:149-51. 430 | introduction a variety of urethral foreign bodies (ufbs) have been reported in the lit-erature; however, it is a rare clinical finding.(1-6) most of the ufbs tend to be self-inserted because of sexual or erotic reasons.(2) presentation is usually with dysuria, poor urinary stream, swelling of external genitalia, urethral discharge, or urinary tract infection. late presentation may be with complications, such as hematuria, periurethral abscess, vesical calculi, urethral calculi, stricture or diverticulum, incontinence, or erectile dysfunction. urethral fistula development due to a ufb is a rare reporting.(1,2) case report a 38-year-old man presented with urine leak from an opening in the perineum near the base of the scrotum every time he voids. local examination revealed a urethrocutaneous fistula in the perineum through which an end of a gold chain was seen coming out. on careful history taking, the patient admitted self-insertion of gold chain while masturbating 18 months earlier. but when he tried to remove the chain, it got stuck in; hence, he left it there for some days. thereafter, he cut the segment of the chain that was lying outside through the urethral meatus, and thus the chain was lost in the urethra. he had intermittent burning micturition and only mild discomfort since then. he did not seek any medical advice. about one month back, he noticed an opening in the perineum and urine leakage through it while voiding. a 2-cm segment of the gold chain came out through it, but when the patient tried to remove onkar singh,1 shilpi singh gupta2 urethral foreign body causing urethral fistula corresponding author: onkar singh, mbbs, ms vpo, sangowal, tehsil, nakodar, distt, jalandhar, 144041, punjab, india tel: +91 989 377 7321 e-mail: dronkarsingh@ gmail.com received december 2009 accepted january 2010 1 department of urology, bhopal memorial hospital & research center, madhya pradesh, bhopal, 462038, india 2 department of surgery, gandhi medical college & hospital, bhopal, madhya pradesh, india case report case report 431vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l the chain by pulling it out, it got stuck again with a small segment hanging out through the perineal opening (figure). plain radiography showed that the distal end of the chain was lying in the penile urethra about 4 cm from the urethral meatus. it was the proximal end of the chain, which had come out through urethroperineal fistula. chain could not be removed by gentle traction on its visible proximal end. cystoscopy was done under local anesthesia and damaged distal end of the gold chain was seen in the penile urethra. chain was easily removed by holding it with a forceps. a foley catheter was placed in situ. he was given oral antibiotics. fistula healed in 15 days, but the catheter was kept for few more days and removed on the 21st day. he voided well and was discharged from the hospital. at 6 months follow-up, he had normal urine flow without obstructive symptoms. discussion urethral foreign bodies include objects of various types, shapes, and sizes, and thus pose a challenge to the urosurgeons.(1-6) these are usually self-inserted and the most common motive associated with the insertion of foreign bodies into the genitourinary tract is a sexual or erotic reason in nature.(2) in adults, this is commonly caused by the insertion of objects used for masturbation and is frequently associated with mental health disorders.(3) reporting their experience with self-inserted urethral foreign bodies in 17 men, rahman and colleagues found that the most important cause was psychiatric disorder, followed by intoxication and erotic stimulation. the most frequent symptom was frequency with dysuria. diagnosis was made by plain radiography in 14 patients while 3 needed computed tomography scan. sixteen were treated successfully by endoscopic retrieval.(1) in an excellent review of published literature between 1755 and 1999, van ophoven and dekernion found that sexual or erotic cause had been the most common etiology, and recommended that whenever possible, endoscopic techniques of retrieval should be used; however, surgical retrieval may be required if severe inflammation is present. they also concluded that the most suitable method of removing a ufb depends on the size and mobility of the object.(2) the most frequent complications of ufb are urethritis, urethral tear with periurethral abscess and/ or fistula, and hemorrhage.(1,7) urethral fistula secondary to ufb, as occurred in the present case, has been rarely reported. it may occur as a result of rupture of an already existing periurethral abscess.(7) majority of the patients with ufb, like ours, are ashamed to admit selfinsertion and the history is often difficult to obtain. unexplained urethral fistula and/or scrotal abscess should point towards the possibility of ufb.(7) once a ufb is suspected or palpated externally, evaluation should be done to know the exact size, location, and number of foreign bodies.(1) plain xray or ultrasonography usually provide sufficient information required to plan the intervention; computed tomography scan is being needed rarely.(2,8) most ufbs often require urgent interventions. the a segment of a gold chain coming out through a urethral fistula in the perineum urethral foreign body causing urethral fistula | singh and gupta 432 | aim is to remove the ufb with minimal trauma to the urethra and avoid compromise of erectile function. the most effective technique to remove or retrieve a ufb depends on the size, type, location, and mobility of ufb.(1,2,4) various methods of removal described in the literature include meatotomy, cystoscopy, internal or external urethrotomy, suprapubic cystotomy, fogarty catheterization, and injection of solvents.(1,2,4) endoscopic removal of these foreign bodies is often considered the treatment of choice that may require a grasper, stone retrieval baskets, snares, or some modified instruments.(1,4) a urethral fistula secondary to a ufb can also be managed by endoscopic removal of the ufb, along with drainage of periurethral abscess if present, control of infection with appropriate antibiotics, and foley catheterization while allowing the fistula to heal spontaneously. in difficult or non-healing cases, fistulectomy and suprapubic cystostomy become necessary.(7) needless to say that the patient should be referred for psychiatric evaluation.(5) our patient was treated by urethroscopic extraction of the gold chain followed by foley catheterization for 21 days, and antibiotics. we referred the patient for psychiatric evaluation, but he refused. conflict of interest none declared. references 1. rahman nu, elliott sp, mcaninch jw. self-inflicted male urethral foreign body insertion: endoscopic management and complications. bju int. 2004;94:1051-3. 2. van ophoven a, dekernion jb. clinical management of foreign bodies of the genitourinary tract. j urol. 2000;164:27487. 3. garcia riestra v, vareal salgado m, fernandez garcia l. [urethral foreign bodies. apropos 2 cases]. arch esp urol. 1999;52:74-6. 4. gonzalgo ml, chan dy. endoscopic basket extraction of a urethral foreign body. urology. 2003;62:352. 5. costa g, di tonno f, capodieci s, laurini l, casagrande r, lavelli d. self-introduction of foreign bodies into the urethra: a multidisciplinary problem. int urol nephrol. 1993;25:77-81. 6. osca jm, broseta e, server g, ruiz jl, gallego j, jimenezcruz jf. unusual foreign bodies in the urethra and bladder. br j urol. 1991;68:510-2. 7. ali khan s, kaiser cw, dailey b, krane r. unusual foreign body in the urethra. urol int. 1984;39:184-6. 8. barzilai m, cohen i, stein a. sonographic detection of a foreign body in the urethra and urinary bladder. urol int. 2000;64:178-80. case report 981vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l 1molecular genetics department, faculty of biological science, tarbiat modares university, tehran, iran 2urology and nephrology research center, labbafi-nejad medical center, shahid beheshti university of medical science, tehran, iran 3cellular and molecular research center, ahvaz jundishapour university of medical science, ahvaz, iran 4parsgenome company, tehran, iran 5genetic research center, baqiyatallah university of medical sciences, tehran, iran hamideh monfared,1 seyed amir mohsen ziaee,2 mahmoud hashemitabar,3 hamid khayatzadeh,1 vahid kheyrollahi,1,4 mahmood tavallaei,5 seyed javad mowla1 co-regulated expression of tgf-β variants and mir-21 in bladder cancer corresponding author: seyed javad mowla, phd molecular genetics department, faculty of biological science, tarbiat modares university, tehran, iran tel: +98 21 82883464 fax: +98 21 82884717 e-mail: sjmowla@modares.ac.ir received may 2012 accepted june 2013 purpose: to investigate a potential alteration in the expression levels of transforming growth factor β (tgf-β) and mir-21 in bladder cancer tissues. material and methods: using real-time polymerase chain reaction (pcr) method, we examined a potential correlated expression of mir-21 and tgf-β variants in 30 bladder tumors and their marginal/non-tumor biopsy specimens obtained from the same patients. results: our data revealed a significant down-regulation of tgf-β variants (p = .03) along with a non-significant alteration in the expression of mir-21 in tumor vs. non-tumor samples. however, in contrast to low-grade tumors, the expression of mir-21 was upregulated in high-grade ones, and the expression level can efficiently discriminate low-grade tumors from high-grade ones (p = .03). conclusion: in accordance to the observed similarity between tgf-β variants and mir-21 gene expression alterations in bladder tumors, treating 5637 bladder cancer cell line with tgf-β recombinant protein caused a significant upregulation of mir-21. the later finding further confirmed a correlated expression of tgf-β and mir-21 in bladder tumors. keywords: biological markers; analysis; urinary bladder neoplasms; mir-21; tgf-β; gene expression profiling cellular and molecular urology 982 | introduction recently, several high-throughput studies have fo-cused on delineating genomic changes and gene expression alterations in bladder cancer, in hope to find novel markers correlated to different grades and stages of the tumors.(1) the recent studies have also documented a link between the expression of micrornas (mirnas or mirs) and cancer pathogenesis. mirnas are a class of noncoding rna molecules with 19–24 nucleotides in length. they contribute to cancer initiation and progression, and are differentially expressed in normal and tumor tissues.(2) mirnas exert their effects by silencing the expression of their target mrnas via a perfect and/or an imperfect complementary base-pairing, causing either mrna degradation or translational inhibition.(3) almost 50% of human mirna genes are located in fragile chromosomal regions, which are frequently amplified, deleted, or translocated in various cancers.(4) based on accumulating data, some mirnas can function as either tumor suppressors or oncogenes.(5,6) deregulations of mirna expression have been already reported for several human cancers. for example, elevated expression of mir-21 has been implicated in the acquisition of invasive and metastatic properties of human cancer cells. mir-21 functions as an oncomir, by targeting multiple tumor suppressor genes such as: pten, pdcd4, tpm1, and maspin.(7,8) likewise, overexpression of mir-21 is linked to higher stages and lymph node metastasis in human breast cancer.(9) mirna's biogenesis begins with the transcription of its gene, followed with the maturation of the primary transcript (primirna) into a hair-pin structure (pre-mirna), and then processing of a ~20-24 nucleotides mature form. based on a recent report, mir-21 was rapidly induced by the growth factors bone morphogenetic protein-4 (bmp-4) and transforming growth factor-β (tgf-β) in vascular smooth muscle cells. (10) these factors induced a rapid elevation of mature mir-21, by enhancing the processing of primary transcripts of mir21 (pri-mir-21) into its precursor form (pre-mir-21).(10) the later finding suggests that the autocrine tgf-β signaling can contribute to an altered expression of mir-21 in cancer cells. tgf-β, a family of multifunctional homodimeric polypeptides, has three different isoforms in mammalian cells: tgf-β1, tgf-β2, and tgf-β3. the 25-kda mature forms of all isoforms are structurally and functionally similar.(11) this family of cytokines can regulate cell growth, differentiation, inflammatory responses, apoptosis and extracellular matrix (ecm) production.(12) because of its potent anti-proliferative effects on many cell types, such as endothelial and epithelial cells, tgf-β1 is regarded as a tumor suppressor gene.(11) however, an unexpected overexpression of tgf-β has been described in several tumor tissues, which demonstrated to be associated with the tumor progression and metastasis.(13-16) in the present study, we employed a quantitative real-time polymerase chain reaction (pcr) method to investigate whether the expression level of tgf-β variants is altered in bladder tumor tissues. we also measured the expression level of mature mir-21, a direct target of tgf-β, in tumor and non-tumor specimens of bladder. we then investigated the possibility of any correlation between tgf-β and mir-21 expression levels in bladder cancer tissues. material and methods table 1. clinicopathological characteristics of patients with bladder cancer variables value. number of patients 30 age groups, years 30-60 10 61-90 20 mean age at diagnosis, year 63.8 gender male 28 female 2 number of specimens tumor 30 non-tumor 30 tumor stage at diagnosis pt a -pt 1 26 pt 2 -pt 3 3 cis 1 tumor grade at diagnosis high grade 10 low grade 20 cellular and molecular urology 983vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l patients and clinical samples thirty pairs of human tumor and non-tumor (apparently normal tissue biopsy from the same patients) specimens of bladder were obtained from labbafi-nejad hospital in tehran, iran. the samples had been immediately snap-frozen in liquid nitrogen and had been stored in -70ºc, until being used for rna extraction. for each patient, the clinicopathological information including: gender, age, grade, and stage of tumors were gathered (table 1). the experimental procedure was approved by the ethical committee of tarbiat modares university. cell culture the 5637 bladder cancer cell line was obtained from the national cell bank of iran (pasteur institute of iran, tehran) and was cultured in rpmi-1640 (gibco, usa) medium, supplemented with penicillin/streptomycin (100 u/ml and 100 µg/ ml, respectively) and 10% fetal bovine serum (fbs), at 37°c in a humidified atmosphere of 5% co2. after reaching to a confluency of 70-80%, cells were treated with 400 µm/ml of tgf-β recombinant protein (peprotech, usa) for different time-points. the cells were then lysed for rna extraction and performance of real-time pcr. rna extraction and real-time pcr total rna was isolated from the homogenized cell culture or tissue specimens; using trizol solution (invitrogen, usa), according to the manufacturer’s instructions. the 260/280 absorbance ratio was determined by the nano drop nd-100 spectrometer (nano drop technologies, wilmington, de). rnase-free dnase (takara, japan) treatment of the total rna was performed to eliminate any potential contamination with genomic dna. cdna synthesis was carried out by using two commercial kits: “universal cdna synthesis kit” (exiqon, denmark) for mir-21 cdna synthesis, and “primescripttm 1st strand cdna synthesis kit” (takara, japan) for tgf-β cdna synthesis. for mir-21 amplification, the real-time pcr reactions were performed using 8µl of diluted cdna(20x) products, mir21 lna™ primers (exiqon, denmark), and sybr premix ex taq ii (perfect real time) (takara, japan), according to the manufacturer’s protocol. the pcr reactions were conducted at 95˚c for 30 seconds, followed by 40 cycles of 95˚c for 10 seconds, and 60˚c for 1 minute, in an abi 7500 real-time quantitative pcr system (applied biosystems, usa). u6 snrna gene was used as a housekeeping internal control. all real-time pcr reactions were done in duplicates. to minimize the data variation in separate runs, paired tumor and non-tumor samples from the same patient were always examined on the same runs. to amplify tgf-β variants, the real-time pcr reactions were performed using 2µl of cdna products, specific primers for each variant (table 2), sybr premix ex taq ii (perfect real time) (takara, japan), and the abi 7500 real-time quantitative pcr instrument. the specific primers for tgf-β variants as well as gapdh (as an internal control) were designed by gene runner software, version 3.5 (hastings software, new york, usa), and synthesized by tag company (copenhagen a/s, denmark), as high purified salt-free grade. to make sure about the uniqueness of all pcr products, all designed primers were blasted against human genome. statistical analysis: table 2. the sequences of the designed primers and the pcr product sizes for each primer pairs gene bank access number forward primer sequence reverse primer sequence amplicon size tgf-β1 nm_000660 5´-tggcgatacctcagcaac-3´ 5´-acccgttgatgtccacttg-3´ 181-bp tgf-β2 nm_001135599 (variant 1) nm_003238 (variant 2) 169 bp (variant 2) 5´-aggagcgacgaagagtactac-3´ 5´-actctgctttcaccaaattg-3´ 169 bp (variant 1) tgf-β3 nm_003239 5´-tgtccatgtcacacctttcag-3´ 5´-tgtggtgatccttctgcttc-3´ 145 bp gapdh nm_002046 5´-gtgaaccatgagaagtatgacaac-3´ 5´-catgagtccttccacgatacc-3´ 123 bp tgf-β variants and mir-21 in bladder cancer | monfared et al 984 | all real-time pcr data were analyzed with representational state transfer (rest) 2008 (corbett research pty ltd, australia) software, and statistical program for social sciences (spss) software version 13.0 (spss inc., chicago, usa). rest software was used to analyze and normalize the real-time pcr data. kolmogorov–smirnof normality test (ks-test) was used to examine the normal distribution of the samples. statistical differences between tumor and nontumor samples were determined by paired t-test (if ks-test was passed) or mann-whitney non-parametric test (if kstest wasn’t passed). the probability of a statistically significant difference between the clinicopathological parameters and the gene of interest expression fold change was tested by mann-whitney non-parametric test. receiver operating characteristics (roc) curve was plotted to determine the suitability of the mir-21 expression level as a potential tumor marker for bladder cancer. all tests were performed as two-tailed, and a p-value of <.05 was considered as statistically significant. cellular and molecular urology figure 1. (a) a representative acryl-amid gel electrophoresis result demonstrating a single amplified product for each tgf-β variant, as well as the internal house-keeping control gene, gapdh. the sizes of all pcr products appeared to be identical to the ones expected by primer designing. representative melt curve graphs of real-time pcr products of tgf-β variants and gapdh (b), as well as mir-21 and the internal control u6 (c) confirmed the authenticity of amplified products. figure 2. the real-time rt-pcr quantification of the expression levels of tgf-β1 (a), tgf-β2 (b), and tgf-β3 (c) variants is compared between tumor vs. non–tumor (total samples), and in high-grade vs. low-grade tumors of bladder. the expression of each variant is normalized to that of gapdh (the internal control). histograms show the mean values of tgf-β’s relative expression, with standard deviation as error bar. note that the expression of all tgf-β variants is significantly down-regulated in tumor samples, compared to their non-tumor counterparts. 985vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l results overall, tissue specimens from 30 patients were collected (30 tumor and 30 non-tumors) and examined. to categorize tumor samples based on their stages and grades, the clinicopathological characteristic of all patients were obtained and further confirmed by an expert urologist (table1). optimization of real-time pcr experiments after rna extraction with trizol reagent, to assure that equal amounts of rna were used for each pcr, we used gapdh and u6 as internal controls (reference genes), and normalized the relative tgf-β and mir-21 expression of each sample with its own reference expression. the specificity of all primers was determined by examining the melting curves and the sizes of pcr products (figure1). statistical analysis of primers efficiencies was done by linreg pcr software. direct sequencing of the pcr products was further confirmed the accuracy and authenticity of each pcr product. altered expression of tgf-β variants and mir-21 in bladder tumors real-time pcr was performed as duplicates for all samples, under similar conditions. the obtained data revealed a significant down-regulation of tgf-β variants in tumor samples, in comparison to non-tumor ones (figure 2). the relative (normalized to that of internal control, gapdh) down-regulation for each variant of tgf-β in tumor vs. non-tumor samples was as follow: tgf-β1 (0.35 times, p = .029), tgf-β2 (0.13 times, p = .001), and tgf-β3 (0.17 times, p = .000). the down-regulation of tgf-β variants was more significant in low grade samples: tgf-β1 (0.33 times, p = .041), tgf-β2 (0.08 times, p = .006), and tgf-β3 (0.11 times, p = .000). however, the down-regulation of all variants was much less in high grade specimens, where there was no statistically significant difference between the expression of all variants in high-grade tumors and their non-tumor counterparts (figure 2). we observed a similar down-regulation of mir-21 in total bladder tumors (0.33 times) as well as in low-grade tumors (0.17 times), compared to their non-tumor counterparts (figure 3a). interestingly, mir-21 expression was much higher in high-grade tumors, compared to their non-tumor counterparts (2.2 times); nevertheless, the difference was not statistically significant. but, a comparison between high-grade and low-grade tumor samples revealed that mir-21 is significantfigure 3. (a) the relative expression of mir-21 in tumor vs. nontumor tissue samples and high-grade vs. low-grade tumors, normalized to the expression level of u6, as the internal control. note that the altered expression between tumor and non-tumor samples is not statistically significant. however, in contrast to lowgrade tumors, mir-21 is upregulated in high-grade ones, in a way that it could significantly discriminate between high-grade and low-grade tumor samples (b). c and d) roc curve analysis was performed to determine the sensitivity and specificity of mir-21 expression level to discriminate between tumor and non-tumor (c), as well as low-grade and high-grade states of the samples (d). note that the area under curve (auc) is much bigger in (d), suggesting that mir-21 could discriminate high-grade tumors from low-grade ones much better than tumor from non-tumor states of the samples. figure 4. mir-21 expression level is significantly elevated after treatment of 5637 bladder cancer cell line with tgf-β protein, at different time points. tgf-β variants and mir-21 in bladder cancer | monfared et al 986 | cellular and molecular urology ly upregulated (9.8 times, p = .031) in high grade specimens (figure 3b). to determine the suitability of mir-21 expression level in discriminating tumor and non-tumor samples of bladder, their roc curve plots were created and analyzed. as shown in figure 3c, the area under the curve (auc) for mir21 expression level in tumor vs. non-tumor samples was 61% (larger auc value means better overall performance of the medical test to correctly discriminate two groups of samples). the finding suggests that mir-21 expression level is not a good tumor marker in discriminating tumors from non-tumor samples (p = .1548). in contrast, the auc was much bigger (0.79) and statistically significant (p = .0251), when mir-21 expression level were used to discriminate high-grade from low-grade tumors (fig 3d). however, despite this significant result, we couldn’t define a valid and applicable cut-off range to determine the specificity, sensitivity, and predictive value for expression level of mir-21 as a grading marker. co-regulation of tgf-β and mir-21 expression the similar expression pattern of tgf-β and mir-21 suggested a potential co-expression regulation of the genes. to examine this possibility, we treatedthe 5637 bladder cancer cell line with recombinant tgf-β protein. the addition of tgf-β significantly elevated the expression of mir-21 in treated cells. as it is evident in figure 4, following a slight decline at the beginning of the experiment, mir-21 was rapidly upregulated at 2, 3, and 4 hours after treatment of the cells. discussion in this study, we examined a potential alteration in the expression of tgf-β and mir-21 in bladder tumors. our data revealed that all variants of tgf-β were down-regulated in bladder tumors. the finding is in accordance with the common knowledge about tgf-β function as a potent inhibitor of normal epithelial cell proliferation.(17) tgf-β is probably one of the regulatory factors that are genetically or epigenetically altered during bladder tumorigenesis.(11) an altered expression of tgf-β, its receptors (tgf-βr1 and tgf-βr2), and its signaling components (the smad family) are already reported for several tumors.(13,14,18-26) our finding is in conflict with a previous report,(16) which claimed a significant elevation of serum tgf-β1 levels in patients with invasive bladder cancer. the inconsistency between the two reports could be due to examining different samples, as the same group failed to show similar finding in the urine of the same patients.(16) moreover, the tumor cells are not the sole source of tgf-β1 release within the serum. consistence with our finding, and in a follow-up research, the same group reported a downregulation of tgf-β variants in bladder tumor tissues.(27) in this study, we discriminate the expression of each variant of tgf-β in our samples. the data revealed that the variants of the gene had a similar pattern of expression in tumor vs. non-tumor samples. the later finding implies that all variants of tgf-β are under the same regulatory elements inside the cells, despite being located on different chromosomes. the most significant down-regulation of tgf-β was observed in low-grade tumors. a logical interpretation of this observation is that the alteration of the gene is a vital step in tumor initiation, but not that critical in tumor progression. we also investigated a potential alteration in the expression of mir-21, which its biogenesis is directly regulated by tgf-β. despite previous reports on upregulation of mir-21 in most cancer types and cancer-derived cell lines,(28,29) the expression level of mir-21 failed to show any statistically significant difference between tumor and non-tumor samples of bladder. however, while mir-21 showed a slight down-regulation in low-grade tumors, its expression was noticeably elevated in high-grade ones. indeed, the expression level of mir21 could strongly discriminate high-grade from low-grade tumors. in contrast to the conclusion we made for tgf-β, mir-21's upregulation seems to be a vital step for tumor progression, but not for tumor initiation. our data demonstrated a significant correlation between expression levels of mir21 and tgf-β variants. in low-grade tumor samples which tgf-β expression was significantly down-regulated, mir-21 expression was also down-regulated. and in high grade samples, where the tgf-β expression level was increased, the expression level of mir-21 was accordingly elevated. conclusion our data suggest a significant down-regulation of all tgf-β variants in bladder cancer samples, mostly in low-grade tumors. we also observed a non-significant down-regulation 987vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l tgf-β variants and mir-21 in bladder cancer | monfared et al of mir-21 in low-grade bladder tumors. in contrast, mir21 showed upregulation in high-grade bladder tumors, in a way that the expression level of mir-21 could discriminate low-grade tumors from high-grade ones. similar pattern of gene expression for tgf-β variants and mir-21 suggests a co-regulated expression for these genes. acknowledgments this work was supported partially by a research grant from the urology and nephrology research center and the research deputy of ahvaz jundishapur university of medical science. conflict of interest none declared. references 1. dyrskjot l, zieger k, orntoft tf. recent advances in high-throughput molecular marker identification for superficial and invasive bladder cancers. front biosci. 2007;12:2063-73. 2. croce cm, calin ga. mirnas, cancer, and stem cell division. cell. 2005;122:6-7. 3. bartel dp. micrornas: genomics, biogenesis, mechanism, and function. cell. 2004;116:281-297. 4. calin ga, sevignani c, dumitru cd et al. human microrna genes are frequently located at fragile sites and genomic region sinvolved in cancers. proc natl acad sci usa. 2004;101:2999-3004. 5. esquela-kerscher a, slack fj. oncomirs micrornas with a role in cancer. nat rev cancer. 2006;6:259-69. 6. baffa r, fassan m, volinia s et al. microrna expression profiling of human metastatic cancers identifies cancer gene targets. j patholo. 2009;219:214-221. 7. zhu s, wu h, wu fet al. microrna-21 targets tumor suppressor genes in invasion and metastasis. cell res. 2008;18:350-359. 8. asangani ia, rasheed sak, nikolova da,et al. microrna-21 (mir21) post-transcriptionally downregulates tumor suppressor pdcd4 and stimulates invasion, intravasion and metastasis in colorectal cancer. oncogene. 2008;27:2128-2136. 9. yan lx, huang xf, shao q, et al. microrna mir-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. rna. 2008;14:2348-2360. 10. davis bn, hilyard ac, lagna g, hata a. smad proteins control drosha-mediated microrna maturation. nature. 2008;454:56-61. 11. massague j. tgf-β in cancer. j cell. 2008;134:215-230. 12. keski-oja1 j, koli k, von melchner h. tgf-β activation by traction? j cell biology. 2004;14:657-659. 13. gorsch sm, memoli va, stukel ta, et al. immunohistochemical staining for tgf-β1 associates with disease progression in human breast cancer. cancer res. 1992;52:6949-6952. 14. thompson tc, truong ld, timme tl, et al. transforming growth factor β1as a biomarker for prostate cancer. j cell biochem. 1992; 16h:54-61 15. weidner n, semple jp, welch wr, folkman j. tumor angiogenesis and metastasis correlation in invasive breast carcinoma. n engl j med. 1991;324:1-8. 16. eder ie, stenzl a, hobisch a, et al. transforming growth factors-beta 1 and beta 2 in serum and urine from patients with bladder carcinoma. j urol. 1996;156:953-7. 17. huang ss, huang js. tgf-beta control of cell proliferation. j cell biochem. 2005; 96(3):447-62. 18. coombes rc, barrett-lee p, luqmani y. growth factor expression in breast tissue. j steroid biochem mol biol. 1990;37:833-6. 19. jonson t, albrechtsson e, axelson j, et al. altered expression of tgfb receptors and mitogenic effects of tgfb in pancreatic carcinomas. int j oncol. 2001;19:71-81. 20. ryu b, kern se. the essential similarity of tgf beta and activin receptor transcriptional responses in cancer cells. cancer biol ther. 2003;2:164-70. 21. johnson md, shaw ak, o'connell mj et al. analysis of transforming growth factor β receptor expression and signaling in higher grade meningiomas. j neurooncol. 2011;103:277-85. 22. kim sh, lee sh, choi yl et al. extensive alteration in the expression profiles of tgfb pathway signaling components and tp53 is observed along the gastric dysplasia-carcinoma sequence. histol histopathol. 2008; 23:1439-52. 23. bertuccif, finetti p, cervera n et al. how different are luminal a and basal breast cancers? int j cancer. 2009;124:1338-48. 24. wang jc, su cc, xu jb et al. novel microdeletion in the transforming growth factor beta type ii receptor gene is associated with giant and large cell variants of non-small cell lung carcinoma. genes chromosomes cancer. 2007;46:192-201. 25. guzinska-ustymowicz k, kemona a. transforming growth factor beta can be a parameter of aggressiveness of pt1 colorectal cancer. world j gastroenterol. 2005;11:1193-5. 26. barlow j, yandell d, weaver d et al. higher stromal expression of transforming growth factor-beta type ii receptors is associated with poorer prognosis breast tumors. breast cancer res treat. 2003;79:149-59. 27. eder ie, stenzl a, hobisch a et al. expression of transforming growth factors beta-1, beta 2 and beta 3 in human bladder carcinomas. br j cancer. 1997;75:1753-60. 28. selcuklu sd, donoghue mt, spillane c. mir-21 as a key regulator of oncogenic processes. biochem soc trans. 2009;37:918-25. 29. pan x, wang zx, wang r. microrna-21: a novel therapeutic target in human cancer. cancer biol ther. 2011;10:1224-32. fall 2012 08.pdf 711vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l preservation of erectile function and urinary continence in squamous cell carcinoma of the bulbomembranous urethra mohammad samzadeh, abbas basiri keywords: urethra, squamous cell carcinoma, urethral neoplasms introduction c arcinoma of the male urethra is an uncommon neoplasm accounting for less than 1% of all malignancies,(1) and generally occurs in the 5th decade of life. it is a very serious disease, often with a late diagnosis and lymph node involvement, which usually manifests as ure(2-4) dysuria is the most common symptom, sometimes associated with pain during urination, later with hematuria.(5) the epithelial neoplasms in the male urethra are usually squamous cell carcinoma (scc), transitional cell carcinoma (tcc), and adenocarcinoma in order of prevalence.(2,3,6,7) management of the urethral carcinoma is still controversial. the surgical approach to the urethral are of less importance. radical cystoprostatectomy, pelvic lymphadenectomy, and total penectomy of treatment. case report tive urinary symptoms in september 2006. traumatic postoperative catheterization 2 years earlier was considered the possible cause of urethral stenosis, which was diagnosed by rigid cystoscopy. corresponding author: abbas basiri, md urology and nephrology research center, no.103, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir received december 2011 accepted may 2012 urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran point of technique 712 | ineal swelling and urinary retention in march 2009, a perineal drainage was performed and suprapubic catheter was continuous purulent discharge. urinary stone disease, fever, bone pain, bowel habit changes, or rectorrhagia, but losing appetite, 8 kg weight loss, and recurrent urinary tract infections. charge without any regional and systemic lymphadenopathy. no obvious collection, with normal corpora cavernosa and urethrography showed irregular bulbomembranous urethra giosum and possibly left the corpus cavernosum without puted tomography (ct) scan, and bone scintigraphy revealed no evidence of distant metastasis or regional organ involvement. up and down cystourethroscopy revealed multiple irregular bulbomembranous mucosal lesions protruded to the prostatic urethra covering with necrotic debris, normal penile and prostatic urethra, and a normal tumor-free bladder with normal lar follow-up plan was considered. technique the patient was diagnosed with urethral cancer (ct2 or cal surgery was performed with total corpus spongiourethrectomy, radical nerve-sparing prostatectomy, pelvic lymphadenectomy, and appendicovesicostomy (mitrofanoff procedure) as a continent urinary diversion (figure 2). scc of the urethra with corpus spongiosum and left crus of corpora cavernosa invasion and no vascular, perineural, and prostatic invasion was made (figure 3). all the resected pelpoint of technique figure 1. magnetic resonance imaging shows the bulbomembranous involvement. figure 2. removed enbloc specimen (1. mea; 2. penile urethra + corpus spongiosum; 3. cutaneous fistula; 4. bulbomembranous tumor; 5. left corpus cavernosum crura; 6. membranous urethra; 7. prostate; and 8. seminal vesicles). figure 3. squamous cell carcinoma of the urethra. cellular polymorphism and atypia (×200 hematoxylin and eosin stain). 713vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l erectile function in bulbomembranous carcinoma | samzadeh and basiri vic lymph nodes were negative for malignancy and it was suggested as having t3n0m0 disease. the patient subsequently received 40 gy/ 20 fractions pelvic radiotherapy and 6 cycles of cisplatin-based chemotherapy. results month perineal pain post operation, which was controlled by medication, all the metastatic lab tests and paraclinic studies, including whole body bone scan and thoracoabdominopelvic invasion, or lymphadenopathy at his regular follow-ups (at 6, 12, 24, and 36 months post operation). discussion treatment of urethral carcinoma is controversial due to rarity of the disease and the lack of uniformity and detailed comparative studies in the literature. surgery plays a basic role in the management of urethral cancers, and various approaches have been employed. the standard primary mode of treatthe tumor within the urethra together with the clinical stage in summary, stage, grade, and site of the disease are predictors of survival. it may be possible that with proper selection, the bladder, prostate, and penile-preserving surgery could be considered in the management of male urethral cancers. conflict of interest none declared. references 1. sharp ds, angermeier kw. surgery of penile and urethral carcinoma. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. 9 ed. philadelphia: saunders; 2007:993-1022. 2. dalbagni g, zhang zf, lacombe l, herr hw. male urethral carcinoma: analysis of treatment outcome. urology. 1999;53:1126-32. 3. gheiler el, tefilli mv, tiguert r, de oliveira jg, pontes je, wood dp, jr. management of primary urethral cancer. urology. 1998;52:487-93. 4. gerbaulet a, haie-meder c, marsiglia h, et al. [brachytherapy in cancer of the urethra]. ann urol (paris). 1994;28:312-7. 5. farrer jh, lupu an. carcinoma of deep male urethra. urology. 1984;24:527-31. 6. gillitzer r, hampel c, wiesner c, hadaschik b, thuroff j. single-institution experience with primary tumours of the male urethra. bju int. 2008;101:964-8. 7. smith y, hadway p, ahmed s, perry mj, corbishley cm, watkin na. penile-preserving surgery for male distal urethral carcinoma. bju int. 2007;100:82-7. endourology and stone disease 217urology journal vol 4 no 4 autumn 2007 changes in intrarenal resistive index following electromagnetic extracorporeal shock wave lithotripsy mohammad ghasem mohseni, mahziar h khazaeli, seyed mohammad kazem aghamir, farzad biniaz introduction: our aim was to study the changes in resistive index (ri) of the ipsilateral and contralateral kidneys following electromagnetic extracorporeal shock wave lithotripsy (swl) of the kidney calculi. materials and methods: using color doppler ultrasonography, the ri was determined in 21 patients with unilateral caliceal and pelvic kidney calculi. the ri of the interlobar renal arteries were measured for the regions near and far from the calculi (distance, less and more than 2 cm), before, 30 minutes after, and 1 week after swl. the same measurements were carried out for the contralateral kidney. changes in the ri values and their relation with age were evaluated. results: the ri near the calculi increased 30 minutes after swl from 0.594 ± 0.062 to 0.620 ± 0.048 (p = .003; 95% confidence interval, 0.020 to 0.073), but returned to the pre-swl values 1 week later. the ri values of the region remote from the calculus and in the contralateral kidney did not change significantly. there was a weak correlation between age and the ri far from the calculus before and 1 week after swl. there were no relationships between the ri and age, sex, weight, blood pressure, and smoking. conclusion: the results suggest that swl of the kidney calculi changes the ri only near the calculus which is immediate, transient, and not age-related. urol j. 2007;4:217-20. www.uj.unrc.ir keywords: lithotripsy, kidney calculi, vascular resistance, ultrasonography department of urology, sina hospital, tehran university of medical sciences, tehran, iran corresponding author: mahziyar h khazaeli, md department of urology, sina hospital, hassanabad sq, tehran, iran tel: +98 916 113 1895 fax: +98 21 6673 7741 e-mail: mkhazaali@razi.tums.ac.ir received may 2007 accepted july 2007 introduction extracorporeal shock wave lithotripsy (swl) is a commonly used procedure in urology. however, despite its widespread use, some of its effects and complications are still unknown, one of them being changes in renal blood flow.(1,2) the decrease in the renal blood flow is important, because it may cause kidney failure after swl, especially in patients with a single kidney.(3,4) resistive index (ri), which is measured by color doppler ultrasonography (cdu), reflects resistance of intrarenal arteries that indirectly shows the renal blood flow.(5,6) some researchers have tried to follow the changes in the ri after swl, but there are still controversies about the pattern and timeline of ri changes,(2-5,7-10) and no study has used electromagnetic generator. although most studies reported that the intrarenal ri increased immediately after swl, which returned to the pre-swl levels one week later, what happens to the contralateral kidney has remained unclear. in this study, we investigated the changes in intrarenal ri following electromagnetic swl in the ipsilateral (nearby and remote from the calculus) and contralateral kidney and also looked for the age–related differences. changes in intrarenal resistive index following shock wave lithotripsy—mohseni et al 218 urology journal vol 4 no 4 autumn 2007 materials and methods this study was approved by ethics committee of tehran university of medical sciences and the patients provided informed consent. between january 2005 and january 2007, patients with unilateral kidney calculi who had been referred to our swl unit were enrolled in the study. history, physical examination, laboratory data, and imaging characteristics of the patients were recorded. those with 2-cm or smaller kidney calculi in either the renal pelvis or the calyxes, and those with 1-cm or smaller lower caliceal calculi were included. patients with diabetes mellitus, hypertension, renal parenchymal disease, hydronephrosis, abnormal corticomedullary echo, and kidney failure were excluded. patients taking vasopressor drugs during the past 30 days were excluded, as well. strict adherence to the inclusion and exclusion criteria was made; therefore, even patients with mild hydronephrosis did not enter the study. before the swl, we measured the ri of the interlobar arteries using cdu (dynaview ii, ssd1700, aloka, tokyo, japan). the ri was calculated as (peak systolic velocity peak end diastolic velocity)/ peak systolic velocity.(4) the measurements were done in 2 regions of the ipsilateral kidneys: near the calculus (in 2-cm distance or less, nearby region) and far from the calculus (farer than 2 cm, remote region). the ri was also determined in the contralateral kidney. in each area, at least 3 measurements were done and the algebric means of the values were calculated as the ri. lithotripsy was done by swl (dornier medical systems, marietta, georgia). our protocol was to use at least 3000 shock waves with increasing voltage to 19 kv, unless the patient could not tolerate the pain or the clinical condition imposed limitations. thereafter, at least 30 minutes after the swl, we repeated cdu and measurement of the ri in the aforementioned areas. the follow-up visits of the patients were arranged for 1 week after the procedure and the ri of the ipsilateral and contralateral kidney was measured for the third time. all of the ri measurements were done by 1 experienced radiologist. the collected data were analyzed using the paired t test for comparison of the pre-swl and postswl values of the ri, independent-sample t test for comparison of the ri values between men and women, the pearson correlation test for evaluation of the relation between the ri and the clinical and demographic parameters, and the kolmogrovsmirnov test for examination of data distributions. results we studied on 21 patients who underwent swl at our center. the median age of the patients was 46.5 (range, 24 to 71 years) and they were 13 men (61.9%) and 8 women (38.1%). their mean body weight was 69.1 ± 10.5 kg. the calculi were located in the upper, middle, and lower calyxes in 3 (14.3%), 2 (9.7%), and 9 (42.8%) of the patients, respectively, and 7 (33.4%) had calculi in the renal pelvis. the median calculus size was 12.6 mm. the clinical and swl parameters are shown in table 1. serum creatinine level did not increase after the swl. in the contralateral kidney, the ris remained steady after swl, while in the ipsilateral kidney, the ris measured near and far from the calculus had a slight increase immediately after swl, which returned to their pre-swl values 1 week after the procedures. these values had normal distributions and were demonstrated as mean ± standard deviation (table 2). variable median value number of shock waves 3290 shock wave voltage, kv 18.73 total energy, kv 57000 pre-swl systolic blood pressure, mm hg 118 pre-swl diastolic blood pressure, mm hg 70 pre-swl serum creatinine, mg/dl 1.10 post-swl serum creatinine, mg/dl 1.10 table 1. characteristics of shock wave lithotripsy (swl) and clinical parameters time of ri location of ri before swl 30 minutes after swl 1 week after swl nearby the calculus 0.594 ± 0.062 0.620 ± 0.048 0.594 ± 0.061 remote from the calculus 0.590 ± 0.056 0.621 ± 0.068 0.595 ± 0.069 contralateral kidney 0.597 ± 0.065 0.582 ± 0.040 0.582 ± 0.061 table 2. mean ri values before, 30 minutes after, and 1 week after shock wave lithotripsy (swl) changes in intrarenal resistive index following shock wave lithotripsy—mohseni et al urology journal vol 4 no 4 autumn 2007 219 no significant difference was detected in the ris between the men and the women. only the ris nearby the calculus before and immediately after swl were significantly different with the post-swl being higher (p = .003; 95% confidence interval, 0.020 to 0.073). there were weak correlations between the age and the ri remote from the calculus before and 1 week after swl (r = 0.03 and r = 0.02, respectively). there were no significant correlations between age and ri in other areas or between the ri and weight, systolic and diastolic blood pressures, numbers of the shocks, voltage of the shock wave, and total energy applied. discussion shock wave lithotripsy is a commonly used procedure for the treatment of urinary calculi. although it is noninvasive and a safe option, complications do occur after swl.(7,8) these are conveniently grouped under structural and functional injuries. structurally, swl can cause renal hematoma and contusions, like other renal traumas.(8,9) from the functional perspective, swl has the potential of causing or aggravating kidney failure.(10-12) this is, at least, in part due to vasoconstriction and reduction in renal blood flow. this complication can be monitored by measuring the ri of the intrarenal arteries using cdu. there are some published studies that followed the ri after swl, but our study is the first in using the electromagnetic lithotripter. electromagnetic lithotripters have small focal points relative to electrohydrolic and piezoelectric lithotripters, which are responsible for greater risk of subcapsular hematoma formation in the former.(13,14) also, the pattern and timeline of ri values are controversial, as is its correlation with age. beduk and colleagues(2) used dornier mpl 9000 (electrohydrolic generator) to perform swl and found no significant changes in ri of the treated kidney 24 hours after the procedure. earlier measurements showed increased ri in other studies; kataoka and coworkers (3) treated 23 patients with dornier mpl 9000. they made measurements immediately after swl and found a significant increase in the treated kidneys immediately after swl. measurement of the ri 3 hours after swl with electrohydrolic lithotripter demonstrated similar age-related results.(4) aoki and associates(5) measured the ri 30 minutes and 1 week after swl with edap lt-01 (piezoelectric generator) in 70 patients. a significant increase was noted in the treated kidneys which was not age-related. the authors also reported the ris in the contralateral kidneys indicating significant increases in elderly patients. in other studies, no significant changes in the contralateral kidneys were reported.(3,4) using a nova lithotripter (electrohydrolic generator), nazaroglu and colleagues(6) measured ri before, 30 minutes, 3 hour, and 2 weeks after swl in the nearby and remote regions of the ipsilateral and contralateral kidneys in 43 patients (30 with kidney calculi). in patients with kidney calculi, the ri increased 30 minutes and 3 hours after swl in the nearby and remote regions, and more markedly in the former. in the contralateral kidney, there was an increase in the ri only at 3 hours, which was less than the ipsilateral kidney. the ri at 2 weeks post-swl in the nearby region and the contralateral kidney did not differ from the pre-swl values. in our study, the ri increased in the nearby region immediately and returned to the pre-swl levels 1 week after swl. this was in accordance with the results of the previous studies.(35) however, we have not seen the ri changes in the remote region as nazaroglu and colleagues noted.(6) also, the ri did not increase in the contralateral kidneys as other researchers stated.(5,6) although some weak correlations existed between the ri in the remote region and age, we did not find age-related changes as knapp and coworkers found.(4) our study cohort was relatively young and this may be why we had no strong age-related changes. overall, our results agree with those of kataoka and colleagues.(3) these differences may be due to small focal point inherent to electromagnetic lithotripters, so that the ri changes occur only in the nearby region which is the focus of swl. also, lack of correlations between the ri and weight, sex, blood pressure, and shock wave characteristic may point to independent mechanism of shock-wave-induced injuries. we propose that monitoring the changes in the ri after swl may be useful for investigating the protective and prophylactic effects of the drugs (eg, sympatholytics or diuretics) to reduce post-swl renal injuries and kidney failure, especially in patients with a single kidney. changes in intrarenal resistive index following shock wave lithotripsy—mohseni et al 220 urology journal vol 4 no 4 autumn 2007 conclusion we showed that after electromagnetic swl of the kidney calculi, intrarenal ri value increases in the vicinity of the calculus immediately, but it returns to the pre-swl values 1 week later. this response is unrelated to the age and does not occur remote from the calculus or in the contralateral kidney. conflict of interest none declared. financial support tehran university of medical sciences financially supported this study. acknowledgment the authors would like to thank dr alipasha meysamie, dr mehdi atayi, dr behrouz jafariea, and mrs f etezadi for their technical assistance. references 1. terry jd, granger sh, chen bc, et al. adjusted resistive index: a method to estimate rapidly renal blood flow: preliminary validation in hypertensives. j ultrasound med. 1993;12:751-6. 2. beduk y, erden i, gogus o, sarica k, aytac s, karalezli g. evaluation of renal morphology and vascular function by color flow doppler sonography immediately after extracorporeal shock wave lithotripsy. j endourol. 1993;7:457-60. 3. kataoka t, kasahara t, kobashikawa k, et al. [changes in renal blood flow after treatment with eswl in patients with renal stones. studies using ultrasound color doppler method]. nippon hinyokika gakkai zasshi. 1993;84:851-6. japanese. 4. knapp r, frauscher f, helweg g, et al. age-related changes in resistive index following extracorporeal shock wave lithotripsy. j urol. 1995;154:955-8. 5. aoki y, ishitoya s, okubo k, et al. changes in resistive index following extracorporeal shock wave lithotripsy. int j urol. 1999;6:483-92. 6. nazaroglu h, akay af, bükte y, sahin h, akkus z, bilici a. effects of extracorporeal shock-wave lithotripsy on intrarenal resistive index. scand j urol nephrol. 2003;37:408-12. 7. kaude jv, williams cm, millner mr, scott kn, finlayson b. renal morphology and function immediately after extracorporeal shock-wave lithotripsy. ajr am j roentgenol. 1985;145:305-13. 8. knapp pm, kulb tb, lingeman je, et al. extracorporeal shock wave lithotripsy-induced perirenal hematomas. j urol. 1988;139:700-3. 9. knorr pa, woodside jr. large perirenal hematoma after extracorporeal shock-wave lithotripsy. urology. 1990;35:151-3. 10. gilbert br, riehle ra, vaughan ed jr. extracorporeal shock wave lithotripsy and its effect on renal function. j urol. 1988;139:482-5. 11. daniel mp, burns jr. renal function immediately after piezoelectric extracorporeal lithotripsy. j urol. 1990;144:10-2. 12. assimos dg, boyce wh, furr eg, et al. selective elevation of urinary enzyme levels after extracorporeal shock wave lithotripsy. j urol. 1989;142:687-90. 13. lingeman je, lifshitz da, evan ap. surgical managementof urinary lithiasis. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 33983412. 14. lingeman je, matlaga br, evan ap. surgical management of upper urinary tract calculi. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1465-80. v08_no_3_final.pdf urological calendar 255urology journal vol 8 no 3 summer 2011 urological calendar urol j. 2011;8: 255. www.uj.unrc.ir hamburg, germany october 5 7, 2011 e-mail: nfo@erusmasterclass.com website: www.erus2011.com/ 1st joint meeting of the eau section of tübingen, germany october 6 8, 2011 e-mail: m.koops@congressconsultants.com website: www.esffu-esgurs.uroweb.org 67th annual meeting of the american orlando, fl, usa october 15 19, 2011 e-mail: asrm@asrm.org website: www.asrm.org/ 31st congress of the société internationale d’urologie berlin, germany october 16 20, 2011 e-mail: congress@siu-urology.org website: www.siucongress.org/ 84th congress of the siu rome, italy october 23 26, 2011 e-mail: info@siu.it website: www.siu.it buenos aires, argentina november 24, 2011 e-mail: sau@sau-net.org website: www.sau-net.org cancers barcelona, spain november 4 6, 2011 e-mail: emuc-meeting2011@congressconsultants. com website: www.emucbarcelona2011.org 4th esu mc female and functional berlin, germany november 11 13, 2011 e-mail: esu@uroweb.org website: www.uroweb.org swl kyoto, japan november 30 3 december, 2011 e-mail: wce2011@congre.co.jp website: www.congre.co.jp/wce2011/ kidney transplantation 155urology journal vol 4 no 3 summer 2007 is preemptive kidney transplantation preferred? updated study fatemeh pour-reza-gholi, mohsen nafar, nasser simforoosh, behzad einollahi, abbas basiri, ahmad firouzan, behrang alipour abedi, soudabeh farhangi introduction: for eligible patients with end-stage renal disease, the dialysis stage could be bypassed by preemptive kidney transplantation (pkt), when the organ is available. we compared this treatment option with kidney transplantation in patients with pretransplant dialysis (ptd). materials and methods: we retrospectively studied on 300 patients who received pkt between 1992 and 2006 from living donors. they were compared with 300 kidney recipients with ptd matched for the time of transplantation that had been on hemodialysis for at least 6 months. episodes of rejection, graft function, and graft and patient survivals were compared between the two groups. results: no significant differences were noted in the sex of the recipients, age and sex of the donors, donor source, and posttransplant immunosuppressive therapy, but posttransplant follow-up was longer (p < .001) and the recipients were older (p < .001) in the ptd group. seventy-one patients (23.7%) in the pkt group and 64 (21.3%) in the ptd had at least 1 rejection (p = .49). the kidney allografts were functional in 272 (90.7%) kidney recipients in the pkt group and 278 (92.7%) in the ptd group during their follow-ups (p = .30). five-year graft and patient survival rates were slightly higher in the ptd group, which were not statistically significant (p = .06 and p = .07, respectively). conclusion: in addition to comparable patient and graft survivals with the pkt and kidney transplantations after a period of dialysis, pkt eliminates hemodialysis costs and complications. we recommend pkt as a better choice for transplantation whenever possible. urol j. 2007;4:155-8. www.uj.unrc.ir keywords: kidney transplantation, dialysis, kidney allograft, survival, acute allograft rejection department of kidney transplantation, shaheed labbafinejad medical center and urology and nephrology research center, shaheed beheshti medical university, tehran, iran corresponding author: fatemeh pour-reza-gholi, md department of kidney transplantation, shaheed labbafinejhad medical center, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2254 8886 e-mail: poorreza@hotmail.com received february 2007 accepted june 2007 introduction kidney transplantation is the treatment of choice among several renal replacement therapies at any time for end-stage renal disease (esrd). patients usually undergo transplantation after a variable period of dialysis (pretransplant dialysis; ptd). if the allograft organ is available immediately when the patient reaches the last stage of chronic kidney disease, transplantation can be performed without starting on maintenance dialysis (preemptive kidney transplantation; pkt). in iran, the waiting list for transplantation is not long and many patients enjoy the opportunity to receive pkt.(1) the potential cost-effectiveness of pkt has encouraged the transplant community to investigate its safety and effectiveness. graft and patient survival rates have been compared between recipients of pkt and those with ptd in different studies and the outcomes have been shown to be comparable or even better for pkt.(2-4) in this study with a large number of preemptive kidney transplantation—pour-reza-gholi et al 156 urology journal vol 4 no 3 summer 2007 patients, we compared the results of living donor transplantation in the recipients with pkt and ptd. this report is the update of the previous one from shaheed labbafinejad medical center in tehran, iran.(5) materials and methods preemptive kidney transplantation is being performed at our center since 1992. we retrospectively studied 300 patients who received pkt between 1992 and 2006 from living donors. they were compared with 300 kidney recipients with ptd matched for the time of transplantation that had been on hemodialysis for at least 6 months. stratified randomization was used to select the patients for the control group. posttransplant immunosuppressive therapy included one of the following regimens: prednisolone, cyclosporine, and azathioprine; prednisolone, cyclosporine, and mycophenolate mofetil; prednisolone, cyclosporine, mycophenolate mofetil, and daclizumab; and prednisolone, cyclosporine, and sirolimus (table). diagnosis of acute rejection was made based on elevation of serum levels of creatinine, clinical findings, need for antirejection therapy, cyclosporine trough level, diethylenetriamine pentaacetic acid renography, and kidney biopsy (if required). in addition to the patients and transplant data, episodes of rejection, graft function, and graft and patient survivals were compared between the two groups. quantitative variables were compared by the t test. for categorical variables, the chi-square test and the fisher exact test were used. patient and graft survival rates were analyzed by kaplan-meier method and compared by the log-rank test. p values of less than .05 were considered significant. results since 1992, a total of 300 pkts were performed at our center. demographic and clinical characteristics of the patients with pkt and the controls with ptd are depicted in the table. all of the patients in the two groups had received their kidney allografts from living donors. no significant differences were noted in the sex of the recipients, age and sex of the donors, donor source, and posttransplant immunosuppressive therapy. the mean duration of posttransplant follow-up was longer (p < .001) and the mean age at transplantation was greater (p < .001) in the patients of the control group than those in the pkt recipients. seventy-one patients (23.7%) in the pkt group and 64 (21.3%) in the ptd experienced at least 1 rejection (p = .49). of acute rejections, 5.2% (7.2% in pkt and 3.0% in ptd groups) were biopsy proven. the kidney allografts were functional in 272 characteristics pkt group ptd group recipients’ sex male 170 (56.6) 172 (57.3) female 130 (43.4) 128 (42.7) recipients’ mean age (range), y 29.4 ± 17.2 (3 to 75) 34.2 ± 15.5 (4 to 73) immunosuppressive therapy csa + pred + aza 146 (48.7) 175 (58.3) csa + pred + mmf 128 (42.7) 109 (36.3) csa + pred + mmf + doc 16 (5.3) 3 (1.0) csa + pred + sir 10 (3.3) 13 (4.3) ptd duration (range), mo 0 15.70 ± 14.56 (4 to 106.8) donor source living related 275 (91.7) 280 (93.3) living unrelated 25 (8.3) 20 (6.7) donors’ sex male 238 (79.3) 255 (85.0) female 62 (20.7) 45 (15.0) donors’ mean age (range), y 28.3 ± 5.9 (20 to 62) 28.1 ± 5.0 (19 to 53) follow-up (range), mo 27.38 ± 24.79 (0 to 92.4) 35.28 ± 25.96 (0.1 to 95.9) recipient and donor characteristics* *values in parentheses are percents unless otherwise indicated. pkt indicates preemptive kidney transplantation; ptd, pretransplant dialysis; csa, cyclosporine; pred, prednisolone; mmf, mycophenolate mofetil; aza, azathiprine; doc, doclizumab; and sir, sirolimus. preemptive kidney transplantation—pour-reza-gholi et al urology journal vol 4 no 3 summer 2007 157 (90.7%) kidney recipients in the pkt group and 278 (92.7%) in the ptd group during their follow-ups (p = .30). figures 1 and 2 depict patient and graft survival curves in the two groups. one-, 2, 3-, and 5-year graft survival rates were 93.5%, 89.6%, 87.1%, and 84.3% in the pkt group and 96.4%, 95.4%, 94.7%, and 89.7% in the ptd group, respectively (p = .06). at the end of the 1st, 2nd, 3rd, and 5th year of transplantation, the rate of patient survival was 96.3%, 95.6% , 94.8%, and 92.7% in the pkt group, and 98.5%, 98.5%, 97.9%, and 97.9% in the ptd group, respectively (p = .07). discussion in the present study, we compared 300 kidney recipients with pkt and 300 with ptd. our findings demonstrated that the graft and patient survival rates at 5 posttransplant years were similar in the two groups with a slight insignificant superiority of those in the ptd group. clinically, the outcomes are favorable in both groups. this was also seen in acute rejection episodes and graft loss rates among the patients of the pkt and ptd groups. these findings are consistent with the results of previous studies,(2-4,6,7) but in contrast with our previous results in which we found better outcomes in pkt group within the first posttransplant 2 years.(5) a higher graft survival with pkt has also been reported in some studies.(8-10) roake and colleagues showed better patient and graft survival rates in patients receiving pkt from cadaveric donors.(10) an explanation in favor of cadaveric pkt is that the recipients may not experience uremic status before transplantation. however, in a study on the data from the united stats renal data system, mange and colleagues noted a reduction in the risk of graft function by pkt from living donors, especially in the long-term.(9) our control group consisted of randomly selected kidney recipients mostly from unrelated living donors without matching for human leukocyte antigens that may explain the slight differences from other studies. however, the consensus is that pkt provides favorable transplantation outcomes, and the other advantages such as eliminating dialysis costs and preventing from the low quality of life and reduced daily activity of the patients during dialysis period make pkt a considerable option.(8) of other factors that have been studied are delayed graft function and glomerular filtration rate in patients who receive pkt. debska-slizien and coworkers reported that delayed graft function was 2 times more frequent in patients with ptd compared to that in pkt recipients, which was confirmed by other researchers.(2,4) gill and colleagues reported a slower decline, but of modest clinical significance, in glomerular filtration rate within 6 posttransplant months in pkt recipients.(3) these findings should be tested in multivariate analyses on data from larger study groups in order to elucidate the benefit of pkt and its effects on transplantation. figure 1. graft survival curves of the kidney recipients of in the pkt and ptd groups. figure 2. patient survival curves of the kidney recipients of in the pkt and ptd groups. preemptive kidney transplantation—pour-reza-gholi et al 158 urology journal vol 4 no 3 summer 2007 conclusion our findings in concert with the previous studies on pkt suggest that it can provide clinically comparable results with kidney transplantation in patients on maintenance dialysis. furthermore, pkt eliminates hemodialysis costs and arteriovenous fistula formation. thus, we recommend pkt as a better choice for transplantation whenever it is possible. cost-effectiveness of pkt is another advantage; however, it should be assessed in national scales to yield precise conclusions. we are continuing our study with further cases and over a longer follow-up period. conflict of interest none declared. refferences 1. ghods aj, savaj s. iranian model of paid and regulated living-unrelated kidney donation. clin j am soc nephrol. 2006;1:1136-45. 2. innocenti gr, wadei hm, prieto m, et al. preemptive living donor kidney transplantation: do the benefits extend to all recipients? transplantation. 2007;83:144-9. 3. gill js, tonelli m, johnson n, pereira bj. why do preemptive kidney transplant recipients have an allograft survival advantage? transplantation. 2004;78:873-9. 4. debska-slizien a, wolyniec w, chamienia a, et al. a single center experience in preemptive kidney transplantation. transplant proc. 2006;38:49-52. 5. simforoosh n, basiri a, pourrezagholi f, et al. is preemptive renal transplantation preferred? transplant proc. 2003;35:2598-601. 6. becker bn, rush sh, dykstra dm, becker yt, port fk. preemptive transplantation for patients with diabetes-related kidney disease. arch intern med. 2006;166:44-8. 7. katz sm, kerman rh, golden d, et al. preemptive transplantation--an analysis of benefits and hazards in 85 cases. transplantation. 1991;51:351-5. 8. abou ayache r, bridoux f, pessione f, et al. preemptive renal transplantation in adults. transplant proc. 2005;37:2817-8. 9. mange kc, joffe mm, feldman hi. effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. n engl j med. 2001;344:726-31. 10. roake ja, cahill ap, gray cm, gray dw, morris pj. preemptive cadaveric renal transplantation--clinical outcome. transplantation. 1996;62:1411-6. small cell carcinoma of bladder; still a diagnostic and therapeutic challenge: seven years of experience and follow-up in a referral center reza kaffash nayeri¹, mohammad sadri2, hossein shahrokh ¹, maryam abolhasani3, farhood khaleghimehr¹, ehsan zolfi¹, naser yousefzadeh kandevani¹, amir h kashi4* purpose: to report clinical, histopathological, and treatment features of small cell carcinoma of (smccb) bladder during 7 years in a referral center. methods: the clinical, histopathological features, treatment modalities, and outcome of all patients with bladder smccb treated between 2009 and 2016 who were managed in hasheminejad kidney center (hkc) were retrospectively collected. results: thirteen patients were diagnosed and managed with smccb. the average age of patients was 64.92 years. for each patient, 8 markers were used for ihc staining on average. neuroendocrine markers such as cd 56, neuron specific enolase, synaptophysin, and chromogranin were found in a significant percentage of patients (69%, 38%, 54%, and 31% respectively). patients were managed with turbt alone (n=3), chemotherapy after turbt (n=4), chemotherapy plus radical surgery (n=4) and radical surgery alone (n=2). the best clinical result was seen in chemotherapy received patients with or without radical surgery. the mean(se) of survival rate in patients who received only chemotherapy alone was 42.4 (10.0) months, while in those who were managed with chemotherapy plus radical surgery it was 47.7 (10.1) months. conclusion: in our center immunohistochemistry was needed for definitive diagnosis in 17/19 samples. misdiagnosis happened in two samples without ihc request. we think that use of immunohistochemistry should be mandatory for diagnosis of smccb to exclude misdiagnosis. chemotherapy is the most important part of treatment and the addition of radical surgery can slightly improve patients’ survival. keywords: bladder neoplasms; immunohistochemistry; small cell carcinoma; urinary bladder introduction primary small cell carcinoma of the bladder (smccb) is a highly invasive and rare tumor of the urinary system(1). although the lung is the most common organ involved by small cell carcinoma, this type of tumor can also affect many extra-pulmonary organs(1,2). as many as 2-9% of cases of small cell carcinoma (smcc) are extra-pulmonary, and following gastrointestinal tract, the bladder is the third most common site of involvement(3). smccb accounts for 0.5 to 0.7% of all bladder tumors (4,5). although this tumor is rare, it is not insignificant in any way(6). this tumor has been considered by many scholars due to its difficulties in diagnosis, aggressive behavior, poor prognosis, rapid progression, and systemic nature(1). the rarity of smccb has limited our knowledge of the biological progression of this malignancy and thus prevented the ability to plan randomized prospective studies(1,7). in the literature, a few papers have been published on the optimal clinical guidelines for smccb(6). there is still no therapeutic approach which is universally accepted and because of the rarity of the disease, the treatment modalities are not standard. 1hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. 2urumia university of medical sciences, urumia, iran. 3oncopathology research center, iran university of medical sciences (iums), tehran, iran. 4urology and nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. * corresponence: urology and nephrology research center (unrc),no. 103, 9th boustan alley, pasdaran ave., tehran, iran. email address: ahkashi@gmail.com. received april 2019 & accepted april 2020 the behavior of smccb is far more invasive than that of urothelial cell carcinoma (ucc). despite similar clinical and demographic risk factors, and diagnostic methods, the prognosis of smccb is much worse than ucc (7), and therefore, its definitive diagnosis is very important. pathologic diagnosis according to who criteria is performed through light microscopy, but some pathologists recommend immunohistochemical (ihc) staining for diagnosis and some others consider it mandatory. in this study, we present the clinical as well as histopathological characteristics, therapeutic options, and outcomes of the smccb patients managed in our center during a seven-year period, and emphasize the use of ihc staining for confirmation of pathologic diagnosis. materials and methods from march 2009 until march 2016, 2763 patients with suspicious diagnosis of bladder tumors underwent transurethral resection of bladder tumor (turb) in our center. a total of 301 cases later underwent radical cystectomy with urinary diversion. hospital files of all patients with a final diagnosis of smccb were reviewed. urological oncology urology journal/vol 17 no. 4/ july-august 2020/ pp. 363-369. [doi: 10.22037/uj.v0i0.5289 ] demographic characteristics, clinical symptoms, and the most common cause of referral were extracted and recorded. the results of imaging studies including size and location of the mass, the presence or absence of hydronephrosis, local extension of tumor, and ultimately, lymph node involvement were recorded. serum hemoglobin and creatinine levels, preoperative urine cytology, therapeutic options including type of surgical procedure, chemotherapy regimen, and final pathological staging of tumor as well as multiple markers used in ihc staining of patients were recorded. the patient’s latest health status was obtained via phone call (at the end of october 2016) data was entered into spss software ver.19. kaplan-meier curves were employed to display survival and comparison of survivals across treatment groups was performed by logrank test. statistical significance was set a p-value less than 0.05. results during this period, 13 patients with a mean age of 64.92 years (range; 41-83) were diagnosed with smccb. three patients were female and ten were male. the reasons for referral were gross hematuria (12/13), uremia due to bilateral hydroureteronephrosis (6/13), lower abdominal pain due to large bladder mass (3/13), and flank pain (1/13). the mean (range) of presentation hemoglobin (hb) was 10.7 (7.7-14.8) mg/dl. renal functional impairment (cr > 1.5 mg/dl) was observed in six patients. the mean (range) of presentation creatinine was 2.1 (0.9-4.7) mg/dl. the findings of imaging modalities were large bladder mass, which had often a size greater than 5 cm. unilateral (n=1) or bilateral hydronephrosis (n=6) was observed in seven patients. in all patients, urinary cytology was positive for the presence of malignant cells. demographic, clinical, and laboratory data on patients has been presented in table 1. all patients underwent turbt. in 11 patients, histologic examination on primary turb specimen was not diagnostic and only after ihc staining smccb diagnosis was confirmed. in two patients in whom ihc was not performed, the initial histologic report of turbt specimen was high grade poorly differentiated urothelial carcinoma (figure 1). these two patients underwent radical cystectomy and the pathology report after radical cystectomy revealed smccb of bladder. details of pathological reports are presented in table 2. treatment methods in our patients were turbt alone (3/13), turbt with chemotherapy (4/13), radical surgery combined with chemotherapy (4/13), and radical surgery alone (2/13) (figure 1). the chemotherapy regimen included six courses of cisplatin and gemcitabine. smccb of bladder-kaffash nayeri et al. table 1. summary of demographic and clinical characteristics of 13 patients. table 2. pathologic and histologic details.. characteristics gender; male/female 10/3 age; mean, range 64.92 ( 41-83 ) years gross hematuria 12/13 lower abdominal pain ( large pelvic mass ) 3/13 uremia 6/13 flank pain 1/13 creatinine at diagnosis; mean, range 2.13 mg/dl ( 0.9 – 4.7 ) hemoglobin at diagnosis; mean, range 10.7 mg/dl ( 7.7 – 14.8 ) tumor size in imaging; mean, range 7.54 cm ( 2 – 12 ) bilateral hydronephrosis 6/13 unilateral hydronephrosis 1/13 abbreviation: smccb, small cell carcinoma of bladder stage at least t2 7/13 t3a n ̶ 1/13 t3a n+ 1/13 t3b n+ 1/13 t4a n+ 3/13 pure smccb 10/13 smccb + ucc 1/13 smccb + ucc + cis 2/13 abbreviations: smccb, small cell carcinoma of bladder; ucc, urothelial cell carcinoma; cis, carcinoma insitu figure 1. summary of treatments and survival. abbreviations: turbt, transurethral resection of bladder tumor; cmt, chemotherapy; rc, radical cystectomy urological oncology 364 vol 17 no 04 july-august 2020 365 the reasons for the differences in the treatment modalities were clinical judgment, patient's health, serum creatinine, performance status as well as his/her desire. the summary of treatment and survival has been shown in table 3 and figures 2 through 5. the mean (standard error (se)) of survival in patients who received and did not receive chemotherapy were 36.4 (8.5) vs. 6.5 (1.0) months (p = .009; figure 2) while the difference based on receiving surgery was not statistically significant (figure 3). the mean (se) survival of patients in clinical / pathological stages of t2, t3, and t4 independently of their treatment strategy were 41.1 (11.1), 25.1 (12.6), and 28.4 (11.6) months respectively (p = .73; figure 4) the mean (se) of survival in patients without any treatment, only surgery, only chemotherapy, and chemotherapy with radical surgery were 4.9 (1.2), 8.8 (0.6), 42.4 (10.0), and 47.7 (10.9) months respectively (p = .001; figure 5) in macroscopic pathologic examination, all cases showed a large tumor, filling most of the bladder cavity. gross areas of necrosis were also evident. in all cases, areas of invasion into muscularis propria were noted. diagnosis of smccb, however, was suggested in simple microscopic examination of tissues but for definitive diagnosis, ihc staining was recommended for 17 pathology samples (11 turbt and 6 radical surgery cases; figure 6). as previously stated the pathology diagnosis in the only two samples which were reported without ihc staining was inaccurate (figure 1). ihc staining was performed with an average of eight markers(6–16) for each patient. we used a panel of neuroendocrine markers as cd 56, neuron specific enolase (nse), synaptophysin, and chromogranin to confirm the diagnosis (figure 6). at least two of these markers were positive in each patient (table 4). we also performed a combination of ihc staining for ck 7, ck 20, p63, cd 45, psa, cd 99, desmin, and myogenin to rule out urothelial carcinoma, lymphoma, prostatic adenocarcinoma, ewing sarcoma, and rhabdomyosarcoma. discussion table 3. summary of all patients’ data. n age gender serum cr c stage* rc cmt p stage survival follow up (months) 1 77 male 1.63 t2 nd d t2* alive 54 2 41 male 3.3 d d t3b n+ alive 52.8 3 75 female 1.0 t3 nd nd t2* deceased 6.2 4 59 male 1.4 d d t4a n+ alive 50.5 5 47 male 1.3 t2 nd d t2* alive 40.7 6 75 male 4.7 t2 nd nd t2* deceased 2.6 7 62 male 1.9 t4 n+ nd nd t2* deceased 6 8 62 male 2.8 d d t4a n+ alive 60.3 9 62 female 1.3 d d t3a n+ deceased 10 10 61 female 2.2 d nd t4a n+ deceased 8 11 66 male 4.1 t4 nd d t2* deceased 7.6 12 74 male 1.2 d nd t3a nalive 9.6 13 83 male 0.9 t2 nd d t2* alive 9.4 abbreviations: rc, radical cystectomy; cmt, chemotherapy; p stage, pathological stage; d, done; nd, not done; cr, creatinine t2*: least pathological stage because patient only underwent turbt c stage*: clinical stage according to imaging in patients only underwent turbt figure 2. kaplan-meier curves to compare survival across survival based on receiving chemotherapy (dotted line denoted patients who received chemotherapy and solid line indicates patients who did not receive chemotherapy) figure 3. kaplan-meier curves to compare survival across survival based on receiving surgery or not (dotted line denoted patients who received surgery and solid line indicates patients who did not receive surgery) smccb of bladder-kaffash nayeri et al. the results of this study reveals that for definitive diagnosis of smccb, ihc is necessary as in all properly diagnosed pathology specimens, ihc was performed and in 2 improperly diagnosed samples, ihc was not requested. furthermore, chemotherapy seems to be the mainstay of treatment, however adding surgery to chemotherapy may increase patient survival; however this benefit was not statistically significant in our series. smcc is a rare tumor with a very aggressive behavior, and accounts for less than 1% of bladder malignancies (2,8). despite the recognition of disease since 1981 by cramer et al.(9), less than 1,000 cases of this disease have been reported so far, and most published studies are small case series(6). this type of bladder cancer has many challenging aspects especially in diagnosis and treatment methods. the histological diagnosis of the disease is not so easy and evidence suggests that diagnostic errors in the bladder smcc may occur frequently. a large study by linder and his colleagues reclassified smccb in 9% of the cases with inconsistency in previous histopathological diagnosis(10). in another study by kaushik et al., a review by a uropathologist, the rate of smccb detection increased(11). diagnosis of smccb is based on the who criteria by light microscopic examination(12). on microscopic examination, discrimination of smccb from pulmonary type is impossible(13). the tumor usually shows a patternless diffuse growth, composed of round small cells in nests or sheets with scant cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli. the nuclei show nuclear crowding and molding. geographic necrosis, crush artifact, azzopardi effect, and frequent mitotic figures are usually evident(14). the microscopic features of hematoxylin and eosin staining (h&e) sections usually lead to diagnosis. nevertheless, for further confirmation and ruling out major differential diagnoses including malignant lymphoma, poorly differentiated urothelial carcinoma and rhabdomyosarcoma, ihc studies are usually performed. for the first time in 1986, ordonez and colleagues used ihc staining to detect the differentiation of neuroendocrine cells, constituting the origin of this type of cancer (15). smccb exhibits both neuroendocrine and epithelial markers(6). a recent study has reported that cd56 may be among the most sensitive neuroendocrine markers, staining 71.4% of bladder smcc cases, followed by synaptophysin and chromogranin(16). neuron specific enolase (nse) is positive in 25-100%, chromogranin in 22-89%, and synaptophysin in 67-76% of smccb patients(14,17,18). several epithelial markers are also positive in this cancer. ck-7 and epithelial membrane antigen (ema) are positive in 60% and 80% of smccb patients, respectively(4,19). tumors show a dot-like positivity for pancytokeratin. markers of neuroendocrine differentiation including synaptophysin, chromogranin, cd 56, nse are usually positive in tumoral cells. however, cd 45, myogenin, and desmin are negative(20). ihc panel should include cd56, cd45, synaptophysin, cam-22, and ck8/18(6). in our experience, the ihc staining was performed with the aim of demonstrating the neuroendocrine differentiation, presence of epithelial elements, and excluding other malignancies. for each patient, between 6 and 16 markers and on average 8 markers were used. the use of ihc staining to diagnose smccb routinely is still controversial. some pathologists only use ihc staining for supplementation of morphological recognition, and believe that neuroendocrine markers are not required to make diagnosis(21). on the other hand, a ihc marker positive negative not performed cd56 9 (69%) 1 (8%) 3 (23%) nse 5 (38%) 1 (8%) 7 (54%) synaptophysin 7 (54%) 3 (23%0 3 (23%) chromogranin 4 (31%) 6 (46%) 3 (23%) table 4. positivity of markers of neuroendocrine differentiation in patients abbreviations: ihc, immunohistochemical; nse, neuron specific enolase figure 4. kaplan-meier curves to compare survival across survival based on pathological or clinical stage (narrow spaced dotted line indicates stage t2, wide dotted line indicates stage t4 and solid line indicates stage t3) figure 5. kaplan-meier curves to compare survival across survival based on treatment strategy (solid line indicates chemotherapy plus surgery, dashed line indicates only chemotherapy, wide spaced dotted line indicates only surgery, and narrow spaced dotted line indicates no treatment) smccb of bladder-kaffash nayeri et al. urological oncology 366 vol 17 no 04 july-august 2020 367 significant number of uropathologists also perform ihc staining to help and support smccb diagnosis(13). another opinion emphasizes the use of ihc staining for diagnostic confirmation ruling out some malignancies including lymphoma(6). in our experience, only ihc stained samples were correctly diagnosed at initial pathology examination of turbt samples despite evaluation of pathology samples by an experiences uro-pathologist with more than 20 years of experience. therefore, we strongly recommend the use of ihc for diagnosis of smccb in turbt samples. the rarity of this cancer has created many difficulties in the design of appropriate prospective clinical trials with the aim of finding better treatment modalities(22,23). for this reason, treatment modalities are not standard, and current therapeutic options are mainly based on limited retrospective small case series. the treatment requires a multiple and different clinical approach. the physician should be aware of the clinical stage of cancer in the initial presentation and the patient’s status , as it may impose some restrictions on the use of certain therapies (8,22). in this regard, in our experience, renal function impairment significantly affected proper chemotherapy and radical surgery in some patients. in a study, kouba et al. compared the results of 23 articles in the treatment of bladder small cell carcinoma (7). of these, only one paper was prospective and the rest were retrospective. the results of this study indicated that the highest average survival rate was observed in patients who underwent radical cystectomy with chemotherapy and/or radiotherapy, while the minimum survival was observed in the bladder sparing only without referring to the pathologic stage of the cancer. the primary manifestation in more than one-third of patients is advanced disease and distant metastases, and the average survival rate for all patients is 10-21 months. on the other hand, distant metastases, the most common cause of death in these patients, occur in 7080% of patients who do not respond to the treatment (24,25). therefore, chemotherapy plays an important role in the treatment of smccb, which is indeed the mainstay of smccb treatment(26). also, our patients’ data revealed that the therapeutic results in the chemotherapy received group were far better than those who did not receive chemotherapy for any reason. out of 8 chemotherapy receiving patients, six (75%) patients with an average survival of 46.377 months (range: 9.4 – 60.3) were alive at the last follow-up. interestingly, the percentages of patients undergoing radical surgery in stage t2, t3, and t4 were 0%,75%, and 60% respectively (table 3). on the other hand, 75% of patients in stage t2, 50% in stage t3, and 60% in stage 4 received chemotherapy. two patients with a pathological stage of t4a n+ with a mean 55.4-month follow up were alive at the last follow-up. for local cancer control, we only used radical surgery, and none of our patients was managed with radiotherapy. the difference in survival in patients undergoing surgery with those who were not operated is not significant. our study indicated that the average survival rate in patients undergoing radical surgery plus chemotherapy (47.7 months) was slightly superior however not statistically significant to patients who received only chemotherapy (42.4 months). according to these findings, we believe that the most effective treatment option for smccb given the clinical or pathological stage is chemotherapy and addition of radical surgery may offer a better survival. one of the clinical findings that attracted our attention was the relatively high prevalence of impaired renal function secondary to ureteral obstruction, of which six patients had serum creatinine levels above 1.5mg/dl. average serum cr levels in this group was 3.06 mg/ dl (1.6-4.7). this finding, together with the high prevfigure 6. a) microscopic examination of tumor shows patternless growth of discohesive small neoplastic cells with scant cytoplasms and hyperchromatic nuclei. the picture shows invasion of tumoral cells into muscularis propria; b) immunohistochemical staining reveals diffuse positive immunoreactions for cd 56 and nse in tumoral cells in one case (x20). c) immunohistochemical staining reveals diffuse positive immunoreactions for cd 56 and nse in tumoral cells in one case (x20). smccb of bladder-kaffash nayeri et al. alence of hydronephrosis, is associated with advanced disease at presentation and is consistent with the pathologic stage of the patients. in our patients, as mentioned above, the average size of the bladder mass in the first imaging was 7.54 cm. hydronephrosis and impaired renal function were seen in more than half of the patients in the first manifestation of the disease. in addition, the mean total creatinine in all 13 patients also lied within the range of renal failure. this issue, in addition to the advanced stage of the disease, will be a barrier to optimal radiological diagnosis with contrast agents and effective chemotherapy which as we discussed earlier constitutes the mainstay of treatment. the limitations of our study for clinical judgment are small number of cases, retrospective nature, different disease stage, different treatment modalities, and small cases in each stage. conslusions definitive diagnosis of smccb requires the help of ihc in most cases. chemotherapy constitutes the mainstay of treatment with additional surgery offering a slightly better survival. conflicts of interest all authors declare that there is no conflict of interest. references 1. shatagopam, k., et al., genitourinary small cell malignancies: prostate and bladder. future oncol, 2015. 11: 479-88. 2. pant-purohit, m., et al., small cell carcinoma of the urinary bladder. histol histopathol, 2010. 25: 217-21. 3. wong, y.n., et al., the epidemiology and survival of extrapulmonary small cell carcinoma in south east england, 1970-2004. bmc cancer, 2009. 9: 209. 4. blomjous, c.e., et al., small cell carcinoma of the urinary bladder. a clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. cancer, 1989. 64: 1347-57. 5. holmang, s., g. borghede, and s.l. johansson, primary small cell carcinoma of the bladder: a report of 25 cases. j urol, 1995. 153: 1820-2. 6. moretto, p., et al., management of small cell carcinoma of the bladder: consensus guidelines from the canadian association of genitourinary medical oncologists (cagmo). can urol assoc j, 2013. 7: e4456. 7. kouba, e.j. and l. cheng, understanding the genetic landscape of small cell carcinoma of the urinary bladder and implications for diagnosis, prognosis, and treatment: a review. jama oncol, 2017. 3: 1570-1578. 8. pasquier, d., et al., small cell carcinoma of the urinary bladder: a retrospective, multicenter rare cancer network study of 107 patients. int j radiat oncol biol phys, 2015. 92: 904-10. 9. cramer, s.f., m. aikawa, and m. cebelin, neurosecretory granules in small cell invasive carcinoma of the urinary bladder. cancer, 1981. 47: 724-30. 10. linder, b.j., et al., the impact of histological reclassification during pathology re-review-evidence of a will rogers effect in bladder cancer? j urol, 2013. 190: 1692-6. 11. kaushik, d., et al., long-term results of radical cystectomy and role of adjuvant chemotherapy for small cell carcinoma of the bladder. int j urol, 2015. 22: 549-54. 12. bajetta, e., et al., is the new who classification of neuroendocrine tumours useful for selecting an appropriate treatment? ann oncol, 2005. 16: 1374-80. 13. thota, s., et al., a clinical review of smallcell carcinoma of the urinary bladder. clin genitourin cancer, 2013. 11: 73-7. 14. abrahams, n.a., et al., small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases. histopathology, 2005. 46: 57-63. 15. ordonez, n.g., et al., oat cell carcinoma of the urinary tract. an immunohistochemical and electron microscopic study. cancer, 1986. 58: 2519-30. 16. buza, n., et al., inverse p16 and p63 expression in small cell carcinoma and highgrade urothelial cell carcinoma of the urinary bladder. int j surg pathol, 2010. 18: 94-102. 17. trias, i., et al., small cell carcinoma of the urinary bladder. presentation of 23 cases and review of 134 published cases. eur urol, 2001. 39: 85-90. 18. zhao, x. and e.a. flynn, small cell carcinoma of the urinary bladder: a rare, aggressive neuroendocrine malignancy. arch pathol lab med, 2012. 136: 1451-9. 19. wang, x., et al., small cell carcinoma of the urinary bladder--histogenesis, genetics, diagnosis, biomarkers, treatment, and prognosis. appl immunohistochem mol morphol, 2007. 15: 8-18. 20. amin, m.b., histological variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications. mod pathol, 2009. 22 suppl 2: s96-s118. 21. berniker, a.v., et al., extrapulmonary small cell carcinoma: imaging features with radiologic-pathologic correlation. radiographics, 2015. 35: 152-63. 22. lynch, s.p., et al., neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the md anderson cancer center. eur urol, 2013. 64: 307-13. 23. bhatt, v.r., et al., risk factors, therapy and smccb of bladder-kaffash nayeri et al. urological oncology 368 vol 17 no 04 july-august 2020 369 survival outcomes of small cell and large cell neuroendocrine carcinoma of urinary bladder. rare tumors, 2014. 6: 5043. 24. bryant, c.m., et al., treatment of small cell carcinoma of the bladder with chemotherapy and radiation after transurethral resection of a bladder tumor. am j clin oncol, 2016. 39: 69-75. 25. schreiber, d., et al., characterization and outcomes of small cell carcinoma of the bladder using the surveillance, epidemiology, and end results database. am j clin oncol, 2013. 36: 126-31. 26. boyer, a.c., et al., neuroendocrine carcinoma of the urinary bladder: a retrospective study of ct findings. abdom imaging, 2013. 38: 8706. smccb of bladder-kaffash nayeri et al. u j 03 all-2.pdf 600 | is bowel preparation necessary before kidney-ureter-bladder radiography and intravenous urography? farid dadkhah,1 mohammad reza safarinejad,2 erfan amini,1 mohammad soleimani,1 alireza lashay1 purpose: materials and methods: results: mean total score for visualization of the urinary system on plain and contrast images did p images (p = .001). conclusion: keywords: castor oil, cathartics, radiography, urography corresponding author: mohammad reza safarinejad, md p.o. box: 19395-1849, tehran, iran tel: +98 21 2245 4499 fax: +98 21 2245 6845 e-mail: info@safarinejad. com received august 2011 accepted january 2012 1department of urology, shahid modarress hospital, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran 2private practice of urology and andrology, tehran, iran miscellaneous miscellaneous 601vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l introduction b centers to improve the image quality and visibility of the uriand impair the quality of images. (1-9) suffering from functional constipation. we conducted this prospective randomized trial to assess tion. materials and methods patient prior to inclusion and the local medical ethics committee approved the study protocol. (10) cal indications. vided into 5 anatomical regions, including the right renal, left renal, right ureteral, left ureteral, and pelvic regions, and quality in this study (table 2).(11) tient belonged to. table 1. rome iii diagnostic criteria for functional constipation.* 1. must include two or more of the followings: straining during at least 25% of defecations lumpy or hard stools in at least 25% of defecations sensation of incomplete evacuation for at least 25% of defecations sensation of anorectal obstruction or blockage for at least 25% of defecations manual maneuvers to facilitate at least 25% of defecations (eg, digital evacuation, support of the pelvic floor) fewer than three defecations per week 2. loose stools are rarely present without the use of laxatives 3. insufficient criteria for irritable bowel syndrome *criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. bowel preparation prior to kub and ivu | dadkhah et al 602 | tion method as not unpleasant, unpleasant, or very unpleasresults p = .253, mannwhitney u p = .101, mann-whitney u test). 4). subjects. mean total score for visualization of the urinary p = .694, mann-whitney u test). p = .463, mann-whitney u sus 16.1%, p severe abdominal pain occurred in 21 (23.1%), nausea in 9 (9.9%), and vomiting in 4 (4.4%) patients. thirty-seven (40.6%) patients reported the effects of castor oil as unpleasant and 15 (16.5%) as very unpleasant. discussion ureter-bladder radiography in evaluation of the ureteral and (12) table 2. european commission guidelines for evaluation of image quality. image criteria before administration of contrast medium criterion 1 reproduction of the area of the whole urinary tract from the upper pole of the kidney to the base of the bladder criterion 2 reproduction of the kidney outlines criterion 3 visualization of the psoas outlines criterion 4 visually sharp reproduction of the bones image criteria after administration of contrast agent criterion 1 increase in parenchymal density (nephrographic effect) criterion 2 visually sharp reproduction of the renal pelvis and calyces (pyelographic effect) criterion 3 reproduction of the ureteropelvic junction criterion 4 visualization of the area normally traversed by the ureter criterion 5 reproduction of the whole bladder area miscellaneous 603vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l bowel preparation prior to kub and ivu | dadkhah et al ning technique, is becoming more common in investigation urography has a high diagnostic accuracy and may simplify (13) performed in many radiologic centers. to improve the diagnostic quality of the image. a survey at administered at 14 of 15 departments.(2) schuster and col(5) and associates reported moderate or severe side effects in (1) effects of the laxatives to be unpleasant or very unpleasant. (2) of fecal peritonitis.(14) preparation are common and can be especially devastating for bedridden and elderly patients. high incidence of adverse effects and discomfort. we found trast images in this subgroup of patients. dressed previously in several clinical trials.(1-9) they condecrease the fecal residue at the expense of patient discomfort. create excessive gas that compromises the image quality and diagnostic accuracy.(6) guo and colleagues selected 3 laxanecessary for satisfactory visualization of the urinary system table 3. patients’ characteristics. gender, n (%) male female 60 (65.9) 61 (64.2) .805* 31 (34.1) 34 (35.8) constipation, n (%) yes no 17 (18.7) 22 (23.2) .453† 74 (81.3) 73 (76.8) mean age, y 42.2 ± 14.8 42.0 ± 14.0 .9372 mean body mass index, kg/m2 23.9 ± 2.9 23.6 ± 2.8 .4962 *chi-square test † t test table 4. comparing the quality of plain images in prepared and unprepared subjects considering their bowel habit patterns. number of patients visualization score p image quality based on european commission guidelines p patients with constipation group 1 group 2 17 11.53 ± 2.40 .001 3.47 ± 0.87 .005 22 8.81 ± 2.32 2.54 ± 0.80 patients with normal bowel habits group 1 group 2 74 12.04 ± 1.91 .253 3.60 ± 0.66 .101 73 12.36 ± 1.62 3.70 ± 0.62 604 | anatomical section in control images, guo and associates noted a higher visualization score of the right renal region visualization score of the right renal region on the control image. including polyethylene glycol, dietary restriction, and no preparation at all. they noted an equal amount of gas in the (9) dehydration has been considered to provide greater concentration of contrast and better visualization of the collecting system.(15) (16) (17-19) and noted that active hydration may even produce a diagnostic quality urogram.(19) cially in diabetic patients.(20,21) ologists (2005) does state that dehydration prior to contrast contrast-induced nephropathy.(22) may suffer from constipation due to medication or immobility. chronic constipation has not been evaluated previously. to has been evaluated in patients suffering from functional constipation. conclusion from historical reports and do not seem to be evidence-based practices. type and amount of contrast agents, the radiographic equipments, and the availability of tomography also affect the trast, the larger volumes used, and advances in radiographic equipment and technique, the routine use of catharsis and ditable 5. comparing the quality of contrast images in prepared and unprepared subjects considering their bowel habit patterns. number of patients visualization score p image quality based on european commission guidelines p patients with constipation group 1 group 2 8 13.00 ± 1.31 .694 4.38 ± 0.52 .463 7 12.71 ± 1.25 4.14 ± 0.38 patients with normal bowel habits group 1 group 2 35 13.26 ± 1.31 .282 4.29 ± 0.46 .443 27 12.93 ± 1.17 4.37 ± 0.56 miscellaneous 605vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l conflict of interest none declared. references 1. roberge-wade ap, hosking dh, macewan dw, ramsey ew. the excretory urogram bowel preparation--is it necessary? j urol. 1988;140:1473-4. 2. bailey sr, tyrrell pn, hale m. a trial to assess the effectiveness of bowel preparation prior to intravenous urography. clin radiol. 1991;44:335-7. 3. george cd, vinnicombe sj, balkissoon ar, heron cw. bowel preparation before intravenous urography: is it necessary? br j radiol. 1993;66:17-9. 4. jackson s, buxton p, hacking cn. bowel preparation before intravenous urography: is it necessary? br j radiol. 1994;67:417-8. 5. schuster ga, nazos d, lewis ga. preparation of outpatients for excretory urography: is bowel preparation with laxatives and dietary restrictions necessary? ajr am j roentgenol. 1995;164:1425-8. 6. bradley aj, taylor pm. does bowel preparation improve the quality of intravenous urography? br j radiol. 1996;69:9069. 7. dixon gd. bowel preparation for excretory urography. ajr am j roentgenol. 1996;166:721; author reply 2. 8. guo h, huang y, xi z, song y, guo y, na y. is bowel preparation before excretory urography necessary? a prospective, randomized, controlled trial. j urol. 2006;175:665-8; discussion 9. 9. jansson m, geijer h, andersson t. bowel preparation for excretory urography is not necessary: a randomized trial. br j radiol. 2007;80:617-24. 10. longstreth gf, thompson wg, chey wd, houghton la, mearin f, spiller rc. functional bowel disorders. gastroenterology. 2006;130:1480-91. 11. european commission. european guidelines on quality criteria for diagnostic radiographic images, report eur 16260. luxembourg: office for official publications of the european communities, 1996. 12. alshamakhi ak, barclay lc, halkett g, et al. ct evaluation of flank pain and suspected urolithiasis. radiol technol. 2009;81:122-31. 13. stacul f, rossi a, cova ma. ct urography: the end of ivu? radiol med. 2008;113:658-69. 14. galloway d, burns hj, moffat le, macpherson sg. faecal peritonitis after laxative preparation for barium enema. br med j (clin res ed). 1982;284:472. 15. benness gt. urographic excretion study dehydration and dose. australas radiol. 1967;11:261-4. 16. sherwood t, doyle fh, breckenridge a, dollery ct, steiner re. value of fluid deprivation in large-dose urography. lancet. 1968;2:754-5. 17. bell ke, mcilrath em. dehydration in urography: is it really necessary? clin radiol. 1985;36:311-2. 18. bergman la, ellison mr, dunea g. acute renal failure after drip-infusion pyelography. n engl j med. 1968;279:1277. 19. dure-smith p. fluid restriction before excretory urography. radiology. 1976;118:487-9. 20. spangberg-viklund b, nikonoff t, lundberg m, larsson r, skau t, nyberg p. acute renal failure caused by low-osmolar radiographic contrast media in patients with diabetic nephropathy. scand j urol nephrol. 1989;23:315-7. 21. berg kj. nephrotoxicity related to contrast media. scand j urol nephrol. 2000;34:317-22. 22. board of the faculty of clinical radiology. the royal college of radiologists, standards for iodinated intravascular contrast agent administration to adult patients. london: royal college of radiologists, 2005. bowel preparation prior to kub and ivu | dadkhah et al review 62 urology journal vol 4 no 2 spring 2007 penile replantation, science or myth? a systematic review ali reza babaei,1 mohammad reza safarinejad2 introduction: penile amputation is a rare urologic condition for which immediate surgical replantation is warranted. the surgical technique used for repair has been modified and refined. our aim was to assess the effects of several interventions and management for amputated penis after replantation. materials and methods: we searched the medline (january 1966 to may 2007), embase (january 1988 to january 2007), cinahl (january 1982 to january 2007), psyclit (january 1984 to january 2007), eric (january 1984 to january 2007), and the bibliographic data of relevant articles; hand-searched conference proceedings; and contacted investigators to locate studies. all reported cases of penile replantation were studied. we assessed all titles, abstracts, and extracted data from the articles identified for inclusion. outcome measures included cosmetic outcomes, acceptability, operative time, restoration of erectile function, sensibility of the glans, and long-term outcomes. results: eighty patients had undergone penile replantation. there was considerable variation in the interventions, patients, and outcome measures. the majority of the reported cases in this area continue to be of moderate quality, although more recent cases have been of higher quality in terms of both patients’ demographics and surgical techniques. data were not available in all of the cases for many of the outcomes expected to be reported. there were several important variations in the cases studied. conclusion: the value of the various microsurgical techniques for replantation of the penis remains uncertain. meticulous microsurgical techniques by experienced surgeons can reduce skin, urethra, and graft loss complications and produce a functional organ; nonetheless, such complications are still highly prevalent. urol j. 2007;4:62-5. www.uj.unrc.ir keywords: amputation, penile replantation, microvascular surgery, penis 1artesh university of medical sciences, tehran, iran 2urology and nephrology research center, shaheed beheshti medical university, tehran, iran corresponding author: mohammad reza safarinejad, md po box: 19395-1849 tehran, iran tel: +98 21 2245 4499 fax: +98 21 2245 6845 e-mail: safarinejad@unrc.ir introduction penile amputation is a rare condition. it has been reported in both adult and pediatric groups,(1,2) but the majority are in adult patients. they can occur as a result of self-mutilation of psychiatric patients, accidents, circumcision, and workplace injury,(3,4) or can be caused by other people’s actions such as violence, envy, and crime. self-mutilations of the external genitals are also known as klingsor syndrome.(5) stepwise complete selfemasculation and self-castration has also been reported.(6) at least 4 patients with self-amputation have been reported who died of hemorrhage.(7) penile replantation was first described in the medical literature in 1929.(8) in the last decade, numerous successful operative techniques have been described for penile replantation with microsurgical methods. the current standard of care for this rare entity is replantation with approximation penile replantation—babaei and safarinejad urology journal vol 4 no 2 spring 2007 63 of the urethra, corporal bodies, and microsurgical dorsal vein anastomosis. in 1977, the first successful replantation of an amputated penis using microsurgical techniques was reported.(9) due to the rarity of penile amputation, the number of reports dealing with this procedure and the postoperative patient care is limited. evaluation of the relative effectiveness, safety, restoration of functional penis, and sensibility of the glans of different methods for penile replantation is crucial for surgeons who make decision. a review of the published data and future methods of increasing success of microsurgical procedures is provided. additionally, a systematic approach to dealing with this devastating injury is presented. the studied outcome measures were return of penile sensation, acceptable sexual function, and normal urination. materials and methods a comprehensive search and review protocol was designed and processed all by the authors. sources all reports that have described penile replantation were obtained. the medline (january 1966 to may 2007), embase (january 1988 to january 2007), cinahl (january 1982 to january 2007), psyclit (january 1984 to january 2007), and eric (january 1984 to january 2007), were searched. the following keywords were used for the search as text words or subject headings without language restriction using ovid software: amputation, autoamputation, penile replantation, microvascular surgery, and penis. in addition, hand searching of the bibliographies and citation lists of all relevant reviews and primary studies was performed to identify articles not captured by electronic searches as well as the proceedings of the urological associations in the past 2 decades. study selection all case reports and articles were selected. the authors selected the articles for inclusion after using the search strategy described previously. description of studies after evaluation of the abstracts, we excluded articles that were clearly not on penile replantation or had not focused on interventions or outcome measures considered in this review. ultimately, we retrieved copies of 46 potentially relevant reports. data abstraction and quality assessment all assessments and data extraction were performed independently by the 2 authors of the review. data on characteristics of the study participants including age, medical illnesses, type of injury, time since amputation, measures to preserve the amputated organ, type of surgical interventions, follow-up period, and methods used to measure success and adverse events were extracted. when possible, we described the method used by the investigators to assess objective outcomes. preoperative adjunctive measures for organ preserving and preparing the amputated part of the penis, various preoperative adjunctive measures have been used.(10-13) these measures are as follows: (1) thoroughly washing the amputated penis with 0.9% saline and placing it in a pressurized hypothermic container at 4°c; (2) wrapping the amputated penis in moist gauze inside a plastic bag sealed within a second plastic bag containing iced slush; (3) placing the amputation part of penis in an ice container; (4) sterilization of the amputated penis and preparing it for anastomosis with 1% chlorhexidine solution, and immersing it in a 1% sodium heparin-saline solution; and (5) irrigation of the amputated penis with normal saline and antibiotics. postoperative adjunctive measures for protection of anastomoses sites and the phallus, and for preserving the amputated part of the penis, various wound care methods have been used postoperatively,(10-13) including (1) administration of broad-spectrum antibiotics and heparin or low-molecular-weight heparin; (2) treatment with hyperbaric oxygen; and (3) immobilization and protection of the penis by bulky dressing, frames, cages, removal of the penile skin with subsequent burying of the penis in the scrotum, and a subcutaneous tunnel created in the suprapubic area. surgical methods before replantation, a suprapubic cystostomy penile replantation—babaei and safarinejad 64 urology journal vol 4 no 2 spring 2007 was being performed, routinely. debridement of nonviable tissue was being done to allow clear identification of the veins, nerves, and arteries. in all of the cases, end-to-end anastomosis of the urethra and corpus spongiosum was also done using interrupted synthetic absorbable suture. then, reaproximation of the tunica albuginea of the corpora cavernosa was being performed. as a last step, the buck’s and colles’ fasciae were being reapproximated, and the skin was being closed. in dealing with arteries, veins, and nerves, one of the following methods were being employed: (1) realignment of the penile structures (urethra, corpus spongiosum, and corpus cavernosum) without anatomizing the blood vessels or nerves; (2) microsurgical end-to-end anastomosis of the dorsal penile artery; (3) creating a spongiocavernosal shunt distally to provide venous drainage, in patients whose dorsal vein was severely injured, thus preventing primary reanastomosis with a microsurgical technique; (4) anastomosing 2 dorsal veins using nylon nonabsorbable sutures; (5) microvascular anastomosis of the deep dorsal vein and 1 artery; (6) microvascular anastomosis of the deep dorsal vein and the dorsal arteries; (7) anastomosing 2 dorsal veins, the dorsal artery, and 1 dorsal nerve using microsurgical technique; and (8) anastomosing 2 dorsal veins, the dorsal artery, and 2 dorsal nerves using microsurgical technique. heretofore, microsurgical anastomosis of the dorsal veins, dorsal artery, and dorsal nerve has been accomplished in about 27 cases. results fifty cases of replantation using nonmicrosurgical technique, and at least 30 cases of replantation by microsurgical technique were reported. varying degrees of reanastomosis of the dorsal vein, arteries, and nerves have been reported using microsurgical technique. even after microsurgical replantation, spontaneous erections and the ability to intromit during sexual intercourse with full sensation in the glans are very rare. of amputations that were microsurgically replanted, at least 27 cases were successful. replantation of the penis without microsurgery techniques was associated with a high rate of fistula formation, urethral stenosis, skin necrosis, loss of sensation, and erectile dysfunction. venous outflow was a critical factor for the success of replantation. by reviewing and compiling case reports of microsurgical replantation, we concluded that microsurgical reanastomosing of the dorsal penile vein, penile arteries, and dorsal nerves can be identified as the “standard” method for penile replantation. microsurgical repair was associated with greater graft survival, decreased amount of skin loss, better erectile function, and better cosmetic results. various patient variables play an important role in the success of replantation. discussion the first documented case of penile replantation was reported in 1929 by ehrich(8) who realigned the penile structures without anatomizing the blood vessels or nerves. the first microvascular replantation was reported by cohen and colleagues in 1977.(9) because of the paucity of penile amputation, management of this entity has evolved on the basis of only a few case reports and small series. many factors contribute to positive final results: the degree of injury, type of injury (crushed, lacerated, or incised), duration of warm ischemia, the equipment used, and experience of the operative team.(14,15) graft survival without microvascular anastomosis depends on corporal sinusoidal blood flow. in this instance, glans and distal penile amputations are created as composite grafts by anastomosing the urethra and the corpora. nonmicrovascular anastomosis has been associated with multiple complications such as fistula formation, skin necrosis, urethral stricture, absent sensation, and erectile dysfunction. in a series from thailand, 14 of 18 replantations were done with a nonmicrosurgical technique. skin loss was reported in 12 of 14 and graft loss in 6 of 14 patients.(16) treatment of penile amputation has been greatly improved by microvascular techniques. early restoration of blood flow provides the best prospect for graft survival and normal erectile functional. the literature shows at least 27 cases of penile autoamputation with successful microsurgical replantation since 1970. penile amputation is seen most frequently in psychotic individuals with an acutely decompensated schizophrenia. in the early postoperative course, the risk of self-mutilation of the replanted penis is high. harris and coworkers recommended the use penile replantation—babaei and safarinejad urology journal vol 4 no 2 spring 2007 65 of a subcutaneous tunnel created in the suprapubic area to protect the penis from re-injury.(17) all nonviable tissues must be debrided to allow clear identification of the veins, arteries, and nerves. at the completion of replantation, revascularization must be checked. color of the distal penis is a good predictor of revascularization. gradual increase in redness and size of the distal penis demonstrates good blood supply. presence of the arterial pulse and appearance of superficial penile veins are other signs of revascularization. doppler ultrasonography is a good modality for monitoring of vascularity. venous outflow is a critical factor for the success of replantation. in cases that restoration of venous drainage is impossible, leech therapy can be successful.(11,12) leech therapy is a well documented means of relieving venous congestion in both plastic and reconstructive surgery literature.(18-20) the current concept is that microsurgical reaproximation of the penile shaft structures provides the optimal benefit owing to having the fewest complications. conclusion for penile amputation, microvascular replantation is the treatment of choice. microsurgical anastomoses of the vessels and nerves provide preservation of sensation, physiologic micturition, and normal erectile function. acknowledgements we would like to thank dr farhat farrokhi for his editorial assistance. conflict of interest none declared. references 1. yamano y, tanaka h. replantation of a completely amputated penis by the microsurgical technique: a case report. microsurgery. 1984;5:40-3. 2. sanger jr, matloub hs, yousif nj, begun fp. penile replantation after self-inflicted amputation. ann plast surg. 1992;29:579-84. 3. aydin a, aslan a, tuncer s. penile amputation due to circumcision and replantation. plast reconstr surg. 2002;110:707-8. 4. fuller a, bolt j, carney b. successful microsurgical penile replantation after a workplace injury. urol int. 2007;78:10-2. 5. schweitzer i. genital self-amputation and the klingsor syndrome. aust n z j psychiatry. 1990;24:566-9. 6. rana a, johnson d. sequential self-castration and amputation of penis. br j urol. 1993;71:750. 7. al-waili ns, butler gj. effects of hyperbaric oxygen on inflammatory response to wound and trauma: possible mechanism of action. sci world j. 2006;6:425-41. 8. ehrich ws. two unusual penile injuries. j urol. 1929;21:239-41. 9. cohen be, may jw jr, daly js, young hh. successful clinical replantation of an amputated penis by microneurovascular repair. case report. plast reconstr surg. 1977;59:276-80. 10. yeniyol co, yener h, keçeci y, ayder ar. microvascular replantation of a self amputated penis. int urol nephrol. 2002;33:117-9. 11. mineo m, jolley t, rodriguez g. leech therapy in penile replantation: a case of recurrent penile selfamputation. urology. 2004;63:981-3. 12. pantuck aj, lobis mr, ciocca r, weiss re. penile replantation using the leech hirudo medicinalis. urology. 1996;48:953-6. 13. zhong z, dong z, lu q, et al. successful penile replantation with adjuvant hyperbaric oxygen treatment. urology. 2007;69:983.e3-5. 14. darewicz b, galek l, darewicz j, kudelski j, malczyk e. successful microsurgical replantation of an amputated penis. int urol nephrol. 2001;33:385-6. 15. darewicz j, gatek l, malczyk e, darewicz b, rogowski k, kudelski j. microsurgical replantation of the amputated penis and scrotum in a 29-year-old man. urol int. 1996;57:197-8. 16. bhanganada k, chayavatana t, pongnumkul c, et al. surgical management of an epidemic of penile amputations in siam. am j surg. 1983;146:376-82. 17. harris dd, beaghler ma, stewart sc, freed jr, hendricks dl. use of a subcutaneous tunnel following replantation of an amputated penis. urology. 1996;48:628-30. 18. kraemer ba, korber ke, aquino ti, engleman a. use of leeches in plastic and reconstructive surgery: a review. j reconstr microsurg. 1988;4:381-6. 19. mutimer kl, banis jc, upton j. microsurgical reattachment of totally amputated ears. plast reconstr surg. 1987;79:535-41. 20. gross mp, apesos j. the use of leeches for treatment of venous congestion of the nipple following breast surgery. aesthetic plast surg. 1992;16:343-8. 52 urology journal vol 4 no 1 winter 2007 case report plexiform neurofibroma of penis—mazdak and gharaati urology journal vol 4 no 1 winter 2007 53 plexiform neurofibroma of penis hamid mazdak, mohammad reza gharaati urol j (tehran). 2007;4:52-4. www.uj.unrc.ir keywords: urogenital cancers, penis, neurofibroma department of urology, al-zahra hospital, isfahan university of medical sciences, isfahan, iran corresponding author: mohammad reza gharaati, md department of urology, al-zahra hospital, sofeh st, isfahan, iran tel: +98 311 265 4766 e-mail: gharaati@resident.mui.ac.ir received january 2006 accepted december 2006 introduction neurofibromas are tumors originating from the schwann cells in the neural sheath of the cranial, peripheral, and visceral nerves. the gross appearance of neurofibromas varies greatly in different lesions. superficial tumors appear as small, soft, pedunculated, or sessile nodules protruding from the skin. but, deeper tumors are larger. tumors resulting in diffuse tortuous enlargement of the peripheral nerves are designated as plexiform neurofibromas.(1) this particular form of neurofibroma is more commonly seen in the orbit, the neck, the back, and the inguinal region, and diffuse involvement of the nerves may make complete resection impossible. primary neurofibromas of the penis are extremely rare. to our knowledge, since 1970, only 7 cases have been reported.(2,3) we hereby report another case of plexiform neurofibroma of the penis. case report a 5-year-old mentally and developmentally retarded boy presented with massive penile enlargement started shortly after circumcision 2 years earlier. he had a history of laryngomalacia in infancy, which had improved without surgery, and a history of tonsillectomy and left orchiopexy. there was no family history of a similar condition. physical examination revealed massive enlargement of the entire penis with firm consistency and no tenderness (figure 1). he did not have any cafeau-lait spots anywhere. in addition, he had dysarthria. the kidneys and the bladder were normal on ultrasonography. magnetic resonance imaging (mri) revealed a large penile mass with extensive involvement of the cavernous bodies and corpus spongiosum (figures 2 and 3). figure 2. magnetic resonance imaging shows a penile mass with involvement of the cavernous bodies (t1 weighted imaging). figure 1. penile shaft enlargement. 52 urology journal vol 4 no 1 winter 2007 case report plexiform neurofibroma of penis—mazdak and gharaati urology journal vol 4 no 1 winter 2007 53 cystoscopy was indicative of a nonobstructive urethra. he underwent operative treatment through a circumferential subcoronal incision and the penis was degloved. the large penile mass was adherent to the underlying the tunica albuginea of both corpora cavernosa and corpus spongiosum. complete excision of the mass was impossible in the base and the dorsal aspect of the penis because of the large size of the lesion and the risk of neurovascular injury. partial excision of the mass was therefore performed. histopathologic study revealed bundles of spindle cells separated by fibrous septa in a mixoid matrix, suggestive of plexiform neurofibroma (figure 4). immunostaining was positive for s-100 protein (a marker of the glial and schwann cells), but negative for actin (a marker of the smooth muscle cells and myofibroblasts), desmin, and myo-d1 (markers of the smooth and striated muscle cells). at the 13th postoperative month, there was no significant increase in the size of the residual tumor on physical examination. discussion multiple neurofibromas represent the most important component of the genetically determined disorder known as neurofibromatosis or von recklinghousen’s disease. cafe-au-lait spots are characteristic cutaneous lesions of classic neurofibromatosis. plexiform neurofibromas, which are usually seen in the context of type 1 neurofibromatosis, may result in massive enlargement of a limb or some other part of the body (elephantiasis neuromatosa).(1) primary neurofibroma of the penis in children is an extremely rare disease, and since 1970, only 7 cases have been reported.(2,3) all of the reported patients had presented with an abnormally enlarged penis. some of them had cafe-au-lait spots on their skin, but some others had no skin lesion or any sign suggestive of cranial or visceral nerve involvement, and the huge plexiform neurofibroma of the penis had been the only manifestation of the disease.(3) one reported patient had a large penile mass, numerous cafe-au-lait spots over his entire body, trouble in coordinating upper extremities, dysarthria, and dysphagia.(2) in most of the previously reported cases, tumors have been small and completely excised. in 1 case, the mass was contiguous with the dorsal neurovascular bundle of the penis, and therefore, was only partially excised.(2) in 2 other cases, partial penectomy was done because of extensive involvement of the cavernous bodies and the corpus spongiosum.(3,4) unlike cutaneous neurofibromas, plexiform neurofibroma may undergo malignant transformation.(3) therefore, the optimal treatment figure 3. penile mass (t2 weighted imaging). figure 4. histopathologic study revealed bundles of the spindle cells separated by fibrous septa in a mixoid matrix (hematoxylineosin, × 40). plexiform neurofibroma of penis—mazdak and gharaati 54 urology journal vol 4 no 1 winter 2007 is complete excision of the tumor. however, partial resection with close follow-up is recommended when complete resection might result in major neurovascular or functional defect of the penis. follow-up consists of periodic physical examination and mri.(3) references 1. rosenblum mk. neuromuscular system. in: rosay j, editor. rosai and ackerman’s surgical pathology. 9th ed. st louis: mosby; 2004. p. 2266-9. 2. littlejohn jo, belman ab, selby d. plexiform neurofibroma of the penis in a child. urology. 2000;56: 669. 3. rodo j, medina m, carrasco r, morales l. enlarged penis due to a plexiform neurofibroma. j urol. 1999;162:1753-4. 4. mathews r, patil u, uner a, landas s, mahanta rk. giant neurofibroma of the penis in a child. br j urol. 1996;78:649-50. case report appendiceal conduit: a novel technique to be applied after radical cystectomy: a case report emadoddin moudi1*, seyyed hosein ghasemi shektaie2, ghasem rostami2 1department of urology, babol university of medical sciences, babol, iran. cancer research center, health research institute, babol university of medical sciences, babol, iran. 2student research committee, babol university of medical sciences, babol, i.r. iran. *correspondence: cancer research center, health research institute, babol university of medical sciences, babol, iran. tel: 09111133690. 01132326907 email: emadmoudi@gmail.com. received august 2019 & accepted june 2020 this paper introduces a novel technique, known as appendiceal conduit. it could be used as an alternative for ileal conduit and cutaneous ureterostomy, ultimately applied after radical cystectomy. the six-month follow-up indicated that the patient had appendix-stoma as nipple without any stenosis, nor did he have any hydronephrosis, as confirmed by abdominal sonography. keywords: radical cystectomy; ileal conduit, cutaneous ureterostomy; orthotopic neobladder; appendix introduction it is generally assumed that bladder carcinoma is one of the most common types of cancer in many countries.(1,2) it is widely thought that about 30% of bladder carcinoma cases are muscle invasive, for which the radical cystectomy (rc) is a gold standard treatment.(3,4) moreover, it is believed that after radical cystectomy, urinary diversion (ud), ranging from simple cutaneous ureterostomy (cu) to difficult reconstructive procedures, is applied for treatment.(5) also, ileal conduit (ic) and orthotopic neobladder (onb) are supposedly deemed as the most common procedures used for ud, which could be followed by rc.(4) according to the ethical code of ir.mubabol. rec.1398.017, we introduced a new technique, called the appendiceal conduit (ac), to replace ic and cu. this novel technique could be used as a less complex and more time-saving technique after rc. case report an 85-year-old man with refractory dysuria was referred to the hospital, and the sonography evidence demonstrated a mass, 63×59×58 mm, in a bladder diverticulum. cold biopsy was also taken from the mass, which represented a squamous cell carcinoma. abdominopelvic ct was subsequently done (figure 1). surgical technique after spinal anesthesia, rc with lymphadenectomy was performed. in the retroperitoneum, the left ureter was transposed to the right. the length of detected appendix was 12 cm, which was proper for brining to the skin, and a window was made in the mesoappendix, adjacent to its base (figure 2a). the appendix was separated from the cecum. the cecum was then sutured (figure 2b). both ureters were spatulated anteriorly, and the medial borders of both ureters were sutured together (figure 2c). a small vertical incision was made in the antimesenteric border of the appendix tip. two ureteral stents were inserted, and the ureters were anastomosed to the appendix tip (figure 2d). the base of the appendix was brought to the skin as nipple stoma (figure 2e). urology journal/vol 18 no. 1/ january-february 2021/ pp. 131-133. [doi: 10.22037/uj.v0i0.5513] figure 1. abdominopelvic ct scan. follow-up the patient was discharged with ureteral stents on the fourth day. two weeks later, the ureteral stents were removed. no hydronephrosis was found by abdominopelvic ultrasonography (figure 3). no urine leakage was observed around the urine bag and the stoma retained its nipple state (figure 4) six months after the surgery. discussion it is generally presumed that onb and ic are the most frequently used techniques after rc.(4) with regard to the health quality of life, onb is undoubtedly regarded as the best option for ud.(5) but it is not suitable for old patients with comorbidity. as a result, ic and uc should be applied as alternative procedures for treatment.(4,6) in the case of the elderly, due to the complications of bowel manipulation and metabolic disturbance, cu is preferred to ic.(6) cu, nevertheless, could have many stomal complications such as retraction, stricture, and necrosis; therefore, the ureteral stents should be used and changed monthly to minimize the potential risks.(7) in an attempt to mitigate these potential complications, the ac, as a novel technique, was applied. the benefits of ac are as follows: ac is devoid of metabolic disturbances. it has the least intestinal manipulation as well as complications. furthermore, it can lead to minimal stomal retraction and stricture. that could be due to the fact that the wide appendix base is brought to the skin without the use of permanent stents. nonetheless, the ac has the following drawbacks: it is difficult or impossible to apply it in the case of obese patients or patients with short appendix. under such conditions, the cecum and terminal ileum ought to be released and fixed to the abdominal wall. the left to right transureteroureterostomy should be done, and the right ureter should be anastomosed to the appendix. ultimately, the simultaneous use of both options is recommended. case report 413 appendiceal conduit-moudi et al. figure 2. a) a window in mesoappendix b) separated appendix and cecum repair, c) spatulation of the ureters and sutures together, d) anastomosis of the ureters to appendix tip, e) nipple stoma of the appendix figure 3. post-operative ultrasonography unclassified 132 vol 18 no 1 january-february 2021 20 in the case of our patient, the stoma had no stricture and was prominent without leakage around the urine bag during the six-month follow-up. references 1. aliramaji a, kasaeean a, yousefnia pasha yr, et al. age distribution types of bladder cancers and their relationship with opium consumption and smoking. caspian journal of internal medicine. 2015; 6(2): 82-86. 2. shafi h, ramaji aa, yosefnia pasha yr, et al. a surgery on 175 cases of bladder cancer in the patients who referred to the hospitals affiliated to babol university of medical sciences, iran (2001-2011). journal of babol university of medical sciences. 2013; 15(2): 116-122. 3. d. hurst c, a. knowles m. molecular subtyping of invasive bladder cancer: time to divide and rule? cancer cell. 2014; 25: 135136. 4. crozier j, hennessey d, sengupta s, bolton d, lawrentschuk n. a systematic review of ileal conduit and neobladder outcomes in primary bladder cancer. urology; 2016: 96: 74-79. 5. cerruto ma, elia cd, siracusano s, et al. systematic review and meta-analysis of non rct's on health related quality of life after radical cystectomy using validated questionnaires: better results with orthotopic neobladder versus ileal conduit. ejso the journal of cancer surgery. 2016' 42: 343-360. 6. longo n, imbimbo c, fusco feridinando, ficarra vincenzo, mangiapia f, di lorenzo g, creta m, imperatore v, mirone v. complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. 2016: 118; 521-526. 7. kizlay f, simsir a, curekibatir i, cal c. longterm iutcomes of patients who underwent ureterocutaneostomy. 2018: 17: 54-58. case report 212case report 428 figure 4. stoma of the appendix a: 1 month b&c: 6 months after surgery appendiceal conduit-moudi et al. vol 18 no 1 january-february 2021 133 966 | 1 urology resident, patras university hospital, urology department, greece 2 professor of urology, patras university hospital, urology department, greece stavros sfoungaristos,1 petros perimenis2 bilateral cancer in prostate biopsy associates with the presence of extracapsular disease and positive surgical margins in low risk patients: a consideration for bilateral nerve sparing radical prostatectomy decision corresponding author: stavros sfoungaristos, md patras university hospital, urology department, building a, 4th floor, rion, patras, 26500 greece, tel: +30 261 099 9367 fax: +30 261 099 3981 e-mail: sfoungaristosst@ gmail.com purpose: to evaluate the epidemiological, clinical and pathological parameters that may predict the presence of positive surgical margins and extraprostatic disease in patients with low risk [prostate specific antigen (psa) < 10, and gleason score ≤ 6, stage t1c)] prostate cancer. materials and methods: we retrospectively analyzed the medical records of patients who had undergone radical prostatectomy from january 2005 until january 2011. the analysis comprised patients’ age, preoperative serum prostate specific antigen (psa) level, prostate volume, psa density, biopsy gleason score, the presence of bilateral disease according to the results of biopsy cores analysis, the percentage of cancer in biopsy material and the presence of high grade prostatic intraepithelial neoplasia. results: a total of 117 patients were included in the study. positive surgical margins were found in 37 (31.6%) patients and 23 (19.7%) had advanced disease. the results of the multivariate analysis showed that bilateral disease was the single significant predictor for advanced disease prediction (p = .04). same results was obtained by the univariate analysis of the variables for prediction of positive surgical margins, where bilateral disease after biopsy cores analysis was the only factor to be statistical significant (p = .018). conclusion: bilateral prostate cancer in prostate biopsy is significantly associated with positive surgical margins and advanced disease in patients that are operated for prostate cancer of low risk. this observation may assist the selection of patients in whom a bilateral nerve sparing radical prostatectomy is planned to be performed. keywords: prostatic neoplasms; risk assessment; prostate-specific antigen; prostatectomy; risk urological oncology urological oncology 967vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l indications for nerve sparing radical prostatectomy introduction since the first retropubic radical prostatectomy (rp), described by millin in 1948,(1) a number of surgi-cal modifications have been made to offer a better cancer control and, additionally, to minimize morbidity by decreasing postoperative functional complications, mainly incontinence and sexual dysfunction. in 1982, walsh and donker(2) described the neurovascular bundles and their relations to the, and they proposed technical modifications of the rp. actually, they reported that preservation of the neurovascular bundles (nvb) can be performed with safety in previously potent patients with prostate cancer, without affecting the oncological outcome, while this modification can preserve erectile function. the addition of prostate specific antigen (psa) in everyday practice have increased the number of patients diagnosed with low volume and organ confined prostate cancer. since most of the patients are young in age and interesting in preserving their potency, the implementation of nvb-sparing rp has become imperative. several studies have evaluated the criteria that should be used for identifying the appropriate candidates for bilateral nvb-sparing rp. the most used nomograms for decisionmaking, nowadays, are partin tables.(3) clinical stage t1c, preoperative gleason score ≤ 6 and serum psa< 10 ng/ml are the recommended criteria for bilateral nerve sparing rp (bnsrp) of the european association of urology latest guidelines.(4) based on the same guidelines, clear contraindications for bnsrp are those patients with preoperative extracapsular disease, such as any clinical stage t3 or t2c, any gleason score > 7 on biopsy, or more than one biopsy with gleason score > 6 at the ipsilateral side. in patients with t2a or t2b clinical disease, a unilateral nerve sparing procedure may be performed. the optimal scenario for patients with prostate cancer would be the preoperative estimation of tumor status, mainly cancer extension, in order cancer control not to be harmed, especially in patients in whom low risk characteristics might hide a more aggressive malignancy. unfortunately, since now, no imaging technique or clinical algorithm can definitive exclude the presence of extracapsular disease even in patients with low risk characteristics. the aim of the present study was to evaluate several preoperative epidemiological, clinical and pathological characteristics and to analyze their association with the presence of extended prostate cancer in patients with preoperative low risk cancer whom are planned to be treated with bnsrp. materials and methods a retrospective analysis of the medical records from 144 patients who had undergone radical prostatectomy for low risk prostate cancer between january 2005 and january 2011 in our institution was performed. as low risk patient was defined the one with preoperative serum psa < 10ng/ml, biopsy gleason score ≤ 6 and clinically t1c disease. twenty seven patients were excluded from the analysis due to incomplete or missing data. an open or laparoscopic radical prostatectomy was performed in all cases. the procedure included the removal of the prostate gland and the seminal vesicles. a pelvic lymph node dissection was performed in 54 (46.2%) of studied patients. prostate cancer was diagnosed by a previous transrectal ultrasound biopsy. during the procedure, a minimum of 3 cores from each lobe were obtained. the surgical specimen of radical prostatectomy was examined by our institution pathologists and a histological report concerning the prostate dimensions, the tumor extend, the presence of positive surgical margins (psm), and the pathological grade and stage was obtained. any extend of tumor outside of the prostatic capsule in the periprostatic fat was considered as advanced disease (ad) while the infiltration of the capsule without penetration was considered as localized disease. invasion of the seminal vesicles and/or of the dissected lymph nodes was considered as ad, as well. the 2009 tnm (tumor node metastasis) classification for prostate cancer was used to classify the pathological stage. according to the information of prostate’s maximum transverse diameter (d1), maximum anteroposterior diameter (d2) and maximum longitudinal diameter (d3), reported by the pathologists, the pathological prostate volume was calculated by using the prostate ellipse dimension theory formula (d1 × d2 × d3 × π/6). psa density was calculated by dividing the preoperative psa value and prostate volume. even though prostate volume was calculated postoperatively according to the pathological prostate dimensions, there is a 968 | great positive correlation between preoperative (during transrectal ultrasound) and postoperative calculation of prostate volume, reaching 90%.(5) the analysis of the present study comprised patients’ age, preoperative serum psa, prostate volume, psa density, biopsy gleason score, the presence of bilateral disease according to the results of biopsy cores analysis, the percentage of cancer in biopsy material (pcbm) and the presence of high grade prostatic intraepithelial neoplasia (hgpin). statistical analysis was performed by using spss version 17 (spss inc, chicago, il, usa). the descriptive statistics are presented as the mean ± standard deviation (std) and interquartile range (iqr) for continuous variables and as the absolute and percent frequency for categorical variables. the normality condition of the numerical variables was studied by means of the kolmogorov-smirnov test. preoperative serum psa was the only variable with normal distribution. student’s t test was used to compare psa means between groups and mann-whitney u test was used to compare means between groups for the not-normally distributed numerical variables. the chi-square χ2 test was used for categorical variables. a univariate analysis was performed to identify the predictive significance of age, preoperative psa, prostate volume, psa density, preoperative gleason score, bilateral urological oncology table 2. characteristics of patients regarding the presence of positive surgical margins after radical prostatectomy characteristics no psm psm p value no. of patients, n (%) 80 (68.4) 37 (31.6) age (years) .547† mean ± std, iqr 65.5 ± 7.0, 11 66.4 ± 6.1, 10 prostate volume (ml) .803† mean ± std, iqr 47.1 ± 25.1, 33 45.3 ± 22.8, 25 serum psa (ng/ml) .059‡ mean ± std, iqr 7.1 ± 1.6, 2.2 7.7 ± 1.3, 1.8 psad (ng/ml2) < .207† mean ± std, iqr 0.19 ± 0.12, 0.17 0.20 ± 0.08, 0.11 bilateral disease, n (%) .017§* no 45 (78.9) 12 (21.1) yes 35 (58.3) 25 (41.7) pcbm (%) .130† mean ± std, iqr 17.7 ± 15.8, 14 23.8 ± 19.3, 31 biopsy gs, n (%) .558§ 2 1 (100.0) 0 (0.0) 3 6 (75.0) 2 (25.0) 4 9 (81.8) 2 (18.2) 5 18 (75.0) 6 (25.0) 6 46 (63.0) 27 (37.0) hgpin, n (%) .645§ no 31 (66.0) 16 (34.0) yes 49 (70.0) 21 (30.0) *statistically significant, †mann-whitney u test, ‡student’s t test, §chisquare test, keys: psm=positive surgical margins, other abbreviations like in table 1. table 1. characteristics of patients with organ confined and extraprostatic disease after radical prostatectomy characteristics confined disease advanced disease p value no. of patients, n (%) 94 (80.3) 23 (19.7) age (years) .912† mean ± std, iqr 65.7 ± 6.9, 11 66.0 ± 6.2, 10 prostate volume (ml) .001†* mean ± std, iqr 49.9 ± 25.3, 35 32.5 ± 12.3, 11 serum psa (ng/ml) .428‡ mean ± std, iqr 7.2 ± 1.6, 2.2 7.5 ± 1.3, 1.5 serum psad (ng/ml2) < .001†* mean ± std, iqr 0.18 ± 0.11, 0.11 0.26 ± 0.08, 0.08 bilateral disease, n (%) .015§* no 51 (89.5) 6 (10.5) yes 43 (71.7) 17 (28.3) pcbm (%) .076† mean ± std, iqr 18.4 ± 16.9, 19 24.5 ± 17.6, 27 biopsy gs, n (%) .522§ 2 1 (100.0) 0 (0.0) 3 7 (87.5) 1 (12.5) 4 10 (90.9) 1 (9.1) 5 21 (87.5) 3 (12.5) 6 55 (75.3) 18 (24.7) hgpin, n (%) .718§ no 37 (78.7) 10 (21.3) yes 57 (81.4) 13 (18.6) *statistically significant, †mann-whitney u test, ‡student’s t test, §chisquare test, keys: std = standard deviation, iqr = interquartile range, psa = prostate specific antigen, psad = psa density, pcbm = percentage of cancer in biopsy material, gs = gleason score, hgpin = high grade prostatic intraepithelial neoplasia 969vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l disease, pcbm and hgpin in biopsy cores in prediction of ad and psm. a multivariate logistic regression analysis was performed then for the variables identified as statistically important in univariate analysis, using logistic regression. all tests were 2-tailed with p <.05 to be considered as statistically significant value. results a total of 117 patients found to have clinically t1c disease with low risk characteristics (psa < 10 ng/ml and preoperative gleason score ≤ 6). the median age was 67 years (65.8 ± 6.7, 11) and median preoperative psa was 7.3 ng/ml (7.3 ± 1.6). based on the pathological evaluation of the biopsy material, invasion of cores from both prostatic lobes was observed in 60 (51.3%) patients. from those, 17 (28.3%) patients had extracapsular disease, 25 patients (41.7%) had psm, while 1 patient (1.7%) had lymph node and seminal vesicle invasion. after pathological analysis of the radical prostatectomy specimen, 37 (31.6%) patients had psm and 80 (68.4%) had complete cancer removal, while 94 (80.3%) patients had pathological confined disease and 23 (19.7%) had cancer extended outside of the prostatic capsule border. in specific, 14 (12%) patients found to have pt2a disease, 5 (4.3%) pt2b, 75 (64.1%) had pt2c, 19 (16.2%) had pt3a and 4 (3.4%) patients had pt3b disease. fifty four patients undergone a pelvic lymph node dissection and positive nodes found in 2 of them (both patients had pt3b disease). in the 63 (53.8%) remained patients a lymph node sparing radical prostatectomy was performed. patients’ characteristics regarding the presence or not of organ confined prostate cancer and psm are seen in tables 1 and 2, respectively. prostate volume, psa density and biopsy-based bilateral disease were the variables found to be significant in univariate analysis for advanced disease prediction, with p values to reach .04, .013, .019, respectively (table 3). in the multivariate analysis, bilateral disease was the single significant predictor with p = .04 (table 3). same results was obtained by the univariate analysis of the variables for prediction of psm (table 4), where bilateral disease in biopsy cores analysis was the only factor to be statistical significant (p = .018). discussion the main concern, when a bnsrp is performed, is complete eradication of prostate tumor and preservation of sexual function. since the surgical boundaries are closer to the prostatic capsule by preserving the nvb, this may increase the rates of incomplete tumor removal and psm. moreover, it has been shown that postero-lateral prostate surface, which is the region of the nvb, is the most common site of psm.(6,7) that means that in patients with ad, and mainly extraprostatic extension, the preservation of the bundles may lead to psm and limited cancer control. catalona and bigg(8) have table 4. univariate analysis for prediction of positive surgical margins 95% c.i. for exp (b) significance exp (b) lower upper age .461 1.023 .963 1.086 prostate volume .717 .997 .981 1.013 psa .061 1.289 .988 1.682 psa density .676 2.107 .064 69.668 bilateral disease .018* 2.679 1.182 6.069 pcbm .076 1.021 .998 1.044 gleason score .135 1.426 .896 2.270 hgpin .645 .830 .377 1.831 keys: ci=confidence interval, other abbreviations like in table 1 table 3. univariate and multivariate analysis for advanced disease prediction 95% c.i. for exp (b) significance exp (b) lower upper univariate analysis age .821 1.008 .941 1.080 prostate volume .004* .952 .921 .984 psa .425 1.130 .837 1.525 psa density .013* 311.227 3.347 28943.627 pcbm .135 1.019 .994 1.044 bilateral disease .019* 3.360 1.217 9.276 gleason score .127 1.625 .872 3.029 hgpin .718 .844 .335 2.123 multivariate analysis prostate volume .083 .959 .914 1.006 psa density .691 3.494 .007 1669.111 bilateral disease .040* 3.123 1.056 9.237 keys: ci=confidence interval, other abbreviations like in table 1 indications for nerve sparing radical prostatectomy 970 | urological oncology reported that, when a nerve sparing rp was performed, psm were identified in all cases that an extracapsular disease was present in at the nvb region. adverse prognostic events, like biochemical failure and systemic relapse, have been found to be associated with positive surgical margins.(9-11) in a series of 377 patients who had rp for localized prostate cancer, a decreased 5-year progression free survival was associated with positive surgical margins (90% vs. 78%), irrespective of the presence of extracapsular disease.(11) another study reported a 10-year progression-free survival of 79% and 55% for patients with negative and positive surgical margins, respectively. better prognosis was found even after the exclusion of patients with seminal vesicles invasion.(12) the prognostic value of surgical margin status appeals clinically important in planning treatment especially for those patients who are considered to undergone a nerve-sparing procedure, a subgroup with a continuously increasing number members nowadays. despite the wide use of nerve sparing rp, the overall rate of psm is declined. this may be explained by a shift in early prostate cancer diagnosis and consequently the increase in organ confined disease and the improvements in the surgical expertise.(13) several studies have evaluated the rates of cancer presence at the level of the surgical margins who underwent a rp with or without an excision of the nvb.(1418) actually, positive surgical margins rates and biochemical free survival are not influenced by nerve-sparing technique. based on the reported results, in most of the cases the rates of psm are higher when a wide excision of the bundles was performed. taken together these results, someone may conclude that the preservation of the nvb does not affect the prostate cancer control, in terms of complete eradication of the disease. the main problem seems to be the preoperative identification of an advanced cancers that harbor the danger of incomplete control when bundles preservation is performed. in the absence of specific and reliable imaging techniques that can define the tumor extend preoperatively, patients selection is mainly supported by preoperative and intraoperative criteria. several parameters have been proposed for the selection of the appropriate candidates for bnsrp. most of the reports are agreed that preoperative psa, biopsy gleason score and clinical stage are the most reliable criteria for patients stratification. (19-27) as seen in table 5, the majority of the investigators have reported that patients with clinical stage > t2, psa >10ng/ ml and preoperative gleason score > 7 are of increased risk for advanced disease and therefore a bnsrp should omitted. kamat and associates,(28) and naya and associates(29) have tried to further refine the criteria for a non-nerve sparing rp. they reported that the presence of a prostate biopsy core with a tumor length of at least 7mm plus a positive biopsy core of at the prostate base, irrespective of the length and tumor grade, is predictive of extraprostatic disease. in the contemporary practice, partin tables are the most used nomograms to predict the risk of adverse events, including extracapsular cancer, by using preoperative psa, grade and clinical stage.(3) based on these nomograms, a patient with preoperative characteristics like the ones our study group fulfils (stage ≤t1c, psa < 10, gleason score ≤ 6), have 81% possibilities to have an organ confine prostate cancer, 18% to have extraprostatic disease and 1% to have seminal vesicle invasion. in our series, 19 patients (16.2%) had capsule penetration and 4 patients (3.4%) had seminal vesicles metastasis. a simple analysis of these statistics is showing us that approximately 1 to 5 or 6 patients that will undergo a rp for a low risk prostate cancer will have ad. if we consider that in the vast majority of these patients, a bnsrp will be performed, the danger for psm is high. since this scenario will affect the oncological outcome and the prognosis, sometable 5. summary of indications for not performing a bilateral nerve sparing radical prostatectomy clinical stage psa gs pt psm (%) zorn et al. [18] ≥ t2b > 7 20.4 bianco et al. [19] > t2 + 5 tsuzuki et al. [20] ≥ 10 ≥ 7 > 10 shah et al. [21] > t2 8 sofer et al. [22] > t2 > 10 > 7 24 graefen et al. [23] > t2 > 10 > 7 15.9 walsh [24] > t2 + 5 scardino and kim [25] > t2 + 5 alsikafi and brendler [26] > t2 ≥ 7 11 keys: psa = prostate specific antigen, gs = gleason score, pt = partin tables, psm = positive surgical margins. 971vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l one can easily conclude that the present criteria for bnsrp decision-making might not be sufficient and should be supported with new ones. in the current study, we focused on the presence of advanced prostate cancer and positive margins after rp, irrespective of location, in patients with low risk cancer. our data showed that extraprostatic disease was found in 16.2% and psm in 31.6% of the studied cases. the incidence of capsular penetration is consistent with that reported in the literature. however, an increased incidence of positive margins was identified in our series of patients. this may be explained by the fact that not all patients operated by one surgeon and therefore the learning curves are different among them. the aim of the present study was to identify potential association between several factors and the presence of ad in low risk patients in order to assist patients’ selection for bnsrp. our analysis results showed that the presence of malignancy in biopsy cores from both lobes was the only significant parameter, among several clinical and pathological factors, that can predict was associated with both psm and ad. these data may be used as an auxiliary tool to the standard criteria used so far, like preoperative risk assessment, for the selection of patients who may be candidates for bilateral nerve sparing radical prostatectomy. however, these results should further defined in contemporary series. the value of positive biopsy laterality in prediction of the surgical outcome has been studied in 2 other studies. buyyounouski and associates(30) studied1038 patients with clinical t1-t3nx-0m0 prostate cancer who were treated with radiotherapy alone. in contrast to our results, the authors reported that positive biopsy results from both prostate lobes should not be used for clinical staging, since it can cause stage migration without reflecting a change in outcome. similar results were revealed by bulbul and associates(31) who aim to evaluate the accuracy of prostate biopsies in predicting pathological grading and tumor distribution in the final pathological specimen. they reported that 66% of patients with unilateral disease on needle biopsy had bilateral disease on final pathology, but this did not increase their rate of having positive margins. we have to notice that both previous studies were conducted in patients with patients with localized or locally advanced disease without limitations in inclusion criteria. in contrast, we specifically studied patients who were preoperatively stratified as low risk in whom the surgical modifications and oncological expectations are different from these of the rest prostate cancer patients. our study has a number of limitations that we should report. apart of the retrospective nature of the study, the main limitation is that operations have been made by more than one surgeon and these this may significantly affect the outcome concerning the rates of psm. furthermore, prostate biopsy procedures were made by several different operators. therefore, different methods and experience may influence the biopsy results and consequently the presence of unilateral or bilateral disease. the way of psa density calculation is another limitation. officially, psa density is calculated during transrectal ultrasound but due to the retrospective fashion of the study, we used postoperative prostate volume to estimate it. another significant limitation of the study was the absence of data regarding vascular and/or peri-neural invasion. conclusions the presence of bilateral prostate cancer, based on the results of pathological analysis of biopsy cores, is a significant predictor for positive surgical margins 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11th congress of the iranian endourology and urolaparoscopy society, 2019 video presentation 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic anatrophic nephrolithotomy mohammad aslzare1*, amir abbas asadpour2, alireza akhavan rezayat3, abdolhay etesami4 associate prof. of urology , endourology & laparoscopy, robotic & urooncology , mashhad university of medical sciences assistant prof. of urology, mashhad university of medical sciences, mashhad, iran. assistant prof. of urology, mashhad university of medical sciences, mashhad, iran. resident of urology , mashhad university of medical sciences, mashhad, iran. *presenting author: mohammad aslzare introduction: nowadays eswl, pcnl & rirs are therapeutic options for kidney stones in different conditions. sometime laparoscopic procedures can be used for upper ureteral stone & single renal pelvic stones. methods: a 33years old man with left flank pain gross hematuria referred to us with a left complete staghorn. results: he underwent, laparoscopic antrophic nephrolithotomy operative time was 120min, estimated blood loss was about 50cc. conclusion: hospitalization was uneventful for 3day. there was no urine leak from drain laparoscopic antrophic nephrolithotomy is an feasible & safe option and can be performed as a minimally invasive procedure instead of open surgery. keywords: laparoscopy; nephrolithotomy v. 101 1 11th congress of the iranian endourology and urolaparoscopy society, 2019 rare presentation of h-type ectopic ureter in a single system managed by laparoscopic nephroureterectomy pejman shadpour, asghar alizadeh, kaveh mehravaran, m mehdi atarod, farshad gouran, roozbeh roohinezhad* hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *presenting author: roozbeh roohinezhad background: by definition, an ectopic ureter is any ureter, single or duplex, that does not enter the trigonal area of the bladder. in a duplex system this is usually the upper pole ureter, presumably because of its budding from the mesonephric duct later than the lower pole with later incorporation into the developing urogenital sinus. theoretically in males the orifice may end ectopically anywhere in the urogenital system above the external sphincter or pelvic floor, but in reality this is almost always at the bladder neck or prostatic urethra. the least common presentation is ending into wolffian structures, ie, the vas, seminal vesicle, or ejaculatory duct entailing infection and pain in the affected organs. single-system ectopic ureters are far less common, and one presenting with h type ectopia manifesting in an apparently absent kidney is extremely exceptional. case report: this 44 year old man had suffered from recurrent epididymo-orchitis many years ago. his sonography reported no left kidney. on ct scan with iv contrast the left ureter led to a nonfunctioning remnant cephalad, and to the left seminal vesicle caudally, hence an h type ectopia without duplication. laparoscopic nephroureterectomy in modified flank approach was utilized in this case. conclusion: this is the rarest type of ectopia and laparoscopy affords definitive diagnosis and definitive surgical management all at once. keywords: ectopic ureter; single system ectopic ureter; h type ectopic ureter; laparoscopic; nonfunctional kidney v. 102 2 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic right side donor nephrectomy with inadvertent clipping of renal artery branch and its management naser simforoosh¹, mohammad najafi-semnani¹, saman farshid²*, hamid-reza akbari gilani¹, iman ganaat¹,³ 1shahid labbafinejad hospital, urology and nephrology research centre (unrc), shahid beheshti medical university, tehran, ir iran. ² department of urology, urmia university of medical sciences, urmia, iran. ³ department of urology, isfahan university of medical sciences, isfahan, iran. *presenting author: saman farshid introduction: laparoscopic right donor nephrectomy is reserved for instances when the left kidney is determined to be unacceptable for transplantation. indications most often cited are multiple left renal arteries or veins, anomalous left anatomy, smaller right kidney, or a cystic mass in the right kidney , duplication of renal vein is more common on the right side and is reported as much as 15% of potential renal donors. case presentation: recipient was 55 y/o female with history of graft rejection 2 years ago donor was 32 y/o male without any surgical history, according to ctangiography multiple artery in left side and single right side artery with early branching was noticed , so donor was scheduled for right side laparoscopic nephrectomy , during laparoscopiy accessory right side vein was found, right renal artery was freed under ivc upto 1cm before early branching, at the time of clipping the accessory renal vein , renal artery branch benhind the vein was being stuck inside vein hemo-lock,so another double homolock was placed proximal to previous accessory vein hemolock , renal accessory vein was cut off from ivc with out cutting artery branch , renal artery was cut-off after clipping the artery proximal to early branching , renal artery branch stucked inside vein hemolock was separated after extraction of vein homo-lock back-table , finally after graft anastomosis in recipient urine output was 2.5 liter ,during follow up evaluation there was no sign of vascular thrombosis in color doppler study. conclusion: studies on right side laparoscopic donor nephrectomy confirm that right laparoscopic donor nephrectomy provides similar patient benefits, including early return to diet and discharge. long-term creatinine values were no higher than in traditional open donor or left laparoscopic donor cohorts. concerns about high thrombosis rates are not supported by a multiinstitutional review of laparoscopic right donor nephrectomies. keywords: laparoscopy; veins; kidney transplantation v. 103 3 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic pyeloplasty in a boy with upjo secondary to high grade reflux farzaneh sharifi aghdas¹,saman farshid² ,hamid akabri gilani¹ ¹shahid labbafinejad hospital, urology and nephrology research centre (unrc), shahid beheshti medical university, tehran, ir iran. ²department of urology, urmia university of medical sciences, urmia, iran. *presenting author: saman farshid introduction: ureteropelvic junction obstruction (upjo) and vesicoureteric reflux (vur) are the most common pathological conditions in pediatric urology, with 9%–14% of patients with upjo likely to have concomitant vur. whether the coexistence is a random event, attributable to a single developmental abnormality or due to ureteral kinking and inflammation caused by vur has not yet been established. case presentation: patient was 8 y/o boy with history of recurrent episode of uti after imaging evaluation , right side upjo and vur was identified , right side drf was 30 % according dmsa-scan this patient was scheduled for pyeloplasty and vur correction with deflux injection , during laparoscopy after releasing the upj from peripheral attachments ,severe tortuosity of proximal ureter lead to upjo was noticed , the excess and tortuous part of ureter was cut and dismembered pyeloplasty with 5-0 vicryl was done ,2 months later patient underwent deflux injection for vur correction , during follow-up visits up to 6 months after surgery fortunately patient hasn’t experienced any episode of uti. conclusion: at the time of surgery, if a dilated ureter is found below the upjo, the operating surgeon will not be sure if it is due to vesicoureteric junction obstruction, megaureter or vur if a preoperative vcug has not been done, improvement in kidney drainage in patients who had upjo secondary to high grade reflux lead to function improvement despite the existence of vur and pyeloplasty should not be postponed until reflux resolves. keywords: pyeloplasty; ureteropelvic junction obstruction; vesicoureteric reflux v. 104 4 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic ureteric reimplantation of a single system ectopic ureter in a girl alireza golshan mashhad university of medical sciences, mashhad , iran. introduction: in published literature, 80% of ectopic ureters arise from the upper pole of a completely duplicated system. ectopic ureters draining single systems are not common, occurring only in 20% of cases. again, ectopic ureter draining single system in case of females is extremely rare. we report a case of a 15-year-old girl having single-system ectopic ureter undergoing laparoscopic ureteric reimplantation. methods: a 15-year-old girl presented with continuous dribbling of urine along with normal voiding pattern since childhood. there was no urgency, frequency, dysuria . there was no history suggesting stress incontinence. physical examination was unremarkable. urinalysis showed 2-3 pus cells/hpf, and urine culture revealed no growth. blood biochemical parameters were within normal limits. ultrasonography of the kidneys, ureters revealed sever left hydroureteronephrosis , with normal cortical echotexture and corticomedullary differentiation. right kidney was normal,. intravenous urography showed excretion of contrast through both kidneys, with delay from the left kidney. both pelvicalyceal systems and ureters were visible and showed bilateral single system. on cystourethroscopy, urethra, bladder, right ureteric orifice were found to be normal, but left ureteric orifice was dilated and located on the bladder neck. results: under general anaesthesia, patient was placed supine in 20-degree trendelenberg position. four-ports technique was used. procedure was started by incising the peritoneum just above the bifurcation of common iliac vessel. right ovary and fallopian tube were mobilized, and infundibulopelvic ligament was transacted after clipping. ureter was dissected and followed up to its insertion into the bladder, avoiding any injury to advential tissue. ureter was clipped near its insertion into bladder and transected . a tunnel was adequately dissected to obtain 5:1 ratio of length to width. ureter was spatulated, bladder mucosa was incised, and mucosal-to-mucosal anastomosis was done initially with three interrupted sutures at the heel of spatulation using 4-0 polyglycolic suture, and 5-fr dj stent was put . rest of the anastomosis was completed with continuous suturing. bladder muscle flaps were then approximated using 4-0 polyglycolic suture. abdominal tube drain was put via right lateral 10-mm port. operative time was 165 minutes. one month postoperatively, the stent was removed. at 3 months’ follow-up, intravenous urography showed no obstruction, and micturating cystourethrogram showed no reflux.and the patient has no complain of incontinency. conclusion: laparoscopic procedures offer reduced morbidity due to less postoperative pain, better cosmesis, earlier return of bowel function, earlier discharge and a quicker return to work. in view of these advantages and significant renal function in our patient, we preferred laparoscopic ureteric reimplantation in our patient. keywords: ectopic ureter; laparoscopic reimplantation v. 105 5 11th congress of the iranian endourology and urolaparoscopy society, 2019 bilateral laparoscopic ureteral reimplantation in a patient with endometriosis: a case presentation robab maghsoudi1*, ameneh sadat haghgoo2, saeed esmaeil soufian1, mehran moghimian1 1urology department of firoozgar hospital, iran university of medical sciences, tehran, iran. 2gynecology and infertility department of nikan hospital, tehran,iran. *presenting author: robab maghsoudi purpose: ureteral involvement is one of the most important problems that can be occurred during endometriosis and usually lead to urinary tract obstruction, with subsequent hydroureter, hydronephrosis, and potential kidney loss. in this video we present our experience in a patient with bilateral ureterovesical junction obstruction by laparoscopic procedure. case presentation: a 35 years old woman with advanced endometriosis referred to our department. she had a history of multiple surgeries for her problem in the past years. despite the surgical intervention there was documentation of renal atrophy and function loss due to bilateral obstruction on subsequent workup, so we decided to perform another surgical intervention and we planned bilateral laparoscopic reimplantation for her. by a transperitoneal laparoscopic approach bilateral ureteroneocystostomy performed. dj stents inserted for both ureter and after 8 weeks they removed. we didn’t have any major complication during the intra and post-operative period and in 3 months' post-surgery intravenous pyelogram there wasn’t any significant obstruction. conclusion: in endometriosis related ureteral obstruction tolaparoscopic reimplantation can be an option in hands of enough experience safely. keywords: endometriosis; laparoscopy; ureteroneocystostomy v. 106 6 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic ureteropyelolithotomy in pediatric age mohammad-hossein soltani1, mohsen varyani2, hamid-reza akbari gilani1* 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2khanevade hospital, iran army university of medical sciences, tehran, iran. *presenting author: hamid-reza akbari gilani purpose: to evaluate the feasibility of simultaneous laparoscopic surgery of renal and ureteral stone in pediatrics. materials and methods: a 9 y old girl with pmh of open pyelolithotomy refered for left renal and proximal ureteral stone. she underwent laparoscopic ureteropyelolithotomy in the same session. the ureter over the stone was opened and after ureteral stone extraction, the incision was extended proximally toward renal pelvis and renal stone was extracted. result: the renal and ureteral stone was extracted laparoscopically in a 9 year old child an one session. conclusion: simultaneous laparoscopic surgery of ureteral and renal stone is safe and feasible in pediatric age group. keywords: laparoscopy; urinary stone; pediatrics v. 107 7 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic pyelolithotomy in 11 month old infant mohammad-hossein soltani1, saman farshid2, hamid-reza akbari gilani1* 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2nephrology and kidney transplant research center, urmia university of medical sciences, urmia, iran. *presenting author: hamid-reza akbari gilani purpose: to evaluate safety and feasibility of mini laparoscopic renal stone surgery in infancy. materials and methods: a 11 m old infant with fever, and left hydronephrosis refered from a pediatric center. he was diagnosed by ultrasonography and plain abdominal x ray to have renal stone. he underwent mini laparoscopic pyelolithotomy. result: the patient had no fever and improved general condition immediately after surgery. the operation and postoperative convalescence period were uneventful. conclusion: laparoscopic pyelolithotomy is safe and feasible in infancy period and can be done in even febrile patient. key words: laparoscopy; urinary stone; infancy v. 108 8 11th congress of the iranian endourology and urolaparoscopy society, 2019 69 laparoscopic partial nephrectomy with zero ischemia time mohammad-hossein soltani1, mohsen varyani2, hamid-reza akbari gilani1*, sa aslani1 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2khanevade hospital, iran army university of medical sciences, tehran, iran. presenting author: hamid-reza akbari gilani purpose: to evaluate the feasibility of zero ischemia laparoscopic partial nephrectomy in a young adult woman. materials and methods: a 34 y old woman with incidentally found 18 mm right upper pole renal mass in ultrasonography and ct scan was refered to our hospital. he underwent laparoscopic partial nephrectomy with zero ischemic time. result: the operation and postoperative convalescence period were uneventful. the final pathology was metanephric adenoma. conclusion: laparoscopic zero ischemia partial nephrectomy in small exophitic renal mass is safe and feasible. key words: laparoscopy; renal tumor; partial nephrectomy; zero ischemia v. 109 9 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic radical nephrectomy and pelvic cyst removal farzaneh sharifi aghdas1, mohsen varyani2, z bartani1, hamid-reza akbari gilani1* 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2khanevade hospital, iran army university of medical sciences, tehran, iran. *presenting author: hamid-reza akbari gilani purpose: to evaluate feasibility of simultaneous radical nephrectomy and ovarian cyst removal in one session. materials and methods: a 51 y old woman with left renal mass and large pelvic cyst refered to our center. she underwent lt lap radical nephrectomy and pelvic cyst was removed through pfan incision at the time of kidney extraction. result: the operation and postoperative convalescence time were uneventful. the final pathology was renal rcc t2 n0 m0 and ovarian mucinous cystadenoma. conclusion: simultaneous laparoscopic radical nephrectomy and ovarian cyst removal is safe and feasible. keywords: laparoscopy; renal tumor; pelvic cyst v. 110 10 11th congress of the iranian endourology and urolaparoscopy society, 2019 71 laparoscopic rplnd abbas basiri1, saman farshid2, hamid-reza akbari gilani1*, iman ghanaat1 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2nephrology and kidney transplant research center, urmia university of medical sciences, urmia, iran. *presenting author: hamid-reza akbari gilani purpose: to evaluate the feasibility of laparoscopic rplnd in testicular stage 1 mixed germ cell tumor. materials and methods: a 36 y old man with pmh of left testis tumor refered to our hospital after radical orchiectomy. the pathology was mixed germ cell tumor (80% seminoma, 20% yolk sac tumor), tunica, margin and spermatic cord were intact. lymphovascular invasion was present. tumor markers became normal after orchiectomy( afp: 10261.6 bhcgwas normal). abdominopelvic ct scan was normal. he underwent laparoscopic rplnd. results: the operation and postoperative convalescence period were uneventful. the pathology report was free of germ cell tumor. conclusion: laparoscopic rplnd if safe and better tolerated especially in stage 1 mixed germ cell tumor. keywords: laparoscopy; rplnd; testis tumor v. 111 11 11th congress of the iranian endourology and urolaparoscopy society, 2019 is it possible to do laparascopic live donor nephrectomy in presence of left inferior vena cava nasser simforoosh1, iman ghanaat1*, hamidreza akbari gilani1 1urology and nephrology research center,shahid beheshti university of medical sciences,tehran,iran. *presenting author:iman ghanaat introduction: left inferior vena cava(ivc) is a rare anatomic vascular variation in normal popular.when we decide to do live donor nephrectomy in this case,selection of modality of surgery could be debate.we want to show feasibility of laparascopic method and complications. material and methods: we encounterd to a 24years old male , was ideal candidate for live donor nephrectomy ,that in it’s ct-angio had left sided ivc with single renal artery and vein in both kidneys.so we decided to do laparascopic left sided live donor nephrectomy. result: in october 2019,we did laparascopic nephrectomy of live donor in transperituneal method after colon medialization and clipping ureter ,renal vein of its origin at left ivc ,that was closer to the left kidney from renal artery,and renal artery without any complication or abnormal bleeding or conversion to open surgery.the patient discharge was done 2 days after with good condition. conclusion: in left sided ivc we can perform laparascopic live donor nephrectomy without any difficulty or complication and help the pathient to pass shorter recovery period . keywords:laparascopy,live donor nephrectomy,left inferior vena cava. v. 112 12 11th congress of the iranian endourology and urolaparoscopy society, 2019 feasibility of laparascopic resection of renal capsular endometriosis abbas basiri1 , iman ghanaat1*, hamidreza akbari gilani1 1urology and nephrology research center,shahid beheshti university of medical sciences,tehran,iran. presenting author: iman ghanaat introduction: the ectopic endometrial tissue,endometriosis, seldom occurs outside of the reproductive organs. urinary tract endometriosis is uncommon, accounting for only 1.2% and endometriomas involving the kidneys are extremely rare, accounting for less than 1%.there are a few report of renal endometriosis objective: the aim was to evaluate the possibility of laparascopic resection of renal endometriosis in malrotated kidney. material and method:in september 2019,a 37 years old female with menstrual-related right flank pain , microscopic hematuria and right renal capsular mass that was proven to be endometriosis in percutaneous renal mass biopsy without another problem or endometriosis in the other site of body,underwent laparascopic renal mass resection result: capsular malrotated-renal endometriosis resection done in transperituneal laparascopic method after colon medialization and access to mass with safe margin without any complication or abnormal bleeding intra or postoperation.the patient discharge done 2 days after with good condition and pain and hematuria disappeared in follow up. conclusion: laparascopic transperituneal resection of renal capsular endometriosis is possible without significant complication or extended incision with minimally invasive surgery. keywords: laparascopy; endometriosis; renal capsul; malrotated kidney v. 113 13 11th congress of the iranian endourology and urolaparoscopy society, 2019 endoscopic management of large ureteral tumor: a video presentation akbar nooralizade, seyed arsalan aslani* labafenejad hospital, shahid beheshti university medical science. *presenting author: seyed arsalan aslani purpose: evaluation of endoscopic management of ureteral tumor method: 36 years old woman, referral to our clinic due to it side hydronephrosis, intraversus pyelography was due a large ureteral tumour was detected patient ureter went uretero... and tumour was found, with biopsy grasper tissue send for pathologist, the primary result is von-burn-nest hyperplasia. results: the final pathology, is pyelitis cystically and glanoluaris. this tumour has benign behaviour with high rate of recurence. conclusion: endoscopic management of benign tumour in ureter is feasible but need long follow up. keywords: endoscopy; ureter; tumor v. 114 14 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic management of ureteral stricture in kidney transplant, a video presentation nasser simforoosh, seyed arsalan aslani* labafenejad hospital, shahid beheshti university medical science. *presenting author: seyed arsalan aslani purpose: ureteral stricture is a common problem in patients with history of kidney transplantation. laparoscoic management of ureteral stricture is challenging and the efficacy of this surgical method is under question. methods: a patient who referral to our clinic due to rising creatinine with hydronephrosis on transplanted kidney. nephrostomy inserted and nephrostography showed a stricture at the distal part of ureter. the patient scheduled for laparoscopic ureteroneocystostomy results: on the general anasthesia at supine position laparoscopic ureteral-feimplantation trocars, 12mm, 5mm, 5mm, 5mm, inserted with diamond shape, after hard efford, the ureter was found at level of uretropelvic junction, so dissection was continious meticulously up to site of ureteral stricture. the ureteres dissected , and anestomas to bladder with modified lick method. conclusion: laparoscopic management of ureteral stricture in kidney transplant is safe and effective, but need long follow up. keywords: laparoscopy; stricture, transplantation, ureter v. 115 15 11th congress of the iranian endourology and urolaparoscopy society, 2019 antegrade ureteroscopy in patient with history of illeal loop diversion and distal ureteral stenosis. kaveh mehravaran, massoud etemadian, pejman shadpour, mayhar fasihi *, ahmadreza rafati, asghar alizadeh, said pakdel , mohamad mehdi atarod , farshad gooran, roozbeh roohinezhad . hasheminejad kidney center, iran university of medical sciences, tehran, iran. *presenting author: mayhar fasihi the patient is a 60 years-old male who had presented with left flank pain and raising of creatinine and left hydronephrosis. in nephrostography ,left distal ureteral stenosis were observed. the patient had under went one previous failed attempts at retrograde uretroscopy in our center before .during flexible uretroscopy, the site of stenosis was found and check by fluoroscope and the gaid wire pass from stricture and confirmed by fluoroscope then by a zebra dilator through guide wire the stenos was dilated and retrograde ureteroscopy done to check it and then dj stent was inserted in the system . operation duration was 1 hours. postoperative pain was minimal not necessitating administration of narcotics. the patient was discharged 1 days after operation with no complication. keywords: ureterescopy; illeal loop; diversion; stenosis v. 116 16 11th congress of the iranian endourology and urolaparoscopy society, 2019 lower calyce stone with calyceal stenosis treated with retrograde intera renal surgery ( rirs). kaveh mehravaran ,massoud etemadian, pejman shadpour, mayhar fasihi *, ahmadreza rafati, asghar alizadeh, said pakdel , mohamad mehdi atarod ,farshad gooran, roozbeh roohinezhad . hasheminejad kidney center, iran university of medical sciences, tehran, iran. *presenting author: mayhar fasihi the patient is a 43 years-old female who had presented with left flank pain. in ultrasonography and ct scan without contrast, left lower calyceal stone were observed. the patient had underwent 2 previous failed attempts at eswl in another center before referral. during flexible uretroscopy, the all calyce search for stone but stone not found and at the end one pin point orifice was found that by a fiber of holmium laser the orifice was dilated and passed uretroscop in to the calyce and found stone in stenotic calyce. operation duration was 1 hours. postoperative pain was minimal not necessitating administration of narcotics. the patient was discharged 1 day after operation with no complication. keywords: rirs; nephrolithiasis; stenosis v. 117 17 11th congress of the iranian endourology and urolaparoscopy society, 2019 partial nephrectomy with two-layer reconstruction of resection bed: iranian adoption alternative (video) amir h kashi, hamid-reza akbari gilani*, seyed arsalan aslani labbafinejad hospital; urology and nephrology research center (unrc), shahid beheshti university of medical sciences (sbmu), tehran, iran. *presenting author: hamid akbari gilani purpose: two-layer reconstruction of renal bed in laparoscopic partial nephrectomy results in better cosmetic appearance and better salvage of renal parenchyma. this video represents an iranian adopted model for two layer reconstruction of renal parenchymal bed using available sutures in iran. methods: a middle aged man, known case of tuberous sclerosis presented with a 5cm central endophytic enhancing mass in right kidney. brain ct scan revealed asterocytoma and eye exam revealed two hamartomatous lesion not needing any intervention. skin hamartomatous lesions were observed on his back. results: a transperitoneal laparoscopic partial nephrectomy was planned. the tumour was resected after applying bulldog clamps on both renal artery and vein. resection bed was reconstructed in first layer using 2-0 monocryl sutures. warm ischemic time was 20 minutes. bulldog clamps were released and after ensurance hemostasis, the edges of renal parenchyma was reconstructed using 2-0 vicryl sutures. conclusion: this adaption ensures suturing of renal resection bed in 2 layers using common available sutures in iran. keywords: partial nephrectomy; laparoscopy; bleeding v. 118 18 oral presentation 11th congress of the iranian endourology and urolaparoscopy society, 2019 a 5 years missed nelatone tube as a stent ureter which had been inserted post peylonphrotomy afshar zomorrodi professor of urology and kidney transplant surgeon, head of organ transplantation department, imam reza hospital, tabriz medical science university, tabriz – iran. background: stenting of ureter is necessary sometimes after operation of ureter for prevention of leak and obstruction. it has been advised that at the maximum after three months, the stent must be removed. many complications have been described for stent or jj in ureter. even death may be associated with remained double j.in this paper we present a case with nelatone tube which had been inserted five years ago. case: a 40-year-old man with a history of nepherolithiasis was referred for luts and bladder stone.in evaluation of bladder stone, it was discovered that there is a stent in urinary system of left kidney (figure1). the patient was candidate for eswl, after one eswl, he was scheduled out for cystoscopy to remove the stent and remained of bladder stone. in cystoscopy with covering of antibiotic, nelatone in the ureter was easily removed which was intact (figure 2) and also the remained bladder stone. discussion: stenting of ureter is important for prevention of leak and obstruction of ureter. in almost all of ureter anastomo-sing of ureter in grafting of kidney stent is placed. although stent prevents obstruction and helps the repairmen of ureter, it may induce obstruction, infection and stone making. time duration of stent and kind of stent, size of stent are important for inducing complication. if stent remains in ureter for a longer time, it may be associated with fragmentation and infection and stone. late complications including stone, infection and migration and figure1. kub: nelatone with left kidney figure2. nelatone tube after 5 years missed, intact stent with a little encrustation o. 101 20 11th congress of the iranian endourology and urolaparoscopy society, 2019 fragmentation in one third of patient may occurr. any complicated obstruction of urinary system may be need for inserting stent for treatment. encrustation is precipitation of calcium and oxalate on biofilm on surface of stent, for forming biofilm on surface of stent it is necessary to adherence protein that it is presence in the urine and production of bacteria. encrustation of stent depends to many factor including: time of presence of stent in system, history of nephrolithiasis, infection, biofilm, pregnancy and kind of stent. forgotten stent may have many complications even death. in this case the stent was nealtone tube which after remaining for 5 years forgotten it was not associated with a mojor problem. key words: stent; dj; ureter stent; missed stent; missed dj o. 101 21 11th congress of the iranian endourology and urolaparoscopy society, 2019 minimal invasive pcnl(mpcnl) in patients under age of 18 mohammad mehdi hosseini*, alaa altofeyli, ali eslahi,reza haghpanah, mitra basratnia shiraz nephrology-urology research center, shiraz university of medical sciences, shiraz ,iran. *presenting author: mohammad mehdi hosseini purpose: nowadays, renal calculi is a common problem in children.eswl is the first choice in this age group,but sometimes other interventions may be indicated.in such cases pcnl seems the less invasive and more safe option than open surgery.we evaluated the results and complications of the minimally invasive pcnl (mpcnl) in our referral training center. materials and methods: between september 2012 and may 2019,a total of 98 children under age 18 who had failure of and/or their parents refuse swl underwent mpcnl(15 fr). the procedure was done under general anesthesia, in prone position, with ureteral catheter 3 or4 f,diluted contrast injection and fluoroscopic or ultrasonographic guided nephrostomy by chiba needle 18g.tract dilation performed with alken telescopic dilators. nephroscopy were done with 15 fr. nephroscope.lithotripsy was done with pneumatic lithoclast and saline solution used as irrigation.nephrostomy tube was inserted in 17,tubeless(no nephrostomy) in 52,jj in 4 and totally tubeless in 25 patients.ureteral stent and foley catheter were removed 12-24 hours after operation. results: of total 98 patients,61 were boys and 37 girls.mean age was 8.6 years(14months-18years)and mean stone size=>20mm. mean operation time was 65min(35-100) and radiation 0.6 min(0.2-1.4). 88 were stone-free,5 patients had residual fragment less than 5mm, passed spontaneously in 2 weeks after operation,3 underwent second look nephroscopy, and 2 ureteroscopy for migrated stone fragments to distal ureter.postoperatively,14 patients developed low grade fever,1 sepsis,4 transfusion,and 2 raising of normal creatinine which improved with conservative management. conclusion: mpcnl is recommended as safe alternative option for treatment of the nephrolithiasis in children. keywords: nephrolithiasis; pediatric; percutaneous o. 102 22 11th congress of the iranian endourology and urolaparoscopy society, 2019 comparison of the monoplanar and biplanar renal access in percutaneous nephrolithotomy:a single center experience dariush irani, mohammad mehdi hosseini*, reza haghpanah,kian omidbakhsh endourology & stone unit,urology department,shiraz university of medical sciences,shiraz,iran. presenting author: mohammad mehdi hosseini purpose: the aim of this study was to compare the clinical outcomes and complications of monoplanar and biplanar access techniques for percutaneous nephrolithotomy (pcnl). methods: in a prospective study, between march 2018 and august 2019, the data from patients who underwent monoplanar or biplanar fluoroscopy-guided access for pcnl in faghihi hospital were compared. in monoplanar technique, a c-arm fluoroscope was brought into vertical position, the collecting system was visualized with a contrast agent, and the most appropriate calix was selected for access.in biplanar technique, puncture is adjusted based on different fluoroscopic projections including vertical and 30 degree positions. results: the monoplanar technique was performed for renal access in 176 patients (group 1), and the biplanar technique was used for renal access in 217 patients (group 2). there were no statistically significant differences between the two groups for demographic data, mean operative times, hospital stay (p > 0.05). while the mean puncture time and fluoroscopy screening time were significantly lower in monoplanar group when compared with that of biplanar group (p = 0.000). the monoplanar and biplanar groups had similar success rates of 84% and 86%, respectively (p > 0.05) and the rates of early postoperative complications also were similar for both groups. conclusion: there is similar success rates for monoplanar and biplanar access techniques, while monoplanar access technique is a safe technique with decreased puncture time and minimized surgical team and the patient’s radiation exposure time. keywords: percutaneous nephrolithotomy; monoplanar; biplanar; fluoroscopy o. 103 23 11th congress of the iranian endourology and urolaparoscopy society, 2019 a randomized, crossover, pilot study of carvedilol and terazosin on urinary symptoms of patients with hypertension and benign prostate hyperplasia. alireza farshi1, nooriyeh dalirakbari2*, afshar zomorrodi3, mohammad khalili4 1assistant professor of urology, department of urology, imam reza hospital, tabriz university of medical sciences. 2urology resident, department of urology, tabriz university of medical sciences. 3assistant professor of urology, department of urology, tabriz university of medical sciences. 4ph.d of nutrition, neurosciences research center,tabriz university of medical sciences. *presenting author: nooriyeh dalirakbari purpose: the aim of the present study was to assess and compare the effects of carvedilol and terazosin plus enalapril on lower urinary tract symptoms (luts), urine flow, and blood pressure (bp) in patients with moderate hypertension (htn) and benign prostatic hyperplasia (bph). methods: in this randomized crossover trial, 40 men with htn and luts symptoms were enrolled. the first group was treated with carvedilol, and the other group received terazosin plus enalapril. after eight weeks of treatment patients followed a one-month washout period, and then the treatments were changed and continued for eight weeks. to diagnose bph, international prostate symptom score (ipss) questionnaire was used in the study. moreover, prostate-specific antigen (psa), post-void residual (pvr) urine volume, and maximum urinary flow rate (q-max) were measured using uro-flowmetry test too. results: treatment with carvedilol or terazosin plus enalapril could significantly reduce systolic and diastolic blood pressure, pvr and psa levels; however, changes in ipss were not statistically significant. also qmax measurements in both groups indicated an increase in urinary flow rate. there were no significant differences between the mean values of systolic bp, ipss, qmax, and psa reduction in both groups following the treatment (p > 0.05). conclusion: carvedilol as compared with terazosin plus enalapril indicates similar effects on controlling luts in patients with moderate htn and bph. further studies are required to investigate the efficacy of carvedilol compared with other alpha-blockers involving a large sample size and over a longer period of time. keywords: benign prostatic hyperplasia; blood pressure, carvedilol o. 104 24 11th congress of the iranian endourology and urolaparoscopy society, 2019 comparison of presence of detrusor muscle in pathology report of monopolar conventional turbt and en-bloc turbt koosha kamali, pejman shadpour, ehsan zolfi, nasrollah abian3* hasheminejad kidney center (hkc), hospital management research center (hmrc), iran university of medical sciences (iums), tehran, iran. *presenting author: nasrollah abian purpose: according to eau 2018 guidelines, turbt is the gold standard method for diagnosis and treatment of non-muscle invasive bladder tumor. it has been reported that in 50% of cases no detrusor was found in the specimen. the aim of this study is to compare presence of detrusor in specimens taken by conventional and en-bloc method. method: from september 2017 to september 2018, 60 patients with solitary papillary tumor sized less than 3 cm, and no prior history of bladder cancer were randomly divided into two groups: conventional turbt and enbloc turbt with monopolar hook. mean operation time, perforation rate, and presence of detrusor muscle were compared between two groups. result: mean operation time in en-bloc turbt was 15.46 ± 3.52 minutes and in conventional turbt was 20.6 ± 5.04 minutes. the mean operation time was significantly different between the two groups. no clinical bladder perforation was seen in the two groups. in 28 cases (93/3%) of en-bloc group the detrusor was seen in pathologic reports while presence of detrusor in pathology report was positive in 25 cases (83.3%) of the conventional group, this difference was not statistically significant. conclusion: en-bloc turbt with monopolar hook was as effective as conventional method with no increase in bladder perforation and due to lower operation time it is a better option than conventional turbt. keywords: bladder cancer; turbt; en-bloc; detrusor; hook electrod o. 105 25 11th congress of the iranian endourology and urolaparoscopy society, 2019 a posteriori dietary patterns are associated with urinary risk factors of nephrolithiasis: findings from a cross-sectional study on iranian men niloofarsadat maddahi1, khadijeh mirzaei1, seyed mohammad kazem aghamir2, seyed saeed modaresi3, mir saeed yekaninejad4 1department of community nutrition, school of nutritional sciences and dietetics, tehran university of medical sciences (tums), tehran, iran. 2department of urology, sina hospital, tehran university of medical sciences, tehran, iran. 3urology research center, sina hospital, tehran university of medical sciences, tehran, iran. 4 department of epidemiology and biostatistics, school of public health, tehran university of medical sciences, tehran, iran. *presenting author: niloofarsadat maddahi background & aim: dietary patterns have been identified as useful indicators of diet quality, but evidence regarding their association with the nephrolithiasis risk factors is still scarce. therefore, we aimed to verify the relationship between dietary patterns and urinary risk factors of nephrolithiasis, including hypercalciuria, hyperuricosuria, hyperoxaluria, hypocitraturia, and abnormal creatinine. methods: a total of 264 apparently healthy male subjects, with mean age of 18-89 years, were enrolled in this cross-sectional study from september to december 2016, in tehran, iran. dietary intake of participants during the preceeding year was obtained using a 168-item semi-quantitative food frequency questionnaire and dietary patterns were derived by using factor analysis. the 24h urine samples were collected to measure urinary levels of nephrolithiasis risk factors. the relationships were tested with the use of binary logistic regression. results: three major dietary patterns, explaining 45.87% of total variance of diet, including unhealthy, healthy and spice-caffeine patterns were identified. after adjustment for body mass index, age and energy intake, compared with people in the lowest tertile, the highest tertile of healthy dietary pattern was associated with the decreased odds of hypocitraturia (or = 0.24, 95%ci = 0.10-0.56, p = 0.001) and hypercalciuria (or= 0.20, 95%ci= 0.10-0.46, p < 0.001). in contrast, higher adherence to the unhealthy pattern was found to be positively related to the increased risk of hypocitraturia (or = 5.14, 95%ci = 2.04-12.96, p = 0.001) and hypercalciuria (or=4.11, 95%ci = 1.77-9.56, p = 0.001). moreover, there was a direct association between the spice-caffeine dietary pattern with hyperoxaluri (or = 2.90, 95%ci = 1.51-5.60, p = 0.001) and hypercalciuria (or = 2.41, 95%ci = 1.17-4.95, p = 0.02). conclusion: higher adherence to the unhealthy and spice-caffeine dietary patterns and lower adherence to the healthy pattern is related to some urinary risk factors of nephrolithiasis keywords: dietary patterns; nephrolithiasis; kidney stone; hypercalciuria; hyperuricosuria; hyperoxaluria; hypocitraturia; creatinine o. 106 26 11th congress of the iranian endourology and urolaparoscopy society, 2019 comparison of tubeless intercostal percutaneous nephrolithotomy with its standard method seyed habibollah mousavi-bahar¹, shahryar amirhasani¹, mehdi shahmirzaei¹* ¹urology & nephrology research center, hamadan university of medical sciences, hamadan, iran. *presenting author: mehdi shahmirzaei introduction: tubeless percutaneous nephrolithotomy (pcnl) has been found to be safe and have some advantages without increasing complications. supracostal access may increase pulmonary complications.in this study, the outcomes of tubeless intercostal pcnl were compared with its standard method. methods and materials: in this randomized clinical trial, from march 2017 to march 2019, 70 patients with kidney stones who were candidate for intercostal pcnl referring to shahid beheshti hospital of hamedan and were randomly assigned to tubeless intercostal pcnl (intervention group) and standard intercostal pcnl (control group). post operative observation and chest x-ray were done to detect any pleural injuries. the hemoglobin, hematocrit and creatinine changes, the average need for opiate,the average duration of hospitalization and complications according to the modified clavien classification were evaluated and compared in two groups. data were analyzed by spss software version 16 at 95% confidence level. results: the mean age of the patients in the intervention and control group was 46.17 and 49.66 years (p = 0.249), and in each group, 25 were men and 10 women (p = 1.00). in the intervention and control group, the mean duration of surgery time was 52.85 and 56.71 minutes, the mean duration of hospital stay was 2.2 and 2.74 days, the mean opioids use were 4.64 and 4.88 mg morphine sulphate(need for opiate 40% vs 60%), anti-febrile administration 20 and 31.4%, need for blood transfusion, 5.7% and 5.7%, and total complications including fever, hematoma, bleeding, pleural damage and hydrothorax was 28.58% and 31.43% (p > 0.05).two patients in standard group and no one in tubeless group required chest tube. conclusion: tubeless intercostal pcnl in comparison to its standard intercostal pcnl reduces the mean duration of operation, the hospitalization and analgesic use however, no statistically significant difference was observed between the two methods.complications according to the modified clavien classificationis is the same in both groups. keywords: kidney stons, percutaneous nephrolithotomy, tubless, standard o. 107 27 11th congress of the iranian endourology and urolaparoscopy society, 2019 efficacy of ureteral stent in children with distal ureteral stones treated by adult type semi-rigid ureteroscope seyed mohammadreza rabani1*, seyedeh maryam rabani2 1beheshti teaching hospital; yasuj university of medical sciences; yasuj, iran. 2seyedeh maryam rabani; cellular and molecular research center; yasuj university of medical sciences; yasuj, iran. *presenting author: seyed mohammadreza rabani introduction: the development of high quality, miniaturized ureteroscopes has led to the adoption of transurethral lithotripsy (tul) as first line therapy in children, but this equipment is not available in every center. on the other hand, pre-operative ureteral stent insertion may results in passive dilatation of the ureter. to assess the impact of pre-operative stent insertion on the success rate of transurethral lithotripsy (tul) by adult ureteroscope(8-9.8f) in children with history of failed previous attempt to access the ureteral stone, we have designed this study prospectively. material and methods: 24 patients between 4 and 12 years old (mean age 10), were enrolled in this study. mean stone size was 7mm(5-11mm). the ureteroscope was adult type (8-9.8f) wolf germany. inclusion criteria were pediatric patients with distal ureteral stone and a history of failed previous attempt to access the stone by the same size ureteroscope, that underwent indwelling ureteral stent insertion for at least 3 days and exclusion criteria consisted of cases who failed to follow up. results: in 20 patients (83%) after removing the stent, stone access was achieved in redo operation and transurethral lithotripsy was successful, but in 4 patients ureteroscopy and stone access was impossible and again a ureteral stent was inserted for a third intervention in another center. conclusion: improvement in ureteroscopic access to stones throughout the pediatric urinary tract and stone-free rates that are comparable to the adult population have led to the adoption of tul as first line therapy in children at many urologic centers, this success is really due to high quality, miniaturized ureteroscopes, but in our country availability of these instruments is not easy for every center. so that we have to use adult type ureteroscope both for adults and children. it was well known that the ureter of a child frequently admits a 5-f ureteral catheter, but using an adult (8-9.8f) ureteroscope may be associated with a forceful ureteroscopy. although rigid ureteroscopy can be a safe and efficient treatment for ureteral stones in every location in children, its proper size in pediatric age group is essential. keywords: ureteroscopy; stent; lithotripsy; children o. 108 28 11th congress of the iranian endourology and urolaparoscopy society, 2019 retrograde intrarenal surgery for management of nephrolithiasis : outcomes of fellows in training kaveh mehravaran, massoud etemadian, pejman shadpour, mayhar fasihi *, ahmadreza rafati, asghar alizadeh, said pakdel , mohamad mehdi atarod ,farshad gooran, roozbeh roohinezhad . hasheminejad kidney center, iran university of medical sciences, tehran, iran. *presenting author: mayhar fasihi background and aim: to evaluate the outcome of retrograde intrarenal surgery (rirs) in the management of renal stone less than 20 mm by fellows in training in a referral center. method: 100 patient were enrolled from september 2017 to april 2019 who underwent rirs under ga or sa with holmium yag laser for management of renal calculi less than 20 mm in after failure of other treatments like eswl .operation were performed by hasheminejad kidney center endourology fellows .they had no prior experience in performing rirs. all data consisting of demographic and routine blood and urine tests were gathered and stone size before and after surgery was measured by none-contrast spiral ct scan. result: 100 patients were operated during 20 months of whom 72 were male and 28 were female .the mean patient's age was 42 year (10-62 yrs). mean size of the renal stone was 15.51‚mean operating time was 58 minutes (20-100 mios) and mean hospitalization time of patients was 1.12 (1-3 days). the location of stones were lower calyx in 76 cases‚ renal pelvis in 10 cases ‚middle calyx in 9 cases ‚upper calyx in 5 case. regarding the success rate‚ 40 patient (%40) were stone free after the surgery‚22 patient (%22) had residual stone less than 4 mm and 44 (%44) had residual fragments more than 4 mm and in 4 patient ‚the stone was not found as a result of obstacle calyx. regarding the complication, we found 3 cases of urinoma after the surgery ‚of them 2 cases were managed conservatively and one case underwent open drainage‚2 case of seizure ‚one case of intracranial hemorrhage‚ 3 case of uti and fever and 10 case needed narcotics due to postoperative pain. conclusion: rirs is at the beginning of its way in iran . the fellows had no prior experience in rirs, nevertheless‚ the outcomes of rirs was acceptable and comparable to other currently conventional methods for treatment of small sized kidney stones. because of short hospitalization time and lack of hemorrhage and non-invasive nature of the operation ‚it seems that, it will become more popular in the future . keywords: rirs; nephrolithiasis; fellow o. 109 29 11th congress of the iranian endourology and urolaparoscopy society, 2019 case report of endourologic management of basket entrapment pejman shadpour, kaveh mehravaran, masoud etemadian, roozbeh roohinezhad*, farshad gouran, m mehdi atarod hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. presenting author: roozbeh roohinezhad background: entrapment of a basket device on a stone occurs in approximately 0.5% of cases where a basket is used. this is attributed to grasping a stone or fragment too large for removal through the ureter, resulting in a stone entrapped by the basket or snaring of the urothelium. two strategies have been tried for management. first is to gently advance the stone more proximally and disengage the stone. second is to cut the basket wiring just beyond the sheath or basket disassembly if basket preservation is necessary. case: a 41 year old man who was referred emergently to our center. originally he had an impacted stone resistant to swl in the upper ureter. during ureteroscopy treatment had begun with basket insertion for lithotripsy, but the basket became entrapped proximally and ureteral injury was incurred. he was referred to our center where laser fracturing of the nitinol wires successfully disengaged and relieved the entrapment for stone clearance. conclusion: entrapment of the basket device on a stone is uncommon. we used lasing two nitinol wires of the basket for management of this basket entrapment. keyword : basket entrapment; ureteroscopy; laser lithotripsy o. 110 30 11th congress of the iranian endourology and urolaparoscopy society, 2019 endoscopic management for uretero-ileal anastomotic obstruction in ileal loop diversion: a case series pejman shadpour, kaveh mehravaran, masoud etemadian, kiarash attar, roozbeh roohinezhad*, farshad gouran, mehdi atarod hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. presenting author: roozbeh roohinezhad background: uretero-enteric stricture and stone represent uncommon but potentially complicating and difficult to treat complication of urinary diversion and may occur in 4-8% of cases. the incidence of renal stone is 3% to 4% in colon conduits and 10% to 12 % for ileal conduits. the surgical treatment of urinary diversion presents a unique challenge even in skilled hands. percutaneous approach can prove as efficacious as open surgery but decreased morbidity of primary endoscopic management has led to increased interest in this approach. case series: all four cases had undergone non continent urinary diversion for muscle invasive bladder transitional cell carcinoma and presented with loss of apetite, nausea, dull flank pain and rising creatinine. further work up in 3 cases led to ureteral stone plus relative uretero-enteric anastomosis stricture. in the last case stricture alone had caused hydroureteronephrosis. a percutaneous approach with antegrade flexible ureteroscopy was successful in providing access to the stricture site for ho-yag laser lithotripsy or laser endo ureterotomy and stenting. conclusion: in the experienced hands, percutaneous approach can be utilized as a safe and effective method for management of stones and strictures with equal or better results than open surgery but obviously less morbidity in these difficult cases. keywords: ileal loop diversion; laser lithotripsy; flexible ureteroscopy; percutaneous access o. 111 31 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic pyeloplasty and pyelolithotomy in a case with history of midline laparotomy for ipsilateral bowel cancer surgery and chemoradiation pejman shadpour, mohammad mehdi atarod, kaveh mehravaran, masoud etemadian farshad gouran, roozbeh roohinezhad* hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *presenting author: roozbeh roohinezhad background: although laparoscopic pyeloplasty is standard of care for minimally invasive treatment of primary ureteropelvic junction obstruction capsul, secondary upjo is an entirely different matter. laparoscopy can potentially provide lower patient morbidity, shorter hospitalization, and faster convalescence. in upj obstruction with stones, pyeloplasty can be performed with simultaneous stone removal. case: a 58 year old male with a history of chemoradiation plus right colectomy for colon cancer and a midline laparotomy scar who presented with flank pain due to a chronically impacted right renal pelvic stone leading to hydronephrosis and secondary ureteropelvic junction stricture, had been triaged for the past three years as unfit for subjecting to urologic treatments. he now had compromised renal function (gfr of 38 cc/min). conclusion: transperitoneal adhesiolysis, pyelolithotomy for stone removal and laparoscopic pyeloplasty was tedious, but led to relief of symptoms and correction of elevated creatinine with no additional morbidity. keywords: laparoscopic pyeloplasty , pyelolithotomy , chemoradiation , colectomy o. 112 32 11th congress of the iranian endourology and urolaparoscopy society, 2019 comparison of ultra-rapid and rapid dilation techniques for access in percutaneous nephrolithotomy sasan mehrabi1*, alidad kiani1, behzad mohammad soori1 1urology & nephrology research center, hamadan university of medical sciences, hamadan, iran. *presenting author: sasan mehrabi purpose: comparaison of ultra-rapid (one step amplatz insertion) and rapid dilation (two step amplatz insertion) techniques for access in percutaneous nephrolithotomy in patients referred to beheshti’s hospital of hamadan university of medical sciences between 2017-2018. methods: between april 2017 and november 2018, patients who were candidates for percutaneous nephrolithotomy were enrolled in this prospective study. patients were randomly assigned to dilation by ultra-rapid technique (group i, 25 patients) or dilation by rapid technique (group ii, 25 patients). the primary endpoint of interest was access and fluoroscopy time. secondary endpoints included success rate, decrease of hb, hospitalization time and complications. results: age, stone size, hospitalization time and success rate were not significantly different between the studied groups. the mean ± standard deviation of access and fluoroscopy times and hb decrease in groups i and ii were 3.2 ±.7 min vs. 5.5 ±1.2 min (p < 0.05) ,11.5 ± 2.7 s vs. 21.1 ± 4.7 s (p < 0.001) 1.4± 0.5 mg/dl vs 2.3 ± 0.9 mg/dl, respectively. postoperative complications were not observed in both group. conclusion: percutaneous tract dilation by the one-stage ultra-rapid method is safe and effective. also, it is associated with considerably less radiation exposure in patients and surgeons. keywords: ultra-rapide dilation technique; percutaneous nephrolithotomy o. 113 33 11th congress of the iranian endourology and urolaparoscopy society, 2019 results and complicatins of tubeless ultra-mini pcnl in children mohammad mehdi hosseini*, ali eslahi, reza haghpanah, ali mirzakhanlouei endourology & stone unit,urology department,shiraz university of medical sciences,shiraz,iran. *presenting author: mohammad mehdi hosseini purpose: percutaneous nephrolithotomy (pcnl) has rapid advancements, the newest being ultra-mini-percutaneous nephrolithotomy (ump) which makes use of 11–13f sheaths.this miniaturization aims to reduce morbidity and improve patient outcomes. we evaluated the safety and efficacy of ump and report our preliminary report in children. patients and methods: a total of 34 children including 19 boys and 15 girls underwent ump from march 2016 to feb 2019. these patients had mean age of 8.6 years(1-15) and renal stone measuring between 12 and 25 mm. all patients underwent ump using a 6f tip semi-rigid ureteroscope instead of nephroscope, and the 12f metallic sheath of the alken telescopic dilators was used as the amplatz sheath. stone fragmentation was done with pneumatic lithotriptor(lithoclast). no nephrostomy was used and ureteral catheter also removed 6 to 12 hours postoperatively. results: complete stone fragmentation was achieved in 29 of 34 patients (85%). the mean operative time was 55 min, and the mean postoperative hospital stay was 26.6 hrs.there were no significant postoperative complications. conclusion: ump seems to be an effective and safe procedure for managing stones.this procedure is a good alternative to swl or rirs for managing stones in children. keywords:nephrolithiasis,percutaneous,ultramini o. 114 34 11th congress of the iranian endourology and urolaparoscopy society, 2019 comparison efficacy of peganum harmala seeds on improving ppain and passage of 6 to 10 mm stones of kidney and ureter sadrollah mehrabi1*, nahid shakeri1 1medicinal plant research center, yasuj university of medical sciences, yasuj, iran. *presenting author: sadrollah mehrabi purpose: considering the diuretic, analgesic and antiseptic effects of peganum harmala, the purpose of this study was evaluating effects of harmala seeds on improving pain and expulsion rate of 6 to 10 mm stones of kidney and ureter candidate for medical therapy. methods: in this randomized clinical trial, 80 patients ≥ 18 years-old with kidney and ureteral stones sized 6 to 10 after taking informed consent from were randomly allocated to one of two groups by simple random sampling method. in group 1, after performing ultrasonography and confirming the presence of 6 to 10 mm stones, one capsule of tamsulosin 0.4 mg was prescribed per night for 2 weeks. in group 2, harmala seed with dose of 20 mg/ kg per day was prescribed after meal with a glass of water for two weeks. also they were advised to do at least 30 minutes of exercise and walking. 2 weeks later patients were visited and kub sonography was conducted and the change in size of stones and presence of residual stones was measured and recorded. the severity of pain was checked using vas (visual analogue scale) and the data was collected and analyzed during treatment and at the end of the study. all the information were collected and analyzed by spss software version 21. results: mean sizes of stones before treatment were respectively 13.3 ± 9.163 and 10.79 ± 7.828 millimeter (p = 0.21. mean number of stones before and after treatment was 0.59 ± 1.38 and 1.18±0.94 and there was no significant difference between two groups. there was no significant differences between two groups regarding average of pain score before treatment (p = 0.065) but pain score decreased significantly in two group that was more significant in peganum harmala group(p = 0. 002).regarding efficacy of treatment, there was no significant differences between two groups but in two groups efficacy was more than 75. conclusion: this study showed that both pejanum harmala seed and tamsulosin without any significant side effects decreased urinary stone size and numbers without significant difference, but pain score decrease significantly by pejanum harmala. key words: pejanum harmala; tamsulosin; treatment; urinary stones o. 115 35 11th congress of the iranian endourology and urolaparoscopy society, 2019 renal pelvic trauma management after percutaneous nephrolithotomy which one is recommended: nephrostomy or dabble j stent? robab maghsoudi1, mohammad kolbadinezhad2, masoud etemadian2, amir h kashi3, kaveh mehravaran2, nasrollah abian2*, vahid fakhar2 1urology department of firoozgar hospital, iran university of medical sciences, tehran, iran. 2hasheminejad kidney center, iran university of medical sciences, tehran, iran. 3urology and nephrology research center, shahid behesti university of medical sciences, tehran, iran. *presenting author: nasrollah abian purpose: this study was conducted to compare the insertion of double j or nephrostomy tube for management of pcnl induced renal pelvic trauma. methods: 58 patients who had renal pelvic trauma during pcnl, were randomly allocated in two groups for injury management. the first group was embedded with double j stent and the second group was treated by using nephrostomy tube insertion. 3 months after removal of nephrostomy or double-j stent, ivu was taken from patients. variables such as fever, urinary tract infection, urinary leakage, surgical complications (abscess, urinoma), and need for postoperative procedures were recorded to evaluate. results: 58 patients were enrolled in the study: 31 (54.0%) were under nephrostomy and 27 (46.0%) under double-j stent. there was no significant difference in mean age, genders, mean of hemoglobin values, number of access, surgical duration, involved side, type of stone and place of entry between nephrostomy and double-j stent groups (p > 0.05). the frequency of fever and leakage didn’t have statistically significant difference between two groups (p > 0.05). prevalence of urinoma was 16.1% in the nephrostomy group and 40.7% in the double-j group and there was a statistically significant difference between the two groups (p = 0.036). conclusion: overall findings showed that although there was no significant difference between two methods of double-j and and nephrostomy in patients with pcnl, however, due to less complication of urinoma in the nephrostomy group, this method is recommended as the preferred method of treatment of renal pelvic trauma during pcnl. keywords: pcnl, double-j; nephrostomy; pelvic trauma o. 116 36 11th congress of the iranian endourology and urolaparoscopy society, 2019 necrotizing fasciitis after percuteneous nephrolithotomy: a case report robab maghsoudi, asaad moradi, behnam shakiba, saeed esmaeil soufian* urology department of firoozgar hospital, iran university of medical sciences, tehran, iran. *presenting author: saeed esmaeil soufian purpose: percutaneous nephron lithotomy (pcnl) is a standard procedure for treatment of patients with large kidney stones. although pcnl is generally considered safe, it rarely causes serious complications. we review a patient presenting with necrotizing fasciitis following pcnl. case presentation: in a 65 year-old woman pcnl was performed for a single kidney staghorn stone, she didn’t have any major complication intra or post operatively. she had dj stent that removed 4 weeks after surgery in an outpatient setting. 2 weeks after dj removal she referred to our department by chills and fever and a small perinephric collection. also due to lower limb edema and necrotizing fasciitis, right lower limb fasciotomy was performed for her by orthopedic service in another hospital. aspiration of perinephric abscess and antibiotic therapy was planned for patient. after 10 days of hospital stay with antibiotic therapy and wound care she discharged from hospital. in her follow up visit after 10 days, her wound was healed and she didn’t have any complain. conclusion: it seems that as a rare complication of pcnl, necrotizing fasciitis can be considered. keywords: pcnl, complication; necroziting fasciitis o. 117 37 11th congress of the iranian endourology and urolaparoscopy society, 2019 early detection and endoscopic management of post cesarean section ureterovaginal fistula seyed mohammadreza rabani1*, seyedeh maryam rabani2 1beheshti teaching hospital, yasuj university of medical sciences, yasuj, iran. 2cellular and molecular research center; yasuj university of medical sciences, yasuj, iran. *presenting author: seyed mohammadreza rabani introduction: the mechanism of ureteral injury during a pelvic surgery resulting in ureterovaginal fistula (uvf) is different and includes ureteral laceration, transection, avulsion, partial or complete suture ligation, and finally, ischemia due to cautery injury. the aim of this study was to evaluate the early detection and endourological management of post cesarean section uvf. materials and methods: between february 2016 and march 2019, 8 patients were referred for vaginal leakage after cesarean section (cs), 3 of them were operated by general surgeons in emergency states. all of them were referred within 15 days from their original operations (the earliest after 6 days and the last after 15 days). 3 patients had a vague lower abdominal pain and 5 had ipsilateral flank pain, but all had per vaginal leakage. physical examination, ultrasography, and ivp were done for confirming the diagnosis. ureteroscopy was the first attempt, using 2 or 3 guide wires for finding the more proximal part of the ureter and insertion of a jj stent. results: the procedure was successful in 6 patients (75%). in two patients the guide wire could not pass, so we changed the position and ureteral reimplantation was planed. the stents were removed after 4 weeks, and after 3 months an ivp was planned that showed no evidence for ureteral stricture. conclusion: the only portion of the ureter that its injury may cause uvf is the distal portion, which always occurs during pelvic surgeries such as cs. the most common cause for uvf is gynecological procedures. by an attempt to control the active bleeding in deep pelvis especially in difficult cs there is a possibility to develop uvf. in a patient with total urinary incontinence after cs, physical examination, ultrasonography, and ivp with lateral view x ray may confirm the diagnosis of uvf. the traditional treatment for uvf is ureteral re-implantation, but endoscopic management may be a viable technique with less invasiveness and faster results and recovery. keywords: urinary; fistula; endoscopy; stent; cesarean section o. 118 38 11th congress of the iranian endourology and urolaparoscopy society, 2019 the safety of continued low dose aspirin therapy during complete supine percutaneous nephrolithotomy (cspcnl) siavash falahatkar, samaneh esmaeili, nadia rastjou herfeh, ehsan kazemnezhad, reza falahatkar*, masoumeh yeganeh, alireza jafari urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran. *presenting author: reza falahatkar purpose: using antiplatelet or anticoagulant in patients with cardiovascular and medical comorbidities is prevalent. because of hyper vascular nature of kidney, physicians tend to stop using aspirin before percutaneous nephrolithotomy (pcnl). we have shown the effects of remaining on low dose aspirin in complete supine pcnl (cspcnl). materials and methods: surgical outcomes and complications of patients who were on aspirin therapy and continued it daily (group a) were compared with patients not taking aspirin (group b). results: of the 643 cspcnls, 40(6%) were performed in patients of group a and the rest of 603(94%) cases were in group b. the differences between the mean age of groups were statistically significant (60.08 ± 9.45, group a and 48.66 ± 12.32, group b) (p < 0.001). thirty-nine (97.5%) patients in group a and 548(90.9%) group b were stone free which was not statistically significant (p = 0.118). the mean operative time between groups a and b (43.20 ± 21.37 and 44.83 ± 16.83, respectively) was not considered significant (p = 0.561). there was also no significant difference between 2 groups in any types of complications. multivariate analysis showed that, perioperative aspirin use was not a significant predictor of transfusion, hb drop, operative time and other complications. conclusion: remaining on aspirin does not increase the risk of bleeding, transfusion and other complications. consequently, continuing aspirin prioperatively in cspcnl appears safe. there is no fear for continuing aspirin in cspcnl. keywords: percutaneous nephrolithotomy; supine, aspirin; cspcnl; transfusion b s.e. sig. or %95 c.i. for or lower upper complication constant 1.475 0.169 0.000 .229 antibiotic before operation 0.903 0.199 0.000 2.466 1.669 3.643 success rate constant 2.313 0.159 0.000 10.106 aspirin intake 1.908 1.058 0.071 6.741 0.848 53.603 diabetes 0.848 0.473 0.073 2.336 0.925 5.899 ischemic heart disease 1.6700.471 0.000 .188 0.075 0.474 transfusion constant 2.471 0.245 0.000 0.085 antibiotic before operation 0.999 0.278 0.000 2.716 1.576 4.681 table 1. multiple logistics regression o. 119 39 11th congress of the iranian endourology and urolaparoscopy society, 2019 comparison of the effect of pregabalin, solifenacin and the adminitration of combination of them on symptoms related to ureteral double-j stent insertion (usrs) following ureteroscopy and transureteral lithotripsy in patients with ureteral stone siavash falahatkar, mohammadreza beigzade*, gholamreza mokhtari, ehsan kazamnazhad, samaneh esmaeili urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran. *presenting author: mohammadreza beigzade purpose: the ureteral stent symptom questionnaire (ussq) is a critical and important tool for comparing different types of stents and to evaluate the effectiveness of various drugs in resolving the usrs. in this study, we evaluated the results of drug administration of pregabalin, solifenacin, their combined use and control group through persian translation of ussq questionnaire. methods: this study was a randomized clinical trial with controlled group that was performed on 256 patients with ureteral urethra and lithotripsy transurethral candidates (tul) referred to the razi hospital of rasht for double-j stenting. results: of the 256 patients studied, 152 were male and 104 were females with a mean age of 43.52 ± 7.68 years. the mean age of males was 43.47 ± 7.75 (range 26-60) years, and in women it was 43.59 ± 7.6 (range 30-60) years. the mean age of the patients in the four groups was not significantly different. there were no significant differences between sexes in the four groups. in the pregabalin group, only the overall result of urinary symptoms was significant in the 4 weeks after operation compared to the control group. in addition, in the solifenacin group, there was a significant difference between the groups used pregabaline and compare to other groups. compared to the control group, solifenasin and pregabalin in comparison with the control group, the rate of analgesia use, ultrasound, nocturia, dysuria during 2 weeks and 4 weeks after surgery, pain, use of pain, urinary symptoms within 2 weeks of surgery, and pain and urinary symptoms were significant for 4 weeks after surgery conclusion: according to the results, the combined consumption of pregabalin and solifenacin in combination with pregabalin and solifenacin on symptoms related to ureteral double-j stent insertion (usrs) following ureteroscopy and transureteral lithotripsy in patients with ureteral stone. no adverse drug reactions were reported in either of the three drug-user groups. keywords: pregabalin; solifenacin; ureteral double-j stent insertion o. 120 40 11th congress of the iranian endourology and urolaparoscopy society, 2019 efficacy of bimanual abdomino-flank compression in control of postoperative bleeding in percutaneous nephrolithotomy robab maghsoudi1, masoud etemadian2, amir h kashi3, nasrollah abian2, mehran moghimian1* 1urology department of firoozgar hospital, iran university of medical sciences, tehran, iran. 2hasheminejad kidney center, iran university of medical sciences, tehran, iran. 3urology and nephrology research center, shahid behesti university of medical sciences, tehran, iran. *presenting author: mehran moghimian purpose: to investigate the efficacy of postoperative bimanual abdominal-flank compression in controlling postoperative bleeding from percutaneous nephrolithotomy (pcnl). methods: 90 patients who underwent pcnl were randomly divided into groups of abdomino-flank compression for 0 (group a), 2 (group b), and 7 minutes (group c) after completion of tubeless pcnl. the primary endpoint of interest included the percentage drop in hemoglobin 24 and 48 hours operation. secondary endpoint included complications. the study was approved by the ethics committee of the relevant university. results: 29, 30 and 29 patients were included in treatment groups of 0, 2 and 7 minutes compression groups. the stone surface area in groups a, b, and c were 376 ± 509, 371 ± 571, and 277 ± 160. hospitalization duration in groups a, b, and c were 3.13 ±.34, 3.29 ±.69, and 3.08±.28 (all p > 0.05). the percent drop in 24 hour postoperative hb in groups a, b, and c were 11.5 ± 8.6, 9.2 ± 7.3 and 9.3 ± 6.8 respectively (p = 0.44). the percent drop in 48 hour postoperative hb in groups a, b, and c were 8.6 ± 8.7, 9.5 ± 9.9 and 7.2 ± 9.6, respectively (p = 0.64) conclusion: the results of this study reveals that postoperative bimanual compression of abdomino-flank has no substantial influence on control of postoperative bleeding after pcnl. keywords: bleeding; nephrolithiasis; percutaneous nephrolithotomy; hemoglobin o. 121 41 11th congress of the iranian endourology and urolaparoscopy society, 2019 comparison of the effect of tamsulosin, tadalafil and placebo in stone expulsion of patients with distal ureteral stones siavash falahatkar, ardalan akhavan*, ehsan kazamnazhad, samaneh esmaeili urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran. *presenting author: ardalan akhavan purpose: in order to facilitate distal urethral stone passage, different drugs have been used; tamsulosin as the most known medical exulsive therapy(met) for stone passage has been used. the other drugs such as nifidipin and prednisolone have been studied. tadalafil has been used in the late studies as a met. we aim to compare the effects of tadalafil, tamsulosin and placebo as a (met). method: between september 2017 and december 2018, 142 renal colic patients with distal ureteral stone (less than 1 cm) were equally divided into three groups of tamsulosin, tadalafil and placebo. therapy was given for a maximum of four weeks. stone expulsion rate, stone expulsion time, analgesic use and dose, surgical treatment as long as adverse effects of drugs were noted. data were collected and categorized then analyzed by chi-square test, one way anova and lsd exam. results: one hundred & forty-two patients were divided into three groups. the mean age of patients was 37.08 ± 11.62 and the ratio of males/females was 1.28. stone sizes were the same in all three groups. the stone expulsion rate was 72.7% in tamsulosin group, 63.6% in tadalafil group and 56.6% in placebo group. this difference in expulsion rate was not statistically significant. shorter stone expulsion time and the need for lower analgesic dosage along with analgesic time use in groups were seen in tamsulosin group (72.7% vs. 63.6% vs. 56.6 %.). the occurrence of side effects was higher with tadalafil and tamsulosin than with placebo, this difference was not significant (p = 0.002). the occurrence of headache in tadalafil group was significant. (p = 0.011) conclusion: tamsulosin as a met is effective and safe. although tadalafil facilitates stone passage more than placebo does, regarding side effects and poor pain relief, further studies for evaluating it as a met are recommended. key words: tamsulosin; tadalafil; stone expulsion; ureteral stones o. 122 42 11th congress of the iranian endourology and urolaparoscopy society, 2019 evaluation of applicable protocols to radiation dose reduction during percutaneous nephrolithotomy hadi radfar¹, amir hossein kashi¹, saman farshid²* ¹urology and nephrology research center, shahid labbafinejad hospital, shahid beheshty university of medical sciences, tehran, iran. ²department of urology, urmia university of medical sciences, urmia, iran. *presenting author: saman farshid introduction: despite the minimally invasive nature of percutaneous nephrolithotomy (pcnl) for the patients, there are some hazardous effects on operating room personnel. in order to avoid radiation hazard, some surgeons substitute fluoroscopy with ultrasonography that need some expertise in applying ultrasonography, but using ultrasonography makes accessibility to non-hydronephrotic kidneys harder and depends on the surgeon's skill. there are some superiority for fluoroscopy such as good localization of the opaque stones, and visualization of the needle and guide wire during the procedure, there properties make fluoroscopy more preferable than ultrasonography during pcnl. according to articles, mean fluoroscopy time during pcnl is 3-5 minutes (range from 1 to 8 minutes) and mean radiation exposure to the surgeon is 2.4 ± 1.9 msv and about 0.28 msv to surgeons hand, 2.4 ± 1.9 msv. the maximum permissible eye exposure is recommended 20 msv per year. this study was aimed to evaluate the radiation dose reduction protocols during pcnl to prevent the hazardous effect of radiation. materials and methods: this study was descriptive conducted on 56 patients undergone pcnl between 1 january 2018 and 1 april 2018 in labbafinezhad hospital of tehran, iran by a same surgeon. the data collection form were included demographic data, surgery data such as stone size, site, location, access number, access site, fluoroscopy time, radiation dosage, operation time, stone free rate, surgery complications, and paraclinical data such as hb (g/dl) creatinine (mg/dl) before and after surgery. some techniques were used to reduce the radiation dosage including measuring the size of needle distance from the skin to kidney and use of marker for accurate dilation alignment, measuring the length difference of amplatz sheath and dilator to understand the accurate length of amplatz sheath advancement from the skin, and use of single pulse per second radiation instead of continuous. another method that helped us to reduce exposure was saving the first pyelogram view in our c-arm and matching calyx numbers and stone location with calyces during nephroscopy that guide to find the residual stones instead of using multiple radiation. the data were analyzed using descriptive analysis and pearson test for data with normal distribution (parametric) and spearman for data without normal distribution (nonparametric).p value less than 0.05 was reported significant. results: in this study, 56 patients were evaluated, mean bmi was 26, mean stone size was 2.5 ± 1 cm and 12 patients had staghorn stone, mean operation time was 63 minute, mean fluoroscopy time was 82 second, and stone free rate was 74%, mean hb drop was 2.2 (g/dl). of a total 56 patients, only 6 patients needed multiple accesses. conclusion: according to the results, applying these protocols leads to reduceed radiation time and dosage during the procedure which cause less harm to operating room personnel. keywords: percutaneous nephrolithotomy; fluoroscopy; radiation dosage; personnel o. 123 43 11th congress of the iranian endourology and urolaparoscopy society, 2019 factors affecting fluoroscopic screening time and radiation dose during percutaneous nephrolithotomy siavash falahatkar, keivan gholamjani moghaddam urology research center, razi hospital, school of medicine, guilan university of medical sciences. *presenting author: hamidreza nasseh introduction & objective: in this study, the factors that affect fluoroscopic screening time (fst) and radiation dose (rd) during percutaneous nephrolithotomy (pcnl) were determined. methods: from december 2010 to july 2012 , 161 patients with upper urinary tract stones who underwent pcnl under general anesthesia and fluoroscopic guidance were included in study . factors including previous stone surgery, previous extracorporeal shockwave lithotripsy (eswl), stone burden, stone opacity, multiplicity of stone, stone location, staghorn stone, complex stones, hydronephrosis , kidney side, calyx for access and stone-free result, body mass index (bmi) were analyzed by univariate and multivariate tests. results: the mean patient’s age and bmi were 46.18 ± 12.13 years and 28.29 ± 5.56 kg/m2. the mean stone burden was 34.95 ± 13.23 milimeters. the mean fst and rd were 106.36 ± 57.19 seconds and 475.54 ± 528.66 cgy respectively. in univariate analysis fst and rd were significantly increased with bmi (p < 0.05).the mean fst was 143.00 ± 29.48 and 104.69 ± 57.64 seconds in supracostal and subcostal groups respectively (p = 0.083). in multiple tract access (165.14 ± 70.02 seconds), the mean fst was significantly (p = 0.005) longer than single tract access (103.69 ± 55.34 seconds). the mean rd was 455.43±486.08 cgy in single tract group and 1038 ± 1200.12 cgy in multiple tracts group(p = 0.069). in multivariate analysis, bmi (p = 0.027), supracostal access (p = 0.019) and number of tract (p = 0.002) were effective factors of fst. the fst was increased 1.77 seconds with one unit increase in bmi. multiple tracts access were 65.484 seconds longer than single tract access. the only effective factors of rd was supracostal access (p = 0.031) conclusion: bmi, supracostal access and number of tract were factors that affected fst supracostal access was the factor that affected rd during percutaneous nephrolithotomy keywords: percutaneous nephrolithotomy; radiation dose; fluoroscopic screening time o. 124 44 11th congress of the iranian endourology and urolaparoscopy society, 2019 pneumatic lithotripsy versus laser lithotripsy for ureteral stones amir reza abedi1 , mohammad reza razzaghi1, farzad allameh1, fereshte aliakbari2, morteza fallahkarkan3*, arash ranjbar3 1laser application in medical science research center, shahid beheshti university of medical sciences, tehran, iran 2infertility & reproductive health research center, shahid beheshti university of medical sciences, tehran, iran 3shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *presenting author: morteza fallahkarkan purpose: several different modalities are available for ureteral stone fragmentation. from them pneumatic and holmium: yttrium-aluminum-garnet (ho: yag) lithotripsy have supportive outcomes. in this study we studied 250 subjects who had ureteroscopic pneumatic lithotripsy (pl) or laser lithotripsy (ll). methods: two-hundred & fifty patients with ureteral stones underwent ureteroscopic lithotripsy (115 subjects in the pl group, 135 subjects in the ll group) from august 2010 to april 2016. the purpose of this investigation was to evaluate stone-free rate (sfr), mean operation time (mot), mean hospital stay (mhs), stone migration and complications. results: two groups were similar in age, gender, mean size of stones, side of stone, and complications. there was a statistical difference in terms of sfr, stone migration and mhs in favor of the ll group (p ≤ 0.05, p ≤ 0.05 respectively), and mot in favor of the pl group (p ≤ 0.05). conclusion: both the pl and ll techniques were effective and safe for ureteral stones, however a slightly higher sfr was found in the ll group. keywords: pneumatic lithotripsy; laser lithotripsy; ureteral stone; ho: yag laser o. 125 45 11th congress of the iranian endourology and urolaparoscopy society, 2019 incidence and underlying factors for occurrence of new post-intervention new contralateral reflux in patients undergoing unilateral antireflux surgery pejman shadpour, maryam emami, nasrollah abian*, delaram beirami hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *presenting author: nasrollah abian purpose: post-intervention contralateral reflux refers to the occurrence or increase in grade of reflux in the contralateral ureter following treatment for unilateral urinary reflux. in this study, we evaluated its incidence and related factors. method: preoperative reflux grade was determined by vcug or rnc and kidney function by dmsa. according to vcug, the reflux units were divided into four groups: normal (no reflux), high (grade 4 and 5 equivalent), medium (grade 3) and low (grade 2 and 1). patients were evaluated by cystography 2 to 3 months after surgery. in this case series study, patients with post-intervention reflux were assessed in terms of gender, type of intervention, presence of bladder dysfunction, reflux grade, dmsa, fever during admission, need for readmission due to uti, and the need for re-intervention. results: of 442 patients undergoing endoscopic or open reflux surgery between 1391 and 1395 at our referral center 150 had unilateral reflux. six patients (4%) displayed post-intervention contralateral reflux. all patients were female. five patients had undergone endoscopic treatment. four patients had bowel bladder dysfunction. the primary grade of reflux was moderate to severe in all patients. only in one patient dmsa showed significant difference between the two kidneys. none of the patients developed immediate post op fever. however, two required readmission for febrile uti. two underwent re-intervention (one open, the other endoscopic). conclusion: the incidence of post-intervention contralateral reflux was 4%. there seemed to be a high association between post-intervention reflux and bbd, which emphasizes the importance of attention to bladder and bowel dysfunction in vur patients. also, all cases were high grade primarily. with exception of two patients who were re-treated, all other cases had no problem in follow-up and did not require re-intervention. keywords: vesicoureteral reflux; anti-reflux surgery; post-intervention contralateral reflux o. 126 46 11th congress of the iranian endourology and urolaparoscopy society, 2019 our novel scoring system for triage in management of intrarenal vascular complications of percutaneous nephrolithotomy: presenting the popvesl score pejman shadpour, robab maghsoudi, masoud etemadian, nasser yousefzadeh*, nasrollah abian hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *presenting author: nasser yousefzadeh purpose: percutaneous nephrolithotomy (pcnl) is the less invasive modality of choice for large renal stones. delayed bleeding usually points to the likelihood of pseudoaneurysm (pa) or arteriovenous fistula (avf), which may require expensive and non-uniformly uniformly accessible angioembolization. we have analyzed the large-volume experience accumulated at our high volume center to detect critical predictors of success with conservative management. method: we reviewed the data of all patients who were re-admitted for gross hematuria after undergoing pcnl at our center between dec 2011 and jan 2016. all stable patients diagnosed with intra-renal vascular lesions had a period of watchful conservative management. patients requiring repeated transfusion beyond initial stabilization were generally scheduled for elective angioembolization. perioperative findings, factors related to the stone, and management details were subjected to multifactorial analysis. thresholds were calculated for the most critical variables through roc curve analysis. results: of the 4403 pcnls performed over four years, 83 (1.9%) patients with delayed bleeding were diagnosed to have an intrarenal vascular lesion. of these, 54 were arteriovenous fistulas (avf, 65%) and 29 pseudoaneurysms (pa, 35%). overall 49 (59%) responded to conservative treatment and 34 (41%) eventually required angioembolization. in multivariable analysis, predictive factors for poor response to conservative treatment were requiring transfusion beyond initial stabilization, pseudoaneurysm, history of open renal surgery, longer pcnl-to-second-admission interval, and size of the vascular lesion. our proposed popvesl score (short for post pnl vascular embolization selection) when below 11, correctly predicts those who shall not need vascular intervention (positive predictive value=1 and negative predictive value=0.75). conclusion: these findings including the proposed popvesl score have potential for clinical application and enhancing practical guidelines on the management of post-pcnl bleeding. keywords: percutaneous nephrolithotomy; arteriovenous fistula; pseudoaneurysm; angioembolization o. 127 47 11th congress of the iranian endourology and urolaparoscopy society, 2019 prospective trial comparing fluoroscopic guidance and combined fluoroscopic and ultrasonographic guidance in percutaneous nephrolithotomy in term of safety, efficacy, perioperative facors and total x-ray dosage seyed hossein hosseini sharifi¹, ali tabibi¹, vahid najjaran tousi¹*, flora khaledi¹, parham rabiee², abbas basiri¹ ¹urology department, erfan private hospital, tehran, iran. ²radiology department, shahid rajayi heart center,iums, tehran,iran. *presenting author: vahid najjaran tousi purpose: to compare fluoroscopic guidance vs combined ultrasonographic and fluoroscopic guidance for percutaneous renal access in standard percutaneous nephrolithotomy (pcnl) in term of safety, efficacy, total x-ray dose and perioperative factors materials and methods: this study was conducted from february 2016 to july 2018 as a randomized clinical trial in erfan hospital. one hundred and fourteen consecutive patients with renal stone, candidate for pcnl were randomly assigned to two equal groups. in group1 renal access was achieved using fluoroscopic guidance and in group-2 access was achieved using both ultrasonography and fluoroscopy. ultrasonography was used to enter the desired calyx and to introduce j-tip guide wire. the rest of procedure; dilatation of the tract and access creation was done using x-ray. we used one shot dilation by amplatz dilator in all cases. all procedures were performed by one surgeon in prone position and under general anesthesia. results: the two groups were matched by mean age, distribution of stone location, and stone burden. mean operative time, hospital stay, stone-free rate, requirement for additional tracts and mean hemoglobin drop were comparable between the two groups. there was no visceral injury in two groups. in three cases of combined imaging group, getting access by ultrasonography was not successful (4.2%). radiation dose was significantly lower in group-2. (mean radiation dose in group-1 and group-2 was 3.65 and 1.58 mgy respectively. (pvalue <0.005) conclusion: to reduce the radiation dose to surgical team and to patient in addition to high success rate for finding the best targeted posterior calyx without sacrificing results of surgery, by using this step-by step technique and getting access and introducing guide wire using ultrasonography and dilator advancing using x-ray is highly recommended. keywords: percutaneous nephrolithotomy; imaging o. 128 48 11th congress of the iranian endourology and urolaparoscopy society, 2019 determining the impact of preoperative asa score on pcnl results sepehr hamedanchi1*, shahryar sane2, melina eqbal3 1endourologist, assistant professor of urology, imam medical center, urmia university of medical sciences, urmia, iran. 2associate professor of anesthesiology, imam medical center, urmia university of medical sciences, urmia, iran. 3urology resident, imam medical center, urmia university of medical sciences, urmia, iran. *presenting author: sepehr hamedanchi purpose: to determine the role of asa classification in results of pcnl patients under spinal anesthesia. methods: in this randomized clinical trial, 286 patients were enrolled. patients were classified in preoperative phase in clinic to three classes of asa i, ii, and iii by expert anesthesiologist. all patients underwent pcnl with spinal anesthesia in prone position. blood transfusion, bleeding, hospital stay, urine leak, adjacent organs injury, fever, number of accesses, retained stones, and duration of operation were recorded. results: seven cases required blood transfusion among them five subjects were in asa i and 2 patients were in asa ii class with significant difference (p > 0.05). the preoperative hemoglobin was comparable across asa groups but after operation it was differed across the groups (p = 0.080). also the mean hemoglobin alteration was similar across the asa classes (p > 0.05). there were nine retained stones after pcnl including six and three cases in those with asa ii and iii, respectively without significant difference (p > 0.05). the mean duration of procedure and mean hospital stay were alike across the groups (p > 0.05). conclusion: complications and outcomes during and after pcnl are same across asa groups and pcnl may be used safely in high-risk patients. keywords: urolithiasis; pcnl; asa; nephrolithotomy o. 129 49 11th congress of the iranian endourology and urolaparoscopy society, 2019 efficacy of nigella sativa seeds and tamsulosin on improving pain and passage of 4 to 10 mm stones of kidney and ureter sadrollah mehrabi1*, nahid shakeri1 medicinal plant research center, yasuj university of medical sciences, yasuj, iran. *presenting author: sadrollah mehrabi purpose: aim of this study was comparing efficacy of nigella sativa seeds and tamsulosin on pain improvement and expulsion of renal and ureteral stones of less than 10 millimeter. methods: in this randomized clinical trial, 80 patients older than 18 years old with kidney and ureteral stones sized 4 to 10 millimeters after taking history and complete physical exam and informed consent form, were randomly allocated to one of two groups by simple sampling method. in group 1, after performing ultrasonography and confirming the presence of 4 to 10 mm stone one capsule of tamsulosin 0.4 mg was prescribed per night for 2 weeks. in group 2, nigella sativa seeds with dose of 2gr per day, divided in 2 capsules every 12 hr were prescribed after meal with one glass of water for two weeks. two weeks later patients were visited and kub sonography was conducted and the change in size of stones and presence of residual stones was measured and recorded. the severity of pain was checked using vas (visual analogue scale) by the patient and the data was collected and analyzed during treatment and at the end of the study. results: mean sizes of stones before treatment were 1.81 ± 10.03 and 9.41 ± 1.68 millimeter, respectively (p=0.06).mean size of stones after treatment were 4.33 ± 4.97 and 5.21± 3.63 millimeter respectively. mean number of stones after treatment was 0.83 ± 0.59 and 1.18 ± 0.94 and there was no significant differences between two groups) (p = 0.52).there was no significant differences between two groups regarding average of pain score before treatment (p = 0.05), but pain score decreased significantly in two group that was more significant in nigella sativa group (p = 0.015).regarding efficacy of treatment in two groups it was more than 65 % (p = 0.065). conclusion: this study showed that both nigella sativa seed and tamsulosin decrease urinary stone size and numbers and pain intensity during passage of stones without significant difference. it seems that nigella seeds reduce pain and size of urinary stones and can be used as an alternative treatment in urinary stones. keywords: urinary stone; nigella sativa; tamsulosin; treatment o. 130 50 11th congress of the iranian endourology and urolaparoscopy society, 2019 challenges in laparascopic pyeloplasty of ureteropelvic junction obstruction in intrarenal renal pelvis amir-hossein kashi1, iman ghanaat1*, saman farshid2 1urology and nephrology research center,shahid beheshti university of medical sciences,tehran,iran. 2nephrology and kidney transplant research center,urmia university of medical sciences,urmia,iran. *presenting author:iman ghanaat introduction: pyeloplasty for treatment of ureteropelvic junction obstruction(upjo) in cases of intrarenal renal pelvis is difficult and challenging.in this condition ureterocalicostomy is one of the options.we did this surgery with laparascopic method to understand feasibility and complications. material and method: in august 2019, a 33 year-old female with left flank pain and upjo documented in imaging and nuclear scan with intrarenal renal pelvis in left kidney underwent laparascopic ureterocalicostomy and middle pole stone extraction. result: laparascopic ureterocalicostomy with double j(dj)insertion was done in transperitoneal method after colon medialization and ligation of renal pelvis and middle pole renal stone extraction without any intra or postoperative complication and in follow up renal pelvis urine drainage and flank pain were corrected after dj extraction conclusion: laparascopic ureterocalicostomy and renal stone extraction is a good treatment option in the case of upjo in intrarenal renal pelvis with simultaneous renal stone simultaneously. keywords: laparascopy; ureteropelvic junction obstruction; pyeloplasty; ureterocalicostomy; renal stone o. 131 51 11th congress of the iranian endourology and urolaparoscopy society, 2019 the necessity of ureterolysis during laparoscopic excision of deep infiltrating endometriosis lesions roya padmehr*, khadijeh shadjoo, atefeh googin, abolfaz ghodgani research institute, acecr, reproductive immunology research center, tehran, iran. *presenting author: roya padmehr introduction and objective: surgical interventions aim to remove visible areas of endometriosis and restore the anatomy. comparing with incomplete excision, the complete excision of deep infiltrative endometriosis has been shown to significantly decrease post-operative pain, recurrence rate and also postoperative complications. we aimed to demonstrate the frequency of ureterolysis in deep endometriosis laparoscopic surgeries in order to do complete excision of deep endometriosis lesions and to reduce damage to ureters during these difficult surgeries. methods: 201 patients with main chief compliant of dysmenorhea and dysparuenea (measured by verbal analog scale) were referred to our center for laparoscopic surgery. we defined expected difficulty of the surgery and also difficulty and complication score of the surgery which were scored for each patient (0=the least difficulty or complications and 10=the greatest difficulty or complications). we used a logistic regression model to analyze the correlation between doing uretrolysis with the scores of dysmenorhea , dispareunia , expected difficulty , difficulty and complications of the surgery. mann–whitney and independent t test were also used for evaluating relation of doing uretrolysis with dysmenorrhea ,dyspareunea and expected difficulty scores. results: mean age of patients was 31.17 years (se = 0.416). mean dysmenorhea score in non uretrolysis and uretrolysis groups were 3.97 ± 0.657 and 6.92 ± 0.236 respectively. also mean dyspareunea score for non uretrolysis and uretrolysis groups were 1.91±2.87 and 2.47 ± 3.16 respectively. the overall percentage of our logistic regression model was 90%. there was a significant correlation between doing ureterolysis and difficulty score of surgery (b = 0.698 p = 0.007) and complication score (β = 0.896,p = 0.021). there was significant relationship between uretrolysis and dysmenorhea score( p = 0.000), uretrolysis and dyspareunea score was not significant ly related(p = 0.348) (independent t test p = 0.312). only 61 patients had expected difficulty score. mean expected difficulty for non uretrolysis and for uretrolysis group was ( 6.29 ± 0.993) and ( 8.17 ± 0.274), respectively. there was significant relationship between doing uretrolysis and expected difiiculy score (p = 0.02) conclusion: uretrolysis in endometriosis laparoscopic surgeries significantly can increase difficulty of our surgeries, however, it can significantly decrease postoperative complications. key words: endometriosis; deep infiltrating endometriosis; uretrolysis; recurrence; pelvic pain o. 132 52 11th congress of the iranian endourology and urolaparoscopy society, 2019 comparative study of nitroglycerin and magnesium sulfate effect on endoscopic surgical outcome of ureteral stones salman soltani1*,mahmoud tavakkoli1 1kidney transplantation and complications research center, mashhad university of medical sciences, mashhad, iran. *presenting author: salman soltani introduction: endoscopic surgery is a popular treatment of ureteral stones. the surgeons encounter two problem in endoscopic treatment. the first problem is the inability to reach to the stone and the second is ureteral damage because of ureteral stenosis or ureteral kink. our purpose was to decrease these two complications by using nitroglycerin and magnesium sulfate dilating property. methods & materials: the present clinical trial study evaluated the efficacy of nitroglycerin and magnesium sulfate on endoscopic ureteral stone surgery. in this study, patients were divided into three groups of 40 (nitroglycerin, mgso4 and control) and evaluated based on inclusion criteria and written consent. after examining the patient's condition and controlling his vital signs by anesthesiologist, the patient was placed in one of three groups: control groups, serum nitroglycerin or magnesium sulfate group. the anesthesiologist was aware of the group assignment, but the surgeon, patient, and analyzer were blind to the grouping. after surgery, duration of operation and success rate of surgery were included in the checklist. also two weeks after, when the patient was referred for stent removal, checklist was completed for complications and final information. finally, data were analyzed in spss ver 22 software. results: the mean duration of surgery in the present study was significantly higher in the control group than the two groups receiving nitroglycerin and magnesium (p < 0.001). however, there was no significant difference between the groups receiving magnesium sulfate and nitroglycerin (p = 0.708). there was no significant difference in postoperative infection between all three groups (p = 0.812). in terms of stone accessibility, the lowest level of stone access was in the control group (59.1%). but there was no significant relationship between the rate of stone accessibility in the two intervention groups. meanwhile, there was a significant difference between the control group and the intervention group regarding stone accessibility. there was no significant difference between the case groups in terms of complete stone clearance parameter.although there was a significant difference between the control group and the two drug recipient groups (p = 0.004). conclusion: in general, nitroglycerin and magnesium sulfate were significantly better than control group in terms of duration of surgery and success rate. however, there was no significant functional difference between the two drugs. keywords: endoscopic ureteral surgery; nitroglycerin; magnesium sulfate o. 133 53 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic adrenal sparing surgery in management of adrenal tumors nasser simforoosh, seyed arsalan aslani*, mehdi dadpour labafinejad hospital, shahid beheshti university medical science. *presenting author: seyed arsalan aslani introduction and objective: laparoscopic adrenalectomy is the standard of care for adrenal tumors from incidentaloma to cancer. partial adrenalectomy is considered recently to preserve adrenal function. we evaluated the feasibility and outcomes of adrenal sparing technique in managing adrenal tumors in a single surgeon series. in this video, we present 3 cases of conn’s adenoma, cushing adenoma and bilateral pheochromocytoma. materials and methods: between 1997 to 2018 a total number of 284 patients underwent clipless laparoscopic adrenalectomy. adrenal sparing technique was done in 48 of them (partial adrenalectomy or adenomectomy). after mobilization of colon, adrenal gland was dissected free from neighboring organs. adrenal tumor was exposed and enucleated in conn’s adenoma and tumorectomy was done in the other cases (partial adrenalectomy). all patients were followed by lab data, imaging and clinical outcome. results: the mean age was 39.6 years (6 months to 83 years). mean tumor size was 5.1cm (range 1 to 18 cm). tumor pathologies were 12 cases of pheochromocytoma, 7 cases of conn’s adenoma, 3 cases of cushing adenoma, 3 cases of myelolipoma, 1 case of hydatid cyst, 16 cases of simple cyst and 6 cases of incidental adenoma. the number of 14 patients of total adrenalectomy group and 3 patients of adrenal sparing group underwent bilateral surgery. no clavien grade 3,4 or 5 or any major complication because of surgery occurred. hematocrit change and hospital stay were similar in these 48 cases and other patients. in the follow up period, imaging and hormonal test were normal for all patients and sign and symptoms such as blood pressure became normal post operatively. conclusion: laparoscopic adrenal sparing technique for adrenal tumors is safe and feasible and preserves adrenal function and the patients does not require receiving long term steroid supplement. keywords: laparoscopy; adrenal; adrenalectomy o. 134 54 11th congress of the iranian endourology and urolaparoscopy society, 2019 investigating eswl success rate in the treatment of renal and ureteral stones in children mohammad javad soleimani1, hossein shahrokh2, vahid vahedi soraki3*, vahid fakhar4 hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *presenting author: vahid vahedi soraki introduction: extracorporeal shock wave lithotripsy(eswl) is one of the methods of treatment of stone in children. this study was conducted to determine success rate of eswl in treatment of kidney and ureteral stones in children referred to hasheminejad kidney center during second half of 2018. methods: this observational prospective cohort study was conducted on 144 children referred to hasheminejad kidney center during second half of 2018. the subjects were selected using convenience sampling method. the preset study investigated the success rate of eswl in treatment of kidney and ureteral stones and effective factors in this regard. results: a total of 133 patients (92.4%) had stone passage. a total of 37.5% of patients had residual stones, 28.5% of which were less than 5 mm in diameter. successful results were seen in 131 cases (91%). successful results were significantly higher in males (p = 0.011) and lower in simultaneous stones in middle calyx and lower calyx (p = 0.0001). conclusion: according to the results, it can be inferred that eswl success rate was above 90% in treatment of kidney and ureteral stones in children in such way that with an eswl session in patients who have been properly selected for this procedure. the present study identifies gender and stone locations as the factors contributing to the successful lithotripsy and identifies female gender and presence of the stone in lower and middle calyx as a risk factor for the lower lithotripsy success rate. keywords: eswl, sfr; urinary stones; children o. 135 55 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic pyelolithotomy for management of renal stones: 15 years of experience in a pioneering referral center amir h kashi, akbar nouralizadeh, arsalan aslani, milad bonakdar hashemmi, nasser simforoosh, abbas basiri, seyed amir mohsen ziaee, ali tabibi, mohammad hadi radfar, mohammad hossein soltani, reza valipour shahid labbafinejad medical center; urology and nephrology research center; shahid beheshti university of medical sciences (sbmu); tehran; iran. *presenting author: arsalan aslani purpose: to report the outcomes of laparoscopic pyelolithotomy for management of large kidney stones during 15 years in a pioneering referral center. methods: patients with large stones who underwent laparoscopic pyelolithotomy were enrolled during 2005 to 2018 retrospectively. medical records of patients were used to extract preoperative, operative and early postoperative data. results: 310 patients were included during 2002 to 2017. the average yearly number of pyelolithotomies performed in the first 10 years was 15 which increased to an average of 50 during the next 5 years. the length of operation duration was 172 minutes on average during the first 10 years which decreased to 121 minutes during the last 5 years. stone free rate was 85% during the first 10 years which increased to 91% during the last 5 years. conclusion: our longterm experience with laparoscopic pyelolithotomy for management of renal stones in patients with solitary stones or limited stones within kidney with hydronephrosis reveals that laparoscopic pyelolithotomy is a feasible option in centers with laparoscopic expertise and experience in performing laparoscopic pyelolithotomy and the performance matures with continual practice. keywords: laparoscopy; pyelolithotomy; nephrolithiasis o. 136 56 11th congress of the iranian endourology and urolaparoscopy society, 2019 head to head comparison of clinical and radiological success rate of endoscopic vs open anti-reflux surgery pejman shadpour, nasrollah abian*, maryam emami, delaram beirami hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *presenting author: nasrollah abian purpose: comparing the results of endoscopic urinary reflux treatment against open surgery and the concepts of clinical vs radiological success, and factors associated with them. method: 442 patients (732 units) with urinary reflux treated by either of two surgical procedures (endoscopic or open) were reviewed. reflux grade was determined by vcug or rnc and kidney function by dmsa. postoperative success was assessed from three aspects: clinical success (no febrile uti in follow up), relative radiologic improvement (downgraded postop) and absolute radiological success (no reflux on postoperative imaging). patients were compared for success by surgical method, sex, grade, scarring, bladder bowel dysfunction (enuresis / constipation), and early or late febrile uti. results: between 1391-95(2012-2016), 220 patients had endoscopic surgery and 222 underwent open procedures at our referral center. total clinical success rate was 91.2%, relative radiological success was 98.6% and absolute radiological success 82.5%. all three types of success were significantly higher with open surgery than endoscopic surgery (p < 0.001). clinical success did not require absolute radiological success (kappa = 0.45), although absolute radiological success was correlated with clinical success, 73 patients with perfect clinical success had not achieved absolute radiological success. most significant factors contributing to success of treatment were: grade (the higher the grade the less success in all three forms); and presence of both constipation and enuresis, correlated with significant decrease in clinical success (p < 0.001). conclusion: the results of open reflux surgery are better than endoscopic in both clinical and radiological terms. clinical success after treatment does not necessarily require absolute radiologic success although absolute radiological success is associated with clinical success. higher grade negatively impacts all types of success while bbd only affects clinical success. keywords: vesicoureteral reflux, endoscopic anti-reflux surgery, clinical success, radiological success o. 137 57 11th congress of the iranian endourology and urolaparoscopy society, 2019 re-operation after endoscopic or open antireflux surgery, can it be foreseen? pejman shadpour, nasrollah abian*, maryam emami, delaram beirami hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *presenting author: nasrollah abian purpose: study of the need for urinary reflux reoperation (endoscopic or open) following primary intervention by endoscopic or open methods and its associated factors method: patients with history of primary endoscopic or open reflux surgery at our center were reviewed. preoperative reflux grade was determined by vcug or rnc and kidney parenchyma was evaluated by dmsa. cases of clinical failure (recurrent febrile uti after discharge with unresolved reflux at follow-up cystography or presence of reflux in follow-up with positive urine culture and progressive scarring) had endoscopic or open re-intervention depending on surgeon's preference, clinical presentation and radiologic findings). reoperation and its associated factors were evaluated. the studied variables were age, sex, bladder and bowel dysfunction, reflux grade, dmsa and fever during hospitalization. results: 442 patients with 732 reflux units underwent endoscopic (220) or open surgery (222) between 1391 and 1395. of these 31 patients (7%) required re-intervention 26 cases (11.8%) for endoscopic, and 5 (2.2%) for open surgery. no patient with primarily low grade reflux needed reoperation. among other variables, early post-operative fever was associated with the need for re-operation (p = 0.03). other variables were not associated with the need for repeated surgery. conclusion: post-operative fever is associated with the need for re-operation following urinary reflux intervention, and the surgeon may consider this fact for following such patients closely after reflux surgery. keywords: vesicoureteral reflux; reoperation; open anti-reflux surgery; endoscopic anti-reflux surgery o. 138 58 11th congress of the iranian endourology and urolaparoscopy society, 2019 clinical outcomes of simultaneous bilateral percutaneous nephrolithotomy (pcnl) in patients with kidney stones: a prospective cohort study mohammad reza darabi1 , salman soltani1*, alireza akhavan rezayat1, mahmoud tavakkoli1 1kidney transplantation and complications research center, mashhad university of medical sciences, mashhad, iran. *presenting author: salman soltani introduction: urinary tract stones are one of the most frequent medical emergencies which lead to life-threatening complications, namely obstructive uropathy as well as renal failure in some situations. previously, bilateral stones were treated with either open surgery or percutaneous nephrolithotomy (pcnl). however, these treatment options were associated with lengthy operation time, need for more anesthesia, further bleeding, and long hospitalization. therefore, much effort has been made to treat both sides simultaneously. materials and methods: in this prospective cohort study, 39 adult patients with bilateral renal stones were randomly recruited at imam reza hospital in mashhad, iran between january 2016 and january 2017. adult patients with bilateral renal stones were included in this study. exclusion criteria were as follows: patients with severe heart or lung disease, patients with coagulation disorders, pregnant women, and cases with any contraindications for general anesthesia. after insertion of bilateral ureteral catheters, all patients underwent simultaneous bilateral pcnl in prone position. transureteral lithotripsy was performed for patients with ureteral stones. the surgery was initially carried out on the symptomatic side and then iterated on the remaining kidney. major complications including bleeding, fever, pain, urine leakage, and residual stones were recorded. spss software was used for data analysis. data were expressed as percentage and mean ± sd. p value less than 0.05 was considered significant. results: a total of 39 patients (27 males with mean age of 37.6 years and 12 females with mean age of 45.7 years) were studied. as many as 15 (38%) patients received a unilateral nephrostomy. three underwent totally tubeless surgery. bleeding (41.0%) was the most common complication, followed by residual stones (20.5%) and fever (20.5%), urine leakage (15.3%), pain (12.8%), blood transfusion (2.5%) and colon perforation (2.5%). conclusion: it was concluded that simultaneous bilateral pcnl is not associated with higher morbidity than the unilateral method. keywords: bilateral calculi; complications; percutaneous nephrolithotomy; pcnl; renal stones o. 139 59 11th congress of the iranian endourology and urolaparoscopy society, 2019 laparoscopic donor nephrectomy is a safe surgical approach in healthy obese kidney donors; ten-year single-center experience, retrospective study nasser simforoosh, mohsen variani, seyed arsalan aslani* *lanafinejed hospital,shahid beheshti university medical science. *presenting author: seyed arsalan aslani background and objectives: lack of donors is always a great problem. kidney donor with a body mass index (bmi) ≥ 30kg/m2 are not suitable for laparoscopic donor nephrectomy, however, some studies have suggested that obese donor could be an appropriate donor with similar surgical outcomes. therefore, we report the results of our 10-year experience of laparoscopic donor nephrectomy (ldn), examining the effect of bmi on the surgical results of ldn. materials and methods: we retrospectively reviewed medical records of people who underwent ldn at the urology ureter of shahid beheshti university of medical science,tehran, iran. from 2005 to 2015. the collected information included preand post-operative serum levels of hemoglobin and creatinine and we also investigated the surgical outcomes (operation time, cold and warm ischemia, need for blood transfusion, and conversion to open surgery, length of hospital stay and complications rates) with respect to bmi categories (≤ 24.9, 25-29.9, and ≥ 30kg/m2). results: out of 1083 kidney donors, 732 donors had bmi ≤ 24.9 kg/m2, 256 donors had bmi within 25-29.9, and 95 donors had bmi ≥30 kg/m2. there was no significant difference among the groups in terms of operation time (p = 0.558), warm or cold ischemic time (p = 0.829 and 0.951, respectively), blood transfusion (p = 0.873) and length of stay (p = 0.850). conclusion: laparoscopic approach for donor nephrectomy is identified as a safe and effective method in obese donor without significant postoperative complications. keywords: kidney donor laparoscopy; obese o. 140 60 11th congress of the iranian endourology and urolaparoscopy society, 2019 evaluation and comparison of metabolic disorders between patients with unilateral and bilateral staghorn renal stones mehrdad mohammadi sichani*, amir jafarpisheh, alireza ghoreifi isfahan kidney transplantation research center. department of urolog, alzahra research center, isfahan university of medical sciences, isfahan/iran. *presenting author: mehrdad mohammadi sichani purpose: metabolic disorders are common in patients with staghorn renal stones. aim of this study was to evaluate and compare the metabolic disorders in patients with unilateral and bilateral staghorn stones. materials and methods: in this cross sectional study, 78 patients who underwent percutaneous nephrolithotomy (pcnl) for staghorn renal stones were included. the urine volume, the level of calcium, oxalate, uric acid, phos phate, sodium, citrate, creatinine, and cystine from 24 hour urine collection as well as the serum levels of calcium, phosphorus, magnesium, creatinine, blood urea nitrogen (bun), parathyroid hormone (pth) and uric acid were recorded and compared among the two groups with unilateral and bilateral renal stones. results: 56 patients (71.8%) had unilateral and 22 (28.2%) had bilateral renal stones. at least one abnormal meta bolic factor was found in 32 (57.1%) and 15 (68.2%) patients with unilateral and bilateral renal stones, respectively (p = .044). cystine urine levels and serum levels of bun were higher in cases with bilateral compared to unilateral renal stones (36.4% vs. 12.5%, p = .025 and 27.3% vs. 1.8%, p = .002, respectively). conclusion: metabolic factors are strongly correlated with the formation of staghorn renal stones specially bilateral ones. in our study among different metabolic factors, cystine urine levels and serum levels of bun were significantly higher in patients with bilateral renal stones. proper metabolic assessments are recommended in patients with staghorn urolithiasis. keywords: metabolic diseases; risk factors; staghorn calculi o. 141 61 11th congress of the iranian endourology and urolaparoscopy society, 2019 functional results and recurrence after laparoscopic partial adrenalectomy versus total adrenalectomy nasser simforoosh, mohammad hossein soltani, hamid-reza shemshaki, milad bonakdar hashemi*, mehdi dadpour urology/nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. *presenting author: milad bonakdar hashemi background: partial adrenalectomy is typically performed for the treatment of hereditary and sporadic bilateral tumors, to reduce the risk of adrenal failure particularly in younger patients. partial adrenalectomy proposes a postoperative steroid-free course, nevertheless, is associated with the risk of local recurrence. in this study we evaluate the recurrence and functional outcomes after partial and total adrenalectomy. materials and methods: between march 2005 to july 2018, 284 patients underwent partial or total laparoscopic adrenalectomy for conn's syndrome, cushing’s disease and pheochromocytoma. pre-operative and operative variables were collected from a prospective database. long-term follow-up was obtained via patient survey. results: the overall recurrence rate was 5%, and 89% of the patients were steroid free. recurrence rates were about 1% for conn's syndrome, 3% for cushing’s diseases and 8% for pheochromocytoma. conclusion: in our experience, partial adrenalectomy can provide excellent palliation of the symptoms and there was no significant difference in recurrence between partial adrenalectomy and total adrenalectomy. keyword: recurrence; laparoscopy; adrenalectomy o. 142 62 11th congress of the iranian endourology and urolaparoscopy society, 2019 ultrasound guided percutaneous access to kidney for percutaneous nephrolithotomy in patients with retrorenal colon amir h kashi; iman ghanaat* shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences (sbmu), tehran, iran. *presenting author: iman ghanaat purpose: to report the feasibility of total ultrasound guided access for access establishment in cases of percutaneous nepohrolithotomy (pcnl) candidates with retrorenal colon in preoperative computed tomography (ct) scan. methods: three patients who were candidates for percutaneous nephrolithotomy and in their preoperative ct scans, there was evidence of retrorenal colon in all parts of the kidney or in some parts are reported. the ultrasound guided access was pre-planned. results: in two cases insertion of ureteral catheter during cystoscopy was possible and in one case it was not possible due to high riding prostate and urethral narrowing and bleeding during cystoscopy. in this latter case furosemide was administered after prone positioning and ensuring stable blood pressure after change of position to prone. totally ultrasound guided access was planned in two cases and in one case additional fluoroscopy was used after ultrasound guided percutaneous access with shiba needle for dilation step because of l shaped rotated kidney with lower pole traversing in front of vertebral column to the lower pole of the opposite kidney. percutaneous access was successfully achieved in all cases. operation was terminated as tubeless and the tract was visualized during nephroscope withdrawal in all cases for ensuring no passage through colon. stone free status was achieved in 2 cases and in one case a residual stone was left due to vertical access tract in a horseshoe kidney and failure of rigid nephroscope to reach the upper pole of kidney with one residual 1 cm stone. conclusion: using ultrasonography in patients with retrorenal colon who are candidates for pcnl can be an alternative to laparoscopy assisted pcnl in selected patients and for surgeons with experience in ultrasound guided pcnl. the advantage of this approach is avoidance of peritoneal entry. keywords: percutaneous nephrolithotomy; retrorenal colon; ultrasonography o. 143 63 11th congress of the iranian endourology and urolaparoscopy society, 2019 the effects of intravenous mannitol in reducing acute kidney injury following percutaneous nephrolithotomy kaveh mehravaran, masood etemadian, pejman shadpour, mohammad-mehdi atarod*, nasrollah abian, farshad gouran, roozbeh roohinezhad hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *presenting author: mohammad-mehdi atarod introduction: percutaneous nephrolithotomy is the procedure of choice in renal calculi greater than 20 millimeters. previous studies have shown a reduction in gfr in the first few days following pcnl. proposed mechanism for this phenomenon is bilateral renal vessel, vasospasm due to neural and hormonal mechanisms. previous studies in partial nephrectomies have shown that using intravenous mannitol prior to renal artery clamping can reduce the risks of nephron loss. considering these two findings, we decided to evaluate mannitol’s effect on gfr following pcnls. methods: in an interventional cohort study, 110 candidate patients for pcnl who met our inclusion criteria were divided into two equal groups by random. in the intervention group, 25 grams of mannitol was injected intravenously 15 minutes prior to surgery. both intervention and control groups were compared by demographic and renal stone characteristics. hb and gfr (by cockcroft-gault equation) were checked one day before the surgery, 6 hours, one day, two days, and 2 weeks post operation. results: 110 candidate patients for pcnl who met our inclusion criteria were divided into two equal groups by random. both groups were equal in demographic and renal stone characteristics. mean preoperative gfr were 73.91 and 85.87 in the intervention and control groups respectively which were both classified in the 2nd stage of ckd classification. mean gfr in intervention group increased 6 hours after surgery (80.15), then decreased to 78.48 in two next days and finally improved to the level of 85.51 after two weeks. in the control group it decreased to the level of 78.63 gradually in the next two days following surgery but it increased to the approximately same level of preoperation’s gfr (84.77). mixed between-within analysis of variance shows a meaningful effect of mannitol in improving gfr (p < 0.001) rather than control group with the effect size of 0.41. conclusion: intravenous mannitol prior to pcnl reduces the risk of gfr drop especially in the first 48hours after surgery. keywords: pcnl, mannitol, acute kidney injury, gfr o. 144 64 11th congress of the iranian endourology and urolaparoscopy society, 2019 role of flexible ureteroscopy in diagnosis of the cause of chronic unilateral essential hematuria asghar alizadeh1*, m. r. mokhtari1, kaveh mehravaran2, pejman. shadpour2 1shahid mahallati hospital, tabriz, iran. 2hasheminejad hospital, tehran, iran. *presenting author: asghar alizadeh background and aim: to show the efficacy of flexible ureteroscopy in detection of the location and cause of intrarenal bleeding lesions. methods: a 35 year old female with total gross hematuria and clot passage came to hospital. she had history of periodic gross hematuria and several blood transfusions from 10 years ago. hematuria is usually asymptomatic. during these years all efforts to detect the cause and source of hematuria hadbeen unsuccessful. she had no weight loss. urine analysis showed many eumorphic rbc, wbc 2-3. hb had always been low and other laboratory tests including cr, na, k, ca, u/c, pt, ptt, inr, sgot, sgpt, alkp, c3, c4, ana, rf, hbsag, hcv ab, hiv, urinary 24 ca, urinary cytology, urine smear for bk were all normal. all imaging studies including renal ultrasonography (many times), abdominopelvic ct scan (figure 1) without and with iv contrast, renal ct angiography (figure 2), abdominal mri with gadolinium , renal color doppler ultrasonography for avm were also normal except one renal sonography that mild right hydronephrosis was shown. several times cystoscopy and a few times bilateral ureteroscopy were done and they were normal or the site of hematuria had not been detected. results: at admission, her primary hb was 5 mg/dl so 4 units of packed cell was transfused. then we did cysto ureteroscopy. the bladder was washed out and seemed normal. the clear urine efflux was seen in left ureteral orifice. right ureteral orifice was found challenging and completely bloody urine efflux was seen from it. with gentle use of guide wire right semi rigid ureteroscopy was done. ureter was normal in all its course but the pelvis was completely bloody. no more evaluation was possible. ureteral catheter was placed and retrograde ureterography was done the other day which was also normal . a few days later gross hematuria resolved and the patient was discharged. a few weeks later at the time of no bleeding, she was referred to another center and diagnostic right flexible ureteroscopy was done for her. systematic evaluation of all calices from superior-to-inferior was done. lower calyx papillary were so large and congested and seemed to be the source of bleeding. because of the large size of lesions and instrumental defects therapeutic fulguration was not possible. conclusion: direct endoscopic systemic inspection of all calices with ureteropyeloscopy is recommended for chronic unilateral essential hematuria as a diagnostic and potentially therapeutic modality. keywords: hematuria; ureterescopy o. 145 65 11th congress of the iranian endourology and urolaparoscopy society, 2019 o. 145 66 11th congress of the iranian endourology and urolaparoscopy society, 2019 our experience in transperitoneal laparoscopic pyelolithotomy for large renal pelvic stones hamid pakmanesh*, rayka sharifian amiri, sohrab mohammadsalehi department of urology, kerman university of medical sciences, kerman, iran *presenting author: hamid pakmanesh introduction: pcnl superseded open surgery for the treatment of large kidney stones; however, recently, laparoscopic pyelolithotomy was evolved and is finding its role in the management of renal pelvic stones. we are reporting our results of selected patients with large pelvic stones who underwent laparoscopic pyelolithotomy. method: after obtaining informed consent, 49 patients with renal pelvic stones larger than 20mm were included in our study and underwent transperitoneal laparoscopic pyelolithotomy in flank position. demographic data and stone size as well as operative time and complications were recorded. results: the average age was 52 years in men and 45 years in women. average bmi was 23.3 kg. three, six and two patients had previously underwent pcnl, swl or tul for stones in the same kidney respectively. three kidneys had horseshoe anomaly, one patient had polycystic kidney and four patients had single functional kidney. mean stone size was 25.34 mm. stones were in the right kidney in 60 % of patients. mean operation time was 136 minutes from induction to the end of anesthesia. hemoglobin dropped 1.6 g/dl on average. serum creatinine did not rise in our series. patients were discharged after 3.33 days admission on average. stone free rate was 93.88%. conclusion: laparoscopic pyelolithotomy is safe and effective for selected cases in experienced hand and has excellent results. keywords: pyelolithotomy; laparoscopy urolithariasis o. 146 67 11th congress of the iranian endourology and urolaparoscopy society, 2019 15-years experience with laparoscopic adrenalectomy at hsheminejad kidney center(hkc) pejman shadpour, kaveh mehravaran, masoud etemadian,farshad gouran, mohammad mehdi atarod*, ruzbeh rouhinezhad hasheminejad kidney center( hkc), iran university of medical sciences(iums),tehran, iran. *presenting author: m mehdi atarod introduction & objectives: laparoscopic adrenalectomy(la) has become the golden standard for the surgical treatment of most adrenal conditions except known carcinoma. the benefits of a minimally invasive approach for various pathology and size are widely accepted. the present study updates the results of the past 15 years of experience of using la in a single tertiary center in tehran. material & methods: in this study, 129 patients who had undergone la over the past 15 years from 2004 to 2018 in hkc, were reviewed . the information of patients before , during , and post operation were extracted. all procedures were performed by using trans peritoneal methods . results: 129 patients including 43 men (33.3%) with mean age of 43.55 years were studied. all cases were successfully completed without any conversion. the average tumor size in these patients was 52.74 mm( 10 to 180 mm). lesions in 85 cases were in rightside , 42 in left-side and 2 cases were bilateral. pheochromocytoma was the most common pathology (31.8%), followed by adenoma (31%), myelolipoma (10.1%), endothelial cyst (6.2%) , spindle cell and malignant pheochromocytoma (8%), gangelionuroma and adrenal cortical carcinoma (5.4%), psudocyst (4.7%) cortical hyperplasia (2.3%) and onchocytoma(1.6%). the average operative time was 87 minutes mean bleeding volume was 107 cc and mean hospital stay was 2 days. conclusion: our results in this series suggest that la is not only feasible and safe but capable of handling large masses too. keywords: adrenalectomy , laparoscopy o. 147 68 11th congress of the iranian endourology and urolaparoscopy society, 2019 epidemiology of escherichia coli st131 as an emerged high-risk clone in patients with urinary tract infections in western asia: a systematic review and meta-analysis alireza jafari1†*, siavash falahatkar1†, kourosh delpasand2, hoda sabati3, hadi sedigh ebrahim-saraie2 1urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran. 2biotechnology and biological science research center, faculty of science, shahid chamran university of ahvaz, iran. 3razi clinical research development center, razi hospital, guilan university of medical sciences, rasht, iran † these authors contributed equally to this work. *presenting author: alireza jafari escherichia coli sequence type (st) 131 was identified as a high-risk pandemic clone and frequently extended-spectrum β-lactamase (esbl) producing clone that is strongly associated with the worldwide dissemination of ctx-m-15 type. the emergence of st131 has become a public health threat because this clonal group typically exhibit multiple virulence factors and antimicrobial resistance. therefore, the present study aimed to analyze the published literatures to estimate the prevalence of st131 clone among e. coli strains isolated from patients with urinary tract infection (uti) in western asia, where antibiotics consumption is high. a systematic search was carried out to identify eligible papers in the web of science, pubmed, scopus, embase, and google scholar electronic databases from january 2010 to december 2018. then, 13 articles which met inclusion criteria were selected for data extraction and analysis by comprehensive meta-analysis software. the included articles consisted of studies conducted in iran, jordon, kuwait, pakistan, saudi arabia, turkey, and yemen. in all, the pooled prevalence of st131 in wild type isolates was 24.6% (95% ci: 13.5%-40.4%). the prevalence of st131 among esbls-producing isolates was 42.7% (95% ci: 32.5%-53.5%). the prevalence of st131 clone among multiple-drug resistant (mdr) isolates was 64.8% (95% ci: 36%-85.5%). moreover, the prevalence of st131 isolates carrying ctx-m-15 type was 68% (95% ci: 48.4%-82.8%). our study demonstrates a high prevalence of broadly disseminated st131 clone among mdr and esbls in western asia. moreover, o25b was accounted as the predominant st131 clone type, which was mostly associated with ctx-m-15 type. keywords: escherichia coli; st131; esbl; ctx-m-15; asia o. 148 69 946 | 1department of pharmacology, government medical college and sir takhtasinhji general hospital, bhavnagar-364001 (gujarat), india. 2department of pathology, government medical college and sir takhtasinghji general hospital, bhavnagar-364001 (gujarat), india. divyesh r. mandavia,1 mahendra k. patel,1 jayshree c. patel,1 ashish p. anovadiya,1 seema n. baxi,2 chandrabhanu r. tripathi1 anti-urolithiatic effect of ethanolic extract of pedalium murex linn. fruits on ethylene glycol-induced renal calculi corresponding author: chandrabhanu rajkishor tripathi, md cm 31/13, shantinagar 2, kalvibid, bhavnagar-364002, gujarat, india. tel: +91 9825951678 e-mail: cbrtripathi@ yahoo.co.in received july 2012 accepted november 2012 purpose: to evaluate effect of ethanolic extract of pedalium murex linn. fruits on experimental model of calcium oxalate nephrolithiasis. materials and methods: thirty-six male wistar albino rats were randomly divided in 6 groups. normal controls received distilled water for 28 days. other five groups received ethylene glycol (1% v/v) in distilled water for 28 days. pedalium murex ethanolic extract was given 200 mg/kg and 400 mg/kg orally in distilled water for 28 days in prophylactic groups (iii and iv) and from 15th to 28th days in treatment groups (v and vi). the urea, creatinine, random blood sugar, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin and calcium were measured on 28th day. 24 hr urinary oxalate and volume were measured on day 0 and 28. on day 28, kidneys were removed, weighed and subjected to histopathological examination. calcium oxalate crystallization was evaluated by renal histopathology and in-vitro method of mineralization. all parameters were analyzed by kruskal-wallis or one-way anova with post-hoc test. results: pedalium murex showed significant improvement in renal function and kidney weight in prophylactic groups as compared to ethylene glycol controls. it did not show any effect on urinary oxalate, urine volume and any other serological parameters. calcium oxalate crystallization was significantly reduced in all the pedalium murex treated groups (p < .05). calcium oxalate and phosphate mineralization were also inhibited by 33% and 57%. conclusion: ethanolic extract of pedalium murex fruits possess significant activity for prevention of renal calculi. keywords: calcium oxalate; nephrolithiasis; polyethylene glycols; pedalium murex linn.; kidney calculi; pathology endourology and stone disease endourology and stone disease 947vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l introduction renal calculi are the third leading cause among uri-nary diseases. in the united states, incidence of renal calculi was 1116 per 1,000,000 population in the year 2000 among adults.(1,2) recurrence of calculi is a serious problem. recurrence rate is 30 to 40 % at 5 years as seen in observational study.(3) studies have shown that effective treatment like dietary modification or medication can reduce the recurrence rate significantly.(4-6) so recurrence of renal stone is partially preventable. seventy to eighty percent of calculi are made up of calcium oxalate and phosphate. the most common abnormality among stone formers is hyperoxaluria. consumption of high dietary oxalate is a major risk factor for stone formation.(7,8) at present, management of stone depends mainly on surgical treatment i.e. extracorporeal shock wave lithotripsy, percutaneous lithotripsy, and transureteral lithotripsy.(9) these surgeries are expensive with higher complication rate than medical management, and do not affect the recurrence of stones. so there is need for medical treatment of renal stone that has curative as well as preventive action on stone formation. medicinal plants are used for various chronic disorders worldwide. pedalium murex (p. murex) linn. (name in vernacular language – hindi, is bada gokhru) is a member of pedaliacae. it has been used as an important medicinal herb in india. according to indian medicinal literature, it has aphrodisiac, antitussive, appetizer properties and useful in vesical calculi, urinary discharge, gonorrhea etc.(10-14) fruits of p. murex linn. are used traditionally for treatment of genito-urinary disorders, infertility, impotency, intestinal colic, diabetes. a few studies had been done for its antimicrobial, aphrodisiac, nephroprotective, hypolipidemic and anti-inflammatory activities.(15-19) though it is used as a folk medicine for renal calculi, its effectiveness and mechanism as anti-urolithiatic agent is still unknown. we have done this study to explore its effect and mechanism for prevention and treatment of renal calculi. material and methods animals all the experiments were performed after prior approval from institutional animal ethics committee (iaec), government medical college, bhavnagar, gujarat, india. male wistar albino rats were procured from the central animal house of the institute. they were housed in standard transparent polycarbonate cages and kept in a 12 hr light-dark cycle under controlled room temperature (24 ± 2° c) and humidity. animals were given standard laboratory diet and allowed to acclimatize at least three days before starting experiments. the animal handling was performed according to the good laboratory practice (glp) guidelines. drugs and chemicals p. murex linn. 10% ethanolic fruit extract (tulsi amrit pvt. ltd., indore, madhya pradesh, india), ethylene glycol (fisher scientific co., mumbai, india), oxalate kit (trinity biotech, ireland), sodium phosphate (aldrich, india), sodium oxalate and calcium acetate (alfa aesar, hyderabad, india) were used in this study. acute toxicity studies of ethanolic fruit extract of p. murex linn. showed that it was safe to administer it up to 2000 mg/ kg in rat.(17) based on these studies, we have taken 1/10th of the highest safe dose for the present study. we have done the study with two incremental doses of 200 and 400 mg/kg of p. murex linn. ethanolic extract to see its dose dependent action. study design thirty six male wistar albino rat (250 350 g) were randomly divided into six equal groups. group i received distilled water instead of tap water and served as normal control. group ii to vi received ethylene glycol 1% v/v in distilled water for 28 days. group ii served as ethylene glycol control. group iii and iv animals received p. murex ethanolic extract in 200 mg/kg and 400 mg/kg orally in distilled water for 28 days, respectively and served as prophylactic groups. group v and vi animals did not receive p. murex for first 14 days. these groups received p. murex ethanolic extract in 200 mg/kg and 400 mg/kg orally in distilled water from 15th to 28th day, respectively and served as treatment groups. outcome measures biochemical parameters blood samples were collected in plain vaccuates from the retro-orbital plexus under ketamine (50 mg/kg intra peritoneally) and xylazine (10 mg/kg intra peritoneally) anaesthesia effect of pedalium murex linn. on ethylene glycol | induced renal calculi 948 | 24 hr after the last dose of drug. serological parameters for renal and hepatic functions were measured. urinary parameters twenty-four hr. urine specimens were collected on day 0 and 28 of the study by keeping each rat in separate metabolic cage (b.i.k. industries, mumbai, india). urine volume was measured. it was acidified and kept under refrigeration (2 8° c). urinary oxalate was measured by oxalate kit within 7 days of collection of sample by spectrophotometer.(20) histopathological parameters the animals were sacrificed soon after blood collection under the continued effect of anesthesia. both kidneys were removed and kept in formaldehyde (10% v/v) for at least 24 hours. then 5 mm thick sections were taken and enclosed in paraffin. they were cut into 5 µm thin sections, stained with hematoxylin-eosin (h & e) and evaluated under optical light binocular microscope. calcium oxalate crystal depositions were calculated in 10 microscopic fields (159 × 10-9 m2 each) and other changes e.g. necrosis, leukocyte infiltration and tubular dilatations were also noted. in-vitro method of mineralization to evaluate the inhibition of calcium oxalate and phosphate mineralization by p. murex linn,; we used simultaneous flow static model (s.s.m.) described by farook et al.(21) we used p. murex linn. 200 mg/ml, calcium acetate (0.1 m) and sodium oxalate (0.1 m) (for calcium oxalate) or sodium phosphate (for calcium phosphate) in three separate burettes (25 ml) and were allowed to fall simultaneously into a 250 ml beaker with a slow and steady pace. after 30-40 min, the mixture was kept in a hot water bath for 10 min, cooled to room temperature and the precipitate was collected into a pre-weighed centrifuge tube. supernatant fluid was discarded. then, these tubes were dried in a hot air oven at 120° c, cooled to room temperature and weighed till constant weight is achieved. weight of the precipitates (ppt.) was calculated. then percentage inhibition was calculated by following formula: inhibition (%) = (weight of ppt. in blank set weight of ppt. in experimental set x 100) / weight of ppt. in blank set statistical analysis endourology and stone disease table 1. effect of pedalium murex linn. on various biochemical parameters parameter random blood sugar (mg/dl) blood urea (mg/dl) serum creatinine (mg/dl) alanine aminotrnasferase (iu/l) aspartate aminotrnasferase (iu/l) alkaline phosphatase (iu/l) serum bilirubin (mg/dl) serum calcium (mmol/l) group i (normal control) 110.17 ±21.04 34.83 ± 4.51 0.65 ± 0.15 75.17 ± 14.93 247.83 ± 20.05 280.33 ± 42.45 0.68 ± 0.22 1.08 ± 0.05 group ii (eg control) 82.67 ± 11.27 258.50 ± 85.75* 2.90 ± 0.63* 154.33 ± 94.94 272.33 ± 112.00 343.67 ± 95.36 0.80 ± 0.27 1.21 ± 0.07 group iii (pm 200 mg/kg – 28 days) 176.33 ± 21.43 48.00 ± 1.57 0.78 ± 0.17 ** 74.50 ± 7.62 148.17 ± 39.70 300.33 ± 50.72 0.32 ± 0.03 1.20 ± 0.03 group iv (pm 400 mg/kg – 28 days) 58.00 ± 11.08 35.83 ± 11.60 ** 0.82 ± 0.27 49.00 ± 3.52 141.00 ± 32.76 186.33 ± 17.05 0.22 ± 0.02 1.28 ± 0.04 group v (pm 200 mg/kg – 1528 days) 151.83 ± 38.81 82.00 ± 22.22 0.98 ± 0.25 89.50 ± 4.71 103.83 ± 45.11 282.33 ± 44.29 0.27 ± 0.03 1.19 ± 0.02 group vi (pm 400 mg/kg – 15 28 days) 241.17 ± 51.63 53.00 ± 3.82 0.77 ± 0.09 46.67 ± 8.66 225.50 ± 80.34 132.17 ± 15.18* 0.32 ± 0.10 1.14 ± 0.08 all values are expressed as mean ± sem. n=6 for all groups. *p < .05 as compared to group i, **p < .05 as compared to group ii by kruskal-wallis test followed by dunn’s multiple comparisons. keys: pm, pedalium murex linn. eg, ethylene glycol. 949vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l data were expressed as mean ± standard error of mean (sem). all the quantitative variables (urinary parameters for day 0 and 28, biochemical parameters, kidney weight and calcium oxalate crystal depositions) were compared by oneway anova or kruskal-wallis test followed by post hoc test as per gaussian distribution of the data. all the statistical analysis was done using graphpad instat 3.0 (demo version). p < .05 was considered as the significant difference. results biochemical parameters ethylene glycol administration increased the values of blood urea and serum creatinine significantly as compared to normal control. p. murex linn. showed the significant improvement in renal parameters in prophylactic groups (p < 0.05). renal parameters were non-significantly improved in treatment groups. random blood sugar, alt, ast, alp, serum bilirubin and serum calcium were not significantly affected by either ethylene glycol or p. murex linn. (table 1). urinary parameters there was no statistically significant difference in urinary volume and oxalate in all the groups on day 0. urinary oxalate was significantly increased after ethylene glycol administration. p. murex linn. did not show significant effect on urinary oxalate. urine volume was not significantly affected by ethylene glycol or p. murex linn. (table 2). kidney weight ethylene glycol significantly increased the kidney weight as compared to normal control. p. murex linn. restored kidney weight in prophylactic group in lower dose. (p < .05 for group ii vs. iii) in other groups, kidney weights were improved but they were not statistically significant (table 3). histopathological examination ethylene glycol caused significant calcium oxalate crystal depositions in the renal tubules. these crystals were found in proximal tubules, loop of henle, distal tubules and associated with significant leukocyte infiltration, necrosis, hemorrhage and tubular dilatation. these crystals were large polygonal in shape, heterogeneous in distribution and pattern (figure). treatment with p. murex showed significant reduction in number of crystal depositions all the groups (p < .05). there was no significant difference between the p. murex treated groups. calcium oxalate crystals were small and found in lesser area in group iii, iv, vi as compared to group ii. tubular dilatation and leukocyte infiltration were found to lesser extent in these groups but necrosis was not detected (table 3). in vitro mineralization p. murex linn. 200 mg/ml showed 33% inhibition of calcium oxalate and 57% inhibition of calcium phosphate crystallization. discussion table 2. effect of pedalium murex linn. on urinary parameters urine oxalate (mmol/l) day group i (normal control) group ii (eg control) group iii (pm 200 mg/kg – 28 days) group iv (pm 400 mg/kg – 28 days) group v pm 200 mg/kg – 15 28 days) group vi (pm 400 mg/kg – 15 28 days) day 0 0.48 ± 0.14 0.35 ± 0.15 0.28 ± 0.07 0.56 ± 0.32 0.85 ± 0.39 1.68 ± 0.26 day 28 0.18 ± 0.05 1.53 ± 0.19 * 1.74± 0.41* 1.58 ± 0.46 1.52 ± 0.23 1.86 ± 0.42 * urine volume (ml) day group i (normal control) group ii (eg control) group iii (pm 200 mg/kg – 28 days) group iv (pm 400 mg/kg – 28 days) group v pm 200 mg/kg – 15-28 days) group vi (pm 400 mg/kg – 15 28 days) day 0 17.58 ± 4.34 11.75 ± 1.82 14.50 ± 3.62 13.67 ± 2.54 16.17 ± 3.0 13.83 ± 2.52 day 28 33.33 ± 4.22 24.00 ± 5.13 21.83 ± 5.7 30.67 ± 5.87 32.00 ± 8.21 12.83 ± 7.44 all values are expressed as mean ± sem. n=6 for all groups. *p <.05 as compared to group i by kruskal-wallis test followed by dunn’s multiple comparisons. keys: pm, pedalium murex linn. eg, ethylene glycol. effect of pedalium murex linn. on ethylene glycol | induced renal calculi 950 | endourology and stone disease urolithiasis is a multifactorial, urological disorder in which super saturation of urine with oxalate plays a key role in pathogenesis. presently, medical management of renal stone consists of lifestyle modification, calcium channel blocker, diuretics, citrate and magnesium-rich diet.(22) this therapy does not affect recurrence of stone, so traditional medicinal plants have been tried for the prevention of recurrence. we have found increased level of urinary oxalate and calcium oxalate crystal depositions in ethylene glycol control group (p <.05). ethylene glycol administration leads to development of nephrolithiasis by producing hyperoxaluria. it also increases urinary calcium and phosphate. studies have shown that hyperoxaluria causes proximal renal tubular damage and shedding of brush border cells. it would become a site for calcium oxalate monohydrate (com) crystal attachment with renal papilla.(23,24) urinary calcium and super saturation of oxalate develop into nucleation, aggregation and formation of renal stone. so rat model of ethylene glycol is useful for evaluation of renal papillary stone. in present study, all the p. murex treated groups showed significant reduction in calcium oxalate crystal depositions as compared to ethylene glycol control but urinary oxalate was not affected (table 3). this may be due to lack of diuretic activity of the extract (table 2). this suggests direct action of p. murex extract on calcium oxalate crystallization in kidney. in addition, p. murex extract has shown significant inhibition of calcium oxalate and phosphate mineralization as seen by in vitro model. we also found significant improvement in renal function (urea and creatinine) in prophylactic groups (p < .05). it suggests that p. murex extract can prevent renal damage caused by hyperoxaluria. ethylene glycol administration also leads to hypertrophy of renal papilla and increased kidney weight probably by inflammation and fluid accumulation.(25) restoration of renal function is also associated with improvement in kidney weight in p. murex treated rats in prophylactic group in low dose (p < .05). previous study of p. murex fruit extract showed significant improvement in acidic phosphatase (acp), alt, alp, and lactate dehydrogenase (ldh) in urine, serum and kidney homogenate in ethylene glycolinduced renal damage.(26) these enzymes are non-specific and may increase in many other pathological conditions of liver, kidney and muscles. we have considered more specific parameters for renal calculi like renal function test, kidney weight, urinary oxalate, volume and calcium oxalate crystal depositions in kidney. calcium oxalate crystal deposition is associated with severe oxidative stress to renal tissue. it leads to lipid peroxidation of membranes by generation of reactive oxygen species like hydroxyl, superoxide ions.(27) it causes accumulation of non protein nitrogenous (npn) compounds like urea and creatinine in blood as found in our study. several antioxidants like vitamin e, vitamin c, flavonoids and phenolic compounds table 3. effect of pedalium murex linn. on body weight, kidney weight, calcium oxalate crystal depositions groups body weight (g) kidney weight (g) no. of calcium oxalate crystals in 10 microscopic fields group i (normal control) 286.67 ± 12.56 1.19 ± 0.05 0.333 ± 0.211 group ii (eg control) 300.00 ± 8.16 2.03 ± 0.09* 17.667 ± 1.961# group iii (pm 200 mg/kg – 28 days) 263.33 ± 15.42 1.32 ± 0.14** 4.833 ± 1.887## group iv (pm 400 mg/kg – 28 days) 263.33 ± 17.26 1.50 ± 0.24 6.833 ± 2.915** group v (pm 200 mg/kg – 1528 days) 255.00 ± 15.86 1.65 ± 0.1* 6.500 ± 2.579** group vi (pm 400 mg/kg – 15 28 days) 293.33 ± 17.26 1.64 ± 0.24 1.833 ± 0.872## one way anova f (df ) p = 0.199 1.601 (5, 30) p = 0.0166 3.322 (5, 30) p < 0.0001 9.619 (5, 30) all values are expressed as mean ± sem. n=6 for all groups. *p < .05 as compared to group i, **p < .05 as compared to group ii, #p < .001 as compared to group i, ##p < .001 as compared to group ii by one way anova followed by tukey-kramer multiple comparison tests. keys: pm, pedalium murex linn. eg, ethylene glycol. 951vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l effect of pedalium murex linn. on ethylene glycol | induced renal calculi are found to be effective in prevention of oxidative damage and deterioration of renal function.(28,29) studies have shown that p. murex fruit extract possess strong nitric oxide, 2,2-diphenyl-1-picrylhydrazyl (dpph), hydrogen peroxide, and hydroxyl radical scavenging activities.(30) phytochemical analysis of ethanolic extract p. murex linn. fruits show that it contains high levels of flavonoids, glycosides, steroids, phenols, terpenoids, saponins and tannins.(31) among these components, flavonoids and tannins possess significant antioxidant property.(32) saponins and steroids possess antibacterial and antioxidant properties.(33) in present study, inhibition of crystallization may have decreased oxidative stress to the tissue. antioxidants present in the extract also may have decreased lipid peroxidation–induced renal tubular damage and may contribute to its antiurolithiatic action. overall, p. murex fruit extract shows significant improvement of renal function, kidney weight, and calcium oxalate crystal depositions in prophylactic groups (iii and iv) more than treatment groups (v and vi). reason for this finding can be hypothesized as crystallization is ongoing process associated with continued oxidative damage. p. murex fruit extract may not reverse oxidative damage that as already occurred in 14 days treatment with ethylene glycol in group v and vi. so, renal function and kidney weight have not improved significantly in treatment groups. in addition, group vi had lowest calcium oxalate crystal depositions and group v had also similar rate of crystal depositions with prophylactic groups which is suggestive of solubilizing effect of the p. murex on already formed crystals. it suggests that p. murex fruit extract may have substantial action on process of crystallization. further studies are needed to confirm above hypothesis. nowadays, there is increased concern about toxicity profile of phytotherapy. in present study, we have found that p. murex fruit extract does not affect hepatic function and blood sugar significantly even in ethylene glycol treated rats. it is safe to use for prevention of renal stone. further clinical studies are required to evaluate efficacy and safety in human beings. conclusion pedalium murex linn. ethanolic fruit extract has significant anti-urolithiatic activity for prevention of renal calculi probably by affecting calcium oxalate crystallization. there was no dose dependent increment in the effects. conflict of interest none declared. references 1. hadjzadeh ma, khoei a, hadjzadeh z, parizady m. ethanolic extract of nigella sativa l seeds on ethylene glycol-induced kidney calculi in rats. urol j. 2007;4:86-90. 2. romero v, akpinar h, assimos dg. kidney stones: a global picture of prevalence, incidence, and associated risk factors. rev urol. 2010;12:e86-96. 3. johnson cm, wilson dm, o’fallon wm, malek rs, kurland lt. renal stone epidemiology: a 25year study in rochester, minnesota. kidney int. 1979;16:624-31. 4. borghi l, schianchi t, meschi t, et al. comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. n engl j med. 2002;346:77-84. 5. ettinger b, pak cy, citron jt, thomas c, adams-huet b, vangessel a. potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. j urol. 1997;158:2069-73. figure . histopathological images of kidney sections after hematoxylin & eosin staining under light microscope from (a) normal control showing normal renal tubules and glomeruli (10 × magnification), (b) ethylene glycol control showing calcium oxalate crystals (arrows), (c) group treated with p. murex 200 mg/kg for 28 days, (d) group treated with p. murex 400 mg/kg for 28 days, (e) group treated with p. murex 200 mg/kg from 15th – 28th days, (f) group treated with p. murex 400 mg/kg from 15th – 28th days (images from b to f are of 40 × magnification). 952 | 21. farook nam, dameem gas, alhaji nmi, sathiya r, muniyandi j, sangeetha sj. inhibition of mineralization of urinary stone forming minerals by hills area fruit. e-j chem. 2004;1:137-41. 22. shekarkumaran mg, patki ps. evaluation of an ayurvedic formulation (cystone) in urolithiasis: a double blind, placebo-controlled study. european journal of integrative medicine 2011;3;23-8. 23. kuo rl, lingeman je, evan ap, et al. urine calcium and volume predict coverage of renal papilla by randall’s plaque. kidney int. 2003;64:2150-4. 24. kim sc, coe fl, tinmouth ww, et al. stone formation is proportional to papillary surface coverage by randall’s plaque. j urol. 2005;173:117-9. 25. de water r, noordermeer c, van der kwast th et al. calcium oxalate nephrolithiasis: effect of renal crystal deposition on the cellular composition of the renal interstitium. am j kidney dis. 1999;33:761-71. 26. ananta teepa ks, kokilavani r, balakrishnan a, gurusamy k. effect of ethanolic fruit extract of pedalium murex linn. in ethylene glycol induced urolithiasis in male wistar albino rats. anc sci life. 2010;29:29–34. 27. thamilselvan s, hackett rl, khan sr. lipid peroxidation in ethylene glycol induced hyperoxaluria and calcium oxalate nephrolithiasis. j urol 1997;157:1059-63. 28. khan sr. hyperoxaluria-induced oxidative stress and antioxidants for renal protection. urol res. 2005;33:349-57. 29. thamilselvan s, menon m. vitamin e therapy prevents hyperoxaluria-induced calcium oxalate crystal deposition in the kidney by improving renal tissue antioxidant status. bju int. 2005;96:117-26. 30. sermakkani m, thangapandian v. phytochemical screening for active compounds in pedalium murex l. rec res sci tech. 2010;2;110-4. 31. patel dk, kumar r, prasad sk, hemalatha s. pedalium murex linn (pedaliaceae) fruits: a comparative antioxidant activity of its different fractions. asian pac j trop med. 2011;1:395400. 32. polterait o. antioxidants and free radical scavengers of natural origin. current org chem. 1997;1:415-40. 33. mandal p, sinhababu sp, mandal nc. antimicrobial activity of saponins from acacia auriculiformis. fitoterapia. 2005;76:462-5. 6. ettinger b, tang a, citron jt, livermore b, williams t. randomized trial of allopurinol in the prevention of calcium oxalate calculi. n engl j med. 1986;315:1386-9. 7. finkielstein va, goldfarb ds. strategies for preventing calcium oxalate stones. cmaj. 2006;174:1407-9. 8. leonetti f, dussol b, berthezene p, thirion x, berland y. dietary and urinary risk factors for stones in idiopathic calcium stone formers compared to healthy subjects. nephrol dial transplant. 1998;13:617-22. 9. miller nl, lingeman je. management of kidney stones. bmj. 2007;334:468-72. 10. nadkarni km. indian materia medica. 3rd ed. vol 2. bombay; popular prakashan: 1982. 11. mhaskar ks, blatter e, caiur jf. in: kritikar and basu’s illustrated indian medicinal plants, their usage in ayurveda and unani medicines, vol 8, indian medicinal science series no 93, pid; new delhi, 2000, p. 2555-59. 12. shukla, yn, khanuja sps. chemical, pharmacological and botanical studies on pedalium murex. j med arom pl sci. 2004;26:64-9. 13. sinha rk. herbal remedies of street vendors for some urinogenital diseases. anc sci life. 1992;11:187-92. 14. singh np, panda h. meditional herbs with their formulation. new delhi: daya publishiag house; 2005. 15. nalini k, ashokkumar d, venkateswaran v. antimicrobial activity of petroleum ether and methanol extracts of pedalium murex leaves. ijpfr 2011;1:1-10. 16. balamurugan g, muralidharan p, polapala s. aphrodisiac activity and curative effects of pedalium murex (l.) against ethanol-induced infertility in male rats. turk j biol. 2010;34:153-63. 17. balasubramanian mn, muralidharan p, balamurugan g. anti hyperlipidemic activity of pedalium murex (linn.) fruits on high fat diet fed rats. int j pharmacol. 2008;4:310-13. 18. adikay s, latha jp, koganti b. effect of fruits of pedailum murex against cadmium chloride-induced nephrotoxicity in rats. int j drug dev & res. 2010;2:40-6. 19. muralidharan, p, balamurugan g. analgesic and anti inflammatory activities of aqueous extract of pedalium murex linn. biomedicine. 2008;28:84-7. 20. li mg, madappally mm. rapid enzymatic determination of urinary oxalate. clin chem. 1989;35:2330-3. endourology and stone disease v08_no_4_final_new.pdf urological oncology 291urology journal vol 8 no 4 autumn 2011 risk factors for disconcordance between pre and post radical cystectomy stages seyed hossein saadat, mohammad omar al-tawil purpose: to investigate the correlation between pre and post surgical staging in patients undergoing radical cystectomy (rc), and study the possibility of predicting their disconcordance. materials and methods: we reviewed medical records of 186 patients diagnosed with transitional cell carcinoma of the bladder, who had undergone rc between the years 2007 and 2010. we determined the correlation between pre and post surgical stages and then studied the association between stage disconcordance and age, gender, smoking, history of previous transurethral resection of bladder tumor (turbt) and intravesical treatments, re-turbt in high-risk superficial bladder tumors, and the treatment delay between diagnosis and rc. analysis was performed using chi-square and fisher’s exact tests. results: post surgical up-staging occurred in 86 (46.24%) patients and even more (69.35%) if lymph node involvement was also considered as up-staging. of re-turbt had a significantly increased risk of disconcordance. the risk of up-staging was almost halved by an early re-turbt in high-risk patients. conclusion: disconcordance between pre and post surgical stages in patients undergoing rc is common. until better ways of staging are developed, decision making in patients with bladder tumor should be done by extra attention to patients who have risk factors associated with increased risk of up-staging, including smokers and those with nonmuscle-invasive bladder tumors or t2 tumors. an early re-turbt will decrease the up-staging rate. urol j. 2011;8:291-7. www.uj.unrc.ir keywords: urinary bladder neoplasms, neoplasm staging, cystectomy, smoking department of urology, al-moassat university hospital, damascus university, damascus, syria corresponding author: seyed hossein saadat, md department of urology, al-moassat university hospital, damascus university, damascus, syria tell/fax: +963 955 461 684 e-mail: saadat_hos@yahoo.com received april 2011 accepted july 2011 introduction bladder cancer is the second most common urologic tumor and the fourth common cancer in men.(1) upon diagnosis, 75% of newly diagnosed bladder tumors (bt) are nonmuscle-invasive bladder tumors (nmibt).(2) of those patients with muscle-invasive bladder tumors (mibt), 57% are primary (have muscle invasion upon diagnosis and have no previous history of bt), while 43% have progressed from a superficial state.(3,4) one-third of patients with bt have metastasized at diagnosis.(4) defining the exact stage of the bt is essential for planning right treatment and determining the patient’s prognosis. this goal is being chased by transurethral resection of bladder tumor (turbt) and imaging modalities, such as computed tomography (ct) scan, magnetic resonance imaging (mri), or positron emission tomography (pet) pre and post radical cystectomy stages— saadat and al-tawil 292 urology journal vol 8 no 4 autumn 2011 scan. currently, these tumors are being staged according to the tnm staging, which was developed in 1997 and modified in 2002. world health organization grading system (1973 and 2004) was used for grading.(5,6) radical cystectomy (rc) is the best treatment option for mibts.(3,4,7) although improvements in surgical techniques and peri-operative care have resulted in less morbidity and mortality,(8) unpredictable surprises, such as the 46% to 52% rate of disconcordance between pre and post surgical stages (9-11) and the 50% rate of local and distant recurrence(9) might change treatment modalities and prognosis to a great deal. in order to help physicians and patients with preoperative decision making, we made a comparison between pre and post surgical stages and tried to see if the disconcordance between these two situations (stages) could be predicted by any suggested risk factors. materials and methods we reviewed medical records of 186 patients diagnosed with transitional cell carcinoma of the bladder, who had undergone rc and bilateral pelvic lymph node dissection, with curative intent between the years 2007 and 2010. all specimens were fixed in 10% formalin. thereafter, standard sections were taken of the bladder and resected lymph nodes, and stained with hematoxylin and eosin. the studied parameters include age, gender, smoking, history of previous turbt and intravesical treatment, re-turbt (in high-risk nmibts), time interval between diagnosis and rc (treatment delay), and pre and post surgical stages (tnm staging before and after rc). returbt was performed within 2 to 6 weeks after the first turbt if it had shown a high-risk nmibt. high-risk nmibts in whom returbt was indicated were defined as those with incomplete turbt or when a high-grade or t1 tumor was detected.(4) in this study, the pre and post surgical stages were referred to as clinical stage (eg, ct1) and surgical stage (eg, st1), respectively. radical cystectomy specimens were divided into primary radical cystectomy (prc) and secondary radical cystectomy (src) specimens. primary radical cystectomy specimens were those who underwent rc because: 1their first first turbt showed a high-risk nmibt and underwent an early re-turbt that showed a secondary radical cystectomy specimens were those with a nmibt that had multiple recurrences or progression after several sessions of turbts and intravesical treatments. in our centers, the patients who had a highgrade ct1c tumor in their re-turbt specimen were offered the chance to choose surgery. radical cystectomy in these patients and those who had a mibt in their re-turbt specimen was considered as prc. the rc after an early re-turbt was not considered a src because these patients had not received any intravesical treatments between these two turbts and the presence of tumor in the re-turbt specimen (2 to 6 weeks after the first resection) was not considered recurrence or progression. we determined the correlation between pre and post surgical stages and then studied the association between stage disconcordance and aforementioned risk factors. analysis was performed using chi-square test and fisher’s exact test. a confidence interval (ci) of 95% was considered significant. results the median age of our patients was 65 years (range, 40 to 73 years). of 186 patients who underwent rc, 7.53% were women and 92.47% were men. clinical data are summarized in table 1. forty-eight (25.81%) patients underwent rc upon diagnosis or after a re-turbt (prc) while src was performed in 138 (74.19%) patients. the median time interval between diagnosis of mibt and surgery was 4 weeks (range, 0 to 72 weeks). before rc, 26 patients had a ct1 tumor (rc was src in all of them). twenty-four patients pre and post radical cystectomy stages— saadat and al-tawil 293urology journal vol 8 no 4 autumn 2011 underwent prc because the re-turbt of their high-risk nmibt showed either a ct2 (23 patients) or a high-grade ct1c tumor (1 patient). seventy-two patients had ct2 tumors before rc (either primary or secondary), 48 had ct3, and 16 patients had ct4a stages before rc. pre surgical stages (ct), post surgical stages (st), and the upstaging rate have been shown in table 2. while concordance was seen only in 47.31% of patients, post surgical up-staging occurred in 46.24% of patients and down-staging in 6.45%. since only 19 patients were diagnosed to have enlarged lymph nodes before surgery and this number increased to 43 after rc, we could say that 129 (69.35%) patients were upstaged if lymph node involvement was also considered as upstaging. fourteen (16.27%) patients who upstaged were ct1 or less before the surgery. the re-turbt group composed of only 9.3% of the upstaged patients. forty-nine (56.97%) upstaged patients were ct2 (49) and 15 (17.4%) were ct3 before the surgery. table 3 demonstrates the relationship between pre surgical parameters with post surgical stage. it shows that smoking and pre surgical stage are important predicting factors for stage disconcordance. smokers and patients with pt2 had the highest rate of up-staging while nonsmoker pt3 and re-turbt patients had the lowest risk. since smoking showed to be an important factor and in order to study its impact on up-staging further, we divided the smokers into two groups; those who underwent surgery within 90 days and those who underwent rc after 90 days, and studied the up-staging rate in these groups. of 25 patients, 20 (80%) of the smokers who experienced surgery after 90 days were upstaged while this percent was 50.53% (48 patients out of 95) in smokers on whom surgery was performed before 90 days (p = .008). neither age nor gender showed any significant association with stage disconcordance (p = .988 and p = .941). previous intravesical treatments (src) or longer time interval to surgery also had no influence on stage disconcordance (p = .688 and p = .510). discussion transurethral resection of bladder tumor can not comment on stages more than pt2 unless the bladder perforation occurs. computed tomography scan and mri have limited sensitivity in identifying extra bladder tumors, especially pt3a and pelvic lymph nodes less than 8 mm. these imaging modalities also clinical characteristics number percentage age, y 40 to 50 23 12.37 51 to 60 61 32.79 61 to 70 91 48.92 11 5.92 gender male 172 92.47 female 14 7.53 smoking 66 35.48 + 120 64.52 radical cystectomy prc 48 25.81 src 138 74.19 delay interval, d < 90 132 70.97 > 90 54 29.03 table 1. clinical characteristics of patients undergoing radical cystectomy prc indicates primary radical cystectomy; and src, secondary radical cystectomy. pre surgical stage post surgical stage up-staging (n/%) row percentagept2 pt3 pt4 pn+ ct1 or less(n = 26) 12 9 3 2 14/26 = 53.84% ct1c or ct2 after re-turbt(n = 24) 4 12 8 8/24 = 33.33% ct2 (initially) (after progression or at first presentation) (n = 72) 4 19 40 9 49/72 = 68.05% ct3 (n = 48) 2 31 15 15/48 = 31.25% ct4 (n = 16) 2 14 cn+ (n = 19) 43 table 2. pre and post surgical stages in patients undergoing radical cystectomy pre and post radical cystectomy stages— saadat and al-tawil 294 urology journal vol 8 no 4 autumn 2011 lack specificity, not being able to distinguish inflammatory lymph node enlargement from malignant ones. the accuracy of ct scan for diagnosing extra bladder tumors is about 55% to 92%.(4,12) this accuracy is somewhat better for mri and ranges from 73% to 96%. magnetic resonance imaging also seems more accurate for determining lymph node involvement.(3,4) there are ongoing and promising researches on pet scan and immunohistochemical markers, such as p53, hoping to improve pre surgical staging.(9,13) until better imaging modalities or biomarkers are developed, it seems reasonable to identify the risk factors associated with post surgical up-staging in order to help physicians and patients in preoperative decision making. kunze and colleagues demonstrated the association of smoking (cigarettes or pipes) and risk of bladder cancer in agreement with many other studies.(14-16) smoking continues to be the most important risk factor for the development of bladder cancer, and this risk has increased over time.(17) the very common habit of smoking in syria, very high rate of water pipe smoking, might be the cause of high prevalence of bladder cancer in this country. our study showed that one of the pre-operative parameters contributing to a significant increased risk of up-staging is smoking. on the other hand, we also showed that smokers who waited a longer time for surgery (> 90 days) had a higher risk of up-staging. furthermore, the fact that time interval to surgery, on its own, showed no effect on the risk of up-staging, not only shows the importance of smoking regarding up-staging, but also suggests its dose-response relation. nonmuscle-invasive bladder tumors can be treated with turbt and appropriate intravesical treatments, but this treatment is absolutely insufficient if there is an error in stage determination. our study showed that there is a 53.84% rate of up-staging in nmibts and a very modest concordance rate (46.15%) was seen (table 3). on the other hand, patients with ct2 had the highest rate of up-staging (68.05%). since these upstaged patients (with st3 or higher stages postoperatively) might need further treatment, adjuvant chemotherapy, this high rate of upstaging strongly shows the need for pre-operative patient counseling and discussing the possibility of needing such adjuvant treatments. the overall disconcordance rate in our study was shown to be 52.69% (46.24% up-staging and 6.45% down-staging). the high rate of up-staging found in nmibts, ct2 tumors, or in all stages, in our study, is consistent with other studies.(9-11,1821) summary of findings of other researchers are shown in table 4. presurgical parameters down-staging same stage up-staging p mean age, y 60 59 60.69 .988 gender .941male 11/172 = 6.39% 82/172 = 47.67% 79/172 = 45.93% female 1/14 = 7.14% 6/14 = 42.86% 7/14 = 50% smoking .000+ 9/120 = 7.5% 43/120 = 35.83% 68/120 = 53.13% 3/66 = 4.54% 45/66 = 68.18% 18/66 = 27.27% stage .000 ct1 or less 12/26 = 46.15% 14/26 = 53.84% ct1c or ct2 after re-turbt 4/24 = 16.66% 12/24 = 50% 8/24 = 33.33% ct2 4/72 = 5.55% 19/72 = 26.38% 49/72 = 68.05% ct3 2/48 = 4.1% 31/48 = 64.58% 15/48 = 31.25% rc .688prc 4/48 = 8.33% 24/48 = 50% 20/48 = 41.67% src 8/138 = 5.80% 64/138 = 46.38% 66/138 = 47.83% delay interval, d .510 90 7/132 = 5.30% 65/132 = 49.24% 60/132 = 45.45% > 90 5/54 = 9.26% 23/54 = 42.59% 26/54 = 48.19% turbt indicates transurethral resection of bladder tumor; prc, primary radical cystectomy; and src secondary radical cystectomy. table 3. association of pre surgical (clinical or pathological) findings with post surgical stage pre and post radical cystectomy stages— saadat and al-tawil 295urology journal vol 8 no 4 autumn 2011 although some authors have denied the usefulness of re-turbt unless smooth muscle is absent in the initial turbt specimen;(22) our study showed that the probability of up-staging could be halved by a re-turbt in high-risk nmibts, reaching a 33.33% of up-staging instead of 68.05% and 53.84% for ct2 and ct1 groups, respectively. these findings are also compatible with other studies demonstrating that 24% to 49% of patients with nmibt will change to the diagnosis of a ct2 tumor with a re-turbt.(4,23-25) furthermore, dalbagni and coworkers also showed that of the patients who were diagnosed to have a ct1 or less bt by a re-turbt, only 13.3% upstaged to a st2 or higher tumor after prc.(23) as we mentioned before, high-risk nmibts (who need re-turbt) are defined as those with incomplete resection (no muscle in the specimen) or when a high-grade or ct1 tumor is detected.(4) it should also be mentioned that although the importance of t1 subclassifications (t1a, t1b, and t1c) is not clear and not universally accepted,(26) it is the policy of our centers to offer rc to those patients with high-grade ct1c tumors in their turbt specimens, after discussing the risks and benefits. we had only 1 patient who fell into this category. mclaughlin and colleagues showed that patients undergoing prc had a higher risk of up-staging compared to those with a history of intravesical treatments and turbts.(9) this was not the same in our study and neither of the groups showed to have an increased risk of up-staging. the difference between our results and mclaughlin’s results might be due to the difference between patients included in the prc and src groups. in our study, some of the patients included in the prc group were those who underwent rc after an early re-turbt, which showed a highgrade ct1c or a ct2 tumor, and we described that up-staging significantly decreased in returbt patients; therefore, the overall risk of up-staging in prc patients might be decreased due to this selection bias. on the other hand, after extracting the patients with ct2 out of the nmibts by re-turbt, we have ended up with two kinds of nmibts: 1) those with a highgrade ct1c tumor who underwent a prc; and 2) those with a nmibt who were unresponsive to turbt and intravesical treatments, and experienced recurrence or progression, and therefore underwent srp. it would be logical that these patients with their high tendency towards recurrence or progression have more risk of up-staging than src patients described in mclaughlin’s study. the delay between diagnosis and surgery was mostly due to the patient’s reluctance, seeking different opinions, completing pre-operation laboratory tests, consultations, imaging studies, or receiving neoadjuvant treatment. although several authors have considered surgical delay more than 3 months to be associated with the worst staging outcome,(27-30) but this matter is not certain because these studies are not randomized controlled studies and there is a vast variation among published studies, including inconsistent studied cohorts, diverse durations and types of delays, variable treatments, dissimilar investigated end points, and use of different statistical methods.(31) furthermore, some studies have shown that surgical delay had no influence on outcome.(32) our study also showed that this delay caused no significant increase in up-staging (p = .51). one limitation of our study is that it was a retrospective study with patients being referred to us by different urologists, different turbt techniques, and pathologic examination of the biopsy specimens being done by different pathologists. conclusion since disconcordance between pre and post surgical stages in patients undergoing rc is a common problem, until better ways of staging are developed, decision making in patients with first author number ofpatients clinical stage up-staging rate, % chang(11) 169 all 46 cheng(12) 105 all 52.3 dutta(19) 78 37 ficarra(22) 156 42.9 ct2 74.3 table 4. results of other studies regarding up-staging of bladder tumor after radical cystectomy. pre and post radical cystectomy stages— saadat and al-tawil 296 urology journal vol 8 no 4 autumn 2011 bladder tumor should be done by caution, and extra attention should be paid to those who have risk factors associated with increased risk of disconcordance, including smokers and those with nmibts or ct2 tumors. an early re-turbt will decrease this disconcordance. conflict of interest none declared. references 1. messing em. urothelial tumors of the bladder. in: wein aj, kavoussi lr, novick ac, peters ca, eds. campbell-walsh urology. 9 ed. philadelphia: saunders elsevier; 2007:2407-46. 2. jones js, campbell sc. non–muscle-invasive bladder cancer (ta, t1, and cis). in: wein aj, kavoussi lr, novick ac, peters ca, eds. campbellwalsh urology. 9 ed. philadelphia: saunders elsevier; 2007:2447-67. 3. schoenberg mp, gonzalgo ml. management of invasive and metastatic bladder cancer. campbellwalsh urology. 9 ed. philadelphia: saunders elsevier; 2007:2468-78. 4. stenzl a, cowan nc, de santis m, et al. guidelines on bladder cancer: muscle-invasive and metastatic uroweb. 2011. available at: http://www.uroweb.org/ gls/pdf/07_%20bladder%20cancer.pdf. accessed october 1, 2011. 5. epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998;22:1435-48. 6. sauter g, algaba f, amin m, et al. tumours of the urinary system: non-invasive urothelial neoplasias. in: eble j, sauter g, epstein j, sesterhenn i, eds. who classification of tumours of the urinary system and male genital organs. lyon: iarcc press; 2004:29-34. 7. herr hw. surgical factors in the treatment of superficial and invasive bladder cancer. urol clin north am. 2005;32:157-64. 8. hautmann re, gschwend je, de petriconi rc, kron m, volkmer bg. cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. j urol. 2006;176:486-92; discussion 91-2. 9. mclaughlin s, shephard j, wallen e, maygarden s, carson cc, pruthi rs. comparison of the clinical and pathologic staging in patients undergoing radical cystectomy for bladder cancer. int braz j urol. 2007;33:25-31; discussion -2. 10. chang bs, kim hl, yang xj, steinberg gd. correlation between biopsy and radical cystectomy in assessing grade and depth of invasion in bladder urothelial carcinoma. urology. 2001;57:1063-6; discussion 6-7. 11. cheng l, neumann rm, weaver al, et al. grading and staging of bladder carcinoma in transurethral resection specimens. correlation with 105 matched cystectomy specimens. am j clin pathol. 2000;113:275-9. 12. paik ml, scolieri mj, brown sl, spirnak jp, resnick mi. limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. j urol. 2000;163:1693-6. 13. schoder h, larson sm. positron emission tomography for prostate, bladder, and renal cancer. semin nucl med. 2004;34:274-92. 14. kunze e, chang-claude j, frentzel-beyme r. life style and occupational risk factors for bladder cancer in germany. a case-control study. cancer. 1992;69:1776-90. 15. alberg aj, kouzis a, genkinger jm, et al. a prospective cohort study of bladder cancer risk in relation to active cigarette smoking and household exposure to secondhand cigarette smoke. am j epidemiol. 2007;165:660-6. 16. boffetta p. tobacco smoking and risk of bladder cancer. scand j urol nephrol suppl. 200845-54. 17. morgan tm, keegan ka, clark pe. bladder cancer. curr opin oncol. 2011;23:275-82. 18. dutta sc, smith ja, jr., shappell sb, coffey cs, chang ss, cookson ms. clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. j urol. 2001;166:490-3. 19. bayraktar z, gurbuz g, tasci ai, sevin g. staging error in the bladder tumor: the correlation between stage of tur and cystectomy. int urol nephrol. 2001;33:627-9. 20. ploeg m, kiemeney la, smits ga, et al. discrepancy between clinical staging through bimanual palpation and pathological staging after cystectomy. urol oncol. 2010 [epub ahead of print] 21. ficarra v, dalpiaz o, alrabi n, novara g, galfano a, artibani w. correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma. bju int. 2005;95:786-90. 22. millan-rodriguez f, palou j, chechile-toniolo g, montlleo-gonzalez m, huguet-perez j, salvadorbayarri j. re: the value of a second transurethral resection in evaluating patients with bladder tumors. j urol. 2000;163:1258. 23. dalbagni g, herr hw, reuter ve. impact of a second transurethral resection on the staging of t1 bladder cancer. urology. 2002;60:822-4; discussion 4-5. 24. lee se, jeong ig, ku jh, kwak c, lee e, jeong js. impact of transurethral resection of bladder tumor: analysis of cystectomy specimens to evaluate for residual tumor. urology. 2004;63:873-7; discussion 7. 25. bianco fj, jr., justa d, grignon dj, sakr wa, pontes je, wood dp, jr. management of clinical t1 bladder transitional cell carcinoma by radical cystectomy. urol oncol. 2004;22:290-4. 26. lopez-beltran a. bladder cancer: clinical and pathological profile. scand j urol nephrol suppl. 200895-109. pre and post radical cystectomy stages— saadat and al-tawil 297urology journal vol 8 no 4 autumn 2011 27. chang ss, hassan jm, cookson ms, wells n, smith ja, jr. delaying radical cystectomy for muscle invasive bladder cancer results in worse pathological stage. j urol. 2003;170:1085-7. 28. sanchez-ortiz rf, huang wc, mick r, van arsdalen kn, wein aj, malkowicz sb. an interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. j urol. 2003;169:110-5; discussion 5. 29. may m, nitzke t, helke c, vogler h, hoschke b. significance of the time period between diagnosis of muscle invasion and radical cystectomy with regard to the prognosis of transitional cell carcinoma of the urothelium in the bladder. scand j urol nephrol. 2004;38:231-5. 30. mahmud sm, fong b, fahmy n, tanguay s, aprikian ag. effect of preoperative delay on survival in patients with bladder cancer undergoing cystectomy in quebec: a population based study. j urol. 2006;175:78-83; discussion 31. fahmy nm, mahmud s, aprikian ag. delay in the surgical treatment of bladder cancer and survival: systematic review of the literature. eur urol. 2006;50:1176-82. 32. liedberg f, anderson h, mansson w. treatment delay and prognosis in invasive bladder cancer. j urol. 2005;174:1777-81; discussion 81. 356 | prevalence and management of complications of ureteroscopy a seven-year experience with introduction of a new maneuver to prevent ureteral avulsion karim taie,1 majid jasemi,1 dinyar khazaeli,2 ali fatholahi 2 purpose: to evaluate the prevalence and type of rigid ureteroscopy complications and suggest a new method for ureteral avulsion prevention. materials and methods: between march 2002 and march 2009, we retrospectively evaluated 2955 patients who had undergone diagnostic or therapeutic ureteroscopy for asymptomatic hematuria, migrated ureteral stent, or transurethral lithotripsy. they were enrolled from four hospitals in ahvaz, iran. results: complications were encountered in 241 (8%) patients, including transient hematuria (4.2%), mucosal erosion (1.4%), stone migration (1.3%), ureteral perforation (1.2%), and fever and/or sepsis (1.0%). ureteral avulsion occurred in 6 (0.2%) patients. mostly, complications were managed conservatively, using ureteral stenting. ureteral avulsions were managed using a new technique. conclusion: in our series, the complication rate is comparable with the literature. a new technique was used in case of ureteroscope entrapment in the ureter, to lessen the occurrence of ureteral avulsion. keywords: ureteroscopy, ureteral calculi, treatment outcome, lithotripsy, intraoperative complications corresponding author: karim taie, md department of urology, imam khomeini grand hospital, jondishapour university of medical sciences, ahvaz, iran tel: +98 916 111 0545 fax: +98 611 222 2229 e-mail: ktaee@yahoo.com received april 2010 accepted march 2011 1 department of urology, imam khomeini grand hospital, jondishapour university of medical sciences, ahvaz, iran 2 department of urology, golestan grand hospital, jondishapour university of medical sciences, ahvaz, iran endourology and stone disease endourology and stone disease 357vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l complications of ureteroscopy | taie et al introduction transurethral lithotripsy (tul) is the treat-ment of choice for lower and middle ureter-al calculi.(1-4) it has also been used for treatment of upper ureteral and renal stones. based on recent studies, its use as a treatment modality for upper third ureteral stones has become popular;(1-3) however, extracorporeal shockwave lithotripsy (swl) is still the treatment of choice.(3) besides its therapeutic benefits, tul may be associated with some minor or major complications, which may range from a subtle flank pain and transient hematuria to ureteral perforation, ureteral avulsion, and sepsis.(5,6) recently, these complications have become less prevalent due to the introduction of semi-rigid and flexible ureteroscopes and increasing experience and familiarity of surgeons with tul.(6) nonetheless, ureteroscopy is still the most common cause of ureteral injury.(7) therefore, surgeons should be aware of potential complications and their management strategies. in this study, we evaluated the prevalence and type of these complications and also suggested a method to prevent ureteral avulsion. materials and methods a total of 2955 patients who had undergone diagnostic ureteroscopy were retrospectively evaluated. they were recruited from four hospitals namely, golestan, imam khomeini, arvand, and apadana, in ahvaz, iran. the indications for ureteroscopy were asymptomatic hematuria, ureteral stent migration, and tul. ureteroscopies were performed by eight urologists who had at least ten years of experience. in all the subjects, procedures were performed using a rigid ureteroscope 6.75 to 9.0f, and tul was carried out by pneumatic swiss lithoclast lithotripter. the pre-operative urine culture was negative and prophylactic antibiotics were administered to all the subjects. the following data were obtained from medical records: age, gender, stone characteristics (volume and location), complications, and management strategies. results of participants, 2165 and 790 were male and female, respectively. the mean age of the patients was 38 years (range, 3 to 80 years). the mean stone diameter was 11.5 mm (range, 4 to 20 mm). more than one ureteral stone was treated in 24% of patients and stone street was encountered in 57 (2%). the locations of stones were upper, middle, and lower third of the ureter, in 8%, 25%, and 66.8%, respectively. renal pelvic stone accounted for 0.2% of cases. bilateral tul was performed in 3% of patients. stones were not amenable to tul in 7 patients; hence, ureterolithotomy and/or double-j ureteral stent insertion were performed. complications included fever and/or sepsis, transient hematuria (lasting less than 4 days), stone migration, ureteral mucosal injury (abrasion and false passage formation), ureteral perforation, and uretable 1. distribution of urologists and study population in different hospitals hospitals urologists (n = 8)* study population (n = 2955) male (n = 2165) female (n = 790) imam khomeini 3 867 (29.34%) 316 (10.69%) golestan 5 822 (27.82%) 300 (10.15%) apadana 3 195 (6.60%) 71 (2.40%) arvand 4 281 (9.51%) 103 (3.48%) * some of the urologists work in more than one hospital 358 | teral avulsion (table 2). death, severe hemorrhage, stone expulsion to retroperitoneum, urinoma, or abscess formation did not occur in any patient. upward stone migration occurred mostly in patients with upper third ureteral stones and those with severe hydroureteronephrosis. all cases of fever and hematuria were managed successfully using conservative management. ureteral perforation, ureteral mucosal trauma, and false passage formation were also successfully managed with double-j ureteral stent insertion for 4 to 6 weeks in all of the patients except one, who underwent open surgery since ureteral stenting was impossible. ureteral avulsion occurred in 6 patients (1 woman and 5 men), of whom 4 had upper third ureteral stones, one had impacted ureteral stone, and one had large stone. in all subjects with ureteral avulsion, the avulsed ureter exited from the urethral meatus, coating the ureteroscope, while the surgeon was attempting to pull back the ureteroscope with force. the ureter has been detached from ureterovesical junction (uvj) in 1 patient; and in 5 patients simultaneous uvj and ureteropelvic junction (upj) avulsion occurred. management consisted of nephrectomy (1 patient), ureteral re-implantation (1 patient), using boari flap (2 patients), and ileal interposition (1 patient). in a patient with complete ureteral avulsion, we performed proximal anastomosis and distal refluxing ureteral re-implantation. double-j ureteral stent was inserted in all the 6 patients. the last patient, who had undergone proximal anastomosis with distal re-implantation, underwent swl consequently due to renal stones, but unfortunately, stone fragments did not pass completely. double-j stent was inserted for the patient and was replaced every 3 to 6 months. the table 2. demographic and clinical characteristics of study population variables male (n = 2165) female (n = 790) age (mean ± sd), y 38.1 ± 10.2 37.5 ± 9.8 indications, no (%) calculus 2081 (70.42%) 758 (25.65%) diagnostic 65 (2.20%) 23 (0.78%) retained or migrated stent 22 (0.74%) 8 (0.27%) complications, no (%)* hematuria 66 (2.23%) 58 (1.96%) stricture 0 (0%) 0 (0%) perforation 21 (0.71%) 14 (0.47%) avulsion 5 (0.17%) 1 (0.03%) mucosal erosion/false passages 23 (0.78%) 17 (0.58%) fever/sepsis 16 (0.54%) 13 (0.44%) stone migration 12 (0.41%) 26 (0.88%) total 143 (4.84%) 129 (4.37%) * some cases showed more than one complication; overall complication rate was 8.1%. endourology and stone disease 359vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l complications of ureteroscopy | taie et al patient was followed up for 2 years, but he was not compliant enough. he did not return for further follow-up; therefore, he missed the chance of reconstructive surgery and finally underwent nephrectomy in another center because of ureteral stricture and severe renal damage. discussion compared with swl, tul is more effective in treatment of the lower third ureteral stones.(1-3) although swl is still the modality of choice in the treatment of upper and middle third ureteral stones, tul is being performed increasingly with the same efficacy.(1-4,8) today, open surgery is rarely done for treating ureteral and renal stones, since these may also be treated with flexible ureteroscopy and holmium laser. besides its therapeutic benefits and despite its widespread use, tul may be associated with a number of complications, especially when used for treating proximal ureteral stones.(4,9) diagnosing these complications and managing them have utmost importance for surgeons undertaking this procedure. in a study by gleavlete and associates, 2735 tul procedures were assessed with regards to the rate and type of complications. immediate complications occurred in 10.64% of patients, including fever and sepsis (1.13%), persistent hematuria (2.04%), renal colic (2.23%), transient vesicoureteral reflux (4.58%), and ureteral stent migration (0.66%). intra-operative complications happened in 3.6% of subjects and included ureteral mucosal trauma (false passage formation) (1.0%), abrasion (1.50%), ureteral perforation (0.65%), stone expulsion (0.18%), bleeding (0.10%), and ureteral avulsion (0.11%).(5) in another study, elashry and colleagues stated that with increasing surgeon’s experience and evolving devices, the rate of ureteral perforation and avulsion have decreased from 3.3% to 0.5% and from 1.3% to 0.1%, respectively.(6) in a study of 2273 patients who had undergone ureteroscopy, bultler reported 1% complication rate, which was mostly ureteral trauma and managed conservatively while 22% required open surgery due to ureteral perforation or avulsion.(10) in our study, 8% of patients developed complication, which were mostly minor complications, including transient hematuria, stone migration, false passage formation, and ureteral mucosal trauma. except for one patient, all the cases of ureteral perforation were managed by ureteral double-j stent insertion for 6 weeks. fever and sepsis were also treated with conservative therapy. ureteral avulsion was the most serious complication, which occurred in 0.2% of patients, and resulted in nephrectomy in 1 out of 6 subjects. the affected kidney was salvaged in the other 5 patients with open surgery. our complication rate is comparable with previous studies. the most catastrophic complication of ureteroscopy is ureteral avulsion. although it occurred in only 0.2% of patients, appropriate strategies should be considered to prevent it due to its serious consequences and potential sequel. once it occurs, however, proximal anastomosis and distal re-implantation of the avulsed ureter may be done as a temporary option until further reconstructive procedures can be undertaken in more suitable settings. if ureteroscope is trapped in the ureter, it cannot be taken out and ureteral avulsion may occur in case of excessive force. the authors suggest the following maneuver to prevent ureteral avulsion: a. increase irrigation pressure in the ureter; hence, the ureteral mucosa would be released from the ureteroscope. b. perform rectal examination in men with your left index finger or insert two fingers in the vaginal fornix in women, and try to push uvj and the lower ureteral segment upward and against the ureteroscope’s sheath. while the ureter is dilated, wave and rotate the ureteroscope 45º clockwise and counter clockwise gently and remove it if no resistance is encountered. at the same time, control 360 | references 1. anagnostou t, tolley d. management of ureteric stones. eur urol. 2004;45:714-21. 2. wolf js, jr. treatment selection and outcomes: ureteral calculi. urol clin north am. 2007;34:421-30. 3. nikoobakht mr, emamzadeh a, abedi ar, moradi k, mehrsai a. transureteral lithotripsy versus extracorporeal shock wave lithotripsy in management of upper ureteral calculi: a comparative study. urol j. 2007;4:207-11. 4. tanaka st, makari jh, pope iv jc, adams mc, brock iii jw, thomas jc. pediatric ureteroscopic management of intrarenal calculi. j urol. 2008;180:2150-4. 5. geavlete p, georgescu d, ni, et al. complications of 2735 retrograde semirigid ureteroscopy procedures: a singlecenter experience. j endourol. 2006; 20:179-85. 6. elashry om, elgamasy ak, sabaa ma, et al. ureteroscopic management of lower ureteric calculi: a 15‐year single‐centre experience. bju int. 2008;102:1010-7. 7. johnson db, pearle ms. complications of ureteroscopy. urol clin north am. 2004;31:157-71. 8. ziaee sa, basiri a, nadjafi-semnani m, zand s, iranpour a. extracorporeal shock wave lithotripsy and transureteral lithotripsy in the treatment of impacted lower ureteral calculi. urol j. 2006;3:75-8. ureteral mucosal movement proximally against the direction of ureteroscope. retry if it was not successful. writers of this study have tried this maneuver in many cases, and in all cases ureteroscope could be released easily. conclusion in case of ureteral avulsion, proximal anastomosis and distal refluxing re-implantation of the avulsed ureter and double-j stent insertion can buy the patient’s time for reconstructive surgery in a more suitable situation. conflict of interest none declared. endourology and stone disease 9. francesca f, scattoni v, nava l, pompa p, grasso m, rigatti p. failures and complications of transurethral ureteroscopy in 297 cases: conventional rigid instruments vs. small caliber semirigid ureteroscopes. eur urol. 1995;28:112-5. 10. butler mr, power re, thornhill ja, et al. an audit of 2273 ureteroscopies--a focus on intra-operative complications to justify proactive management of ureteric calculi. surgeon. 2004;2:42-6. case reports 177urology journal vol 4 no 3 summer 2007 laparoscopic removal of a migrated intrauterine device farzaneh sharifiaghdas, faramarz mohammadali beigi, hamidreza abdi urol j. 2007;4:177-9. www.uj.unrc.ir keywords: laparoscopy, intrauterine device, migration department of urology, shaheed labbafinejad medical center, shaheed beheshti medical university, tehran, iran corresponding authors: farzaneh sharifiaghdas, md department of urology, shaheed labbafinejad medical center, pasdaran, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: fsharifi@yahoo.com received january 2007 accepted march 2007 introduction using intrauterine device (iud) is the most common method of contraception worldwide. however, there is a risk of its migration and damage to the intra-abdominal organs.(1) according to the recent reports, perforation of the uterus by iud is seen in 0.05 to 13 cases out of 1000 iud insertions.(2) the primary rupture of the uterus has been reported at the time of iud insertion; however, the secondary or delayed rupture is more common and seems to be due to the spasms of the uterus.(2) concerning the risk of adhesion and injury to the intestine and bladder, surgical removal of the intra-abdominally migrated iud is recommended and 2 methods of open surgery and laparoscopy have been reported for this purpose.(3) open surgery is accompanied by complications such as cosmetic problems and longer hospitalization, and laparoscopy may be an appropriate treatment of iud migration because of a better view, more magnification, and a smaller surgical incision. we report a case of iud migration into the pelvis in a young woman. case report our patient is a 35-year-old woman who has been using iud for 5 years after her first labor. the iud was removed because of her willingness for pregnancy, and thereafter, she had bleeding for 20 days. she conceived her second child and after the second labor, an iud was inserted. three months later, she experienced suprapubic pain during diuresis. she did not have hematuria or other urinary symptoms and her medical examination was unremarkable. routine laboratory tests including urinalysis had normal results. the patient underwent ultrasonography and increased thickness of the anterior wall of the bladder with a soft tissue mass and the iud in the space between the bladder and the uterus were detected. on plain abdominal radiography, the shadow of the iud was seen in the middle of the pelvic space, and computed tomography confirmed the iud in the space between the uterus and the bladder (figure 1). the patient then underwent cystoscopy and a prominent mucosal dome was detected in the bladder formed due to the pressure from the outside. the iud was not seen in the bladder and the bladder mucosa was intact. finally, the diagnosis of iud migration from the uterus into the space between the bladder and the uterus was confirmed and laparoscopic method was chosen to remove it. following general anesthesia, 3 ports were made with the patient in the supine position. one was placed 10 laparoscopy for intrauterine device migration—sharifiaghdas et al 178 urology journal vol 4 no 3 summer 2007 mm from the umbilicus for the camera and 2 were placed in 5-mm distance in the pararectal parts at the level of the umbilicus on the right and left (figure 2). in laparoscopy, a space in the anterior part of the uterine covered by the omentum was seen. after releasing the adhesions, the iud was removed within 15 minutes (figure 3). the patients’ catheter was removed 2 days later, and then, she was discharged from the hospital. no complication was seen during the procedure and the patient did not have any problems during the 3-month follow-up. discussion migration of the iud into the abdominal cavity is very rare. in our review of the literature, 165 cases of iud migration have been reported since 1999. the most common places for this migration are the omentum, rectosigmoid colon, peritoneum, and bladder. other rare places for iud migration include the appendix, small intestine, adenexes, iliac veins, secum, perirectal fat, retroperitoneal space, douglas pouch, and ovaries.(4-9) most of the authors recommend removal of the copper iud in case of migration, because inflammatory responses can cause intestinal obstruction and visceral perforation. laparotomy and laparoscopic management have been used for iud removal in the cases with iud migration. since laparatomy is accompanied by more manipulations, more scarring, and longer hospitalization, and has a more limited view during the operation, laparoscopy has now become the method of choice for the treatment. successful treatment of iud migration by laparoscopy has been reported in a few cases.(3,6-8) the average period of laparoscopy has been reported to be 25 minutes and the maximum hospital stay to be 1 day, which are significantly shorter than those for open surgery. figure 2. trocar insertion sites for laparoscopy. large midline incision was avoided by this approach. figure 3. the intrauterine device was freed from the adjacent adhesions between the bladder and the uterus. figure 1. detection of the intrauterine device by imaging. top, plain abdominal radiography. bottom, intrauterine device in the space between the bladder and the uterus on computed tomography scan. laparoscopy for intrauterine device migration—sharifiaghdas et al urology journal vol 4 no 3 summer 2007 179 no complication has so far been reported by this method. injury to the intestine needing repair and sepsis have been considered as the contraindications for laparoscopy.(6,8) however, in such cases, laparoscopy is a fast, easy, and noninvasive method for the diagnosis of the place of the iud and its removal. references 1. stuckey a, dutreil p, aspuru e, nolan te. symptomatic cecal perforation by an intrauterine device with appendectomy removal. obstet gynecol. 2005;105:1239-41. 2. grimaldi l, de giorgio f, andreotta p, d>alessio mc, piscicelli c, pascali vl. medicolegal aspects of an unusual uterine perforation with multiload-cu 375r. am j forensic med pathol. 2005;26:365-6. 3. gungor m, sonmezer m, atabekoglu c, ortac f. laparoscopic management of a translocated intrauterine device perforating the bowel. j am assoc gynecol laparosc. 2003;10:539-41. 4. kassab b, audra p. [the migrating intrauterine device. case report and review of the literature]. contracept fertil sex. 1999;27:696-700. french. 5. sarkar p. translocation of a copper 7 intra-uterine contraceptive device with subsequent penetration of the caecum: case report and review. br j fam plann. 2000;26:161. 6. silva pd, larson km. laparoscopic removal of a perforated intrauterine device from the perirectal fat. jsls. 2000;4:159-62. 7. roy kk, banerjee n, sinha a. laparoscopic removal of translocated retroperitoneal iud. int j gynaecol obstet. 2000;71:241-3. 8. demir sc, cetin mt, ucunsak if, atay y, toksoz l, kadayifci o. removal of intra-abdominal intrauterine device by laparoscopy. eur j contracept reprod health care. 2002;7:20-3. 9. ozdemir h, mahmutyazicioglu k, tanriverdi ha, gundogdu s, savranlar a, ozer t. migration of an intrauterine contraceptive device to the ovary. j clin ultrasound. 2004;32:91-4. endourology and stone disease 84 urology journal vol 5 no 2 spring 2008 solo extracorporeal shock wave lithotripsy for management of upper ureteral calculi with hydronephrosis sushant wadhera, rajkumar k mathur, sudershan odiya, ram sharan raikwar, govindaiyah girish introduction: the aim of this study was to evaluate extracorporeal shock wave lithotripsy (swl) outcomes as a solo therapy in patients with upper ureteral calculi and varying degrees of hydronephrosis. materials and methods: eighty patients with upper ureteral calculi and a body mass index between 19.5 kg/m2 and 22.5 kg/m2 were included. they were categorized into 4 groups according to the severity of hydronephrosis as seen on ultrasonography and intravenous urography: group 1, no dilatation; group 2, mild dilatation; group 3, moderate dilatation; and group 4, severe dilatation of the pyelocaliceal system. the size of calculi, time to calculus clearance, success rate of solo swl, and the need for additional therapeutic methods were recorded and compared between the four groups of patients. results: the median size of the calculi was 13.5 mm, and the mean time to calculus clearance was 56.0 ± 24.2 days. in 71.3% of the patients, solo swl was successful in the treatment of the calculi. twenty-three patients required other therapies including double-j stenting, ureteroscopy, and nephrolithotomy. the patients without hydronephrosis and those with severe hydronephrosis (groups 1 and 4) showed a significant difference in the days to clearance of the calculus (mean, 31.7 days versus 85.6 days; p < .001). conclusion: patients with upper ureteral calculi and mild hydronephrosis can be effectively treated with solo swl therapy. in those with moderate hydronephrosis, clearance takes longer or requires secondary interventions. in patients with severe hydronephrosis, we recommend alternative/adjunctive procedures. urol j. 2008;5:84-8. www.uj.unrc.ir keywords: shock waves, lithotripsy, hydronephrosis, ureteral calculi, upper ureter department of surgery, maharaja yashwantrao hospital, indore, madhya, pradesh, india corresponding author: sushant wadhera, mbbs, ms department of surgery, my hospital, indore, madhya, pradesh, india tel: +91 989 363 6012 fax: +91 731 270 2088 e-mail: sushantwadhera@gmail. com received october 2007 accepted april 2008 introduction modern surgical management of urinary calculi was revolutionary changed by the introduction of extracorporeal shock wave lithotripsy (swl) in february 1980. chaussy and colleagues confirmed it as a routine clinical practice in 1982.(1) it has been the preferred treatment of urinary calculi, especially in the kidney and the upper ureter, and it works best with the calculi between 4 mm and 20 mm in diameter.(2-4) success of swl depends on factors such as calculus composition, pyelocaliceal height, proximity of the calculus to a bony structure, presence and extracorporeal shock wave lithotripsy and upper ureteral calculi—wadhera et al urology journal vol 5 no 2 spring 2008 85 degree of hydronephrosis, presence of ureteral obstruction, operator experience, and machine design.(3-6) there has been a great debate on the efficacy of swl in a dilated pyelocaliceal system. while some authors claim no difference in the rate of the clearance and time to clearance in these systems, others believe that the time for clearance and success rates are indeed affected by the degree of hydronephrosis.(7-10) we sought to evaluate the efficacy of solo swl therapy for the treatment of upper ureteral calculi with hydronephrosis focusing on calculus clearance and time needed for clearance. this would help us determine the appropriate management for the patients with upper ureteral calculi and varying degrees of hydronephrosis. material and methods a total of 80 patients with documented upper ureteral calculi with or without hydronephrosis were included in this study. upper ureteral calculi were radiographically defined as those located between the ureteropelvic junction and the pelvic brim. we selected patients with a body mass index between 19.5 kg/m2 and 22.5 kg/m2 who consented to enroll in the study. a single radiologist evaluated and assigned the patients into 4 groups according to the severity of hydronephrosis on ultrasonography and intravenous urography: group 1, no dilatation; group 2, mild hydronephrosis; group 3, moderate hydronephrosis; and group 4, severe hydronephrosis.(8) laboratory tests including complete blood count, leukocyte count, blood glucose, blood urea and serum creatinine, coagulation profiles, and urinalysis and urine culture were performed in all patients. plain abdominal radiography, ultrasonography, and intravenous urography were performed before the procedure. patients with a positive urine culture were treated by antibiotics for 2 weeks, and after achieving a negative urine culture, they underwent the procedure. no prophylactic antibiotic was used during or after the procedure. mild sedatives such as pethidine were needed in a few cases. a first-generation lithotripter (dornier hm3, dornier medizintechnik gmbh, germering, germany) was used and an average of 3000 shocks was given at 15 kv to 18 kv. the patients attended a maximum of 4 sessions of swl. size of the calculus was recorded before the first procedure and before any subsequent swl session. the patients received ofloxacin, 200 mg twice a day, and rabeprazole, 20 mg, for 7 days postoperatively. they were recommended to increase their daily water intake up to 3 l to 4 l following the procedure. follow-up program consisted of plain abdominal x-ray and ultrasonography every 2 weeks for 3 months or until complete clearance of the calculus. the following data were recorded: days from swl to complete calculus clearance, number of the shock waves, intensity of the shock waves, and number of required sessions. success was defined as clearance of the calculus within 3 months after a maximum of 4 sessions and no requirement for adjunctive procedures. treatment failure was defined as persistence of fragments larger than 3 mm in diameter after 3 months and/or recurrent colic pain after 4 swl sessions with the need for adjunctive procedures such as double-j stenting, ureterorenoscopy, or nephrolithotomy. the results were evaluated using the t test, mann-whitney u test, and chisquare test, where appropriate. a p value less than .05 was considered significant. results characteristics of the patients are shown in table 1. we had 57 out of 80 patients with complete calculus clearance following solo swl therapy (a success rate of 71.3%). additional treatments were used in 23 patients (table 2). presence of hydronephrosis up to a moderate degree did not affect the success of calculus clearance (p = .70), but severe hydronephrosis was associated with failure of solo swl in all patients. table 3 demonstrates the final results in each group of hydronephrosis. the time to clearance considerably varied between groups 1 and 2 (p = .04). also, patients in the two extreme groups of the study (group 1 and group 4) showed a significant difference in the days to clearance of the calculus (p < .001). extracorporeal shock wave lithotripsy and upper ureteral calculi—wadhera et al 86 urology journal vol 5 no 2 spring 2008 discussion the effect of hydronephrosis on calculus clearance following swl has been under debate. many studies have shown changes in the ureteral musculature and redistribution of blood flow within the kidney. this would definitely appear to hamper the calculus clearance. lackner and barton reported that ureteral obstruction resulted in a progressive decrease in renal excretory function due to rapid redistribution of blood from the medulla to the cortex.(11) also in 1989, jones and colleagues studied the effect of obstruction using lithium clearance.(12) both these studies showed a decrease in both glomerular and tubular function. gee and kiviat reported that obstruction also produced hypertrophy of ureteral musculature and connective tissue proliferation within as fast as 3 days.(13) this leads to decreased peristalsis and decreased pressure, which might lead to decreased migration of the calculus.(13) kageyama and associates evaluated middle and lower ureteral calculi with moderate or severe hydronephrosis and found poor outcomes in the obstructed systems.(14) kumar and coworkers showed that an obstructed and dilated system provided a good water patient groups characteristics no hydronephrosis mild hydronephrosis moderate hydronephrosis severe hydronephrosis total number of patients 12 24 32 12 80 mean age, y 35.7 39.7 32.8 30.3 34.6 sex male 8 20 24 12 64 female 4 4 8 0 16 median calculus size, mm 13.0 12.5 14.0 14.5 13.5 total swl sessions 36 72 108 36 252 median swl sessions 3 3 3† 3 3 table 1. demographic characteristics of patients with upper ureteral calculi and treatment* *swl indicates shock wave lithotripsy †twenty patients required 3 swl sessions, while 12 required 4 sessions. patient groups additional treatments no hydronephrosis mild hydronephrosis moderate hydronephrosis severe hydronephrosis total number of patients 1 4 6 12 23 number of treatment sessions 1 4 10 20 39 treatment modality double-j stent 1 3 4 4 12 ureteroscopy … 1 5 12 18 nephrolithotomy* … … 1 8 9 table 2. additional therapies required after extracorporeal shock wave lithotripsy in patients with upper ureteral calculi *at our institute, since the facilities for percutaneous nephrolithotomy were not available, open nephrolithotomy was done. ellipses indicate that the treatment method was not used. patient groups parameters no hydronephrosis mild hydronephrosis moderate hydronephrosis severe hydronephrosis total mean time to clearance, d 31.7 38.4 65.3 85.6 56.0 failures 1 4 6 12 23 success rate, % 91.7 83.3 81.3 0 71.3 table 3. outcomes of solo extracorporeal shock wave lithotripsy in patients with upper ureteral calculi extracorporeal shock wave lithotripsy and upper ureteral calculi—wadhera et al urology journal vol 5 no 2 spring 2008 87 head for fragment separation proximally, but little space for separation distally. therefore, fragments float in a retrograde direction and are retained as residual calculi.(15) demirbas and colleagues found that in patients with solitary calculus in the lower ureter, the degree of urinary obstruction caused by the calculus did not affect the success of calculus clearance with swl.(7) seitz and coworkers reached the similar findings and concluded that presence or degree of hydronephrosis caused by an upper ureteral calculus did not affect the time of clearance or success rate after swl.(8) in the study by iqbal and associates, the patients with severe hydronephrosis were not included and they had a result similar to the study by demirbas and colleagues.(7,9) meanwhile, in slight contradiction to these studies, el-assmy and colleagues conducted a study on the effect of hydronephrosis on calculus clearance following swl and concluded that in the patients with a solitary lumbar ureteral calculus, even though the degree of hydronephrosis caused by the calculus did not affect the overall treatment success with swl, the calculi in obstructed systems were associated with a tendency for repeated treatments and a prolonged period of calculus clearance.(10) we had similar findings in our study. of the 80 patients in the present study, 68 had varying degrees of hydronephrosis. in the group with mild hydronephrosis, the mean time to clearance was 38.4 days, while in the group with moderate hydronephrosis, it was 65.3 days. group 4 did not show any calculus clearance following swl and all the patients needed additional therapies such as double-j stenting, ureteroscopy, and/or nephrolithotomy. also, in the group with moderate hydronephrosis, 6 patients needed additional therapies (either single or in combination). in the group without hydronephrosis, only 1 patient experienced failure of solo swl therapy and required double-j stenting. in the group with mild hydronephrosis, 4 patients required interventions, 3 of whom passed the calculus by double-j stenting followed by swl and 1 required ureteroscopic evacuation. conclusion our findings showed that patients with upper ureteral calculi and no or mild hydronephrosis can be effectively treated by solo swl therapy, and those with moderate hydronephrosis can undergo swl as a single therapy, but the time taken for calculus clearance is much longer and these patients may require further interventions. we do not recommend solo swl therapy in patients with severe hydronephrosis; alternative or adjunctive procedures may be needed in these patients. conflict of interest none declared. references 1. chaussy c, schmiedt e, jocham d, brendel w, forssmann b, walther v. first clinical experience with extracorporeally induced destruction of kidney stones by shock waves. j urol. 1982;127:417-20. 2. tiselius hg, ackermann d, alken p, buck c, conort p, gallucci m; working party on lithiasis, european association of urology. guidelines on urolithiasis. eur urol. 2001;40:362-71. 3. segura jw, preminger gm, assimos dg, et al. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. the american urological association. j urol. 1997;158:1915-21. 4. anagnostou t, tolley d. management of ureteric stones. eur urol. 2004;45:714-21. 5. lingeman je, newman dm, mertz jh, et al. extracorporeal shock wave lithotripsy: the methodist hospital experience. j urol. 1986;135:1134-7. 6. leveillee rj, carey ri. extracorporeal shock-wave lithotriptors: why newer may not be better. nat clin pract urol. 2006;3:76-7. 7. demirbas m, kose ac, samli m, guler c, kara t, karalar m. extracorporeal shockwave lithotripsy for solitary distal ureteral stones: does the degree of urinary obstruction affect success? j endourol. 2004;18:237-40. 8. seitz c, fajkovic h, waldert m, et al. extracorporeal shock wave lithotripsy in the treatment of proximal ureteral stones: does the presence and degree of hydronephrosis affect success? eur urol. 2006;49:378-83. 9. iqbal s, gupta np, hemal ak, et al. impact of power index, hydroureteronephrosis, stone size, and composition on the efficacy of in situ boosted eswl for primary proximal ureteral calculi. urology. 2001;58:16-22. 10. el-assmy a, el-nahas ar, youssef rf, el-hefnawy extracorporeal shock wave lithotripsy and upper ureteral calculi—wadhera et al 88 urology journal vol 5 no 2 spring 2008 as, sheir kz. impact of the degree of hydronephrosis on the efficacy of in situ extracorporeal shock-wave lithotripsy for proximal ureteral calculi. scand j urol nephrol. 2007;41:208-13. 11. lackner h, barton lj. cortical blood flow in ureteral obstruction. invest urol. 1970;8:319-23. 12. jones da, atherton jc, o’reilly ph, barnard rj, george nj. assessment of the nephron segments involved in post-obstructive diuresis in man, using lithium clearance. br j urol.1989;64:559-63. 13. gee wf, kiviat md. ureteral response to partial obstruction. smooth muscle hyperplasia and connective tissue proliferation. invest urol. 1975;12:309-16. 14. kageyama s, hirai s, higashi y. [an investigation of factors associated with failure of extracorporeal shock wave lithotripsy for ureteral calculi]. hinyokika kiyo. 2000;46:371-6. japanese. 15. kumar a, kumar rv, mishra vk, ahlawat r, kapoor r, bhandari m. should upper ureteral calculi be manipulated before extracorporeal shock wave lithotripsy? a prospective controlled trial. j urol. 1994;152:320-3. pdf-524.pdf 433vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l keywords: testis, orchiopexy, abnormalities, diagnosis introduction pjohn hunter in 1786.(1) an undescended testis can be located anywhere in the pathway of testicular descent outside the scrotum. the testis can also be located in an ectopic position. the most common regions in descending order canal, contralateral scrotum, and prepenile region. perineal ectopic testis is seen approximately in 1% of all cases of undescended testes.(2) an empty hemiscrotum with palpable perineal soft mass is suggestive of an ectopic testis in the perineum. antenatal diagnosis of perineal ectopic testis can be made ultrasonographically.(3) agement. case report a 19-year-old man presented to our outpatient clinic with a perineal mass and discomfort. examination showed an empty and poorly developed left hemiscrotum. the contralateral testis was in its normal location in the right hemiscrotum (figure 1). an oval-shaped soft mass was detected in the perineum measuring 4 × 5 × 6 cm. a clinical diagnosis of perineal ectopic testis was made. we recommended orchidectomy for the left perineal testis because of the pagokhan koc, selim yavuz sural, devrim nihat filiz, yuksel yilmaz perineal ectopic testis corresponding author: gokhan koc, md tepecik teaching and research hospital, izmir, turkey tel: +90 232 469 6969 fax: +90 232 433 0756 e-mail: gokfekoc@gmail. com received january 2010 accepted december 2010 tepecik teaching and research hospital, izmir, turkey case report 434 | tient’s age. however, the patient wanted his testis placed in the scrotum; hence, a left orchiopexy was performed. surgical exploration was performed through inguinal skin crease incisions. using the dartos pouch technique (figure 2). postoperative examination at one month revealed a normally located left testis in the scrotum (figof the surgery. discussion descent of the testis is thought to occur in two phases; intra-abdominal migration and inguinal migration. testicular development and descent from the abdomen to the scrotum is a complex hormonal, and certain mechanical factors. the ectopic testis completes normal transinguinal migration, but is misdirected outside the normal path of descent below external ring. perineal testis is the commonest form of true testicular ectopia, testis is a rare congenital anomaly.(4) the etiology of testicular ectopia is unknown; however, some theories like gubernacular abnormalities, genitofemoral nerve disorders, increased intra-abdominal pressure, and endocrine disorders are the most prominent ones.(5) lockwood suggested that distal part of the gubernaculum has normal descent is seen and if another insertion is dominant, the insertion diverts the testis toward itself leading to ectopy.(6) furthermore, it is posthe gubernaculum prohibits natural descent of the testes.(7) hutson suggested that abnormal position of genitofemoral nerve leads to an abnormal migration of the gubernaculum and pushes the testis to abnormal position.(8) middleton and colleagues also reported that increased intra-abdominal presfigure 1. a left empty hemiscrotum and a mobile testicular mass in the perineum. figure 2. surgical exploration of the left ectopic testis through inguinal incision. figure 3. scrotum at one-month following surgery. case report 435vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l perineal ectopic testis | koc et al sure could facilitate testicular descent.(9) lozano ortega and associates stated that inadequate hormonal stimulation may lead to ectopy. the ectopic location of the testis is associated with a number of complications, such as trauma, torsion, and infertility in bilateral cases.(11) therefore, treatment is warranted. most authors recommend surgical correction at approximately 1 year be demonstrated in the undescended testes.(12) orchiopexy is the treatment of choice under 2 years of age. but if an atrophic testis is detected, orchidectomy should be performed. sition, all the possible sites for an ectopic testis cated that in cases of perineal ectopic testis, surgery should be performed before 6 months of age even if not associated with inguinal hernia.(2) testicular cancer is more common in an ectopic testis than in a normally descended organ. therefore, we recommended the patient an orchidectomy. however, he wanted his testis placed in the scrotum. thus, we proceeded with orchiopexy; however, long-term follow-up was advised. we believe orchiopexy is the treatment of choice in selected patients with perineal ectopic testis. however, self testicular examination and longterm follow-up is mandatory. conflict of interest none declared. references 1. hunter j. observations on certain parts of the animal economy. london: woellner; 1786. 2. celayir ac, sander s, elicevik m. timing of surgery in perineal ectopic testes: analysis of 16 cases. pediatr surg int. 2001;17:167-8. 3. mazneikova v, markov d. antenatal ultrasound diagnosis of perineal ectopic testis--a case report. eur j ultrasound. 2001;13:31-3. 4. murphy dm, butler mr. preperitoneal ectopic testis: a case report. j pediatr surg. 1985;20:93-4. 5. heyns cf, hutson jm. historical review of theories on testicular descent. j urol. 1995;153:754-67. 6. lockwood cb. development and transition of the testis, normal and abnormal. j anat physiol. 1888;22:505-41. 7. maidenberg m. [a case of an ectopic testis in the perineum]. prog urol. 1993;3:268-71. 8. hutson jm. undescended testis, torsion, and varicocele. in: gross feld jl, o'neil jaj, fonkalsrud ew, coran ag, eds. pediatric surgery. 6 ed. philadelphia: mosby; 2006:1193-214. 9. middleton gw, beamon cr, gillenwater jy. two rare cases of ectopic testis. j urol. 1976;115:455-8. 10. lozano ortega jl, escolano a, rey a. [perineal ectopic testicle]. arch esp urol. 1983;36:289-92. 11. jlidi s, echaieb a, ghorbel s, khemakhem r, ben khalifa s, chaouachi b. [perineal ectopic testis: report of four paediatric cases]. prog urol. 2004;14:532-3. 12. lugg ja, penson df, sadeghi f. early orchiopexy reverses histologic changes in cryptorchid testes. j urol. 1995153: 235a. case reports 248 urology journal vol 4 no 4 autumn 2007 metachronous emphysematous pyelonephritis and xanthogranulomatous pyelonephritis in the contralateral kidney an extremely rare condition mishari h alshyarba urol j. 2007;4:248-50. www.uj.unrc.ir keywords: emphysematous pyelonephritis, xanthogranulomatous pyelonephritis, nephrectomy department of surgery, college of medicine, king khalid university, abha, saudi arabia corresponding author: mishari h alshyarba, md department of surgery, college of medicine, king khalid university po box: 641, abha – 61421, kingdom of saudi arabia tel: +966 7 224 7800, ext 2126 fax: +966 7 224 7570 e-mail: mhalshyarba@gmail.com received april 2007 accepted august 2007 introduction emphysematous pyelonephritis is an uncommon and severe acute bacterial infection of the kidney. diagnosis is usually made very late due to changing manifestations and infrequent occurrence. on the other hand, xanthogranulomatous pyelonephritis is a rare severe renal infection which typically results in diffused destruction of the kidney in a chronic course. it has been reported that the peak incidence of the disease is between the 4th and 6th decades of life.(1) nonfunctioning kidneys in xanthogranulomatous pyelonephritis have been reported in 50% to 70% of cases, and in 22% to 70%, nephrolithiasis has been an associated finding.(1) according to radiological backgrounds, the disease can mimic the features of a renal tumor. therefore, nephrectomy is the treatment of choice.(1) i report a metachronous occurrence of emphysematous pyelonephritis and xanthogranulomatous pyelonephritis in the contralateral kidney. case report a saudi 50-year-old woman with confirmed diagnoses of diabetes mellitus, hypertension, chronic liver disease, and end-stage renal disease (esrd) was admitted to the emergency room. her chief complaint was right loin pain and fever for the past 2 weeks. urinary symptoms were absent. three years earlier, the diagnosis of atrophic nonfunctioning right kidney had been made for her with a suspicion of left renal tumor (figure 1). left partial nephrectomy had been performed and the histological evaluation had turned out to be xanthogranulomatous pyelonephritis (figure 2). five months after the operation, the patient was figure 1. nonenhanced ct scan is showing atrophic right kidney and left renal mass in the lower pole. emphysematous and xanthogranulomatous pyelonephritis—alshyarba urology journal vol 4 no 4 autumn 2007 249 put on maintenance hemodialysis due to esrd. at presentation, she seemed ill and toxic on physical examination. the body temperature and blood pressure of the patient were 38°c and 80/40 mm hg, respectively. scar of the previous partial nephrectomy was seen on the abdominal wall and mild tenderness in the right loin was detected. results of laboratory investigations were as follows: white blood cells, 10.3 × 109/l; blood hemoglobin, 10.3 g/dl; and platelet count, 155 × 109/l. serum levels of sodium, potassium, urea, and creatinine were 119 mmol/l, 4.9 mmol/l, 59 mmol/l, and 4.5 mmol/l, respectively. serum bicarbonate and ph levels were 9 mmol/l and 7.025 (compensated metabolic acidosis), respectively. urine culture which was repeated twice showed no growth of microorganisms. abdominal ultrasonography revealed multiple hyperechoic foci in the right kidney suggesting intraparenchymal gas. nonenhanced computed tomography (ct) of the abdomen showed an enlarged right kidney with intraparenchymal gas extending to the perinephric fat (figure 3). the left kidney was atrophic with irregular outlines. hence, the diagnosis of emphysematous pyelonephritis of the right kidney was established. after resuscitation of the patient in the operation room, emergent nephrectomy was performed without any complications. postoperatively, the patient became normotensive and acidosis was corrected. the patient developed wound infection which was treated with daily dressing and secondary wound closure. histopathology of the right kidney showed acute pyelonephritis with micro-abscesses. the patient was discharged in a fair condition. discussion emphysematous pyelonephritis and xanthogranulomatous pyelonephritis are rare but severe renal infections. they are accompanied by high rates of morbidity and mortality. they usually present as isolated entities. very few cases have been reported with the association of emphysematous and xanthogranulomatous pyelonephritis in a same kidney.(2-4) langdale and colleagues reported the first case of emphysematous pyelonephritis in a xanthogranulomatous kidney in 1988.(5) the primary factors necessary for the development of emphysematous pyelonephritis are urinary tract infection and a compromised immunity which occur in diabetic patients. few cases, however, have been reported in nondiabetic patients who were either children or patients on immunosuppressant therapy.(6) although the first case of pneumaturia was reported a century before,(7) the pathogenesis of renal tissue damage and gas production is still unknown. glucose fermentation by the uropathogens and production of gases such as carbon dioxide and nitrogen has been implicated. high mortality rate of emphysematous pyelonephritis has been attributed to the septicemia and the hypothesis of the gas transport. management of patients with emphysematous pyelonephritis has been a subject of controversy. huang and tseng reviewed the management of 48 patients with emphysematous pyelonephritis. they concluded that for localized emphysematous pyelonephritis (class 1 and 2) according to ct scan, percutaneous drainage with antibiotic treatment figure 2. replacement of renal parenchyma with foamy histiocytes (xanthoma cells) is seen as well as some inflammatory cells (hematoxylin-eosin, × 400). figure 3. nonenhanced ct scan of the same patient shows emphysematous pyelonephritis of the right kidney. emphysematous and xanthogranulomatous pyelonephritis—alshyarba 250 urology journal vol 4 no 4 autumn 2007 can provide a good outcome. for extensive emphysematous pyelonephritis (class 3 and 4) with more benign manifestations, when saving the kidney is possible, percutaneous drainage combined with antibiotic treatment may be attempted because of its high success rate. however, nephrectomy can provide the best management outcome and should promptly be attempted for extensive emphysematous pyelonephritis with a fulminant course.(8) wan and colleagues tried to define the reliable predictors of the outcome of patients with emphysematous pyelonephritis. they found that serum creatinine and platelet count were the most reliable predictors of outcome in patients with emphysematous pyelonephritis.(9) in this case, the occurrence of the emphysematous pyelonephritis and the previous xanthogranulomatous pyelonephritis of the other kidney cannot be explained. the presence of urinary tract infection, however, can be implicated. the decision of prompt nephrectomy for this patient seemed to be justified, although the emphysematous pyelonephritis was localized on ct scan, since the patient was already a case of esrd and was hemodynamically unstable. therefore, attempting percutaneous drainage was not the choice. in conclusion, emphysematous pyelonephritis is a severe life-threatening infection and should be suspected in a diabetic patient presenting with loin pain, fever, and septicemia not responding to antibiotic therapy. immediate diagnosis and proper management can save the patient’s life. conflict of interest none declared. acknowledgement i would like to thank dr mohammad y khan for reviewing this manuscript. i also extend my thanks to dr mahoud r hussein, consultant pathologist at aseer central hospital, for slide preparations and mr jolly mathews for secretarial assistance. references 1. malek rs, elder js. xanthogranulomatous pyelonephritis: a critical analysis of 26 cases and of the literature. j urol. 1978;119:589-93. 2. moríya a, kubota k, morita n. [a case of emphysematous pyelonephritis combined with xanthogranulomatous pyelonephritis]. hinyokika kiyo. 1989;35:295-300. japanese. 3. punekar sv, kinne js, rao sr, madiwale c, karhadkar ss. xanthogranulomatous pyelonephritis presenting as emphysematous pyelonephritis: a rare association. j postgrad med. 1999;45:125. 4. ishigami k, bolton-smith ja, deyoung br, barloon tj. necrotizing fasciitis caused by xanthogranulomatous and emphysematous pyelonephritis: importance of the inferior lumbar triangle pathway. ajr am j roentgenol. 2004;183:1708-10. 5. langdale la, rice cl, brown n. emphysematous pyelonephritis in a xanthogranulomatous kidney. an unusual cause of pneumoperitoneum. arch surg. 1988;123:377-9. 6. al-makadma as, al-akash si. an unusual case of pyelonephritis in a pediatric renal transplant recipient. pediatr transplant. 2005;9:258-60. 7. kelly ha, maccallum wg. pneumaturia. j am med assoc. 1898;31:375. 8. huang jj, tseng cc. emphysematous pyelonephritis: clinicoradiological classification, management, prognosis, and pathogenesis. arch intern med. 2000;160:797-805. 9. wan yl, lo sk, bullard mj, chang pl, lee ty. predictors of outcome in emphysematous pyelonephritis. j urol. 1998;159:369-73. fall 2012 08.pdf 640 | 1department of pediatric nephrology, celal bayar university, manisa, turkey 2department of public health, celal bayar university, manisa, turkey 3department of pediatrics, molecular medicine laboratory, ege university, izmir, turkey gökhan tekin,1 pelin ertan,1 gönül horasan,2 afig berdeli3 spp1 gene polymorphisms associated with nephrolithiasis in turkish pediatric patients corresponding author: pelin ertan, md mithatpaşa cad. 900/15 göztepe, i̇zmir, turkey e-mail address: pelinertan@ hotmail.com tel: +90 236 232 3133 received october 2011 accepted april 2012 purpose: to investigate the association between spp1 gene polymorphisms and nephrolithiasis. materials and methods: a total of 65 pediatric patients and 50 healthy controls were enrolled in this study. two known polymorphisms of the spp1 gene, c.240t > c and c.708c > t nucleotide substitutions, both of which were also known as synonymous aminoacid polymorphisms, d80d and a236a, respectively, at spp1 gene cdna level, were investigated. spp1 gene polymorphism was evaluated using polymerase chain reaction-restriction fragment length polymorphism method. results: dence interval (ci), 1.170 to 3.880; p = .013] and cc genotype distribution (or, 2.946; 95% ci, 0.832 to 10.431; p = .094) and in c.708c > t polymorphism, t allele frequency (or, 2.183; 95% ci, 1.197 to 3.980; p = .011) and tt genotype distribution (or, 3.056; 95% ci, 0.861 to 10.839; p = .084) were found to be higher in the patient group. conclusion: spp1 polymorphisms were found to be associated with nephrolithiasis and it may be suggested that spp1 gene polymorphism could be a useful marker for evaluation of the early genetic risk factor in childhood nephrolithiasis. keywords: osteopontin, nephrolithiasis, spp1 gene, genotype, case-control studies, polymorphism endourology and stone disease endourology and stone disease 641vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l introduction kenvironmental as well as hereditary factors, and crystals involves stages of nucleation, crystal growth, aggregation, and retention in sequence.(1) urinary analyses of kidney stones show that they contain proteinous ingredients, and several reports have emphasized the importance of proteins in preventing nephrolithiasis.(2,3) many macromolecules, organics, and inorganics are known to inhibit stone formation, including tamm-horsfall, glycosaminoglycans, bikunin, calgranulin, and osteopontin.(1) osteopontin (opn) is a 44-kda negatively-charged acidic hydrophilic, multifunctional protein encoded by the spp1 gene that is located on chromosome 4q21-25 and consists (3-5) tissue, including osteoclasts as well as osteoblasts, and in other cell types, such as endothelial, smooth muscles, and epithelial cells.(4,6) osteopontin has many crucial biological functions, including leucocyte function and recruitment, wound repair, cell survival as well as regulation of normal bone resorption and inhibition of urinary crystallization.(1,7) urinary opn may prevent the renal stone formation by detubular epithelial cells. quantitative and structural investigation of opn have been studied in renal stones previously by various researchers in order to determine its genetic heritance.(1,3,7) our aim was to investigate the spp1 gene polymorphism distribution among pediatric patients with nephrolithiasis and to determine its association with nephrolithiasis. materials and methods the study group consisted of 65 turkish pediatric patients with nephrolithiasis who were followed-up in department of pediatric nephrology of celal bayar university, manisa, turkey, and 50 age and gender-matched healthy subjects without a history of nephrolithiasis or a family history of urinary stone disease. urinary ultrasonography was also performed for the control group to demonstrate that they did not have any urinary calculi. the patients and healthy groups without any history of nephrolithiasis were selected from the same geographical area as well as race. blood samples were obtained from both patient and control groups. written informed consents were obtained from parents of all participants. the study was approved by the local ethics committee. molecular analysis tracted from ethylenediaminetetraacetic acid (edta) anticoagulated venous blood using qiaamp dna blood mini kit (qiagen gmbh, hilden, germany) according to manufacturer’s. c.708c > t polymorphism in the 7th of spp1 gene was genotyped by polymerase chain reaction (pcr) and endonuclease digestion.(5) polymerase chain rein pcr strip tubes containing 100 ng genomic dna solution. platinum taq enhancer 2.0 mmol mgcl 2 , 50 mmol/l each of the dgtp, datp, dttp, and dctp (promega), 5 pmol each of forward and reverse primers, and 1.0 u platinum taq polymerase (invitrogen co, paisley, uk). the sequences of the forward and reverse primers were used; 5’-taccctgatgctacagacgagg-3’ and 5’-ctgactatcaatcacatcggaatg-3’, respectively. the cycling conditions comprised a denaturation step at 95 ºc spp1 gene were analyzed on a 2.0% agarose gel prestained with ethidium bromide. genotyping was performed using the alui (new england biolabs, beverly, ma, usa) reand incubated at 37 ºc during a 16-h period. the fragments of 147 + 61 + 44 bp for the tt genotype, 147 + 105 bp for the ct genotype, and four fragments of 105 + 61 + 44 + 42 bp for the cc genotype were separated on a 3% metaphor agarose gel (fmc bioproducts, bioconcept, allschwill, switzerland) stained with ethidium bromide, and visualized under ultraviolet light (figure 1). spp1 gene polymorphisms and nephrolithiasis | tekin et al 642 | dna sequencing method of the spp1 gene oligonucleotide primers were synthesized and purchased from invitrogen (invitrogen, paisley, uk) as the hplc puprimer details were: 5’-reverse-tacgtttcttgcacctctcg 5’-reverseatggcctgagtgtggctatc ggg; 5’-reverse-tgcaaactgtggtttcctagac 5’-reverse-cagactcaaatagatacacattcaacc on corbett palm-cycler gradient thermal cycler (corbett ca) containing 1 μl genomic dna solution, 1.0 u platinium taq with enhancer buffer (invitrogen ltd. paisley, uk), 50 μmol/l each of the dgtp, datp, dttp, and dctp (promega, madison,wi), 5 pmol each forward and reverse primers. the cycling conditions comprised of a hot start at 95 ºc for 45 sec, 58 to 60 ºc (gradient program) for 45 sec, ing to the appropriate protocol. cycle sequencing pcr was performed using bigdye terminator v.3.1 kit as manufacturer’s (pe applied biosystems, foster city, ca). cycle seterminator kit (pe applied biosystems, foster city, ca) were analyzed by abi 3130×l genetic analyzer. dna sequencing was performed in both directions, initiated from the forward, and the reverse primers was used in the initial pcr reaction. the primers design was similar to the one seqscape 2.0 sequencing analysis software was employed used as reference to determine the nucleotide substitution tion to protein structure could be achieved using ncbi prostatistical analysis all statistical analyses were performed with spss software (the statistical package for the social sciences, version 11.0, spss inc, chicago, illinois, usa) using the chidifferent genotypes and their alleles were calculated using logistic regression models. the hardy-weinberg equilibrium test was done for each polymorphism. results the study population consisted of 37 (56.9%) males and 28 (43.1%) females with the male-to-female ratio of 1.37. the mean age of the patient group was 84.4 months (range, 4 months to 17.5 years) and the mean age at diagnosis was 67.2 months (range, 3 to 210 months). twenty-one (32.3%) children were younger than 12 months of age at diagnosis. followup duration was 13 months (range, 1 to 45 months). family history of nephrolithiasis was found in 46 (70.8%) patients. seventeen (26.2%) patients were born from consanguineous marriages. in 15 (23.0%) patients, stones were bilateral, and 29 (44.0%) patients had multiple stones. only common compound. during the follow-up period, 4 (6.1%) figure 1. agarose gel electrophoresis image of c.708c > t polymorphism. well 1 was 100 bp dna ladder ct genotype was indicated in wells 2, 3, and 6. tt genotype was indicated in wells 4 and 8. cc genotype was indicated in wells 5 and 7. endourology and stone disease 643vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l spp1 gene polymorphisms and nephrolithiasis | tekin et al patients had recurrence. genotype distribution and allele frequency of c.240t > c polymorphism was analyzed in each group. in patient group, c allele frequency was higher than in control group (or, 2.13; 95% ci, 1.170 to 3.880; p = .013). regarding genotype distribution, the tc genotype (or, 2.448; 95% ci, 1.066 to 5.622; p = .035) and the cc genotype (or, 2.946; 95% ci, 0.832 to 10.431; p = .094) were higher in the patient group. genotype distribution and allele frequencies of c.240t > c polymorphism are shown in table 1. genotype distribution and allele frequency of c.708c > t polymorphism was analyzed in each group. in patient group, t allele frequency was higher than in control group (or, 2.183; 95% ci, 1.197 to 3.980; p = .011). regarding figure 2. electropherogram for c.240t > c homozygous nucleotide substitution in exon 6 (d80d) of spp1 gene. figure 3. electropherogram for c.240t > c homozygous nucleotide substitution in exon 6 (d80d) of spp1 gene. figure 4. electropherogram for c.708c > t homozygous nucleotide substitution in exon 7 (a236a) of spp1 gene. figure 5. electropherogram for c.708c > t homozygous nucleotide substitution in exon 7 (a236a) of spp1 gene. 644 | genotype distribution, the ct genotype (or, 2.538; 95% ci, 1.102 to 5.848; p = .029) and the tt genotype (or, 3.056; 95% ci, 0.861 to 10.839; p = .084) were higher in the patient group. genotype distribution and allele frequencies of c.708c > t polymorphism are shown in table 2. in case-only analysis of patients with nephrolithiasis, c.240t > c and c.708c > t polymorphisms were found not to be associated with urinary metabolic risk factors, gender, early age at diagnosis, positive family history, consanguinity, stone recurrence, and bilateral or multiple stones (table 3). discussion nephrolithiasis is a commonly known disease threatening the human kind for many years. there are not many studies investigating the genetic role of opn in renal stones. some researchers have been emphasized the importance of the relation between opn and crystal formation. limited number of studies have been conducted on opn gene structure for familial and recurrent renal stones.(7) single nucleotide polymorphisms (snp) of the human opn gene has been reported to be associated with many diseases. (5,8-11) especially, gao and colleagues have investigated 61 polymorphisms and evaluated four haplotypes among these polymorphisms. two of these haplotypes have been identished a light to understand the mechanism of how the opn gene can change the structure of opn molecule.(7) in this study, we have investigated the difference in spp1 gene polymorphisms between patients with nephrolithiasis endourology and stone disease table 1. genotype distribution and allele frequencies of c.240t > c polymorphism in patients and controls. patient control genotype n (%) n (%) odds ratio 95% confidence interval p cc 10 (15.4) 4 (8) 2.946 0.832 to 10.431 .094 tc 27 (41.5) 13 (26) 2.448 1.066 to 5.622 .035* tt 28 (43.1) 33 (66) 1 (ref ) total 55 (100.0) 50 (100.0) allele c 47 (36.2) 21 (21.0) 2.130 1.170 to 3.880 .013* t 83 (63.8) 79 (79.0) 1 (ref ) total 130 (100.0) 100 (100.0) *p < .05 table 2. genotype distribution and allele frequencies of c.708c > t polymorphism in patients and controls. patient control genotype n (%) n (%) odds ratio 95% confidence interval p tt 10 (15.6) 4 (8) 3.056 0.861 to 10.839 .084 ct 27 (42.2) 13 (26) 2.538 1.102 to 5.848 .029* cc 27 (42.2) 33 (66) 1 (ref ) total 55 (100.0) 50 (100.0) allele t 47 (36.7) 21 (21.0) 2.183 1.197 to 3.980 .011* c 81 (63.3) 79 (79.0) 1 (ref ) total 130 (100.0) 100 (100.0) *p < .05 645vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l spp1 gene polymorphisms and nephrolithiasis | tekin et al and normal subjects. two snps in spp1 gene were found to be associated with nephrolithiasis. as was previously stated in literature, although both nucleotide substitutions take place in the sppi gene coding region, this does not mutations. synonymous substitutions between nucleotides in genes produce structurally identical opn. difference may be present in the sequence of transcription factor binding sites and synthesis of the transcription factors suggesting that a change in transcription step may generate differences in the amount of mrna and protein.(12) was thought to be due to reduced synthesis of opn or its incorporation into growing stones with normal amount of synthesis.(13) in a rat model, opn and its mrna were enhanced in rats in which urinary stone formation was induced (14) furthermore, in an urolithiasis model, opn mrna was observed to enhance in ethylene glycol-administered rats.(3) yamate and colleagues investigated the difference in opn dna between normal subjects and patients with urolithiasis. nucleotide substitution of gcc to gct, encoding synonymous ala-250, was reported to be higher in patients with urolithiasis. based on the difference in gene frequency suggested to be a diagnostic method for patients with urolithiasis and a predisposing hereditary factor.(12) gao and coworkers reported that an snp at position 9401 was determined to be seen more frequently in patients with renal stones. hence, they have speculated on the relationship between opn sequence variants and the risk of nephrolithiasis. due to these results, they have stated that there is an association between opn and calcium stones and it might be a candidate genetic marker for evaluating the genetic risk of renal stone disease(15) in our study, we have found no association between urinary metabolic risk factors and opn polymorphisms. there are certain factors indicating that urolithiasis may be related to genetic predisposition, such as family history of urolithiasis, higher incidence of recurrences, and early onset of the disease in such patients, and drag the clinical table 3. genotype distribution and allele frequencies of c.240t > c and c.708c > t polymorphisms and urinary metabolic risk factors. hypercalciuria hyperoxaluria hypocitraturia hyperuricosuria cystinuria hypomagnesuria n (%) 15 (23.1) 14 (21.5) 23 (35.4) 16 (24.6) 9 (13.8) 10 (15.4) 240t > c tt 6 (40.0) 5 (35.7) 9 (39.1) 6 (37.5) 5 (55.6) 5 (50.0) tc 6 (40.0) 2 (14.3) 8 (34.8) 6 (37.5) 3 (33.3) 4 (40.0) cc 3 (20.0) 7 (50.0) 6 (26.1) 4 (25.0) 1 (11.1) 1 (10.0) p 0.8 0.7 0.2 0.4 0.7 0.8 t 18 (60.0) 17 (60.7) 26 (56.5) 18 (56.3) 13 (72.2) 14 (70.0) c 12 (40.0) 11 (39.3) 20 (43.5) 14 (43.8) 5 (27.8) 6 (30.0) p 0.6 0.6 0.1 0.3 0.4 0.5 708c > t cc 6 (40) 5 (35.7) 9 (39.1) 6 (37.5) 4 (50.0) 5 (50) ct 6 (40) 2 (14.3) 8 (34.8) 6 (37.5) 3 (37.5) 4 (40) tt 3 (20) 7 (50.0) 6 (26.1) 4 (25) 1 (12.5) 1 (10) p 0.8 0.7 0.2 0.4 0.7 0.8 c 18 (60.0) 17 (60.7) 26 (56.5) 18 (56.3) 13 (72.2) 14 (70.0) t 12 (40.0) 11 (39.3) 20 (43.5) 14 (43.8) 5 (27.8) 6 (30.0) p 0.6 0.7 0.2 0.3 0.6 0.4 646 | focus to genetic factors.(16,17) however, we have not found any association between family history and early presentation of nephrolithiasis and opn polymorphisms. in a study from turkey performed on adult patients with nephrolithiasis, the association of a236a snp in 7th as well as -593t > a polymorphism in the promoter region with nephrolithiasis was investigated. in this study, the importance of this polymorphism in the promoter region of the spp1 gene is emphasized.(18) tigated in the present study. we have determined that the snp is located on this region. it was aimed to associate the synonymous aminoacid mutation distributions of the more common snp’s d80d and a236a with phenotypic propergene (unpublished data). the study was performed on a low number of patients and and nephrolithiasis (table 1) or between tt genotype and nephrolithiasis (table 2). this may be due to the low number of study sample. the power for the comparison of cc genotype between patients and controls was 21.4% and that was also found 22.3% for the comparison of tt genotype between patients and controls. therefore, this should be studied in greater number of subjects.(19) conclusion ture to investigate the relationship between childhood nephrolithiasis and opn. spp1 polymorphisms were found to be associated with nephrolithiasis and we suggest that opn may be a useful marker evaluating the early genetic risk of childhood nephrolithiasis. although snps were determined sion of opn mrna in urine and blood to further clarify this association. we believe, in the future, further studies on different races and ethnic groups are required to verify nephrolithiasis and opn. conflict of interest none declared. references 1. wesson ja, johnson rj, mazzali m, et al. osteopontin is a critical inhibitor of calcium oxalate crystal formation and retention in renal tubules. j am soc nephrol. 2003;14:13947. 2. tawada t, fujita k, sakakura t, et al. distribution of osteopontin and calprotectin as matrix protein in calcium-containing stone. urol res. 1999;27:238-42. 3. yasui t, fujita k, sasaki s, et al. expression of bone matrix proteins in urolithiasis model rats. urol res. 1999;27:255-61. 4. mazzali m, kipari t, ophascharoensuk v, wesson ja, johnson r, hughes j. osteopontin--a molecule for all seasons. qjm. 2002;95:3-13. 5. forton ac, petri ma, goldman d, sullivan ke. an osteopontin (spp1) polymorphism is associated with systemic lupus erythematosus. hum mutat. 2002;19:459. 6. xie y, sakatsume m, nishi s, narita i, arakawa m, gejyo f. expression, roles, receptors, and regulation of osteopontin in the kidney. kidney int. 2001;60:1645-57. 7. gao b, yasui t, itoh y, et al. association of osteopontin gene haplotypes with nephrolithiasis. kidney int. 2007;72:592-8. 8. shin hd, park bl, cheong hs, yoon jh, kim yj, lee hs. spp1 polymorphisms associated with hbv clearance and hcc occurrence. int j epidemiol. 2007;36:1001-8. 9. erdogan h, mir s, berdeli a, aksu n. renal scarring and osteopontin gene c/t polymorphism in children with primary vesicoureteral reflux. indian pediatr. 2012;49:311-3. 10. niino m, kikuchi s, fukazawa t, yabe i, tashiro k. genetic polymorphisms of osteopontin in association with multiple sclerosis in japanese patients. j neuroimmunol. 2003;136:125-9. 11. mochida s, hashimoto m, matsui a, et al. genetic polymorphims in promoter region of osteopontin gene may be a marker reflecting hepatitis activity in chronic hepatitis c patients. biochem biophys res commun. 2004;313:107985. 12. yamate t, tsuji h, amasaki n, iguchi m, kurita t, kohri k. analysis of osteopontin dna in patients with urolithiasis. urol res. 2000;28:159-66. endourology and stone disease 647vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l spp1 gene polymorphisms and nephrolithiasis | tekin et al 13. yasui t, fujita k, hayashi y, et al. quantification of osteopontin in the urine of healthy and stone-forming men. urol res. 1999;27:225-30. 14. jiang xj, feng t, chang ls, et al. expression of osteopontin mrna in normal and stone-forming rat kidney. urol res. 1998;26:389-94. 15. gao b, yasui t, okada a, tozawa k, hayashi y, kohri k. a polymorphism of the osteopontin gene is related to urinary calcium stones. j urol. 2005;174:1472-6. 16. ertan p, tekin g, oger n, alkan s, horasan gd. metabolic and demographic characteristics of children with urolithiasis in western turkey. urol res. 2011;39:105-10. 17. koyuncu hh, yencilek f, eryildirim b, sarica k. family history in stone disease: how important is it for the onset of the disease and the incidence of recurrence? urol res. 2010;38:105-9. 18. gogebakan b, igci yz, arslan a, et al. association between the t-593a and c6982t polymorphisms of the osteopontin gene and risk of developing nephrolithiasis. arch med res. 2010;41:442-8. 19. dean ag, sullivan km, soe mm. openepi: open source epidemiologic statistics for public health, version 2.3.1. www. openepi.com, updated 2011/23/06, accessed 2012/02/10. 1485vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l adrenal ganglioneuromas: experience from a retrospective study in a chinese population liping li,1,2 jialiang shao,1 jianjun gu,3 xiang wang,1 lianxi qu1,3 corresponding author: lianxi qu, md department of urology, huashan hospital of fudan university, 12 wulumuqi middle road, shanghai 200040, china. tel: +86 21 5288 7080 fax: +86 21 5288 8279 e-mail: qulianxi@medmail.com.cn received november 2012 accepted april 2013 1 department of urology, huashan hospital of fudan university, shanghai 200040, china. 2 department of urology, zhongshan hospital of fudan university, shanghai 200032, china. 3 department of urology, nanhui branch of huashan hospital, fudan university, shanghai 201300, china. purpose:ganglioneuromas(gns)arebenignneoplasmsofcombinedneuralcrest,schwannian,andconnectivetissueorigin,occurringrarelyintheadrenalglands.thepresentstudyis toshareourexperienceregardingdiagnosticandtherapeuticmanagementofthesetumors. materials and methods:adrenalgnsof15patientswerefoundincidentallywithultrasonographyandwereevaluatedsubsequentlywithcomputedtomography(ct)scan.clinicaldata aswellasfollow-updatawerecollectedretrospectively.allthepatientsreceivedoperative resection. results:themeanageofthepatientswas38.4years(range,25-52years;maletofemaleratio,2:1).ofstudysubjects11patientshadunilateralgnontherightside,andtheremaining 4ontheleftside.allbut1patientwereasymptomatic.nohormonalsecretionwasapparent. meansizeofthetumorsinctscanwas6.27cm(range,2.5-14cm),while10werelarger than5cm.eightpatientsunderwentopenadrenalectomyandtheremaining7underwent laparoscopicanterioradrenalectomy.histologically,all15neoplasmswerecompletelydifferentiated,maturegn.wehadnomortalityorsignificantmorbidity.meandurationofhospitalizationwas5.5days(range,3-7days).therewasnorecurrence,duringameanfollowupof5.4years(range,1-10years). conclusion:pre-operativediagnosisofadrenalgnsremainsdifficultmerelyaccordingto physicalexamination.therefore,werecommendcompleteoperativeresectiononcemalignancycannotbeexcludedbypre-operativeanalyses.laparoscopicadrenalectomyisareasonableoption,atleastfortumors≤5cm. keywords:adrenalglandneoplasms;ganglioneuroma;pathology;diagnosis;humans. miscellaneous 1486 | introduction ganglioneuromas(gns)arebenignneoplasmsmainlyoriginatingfromretroperitoneumandposteriormedi-astinumandlessfrequentlyintheadrenals,andare consideredtooccurmorefrequentlyinchildrenoryoungadults. (1-6) clinically, adrenal ganglioneuromas, usually hormonally non-secreting, may be often incidentally found in radiologic findingwithoutanysymptomsorpresentsecondarytopressure effectsonadjacentstructures.therefore,thesizeofadrenalgns islargerthanthoseoftheirmorecommoncounterpartsinthe posteriormediastinum.(7-9)theaimofthisstudyistoshareour experienceregardingdelineatetheclinicalcourse,diagnosticimaging,andoperativetreatmentofprimaryadrenalganglioneuromasinadultsinchina. materials and methods betweenjune1997andjune2011,atotalof15patientswith histologicallyprovenadrenalincidentalomaswereadmittedto departmentofurologyinhuashanhospitaland itsnanhui branch of fudan university, shanghai, china (table).their clinicaldatawerecollectedretrospectively,aswellasfollowupdata.allthepatientswerefoundwithultrasonographyand wereevaluatedsubsequentlywithcomputedtomography(ct) scan.toevaluatethefunctionalstatusoftheadrenaltumors,biochemicalandhormonalscreeningwascarriedoutinallpatients. thestudyprotocolinvolvinghumanmaterialswereapproved bytheinstitutionalethiccommitteeofhuashanhospitaland itsnanhuibranch. results clinical findings themeanageofthepatientswas38.4years(range,25-52years; maletofemaleratio,2:1).allbut1patientwereasymptomatic. asshowninthetable,patient4hadcomplaintsofatypicalupperabdominalpainanda14-cmadrenalmasswasfoundduring ultrasonographicinvestigation.nohormonalsecretionwasapparent.hormonalevaluationrevealedthatcatecholaminelevel waswithinthenormalrangeinallcases.allthe15casesinour serieshadnormokalemia. imaging findings allneoplasmswerereportedasunilateraladrenallesionsand sevenoftenwererightsidedinctscan.meansizewas6.27cm (range,2.5-14cm),while10werelargerthan5cm(table).all cases had a solid appearance and low unenhanced attenuation value,upto30hounsfieldunits(hu).contrastenhancedct scanshowedincreasedattenuationof40huin1.massessurroundbutnotinfiltratemainaortasand/orveininctscanand arteriography(patient4;figures1,a,b,candd).nonewas shownwithcalcification.arteriographyinthispatientshowed thatthemassdidnotinvadethekidneyartery.theremaining neoplasmswerehomogeneous.ctscanshowedevidencesneitherofsurroundingtissueinfiltrationnorregionallymphnode enlargement. treatment allpatientsunderwentcompleteresections,8openand7laparoscopicadrenalectomies.meanoperativetimeofopenprocedureswas90min(range,65-150min).alllaparoscopieswere completed without conversion. mean laparoscopic operative timewas104min(range,70-200min). therewasnomortality,minormorbidityorcomplicationsinour patients.nopatientneededbloodtransfusion.meanduration ofhospitalizationwas5.5days(range,3-7days).therewasno recurrence,duringameanfollow-upof5.4years(range,1-10 years).theabdominalpainofpatient4wasrelievedaftertheadrenalectomy.intheprocedureofpatient4,thetumorwasfound toconglutinatewithposteriorwallofinferiorvenacava,upper poleofrightkidney,righterectorspinaeandpartoftheliver. aftercompleteresectionofthemass,regionallymphnodebetweeninferiorvenacavaandaortawasfoundtobeenlargement andgatherintoamass.itwasimpossibletocompletelyseparate thelymphnodefromthevein.therefore,onelymphnodewas removedtohistopathology.nobloodpressurefluctuationwas foundinallthesurgeryprocedures. histopathology meantumorsizeonpathologicexaminationwas6.93cm(range, 3-15cm)onmaximumdiameter,whilethemeanradiologicpreoperativesizeof6.27cm.alltumorswerenodularandwell encapsulated.thecutsurfacewasstramineousin6casesand tan-whitein9cases.eighttumorswerehardasrubber;theremainingtwotumorsweresoft.microscopically,allneoplasms consistedoffasciclesofschwann-likecellsanddispersedmatureganglioncells(figure2).noneoplasmshowedimmature neuroblasticcellsorareasofpheochromocytoma.nocalcificationswerefound. inpatient4,theneoplasmmacroscopicallyseemedtodestruct thesurroundinggland(figure3).onelymphnodewasremoved fromthatpatientandthehistopathologyshowedmatureganglimiscellaneous 1487vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l adrenal ganglioneuromas | li et al oncells.immunohistochemistrywasemployedinpatients3and 4,showingpositivestainingofganglioncellsforneuron-specific enolase(nse)(figure4),synaptophysinandpositivestainingof schwanncell-specificmarker(s100)(figure5). disscussion neoplasmsofganglioncelloriginincludeneuroblastomas,ganglioneuroblastomas,andgns,amongwhichgnsarebenign neoplasmsofcombinedneuralcrest,schwannian,andconnectivetissueorigin.gnsareconsideredtooccurmorefrequently inchildrenoryoungadults.thelargestseriesofprimarygns camefromtheenzingerandcolleagues,where42%oftheirpatientswerelessthan20yearsoldinaseriesof88gnpatients. (1)otherstudiesalsohadsimilarresults.(2-6)however,only20% (3/15)were≤30yearsold(mean,38.4years)inourseries,which isconcordantwithotherstudieswherethemeanageatdiagnosis tobearound39to50years.(8-10)infact,thisadrenalpathology canaffectallagegroups,includingolderpatients,becausegn patientsareusuallyasymptomaticandwithoutphysicalexaminationsitisdifficulttofindgnsforothermedicalproblems.occasionallygnsmayproducenonspecific,mass-relatedsymptoms,asinpatient4.gnsmaysecretecatecholamineoftenin pediatricganglioneuromasandneuroblastomas,(4,11) but rarely in maturegns,(8-10,12)whichisconsistentwithourfindings. radiologicdiagnosisofadrenalgnonctscanhavebeenwell described that low attenuated ( non-enhanced attenuation below 40 hu ), homogeneous masses which demonstrate slight to moderateenhancement,(5,6,10)andoftensurroundbutnotinfiltratemainaortasand/orvein.ourseriesalsoshowedthisfeature eveninarteriography.approximate2.4to60%ofgncaseswith calcificationshavebeenreportedintheliteratures.(13-15) in our series,therewasnocalcification. itisreportedthatradiologicfindingsareapttounderestimate tumorsize.inourseries,themeanradiologicsizewas6.27cm, whilethemeanhistologicsizewas6.93cm.tumorsize>5cm, heterogeneity,andcalcificationsareconsideredtoberadiologic signsindicatingmalignantadrenaltumor.thelargesttumorof ourserieswasmeasured14cm,andresectedbyopen,transabdominaladrenalectomyduetothesuspicionofcancer.(16-19) however,manyaggressive tumorsshare these features.pretable. clinical and imaging features of the series. patient gender age (years) symptom ct size pre contrast hu post contrast hu functiona status surgical technique histological size (cm) 1 f 45 none (cm) <30 <30 none laparoscopic 3 2 m 30 none 2.5 <30 <30 none laparoscopic 5 3 m 33 none 5 30 30 none open anterior 14 4 m 25 abdominal pain 12 <30 40 none open anterior 15 5 f 41 none 14 <30 <30 none laparoscopic 3 6 f 44 none 3 <30 <30 none open anterior 8 7 m 49 none 7 <30 <30 none open anterior 7 8 f 52 none 6.5 30 30 none open anterior 8 9 m 29 none 8 <30 <30 none laparoscopic 5 10 m 38 none 4.5 <30 <30 none open anterior 5 11 m 31 none 5 <30 <30 none laparoscopic 4 12 f 33 none 4 <30 <30 none laparoscopic 4 13 m 45 none 3.5 <30 <30 none laparoscopic 5 14 m 40 none 4 <30 <30 none open anterior 9 15 m 41 none 8 <30 <30 none open anterior 9 keys: m, male; f, female; ct, computerized tomography; hu, hounsfield unit. 1488 | operativediagnosisofadrenalgnsremainsdifficult.thefinal diagnosisdependedonhistopathology.macroscopically,most gnsarelarge,encapsulatedmassesoffirmconsistencywith a solid, homogenous, grayish-white cut surface. microscopically,gnsmainlyconsistofmatureandmaturingganglionsand schwanncellsinourseries.ourimmunohistochemicalanalysis showedthattheywerecharacterizedbyreactivitywiths100and neuronalmarkerssuchasnse.(1,9,15) fineneedleaspirationbiopsy(fnab)inthediagnosisofadrenal lesions has a long history,(20)however,insufficientmaterial fordiagnosisanditscomplicationsrestrictitsapplication.(21-24) it isonlysuggestedindoubtedmetastaticadrenalcarcinoma.(25-27) nopatientofourserieswasundergonefnab. whenadrenalincidentalomasarefound,completeresectionis figure 1. (a) computed tomography scan showing a right adrenal ganglioneuroma with postcontrast enhancement of 40 hounsfield and surround the renal artery, (b) a right adrenal ganglioneuroma pushing forward inferior vena cava, conglutinating with posterior wall of inferior vena cava and surrounding tissues, (c) the coronal computed tomography scan reconstruction showing a right kidney pushed downward and a vasa vasorum from abdominal aorta to tumor and (d) renal arteriography showing a vasa vasorum from abdominal aorta to tumor. figure 2. mixture of large mature ganglion cells and spindleshaped schwann like cells. hematoxylin and eosin staining ×100, original magnification. figure 3. the neoplasm macroscopically seemed to destruct the surrounding gland. figure 4. neuron-specific enolase positive ganglion cells, stained brown. schwann-like cells are also weakly positive, while adrenal cortical cells are negative. miscellaneous 1489vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l 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radiographics. 1999;19:569-81. 14. guo yk, yang zg, li y, et al. uncommon adrenal masses: ct and mri features with histopathologic correlation. eur j radiol. 2007;62:35970. 15. linos d, tsirlis t, kapralou a, kiriakopoulos a, tsakayannis d, papaioannou d. adrenal ganglioneuromas: incidentalomas with misleading clinical and imaging features. surgery. 2011;149:99-105. adrenal ganglioneuromas | li et al suggestedifthesizeismorethan4cm.(28-30)inourseries,3patientsstronglyrequestedtoresectthetumorsevenwhenthesize waslessthan4cm.prognosisofmatureadrenalganglioneuromasaftersurgeryisterrific.allsurgerieswerecarriedoutwith nomortalityandminimalmorbiditydespitethelargesizeofthe neoplasms.afterameanfollow-upof5.4years(range,1-10 years),norecurrencewasobserved.intheprocedure,complete resectionisrecommendedincaseofmalignanttransformation ofadrenalgn.(31-33) as the laparoscopic approach develops, almost all adrenal massescouldberesectedlaparoscopicallyregardlessofthesize. recently,zografosetandcolleagueshavesucceededtoresect largeadrenalgnwiththesizeupto13cmbytransabdominal laparoscope.(7) conclusion pre-operativediagnosisofadrenalgnsremainsdifficult;therefore,werecommendcompleteoperativeresectiononcemalignancycannotbeexcludedbypre-operativeinvestigations.to weightheprosandconsaccordingtoourexperience,laparoscopicadrenalectomyisareasonableoption,atleastfortumors ≤5cm. acknowledgment lipingliandjialiangshaocontributedequallyinthiswork. conflict of interest none declared. figure 5. schwann cell-specific marker (s100) positive cells stained brown. 1490 | 16. lau h, lo cy, lam ky. surgical implications of underestimation of adrenal tumour size by computed tomography. br j surg. 1999;86:385-7. 17. kouriefs c, mokbel k, choy c. is mri more accurate than ct in estimating the real size of adrenal tumours? eur j surg oncol. 2001;27:487-90. 18. fajardo r, montalvo j, velazquez d, et al. correlation between radiologic and pathologic dimensions of adrenal masses. world j surg. 2004;28:494-7. 19. fassnacht m, kenn w, allolio b. adrenal tumors: how to establish malignancy? j endocrinol invest. 2004;27:387-99. 20. katz rl, shirkhoda a. diagnostic approach to incidental adrenal nodules in the cancer patient. results of a clinical, radiologic, and fine-needle aspiration study. cancer. 1985;55:1995-2000. 21. harisinghani mg, maher mm, hahn pf, et al. predictive value of benign percutaneous adrenal biopsies in oncology patients. clin radiol. 2002;57:898-901. 22. frilling a, tecklenborg k, weber f, et al. importance of adrenal incidentaloma in patients with a history of malignancy. surgery. 2004;136:1289-96. 23. paulsen sd, nghiem hv, korobkin m, caoili em, higgins ej. changing role of imaging-guided percutaneous biopsy of adrenal masses: evaluation of 50 adrenal biopsies. ajr am j roentgenol. 2004;182:1033-7. 24. bülow b, ahrén b; swedish research council study group of endocrine abdominal tumours. adrenal incidentaloma--experience of a standardized 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metastases. report of a case. cancer. 1984;54:357-60. 32. kulkarni av, bilbao jm, cusimano md, muller pj. malignant transformation of ganglioneuroma into spinal neuroblastoma in an adult. case report. j neurosurg. 1998;88:324-7. 33. hayashi y, iwato m, hasegawa m, tachibana o, von deimling a, yamashita j. malignant transformation of a gangliocytoma/ganglioglioma into a glioblastoma multiforme: a molecular genetic analysis. case report. j neurosurg. 2001;95:138-42. miscellaneous u j 02 spring 2012 all 008without adv.pdf 465vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l pediatric percutaneous nephrolithotomy using adult sized instruments our experience masoud etemadian,1 robab maghsoudi,1 1 mohammad reza mokhtari,1 behkam rezaeimehr,1 mohsen shati2 purpose: lithiasis. materials and methods: we retrospectively reviewed the medical records of 38 results: ard pcnl was performed in 8 patients and tubeless pcnl in the next 37 subjects. simultaneous transurethral lithotripsy was done in 9 patients. stone clearance rate had postoperative fever beyond day 1. blood transfusion was required in only one occurred, which were treated conservatively without any adverse sequela. there was (p conclusion: we concluded that pcnl using adult sized instruments was relatively safe in children, with a clearance rate of 67%. we suggest prospective randomized studies to compare mini-perc and adult sized instruments use in pediatric pcnl. keywords: percutaneous nephrolithotomy, child, kidney calculi, treatment outcome corresponding author: robab maghsoudi, md department of urology, hasheminejad kidney center, valinejad st., vanak square, tehran, iran tel: +98 21 8864 4486 fax: +98 21 8864 4497 e-mail: rmaghsudy@yahoo. com received may 2011 accepted august 2011 1hasheminejad clinical research development center (hcrdc), tehran university of medical sciences (tums), tehran, iran 2 school of public health, tehran university of medical sciences (tums), tehran, iran endourology and stone disease 466 | introduction uin developed countries, of which 1% to 3% are children. certain factors, such as anatomical and metabolic abnormalities, small children stone treatment. surgical management of stone has evolved over the past two decades. in the 1980s, most stones have been treated with this modality. although swl is the treatment of choice for stones in children, percutaneous nephrolithotomy tions, including large stone burden, cysteine stones, and residual stones after failed swl or open surgery. by fernstrom and johansson in 1976 and the sides and colleagues with adult sized instrument in 1985. today, pcnl is a well established treatment option for pediatric nephrolithiasis. concerns about major complications and sequelae of renal puncture with adult sized instruments lead to the design of small sized instruments and the mini-perc technique. nonetheless, singlecrease in the tract site. wadhwa and associates and dmsa scans pre-operatively and 3 months after the procedure, and showed that adult sized instruments had no adverse effect on renal funcfunction improved after stone removal and there was no new scar on renal dmsa scan after standard pcnl. similarly, other studies using radioisotope scans found no change in differential renal cant increase in gfr in the long-term follow-up after pcnl. li and coworkers prospectively showed that acute vasiveness remains unproven. it is reported that bleeding and transfusion are more common after standard pcnl. in this study, we present our exprience in this area. materials and methods study population we retrospectively reviewed medical records of 38 children younger than 15 years who had unthe pre-operative workup included urinalysis, urine culture, serum level of creatinine, coagulacontrast abominal ct scan. patients with positive antibiotics. prophylactic antibiotics were administered to all other children. surgical technique eter was inserted in retrograde fashion for opacioscopy-guided punctures were made at the lower posterior calyx with the patient in the prone posi30f amplatz sheath based on the degree of hydroinjection and surgeon preferance. intercostal access was obtained by creating skin punctures over the lateral portion of the rib during full expiration. pneumatic and/or ultrasonic stone fragmentation endourology and stone disease 467vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l was done using the swiss lithoclast master. a nephrostomy tube was left in the kidney at the during our experience with standard pcnl, we observed that spontaneous displacement of the nephrostomy tube in some of our patients caused ver, protracted urine leakage, or transfusion; thus, we performed tubeless pcnl in our next subjects. sidual fragments or the presence of fragments less this study was approved by the medical ethics committee of hasheminejad clinical research development center and was fully explained to the patients’ parents. a written informed consent was obtained from all the parents. statistical analysis the data were analyzed using spss software (the statistical package for the social sciences, univariate analyses were perfomed to detect any pendent and independent variables. the 95% conresults percutaneous nephrolithotomy was done on the family history of stone disease in 30% of patients. three patients had history of open surgery and 6 had unsuccessful swl. twelve patients had compelete staghorn stones. mean stone burden was access was gained from the lower posterior calyx access. the tract was dilated to 30f in 33 renal was done in 37 renal units and a nephrostomy tube was inserted in 8 patients. in 37 renal units, there was subcostal access, 7 had intercostal access, and one was a transplanted kidney. simultaneous transurethral lithotripsy was done in 9 patients. table 1 shows patients’ characteristics in a comparison of pre and postoperative parametres in the standard and tubeless groups. based on the table 1. basic information in the tubeless and standard pcnl.* variable tubeless pcnl standard pcnl p gender .033 male female 12 0 side .030 right 22 1 left 15 7 mean age, y 6.3 ± 2.2 mean stone burden, cm 3.0 ± 0.9 2.5 ± 0.5 .19 *pcnl indicates percutaneous nephrolithotomy. percutaneous nephrolithotomy with adult instruments | etemadian et al 468 | eight subjects had postoperative fever beyond day 1 up to 7th postoperative day, and were treated conservatively without any other intervention. no readmission occurred because of fever or other complications. transfusion was required only in one patient because of hb drop below 7 g/dl. mosis sterile water. in a 3-year-old patient with staghorn stone, seizure occurred after tubeless pcnl; workup showed hyponatremia (na = 113 through slow correction of hyponatremia, and discharged from the icu without any adverse tions in the two groups. between tubeless and standard pcnl groups (p < operative fever, stone burden, hb drop, and amgroup differences in hb drop and amplatz size (p access site. disscusion anatomic and metabolic abnormalities in children have made stone recurrence and multiple surgical interventions more likely. to avoid any sequela, less invasive procedures, such as swl and pcnl, are treatments of choice. stone-free rates after pediatric pcnl range from 67% to 100%. large retrospective studies have shown success rates as high as 90% with pcnl monotherapy. mahmud and zaidi achieved a stone-free rate of 60% with pcnl monotherapy, which was improved to 100% with swl sandwich therapy. our stone-free rate was 67% at center over the country, many patients are followed up elsewhere and most of our patients were lost due to long-term follow-up period. our relatively lower stone-free rate can be attributed to more complex stones and usage of a single tract only. although multiple access tracts increase the stone-free rate, we refrained from this approach table 3. frequency of complications in the tubeless and standard percutaneous nephrolithotomy. complication tubeless standard transfusion 1 0 fever 6 2 extravasation 0 0 0 0 0 0 hyponatremia (seizure) 1 0 table 2. pre and postoperative parameters in tubeless and standard percutaneous nephrolithotomy.* parameters tubeless standard p pre-operative hb, g/dl 12.67 ± 1.7 12.71 ± 1.9 .95 postoperative hb, g/dl 11.39 ± 1.6 .65 pre-operative cr, mg/dl 0.73 ± 0.19 .60 postoperative cr, mg/dl 0.63 ± 0.19 .11 mean hb drop, g/dl 1.5 ± 0.69 .24 mean hospital stay, day 3.5 ± 1.1 5 ± 1.6 .001 endourology and stone disease 469vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l to avoid the associated complications. on the other hand, attempts to extract staghorn stones from a single tract can result in nephroscope torque on the renal parenchyma and inadvertent injury and bleeding; therefore, we did not stress on this maneuver. in an effort to decrease renal damage, jackman and colleagues introduced the “mini-perc” technique using a 15f peel-away vascular sheath that needs a smaller skin incision and smaller tract size, and low complication rates and less pain were reported. gunes and associates reported a higher incidence of complications, such as bleeding, in children younger than 7 years with adult sized instruments and standard pcnl. although we did not use the mini-perc technique, our study did tal stay. the reason for lower complications at our center may be that pediatric pcnl is only performed by experienced surgeons. wadhwa and coworkers showed marginal renal function improvement after stone removal on isotope scan. although creatinine level is not a sensetive indicator for small parenchymal damage, access to patients’ renal radioisotope scans was limited due to the retrospective nature of the study; thus, we used increasing serum levels of creatinine as a proxy for renal function. there pre and postoperatively in our subjects. despite encouraging results, concern remains regarding safety of endourologic treatment in pediatric patients and its subsequent effects on the growing kidney. candidates for pediatric pcnl had uti in the past. a history of documented uti was positive in 13.3% of our patients probably because of the general use of antibiotics without any evaluation in febrile children. result in overload and hyponatremia; hence, a should be used to prevent this complication. at the same time, irrigation solutions must be warmed to prevent hypothermia, which can only one subject, who had a prolonged operative time because of a staghorn stone. we had no case of hypothermia, and assume that we can use reversed osmosis sterile water for irrigation in children without fear of hyponatremia, especially in patients with small stone burden. drop and transfusion rate were number and size of the tract. mean hb decrease in our study was ference in hb drop between tubeless and nephrostomy cases or those done with two different amplatz sheath sizes. zeren and associates reported operative time and larger amplatz sheath and stone burden were associated with greater transfusion rates. in line with other studies, the most common complication in our study was fever, which perst postoperative day. only one of our patients with a large culture had fever for 6 days. all the patients with fever were managed conservatively without any intervention. samad and colleagues reported a stone-free rate of 59% with pcnl monotherapy and a 3.6% transfusion rate. only one of our patients or our patients’ higher levels of pre-operative hb. tubeless pcnl is less painful and less troublesome for adults and it shortens their hospital stay. the literature on this subject in the pediatric population is scant. our study showed that percutaneous nephrolithotomy with adult instruments | etemadian et al 470 | less group compared to the standard group. in the pediatric population, urolithiasis is more prevaratio; this may be because of the higher incidence of anatomical abnormalities in the male gender. this study has some limitations, such as lack of a control group, short follow-up period, and low sample size. conclusion in our study, pcnl using adult sized instruments appeared to be safe and effective. however, further prospective randomized studies with larger sample sizes are needed to compare mini-perc with adult sized instruments used in pcnl. conflict of interest none declared. references 1. hiatt ra, dales lg, friedman gd, hunkeler em. frequency of urolithiasis in hospital discharge diagnosis in the united 2. schultz-lampel d, lampel a. the surgical management of 3. kroovand rl. pediatric urolithiasis. urol clin north am. 4. lottmann hb, traxer o, archambaud f, mercier-pageyral b. monotherapy extracorporeal shock wave lithotripsy for the treatment of staghorn calculi in children. j urol. 5. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 6. woodside jr, stevens gf, stark gl, borden ta, ball ws. percutaneous stone removal in children. j urol. 7. jackman sv, hedican sp, peters ca, docimo sg. percutaneous nephrolithotomy in infants and preschool age children: 701. moskovitz b, halachmi s, sopov v, et al. effect of percutaneous nephrolithotripsy on renal function: assessment with quantitative spect of (99m)tc-dmsa renal scintigraphy. j 9. wadhwa p, aron m, bal cs, dhanpatty b, gupta np. critical prospective appraisal of renal morphology and function in children undergoing shockwave lithotripsy and percutane10. mor y, elmasry ye, kellett mj, duffy pg. the role of percutaneous nephrolithotomy in the management of pediatric 11. dawaba ms, shokeir aa, hafez at, et al. percutaneous nephrolithotomy in children: early and late anatomical and 12. li ly, gao x, yang m, et al. does a smaller tract in percutaneous nephrolithotomy contribute to less invasiveness? a 13. gupta np, mishra s, suryawanshi m, seth a, kumar r. comparison of standard with tubeless percutaneous nephroli14. samad l, aquil s, zaidi z. paediatric percutaneous nephro15. sahin a, tekgul s, erdem e, ekici s, hascicek m, kendi s. percutaneous nephrolithotomy in older children. j pediatr 16. zeren s, satar n, bayazit y, bayazit ak, payasli k, ozkeceli r. percutaneous nephrolithotomy in the management of 17. mahmud m, zaidi z. percutaneous nephrolithotomy in children before school age: experience of a pakistani centre. jackman sv, docimo sg, cadeddu ja, bishoff jt, kavoussi lr, jarrett tw. the "mini-perc" technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol. 19. gunes a, yahya ugras m, yilmaz u, baydinc c, soylu a. percutaneous nephrolithotomy for pediatric stone disease-our experience with adult-sized equipment. scand j urol 20. schuster tk, smaldone mc, averch td, ost mc. percutane705. 21. during percutaneous nephrolithotomy: does it matter? j endourology and stone disease 471vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l 22. docimo sg, peters ca. pediatric endourology and laparoscopy. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 4. 9 ed. philadelphia: 23. nephrolithotomy for complex pediatric renal calculus 24. kapoor r, solanki f, singhania p, andankar m, pathak hr. percutaneous nephrolithotomy with adult instruments | etemadian et al v08_no_2_final.pdf point of technique 149urology journal vol 8 no 2 spring 2011 laparoscopic repair of vesicouterine fistula a brief report with review of literature vishwajeet singh,1 pallavi aga mandhani,2 seema mehrotra,3 rahul janak sinha1 urol j. 2011;8:149-52. www.uj.unrc.ir keywords: laparoscopy, fistula, uterus, urinary bladder 1department of urology, csmmu (formerly kgmu), lucknow, india 2department of radiodiagnosis, csmmu (formerly kgmu), lucknow, india 3department of obstetrics and gynecology, queen mary hospital, csmmu (formerly kgmu), lucknow, india corresponding author: rahul janak sinha, ms, mch department of urology, csmmu (formerly kgmu), lucknow, (u.p.), india tel: +91 941 500 3051 e-mail: rahuljanaksinha@rediffmail.com received june 2010 accepted february 2011 introduction vesicouterine fistula (vuf) is a rare type of genitourinary fistula that accounts for 1% to 4% of all reported urogenital fistulas.(1) with the rising rate of lower segment cesarean section (lscs) all over the world, the management of this entity becomes even more important, both from clinical as well as medico-legal points of view.(2) herein, we report the laparoscopic management of a patient with vuf following lscs. case report a 34-year-old woman presented with history of recurrent suprapubic pain, secondary amenorrhea along with menouria following lscs ten years earlier. she developed these complications one month after she underwent the lscs. she had menouria and suprapubic pain at monthly intervals for 3 to 5 days. apart from these symptoms, no other symptoms were reported. physical examination of the abdomen and per-vagina were unremarkable. ultrasonography of the kidney, ureter, and bladder and renal function tests were within normal limits. intravenous urography was unremarkable. cystoscopy revealed an opening of approximately 10 mm in the supratrigonal region (figure 1). cystoscopy was repeated after one week (at the the time she was having menouria) and showed blood clots emerging from a fistulous opening (figure 2). a 6-f figure 2. cystoscopic view of the fistula in supratrigonal region with blood clots. figure 1. cystoscopy showing a round to oval 10-mm opening in the supratrigonal region. laparoscopic repair of vesicouterine fistula—singh et al 150 urology journal vol 8 no 2 spring 2011 ureteral catheter over a j-tip guidewire (0.035”) (terumo; glidewire) was inserted through this opening. with little manipulation, it entered the uterine cavity and coiled inside. in the same operative sitting, hysteroscopy was performed with the aid of a 7.5-f ureteroscope. it confirmed the position of the coiled ureteral catheter and the guidewire inside the uterine cavity. technique this patient was managed by laparoscopic surgery. in lithotomy position, bilateral ureteral orifices and the fistulous opening were catheterized with 6 f ureteral catheters. a 22-f foley catheter was inserted inside the urinary bladder. thereafter, the patient was placed in supine position with the head tilted down. pneumoperitoneum was created and 3 ports were inserted; a 12-mm supraumbilical port for camera and two 5-mm para-rectal ports on either side laterally (halfway between the umbilicus and the anterior superior iliac spine). dissection was started in the vesicouterine peritoneal fold. the bladder was densely adhered to the uterus. a plane between the bladder and uterus was created by sharp dissection. the fistulous tract was identified by the presence of the ureteral catheter entering the uterine cavity. a deliberate cystotomy was made (2 cm wide) in the posterior bladder wall, which was extended downwards to incorporate the fistulous opening in a circumferential manner and this was excised later on. the uterine fistulous opening was closed in interrupted fashion with 3-0 polyglactin suture. the ureteral catheter was pulled out just before the final knots were tied (figure 3). the bladder was repaired in two layers in continuous manner with 3-0 polyglactin sutures (figure 4). the bladder was then gently filled with normal saline to rule out any leak. the uterovesical fold of the peritoneum was mobilized and tucked onto the anterior wall of the uterus to cover the suture line. a 16-f tube drain was inserted in the uterovesical pouch and brought on the surface through the right para-rectal region. results the operation time was 180 minutes and the total blood loss was 50 ml. postoperative course was uneventful and the patient was discharged after one week. foley catheter was removed after 3 weeks. micturating cysto-urethrogram was done following catheter removal and depicted normal bladder contour. post-void film did not show any evidence of contrast extravasation. now, the patient has started menstruating following the operation and is doing well at 6 months of followup period. discussion cesarean section (cs) accounts for more than 75% of vuf(3,4) and menouria is the classical presentation following vuf after emergency cs. our patient had menouria and secondary infertility for 10 years following cs. the figure 3. laparoscopic view of the intracorporeal suturing of the vesicouterine fistula. figure 4. laparoscopic view of the intracorporeal suturing of the cystotomy. laparoscopic repair of vesicouterine fistula—singh et al 151urology journal vol 8 no 2 spring 2011 treatment of choice in such a case is vuf disconnection and closure of the bladder and uterine fistulous openings with interposition graft. our patient was managed by laparoscopic transperitoneal fistula disconnection and closure of the bladder and uterine fistulous openings by intracorporeal suturing with the peritoneal fold as interposition graft. depending on the menstrual flow, jozwik divided vuf into 3 categories: type i with menouria; type ii with menouria and vaginal flow; and type iii with normal vaginal menses.(5) this condition is popularly known as youssef syndrome and characterized by menouria with absence of urinary incontinence and vaginal bleeding.(6) for diagnosis, detailed history, vaginal examination, cystoscopy, cystography, and/ or hysterography are needed. in recent years, new diagnostic modalities, such as transvaginal ultrasonography (with or without doppler study), contrast-enhanced computed tomography scan, and magnetic resonance imaging have been added to the armamentarium for rapid and clear diagnosis.(7-9) conservative management, including continuous bladder drainage with antibiotics and anticholinergics are recommended if the patient is in early postpartum phase and has a small fistula. the success rate of conservative management is less than 5%.(10) open surgical management also has good results.(10,11) the advantages of laparoscopic technique are quicker convalescence, shorter hospital stay, and better cosmetics with similar success rates to open surgery.(12-15) technically, laparoscopy provides better visualization due to the magnification, but intracorporeal suturing is the difficult part of the operation (table). this report points to following unique features not reported earlier in literature: (i) the patient had menouria and secondary infertily for a long duration (10 years); (ii) for the purpose of diagnosis, a ureteral catheter was passed in the uterine cavity under cystoscopic guidance and then with the help of a ureteroscope, hysteroscopy was performed to confirm the fistulous tract; and (iii) vesicouterine peritoneal fold was used as an interposition graft which has not been reported previously. conflict of interest none declared. references 1. ramamurthy s, vijayan p, rajendran s. sonographic diagnosis of a uterovesical fistula. j ultrasound med. 2002;21:817-9. 2. alkatib m, franco av, fynes mm. vesicouterine fistula following cesarean delivery--ultrasound diagnosis and surgical management. ultrasound obstet gynecol. 2005;26:183-5. 3. porcaro ab, zicari m, zecchini antoniolli s, et al. vesicouterine fistulas following cesarean section: report on a case, review and update of the literature. int urol nephrol. 2002;34:335-44. 4. rao mp, dwivedi us, datta b, et al. post caesarean vesicouterine fistulae-youssef syndrome: our experience and review of published work. anz j surg. 2006;76:243-5. 5. jozwik m. clinical classification of vesicouterine fistula. int j gynaecol obstet. 2000;70:353-7. 6. youssef af. menouria following lower segment cesarean section; a syndrome. am j obstet gynecol. 1957;73:759-67. 7. majeed hg, christensen hb, rasmussen kl. [ultrasonically verified vesicouterine fistula]. ugeskr laeger. 2006;168:1037-8. 8. kaaki b, gyves m, goldman h. spontaneous intrapartum vesicouterine fistula. obstet gynecol. 2006;107:449-50. 9. smayra t, ghossain ma, buy jn, moukarzel m, jacob d, truc jb. vesicouterine fistulas: imaging findings in first author (year of publication) no. of cases attempted no. of cases converted to open surgery no. of successful cases by laparoscopic surgery operation time, min blood loss, ml hemal(15) (2001) 2 1 1 140 <100 das mahapatra(13) (2007) 1 1 140 100 to 150 chibber(12) (2005) 2 1 1 220 nr* ramalingam(14) (2008) 1 1 140 50 highlights of published reports on laparoscopic vesicouterine fistula repair. *nr indicates not reported. laparoscopic repair of vesicouterine fistula—singh et al 152 urology journal vol 8 no 2 spring 2011 three cases. ajr am j roentgenol. 2005;184:139-42. 10. hadzi-djokic jb, pejcic tp, colovic vc. vesico-uterine fistula: report of 14 cases. bju int. 2007;100:1361-3. 11. drissi m, karmouni t, tazi k, et al. [vesicouterine fistulas: an experience of 17 years]. prog urol. 2008;18:173-6. 12. chibber pj, shah hn, jain p. laparoscopic o’conor’s repair for vesico-vaginal and vesico-uterine fistulae. bju int. 2005;96:183-6. 13. das mahapatra p, bhattacharyya p. laparoscopic intraperitoneal repair of high-up urinary bladder fistula: a review of 12 cases. int urogynecol j pelvic floor dysfunct. 2007;18:635-9. 14. ramalingam m, senthil k, pai m, renukadevi r. laparoscopic repair of vesicouterine fistula--a case report. int urogynecol j pelvic floor dysfunct. 2008;19:731-3. 15. hemal ak, kumar r, nabi g. post-cesarean cervicovesical fistula: technique of laparoscopic repair. j urol. 2001;165:1167-8. fall 2012 08.pdf 714 | male infertility after transpelvic gunshot wound injury a case of clinical and forensic relevance rafael boscolo-berto,1,2 guido viel,2 daniela i. raduazzo,3 giovanni cecchetto,2 walter artibani4 corresponding author: rafael boscolo-berto, md; febu department of oncological and surgical sciences, urology clinic, university of padova via giustiniani 2 – 35128, padova, italy tel: +39 339 113 1099 fax: +39 049 821 2721 e-mail: boscolorafael@tiscali.it received august 2010 accepted march 2011 1department of oncological and surgical sciences, urology clinic, university of padova, italy 2department of environmental medicine and public health, section of legal medicine and forensic pathology, university of padova, italy 3department of clinical and experimental medicine, university of padova, italy 4urology clinic, university of verona, italy keywords: introduction a active and non-contracepting couple. currently, about 15% of couples suffer from infertility. around 50% of cases of infertility are male factors.(1) clude chromosomal abnormalities, such as klinefelter syndrome, autosomal karyotype ablinked abnormalities, kallmann syndrome, reifenstein syndrome (androgen insensitivity), y microdeletions, unilateral or bilateral absence or abnormality of the vas and renal anomalies, (1) condition subtended to infertility picture, with possible sequelae on inheritors whenever unrecognized in urological daily practice. case report a 35-year-old caucasian man presented to our facility for infertility. his past medical and surgical history revealed only a prior transpelvic gunshot wound injury due to a high-power case report case report 715vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l anterior abdominal wall on an umbilical-pubic and a right inguinocrural route (figure 1). a bullet entrance wound was detectable on the lateral surface of the upper right thigh wound was recognizable a little bit higher on the lateral surappeared normal and vas deferens was bilaterally palpable. semen analysis showed a normal ph (7.5) and volume of ejaculated sperm (3.0 ml). scrotal ultrasonography revealed a normal appearance of the epididymis, vas deferens, and testicular parenchyma. fine-needle biopsy recognized a bilateral normal spermatogenesis, leading to the diagnosis of obstructive azoospermia. therefore, the patient resolutely was asked for a vasa deferens recanalization by bilateral vaso-vasostomy. to evaluate the possible outcome of such a surgical reconstruction, we performed a retrograde and micturitional urethrocystography demonstrating a regular morphology of the urethral segments with an adequate vesical neck opening in the absence of deforming outcomes due to previous surgery (figure 2). to establish the vas deferens length into the pelvis, we performed a simultaneous transperineal ultrasoundguided vesiculography demonstrating the bilateral presence of normal seminal vesicles (figure 3), and an antegrade scrotal vasography surprisingly revealing the vas deferens truncated at the upper level of the scrotum (figure 4), without a pathogenetic correlation with patient’s past clinical history. on this basis, hormonal and genetic evaluation investigated the etiology of what seemed to be a congenital (and not post-traumatic) malformation, especially focusing on eral absence of the vas deferens. while we found no ablating hormone, prolactin, 17-ß-estradiol, and testosterone, screening for cf transmembrane conductance regulator (cftr) gene mutations revealed a heterozygosis for delta f508 mutation on a background of a poly-t genotype of 7t/9t. therefore, the diagnosis was congenital bilateral absence of the vas deferens (cbavd) associated with cftr mutation and poly-t genotype of 7t/9t. as a result, there were no chances for a surgical reconstruction of a spermatic route to regain a natural fertility. nevertheless, it would be possible to obtain pregnancy using the intracytoplasmic sperm injection; hence, we advised endocrinologic and genetic counseling. discussion male side routine investigations for infertility include semen analysis, hormonal determinations, and eventually adfigure 1. appearance of patient on physical examination. the entrance and exit sites of bullet are shown (route of bullet signed with the broken line). figure 2. retrograde and micturitional urethrocystography demonstrating normal bladder and urethra. infertility after transpelvic gunshot wound injury | boscolo-berto et al 716 | (1) initially, an obstructive azoospermia diagnosis was made in our patient. the hypothesized bilateral lesion that occurred to the vas deferens was anatomically compatible with both the primary bilateral transection of the spermatic routes due to the gunshot wound and the outcome of an emergent sur(2) in literature, iatrogenic injury to the vas deferens during the inguinal, pelvic, and scrotal surgery are described as acquired factors of male infertility, and are probably underestimated.(3,4) furthermore, a bilateral transection of the vas deferens in a patient with a cross stab injury to the root of scrotum has been previously reported.(5) erens at the upper level of the scrotum was not compatible with our previous suppositions, raising up the suspicion of a cbavd due to a genetic disorder, as typically occurs in cf. the clinical diagnosis of the absent vas deferens can be missed easily, and all men with azoospermia should unthose with a low semen volume and ph.(6) cftr gene. it is the most common genetic disease of caucasians, as 4% of the general population is carrier of gene mutations. this gene is located on the short arm of chromosome 7, and encodes for a membrane protein functioning as a chloride ion channel, basic for the formation correct development of the ejaculatory duct, seminal vesicle, vas deferens, and distal part of the epididymis. congenital bilateral absence of the vas deferens is associare known and may be found in one or both copies of the cftr gene, sometimes presenting only mild clinical stigmata, especially in heterozygosis. a mild allele associated with cbavd is the rna splice variant named ‘the 5t allele’. this is characterized by a variable number of thymidine residues at the splice acceptor site of intron eight.(7) the 5t allele is associated with the lowest amounts of functional cftr protein, and in patients affected by cbavd is frequently associated with a severe mutation on the other allele, such as the df508 mutation, with an incomplete penetrance.(7-9) ple for cf mutations, determining both the genotypes and the consequent risk to transmit cf by assisted reproduction. indeed, when the female partner is found to be a carrier of cftr, the chance of having a baby with cf will be 25% if the man is heterozygous and 50% if the man is homozygous. even in the case of negative female partner for known mutations, her chance of harboring an unknown mutation is about 0.4%. figure 3. transperineal ultrasound-guided vesiculography demonstrating the bilateral presence of the normal seminal vesicles, without visualization of the vas deferens (arrows). figure 4. antegrade scrotal vasography revealing the vas deferens truncated at the upper level of the scrotum (arrows). case report 717vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l conflict of interest none declared. references 1. rowe pj, comhaire fh, hargreave tb, mahmoud ama. who manual for the standardized investigation, diagnosis and management of the infertile male: cambridge university press; 2000. 2. hudak sj, morey af, rozanski ta, fox cw, jr. battlefield urogenital injuries: changing patterns during the past century. urology. 2005;65:1041-6. 3. sheynkin yr, hendin bn, schlegel pn, goldstein m. microsurgical repair of iatrogenic injury to the vas deferens. j urol. 1998;159:139-41. 4. shin d, lipshultz li, goldstein m, et al. herniorrhaphy with polypropylene mesh causing inguinal vasal obstruction: a preventable cause of obstructive azoospermia. ann surg. 2005;241:553-8. 5. dorairajan ln, kumar s, madhekar n. bilateral transection of the vas deferens: an unusual trauma from a cross stab injury of the scrotum. urol int. 2001;66:169-70. 6. dohle gr, colpi gm, hargreave tb, papp gk, jungwirth a, weidner w. the eau working group on male infertility. eau guidelines on male infertility. eur urol. 2005;48:703-11. 7. daudin m, bieth e, bujan l, massat g, pontonnier f, mieusset r. congenital bilateral absence of the vas deferens: clinical characteristics, biological parameters, cystic fibrosis transmembrane conductance regulator gene mutations, and implications for genetic counseling. fertil steril. 2000;74:116474. 8. costes b, girodon e, ghanem n, et al. frequent occurrence of the cftr intron 8 (tg)n 5t allele in men with congenital bilateral absence of the vas deferens. eur j hum genet. 1995;3:285-93. 9. shin d, gilbert f, goldstein m, schlegel pn. congenital absence of the vas deferens: incomplete penetrance of cystic fibrosis gene mutations. j urol. 1997;158:1794-8; discussion 8-9. infertility after transpelvic gunshot wound injury | boscolo-berto et al v08_no_3_final.pdf urological oncology 197urology journal vol 8 no 3 summer 2011 importance of the number of retreived lymph nodes during cystectomy tahir karadeniz, caner baran, medih topsakal, ender kavukcu purpose: to evaluate the effect of the number of dissected lymph nodes (lns) during radical cystectomy on survival outcomes. materials and methods: medical files of 211 patients who underwent cystectomy between 1996 and 2009 were retrospectively evaluated. seventyfour patients were included in the study and divided into two groups regarding the median number of retrieved lns (median number = 13); 36 patients in the 1st and 38 in the 2nd group. radical cystectomy, urinary diversion, and pelvic ln dissection were done in all the patients. when necessary, adjuvant chemotherapy was applied. kaplan-meier survival analysis was performed to compare survival outcomes of the groups. results: of 74 patients, 67 (90.5%) were men and 7 (9.5%) were women, with the mean age of 61.7 years (range, 39 to 83 years). age distribution, pathologic stages, carcinoma in situ occurrence, adjuvant chemotherapy rates, ln involvement, and median follow-up period were similar in both groups. mean dissected lns number in the 1st and 2nd groups was 6.17 (range, 1 to 12) and 21.6 (range, 13 to 41), respectively. five-year estimated overall survival rates were 24.5% and 60.5% (p = .002) while five-year estimated disease-specific survival rates were 43.7% and 74.4% (p = .049), respectively. conclusion: although exact guidelines are not described, it seems that dissection of high number of lns during radical cystectomy is crucial. urol j. 2011;8:197-202. www.uj.unrc.ir keywords: lymph nodes, lymph node excision, cystectomy, prognosis, transitional cell carcinoma department of 2nd urology, okmeydani training and research hospital, istanbul, turkey corresponding author: caner baran, md okmeydani egitim ve arastirma hastanesi, darul-aceze cad. no:25 okmeydani-sisli, istanbul, turkey tel: +90 212 584 2827 fax: +90 212 221 7800 e-mail: drcanerbaran@hotmail.com received november 2010 accepted may 2011 introduction radical cystectomy plays an important role in the treatment of muscle-invasive bladder cancer. the aim of radical cystectomy is complete eradication of local and regional disease with excision of the bladder, perivesical soft tissues, adjacent organs, and regional lymph nodes (lns). consequently, lymph node dissection (lnd) is considered as one of the most important steps of surgery. exact staging of primary tumor and lns have paramount importance due to the fact that pathologic stage and ln status are the most significant predictors for recurrence-free and overall survival.(1) debate on lnd concerning the extent and curative value is still ongoing in literature.(2) although the number of dissected lns is an important factor in interpretation of accurate nodal status, different cut-off values have been described. (1,3,4) therapeutic effect of lnd is another question that has to be addressed. various studies have indicated the therapeutic effect of lnd and demonstrated the importance of careful lymphadenectomy.(5) impact of the lns on survival outcomes—karadeniz et al 198 urology journal vol 8 no 3 summer 2011 in this study, our radical cystectomy series was retrospectively reviewed and the effect of the number of retrieved lns on survival outcomes was discussed in the light of current literature. materials and methods between 1996 and 2009, 211 radical cystectomy procedures with different indications were performed by a single attending surgeon (t.k.). prior to surgery, a written informed consent was obtained from all the patients, and principals of declaration of helsinki were followed. to analyze a homogeneous group, only those patients with no evidence of ln or distant organ metastasis pre-operatively, who underwent radical cystectomy, pelvic lnd, and urinary diversion for curative intend with transitional cell carcinoma histology, and who did not receive any neoadjuvant chemotherapy were included in the study. according to cystectomy specimen pathology, patients with pt2 or pt3 disease with negative surgical margins and a minimum of one ln reported in pathologic examination were also included. patients without adequate followup period or with peri-operative deaths (0 to 2 months after surgery) were excluded from the study. pathologic stages were determined using the 2002 tnm system and previous pathology reports were reappraised and transformed to 2002 tnm system. standard radical cystectomy and pelvic lnd were performed. en bloc lnd that comprised the external iliac, hypogastric, and obturator lns where the cranial limit was the iliac bifurcation was carried out. the specimens were fixed immediately in formalin and interpreted by different pathologists; however, all pathologic evaluations were made in the same manner. the lns were evaluated microscopically and the number of lns retrieved and tumor containing nodes were noted. during ln evaluation, fat solvent was not applied. all specimens were stained by hematoxylin and eosin. following radical surgery, patients with ln involvement or pt3b disease received adjuvant chemotherapy. all patients were followed up regularly after the surgery with comprehensive metabolic panel as well as computed tomography of the chest, abdomen, and pelvis every 6 months for 2 years and annually thereafter. demographic characteristics and survival outcomes were assessed for all the patients. since the aim of this study was to evaluate the effect of the number of dissected lns on survival outcomes, two groups were formed according to the median number of dissected lns in all the patients (median dissected ln = 13). the 1st group consisted of 47 patients, who had 12 or less retrieved lns, and the 2nd group included 45 patients, who had 13 or more retrieved lns. after data gathering, 92 patients were eligible for the study. however, 11 patients in the 1st and 7 patients in the 2nd groups were lost to the followup and were excluded from the study (statistically insignificant, p = .052). eventually, 74 patients, including 36 patients in the 1st and 38 patients in the 2nd group, met the criteria and remained for the data analysis. statistical analysis was performed with spss software (the statistical package for the social sciences, version 13.0, spss inc., chicago, illinois, usa) using chi-square or fisher’s exact test and mann-whitney u test to compare nonparametric and parametric variables, respectively. the kaplan-meier method was used to calculate the estimated survival rates. the log-rank test p values were used to evaluate the significance of differences in univariate analyses. p values less than .05 were considered statistically significant. results of 74 patients, 67 (90.5%) were men and 7 (9.5%) were women, with the mean age of 61.7 years (range, 39 to 83 years). thirty (40.5%) and 44 (59.5%) patients had pt2 and pt3 disease, respectively. concomitant carcinoma in situ was diagnosed in cystectomy specimens of 27 (36.5%) patients. mean and median dissected lns were 14.4 (range, 1 to 41 nodes) and 13, respectively (figure 1). in total, 18 (24.3%) patients had transitional cell carcinoma involvement in the lns. mean and median number of involved lns were 2.44 (range, impact of the lns on survival outcomes—karadeniz et al 199urology journal vol 8 no 3 summer 2011 1 to 7) and 2, respectively. a total of 24 (32.4%) patients received adjuvant chemotherapy. median follow-up period for all the patients was 20 months. half of the patients (37) were alive at the time the study was planned. in univarite analyses, pt3 pathologic stage and ln involvement showed negative impact on overall and diseasespecific survival (figures 2 and 3). characteristics of the groups constituted according to the median number of dissected lns are presented in table. five-year estimated overall survival rate in kaplan-meier survival analyses was 24.5% in the 1st and 60.5% in the 2nd group (p = .002). furthermore, statistical difference was found in five-year estimated disease-specific survival rates, which were 43.7% and 74.4% in the 1st and 2nd groups, respectively (p = .049; figure 4). moreover, when node-positive patients in both groups were compared, a survival advantage was observed in the 2nd group. estimated overall two-year survival rates p n 36 38 gender .43male 34 33 female 2 5 age, mean (range), y 62.2 (41 to 83) 61.3 (39 to 79) .84 p stage .089pt2 11 19 pt3 25 19 carcinoma in situ (+) 12 15 .58 mean dissected lymph nodes (range) 6.17 (1 to 12) 21.6 (13 to 41) <.001 patients with lymph node involvement 8 10 .79 patients received adjuvant chemotherapy 13 11 .1 median follow-up, months 16 22.5 .13 features of the groups constituted according to median number of dissected lymph nodes. figure 1. distribution of retrieved lymph nodes in 74 patients individually. figure 2. (a) overall and (b) disease-specific survival of 74 patients stratified by pt stage. p = .011 p = .011 a b impact of the lns on survival outcomes—karadeniz et al 200 urology journal vol 8 no 3 summer 2011 in the 1st and 2nd groups were 12.5% and 45.7%, respectively (p = .016). none of the patients in the 1st group with ln metastasis survived for five years. estimated two-year disease-specific survival rate was 20.8% in the 1st and 63.5% in the 2nd group (p = .034). statistical analyses revealed that the 2nd group had a significant advantage in both overall and disease-specific survival rates as well as in nodepositive patients. discussion bladder cancer is a challenging disease for the urologists as the major curative treatment is radical surgery and urologists have the main responsibility in management. therefore, every single determiner of survival has to be taken into consideration in surgical intervention. different variables, such as pathologic stage, ln status, surgical margin status, and the number of dissected lns, have been addressed in literature as factors that may affect survival outcomes.(6) before grouping the patients, we also found a statistically significant survival advantage in patients with pt2 stage and negative lns. surgical margins were figure 3. (a) overall and (b) disease-specific survival of 74 patients stratified by nodal status. a b p = .018 p = .031 figure 4. (a) overall and (b) disease-specific survival of groups stratified by median number of retrieved lymph nodes. a b p = .002 p = .049 impact of the lns on survival outcomes—karadeniz et al 201urology journal vol 8 no 3 summer 2011 not assessed since all the patients with positive surgical margins had already been excluded. in this study, after grouping the patients according to the number of lns, distribution of the patients in compliance with the pathologic stage and ln status was not different. interestingly, although the number of retrieved lns was significantly different in two groups, the number of node-positive patients was not different. leissner and colleagues commented that extended lnd increased nodal staging.(7) herr(8) and abdel-latif and associates(9) also showed a correlation between the number of removed lns and the number of patients detected with positive lns. however, correlation coefficients were low in both studies and diagnostic power of lnd is controversial according to our results, which did not reveal any statistical difference. the rates of patients with positive nodes were 22.2% in the 1st and 26.3% in the 2nd group (p = .79). based on our results, retrieval of more nodes during radical cystectomy does not provide any nodal staging advantage when the groups are compared according to ln-positive patient rates. on the other hand, skinner clearly showed the importance of pelvic lnd three decades ago and commented that lnd can make a difference in patients with metastatic disease.(10) several authors from different centers have also figured the importance of extended pelvic lnd.(7,11) in our study, we found a statistically significant difference between the two groups concerning overall and disease-specific survival rates. similar results have been reported in literature. honma and coworkers stated that removal of 13 or more lns has an advantage in disease-specific survival in node-positive patients.(12) however, their patient group was not homogeneous as they had included patients in every pathologic stage into the study. patients with pt0, pt1, or pt4 which might distort survival outcomes were excluded from our study. additionally, an overall survival advantage between the groups was observed in our study. herr stated that the number of retrieved lns depends on the extent of dissection and also showed a survival advantage with the increase in the number of dissected lns. patients without any ln in pathologic specimen were included as pn0 in his study whereas they had to be defined as pnx.(4) in our study, however, all the patients without any reported lns in pathologic evaluation were excluded. dhar and colleagues reported the results of two referral centers (cleveland clinic and university of bern), where the median numbers of dissected lns were 12 and 22, respectively. they showed a statistically significant difference in survival rates in favor of the university of bern where the extended lnd had been performed. similar to our results when limited lnd was performed, survival outcomes especially in node-positive patients were poorer.(3) different cut-off values for survival benefit from lnd have been mentioned in the literature. stein and coworkers showed that dissection of 15 or more lns yields better recurrence-free survival.(5) herr and associates indicated the removal of at least 11 nodes in order to improve survival outcomes in node-positive patients. (13) defining different cut-off values in different studies is logically normal since when the median numbers of dissected lns are different, so are the minimum number of lns retrieved to observe the survival effect. due to this fact, a cut-off value that would probably differ from other studies in the literature was not established in this study. instead, patients were divided into two groups based on the median number of dissected lns in order to evaluate the effect of the number of retrieved lns on survival. leissner and colleagues also employed a similar grouping in their study and suggested that 16 or more lns should be recovered to identify the ln metastasis. this correlation was only limited to patients with pt3 or pt4 tumor. on the other hand, they reported an increased survival rate when 16 or more nodes are removed.(14) our results are in parallel with all these observations recommending the dissection of more lns during radical cystectomy. limitations of this study are the retrospective design without randomization and limited experience due to restrictive study inclusion criteria. impact of the lns on survival outcomes—karadeniz et al 202 urology journal vol 8 no 3 summer 2011 conclusion our results show a statistically significant survival advantage in patients with higher numbers of dissected lns during radical cystectomy. we recommend that all urologists who perform radical cystectomy for the bladder cancer should attempt to dissect more lns as current literature supports the retrieval of higher numbers of lns, which improves survival rates. conflict of interest none declared. references 1. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001;19:666-75. 2. stenzl a, cowan nc, de santis m, et al. the updated eau guidelines on muscle-invasive and metastatic bladder cancer. eur urol. 2009;55:815-25. 3. dhar nb, klein ea, reuther am, thalmann gn, madersbacher s, studer ue. outcome after radical cystectomy with limited or extended pelvic lymph node dissection. j urol. 2008;179:873-8; discussion 8. 4. herr hw. extent of surgery and pathology evaluation has an impact on bladder cancer outcomes after radical cystectomy. urology. 2003;61:105-8. 5. stein jp, cai j, groshen s, skinner dg. risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: concept of lymph node density. j urol. 2003;170:35-41. 6. herr hw, faulkner jr, grossman hb, et al. surgical factors influence bladder cancer outcomes: a cooperative group report. j clin oncol. 2004;22: 2781-9. 7. leissner j, ghoneim ma, abol-enein h, et al. extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. j urol. 2004;171:139-44. 8. herr hw. superiority of ratio based lymph node staging for bladder cancer. j urol. 2003;169:943-5. 9. abdel-latif m, abol-enein h, el-baz m, ghoneim ma. nodal involvement in bladder cancer cases treated with radical cystectomy: incidence and prognosis. j urol. 2004;172:85-9. 10. skinner dg. management of invasive bladder cancer: a meticulous pelvic node dissection can make a difference. j urol. 1982;128:34-6. 11. karl a, carroll pr, gschwend je, et al. the impact of lymphadenectomy and lymph node metastasis on the outcomes of radical cystectomy for bladder cancer. eur urol. 2009;55:826-35. 12. honma i, masumori n, sato e, et al. removal of more lymph nodes may provide better outcome, as well as more accurate pathologic findings, in patients with bladder cancer--analysis of role of pelvic lymph node dissection. urology. 2006;68:543-8. 13. herr hw, bochner bh, dalbagni g, donat sm, reuter ve, bajorin df. impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. j urol. 2002;167:1295-8. 14. leissner j, hohenfellner r, thuroff jw, wolf hk. lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. bju int. 2000;85:817-23. 1165vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l renal cell carcinoma dwelling upon a renal cyst wall and laparoscopic management yaşar özgök,1 mutlu ateş,1 mustafa burak hoşcan,2 okan i̇stanbulluoğlu,1 şeref başal,1 murat zor1 keywords: renal cell carcinoma; cysts; therapy; laparoscopy; kidney diseases. introduction simple renal cysts are mostly benign and asymptomatic disease and managed conserv-atively. renal cell carcinomas (rcc) sometimes presents as a cystic tumor. at least 4-15 % of renal tumors encountered are cyst-associated renal cell carcinoma (crcc). (1) findings suggestive of malignancy in a renal cyst include thickened, irregular or smooth walls or septa, and enhancement after contrast injection.(2) some cystic rcc are known to arise from simple renal cysts. transformation of a simple renal cyst into rcc, however, is extremely rare.(1,3) according to our knowledge no reports have demonstrated a clinical course of rcc dwelling upon a renal cyst wall (or localized at outer side of cyst wall). we describe a laparoscopic decortication of a simple renal cyst with an overlaying rcc. case report a 70-year old man was found to have a mass dwelling upon a right inferior pole 6 cm renal cyst on computed tomography (ct), in june 2008 with a past history of local-advanced prostate cancer treated with radiotherapy and hormone therapy in 2004. the cyst was categorized as bosniak type 1 by ct when it was first diagnosed. three years later, ultrasonography (usg) showed septations in the cyst but none of the usg was able to reveal a mass until june 2008 (figures 1a and 1b). the cyst has been followed as a simple renal cyst. thereafter a cystic lesion with a contrast enhancing solid focus was revealed by ct 4 years after the first diagnose. laboratory examinations including serum chemistry and urine analyze were within corresponding author: mustafa burak hoşcan, md department of urology, başkent university, alanya research and practice center, 07400 alanya-antalya, turkey. tel: +90 532 436 4855 fax: +90 242 511 2350 e-mail: drburakhoscan@yahoo.com received november 2011 accepted january 2012 1 department of urology, gülhane military medical academy, ankara, turkey 2 department of urology, baskent university, alanya research and practice center, alanya-antalya, turkey case report 1166 | normal limits. prostate specific antigen was normal and ct or bone scintigraphy revealed no local or distant metastasis. right laparoscopic retroperitoneal access was performed. the cyst was at inferior pole. the tumor was overlaying on cyst wall 1 cm away from parenchyma (figure 2). using bipolar coater, cyst decortication together with tumor excision was performed, having security surgical margin minimally 2 cm. pathological examination confirmed the diagnosis of rcc 2.5 cm in diameter, clear cell subtype, grade i (t1n0m0) (figure 3). ct revealed no cystic lesion or tumoral recurrence 6 months after the operation. discussion rcc in cystic kidney disease generally develops on a background acquired cystic kidney disease (ackd),(4,5), particularly in patients with long-term renal failure and dialysis. it may be related with a toxic effect of uremia, but the pathogenesis remains undermined.(6) however, transformation of a simple renal cyst into a rcc is extremely rare. according to a review of the literature of the past several decades, only few cases have been reported. distinctive from others this case shows a natural history of a simple renal cyst to rcc dwelling upon the cyst wall. the mass was unlikely placed at outer side of cyst wall as it has generally been reported at the localization of septum or inner wall of the cyst in literature.(1,3) six cm diameter right renal cystic lesion was found to be simple on initial ultrasound and subsequent ct scan was assigned a bosniak rank of category i, during the follow-up of locally advanced prostate cancer. this right renal simple cyst was followed by usg. the revelation of the mass overlaying on the cyst was possible 4 years after the first ct. during this 4 years time, none of ultrasonic imaging was able to show any mass except thin septations in the cyst revealed at third year of follow-up. although the presence of septations in a renal cyst itself does not imply malignancy, one must exclude the possibility of malignancy in an apparently simple cyst when the lesion progresses to septations. our case emphasizes the importance of recognizing that rcc may occur in a simple renal cyst. further evalucase report figure 1. preoperative ultrasound (a and b) and computed tomography (c) imaging of the cyst. (arrows show the cystic lesion). figure 2. tumor overlaying on the cyst wall (operative field). figure 2. histopathological image of normal cyst tissue and the tumor. 1167vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l rcc in a renal cyst | özgök et al ation like ct or diagnostic laparoscopy is warranted when atypical findings are present. references 1. hartmen ds, davis cj, johns t, goldman sm. cystic renal cell carcinoma. urology. 1986;28:145-53. 2. curry ns. small renal masses (lesions smaller than 3 cm): imaging evaluation and management. ajr. 1995;164:355-62. 3. ljungberg b, holmberg g, sjödin jg, hietala so, stenling r. renal cell carcinoma in a renal cyst: a case report and review of the literature. j urol. 1990;143:797-9. 4. kojima y, takahara s, miyake o, nonomura n, morimoto a, mori h. renal cell carcinoma in dialysis patients: a single center experience. int j urol. 2006;13:1045-8. 5. liu js, ishikawa i, horiguchi t. incidence of acquired renal cysts in biopsy specimens. nephron. 2000;84:142-7. 6. vaseemuddin m, kraus ma. quiz page. acquired kidney disease (ackd) with associated bilateral renal cell carcinoma. am j kidney dis. 2005;46:a48, e47-9. 1114 | use of desipramine for the treatment of overactive bladder refractory to antimuscarinic therapy joel h. hillelsohn, soroush rais-bahrami, neeti bagadiya, mahyar kashan, gary h. weiss corresponding author: joel h hillelsohn, ba the arthur smith institute for urology, hofstra north shore-lij school of medicine, 450 lakeville rd, suite m-41, new hyde park, ny 11040, usa. tel: +1 516 734 8500 fax: +1 516 734 8537 e-mail: jhillelsohn@gmail.com received september 2012 accepted january 2013 hofstra north shore-lij school of medicine, the arthur smith institute for urology, new hyde park, ny, 11042, usa. miscellaneous purpose: to evaluate the use of desipramine in the treatment of overactive bladder (oab). materials and methods: we retrospectively evaluated 43 patients who were treated with desipramine for oab refractory to antimuscarinic therapy. these oab patients were stratified by the presence or absence of bladder pain. results: forty-three patients were evaluated with a mean follow up time of 12.2 ± 4.6 months. the mean age of the patients was 71 ± 16 years. twelve patients (28%) discontinued desipramine, 9 due to perceived lack of efficacy, 2 due to central anticholinergic side effects, and 1 due to the development of oropharyngeal sores. patients were stratified into two subgroups based upon treatment with desipramine for oab alone (n = 29) or oab and bladder pain (n = 14). there was no difference between the groups in regard to sex (p = .34), prior history of radiation (p = .19), side effects (p = .16), and specifically evaluated central anti-cholinergic side effects (p = .66). there was no statistical difference in the self-reported success rate of the medication (p = .48). in the oab plus bladder pain subgroup, 71% of patients reported improvement in their pain. overall, 13 (30%) patients had history of prior pelvic radiation and 10 of those (77%) reported improvement with desipramine. conclusion: desipramine is a potential useful treatment for patients with oab. in addition, it can be used in patients with oab and bladder pain and patients with complex oab such as oab caused by pelvic radiation. keywords: urinary incontinence, urge; cholinergic antagonists; drug therapy; antidepressive agents, tricyclic; treatment outcome. miscellaneous 1115vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction overactive bladder (oab) is a condition character-ized by increased urinary urgency, with or without incontinence.(1) its prevalence has been estimated to range between 11.8% and 14%, slightly lower in men than in women.(2,3) this symptom profile has been shown in several studies to increase with age.(2,4,5) the incidence increases from 10.5% for patients aged 18-24, up to 21.9% for those aged greater than 65 years.(3) in elderly patients who fail conservative treatments for oab, pharmacologic management can be challenging.(6) traditionally, anticholinergic agents such as oxybutynin are used as a first-line pharmacologic treatment.(7) if the patient symptoms are refractory to treatment with traditional first-line anticholinergic agents, tricyclic antidepressants (tcas) such as amitriptyline and imipramine can be prescribed. however, a limitation of all anticholinergic agents on the market is their lack of specificity for muscarinic receptors of the bladder. as a result, central anticholinergic side-effects including memory defects, fatigue, and impaired balance can often be experienced.(6) furthermore; elderly patients are particularly vulnerable to these side-effects associated with the central anticholinergic effects of tcas. this is due in part to an increased anticholinergic load, polypharmacy, a natural age-related decline in cholinergic function, and declining function of the blood brain barrier.(6) desipramine is an active metabolite of imipramine. it is distinguished by the presence of only one n-methyl group on its side chain.(7) it has been shown in several studies to have less central nervous system (cns) side effects than other tca agents including imipramine and amitriptyline.(7-9) no published study has evaluated the use of desipramine as a treatment for oab. herein, we report on our experience with desipramine for the primary treatment of symptomatic oab with the goal of minimizing cns-related side-effects. materials and methods data collection data was prospectively collected on patients that were prescribed desipramine by a single physician (ghw) for the second-line treatment of oab over a two year period spanning between 2010 and 2011. diagnosis of oab was based upon established aua guidelines.(10) patients were informed about the off-label use of desipramine for this purpose. an inclusion criterion was oab refractory to prior anticholinergic treatment. patient demographics, clinical characteristics, and patient-reported outcomes, and side-effect profiles while taking desipramine were retrospectively reviewed. patients were followed serially at monthly visits to assess the therapeutic effects as well as side effects of the medication regimen. data collection and analysis for this study was approved by the institutional review board (irb) and all patient data was stored in a secure patient de-identified database in accordance with the irb approval. statistical analyses all statistical analyses were conducted on microsoft excel 2007 platform. continuous and categorical variables were analyzed using mann-whitney u test and chi-squared test, respectively. results forty-three patients were evaluated who were prescribed desipramine after failing treatment with at least one antimuscarinic agent. failure from an antimuscarinic agent was determined through chart review. the initial dosing of all patients was 10 mg. the range of final dosing was 10 mg to 75 mg. two patients (5%) dosages were raised to 25 mg, 3 (7%) to 50 mg and 1 (2%) to 75 mg. their dosages were raised based on clinical evaluation of patient self-reported symptom benefit and side effects. the mean age of the patients was 71 ± 16 years (table 1). twenty-three patients (53%) were male and 20 (47%) were female. overall, 13 (30%) patients had history of prior pelvic radiation and 10 of those (77%) reported improvement with desipramine. thirty-one (72%) of the original 43 patients continue to take desipramine as prescribed at a mean follow up of 12.2 ± 4.6 months, reporting clinical benefit and improvement of their oab symptoms. twelve patients (28%) discontinued desipramine, 9 (75%) due to perceived lack of efficacy, 2 (17%) due to central anticholinergic side effects, and 1 (8%) due to the development of oropharyngeal sores. the average duration of compliant use of the medication in these patients who discontinued use was calculated at 6 ± 3.4 months. overall, 12 patients use of desipramine for overactive bladder | hillelsohn et al 1116 | reported side effects from the medication, the most common being dry mouth (n = 5, 42%), constipation (n = 2, 17%), and fatigue (n = 3, 25%). furthermore, patients were stratified into two subgroups based upon desipramine treatment for oab alone (n = 29) or oab combined with bladder pain (n = 14) (table 2). there was no difference noted between the groups in regard to sex (p = .34), prior history of pelvic radiation (p = .19), side effects (p = .16), and specifically assessed central anticholinergic side effects (p = .66). however, the oab plus bladder pain group was significantly older (p = .05). there was no statistical difference in the self-reported success rate of the medication (p = .48). in the oab plus bladder pain group 10 (71%) patients reported improvement in their pain in addition to oab symptoms. discussion cns side effects from treatment with anti-muscarinic agents include headache, fatigue, dizziness, cognitive impairment, confusion, and insomnia.(11) tcas have similar side-effects due to their adjunct anticholinergic properties.(11-13) more elderly patients are more likely to suffer from oab and are also more likely to experience anticholinergic side-effects from the medications used to treat their symptoms.(12) this increased risk is commonly attributed, at least in part, to polypharmacy which is more prevalent in this population with more comorbidity. gardner and colleagues estimated that between 21% and 32% of nursing home residents are simultaneously prescribed two or more medications with anticholinergic activity.(3,13) in addition, the elderly may have diminished efficiency of drug metabolism and elimination, leading to an increased anticholinergic “load” effectively.(14) delirium can be caused by blockage of brain muscarinic receptors and drugs with anticholinergic activity are the most common cause of drug-induced delirium.(15,16) among the tca agents, desipramine has been noted to have the least anticholinergic affect.(15) in initial clinical trials, it was noted to have less cns side effects when compared to imipramine.(9) these findings were corroborated in two subsequent studies.(7,11) a randomized control trial of 20 patients comparing imipramine and desipramine use for the treatment of major depression, found that although desipramine was not superior to imipramine in its treatment of depression symptoms, it is less likely to produce central anticholinergic side effects such as headache, tremors, and dizziness.(10) di mascio and colleagues enrolled 7 blinded subjects who were given either a dose of imipramine (50 mg, 100 mg or 200 mg) desipramine (50 mg, 100 mg, and 200 mg) or a placebo. subjects were then tested performing various cognitive and visoumotor tasks such as typing, aiming and performing calculations. they found that imipramine produced marked impairment in intellectual and visuo-motor function in comparison to desipramine.(7) desipramine has also been compared to amitriptyline in headto-head investigation. in a double blinded crossover study by blackwell and colleagues, nine healthy female volunteers table 1. baseline characteristics of patients prescribed desipramine for overactive bladder. patients number 43 male 23 female 20 age ± sd, years 71 ± 16 side effects, n (%) 12 (28) central anticholinergic side effects, n (%) 7 (16) prior pelvic radiation, n (%) 13 (30) patients doing well on medication, n (%) 31 (72) key: sd, standard deviation. table 2. comparison of patients prescribed desipramine for overactive bladder only and for overactive bladder plus bladder pain. oab only oab and bladder pain p number 29 14 male 18 5 .19 female 11 9 age ± sd, years 68.4 ± 18.0 76.7 ± 8.5 .05 side effects, n (%) 6 (21%) 6 (43) .16 central anticholinergic side effects, n (%) 4 (14) 3 (21) .66 with prior pelvic radiation, n (%) 9 (31.0) 4 (28.6) .34 patients doing well on medication, n (%) 22 (75.8) 9 (64.3) .48 key: sd, standard deviation; oab, overactive bladder. miscellaneous 1117vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l use of desipramine for overactive bladder | hillelsohn et al were given three different doses of desipramine (25 mg, 50 mg, and 100 mg), three different doses of amitriptyline (25 mg, 50 mg, and 100 mg) and placebo. the patients then were asked to rate their sedation on clyde mood scale. amitriptyline was noted to produce more sedation at all levels and was clinically significant at 50 mg (p < .01).(8) in a study of pigeons by vaillant, the central anticholinergic effects of desipramine, amitriptyline and imipramine were assessed by measuring their ability to mask the central muscarinic effects of physostigmine.(17) desipramine was found to be the least effective in cns function of the tcas tested, requiring the highest dose to reverse the central muscarinic activity of physostigmine. furthermore, in a study by abernethy and colleagues, metabolic clearance of desipramine was found to be less affected by increasing age than that of imipramine.(18) in consideration of its decreased central anticholinergic activity, we sought to report on the use of desipramine for patients with oab refractory to treatment with first-line antimuscarinic agents. to our knowledge this is the first study reporting on the use of desipramine for oab. our results indicate that it is well tolerated in a population of patient’s refractory to antimuscarinic therapy. also significant was that 77% of patients with prior history of pelvic radiation reported improved symptoms following desipramine treatment, as this population can be difficult to treat.(21) furthermore, only two patients discontinued the medication due to central anticholinergic side-effects and the vast majority (72%) reported improvement on the prescribed therapy with desipramine. patients with bladder pain and oab can be difficult to manage, since many of them can fall into the interstitial cystitis/ bladder pain syndrome (ic/bps) spectrum.(19) for ic/bps patients’ amitriptyline has been the most extensively tca agent studied. in a large double blinded randomized control trial by foster and colleagues comparing behavior modification and education with and without amitriptyline, they found that patients who could tolerate a low dosing (25 mg) had significant benefit from the drug.(20) desipramine has also been studied in the setting of ic/pbs. renshaw reported on the successful use of desipramine in a single patient.(21) in our study we reported 71% of patients subjectively reported an improvement in their bladder pain. our study is limited by its retrospective nature and singlearm design which cannot fully access the comparative efficacy of desipramine as a single-agent treatment modality for oab. future, prospective randomized studies are needed on this topic to fully elucidate the utility and side-effect profile of desipramine over other agents as a treatment option for oab. conclusion our experience to date has demonstrated desipramine as a useful potential treatment for patients with oab refractory to first-line antimuscarinic therapy, possibly providing an alternative treatment modality with a mechanistically minimized risk of cns side-effects compared to other tcas. conflict of interest none declared. references 1. van kerrebroeck p, abrams p, chaikin d, et al. the standardization of terminology in nocturia: report from the standardization subcommittee of the international continence society. bju int. 2002;90:11-5. 2. irwin de, milsom i, hunskaar s, et al. population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the epic study. eur urol. 2006;50:1306-14. 3. herschorn s, gajewski j, schulz j, corcos j. a populationbased study of urinary symptoms and incontinence: the canadian urinary bladder survey. bju int. 2008;101:52-8. 4. brown js, grady d, ouslander jg, herzog ar, varner re, posner sf. prevalence of urinary incontinence and associated risk factors in postmenopausal women. heart & estrogen/ progestin replacement study (hers) research group. obstet gynecol. 1999;94:66-70. 5. corcos j, schick e. prevalence of overactive bladder and incontinence in canada. can j urol. 2004;11:2278-84. 6. chancellor m, boone t. anticholinergics for overactive bladder therapy: central nervous system effects. cns neurosci ther. 2012;18:167-74. 7. dimascio a, heninger g, klerman gl. psychopharmacology of imipramine and desipramine: a comparative study of their effects in normal males. psychopharmacologia. 1964;5:361-71. 8. blackwell b, stefopoulos a, enders p, kuzma r, adolphe a. anticholinergic activity of two tricyclic antidepressants. am j psychiatry. 1978;135:722-4. 1118 | 9. ban ta, lehmann he. clinical trial with desmethylimipramine (g-35020), a new antidepressive compound. can med assoc j. 1962;86:1030-1. 10. gormley ea, lightner dj, burgio kl, et al. diagnosis and treatment of overactive bladder (non-neurogenic) in adults: aua/sufu guideline. available from: http://www.auanet. org/content/media/oab_guideline.pdf. 11. edwards g. comparison of the effect of imipramine and desipramine on some symptoms of depressive illness. br j psychiatry. 1965;111:889-97. 12. remick ra. anticholinergic side effects of tricyclic antidepressants and their management. prog neuropsychopharmacol biol psychiatry. 1988;12:225-31. 13. staskin dr, zoltan e. anticholinergics and central nervous system effects: are we confused? rev urol. 2007;9:191-6. 14. glassman ah, carino js, roose sp. adverse effects of tricyclic antidepressants: focus on the elderly. adv biochem psychopharmacol. 1984;39:391-8. 15. mintzer j, burns a. anticholinergic side-effects of drugs in elderly people. j r soc med. 2000;93:457-62. 16. feinberg m. the problems of anticholinergic adverse effects in older patients. drugs aging. 1993;3:335-48. 17. vaillant ge. clinical significance of anticholinergic effects of imipramine-like drugs. am j psychiatry. 1969;125:1600-2. 18. abernethy dr, greenblatt dj, shader ri. imipramine and desipramine disposition in the elderly. j pharmacol exp ther. 1985;232:183-8. 19. wein aj, kavoussi lr, campbell mf. campbell-walsh urology / editor-in-chief, alan j. wein; [editors, louis r. kavoussi ... et al.]. fundamentals of laparoscopic and robotic urologic surgery. 10th ed. philadelphia, pa: elsevier saunders; 2012. p. 358. 20. foster he jr., hanno pm, nickel jc, et al. effect of amitriptyline on symptoms in treatment naive patients with interstitial cystitis/painful bladder syndrome. j urol. 2010;183:1853-8. 21. renshaw dc. desipramine for interstitial cystitis. jama. 1988;260:341. miscellaneous kidney transplantation 14 urology journal vol 4 no 1 winter 2007 pregnancy and kidney transplantaion— yassaee et al urology journal vol 4 no 1 winter 2007 15 pregnancy outcome in kidney transplant patients fakhrolmolouk yassaee, farnaz moshiri introduction: advances in surgical techniques and immunosuppressive therapy have improved the survival and quality of life in organ transplant patients. thus, the number of organ transplant women at their reproductive age has also increased. we sought to investigate the allograft and obstetric outcomes in pregnant kidney recipients. materials and methods: seventy-four kidney recipient women with 95 conceptions during their posttransplant period were evaluated. pregnancy outcome, kidney allograft function, and maternal, fetal, and neonatal complications were evaluated in these patients. results: the mean interval between kidney transplantation and pregnancy was 41.0 ± 9.5 months. twenty-three pregnancies (24.2%) were unsuccessful due to abortion and stillbirth. the mean birth weight was 2385.0 ± 161.7 g and 45 newborns (62.5%) had a birth weight less than 2500 g (low birth weight). the mean apgar score of the live babies was 7.9 ± 0.7. forty-four (61.1%) babies were admitted to neonatal intensive care unit and early neonatal death happened in 4 (5.5%). fifteen mothers (15.78%) had an uneventful perinatal period. the most common maternal complications in the 95 pregnancies were anemia in 62 (65.3%) and preeclampsia in 45 (47.4%). three patients 3 (3.2%) lost their graft and 6 (6.3%) had impaired kidney allograft function 2 years after pregnancy. conclusion: pregnant kidney allograft recipients should be considered as highrisk patients needing special care under the supervision of a team of obstetricians and nephrologists. urol j (tehran). 2007;4:14-7. www.uj.unrc.ir keywords: kidney transplantation, pregnancy, complications, allograft dysfunction, live birth department of obstetrics and gynecology, perinatology center, taleghani hospital, shaheed beheshti university of medical sciences, tehran, iran corresponding author: fakhrolmolouk yassaee, md department of obstetrics and gynecology, taleghani hospital, velenjak, tehran, iran tel: +98 21 2240 0205 fax: +98 21 2240 3694 e-mail: dr_fyass@yahoo.com received april 2006 accepted october 2006 introduction in the past, pregnancy was considered to be a serious hazard after kidney transplantation, especially because of possible side effects of the immunosuppressive drugs on the development of fetus and the risk of worsening of the mother’s kidney function. now, the number of the papers reporting successful pregnancies in kidney-transplanted mothers is increasing. ovarian dysfunction, anovulatory vaginal bleeding, amenorrhea, high prolactin levels, and loss of libido are the causes of infertility in women with chronic kidney failure. endocrine function generally improves after recovery of the kidney allograft function.(1) reportedly, fertility rate, being 1:200 in patients under dialysis, reaches 1: 50 in kidney transplant recipients.(2) the criteria of a safe pregnancy in kidney-transplanted patients include transplantation at least 1.5 to 2 years before pregnancy,(2-5) good kidney function (serum creatinine level less than 1.5 mg/dl),(1,5,6) no recent acute allograft rejection,(6) normal blood pressure or use of minimum dose of antihypertensive drugs,(1,3,6,7) negative urinary protein or minimum kidney transplantation 14 urology journal vol 4 no 1 winter 2007 pregnancy and kidney transplantaion— yassaee et al urology journal vol 4 no 1 winter 2007 15 protein excretion,(1,3,7) normal kidney allograft on ultrasonography,(6) prednisolone dose less than 1.5 mg, and cyclosporine dose within the therapeutic level.(5) even if all these consideration are followed, pregnancy can be a high-risk condition in kidney allograft recipients. nonetheless, most authors have reported encouraging obstetrics and graft outcomes.(5-15) the aim of this study was to investigate pregnancy outcomes and kidney allograft function in 74 female kidney transplant patients. materials and methods in this retrospective study, we reviewed the records of 74 kidney recipient women at their reproductive age (18 to 38 years) who had 95 conceptions during their posttransplant period. data were collected between 1996 and 2001, from 3 university hospitals with transplant departments in tehran. all patients had received their kidney allografts from living donors. pregnancy outcome, kidney allograft function, and maternal, fetal, and neonatal complications were evaluated in these patients. their kidney allograft function was assessed during the 2 years after pregnancy. results the outcomes of 95 pregnancies were evaluated in 74 kidney transplant women. the mean age of the patients was 29.3 ± 6.7 years (range, 18 to 38 years). the mean interval from kidney transplantation to pregnancy was 41.0 ± 9.5 months (range, 22 to 59 months) and the mean interval from kidney transplantation to delivery was 49.5 ± 10.1 months (range, 30.5 to 68 months). overall, 17 pregnancies (17.89%) were unplanned, while 25 (26.3 %) patients had preconception counseling. seventy-two pregnancies (75.8%) ended in live birth and 23 (24.2%) were unsuccessful due to abortion in 21 (91.3%) and stillbirth in 2 (8.7%). of 21 abortions, 16 (76.2%) were spontaneous and 5 (23.8%) were therapeutic. fourteen (18.9%) babies were vaginally delivered and the remainders were born through cesarean section (81.1%). the mean birth weight was 2385.0 ± 161.7 g and 45 newborns (62.5%) had a birth weight less than 2500 g (low birth weight). the mean apgar score of the live babies was 7.9 ± 0.7. forty-four (61.1%) babies were admitted to neonatal intensive care unit and early neonatal death was reported in 4 (5.5%). table 1 demonstrates the fetal/neonatal complications. the perinatal period was uneventful in 15 mothers (15.78%). the most common complication was anemia in 62 mothers. overall, 2 patients (2.7%) lost their graft and 6 (8.1%) had impaired kidney allograft function (serum creatinine > 2mg/dl) 2 years after pregnancy. complications in the patients are listed in table 2. discussion according to our study, pregnancy in women with kidney transplantation can be safe. this finding is in accordance with the study of pezeshki and colleagues who concluded that pregnancy was possible and could be safe and successful after kidney transplantation in recipients with normal kidney function.(8) deterioration of the kidney function occurred in table 1. complications in fetuses or neonates of conceived kidney allograft recipients complication number (%) ectopic pregnancy 0 abortion spontaneous 16 (16.8) therapeutic 5 (5.3) stillbirth 2 (2.1) preterm delivery 21 (22.1) oligohydramnios 4 (4.2) intrauterine growth retardation 3 (3.2) low birth weight 45 (47.4) small for gestational age 6 (6.3) congenital abnormality 0 admission to neonatal intensive care unit 44 (46.3) table 2. complications in kidney recipient mothers and kidney allografts* *percents are in proportion to the 95 pregnancies. †serum creatinine level greater than 2 mg/dl, 2 years after pregnancy. complication number (%) kidney allograft dysfunction graft loss 3 (3.2) acute rejection 2 (2.1) recurrent glomerulonephritis 1 (1.1) allograft dysfunction� 6 (6.3) other complications anemia 62 (65.3) preeclampsia 45 (47.4) aggravation of hypertension 34 (35.8) urinary tract infection 16 (16.8) obstruction of transplanted ureter 1 (1.1) pregnancy and kidney transplantaion— yassaee et al 16 urology journal vol 4 no 1 winter 2007 pregnancy and kidney transplantaion— yassaee et al urology journal vol 4 no 1 winter 2007 17 only 6 cases (6.31%) within 2 years after the delivery that is in accordance with the studies of o’connell and coworkers and rudolph and associates.(6,7) even, some studies reported no deterioration of the kidney function.(1,4,5,9-11) basaran and colleagues showed that pregnancy had no negative impact on kidney allograft function during a 2-year follow-up and no acute rejection episode occurred in their study.(1) in our study, impaired kidney allograft function and acute rejection occurred in 6 (6.31%) and 2 (2.1%) subjects, respectively. allograft rejection during or after pregnancy is reported by most studies.(7,11-15) however, bar and associates observed no rejection episode during or after conception.(3) rowemeier and colleagues studied 13 pregnant women after kidney transplantation. their findings indicated that pregnancy after kidney transplantation is associated with a high risk for both mother and child. an irreversible elevation in serum creatinine concentration occurred in 5 women and hypertension aggravated in 8, which was similar to our finding (3.2% graft loss). they concluded that pregnancy requires an intensive joint care between the obstetrician, pediatrician, and nephrologist in these women.(12) numerous studies showed that the incidence of spontaneous abortion and preterm deliveries in kidney transplant women was higher than that in healthy individuals. babies delivered by these patients had a lower birth weight, but no congenital defects were noted.(1-4,6,7,9-17) in our series, 6 newborns (6.3%) were small for gestational age and 3 (3.2%) had intrauterine growth retardation (iugr). we did not detect any congenital abnormalities either. maternal anemia and superimposed hypertension may be the causes of iugr and low birth weight in these babies.(9,12-14) these 2 complications were frequent in our patients. prematurity is a frequent condition in posttransplant conceptions and is related to kidney dysfunction and the time interval from transplantation to conception. we noted premature rupture of the membranes and preterm deliveries in 21 cases (22.1%), which is in accordance with other studies.(3,7,8,13,14) as we observed in our patients, the number of admissions to the neonatal intensive care unit would be increased due to preterm deliveries. little and colleagues found that of 23 live births in transplant cases, 73.9% were premature, 65.2% were of low birth weight, and 61% were admitted to the neonatal intensive care unit.(11) furthermore, the rate of cesarean section would be increased due to complications such as prematurity, preeclampsia, and iugr.(4) in our study, 60 (81.1%) deliveries were performed through cesarean section. overall, if pregnancy is not desired, effective contraception must be used to prevent unwanted conception.(17) conclusion our study confirms that kidney allograft recipients can have a successful pregnancy after transplantation and give birth to healthy infants, but these are to be regarded as high-risk pregnancies and require a multidisciplinary approach. conflict of interest none declared. references 1. basaran o, emiroglu r, secme s, moray g, haberal m. pregnancy and renal transplantation. transplant proc. 2004;36:122-4. 2. tommasi gv, casolino v, fontana i, et al. [pregnancy in women undergoing a kidney transplant. our experience and a review of the literature]. minerva ginecol. 1996;48:553-6. italian. 3. bar j, wittenberg c, hod m, et al. pregnancy outcome in renal allograft recipients in israel. israel j med sci. 1996;32:1183-5. 4. saito s, sakagami k, fujiwara t, et al. successful pregnancy in renal transplant recipients. acta med okayama. 1993;47:347-9. 5. gaughan wj, moritz mj, radomski js, burke jf jr, armenti vt. national transplantation pregnancy registry: report on outcomes in cyclosporine-treated female kidney transplant recipients with an interval from transplant to pregnancy of greater than five years. am j kidney dis. 1996;28:266-9. 6. o’connell pj, caterson rj, stewart jh, mahony jf. problems associated with pregnancy in renal allograft recipients. int j artif organs. 1989;12:147-52. 7. rudolph je, schweizer rt, bartus sa. pregnancy in renal transplant patients: a review. transplantation. 1979;27:26-9. 8. pezeshki m, taherian aa, gharavy m, ledger wl. menstrual characteristics and pregnancy in women after renal transplantation. int j gynaecol obstet. 2004;85:119-25. 9. tan pk, tan as, tan hk, vathsala a, tay sk. pregnancy after renal transplantation: experience in singapore general hospital. ann acad med singapore. 2002;31:285-9. pregnancy and kidney transplantaion— yassaee et al 16 urology journal vol 4 no 1 winter 2007 pregnancy and kidney transplantaion— yassaee et al urology journal vol 4 no 1 winter 2007 17 10. horcickova m, reneltova i, simova m, et al. [pregnancy after kidney transplantation]. vnitr lek. 1999;45:224-7. czech. 11. little ma, abraham ka, kavanagh j, connolly g, byrne p, walshe jj. pregnancy in irish renal transplant recipients in the cyclosporine era. ir j med sci. 2000;169:19-21. 12. rowemeier h, kemmer fw, somville t, grabensee b. [pregnancy after kidney transplantation]. dtsch med wochenschr. 1993;118:649-55. german. 13. miniero r, tardivo i, curtoni es, et al. pregnancy after renal transplantation in italian patients: focus on fetal outcome. j nephrol. 2002;15:626-32. 14. tardivo i, curtoni es, segoloni gp, dall’omo am, miniero r. [pregnancy after kidney transplantation. review of the international literature and presentation of personal case reports]. minerva urol nefrol. 2002;54:119-26. italian. 15. pour-reza-gholi f, nafar m, farrokhi f, et al. pregnancy in kidney transplant recipients. transplant proc. 2005;37:3090-2. 16. haugen g, fauchald p, sodal g, halvorsen s, oldereid n, moe n. pregnancy outcome in renal allograft recipients: influence of ciclosporin a. eur j obstet gynecol reprod biol. 1991;39:25-9. 17. lessan-pezeshki m, ghazizadeh s, khatami mr, et al. fertility and contraceptive issues after kidney transplantation in women. transplant proc. 2004;36: 1405-6. 1377vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l 1 department of urology, nanfang hospital, southern medical university, guangzhou, china. 2 section 5 department of internal medicine, guilin tcm hospital of china, guilin, china. yongtong zhu,1 chunyan wang,2 xiang pang,1 fei li,1 wei chen,1 wanlong tan1 antibiotics are not beneficial in the management of category iii prostatitis: a meta-analysis corresponding author: wan-long tan, md department of urology, nanfang hospital affiliated to southern medical university, guangzhou 510515, china. tel: +86 020 61641762 e-mail: tanwanlong@gmail.com received october 2012 accepted march 2013 purpose:todeterminewhetherantibioticsarebeneficialinthemanagementofcategoryiii prostatitis. materials and methods:thepubmed,medlineandembasedatabasesweresearchedforall publisheddocumentsfromjanuary1,1965toseptember1,2012withoutlanguagerestriction. therandomizedcontrolledtrialsthatmentionedcomparablegroupsofantibioticstreatment versusplaceboorothercontrolgroupforpatientswithcategoryiiiprostatitiswereincluded basedonspecificcriteria.thequalityofstudieswasassessedbythemodifiedjadadscale,and revman5.0softwarewasusedfordatasynthesesandanalysis. results:sevenstudieswhichmettheselectioncriteriawereincludedinthisreview.allof themwerehighqualityaccordingtothemodifiedjadadscale.arandomeffectmodelwasappliedbecauseofthehighheterogeneity.themeta-analysisshowedthatsummaryassociation betweencategoryiiiprostatitisandantibioticswerenotstatisticallysignificant. conclusion:ourmeta-analysisrevealsthatantibioticsarenotbeneficialinthemanagementof categoryiiiprostatitis.therefore,wemayreducetheusageofantibioticsinsuchapopulation. keywords:prostatitis;drugtherapy;treatmentfailure;classification;treatmentoutcome;metaanalysis. review article 1378 | review article introduction antibioticsareoneofthemostcommontreat-mentsemployedbyurologistsforpatientspre-senting with prostatitis, regardless of culture results.morethan90%ofprostatitiscasesarecategory iiiprostatitiswhichisnotassociatedwithasignificant bacteriuria.whereas,itisaconditionreferredtochronic prostatitis/chronicpelvicpainsyndrome(cp/cpps).(1,2) subgroupsofcppsareinflammatorycpps(iiia)where leukocytes are found in the expressed prostatic secretions,andnon-inflammatorycpps(iiib).(3) according tothesummaryofnationalinstitutesofhealth(nih), patientswithcategoryiiiprostatitisareadvisedtotake antimicrobialagentsfor3-6weeksasthefirst-linetreatment,(3,4) which response to the anti-infective therapy. one systematic review published bythakkinstian and colleagues(5) suggested that antibiotics appeared to be beneficialforpatientswithcp/cppsandmostappropriatefortherapyofcp/cpps. nevertheless,asthediagnosisofcategoryiiiprostatitis demands theexclusionof infection, thereasonfor the responseassociatedwithantibioticsisnotimmediately clear.(6) some people suggested that there was a poor benefitafterantibiotictherapy,(7)nickelandcolleagues(8) found that the levofloxacin therapeutic effect in men diagnosedwithcpwasnotsignificantlydifferentfrom placebo. then derose and colleagues(9) and kim and colleagues(10)alsodemonstratedthatantibioticsdidnot markedlyreducethesymptomsinmenwithcpps. sincethediagnosticcriteriaandtreatmentwerenotunified,manyearlycasesledtocp,andtheoveruseofantibiotics caused bacterial resistance.(11) in order to strictly control the clinical applying indications for fluoroquinoloneandstrengthenmanagement,ourcountryexecutedtheclinicaluseofantibioticsguidingprinciplein 2004 and theclinicaluse ofantibioticsmanagement approachinaugust1,2012.therefore,thepurposeof thisstudyistoassesswhetherantibioticsareeffectivein treating category iii prostatitis by synthesizing the data from all related available randomized controlled trials (rcts). there are several systematic reviews discuss the relationshipbetweentherapeuticinterventionandcp/cpps. twostudies(5,6)onlyincludedthreerctstodiscussthe relationshipbetweenantibioticsandcp/cpps,oneothers(12)includedtworcts.regardingouremphasisand the inconsistent findings on the relationship between antibiotics and category iii prostatitis, we conducted an updatedmeta-analysisofrctsonthissubject.ourgoal wastodeterminewhetherantibioticsareassociatedwith themanagementofcategoryiiiprostatitis. materials and methods literature search weconductedasystematicliteraturesearchinthepubmed, medline and embase databases to identify the eligiblestudiesbeforeseptember1,2012.thefollowingtermswereusedintheprimarysearch:(randomized controlledtrial[pt]orcontrolledclinicaltrial[pt]or randomized[tiab]orplacebo[tiab]orclinical trials astopic[mesh:noexp]orrandomly[tiab]ortrial[ti]) not(animals[mh]nothumans[mh])and(prostatitis)and(antibioticsor*xacinorantibacterialor antimicro*).thesearchwasfocusedonhumanstudies, withoutlanguagerestriction.inaddition,wecheckedthe relevantreviewarticlesandtheirreferencestoidentifyall availableliteraturethatmaynothavebeenincludedinthe databaseresults.thesearchfollowingchatispresented infigure1. inclusion and exclusion criteria thestudywasincludedifitmetthefollowingcriteria: (1)itwasanoriginalrct;(2)thediseasehasbeenclearlydefinedascategoryiiiprostatitisorcp/cpps;(3)the paper had a conclusion about the association between antibioticsandcategoryiiiprostatitisand(4)thestudy hadprovidedenoughinformationtoestimatetheeffect sizes.theexclusioncriteriawere: (1)duplicatestudy; (2)reviewpaper;(3)systematicreview;(4)abstract/title only;(5)noncategoryiiiprostatitisstudy;(6)otherinterventions;(7)noncomparativestudyand(8)noninterest outcome. data extraction tworeviewersindependentlyextractedtheinformation fromtheeligiblestudiesaccordingtotheinclusionand 1379vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l antibiotics and category iii prostatitis | zhu et al exclusion criteria. disagreement was resolved through discussion.thecollecteddataincludedfirstauthor,publicationyear,studydesign,durationoftherapy,age,intervention,samplesizeandtheoutcomedata. outcome measures the following variables were examined: chronic prostatitissymptomindex(cpsi)score,whichincludepain score,voidingscore,qualityoflife(qol)scoreandtotal score,atthebaseline,attheendofstudyandthechange fromthebaselinetotheend. study quality evaluation two reviewers graded each study independently using themodifiedjadadscale(13)(table1).thescoreforeach articlecanrangefrom0(lowestquality) to8(highest quality).scoresof4-8representgoodtoexcellent(high quality),whereas,0to3representpoororlowquality. statistical analysis allanalyseswereperformedinreviewmanager5statisticalsoftware.thecontinuousdataweresummarizedas theweightedmeandifferences(wmd)withthestandard deviations(sd). ifthestudyonlyreportedthemedian,therangeofcontinuousdataandthesizeofthetrial,weusedprevious formula(14) totranslatethesedatatowmdandsd.when itwasdesirabletocombinetworeportedsubgroupintoa singlegroup,weusedtheformulareportedintable7.7.a ofthecochranehandbook5.0.2tocombinethem.if therewasalackofwmdandsdofthechangesfrom baseline,whilethebaselineandfinalwmdandsdwere known,weimputedsdfor thechangesfrombaseline usingtheformulareportedin16.1.3.2ofthecochrane handbook5.0.2.whenconsideringthesensitivityanalysis,thevalueofcorrwasimputedas0.5.weusedthei2 statistic to assess the statistical heterogeneity between the trials.ifaheterogeneityof(i2>50%)existedweused therandomeffectmodeltoperformthemeta-analysis. otherwise,thefixedeffectmodelwasused.thesignificanceoftheoveralleffectwastestedwithfisher’sz-test, p<.05wasconsideredasasignificantlevel.allresults representingtheeffectsizewerestatedwith95%confidenceintervals(ci).thesensitivityanalysiswasperformedbyexcludinglowqualitystudiestoassessifthe resultsweresignificant.ifthescoreoftrialsweremore than5,thepublicationbiasofthestudywasassessedby afunnelplot. results study selection, characteristics and quality table 1. the modified jadad scale. eight items yes no not described was the research described as randomized? 1 0 ----was the approach of randomization appropriate?* 1 -1 0 was the research described as blinding? 1 0 ----was the approach of blinding appropriate? 1 -1 0 was there a presentation of withdrawals and dropouts? 1 0 ----was there a presentation of the inclusion/exclusion criteria? 1 0 ----was the approach used to assess adverse effects described? 1 0 ----was the approach of statistical analysis described? 1 0 ----* double-blind got 1 score, single-blind got 0.5 score. 1380 | thestudyselectionflowisdescribedinfigure1.atotal ofsevenrctswith539men(8-10,15-18) were included in ouranalysis.ofstudysubjects267wererandomizedto anexperimentalgroupandtheremaining272menwere assignedtoacontrolledgroup.onetrial(15)enrolled patientsclassifiediiiaandiiib,theremainingstudiesenrolledpatientswithcpps,allof themwerebelongto categoryiiiprostatitis.themeanagerangedfrom17to 78yearswhilethisinformationwasnotprovidedinone trial.(15)themeandurationoftreatmentrangedfrom6 weeksto12weeks.theinterventioninthetrialsincluded levofloxacin,(8,15,16)mepartricin,(10)ciprofloxacin(9,17) and tetracycline.(18)themanagementofcontrolgroupswere broadlyclassifiedintotwomethods:placebo(8,10,17,18)and others.(9,15-17)twoarticles(15,17)hadtwosetsofdata,we calculatedthemwithdividedandcombineddata,respectively.all included studies had the high quality score ofthemodifiedjadadscale.thecharacteristicsandthe qualityofallincludedstudiesarepresentedintable2. meta-analysis for the change of total score of cpsi allthetrialsevaluatedtheeffectofinterventionsontotalscoreofcpsi.amongthesercts,threetrials(8,10,18) comparedplacebowithantibiotics,threetrials(9,15,16)comparedα-blockerwithα-blockerplusantibiotics,andthe review article table 2. characteristics and quality of studies. study patient intervention no. of subjects withdrawn duration of therapy age modified jadad scale nickel et al., 2003(8) cp/cpps levofloxacin 45 12 weeks 56.0 (39-77) 8 placebo 35 56.2 (36-78) derose et al., 2004(10) cp/cpps mepartricin 15 60 days 34.75 ± 6.69 5 placebo 15 36.5 ± 7.54 alexander et al., 2004(17) cp/cpps placebo 45 (4) 6 weeks 42.6 ± 12.0 8 ciprofloxacin 42 (7) 45.9 ± 11.7 tamsulosin 45 (4) 45.3 ± 9.7 ciprofloxacin + tamsulosin 42 (7) 44.5 ± 11.4 jeong et al., 2008(16) cp/cpps doxazosin 26 6 weeks 41.5 (23-56) 4 levofloxacin + doxazosin 29 41.1 (27-60) ye et al., 2008(15) iiia tamsulosin 21 45 days no mentioned 5 tamsulosin + levofloxacin 21 iiib tamsulosin 21 tamsulosin + levofloxacin 21 zhou et al., 2008(18) cpps tetracycline 24 12 weeks 29-50 (all) 4 placebo 24 kim et al., 2011(9) cp/cpps tamsulosin 40 12 weeks 45.7 5 tamsulosin + ciprofloxacin 28 46.1 keys: cp, chronic prostatitis; cpps, chronic pelvic pain syndrome. 1381vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l other one study(17)includedallthemanagementmethods. onetrial(17) gotthechangefromthebaselinedirectly;the remainingtrialsreportedthemeanscoresatfollow-up andgotthechangeviatheformula. ourquantitativeaccumulationanalysiswiththerandomeffectmodel(i2>75%)revealedthatpatientsusingantibioticshadagreaterreduceintotalscorefrombaseline whencomparedwiththecontrolgroup(p=.01;figure 2a).however, thesubgroupanalysisshowed that this differencewasnotstatisticallysignificantbothintheantibioticsgroupversustheplacebogroup(p =.05)andin theα-blockergroupversustheα-blockerplusantibiotics group (p=.13).thesensitivityanalysiswasnotdone necessarilybecauseofthemedianorthehighqualityof allthesevenstudies.therewasapotentialpublication biasinouranalysisaccordingtothefunnelplotpresented infigure3. consideringalongertreatmentintervalmayhaveamore positiveroleintheeffectofthesymptomscoresimproving,weconductedasubgroupanalysis(table3)basedon thetreatmentdurationby12weeks,whichwaschosenas thedividingline.theanalysisresultbasedontheeligibilitydatashowedthatantibioticswerenotbeneficialin themanagementofcategoryiiiprostatitiswhenthetreatmentdurationwasmorethan12weeks. meta-analysis for the change of pain score, voiding score and qol score of cpsi excludedthestudybyzhou,2008asthedatawereincomplete,thereweresixtrials(8-10,15-17) (491men)which had evaluated the effect of the interventions on pain score,voidingscoreandqolscoreofcpsi. witharandom-effectmodel(i2>50%),thepooledanalysisrevealedthatpatientsusingantibioticshadagreater reduceinpainscorewhencomparedtothecontrolgroup (p=.02;figure2b).thesubgroupanalysesshowedthe samedifferencewhencomparingplacebotoantibiotics (p=.04),however,thedifferencebetweenα-blockerand α-blockerplusantibioticswasnotstatisticallysignificant (p=.16). we used a random-effect model to estimate the voidingscorebecauseofthehugeheterogeneitybetweenthe studies(i2>75%).aquantitativeaccumulationrevealed antibiotics and category iii prostatitis | zhu et al table 3. subgrouping based on the treatment duration. variables no. of studies antibiotics/control wmd 95% ci p i2 < 12 weeks antibiotics vs. placebo 2 57/60 -4.18 -6.55 -1.81 .00 81% antibiotics + α-blocker vs. α-blocker 2 84/87 -5.34 -7.06 -3.62 .00 97% >12 weeks antibiotics vs. placebo 1 45/35 -2.50 -6.48 -1.48 .22 na antibiotics + α-blocker vs. α-blocker 1 28/40 -0.07 -2.47 -2.33 .95 na keys: ci, confidence interval; na, not applicable; wmd, weighted mean differences. 1382 | review article thatpatientsusingantibioticshadnosignificantlygreater reduceinvoidingscorewhencomparedtothecontrol group (p=.10;figure2c).theresultsofthesubgroup analyseswerethesamebothinplaceboversusantibiotics (p =.08)andinα-blockerversusα-blockerplusantibiotics (p=.21). withapotentialheterogeneity(i2>50%),therandomeffectmodelanalysisrevealedthatpatientsusingantibioticshadasignificantlygreaterreduceinqolscorewhen comparedtothecontrolgroup(figure2d).thesubgroup analysesshowedthatthedifferencewasalsoexistwhen comparingα-blockertoα-blockerplusantibiotics(p = .04),whereastherewasnosignificantdifferenceinthe subgroupofplaceboversusantibiotics(p=.10). discussion category iii prostatitis is the most common urologic diseases. the medicine treatment contains antibiotics, α-blockers,anti-inflammatoryanalgesics,andsoon.in ourstudy,therewerefourinterventionsinthetreatment ofcategoryiiiprostatitis:placebo,antibiotics,α-blockers and α-blockers plus antibiotics. in the same baseline levelofcpsi, thedifferenceof thescorereductionin theα-blockersgroupandtheα-blockersplusantibiotics groupreflectedtheroleofantibioticsinthetreatment, althoughα-blockersalsoplayarole.sothesefourinterventionsweredividedintotwosubgroupsinourmetaanalysis. inthismeta-analysis,thequantitativeaccumulationresultsshowedthatantibioticshadasignificantlygreater roleinthereductionintotalscore,painscoreandqol score,weresamewiththeformerrecommendationthat antibioticsareusefulincategoryiiiprostatitis.(8) however,theanalysisofthesubgroupshowedtheopposite result; that summary association between category iii prostatitis and antibiotics were not statistically significant, especially in total score and voiding score. our findings revealed that antibiotics are not beneficial in themanagementofcategoryiiiprostatitis.inpartofthe sub-scoreanalysis,antibioticshadasignificantlygreater reduceinpainandqolscore,butnotinvoidingscore. suchresultmetthepointofviewthattheantibioticshad anti-inflammatoryandanalgesicproperties.(19) antibiotics,especiallythefluoroquinolones,hadbeenprovento influencethecytokineactivity.forexample,levofloxacinhadanimmunomodulatoryfunctiononthecytokine productionnotrelyingontheantimicrobialactivity;(20) cotrimoxazolewasprescribedfortheanti-inflammatory or immunosuppressiveeffectson thenoninfectious illness,(21)andsoon.thesubgroupanalysisbasedonthe treatmentdurationshowedthatantibioticswerenotbeneficialinthemanagementofcategoryiiiprostatitiswhen the treatment duration was more than 12 weeks, even where beneficial when less than 12 weeks.the shortterm curative effect is actually the analgesic effect of antibiotics,whichcausedbypatients’subjectivefeeling. infact,thelong-termcurativeeffectshowedthattheantiinflammatoryeffectsofantibioticswerenotobviousin prostate category iii, which was the reason that antibioticscouldnotimprovecategoryiiiprostatitis. inourdata,severalissueswarrantfurtherdiscussion.the etiologyforcategoryiiiprostatitishasnotbeenfullyelucidatedandthecriteriausedforclassifyingthetreatment responsewerevaried,sowedidnotanalyzethetreatment responsiveness.comparedwiththesystematicreviews publishedbythakkinstianandcolleaguesandcohenand colleagues,(5,12)weincludedthelatestsevenrandomized figure 1. study selection strategy. 1383vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l antibiotics and category iii prostatitis | zhu et al controlledtrials,whichhavethehighestqualityinpublished literature. although the search strategy was withoutrestrictiononlanguage,someliteraturemaybeomittedbecauseofthelimitationoftheinternet.meanwhile, asweknow,thegreyliteraturewasdifficulttoobtain. in addition, we included the trials representing the opposite results, so a high heterogeneity was detected in the studiesandforcedustoapplytherandomeffectmodel reducingthecredibilityandincreasingtheimprecisionof theresults.asweknow,itwasquestionablethatpooled thedatabyameta-analysiswhentheheterogeneitywas toohigh(i2>75%),anditseffectwouldnotbeovercome bytherandomeffectmodel.however,accordingtosome authoritativeliteratures,(22,23) wealsousedthismethodto figure 2. forest plot of change in (a) total score, (b) pain score, (c) voiding score and (d) qol score of national institutes of health chronic prostatitis symptom index. 1384 | evaluatetheresults,eventhoughitcouldnotavoidthe hugeheterogeneity.consideringahighheterogeneityand apublicationbiasexisted,wefoundseveralsourcesin thesercts.first,thepatientschosentostudyweredifferent.themenwithrefractorylong-standingsymptoms representedasmallsubpopulationoftheoverallgroup withcp/cpps.second,theagentsmightbemoreeffective inmenwhohadreceivedlessprevious treatment. theidealstudyshouldinvolvepatientswhowerenaïve totheantimicrobialtherapy.third,thedurationoftreatmentwasdifferent.somestudiesdidnottesttheuseof drugsforlongerthan6weeksbutlongertreatmentmay bewarranted.fourth,thecombinationtherapywasdifferentfromthemono-therapy.fifth,theantibiotictherapyforcategoryiiiawasjustified,butnotforcategory iiibinsometrials;othersfoundnosignificantdifferencesbetweencategoriesii,iiia,oriiibtotheantibiotic treatment.sixth,thedoseofantibioticswaschangefrom 100mgtwicedailyto500mgdailyindifferentcountries. seventh,therevisitingtimefortreatmentrangedfrom3 monthsto1yearfollow-upperiod.lastly,somepatients werewronglydiagnosed.althoughthecombiningestimatesweregreatlyheterogeneous,themixedmodelwith randominterceptgaveconsiderationtovariationsatthe studylevel.what’smore,themeasurementthatweused wasthescorereduceddifferenceinsteadofthescoreof cpsidirectly,whichmayreflecttheroleofantibiotics betterthanthedirectcpsiscore. thereweresomelimitationsthatneededtobetakeninto account.thenumberofpatientsenrolledwassmalland thetotalsamplesizeswererelativelysmall,sothecredibilityoftheconclusionwasnotstrongenoughandthe representativerequiredconsidering.thesamplesizesof thestudiesweresodifferentthattheweightwasnotthe same,whichledtoahighheterogeneityafter thedata combination.theincorporativeresultswereoftenheterogeneousandtheoriginofthisdifferencewasnotobvious.categoryiiiprostatitisremainsadisputedcondition withlittleconsensusregardingthebesttreatmentoption. (1)thetreatmentbenefitsweremodestforsometherapies andnonexistentforothers,whichprobablyreflectedthe individualdifferences. conclusion althoughitiscommonlyknownthatthereisagreatbenefitfromantibioticsforcategoryiiiprostatitis,wefound nosignificantassociationsbetweenthemwhenanalyzing the published studies by meta-analysis. our metaanalysisrevealsthatantibioticsarenotbeneficialinthe managementofcategoryiiiprostatitis.futureresearchto confirmthesefindingsiswarranted,andwemayreduce theusageofantibioticsinsuchapopulation. acknowledgment yongtongzhu,chunyanwangandxiangpangcontributedequallytothiswork. conflict of interest none declared. references 1. lee ks, choi jd. chronic prostatitis: approaches for best management. korean j urol. 2012;53:69-77. 2. guo yl, li hj. prostatitis. beijing, china, people's military medical press; 2007. p. 63-8. 3. schaeffer aj. classification (traditional and national institutes of health) and demographics of prostatitis. urology. 2002;60:5-6. 4. kim sh, ha us, sohn dw, et al. preventive effect of ginsenoid on chronic bacterial prostatitis. j infect chemother. 2012;18:709-14. review article figure 3. funnel plot of change in total score of national institutes of health chronic prostatitis symptom index. 1385vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l 5. thakkinstian a, attia j, anothaisintawee t, nickel jc. alpha-blockers, antibiotics and anti-inflammatories have a role in the management of chronic prostatitis/chronic pelvic pain syndrome. bju int. 2012;110:1014-22. 6. anothaisintawee t, attia j, nickel jc, et al. management of chronic prostatitis/chronic pelvic pain syndrome: a systematic review and network meta-analysis. jama. 2011;305:78-86. 7. lombardo f, fiducia m, lunghi r, et al. effects of a dietary supplement on chronic pelvic pain syndrome (category iiia), leucocytospermia and semen parameters. andro. 2012;44 suppl 1:672-8. 8. nickel jc, downey j, clark j, et al. levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized placebocontrolled multicenter trial. urology. 2003;62:614-7. 9. kim th, lee ks, kim jh, et al. tamsulosin monotherapy versus combination therapy with antibiotics or anti-inflammatory agents in the treatment of chronic pelvic pain syndrome. int neurourol j. 2011;15:92-6. 10. de rose af, gallo f, giglio m, carmignani g. role of mepartricin in category iii chronic nonbacterial prostatitis/chronic pelvic pain syndrome: a randomized prospective placebo-controlled trial. urology. 2004;63:13-6. 11. wang wf, dong dx, cen s, et al. preliminary study of incurable causes of chronic prostatitis. nat j andro. 2001;7:233-6. 12. cohen jm, fagin ap, hariton e, et al. therapeutic intervention for chronic prostatitis/chronic pelvic pain syndrome (cp/cpps): a systematic review and meta-analysis. plos one. 2012;7:e41941. 13. dong j, su sy, wang my, zhan z. shenqi fuzheng, an injection concocted from chinese medicinal herbs, combined with platinumbased chemotherapy for advanced non-small cell lung cancer: a systematic review. j exp clin cancer res. 2010;29:137. 14. hozo sp, djulbegovic b, hozo i. estimating the mean and variance from the median, range, and the size of a sample. bmc med res methodol. 2005;5:13. 15. ye zq, lan rz, yang wm, yao lf, yu x. tamsulosin treatment of chronic non-bacterial prostatitis. j int med res. 2008;36:244-52. 16. jeong cw, lim dj, son h, lee se, jeong h. treatment for chronic prostatitis/chronic pelvic pain syndrome: levofloxacin, doxazosin and their combination. urol int. 2008;80:157-61. 17. alexander rb, propert kj, schaeffer aj, et al. ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial. ann intern med. 2004;141:581-9. 18. zhou z, hong l, shen x, et al. detection of nanobacteria infection in type iii prostatitis. urology. 2008;71:1091-5. 19. nickel jc, downey j, johnston b, clark j. predictors of patient response to antibiotic therapy for the chronic prostatitis/chronic pelvic pain syndrome: a prospective multicenter clinical trial. j urol. 2001;165:1539-44. 20. yoshimura t, kurita c, usami e, et al. immunomodulatory action of levofloxacin on cytokine production by human peripheral blood mononuclear cells. chemotherapy. 1996;42:459-64. 21. roblot p, becq-giraudon b. [non-antibiotic effects of antibiotics: from side effects to therapeutic uses]. pathol biol (paris). 1997;45:751-7. antibiotics and category iii prostatitis | zhu et al 22. aboumarzouk om, stein rj, eyraud r, et al. robotic versus laparoscopic partial nephrectomy: a systematic review and meta-analysis. eur urol. 2012;62:1023-33. 23. wu lm, hu j, gu hy, hua j, xu jr. can diffusion-weighted magnetic resonance imaging (dw-mri) alone be used as a reliable sequence for the preoperative detection and characterisation of hepatic metastases? a meta-analysis. eur j cancer. 2013;49:572-84. urol_v03_no4_001_editorial.indd editorial 191urology journal vol 3 no 4 autumn 2006 duplicate publication: justifiable in a different language? urol j (tehran). 2006;4:191-2. www.uj.unrc.ir the final goal of professional medical publication is to make the results of studies accessible for the medical community. this can be more easily achieved, regardless of origin and language, these days thanks to the internet. the urology journal now enjoys its electronic archive and can be searched by google. other than electronic archiving, most iranian biomedical publications have joined the international indexing systems. since almost all journals published in a local language provide english abstract, their visibility on the internet is fairly comparable to the english medical journals, either internationally well-known or just locally distributed. all these have raised a serious concern about duplicate publication, warranting a reconsideration of its boundaries. duplicate publication, also known as redundant or dual publication, simply means “publication of a paper that overlaps substantially with one already published.”(1) it is condemned and considered unethical, but there are some exceptions. in the guidelines on good publication practice published by the committee on publication ethics, it is stated that “republication of a paper in another language is acceptable, provided that there is full and prominent disclosure of its original source at the time of submission.”(2) in the international committee of medical journal editors (icmje) uniform requirements for manuscripts submitted to biomedical journals, the term secondary publication is used and considered acceptable and beneficial provided that specific conditions are met, including approval from the editors of both journals, presence of a different group of readers for the secondary publication, proper reference to the primary publication, and faithful reflection of the data and interpretations of the primary version.(3) despite the above, certain issues are still open to question: when is it beneficial to republish a paper? who decides that a paper is beneficial to be republished? who are a different group of readers? during the recent years, we have witnessed an astonishing growth in the number of scientific papers by iranian researchers (nearly 10-fold within 5 years). however, most authors are not familiar with all principles that govern the sophisticated world of the publication. pessimistically thinking, some authors try to make their cvs voluminous by duplicate publication. however, it seems that most authors—unaware of the publication ethics— just want to make their study results not only internationally accessible, but also available for the iranian readers in persian. justifications put forward by authors are mostly the following: publication of medical literature in persian language should not be neglected, we should appreciate iranian readers’ preferences, and we have to be in concert with the funders of research—mostly the government—who prefer to sponsor studies that are directly beneficial for the iranian population, and thus, expect that the study results be published in persian as well. in my opinion, these are not acceptable; firstly, adding too many medical papers in persian does not necessarily help the medical terminology in persian language evolve. secondly, all the studies on iranian subjects address the health issues of the iranian; however, they may not have a great or direct benefit for iranian people and they are not all nationally important. an abbreviated version or a gist of the study in nonpeer-review persian journals could be sufficient to meet the needs of the public. and thirdly, the main-stream biomedical journals are currently being published in english, and irrespective of their mother tongue, researchers and physicians have to first browse the literature in the most creditable international journals when they want to do research or update their knowledge, so they have to know english. consequently, a different group of readers (who might make duplicate publication reasonable according to the icmje) may not exist! the audience of all local and international journals in english, persian, etc could be everyone around the world who connects to the worldwide web to find their information of interest. in other words, terms such as local and international are disputable in medical journalism. consensus almost exists on the issue of duplicate duplicate publication: justifiable in a different language 192 urology journal vol 3 no 4 autumn 2006 publications in another language. our enquiry from the thomson scientific was answered as “one of the criteria for inclusion in our products is that a journal publishes articles that have not been published elsewhere, regardless of the language [personal correspondence].” rogers, the editor of the american journal of roentgenology, describes previously published—an unacceptable characteristic—as “previously published in any language, previously published anywhere in the world, previously published in part or in whole, previously published in print or on electronic media, previously published regardless of whether that publication is listed in the index medicus, and previously published with or without the requirement for signing a transfer of copyright.”(4) of course, some papers are worth or even necessary to be republished. however, it is not the author but the editor who can decide on this. it is shown that 67% of authors, but only 31% of editors, justify publication of a duplicate paper in a non-peer reviewed symposium supplement. also, only 15% to 30% of both groups agree that it is justified to publish overlapping articles when there are different or non-english-speaking audiences, new data, strengthened methods, or disputed findings.(5) other than the content of papers, an editor has to consider the costs of duplicate publication. each published page in the urology journal roughly costs us$ 100. duplicate publishing costs and duplicate peer review are not reasonable unless a definite benefit for the audience is recognized by the editors of the journals. in this case, clear reference to any previous or expected future publications in the article is not only a requisite, but also necessary to avoid overemphasis of findings by the future meta-analyses. there are reports on such overestimations by erroneously taking into account one study as 2 separate papers in meta-analyses.(6) it has been 3 years since we changed the language of our journal to english, which has been welcomed by our audience. however, many authors had questions about secondary publication of the articles in other journals that are indexed in index medicus or those published in persian. unfortunately, we encountered some cases of duplicate publication in our journal. one of the cases was easily detectable by google, although the other journal was in persian; there were 2 identical articles appearing next to each other in the search results. to avoid this problem we have updated our authors’ agreement form that should be signed by all authors. this helps us inform all contributors of the regulations. in the recent form, we added “in any language” to emphasize its unacceptability. a notice of duplicate publication will be published if this ever happens. to our knowledge, such notices have not appeared in iranian journals so far. nonetheless, as those responsible for preservation of the standards of biomedical journalism, the editors of the urology journal are willing to actively approach this issue and publish notices in case any duplicate publication is detected. from a national point of view, it is time to add publication ethics to the regulations and the authors and editors should be asked to comply with them. education of good publication practice, even for medical students is crucial. on the other hand, a shift from quantitative evaluation to a qualitative one for promotions and grants should be considered. the number of publications as a criterion, although has encouraged the faculties to be more research minded, is not favorable in the long run. to summarize, after a national success in promoting the number of scientific publications, it is time to take quality and standards more seriously. farhat farrokhi executive editor, urology journal references 1. hudson aj, mclellan f, editors. ethical issues in biomedical publication. baltimore: johns hopkins university press; 2000. 2. committee on publication ethics [homepage on the internet]. guidelines on good publication and the code of conduct [cited 2006 december 12]. available from: http://www.publicationethics.org.uk/reports/2003/ 2003pdf15.pdf 3. international committee of medical journal editors [homepage on the internet]. uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication. iii.d.3. acceptable secondary publication [cited 2005 june 21]. available from: http://www.icmje.org 4. rogers lf. in any language. ajr am j roentgenol. 2000;174:1487. 5. yank v, barnes d. consensus and contention regarding redundant publications in clinical research: cross-sectional survey of editors and authors. j med ethics. 2003;29:109-14. 6. tramer mr, reynolds dj, moore ra, mcquay hj. impact of covert duplicate publication on metaanalysis: a case study. bmj. 1997;315:635-40. reconstructive surgery major complications after male anti-incontinence procedures: predisposing factors, management and prevention miklós romics1*, gergely bánfi1, attila keszthelyi1, hans christoph klingler2, tibor szarvas1, marcell szász3 ,péter nyirády1, attila majoros1 purpose: significant post-prostatectomy incontinence (ppi) is a crippling condition and managed best through sling or artificial urinary sphincter (aus) implantation. these procedures are often associated with complications requiring surgical intervention. the aim of our retrospective study was to evaluate the occurrence of major complications and identify risk factors. materials and methods: between 2010 and 2018 ninety-one patients have been implanted with sling (22; 24.2%) or aus (69; 75.8%) in our department. the cases where surgical revision was needed were examined regarding the etiology (mechanical failure (mf), urethral erosion (ue), urethral atrophy (ua), surgical site infection (ssi), combined reasons (comb) and analyzed, using 16 possible perioperative risk factors. results: surgical intervention was carried out by 19 / 91 (20.9%) patients. (in 16 / 69 cases after aus (23.1%), 3 / 13 after slings (23%)). the indication was in 6 (31.6%) cases mf, in 3 (15.8 %) comb, in 4 (21.1%) ue, in 5 (26.3 %) ssi, in 1 (5.2%) ua. the type of reoperation was either explantation (12 / 19), system replacement (6 / 19), or cuff replacement (1 /19). regarding the surgical intervention requiring complications only preoperative bacteriuria (p = .006) and postoperative surgical site oedema (p = .002) proved to be independent predictive factors. conclusion: preoperative bacteriuria and surgical site oedema seemed to be good predictors for obligate surgical revision. patients with aus were more prone to have major complications. in most cases it was mechanical failure, infection or erosion. by reducing the frequency of these risk factors we might be able to decrease the amount of complications. keywords: post-prostatectomy incontinence, anti-incontinence surgery, implantation, sling, artificial urinary sphincter, complication introduction post-prostatectomy incontinence (ppi) is a frequent and often debilitating complication occurring mainly due to radical prostatectomy (rp) or other prostate operations (transurethral resection of the prostate– turp or open prostatectomy – op). may it be temporary or permanent, it can have a huge impact on the life quality, not to mention the financial burden the patient and the healthcare system has to carry.(1) the incidence fluctuates between 5 and 40 percent (depending on the definition), however the urine loss is often slight, and many of those affected will be continent again at the end of the first year.(2) only a small fraction (about 7%) requires surgical intervention: suburethral sling (much like the female mid-urethral slings) or artificial urinary sphincter (aus) implantation.(3,4,5,6) despite the long time it took to achieve relative safety, there are still numerous complications where we have to intervene. (5,6) some of these problems can only be solved with replacement, some only with explantation. the revision rate between aus (8 45 %) and slings (9,7 35 %) differs somewhat with aus predominance.(7,8) 1department of urology and centre of urooncology, semmelweis university, budapest, hungary. 2department of urology, wilhelminenspital & krankenhaus hietzing, vienna, austria. 3cancer center, semmelweis university, budapest, hungary. *correspondence: department of urology and centre of urooncology, semmelweis university, üllői way 78/b budapest, 1082, hungary. tel: +36204806092. e-mail: miklos.romics@gmail.com. e-mail2: romics.miklos@med.semmelweis-univ.hu. received october 2019 & accepted march 2020 our goal was to examine the frequency of major complications after male anti-incontinence procedures and to identify possible risk factors. materials and methods study population – between 2010 and 2018 ninety-one consecutive ppi patients have been operated in our department. inclusion and exclusion criteria – all of these implantees have been included in our investigation and there was no reason to exclude anyone of them. (those, who were operated but could not receive implant due to intraoperative complications are obviously got not involved in our examination.) data was collected retrospectively. our patients of the study population (n = 91) were all caucasian without significant diversity across demographic or comorbidity variables. among the study population 71 (78%) patients had radical prostatectomy, 15 (16.5%) had transurethral prostate resection and 4 (4.4%) had open prostatectomy. (only a fraction of these operations were performed at our clinic). urology journal/vol 18 no. 1/ january-february 2021/ pp. 92-96. [doi: 10.22037/uj.v0i0.5712] vol 18 no 1 january-february 2021 93 according to the 24h pad test, 66 (72.5%) patients belonged to severe (over 400 ml/day), and 25 (27.5%) to the mild to moderate incontinence group (100 400ml/ day). procedures – the following implants were used in our department: the ams800® (69 pts) artificial urinary sphincter system (boston scientific, marlborough, ma, usa), atoms® (13 pts) (a.m.i. gmbh, feldkirch, austria) and argus® (8 pts) (promedon sa, cordoba, argentina) transobturator adjustable sling systems, and the surgimesh m-sling® (1 patient) (aspide médical, la talaudière, france), a non-adjustable transobturator sling. the choice of which device to implant was based on the level of incontinence (aus was usually used for more severe cases, slings for mild or moderate incontinence but patient’s preference was taken into account as well. the operations were all performed by the same surgeon and assistant team. the follow-up time after the primary operation was avg 39 +/22.3 months (6 87 mo). all operated patients had complete diagnostic assessment preoperatively: physical examination, urine test and culture, 24-h pad test and urine loss ratio (urine loss during 24 hours/total daily urine production), urotable 1. the analyzed perioperative factors and risk analysis (p = < .05) perioperative parameters value risk for major (surgical intervention risk for obligate intervention risk for optional intervention requireing) complication age avg. +/-sd (yr) 69.3+/-5.83 .594 .991 .425 elderly pts (>75yr) n(%) 21 (23.1) .807 .943 .777 bmi avg.+/-sd (kg/m2) 28.6+/-3.75 .504 .8 .486 etiology of msui .549 .556 .937 rrp n(%) 41 (45.1) lrp n(%) 29 (31.8) prp n(%) 2 (2.2) turp n(%) 15 (16.5) op n(%) 4 (4.4) grade of incontinence .899 .837 .946 severe n(%) 66 (72.5) moderate n(%) 25 (27.5) adjuvant irradiation n( %) 18 (19.7) .421 .626 .543 operated anastomotic stricture n(%) 38 (41.7) .432 .357 .944 previous perineal operation n(%) 11 (12.1) .178 .141 .853 diabetes n(%) 21 (23.1) .706 .101 .131 bacteriuria n(%) 42 (46.1) .248 .006 (.025a) .078 prevoius anticoagulant th n(%) 40 (43.9 .222 .156 .951 cuff size avg. (up-to) cm 4.5 (3.5-6.5) .582 .728 .686 surgical site oedema (%) 16 (17.5) .072 .002 (.012**) .203 p.op. voiding diff. n (%) 7(7.7) .655 .929 .427 postop. uti n (%) 6 (6.6) .793 .794 .464 postop. pain n (%) 7 (7.7) .655 .929 .427 asignificant, independent predictive factor in multivariate analyses abbreviations: bmi: body mass index, msui: male stress incontinence, rrp: retropubic radical prostatectomy, lrp: laparoscopic radical prostatectomy, prp: perineal radical prostatectomy, turp: transurethral resection of the prostate, op: open prostatectomy, uti: urethral tract infection figure 1. complications and their incidence (mf: mechanical failure, ssi: surgical site infection, ue: urethral erosion, comb: combined reasons, ua: urethral atrophy complications after male anti-incontinence procedures-romics et al. flowmetry and post-void residual (pvr) urine measurement, upper urinary tract ultrasound, urodynamic investigation and urethro-cystoscopy. bacteriuria was always treated with targeted antibiotic therapy before the operation and every patient received iv. antibiotics on the ward and for another 5 days per os after emission. if urine culture was negative, we automatically administered prophylactic cephalosporin. (if the urine culture was positive before the operation, the patient received preoperative, targeted antibiotic therapy. in these cases, no control culture has been done right before the implantation.) evaluations – the complications were classified by the following: infection (inf), urethral atrophy (ua) and erosion (ue), mechanical failure (mf) and combined causes (comb: mf with ue). in our analysis we investigated all major complications that led to (obligate or optional) reoperation and looked for possible predisposing factors. we have examined the different types of anti-incontinence operations regarding the frequency of reoperations as well. a reoperation was obligate, if inf, ue or comb type of complications made the intervention a must. it was optional if there was no imminent danger to the patient’s health, but mf or ua made the continence to significantly deteriorate. in these cases, the surgical goal was to reinstate continence with a partial or total replacement. the statistical analysis was performed as described in the following. for paired group comparisons, the nonparametric, 2-sided wilcoxon rank-sum test (mann-whitney test) was applied. to analyze the potential impact of perioperative factors on reoperation we applied the chi-square test. factors occurred less than 5% in the study cohort, such as postoperative hematuria (n = 1), retention (n = 2) and fever (n = 2) were excluded, leaving 16 factors for analysis. all statistical calculations were done with the spss software package (24.0; spss, chicago, usa). in all tests, p values < 0.05 were considered statistically significant. multivariate analysis has been performed with the collected data. patients’ characteristics, the examined perioperative parameters and their role as possible risk factors are demonstrated in table 1. table 2 shows the relation between the type of the anti-incontinence surgeries and the number of reoperations. results surgical revision was necessary in 19 cases (20,9 %). in 16 (84,2%) pts with the aus, and in 3 pts (23%) after atoms implantation. (with argus or m-sling there was no reoperation.) the elapsed time between implantation and reoperation was 14.2 months in average (0.5 43). the most common major complication was mechanical failure (mf) (6 / 19; 31.6%), followed by infection (inf) (5 cases; 26.3%). urethral erosion (ue) was seen in 4 cases (21%). in 3 occasions a mechanical failure led to urethral erosion (comb) (15.8%). in these cases the aus could not be completely deactivated after the implantation and it led to urethral erosion table 2. the association between the reoperations and the type of the anti-incontinence surgery. a p only for acute obligate reoperation. (p = < .05) comparison of the antin (%) vs n (%) risk for major compl risk for obligate reop. risk for optional reop. requiring incontinence surgeries requiring complications complications ams 800 vs. slings 69(75.8) vs 22(24.2) .377 .074a .777 (atoms, argus,m-sling) .169 ams 800 + atoms vs. simpler 89(90.1) vs 9(9.9) .104 .218 .362 slings (argus, m-sling) figure 2. types and incidence of reoperations (n = 19) complications after male anti-incontinence procedures-romics et al. reconstructive surgery 94 vol 18 no 1 january-february 2021 95 – these were categorized as combined complications. urethral atrophy was seen only once (5.2%)(figure 1). because of these unfortunate events we had to remove the implant (exp) in 12 cases (13.2%). system replacement (rep) was carried out in 6 (6.6%) cuff change (cch) in only one case (1.1 %). (figure 2) based on the categories mentioned above, if we elicit the 9 (partly or totally) mechanical complications from the whole “reoperated” population (19 cases), we end up with 10 cases (9 aus, 1 atoms), where the root of the problem lay somewhere else. only preoperative bacteriuria and surgical site oedema proved to be an independent significant predictive factors in multivariate analysis (p = .025 and p = .012;) for obligate reoperations.(table 1) we recognize that surgical site oedema (or swelling) is a relative term that has no dimension; however, it is a well-knownphenomenon also presented as possible warning sign on the user’s guide for aus patients. (it was categorized as a “swelling at the surgical site” – probably due to hematoma, infection or dysfunctional lymph circulation – if itpersisted over 48 hours postoperatively or was much bigger in size than what is usually expected after these operations.) the type of the implant was also an important (although, not significant) predicting factor, since over 80 percent of our complications happened after aus implantations and many of these were mechanical a type of problem which usually occurs in a much lower number with slings.(9) discussion as we come across complications, we should always look for the origin even if the incidence does not differ much from the previously published data.(10) in our experience there are three ways to deal with this question. the root of the event can either be a mechanical problem, human error or the unlucky attributes of the patient. since often there are combined reasons, it is not easy to decide which is which, although it is quite clear that failures arising from surgical inexperience counts to the expense of the surgeon, and mechanical failures can usually be blamed on the manufacturer.in our work, mechanical failure was the most common complication which represented the half of all cases (9 out of 19 – 47%) either as a single complication or as a part of it. in contrast to others, however, we rarely saw erosion under the cuff (4 / 69). this difference (5.7 vs 10.7 10.8 %) may be related to the fact that others (like mckibben) used 3.5 – 4 cm cuffs, our average cuff-size was 4.5 cm.(11) bugeia detected mechanical failures with aus in 62 %, mostly due to the dysfunction of the pressure regulating balloon.(12) urethral atrophy was only seen in a few cases, just like in our investigation (1 / 69). as we present in our study, the factors that showed a significant correlation with major complications required obligate surgical revision were the preoperative bacteriuria and the surgical site oedema which could be related to the patient’s inadequate preparation giving us room to improve and change our routine. when discussing major complications, it is also recommended to distinguish one from the other, based on the necessity of reoperation: i.e. the indication is obligate or imperative (the procedure is unavoidable) in case of acute infection or urethral erosion. chronic infection, or skin erosion without signs of acute infection (around the pump, port or access kit) can be mended with exploration, debridement, total – or in some selected cases – partial exchange of the device. evidently, we only turned to this solution, when the chronical, superficial skin (or subcutaneous) infection and consequential skin erosion did not reach the urethra, and the patient specifically requested the exploration and debridement, hoping that his continence will be preserved this way. (even tough, because of the recurrent problems we later ended up removing the implant after all.) the other group of complications which require surgical attention is where malfunction appears in the form of recurrent incontinence: the main cause is usually a mechanical problem or urethral atrophy. (here we have to add, that there is growing evidence that many of the cases which one could easily qualify as atrophy are not atrophies at all. in fact, it’s only fibrous sheet (a.k.a. capsule) growing over the inner surface of the cuff that gives the impression of a urethral atrophy.(11,13)) in these cases the patient’s health is not in imminent danger, but the deteriorating quality of life makes the surgical intervention (replacement, or exchange) indisputably needed. in these cases, the (optional) replacement can be performed in a single operation. these types of complications (mechanical failures without any infection) were the most common in our experience (6 / 19) – four with auss and two with atoms slings. (here we would like to add that aus systems are notoriously more prone to suffer mechanical failures (in 12 53%) than any type of slings. this is partly due to their complex structure and partly to the fact that they have to be assembled on sight.(14,15) the incidence comparison of complications between the patients operated early and late in the learning curve showed no significant difference. this is contradicted by a large study published in european urology, which pointed out the extremely long learning process of aus implantation but also called for structured, thematic, training-based surgical education to reduce the learning curve.(16) (in our case, we tried to reach the needed experience by accredited trainings and operating with practiced guest operators.) our patients all received targeted or empiric antibiotic therapy however it looks like some patients (having had significant bacteriuria and treatment but no control urine culture before the operation) still suffer more complications. (probably because the surgical site is still being contaminated through the non-sterile urine.) after what we learned we decided that to do another urine culture before the operation (even after the targeted antibiotics therapy), to see if we can improve our numbers. the other independent risk factor was the postoperative surgical site oedema (which is a relative concept, though we have tried to define the phenomenon above). in its development postoperative hematoma, diminished lymphatic drainage, or infection could all play a part to varying degrees. the possibility of this complication could be reduced by more precise surgical technique and hemostasis. unlike hüsch et al., we did not find preoperative irradiation to be an independent, predisposing risk factor for complications, however, the role and significance of the independent risk factors we described are obviously enhanced in tissues where the circulation is damaged(17). whereas most of the previous papers dealing with complications of male anti-incontinence operations involved only a handful of perioperative factors the curcomplications after male anti-incontinence procedures-romics et al. rent one has examined 16 parameters. reconstructive male urogenital surgery with implants is more effective than with the use of autografts, however – just as with female patients, the surgical management of stress urinary incontinence and prolapsed surgery comes with a number of complications, which we aim to reduce in the future.(17,18) our study’s obvious limitation is the low patient number. however, we tried to compensate this number with a large collection of assessed perioperative factors. our initial results are promising and we intend to investigate our objectives further with a multicenter study, including measures designed to reduce complications mentioned in this study. conclusions the rate of major complications after male anti-incontinence surgery in our department is in line with the international data. among the male anti-incontinence operations the aus implantation came with the most complications (requiring acute surgical revisions) but the difference has not proved to be significant. the leading indication for reoperation was the mechanical failure. complications without the possible presence of mechanical failure were seen in only 10 pts (52.6 %). between these investigated perioperative factors, only the preoperative bacteriuria and the surgical site oedema could be identified as independent risk factors to predict major (surgical intervention requiring) complications with obligate necessity of surgical revisions. according to these findings we will alter our clinical protocol and do a preoperative control urine culture (just before the patient gets admitted) after the targeted antibiotic therapy! also, we will try to reduce the possible trigger factors leading to postoperative oedemas. these might help us reduce the number of reoperations and report about an improving complication rate in our follow-up publication. references 1. herschorn s. update on management of postprostatectomy incontinence in 2013. can urol assoc j. 2013;7:189-91. 2. anger jt, saigal cs, stothers l, et al. theprevalence of urinary incontinence among community dwelling men: results from the national health and nutrition examination survey. j urol 2006; 176:2103–2108. 3. bianco fj, riedel er, begg cb, kattan mw, scardino pt, scardino pt. variations among high volume surgeons in the rate of complications after radical prostatectomy: further evidence that technique matters. j urol 2005; 173:2099-2103 4. emami m, momtazan a, maghsoudi r et al.a.transobturator tape and mini-sling methods in stress urinary incontinence:results of a randomized clinical trial.urologia 2019; 86:152-155. 5. bauer rm, rutkowski m, kretschmer a et al. efficacy and complications of the adjustable sling system argust for male incontinence: results of a prospective 2-center study. urology. 2015;85:316-20. 6. ravier e, fassi-fehri h, crouzet s, gelet a, abid n, martin x. complications after artificial urinary sphincter implantation in patients with or without prior radiotherapy. bju int. 2015;115:300-7. 7. gousse ae, madjar s, lambert mm, fishman ij. artificial urinary sphincter for post radical prostatectomy urinary incontinence: long-term subjective results. j urol, 2001; 166:1755-8. 8. kretschmer a, hüsch t, thomsen f etal. targeting moderate and severe male stress urinary inconetinence with adjustable male slings and the perineal artificial urinary sphincter: focus on perioperative complications and device explantations. int neurourol j 2017, 21:109-115 9. european association of urology, urinary incontinence guidelines, 2018 10. pic g, terrier je, ozenne b, morel-journel n, paparel p. impact of anastomotic strictures on treatment of post-prostatectomy stress incontinence by artificial urinary sphincter. prog urol. 2016 ;26:635-641. 11. mckibben mj, shakir n, fuchs js, scott jm, morey af. erosion rates of 3.5-cm artificial urinary sphincter cuffs are similar to larger cuffs. bju int.2019;123:335-341. 12. bugeja s, ivaz sl, frost a, andrich de, mundy ar. urethral atrophy after implantation of an artificial urinary sphincter: fact or fiction? bju int. 2016 ;117:669-76.. 13. comiter cv, dobberfuhl ad. the artificial urinary sphincter and male sling for postprostatectomy incontinence: which patient should get which procedure? invest clin urol. 2016;57:3-13. 14. abrams p, andersson ke, artibani a. recommendations of the international scientific committee. chapter 11b: surgical treatment of urinary incontinence in men. 2nd international consultationon continence, paris, france (2002) 15. badry ms, e hefnawy as, gabr ah, hammady ar. use of the adjustable transobturator male sling system for the treatment of male incontinence. an initial experience. afr jurol 2016; 22: 127–130. 16. sandhu js, maschino ac, vickers aj. the surgical learning curve for artificial urinary sphincter procedures compared to typical surgeon experience. eur urol. 2011;60:128590. 17. hüsch t, kretschmer a , thomsen f et al. risk factors for failure of male slings and artificial urinary sphincters: results from a large middle european cohort study. urol int 2017, 99:14-21 18. oride a, kanasaki h, hara t, kyo s. postoperative outcomes following tensionfree vaginal mesh surgery for pelvic organ prolapse: a retrospective study. urol j. 2019 24;16:581-585. complications after male anti-incontinence procedures-romics et al. reconstructive surgery 96 1338 | laparoscopic repair of intraperitoneal bladder rupture after blunt abdominal trauma dianne mortelmans, nouredin messaoudi, joris jaekers, raymond bestman, steven pauli, marc van cleemput keywords: abdominal injuries; surgery; laparoscopy; methods; rupture; urinary bladder; injuries. introduction urinary bladder rupture following blunt abdominal trauma is frequently encountered in multiple trauma patients with pelvic-ring fractures.(1-3) rupture of the bladder can be extraperitoneal (50%-71%), intraperitoneal (25%-43%) or combined (7%-14%). (4,5) conventionally, this injury has been managed with explorative laparotomy and repair. we report a case of a 30 years old woman diagnosed with an isolated intraperitoneal bladder rupture which was successfully treated using a minimal invasive laparoscopic approach. case report a 30-year-old woman was admitted to the emergency department after being involved in a car accident. on physical examination, she was agitated with glasgow coma scale 15, but no neurological deficit. the patient had normal vital signs with blood pressure of 115/63 mmhg, a pulse rate of 84 beats per min and normal oxygen saturation. she complained of severe pain in the lower abdomen. palpation revealed muscular defense and rebound tenderness. multiple abrasions on both pelvic crests were present, however no sign of pelvic instability was noted. corresponding author: nouredin messaoudi, md department of general surgery, monica hospital, florent pauwelslei 1, b2100 deurne, belgium. tel: +32 4 9485 3011 fax: +32 3 320 5600 e-mail: nouredinmessaoudi@gmail. com received january 2012 accepted april 2012 department of general surgery, monica hospital, deurne, belgium. case report case report 1339vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l intraperitoneal bladder rupture | mortelmans et al laboratory findings showed no abnormalities, except for a blood alcohol level of 2.06 g/dl. computed tomography demonstrated free fluid in the abdominal cavity. solid organs showed no pathological signs. anterograde filling of the bladder after intravenously injected contrast confirmed an empty urinary bladder. hence, a bladder rupture was suspected. there was no pelvic fracture (figure 1). associated thoracic injuries were a ruptured breast implant and a fracture of the clavicle, both on the left side. as there was no sign of urethral injury, a foley catheter was inserted draining gross hematuria. the patient was prepared for laparoscopic exploration and repair under general anesthesia. upon inserting a veress needle to establish pneumoperitoneum of 15 mmhg, the urine collecting bag started to distend. using a 30-degree scope, meticulous laparoscopic exploration was underwent. a large amount of free bloodstained fluid was found around the liver and the spleen, and in the pouch of douglas. systematic inspection of the abdomen revealed an intact liver, spleen, stomach, intestines and ovaries. in the dome of the bladder, a 2 cm laceration was noted. the bladder rupture was repaired using an interrupted single layer of absorbable vicryl 3/0 sutures (figure 2). postoperatively, the patient made an uneventful recovery. the urinary catheter was removed after eight days, following a retrograde cystography confirming an intact urinary bladder without leakage (figure 3). the associated thoracic injuries were managed accordingly by the relevant specialists. discussion often accompanied by visceral organ damage and pelvic bone fractures, we report a case of an isolated intraperitoneal urinary bladder rupture diagnosed after blunt abdominal trauma. in his case series, wirth et al and colleagues reported only 17% of traumatic bladder ruptures to be associated with no other injury.(2) furthermore, intraperitoneal laceration is uncommon, ranging from 25% to 43% of all bladder ruptures following external trauma.(5) in the present case, the diuretic effect of alcohol aggravated by sudden increase of intravesical pressure following blunt abdominal trauma resulted in a lacerated bladder. nonetheless, spontaneous ruptures of the bladder have been described in previous reports.(6-8) conservative approach by prolonged catheterization is insufficient in the treatment of bladder rupture.(9) adequate surgical repair is the treatment of choice. advances in minimal invasive techniques over the last decade changed the initial approach of trauma patients. laparoscopy has proven to be an efficient diagnostic and therapeutic tool in selected trauma cases. conventionally, injury to the bladder was repaired by laparotomy allowing simultaneous evaluation of potentially associated visceral organ damage. in hemodynamically unstable patients this remains the golden standard.(10) following a systematic approach described by gorecki and colleagues,(11) laparoscopic exploration for trauma can be safely preformed in hemodynamically stable patients. in our case, diagnosis was confirmed using laparoscopy, both by visualization of the rupture in the dome of the bladder, as well as distension of the urine collecting bag due to pneumoperitoneum. the laceration of the bladder rupture was repaired using a single layer suture. there seems to be no advantage difference in outcome between a single layer(3,9,12) figure 1. computed tomography scan showing fluid collection in the abdominal cavity and an empty bladder. 1340 | case report and double layer suturing technique.(10,13-15) the placement of a supra-pubic catheter is not needed.(9) watertight closure can be confirmed by the injection of normal saline or methylene blue through the urinary catheter.(3,9,15) in conclusion, laparoscopic repair of an isolated intraperitoneal bladder laceration using single layer interrupted suturing technique is a feasible alternative to laparotomy in hemodynamically stable trauma patients with no other intraabdominal injury, resulting in reduced morbidity, faster recovery and better cosmetic results. conflict of interest none declared. figure 2. a) laparoscopic view of the abdomen demonstrating free blood-stained fluid in the pelvic cavity and the intraperitoneal bladder rupture in the dome. b) repair of urinary bladder with vicryl 3/0 single interrupted suture layer. figure 3. postoperative cystogram on day 8 showing an intact wall of the urinary bladder. references 1. morey af, iverson aj, swan a, harmon j, spore ss, bhayani s, brandes sb. bladder rupture after blunt trauma: guidelines for diagnostic imaging. j trauma. 2001;51:683-8. 2. wirth gj, peter r, poletti pa, iselin ca. advances in the management of blunt traumatic bladder rupture: experience with 36 cases. bju int. 2010;106:1344-9. 3. bhanot a, bhanot a. laparoscopic repair in intraperitoneal rupture of urinary bladder in blunt trauma abdomen. surg laparosc endosc percutan tech. 2007;17:58-9. 4. corriere jn. extraperitoneal bladder rupture. in: mcaninch jw, ed. traumatic and reconstructive urology. 1996:269-73. 5. brown sl, persky l, resnick mi. intraperitoneal and extraperitoneal. atlas of urol clin of n amer. 1998;6:59-70. 6. haddad fs, pense s, christenson s. spontaneous intraperitoneal rupture of the bladder. j med liban. 1994;42:149-54. 7. lynn sj, mark sd, searle m. idiopathic spontaneous bladder rupture in an intoxicated patient. clin nephrol. 2003;60:430-2. 8. fahlenkamp d, voge w, andrehs g. laparoscopic bladder repair after intraperitoneal bladder rupture. min lnvas ther allied technol. 1998:7:467-9. 9. kim fj, chammas mf jr, gewehr ev, campagna a, moore ee. laparoscopic management of intraperitoneal bladder rupture secondary to blunt abdominal trauma using intracorporeal single layer suturing technique. j trauma. 2008;65:234-6. 10. matsui y, ohara h, ichioka k, terada n, yoshimura k, terai a. traumatic bladder rupture managed successfully by laparoscopic surgery. int j urol. 2003;10:278-80. 11. gorecki pj, cottam d, angus ld, shaftan gw. diagnostic and therapeutic laparoscopy of trauma: a technique of safe and systematic exploration. surg laparosc endosc percutan tech. 2002;12:195-8. 12. figueiredo aa, tostes jgt, jacob mvm. laparoscopic treatment of traumatic intraperitonealbladder rupture. international braz j urol. 2007;33:380-2. 13. cottam d, gorecki pj, curvelo m, shaftan gw. laparoscopic repair of traumatic perforation of the urinary bladder. surg endosc. 2001;15:1488-9. 14. yee ds, kalisvaart jf, borin jf. preoperative cystoscopy is beneficial in selection of patients for laparoscopic repair of intraperitoneal bladder rupture. j endourol. 2007;21:1145-8. 15. appeltans bm, schapmans s, willemsen pj, verbruggen pj, denis lj. urinary bladder rupture: laparoscopic repair. br j urol. 1998;81:7645. the discrepancy between needle biopsy and radical prostatectomy gleason score in patients with prostate cancer amir reza abedi1, abbas basiri2, nasser shakhssalim2, ghazal sadri3, mahsa ahadi4, seyyed ali hojjati1,* samad sheykhzadeh5, sajjad askarpour2, saleh ghiasy1 purpose: gleason score (gs), as well as other prognostic and diagnostic modalities, can predict the possibility of tumor growth and metastasis during the life of patients with prostate cancer. based on the prostate biopsy gs, clinicians choose the most appropriate therapy for managing patients. the objective of this cross-sectional study was to determine the discrepancy between needle biopsy and radical prostatectomy gs and to identify its predictive factors in the iranian population. materials and methods: a total of 1147 patients who underwent radical prostatectomy from 2009 to 2019 were initially enrolled in this study. after consideration of the inclusion and exclusion criteria, 439 patients were finally included. the demographic variables and clinical data including age, psa level, prostate volume, psa density, gs derived from ultrasonography-guided core needle biopsy specimen, and gs derived from radical prostatectomy specimen were collected from the medical records of patients with prostate adenocarcinoma and were reviewed by a urology resident. results: the average age of patients was 64.5 years (range 48‐84 years), and the average preoperative psa level was 14.8 ng/ml. on histopathological examination, no changes in gs were observed in 237 (53.9%) patients, whereas gs was upgraded in 144 (32.8%) patients and downgraded in 58 (13.2%) patients at radical prostatectomy. the number of patients who had extracapsular extension, seminal vesicle invasion, and positive lymph nodes was significantly higher in the upgraded group compared with the non-upgraded group. conclusion: in this study, there was a steady decrease in gs upgrading with the prostate size extending up to 49.7 g. there was also an association between downgrading and extending prostate size. due to the greater risk of high-grade disease in men with small prostates, smaller prostate bulks are most probably upgraded after radical prostatectomy. a higher maximum percentage of involvement per core was an independent predictive factor of upgrading from biopsy grade 1 to grade ≥ 2. our study showed that patients’ age was not predictive of upgrading, which is consistent with other studies. also, we demonstrated a non-significant relationship between psa level and upgraded gs. findings in this study did not demonstrate a significant relationship between psa level and upgrading. keywords: gleason score; needle biopsy; prostate cancer; psa; radical prostatectomy introduction gleason score (gs), as well as other prognostic and diagnostic modalities including serum prostate specific antigen (psa) and prostate volume, can predict the possibility of tumor growth and metastasis during the life of patients with prostate cancer(1,2). since psa and prostate volume are not as accurate as gs, most physicians rely on biopsy results, especially gleason score, in order to counsel their patients(3). based on the prostate biopsy gs, clinicians choose the most appro1department of urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 2department of urology, shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 3department of radiology, iran university of medical sciences, tehran, iran. 4department of pathology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 5department of urology, shahid modares hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: department of urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. phone: +989112166808. email: sah_hojjati@yahoo.com received june 2020 & accepted october 2020 priate treatment for the management of patients; these therapeutic approaches range from non-invasive therapies such as active surveillance to invasive therapies such as ablative therapies (radiation therapy or cryotherapy) and even more invasive therapies such as radical prostatectomy (rp)(4-6). therefore, gs, as one the main diagnostic and prognostic factors, must be reliable enough so that physicians could make the best clinical decision. more recently, literature has emerged that offers contradictory findings about the discrepancy between urological oncology urology journal/vol 18 no. 4/ july-august 2021/ pp. 395-399. [doi: 10.22037/uj.v16i7.5985] vol 18 no 4 july-august 2021 138 preoperative gs and rp gs. upgrading of gs on rp specimens compared with transrectal ultrasound-guided biopsy (trus-gb) gs is observed in 31.8% to 52% of the cases, according to different studies(7,8). in a study conducted by dolatkhah et al. that included 100 patients, the rate of discrepancy for group and individual scoring of gs was 41% and 56%, respectively. the findings of their study indicated that although the agreement between core needle biopsy (cnb) gs and rp gs is fair to moderate, the feature of discrepancy, i.e. under-grading in low and intermediate grades and over-grading in high grades of cnb gs, could help in making more appropriate clinical decisions (9). in addition, although many studies have assessed the discrepancy between cnb gs and rp gs, there is a paucity of evidence regarding its predictive factors. identification of these factors can help clinicians to perform additional diagnostic tests and take more effective treatment measures for patients who have a higher risk of tumor progression when compared with their initial biopsy. consequently, the mismanagement of patients who have been incorrectly classified as low-risk could be significantly reduced. few articles have analyzed the discrepancy of gs between transrectal biopsy and radical prostatectomy in iran. in addition, we found no studies that have assessed the predictive factors of discrepancy in gs among the iranian population. therefore, in this cross-sectional study, we aimed to determine the discrepancy between cnb gs and rp gs and to identify its predictive factors among the iranian population. materials and methods study design and setting this retrospective cross-sectional study was conducted between december 2017 and september 2019 in tehran, iran. this study was performed in the urology department of three affiliated hospitals of shahid beheshti university of medical sciences (smbu), labdiscrepancy of biopsy and rp gleason scoreabedi et al. endourology and stones diseases 130 bafinezhad hospital, shohadaye tajrish hospital, and shahid modarres hospital that are located in the east, north, and west of tehran, respectively. study participants a total of 1147 patients who underwent radical prostatectomy from 2009 to 2019 in the three previously mentioned hospitals were initially enrolled in the study. after consideration of the inclusion and exclusion criteria, 439 patients were finally included. among the 708 excluded patients, 423 patients had incomplete medical records, and 285 patients had received neo-adjuvant hormone therapy, chemotherapy, or radiotherapy. all the patients had undergone standard 12 core biopsy. patients who had undergone fusion biopsy or saturation biopsy were not included in this study. variables and data collection the demographic variables and clinical data including age, psa level, prostate volume, psa density, gs derived from ultrasonography-guided core needle biopsy cnb specimens, gs derived from rp specimens were collected from the medical records of patients with prostate adenocarcinoma and were reviewed by a urology resident. incomplete medical records were also completed after direct phone calls to the patients. radical prostatectomies were performed with the retropubic method by expert urologists. prostate volume was measured using prostate ellipse dimension theory. the specimens that were extracted from cnb and rp were reviewed by a single pathologist in order to reduce possible diagnostic biases. upgrading of gs was defined as an increase in gs of the pathological specimen derived from rp compared with gs of the pathological specimen derived from cnb, whereas downgrading of gs was defined as a decrease in rp gs compared with cnb gs. statistical analysis statistical analysis was done by using the social sciences software version 21. qualitative data were analyzed table 1. a comparative analysis between the upgraded and the non-upgraded groups. parameters total group 1 (upgraded) group 2 (non-upgraded) p-value number (%) 439 (100) 144 (32.8) 295 (67.2) age, mean ± sd (years) 64.5 ± 7.2 64.3 ± 8.2 64.6 ± 6.7 0.7 psa (ng/ml/gr) 14.8 (2.5-107) 18.7 (6.1-107) 14.7 (2.5-54) 0.2 abnormal finding in dre, n (%) 77 (17.6%) 37 (25.7%) 40 (13.5%) 0.01 prostate volume, ml 44.4 ± 16.4 32 ± 5.7 49.7 ± 14.6 0.0001 positive cores, mean ± sd 4.3 ± 1.4 5.1 ± 1.4 3.8 ± 1.2 0.0001 maximum % cancer per core 50.7 52 47.2 0.2 gleason score upgrading, n (%) grade 1 179 (41) 94 (52) 85 (48) 0.0001 grade 2 54 (12) 11 (17) 43 (83) 0.1 grade 3 41 (9) 15 (35) 26 (65) 0.7 grade 4 76 (17) 24 (31) 52 (69) 0.8 grade 5 89 (20) 0 (0) 89 (100) 0.0001 pathologic t stage, n (%) pt2a 18 (4) 0 (0) 18 (6.1) 0.02 pt2b 15 (3) 10 (6.9) 5 (1.6) 0.2 pt2c 165 (37) 57 (27.7) 108 (36.6) 0.8 pt3a 144 (32) 51 (35) 93 (31.5) 0.4 pt3b 128 (29) 40 (30) 88 (29.8) 0.4 perineural invasion, n (%) 235 (53.5) 97 (67.3) 138 (46.7) 0.5 extracapsular extension, n (%) 216 (49.2) 89 (61.9) 127 (43) 0.002 positive surgical margins, n (%) 135 (30.7) 50 (34.7) 85 (29) 0.3 seminal vesicle invasion, n (%) 44 (10) 28 (19) 16 (5.4) 0.001 positive lymph nodes, n (%) 21 (4.7) 14 (9.6 ) 7 (2.3) 0.008 abbreviations: psa, prostate specific antigen; dre, digital rectal examination; sd, standard deviation vol 18 no 4 july-august 2021 396 using the chi-square test, and quantitative data were analyzed using the independent t-test and mann-whitney u test. a p-value of 0.05 or less was considered statistically significant in this study. results a total of 439 patients were finally included in our study. the average age of patients was 64.5 years (range 48‐84 years), and the average preoperative psa was 14.8 ng/ ml. after histopathological examination, no changes in gs were observed in 237 (53.9%) patients, whereas gs was upgraded in 144 (32.8%) patients and downgraded in 58 (13.2%) patients at rp (table 1). prostate volume in the upgraded group was significantly lower than the non-upgraded group (p < .001). the number of positive core biopsies and patients with an abnormal finding in dre were significantly higher in the upgraded group compared with the non-upgraded group (p < .001, p = .01, respectively). the highest increase in gs was seen in the grade 1 group (p < .001). the non-upgraded group had a lower pathology stage as opposed to the upgraded group (p = .02). the number of patients who had extracapsular extension, seminal vesicle invasion and positive lymph nodes was significantly higher in the upgraded group compared with the non-upgraded group (p = .002, p = .001, p = .008, respectively) (table 1). discussion in terms of prostate cancer management, gs determined by cnb has an important role in treatment selection (10,11). precision of gs is of significant importance in patients undergoing active surveillance or radiotherapy. underestimated gs contributes to an inappropriate treatment strategy and thus, patients may not receive the best treatment. although trus-gb is the most cost-benefit modality for prostate cancer diagnosis, pathology errors, borderline pathology grades, and sampling errors contribute to a mismatch between cnb gs and the corresponding rp gs (12). the most common sampling error happens when biopsies are taken from different places of the higher grade components at rp, which leads to the undergrading of prostate cancer. sampling a tertiary higher grade component on cnb, which is not routinely mentioned in rp reporting, results in an apparent upgrading on ultrasound-guided biopsy. an underestimated gs is the most common problem associated with trus-gb (13). our study showed that gs was upgraded at rp in 32.8% of the cases; consistent with other studies. according to many studies, an enlarged prostate size is associated with lower rates of upgrading (14,15). in our study, there was a steady decrease in upgrading with the prostate size extending up to 49.7 g. there was also an association between downgrading and extending prostate size. in multivariate logistic regression analysis, we discovered that smaller prostate volumes (< 32 ml) were independent predictors of upgraded gs at rp. likewise, freedland et al.(16) showed that smaller bulks of the prostate are associated with advanced gs. due to the greater risk of high-grade disease in men with small prostates, smaller prostate volumes are most probably upgraded after rp. the other reason is that prostate size has an effect on the psa level; hence, the prostate size is a confounding factor in the interpretation of psa levels. several studies have shown a correlation between the number of positive cores on biopsy and upgrading(17-19). the number of involved cores and the maximum percentage of involvement per core were predictive factors of upgrading in our study. in addition, a higher maximum percentage of involvement per core was an independent predictive factor of upgrading from biopsy grade 1 to grade ≥ 2. our results showed that patients’ age was not predictive of upgrading, which is in parallel with other studies (17,20). also consistent with other studies, we demonstrated that the clinical stage of disease was not a predictive factor(21,22). most of the previous studies have stated that serum psa levels weakly predict upgrading(15,18,21). higher psa levels are correlated with larger tumor bulks, and on the other hand, a relationship exists between tumor size and tumor grade after rp. therefore, it is highly likely that patients with gs 6 on transrectal biopsy and higher psa levels will be upgraded at rp. our study demonstrated a relationship, although non-significant, between serum psa level and upgraded gs. one study revealed a correlation between the percentage of free psa and upgrading(23). psa velocity and free psa percentage were not evaluated in our study. because both higher serum psa levels and lower prostable 2. comparing peak flow rate (q max) and international prostate symptom score (ipss) variables in op and turp group without re-operation. variable turp (n=61) op (n=80) pvalue peak flow rate (q max), mean ± sd (range) before 9.1 ± 1.3 (8-11) 9.2 ± 1.3 (8-11) 0.61 after 1 month 14.2 ± 1.5 (10-16) 14.3 ± 1.5 (13-16) 0.99 after 3 month 16 ± 1.6 (13-17) 16.4 ± 2.3 (15-18) 0.25 after 6 month 16.7 ± 2.2 (13-18) 17.2 ± 2.4 (16-19) 0.48 after 9 month 16.7 ± 1.9 (14-18) 17.1 ± 2.2 (16-19) 0.23 after 12 month 17 ± 2.4 (14-19) 17.3 ± 1.6 (16-19) 0.14 international prostate symptom score (ipss) before 28.4 ± 3.2 (23-30) 29.2 ± 3.1 (27-32) 0.11 after 3 month 19.3 ± 2.8 (17-22) 18.4 ± 2.6 (16-20) 0.53 after 6 month 17.6 ± 3.1 (15-19) 17.5 ± 2.4 (16-20) 0.93 after 12 month 17.5 ± 2.5 (15-19) 17.3 ± 2.4 (16-20) 0.82 abbreviations: op, open prostatectomy; turp, transurethral resection of the prostate; sd, standard deviation; ipss, international prostate symptom score discrepancy of biopsy and rp gleason scoreabedi et al. urological oncology 397 tate weights are correlated with upgrading, psa density is speculated to be more specifically associated with upgrading rather than psa level alone(24). however, the findings of this study did not demonstrate a significant relationship between psa level and upgrading. many studies have reported that widespread biopsies are correlated with decreased rates of upgrading (20,25,26). however, in our study, widespread transrectal biopsies were not performed and were regarded as the yardstick of care; hence, this factor was not considered in our study. a few studies have mentioned gs downgrading after rp, with percentages ranging from 29% to 56% (15,17) (16, 21). in the current study, the reported gs on needle biopsy was lower than rp gs in 13.2% of the cases. moussa et al. mentioned a 7.3% occurrence of downgrading from gs 3 + 4 = 7 to gs ≤ 6 (14,15). furthermore, some researchers have reported that mri-ultrasound fusion guided biopsy is less likely associated with gs upgrading; however, this issue was not investigated in our study. conclusions according to previous studies, an enlarged prostate size is associated with lower rates of upgrading. in our study, there was a steady decrease in upgrading with the prostate size extending up to 49.7 g. there was also an association between downgrading and extending prostate size. due to the greater risk of high-grade disease in men with small prostates, smaller prostate volumes are most probably upgraded at rp. a higher maximum percentage of involvement per core was an independent predictive factor of upgrading from biopsy grade 1 to grade ≥ 2. our results showed that patients’ age was not predictive of upgrading, which is consistent with other studies. also, our study demonstrated a non-significant relationship between psa level and upgraded gs. acknowledgement we would like to appreciate archive staff in shohada-e-tajrish and modarres and labbafinejad hospitals for their cooperation. conflict on interest the authors declare that they have no conflict of interest. references 1. 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bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent—update 2013. eur urol. 2014;65:124-37. 12. epstein ji, feng z, trock bj, pierorazio pm. upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified gleason grading system and factoring in tertiary grades. eur urol. 2012;61:1019-24. 13. xu n, wu y-p, li x-d, et al. risk of upgrading from prostate biopsy to radical prostatectomy pathology: is magnetic resonance imagingguided biopsy more accurate? j cancer. 2018;9:3634. 14. moussa as, kattan mw, berglund r, yu c, fareed k, jones js. a nomogram for predicting upgrading in patients with low‐ and intermediate‐grade prostate cancer in the era of extended prostate sampling. bju int. 2010;105:352-8. 15. moussa as, li j, soriano m, klein ea, dong f, jones js. prostate biopsy clinical and pathological variables that predict significant grading changes in patients with intermediate and high grade prostate cancer. bju int. 2009;103:43-8. 16. freedland sj, isaacs wb, platz ea, et al. prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: a search database discrepancy of biopsy and rp gleason scoreabedi et al. vol 18 no 4 july-august 2021 398 study. j clin oncol. 2005;23:7546-54. 17. ruijter e, van leenders g, miller g, debruyne f, van de kaa c. errors in histological grading by prostatic needle biopsy specimens: frequency and predisposing factors. the journal of pathology: j pathol. 2000;192:22933. 18. richstone l, bianco fj, shah hh, et al. radical prostatectomy in men aged≥ 70 years: effect of age on upgrading, upstaging, and the accuracy of a preoperative nomogram. bju int. 2008;101:541-6. 19. stav k, judith s, merald h, leibovici d, lindner a, zisman a. does prostate biopsy gleason score accurately express the biologic features of prostate cancer? paper presented at: urol oncol: seminars and original investigations, 2007 sep 1(vol .2, no.5, pp. 383-386). elsevier. 20. hong sk, han bk, lee st, et al. prediction of gleason score upgrading in low-risk prostate cancers diagnosed via multi (≥ 12)-core prostate biopsy. world j urol. 2009;27:271-6. 21. gofrit on, zorn kc, taxy jb, et al. predicting the risk of patients with biopsy gleason score 6 to harbor a higher grade cancer. j urol. 2007;178:1925-8. 22. budäus l, graefen m, salomon g, et al. the novel nomogram of gleason sum upgrade: possible application for the eligible criteria of low dose rate brachytherapy. int j urol. 2010;17:862-8. 23. davies jd, aghazadeh ma, phillips s, et al. prostate size as a predictor of gleason score upgrading in patients with low risk prostate cancer. j urol. 2011;186:2221-7. 24. corcoran nm, hovens cm, hong mk, et al. underestimation of gleason score at prostate biopsy reflects sampling error in lower volume tumours. bju int. 2012;109:660-4. 25. freedland sj, kane cj, amling cl, et al. upgrading and downgrading of prostate needle biopsy specimens: risk factors and clinical implications. urology. 2007;69:495-9. 26. capitanio u, karakiewicz pi, valiquette l, et al. biopsy core number represents one of foremost predictors of clinically significant gleason sum upgrading in patients with lowrisk prostate cancer. urology. 2009;73:108791. discrepancy of biopsy and rp gleason scoreabedi et al. urological oncology 399 endourology and stone disease efficacy and safety of ntrap® stone entrapment and extraction device for ureteroscopic lithotripsy kehua jiang1†, musa male2†, xiao yu2, zhiqiang chen2, fa sun1*, huixing yuan2** purpose: ntrap® stone entrapment and extraction device (ntrap®) is a device used to extract and remove stones from the urinary tract and to minimize retrograde stone migration during ureterolithotripsy (urs). this study aimed to evaluate the efficacy and safety of ntrap® in urs. methods: from jan 2014 to june 2017, 148 patients underwent urs with the aid of ntrap® (group a), and 209 patients underwent standard urs without any anti-retropulsion device (group b). their demographics, operation time, complications, stone migration rate, and stone-free rate (sfr) were recorded for comparison. results: compared with group b, group a had a significantly shorter operative and lasering time (p = 0.003, p<0.001, respectively). there was no significant difference between the 2 groups in overall complications, a decrease in mean hemoglobin, and length of stay (los) (p = 0.426, p = 0.097, p = 0.058, respectively). the incidence of stone migration was significantly lower in group a than group b (p = 0.035). the postoperative auxiliary procedure rate (in patients with stones retropulsion during the operation) was significantly lower in group a compared to group b (p = 0.024). the sfr was considerably higher in group a than group b (p = 0.009). conclusion: urs, with the aid of ntrap®, is an effective and safe method for treating ureteric stones. it may prevent stones from retropulsion and shorten the operative time. keywords: ureteroscopic lithotripsy; ntrap®; ureteric stones; stone free rate introduction retropulsion migration of stone fragments into the renal pelvis, calyces or both during ureterolithotripsy (urs) is a persistent problem that increases the chances of re-treatment or auxiliary procedures and subsequent cost. it is one of the challenges to deal with during ureteric stone management, especially proximal ureteric stones(1-3). migration of stone fragments is influenced by several factors such as the pressure of irrigation fluid, degree of proximal ureteral dilation, stone site, the degree of stone impaction, lithotripter type and experience of the surgeon(4). an estimate of 5% to 40% of retropulsion of stone fragments occurs during intracorporeal lithotripsies(5). however, some other studies reported that stone migration rate might reach up to 60% when patients undergo urs by pneumatic lithotripsy (urs-pl)(6-8). with the advancement in technology, several devices have been developed to prevent stone retropulsion and facilitate fragments extraction during urs(5,9-16). these traverse from stone trap devices such as ntrap®, stone cone™, accordion™ backstop™, escape™, and lithocatch™ to suction devices (lithovac™) and even balloon catheters (passport™)(17-23). the ntrap® is a relatively novel device designed to minimize retrograde 1department of urology, guizhou provincial people’s hospital, guiyang, 550002, china. 2department of urology, tongji hospital, tongji medical college, huazhong university of science and technology, wuhan 430030, china. *correspondence: department of urology, guizhou provincial people’s hospital, guiyang, china. phone: 86-851-85922979. fax: 86-851-85922979. email: sfgmc@sina.com. ** department of urology, tongji hospital, tongji medical college, huazhong university of science and technology, wuhan 430030, china. phone: 86-27-836-65208. fax: 86-27-836-65208. email: tjmwyhx@163.com. received september 2019 & accepted february 2020 migration of ureteral stones and enables extraction and removal urinary stone fragments plus other foreign bodies from the urinary tract during urs (laser, ultrasonic, electrohydraulic, or pneumatic lithotripsy). we performed this study to evaluate the safety and efficacy of ntrap® during holmium laser urs for the management of ureteral stones. patients and methods study population from january 2014 to june 2017, patients diagnosed with ureteric stone were retrieved from the archives of tongji hospital of huazhong university of science and technology. patients were divided into 2 groups, group a contained 148 patients undertaking holmium laser (lumenis, usa) ursl and with the aid of ntrap® (cook urological, bloomington, in, usa), while group b contained 209 patients undertaking the standard holmium laser ursl without the aid of any anti-retropulsion device. all patients were diagnosed with ureteral stones by computed tomography (ct) and intravenous urography (ivu). the demographic characters, including age, gender, bmi, stone size, stone location, stone laterality, and hydronephrosis severity were recorded. routine blood examinations, urine analurology journal/vol 18 no. 2/ march-april 2021/ pp. 160-164. [doi: 10.22037/uj.v0i0.5584] ysis and culture, serum biochemistry, abdominal ultrasonography, ct, and ivu were evaluated. the inclusion criteria were: patients with ureteric stones (as diagnosed and measured by multi-slice spiral ct and ivu) who undertook standard urs or urs with the aid of ntrap stone extractor, and age >18 years. the exclusion criteria were: patients with ureteral stricture, ureteral stones combined with ipsilateral intrarenal stones, sepsis, age < 18 years, history of open surgery, congenital anomalies or pregnancy. surgical technique ntrap® stone entrapment and extraction device consist of a 2.8-fr flexible sheath 145-cm in length, a removable handle, and a 7 mm basket design. it is made from tightly woven nitinol wires with resilient shape memory characteristics that allow the basket to retain its shape after deployment. all the procedures were performed in lithotomy position under general anesthesia using semirigid ureteroscopic (8f/9.8 f wolf) combined with holmium laser (lumenis, usa) to disintegrate the stones(24,25). in group a, the basket of ntrap® bypassed the stone to entrap stones in place for laser disintegration and prevent retropulsion migration of stone fragments into the renal pelvis. all fragments were extracted from the ureter under direct vision with the ntrap® and released into the bladder. if the stone was embedded inside the ureteric mucosa (polypoid or edema), laser polypectomy was done first to create a channel through which the ntrap® device was passed. in group b, laser lithotripsy was conducted to fragment stones into small pieces. stone fragments were retrieved from the ureter with the help of ureteroscopic forceps. surgery was concluded when no fragments remained in the whole ureter. double-j stents were placed in those patients with ureteric injuries in either group. variables in observation were both clinical and surgical characteristics, which included lasering time, overall operative time, ureter stent insertion, intraand post-operative complications according to clavien–dindo classification systems, and stone-free rates (sfr). postoperative ct was performed after 6 weeks to evaluate the sfr. ancillary procedures such as swl, and flexible urs were recorded. no residual stones or presence of any asymptomatic fragments ≤ 4 mm on ct at 6 weeks after the operation was considered as successful outcomes. postoperative follow-up lasted for at least 3 to ntrap® device for ureteroscopic lithotripsy-jiang et al. table 1. baseline data of selected patients variable group a (n=148) group b (n=209) p value age, year 44.9 ±.0.8 42.5 ± 14.2 0.084 gender, n 0.280 male 103 134 female 45 75 bmi, kg/m2 24.2 ± 3.8 23.4 ± 3.4 0.069 stone laterality 0.188 left 61 102 right 87 107 mean stone size, mm 16.0 ± 3.2 16.7 ± 3.6 0.081 stone site 0.178 proximal 132 176 distal 16 33 hydronephrosis 0.197 no or mild 52 60 moderate or severe 96 149 urinary infection 21 30 0.965 positive urinary culture 6 11 0.597 surgery history swl 19 26 0.911 urs 12 18 0.866 group a: urs with the aid of ntrap stone extractor; group b: urs without any anti-retropulsion device; bmi: body mass index. group a: urs with the aid of ntrap stone extractor; group b: urs without any anti-retropulsion device abbreviations: los: length of hospital stay; sfr: stone-free rate; swl: shockwave lithotripsy; furs: flexible ureteroscope. variable group a (n=148) group b (n=209) p value operative time, min 41.8 ± 8.7 44.8 ± 9.3 0.003 mean lasering time, min 10.6 ± 3.7 16.9 ± 5.0 0.000 mean hemoglobin reduced, g/dl 0.88 ± 0.42 0.80 ± 0.39 0.097 stone migration rate (%) 5(3.4%) 19(9.1%) 0.035 overall complications, n (%) 4 9 0.426 bleeding 0 2 postoperative fever 2 3 ureteric injury 2 4 los 4.0 ± 0.6 4.2 ± 0.7 0.058 ureter stent remove, d 30 30 sfr at 6 weeks follow up 95.9% (142/148) 88.0% (184/209) 0.009 auxiliary procedures 5 20 0.024 swl 1 4 immediately furs 4 16 table 2. operative and postoperative data statistics. endourology and stones diseases 161 6 months. the ethics committee approved the study, and all patients were informed about this study and a signed written consent were obtained. statistical analysis statistical package for the social sciences (spss) version 16 was utilized for statistical analysis. descriptive statistics were used to present the general data. the chisquared test and fisher exact test were utilized to compare the differences between the 2 groups. a p < 0.05 was considered statistically significant. results characteristics of all patients are summarized in table 1. both groups had comparable preoperative parameters such as age, gender, bmi, stone size, stone location, stone laterality, degree of hydronephrosis, urinary tract infection (uti) rate, and surgical history (p > 0.05; table 1). compared with group b, patients who underwent urs with the aid of ntrap (group a) had a significantly shorter operative time and lasering time (p = 0.003, p=0.000, respectively) (table 2). in group a, 2 patients suffered from postoperative fever and 2 from ureteric injury. in group b, 2 patients presented with hemorrhage, 3 with postoperative fever, and 4 with a ureteric injury. the overall complications in group a and group b were comparable (p = 0.426; table 2). there was no significant difference between the 2 groups with regards to mean hemoglobin reduction and length of hospital stay (los) (p = 0.097, p = 0.058, respectively; table 2). the instantaneous success rate of stone fragmentation during the operation was significantly higher in group a (only 5 patients with stone retropulsion) than in group b (19 patients with stone migration into the pelvic or calyx). the incidence of stone migration was significantly lower in group a compared to group b (p = 0.035; table 2). regarding subsequent treatment, 1 patient in group a underwent swl and 4 furs while in group b, 4 patients underwent swl and 16 furs. the rate of requiring a postoperative auxiliary procedure was significantly lower in group a than group b (p = 0.024; table 2). no residual stones or the presence of asymptomatic fragments ≤ 4 mm on ct at 6 weeks after the operation was considered as a successful outcome. the sfr was 95.9% (142/148) and 88.0% (184/209) in group a and group b, respectively which was statistically significant (p = 0.009; table 2). discussion both the american urological association (aua) and the european association of urology (eau) recommend urs as the first-choice treatment for ureteral stones > 10 mm. with the advancement of surgical technology, an increase in higher sfr and low morbidity have been achieved in urs(2,3,26,27). lam et al. reported that urs had achieved higher sfr and lower complication rates analogous to those of swl when managing large upper ureteric stones(2). moreover, the miniaturization of ureteroscopy and improved intracorporeal lithotripsy technology have made it possible to successfully access and manage any stone within the ureter by relatively atraumatic fashions(28). however, some limitations remain, including incomplete fragmentation, lack of stone extraction, stone migration and residual fragments. some studies reported that stone migration rate might reach as high as 60% after ureteroscopic lithotripsy(6,29,30) indicating that ureteral stone migration is one of the most significant challenges during ursl. knispel et al.(7) reported that 40% and 5% of ureteric stone migrations occurred from the proximal and distal ureter, respectively during urs. stone retropulsion might increase operative time along with complication rate as a result of a change from semi-rigid to flexible ureteroscope(31). migrated stones might require an auxiliary procedure even after the surgical procedure(6,8,32). migration of stone fragments is influenced by many factors, which include pressure of irrigation fluid, stone location, degree of stone impaction, lithotripter, and experience of the surgeon(4). various strategies have been employed to obviate retrograde migration of stone fragments during intracorporeal lithotripsy. fortunately, the new emerging occlusive instruments may primarily overcome this great existing dilemma. amongst the commercially available novel devices (accordion™, stone cone™, and ntrap®, etc.), stone cone™ has been reported to be highly effective in preventing stone retropulsion in several studies with 100% success rate during urs for proximal ureteral stones(19-22,33). the accordion™ device, on the other hand, is among the most recent development and now is under investigation in clinical trials(34). there is, however, a limited number of studies concerning the effectiveness of ntrap® in endourological practice. the ntrap® stone occlusion device is also a relatively new ureteral occlusive device that prevents migration of stone fragments during urs. the ntrap® is composed of a tightly woven mesh of nitinol wires that mainly consists of the inner wire and the outer radio-opaque carrying catheter. the inner wire is a shape memory alloy that has a 7 mm sized umbrella designed basket. ntrap® device has 2.8 fr diameter with a total length of 145 cm. lee et al. reported the efficacy of the ntrap for managing ureteric stones with a 98.7% success rate(5). ouwenga et al. reported that the difference in strength for inner wire advancing was clinically insignificant between stone cone™ and ntrap®(35). a meta-analysis demonstrated that ntrap® stone occlusion device was efficient in halting stone retropulsion during ursl for proximal ureteric stones(17). nevertheless, this meta-analysis included only included 3 studies with a small sample size. therefore, occlusive devices represent a new generation of technology that can minimize proximal ureteric stone migration. our study demonstrated a significantly lower incidence of stone migration (table 2) with the use of ntrap® device than without any anti-retropulsion device, especially for proximal ureteric stones. the ntrap® not only prevents stone migration but may also function as a useful tool for stone fragment extraction. economic efficiency can be another strong reason for choosing ntrap®, which can save time and cost by lowering the stone retropulsion rates. stone retropulsion involves unnecessary procedures, for instance, prolonged operative time, rigid-flexible ureteroscope alteration, besides additional operations. our study showed that patients who underwent ursl with the aid of ntrap® had a significantly shorter operative time and lasering time (table 2). furthermore, our study showed that the ntrap® device for ureteroscopic lithotripsy-jiang et al. vol 18 no 2 march-april 2021 162 rate of requiring a postoperative ancillary procedure for the management of stone retropulsion was also significantly lower in ntrap group® (table 2). although we have achieved promising results with the use of ntrap® device during urs, the limited sample size might have thwarted an ultimate conclusion in favor of ntrap® stone entrapment and extraction device. therefore, prospective randomized control studies with larger sample sizes as well as multicenter trials are still necessary. there were some limitations in our study. the major limitation is that our study is a retrospective study, preoperative data evaluation is insufficient, selective bias and data heterogeneity may exist in our study. secondly, the sample size in our study was relatively small that had limited impact on the outcomes. some variables were influenced by the heterogeneities of patients’ conditions, surgeon's surgical skills and the sample size of studies. therefore, multicentre, larger sample size, randomized control studies are very necessary in the future. conclusions the ntrap® stone entrapment and extraction device is an effective and safe tool for minimizing retrograde stone migration or stone retropulsion together with facilitating the extraction of stone fragments from the urinary tract during ursl. acknowlegement this study was funded by the natural science foundation of hubei province of china (number: 2017cfb516, 2017cfb638), national natural science foundation of china (number: 81873608), foundation of health and family planning commission of guizhou province (number: gzwjkj2019-1-127) and doctoral foundation of guizhou provincial people’s hospital (gzsybs[2018]02). conflict of interest the authors declare no conflicts of interest. references 1. hollenbeck b, k., schuster t, g. , faerber g, j . , wolf j, jr . . comparison of outcomes of ureteroscopy for ureteral calculi located above and below the pelvic brim. urology. 2001;58:351-6. 2. lam js gt, gupta m. treatment of proximal ureteral calculi: holmium:yag laser ureterolithotripsy versus extracorporeal shock wave lithotripsy. j urol. 2002;167:1972-6. 3. ho a, sarmah p, bres-niewada e, somani bk. ureteroscopy for stone disease: expanding roles in the modern era. cent european j urol. 2017;70:175-8. 4. desai mr ps, desai mm, kukreja r, sabnis rb, desai rm, patel sh. the dretler stone cone: a device to prevent ureteral stone migration-the initial clinical experience. j urol. 2002;167:1985-8. 5. lee mj, lee st, min sk. use of ntrap(r) during ureteroscopic lithotripsy for upper ureteral stones. korean j urol. 2010;51:71923. 6. tunc l, kupeli b, senocak c, et al. pneumatic lithotripsy for large ureteral stones: is it the first line treatment? int urol nephrol. 2007;39:759-64. 7. knispel hh kr, heicappell r, miller k. pneumatic lithotripsy applied through deflected working channel of miniureteroscope: results in 143 patients. j endourol. 1998;12:513-5. 8. cimino s fv, russo gi, saita a, sortino g, castelli t, veroux m, madonia m, morgia g. pneumatic lithotripsy versus holmium:yag laser lithotripsy for the treatment of single ureteral stones: a prospective, single-blinded study. urol int. 2014;92:468-72. 9. zehri aa, ather mh, siddiqui km, sulaiman mn. a randomized clinical trial of lidocaine jelly for prevention of inadvertent retrograde stone migration during pneumatic lithotripsy of ureteral stone. j urol. 2008;180:966-8. 10. ali aa, ali za, halstead jc, yousaf mw, ewah p. a novel method to prevent retrograde displacement of ureteric calculi during intracorporeal lithotripsy. bju int. 2004;94:441-2. 11. mohseni mg, arasteh s, alizadeh f. preventing retrograde stone displacement during pneumatic lithotripsy for ureteral calculi using lidocaine jelly. urology. 2006;68:505-7. 12. delvecchio fc kr, preminger gm. clinical efficacy of combined lithoclast and lithovac stone removal during ureteroscopy. j urol. 2000;164:40-2. 13. kesler ss, pierre sa, brison di, preminger gm, munver r. use of the escape nitinol stone retrieval basket facilitates fragmentation and extraction of ureteral and renal calculi: a pilot study. j endourol. 2008;22:1213-7. 14. feng cc, wu z, jiang hw, ding q. a new stone occlusion device for upper ureteral calculi: preliminary clinical outcomes. minim invasive ther allied technol. 2012;21:351-4. 15. sanguedolce f, montanari e, alvarez-maestro m, et al. use of xenx, the latest ureteric occlusion device with guide wire utility: results from a prospective multicentric comparative study. world j urol. 2016;34:1583-9. 16. ahmed m, pedro rn, kieley s, akornor jw, durfee wk, monga m. systematic evaluation of ureteral occlusion devices: insertion, deployment, stone migration, and extraction. urology. 2009;73:976-80. 17. ding h, wang z, du w, zhang h. ntrap in prevention of stone migration during ureteroscopic lithotripsy for proximal ureteral stones: a meta-analysis. j endourol. 2012;26:130-4. 18. feng c, ding q, jiang h, et al. use of ntrap during ureteroscopic holmium:yag laser lithotripsy of upper ureteral calculi. minim invasive ther allied technol. 2012;21:78-82. 19. maislos sd vm, albert ps, raboy a. efficacy of the stone cone for treatment of proximal ureteral stones. j endourol. 2004;18:862-4. 20. shabana w tm, dawod t. safety and efficacy of using the stone cone and an entrapment and ntrap® device for ureteroscopic lithotripsy-jiang et al. endourology and stones diseases 163 extraction device in ureteroscopic lithotripsy for ureteric stones. arab journal of urology. 2015;13:75-9. 21. dretler sp. the stone cone: a new generation of basketry. j urol. 2001;165:1593-6. 22. springhart wp, tan yh, albala dm, perelman j, teichman jm, preminger gm. use of stone cone minimizes stone migration during percutaneous nephrolithotomy. urology. 2006;67:1066-8. 23. wang cj, huang sw, chang ch. randomized trial of ntrap for proximal ureteral stones. urology. 2011;77:553-7. 24. mohammadzadeh rezaei ma, akhavan rezayat a, tavakoli m, jarahi l. evaluation the result of warm normal saline irrigation in ureteral endoscopic surgeries. urol j. 2018;15:83-6. 25. kashi ah. re: the evaluation of the result of warm normal saline irrigation in ureteral endoscopic surgeries: a randomized clinical trial. urol j. 2018;15:222-3. 26. kadyan b, sabale v, mane d, et al. large proximal ureteral stones: ideal treatment modality? urol ann. 2016;8:189-92. 27. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 28. zheng w, denstedt jd. intracorporeal lithotripsy. update on technology. urol clin north am. 2000;27:301-13. 29. osorio l, lima e, soares j, et al. emergency ureteroscopic management of ureteral stones: why not? urology. 2007;69:27-31; discussion -3. 30. leveillee rj, lobik l. intracorporeal lithotripsy: which modality is best? curr opin urol. 2003;13:249-53. 31. li j, yu h, zhou p, et al. application of flexible ureteroscopy combined with holmium laser lithotripsy and their therapeutic efficacy in the treatment of upper urinary stones in children and infants. urol j. 2019;16:343-6. 32. dretler sp. ureteroscopy for proximal ureteral calculi: prevention of stone migration. j endourol. 2000;14:565-7. 33. pardalidis np, papatsoris ag, kosmaoglou ev. prevention of retrograde calculus migration with the stone cone. urol res. 2005;33:61-4. 34. olbert pj, keil c, weber j, schrader aj, hegele a, hofmann r. efficacy and safety of the accordion stone-trapping device: in vitro results from an artificial ureterolithotripsy model. urol res. 2010;38:41-6. 35. ouwenga mk, sharma sk, holley pg, turk tm, perry kt. load-release points of two novel ureteral stone-trapping devices. j endourol. 2005;19:894-7. ntrap® device for ureteroscopic lithotripsy-jiang et al. vol 18 no 2 march-april 2021 164 endourology and stone disease 147urology journal vol 4 no 3 summer 2007 percutaneous nephrolithotomy of kidney calculi in horseshoe kidney mohammad reza darabi mahboub, ali ahanian, maryam zolfaghari introduction: the aim of this study was to evaluate percutaneous nephrolithotomy (pcnl) in horseshoe kidneys with calculi. materials and methods: between 1995 and 2005, we performed pcnl in 9 patients with horseshoe kidney. in 3 of them, there was a single calculus and the rest had multiple calculi in the pelvis and at least 1 in the calyxes. ultrasonography, plain abdominal radiography, and intravenous urography (ivu) were performed in all patients. we used fluoroscopy for entering the system and then, pneumatic or ultrasonic lithotripsy was used. results: in all except 1 patient (88.9%) we could access the system. single calculi in 3 patients were removed. in 5 patients with multiple calculi, the calculus causing obstruction was removed, and in 3, the calculi located in the calyxes were removed too. consequently, 66.7% were stone-free at the end of the procedure. in 2 patients, there were residual calculi in the calyxes and they underwent candidates for extracorporeal shockwave lithotripsy. conclusion: percutaneous nephrolithotomy can be used in patients with horseshoe kidney if the patient selection is appropriate and the surgeon is experienced enough. the success rate and complications are the same as the patients with normal anatomy. however, access to the lower calyx is more difficult due to its anatomic status. urol j. 2007;4:147-50. www.uj.unrc.ir keywords: urogenital abnormalities, horseshoe kidneys, percutaneous nephrolithotomy, urinary calculi department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran corresponding author: mohammadreza darabi, md department of urology, imam reza hospital, mashhad, iran tel: +98 511 854 3031 e-mail: j_darabi@yahoo.com received september 2006 accepted june 2007 introduction horseshoe kidney is the most common fusion abnormalities in the kidney and occurs in 1 per 400 people with the male-female ratio of 2:1.(1) urogenital abnormalities are detected clinically in all age groups; however, they are more common in the autopsy specimens of children. this is due to the higher incidence of the congenital abnormalities in pediatric patients some of which being in contrast to long survival.(2) the most common complication of horseshoe kidney is kidney calculus.(3) it was previously believed that such a high frequency of calculus formation in these patients was due to the higher rate of infection, stasis, and obstruction because of the abnormal position of the pelvis and the ureter. however, the last reviews are suggestive for metabolic causes in most of the patients.(4) extracorporeal shock wave lithotripsy (swl) is the method of choice for the treatment of small calculi.(5) for calculi larger than 2 cm, those in the anterior middle calyx, or those that do not respond to swl, percutaneous nephrolithotomy (pcnl) is preferred.(3) although the anatomical position of the collecting tubules in a horseshoe kidney interfere with the calculus passage after swl, percutaneous nephrolithotomy in horseshoe kidney—darabi mahboub et al 148 urology journal vol 4 no 3 summer 2007 this abnormal anatomic position causes pcnl to be easier and more safe.(3) also, the arteries entering the umbilicus of the kidney may originate from the aorta, hypogastric artery, or common iliac artery, and the site of kidney puncture is far from the main arteries.(2) the posterior position of the calyxes reduce the possibility of intestinal injury, as well.(3) hereby, we report our experience in pcnl for kidney calculi in patients with horseshoe kidney. materials and methods between october 1995 and october 2005, we had 9 patients with horseshoe kidney referred to imam reza hospital for pcnl. the major complaint of the patients was flank pain accompanied by gastrointestinal symptoms including nausea and vomiting. five patients had gross hematuria. laboratory tests including complete blood count, fasting blood glucose, blood urea nitrogen, serum creatinine, urinalysis, and urine culture (in case of positive urinalysis for infection) were performed in all patients. radiological assessments included plain abdominal radiography and intravenous urography (ivu) in all patients, and ultrasonography in 3. size and number of the calculi (stone burden) were determined. the horseshoe kidney was confirmed by ivu. due to the impossible spontaneous passage of the calculi and low success rate of swl, the patients were candidates for pcnl. potential complications of the pcnl were discussed with the patients and their families before the procedure and after taking written consent, they underwent pcnl. patients with urinary tract infection were treated, and 1 hour before the procedure, received prophylactic antibiotic (intravenous cephalothin, 1g). after induction of anesthesia, a 5-f ureteral catheter was inserted via cystoscope. in the prone position, the entrance site into the kidney was determined using fluoroscopic guidance and injection of diluted contrast medium. tilting the side of the calculus up to 30 degrees, the site of entrance was determined. due to deviation of the horseshoe kidney axis, a more medialized pathway was needed for entering the kidney. the appropriate place was the posterior auxiliary line at the end of the 12th rib. since most of the horseshoe kidney calyxes are dorsomedial or dorsolateral, a better position for kidney puncture in comparison with that in normal kidneys can be achieved.(2) we accessed the system from the lateral side of the sacrospinalis muscle. after entering the targeted calyx, a guide wire was placed, and using facial dilators, the tract was dilated up to 16 f. then, the tract was dilated up to 28 f, using metal dilators. a 28-f amplatz sheath was utilized and the relation between the interior part of the kidney and outside was maintained and nephroscopy was performed by a 24-f nephroscope. after washing the kidney and removal of the blood clots, the calculi were identified. a grasping forceps was used for removal of small calculi, and pneumatic and ultrasonic lithotripters were used for fragmentation of large calculi. results six patients (66.7%) were men and 3 (33.3%) were women with the age range of 20 to 59 years. five patients had the calculi in the left side and the 4 in the right. in 3 patients (33.3%), the calculus was solitary and in the other 6 (66.7%), there were multiple calculi in the pelvis and calyxes. four patients (44.4%) had previously undergone swl which was unsuccessful and in 1 (11.1%), the calculus was fragmented into small pieces which had not passed spontaneously. history of the surgery due to previous calculi was positive in 2 patients (22.2%). in 4 (44.4%), metabolic evaluations had been performed for the diagnosis of the cause of the calculus formation which were unremarkable. based on the results of urinalysis and urine culture, urinary tract infection was detected in 2 patients (22.2%) who underwent appropriate treatment. we could access the collecting system in 8 patients (88.9% success rate). after entering the kidney, the single calculi in 3 patients were removed. in 5 patients with multiple calculi, the one that had caused the obstruction was removed, and 3 patients became stone free. in the remaining 2 patients, all of the calculi could not be removed. overall, the stone-free rate was 66.7% (6 out of 9). residual calculi were present in 2 out of 8 patients with successful access (25%) in whom nephrostomy tube was placed and fixed. these patients underwent swl. tubeless and standard (nephrostomy tube and ureteral catheter) methods were used in 1 and 5 patients without residual calculi, respectively. in 1 patient that access to the system was not achieved, open surgery was performed. percutaneous nephrolithotomy in horseshoe kidney—darabi mahboub et al urology journal vol 4 no 3 summer 2007 149 intraoperative and postoperative bleeding that would require transfusion did not occur in any of the patients. in patents with nephrostomy catheter, it was clamped for 4 hours and then opened. on the 3rd postoperative day, it would be removed if there was no bleeding from the tube. the patients were discharged on the 4th postoperative day after removal of the ureteral catheter. the patient in the tubeless group was discharged on the 3rd day. discussion many factors affect the pcnl success rate in horseshoe kidneys. these kidneys are located inferior and medial to the normal place of the kidneys, and the superior and medial calyxes are more dorsalized. due to the anterior movement of the kidneys, we need a longer tract for achieving access to the kidney which may result in limitations in using the conventional rigid nephroscopes.(6) also, the abnormal position of the kidney causes abnormal neighboring with other organs, especially the colon that can be placed at the posterior part of the kidney.(7) therefore, antegrade access is safer than the retrograde access which needs computed tomography (ct) before the procedure.(8) in most cases, nephrostomy tract should be placed medially crossing the erector spinae and quadratus lumborum muscles. this makes a long and rigid tract accompanied by the rather immobility of the kidneys, and therefore, evaluation of all calyxes with a rigid nephroscope via a single nephrostomy tract is commonly impossible. in centers that routinely use antegrade nephrostomy techniques (as our center), nephrostomy tract is made medially, and there is no need for ct to evaluate the position of the colon in cases with horseshoe kidneys.(8) in 1985, the relation between the horseshoe kidney and retrorenal colon was firstly reported and it was stated that preoperative ct scan could show the retrorenal colon.(4) however, due to the low incidence of this condition (1%),(2) we did not use ct before the procedure. we routinely chose a more medial position than usual for the tract (nearer to the spine) in cases of horseshoe kidney. the ureter of the horseshoe kidney typically originates from the upper part of the pelvis and this may be accompanied by ureteropelvic junction obstruction and calculus formation.(9,10) entering the kidney via the upper pole facilitates access to the upper pole calyxes, the pelvis, the calyxes of the lower pole, and the proximal ureter. additionally, because the longitudinal axis of the nephroscope is along with the longitudinal axis of the kidneys, pressure on the kidney tissue by nephroscope and the subsequent bleeding reduces.(6) in 1 patient, we successfully accessed the kidney via the upper calyx. in patients with normal kidney anatomy, calyxes of the upper pole are in front of the ribs 11 and 12 and entering them needs a supracostal approach that may cause thoracic complications such as pneumothorax.(11) however, in a horseshoe kidney, since the kidney is placed lower than the normal position, there is usually no need for supracostal approach. usually, we can reach the pelvic calculi by a rigid nephroscope and fragment them using rigid instruments such as pneumatic and ultrasonic probes, but we can only reach calculi in the calyxes with flexible nephroscopes and should guide them to the parts that can be accessed by rigid or flexible instruments such as electrohydraulic or laser probes.(8) the medial calyxes of the lower pole may be hided by the spine and the calculus in them may not be seen during fluoroscopy; therefore, repeated pcnl may be needed. blood circulation is often abnormal in the horseshoe kidneys; however, in most cases, this is related to the displaced vessels in the isthmus and causes no problem for pcnl. the blood enters the kidney from the antromedial site and sometimes, the lower pole and isthmus of these kidneys are getting their blood supply directly from the aorta or the inferior hypogastric, external iliac, or common iliac arteries. consequently, the collecting system and blood supply provide a proper position for percutaneous procedure, and access can be made from the upper pole calyx. however, direct access to the isthmus calyxes are not suggested because the aberrant vessels often enter the kidney in a dorsomedial direction.(8) finally, it should be noted that flexible nephroscopes, longer rigid nephroscopes, and multiple access attempts are necessary to increase the possibility of achieving a stone-free outcome. the possibility of calculus fragmentation in horseshoe kidneys by swl is high, but the possibility of spontaneous passage of fragmented residues is low and often needs further intervention.(12,13) it has been reported that the most common type of the percutaneous nephrolithotomy in horseshoe kidney—darabi mahboub et al 150 urology journal vol 4 no 3 summer 2007 crystal in these kidneys is calcium oxalate which is similar to the normal kidneys and addresses the same metabolic factors.(6) additionally, results of the treatment with swl is different in these patients and the rate of becoming stone free is 27% to 28%, and these patients need more shocks in each swl session; incidence of repeated treatment is 30% in comparison with 10% in patients with normal kidneys.(2) conclusion it seems that performing pcnl is not more difficult in horseshoe kidneys than in normal kidneys. also, the rate of success and becoming stone free is comparable with the patients without anatomical abnormalities. therefore, we believe that pcnl is the treatment of choice for kidney calculi in a patient with horseshoe kidney who has not responded to or is not an appropriate candidate for swl. regarding the low prevalence of retrorenal colon, ct is not needed and the pelvis or upper calyxes can be served as proper access entrance sites if antegrade method is used. conflict of interest none declared. references 1. evans rm. percutaneous access in difficult kidney. in: sosa re, editor. textbook of endourology. 1st ed. philadelphia: wb saunders; 1997. p. 114-28. 2. campbell 2007 p. 1497-8. 3. yohannes p, smith ad. the endourological management of complications associated with horseshoe kidney. j urol. 2002;168:5-8. 4. evans wp, resnick mi. horseshoe kidney and urolithiasis. j urol. 1981;125:620-1. 5. esuvaranathan k, tan ec, tung kh, foo kt. stones in horseshoe kidneys: results of treatment by extracorporeal shock wave lithotripsy and endourology. j urol. 1991;146:1213-5. 6. raj gv, auge bk, weizer az, et al. percutaneous management of calculi within horseshoe kidneys. j urol. 2003;170:48-51. 7. skoog sj, reed md, gaudier fa, dunn np. the posterolateral and the retrorenal colon: implication in percutaneous stone extraction. j urol. 1985;134:1102. 8. al-otaibi k, hosking dh. percutaneous stone removal in horseshoe kidneys. j urol. 1999;162:674-7. 9. pitts wr, muecke ec. horseshoe kidneys: a 40-year experience. j urol. 1975;113:743-6. 10. baskin ls, floth a, stoller ml. the horseshoe kidney: therapeutic considerations with urolithiasis. j endourol. 1989;3:51-54. 11. munver r, delvecchio fc, newman ge, preminger gm. critical analysis of supracostal access for percutaneous renal surgery. j urol. 2001;166:1242-6. 12. jones dj, wickham je, kellett mj. percutaneous nephrolithotomy for calculi in horseshoe kidneys. j urol. 1991;145:481-3. 13. lampel a, hohenfellner m, schultz-lampel d, lazica m, bohnen k, thürof jw. urolithiasis in horseshoe kidneys: therapeutic management. urology. 1996;47:182-6. vol 17 no 04 july-august 2020 112 andrology the effects of microfluidic sperm sorting, density gradient and swim-up methods on semen oxidation reduction potential funda göde1,2*, ali sami gürbüz3, burcu tamer2, ibrahim pala2, ahmet zeki isik2 purpose: to compare the effects of microfluidic sperm sorting, density gradient and swim-up methods on the oxidative reduction potential (orp) of split semen samples from a single patient population. materials and methods: a prospective controlled study was conducted to compare the effects of three different semen processing methods using split semen samples from the same population of infertile men. the primary outcome was the orp. secondary outcomes were the sperm concentration, progressive motility rate and total sperm motility. results: a total of 57 split semen samples were included in this study. the orp was significantly lower in the microfluidic group compared to the density gradient and swim-up groups (p < 0.05). the orp/sperm concentration ratio was significantly lower in the microfluidic and density gradient groups compared to the swim-up group (p < 0.05). total sperm concentration was significantly higher in the density gradient group than the microfluidic and swim-up groups (p < 0.05). motility was significantly higher in the microfluidic and swim-up groups than the density gradient group (p < 0.05). the progressive motile sperm rate was significantly higher in the microfluidic and swim-up groups than the density gradient group (p < 0.05). conclusion: microfluidic sperm sorting was better for selecting highly motile sperm and yielded a lower orp than conventional sperm preparation methods. keywords: microchip; orp; ros; spermiogram; male infertility introduction the main aim of sperm preparation before intra-uterine insemination (iui) is to remove viruses, antibodies, leucocytes and debris from sperm, as well as to remove inhibitors of sperm capacitation factors, such as prostaglandins and reactive oxygen radicals(1,2). increased levels of reactive oxygen radicals and lipid peroxidation lead to dna damage and apoptosis of spermatozoa. this might be related to decreased fertilisation rates, implantation failure and abnormal embryo development(3). the standard sperm preparation techniques are simple washing, density gradient and swim-up procedures. in swim up method, motile sperm swim from a prewashed pellet up towards a layer of fresh medium for selection(4,5). in density gradient centrifugation method, sperm are filtered through layers of silane-coated silica particles suspended in nutritive media(6). centrifugation is used in both of these methods, and sperm prepared with centrifugation based methods showed a higher generation of ros and dna fragmentation in previous reports(7,8). therefore, these methods might be harmful to healthy spermatozoa. microfluidic sperm sorting is a new sperm preparation method that uses a microfluidic system to select sperm. microfluidic technology considers the flow of fluid from millimetric microchannels similar to the vaginal 1department of obstetrics and gynecology, bahçeşehir university school of medicine, istanbul, turkey. 2in vitro fertilization unit, izmir medicalpark hospital, izmir, turkey. 3department of obstetrics and gynecology, kto karatay university, konya, turkey. *correspondence: department of obstetrics and gynecology, bahçeşehir university school of medicine, istanbul, turkey. phone: 00905342544678. email: funda.gode@gmail.com received october 2019 & accepted april 2020 rugae system(9,10). most motile and healthy sperm swim through the pores of the membrane and are filtered into the upper part of the system, where they are finally taken from the outlet. centrifugation and other mechanical methods are not applied to sperm cells; therefore, most functional sperm with high dna integrity are selected via a physiological sorting system. it has been observed that there was less dna fragmentation and ros formation of sperm with microfluidic technology when compared with standard techniques(11). also one study showed that microfluidic sorting of unprocessed semen can be used to select clinically usable, highly motile sperm with nearly undetectable levels of dna fragmentation(12). oxidative reduction potential (orp) is a novel marker of oxidative stress and redox imbalance in biological samples(13,14). it is calculated by measuring the transfer of electrons from a reductant to an oxidant, to determine the balance between total oxidants and reductants in a biological system(14). therefore, orp can be used to distinguish abnormal and normal semen, and is also helpful to discriminate sperm from fertile and infertile patients(15-17). thus, orp has been suggested as a marker for evaluating semen quality in infertile males(18). microfluidic sperm sorting systems are now being used to aid assisted reproduction in many clinics; however, data are currently insufficient to warrant using these systems in routine clinical practice. in addition, there urology journal/vol 17 no. 4/ july-august 2020/ pp. 397-401. [doi: 10.22037/uj.v0i0.5639 ] are insufficient data on the effects of standard semen preparation methods and microfluidic sperm sorting systems on sperm quality and oxidative stress. therefore, in the present study, we compared the effects of the microfluidic sperm sorting, density gradient and swim-up methods on orp levels in split semen samples obtained from a single patient population. materials and methods this prospective study was a laboratory evaluation of split semen samples obtained from a single patient population; the samples were discarded after a routine semen analysis. this study was conducted at the in vitro fertilisation unit of izmir medical park hospital (izmir, turkey). bahçesehir university institutional review board approval was obtained for this study. semen preparation procedure semen samples were obtained by masturbation after 2–5 days of abstinence into a sterile, labelled container. all semen samples were incubated at 37°c for 30 min. density gradient technique the density gradient technique was performed according to the following steps. first, a gradient column was prepared by placing 1 ml of 80% gradient media (origio/medicult media) in a centrifuge tube with an additional 1 ml of 55% gradient media layered on top. next, 3 ml of semen was layered on top of the 55% layer and centrifuged at 1,400 rpm for 10 min. the supernatant and gradient medium just above the sperm pellet were removed and discarded. the sperm pellet was washed with 3 ml of sperm wash media and centrifuged at 1,600 rpm for 10 min. the supernatant was collected and resuspended to the final volume in 0.5 ml of sperm wash medium. swim-up technique a liquefied semen sample was placed in a tube and diluted 1:1 with sperm washing medium. the mixture was centrifuged for 10 min at 1,200 rpm. the supernatant was extracted and 1 ml fresh culture medium was layered above the pellet. the tube was placed on a stand, tilted at a 45° angle and incubated for 1 hour at 37°c. after incubation, 0.6 ml of the supernatant was placed into an empty tube for evaluation. microfluidic technique microfluidic sperm sorting was performed using the fertile plus chip (koek biotechnology, izmir, turkey), which is a flow-free, dual-chambered microfluidic single-use chip. the first collection chamber is the sample inlet, and fluid channels are separated from the second collection chamber by a microporous membrane. an untreated 850 µl semen sample was injected into the inlet chamber, and 700 µl sperm wash medium heated to 37°c was added to the microporous membrane (outlet chamber); the chip was incubated for 30 min at 37°c. the processed 650 µl sperm sample was collected from the outlet. oxidation reduction potential the orp was evaluated by a galvanostat-based system that measures redox potential using the male infertility oxidative system (mioxsys; aytu bioscience inc., englewood, co, usa). the system consists of a mioxsys analyser and a sensor strip. in total, 30 µl of a completely liquefied semen sample was loaded on the sample port and measured in millivolts (mv) for 4 min. the orp values were normalised by the sperm concentration and expressed as mv/106 sperm/ml. orp values > 1.37 mv/106 sperm/ml are indicative of oxidative stress(13-15). outcome measures and statistical analysis the primary outcome measure was the orp of the semen samples. secondary outcome measures were the total sperm concentration and motility. the statistical analysis was performed using spss software (version 20.0; spss inc., chicago, il, usa). for the statistical methods, for a comparison between k-related samples friedman test was used. for paired comparison between groups wilcoxon signed rank test was used. a two-sided p-value < 0.05 was considered significant. results a total of 57 split semen samples were evaluated in this study, and three sperm processing groups (microfluidic, density gradient and swim-up groups) were compared. raw liquefied semen samples were evaluated for each patient. the basal spermiogram parameters and basal orp levels are shown in table 1. the spermiogram parameters and orp levels of the three sperm processing groups are shown in table 2. when the orp and orp/sperm ratio were compared between in all groups (raw sample, microfluidic, density gradient and swim-up groups) there was a significant difference between all groups. to investigate the sperm parametersa basal volume (ml) 3.24 ± 1.57 concentration (106/ml) 55.63 ± 37.12 motility (%) 59.05 ± 14.96 progressive motility (%) 15.15 ± 9.02 tpmsc 97.35 ± 94.39 orp 39.24 ± 19.95 orp/conc 1.40 ± 1.68 table 1. basal spermiogram parameters of liquefied raw semen of patients. adata are presented as mean ± sd or number(percent) abbreviations: orp: oxidation reduction potential; tpmsc:total motile sperm count; conc:concentration sperm parameters microfluidic density-gradient swim-up p concentration (106/ml) 20.29 ± 19.01 35.70 ± 20.97 15.00 ± 13.33 0.007 motility (%) 98.57 ± 1.42 75.30 ± 14.32 95.33 ± 9.59 0.000 progressive motility (%) 60.00 ± 20.81 24.90 ± 6.26 59.55 ± 16.21 0.000 tpmsc 12.29 ± 11.25 15.40 ± 10.90 7.60 ± 6.74 0.386 orp 84.38 ± 26.19 259.83 ± 13.64 248.63 ± 23.27 0.000 orp/conc 8.52 ± 7.33 10.17 ± 7.57 57.53 ± 84.42 0.000 adata are presented as mean ± sd or number(percent) abbreviations: orp: oxidation reduction potential; tpmsc:total motile sperm count; conc:concentration table 2. comparison of spermiogram parameters and orp levels in microfluidic sperm sorting, density-gradient and swim-up groups. semen oxidation reduction potential variables-gode et al. andrology 398 vol 17 no 04 july-august 2020 399 difference between each group paired comparison were established in each group separately. basal level of orp and orp/sperm concentration ratio were found to be significantly lower in raw semen sample than three other groups (p < 0.05). also orp levels were significantly lower in the microfluidic group than the density gradient and swim-up groups (p < 0.05). the orp/ sperm concentration ratio was significantly lower in the microfluidic and density gradient groups than the swimup group (p < 0.05). total sperm concentration, motility, progressive motile sperm rate and total motile sperm count were significantly different between raw semen sample and three sperm processing groups (p < 0.05). when each group was evaluated by paired comparison, total sperm concentration was significantly higher in the density gradient group than the microfluidic and swim-up groups (p < 0.05). motility was significantly higher in the microfluidic and swim-up groups than the density gradient group (p < 0.05). the progressive motile sperm rate was significantly higher in the microfluidic and swimup groups than the density gradient group (p < 0.05). total motile sperm count was not significantly different among the groups (p = 0.386). discussion assisted reproductive technologies have improved very rapidly over the last decade. however, sperm processing and selection methods have shown few changes during this time. it is clear that selecting healthy spermatozoa is imperative to ensure a successful pregnancy and healthy offspring. moreover, using the optimal semen processing method should provide the healthiest spermatozoa for assisted reproductive treatments. reactive oxygen species (ros) are vital for sperm maturation and capacitation, and for the acrosome reaction and oocyte fusion(19,20). however, excess ros can harm spermatozoa dna and cause apoptosis, which leads to reduced fertilisation, implantation failure, embryonic developmental problems and poor pregnancy outcomes(21,22). therefore, the orp is extremely important during sperm maturation and processing. conventional spermiogram parameters (concentration, motility and morphology), which are related to pregnancy rates, can vary within the same individual at different times, and among different populations(23,24). interobserver variability is also an important issue during spermiogram analysis(25). the orp can function as an advanced and independent marker of semen quality in infertile males(18). thus, we compared the effects of the two most common conventional sperm processing methods (density gradient and swim-up) to those of the microfluidic sperm sorting technique, in terms of basic spermiogram parameters and the orp. sperm concentration was higher in the density gradient group than the swim-up and microfluidic groups. at first glance, this would seem to be advantageous; however, the pellet includes both immotile and motile sperm after density gradient centrifugation. thus, swim-up and microfluidic sperm sorting were superior with respect to sperm motility than the density gradient technique. the proportion of motile sperm was significantly higher in specimens that underwent the microfluidic and swimup techniques versus the density gradient technique. in addition, the progressive motile sperm rate was significantly higher in the microfluidic and swim-up groups than the density gradient group. the number of progressive motile spermatozoa inseminated is one of the most important prognostic factors for pregnancy after iui(26). thus, we conclude that the microfluidic system is a good alternative to conventional methods, yielding a high motile sperm rate during iui cycles. it is clear that a high orp exposes the sperm to dna damage(27). dna integrity might be the most important factor in sperm processing, as it directly affects the dna of the embryo, and the subsequent offspring. normal spermiogram parameters do not always indicate healthy spermatozoa, and high dna fragmentation rates have been detected even in normozoospermic male partners in unexplained infertile couples undergoing iui(28,29). sperm dna damage is correlated with a lower pregnancy rate and longer time to pregnancy during both natural and iui cycles(30-34). in addition, significantly lower clinical pregnancy and delivery rates were reported in the context of high dna fragmentation rates, in both ivf and iui cycles(32,34). sperm chromatin assay parameters have been reported to be related to spontaneous abortion rates, where sperm dna damage may adversely affect the quality of post-implantation embryos(35). based on these findings, sperm preparation techniques might be an important factor in the dna fragmentation rate. conventional sperm preparation techniques depend on sedimentation and migration to separate spermatozoa, which exposes the sperm to dna-damaging ros(36). the results of previous studies are conflicting and there are limited data on this subject. amiri et al. reported higher levels of dna fragmentation in swimup versus density gradient samples(37). another report found no significant difference in the amount of apoptotic sperm recovered between the density gradient and swim-up methods(38). in contrast, improved dna fragmentation was reported after processing sperm using both the swim-up and density gradient methods in teratozoospermic men(39). few data are available on microfluidic sperm sorting(11,40-41). recently some studies noted that microfluidic-sorted sperm showed significantly less ros and dna fragmentation compared to those treated by the conventional swim-up method(11,41). also, quinn et al. reported that microfluidic sorting of unprocessed sperm was associated with nearly undetectable levels of dna fragmentation compared to the density gradient centrifugation and swim-up methods(12). our results support the aforementioned studies by showing that the orp was lower after microfluidic sperm sorting compared to the density gradient and swim-up methods. the advantages of microfluidic technology lie in the selection of higher concentrations of highly motile sperm, but with a shorter processing time, while also preserving overall sperm dna quality and integrity without a centrifugation step. no special technical skills or equipment are needed for the procedure. reduced variability due to human error and less potential for environmental contamination are other possible advantages(11). a limitation of this study was its laboratory-based design; we did not evaluate the effects of these sperm processing methods in the clinical setting. therefore, it was not possible to draw definitive conclusions regarding the clinical effects of microfluidic sperm sorting based on our results. however, this is the first study to compare the effects of the microfluidic sperm sorting, semen oxidation reduction potential variables-gode et al. density-gradient centrifugation and swim-up methods on the orp of semen. the adverse effects of centrifugation were demonstrated in the present study, and the orp was lower in unprocessed semen than in all of the processed semen samples. conclusions as a conclusion; microfluidic sperm sorting allows for the selection of highly motile sperm with a lower orp than conventional sperm preparation methods. however, randomised controlled studies are needed to evaluate the effects of this procedure in the clinical setting. conflict of interest the authors report no conflict of interest. references 1. aitken rj, buckingham dw, brindle j, gomez e, baker hw, irvine ds. analysis of sperm movement in relation to the oxidative stress created by leukocytes in washed sperm preparations and seminal plasma. hum reprod. 1995;10: 2061–71. 2. pasqualotto ff. investigation and assisted reproduction in the treatment of male infertility. rev bras ginecol obstet. 2007; 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4:439-45. 37. amiri i, ghorbani m, heshmati s. comparison of the dna fragmentation and the sperm parameters after processing by the density gradient and the swim up methods. j clin diagn res 2012; 6:1451-3. 38. jayaraman v, upahya d, narayan pk, adiga sk. the sperm processing by swim-up and density gradient is effective in the elimination of the sperm with dna damage. j assist reprod genet 2012; 29:557-63. 39. xue x, wang ws, shi jz, zhang zl, zhao wq, shi wh et.al. efficacy of swim-up versus density gradient centrifugation in improving sperm deformity rate and dna fragmantation index in semen samples from teratozoospermic patients. j assist reprod genet 2014; 31:1161-6. 40. schulte r, chung yk, ohl da, takayama s, smith gd. microfluidic sperm sorting device provides a novel method for selectingmotile sperm with higher dna integrity. fertil steril 2007; 88 (supp 1):576. 41. shirota k, yotsumoto f, itoh h, obama h, hidaka n, nakajima k, miyamoto s. seperation efficiency of a microfluidic sperm sorter to minimize sperm dna damage. fertil steril 2016; 105:315-21. unclassified changes in apoptosis-related proteins in the urothelium of rat bladder following partial bladder outlet obstruction and subsequent relief jong mok park1†, ji yong lee1†, yong gil na1, ki hak song1, jae sung lim1, seung woo yang1, seung hwan lee2, gun hwa kim2,3*, ju hyun shin1** purpose: to compose a comprehensible and fluent persian translation of the national institute of health chronic prostatitis symptom index (nih-cpsi), and to determine its linguistic validity in a persian sample population. methods: the standard double-back translation method, provided by the previous studies were utilized by three professional linguists to translate the english version of the nih-cpsi to persian, and a group of 10 urologists further reviewed and translated questionnaire. the questionnaire was then presented to the sample study, comprised of 60 men with cp/cpps and 60 controls with adverse urological history, and the collected data was analyzed through ibm-spss software to test its validity, evaluative, and discriminatory power, psychometric qualities and internal consistency. results: a total of 80 subjects (42 cp/cpps patients and 38 healthy controls) were considered eligible for this study. the total persian nih-cpsi scores and each subdomain showed significant difference (p < 0.001) between the two study groups, indicating a satisfactory discriminant validity for the index. psychometric analysis established the index to benefit from a high internal consistency. the translation was also considered by both the subjects and the physicians to be easily comprehensible. conclusion: the persian nih-cpsi is a reliable and valid instrument for evaluating cp/cpps symptoms in general population, while also benefitting from high discriminatory power, and can be utilized with ease in both clinical practice and laboratory studies. keywords: asymptomatic inflammatory prostatitis; asymptomatic inflammatory prostatitides; chronic prostatitis with chronic pelvic pain syndrome; national institute of health chronic prostatitis symptom index; prostatitis; prostatitides introduction partial bladder outlet obstruction (pboo) is a com-mon urinary tract disorder caused by a variety of urologic diseases, such as benign prostatic hyperplasia (bph), bladder neck contracture, and urethral stricture. sustained bladder overdistension caused by pboo decreases the blood flow and worsens the denervation of the bladder, resulting in functional change and oxidative damage of the urothelium(1,2). various animal studies have reported that repeated ischemic injury due to pboo leads to chronic damage to the urothelium(3). currently, research indicates that chronic ischemia/ reperfusion (i/r) may develop due to pathological pboo-induced oxidative stress(4). although various 1department of urology, school of medicine, chungnam national university hospital, daejeon 35015, republic of korea. 2tunneling nanotube research center, division of life science, korea university, seoul 02841, republic of korea. 3drug & disease target team, division of bioconvergence analysis, korea basic science institute (kbsi), cheongju 28119, republic of korea. *correspondence: tunneling nanotube research center, division of life science, korea university, seoul, republic of korea drug & disease target team, division of bioconvergence analysis, korea basic science institute (kbsi), cheongju, republic of korea. tel: +82 43 2405420. fax: +82 43 2405416. e-mail: genekgh@kbsi.re.kr. ** department of urology, school of medicine, chungnam national university, daejeon, republic of korea tel: +82 42 2807810. fax: +82 42 2807206. e-mail: sjh0402@cnu.ac.kr. † authors contributed equally to this work received november 2019 & accepted march 2020 mediators are reportedly related to changes in the bladder(5), the early stages of pboo-induced changes of the urothelium and related molecular signal pathways have not been well elucidated. hypoxia, due to i/r injury plays an essential role in the generation of various chronic diseases by increasing the levels of reactive oxygen species (ros)(6). thus far, many studies have described a significant association between ros and the mechanism of i/r(7). increased ros produce oxidative stress in the bladder and changes in the bladder occur via alterations in the blood vessels, nerves, and cellular fibrosis(8). if this oxidative damage exceeds the compensatory capacity of the bladder, the bladder proceeds to the decompensatory phase, resulting in apoptosis of the bladder tissue(5). to date, urology journal/vol 18 no. 2/ march-april 2021/ pp. 230-236. [doi: 10.22037/uj.v0i0.5799] it has reported that apoptosis is significantly associated with cellular death following i/r(9). however, there are few studies describing the molecular mechanisms related to the restoration of bladder dysfunction in its early stages followed by i/r-induced apoptosis. survivin, known as a member of the apoptosis inhibitor family, inhibits apoptosis through intracellular expression(10). several studies have described survivin as a tumor marker for the diagnosis of urinary cancer(11). in addition, survivin revealed a protective effect on oxidative stress caused by i/r in kidney, testis, and cerebra (12,13). at present, no study has described the role of survivin concerning the recovery of i/r-induced apoptosis and cellular alteration in the urothelium. in the present study, we investigated changes of apoptosis-related protein after pboo following subsequent relief and expression of survivin associated with apoptosis in the urothelium of a rat bladder. materials and methods animal model and experimental groups the experimental animals used in this study were female sprague-dawley white rats with a bodyweight of 180-220mg. we purchased sprague-dawley rats from damul science (daejeon, korea). all animals were fed normal chow and were exposed to a 12 h day/night light cycle. all processes were handled following the guidelines of the ethics committee of chungnam national university and the institutional animal care and use committee (irb no. cnu-099). sixty rats were subdivided into three groups: sham-operated (n = 20), pboo only (n = 20), and pboo plus subsequent relief (n = 20). all rats were anesthetized using by intramuscular injection of ketamine and xylazine before a lower midline incision was made. to expose the bladder and urethra, the pre-vesical fats were retracted. in the pboo group, the urethra was ligated to a 1 mm steel rod using a 3-0 nylon ligature. the steel rod was then removed, and the incision was sutured layer by layer. we followed a modified surgical method(14) to induce relief in the partial pboo group. a 4-0 stay suture was done to pull up the vaginal epithelium to make it easy to make an incision in the vaginal epithelium. the 3–0 nylon ligature was inserted through the paraurethral small incision, passed through the vagina. the nylon ligature was tied gently around the urethra with the vaginal epithelium in the presence of a 1 mm steel rod placed along the urethra. the steel rod was removed after suturing. the ends of knots were pulled down through the paraurethral incision, the knot was located in the vaginal space to easily remove the knots. sham surgery was performed as described above, and a 3–0 nylon ligature was tied around the urethra and vaginal epithelium without adding tension. the end of the knots was also placed in the vaginal space. in the sham-operated group, the loose knot was removed through the vagina. the de-obstruction period lasted 2 weeks, and then the bladder was harvested from the sham-operated group and pboo relief group (supplement figure 1). we sacrificed the rat with co2 gas after study following the irb guidelines for the euthanasia of animals. detection of apoptosis for the detection of apoptosis, the terminal deoxynucleotidyl transferase-mediated dutp-biotin nick end labeling (tunel) method was used. briefly, slides containing 5 μm sections of bladder tissue were de-paraffinized and rehydrated in a graded series of xylene and methanol. slides were then treated with 20 μg/ml proteinase k and quenched in 3% hydrogen peroxidase in pbs for 20 min. after equilibration, all tissue sections were incubated for 1 h with a terminal deoxynuurothelial protein changes following pboo and relief-park et al. unclassified 231 figure 1. detection of apoptosis. representative micrographs (magnification x400) show tunel-positive cells presenting brown or black color in the urothelium of the rat bladder. bar graphs show the quantitative analysis. the apoptosis index represents the fraction of apoptosis cells in the field. the sham-operated group (a); the pboo only group (b); and the pboo plus subsequent relief group (c); *indicates that the pboo group is significantly different from the sham-operated group (p < 0.001); † indicates that the pboo plus subsequent relief group is significantly different from the pboo group (p < 0.001). cleotidyl transferase enzyme and an anti-brdu-biotin monoclonal antibody in a dark humidified chamber at 370c. the slides were incubated with an anti-digoxigenin-peroxidase conjugate for 30 min and stained with 0.05% diaminobenzidine and then analyzed using a microscope. when dark brown apoptotic bodies were detected, slides were counterstained in 0.5% methyl green for 10 min. the slides were then washed with 100% n-butanol (ethanol and xylene) and mounted. three high-power (×400) fields were randomly selected for each slide. quantitative pcr assay of urothelium rna extraction and generation of cdna were conducted according to the protocols as previously described(15). reverse transcription was performed at 50°c for 50 min, followed by 70°c for 10 min. the pcr conditions were as follows: initial denaturation at 95°c for 5 min; followed by 35 cycles of 95°c for 25 s; 54.5°c for 25 s; and 72°c for 25 s; and then a final extension step of 72°c for 5 min. pcr products were analyzed by electrophoresis on 1.5% agarose gels. gapdh was used as a housekeeping gene. the primer sequences were as follows: erk (515 bp), 5’-gccttgcccggattgctgac-3’ (forward) and 5’-aggccggacactgggaa-cactaa-3’ (reverse); jnk (354 bp), 5'-cacagtcctaaaacgatacc-3' (forward) and 5'-ccacacagcatttgatagag-3' (reverse); p38 (468 bp), 5'-gtgcccgagcgatac-cagaac-3' (forward) and 5'-agtgtgccgagccagcccaaaatc-3' (reverse); bax (246 bp), 5'-actggggccgggtggttg -3' (forward) and 5'-agatggtgagtgaggc-agtgagga-3' (reverse); bcl-2 (411 bp), 5'-tgccaagggggaaacaccagaatc-3' (forward) and 5'-gcgacaaggggccgtagagg-3' (reverse); caspase-3 (282 bp), 5'-acggtacgcgaagaaaagtgac-3' (forward) and 5'-tcctgacttcgtatttcagg-gc-3' (reverse); survivin (460 bp), 5’-tgcgccttccttacagtcaa-3’ (forward) and 5’-ccccctccccacccatag-3’ (reverse); and gapdh (189 bp), 5’-cacggcaagttca-acggcac-3’ (forward) and 5’-agcggaaggggcggagatga-3’ (reverse). western blot assay of urothelium the urothelium tissues were homogenized at 4°c in 1 × radio-immunoprecipitation assay buffer (sigma-aldrich), whole tissue homogenates were centrifuged at 13,000 ×g for 20min and the supernatants were collected and stored at –70°c. western blot were performed according to the protocols as previously described (16). the membrane was incubated overnight at 4°c with an antibody targeting erk1 (1:500), jnk1 (1:1000), p38 mitogen-activated protein kinase (mapk) (1:1000), bax (1:200), bcl-2 (1:200), caspase-3 (1:1000), or survivin (1:200). all antibodies were purchased from santa cruz biotechnology (ca, usa) or cell signaling technology (ma, usa). immunoreactive proteins were visualized and detected using chemiluminescence reagent (dogen, korea) and the scanned films were quantified using a documentation system (vivid, korea). statistical analysis all data were statistically analyzed using the statistical package for the social sciences (spss), version 18.0 (spss inc., chicago, il, usa). three groups were compared by kruskal-wallis test and the p-value was adjusted with the bonferroni correction, and comparison between the two groups and other variables were made using a mann–whitney u tests. p < 0.05 was considered statistically significant in each case. results tunel findings tunel staining was performed to detect apoptotic figure 2. representation of the quantitative pcr analysis. erk, jnk, p38 mapks, bax, bcl-2, caspase-3, and surviving mrnas from the sham-operated, pboo only, and pboo plus subsequent relief groups in the rat urothelium. each bar data shows the mean ± sem. the expression of each mrna was normalized to gapdh. *p < 0.001, compared with the sham-operated group; † p < 0.001, compared with the pboo only group. urothelial protein changes following pboo and relief-park et al. vol 18 no 2 march-april 2021 232 cells in the urothelium of the rat bladder (figure 1). compared with the sham-operated group, the pboo group exhibited a significant increase in the number of tunel positive cells at 2 weeks post-pboo, as well as a significant decrease in the number of these positive cells 2 weeks after relief. there was no statistically significant difference between the numbers of tunel-positive cells in the sham-operated and pboo plus relief groups (p < 0.001). mrna expression in the urothelium we investigated the mrna expression levels of erk (515 bp), jnk (354 bp), p38 (468 bp) mapks, bcl-2 (411 bp), bax (246 bp), caspase-3 (282 bp), and survivin (460 bp) in the urothelium of the bladders from sham-operated, pboo only, and pboo relief groups using quantitative pcr (figure 2). compared with the sham-operated group, mrna expression levels of bax, caspase-3, jnk, and p38 significantly increased in the pboo only group. a significant decrease in expression levels of these kinases was also observed after pboo relief (p < 0.001). conversely, mrna expression levels of erk and bcl-2 were significantly decreased in the pboo group as compared to the sham-operated group (p < 0.001). a significant increase in the expression of erk and bcl-2 after pboo relief of the obstruction was also observed (p < 0.001). mrna expression levels of survivin were significantly higher in both the pboo only, and pboo relief groups as compared to the sham-operated group (p < 0.001). in addition, the expression levels of survivin were significantly different between the pboo only and pboo relief groups (p < 0.001). western blot assay we evaluated the expressions levels of mapks (erk, jnk, p38), bcl-2, bax, caspase-3 and survivin in the urothelium of rat bladders from sham-operated, pboo only and pboo relief groups used by western blot analysis (figure 3). in the western blot assay, these proteins showed similar patterns as those obtained from the quantitative pcr results. western blotting revealed that the protein levels of jnk and p38 mapk were higher while protein expression levels of erk were lower in the urothelium sample from the pboo rats when compared with those of the control rats (p < 0.001). conversely, relief of the obstruction significantly reduced the i/r-related increase in jnk and p38 expression, while simultaneously increasing erk protein expression levels (p < 0.001). when compared with the control group, the protein levels of bax and caspase-3 increased significantly in the pboo group. a significant decrease in expression levels of these kinases was also observed after pboo relief (p < 0.001). in contrast, the reduced expression of bcl-2 as a pro-survival protein in pboo rats was recovered after pboo relief (p < 0.001). survivin protein expression levels were significantly increased in both the pboo and pboo relief rats as compared to the control rats, and the expression of survivin was significantly different between these two groups (p < 0.001). discussion in the present study, we determined an experimental model for analyzing i/r injury in rat urothelium caused by pboo and subsequent relief. through the detection of proteins and measurement of mrna expression of erk, jnk, p38 mapks, bax, bcl-2, caspase-3, and survivin along with the detection of apoptosis, we analyzed the molecular mechanisms associated with i/r in the urothelium of the rat bladder. apoptosis has a potent role in maintaining structural integrity and homeostasis in many organisms. in addiunclassified 233 urothelial protein changes following pboo and relief-park et al. figure. 3. representation of the immunoblots. erk, jnk, p38 mapks, bax, bcl-2, caspase-3, and survivin protein levels of the sham-operated, pboo only, and pboo plus subsequent relief group in the rat urothelium. expression levels of each protein were normalized to β-actin. data show mean ± sem. * p < 0.001, compared with the sham-operated group; † p < 0.001, compared with the pboo only group. tion, apoptosis also as acts as a major mechanism of cellular destruction in i/r injury of rat urothelium (17). i/r-induced apoptosis is more prominent in the mucosal layer rather than the detrusor muscle of the bladder(18). despite many experimental studies, the mechanisms underlying the pathologic changes in the urothelium caused by pboo following subsequent relief, along with an analysis of the changes occurring in apoptosis-related proteins have not been demonstrated. here, we demonstrated, in a rat model, that the number of apoptotic cells significantly increased 2 weeks after the induction of pboo; moreover, the levels decreased 2 weeks after relief of the obstruction in the rat urothelium took place. in addition, apoptosis induced by i/r after pboo and subsequent relief was associated with the activation of mapk pathways and an imbalance of pro-apoptotic and anti-apoptotic proteins in the rat urothelium. pboo is a common clinical urologic disease that causes voiding problems, acute urinary retention, and detrusor overactivity, leading to structural instability and dysfunction of the bladder(2). human and animal studies have reported that over-distension of the bladder secondary to pboo causes hypoxia by decreasing blood flow to the bladder(19). repeat i/r caused by pboo can lead to oxidative damage of tissue, inflammatory changes, and cell apoptosis in the urothelium(20). ischemic cellular damage is closely related to the activation of mapks, including jnk and p38(21). conversely, pro-survival kinases such as erk may also be activated to restore tissue against i/r(22). eventually, the relative expressions of proand anti-apoptotic kinases may be involved in the determination of the cell survival or death. in the present study, expression levels of jnk and p38 were significantly higher in the pboo group as compared to the sham operated group; moreover, they reduced significantly after pboo relief. by contrast, erk showed the opposite pattern of expression following pboo and subsequent relief. the relatively higher activity of erk, compared with p38 and jnk, may favor cell survival during ischemic insult. bax and bcl-2 are considered important apoptosis modulators, and their relative values are used to judge cellular state. it has been reported that bcl-2 can prevent apoptosis and prolong cell survival, while bax is known as the apoptotic antagonist of the bcl-2 protein(23). relative activity of bax and bcl-2 has been reported in several ischemic animal models, particularly in renal ischemic injury(24). in this regard, upregulation of erk and mapk reportedly prevents apoptosis by blocking translocation to mitochondria(25,26). however, there are limited data describing the changes of apoptosis-related proteins after pboo and subsequent relief in the urothelium of rat bladder. in this study, expression of bax paralleled bladder apoptosis in the pboo group. in addition, increased expression levels of bcl-2 and erk along with decreased expression levels of bax and caspase-3 were observed after relief of the obstruction. these results suggest that upregulation of erk and an imbalance of bcl-2 family proteins could play a critical role in the development and restoration after bladder apoptosis following pboo and subsequent relief. survivin is a member of the inhibitor of apoptosis protein family, and upregulation of survivin is known to inhibit apoptosis in cells(27). one mechanism through which occurs involves inhibition of caspase-3 and caspase-7, which are downstream effector proteins in the cascade of proteolytic caspase family enzymes. survivin and bcl-2 may have common mechanisms guiding transcription and activation that work synergistically to exert anti-apoptotic effects(28). several studies reported that the expression of the survivin protein increases after cerebral i/r damage, which affects amelioration of the tissues(29,30). in the present study, ischemic bladder injury induced the expression of survivin in the pboo groups. there was statistically significant difference supplement 1. experimental design. 60 rats were divided randomly into three groups: the sham-operated group (sham; n = 20), the pboo group (pboo; n = 20), and the pboo relief group (pboo + relief; n = 20). two weeks after the bladder outlet partial obstruction surgery, the pboo group was sacrificed, the pboo relief group and sham group were removed the knot around the urethra. at 2 weeks after removal of the obstruction, the sham and pboo relief groups were sacrificed. urothelial protein changes following pboo and relief-park et al. vol 18 no 2 march-april 2021 234 between the expressions of survivin in the pboo and pboo plus relief groups. however, expression of bcl-2 does not parallel that of expression of survivin following relief of the obstruction. our results suggest that the effect of survivin on tissue survival after i/r damage by pboo and subsequent relief in the urothelium of the rat bladder is unclear. conclusions the results of this study demonstrate that pboo-induced bladder apoptosis is associated with an imbalance in the mapk pathways and that the pro-survival erk signaling cascade is activated in response to i/r damage and associated with restoration of urothelium after relief of the obstruction. our results enhance current knowledge regarding apoptosis-related molecular changes involved in urothelial ischemic damage and cell survival after pboo plus subsequent relief. our study suggests that the role of survivin for cellular recovery against i/r injury after pboo relief in rat urothelium remains unclear. however, large scale studies must be done to investigate the effect of survivin against i/r in the urothelium and determine its driving mechanisms. acknowledgement this research was supported by the research fund of chungnam national university, the korea basic science institute research program (t39730), the science research center program (2015r1a5a1009024) of the national research foundation (nrf) funded by the ministry of science, ict and future planning, and the korea health technology r&d project (hi16c0312) through the korea health industry development institute (khidi) funded by the ministry of health & welfare. conflict of interest the authors declare that there is no conflict of interest regarding the publication of this article. references 1. boyle p, robertson c, mazzetta c et al: the prevalence of male urinary incontinence in four centres: the urepik study. bju int. 2003; 92:943-7. 2. solomon e, yasmin h, duffy m, rashid t, akinluyi e, greenwell tj: developing and validating a new nomogram for diagnosing bladder outlet obstruction in women. neurourol urodyn. 2018; 37:368-78. 3. pinggera gm, mitterberger m, steiner e et al: association of lower urinary tract symptoms and chronic ischaemia of the lower urinary tract in elderly women and men: assessment using colour doppler ultrasonography. bju int. 2008; 102:470-4. 4. yamaguchi o, nomiya m, andersson ke: functional consequences of chronic bladder ischemia. neurourol urodyn. 2014; 33:54-8. 5. steers wd, de groat wc: effect of bladder outlet obstruction on micturition reflex pathways in the rat. j urol. 1988; 140:864-71. 6. islam mt: oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. neurol res. 2017; 39:73-82. 7. kahraman a, erkasap n, serteser m, koken t: protective effect of quercetin on renal ischemia/reperfusion injury in rats. j nephrol. 2003; 16:219-24. 8. nomiya m, sagawa k, yazaki j et al: increased bladder activity is associated with elevated oxidative stress markers and proinflammatory cytokines in a rat model of atherosclerosisinduced chronic bladder ischemia. neurourol urodyn. 2012; 31:185-9. 9. vinas jl, sola a, genesca m, alfaro v, pi f, hotter g: no and nos isoforms in the development of apoptosis in renal ischemia/ reperfusion. free radic biol med. 2006; 40:992-1003. 10. deveraux ql, reed jc: iap family proteins-suppressors of apoptosis. genes dev. 1999; 13:239-52. 11. jia x, gao y, zhai d et al: survivin is not a promising serological maker for the diagnosis of hepatocellular carcinoma. oncol lett. 2015; 9:2347-52. 12. hussein am, sakr hf, alenzi fq: possible underlying mechanisms of the renoprotective effect of remote limb ischemic preconditioning against renal ischemia/reperfusion injury: a role of osteopontin, transforming growth factorbeta and survivin. nephron. 2016; 134:11729. 13. al-maghrebi m, renno wm: the tace/ angiotensin (1-7)/mas axis protects against testicular ischemia reperfusion injury. urology. 2016; 94:312. e1-8. 14. jin lh, andersson ke, han ju et al: persistent detrusor overactivity in rats after relief of partial urethral obstruction. am j physiol regul integr comp physiol. 2011; 301:r896904. 15. yang sw, jeong sw, song kh: increased expression of neuregulin 1 in the urothelium of rat bladder with partial bladder outlet obstruction. bmc urol. 2017; 17:115. 16. shin jh, chun ks, na yg et al: allopurinol protects against ischemia/reperfusioninduced injury in rat urinary bladders. oxid med cell longev. 2015; 2015:906787. 17. yenilmez a, kilic fs, sirmagul b, isikli b, aral e, oner s: preventive effects of ginkgo biloba extract on ischemia-reperfusion injury in rat bladder. urol int. 2007; 78:167-72. 18. steers wd: pathophysiology of overactive bladder and urge urinary incontinence. rev urol. 2002; 4 suppl 4:s7-s18. 19. kershen rt, azadzoi km, siroky mb: blood flow, pressure and compliance in the male human bladder. j urol. 2002; 168:121-5. 20. yu hj, chien ct, lai yj et al: hypoxia preconditioning attenuates bladder overdistension-induced oxidative injury by up-regulation of bcl-2 in the rat. j physiol. 2004; 554(pt 3):815-28. 21. yin t, sandhu g, wolfgang cd et al: tissuespecific pattern of stress kinase activation in ischemic/reperfused heart and kidney. j biol chem. 1997; 272:19943-50. urothelial protein changes following pboo and relief-park et al. unclassified 235 vol 18 no 2 march-april 2021 236 22. deng zh, jr., yan gt, wang lh, zhang jy, xue h, zhang k: leptin relieves intestinal ischemia/reperfusion injury by promoting erk1/2 phosphorylation and the no signaling pathway. j trauma acute care surg. 2012; 72:143-9. 23. oltvai zn, milliman cl, korsmeyer sj: bcl2 heterodimerizes in vivo with a conserved homolog, bax, that accelerates programmed cell death. cell. 1993; 74:609-19. 24. basile dp, liapis h, hammerman mr: expression of bcl-2 and bax in regenerating rat renal tubules following ischemic injury. am j physiol. 1997; 272(5 pt 2):f640-7. 25. yamaguchi h, wang hg: the protein kinase pkb/akt regulates cell survival and apoptosis by inhibiting bax conformational change. oncogene. 2001; 20:7779-86. 26. tsuruta f, masuyama n, gotoh y: the phosphatidylinositol 3-kinase (pi3k)-akt pathway suppresses bax translocation to mitochondria. j biol chem. 2002; 277:140407. 27. chen d, xu j, zhang q: detection of survivin expression in bladder cancer and renal cell carcinoma using specific monoclonal antibodies. oncol rep. 2018; 39:2817-28. 28. rajesh kg, suzuki r, maeda h, murio y, sasaguri s: 5-ht2 receptor blocker sarpogrelate prevents downregulation of antiapoptotic protein bcl-2 and protects the heart against ischemia-reperfusion injury. life sci. 2006; 79:1749-55. 29. chu sf, zhang z, zhang w et al: upregulating the expression of survivin-hbxip complex contributes to the protective role of imm-h004 in transient global cerebral ischemia/reperfusion. mol neurobiol. 2017; 54:524-40. 30. liu xy, yao ll, chen yj et al: survivin is involved in the anti-apoptotic effect of edaravone in pc12 cells. mol cell biochem. 2009; 327:21-8. urothelial protein changes following pboo and relief-park et al. v08_no_2_final.pdf review 83urology journal vol 8 no 2 spring 2011 elderly and prostate cancer screening konstantinos n stamatiou purpose: to discuss the issue of screening for prostate cancer in elderly individuals. the impact of life expectancy on the choice of treatment in both patients and health care providers has been investigated as well. materials and methods: we identified studies published from 1990 onwards by searching the medline database of the national library of medicine. initial search terms were “localized prostate cancer” and “early stage prostate cancer” combined with “elderly patients, life expectancy, palliative, curative, quality of life, watchful waiting, radical prostatectomy, brachytherapy, and external beam radiotherapy”. results: despite the decrease in prostate carcinoma-specific mortality, the use of prostate-specific antigen (psa) has been shown to increase the prostate cancer detection rate with a shift to detection at earlier and less invasive pathological stages, overriding concerns about over-diagnosis and overtreating. however, psa screening is mainly offered to younger individuals, and older patients are more likely to have progressive disease and high-risk prostate cancer at diagnosis. given that psa screening diagnoses mainly curable, early prostate cancer, screening decision could be offered to otherwise healthy elderly patients who are likely to benefit from aggressive treatment. conclusion: prostate-specific antigen screening is not officially recommended and most scientific associations promote shared decision making. while psa screening decision is currently based on physician’s judgment, it is clear that a strict age cut-off of 75 years reduces over-screening, but also prohibits screening in healthy older men with a long life expectancy. urol j. 2011;8:83-7. www.uj.unrc.ir keywords: prostate cancer, aged, prostate-specific antigen, life expectancy department of urology, tzaneion hospital, piraeus, attica, greece corresponding author: konstantinos n stamatiou, md 2 salepoula str., 18536, piraeus, attica, greece tel: +302 104526651 fax: +302 104296987 e-mail: stamatiouk@gmail.com, stamatiouk@yahoo.com received april 2011 accepted april 2011 introduction a definitive cause of prostate cancer (pc) has not been identified and the specific mechanisms that lead to development of the disease are still unknown.(1) although several risk factors have been proposed, the only ones that can be considered established are age, race, and family history. currently, it is not known how ageing facilitates pc development; however, this association may be mediated through androgenic action. on one hand, development and function of the prostate gland are endocrine-controlled and androgen/estrogen synergism is necessary for the integrity of the normal human prostate. on the other hand, androgen action is critical to the development, progression, and cure of pc. actually, androgens undergo a significant age-dependent alteration. with ageing, the production of testosterone by the testes is decreasing, leading thus to a significant reduction in the endogenous testosterone levels. elderly and prostate cancer screening—stamatiou 84 urology journal vol 8 no 2 spring 2011 dihydrotestosterone (dht) activity decreases in the epithelium while it remains constant in the stroma over the whole age range.(2) the agedependent decrease in the dht accumulation in the epithelium and the concomitant increase in the estrogen accumulation in the stroma lead to a tremendous increase of the estrogen/androgen ratio in the human prostate. although the specific pathway remains partially investigated, it is widely accepted that these alterations promote the initiation of neoplastic lesions.(3) actually, pc is a disease of the elderly and its incidence increases with age. it seldom develops before the age of 40 and is chiefly a disease found in men over the age of 65 years. furthermore, epidemiological evidence from autopsy studies shows that a high percentage of the elderly men has histological evidence of the disease.(4) the aim of the present study is to discuss the issue of screening for pc in elderly individuals. a secondary aim is to examine whether or not advanced age impacts on pc risk. the impact of life expectancy on the choice of treatment in both patients and health care providers has also been investigated. materials and methods we identified studies published from 1990 onwards by searching the medline database of the national library of medicine. initial search terms were “localized prostate cancer” and “early stage prostate cancer” combined with “elderly patients, life expectancy, palliative, curative, quality of life, watchful waiting, radical prostatectomy, brachytherapy, and external beam radiotherapy”. references in the selected publications were checked for relevant publications not included in the medline or pubmed search. results achievements in the 20th century, such as decline in mortality at younger ages, medical advances, and better health care, have resulted in longer life expectancy in both the developing and the developed world.(5) statistics compiled by the united nations showed that in 1999, 10% of the world population was 60 years and older. by 2050, this percentage will rise to 22%. in hong kong, where the proportion of elderly is even higher, it is estimated to rise to 40%.(6) regarding male gender, the population over 65 years is expected to increase 4-fold worldwide by 2050.(7) the increased life expectancy enjoyed by the world population also means that the life span beyond the age of 60 is much longer than demographers have previously envisaged. a large proportion of the population remains active beyond the age of 70 and lives beyond the age of 80. changes in the world’s demographic proportions and introduction of the prostate-specific antigen (psa) blood test in the last three decades altered the epidemiology of pc, which still remains a disease of the elderly.(8) prostate cancer is the second most frequent malignant disease in men and the most commonly diagnosed cancer in elderly men.(9) due to the steadily growing ageing population, the number of elderly men who will be diagnosed with pc and those who will require treatment will further increase in the coming years.(10) while the majority of elderly patients with pc in the past were diagnosed with the advanced or metastatic disease, a rising number of elderly men are now diagnosed with early stage of pc. it is not known whether this is due to the effective utilization of health care resources or to the use of psa testing. at the moment, psa screening is being performed unofficially in elderly patients. the magnitude of this opportunistic screening is not known. hoffman and associates and walter and colleagues found a 56% and 50% psa screening rate in their cohort of elderly men in 2003 and 2010, respectively.(11,12) interestingly, bowen and coworkers found that pc screening rates among men at the age of 80 and older are even higher than that of men in the age range of 50 to 64 years (64% versus 56%).(13) similarly, in the study by d’ambrosio and colleagues, the highest yearly exposure to psa screening (55%) and the highest frequency of repeat testing were observed in the age range of 70 to the 79 years. according to these authors, psa screening practice has continued to increase in italy and is often performed in elderly people without any scientific rationale.(14) in contrast, zeliadt and associates demonstrated that elderly and prostate cancer screening—stamatiou 85urology journal vol 8 no 2 spring 2011 psa testing among men older than 75 years has declined slightly following the recommendations by the us preventive services task force in 2008 and is still continuing to decline.(15) several studies showed an eventual increase in the pc detection rate and a shift towards earlier pathological stage and less invasive forms, not without justifiable concern about over-diagnosis and over-treating.(16,17) this fact is of outmost importance when deciding to treat elderly patients with pc. given that life expectancy of american men at the age of 65 is 16 years(18) and the mean time to cancer-specific death of apparently clinically localized low risk prostate cancer is 17 years,(19) it becomes obvious why pc screening and treatment of psa-detected pcs in elderly patients are very controversial issues. on the other hand, evidence suggests that psa may be useful in diagnosis of aggressive early pc in a subset of elderly patients. a current study by brassell and colleagues demonstrated that as men age, parameters consistent with more aggressive disease become more prevalent.(20) autopsy studies showed that a proportion of elderly men with histologically apparent disease may develop lethal pc.(21) in fact, most of these cancers are likely to progress and become clinically significant (advanced gleason score and greater volume) and therefore it is not surprising that older individuals with clinically apparent pc usually die from pc. it is noticeable that these two clinical (age-related) forms of the pc are still undistinguishable in clinicopathology reports.(22) these data may have implications for future screening and treatment recommendations since currently, patients bearing different diseases are offered the same treatment. currently, age plays an important role in treatment choice and thus elderly patients are less likely to receive local therapy. in fact, only a small number of elderly patients with early stage of pc are treated with intent to cure. despite the limited data, there is clear evidence of survival benefit in several elderly patients receiving radical treatment.(23,24) given that psa screening mainly diagnoses early pc, it may be justifiable for otherwise healthy elderly men to undergo psa test. this is of outmost importance since older patients are more likely to have high-risk prostate cancer at diagnosis and lower overall survival. in fact, under-use of potentially curative local therapy among older men with high-risk disease may explain, at least in part, the observed differences in cancer-specific survival across age strata.(25) to the best of our knowledge, global pc mortality is constantly decreasing. as yet it is not possible to say what proportion of the fall in mortality is the result of improvement in treatment, changes in cancer registration coding, the attribution of death to pc, and the effects of psa testing. accumulative evidence, however, suggests that early screening of pc in asymptomatic men reduces risk of death from metastatic disease. interestingly, the recently published results of the european randomized study for screening of prostate cancer reported a relative pc mortality reduction of at least 20% by psa-based population screening(26) while kopec and colleagues reported a relatively high risk of death from metastatic pc among men who were not screened regularly as part of a screening program.(27) on the other hand, data from us cancer of the prostate strategic urological research endeavor showed a significant reduction in risk of death from metastatic pc in the last two decades in the us, with most of the patients being found with low or intermediate disease at diagnosis.(28) taking in consideration these findings along with observations of brassell and coworkers,(20) it became obvious that evidence supports making decisions regarding screening and treatment on the basis of disease risk and life expectancy rather than chronologic age. to our knowledge, no standard recommendation for pc screening exists. recently, the american urological association recommends pc screening to men aged 40 years or older. in contrast, screening is presently discouraged by the european commission advisory committee on cancer prevention for its negative effects are evident and its benefits are still uncertain.(29) according to the u.s. preventive services task force, evidence is insufficient to recommend in favour of or against routine pc screening.(12) elderly and prostate cancer screening—stamatiou 86 urology journal vol 8 no 2 spring 2011 on the other hand, treatment recommendations are now recognizing that older men with pc should be managed according to their individual health status, which is mainly driven by the severity of associated comorbid conditions, and not according to chronological age. according to the international society of geriatric oncology prostate cancer task force, it is possible, based on a rapid and simple evaluation, to classify patients into four different groups: 1) “healthy” patients (controlled comorbidity, fully independent in daily living activities, and no malnutrition) should receive the same treatment as younger patients; 2) “vulnerable” patients (reversible impairment) should receive standard treatment after medical intervention; 3) “frail” patients (irreversible impairment) should receive adapted treatment; 4) patients who are “too sick” with “terminal illness” should receive only symptomatic palliative treatment.(30) the same rapid and simple evaluation may help physicians who perform psa screening to decide who to screen. conclusion evidence supports serum evaluation of psa for screening of prostate cancer in elderly individuals. a strict age cut-off of 75 years reduces over screening, but also prohibits screening in healthy older men with a long life expectancy who may benefit from screening. therefore, recommendations for pc screening in the elderly individuals should be based upon health status and life expectancy. certainly, physicians who perform psa screening should maintain sound clinical acumen and judgment when deciding who to screen. conflict of interest none declared. references 1. knudsen bs, vasioukhin v. mechanisms of prostate cancer initiation and progression. adv cancer res. 2010;109:1-50. 2. risbridger gp, ellem sj, mcpherson sj. estrogen action on the prostate gland: a critical mix of endocrine and paracrine signaling. j mol endocrinol. 2007;39:183-8. 3. krieg m, nass r, tunn s. effect of aging on endogenous level of 5 alpha-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate. j clin endocrinol metab. 1993;77:375-81. 4. stamatiou k, alevizos a, agapitos e, sofras f. incidence of impalpable carcinoma of the prostate and of non-malignant and precarcinomatous lesions in greek male population: an autopsy study. prostate. 2006;66:1319-28. 5. fuchshuber pr. age and cancer surgery: judicious selection or discrimination? ann surg oncol. 2004;11:951-2. 6. cheung fm. ageing population and gender issues. in: yeung ym, ed. new challenges for development and modernization: hong kong and the asia-pacific region in the new millennium. hong kong: chinese university press; 2002:207-23. 7. united nations economic and social council. concise report on world population (2000). report of the secretary-general to the 33rd session of the commission on population and development, 27-31 march 2000 available at: http://www.un.org/ documents/ecosoc/cn9/2000/ecn92000-3.pdf. 8. jemal a, siegel r, ward e, murray t, xu j, thun mj. cancer statistics, 2007. ca cancer j clin. 2007;57: 43-66. 9. crawford ed. epidemiology of prostate cancer. urology. 2003;62:3-12. 10. airtum working group. italian cancer figures, report 2010: cancer prevalence in italy. patients living with cancer, long-term survivors and cured patients. epidemiol prev. 2010;34 (5-6 suppl 2):1-188. 11. hoffman ke, nguyen pl, ng ak, d’amico av. prostate cancer screening in men 75 years old or older: an assessment of self-reported health status and life expectancy. j urol. 2010;183:1798-802. 12. walter lc, bertenthal d, lindquist k, konety br. psa screening among elderly men with limited life expectancies. jama. 2006;296:2336-42. 13. bowen dj, hannon pa, harris jr, martin dp. prostate cancer screening and informed decision-making: provider and patient perspectives. prostate cancer prostatic dis. 2011[epub ahead of print]. 14. d’ambrosio gg, campo s, cancian m, pecchioli s, mazzaglia g. opportunistic prostate-specific antigen screening in italy: 6 years of monitoring from the italian general practice database. eur j cancer prev. 2010;19:413-6. 15. zeliadt sb, hoffman rm, etzioni r, gore jl, kessler lg, lin dw. influence of publication of us and european prostate cancer screening trials on psa testing practices. j natl cancer inst. 2011;103:520-3. 16. ciatto s, zappa m, villers a, paez a, otto s, auvinen a. contamination by opportunistic screening in the european randomized study of prostate cancer screening. bju international. 2003;92:97-100. 17. de koning hj, auvinen a, berenguer sanchez a, et al. large-scale randomized prostate cancer screening trials: program performances in the european randomized screening for prostate cancer trial and elderly and prostate cancer screening—stamatiou 87urology journal vol 8 no 2 spring 2011 the prostate, lung, colorectal and ovary cancer trial. int j cancer. 2002;97:237-44. 18. minino am, smith bl. deaths: preliminary data for 2000. natl vital stat rep. 2001;49:1-40. 19. horan ah, mcgehee m. mean time to cancer-specific death of apparently clinically localized prostate cancer: policy implications for threshold ages in prostatespecific antigen screening and ablative therapy. bju int. 2000;85:1063-6. 20. brassell sa, rice kr, parker pm, et al. prostate cancer in men 70 years old or older, indolent or aggressive: clinicopathological analysis and outcomes. j urol. 2011;185:132-7. 21. schutze u. [latent prostatic carcinoma--an autopsy study of men over 50 years of age]. zentralbl allg pathol. 1984;129:357-64. 22. drewa t, jasinski m, marszalek a, chlosta p. prostate cancer which affects an elderly man is a feature of senescence (cellular) a biology phenomenon. exp oncol. 2010;32:228-32. 23. ojea calvo a, lópez garcía s, rey rey j, alonso rodrigo a, rodriguez iglesias b, barros rodriguez jm. [do older men with localized prostate cancer gleason 8-10 benefit from curative therapy?]. actas urol esp. 2008;32:589-93. 24. liu l, coker al, du xl, cormier jn, ford ce, fang s. long-term survival after radical prostatectomy compared to other treatments in older men with local/ regional prostate cancer. j surg oncol. 2008;97: 583-91. 25. bechis sk, carroll pr, cooperberg mr. impact of age at diagnosis on prostate cancer treatment and survival. j clin oncol. 2011;29:235-41. 26. schröder fh, hugosson j, roobol mj, et al. screening and prostate-cancer mortality in a randomized european study. n engl j med. 2009;360:1320-8. 27. kopec ja, goel v, bunting ps, et al. screening with prostate specific antigen and metastatic prostate cancer risk: a population based case-control study. j urol. 2005;174:495-9; discussion 9. 28. cooperberg mr, lubeck dp, mehta ss, carroll pr. time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from capsure). j urol. 2003;170:s21-5; discussion s6-7. 29. advisory committee on cancer prevention. position paper, recommendations on cancer screening in european union. eur j cancer 2000;36:1473–8. 30. droz jp, balducci l, bolla m, et al. management of prostate cancer in older men: recommendations of a working group of the international society of geriatric oncology. bju int. 2010;106:462-9. case reports 118 urology journal vol 4 no 2 spring 2007 hygroma renalis: an extremely rare renal lesion reza mahdavi, alireza khooei, ladan asadi urol j. 2007;4:118-20. www.uj.unrc.ir keywords: lymphangioma, hygroma renalis, renal tumor, malformation, cyst department of urology, bentolhoda hospital, mashhad university of medical sciences, mashhad, iran correspondance author: reza mahdavi, md imam reza hospital, mashhad, iran tel: +98 915 111 0628 fax: +98 511 859 1922 e-mail: drrezamahdavi@yahoo.com received july 2006 accepted march 2007 introduction lymphangiomas are benign tumors or malformations of lymphatic vessels. they are most commonly seen in the neck, axillary region, and mediastinum. hygroma renalis is a type of lymphangioma (lymphangiectasia) located in the pericalyceal area and is therefore named as pericalyceal lymphangiectasis.(1,2) hygroma renalis is usually asymptomatic and easily detectable by ultrasonography or computed tomography (ct). we present a patient with vague right lumbar pain and fullness. radiologic examination revealed a multicystic pericalyceal and perirenal lesion. histological examination and immunohistochemistry analysis were consistent with the diagnosis of hygroma renalis. case report a 30-year-old woman presented to our center complaining of vague right lumbar pain and fullness. she had undergone partial nephrectomy about 4 years before due to a simple renal cyst associated with chronic nonspecific pyelonephritis. physical examination, kidney function tests, and hemagglutination test were negative for hydatid cyst. abdominal ultrasonography and ct scan revealed a huge multiloculated cystic mass that was attached to the atrophic right kidney. the mass was extended up to the umbilicus via the retroperitoneum with sharp lobulated contours (figure 1). the left kidney, liver, pancreas, spleen, and bladder were normal. no intraperitoneal fluid accumulation was detected. the patient underwent right nephrectomy. a 700-g mass sized 16 × 10 × 8 cm was excised. on pathologic examination, remnants of the kidney surrounded by a figure 1. ct scans. left, a cystic mass surrounding the right kidney (black asterisk). right, the obvious cystic mass with sharp and lobulated border extending near the midline (white asterisk). hygroma renalis—mahdavi et al urology journal vol 4 no 2 spring 2007 119 multiloculated cyst were identified, extending to the pericalyceal and hilar area covering the ureter. the cyst contained a creamy fluid and its wall was extremely thin; in most areas, the thickness was about 1 mm (figures 2 and 3). microscopic examination revealed a multicystic lesion with flat endothelial cells. the cystic spaces were filled with a proteinous fluid and thin fibrous walls. the renal tissue had features of nonspecific chronic pyelonephritis without any intraparanchymal cyst (figures 3 to 5). the most possible histopathological diagnosis was cystic lymphangioma; however, in order to rule out other probable diagnoses such as mesothelial, epithelial, and mullerian serous cysts, immunohistochemical staining was performed using cytokeratin and calretinin and both were reported to be negative. thus, the final histologic diagnosis was hygroma renalis. the patient made a complete recovery and was disease-free 20 months postoperatively. discussion lymphangiomas are benign malformations or postulate, benign, cystic tumors of the lymphatic vessels that are most frequently discovered in childhood with few cases reported in adults.(1) they are mostly located in the neck, axillary region, mediastinum, abdominal cavity, and in extremely rare cases, in the retroperitoneum (less than 1% of all lymphangiomas).(2) four histologic subtypes of lymphamgioma have been described that include cystic, papillary, cavernous, and vasculolymphatic malformations. a combination of these types may be seen in the same lesion. the presence of endotheliallined lymphatic channels separated by the connective tissue is the main histologic feature of the disease.(2) figure 2. gross appearance of the lesion diagnosed as hygroma renalis. figure 3. microscopic view shows the thin wall of the cyst (arrow) adjacent to the renal tissue (white asterisk) with ectatic capsular vessels (black asterisk; hematoxylin-eosin, × 100). figure 4. a close-up view of figure 4 demonstrating the cyst wall (arrow) lined by a layer of the flat cells (hematoxylin-eosin, × 200). figure 5. thin wall of the cyst (arrow) lined by one layer of flat cells containing proteinous material (hematoxylin-eosin, × 100). hygroma renalis—mahdavi et al 120 urology journal vol 4 no 2 spring 2007 in the renal region, these lesions are often located adjacent or attached to the kidney, especially around the renal pelvis and are, therefore, called pericalyceal lymphangiectasis (lymphangioma) or hygroma renalis. the lesion may consist of a single or multiple cysts and may be either unilateral or bilateral.(3) it has variously been considered to be hamartomatous malformation analogous to cystic hygromas of the head, neck, and mediastinum, as an acquired lesion resulting from lymphatic obstruction, or as a true vascular neoplasm. occasionally, the lymphatics of the renal capsule are also involved and therefore, the whole kidney is covered by cysts that give a superficial appearance similar to polycystic disease. although preoperative diagnosis is usually possible by ct or magnetic resonance imaging, confirmatory diagnosis of hygroma lesions requires laparotomy and complete excision in most cases, followed by histopathological examination.(4,5) confusion with other cystic lesions of the kidney such as calyceal diverticula, renal cysts, and cystic tumors of the liver, pancreas, and retroperitoneum may occur.(6) to our best knowledge, only 24 cases of hygroma renalis have been previously reported in the world literature.(2) it is usually asymptomatic, but it may be associated with urinary tract obstruction that can be treated by conservative management. operation should be considered only in patients with complications.(2) in the case of surgery, simple resection of the hygroma is adequate and radical nephrectomy is contraindicated in the management of uncomplicated patients or patients with normal kidneys.(2) although very uncommon, potential aggressive behavior of lymphangiomas has been reported.(7,8) references 1. cherk m, nikfarjam m, christophi c. retroperitoneal lymphangioma. asian j surg. 2006;29:51-4. 2. vibhav, amarapurkar ad. cystic lymphangioma as mesenteric tumor--a case report. indian j pathol microbiol. 2005;48:491-3. 3. cruz guerra na, salvador fernandez l, solera arroyo jc, albarran fernandez m, lopez mourino vm, alonso alonso m. [giant retroperitoneal cystic lymphangioma in adults]. arch esp urol. 2005;58:685-8. spanish. 4. ozdemir h, kocakoc e, bozgeyik z, cobanoglu b. recurrent retroperitoneal cystic lymphangioma. yonsei med j. 2005;46:715-8. 5. minor tx, yeh bm, horvai ae, abrahams hm, meng mv, stoller ml. symptomatic perirenal serous cysts of mullerian origin mimicking renal cysts on ct. ajr am j roentgenol. 2004;183:1393-6. 6. mullins jr, shield cf 3rd, porter mg. hygroma renalis: two cases within a family and a literature review. surgery. 1992;111:339-42. 7. colin d, meunier p, forestier d, le fur jm, le guyader j, bellet m. [the value of echography in the early diagnosis of renal lesions in the laurence-moonbardet-biedl syndrome. apropos of a case]. j radiol. 1989;70:61-4. french. 8. ates le, kapran y, erbil y, barbaros u, dizdaroglu f. cystic lymphangioma of the right adrenal gland. pathol oncol res. 2005;11:242-4. 1035vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l department of urology, first hospital of jilin university, changchun, china yanbo wang, zhihua lu, jinghai hu, xiaoqing wang, ji lu, yuanyuan hao, yan wang, qihui chen, fengming jiang, haifeng zhang, ning xu, yuchuan hou, chunxi wang renal access by sonographer versus urologist during percutaneous nephrolithotomy corresponding author: chunxi wang, md department of urology, the first hospital of jilin university, 71 xinmin street, changchun, jilin province, china. tel: +86 0431 8878 2321 fax: +86 0431 8187 5801 email: chunxi_wang@126. com received august 2012 accepted february 2012 purpose: to evaluate the percutaneous access outcomes and complications following percutaneous nephrolithotomy (pcnl) that was obtained by sonographer or urologist at a single academic institution. material and methods: a retrospective chart review of 259 patients who underwent pcnl was performed. patients were stratified according to percutaneous access by sonographer (group 1) or urologist (group 2) in 174 and 85 patients, respectively. demographic, stone characteristics, operative variables, percutaneous access complications and stone-free rates were compared between groups. results: the major complication rate and minor complication rate, mean blood loss and rates of blood transfusion were comparable between groups. compared with urologist, sonographer preferred to choose subcostal rib puncture instead of intercostal rib puncture. the lower calyx was the most frequent site of target calyx puncture in group 1 (165 cases, 94.8%), while the percentage of lower calyx in group 2 was 82.3% (72 cases) (p = .001). the overall stone-free rates were significantly higher in group 2 than that in group 1 (90.6% vs. 79.9%, p = .03). in group 1, 23 cases (13.2%) needed post-operative extracorporeal shock wave lithotripsy (swl), while, the percentage of post-operative swl in group 2 was only 4.7% (4 cases) (p = .035). conclusions: renal access in pcnl can be safely and successfully obtained by both sonographer and urologist. infracostal and lower calyx access in our study has poor stone-free rates and sonographer prefers infracostal and lower access. we encourage urologists establish renal access by themselves during pcnl. keywords: nephrostomy; percutaneous; retrospective studies; ultrasonography; treatment outcome; physician's role. endourology and stone disease 1036 | introduction percutaneous nephrolithotomy (pcnl) has become a mainstay for the treatment of renal stones since the first successful removal of a renal calculus via a nephrostomy tract in 1976(1) implications of pcnl include stones > 2.0 cm in diameter, complex and special renal stones. in china, historically, access to the kidney for stone has been performed by radiologists or sonographers. recent studies compare the outcomes of renal access for pcnl that is obtained by radiologists or urologists.(2-5) however, to our knowledge, no study has yet been discussed about the difference between sonographers and urologists. we evaluated percutaneous access for pcnl that was obtained by sonographer or urologist and compared access outcomes and complications. material and methods clinical data a total of 259 patients (148 men and 111 women, mean age 42.1 years, range from 20 to 67 years) were prospectively enrolled in this study from january 2009 to may 2012 in the first hospital of jilin university. patients were stratified according to percutaneous access by sonographer (group 1) or urologist (group 2) in 174 and 85 patients, respectively. patients in group 1 were consecutively performed by sonographer from january 2009 to may 2011. patients in group 2 were consecutively performed by urologist from may 2011 to may 2012. preoperative factors that were analyzed included gender, age, body mass index (bmi), stone position, mean maximum stone diameter, presence of hydronephrosis, stone type (complete staghorn, partial staghorn or pelvic), associated comorbidities (hypertension, diabetes mellitus, pulmonary disease or coronary artery disease) and previous medical or surgical history. kidney patients were excluded from the study if they had 1 phase nephrostomy. all surgeries were finished by the same surgeon. furthermore, the sonographer was the same person in this study. procedure of pcnl the entire procedure was performed under general anesthesia. ureteral catheter was inserted retrograde into the pelvicaliceal system with the patient in lithotomic position. the patient was repositioned to the prone position and a specially designed cushion was placed on the table to enable a deflected position. an 18-gauge coaxial needle (cook inc., bloomington, indiana, usa) was introduced into the targeted calyx under the guide of doppler ultrasound (aloka 5) by the sonographer or surgeon. selection of the targeted calyx and number of access tracts were dependent on stone location, pelvicaliceal anatomy and the preference of sonographer or surgeon. the working channel was then dilated by using the plastic dilator system (cook inc., bloomington, indiana, usa) or x-force nephrostomy balloon dilation catheter (bcr inc., tainan, taiwan), followed by placement of either 18f or 26f working sheath. the lumenis 60 w lithotripter (lumenis, santa clara, ca, usa) or cybersonics double-catheter system (gyrus/acmi, southborough, mass., usa) was used to fragment the renal stone. at the end of the procedure, an x-ray check for residual stone fragments was performed. a 20 fr foley catheter was placed as a nephrostomy tube and it was removed if there was no extravasation at approximately 3 days post-operation. patients were considered stone-free when no stone > 4 mm was visualized. residual fragments > 5 mm in diameter were treated with extracorporeal shock wave lithotripsy (swl) or the second phase pcnl. major complications were considered as septicemia, hemorrhage requiring angiographic renal embolization or nephrectomy, thoracic or abdominal organ injury, acute pancreatitis. transient fever, clinically insignificant bleeding, urinary tract infection without signs of urosepsis, renal colic, and prolonged urinary leakage from the percutaneous access were considered minor complications. statistical analysis the statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0 was used for all statistical analyses. comparisons were made using student’s t tests and pearson’s chi-square tests, where p value < .05 was considered statistically significant. results of the 259 patients reviewed, 67.2% and 32.8% underwent percutaneous access by sonographer or urologist, respectively. the patients and stone characteristics of the study groups are summarized in table 1. there was no statistically significant difference between the groups with regard to sex, age, endourology and stone disease 1037vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l mean bmi, stone position, stone diameter, presence of hydronephrosis, stone type (complete staghorn, partial staghorn or pelvic), associated comorbidities (hypertension, diabetes mellitus, pulmonary disease or coronary artery disease) and previous medical or surgical history. double accesses were required in 8 cases (4.6%) in group 1 and in 6 cases (7.1%) in group 2 (p < .05) (table 2). sonographer preferred to choose subcostal rib puncture (166 cases, 95.4%) instead of intercostal rib puncture (8 cases, 4.6%), however, in urologist group, 74 cases (84.7%) were subcostal rib puncture and 13 cases (15.3%) were intercostal rib puncture (p = .003). the lower calyx was the most frequent site of target calyx puncture in group 1 (165 cases, 94.8%), while the percentage of lower calyx in group 2 was 82.3% (72 cases) (p = .001). the major complication rate (1.7% vs. 1.2%; p = .737) and minor complication rate (7.5% vs. 8.2%; p = .829) were comparable between groups. mean blood loss and rates of blood transfusion were also similar between groups. the overall stone-free rates were significantly greater in the urology access group than that in the sonographer access group (90.6% vs. 79.9%, p = .03). there was no statistically significant difference between the groups with regard to mean operation time (defined as the time from ureteral catheterization to the placement of the nephrostomy tube), mean hospital stay and stage 2 pcnl. however, 23 cases (13.2%) needed postoperative swl in group 1 and the percentage was only 4.7% (4 cases) in group 2 (p = .035). discussion improvement of technology and increasing experience has led to enhancement of safety and efficacy of pcnl. however, reported complication rates still reach 3% to 18% according to different scholars.(6-8) proper selection of the targeted calyx and successful puncture could raise the stone-free rate and avoid injuring important blood vessels. dependent on the ultrasonography or fluoroscopy guided pcnl, historically, access to the kidney for stone treatment has been performed by sonographers or radiologists. however, recently, in the past several years, urologists attempted to puncture by themselves.(9,10) recent studies discussed the outcomes of percutaneous access for pcnl that was obtained by rarenal access by sonographer in pcnl | wang et al table 1. patients and stones characteristics in the two study groups. sonographer-made access (group 1) urologist-made access (group 2) p patients, no. 174 85 ----male to female ratio 96/78 52/33 .359 mean age, year (range) 41.6 (21-65) 42.5 (20-67) .745 mean bmi, kg/m2 25.3 (20-28) 24.6 (21-28) .426 renal/ureter stone, no. 139/35 63/22 .293 stone side, right/left 88/86 45/40 mean maximum stone diameter, cm (range) 3.2 (1.6-7.2) 3.1 (1.8-6.8) .395 hydronephrosis, yes/no 151/23 69/16 .236 stone type, n (%) complete staghorn 31 (17.8) 16 (18.8) .843 partial staghorn 45 (25.9) 23 (20.1) .837 pelvic 62 (35.6) 34 (40) .494 multiple stones, no. 102 (58.6) 58 (68.2) .135 associated comorbidities n (%) hypertension 23 (13.2) 10 (11.8) .742 diabetes mellitus 12 (6.9) 7 (8.2) .698 pulmonary disease 9 (5.2) 5 (5.9) .812 coronary artery disease 8 (4.6) 5 (5.9) .657 previous medical and surgical history (%) 8 (4.6) 5 (5.9) .657 1038 | diologists or urologists. to our knowledge, no study has yet been discussed about the difference between sonographers and urologists. jeffrey and colleagues(11) retrospectively evaluated pcnl performed by interventional radiologists or urologists with regard to use of multiple access tracts, percentage of supracostal tracts, mean access difficulty parameters, accessrelated complications, overall stone-free rate and additional access tract placement at the time of surgery. access-related complications were the same in the two groups. however, overall stone-free rate was higher in the urologists’ access group, and 36.8% of access obtained by radiologists could not be used, which need additional access at the time of surgery. conversely, el-assmy and colleagues(2) found that access related complications and stone-free rates were comparable in urologist group and radiologist group. in this study, there was no statistically significant difference between the groups with regard to major and minor complications. three cases (1.7%) in group 1 and 1 case (1.2%) in group 2 encountered septic shock which was considered major complications. minor complications were comparable in both groups (7.5% vs. 8.2%, p = .829). mean blood loss and rates of blood transfusion were also similar between groups. the reasons of high stone-free rates in the urologist-made access group, in our opinion, were that sonographer was not familiar with and not care about the subsequent steps of pcnl. furthermore, compared to urologist, sonographer preferred to subcostal rib puncture (95.4%) and lower calyx puncture (94.8%). lack of suitable intercostal rib puncture and middle calyx puncture might result in the difficult fragment during pcnl. the lower stone-free rate in sonographer-made access group resulted in higher stage 2 swl. our study has several limitations. main limitation of study was that it was not randomized and prospective. a selection bias is inherent for its retrospective nature. furthermore, the number of cases in the study was comparatively smaller, which result in lack of enough confidence on statistical analysis of the data. conclusion renal access in pcnl can be safely and successfully obtained by both sonographer and urologist. infracostal and endourology and stone disease table 2. operative details and outcomes in the two study groups. sonographer-made access (group 1) urologist-made access (group 2) p no. of sites required (%) single 166 (95.4) 79 (92.9) .411 multiple 8 (4.6) 6 (7.1) no. of rib puncture (%) subcostal 166 (95.4) 72 (84.7) .003 intercostal 8 (4.6) 13 (15.3) calyx puncture (%) lower 165 (94.8) 70 (82.3) .001 middle 9 (5.2) 15 (17.7) upper 0 0 mean operative time, min (range) 74.5 (43-145) 75.6 (38-163) .853 stone free rate, n (%) 139 (79.9) 77 (90.6) .03 mean hospital stay, day, (range) 8.2 (6-16) 7.9 (6-15) .385 stage 2 pcnl, n (%) 8 (4.6) 1 (1.2) .158 stage 2 eswl, n (%) 23 (13.2) 4 (4.7) .035 mean blood loss(δhb), g/dl -2.2 (3.5-0.4) -2.3 (3.6-0.4) .355 need of blood transfusion, n (%) 4 (2.3) 3 (3.5) .566 major complications, n (%) 3 (1.7) 1 (1.2) .737 minor complications, n (%) 13 (7.5) 7 (8.2) .829 1039vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l renal access by sonographer in pcnl | wang et al references 1. fernstroem i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. el-assmy am, shokeir aa, mohsen t, et al. renal access by urologist or radiologist for percutaneous nephrolithotomyis it still an issue? j urol. 2007;178:916-20. 3. watterson jd, soon s, jana k. access related complications during percutaneous nephrolithotomy: urology versus radiology at a single academic institution. j urol. 2006;176:1425. 4. spann a, poteet j, hyatt d, chiles l, desouza r, venable d. safe and effective obtainment of access for percutaneous nephrolithotomy by urologists: the louisiana state university experience. j endourol. 2011;25:1421-5. 5. aslam mz, thwaini a, duggan b, et al. urologists versus radiologists made pcnl tracts: the u.k. experience. urol res. 2011;39:217-21. 6. michel ms, trojan l, rassweiler jj. weiler. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899-906 7. de la rosette j, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol. 2011;25:11-7. 8. wang yanbo, jiang fengming, wang yan, et al. post-percutaneous nephrolithotomy septic shock and severe hemorrhage: a study of risk factors. urol int. 2012;88:307-10. 9. armitage jn, irving so, burgess na. percutaneous nephrolithotomy in the united kingdom: results of a prospective data registry. eur urol. 2012;61:1188-93. 10. gamal wm, hussein m, aldahshoury m, et al. solo ultrasonography-guided percutaneous nephrolithotomy for single stone pelvis. j endourol. 2011;25:593-6. 11. tomaszewski jj, ortiz td, gayed ba, smaldone mc, jackman sv, averch td. renal access by urologist or radiologist during percutaneous nephrolithotomy. j endourol. 2010;24:1733-7. lower calyx access in our study has poor stone-free rates and sonographer prefers infracostal and lower access. we encourage urologists establish access by themselves during pcnl. conflict of interest none declared. review association of transforming growth factor-β1 rs1982073 polymorphism with susceptibility to acute renal rejection: a systematic review and meta-analysis farzaneh najafi1, seyed alireza dastgheib2, jamal jafari-nedooshan3,*, mansour moghimi4, naeimeh heiranizadeh3, mohammad zare3, elham salehi5, hossein neamatzadeh6,7 purpose: the association of rs1982073 (codon 10) polymorphism at transforming growth factorβ1 (tgf-β1) gene with acute renal rejection (arr) has been reported by several studies. however, the results were controversial. to derive a more precise estimation of this association, a meta-analysis was performed. methods: the eligible literatures were identified through pubmed, scopus, web of science, embase, scielo, wanfang, and cnki databases up to july 01, 2019. the pooled odds ratios (ors) with corresponding 95% confidence intervals (cis) were used to calculate the strength of the association. results: a total of 23 case-control studies with 795 arr cases and 1,562 non-ar controls were selected. pooled data revealed that there was no significant association between tgf-β1 codon 10 polymorphism and an increased risk of arr in the overall population (c vs. t: or=0.908, 95% ci 0.750-1.099, p = 0.322; ct vs. tt: or=1.074, 95% ci 0.869-1.328, p = 0.507; cc vs.tt: or=0.509, 95% ci=0.738-1.253, p = 0.770; cc+ct vs. tt: or = 0.917, 95% ci 0.756-1.112, p = 0.376, and cc vs. ct+tt: or=0.995, 95% ci 0.809-1.223, p = 0.959). moreover, stratified analysis revealed no significant association between the tgf-β1 rs1982073 polymorphism and arr risk by ethnicity and cases type (recipient and donor). conclusion: the current meta-analysis demonstrated that the tgf-β1 rs1982073 polymorphism was not significantly associated with increased risk of arr. however, studies with a larger number of subjects among different ethnic groups are needed to further validate the results. keywords: acute renal rejection; tgf-β1; polymorphism; meta-analysis. introduction acute renal rejection (arr) has been identified as the main cause of renal graft dysfunction during the first year after transplantation(1–3). arr is associated with chronic structural and functional damage, which causes loss of graft and decrease in patient survival. moreover, it is associated with other conditions such as cardiovascular disease and overall mortality(4). the improvement of renal transplantation results in the last two decades is largely due to a progressive decrease in the incidence of acute rejection(5). many scientists acknowledge that arr is a multifactorial disease which mediated by complex immunological mechanisms and a network of interactions between cytokines regulates the immune response to transplanted renal(6,7). several risk factors for arr have been identified including low histocompatibility between donor and recipient, the age of donor and recipient, ethnicity, gender, ischemia time, delayed graft function, graft non-adherence, and reduced immunosuppression(8,9). in the recent years, there is an increasing body of re1department of internal medicine, shahid sadoughi university of medical sciences, yazd, iran. 2department of medical genetics, school of medicine, shiraz university of medical sciences, shiraz, iran. 3department of surgery, shahid sadoughi university of medical sciences, yazd, iran. 4department of pathology, shahid sadoughi university of medical sciences, yazd, iran. 5department of basic science, faculty of veterinary medicine, ardakan university, ardakan, iran. 6department of medical genetics, shahid sadoughi university of medical sciences, yazd, iran. 7mother and newborn health research center, shahid sadoughi university of medical sciences, yazd, iran. *correspondence: department of surgery, shahid sadoughi hospital, ave sina st, shahid ghandi blvd, yazd, iran. tel: +98-9372726153. email: jamalnedooshan@yahoo.com received july 2019 & accepted april 2020 search highlighting the effects of genetic variants in different cytokines such as il-2, il-4, il-10, tnf‐α, and tgf-β1 in development of arr (10–12). tgf‐β1 is a multifunctional cytokine with immunosuppressive and fibrogenic properties. tgf-β1 belongs to a family of multi-functional polypeptides, produced by many cell types, including t lymphocytes, monocytes, vascular endothelium and fibroblasts(13,14). tgf-β1 has been conventionally recognized as a guardian against different organ acute rejection(15). the pivotal function of tgf-beta in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, survival and in both suppressive and inflammatory immune responses(16,17). it has been known that tgf-β is a cytokine required for the induction and maintenance of transplantation tolerance. central for transplantation tolerance is the role for tgf-β in the induction of foxp3 and regulatory capacity in cd4(+) t cells(18,19). moreover, tgf-β1 has been implicated in many different disorders development of various disorders, including coronary heart disease, human cancers, urology journal/vol 18 no. 1/ january-february 2021/ pp. 1-10. [doi: 10.22037/uj.v0i0.5437] rheumatoid arthritis, and asthma(20,21). the human tgf-β1 gene has previously been mapped to chromosome 19q13.1–13.3, consists of seven exons and spanning a region of 23 kbp(22,23). several common single nucleotide polymorphisms (snps) such as +869t>c, +915g>c, -509c>t, and codon 25 (+74g>c) have been identified at tgf-β1 gene(23). among them, tgf-β1 rs1982073 (codon 10) polymorphism has been extensively studied in organ translation outcomes(15). tgf-β1 rs1982073 polymorphism is lotgf-β1 rs1982073 and acute renal rejection-najafi et al. review 2 table 1. characteristics of studies included in the meta-analysis. first author country subjects genotyping immunosuppressive ar/non-ar ar non-ar mafs hwe (ethnicity) method protocol genotype allele genotype allele tt ct cc t c tt ct cc t c marshall 2000a uk r ssp-pcr csa, aza, 114/76 46 55 13 147 81 39 48 8 126 64 0.336 0.201 (caucasian) steroids marshall 2000b uk d 77/68 34 32 11 100 54 30 24 14 84 52 0.382 0.037 (caucasian) alakulppi 2004 finland r ssp-pcr csa/fk506, 50/241 31 19 115 126 na na (caucasian) mmf/aza, steroids (ct+cc) (ct+cc) ligeiro 2004a usa r ssp-pcr csa, aza, steroids 31/35 12 12 7 36 26 14 15 6 43 27 0.385 0.571 (caucasian) ligeiro 2004b usa d 31/35 5 22 4 32 30 14 14 7 120 60 0.400 0.324 (caucasian) park 2004 korea r ssp-pcr csa, aza, steroids 28/100 3 18 7 24 32 25 50 25 100 100 0.937 1.000 (asian) dmitrienko 2005 canada r rflp-pcr csa/fk506, mmf/aza 50/50 16 24 10 56 44 16 24 10 56 44 0.440 0.854 (caucasian) , steroids guo 2005a china r microarray csa/fk506, mmf, 39/90 18 15 6 51 27 18 57 15 93 87 0.483 0.011 (asian) steroids guo 2005b china d 39/90 6 33 0 45 33 (asian) chow 2005 china r ssp-pcr csa 52/77 8 44 13 64 na na (asian) (ct+cc) (ct+cc) gendzekhadze 2006 venezuela r ssp-pcr csa, mmf, 30/33 12 12 6 36 24 10 14 9 34 32 0.484 0.386 (mixed) steroids hueso 2006 spain r rflp-pcr csa/fk506, steroids, 14/63 6 5 3 17 11 20 28 15 68 58 0.460 0.402 (caucasian) mmf/srl canossi 2007a italy r ssp-pcr csa, mmf/aza, 25/61 4 15 6 23 27 14 29 18 57 65 0.532 0.725 (caucasian) steroids canossi 2007b italy d 20/50 5 12 3 13 26 11 52 48 0.480 0.768 (caucasian) brabcova 2007 czech r ssp-pcr csa/fk506, mmf, 190/246 32 91 67 155 225 34 128 84 196 296 0.601 0.179 (caucasian) steroids grinyo 2008 spain r as-pcr csa, mmf, steroids 63/161 18 34 11 70 56 66 69 26 201 121 0. 272 0.272 (caucasian) mendoza 2008 mexico r ssp-pcr csa/fk506, aza, 19/32 11 8 25 7 na na (mixed) steroids (tt+ct) (ct+cc) manchanda 2008a india r arms-pcr csa, aza, steroids 18/82 1 11 6 13 23 19 45 18 83 81 0.493 0.376 (asian) manchanda 2008b india d 18/82 3 6 9 12 24 13 48 21 74 90 0.591 0.011 (asian) karimi 2012 iran(asian) r arms-pcr csa, mmf, steroids 29/71 5 8 16 18 40 17 24 30 58 84 0.591 0.011 seyhun 2012 turkey r ssp-pcr csa/fk506, mmf, 19/71 6 10 3 22 16 16 31 24 63 79 0.556 0.330 (caucasian) steroids saigo 2014 japan(asian) r ds na 24/111 5 16 3 26 22 22 51 36 95 123 0.564 0.612 seyhun 2015 turkey r ssp-pcr csa, tac/ mpa, 28/62 6 15 7 27 29 16 28 18 60 64 0.516 0.450 (caucasian) mmf, aza 28 18 60 64 0.516 0.450 abbreviations: arr: acute renal rejection; r: recipient; d: donor; pcr: polymerase chain reaction; ssp: single specific primer; rflp: restriction fragment length polymorphism; as: allele-specific; arms: amplification refractory mutation system; ds: direct sequencing; ar: acute rejection; nonar: non acute rejection; na: not applicable; mafs: minor allele frequencies; hwe: hardy–weinberg equilibrium. vol 18 no 1 january-february 2021 3 cated at position 10 (exon 1) in the signal peptide and has a central role in exporting of the newly synthesized protein through endoplasmic reticulum (er) membrane (24). in the recent decade, an increasing number of studies are being conducted on the impact of tgf-β1 rs1982073 (codon 10) polymorphism on the clinical outcomes of renal transplantation(15,25). nevertheless, the results of these studies were not always consistent and controversial. for example, li et al., reported that tgf-β1 rs1982073 polymorphism might be useful in predicting the risk of arr. by contrast, karimi et al., in a case-control study showed that tgf-β1 rs1982073 (codon 10) polymorphism was not significantly associated with risk of arr in the iranian patients(26). to clarify the association between tgf-β1 rs1982073 polymorphism and arr risk, we performed this meta-analysis of all eligible published studies. materials and methods literature search strategy a comprehensive literature search in pubmed, scopus, embase, cochrane library, web of science, elsevier, scielo, sid, wanfang, vip, chinese biomedical database (cbd) and chinese national knowledge infrastructure (cnki) to identify all eligible studies on tgf-β1 rs1982073 polymorphism with risk of arr published up to july 01, 2019. the combination of following keywords and terms were adopted in the electronic searches: (‘’acute renal’’ or ‘’renal graft rejection’’ or “acute renal rejection” or “renal allograft rejection”) and (“transforming growth factor-β1” or ‘’tgf-β1’’) and (‘’codon 10’’ or ‘’+869t>c’’ or ‘’+10t>c’’ or ‘’t869c’’ or ‘’rs1982073’’ or ‘’leu10>pro10’’) and (‘’gene’’ or “single nucleotide polymorphism” or “snps” or ‘’genotype’’ or ‘’allele’’ or ‘’variation’’ or “variant” or ‘’mutation’’). moreover, a manual search of the reference lists performed to retrieved articles for heterogeneity odds ratio publication bias subgroup genetic model type of model i2 (%) ph or 95% ci z test por pbeggs peggers overall population c vs. t random 52.32 0.004 0.908 0.750-1.099 -0.999 0.322 0.944 0.521 ct vs. tt fixed 33.07 0.076 1.074 0.869-1.328 0.664 0.507 0.381 0.249 cc vs.tt fixed 0.00 0.509 0.961 0.738-1.253 -0.293 0.770 0.871 0.880 cc+ct vs. tt fixed 36.87 0.047 0.917 0.756-1.112 -0.885 0.376 0.096 0.056 cc vs. ct+tt fixed 6.70 0.372 0.995 0.809-1.223 -0.051 0.959 0.032 0.163 by ethnicity caucasians c vs. t random 57.76 0.009 0.852 0.662-1.096 -1.248 0.212 0.212 0.196 ct vs. tt fixed 2.45 0.420 1.137 0.889-1.452 1.024 0.306 9.303 0.290 cc vs.tt fixed 0.00 0.918 0.969 0.712-1.319 -0.199 0.842 0.837 0.902 cc+ct vs. tt fixed 28.16 0.161 0.943 0.719-1.238 -0.423 0.672 0.246 0.253 cc vs. ct+tt fixed 0.00 0.947 0.917 0.715-1.176 -0.681 0.496 0.114 0.074 asians c vs. t random 53.86 0.043 1.048 0.738-1.487 0.262 0.793 0.133 0.042 ct vs. tt random 62.30 0.014 1.133 0.528-2.432 0.321 0.748 0.548 0.162 cc vs.tt fixed 50.94 0.057 1.031 0.588-1.809 0.107 0.915 1.000 0.921 cc+ct vs. tt random 58.65 0.024 1.159 0.582-2.309 0.421 0.674 0.229 0.037 cc vs. ct+tt random 53.81 0.043 1.060 0.560-2.004 0.178 0.858 0.386 0.122 by subjects recipient c vs. t fixed 19.61 0.235 0.960 0.837-1.101 -0.588 0.556 0.692 0.950 ct vs. tt fixed 32.29 0.110 0.984 0.776-1.249 -0.130 0.897 0.234 0.348 cc vs.tt fixed 0.00 0.450 0.983 0.734-1.315 -0.118 0.906 1.000 0.797 cc+ct vs. tt random 41.16 0.044 0.889 0.661-1.196 -0.778 0.437 0.095 0.127 cc vs. ct+tt fixed 0.00 0.699 1.019 0.814-1.275 0.162 0.872 0.095 0.468 donor c vs. t random 84.00 ≤0.001 0.687 0.313-1.511 -0.933 0.351 0.806 0.597 ct vs. tt fixed 23.63 0.264 1.495 0.941-2.374 1.703 0.083 1.000 0.867 cc vs.tt fixed 2.04 0.395 0.866 0.460-1.632 -0.444 0.657 0.462 0.639 cc+ct vs. tt fixed 0.00 0.458 1.261 0.815-1.950 1.041 0.298 1.000 0.518 cc vs. ct+tt fixed 57.47 0.052 0.866 0.505-1.486 -0.523 0.601 0.806 0.778 genotyping methods ssp-pcr c vs. t random 58.99 0.009 0.817 0.621-1.076 -1.437 0.151 0.152 0.291 ct vs. tt fixed 12.18 0.328 1.106 0.845-1.446 0.733 0.463 0.008 0.054 cc vs.tt fixed 0.00 0.822 0.929 0.666-1.296 -0.433 0.665 0.755 0.672 cc+ct vs. tt fixed 28.29 0.167 0.862 0.678-1.097 -1.208 0.227 0.046 0.027 cc vs. ct+tt fixed 0.00 0.619 0.908 0.710-1.162 -0.767 0.443 0.062 0.089 arms-pcr c vs. t fixed 0.00 0.947 1.648 1.092-2.486 2.379 0.017 1.000 0.425 ct vs. tt fixed 23.61 0.270 1.128 0.464-2.738 0.265 0.791 1.000 0.527 cc vs.tt fixed 0.00 0.597 2.195 0.941-5.116 1.820 0.069 0.296 0.241 cc+ct vs. tt fixed 0.00 0.412 1.542 0.695-3.419 0.287 1.066 1.000 0.495 cc vs. ct+tt fixed 0.00 0.711 2.010 1.133-3.567 2.386 0.017 1.000 0.694 hwe* c vs. t random 54.61 0.004 0.877 0.712-1.080 -1.233 0.218 0.773 0.435 ct vs. tt random 11.86 0.318 1.151 0.906-1.462 1.152 0.249 0.324 0.251 cc vs.tt fixed 0.00 0.482 0.954 0.718-1.268 -0.322 0.748 0.820 0.789 cc+ct vs. tt random 41.50 0.031 0.949 0.715-1.261 -0.360 0.719 0.107 0.068 cc vs. ct+tt fixed 5.570 0.388 0.989 0.794-1.232 -0.097 0.922 0.014 0.160 table 2. summary risk estimates for association of tgf-β1 rs1982073 polymorphism with risk of arr. abbreviations: arr: acute renal rejection; pcr: polymerase chain reaction; ssp: single specific primer; arms: amplification refractory mutation system. *by excluding hwe violating studies. tgf-β1 rs1982073 and acute renal rejection-najafi et al. additional potential studies. publication language was restricted to english, chinese, and farsi. moreover, non-english publications were translated and included in the meta-analysis. inclusion and exclusion criteria the inclusion criteria for the gene association studies in this meta-analysis were as follows: 1) studies with case-control or cohort design; 2) only full-text published studies; 3) studies evaluated the association of tgf-β1 rs1982073 (codon 10) polymorphism with arr risk; 4) provided the genotype distribution in both cases and controls for estimating an odds ratio (or) with 95% confidence interval (ci); and 5) at least two comparison groups (arr group vs. non-ar group). the exclusion criteria were as follows: 1) case only studies (without controls); 2) non-human studies; 3) family‐based, sibling, twins and linkage studies; 4) studies without details of genotype frequencies, which were unable to calculate ors; 5) studies on other polymorphisms of tgf-β1 gene; 6) abstracts, case reports, case series, letters, comments, conference presentations, posters, editorials, reviews, and previous meta-analyses; and 7) duplica¬tion of the previous publication; and 8) duplicates or overlapping studies. if the authors published two or more studies using the same data or overlapping data, the newest publication or the publication with the largest sample size was selected. there was no any limitation by ethnicity, race, placed or geography area. data extraction two authors (hn and mja) carefully extracted data from all eligible studies using a standardized form. then, they have checked the data extraction results and reached consensus. any disagreement between the two authors was resolved by discussion with a third author. the following data were collected from each study: first author, year of publication, country of origin, ethnicity (asians, caucasians, african, mixed population), type of cases (recipient and donor), genotyping method, number of cases and controls, genotypes frequencies of cases and controls, minor allele frequencies (mafs) and hardy-weinberg equilibrium test in control subjects (non-arr). in this meta-analysis the diverse ethnicities were categorized as caucasian, asian, africans, and mixed population (unknown or more than one racial group). statistical analysis an ethical approval was not necessary as this study was a meta-analysis based on previous studies. the strength of the association between tgf-β1 rs1982073 (codon 10) polymorphism and arr risk was measured by odds ratios (ors) with 95% confidence intervals (cis). the statistical significance of the pooled or was determined using the z-test. pooled estimates of the or were obtained by calculating a weighted average of or from each study. the pooled ors was calculated under all five genetic models, i.e., allele (c vs. t), homozygote (cc vs. tt), heterozygote (ct vs. figure 1. flow diagram of selecting eligible studies for the meta-analysis. tgf-β1 rs1982073 and acute renal rejection-najafi et al. review 4 vol 18 no 1 january-february 2021 20 tt), dominant (cc+ct vs. tt) and recessive (cc vs. ct+tt). between-study heterogeneity was estimated by cochran’s χ2 based q-statistic test, in which it was considered to be statistically significant at p ≤ 0.05. in addition, i2-value was used to quantify the proportion of heterogeneity, with the range of 0 to 100% (‘‘i2<25% represents no heterogeneity, i2 = 25–50% represents moderate heterogeneity, i2 = 50–75% represents large heterogeneity, and i2>75% represents extreme heterogeneity). accordingly, when between-study heterogeneity existed (p < 0.05, i2 > 50%) a random-effects model weighted (the dersimonian-laird method) was applied to give a more conservative result; otherwise, a fixed-effects model weighted (the mantel-haenszel method) method was selected. fisher’s exact test was used to assess the hardy-weinberg equilibrium (hwe) in the control group, in which the significance set at p<0.05. a stratification analysis was conducted by ethnicity, type of subjects, genotyping methods and hwe to found out the source of heterogeneity. to check the stability and reliability of the pooled ors, a sensitivity analysis was performed by omitting a single study each time from the all selected studies and reanalyzing the remainder. begg’s funnel plot a scatter plot of effect against a measure of study size and egger’s test were used to determine the presence of publication bias in the current meta-analysis; which p<0.05 indicated that the result was statistically significant. all statistical analyses were performed using comprehensive meta-analysis (cma) software version 2.0 (biostat, englewood, nj). all tests were two-sided, and the p values of < 0.05 were considered statistically significant. results studies characteristics as shown in figure 1, initially, a total of 403 results were identified by electronic and manual searches up to july 01, 2019. after reading the titles and abstracts, 365 were excluded because they were obviously irrelevant papers to tgf-β1 rs1982073 polymorphism or duplicates. then, 19 articles were excluded because they were case reports, case only studies, reviews, previous meta-analysis, did not report usable data. finally, a total of 23 case-control studies in 18 publications with 795 arr cases and 1,562 non-ar controls were selected (10,11,26–41). the characteristics of each study are summarized in table 1. all eligible studies were published in english between november, 2000 and june, 2015. among them, 13 studies were based on caucasian populations (5,410 cases and 6,438 controls), eight studies were based on asian populations (3,137 cases and 3,700 controls), and two studies were based on mixed populations (331 cases and 405 controls). the included studies were performed in uk, usa, canada, china, venezuela, italy, czech, india, iran, spain and turkey. the genotypes and allele frequency was not applicable review 438 figure 2. forest plot for association of tgf-β1 rs1982073 polymorphism with risk of arr in the overall population. a: allele model (c vs. t); b: recessive model (cc vs. ct+tt). tgf-β1 rs1982073 and acute renal rejection-najafi et al. vol 18 no 1 january-february 2021 5 for three studies. the allele, genotype and minor allele frequency (maf) distributions in the cases and controls are shown in table 1. moreover, the distribution of genotypes in the controls was in agreement with hardy-weinberg equilibrium (hwe) for all selected studies, except for four studies (table 1). quantitative data synthesis the summary of the meta-analysis of the association of between tgf-β1 rs1982073 polymorphism and risk of arr are shown in table 2. pooled data revealed that there was no significant association between tgf-β1 rs1982073 polymorphism and an increased risk of arr under all five genetic models, i.e., allele (c vs. t: or = 0.908, 95% ci 0.750-1.099, p = 0.322, fig 2a), heterozygote (ct vs. tt: or = 1.074, 95% ci 0.869-1.328, p = 0.507), homozygote (cc vs.tt: or = 0.509, 95% ci 0.738-1.253, p = 0.770), dominant (cc+ct vs. tt: or = 0.917, 95% ci 0.756-1.112, p = 0.376), and recessive (cc vs. ct+tt: or = 0.995, 95% ci 0.809-1.223, p = 0.959, fig 2b). moreover, we performed subgroup analyses by ethnicity, type of cases (recipient and donor) and genotyping methods. when stratified by ethnicity, no significant association was found in caucasian and asian populations (figure 3a, 3b). moreover, subgroup analysis type of cases (recipient and donor) revealed that tgf-β1 rs1982073 polymorphism was not significantly associated with arr risk in recipient and donor groups (table 2). however, there was a significant association between tgf-β1 rs1982073 polymorphism and an increased risk of arr in arms-pcr group of studies (c vs. t: or = 1.648, 95% ci 1.0922.486, p = 0.017 and cc vs. ct+tt: or=0.2.010, 95% ci 1.133-3.567, p = 0.017), but in sscp-pcr group of studies. between-study heterogeneity test as shown in table 2, there was a significant between-study heterogeneity only under the allele model (i2 =52.32; ph=0.004) in the overall population. we conducted subgroup analysis by ethnicity, type of cases, genotyping methods and hwe to found the potential source of heterogeneity in the meta-analysis. results showed that the heterogeneity was significantly decreased by type of cases and genotyping methods. however, after subgroup analysis by ethnicity and excluding hwe-violating studies a moderate to high heterogeneity was appeared, indicating that ethnicity and hwe might be potential source of between-study heterogeneity in the current met-analysis (table 2). sensitivity analysis we performed a sensitivity analysis to assess the influence of each individual study on the pooled ors by sequential omission of individual studies. however, the corresponding pooled ors were not materially altered by removing any individual study. moreover, we have figure 3. forest plot for association of tgf-β1 rs1982073 polymorphism with risk of arr by ethnicity. a: caucasians (homozygote model: cc vs.tt); b: asians (recessive model: cc vs. ct+tt). tgf-β1 rs1982073 and acute renal rejection-najafi et al. review 6 vol 18 no 1 january-february 2021 7 performed sensitivity analysis by excluding hwe-violating studies. as shown in table 2 and figure 4, sensitivity analysis showed that the initial results were not considerably adjusted by omitting the hwe-violating studies. therefore, the sensitivity analysis confirmed that the results of the present meta-analysis were statistically stable. publication bias publication bias was assessed by begg’s funnel plot and egger’s test. the shape of the funnel plots did not revealed any asymmetry under all five genetic models in the overall population (figure 3). then, egger’s test was performed to provide statistical evidence of funnel plot asymmetry. the results indicated a lack of publication bias under all five genetic models, i.e., allele (pbeggs = 0.661; peggers = 0.856), heterozygote (pbeggs = 0.381; peggers = 0.508), homozygote (pbeggs = 0.661; peggers = 0.991, figure 5a), dominant (pbeggs = 0.191; peggers = 0.199, fig 2b) and recessive (pbeggs = 0.137; peggers = 0.485). discussion to date, the cause of arr has not yet been fully clarified. in recent years, numerous studies have revealed an association between tgf-β1 rs1982073 and arr risk (15). however, the relationship remains controversial. in the current meta-analysis, a total of 23 case-control studies with 795 arr cases and 1,562 non-ar controls were selected. after pooling the data from all eligible studies, we have shown that tgf-β1 rs1982073 polymorphism was not significantly associated with an increased risk of arr in the overall population and by ethnicity. moreover, our subgroup analysis revealed that arr was not associated with genotype of tgf-β1 rs1982073 polymorphism in renal recipients or donors (table 2). thus, our results indicated that tgf-β1 rs1982073 polymorphism might not be useful biomarker to identify patients predisposed to arr. the current meta-analysis results are inconsistent with a previous meta-analysis in that revealed that tgf-β1 rs1982073 polymorphism was not significantly associated with risk of arr. ge et al., in a meta-analysis have found a positive association between tgf-β1 rs1982073 polymorphism and arr. in recent years, some studies already studied potential associations tgf-β1 rs1982073 polymorphism with risk of arr. however, by including recently published studies which have strong reverse association with tgf-β1 rs1982073 polymorphism, our pooled data did not show a significant association between tgf-β1 rs1982073 polymorphism and arr in the overall population under all five genetic models. omrani et al., showed that the tgf-β1 rs1982073 polymorphism did not play a major role in kidney allograft survival(42). in a meta-analysis, warlé et al., also failed to show a significant association of tgf-β1 rs1982073 (codon 10) and rs1800471 (codon 25) polymorphisms with an increased risk of acute liver graft rejection(43). hueso et al., found an independent association between t allele at tgf-β1 rs1982073 polymorphism in recipient and independent predictors of subclinical rejection (scr)(28). moreover, cho et al., reported that tgf-β1 rs1982073 (codon 10) and rs1800471 (codon 25) polymorphisms were not significantly associated with an increased risk of development of chronic allograft nephropathy in korean renal transplant recipients(25). therefore, our findings are in accordance with the mentioned studies revealed that c allele of tgf-β1 rs1982073 loci was not associated with an increased risk of arr. however, this result was contradictory to studies performed by chow et al., park et al., and ge et al., which observed an increased risk in renal transplant recipients. in 2005, chow et al., have demonstrated that the cc genotype of tgf-β1 rs1982073 polymorphism was a potential risk factor for failure of kidney allograft function(41). in 2004, park et al., have evaluated the association of tgf-β1 polymorphisms with arr risk in renal transplant recipients and their donors. they found that the cc genotype in the renal transplant recipients were associated with recurrent acute rejection episodes in korean population(38). ge et al., have found recipient tgf-β1 haplotypes were significantly associated with an increased risk of acute rejection in solid organ transplant recipients, particutgf-β1 rs1982073 and acute renal rejection-najafi et al. figure 4. forest plot for association of tgf-β1 rs1982073 polymorphism with risk of arr after excluding hwe-violating studies under the heterozygote model (ct vs. tt). larly in patients receiving cardiac allograft. in addition, they revealed that the donor tgf-β1 rs1982073 polymorphism was significantly associated with acute rejection of solid organ transplant in recipients under the heterozygote and dominant models, especially among patients in csa/ fk 506 group compared with those in csa group(44). as shown in table 2, there was a global variation for mafs of tgf-β1 rs1982073 in the healthy subjects, suggesting a potential subgroup analysis in the worldwide population. however, analysis by ethnicity did not show a significant association between tgf-β1 rs1982073 and arr under all five genetic models. in addition, most of the selected studies were conducted in caucasian population, which might be caused to reduce the potential effects of subgroup analysis by ethnicity. between-study heterogeneity is a common issue when interpreting the pooled data of meta-analyses(45–47). it could be attributable to differences in several factors such as environmental factors, criteria or methodological factors in study design, sample size, source of controls, type of cases, genotyping methods, and so on (48,49). in the present meta-analysis there was a significant heterogeneity under two genetic models. however, after subgroup analysis a moderate to high heterogeneity appeared in the asians under four genetic models, indicating that ethnicity might be potential source of between-study heterogeneity in the met-analysis. all of the studies included in this meta-analysis met our inclusion criteria. in spite of these, several limitations that exist in the current meta-analysis have to be addressed. first, the sample size was relatively small which may lead to a relatively small power. second, we only selected published studies electronically in english, chinese, and farsi, so it is possible that some pertinent studies published in other languages or unpublished studies with negative results may have been missed. therefore, publication bias may exist; even no statistical evidence suggests publication bias in the current meta-analysis. third, there were only two studies that evaluated the association in mixed populations and subgroup analysis was performed only in caucasians and asians. therefore, it is unknown whether the results will extend to other populations such as africans and mixed populations. fourth, only small numbers of studies were included in some subgroups such as donors and arms-pcr group of studies. therefore, these subgroup analyses may not have enough statistical power with the small sample size and the conclusions may be biased. fifth, our study was designed to analyze the association of tgf-β1 rs1982073 polymorphism with arr; however, a haplotype analysis may be more powerful to find a significant association between tgf-β1 polymorphisms (such as rs1982073 and rs1800471 polymorphisms) and arr risk. moreover, due to lack of data, we did not evaluate the effects of gene-gene and gene-environment interactions on development of arr. conclusions this meta-analysis result revealed that tgf-β1 rs1982073 (codon 10) polymorphism was not significantly associated with an increased risk of arr. moreover, there was no significant association by ethnicity and genotypes of recipients or donors. thus, our results indicated that tgf-β1 rs1982073 polymorphism might not be useful biomarker to identify patients predisposed to arr. data from large-scale, multicenter, epidemiological studies are still needed to validate our findings and the molecular mechanism for the association need to be elucidated in future studies. conflicting interests the authors declared no potential conflicts of interest with respect to the research or publication of this article. references 1. cecka jm. the optn/unos renal transplant registry. clin transpl. 2005:1-16. 2. lemoine m, titeca beauport d, lobbedez t, choukroun g, hurault de ligny b, hazzan m, et al. risk factors for early graft failure and death after kidney transplantation in recipients older than 70 years. kidney int rep. 2019;4:656-666. 3. köhnke r, kentrup d, schütte-nütgen k, schäfers m, schnöckel u, hoerr v, et al. update on imaging-based diagnosis of acute renal allograft rejection. am j nucl med mol imaging. 2019;9:110-126. 4. israni a, leduc r, holmes j, jacobson pa, lamba v, guan w, et al. single-nucleotide polymorphisms, acute rejection, and severity of tubulitis in 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[impacts of donor and recipient’s snp of cytokine and cytokine receptor on early acute renal allograft rejection]. zhonghua yi xue za zhi. 2005;85:3126-33. 41. ming chow k, chun szeto c, poon p, yan lau w, mac-moune lai f, kam-tao li p, et al. transforming growth factor-β1 gene polymorphism in renal transplant recipients. ren fail. 2005;27:671-5. 42. omrani md, mokhtari m-r, bagheri m, ahmadpoor p. association of interleukin-10, interferon-gamma, transforming growth factor-beta, and tumor necrosis factoralpha gene polymorphisms with long-term kidney allograft survival. iran j kidney dis. 2010;48:141-6. 43. warlé mc, metselaar hj, hop wcj, tilanus hw. cytokine gene polymorphisms and acute liver graft rejection: a meta-analysis. liver transpl. 2005;11:19-26. 44. ge yz, yu p, jia r-p, wu r, ding a-x, li l-p, et al. association between transforming growth factor beta-1 +869t/c polymorphism and acute rejection of solid organ allograft: a meta-analysis and systematic review. transpl immunol. 2014;30:76-83. 45. niktabar sm, latifi sm, moghimi m, jafarinedooshan j, aghili k, miresmaeili sm, et al. association of vitamin d receptor gene polymorphisms with risk of cutaneous melanoma. a meta-analysis based on 40 case-control studies. dermatol rev/przegl dermatol. 2019;106:268–79. 46. karimi-zarchi m, moghimi m, abbasi h, hadadan a, salimi e, morovati-sharifabad m, et al. association of mthfr 677c>t polymorphism with susceptibility to ovarian and cervical cancers: a systematic review and meta-analysis. asian pac j cancer prev. 2019;20:2569-2577. 47. bahrami r, shajari a, aflatoonian m, noorishadkam m, akbarian-bafghi mj, morovati-sharifabad m, et al. association of rearranged during transfection (ret) c.73 + 9277t > c and c.135g > a polymorphisms with susceptibility to hirschsprung disease: a systematic review and meta-analysis. fetal pediatr pathol. 2019:1-15. [epub ahead of print]. 48. jafari-nedooshan j, moghimi m, zare m, heiranizadeh n, morovati-sharifabad m, akbarian-bafghi mj, et al. association of promoter region polymorphisms of il-10 gene with susceptibility to lung cancer: systematic review and meta-analysis. asian pac j cancer prev. 2019;20:1951–7. 49. farbod m, karimi-zarchi m, heiranizadeh n, seifi-shalamzari n, akbarian-bafghi mj, jarahzadeh mh, et al. association of tnf-α -308g>a polymorphism with susceptibility to cervical cancer and breast cancer: a systematic review and meta-analysis. klinicka onkologie. 2019;32:170–80. tgf-β1 rs1982073 and acute renal rejection-najafi et al. review 10 case reports 180 urology journal vol 4 no 3 summer 2007 surgical treatment of retroperitoneal leiomyosarcoma with adjuvant radiotherapy ilter tufek,1 haluk akpınar,2 cuneyd sevinc,2 bulent alıcı,3 ali rıza kural3 urol j. 2007;4:180-3. www.uj.unrc.ir keywords: leiomyosarcomas, adjuvant radiotherapy, surgery, treatment 1department of urology, group of florence nightingale hospitals, istanbul, turkey 2department of urology, bilim university, istanbul, turkey 3department of urology, istanbul university, cerrahpasa school of medicine, istanbul, turkey corresponding author: ilter tufek, md urology department, group florence nightingale hospitals, abide-i hurriyet cad no: 290 80220 sisli, istanbul, turkey tel: +90 532 292 0069 fax: +90 212 224 7363 e-mail: iltertuf@iris.com.tr received april 2007 accepted june 2007 introduction although leiomyosarcoma is among the most common nonepithelial retroperitoneal tumors along with fibrosarcoma, liposarcoma, and malignant lymphoma, it only constitutes 5% to 15% of all retroperitoneal tumors. about 70% of leiomyosarcomas are found in the retroperitoneal space.(1) extensive surgical resection for achieving complete removal and providing negative surgical margins is the treatment of choice. this is also the most important factor in preventing local recurrence.(2-4) we present 2 cases with retroperitoneal leiomyosarcomas invading the inferior vena cava and the ureter. preoperative workup was made for complete resection and achieving negative margins. adjuvant radiotherapy was administered following surgical therapy to decrease the risk of local recurrence. case report case 1 a 31-year-old man presented with abdominal discomfort and weight loss. physical examination revealed a palpable right upper quadrant mass and a 12-cm retroperitoneal mass was confirmed by computed tomography (ct). the lesion was surrounding the anterior part of the inferior vena cava (ivc; figure 1). the right pelvicalyceal system and the proximal ureter were dilated and the testicles were normal. testis tumor markers (β-human chorionic gonadotropin and α-fetoprotein) were measured which were in their reference ranges. the ct-guided biopsy revealed no malignancy and probable diagnosis was schwannoma. surgical exploration was performed and the mass invading the mesothelium of the ascending colon, ureter, and the ivc was detected. dissection of the ivc was performed by a vascular surgeon and the mass was removed with a patch of the ivc. intraoperative frozen section analysis revealed no malignancy, but the final histopathology examination confirmed a grade 2 leiomyosarcoma with negative surgical margins (figure 2). thorax ct scan showed no abnormality. adjuvant radiotherapy was administered with 50.4 gy/28 fractions. twelve months later, a 2-cm spot of liver recurrence was detected and then resected. subsequently, chemotherapy figure 1. preoperative ct showing large retroperitoneal mass on the right side in case 1. leiomyosarcoma and adjuvant radiotherapy—tufek et al urology journal vol 4 no 3 summer 2007 181 with ifosfamide, adriamycin, and dacarbazine was instituted. the patient was without any new recurrences during the 24 months’ follow-up. case 2 a 52-year-old woman presented to our center with the chief complaint of right lumbar pain and nausea. tenderness of the right costovertebral angle was detected on physical examination. on ct scan, we detected a 30-mm mass in the right retroperitoneal area anterolateral to the ivc. the mass was compressing the ureter causing mild hydronephrosis (figure 3). the result of thorax ct was normal. following dissection of the stented ureter, the mass was removed. histopathology examination revealed high-grade leiomyosarcoma with negative surgical margins (figure 4). adjuvant radiotherapy was administered figure 2. top, tumor cells were revealed by positive staining with smooth muscle actin in case 1 (smooth muscle actin, × 400). bottom, cellular pleomorphism and cellularity of the tumor in case 1 (hematoxylin-eosin, × 400). figure 3. preoperative ct showing retroperitoneal mass on the right side in case 2 (coronal view). figure 4. top, immunoreactivity of the tumor with smooth muscle actin in case 2 (smooth muscle actin, × 400). bottom, cellular pleomorphism and cellularity of the tumor in case 2 (hematoxylin-eosin, × 400). leiomyosarcoma and adjuvant radiotherapy—tufek et al 182 urology journal vol 4 no 3 summer 2007 with 50 gy/25 fractions. no recurrence was detected during the 32 months’ follow-up. discussion sarcomas of the retroperitoneum and the urogenital tract grow slowly and typically remain asymptomatic until the tumor becomes evident as a large mass.(1) imaging techniques, notably magnetic resonance imaging and ct, have improved permitting excellent visualization, evaluation, and preparation.(5) preoperative histopathologic diagnosis of a retroperitoneal mass can help planning the operative procedure. however, interpretation of a retroperitoneal mass using needle biopsies may be difficult and inconclusive, as it was in our first case. guz and colleagues published their experience with retroperitoneal neural sheath tumors. they performed preoperative ct-guided needle biopsies in 3 patients and all yielded inaccurate or inconclusive results.(6) complete resection often needs extended dissection which may include the vascular structures, kidneys, bladder, and gastrointestinal tract.(4,7) management can need to be provided by a specialized team of surgeons. in case 1, although needle biopsy result was schwannoma, ivc dissection was made by a vascular surgeon to achieve negative surgical margins. in addition to incomplete resection, tumor grade is another prognostic factor predicting local recurrence and metastasis.(2,3) different studies report recurrence rates ranging from 45% to 82% after complete resection.(7,8) extirpating the retroperitoneal leiomyosarcomas with negative margins cannot be accomplished due to some limitations on dissection which result in high incidence of local recurrence. it has been stated in many studies that in most patients, disease recurs locally within 3 years of definitive treatment of the primary tumor.(7) some series have reported that approximately 80% to 87% of all local recurrences become evident within 2 years and 100% are detected within 3 years.(7,9) in a series of sarcomas of the retroperitoneum and the urogenital tract, local relapse was detected in 83% of the patients within 3 years.(7) patients with retroperitoneal sarcomas should be followed closely especially for the first 3 years after the primary treatment. high incidence of the local recurrence remains as a major problem in longterm and follow-up, perhaps as long as 10 years, is mandatory.(10) radiation therapy seems to be favorable for local control. in a series of retroperitoneal sarcomas, 13 of 34 patients received high-dose postoperative radiotherapy which was found to have a significant favorable effect on recurrence.(11) the employment and dosage of radiotherapy have not been standardized and differ considerably in the literature.(4,12,13) in a study about leiomyosarcoma of the ivc, routine administration of postoperative radiotherapy with 45 gy to 50 gy was reported to be effective.(12) to decrease the risk of local recurrence, our patients underwent adjuvant radiotherapy with 50 gy. although follow-up was short, none of our patients had local relapse after 24 and 32 months. information on the value of chemotherapy is scarce. there are investigational studies concerning combined-modality therapy for retroperitoneal sarcomas.(4) in a case report, beneficial effect of neoadjuvant chemotherapy for complete resection of advanced leiomyosarcoma was depicted.(14) however, no study or report has offered a consistent advantage of chemotherapy.(4,12) references 1. felix el, wood dk, das gupta tk. tumors of the retroperitoneum. curr probl cancer. 1981;6:1-47. 2. storm fk, mahvi dm. diagnosis and management of retroperitoneal soft-tissue sarcoma. ann surg. 1991;214:2-10. 3. hill ma, mera r, levine ea. leiomyosarcoma: a 45-year review at charity hospital, new orleans. am surg. 1998;64:53-60. 4. raut cp, pisters pw. retroperitoneal sarcomas: combined-modality treatment approaches. j surg oncol. 2006;94:81-7. 5. van rooij wj, martens f, verbeeten b, dijkstra j. ct and mr imaging of leiomyosarcoma of the inferior vena cava. comput assist tomogr. 1988;12:415-9. 6. guz bv, wood dp jr, montie je, pontes je. retroperitoneal neural sheath tumors: cleveland clinic experience. j urol. 1989;142:1434-7. 7. zhang g, chen kk, manivel c, fraley ee. sarcomas of the retroperitoneum and genitourinary tract. j urol. 1989;141:1107-10. 8. mcgrath pc, neifeld jp, lawrence w jr, et al. improved survival following complete excision of retroperitoneal sarcomas. ann surg. 1984;200:200-4. 9. shiu mh, castro eb, hajdu si, fortner jg. surgical treatment of 297 soft tissue sarcomas of the lower extremity. ann surg. 1975;182:597-602. leiomyosarcoma and adjuvant radiotherapy—tufek et al urology journal vol 4 no 3 summer 2007 183 10. shindo s, matsumoto h, ogata k, et al. surgical treatment of retroperitoneal leiomyosarcoma invading the inferior vena cava: report of three cases. surg today. 2002;32:929-33. 11. van doorn rc, gallee mp, hart aa, et al. resectable retroperitoneal soft tissue sarcomas. the effect of extent of resection and postoperative radiation therapy on local tumor control. cancer. 1994;73:637-42. 12. hines oj, nelson s, quinones-baldrich wj, eilber fr. leiomyosarcoma of the inferior vena cava: prognosis and comparison with leiomyosarcoma of other anatomic sites. cancer. 1999;85:1077-83. 13. stoeckle e, coindre jm, bonvalot s, et al. prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the french cancer center federation sarcoma group. cancer. 2001;92:359-68. 14. kamba t, kawakita m, noguchi t, et al. [neoadjuvant cyvadic (cyclophosphamide, vincristine, adriamycin and dacarbazine) therapy for retroperitoneal leiomyosarcoma: a case report]. hinyokika kiyo. 1997;43:577-80. japanese. pdf-797.pdf 361vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l therapeutic effects of aqueous extracts of petroselinum sativum on ethylene glycol-induced kidney calculi in rats jafar saeidi, 1 hadi bozorgi,2 ahmad zendehdel,3 jamshid mehrzad4 purpose: to investigate the therapeutic effects of the aqueous extract of petroselinum sativum aerial parts and roots on kidney calculi. materials and methods: thirty-six male wistar rats were randomly assigned into of root aqueous extract in drinking water, respectively, from the 14th day of the h experiment. results: on the 14thh th days of the experiment, serum level of magnesium h cantly in group b compared with the control group (14th day: magnesium = 2.87 ± h thh pp th day (p((p groups (p((p conclusion: petroselinum sativum has a therapeutic effect on calcium oxalate stones in rats with nephrolithiasis and reduces the number of calcium oxalate deposits. keywords: petroselinum, kidney calculi, ethylene glycol, calcium oxalate corresponding author: jafar saeidi, phd department of physiology, neyshabur branch, islamic azad university, neyshabur, iran tel: +98 551 661 0455 fax: +98 551 221 0673 e-mail: s_milad2003 @ yahoo.com received november 2010 accepted june 2011 1 department of physiology, neyshabur branch, islamic azad university, neyshabur, iran 2 department of toxicology, neyshabur health center, neyshabur, iran 3 department of statistics, neyshabur branch, islamic azad university, neyshabur, iran 4 department of biochemistry, neyshabur branch, islamic azad university, neyshabur, iran endourology and stone disease 362 | introduction urinary stone is the third prevalent disorder in the urinary system.(1) the annual incicumulative recurrence rate was 16% after 1 year, (2) the (3) the recurrence of urolithiasis represents a serious problem and thus stone prevention and treatment are highly recommended. the use of extracorporeal shockwave lithotripsy (swl) method may cause acute renal injury, a decrease in renal function, and an increase in stone recurrence.(4) furthermore, some medications used to prevent and treat the disease are not effective in all patients and of-ff ten have adverse effects.(5) ethylene glycol (eg) has two toxic metabolites; glycolic acid, which is responsible for the acidosis, and oxalic acid, which precipitates as calcium oxaproximal tubular cell necrosis.(6) studies have condeath.(7-9) the toxic effects increase free radical production and lipid peroxidation. the petroselinum sativum (ps) or parsley, which is a member of the family of umbelliferae, is widely anti-diabetic, anti-microbial, anti-oxidant, and laxative in the digestive tract. furthermore, it balances enzyme activities, increases glutathione in the kidney, and repairs the kidney tissue after nephrotoxicity.(11-13) however, there is no evidence for the therapeutic usage of this traditional medicine. therefore, we aimed to evaluate the effects of aqueous extract of parsley on the treatment of y materials and methods ter. they were divided randomly into 6 groups and remained untreated and served as normal control days. rats in group b served as eg control group. mg/kg body weight of aerial parts aqueous extract, respectively. those in groups e and f also received extract in drinking water, respectively, from the 14th day up to the end of the experiment.h (14) the experiment was conducted in accordance animals and the study was approved by the ethendourology and stone disease figure 2. serum level of magnesium (mg/100cc serum) in control group, ethylene glycol group, and treatment groups (c = 200 mg/kg body weight and d = 600 mg/kg body weight of aerial parts, e = 200mg/kg body weight, and f = 600 mg/kg body weight of root aqueous extract). data were expressed as mean ± standard error, n = 6,*p < .001.p figure 1. serum level of calcium (mg/100cc serum) in control group, ethylene glycol group, and treatment groups (c = 200 mg/kg body weight and d = 600 mg/kg body weight of aerial parts, e = 200 mg/kg body weight, and f = 600 mg/kg body weight of root aqueous extract). data were expressed as mean ± standard error, n = 6, *p < .001.p 363vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l petroselinum sativum on kidney calculi | saeidi et al science. the parsley was purchased from the farmers of parts and roots were separated and dried under suspended in distilled water as aqueous suspension. after removing the solvent from the extract in vacuum, the extract was dried in an oven with a refrigerator and added daily to the drinking water of the rats. ether. blood was collected from orbital venous plexus in non-heparinized tubes and centrifuged at levels of calcium and magnesium were measured for histological examination at the end of the experiment (the 31st day), all the rats were decapitated t by guillotine after they were anesthetized. thereaf-ff matoxylin and eosin, and then examined by light the renal tubules were counted by dp2-bsw-eb6212, v2.2 olympus bx51 microscope digital (14) each 9 nm2. data were analyzed with spss software (the statisanova followed by duncan’s test for multiple comparisons among all groups. p values less than p were presented as mean ± standard error. results serum levels of magnesium (p((p = .989, d = .372, e = .492, and f = .885) and calcium (p((p all the experimental groups on day zero (for details see table, figures 1 and 2). normalities in different segments of the nephrons 3 to 4 large polygonal crystals, were found abundantly in all the segments of the urinary tubules in serum levels of calcium and magnesium, number of calcium oxalate crystals, and weight of the kidney in study groups parameters days group a group b group c group d group e group f serum level of calcium, mg/100 cc serum 0 8.95 ± 0.15 8.65 ± 0.13 8.57 ± 0.21 9.33 ± 0.34 9.27 ± 0.24 9.03 ± 0.23 14 8.80 ± 0.00 10.45 ± 0.26 9.62 ± 0.24* 10.3 ± 0.21* 10.33 ± 0.23* 9.98 ± 0.26* 30 8.30 ± 0.22 11.33 ± 0.18 9.70 ± 0.07* 10.02 ± 0.46* 9.20 ± 0.07* 10.19 ± 0.4* serum level of magnesium, mg/100 cc serum 0 4.35 ± 0.11 4.33 ± 0.35 4.3 ± 0.18 4.87 ± 0.35 3.95±0.26 4.18±0.26 14 2.87 ± 0.17 1.71 ± 0.12 2.11 ± 0.06* 2.08 ± 0.35* 2.01 ± 0.05* 2.30 ± 1.60* 30 6.01 ± 0.00 3.81 ± 0.25 5.87 ± 0.18* 7.05 ± 0.10* 4.70 ± 0.00* 6.63 ± 0.23* number of calcium deposits, in 10 microscopic fields 30 0.00 ± 0.00 16.72 ± 2.22 6.15 ± 1.85* 11.15 ± 0.93* 10.62 ± 0.45* 8.88 ± 0.53* weight of the kidney, gr 30 1.52 ± 0.07 2.01 ± 0.17 1.42 ± 0.01*** 1.36 ± 0.03** 1.36 ± 0.03** 1.49 ± 0.03** data were expressed as mean ± standard error, n = 6,*p < .001, **p p < .01, ***p p < .05p 364 | eg group (figure 4). renal tubular dilation with epithelial damage and leukocyte reaction were also observed on pathology examination (figure higher than that in the control group (p((p eg group in both doses of aqueous extract of ps thh pp renal tubules of the treatment groups were smaller in comparison with eg group. discussion our results showed that eg administration can crease in serum levels of calcium and magnesium, culi may have a bacterial origin, such as nanobacteria.(15) antimicrobial activity of ps materials s staphylococcus aureus has been reported;(12) therecalculus. the mechanisms of action of ps extract s seem to be mediated by inhibition of the na+-k+kk pump, which leads to reduction in na+ and k+kk reabsorption, and thus results in an osmotic water (16,17) the decrease in serum level of calcium indicates plemented with aqueous extract of pss mostly recovered from nephrolithiasis. nephrolithiasis induction by eg has been established in many researches.(14,18,19) the mechanism underlying the effect of aqueous extract of ps ons nephrolithiasis induced by eg is apparently related to increasing diuresis and lowering urinary concentrations of stone forming constituents.(16,17) v08_no_2_final.pdf case report 153urology journal vol 8 no 2 spring 2011 spontaneous migration of a surgical clip following partial nephrectomy walid atef massoud urol j. 2011;8:153-4. www.uj.unrc.ir keywords: nephrectomy, renal colic, urinary tract department of urology, 78, rue du général leclerc, 94275 le kremlinbicêtre, france corresponding author: walid atef massoud, md department of urology, 78, rue du général leclerc, 94275 le kremlinbicêtre, france tel: +33 699 114 939 fax: +33 145 212 047 e-mail: walidmassoud@yahoo.fr received august 2009 accepted march 2010 introduction migration of surgical materials into the urinary tract is a rare condition. we present a case of spontaneous migration of a metal clip into the ureter 9 years after upper pole partial nephrectomy. case report a 48-year-old woman presented with a sudden right flank pain radiating to her right groin. she was found to have a 5-cm upper pole angiomyolipoma of the right kidney 9 years earlier. therefore, she had undergone open partial nephrectomy. violation of the collecting system had been repaired using a 3-0 vicryl. tightness had been checked by administrating indigo carmine through a ureteral stent. surgical bed hemostasis had been achieved by 2-0 vicryl running sutures and automatic nonabsorbable surgical clips (autosuture premium surgiclip). the parenchymal bed had been then covered by absorbable bolsters. the postoperative course was uneventful and the patient had been discharged from the hospital. plain radiography of the kidney, ureter, and bladder demonstrated a 4-mm opacity projected over the pelvic portion of the right ureter as well as multiple additional small opacities bordering and within the partial nephrectomy site (figure 1). spiral abdomino pelvic computed tomography scan confirmed the diagnosis of right renal colic following migration of a figure 1. kidney, ureter, and bladder x-ray showing surgical clips projected within the partial nephrectomy area and the right distal part of the ureter. surgical clip migration—massoud 154 urology journal vol 8 no 2 spring 2011 surgical clip (figure 2). the patient was managed conservatively with hydration and narcotic analgesia. few days later, the patient passed the clip spontaneously. discussion migration of clips into the common bile duct has been previously reported in several laparoscopic cholecystectomies.(1,2) furthermore, it has been reported that surgical clips can act as a nidus for stone formation when they are in contact with urine.(3) in this patient, nonabsorbable surgical clip has probably eroded into the collecting system. a similar case with absorbable lapra-ty suture clips (ethicon endosurgery, cincinnati, ohio) has been reported by miller and colleagues.(4) several cases of surgical clip migration into the bladder following retropubic radical prostatectomy have been reported.(5) long and associates reported a 61-year-old man who had undergone radical prostatectomy for localized prostate cancer. the postoperative course was marked by recurrent urinary retention and several urethrotomies failed to restore spontaneous voiding. a clip was finally visualized and removed by endoscopy.(6) metal clips may migrate postoperatively and cause secondary complications. therefore, they should be absorbable and applied selectively over vessels and far from the collecting system. conflict of interest none declared. references 1. dell’abate p, del rio p, soliani p, colla g, sianesi m. choledocholithiasis caused by migration of a surgical clip after video laparoscopic cholecystectomy. j laparoendosc adv surg tech a. 2003;13:203-4. 2. yoshizumi t, ikeda t, shimizu t, et al. clip migration causes choledocholithiasis after laparoscopic cholecystectomy. surg endosc. 2000;14:1188. 3. gronau e, pannek j. reflux of a staple after kock pouch urinary diversion: a nidus for renal stone formation. j endourol. 2004;18:481-2. 4. miller m, anderson jk, pearle ms, cadeddu ja. resorbable clip migration in the collecting system after laparoscopic partial nephrectomy. urology. 2006;67:845 e7-8. 5. kadekawa k, hossain rz, nishijima s, et al. migration of a metal clip into the urinary bladder. urol res. 2009;37:117-9. 6. long b, bou s, bruyere f, lanson y. [vesicourethral anastomotic stricture after radical prostatectomy secondary to migration of a metal clip]. prog urol. 2006;16:384-5. 7. blumenthal kb, sutherland de, wagner kr, frazier ha, engel jd. bladder neck contractures related to the use of hem-o-lok clips in robot-assisted laparoscopic radical prostatectomy. urology. 2008;72:158-61. 8. tugcu v, polat h, ozbay b, eren ga, tasci ai. stone formation from intravesical hem-o-lok clip migration after laparoscopic radical prostatectomy. j endourol. 2009;23:1111-3. figure 2. spiral pelvic computed tomography scan demonstrating a 4-mm opacity in the lumen of the right pelvic ureter. renal parenchymal volumetric expansion assessed by ct imaging after laparoscopic cyst decortication mehmet hamza gultekin1*, ahmet yalcin2, guven erbay3 purpose: to delineate the expansion of the renal parenchyma using volumetric ct imaging before and after the laparoscopic cyst decortication procedure and to determine the possible associations between parenchymal expansion and laboratory parameters and cyst volume. materials and methods: thirty-five patients who underwent laparoscopic cyst decortication were included in this prospective study. abdominal contrast-enhanced ct was performed in all patients in the preoperative and postoperative period. semi-automatic volume quantification was undertaken offline, and renal parenchymal volumes before and after cyst decortication, as well as serum creatinine and estimated glomerular filtration rate (egfr) were compared. results: the changes in serum creatinine and egfr in the postoperative period were non-significant. the mean postoperative renal parenchymal volumes were higher compared to the preoperative measurements for both observations (p = .014 and .034 for the first and second measurements, respectively). there was no correlation between the volumetric change and the cyst volume (r = -0.18, p = .560). conclusion: in patients undergoing laparoscopic cyst decortication, post-operative parenchymal expansion can be detected using volumetric ct imaging to confirm the immediate benefits of the procedure. keywords: computed tomography; laparoscopic cyst decortication; renal cyst; renal parenchyma; laparoscopic surgery; volumetric evaluation introduction renal cysts are very common in the adult population with approximately 50% prevalence.(1) these cysts are rarely symptomatic and do not require treatment in most cases. treatment strategies include percutaneous cyst aspiration with or without sclerosing agent application, and open or laparoscopic cyst decortication. however, laparoscopic cyst decortication, first described by hulbert et al.(2) as an alternative option to open surgery, has gradually lost popularity and been replaced by new methods, such as laparoendoscopic single-site surgery and mini-laparoscopic cyst decortication that cause less pain in the postoperative period and less scarring.(3) the main target of cyst decortication is to relieve to pain caused by the cyst and maintain renal function which can be affected by the pressure of the cyst that eventually leads to renal atrophy.(4) apart from laboratory tests, the functionality of the kidneys can be determined based on data derived from radiological studies. it has been reported that renal parenchymal thickness and related measurements, such as volumetric data calculated from ct imaging can estimate renal function.(5,6) our hypothesis was that laparoscopic cyst decortication and relieving the pressure of the cyst would alter the function of the renal parenchyma and result in parenchymal expansion in the postoperative period. thus, in this study, we aimed to delineate renal parenchymal expansion using volumetric ct imaging before and after the laparoscopic cyst decortication procedure. we also aimed to determine the possible associations between parenchymal expansion and laboratory parameters and cyst volume. materials and methods this study received institutional approval from the ethical committee of erzincan binali yildirim university medical faculty with the irb number of 9059, and informed consent was obtained from all patients. patients between february 2017 and february 2018, 102 patients that presented to the outpatient clinic with symptomatic renal cysts were enrolled in our study. from this patient population, 35 patients were selected according to the inclusion criteria. after excluding seven patients based on the exclusion criteria, the final assessment included 28 patients (figure 1). evaluation of renal functions renal function was evaluated with serum creatinine levels and egfr. serum creatinine levels below 1.4 mg/ dl were accepted as normal. creatinine clearance was calculated using the cockcroft-gault equation. for indi1department of urology, faculty of medicine, erzincan binali yildirim university, erzincan, turkey. 2department of radiology, faculty of medicine, erzincan binali yildirim university, erzincan, turkey. 3 department of urology, faculty of medicine, niğde ömer halisdemir university, nigde, turkey. *correspondence: department of urology, faculty of medicine, erzincan binali yildirim university 24100, erzincan, turkey. telephone: +90 505 244 49 62 facsimile: +90 446 212 11 11. e-mail mhamzagultekin@hotmail.com. received april 2019 & accepted october 2020 urology journal/vol 17 no. 6/ november-december 2020/ pp. 645-649. [doi: 10.22037/uj.v0i0.5291] unclassified vidual comparisons, a >20% decrease in egrf was considered to indicate deterioration of renal function. biochemical tests were conducted preoperatively (one day before the surgery) and postoperatively (immediately after the surgery and at the third, ninth and 18th months. evaluation of the degree of pain pain was the only indication of operation in our study. there was no other renal disease or pathology (e.g., hypertension, urinary tract infection, hydronephrosis, and macroscopic hematuria) (figure 1). the degree of pain was evaluated by the visual analog scale (vas) preoperatively at the same time as imaging, and the vas scores were recorded for each patient. a postoperative evaluation of pain was performed three months after the surgery for comparison. imaging method and volumetric analysis all patients were examined using a 16-row multi-detector computed tomography device (somatom emotion 16, siemens healthcare, erlangen, germany) one month before the surgery and at the postoperative third month. the abdominal ct imaging parameters were as follows: collimation 1 mm, tube current 150 mas, fov 300 mm, and matrix 512x512. all patients received an intravenous contrast administration at a dose of 1 ml/kg (ultravist, bayer schering pharma, berlin, germany). the infusion started 35 seconds before image acquisition to ensure that the kidneys were scanned during the late arterial phase. the data obtained from ct imaging were transferred to an offline workstation, and the parenchymal volume was calculated semi-automatically using dedicated software (3d slicer v4.9.0 software, http://www. slicer.org). a single radiologist with ten years’ of experience in abdominal radiology, who was blinded to patient information, processed the data. volumetric analysis was performed through the segmentation of the selected kidney and labeling the cyst and renal parenchyma in each slice. the level tracing method, which allows highlighting similar densities in the pixels, was used to label the kidney and renal cyst. the renal pelvis, ureter, renal arteries, and veins were excluded from this evaluation. other small cysts smaller than 1 cm in diameter were disregarded and included in the renal parenchyma. one week after the first measurement, the same radiologist reassessed the patients in mixed order for intra-observer variability. statistical analysis the sample size was calculated considering the requirements for pairwise comparisons. a minimum of preoperative postoperative mean (median) 95% ci for mean (median) mean(median) 95% ci for mean (median) p value creatinine, mg/dl 0.879 0.758–0.972 0.860 0.803–0.918 0.535* egfr, ml/min 81.6 75.6–87.5 81.5 75.1–87.8 0.976* parenchymal volume, cm3 132.4 119.4–145.4 136.4 122.7–150.0 0.014* 1st measurement parenchymal volume, cm3 132.5 119.3–145.7 136.8 122.6–151.1 0.034* 2nd measurement median vas score 6 5–6.25 1 0–2 < 0.001** table 1. preoperative and postoperative data with the corresponding p values. abbreviations: egfr, estimated glomerular filtration rate; vas, visual analog scale * p value for the paired t-test; ** p value for the wilcoxon test figure 1. inclusion and exclusion criteria. laparoscopic cyst decortication and renal volumegultekin et al. vol 17 no 06 november-december 2020 646 unclassified 647 14 pairs were needed for the 95% confidence interval (ci), and the power was 0.80 at the significance level of 0.05. the summary statistics of all patients were obtained as mean and standard deviation values. the distribution of normality was assessed using the d’agostino-pearson test. the continuous variables with normal distribution belonging to the same patient group were compared using the paired t-test. the wilcoxon test was used for the non-normally distributed data. intra-observer variability was assessed with the intra-class correlation coefficient (icc). a two-tailed p value of < 0.05 was considered statistically significant. all statistical analyses were performed using medcalc statistical software version 14 (ostend, belgium). results the mean age of the study population was 62.7 ± 7.8 years. sixteen of the 28 patients were female (57.1%). the preoperative and postoperative data regarding the creatinine level, egfr, renal volume, and median vas scores were summarized in table 1. the mean postoperative renal parenchymal volume was higher compared to preoperative measurements (table 1). icc showed very good agreement between the two measurements (icc: 0.89, 95% ci: 0.88–0.90). the mean cyst volume was 143.9 cm3, and the range of cyst diameter was 6.1–13.2 cm. there was no correlation between the volumetric change and cyst volume (r = -0.18, p = .560). laparoscopic decortication procedures were successfully performed in all cases except for one patient (3.5%) who was found to have a residual cyst after the surgery. none of the patients required blood transfusion during or after the operation. there were no signs of malignancy in the pathological specimens. all patients were asymptomatic after a mean follow-up of 18 months, and their biochemical test results were within the normal range. discussion in this study, we showed that the renal parenchyma had a volumetric expansion without altering its functionality after laparoscopic decortication surgery. based on the data acquired at the third month after surgery, the volume of the renal parenchyma increased compared to the preoperative measurement while the creatinine and egfr levels did not change. volumetric increment was independent of the renal cyst volume since we found no correlation between the amount of volumetric expansion and cyst volume. renal cysts are common in the adult population with an estimated prevalence of 50%.(1) this rate ranges from 20% to 50% when applied to the general population.(7,8) furthermore, the prevalence of these cysts tends to increase with aging.(9) the etiology of the development of simple renal cysts is not clear, and its association with genetics is unknown.(10) renal cysts are often overdiagnosed with the frequent use of imaging modalities. (11) although they usually do not require any intervention due to their benign and clinically silent nature, they can cause lumbar and abdominal pain, hypertension, infection, urinary obstruction, and hematuria in symptomatic patients.(12,13) in a recent systematic review, the most common symptom and indication for intervention was pain.(11) medical treatment aims to reduce the effects of symptoms whereas surgery is indicated when cyst-related pain, infection, and obstruction develop. medical therapy consists of anti-inflammatory agents mainly used to relieve pain. if medical treatment is inefficient, surgical options for the decompression of the cystic mass by either percutaneous aspiration or open surgery are considered.(14) percutaneous aspiration of a simple renal cyst is the first choice of intervention and consists of transcutaneous needle placement with or without sclerosing agent application. although this technique is simple and requires no anesthesia, it has a high recurrence rate.(15) it was reported that over half of the patients that underwent percutaneous aspiration of cysts had reaccumulation of the cystic fluid.(16) hulbert et al. were the first to describe laparoscopic cyst decortication as an alternative method to conventional surgery.(2) the effectiveness of this technique compared to classical aspiration with sclerotherapy was investigated by okeke et al., who reported results in favor of laparoscopic cyst deroofing.(17) the pressure applied by the cyst and its effect on the adjacent parenchyma is less discussed in the literature. in a previous study on cyst pressure, it was reported that intra-cystic pressure could reach 31 cm of water. (18) we considered that increased intra-cystic pressure compressed the neighboring parenchyma based on the fact that liquids transmit pressure evenly in all directions. this pressure is thought to be followed by blood supply deficiency. this mechanism is well known to eventually lead to renal atrophy. some studies associated the compression applied by a cyst with renal arterial compression. several authors suggested that laparoscopic cyst decortication and renal volumegultekin et al. figure 2. a three-dimensional volume-rendered image showing the labeled kidney and renal cyst in preoperative (a) and postoperative (b) periods. this kind of pressure led to subsequent ischemia and ultimate activation of the renin-angiotensin, system which results in hypertension in patients. furthermore, by relieving the pressure of the cyst by needle puncture or surgical decortication, it was shown that blood pressure returned to the normal range.(19,20) another study conducted with cases of symptomatic autosomal dominant polycystic kidney disease showed that relieving the pressure of the cystic mass also reduced renal capsule tension and parenchymal compression, thereby eliminating symptoms.(21) in another study, yu et al. performed laparoscopic cyst decortication for patients with autosomal dominant polycystic kidney disease who had renal volumes between 500-1500 cc and found that reducing the pressure on the renal parenchyma increased renal blood supply, improved renal function, and delayed disease progression.(22) to the best of our knowledge, there is no study in the literature that shows the recovery of the parenchymal volume after laparoscopic surgery in simple renal cysts. as summarized above, some authors associated the decompression of the cyst with functional or clinical outcomes. in our study, we revealed the effect of the elimination of this pressure on the volume of the parenchyma. ct imaging with three-dimensional (3d) volume rendering has been proven to be a useful imaging technique that allows the delineation of the detailed renal anatomy and adjacent structures, which is important for surgical planning.(6) furthermore, 3d images have been used to assess the split renal function, and it has been shown that volumetric calculation can be used for the follow-up of the alteration of renal function over time.(23,24) the volumetric data derived from cross-sectional imaging were reported to be more closely associated with egfr.(25) in this study, we used the data obtained from multi-detector computed ct imaging for the calculation of renal parenchymal volumes and compared them with the postoperative data. we showed that kidneys tended to expand after the operation without alteration of egfr. this volumetric expansion occurred most likely due to the relieving of the cystic pressure. we utilized a 3d volumetric evaluation that is more suitable for the assessment of the success of laparoscopic cyst decortication in the absence of evident atrophy (i.e., egfr was within the normal range). this study has certain limitations. first, our study population was relatively small. our results should be confirmed by studies conducted with a larger patient population. second, we evaluated the patients’ renal function only by measuring their egfr and serum creatinine levels. renal scintigraphy could have provided more reliable information regarding the function of a single kidney. finally, our mean follow-up duration was 18 months, was relatively short. the effectiveness of the volumetric parenchymal evaluation should be tested over a longer follow-up. lastly, we chose to perform ct for volumetric imaging. although this technique has better spatial resolution compared to other cross-sectional imaging methods, the use of radiation and contrast agent places a burden on the excretion system and involves risk of complications. conclusions laparoscopic cyst decortication is an effective and less invasive treatment option compared to conventional surgery for symptomatic renal cysts. it has excellent long-term results. the postoperative volumetric changes seen in ct imaging can confirm the immediate benefits of the procedure, and volumetric parenchymal evaluation is a reliable method for a long-term follow-up. conflict of interest the authors declare that they have no conflict of interest. references 1. hemal ak. laparoscopic management of renal cystic disease. urol clin north am. 2001;28:115-26. 2. hulbert jc, shepard tg, evans re. laparoscopic surgery for renal cystic disease. j urol. 1992;147,433a 3. chen w, xu zb, xu l, cang c, guo jm. modified mini-laparoscopic surgery optimized the laparoscopic decortication of renal cyst. urol j. 2019 may 28. doi: 10.22037/uj.v0i0.5029. [epub ahead of print] 4. king bf, reed je, bergstralh ej. quantification and longitudinal trends of kidney, renal cyst, and renal parenchyma volumes in autosomal dominant polycystic kidney disease. j am soc nephrol. 2000;11:1505-11. 5. singh i, strandho jw, assimos dg. upper urinary tract obstruction and trauma. in: wein aj, kavoussi lr, novick ac, eds. campbellwalsh urology (10th edition). philadelphia: elsevier saunders;2009: 2;40:1087–1121. 6. coll dm, herts br, davros wj. preoperative use of 3d volume rendering to demonstrate renal tumors and renal anatomy. radiographics. 2000;20:431-8. 7. rane a. laparoscopic management of symptomatic simple renal cysts. int urol nephrol. 2004;36:5-9. 8. skolarikos a, laguna mp, de la rosette jj. conservative and radiological management of simple renal cysts: a comprehensive review. bju int. 2012;110:170-8. 9. laucks sp jr, mclachlan m. aging and simple cysts of the kidney. br j radiol. 1981;54: 12-4. 10. tadayon a, ayanifard m, mansoori d. endoscopic renal cyst ablation. urol. j. 2004;1: 170-3. 11. nalagatla s, manson r, mclennan r, somani b, aboumarzouk om. laparoscopic decortication of simple renal cysts: a systematic review and meta-analysis to determine efficacy and safety of this procedure. urol int. 2019;103:235-241. 12. abbaszadeh s, taheri s, nourbala mh. laparoscopic decortication of symptomatic renal cysts: experience from a referral center in iran. int j urol. 2008;15:486-9. 13. pope jc. renal dysgenesis and cystic disease of the kidney. in: wein aj, kavoussi lr, novick ac, eds. campbellwalsh urology (10th edition). philadelphia: elsevier saunders;2012;4, 118:3161–3196. laparoscopic cyst decortication and renal volumegultekin et al. vol 17 no 06 november-december 2020 648 unclassified 649 14. atug f, burgess sv, ruiz-deya g. long-term durability of laparoscopic decortication of symptomatic renal cysts. urology. 2006;68:272-5. 15. holmberg g, hictala so. treatment of simple renal cysts by percutaneous puncture and instillation of bismuthphosphate. scand j urol nephrol. 1989;23:207-12. 16. hanna rm, dahniya mh. aspiration and sclerotherapy of symptomatic simple renal cysts: value of two injections of a sclerosing agent. ajr am j roentgenol. 1996;167:781-3. 17. okeke aa, mitchelmore ae, keeley fx. a comparison of aspiration and sclerotherapy with laparoscopic deroofing in the management of symptomatic simple renal cysts. bju int. 2003; 92:610-3. 18. derezic d, cecuk l. hydrostatic pressure within renal cysts. br j urol. 1982 apr;54:93-4. 19. lüscher tf, wanner c, siegenthaler w, vetter w. simple renal cyst and hypertension: cause or coincidence? clin nephrol. 1986 aug;26:91-5. 20. pedersen jf, emamian sa, nielsen mb. significant association between simple renal cysts and arterial blood pressure. br j urol. 1997 may;79:688-91. 21. mcnally ml, erturk e, oleyourryk g, schoeniger l. laparoscopic cyst decortication using the harmonic scalpel for symptomatic autosomal dominant polycystic kidney disease. j endourol. 2001 aug;15:597-9. 22. yu j, li b, xiang yz, qi tg, jin xb, xiong h. should kidney volume be used as an indicator of surgical occasion for patients with autosomal dominant polycystic kidney disease? medicine (baltimore). 2018 ;97:e11445. 23. hackstein n, buch t, rau ws. split renal function measured by triphasic helical ct. eur j radiol. 2007;61:303-9. 24. summerlin al, lockhart me, strang am. determination of split renal function by 3d reconstruction of ct angiograms: a comparison with gamma camera renography. ajr am j roentgenol. 2008;191:1552-8. 25. cheung cm, shurrab ae, buckley dl. mrderived renal morphology and renal function in patients with atherosclerotic renovascular disease. kidney int. 2006;69:715-22. laparoscopic cyst decortication and renal volumegultekin et al. 1154 | bilateral segmental renal artery thrombosis from blunt abdominal trauma: a rare presentation phitsanu mahawong,1 tanop srisuwan2 keywords: renal artery obstruction; thrombosis; wounds; nonpenetrating; abdominal injuries. introduction the incidence of renal injury in a normal population is 4.8% and renovascular injuries comprise 4% of all renal injuries.(1) segmental renal artery injury is not uncom-mon in blunt abdominal trauma and most of them can be conservatively managed.(2) there are some reports about unilateral segmental renal artery thrombosis (srat) but there are no reports of bilateral srat.(3) we will demonstrate the present case and discuss about treatment options. case report the patient was a previously healthy 19-year old male with a history of blunt abdominal trauma from a motorcycle accident 15 minutes prior to admission. the patient could not remember the events of the accident because he had drunk a lot of alcohol. in our trauma center, the glasgow coma scale (gcs) of the patient was 15. initial blood pressure was 80/50 mmhg and then rose to 120/60 mmhg after fluid resuscitation with 2000 ml of normal saline solution. the heart rate was 90 beats per minute and the respiratory rate was normal. abdomen was generally distended, and guarded. swelling of the left wrist was detected and a pelvic compression test was positive. tenderness at the lower thoracic spines without stepping was demonstrated. focused abdominal ultrasonography for trauma was performed and its finding was equivocal. fractures of the left distal radius, and the left superior pubic rami corresponding author: phitsanu mahawong, m.d. division of urology, department of surgery faculty of medicine, chiang mai university 110 intawaroros road, sriphoom, muang, chiang mai 50200, thailand. tel: +66 53 945 532 fax: +66 53 946 139 e-mail: pmahawon@med.cmu.ac.th, received august 2011 accepted april 2012 1 division of urology, department of surgery, faculty of medicine, chiang mai university, chiang mai 50200, thailand 2 division of diagnostic radiology, department of radiology, faculty of medicine, chiang mai university, chiang mai 50200, thailand case report case report 1155vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l bilateral segmental renal artery thrombosis | mahawong et al were revealed. gross hematuria was seen in the foley catheter after urethral catheterization. laboratory studies showed the hemoglobin level of 8.4 gm/ dl and the hematocrit level was 26.5%. the leukocyte count was 20 200/µl (predominantly neutrophils) and the platelet count was normal. blood urea and creatinine levels were 19 mg/dl, 2.7 mg/dl respectively. an abdominal computed tomography (ct) scan demonstrated minimal retroperitoneal hematoma around the paraaortic region with infarction of the right anterior renal and left posterior renal parenchyma (figure 1). these findings indicated the diagnosis of right anterior srat and left posterior srat. due to a renal insufficiency, an early diagnosis of bilateral srat, and the young age of the patient, we did not choose a conservative treatment. the patient underwent exploratory laparotomy 3 hours after diagnosis. the right anterior srat was found (figure 2). thrombectomy was done along with segmental resection and end to end anastomosis with prolene 6-0 was performed (figure 3). the left posterior srat was corrected the same way as the right one. the areas of infarction in both kidneys were slightly decreased right after revascularization. the operative time was 270 minutes and estimated blood loss was 500 ml. clamp time of the right anterior and left posterior segmental arteries were 45 and 30 minutes, consecutively. renal function and urine output were closely monitored after surgery. at the 3 month follow up, blood urea and creatinine were 15 mg/dl, 1.6 mg/dl, respectively. abdominal ct scan and renal scan were planned but the patient refused any imaging and all follow up appointments after that. discussion treatment of unilateral srat with normal contralateral kidney is not controversial. most patients are hemodynamically stable or may be asymptomatic. hypertension occurs in less than 10 % of traumatic unilateral srat. unilateral srat initially should be managed nonoperatively.(3) on the other hand, late hypertension is found in 50% of patients with main renal artery thrombosis (mrat) when managed conservatively.(4) excision of ischemic parenchyma in srat is indicated only when intractable hypertension associated with increased renin secretion can be identified.(5) mrat in a solitary kidney is rare and most of them are not caused from blunt external trauma.(6) their treatments are percutaneous revascularization or open endarterectomy.(7) traumatic bilateral mrat is also uncommon. a high index of suspicion, early diagnosis, and prompt revascularization are essential in obtaining optimal results without hypertension or permanent impairment of renal function.(8,9) to the best of our knowledge, the present case is the first figure 1. segmental renal infarction of both kidneys. enhanced ct scan in nephrographic phase in axial view (a) and excretory phase in coronal view (b) demonstrate the sharply defined area of unenhanced parenchyma of the anterior right renal (arrow) and posterior left renal parenchyma (blank arrow). minimal retroperitoneal hematoma around the paraaortic region is noted. 1156 | reported case of bilateral srat from blunt abdominal trauma in literature. bilateral srat as the present case poses a unique consideration to treatment because they cause ischemia to the right anterior and the left posterior renal parenchyma. the rest of overall renal function may be equal to renal function of only one kidney. if the patient was unstable from other injuries, we must correct the causes of the hemodynamic unstability, first. the further kidneys exploration may be warranted when the patient has normal and the renal ischemic time is less than 12 hours. although, we tried to counteract the ischemic parenchyma by bilateral open thrombectomies and revascularizations, the serum creatinine was not completely normal at the 3 month follow up. nowadays, we still do not know the most appropriate treatment for bilateral srat as in the reported case because of the rarity of this condition. conflict of interest none declared. references 1. wessells h, suh d, porter jr, et al. renal injury and operative management in the united states: results of a populationbased study. j trauma. 2003;54:423-30 figure 3. both ends of the right anterior segmental renal artery before end to end anastomosis (arrow). 2. elliott sp, olweny eo, mcaninch jw. renal arterial injuries: a single center analysis of management strategies and outcomes. j urol. 2007;178:2451-5. 3. cass as, luxenberg m. traumatic thrombosis of a segmental branch of the renal artery. j urol. 1987;137:1115-6. 4. cass as. renovascular injuries from external trauma. diagnosis, treatment, and outcome. urol clin north am. 1989;16:213-20. 5. bertini je jr, flechner sm, miller p, ben-menachem y, fischer rp. the natural history of traumatic branch renal artery injury. j urol. 1986;135:228-30. 6. mbanugo c, grey dp, moss r, orloff g. thrombosis of the renal artery of a small, solitary kidney: successful return of renal function after prolonged anuria. tex heart inst j. 1988;15:121-3. 7. bessias n, sfyroeras g, moulakakis kg, karakasis f, ferentinou e, andrikopoulos v. renal artery thrombosis caused by stent fracture in a single kidney patient. j endovasc ther. 2005;12:516-20. 8. klink bk, sutherin s, heyse p, mccarthy mc. traumatic bilateral renal artery thrombosis diagnosed by computed tomography with successful revascularization: case report. j trauma. 1992;32:259-62. 9. letsou gv, gusberg r. isolated bilateral renal artery thrombosis: an unusual consequence of blunt abdominal trauma-case report. j trauma. 1990;30:509-11. case report figure 2. intraoperative finding: the right anterior segmental renal artery thrombosis is identified (arrow). demarcation of the right anterior renal parenchymal infarction (blank arrow). urological oncology single umbilical stoma for bilateral ureterostomy after radical cystectomy abbas basiri*, mohammad hossein soltani, nasser shakhssalim, hamid reza shemshaki, pouria rezvani, milad bonakdar hashemi purpose: cutaneous ureterostomy after radical cystectomy is less preferred compared with other permanent urinary diversions due to bilateral stomas. single umbilical stoma for bilateral ureterostomy (susbu) may be a choice, in this study we reviewed the outcomes of susbu in seventeen patients who underwent radical cystectomy. methods and materials: this was a case-series study conducted from april 2016 to dec 2017. seventeen male patients with confirmed pt2 bladder urothelial carcinoma who were not suitable for performing conduit or orthotopic urinary diversion, including those with high-risk patients underwent single umbilical stoma for bilateral ureterostomy after radical cystectomy. all patients were prospectively followed up for 24 months ± 2 months, this study was done in a teaching center mainly by senior residents. results: the mean age of patients was 68.6 ± 6.41 years. the mean length of operation time was 176.7 ± 15.1 minutes (from intubation to extubation from anesthesia). sixteen patients were diagnosed with pt2 and one patient had a pt4 diagnosis. the decrease in hemoglobin level after surgery was 1.72 mg/dl ± 0.35 and creatinine increased by 0.15 ± 0.05 mg/dl. none of our patients had oliguria. one case developed constipation and no gas passing, with the suspicion of obstruction, underwent abdominal exploration, however, no obstruction or urine leakage was found and the patient was treated conservatively. one patient developed a fever during admission, in which atelectasis was identified as the cause. one patient underwent a second operation because of fascia dehiscence. conclusion: it seems that this technique is suitable for high-risk patients with acceptable operating time, surgical complications, and fast recovery after the operation and one ureterostomy bag instead of two one’s comparing to bilateral cutaneous ureterostomy. keywords: umbilical stoma; radical cystectomy; single ureterostomy introduction the treatment of invasive bladder cancer generally involves radical cystectomy followed by urinary diversion. currently, cutaneous ureterostomy, ileal conduit, and orthotopic ileal neobladder reconstruction are the most frequently used methods. although cutaneous ureterostomy is less preferred compared to other permanent urinary diversions, it is a more appropriate approach in elderly patients, patients with poor performance status, and cases for whom an intestinal segment cannot be used to form the internal reservoir 1. the efficacy of cutaneous ureterostomy is the same as other types of incontinent diversions 2. however, the ureter should have a sufficient length to be able to insert the stoma site in the lower quadrants of the abdominal wall. moreover, due to proximity to the tumor tissue, the lower quadrants of the abdomen are at risk of both cancer seeding and irradiation, in cases in which radiotherapy is indicated. for classic cutaneous diversion, creating two stomas and bilateral ureterostomy is required. this is found to be unappealing by most patients. therefore, a single umbilical stoma after radical cystectomy might be a choice to solve the above-mentioned problem. in the 1960s, higgins reported his initial experience with urology and nephrology research, center, shahid labbafinejad, medical center, shahid beheshti university of medical sciences, tehran, iran *correspondence: urology and nephrology research, center, shahid labbafinejad, medical center, shahid beheshti university of medical sciences, tehran, iran. email: basiri@unrc.ir received january 2020 & accepted july 2021 umbilical cutaneous ureterostomies on six patients, showing safe and efficient results 3. however, the lack of data in this field is evident. theoretically, this surgical method is associated with advantages such as less required length of the ureter, more distance from the tumor site, and a protective role of the umbilical skin for the ureteral epithelium. in this case series, we have reported the results of a single umbilical stoma for bilateral ureterostomy (susbu) in 17 patients with bladder cancer. materials and methods this was a case-series study conducted between april 2016 des 2017 at the urology departments of labbafinejad (teaching hospital, 14 cases) and erfan (private hospital, 3 cases), tehran, iran. all patients with confirmed pt2 urothelial carcinoma of the bladder who were unfit for undergoing conduit or orthotopic urinary diversion were consecutively included in this study. baseline characteristics of the patients are presented in table 1. surgical technique and post-operative care a lower abdominal midline incision was made two centimeters below the umbilicus, dividing the rectus muscle urology journal/vol 18 no. 6/ november-december 2021/ pp. 646-651. [doi: 10.22037/uj.v18i.5857] and separating the muscles and fascia. in the intra-peritoneal approach, the peritoneum was opened lateral to uracus. then posterior peritoneum was incised and the ureters were released only in 2-3 cm and divided from the distal tip near the bladder. in the extra-peritoneal approach, the peritoneum was separated from the posterior wall of the bladder and the ureters were exposed and divided retroperitoneally. after that, lateral pedicles of the bladder were coagulated and divided with ligasure until receiving the base of the prostate. then we have coagulated and divided the dorsal vein of the prostate in antegrade until receiving the urethra. after that, the prostate and bladder were removed retrograde with caution to the rectum. extended lymphadenectomy has been done with the area that contains common iliac bifurcation superiorly; the superior edge of iliac vein laterally and obturator nerve caudally. each ureter was sutured to the abdominal wall to decrease the chance of bowel obstruction. after incision of the umbilicus, the posterior rectus sheath was cranially incised to allow for one finger to pass easily (figure 1). in the end, the bilateral ureters were raised to the level of the abdominal wall. the distal end of the ureters was pulled out 2 4 cm above the skin surface and then longitudinally incised at 2 cm from their terminal end. 4-0 vicryl was used to suture the incised ureter to the skin. finally, 8f splint catheters or double-j stents were inserted in both ureters and after wound closure; a collecting bag was placed on the skin, adjacent to the umbilicus (figure 1). on the first day after surgery, patients were mobilized and oral nutrition was initiated. serum creatinine and hemoglobin level were checked daily. the drainage system and the foley catheter were removed when the amount of drainage reached less than 50 ml per day. the patients were initially visited following two weeks after discharge. they were recommended to change their catheters or double-j stents monthly until three months post-surgery. finally, after 24 months (man of follow-up), four patients who had hydro-uretero-nephrosis before surgery became stent-free. regarding the other patients who did not show hydro-uretero-nephrosis (n=13), three patients were maintained on double-j stents, seven patients became stent-free, and three cases were missed to follow-up. outcomes demographic data (age, gender, and bmi), tumor characteristics (including pathological stage, the status of receiving neoadjuvant chemotherapy and presence of hydro-nephrosis), pre and post-operative laboratory data (serum creatinine and hemoglobin level), operation time, need for transfusion and treatment-related complications were recorded. in this study, we did not use a specific questionnaire but patients were asked to express their satisfaction between the numbers one to four. 1; very bad, 2; bad; 3; good, 4; very good. results seventeen patients with a mean age of 68.6 ± 6.41 years old were included in this study. all patients were male. the mean bmi of patients was 24.3 ± 2.4 kg/m2. the mean duration of operation was 176.7 ± 15.1 minutes. sixteen patients were diagnosed with pt2 and one had a pt4 diagnosis (case 6). only one patient (case 6) received neoadjuvant chemotherapy before surgery. the mean decrease in serum hemoglobin after surgery was susbu after radical cystectomy-basiri et al. table 1. basic characteristics of patients. case number age bmi hydro ureteronephrosis hb before surgery cr before surgery 1 63 26 no 12.2 1.2 2 74 24.4 no 11.9 0.95 3 69 23.2 no 14.4 1.1 4 69 25.1 no 14.4 1.5 5 69 23.3 yes 10.4 2.21 6 80 25.5 yes 11.4 1.35 7 62 25.7 no 11.7 1.16 8 42 27.2 no 13 1.19 9 71 25.1 no 14 1.19 10 73 26.5 no 11.1 1.08 11 66 22.4 no 12.5 1.35 12 72 25.4 no 13.8 1.63 13 70 21.7 yes 10.9 1.99 14 73 20.9 no 12.7 2.77 15 69 27.2 no 14.6 1.69 16 71 22.6 yes 12.8 2.76 17 74 21.2 no 12.2 1.83 figure 1. both ureters were raised to the level of the abdominal wall. vol 18 no 6 november-december 2021 647 urological oncology 648 1.72 ± 0.35mg/dl and seven patients (cases 5,6,7,10, 13,16,17) required whole blood or packed cell transfusion. the mean increase in the creatinine level after surgery was 0.15 ± 0.05 mg/dl. overall, renal function remained stable during the entire follow-up period. the mean length of hospital stay was 4.0 ± 1.0 days. none of our patients developed oliguria. one case (case number 6) developed constipation and no gas passing, with the suspicion of obstruction, underwent abdominal exploration, however, no obstruction or urine leakage was found and the patient was treated conservatively. one patient underwent a second operation due to fascia dehiscence (case number 7). during follow-up, one of the double-j stents in case 5 had got removed accidentally, and efforts to insert another double-j stent in the same orifice were unsuccessful. however, after administering diethylene-triamine pentaacetic acid (dtpa), no obstruction was seen. one patient (case number 8) developed fever before discharge but the urine was sterile. atelectasis was found to be the cause and he was treated with antibiotics and conservative management. in case number 13, the patient was re-admitted because of purulent discharge from the suture line. ultrasonography of the involved site revealed a 26cc collection in subcutaneous tissue. several stitches were removed and after draining the collection, conservative treatment was given. the patient satisfaction was subcategorized into four categories in which no patient-reported very bad; two patients report bad; nine patients reported good, and six patients reported very good. overall, a high level of satisfaction was achieved. we have not performed a comparative study between table 2. data of the patients with benign prostatic hyperplasia case hospitalization operation time transfusion post-op hb patients’ complications pathological satisfaction number (day) (minutes) creatinine stage at discharge 1 3 165 no 11 1.51 no pt2n0m0 very good 2 3 130 no 11 1.2 no pt2n0m0 very good 3 3 140 no 13 1.3 no pt2n0m0 good 4 3 240 no 12.2 1.22 no pt2n2m0 very good 5 4 155 yes 9.4 1.83 no pt2n0m0 good 6 8 180 yes 10 1.0 yes / abdominal pt4n1m0 bad exploration 7 5 140 yes 8.9 1.11 no pt2n0m0 good 8 6 225 no 11 1.15 yes / fever pt2n0m0 good 9 5 230 no 12.7 2.15 no pt2n0m0 good 10 4 215 yes 9.7 1.06 no pt2n0m0 very good 11 3 155 no 11.3 1.41 no pt2n0m0 good 12 3 175 no 11.6 1.55 no pt2n0m0 very good 13 5 200 yes 9.6 1.90 yes / purulent discharge pt2n0m0 bad from suture line 14 4 150 no 10.3 3.1 no pt2n2m0 good 15 4 165 no 11.7 1.96 no pt2n0m0 good 16 3 170 yes 10.9 2.97 no pt2n2m0 good 17 3 170 yes 10.4 2.08 no pt2n0m0 very good figure 2. release both ureters and bring them to the umbilical stoma. susbu after radical cystectomy-basiri et al. the umbilical ureterostomy and conduit but in general, the complaints of patients with umbilical ureterostomy were not more than other patients with conduit. the location of the stoma was satisfactory for the patients and if the ureterostomy bag was installed correctly, urine leakage would not be more than other types of the stoma. patients’ stents were removed after three months routinely in patients who had hydroureteronephrosis (4 cases), in other patients who had not hydroureteronephrosis (13 cases), three patients have had j stent indefinitely, seven patients became stent free and 3 cases were missed in follow-up. in our study, the follow-up period was 24 ± 2 months, which is a suitable duration to evaluate early complications such as wound infection, renal impairment, and bowel obstruction. discussion currently, the most common procedure used for permanent urinary diversion is the ileal conduit and orthotopic ileal neobladder. however, this procedure utilizes intestinal segments, causing several major complications 4. in the complicated patients included in this study (i.e., advanced age, comorbidity, and low-performance status) we avoided using intestinal segments for urinary diversion. the simplest alternative method for permanent urinary diversion was introduced to be cutaneous ureterostomy. umbilical cutaneous ureterostomy is not indicated for all patients, since laparotomy involves a long midline incision. moreover, the central position of the wound makes the process of making a pouch and also patient management difficult. however, this approach is figure 3. two ureters were sutured with vicryl 4-0 to the skin.. figure 4. single umbilical stoma after radical cystectomy susbu after radical cystectomy-basiri et al. vol 18 no 6 november-december 2021 649 urological oncology 650 appealing for patients who suffer from an inadequate ureter length or those who are at high risk of tumor recurrence. with susbu, our success rate was comparable to previous reports applying regular cutaneous ureterostomy 5, with only one patient requiring abdominal exploration. surgical resection of a cancerous bladder with ureteral invasion or the presence of a concomitant ureteral lesion does not allow for an adequate ureteral length to be preserved and also disrupts the blood supply to the ureter. also, in such cases, the usual site of cutaneous ureterostomy (lower quadrant of the abdominal wall) may be too remote to achieve 6. almost half of the patients develop stenosis and require periodic dilation or chronic catheterization. alternatively, susbu does not involve a midline scar, and reconstruction is made easier compared to the urinary diversion using the intestine. with at least a 12cm ureteral length, susbu is feasible without excess tension 3. the achievement of this length is possible after release and dislocation of the kidney or after individually adjusting the tunnel to establish the most direct path between the kidney and the umbilicus. invasion of the bladder tumor into the ureteral orifice leads to a three-time higher tumor recurrence rate of the upper urinary tract after radical cystectomy, as well as poor survival outcome 7. therefore, early detection of upper urinary tract tumor recurrence has a determinative role in a patient’s survival outcome after cystectomy. nearly half of the positive signals in computed topography and cytology are benign lesions, and the appropriate approach for follow-up is controversial. thus, the application of ureteroscopy for the diagnosis of upper urinary tract tumor recurrence could be a better option. with susbu, it is feasible to use a ureteroscope for these patients appropriately and detect any upper urinary tract recurrence. in short ureters and in obese people where the ureters are difficult to reach the skin, the umbilical stoma can be a suitable alternative another advantage is the use of umbilical skin as a protection of the ureteral mucus from external damage. however, this advantage should be considered carefully in cases with ureteral stenosis. we found no stenosis in our patients. also in obese patients, the fat under the umbilicus eases the performance of this procedure. there are limitations associated with this study; only seventeen cases have been described. furthermore, the surgeons and surgical techniques are not entirely identical, influencing the outcome. in our study, the follow-up period was 24 ± 2 months, which is a relatively optimal time to evaluate the early complications of surgery such as wound infection, renal impairment, and mechanical bowel obstruction. conclusively, the decision to perform umbilical cutaneous ureterostomy must be made on an individual basis, after considering the pros and cons for each patient. we suggest this approach as an alternative but not as a recommendation. figure 5. patient became stent free. susbu after radical cystectomy-basiri et al. figure 6. schematic figures of procedures. conflict of interest the authors declare that they have no conflict of interest. references 1. deliveliotis c, papatsoris a, chrisofos m, et al. urinary diversion in high-risk elderly patients: modified cutaneous ureterostomy or ileal conduit? urology. 2005;66:299-304. 2. kim cj, wakabayashi y, sakano y, et al. simple technique for improving tubeless cutaneous ureterostomy. urology. 2005;65:1221-1225. 3. higgins rb. bilateral transperitoneal umbilical ureterostomy. j urol. 1964;92:289294. 4. pycha a, comploj e, martini t, et al. comparison of complications in three incontinent urinary diversions. eur urol. 2008;54:825-832. 5. kim cj, sano t, murai r. evaluations for hydronephrosis after the establishment of tubeless cutaneous ureterostomy. korean j urol. 2013;54:168-171. 6. wada y, kikuchi k, imamura t, et al. modified technique for improving tubeless cutaneous ureterostomy by ariyoshi method. int j urol. 2008;15:144-150; discussion 150. 7. picozzi s, ricci c, gaeta m, et al. upper urinary tract recurrence following radical cystectomy for bladder cancer: a meta-analysis on 13,185 patients. j urol. 2012;188:20462054. susbu after radical cystectomy-basiri et al. vol 18 no 6 november-december 2021 651 pdf-525.pdf 436 | keywords: stress urinary incontinence, complications, prosthesis implantation, surgery, female introduction urethral erosion is an uncommon, but serious complication following syn-discuss a woman who presented with urethral erosion, vaginal erosion, ment. she was managed by sling excision with simultaneous rectus fascia sling surgery. most such patients have been managed by urethral reconstruction and subsequent staged incontinence surgery, for fear of urethral complications. we thral erosion was carried out along with an autologous rectus fascia sling.(1,2) case report where. details of the type of the tape used and operative notes were not available. the patient mentioned that a transobturator polypropylene mesh had been placed using a mesh kit. early in the postoperative period, she had storage symptoms that initially responded to empirical 4 mg long-acting tolterodine. she presented 4 months postoperatively nal erosion and nodular induration at the groin exit wounds. urodynamic study 2 sanjay sinha, rooma sinha, jyotsna b reddy, srinivas r sirigiri, srinivas k kanakamedala urethral erosion with recurrent stress incontinence following transobturator tape surgery urethral repair with simultaneous pubovaginal sling corresponding author: sanjay sinha, mch department of urology, apollo hospital, hyderabad, india tel: +91 406 673 7937 fax: +91 402 320 1015 e-mail: drsanjaysinha@ hotmail.com received january 2010 accepted september 2010 departments of urology and gynecology, medwin hospital, hyderabad, india case report case report 437vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l distal to the bladder neck (figure 1). urine culture magnetic resonance imaging did not show any abthe patient underwent excision of the suburethral tape, 2-layered reconstruction of the urethra using tius labial fat pad interposition, and simultaneous rity was checked by methylene blue. labial fat was interposed between sling and the urethra. the suprapubic and urethral catheters were removed after 3 weeks. at 27 months follow-up, she had no subjective incontinence, urgency, or pain. show any leak. she had negligible residual on ultrasonographic evaluation. discussion since the initial descriptions of the tension-free these procedures have become the most commonly (3,4) urethral erosion (5) sign of a technical error.(6) erosion occurs following slings that are too tight or too close to the urethra and presentation may be delayed up to 2 years. type of sling material (biological or synthetic, macroporous polypropylene or otherwise) and quality erosion may present with urethral discomfort, urinary incontinence. diagnosis requires a high index of suspicion, and cystoscopy is important in patients with intractable symptoms. patients with urethral erosion or recurrent incontinence should undergo detailed evaluation, including urodynamic study and ultrasonography. simple out-patient transvaginal introital ultrasonography may provide valuable clues to the presence of an erosion.(5,7) ed sepsis, magnetic resonance imaging can help in (8) this may dictate the need for more extensive tape removal. magnetic resonance imaging, however, is not suitcontrast to delayed secondary urethral erosion, primary intra-operative urethral injury should be tape procedure may proceed only if the injury is deemed minor. there is no consensus regarding the optimal management of these patients. a range of reconstructive surgeries have been described, including endoscopic tape removal alone and vaginal removal with urethral reconstruction with or without interposition of vascularized autologous tissue. mild ter transurethral tape excision.(9) of 34 patients in a agement of sling erosion.(5) however, only three patients have so far been reported to have undergone simultaneous autologous pubovaginal sling placement at the time of erosion management.(1,2) not warranted and removal of the sub-urethral porfigure 1. cystoscopic image of erosion in the floor of the urethra showing the tape mesh. there was an extensive erosion encompassing more than one quadrant of the urethral lumen. pubovaginal sling erosion | sinha et al 438 | tape excision was performed in view of severe painful groin indurations along with the erosion. the duration of postoperative catheter placement is not standardized and the surgeon must use discretion based on the severity of the problem and or coated tapes, in view of the risk for progressive erosions, strong consideration must be given for total tape excision. stress urinary incontinence does not always recur after tape excision; hence, prophylactic re-do incontinence surgery is unwarranted.(5,11,12) however, entation, careful consideration must be given to the simultaneous placement of a pubovaginal sling at the time of erosion repair. this is technically feato explore the doubly-scarred periurethral area in pose healthy vascularized tissue, such as a martius such women. synthetic tapes may carry higher risk of erosion and should be used with caution. poor quality of vaginal and periurethral tissues may anyway dictate the need for staged reconstruction. reconstruction, a standard autologous pubovaginal sling can be performed.(13) tients, synthetic sling may be placed as an interval procedure. conflict of interest none declared. references 1. starkman js, wolter c, gomelsky a, scarpero hm, dmochowski rr. voiding dysfunction following removal of eroded synthetic mid urethral slings. j urol. 2006;176:1040-4. 2. powers k, lazarou g, greston wm. delayed urethral erosion after tension-free vaginal tape. int urogynecol j pelvic floor dysfunct. 2006;17:422-5. 3. ulmsten u, henriksson l, johnson p, varhos g. an ambulatory surgical procedure under local anesthesia for treatment of female urinary incontinence. int urogynecol j pelvic floor dysfunct. 1996;7:81-5; discussion 5-6. 4. delorme e. [transobturator urethral suspension: mini-invasive procedure in the treatment of stress urinary incontinence in women]. prog urol. 2001;11:1306-13. 5. velemir l, amblard j, jacquetin b, fatton b. urethral erosion after suburethral synthetic slings: risk factors, diagnosis, and functional outcome after surgical management. int urogynecol j pelvic floor dysfunct. 2008;19:999-1006. 6. boublil v, ciofu c, traxer o, sebe p, haab f. complications of urethral sling procedures. curr opin obstet gynecol. 2002;14:515-20. 7. tunn r, gauruder-burmester a, kolle d. ultrasound diagnosis of intra-urethral tension-free vaginal tape (tvt) position as a cause of postoperative voiding dysfunction and retropubic pain. ultrasound obstet gynecol. 2004;23:298-301. 8. zumbe j, porres d, degiorgis pl, wyler s. obturator and thigh abscess after transobturator tape implantation for stress urinary incontinence. urol int. 2008;81:483-5. 9. wai cy, atnip sd, williams kn, schaffer ji. urethral erosion of tension-free vaginal tape presenting as recurrent stress urinary incontinence. int urogynecol j pelvic floor dysfunct. 2004;15:353-5. 10. mesens t, aich a, bhal ps. late erosions of mid-urethral tapes for stress urinary incontinence--need for long-term followup? int urogynecol j pelvic floor dysfunct. 2007;18:1113-4. 11. madjar s, tchetgen mb, van antwerp a, abdelmalak j, rackley rr. urethral erosion of tension-free vaginal tape. urology. 2002;59:601. 12. haferkamp a, steiner g, muller sc, schumacher s. urethral erosion of tension-free vaginal tape. j urol. 2002;167:250. 13. vassallo bj, kleeman sd, segal j, karram mm. urethral erosion of a tension-free vaginal tape. obstet gynecol. 2003;101:1055-8. figure 2. a total of 8 cm of tape was excised leaving behind small segments passing through the obturator foramen. tape microbiology showed candidal growth. details of the type of tape used were not available. case report fall 2012 09 resized.pdf 648 | 1department of urology, sina hospital, tehran university of medical sciences, tehran, iran 2urology research center, sina hospital, tehran university of medical sciences, tehran, iran 3research development center, sina hospital, tehran university of medical sciences, tehran, iran 4department of epidemiology and bioinformatics, sina hospital, tehran university of medical sciences, tehran, iran seyed mohammad kazem aghamir,1 seyed saeed modaresi,1 alborz salavati,1 mehdi aloosh,2,3 ali pasha meysami4 is intravenous urography required when ultrasonography and kub evidence a ureteroscopy plan? corresponding author: seyed saeed modaresi, md sina hospital, hassan abad sq., imam khomeyni ave., tehran, iran tel: +98 912 404 6303 e-mail: modaresis@razi. tums.ac.ir received may 2011 accepted may 2011 purpose: kidneys, ureters, and bladder (kub) plus an ultrasonography in the case of ureteral calculi. materials and methods: from october 2005 to november 2007, 139 use candidates were selected based on ultrasonography and kub, and were randomly divided into two groups. each patients underwent an ivu pre-operatively and were evaluated for the second time by the other of a density in the probable tract of the ureter on kub, and previous episodes of renal colic were ity to contrast media, and serum creatinine > 1.5 mg/dl. results: candidate for use. according to secondary ivu-based planning, of 139 patients, 127 (91.3%) required use, 10 (7.1%) ureteroscopy, and 2 (1.4%) non-operative treatment. about 8.7% of treatp = .35). positive predictive value of ultrasonography plus kub to diagnose a ureteral stone which needed use was 92.8% conclusion: intravenous urography is not useful enough to be performed routinely before entire uses. keywords: ultrasonography, ureteroscopy, hydronephrosis, ureteral obstruction, patient safety endourology and stone disease endourology and stone disease 649vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l introduction u -monly used endourological procedure in the treatment of ureteral calculi. furthermore, it has been revealed that open surgery is necessary in a considerable portion of ureteral stones.(1-3) despite the high sensitivity of spiral computed tomography (ct) scan for detecting renal calculi, intravenous urography (ivu) is still considered as the gold standard imaging modality for evaluation approach comprising of ultrasonography plus a plain abcolic in many countries.(1,4) this prospective study was designed to determine whether performing ivu as the routine pre-use evaluation can sigkub and ultrasonography or not. materials and methods after receiving the approval from tehran university of medical sciences’ medical ethics committee, the current study was conducted on a consecutive group of patients with renal colic who presented to the department of emergency of sina hospital from october 2005 to november 2007. all the patients underwent ultrasonography, kub, and urinalysis. due to our limited accessibility to ct scan, we did not perform spiral ct scan for all the patients. computed tomography was only done for diagnosing non-opaque stones. phy, a density in the probable tract of the ureter on kub, and previous episodes of renal colic were considered as inclusion hypersensitivity to contrast media, and serum creatinine > 1.5 mg/dl. tients who did not respond to this conservative treatment were planned to undergo use. one hundred and thirty-nine ultrasonography and kub results. all of these patients were admitted to the department of urology and underwent ivu on the same day. patients were randomly divided into two groups. group a consisted of 70 patients and group b composed of the rest endourologists. while ultrasonography and kub of patients group was assessed by the second endourologist. they made their decisions about patients’ treatments. thereafter, the patients in each group underwent an ivu pre-operatively and were evaluated for the second time by the other urologist considering ivu. at last, we compared treatment plans of these patients that were once provided by ultrasonography plus kub and another time by ivu. data were analyzed by spss software (the statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa), and p values less than .05 were considered results patients consisted of 84 (60.4%) men and 55 (39.6%) women, with the mean age of 43 years (range, 19 to 75 years). mean serum level of creatinine was 1.3 mg/dl (range, 0.7 to 1.5 mg/dl). one hundred and thirty-two (94.9%) patients had hematuria. ultrasonography revealed mild hydronephrosis in 20 (14.3%), moderate hydronephrosis in 67 (48.2%), and severe hydronephrosis in 52 (37.4%) patients. all of these patients had one or more densities with a mean size of 10 mm (range, 4 to 20 mm) in the probable tract of the ureter on the kub. intravenous urography revealed mild, moderate, and severe hydronephrosis in 18 (12.9%), 67 (48.2%), and 52 (37.4%) patients, respectively. intravenous urography was normal in 2 (1.4%) patients, while these patients had mild hydronephrosis on ultrasonography and a 5-mm density in the distal ureter on kub, which resembled a stone. on the other hand, intravenous urography evidenced hydronephrosis in 10 (7.1%) patients, while those densities were not inside the urefor ureteroscopy and not for use (figure). according to ivu, 127 (91.3%) patients were candidate for ivu before ureteroscopy? | aghamir et al 650 | use. the indications for use in these patients are shown in table. if we postulate that the acceptable limit of plan change with ivu is 10%, only 8.7% of plans was changed by ivu in our p = .35). positive predictive value of ultrasonography plus kub to diagnose a ureteral stone which needed use was 92.8% while 93.22). discussion 1923,(5) is a diagnostic test of choice for many indications. intravenous urography has been a mainstay of urologic imaging for several years.(1) current literature suggests that performing ivu is mandatory prior to endourological procedures and it should be done routinely before use.(2) intravenous urography is still indicated when a urologist requests a map of the urinary tract for percutaneous, endoureteral, or surgical procedures. intravenous urography is indicated when: 1) ultrasonography evidences hydronephrosis in the absence of a stone on the kub; 2) a stone is suspected on the kub in the absence of any evidence of stones or hydronephrosis on ultrasonography; and 3) the colic recurs with negative kub and ultrasonography.(6,7) however, ivu should not be performed routinely because with a mean imaging time of 75 minutes.(8) furthermore, bowel preparation is needed and a pregnancy test may be required. intravenous urography requires an intravenous cannulation and injection of the contrast media, which is bothersome for the patient. intravenous urography utilizes ionizing radiation and contrast media, which carry health risks, morbidity, and mortality.(9) the risk of contrast reaction during ivu is between 5% and 10%, with a mortality rate of ap(10) another negative point of ivu indications for ureteroscopic stone extraction in 127 patients. indication for ureteroscopic stone extraction definition number of patients unresponsiveness to expectant management no spontaneous stone passage after 2 weeks of medical therapy 59 prolonged symptoms colic pain > 1 month prior to the first visit 29 large ureteral stone not probably passing spontaneously (> 9 mm) 19 impacted stones no change in stone position within 2 months 11 severe acute symptoms refractory to medical treatment 6 single kidney 2 special considerations like hazardous occupations, such as pilot 1 endourology and stone disease treatment plans based on intravenous urography. 651vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l ivu before ureteroscopy? | aghamir et al msv for an ivu.(11) in the current study, all the patients who had hydronephrosis on ultrasonography and a density in favor of calculi in the course of the ureter on kub were planned for use. there(1.4%) patients did not need any endourologic procedure. this means, only the plan of two patients was changed significantly and they were not transferred to the operating room, cedure (use for 127 and ureteroscopy for 10 patients). costs and complications of ivu make it more reasonable to conclude that performing ivu is a redundant test in these conditions. consequently, ivu did not change the treatment dure. conclusion we concluded that ivu should not be performed routinely before the entire uses. conflict of interest none declared. 6. dalla palma l. what is left of i.v. urography? eur radiol. 2001;11:931-9. 7. pollack hm, banner mp. current status of excretory urography. a premature epitaph? urol clin north am. 1985;12:585-601. 8. thomson jm, glocer j, abbott c, maling tm, mark s. computed tomography versus intravenous urography in diagnosis of acute flank pain from urolithiasis: a randomized study comparing imaging costs and radiation dose. australas radiol. 2001;45:291-7. 9. andrews sj, brooks pt, hanbury dc, et al. ultrasonography and abdominal radiography versus intravenous urography in investigation of urinary tract infection in men: prospective incident cohort study. bmj. 2002;324:454-6. 10. lindbloom ej, chang si. clinical inquiries. what is the best test to diagnose urinary tract stones? j fam pract. 2001;50:657-8. 11. homer ja, davies-payne dl, peddinti bs. randomized prospective comparison of non-contrast enhanced helical computed tomography and in-travenous urography in the diagnosis of acute ureteric colic. australas radiol. 2001;45:285–90 references 1. chew bh, denstedt jd. ureteroscopy and retrograde ureteral access. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 2. 9 ed. philadelphia: saunders; 2007:1508-25. 2. bichler kh, lahme s, strohmaier wl. indications for open stone removal of urinary calculi. urol int. 1997;59:102–8. 3. aghamir sk, mohseni mg, ardestani a. treatment of ureteral calculi with ballistic lithotripsy. j endourol. 2003;17:887-90. 4. türk c, knoll t, petrik a, sarica k, seitz c, straub m. guidelines on urolithiasis. european association of urology 2010; 2011. 5. worster a, haines t. does replacing intravenous pyelography with noncontrast helical computed tomography benefit patients with suspected acute urolithiasis? can assoc radiol j. 2002;53:144-8. v08_no_4_final_new.pdf sexual dysfunction and infertility 298 urology journal vol 8 no 4 autumn 2011 is microsurgery necessary in grade 3 varicocele? mehmet kalkan,1 soner yalcinkaya,2 omer etlik,3 1 purpose: to compare the results of microsurgical and naked eye varicocelectomy in patients with grade 3 varicocele. materials and methods: this study was conducted on 84 patients with grade 3 varicocele, between 2007 and 2009. patients were randomized into two groups, equal in number. thereafter, microsurgical varicocelectomy was performed in the first group, while the other group underwent naked eye varicocelectomy. groups were compared in terms of operation duration, number of ligated internal and external spermatic veins, early and late postoperative complications, and postoperative color doppler ultrasonography findings. parametric and nonparametric values were compared using student’s t test and chi-square test, respectively. results: the mean duration of surgery was 19 ± 2.3 minutes (range, 12 to 25 minutes) in the naked eye surgery group and 43 ± 3.9 minutes (range, 25 to 75 minutes) in the microsurgery group (p = .008). the number of ligated internal and external spermatic veins, the incidence of early and late postoperative complications, and color doppler ultrasonography findings were not significantly different between the two groups (p = .12, p = .09, p = .17, and p = .22, respectively). conclusion: in patients with grade 3 varicocele, microsurgery and naked eye surgical methods proved similar results in terms of success and complications. because the operation time of the classical varicocelectomy is significantly shorter, it may be preferred in this subset of patients. urol j. 2011;8:298-301. www.uj.unrc.ir keywords: varicocele, infertility, microsurgery, postoperative complications 1department of urology, sema hospital, antalya, turkey 2department of urology, antalya training and research hospital, antalya, turkey 3department of radiology, sema hospital, antalya, turkey corresponding author: soner yalcinkaya, md antalya education and research antalya, turkey tel: +90 533 478 4988 fax: +90 242 249 4462 e-mail: drs1092@gmail.com received april 2011 accepted august 2011 introduction microsurgery is usually recommended as the method of choice in patients with low-grade varicocele referred to infertility clinics. this is due to the difficulty of naked eye dissection of the spermatic veins with relatively smaller diameters in such patients, especially in low ligation methods, because these veins generally present conglomeration.(1,2) however, we know that patients with grade 3 varicocele do not encounter problems in diagnosis and dissection during operation due to reduction in the number and diameter of the spermatic veins.(3) on the other hand, opinions concerning the degree of reflux in patients with varicocele and its effect on the sperm parameters as well as the degree of postoperative reflux and whether it represents clinical recurrence remain unclear.(2) this study compares operation time, postoperative early and late stage complications, the number of ligated internal and external spermatic veins, and the preoperative and postoperative color doppler ultrasonography (cdus) microsurgery in grade 3 varicocele—kalkan et al 299urology journal vol 8 no 4 autumn 2011 findings in patients with grade 3 varicocele who underwent microsurgery and naked eye surgery. materials and methods this prospective randomized clinical study was conducted on 84 patients between december 2007 and july 2009. all the patients presented with grade 3 varicocele that were observable with inspection on the left side. all the patients were in military service and unmarried. scrotal swelling and pain were the chief complaints. the indications for varicolectomy were pain and fear of late onset infertility. we randomized the patients into two groups based on their application number. even numbered patients were in the naked eye group and odd numbered ones were in the microsurgery group. each group was composed of 42 patients. spermiography and cdus were performed in all the patients. no patient had history of pelvic, scrotal, or inguinal operations. subjects with previous scrotal and inguinal operations as well as bilateral cases were excluded from the study. all the patients were examined in supine position by using powervision 6000 ultrasonography (toshiba inc., tokyo, japan) 7.5 mhz linear duplex probe with spontaneous respiration and valsalva maneuver prior to the operation. presence and duration of reverse flow in the pampiniform plexus were calculated. participants with no sign of reverse flow were later evaluated during spontaneous respiration and valsalva maneuver while standing. under general anesthesia, all the subjects were low inguinal incision. the spermatic cord was suspended and taken off from the incision line in all the operations. we directed to more cephalad position in conglomerulate veins to make the dissection easier in the naked eye operation group. we used muller-weller® microscope (6 to 10× magnification) for the microsurgery group and recorded the type and number of ligated veins in both groups. control cdus was performed 3 months after the operation by a radiologist unaware of the type of operation. results were compared in terms of operation duration, number of ligated internal and external spermatic veins, presence of postoperative reflux, and early (1st week) and late (3rd to 6th months) complications, including bleeding, hematoma, testicular atrophy, and hydrocele formation. parametric values were compared using student’s t test. all the nonparametric comparisons were done by chi-square test. p values less than .05 were considered statistically significant at 95% confidence interval (ci). results mean age of the patients was 21.6 ± 2.7 years and 20.8 ± 2.9 in groups 1 and 2, respectively. pre-operative spermiography in microsurgery group revealed normal parameters in 28 (66.6%), oligospermia in 11 (26.2%), and oligospermia and low motility in 3 (7.2%) patients versus 32 (76.2%), 8 (19.1%), and 2 (4.7%) subjects in naked eye surgery group, respectively. the mean duration of surgery was 19 ± 2.3 minutes (range, 12 to 25 minutes) in the naked eye surgery group and 43 ± 3.9 minutes (range, 25 to 75 minutes) in the microsurgery group (p = .008). the mean number of ligated internal spermatic veins was 4.5 (range, 3 to 6) while the number of ligated external spermatic veins was 1 in 26 patients and 2 in 16 subjects in the naked eye surgery group. in the microsurgery group, the mean number of ligated internal spermatic veins was 4.8 (range, 3 to 7) while the number of ligated external spermatic veins was 1 in 28 patients and 2 in 14 subjects. there was not a statistically significant difference between groups in terms of the number of ligated external spermatic veins (p = .09). two patients in the naked eye surgery group developed peritesticular hematoma in the 1st week. none of the participants in the microsurgery group developed early postoperative complications. we did not identify a statistically significant difference in terms of early stage complications between the two groups (p = .17). prior to the operation, all the patients with grade 3 varicocele were identified to have reflux for longer than 5 seconds in cdus, asserted with microsurgery in grade 3 varicocele—kalkan et al 300 urology journal vol 8 no 4 autumn 2011 spontaneous respiration and valsalva maneuver. the cdus examination conducted 3 months after the operation did not find reflux for more than 5 seconds in any of the operated participants. there was no sign of hydrocele or testicular atrophy in any of the patients in both groups six months after the operation. discussion varicocele is one of the most frequent causes of infertility among men referring to infertility clinics. clinically, varicocele can be classified into three grades. in grade 3, the presence of dilated varicose veins can be seen by observation alone. in grade 2, the presence of veins can be felt by palpation without the need for valsalva maneuver. in grade 1, on the other hand, the presence of the scrotal veins can only be felt by palpation with the valsalva maneuver.(4) in low ligation methods, as the grade of varicocele drops, the diameter of the spermatic veins declines whilst their numbers increase revealing conglomeration with each other. it might be difficult to maintain the integrity of testicular artery and lymphatic veins when performing naked eye dissection in these conditions. research suggests that microsurgical varicocelectomy is not only beneficial, but also necessary, especially in these cases. actually, it is recommended that a microscope should be used instead of dilating loop.(2,5) the demand for experience, preparation stage for the operation, and prolonged operation durations involved in microsurgical varicocelectomy are undesirable factors, especially in clinics with heavy workload. the surgical duration of a varicocele operation is directly related to the experience of the surgeon, number of veins to be ligated, and development of potential peri-operative complications, such as hemorrhage during the procedure. in our study, there was a statistically significant difference in operation periods between the two groups (p = .008). this difference is associated with longer times required by microsurgery as well as equipment preparation and orientation for the operation area. the reason behind the popularity of low ligation methods is the fact that external and internal veins can only be observed with this approach.(1) no statistically significant difference between our groups concerning the number of ligated external spermatic veins demonstrates that these veins are observable by the naked eye. compared to grades 1 and 2 varicocele, the number of internal spermatic veins in grade 3 is lower whilst vein diameters are larger.(1,6) this fact not only makes it easier to notice the veins, it also makes their dissection simpler. however, we came across very fine veins presenting conglomeration in low-grade varicocele, especially in patients with subclinical varicocele that were operated according to cdus findings. this characteristic makes the dissection of fine veins more difficult. sometimes the total ligation of vein clusters in such cases calls out for the formation of testicular atrophy or hydrocele. microsurgical varicocelectomy is the undisputed recommendation for such conditions. however, the benefit of varicocelectomy on sperm parameters in these cases should be opened to debate.(2,7) the number of internal ligated veins among our patients was similar in both groups (p = .12). spermatic veins displaying pronounced tortuosity and larger vein diameters might explain this condition. we observed that the number of veins ligated in the study by orhan and colleagues is higher than ours (range, 3 to 14). this finding may be explained by inclusion of more grades 1 and 2 varicocele in their study.(6) anticipated complications in varicocele surgery include wound infection, scrotal hematoma, testicular atrophy, inadequate venous ligation (recurrence), and hydrocele formation.(4) only 2 patients undergoing naked eye varicocelectomy developed minimal hematoma in the early postoperative stage; however, it was spontaneously reabsorbed within ten days in both subjects. hydrocele and testicular atrophy did not develop in any patients. clinical examination is fundamental in the diagnosis of varicocele. additional screening methods are unnecessary in grade 3 varicocele.(2) color doppler ultrasonography is applied especially to diagnose subclinical varicocele and reveal the presence of recurrences. although microsurgery in grade 3 varicocele—kalkan et al 301urology journal vol 8 no 4 autumn 2011 studies suggest that subclinical varicocele does not benefit greatly from surgery, in clinical practice, it is not uncommon for these patients to be advised and being subject to surgery.(8) we performed cdus on all the patients to investigate whether their clinical findings correlate with doppler findings and if this correlation persisted following both surgical methods. we tried to find out if the presence of pathological reflux is an anticipation of poor surgical results. reflux presence in patients with clinical varicocele can reach upto 90%.(6,7) this ratio was determined to be 100% in our study. this condition was explained by the presence of high-grade varicocele in all of our patients. although there is some controversy whether reflux is an indicator of recurrence in the postoperative period, we did not come across reflux during controls in the postoperative 3rd months. this condition was interpreted as effective ligation of the spermatic veins in both groups. conclusion in conclusion, naked eye and microsurgical varicocelectomies reveal similar results in terms of postoperative complications and recurrence rates amongst grade 3 varicocele. because the number of the spermatic veins to be ligated is less and the vein diameter is greater in both methods. we are convinced that shorter surgical periods can be a motive for preferring naked eye varicocelectomy in grade 3 varicocele. conflict of interest none declared. references 1. hopps cv, lemer ml, schlegel pn, goldstein m. intraoperative varicocele anatomy: a microscopic study of the inguinal versus subinguinal approach. j urol. 2003;170:2366-70. diagnosis and treatment of varicocele. turk j urol. 2005;31:57-63. 3. belani js, yan y, naughton ck. does varicocele grade predict vein number and size at microsurgical subinguinal repair? urology. 2004;64:137-9. 4. schneck fx, bellinger mf. abnormalities of the testes and scrotum and their surgical management. in: wein aj, kavoussi lr, novick ac, et al., eds. campbell-walsh urology. vol 4. 9 ed. philadelphia: saunders elsevier; 2007:3795. 5. schiff j, kelly c, goldstein m, schlegel p, poppas d. managing varicoceles in children: results with microsurgical varicocelectomy. bju int. 2005;95:399402. f. anatomic vascular variations in sub-inguinal 7. al-said s, al-naimi a, al-ansari a, et al. varicocelectomy for male infertility: a comparative study of open, laparoscopic and microsurgical approaches. j urol. 2008;180:266-70. echocolor doppler in diagnosis of varicocele. turk j urol 2000;26:61-70. 1474 | short-term survival in renal transplantation from brain-death donors: focusing on recipients with diabetes background manoochehr nakhjavani,1 fatemeh ghaemi,2 hamid ravaghi,3 mohammad aghighi,4 farahnaz ghaemi5 corresponding author: fatemeh ghaemi, md ministry of health and medical education, tehran university of medical sciences, tehran, iran. tel: +98 21 88562426 fax: +98 021 66911294 e-mail: ghaemifatemeh@yahoo. com received november 2012 accepted january 2014 1 department of endoctrinology, tehran university of medical sciences, vali’asr hospital, tehran, iran. 2 ministry of health and medical education, tehran university of medical sciences, tehran, iran. 3 department of health services management, health management and economics research center, school of health management and information sciences, iran university of medical science, tehran, iran. 4 management center of transplantation and special diseases, tehran university of medical sciences, tehran, iran. 5 department of microbiology, islamic azad university, kerman branch, kerman, iran. kidney transplantion kidney transplantion purpose:ouraimwastoevaluateshorttermsurvivalratesinrenaltransplantrecipientsfrom deceaseddonors,whilefocusingonrecipientswithdiabetesmellitusbackground. materials and methods:thisisalongitudinalfollow-upstudybasedonnationalregistryof recipientsinministryofhealthandmedicaleducationiniranfrom2010-11.fivehundred fifty-fiverecipients,226(40.8%)femalesand328(59.2%)males,wereincludedinthestudy. mean(±sd)ageoftherecipientswas39±14years.ofdonors18.4%werefemalesand81.6% weremales.ageofthedonorswas33±14years.allallograftrecipientsfromdeceaseddonors enrolledinthestudy.short-termgraftsurvival(1year)wasdetermined.dataregardingage, gender,backgrounddiseaseandcoldischemictimeofrecipientsanddonorswerecollected fromtheorganprocurementunits. results:allograftswerefunctioningin499(90.1%)ofrecipientsafteroneyear.ofrecipients38(6.9%)diedandrejectionoftransplantedkidneyoccurredin17(3.1%)cases.so, in55(9.9%)cases,allograftswerenotfunctioning.thereweresignificantrelationshipsbetweenshorttermgraftsurvivalofdonors'gender,ageofrecipients,coldischemictimeand levelofclearanceofcreatinineofrecipients. conclusion:inadditiontocoldischemictime,graftsurvivalcanbeaffectedbyrecipients’ age.therearesomeotherconsiderationsandimplicationsregardingtheshorttermgraftsurvivalinrenaltransplantationfromcadaverdonorswhicharediscussedinthispaper. keywords:graftsurvival;kidneytransplantation;tissueandorganprocurement;survival rate;renaldiabetesmellitus. 1475vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l survival in renal transplantation from brain-death donors | nakhjavani et al introduction chronicrenalfailureisdefinedasglomerularfiltra-tionrate>60mlperminutefor1.73squareme-tersofbodysurfaceareaformorethan3months, whichcanleadtoadvancedkidneydisease.(1)thefirstkidneytransplantiniranwasperformedinshirazin1967and nowthenumberofkidneytransplantsiniranis30transplantsper1millionpeopleineachyear,ofwhich25%is frombraindeath. accordingtothereportofthedepartmentoftransplantation andspecificdiseasesattheministryofhealthandmedicaleducation(mohme)iniranin2011,thenumberofnew casesdiagnosedwithend-stagerenaldisease(esrd)was 4864[64permillionpopulation(pmp)]andthenumberof kidneytransplantationsfromallsources(livingrelated,livingunrelated,decreaseddonors)was2273(30pmp).(2)the common methods of treating patients with esrd include hemodialysis,peritonealdialysisandkidneytransplantation. kidneytransplantationisconsideredthemosteffectivetreatmentstrategytoincreasethequalityoflifeforrecipients.(3) graftsources includefamily living,non-family livingand dead.oneofthemaingoalsoftransplantprogramsisprovidingasuitablegraftforeachpatientwhorequiresit.nowadays, the inadequate number of volunteer donors is consideredthebiggestobstacletoachievethisgoal.(4)kidney transplantationfromcadaverisoneoftheimportantsources ofgettingakidneytransplantintreatingpatientswithesrd. thenumberofkidneytransplantsfromlivingdonorandcadaverisconsiderablyvariousacrossdifferentcountriesandis relatedtovariousfactorsincludingspecificlegal,culturaland religious restrictions.(5) thepurposeofrenaltransplantistoprolongandmaintain agoodqualityoflifeforrecipientswithesrd;(6)itismore costeffectiveanditallowsreturntoamorenormallifestyle thandoesmaintenancedialysistherapy.(7-9) in industrialized countries,themajorityoforganscomefromdeceaseddonors whereas in countries with lower incomes, the majority of casesarefromlivingdonors.(10) in both groups, the introductionofnewimmunosuppressiveagentsinthepast20years, alongwithimprovementsachievedininfectionprophylaxis strategies,haveresultedinaremarkableimprovementinboth recipientsandgraftsurvivalrates.thesefactorshavemade kidneytransplantationasthetreatmentchoiceforrecipients withesrsd.(11,12)however,otherfactorssuchasageand gender of recipients and donors, background diseases and cold ischemic time can affect graft survival rate too.(13-15) therefore,weaimedtoevaluatetheshorttermgraftsurvival ratesinrenaltransplantationfromdeceaseddonorsbasedon datainmohmeregistryiniran.weinvestigatedthesurvival ratesofkidneytransplants(graftsurvivalrates)frombraindeathcasesfrom2010to2011iniran. materials and method thisisalongitudinalfollow-upstudythatwasdonebasedon mohmeregistryin2010and2011.allrecipientswhohad registeredintheabovementionedregistryandhadreceived kidneyallograftsfrombrain-deathdonorswereincludedin thestudyandfollowed-upforawholeyear.thefollowing data were collected regarding donors and recipients; short termgraftsurvival (1year),ageof recipientsanddonors, genderofrecipientsanddonors,theirbackgrounddiseases andcoldischemictime.theexacttimeoftransplantationis consideredastheprimaryevent,andtheonsetofdialysisof therecipientsbecauseofrejectionaswellasthedeathofthe recipientsareconsideredasthefinalevent. therewere595casesofkidneytransplantationin2010-2011. outofthese,41recipients(6.8%)wereexcludedduetolack ofinformationontheirstateaftertransplantation;i.e.itisnot cleartouswhetherthetransplantedkidneyisstillfunctioning intheserecipientsornot.theremaining554caseswhohave been transplanted and followed-up in different transplant centersfromthebeginningof2010totheendof2011were studied.thereare30transplantunits,14organprocurement unitsand30identificationunitsindifferenthospitalsallover the country. therequireddataforthisstudywereobtainedfrommohme registry. to evaluate the survival rates of recipients from brain-deathdonors,creatininelevelwasdetermined.itshould benotedthatinthisstudyallethicalstandardswereobserved. thedataarepresentedassimplenumber(%). results ofstudysubjects226(40.8%)werefemalesand328(59.2%) weremales.mean(±sd)ageoftherecipientswas39±14 years.thebloodgroupsoftherecipientsinthisstudywere o+in38.4%,a+in26.3%,b+in21.5%,ab+in9.6%and 1476 | kidney transplantion negativebloodgroupsin4.2%.thebackgrounddiseasesare shownintable. allrecipientsreceivedorgansfrombrain-deathdonors.of donors18.4%werefemalesand81.6%weremales.mean age(±sd)ofthedonorswas33±14years.transplanted kidneyswerefunctioningin499(90.1%)recipientsin1year follow-upperiod.ofrecipients38(6.9%)diedand17(3.1%) losttransplantedkidney;thereforein55(9.9%)ofcasesthe transplantedkidneywasnon-functioning. therecipientswhoexperiencedgraftlossshowedahigher levelofcreatinine(3.8±2.5mg/dl).thecoldischemictime inthisstudyrangedfrom4.4±1.6to6.8±1.3hours.moreover,theageofrecipientswhosufferedfromgraftlosswas greaterthantheaverageage,whichwas44.2±14.7years. itisnoteworthythatthenumberofrecipientswithdiabetes mellitusasbackgrounddisease(29.4%)isthelargestcomparedtootherbackgrounddiseases.furthermore,in30cases (54.5%)outof55wherethetransplantedkidneywasnonfunctioning,thebackgrounddiseaseoftherecipientswasdiabetesmellitus.thus,wemaysaythat,inthisstudy,diabetesis themostcommonbackgrounddiseaseinesrdpatientsand alsothelargestnumberoftransplantationfailuresoccurredin diabetic patients. discussion nowadays,survivalratesinrenaltransplantation,owingto recentadvances,appropriatefollow-upandtheuseofimmunosuppressive drugs, has increased significantly compared with past decades.(11,12)thepresentstudywasanattemptto examineshorttermsurvivalrateinrenaltransplantrecipients frombrain-deathdonors,withaspecialfocusonrecipients withdiabetesmellitus.theresultsofthestudyshowedthatin 90.1%ofrecipientsthetransplantedkidneywasfunctioning afteroneyear.similarresultswereobtainedinotherstudies. forinstance,thestudybysimforooshandcolleaguesshowed asimilarsurvivalrate.(16)theycomparedshort-termsurvival oftransplantedpatientsfromcadaverwithtransplantedrecipientsoflivingpeopleandconcludedthatwehavetoincrease kidneytransplantfromcadaver.(16)inanotherstudy,graftsurvivalfromcadaverwas82.1%.(17)oneoftheotherfindings ofthepresentstudywasthatrecipientswithgraftlosshada higherlevelofcreatinine.insomeotherstudiestoo,survival ratesofrecipientsaftertransplantationwasassociatedwith higherlevelsofcreatinine.(18) thethirdfindingofthisstudyisthatthenumberofrecipientswithdiabetesmellituswasthelargestcomparedtoother backgrounddiseases,andinmorethan50%ofthepatients studied, non-functioning kidney transplants belonged to thesepatients.similarresultswerereportedinotherstudies.gilbertsonandcolleagues,forinstance,havestatedthat “inwesterncountries,diabetesistheleadingsinglecauseof esrd”.(19)inanotherstudyin2006,itwasshownthat“in manycountriessuchastheunitedstates,morethan50%of patientsinrenalreplacementtherapyprogramshavediabetes mellitusasthemajorcauseoftheirrenalfailure”.(20) conclusion mostofesrdpatientshavediabetesmellitusandencounterproblemssuchasavailabilityoftherequiredorgan,constantfollow-up,immunosuppressivetherapies,mortalityand morbidity,andalsotheburdenofthedisease.therefore,itis highlyrecommendedtopreventdiabetesmellitusoritscomplicationslikediabeticnephropathy. acknowledgments theauthorswouldliketopayhighesttributetothedonors' families.wealsoowesincereappreciationtoalldedicated colleagues in all procurement units and transplant centers countrywidefortheirpreciouscontributionbytimelyreportingtheiractivitieswhichmakesuchannualsurveysfeasible. conflict of interest none declared. table. background diseases in recipients. background disease frequency no. (%) diabetes mellitus 163 (29.4) hypertension 98 (17.6) glomerulonephritis 94 (16.9) polycystic kidney 23 (4.1) congenital 16 (2.9) urological diseases 12 (2.2) unknown 148 (26.8) total 554 (100) 1477vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l references 1. bosan ib. recommendations for early diagnosis of chronic kidney disease. ann afr med. 2007;6:130-6. 2. national registry department of transplantation and special disease. ministry of health and medical education, iran. 2010. available from: http://www.irantransplant.org. 3. abboud o. incidence, prevalence, and treatment of end-stage renal disease in the middle east. ethn dis. 2006;16:s2-2-4. 4. foster ce, weng rr, smith cv, imagawa dk. the influence of organ acceptance criteria on long-term graft survival: outcomes of a kidney transplant program. am j surg. 2008;195:149-52. 5. danovitch gm. handbook of kidney transplantation. philadelphia, pa: lippincott williams & wilkins; 2009. p. 90-104 6. ahmadnia h, shamsa a, yarmohammadi a, darabi m, asl zare m. kidney transplantation in older adults: does age affect graft survival? urol j. 2005;2:93-96. 7. kazemeyni sm, bagheri ar, heidary ar. worldwide cadaveric organ donation systems. urol j. 2004;1:157-64. 8. feest tg, rajamahesh j, byrne c, et al. trends in adult renal replacement therapy in the uk: qjm. 2005;98:21-8. 9. ballesteros sj. indications, morbidity and mortality of the open nephrectomy: analyses of 681 cases and bibliographic review. arch esp urol. 2006;59:59-70. 10. cusumano a, garcia-garcia g, di gc, et al. end-stage renal disease and its treatment in latin america in the twenty¬ first century. ren fail. 2006;28:631-7. 11. el-husseini aa, foda ma, shokeir aa, shehab b, sobh m, ghoneim m. determinants of graft survival in pediatric and adolescent live donor kidney transplant recipients: a single center experience. pediatr transplant. 2005;9:763-9. 12. shoskes d, lapierre c, cruz-correra m, et al. beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial. transplantation. 2005;80:1556-9. 13. rezaei m, kazemnejad a, bardideh a, mahmoudi m. factors affecting survival in kidney recipients at kermanshah. urol j. 2004;1:1807. 14. meier-kriesche hu, ojo ao, port fk, arndorfer ja, cibrik dm, kaplan b. survival improvement among patients with end-stage renal disease: trends over time for transplant recipients and wait-listed patients. j am soc nephrol. 2001;12:1293-6. 15. gillen dl, stehman-breen co, smith jm, et al. survival advantage of pediatric recipients of a first kidney transplant among children awaiting kidney transplantation. am j transplant. 2008;8:2600-6. 16. simforoosh n, gooran s, tabibi a, bassiri a, gharaati mr. cadaver transplantation in recent era: is cadaveric graft survival similar to living kidney transplantation? ijotm. 2011;2:168-70. 17. almasi a, hassanzade j, rajaeefard ar, salahi h. the relationship between graft survival rate of renal transplantation and donor source in transplanted patients at the transplantation center of namazi hospital of shiraz. amuj. 2011;14:10-7. 18. sundaram h, maureen am, wida sc, christine bt, barbara ab, christopher pj. post-transplant renal function in the first year predicts long-term kidney transplant survival. kidney int. 2002;62:311-8. 19. gilbertson dt, liu j, xue jl, et al. projecting the number of patients with end-stage renal disease in the united states to the year 2015. j am soc nephrol. 2005;16:3736-41. 20. u.s. renal data system. usrds 2006 annual data report: atlas of end-stage renal disease in the united states. bethesda, md: national institutes of health, national institute of diabetes and digestive and kidney diseases; 2006. survival in renal transplantation from brain-death donors | nakhjavani et al fall 2012 08.pdf 718 | 1medical laser application research center; department of urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran 2 department of radiology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran mohammad reza razzaghi,1 mohammad mohsen mazloomfard,1 hooman bahrami-motlagh,2 babak javanmard1 isolated renal hydatid cyst diagnosis and management corresponding author: mohammad mohsen mazloomfard, md medical laser application research center; department of urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran tel: +98 21 2271 8001 fax: +98 21 8852 6901 e-mail: mazloomfard@ yahoo.com received november 2010 accepted march 2011 case report keywords: hydatid disease, echinococcosis, kidney neoplasms, cysts introduction h ydatid cyst involving the urinary tract is relatively uncommon.(1,2) the cyst growing in the kidney is slow and usually asymptomatic lasting for 5 to 10 years.(1) this disease is endemic in parts of the middle east, south america, australia, new zealand, and alaska.(3) of fullness in the abdomen. successful treatment was accomplished with a kidney-sparing pericystectomy. case report abdomen. the patient’s medical history was unremarkable. he was living in an urban area and working as a shopkeeper. laboratory tests revealed eosinophilia, an erythrocyte sedimentation rate urinalysis. chest radiography was unremarkable. ultrasonography of the right kidney depicted renal enlargement and contour deformity due to a multi-loculated cystic lesion with an echogenic center measuring 4 cm in diameter (figure 1). thin septum was found in some cysts. intravenous pyelography showed mass effects on the right kidney. computed tomography (ct) scan revealed the presence of a multicystic lesion with thick and thin internal septations. no cystic or solid lesions were found in the liver, spleen, and left kidney. case report 719vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l isolated renal hydatid cyst | razzaghi et al agglutination were performed, which had positive results. the patient was candidate for surgery. kidney-sparing pericystectomy was performed, and the cyst was removed. the surgical specimen was occupied with considerable numbers of daughter cysts (figure 3). the postoperative period was uneventful, and the patient was prescribed albendazole 400 mg twice daily for 4 weeks to prevent metastatic cyst formation. pathologically, a multilocular hydatid cyst with invaginated scolices in the cystic specimen was reported. the patient’s follow-up with abdominopelvic ct scan and chest radiography was normal in period of 2 years. discussion areas. imaging studies are suggestive, but usually inconclusive, especially in a complicated cyst that mimics renal tumor or ureteropelvic junction obstruction appearance.(1,4,5) intravenous urography may demonstrate pyelocaliceal dilatation (6) ultrasonography has been used to demonstrate multicystic or multiloculated masses. advanced radiologic techniques, such as ct and magnetic resonance imaging, play an important role in the diagnosis. (6,7) a multiloculated cystic mass with heterogeneous density and daughter cysts.(8) renal hydatid disease. in 20% to 50% of cases, moderate eofigure 1. longitudinal ultrasonography demonstrates a multicystic lesion in the upper pole of the right kidney. calipers indicate approximate size of the lesion. figure 2. computed tomography after intravenous bolus of contrast medium showing a multicystic lesion in the upper pole of the right kidney. mass does not show contrast enhancement of the wall. rosette structural pattern with presence of peripheral daughter cyst is seen with fluid density lower than that of parental matrix. figure 3. surgical specimen exhibited multiple daughter cysts. 720 | sinophilia is present.(4) the casoni and weinberg tests have (9) serologic and hemagglutination tests have low reliability, immunoelectrophoresis against arch-5.(10) in general, surgery is the best treatment for renal hydatid cyst, and if it is possible, kidney-sparing protocol is the logical option, but nephrectomy must be reserved for non-functioning kidneys.(1,6) conflict of interest none declared. case report references 1. angulo jc, sanchez-chapado m, diego a, escribano j, tamayo jc, martin l. renal echinococcosis: clinical study of 34 cases. j urol. 1997;157:787-94. 2. kirkland k. urological aspects of hydatid disease. br j urol. 1966;38:241-54. 3. vuitton da. the who informal working group on echinococcosis. coordinating board of the who-iwge. parassitologia. 1997;39:349-53. 4. sayilir k, iskender g, ogan c, arik ai, pak i. a case of isolated renal hydatid disease. int j infect dis. 2009;13:110-2. 5. yaycioglu o, ulusan s, gul u, guvel s. isolated renal hydatid disease causing ureteropelvic junction obstruction and massive destruction of kidney parenchyma. urology. 2006;67:1290 e15-7. 6. fazeli f, narouie b, firoozabadi md, afshar m, naghavi a, ghasemi-rad m. isolated hydatid cyst of kidney. urology. 2009;73:999-1001. 7. von sinner wn, hellstrom m, kagevi i, norlen bj. hydatid disease of the urinary tract. j urol. 1993;149:577-80. 8. kalovidouris a, pissiotis c, pontifex g, gouliamos a, pentea s, papavassiliou c. ct characterization of multivesicular hydatid cysts. j comput assist tomogr. 1986;10:428-31. 9. sountoulides p, zachos i, efremidis s, pantazakos a, podimatas t. nephrectomy for benign disease? a case of isolated renal echinococcosis. int j urol. 2006;13:174-6. 10. zmerli s, ayed m, horchani a, chami i, el ouakdi m, ben slama mr. hydatid cyst of the kidney: diagnosis and treatment. world j surg. 2001;25:68-74. 1551vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l 1 department of urology, endourology division, urology nephrology research center, shiraz university of medical sciences, shiraz, iran. 2 department of urology, jahrom university of medical sciences, jahrom, iran. 3 department of anesthesiology, jahrom university of medical sciences, jahrom, iran. 4 hematology research center, shiraz university of medical sciences, shiraz, iran. mohammad mehdi hosseini,1 abbas hassanpour,1 farhad manaheji,1 alireza yousefi,2 mohammad hassan damshenas,3 sezaneh haghpanah4 percutaneous nephrolithotomy: is distilled water as safe as saline for irrigation? corresponding author: abbas hassanpour, md department of urology, urology and nephrology research center, shiraz university of medical sciences, shiraz, iran. tel: +98 711 233 1006 fax: +98 711 233 0724 e-mail: hassanpour74@yahoo. com received july 2012 accepted april 2014 purpose: to compare dilutional effect of distilled water with saline solution as an irrigation fluid in percutaneous nephrolithotomy (pcnl). materials and methods: three hundred twenty eight adult patients (191 men, 137 women) who were candidates for pcnl were randomly assigned into two groups (distilled water, n = 158, group 1; saline solution, n = 162, group 2). stone size, operation time, irrigation fluid volume, blood hemoglobin level, urea nitrogen, creatinine, sodium and potassium levels were checked before and at 6 and 12 hours after operation. results: the mean age of the patients was 37.8 years, and the mean stone diameter was 31.5 mm. there was no clinical case of transurethral resection (tur) syndrome. serum sodium depletion was significantly more in group 1 than group 2 (p < .0001). group 1 had significant decreased post-operative serum sodium levels (p < .0003). similarly in group 2, postoperative serum sodium levels were significantly lower than the preoperative concentration (p < .01), but it was not the same 6 hours after the operation (p = .23). serum sodium concentrations remained within normal limits in all cases, without causing clinical signs and symptoms of hyponatremia. conclusion: we found that distilled water is safe irrigation fluid for pcnl in adults. in addition, it is more available and cost effective. keywords: nephrostomy; percutaneous; postoperative complications; intraoperative care; therapeutic irrigation. endourology and stone disease 1552 | endourology and stone disease introduction nowadays, percutaneous nephrolithotomy (pcnl) is a technique to remove large and complex renal stones which cannot be treated with extracorporeal shock wave lithotripsy (swl). irrigation fluid is used in endoscopic urological surgeries to dilate the target organ and also for a better vision. physiologic saline is the most commonly used fluid because it is isotonic and also compatible with interventions, unless electro-cautery is needed. by the use of hypotonic solutions such as distilled water (dw), the visibility would be improved; however, it can result in dangerous complications especially in younger age groups.(1) in transurethral resection of the prostate (turp), this manifestation is called tur syndrome which includes cardiovascular and neurologic derangements. absorption of irrigation fluid during pcnl has also been reported, and a variety of significant complications have been reported.(2-5) some studies have evaluated the absorbed fluid by breath-alcohol test.(6) in our center, two cases with hyponatremia were occurred in children using dw as an irrigation fluid for pcnl, which is routine in urology practice; because it is cheaper than saline solution and is more available in large amounts at some health centers. in this study, we compared dw and saline solution (ss) as irrigation fluid during pcnl in adult patients (≥ 19 years old). materials and methods in this study, we considered more than 2 meq/l of depletion in serum sodium level as a significant change. considering α = 0.05 and 90% power, the sample size was calculated as 38. since we work in a center with a high rate of pcnl operation, 328 patients including 191 men and 137 women were included in this study. exclusion criteria were patients with solitary kidney and abnormal renal function (serum creatinine level > 2.3 mg/dl). thus, 8 patients were excluded from the study and as a results 320 patients were randomly divided into two groups. group 1 included 158 patients and group 2 consisted of 162 patients. patients with stone above the ureteropelvic junction level, and more than 2 cm in diameter were included. the minimum age for inclusion into this study was 18 years. no upper limit for stone size or age was considered. informed consent was signed by all patients prior to the operation, and the study was conducted based on the approval of ethical committee of shiraz university of medical sciences. in group 1 dw and in group 2 ss was used as the irrigation fluid during the operation. all patients were evaluated by intravenous urography (ivu), and complete blood count (cbc), coagulation profile, blood urea nitrogen (bun), creatinine (cr), sodium (na+) and potassium (k+) levels were determined; urine analysis and urine culture before operation were also performed. the patients were admitted 6 hours before the operation and received intravenous antibiotic (cephalotin 1 g) and 125 ml/h of intravenous fluid (33.3% dextrose 5% + 66.6% saline 0.9%) and oral diet was started about 12 hours after the operation. blood sample was taken just before, at the end, 6 and 12 hours after operation for determining the serum hemoglobin (hb), bun, na+, k+ and cr levels. pcnl was performed in the prone position, under general anesthesia after insertion of a 6 french (f) ureteral catheter. fluoroscopy guidance was applied for nephrostomy tract creation, and metal telescopic dilator system was used for tract dilation and pneumatic lithotripsy was used for stone fragmentation. when multiple calyceal stones or a staghorn stone was present, two tracts were created. since fluid irrigation was the main variant of the study, operation time was considered from when nephroscopy was started and it lasted until the removal of nephroscope. the patients were visited for clinical signs of hyponatremia such as lethargy, restlessness, headache, nausea, vomiting, confusion and seizure. the diet was started 12 hours after the operation. stone-free state was defined as no residual stone in postoperative kidney urinary bladder (kub) xrays. it is the most common definition for stone-free state in the literature.(7) urinary tract ultrasonography was requested if the stone was nonopaque in x-ray images. ureteral stent and urethral catheter were removed 12 to 24 hours after the operation depending on the patients' condition, and the patients were usually discharged from hospital two days post-operatively. no nephrostomy tube was inserted for patients. the data were analyzed using chi-square test, student t test or paired t test, and the p value less than .05 was considered as significant. 1553vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l distilled water as safe as saline for irrigation | mehdi hosseini et al results no significant preoperative difference was seen between the groups considering the stone size, serum hb, bun, k+ and cr levels, but significant differences in age and serum sodium level were noted (table 1). before the operation, eight patients were excluded from the study because they had one or more exclusion criteria. fourteen patients were excluded after the operation due to perforation of collecting system, prolonged operation time (> 90 minutes), or high irrigation volume (> 15 liters) used. the stone-free rates were 92.76% and 94.15%; the mean operation times were 57 and 65 minutes, and the mean irrigation volume were 10.4 and 10.6 liters in groups 1 and 2, respectively. complications included fever (5 vs. 3), perforation of pelvicalyceal system (1 vs. 2), bleeding (3 and 5), and transfusion (2 and 2) in groups 1 and 2, respectively (table 2). table 1. demographic and clinical characteristics of study population. variables group 1 (n = 158) group 2 (n = 162) p gender no. (%) gender male 94 (58) 97 (58) na women 67 (42) 70 (42) na mean age (years) 134 (70-170) 36.8 ± 6.8 .004 mean stone size (mm) 29 ± 12 30 ± 14 .021 site of kidney right kidney 86 66 na left kidney 72 96 .018 mean serum parameters hemoglobin (mg/dl) 14.3 ± 2.3 14.6 ± 2.5 .25 bun (mg/dl) 17.3 ± 3.5 16.9 ± 2.5 .23 creatinine (mg/dl) 1.2 ± 0.8 1.2 ± 0.9 .75 sodium (meq/l) 138 ± 75 136 ± 8.3 .02 potassium (meq/l) 4.4 ± 1.9 4.5 ± 2.1 .65 key: bun, blood urea nitrogen. table 2. data in study groups. variables group 1 (n = 152) group 2 (n = 154) p stone-free rate, % 92.76 94.15 .651 mean operation time (min) 57 ± 34 65 ± 41 .064 mean irrigant volume (liters) 10.4 ± 5.8 10.6 ± 6.9 .784 mean hospital stay (days) 2.2 ± 1.1 2.5 ± 1.3 .030 fever (t ≥ 38◦c), no. (%) 5 (3.28) 3 (1.94) .499 bleeding, no. (%) 3 (1.97) 5 (3.24) .722 transfusion, no. (%) 2 (1.3.1) 2 (1.29) 1.0 pelvicalyceal system perforation, no. (%) 1 (0.65) 2 (1.29) 1.0 operation time > 90 min, no. (%) 3 (1.97) 4 (2.59) 1.0 irrigant > 15 liters, no. (%) 2 (1.31) 2 (1.29) 1.0 1554 | the mean serum na+ level in group 1 significantly decreased 6 and 12 hours after the operation. also, it significantly decreased in group 2 just after the operation, and 12 hours later; however, serum na+ level in group 2 showed no significant changes 6 hours after the operation. changes in the serum level of na+ were significantly greater in group 1 compared to group 2, in all postoperative measurements (tables 4 and 5). fortunately, no case of tur syndrome was seen. the mean blood hb level decreased at the end of operation in both groups, but it remained in normal range without any significant difference in both groups. the mean serum bun and cr levels increased in both groups postoperatively. the mean serum k+ level also showed minimal changes without any statistical significance (table 3). discussion pcnl is a commonly used technique for treatment of kidney stones, and has significant advantages in comparison to open stone surgery. these advantages include lower morbidity rate, decreased amount of postoperative pain, minimal surgical scars, and faster postoperative recovery. complications include hemorrhage, fever, infection, pneumothorax, colon perforation, extravasation and etc. the absorption of irrigation fluid during this operation causes tur syndrome in some cases. this dangerous complication occurred when a hypoosmolar fluid is used.(8-14) most authors have suggested ss as the best fluid for irrigation due to its isoosmolar properties. when electro-surgery is used, ion-free fluids such as glycine or dw are preferred. (1,3,15) hahn found that hyponatremia is depended on both volume of fluid absorption and the time of turp.(16) amr hawary and colleagues reported that the rate of tur syndrome is related to the type of irrigating fluid, operation time, patient position, prostate size, fluid bag height, surgeon experience, intraprostatic vasopressin injection, table 3. perioperative laboratory data in study groups.* variables group 1 group 2 hb bun cr k hb bun cr k before operation 14.4 17.1 1.14 4.4 14.8 16.2 1.18 4.3 at the end of operation 13.2 22.4 1.3 4.4 13.3 21.8 1.24 4.3 six hours after operation 13.5 22.6 1.34 4.3 13.4 22.1 1.28 4.3 twelve hours after operation 13.6 22.1 1.32 4.5 13.7 22.7 1.28 4.6 keys: hb, hemoglobin (g/dl); bun, blood urea nitrogen (mg/dl); cr, creatinine (mg/dl); k, potassium (meq/l). * data are presented as means. table 4. comparison of serum sodium levels (meq/l) at different times in study groups.* study groups group 1 p group 2 p before operation 138 ± 7.5 136 ± 8.3 ns at the end of operation 132 ± 6.5 < .0001 132 ± 7.1 < .0001 6-hour postoperatively 132 ± 7.0 .23 135 ± 6.9 < .0001 12-hour postoperatively 135 ± 7.3 < .0003 134 ± 6.7 4.5 key: ns, not significant. * all reported p values are compared to baseline. endourology and stone disease 1555vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l low pressure irrigation and etc. they have mentioned that “an ideal irrigating fluid should be isotonic, nonhemolytic, electrically inert, nontoxic, transparent, easy to sterilize and inexpensive”. glycine, crystal and physiological saline have been recommended to be used as irrigation fluid in turp. (17) in the present study, distilled water has been compared to physiological saline in respect of tur syndrome clinical signs and subclinical hyponatremia. aghamir and colleagues compared sterile water and isotonic saline solution as irrigation fluid in pcnl. they looked for blood hb level drop, haptoglobin level, electrolyte level and any sign of tur syndrome. they found no significant difference between dw and saline for their safety. they introduced dw as a safe and inexpensive irrigation fluid during pcnl operation.(18) gariou and colleagues investigated the amount of glycine absorption during pcnl. they indicated that glycine can cause a significant hemo-dilution in pcnl compared to turp. they suggested that ss is a proper irrigation fluid for pcnl. (19) in another study, 1.5% glycine induced post-nephrolithotomy syndrome in 2% of the patients. this study was conducted by fellahi and his colleagues, and they have reported that physiologic saline is a better choice for pcnl.(20) in contrast, some studies showed no significant derangement with hypotonic solution such as water. they have suggested that these solutions are as safe as physiological saline solution during pcnl.(21-23) in the present study, the effect of physiological saline solution and dw was compared on blood hb, bun, cr, and especially na+ levels. na+ is the main effective ion in tur syndrome. as we demonstrated, a significant decrease in serum na+ level was found in group 1 (distilled water) in comparison to group 2 (saline solution). this difference was in the normal range of serum sodium level. because no clinical case of tur syndrome was observed, this change was considered clinically insignificant. conclusion distilled water can be used for pcnl in adult patients, while postoperative serum na is monitored. its usage needs some precautions. the authors do not recommend dw as an irrigation fluid for pediatric patients. acknowledgement the authors would like to thank mr. abdolhossein hanaee for his assistance, and mrs. salami for her cooperation and typing the draft. conflict of interest none declared. distilled water as safe as saline for irrigation | mehdi hosseini et al table 5. comparison of serum sodium (meq/l) changes between the study groups compared to baseline. study groups at the end of operation 6-hour post-operatively 12-hour post-operatively* group a -6 ± 2.3 -6 ± 2.3 -3 ± 2.1 group b -4 ± 1.4 -1 ± 1.3 -2 ± 1.6 p < .0001 < .0001 < .0001 references 1. zeltser i, pearle ms, bagley dh. saline is our friend. urology. 2009;1:28-9. 2. mohta m, bhagchandani t, tyagi a, pendse m, sethi ak. hemodynamic, electrolyte, and metabolic change during percutaneous nephrolitotomy. int urol nephrol. 2008;40:477-82. 3. schultz re, hanno pm, wein aj, levin rm, pollack hm, van arsdalen kn. percutaneous ultrasonic lithotripsy: choice of irrigant. j urol. 1983;130:858-60. 4. köroğlu a, toğal t, ciçek m, kiliç s, ayas a, ersoy mo. the effect of irrigation time on fluid volume and irrigation time on electrolyte balance and hemodynamics in percutaneous nephrolithotripsy. int urol nephrol. 2003;35:1-6. 5. chou ch, chau t, yang ss, lin sh. acute hyponatremia and renal failure following percutaneous nephrolithotomy. clin nephrol. 2003;59:237-8. 6. stalberg hp, hahn rg, wayne jones a. ethanol monitoring of transurethral prostatic resection during inhaled anesthesia. anesth analg. 1992;75:983-8. 7. deters la, jumper cm, steinberg pl, paris jr vm. evaluating the definition of "stone free status" in contemporary urologic literature. clin nephrol. 2011;76:354-7. 8. alken p, hutschenreiter g, gunther r, marberger m. percutaneous stone manipulation. j urol. 1981;125:463-6. 1556 | 9. grammo e, balianger p, dore b, aubert j. hemorrhagic complications during percutaneous nephrolithotomy. retrospective study of 772 cases. prog urol. 1999;9:460-5. 10. kukreja ra, desai mr, sabins rb, patel sh. fluid absorption during percutaneous nehprolithotomy: does it matter? j endourol. 2002;16:221-5. 11. cadeddu ja, chen r, bishoff j, micali s, kumar a, moore rg, kavoussi lr. clinical significance of fever after percutaneous nephrolithotomy. urology. 1998;52:48-50. 12. goswami ak, shrivastava p, mukherjee a, sharma sk. management of colonic perforation during percutaneous nephrolithotomy in horse-shoe kidney. j endourol. 2001;15:989-91. 13. stables dp, ginsberg ns, johnson ml. percutaneous nephrostomy: a series and review of the literature. ajr am j roentgenol. 1978;130:75-82. 14. rao pn. fluid absorption during urological endoscopy. br j urol. 1987;60:93-9. 15. hahn ru. early detection of the tur syndrome by marking the irrigation fluid with 1% ethanol. acta anaesthesiol scand. 1989;33:146-51. 16. hahn ru. relations between irrigant absorption rate and hyponatremia during transurethral resection of the prostate. acta anaesthesia scand. 1988;32:53-60. 17. harway a, mukhtar k, sinclair a, pearce i. transurethral resection of prostate syndrome: almost gone but not forgotten. j endourol. 2009;23:2013-20. 18. aghamir smk, alizadeh f, meysamie a, assefi rad s, edrisi l. sterile water versus isotonic saline solution as irrigation fluid in percutaneous nephrolithotomy. urol j. 2009;6:249-53. 19. cariou g, le duc a, serrie a, cortesse a, teillac p, ziegler f. reabsorption of the irrigation solute during percutaneous nephrolithotomy. ann urol. 1985;19:83-6. 20. fellahi jl, richard jp, bellezza m, autonini a, thouvenot jp, cathala b. the intravascular transfer of glycine during percutaneous kidney surgery. cah anesthesiol. 1992;40:343-7. 21. feizzadeh b, doosti h, movrrekh m. distilled water as an irrigation fluid in percutaneous nephrolithotomy. urol j. 2006;3:208-11. 22. falahatkar s, khosropanah i, atrkar roshan z, golshan m, emadi sa. decreasing the complications of pcnl with alternative technique including complete supine pcnl and subcostal approach. pak j med sci. 2009;25:353-8. 23. grundy pl, budd dwg, england r. a randomized controlled trial evaluating the use of sterile water as an irrigation fluid during transurethral electro vaporization of the prostate. br j urol. 1997;80:894-7. endourology and stone disease unclassified anastomosing hemangioma incidentally found in kidney or adrenal gland: study of 10 cases and review of literature jun zhou1*, xiaoqun yang1*, luting zhou1,ming zhao2, chaofu wang1 purpose: to describe and report a series of renal and adrenal anastomosing hemangioma (ah) and to investigate its distinctive clinicopathologic features and review its clinical data available in the literature. materials and methods: clinical data of 10 ahs were retrospectively studied. imaging and histologic features were re-evaluated and summarized. immunostaining markers performed include cd31, cd34, erg, fil-1, d2-40, ae1/ae3, sma, cd10, hhv8, s100, ki-67. a follow-up of all cases was performed. other ahs published in pubmed and web of science were reviewed. results: all of 10 ahs were found incidentally in 5 female and 5 male patients (median age, 48.5 years; mean, 51.7 years) and involved unilateral kidney (n=7) and adrenal glands (n=3) respectively. all lesions were well-defined in imaging and histologic examination. ahs were morphologically characterized by prominent anastomosing vascular channels without evidence of infiltration to surrounding normal tissues and significant cellular atypia. cd31, cd34, erg were positive and ki-67 showed typically low positivity (< 3%). all patients underwent a mass resection and none of them had evidence of recurrence. together with other cases published, the ahs showed distinctive clinicopathologic features with an excellent prognosis. conclusion: renal or adrenal ah is a very rare vascular tumor. they have distinctive histologic features and a favorable prognosis. it is frequently mimicking well-differentiated angiosarcomas which easily results in unnecessary overtreatment in clinical practice. keywords: anastomosing hemangioma; clinicopathology; prognosis; kidney; adrenal gland introduction vascular tumors are large and heterogeneous en-tities with varying endothelial differentiation.(1) their complex categorization and clinical-biologic behaviors are usually not familiar to the clinicians.(2) so are the pathologists due to the broadly morphologic and relevant little genetically available information for the majority of vascular lesions and hence the differential diagnosis could be pretty challenging.(3) primary benign vascular lesions arising in the kidney or adrenal gland are distinctly rare, among which arteriovenous malformation, angiomatous endothelial cysts, hemangioma, and angiosarcoma are the most common types.(4,5) anastomosing hemangioma (ah), a very rare vascular tumor and was firstly described by montgomery and epstein in 2009.(6) one issue of concern for ah is mimicking malignancy histologically that may result in unnecessary overtreatment. although ah was originally considered to be a distinct vascular tumor exclusively 1department of pathology, ruijin hospital, shanghai jiaotong university school of medicine shanghai, china. 2department of pathology, zhejiang provincial people’s hospital, hangzhou, zhejiang, china. * j. z. and x. y. contributed equally. *correspondence: department of pathology, ruijin hospital, shanghai jiaotong university school of medicine, no. 197 ruijin er road, huangpu district, shanghai, 200025, china, tel: +86 17321086332, e-mail: wangchaofu@126.com. *department of pathology, ruijin hospital, shanghai jiaotong university school of medicine, no. 197 ruijin er road, huangpu district, shanghai, 200025, china, tel: +86 17701879546, e-mail: yangxiaoqun963@163.com. received may 2020 & accepted august 2020 occurring in the genitourinary tract, the following reports indicated they can develop in various anatomic locations such as soft tissue, liver, colon, bladder, skin, etc.(7-10) although some renal and adrenal ahs were sporadically reported, most pathologists and clinicians are still unfamiliar with this entity. herein, we added 10 ahs arising in the kidney or adrenal gland ah to further investigate their clinicopathologic features and emphasize its diagnostic pitfalls and mimickers. materials and methods subjects this study was approved by the institutional review board at the department of pathology, ruijin hospital, shanghai jiaotong university school of medicine (shanghai, china). a total of 10 patients specimens entered our study, including 2 consultant cases and 8 surgical specimens. all of them have complete clinical data. all hematoxylin and eosin (he)-stained (dako urology journal/vol 17 no. 6/ november-december 2020/ pp. 650-656. [doi: 10.22037/uj.v0i0.5514] coverstainer; agilent, santa clara, ca, usa) slides were independently reviewed by 2 experienced pathologists (c.f.w. and j. z.) under a light microscope (bx43; olympus corporation, tokyo, japan). follow-up was performed in the office setting or by telephone interview. immunohistochemistry (ihc) ihc evaluation of consultant cases was recorded according to the submitted immunostaining slides. each surgical specimen was specially re-sectioned. 4-μm thick sections were taken from 10% formalin-fixed and paraffin-embedded tissue blocks followed by immunohistochemical staining using commercially available antibodies as follows: cd31 (monoclonal, prediluted; dako, glostrup, denmark ), cd34 (qbend, prediluted; dako, glostrup, denmark), erg (ep111, 1:200 dilution; zsgb-bio, beijing, china), fil-1(mrq-1, 1:50 dilution; zsgb-bio, beijing, china), d2-40 (d240, prediluted, dako, carpinteria, ca, us), ae1/ae3 (ae1/ae3, prediluted; dako, carpinteria, california, usa), sma(1a4, 1:200; zsgb-bio, beijing, china), cd10(56c6, 1:100 dilution; leica biosystem, newcastle, uk), hhv8(ln35, 1:100 dilution; abcam, hongkong, china), s100 (polyclonal, prediluted; dako, glostrup, denmark), and ki-67 (mib-1, prediluted; dako, glostrup, denmark). detection of antibody binding was obtained using the universal immunoperoxidase polymer method (envision-kit; dako, carpinteria, ca, usa). a dako automated immunohistochemistry system (dako, carpinteria, ca, usa) was performed according to the manufacturer's protocol. the ihc results were independently interpreted by 2 experienced pathologists (l. z. and c.f.w.). literature review and data analysis literature in pubmed and web of science before april 2019 were reviewed. only the cases that met the diagnosis of ah and had complete clinicopathologic and follow-up data entered our analysis. descriptive statistics of the common features of ahs (epidemiology, demography and clinical features) were performed using the ms-office 2016 excel software (microsoft, redmond, wa, usa). results clinical features and follow-up as a regional consultation and treatment center, the patients in our group mainly came from the eastern china during april 2015 to january 2019. the main clinical data of ahs are summarized in table 1. a total of 8 renal and 2 adrenal lesions in 5 females and 5 males, ranging in age from 28 to 71 years (median, 48.5 years; mean, 51.7 years) were investigated. all the patients were asymptomatic and laboratory test results did not show significant abnormalities. each lesion was accidentally found by routine physical examination, 1 of which was appreciated by imaging before her preoperative preparation for hepatic carcinoma. all lesions anastomosing hemangioma-xiaqun et al. unclassified 651 figure 1. represented imaging features of ah. a contrast-enhanced ct scan showed a well-circumscribed solid tumor in the right kidney with peripheral enhancement at the arterial phage (a. axial; b. coronal), and homogeneous enhancement at portal phase (c). coronal enhanced ct demonstrated a homogeneous enhanced lesion arising on the adrenal gland at arterial phage (d). demonstrated a blurred mass with a soft-tissue density in computed tomography (ct), 8 cases showed peripheral enhancement at arterial phage and homogeneous enhancement at portal phase (figure 1a-c); 2 cases directly displayed diffuse even enhancement at arterial phage (figure 1d). all ahs were generally small, ranging in size from 0.8 to 3.9 cm (mean, 2.0 cm; median, 2.0 cm). all follow-up data were available, showing no evidence of recurrence (average follow-up 33 months, range 10 to 46 months). pathologic features grossly, the tumors imparted gay-red or purple-red solid appearance. microscopically, all ahs were well-circumscribed and unencapsulated (figure 2a). they typically consisted of anastomosing capillary-like vascular channels with no or mild atypia of tumor cells (figure 2b). mitosis was consistently absent. alternating cellular (figure 2c) and acellular regions were readily apparent in 4 cases (cases 1, 2, 8 and 9). the acellular areas were characterized by loosely edematous or hyaline stroma (figure 2d). proliferated vessels formed the glomerulus-like structure in 2 cases (cases 1, and 6). case 10 had focally and centrally fibrosis. extramedullary hematopoiesis (case 2), extracellular eosinophilic granular materials (case 1, figure 2e), or foamy cells (case 4, figure 2f) were also seen. immunohistochemically, tumor cells of all the cases were consistently positive for vascular endothelial markers including cd31, cd34 (figure 3a), erg (figure 3b), and fli-1. none of the cases were immunoreactive for ae1/ae3, ema, pax8, cd10, sma, hhv8, s100, and d2-40. the proliferative index labeled by ki-67 was typically low (range, 1%-4; mean, 2.2%; figure 3c). clinical features summarized from publication almost all ahs in the available literature were included to summarize the clinicopathologic features. (4,6-34) as depicted in figure 4a, the 131 cases ahs (including our 9 cases) mostly reported from north america figure 3. immunophenotype of ah. the tumor cells expressed cd34 (a; magnification, 200×) and erg (b; magnification, 200×), with a low proliferated index ki-67 (c; staining h&e; magnification, 100×). figure 2. histologic features of ah. low power showed a well-delineated lesion developing in the renal parenchyma (a, staining h&e; staining h&e; magnification, 40×). at medium power, ah was characterized by prominent anastomosing vascular lining by singly bland endothelial cells (b, staining h&e; magnification, 200×). cellular regions were a florid proliferation of interconnecting capillary-like vessels (c, staining h&e; magnification, 100×). this adrenal ah showing distinct loosely edematous stroma may obscure the anastomosing growth pattern (d, staining h&e; magnification, 40×), however, the typical growth areas can be focally appreciated (inset). eosinophilic granular materials (e, staining h&e; magnification, 200×), or foamy cells (f, staining h&e; magnification, 200×) was occasionally seen. anastomosing hemangioma-xiaqun et al. vol 17 no 06 november-december 2020 652 unclassified 653 (68%), asia (17%), and europe (11%). the patient's age ranged from 2 to 85 years (mean, 55.9; median, 56 yr.) with female average age slightly older than male. of available cases, 80% is found incidentally without related symptoms (figure 4c), and the remaining adopts pain, palpable mass, paresthesia, pleural effusion, neurologic deficits, hematuria, and other concurrent tumors (hepatic, renal, ovarian, endometrial carcinoma, etc.). among all renal ahs, 24.4% associated with end-stage renal disease (esrd). (4,18,25,30,31,34,35) various involved anatomic locations were has been appreciated with the majority developing in kidney (n=51, 38.3%), spinal/ paraspinal region (n=20, 15%), adrenal gland (n=18, 13.5%), and liver (n=9, 6.8%) (figure 4d). ah is usually solitary, but multiple lesions are also appreciable (figure 4e); locations of the latter include kidney (45%), liver (20%), adrenal gland (10%), intestine (10%), paraspinal region (5%), ovary (5%), and breast (5%). the tumor can be solid, cystic, and solid-cystic in either imaging or gross examination (figure 4f), ranging in size from 0.5 to 12 cm (mean, 3.0 cm; median, 2.6 cm; figure 4g). identical to the most reported cases, all tumors in our series were asymptomatic and found incidentally. as depicted in figure 4h, the reported ways of resection are listed as follows by decreasing percentage: simple lesion resection (47%), organ resection (26%), partial organ resection (18%), radical resection (9%). almost all the patients were alive without evidence of disease during the follow-up (range: 1 to 156 months; median, 14 months; mean, figure 4. clinical data of ah from literature. the cases reported from a distinct region around the world, most of which derived from north america (a). the female average age is slightly older than male (b). most of the tumors were incidentally found (c). various involved locations were reported as yet, of which the most location was kidney (d). the majority demonstrated solitary lesion, but a subset of multiple lesion can also be appreciable (e). the texture of ah can be solid, cystic and solid-cystic (f). the tumors ranged in size from 0.5 to 12 cm, most of which clustering in 0.5 to 3.5 cm (g). the surgical method includes simple lesion resection, organ resection, partial organ resection, radical resection (f). anastomosing hemangioma-xiaqun et al. 26.2 months), except that one patient was dead after 107 months since ah arising in the explant was found. discussion hemangioma is a common soft tissue lesion and frequently arise in skin and subcutis.(7) the renal or adrenal hemangiomas are relatively rare, some of which have underlying other vascular diseases, such as sturge-weber syndrome, klippel-trenaunay syndrome, von hippel-lindau syndrome or systemic angiomatosis. (36-39) ah is an extremely rare benign tumor. although cases of ahs have been continuously reported since 2009, most arein the form of case reports, many clinicians were still unfamiliar with this entity. originally, it is uncertain whether ahs represent a bona fide endothelial tumor or reactive or malformation.(7) however, from the views of the pathologist, the distinct morphologies resemble hemangioma, suggesting their tumor nature(7). recently, recurrent gnaq and gna14 mutations were discovered in ah, supporting a role for this pathway in the pathogenesis of ahs and further indicating its true tumor nature.(11,28) clinically, unlike the other vascular lesions, ahs tend to be asymptomatic without typical manifestation such as hematuria or flank pain(40). therefore, it’s difficult to early find this lesion unless in few patients associated with some symptoms or esrd who need additional renal examination. radiologically, non-contrast ct may show hypodense solid or cystic lesions and contrast-enhanced ct usually exhibits homogeneous enhancement or heterogeneous enhancement in the periphery. (9,16,24,33) however, imaging also seems not to help in differentiating ahs from other mimickers(15), although the angiosarcomas or renal cell carcinomas commonly demonstrate central necrosis that large ahs still can have.(32) the rarely possible pre-operative diagnosis by radiologic studies may give rise to clinically conservative management.(16) laboratory biologic markers do not also help to recognize this disease. nonetheless, the risk of ahs in patients who suffer from the chronic renal disease should be noted, due to its association with esrd, particularly when there are relevant symptoms. histologically, ah is typically well-demarcated without evidence of peripherally infiltration and neoplastic necrosis, the features practically pathognomonic when making a diagnosis.(4) it is characterized by interconnected sinusoidal capillary-like vessels lined by hobnail or flat endothelial cells with no obvious atypia, multilayering, and mitosis, although focal regions may demonstrate dilated cavernous-like vasculature.(9,30,33) some cases have prominent sclerotic areas and hence form an alternating acellular and hypocellular pattern. (33) mast cells with dark granules sometimes could be appreciable, which is likely to be considered as atypical endothelium resulting in a misdiagnosis of malignancies.(7,34) in the peripheral regions of ahs, one usually finds the thrombotic fibrin-filled vessels, another feature of this entity.(7) tumor cells prototypically stain positive with endothelial markers such as cd31, cd34, erg, factor viii-related protein. the flagship diagnostic differentiation from ah is well-differentiated angiosarcoma due to its deficiency in limited atypia at times. the prominent anastomosing growth pattern is traditionally considered as a practically pathognomonic feature of angiosarcoma. the morphologic overlap between these two may facilitate diagnostic pitfalls, particularly for the junior pathologist or in the small biopsy. in a contrast to well-differentiated angiosarcoma, ah does not show prominent nuclear atypia, increased proliferative activity, and mitosis, as well as multilayering of tumor cells.(7,13) necrosis, other than some cases with regressive changes, is usually not present in ah.(13) however, a subset of highly differentiated sarcomas only shows very little atypia thoroughly, which may obscure their true malignant nature and give rise to erroneous diagnosis when telling ahs apart from angiosarcomas. the most crucial and consistent features are that contrary to ahs, angiosarcomas always have an infiltrative border with extensive destruction of renal parenchymal, peripheral collagen or adipose tissue.(4) papillary endothelial hyperplasia (masson’s tumor) can also form loosely anastomotic vascular structures mimicking ah or angiosarcoma, but the intravascular growth and reactive vessel wall can provide useful diagnostic clues(41). concerning the treatment to ahs, the mainstay in the surgical resection. as discussed above, the primary surgical way of ahs is lesion resection only due to the difficulty to recognize their true nature of aggressiveness. no matter what surgical procedures were taken, almost all patients lead a calm period in the follow-up. anyway, the long-term follow-up data further support the bona fide benign biologic behavior of ah that warrants the surgeon's consideration to avoid unnecessary overtreatments, such as radical resection, extended lymph node dissection, and unnecessary pre-/post-operative chemotherapy or radiotherapy(42,43). however, there has been no consensus on the treatment for ahs. if the biopsy diagnosis can be established, the concrete treatments such as embolization, lesion resection, partial or total nephrectomy may depend on the lesion size, location, and presence of symptoms(32). in our series, the surgical ways included lesion resection, organ resection, partial organ resection, none of the patients have evidence of recurrence, metastasis, and death, further indicating the innocent nature of ah. conclusions renal or adrenal ah is a very rare vascular tumor. they have distinctive histologic features and 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mehravaran k, kashi ah. laser treatment for urethral hemangiomas: report of three cases. urol j. 2017;14:3094-9. 41. hashimoto h, daimaru y, enjoji m. intravascular papillary endothelial hyperplasia. a clinicopathologic study of 91 cases. am j dermatopathol. 1983;5:539-46. 42. capitanio u, becker f, blute ml, et al. lymph node dissection in renal cell carcinoma. eur urol. 2011;60:1212-20. 43. bindayi a, hamilton za, mcdonald ml, et al. neoadjuvant therapy for localized and locally advanced renal cell carcinoma. urol oncol. 2018;36:31-7. anastomosing hemangioma-xiaqun et al. urol_v03_no4_001_editorial.indd endourology and stone disease 208 urology journal vol 3 no 4 autumn 2006 distilled water as an irrigation fluid in percutaneous nephrolithotomy behzad feizzadeh, hassan doosti, mohammad movarrekh introduction: the aim of this study was to evaluate the effect of distilled water as an irrigation fluid for percutaneous nephrolithotomy (pcnl) on the serum concentrations of sodium. materials and methods: a total of 30 patients with kidney calculi underwent tubeless pcnl using distilled water as the irrigation fluid. during the procedure, intravenous ringer lactate solution was used if necessary. the patients received infusion of two-thirds dextrose 5% and one-third normal saline solution postoperatively. four blood samples were taken to determine serum sodium and potassium levels at admission, just before the operation, after the operation, and on the first postoperative day. results: the mean distilled water used was 8.1 l (range, 5.6 l to 11.2 l). target and complete stone-free rates were 100% and 80%, respectively. none of the patients developed hyponatremia. the mean serum levels of sodium (meq/l) were 141.5 (range, 140 to 143), 140.7 (range, 125 to 159), 139.7 (range, 125 to 164), and 138.9 (range, 125 to 146), respectively (p = .005). comparing every 2 samples, a significant difference was seen only between samples 1 and 4 (p = .005). serum levels of potassium were all in normal range and there was no difference between the 4 samples (p = .12). conclusion: our findings showed that using distilled water as an irrigation fluid during pcnl does not result in a clinically significant decrease in the serum level of sodium and can be used if necessary. however, evaluation of the serum sodium level on the postoperative day is mandatory. urol j (tehran). 2006;4:208-11. www.uj.unrc.ir keywords: distilled water, percutaneous nephrolithotomy, kidney calculi, hyponatremia department of urology, qaem hospital, mashhad university of medical sciences, mashhad, iran corresponding author: behzad feizzadeh, md ghaem hospital, mashhad, iran tel: +98 511 841 7404 e-mail: behzadfeizzadeh@yahoo.com received april 2006 accepted september 2006 introduction percutaneous nephrolithotomy (pcnl) is the preferred method of treatment for complex kidney calculi and may be performed solely or as a part of a sandwich therapy.(1,2) the irrigation fluid routinely used during the pcnl has systemic absorption and results in hemodilution similar to the fluid absorption in transurethral prostate resection.(3) also, there are some published studies that have reported hyponatremia after pcnl.(4,5) to prevent this complication, normal saline has been recommended for irrigation purposes.(6) to our best knowledge, there is no study on the safety of using distilled water in pcnl and its effect on the serum levels of sodium. distilled water is available and cheap, but the risk of hyponatremia can be high with it. however, we had been using distilled water for pcnl in our center during the past years due to limitations in the availability of appropriate irrigation fluids. since we did not experience any significant complication, we decided to evaluate the effect of distilled water as the irrigation fluid for pcnl on the level of serum sodium. distilled water for percutaneous nephrolithotomy—feizzadeh et al urology journal vol 3 no 4 autumn 2006 209 materials and methods between august 2005 and january 2006, 30 patients with kidney calculi were randomly selected and enrolled in our study. they were all candidates for tubeless pcnl. this study was approved by the review board of mashhad university of medical sciences and all of the patients provided informed consent. the inclusion criteria were normal serum creatinine level, normal serum sodium (≥ 135 meq/ l), unilateral pcnl in one session, using one access site, and no extensive extravasation. intravenous urography (ivu) was performed and laboratory studies including complete blood count, blood urea, serum creatinine, urinalysis, and urine culture were done for all patients. the laboratory studies were repeated 1 day after the operation, as well as plain abdominal radiography (kidney, ureter, and bladder [kub]) and ultrasonography. four additional blood samples were taken to determine serum sodium and potassium levels; sample 1, at admission; sample 2, just before the operation; sample 3, after the operation (in recovery room); and sample 4; on the first postoperative day. the reference ranges for serum levels of sodium and potassium were 135 meq/l to 145 meq/l and 3.7 meq/l to 5.2 meq/l, respectively. percutaneous nephrolithotomy was performed using distilled water instead of other irrigation fluids. the height of water was about 100 cm above the patients’ body level. anesthesia was achieved by a same method for all patients: induction with thiopental, 5 mg/kg; atracurium, 0.5 mg/kg; and fentanyl, 2 µg/kg. it continued using halothane, 0.6% to 0.7%, and atracurium, one-third of the initial dose, every 30 minutes. if necessary, ringer lactate solution was infused intravenously during the procedure. the patients received infusion of two-thirds dextrose 5% and one-third normal saline solution after the procedure (1000 ml for the first 10 kg, 500 for the second 10 kg, and 20 ml/kg, for the remaining body weight). the operative time, from the first incision to its suturing, was recorded. the amount of the used distilled water, body mass index (bmi), complete and target stone-free rates, hospital stay, and the history of previous interventions were also recorded. complete stone-free status was considered as not having a calculus larger than 5 mm.(7) the sizes of the calculi were measured in millimeters by kub and ultrasonography (for nonopaque calculi). the data of the patients were analyzed by spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa) and the statistical tests including repeated measures and bonferroni test were used. results the clinical and demographic characteristics of the patients are listed in table 1. in all patients, pcnl was performed using the access from the inferior calyx. the mean operative time was 46.1 minutes (range, 25 to 120 minutes; 95% confidence interval [ci] = 38.82 to 53.30), and the mean distilled water used was 8.1 l (range, 5.6 l to 11.2 l; 95% ci = 6.88 to 9.31). target stone-free rate was 100%, while complete stone-free rate was 80%. the mean hospital stay was 2.3 days (range, 2 to 4 days; 95% ci = 2.05 to 2.54). the serum levels of sodium and potassium are listed in table 2. all the measured electrolytes were within the reference ranges. none of the patients developed hyponatremia and no transfusion was required. the mean serum level of sodium showed a decreasing trend within the reference range. using the repeated table 1. patients’ demographic and clinical characteristics* characteristics values mean age (range), y 45.2 (10 to 73) male/female 16/14 mean bmi (95% ci), kg/m 2 24.84 (23.20 to 26.65) mean calculus size (range), mm 37.9 (25.0 to 75.1) side of calculi right 11 (36.7) left 19 (63.3) location renal pelvis 13 (43.3) renal pelvis and the lower calyx 7 (23.3) superior calyx 3 (10.0) inferior calyx 2 (6.7) superior ureter 1 (3.3) staghorn 4 (13.3) previous interventions open surgery 2 (6.7) swl 1 session 7 2 sessions 0 3 sessions 1 transurethral pneumatic lithotripsy 3 *values in parentheses are percents unless otherwise indicated. swl indicates shock wave lithotripsy. distilled water for percutaneous nephrolithotomy—feizzadeh et al 210 urology journal vol 3 no 4 autumn 2006 measurement method, the 4 samples where different significantly (p = .005; figure). using the bonferroni test (for comparison of every 2 samples), a significant difference was seen only between samples 1 and 4 (p = .005). serum levels of potassium were all in normal range and there was no difference between the 4 samples (p = .12). discussion absorption of the irrigation fluid during the endoscopic procedures has been reported even in ureteroscopy.(8) since 1980, when pcnl began to be routinely used, glycine 1.5% has been used as the irrigation fluid in this procedure. in a study on 12 patients, it was revealed that the systemic absorption exists in the pcnl procedure similar to the transurethral resection of prostate.(3) in another study on 150 patients, glycine 1.5% induced hyponatremia during the pcnl (a postnephrolithotomy syndrome) in 2% of the patients, and therefore, normal saline was recommended to be used instead.(9) in a study on 32 patients for whom ethanol 1% was used for monitoring the absorption of the irrigation fluid, it was revealed that a mean volume of 696.7 ml was absorbed during pcnl.(10) in a similar study on 148 patients, none of them showed electrolyte imbalance and it was concluded that using the amplatz system, reducing the amount of the irrigation fluid, and operating in multiple stages might significantly reduce fluid absorption.(11) in a study on 23 patients whose irrigation fluid was normal saline, koroglu and colleagues reported that the amount of fluid used and the duration of the procedure did not affected the level of electrolytes during pcnl.(12) to our knowledge, there is no study evaluating distilled water as irrigation fluid for pcnl. distilled water is cheap and available and is especially appropriate in developing countries; however, it may cause hyponatremia. according to the results of our study, there was a significant difference between the serum sodium levels of the serial samples taken before and after the operation. this may be explained by the absorption of the extravasated fluid or the routine use of two-thirds dextrose 5% and one-third saline solution during the procedure. however, the lowest measured serum sodium concentration in the laboratory studies of the first postoperative day was 127 meq/l, which was within the reference range for serum sodium level. we found no case of symptomatic or asymptomatic hyponatremia among our patients. finally, regarding the mean levels of sodium in samples 2 and 3, which were not different significantly, it can be concluded that the duration of the procedure, the fluid used, the side of pcnl, and mean level of serum sodium in samples 1 to 4. the levels of sodium on the days before and after the procedure (samples 1 and 4) had statistical significant difference. 125 130 135 140 145 150 1 2 3 4 samples s e ru m s o d iu m l e v e ls . m e q /l table 2. serum levels of sodium and potassium in blood samples before and after pcnl* electrolyte sample 1 sample 2 sample 3 sample 4 sodium, meq/l mean 141.5 ± 3.0 140.7 ± 5.8 139.7 ± 6.8 138.9 ± 4.4 range 140 to 143 125 to 159 125 to 164 127 to 146 95% ci 141.5 to 142.1 138.5 to 142.9 137.1 to 142.2 137.3 to 140.6 potassium, meq/l mean 4.14 4.26 4.34 4.14 range 3.8 to 5.2 3.9 to 5.0 4.0 to 5.1 3.8 to 5.2 95% ci 4.01 to 4.26 4.01 to 4.50 4.10 to 4.59 3.96 to 4.35 *pcnl indicates percutaneous nephrolithotomy and ci, confidence interval. distilled water for percutaneous nephrolithotomy—feizzadeh et al urology journal vol 3 no 4 autumn 2006 211 bmi had no significant effect on the serum level of sodium. conclusion according to our findings, using distilled water during pcnl for irrigation does not cause any clinically significant decrease in serum levels of sodium. as an alternative irrigation fluid, it can be used with special attention to the level of serum sodium on the postoperative day. larger studies on the efficacy and safety of distilled water for irrigation in endoscopic procedures are warranted. conflict of interest none declared. references 1. chatham jr, dykes te, kennon wg, schwartz bf. effect of percutaneous nephrolithotomy on differential renal function as measured by mercaptoacetyl triglycine nuclear renography. urology. 2002;59:522-5. 2. streem sb, lammert g. long-term efficacy of combination therapy for struvite staghorn calculi. j urol. 1992;147:563-6. 3. cariou g, le duc a, serrie a, cortesse a, teillac p, ziegler f. reabsorption of the irrigation solute during percutaneous nephrolithotomy. ann urol (paris). 1985;19:83-6. 4. lauritz jb. hyponatremic coma following percutaneous nephrolithotomy. anaesth intensive care. 1986;14:210-1. 5. chou ch, chau t, yang ss, lin sh. acute hyponatremia and renal failure following percutaneous nephrolithotomy. clin nephrol. 2003;59:237-8. 6. lingeman je, lifshitz da, evan ap. surgical management of urinary lithiasis. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3425. 7. shah hn, kausik vb, hegde ss, shah jn, bansal mb. tubeless percutaneous nephrolithotomy: a prospective feasibility study and review of previous reports. bju int. 2005;96:879-83. 8. cybulski p, honey rj, pace k. fluid absorption during ureterorenoscopy. j endourol. 2004;18:739-42. 9. fellahi jl, richard jp, bellezza m, antonini a, thouvenot jp, cathala b. the intravascular transfer of glycine during percutaneous kidney surgery. cah anesthesiol. 1992;40:343-7. 10. malhotra sk, khaitan a, goswami ak, gill kd, dutta a. monitoring of irrigation fluid absorption during percutaneous nephrolithotripsy: the use of 1% ethanol as a marker. anaesthesia. 2001;56:1103-6. 11. kukreja ra, desai mr, sabnis rb, patel sh. fluid absorption during percutaneous nephrolithotomy: does it matter? j endourol. 2002;16:221-4. 12. koroglu a, togal t, cicek m, kilic s, ayas a, ersoy mo. the effects of irrigation fluid volume and irrigation time on fluid electrolyte balance and hemodynamics in percutaneous nephrolithotripsy. int urol nephrol. 2003;35:1-6. u j 02 spring 2012 all 008without adv.pdf 472 | effect of hydroalcoholic extract of hypericum perforatum l. leaves on ethylene glycol-induced kidney calculi in rats mohsen khalili,1 mohammad reza jalali,2 mohammad mirzaei-azandaryani3 purpose: to investigate the effects of the hydroalcoholic extract of hypericum perforatum (h. perforatum) leaves on the kidney calculi in rats. materials and methods: h. perforatum solution was fed at the same time of eg application and was repeated once for two days eg-ammonium chloride-added drinking water and was fed with normal chow. h. perforatum in low were removed and prepared for histologic evaluation of calcium oxalate deposits. results: h. perforatum (300 h. perforatum creased compared to controls (p < .01; p < .05; and p ment of the rats with high dose of h. perforatum decrementing effect of eg on serum level of free calcium (p experiments showed that chronic feeding of h. perforatum (300 and 500 mg/kg, in eg group. conclusion: chronic treatment of rats with hydroalcoholic extract of h. perforatum reduced the size and number of calcium oxalate deposits in eg-induced calculi. keywords: hypericum perforatum, kidney calculi, ethylene glycol, calcium oxalate corresponding author: mohammad mirzaeiazandaryani, md department of physiology, medicinal plant, school of medicine, shahed university of medical sciences, tehran, iran tel: +98 21 8896 4792 fax: +98 21 8896 6310 e-mail: mohammadmirzaei89@yahoo.com received december 2010 accepted june 2011 1department of physiology, medicinal plant, school of medicine, shahed university of medical sciences, tehran, iran 2department of pathology, school of medicine, shahed university of medical sciences, tehran, iran 3shahed university student research committee (shusrc), school of medicine, shahed university of medical sciences, tehran, iran endourology and stone disease endourology and stone disease 473vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l hypericum perforatum on kidney calculi | khalili et al introduction urinary stone is a prevalent disorder in the urinary system. genetics, low activity, and diet are the most common factors that could lead to calculi formation by high saturation of calcium and production of calcium oxalate calcium oxalate and calcium phosphate are the most common kidney stones and may cause various adverse effects, such as obstruction, infection, hemorrhage, and pain resulted from passage of stones in the urinary tract system. unfortunately, chemical drugs for prevention or treatment of the kidney stones could not successfully dissolve the problem. meanwhile, if laser therapy as a cost-effective procedure is used for disruption of calculi, many severe complications may yield. therefore, the wisely clinical method for prevention, disaggregation, or disruption of calculi is the usage of a safe, cheap, and with low side effects medication, like medicinal plants. hypericum perforatum l., commonly known as st. especially grown in iran, india, china, turkey, and some other countries. the most common sjw preparations used are hydroalcoholic extracts of the aerial portion of the plant that contain at least ten different kinds of biochemical compounds. the essential and active ingredients of this herb include vorable effects have been reported. many studies show that sjw could relieve mild to moderate forms of depression. furthermore, antioxidant, urinary system relaxant effects, and inhibition of calcium crystallization in the urinary system have been reported. the present study has experimentally evaluated the effect of sjw extract on ethylene glycol-induced caox crystallization in rat model. materials and methods animals were procured from pasteur institute in tehran, four per cage in a temperature-controlled colony they were given free access to water and kept at 80% to 85% of their free-feeding body weight throughout the experiment. this study was conducted in accordance with the policies set forth in the guide for the care and the research council of shahed university of medical sciences. preparation of plant hydroalcoholic extract hypericum perforatum (h. perforatum) was prouniversity. the hydroalcoholic extract was prepared as described elsewhere. experimental procedure inducer in the rats. this component in the body is broken down to some organic acids, especially oxalic acid, which precipitates as caox crystals in the kidney. however, concomitant adminisby eg application solely. in the present study, the animals were randomly ed drinking water throughout the entire experih. perforatum solutions were fed by gastric gavage at the same time of eg application and repeated once for two days till the end of the experimental period. access to food and normal drinking water. group chloride-added drinking water and was fed with 474 | h. perforatum doses, respectively. serum and urine analysis at the beginning and end of the experiment, the pose, each rat was individually kept in a metathe blood serum was obtained for biochemical th week. blood was collected from retro-orbital plexus by capillary tube at the beginning and from the heart following anesthesia, at the end of the experiments. laboratory examination included measurement of free calcium, phosphorus, magnesium, potassium, and sodium. evaluation of the severity of renal crystal deposition at the end of the experiment after blood sample collection, the rats were killed by carbon dioxide inhalation. thereafter, the right and left kidneys were removed from the body and weighed. the kidneys were kept in formalin and then blocked tally right and left kidney sections in 5 μm were prepared by microtome and then the slides were stained by hematoxylin and eosin. finally, a light microscope was used in order to examine the presence of crystal depositions in histological sections. for this purpose, aggregation of caox deposits were counted in 10 microscopes each group. for accuracy in counting of caox deposits, we hypothetically divided each sagittal renal specimen into 10 equal–square size regions by table 1. biochemical data of rats at baseline. baseline data, mmol/dl group 1 control (n = 10) group 2 eg (n = 12) group 3 eg + hp (low dose) (n = 15) group 4 eg + hp (high dose) (n = 15) urine level phosphorus 117.15 ± 21.20 120.00 ± 15.90 145.00 ± 21.14 115.75 ± 26.60 free calcium 51.10 ± 9.3 54.66 ±10.10 44.02 ± 12.77 magnesium 113.16 ± 15.17 127.00 ± 13.14 131.75 ± 24.25 sodium 111.00 ± 3.71 potassium 59.00 ± 7.07 72.25 ± 7.33 serum level phosphorus free calcium 11.24 ± 0.11 10.93 ± 0.23 11.10 ± 0.23 11.43 ± 0.35 magnesium 2.21 ± 0.43 2.71 ± 0.50 sodium 150.51 ± 1.21 152.33 ± 1.45 151.50 ± 1.32 149.50 ± 0.95 potassium 6.35 ± 0.73 7.10 ± 0.07 hypericum perforatum. data are expressed as mean ± standard error. endourology and stone disease 475vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l data analysis one-way anova and post-hoc tukey tests were used for analysis of serum and urine parameters. the non-parametric kruskal-wallis test and mann-whitney u test were used for comparison of caox deposites. p values of less than .05 were results biochemical analysis in baseline biochemical parameters among conthere were no differences in serum and also urine levels of phosphorus, free calcium, magnesium, sodium, and potassium at the beginning of the study. parameters after the experiment are shown. as indicated, urine level of free calcium in groups eg h. perforatum and phosphorous in h. perforatum compared to controls (p < .01; p < .05; and p rats have markedly raised the urine level of magnesium (p administration of h. perforatum serum levels of phosphorus and free calcium in to normal rats (p < .05 and p however, treatment of rats with high dose of h. perforatum decremented effect of eg on serum level of free calcium (p body and kidney weights gain or loss between histological examination as figure 1 shows, no caox deposits were found table 2. effect of h. perforatum on urine and serum biochemical data in rats.†£ baseline data, mmol/dl group 1 control (n = 10) group 2 eg (n = 12) group 3 eg + hp (low dose) (n = 15) group 4 eg + hp (high dose) (n = 15) urine level phosphorus 114.11 ± 19.2 117 ± 13.9 95.75 ± 16.65 a* free calcium 29.54 ± 9.14 a** 34.30 ± 11.67 a* 41.32 ± 9.21 magnesium 110.13 ± 14.14 147 ± 12.12 a* 141.75 ± 14.2 a* a* sodium potassium 47.70 ± 05.32 64.31 ± 2.27 serum level phosphorus 9.75 ± 0.90 a* free calcium 10.72 ± 0.41 6.6 ± 0.24 a** 5.1 ± 0.33 a* 9.3 ± 0.43 b* magnesium 3.39 ± 0.06 2.95 ± 0.17 sodium 150.75 ± 2.13 151.66 ± 1.66 151.25 ± 1.1 potassium 7.45 ± 0.92 6.75 ± 0.26 7.12 ± 0.06 6.90 ± 0.2 † hypericum perforatum. £ data are expressed as mean ± standard error. a and b show significant group compared to normal and eg groups, respectively. *p < .05 and **p < .01. hypericum perforatum on kidney calculi | khalili et al 476 | in control animals. but due to eg application, a in the proximal tubules, loops of henle, distal tubules, and collecting ducts (p ment of the eg group with low and high doses of h. perforatum p < in addition to decrement of the number of calcuh. perforatum groups, we also found a marked reduction in the animals which were treated with h. perforatum discussion in the present study, we successfully induced caox formation in the rat’s kidney by adding eg to dinking water, which is in line with other studies. we added ammonium chloride to eg drinking water for masking the metabolic acidosis induced by eg-derivative acids, such as glycolaldehyde acid, glycolic acid, glyoxylic acid, and oxalic acid. our data showed that ethanolic extract of h. perforatum had a preventive effect on caox calculus formation in the rat’s kidney. the low and high doses of extract also reduced the number of complementary data indicated a low level of free calcium in urine and serum in eg-group in comparison with control animals. this is because most of the serum or urine calcium was bound with oxalate to form crystals; hence, very little free calcium was detected. to the best of our knowledge, the present study of the h. perforatum on the prevention and treatment of caox kidney calculus. the exact mechanisms through which h. perforatum affects caox calculi are still under debate. table 3. effect of h. perforatum on the body and kidney weight of rats.†£ group 1 control (n = 10) group 2 eg (n = 12) group 3 eg + hp (low dose) (n = 15) group 4 eg + hp (high dose) (n = 15) body weight gain, g* 175.11 ± 16.22 157.63 ± 23.9 166.25 ± 17.65 right kidney weight, g 1.99 ± 0.31 1.66 ± 0.47 left kidney weight, g 1.91 ± 0.5 1.74 ± 0.21 1.79 ± 0.49 † hypericum perforatum. £ data are expressed as mean ± standard error. * body-weight gain is computed as the final body weight of each rat minus the baseline body weight of the same rat. figure 1. calcuim oxalate deposition in study groups.£¥ £ bars represent the mean number of calculi in each group. ¥ hypericum perforatum. * and # show difference compared to control and eg groups, respectively. **p < 0.01, ***p < .001, and # p < .05. endourology and stone disease 477vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l calcium oxalate crystals and high levels of oxalate in the nephrons can damage the epithelial cells, and consequently, the cells may produce some products as well as free radicals, inducing heterogeneous crystal nucleation and cause aggregation of crystals. h. perforatum quercetin and quercetin-3. several studies fects. therefore, it is speculated that h. perforatum could prevent the formation of caox calculi and their disaggregation through its antifurthermore, h. perforatum extract may interfere with the process of epithelial cell damage induced by crystals. the reports about the suppression of each step of caox crystal formation, growth, and aggregation in vitro are concomitant with the same results in vivo trial in our experiment. therefore, prevention of crystal nucleus production by h. perforatum can be speculated. the most important protein that plays the role of crystal nucleus is chondroitin sulphate. in addition to afore-mentioned mechanisms in the formation of caox crystals, the role of bacterial origin, such as nanobacteria, should also be mentioned. however, the powerful antibacterial effect of h. perforatum could yield its antilithiatic effect. of notice is the diuretic effect of h. perforatum, which could help in prevention of calculi. figure 2. (a) normal medullary and papillary tubules are shown in a control rat’s kidney. (b) the large size of calcium oxalate crystals (arrow) in a renal tubule in ethylene glycol-indoced calculi in rats. (c) arrow shows the reduction of calculi size in ethylene glycol + hypericum perforatum group. hypericum perforatum on kidney calculi | khalili et al 478 | conclusion the oral feeding of the alcoholic extract of h. perforatum could diminish the number and size of caox crystals produced by eg application in clusion, further studies are needed to replicate our results. conflict of interest none declared. references 1. ho sz, kuo hc. pathogenesis and epidemiology of urolithi2. bushinsky da, michalenka ac, strutz kl, donahue s, asplin jr. effect of bolus and divided feeding on urine ions and supersaturation in genetic hypercalciuric stone-forming 3. pak cy, rodgers k, poindexter jr, sakhaee k. new methods of assessing crystal growth and saturation of brushite in whole urine: effect of ph, calcium and citrate. j urol. 4. hall pm. nephrolithiasis: treatment, causes, and prevention. 5. corley ra, wilson dm, hard gc, et al. dosimetry considerations in the enhanced sensitivity of male wistar rats to chronic ethylene glycol-induced nephrotoxicity. toxicol 6. john's wort (hypericum perforatum): drug interactions and 7. ganzera m, zhao j, khan ia. hypericum perforatum-chemical profiling and quantitative results of st. john's wort products by an improved high-performance liquid bais hp, vepachedu r, lawrence cb, stermitz fr, vivanco jm. molecular and biochemical characterization of an enzyme responsible for the formation of hypericin in st. john's wort (hypericum perforatum l.). j biol chem. 9. medina ma, martínez-poveda b, amores-sánchez mi, 10. cervo l, rozio m, ekalle-soppo cb, guiso g, morazzoni p, caccia s. role of hyperforin in the antidepressant-like activity of hypericum perforatum extracts. psychopharmacol11. zheleva-dimitrova d, nedialkov p, kitanov g. radical scavenging and antioxidant activities of methanolic extracts from hypericum species growing in bulgaria. pharmacogn 12. capasso r, borrelli f, montanaro v, altieri v, capasso f, izzo aa. effects of the antidepressant st. john's wort (hypericum perforatum) on rat and human vas deferens contrac13. combest w, newton m, combest a, kosier jh. effects of 6, 403. 14. khalili m, kiasalari z, roghani m, azizi y. anticonvulsant and antioxidant effect of hydro-alcoholic extract of cyperus rotundus rhizome on pentylentetrazole-induced kindling 15. lee yh, chang ls, chen mt, chiang h, huang jk, huang wc. characterization of ethylene glycol-induced urolithi16. lee yh, huang wc, chiang h, chen mt, huang jk, chang ls. determinant role of testosterone in the pathogenesis of 17. lee yh, tsai jy, huang jk. combined use of 30% lactose rich diet and 1% ethylene glycol: a new animal model for study leth pm, gregersen m. ethylene glycol poisoning. forensic 19. khan sr, thamilselvan s. nephrolithiasis: a consequence of renal epithelial cell exposure to oxalate and calcium 20. ies on hypericum perforatum fractions and constituents. 21. butterweck v, jurgenliemk g, nahrstedt a, winterhoff h. flavonoids from hypericum perforatum show antidepressant activity in the forced swimming test. planta med. 22. ahmed ms, el tanbouly nd, islam wt, sleem aa, el senousy as. antiinflammatory flavonoids from opuntia dillenii (ker-gawl) haw. flowers growing in egypt. phytother res. endourology and stone disease 479vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l 23. comalada m, ballester i, bailon e, et al. inhibition of proinflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship. biochem 24. quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the nf-kappa 25. itoh y, yasui t, okada a, tozawa k, hayashi y, kohri k. preventive effects of green tea on renal stone formation and the role of oxidative stress in nephrolithiasis. j urol. 26. yuen jw, gohel md, poon nw, shum dk, tam pc, au dw. the initial and subsequent inflammatory events during 27. jeong bc, kim bs, kim ji, kim hh. effects of green tea on urinary stone formation: an in vivo and in vitro study. j michelacci ym, boim ma, bergamaschi ct, rovigatti rm, schor n. possible role for chondroitin sulfate in urolithiasis: in vivo studies in an experimental model. clin chim acta. 29. tion of upper urinary tract stone's bacterial spectrum]. 30. saddiqe z, naeem i, maimoona a. a review of the antibacterial activity of hypericum perforatum l. j ethnopharma31. izzo aa, ernst e. interactions between herbal medicines and prescribed drugs: an updated systematic review. hypericum perforatum on kidney calculi | khalili et al reduction of radiation dose received by surgeons and patients during percutaneous nephrolithotomy: a new shielding method shahriar amirhasani1, rezgar daneshdoost2, seyedhabibollah mousavibahar1*, karim ghazikhanlou-sani3, roya raeisi4 purpose: due to high prevalence of urolithiasis, endourologic interventions have increased for the treatment of patients with urinary stones. during fluoroscopy-guided percutaneous nephrolithotomy (pcnl), the surgeon and the patient are exposed to x-ray and its harmful effects. this study aimed to assess the reduction of the radiation dose received by surgeons and patients after using a new shielding method. materials and methods: in this study, the dose of radiation exposure by the surgeon and patient during pcnl under fluoroscopic procedure with conventional shielding methods was compared to a new shielding method designed by the researcher. for this purpose, shields and lead cones with a thickness of 0.5 mm were used. also, to evaluate the dose of radiation received by surgeons and patients in different parts of the body, thermoluminescent dosimeters (tld) were used. results: by using the new shielding method, a 37 ± 2% reduction was found in the dose exposure as compared to the conventional shielding method. the maximum reduction in radiation dose was specified to the surgeon's hands, while the lowest reduction in radiation dose was related to the surgeon's thyroid gland. the maximum and minimum reductions in radiation exposure for patients were specified to patients' feet and chest respectively. conclusion: there is a significant difference between the total dose received by the surgeons and the patients following the use of the new shielding method and the standard shielding method. the new shielding method can reduce 37 ± 2% of the x-ray received by the patient and the surgeon during fluoroscopy-guided pcnl. keywords: endourologic interventions; percutaneous nephrolithotomy; radiation exposure; shielding; urinary stone introduction urinary tract stones are the third most common dis-orders of the urinary tract system after infections and prostate diseases.(1) one of the most applicable endourology methods widely used today to treat urinary stones is percutaneous nephrolithotomy (pcnl).(2) percutaneous approach is a common urological procedure for the treatment of urinary stones, tumors and upper urogenital tract stenosis. this method is now popularized because of its considerable benefits including low post-procedural morbidity, high patients' satisfaction, and early return to work and social activities. the efficiency of this method minimizes the need for open surgery. one of the most common methods is fluoroscopy-guided pcnl with x-ray radiation.(3) this method can effectively facilitate dilation of the urinary tract, renal access, as well as stone manipulation. however, long-term fluoroscopic exposures for the localization of calculus necessitate the determination of absorbed radiation dose for physicians, operating room personnel, and patients. therefore, endourologists, operating room personnel, and urology patients are potentially exposed to x-ray and its-related complications, and therefore should be aware of the safety principles of work with radiation.(4) the effects of radiation on increasing the likelihood of cancer and its other destructive effects have been well proven.(5,6) the major dose of radiation received by surgeons during pcnl is the radiation dispersed from the patient, radiography bed, and equipment. in this regard, the initial radiation dose plays a minor role in increasing the received radiation dose.(7) in other words, the radiation dose exposure can depend on the time of exposure to radiation, distance to the source of radiation, and shielding. it is now hypothesized that the use of shielding is differentially effective on reducing received radiation dose. for this purpose, a new shielding method is proposed in the present study to reduce the dose of radiation received by surgeons and patients. materials and methods this experimental study was conducted between april 2017 and october 2017 at shahid beheshti hospital in hamadan. the study subjects were selected from paurology journal/vol 18 no. 3/ may-june 2021/ pp. 271-276. [doi:10.22037/uj.v16i7.5200] 1urology & nephrology research center, hamadan university of medical sciences, hamadan, iran. 2department of urology, kurdistan university of medical sciences, kurdistan, iran 3radiology department, paramedical school, hamadan university of medical sciences, hamadan, iran 4department of pediatrics, hamadan university of medical sciences, hamadan, iran. *correspondence: urology & nephrology research center, hamadan university of medical sciences, hamadan, iran. email:mousavi47@gmail.com. received march 2019 & accepted december 2020 endourology and stone disease tients with upper urinary tract stones who were candidates for pcnl. this study was an interventional study in terms of radiation received by surgeons and the staff. the inclusion criteria included patients with pelvic or calyceal stones larger than two centimeters or staghorn calculi. exclusion criteria included patients with untreated coagulation disorders or active urinary tract infections. the patients were randomly divided into two groups using simple randomization method aided by the random number table. in the first group (using the common shielding method), 30 patients were selected, and the duration of radiation in the first group was calculated. based on the duration of radiation in the first group, the number of patients in the second group (using the new shielding method) was determined at 23 patients where both groups received the same duration. in the first group, pcnl was performed with the conventional shielding technique including lead apron, thyroid shield and lead glasses, and in the second group, pcnls were performed by the researcher's new designed shielding method plus conventional shielding technique. in the routine pcnl procedure, after regional or general anesthesia by the anesthetist, in the frog leg position and using a cystoscope, a 5f ureteral catheter 5f is inserted into the ureter and the corresponding pelvic cavity, and then fixed to the foley catheter. this catheter is utilized to inject air or contrast agents. the patient is then placed on a special endourology bed compatible with c-arm in the prone position. to view the renal pelvis, we can use the injection of air or contrast agent into the ureter catheter. the advantage of the air is that, due to the lightness in the prone state, the posterior calyces first appear. after the needle was incorporated in calyx, it was necessary to aspirate it to ensure that air or water was aspirated. then, from the middle of the needle, an 0.380 inch j-shaped guide wire was passed through the floppy tip to enter the pelvis. then, the needle entry point was cut about 1cm, the needle was removed, and the guide wire was retained. eventually, the tract around the guide wire was extended to 30f, using an amplatz dilator set or a balloon. both these techniques can be used after passing a guide wire into the system.(8) the patient lay on a stretcher next to the main surgical bed. then, her flank area was adjusted to about 30 by 30 cm in the window area, and the patient's kidneys were adjusted accordingly. the kidney itself was in the upper half of the window when the nephrostomy needle was inserted, where its passageway was exposed to the surgeon. in the first group, the dose received by patients and surgeons during pcnl was considered under conventional reduction of radiation during pcnl-mousavi-bahar et al. table 1. the average dose reached to different parts of the body in the first and second stages in millisieverts and the percentage of radiation dose reduction after applying the new shielding method area the dose reached the chips in the first stage (msv) the dose reached the chips in the second stage (msv) radiation dose reduction p-values surgeon group hand 0.2 ± 0.06 0.1 ± 0.003 55.1 ± 8.2 % p < .001 foot 0.1 ± 0.007 0.05 ± 0.004 54 ± 1.7 % p < .001 chest 0.07 ± 0.005 0.04 ± 0.002 48.4 ± 7% p < .001 thyroid 0.073 ± 0.002 0.072 ± 0.009 0.67 ± 11.9 % p < .001 forehead 0.1 ± 0.004 0.08 ± 0.006 16.8 ± 7.5 % p < .001 patient group foot 0.07 ± 0.006 0.03 ± 0.001 51.3 ± 1.9 % p < .001 chest 0.5 ± 0.02 0.4 ± 0.01 23.2 ± 4.4 % p < .001 thyroid 0.1 ± 0.002 0.6 ± 0.002 46.4 ± 1.3 % p < .001 total 0.16710 ± 0.014 0.10760 ± 0.011534 37 ± 2 % p < .001 figure 1. tld badge opened up. endourology and stones diseases 272 vol 18 no 3 may-june 2021 273 protective conditions (lead glasses and a simple cover on neck, trunk and lower extremities). first, 20 thermoluminescence dosimetry (tlds) chips were set on various parts of the surgeon's body (legs, hands, chest, thyroid, and above eyes, with three chips on each part) and 12 chips on different parts of the patient's body (feet, chest, and thyroid). in order to locate tlds in the desired areas, special tld badges were designed (figure 1). in the second stage of the implementation of the protective design, a layer of 0.5-mm-thick lead was fitted with a length of 1.8 m and a width of 1.2 m on the patient's bed. the protective shield was hanged from the patient's bed up to 50 cm in the surgeon's side and 10 cm in front of the surgeon. also, a square hole with a length of 30 cm and a width of 30 cm was created in the protective shield of the lead to facilitate the operative procedure. for easier movement of the shield on the bed, it was designed in three sections. in order to better protect the scatter rays, a lead cone with a height of 15 cm was inserted around the fluoroscopic tube (figures 2 and 3). in order to remove radiation from the results of the study, four tlds were installed in the personnel rest room, and the radiation dose shown by these chips was deducted from the dosage to the pure dose surgeons received during the first period of the test. descriptive analysis was used to describe the data, including mean ± standard deviation (sd) for quantitative variables and frequency (percentage) for categorical variables. chi square test, independent t-test and mann-whitney u test were used for the comparison of variables. for the statistical analysis, the statistical software ibm spss statistics for windows version 22.0 (ibm corp. released 2013. armonk, new york) was employed. p-values <.05 were considered statistically significant. figure 2. the protective lead layer designed in the new shielding method. figure 3. fluoroscope tube with designed lead connector. reduction of radiation during pcnl-mousavi-bahar et al. results all surgical procedures were performed without any special problems or complications related to shielding. anesthesia and surgery time were not significantly increased (3 minutes required to install the shields). there was no significant difference between the groups in terms of stone removal. the two groups planned for standard protective method and the new shielding method were comparable in the mean age (48.5 ± 2.6 years versus 45.0 ± 2.2 years, p = .456) and mean body mass index (25.6 ± 1.5 kg/m2 versus 26.4 ± 1.6 kg/m2, p = .789). the number of surgeries in the two groups was 30 and 23 respectively with a total mean radiation time of 1482 and 1587 seconds, respectively, indicating 106 seconds (7%) longer radiation duration in the latter group. thus, to match the two groups, this extra amount was deducted from the amount of charge received in the second group. in the first and second groups, the average tube potential of the fluoroscope was 79.3kv and 78.8kv, respectively, with no meaningful difference (p = .124). also, the mean currents in the tube of fluoroscope were the respective 2.89ma and 2.86ma with no significant difference (p = .897). the average distance between the lower limbs of the surgeon and the fluoroscope tube was 41.3cm in both groups. in the two groups with the standard protective method and the new shielding method, the average dose reached the total dosimeters of 0.16710 ± 0.014 msv and 0.10760 ± 0.011534 msv respectively (p < .001). in both groups, the highest doses were recorded in the dosimeters on figure 4. percentage of received dose reduction of different parts of the body among surgeons after insertion of the new shielding. figure 5. percentage of received dose reduction of different parts of the body among patients after insertion of the new shielding. reduction of radiation during pcnl-mousavi-bahar et al. endourology and stones diseases 274 vol 18 no 3 may-june 2021 275 patients' chest, the second recorded in the dosimeters on surgeon's hands and the lowest doses in the patient's leg (table 1). in general, the maximum reduction in radiation dose was specified to the surgeon's hands (55.1 ± 8.2%) followed by the surgeon's foot (54.0 ± 1.7%), while the lowest reduction in radiation dose was related to surgeon's thyroid gland (0.67 ± 11.9%) (table 1 and figure 4). the maximum and minimum reductions in radiation exposure for patients were specified to patients' feet (51.3 ± 1.9%) and chest (23.2 ± 4.4%) respectively (table 1 and figure 5). discussion with the advent of pcnl surgery, as one of the major treatments for upper urinary tract stones, the association of this surgical technique with radiation emitted from the fluoroscope was taken into consideration. the presence of a fluoroscope device has led to the progression of pcnl surgery. from the early stages of using x-rays in pcnl surgery, harmful effects of radiation on the patient and surgeon have been a challenge for urologists. the task was first to identify these harmful effects and, second, to minimize these effects. for this reason, researchers have taken steps to find ways to reduce radiation by the patient and surgeon. reducing the amount of radiation reaching the surgeon and the patient is very important. a urologist will perform more than 100 pcnl surgeries annually for several consecutive years. therefore, the need to protect the surgeon against x-rays is felt more than ever on the other hand, urinary stone is a recurrent disease where patients may need to have urological surgeries with x-ray intervention. it is also important for infants with metabolic disorders or cystinuria to undergo multiple pcnl surgeries during their life. moreover, the operating room staff and the relevant anesthesia department staff are directly or indirectly exposed to x-ray damage. observing the safety principles to create a work environment with the highest safety factor is necessary to continue the work of this group of medical personnel. accordingly, we thought to introduce a new method to protect the surgeon, the operating room staff, and the patients against the x-rays of the fluoroscope. in general, through the new shielding method, we found a 37 ± 2% reduction in dose exposure as compared to the conventional shielding method. the maximum dose reduction in the surgeon's body was observed in the hands and the least in the thyroid. consequently, we found the effect of the new shielding method on reducing the radiation dose in the parts closer to the radiation tube. the least distance of the tube in the surgeon's body was related to the surgeon's hand and foot, which has the highest dose reduction, and the maximum distance between the tube and surgeon's body was related to the surgeon's thyroid and forehead, where the dosage is minimized by applying the new shielding method. in the patient's body after applying the new shielding method, the maximum and minimum dose reduction was related to the patient's leg and chest, respectively. the square cavity formed on the lead layer used on the patient's bed has dimensions of 30 × 30 cm. in addition, pcnl surgery sometimes requires a 30-degree angle fluoroscopy, and in some patients the new shields did not cause any problems for fluoroscopy at a 30-degree angle. it seems that a lower reduction in the dose of radiation received by the patient in the chest area might be due to the large size of this cavity. it can also be suggested that another reason for lowering the amount of radiation received in the thyroid region and the forehead could be related to the large cavity in the middle of the lead layer. because of this large cavity, there is a possibility of greater scattering of radiation, and the surgeon's forehead and thyroid are also in the direction of the radiation emitted out of this square region which is formed on the lead layer. giblin et al. examined the amount of radiation emitted by surgeons during ureteroscopy and cystoscopy aided by fluoroscope. in this study, a 0.5-mm thick lead layer was used between the surgeon and the patient, which was eventually reported to decrease the radiation dose reached by the surgeon by 70 times.(9) the mentioned study focused solely on reducing the radiation received by the surgeon, and the shield embedded to protect the surgeon causes a limitation for surgical activity. in our study, a survey was conducted on the amount of radiation emitted by a surgeon and a patient in a pcnl surgery. it should be noted that the new shielding designed in this study does not interfere with surgical procedures. in a study by yang et al in 2002, a new shielding method was introduced in which a 0.5-mm thick lead layer was placed between the surgeon and the patient, and the dose of radiation received by the chest and forehead of the surgeon were measured before and after shielding. the study was performed on 6 patients in each group. according to the findings, the surgeon's dose reduction was 76% and the dose reduction in the surgeon was 96%.(10) in our study, we have a larger sample size and our shielding method is different and designed to protect all parts of the surgeon's body and patient from radiation. also, in contrast to the study by yang where only two points on the surgeon's body were considered, our study examined five points of the surgeon's body to measure radiation dose. in a study by politi et al., in 2012, the effect of using a new type of protective coating around the patient's body to absorb dispersed radiation from the patient's body was studied to reduce the dose received by the operator during coronary artery angiography. the study was performed on 60 patients. a sterile lead shield was used with dimensions of 35 × 45 cm covered around the radial artery (from the access point to the chest wall). dosimetry through the tld chips inserted in various points of the cardiologists' body (wrist, chest, thyroid, and eye) showed that the mean dose administered to the whole body of the operator decreased from 367.8 ± 105.4 msv to 282.8 ± 32.55 msv after using a new protective method. therefore, a 23 percent reduction in personnel dose was evident in their method. reducing the dose delivered to various parts of the body was also evaluated by using this new protective method between 13% and 34%.(11) in a study by iball et al., the effect of a new shielding method on patients' reception of the dose during ct scan was studied. in this study, a lead layer around the abdomen and pelvis of the patient during chest ct scan was used, and the authors reported that the amount of radiation in different phases of the study ranged from 5% to 73%.(12) conclusions based on the findings of this study, there is a significant difference between the total dose received by the surgeons and the patients following the use of the new shielding method and the standard shielding method. the new shielding method can reduce 37% ± 2 of the reduction of radiation during pcnl-mousavi-bahar et al. x-ray received by the patient and the surgeon during pcnl surgery under fluoroscopic procedures. dose reduction in different parts of the body of the surgeon was 34.7 ± 2.7%, and in different parts of the patients' body was 40.3±2.5%. the highest reduction in radiation dose in the surgeon was specified to hands, while the lowest reduction in radiation dose was related to the surgeon's thyroid gland. the maximum and minimum reductions in radiation exposure for patients were specified to patients' feet and chest respectively. based on the findings of the current study, in order to reduce the dose of radiation received by the patient, surgeon and operating room personnel, it is recommended that in all pcnl surgeries under fluoroscopic procedures, the new protective method introduced in this study be adopted to reduce the harmful effects x-ray. acknowledgement this study was approved in hamadan university of medical sciences, as a research project. conflict of interest the authors report no conflict of interest references 1. wagh nd, pachpande bg, patel vs, attarde sb, ingle st. the influence of workplace environment on lung function of flour mill workers in jalgaon urban center. j occup health. 2006;48:396-01 2. brannen ge, bush wh, correa rj, gibbons rp, elder js. kidney stone removal: percutaneous versus surgical lithotomy. j urol. 1985; 133:6-12. 3. lam hs, lingeman je, mosbaugh pg, et al. evolution of the technique of combination therapy for staghorn calculi: a decreasing role for extracorporeal shock wave lithotripsy. j urol. 1992; 148:1058-62. 4. kumari g, kumar p, wadhwa p, aron m, gupta np, dogra pn. radiation exposure to the patient and operating room personnel during percutaneous nephrolithotomy. int urol nephrol. 2006; 38:207-10. 5. quinn ad, taylor cg, sabharwal t, sikdar t. radiation protection awareness in nonradiologists. bjr. 1997; 70:102–6. 6. george j, eatouch jp, mountford pj, koller cj, oxtoby j, frain g . patient dose optimization in plain radiography based on standard exposure factors. bjr. 2004; 77: 858–63. 7. soufi majidpour h. risk of radiation exposure during pcnl. urol j. 2010; 7:87-9 8. mousavi-bahar s h, amirhasani s, mohseni m, daneshdoost r. safety and efficacy of percutaneous nephrolithotomy in patients with severe skeletal deformities. urol j. 2017; 3:3054-58. 9. giblin jg, rubenstein j, taylor a, pahira j. radiation risk to urologist during endourologic and a new shield that reduce exposure. urology. 1996; 48:624-7. 10. yang rm, morgan t, bellman gc. radiation protection during percutaneous nephrolithotomy: a new urologic surgery radiation shield. j endourol. 2002; 16:72731. 11. politi l, biondi-zoccai g, nocetti l, et al. reduction of scatter radiation during transradial percutaneous coronary angiography: a randomized trial using a lead-free radiation shield. catheterization and cardiovascular interventions. 2012; 79:97–102 12. iball gr, brettle ds. organ and effective dose reduction in adult chest ct using abdominal lead shielding. bjr. 2011; 84:1020-26. reduction of radiation during pcnl-mousavi-bahar et al. endourology and stones diseases 276 sexual dysfunction and infertility 159urology journal vol 4 no 3 summer 2007 effect of cigarette smoke on spermatogenesis in rats hassan ahmadnia,1 mohsen ghanbari,1 mohammad reza moradi,2 mohammad khaje-dalouee3 introduction: the aim of this study was to evaluate the process of spermatogenesis in rats exposed to the cigarette smoke. materials and methods: thirty adult male rats were divided into 2 groups of cases and controls. an apparatus made especially for this study was used to produce smoke from a commonly used cigarette and expose the rats to the smoke. the rats in the case group were exposed to the cigarette smoke for 10 weeks (90 minutes every day for 6 days in each week). the rats in the control group were meanwhile in the fresh room air. results: development of the sperms was mildly reduced in 14 (93.3%) and 4 (26.7%) rats in the case and control groups, respectively (p < .001). the mean average diameter of the seminiferous tubules was reported to be 0.421 ± 0.097 mm and 0.493 ± 0.026 mm in the case and control groups, respectively (p = .04). the mean numbers of sertoli cells were 9.2 ± 1.2 and 13.3 ± 1.8 in the case and control groups, respectively (p < .001). a concurrent reduction in the number of germ cells and leydig cells with the decrease in the number of sertoli cells was seen in the rats of the case group. conclusion: cigarette smoke has a rather obvious effect on spermatogenesis in rats which may be due to toxic substances in the cigarette or the histologic reactions due to hypoxemia induced by smoke. although further documentation, especially in humans is required, the potential impact of smoking on fertility in men should be considered in public health education. urol j. 2007;4:159-63. www.uj.unrc.ir keywords: smoking, spermatogenesis, animal model, rats, seminiferous tubules, sertoli cells 1department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran 2department of urology, kermanshah university of medical sciences, kermanshah, iran 3department of community medicine, mashhad university of medical sciences, mashhad, iran corresponding author: mohsen ghanbari, md deputy of education, mashhad university of medical sciences, daneshgah st, mashhad, iran tel: +98 511 843 3999 fax: +98 511 843 6828 e-mail: mohsen_ghanbarius@yahoo.com received february 2007 accepted july 2007 introduction smoking and its complications are of the most important social and health problems in all countries.(1,2) evaluation of the cigarette smoke on the urogenital system is very important especially in young population. many studies have been performed on smoking and its deleterious effects on different parts of the body and reproductive system of animals and human.(3-6) in these researches, different methods of exposure to smoke, animal models, and period of exposure have been evaluated, the results of which show apoptosis in the progenitor cells of the testis, reduction in the number and epithelial height of the germ cells, problems in the function of the germ cell mitochondria, and increment in the oxygen-free radicals.(7-12) due to the ethical matters and lack of access to testicular tissue, clinical trials cannot be performed on human. thus, we evaluated the potential risks and complications of cigarette smoking on the process of spermatogenesis in an animal model. owing to the similarity of the cigarette smoke and sperm development process—ahmadnia et al 160 urology journal vol 4 no 3 summer 2007 testicular tissues between the humans and rats, we used rats in this study. materials and methods a total of 30 male rats of the sprague race with the mean age of 10 weeks were purchased from the khorasan pastor institute and were randomly assigned into 2 groups of cases and controls. the ethics committee of mashhad university of medical sciences approved the study protocol. they were examined in the experimental research center of mashhad university of medical sciences. the cigarette we had chosen for this purpose was pine light with filter as a cigarette with average smoke production and price commonly used in iran. for achieving the smoke according to the predicted goals, a special apparatus was designed to have the ability to keep the rats for 2 hours in a very similar situation caused by smoking by human. inspired based on the similar previous studies,(11-13) it had a vp800 vacuum suction with a 200-ml shield cylinder for condensation of the smoke, a glass box in a cube shape (aquarium shape) with the size of 30 × 40 × 80 cm for keeping the rats, and a hood over the aquarium-shaped box to evacuate the extra smoke from the environment (figure 1). firstly, the rats in the case group were put in the box, and after closing the system, the cigarette was lit and the suction was concurrently turned on. the vacuum in the cylinder which was formed by the suction made the cigarette smoked. after finishing the cigarette, the suction was automatically turned off, and the smoke accumulated in the cylinder was moved to the aquarium by convection and exposed to the rats. each smoking procedure lasted 15 minutes including making the smoke and exposing the rats to the smoke for 10 minutes (1 minute, smoke condensation and 9 minutes, smoke exposure) and then, 5 minutes of rest and ventilation by uncovering the aquariumshaped box and turning the hood on. this 15-minute operation was repeated 10 times a day for a total of 2.5 hours, yielding 90 minutes of exposure to smoke. since the period of complete maturity of the sperms is about 52 days in rats, the time for smoke exposure was chosen to be 10 weeks. each week, the rats were exposed to the smoke for 6 days, each day for 1.5 hours. therefore, the rats in the case group were exposed to the smoke of a total number of 600 cigarettes. during the study period, 15 rats in the control group were maintained in a similar place but exposed to the room air. after 10 weeks, the rats in the two groups were anesthetized by chloroform and then sacrificed by its slow increment in concentration. the testicular tissue was then excised, fixed in 10% formalin, and stained by hematoxylin-eosin. two specimens were taken from each rat, each taken from one testicle. histopathological examination was done by a single pathologist blinded to the rat groups. development of spermatogenesis was classified into “normal,” “mildly reduced,” “severely reduced,” and “no spermatogenesis” (table 1). in addition, the average diameter of the seminiferous tubules in a microscopic field magnified at × 400, the mean number of sertoli cells in 1 high-power field (hpf), and indexes of the leydig cells and germ cells were determined. the indexes were calculated as follows: leydig cell index = leydig cells per hpf/ sertoli cells per hpf figure 1. the smoking apparatus is was constructed for simulating exposure of rats to cigarette smoke. left, before exposure to smoke. right, exposure to smoke. cigarette smoke and sperm development process—ahmadnia et al urology journal vol 4 no 3 summer 2007 161 germ cell index = germ cells per hpf/ sertoli cells per hpf data analyses were performed by the spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa). the chi-square test and the mann-whitney test were used for comparison of the status of spermatogenesis and the diameter of the seminiferous tubules, respectively. evaluation of the mean sertoli cells in a microscopic field was performed by the t test, since a normal distribution of the variable was noted. a p value of less than .05 was considered significant. results a significant difference was detected between the case and control groups regarding the effect of cigarette smoke on the process of spermatogenesis (p < .001). development of the sperms was mildly reduced in 14 and 4 rats in the case and control groups (table 2). figures 2 and 3 demonstrate specimens with normal and mildly reduced spermatogenesis. the mean average diameter of the seminiferous tubules was 0.421 ± 0.097 mm and 0.493 ± 0.026 mm in the case and control groups, respectively (p = .04; figures 2 and 3). the mean numbers sertoli cells were 9.2 ± 1.2 and 13.3 ± 1.8 in the case and control groups, respectively (p < .001). we did not found any differences between the two groups in the indexes of the leydig cells and germ cells, due to the concurrent reduction in the number of germ cells and leydig cells with the decrease in the number of sertoli cells in the rats of the case group. discussion several studies have been performed on the harmful effects of smoking on the genital system of humans and rats.(1-16) also, as it was previously mentioned, figure 2. testicular tissue of a rat in the control group. left, the developing sperms. right, the seminiferous tubules (hematoxylin eosin, × 400). class stages normal complete spermatogenesis and normal tubules mildly reduced normal sperm count but disorganized spermatogenesis few sperms present severely reduced no spermatozoa but abundant spermatids few spermatids no spermatozoa or spermatids but abundant spermatocytes few spermatocytes no spermatogenesis only spermatogonia no germ cells but sertoli cells no germ cells or sertoli cells table 1. pathologic classification of spermatogenesis spermatogenesis case group control group normal 1 (6.7) 11 (73.3) mildly reduced 14 (93.3) 4 (26.7) severely reduced 0 0 no spermatogenesis 0 0 table 2. development of spermatogenesis in rat of case and control groups* *values in parenthesis are percents. the two groups were significantly different (p < .001). cigarette smoke and sperm development process—ahmadnia et al 162 urology journal vol 4 no 3 summer 2007 indirectly impair spermatogenesis. these changes may be because of the presence of many toxic substances in cigarette that affect all tissues including the testes. also, the tissue reactions due to generalized hypoxia in the body can be another negative factor affecting the spermatogenesis in rats. however, the severity of smoke impact on the reproductive system is highly dependent on the using pattern, type, and number of cigarettes that are studied.(13-16) due to the metabolic similarity of the human and rat tissues, it can be concluded that cigarette smoke may affect the sperm development process; however, this needs more research on human. due to the importance of fertility in human and the high prevalence of smoking among general population, especially young people, smokers should be warned of the unwanted effects of cigarette smoking on fertility. conclusion our study showed a significant relationship between cigarette smoking and impaired testicular histology, reduced diameter of seminiferous tubules, and decrease in the index of the sertoli cells in rats. all these elements are directly linked with the reduction in the sperm development process in rats which can be generalized to human; however, studies on human are warranted in this regard. acknowledgement the authors would like to thank the research deputy of mashhad university of medical sciences, dr mehdi balali, dr mahmoudreza kalantari, and dr aliasghar yarmohammadi for their great help and support. the relationship between smoking and heart disease, lung disease, and cancers has been proved.(1,2,17,18) in 2 studies performed by rajpurkar and colleagues, during the 15-, 30-, and 45-day periods, the effects of smoking were evaluated on the morphometric changes of the testicular tissue and showed reduction in the number of germ cells, decrease in the height of germinal epithelium, diameter of the tubules, and induced apoptosis in the genital cells of the testis.(11,12) most of their results have been achieved in the present study as well, but we considered a 10-week study period to cover all spermatogenesis phases in rats (52 days), so that we were able to evaluate all possible changes during spermatogenesis that had not been evaluated previously. of the factors that had not been well evaluated were the diameter of the seminiferous tubules, number and index of the sertoli cells, percentage and quality of germ cells, and the leydig cell and germ cell indexes. in another study by yamamoto and associates, reduced condensation and motility of the sperms, dysfunction of leydig cells, and reduced ability of the genital system in hormonal secretions were shown after exposure of rats to cigarette smoke.(8) however, their results showed a few differences with ours that seemed to be due to the differences in methods such as the days of smoke exposure. the most important point in these all these studies is the apparent effect of cigarette smoke on the sperm development process in rats. as we showed in this study, the process of spermatogenesis was impaired. in addition, the mean diameter of the seminiferous tubules and the index and number of the sertoli cells reduced which could figure 3. testicular tissue of a rat in the case group. left, the developing sperms with abnormalities in both number and maturity. right, the reduced diameter of the seminiferous tubules and number of the sertoli cells (hematoxylin-eosin, × 400). cigarette smoke and sperm development process—ahmadnia et al urology journal vol 4 no 3 summer 2007 163 conflict of interest none declared. references 1. czekaj p, pałasz a, lebda-wyborny t, et al. 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kinase isoenzyme patterns upon chronic exposure to cigarette smoke: protective effect of bacoside a. vascul pharmacol. 2005;42:57-61. 8. yamamoto y, isoyama e, sofikitis n, miyagawa i. effects of smoking on testicular function and fertilizing potential in rats. urol res. 1998;26:45-8. 9. gossain vv, sherma nk, srivastava l, michelakis am, rovner dr. hormonal effects of smoking--ii: effects on plasma cortisol, growth hormone, and prolactin. am j med sci. 1986;291:325-7. 10. sofikitis n, miyagawa i, dimitriadis d, zavos p, sikka s, hellstrom w. effects of smoking on testicular function, semen quality and sperm fertilizing capacity. j urol. 1995;154:1030-4. 11. rajpurkar a, li h, dhabuwala cb. morphometric analysis of rat testis following chronic exposure to cigarette smoke. j environ pathol toxicol oncol. 2000;19:363-8. 12. rajpurkar a, jiang y, dhabuwala cb, dunbar jc, li h. cigarette smoking induces apoptosis in rat testis. j environ pathol toxicol oncol. 2002;21:243-8. 13. güven mc, can b, ergün a, saran y, aydos k. ultrastructural effects of cigarette smoke on rat testis. eur urol. 1999;36:645-9. 14. collin o, kilter s, bergh a. tobacco smoke disrupts testicular microcirculation in the rat. int j androl. 1995;18:141-5. 15. patterson tr, stringham jd, meikle aw. nicotine and cotinine inhibit steroidogenesis in mouse leydig cells. life sci. 1990;46:265-72. 16. chia se, ong cn, lee st, tsakok fh. study of the effects of occupation and industry on sperm quality. ann acad med singapore. 1994;23:645-9. 17. anbarasi k, vani g, devi cs. protective effect of bacoside a on cigarette smoking-induced brain mitochondrial dysfunction in rats. j environ pathol toxicol oncol. 2005;24:225-34. 18. chitra s, semmalar r, shyamala devi cs. effect of fish oil on cigarette smoking induced dyslipidemia in rats. indian j of pharmacolgy. 2000;32:114-9. v08_no_3_final_last.pdf urological oncology 203urology journal vol 8 no 3 summer 2011 urinary level of ca19-9 as a tumor marker in urothelial carcinoma of the bladder keya pal,1 suparna roy,1 samim ali mondal,1 uttara chatterjee,2 punit tiwari,3 malay bera3 purpose: to diagnose the urothelial carcinoma of the bladder by measuring ca19-9 level in the urine. materials and methods: this study was conducted on 47 patients with histopathologically confirmed urothelial cancer and 50 control subjects. the urinary level of ca19-9 was measured in both groups by enzyme-linked immunosorbent assay after concentration of urine with bio-gel dry beads. urine cytology was also done in both controls and patients. results: the mean urinary level of ca19-9 was 194.59 ± 110.56 u/ml in patients and 11.67 ± 8.42 u/ml in controls (p = .0001). the mean urinary level of ca19-9 in patients with low-grade and high-grade bladder cancer was 206.56 ± 114.56 u/ml and 174.80 ± 94.06 u/ml, respectively (p = .56). urine cytology by papanicolaou stain was mostly negative. conclusion: it can be concluded that ca19-9 may be a useful non-invasive test to diagnose the urothelial carcinoma of the bladder. urol j. 2011;8:203-8. www.uj.unrc.ir keywords: urinary bladder neoplasms, tumor markers, ca-19-9 antigen, urinalysis 1department of biochemistry, ipgme & r, 244-ajc, bose road, kolkata, 700020, west bengal, india 2department of pathology, ipgme & r, 244-ajc, bose road, kolkata, 700020, west bengal, india 3department of urology, ipgme & r, 244-ajc, bose road, kolkata, 700020, west bengal, india corresponding author: keya pal, md department of biochemistry, ipgme & r, 244-ajc, bose road, kolkata, 700020, west bengal, india tel/fax: +91 33 2241 0071 e-mail: prot.samim@gmail.com received december 2010 accepted may 2011 introduction bladder cancer is a major health problem in the world with more than 63 000 new cases predicted in the us yearly.(1) smoking is the greatest risk factor for urothelial carcinoma and increases risk of developing the disease four-fold compared to non-smokers.(2) age, diet, occupational chemical exposure to benzidine dye, and painting industry are other risk factors.(3) bladder cancer is generally more common in men, but the reason behind this gender biasness is unknown. early diagnosis of the bladder cancer is very difficult because there is no distinct associated symptom. (4) hematuria is one of the most common presenting symptom; however, 90% of individuals with hematuria do not have bladder cancer.(5) furthermore, gross hematuria usually denotes large tumors; hence, most likely correlates with more advanced disease. diagnosis of bladder cancer mostly depends on urine cytology and cystoscopy. cystoscopy has been proven quite successful in surveillance and follow-ups of patients with previously diagnosed bladder cancer. the drawback of cystoscopy is that it is somewhat expensive, invasive, and uncomfortable.(6) therefore, it is not a suitable tool for lifelong surveillance of patients with bladder cancer.(7) ca19-9 as a tumor marker in bladder tcc—pal et al 204 urology journal vol 8 no 3 summer 2011 in conjunction with cystoscopy, urine cytopathology helps identify precancerous and cancerous cells in the urine. but urine cytology is mostly positive in high-grade lesions and its sensitivity to detect low-grade bladder cancer is very low.(8,9) so other than cystoscopy, it is difficult to diagnose the urothelial carcinoma in early stage. in an isolated paper, it has been shown that a reliable tumor marker is a potential diagnostic tool for urothelial carcinoma along with cystoscopy.(10) carbohydrate antigen (ca) 19-9 marker is 210 kd tumor-associated glycoprotein antigen present as carbohydrate determinant on glycoprotein. ca 19-9 is characterized by monoclonal antibody 1116-ns19-9 by immunizing balb/c mice with human colorectal cancer line. this antibody reacts with ca19-9, which has been identified as a sialylated lacto-n-fucopentose ii, an oligosaccharide sharing structural features with lewis blood group substances. this antigen was localized immunohistologically on fetal epithelia of the colon, small intestine, stomach, pancreas, and liver, and very small concentration on adult gastrointestinal tract and lung tissue. considerable concentration of ca19-9 is also present in the mucin-rich saliva, seminal fluid, gastric juice, amniotic fluid, urine, ovarian cyst fluid, gall bladder, and duodenal secretions. ca19-9 is neither tumor nor organ-specific. however, the highest diagnostic sensitivity (85%) and specificity (95%) of ca19-9 are reported for adenocarcinoma of the pancreas. sensitivity of 70% has been observed in cholangiocarcinomas and gallbladder carcinomas. very low sensitivity has been reported for the colorectral, stomach, primary liver, bronchial, mucinous ovarian, uterus, and breast carcinomas.(11,12) the ca19-9 concentration correlated well with the clinical response to treatment. in addition to its use as a diagnostic tool, ca19-9 appears to be a promising marker that can predict recurrence of tumor after pancreatectomy prior to clinical or radiographic evidence of disease relapse.(11,12) the aim of this study was to determine urinary level of ca19-9 in different stages of bladder cancer and its role as a non-invasive diagnostic tool in low-grade cases of the bladder tumors. materials and methods this case-control study was conducted in the biochemistry, urology, and pathology departments of i.p.g.m.e & r over a period of 18 months and was approved by the ethics committee of i.p.g.m.e & r. the cases and controls were selected from urology outpatient department and indoor patients. fortyseven patients were selected from those with histopathologically confirmed bladder carcinoma. fifty controls were selected from those who had no previous history of any urological disorders. patients with hematuria, any age, and any gender were included in the study. abdominal mass, history of prostatism, urinary tract infection, anorexia, weight loss, or proteinuria were considered as exclusion criteria. a written informed consent was then obtained from each remained participant. reagents -enzyme-linked immunosorbent assay (elisa) kit (monobind-accubind elisa kit96 wells) -bio-gel p -mayer’s hematoxylin and eosin solution -gram’s or lugol’s iodine -95% alcohol -orange g solution -polychrome stain specimen collection and handling blood samples were obtained by venipuncture and the serum was separated according to common procedures. urine was collected as midstream urine in sterile urine container. thereafter, it was concentrated passing through bio-gel p column and supernatant was collected. the samples were stored at -20°c for 24 hours. for longer period, samples were stored at -70°c or below. samples were brought to room temperature before analysis. ca19-9 as a tumor marker in bladder tcc—pal et al 205urology journal vol 8 no 3 summer 2011 urine concentration method bio-gel p gels are porous polyacrylamide beads prepared by copolymerization of acrylamide and n,n’-methylene-bis-acrylamide. the gels are extremely hydrophilic and essentially free of charge and provide efficient, gentle gel filtration of sensitive compounds. their synthetic composition and freedom from soluble impurities preclude elute contamination. high resolution is assured by consistent narrow distribution of bead diameters and excellent molecular weight discrimination. dried gels having pore size of 90 to 180 μm were added to a measured volume of urine as weighed granules. water and small molecules were attracted into the gel by osmosis. the exclusion limit of the bio-gel p is 6000 d, but those molecular weight > 6000 d were excluded by pore size. it is almost always necessary to concentrate the urine before the test. the urine was taken and concentrated by passing it through bio-gel in 1 to 20 ratio. fifty μg of bio-gel was taken in an aliquot and 1000 μl of urine was added and kept at 2° to 4°c for 5 hours. the supernatant urine will contain the ca19-9 molecules that are 210 kd and the low molecular weight particles will be absorbed by the gel. the supernatant of the urine sample were collected and tested for ca199 level by elisa. urine cytology was done by papanicolaou stain. procedure for measurement of ca19-9 the quantitative determination of ca19-9 concentration in human sample is done by a microplate immunoenzymometric assay. in this method, ca19-9 calibrator, patients’ specimen or controls’ are first added to a streptavidin coated well. biotinylated monoclonal and enzymelabeled antibodies (directed against distinct and different epitopes of ca19-9) are added and the reactants are mixed. reaction between the various ca19-9 antibodies and native ca19-9 forms a sandwich complex that binds with the streptavidin coated well. after the completion of the required incubation period, the enzymeca19-9 antibody bound conjugate is separated from the unbound enzyme-ca19-9 conjugate by aspiration or decantation. the activity of the enzyme present on the surface of the well is quantitated by reaction with a suitable substrate to produce color. the employment of several serum references of known ca19-9 level permits the construction of a dose response curve of activity and concentration. by comparison to the dose response curve, an unknown specimen’s activity can be correlated with ca19-9 concentration. statistical analysis data were analyzed by spss software (the statistical package for the social sciences, version 14.0, spss inc., chicago, illinois, usa) using student’s independent sample t test and mannwhitney u test. results the mean age of the patients and controls was 58.74 ± 8.65 years and 61.76 ± 8.25 years, respectively. the mean urinary levels of ca19-9 and creatinine in patients were 194.59 ± 110.56 u/ml and 26.19 ± 9.32 mg/dl while they were 11.67 ± 8.42 u/ml and 63.05 ± 40.90 mg/dl in controls, respectively (p = .0001 and p = .0001) (figure 1). of 47 patients, 35 had low-grade lesions (no invasion of the lamina propia), 10 high-grade lesions (extensive muscle involvement with distant metastasis), and 2 adenocarcinoma with deep muscle involvement. comparison of patients with low-grade and high-grade urothelial carcinoma is presented in figure 1. the bar diagram showing mean urinary level of ca199 between patients and controls. ca19-9 as a tumor marker in bladder tcc—pal et al 206 urology journal vol 8 no 3 summer 2011 table. as it is shown, the mean urinary level of ca19-9 in patients with low-grade and high-grade bladder cancer was 206.56 ± 114.56 u/ml and 174.80 ± 94.06 u/ml, respectively (p = .56). in figure 2, pearson’s correlation showed poor linear correlation between serum and urinary level of ca19-9 in patients with the bladder cancer. sensitivity and specificity of urinary ca19-9 were 71% and 82%, respectively. discussion the current standard diagnostic procedure for detection and follow-up of urothelial carcinoma of the bladder consists of urethrocystoscopy, which is the gold standard, and analysis of urine cytology in particular interval of time. urethrocystoscopy is an invasive procedure and has a high risk of urinary tract infection.(13) urine cytology is less sensitive in low-grade cases. under this circumstance, the biomarker may play a role. (14,15) it has been found that serum level of ca199 may be an important tumor marker in pancreatic cancer, but in early stage its value is questionable;(16) since a significant tumor size is required before the serum level is sufficiently high. sakamato and colleagues demonstrated that the serum level of ca19-9 was not significantly raised in benign gut disorder while high incidence of raised concentration was observed in malignant gut lesion. another study proposed that serum level of ca19-9 was extremely high in case of benign biliary tract disease.(17) in some papers, it has been shown that the urinary ca19-9 concentration is increased in case of normal epithelia of the bladder. (18) vriesema and associates determined that cystoscopy was 89% preferable over biomarkers when the sensitivity of urinary cytology was 90% or less.(19) in other study, it was found that urinary biomarkers have low sensitivity; however, their diagnostic accuracy was 90%. the researchers have reported the significant variation in the performance and characteristics of available biomarkers.(20,21) theoretically, an ideal tumor marker should be highly sensitive, specific, and 100% accurate in differentiating between neoplastic and non-neoplastic lesions, and should be able to predict early recurrence.(22) the significant finding was that the urinary level of ca19-9 was higher than the reference value in both high and low-grade lesions (figure 2), but the urinary cytology was negative. the serum level of ca19-9 was also within the normal limit. the urinary level of ca19-9 was statistically significant (p < .005) and much higher in lowgrade than in high-grade cases. but this study did not correlate the level of ca19-9 with the tumor progression. we did not compare the urinary biomarker with cystoscopy and other variety of biomarkers. maerstranzi and coworkers demonstrated that the urinary tract infection, especially associated with the urinary tract obstruction, significantly correlated with an elevated serum level of ca199 due to decreased clearance. but as this tumor figure 2. scatter plot shows linear correlation between serum and urinary levels of ca-19.9 in patients. categor low-grade urothelial carcinoma high-grade urothelial carcinoma mean urinary level of ca19-9, u/ml 206.56 ± 114.56 174.80 ± 94.06 median urinary level of ca19-9 ,u/ml 188 188.15 mean serum level of ca19-9, u/ml 25.86 12.99 urinary cytology positive subjects 7 4 comparison between low-grade and high-grade transitional cell carcinoma ca19-9 as a tumor marker in bladder tcc—pal et al 207urology journal vol 8 no 3 summer 2011 marker is produced by epithelial cell of the renal pelvis, the urinary level may or may not be acted in case of bladder cancer and should be needed for long-term study.(23) patients with the bladder cancer mostly present with painless hematuria. in this study, we added hemoglobin as a crossreactant to control sample, but no cross reaction was found in this assay. although cystoscopy is the main diagnostic tool in urothelial carcinoma, it is an invasive procedure and painful, and small peripheral tumors may be missed by an expert urologist. (24,25) therefore, the long-term study is needed for urinary biomarkers as an important non-invasive diagnostic tool to overcome this problem. studies are also needed for other tumor markers because the malignant process is known to elaborate a group of markers. conclusion it can be concluded that urinary level of ca199 may play a diagnostic role in early stages of urothelial carcinoma of the bladder along with urinary cytology and cystoscopy. however, more extensive studies with greater number of patients are needed. acknowledgements we are grateful to the director, ethics committee, and head of department for giving permission to perform the study in this institution. we would also like to thank all the staff as well as patients of the department of urology for their cooperation. conflict of interest none declared. references 1. american cancer society. cancer facts and figure 2005. atlanta. 2. morrison as. advances in the etiology of urothelial cancer. urol clin north am. 1984;11:557-66. 3. burch jd, rohan te, howe gr, et al. risk of bladder cancer by source and type of tobacco exposure: a case-control study. int j cancer. 1989;44:622-8. 4. whelan p, britton jp, dowell ac. three year follow up of bladder tumours found on screening. br j urol. 1993;72:893-6. 5. messing em, madeb r, young t, et al. long-term outcome of hematuria home screening for bladder cancer in men. cancer. 2006;107:2173-9. 6. rodriguez-rubio f, sanz g, garrido s, sanchez c, estudillo f. patient tolerance during outpatient flexible cystoscopy--a prospective, randomized, double-blind study comparing plain lubrication and lidocaine gel. scand j urol nephrol. 2004;38:477-80. 7. almallah yz, rennie cd, stone j, lancashire mjr. urinary tract infection and patient satisfaction after flexible cystoscopy and urodynamic evaluation* 1. urology. 2000;56:37-9. 8. schwalb dm, herr hw, fair wr. the management of clinically unconfirmed positive urinary cytology. j urol. 1993;150:1751-6. 9. rife cc, farrow gm, utz dc. urine cytology of transitional cell neoplasms. urol clin north am. 1979;6:599-612. 10. sherman ab, koss lg, adams se. interobserver and intraobserver differences in the diagnosis of urothelial cells. comparison with classification by computer. anal quant cytol. 1984;6:112-20. 11. steinberg wm, gelfand r, anderson kk, et al. comparison of the sensitivity and specificity of the ca19-9 and carcinoembryonic antigen assays in detecting cancer of the pancreas. gastroenterology. 1986;90:343-9. 12. saraswati a, malati t. superiority of ca 125 over ca 19-9 and cea for epithelial ovarian malignancies indian j clin biochem. 1995;10:23-8. 13. burke dm, shackley dc, o’reilly ph. the communitybased morbidity of flexible cystoscopy. bju int. 2002;89:347-9. 14. bigbee w, herberman rb. tumor markers and immunodiagnosis. 6 ed. hamilton, ontario: bc decker; 2003. 15. vrooman op, witjes ja. urinary markers in bladder cancer. eur urol. 2008;53:909-16. 16. kau sy, shyr ym, su ch, wu cw, lui wy. diagnostic and prognostic values of ca 19-9 and cea in periampullary cancers. j am coll surg. 1999;188: 415-20. 17. taylor b. carcinoma of the head of the pancreas versus chronic pancreatitis: diagnostic dilemma with significant consequences. world j surg. 2003;27:1249-57. 18. hegele a, mecklenburg v, varga z, olbert p, hofmann r, barth p. ca19. 9 and cea in transitional cell carcinoma of the bladder: serological and immunohistochemical findings. anticancer research. 2010;30:5195. 19. vriesema jl, poucki mh, kiemeney la, witjes ja. patient opinion of urinary tests versus flexible urethrocystoscopy in follow-up examination for superficial bladder cancer: a utility analysis. urology. 2000;56:793-7 20. van rhijn bw, van der poel hg, van der kwast th. urine markers for bladder cancer surveillance: a systematic review. eur urol. 2005;47:736-48. ca19-9 as a tumor marker in bladder tcc—pal et al 208 urology journal vol 8 no 3 summer 2011 21. nagao k, itoh y, fujita k, fujime m. evaluation of urinary ca19-9 levels in bladder cancer patients classified according to the combinations of lewis and secretor blood group genotypes. int j urol. 2007;14:795-9. 22. droller mj. current concepts of tumor markers in bladder cancer. urol clin north am. 2002;29:229-34. 23. maestranzi s, przemioslo r, mitchell h, sherwood r. the effect of benign and malignant liver disease on the tumour markers ca19-9 and cea. ann clin biochem. 1998;35:99. 24. liou ls. urothelial cancer biomarkers for detection and surveillance. urology. 2006;67:25-33; discussion -4. 25. nam rk, redelmeier da, spiess pe, sampson ha, fradet y, jewett ma. comparison of molecular and conventional strategies for followup of superficial bladder cancer using decision analysis. j urol. 2000;163:752-7. 999vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l autologous fibrin sealant in tubeless percutaneous nephrolithotomy; a prospective study seyyed amir mohsen ziaee, reza sarhangnejad, hassan abolghasemi, peyman eshghi, mohammad hadi radfar, ali ahanian, mehdi kardoust parizi, nasser amirizadeh, akbar nouralizadeh purpose: to evaluate the efficacy of autologous single-donor fibrin glue after tubeless percutaneous nephrolithotomy (pcnl). materials and methods: forty-three patients were planned for tubeless pcnl in a prospective cohort study and randomized in two groups with or without using fibrin glue. randomization method was based on the computer-generated random numbers. results: transfusion, urinary leakage, or major complications were found in neither of the groups. there was no difference between two groups in stone free rate (p = .53), and changes in hemoglobin (p = .61) and serum creatinine (p = .63) level. conclusion: although autologous fibrin glue did not play any significant role in improving results or decreasing complications after tubeless pcnl in our study, its use was safe and did not increase complications. keywords: percutaneous; surgery; kidney calculi, treatment outcome; fibrin tissue adhesive; wound closure techniques corresponding author: akbar nouralizadeh, md urology and nephrology research center, no. 103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: nouralizadeh@yahoo. com received october 2012 accepted may 2013 brief communication 1000 | brief communication introduction renal stone disease is one of the most common diseases in the world with the lifetime prevalence of 1% to 15% worldwide(1) and 5.7% in iran.(2) percutaneous nephrolithtomy (pcnl) is the gold standard method to treat large kidney stones.(3) hemorrhage and urine extravasation are the most common complications of pcnl.(4) to decrease these complications, a nephrostomy tube is inserted.(5) however, because the nephrostomy tube can cause pain and discomfort for patients, tubeless pcnl has been introduced as an alternative. adhesive and hemostatic substances, such as fibrin glue, have been used to decrease the risk of bleeding and extravasation after tubeless pcnl.(5-7) fibrin sealants usually used in pcnl are commercially available products prepared from large pools of blood plasma.(5-7) in this study, we used autologous single-donor fibrin sealant to compare results of tubeless pcnl with and without fibrin sealant. to the best of our knowledge, this is the first prospective study evaluating autologous single-donor fibrin sealant application in pcnl. materials and methods from september 2010 to december 2011, 43 patients were recruited into this prospective cohort study. randomization method was done using computer-generated random numbers. to prepare autologous fibrin sealant, all the patients should have a body weight of over 40 kg, without any clinical restriction for plasmapheresis according to the national standards of the iranian blood transfusion organization (ibto).(8) patients were randomly divided into two groups: experimental group, tubeless pcnl with the use of fibrin glue at the end of the procedure and control group, tubeless pcnl without fibrin glue. of 43 patients, fibrin sealant was instilled in 15. at the beginning of the study, 28 patients were included in sealant group. because many patients were coming from far cities and could not follow the necessary steps of fibrin glue preparation, their sealant was not prepared at the time of surgery. therefore, 13 patients were added to the control group. the mean cost per case for fibrin sealant preparation was 5 000 000 rials (# 150 us$) provided by ibto. the principles of fibrin sealant preparation have been described elsewhere.(9) total volume of fibrin glue was 10 cc, consisting of 5 cc fibrinogen and 5 cc thrombin.(10) the study was approved by the ethics committee of our institute. the outcome of patients in the experimental group was compared with the control group using the independent sample t test with 95% confidence interval. differences were considered significant at p values of less than .05. results no double-j catheter was placed in 43 subjects. according to table 1, there was no significant difference in demographic data, side of surgery, and pre-operative hemoglobin and creatinine levels between two groups. table 2 shows post tubeless pcnl results in two groups. transfusion, urine leakage, and major complications were seen in neither of the groups. in fibrin glue group, there was no complication. in the control group, only one patient had hematuria that improved with conservative management, and one patient had fever that was treated with one extra dose of antibiotic. there was significant difference in mean catheterization days between two groups (p = .027), but no difference was seen in mean hospitalization (p = .11). there was no difference in hemoglobin and creatinine changes between two groups (p = .29 and p = .46, respectively). during followup period, 2 patients in the control group had residual stone that were managed with swl. discussion to decrease urinary leakage and bleeding after tubeless pcnl, adhesive products, such as fibrin glue, have been studied. fibrin sealants have been used in a broad spectrum of surgical specialties with a hemostatic or sealing role. (11,12) there is an increasing tendency to use fibrin sealants in laparoscopic partial nephrectomy and tubeless pcnl.(13) fibrinogen and thrombin constitute the components of fibrin sealants. the components are extracted from two main sources; plasma pools or single-donor plasma donation, which are described as commercial and blood bank products, respectively. the use of commercial sealants has been 1001vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l associated with some safety issues including the transmission of blood-borne diseases, bleeding, anaphylaxis, allergic reaction, and prions.(14-18) to decrease the concerns of using commercial products, autologous blood was applied to prepare fibrinogen and fibrin glue. in our preparation method, mean fibrinogen concentration measured by elisa and clauss method was 73 ± 8 mg/ml and 71 ± 7 mg/ml, respectively.(10) the tensile strength of tissel® could be provided by a fibrinogen concentration of 30 to 60 mg/ml(19) autologous fibrin glue has been applied in various surgeries, such as ophthalmologic procedures, hernia repair, urological procedures, and lung surgery.(20-27) to the best of our knowledge, there is no report about its application in pcnl. shah and associated compared tubeless pcnl with and without instillation of tisseel retrospectively. they showed significant decrease in analgesic consumption (p = .05) and earlier discharge (7 hours) in the fibrin glue group. there were no differences in hemoglobin drop, transfusion rate, and other complications between two groups.(28) in another retrospective study, mikhail and colleagues compared tubeless pcnl with and without fibrin glue. fibrin glue led to significant decrease in hospitalization by 0.71 day (p < .05), but there was no significant difference in hematocrit drop, analgesic use, and operative time. postoperative fever and wound seroma had occurred in fibrin glue group.(29) in our study, there was no statistical difference between two groups regarding complications and hospital stay. there was no complication due to fibrin glue, urinary leakage, or significant change in hemoglobin. possible obstruction of the pyelocaliceal system is a concern about fibrin glue application in pcnl,(16,30) in the present study, although fibrin glue did not play any significant role in reduction of complications or improvement of table 1. patients’ demographic and pre-operative data. variables with fibrin glue without fibrin glue p no. of patients 15 28 male/female, n (%) 11 (73.3%)/4 (26.7%) 16 (57.1%)/12 (42.9%) .29 mean age ± sd, y 39.87 ± 10.35 43.89 ± 13.74 .32 mean weight ± sd, kg 74.2 ± 8.66 74.89 ± 10.39 .82 mean stone size ± sd, cm 2.77 ± 0.86 2.71 ± 1.27 .86 right/left side, n (%) 9 (60%)/6 (40%) 14 (50%)/14 (50%) .53 mean pre-op hemoglobin ± sd, mg/dl 14.97 ± 1.09 14.20 ± 1.58 .06 mean pre-op creatinine ± sd, mg/dl 1.02 ± 0.12 1.08 ± 0.31 .05 sd indicates standard deviation. table 2. post tubeless percutaneous nephrolithotomy results. postoperative data with fibrin glue without fibrin glue p approach supracostal intercostal subcostal 2 (13.3%) 2 (13.3%) 11 (73.3%) 11 (39.3%) 2 (7.1%) 15 (53.6%) .20 mean post-op creatinine ± sd, mg/dl 1.22 ± 0.26 1.22 ± 0.30 .63 mean post-op hemoglobin ± sd, mg/dl 12.93 ± 1.43 12.54 ± 1.55 .61 transfusion 0 0 residual stones at day 1, n of patients 0 1 1 residual stones at 2 weeks, n of patients 0 2 .53 mean catheterization ± sd, day 2.2 ± 0.41 1.79 ± 0.62 .02 mean hospitalization ± sd, day 2.27 ± 0.59 2.0 ± 0.47 .11 sd indicates standard deviation. autologous fibrin sealant in tubeless pcnl | ziaee et al 1002 | 10. hashemi teir a, amirizadeh n, eshghi p, abolghasemi h, amani m, jabbari a. study of in vitro properties of fibrin sealant prepared from single donor plasma. khoon. 2009;6:181-9. 11. singh k, moyer h, williams jk, schwartz z, boyan bd. fibrin glue: a scaffold for cellular-based therapy in a critical-sized defect. ann plast surg. 2011;66:301-5. 12. wolter tp, fuchs p, pallua n. alloplastic cancellous bone replacement and fibrin glue in hand surgery. handchir mikrochir plast chir. 2010;42:317-21. 13. joch c. the safety of fibrin sealants. cardiovasc surg. 2003;11:23-8. 14. hong ym, loughlin kr. the use of hemostatic agents and sealants in urology. j urol. 2006;176:2367-74. 15. hino m, ishiko o, honda ki, et al. transmission of symptomatic parvovirus b19 infection by fibrin sealant used during surgery. br j haematol. 2000;108:194-5. 16. taylor dm. inactivation of tse agents: safety of blood and bloodderived products. transfus clin biol. 2003;10:23-5. 17. oswald am, joly lm, gury c, disdet m, leduc v, kanny g. fatal intraoperative anaphylaxis related to aprotinin after local application of fibrin glue. anesthesiology. 2003;99:762-3. 18. alston sm, solen ka, broderick ah, sukavaneshvar s, mohammad sf. new method to prepare autologous fibrin glue on demand. transl res. 2007;149:187-95. 19. de hingh ih, nienhuijs sw, overdevest ep, scheele k, everts pa. mesh fixation with autologous platelet-rich fibrin sealant in inguinal hernia repair. eur surg res. 2009;43: 306-9. 20. moser c, opitz i, zhai w, et al. autologous fibrin sealant reduces the incidence of prolonged air leak and duration of chest tube drainage after lung volume reduction surgery: a prospective randomized blinded study. j thorac cardiovasc surg. 2008;136:843-9. 21. ozcan aa. autologous human fibrin glue in multilayered amniotic membrane transplantation. ann ophthalmol. 2008;40:107-9. 22. foroutan a, beigzadeh f, ghaempanah mj, et al. efficacy of autologous fibrin glue for primary pterygium surgery with conjunctival autograft. iran j ophthalmol. 2011;23:39-47. 23. gammon rr, prum be jr, avery n, mintz pd. rapid preparation of small-volume autologous fibrinogen concentrate and its same day use in bleb leaks after glaucoma filtration surgery. ophthalmic surg lasers. 1998;29:1010-2. 24. asrani sg, wilensky jt. management of bleb leaks after glaucoma filtering surgery. use of autologous fibrin tissue glue as an alternative.ophthalmology. 1996;103:294-8. 25. mandel ma. minimal suture blepharoplasty: closure of incisions with autologous fibrin glue. aesthetic plast surg. 1992;16:269-72. tubeless pcnl results, no complication was seen due to fibrin glue. short-term follow-up period and small number of included patients are our study limitations. additional prospective randomized trials with larger number of patients are required to evaluate the efficacy and outcome of fibrin glue application after tubeless pcnl. conclusion although fibrin glue did not play any significant role in improving results or decreasing complications of tubeless pcnl in our study, our results suggest that it can be used safely. due to numerous applications of this substance in a wide variety of surgical fields, the autologous method used to produce fibrin sealant could be a solution to some safety concerns. conflict of interest none declared. references 1. stamatelou kk, francis me, jones ca, nyberg lm, curhan gc. time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003;63:1817-23. 2. safarinejad mr. adult urolithiasis in a population based study in iran. prevalence, incidence, and associated risk factors. urol res. 2007;35:73-82. 3. kim iy, eichel l, edwards r, et al. effects of commonly used hemostatic agents on the porcine collecting system. j endourol. 2007;21:652-4. 4. shah hn, hegde s, shah jn, et al. a prospective, randomized trial evaluating the safety and efficacy of fibrin sealant in tubeless percutaneous nephrolithotomy. j urol. 2006;176:2488-92. 5. noller mw, baughman sm, morey af, et al. fibrin sealant enables tubeless percutaneous stone surgery. j urol. 2004;172:166-9. 6. limb j, bellman gc. tubeless percutaneous renal surgery: review of first 112 patients. urology. 2002;59:527-31. 7. lee di, uribe c, eichel l, et al. sealing percutaneous nephrolithotomy tracts with gelatin matrix hemostatic sealant: initial clinical use. j urol. 2004;171:575-8. 8. rezvan h, ahmadi j, mirbod v. the iranian blood transfusion donor safety program: effect of long-term plasmapheresis on plasma proteins. iranian journal of medical science. 2003; 28: 33-6. 9. shekarriz b, stoller ml. the use of fibrin sealant in urology. j urol. 2002;167:1218-25. brief communication 1003vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l autologous fibrin sealant in tubeless pcnl | ziaee et al 26. kajbafzadeh am, abolghasemi h, eshghi p, et al. single-donor fibrin sealant for repair of urethrocutaneous fistulae following multiple hypospadias and epispadias repairs. j pediatr urol. 2011;7:422-7. 27. hong ym, loughlin kr. the use of hemostatic agents and sealants in urology. j urol. 2006;176:2367-74. 28. shah hn, kausik v, hedge s, et al. initial experience with hemostatic fibrin glue as adjuvant during tubeless percutaneous nephrolithotomy. j endourol. 2006;20:194-8. 29. mikhail aa, kaptein js, bellman gc. use of fibrin glue in percutaneous nephrolithotomy. urology. 2003;61:910-4. 30. uribe ca, eichel l, khonsari s, et al. what happens to hemostatic agents in contact with urine? an in vitro study. j endourol. 2005;19:312-7. point of technique 192 urology journal vol 5 no 3 summer 2008 synchronous bilateral laparoscopic radical nephrectomy for solid renal masses using a hybrid approach pedram ilbeigi, daniel brison, hossein sadeghi-nejad urol j. 2008;5:192-6. www.uj.unrc.ir keywords: laparoscopy, nephrectomy, kidney neoplasms, surgical procedures, kidney transplantation department of urology, hackensack university medical center and umdnj new jersey medical school, hackensack, new jersey and section of urology, va new jersey health care system, east orange, new jersey, usa corresponding author: hossein sadeghi-nejad, md, facs umdnj new jersey medical school, department of surgery, division of urology, 185 south orange ave, msb g 536, newark, nj 07103-2714, usa tel: +1 973 972 4488 fax: +1 973 395 7197 e-mail: hossein@ix.netcom.com received march 2008 accepted april 2008 introduction bilateral synchronous laparoscopic nephrectomies are rare procedures usually performed to treat uncontrolled hypertension and polycystic kidney disease in patients on dialysis and kidney transplant recipients.(1-3) only a few case reports exist today describing synchronous laparoscopic treatment of bilateral solid masses in the kidneys.(4,5) both conventional (“pure”) and hand-assisted techniques have been described to simplify port placements and standardize the procedure.(4-6) however, optimal methods and details of various approaches remain controversial. in this report, we demonstrate that as clinical scenarios differ (ie, body habitus, size, and location of diseased renal units), a customized approach may become necessary to treat these challenging cases. to the best of our knowledge, this is also the first reported case of bilateral posttransplant radical nephrectomy employing both conventional and hand-assist laparoscopy for synchronous bilateral renal masses. case report a 61-year-old african-american man with a history of end-stage renal disease, uncontrolled hypertension, insulin-dependent diabetes mellitus, and obesity was referred for the management of bilateral renal masses. he had undergone kidney transplantation 11 years prior to presentation. he measured 6 feet tall and weighed 111 kg. computed tomography revealed bilateral and multiple synchronous solid renal masses. the right kidney measured 11 cm × 8 cm and contained 3 distinct solid masses in the upper, mid, and lower poles measuring 3.5 cm, 3 cm, and 2.2 cm in diameter, respectively. the left kidney measured 18 cm × 12 cm and was replaced almost entirely with multiple large solid renal masses encompassing the upper, mid, and lower poles (figures 1 and 2). the extraperitoneal transplanted kidney was moderately hydronephrotic and palpable in the right lower quadrant of the abdomen. it measured 13 cm in length, extended to the level of the umbilicus (figure 3). baseline serum creatinine was 2.1 mg/dl. metastatic workup revealed no evidence of disease outside the renal units. considering the body habitus, the sizes of the individual renal units and their encompassing solid masses, and the location of a rather large transplanted kidney in the bilateral laparoscopic radical nephrectomy—ilbeigi et al urology journal vol 5 no 3 summer 2008 193 right lower quadrant, a conventional (“pure”) transperitoneal laparoscopic radical nephrectomy was planned and executed on the right side, and a hand-assisted laparoscopy was performed for the left side. technique the patient was placed in a modified semiflank position for both sides. on the right side, 4 trocars were placed as depicted in figure 4. a 5-mm trocar was placed approximately 4 cm off midline above the umbilicus under direct telescopic vision. the abdominal cavity was surveyed and there were minimal adhesions noted in the right lower abdomen. a 12-mm trocar (used for the vascular stapler) was inserted approximately 3 cm above the most cephalad portion of the large extraperitoneal transplanted kidney in the right lower quadrant. two additional 5-mm trocars were then placed midway between the xiphoid process and the umbilicus (for the camera), and anterior axillary line at the level of the umbilicus, serving as the port for liver retraction. as dissection ensued, a single artery figure 1. computed tomography showed bilateral renal masses (arrows). figure 2. computed tomography showed multiple renal tumors in both kidneys. figure 3. computed tomography showed large transplant kidney encompassing the right lower abdomen (arrow). figure 4. schematic illustration shows port hand-assist and port positioning in the obese man. bilateral laparoscopic radical nephrectomy—ilbeigi et al 194 urology journal vol 5 no 3 summer 2008 and vein were identified and clipped/stapled. once the right kidney was free of all attachments, it was placed in a large impermeable specimen bag and tied to prevent spillage of fluids. it was placed in the lateral gutter until the left side was completed. afterwards, the trocar sites were closed and the patient was repositioned for the contralateral side. a 7-cm longitudinal paramedial incision was made about the peri-umbilicus area and a handport disc was placed. a 5-mm trocar was placed through the lap disc and pneumoperitoneam was re-established. under direct telescopic vision, a 12-mm trocar (used for the vascular stapler) was placed in the left lower quadrant midway between the umbilicus and the anterior superior iliac spine. an additional 5-mm trocar was placed midway between the xiphoid process and the umbilicus in the paramedial plane. as depicted on the computed tomography image, the left kidney was very large, heavy, and bulky. there was a significant amount of inflammation about the hilum and the superior pole making the planes adherent and difficult to develop. the hand-assisted technique facilitated this dissection. a single vein and artery were identified and controlled in a similar fashion on this side. once completely mobilized, the left kidney was also placed in an impermeable extralarge laparoscopic specimen bag. the hand-assist incision was extended another 3 cm inferiorly and both specimen bags were removed without difficulty. the fascia was closed along with the two trocar sites. the patient was extubated and transferred to the recovery room without incident. results the operative time was 92 minutes for the dissection of the right kidney. twenty minutes were spent on repositioning. the operative time for the left kidney was 124 minutes. the estimated blood loss was less than 100 ml. the postoperative period was uneventful. hospital stay was 4 days and the patient returned to his normal activities within 2 weeks. final pathology revealed 3 distinct papillary and clear-type renal cell carcinomas on the right kidney measuring 8 cm, 7 cm, and 6.5 cm in their greatest dimension. on the left, there were multiple large papillary-type renal cell tumors, the largest of which were 14 cm, 13 cm, and 9 cm in diameter. the patient has done well postoperatively with no evidence of tumor recurrence at 6-month follow-up. discussion the role of laparoscopic nephrectomy for the management of kidney neoplasms has been well established.(7) on rare occasions, bilateral nephrectomy becomes necessary in the management of synchronous disease. in these cases, the kidneys can be removed safely and efficiently using laparoscopic techniques.(4-5,8) however, the optimal approach and techniques remain controversial. schwartz and vestal recently described a case where pure bilateral nephrectomies were performed using only 5 ports without repositioning the patient.(4) as expected, the authors demonstrated a very good outcome with comparable operative times and excellent cosmetic results. it is conceivable that the operation may have been rendered “easier” by the fact that the patient described by these authors was a relatively small 42-year-old woman on dialysis with small kidneys. to their credit, the authors individualized and optimized their operative technique for their specific case. the problem remains that most patients treated with bilateral synchronous nephrectomies often suffer from very large polycystic kidneys in which the dissection, positioning, and trocar placement must be individualized.(9) reports of hand-assisted laparoscopy to facilitate dissection in these complex situations indicate generally excellent results and outcomes.(3,6,9) the common goal is to provide rapid recovery, patient comfort, shorter hospital stay, and improved cosmetic results. there are very few case reports that describe laparoscopic treatment of bilateral synchronous renal solid masses. both “pure” and hand-assisted techniques have been described to simplify and standardize these operations.(4-5,8) to our knowledge, there are no reports of bilateral synchronous multiple renal masses in a bilateral laparoscopic radical nephrectomy—ilbeigi et al urology journal vol 5 no 3 summer 2008 195 transplanted patient. there are also no reports of the concomitant use of hand-assistance and a pure laparoscopic approach in the same patient. the focus of this paper was to present a difficult clinical scenario in which an obese man with a history of prior kidney transplantation presented with bilateral multiple large tumors in the kidneys. a customized approach was devised to give this patient all the benefits of laparoscopy and minimally invasive surgery while limiting potential complications. conventional “pure” laparoscopic radical nephrectomy was performed on the right kidney since the renal unit was relatively small and the hydronephrotic transplant kidney occupied much of the right lower abdomen. the left kidney was large and heavy. therefore, a hand port was placed to facilitate dissection. furthermore, the trocars had to be placed quite laterally on both sides in order to optimize access and to facilitate dissection in this obese patient. although retroperitoneal laparoscopic dissection was feasible on the right side, this approach would not have been optimal for the left side: the sheer size of the left kidney and the necessity of placing the patient in a full flank position (with potential compression of the transplanted kidney) weighed against retroperitoneal dissection. the traditional advantages of hand-assisted laparoscopy have been well described. several studies have shown that hand-assisted techniques do not prolong hospital stay, nor do they increase narcotic requirements or adversely affect patient outcome.(10) the hand in the operative field allows for excellent manual retraction and blunt dissection with great vascular control. during laparoscopic radical nephrectomy, the hand port will facilitate removal of large renal units and allow strict adherence to surgical oncologic principles. if bleeding is encountered, manual compression of the vessels can be performed similar to open surgery. it became apparent early during our dissection that tactile feedback and manual retraction were critically important in removing the large left kidney. the hand-assist port was used to extract both kidneys en bloc instead of morcellation. organ extraction in the face of malignancy remains controversial and some argue that the truly minimally invasive surgeon should morcellate renal masses within a specimen bag and extract them through one of the port sites. while it is not our intention to argue the long-debated topic of morcellation, we prefer precise tumor staging and duplication of open surgical techniques with proven oncologic equivalence.(10) in summary, bilateral synchronous laparoscopic radical nephrectomy for the treatment of bilateral renal malignancies can be performed safely and efficiently. single patient positioning, standardized trocar placement, and pure conventional laparoscopy may be preferred in most instances. however, the operative surgeon must be able to tailor his or her surgical technique to provide optimal methods of dissection and extraction in various clinical scenarios. handassisted laparoscopy enables surgeons of various skill levels to expedite surgery while minimizing the risk of complications. the hybrid technique employed in this case allowed for efficient and expeditious synchronous bilateral radical nephrectomy in the face of a complex clinical scenario while providing all the benefits of minimally invasive surgery. conflict of interest none declared. references 1. fornara p, doehn c, fricke l, durek c, thyssen g, jocham d. laparoscopic bilateral nephrectomy: results in 11 renal transplant patients. j urol 1997;157:445-9. 2. sanjeevan kv, bhat hs, sudhindran s. laparoscopic simultaneous bilateral pretransplant nephrectomy for uncontrolled hypertension. transplant proc. 2004;36:2011-2. 3. zaman f, nawabi a, abreo kd, zibari gb. pretransplant bilateral hand-assisted laparoscopic nephrectomy in adult patients with polycystic kidney disease. jsls. 2005;9:262-5. 4. schwartz bf, vestal jc. bilateral purely laparoscopic nephrectomy for renal masses using five ports without repositioning: a case report. j endourol. 2004;18:44951. 5. flasko t, tallai b, varga a, toth c, salah m. singlesession laparoscopic radical and contralateral partial nephrectomy. j endourol. 2005;15:322-4. 6. schmidlin fr, iselin ce. hand-assisted laparoscopic bilateral laparoscopic radical nephrectomy—ilbeigi et al 196 urology journal vol 5 no 3 summer 2008 bilateral nephrectomy. urology. 2000;56:153-4. 7. ruiz-deya g, cheng s, palmer e. open donor, laparoscopic donor and hand-assisted laparoscopic donor nephrectomy: a comparison of outcomes. j urol. 2000;163:1650-3. 8. chen ch, huan sk, lin jt, chiu aw. laparoscopic bilateral nephro-ureterectomy and bladder cuff excision for native renal pelvic and ureteral transitional cell carcinoma after renal transplantation. j postgrad med. 2003;49:148-50. 9. gill is, kaouk jh, hobart mg, sung gt, schweizer dk, braun we. laparoscopic bilateral synchronous nephrectomy for autosomal dominant polycystic kidney disease: the initial experience. j urol. 2001;165:1093-8. 10. munver r, del pizzo jj, sosa er. the advantages of hand-assisted laparoscopy. curr urol rep. 2004;5:100-7. case reports 121urology journal vol 4 no 2 spring 2007 results of inadvertent administration of bacillus calmette-guerin for treatment of transitional cell carcinoma of bladder aliasghar yarmohammadi, hassan ahmadinia, mehran abolbashari, mahmood molaei urol j. 2007;4:121-2. www.uj.unrc.ir keywords: bladder cancers, transitional cell carcinoma, bacillus calmette-guerin, intravesical instillation, intramuscular injection department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran corresponding author: aliasghar yarmohamadi, md no 13, 6th mina st, ibne sina st, bahar ave, mashhad, iran tel: +98 511 761 1868 fax: +98 511 841 7404 e-mail: yaghoti2005@yahoo.com received october 2006 accepted march 2007 introduction intravesical instillation of bacillus calmette-guerin (bcg) is a known treatment method in superficial bladder cancers after transurethral resection of the bladder tumor (turbt).(1) moreover, its polysaccharide nucleotide is used in the treatment of asthma.(2) however, the most familiar usage of the bcg to the public is vaccination against tuberculosis (tb) as a subcutaneous injection or oral administration.(3) physicians should explain method of its use to the patients in order to avoid wrong injection and its side effects. in this study, we present a patient with transitional cell carcinoma (tcc) of the bladder in whom 4 vials of bcg were wrongly injected intramuscularly. case report a 60-year-old man with a history of turbt was recommended to have 1 course (6 doses) of intravesical bcg instillation. however, the patient traveled to another city and the injection was done erroneously; 2 vials of bcg (120 mg) were intramuscularly injected 2 weeks after turbt with an interval of 12 hours. after the second injection, the patient experienced severe headache, sweating, and fever. the following day, 2 other vials of bcg were injected in the gluteal muscles and headache and sweating developed again. three days after the intramuscular injections, the patient experienced pain and induration in the site of injections and severe pain in the hypogastric area. he referred to his own physician and inravesical instillation of bcg was administered. the first and second intravesical bcg vials, diluted in 50 milliliters of normal saline were used intravesically about 3 and 4 weeks after the turbt. he presented to our center almost 1.5 months after the turbt. on physical examination, pain, erythema, tenderness, and induration were detected bilaterally in the gluteal muscles. ultrasonographic evaluations revealed no abscess. urinalysis showed abundant red blood cells, 15 to 16 white blood cells per high-power field, and fungal mycelium. mantoux screening test was negative after 48 hours. morning urine samples and gastric lavage in 3 consecutive days were negative for mycobacterium tuberculosis. chest radiography was performed and no active or old lesion of tb was detected. on the intravenous urography, delay in the secretion of the right kidney, dilatation in the pyelocaliceal system and the right ureter, and irregularities in the ureteropelvic junction were bacillus calmette-guerin and transitional cell carcinoma of bladder—yarmohammadi et al 122 urology journal vol 4 no 2 spring 2007 detected. according to the consultation with the experts in tb, oral isoniazid, 300 mg/d, and rifampin, 600 mg/d, were started for the patient. the classic treatment of bladder tcc was continued after making sure that no side effect of bcg administration remained. discussion for achieving useful results by bcg therapy for the superficial bladder tumors, its appropriate use is crucial. otherwise, unwanted side effects may develop. this necessitates giving complete information to the patients. bacillus calmette-guerin is generally used subcutaneously, and sometimes, its oral or intranasal administration is used for vaccination. its intravesical instillation is applied for the superficial bladder tumors.(1-3) side effects of subcutaneous injection of bcg are usually restricted to the injection area, and systemic involvement is rarely seen.(4,5) the adverse effects include lymphadenopathy, local scar, and systemic tb. to our knowledge, intramuscular injection of bcg has only been reported in 2 patients.(6,7) in one of those patients, abscess was formed in the muscle which was resolved by conservative treatment.(7) the amount of injected solution was very lower in these cases in comparison with ours. due to the scarcity of intramuscular injection of bcg, the treatment and follow-up strategies of the affected patients is not clear yet. in our patient, in spite of 2 injections of bcg in the gluteal muscles and then, instillation into the bladder, no paraclinical findings indicative of the disease were found. however, empirical treatment with oral isoniazid and rifampin was initiated and continued for 3 months according to the consultation with the specialists in infectious diseases. during this period, no sign of tb or gluteal abscess was detected. the literature lacks evidence to support our treatment of tb for the patient. however, due to the large amount of injection and the history of fever, pain, tenderness, swelling, and redness in the gluteal region during the first days after injections, we preferred to perform prophylactic treatment with isoniazid and rifampin. after 8 months, no complication was detected. however, some gastrointestinal problems, delayed intravesical treatment with bcg, loss of time and money of the patient, and negative psychological effects on the patient were the consequences of the inadvertent intramuscular injections of bcg. such problems are the things that should be prevented by educating the patients and the health care personnel. on the other hand, there is an interesting question to be brought forward: does the intramuscular injection of bcg affect—either negatively or positively—the clinical course of bladder cancer? conflict of interest none declared. references 1. prapotnich d. [bcg therapy of superficial tumors of the bladder]. bull cancer. 1998;85:135-9. french. 2. li j, luo df, li sy, sun bq, zhong ns. efficacy of intramuscular bcg polysaccharide nucleotide on mild to moderate bronchial asthma accompanied with allergic rhinitis: a randomized, double blind, placebocontrolled study. chin med j (engl). 2005;118:1595603. 3. lamm dl, sarodosy ms, dehaven ji. percutaneous, oral, or intravesical bcg administration: what is the optimal route? prog clin biol res. 1989;310:301-10. 4. bolger t, o>connell m, menon a, butler k. complications associated with the bacille calmetteguerin vaccination in ireland. arch dis child. 2006;91:594-7. 5. bellet js, prose ns. skin complications of bacillus calmette-guerin immunization. curr opin infect dis. 2005;18:97-100. 6. [intramuscular administration of bbc vaccine--a warning]. lakartidningen. 1977;74:445. swedish. 7. pasteur mc, hall dr. the effects of inadvertent intramuscular injection of bcg vaccine. scand j infect dis. 2001;33:473-4. case report 63urology journal vol 7 no 1 winter 2010 bladder paralysis due to foodborne botulinum toxin type b karine loiseau,1 maria-carmelita scheiber-nogueira,1 caroline tilikete,2 alain vighetto,2 gilles rode1 urol j. 2010;7:63-5. www.uj.unrc.ir keywords: bladder diseases, foodborne diseases, botulinum toxin type b 1université de lyon, lyon; inserm umr-s 864, bron, hospices civils de lyon; service de médecine physique et réadaptation, hôpital henry gabrielle, saint genis-laval, france 2université de lyon, lyon; inserm umr-s 864, bron, hospices civils de lyon, service de neurologie d, hôpital neurologique pierre wertheimer, bron, france corresponding author: karine loiseau, md service de médecine physique et réadaptation, hôpital henry gabrielle, hospices civils de lyon, 20 route de vourles, f-69230 saint genis-laval, france tel : +33 478 86 50 68 e-mail: karineloiseau@hotmail.com received february 2009 accepted april 2009 introduction foodborne botulism is a rare toxi-infection in france (20 to 30 cases per year).(1) incubation time is comprised between few hours to 8 days. clostridium botulinum is an anaerobic gram-positive organism which is ubiquitously found in soil and aquatic sediments in the spore form. several forms of botulism exist. the foodborne form is the most frequent in the human botulism. clostridium botulinum produces 7 different toxins of type a, b, c, d, e, f, and g. toxin type a is the most frequent and is found in the home-canned. toxin type b is found in the cooked pork meats. all forms of botulism produce the same clinical symptoms: symmetrical cranial nerve palsies followed by descending, flaccid paralysis of voluntary muscles, which may progress to respiratory arrest. prominent autonomic symptoms include accommodative paralysis with mydriasis, anhydrosis with severe dry mouth and throat, and orthostatic hypotension. constipation and bladder paralysis are rarely reported.(2) all toxins exert their action on the cholinergic system at the presynaptic motorneuron terminal by blocking acetylcholine transmission across the neuromuscular junction. it causes neuromuscular blockade, resulting in a flaccid paralysis.(3) this article describes a case of a 43-year-old man who presented with severe botulism manifestations. in addition to the severe cranial motor nerves paralysis, a complete bladder paralysis was observed. case report a 43-year-old man, without a previous medical disorder presented to the neurological unit with progressive cranial motor nerves impairment, including bilateral and complete intraocular and extra-ocular muscles paralysis, swallowing deficit, and dysphonia. a few days before, he had experienced a painful abdominal syndrome with diarrhea and vomiting. the patient did not display any motor or sensory limb deficit. vigilance and cognition were not affected. the patient, required hospitalization in intensive care unit due to respiratory failure 24 hours following the first neurological signs. moreover, he showed a complete bladder paralysis with preservation of bladder-filling sensation, imposing indwelling urethral catheterization. dysautonomic symptoms were also noted with bilateral mydriasis (without reaction to light), constipation due to a paralytic ileus, orthostatic hypotension, and oral dryness. bladder paralysis due to foodborne botulinum— loiseau et al 64 urology journal vol 7 no 1 winter 2010 brain tomodensitometry and lumbar puncture were normal. electroneuromyography examination revealed dysfunction at the presynaptic neuromuscular junction which was suggestive of botulism. botulism toxin type b was present in blood. a diagnostic of botulism was confirmed by mouse inoculation few days after the first symptoms. a complete sanitary investigation was made and no contaminated food was founded. there was no other similar case in the family. the spontaneous recovery of different neurological symptoms was assessed by clinical examination and urodynamic investigation. two periods of recovery could be distinguished: a first period from day 30 to day 45 postonset, and a second later period from day 120 to day 150 postonset. during the first period, improvement was seen in ptosis, swallowing deficit, dysautonomic symptoms (constipation and orthostatic hypotension), and external ophtalmoplegia. at this stage, the patient kept accommodative deficit. a first urodynamic investigation at day 30 revealed a normal bladder-filling sensation and normal compliance with detrusor acontractility. increased urethral closure pressure was observed. a vesicosphincter dyssynergia was present. self intermittent catheterization was decided. during the second period, the patient recovered from spontaneous micturition, and self catheterization was progressively stopped from day 120 to day 150. moreover, at the same time, the patient regained normal accommodative function. on day 120, urodynamic investigation revealed a hyposensitive and hypocompliant bladder. detrusor contractility was reduced. micturition during urodynamic test was impossible despite a good external sphincter relaxation and a transient falling of urethral pressure. the pressure flow analysis revealed a dysuric urination without residual urine in the bladder. all the urinary disorders disappeared 3 months later. discussion the only reported case of a bladder paralysis due to botulism was a wound-botulism due to toxin type a in a context of an intravenous drug use. (4) the patient also had a severe limbs paralysis and respiratory failure which led to intubation and tracheotomy. he presented bladder paralysis resulting in self intermittent catheterization. three months later, the patient was able to void spontaneously and correctly.(4) we report a similar bladder paralysis due to a foodborne botulism (toxin type b). our patient presented with bladder paralysis due to botulism toxiinfection with cranial motor nerves paralysis and several dysautonomic disorders. the table compares characteristics of the two reported bladder paralysis cases due to botulism. the clinical manifestations are similar: diplopia, dysarthia, dysphagia, and internal ophtalmoplegia. our patient did not show limb characteristic sautter et al(4) present report cause of botulism wound foodborne type of toxin a b clinic data ophtalmoplegia + + dysarthria + + facial paresis + + dysphagia + + limb paralysis + respiratory failure + + oral dryness … + constipation paralytic ileus … + bladder paralysis + + orthostatic hypotension … + paraclinic data electroneurographical examination + + lumbar puncture normal normal presence of the toxin in the blood … + mouse inoculation + + first urodynamic investigation bladder filing sensation normal normal compliance … reduced detrusor activity acontractility acontractility vesicosphincter dyssynergia … + final pressure flow analysis micturition volume, ml 600 596 micturition time, s … 80 peak flow, ml/s 23.1 12.0 residual urine, ml 0 0 comparison of 2 cases of bladder paralysis due to botulism* *plus sign indicates the presence of the condition; minus sign, the absence of the condition; and ellipses, no data available. bladder paralysis due to foodborne botulinum— loiseau et al 65urology journal vol 7 no 1 winter 2010 paralysis or respiratory failure, but he displayed several dysautonomic symptoms (orthostatic hypotension, oral dryness, constipation, and bladder paralysis). the diagnosis was established in the presence of the toxin in the blood and the positive mouse inoculation. urodynamic investigations are not really comparable because details of the compliance and the dyssynergia were not provided in the other published case.(4) the final pressure flow analysis shows complete micturations while detrusor hypocontractility is still present. recovery period was longer in our case, particularly for the bladder paralysis that lasted for 150 days. therapeutic approach for botulism is first intensive care (mechanical ventilation). antitoxin therapy could be used in serious cases, which can stop progression of the paralysis. antitoxin should be given early, ideally at the first 24 hours from the onset of the first symptoms. antitoxin therapy is associated with adverse effects (anaphylaxis). skin testing must be made to test sensitivity. in our patient, the diagnosis was made a week after the first symptoms, so it was too late to use antitoxin.(2) lastly, the botulinum toxin has been largely used in therapy for several years. in particular, it is an important treatment for dystonia, selective spasticity, and detrusor overactivity.(3, 5-7) for the detrusor hyperactivity, the toxin type a is predominantly used.(8-10) toxin type b is also used, but duration of its therapeutic action is shorter than type a. this is somewhat contrasting with the delayed recovery due to foodborne botulism toxin type b in our patient. conflict of interest none declared. references 1. abgueguen p, delbos v, chennebault jm, et al. nine cases of foodborne botulism type b in france and literature review. eur j clin microbiol infect dis. 2003;22:749-52. 2. sobel j. botulism. clin infect dis. 2005;41:1167-73. 3. poulain b, humeau y. [mode of action of botulinum neurotoxin: pathological, cellular and molecular aspect]. ann readapt med phys. 2003;46:265-75. french. 4. sautter t, herzog a, hauri d, schurch b. transient paralysis of the bladder due to wound botulism. eur urol. 2001;39:610-2. 5. pistolesi d, selli c, rossi b, stampacchia g. botulinum toxin type b for type a resistant bladder spasticity. j urol. 2004;171:802-3. 6. reitz a, schurch b. botulinum toxin type b injection for management of type a resistant neurogenic detrusor overactivity. j urol. 2004;171:804. 7. sangla s. aspects thérapeutiques actuels de la toxine botulique en neurologie. paris: emc elsevier masson; 2006. 8. schurch b, stohrer m, kramer g, schmid dm, gaul g, hauri d. botulinum-a toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? preliminary results. j urol. 2000;164:692-7. 9. schmid dm, sauermann p, werner m, et al. experience with 100 cases treated with botulinum-a toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. j urol. 2006;176:177-85. 10. hirst gr, watkins aj, guerrero k, et al. botulinum toxin b is not an effective treatment of refractory overactive bladder. urology. 2007;69:69-73. case report the effectiveness of sacral neuromodulation on a patient with a previous successful cystoplasty augmententation: a case report farzaneh sharifiaghdas* this report is about the effectiveness of sacral neuromodulation in a 32-year-old woman with a history of augmented cystoplasty who required clean intermittent catheterization. she was referred to our center with a medical history of bilateral vesicoureteral reflux because of neuropathic lower urinary tract dysfunction. we successfully did a sacral neuromodulation on her which lead to promising results. keywords: clean intermittent catheterization; cystoplasty; sacral neuromodulation introduction sacral neuromodulation is a minimally invasive approach, which has been approved officially as a well-estab-lished procedure in the treatment of refractory urinary urge incontinence, non-obstructive urinary retention, urgency, and frequency(1,2). it has been reported to have promising results in the treatment of chronic disorders resistant to conventional therapy, including interstitial cystitis and women’s sexual dysfunction. however, none has been approved officially(3,4). this report is about the effectiveness of sacral neuromodulation in a patient with urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran *correspondence: urology nephrology research center, labbafinejad medical center, no. 103, 9th boostan st, pasdaran avenue, tehran, iran. tel: +98 21 22567222. fax: +98 21 22567282. email: f.sharifiaghdas@gmail.com received july 2019 & accepted april 2020 urology journal/vol 17 no. 6/ november-december 2020/ pp. 674-676. [doi: 10.22037/uj.v0i0.5439] figure 1. voiding cystourethrography of the patient demonstrating the augmented bladder with a high capacity. a history of augmented cystoplasty who required clean intermittent catheterization (cic). case report a 32-year-old woman was referred to our center with a past medical history of bilateral high grade vesicoureteral reflux(vur), and two times failure of endoscopic and open surgical repair of vur. with an obvious low back dimple sign and very low capacity, low compliance bladder and evidence of several episodes of high amplitude detrusor over activity (according to multi channel urodynamic study )and urinary incontinence. she was finally diagnosed as a case of neuropathic lower urinary tract dysfunction. she underwent augmentation cystoplasty with a segment of ileum about 15 years before referring to us. the patient was in need of cic to empty the bladder. however, she refused to perform regular daily cic and had been admitted to hospital several times because of bladder over-distention and residual urine, abdominal pain, symptomatic urinary tract infection or increased level of serum creatinine. she even had committed suicide due to her mood changes related to the mentioned chronic urinary problems (this was mentioned in her psychologic and psychiatric consultation reports). all procedures done in this study were in accordance with the principles of the declaration of helsinki. the patient insisted to have a more natural way of voiding. she signed a written informed consent before undergoing sacral neuromodulation to increase the ability of voiding. the preoperative evaluations including the genitourinary physical examination and cystourethroscopy results were within normal limits. voiding cystourethrography showed that she had a large augmented bladder, low-grade left vesicoureteral reflux and high residual urine (figure 1). multichannel urodynamic study showed a high capacity bladder (>800 ml), high compliance, acontractile detrusor with a very weak sensation (just the first sensation at 400 ml). she was undergoing self-catheterization once every day. there was no evidence of volitional voiding or urinary incontinence in her three-day frequency volume chart. she underwent unilateral peripheral nerve evaluation (pne) by placing a temporary wire (305765sc, medtronic, minneapolis, inc.) in the right s3 foramen which was connected directly to the external pulse generator (brown box, verify 3531, medtronic, minneapolis, inc.). according to the second frequency volume chart during the first week of pne, the patient stated that she had regained the ability to void. the first pne period lasted ten days. pne test was repeated in the contralateral s3 foramen for eight days (table 1). according to the three-day frequency volume chart, the response rate to the pne test phase for both sides was more than 50%. therefore, she underwent implantation of quadripolar tined lead (3889-28, medtronic, minneapolis, inc.) and implantable pulse generator (3058, medtronic, minneapolis, inc.) in a one stage surgery. at the time of writing this report, that is 12 months after the surgery, she voids volitionally and does cic once every night in case of need. she is very satisfied with the clinical results (figure 2). there has been no incidence of symptomatic urinary tract infection or abdominal pain and she has not stayed at the hospital since the operation. the urodynamic study four months after the surgery revealed regaining more bladder sensations at lower volumes. the detrusor pressure at the maximum flow rate was 10 cmh2o. discussion sacral neuromodulation’s exact mechanism of action is unclear. a few studies suggest an effect on the afferent sensory never fibers mainly corresponding to the s3 root, modulating the filling and voiding phase of the bladder(1). rasmussen and colleagues(5) reported the successful use of sacral neuromodulation in two women with intractable urinary frequency, urgency and urgency-incontinence following bladder augmentation with ileum. symptoms of both cases had improved after sacral neuromodulation. our case had no continence and lower urinary tract symptoms, which is typically what we would expect from a successful augmented bladder. but she became intolerant to cic. her urodynamic study result in follow-up revealed only 10 cmh20 increase in the augmented detrusor pressure during the void. so, it is not clear whether sacral neuromodulation works by increasing the contractility of neo-bladder or decreasing the muscle resistance of bladder outlet (pelvic floor muscles or external sphincter) especially in the present case. to our knowledge, this is the first report of a successful sacral neuromodulation in a patient with a successful augmented bladder who was dependent on cic with a promising result. conflict of interest the author has no conflicts of interest. sacral neuromodulation with previous cystoplasty-sharifiaghdas figure 2.a) voiding cystourethrography of the patient, full bladder with implanted tined lead and implantable pulse generator; b) her voiding cystourethrography demonstrating the residual urine after implanting the pulse generator. case report 675 acknowledgement the authors thank muhammed hussein mousavinasab for editing this text. references 1. indar a, young-fadok t, cornella j. a dual benefit of sacral neuromodulation. surg innov. 2008;15:219-22. 2. al-sannan b, banakhar m, hassouna mm. the role of sacral nerve stimulation in female pelvic floor disorders. curr obstet gynecol rep. 2013;2:159-68. 3. chai tc, zhang c, warren jw, keay s. percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary hb-egf levels and antiproliferative activity in patients with interstitial cystitis. urology. 2000;55:643-6. 4. chartier-kastler ej, ruud bosch jl, perrigot m, chancellor mb, richard f, denys p. longterm results of sacral nerve stimulation (s3) for the treatment of neurogenic refractory urge incontinence related to detrusor hyperreflexia. j urol. 2000;164:1476-80. 5. rasmussen nt, guralnick ml, o'connor rc. successful use of sacral neuromodulation after failed bladder augmentation. canadian urological association journal = journal de l'association des urologues du canada. 2009;3:e49-e50. vol 17 no 05 september-october 2020 527 sacral neuromodulation with previous cystoplasty-sharifiaghdas vol 17 no 06 november-december 2020 676 special feature 66 urology journal vol 4 no 2 spring 2007 renal replacement therapy in iran mitra mahdavi-mazdeh,1, 2 alireza heidary rouchi,2 shahram norouzi,2 mohammad aghighi,2 hamid rajolani,2 sadegh ahrabi2 urol j. 2007;4:66-70. www.uj.unrc.ir 1department of nephrology, imam khomeini hospital, tehran university of medical sciences, tehran, iran 2management center for transplantation and special diseases, ministry of health, iran corresponding author: mitra mahdavi-mazdeh, md management center for transplantation and special diseases, vanak sq, tehran, iran tel: +98 21 8864 4515 fax: +98 21 8864 4516 e-mail: mmahdavi@tums.ac.ir dialysis and kidney transplantation are the only treatment options available for patients suffering from end-stage renal disease (esrd). more than 1 million patients are on renal replacement therapy (rrt) worldwide, and it is forecasted that their population will be doubled within the next decade. there is a clear direct relationship between a nation’s gross national product and the availability of rrt. approximately, 90% of patients with esrd come from developed nations.(1-3) conversely, for the vast majority of patients who live in developing countries (roughly 85%), dialysis and transplantation are unaffordable.(4) generally, a series of influencing factors dictate the gross diversity in making decisions about the rates and modalities of the rrt. there are different reported incidences of esrd in different countries, on the one hand, and significant variations in the culture, socioeconomic status, dialysis costs and quality, reimbursement structures, and discrepancy between the demand and supply of organs for transplantation, on the other hand. to facilitate effective future planning by healthcare authorities, reliable and up-to-date information on the number of patients with esrd, development trends, treatment modalities, and treatment outcomes are indispensable. worldwide, many national and international renal registries provide demographic and epidemiologic information on patients with kidney failure. the united states renal data system, the japanese renal registry, and the european renal association/ european dialysis and transplant association registry are the most famous ones. such databases provide a valuable basis for comparisons between the specified patient populations and aid understanding of treatment practices, policies, and the implications for the well-being of patients who undergo treatment for esrd. meanwhile, such information regarding esrd incidence and different modalities of treatments are not available from large parts of developing world.(2,5,6) in iran, there is a central registry system and the data of rrt centers of the country are updated every 3 months in the management center for transplantation and special diseases (mctsd), affiliated to the ministry of health (moh). this article reviews the status of esrd and rrt in iran with emphasis on its incidence, prevalence, and treatment. although the total health expenditure is 6% of the gross domestic product (gdp) and the gdp per capita is us$ 8900 (2006 statistics),(7) different modalities of rrt are free of charge and accessible for all in iran. a fixed reimbursement rate for dialysis and renal replacement therapy in iran—mahdavi-mazdeh et al urology journal vol 4 no 2 spring 2007 67 transplantation in both public and private hospitals is paid by the government. according to our database at the mctsd, the number of esrd patients on rrt in iran, with the population of 70 million, reached about 25 000 in 2006 and regarding the increasing trend of 12% per year, it will be around 40 000 by the next 5 years. the prevalence and incidence of esrd are 357 per million population (pmp) and 66 pmp, respectively. currently, 48.5% of the patients are on hemodialysis, 48.5% have received transplantation, and 3% are on peritoneal dialysis. although there are several governmental and private organizations engaged in esrd issue, the moh is the main sponsor of this program through the mctsd. this organization is responsible for not only supporting the provision of the products and services needed for patients with esrd, but also policy making and strategic planning to implement effective mechanisms for activities that will lead to improvement of the health status of patients and to establish higher standards of treatment.(8) transplantation in iran, the first kidney transplantation was performed in 1968, but until 1988, transplantation program severely lagged in growth in comparison with dialysis. between 1980 and 1985, more than 400 patients traveled abroad to receive a kidney transplant. in 1985, the high expense of transplantation in other countries and the increasing number of patients who were on the kidney transplant waiting list urged the health authorities to establish transplant facilities inside the country. consequently, a total of 274 kidney transplantations from living related donors were performed between 1985 and 1987. the large number of patients with esrd with no living related donor and unestablished cadaveric donor procurement program led to adoption of a government-funded, -regulated, and -compensated living unrelated donor kidney transplantation program in 1997. currently, iran has the largest reported experience of living unrelated donor transplants.(9-13) as a result, the number of transplant teams increased. at present, there are 25 kidney transplantation centers nationwide, and by the end of 2006, a total of 21 359 kidney transplantations have been performed in iran. kidney transplant activity in iran reached a record of 23 transplants per million per year in 2006. graft survivals at 1 year and 2 years are 89.1% and 87.7%, respectively. it should be mentioned that workups for the potential donor and the recipient are very similar in different transplant centers.(10) the annual rate of kidney transplantation is between 1800 and 1900 with 75%, 12%, and 13% from living unrelated, living related, and cadaveric donors, respectively. brain-death organ donors are 1.8 pmp, nonheart-beating tissue donors are 26 pmp, and living donors are 23 pmp. according to our registration at the mctsd, the male-female ratio in 21 359 kidney transplants was 1.6:1. the trend of that ratio has not shown any significant changes during the previous 5 years. all of the kidney transplant teams belong to university hospitals. to prevent transplant tourism, foreigners are not allowed to undergo transplantation from iranian living unrelated donors. also, they are not permitted to volunteer as kidney donors to iranian patients. the donor and the recipient should be from the same nationality, and authorization for such transplantation should be obtained from the mctsd.(10) in 1997, governmental rewarding donation was legislated, and now, the living unrelated donor receives an award and 1-year health insurance following transplantation. the majority of living unrelated donors also receive compensation from recipient (overseen by the kidney foundation of iran, a charity involved in this process). the results of living unrelated donor kidney transplantation in longterm follow-up with a large number of cases show that this approach (iranian model) is as good as living related donor kidney transplantation. the organ shortage can be alleviated by using living unrelated donor kidney transplantation.(9,12-15) after legislation for cadaveric transplantation in 2000, a virtual network was developed. the numbers of organ procurement units and brain death identification units are 13 and 18, respectively, in iran with 30 provinces and an area of 1.648 million km2. each case of brain death is determined by 5 physicians at the university hospitals and 1 of them is specialist in forensic medicine. physicians in charge of brain death determination are appointed by the minister of health. the steps taken for cadaveric kidney donation system in iran is similar to that of many other countries.(8) it should also be mentioned renal replacement therapy in iran—mahdavi-mazdeh et al 68 urology journal vol 4 no 2 spring 2007 that cadaveric transplantation is purely altruistic and there is no gift to families except for funeral expenses in few cases. there are national formularies for immunosuppressive drugs. before 1996, the available immunosuppressive drugs for maintenance therapy consisted of cyclosporine (neoral), generic azathioprine, and prednisone. since 2000, mycophenolate mofetil has been used instead of azathioprine and now over 95% of patients are on cellcept. induction therapy is carried out with antithymocyte globulin, and in some cases, with interleukin-2 receptor antibodies. the government subsidizes the essential immunosuppressive drugs (cyclosporine, mycophenolate mofetil) and provides them for all transplant recipients in a much reduced price. all patients with esrd including kidney transplant recipients belong to a group of patients called “patients with special diseases” that are eligible for a government-provided health insurance. hemodialysis there was an increasing incidence of esrd from 49.9 pmp in 2000 to 64 pmp in 2006.(13) the increase in the number of admitted patients to rrt was mirrored by an increase in the number of dialysis centres (227 in 2000 to 316 in 2006) and dialysis machines, transplantation centres, and preemptive transplantation (figure 1). the mean age of the patients on dialysis is 52.8 years (in contrast with that in transplant recipients which is 38.0 years) and malefemale ratio is 1.3:1, which have not shown significant changes during this period. the advocated policy for younger patients is transplantation as soon as possible.(16) the number of preemptive transplantations increased from 328 in 2001 to 491 in 2006. the average cost of dialysis (without the human resource and maintenance drugs expenditures) is us$ 43.2 per treatment session that is covered by the government. in 2001, less than 5% to 10% of dialysis sessions were performed using bicarbonatecontaining dialysis solution. by 2006, the target of 63% of dialysis sessions with bicarbonate-containing dialysis solution all over the country was achieved. the potassium concentration of dialysate can be varied, but 2.0 mmol/l is the usually accepted concentration. depending on the quality of the water source, water for the dialysate is ultimately purified by reverse osmosis in all centres. two types of biocompatible dialyzers (hemophan and polysulfone) were in use in 2005, but by the end of 2006, polysulfone replaced hemophan entirely. reprocessing of hemodialyzers for reuse is not practiced in iran.(16) according to the regulations, dialysis membranes must be disposable. since obtaining and maintaining adequate access to the circulation remains a major impediment to the longterm success of hemodialysis, arteriovenous fistula is the advocated formulary of the country due to its being the most durable and cheapest option; 61% of patients were treated with the standard thrice-weekly regimen and its trend in the last 5 years is shown in figure 2. regarding anemia management, the type of intravenous iron preparation provided for patients differs substantially by country; ferric hydroxide 52 51.6 50.8 50.3 50 48.5 47.5 47.7 48 47.5 47.4 48.5 0.5 0.7 1.2 32.62.2 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2001 2002 2003 2004 2005 2006 year p er ce nt hemodialys is peritoneal dialysis trans plant figure 1. renal replacement therapy trend in iran between 2001 and 2006 figure 2. weekly dialysis sessions in iran between 2001 and 2006 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2001 2002 2003 2004 2005 2006 year p er ce nt once a week twice a week thrice a week renal replacement therapy in iran—mahdavi-mazdeh et al urology journal vol 4 no 2 spring 2007 69 polymaltose (maltofer) served as the only intravenous iron preparation used in france, while ferric or ferrous gluconate comprises more than 80% of the intravenous iron used in germany, italy, and spain. iron sucrose (venofer) accounts for more than 93% of the intravenous iron used in the united kingdom.(17) in iran, we use venofer in all cases. ferritin was the most commonly performed measure of iron status of patients on hemodialysis in iran (76.7%), similar to the reports from france, italy, spain, and the united kingdom (90%), and in contrast to that in germany (63%).(17) peritoneal dialysis continuous ambulatory peritoneal dialysis (capd) has come a long way since its introduction 25 years earlier. it has become a viable alternative of rrt in many developing countries.(4) continuous ambulatory peritoneal dialysis was started as pilot in 1997 in iran. the number of patients on peritoneal dialysis (pd) is increasing, but very slowly. the conventional singlebag system, once the predominant capd system, has been replaced by the disconnect system. swanneck catheters, with a resulting increase in the cost of pd are used. to reduce the costs, local production of the dialysis solution was started. although the annual cost of capd is not greater than that for hemodialysis, it is not supported by public insurance agencies yet. the government provides the fund for treating dialysis patients. overall, this situation may reflect the fact that the dialysis facilities and the physicians receive a higher payment for hemodialysis than for pd as it has been well established. the tendency to biphasic distribution of pd utilization rate has also been previously noted.(4) the disparity in pd utilization across developing countries is often inextricably linked to the local government and insurance reimbursement policies. it seems that lack of incentive to prescribe pd like that in many other developing countries with unequal reimbursement for pd and hemodialysis is a possible barrier for its publicity which needs more attention. conclusion as a developing country, the achieved standard of rrt in iran is acceptable, and in some aspects, comparable with the western countries, but the number of esrd patients is increasing in line with global trends. increases in hemodialysis centers, machines, and shifts, and increase in peritoneal dialysis coverage and kidney transplantation rate are being practiced, but these cannot keep pace with the increase in the number of patients. it is highly recommended that we should try to increase pd coverage and cadaveric transplantation with regard to the fact that the prevalent population of individuals with chronic kidney disease (ckd) is estimated to be at least 20 times larger than that the esrd population.(18,19) if no intervention is made, these people will experience progression to esrd and need one of the rrt modalities. in the current year, provision of hemodialysis sessions for patients costs us$ 77.4 million for the country. moreover, the most important adverse outcomes of ckd include not only complications of decreased glomerular filtration rate and progression to kidney failure, but also increased risk of cardiovascular diseases. decision makers in public health and biomedical sciences should view ckd differently.(19-20) we can focus initially on strategies and treatments that slow progression of ckd. acknowledgment the authors wish to acknowledge the leadership role of all transplant surgeons and nephrologists in establishing the rrt as a well-organized activity in the whole country. references 1. nwankwo e, bello ak, el nahas am. chronic kidney disease: stemming the global tide. am j kidney dis. 2005;45:201-8. 2. grassmann a, gioberge s, moeller s, brown g. esrd patients in 2004: global overview of patient numbers, treatment modalities and associated trends. nephrol dial transplant. 2005;20:2587-93. 3. world kidney day [homepage on the internet]. inaugurating world kidney day-the fact sheets [cited 2006 march 9]. available from: http://www. worldkidneyday.org/. 4. li pk, chow km. the cost barrier to peritoneal dialysis in the developing world--an asian perspective. perit dial int. 2001;21 suppl 3:s307-13. 5. grassmann a, gioberge s, moeller s, brown g. endstage renal disease: global demographics in 2005 and observed trends. artif organs. 2006;30:895-7. 6. modi gk, jha v. the incidence of end-stage renal 42_3.pdf 42_35.pdf pdf-531.pdf 439vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l keywords: collision tumor, cystic nephroma, neuroblastoma, childhood introduction acollision tumor is present when two distinct primary tumors are found and a neuroblastoma. case report symptoms. on her physical examination, a mass at the right upper lateral abdomen nearly 7 × 6 cm in diameter was palpated. her past and family histories were unremarkable. the abdominal ultrasonography and tomography scan revealed a 93 × 75 × 81 mm mass in the right renal localization, which had a smooth surface and multiple septae with solid and cystic areas. the 24-hour urine sample examination revealed increased amounts of vanilylmandelic acid and homovanilic acid (2.8 mg/day and within normal limits. right radical nephrectomy was performed and a mass at the inferior region of the right adrenal gland was removed. the renal tumor was well circumscribed with ceyhun bozkurt,1 ulya ertem,1 sema apaydın,2 ferda şenel,3 gürses şahin,1 nazmiye yüksek,1 sonay i̇ncesoy özdemir,1 esin boduroğlu2 coexistence of cystic nephroma and neuroblastoma a rare case of a childhood collision tumor corresponding author: ceyhun bozkurt, md department of pediatric oncology, dr. sami ulus children’s hospital, i̇lkbahar mah. 590. sok. no: 9/7, 06550, çankaya, ankara, turkey tel: + 90 312 305 6061 fax: + 90 312 317 0353 e-mail: bozkurt.ceyhun@ gmail.com received january 2010 accepted june 2010 1 department of pediatric oncology, dr. sami ulus children’s hospital, ankara, turkey 2 department of pathology, dr. sami ulus children’s hospital, ankara, turkey 3 department of urology, dr. sami ulus children’s hospital, ankara, turkey case report 440 | mm. the cut surface of the tumor was multicystic with non-communicating cysts that varied in size from a few millimeters to 4 cm. the other was soft, mm in size. on microscopic examination, the cysts were lined differentiated tubules (figure 1). the surrounding kidney tissue showed minimal mesangial proliferation and tubule epithelium with no evidence of any other dysplastic lesions. no blastemal rest or other precursor lesions of wilms tumor were encountered. microscopic examination of the other tumor in the inferior region of the adrenal gland revealed all stages of neuronal differentiation throughout the tumor. the tumor had a lobular appearance between the groups of tumor cells, and was composed of sheets of small cells with hyperchromatic nuclei and scanty cytoplasm. between the tumor cells were immature, multinucleated, or completely abnormal ganglion cells that were placed either seen between the masses of cells. to express synaptophysin and chromogranin (figbecause of technical problem. this pathologic diagnosis was well differentiated neuroblastoma and for nine years. discussion neuroblastic tumors are mainly originated from primordial neural crest cells that generate adrenal medulla and sympathetic ganglia. and cystic, partially-differentiated nephroblastoma on the benign end and polycystic wilms tumor on the malignant end.(1,2) there are two peaks in the incidence of the tumor, one in the childhood and one in the middle age. most childhood cases occur between the ages of 3 months and 2 years and 73% of the subjects are male. the second peak consists (3) neoplasms were reported.(4) unknown.(5) painless abdominal mass(6) nephroma may also cause infection, hypertension, and pain.(7) pre-operative diagnosis with radiological methods may be imprecise or even inadequate.(8) some authors suggest that ultrasonography is better than computed tomography in terms of showing inter(9) childhood has previously been reported as coexistent mesoblastic nephroma and neuroblastoma, (12) mor,(13) and neuroblastoma and nephroblastoma.(14) nisen and colleagues have reported a 2.5-year-old roblastoma on the left kidney.(15) but in our patient, both tumors were on the same side. vegunta and associates have discussed the etiology of collision figure 1. cystic nephroma which consists of varied size cysts and septae (hematoxylin and eosin, × 80) case report 441vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l coexistence of cystic nephroma and neuroblastoma | bozkurt et al tumors and proposed that a common tumorigenic stimulus triggers the neoplastic transformation of different cell types and their tumorigenic development. we propose that therapy for collision tumor must be designed for both tumors if they have a malignant component. conflict of interests none declared. references 1. joshi vv, beckwith jb. multilocular cyst of the kidney (cystic nephroma) and cystic, partially differentiated nephroblastoma. terminology and criteria for diagnosis. cancer. 1989;64:466-79. 2. sacher p, willi uv, niggli f, stallmach t. cystic nephroma: a rare benign renal tumor. pediatr surg int. 1998;13:197-9. 3. madewell je, goldman sm, davis cj, jr., hartman ds, feigin ds, lichtenstein je. multilocular cystic nephroma: a radiographic-pathologic correlation of 58 patients. radiology. 1983;146:309-21. 4. jenkner a, camassei fd, boldrini r, et al. 111 renal neoplasms of childhood: a clinicopathologic study. j pediatr surg. 2001;36:1522-7. 5. eble jn, bonsib sm. extensively cystic renal neoplasms: cystic nephroma, cystic partially differentiated nephroblastoma, multilocular cystic renal cell carcinoma, and cystic hamartoma of renal pelvis. semin diagn pathol. 1998;15:220. 6. boulanger sc, brisseau gf. cystic nephroma: a benign renal tumor of children and adults. surgery. 2003;133:596-7. 7. castillo oa, boyle et, jr., kramer sa. multilocular cysts of kidney. a study of 29 patients and review of literature. urology. 1991;37:156-62. 8. babut jm, bawab f, jouan h, coeurdacier p, treguier c, fremond b. renal cystic tumours in children--a diagnostic challenge. eur j pediatr surg. 1993;3:157-60. 9. hopkins jk, giles hw, jr., wyatt-ashmead j, bigler sa. best cases from the afip: cystic nephroma. radiographics. 2004;24:589-93. 10. vegunta rk, morotti ra, shiels we, 2nd, rauck a, besner ge. collision tumors in children: a review of the literature and presentation of a rare case of mesoblastic nephroma and neuroblastoma in an infant. j pediatr surg. 2000;35:1359-61. 11. hero b, kremens b, sudermann t, haas rj. collision tumor in children: a review of the literature and presentation of a rare case of mesoblastic nephroma and neuroblastoma in an infant. j pediatr surg. 2001;36:1607-8. 12. delahunt b, thomson kj, ferguson af, neale tj, meffan pj, nacey jn. familial cystic nephroma and pleuropulmonary blastoma. cancer. 1993;71:1338-42. 13. vujanic gm, jenney me, adams h, meyrick sm. juxtaposed cystic nephroma and wilms' tumor. pediatr dev pathol. 2000;3:91-4. 14. bissig h, staehelin f, tolnay m, et al. co-occurrence of neuroblastoma and nephroblastoma in an infant with fanconi's anemia. hum pathol. 2002;33:1047-51. 15. nisen pd, rich ma, gloster e, et al. n-myc oncogene expression in histopathologically unrelated bilateral pediatric renal tumors. cancer. 1988;61:1821-6. figure 2. (a) diffuse synaptophysin staining in neoplasm, antisynaptophysin (× 200). (b) chromogranin positive areas of the neoplasm, anti-chromogranin (× 200) a b case reports 184 urology journal vol 4 no 3 summer 2007 endovascular treatment of a delayed renal artery pseudoaneurysm following blunt abdominal trauma ashwin garg, ashwini gokhale, prerna garg, prajakta patil urol j. 2007;4:184-6. www.uj.unrc.ir keywords: abdominal trauma, hematuria, renal artery, pseudoaneurysm, embolization department of radiology, lokmanya tilak medical college and municipal general hospital, sion, mumbai, india corresponding author: ashwin garg, md 123/9 civil lines north, across from the railway station, muzaffarnagar (up)-251001, india tel: +91 131 240 2348 fax: +91 22 2418 5678 e-mail: ashwin_garg@yahoo.co.in received may 2007 accepted august 2007 introduction pseudoaneurysms of the renal artery occur most commonly after a penetrating trauma or as a complication of some renal interventional procedures such as kidney biopsy, percutaneous nephrostomy, and open or endoscopic surgeries on the kidney; however, their occurrence after blunt abdominal trauma is rare.(1) the average interval between injury and onset of the secondary renal hemorrhage is approximately 12 days (range, 2 to 36 days).(2) we present a case with renal artery pseudoaneurysm presented with gross hematuria 8 years after a blunt abdominal trauma. case report a 30-year-old man was referred to the emergency room of our center with spontaneous onset of painless hematuria. on physical examination, the patient was conscious. blood pressure and pulse rate were normal and the abdomen was soft. joint movements were normal and there were no skin or mucosal sores or any other signs related to vasculitides such as behcet syndrome. history of hypertension was found neither in the patient nor in his family. urinalysis revealed presence of albumin (3+) and 100 to 120 red blood cells per high-power field. abdominal ultrasonography showed a large pseudoaneurysm at the upper pole of the right kidney. the pyelocaliceal system was dilated with internal echoes suggesting rupture of the pseudoaneurysm into the pyelocaliceal system. these findings were confirmed by ct angiography (figure 1). there were no findings suggesting renal tumor or figure 1. multiplanar reformatted computed tomography (left) and axial computed tomography (right) showed pseudoaneurysm (arrows) arising from the segmental branch in the upper pole of the right kidney. endovascular treatment of renal artery pseudoaneurysm—garg et al urology journal vol 4 no 3 summer 2007 185 angiomyolipoma. initially, the patient denied any history of medical or surgical traumas, but on repeated enquiry, he recalled an abdominal trauma due to car accident 8 years earlier associated with stab wounds resulting from a few glass pieces piercing the abdominal wall. exploratory laparotomy had not been performed for the patient. glass pieces had been removed percutaneously and the patient had been discharged after 6 days of observation without hematuria. he has remained asymptomatic until the day of reference to our center. right renal arteriography was performed later with a 4-f cobra catheter (cordis, rhoden, the netherlands). bleeding was detected on the segmental renal artery of the upper pole in the right kidney (figure 2). over the 0.035-in glidewire (terumo, tokyo, japan), the catheter was advanced into the bleeding artery and embolization was performed using a 35-5-5 stainless steel coil (cook, bloomington, usa). control arteriography after the embolization showed complete obliteration of the pseudoaneurysm (figure 3). the accessory renal artery was intact. hematuria ceased completely and the patient was discharged 5 days thereafter. discussion nontraumatic causes of renal aneurysms are rare,(1) mainly including atherosclerosis and fibromuscular disease. additionally, aneurysms may be associated with kidney tumors, angiomyolipoma, or vasculitides such as polyarteritis nodosa or behcet syndrome. although behcet syndrome affects mostly young people in asia, middle east, and far east, it is rarely thought of as initial diagnosis because its symptoms present occasionally and it may take months or sometimes years to have full spectrum of the symptoms. the pathogenesis of renal pseudoaneurysms after blunt trauma is not as well understood as those after penetrating trauma or iatrogenic injuries. in blunt trauma, psueudoaneurysms are most likely secondary to rapid deceleration injury with laceration of the arterial wall.(1,3) after the disruption of the artery, bleeding is stopped temporarily due to the tamponade effect of the surrounding hematoma; however, with resolution of hematoma, artery may restart bleeding into the resultant cavity and form a pseudoaneurysm days or even weeks after the initial injury. clinically, pseudoaneurysms may present with gross hematuria, lumbar pain, renovascular hypertension, or azotemia. they may also be asymptomatic for a long time or may be even thrombosed spontaneously. it has been described that the average interval between injury and onset of the secondary renal hemorrhage was approximately 12 days (range, 2 to 36 days).(2) pastorin and colleagues reported a case of a patient with blunt abdominal trauma who presented with figure 2. arteriography confirmed the giant right renal pseudoaneurysm (black arrow), arising from the segmental branch demonstrating contrast outflow jet (white arrow). figure 3. postembolization control angiography revealed coil (arrow) occluding the renal artery branch that fed the pseudoaneurysm. no further extravasation of contrast was noted. endovascular treatment of renal artery pseudoaneurysm—garg et al 186 urology journal vol 4 no 3 summer 2007 hematuria 5 months after the initial trauma.(3) to our best knowledge, our present case is the only one with such a delayed presentation of the disease. after taking the history of abdominal trauma, we reevaluated the ct images; however, no foreign body or streak artifact attributed to the possible penetrated glass pieces was found. although clinically silent and small pseudoaneurysms may be managed conservatively, because of the risk of spontaneous rupture and mortality, many physicians recommend surgical management. surgical exploration or nephrectomy used to be the only treatment; however, recent advances in interventional radiological techniques allow superselective catheterization. thus, nowadays, pseudoaneurysms can be treated with minimally invasive procedures such as embolization using either coils alone or combined with other materials like nonresorbable glues or onyx which result in rapid hemostasis and more effective preservation of kidney function.(4,5) in conclusion, renal artery pseudoaneurysm is a rare complication after blunt abdominal trauma which may form days, weeks, or even years after the initial injury. hence, a follow-up is recommended while conservative management of the blunt abdominal trauma.(6) conflict of interest none declared. references 1. lee rs, porter jr. traumatic renal artery pseudoaneurysm: diagnosis and management techniques. j trauma. 2003;55:972-8. 2. heyns cf, de klerk dp, de kock ml. stab wounds associated with hematuria--a review of 67 cases. j urol. 1983;130:228-31. 3. pastorin r, rodriguez n, polo am, vicente jm, lujan m. posttraumatic giant renal pseudoaneurysm. emerg radiol. 2007;14:117-21. 4. sofocleous ct, hinrichs c, hubbi b, et al. angiographic findings and embolotherapy in renal arterial trauma. cardiovasc intervent radiol. 2005;28:39-47. 5. poulakis v, ferakis n, becht e, deliveliotis c, duex m. treatment of renal-vascular injury by transcatheter embolization: immediate and long-term effects on renal function. j endourol. 2006;20:405-9. 6. blankenship jc, gavant ml, cox ce, chauhan rd, gingrich jr. importance of delayed imaging for blunt renal trauma. world j surg. 2001;25:1561-4. urol_v03_no4_001_editorial.indd news 258 urology journal vol 3 no 4 autumn 2006 the second congress of the iranian endourolgoy and urolaparoscopy society the second congress of the iranian endourolgoy and urolaparoscopy society (ieus) was held in tehran from october 31 to november 2, 2006. the ieus was founded in 2003 and now it has members. following a vigorous start and successful programs during the last 3 years, professors board of directors of the ieus could plan an outstanding meeting this year. after a warm and friendly opening ceremony on monday night at azadi grand hotel, the congress was started on tuesday, october 31. there were 18 videos and 38 paper accepted for presentation at the main hall. in addition, diverse programs were held including postgraduate sessions, state-of-the-art lectures, panels, and cons and pros lectures. during the 3 days, a fruitful exchange of experiences between endourologist from different areas of iran and their colleagues from other countries was made. distinguished international faculties were invited and the most up-to-date information was released by lectures and debates made by the prominent urologists from iran and other countries. professor loening and his colleagues, drs deger and taymoorian, from germany, gave their lectures on laparoscopic radical prostatectomy, transperitoneal laparoscopy, and laparoscopic donor nephrectomy. professor gaur, from india, gave a lecture on “what not to do in laparoscopy”. robotic laparoscopic pyeloplasty, stone management, holmium laser prostatectomy, and diagnosis of lymph node metastasis in prostate cancer were some other topics covered by drs al-zahrani (saudi arabia), allousi (germany), bhatia (uae), and tabatabaie (usa). the most impressing part of the congress was the live televised surgeries on the second day. for the first time in iran simultaneous surgeries from 3 hospitals were presented at the meeting hall and a live discussion with the surgeons in the operating rooms was run. percutaneous nephrolithotomy with fluoroscopy, ultrasonography, and urol j (tehran). 2006;4:258-60. www.uj.unrc.ir the second congress of the iranian endourolgoy and urolaparoscopy society urology journal vol 3 no 4 autumn 2006 259 blind access; retrograde endoscopic upper ureteral dilation of iatrogenic stricture, and urocol injection for stress urinary incontinence were performed live with the highest quality. at the end of the meeting, the award committee selected and appraised the following: 1. dr shahin tabatabaie (usa) as the best lecturer 2. dr parham halimi asl (iran) for the best oral presentation and as the best young researcher 3. dr abbas basiri for the best video presentation more information as well as some presentations and a take-home message are available from the congress website: http://www.iranendourology.org/ieus2006 the best oral presentation efficacy of transurethral lithotripsy with holmium laser versus extracorporeal shockwave lithotripsy in upper ureteral stones between 1 cm and 1.5 cm ziaee sam , mohammad-ali-beygi f , halimi asl p department of urology, shaheed labbafinejad medical center introduction: we compared the safety and efficacy of transureteral lithotripsy (tul) with intracorporeal holmium:yag laser lithotripsy with extracorporeal shockwave lithotripsy (swl) for proximal ureteral calculi between 1 cm and 1.5 cm. material and methods: of 197 patients with upper ureteral stone, 166 patients met our criteria. patients were allocated into two groups based on their treatment option preference (40 tul and 126 swl). swl was carried out by swl motion (dornier doli compact and mpl 9000 lithotripter) with approximately 1250 shock waves (range, 723 to 2544). tul was done with a semirigid ureteroscope (wolf 7-8.9 f). results: demographic results of two groups were similar. our findings, including operative time, stone-free rate, efficacy quintet, hospitalization due to fever or pain, ancillary and procedures are shown in table. there was not any difference between the groups. in tul with holmium laser group we had 1 patient with ureteral stricture who underwent laparoscopic ureteroureterostomy and 3 patients underwent dj insertion 3 months later. the second congress of the iranian endourolgoy and urolaparoscopy society 260 urology journal vol 3 no 4 autumn 2006 the best video presentation laparoscopic boari bladder flap ureteroneocystostomy for distal ureteral tumor: a case report basiri a , mehrabi s , karami h urology and nephrology research center and shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran introduction: using the bladder or boari flap is a useful technique for ureteroneocystostomy when the distal ureter is too short to reach the bladder without undue tension. we report a case of laparoscopic boari flap ureteroneocystostomy for the treatment of distal ureteral tumor. material and methods: a 52-year-old man who presented with flank pain, gross hematuria, and moderate hydronephrosis on sonography was diagnosed as having a distal ureteral tumor by further evaluation, and underwent unilateral laparoscopic boari bladder flap ureteroneocystostomy. the operation was done by transperitoneal approach in semilateral position with two 10-mm trocars in the umbilicus and the right llmc and two 5-mm trocars in llaa and rlmc for instruments. results: no intraoperative or postoperative complications were noted. operative time was 406 minutes. postoperatively, serum creatinine and hemoglobin were normal. the patient was discharged from hospital at the fourth postoperative day. pathologic evaluation of specimen revealed transitional cell carcinoma of the distal ureter with a free margin. conclusion: the laparoscopic boari flap is an alternative surgical technique in patients with long distal ureteral pathology. more cases with longer follow-ups are needed to show the long-term results in comparison with the standard open technique. holmium laser tul group 1 eswl group 2 p operative time, min 29.3 (20-60) 20.5 (19-32) 0.6 stone free rate 29 (72.5%) 99 (78.1%) 0.9 efficacy quotient 0.43 0.59 hospitalization 4 (10%) 3 (24%) 0.5 ancillary procedure 8 (20%) 22 (17.6%) 0.5 conclusion: it seems swl is a better treatment option in comparison with tul holmium-laser due to less morbidity and lesser anesthesia and analysis requirement. case reports 251urology journal vol 4 no 4 autumn 2007 fluoroscopy-guided percutaneous biopsy of kidney an alternative to open or laparoscopic approaches kia nouri-mahdavi,1 abbas basiri2 urol j. 2007;4:251-3. www.uj.unrc.ir keywords: needle biopsy, kidney, fluoroscopy 1department of urology, isfahan university of medical sciences, isfahan, iran 2department of urology, shaheed labbafinejad medical center & urology and nephrology research center, shaheed beheshti medical university, tehran, iran corresponding author: abbas basiri, md department of urology, shaheed labbafinejad medical center, 9th boustan, pasdaran ave, tehran 1666668111, iran tel: +98 21 2245 6845 fax: +98 21 2245 6845 e-mail: basiri@unrc.ir received january 2007 accepted july 2007 introduction percutaneous kidney biopsy is most frequently performed under the guidance of ultrasounography or computed tomography (ct).(1) in some patients, however, other options for kidney biopsy should be resorted to in order to obtain an adequate specimen. we hereby describe the technique of fluoroscopy-guided percutaneous needle biopsy of the kidney after retrograde contrast injection through a ureteral catheter in patients with previously failed ultrasonography-guided percutaneous needle biopsy of the kidney. case reports we report on 4 men who underwent fluoroscopy-guided percutaneous needle biopsy of the kidney after retrograde contrast injection. ultrasonography-guided percutaneous biopsy had failed in all of the patients. the relevant clinical and laboratory data are shown in the table. after inducing general endotracheal anesthesia, cystoscopy was performed in the dorsal lithotomy position and the ureter was catheterized with a 6-f ureteral catheter. the ureteral catheter was taped to a foley catheter and the patient was then placed in the prone position. the lower pole of the kidney was identified using a c-arm fluoroscope after gentle retrograde contrast injection through the ureteral catheter. a tru-cut biopsy needle targeted at the lower pole was inserted under fluoroscopic guidance. displacement of the kidney on short to-and-fro movements of the biopsy needle confirmed proper needle position, and several biopsy cores were taken from each patient (figures 1 and 2). the specimens were placed in saline and sent for light, immunofluorescence, and electron microscopy studies. the ureteral catheter was removed at the completion of the procedure. vital signs were monitored for approximately 6 to 8 hours and the hematocrit was measured 4 to 6 hours after the biopsy. the patient was patient age, y clinical and laboratory findings final diagnosis 1 22 hematuria, severe proteinuria iga nephropathy 2 25 hematuria, elevated serum creatinine (3 mg/dl), no family history of alport syndrome alport syndrome 3 28 hypertension, hematuria, proteinuria (1.8 g/d), elevated serum creatinine (2.5 mg/dl), kidney size at the lower limit of normal diffuse proliferative glomerulonephritis 4 36 hematuria, proteinuria (2.5 g/d), morbid obesity (body mass index, 37.8 k/m2) focal segmental glomerulosclerosis clinical and laboratory data of patients fluoroscopy-guided percutaneous kidney biopsy—nouri-mahdavi and basiri 252 urology journal vol 4 no 4 autumn 2007 discharged at that point if there was no evidence of complications. perioperative antibiotic prophylaxis was provided in all 4 patients. the median operative time (including cystoscopy and ureteral catheterization) was 25 minutes. adequate biopsy cores were obtained in all 4 patients. no medical or surgical complications were noted after the procedure, and all of the patients were discharged within 8 hours after the biopsy. discussion percutaneous kidney biopsy is usually a minimally invasive procedure performed under local anesthesia using a standard biopsy needle or a biopsy gun. ultrasonographic guidance can be used to aid in the biopsy procedure. should ultrasonographyguided biopsy fail, however, other options for biopsy of the kidney may prove necessary.(1) computed tomography-guided biopsy can be performed on an outpatient basis without the need for general anesthesia. real-time visualization or intervention to achieve hemostasis is not possible, however, and extreme obesity may preclude ct-guided kidney biopsy.(1) although endovascular transjugular or transfemoral biopsy of the kidney can be safely performed in patients with percutaneous kidney biopsy contraindications or failures,(2,3) radiation exposure, allergic reactions to intravenous contrast, risk of contrast nephropathy, and difficulty in achieving hemostasis are significant drawbacks for this approach. open renal biopsy can provide adequate samples of the renal tissue in almost every patient. it entails, however, increased hospital stay and significant morbidity associated with the surgical incision. laparoscopic transperitoneal or retroperitoneal biopsy of the kidney offers the advantages of open biopsy with the decreased morbidity of a 2-port outpatient procedure.(4,5) we used retrograde pyelography to aid in localization of the kidney for percutaneous biopsy in 4 patients with prior failed ultrasonography-guided biopsy. the median operative time was 25 minutes and no complications occurred. few authors have reported this technique of kidney biopsy.(6,7) lindqvist and nystrom performed percutaneous kidney biopsy in severely uremic patients with the aid of retrograde pyelography,(6) and mccanse and colleagues reported the same technique in 6 patients.(7) they had no complications with this procedure and obtained adequate tissue in all cases. some patients with failed ultrasonography-guided percutaneous kidney biopsy can thus benefit from retrograde pyelography for localization of the kidney. open and laparoscopic biopsy require general anesthesia, dissection of perinephric tissues, and longer hospital stay, and are associated with longer operative time and convalescence. in contrast, percutaneous kidney biopsy aided by retrograde pyelography is a fast, safe, and efficient technique that is familiar to endourologists and is associated with minimal radiation exposure. the risks of allergic reactions to contrast media and development of contrast nephropathy are virtually nonexistent. although general anesthesia was employed in our small case figure 1. biopsy needle properly positioned within the renal cortex. figure 2. adequate renal tissue was obtained. fluoroscopy-guided percutaneous kidney biopsy—nouri-mahdavi and basiri urology journal vol 4 no 4 autumn 2007 253 series, the entire procedure can be done under local anesthesia and in an outpatient setting, especially if the flexible cystoscope is used for ureteral catheterization. references 1. croger bp, tisher cc. indications for and interpretation of the renal biopsy: evaluation by light, electron, and immunofluorescence microscopy. in: schrier rw, editor. diseases of the kidney and urinary tract. 7th ed. philadelphia: lippincot williams & wilkins; 2001. p. 457-87. 2. mal f, meyrier a, callard p, et al. transjugular renal biopsy. lancet. 1990;335:1512-3. 3. cluzel p, martinez f, bellin bilbao ji, et al. renal biopsy with forceps through femoral vein. cardiovasc intervent radiol. 1995;18:232-6. 4. gimenez lf, micali s, chen rn, moore rg, kavoussi lr, scheel pj jr. laparoscopic renal biopsy. kidney int. 1998;54:525-9. 5. gaur dd, agarwal dk, khochikar mv, purohit kc. laparoscopic renal biopsy via retroperitoneal approach. j urol. 1994;151:925-6. 6. lindqvist b, nystrom k. percutaneous renal biopsy in severely uraemic patients with the aid of retrograde pyelography and roentgen television. scand j urol nephrol. 1967;1:297-8. 7. mccanse l, whittier f, cross d, mebust w. percutaneous renal biopsy with localization by retrograde pyelography. j urol. 1975;114:521-3. 1072 | evaluating the efficacy of vacuum constrictive device and causes of its failure in impotent patients feraidoon khayyamfar, 1,2 seyed kazem forootan,1,2 hassan ghasemi,3 seyed roohollah miri,4 ehsan farhadi4 purpose: this study evaluates the efficacy of vacuum constrictive device (vcd) and the reasons for its failure. materials and methods: in this cross-sectional study, 1500 men with organic erectile dysfunction (ed) were enrolled from july 2003 to july 2010. the treatment efficacy was analyzed using international index of erectile function (iief) and questioning patient's partner regarding the man’s ability to perform vaginal penetration (apvp). the patient’s spouses, who responded negatively to apvp, were evaluated by a midwife for virginity, vaginal atrophy and abstained sex. results: totally 1310 (87.4%) patients attained full erection at first training session, remaining 188 (12.6%) were able to have full erection one week after practicing with vcd, 1419 (94.6%) were able to have successful intercourse and responded positively to apvp, 81 (5.4%) were unable to have intercourse as stated by their wife's (negative response to apvp) that in 43 (53%), 30 (37%), and 8 (9.8%) cases the causes of failures were their wife's virginity, sex abstinence, and senile vaginal atrophy, respectively. regarding erectile issue of iief scores in patients responded positive to apvp there were significant improvement from the scores of 9.3 ± 3.0 to 27.5 ± 5.0 after treatment (p < .05). conclusion: with proper training and appropriate devices, vcd could induce sufficient erection in all patients. vcd in patients with virgin wife is ineffective, and female factors affect on success rate in vcd therapy. keywords: erectile dysfunction; therapy; treatment outcome; vacuum; penile erection. corresponding author: hassan ghasemi, md associate professor, department of ophthalmology, medical school, shahed university, tehran, iran. tel: +98 21 8896 3122 fax: +98 21 889 63122 e-mail: ghasemi518@yahoo. com received may 2012 accepted april 2013 1family sexual health clinic and research center, shahed university, tehran, iran 2department of urology, shahed university, tehran, iran 3department of ophthalmology, shahed university, tehran, iran 4medical student, school of medicine, shahed university, tehran, iran sexual disfunction and infertility sexual disfunction and infertility 1073vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction currently, erectile dysfunctions (ed) are managed based on the couples interactions, in which the patient and his wife’s satisfactions are the main factors for eventual therapeutic purposes.(1) american urological association has recommended to use vcd as a safe therapeutic tools for treatment of ed since 1996.(2) introduced in 1998, sildenafil is already the first line therapy for most men with ed, delegating traditional vcd therapies and injectable agents to the second line of approaches.(3,4) patients that failed to respond or develop side effects when receiving the first and second lines of treatment are candidate for surgical approaches.(4) patients that are not suitable for oral medications due to ineffectiveness, development of side effect or having any contraindications may be considered for intracavernosal injection (ici) of vasodilators or vcd.(5, 6) vcd can be used successfully in treatment of ed with any kinds of etiology.(7) the vcd mechanism is due to its ability in raising the arterial inflow by the vacuum effect. the venous outflow decrease from the penis by applying a constructive rubber band while the penis is erected. the purposes of this study were 1) to evaluate the efficacy of vcd in inducing erection and to find out the causes of its failure in impotent patients, and 2) the success rates of vcd in performing vaginal penetration. materials and methods patient selection totally 1530 men with ed due to an organic etiology for more than 3 months, who were referred for treatment to the ed clinic of the family health center shahed university, participated in this cross-sectional study. the participants were informed of the purpose of study and gave their informed consent. the study protocol was based on the declaration of helsinki and approved by ethics committee of shahed university. the diagnosis of ed was established according to the national institute of health statement of ed.(8) at first visit, all patients would provide their detailed medical and sexual histories, and would undergo specific physical examinations, also the level of free and total testosterones would be determined if patients lack secondary sex characters. patients with low testosterone level were offered hormonal replacement and were excluded from the study. patients with psychogenic impotence (i.e. normal non-sexual erection, performance anxiety, premature ejaculation), who were determined by history, if required further evaluation was done by testing nocturnal penile tumescence (npt), and if this showed normal patterns of nocturnal erection, the patient were excluded from the study. based on the patient's history and physical examination, an attempt was made to determine the etiology of impotence. each participant had a steady co-operative female partner. partner's were not evaluated medically before the initiation of the study but were given the opportunity and encouraged to attend, each appointment. during evaluation if patients’ wife was suspicious of having any medical or psychological problem regarding sexual performance, couple were excluded from the study. patients using medication that affect sexual performance where referred to the physician or psychiatrist for modification of treatment and advice of oral drugs for treatment of ed but if it was failed or modification of drugs were not possible the patient was advised to use vcd for treatment of ed. treatment evaluation the clinical efficacy of the various treatments was evaluated using the international index of erectile function (iief) questionnaire that is based on the scores for five separate response domains. these domains addressed as the issues of erectile function (ef) and also intercourse satisfaction (is), orgasmic function (of), sexual desire (sd) and finally overall satisfaction (os). because of the absence of a validated questionnaire for iranian population, we translated the iief questionnaire(2) in to the persian. the entire questionnaires were completed after full explanations to the patients by urologist. the ultimate score for each field was calculated as the summation of the scores attained for each individual question in that field or domain. in addition to the iief questionnaire, the men were asked about the state of their wife's virginity by answering yes or no; moreover all patients’ partner were requested to respond either yes or no, regarding the men’s ability to perform vaginal penetration (apvp). vacuum and impotence | ghasemi et al 1074 | treatment method all patients were trained by an urologist who was expert in vcd as well as watching an instructional locally produced video for vcd (hamrah medical group, tehran, iran). the manufacturer had provided vacuum device cylinders and constrictive rings of different sizes that could be adapted to the patient’s penis sizes. furthermore, if patient did not achieve full erection that was considered by the patient and the physician to be unsatisfactory for penetration at the first visit, he was advised to practice with vcd for one week by putting penis inside vcd cylinder, producing negative vacuum pressure until achieving full erection and maintaining it for 20 minutes three times a day without using single constrictive ring.(6,9,10,11,12) technical advice was made available by revisiting the patients on a daily basis if demand. study protocol the iief questionnaire was administrated before the treatment, and after 15 times using of this method during one year of follow up. patients were asked for any bruising injury or skin changes sufficient to decrease the number of the times using the device, or stop using of the treatment altogether. if there was a failure the patient was advised to revisit in the clinic with his partner for re-valuation, all of the patients were examined by both an urologist and a midwife for the status of wife's virginity, and vaginal atrophy. statistical analysis the scores of iief in each domain compared with vcd before and after treatment. to determine the changes in response to vcd treatment we used chi square and paired t test using the statistical package of social science (spss inc, chicago, illinois, usa) version 16. the p value less than .05 was considered statistically significant. the use of vcd for apvp was also assessed by asking the patients’ spouses to respond either positive or negative. using mean statistics values, these responses were compared before and after treatment with vcd regarding various response domains. the patients responses’ were compared with each other in domains of ef, is, of, sd, and os. the ultimate score for each domain was calculated as the summation of the scores attained for each individual query in that domain. the data were presented as means and percentage as summary statistics. finally the positive and negative responses to apvp question were compared with each other in patients’ with virgin wife regarding abridge six items of ef post treatment to assess the exact difference induced by vcd on the erectile function of these patients. results a total of 1530 referred patients with ed were enrolled in this study. age range was between 22 to 85 years (mean ± sd, 48.2 ± 12.5). thirty patients out of 1530 cases were excluded from the study. of those, 15 patients reported that vcd was socially inconvenient. thirteen cases discontinued their treatment because of psychological discomfort in performing sex and attempting sexual intercourse less than 15 times using their devices during one year of follow up and were excluded from the study and referred to psychologist. the two remainder patients were unable to get full erection in clinic due to the history of prolonged priapism and severe corporal fibrosis and therefore were excluded from the study. vcd was able to induce full erection in clinic during initial training and we didn’t have any failure in inducing and maintaining erection in all patients. because of attaining full erection in all patients, we didn’t separate the patients to age subgroups. sum of 1500 pasexual disfunction and infertility table 1. iief scores before and after the treatment with vacuum constrictive device. os (p value) s des (p value) of (p value) is (p value) ef (p value) stage of treatment 3.9 ± 1.7 6.3 ± 1.9 5.6 ± 2.4 6.7 ± 2.4 9.3 ± 2.9 pretreatment (sd) 8.6 ± 1.5 (p < .0001) 7.4 ± 3.1 (p < .0001) 11.1 ± 1.2 (p < .0001) 11.1 ± 1.2 (p < .0001) 26.6 ± 4.9 (p < .0001) post-treatment (sd) key: iief, international index of erectile function; ef, erectile function; is, intercourse satisfaction; of, orgasmic function; s des, sexual desire; os, overall satisfaction; sd, standard deviation. 1075vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l tients were evaluated in this study. those patients with penile bruising were advised to stop using vcd for 2 weeks. full erection was achieved on the first training session in 1310 (87.4%) patients, but 188 (12.6%) of the patients were able to have full erection one week after practicing with vcd. of 1500 patients a total of 1419 (94.6%) were able to have successful intercourse and responded positively to apvp (table 1). in different domains of ef, is, of, sd and os scores, all patients with positive apvp had improvement compared with the pretreatment scores (p < .05). eighty one patients (5.4%) were unable to have intercourse as stated by their wife, (responded negatively to apvp) in spite of having full erection on clinical trainings. among these patients 43 (53%) were having virgin wife, 30 patients (37%) had histories of sexual abstinence (sex abstinence defined as couples whom had not having intercourse with full rigid penis for more than six months that had lead to vaginal lumen narrowing) and a number of 8 (9.8%) patients had senile vaginal atrophy. regarding the technical problems, 78 patients needed retraining sessions. in addition, 50, 20, and 5 patients needed repeated 2, 3 and 4 training sessions by the urologist, respectively, of them, 3 patients needed their wives attendance and training due to their husband's illiteracy and physical inadequacy. table 1 demonstrated the iief score before and after vcd therapy in all of the patients. table 2 summaries the iief scores of patients with apvp positive in which there were significant improvement between pretreatment and post treatment regarding various issues of erectile function (p < .05). iief scores of patients with apvp negative whom were not having significant improvement compared with pretreatment, except ef in which sum score of domain was improved from 9.2 ± 1.5 pretreatment to 13.77 ± 3.03 (p < .05). table 3 shows that vcd can induce full erection in all patients. iief q1 and iief q2 have similar domains score in men with virgin wife and men whom their wife weren't virgin. but regarding iief q3, q4, q5, and q15 patients whom were not having virgin wife had improve iief domains as compared to pretreatment. comparing iief scores erectile function issue among apvp negative and apvp positive after treatment that regards various domains, we find that it was similar at iief q1 and q2 (p > .05). in both group but there were significant differences at iief q3, q4, q5 and q15 (p < .05). discussion previous studies on vcd had demonstrated variable success rates. some studies have shown high success rates(4,6,7,10,13,14,16,17) but other studies have come up with lower success rates.(15,18,19,20,21) some researchers have agreed those success rates are highly affected by the degree of the training.(6, 22) the reason for the wide range in success rates in different studies was applying of the different evaluation criteria. for example, in moulmein’s study(23) their criterion for success was the ability to attain erection. table 2. iief scores of patients according to ability to perform vaginal penetration. response to apvp age, years treatment period patients (no.) ef p value is p value of p value s des p value os p value apvp positive 23-88 (mean = 49) pretreatment (sd) 1419 9.3 ± 3.0 6.7 ± 2.4 5.6 ± 2.1 1.8 ± 6.3 3.9 ± 1.8 posttreatment (sd) 27.3 ± 5.1 (p < .0001) 11.3 ± 1.2 (p < .0001) 6.3 ± 1.8 (p < .0001) 7.5 ± 3.2 (p < .0001) 8.9 ± 1.5 (p < .0001) apvp negative 22-55 (mean = 34) pretreatment (sd) 81 9.2 ± 1.5 7.6 ± 2.7 5.3 ± 2.3 6.4 ± 3.3 4.4 ± 1.6 post-treatment (sd) 13.77 ± 3.03 (p < .001) 7.2 ± 2.7 5.2 ± 2.3 6.3 ± 2.1 4.1 ± 1.2 key: iief, international index of erectile function; apvp, ability to perform vaginal penetration; ef, erectile function; is, intercourse satisfaction; of, orgasmic function; s des, sexual desire; os, overall satisfaction; sd, standard deviation. vacuum and impotence | ghasemi et al 1076 | in cookson and nadig’s study,(14) long-term use of vcd was taken as a criterion of success, and in broderick and colleagues’(9) study patient satisfaction was considered for evaluation and success. in our study the criterion for success was patient’s ability for vaginal penetration along with fully erected penis. moreover our success rate were higher than the other studies, because of the using proper sizes of vcd cylinders or constrictive rings and proper training of the patients by an expert urologist that was also advised in other studies.(10,22) our research was a first study that noticed the importance of female factor in vcd failure. denil and colleagues(24) also reported 93% of their patients obtained erection, but only 83% of them were having sufficient rigidity for vaginal penetration, and we think that it was not only quality of penis rigidity, but also the vaginal resistivity that was the main cause of failure for their patients whom were unable to have vaginal intercourse despite having erections. in wada and colleagues’ study25 they used locally manufactured vcds and their ability to induce successful erection was hundred percent (in 20 patients) of their patients which is similar to finding in our study, having a same finding on a much larger scale. in earle and colleagues study,(26) 81% of patients abandoned the vcd that is quite high, but in our clinic vcd was found acceptable by most of the patients who were advised; it might be due to the good explanation of different therapeutic methods, the proper training of the patients, solving side effects, explaining their advantages, disadvantages to the patients and their wife. nadig and colleagues(7) mentioned that one of his patient’s penile rigidity began to decrease five to ten minutes after the sexual activity, even though it would not change over a thirty-minute period that once originally tested in the laboratory. in gilbert and gingell’s study although 38 patients were able to obtain an erection-like state using a vacuum constriction device, only 12 were able to enjoy satisfactory sexual intercourse. (18) in a retrospective study, sidi and colleagues concluded that the pain, inconveniency, and early loss of rigidity were the most important causes for dissatisfactions.(12) our findings indicate that vaginal resistance causes early loss of rigidity and failure to penile entrance during the intercourse. in this research, 43 patients had virgin wife that were not noticed in any of the studies, this may be due to the fact that our clinic has known as is a referral center, and virginity is culturally preserved in unmarried ladies in our country. as we attained hundred percent erections in our study so we believe the effect of vcd on quality of erection is not affected by the etiologies e.g. arteriogenic,(13) corporeal venoocclusive dysfunction(21) and diabetic ed(27,28) which was mentioned in other studies as well. comparing iief erectile function issue among apvp negative and apvp positive before and after the treatment that including various domains, we found that it was similar in iief q1, q2 in both groups but there was significant differences for iief q3, 4, 5 that showed loose of erection despite having full tumescence before the intercourse which is believed to arise from severe vaginal resistance in patients with narrow vagina (virginity, abstinence sex, and vaginal atrophy) causing an escape of blood from the corpus cavernosa through the constrictive ring at the penis base. moreover, patients whom wife responded negative to apvp had lower scale in iief q15 too. in this study we encountered with some limitations. the patients’ spouses that had positive response to apvp were not advised to admit the clinic if they were having successful sexual intercourse. because they have not examined by the midwife, we could not provide any comments regarding the significance of the vaginal atrophy or abstinence in vcd sexual disfunction and infertility table 3. response to the abridged six-item (erectile function) version of the iief questionnaire comparing the apvp positivity and apvp negativity in all patients, post-treatment among patient having virgin wife. iief questionnaire apvp positive apvp negative p value iief q1 (sd) 4.71 ± 0.86 4.60 ± 0.84 .255 iief q2 (sd) 4.60 ± 0.96 4.75 ± 0.75 .088 iief q3 (sd) 4.10 ± 0.86 1.02 ± 0.23 < .001 iief q4 (sd) 4.61 ± 0.86 1.11 ± 0.35 < .001 iief q5 (sd) 4.76 ± 0.74 0.86 ± 0.21 < .001 iief q15 (sd) 4.52 ± 0.73 1.43 ± 0.65 < .001 total (sd) 27.3 ± 5.01 13.77 ± 3.03 < .001 key: iief, international index of erectile function; q, question; apvp, ability to perform vaginal penetration; sd, standard deviation. 1077vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l failure. this issue could be of importance for future investigations. also due to significance of the issue we suggest to validate a questionnaire for iranian population. comparing the patients' partner for the virginity, none of the partners responding positive to apvp were virgin. on the other hand, all patients with virgin wife were unable to have sexual intercourse with their partner that means vaginal tightness could directly affect the success of the intercourse in patients using vcd. therefore, we could consider the presence of virginity as one of the major factors in vcd failure. we tried to suggest non-invasive treatments to our patients and believe careful training decreases the side effects, and increase the effectiveness of vcd. handling problems regarding its failure can prevent more invasive alternative therapy. patients with bleeding disorders or those on anticoagulation therapy are considered at high risk to develop petechiae, echymosis or hematoma.(6) in our study we had 53 patients whom were using anticoagulant therapy and we did not observed any major side effects to be developed in them, it was shown that the risk did not exceed that of the general population. all patients whose wife accepted vaginal, dilatation could take advantage of vcd for the sexual intercourse. mechanisms of erection induced by vcd are entrapment of blood in corporal sinusoids.(29) most probably practicing with vcd in initial steps would be of great help on its effectiveness.(30) conclusion the vcd device could induce sufficient effective erection in all patients provided that using proper training and appropriate vacuum cylinders size and constrictive rings. moreover; using vcd in patients with virgin wife is ineffective, and female factors could affect the success rate in vcd therapy. acknowledgments kind thanks to shahed university due to logistical supports. also we kindly appreciate mrs. khadijeh mohammadi the midwife, for her help in patients’ partner examination. conflict of interest dr. f khayyamfar owns patent on the vcd described in this report. he has received financial supports as a member of hamrah medical group (manufacturer and seller of study vcd). the other authors declare no potential conflict of interest. references 1. chen j, sofer m, kaver i, matzkin h, greenstein a. concomitant uses of sildenafil and a vacuum entrapment device for the treatment of erectile dysfunction. j urol. 2004;171:292-95. 2. montague dk, barada jh, belker am, et al. clinical guidelines panel on erectile dysfunction: summary report on the treatment of organic erectile dysfunction. the american urological association. j urol. 1996;156:2007-11. 3. montague dk, jarow jp, broderick ga, et al. chapter 1: the management of erectile dysfunction: an aua update. j urol. 2005;174:23039. 4. canadian urological association guidelines committee. erectile dysfunction practice guidelines. can j urol. 2002;9:1583-87. 5. chen j, godschalk mf, katz pg, mulligan t. combining intracavernous injection and external vacuum as treatment for erectile dsfunction. j urol. 1995;153:1476-77. 6. lewis rw, witherington r. external vacuum therapy for erectile dysfunction: use and results. world j urol. 1997;15:78-82. 7. nadig pw, ware jc, blumoff r. noninvasive device to produce and maintain erection-like state. urology. 1986;27:126-31. 8. nih consensus conference. impotence. nih consensus development panel on impotence. jama. 1993;270:83-90. 9. broderick ga, allen g, mcclure rd. vacuum tumescence devices: the role of papaverine in the selection of patients. j urol. 1991;145:284-86. 10. witherington r. vacuum constriction device for management of erectile dysfunction. j urol. 1989;141:320-22. 11. user survey report 1995. data on file. osbon medical syatems: augusta, ga, usa, 1995. 12. sidi aa, becher ef, zhang g, lewis jh. patient acceptance of and satisfaction with an external negative pressure device for impotence. j urol. 1990;144:1154-56. 13. baltaci s, aydos k, kosar a, anafarta k. treating erectile dysfunction with vacuum tumescence device: a retrospective analysis of acceptance and satisfaction. br j urol. 1995;76:757-60. 14. cookson ms, nadig pw. long-term results with vacuum constriction device. j urol. 1993;149:290-94. 15. dutta tc, eid jf. vacuum constriction devices for erectile dysfunction: a long-term, prospective study of patients with mild, moderate, and severe dysfunction. urology. 1999;54:891-3. vacuum and impotence | ghasemi et al 1078 | sexual disfunction and infertility 16. bosshardt rj, farwerk r, sikora r, sohn m, jakse g. objective measurement of the effectiveness, therapeutic success and dynamic mechanisms of the vacuum device. br j urol. 1995;75:786-791. 17. segenreich e, shmuely j, israilov s, raz d, servadio c. treatment of erectile dysfunction with vacuum constriction device. harafuah. 1993;124:326-28,. 18. gilbert hw, gingell jc. vacuum constriction devices: second-line conservative treatment for impotence. br j urol. 1992;70:81-83. 19. meinhardt w, lycklama a, nijeholt aa, kropman rf, zwartendijk j. the negative pressure devices for erectile disorders: when does it fail? j urol. 1993;149:1285-87. 20. vrijhof hj, delaere kp. vacuum constriction devices in erectile dysfunction: acceptance and effectiveness in patients with impotence of organic or mixed etiology. br j urol. 1994;74:102-5. 21. kolettis pn, lakin mm, montague dk, ingleright bj, ausmundson s. efficacy of vacuum constriction device in patients with corporeal venous occlusive dysfunction. urology. 1995;46:856-58. 22. tan hl. economic cost of male erectile dysfunction using a decision analytic model: for a hypothetical managed-care plan of 100 000 members. pharmacoeconomics. 2000;17:77-107. 23. meuleman ej. experiences with a vacuum apparatus in the treatment of erection disorders. ned tijdschr geneeskd 1993;137:41216. 24. denil j, ohl da, smythe c. vacuum erection device in spinal cord injured men: patient and partner satisfaction. arch phys med rehabil. 1996;77:750-53. 25. wada h, sato y, suzuki n, et al. a study on the erectile response with the vacuum constriction device compared with intracavernous injection of a vasoactive drug. nippon hinyokika gakkai zasshi. 1995;86:321-24. 26. earle cm, seah m, coulden se, stuckey bg, keogh ej. the use of the vacuum erection device in the management of erectile impotence, int j impot res. 1996;8:237-40. 27. arauz-pacheco c, basco m, ramirez lc, pita jm, pruneda l, raskin p. treatment of diabetic impotence with a vacuum device: efficacy and effects on psychological status. am j med sci. 1992;303:281-84 . 28. bodansky hj. treatment of male erectile dysfunction using the active vacuum assist device. diabet med. 1994;11:410-12. 29. yuan j, hoang an, romero ca, lin h, dai y, wang r. vacuum therapy in erectile dysfunction--science and clinical evidence. int j impot res. 2010;22:211-9. 30. engel jd. effect on sexual function of a vacuum erection device post-prostatectomy. can j urol. 2011;18:5721-5. endourology and stone disease 89urology journal vol 5 no 2 spring 2008 treatment of steinstrasse by transureteral lithotripsy sayed mohammad reza rabbani introduction: extracorporeal shock wave lithotripsy (swl) is an essential treatment for urinary calculi, but post-swl steinstrasse is a potential complication, especially in large-burden calculi. our purpose was to evaluate the efficacy of transureteral lithotripsy (tul) in the treatment of steinstrasse caused by swl. materials and methods: twenty-four patients with steintrasse following swl were treated by tul. the length of steinstrasse varied from 1.5 cm to 6 cm. the patients were followed up after tul and failed treatment was considered if the steinstrasse was not cleared within 6 weeks. results: fourteen patients (58.3%) became stone free, of whom 8 had a double-j stent before swl. partial response was seen in 6 patients (25.0%). the remained 4 patients (16.7%) with failed tul underwent open ureterolithotomy. one patient developed nonfunctioning kidney during the follow-up. transureteral lithotripsy was successful in 6 out 8 patients with type 1, 8 out of 12 with type 2, and none of those with type 3 steinstrasse. all of the successful cases of tul were in the patients with lower ureteral calculi. conclusion: successful treatment of steinstrasse by tul can be achieved in less than two-thirds of the cases. type and location of steinstrasse may influence the outcomes. this complication seems sometimes to be troublesome and may even cause kidney loss. urol j. 2008;5:89-93. www.uj.unrc.ir keywords: urinary calculi, complications, steinstrasse, ureteroscopy, shock wave lithotripsy department of urology, shaheed beheshti hospital, yasuj university of medical sciences, yasuj, iran corresponding author: seyed mohammad reza rabbani, md shaheed beheshti hospital, yasuj, iran tel: +98 917 741 1389 fax: +98 741 222 1811 e-mail: smrrabani@yahoo.com received december 2007 accepted march 2008 introduction steinstrasse or “stone street,” is an aggregation of particles in the ureter formed following extracorporeal shock wave lithotripsy (swl). it is a well-recognized, but usually transient and asymptomatic, complication of swl and is a common radiological finding on routine radiographic images taken between 24 and 48 hours after lithotripsy (15%).(1) however, it may cause partial or complete ureteral obstruction, often superimposed with urinary tract infection. steinstrasse has 3 types(1); type 1 is made up of particles 2 mm in diameter or smaller. type 2 has a leading large fragment of 4 mm to 5 mm in diameter with a tail of 2-mm particles. type 3 is composed of large fragments. all patients with steinstrasse are initially treated conservatively. in case of obstruction, infection, pain, or failed passage of the calculus fragments, further treatment should be used, ranging from repeated swl, percutaneous nephrostomy (pcn), endoscopic manipulation, and finally, open surgery.(1-3) there is no standard treatment protocol for the steinstrasse and choosing transureteral lithotripsy for steinstrasse—rabbani 90 urology journal vol 5 no 2 spring 2008 a therapeutic modality depends on the degree of obstruction, infection, kidney function, and response to each kind of therapy.(1-3) in this study, we used transureteral lithotripsy (tul) as an available procedure for the treatment of steinstrasse, when there was an indication for intervention, regardless of the type of the steinstrasse. materials and methods we diagnosed 76 patients with steinstrasse after swl in a period of 26 months beginning from april 2005. steinstrasse was defined as fragments of calculi that form a column occupying more than 17% of the length of the ureter.(1,4) all of the patients had received analgesics, antibiotics, and hydration in the period of conservative management after swl with a plain abdominal radiography, every week, and ultrasonography, every 2 weeks. during a maximum follow-up period of 1.5 month, passage of the calculus fragments occurred in 52 patients (68.4%) without the need for further surgical intervention. the remained 24 patients (31.6%) underwent tul. the mean length of steinstrasse in this group was 2.62 cm (range, 1.5 cm to 6 cm). type 1 steinstrasse was present in 8 patients (33.3%), type 2 in 12 patients (50%), and type 3 in 4 patients (16.7%). the calculi were in the lower, middle, and upper ureter in 17 (70.8%), 2 (8.3%), and 5 (20.8%) patients, respectively. all of the patients underwent tul by 8-f to 9.8-f semirigid ureteroscopes (richard wolf, knittlingen, germany). function of the kidneys was checked before tul by blood urea nitrogen and serum creatinine levels, intravenous urography, and ultrasonography. intervention was done at least 1 month after the initial swl and conservative management. fourteen patients (58.3%) had double-j stents before swl. the patients were followed up after tul and failed treatment was considered if the steinstrasse was not cleared within 6 weeks. in cases with failed tul, the treatment was repeated or other modalities were used based on the availability of the facilities and the patient and surgeon’s preferences. results we managed 24 patients with steinstrasse following swl. there were 16 men (67%) and 8 women (33%) with a mean age of 34.5 years (range, 22 to 48 years). fourteen patients (58.3%) had successful tul and became stone free, 8 of whom had a double-j stent before swl. six patients (25.0%) had only partial response to tul (debulking, but not stone free), 1 of whom responded to the second tul, and 1 developed nonfunctioning kidney during the follow-up, and 4 responded to swl. the remained 4 patients (16.7%) underwent open ureterolithotomy. no procedure-related complication was detected in our patients. transureteral lithotripsy was successful in 6 out 8 patients with type 1, 8 out of 12 with type 2, and none of those with type 3 steinstrasse. all of the successful cases of tul were in the patients with lower ureteral calculi. the table shows the outcomes in relation to the calculi location and type. discussion since the introduction of percutaneous nephrolithotripsy, calculi greater than 2 cm are more commonly treated by this method rather than swl. as a result, the incidence of complicated steinstrasse has been reduced. management of the three types of steinstrasse has been previously discussed. type 1 is more likely to be passed by conservative management. type 2 steinstrasse that usually has a herald calculus greater than 4 mm to 5 mm may respond well to swl or tul. type 3 steinstrasse almost always does not respond to conservative management and needs a suitable intervention.(1) the use of double-j stenting before lithotripsy significantly lowers the incidence of steinstrasse in patients with a stone burden of 1.5 cm to 3.5 cm; however, the incidence of steinstrasse increases with the size of the calculi, whether or not a double-j stent is placed.(5-7) overall, steinstrasse occurs in about 5% of cases in most series.(8) fedullo and colleagues reported that 75% of steinstrasse cases occurred in the lower ureter;18%, in the upper ureter; and 6%, in the transureteral lithotripsy for steinstrasse—rabbani urology journal vol 5 no 2 spring 2008 91 middle ureter. they also reported 35% of patients required intervention and 75% of interventions were endoscopic.(9) in our study, only about 30% of the patients with steinstrasse needed intervention, the calculi of whom were located in the lower, upper, and middle ureter in 71%, 21%, and 8%, respectively. nearly 70% of the patients had spontaneous passage of the calculi within a 4-week follow-up. indications for intervention in steinstrasse are basically the same as those used for calculusinduced obstruction of a solitary kidney with rising creatinine levels, urosepsis, and failure of fragments passage within a reasonable time. steinstrasse should be treated if it is symptomatic (pain and sepsis) or causes a silent obstruction over a 30-day period.(8) the alternatives include placement of a drainage percutaneous tube to allow fragments to pass, ureteroscopy and tul, swl of a lead fragment, or open ureterolithotomy.(8) the choice of tul or swl for the treatment of lower ureteral calculi is still open to debate.(10) in our series, swl was not easily available and the patients would have to travel to other cities nearby. on the other hand, due to the costs, they preferred tul. regarding our speculation of the ease and efficacy of tul especially in lower ureteral steinstrasse, we decided to attempt tul. several studies have shown that repeat swl is a safe and efficient sort of treatment for steinstrasse after failed conservative management,(11-13) but in our experience, only type 2 steinstrasse was a suitable case for repeat swl. there is continuing controversy in the literatures about the success rate of conservative management of steinstrasse, mainly due to different designs of the studies. we evaluated the patients for steinstrasse during the first 48 hours after swl; however, in other studies, they started evaluation at least 1 week after swl, and this causes different rates of detected steinstrasse.(14) in a study by mahmod and colleagues, 29 patients with steinstrasse were followed for 2 months of conservative management with weekly radiography and ultrasonography. they found 51.7% spontaneous calculus passage and treated 13.8% by repeat swl and 34% by tul. in steinstrasse ureteral location outcome lower middle upper all calculi type 1 steinstrasse successful tul 6 0 0 6 repeat tul 0 1 0 1 swl 0 0 0 0 open lithotomy 1 0 0 1 type 2 steinstrasse successful tul 8 0 0 8 repeat tul 0 0 0 0 swl 2 0 2 4 open lithotomy 0 0 0 0 type 3 steinstrasse successful tul 0 0 0 0 repeat tul 0 0 0 0 swl 0 0 0 0 open lithotomy 0 1 2 3 nonfunctioning kidney 0 0 1 1 all types successful tul 14 0 0 14 repeat tul 0 1 0 1 swl 2 0 2 4 open lithotomy 1 1 2 4 nonfunctioning kidney 0 0 1 1 outcome of tul for steinstrasse in relation to type and location of calculi* *tul indicates transureteral lithotripsy and swl, shock wave lithotripsy. transureteral lithotripsy for steinstrasse—rabbani 92 urology journal vol 5 no 2 spring 2008 their study, a 100% success rate was seen. they concluded that tul was a definitive treatment modality with about 100% success rate.(15) in our opinion, this may be true only in selected cases within such a multimodality options of treatments. ibrahim used tul and swl in his study for the treatment of steinstrasse in 22 patients. he performed tul in 12 selected cases, with good results.(14) goyal and associates treated 27 patients with steinstrasse and selected 3 of them for tul with good results.(3) sulaiman and colleagues, in their experience on treating steinstrasse with swl, mentioned that failed swl cases could be cleared by laser lithotripsy even if they were extended and persistent. we did not have laser lithotripter in our center.(12) all of these studies show that different modalities of treatment may be used to treat steinstrasse depending on the type and location of the calculi and the overall situation of the patients. hence, careful selection of the patients for each option has a major role in this way. however, selection of the optimal surgical therapy for complicated steinstrasse remains one of the controversial topics in urology. we used tul, which was easily available for us, regardless of the type or location of steinstrasse in our series. since we had limited number of cases, the results cannot be definitive; nonetheless, we can speculate that successful tul is not dependent on the length of the steinstrasse, but on its type. for instance, a 6-cm type 1 steinstrasse in the lower ureter was treated successfully, while a 2-cm type 3 in the middle ureter was not cleared by tul. also, presence of a double-j stent could ease ureteroscopy. in this study, we encountered some difficulties. first, a wire cannot be passed through the steinstrasse, because the ureter is fully packed. therefore, the usual over-the-wire dilating balloon cannot be used to open the ureteral orifice which is usually smaller than normal; large amount of fragments displaced upward in the dilated ureter towards the kidney that again might cause obstruction. second, endoscopic intervention is sometimes very difficult, especially in a large type 1 steinstrasse, because the small particles interlock in a similar way to the resilient dry calculus walls, making it impossible to pass a guide wire through this wall. although it may be possible to destruct this wall gradually by water jet, it takes too much time. third, we had 1 case of kidney loss is our study. the loss of renal units following steinstrasse is a risk if the swl followup is suboptimal.(16) conclusion steinsrasse is sometimes troublesome and may cause even kidney loss. in our experience, success rate of tul in the treatment of this complication is only about 60%. the most important factors to predict the efficacy of tul in steinstrasse might be its type and location, with type 3 having the most negative impact. larger series are warranted to confirm our conclusions. conflict of interest none declared. references 1. coptcoat mj, webb dr, kellet mj, whitfield hn, wickham je. the steinstrasse: a legacy of extracorporeal lithotripsy? eur urol. 1988;14:93-5. 2. sayed ma, el-taher am, aboul-ella ha, shaker se. steinstrasse after extracorporeal shockwave lithotripsy: aetiology, prevention and management. bju int. 2001;88:675-8. 3. goyal r, dubey d, khurana n, et al. does the type of steinstrasse predict the outcome of expectant therapy? indian j urol. 2006;22:135-8. 4. weinerth jl, flatt ja, carson cc 3rd. lessons learned in patients with large steinstrasse. j urol. 1989;142:1425-7. 5. soyupek s, armagan a, kosar a, et al. risk factors for the formation of a steinstrasse after shock wave lithotripsy. urol int. 2005;74:323-5. 6. al-awadi ka, abdul halim h, kehinde eo, al-tawheed a. steinstrasse: a comparison of incidence with and without j stenting and the effect of j stenting on subsequent management. bju int. 1999;84:618-21. 7. madbouly k, sheir kz, elsobky e, eraky i, kenawy m. risk factors for the formation of a steinstrasse after extracorporeal shock wave lithotripsy: a statistical model. j urol. 2002;167:1239-42. 8. satar n, doran s, ozkeceli r, turkyilmaz rk. treatment of multiple small stone particles (steinstrasse) in the lower ureter after the extracorporeal shock wave lithotripsy treatment. tr j med sci.1998;28:269-71. 9. fedullo lm, pollack hm, banner mp, amendola ma, van arsdalen kn. the development of steinstrassen after eswl: frequency, natural history, and radiologic management. ajr am j roentgenol. 1988;151:1145-7. transureteral lithotripsy for steinstrasse—rabbani urology journal vol 5 no 2 spring 2008 93 10. ziaee s, basiri a, nadjafi-semnani m, zand s, iranpour a. extracorporeal shock wave lithotripsy and transureteral lithotripsy in the treatment of impacted lower ureteral calculi. urol j. 2006;3:75-8. 11. lee hs, park ks, min bk; repeated eswl treatment on steinstrasse. korean j urol. 1995;36:531-5. 12. sulaiman mn, buchholz np, clark pb. the role of ureteral stent placement in the prevention of steinstrasse. j endourol. 1999;13:151-5. 13. kim hh, byeon ss, lee jh, lee sk, kim sw. characteristic and treatment of steinstrasse after eswl. korean j urol. 1996;37:339-45. 14. ibrahim hm. steinstrasse after eswl. arab j urol. 2007;5:23-7. 15. mahmod m, hamid a, tandon v, dwivedi us, singh h, singh bp. the steinstrasse: a legacy of extracorporeal lithotripsy. indian j urol. 2003;20:46-9. 16. puppo p. steinstrasse 20 years later: still a problem after eswl? eur urol. 2006;50:643-7. fall 2012 08.pdf 721vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l adrenal lipoma with hemorrhage a cause of abdominal pain deepali jain, prem chopra, ajay sharma keywords: lipoma, hemorrhage, abdominal pain introduction n on-functional adrenal tumors are uncommon lesions; one of these is lipoma. lipomas been described in the literature so far, to the best of authors’ knowledge (table 1).(1-13) case report the pain was of moderate intensity and non-radiating. there was no history of fever, nausea, or vomiting. no symptoms related to the lower urinary tract were present. the patient was diabetic tory was noncontributory. was soft and there was no organomegaly. ultrasonography revealed a hyperechoic well-circumscribed lesion on the upper pole of the right kidney. computed tomography scan showed a large well-circumscribed right-sided mass measuring 12.8 × 10 × 10 cm with fat density. internal areas of hemorrhage were seen (figure 1). features were suggestive of myelolipoma. patient was planned for surgery. laparoscopic removal of tumor was done. grossly, tumor was well circumscribed measuring 12 × 10 × 9.5 cm. the cut surface revealed a corresponding author: deepali jain, md; dnb department of pathology, sir ganga ram hospital, rajinder nagar, new delhi, india 110060 tel: +91 986 889 5112 fax: +91 522 264 9389 e-mail: deepalijain76@ gmail.com received december 2010 accepted february 2011 departments of pathology and urology, sir ganga ram hospital, new delhi, india case report 722 | yellow colored mass with central areas of hemorrhage (figcomposed of lobules of mature adipose tissue with collection of foamy macrophages at places (figures 3a and b). large areas of hemorrhage were present throughout the tumor (figure 3c) with few clusters of hemosiderin-laden macrophages signifying old hemorrhage (figure 3d). however, no hematopoietic elements were evident despite thorough sampling seen. discussion adrenal lipomas are rare lesions. review of the literature reveals only 16 cases described to date (table 1).(1-13) lam and lo found 4.8% of the adrenal lipomatous tumors in the 30year period, of which 0.7% were adrenal lipomas.(6) there is male predominance (male-to-female ratio of 3:1); however, our case was a female patient. age ranges from 35 table 1. summary of the reported cases of adrenal lipomas. first author age, y/ gender diameter, cm side presentation treatment remarks lange (1) 54/m 2.5 rt paroxysmal hypertension prinz(2) 73/f 3.0 rt incidental finding by computed axial tomography scan adrenalectomy avinoach(3) 40/f 1.3 rt incidental finding at laparotomy sharma(4) 45/m 12.0 rt abdominal pain, hypertension laparoscopic removal 1-year follow-up ghavamian(5) 50/f 8 lt incidental finding by ct scan partial adrenalectomy bilateral adrenal tuberculosis, necrosis, and calcification lam(6) 64/f 78/m 65/m 8.0 4.5 2.0 rt rt lt incidental finding by ultrasonography incidental finding at autopsy incidental finding at autopsy resection calcification and ossification milathianakis(7) 39/m 20 cm/2900 g rt incidental finding by ultrasonography transperitoneal resection giant, calcification on ct rodríguez-calvo(8) 70/m 45/m 1 cm 2 cm/18 g lt rt incidental finding at autopsy incidental finding at autopsy pheochromocytoma in the contralateral gland büttner(9) 50/m 1.1 rt incidental finding at autopsy shumaker (10) 68/m 7.0 lt incidental finding by ct scan laparoscopic left adrenalectomy singaporewalla(11) 44/m 15.6 lt acute abdomen resection reteroperitoneal bleeding shah(12) 35/m 5 rt pain in right loin right adrenalectomy gupta(13) 51/m 9 rt incidental finding by ct scan laparoscopic removal detected 3 months after nephrolithotomy present case 55/f 12 rt flank pain laparoscopic removal with internal hemorrhage m indicates male; f, female; rt, right; lt, left; and ct, computed tomography. case report 723vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l adrenal lipoma | jain et al to 78 years. most of the subjects have been reported from eastern region of the world; however, real racial difference right-side adrenal has been affected more commonly, including the present case.(6) size of the tumor varies from 1 cm to 20 cm.(7) most of the tumors have been detected incidentally. in other subjects, abdominal pain was the most frequently encountered symptom presumably due to their large size.(4) however, milathianakis and colleagues described a case of giant lipoma of 20 cm, which was detected incidentally.(7) our patient presented with abdominal pain presumably due to hemorrhage within the lesion. patient may present with acute abdomen due to retroperitoneal bleeding.(11) the origin of the adrenal lipomas is not well understood. these may arise from metaplasia of either stromal cells or adrenal cortical cells.(14) histologically, they are similar to lipomas elsewhere in the body. these are well-demarcated lesions composed of lobules of mature adipose tissue. focal areas of (6) histopathologic differential diagnoses are described in table 2. radiological and clinical differential diagnoses include more common lesions, such as myelolipoma and adrenal cortical adenoma with myelolipomatous metaplasia. computed tomography and magnetic resonance imaging help in accutent of adipose and hematopoietic components.(15) however, from myelolipoma due to internal hemorrhage within the tumor. furthermore, the lesion did not harbor hematopoietic elements despite thorough sampling. twelve sections were cal presence of hematopoietic elements. another differential diagnosis was well-differentiated liposarcoma due to large size of the tumor. the absence of lipocoma. surgery is adopted for large tumors because of the risk of malignancy in large adrenal tumors and for the potential relief of symptoms in some patients. currently laparoscopic surgery is the method of choice for removal of these tumors unless it is voluminous and complicated by rupture, bleeding, or sarcomatous changes.(16) figure 1. computed tomography scan shows a large well-circumscribed fat density mass with internal areas of hemorrhage (white arrow). figure 2. well-circumscribed globular mass, cut surface of which is largely yellow with areas of hemorrhage. figure 3. (a) histology shows lobules of mature adipose tissue (hematoxylin and eosin stain ×200); (b) rim of adrenal cortex (asterisk) is seen (hematoxylin and eosin stain ×200); (c) areas of hemorrhage are evident (hematoxylin and eosin stain ×100); and (d) few clusters of hemosiderin-laden macrophages focally signifying areas of old hemorrhage (hematoxylin and eosin stain ×200). a b c d 724 | case report conflict of interest none declared. table 2. histopathologic differential diagnoses of adrenal lipoma. lesion pathology adrenal cortical adenoma with myelolipomatous metaplasia gross: small encapsulated with solid homogeneous yellow cut surface micro: cells of adrenal cortex intermixed with myelolipomatous areas adrenal myelolipoma gross: grayish-red, with a pseudocapsule micro: encapsulated, and composed of various proportions of mature adipose tissue and bone marrow elements; the myeloid component is best characterized by the large megakaryocytes well-differentiated liposarcoma gross: yellow, soft, and greasy, and contains lobules with white septa micro: adipocytic tumor with widened fibrous septa and enlarged, hyperchromatic atypical lipocytes within both the septa and fat ; s-100 immunostains for lipoblasts adrenal pseudocyst gross: fibrous, well-encapsulated cyst with or without hemorrhagic adrenal tissue and calcification micro:wide range of histological appearances and sometimes contains intracystic mature adipose tissue angiomyolipoma gross: yellow to gray, with cysts if associated with tuberous sclerosis micro: mixture of adipose tissue, smooth muscle cells, epithelioid cells, and blood vessels, in varying proportions, and shows at least focal immunoreactivity for hmb-45 teratoma gross: solid and cystic components micro: various types of epithelium of ectodermal and endodermal origin, glial tissue, and mesodermal components references 1. lange hp. lipoma of the adrenal gland simulating the signs of phaeochromocytoma. ger med mon. 1966;11:190-2. 2. prinz ra, brooks mh, churchill r, et al. incidental asymptomatic adrenal masses detected by computed tomographic scanning. is operation required? jama. 1982;248:701-4. 3. avinoach i, robinson cr, avinoah e, peiser j. adrenal lipoma: a rare tumour of the adrenal gland. histopathology. 1989;15:195-6. 4. sharma mc, gill ss, kashyap s, nabi g, mishra mc. adrenal lipoma. a case report. urol int. 1998;60:245-7. 5. ghavamian r, pullman jm, menon m. adrenal lipoma: an uncommon presentation of the incidental asymptomatic adrenal mass. br j urol. 1998;82:136-7. 6. lam ky, lo cy. adrenal lipomatous tumours: a 30 year clinicopathological experience at a single institution. j clin pathol. 2001;54:707-12. 7. milathianakis kn, farfarelos cd, mpogdanos im, karamanolakis dk. giant lipoma of the adrenal gland. j urol. 2002;167:1777. 8. rodriguez-calvo ms, suarez-penaranda jm, alvarez mt, munoz ji, ortiz-rey ja, concheiro l. adrenal lipomas: incidental autopsy findings. pathol int. 2007;57:751-3. 9. buttner a. lipoma of the adrenal gland. pathol int. 1999;49:1007-9. 10. shumaker nr, rochman cm, legallo rd, northup cj, hanks jb. incidentally identified adrenal lipoma: case report and review of related literature. endocr pract. 2008;14:209-12. 11. singaporewalla rm, thamboo tp, rauff a, cheah wk, mukherjee jj. acute abdominal pain secondary to retroperitoneal bleeding from a giant adrenal lipoma with review of literature. asian j surg. 2009;32:172-6. 12. shah s, bhatti su. primary adrenal lipoma. j coll physicians surg pak. 2009;19:450-1. 13. gupta m, sood d, singh a. adrenal lipoma complicated by perinephric abscess. urol j. 2009;6:162. 14. lam ky, chan ac, ng io. giant adrenal lipoma: a report of two cases and review of literature. scand j urol nephrol. 1997;31:89-90. 15. kenney pj, wagner bj, rao p, heffess cs. myelolipoma: ct and pathologic features. radiology. 1998;208:87-95. 16. grumbach mm, biller bm, braunstein gd, et al. management of the clinically inapparent adrenal mass ("incidentaloma"). ann intern med. 2003;138:424-9. association of long non-coding rna meg3 polymorphisms and risk of prostate cancer in chinese han population bin xu1,2, minhao zhang1,2, chunhui liu2, can wang1,2, zonghao you1,2, yali wang1,2*, ming chen1,2** purpose: to explore the association between meg3 polymorphisms and the risk of prostate cancer in the chinese han population. materials and methods: two meg3 single-nucleotide polymorphisms (snps) (rs11627993 c >t rs7158663 a>g) were genotyped in a case-control study in which 165 prostate cancer patients and 200 healthy controls were recruited by a real-time polymerase chain reaction (pcr) with the taqman assay. the odds ratios (ors) and 95% confidence intervals (cis) were used to estimate the strength of association. results: no statistically significant differences were found in the allele or genotype distributions of the meg3 rs11627993 c >t and rs7158663 a > g polymorphisms among cases or healthy control subjects (rs11627993: cc vs ca: 95% ci = 0.54-1.95, ors = 1.03; cc vs aa: 95% ci = 0.67-2.54, ors = 1.30 ; cc/ca vs aa: 95% ci = 0.81-1.98, ors = 1.26 , p = .29 ; c vs a: 95% ci = 0.85-1.57, ors = 1.16, p = .35; rs7158663: aa vs ag: 95% ci = 0.76-5.08, ors = 1.97, aa vs gg: 95% ci = 0.57-3.29, ors = 1.37; aa/ag vs gg : 95% ci = 0.56-1.32, ors = 0.86, p = .49; a vs g: 95% ci = 0.69-1.39, ors = 0.98, p = .91) further stratified analysis detected no significant association. conclusion: the meg3 polymorphisms (rs11627993 c>t and rs7158663 a>g) does not influence the susceptibility to prostate cancer. keywords: maternal-expressed gene 3; polymorphism; susceptibility; prostate cancer; lncrna introduction according to recent reports, prostate cancer is the most common non-cutaneous malignancy and the second leading cause of cancer-related deaths of men in the developed world(1). the incidence and mortality of prostate cancer in the chinese han population have also been increasing in the last several decades(2). the 2019 china national cancer center reported that prostate cancer ranked sixth and tenth among male malignancies in terms of morbidity and mortality in 2015(2). to date, the mechanisms of prostate cancer remains largely unknown. lncrnas are important for cancer initiation and progression with the development of advanced genomic methods(3). the genome-wide association study have identified so many cancer risk snps which are located in noncoding regions(4). snps may affect the normal function of genes through various mechanisms, thereby affecting individual tumor susceptibility(5). meg3 is abnormally expressed in various human can1department of urology, affiliated zhongda hospital of southeast university, nanjing, 210009, china. 2surgical research center, institute of urology, medical school of southeast university, nanjing, 210009, china. *correspondence: department of urology, affiliated zhongda hospital of southeast university, 87 dingjia qiao, nanjing, jiangsu province,210009, people’s republic of china. tel: +86 150666260. e-mail: 15150666260@163.com **department of urology, affiliated zhongda hospital of southeast university, 87 dingjia qiao, nanjing, jiangsu province, 210009, people’s republic of china. tel: + 86 13913009977, e-mail: mingchenseu@126.com. received september 2019 & accepted may 2020 cers, such as hepatocellular carcinoma(6,7), bladder cancer(8), glioma(7), and gastric cancer(9). ribarska found low expression of meg3 in prostate cancer(10). luo found that meg3 can inhibit the proliferation of prostate cancer cells and promote apoptosis(11). however, little is known about the association between snps in meg3 and prostate cancer risk. based on the previous findings mentioned above, we hypothesized that genetic variants of meg3 may influence the susceptibility of prostate cancer. to test the hypothesis, we carried out an association study between snps in meg3 and prostate cancer risk in a hospital-based prostate cancer case-control study, in which 165 patients and 200 control subjects were recruited. patients and methods study subjects this study recruited 165 prostate cancer cases and 200 control subjects from the affiliated zhongda hospital of southeast university. cap patients were diagnosed beurological oncology urology journal/vol 18 no. 2/ march-april 2021/ pp. 176-180. [doi: 10.22037/uj.v16i7.5585] tween july 2017 and july 2019 and were pathologically proven to have prostate adenocarcinoma after biopsy in the affiliated zhongda hospital of southeast university. the control group was age-matched, and the subjects were healthy checkup examinees without cancer history and were collected in the same period. all the patients were southern chinese han population. controls were excluded if they had an abnormal prostate-specific antigen (psa) level, or abnormal digital rectal examination (dre). after informed consent was obtained, 2ml of peripheral blood sample was collected and each subject was asked to finish a questionnaire including age, race, tobacco use, alcohol use, family history of cancer, and so on. in the present research, smoking more than five cigarettes per day for more than 5 years was defined as smoking. drinking habit was defined as drinking at least three times per week and lasting more than 10 years. family history of cancer was defined as cancer in first-degree relatives (parents, siblings, or children). disease stage was determined by pathologic findings, pelvic computed tomography, magnetic resonance image, and radio-nucleotide bone scans. the tumor stage was determined using tnm classification and graded according to who guidelines. pathologic grade was recorded as the gleason score. all participants provided informed consent after the interview. this research protocol was approved by the institutional review board of affiliated zhongda hospital of southeast university snps selection and genotyping we selected the snps of meg3 with the minor allele frequency (maf) > 0.05 in han chinese from the 1000 genome projects. as a result, rs11627993 and rs7158663 were selected. genomic dna was extracted from peripheral blood using the tian amp blood dna kit (tian gen, china). genotyping was performed by taqman snp genotyping assay. furthermore, about 3% of selected samples were blindly repeated for genotyping to confirm the results. statistical analysis tests for the hardy-weinberg equilibrium in cases and controls were performed by the good-of-fit χ2 test. we estimated the association between genotypes and prostate cancer risk by odds ratios (ors) and 95% confidence intervals (cis) using the logistic regression. the ors and 95%cis were further adjusted for age, bmi (body mass index), and cigarette smoking, alcohol drinking, family history of cancers. all analyses were two-sided and p < .05 was considered significant. all statistical calculations were conducted with spss 13.0 software (spss inc., chicago, il, usa). association of meg3 and risk of cap-xu et al. urological oncology 177 characteristics cases (n=165) controls (n=200) p-valuea n % n % age(years) ≤ 70 76 46.10 101 50.50 0.39 > 70 89 53.90 99 49.50 body mass index (kg/m2) ≤ 23 56 33.90 68 34.00 0.99 > 23 109 66.10 132 66.00 cigarette smoking never 98 59.40 102 51.00 0.11 ever 67 40.60 98 49.00 alcohol drinking never 100 60.60 132 66.00 0.29 ever 65 39.40 68 34.00 family history of cancers no 118 71.50 168 84.00 p < 0.01 yes 47 28.50 32 16.00 atwo-sided x2 test for the distributions between the cases and controls. table 1. demographic characteristics of cap cases and controls characteristics. snps genotypes cases ,n(%) controls ,n(%) p-valueb adjusted or (95% ci)c rs11627993a1 total 165 200 0.62 cc 24(14.55) 27(13.50) 1.00(reference) ca 85(51.51) 94(47.00) 1.03(0.54-1.95) aa 56(33.94) 79(39.50) 1.30(0.667-2.54) cc/ca 109(66.06) 121(60.50) 0.29 1.00(reference) aa 56(33.94) 79(39.50) 1.26(0.81-1.98) allele 0.35 c allele 133(40.30) 148(37.00) 1.00(reference) a allele 197(59.70) 252(63.00) 1.16(0.85-1.57) rs7158663a2 0.34 aa 13(7.88) 11(5.50) 1.00(reference) ag 54(32.73) 78(39.00) 1.97(0.76-5.08) gg 98(59.39) 111(55.50) 1.37(0.57-3.29) aa/ag 67(40.61) 89(44.50) 0.49 1.00(reference) gg 98(59.39) 111(55.50) 0.86(0.56-1.32) allele 0.91 a allele 80(24.20) 100(25.00) 1.00(reference) g allele 250(75.80) 300(75.00) 0.98(0.69-1.39) athe genotype frequencies among the control subjects were in agreement with the hardy–weinberg equilibrium (a1:x2 =0.003 p=0.99 a2:x2 =0.24 p = 0.89). btwo-sided x2test for the distributions or allele frequencies between the cases and controls. codds ratios (ors) were obtained from a logistic regression model with adjusting for age, bmi, cigarette smoking, alcohol drinking, family history of cancers. table 2. genotypes in patients with cap and controls. results characteristics of the study population the demographic characteristics of participants are described in table 1. there was no significant difference in age (p = .39), bmi (p = .99), cigarette smoking (p = .11), and alcohol drinking distribution (p = .29). however, there was a significant difference in the family history of cancer between cases and controls (p < .001), which may suggest the incidence of prostate cancer is related to genetic factors. genotype distributions of meg3 polymorphism and risk of cap both of polymorphisms (rs11627993 c>t and table3. meg3 polymorphisms and clinicopathological characteristics in patients with cap. variables rs11627993 cc/ca,n(%) aa,n(%) p-valuea adjusted or (95% ci)b clinical stagec localized(84) 53(63.10) 31(36.90) 0.75 1.00(reference) advanced(81) 56(69.14) 25(30.86) 0.91(0.51-1.62) gleason score < 7(14) 13(92.86) 1(7.14) 1.00(reference) = 7(64) 39(60.94) 25(39.06) 0.05 8.33(1.03-67.71) > 7 (87) 57(65.52) 30(34.48) 0.07 6.84(0.85-54.85) psa ≤20 (74) 48(64.86) 26(35.14) 0.75 1.00(reference) > 29(91) 61(67.03) 30(32.97) 0.90(0.47-1.73) rs7158663 aa/ag,n(%) gg,n(%) clinical stagec localized(84) 33(39.29) 51(60.71) 0.67 1.00(reference) advanced(81) 34(41.98) 47(58.02) 0.87(0.45-1.66) gleason score < 7 (14) 5(35.71) 9(64.29) 1.00(reference) = 7 (64) 22(34.38) 42(65.62) 0.75 1.23(0.36-4.24) > 7 (87) 40(45.98) 47(54.02) 0.60 0.72(0.22-2.42) psa ≤ 20 (74) 27(36.49) 47(63.51) 0.32 1.00(reference) > 29(91) 40(43.96) 51(56.04) 0.72(0.38-1.36) atwo-sided w2 test for the distributions or allele frequencies between the cases and controls. bodds ratios (ors) were obtained from a logistic regression model with adjusting for age, bmi, cigarette smoking, alcohol drinking, family history of cancers. clocalized: t1–2n0m0; advanced: t3–4nxmx or txn1mx or txnxm1 [according to the international tumor–node–metastasis (tnm) staging system for cap.] table 4. association and stratification analysis between meg3 polymorphism and risk of cap. rs11627993(cases/controls) n (cases /controls) cc/ca aa variables n % n % p-valuea adjusted or (95% ci)b total 165/200 109/121 66.06/60.50 56/79 33.94/39.50 0.29 1.27(0.82-1.98) age (years) ≤ 70 76/101 52/62 68.42/61.39 24/39 31.58/38.61 0.40 1.32(0.69-2.53) > 70 89/99 57/59 64.04/60.00 32/40 35.96/40.00 0.21 0.66(0.35-1.26) body mass index (kg/m2) ≤ 23 56/68 35/42 62.50/61.76 21/26 37.50/38.24 0.86 1.07(0.51-2.24) > 23 109/132 74/79 67.89/59.85 35/53 32.11/40.15 0.17 1.49(0.85-2.62) cigarette smoking never 98/102 68/63 69.39/61.76 30/39 30.61/38.24 0.37 1.32(0.72-2.41) ever 67/98 41/58 61.19/59.18 26/40 38.81/40.82 0.70 1.14(0.59-2.22) alcohol drinking never 100/132 68/83 0.68/62.88 32/49 0.32/37.12 0.71 1.12(0.63-1.98) ever 65/68 41/38 63.08/55.88 24/30 36.92/44.12 0.32 1.44(0.70-2.93) family history of cancers no 118/168 76/103 64.41/61.31 42/65 35.59/38.69 0.64 1.12(0.69-1.84) yes 47/32 33/18 70.21/56.25 14/14 29.79/43.75 0.21 1.83(0.72-4.68) rs7158663(cases/controls) aa/ag gg n % n % total 165/200 67/89 40.61/44.50 98/111 59.39/55.50 0.51 0.87(0.56-1.33) age (years) ≤70 76/101 33/53 43.42/52.48 43/48 56.58/47.52 0.27 0.71(0.38-1.31) >70 89/99 34/36 38.20/36.36 55/63 61.80/63.64 0.87 1.05(0.57-1.93) body mass index (kg/m2) ≤23 56/68 20/28 35.71/41.18 36/40 64.29/58.82 0.48 0.77(0.37-1.60) ＞23 109/132 47/61 43.12/46.21 62/71 56.88/53.79 0.86 0.95(0.56-1.64) cigarette smoking never 98/102 39/42 39.80/41.18 59/60 60.20/58.82 0.73 0.91(0.50-1.63) ever 67/98 28/47 41.79/47.96 39/51 58.21/52.04 0.41 0.76(0.39-1.46) alcohol drinking never 100/132 38/58 38.00/43.94 62/74 62.00/56.06 0.60 0.86(0.49-1.51) ever 65/68 29/31 44.62/45.59 36/37 55.38/54.41 0.71 0.87(0.43-1.78) family history of cancers no 118/168 43/76 36.44/45.24 75/92 63.56/54.76 0.27 0.76(0.46-1.24) yes 47/32 24/13 51.06/40.63 23/19 48.94/59.37 0.42 1.46(0.58-3.65) a two-sided w2 test for the distributions between the cases and controls. b odds ratios (ors) were obtained from a logistic regression model with adjusting for age, bmi, cigarette smoking, alcohol drinking, family history of cancers. association of meg3 and risk of cap-xu et al. vol 18 no 2 march-april 2021 178 urological oncology 179 rs7158663 a>g) were in accordance with hardy-weinberg equilibrium (hwe) in the control subjects (rs11627993:x2 = 0.003 p = .99 rs7158663:x2 = 0.24 p = .89). however, neither of the two meg3 polymorphisms was associated with prostate cancer susceptibility, even after being adjusted for potential covariates (age, bmi, cigarette smoking, alcohol drinking, family history of cancers). we next evaluated the effects of combined risk genotypes on prostate cancer susceptibility. similarly, no significant association was found (table 2). for rs11627993, after adjusting for potential covariates, compared with cc homozygotes, subjects carrying ca heterozygotes (95% ci = 0.54-1.95, ors = 1.03) or aa homozygotes (95%ci = 0.67-2.54, ors = 1.30) had a decreased risk of cap. in addition, subjects carrying aa homozygotes had a 1.26-fold reduced risk (95%ci = 0.81–1.98 , p = .29) than these carrying cc/ca genotypes, and the a allele displayed a higher prevalence of cap compared with the c allele (95%ci = 0.85–1.57, ors = 1.16, p = 0.35). similarly, for rs7158663, after adjusting for potential covariates, compared with aa homozygotes, subjects carrying ag heterozygotes (95%ci = 0.76-5.08, ors = 1.97) or gg homozygotes (95%ci=0.57-3.29, ors=1.37) had an increased risk of cap (table 3). the g allele displayed a lower prevalence of cap compared with the a allele (95%ci = 0.69–1.39, ors = 0.98, p = .91). stratified analyses we next evaluated the stratified association of rs11627993 and rs7158663 with prostate cancer risk by clinical stage (localized: t1–2n0m0; advanced: t3–4nxmx or txn1mx or txnxm1), pathologic grade (gleason score <7, 7, and >7) and serum psa level (≤ 20 and >20) (table3), potential covariates(table 4). no association with rs11627993 or rs7158663 and prostate cancer was found. discussion it is well known that environmental and genetic factors such as genetic mutations and polymorphisms contribute to prostate cancer carcinogenesis(12,13). long non-coding rnas are molecules larger than 200 nucleotides, which do not code protein(14). it has been reported that lncrnas affect not only biologic processes such as metabolism, proliferation, tissue differentiation, cell type identity maintenance, apoptosis, cell signal regulation, organ development, and aging but also tumorigenesis(15,16). maternally expressed gene 3 (meg3) is a lncrna which is expressed in many normal tissues, and located on chromosome 14q32.3(17). it is the first lncrna identified as a tumor suppressor, preventing cancer initiation and development(18). recent studies demonstrated decreased meg3 levels in a variety of primary human cancer(19). meg3 expression level is decreased in lung cancer(20). the downregulation of meg3 usually led to more aggressive cancers and meg3 expression level correlated with tumor grade and prognosis in colorectal cancer, and gastric cancer(21,22). yin et al. analyzed 62 crc cases and demonstrated that a lower meg3 level correlates with lower pathological grade, deeper tumor invasion, and advanced tnm stage(23). sun et al. reported that downregulated meg3 is associated with poor prognosis and promotes cell proliferation in gastric cancer(24). li et al. found meg3 expression level is significantly lower in invasive nfpas compared to noninvasive nfpas(25). snps play important roles in carcinogenesis by affecting gene expression and function(26). some polymorphisms may affect the expression and secondary structure of lncrna, which contribute to the development of cancer(27-29). cao et al. genotyped five tagsnps in the meg3(rs3087918, rs11160608, rs4081134, rs10144253, and rs7158663) to investigate their role in colorectal cancer risk in a case-control study. they demonstrated that rs7158663 may be associated with colorectal cancer risk(23). another study reported that meg3 rs4081134 was associated with the risk of neuroblastoma in chinese children(30). however, no studies on the association between meg3 polymorphisms and the risk of the prostate cancer have been conducted until now. this is the first study to explore the correlation between the meg3 polymorphisms and prostate cancer susceptibility in china. the results showed that a family history of cancer increases the risk of prostate cancer. but no significant association was found between meg3 polymorphisms and the risk of prostate cancer. our study had several limitations. the primary limitation was a small sample size, which may impair the strength of the statistical power, especially for the stratification analysis. secondly, only two meg3 polymorphisms were genotyped. more potentially functionally polymorphisms in meg3 needed to be studied \ conclusions in conclusion, our study showed that the meg3 polymorphisms (rs11627993 and rs7158663) have no impacts on the risk of prostate cancer. a study based on multi-hospitals with larger sample should be conducted. moreover, in vitro and in vivo functional analysis to reveal the mechanism how the genetic polymorphisms in meg3 affect the prostate cancer risk also need to be studied. acknowledgements this study was funded by the national natural science foundation of china (no. 81872089, 81370849, 81672551, 81300472, 81070592, 81202268, 81202034), natural science foundation of jiangsu province (bk20161434, bl2013032, bk20150642 and bk2012336), six talent peaks project in jiangsu province (wsw-034) conflict of interest the authors report no conflicts of interest in this work. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2019. ca cancer j clin. 2019;69:734. 2. chen w, sun k, zheng r, et al. cancer incidence and mortality in china, 2014. chin j cancer res. 2018;30:1-12. 3. kumar v, westra hj, karjalainen j, et al. human disease-associated genetic variation impacts large intergenic non-coding rna expression. plos genet. 2013;9:e1003201. 4. frazer ka, murray ss, schork nj, topol ej. human genetic variation and its contribution to complex traits. nat rev genet. 2009;10:241association of meg3 and risk of cap-xu et al. 51. 5. sachidanandam r, weissman d, schmidt sc, et al. a map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. nature. 2001;409:928-33. 6. braconi c, kogure t, valeri n, et al. microrna-29 can regulate expression of the long non-coding rna gene meg3 in hepatocellular cancer. oncogene. 2011;30:4750-6. 7. wang p, ren z, sun p. overexpression of the long non-coding rna meg3 impairs in vitro glioma cell proliferation. j cell biochem. 2012;113:1868-74. 8. ying l, huang y, chen h, et al. downregulated meg3 activates autophagy and increases cell proliferation in bladder cancer. mol biosyst. 2013;9:407-11. 9. yan j, guo x, xia j, et al. mir-148a regulates meg3 in gastric cancer by targeting dna methyltransferase 1. med oncol. 2014;31:879. 10. ribarska t, goering w, droop j, bastian km, ingenwerth m, schulz wa. deregulation of an imprinted gene network in prostate cancer. epigenetics. 2014;9:704-17. 11. luo g, wang m, wu x, et al. long noncoding rna meg3 inhibits cell proliferation and induces apoptosis in prostate cancer. cell physiol biochem. 2015;37:2209-20. 12. leitzmann mf, rohrmann s. risk factors for the onset of prostatic cancer: age, location, and behavioral correlates. clin epidemiol. 2012;4:1-11. 13. giri vn, beebe-dimmer jl. familial prostate cancer. semin oncol. 2016;43:560-5. 14. quinn jj, chang hy. unique features of long non-coding rna biogenesis and function. nat rev genet. 2016;17:47-62. 15. schmitt am, chang hy. long noncoding rnas in cancer pathways. cancer cell. 2016;29:452-63. 16. jin g, sun j, isaacs sd, et al. human polymorphisms at long non-coding rnas (lncrnas) and association with prostate cancer risk. carcinogenesis. 2011;32:1655-9. 17. miyoshi n, wagatsuma h, wakana s, et al. identification of an imprinted gene, meg3/ gtl2 and its human homologue meg3, first mapped on mouse distal chromosome 12 and human chromosome 14q. genes cells. 2000;5:211-20. 18. zhou y, zhang x, klibanski a. meg3 noncoding rna: a tumor suppressor. j mol endocrinol. 2012;48:r45-53. 19. wang c, yan g, zhang y, jia x, bu p. long non-coding rna meg3 suppresses migration and invasion of thyroid carcinoma by targeting of rac1. neoplasma. 2015;62:541-9. 20. liu j, wan l, lu k, et al. the long noncoding rna meg3 contributes to cisplatin resistance of human lung adenocarcinoma. plos one. 2015;10:e0114586. 21. zhang x, rice k, wang y, et al. maternally expressed gene 3 (meg3) noncoding ribonucleic acid: isoform structure, expression, and functions. endocrinology. 2010;151:93947. 22. yin dd, liu zj, zhang e, kong r, zhang zh, guo rh. decreased expression of long noncoding rna meg3 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. tumour biol. 2015;36:4851-9. 23. cao x, zhuang s, hu y, et al. associations between polymorphisms of long non-coding rna meg3 and risk of colorectal cancer in chinese. oncotarget. 2016;7:19054-9. 24. shiah sg, hsiao jr, chang wm, et al. downregulated mir329 and mir410 promote the proliferation and invasion of oral squamous cell carcinoma by targeting wnt-7b. cancer res. 2014;74:7560-72. 25. li z, li c, liu c, yu s, zhang y. expression of the long non-coding rnas meg3, hotair, and malat-1 in non-functioning pituitary adenomas and their relationship to tumor behavior. pituitary. 2015;18:42-7. 26. gao p, wei gh. genomic insight into the role of lncrna in cancer susceptibility. int j mol sci. 2017;18. 27. wu h, zheng j, deng j, et al. a genetic polymorphism in lincrna-uc003opf.1 is associated with susceptibility to esophageal squamous cell carcinoma in chinese populations. carcinogenesis. 2013;34:290817. 28. zhu z, gao x, he y, et al. an insertion/ deletion polymorphism within rert-lncrna modulates hepatocellular carcinoma risk. cancer res. 2012;72:6163-72. 29. choi jw, park cs, hwang m, et al. a common intronic variant of cxcr3 is functionally associated with gene expression levels and the polymorphic immune cell responses to stimuli. j allergy clin immunol. 2008;122:1119-26 e7. 30. zhuo zj, zhang r, zhang j, et al. associations between lncrna meg3 polymorphisms and neuroblastoma risk in chinese children. aging (albany ny). 2018;10:481-91. association of meg3 and risk of cap-xu et al. vol 18 no 2 march-april 2021 180 effects of δnp63 gene down-expression on invasion of bladder carcinoma cells in vitro peng jing1#*, jiaqiong zou2# purpose: this work aims to investigate the effects of δnp63 gene down-expression on invasion of bladder carcinoma cells in vitro. materials and methods: bladder carcinoma cell lines um-uc-3 and 5637 were cultured. the expression plasmids encoding δnp63 were constructed and transfected into um-uc-3 and 5637 cells. the migration and adhesion of cells were detected. the expressions of δnp63 and invasion-related zonula occludens protein-1 (zo-1) in cells were determined by real-time polymerase chain reaction (pcr) and western blot analysis. confocal microscopy was used to observe the location of zo-1 in cells. results: results showed that the down-expression of δnp63 reduced the migration of um-uc-3 and 5637 cells, decreased the heterogeneity adhesion, and increased homogeneous adhesion. after transfection with δnp63, the zo-1 expression in cell membrane and cell cytoplasm was inhibited, also the zo-1 mrna and protein levels in cells were significantly decreased. conclusion: this study indicates thatδnp63 gene down-expression can reduce the invasion of bladder carcinoma cells in vitro. keywords: δnp63; zo-1; bladder cancer; invasion introduction bladder cancer is a multi-factor mixed and multiple genes involved disease. accumulation of abnormal genotypes and the role of external environments eventually leads to the occurrence of this disease. a previous study showed that p63 is present in all cell layers of papillary urothelial neoplasm(1), and other studies showed that δnp63 is expressed in some invasive carcinomas using immunoblotting and quantitative reverse transcriptase-polymerase chain reaction assays(2,3). δnp63 is an important member of p53 family, and the p63 gene located at chromosome 3q27-29 shows strong homology with the tumor suppressor gene p53(4). although p63 owes high sequence and structural similarities with p53, their function and expression profiles are different. wei et al(5) found that δnp63 is the predominant isoform during bladder development. castillo-martin et al (6) have characterized its role for bladder tumor progression by a p63 positive basal/intermediate cells and "umbrella" cells. however, the role of δnp63 in bladder cancer cell lines is not clear. δnp63 isoform is selectively highly expressed in cell compartments of stratified and glandular epithelia(4,7). our previous study(8) found that δnp63 is located in the nucleus. silence of δnp63 suppressed the invasion and metastasis of um-uc-3 cells and reduced claudin-1 expression. claudin-1 is located in the cell membrane, especially in tight junctions. in this study, we focused 1department of pediatric surgery, the affiliated hospital of north sichuan medical college, nanchong, sichuan 637000, p.r. china. 2medical laboratory of the first affiliated hospital of chengdu medical college,chengdu. #co-first authors *correspondence: the affiliated hospital of north sichuan medical college, nanchong, sichuan tel: +86 0817 2262409. fax: +86 0817 2262409. e-mail: 820128944@qq.com received february 2020 & accepted october 2020 on another tight junction associated protein-zonula occludens protein-1 (zo-1) and investigated the effects of δnp63 gene down-expression on zo-1 expression and invasion of bladder carcinoma cells in vitro. materials and methods cell culture and transfection assay the human bladder carcinoma cell lines, um-uc-3 and 5637, were purchased from the institute of cell research of chinese academy of sciences (shanghai, china). the study was approved by the ethics committee of north sichuan medical college, nan chong, china. um-uc-3 cells were cultured in mem medium (gibco inc., ca, usa) supplemented with 10% fetal bovine serum (fbs; sijixin inc., beijing, china) and 1% penicillin-streptomycin (invitrogen, shanghai, china); 5637 cells were cultured in rpmi-1640 medium (gibco inc., ca, usa) supplemented with 10% fbs and 1% penicillin-streptomycin. all cells were cultured at 37 oc with 5% co2. the sh-δnp63 plasmid was kindly provided by dr yunfeng he (the first affiliated hospital, chongqing medical university, chongqing, china) . the structure consisting of two 19 bp stem-targeting δnp63 mrna, a 9 bp loop and a short poly(a) 6 sequence. the sequences of two oligonucleotides were as follows: forward,5'-gatccgtgcccagactcaatttagtttcaagacgactaaattgagtcturological oncology urology journal/vol 18 no. 4/ july-august 2021/ pp. 404-410. [doi: 10.22037/uj.v16i7.5991] gggcattttgtcttca agacgactaaattgagtctgggcattttttgtcgaca-3' and reverse, 5'-agcttgtcgacaaaaaatgcccagactcaatttagtcgtcttgaaactaaattgagtctgggcacg-3'. the sequences of the vector plasmid were as follows: forward, 5'-gatccgacttcataaggcgcatgcttcaagacggcatgcgccttatgaagtcttttttgtcgaca-3' and reverse, 5'-agcttgtcgacaaaaaagacttcataaggcgcatgccgtcttgaagcatgcgccttataagtcg-3'. transfection was performed using lipofectamine 2000 (invitrogen) according to the manufacturer's instructions. cell wound healing assay cells were plated in six well plates for the wound healing assay. a wound was created on the monolayer cells when the cells reached 90% confluence by scraping a gap using a micropipette tip. the 5637 cells plate was then washed with serum-free rpmi-1640 medium to clean the dissociated cells, and um-un-3 cells were washed by serum-free mem medium. 5637 cells were then incubated with serum-free rpmi-1640 medium at 37 oc in 5% co 2 , and um-un-3 cells were then incubated with serum-free mem medium at 37 oc in 5% co2. cells that migrated into the unit length area were counted five times for each group at 0, 12, 24 and 48 h following scraping. cell homogeneous adhesion assay cell homogeneous adhesion assay could indicate the adhesion ability of 5637 and um-uc-3 cells, which could indirectly reflect the invasion ability of tumor cells. cells were plated in 48 well plates for the homogeneous adhesion assay. the culture medium was sucked out, followed by twice washing with phosphate-buffered saline (pbs) to remove the suspended cells, then the cells reached 90% confluence. 5637 cells were re-suspended with rpmi640 medium and um-un-3 cells with dmem medium. the cell re-suspension concentration in each group was 1×105/ml. 200 ul cells were added to a 48-well plate incubated at 37 oc in 5% co 2 for 8 h. the non-adherent cells were sucked out, followed by washing with pbs twice. all non-adherent cells were counted. the number of homogeneity adherent cells was equal to seeded 200 ul cells minus non-adherent cells. each group was repeated for four times. cell heterogeneity adhesion assay cell heterogeneity adhesion assay could verify the adhesion ability between tumor cells and matrix, which indirectly reflected the invasion of cells. cells (1×105 / ml) were added into a 96-well plate covered with collagen iv and incubated at 37 oc in 5% co 2 for 120 min. the plate was washed with pbs to clean the dissociated cells. approximately 20 μl of 5 mg/ml mtt (sigma aldrich inc., mo, usa) was added to the culture medium. following incubation for 10 min at room temperature, the culture medium was removed, and then 200 μl dimethylsulfoxide was added to each well. absorbance (a value) was measured at 570 nm. each sample was assayed four times. real-time polymerase chain reaction (pcr) total rna was isolated using an rneasy mini kit (qiagen inc., hilden, germany) and treated with dnase i (qiagen inc., hilden, germany). real-time pcr was conducted using an icycler bio-rad laboratories, inc., pa, usa) with an iq sybr-green supermix (biorad), according to the manufacturer's instructions. the δnp63 primer and β-actin as described previously (8). the zo-1 primer was as follows: zo-1, 5’-tccagtcccttacctttcgc-3’ (sense) and 5’-ccc tgggtgactaacggc-3’ (antisense). the pcr conδnp63 gene and invasion in bladder cancer-jing et al. urological oncology 405 figure 1. down-expression of δnp63 reduced the migration of cells. 5637 and um-uc-3 cells were cultured and transfected with vector plasmid or sh-δnp63 plasmid for 48 hr, respectively. transfected cells were used for scratch assay. cells migrating to the unit length area after 0, 12, 24, and 48 hr scraping were counted (magnification×20). ditions were as follows: 94 oc for 4 min, followed by 35 cycles at 94 oc for 20 sec, 60 oc for 30 sec and 72 oc for 30 sec, with data acquisition during each cycle. melting curve analysis was conducted following pcr cycling to verify the purity and quality of the pcr product. western blot analysis the protein was quantified with the bio-rad protein colorimetric assay. protein was separated using 8% sodium dodecyl sulfate polyacrylamide gel electrophoresis following addition of the sample buffer to the cellular extract and boiling the samples at 95 oc for 5 min. the protein was transferred onto a polyvinylidene difluoride membrane (millipore inc., ma, usa) and the membrane was then blocked for 1 h at room temperature with 5% bsa in tris-buffered saline containing 0.05% tween-20 (tbst). then, the blots were washed figure 2. down-expression of δnp63 increased homogeneous adhesion of 5637 and um-uc-3 cells. 5637 and um-uc-3 cells or cells transfected with vector plasmid or sh-δnp63 plasmid were used for homogeneous adhesion assay. the adherent cells were calculated. the data are shown as the mean ± sd (n = 4). ***, p < .001; ns, not significant. figure 3. down-expression of δnp63 reduced the heterogeneity adhesion of 5637 and um-uc-3 cells. 5637 and um-uc-3 cells or cells transfected with vector plasmid or sh-δnp63 plasmid were used for heterogeneity adhesion assay. mtt assays were used to determine the adherent cells. the data are shown as the mean ± sd (n = 4). ***, p < .001; ns, not significant. δnp63 gene and invasion in bladder cancer-jing et al. vol 18 no 4 july-august 2021 406 and incubated overnight at 4˚c in tbst containing 1% bsa with primary antibodies against δnp63 (1: 200), zo-1 (1: 200) and gapdh (1: 3,000). the membranes were washed three times with tbst, incubated with goat anti-rabbit horseradish peroxidase-conjugated secondary antibodies (1: 2,500 dilution in tbst containing 1% bsa) for 120 min at room temperature and then washed three times with tbst. following the chemiluminescence reaction, bands were detected by exposing the blots to x-ray films for the appropriate time. for urological oncology 407 figure 4. zo-1 expression was inhibited in 5637 and um-uc-3 cells transfected with sh-δnp63. zo-1 and δnp63 expression were analyzed by immunofluorescence assays. representative pictures of three independent experiments with consistent outcome are shown. figure 5. zo-1 expression both in mrna and protein levels was decreased in cells transfected with sh-δnp63. zo-1 and δnp63 expression were analyzed by pcr and western blot assays. for 5637 cells: 1, negative control; 2, vector plasmid; 3, sh-δnp63 plasmid; for um-uc-3 cells: 4, negative control; 5, vector plasmid; 6, sh-δnp63 plasmid. for western blot analysis, representative blots of three independent experiments with consistent outcome are shown. the data are shown as the mean ± sd (n = 3). ***, p < .001; ns, not significant. δnp63 gene and invasion in bladder cancer-jing et al. quantitative analysis, bands were detected and evaluated densitometrically with uvp gelatin image processing system labworks 4.6 software and normalized against gapdh density. confocal microscopy cells were seeded on polylysine (10 μg/ml) coated glass chamber slides at a density of 2,000 cells/chamber and washed, fixed in ice-cold 4% paraformaldehyde for 15 min and permeabilized in 100 mm phosphate buffer containing 0.2% triton x-100 (sigma-aldrich corp., mo, usa) for 4 min. cells were then incubated with 5% bovine serum albumin (bsa; sigma-aldrich corp., mo, usa) and immunolabeled with anti-δnp63 (1: 500; santa cruz biotechnology inc., ca, usa) and anti-zo-1 antibodies (1: 500; santa cruz biotechnology inc., ca, usa) at room temperature for 1 h. normal goat igg instead of anti-δnp63 antibody was used in specific experiments to serve as the negative control. following incubation with the primary antibodies, the cells were washed and incubated for 1 h with fluorescein isothiocyanate-conjugated anti-δnp63 antibodies (1: 500; santa cruz biotechnology inc., ca, usa) and cy3-conjugated anti-zo-1 antibodies (1: 500; santa cruz biotechnology inc., ca, usa) for 1 h. additional washes were performed and the cells were mounted using fluorescent mounting medium (applygen technologies, inc., beijing, china). cells were viewed with a leica sp2 upright microscope and the images were captured in lcs light (leica science lab, berlin, germany). statistical analysis all statistical analysis was carried out using spss17.0 software (spss inc., chicago, il, usa). data were expressed as mean±sd. one-way anova was used to determine the levels of difference between all groups. p <.05 was considered as statistically significant. results down-expression of δnp63 reduced the migration of cells cell wound healing assay showed that, at 12 h, the densities of um-un-3 cells in negative control, vector plasmid, and sh-δnp63 plasmid groups were 14.2±3.7, 13.9 ± 3.3 and 6.2 ± 2.3 cells/mm2, respectively. at 24 h, the densities of um-un-3 cells in negative control, vector plasmid, and sh-δnp63 plasmid groups were 22.0 ± 1.2, 18.2 ± 2.1 and 12.6 ± 1.4 cells/mm2, respectively. at 48 h, the densities of um-un-3 cells in negative control, vector plasmid, and sh-δnp63 plasmid groups were 35.2±1.7, 33.5±1.3 and 27.2±2.3 cells/mm2, respectively. at 12h, the densities of 5637 cells in negative control, vector plasmid, and sh-δnp63 plasmid groups were11.8 ± 3.7, 11.2 ± 3.3 and 8.2 ± 3.3 cells/mm2, respectively. at 24 h, the densities of umun-3 cells in negative control, vector plasmid, and shδnp63 plasmid groups were 19.0±3.2, 16.2±3.1 and 11.6±2.4 cells/mm2, respectively. at 48 h, the densities of um-un-3 cells in negative control, vector plasmid, and sh-δnp63 plasmid groups were 30.2 ± 1.2, 27.5 ± 2.3 and 26.2 ± 2.1 cells/mm2, respectively. at each time point, the densities of um-un-3 and 5637 cells in sh-δnp63 plasmid group were significantly lower than that in other groups (p < .05). this indicated that the down-expression of δnp63 could reduce the migration of bladder cancer cells (figure 1). down-expression of δnp63 reduced the heterogeneity adhesion, but increased homogeneous adhesion of cells cell homogeneous adhesion assay showed that the numbers of adherent 5637 cells in the negative control, vector plasmid, and sh-δnp63 plasmid groups were 1020.25 ± 20.25,1025.5 ± 17.48, and 2012.75 ± 9.54 cells/ml, respectively. the numbers of adherent um-uc-3 cells in the vector plasmid, negative control and sh-δnp63 plasmid groups were 1521.95 ± 35.45, 1536.35 ± 20.65, and 2475.45 ± 15.35 cells/ml, respectively (figure 2). the cell heterogeneity adhesion assay showed that the a values of 5637 cells in negative control, vector plasmid, and sh-δnp63 plasmid groups were 0.459 ± 0.035, 0.412 ± 0.014 and 0.295 ± 0.017, respectively. the a values of um-un-3 cells in negative control, vector plasmid, and sh-δnp63 plasmid groups were 0.412 ± 0.017, 0.398 ± 0.013 and 0.267 ± 0.021, respectively (figure 3). this indicated that, after transfection with δnp63, the heterogeneity adhesion capacity of bladder cancer cells was decreased. taken together, these results indicated that down-expression of δnp63 inhibited the invasion ability of 5637 and um-uc-3 cells. location and expression of zo-1 in cells laser confocal microscopy showed that zo-1 protein was mainly located in the cell membrane and cell cytoplasm. our results showed that, after transfection with sh-δnp63, zo-1 expression was inhibited (figure 4). real-time pcr and western blot analysis demonstrated that, after transfection with sh-δnp63, both zo-1 mrna and protein expression in 5637 and um-un-3 cells were significantly decreased (figure 5). discussion approximately 90% of cancers occur in epithelial original cells (9), so understanding the events that allow epithelial cells to progress towards tumorigenic pathways is required. usually, δnp63 is over-expressed in epithelial cancers, showing correlation with poor prognosis(11). some studies(7,9,11,12) have focused on the signaling pathways regulated by δnp63 and studied p63 levels in the mature epidermis. δnp63 was the main isoform detected and expressed mainly in the basal layers. its expression was down regulated in well differentiated layers(13,14). in addition, δnp63 opposes the tumor suppressive effects of cellular senescence suggesting a role in oncogene initiation(15,16). molecular mechanisms about the role of δnp63 in cell migration and invasion to date mainly comprised the identification of specific genes known to influence cell motility, including n-cadherin, e-cadherin, epithelial cell-cell adhesion molecule, and so on(17-19). further research is still needed. tight junctions proteins are important in effecting invasive phenotype of cancer cells, also important in influencing intracellular signaling pathways of these cells. our previous study(8) found that the down-expression of δnp63 changed the cell adhesion, and there was correlation between δnp63 and claudin-1. whether other tight junction associated proteins are involved in this process is still unknown. in this study, we further proved that δnp63 influence the invasion ability of bladder cancer cells partially through regulating the expression of zo-1. down expression of δnp63 leaded to decreased expression of zo-1, which contributed to δnp63 gene and invasion in bladder cancer-jing et al. vol 18 no 4 july-august 2021 408 the impaired adhesive and invasive ability of bladder cancer cells transfected with sh-δnp63 plasmid. zo-1 is membrane-associated guanylate kinase-family proteins presenting in tight junctions. in epithelial cells, zo-1 is exclusively located at the zonula occludens which is composed of tight junctions. zo-1 could promote tumor cell invasion. reduced expression of zo-1 correlated with decreased proliferation and/or transformation of epithelial cells(20-22). the depletion of zo-1 in cultured epithelial cells resulted in a delay in barrier formation(23,24), and zo-1 gene deletions were embryonic lethal in mice(25). zo-1 has been reported to accumulate transiently in the nucleus of proliferating cells(26), playing a role in cell differentiation rather than cell proliferation(27). how δnp63 influences cell-cell adhesion is still not well defined. we tried to demonstrate this by confocal microscopy and western blot analysis. our results indicated that zo-1 is located both in the cell membrane and cell cytoplasm. confocal microscopy and western blot analysis showed that zo-1 expression reduced in cells transfected with sh-δnp63. δnp63 silence in the human bladder carcinoma cell lines, umuc-3 and 5637, was confirmed by pcr and western blot assays. to date, we have demonstrated the down expression of zo-1 and claudin-1 in δnp63-silenced cells. the regulatory role of δnp63 in cell adhesive ability was explored by wound healing and adhesion assays in vitro. it may also promote cell migration during tumor invasion and metastasis. in addition, δnp63 modulated extensive adhesive gene spectrum, including n-cadherin, β4-integrin, and tight junction-associated protein (17,28). although the role of p63 in tumor formation and progression has been well studied, as a member of p53 gene family, its role in tumors’ metastasis is complex and remains unclear. the role of δnp63 expression in urothelial carcinomas still remains to be elucidated (2,29). because of rare mutations or allelic deletions of p63 gene in human bladder carcinomas(30), the loss of δnp63 mrna may attribute to epigenetic alterations. based on recent researches, δnp63 expression correlates with the severity of bladder cancer. in conclusion, δnp63 regulated the invasive ability of tumor cells partially through tight junction associated proteins, especially zo-1 in bladder cancer cells. this study lays the basis for further understanding on the role of p63 in tumors. conclusions this study indicates thatδnp63 gene down-expression can reduce the invasion of bladder carcinoma cells in vitro, laying the basis for further understanding of the role of p63 in tumors. acknowledgement the authors would like to thank dr. hong zhang and appreciate her support for the preparation of this manuscript. conflict of interest the authors report no conflict of interest. references 1. compérat e, camparo p, haus r, et al. immunohistochemical expression of p63, p53 and mib-1 in urinary bladder carcinoma. a tissue microarray study of 158 cases. virchows arch. 2006; 448: 319-24. 2. urist mj, di como cj, lu ml, et al. loss of p63 expression is associated with tumor progression in bladder cancer. am j pathol. 2002; 161: 1199-1206. 3. buza n, cohen pj, pei hui, parkash v. inverse p16 and p63 expression in small cell carcinoma and high-grade urothelial cell carcinoma of the urinary bladder. int j surg pathol. 2010; 18: 94-102. 4. yang a, kaghad m, wang y, et al. p63, a p53 homolog at 3q27-29,encodes multiple products with transactivating, death-inducing, and dominant-negative activities. molecular cell. 1998; 2: 305-316. 5. cheng w, jacobs wb, zhang jj, et al. deltanp63 plays an anti-apoptotic role in ventral bladder development. development. 2006; 133: 4783-4792. 6. castillo-martin m, domingo-domenech j, karni-schmidt o, matos t, cordon-cardo c. molecular pathways of urothelial development and bladder tumorigenesis. urol oncol. 2010; 28: 401-408. 7. pignon jc, grisanzio c, geng y, song j, shivdasani ra, signoretti s. p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia. proc natl acad sci u s a. 2013; 110: 8105-8110. 8. peng j, jiaqiong z, jun zh, jiang xl. δnp63 promotes um-uc-3 cell invasiveness and migration through claudin-1 in vitro. mol med rep. 2013; 7: 1026-1030. 9. wu g, osada m, guo z, et al. deltanp63alpha up-regulates the hsp70 gene in human cancer. cancer res. 2005; 65: 758-766. 10. chiang ct, chu wk, chow se, chen jk. overexpression of delta np63 in a human nasopharyngeal carcinoma cell line downregulates ckis and enhances cell proliferation. j cell physiol. 2009; 219: 117122. 11. lin yl, sengupta s, gurdziel k, bell gw, jacks t , flores er. p63 and p73 transcriptionally regulate genes involved in dna repair. plos genet. 2009; 5: e1000680. 12. romano ra, smalley k, magraw c, et al. δnp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. development. 2012; 139: 772-782. 13. nylander k, vojtesek b, nenutil r, et al. differential expression of p63 isoforms in normal tissues and neo-plastic cells. j pathol. 2002; 198: 417-427. 14. thurfjell n, coates pj, uusitalo t, et al. complex p63 mrna isoform expression patterns in squamous cell carcinoma of the head and neck. int j oncol. 2004; 25: 27-35. 15. keyes wm, pecoraro m, aranda v, et al. deltanp63alpha is an oncogene that targets chromatin remodeler lsh to drive skin stem cell proliferation and tumorigenesis. cell stem urological oncology 409 δnp63 gene and invasion in bladder cancer-jing et al. vol 18 no 4 july-august 2021 410 cell. 2011; 8: 164-176. 16. lindsay j, mcdade ss, pickard a, mccloskey kd , mccance dj. role of δnp63γ in epithelial to mesenchymal transition. j biol chem. 2011; 286: 3915-3924. 17. higashikawa k, yoneda s, tobiume k, taki m, shigeishi h, kamata n. snail-induced down-regulation of deltanp63alpha acquires invasive phenotype of human squamous cell carcinoma. cancer res. 2007; 67: 9207-9213. 18. fukushima h, koga f, kawakami s, et al. loss of deltanp63alpha promotes invasion of urothelial carcinomas via n-cadherin/src homology and collagen/extracellular signalregulated kinase pathway. cancer res. 2009; 69: 9263-9270. 19. higashikawa k, yoneda s, tobiume k, et al. deltanp63alpha-dependent expression of id-3 distinctively suppresses the invasiveness of human squamous cell carcinoma. int j cancer. 2009; 124: 2837-2844. 20. unger re, oltrogge jb, von briesen h, et al. isolation and molecular characterization of brain microvascular endothelial cells from human brain tumors. in. vitro cell dev. biol. anim. 2002; 38: 273-281. 21. kurrey nk, k a, bapat sa. snail and slug are major determinants of ovarian cancer invasiveness at the transcription level. gynecol oncol. 2005; 97: 155-165. 22. de iongh ru, wederell e, lovicu fj, mcavoy jw. transforming growth factor-beta-induced epithelial-mesenchymal transition in the lens: a model for cataract formation. cells tissues organs. 2005; 179: 43-55. 23. umeda k, matsui t, nakayama m, et al. establishment and characterization of cultured epithelial cells lacking expression of zo-1. j biol chem. 2004; 279: 44785-44794. 24. mcneil e, capaldo ct, macara ig. zonula occludens-1 function in the assembly of tight junctions in madin-darby canine kidney epithelial cells. mol biol cell. 2006; 17: 19221932. 25. katsuno t, umeda k, matsui t, et al. deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. mol biol cell. 2008; 19: 2465-2475. 26. balda ms, matter k. tight junctions and the regulation of gene expression. biochim biophys acta. 2009; 1788: 761-767. 27. khoury h, naujokas ma, zuo d, et al. hgf converts erbb2/neu epithelial morphogenesis to cell invasion. mol biol cell. 2005; 16: 550561. 28. yang x, lu h, yan b, et al. δnp63 versatilely regulates a broad nf-κb gene program and promotes squamous epithelial proliferation, migration, and inflammation. cancer res. 2011; 71: 3688-3700. 29. koga f, kawakami s, kumagai j, et al. impaired δnp63 expression associates with reduced β-catenin and aggressive phenotypes of urothelial neoplasms. br j cancer. 2003; 88: 740-747. 30. park bj, lee sj, kim ji, et al. frequent alteration of p63 expression in human primary bladder carcinomas. cancer res. 2000; 60: 3370-3374. δnp63 gene and invasion in bladder cancer-jing et al. fall 2012 08.pdf 652 | urology and nephrology research center; department of urology and renal transplantation, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran seyed amir mohsen ziaee, valiollah azizi, akbar nouralizadeh, shahram gooran, mohammad hadi radfar, mahboobeh mirzaei laparoscopic nephroureterectomy with concomitant open bladder cuff excision a single center experience corresponding author: akbar nouralizadeh, md urology and nephrology research center; department of urology and renal transplantation, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran tel: +98 914 323 2025 fax: +98 21 2258 8016 e-mail: nouralizadeh@ yahoo.com received august 2011 accepted april 2012 purpose: sion for management of upper urinary tract urothelial carcinoma. materials and methods: twenty-two patients with upper urinary tract urothelial carcinoma, who ber 2004 and october 2010, were studied retrospectively. operation time, blood loss, analgesic dose, and complications were recorded. local and port site recurrence, distant metastasis, and survival rate were also evaluated. results: patients consisted of 18 men and 4 women, with the mean age of 64.1 years (range, 52 to 83 years). right upper urinary tract was the involved site in 12 patients and left in 10 patients. mean operation time was 216 minutes (range, 145 to 395 minutes) and mean hospital stay was 4.3 days. mean follow-up period was 36.57 months (range, 6 to 65 months). no trocar site recurrence occurred. three-year overall survival and metastasis-free survival were 95% and 90%, respectively. conclusion: and bladder cuff through the same inevitable incision that is needed for specimen retrieval, without adding any more morbidity to the patient, a win-win radical surgery. keywords: laparoscopy, transitional cell carcinoma, kidney pelvis, neoplasm invasiveness laparoscopic urology laparoscopic urology 653vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l introduction p rimary upper urinary tract urothelial carcinoma (uc) constitutes about 5% of all urothelial malignancies. (1) although relatively uncommon, the incidence of upper urinary tract uc appears to increase gradually.(2-4) traditional treatment for upper urinary tract uc is open radical (5) laparoscopic nephroureterectomy (lnu). they reported reduced peri-operative morbidity, shorter hospital stay, and lower blood transfusion rate compared to open nephroureterectomy (onu).(6-8) despite initial concerns about oncological outcomes, lnu and onu had similar oncological effectiveness.(9) different approaches, such as open, laparoscopic (transperitoneal and retroperitoneal), hand-assisted, and endoscopic techniques have been used for distal ureterectomy. while each approach has own advantages and disadvantages, the gold standard technique for distal ureterectomy has not yet (10,11) sion through a pfannenstiel incision for patients with upper urinary tract uc, who are candidate for laparoscopic radical surgery. here, we present results of the procedure in a retrospective study. this method adds no morbidity to the patients because the incision, which is inevitably required for specimaterials and methods twenty-two patients with upper urinary tract uc who had october 2010 were studied retrospectively. and computed tomography of the abdomen and pelvis. all geons. after induction of general anesthesia, patients were car was inserted at the umbilicus using the open technique. then, a 10-mm pararectal and two 5-mm epigastric ports were introduced for instruments. laparoscopic transperitoneal nephrectomy was performed classically, and then, the ureter was dissected down up to the level of the pelvic brim, but not divided. then, patient’s position was changed to supine, and a pfannenstiel incision was made. retzius space was developed, the bladder was opened, and the ipsilateral distal ureter with a 1-cm margin of the bladder cuff adjaureter was released completely from the bladder wall transperitoneally. the specimen, including the kidney and ureter attached to the bladder cuff, was removed intact and en bloc from the pfannenstiel incision. bladder wall was repaired in 2 layers using absorbable sutures. after insertion of a drain, wound was closed anatomically. all the patients were ambulated on the 1st postoperative day. foley catheter was removed on the 5th to 7th postoperative day if drain discharge was not too much. wound drain was removed when drain discharge was less than 30 cc in 24 hours. intra-operative and postoperative features were also reviewed. results patients consisted of 18 men and 4 women, with the mean age of 64.1 years (range, 52 to 83 years). demographic data of the patients are shown in table. mean operation time was 216 minutes (range, 150 to 400 minutes). mean intra-operative blood loss was 314 cc (range, 150 to 1500 cc). one patient needed blood transfusion intra-operatively. mean hospital stay was 4.3 days. postoperative blood transfusion was required for two patients. none of the patients had postoperative analgesic dose requirement was morphine sulfate 12 mg. pathologic reports of all the patients were uc, with stage ta, t1, t2, t3, and t4 seen in 3, 9, 7, 2, and 1 patients, respectively. tumor was high grade in 4 patients (one t1, two t3, and one t4), and low grade in 18. mean follow-up period was 36.57 months (range, 6 to 65 months). one patient with high-grade t4 tumor died because of tumor recurrence in the bladder and distant metastasis at 1 year after the operation. one patient with high-grade t3 tumor developed the bowel and liver metastasis at 1 year after the operation, and received chemotherapy. bladder recurlaparoscopic nephroureterectomy with open bladder cuff excision | ziaee et al 654 | rence was seen in 3 patients. all the bladder recurrences were ta according to transurethral resection of the bladder tumor pathology reports. no trocar site tumor recurrence was seen. in this study, overall 3-year survival and metastasis-free survival were 95% and 90%, respectively. discussion although uc of the upper urinary tract is much less common than the bladder uc, it usually presents at a higher grade and stage compared to the bladder uc. low-grade and highgrade ucs represent 18% to 59% and 41% to 47% of the upper urinary tract ucs, respectively.(12,13) regarding the correlation between grade and stage of these tumors, it is not surprising that almost 50% of the patients present with stage t2 tumors at diagnosis.(10) low-grade and low-stage tumors could be managed by various strategies other than nephroureterectomy; however, standard treatment with nephrourecentage of the patients. in parallel with technical and instrumental advances, laparoscopy is increasingly used in uro-oncology surgeries. clay(6) later, several authors reported case series of lnu and compared its peri-operative results with onu.(14,15) there a review by stewart and associates showed that long-term oncological outcome of lnu is similar to onu.(9) in another long-term oncological outcomes of lnu are not different from onu.(10) a point of controversy still debated is the management of the distal ureter and bladder cuff. while various minimallyinvasive techniques have been described, it is not yet clari(16) the main used techniques include transurethral resection of the ureteral orical laparoscopic detachment and ligation technique, laparoscopic stapling of the distal ureter and bladder cuff, and open technique. each technique offers certain advantages and disadvantages.(17) pluck technique involves aggressive transurethral into the perivesical fat. although it is a rapid and easy technique, there are two main drawbacks. there is a risk for incomplete removal of the ureter and potential for leakage of urine containing malignant cells into the retroperitoneal space.(11) these risks are associated with potential for local tumor recurrence and tumor implantation, as reported by several authors.(18,19) intussusception technique, which is a transurethral procedure, was initially used in onu, and its long-term results in contraindicated in any ureteral tumor, and does not guarantee complete removal of the intramural ureter and bladder cuff. the ureteral mucosa.(5) transvesical laparoscopic detachment and ligation technique, transvesical laparoscopic ports. it adheres to the oncological the distal ureter. gill and colleagues compared the oncological outcomes of lnu using this technique with onu, and re(14) drawbacks include need for repositioning the patient, adding 60 to 90 minutes to the operation time, risk of tumor spillage from the bladder ports, laparoscopic urology demographic data of the patients. variable n side right 12 left 10 chief complaint gross hematuria 17 flank pain 2 irritative luts* 3 tumor location renal pelvis 19 calyx 1 ureter 2 urine cytology positive 12 negative 10 *luts indicates lower urinary tract symptoms 655vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l laparoscopic nephroureterectomy with open bladder cuff excision | ziaee et al (17) laparoscopic stapling of the distal ureter and bladder cuff offers the advantage of maintaining the urinary system closed and reducing the operation time of lnu. however, the main concern is related to the likelihood for remaining viable urothelial tissue in the staple line. this viable tissue, which could be a source for local recurrence, may not be evaluated endoscopically.(20) matin and gill compared the results of lnu using various techniques for distal ureter management, and reported higher frequency of positive surgical margin and also poorer recurrence-free survival following stapling technique.(21) thors.(22) open technique is the standard approach for distal ureter management and the most reliable method from the oncological viewpoint. regarding the need for an incision for specimen retrieval after lnu, the same incision could be added morbidity. it is a simple and easy to learn technique, which guarantees the best adherence to oncological princision of the distal ureter and bladder cuff. furthermore, secure repair of the bladder incision in a watertight manner prevents and pelvic space to urothelial cells, an important source for local tumor recurrence.(9,16) waldert and associates reported the results of lnu using the open technique for distal ureter management, and showed that the procedure is as oncologically effective as onu.(23) in 2004. twenty-two patients underwent the procedure withstiel incision, which was inevitably needed for intact specimen removal. it is noteworthy that none of the patients with low-grade tumor had metastasis during the follow-up period, tasis. the small sample size is a limitation of our study. this technique seems to be an acceptable option for management of the upper urinary tract uc providing the advantages of a minimally-invasive procedure along with the oncological precision of an open technique. conclusion laparoscopic nephroureterectomy along with open bladder conflict of interest none declared. references 1. remzi m, shariat s, huebner w, fajkovic h, seitz c. upper urinary tract urothelial carcinoma: what have we learned in the last 4 years? ther adv urol. 2011;3:69-80. 2. jemal a, tiwari rc, murray t, et al. cancer statistics, 2004. ca cancer j clin. 2004;54:8-29. 3. munoz jj, ellison lm. upper tract urothelial neoplasms: incidence and survival during the last 2 decades. j urol. 2000;164:1523-5. 4. mellemgaard a, carstensen b, norgaard n, knudsen jb, olsen jh. trends in the incidence of cancer of the kidney, pelvis, ureter and bladder in denmark 1943-88. scand j urol nephrol. 1993;27:327-32. 5. gkougkousis eg, mellon jk, griffiths tr. management of the distal ureter during nephroureterectomy for upper urinary tract transitional cell carcinoma: a review. urol int. 2010;85:249-56. 6. clayman rv, kavoussi lr, figenshau rs, chandhoke ps, albala dm. laparoscopic nephroureterectomy: initial clinical case report. j laparoendosc surg. 1991;1:343-9. 7. mcdougall em, clayman rv, elashry o. laparoscopic nephroureterectomy for upper tract transitional cell cancer: the washington university experience. j urol. 1995;154:975-9; discussion 9-80. 8. shalhav al, elbahnasy am, mcdougall em, clayman rv. laparoscopic nephroureterectomy for upper tract transitional-cell cancer: technical aspects. j endourol. 1998;12:345-53. 9. stewart gd, humphries kj, cutress ml, riddick ac, mcneill sa, tolley da. long-term comparative outcomes of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial-cell carcinoma after a median follow-up of 13 years*. j endourol. 2011;25:1329-35. 10. berger a, fergany a. laparoscopic nephroureterectomy: oncologic outcomes and management of distal ureter; review of the literature. adv urol. 2009;1-4. 656 | 11. srirangam sj, van cleynenbreugel b, van poppel h. laparoscopic nephroureterectomy: the distal ureteral dilemma. adv urol. 2009;1-9. 12. hall mc, womack s, sagalowsky ai, carmody t, erickstad md, roehrborn cg. prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. urology. 1998;52:594-601. 13. clements t, messer jc, terrell jd, et al. high-grade ureteroscopic biopsy is associated with advanced pathology of upper-tract urothelial carcinoma tumors at definitive surgical resection. j endourol. 2012;26:398-402. 14. gill is, sung gt, hobart mg, et al. laparoscopic radical nephroureterectomy for upper tract transitional cell carcinoma: the cleveland clinic experience. j urol. 2000;164:1513-22. 15. simone g, papalia r, guaglianone s, et al. laparoscopic versus open nephroureterectomy: perioperative and oncologic outcomes from a randomised prospective study. eur urol. 2009;56:520-6. 16. ghazi a, shefler a, gruell m, zimmermann r, janetschek g. a novel approach for a complete laparoscopic nephroureterectomy with bladder cuff excision. j endourol. 2010;24:415-9. 17. steinberg jr, matin sf. laparoscopic radical nephroureterectomy: dilemma of the distal ureter. curr opin urol. 2004;14:61-5. 18. arango o, bielsa o, carles j, gelabert-mas a. massive tumor implantation in the endoscopic resected area in modified nephroureterectomy. j urol. 1997;157:1839. 19. hetherington jw, ewing r, philp nh. modified nephroureterectomy: a risk of tumour implantation. br j urol. 1986;58:368-70. 20. venkatesh r, rehman j, lee d, vanlangendonk r, ragab m, landman j. cell viability within the stapled tissue following laparoscopic tissue stapling in a porcine model. j urol. 2003;169:150. 21. matin s, gill i. laparoscopic radical nephrectomy with various forms of bladder cuff control ii: patterns of survival. j endourol. 2003;17:a74. 22. shalhav al, dunn md, portis aj, elbahnasy am, mcdougall em, clayman rv. laparoscopic nephroureterectomy for upper tract transitional cell cancer: the washington university experience. j urol. 2000;163:1100-4. laparoscopic urology 23. waldert m, remzi m, klingler hc, mueller l, marberger m. the oncological results of laparoscopic nephroureterectomy for upper urinary tract transitional cell cancer are equal to those of open nephroureterectomy. bju int. 2009;103:66-70. urological oncology the influences of metformin on prostate in terms of psa level and prostate volume eray atalay1, aslan demir2*, huseyin avni eroglu3 purpose: the effects of metformin on prostate volume and prostate-specific antigen (psa) were investigated. materials and methods: we enrolled 384 newly diagnosed diabetes mellitus (dm) patients and 152 controls all of whom were >50 years into our prospective cross-sectional observational study. the first group contained patients receiving metformin only, the second group patients were taking a mixture of medications, including metformin plus other oral anti-diabetics, and the third was the control group. before beginning treatment, body mass indices (bmi) of all cases were obtained. prostate volumes were evaluated using transabdominal ultrasonography at the sixth and twelfth months. insulin, glycosylated hemoglobin (hba1c), insulin sensitivity index (isi), insulin-rich growth factor (igf-1), psa, free psa, and total testosterone levels were measured. results: the differences in bmi between the first and third groups were statistically significant (p < 0.05). there were no statistical differences among the groups in terms of prostate volumes (p > 0.05). the differences between the groups for insulin, hba1c, isi, igf-1 (somatomedin), psa, free psa, and total testosterone levels were not statistically significant (p > 0.05). free psa and total testosterone levels in groups 1 and 2 were not statistically different at the beginning of treatment and the sixth month (p >0.05), but within groups 1 and 2, only psa levels were different at the start of the study until completion. no differences were seen in the third group. conclusion: metformin appears to cause a decrease in psa levels. the mechanism and any effects on prostate tissue will be studied in future randomized, prospective studies. keywords: metformin; prostate; psa; prostate biopsy introduction prostate cancer (pca) is the most common non-cu-taneous cancer and the second-leading cause of cancer deaths in the united states (us). however, only ~16% of men diagnosed with pca ultimately die from pca because of effective treatments and biological indolence.(1) although it has been suggested that the risk of several malignancies is increased in diabetes, there have been studies suggesting that the risk of (pca) in diabetic patients is reduced second to lowering of testosterone levels during the state of hyperinsulinemia.(2) metformin is a biguanide oral antihyperglycemic agent that abrogates hyperinsulinemia in individuals with and without diabetes.(3,4) it is a promising therapeutic agent for pca(5) and may be useful for preventing and managing various cancer types through direct or indirect mechanisms.(2) however, there are some conflicting data in terms of its utility because the exact pharmacological mechanism of metformin is not clearly understood. if metformin is proven to affect prostate-specific antigen (psa) levels, a more accurate assessment of the decision to take a biopsy in patients who have not been diagnosed with pca or perhaps for prognostic purposes in pca patients can be made according to the adjusted psa value in patients using metformin. in this study, we investigated the effects of metformin on prostate volume and psa, which is the most commonly used marker for the diagnosis and over the course of pca. 1kafkas university faculty of medicine, department of internal medicine, kars, turkey. 2bezmialem vakif university, faculty of medicine, department of urology, istanbul, turkey. 3onsekiz mart university, faculty of medicine, department of physiology, çanakkale, turkey. *correspondence: bezmialem university, faculty of medicine, department of urology, istanbul, turkey. phone: +90 532 465 82 25. e mail: benaslandemir@yahoo.com.tr. received october 2019 & accepted may 2020 materials and methods the study was designed as a prospective, cross-sectional observational study. permission was obtained from the regional ethics committee with the number of 80576354-050-99/86 and performed in accordance with the world medical association’s helsinki declaration. the patients newly diagnosed with diabetes mellitus (dm) in patient groups 1 and 2 were enrolled into the study from the internal medicine clinic of our institute between 2013 and 2018, and the patients in the control group were enrolled from the check-up unit. informed consent was obtained from all patients. all participants were chosen from a single center that is located in the east of our country. a total of 2123 patients were evaluated for this investigation between 2013 and 2018. one-thousand five-hundred eighty-five patients were excluded due to concomitant disorders. we enrolled 536 patients (men) who were >50 years old with a psa level < 4 ng/dl; 384 patients were newly diagnosed as diabetes mellitus (dm) at the beginning of the study as were the 152 controls and both sets were followed over a 12-month period. the determination of this time was based on the duration of the actions of five alpha-reductase inhibitors (at least six months) on the prostate.(6) for that reason, we evaluated the groups both at the sixth and 12th months. lower urinary tract symptoms were evaluated by international prostate symptom score (ipss), urology journal/vol 18 no. 2/ march-april2021/ pp. 181-185. [doi: 10.22037/uj.v16i7.5645] and digital rectal examinations (dre) was performed. the dm patients were separated into two groups according to their medications. thus, three groups were formed. the first group consisted of patients who were taking metformin 2000 mg/day (split over two different times), and the second group consisted of those who were taking a mixture of medications that include metformin plus other oral anti-diabetics, including sulfonylurea and glinides. this group allowed us to clarify the effect of the oral anti-diabetic drugs on our results. the third group consisted of patients who did not have any diseases. before beginning treatment, body mass indices (bmi) of all cases were obtained. the prostate volumes of all patients were counted using transabdominal ultrasonography (usg) by the same urologist in our clinic and recorded at the beginning of treatment. this ultrasonography was repeated at the sixth and 12th month of treatment. during the same period, the psa, free psa, glycosylated hemoglobin (hba1c), and total testosterone levels were measured and reported. all blood samples were obtained at the same time of the day due to fluctuations in some blood values, such as total testosterone and when the patients were on an empty stomach, over the course of the day. in addition, insulin, insulin sensitivity index (isi), and insulin-like growth factor (igf)-1 (somatomedin) were measured at the beginning and at the12th month. all measurements for psa and total testosterone were performed with the same kit. the access hybritech psa assay, which is a two-site immunoenzymatic (‘sandwich’) assay, was used to measure psa. the parameters were analyzed between groups and also repetitive psa measurements for the same patients were analyzed within groups. in addition to these parameters, some parameters that could affect the results, including compliance to treatment, physical activity, and diet, were evaluated. the comparative statistical analysis was made both between times in each group and between groups at different times in terms of the investigated parameters. exclusion criteria: the cases with problems that could increase psa levels, such as lower urinary tract disorders and chronic prostatitis, the situations in which the international prostate symptom score (ipss) is >7, urinary tract infections, abnormal digital rectal examination findings, patients with the psa levels > 4 ng/ dl, and patients who were using medications for other chronic diseases were excluded from the study in order to prevent their effects on psa and total testosterone levels. these criteria were evaluated during the study period in order to catch the status of the new patients related to the exclusion criteria. statistical analysis the results are presented as mean ± standard deviation. the data were analyzed using spss 16.0 for windows (spss, inc., chicago, il, usa). differences between the results in terms of investigated parameters were analyzed using paired-samples student t tests with regard to repeated parameters in groups, one-way analysis of metformin effect on psa-atalay et al. table 1. baseline characteristics of patients. parameters group 1 n=216 group 2 n=168 group 3 n=152 p age 58.81 ± 8.28 59.52 ± 8.54 60.89 ± 7.14 >0.05 bmi 29.81 ± 2.9 28.48 ± 2.5 26.32 ± 6.9 *0.027 for prostate volume first 28.33 ± 15.1 27.01 ± 9.39 27.42 ± 10.4 > 0.05 6th month 28.16 ± 15.4 27.18 ± 8.6 28.01 ± 10.7 12th month 27.09 ± 14.13 26.75 ± 9.5 28.12 ± 18.3 for psa first 1.59 ± 1.86 1.56 ± 1.59 1.64 ± 1.56 > 0.05 6th month 1.24 ± 1.29 1.46 ± 1.48 1.67 ± 1.31 12th month 1.22 ± 1.25 1.15 ± 1.29 1.64 ±1.38 for free psa first 0.3 ± 0.23 0.32 ± 0.28 0.41 ± 0.35 > 0.05 6th month 0.36 ± 0.42 0.35 ± 0.34 0.36 ± 0.36 12th month 0.3 ± 0.35 0.24 ± 0.26 0.45 ± 0.38 for total testosterone first 360.4 ± 129.11 399.01±167.46 349.8 ± 146.7 > 0.05 6th month 325.68 ± 106.64 403.8 ± 179.41 340.42 ± 134.48 12th month 356.51 ± 136.48 370.06 ± 174.71 365.74 ± 144.58 for insulin first 5.39 ± 1.92 6.8 ± 2.73 5.22 ± 1.44 > 0.05 6th month 5.16 ± 1.88 6.4 ± 1.48 5.03 ± 1.35 > 0.05 12th month 5.27 ± 1.61 6.62 ± 2.56 4.96 ± 1.68+ 0.02 for hba1c first 8.29 ± 1.76 9.37 ± 1.43 > 0.05 6th month 7.48 ± 1.28 8.11 ± 1.34 12th month 7.52 ± 1.23 7.95 ± 0.99 for isi first 2.02 ± 1.3 2.73 ± 1.32 1.25 ± 0.38 > 0.05 12th month 1.81 ± .22 2.44 ± 1.19 1.31 ± 0.53+ 0.004 for igf-1 (somatomedine) first 170.26 ± 75 182.00 ± 53.08 146.62 ± 32.5 > 0.05 12th month 179.26 ± 76.8 191.29 ± 44.3 140.63 ± 34.7+ 0.02 *statistical difference between first and third groups, p < 0.05 +statistical difference between second and third groups, p < 0.05 prostate-specific antigen (psa), free psa, and total testosterone in ng/dl insulin reference range: 1.9–23 microunits/ml abbreviations: insulin-like growth factor (igf)-1 (somatomedine) reference range: 78–258 ng/ml hba1c: glycosylated hemoglobin; bmi: body mass index; igf-1: insulin-like growth factor; isi: insulin sensitivity index vol 18 no 2 march-april 2021 182 variance (anova) in terms of the differences between groups, and chi-squared test for categorical parameters. results there were 216, 168, and 152 patients in groups 1, 2, and 3, respectively. demographic variables were analyzed between groups (table 1) and also repetitive psa measurements for the same patients were analyzed within groups (table 2). the demographic characteristics of the groups are presented in table 1. the differences between the first and third group for bmi were statistically significant (p = 0.027). there were no statistical differences among the groups in terms of prostate volumes (p > 0.05) as shown in table 1. the differences between the groups with regard to hba1c, psa, free psa., and total testosterone levels were studied during each period, including the beginning of the treatment and the sixth and 12th months ( p > 0.05). insulin levels, isi, and igf-1 (somatomedin) both at the beginning and at the 12th month (p > 0.05) were evaluated as shown in table 1. free psa and total testosterone levels in groups 1 and 2 were not statistically different at the beginning of treatment and during the sixth month (p > 0.05), but within groups 1 and 2, only psa levels were different by month 12 (p = 0.049) as shown in table 2. no differences were seen in the third group. in addition to these, compliance to treatment, diet intervention, and physical activity were assessed at the 12th month, and their results are presented in table 3. in general, compliance to treatment rates were lower in group 2. discussion hyperinsulinemia and hyperglycemia are thought to promote carcinogenesis in patients with dm. several meta-analyses have demonstrated that diabetes is associated with increased risk of some cancers, such as breast, endometrium, bladder, liver, colorectum, and pancreatic in addition to a decrease in the risk of pca, but other studies do not demonstrate an association of hyperinsulinemia and hyperglycemia with an increase in the risk of cancer.(2,7–9) thus, the evidence has been conflicting. for that reason, this situation needs further studies to clarify this matter. there are conflicting data about the effect of metformin on controlling cancer.(2, 10–16) the effects of metformin, such as weightand tissue-specific reducing effects (17,18) occur through several pathways. because of its effect on colon cancer and hepatoblastoma(10) , activation of adenosine 5’-monophosphate-activated protein kinase (ampk), which is a tumor suppressor protein kinase(19,20), has an inhibitory effect on protein synthesis and gluconeogenesis during cellular stress. ampk also presents inhibitory effects on the mammalian target of rapamycin (mtor), a downstream effector of growth factor signaling that is frequently activated in malignant cells(7) and has inhibitory effects on hypoxic inducible factor 1-alpha (hif1-alpha).(21) according to a study by ranasing, nonspecific hif1-alpha inhibitors increase progression-free survival and reduce the risk of developing castrate-resistant pca and metastases in patients on continuous androgen deprivation treatment.(21) metformin can affect cancer development via one or all of these mechanisms. also, according to a study by jayalath, mean psa levels were 30% lower among metformin users compared to nonusers. psa levels of intermediateand high-dose metformin users were32% and 37% lower, respectively, compared to the low-dose group. psa levels were not different between intermediateand high-dose users.(22) drugs that affect psa levels may provide protective effects to pca patients relative to those that decrease psa levels. there are many conflicting sets of data about the effects of metformin on prostate tissue. if the effects of metformin on psa levels and prostate tissue can be explained with respect to all aspects, these findings may provide a guide for pca development and its course. in this study, we investigated the metformin effects to understand its effect on the prostate in terms of psa levels and volume. currently, the psa test is the least invasive method that provides information on prostate tissue development. we have investigated the effect of metformin especially in terms of psa level and prostate volume. if it causes a decrease in the psa levels, this effect may then occur for multiple reasons and may be important while deciding for obtaining a prostate biopsy according to the adjusted psa value. for example, it may only inhibit prostate tissue via protective effects on the prostate tissues for pca. we found that metformin and combination therapies caused a decrease in psa levels at the 12th month versus baseline. the means of psa at pretreatment and at the 12th month for group 1 were 1.59 ± 1.86 and 1.22 ± 1.25 (p = 0.049), respectively. the same parameters for group 2 were 1.56 ± 1.59 and 1.15 ± 1.29 (p = 0.001), respectively, as shown in table 2. the difference in rates within groups were 0.37 and 0.41 for groups 1 and 2, respectively. the difference in rates between the groups for pretreatment and 12-month psa values were statistically significant (table 2), whereas the differences between groups 1 and 2 were not (table 1). in fact, the main result, the psa decline rate between baseline and 12th month, may not be attributed only to metformin since group 2 also demonstrated improvement. however, the decline rates between groups 1 and 2 are very close to each other. if the other drugs in group 2 affected the psa levels in addition to the metformin effect, the psa decline would decrease even further. for that urological oncology 183 groups pretreatment psa 6th psa 12th psa p ng/dl ng/dl ng/dl group 1 1.59 ± 1.86* 1.24 ± 1.29 1.22 ± 1.25* *0.049 group 2 1.56 ± 1.59* 1.46 ± 1.48 1.15 ± 1.29* *0.001 group 3 1.64 ± 1.56 1.67 ± 1.31 1.64 ± 1.38 > 0.05 table 2. the comparative results in groups 1 and 2 with regard to repetitive psa measuremets for the same patients in groups. *statistically significant between pretreatment and 12-month results table 3. the rates of the compliance with treatment and recommendations (diet and physical activity). parameters group 1 group 2 n=216 (%) n=168 (%) compliance with treatment 120 (55.5%) 72 (42.8%) compliance with physical activity 140 (64.8%) 56 (33.3%) compliance with diet 124 (57.4%) 68 (40.4%) metformin effect on psa-atalay et al. reason, the decline in psa in group 2 may be attributed to the metformin effect. also, since psa values in both groups decreased compared to baseline values, it can be interpreted that this effect may be due to metformin. from another point of view, there were no statistical differences between groups 1 and 2 with regard to psa levels (table 1). this result could be based on the use of metformin in both groups. nevertheless, prospective, randomized trials with larger study populations are needed to prove these findings. in addition; according to our results, a significant reduction in psa levels at the 12th month was shown within groups 1 and 2 (table 2); however, no significant differences were established with regard to insulin, isi, and igf-1 (somatomedin) levels at six month in terms of our comparative results between groups 1 and 2. for that reason, the decrease in psa levels can be associated with metformin use and/or diabetes improvements because of the presence of metformin use in both groups 1 and 2. however, further and more detailed studies are needed in order to clarify the factors related to psa levels. although our results have been confirmed by preston et al.(16) and rothermundt et al.(17). a study by randazzo showed no significant differences in psa levels or pca incidence/grade in metformin patients.(14) in addition, nordström et al.(12) and merrick et al.(13) found no protective effects from aspirin, statins, or antidiabetic drugs in terms of pca risk. lee et al. found that metformin could reduce androgen-dependent cell growth and the expression of androgen receptor target genes by inhibiting androgen receptor function in prostate cancer cells.(15) patel et al. showed the effects of metformin on clinical outcomes after radical prostatectomy in terms of biochemical recurrence of psa level. they found that metformin use did not have any benefits in this group of patients.(8,11) however, according to their methodology, they analyzed this effect after radical prostatectomy. in addition to these results, the bmi results should be taken into consideration. according to our results, bmi differences between the first and third groups were statistically significant (p = 0.027) as shown in table 1. goodwin and becker showed that the weight-reducing effects of biguanides may partially explain their antitumor activity.(17,18) again, high bmis have been directly associated with risk of aggressive or fatal pca. one possible explanation for this finding may be an effect of bmi on serum psa levels.(23) according to some studies about the weight management resulting from metformin use, metformin may be a useful weight management aid in children in a clinical setting although the use of metformin for this purpose in children in a clinical setting has not been well described.(24,25) we believe that more clinical and histo-morphological studies should be performed to clarify this issue. the relationship between psa and total testosterone is well known. thus, we also studied the relationship between metformin use and total testosterone in order to understand whether the effect of metformin is through the testosterone pathway. we found no relationship between metformin use and total testosterone (p > 0.05). although testosterone levels within and among the groups were not statistically different from their baseline values, there was a slight decrease in groups 1 and 2 by the 12th month. this situation needs to be reevaluated in studies with larger numbers of patients. we also investigated the effect of metformin use on prostate volume and benign prostate hyperplasia (bph). there was no statistical difference among the groups in terms of prostate volumes (p > 0.05). according to our results, although no statistical differences were established with regard to insulin, igf-1 (somatomedin), hba1c, and isi values between groups 1 and 2, psa and testosterone levels were a bit higher (statistically insignificant) in group 2, which was a bit higher for insulin, igf-1, and isi. this situation may be associated with the numbers of the groups and/or patient lifestyle because the patient lifestyles in group 2 is generally worse (unhealthier) than those in the group 1 (table 3). the limitations of our study were that no evaluation of diabetic patients was performed as a separate group who received anti-diabetic drugs other than metformin in addition to conducting the study only in a single center. conclusions we found that metformin may decrease psa levels. this should be taken into consideration in order to prevent other unnecessary interventions in this patient group when it is time to make a decision for prostate disease diagnosis and treatment. however, the findings of this study and mechanism in addition to any effects on prostate tissue will be studied in future randomized, prospective and histo-morphological studies. this issue needs to be re-studied for different doses or differently designed studies in order to clarify the effects and mechanisms of metformin actions on prostate tissue. conflict of interest the authors declare that they have no conflict of interest references 1. demir a, karadag ma, turkeri l. is there a relationship between the number of lymph nodes and disease parameters in patients who underwent retropubic prostatectomy. int urol and nephrol. 2014;46:1537–1541 2. park js, lee ks, ham ws, chung bh, koo kc. impact of metformin on serum prostatespecific antigen levels: data from the national health and nutrition examination survey 2007 to 2008. medicine 2017; 96(51) 3. murtola tj, tammela tl, lahtela j, auvinen a. antidiabetic medication and prostate cancer risk: a population-based case control study. am j epidemiol. 2008; 168:925–931 4. sadeghi n, abbruzzese jl, yeung sc, hassan m, li d. metformin use is associated with better survival of diabetic patients with pancreatic cancer. clin cacer res. 2012; 18:2905–2912. 5. clements a gao b, yeap sh, wong mk, ali ss, gurney h. metformin in prostate cancer: two for the price of one. ann oncol. 2011; 22:2556–2560 6. gormley gj, stoner e, bruskewitz rc, et al: the effect of finasteride in men with benign prostatic hyperplasia. n engl j med 1992;327:1185–1191 7. noto h, goto a, tsujimoto t, noda m. cancer risk in diabetic patients treated with metformin: a systematic review and metametformin effect on psa-atalay et al. vol 18 no 2 march-april 2021 184 analysis. plos one 2012; 7:3 8. van staa tp, patel d, gallagher am, de bruin ml. glucose-lowering agents and the patterns of risk for cancer: a study with the general practice research database and secondary care data. diabetologia 2011;55:654–665 9. wotton cj, yeates dg, goldacre mj. cancer in patients admitted to hospital with diabetes mellitus aged 30 years and over: record linkage studies. diabetologia 2011;54:527–534 10. berstein lev m. metformin in obesity, cancer and aging: addressing controversies. aging 2012; 4:5 11. patel t, hruby g, badani k, abate-shen c, mckiernan jm. clinical outcomes after radical prostatectomy in diabetic patients treated with metformin. urology 2010; 76:1240-4 12. nordström t, clements m, karlsson r, adolfsson j, grönberg h. the risk of prostate cancer for men on aspirin, statin or antidiabetic medications. eur j cancer 2015; 51:725–733 13. merrick gs, bennett a, couture t, butler wm, galbreath rw, adamovich e. metformin does not predict for prostate cancer diagnosis, grade, or volume of disease after transperineal template-guided mapping biopsy. am j clin oncol 2015; jan 8 14. randazzo m, beatrice j, huber a, et al. influence of metformin use on psa values, free-to-total psa, prostate cancer incidence and grade and overall survival in a prospective screening trial (erspc aarau). world j urol 2014; oct 31 15. lee sy, song ch, xie yb, jung c, choi hs, lee k. smile upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells. cancer lett 2014; 28:354:390-7 16. preston ma, riis ah, ehrenstein v, breau rh, et al. metformin use and prostate cancer risk. eur urol 2014; 66:1012–1020 17. goodwin pj, and stambolic v. obesity and insulin resistance in breast cancer— chemoprevention strategies with a focus on metformin. breast; suppl 2011; 3:s31-35 18. becker s, dossus l, and kaaks r. obesity related hyperinsulinaemia and hyperglycaemia and cancer development. arch physiol biochem 2009; 115:86-96 19. morss as, edelman er. glucose modulates basement membrane fibroblast growth factor-2 via alterations in endothelial cell permeability. j biol chem 2007; 282:14635-14644 20. barclay aw, petocz p, mcmillan-price j, flood vm, prvan t, et al. glycemic index, glycemic load, and chronic disease risk—a metanalysis of observational studies. am j clin nutr 2008; 87:627–637 21. ranasinghe wkb, sengupta s, williams s, et al. the effects of nonspecific hif1alpha inhibitors on development of castrate resistance and metastases in prostate cancer. cancer medicine 2014; 3(2):245–251 22. jayalath vh, ireland c, fleshner ne, hamilton rj, jenkins dja. the relationship between metformin and serum prostatespecific antigen levels. the prostate 2016; 76:1445–1453 23. bonn se, sjölander a, tillander a, wiklund f, grönberg h, balter k. body mass index in relation to serum prostate-specific antigen levels and prostate cancer risk. int j cancer 2016;1;139(1):50–57 24. kyler ke, kadakia rb, palac hl, kwon s, ariza aj, binns hj. use of metformin for weight management in children and adolescents with obesity in the clinical setting. clin pediatr (phila) 2018;57(14):1677–1685 25. ellul p, delorme r, cortese s. metformin for weight gain associated with second-generation antipsychotics in children and adolescents: a systematic review and meta-analysis. cns drugs 2018; doi: 10.1007/s40263-018-0571-z (epub ahead of print) urological oncology 185 metformin effect on psa-atalay et al. v08_no_4_final_new.pdf reconstructive surgery 302 urology journal vol 8 no 4 autumn 2011 comparing absorbable and nonabsorbable sutures in corporeal plication for treatment of congenital penile curvature abbas basiri,1 reza sarhangnejad,1 seyyed mohammad ghahestani,1 mohammad hadi radfar2 purpose: to compare the outcome of corporeal plication using absorbable versus nonabsorbable sutures for the treatment of congenital penile curvature. materials and methods: thirty-eight men older than 15 years old with congenital penile curvature were enrolled in the study. patients were randomly divided into two equal groups based on the suture material (nylon versus vicryl) used in corporeal plication. patients were followed up for a mean period of 8.1 ± 1.4 months (range, 6 to 9.1 months). a standardized questionnaire was used to evaluate long-term outcome and patient’s satisfaction. results: thirty-five patients (17 in vicryl group and 18 in nylon group) completed the study. mean age of the patients and degree of penile curvature were not significantly different between the two groups (p = .74). postoperatively, 15 (88.2%) and 16 (88.9%) patients in vicryl and nylon groups had 75% or greater correction in penile curvature, respectively (p = .61). patient’s satisfaction rate differed between two groups (82% in vicryl group versus 66% in nylon group), which did not reach statistical significance (p = .44). palpable sutures were reported by 7 (39%) patients in nylon group and only 1 (6%) in vicryl group (p = .04). shortening of penile length was reported by 3 (16.7%) patients in nylon group and 4 (23.5%) in vicryl group (p = .69). conclusion: corporeal plication technique using absorbable suture provides reasonable success rate with less frequent palpable suture knots. urol j. 2011;8:302-6. www.uj.unrc.ir keywords: suture techniques, urologic surgical procedures, cosmetic techniques, male, penis 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2hospital managemnt research center, hasheminejad kidney center, tehran university of medical sciences, tehran, iran corresponding author: abbas basiri, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir received october 2010 accepted march 2011 introduction congenital penile curvature (cpc) has an incidence of approximately 0.6%.(1) acquired penile curvature is much more common than cpc.(2) in acquired condition, inflammation and fibrosis resulting from autoimmune disease or repeated trauma can lead to plaque formation on the tunica albuginea, and subsequent penile curvature.(3) congenital penile curvature is caused by length disproportion of the corpora cavernosa and corpora spongiosa.(4) congenital penile curvature usually causes a few, if any, symptoms. however, in some patients severe penile deviation of the erect penis can cause pain during sexual intercourse and interferes with intromission.(2) various surgical techniques have corporeal plication using absorbable and nonabsorbable sutures—basiri et al 303urology journal vol 8 no 4 autumn 2011 been proposed to treat penile curvature with the aim of achieving the best possible outcome with minimal complications. two most commonly used methods include nesbit procedure and corporeal plication.(5) nesbit procedure was the standard method for treating penile curvature.(6) due to technical complexity and considerable morbidity of the nesbit procedure, corporeal plication was introduced in 1973.(7) traditionally, nonabsorbable sutures have been used for corporeal plication, and are thought to cause certain complications.(8) hsieh and colleagues suggested using absorbable suture for corporeal plication to reduce suturerelated complications.(9) to the best of our knowledge, we compared for the first time the results of corporeal plication using absorbable versus nonabsorbable suture for treating cpc. materials and methods this prospective study was carried out following approval by the local ethics committee, and written informed consent was obtained from each participant. eligible study participants were men older than 15 years old with cpc who referred to shahid labbafinejad medical center between 2005 and 2008. exclusion criteria included having a history of penile surgery, peyronie’s disease, pain, and/or chordee associated with hypospadias. patients were considered as candidates for surgery because of difficulty in sexual intercourse or being severely concerned with the appearance of their penile curvature. thirty-eight patients were recruited in the study pre-operatively and were randomly (computerized random-number generator) divided into two equal groups based on the suture material (nylon versus vicryl) used for corporeal plication. all the patients were evaluated with a general medical history, sexual history, and physical examination pre-operatively, and were instructed to present a photograph of the curvature. data including degree and direction of the penile curvature were recorded prospectively. degree of curvature was measured using artificial erection during surgery. all the patients underwent corporeal plication using 2-0 vicryl or nylon suture under the supervision of one attending urologist using the modified technique explained by thiounn and associates.(10) all procedures were performed on an outpatient basis. postoperatively, patients were instructed to have sexual abstinence for 8 weeks. patients were followed up for a mean period of 8.1 ± 1.4 months (range, 6 to 9.1 months). to evaluate long-term outcome and patient’s satisfaction, we used a modified form of the standardized questionnaire previously designed and deployed by chien and aboseif.(11) patients answered the questionnaire by telephone interviews (appendix). we used student t test and fisher’s exact test to analyze our findings. p values less than .05 were considered statistically significant. results of 38 subjects included, 35 patients completed the study. seventeen (48.6%) and 18 (51.4%) patients were treated with vicryl and nylon sutures, respectively. mean age of the patients and degree of penile curvature were not significantly different between the two groups (p = .74). preoperative data are illustrated in table. postoperatively, 15 (88.2%) patients in vicryl and 16 (88.9%) patients in nylon group had 75% or greater correction of penile curvature variables nylon group vicryl group p age, y (mean ± sd) 35.1 ± 11.9 33.6 ± 13.9 = .74 penile curvature, degree (mean ± sd) 54.2 ± 15.6 56.5 ± 10.6 = .061 curvature direction, no. = .54 ventral 12 10 dorsal 1 2 right lateral 4 2 left lateral 1 3 demographic and clinical characteristics of the study groups. corporeal plication using absorbable and nonabsorbable sutures—basiri et al 304 urology journal vol 8 no 4 autumn 2011 (p = .61). two patients in vicryl group and 1 patient in nylon group were not sexually active before and after the surgery.the remaining patients in both groups had sexual intercourse pre and postoperatively. although there was a difference in patients’ satisfaction rate between two groups (82% in vicryl group versus 66% in nylon group), the difference was not statistically significant (p = .44). palpable sutures were reported by 7 (39%) patients in nylon group and only 1 (6%) in vicryl group (p = .04). shortening of penile length was reported by 3 (16.7%) patients in nylon group and 4 (23.5%) in vicryl group (p = .69). discussion the nesbit procedure, originally described in 1965, was formerly considered as the method of choice for treating penile curvature. initially, nesbit reported three subjects who underwent the procedure with successful results.(6) later, several studies reported success rates of 96.2% and 100% for the procedure for treating both congenital and acquired penile curvature, respectively.(12,13) however, the procedure is time-consuming and has a high incidence of complications, such as hematoma, glans numbness, de novo erectile dysfunction, and over-correction.(14) various modifications have been made in the original technique to decrease the complications. in 1973, horton and devine introduced the corporeal plication technique to treat penile curvature.(7) plication surgery has been reported to have high success rates, generally between 80% and 95%, compared with the nesbit technique.(15) furthermore, it is a simpler and less invasive procedure with fewer complications. bleeding, hematoma, penile numbness, erectile dysfunction, and over or under correction occurs less frequently. chien and aboseif reported 25 patients with cpc who underwent corporeal plication. they achieved a success rate of 95% in a mean followup period of 18 months.(11) another study with a larger studied population described corporeal plication in 106 subjects, which resulted in excellent straightening in 91% of patients with a mean follow-up of 69.3 months.(16) most surgeons use nonabsorbable sutures (nylon or prolene) in corporeal plication to avoid suture breakage, which may potentially lead to recurrent curvature.(11,16,17) however, using nonabsorbable suture does not prevent suture breakdown completely, as it is reported to occur in between 6% and 50% of patients.(10,18) it should be noted that suture failure does not necessarily lead to recurrent deformity. hsieh and coworkers reported recurrent curvature in only half of the patients who developed suture failure.(15) on the other hand, about a third of patients have discomfort due to the suture material.(8) suture granuloma, palpable knots, and pain during erection are complications related to the suture material. lee and colleagues reported that 51% of their patients who underwent plication using braided polyester suture felt palpable indurations (suture knots) on the penis.(16) van der horst and associates reported that 88% of their patients who received tunical plication with nonabsorbable polypropylene sutures could palpate the suture, and 40% had discomfort during erection. using nonabsorbable polytetrafluoroethylene in the same study, 50% of patients could palpate the sutures and 10% had discomfort during erection.(8) in 2001, hsieh and coworkers introduced a modified tunical plication technique using absorbable polyglactin sutures. ten of their 11 patients were very satisfied with the procedure, and had less morbidity in comparison with the nesbit technique. they instructed the patients an 8-week period of sexual abstinence to prevent suture failure due to increased tension on the tunica albuginea during sexual intercourse.(9) later, hsieh and associates reported 103 patients with cpc who underwent the above-mentioned technique. of their patients, 57% had a straight erect penis and 28.9% had curvature of 15 degrees or less postoperatively. suture-related complications were rare in their study. they mentioned that the scars formed in the suture region after absorption of the suture (8 weeks postoperatively) prevents curvature recurrence.(15) to the best of our knowledge, this is the first study comparing the success rate, morbidity, and patient’s satisfaction after corporeal corporeal plication using absorbable and nonabsorbable sutures—basiri et al 305urology journal vol 8 no 4 autumn 2011 plication using absorbable vicryl suture versus nonabsorbable nylon suture. our results show that both groups have high success rates. patient’s satisfaction was higher in vicryl group, but the difference was not significant probably due to small sample size. suture-related complication, palpable knot, was significantly lower in vicryl group than nylon group. conclusion we concluded that corporeal plication technique using absorbable suture has a high success rate with less frequent suture-related complications. conflict of interest none declared. references 1. yachia d, beyar m, aridogan ia, dascalu s. the incidence of congenital penile curvature. j urol. 1993;150:1478-9. 2. ebbehoj j, metz p. congenital penile angulation. br j urol. 1987;60:264-6. 3. aboseif s, tamaddon k. peyronie’s disease: an update. sex dysfunct med. 1999;1:34-41. 4. donnahoo kk, cain mp, pope jc, et al. etiology, management and surgical complications of congenital chordee without hypospadias. j urol. 1998;160: 1120-2. 5. van der horst c, martinez portillo fj, seif c, et al. [quality of life after surgical correction of penile deviation with the schroeder-essed plication]. aktuelle urol. 2003;34:109-14. 6. nesbit rm. congenital curvature of the phallus: report of three cases with description of corrective operation. j urol. 1965;93:230-2. 7. horton ce, devine cj, jr. plication of the tunica albuginea to straighten the curved penis. plast reconstr surg. 1973;52:32-4. 8. van der horst c, martinez portillo fj, melchior d, bross s, alken p, juenemann kp. polytetrafluoroethylene versus polypropylene sutures for essed-schroeder tunical plication. j urol. 2003;170:472-5. 9. hsieh jt, huang he, chen j, chang hc, liu sp. modified plication of the tunica albuginea in treating congenital penile curvature. bju int. 2001;88:236-40. 10. thiounn n, missirliu a, zerbib m, et al. corporeal plication for surgical correction of penile curvature. experience with 60 patients. eur urol. 1998;33:401-4. 11. chien gw, aboseif sr. corporeal plication for the treatment of congenital penile curvature. j urol. 2003;169:599-602. 12. andrews ho, al-akraa m, pryor jp, ralph dj. the nesbit operation for congenital curvature of the penis. int j impot res. 1999;11:119-22. 13. rolle l, tamagnone a, timpano m, et al. the nesbit operation for penile curvature: an easy and effective technical modification. j urol. 2005;173:171-3; discussion 3-4. 14. popken g, wetterauer u, schultze-seemann w, deckart ab, sommerkamp h. a modified corporoplasty for treating congenital penile curvature and reducing the incidence of palpable indurations. bju int. 1999;83:71-5. 15. hsieh jt, liu sp, chen y, chang hc, yu hj, chen ch. correction of congenital penile curvature using modified tunical plication with absorbable sutures: the long-term outcome and patient satisfaction. eur urol. 2007;52:261-6. 16. lee ss, meng e, chuang fp, et al. congenital penile curvature: long-term results of operative treatment using the plication procedure. asian j androl. 2004;6:273-6. 17. nooter ri, bosch jl, schroder fh. peyronie’s disease and congenital penile curvature: long-term results of operative treatment with the plication procedure. br j urol. 1994;74:497-500. 18. poulsen j, kirkeby hj. treatment of penile curvature-a retrospective study of 175 patients operated with plication of the tunica albuginea or with the nesbit procedure. br j urol. 1995;75:370-4. corporeal plication using absorbable and nonabsorbable sutures—basiri et al 306 urology journal vol 8 no 4 autumn 2011 name: age: date of surgery: kind of suture: vicryl 2-0 nylon 2-0 degree of curvature: direction of curvature: ventral dorsal right lateral left lateral were you sexually active with intercourse prior to the surgery? yes no do you have any difficulties during sexual intercourse? yes no if yes, how long have you had difficulties with sexual intercourse prior to the surgery? are you currently sexually active? yes no if yes, how satisfied are you with your surgical results? 100% 75% 50% 25% has the curvature of your penis been corrected? yes no if yes, please quantify. do you notice any changes in your penile length? became shorter became longer no change do you notice any foreign body or suture materials in your penis? yes no appendix “postoperative patient’s questionnaire” pediatric urology 226 urology journal vol 4 no 4 autumn 2007 guide wire-assisted urethral dilation in pediatric urology experience of a single surgeon david t chiang,1 paddy a dewan2 introduction: a simple technique to dilate urethral stricture using guide wire and sheath dilator has been described in pediatric urology. the aim of this study was to report the long-term outcome of the children who underwent dilation of the urethral stricture using guide wire and sheath dilator. materials and methods: from 1999 to 2004, a total of 52 children with documented urethral stricture were managed by urethral dilation using guide wire. data on the cause of urethral stricture, operation, postoperative recovery, followup cystoscopic appearance, and patient’s outcome were audited and analyzed. results: the mean age of the patients was 5.6 ± 2.3 years (range, 2 to 18 years). the mean period of the follow-up was 4.5 ± 2.4 years (range, 3.8 to 6.5 years). twenty-two patients (42.3%) did not require any further surgical treatments. however, urethral stricture in 13 patients (25.0%) progressed significantly, and therefore, they needed further surgical interventions. the complications included minor urinary tract infections in 3 and bladder spasm in 2 patients. no case of false passage or sepsis was encountered. conclusion: guide wire-assisted urethral dilation avoids the risks associated with blind dilation techniques and continues to be a safe alternative for urethral strictures in selected cases. however, in our experience, less than half of the patients became “recurrence free” after two dilation attempts. we recommend that urethral dilation be considered only in selected cases and emergency settings. urol j. 2007;4:226-9. www.uj.unrc.ir keywords: urethra, stricture, guide wire, dilation, pediatrics 1department of pediatric urology, sunshine hospital, western health, melbourne, australia 2department of pediatrics, university of melbourne, victoria, australia corresponding author: david t chiang, md 80 lister st, sunnybank, brisbane, queensland, australia tel: +61 7 3423 7462 fax: +61 7 3423 7462 e-mail: davidtwchiang@yahoo.com.au received july 2007 accepted september 2007 introduction the management of urethral stricture in children is similar to adults in some ways; nevertheless, due to the small size of the urethra and delicacy of pediatric tissue, the tasks can be technically challenging.(1) although some urethral strictures can be treated with conventional dilation, the “blind” approach can cause false passages and other significant complications.(2,3) optical urethrotomy and urethroplasty can produce promising results in management of a scarred urethra(4); however, surgical correction requires hospitalization and a major surgical procedure (or multiple procedures). thus, it is usually reserved for complicated strictures.(5) we previously described a technique for safe urethral dilation in pediatric cases and reported the short-term patient’s outcomes.(6) this technique basically involved a guide wire placed through the stricture under cystoscopic guidance, and the dilation was subsequently directed appropriately. consequently, a precise and safe dilation could be achieved. the short-term outcome of this guide wire-assisted urethral dilation—chiang and dewan urology journal vol 4 no 4 autumn 2007 227 technique was impressive, with 84.3% of patients who had a satisfactory result in terms of the urinary stream and the subsequent cystoscopic findings.(6) however, the long-term outcomes of this technique and effectiveness of urethral dilation remained unknown. this retrospective study aimed to investigate the long-term safety and efficacy of this technique on children with urethral stricture based on the experience of a single surgeon. materials and methods medical records of 52 patients referred to the senior author between 1999 and 2004 for management of the urethral stricture were retrospectively reviewed. all of the children were evaluated preoperatively with a complete history and physical examination, urine culture, and cystoscopy. in addition, urethrography was carried out if clinically indicated, especially when delineation of the anterior urethra was required. boys with proven urethral strictures were managed by urethrocystoscopy and guide wire-assisted urethral dilation under general and caudal anesthesia.(6) the only exclusion criteria was complete occlusion of the urethra on urethrography. cystoscopy could be used for diagnosis only, but more often, dilation was performed during the same session. if a different diagnosis was made during cystoscopy or in case of no feasibility to perform urethral dilation, the children would be managed otherwise. prophylactic antibiotic was used in all cases and included intravenous injection of gentamicin, 80 mg, unless there was a contraindication. in this case, other antibiotics would be used. general and caudal anesthesia was administered and the procedures were performed by a single surgeon. lidocaine jelly was instilled into the urethra at the commencement of the procedure. the patients were followed up at 3, 6, and 9 months postoperatively and then, they were visited annually after the initial procedure. the follow-up procedure was performed in the outpatient clinic by cystoscopy or radiography if recurrence was suggested by symptoms. when urethral strictures recurred over a short period of time during the follow-up, cystoscopy and urethral dilation would be repeated and clean intermittent catheterization (cic) might be recommended with appropriate sizes of the foley catheters for stabilization of the urethral dilation. age of the patient, cause of the urethral stricture, level of difficulty during the previous passage of the dilators, and social situation of the patient were taken into consideration when prescribing cic. results fifty-two consecutive patients with urethral stricture were managed by this technique. table 1 shows the patients’ demographic characteristics and causes of the stricture. the mean age of the patients was 5.6 ± 2.3 years (range, 2 to 18 years). the mean period of the follow-up was 4.5 ± 2.4 years (range, 3.8 to 6.5 years). four patients were lost to follow up. table 2 outlines the outcomes and complications. overall, 235 guide wire-assisted urethral dilation attempts were performed by the same surgeon. twenty-two patients had 1 or 2 dilations with no urethral stricture patients (%) location anterior urethra 32 (61.5) posterior urethra 20 (38.5) etiology* hypospadias repair 38 (73.1) idiopathic 4 (7.7) cobb’s collar 4 (7.7) trauma 2 (3.8) urethritis 2 (3.8) posturethral membrane 2 (3.8) table 1. urethral stricture characteristics *percents do not total 100% due to rounding. urethral dilation patients (%) outcome recurrence-free 22 (42.3) after 1 dilation 20 (38.5) after 2 dilations 2 (3.8) requiring cic 13 (25.0) unable to complete cic 4 (7.7) requiring alternative surgeries urethrotomy 4 (7.7) urethroplasty 9 (17.3) complications aborted attempt* 11 (4.7) tight stricture 6 (2.6) hemorrhage 5 (2.1) cystitis 3 (5.8) bladder spasm 2 (3.8) table 2. urethral dilation outcomes and complications *percentages of aborted dilation attempts are calculated in proportion to 235 attempts. cic indicates clean intermittent catheterization. guide wire-assisted urethral dilation—chiang and dewan 228 urology journal vol 4 no 4 autumn 2007 recurrence (suggested by symptoms and endoscopy in selected cases) after 2 years and were considered to be recurrence free (42.3%). eighteen patients required 3 sessions of dilation and 12 required more than 3. none of the patients needed more than 2 dilations in any 12-month period. in 13 children (25.0%), the stricture had significantly progressed according to the symptoms and cystoscopic and/or urethrographic results. four of them underwent urethrotomy and 9 required urethroplasty. dilation attempts were unsuccessful in 11 occasions (4.7%) because of tight strictures or bleeding. in 5 cases, bleeding precluded the attempts of dilation; in 2, cystoscopic vision was not optimal due to urethral bleeding and the urethral lumen was not visualized. therefore, we inserted suprapubic catheters by ultrasonographic guidance, and urethral bleeding was spontaneously resolved. in the other 3 cases of bleeding, we did not perform urethral dilation, but we were still able to see the urethral lumen. thus, we inserted the guide wires and passed small urinary catheters through the wires. again, the urethral bleeding was resolved without further intervention. although bleeding was to an extent that precluded the dilations, the patients did not require transfusion of any blood products. false passage or significant sepsis did not happen. complications of the procedure included cystitis in 3 and bladder spasm in 2 patients. discussion the management of the pediatric urethral stricture is controversial and there is considerable debate regarding the long-term outcome of all approaches. while urethroplasty offers the best long-term outcome, the procedure should be performed by experienced pediatric urologists with expertise in reconstructive urology.(4,5) however, even in the experienced hands, the postoperative complications are not minor.(7) this paper reported a safe and minimally invasive procedure that offered 42.3% of the patients with recurrence-free outcome after 1 or 2 dilations. complications associated with conventional “blind” dilation techniques are common, including recurrence with scarring tissue, creation of a false passage, impotence, incontinence, and rupture of the rectum and other neighboring organs. these complications can be made worse when a narrow tunnel is located eccentrically in the urethral cross section and the urethra does not taper gradually onto the stricture.(8-10) therefore, if a guide wire is placed through the stricture endoscopically, dilation can be subsequently directed in an appropriate, precise, and safe way. we did not experience any false passage or significant sepsis in 235 urethral dilations that we performed. to some urologists, dilation is not a cure. bleeding from the urethra during dilation means that the scar is torn and further mucosal and spongy injury has occurred. the stricture will soon recur and result in worsened stricture length and density. in this study, 13 patients (25.0%) with urethral stricture had multiple recurrences with worsened cystoscopic and/or radiological appearance. these patients eventually required more definitive surgical alternatives, such as urethrotomy and urethroplasty. although urethrotomy, overall, yields more definitive recurrence-free rate than urethral dilation,(11) the recurrence rate and associated morbidity should not be underestimated.(5,12) even with insertion of a foley catheter after dilation and supplement with cic in selective cases to prevent urethral adhesion and recurrence, this approach was only proven effective in some patients. criticism has arisen from the patient selection for urethral dilation and other surgical options. certainly, for the strictures that have recurred early after 2 dilations, definitive surgical options should be considered.(5) however, the decision to perform “one-stop” urethroplasty is a complex and challenging one, especially when considering long-term major morbidities in young children, such as erectile dysfunction and urinary incontinence.(7) although the initial short-term audit reported 84.3% of the patients had a satisfactory result with respect to the urinary stream and the subsequent cystoscopic findings,(6) this long-term audit showed that the majority of patients (57.7%) required multiple dilations, cic, or definitive surgeries such as urethrotomy and urethroplasty. we believe that this approach certainly was not for all urethral strictures; nevertheless, this technique can be useful in settings such as requiring an alternative to suprapubic catheter, management of “simple” strictures, and treatment of patients (or parents) refusing or waiting for urethroplasty. guide wire-assisted urethral dilation—chiang and dewan urology journal vol 4 no 4 autumn 2007 229 other minimally invasive techniques, laser urethrotomy and balloon dilation, in the management of urethral stricture in pediatric urology have been described. the initial results from those studies have been promising and certainly would have their roles in the management of this condition in the future.(13,14) the issues with those techniques were the availability of the equipments, hospital accreditation to operate those equipments, and surgeons’ preference. further studies to compare such modern techniques with the current dilation method should be encouraged. conclusion guide wire-assisted urethral dilation avoids the risks associated with blind dilation techniques and continues to be a safe alternative for urethral strictures in pediatric urology. we performed this technique 235 times in 52 children without any major complication. however, only 42.3% of the patients were considered “recurrence free” after a maximum of 2 dilations and 25% with strictures had progressed significantly, requiring definitive surgical intervention. urethral dilation should be considered only in selected cases and emergency settings. conflict of interest none declared. references 1. noe hn. complications and management of childhood urethral stricture disease. urol clin north am. 1983;10:531-6. 2. harshman mw, cromie wj, wein aj, duckett jw. urethral stricture disease in children. j urol. 1981;126:650-4. 3. russinovich na, lloyd lk, griggs wp, jander hp. balloon dilatation of urethral strictures. urol radiol. 1980;2:33-7. 4. peterson ac, webster gd. management of urethral stricture disease: developing options for surgical intervention. bju int. 2004;94:971-6. 5. greenwell tj, castle c, andrich de, macdonald jt, nicol dl, mundy ar. repeat urethrotomy and dilation for the treatment of urethral stricture are neither clinically effective nor cost-effective. j urol. 2004;172:275-7. 6. dewan pa, gotov e, chiang d. guide wire-assisted urethral dilatation for urethral strictures in pediatric urology. j pediatr surg. 2003;38:1790-2. 7. al-qudah hs, santucci ra. extended complications of urethroplasty. int braz j urol. 2005;31:315-23. 8. scherz hc, kaplan gw. etiology, diagnosis, and management of urethral strictures in children. urol clin north am. 1990;17:389-94. 9. smith pj, dunn m, roberts jb. surgical management of urethral stricture in the male. urology. 1981;18:5827. 10. petrone af. urethral dilatation: technique, precautions, and complications. surg clin north am. 1969;49:13614. 11. hafez at, el-assmy a, dawaba ms, sarhan o, bazeed m. long-term outcome of visual internal urethrotomy for the management of pediatric urethral strictures. j urol. 2005;173:595-7. 12. hsiao kc, baez-trinidad l, lendvay t, et al. direct vision internal urethrotomy for the treatment of pediatric urethral strictures: analysis of 50 patients. j urol. 2003;170:952-5. 13. futao s, wentong z, yan z, qingyu d, aiwu l. application of endoscopic ho:yag laser incision technique treating urethral strictures and urethral atresias in pediatric patients. pediatr surg int. 2006;22:514-8. 14. li s, tang f, dai s, zhou h, gu l. [balloon dilatation for lower urethral obstruction in children]. zhongguo xiu fu chong jian wai ke za zhi. 2006;20:238-40. chinese. urological oncology randomized, double-blind pilot study of nanocurcumin in bladder cancer patients receiving induction chemotherapy saleh sandoughdaran1, abolfazl razzaghdoust2,**, ali tabibi3, abbas basiri3, nasser simforoosh3, bahram mofid1,* purpose: to evaluate the feasibility and potential efficacy of nanocurcumin supplementation in patients with localized muscle-invasive bladder cancer (mibc) undergoing induction chemotherapy. materials and methods: in this double-blind, placebo-controlled trial, 26 mibc patients were randomized to receive either nanocurcumin (180 mg/day) or placebo during the course of chemotherapy. all patients were followed up to four weeks after the end of treatment to assess the complete clinical response to the chemotherapy as primary endpoint. secondary endpoints were the comparisons of chemotherapy‐induced nephrotoxicity, hematologic nadirs, and toxicities between the two groups. hematologic nadirs and toxicities were assessed during the treatment. results: nanocurcumin was well tolerated. the complete clinical response rates were 30.8 and 50% in the placebo and nanocurcumin groups, respectively. although nanocurcumin was shown to be superior to placebo with respect to complete clinical response rates as the primary endpoint, there was no significant difference between the groups (p = 0.417). no significant difference was also found between the two groups with regard to grade 3/4 renal and hematologic toxicities as well as hematologic nadirs. conclusion: these preliminary data indicate the feasibility of nanocurcumin supplementation as a complementary therapy in mibc patients and support further larger studies. moreover, a substantial translational insight to fill the gap between the experiment and clinical practice in the field is provided. keywords: curcumin; induction chemotherapies; neoplasm; urinary bladder introduction bladder cancer is one of the most common forms of cancer in men and women worldwide(1). despite several efforts to improve the treatment outcome of patients with muscle-invasive bladder cancer, the complete response rate of neoadjuvant chemotherapy remains to be around 30% over the last decade(2). therefore, an effective complementary therapy to the chemotherapy is needed to achieve better outcomes. in some in vitro and in vivo studies, substantial chemosensitization by curcumin has been shown in the bladder tumor cells as well as many other cancers(3-15). the emergence of such preclinical evidence for synergistic effect of curcumin with other chemotherapeutic drugs makes it a potential complementary therapy to be used in clinical practice(16). at the cellular level, synergistic anticancer effect of sinacurcumin® in combination with cisplatin has also been shown(15). in spite of several promising roles for the curcumin in preclinical models, clinical evidence is equivocal due to inappropriate clinical pharmacokinetics such as low oral bioavailability and rapid metabolism(17). novel drug delivery systems have recently been designed to 1department of radiation oncology, shohada-e-tajrish hospital, school of medicine, shahid beheshti university of medical sciences, tehran, iran. 2urology and nephrology research center, student research committee, shahid beheshti university of medical sciences, tehran, iran. 3urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: shohada-e-tajrish medical center, shahrdari st, tajrish sq., tehran, iran. postal code: 1989934148, tel/fax: +98 21 22739200, email: mofid429@sbmu.ac.ir. **urology and nephrology research center, no.103, boostan 9th st., pasdaran ave., tehran, iran. postal code: 1666663111, tel: +98 21 22567222, fax: +98 21 22567282, email: razzaghdoust@sbmu.ac.ir received november 2019 & accepted april 2020 improve pharmacokinetics of anticancer phytochemicals including curcumin(18). curcumin nanoformulations have shown substantial potential to overcome the problem(19). in a recent study, yu et al. have reviewed the recent progress of the drug delivery systems aiming at bladder cancer therapy(20). recently, various clinical trials have focused on the use of sinacurcumin®, a novel nanoformulation of curcuminoids, in different settings and disorders(21-24). the results of these clinical studies are encouraging and suggest further research. although some larger studies have investigated the complementary role of nanocurcumin in diverse range of cancer patients, but its value in the setting of bladder cancer patients undergoing induction chemotherapy has not yet been assessed. therefore, we conducted this pilot randomized trial to investigate the feasibility and clinical efficacy of nanocurcumin in this setting. in the light of this pilot study, further larger definitive trials could clarify the clinical utility of nanocurcumin as a complementary therapy in these patients. urology journal/vol 18 no. 3/ may-june 2021/ pp. 295-300. [doi: 10.22037/uj.v0i0.5719] material and methods study design this stratified, randomized, double‐blind, placebo‐controlled pilot study was conducted at two tertiary hospitals in tehran, iran, from september 2016 to february 2018. consecutive male and female patients with histologically confirmed muscle-invasive bladder cancer (clinical stage t2-t4a) who had undergone initial transurethral resection of bladder tumor (turbt) were assessed for eligibility. all patients were candidates for platinum-based neoadjuvant chemotherapy and have the performance status of 0 or 1. all participants had to have adequate baseline bone marrow and hepatic function. patients with metastatic disease (n+, m+) were excluded from the study. the protocol of this study was in accordance with the helsinki declaration and approved by the ethics committee of shahid beheshti university of medical sciences (ir.sbmu.msp.rec.1396.227). all patients provided signed informed consent before inclusion in the study. this trial was registered on www.irct.ir (identifier: irct20180226038875n1). since julious (2005) recommended a sample size of 12 per group as a rule of thumb in pilot studies, we planned to enroll a total of 24 participants in two groups(25). eligible patients were randomly assigned to one of two parallel groups in a 1:1 ratio to receive chemotherapy with either oral capsule nanocurcumin (sinacurcumin®) or placebo using an internet‐generated randomization list prepared by an investigator with no clinical involvement in the trial. the participants were stratified by the chemotherapy regimens (gemcitabine/cisplatin vs. gemcitabine/carboplatin) and treatment centers. the nanocurcumin capsules were prepacked in sequentially numbered containers according to the randomization list. the randomization list was concealed from patients and all clinical investigators. an off-site person has labeled the drug packages with coded numbers. each block of eight numbers was transmitted from the central office to an independent individual (a person not involved in the patient recruitment and treatment) in each center. each participant was assigned an order number and received the capsules in the corresponding numbered containers. treatment schedule all participants were randomized to receive chemotherapy with either oral capsule nanocurcumin 80 mg (sinacurcumin®) or placebo two times daily. sinacurcumin®, a commercially available capsule containing curcuminoids as nanomicelles, was prepared by the exir nano sina company, tehran, iran. placebo capsules were provided by the same company as nanocurcumin and were perfectly matched in size, shape, odor, and color. the mean diameter of nanomicelles is around 10 nm, according to dynamic light scattering. pharmacokinetic features of sinacurcumin® have been recently published(26). the authors declared that the bioavailability of sinacurcumin® as a nanomicelle was estimated to be 59.2 times higher than its free form. all patients were administered gemcitabine (1000 mg/m2, intravenous (iv), 30 min) on days 1 and 8, every 21 days. following gemcitabine administration, patients with a creatinine clearance >60 ml/min received cisplatin on days 1 and 2 every 21 days (70 mg/m2, 60 min) whereas those with a creatinine clearance <60 ml/min received carboplatin (auc = 5, iv over 30 min) on day 1 every 21 days. carboplatin doses were adjusted for renal function as per label using the cockcroft-gault formula. outcomes and assessment the primary endpoint was complete clinical response to the chemotherapy as assessed four weeks after the end of treatment, using cystoscopy procedure performed by an independent blinded urologist. eligible patients who received the treatment and had the follow-up tumor assessment were assessable for response. a clinical complete response to the induction chemotherapy defined as no evidence of primary tumor (t0) on cystoscopic assessment with biopsy. complete blood count (cbc) test, hemoglobin, platelets, creatinine level, serum urea, liver enzymes, creactive protein, and erythrocyte sedimentation rate were evaluated at baseline, prior to each chemotherapy cycle, and after the treatment course. secondary endpoints were the comparisons of chemotherapy‐induced nephrotoxicity, hematologic toxicities, and nadirs between the two groups. the lowest level of the hematologic parameters obtained after start of the chemotherapy course was selected as the nadir value. all toxicities were graded using the national cancer institute (nci) common terminology criteria for adverse event (ctcae) version 4.03. statistical analyses pearson's chi‐square and fisher's exact tests were used to compare the complete response rate as well as toxicities between the nanocurcumin and placebo groups. the baseline-adjusted hematologic nadirs were compared by analysis of covariance (ancova) test. mann-whitney u test and fisher's exact test were used for between-group comparison of the baseline characnanocurcumin in bladder cancer patients receiving induction chemotherapy-sandoughdaran et al. figure 1. the consort flow chart of patients urological oncology 296 vol 18 no 3 may-june 2021 297 teristics. missing data were handled by the complete case analysis. the statistical analyses were performed using the ibm spss statistics for windows, version 23.0 (ibm corp., armonk, n.y., usa). all statistical tests were performed at the two-tailed 5% level of significance. results patient characteristics from september 2016 to february 2018, a total of 36 patients were assessed for eligibility. of these, 26 patients were included in the study and randomized to receive placebo or nanocurcumin (figure 1). patient demographics are summarized in table 1. nanocurcumin was well tolerated. one patient in the nanocurcumin group had a cardiac arrest from previously unrecognized 3-vessel coronary artery disease. cisplatin-related pulmonary infection, renal failure, and skin rash were also reported in three patients receiving nanocurcumin. tumor response using a per-protocol approach, 13 patients in the placebo group and 10 patients in the nanocurcumin group were analyzed for treatment response. tumor downstaging to pt0 was achieved in 39.1% of all patients. the complete clinical response rate was 30.8% (4/13) in the placebo group and 50% (5/10) in the nanocurcumin group. although nanocurcumin was shown to be superior to placebo with respect to the primary endpoint, there was no significant difference between the groups (p = 0.417). there was no significant difference between the patients receiving cisplatin and carboplatin regarding the complete clinical response rate (p = 0.999). hematologic nadirs and toxicity secondary outcomes were analyzed on an intention-to treat basis and all patients receiving treatment (n = 26) were included in the toxicity assessment. the baseline-adjusted hematologic nadirs in the placebo and nanocurcumin groups are indicated in table 2. no significant differences were found in the nadir levels between the two groups. grade 3/4 toxicities are indicated in table 3. as shown in the table, no significant differences were observed between the two groups in terms of grade 3/4 renal and hematologic toxicities. discussion chemotherapeutic agents e.g. cisplatin could induce inflammatory responses and this inflammation may reduce the treatment efficacy(27). hence, targeting of inflammation via combined use of anti-inflammatory agents and conventional cancer therapy is a rational approach(28,29). several studies have shown that curcumin could inhibit pro-inflammatory and inflammatory factors e.g. nuclear factor-kappa b (nf-κb), and consequently result in chemosensitization in the cancer cells as well as chemoprotection in the normal cells (12,3033). furthermore, a series of target molecules e.g. apoptable 1. baseline characteristics of patients characteristics placebo (n = 14) nanocurcumin (n = 12) p-value age, mean (se), years 64.7 (2.4) 68.2 (3.7) 0.462a height, mean (se),cm 166.5 (2.9) 169.5 (1.9) 0.595a weight, mean (se), kg 77.0 (4.9) 74.3 (2.7) 0.999a regimen, n (%) gem/cis 8 (57.1) 8 (66.7) 0.701b gem/carbo 6 (42.9) 4 (33.3) creatinine clearance, mean (se), ml/min 59.3 (7.3) 62.6 (5.8) 0.432a hemoglobin, mean (se), g/dl 13.0 (0.5) 13.5 (0.4) 0.899a platelets, mean (se), 109/l 277 (20) 240 (15) 0.131a leucocytes, mean (se), 109/l 7.9 (0.7) 8.2 (0.6) 0.467a se, standard error of mean; gem, gemcitabine; cis, cisplatin; carbo, carboplatin a mann-whitney u test was used b fisher's exact test was used parameter nadir value a, mean (se) between-group difference, mean (95% ci) p-value b placebo nanocurcumin leucocytes 3.3 (0.1) 3.0 (0.2) 0.3 (-0.2 to 0.9) 0.203 neutrophils 1.2 (0.2) 1.0 (0.2) 0.2 (-0.2 to 0. 8) 0.323 lymphocytes 1.7 (0.2) 1.3 (0.2) 0.4 (-0.2 to 0.9) 0.177 hemoglobin 9.5 (0.4) 10.2 (0.4) 0.7 (-0.7 to 0.1.9) 0.354 platelets 170 (7) 167 (7) 3 (-18 to 26) 0.732 creatinine clearance 56.4 (3.8) 47.7 (4.1) 8.7 (-3.1 to 20.5) 0.142 table 2. hematologic nadirs with adjustment for baseline values a units of the parameters: creatinine clearance (ml/min); leucocytes, neutrophils, lymphocytes, and platelets (109/l); hemoglobin level (g/dl) b ancova test was used for all parameters with adjustment for baseline values of each parameter nanocurcumin in bladder cancer patients receiving induction chemotherapy-sandoughdaran et al. tosis-related proteins, adhesion molecules, transcription factors, growth factors, and some key enzymes such as cyclooxygenase-2 (cox-2), lipoxygenase (lox), and inducible nitric oxide synthase (inos) may be involved in this dual function(30,31,34). the direct antitumor activity of curcumin in bladder cancer cells has also been shown in several previous studies in vitro and in vivo(35,36). the post-transcriptional activity of curcumin via down-regulation of mir-7641 and subsequent up-regulation of p16 has been reported in bladder cancer cells(37). wang et al. (2018) concluded that this regulation could lead to the decreased invasion and increased apoptosis of the bladder cancer cells. the administration of curcumin, as a chemopreventive agent, following the bcg therapy of bladder cancer has also been suggested by hauser et al. (2007)(36). several promising preclinical studies have reported the complementary role of curcumin in combination with chemotherapy in different types of cancer(3-7). du et al.(2006) indicated a synergism between curcumin and 5-fluorouracil in ht-29 cell line, associated with a 6-fold reduction in the expression of cox-2 protein(3). dhandapani et al. (2007) showed that curcumin could suppress the cancer cell growth and chemoresistance of several chemotherapeutic agents such as cisplatin(4). also, the reduced chemoresistance of both cisplatin-resistant and wild-type cancer cells was also reported by montopoli et al. (2009)(5). in the mentioned study and another in vitro study on mcf-7 and mda-mb-231 cells(6), the cell cycle inhibition and apoptosis induction were observed. furthermore, zhang et al.(2018) demonstrated that curcumin in combination with cisplatin could significantly decrease proliferation and increase the apoptosis of a549 cells(8). the authors also indicated that curcumin may hinder copper influx and increase uptake of platinum ion in cancer cells. they concluded that the process of chemosensitization to cisplatin therapy is regulated by the cu-sp1-ctr1 regulatory loop. in a former study, the direct antitumor activity of curcumin as a copper chelator is also described by zhang et al. (2016)(38). in preclinical models, the complementary role of curcumin in combination with antineoplastic agents has been well documented in bladder cancer cells(9-12). in an in vitro study, amanolahi et al.(2018) reported the synergistic effect of curcumin and mitomycin in bladder cancer cells(9). in their study, curcumin significantly decreased cell viability with increasing curcumin concentrations. they also declared that beside the antineoplastic activity in cancer cells, curcumin could protect normal cells from adverse effects of mitomycin. although the potential chemoprotective role of curcumin against chemotherapy-induced myelosuppression and nephrotoxicity has been previously discussed in the literature(30,32,33), no protective effect was established in this study. moreover, afsharmoghadam et al.(2017) indicated a concentration-dependent effect of curcumin on antineoplastic activity of 5-fluorouracil in bladder cancer cells(10). their results suggest a critical role for curcumin concentration in the degree of cytotoxicity induced by chemotherapeutic agents. in another study, park et al.(2016) explored the synergistic effect of curcumin combined with cisplatin to induce apoptosis in 253j-bv (p53 wild-type) and t24 (p53 mutant) bladder cancer(11). in both p53 wild-type and mutant bladder cancer cells treated with combination therapy, the apoptosis rate was increased compared to that in cells exposed to monotherapy. this synergistic interaction was found to be associated with the activation of reactive oxygen species (ros) and extracellular regulated kinase (erk) signaling. the authors hypothesized that curcumin and cisplatin combination therapy can be an effective and reliable approach for the management of human bladder cancer. beside the cisplatin, a significant synergistic inhibitory effect of curcumin in combination with gemcitabine and carboplatin, as two other agents used in this study, was also reported(12,13). for instance, the combined apoptotic effect of curcumin and gemcitabine in bladder cancer cells was investigated by kamat et al. (2007)(12). they interestingly found that curcumin suppressed the gemcitabine-induced nf-κb activation in the bladder cancer cells. while mentioned studies have addressed the complementary role of curcumin as a chemosensitizer in preclinical models, several gaps between the experiment and clinical practice remain to be filled. recent studies have indicated that the poor clinical pharmacokinetics of curcumin could be improved using novel drug delivery systems e.g. nanoformulations(17-19). in a recent study by cheng et al.(2018) curcumin and cisplatin were co-encapsulated into the nanoliposomes(14). the encapsulated curcumin and cisplatin as nanoparticles indicated the higher antineoplastic activity in comparison with free drug or encapsulated mono-drug therapy. in a recent in vitro study on sinacurcumin®, synergistic antineoplastic effect of high dose nanocurcumin in combination with cisplatin has been reported(15). importantly, the authors declared that the effect was doseand cell type-dependent. in the light of this pilot trial, further clinical study is needed to determine the suitable effective doses of nanocurcumin in the clinical setting. the lack of enough power and statistical significance to accept or reject the study hypothesis may expectedly be associated with the small sample size as the main limitation of the study. the authors acknowledge that the small sample size of the trial prevents any meantable 3. chemotherapy-induced toxicities (grade 3/4) endpoint placebo group (n = 14) nanocurcumin group (n = 12) p-value leukopenia, n (%) 2 (14.3) 1 (8.3) 0.999a neutropenia, n (%) 5 (35.7) 7 (58.4) 0.249b anemia, n (%) 1 (7.1) 1 (8.3) 0.999a thrombocytopenia, n (%) 0 0 nephrotoxicity, n (%) 1 (7.1) 2 (16.7) 0.580a a fisher's exact tests was used b pearson's chi‐square test was used nanocurcumin in bladder cancer patients receiving induction chemotherapy-sandoughdaran et al. urological oncology 298 vol 18 no 3 may-june 2021 299 ingful inferences based on the study results. however, the present study describes the first clinical experience of nanocurcumin in bladder cancer patients undergoing chemotherapy and provides new insight into future clinical directions. additional trials with a large number of patients will explain whether the nanocurcumin acts as a complementary therapy in these patients. considering several experiences with different times of sinacurcumin® supplementation(21-24), we believe that a longer duration of supplementation seems to yield a better outcome. in a future well-designed trial, the pathologic response to chemotherapy could be used as a stronger surrogate endpoint. since the majority of patients with the complete clinical response in the study received chemo-radiation instead of surgery procedure, the assessment of pathologic response as the primary endpoint was impossible in our study. in order to high rate of false positive results, ct scan and mri are rarely used in the clinical setting after neoadjuvant chemotherapy(39). moreover, considering the role of distinct genetic subtypes of bladder cancer in sensitivity of tumor to frontline chemotherapy, the identification of different subtypes of bladder tumors may be helpful in future studies(40,41). finally, as the first report in the setting, this report summarized the possible mechanisms of action and some clinical directions for future investigations. conclusions these preliminary data suggest feasibility of nanocurcumin supplementation in this clinical setting and support further larger studies. this pilot study may also provide a substantial translational insight to fill the gap between the experiment and clinical practice. a largescale randomized trial in the setting is warranted. conflict of interest the authors have declared that there is no conflict of interest. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 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active copper chelator with antitumor activity. phytomedicine. 2016;23:18. 39. patel sr, hensel cp, he j, et al. clinical utility of post-neoadjuvant chemotherapy computed tomography for muscle-invasive urothelial bladder cancer. urology practice. 2020 10.1097/upj. 0000000000000135. 40. mcconkey dj, choi w, dinney cp. genetic subtypes of invasive bladder cancer. curr opin urol. 2015;25:449-58. 41. choi w, porten s, kim s, et al. identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. cancer cell. 2014;25:152-65. nanocurcumin in bladder cancer patients receiving induction chemotherapy-sandoughdaran et al. urological oncology 300 953vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l 1department of pediatric surgery and division of pediatric urology, karadeniz technical university, faculty of medicine, trabzon, turkey 2department of histology and embryology, karadeniz technical university, faculty of medicine, trabzon, turkey mustafa imamoğlu,1 levent sapan,1 yavuz tekelioğlu,2 haluk sarihan1 long-term effects of elevated intra-abdominal pressure on testes an experimental model of laparoscopy corresponding author: mustafa imamoğlu, md department of pediatric surgery, karadeniz technical university, faculty of medicine, trabzon, turkey tel: + 90 462 325 5355 fax: +90 462 325 0518 e-mail: mimamoglu61@ yahoo.com received september 2011 accepted april 2012 purpose: to determine the long-term outcomes of pneumoperitoneum on the testes in an experimental laparoscopy model. materials and methods: twenty-four rats were divided into three groups: group a, the control group; group b, exposed to a 10 mmhg intra-abdominal pressure (iap); and group c, exposed to a 20 mmhg iap with co2 pneumoperitoneum for 60 minutes. after 6 weeks, the testes were removed, and testicular injury score and johnson score were examined histologically. germ cell apoptosis was also detected using flow cytometry. results: a significant difference was determined between all groups in terms of testicular injury scores, johnson scores, and germ cell apoptosis percentages. for the testicular injury score, there were significant differences between the groups for the right testis (group a versus b, p = .009; group a versus c, p < .0001; and group b versus c, p = .001) and for the left testis (group a versus b, p = .001; group a versus c, p < .0001; and group b versus c, p = .002). significant differences were determined in the johnson scores for the right testis between all groups (group a versus b, p = .001; group a versus c, p < .0001; and group b versus c, p = .008, respectively). percentage of apoptotic testis cells were significantly differed between all groups (p = .001 for each). conclusion: this study shows that increased iap during pneumoperitoneum causes histopathology and apoptotically-evident damage to the testes in the long-term, depending on the magnitude of iap increase, which may cause sub/infertility. considering the experimental nature of this study, further clinical studies are needed for a more decisive conclusion. keywords: laparoscopy; pneumoperitoneum; fertility; testis; treatment outcome laparoscopic urology 954 | introduction despite many potential advantages for the patients, laparoscopic surgery is not completely free of complications. increased intra-abdominal pressure (iap) is one of the main potential causes of laparoscopy-associated complications, which are subject to current investigations.(1-4) studies have focused on changes in blood flow to intraand extra-abdominal organs, including the intestine, liver, kidney, spleen, bladder, and even the testes and ovaries, during pneumoperitoneum caused by laparoscopic procedure and its effects in both the early postoperative period and the long-term.(1-10) during the laparoscopic procedure due to increased venous resistance, blood flow to the organs is reduced, which restores following desufflation of the abdominal cavity. this ischemia/reperfusion condition promotes the generation of various reactive oxygen species (ros), causing oxidative tissue damage. in tissues subject to the ischemic-reperfusion, the increase in ros production is suggested to involve two phases. immediately after reperfusion, the first phase occurs, which extends for a few hours. this is a typical oxidative stress situation, “reversible” in terms of cellular injury. the first phase is followed by the second phase, which extends from hours to days. “irreversible” tissue damage occurs during the second phase. this is the most important outcome, because the long-term consequences of these changes may affect organ functions. since there is evidence of laparoscopic procedure-associated ischemia, which may underline pathogenesis of some early or long-term adverse clinical outcomes after laparoscopic procedures.(11-14) therefore, various strategies, such as minimization of the iap, ischemic preconditioning, and pretreatment with erythropoietin, mesna and/or antioxidants, are needed and indeed currently under consideration for the prevention of these laparoscopy-associated adverse outcomes. (15-18) the blood supply of the testis is through the “testicular artery”, which has a high vascular resistance. therefore capillary hydrostatic pressure in the testis low and is prone to affected from increase in venous pressure. oxygen tension in the testis is low. the seminiferous tubules are apparently adapted to this condition of low oxygen, low vascular perfusion pressure, and high metabolic activity, and normally this vasculature is sufficient to supply the testis with adequate amounts of perfusion. this suggests that moderate disturbances in the blood supply to the organ may affect testicular function, resulting in sub/infertility.(19,20) it has been well documented that elevated intraabdominal pressure during laparoscopic surgery may cause ischemia/ reperfusion injury in primarily affected and also in distant organs and tissues; the effect is timeand pressure-dependent. (1,8,10,11,14,15,18) thus, it is not surprising that testicular damage may develop and lead to, as a long-term consequence of laparoscopy, sub/infertility. indeed, the experimental models have demonstrated that the increased iap during laparoscopy reduces testis blood flow, which in turn causes a significant rise in oxidative stress in the testis tissue and, secondary to this, various degrees of damage occur in the parenchyma in the early stage.(19,20) however, the long-term effects of increased iap on the testes have not been studied to date. this study was planned with the aim of investigating whether damage arising in the early period had a negative impact on the testis function in the long term, which is the most important potential cause of sub/infertility. if it is determined that damage arises in the testis tissue in conventional pressures used in laparoscopy, such as 10 mmhg, then it may be necessary to review the range of pressures used during laparoscopy, especially in patients with conditions for subfertility. materials and methods experimental protocol and operative technique the study protocol was approved by the university animal care and ethics committee. anesthesia was inducted by intramuscular injection of ketamine hydrochloride 90 mg/kg (ketalar, parke-davis, berlin, germany) plus xylazine 10 mg/kg (rompun, bayer, germany). after tracheostomy, a 16 g cannula was inserted in the trachea. thereafter, maintenance was performed by intramuscular injection of 10 mg/ kg xylazine at hourly intervals. continuous intravenous infusion was performed through cannula in the right femoral vein. the animals were continuously infused with physiological saline at 4 ml/kg/h. muscle relaxation was attained and maintained by hourly intramuscular injections of 2.0 mg/kg pancuronium bromide (pavulon; organon teknika, boxtel, laparoscopic urology 955vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l the netherlends). then, the rats were mechanically ventilated with a pressure-controlled mode (peak inspiratory pressure of 12 cm h2o, a positive end-expiratory pressure of 8 cm h2o, a fraction of inspired oxygen of 1.0, a frequency of 50 beats per minute, a tidal volume of 10 ml/kg, and an inspiration/expiration ratio of 1:1. by placing an 18-gauge angiocatheter caudally to the sternum a peritoneal cavity puncture was achieved for performing the pneumoperitoneum. insufflation of carbon dioxide was also performed through this catheter. the targeted iap was achieved and controlled for 60 min using an electronic laparoflator (karl storz gmbh, tuttlingen, germany). groups twenty-four adult male sprague-dawley rats (weighing between 400 and 450 g) were randomly allocated to one of three groups: group a (n = 8), the gasless group (control group, an angiocatheter alone being inserted into the abdomen); group b (n = 8), 10 mmhg iap with pneumoperitoneum for 60 min; and group c (n = 8), 20 mmhg iap with pneumoperitoneum for 60 min. after six weeks, the testes were removed and longitudinally bisected. half of the testes were fixed in bouin’s solution for histological examination. the other half were fixed in 10% buffered formalin solution and then embedded in paraffin blocks for apoptosis evaluation. histology light microscopic examination of the tissue sections was performed after hematoxylin and eosin (h & e) staining. histological evaluations were performed by a histologist blind to the protocol of the study. two microscopic parameters were used for this evaluation; testicular injury score and maturation of the germinative epithelium. quantification of the histological injury was performed by a 4-level grading scale.(21) testicular histology with oorderly arrangement of germinal cells was rated as grade 1. injuries presenting less orderly, with noncohesive germinal cells and seminiferous tubules in the form of tightly-packed were rated as grade 2. tissues in the form of disordered sloughed germinal cells with shrunken pyknotic nuclei and unclear seminiferous tubule borders were considered as grade 3. injuries characterised by seminiferous tubules closely packed with coagulative necrosis of the germinal cells were rated as grade 4. the mean injury score for each testis was then calculated. figure 1. a) histopathological image of grade 2 testis damage in group b (showing histological testis structure comprising a small number of closely packed, orderly, damaged seminiferous tubules and non-cohesive germinal cells) (hematoxylin and eosin stain, original magnification ×4); b) histopathological image of grade 3 testis damage in group c (showing histological testis structure with mildly damaged seminiferous tubules and slightly damaged germinal cells and pyknotic cells in the tubules) (hematoxylin and eosin stain, original magnification ×10) figure 2. a) histopathological image of testicular biopsy score 8 in group b (a large number of spermatid and spermatogenetic cells appear undifferentiated in the seminiferous tubule) (hematoxylin and eosin stain, original magnification ×25); b) histopathological testicular biopsy score 6 image in group c (with a small number of spermatogonia cells and spermatids) (hematoxylin and eosin stain, original magnification ×40) long-term effects of laparoscopy on testes | imamoğlu et al 956 | second, testicular biopsy score (tbs) modified by johnson was used for grading the maturity of the germinative epithelium of the seminiferous tubules.(22) for this purpose evaluation of 25-50 tubules were performed for each section under 25×objective. for each testis the mean tbs was calculated by scoring system ranging from 1-10. apoptosis tissue preparation was performed according to hedley’s method.(23) material was treated with pepsin solution at room temperature, and thereafter, lysis and permeability reactive dna-prep (pn 4238055-b) was added to lyse erythrocytes and increase the permeability of cell membranes. dna prep stain (pn 4238055-br) including propidium iodide was finally added to stain cell dnas. flow cytometric analysis was carried out with epics elite esp (coulter). for each histogram, 5000 to 10 000 cells were analyzed. chicken erythrocyte nuclei (coulter dna prep pn 6604453) were used as dna-diploid standard. results of the histograms were analyzed using a multicycle dna analysis program.(24) statistical analysis comparisons among the groups were performed using kruskal-wallis anova (mann-whitney u test with bonferroni correction as a post hoc test) for testicular injury score, tbs, and apoptosis values. measured data are presented as median for testicular injury scores and arithmetic mean ± standard deviation for tbs and apoptosis, and data obtained by counting are shown as percentage. p < .05 was considered statistically significant. results testicular injury score group analysis revealed significant differences between all groups with regard to the degree of damage for both right and left testis (table 1). for the right testis, this difference arose from the differences between group a versus group b and group a versus group c, and group b versus group c (p = .009, p < .0001, and p = .001, respectively). for the left testis, this difference arose from the comparisons between group a versus group b and group a versus group c, and group b versus group c (p < .001, and p < .0001, and p = .002, respectively). median values of damage was grade 1 in group a, grade 2 in group b (figure 1a), and grade 3 in group c (figure 1b). in the 10 mmhg iap group specimens, seminiferous tubules were packed closely, and germinal cells were noncohesive and less orderly, particularly in the peripheral testicular parenchyma. in the 20 mm hg iap group, the specimens showed sloughed germinal cells with shrunken pyknotic nuclei and less distinct seminiferous tubule borders, these changes occurring diffusely in the testicular parenchyma. testicular biopsy score mean tbs revealed almost full spermatogenesis in both right and left testes in group a, whereas disturbance of spermatid differentiation was determined in both right and left testes in groups b and c. for the right testis, this difference arose from group a versus group b, group a versus group c, and group b versus group c (p = .001, p < .0001, and p = .008, respectively). for the left testis, this difference arose from group a versus group b and group a versus group c (p = .001 and p = .001, respectively; table 1). median tbs was 10 in group a and 8 in group b (figure 2a), which was as low as 6 in group c (figure 2b). apoptosis there was a statistically significant difference in both right and left testes apoptosis percentages between all groups (table 1). for both the left and right testes, this difference arose from group a versus group b and group a versus group c, and group b versus group c (p = .001 and p = .001, and p = .001, respectively). in group a, apoptosis level was over 5% in both testes in two rats, and below 5% in both testes in others. total apoptosis level was 4.4%. in group b, apoptosis level was over 20% in both testes in one rat, over 18% in both testes in two, over 14% in both testes in three, and below 14% in the right testis and above 14% in the left testis in one rat. total apoptosis level was 22.4%. in group c, apoptosis level was above 30% in both testes in one rat, above 28% in both testes in three, above 24% in both testes in three, and below 24% in both testes in one rat. total apoptosis level was 31.0%. laparoscopic urology 957vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l long-term effects of laparoscopy on testes | imamoğlu et al table. testicular injury score, testicular biopsy score and apopitosis results parametres and groups right testis left testis testicular injury scores median (min-max) median (min-max) a 1 (1-1) 1 (1-1) b 2 (1-2) 2 (1-2) c 3 (2-3) 3 (2-3) p .0005 .0005 testicular biopsy scores mean ± sd median (min-max) mean ± sd median (min-max) a 9.9 ± 0.4 10 (9-10) 9.8 ± 0.5 10 (9-10) b 7.9 ± 0.8 8 (7-9) 8.0 ± 0.8 8 (7-9) c 6.3 ± 0.4 6 (5-8) 6.8 ± 1.0 6 (5-8) p .0005 .0005 apopitosis mean ± sd (min-max) mean ± sd (min-max) a 4.5 ± 0.7 (3.9-5.7) 4.6 ± 0.6 (3.5-5.5) b 16.6 ± 3.3 (12.2-22.4) 16.7 ± 3.0 (13.4-21.5) c 27.3 ± 2.8 (23.4-30.8) 27.2 ± 2.7 (22.8-31) p .0005 .0005 discussion by aiming obtaining information on the long-term effects of laparoscopy-associated iap increase on testicular function, this experimental study evaluated impacts of a low (10 mmhg reflecting conventional abdominal pressure during laparoscopy) and a high increase (20 mmhg) in iap, obtained by pneumoperitoneum, on testicular morphology after 6 weeks, and documented pressure-dependent histopathological and apoptotic evidences implicating ischemia/reperfusion related damage in iap increased groups compared to the control. although not investigated in detail, the obtained effects on testes are most likely due to reduction of its blood flow secondary to increased iap occurring through two possible main mechanisms. the first is the direct effect of iap on the testicular artery and vein, with their long course. veins are subjected to greater pressure than arteries, and high venous resistance develops related to the increased hydrostatic pressure in the testes. the non-elasticity of the testis tunica albuginea also makes an additional contribution to the venous congestion, and then to impaired arterial circulation. furthermore, this state of hypoperfusion may persist even after iap has returned to normal. in a previous study, we determined, by color doppler ultrasonography, that a level of 10 mmhg iap at 30% to 35% and 20 mmhg iap at 40% to 45% caused a decrease in testicular blood flow.(19) in that study, we also showed that 10 minutes after desufflation, testicular reperfusion blood flow levels were still lower than basal testicular blood flow levels. second, it has been demonstrated that vena cava inferior pressure and vascular resistance significantly increased during prolonged periods of pneumoperitoneum, and remained so during the whole post pneumoperitoneum period.(25) valveless testicular veins having to pump blood to a higher pressure venous system after a long course will further increase the hydrostatic pressure reflected in the testes. this high venous hydrostatic pressure contributes to the impairment of arterial circulation and deepening of the hypoxia. sweeney and associates reported that in conditions of increased testicular venous pressure, microvascular fluid changes declines dramatically, and spermatogenesis and gametogenesis are harmed in consequence.(26) in our previous study, oxidative stress response and histological outcomes of testes in 10 and 20 mmhg iap groups were also compared with the control group. in that study, we demonstrated that 10 mmhg iap, which is accepted as conventional abdominal pressure, in association with the testicular hypoperfusion, increased free radical production, and subsequent testicular damage occurred in the early period that is 30 958 | laparoscopic urology minutes after pneumoperitoneum deflation.(19) recently, istanbulluoğlu and coworkers also showed in a porcine model that laparoscopic nephrectomy caused ischemic changes in the testes in the acute stage.(20) most importantly, they found that germ cell apoptosis was increased. no significant difference was noted in johnson’s scores between their two groups; however, congestion and necrosis, which were not documented in the control group, were observed in the increased iap group. the key question is that whether these changes in the testicular tissue might be correlated with longterm testicular function. with respect to the consequences of sub-/infertility, long-term effects of different iap levels in association with laparoscopy on spermatogenesis and testicular tissue histology was evaluated, and the results indicated the need for further studies. the evidence from these two studies leads us to design the present study to investigate the longterm effects of increased iap on testes. in the present study, two microscopic parameters were used for histological examination. as can be seen in table 1, compared with the control group (grade 1), the mean “testicular injury score” was significantly increased in both, the 10 (grade 2) and 20 mmhg iap groups (grade 3). in the 10 mmhg iap group, injury was observed, especially in the peripheral portion of the testicular parenchyma; however, in the 20 mmhg iap group, the changes occurred diffusely in the testicular parenchyma. the testicular injury scores were also confirmed by tbs. almost full spermatogenesis was observed in the control group, whereas disturbance of spermatid differentiation was determined in the 10 and 20 mmhg iap groups. the mean tbs values of the study groups (the 20 mmhg group being even lower) were significantly lower than the control group (table 1). testicular injury and tbs scores are excellent parameters in the study of spermatogenesis, being widely used in the evaluation of testicular atrophy. therefore, our experimental histopathological results indicate that increased iap during laparoscopy may cause testicular damage, which could lead to sub-/infertility. khoury and colleagues recently suggested that the pneumoperitoneum induces apoptosis, increasing in parallel with rising iap and pneumoperitoneum exposure duration, and this may be a mechanism involved in renal “delayed graft dysfunction’’ in recipients of laparoscopically harvested kidneys. (27) bergh and associates observed that in conditions of testicular hypoperfusion, apoptosis may develop in sertoli and germ cells in the seminal tubules, as a result of which fertility will be negatively affected.(28) our study also indicates similar outcomes for apoptosis evaluation. in the 10 mmhg iap group, total apoptosis level from the testis tissues was significantly higher than that of the control group (22.4% versus 4.4%). in the 20 mmhg iap group, the level of apoptosis rose even higher (total apoptosis level of 31.0%; table 1); indicating that the damage had a pressure-dependence. we therefore suggest that this importantly increased apoptosis levels exhibits an additional risk for impairment of fertility, considered in association with our histopathological results. one might wonder whether the scrotal pressure increased similar to intraperitoneal pressure and played a role in the obtained results. although we did not perform any pressure measurements during the experiments, we did not notice any scrotal swelling and therefore we believe that the scrotal pressure remained normal during the abdominal insufflation. furthermore, communication between the peritoneum and scrotum with patent processus vaginalis is necessary for increase in testicular pressure in parallel to intraperitoneal pressure. therefore, the obtained results are more likely due to the increased pressure exerted on the vessels supplying the testes. conclusion this experimental study shows that increased iap during pneumoperitoneum may cause potential adverse effects on fertility by causing gradual testicular hypoperfusion and related oxidative stress in the long-term, evidenced by histopathology and apoptosis index, depending on the magnitude of iap increase. the results of this experimental study warrant further clinical studies to evaluate fertility of boys undergoing laparoscopy. conflict of interest none declared. 959vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l long-term effects of laparoscopy on testes | imamoğlu et al references 1. schafer m, sagesser h, reichen j, krahenbuhl l. alterations in hemodynamics and hepatic and splanchnic circulation during laparoscopy in rats. surg endosc. 2001;15:1197–1201. 2. unsal ma, imamoglu m, cay a, et al. the acute alterations in biochemistry, morphology and contractility of the rat isolated urinary bladder induced by increased intra-abdominal pressure. gynecol obstet invest. 2006;61:179-87. 3. unsal ma, imamoglu m, kadıoğlu m, et al. the acute alterations in biochemistry, morphology, and contractility of rat-isolated terminal ileum via increased intra-abdominal pressure. pharmacol res. 2006;53:135-41. 4. schilling mk, redaelli c, krahenbühl, et al. splanchnic microcirculatory changes during co2 laparoscopy. j am coll surg 1997;184:37882. 5. jakimowicz j, stultiens g, smulders f. laparoscopic insufflation of the abdomen reduces portal venous flow. surg endosc 1998;12:129-32. 6. alexakis n, gakiopoulou h, dimitriou c, et al. liver histology alterations during carbon dioxide pneumoperitoneum in a porcine model. surg endosc. 2008;22:415-20. 7. guven s, muci e, unsal ma, yulug e, alver a, kadioglu duman m, mentese a.the effects of carbon dioxide pneumoperitoneum on ovarian blood flow, oxidative stress markers, and morphology during laparoscopy: a rabbit model. fertil steril. 2010;93:1327-32. 8. szold a, weinbroum aa. carbon dioxide pneumoperitoneumrelated liver injury is pressure dependent: a study in an isolatedperfused organ model. surg endosc. 2008;22:365-71. 9. demyttenaere s, feldman ls, fried gm. effect of pneumoperitoneum on renal perfusion and function: a systematic review. surg endosc. 2007;21:152-60. 10. unsal ma, guven s, imamoglu m, aydin s, alver a. the effect of co2 insufflation-desufflation attacks on tissue oxidative stress markers during laparoscopy: a rat model. fertil steril. 2009;92:363-8. 11. polat c, yılmaz s, serteteser m, et al. the effects of different intraabdominalpressures on lipid peroxidation and protein oxidation status during laparoscopic cholecystectomy. surg endosc 2003;17:1719-22. 12. eleftheriadis e, kotzampassi k, botsios d, et al. splanchnic ischemia during laparoscopic cholecystectomy. surg endos 1996;10:324-6. 13. richards wo, scovill w, shin b, reed w. acute renal failure associated with increased intra-abdominal pressure. ann surg 1983;197:183-7. 14. glantzounis gk, tselepis ad, tambaki ap, et al. laparoscopic surgery-induced changes in oxidative stress markers in human plasma. surg endosc 2001;15:1315-9. 15. cay a, imamoglu m, unsal ma, et al. does anti-oxidant prophylaxis with melatonin prevent adverse outcomes related to increased oxidative stress caused by laparoscopy in experimental rat model? j surg research. 2006;135:2-8. 16. ypsilantis p, tentes i, anagnostopoulos k, et al. mesna protects splanchnic organs from oxidative stress induced by pneumoperitoneum. surg endosc. 2009;23:583-9. 17. yılmaz s, köken t, tokyol c, et al. can preconditioning reduce laparoscopy-induced tissue injury? surg endosc. 2003;17:819-24 18. cevrioglu as, yılmaz s, koken t, tokyol c, yılmazer m, fenkci iv. comparison of the effects of low intra-abdominal pressure and ischaemic preconditioning on the generation of oxidative stress markers and inflammatory cytokines during laparoscopy in rats. hum reprod. 2004;19:2144-51. 19. imamoglu m, cay a, unsal ma, et al. the effects of increased intraabdominal pressure on testicular blood flow, oxidative stress markers, and morphology. j pediatr. surg. 2006;41:1118–24. 20. istanbulluoğlu mo, pişkin m, zor m, et al. the acute effects of increased intra-abdominal pressure on testicular tissue: an experimental study in pigs. urol. 2011;77:510.e12-510.e16. 21. cosentino mj, nishida m, robinowitz r, et al. histopathology of prepubertal rat testes subjected to various durations of spermatic cord torsion. j androl 1986;7:23-31. 22. johnsen sg. testicular biopsy score count – a 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02 spring 2012 all 008without adv.pdf 480 | laparoscopic urology clipless laparoscopic retroperitoneal lymph node dissection using bipolar electrocoagulation for sealing lymphatic vessels initial series nasser simforoosh,1 hamidreza nasseh,1 parham masoudi,1 mohammad aslzare,1 seyyed mohammad ghahestani,1 ramin eshratkhah,1 mohammad hadi radfar2 purpose: to evaluate the outcome of laparoscopic retroperitoneal lymph node disphatic vessels. materials and methods: tients underwent transperitoneal lprlnd for nonseminomatous germ cell tumor of the testis. in this experience, in contrast to other techniques, we did not use clips for ligation of the lymphatic vessels; instead, we used bipolar cautery for coagulation of the lymphatic vessels. we followed up the patients for lymphocele formation or lymphatic leakage using abdominal computed tomography scan. results: age or lymphocele formation during the follow-up period. conclusion: our study demonstrates that using bipolar electrocoagulation instead of clips, for sealing of the lymphatic vessels during lrplnd, does not hamper the outcome of the procedure. this should be further evaluated in randomized clinical trials with more subjects. keywords: lymphatic vessels, electrocoagulation, laparoscopy, lymph node excision, postoperative complications corresponding author: nasser simforoosh, md urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran tel: +98 21 2258 8016 e-mail: simforoosh@iurtc. org.ir received may 2011 accepted february 2012 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2hospital management research center, tehran university of medical sciences, tehran, iran laparoscopic urology 481vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l laparoscopic rplnd using bipolar electrocoagulation | simforoosh et al introduction after the introduction of laparoscopic ret-roperitoneal lymph node dissection (lr-sible method, many studies were performed to investigate its safety, reproducibility, and long-term results. today, several institutions have published and updated their experience with lrplnd. complications associated with lrplnd are reported to occur in 6% to 17% of patients, the majority of which are minor. chylous ascites and lymphocele are among minor complications, which are reported in up to 6.6% of patients following lrplnd. it is proposed that prevention of chylous ascites and lymphocele can be achieved by meticulous ligation of the lymphatic vessels with clips. however, using electrocoagulation instead of ligation could be time-saving and cost-effective without increase of lymphocele incidence. we evaluated the outcome of lrplnd eliminating clips and using bipolar cautery to seal the lymphatic vessels. we did not focus on oncologic outcomes, but on technical aspects of using bipoformation. materials and methods we reviewed our experience with transperitoneal lrplnd for nonseminomatous germ cell tumor der general anesthesia. thereafter, we introduced four trocars, including three ports in the midline and one pararectally. in a transperitoneal approach, a wide dissection of the ascending colon and the with transection of the splenocolic ligament (left the lymphatic vessels between the aorta and the left sympathetic trunk, however, was preserved. furthermore, the pre-aortic and inter-aortocaval and precaval lymphatic vessels cephalic to the inferior mesenteric artery insertion were removed right side included all the tissue around the vena the pre-aortic tissue cephalic to the inferior mesenteric artery insertion. only in one patient with positive lymph nodes silateral to the contralateral ureter, including both we dissected the lymphatic vessels as much as possible en block with split and roll technique and removed the gonadal vein together with the surrounding lymphatic tissue from the ipsilateral orchiectomy ligature to insertion end point (the the cases. in this experience, in contrast to other techniques, we did not use clips for ligation of the lymphatic vessels. instead, we used bipolar cautery for coagulation of the lymphatic vessels (figures for lymph leakage or lymphocele formation using abdominal computed tomography scan. results toneal lrplnd for nonseminomatous germ cell tumor of the testis. testis tumors were on the left side in 7 patients and on the right side in 6. twelve patients had stage i and one had stage iia tumor. one conversion occurred during our early experience with lrplnd, due to bleeding of the lumbar vessels. no re-operation was needed in any of the patients. blood transfusion was needed only in tumor pathology and peri-operative results are 482 | shown in table. because of success in performing lymph node dissection and low-stage disease, chemotherapy was not needed postoperatively in any of the patients. no case of chylous ascites or prolonged lymphatic leakage from the drains was encountered during the postoperative period. follow-up, lymphocele was not observed in the padiscussion laparoscopic rplnd is a technically demanding procedure that should be undertaken only by laparoscopic urology figure 1. removing lymphatic tissue using bipolar cautery cautery during retroperitoneal lymph node dissection. figure 2. paracaval and inter-aortocaval lymphatic tissue are removed. sl indi483vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l experienced laparoscopic surgeons, who are also comfortable and adept at advanced vascular techniques in the event of open conversion. the indications for lrplnd in low-stage nonseminomatous germ cell tumors of the testis are the same as those for open primary rplnd, namely clinical stage i or iia, negative serum tumor markers, and the absence of comorbidities that would preclude safe surgery, such as a bleeding diathesis. as experience with lrplnd has improved, sevin order to make it more feasible and less complicated. one of the rplnd complications either in open or laparoscopic manner is lymphatic leakage or lymphocele formation. chylous ascites is the result of surgical transection of the major lymphatic vessels. a symptomatic lymphocele occurring after transperitoneal rplnd is relatively uncommon. the presenting symptom may be a sense to ureteral obstruction. imaging studies, including ultrasonography and computed tomography, may reveal a thin-walled cystic lesion, but one must be aware of the possibility of a thick-walled lesion, which must be distinguished from a cystic teratoma through biopsy. prevention of these problems requires marked attention to closing the suspected lymphatic structures. traditionally, clip-ligation and division of the lymphatic channels is being practiced and believe that care must be taken to clip as many of the main lymphatic channels as possible to decrease the risk of postoperative lymphatic leakage. however, bipolar electrocoagulation and division is an alternative technique. although this technique is criticized by some for the increased frequency of lymphatic leakage or lymphocele, phocele formation. box and colleagues described an animal study comparing monopolar, bipolar, and ultrasonic energy devices for in-vivo lymphatic sealing in a porcine model. they assessed the capability of the devices for sealing the thoracic duct. they concluded that bipolar electrocautery and ultrasonic devices, not monopolar device, provide a supraphysiological seal of lymphatic vessels, and are appropriate for being utilized in laparoscopic surgery. the phatic vessels in comparison with suture ligation has been previously evaluated in the kidney transplantation. farouk and bano compared electrocoagulation with ligation of lymphatic vessels in the kidney transplant recipients. their results showed that electrocoagulation is time-saving and cost-effective, with no increase in lymphocele incidence. to the best of our knowledge, using bipolar electrocoagulation to close lymphatic vessels in lrplnd has not been assessed. we eliminated the use of clips for ligation of the lymphatic and blood vessels; instead, we used bipolar cautery. however, we did not confront chylous ascites or prolonged lymphatic leakage from the drains or lymphocele during long-term follow-up period. table . outcome of transperitoneal lymph node dissection without using clips for ligation of the lymphatic vessels. valueparameters 29.9 (3 to 70)mean follow-up (range), month testicular tumor pathology 1 mixed germ cell tumor 1 pure embryonal cell carcinoma lymph node pathology 12 free of tumor 1 embryonal + teratoma mean operation time (range), hr 1conversion to laparotomy 1.33 (0.2 to 2.7)mean hemoglobin drop (range), mg/dl 4.2 (3 to 6)mean drain leakage (range), day 0symptomatic lymphocele 0lymphocele on follow-up imaging laparoscopic rplnd using bipolar electrocoagulation | simforoosh et al 484 | it must be remembered that the most effective approach for the management of symptomatic lymphocele after retroperitoneal lymph node manipulation, such as the kidney transplantation and pelvic lymph node dissection, is surgical intraperitoneal drainage. it seems that because our approach was transperitoneal, minor degrees of lymphorrhea could be absorbed by the exposed peritoneum surface; thus, we did not have any case of lymphatic leakage or symptomatic lymphocele formation. our study is not without limitations. although recurrence occurred in none of our patients, longer follow-up period is needed to more precisely evaluate recurrence. another limitation of our study was lack of a control group; however, this is the ture comparative ones. conclusion our study demonstrates that bipolar electrocoagulation during transperitoneal lrplnd does not adversely affect the outcome of the procedure. furthermore, the use of bipolar coagulation greatly facilitates a bloodless tissue dissection, shortens the operation time, prevents unnecessary application of intraperitoneal foreign bodies, reduces the costs, and brings more convenience for the surgeon. furconflict of interest none declared. references 1. rukstalis db, chodak gw. laparoscopic retroperitoneal lymph node dissection in a patient with stage 1 testicular 2. stone nn, schlussel rn, waterhouse rl, unger p. laparoscopic retroperitoneal lymph node dissection in stage a 3. janetschek g, peschel r, hobisch a, bartsch g. laparoscopic retroperitoneal lymph node dissection. j endourol. laparoscopic urology 4. zhuo y, klaen r, sauter tw, miller k. laparoscopic retroperitoneal lymph node dissection in clinical stage i nonseminomatous germ cell tumor: a minimal invasive alternative. 5. rassweiler jj, frede t, lenz e, seemann o, alken p. longterm experience with laparoscopic retroperitoneal lymph node dissection in the management of low-stage testis 6. giusti g, beltrami p, tallarigo c, bianchi g, mobilio g. unilateral laparoscopic retroperitoneal lymphadenectomy for clinical stage i nonseminomatous testicular cancer. j 7. klotz l. laparoscopic retroperitoneal lymphadenectomy for high-risk stage 1 nonseminomatous germ cell tumor: kenney pa, tuerk ia. complications of laparoscopic retroperitoneal lymph node dissection in testicular cancer. world 9. smith rb, ehrlich rm, eds. complications of urologic surgery. 10. farouk k, bano u. electocoagulation versus suture-ligation of lymphatics in kidney transplant recipient surgery. j 11. sheinfeld j, bartsch g, bosl gj. surgery of testicular tumors. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. 9 ed. philadelphia: wb 12. janetschek g. laposcopic retroperitoneal lymph node dissection: evolution of a new technique. world j urol. 13. corvin s, kuczyk m, anastasiadis a, stenzl a. laparoscopic retroperitoneal lymph node dissection for nonseminoma14. box gn, lee hj, abraham jb, et al. comparative study of in vivo lymphatic sealing capability of the porcine thoracic duct using laparoscopic dissection devices. j urol. 15. 16. musch m, klevecka v, roggenbuck u, kroepfl d. complicagoing radical retropubic prostatectomy between 1993 and 485vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l laparoscopic rplnd using bipolar electrocoagulation | simforoosh et al 17. stolzenburg ju, rabenalt r, do m, et al. complications of endoscopic extraperitoneal radical prostatectomy (eerpe): 75. zargar-shoshtari ma, soleimani m, salimi h, mehravaran k. symptomatic lymphocele after kidney transplantation: a 19. abou-elela a, reyad i, torky m, meshref a, morsi a. laparoscopic marsupialization of postrenal transplantation 20. varga z, hegele a, olbert p, hofmann r, schrader aj. laparoscopic peritoneal drainage of symptomatic lymphoceles after pelvic lymph node dissection using methylene blue 367vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l detection of recurrent bladder cancer nmp22 test or urine cytology? jalil hosseini,1 ali reza golshan,2 mohammad mohsen mazloomfard,1 abdolrasoul mehrsai,3 mohammad ali zargar,4 mohsen ayati,5 saeed shakeri,6 majid jasemi,7 mahmoud kabiri8 purpose: to assess the accuracy of voided urine cytology versus urinary nuclear matrix protein 22 (nmp22) qualitative assay in the diagnosis of various grades and stages of recurrent bladder transitional cell carcinoma (tcc). materials and methods: from july 2007 to february 2009, all patients with history of superficial bladder tcc were included in this multi-center study. each patient provided three serial voided urine samples for cytologic examination and one sample for the nmp22 qualitative assay prior to urethrocystoscopy. the sensitivity and specificity of urine cytology and the nmp22 test were determined. results: the sensitivities of the nmp22 test and cytology for detection of recurrence were 78.8% and 44.2%, respectively (p = .001), while the specificities were 69.6% and 83.7%, respectively (p = .019). the nmp22 test showed significantly higher sensitivity than cytology in detecting recurrences in low-risk and intermediate-risk groups. conclusion: the nmp22 assay could be used for detection of superficial bladder cancer, especially in lowand intermediate-risk groups; however, the value of the test is limited by its low specificity. keywords: transitional cell carcinoma, urinary bladder neoplasms, diagnosis, nuclear matrix proteins, tumor markers corresponding author: jalil hosseini, md infertility and reproductive health research center, reconstructive urology, shohada-etajrish hospital, shahid beheshti university of medical sciences, tehran, iran tel: +98 21 2243 2558 fax: +98 21 2203 8462 e-mail: jhosseinee@gmail.com received march 2010 accepted september 2010 1 infertility and reproductive health research center, reconstructive urology, shohada-etajrish hospital, shahid beheshti university of medical sciences, tehran, iran 2 north khorasan university of medical sciences, bojnurd, iran 3 sina hospital, tehran university of medical sciences, tehran, iran 4 hasheminejad kidney center, tehran university of medical sciences, tehran, iran 5 imam khomeini hospital, tehran university of medical sciences, tehran, iran 6 namazi hospital, shiraz university of medical sciences, shiraz, iran 7golestan hospital, ahvaz university of medical sciences, ahvaz, iran 8alzahra hospital, isfahan university of medical sciences, isfahan, iran urological oncology 368 | urological oncology introduction the most common genitourinary cancer among our population is the bladder carci-noma with prevalence of 48.3%.(1) superficial type accounts for 70% of the urothelial cell carcinoma of the bladder that has a high probability of recurrence (60% to 85%).(2,3) long-term follow-up is recommended to detect any cancer recurrence or progression. therefore, cystoscopy, the gold standard test, and urine cytology every 3 to 4 months for the first two years and at a longer interval in subsequent years are recommended as the current standard of care for detection of tumor recurrence.(4,5) due to invasiveness and high cost of this approach, new techniques and markers, including flow cytometry, quantitative fluorescence image analysis, and nuclear matrix protein 22 (nmp22), etc, have been introduced and studied for their accuracy in detection of recurrent bladder cancers.(6-10) the nmp22 test detects the nuclear matrix protein qualitatively, which is part of the nuclear mitotic apparatus released from urothelial nuclei upon cellular apoptosis.(11-13) nuclear matrix protein 22 is shed into the urine and has a 20 to 80-times higher concentration in the urine of the patients with bladder cancer compared to noncancerous controls.(12) this test has been approved by the food and drug administration (fda) for patient surveillance.(14) this test has sensitivity and specificity as high as urine cytology. we compared the sensitivity and specificity of voided urine cytology in the diagnosis of various grades and stages of recurrent bladder transitional cell carcinoma (tcc) with the urinary nmp22 qualitative test. materials and methods from july 2007 to february 2009, all patients with history of superficial bladder tcc from seven academic centers were enrolled in this study. patients with urinary tract infections, concurrent urolithiasis, a history of bladder substitution, and other malignancies were excluded from the study. written informed consent was obtained from each participant and the study was approved by the ethics committee of the infertility and reproductive health research center (irhrc). each patient provided three serial voided urine samples within 3 days for cytologic examination and one sample for the nmp22 qualitative assay. in each center, one cytopathologist performed cytologic examination, who was unaware of the cystoscopy and nmp22 results. malignant and suspicious results for malignancy were classified as positive. the nmp22 assay was performed according to the instructions provided in the nmp22 point-of-care device (matritech inc, 330 nevada st, newton, ma). the quality of nmp22 in patients’ urine was assessed using a lateral flow immunochromatographic strip. four drops of urine at room temperature were added to the point-of-care device and results were interpreted within 30 minutes. positive result yielded a colored band in the test position. all the nmp22 test results were interpreted by a single observer at each center, who was blind to the cystoscopy and cytology results. urethrocystoscopy, using a rigid cystoscope and video camera, was performed for all the patients. any visible tumor or suspicious lesion was biopsied for histopathologic examination, using the tnm staging system(15) and world health organization grading.(16) findings from histopathologic evaluation of biopsies were considered as a gold base for comparing the results of other two tests. either normal appearance in endoscopy or histopathologically nonmalignant tissue in biopsy was defined as negative for tcc. if no tumor was observed endoscopically, patients with positive isolated cytology or nmp22 test were further evaluated by random biopsies from the bladder and urethra and by imaging, like intravenous urography or contrast-enhanced computed tomography, 369vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l nmp22 and bladder cancer | hosseini et al in order to rule out any missed lesion in the genitourinary system. patients with a higher index of suspicion were re-evaluated every 4 weeks until 6 months. patients who were found to have an upper tract lesion or a bladder lesion in the next cystoscopy were considered true positives for the test. data analysis was performed by using spss software (the statistical package for the social sciences, version 15.0, spss inc, chicago, illinois, usa) using chi-square, fisher’s exact, and mann-whitney u tests and by calculating the 95% confidence interval (ci) to determine the sensitivity and specificity of urine cytology and the nmp22 assay. results of 320 recruited participants, 144 patients, 125 men and 19 women, met the inclusion criteria, diagnostic tests, and follow-up period. the mean age of the entire group was 61.8 years (range, 26 to 86 years). of 144 patients, 52 (36.11%) were diagnosed with recurrent bladder tcc; 48 patients were detected with cystoscopy and 4 after the first follow-up cystoscopy. one of these 4 patients had carcinoma in situ (cis) in his pathology and was positive for cytology; but other 3 subjects were nmp22-positive with small tumor size, 2 of them had t1g2 and the other one had t1g3. of 52 patients with tumor recurrence, 16 had grade i, 20 had grade ii, and 16 had grade iii disease, while 18 had stage ta, 22 had stage t1, 3 had cis, and 9 had stage t2 or more. on histopathology, 41 were positive for the nmp22 test and 23 were positive for cytology. the sensitivity, specificity, positive predictive value, and negative predictive value of the nmp22 test and voided urine cytology for detection of recurrence are presented in table 1. the sensitivities of urine cytology and urinary nmp22 regarding the stage, grade, and risk stratification are shown in table 2. pathological data were grouped according to risk for recurrence, progression, and invasion into a low-risk group (single ta, g1 < 3 cm), a high-risk group (multiple t1g2, tis, t1g3, and tag3), and an intermediate-risk group (rather than two other groups). the nmp22 test showed significantly higher sensitivity than cytology in detecting lowrisk and intermediate-risk groups recurrences. however, this test detects recurrence as same as cytology in the high-risk group (table 2). after combining the results of the nmp22 test and cytology, nmp22 test and cystoscopy, and cytology and cystoscopy, the overall sensitivity increased to 88.5% (46/52), 98.1% (51/52), and 94.2% (49/52), respectively, rather than cytology or nmp22 test alone. discussion cystoscopy is the gold standard modality for the diagnosis of bladder carcinoma; however, it is invasive and relatively expensive.(17) voided urine cytology is based on morphologic assessment in intact cells shed in urine; hence, small tumors table 1. sensitivity, specificity, positive predictive value, and negative predictive value of the nmp22 test and voided urine cytology urine cytology nmp22 test p sensitivity (%) 44.2 (23/52) 78.8 (41/52) .001 specificity (%) 83.7 (77/92) 69.6 (64/92) .019 negative predictive value (%) 72.6 (77/106) 85.3 (64/75) ns* positive predictive value (%) 60.5 (23/38) 59.4 (41/69) ns *ns indicates non-significant 370 | or well-differentiated ones are difficult to recognize because cells less likely exfoliate spontaneously. this fact explains its low sensitivity (15% to 30%) in low-stage cancers.(13) therefore, many new urine-based tests for substitution of urine cytology have been developed. of which, bta stat, bta trak, nmp22, fdp, immunocyt, and fish (urovysion) have been approved by the fda.(18) nuclear matrix, first described in 1974, is a nonchromatin structure that supports nuclear shape, organizes dna, and takes part in dna replication and transcription, and in rna processing. nuclear matrix protein 22 is a nuclear protein which plays a role in control of the chromatid regulation and cell separation during replication. the nmp22 test is an office-based procedure that can be interpreted by a urologist within 30 minutes; therefore, it can be used as an alternative to urine cytology.(19,20) various published studies have reported nmp22 (sensitivity: 70% to 80%) to be at least twice more sensitive than urine cytology (sensitivity: 10% to 40%) in detecting bladder cancer.(8,21-23) in our study, the sensitivity of the nmp22 test was significantly higher, but the specificity was lower than that for cytology (77.8% versus 44.2% and 69.6% versus 83.7%, respectively). these findings are compatible with the quantitative analyses of nmp22 performed by other investigators.(8,22,23) it was demonstrated that the quantitative nmp22 test had an overall sensitivity of 70% to 80% for the detection of recurrent superficial bladder tcc in approximately 400 patients. in comparison, cytology showed sensitivity of 10% to 40%.(20,24,25) a higher sensitivity for urine cytology rather than other published articles was detected in this study, may be due to examining of three urine samples instead of one. few drawbacks have been mentioned for nmp22, including lack of exact cutoff point for quantitative assessment.(26) jamshidian and colleagues suggested a cutoff point of 10.1 u/ml for iranian patients for detection of the bladder cancer.(19) using nmp22 point-of-care device (matritech bladderchek test), bladder cancer can be evaluated qualitatively by cutoff point of 10 u/ml, as a positive result for test. our study showed that the nmp22 test had consistently higher sensitivity than cytology in detecting urological oncology table 2. diagnostic value of urine cytology and nmp22 test in each tumor grade and stage, and risk of recurrence and progression tumor class (n = 52) sensitivity of urine cytology (%) sensitivity of nmp22 test (%) p stage cis (n = 3) ta (n = 18) t1 (n = 22) ≥ t2 (n = 9) 100 (3/3) 11.1 (2/18) 45.5 (10/22) 88.9 (8/9) 66.7 (2/3) 61.1 (11/18) 95.5 (21/22) 77.8 (7/9) .00 .002 .021 ns grade g i (n = 16) g ii (n = 20) g iii (n = 16) 0.0 (0/16) 40.0 (8/20) 93.8 (15/16) 68.8 (11/16) 85.0 (17/20) 81.3 (13/16) .00 .022 ns risk stratification low (n = 15) intermediate (n = 20) high (n = 8) 0.0 (0/15) 40.0 (8/20) 87.5 (7/8) 66.7 (10/15) 85.0 (17/20) 87.5 (7/8) .00 .022 ns * cis indicates carcinoma in situ; and ns, non-significant. 371vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l different stages and grades of recurrence in patients with a history of superficial bladder cancer. but in detection of high-grade or advanced tumor, there was no significant difference between two tests. it was already demonstrated that there is no significant difference in risk of progression in the low and intermediate-risk groups. kumar and associates showed that the nmp22 test was eight times more sensitive than cytology to detect the low-risk group, but not intermediateand high-risk groups. (20) tendency of the nmp22 assay to detect recurrent bladder tumor in patients with intermediaterisk in our study is in contrast to kumar’s study. traditionally, diagnosis of these groups has been the greatest challenge for non-invasive assays. by use of nmp22 test as a surveillance marker, repetition of cystoscopy or transurethral resection of the bladder tumors may be avoided or can be delayed in such patients. conclusion the nmp22 test is a non-invasive and rapid test for the diagnosis of low-stage bladder cancer. acknowledgements this study was approved in infertility and reproductive health research center (irhrc, sbmu) as a research project. we appreciate all colleagues in shohada-e-tajrish hospital (sbmu), sina hospital (tums), imam khomeini hospital (tums), hasheminejad kidney center (iums), shiraz university, ahwaz university, and isfahan university for their valuable inputs. conflict of interest none declared. references 1. akbari me, hosseini sj, rezaee a, hosseini mm, rezaee i, sheikhvatan m. incidence of genitourinary cancers in the islamic republic of iran: a survey in 2005. asian pac j cancer prev. 2008;9:549-52. 2. babjuk m, oosterlinck w, sylvester r, kaasinen e, böhle ja. eau guidelines on non-muscle-invasive bladder cancer (ta, t1, and carcinoma in situ [cis]); available from: http://www. uroweb.org/guidelines/online-guidelines; 2010. 3. jones js, campbell sc. non-muscle-invasive bladder cancer (ta, t1, and cis). in: wein aj, kavousi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 3. 9 ed. philadelphia: saunders; 2007:2447-78. 4. mufti gr, singh m. value of random mucosal biopsies in the management of superficial bladder cancer. eur urol. 1992;22:288-93. 5. kriegmair m, baumgartner r, knuchel r, stepp h, hofstadter f, hofstetter a. detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. j urol. 1996;155:105-9; discussion 9-10. 6. berezney r, coffey ds. identification of a nuclear protein matrix. biochem biophys res commun. 1974;60:1410-7. 7. cordon-cardo c, wartinger dd, melamed mr, fair w, fradet y. immunopathologic analysis of human urinary bladder cancer. characterization of two new antigens associated with low-grade superficial bladder tumors. am j pathol. 1992;140:375-85. 8. soloway ms, briggman v, carpinito ga, et al. use of a new tumor marker, urinary nmp22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. j urol. 1996;156:363-7. 9. sarosdy mf, devere white rw, soloway ms, et al. results of a multicenter trial using the bta test to monitor for and diagnose recurrent bladder cancer. j urol. 1995;154:379-83; discussion 83-4. 10. parry wl, hemstreet gp, 3rd. cancer detection by quantitative fluorescence image analysis. j urol. 1988;139:270-4. 11. yang ch, snyder m. the nuclear-mitotic apparatus protein is important in the establishment and maintenance of the bipolar mitotic spindle apparatus. mol biol cell. 1992;3:1259-67. 12. keesee sk, briggman jv, thill g, wu yj. utilization of nuclear matrix proteins for cancer diagnosis. crit rev eukaryot gene expr. 1996;6:189-214. 13. talwar r, sinha t, karan sc, et al. voided urinary cytology in bladder cancer: is it time to review the indications? urology. 2007;70:267-71. 14. us food and drug administration premarket clearance (510[k]) database: k021231. available at: http://www. accessdata.fda.gov/scripts/cdrh/cfdocs /cfpmn/pmn. cfm?id=7920. accessed february 10, 2005. nmp22 and bladder cancer | hosseini et al 372 | 15. american joint committee on cancer (ajcc). urinary bladder. in: fleming id, cooper js, henson de, eds. ajcc cancer staging manual. 5 ed. philadelphia: lippincott-raven; 1997:241-3. 16. mostofi fk, davis cj, sesterhenn ia. pathology of tumors of the urinary tract. in: skinner dg, lieskovsky g, eds. diagnosis and management of genitourinary cancer. philadelphia: wb saunders; 1988:83-117. 17. lotan y, roehrborn cg. cost-effectiveness of a modified care protocol substituting bladder tumor markers for cystoscopy for the followup of patients with transitional cell carcinoma of the bladder: a decision analytical approach. j urol. 2002;167:75-9. 18. van rhijn bw, van der poel hg, van der kwast th. urine markers for bladder cancer surveillance: a systematic review. eur urol. 2005;47:736-48. 19. jamshidian h, kor k, djalali m. urine concentration of nuclear matrix protein 22 for diagnosis of transitional cell carcinoma of bladder. urol j. 2008;5:243-7. 20. kumar a, kumar r, gupta np. comparison of nmp22 bladderchek test and urine cytology for the detection of recurrent bladder cancer. jpn j clin oncol. 2006;36:172-5. 21. stamfer s, gennaro a, lance w. willsey et al. evaluation of nmp22 in the detection of tcc of bladder. j urol. 1998;159:394-8. 22. miyanaga n, akaza h, ishikawa s, et al. clinical evaluation of nuclear matrix protein 22 (nmp22) in urine as a novel marker for urothelial cancer. eur urol. 1997;31:163-8. 23. landman j, chang y, kavaler e, droller mj, liu bc. sensitivity and specificity of nmp-22, telomerase, and bta in the detection of human bladder cancer. urology. 1998;52:398402. 24. grossman hb, soloway m, messing e, et al. surveillance for recurrent bladder cancer using a point-of-care proteomic assay. jama. 2006;295:299-305. 25. badalament ra, hermansen dk, kimmel m, et al. the sensitivity of bladder wash flow cytometry, bladder wash cytology, and voided cytology in the detection of bladder carcinoma. cancer. 1987;60:1423-7. 26. shariat sf, zippe c, ludecke g, et al. nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with ta, t1 or cis transitional cell carcinoma of the bladder. j urol. 2005;173:151825. urological oncology 1088 | reconstructive urology pendulous urethral stricture: peculiarities and relevance of longitudinal penile fascio-cutaneous flap reconstruction in poor resource community abdulkadir a. salako,1 abimbola o. olajide,1 ademola a. aremu,2 michael o. afolayan,3 ifeoluwa e. adejare,4 oyediran g. oseni1 purpose: to describe peculiarities of pendulous urethral stricture in south western nigeria and how prevalent social and environmental factors have made longitudinal distal penile island flap the preferred option for reconstruction of pendulous urethral stricture in such a poor resource community. materials and methods: all patients presenting with stricture located in the pendulous urethra in 3 hospitals in south western nigeria, over a 5 year period were interviewed and had urethral reconstruction using longitudinal distal penile fascio-cutaneous island flap under spinal anesthesia. results: thirty four cases were treated by this method during this period. complications were found in 4 patients (11.8%) which include urethrocutaneous fistula, penile skin necrosis and wound infection. all cases had satisfactory overall outcome. conclusion: longitudinal penile fascio-cutaneous flap remains a viable option for a single stage repair of pendulous urethral stricture especially in poor resource communities. keywords: urethral stricture; urologic surgical procedures; treatment outcome; surgical flaps; postoperative complications. corresponding author: abimbola o. olajide, md department of surgery, ladoke akintola university teaching hospital, osogbo, nigeria. tel: +23 480 372 51893 email: lajidea@yahoo.com received august 2012 accepted march 2012 1department of surgery, obafemi awolowo university, ile-ife, nigeria. 2department of surgery, ladoke akintola university teaching hospital, osogbo, nigeria. 3department of surgery, university of lagos, lagos, nigeria. 4department of surgery, federal medical centre, owo, nigeria. reconstructive urology 1089vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction male urethral is conventionally classified as an-terior and posterior segments. posterior urethra (within the pelvis) is constituted by the prostatic and membranous urethra while anterior part is further divided into the pendulous / penile (within the penile shaft) and the bulbar (in the perineum).(1) the length of pendulous urethra is critical for proper sexual activity because it has to tolerate increase in the length of phallus during turgidity. length discrepancy caused by disease or reconstruction may lead to incongruity with subsequent deformity of the penile tissue during erection (chordee) with associated sexual dissatisfaction.(2,3) wide arrays of techniques are available for management of urethral stricture but not all can be applied to pendulous urethral stricture. resection and anastomosis, though preferred, is not favored because it causes chordee; substitution urethroplasty is therefore recommended.(4) several tissues have been used for urethral substitution either as a single or a multi-staged procedure, but no tissue is appropriate for all cases of urethral stricture disease.(5) several factors influence the choice of reconstruction technique for each case. these factors may include available facility, patients’ choice, and preference of the attending surgeon. however, peculiar environmental factors can also play a significant role in the choice of methods for treatment of urethral stricture.(6) we carried out this study to report the epidemiology of pendulous urethral stricture and to illustrate why longitudinal distal penile island flap reconstruction may still be the best option in poor resource communities like south-western nigeria. materials and methods a prospective study of cases of pendulous urethral stricture disease treated by longitudinal distal penile fascio-cutaneous island flap over a 5 year period (january 2006-december 2010) in 3 tertiary hospitals in south western nigeria. all the hospitals are referral centers for urological diseases in the various states. approval was obtained from research and ethical committees in the centers and informed consent was obtained from the patients before being enlisted for the study. pre-operative clinical evaluation for the study was done at the outpatient unit and all the patients had longitudinal penile fascio-cutaneous island flap re-construction under spinal anesthesia by same group of surgeons. information on age of patients, occupation, source of funding, etiology, investigation, intra-operative findings, intra-operative complications, post-operative complications and overall outcome of the treatment was collected on a proforma. the data generated was entered into the computer and analyzed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. operative technique we wash the external genitalia thoroughly with soap on the morning of surgery. the penile skin is marked to demarcate the hair bearing proximal skin thereby avoiding its inclusion in the flap. following administration of spinal anesthesia, the patient is placed in dorsal position and skin prepped and draped to expose the genitalia and suprapubic region. peri-operative intravenous ciprofloxacin and metronidazole is given immediately after administration of anesthesia. penile shaft is put under traction and stabilized using 4-0 silk suture applied to the glans. size 18f foley’s catheter is passed through the external meatus and advanced proximally to mark the stricture site. incision is made on one side of the midline, on the ventral surface of the non-hair bearing distal penile skin adjacent the strictured urethral segment. this is deepened through the dartos layer and buck’s fascia onto the tunica albuginea of the corpus cavernosum on this side. the edge of the skin and the subcutaneous tissue are elevated and dissected across the midline to the other corpus cavernosum to expose the diseased urethra. exposure of the urethra lumen is done by longitudinal urethrotomy incision on the lateral surface of the urethra, on the contralateral side of the skin incision extended l cm into normal urethra distally and proximally. foley’s catheter is passed from the meatus and advanced proximally into the bladder to rule out concomitant stricture in the proximal urethral segment (figure 1). based on the measured urethral defect, another incision is made on the skin, some distance from the initial incision to map out the skin to be used for urereconstruction of pendulous urethral stricture in poor community | salako et al 1090 | thral reconstruction. the length and width of this skin is based on the defect to be bridged on the exposed urethra. this incision is deepened to just below the dermis; both blunt and sharp dissections are carried out on this plane to separate the isolated skin flap on its vascularized pedicle made of the dartos fascia (figure 2). the skin flap is flipped over unto the urethral defect and a watertight anastomosis is done with interrupted 4-0 or 5-0 vicryl, over a size 16 or 18 french (fr) foley’s catheter which serves as a stent (figures 3 and 4). a layer of dartos fascia is closed over the repair to reinforce and protect the anastomosis (figure 5). thereafter, the skin is closed using 3-0 nylon suture with interrupted knots (figure 6). urine is left un-diverted in all the patients except those with pre-operative suprapubic diversion who were maintained on diversion after the surgery. intravenous antibiotics are maintained till 48 hours post-operation and then converted to oral. skin sutures are removed between 8 and 10 days and peri-catheter urethrography is done between 14 and 21 days to assess the neo-urethra following which urethral catheter is removed and patient is discharged to outpatient clinic thereafter (figures 7 and 8). at 6 weeks post-operation, symptoms are re-assessed, urinary flow rate is obtained and post void residual urine measured by ultrasound. the treatment is judged successful if the pre-operative symptoms have subsided, post void residual urine less than 50 ml and the urine flow rate is above 10 ml/s. results one hundred and nine cases of urethral stricture diseases were managed in the three centers during the period of study out of which 34 patients (31.2%) had stricture located in the pendulous urethra. the ages of those with pendulous urethral disease ranged between 28 to 89 years with mean age of 53.6 years. none of the patients had insurance coverage for their treatment cost; all of the patients were self-sponsored with only 3 (< 1%) having hope of partial or full reimbursement from their employer. etiology of the disease is as shown in table with iatrogenic contributing the largest percentage. thirteen of these (39.1%), resulted from urethral catheterization in the cause of treatment of medical and surgical conditions not related to the urinary system like cerebrovascular accident, severe head injury, meningitis and food poisoning. others were due to post-operative complication of cystoscopy and prostatectomy for benign prostatic hyperplasia. although 7 patients (20.6%) were initially diagnosed by urethrocystoscopy, the main diagnostic investigation was retrograde urethrography (figure 6) which was done for all the patients. nine patients (26.5%) had antegrade urethrogram in combination with figure 1. urethrotomy incision exposing lumen of strictured segment with catheter in-situ. figure 2. longitudinal distal penile island flap on a vascularized pedicle. figure 3. anastomosis of flap to native urethra, completed on one side. reconstructive urology 1091vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l retrograde urethrogram for evaluation of the proximal urethral segment due to complete obstruction or involvement of the external meatus and fossa navicularis. all the patients had isolated pendulous urethral stricture of varied lengths except one, who had concomitant short segment stricture in the bulbar urethral segment. thirteen patients (38.2%) had co-morbid conditions like hemiplegia from cerebrovascular accident, hypertension, diabetes and chronic obstructive airway disease. they all had single stage urethroplasty using longitudinal distal penile island flap technique under spinal anesthesia. intra-operative stricture length ranged from 2.5 cm to 6.5 cm with mean stricture length of 3.9 cm. the patient with concomitant bulbar urethral stricture had anastomotic repair of the bulbar urethral stricture along with substitution repair of the pendulous urethral segment. excluding the patient with concomitant bulbar stricture, duration of surgery was observed to be directly related to the stricture length; the duration ranged between 53 and 92 minutes. size 18 fr foley’s catheter was used as stent in all the patients and urine diverted with suprapubic cystostomy in 23 patients (67.6%) with suprapubic cystostomy before reconstruction. mean duration of urethral stent and suprapubic catheters were 21days and 28 days respectively. post-operative complications were found in 4 patients: wound infection in 2, penile skin necrosis in one and urethrocutaneous fistula in one, giving a complication rate of 11.8%. they were managed with wound dressing and antibiotics while the urethrocutaneous fistula was surgically closed 4 months after initial urethroplasty. there was no intra operative complication in any of the patients. hospital stay ranged between 18and 23 days with mean hospital stay of 10.8 days. duration of follow up ranged between 12 to 36 months and all the patients had satisfactory overall outcome, none of the patients reported recurrence of his symptom(s) during the period of follow up. discussion pendulous urethral stricture is not as common as strictures in other segments of the urethra. it constitutes 29.1% of all cases of urethral stricture disease seen in our centers over table. etiologies of penile urethral stricture. etiology frequency percentage iatrogenic 19 55.9 inflammatory 11 32.4 trauma 1 2.9 uncertain 3 8.8 figure 4. ongoing anastomosis of flap to the other side of native urethra. figure 5. reinforcement of repair with layer of dartos fascia before skin closure. figure 6. penile appearance immediately after skin closure. reconstruction of pendulous urethral stricture in poor community | salako et al 1092 | the 5 year period. some other researchers have reported lower percentage of pendulous stricture in comparison with stricture in other parts of the urethra.(7) iatrogenic causes of urethral stricture usually result from procedures such as urethral catheterization and transurethral endoscopy with the former being the leading cause.(8,9) introduction of flexible and small caliber endoscopes coupled with diligent care for patients with indwelling catheters has reduced the incidence of iatrogenic injuries in most centers in developed world.(10) consideration of urethral catheterization as minor procedures may be contributory to high incidence of catheterization induced urethral stricture in our centers; it is left to the junior doctors and interns who may not be experienced in the procedure. we feel there is need to saddle more experienced doctors with this responsibility of urethral catheterization and to increase the supervision of the junior officers during the procedure. we found urethrography adequate to confirm the diagnosis and plan repair for these patients. information obtained on retrograde urethrogram may be limited where there is complete obstruction or when the stricture extends to involve the fossa navicularis due to obscuring of area of interest by injection device.(7) in such situation we used micturating urethrography in isolation or in combination with retrograde urethrography to evaluate the stricture. surgical reconstruction of pendulous urethral stricture is peculiar and challenging because of some inherent complications like tissue necrosis due to precarious vascularization, urethrocutaneous fistula and alterations in sexual functions. (5) anastomotic urethroplasty is contraindicated because it can cause chordee which will have serious consequences on the sexual functions of the penis.(11) whatever technique is employed, the length and appearance of the penis must not be compromised and the neurovascular supply to the penis must not be affected so that the sexual function is not jeopardized.(12) although neurovascular supply of the penis is located on the dorsal and lateral part of the penis, they can be injured while raising the flap if the proper plane of dissection is not maintained. the options in pendulous urethral reconstruction are thus limited considerably to substitution techniques. use of genital skin for urethral reconstruction is not new; it was the preferred tissue prior to the emergence of buccal mucosa.(5) although controversy exists over the use of free grafts or pedicled flaps and literature has made it hard to declare a favorite between the two: nevertheless, only few surgeons still use genital flaps.(13,14) we propose that current interest in buccal mucosal graft should not make genital skin flap obsolete, there is need to define indications which may make either of the procedure appropriate in specific case scenarios. unlike bulbar urethra, figure 1. pre-operative retrograde urethrogram of one of the patients. figure 2. post-operative peri-catheter urethrogram of same patient. reconstructive urology 1093vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l reconstruction of pendulous urethral stricture in poor community | salako et al corpus spongiosum and dartos fascia of the penile urethra segment are thin and may not ensure sufficient graft support for free graft but vascularized genital flap is known to thrive in conditions with inadequate vascular supply.(14,15) genital skin flap reconstruction is contra indicated in patients with pendulous urethral stricture resulting from previous failed hypospadias repair or balanitis xerotica obliterance (lichen sclerosis) because genital skin is involved in these conditions.(15,16) all the patients in this series had grossly normal penile skin considered suitable for reconstruction. use of regional anesthesia (subarachnoid or epidural block) for this procedure is one of the major benefits it has over buccal mucosa urethroplasty which is usually done under general anesthesia. regional anesthesia alleviates the risks associated with general anesthesia and some patients opt for regional block when given the two options. regional block is also preferred for patients with co-morbid conditions where there are definite risks associated with general anesthesia. this fact becomes more important in societies like ours where most hospitals have inadequate anesthetic support (equipment and personnel).(17,18) likewise, the cost of spinal anesthesia is approximately half of that for general anesthesia. thus, in poor resource communities where most patients belong to the low socio-economic group, a cheaper but equally effective treatment method should be considered and embraced rather than a procedure that may add to the financial burden of these patients.(6) this is buttressed by the embryonic state of the health insurance schemes which cover a very small segment of the population and only basic treatment.(19) engagement of 2 teams of surgeons operating simultaneously (one in the buccal cavity and the other in the perineum), is better during buccal mucosal repair otherwise, the procedure will be ‘duly’ prolonged.(14) in poor resource communities, only ‘big’ centers can boast of more than one urologist with some centers having none. buccal mucosal repair in such places means additional burden in a society with dearth of specialists.(17) complications were found in 4 patients (11.8%). regular wound dressing and use of antibiotics based on culture sensitivity brought about complete resolution of wound infection and good re-epithelialization of the penile skin. occurrence of post-operative wound infection may not be surprising because urinary tract infection is common in patients with urethral stricture due to stasis of urine and previous attempts at relieve of symptoms.(17,20) however, ability of flaps to survive in such condition is exemplified by resolution of infection without adverse effect on the flap and overall outcome. donor site complication (penile skin necrosis) is one of the reasons advanced for superiority of buccal mucosa graft over genital skin flaps because the donor site is concealed.(21) however, penile skin is ‘highly forgiving’ with little or no scarification after healing as depicted in this study. comparative studies of buccal mucosal graft and penile skin flap show no significant difference in their outcome and therefore concluded that both tissues have comparable substitution profile in urethral reconstruction.(14,22,23,24) if both methods have similar outcomes, type of anesthesia and cost of repair should argue for the use of longitudinal skin flaps in poor resource communities. one major limitation to this study is the short duration of follow up with most patients lost between 1 and 3 years. this precludes evaluation of long term complications in the patients. we hope to carry out a comparative study of both methods in our community. conclusion longitudinal distal penile fascio-cutaneous island flap is still relevant for reconstruction of pendulous urethral stricture in poor resource communities. with emergence and reemergence of newer methods, available facility and cost of reconstruction coupled with the socio-economic status of a community should be taken into consideration in selection of appropriate method for specific cases. acknowledgement we appreciate all the theatre nurses and anesthetists / anesthesiologists in our hospitals who supported us in carrying out this study. conflict of interest none declared. 1094 | 20. barbagli g, palminteri e, de stefani s, lazzeri m. harvesting buccal mucosal grafts. keys to success. contemp urol. 2006;18:17-24. 21. alsikafi nf, eisenberg m, mcaninch jw. long–term outcomes of penile skin graft versus buccal mucosal graft for substitution urethroplasty of the anterior urethra. j urol. 2005;173:87. 22. gozzi c, pelzer ae, bartsch g, rehder p. genital free skin grafts as dorsal onlay for urethral reconstruction. j urol. 2006;175:38. 23. claasen f. wentzel s. the treatment of complex urethral stricture using ventral onlay buccal mucosa graft or ventral onlay penile skin island flap urethroplasty: a prospective case series. afr j urol. 2011;17:79-84. references 1. jordan gh, rourke kf. the use of flaps in urethral reconstructive surgery. in: reconstructive urethral surgery. schreiter f and jordan gh, (eds.) 130-136, springer; 2005. p. 130-36. 2. raber m, naspro r, scapaticci e et al. dorsal onlay graft urethroplasty using penile skin or buccal mucosa for repair of bulbar urethral stricture: results of a prospective single centre study. eur urol. 2005;48:1013-17. 3. quartey jk. one stage transverse distal penile/ preputial island flap urethroplasty for bulbar stricture. br j urol. 1996;78:929. 4. mundy ar. management of urethral stricture. postgrad med j. 2006; 82: 489-493. 5. ogbonna bc. managing many patients with urethral stricture: cost benefit analysis of treatment option. br j urol. 1998;81:741-44 6. fenton as, morey af, aviles r, garcia c. anterior urethral strictures: aetiology and characteristics. urology. 2005;65:1055-58. 7. tonkin jb, jordan gh. management of distal anterior urethral strictures. nat rev urol. 2009;6:533-38. 8. boujnah h, abid i, trabelsi n, zmerli s. iatrogenic urethral stenosis. apropos of 100 cases. j chir (paris). 1989;126:163-8. 9. lentz hc jr, mebust wk, foret jd, melchior j. urethral strictures following transurethral prostatectomy: review of 2,223 resections. j urol. 1977;117:194-96. 10. andrich de, greenwell tj, mundy ar. the problems of penile urethroplasty with particular reference to 2-stage reconstructions. j urol. 2003;170:87-9. 11. barbagli g, palminteri e, lazzeri m, guazzoni g. anterior urethral strictures. bju int. 2003;92:497-505. 12. barbagli g, palminteri e, de stefani s, lazzeri m. penile urethroplasty. techniques and outcomes using buccal mucosa grafts. contemp urol. 2006;18:25-33. 13. dubey d, vijjan v, kapoor r et al. dorsal onlay buccal mucosa versus penile skin flap urethroplasty for anterior urethral strictures: results from a randomized prospective trial. j urol. 2007;178:2466-69. 14. barbagli g, de angelis m, palminteri e, lazzeri m. failed hypospadias repair presenting in adults. eur urol. 2006;49:887-94. 15. depasquale i, park aj, bracka a. the treatment of balanitis xerotica obliterans. bju int. 2000;86:459-65. 16. mungadi ia, ntia io. management of “watering can” perineum. east afr med j. 2007;84:283-86. 17. quattara k, koungoulba mb, cisse c. current status of urethral stricture in africa/apropos of 72 cases. ann urol. 1990:24;278-92. 18. obianuju nnamuchi. the nigerian social health insurance system and the challenges of access to health care: an antidote or a white elephant? med and law. 2009:28;125-66. 19. olajide ao, salako aa, aremu aa, eziyi ak, olajide fo, banjo oo. complications of transverse distal penile island flap urethroplasty of complex anterior urethral stricture. urol j. 2010;7:178-82. reconstructive urology u j 03 all-2.pdf 606 | point of technique pcnl approach for treatment of hydatid cysts of the kidney a new percutaneous treatment youness el harrech, najib abbaka, omar ghoundale, driss touiti corresponding author: youness el harrech, md service d’urologie, hôpital militaire avicenne, marrakech, morocco tel: +21 266 132 6160 e-mail: youness.elharrech@gmail.com received november 2011 accepted april 2012 department of urology, military hospital avicenne, marrakech, morocco point of technique keywords: introduction ydatid disease, caused by echinococcus granulosus, is a common health problem in ity.(1) rare, comprising only 2% to 4% of all cases.(2) (3,4) mebendazole and albendazole have been used as medical treatment, but their place in the management of the hydatid cysts remains controversial(5,6) and large series for the medical treatment of renal hydatid disease are not available in literature. case report 607vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l echinococcus granulosus. the patient refused any renal operation. percutaneous intertechnique under radiographic control. after the correct position of the structures embedded in gelatinous material came out of the ably useful to do an electrocautery of the germinal layer pcnl for renal hydatid cyst | el harrech et al figure 1. (a) computed tomography of the abdomen demonstrating a large cystic lesion of left anterior renal cortex with a well-defined wall and daughter cysts within, (b) computed tomography scan showing the association between the cyst and the kidney. figure 2. fluoroscopic guidance. opacification through the ureteral catheter allowed direct puncture of the cyst with fine needle (arrow) without crossing the pelvicaliceal system. arrow heads show the daughter cysts. 608 | months. the abdomen computed tomography scan repeated discussion there is no “best” treatment option for hydatid cyst and no clinical trial has compared all the different treatment moextrahepatic sites, the strength of recommendation is even cal recurrence of hydatid cyst after surgery reaches 30% and long hospitalization time after surgery is required.(4,7-9) ment of renal hydatid cyst. both, transperitoneal and retrospillage occurs during the operation using the transperitoneal route.(10) about the results of laparoscopy, and further studies of the long-term outcomes are necessary. injection of a scolicidal agent, and re-aspiration), various extensive use, the puncture of echinococcal cysts is still controversial mainly because of fear of anaphylaxis. neous treatment procedures, the overall fatality rate due to (11) figure 3. (a) multiple flimsy membranous structures embedded in gelatinous material came out of the sheath, (b) hydatid material aspirated. figure 4. endoscopic view showing a daughter cyst grasped by the forceps. point of technique 609vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l of medical and 0.01% of surgical inpatients. antibiotics concerned therapeutic classes. the overall fatality and allergic reactions to radiographic contrast rates are 0.001% to 0.009% and 1%, respectively.(12) lated to percutaneous treatment of hydatid cyst is an extremely rare event and is observed no more frequently than drug-related anaphylactic side effects. tent might improve the success rate and prevent the recurthe drug of choice to treat hydatid cyst, either alone or to(9) a fat-rich meal to increase its bioavailability, it should be toneal cysts. some authors recommend using albendazole (13) our patient received albendazole treatment regimen for three months. sive, and does not require long hospitalization. when the cur. the patient in this report had a huge hydatid cyst in the conflict of interest none declared. figure 5. the abdominal computed tomography scan repeated after 10 months showed no recurrence of cyst with persistent densification of perirenal fat. references 1. vuitton da. the who informal working group on echinococcosis. coordinating board of the who-iwge. parassitologia. 1997;39:349-53. 2. gogus c, safak m, baltaci s, turkolmez k. isolated renal hydatidosis: experience with 20 cases. j urol. 2003;169:186-9. 3. langer jc, rose db, keystone js, taylor br, langer b. diagnosis and management of hydatid disease of the liver. a 15year north american experience. ann surg. 1984;199:412-7. 4. sielaff td, taylor b, langer b. recurrence of hydatid disease. world j surg. 2001;25:83-6. 5. todorov t, vutova k, mechkov g, petkov d, nedelkov g, tonchev z. evaluation of response to chemotherapy of human cystic echinococcosis. br j radiol. 1990;63:523-31. 6. vutova k, mechkov g, vachkov p, et al. effect of mebendazole on human cystic echinococcosis: the role of dosage and treatment duration. ann trop med parasitol. 1999;93:35765. 7. schiller cf. complications of echinococcus cyst rupture. a study of 30 cases. jama. 1966;195:220-2. 8. saimot ag. medical treatment of liver hydatidosis. world j surg. 2001;25:15-20. pcnl for renal hydatid cyst | el harrech et al 610 | 9. franchi c, di vico b, teggi a. long-term evaluation of patients with hydatidosis treated with benzimidazole carbamates. clin infect dis. 1999;29:304-9. 10. khan m, sajjad nazir s, ahangar s, farooq qadri sj, ahmad salroo n. retroperitoneal laparoscopy for the management of renal hydatid cyst. int j surg. 2010;8:266-8. 11. neumayr a, troia g, de bernardis c, et al. justified concern or exaggerated fear: the risk of anaphylaxis in percutaneous treatment of cystic echinococcosis-a systematic literature review. plos negl trop dis. 2011;5:e1154. 12. vervloet d, durham s. adverse reactions to drugs. bmj. 1998;316:1511-4. 13. arif sh, shams ul b, wani na, et al. albendazole as an adjuvant to the standard surgical management of hydatid cyst liver. int j surg. 2008;6:448-51. point of technique 36 urology journal vol 4 no 1 winter 2007 miscellaneous diuresis renography for obstruction—taghavi et al urology journal vol 4 no 1 winter 2007 37 diuresis renography for differentiation of upper urinary tract dilatation from obstruction f+20 and f-15 methods rahim taghavi, kamran ariana, davoud arab introduction: the aim of this study was to evaluate diuresis renography with an intravenous injection of furosemide 20 minutes after administering the radiopharmaceutical (f+20 protocol) or 15 minutes before (f-15 protocol) in patients with upper urinary tract dilatation. materials and methods: twenty-one patients with pyelocaliceal system dilatation, but not ureteral dilatation, on ultrasonography were evaluated. the patients underwent diuresis renography using the f+20 and f-15 protocols. renal scan findings and kidney split function were recorded. then, the patients underwent surgical or conservative treatment according to their clinical conditions and imaging results. follow-up was done 3 and 6 months postoperatively by physical examination, intravenous urography, and diuresis renography. results: eleven patients (52.4%) had complete obstruction in both protocols of renography, and 5 (23.8%) had an equivocal result in the f+20 and an obstructive pattern in the f-15. these patients underwent surgical operation. in 3 patients (14.3%), both protocols demonstrated a normal urinary tract. in 2 patients (9.5%), a nonobstructive response in the f+20 and an equivocal result in the f-15 were seen. one of them underwent surgical operation because of impaired kidney function during the follow-up and 1 was treated conservatively. overall, obstruction was found in 16 out of 21 patients (76.2%) by the f-15 protocol, while it was found in 11 (52.4%) by the f+20 protocol (p = .01). the mean kidney split function was 55.15% ± 7.82% and 54.81% ± 6.87% in f+20 and f-15 protocols, respectively (p = .45). conclusion: using the f-15 protocol may reduce the equivocal results of the f+20 for diuresis renography. urol j (tehran). 2007;4:36-40. www.uj.unrc.ir keywords: diuresis renography, upper urinary tract, diuretics, pyelocaliceal system obstruction department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran corresponding author: rahim taghavi, md department of urology, imam reza hospital, mashhad, iran tel: +98 915 115 8472 fax: +98 511 859 1057 e-mail: r-taghavi@mums.ac.ir received january 2006 accepted december 2006 introduction diuresis renography was first used by o’reilly in 1978 and then by other urologists and radiologists as the method of choice for evaluation of the upper urinary tract.(1,2) this diagnostic tool can differentiate obstruction in the pyelocaliceal system from dilatation without obstruction.(3) the protocols used for this purpose include f+20, f-15, f+0, and combined f-15 and f+20 that are named according to the time of diuretic administration in relation to radiopharmaceutical injection.(4) however, none of these protocols is recognized as a standard method for the time of diuretic administration during renography.(5) some centers use the f-15 technique if the obstruction is suspected and some routinely use the f+20.(6,7) in both protocols, the preferred radiopharmaceuticals are technetium 36 urology journal vol 4 no 1 winter 2007 miscellaneous diuresis renography for obstruction—taghavi et al urology journal vol 4 no 1 winter 2007 37 tc 99m l,l-ethylenedicysteine (99mtc-ec) or 99mtcmercaptoacetyltriglycine (99mtc-mag3).(8) the f+20 protocol leads to 15% to 17% equivocal results and therefore, the alternative method of the f15 has been recommended to reduce this rate to 3%. (7,9-11) the use of the f-15 method results in a longer study period and bladder overdistension that may cause problems in the kidney drainage and misinterpretation of the results.(5) in a comparative study, we performed diuresis renography using the two protocols of f+20 and f-15 in patients with upper urinary tract dilatation. materials and methods patients between march 2004 and december 2005, we studied patients with pyelocaliceal system dilatation, but without ureteral dilatation, on ultrasonography. after physical examination and history taking, imaging and laboratory tests including serum creatinine level, urinalysis, and intravenous urography (ivu) or retrograde pyelography were done. patients without obstructive signs or obstruction due to urinary calculi were excluded. we enrolled 21 patients with pyelocaliceal dilatation on ultrasonography, delayed excretion, pyelocaliceal dilatation, nonvisualized ureter, and caliceal clubbing on ivu, and absence of contrast medium drainage from the pyelocaliceal system after the catheter removal on retrograde pyelography. all patients provided informed consent and the study was approved by the ethics committee of mashhad university of medical sciences, mashhad, iran. procedure diuresis renography was done to evaluate the kidney function and obstruction using the two protocols of f+20 and f-15 with an interval of 24 to 48 hours. first, the f+20 protocol was performed. the patient was recommended to drink 500 milliliter of water before the procedure. then, 99mtc-ec was injected intravenously and 20 minutes thereafter, furosemide (0.5 mg/kg for adults and 1 mg/kg for children) was administered. the patient was then evaluated by siemens gamma camera (siemens ag, erlangen, germany). about 24 to 48 hours after the first procedure, renography was repeated using the f-15 protocol. in this protocol, furosemide was administered 15 minutes before the injection of 99mtc-ec. in both protocols, bladder drainage was performed to prevent from false positive results. drainage curves in renal scans were recorded and classified in 4 patterns for the f+20 protocol and in 3 for the f-15 protocol (figure 1).(1,11,12) according to the diagnoses made, conservative treatment or surgical operation was carried out for each patient. the patients were followed up by physical examination and ivu or diuresis renography, 3 and 6 months after the treatment. the final diagnoses were made based on the clinical course, intraoperative findings, and follow-up findings, and the primary renography results were evaluated accordingly. statistical analyses for comparison of the renal scans, marginal homogeneity test was used and the results of kidney split function in the two protocols were compared by the paired t test. the statistical analyses were done using the spss software (statistical package for the social sciences, version 9.0, spss inc, chicago, ill, usa). a p value less than .05 was considered significant. results a total of 15 men and 6 women were enrolled in the study. the mean age of the patients was 25.0 ± 16.3 years. the chief complaints of the patients were flank pain in 17, hematuria in 2, and urinary tract infection in 2. the pyelocaliceal system dilatation was on the right and left sides in 6 and 15 patients, respectively. ultrasonography also demonstrated a reduction in the cortex thickness (severe reduction in 2 patients). in 19 patients, the ivu was performed and revealed a delay in excretion and dilatation in the pyelocaliceal system and nonvisualized ureter. in patients with high levels of serum creatinine, retrograde pyelography was performed and showed ureteropelvic junction obstruction (upjo). diuretic renal scans yielded by the f+20 and f-15 protocols showed the following results: eleven patients (52.4%) showed complete obstruction or obstructive response (pattern ii) in both protocols. five patients (23.8%) had an equivocal result (pattern iiib) in the f+20, while in the f-15, they had the obstructive pattern ii (figure 2). patients of these two groups underwent surgical operation and the diagnosis was upjo. intravenous urography or diuresis diuresis renography for obstruction—taghavi et al 38 urology journal vol 4 no 1 winter 2007 diuresis renography for obstruction—taghavi et al urology journal vol 4 no 1 winter 2007 39 figure 2. diuresis renal scan in a 15-year-old patient. left, equivocal result in f+20. right, apparent obstruction in f-15. figure 1. top, f-15 diuresis renography. i, nonobstructive; ii, obstructive; and iii, equivocal.(12) bottom, f+20 diuresis renography. i, normal; ii, obstructive; iiia, nonobstructive dilatation; iiib, equivocal; and iv, delayed decompensation.(1,11) diuresis renography for obstruction—taghavi et al 38 urology journal vol 4 no 1 winter 2007 diuresis renography for obstruction—taghavi et al urology journal vol 4 no 1 winter 2007 39 renography was performed 3 months postoperatively that showed improvement of the obstruction in all of the 16 patients. in 3 patients (14.3%), both protocols demonstrated an intact urinary tract (pattern i). in 2 patients (9.5%), a nonobstructive response (pattern iiia) in the f+20 and an equivocal result (pattern iii) in the f-15 were seen (figure 3). the patients in the latter group were followed up with diuresis renography 3 and 6 months postoperatively. one patient underwent surgical operation, because of impairment in kidney function and 1 was treated conservatively. overall, obstruction was found in 16 out of 21 patients (76.2%) by the f-15 protocol, while it was found in 11 (52.4%) by the f+20 protocol (p = .01). the mean kidney function (split function) was 55.15% ± 7.82% and 54.81% ± 6.87% in the f+20 and f-15 protocols, respectively. since the results of the both kidney function tests had normal distribution (kolmogorov-smirnov test), the paired t test was used for their comparison that showed a nonsignificant difference (p = .45). discussion diuresis renography is a noninvasive imaging tool for the evaluation of kidney function and urinary drainage.(2) the main objective of this method is differentiation of obstructive from nonobstructive dilatation.(3) primary investigations suggested the f+20 as the standard protocol; however, no gold standard exists. four classic types of response have been determined for the f+20 protocol (figure 1) including: i, normal response showing plummeted drainage curve before diuretic administration; ii, obstructive response showing lack of washout in spite of diuretic administration; iiia, nonobstructive response or dilatation without obstruction with a collapsing curve by diuretic administration; iiib, partial obstruction or massively dilated system in which the curve does not ascend as in obstructive pattern, but does not descend, either; and iv, delayed decompensation in which the primary washout is acceptable, but the curve flattens and even ascends.(1,11) in pattern iv, the flow rate reaches a level that cannot evacuate the urine, resulting in decompensation and more dilatation.(4) when patterns iiib or iv are seen in the f+20 renal scan, usually renography with f-15 protocol is recommended.(4,6) if hydration is fair and the singlekidney glomerular filtration rate (gfr) is greater than 16 ml/min, f-15 may reduce the equivocal results to 3% and when the single-kidney gfr is less than 16 ml/min, the response to the diuretic is suboptimal and more invasive diagnostic methods such as pressure flow study are warranted.(4) in the f-15 protocol, the most effective response to the diuretic is when the radiopharmaceutical is introduced into the pyelocaliceal system.(6,7) three forms of responses have been defined in the f-15 protocol (figure 1) that include: i, no obstruction; ii, obstruction; and iii, equivocal.(4,12) in a study by english and colleagues on 37 hydronephrotic kidneys using the two protocols of f+20 and f-15, it was shown that 77% of the cases with equivocal patterns and 13% of those with a nonobstructive pattern in the f+20 protocol were obstructive in the f-15.(12) foda and coworkers studied on 88 children with hydronephrotic kidneys and found that equivocal results in the f+20 significantly reduced by the f-15 protocol.(13) these figure 3. diuresis renal scan in a 56-year-old patient. left, nonobstructive hydronephrosis in f+20. right, equivocal result in f-15. diuresis renography for obstruction—taghavi et al 40 urology journal vol 4 no 1 winter 2007 studies suggest that f-15 is the method of choice when the diagnosis is equivocal in the f+20 protocol. in our study, diuresis renography was performed using these two protocols in patients with upper urinary tract dilatation, and we compared the results with the clinical and surgical findings and followup results. of 21 patients, 11 (52.4%) showed obstructive pattern in both protocols. five patients (23.8%) with equivocal patterns in the f+20 protocol had an obstructive pattern in the f-15. of these 5 patients, 4 had intermittent flank pain and pain after drinking water. they underwent pyeloplasty due to upjo. the patients’ symptoms relieved after the surgery and obstruction was improved. two patients had nonobstructive response or dilatation without obstruction in the f+20 who showed an equivocal pattern in the f-15. they both underwent renography 6 months later. one patient was operated due to impairment of kidney function and 1 underwent conservative treatment. obstruction was diagnosed in 52.4% and 76.2% of the patients by the f+20 and f-15 protocols, respectively. in our patients, the split function of the kidneys did not change with the protocol, which is in accordance with the findings of upsdell and associates.(14) conclusion diuresis renography is a noninvasive method for evaluation of the kidney function and dilatation of the upper urinary tract. the f+20 protocol is the routine method of diuretic injection and when the findings are equivocal, the f-15 is recommended. however, to reduce the costs and patients’ dissatisfaction, using the f-15 protocol might be recommendable as the first step for patients with upper urinary tract dilatation, especially those with flank pain after drinking liquids. however, further studies with evaluation of the positive and negative points of each method are warranted. conflict of interest none declared. references 1. o’reilly ph, testa hj, lawson rs, farrar dj, edwards ec. diuresis renography in equivocal urinary tract obstruction. br j urol. 1978;50:76-80. 2. adeyoju aa, burke d, atkinson c, mckie c, pollard aj, o’reilly ph. the choice of timing for diuresis renography: the f + 0 method. bju int. 2001;88:1-5. 3. turkolmez s, atasever t, turkolmez k, gogus o. comparison of three different diuretic renal scintigraphy protocols in patients with dilated upper urinary tracts. clin nucl med. 2004;29:154-60. 4. brown scw. nuclear medicine in the clinical diagnosis and treatment of obstructive uropathy. in: ell p, gambhir s, editors. nuclear medicine in clinical diagnosis and treatment. 3rd ed. philadelphia: churchill livingstone/elsevier; 2004. p. 1587-92. 5. liu y, ghesani nv, skurnick jh, zuckier ls. the f + 0 protocol for diuretic renography results in fewer interrupted studies due to voiding than the f 15 protocol. j nucl med. 2005;46:1317-20. 6. gulmi fa, felsen d, vaughan ed. pathophysiology of urinary tract obstruction. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 415-6. 7. upsdell sm, testa hj, lawson rs. the f-15 diuresis renogram in suspected obstruction of the upper urinary tract. br j urol. 1992;69:126-31. 8. muller-suur r, prigent a. radiopharmaceuticals: their intrarenal handling and localization. in: ell p, gambhir s, editors. nuclear medicine in clinical diagnosis and treatment. 3rd ed. philadelphia: churchill livingstone/ elsevier; 2004. p. 1501-12. 9. brown sc, upsdell sm, o’reilly ph. the importance of renal function in the interpretation of diuresis renography. br j urol. 1992;69:121-5. 10. zechmann w. an experimental approach to explain some misinterpretations of diuresis renography. nucl med commun. 1988 ;9:283-94. 11. o’reilly p, aurell m, britton k, kletter k, rosenthal l, testa t. consensus on diuresis renography for investigating the dilated upper urinary tract. radionuclides in nephrourology group. consensus committee on diuresis renography. j nucl med. 1996;37:1872-6. 12. english pj, testa hj, lawson rs, carroll rn, edwards ec. modified method of diuresis renography for the assessment of equivocal pelviureteric junction obstruction. br j urol. 1987;59:10-4. 13. foda mm, gatfield ct, matzinger m, et al. a prospective randomized trial comparing 2 diuresis renography techniques for evaluation of suspected upper urinary tract obstruction in children. j urol. 1998;159:1691-3. 14. upsdell sm, leeson sm, brooman pj, o’reilly ph. diuretic-induced urinary flow rates at varying clearances and their relevance to the performance and interpretation of diuresis renography. br j urol. 1988;61:14-8. 1341vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l the chiladiti bladder: an entity every urologists should know priyadarshi ranjan, saurabh sudhir chipde, abhishek yadav, rakesh kapoor keywords: urinary bladder; syndrome; cystostomy. introduction suprapubic catheterization (spc) is a routine procedure done in general and urological practice, where per urethral catheterization is not possible (urethral stricture, injury, vul-var carcinoma) or when we require long term alternative drainage (neurogenic bladder trauma to lower urinary tract or prostate abscess). the procedure is simple but blind one, and has the potential to injure the intestine, leading to peritonitis. we describe the radiological findings of such a bladder where bowel lies anterior and can get injured during suprapubic catheter placement. case report a 40-year-old gentleman presented to the emergency department after road side accident with acute urinary retention. a gentle attempt was done to pass a per urethral catheter which failed, so he was taken up for spc. though the bladder was palpable, needle aspiration 3 cm above symphysis pubis did not yield urine. a computed tomography scan done to assess abdominal injuries, showed bowel loops in the retropubic space anterior to bladder (figure). we placed spc in this patient through a mini-laparotomy, instead of a blind trocar procedure. discussion the abdominal chiladiti syndrome was initially described as a radiological finding of difcorresponding author: saurabh s chipde, md department of urology and kidney transplantation, sanjay gandhi post graduate institute of medical sciences, lucknow, india. tel: +91 8004 904 810 e-mail: drsaurabh07@rediffmail. com received february 2012 accepted august 2012 department of urology and kidney transplantation, sanjay gandhi post-graduate institute of medical sciences, lucknow, india. case report 1342 | case report ferential diagnosis of gas under diaphragm. it refers to the usually asymptomatic interposition of the bowel (usually hepatic flexure of the colon) between the liver and the diaphragm, which is seen in 0.1%-0.25% of chest x-rays.(1) factors contributing to its occurrence include redundant colon, as might be seen with chronic constipation or in bedridden individuals, eventration of the right hemidiaphragm, chronic lung disease and cirrhosis. similar physiology may account for the ‘bladder chiladiti syndrome’. normally the peritoneum covers the anterior 1/3rd and dome of bladder, but when the bladder becomes full, usually the peritoneum is displaced from the anterior aspect of bladder. thus in most patients, space anterior to bladder wall has no intestine, rendering trocar spc to be a safe procedure even when done without image assistance. however this may not occur in minority of patients. in obese patients, the retropubic space opens up where bowel segments can lie anterior to bladder. in patients, who have high intra-abdominal pressure, such as chronic cough, constipation, bladder outlet obstruction, intraabdominal space occupying lesions, this potential space may open up, allowing intrusion of bowel. these conditions may lead to bowel injuries during a nonimage guided spc. in these cases radiological imaging to confirm the condition, followed by open spc is advisable. to minimize the risk of spc, guidelines are already issued, like rapid response report by national patient safety agency in europe and guidelines by british association of urological surgeons.(2-4) conclusion the presence of bowel loops anterior to full bladder, can be termed as “chiladiti bladder” similar to the abdomen and should be suspected in patients when needle aspiration is negative. figure. abdominal ct scan demonstrates that the bowel loops can be seen anterior to the urinary bladder even in the distended state. note that the bowel loops are reaching up to the level of symphysis pubis. references 1. gupta m, gupta r, kielar a. intermittent type of chiladiti syndrome mimicking pneumoperitoneum. clin res hepatol gastroenterol. 2011;35:161-2. 2. accessed in: http://www.nrls.npsa.nhs.uk/resources/type/ alerts/?entryid45=61917&p=2 3. accessed in: www.npsa.nhs.uk/nrls/alerts-and-directives/rapidrr/ suprapubic-catheter. 4. harrison cws, lawrence wt, morley r, pearce i, taylor j. british association of urological surgeons’ suprapubic catheter practice guidelines. bju int. 2011;107:77-85. 442 | circumcision boys are born with a hood of skin, called the foreskin, covering the head of the penis. circumcision is the surgical removal of the foreskin (prepuce) from the penis. the circumcision generally heals in five to seven days. parents who decide circumcision often do so based on religious beliefs, concerns about hygiene, or cultural or social reasons. approximately, 55% to 65% of all newborn boys are circumcised in the united states each year. strong evidence demonstrates that circumcision decreases the risk of hiv (aids) infection in heterosexual men by 38% to 66% in populations that are at high risk. the world health organization currently recommends circumcision be recognized as an intervention as part of a comprehensive program for prevention of hiv transmission in areas with high endemic rates of hiv. other health benefits of circumcision include a decreased risk of urinary tract infections, a diminished risk of sexually transmitted diseases in men, protection against penile cancer, and a decreased risk of cervical cancer in female sex partners. see page 423 for full-text article stress urinary incontinence in women to hold urine and control urination, the lower urinary tract and nervous system need to be working normally. stress urinary incontinence is when sneezing, coughing, or laughing causes accidental urine leaks. stress urinary incontinence can happen at any age and it is amazingly common, affecting one in three women at some point in their lives. for some women, the risk of public embarrassment keeps them from enjoying many activities with their family and friends. urine loss can also occur during sexual activity and cause tremendous emotional distress. incontinence occurs because of problems with muscles and nerves that help to hold or release urine. stress urinary incontinence is fundamentally caused by insufficient strength of the pelvic floor muscles. there are several forms of effective treatment, including lifestyle changes, such as weight reduction, pelvic floor muscle training, and bladder training, so you can wait longer between needing to urinate and passing urine. conservative treatments, such as above-mentioned items, can improve stress urinary incontinence in women by two-thirds. if these treatments fail, several medications may be tried, and a growing number of different surgical techniques provide long-term benefits. see page 397 for full-text article urology for people what’s up in urology journal, winter 2012? urology for people urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. 1514 | isolated congenital megacystis with spontaneous resolution: an exceedingly rare entity farshid alizadeh keywords: urinarybladder;abnormalities;intestinaldiseases;colon;infant;newborn. introduction megacystisisarareconditionininfants,whichisusuallyassociatedwithrefluxingmegaureters,prune-bellysyndrome(pbs),infravesicalobstructionorpresentsas themegacystismicrocolonintestinalhypoperistalsissyndrome(mmihs). rarereven,isisolatedcongenitalmegacystis(icm).theetiologyofthisentityisunknown. myentericplexuspathology(1)andamildformofmmihs(2)havebeenproposedasplausible pathologies.hereweaddanothercasethatresolvedspontaneously. case report afull-term4-day-oldneonateboywasreferredtoourcenterbecauseofdelayedandinfrequentvoiding.hisfetalultrasoundhadshownadistended,thinwalledbladderwithouthydroureteronephrosis(hun)andoligohydramniosatweek32.hepassedmeconiumsoonafter birth,howeverdidnotvoidduringthefirst24hours.afterthisperiod,voidingstartedbut infrequently(threetofourtimesaday).ultrasoundstudyofabdomenshowedahugebladder with160mlofvolume.nohunorincreasedbladderwallthicknesswasobserved.serum creatininewasinthenormalrangethroughoutthefollow-up.urineculturewasnegativeand corresponding author: farshid alizadeh, md unit 10, no.22, 16th alley, shams abadi ave., isfahan, iran. tele: +98 311 2350532 e-mail: f_alizadeh@med.mui.ac.ir received november 2012 accepted march 2013 isfahan urology and kidney transplantation research center, isfahan university of medical sciences, isfahan, iran. case report case report 1515vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l isolated congenital megacystis | alizadeh thepatientdidnotdevelopurinarytractinfection(uti)duringthefollow-upperiod.physicalexaminationshowedno abnormalityinthegenital,rectalandsacralareas.neurologicalexaminationwasalsonormal. becauseofthelackofanysignsofbowelobstruction,the pediatricgastroenterologistdidnotrequestbariumenemaor rectalbiopsy.duringperformingthevoidingcystourethrography(vcug),thebabydidnotvoiduptothevolumeof 150mlandthecystogramshowedahugebladderwithout trabeculationorreflux(figure).theradiologiststoppedthe testatthisvolumebecauseofconcernregardingiatrogenic bladderrupture.therefore,therewasnourethrogramforthe evaluationoftheurethra. sincethebladderwallwassmoothandnohunwaspresent, wedecidednottoperformcystoscopy.instead,weadvised theparenttostartcleanintermittentcatheterization(cic). theywerereluctanttoacceptthissuggestion.therefore,we advisedthemtocomeforfrequentfollow-upwhileonantibioticprophylaxis.serialultrasoundshowedprogressive shrinkageofthebladder,reducingto80mlattheageofsix months.bowelhabitwasstillnormal. discussion reportedcasesoficmareveryfewwithdifferentclinical courseandmanagementstrategies. inamdarandcolleaguesreportedacaseof“vesicalgigantism”thatwasinitiallymanagedbybladdercatheterization, then cutaneous vesicostomy because of recurrent bladder distention, and later, by reduction cystoplasty due to high post-voidingresidualurine.(3)theybelievedthatthisentity may“resultsfromanexpansionoftheportionoftheurinary bladderthatdevelopsfromtheallantois”. shsimizu and colleagues reported another case that was managedexpectantlyuptotheageoffouryears,however, thechilddevelopedutiatthatage.ahypocontractiledetrusorandincreasedcomplianceweretheurodynamicfindings. rectalbiopsyrevealedhypoganglionosisofthesubmucous andmyentericplexuseswithoutthinningofthelongitudinal muscleandconnectivetissueproliferation.theymanaged thepatientbycicandproposedthatshemighthaveamild formofchronicintestinalpseudoobstructionsyndrome. recently another case report appeared in the literature, presentingacaseoficmthatresolvedbytheageofoneyear andremainedasymptomaticafterwardswithoutanytherapeuticintervention.(4) sinceicmisaveryrareentity,whenababyisbornwith megacystis, other more prevalent pathologies should be ruledoutfirst.pbsisdiagnosedbytheclassicpresentation ofabdominalmusculaturedefectandundescendedtestes. infravesicalobstructioncouldbediagnosedbyavcug.a completeneurologicalandgastrointestinalevaluationisalso mandatorytolookforanysignsofintestinalobstruction. urodynamicstudycoulddemonstratedetrusorhypocontractility,ifpresent.ifthereisnootheranomaly,thediagnosis oficmissuggested.managementofthesepatientsshould beindividualizedbasedonthepresenceofurinaryretention, highpost-voidingresidualurineanduti. cic,vesicostomyandobservationwithadministrationof antibioticprophylaxisareallviableoptions.regardlessof thechosentherapeuticoption,long-termfollow-upismandatory,becausetheclinicalcourseofthisentityisnotfully understood. conclusion theclinicalcourseinthiscasehighlightthefactthatnotall casesoficmneedextensivework-upandwhentheclinicalsettingjustifies,cystoscopy,urodynamicsandrepeated vcugscouldbeavoided. figure .voiding cystourethrography demonstrates a huge bladder without trabeculation or reflux. 1516 | references 1. perk h, serel ta, anafarta k, kosar a, uluoglu o, sari a. megacystis secondary to myenteric plexus pathology. presentation of two cases. urol int. 2001;67:313-5. 2. shimizu m, nishio s, ueno k, et al. isolated congenital megacystis without intestinal obstruction: a mild variant of chronic intestinal pseudoobstruction syndrome? j pediatr surg. 2011;46:e29-32. 3. inamdar s, mallouh c, ganguly r. vesical gigantism or congenital megacystis. urology. 1984;24:601-3. 4. johnson ek, nelson cp. spontaneous resolution of isolated congenital megacystis: the incredible shrinking bladder. j pediatr urol. 2013;9:e46-50. case report v08_no_2_final.pdf special feature 88 urology journal vol 8 no 2 spring 2011 evidence-based urology how does a randomized clinical trial achieve its designed goals? homayoun sadeghi bazargani,1 sakineh hajebrahimi2 purpose: to discuss the methodological considerations of a standard and applicable randomized clinical trial (rct). materials and methods: using a predefined strategy, we conducted systematic computerized search of the medline (1966 to 2011) and embase (1980 to 2011) databases to identify all english language educational articles discussing the rct methodological aspects. full text versions of identified studies were reviewed in blinded fashion for key methodological and statistical characteristics. results: randomized clinical trials in surgery are the highest level of the primary research evidence in evidence-based medicine. there is increasing demand for implementation of rcts in urological daily practice. conclusion: randomized clinical trials’ report should be absolutely clear, simple, and easy to understand with well-defined internal and external validity. efforts should be made to design high quality rcts in urology. there are substantial needs for urologists to their knowledge about rct. urol j. 2011;8:88-96. www.uj.unrc.ir keywords: randomized clinical trial, evidence-based medicine, urology 1rehabilitation & physical medicine research center, department of statistics and epidemiology, faculty of health and nutrition, tabriz university of medical sciences, tabriz, iran 2international evidence based urology working group, iranian center for evidence based medicine, tabriz university of medical sciences, tabriz, iran corresponding author: sakineh hajebrahimi, md international evidence based urology working group, iranian center for evidence based medicine, tabriz university of medical sciences, tabriz, iran tel: +98 411 336 7373 fax: +98 411 335 7328 e-mail: hajebrahimis@gmail.com received may 2011 accepted may 2011 approximately 1000 years earlier, avicenna (an iranian physician) wrote one of his “canon of medicine” book’s chapters entitled “the recognition of strengths of the medicines characteristics through experimentation”. avicenna had the first known treatise on clinical trials. almost 830 years later, fisher did his famous formal randomized clinical trial (rct).(1) randomized clinical trial is a research method, in which the participants are assigned either as intervention or control groups to compare the study results. randomized clinical trials make the foundation of systematic reviews, evidence-based practice guidelines, and health technology assessment in clinical practice. therefore, appropriate reporting of rcts’ results in published articles is very crucial. consolidated standards of reporting trials (consort) was initially recommended in 1996, which focused on sample size, randomization, allocation concealment, blinding, statistical analysis, primary and secondary (adverse events) outcomes, and overall generality of the evidence.(2) although rcts stay at the top of evidence hierarchy pyramid after systematic reviews, there is a big lack of evidence yet. of 4856 published articles in four leading urology journals from 1996 to 2004, only 4% were rcts, of which only 1% was a surgical rct.(3) according to consort statement, the quality of rcts has improved,(3) but still many evidence-based urology—sadeghi bazargani and hajebrahimi 89urology journal vol 8 no 2 spring 2011 fundamental problems may convert the gold standard position of rcts to bronze situates. furthermore, the strength of rcts depends on internal, external, and social validity of the study design. most of the published evidence of critically analyses of rcts have shown that results of rcts might be invalid. randomization, allocation concealment, blinding, clear statistical method of analysis (intention to treat), and follow-up period are unreported in most of the studies.(3,4) our aim was to demonstrate how an rct achieves its designed goals. this study also discusses limitations of surgical rcts and suggests some solutions. let’s start with a short clinical scenario a 75-year-old man comes to your office with severe lower urinary tract symptoms (luts) and recurrent urinary retention. diagnostic studies confirm outlet obstruction due to the prostate enlargement. your resident asks about effectiveness of green light laser in treatment of this old man. therefore, you intend to search for high quality evidence to support the best intervention. transurethral prostatectomy is considered as the gold standard surgical treatment for benign prostatic hyperplasia.(2) to our knowledge, a gold standard means an intervention or a test with highest effectiveness and reasonable cost, which has been demonstrated in some valid and relevant rcts. on the other hand, an rct is considered as the gold standard study for casualty for an interventional research question. in following sections, we are going to explain what makes an rct acceptable. are the results of the trial valid? (internal validity) what question did the study ask? to provide reliable evidence regarding a research question in any rct, it is quite crucial to have relevant reasonable objectives and to prioritize them based on clinical importance and reliability of the expected emerging evidence from each objective. other than the overall aim of the study, the specific objectives defined in clinical trial studies do not stand at the same level of importance. it is a quite consistent rule in designing middle-phase clinical trials to consider a single primary objective and possibly several secondary ones. the primary objective of an accurate clinical trial is based on estimating a clinically important outcome as objectively as possible. however, it is critical to know that the researcher should not trade off some important and relevant patient reported outcomes (pros) for some other less important ones, just due to lower objectivity in pros measures.(5) based on a relevant hypothesis for primary objective of the study, a primary efficacy variable is defined. it is also helpful to indicate the relevant endpoints. the secondary specific objectives are usually defined for outcomes of less clinical importance, less objective measurement, and those less expected to be affected by the intervention or drug. in designing of an rct, pico must be considered: patients or population, intervention, comparison, and outcomes. in the aforementioned scenario, patient (p): old man with severe luts and urinary retention, intervention (i): green light laser prostate resection, comparison (c): transurethral resection of the prostate (turp), outcome (o): symptoms and quality of life improvement. the sample size estimation is made to fulfill adequate statistical power to test the hypotheses correspondent with primary objective of the clinical trial. however, secondary objectives may passively benefit from power estimation for the primary objective. treatment allocation designs there are several treatment allocation designs in rcts, including parallel design, cross-over design, and sequential design, etc. here, we will only discuss the parallel and cross-over designs. the most popular design in rcts is the parallel design. methodologically, design, analysis, and interpretation of an rct with parallel design appears to be easier than other types.(6) in parallel evidence-based urology—sadeghi bazargani and hajebrahimi 90 urology journal vol 8 no 2 spring 2011 design, subjects in two or more groups (trial arms) are followed up in parallel to compare study outcomes. in this design, each participant is assigned to a single treatment strategy. most rcts consist of two arms. one arm is usually investigating a new treatment strategy, which can be called as test treatment or investigational treatment. the investigational treatment strategy may vary to be a new drug, a different dose of a drug, a different form of a drug, a surgical method, a medical device, an educational plan, a rehabilitation program, other types of interventions, or a combination of interventions. the subjects in second treatment arm may be assigned to an active treatment, which can be a standard treatment or a treatment with previous evidence to have some efficacy in treating the disease or condition of interest. alternatively, the subjects in the second treatment arm may be assigned to receive placebo or even no treatment. however, due to ethical obligations, active treatment is used in many clinical trials. this is of importance for studies on a serious condition for which at least one active treatment is available and known to have some benefits.(6) there may be also a treatment in common use or a traditional remedy. if the new treatment strategy is not compared to the active treatment, the question is raised whether to use placebo or no treatment. placebo seems to be vital if the clinical trial is going to be blinded. the second reason for prioritizing placebo to no treatment is the placebo effect. wikipedia defines placebo effect as follows: “sometimes patients given a placebo treatment will have a perceived or actual improvement in a medical condition, a phenomenon commonly called the placebo effect”. although there is some consistency regarding existence of placebo effect in terms of some subjective measurements, this may not be true for many other outcomes.(7-11) henry k. beecher was possibly the first scientist who quantified the placebo effect in 1955. nevertheless, later analysis of the data used by him showed that, contrary to his claim, no evidence of any placebo effect was found in any of the studies cited by him.(12) another fact to be considered is the possible risk in using placebos, which may be true in using sham surgery or injectable placebos.(13-18) transurethral resection of the prostate is a gold standard procedure. in this scenario, a patient who clinically needs a surgery (by consecration of ethical issues) may be put on green light laser of turp. a sham surgery as a control arm of surgical trials will be acceptable if all ethical issues followed well. in a cross-over design, each subject receives more than one treatment strategy and the order of receiving each treatment is randomized.(6) no doubt, a washout period should be defined between crossing the treatments, based on presumed effect decay rate for the treatments, to prevent additive or interactive effects of two consecutive treatments on the study outcome. each subject in a cross-over design serves its own control, which helps in decreasing the noise and confounding. therefore, smaller sample size is needed for a cross-over rct compared to a parallel design in similar conditions. on the other hand, if a cross-over design is applied, appropriate statistical methods should be used to properly manage the correlated nature of data. other than the limitations in defining a washout period, one major disadvantage of cross-over design is that it may not be practically used in acute conditions or if the outcomes occur only once. furthermore, care should be taken of the diseases like multiple sclerosis having recurrent periods of exacerbations and remissions by nature. millar introduced another drawback of cross-over design where treatment effects become distorted by and confounded with their order of administration, and proposed its prevention.(19) was the assignment of patients to treatments randomized? randomization is a process through which study subjects are assigned to different trial treatments only by chance. control of unknown confounders is the popular, but not the sole advantage of randomization.(20) method of randomization is dependent on sample size, end points, confounding, and prognostic factors. there are several types of randomization in clinical trials.(21) two types of randomization evidence-based urology—sadeghi bazargani and hajebrahimi 91urology journal vol 8 no 2 spring 2011 well-known by the researchers are simple and blocked randomization. in simple randomization, subjects are assigned to treatment strategies by chance. the probability for any eligible nominee would be nonzero without any restriction. it is an easy to do method using random tables even if computer programs are not available. the main drawback in such a randomization strategy is the lack of guarantee for number of subjects in each group to be equal or follow a predefined proportion. if the sample size is large enough, this is not a major concern, but in case of a small sample size, this may lead to some problems. other than design limitations, it may lead to loss of statistical power. blocked randomization, another popular method among researchers, makes it possible to assign subjects to either equal or predefined size of blocks and trial arms. other than what we discussed about equal-sized study groups in simple randomization, blocked randomization has the possibility of a blinded or open label analysis at the end of each block. this may help re-estimate sample size early through the study when the information used for sample size calculation prior to start of the clinical trial appears to be doubtful. another advantage in blocked randomization is that if, for any reason, the rct is stopped before achieving the full enrollment, higher power of study may be reached in case of blocked randomization. nevertheless, one major concern in blocked randomization is allocation predictability in some subjects.(22,23) one acceptable alternative for simple and blocked randomization in case of small sample size and concern on confounding can be the minimization method. although minimization may not be defined as a pure randomization, but has proven to yield reliable results.(24-26) random assignment of participants to study or control group produces comparable groups at the end of the study and ensures that the mere difference between groups is due to intervention. it means each group is a random sample of eligible study subjects; hence, both are representative of that population. equalization of the numbers in the groups is not enough in our scenario; one includes number of patients with moderate luts and other includes same number of severe luts, or younger people in one group versus older ones in the other group. in such situations, stratified recruitment with respect to severity of disease and age must be done. were the groups similar at the beginning of the trial? after an appropriate randomization, we need to separate the person who generates allocation from those who accesses eligibility. in other words, allocation should be concealed by using third party schemes, including pharmacy randomization, telephone randomization service, web-based service, or sealed and opaque envelopes. allocation concealment must be done in patient selection phase, but blinding is in process phase and for intervention. were measures objective or were the patients and clinicians “blinded” to the administered treatment? blinding is a key point in many rcts to reduce information or ascertainment bias. if study subjects are not blinded, knowing which group they are assigned to, may affect their responses to the received intervention. possibly, knowing that they have been assigned to a group who will receive a new treatment may lead to favorable expectations or anxiety. blinding those involved in conducting the research, including investigators, physicians, patient enrollers, randomization implementers, health-care providers, and routine data collectors, is also important.(27) blinding turns vital if the outcome of interest is more subjective while its necessity decreases for more objective outcomes. although blinding is a familiar word among clinical researchers, there seems to be some confusion in understanding the terminology of blinding, such as single-, doubleand triple-blind, masking, and allocation concealment.(28) schulz and colleagues state: blinding (masking) indicates that knowledge of the intervention assignments is hidden from participants, trial investigators, or assessors. while, non-blinded (open or open label) denotes trials in which evidence-based urology—sadeghi bazargani and hajebrahimi 92 urology journal vol 8 no 2 spring 2011 everyone involved knows who has received which interventions throughout the trial.(28) single-blind usually means that participants are blind to the treatment type and stay blind throughout the study period. in a double-blind trial, study subjects, investigators, or assessors usually remain unaware of the intervention assignments throughout the study.(29) in a triple blind rct, the statistician is also blind to the assignment type. some authors have also used triple-blind terminology instead of double-blind when the assessors and investigators have been separate. in such a scenario, if the statistician is also blinded, authors may get persuaded to use quadruple blinding and some have also dared to define quintuple blinding.(27) we think that more important than the terminology used in reporting clinical trials is to clearly explain how the blinding is done in the trial and whether the blinding process remained perfect or not. as discussed earlier, use of placebos compared to no-treatment strategy has at least advantage of making the blinding possible. in clinical research fields, there are situations in which drugs cannot be formulated in a way to ensure similar galenical forms in trial arms. for example, a tablet form of a new drug needs to be compared with another form of an active treatment, eg, capsule or topical ointment. this limitation prevents a simple blinding. in such a situation, a technique called as “double-dummy technique” may be used. a placebo is produced similar to the drug in investigational group and is added to the treatment protocol in active control group. vice versa, a placebo is produced similar to active treatment and will be added to treatment protocol in investigational group. this will help do the blinding, but the number of tablets for instance is increased, reducing compliance of patients.(30) one last note we would like to add is that blinding itself is not a golden guarantee for the rct. thus, a well-designed rct with relevant methodology should not be disqualified due to lack of blinding. application of blinding is after allocation and in procedural phase. therefore, to reduce the emotional effects of the studies, patients have to be blinded to their interventions. however, in most of the surgical trials, blinding of surgeon is impossible. in this situation, outcome assessor should be an independent and blind investigator. therefore, the term of doubleblind in surgical trials is meant as blind patient and outcome assessor. what were the results? it is not uncommon to read an rct with strong conclusions on efficacy of a new treatment, but using only a chi-square test performed as a statistical method resulting in a p value less than .05. this is not the sole pitfall in statistical methodology of published clinical trials and many other examples can easily be found in literature. in this study, we only focus on two statistical considerations crucial to rcts. how large was the treatment effect? when a difference in primary outcome of an rct is observed, the first question will be, “how likely the observed difference is to be by chance?” this can be easily answered using an appropriate statistical test. suppose you are comparing the efficacy of two different surgical procedures (a and b) in treating vesicoureteral reflux and find out that of 80 patients in group a, 40 gained successful treatment, while 20 out of 80 patients in group b achieved successful results. the descriptive statistics are indicative of a difference in success rate between the treatments. as we know, this difference is only observed in our sample and we do not know how likely it would occur in reality in a larger population. this is a random error term which may be understood by p value, but can be derived using a statistical test. the most common statistical test in this situation would be a chi-square test that gives us a p value equal to .001. this means that we have found an association, which is less likely to be due to chance. we call this “assessing randomness of association”. a major flaw is to stop the analysis here and make conclusions only based on these results. the chi-square test gives us a measure of randomness of association, but we may prefer to have a static for strength of association. clinicians prefer to choose a evidence-based urology—sadeghi bazargani and hajebrahimi 93urology journal vol 8 no 2 spring 2011 procedure with a clear effectiveness compared to placebo. sometimes a statistically significant outcome is not clinically important and the results may not be applicable. what was the measure? several measures of strength of association have been developed; three most important of which are discussed here. a: relative risk (rr): in epidemiology, rr is the risk of developing a disease relative to exposure. it is a ratio of risk in one group over the risk in another group. in clinical trials, we may consider it as probability of success for investigational treatment over probability of success for the comparison treatment strategy. a relative risk of 1 means there is no difference in risk between the two groups or it means no difference between treatment strategies in clinical trials. relative risk greater than one suggests higher efficacy of investigational treatment. in preventive clinical trials, like vaccine research, rr is usually expected to be lower than one for the investigational intervention or vaccine. b: risk difference (rd): contrary to rr which is a ratio, rd is an absolute risk measure which is obtained by subtracting risk in one group from the risk in second group. no doubt, many clinicians may be interested in studying the absolute difference in success rates rather than relative success rates when comparing efficacy of treatment strategies. c: number needed to treat (nnt): the number of subjects need to be treated ensuring one subject to benefit compared with a control in a clinical trial. for example, if nnt = 3, it means that if three patients get the treatment, one of them will benefit from that treatment compared to control. the larger the nnt, the lower the effectiveness will be. the best nnt is considered to be 1, where everyone achieves success with investigational treatment and no one with control. in our scenario, if the nnt of green light laser versus turp is 2, it means the number of patients need to be treated ensuring one subject symptom improvement just because of green light is 2, and if we treat two patients with green light, one is going to have expected outcome. contrary to rr and rd, nnt is a measure of effectiveness rather than efficacy, making it more attractive for clinicians and health technology policy makers. epidemiologists may be more interested in rr, but nnt can be an easy to understand and more beneficial index for clinicians. number needed to treat is calculated by inversing the rd. as nnt is derived from rd, we recommend the researchers to report rr and nnt in their reports. it should be taken into account that it is not sufficient to calculate the point estimates of rr, rd, and nnt. we should have an idea how precise the calculated rr, rd, and nnt are. if we have 10 times larger sample size, but with the same response proportions, rr and nnt would also be the same while the results of a larger study can be more reliable. the solution is to estimate some confidence interval (ci) measures of rr and nnt as well. statistical software packages easily provide you with required statistics. table demonstrates the calculated statistics for the two examples. were all the patients who entered the trial accounted for? were they analyzed in the groups to which they were randomized? non-adherence may be an inevitable part of many clinical trials, especially the effectiveness trials, trials with long-term treatment, and when the treatments used are more likely to have adverse effects. follow-up period should be long enough group success failure total rr rd nnt example 1 a 40 40 80 rr = 2 95%ci: 1.3 to 3.1 rd = 0.25 95%ci: 0.1 to 0.4 nnt = 4 95%ci: 2.5 to 10.0b 20 60 80 example 2 a 400 400 800 rr = 2 95%ci: 1.7 to 2.3 rd = 0.25 95%ci: 0.2 to 0.3 nnt = 4 95%ci: 3.3 to 8.0b 200 600 800 two examples of calculating rr, rd, and nnt rr indicates relative risk; rd, risk difference; nnt, number needed to treat; and 95%ci, 95% confidence interval. evidence-based urology—sadeghi bazargani and hajebrahimi 94 urology journal vol 8 no 2 spring 2011 in all rcts; however, there is no ideal definition. on the other hand, all subjects in both groups should be followed up until the end of the study. therefore, the follow-up period has to be long enough and complete. suppose the researcher is going to test the effect of tolterodine on sexual function in women with overactive bladder. the drug is hypothesized to improve sexual function independently or through improving overactive bladder.(31) the patients need to be followed up for several months. imagine you do an rct to compare this drug with another new treatment. despite the researchers wish, the situation may be such that few patients after randomization might discontinue the administered drug or shift to the comparison treatment to which they are not assigned to. using drugs different from what were allocated during the randomization violates the principle of randomization and may introduce confounding. several methods are proposed to handle this problem.(32) 1“intent (ion) to treat” analysis: this approach is the most common method to handle such a problem. the non-adherence is ignored and participants are compared through the analysis based on early randomization results. this method well resolves the problem of confounding due to violation of randomization. however, effect size underestimation is the main limitation of this method.(32) actually, intent to treat analysis can be considered as a measure of effectiveness rather than efficacy. 2“as treated analysis”: the analysis is based on the actual treatment received by the patient ignoring the randomization. no doubt, confounding variables associated both with adherence and outcome will be a major issue in this method. measuring such confounders and controlling them, through possibly multivariate analysis, will be a necessity in this regard. 3“per-protocol” analysis: in this method, non-adheres are eliminated from the analysis. this method may introduce confounding effect more than “as treated” analysis. there may be some instances that non-adherence is due to satisfaction with the treatment and resolution of the main problem in shorter time than expected. therefore, the patient may stop the treatment and not continue with the study. using a per-protocol analysis will lead to underestimation of effect size or loss of statistical power of the study. adalatkhah and colleagues performed a dermatological rct on moderate acne comparing two drugs. they found that the time to improvement is shorter for new drug and checking multiple measurements showed that some of those who received the new drug felt treated and stopped taking more tablets. a per-protocol analysis or pessimistic permutation of missing data in such a situation may reasonably underestimate the efficacy of new drug. therefore, a new terminology as “logical intent to treat analysis” to prevent this problem has been presented.(32) how precise was the estimate of the treatment effect? although p value could show statistical differences between two groups, but for the size and importance of difference, ci is crucial. the true risk of the outcome in the population is not known and the best we can do is to estimate the true risk based on the sample of patients in the trial. this estimate is called “the point estimate”. by looking at ci, we could know how close this estimate is to the true value. if the ci is narrow, then we can be confident that our point estimate is a precise reflection of the population value. the ci also provides us with information about the statistical significance of the result. if the value corresponding to no effect falls outside the 95% ci, then the result is statistically significant at the .05 level. by having a ci even statistically non significant, outcome might be clinically significant. in this situation, we could know how much ci is shifted to true positive rather than true negative. will the results help me in caring for my patient? (external validity/applicability) to apply the results of the study to your patient, before making any clinical decision, you have to evidence-based urology—sadeghi bazargani and hajebrahimi 95urology journal vol 8 no 2 spring 2011 answer to following questions: is my patient similar to those in the study that its results can be applied? is the treatment available, accessible, acceptable, and affordable in my setting? to make a good clinical decision, you have to make sure that new intervention’s benefit is superior to its potential harm in your individual patient. in our scenario, even with acceptable nnt of green light versus turp, applicability of new treatment should be evaluated. take-home message and conclusion a couple of high quality rcts are necessary for a clinical decision making in application of a new technique. it means green light laser can be applicable if: 1) patient oriented characteristics of rct are similar to your patient. 2) randomization and concealment are reported. 3) it is blinded. 4) it is controlled by a placebo, sham, or gold standard group. 5) there is a defined, long enough, and complete follow-up period. 6) patient is oriented to the endpoint. 7) intention to treat and sub group analyses are done (if applicable). 8) clinically importance and effects size are demonstrated by absolute risk difference, nnt, and ci. conflict of interest none declared. references 1. sajadi mm, mansouri d, sajadi mr. ibn sina and the clinical trial. ann intern med. 2009;150:640-3. 2. begg c, cho m, eastwood s, et al. improving the quality of reporting of randomized controlled trials. the consort statement. jama. 1996;276:637-9. 3. scales cd, jr., norris rd, keitz sa, et al. a critical assessment of the quality of reporting of randomized, controlled trials in the urology literature. j urol. 2007;177:1090-4; discussion 4-5. 4. jüni p, altman dg, egger m. assessing the quality of controlled clinical trials. bmj. 2001;323:42-6. 5. hanson bp. designing, conducting and reporting clinical research. a step by step approach. injury. 2006;37:583-94. 6. domanski mj, mckinlay s, ovid technologies i. successful randomized trials: a handbook for the 21st century: lippincott williams & wilkins; 2009.p.21-26. 7. hrobjartsson a, gotzsche pc. powerful spin in the conclusion of wampold et al.’s re-analysis of placebo versus no-treatment trials despite similar results as in original review. j clin psychol. 2007;63:373-7. 8. hrobjartsson a, gotzsche pc. is the placebo powerless? update of a systematic review with 52 new randomized trials comparing placebo with no treatment. j intern med. 2004;256:91-100. 9. hrobjartsson a, gotzsche pc. placebo treatment versus no treatment. cochrane database syst rev. 2003cd003974. 10. furukawa ta. review: placebo is better than no treatment for subjective continuous outcomes and for treatment of pain. acp j club. 2002;136:20. 11. hrobjartsson a, gotzsche pc. is the placebo powerless? an analysis of clinical trials comparing placebo with no treatment. n engl j med. 2001;344:1594-602. 12. kienle gs, kiene h. the powerful placebo effect: fact or fiction? j clin epidemiol. 1997;50:1311-8. 13. antal j. [medical and ethical considerations of sham operation]. magy seb. 2007;60:233-8. 14. clark pa. sham surgery: to cut or not to cut--that is the ethical dilemma. am j bioeth. 2003;3:66-8. 15. horng s, miller fg. ethical framework for the use of sham procedures in clinical trials. crit care med. 2003;31:s126-30. 16. macklin r. the ethical problems with sham surgery in clinical research. n engl j med. 1999;341:992-6. 17. miller fg. a response to commentators on “sham surgery: an ethical analysis”. am j bioeth. 2003;3:w36. 18. miller fg. sham surgery: an ethical analysis. sci eng ethics. 2004;10:157-66. 19. millar k. clinical trial design: the neglected problem of asymmetrical transfer in cross-over trials. psychol med. 1983;13:867-73. 20. shadish wr, cook td, campbell dt. experimental and quasi-experimental designs for generalized causal inference: houghton, mifflin and company; 2002.p.253. 21. efird j. blocked randomization with randomly selected block sizes. int j environ res public health. 2011;8:15-20. 22. berger vw. do not use blocked randomization. headache. 2006;46:343; author reply -5. evidence-based urology—sadeghi bazargani and hajebrahimi 96 urology journal vol 8 no 2 spring 2011 23. toorawa r, adena m, donovan m, jones s, conlon j. use of simulation to compare the performance of minimization with stratified blocked randomization. pharm stat. 2009;8:264-78. 24. xiao l, lavori pw, wilson sr, ma j. comparison of dynamic block randomization and minimization in randomized trials: a simulation study. clin trials. 2011;8:59-69. 25. han b, enas nh, mcentegart d. randomization by minimization for unbalanced treatment allocation. stat med. 2009;28:3329-46. 26. schulz kf, grimes da. blinding in randomised trials: hiding who got what. lancet. 2002;359:696-700. 27. bang h, ni l, davis ce. assessment of blinding in clinical trials. control clin trials. 2004;25:143-56. 28. schulz kf, chalmers i, altman dg. the landscape and lexicon of blinding in randomized trials. ann intern med. 2002;136:254-9. 29. nahler g, mollet a. dictionary of pharmaceutical medicine. 2 ed. new york: springer; 2009.p.55. 30. hajebrahimi s, azaripour a, sadeghi-bazargani h. tolterodine immediate release improves sexual function in women with overactive bladder. j sex med. 2008;5:2880-5. 31. weiss ns. clinical epidemiology. in: rothman kj, greenland s, lash tl, eds. modern epidemiology: lippincott williams & wilkins; 2008:519-28. 32. adalatkhah h, sadeghi-bazargani h, pourfarzi f. flutamide versus cyproterone acetate / ethinyl estradiol combination in moderate acne: a pilot clinical trial. clinical, cosmetic and investigational dermatology 2011(in press) v08_no_3_final.pdf female urology 209urology journal vol 8 no 3 summer 2011 salvage repair of vesicovaginal fistula aliasghar yarmohamadi, mohammad asl zare, hassan ahmadnia, nasser mogharabian purpose: to present the long-term results of failed vesicovaginal fistula repair using flap splitting techniques. materials and methods: nine women with a previous failed vesicovaginal fistula repair, aged 18 to 69 years, underwent salvage vaginal reconstruction for damaged urethra or bladder, at a five-year interval lasting from 2003 to 2007. fistulas were repaired using an interposed pediculated vaginal wall flap. results: the repair was successful in all the patients, even in those with rectovesicovaginal fistula or a large vesicovaginal fistula with sphincter damage. conclusion: pediculated vaginal wall flap is an easily-prepared, well– vascularized tissue, which provides long-term favorable outcomes. urol j. 2011;8:209-13. www.uj.unrc.ir keywords: recurrence, urologic surgical procedures, surgical flaps, vaginal fistula, treatment outcome mashhad university of medical sciences, mashhad, iran corresponding author: aliasghar yarmohamadi, md mashhad university of medical sciences, mashhad, iran tel: +98 511 801 2857 fax: +98 511 841 7404 e-mail: yarmohamadiaa@mums.ac.ir received january 2011 accepted june 2011 introduction a fistula represents an extraanatomic communication between two or more epithelium or mesothelium-lined body cavities or to the skin surface (figure 1). (1) urogenital fistula may be congenital or acquired. vesicovaginal fistulas (vvfs) are the most common type of acquired fistula of the urinary tract.(1-3) the etiology of vvfs differs in various parts of the world.(4) in industrialized world, the most common cause (>75%) of vvf is injury to the bladder at the time of gynecologic, urologic, or other pelvic surgeries (iatrogenic). malignant diseases, pelvic irradiation, and obstetric trauma, including forceps lacerations and the uterine rupture, are other important causes.(1,5,6) in the developing world, where routine perinatal obstetric care may be limited, vvfs most commonly result from prolonged obstructed labor.(1,5) vesicovaginal fistulas may be repaired through a transvaginal or transabdominal (transvesical) approach.(1,4,6) there is no “best” approach for all the patients with vvf, and excellent outcomes can be expected with both approaches, depending on the particular circumstances of the fistula.(1,4,6) although factors, such as size, location, and need for adjunctive procedures often have an impact on choosing the approach, the most important factor is usually the surgeon’s preference.(1,6,7) the majority of vvfs in the industrialized world are amenable to a transvaginal repair.(6) there is a consensus that the best chance for success is the first surgery. (1,4,8,9) two main subgroups of transvaginal repairs are flapsplitting technique and latzko procedure.(6,9) vesicovaginal fistula repair—yarmohamadi et al 210 urology journal vol 8 no 3 summer 2011 our aim was to present the long-term results of failed vvf repair using flap splitting techniques. materials and methods from january 2003 to january 2007, 9 women with previous failed vvf repairs, aged 18 to 69 years, were recruited to this study. the first and youngest subject was an 18-year-old girl, who had a large rectovesicovaginal fistula due to a penetrating trauma to her perineum during cycling, which resulted in total urinary, fecal incontinence, and several unsuccessful surgical repairs. three patients were young women aged 20, 22, and 23 years with a vvf due to delivery at home. another subject was a 19-year-old woman with a vvf due to dystocia and use of devices during delivery at hospital. the next patient was a 29-year-old woman with a history of postpartum stress urinary incontinence (sui) treated with sling surgery. persistent urinary retention occurred immediately after the operation, which has been treated with transurethral resection of the bladder neck. thereafter, she became totally incontinent because of a large urethrovesicovaginal fistula. the last three subjects were 52, 57, and 69-yearold women with vvfs following treatment of the uterine cervix cancer with hysterectomy and adjuvant radiotherapy. all of the patients were evaluated in the same manner. initially, voiding cystourethrography and intravenous pyelography were performed. thereafter, cystoscopy and vaginoscopy were carried out to evaluate the exact size, number, and location of the fistula, and biopsy if there was any history of malignancy to rule out cancer relapse. finally, we did the main surgical procedure in jackknife position, using a pediculated vaginal wall flap technique (figure 2). we did not use other types of flap, such as maritus. figure 2. vaginal wall flap technique for transvaginal vvf repair. figure 1. vesicovaginal fistula before repair. vesicovaginal fistula repair—yarmohamadi et al 211urology journal vol 8 no 3 summer 2011 because the patients were unable to keep their bladder full, we could neither assess their bladder’s capacity nor perform urodynamic study to evaluate coincidental sui. however, after the recovery from the surgery, we did so and there was only mild to moderate sui (urodynamically defined as leak point pressure more than 60 cm h2o) in 4 patients. fistulas repairs were done using classic method (figure 2). indwelling urethral catheters were kept in all the patients postoperatively until cystography confirmed successful repair of the fistula (figure 3). imaging studies were done 10 to 21 days postoperatively or if necessary, including persistent urine leakage. anticholinergic medications were given to decrease the bladder irritability. sexual intercourse was forbidden for 3 months postoperatively. results demographic and clinical characteristics of the patients are demonstrated in table. the patients were followed up for 51 to 100 months. physical examination and urodynamic studies were performed annually for at least 3 years to ensure vaginal and urethral integrity, and exclude any obstruction due to urethral stricture. significant vaginal shortening and stenosis were not observed. urethral integrity and patency were restored in all the patients, with no incontinence. patients were able to empty their bladder voluntarily and completely. patients with combined vvf repair and urethral elongation, subsequently underwent a young diz operation. all of the patients received short-term (3 months) oral anticholinergic to prevent postoperative detrusor hyperactivity. we performed urodynamic study 3 months postoperatively. four patients had mild to moderate sui, who were treated successfully with conservative measures, such as kegel exercises. patients, number age, number of previous repair fistula predisposing factors outcome 1 18 3 rectovesicovaginal penetrating trauma excellent 2 20 2 vesicovaginal delivery at home (obstructed labor) excellent 3 22 2 vesicovaginal delivery at home (obstructed labor) excellent 4 23 3 vesicovaginal delivery at home (obstructed labor) excellent 5 19 2 vesicovaginal dystocia and use of devices during delivery at hospital excellent 6 29 4 vesicovaginal sling surgery for stress urinary incontinence excellent 7 52 2 vesicovaginal endometrial cancers with hysterectomy and adjuvant radiotherapy excellent 8 57 2 vesicovaginal endometrial cancers with hysterectomy and adjuvant radiotherapy excellent 9 69 2 vesicovaginal endometrial cancers with hysterectomy and adjuvant radiotherapy excellent demographic and clinical characteristics of the patients figure 3. vesicovaginal fistula after repair. vesicovaginal fistula repair—yarmohamadi et al 212 urology journal vol 8 no 3 summer 2011 discussion vesicovaginal fistula is an abnormal opening between the bladder and vagina, causes urine leakage from the vagina.(1,2) intra-operative injury to the urinary bladder is clearly a primary risk factor for subsequent development of a postoperative vvf.(6,9) other risk factors include prior uterine surgery (cesarean section), endometriosis, infection, diabetes mellitus, arteriosclerosis, pelvic inflammatory disease, and prior radiation therapy.(1,10) patients with vvf often complain from painless urinary incontinence, which occurs all the time. (10) patients with anatomical urethral damage have usually been repeatedly operated and present with severe incontinence that is difficult to treat. therefore, a thorough clinical and radiological evaluation is required to precisely define the extent of the anatomical defect and to assess the surrounding tissues that might be used in the reconstructive procedures.(6,11,12) repair is usually undertaken 8 to 12 weeks after the injury. this time delay allows resolution of wound inflammation prior to attempting corrective surgery. in postmenopausal patients, estrogen replacement prior to surgery may improve the chance of successful closure. it has been stated that the best opportunity to achieve successful repair of a vvf is with the initial operation. previous failed attempts result in scar formation and anatomic derangement, and may compromise potential reconstructive flaps. therefore, careful pre-operative planning is essential to maximize the chance for a successful result. the low-lying fistula (subtrigonal) is best repaired through the vaginal approach.(7) the indications for tissue interposition are not well-defined, but these measures are most commonly used in the setting of irradiated tissues, obstetric fistulas, failed prior repairs, large fistulas, and fistulas with tenuous repairs. vaginal flap or flap-splitting technique popularized by raz and colleagues results in a three-layer closure without the use of an adjuvant flap and a four-layer closure if a flap is used. it can be performed as an outpatient procedure and is applicable to the most simple, uncomplicated vvfs.(1) anterior vaginal wall usually provides sufficient tissue, especially in primary cases, to cover adequately the urethral or vesical defects. after careful dissection and removal of all scar tissues from the fistula opening, mobilization, and good closure of the communicated organs, the vaginal wall flap is interposed between layers of repair, enhancing secure healing, and is compatible with the classic surgical principles for the fistula repair. (6) anatomical reconstruction of the damaged urethra can be achieved by using mucosal flaps from the vagina alone or with the interposition of surrounding healthy tissues that can be easily mobilized and transferred to the desired position, aiming at a significant improvement of the postoperative outcome.(5) there is no controversy concerning the necessity to interpose well-vascularized flaps between the layers of fistula closure that enhance the healing and secure a watertight repair in cases of complex vvf or previously failed repairs and in those with anatomical urethral defect.(10) the main factor in correcting a vvf is to separate communication between the bladder and vagina. (1) this can be accomplished by interpositioning tissues between the two damaged organs and obtaining a watertight tension-free closure.(4,9,10) the success rate of repairing vesicovaginal and ureterovaginal fistulas through vaginal approach is 90%.(1,7) early repair using a transvaginal approach is recommended.(10) conclusion the vaginal pediculated wall flap is easy to dissect, is close to the operative field, and its use does not cause any cosmetic, sexual, or functional problems for the patient. conflict of interest none declared. references 1. rovner es. urinary tract fistula in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbellwalsh urology. vol 3. 9 ed. philadelphia: saunders 2007:2322-90. 2. zafirakis hg, westney ol. vesicovaginal fistula. vesicovaginal fistula repair—yarmohamadi et al 213urology journal vol 8 no 3 summer 2011 in: glenn jf, ed. glenn’s urologic surgery. 7 ed. philadelphia: lippincott williams & wilkins; 2010: 130-7. 3. webster gd, sihelnik sa, stone ar. urethrovaginal fistula: a review of the surgical management. j urol. 1984;132:460-2. 4. hohenfellner r. commentary: management of vesicovaginal fistula. in: whitehead ed, leiter e, eds. current operative urology. harper and row, philadelphia 1984:981-5. 5. hendren wh. construction of female urethra from vaginal wall and a perineal flap. j urol. 1980;123: 657-64. 6. eilber ks, kavaler e, rodriguez lv, rosenblum n, raz s. ten-year experience with transvaginal vesicovaginal fistula repair using tissue interposition. j urol. 2003;169:1033-6. 7. zimmern pe, hadley hr, raz s. [vaginal approach to non-irradiated vesicovaginal fistula]. j urol (paris). 1984;90:355-9. 8. flisser aj, blaivas jg. outcome of urethral reconstructive surgery in a series of 74 women. j urolo. 2003;169:2246-9. 9. kirschner cv, yost kj, du h, karshima ja, arrowsmith sd, wall ll. obstetric fistula: the ecwa evangel vvf center surgical experience from jos, nigeria. int urogynecol j pelvic floor dysfunct. 2010;21:1525-33. 10. ijaiya ma, rahman ag, aboyeji ap, et al. vesicovaginal fistula: a review of nigerian experience. west afr j med. 2010;29:293-8. 11. rangnekar np, imdad ali n, kaul sa, pathak hr. role of the martius procedure in the management of urinary-vaginal fistulas1. j am coll surg. 2000;191:259-63. 12. hendren wh. construction of a female urethra using the vaginal wall and a buttock flap: experience with 40 cases* 1. j pediatr surg. 1998;33:180-7. 1325vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l giant megaureter of a complete duplex system presenting as peri umbilical mass in an elderly male: a case report tanveer dar, rouf khawaja, ajay sharma, sajid bazaz, manu gupta. corresponding author: tanveer iqbal dar, md sir ganga ram hospital, new delhi, india. e-mail: drtanveerdar@gmail.com received december 2011 accepted january 2012 case report keywords: hydronephrosis; surgery; ureter; abnormalities; laparoscopy; methods. introduction duplication of the collecting system is one of the most common congenital anomalies and is seen in 1 out of 125 (0.8%) people.(1) the ureteric orifice of the upper moiety causes clenching of the distal part of ureter in the area of muscle structures leading to obstruction to its flow and consequent proximal hydroureteronephrosis with atrophy of this segment.(1) in such patients one of the moieties is usually poorly functioning or non-functioning. this poorly functioning moiety is usually hydronephrotic and recurrent urinary tract infections or incontinence with an ectopic ureter might occur.(2) the aim of our report is to have this rare entity in mind while evaluating such a mass in an elderly and laparoscopic upper partial nephroureterectomy as a minimally invasive option for its treatment. case report a 61 years old male from rural background presented with complaints of gradually increasing swelling abdomen associated with heaviness and dragging sensation since last 5 to 6 months. he also gave history of recurrent episodes of turbid urine. on examination a cystic abdominal swelling with slight transverse mobility was noted occupying periumblical region extending into all quadrants, predominantly on left side. an ultrasound abdomen was done elsewhere which revealed cystic abdominal swelling arising from small bowel (figure 1). contrast computed tomography (ct) scan abdomen showed cystic swelling abdomen suggestive of giant 1326 | case report mega ureter with a duplex system displacing the lower moiety ureter medially (figure 2). no contrast was taken up by the upper moiety. no cause for megaureter could be found after evaluation. cystoscopy revealed a dimple inferior to the lower pole ureteric orifice which could not be calibrated by guide wire. retrograde pylogram from the inferior moiety opening showed the ureter pushed medially by the megaureter. the voiding cystourethrogram was normal. on laparoscopy a huge retroperitoneal mass was noted arising from right kidney and crossing the midline, with tapered distal end. laparoscopic upper partial nephroureterectomy was performed with uneventful intra and postoperative course, using standard port sites and dividing the ureter on bladder surface. distal end was clipped. tube drain was removed after 3 days and the patient discharged on 4th day. microscopy was suggestive of chronic ureteritis. he is following our department since last 6 months with good recovery. discussion primary obstructive megaureter is uncommon in adults and is characterized by a congenital obstruction at the lower end of ureter, leading to gross dilatation of the ureter. undiagnosed me-gaureter may progress to occupy the whole abdomen, and impose diagnostic difficulties. bilateral involvement is present in 20% of the cases with a male-to-female ratio of 4:1.(3) duplex kidney and ureter is a developmental condition of incomplete fusion of the upper and lower poles of the kidneys. additionally, an accessory ureteral bud creates complete duplication of the excretory system, with the upper ureter usually protruding into the bladder more medially and inferiorly than the lower ureter (weigert-meyer law). many duplex kidneys are incidental findings and are not the cause of symptoms, although duplex kidneys are more prone to urinary infection, reflux, and obstruction. the upper ureter is more likely to be associated with ectopic insertion, ureterocele, or obstruction, whereas the lower ureter is frequently associated with vesicoureteral reflux.(4) there have been reports of partial nephroureterectomy by either transperitoneal or retroperitoneal approaches, particularly in the pediatric population. an upper pole hemi nephroureterectomy is the standard treatment for a severely compromised upper renal moiety associated with duplicated collecting system due to the potential morbidity of leaving a non functioning renal moiety in place.(2) dorairajan and colleagues, reported a series of 37 cases of adult primary obstructive megaureter and concluded that its problems and complications are different from that of childhood and necessitates an aggressive therapeutic approach except in cases with severe renal failure.(3) botelho and colfigure 1. coronal and axial cuts on ct scan showing grossly dilated and tortuous upper moiety ureter, crossing to the left side. also, a huge hypo dense mass occupying whole of the abdomen, is seen on axial cuts. figure 2. left: ct scan with intravenous contrast showing lower moiety ureter deviated laterally by the dilated ureter, in its upper part. right: excised specimen of the megaureter showing tapered distal end and 9 centimeter diameter after deflation. 1327vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l giant mega ureter managed by laparoscopic partial nephroureterectomy | dar et al references 1. wisniewski p, jarzemski p, listopadzki s, kalinowski r. laparoscopic partial nephroureterectomy in the treatment of hydronephrosis of the upper pole of duplex kidney with megaureter. eur urol suppl. 2010;9:343. 2. shukla ar, cooper j, patel rp, et al. prenatally detected primary megaureter: a role for extended followup. j urol. 2005;173:1353-6. 3. dorairajan ln, hemal ak, gupta np, wadhwa sn. primary obstructive megaureter in adults: need for an aggressive management strategy. int urol nephrol 1999;31:633-641. 4. botelho f, silva p, tomada n, sousa t, cruz f. laparoscopic partial nephroureterectomy for duplex kidney and ureter with megaureter serving a hydronephrotic excluded upper pole: a case report. uro today int j 2008;1(4). 5. patel mn, kaul sa, bhandari a, et al. robot-assisted management of congenital renal abnormalities in adult patients. j endourol. 2010;24:567-70. leagues reported a 25 year old girl with megaureter treated successfully by laparoscopic transperitoneal upper-pole nephroureterectomy.(6) more recently patel and colleagues, reported a similar case treated by robotic upper partial nephroureterectomy.(5). conclusion this is one of the few reports of laparoscopic partial nephroureterectomy done in adults for such a giant megaureter, to our knowledge. this is a safe and effective technique, with good cosmetic and functional results in adults and should be preferred in selected cases. conflict of interest none declared. 935vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l purpose: to discuss the pharmacotherapeutic aspects of mirabegron which is a first-inclass novel β3 receptor agonist drug recently approved by the food and drug administration (fda) for the treatment of overactive bladder (oab). materials and methods: we conducted a computerized search of the medline/pubmed databases with the word mirabegron, β3 receptor agonist and overactive bladder. results: effect of mirabegron on β3 adrenergic receptor purportedly releases nitric oxide (no) by an increase in intracellular ca2+ through accumulation of cyclic adenosine monophosphate (camp). along with no which relaxes the detrusor muscle, it also releases an urothelial-derived inhibiting factor (udif) that inhibits contractions. it increases the bladder capacity by causing bladder relaxation during the storage phase. conclusion: mirabegron appears to be a promising treatment in oab patients by shifting its management from reducing detrusor over-activity to inducing relaxation. also it lacks the troublesome side effects associated with the standard antimuscarinic management. keywords: mirabegron; β3 receptor agonist; urinary bladder; overactive; drug therapy 1department of pharmacology, hamdard institute of medical sciences and research and associated hakeem abdul hameed centenary hospital, jamia hamdard, new delhi -110062, india 2department of pharmacology, faculty of pharmacy, jamia hamdard, new delhi -110062, india 3department of physiology, hamdard institute of medical sciences and research and associated hakeem abdul hameed centenary hospital, jamia hamdard, new delhi -110062, india mohammed imran,1 abul kalam najmi,2 shams tabrez3 review mirabegron for overactive bladder: a novel, first-in-class β3agonist therapy corresponding author: mohammed imran, md assistant professor, department of pharmacology, hamdard institute of medical sciences and research and associated hakeem abdul hameed centenary hospital, jamia hamdard, new delhi-110062, india. tel: +91 954 007 5851 e mail: drimran@aol.in received september 2012 accepted november 2012 936 | review introduction overactive bladder (oab) includes constellation of symptoms such as urinary urgency, urge uri-nary incontinence, nocturia and frequency. urgency is the hallmark of oab. patients may describe it as a sudden compelling desire to urinate that is difficult to defer. while urinary frequency is defined as voiding more than eight times in a 24-hour period, nocturia is defined as the need to wake up one or more times per night for urination.(1) urinary bladder physiology normal bladder stores urine when the sympathetic nervous system (sns) relaxes the detrusor muscle and closes the sphincters at the bladder outlet. it also inhibits the parasympathetic nervous system (pns). when it attains a volume of around 200-400 ml, signal moves from the peripheral nervous system including autonomic, somatic and sensory afferent innervations to the central nervous system resulting in a sensation of urge. normal urination begins after the release of acetylcholine (ach) from the pns and thereby contraction of the detrusor muscle. at the same time sns opens the internal sphincter and somatic nervous system opens the external sphincter. multiple outgoing and incoming neural pathways and neurotransmitters are involved in urine storage and voiding processes.(2,3) pathophysiology of oab oab has multifactorial etio-pathogenesis. causes of the detrusor muscle overactivity may be neurogenic, myogenic, or idiopathic in origin. any of these may result in a constellation of urinary symptoms associated with oab. increased contraction in overactive bladders is due to hypersensitivity to cholinergic agonists through muscarinic (m2 or m3) receptors. acetylcholine released from pns causes activation of m3 receptors which is responsible for bladder contraction. it causes rise in cytosolic calcium (ca2+) from intracellular sarcoplasmic reticulum stores through activation of gprotein coupled receptor (gpcr) mediated phospholipase c breakdown. generation of inositol triphosphate (ip3) triggers ca2+ release. m2 receptor activation conversely causes a fall in cyclic adenosine monophosphate (camp) preventing relaxation.(4) antimuscarinic drug management antimuscarinic drugs antagonize the effects of acetylcholine on muscarinic receptors. they reduce the contractions of the detrusor smooth muscle of the bladder and thus reduce the intensity of urge symptoms. because of the associated troublesome anticholinergic side effects, newer antimuscarinics have been discovered to selectively target m3 receptors to reduce the side effects and increase the efficacy. but they still have limitations of producing adverse events.(5) therefore, now, there would be a shift in management from reducing over activity to producing relaxation of the urinary bladder. mirabegron – a novel β3 agonist the fda, recently in june 2012, has approved a drug called mirabegron in usa which had earlier been approved in japan in 2011. the present review was conducted to have a rationale, pharmacotherapeutic and comprehensive information of this new class of drug for the management of oab. materials and methods we searched the medline/pubmed databases of the national library of medicine for the comprehensive information on the newly introduced mirabegron therapy for oab. the terms used for the search included mirabegron, β3 receptor agonist, overactive bladder and the combinations of these terminologies. all the relevant information obtained from other than pubmed/medline search was also incorporated. results mirabegron it is first-in-class selective β3 adrenergic receptor agonist. it is indicated for treatment of oab in 25 mg extended release once daily starting dose and may be progressed 937vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l to once daily 50 mg recommended dose.(6) activation of β3-adrenoceptors (β3-ars) by mirabegron increases bladder capacity by causing bladder relaxation as induced by sympathetic nerve activation especially during the storage phase of the fill-void cycle.(7) mechanism of action it has been demonstrated in rat experiments that activation of β3-ar by isoproterenol in urothelial cells can release nitric oxide (no) by increasing the intracellular ca2+ through camp accumulation. activation of β3-ar not only causes relaxation by releases no but also inhibits detrusor muscle contraction by releasing an urothelial derived inhibiting factor (udif). this implies that β3-ar agonists helps bladder storing capacity through direct inhibition of the detrusor as well as inhibition of the bladder afferent neurotransduction.(8,9) pharmacokinetics the starting dosage of mirabegron is 25 mg once daily with or without food. it reaches a bioavailability of 29% at a dose of 25 mg which further increases to 35% at a dose of 50 mg. it is extensively distributed in the body with a volume of distribution (avd) of approximately 1670 l. it is moderately bound to the plasma protein (71%) with equal affinity to the albumin and alpha-1-acid glycoproteins. it attains a 2 fold higher concentration in red blood cells than in plasma. (10) there is a difference between linearity of intravenous and oral pharmacokinetics parameters. the drug concentration after i.v. dosing shows the linearity in the range of 7.5 – 50 mg, however there is increased bioavailability through oral route as the dose increases from 29% for 25 mg to 45% at 150 mg.(11) multiple enzymatic pathways are involved in mirabegron metabolism involving dealkylation, oxidation, and glucuronidation and amide hydrolyis. although cyp3a4 and cyp2d6 isoenzymes metabolise this drug their role is limited in overall elimination. other than these isoenzymes, its metabolism may also involve butyrylcholinesterase, uridine diphospho-glucuronosyltransferases and alcohol dehydrogenase. two major pharmacologically inactive metabolites were detected in human plasma and these represent 16% and 11% of the total exposure. approximately 25% of it is excreted unchanged in the urine and there is no excretion in the feces with a terminal half-life of approximately 50 hours. renal clearance is mainly dose dependent due to tubular secretion and glomerular filtration and it (clr) is approximately 13 l/h.(7) there is no apparent age difference in the pharmacokinetics parameters but women show approx. 40% higher cmax (maximum concentration reached) and auc (area under the curve) than men and approx. 20% higher even after the weight correction.(12) it is effective within 8 weeks in doses of 25 mg and 4 weeks in doses of 50 mg respectively after its administration as once a dose. therefore dose may be increased to 50 mg once daily after assessing individual patient efficacy and tolerability. it has been advised in prescribing information to take it with water, swallowed whole and should not be chewed, divided, or crushed. it has been cautioned not to exceed beyond 25mg once daily in patients with severe renal impairment and patients with moderate hepatic impairment (child-pugh class b). it is not recommended for use in patients with end stage renal disease (esrd), or in patients with severe hepatic impairment (child-pugh class c). it is supplied in two different strengths of 25 mg as well as 50 mg extended-release tablets.(13) it has been approved with certain precautions and warnings that should be exercised while prescribing. periodic monitoring of blood pressure is recommended as it can increase blood pressure especially in hypertensive patients. although it is not recommended for use in severe uncontrolled hypertensive patients but randomized placebo-controlled studies (data submitted for its approval) show dose dependent increase in supine blood pressure in healthy volunteers. approximately mean maximum systolic/diastolic blood pressure increase was 3.5/1.5 mmhg over the placebo in healthy volunteers as compared to the 0.5 – 1 mmhg increase over placebo in oab patients. there is also a risk of mirabegron for overactive bladder | imran et al 938 | review urinary retention in patients with bladder outlet obstruction and in patients taking anticholinergic drugs for oab.(7) interactions it is a moderate inhibitor of cyp2d6. it can increase metoprolol and desipramine concentration. appropriate monitoring is recommended and dose adjustment may be necessary for narrow therapeutic index cyp2d6 substrates such as thioridazine, flecainide, propafenone and digoxin. despite these limitations in prescribing information, however, there is no contraindication associated with this drug. (14) it has also shown to interact with warfarin by increasing the cmax by approximately 4% and auc by 9% after the multiple doses of 100mg, however there is no effect following a single dose administration of 25 mg on the warfarin pharmacodynamics endpoints such as international normalized ratio (inr) and prothrombin time. a cautious use is advised along with the warfarin intake.(7) adverse effects the data from four clinical trial studies mentioned in prescribing information released by fda were used to evaluate the safety and efficacy of mirabegron in oab patients.(7) the studies 1, 2 and 3 were done for a period of 12 weeks as double–blind, placebo controlled in 2736 patients including 432 patients on 25 mg, 1375 on 50 mg and 929 on 100 mg strength once daily. study 4 was done to evaluate safety over a period of 1 year as randomized, fixed dose, double blind, active–controlled in 1632 patients including 812 patients on 50 mg and 820 patients on 100 mg strength. out of the 1632 patients in study 4 only 564 patients completed the study for full one year. the most frequent (0.2%) adverse events in three (study 1, 2 and 3) 12 weeks studies that led to the discontinuation of the drugs in clinical studies were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia. the serious adverse events associated with these studies were atrial fibrillation (0.2%) and prostate cancer (0.1%) found in more than one patient and at a rate greater than placebo. while study 4 was discontinued by the participants due to adverse events such as constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eye (0.4%), nausea (0.4%), blurred vision (0.4%) and urinary tract infection (0.4%) which were reported in more than 2 patients and at a rate greater than active control, the serious adverse events in this study included cerebrovascular accidents (0.4%) and osteoarthritis (0.2%). in addition, a few cases of malignancies like breast cancer, lung neoplasm and prostate cancer were reported in more than two patients taking 100 mg dose of mirabegron. the rate of neoplasm in patients taking mirabegron 50 mg, mirabegron 100 mg and active control once daily were 0.1%, 1.5% and 0.5% respectively in study 4.(7) in general, there are some adverse reactions reported which demand caution in use of this therapy. the most common adverse reactions (i.e., in greater than 2% of patients) were hypertension, nasopharyngitis, urinary tract infection and headache. other adverse events exceeding placebo rate and reported by 1% or more patients are hypertension, nasopharyngitis, urinary tract infection, headache, constipation, upper respiratory tract, infection, arthralgia, diarrhea, tachycardia, abdominal pain and fatigue. those side effects developing in less than 1% of patients include palpitations, increased blood pressure, glaucoma, dyspepsia, gastritis, abdominal distension, sinusitis, rhinitis, increased ggt, increased ast, increased alt, increased ldh, nephrolithiasis, bladder pain, vulvovaginal pruritus, vaginal infection, urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema (7) the approval of mirabegron was based on three placebocontrolled phase 3 studies in which 12 weeks treatment from 25 mg and 50 mg dose resulted in statistically significant improvement in co-primary efficacy endpoints. that is the change from baseline to the end of the treatment after 12 weeks in respect of mean number of incontinence episodes per 24 hours and mean number of micturition per 24 hours based on a 3 day micturition diary. mirabegron in 25 mg strength reduced incontinence episodes by 1.36 from a baseline of 2.65 with a significant difference of 0.40 versus 939vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l placebo in 12 weeks (p-value=0.005). the micturition episodes reduced by 1.65 from a baseline of 11.68 with a significant difference of 0.47 versus placebo (p = .007). while 50 mg strength reduced the incontinence episodes by 1.38 from a baseline of 2.51 with a significant difference of 0.42 (p = .001). the micturition episodes reduced by 1.60 from a baseline of 11.66 with a difference of 0.42 versus placebo (p= .015).(7) although antimuscarinic drugs are the standard treatment in oab management but their adverse effects and declining efficacy leads to long term compliance issues. mirabegron is a new class of drug acting through dual mechanism of inhibiting afferents and causing relaxation of detrusor muscle. one of the animal studies compared the effects of oxybutynin with the mirabegron on single unit afferents activities of aδ-fibers and c-fibers in response to the bladder filling. it was found to be superior in inhibiting the afferents and suppressing the micro contractions of urinary bladder.(15) limitations the safety and efficacy studies have not been conducted in pediatrics patients and use for pregnant ladies are only advised after individualizing the risk benefit assessment. however it is excreted in the human milk and therefore not recommended in nursing females while no dose adjustment is required for geriatric patients.(10) conclusion this class of drugs have the great potential in shifting the management of the oab through a different mechanism of action which has never tried earlier. although mirabegron has lower side effects as compared to the earlier drugs used in the management of oab but it has yet to be standardized in respect of the gender pharmacokinetics variations and a few specified populations. the drug is to be used on an individual basis till long term studies prove the safety of the drug for long term intake. conflict of interest none declared. references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002;21:167–78. 2. abrams p. describing bladder storage function: overactive bladder syndrome and detrusor overactivity. urology. 2003;62:28–37. 3. degroat wc. a neurological basis for the overactive bladder. urology. 1997;50(suppl 6a):36–52. 4. morrison j, steers wd, brading af, et al. neurophysiology and neuropharmacology. in: abrams p, cardozo l, khoury s, wein a, editors. incontinence. 2nd ed. plymouth, england: health publications; 2002. p. 86–163. 5. yoshimura n, chancelor mb. current and future pharmacological treatment for overactive bladder. j urol. 2002;168:1897–1913. 6. fda (home). news & events. newsrooms. press announcements. [accesses on 11 sept 2012]. available from url: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm310096.htm. 7. fda (home). drug databases. drugs@fda. [accessed on 11 sept 2012]. available from url: http://www.accessdata.fda. gov/drugsatfda_docs/label/2012/202611s000lbl.pdf. 8. birder la, nealen ml, kiss s, et al. beta-adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. j neurosci. 2002;22:8063–70. 9. murakami s, chapple cr, akino h, sellers dj, chess-williams r. the role of the urothelium in mediating bladder responses to isoprenaline. bju int. 2007;99:669–73. 10. medscape reference. mirabegron(rx)-myrbetriq. pharmacology. [accessed on 11 sept 2012]. available from url: http://reference.medscape.com/drug/myrbetriq-mirabegron-999757#10. 11. eltink c, lee j, schaddelee m, et al. single dose pharmacokinetics and absolute bioavailability of mirabegron, a β3adrenoceptor agonist for treatment of overactive bladder. int j clin pharmacol ther. 2012;50:838–50. 12. krauwinkel w, van dijk j, schaddelee m, et al. pharmacokinetics properties of mirabegron, a β3-adrenoceptor agonist: results from two phase i, randomized, multiple dose studies in healthy young and elderly man and women. clint her. 2012;34:2144–60. mirabegron for overactive bladder | imran et al 940 | review 13. rx list (home). drugs a-z list. myrbetriq (mirabegron) drug center. clinical pharmacology. [accessed on 11 sept 2012]. available from url: http://www.rxlist.com/myrbetriq-drug/ clinical-pharmacology.htm. 14. myrbetriqtm (mirabegron). [accessed at 11 september 2012]. available from url: http://myrbetriq.com/. 15. aizwa n, homma y, igawa y. effects of mirabegron, a novel β3 – adrenoceptor agonist, on primary bladder afferent activity and bladder microcontractions in rats compared with the effects of oxybutynin. eur urol. 2012;62:1165–73. association between 5-alpha reductase inhibitor use and the risk of depression: a meta-analysis tuo deng1, 2, 3 #, xiaolu duan1, 2, 3#, zihao he1, 2, 3, zhijian zhao1,2, 3, guohua zeng1, 2, 3 * purpose: to explore the association between 5α-reductase inhibitors (5aris) use and risk of depression based on published literature through a meta-analysis. materials and methods: a comprehensive literature search was conducted by searching pubmed, embase, cochrane library, cbm, cnki, and vip databases up to june, 2019. summarized risk ratios (rrs) with 95% confidence intervals (cis) were calculated to evaluate the strength of association between 5aris and depression. subgroup analyses were performed according to population, 5ari types, degree of depression, and publication date. registered in prospero under number crd42018096147. results: a total of 6 clinical studies with 265672 participants were included in our meta-analysis. the application of 5aris could significantly increase the risk of depression based on both pooled unadjusted (95% ci: 1.28-2.78, rr = 1.89, p = .001) and multivariable adjusted rrs (95% ci: 1.01-1.17, rr = 1.09, p = .03). in subgroup analyses, dutasteride was associated with depression significantly (95% ci: 1.37-1.70, rr = 1.53, p < .001), while finasteride was not. as to the degree of depression, 5aris mainly caused mild depression (95% ci: 1.91-2.33, rr = 2.11, p < .001), instead of moderate or severe depression. conclusion: we concluded that 5aris could potentially increase the risk of depression. clinicians need to carefully consider the use of 5aris for benign prostatic hyperplasia and androgenic alopecia patients, especially those exhibiting risk factors for depression or those who have a previous history of depression. more studies with larger sample size and comprehensive study design are needed to further verify our outcomes. keywords: association; 5α-reductase inhibitors; depression; meta-analysis introduction benign prostatic hyperplasia (bph) is a major con-tributor to lower urinary tract symptoms (luts) due to bladder outlet obstruction in elderly men. both european association of urology (eau) and american urological association (aua) guidelines recommend 5α-reductase inhibitors (5aris) as the primary pharmacological treatment for luts secondary to bph. (1,2) 5aris could lower the conversion of testosterone to dihydrotestosterone (dht) through targeting the 5α-reductase enzyme family,(3) so 5aris are commonly used for bph and androgenic alopecia. two equally efficacious 5aris are available for clinical use: finasteride and dutasteride. finasteride inhibits only type 2 5α-reductase, whereas dutasteride inhibits both types 1 and 2. the most relevant adverse effect of 5aris is sexual dysfunction, including reduced libido, erectile dysfunction (ed) and ejaculation disorders.(4-6) some studies(7-9) 1department of urology, minimally invasive surgery center, the first affiliated hospital of guangzhou medical university, guangzhou, china. 2guangdong key laboratory of urology, guangzhou, china. 3guangzhou institute of urology, guangzhou, china. *correspondence: department of urology, minimally invasive surgery center, the first affiliated hospital of guangzhou medical university. guangzhou institute of urology. guangdong key laboratory of urology. address: kangda road 1#, haizhu district, guangzhou, guangdong, china, 510230. telephone: +86-020-34294145, email: gzgyzgh@vip.tom.com. #: these authors contribute equally to this work. received december 2019 & accepted june 2020 also reported a significant increase in depressive symptoms among patients exposed to propecia (finasteride 1 mg), which might even exist after discontinuation of the medication. these findings resulted in the addition of depression to the professional labels for propecia in the united states. a recent population-based matched cohort study(10) indicated that the use of 5aris was significantly associated with increased risk of depression. however, another large population-based study showed that the risk of depression did not increase with 5aris. (11) above all, the association between 5aris use and the risk of depression is still controversial. so far, it is difficult to draw a solid conclusion from published studies reporting depression after 5aris because most of them are case series;(12-14) few controlled studies were published, and their results remained contradictory.(8,10,11) additionally, depression is not included in the adverse effects of 5aris in either eau or aua guidelines due to inadequate levels of evidence. urology journal/vol 18 no. 2/ march-april 2021/ pp. 144-150. [doi: 10.22037/uj.v16i7.5866] review (1,2) consequently, we performed this meta-analysis to clarify the association between 5aris use and the risk of depression based on current original controlled studies, hoping to provide some references for clinicians and 5aris users. materials and methods this meta-analysis was conducted in accordance with the meta-analysis of observational studies in epidemiology (moose) guidelines. the protocol of this analysis was registered in prospero, and the registration number is crd42018096147. search strategy a comprehensive electronic literature search using the pubmed, embase, cochrane library, cbm, cnki, and vip databases was performed to identify controlled studies investigating the association between 5aris use and the risk of depression. the date limit of this search was from the inception of these databases to june 2019. search terms were “‘5-alpha reductase inhibitors’ or ‘5α-reductase inhibitors’ or ‘5-a reductase inhibitors’ or ‘5ari’ or ‘5-ari’ or ‘finasteride’ or ‘dutasteride’” in combination with “‘depression’ or ‘depressive’”. references of relevant studies were also checked to identify potential records. no language restrictions existed in this search. inclusion and exclusion criteria only controlled clinical studies exploring the association between 5aris use and the risk of depression were included in this meta-analysis. accordingly, studies without the control group of non-5ari users were excluded. meanwhile, studies as abstracts, case reports, conference proceedings, reviews, animal experiments, or repeated publications were also excluded. relevant studies’ search and screen, quality assessment and data extraction were performed by two reviewers (t.d. and x.d.) independently. discrepancies were resolved via open discussion. study quality assessment and data extraction the level of evidence (loe) of all eligible studies was assessed by the criteria provided by the oxford centre for evidence-based medicine.(15) the quality of non-randomized controlled studies included was evaluated using the newcastle-ottawa scale (nos).(16) data from all eligible studies were attentively extracted as follows: study country, population, institution and period, research methodology, type of 5aris, diagnostic criteria of depression, characteristics of participants, follow-up time, and related outcomes. authors of relevant studies were contacted to obtain incomplete data. statistics analysis for the included case-control studies, odds ratios (ors) association between 5aris and depression-deng et al. table 1. baseline characteristics of included studies. abbreviations: 5ari 5α-reductase inhibitor, loe: level of evidence, nos: newcastle-ottawa scale, nm: not mentioned. a newcastle-ottawa scale points, one star means one point. subgroups number of included studies no. participants heterogeneity rr (95% ci) i2 p study population european population 2 183229 99% < .001 2.04 (1.00-4.17) usa population 3 82403 97% < .001 1.85 (1.01-3.38) 5ari type finasteride 3 99923 94% < .001 1.34 (0.96-1.87) dutasteride 1 93790 na 1.53 (1.37-1.70) degree of depression mild depression 2 3631 0% .32 2.11 (1.91-2.33) moderate and 2 3631 85% .01 4.74(0.14-162.14) severe depression study publication before 2015 2 3631 62% .10 3.93 (1.72-8.98) date after 2015 3 262001 98% < .001 1.39 (1.00-1.91) abbreviations 5ari: 5α-reductase inhibitor, rr: risk ratio, ci: confidence interval, na: not applicable. bold numbers mean the p-value is < .05. table 2. results of subgroup analyses review 145 of 5aris use on the risk of depression were extracted and converted to risk ratios (rrs) based on the formula rr=or/((1-p"0" )+(p"0" ×or)) (p0 indicates the incidence of the outcome of interest in the nonexposed group) according to the cochrane handbook. (17) summarized unadjusted rrs with 95% confidence intervals (cis) were calculated to assess the strength of association between 5aris and the risk of depression. available adjusted rrs of depression risk and mean differences (mds) of the beck depression inventory-second edition (bdi-ii) score in eligible studies were also pooled as references. chi-square test-based qand i2statistic was used to test the heterogeneity among included studies.(18) the fixed-effect model was used when no significant heterogeneity existed with a p value > 0.10. otherwise, the random-effect model was applied. all results in this meta-analysis were considered significant with a two-sided p value < 0.05. subgroup analyses were performed based on the study population, type of 5ari, degree of depression, and study publication date. sensitivity analyses were conducted by excluding every single eligible study in turn. the publication bias among eligible studies was assessed through the inverted funnel plot visual inspection and the egger’s test. all statistical analyses were conducted by revman (version 5.3; cochrane collaboration, oxford, uk) and stata (version 13.0; statacorp, college station, texas, usa) software. results characteristics and quality assessments of eligible studies after article reviewing and screening carefully, six controlled clinical studies(8,10,11,19,20,21) were included in this meta-analysis (figure 1). and a total of 265672 participants were involved. table 1 showed the baseline characteristics of all eligible studies. among them, 4(8,10,11,20) were cohort studies and 2(19,21) were cross-sectional study. as to the study regions, 3 studies(8,11,20) were conducted in the usa, and the other 3 were performed in canada(10), poland(19), and italy(21) respectively. regarding to the study publication date, 2 studies(8,19) were published before 2015, while 4 studies(10,11,20,21) were published after 2015. among the six included studies, the depression rates among 5ari users ranged from 1.95% to 75.41%, with an average rate of 3.68% (3737/101513); whereas the average rate of depression among non-5ari users was 2.98% (4886/164119) with a range of 1.37% to 17.6%. loes of all 6 included articles were listed in table 1. among the 6 clinical studies, 4(8,10,11,20) of them were considered as high quality with a nos score more than 6 stars. meta-analysis unadjusted rrs of 5aris use on the risk of depression could be extracted or calculated from 5 clinical studies(8,10,11,19,20). result of the meta-analysis showed that the use of 5aris could significantly increase the risk of depression (95% ci: 1.28-2.78, rr = 1.89, p = .001), with significant heterogeneity among them (i2 = 98%, p < .001) (figure 2). no obvious publication bias was detected through either inverted funnel plot or egger’s test (t = 1.44, p = .245). multivariable adjusted rrs were available in 2 clinical studies(11,20). and the summarized adjusted rr and its 95%ci also indicated that 5aris use could significantly increase the risk of depression (95% ci: 1.011.17, rr = 1.09, p = .03) without heterogeneity (i2 = 0%, p = .53) (figure 3). mean differences of bdi-ii score were also available figure 1. flow diagram of study selection. association between 5aris and depression-deng et al. vol 18 no 2 march-april 2021 146 in 2 clinical studies(8,21). however, no significant difference was found in bdi-ii scores between 5ari and non-5ari groups (95% ci: -8.62 to 26.25, md = 8.81, p = .32) (figure 4). subgroup analysis subgroup analyses of unadjusted rrs of 5aris use on the risk of depression were conducted according to the study populations, 5ari type, degree of depression, and study publication date. table 2 showed the results of all subgroup analyses. positive association between 5aris use and increased risk of depression was only found in usa population (95% ci: 1.01-3.38, rr = 1.85, p < .05), dutasteride (95% ci: 1.37-1.70, rr = 1.53, p < .001), mild depression (95% ci: 1.91-2.33, rr = 2.11, p < .001), and study published before 2015 (95% ci: 1.72-8.98, rr = 3.93, p = .001) subgroups. sensitivity analysis sensitivity analyses of summarized unadjusted rrs of 5aris use on the risk of depression were conducted to evaluate the stability and reliability of our results by excluding every single eligible study in turn. as shown in table 3, no matter which eligible study was excluded, the pooled result remained significant, which means our results are stable and reliable. however, in the sensitivity analyses, we did not find the source of heterogeneity among the five included studies, cause the exclusion of any single study could not reduce the heterogeneity. discussion in our meta-analysis, we included 6 clinical studies with 265672 participants. we found that the application of 5aris may increase the risk of depression. from our subgroup analyses, dutasteride was associated with the existence of depression, while this relationship could not be observed with finasteride. as to the degree of depression, 5 aris mainly caused mild depression, instead of moderate or severe depression. sensitivity analyses indicated that our results are stable and reliable. according to our unadjusted results from 5 studies, bph or androgenic alopecia patients having a history of 5aris had a significant higher tendency to suffer from depression. in a study conducted by unger et al, an increase in the existence of depression was detected in finasteride users.(20) a large observational study based on the general practice research database also reported similar results, showing a probable positive relationship between 5aris and depression.(22) several clinical researches discovered the occurrences of depression in their patients receiving 5aris and their findings should not be ignored, which need further necessary analysis. although with different affinities with 5α-reductase, finasteride and dutasteride had similar mechanisms when causing potential risk of depression.(23) first, 5α-reductase participates in the synthesis of some neuroactive steroids.(24) these are not only produced by the central nervous system itself, but also by the gonads and adrenal glands and then transported to the brain.(25) 5aris, including finasteride and dutasteride, can pass the bloodbrain barrier and inhibit the activity of 5α-reductase, so the concentration of a variety of neuroactive steroids reduces.(26-28) second, γ-aminobutyric acid (gaba) is an important inhibitory neurotransmitter. 5α-reductase promotes the formation of allopregnanolone, which is responsible for depression, tension and anxiety, owing to its binding to gaba receptor.(29,30) therefore, the table 2. results of subgroup analyses excluded study included participants heterogeneity rr (95% ci) i2 p irwig et al, 2012(8) 265542 98% < .001 1.67 (1.13-2.48) pietrzyk et al, 2015(19) 262091 97% < .001 1.56 (1.12-2.17) unger et al, 2016(20) 251697 97% < .001 2.27 (1.49-3.46) welk et al, 2017(10) 85944 99% < .001 2.21 (1.18-4.13) hagberg et al, 2017(11) 197254 98% < .001 1.91 (1.20-3.03) abbreviations: rr: risk ratio, ci: confidence interval. bold numbers mean the p-value is < 0.05. figure 2. forest plot of unadjusted rr and 95% cis of 5ari use for risk of depression. association between 5aris and depression-deng et al. review 147 application of 5aris decreases the secretion of allopregnanolone and suppresses gaba’s function. third, in laboratory tests, levels of neuroactive steroids were lower in bph patients who received finasteride.31 this phenomenon was also observed among patients with depression,32 further proving the potential association between 5aris and depression. furthermore, some experiments were conducted on animals. rodents tended to have anxiolytic and depressive behaviors after being given finasteride. they were also shown to have a lower level of plasma allopregnanolone compared to controls. (33,34) except for the pharmacological pathways, 5aris have other adverse events, such as loss of libido and ed, which may also lead to depression. taken together, these clinical findings and the experimental research provided some evidence for the increased risk caused by 5aris, confirming our results to some extent. after adjusting for confounding factors, our results still showed that 5aris use was significantly associated with an increased risk of depression. bph and depression could share some kinds of co-risk factors, including old age, smoking, and the presence of chronic disease. (35) apart from this, bph itself could induce depression due to luts. pietrzyk and colleagues confirmed the association between luts and depression, indicating that the severity of urinary urgency, frequency, and increased nocturia really influenced male patients’ quality of life drastically.(19) in our meta-analysis, we adjusted our data for confounding factors based on 2 original studies; however, we did not know the details in the factors included in their researches. in addition, pooled mean differences of bdi-ii score were also calculated by combining two studies, however, no significant difference was found between the two groups. since these data from only 2 articles were not adequate for a valid conclusion, these results should be taken into thorough consideration. in our subgroup analyses, dutasteride was shown to increase the risk of depression significantly, while finasteride did not. there are 3 kinds of 5α-reductase in this family: 5α-reductase 1, 2, and 3. dutasteride inhibits both type 1 and 2; however, finasteride has a specific affinity with only type 2, probably explaining its weak relationship with depression. nevertheless, because only 3 articles were included in the subgroup finasteride and 1 for dutasteride, this result was not reliable enough to provide any guidance in the application of drugs. besides, our data suggested that 5aris could only evoke mild depression, but not moderate or severe. 2 studies were included in this subgroup(8,19) and both used the beck depression inventory to evaluate the severity of depression. perhaps more clinical studies with larger sample sizes were necessary to ensure the accuracy and validity of our results. our meta-analysis had several limitations. firstly, only 6 articles were included for us to reach the pooled refigure 3. forest plot of multivariable adjusted rr and 95% cis of 5ari use for risk of depression. figure 4. forest plot of mean difference in bdi-ii scores between 5ari and non-5ari groups. supplementary material 1: prisma checklist. association between 5aris and depression-deng et al. vol 18 no 2 march-april 2021 148 sults. the lack of original studies was a great obstacle to conduct a comprehensive meta-analysis. subsequently, the number of studies in each subgroup was no more than 3, meaning our results cannot affect the current guidelines. secondly, all studies were observational and no rcts met our inclusion criteria. selection bias and recall bias were apparent in retrospective studies, and for data extracted from databases, it was hard to guarantee the accuracy of diagnoses, because researchers could only judge the existence of disease according to the code recorded. it was also not realistic to achieve detailed information through recalling or scanning databases, such as types of the drugs, severity of diseases and so on. thirdly, bph and depression do share several similar risk factors, and luts from bph could also cause depression. although 2 included studies considered the confounding factors and adjusted for them, we still could not reach a valid conclusion due to the lack of enough evidences. conclusions we finally conclude that 5aris could potentially increase the risk of depression. based on several large observational studies and fda’s suggestions, clinicians need to carefully consider the use of 5aris for bph and androgenic alopecia patients, especially those at risk for depression. more studies with a larger sample size and comprehensive study design are needed necessary to further verify our outcomes. acknowledgments this study was financed by grants from national natural science foundation of china (no. 81802821), natural science foundation of guangdong province (no. 2017a030310547), and china postdoctoral science foundation (no. 2018t110859 and no. 2017m612636). conflict of interest the authors declare that they have no conflicts of in terest. references 1. gravas s, cornu jn, drake mj, et al. european association of urology guidelines on treatment of non-neurogenic male luts 2017. available at: http://uroweb.org/ guideline/treatment-of-non-neurogenic-maleluts/. accessed january 20, 2018. 2. mcvary kt, roehrborn cg, avins al, et al. american urological association guidelines statement on management of benign prostatic hyperplasia (bph) 2014. available at: http:// www.auanet.org/guidelines/benign-prostatichyperplasia-(2010-reviewed-and-validityconfirmed-2014). accessed january 20, 2018. 3. traish am. 5α-reductases in human physiology: an unfolding story. endocr pract. 2012; 18: 965-75. 4. mcconnell jd, roehrborn cg, bautista om, et al. the long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. n engl j med. 2003; 349: 238798. 5. naslund mj, miner m. a review of the clinical efficacy and safety of 5alpha-reductase inhibitors for the enlarged prostate. clin ther. 2007; 29: 17. 6. roehrborn cg, siami p, barkin j, et al. the effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the combat study. eur urol. 2010; 57: 123. 7. rahimi-ardabili b, pourandarjani r, habibollahi p, mualeki a. finasteride induced depression: a prospective study. bmc clin pharmacol. 2006; 6: 7. 8. irwig ms. depressive symptoms and suicidal thoughts among former users of finasteride with persistent side effects. j clin psychiatry. 2012; 73: 1220-3. 9. traish am, mulgaonkar a, giordano n. the dark side of 5areductase inhibitors’ therapy: sexual dysfunction, high gleason grade prostate cancer and depression. korean j urol. 2014; 55: 367-79. 10. welk b, mcarthur e, ordon m, anderson kk, hayward j, dixon s. association of suicidality and depression with 5α-reductase inhibitors. jama intern med. 2017; 177: 683-91. 11. hagberg kw, divan ha, nickel jc, jick ss. risk of incident antidepressanttreated depression associated with use of 5α-reductase inhibitors compared with use of α-blockers in men with benign prostatic hyperplasia: a population-based study using the clinical practice research datalink. pharmacotherapy. 2017; 37: 517-27. 12. altomare g, capella gl. depression circumstantially related to the administration of finasteride for androgenetic alopecia. j dermatol. 2002; 29: 665-9. 13. rahimi-ardabili b, pourandarjani r, habibollahi p, mualeki a. finasteride induced depression: a prospective study. bmc clin pharmacol. 2006; 6: 7. 14. melcangi rc, santi d, spezzano r, et al. neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients. j steroid biochem mol biol. 2017; 171: 229-35. 15. kurahashi n, iwasaki m, sasazuki s, otani t, inoue m, tsugane s. soy product and isoflavone consumption in relation to prostate cancer in japanese men. cancer epidemiol biomarkers prev. 2007; 16: 538-45. 16. stang a. critical evaluation of the newcastleottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. eur j epidemiol. 2010; 25: 603-5. 17. higgins j, thomas j (editors). cochrane handbook for systematic reviews of interventions. version 6. the cochrane collaboration. available at: https://training. cochrane.org/handbook. accessed may 7, 2020. 18. higgins jp thompson sg, deeks jj, altman dg. measuring inconsistency in metaanalyses. bmj. 2003; 327: 557-60. 19. pietrzyk b, olszanecka-glinianowicz m, association between 5aris and depression-deng et al. review 149 vol 18 no 2 march-april 2021 138 owczarek a, et al. depressive symptoms in patients diagnosed with benign prostatic hyperplasia. int urol nephrol. 2015; 47: 43140. 20. unger jm, till c, thompson im jr, et al. longterm consequences of finasteride vs placebo in the prostate cancer prevention trial. j natl cancer inst. 2016; 108. pii: djw168. 21. catalano a, martino g, bellone f, et al. neuropsychological assessment in elderly men with benign prostatic hyperplasia treated with dutasteride. clin drug investig. 2019; 39: 97-102. 22. clifford gm, farmer rdt. drug or symptominduced depression in men treated with alpha1blockers for benign prostatic hyperplasia? a nested case-control study. pharmacother drug saf. 2002; 11: 55-61. 23. traish am, melcangi rc, bortolato m, garcia-segura lm, zitzmann m. adverse effects of 5α-reductase inhibitors: what do we know, don’t know, and need to know? rev endocr metab disord. 2015; 16:177-98. 24. celec p, ostatníková d, hodosy j. on the effects of testosterone on brain behavioral functions. front neurosci. 2015; 9: 1-17. 25. paul sm, purdy rh. neuroactive steroids. faseb j. 1992; 6: 2311-22. 26. pinacho-garcia lm, valdez ra, navarrete a, cabeza m, segovia j, romano mc. the effect of finasteride and dutasteride on the synthesis of neurosteroids by glioblastoma cells. steroids. 2020; 155:108556. 27. litim n, morissette m, caruso d, melcangi rc, di paolo t. effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice. j steroid biochem mol biol. 2017; 174:242-56. 28. clark rv, hermann dj, cunningham gr, wilson th, morrill bb, hobbs s. marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. j clin endocrinol metab. 2004; 89: 2179-84. 29. majewska md, harrison nl, schwartz rd, barker jl, paul sm. steroid hormone metabolites are barbiturate-like modulators of the gaba receptor. science. 1986; 232: 1004-7. 30. melcangi rc, caruso d, abbiati f, et al. neuroactive steroid levels are modified in cerebrospinal fluid and plasma of postfinasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. j sex med. 2013; 10: 2598603. 31. uzunova v, sheline y, davis jm, et al. increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. proc natl acad sci usa. 1998; 95: 3239-44. 32. romeo e, ströhle a, spalletta g, et al. effects of antidepressant treatment on neuroactive steroids in major depression. am j psychiatry. 1998; 155: 910-13. 33. rhodes me, frye ca. inhibiting progesterone metabolism in the hippocampus of rats in behavioral estrus decreases anxiolytic behaviors and enhances exploratory and antinociceptive behaviors. cogn affect behav neurosci. 2001; 1: 287-96. 34. frye ca, walf aa. changes in progesterone metabolites in the hippocampus can modulate open field and forced swim test behavior of proestrous rats. horm behav. 2002; 41: 30615. 35. djernes jk. prevalence and predictors of depression in populations of elderly: a review. acta psychiatr scand. 2006; 113: 372-87. association between 5aris and depression-deng et al. vol 18 no 2 march-april 2021 150 urol_v03_no4_001_editorial.indd kidney transplantation 230 urology journal vol 3 no 4 autumn 2006 skin diseases in kidney transplant recipients abbas zamanian, hossein mahjub, azame mehralian introduction: the aim of this study was to evaluate the frequency of skin diseases in kidney transplant recipients. materials and methods: this cross-sectional study was performed on 233 kidney transplant recipients in ekbatan hospital of hamedan in 2004. the patients were examined by a dermatologist and diagnosis was made on the basis of clinical observations. biopsies and scraping of the lesions were taken whenever necessary. results: of the patients, 226 (97%) suffered from one or more skin lesions. the most common lesions were drug related, including hypertrichosis, gingival hyperplasia, acne, and cushingoid feature which were detected in 86.7% of the patients. also, infectious and premalignant or malignant lesions (actinic keratosis, squamous cell carcinoma, and basal cell carcinoma) were seen in 48.9% and 14.2% of the patients. the mean duration of immunosuppressive therapy was significantly higher in patients with infectious skin diseases (p < .001). conclusion: skin lesions are a significant problem in kidney transplant recipients. a careful monitoring of these patients is recommended in order to detect these lesions in early stages and treat them. urol j (tehran). 2006;4:230-3. www.uj.unrc.ir keywords: kidney transplantation, skin diseases, skin neoplasms, infections, immunosuppressive therapy department of dermatology, sina hospital, hamedan university of medical sciences, hamedan, iran corresponding author: abbas zamanian, md department of dermatology sina hospital hamedan, iran po box: 379 tel: +98 918 111 1704 e-mail: zamanian@umsha.ac.ir received september 2005 accepted september 2006 introduction intensive immunosuppressive therapy is generally warranted to prevent the rejection of a kidney allograft and provide a long-term graft survival. immunosuppressive therapy, as presently available, generally suppresses all immune responses including those to bacteria, fungi, and even tumors. the frequency of internal organs malignancies common in the general population is not increased in transplanted patients; however, a variety of uncommon cancers are more frequent.(1,2) kidney transplant recipients are at the risk of a broad spectrum of skin diseases. the most important lesions are skin and lip cancers, carcinoma in situ of the cervix, and non-hodgkin lymphomas.(3) also, actinic keratosis, squamous cell carcinoma (scc), basal cell carcinoma (bcc), and malignant melanoma have been reported to be more common in these patients.(4-10) immunosuppressive therapy may predispose these patients to various skin infections caused by herpes simplex, herpes zoster, pityriasis versicolor, fungi, etc.(11) drug-related lesions including hypretrichosis, gingival hyperplasia, acne, cushingoid features, and striae frequently occur as a result of the immunosuppressive administration. additionally, there are miscellaneous skin disorders that may be detected in kidney allograft recipients. kidney transplantation has been performed in iran since years ago, but skin diseases have not been assessed adequately in the transplantation recipients. this skin diseases in kidney transplantation—zamanian et al urology journal vol 3 no 4 autumn 2006 231 study was designed to evaluate the spectrum of the dermatological diseases in kidney transplant recipients. materials and methods in 2004, this cross-sectional study was performed on a total of 233 patients who had undergone kidney transplantation at ekbatan hospital, in hamedan. they were visited by a nephrologist and a dermatologist during their monthly follow-ups. a thorough physical examination for skin lesions was done (except for genitalia). skin biopsies and scrapings were taken whenever necessary. diagnosis of the skin diseases was made on the clinical basis and pathological studies. statistical analysis was performed by chi-square test and t test to compare dichotomous and continuous variables, respectively. a p value less than .05 was considered significant. results of 233 patients, 118 (50.6%) were men and 115 (49.4%) were women. the mean age of them was 38.6 years (range, 13 to 65 years; 95% confidence interval [ci] = 36.9 to 40.3) at transplantation. mean time of immunosuppressive therapy after the transplantation (follow-up) was 43.7 months (range, 1 to 145 months; 95% ci = 39.0 to 48.5). immunosuppressive regimen consisted of cyclosporine, prednisolone, and azathioprine in 148 (63.5%) patients; cyclosporine, prednisolone, and mycophenolate mofetil in 83 (35.6%); and cyclosporine and prednisolone in 2 (0.9%). skin lesions were observed in 226 (97%) patients. drug-related, infectious, and premalignant/malignant lesions were seen in 202 (86.7%), 114 (48.9%), and 33 (14.2%) patients, respectively. no relation was found between the age and the skin lesions (p = .84). frequency of skin diseases was not correlated with the immunosuppressive regimen (p = .43). among drug-related skin lesions, hypertrichosis was the most common, followed by gingival hyperplasia, cushingoid features, acne, sebaceous hyperplasia, and striae (table 1). these lesions did not increase with the duration of posttransplant follow-up period (p = .18). viral wart was the most common infectious skin lesion in these patients, followed by pityriasis versicolor, herpes zoster, herpes simplex, folliculitis, candidiasis, varicella, tuberculosis of lymph nodes, and onychomycosis (table 1). the mean duration of immunosuppressive therapy was significantly higher in patients with infectious skin diseases (p < .001). solar keratosis was the most frequent among premalignant/malignant lesions which was seen in 20 patients (8.6%). squamous cell carcinoma was diagnosed more frequently than bcc (table 1). the risk of skin malignancy increased with the increasing of posttransplant duration (p = .049). other skin lesions seen in these patients were pigmented nevi, eczema, seborrheic dermatitis, skin tags, and epidermal cyst (table 1). the frequency of skin diseases based on the follow-up duration is shown in table 2. discussion skin lesions are a significant problem in transplant patients. rafi and colleagues performed a crosstable 1. skin lesions in kidney transplant recipients skin lesions number (%) drug-related lesions hypertrichosis 130 (55.8) gingival hyperplasia 114 (48.9) acne 68 (29.2) cushingoid features 63 (27.0) sebaceous hyperplasia 29 (12.5) striae 2 (0.9) total 202 (86.7) infectious lesions warts 87 (37.3) pityriasis versicolor 58 (24.9) herpes zoster 27 (11.6) herpes simplex 17 (7.3) folliculitis 12 (5.2) mucosal candidiasis 11 (4.7) varicella 2 (0.9) lymphadenitis tuberculosis 1 (0.4) onychomycosis 1 (0.4) total 114 (48.9) premalignant/malignant lesions actinic keratosis 20 (8.6) squamous cell carcinoma 7 (3.0) basal cell carcinoma 5 (2.2) kaposi's sarcoma 1 (0.4) total 33 (14.2) other lesions eczema 29 (12.5) melanocytic nevi 31 (13.3) seborrheic dermatitis 15 (6.4) skin tags 8 (3.4) epidermal cysts 1 (0.4) total 226 (97.0) skin diseases in kidney transplantation—zamanian et al 232 urology journal vol 3 no 4 autumn 2006 sectional study on 60 kidney transplant recipients in saudi arabia. they observed skin lesions in 90% of the patients including infectious lesions in nearly half of them.(12) pityriasis versicolor was the most common skin infection (36%), followed by folliculitis (8%) and warts (6%). in a similar study in puerto rico, the frequency of skin diseases was reported to be 95% in transplant patients.(13) in the study performed by bencini and associates on 105 patients, the frequency of skin diseases was 97% and premalignant/malignant skin lesions were seen in 12% of these patients with the preponderance of scc.(14) reports from saudi arabia, italy, and india agree with our results.(12,15,16) skin lesions in kidney transplant recipients can be divided into 5 groups of drug related, infectious, premalignant, malignant, and miscellaneous.(13,15) certain miscellaneous skin disorders are not related to neither the renal condition nor the immunosuppression. these include pigmented nevi, skin tags, ichthyosis, and seborrheic dermatitis.(13) drug-related, infectious, and premalignant/malignant lesions were seen in 202 (86.7%), 114 (48.9%), and 33 (14.2%) patients of our study, respectively. these frequencies agree with the report from india.(16) lugo-janer and coworkers and bencini and colleagues reported infectious lesions as the most common skin manifestation in transplant recipients.(13,14) we found that the risk of infectious lesions increased in proportion to the time elapsed since transplantation. plain warts were detected in 37.3% of the cases and were considered as the most common infection in the present study, while the prevalence of warts has been reported to be 6.6%, 43%, and 48% in the previous studies.(12,17,18) these differences may be due to the different duration of follow-ups. therefore, cutaneous lesions infected with human papillomavirus may develop later and are related to the follow-up duration. pityriasis versicolor has been shown to be a common fungal infection in transplant patients and more common than the general population.(19) pityriasis versicolor was reported in 24.9% of the patients in this study, 36% in saudi arabia, 13.3% in india, 27.4% in italy, and 36.3% in turkey.(12,16,19,20) hepburn and colleagues performed a study on 52 kidney transplant recipients in new zealand and reported malignancies in 9 (17.3%) and actinic keratosis in 20 (38.46%) patients which had occurred in the exposed areas to sunlight. they showed that scc was more frequent than bcc.(17) the frequency of skin cancers is higher in transplant patients and correlates with the posttransplant duration of followup and immunosuppressive therapy. in this study scc was the most common skin malignancy. in a 23-year follow-up study on 793 transplant recipients in spain, tumors occurred in at least 10% of these patients and included cancers in the skin (46%) and other parts (56%). this study showed that malignancy was an important cause of morbidity and mortality in transplant recipients.(21) in the study by cohen and coworkers on 580 transplant patients, 59 out of 170 skin lesion biopsies showed malignancy on pathologic examination. half of these lesions were scc and they mostly occurred in sun-exposed areas.(22,23) the frequency of malignancies is influenced by age, sex (more frequent in men), duration of the follow-up, immunosuppression with cyclosporine a, color of patient’s eyes (more frequent in those with light colors), pretransplant scc or actinic keratosis, place of residency (tropical areas), smoking, and childhood sunburn.(24-26) bunney and associates reported no difference between the dermatological effects of two immunosuppressive regimens with azathioprine and cyclosporine a in kidney transplant patients except for hypertrichosis.(27) in the present study, it was concluded that the type of immunosuppressive regimens had no influence on the prevalence of skin diseases in these patients. conclusion transplanted patients are at the risk of skin lesions including skin neoplasms, which is an important table 2. frequency of skin diseases in relation to follow-up duration* *values in parentheses are percents. follow-up number of patients drug-related lesions skin neoplasms < 1 year 47 45 (95.7) 1 (2.1) 1 to 5 years 124 119 (96.0) 4 (3.2) > 5 years 62 62 (100.0) 8 (12.9) skin diseases in kidney transplantation—zamanian et al urology journal vol 3 no 4 autumn 2006 233 cause of morbidity and mortality among these patients. therefore, a careful and regular examination of kidney recipients by a dermatologist is mandatory. the physician’s advices such as sun avoidance should be a part of the posttransplant care. conflict of interest none declared. references 1. penn i. tumors of the immunocompromised patient. annu rev med. 1988;39:63-73. 2. penn i. cancers complicating organ transplantation. n engl j med. 1990;323:1767-9. 3. carpenter cb, milford el, sayegh mh. transplantation in the treatment of renal failure. in: kasper dl, braunwald e, fauci as, hauser sl, longo dl, jameson al, editors. harrison’s principles of internal medicine. 16th ed. new york: mcgrow-hill; 2005. p. 1668-74. 4. berg d, otley cc. skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. j am acad dermatol. 2002;47:1-17. 5. jensen p, hansen s, moller b, et al. skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. j am acad dermatol. 1999;40:177-86. 6. boyle j, mackie rm, briggs jd, junor bj, aitchison tc. cancer, warts, and sunshine in renal transplant patients. a case-control study. lancet. 1984;1:702-5. 7. mclelland j, rees a, williams g, chu t. the incidence of immunosuppression-related skin disease in long-term transplant patients. transplantation. 1988;46:871-4. 8. gupta ak, cardella cj, haberman hf. cutaneous malignant neoplasms in patients with renal transplants. arch dermatol. 1986;122:1288-93. 9. hintner h, fritsch p. skin neoplasia in the immunodeficient host. the clinical spectrum: kaposi’s sarcoma, lymphoma, skin cancer and melanoma. curr probl dermatol. 1989;18:210-7. 10. greene mh, young ti, clark wh jr. malignant melanoma in renal-transplant recipients. lancet. 1981;1:1196-9. 11. spencer es, andersen hk. viral infections in renal allograft recipients treated with long-term immunosuppression. br med j. 1979;2:829-30. 12. rafi a, ghacha r, sinha a, issam a, mohammad i. spectrum of skin diseases in renal transplant recipients. dial transplant. 2001;30:282-5. 13. lugo-janer g, sanchez jl, santiago-delpin e. prevalence and clinical spectrum of skin diseases in kidney transplant recipients. j am acad dermatol. 1991;24:410-4. 14. bencini pl, montagnino g, sala f, de vecchi a, crosti c, tarantino a. cutaneous lesions in 67 cyclosporintreated renal transplant recipients. dermatologica. 1986;172:24-30. 15. lesnoni la parola i, citterio f, nanni g, serino f, borzi mt, rotoli m. [skin manifestations in 140 kidney transplants]. recenti prog med. 1992;83:61-3. italian. 16. chugh ks, sharma sc, singh v, sakhuja v, jha v, gupta kl. spectrum of dermatological lesions in renal allograft recipients in a tropical environment. dermatology. 1994;188:108-12. 17. hepburn dj, divakar d, bailey rr, macdonald kj. cutaneous manifestations of renal transplantation in a new zealand population. n z med j. 1994;107:497-9. 18. rudlinger r, smith iw, bunney mh, hunter ja. human papillomavirus infections in a group of renal transplant recipients. br j dermatol. 1986;115:681-92. 19. virgili a, zampino mr, la malfa v, strumia r, bedani pl. prevalence of superficial dermatomycoses in 73 renal transplant recipients. dermatology. 1999;199: 31-4. 20. gulec at, demirbilek m, seckin d, et al. superficial fungal infections in 102 renal transplant recipients: a case-control study. j am acad dermatol. 2003;49: 187-92. 21. dreno b. skin cancers after transplantation. nephrol dial transplant. 2003;18:1052-8. 22. cohen eb, komorowski ra, clowry lj. cutaneous complications in renal transplant recipients. am j clin pathol. 1987;88:32-7. 23. bordea c, wojnarowska f, millard pr, doll h, welsh k, morris pj. skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. transplantation. 2004;77:574-9. 24. marcen r, pascual j, tato am, et al. influence of immunosuppression on the prevalence of cancer after kidney transplantation. transplant proc. 2003;35: 1714-6. 25. lindelof b, granath f, dal h, brandberg y, adami j, ullen h. sun habits in kidney transplant recipients with skin cancer: a case-control study of possible causative factors. acta derm venereol. 2003;83:189-93. 26. ramsay hm, fryer aa, hawley cm, smith ag, nicol dl, harden pn. factors associated with nonmelanoma skin cancer following renal transplantation in queensland, australia. j am acad dermatol. 2003;49:397-406. 27. bunney mh, benton ec, barr bb, smith iw, anderton jl, hunter ja. the prevalence of skin disorders in renal allograft recipients receiving cyclosporin a compared with those receiving azathioprine. nephrol dial transplant. 1990;5:379-82. fall 2012 08.pdf 725vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l 1department of urology, chhatrapati shahuji maharaj medical university, formerly, king george medical university, lucknow, india 2welcome trust center for human genetics, university of oxford, oxford, uk apul goel,1 anuj goel,1 diwakar dalela2 redefining needs for better follow-up in urinary tuberculosis corresponding author: apul goel, ms (surg); mch (urol); dnb (urol); mnams department of urology, chhatrapati shahuji maharaj medical university, formerly, king george medical university, lucknow, 226003, india tel: +91 983 918 1465 e-mail: goelapul1@rediff mail.com received january 2011 accepted march 2011 case report keywords: tuberculosis, urogenital, prevalence, diagnosis, ureter introduction g enitourinary tuberculosis (gutb) is an uncommon form of tuberculosis, and its prevalence has shown a declining trend.(1) tuberculous ureteral involvement is a serious problem with possible grave consequence if not detected and treated timely. therefore, frequent intravenous urographies (ivu) are recommended both during the initial phase when anti-tuberculous treatment (att) is started(1) and even after the completion of therapy.(2) there is paucity in recent literature about the real behavior of ureteral involvement with the advent describe a case of gutb, where ureteral stricture and small capacity urinary bladder developed after 1-year of completion of treatment. this case re-emphasizes the need for long-term follow-up of these cases. case report a 40-year-old man with hematuria, dysuria, and frequency was diagnosed as gutb on the basis of microbiologic evidences. an ivu at that time revealed bilateral normal kidneys with a round bladder and mildly dilated right lower ureter (figure 1). there was no evidence of an immunocomhe was put on standard 9-month att, namely rifampicin, isoniazid, ethambutol, and pyrazinamide. thereafter, the patient’s symptoms, especially hematuria and dysuria, improved. an ivu done at completion of treatment revealed mild right-sided hydroureteronephrosis (figure 2). urine 726 | case report figure 1. initial intravenous urogram shows normal kidneys, right lower ureteral dilation, and a round bladder. figure 3. intravenous urogram after 1-year of completed treatment shows right non-visualized kidney with small capacity irregularly scarred bladder. figure 2. intravenous urogram at completion of therapy shows mild right-sided hydroureteronephrosis with a round bladder and thick walls. figure 4. antegrade study (nephrostogram) revealed a long right lower ureteral stricture. 727vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l evolution of genitourinary tuberculosis | goel et al cating cure of infection. the options of either double j stent placement or close follow-up was discussed. however, at this stage, the patient was lost to follow-up and presented after 1 year with frequency of micturition. intravenous urogram now revealed right-sided non-visualized kidney with irregularly contracted bladder (figure 3). antegrade study revealed a long lower ureteral stricture (figure 4) while radionuclide renal scan showed 20% differential renal function. augmentation cystoplasty with ileal replacebrosis only. tissue culture from the bladder wall for acid fast bacilli was not done at this time. at 2-year of follow-up, the patient is asymptomatic with stable disease (figures 5 and 6). discussion the recommended follow-up protocol, regardless of the manifestation of gutb, is evaluation at 3, 6, and 12 months after the course of chemotherapy.(2) during these visits, liver function tests, three early-morning urine specimens, and an ivu should be performed to ensure patency of the urinary figure 5. intravenous urogram 1-year after augmentation cystoplasty and replacement of the lower ureter with ileum showing some degree of return of function of the right kidney. figure 6. micturating cystourethrogram showing the augmented bladder with bilateral vesicoureteral reflux. 728 | references 1. mcaleer sj, johnson cw, johnson wd. tuberculosis and parasitic and fungal infections of the genitourinary system. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. 9 ed. philadelphia: saunders elsevier; 2007:436-70. 2. johnson cw, lowe fc, johnson jr wd. genitourinary tuberculosis. in: ball jr tp, marshall ff, eds. aua update series. vol 22. houston, texas: american urological association inc.; 2003:303-7. 3. shin ky, park hj, lee jj, park hy, woo yn, lee ty. role of early endourologic management of tuberculous ureteral strictures. j endourol. 2002;16:755-8. 4. goel a, dalela d. options in the management of tuberculous ureteric stricture. indian j urol. 2008;24:376-81. 5. horne nw, tulloch ws. conservative management of renal tuberculosis. br j urol. 1975;47:481-7. 6. gow jg. results of treatment in a large series of cases of genito-urinary tuberculosis and the changing pattern of the disease. br j urol. 1970;42:647-55. 7. prasad k, singh mb. corticosteroids for managing tuberculous meningitis. cochrane database syst rev. 2008cd002244. tract.(2) if disease progression or stricture formation is seen, endourological management at an early stage may be more effective and also prevent renal loss.(3,4) although such an intensive follow-up is recommended, there is a paucity of recent literature where deterioration has been documented on serial follow-up after completion of treatespecially in underdeveloped countries. therefore, emphasis plained to the patient.(4) this case highlights the dilemma faced by urologists in the treatment of tuberculous ureteral infection both at the time of starting treatment and also after apparently adequate and successful treatment in resource-poor situations. obviously, completion of att; thus, underscoring the importance of prolonged follow-up even after successful treatment. timely detection of ureteral involvement could have prevented renal deterioration; however, the patient may still need surgery for small contracted bladder. another option, although not accepted as standard, could have been the use of steroids during the initial period.(5-7) conflict of interest none declared. case report 993vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l comparing the effectiveness of intranasal desmopressin and doxazosin in men with nocturia: a pilot randomized clinical trial cavit ceylan,1 taner ceylan,2 omer gokhan doluoglu,3 selcen yüksel,4 koray ağras5 purpose: we aimed to compare the effectiveness of intranasal desmopressin and doxazosin treatments in patients with nocturia and benign prostatic hyperplasia (bph). material and methods: thirty one men with bph and three or more episodes of nocturia were randomized to receive 2 mg doxazosin at night for two weeks increasing to 4 mg for a further two weeks versus 20 µg intranasal desmopressin at night. for all patients, number of nocturia, urinary flow rate, residual urine volume and quality of life score were checked. outcomes were measured at two months. the comparison of before and after treatment changes between the groups were done by student’s t-test. results: in doxazosin group, mean number of nocturia were 3.2 ± 0.4 (3-4 times) times per night and 1.2 ± 0.8 (0-3 times) times per night before and after treatment, respectively. in desmopressin group, mean number of nocturia were 3.4 ± 0.5 (3-4 times) and 1.5 ± 0.6 (1-3 times) times per night before and after treatment, respectively. in doxazosin group, mean residual urine volumes were 44.3 ± 35.9 ml (range 0-120 ml) and 23.1 ± 18.8 ml (range 0-50 ml) before and after treatment, respectively. in desmopressin group, mean residual urine volumes were 36.6 ± 32.4 ml (range 0-120 ml) and 14.0 ± 26.9 ml (range 0-90 ml) before and after treatment, respectively. improvements in number of nocturia, residual urine volume, quality of life scores and peak urinary flow rates weren’t statistically significant between two groups, whereas change in international prostate symptom score (ipss) score was more significant in doxazosin group. conclusion: intranasal desmopressin, is an effective symptomatic treatment of men with bph complaining of nocturia, as well as doxazosin treatment. key words: desmopressin; prostatic hyperplasia; drug therapy; quality of life corresponding author: omer gokhan doluoglu, md clinic of urology, konya numune hospital, nalcaci/ konya, turkey tel: +90 332 263 1001 fax: +90 332 263 1050 e-mail: drdoluoglu@yahoo. com received november 2011 accepted october 2012 1third clinic of urology, türkiye yüksek ihtisas training and research hospital, ankara-turkey. 2clinic of urology, yenimahalle state hospital, ankara-turkey 3clinic of urology, konya numune hospital, konyaturkey 4 department of biostatistics, faculty of medicine, university of ankara, ankara-turkey 5second clinic of urology, ankara atatürk training and research hospital, ankara-turkey miscellaneous 994 | introduction nocturia is one of the most common cause of in-somnia, negatively affecting the quality of life in elderly population.(1-3) in the past, bladder and prostate diseases were regarded as the cause of nocturia. but today, it is recognized that nocturia can also be caused by excessive urine production, nocturnal detrusor hyperactivity, diminished functional bladder capacity and lower urinary tract abnormalities.(4-7) aging is associated with increased prevalence of bph and decreased nocturnal release of antidiuretic hormone.(8,9) as reported in the literature, desmopressin and alpha-blocker therapy significantly decreased symptoms of nocturia.(10-13) the aim of the study is to compare the effect of intranasal desmopressin to that of alpha blockers in reduction of ipss score and reduction of post void residual urine as much as to compare pre and post intervention, the effect of intranasal desmopressin on nocturnal voiding frequency. in this study the primary outcome variable was the frequency of nocturia. secondary outcome variables were residual urine volume and the international prostate symptom score (ipss). we were interested in the comparison between desmopressin as change from baseline and between desmopressin and doxazosin, an alpha blocker. material and methods our study was a preliminary (pilot) study to evaluate the efficacy of doxazosin and desmopressin. eighty four consecutive patients with advanced ages who admitted to our outpatient clinic between january 2011 and june 2011 with the complaints of lower urinary tract symptoms (luts) and nocturia at three or more times per night were evaluated and randomized into two groups. subjects with pathologically diagnosed prostate cancer (6 patients), positive urine culture (18 patients), prior surgery of the bladder (2 patients), prostate (10 patients), urethra (2 patients), and additional urological pathology (1 patients-trauma) were excluded. besides, patients who do not attend treatment properly (14 patients) excluded from the study. the remaining 31 patients (16 patients group 1 and 15 patients group 2) were included in the study. number of nocturia, residual urine volume, urinary flow rate, ipss symptom scores and quality of life scores were determined for all patients. also, serum total and free prostate specific antigen (psa) levels, urinalysis, urine culture, digital rectal examination (dre) were performed. we used 7-item ipss symptom score for symptom scoring and the eighth question in the ipss form for quality of life scoring. besides, the amount of residual urine was measured by bladder catheterization and peak urinary flow rate by an uroflowmetry device. the number of nocturia was assessed by the 7th question in ipss form. each patient were performed transrectal ultrasonography (trus) in order to evaluate the morphology and volume of prostate and to perform needle biopsy, if necessary. patients with psa above 4 ng/ml or suspicious digital examination findings were done trus guided needle biopsy. all patients were filled information form and our study was approved by ethical committee. patients in the first group were given 2 mg doxazosin orally before bedtime for two weeks, and doxazosin was continued in 4 mg dose orally before bedtime in the following days after two weeks. the second group were given 20 μg intranasal desmopressin before bedtime. after two months, all patients were readmitted for controls and urine culture, number of nocturia, ipss scoring, urinary flow rate and residual urine determination were repeated. all patients were also questioned for side effects. statistical analysis in each group, the difference between peak urinary flow rate and ipss values before and after treatment were analyzed by paired samples t-test. non-parametric tests were used to analyze life quality score, number of nocturia and residual urine differences. the comparison of before and after treatmiscellaneous table 1. mean values of age, serum total and free prostate specific antigen (psa) in two groups. group 1 group 2 p value mean age (years) 58.1 ± 7.8 57.7 ± 9,8 .903 mean total-psa (ng/ml) 1.8 ± 1.4 2.6 ± 3.9 .800 mean free-psa (ng/ml)) 0.5 ± 0.3 0.7 ± 0.6 .545 995vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l ment changes between the groups were done by student’s ttest and the comparison of before and after treatment values within the groups were done by wilcoxon signed rank test. results mean age of the patients was 58.1 ± 7.8 years (range 50-75 years) and 57.7 ± 9.8 years (range 44-79 years) in doxazosin and desmopressin groups, respectively. there were no statistically significant difference between two groups in terms of mean age. mean serum total-psa values and mean serum free-psa values in the first and the second group are shown in table 1. there were no statistically significant difference between two groups in terms of mean serum total and free-psa. in doxazosin group, mean number of nocturia were 3.2 ± 0.4 (3-4 times) times per night and 1.2 ± 0.8 (0-3 times) times per night before and after treatment, respectively. in desmopressin group, mean number of nocturia were 3.4 ± 0.5 (3-4 times) and 1.5 ± 0.6 (1-3 times) times per night before and after treatment, respectively. there were no statistically significant difference between two groups in terms of mean number of nocturia before and after treatment (p = .495 vs. p = .379, respectively). however, in both groups, difference between mean number of nocturia before and after treatment were found to be statistically significant (p = .001). on the other hand, mean change in number of nocturia between two groups was not statistically significant (p = .711). in doxazosin group, mean residual urine volumes were 44.3 ± 35.9 ml (range 0-120 ml) and 23.1 ± 18.8 ml (range 0-50 ml) before and after treatment, respectively. in desmopressin group, mean residual urine volumes were 36.6 ± 32.4 ml (range 0-120 ml) and 14.0 ± 26.9 ml (range 0-90 ml) before and after treatment, respectively. the difference between residual urine volumes within each group before and after treatment was statistically significant (p = .011 and p = .005, respectively). within each groups, mean quality of life scores before and after treatment were found to be statistically significant (p = .001 vs. p = .001, respectively). the difference in the mean rate of improvement in quality of life scores between two groups was not statistically significant (p= 0.358). within each groups, mean ipss scores before and after treatment were found to be statistically significant (p < .001). at the end of two months, change in mean ipss scores was greater in doxazosin group than in desmopressin group (p = .011). in doxazosin group, difference between mean urinary peak flow rates before and after treatment table 2. mean values of residual urine volume, quality of life score, ipss score, peak urinary flow rate, and number of nocturia before and after treatment in both groups. group 1 (doxazosin) group 2 (desmopressin) before treatment after treatment p value before treatment after treatment p value number of nocturia (per night) p = .711b 3.2 ± 0.4 1.2 ± 0.8 .001a 3.4 ± 0.5 1.5 ± 0.6 .001a peak urinary flow rate (ml/s) p = .011b 13.3 ± 5.5 17.8 ± 7.8 .035a 17.6 ± 7.7 19.2 ± 5.3 .470a ipss score (point) p = .011b 14.6 ± 4.3 6.5 ± 2.7 .0001a 12.1 ± 4.9 7.4 ± 4.2 .0001a residual urine (ml) p = .711b 44.3 ± 35.9 23.1 ± 18.8 .011a 36.6 ± 32.4 14.0 ± 26.9 .005a quality of life score (point) p = .358b 3.6 ± 0.8 1.8 ± 0.5 .001a 3.4 ± 0.9 1.8 ± 0.5 .001a a: the difference within each group before and after treatment b: change in parameters between two groups intranasal desmopressin in men with nocturia | ceylan et al 996 | were found to be statistically significant (p = .035), while not statistically significant in the second group (p = .470). on the other hand, change in mean urinary peak flow rates between two groups was not statistically significant (p = .011). no major complications occurred in study groups during treatment. at the end of two months, only one patient in doxazosin group (6.25 %) complained about dizziness and drowsiness during the first two days of treatment. in the following days the complaint of the patient disappeared. only one patient in desmopressin group (6.66%) complained about dry mouth but the complaint was not so much severe to leave the treatment. also in desmopressin group, severe hyponatremia was not observed. discussion normally, antidiuretic hormone secretion increases at night and nocturnal urine output decreases. reduced secretion of antidiuretic hormone at night may lead to nocturnal polyuria and nocturia.(14) nocturia manifests itself in the form of urinating at least once a night in 72 % and three or more times a night in 24 % of elderly patient population.(15-16) in this age group, nocturnal polyuria may depend on both the changes in biological rhythm of the body and bladder outlet obstructions, detrusor overactivity, neurological causes and detrusor hyperactivity. as a result, nocturia is seen with reduced functional bladder capacity.(17-19) on the other hand, it should be noted that nocturia is also an important part of lower urinary tract symptoms of bph. the most popular treatment of lower urinary tract symptoms and nocturia is alpha-blockers while desmopressin (ddavp) therapy, a synthetic derivative of arginine vasopressin (adh = antidiuretic hormone), have come up to clinical practice.(20,21) the aim of ddavp treatment is to substitute the lacking endogenous vasopressin, as well as in parkinson's disease, and to contribute indirectly to eliminate nocturia symptoms. (22) after prostatectomy, 19-33 % of patients have persistent nocturia complaints. this also suggests that lower urinary tract dysfunction is not the only cause of nocturia. in these cases, other possible causes such as excessive fluid intake, diabetes mellitus, neurological diseases, renal and cardiac dysfunction, should also be evaluated.(20) in our study, patients in pure middle age group who have symptoms of bph were included. those with pathologically diagnosed prostate cancer, reproductive positive urine culture, diabetes mellitus, previous bladder, prostatic, urethral surgery and additional urological pathology were excluded from study. in previous studies, it was reported that ddavp treatment in patients with nocturnal polyuria or nocturia significantly reduced the number of nocturia. asplund and associates gave 0.4 mg/day ddavp orally at night to 17 patients with nocturnal polyuria for two weeks. it was reported that nocturnal urine volume reduced to 0.59 ml/min, average number of nocturia reduced to 1.1 per night, average sleep time increased by 1.4 hours, the treatment was well tolerated and no serious side effect was observed.(23) in another study, cannon and associates observed a significant decrease in number of nocturia and nocturnal urine volume in 40μgr ddavp-treated group than the placebo group.(24) in another study of 12 patients with intranasal ddavp, chancellor et al. observed a decline in average aua symptom score index from 19 ± 6 to 12 ± 6 points and in average number of nocturia from 3.6 ± 0.5 to 1.8 ± 1.1 times per night.(25) similarly in our study, mean number of nocturia reduced from 3.4 ± 0.5 to 1.5 ± 0.6 times per night and mean ipss score reduced from 12.1 ± 4.9 to 7.4 ± 4.2 points this reductions were statistically significant. additionally, we studied urinary peak flow rates and residual urine volumes. in ddavp group, we did not observe statistically significant improvement in maximum flow rate. however, we also detected in desmopressin group that significant reduction of nocturia provided an improvement in the life quality via prolonging the duration of uninterrupted sleep. in ddavp group, we also observed statistically significant improvements in ipss score, quality of life score, residual urine volume and number of nocturia, except maximum flow rate. on the other hand, we think that the positive effect of ddavp on the number of nocturia was by reducing nocturnal urine production and similarly reducing residual urine volume. although the patients in desmopressin group were not filled voiding diaries before and after treatment, we think that improvement in ipss scores could be depending on the improvement in bladder storage functions. alpha-blocker therapy in patients with bph increased average urinary flow rate by 20-30%, reduced symptom scores miscellaneous 997vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l intranasal desmopressin in men with nocturia | ceylan et al by 20-50% and reduced residual urine volume by 29%. (26,27) fawzy and associates detected marked improvements in qmax and symptom scores by 88% in 41 patients treated with 8 mg doxazosin, when compared with placebo.(28) lukacs and associates reported that α-blocker therapy provided improvements on quality of life by 30% at the third month and by 43% at the end of one year.(29) in our study, mean number of nocturia reduced from 3.2 ± 0.4 to 1.2 ± 0.8 times per night in doxazosin group and from 3.4 ± 0.5 to 1.5 ± 0.6 times per night in ddavp group. in both groups, changes in residual urine volume, number of nocturia, quality of life score and maximum urinary flow rate were not statistically significant. however, the improvement of mean ipss score was significantly different in doxazosin group, when compared with ddavp group. this difference may be caused by the reducing effect of alpha-blocker treatment on bladder neck, prostatic capsule and prostatic smooth muscle tone. our study is one of the few studies examined the intranasal form of desmopressin in treatment of nocturia and there are also few studies investigated the effect of desmopressin on residual volume. side effects of alpha-blocker therapy especially due to the blockade of receptors in the cardiovascular system are dizziness, syncope, postural hypotension, fatigue, asthenia, headache, flu-like syndrome, nasal congestion and accommodation disorder.(30) in our study , only one patient in doxazosin group (6.25 %) was noted to have occasional dizziness and drowsiness during the first two days of treatment. the most serious and potentially fatal side effect of desmopressin treatment is hyponatremia due to water retention seen in 12-22 % of patients. headache, nausea, vomiting, weakness, dizziness, ataxia, or weight gain have been reported in patients with risk of hyponatremia.(31-33) in our study, one patient was noted to have dry mouth in ddavp group, but patients declared no side effects as serious as to leave the treatment. however, serious side effects should be assessed more properly by extending the follow-up period. limitation of this study is the small number of patients. currently, we are establishing a similar clinical study about the effectiveness of oral form desmopressin. we cannot give you any data or make any comment about the subject, because our study is still going on. conclusion intranasal desmopressin treatment is a safe and effective treatment as alpha-blocker therapy in bph patients suffering from luts and nocturia, with minimal side effects and maximum patient safety. additional multi-center studies with more subjects will support the results of our study. conflict of interest none declared. references 1chute cg, panser la, girman cj, et al. the prevalence of prostatism: a population-based survey of urinary symptoms. j urol. 1993;150:85-9. 2 homma y, imajo c, takahashi s, kawabe k, aso y. urinary symptoms and urodynamics in a normal elderly population. scand j urol nephrol. 1994;157:27-30. 3 imai k, okabe k, kobayashi d, et al. voiding disturbance in elderly males examined by prostate mass screening. gunma urological oncology study group. nippon hinyokika gakkai zasshi. 1991;82:1790-9. 4hunsballe jm, rittig s, pedersen eb, olesen ov, djurhuus jc. single dose imipramine reduces nocturnal urine output in patients with nocturnal enuresis and nocturnal polyuria. j urol. 1997;158:830-6. 5 hye won lee, myung-soo choo, jeong gu lee, et al. desmopressin is an effective treatment for mixed nocturia with nocturnal polyuria and decreased nocturnal bladder capacity. j korean med sci. 2010;25:1792–97. 6 simonsen o, moller-madsen b, dorflinger t, norgaard jp, jorgensen hs, lundhus e. the significance of age on symptoms and urodynamicand cystoscopic findings in benign prostatic hypertrophy. urol res. 1987;15:355-8. 7weiss jp, blaivas jg. nocturia. j urol. 2000;163:5-12. 8 djavan b, fong yk, harik m, et al. longitudinal study of men with mild symptoms of bladder outlet obstruction treated with watchful waiting for four years. urology. 2004;64:1144-8. 9asplund r. the nocturnal polyuria syndrome (nps). gen pharmacol. 1995;26:1203-9. 10mattiasson a, abrams p, van kerrebroeck p, walter s, weiss j. efficacy of desmopressin in the treatment of nocturia: a double-blind placebo-controlled study in men. bju int. 2002;89:855-62. 11nam sg, moon dg, kim jj. efficacy of desmopressin in treatment of adult nocturia. korean j urol. 2004;45:49–55. 12 lepor h. the treatment of benign prostatic hyperplasia: a glimpse into the future. urol clin north am. 1995;22:455-9. 13chancellor mb, atan a, rivas da, watanabe t, tai hl, kumon h. beneficial effect of intranasal desmopressin for men with benign prostatic hyperplasia and nocturia: preliminary results. tech urol. 1999;5:191-4. 998 | 14miller m. nocturnal polyuria in older people: pathophysiology and clinical implications. j am geriatr soc. 2000;48:1321-9. 15 barker jc, mitteness ls. nocturia in the elderly. gerontologist. 1988;28:99-104. 16sommer p, nielsen kk, bauer t, et al. voiding patterns in men evaluated by a questionnaire survey. br j urol. 1990;65:155-60. 17kim et, lee si, lee ks. the etiology and classification of nocturia in adults. korean j urol. 2001;42:1075-79. 18asplund r. nocturia in relation to sleep, health, and medical treatment in the elderly. bju int. 2005;96:15-21. 19 weiss jp, blaivas jg, stember ds, chaikin dc. evaluation of the etiology of nocturia in men: the nocturia and nocturnal bladder capacity indices. neurourol urodyn. 1999;18:559-65. 20weiss jp, blaivas jg, stember ds, brooks mm. nocturia in adults: etiology and classification. neurourol urodyn. 1998;17:467-72. 21ziada a, rosenblum m, crawford ed. benign prostatic hyperplasia: an overview. urology. 1999;53:1-6. 22suchowersky o, furtado s, rohs g. beneficial effect of intranasal desmopressin for nocturnal polyuria in parkinson's disease. mov disord. 1995;10:337-40. 23asplund r, sundberg b, bengtsson p. oral desmopressin for nocturnal polyuria in elderly subjects: a double-blind, placebo-controlled randomized exploratory study. bju int. 1999;83:591-5. 24cannon a, carter pg, mcconnell aa, abrams p. desmopressin in the treatment of nocturnal polyuria in the male. bju int. 1999;84:20-4. 25chancellor mb, rivas da, staas we jr. ddavp in the urological management of the difficult neurogenic bladder in spinal cord injury: preliminary report. j am paraplegia soc. 1994;17:165-7. 26sanda mg, doehring cb, binkowitz b, et al. clinical and biological characteristics of familial benign prostatic hyperplasia. j urol. 1997;157:876-9. 27ford ap, williams tj, blue dr, clarke de. alpha 1-adrenoceptor classification: sharpening occam's razor. trends pharmacol sci. 1994;15:167-70. 28fawzy a, braun k, lewis gp, gaffney m, ice k, dias n. doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study. j urol. 1995;154:105-9. 29lukacs b, mccarthy c, grange jc. long-term quality of life in patients with benign prostatic hypertrophy: preliminary results of a cohort survey of 7,093 patients treated with an alpha-1-adrenergic blocker, alfuzosin. qol bph study group in general practice. eur urol. 1993;24:34-40. 30 jardin a, bensadoun h, delauche-cavallier mc, attali p. alfuzosin for benign prostatic hypertrophy. lancet. 1991;338:947. miscellaneous 31mattiasson a, abrams p, van kerrebroeck p, walter s, weiss j. efficacy of desmopressin in the treatment of nocturia: a double-blind placebo-controlled study in men. bju int. 2002;89:855-62. 32rembratt a, norgaard jp, andersson ke. desmopressin in elderly patients with nocturia: short-term safety and effects on urine output, sleep and voiding patterns. bju int. 2003;91:642-6. 33rembratt a, riis a, norgaard jp. desmopressin treatment in nocturia; an analysis of risk factors for hyponatremia. neurourol urodyn. 2006;25:105-9. 1059vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l siavash falahatkar, hadiseh donyamali, mohammad ali joafshani, reza shahrokhi damavand, saba hoda, samaneh esmaeili, keivan gholamjani moghaddam, sara nikpour the comparison between human leukocyte antigen system incidence in patients with bladder cancer and normal controls corresponding author: nicholas g. cost, md division of pediatric urology, cincinnati children’s hospital medical center, 3333 burnet avenue, mlc 5037, cincinnati, ohio 45229, usa tel: +513 363 0773 fax: +513 636 6753 e-mail: nicholas.cost@sbcglobal.net received january 2012 accepted october 2012 corresponding author: hadiseh donyamali, md urology research center, guilan university of medical sciences, rasht, iran. tell: 0098 912 201 4721 fax: 0098 131 552 5259 e-mail: hadiseh_donyamali@ yahoo.com received april 2012 accepted december 2012 purpose: to determine the frequency of human leukocyte antigen (hla)-b5 in patients with bladder cancer compared with normal population. materials and methods: in this cross sectional study, from november 2009 until november 2010, 35 patients with pathologic diagnosis of bladder cancer who referred to urology clinic of razi hospital were studied. also, 130 healthy transplant donation volunteers who referred for hla-typing to guilan blood transfusion organization, were selected. inclusion criterion was pathologic diagnosis of bladder cancer regardless of stage and grade of tumor. exclusion criteria were presence of other urologic diseases. the information of these cases was extracted from medical records, collected and analyzed. results: hla-b5 was positive in 34.3% of the patient group and in 39.2% of the controls. statistical analysis showed no significant association between hla-b5 and bladder cancer (p = .15). there were no significant differences between grade (p = .107) and relapse (p = .327) of bladder tumor with presence of hla-b5. conclusion: there was no significant association between hla-b5 and bladder cancer. the grade and the relapse of tumor had no association with presence or absence of hla-b5. keywords: antigen presentation; histocompatibility antigens class i; urinary bladder neoplasms; humans; hla-b5 antigen. urological oncology 1060 | urological oncology introduction cancer is a public health problem worldwide, pre-dominantly in developing countries. in all types of malignancies, urogenital cancers have an important role in increasing mortality. every year 132,000 people die from bladder cancer and its mortality rate is 10 per 100000 in men and 2.4 per 100,000 in women.(1) the incidence of urogenital cancers varies in different regions of the world.(2) bladder cancer is the ninth most common cancer in the world(3) and it is the fourth most common cancer in males in iran.(4) in middle-aged and elderly men, bladder cancer is the second most common cause of malignancy after prostate cancer.(5) according to iranian center for disease control and prevention, bladder cancer encompasses 7.04% of all cancers in iran. the incidence rate of bladder cancer has been reported 11.30 in males and 2.86 females per 100,000. amazingly, in some areas of iran the incidence of this cancer reaches to as high as 15.9 per 100,000.(6) despite significant advances in the prevention of disease progression and improvement of survival, treatment of bladder cancer still remains a challenge. the main problem is that, patients who will have a benign clinical course of the disease are not distinguishable from those who will experience an invasive course and conventional histopathologic examination is not able to predict the biological behavior of bladder tumors correctly. prognostic markers could help the physician to differentiate the superficial bladder cancer from invasive. (7,8) recently some studies demonstrated that some specific cell surface antigens are associated with poorer prognosis.(9) human leukocyte antigen (hla) class i molecules has an important role in the cell-mediated immune system, particularly as antigen-presenting molecules for cytotoxic t lymphocytes (ctls). ctl can identify antigenic peptides presented on the cell surface with hla class i molecules, and kill the target cell. down-regulation of hla class i was found to be involved in the immune escape of malignant tumors. it is reported that this event is noted in malignant tumors such as malignant melanoma, colorectal, lung, and ovarian cancers, and would affect survival of some patients with these diseases.(10) distribution of hla antigens varies in different populations. for instance there is complete absence of an antigen in a population (e.g., hla-a1 in the japanese race) and the exclusive presence of an antigen in a specific ethnic population (e.g., hla-bw24 in black).(11) levin and colleagues investigated hla class i expression in 33 patients with bladder transitional cell carcinoma (tcc) and its correlation with tumor differentiation and patients. they reported that the 5-year survival in patients who were positive for hla class i, was significantly better (74% vs. 36%). these results suggest a possible role for expression of hla class i, as a prognostic factor in patients with bladder tumor.(14) hla class i expression has shown as a prognostic marker for muscle-invasive bladder cancer.(10) since hla-b5 has the highest prevalence in the hla-b alleles in iran,(11) and some studies suggest a positive relationship between bladder cancer and hla-b5, we study the prevalence of hla-b5 in patients with bladder cancer and compare the results with hla-b5 prevalence in healthy kidney donors. materials and methods study population from november 2009 until november 2010, 35 patients with pathologically confirmed bladder cancer were enrolled in this study. also 130 healthy kidney donors, who referred for hla-typing were served as controls. inclusion criterion was pathologically confirmed bladder cancer, regardless of tumor stage and grade. exclusion criterion was presence of other urologic diseases. the following data were collected: age, sex, social and family history, occupational exposure related to bladder cancer; and type of drinking water. all patients followed up by cystoscopy every 3-month, and the presence of tumor were defined as a recurrence. comparison was performed using chi-square test. the statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0 was used for statistical analysis. p value <0. 05 was considered significant. results the mean age of patients was 45.13 ± 51.65 years (age range, 36 to 85 years) .of study subjects 34 (97%) were male and one was female. transitional cell carcinoma (tcc) was the most common type of bladder cancer (94.3%). two patients (5.7%) had a family history of bladder cancer. in 8 cases (22.9%), history of occupational exposure to industries of 1061vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l rubber, paint, textiles, resins and aluminum was positive. the relationship between tumor grade and recurrence rate with hla-b5 are shown in table 1. of cases 11 (31.4%) had stage ta, 16 (45.7%) had stage t1 and 8 (22.9%) had stage t2 tumors. hla-b5 was positive in 34.3% (12) of patients group and in 39.2% (51) of controls (table 2). statistical analysis demonstrated that there were no significant differences in the frequency of hla-b5 in patients with bladder cancers as compared with the healthy population (p = .15). as well there was no statistical association between tumor grade and hla-b5 (p = .107) and also there was no significant correlation between recurrence of tumor and hla-b5 (p = .327) (table 1). discussion after confirming the diagnosis of bladder cancer, it is advantageous to determine the likely clinical course and survival outcome. the hla genes are one of the most polymorphic loci in the human genome. the hla complex on chromosome 6 contains more than 200 genes, over 40 of which encode leukocyte antigens. the hla genes express on the surface of the t lymphocytes and, hence, play a major role in the regulation of the immune system. hla molecules have a defending role by detecting self from non-self antigens. the hla genes class i and ii are different in structure and function. the involvement of the hla system in the development of cancer is still scantily understood. cancer cells express a number of genes that normal cells do not, and peptides from some of the protein products of these genes bind to hla molecules. there are different reasons that the t-cell responses which motivated by these hla–peptide complexes are not effective enough to eradicate the cancer cells. one reason for the incompetence of the immune response against tumorassociated antigens is that cancer cells tend to down-regulate the expression of some hla molecules or stop expressing them totally, therefore making them poor targets for cytotoxic t cells. on the other part, the loss of hla molecules from the surface of cancer cells can initiate the activation of natural killer cells, which make a backup system when the cytotoxic t cells fail.(15) associations between hla antigens and susceptibility to different diseases have provided new insight into pathogenetic mechanisms which put someone at higher risk of acquiring some diseases.(16) because of different distribution of antigens in different countries, it is requisite to accommodate the antigens on the base of population. one of the strongest associations is between hla-b27 and ankylosing spondylitis. (15) also falahatkar and colleagues in a study on patients with vesicoureteral reflux (vur) found significant correlation between this disease and hla-b9 and hla-b44.(17) studies of the association between hla antigens and bladder cancer have provided inconsistent results, but do recommend that several hla antigens may be associated with a risk of developing bladder cancer. some studies such as herring and colleagues and colleagues demonstrated positive association between hla-b5 and bladder carcinoma.(12,13) herring and colleagues in a study on 101 patients with bladder tcc found that the antigenic frequency of hlab5 and hlacw4 is higher in patients than in healthy individuals.(12) tokuc and colleagues in a review of hla antigens in 55 patients with bladder tcc found that hlab5 incidence is increased and hlabw35 incidence is decreased and this difference is more noticeable in recurrent tumors.(13) the result of our study is in disagreement with the findings of herring and colleagues investigation, who found a two-fold increase in the frequency of hla-b5 in patients with bladder carcihla system in bladder cancer | falahatkar et al table 1. grade and tumor recurrence distributions of 35 patients with bladder cancer. tumor characteristics n (%) hla-b5 total ppositive (n = 12) negative (n = 23) grade 1 2 (16.7) 6 (26.1) 8 (22.9) .107grade 2 8 (66.6) 7 (30.4) 15 (42.9) grade 3 2 (16.7) 10 (43.5) 12 (34.3) recurrence (+) 4 (33.4) 3 (13) 7 (20) .327 recurrence (-) 8 (66.6) 20 (87) key: hla, human leukocyte antigen system. table 2. hla-b5 frequency in patients with bladder cancer and healthy group. negative positive hla-b5 in healthy group, n (%) 79 (60.8) 51(35.2) hla-b5 in patient group, n (%) 23 (65.7) 12 (34.3) p = .15 key: hla, human leukocyte antigen system. 1062 | noma.(12) however, our study finding is in accord with the observations of braf and colleagues, lytton et and colleagues and saunders and colleagues, who found no change in frequency of the hla-b5 in patients with bladder carcinoma. (18,19,20) some of the contrary results described in different studies may be due to the use of different populations with different risk factors. hla antigen frequencies vary in different ethnic groups and in different geographical regions.(16) our study limitations are very small sample sizes and lack of organized follow up program after treatment to determine prognosis and survival of patients considering their hla-b5 situation. further large scale studies in different ethnic group are needed to draw final conclusion. conclusion this study shows no significant association between hlab5 and bladder cancer. there is no association between the grade and recurrence rate of tumor with the presence or absence of hla-b5, too. acknowledgement we thank all participants and guilan blood transfusion organization that provided the healthy group (kidney donors) data. this study was supported by urology research center of guilan medical university. conflict of interest non declared. references 1. yavari p, sadrolhefazi b, mohagheghi ma, mehrazin r. a descriptive retrospective study of bladder cancer at a hospital in iran (1973-2003). asian pac j cancer prev. 2009;10:681-4. 2. akbari me, hosseini sj, rezaee a, hosseini mm, rezaee i, sheikhvatan m. incidence of genitourinary cancers in the islamic republic of iran: a survey in 2005. asian pac j cancer prev. 2008;9:549-52. 3. badar f, sattar a, meerza f, irfan n, siddiqui n. carcinoma of the urinary bladder in a tertiary care setting in a developing country. asian pac j cancer prev. 2009;10:449-52. 4. kolahdoozan s, sadjadi a, radmard ar, khademi h. five common cancers in iran. arch iran med. 2010;13:143-6. 5. vercelli m, quaglia a, parodi s, crosignani p. cancer prevalence in the elderly. itapreval working group. tumori. 1999;85:391-9. 6. sakhssalim n, hosseini sy, basiri a, eshrati b, mazaheri m, soleimanirahbar a. prominent bladder cancer risk factors in iran. asian pac j cancer prev. 2010;11:601-6. 7. schenkman e, lamm dl. superficial bladder cancer therapy. scientificworldjournal. 2004;4 suppl 1:387-99. 8. stein j, grossfeld g, ginsberg d, et al. prognostic markers in bladder cancer: a contemporary review of the literature. j urol. 1998;160:645-59. 9. amirghofran z, khezri aa, mohammadi s. expression of hla-class i and ii, icam-1 and cd44 antigens in transitional cell carcinoma of bladder. iran j med sci. 1997;22:145-51. 10. homma i, kitamura h, torigoe t et al. human leukocyte antigen class i down-regulation inmuscle-invasive bladder cancer: its association with clinical characteristics and survival after cystectomy. cancer sci. 2009;100:2331-34. 11. nikbin b. immunogenetic. in: immunology. mashhad: astan ghods razavi; 1994. p. 321-68 12. herring dw, cartwright ra, williams dd. genetic associations of transitional cell carcinoma. br j urol. 1979;51:73-7. 13. tokuc r, akdas a, ozerkan k, remzi d. association between hla antigens and bladder tumors. eur urol. 1987;13:207-9. 14. homma i, kitamura h, torigoe t, et al. human leukocyte antigen class i down-regulation in muscle-invasive bladder cancer: its association with clinical characteristics and survival after cystectomy. cancer sci. 2009;100:2331-4. 15. klein j, sato a. the hla system. adv immunol. 2000;343:78286. 16. romano pj, bartholomew m, smith pj, et al. hla antigens influence resistance to lung carcinoma. hum immunol. 1991;31:236-40. 17. falahatkar s, mokhtari gh, askari sa. correlation between hla system and primary vesicoureteral reflux. mjirc. 2005;8:13-5. 18. braf zf, gazit e, many m. hla-a and hla-b antigens in transitional cell carcinoma of the bladder. j urol. 1979;122:465-6. 19. lytton b, o'toole c, tiptaft r, festenstein h, batchelor jr. histocompatibililty testing in patients with carcinoma of the bladder. cancer. 1993;52:645-47. 20. saunders p, anderson s, stogdill v, lamm d. hla-a, b and dr in caucasians with transitional cell carcinoma of the bladder. tissue antigens. 1983;22:389-92. urological oncology special feature 12 urology journal vol 7 no 1 winter 2010 renal artery pseudoaneurysm following a laparoscopic partial nephrectomy hemorrhage after a successful embolization nasser shakhssalim, akbar nouralizadeh, mohammad hossein soltani urol j. 2010;7:12-4. www.uj.unrc.ir keywords: false aneurysm, hemorrhage, renal artery, therapeutic embolization urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran corresponding author: nasser shakhssalim, md urology and nephrology research center, no 101, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2277 0954 e-mail: slim456@yahoo.com received june 2009 accepted november 2009 introduction laparoscopic partial nephrectomy is increasingly practiced by urologists, and its technique is constantly improving. recently, simforoosh and colleagues reported a simplified technique for performing partial nephrectomy. (1) renal artery pseudoaneurysm is an uncommon complication after laparoscopic partial nephrectomy. (2) few cases have been reported so far with this problem, and all of the reported patients who had undergone successful angioembolization were free from hematuria.(3,4) we present a patient who had a massive hematuria and severe drop of the blood pressure in spite of her successful embolization of renal artery pseudoaneurysm after laparoscopic partial nephrectomy. case report a 26-year-old woman presented primarily with a transient left flank pain with no accompanying hematuria and urinary symptoms. ultrasonography showed a 36-mm hypoechoic mass with dimensions in the middle part of her left kidney. computerized tomography (ct) confirmed an enhanced hypodense mass of 30 × 25 mm in the middle lateral part of the left kidney (figure 1). she underwent laparoscopic left partial nephrectomy with transperitoneal approach. the main renal artery was clamped with bulldog (ischemic time, 38 minutes), and then the tumor was resected. the kidney defect was approximated with 0-0 vicryl running sutures buttressed with hemostatic clip instead of knots. after declamping the renal artery, no significant bleeding was detected from the resection bed. on the 2nd postoperative day and due to a gross hematuria and massive clot passage, her hemoglobin dropped from 13.2 mg/dl to 8.5 mg/dl. after transfusion of packed red blood cell and the other conservative therapies, hematuria stopped and hemodynamic state improved. thus, the patient was discharged 7 days after the operation. five days later, she was readmitted with gross hematuria and orthostatic hypotension. her hemoglobin level slumped down to 7.6 mg/dl, and ultrasonography revealed a 50-mm collection in the lower part of the left kidney with suspicious hematoma. the patient underwent angio-embolization for the 2.5-cm pseudoaneurysm which was fed through a branch of the middle segmental artery (figure 2). postembolization hemorrhage in pseudoaneurysm—shakhssalim et al 13urology journal vol 7 no 1 winter 2010 the postembolization images confirmed the successful improvement of the vascular malformation (figure 3). two days later, she had transient hematuria with some fluctuations in her vital signs. then, massive bleeding from the foley catheter occurred and systolic blood pressure decreased to 50 mm hg; hence, she underwent urgent operation. a midline incision was made, and left nephrectomy was performed. after re-operation, hematuria subsided and she was discharged in good condition. a 2-month follow-up showed no signs of morbidity. the final pathology report established the diagnosis of renal cell carcinoma (t1an0m0). discussion the reported incidence of renal artery pseudoaneurysm after a laparoscopic partial nephrectomy is 1% to 2%, while this rate is less than 0.5% for open partial nephrectomy. (2,5,6) it seems, however, there are no significant differences between these two procedures. gross hematuria and flank pain are the most prominent symptoms that raise the suspicion of vascular malformation occurring most frequently within the 3 weeks after the operation.(5) management of renal artery pseudoaneurysm is a challenging issue, and a variety of treatment modalities, such as conservative therapy and selective angio-embolization, have been exploited so far. albani and novick showed a successful conservative treatment of a pseudoaneurysm detected incidentally,(2) but several studies have revealed that selective coil embolization is the ideal alternative with high success rates and low complications.(7,8) there are very few case figure 1. hypodense mass with dimensions of 30 × 25 mm at the middle lateral part of the left kidney. figure 2. pseudoaneurysm was fed through a branch of the middle segmental artery. figure 3. postembolization angiography showed successful occlusion of the arterial malformation. postembolization hemorrhage in pseudoaneurysm—shakhssalim et al 14 urology journal vol 7 no 1 winter 2010 reports on arteriovenous fistula developed after laparoscopic partial nephrectomy that were treated through selective angio-embolization with subsequent subsidence of gross hematuria. (3,4) nonetheless, by presenting this case, we aimed to raise the issue for endourologists to pay more attention to this problem. therefore, a close follow-up of the patient, even after a successful treatment confirmed by postembolization imaging, seems to be crucial to avoid a sudden rupture of the vascular malformation that may end up with a disaster. conflict of interest none declared. references 1. simforoosh n, noor-alizadeh a, tabibi a, et al. bolsterless laparoscopic partial nephrectomy: a simplification of the technique. j endourol. 2009;23:965-9. 2. albani jm, novick ac. renal artery pseudoaneurysm after partial nephrectomy: three case reports and a literature review. urology. 2003;62:227-31. 3. negoro h, kawakita m, koda y. renal artery pseudoaneurysm after laparoscopic partial nephrectomy for renal cell carcinoma in a solitary kidney. int j urol. 2005;12:683-5. 4. wright jl, porter jr. renal artery pseudoaneurysm after laparoscopic partial nephrectomy. urology. 2005;66:1109. 5. cohenpour m, strauss s, gottlieb p, et al. pseudoaneurysm of the renal artery following partial nephrectomy: imaging findings and coil embolization. clin radiol. 2007;62:1104-9. 6. singh d, gill is. renal artery pseudoaneurysm following laparoscopic partial nephrectomy. j urol. 2005;174:2256-9. 7. heyns cf, van vollenhoven p. increasing role of angiography and segmental artery embolization in the management of renal stab wounds. j urol. 1992;147:1231-4. 8. huppert pe, duda sh, erley cm, et al. embolization of renal vascular lesions: clinical experience with microcoils and tracker catheters. cardiovasc intervent radiol. 1993;16:361-7. errata 254 urology journal vol 4 no 4 autumn 2007 errata in volume 3, number 4 of the urology journal, the following error occurred: on page 200, reference 2, the year of publication should have read 1997. in volume 4, number 2 of the urology journal, the following error occurred: on page 105, the name of the second author, fatemeh khatami should have read farideh khatami. in volume 4, number 3 of the urology journal, the following errors occurred: on page 150, reference 2 is not complete. the complete reference is: lingeman je, matlaga br, evan ap. surgical management of upper urinary tract calculi. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1497-8. on page 159, the name of the third author, mohammad reza moradi should have read mahmoud reza moradi. on page 164, the dates of receiving and acceptance of the paper are not mentioned. these dates were as follows: received february 2007 accepted july 2007 we regret the above errors. urol j. 2007;4:254. www.uj.unrc.ir reconstructive surgery 115urology journal vol 5 no 2 spring 2008 penile prosthesis implantation for treatment of postpriapism erectile dysfunction mohammed h durazi, akbar a jalal introduction: our aim was to evaluate the procedure and outcome of penile prosthesis surgery in the treatment of men with postpriapism erectile dysfunction. materials and methods: during the period between 1997 and 2004, a total of 17 patients with postpriapism erectile dysfunction underwent penile prosthesis implantation at our institution. prosthesis implantation was done electively 6 to 18 months after priapism, when the patients presented with erectile dysfunction. of the prosthesis implanted, 11 were malleable, 4 were 2-piece, and 2 were 3-piece prostheses (ams, minnetonka, minnesota, usa). results: all the 17 patients were successfully implanted with penile prosthesis. intra-operatively, corporeal dilation was difficult due to extensive corporeal fibrosis, which led to urethral injury in 2 patients. there were no major postoperative complications. the median hospital stay was 5 days. the follow-up period ranged from 2 to 9 years (median, 6 years). all the patients were satisfied with the prosthesis. conclusion: penile prosthesis implantation is the modality of treatment for patients with postpriapism erectile dysfunction at our institution. it has a high patient satisfaction rate. although procedure-related complications are common due to corporeal fibrosis, they were mostly minor ones and did not affect the outcome of the procedure. urol j. 2008;5:115-9. www.uj.unrc.ir keywords: prosthesis, priapism, erectile dysfunction, satisfaction, infection department of surgery, salmaniya medical complex, manama, kingdom of bahrain corresponding author: akbar a jalal, md, mbbs department of surgery, salmaniya medical complex, manama, kingdom of bahrain tel: +973 3964 6089 e-mail: drakbarjalal@gmail.com received september 2007 accepted april 2008 introduction priapism is a state of prolonged erection of the penis without sexual desire. the delicate balance between arterial inflow and venous drainage in the corporeal bodies is impaired in priapism, resulting in prolonged tumescence. its clinical importance lies largely in the significant consequences that may result from delayed management.(1) priapism can be classified into lowflow and high-flow types. the lowflow type of priapism (ischemic) occurs when there is obstruction to the venous outflow from the tumescent penis, and the highflow type (nonischemic) is caused by increased arterial flow into the tumescent penis. common causes of low-flow type priapism are sickle-cell disease and intracorporeal injection of vasoactive drugs such as papaverine, prostaglandin e1, etc.(1,2) priapism in sicklecell disease occurs as a result of sickling of erythrocytes within the sinusoidal spaces. obstruction to the venous outflow in the lowflow type, leads to ischemia of the penile prosthesis for erectile dysfunction—durazi and jalal 116 urology journal vol 5 no 2 spring 2008 cavernosal smooth muscle after a period of time. this ischemic insult leads to corporeal necrosis, fibrosis, and eventually, erectile dysfunction (ed). phosphodiesterase-5 inhibitors are generally ineffective for treatment of postpriapism ed because of the destruction of erectile tissue and its replacement by fibrosis.(3) penile prosthesis implantation, although associated with significant procedure-related morbidity may be the only effective treatment for these patients with postpriapism ed.(4) since 1988, a total of 605 penile prostheses implantations have been done at our institution, for treatment of penile disorders with various etiologies. in this study, we retrospectively analyzed the procedure and the outcome of prosthesis implantation in patients with postpriapism ed. materials and methods patients between january 1997 and may 2004, a total of 17 patients with postpriapism ed underwent penile prosthesis implantation at our institution. the patients were between 18 and 28 years of age (median, 22 years). all the procedures were performed by one surgeon. sickle-cell disease was the cause of priapism in 16 patients, and in 1 patient with psychogenic ed, priapism resulted from intracorporeal injection of an erectogenic drug. six patients with sickle-cell disease presented to us with priapism and 11 were referred to us from other centers for postpriapism ed. treatment of priapism the median duration of priapism at presentation in the 6 patients treated at our center was 21 hours. they were initially managed conservatively by aspiration and irrigation of the corporeal bodies with saline solution and adrenergic drugs. general measures were taken to relieve pain and to improve hydration and oxygenation status in these sickle-cell disease patients. later, distal corporospongiosal shunt was made in all as they failed to respond to conservative management. proximal corporosaphenous shunt was made in 1 patient. there was no immediate response to shunt surgery in any of these patients. the penile rigidity then gradually decreased and the penis became flaccid. after a few days, the penis was noticed to be hard and fibrous. during the followup, all the 6 patients were clinically diagnosed to have penile fibrosis with ed. in 1 patient, fibrosis was confined to the distal shaft of the penis. penile prosthesis implantation all of the 17 patients with postpriapism ed consented for penile prosthesis implantation. four of them were unmarried at the time of prosthesis implantation. the procedure was done electively 6 to 18 months (median, 10.5 months) after the priapism. penile lengths in these patients varied from 14 cm to 20 cm with a median of 16 cm. they were implanted with the prosthesis manufactured by the american medical systems (ams, minnetonka, minnesota, usa), as they were the only available penile implants in our country. malleable prosthesis (ams 650) was implanted in 11 patients, 2-piece inflatable ambicor prosthesis in 4, and 3-piece inflatable 700cx in 2. selection of the type of the prosthesis depended to a large extent on the patient’s opinion which was mostly based on the costs. the patients were admitted 1 day before the operation. all of them received a third-generation cephalosporin (ceftazidime, 1 gm, twice daily) antibiotic prophylaxis, first dose given 12 hours before the operation and continued for 24 hours after the operation. after 24 hours, oral formulation of amoxicillin plus clavulanic acid was continued for 10 days.(5) the malleable prostheses were implanted through a ventral-distal penile incision, while ambicor prostheses through a penoscrotal incision and the 3-piece devices (700 cx) through a vertical infrapubic incision. ventrolateral corporotomy was done for the penile and penoscrotal approach, while dorsolateral corporotomy was done for implantation of the cylinder of the 3-piece devices. in all these cases, extensive bilateral corporeal fibrosis was encountered. a 3-cm to 4-cm incision was made in the corporeal body (corporotomy) and diathermy straight knife was used to pierce through the middle of the fibrous tissue using cutting current to create a space. penile prosthesis for erectile dysfunction—durazi and jalal urology journal vol 5 no 2 spring 2008 117 in case of severe fibrosis, this maneuver was combined with partial excavation of fibrous tissue at the corporotomy site. later, corporeal dilation was done with hegar’s dilators starting with small-sized dilator (size numbers, 6 or 7), and usually up to 13-sized dilator. biopsy of the corporeal tissue was taken in all the patients. copious irrigation of corporeal bodies with antibiotic solution (gentamicin and cefuroxime) was done throughout the procedure. the cylinder diameter ranged between 11 mm and 12 mm. the cylinder plus rear tip extender length ranged between 14 cm and 20 cm. in cases with difficult closure of corporotomy, small corporeal release incisions were made at different levels on either side of the corporotomy to facilitate closure. a foley catheter was inserted preoperatively in all of the patients, which was removed the next morning. in patients with urethral injury, the catheter was kept for 5 days. postoperatively, the patients were advised to take a 2-week course of antibiotics (amoxicillin plus clavulanic acid), along with anti-inflammatory drugs, analgesics, and local ice-pack application for a few days after the operation. results penile prosthesis implantation was done in all of the 17 patients. intraoperatively, the urethra was injured in 2 patients at the beginning of the dilation. in these 2 patients, the small-sized dilator was passed distally from the penoscrotal corporotomy wound, perforated the distal penile urethra, and was seen protruding at the external meatus. a distal corporeal incision was made at the same site, urethral injury was identified, and a formal 3-layer closure of the urethra was done through the corporotomy over a 12-f silastic foley catheter. both of these patients were implanted with 2-piece ambicor prosthesis after urethral repair in the same sitting. in 1 patient with severely fibrous corpora, corporeal body on one side was incised on the lateral aspect, and the incision was extended both proximally and distally. the intervening septum between the two corporeal bodies could not be identified, and the fibrous corporeal tissue distal to the incision was excised, thus creating a single corporeal cavity in the penile shaft for prosthesis insertion. in this patient, only 1 cylinder (15 mm) of ambicor prosthesis could be placed. the other cylinder was detached from the implant and the tubing was ligated. in another patient, the fibrosis was patchy. the fibrous plaque was mainly confined to the distal shaft making proximal dilation easier. the median duration of the operative procedure was 60 minutes ranging from 30 minutes to 3 hours. the procedure was relatively easy and could be completed in 30 to 60 minutes (median, 45 minutes) in 7 patients who underwent prosthesis insertion within 10 months after the priapism (tables 1 and 2). in the other 10 patients who underwent prosthesis insertion 1 year after the priapism, dilation was difficult and the procedure was completed in 60 to 180 minutes (median, 95 minutes). the procedure was not abandoned during the surgery in any of these patients. there were no major postoperative complications. minor postoperative complications such as penile edema and superficial hematoma were seen in 9 patients that subsided with patient age, y time to presentation, h treatment of priapism* time to surgery, mo operative time, min prosthesis complications 1 25 18 dcs shunt 6 40 malleable superficial hematoma 2 22 12 dcs and cs shunts 13 90 malleable penile edema 3 26 24 dcs and cs shunts 7 45 malleable … 4 19 24 dcs and cs shunts 14 90 malleable … 5 20 18 dcs and cs shunts 11 100 ambicor superficial hematoma 6 22 24 dcs and cs shunts 6 30 malleable … table 1. details of 6 patients presented with priapism due to sickle-cell disease who later underwent penile prosthesis implantation *dcs indicates distal corporospongiosal and cs, corporosaphenous. penile prosthesis for erectile dysfunction—durazi and jalal 118 urology journal vol 5 no 2 spring 2008 observation. there was no case of prosthesis infection. one patient with malleable prosthesis complained of numbness of the penile shaft after the surgery which subsided after a few days. five patients complained of shortened penile length after the surgery in spite of being counseled preoperatively about the penile length. postoperatively, the patients were followed up at 1 week and 3 weeks postoperatively. training by prosthesis specialist was provided after 4 weeks. later, the patients were followed up until their device was assessed to be functioning satisfactorily. corporeal tissue biopsy confirmed fibrosis in all the patients. hospital stay ranged from 3 to 7 days, (median, 5 days). malleable prosthesis in 1 patient was changed to 2-piece ambicor after 1 year for cosmetic reasons. the follow-up ranged from 2 to 9 years with a median of 6 years. during the follow-up, 3 of the 4 unmarried men got married. all the 16 patients who were married had successful sexual intercourse with high satisfaction as assessed subjectively. discussion corporeal fibrosis following priapism is invariably dense and extensive resulting in penile induration and shortening. penile prosthesis surgery in patients with corporeal fibrosis is difficult and is associated with high rates of complications. various techniques have been reported to minimize the complications. montague and angermeier reported a technique of corporeal excavation wherein nearly all of the fibrous corporeal tissue was excised leaving behind the tunica albuginea, and the cylinders were placed in the empty corporeal bed.(6) george and colleagues reported a technique of excision with minimum scar formation and used polytetrafluoroethylene graft to cover the corporotomy defect.(7) recently, shaeer and shaeer reported the techniques of transcorporeal resection and optical corporotomy as adjuvant measures for excavating the fibrous corpora cavernosa under vision, without the use of force against resistance.(8) shaeer also described application of sheathed sharp instruments guided by ultrasonography as an alternative to cavernotomes, allowing fast, efficient, and visually monitored drilling into the fibrous tissue.(9) in our series, dilation of fibrous corpora was possible in all of the patients. in completely fibrous corporeal body, an incision was made in the fibrous tissue at the site of corporotomy using cutting current diathermy. later, the fibrous tissue on either side of the diathermy incision was excised, thus creating a space to accommodate the dilator. nearly total excision of fibrous tissue from the corporeal body was required in only 1 of the 17 patients. we feel that corporeal dilation rather than excavation leaves a rim of fibrous tissue around the cylinder which adds to the rigidity of the device. none of our patients required patch graft to cover the corporotomy defect. in patients with extensive fibrosis and fused corporeal bodies, a single large-diameter patient age, y cause of priapism* time to surgery, mo operative time, min prosthesis complications 1 25 scd 6 30 malleable … 2 20 scd 12 90 700cx penile edema 3 28 intracavernosal injection 12 60 malleable penile edema 4 22 scd 15 100 ambicor urethral injury 5 18 scd 9 45 malleable … 6 25 scd 18 100 malleable superficial hematoma 7 20 scd 14 150 malleable hematoma 8 21 scd 6 60 700cx penile edema 9 18 scd 8 45 malleable … 10 22 scd 10 60 malleable … 11 23 scd 12 180 ambicor urethral injury table 2. details of 11 patients with postpriapism fibrosis referred for penile prosthesis implantation *scd indicates sickle-cell disease. penile prosthesis for erectile dysfunction—durazi and jalal urology journal vol 5 no 2 spring 2008 119 cylinder can be placed to accommodate both of the corporeal bodies. in 1 of our patients with severe corporeal fibrosis, only 1 cylinder was implanted occupying the fused corporeal bodies. with a reported incidence of 0.8% to 8.9%, infection represents the most serious complication of penile prosthesis surgery.(10) we observed that prosthesis insertion in patients with postpriapism corporeal fibrosis is not associated with a higher rate of infection. with the implementation of strict aseptic measures along with prophylactic broad-spectrum antibiotics, none of our patients had prosthesis infection. in addition, no cases of mechanical failure or prosthesis erosions were seen during the follow-up. there are reports of early prosthesis insertion in patients with priapism. rees and associates reported immediate insertion of prosthesis as a definitive management of low-flow priapism.(11) the advantages of immediate prosthesis insertion included simple and rapid placement of the device, which might have accounted for the low rate of infection in their series. early insertion of prosthesis also maintains penile length which results in higher patient satisfaction rates. however, immediate insertion of prosthesis needs a well-motivated patient and a readily available prosthesis. our patients who had normal erectile function before priapism did not agree to undergo immediate prosthesis insertion even after proper explanation about the consequences of longstanding priapism. in some patients, this was due to the lack of finances in procuring the prosthesis and in others, decision-making was difficult as they had never experienced ed before. penile prosthesis implantation is associated with high satisfaction rates and is considered to be the gold-standard treatment for irreversible ed of organic causes.(12) satisfaction rates depend on the sexual function and associated complications. in the present study, all of the patients with partner were satisfied during their sexual intercourse with the function of the device. conclusion prosthesis implantation for patients with postpriapism ed is associated with high patient satisfaction rates. corporeal dilation, though difficult, was possible in all of our patients. diathermy knife incision of the fibrous tissue at the corporotomy site along with minimal excision of the fibrous tissue will aid in corporeal dilation. minor procedural complications are common due to corporeal fibrosis. conflict of interest none declared. references 1. pryor j, akkus e, alter g, et al. priapism. j sex med. 2004;1:116-20. 2. burnett al. priapism pathophysiology: clues to prevention. int j impot res. 2003;15 suppl 5:s80-5. 3. kulmala rv, tamella tl. effects of priapism lasting 24 hours or longer caused by intracavernosal injection of vasoactive drugs. int j impot res. 1995;7:131-6. 4. bertram ra, carson cc, 3rd, webster gd. implantation of penile prostheses in patients impotent after priapism. urology. 1985;26:325-7. 5. lynch mj, scott gm, inglis ja, pryor jp. reducing the loss of implants following penile prosthetic surgery. br j urol. 1994;73:423-7. 6. montague dk, angermeier kw. corporeal excavation: new technique for penile prosthesis implantation in men with severe corporeal fibrosis. urology. 2006;67:1072-5. 7. george vk, shah gs, mills r, dhabuwala cb. the management of extensive penile fibrosis: a new technique of ‘minimal scar-tissue excision’. br j urol. 1996;77:282-4. 8. shaeer o, shaeer a. corporoscopic excavation of the fibrosed corpora cavernosa for penile prosethesis implantation: optical corporotomy and transcorporeal resection, shaeer’s technique. j sex med. 2007;4:218-25. 9. shaeer o. penile prosthesis implantation in cases of fibrosis: ultrasound-guided cavernotomy and sheathed trochar excavation. j sex med. 2007;4:809-14. 10. garber bb, marcus sm. does surgical approach affect the incidence of inflatable penile prosthesis infection? urology. 1998;52:291-3. 11. rees rw, kalsi j, minhas s, peters j, kell p, ralph dj. the management of low-flow priapism with the immediate insertion of a penile prosthesis. bju int. 2002;90:893-7. 12. minervini a, ralph dj, pryor jp. outcome of penile prosthesis implantation for treating erectile dysfunction: experience with 504 procedures. bju int. 2006;97:129-33. brief communication some interesting stories from the iranian model of kidney transplantation hamid tayebi khosroshahi1, bahar bastani2* in this short communication we briefly discuss some aspects of organ shortage for transplantation with a brief characterization of the iranian model of kidney transplantation, and we present 3 interesting stories related to this model. keywords: kidney transplantation; esrd; incentive payment; organ shortage introduction organ shortage for transplantation is an important dilemma for end-stage renal disease (esrd) patients world-wide.(1) several countries have developed different models of approach with respect to this issue. iran has one of the most successful transplantation programs in the middle east. organ procurement in iran includes allografts received from deceased donors, living genetically related, and living genetically unrelated donors. the latter group are either emotionally related (spouses, life partners, friends), or emotionally not related (incentivized donors or vendors).(2,3) in 1988, a government regulated and funded living unrelated kidney transplantation (lukt) program was established in iran that is generally referred to as the “iranian model of kidney transplantation” (imkt). (3-5) during the recent decades, organ transplantation and especially kidney transplantation has been developed and expanded in almost all regions of the country. at present kidney transplantation is performed in more than 30 centers in iran with approximately 2500 kidney transplants being performed per year.(4,6) however, the imkt has not been fully recognized and credited as a successful model in the world and has been challenged by other organ transplant schools. ethical questions on the issue of organ selling are among the most challenging aspects of imkt program.(7) while in the majority of cases of lukt in iran the motivation to donate (actually, to sell) is a financial need, however is some cases it could be a mixture of altruism and financial recovery, and there are still some kidney donors who wish to donate their kidneys as an altruistic humanitarian act. in this communication we would like to present the 3 interesting-stories of living unrelated kidney donation from the imkt program that we have personally encountered. case 1: kidney donation leading to love and union in marriage a 25-year old iranian woman (lady t) with esrd of unknown cause was undergoing regular chronic hemodialysis (3 sessions per week) for nearly one year. she was in a very poor economic condition and could not afford obtaining a kidney transplant. during her regular visits for dialysis she met a 27-year old man (mr. a) who was visiting his sick mother in the same hospital. the young man inquired about lady t’s situation from hemodialysis personnel and found out that she does not have any potential living related donor, and that she did not have financial means to afford paying for a kidney in the imkt. mr. a asked from dialysis personnel how he could become a kidney donor to her. he was referred to the local patient’s kidney foundation office (referred to as “anjoman”) as a volunteer living unrelated kidney donor (lukd) to lady t. after thorough evaluation of his health history, physical examination and the required para-clinical studies he was found to be a suitable kidney donor for lady t. the kidney donation and transplantation were performed successfully after few months of their accidental encounter. two months after transplantation mr. a visited the holy city of mashhad (imam reza shrine), where he expressed his wish to marry lady t asking for guidance and support. he subsequently proposed to her, which was well received by lady t and her family, and a wedding ceremony was established at that time. they got married and have been happily living together. the allograft functioned for almost 14 years. she went back on hemodialysis after 14 years. her husband (mr. a) remains in good health, and continues supporting her. lady t is currently being listed for a second kidney transplantation. case 2: kidney donation and continued financial support of allograft recipient by an altruistic unrelated donor a 23-year old patient with esrd caused by neurogenic bladder with past history of a failed nonfunctioning allograft was listed for a second kidney transplantation in the local anjoman. however, he was from a family in poor economic condition that could not financially afford compensating (rewarding the gift of kidney) an unrelated live donor. at about the same time, a 30year old gentleman decided to donate his kidney to a dialysis patient who is in 1kidney research center, tabriz university of medical sciences, tabriz, iran. drtayebikh@yahoo.com 2division of nephrology, saint louis university school of medicine, saint louis, missouri, usa bahar.bastani@health.slu.edu. *correspondence: professor of medicine – nephrology, saint louis university school of medicine, saint louis mo 63110. tel: 4994-973-314. fax: 0784-771-314. e mail: bahar.bastani@health.slu.edu received july 2019 & accepted october 2019 urology journal/vol 17 no. 4/ july-august 2020/ pp. 422-425. [doi: 10.22037/uj.v0i0.5440 ] poor economic condition. he had good education, had a stable job, and was in no economic distress. he visited the same local anjoman to find a suitable esrd recipient. these two people were introduced together, and after checking the blood group compatibility, they were sent to the designated transplant physician for further evaluation. after full evaluation, including the required laboratory and imaging tests it was noticed that the donor had paid for all of the expense, i.e., costs related to the physician visits, laboratory and imaging studies. subsequently, kidney transplantation was performed successfully without any complications, and with good allograft function. to date, sixteen years later, the recipient is doing very well with good allograft function. the truly altruistic kidney donor is also doing very well with good kidney function. the donor has also been supporting the allograft recipient during these years. case 3: buying kidneys for strangers across religious boundaries, initially motivated by religious belief, self-interest, and nationalism. one of the present authors (bb) together with ms. sigrid fry-revere phd, a medical ethicist and lawyer, in their 6-weeks fact-finding travel to iran (november to december 2008), visiting around 10 transplant centers in 6 iranian provinces, and recording more that 100 live interviews with lukds, recipients, health care and anjoman workers that lead to publication of a book and 4 article,(8-12) encountered this very interesting case story. in a morning that we were recording our live interviews with some living unrelated potential donors and recipients in the anjoman in tehran a well dressed and well groomed lady (lady f) approached us asking if we were interested to hear her story. she said that she had come from los angles, usa, to buy 2 kidneys for 2 young boys. this heightened our interest and curiosity to hear the whole story. she belonged to the iran’s jewish religious minority. she had immigrated to the usa some 30 years earlier (around 10 years before the iran’s islamic revolution in 1979). she lived a good life with her grown up children and her grand children in la, usa. one day they realized that her 13-year-old grand daughter was suffering from vesicoureteral reflux disease, and that it could lead to esrd. she said, she made a “nazr” (a promise to god) that if her grand daughter would be cured she would pay for a poor teen-age girl to receive a transplantation. apparently after a new technique of gel injection (deflux injection) was tried the reflux disease was totally resolved and her grand daughter was considered cured. at this time, in order to fulfill her promise, she planned to come to tehran, iran, where her sister lived, to buy a kidney for a poor teen-age girl. her close family members and friends in the usa had persuaded her to do this humanitarian act in israel. her response was that as an iranian she wanted to serve a fellow iranian. she said that after 3 days of frequent visits to the anjoma in tehran she gave up finding a very poor girl around 13 years old girl with esrd in need of a kidney. on the third day when she had disappointedly left the tehran anjoma she heard being called from distance by the secretary of anjoman. she was informed that they had just located a very poor family living in karaj (~1 hour drive from tehran) who had a teen-age daughter with esrd. the family was poor and could not afford paying for the rewarded gift of a living unrelated kidney, and indeed so poor that they did not have a phone at home, and anjomn personnel could not contact them. this was very happy news for lady f who travelled next day with her sister to the address in karaj. they found a simple house in a poor neighborhood. they encountered a middle-age lady who was curiously surprised of their unexpected visit. they noticed a pale thin chronically ill looking teen-age girl at the end of the hallway. when they explained the reason for their visit, i.e., paying for a kidney, the lady dropped herself at their feet thanking god for such a miracle coming true. apparently the whole night before her sick daughter had been crying and complaining to god why she was created at all, and why she had to lose her kidneys, and why she was borne in a poor family that couldn’t pay for a kidney for her, and so on, and now in the morning 2 strangers from a different religion, one of them travelling from a country thousands of miles away, had driven all the way from tehran to their poor house in a different city to pay for her daughter’s kidney. incidentally, they noticed that the day was a religious mourning day (“ashura”) for the shia sect of islam, where masses of people had filled the streets mourning and lamenting for the martyrdom of their beloved third imam some 1400 years earlier. with lady f’s gift of $2,500 a 25-year-old man, who was in desperate need for cash for his imminent wedding, donated his kidney to the young girl with esrd (girl l). five years later, lady f told us that now girl l remains off dialysis, living in good health, and is a sophomore student of economy in karaj university. lady f also showed us the pictures of the wedding ceremony of the young donor and his beautiful bride, and told us that in her visits to iran she meets both families who feel much in debt to her past generosity. the reason for lady f’s present visit to the anjoman in tehran was to buy 2 kidneys for two teen-age boys after she had made a “nazr” (promise to god) for her very sick grandson to get well. but, then she added that this time i asked myself why am i always bargaining with god for some of my needs, this time i’ll do it for the sake of goodness and kindness, whether or not my grand son will improve or not. that was her beautiful uplifting story. i contemplated then and now too, how acts of kindness with sincerity would transcend us to a higher level of spirituality and a deeper level of conscientiousness. discussion due to the continued worsening in organ shortage at a global stage, the number of kidney transplantations from living unrelated donors (emotionally related or truly altruistic undirected donation) has increased in both economically developed and developing countries in the recent years.(13) according to the organ procurement and transplantation network (optn) as of june 26, 2019 a total of 124,472 people were registered for a solid organ transplant in the usa, 103,011 of whom were waiting for a kidney, while in the year 2018 there were only a total of 21,167 kidney transplantations done in the usa (14,725 deceased donor and 6,442 living donations) and only around 21% of those in the wait list could get a kidney.(14) at the same time in 2018 a total of 8,591 patients (~8.5% of those on the waiting list) were removed from wait list (4,111 had died while waiting, and 4,480 had become too sick to be transplanted).(14) in the year 2017 of the 5,813 live kidney donations in the usa, 44% were genetically related, and 56% were altruistic genetically unrelated (39% iran model of kidney transplantation-tayebi khosroshahi et al. vol 17 no 04 july-august 2020 423 were spousal/life partner or friend, 12.5% were through paired donation, 4.5% were undirected anonymous donation).(15,16) in order to accommodate the large number of esrd patients who had no living related donors, and because of the high cost of dialysis, economic sanctions against iran, and lack of legislation for acceptance of brain death and deceased donor transplantation (legislation was passed later on april 2000) a government sponsored/regulated lukt program was established in iran in 1988.(3-5) in this model that is known as imkt, both the iranian government and the transplant recipients compensate (incentivize) the lukds. moreover, at the same time the number-of-transplant teams were increased from 2 to 25 teams in iran. as the result of these 2 interventions by the year 1998 it was reported that the waiting list for renal transplantation was totally eliminated in iran.(5) in this model all eligible esrd patients (the recipients) and the potential lukds are registered at their local patient’s kidney foundation office (referred to as “anjoman”) that is in charge of matching donors with eligible recipients. moreover, all kidney transplantations were to be performed in the university hospitals by faculty who had no personal financial gain of the procedure, and the iranian government covered all transplant related expenses that occurred in hospital. furthermore, it prevented foreign nationals buying kidneys from iranian donors, thus preventing transplant tourism and rise in the price of a kidney for the locals. while at its conception it allowed foreigners to obtain kidneys from donors of the same nationality, however, because a number of abuses were discovered where some patients from other nationalities had faked iranian identification cards and there was no means to regulate a fair and legally enforceable financial deal between the foreign donors and their recipients, transplantation of foreigners was totally abandoned in august 2014.(17) the imkt is considered a practical and reasonably fair solution for solving a local problem. a study by ghods, et al., comparing socioeconomic characteristics and education level of lukds and their recipients found that more than half of both groups were males (90.2% of lukds vs. 63% of recipients), had high school or college education (69.6% lukds vs. 62% of recipients), and 84% or the lukds vs. 50.4% of the recipients were in the poor socioeconomic category.(18) the imkt intends to eradicate an underground illegal black market where both donors and recipients would be at loss, prevent transplant tourism, and provide a transparent system where the lukds and their recipients enter a reciprocal gifting relationship that is mediated by their local anjoman and is legally enforceable. in some instances a long-term relationship (emotional, economic or both) were observed between the lukds and their recipients. the imkt has improved lives of many thousands of esrd patients by providing them with life saving kidneys and reportedly eliminating the kidney transplant wait list in iran, however, it has been surrounded with many ethical controversies and debates.(7) while the motivation for a majority of lukds is to overcome some financial hardships, however, in some donors the financial reward could supplement their intention for a humanitarian act, and still in some the humanitarian act of kindness maybe the mere motivation to donate. it seems that providing adequate financial incentive and other social benefits to each lukd by the government and eradicating the direct dealing between donors and recipients, making the imkt a non-directed government rewarded kidney donation program, whereby the donors and the recipients would not know each other, at least before transplantation, would overcome some of the short comings in this system. in this short communication we do not intend to discuss pros and cons of the model, but would like to share with the transplant community 3 interesting stories that we had personally observed while dealing with these patients. references: 1. bastani b. the worsening transplant organ shortage in usa; desperate times demand innovative solutions. j nephropathol. 2015;4(4):105-9. 2. bastani b. the iranian model as a potential solution for kidney shortage crisis. j nephropathology. 2018;7(4):220-3. 3. mahdavi-mazdeh m. the iranian model of living renal transplantation. kidney int. 2012;82(6):627-34. 4. ghods aj. the history of organ donation and transplantation in iran. exp clin transplant. 2014;12 suppl 1:38-41. 5. ghods aj, savaj s. iranian model of paid and regulated living-unrelated kidney donation. clin j am soc nephrol. 2006;1(6):1136-45. 6. saidi rf, broumand b. current challenges of kidney transplantation in iran: moving beyond the "iranian model". transplantation. 2018;102(8):1195-7. 7. aramesh k. a closer look at the iranian model of kidney transplantation. am j bioeth. 2014;14(10):35-7. 8. fry-revere s. the kidney sellers: a journey of discovery in iran, carolina academic press. 2014. 9. fry-revere s. the truth about iran. am j bioeth. 2014;14(10):37-8. 10. fry-revere s, chen d, bastani b, golestani s, agarwal r, kugathasan h, et al. coercion, dissatisfaction, and social stigma: an ethnographic study of compensated living kidney donation in iran. int urol nephrol https://doiorg/101007/s11255-018-1824-y. 2018. 11. fry-revere s cd, bastani b, golestani s, agarwal r, kugathasan h, le m. introducing an exploitation/fair dealings scale for evaluating living organ donor polices using iran as the test case. world medical and health policy. 2018;10(5). 12. hamidian jahromi a, fry-revere s, bastani b. a revised iranian model of organ donation as an answer to the current organ shortage crisis. iran j kidney dis. 2015;9(5):354-60. 13. srtr report 2017. accessed in june 28, 2019. https://srtr.transplant.hrsa.gov/annual_ reports/2017/kidney.aspx. brief communiactipn 424 iran model of kidney transplantation-tayebi khosroshahi et al. 14. optn report. accessed in june 26, 2019. https://optn.transplant.hrsa.gov/data/viewdata-reports/national-data/#. 15. united network for organ sharing. accessed in august 31,2018. https://unos.org/data/. 16. organ procurement and transplantation network national data. accessed on august 31, 2018. https://optn.transplant.hrsa.gov/ data/view-data-reports/national-data/#. 17. ossareh s, broumand b. travel for transplantation in iran: pros and cons regarding iranian model. exp clin transplant. 2015;13 suppl 1:90-4. 18. ghods aj, ossareh s, khosravani p. comparison of some socioeconomic characteristics of donors and recipients in a controlled living unrelated donor renal transplantation program. transplant proc. 2001;33(5):2626-7. iran model of kidney transplantation-tayebi khosroshahi et al. vol 17 no 04 july-august 2020 425 endourology and stone disease retrograde intrarenal surgery following laser endopyelotomy; sequential procedures for ureteropelvic junction obstruction and nephrolithiasis ibrahim kartal1*, can tuygun1, nihat karakoyunlu1, fatih sandıkçı1, burhan baylan1, hamit ersoy1 purpose: this study was designed to evaluate the effectiveness and safety of retrograde intrarenal surgery (rirs) following retrograde laser endopyelotomy (rlep) in concomitant ureteropelvic junction obstruction (upjo) and stone disease. materials and methods: patients with concomitant upjo and renal stone disease who were first treated in our clinic by rlep for obstruction and then rirs for stone disease were enrolled. study period went from 2012 to 2017. rirs following rlep was performed earliest at the sixth week. patients who underwent rlep were matched with those with normal anatomy at a 1:1 ratio based on the propensity scores. additionally, clinical results were compared in order to evaluate the effects of rlep surgery on rirs. subsequently, patients who underwent rirs following rlep were independently evaluated and factors affecting the success of sequential procedures were investigated. results: the sole difference between those that underwent rirs following rlep (n=27) and controls with normal anatomy that underwent rirs was in operative times (p = .011). evaluation of potential success factors in the sequential rlep-rirs group revealed that primary etiology, obstruction length less than 1cm, smaller stone size and presence of single stone showed significant effects (p = .047, p = .030, p = .040, p ≤ .001, respectively). rirs following rlep generated an 81.5% stone-free and, after a median follow-up time of 32 months, a 74.1% obstruction-free rate. conclusion: rirs following rlep in patients with upjo and renal stones is an effective treatment method. it can be used safely in patients with single stones < 2cm, short obstruction lengths, and presence of primary etiology. keywords: endopyelotomy; retrograde intrarenal surgery; sequential; stone; ureteropelvic junction obstruction introduction patients with ureteropelvic junction obstruction (upjo) have been reported to develop concomitant ipsilateral renal stone disease at rates of approximately 20.0%.(1,2) in upjo patients, urinary stasis, metabolic anomalies and infection are predisposing factors for stone formation.(3,4) reduced recurrence of renal stone disease following upjo treatment further corroborates the pathophysiology.(5) it has been previously shown that upjo and renal stones can be treated with alternatives to open surgery. specifically, studies have established percutaneous access, antegrade endopyelotomy performed with nephrolithotomy, and stone removal simultaneously with laparoscopic or robotic pyeloplasty. while these methods are minimally-invasive, some of these techniques are associated with disadvantages such as the opening of the peritoneum, risk of intestinal injury, proximity to major arteries, long operative times, and difficult tech1department of urology, university of health sciences, dışkapı yıldırım beyazıt training and research hospital, ankara, 06110, turkey. *correspondence: department of urology, university of health sciences, dışkapı yıldırım beyazıt training and research hospital, ankara, 06110, turkey. address: ziraat mahallesi, şehit ömer halisdemir cad., 06110, dışkapı-altındağ, ankara, turkey. phone: +905556298424. fax number: +903123186690. email: ibrahimguvenkartal@gmail.com. received & accepted niques.(6) therefore, at this time, investigations for alternative treatments is still ongoing. the present study was conducted to evaluate the retrograde intrarenal surgery (rirs) following retrograde laser endopyelotomy (rlep). specifically, this approach could constitute an additional effective and safe minimally-invasive method for patients with concomitant upjo and stone disease. materials and methods in the present retrospective study, patients with upjo and ipsilateral renal stone who underwent rirs following rlep in our clinic between january 2012 and june 2017 were evaluated. ethical committee approval was obtained prior to study commencement. exclusion criteria were as follows; obstruction greater than 2cm, tumor on the side of the obstruction, suspected obstruction related to the crossing vein, extrinsic ureteral obstruction, ureteral high insertion, ipsilateral urology journal/vol 16 no. 6/ november-december2019/ pp. 541-546. [doi: 10.22037/uj.v0i0.5205] renal function (irf) percentage below 20% and patients under the age of 18. furthermore, patients who, by preoperative imaging, demonstrated impacted stone in the upj and whose stone was in contact with upj were excluded from the study. such decision was based on the grounds that in these patients an obstruction might form in the ureteropelvic junction due to edema. also, since guidelines generally recommend rirs procedure for stones < 2cm, 4/31 patients were excluded, leaving 27 patients to be evaluated. excluded patients were referred to other treatment modalities. in order to rule out the upjo related to the stone’s potential impact and to determine the obstruction’s location and length, the rlep process was initiated with retrograde pyelogram. additionally, the obstructing ureteral segment’s length was assessed by endoscopy under direct vision. subsequently, upon visualizing upj with semirigid or flexible ureteroscopy, it was clarified that the obstruction didn't develop secondary to the stone. as a consequence, the process was continued. pulsations at the stricture area were also evaluated. a semirigid ureteroscope (karl storz, tuttlingen, germany) with an 8-fr tip, 9.5-fr shaft, and a 7.5-fr flexible ureteroscope (flex x2; karl storz, tuttlingen, germany) was used. a 365-μ laser fiber was used with the semirigid ureteroscope, and a 200-μ laser fiber was used in the flexible ureteroscope. a posterolateral or lateral incision was performed under direct vision. to this end a ho:yag laser with an energy of 1.5–2.5 j and a frequency of 10–15 hz was used. appropriate incision depth was confirmed by direct vision and by documenting contrast extravasation. no complication such as extravasation of the stone which would have constituted an impediment to perform rirs following rlep. all patients were taken under operation planned to undergo rirs at a median of 6 weeks (6–10 weeks). of note, it was kept in mind the possibility of a dilatation effect of the stent after rlep, coverage of the incised area by the urothelium after 5 days from the uretheral incision, and muscular regeneration taking place in 6 weeks.(8) in order to evaluate extravasation and obstruction, rirs following rlep was commenced with retrograde pyelogram. in a subset of patients for whom the pyelogram did not suggest the presence of leakage and abnormal ureteropelvic junction image, a ureteral access sheet (uas) was placed under the control of the scope, taking care not to advance to the upj. ureteral stents of those patients with no complication and not recommended for additional treatment at the end of the first month after rirs, were removed under local anesthesia. patients who were to undergo rlep were evaluated by computed tomography (ct) and dynamic nuclear scintigraphy. stone size was calculated as the longest diameter of the stone measured by ct. for multiple stones, diameter was evaluated as the sum of the maximum diameter of the stones. preoperative and postoperative upjo was accepted as follows: radiological absence of drainage, presence of obstructive pattern in the clearance curve by dynamic scintigraphy, and t1/2 being > 20 minutes. treatment success was defined as the absence of diagnostic criteria for upjo, signs of symptoms’ regression, preservation of renal function, complete absence of stones, and residue < 3 mm that doesn't require surgery. postoperative patient follow-up occurred at the 1st, 3rd, 6th, and 12th month and thereafter annually, with the goal of evaluating surgical success. at the end of the 3rd month, patients were checked by ct and dynamic nuclear scintigraphy. these investigations were repeated in cases of suspicion of obstruction’s recurrence. patients’ characteristics, obstruction table 1. perioperative characteristics of rirs in control and case groups. control group (n=27) rirs following rlep (case group) (n=27) p-value age 40.4 ± 14.1 39.6 ± 10.6 0.828a gender 0.577b male 9 (33.3%) 12 (44.4%) female 18 (66.7%) 15 (55.6%) side right 13 (48.1%) 13 (48.1%) left 14 (51.9%) 14 (51.9%) bmi (kg/m2) 24.8 ± 3.3 25.9 ± 4.1 0.262a asa score 0.744c i 11(40.7%) 13 (48.1%) ii 14 (51.9%) 11 (40.7%) iii 2 (7.4%) 3 (11.2%) stone size (mm) 13.3 ± 6.82 15.5 ± 2.79 0.126a number of stones 1 (1–6) 1 (1–4) 0.667c single 19 (70.4%) 17 (63.0%) 0.773b multiple 8 (29.6%) 10 (37.0%) stone localization 0.865b lower pole 14 (51.9%) 11 (40.7%) pelvis 6 (22.2%) 8 (29.6%) middle and upper pole 2 (7.4%) 2 (7.4%) multiple calyxes 5 (18.5%) 6 (22.2%) ureteral access sheath 0.080b not used 2 (7.4%) 8 (29.6%) used 25 (92.6%) 19 (70.4%) operative time (min) 45 (15–80) 55 (30–80) 0.011c stone-free state (success) 25 (%92.6) 22 (%81.5) 0.420d hospitalization (days) 1 (1–2) 1 (1–7) 0.078c complications 1 (3.7%) 3 (11.1%) 0.610d abbreviations: a: student’s t test, b:chi-square test, c: mann whitney u test, d: fisher’s exact test. rirs following laser endopyelotomy-kartal et al. endourology and stone diseases 542 vol 16 no 06 november-december2019 543 and stone’s effects on treatment success were investigated. complications were classified according to the clavien-dindo classification. stricture site and length were obtained from the operative notes, as well as the preoperative and intraoperative radiographic studies. evaluation for crossing vessels was performed by ct and by observing pulsations at the stricture area during ureteroscopy. patients with suspicion of polar vessels were excluded. primary upjo was accepted to be of congenital origin and due to functional obstruction without previous renal surgery. secondary etiology was acquired, and linked to a history of surgery in upj, stones in the upj and failed treatment for upjo. preoperative hydronephrosis was evaluated radiologically prior to rlep as grade 2 (moderate) and grade 3 (severe). in the dynamic nuclear scintigraphy performed before rlep, evaluation was made according to irf’s percentage, as below and above 30. stone characteristics were considered to have impact on clinical outcomes. additionally, other factors that play such a role, including: age, gender, side, body mass index (bmi), and american society of anesthesiologists (asa) score. as a consequence, such factors were included in the multivariate logistic regression model and propensity scores of patient groups with normal anatomy who underwent rirs (control) and patient groups who underwent rirs following rlep (case). according to the probability estimations obtained from logistic regression analysis with 27 cases, 27 of the 1229 control cases were matched. two groups were compared in terms of operative and postoperative features. statistical analysis data analysis was performed using the ibm spss statistics software version 17.0 (ibm corporation, armonk, ny, usa). the assumptions of normality and variance homogeneity were examined by kolmogorov-smirnov and levene test, respectively. continuous variables were shown as mean ± sd or median (minmax) where applicable. propensity scores were obtained by using a multiple logistic regression model where the dependent variable indicated whether the patient was sequential rlep and rirs (= 1) or with normal anatomy (= 0). propensity scores estimated the probability of sequential rlep and rirs or with normal anatomy, given the covariates in the model. independent covariates were as follows: age, gender, localization, bmi, asa, duration of operation, status of success and hospitalization. patients were matched 1:1, which randomly selects a case and matches them to the nearest control subject. the mean differences between groups were compared using the student's t-test. additionally, the mann whitney u test was applied for comparison of data with non-normal distribution. categorical data were analyzed by pearson’s chi-square, continuity corrected table 2. demographic and clinical characteristics of cases with successful and unsuccessful outcomes following sequential rlep and rirs treatment. unsuccessful (n=5) successful (n=22) p-value age 37.0 ± 9.2 40.2 ± 11.1 0.551a gender 0.628b male 3 (60.0%) 9 (40.9%) female 2 (40.0%) 13 (59.1%) side 0.648b right 3 (60.0%) 10 (45.5%) left 2 (40.0%) 12 (54.5%) bmi (kg/m2) 26.2 ± 2.1 25.9 ± 4.4 0.873a asa score 1 (1–2) 2 (1–3) 0.524c etiology 0.047b primary 1 (20.0%) 16 (72.7%) secondary 4 (80.0%) 6 (27.3%) preoperative hydronephrosis 0.621b grade 2 1 (20.0%) 9 (40.9%) grade 3 4 (80.0%) 13 (59.1%) incision site 0.616b posterolateral 3 (60.0%) 16 (72.7%) lateral 2 (40.0%) 6 (27.3%) obstruction length 0.030b <1cm 1 (20.0%) 17 (77.3%) ≥1cm 4 (80.0%) 5 (22.7%) ipsilateral renal function 0.079b <30% 2 (40.0%) 1 (4.5%) ≥30% 3 (60.0%) 21 (95.5%) stone size (mm) 17.8 ± 1.48 15.0 ± 2.78 0.040a number of stones 2 (2–4) 1 (1–2) < 0.001c multiple stones 5 (100.0%) 5 (22.7%) 0.003b stone localization 0.295d lower pole 3 (60.0%) 8 (36.4%) pelvis 8 (36.4%) middle and upper pole 2 (9.1%) multiple calyxes 2 (40.0%) 4 (18.2%) ureteral access sheath > 0.999b not used 1 (20.0%) 7 (31.8%) used 4 (80.0%) 15 (68.2%) time between rlep and rirs 7 (6–9) 6 (6–10) 0.650c abbreviations: bmi: body mass index, asa: american society of anesthesiologists score, rlep: retrograde laser endopyelotomy, rirs: retrograde intrarenal surgery, a: student’s t test, b: fisher’s exact test, c: mann whitney u test, d: pearson’s chi-square test. rirs following laser endopyelotomy-kartal et al. chi-square or fisher’s exact test, where applicable. a p-value < 0.05 was considered statistically significant. results as described in table 1, when comparing the rirs procedure following rlep vs. control groups, no differences were found in terms of preoperative demographic data (age, gender, side, bmi, asa score, stone size, number of stones, and stone localization). regarding the perioperative data, median operative time was significantly higher for the case vs. the control group (p = .011). retrograde lep’s operative time, which is naturally only in case group, was calculated as median 52 (36-75) minutes. in patients who underwent rirs following rlep, factors that could affect the overall success of combined sequential therapy were evaluated. having primary etiological origin, an obstruction length < 1cm, the small stone’s size and the small stone’s number were found to be statistically significant (p = .047, p = .030, p = .040, p < .001, respectively). at the end of 3 months, 22 patients (81.0%) achieved stone-free states and success in upjo treatment. although a stone-free state was achieved, one patient manifested symptoms at month 6 and another at year 1. specifically, patients developed obstructive patterns in dynamic scintigraphy that were performed subsequently, amounting to an overall success rate of 74.1% over a median follow-up time of 32 (14–72) months. one patient was referred to another treatment modality due to obstruction continuing in the retrograde pyelogram and the inability to pass the flexible ureteroscope. in this patient, treatment was considered as failure. in absence of leakage suspicion and of an abnormal ureteropelvic junction image on the pyelogram, the uas was placed in 17 patients under the control of the scope, taking care not to advance to the upj. discussion when upjo and stones are detected, active treatment is needed in order to reduce stone recurrence.(3) percutaneous nephrolithotomy (pnl) is the most prominent choice for patients with anatomical anomalies and high stone burdens. however, the optimum treatment option for concomitant upjo and stones, remains unclear to date. earlier studies have shown that cases of renal stones and upjo can be safely and effectively treated by endourological surgery (table 3).(7-15) of note, studies on laparoscopic and robotic pyeloplasty for the simultaneous stone removal usually include limited numbers of patients. in their non-systematic review, skolaris et al. reported mean stone-free rates of 91.3 and 92.3%, obstruction-free rates of 96.1 and 100%, and long operative times of 3.45 and 4.21 hours for of simultaneous laparoscopic and robotic pyeloplasty, respectively.(6) considering the technical difficulty of laparoscopic and robotic pyeloplasty, rirs performed subsequently to rlep possesses serious advantages (e.g., ease of application and short operative times). of note, robotic pyeloplasty’s lack of tactile sensation and high costs should be kept in mind. finally, another advantage of endopyelotomy is that high success rates can be achieved with other treatment modalities following a failed endopyelotomy.(16) studies have investigated the combined use of simultaneous endourological operations (e.g., laparoscopy with pnl). however, these treatment methods have disadvantages.(15) specifically, the irrigation fluid may accumulate between intestinal loops, giving rise to metabolic effects. additionally, stone localization in the obstructed calyxes is complex with laparoscopic procedures. finally, while not reported in the literature, there is a risk of the stone disappearing in the abdomen during laparoscopy with possible related complications. previous reports have recommended the incision to reach the periureteral adipose tissue in endopyelotomy, and the stones are fragmented as well in rirs to achieve stone clearance.(17,18) based on this background, in the present study a sequential, rather than a simultaneous, rlep and rirs procedure was performed. the aim was to decrease the probability of extravasation and minimize the potential effects of uas and/or flexible ureteroscope on the upj. importantly, sequential treatment may reduce the risk of morbidity, which may be higher when the surgeries are performed simultaneously. furthermore, sequential treatment can ensure that the flexible ureteroscope has a greater motion capacity following obstruction treatment. in addition, it must be ensured that the ureteroscope has improved control and greater likeliness to reach the stone following the dilatation effect of the inserted stent on the ureter and the elimination of the obstruction. berkman et al. reported a 90.0% success rate in 41 patients with concomitant upjo and non-obstructive stones, by using antegrade technique number of stone operative hospitalization complications(%) stone obstruction follow-up patients size (mm) time (min) time (days) free % free (%) (months) inagaki(7) laparoscopy 21 98 100 24 stein(8) laparoscopy 15 5.8 174 1.6 6.7 93 80 5.4 stravodimos(11) laparoscopy 13 8.7 218 4 2 84.6 100 30.2 ramakumar(12) laparoscopy 20 1.4 cm2 276 3.4 0 90 90 12 srivastava(13) laparoscopy 20 15 168 4.9 15 75 90 34 mufarrij(9) robotic 13 235 2 0 100 100 28.5 nayyar(10) robotic 10 80 100 berkman(14) endo41 90 90 29 pyelotomy+pnl agarwal(15) laparo10 3–24 234 5.2 20 100 100 6 scopy+pnl current sequential rlep+ rirs 27 15.5 107.1 4.0 11.1 81.5 74.1 32 table 3. minimally-invasive series with over 10 patients that report on the treatments used in cases of concomitant upjo and renal stones providing stone-free and obstruction-free rates. abbreviations: pnl=percutaneous nephrolithotomy, rlep=retrograde laser endopyelotomy, rirs=retrograde intrarenal surgery. rirs following laser endopyelotomy-kartal et al. endourology and stone diseases 544 vol 16 no 06 november-december2019 545 endopyelotomy and simultaneous stone removal. the authors compared patients with upjo and stones to patients without stones that underwent endopyelotomy. they reported that the concern that stone fragments could remain in the periurethral adipose tissue following endopyelotomy was unfounded.(14) by performing rirs after a minimum of 6 weeks from endopyelotomy, we believe that we minimized the potential risks posed by a combined endopyelotomy and lithotripsy procedure. moreover, it is clear that the retrograde approach does not possess the risks associated with percutaneous access. in line with previous reports, a lower success rate for rirs can be observed in cases of greater stone size, higher number of stones, and stones localized in the lower pole and multiple calyxes (table 2). it has been shown that these factors affect stone-free states not only for rirs but for all treatment modalities.(19) additionally, resorlu et al. reported that treatment success also decreased in the presence of anatomical anomalies.(20) however, our study indicates that stone treatment is unaffected by upjo in sequential rlep and rirs treatment. the presence of crossing veins, severe hydronephrosis, long obstructions and obstructions due to secondary reasons stand for an unfavorable prognosis for endopyelotomy. treatments to be performed following a first surgery constitute a serious problem for other minimally-invasive procedures.(21) the majority of these factors were considered exclusion criteria in this study. however, we observed that specifically obstruction length and secondary etiology decreased treatment success, in line with the literature. treatment planning, by combining patients criteria and stone characteristics can help recommend rirs after retrograde lep. rirs has been reported to be very effective and safe even for patients with high asa scores.(22) advances in anesthesia techniques and rirs’s high safety suggest that undergoing anesthesia for a 2nd time for rirs after rlep does not pose a risk. as shown by our results, none of our patients manifested complications due to anesthesia. additionally, patients enrolled in our study, despite undergoing two surgeries, generally had a shorter operative and hospitalization time vs. other techniques. specifically, grade 3 and more severe complications reported in other studies were not encountered here. while pnl is typically recommended for stones > 2cm,(23) stones in concomitant upjo and stone disease that are generally < 2cm (table 3). a link between pnl and a higher rate of complications vs. rirs has been shown. as a consequence, rirs is being recommended as one of the primary options for stones < 2cm,(24) suggesting that rirs will be increasingly popular for the treatment of stone disease following upjo treatment. moreover, rirs has the advantages of its success not being significantly influenced by obesity and lower pole localizations vs. shock wave lithotripsy and pnl, it is easily applied, and it provides high stone-free rates even with limited operator experience.(25) the present study has some limitations. first, its retrospective character and second, the low number of patients. a greater numbers of cases are needed to validate our study. however, as can be understood from the literature, the present report focuses on an uncommon situation. as a consequence, it is difficult to conduct prospective randomized controlled studies. since our rirs following laser endopyelotomy-kartal et al. clinic is a tertiary center for 30-million citizens, the number of patients in this study is not actually very low and is consistent with the literature. conclusions in patients with upj obstruction and renal stones, rirs performed subsequently to rlep can be an alternative treatment method. rirs following rlep may be preferred in patients with relative contraindications to other minimally-invasive methods (e.g., laparoscopy). we believe that due to its numerous advantages (i.e., short operation time, low morbidity, ease of technique, protection of the surgical area from scarring and capacity to minimize disadvantages such as successive treatment and extravasation of stone), it can be safely used especially in patients with a small single stone and short obstruction. references 1. rutchik sd, resnick mi. ureteropelvic junction obstruction and renal calculi. pathophysiology and implications for management. urol clin north am. 1998;25:317-21. 2. bachmann a, ruszat r, forster t, et al. retroperitoneoscopic pyeloplasty for ureteropelvic junction obstruction (upjo): solving the technical difficulties. eur urol. 2006;49:264-72. 3. husmann da, milliner ds, segura jw. ureteropelvic junction obstruction with a simultaneous renal calculus: long-term followup. j urol. 1995;153:1399-402. 4. matin sf, streem sb. metabolic risk factors in patients with ureteropelvic junction obstruction and renal calculi. j urol. 2000;163:1676-8. 5. bernardo no, liatsikos en, dinlenc cz, kapoor r, fogarty jd, smith ad. stone recurrence after endopyelotomy. urology. 2000;56:378-81. 6. skolarikos a, dellis a, knoll t. ureteropelvic obstruction and renal stones: etiology and treatment. urolithiasis. 2015;43:5-12. 7. inagaki t, rha kh, ong am, kavoussi lr, jarrett tw. laparoscopic pyeloplasty: current status. bju int. 2005;95 suppl 2:102-5. 8. stein rj, turna b, nguyen mm, et al. laparoscopic pyeloplasty with concomitant pyelolithotomy: technique and outcomes. j endourol. 2008;22:1251-5. 9. mufarrij pw, woods m, shah od, et al. robotic dismembered pyeloplasty: a 6-year, multi-institutional experience. j urol. 2008;180:1391-6. 10. nayyar r, gupta np, hemal ak. robotic management of complicated ureteropelvic junction obstruction. world j urol. 2010;28:599-602. 11. stravodimos kg, giannakopoulos s, tyritzis si, et al. simultaneous laparoscopic management of ureteropelvic junction obstruction and renal lithiasis: the combined experience of two academic centers and review of the literature. res rep urol. 2014;6:43-50. 12. ramakumar s, lancini v, chan dy, parsons jk, kavoussi lr, jarrett tw. laparoscopic pyeloplasty with concomitant pyelolithotomy. j urol. 2002;167:1378-80. 13. srivastava a, singh p, gupta m, et al. laparoscopic pyeloplasty with concomitant pyelolithotomy--is it an effective mode of treatment? urol int. 2008;80:306-9. 14. berkman ds, landman j, gupta m. treatment outcomes after endopyelotomy performed with or without simultaneous nephrolithotomy: 10year experience. j endourol. 2009;23:140913. 15. agarwal a, varshney a, bansal bs. concomitant percutaneous nephrolithotomy and transperitoneal laparoscopic pyeloplasty for ureteropelvic junction obstruction complicated by stones. j endourol. 2008;22:2251-5. 16. gupta m, tuncay ol, smith ad. open surgical exploration after failed endopyelotomy: a 12year perspective. j urol. 1997;157:1613-8; discussion 8-9. 17. lucas jw, ghiraldi e, ellis j, friedlander ji. endoscopic management of ureteral strictures: an update. curr urol rep. 2018;19:24. 18. van cleynenbreugel b, kilic o, akand m. retrograde intrarenal surgery for renal stones part 1. turk j urol. 2017;43:112-21. 19. assimos d, krambeck a, miller nl, et al. surgical management of stones: american urological association/endourological society guideline, part i. j urol. 2016;196:1153-60. 20. resorlu b, unsal a, gulec h, oztuna d. a new scoring system for predicting stonefree rate after retrograde intrarenal surgery: the "resorlu-unsal stone score". urology. 2012;80:512-8. 21. khan f, ahmed k, lee n, challacombe b, khan ms, dasgupta p. management of ureteropelvic junction obstruction in adults. nat rev urol. 2014;11:629-38. 22. guzel o, tuncel a, balci m, et al. retrograde intrarenal surgery is equally efficient and safe in patients with different american society of anesthesia physical status. ren fail. 2016;38:503-7. 23. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 24. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015;67:125-37. 25. berardinelli f, cindolo l, de francesco p, et al. the surgical experience influences the safety of retrograde intrarenal surgery for kidney stones: a propensity score analysis. urolithiasis. 2017;45:387-92. rirs following laser endopyelotomy-kartal et al. endourology and stone diseases 546 kidney transplantation 168 urology journal vol 5 no 3 summer 2008 donor nephrectomy with and without preservation of gonadal vein while dissecting the ureter majid aliasgari, nasser shakhssalim, farid dadkhah, alireza ghadian, seyyed mohammadmehdi hosseini moghaddam introduction: preservation of the gonadal vein while dissecting the ureter for donor nephrectomy may decrease the distal ureteral ischemia and urological complications in kidney transplant recipients. in this study, we compared the outcome of kidney allografts harvested with preservation of the gonadal vein while dissecting the ureter with allografts harvested without preserving the gonadal vein. materials and methods: we reviewed 167 consecutive kidney transplantations between april 2003 and april 2004. during donor nephrectomy, we preserved the gonadal vein in 106 harvested kidneys (group 1), while we did not preserve this vein in 61 allografts (group 2). the recipients in each group were followed up for a 2-year follow-up on average, and the outcomes including ureteral complications, graft loss, and patient and graft survival were compared between the two groups. results: urine leakage was noted in few patients (2 in group 1 and 3 in group 2) and its frequency was not significantly different between the two groups (p = .26). ureteral stricture was not seen in any of the kidney allograft recipients. no differences were found in the frequencies of acute rejection episodes, graft loss, and death between the two groups. conclusion: preservation of the gonadal veins did not significantly decrease the frequency of ureteral complications in the kidney transplant recipients. we recommend meticulous handling of the ureter in donor nephrectomies to prevent further remote complications regardless of the approach to the gonadal veins while nephrectomy. urol j. 2008;5:168-72. www.uj.unrc.ir keywords: kidney transplantation, nephrectomy, blood supply, ureter, living donors shahid modarress hospital and urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: nasser shakhssalim, md urology and nephrology research center, no 44, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: slim456@yahoo.com received november 2007 accepted june 2008 introduction ureteral problems seem to be of the most urological complications occurring after kidney transplantation. although the frequency of posttransplant urological disorders has declined from a range of 3.5% to 30% to less than 5% in the recent years,(1,2) ureteral obstruction, accounting for up to one-third of all significant urological complications,(3) is still a challenge, and 2% to 10.5% of the recipients develop ureteral stricture.(4-7) the most common cause of ureteral stricture is distal ischemia that may result from a compromised blood supply state due to the operative technique or high-dose immunosuppression.(8) deterioration of blood supply of the ureter and the adjacent tissues has a causative effect in the development of posttransplant ureteral problems. in addition, gonadal vein preservation in donor nephrectomy—aliasgari et al urology journal vol 5 no 3 summer 2008 169 surgical trauma to the ureteral sheath may cause a functional obstruction because of adherence of the ureter to the adjacent structures.(9) surgical errors play independent roles in alternation of blood supply by causing two technical problems. firstly, stripping the ureter of its adventitia and connective tissue leads to ischemia; and secondly, dissection of the renal artery too near to the renal hilum may develop a compromised state of blood flow in the ureteral branch of this artery. in addition, traction on the renal vessels during removal of the kidney may cause distal ureter ischemia.(10) consequently, trauma to the renal artery during donor nephrectomy may cause distal ureteral ischemia through multiple causes.(1) division of the ureter may not cause significant ischemia; secondary branches of the ascending and descending arteries in the ureteral sheath always penetrate the adventitial coat of the ureter, providing a freely anastomotic arterial plexus for the entire length of the ureter. owing to these vascular anastomoses, distal ureteral ischemia is not expected in the site of division of the ureter. since the vessels do not have long branches immediately from the plexuses in one-forth of the patients, injuries to the ureters are not uniformly accompanied by distal ureteral ischemia.(9) some reports addressed the probability of decreasing ureteral complications after dissection of the ureter in conjunction with the gonadal veins rather than its dissection without preservation of the gonadal veins.(4-6) although ureteral blood supply is not directly related to the gonadal vein, it is closely dependent on the surrounding tissues that contain the gonadal vein. it has been proposed that dissection of the ureter together with the gonadal vein would guarantee enough blood supply to the ureter.(6,11,12) in this study, we compared dissection of the ureter with and without preservation of the gonadal veins in donor nephrectomies for kidney transplantation. materials and methods in this study, we reviewed the outcome of kidney transplantation in terms of ureteral complications in 167 consecutive kidney transplants. transplantations were performed in shahid modarres hospital between april 2003 and april 2004, a relatively homogeneous period regarding the surgical techniques and of clinical care. all of the allografts were harvested from living related or unrelated donors. the technique of donor nephrectomy was open classic retroperitoneal approach using flank incision. the harvested kidney was then transplanted to the recipient by the same surgeon and ureterocystostomy was done using the lich-gregoire technique.(13,14) a foley catheter was used to drain the bladders of all patients for at least postoperative 7 days. in 106 donors, we harvested the kidneys and the gonadal veins were preserved while dissecting the ureter (group 1), whereas in 61, we did not preserve the gonadal veins (group 2). the ureter was transected at the level of the common iliac vessels in both groups and particular attention was given to avoiding dissection in the triangular area formed by the kidney, renal hilum, and gonadal vein stump. in group 1, the ureter was dissected conjoint to the gonadal vein. in group 2, we performed double ligation of the gonadal veins and transected just distal to the renal veins. cyclosporine-based immunosuppressive regimen was used for all of the kidney recipients. indwelling ureteral stents were used for approximately one month. daily serum biochemistry as well as careful clinical observation was used for monitoring the allograft function during the hospital stay. following discharge, our protocol consisted of clinical examination and biochemical assay every 15 days for the first month and monthly thereafter. for all patients with increased serum creatinine level (greater than 1.3 mg/dl) or an increasing trend of serum creatinine, ultrasonographic evaluation of the urinary tract was performed. urological complications and graft and patient outcomes were compared between the two groups. statistical analyses were performed using the chi-square test, the t test, and the nonparametric mann-whitney u test for comparisons. the kaplan-meier method and log rank test were used for assessment of rejectionfree graft survival and patient survival in the two groups. a p value less than .05 was considered significant. gonadal vein preservation in donor nephrectomy—aliasgari et al 170 urology journal vol 5 no 3 summer 2008 results table 1 demonstrates the recipients and donors’ characteristics. the mean duration of follow-up was 718 ± 128 days and 687 ± 106 days for the recipients in groups 1 and 2, respectively (p = .34). two patients in group 1 (1.9%) and 3 in group 2 (4.9%) developed urinary leakage (p = .26). this complication was handled by insertion of a bladder catheter and the leakage was eliminated in all of the patients. no ureteral stricture was noted in any of the kidney recipients. table 2 demonstrates the operative parameters and the outcomes in the two groups. there was no significant difference between the recipients in the two group regarding the mean rejection-free graft survival (835.0 ± 19.4 days versus 799.0 ± 31.4 days in groups 1 and 2, respectively; p = .50). similarly, the mean patient survival was not different between the two groups (877.3 ± 10.9 days versus 838.6 ± 23.8 days; p = .26). discussion ureteral complications are one of the most important urologic problems occurring in the recipients of kidney allografts. prevention of urologic complications requires a high level of surgical expertise. extravesical approaches for ureteroneocystostomy, including a short muscular tunnel over the ureteral tip to prevent reflux, have provided a technique with fewer ureteral obstructions.(15,16) since the shorter length of the ureter is required, the ischemic stricture is probably reduced and extrinsic compression from the submucosal tunnel is also avoided.(17) several prospective randomized studies suggested using prophylactic ureteral stents to reduce major ureteral complications.(17-19) some authors recommend preserving gonadal vein with ureter to preserve the normal blood supply of the ureter.(2) however, this technique is still a matter of controversy among transplant surgeons. fisher and colleagues(20) reported the incidence of ureteral complications in 200 consecutive handassisted laparoscopic donor nephrectomies. of the first 25 donors who underwent ureteral dissection without gonadal vein, 2 experienced ureteral complication. in this study, 9 of 175 patients who underwent ureteral dissection accompanied with gonadal vein experienced ureteral complications. low frequency of ureteral complications and performing a different procedure in small number of patients in one group precludes the statistical power to detect the difference between the two groups. in a recent survey on 300 consecutive laparoscopic donor nephrectomies, researchers found no significant ureteral obstruction in those who received kidney allograft using the technique of ureteral dissection without preservation of the gonadal vein.(21) this study, however, had no control group. lind and coworkers reported ureteral complications in recipients of 48 laparoscopic donor nephrectomies versus 49 open donor variables group 1 group 2 p number of transplants 106 61 … mean donor’s age, y 28 ± 4 27 ± 4 .10 donor’s sex male 88 (83.0) 48 (78.7) female 18 (17.0) 13 (21.3) .49 donor’s side of kidney left 76 (71.7) 37 (60.7) right 30 (28.3) 24 (39.3) .14 mean recipient’s age, y 38 ± 13 35 ± 12 .20 recipient’s sex male 65 (61.3) 36 (59.0) female 41 (38.7) 25 (41.0) .77 mean operative time, min 107.0 ± 7.3 109.0 ± 7.5 .14 mean hospital stay, d 17 ± 16 16 ± 6 .40 table 1. characteristics of kidney allograft recipients and donors in two groups of donor nephrectomies with gonadal preservation (group 1) and without gonadal vein preservation (group 2)* *values in parentheses are percents. continuous variables are demonstrated as mean ± standard deviation. variables group 1 group 2 p mean follow-up, d 718 ± 128 688 ± 106 .34 mean serum creatinine at discharge, mg/dl 1.48 ± 0.97 1.23 ± 0.40 .06 urinary leakage 2 (1.9) 3 (4.9) .26 acute rejection 8 (7.5) 6 (9.8) .61 graft loss 2 (1.9) 2 (3.3) .46 death 2 (1.9) 3 (4.9) .26 table 2. outcomes of kidney allograft recipients in two groups of donor nephrectomies with gonadal preservation (group 1) and without gonadal vein preservation (group 2)* *values in parentheses are percents. continuous variables are demonstrated as mean ± standard deviation. gonadal vein preservation in donor nephrectomy—aliasgari et al urology journal vol 5 no 3 summer 2008 171 nephrectomies. they did not dissect the ureter together with the gonadal vein. the ureter was implanted in the bladder using a transvesical implantation technique. in that report, the frequency of ureteral complications was relatively low. therefore, they concluded the requirement for dissection of the ureter together with the gonadal vein still remained under debate.(11) harvesting the kidney without preserving the gonadal vein provides the ureter without the surrounding connective tissue; consequently, it makes easy handling of the ureter during implantation and eliminates interventions for trimming.(21) particularly in this technique, less unnecessary tissue of the donor is delivered to the recipient. in addition, this approach simplifies nephrectomy, and transection of the gonadal vein at the level of renal vein provides more acceptable access to the lumbar vein. dissection of the ureter away from the gonadal vein allows easier evaluation of the ureter. we considered some tips in the surgical technique of our group 2 in whom the gonadal vein was not preserved to guarantee ureteral safety: firstly, we avoided using cautery to dissect the gonadal vein and the ureter; and secondly, we were cautious not to enter the “golden triangle” between the ureter, kidney, and renal artery. probably for this reason, ureteral complications were not significant compared with those in the recipients with gonadal vein-preserving donor nephrectomy. to our best knowledge, this is the first comparative study to compare urological complications in recipients who received kidneys with and without preservation of the gonadal vein while dissecting the ureter in open donor nephrectomy. conclusion to maintain ureteral blood supply in donor nephrectomy, dissection of the ureter in conjunction with the gonadal vein seems unnecessary and remains optional. focusing on gentle handling of the ureter during donor nephrectomy and ureteroneocystostomy might protect the ureter from further complications. conflict of interest none declared. references 1. berger pm, diamond jr. ureteral obstruction as a complication of renal transplantation: a review. j nephrol. 1998;11:20-3. 2. davari hr, yarmohammadi h, malekhosseini sa, salahi h, bahador a, salehipour m. urological complications in 980 consecutive patients with renal transplantation. int j urol. 2006;13:1271-5. 3. kinnaert p, hall m, janssen f, vereerstraeten p, toussaint c, van geertruyden j. ureteral stenosis after kidney transplantation: true incidence and long-term followup after surgical correction. j urol. 1985;133:17-20. 4. waller jr, veitch ps, nicholson ml. laparoscopic live donor nephrectomy: a comparison with the open operation. transplant proc. 2001;33:3787-8. 5. jacobs sc, cho e, foster c, liao p, bartlett st. laparoscopic donor nephrectomy: the university of maryland 6-year experience. j urol. 2004;171:47-51. 6. su lm, ratner le, montgomery ra, et al. laparoscopic live donor nephrectomy: trends in donor and recipient morbidity following 381 consecutive cases. ann surg. 2004;240:358-63. 7. nogueira m, kavoussi lr, bhayani sb. laparoscopic live donor nephrectomy: current status. bju int. 2005;95 suppl 2:59-64. 8. bosma rj, van driel mf, van son wj, de ruiter aj, mensink hj. endourological management of ureteral obstruction after renal transplantation. j urol. 1996;156:1099-100. 9. hinman f jr. kidney, ureter, and adrenal glands. in: hinman f jr, editor. atlas of urosurgical anatomy. philadelphia: wb saunders; 1993. p. 287-9. 10. al-shaer mb, al-midani a. the management of urological complications in renal transplant patients. saudi j kidney dis transpl. 2005;16:176-80. 11. lind my, hazebroek ej, kirkels wj, hop wc, weimar w, ijzermans jn. laparoscopic versus open donor nephrectomy: ureteral complications in recipients. urology. 2004;63:36-9. 12. dunkin bj, johnson lb, kuo pc. a technical modification eliminates early ureteral complications after laparoscopic donor nephrectomy. j am coll surg. 2000;190:96-7. 13. lich r, jr., howerton lw, davis la. vesicourethrography. j urol. 1961;85:396-7. 14. gregoir w. [congenital vesico-ureteral reflux.]. acta urol belg. 1962;30:286-300. dutch. 15. barry jm. unstented extravesical ureteroneocystostomy in kidney transplantation. j urol. 1983;129:918-9. 16. thrasher jb, temple dr, spees ek. extravesical versus leadbetter-politano ureteroneocystostomy: a comparison of urological complications in 320 renal gonadal vein preservation in donor nephrectomy—aliasgari et al 172 urology journal vol 5 no 3 summer 2008 transplants. j urol. 1990;144:1105-9. 17. streeter eh, little dm, cranston dw, morris pj. the urological complications of renal transplantation: a series of 1535 patients. bju int. 2002;90:627-34. 18. benoit g, blanchet p, eschwege p, alexandre l, bensadoun h, charpentier b. insertion of a double pigtail ureteral stent for the prevention of urological complications in renal transplantation: a prospective randomized study. j urol. 1996;156:881-4. 19. bassiri a, amiransari b, yazdani m, sesavar y, gol s. renal transplantation using ureteral stents. transplant proc. 1995;27:2593-4. 20. fisher pc, montgomery js, johnston wk, 3rd, wolf js, jr. 200 consecutive hand assisted laparoscopic donor nephrectomies: evolution of operative technique and outcomes. j urol. 2006;175:1439-43. 21. breda a, bui mh, liao jc, gritsch ha, schulam pg. incidence of ureteral strictures after laparoscopic donor nephrectomy. j urol. 2006;176:1065-8. v08_no_2_final.pdf case report 155urology journal vol 8 no 2 spring 2011 laparoscopic enucleation of leiomyoma of the urinary bladder a case report and review of the literature onkar singh,1 shilpi singh gupta,1 ankur hastir2 urol j. 2011;8:155-8. www.uj.unrc.ir keywords: urinary bladder, neoplasm, leiomyoma, laparoscopy 1department of surgery, m.g.m medical college & m.y. hospital, indore, india 2department of surgery, m.g.m medical college & hospital, navi mumbai, india corresponding author: onkar singh, md vpo, sangowal, tehsil, nakodar, distt., jalandhar, punjab, 144041, india tel: +91 989 377 7321 e-mail: dronkarsingh@gmail.com received august 2009 accepted october 2009 introduction leiomyoma is a rare benign mesenchymal tumor that accounts only for 0.04% to 0.5% of all the urinary bladder tumors.(1) although it is the most common benign tumor of the urinary bladder, less than 200 cases have been reported in the english literature.(2-5) the most common presentation of the bladder leiomyoma is obstructive or irritative urinary symptoms.(6,7) surgical excision is the treatment of choice, but laparoscopic excision or enucleation is also feasible with excellent results.(8) case report a 35-year-old married woman presented with history of occasional painless hematuria for two months; three episodes in the past fifteen days. physical examination was unremarkable. routine blood examination showed hemoglobin 10.4 g/ dl, leucocytes 7800/ mm3, and platelet count 150 000/mm3. blood urea and serum level of creatinine were within normal range. urine analysis showed 8 to 10 red blood cells per high-power field. ultrasonography of the pelvis revealed a large smooth mass with varying echogenicity present in the urinary bladder. computed tomography scan of the pelvis showed a mass measuring 5 × 4.5 cm, arising from the left lateral wall of the urinary bladder and protruding into the lumen (figure 1). cystoscopy revealed a large nodular grey-white mass protruding into the bladder lumen from the left lateral wall. rest of the bladder was normal. biopsy was taken from the mass and sent for histopathological examination, which clearly figure 1. computed tomography scan of the pelvis showing a urinary bladder mass arising from the left lateral wall and protruding into the lumen of the urinary bladder. laparoscopic enucleation of urinary bladder leiomyoma—singh et al 156 urology journal vol 8 no 2 spring 2011 showed it to be a leiomyoma. the patient underwent laparoscopic enucleation of the tumor. histopathology of the final specimen showed that it was composed of whorled interlacing fascicles of spindle-shaped cells (figure 2), confirming the diagnosis of leiomyoma of the urinary bladder (figure 3). postoperative period was uneventful. she was followed up for one year with cystoscopy, and was free of symptoms and recurrence. discussion mesenchymal tumors of the urinary bladder arise from the mesenchymal tissues present in the bladder and constitute 1% to 5% of all the bladder tumors.(9,10) leiomyoma accounts for approximately one-third of these and is the most common benign urinary bladder tumor.(10,11) however, it is still very rare with a frequency of only about 0.04% to 0.5% of all the urinary bladder tumors.(1) the first case of leiomyoma of the urinary bladder was reported 78 years earlier,(12) and since then not more than 200 cases have been reported in the english literature.(2-5) majority of patients have a tumor size of less than 10 cm; however, leiomyomas ranging from a few millimeters to 30 cm have been documented.(6,7,13,14) previously, it was assumed that leiomyoma occurs in all age groups and affects both genders equally.(7,15) but recent literature suggests a more common occurrence in women in their third to sixth decades of life.(6) goluboff and colleagues reviewed a total of 37 reported cases in english literature over a period of 24 years from 1970 to 1994. one-third of the leiomyomas occurred in women and the mean age of the patients was 44 years.(6) although the exact reason for this different occurrence is not yet known, role of estrogen in the growth of leiomyoma has been suggested.(16) as a significant number of patients with leiomyoma of the urinary bladder (especially extravesical) may be asymptomatic,(6) cornella and associates attributed female predominance to the increased use of pelvic ultrasonography in women.(1) broessner and coworkers suggested that leiomyoma of the urinary bladder may have a higher prevalence in asian population, since most reported cases of urogenital leiomyoma are from japan.(13) however, the cause of this different geographical occurrence is unknown. the exact etiology of leiomyomas remains unclear. it is proposed that leiomyomas may arise from chromosomal abnormalities,(1) hormonal influences, bladder musculature infection, figure 2. laparoscopically enucleated specimen of the tumor that was confirmed on histopathological examination as leiomyoma of the urinary bladder. figure 3. histopathology of the removed tumor showing that it is composed of whorled interlacing fascicles of spindle-shaped cells consistent with the diagnosis of leiomyoma. laparoscopic enucleation of urinary bladder leiomyoma—singh et al 157urology journal vol 8 no 2 spring 2011 perivascular inflammation, or dysontogenesis.(6) leiomyoma may occur at any sites in the genitourinary tract.(9) in the urinary bladder, it arises from submucosa, but can develop and grow in any layer.(7) thus, grossly it can be intravesical, intramural, or extravesical. intravesical form has been reported most frequently in the literature (63% to 86%) followed by extravesical (11% to 30%), while intramural type is less common accounting for 3% to 7% of the cases.(6,7) intravesical tumors, first named and described as endovesical tumors by campbell and colleagues, is a result of submucosal growth of leiomyoma.(9) symptoms caused by leiomyoma of the urinary bladder depend on its size and location. small intravesical tumors that are present away from the bladder neck or ureteral openings and those which are extravesical or intramural are asymptomatic. if the patient is symptomatic, the most common symptoms include obstructive urinary symptoms (49%), followed by irritative symptoms (38%), flank pain (13%), and hematuria (11%).(6) however, knoll and colleagues found the irritative symptoms as the most frequent presenting symptoms.(7) larger tumors are more likely to cause irritative symptoms while those arising near the bladder neck or ureteral openings tend to cause obstructive symptoms. dyspareunia has also been described as an unusual presentation of leiomyoma of the urinary bladder.(14) goluboff and associates also reported a palpable pelvic lump in more than half of the women on bimanual examination.(6) various imaging techniques help to make the diagnosis of leiomyoma of the urinary bladder, but none is confirmatory. on ultrasonography, leiomyoma appears as a smooth hypoechoic solid mass, with varying degrees of internal echoes and a thin hyperechoic covering of the mucosa.(17) real-time imaging and transvaginal ultrasonography can give accurate information about localization of the mass and its relation to surrounding structures.(18,19) intravenous urography shows only a smooth filling defect in the urinary bladder.(1) computed tomography scan and magnetic resonance imaging (mri) both can be used to assess the site, dimensions, and any extension of the tumor. but mri is considered as the modality of choice, since it provides better contrast and resolution.(20) the definitive diagnosis of leiomyoma of the urinary bladder and differentiation from leiomyosarcoma requires histopathological examination through urethro-cystoscopy.(17) tissue can be taken by cystoscopic biopsy or otherwise. relying on highly suggestive findings of mri, a completely removed tumor can serve as specimen for histopathological examination. on histology, leiomyomas of the urinary bladder typically have no or less than two mitotic figures per high-power field, and lack infiltration and necrosis.(6,7) malignant transformation of leiomyoma has not been reported.(14) treatment of leiomyoma of the urinary bladder is mainly surgical. however, goluboff and colleagues have successfully treated few asymptomatic patients with leiomyoma of the urinary bladder as an incidental finding.(6) surgical options depend on size and location of the tumor, and include transurethral resection of the tumor and open surgical excision. surgical excision has excellent prognosis and should always be offered. moreover, transurethral resection is a safe and effective initial choice for patients with relatively smaller tumors.(6) larger tumors and those with extravesical growth usually require open surgery with segmental resection or partial cystectomy.(7) successful laparoscopic resection of leiomyoma of the urinary bladder has also been reported.(8) conflict of interest none declared. reference 1. cornella jl, larson tr, lee ra, magrina jf, kammerer-doak d. leiomyoma of the female urethra and bladder: report of twenty-three patients and review of the literature. am j obstet gynecol. 1997;176: 1278-85. 2. teran az, gambrell rd, jr. leiomyoma of the bladder: case report and review of the literature. int j fertil. 1989;34:289-92. 3. alapont perez fm, gil salom m, chuan nuez p, et al. [bladder leiomyoma. review and report of a case]. arch esp urol. 1995;48:1035-7. 4. petracco s, malossini g, tallarigo c, novelli p, bianchi g. considerations regarding a case of leiomyoma of the urinary bladder. int urol nephrol. 1985;17:149-53. laparoscopic enucleation of urinary bladder leiomyoma—singh et al 158 urology journal vol 8 no 2 spring 2011 5. nazir ss, maqbool a, khan m. leiomyoma of the urinary bladder-a case report and brief review of literature. int j nephrol urol. 2009;1:72-4. 6. goluboff et, o’toole k, sawczuk is. leiomyoma of bladder: report of case and review of literature. urology. 1994;43:238-41. 7. knoll ld, segura jw, scheithauer bw. leiomyoma of the bladder. j urol. 1986;136:906-8. 8. patrozos k, westphal j, trawinski j, wagner w. [total laparoscopic excision of a leiomyoma of the urinary bladder -a case report]. aktuelle urol. 2005;36:58-60. 9. campbell ew, gislason gj. benign mesothelial tumors of the urinary bladder: review of literature and a report of a case of leiomyoma. j urol. 1953;70: 733-41. 10. sakellariou p, protopapas a, kyritsis n, voulgaris z, papaspirou e, diakomanolis e. intramural leiomyoma of the bladder. eur radiol. 2000;10:906-8. 11. blasco cfj, sacristán sj, ibarz sl, batalla cjl, ruiz mfj. characteristics of bladder leiomyoma in our setting. archivos españoles de urología. 1995;48: 987-90. 12. kretschmer jl. leiomyoma of the bladder with a report of a case and a review of the literature. j urol. 1931;26:575-89. 13. broessner c, klingler ch, bayer g, pycha a, kuber w. a 3,500-gram leiomyoma of the bladder: case report on a 3-year follow-up after surgical enucleation. urol int. 1998;61:175-7. 14. kim iy, sadeghi f, slawin km. dyspareunia: an unusual presentation of leiomyoma of the bladder. rev urol. 2001;3:152-4. 15. o’connell k, edson m. leiomyoma of bladder. urology. 1975;6:114-5. 16. neri a, rabinerson d. multiple leiomyomata of the urinary bladder in a hysterectomized woman. acta obstet gynecol scand. 1995;74:241-2. 17. greco a, baima c, piana p. [leiomyoma of the bladder. report of a case and review of the literature]. minerva urol nefrol. 1999;51:33-8. 18. fernandez fernandez a, mayayo dehesa t. leiomyoma of the urinary bladder floor: diagnosis by transvaginal ultrasound. urol int. 1992;48:99-101. 19. illescas ff, baker me, weinerth jl. bladder leiomyoma: advantages of sonography over computed tomography. urol radiol. 1986;8:216-8. 20. sundaram cp, rawal a, saltzman b. characteristics of bladder leiomyoma as noted on magnetic resonance imaging. urology. 1998;52:1142-3. female urology association between hyposensitivity of c-fiber afferents at the proximal urethra and storage/voiding dysfunction in female patients with detrusor overactivity osamu ichiyanagi1*, ken-ichi nishimoto2, akira nagaoka3, sei naito4, mayu yagi4, masaki ushijima4,5, tomoyuki kato4, and norihiko tsuchiya4 purpose: we examined the associations between urethral sensation and storage/voiding function in female patients with detrusor overactivity (do) by measuring urethral current perception threshold (cpt). materials and methods: we retrospectively investigated the medical records of 27 consecutive patients with lower urinary tract symptoms who underwent cystometry, uroflowmetry (ufm), and urethral cpt tests from 2000 to 2015. patients were classified into 2 groups: with/without do. seven do-negative cases were selected as normal controls on cystometrogram (cmg) matching the inclusion criteria: bladder compliance ≥ 12.5 ml/cmh 2 o, volume < 275 ml at first sensation, and no comorbidities possibly influencing micturition. finally, 17 patients were included. urethral cpt was evaluated with intraurethral square-wave impulses at 3 hz to stimulate c-fibers. urethral loss coefficient (lc), reflecting urethral resistance during voiding, was calculated by curve-fitting a mathematical model to a ufm waveform. results: urge incontinence (ui) was observed in 7 do-positive patients, but not in those with normal cmg. urethral cpt and lc were significantly higher in patients with do than in those with normal cmg. median urethral cpt significantly increased in patients with both do and ui than in those without these symptoms (p < .005). cpt values were correlated with the volume at first sensation (p=0.53, p < .05) and lc (p =0.59, p < .05). lc was not calculated in 3 cases due to poor curve-fitting. conclusion: in females, urethral c-fiber afferents may become hyposensitive as the detrusor becomes overactive with ui in the storage phase. during voiding, c-fiber hyposensitivity may relate to increased functional resistance of the urethra to urine outflow. keywords: current perception test; c-fiber; cystometry; detrusor overactivity; female; urethra; uroflowmetry introduction micturition depends on a complex neural control system to coordinate the activities of the lower urinary tract (lut) consisting of the urinary bladder, urethra, and urethral sphincters.(1,2) during the storage phase, the guarding reflex (i.e., the bladder-to-urethral rhabdosphincter reflex) and the bladder-to-sympathetic reflex mainly contributes to urinary continence.(1-3) the storage phase can be switched to the voiding phase either involuntarily or voluntarily. the switching mechanism between the storage and voiding phases is mediated by the periaqueductal grey in the midbrain.(1-3) at the voiding phase, the pontine micturition center in the brainstem is released from the tonic inhibition of higher brain structures such as the hypothalamus and prefrontal cortex.(1-3) subsequently, a long-loop spinobulbospinal voiding reflex that passes through the pontine micturition center is activated to initiate a contraction of the bladder and a relaxation of the urethral sphincter followed by an increase in bladder pressure and urinary 1department of urology, yamagata prefectural kahoku hospital, 111 aza-gassando, yachi, kahoku 999-3511, japan. 2department of central clinical laboratory, fuchu hospital, 1-10-17 hiko-cho, izumi 594-0076, japan. 3department of urology, yonezawa city hospital, 6-36 aioi, yonezawa 992-8502, japan. 4department of urology, yamagata university faculty of medicine, 2-2-2 iida-nishi, yamagata 998-9585, japan. 5department of urology, yamagata city hospital saiseikan, 1-3-26 nanoka-mahi, yamagata 990-8533, japan. *correspondence: department of urology, yamagata prefectural kahoku hospital, kahoku, japan. tel: +81-237-73-3131. fax: +81-237-73-4506. e-mail: oichiyan@ab.cyberhome.ne.jp. received august2019 & accepted may 2020 outflow.(1-3) thus, abnormalities in micturition suggests neural dysregulation of the reflex pathways between the urethra and bladder.(2,3) increased frequency of voiding, urgency, urge urinary incontinence (uui), and incomplete emptying of the bladder are clinically bothersome symptoms especially for the elderly people.(2,4) the pelvic, hypogastric, and pudendal nerves transmit sensory information in afferent fibers from receptors in the lut to second-order neurons in the lumbosacral spinal cord.(2,3) afferent fibers traveling in the pelvic nerve to the sacral spinal cord are the most important for the initiation of micturition. sacral afferent nerve terminals are uniformly distributed to all areas of the detrusor and urethra, whereas lumbar afferent nerve endings are most frequently found in the trigone and are scarce in the bladder body.(3) two types of neural fibers constitute the afferent nerves: a-δ (myelinated) and c-fibers (unmyelinated).(2) the afferent axons in the urothelial submucosa and detrusor muscle are a-δ or c-fibers, while those in the mucosa are composed urology journal/vol 17 no. 6/ november-december 2020/ pp. 631-637. [doi: 10.22037/uj.v16i7.5515] vol 17 no 06 november-december 2020 632 of c-fiber alone.(2,5) physiologically, a-δ afferents fire at low thresholds by responding to passive bladder distention and active detrusor contraction.(2) c-fibers are primarily activated by a low temperature, chemicals, inflammation or noxious stimulation under pathological conditions.(2) since the firing threshold is higher in c-fibers than a-δ afferents, the c fiber activation is not physiologically involved with normal micturition.(2) measurement of current perception threshold (cpt) is semi-objective evaluation of lut sensation.(6-8). kenton et al.(8) reported that the urethral cpt is significantly higher in older females symptomatic of uui, indicating that urethral sensation may be potentially impaired in parallel with aging and appearance of overactive bladder (oab) symptoms. we previously demonstrated significant differences in the cpt of c-fiber afferents at the proximal urethra among 53 patients with neurogenic do, idiopathic do, or normal configuration and specifically between the patients with and without uui on filling cystometry, suggesting that urethral c-fiber hyposensitivity may underlie the appearance of uui.(9) however, it remains unclear how such an impairment of the urethral c-fiber afferents affects urination. there are more complex relations between the bladder and the proximal urethra in men than in women. in the present study, we investigated the relationships between cystometric/uroflowmetric parameters and urethral cpt values in female patients for simple interpretation. patients and methods study patients we retrospectively identified consecutive eighty patients with lower urinary tract symptoms (luts) who underwent urodynamic study and urethral cpt determination in yamagata university hospital from 2000 to 2015. the exclusion criteria were male gender (n=46) and missing data on uroflowmetry (n=7). the remaining 27 females were divided into do-positive or -negtable 1. cystometric patterns and background diseases of the female patients case no. age (years) patterns of cmg pattern of do uui background diseases / comorbidities pt_01 68 normal cmg absence of do no diabetes mellitus pt_02 51 normal cmg absence of do no endometriosis pt_03 63 normal cmg absence of do no nervous pollakisuria pt_04 23 normal cmg absence of do no nervous pollakisuria pt_05 69 normal cmg absence of do no stress incontinence pt_06 45 normal cmg absence of do no progressive muscular dystrophy pt_07 75 normal cmg absence of do no osteoporosis pt_08 68 idiopathic do phasic do yes nervous pollakisuria pt_09 84 idiopathic do phasic do no vertebral compression fracture (l1) pt_10 64 neurogenic do terminal do yes cervical cancer (radical hysterectomy, postoperative) pt_11 54 neurogenic do terminal do no cervical cancer (radical hysterectomy, postoperative) pt_12 78 neurogenic do phasic do yes rectal cancer (trans-anal resection, adjuvant radiation therapy) pt_13 70 neurogenic do terminal do yes cerebral infarction (left hemiplegia) pt_14 51 neurogenic do terminal do yes multiple sclerosis, subacute myelo-optico-neuropathy pt_15 14 neurogenic do phasic do no spina bifida (postoperative) pt_16 75 neurogenic do terminal do yes diabetes mellitus, bladder diverticulum pt_17 76 neurogenic do terminal do yes spinal canal stenosis (lumber) do-positive, n=10 (%) normal cmg, n=7 (%) p; u-test patterns of do; phasic / terminal do 4 (40.0%) / 6 (60.0%) 0 (0.0%) / 0 (0.0%) qualification according to cause of do; idiopathic / neurogenic do 2 (20.0%) / 8 (80.0%) 0 (0.0%) / 0 (0.0%) urge urinary incontinence 7 (70.0%) 0 (0.0%) median range median range age (years) 69 14 −84 63 23 −75 0.241 filling cystometry and cpt test first sensation of bladder filling (ml) 136.0 37.0 −343.0 85.0 34.0 −158.0 0.187 maximum cystometric capacity (ml) 254.1 34.9 −476.5 403.0 197.5 −625.0 0.055 compliance (ml/cmh2o) 12.7 1.9 −145.7 116.8 40.0 −357.5 < 0.005 urethral cpt(ma) 9.7 3.6 −26.0 3.0 1.0 −5.2 < 0.005 free uroflowmetry qmax (ml/s) 8.4 3.7 −16.9 16.5 5.2 −37.2 0.172 vv (ml) 100.3 20.5 −343.3 171.6 49.0 −442.0 0.133 pvr (ml) 28.6 0 −117.0 12.4 0 −85.0 0.404 loss coefficienta 3.42 1.06 −15.36 2.01 0.20 −2.26 < 0.01 lci 0.17 0.12 −0.50 0.07 0.05 −0.30 0.124 lcf 1.11 0.00 −9.43 0.49 0.01 −0.59 0.240 lce 2.83 0.92 −9.64 1.38 0.03 −1.50 < 0.01 abbreviations: cmg, cystometrogram; do, detrusor overactivity; cpt, current perception threshold; qmax, maximum flow rate; vv, voided volume; pvr, post void residual. a loss coefficients cannot be calculated in patients with do-positive (n=1) and normal cmg (n=2) due to insufficient curve fitting. lci, lcf, and lce indicate loss coefficients due to inertial, frictional and elastic resistances in the urethra, respectively. table 2. clinical background of seventeen female patients urethral c-fiber function in storage/voiding−ichiyanagi et al. ative groups according to cystometric observations (n=10 and n=17, respectively). seven of the 17 patients without do who met the criteria of compliance ≥ 12.5 ml/cmh2o(10), bladder volume at the first sensation of bladder filling (fsf) < 275 ml, and no diseases potentially causing lut dysfunction were designated as normal controls on cystometrogram (cmg). finally, 17 female patients were eligible for the analyses (fig. 1). none of the patients in the study had detrusor-sphincter dyssynergia (dsd) on cmg with electromyogram or urethral stricture at insertion of a 14fr electric stimulating catheter for urethral cpt measurement. the present study was approved by the ethical committee of the yamagata university faculty of medicine (no. 217, approved on september 5, 2018). the requirement for individual informed consent was waived, because the present study was retrospective and the anonymity of the participants was ensured. this study has conformed with the ethical standards in the 1964 declaration of helsinki and its later amendments or comparable ethical standards. urodynamic study water-filling cystometry with electromyography, uroflowmetry and ultrasonographic measurement of postvoid residual (pvr) were performed in conventional procedures as described elsewhere.(9) cpt measurement of the proximal urethra detailed procedures for cpt measurement were previously depicted.(9,11) briefly, immediately after filling cystometry, cpt was determined at the proximal urethral mucosa by evaluating c-fiber sensation as stimurethral c-fiber function in storage/voiding−ichiyanagi et al. figure 1. flow chart of female patients’ classification abbreviations: do: detrusor overactivity; cmg: cystometrogram; ufm: uroflowmetry; fsf: first sensation of bladder filling; lut: lower urinary tract figure 2. approximation of actual ufm curves with a mathematical model actual traces of ufm were sufficiently curve-fitted to the mathematical model.(13-15) representative cases of normal cmg (pt_05) and positive do (pt_08) are shown in fig. 2a and 2b, respectively. however, the model was not applicable in 3 cases (pt_01, 04, and 13) because of abnormal ufm waveforms (fig. 2c, d, and e, respectively). continuous and dashed lines in the panels indicate actual traces of ufm and approximation with the mathematical model, respectively. here, patient numbers in the parenthesis are compatible with those presented in table 1. abbreviations: do: detrusor overactivity; cmg: cystometrogram; ufm: uroflowmetry; lc: loss coefficient female urology 633 80 patients 34 females do-positive (n=10) do-negative (n=17) normal cmg (n=7) exclusion due to male gender (n=46) 10 female patients were excluded due to low-compliance of the detrusor < 12.5 ml/cmh2o (n=2) active chronic cystitis at cytometry (n=1) reduced sensation with fsf > 275 ml (n=2) diseases potentially affecting lut function (n=5) 27 females exclusion due to ufm data missing (n=7) 0 2 4 6 8 10 0 20 40 60 80 pt_01 fl ow (m l/ se c) time (s) 0 2 4 6 8 10 0 10 20 30 40 pt_13 fl ow (m l/ se c) time (s) 0 2 4 6 8 10 0 20 40 60 80 pt_04 fl ow (m l/ se c) time (s) a b c d e 0 10 20 30 40 50 0 5 10 15 20 25 pt_05 fl ow (m l/ se c) time (s) lc = 2.01 0 2 4 6 8 10 12 0 5 10 15 20 25 pt_08 fl ow (m l/ se c) time (s) lc = 7.83 vol 17 no 06 november-december 2020 634 ulation impulses (0.5-ms square-wave, 3 hz) applied via transurethral electrodes were gradually increased to patients’ first perception of the impulses.(7,12) the least intensity of the electrical stimulation at first perception was defined as urethral c-fiber cpt at the proximal portion.(7,12) calculation of urethral loss coefficient during the voiding phase urethral loss coefficient (lc) can be calculated from the relation of kinetic energy and pressure loss obtained by approximating ufm waveforms using a mathematical voiding model.(13-15) in brief, urine-expelling is dynamically considered as a balanced consequence of intravesical pressure as a driving force and an outlet resistance system of the urethra. the resistance system consists of inertial, frictional and elastic resistances. the interaction among these dynamic factors changes in a time course (during voiding) and is expressed as a ufm curve. the pressure differences against the inertial, frictional, and elastic resistances are proportional to the change in urinary flow rate in a time course (dq(t)/ dt), urinary flow rate (q(t)), and the voided volume (vv) at the moment (∫qdt), respectively. herein, the intraurethral pressure difference (∆p(t)) can be described as follows: (1) where l, r, and c are constants that can be determined by the curve-fitting of actual ufm configurations with the mathematical model (figure 2a and b).(13,15) the integral values of pressure loss during voiding time contributing to urethral inertial, frictional, and elastic resistances (∆ pi , ∆ pf , and ∆p e , respectively), and the energy used for inertial resistance is wi. in the present study, we defined urethral lc as follows: (2) where lc i , lc f , and lc e indicate loss coefficients due to inertial, frictional, and elastic resistances in the urefigure 3. cpt values at the proximal urethra. (a) association between urethral cpt and bladder fsf. positive correlation between median cpts at the proximal urethra and fsf on filling cystometry for patients with and without do was demonstrated on the scatter plot. (b) differences in urethral cpt among patient groups with normal cmg, do, and/or uui. median cpts were 11.5, 6.8, and 3.0 ma for the 3 groups of do+ and uui+, do+ and uui−, and normal cmg, respectively, with statistical significance between patients with both do and uui and those with neither. note that patients with normal cmg exhibited neither do nor uui. abbreviations: cpt: current perception threshold; do: detrusor overactivity; cmg: cystometrogram; uui: urge urinary incontinence; +: positive; −: negative; fsf: first sensation of bladder filling; figure 4. association between urethral cpt and lc. urethral cpt was positively correlated with urethral lc. note that patients with normal cmg were all plotted near the origin. three patients were omitted from this graph due to the unavailability of lc calculation. abbreviations: cpt: current perception threshold; do: detrusor overactivity; cmg: cystometrogram; uui: urge urinary incontinence; lc: loss coefficient urethral c-fiber function in storage/voiding−ichiyanagi et al. a u re th ra l c p t ( m a ) 0 5 10 15 20 25 30 do−, uui− (normal cmg) do+, uui− do+, uui+ (n=7) (n=3) (n=7) p < 0.005 p = 0.16 p = 0.20 3.0 ma 6.8 ma 11.5 ma patient group b do+, uui+normal cmg do+, uui− 50 100 150 200 250 300 350 0 5 10 15 20 25 u re th ra l c p t ( m a ) bladder fsf (ml) ρ = 0.528 (p < 0.05) do+, uui+normal cmg do+, uui− 0 5 10 15 0 5 10 15 20 25 u re th ra l c p t ( m a ) urethral lc ρ = 0.578 (p < 0.05) thra, respectively. statistical analysis statistical analysis was done non-parametrically using the mann-whitney u test, kruskal-wallis test, and post-hoc test with the steel-dwass method between groups. spearman’s correlation analysis was performed to examine the relationships between the 2 groups. statistical significance was considered with p-value < 0.05. all statistical analyses were done using r3.4.1 (http:// cran.r-project.org/, accessed on june 30, 2017). results table 1 shows the background diseases of the 17 patients. the study patients were classified into 2 groups according to the cmg findings: normal cmg (n=7) and do-positive (n=10). table 2 shows the clinical data on the types of do, uui, age, sex, and urodynamic study results in the 2 groups of patients. patients’ age, the volume at fsf, and maximum cystometric capacity did not vary between the groups. however, the median values of bladder compliance and urethral cpt were significantly different between the groups (mann-whitney u-test, p < .05). as for the ufm parameters, peak flow rate (qmax), vv, and pvr appeared to have better median values in patients with normal cmg, but the differences between the 2 groups did not reach statistical significance. figure 3a demonstrates that the urethral cpt values were significantly correlated with bladder capacity at fsf on filling cystometry (spearman’s correlation coefficient, p =0.528, p < .05). figure 3b shows significant differences in the median cpt values of the urethra among patients with normal cmg, do, and/or uui (kruskal-wallis test, p < .005). median urethral cpt significantly increased in patients with both do and uui compared to those with neither (post-hoc test with the steel-dwass method, p < .005; figure 3b). patients who exhibited urodynamic do without symptomatic uui had urethral cpt values that were intermediate between those of the 2 groups of patients. lc could not be calculated in 3 cases (n=1 and n=2 for groups with do and normal cmg, respectively) due to poor curve-fitting of the mathematical model to the individual actual traces of ufm configurations (figure 2c, d, and e). urethral lc was significantly larger in do-positive patients than in those with normal cmg (u-test, p < .01; table 2). lc e , one of the 3 components constituting a total value of urethral lc, contributed mainly to the difference in urethral lc between the 2 groups (u-test, p < .01; table 2). figure 4 shows a positive correlation between the urethral cpt values and lc for the entire cohort in the present study (spearman’s correlation coefficient, p =0.578, p < .05). discussion urgency and uui are not necessarily observed clinically in patients who exhibit do in cmg tests.(16) however, easy excitability of bladder c-fiber afferents has been regarded as the underlying mechanism for urgency and do.(2,5) the number of urgency and uui episodes was found to have a significantly negative correlation with bladder cpt values determined at 5-hz stimuli to c-fiber activation.(17) the proximal urethral c-fibers were significantly hyposensitive to electrical stimulation (1-5 hz) in patients with oab, uui, and/ or other pathological conditions.(8,18-20) kenton et al.(11) described that impaired sensation of the urethra in uui female patients restored after a 2-month administration of tolterodine for detrusor relaxation. oab patients showed significantly more do, more hypersensitivity, and lower cpt of the bladder compared with non-oab patients.(17) in the present study, the proximal urethra became more hyposensitive to c-fiber stimuli, in parallel with the increased volume at fsf and the emergence of do and/ or uui. these findings support the conclusion that the c-fiber impairment of the urethra may work synergistically with do to cause uui in female patients. however, the development of do in female patients with early-stage type ii diabetes was not associated with the dysfunction of intravesical c-fibers.(21) in the present study, we were unable to refer to this point because bladder cpt determination was out of the investigation. however, positive correlation between urethral cpt values and bladder volumes at fsf in our study may indicate that bladder a-δ afferents became impaired together with urethral c-fiber hyposensitivity in the female patients. various reflexes between the urethra and bladder that are activated to facilitate or inhibit urination by sensory signals from the proximal urethra have been identified. (2,6,22) the urethral afferents fire in response to fluid flow in the urethra, with an increasing tendency of the firing rate in proportion to increases in the flow.(23) sensory input from the urethra has been found to initiate bladder contractions in the quiescent bladder and augment ongoing contractions in ewes(24), rats(25,26), and humans. (27,28) administered into the urethral lumen, prostaglandin e2 activates the micturition reflex via stimulation of c-fiber afferent nerves.(22) similarly, capsaicin increases the bladder contraction frequency within a few minutes after intraurethral administration.(22,26) by contrast, silencing urethral afferents with anesthesia reduces bladder contraction frequency and bladder emptying efficiency.(25-27) in patients with benign prostatic hyperplasia (bph), prostatic urethral anesthesia resulted in significant increases in first sensation volume and maximum cystometric capacity.(22) bladder neck and urethral injections of botulinum toxin significantly lessened luts and increased qmax in mild bph patients, accompanied by a transient increase in bladder capacity and decrease in pvr at 1 and 3 months after treatment. (29) thus, sensory information from the proximal urethra modulates the afferent activities to influence micturition.(22) accordingly, a positive correlation between urethral cpt and lc values in the present study support that sensory impairment of the proximal urethral c-fibers may be involved in functional rigidity of the urethra during voiding. ufm with pvr measurement is a widely used firstline urodynamic test in urologic practice for screening patients with suspected lut dysfunction.(30) the test provides objective and quantitative information on voiding, and the patterns of the ufm curve may reflect certain types of voiding abnormality.(30) in general, a multichannel pressure/flow (pf) study is required for a detailed investigation because the shape of the ufm curve is largely affected by detrusor contractility, bladder outlet resistance, and/or bladder volume.(30) however, the pf study is cumbersome, invasive, and costly compared with ufm. in the pf study, examinees are asked to store and void urine under the non-physiologurethral c-fiber function in storage/voiding−ichiyanagi et al. female urology 635 vol 17 no 06 november-december 2020 636 ical condition of 2 catheters that are indwelled via the urethra and anal canal to record intra -vesical and -abdominal pressures, respectively. in addition, electrodes are attached to the perineal/perianal regions to electromyographically monitor sphincter activities. from the perspective of energy balance, we have put proposed a novel analytical theorem of ufm curves based on the premise that energy produced by intravesical pressure as a driving force during voiding should be equivalent to the sum of the energy consumed by the resistance systems through the urethra and the kinetic energy of urine outflow from the urethral outlet.(13-15) in the present study, the resistance systems were defined as comprising the inertial, frictional, and elastic resistances of the urethra. using this theorem, urethral lc, a type of urethral resistance, can be calculated from the kinetic energy and pressure loss obtained by the mathematical approximation of ufm waveforms.(13,14) and pf relationships during voiding can be plotted.(13-15) we reported that urethral lc in bph patients who undertook transurethral resection of the prostate significantly decreased after the surgery, to the levels comparable with normal women and men with unobstructed bladder outlet.(14) in the present study, urethral lc and the elastic component of the lc (lc e ) were significantly higher in do-positive patients than in those with normal cmg. these findings suggest a possible association between urethral rigidity during voiding and hyposensitivity of c-fiber afferents in the proximal urethra, considering that neither anatomical stenosis of the urethra nor dsd were found in the study cohort. there were no statistical differences in qmax, vv, and pvr between the do-positive and normal cmg groups in the present study, which may be attributable to the small number of patients, all-female cohort, and/or lack of healthy subjects referenced as a control. herein, the patients with normal cmg had higher values of urethral lc than did normal females in a previous study(14), which may be because patients with normal cmg potentially suffer from c-fiber impairments of the proximal urethra owing to unknown etiologies, given the general vulnerability of the c-fiber afferents(2,22). in this retrospective study, we were unable to examine the relationships among cpt, urethral lc, and pf parameters, including detrusor contractility and obstruction grade, since no patients undertook urodynamic evaluation with a conventional pf study for luts. the present study includes some limitations in data interpretation.(1) the study was retrospectively designed based on only a small number of female patients.(2) reference controls for comparison of cpt were set to patients with normal cmg, but not healthy volunteers. (3) cpt test for lut has not been a methodologically standardized procedure.(5,12) in this situation, the bladder cpts of a-δ and c -fibers were not determined.(4,21) data on subjective evaluation of luts severity were lacking. (5) we did not perform a conventional pf study for evaluating voiding dysfunction, and calculation of urethral lc from ufm curves is not yet common in the urology field. thus, large-scale and prospectively designed studies are further required to confirm and validate the present results. conclusions urethral c-fiber hyposensitivity was significantly related to urodynamic do and/or uui during urine storage as well as increased urethral lc at voiding in luts females. the firing threshold of urethral c-fiber afferents may increase to weaken the continence mechanism according as the detrusor becomes overactive. when the storage phase of the bladder is switched to the voiding phase, the c-fiber impairment of the proximal urethra may associate with the increase in functional rigidity of the urethra during urine outflow. acknowledgements this study was financially supported by funds from the department of urology, yamagata university faculty of medicine and yamagata prefectural kahoku hospital. conflict of interest the authors declare no conflict of interest. references 1. merrill l, gonzalez ej, girard bm, vizzard ma. receptors, channels, and signalling in the urothelial sensory system in the bladder. nat rev urol. 2016;13:193-204. 2. de groat wc, griffiths d, yoshimura n. neural control of the lower urinary tract. compr physiol. 2015;5:327-96. 3. andersson ke, wein aj. pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. pharmacol rev. 2004;56:581-631. 4. irwin de, milsom i, hunskaar s, et al. population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the epic study. eur urol. 2006;50:1306-14. 5. wyndaele jj. investigating afferent nerve activity from the lower urinary tract: highlighting some basic research techniques and clinical evaluation methods. neurourol urodyn. 2010;29:56-62. 6. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002;21:167-78. 7. knupfer sc, liechti md, gregorini f, de wachter s, kessler tm, mehnert u. sensory function assessment of the human male lower urinary tract using current perception thresholds. neurourol urodyn. 2017;36:46973. 8. kenton k, lowenstein l, simmons j, brubaker l. aging and overactive bladder may be associated with loss of urethral sensation in women. neurourol urodyn. 2007;26:981-4. 9. ichiyanagi o, nagaoka a, naito s, et al. possible role of hyposensitivity of c-fiber afferents at the proximal urethra in the development of urge urinary incontinence in patients with detrusor overactivity. low urin tract symptoms. 2019;11:o21-7. 10. weld kj, graney mj, dmochowski rr. differences in bladder compliance with time urethral c-fiber function in storage/voiding−ichiyanagi et al. and associations of bladder 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jj, van meel td, de wachter s. detrusor overactivity. does it represent a difference if patients feel the involuntary contractions? j urol. 2004;172:1915-8. 17. lee sr, kim hj, kim a, kim jh. overactive bladder is not only overactive but also hypersensitive. urology. 2010;75:1053-9. 18. kinn ac, nilsson by. urethral sensitivity in incontinent women. eur urol. 2005;48:11620. 19. kessler tm, studer ue, burkhard fc. increased proximal urethral sensory threshold after radical pelvic surgery in women. neurourol urodyn. 2007;26:208-12. 20. van meel td, wyndaele jj. reproducibility of electrical sensory testing in lower urinary tract at weekly intervals in healthy volunteers and women with non-neurogenic detrusor overactivity. urology. 2012;79:526-31. 21. lee wc, wu hp, tai ty, yu hj, chiang ph. investigation of urodynamic characteristics and bladder sensory function in the early stages of diabetic bladder dysfunction in women with type 2 diabetes. j urol. 2009;181:198-203. 22. yokoyama o, miwa y, oyama n, et al. urethral sensations are related to the development of detrusor overactivity. low urin tract symptoms. 2011;3:59-63. 23. snellings ae, yoo pb, grill wm. urethral flow-responsive afferents in the cat sacral dorsal root ganglia. neurosci lett. 2012;516:34-8. 24. combrisson h, allix s, robain g. influence of temperature on urethra to bladder micturition reflex in the awake ewe. neurourol urodyn. 2007;26:290-5. 25. peng cw, chen jj, cheng cl, grill wm. role of pudendal afferents in voiding efficiency in the rat. am j physiol regul integr comp physiol. 2008;294:r660-72. 26. jung sy, fraser mo, ozawa h, et al. urethral afferent nerve activity affects the micturition reflex; implication for the relationship between stress incontinence and detrusor instability. j urol. 1999;162:204-12. 27. shafik a, shafik aa, el-sibai o, ahmed i. role of positive urethrovesical feedback in vesical evacuation. the concept of a second micturition reflex: the urethrovesical reflex. world j urol. 2003;21:167-70. 28. yoo pb, horvath ee, amundsen cl, webster gd, grill wm. multiple pudendal sensory pathways reflexly modulate bladder and urethral activity in patients with spinal cord injury. j urol. 2011;185:737-43. 29. chen jl, chen cy, kuo hc. botulinum toxin a injection to the bladder neck and urethra for medically refractory lower urinary tract symptoms in men without prostatic obstruction. j formos med assoc. 2009;108:950-6. 30. schäfer w, abrams p, liao l, et al. good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies. neurourol urodyn. 2002;21:261-74. urethral c-fiber function in storage/voiding−ichiyanagi et al. female urology 637 fall 2012 08.pdf 657vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l department of urology, laparoscopy research center, shiraz university of medical sciences, shiraz, iran alireza aminsharifi, bahman goshtasbi, firoozeh afsar laparoendoscopic single-site nephrectomy using standard laparoscopic instruments our initial experience corresponding author: alireza aminsharifi, md shaheed faghihi hospital, zand street, shiraz, iran tel: +98 917 700 0656 fax: +98 711 233 1006 e-mail: aminsharifi_ar@ yahoo.com received september 2012 accepted october 2012 purpose: using a gelpoint single port and standard laparoscopic instruments. materials and methods: laparoendoscopic single-site transperitoneal nephrectomy was done for 6 adult patients with a poorly functioning small or hydronephrotic kidney. the procedure was standard laparoscopic instruments were used and the renal pedicle was controlled with 10-mm hem-o-lok clips. results: the participants were 3 men and 3 women with the median age of 29.5 years. laparoendoscopic single-site nephrectomy was successfully done in all the patients without any major complications. median operation time was 110 minutes (range, 90 to 130 minutes). there was no need for blood transfusion in any patient. the recovery phase was uneventful and all the patients were discharged after a median hospital stay of 2.5 days (range, 2 to 3 days). renal function remained stable in all the patients after the operation. the incision site healed well on postoperative follow-up. conclusion: point single port and standard laparoscopic instruments. this report may remove barriers to furthis novel technology. keywords: laparoscopy, nephrectomy, kidney diseases, methods, adverse effects laparoscopic urology 658 | introduction r ecently, laparoendoscopic single-site (less) surgery has become a popular advance in laparoscopic surgery. using multichannel single ports inserted via a single incision and applying articulating devices or robotic systems, less surgery aims to offer a less morbid procedure with a better cosmetic outcome compared to standard laparoscopy.(1) have been documented in multiple trials while improvement in convalescence measures remains questionable.(2,3) the main obstacle to the widespread use of less nephrecdoes not follow the triangulation principle of conventional laparoscopy. various single port systems, along with specialized curved, articulating, or robotic systems, have been colleagues compared the surgeon’s performance on a surgical simulator with the three most widely available single port systems (triport, olympus america inc, center valley, gelpoint, applied medical, rancho santa margarita, ca, usa). they showed that the gelpoint system offered better results in terms of surgeon’s performance and convenience.(4) gelpoint single port approach and standard laparoscopic report of outcomes obtained with less nephrectomy in our region. materials and methods from october 2011 to february 2012, we performed 6 less and the possible need for conversion to standard laparoscopy all the patients had symptomatic poorly functioning small or hydronephrotic kidneys because of chronic pyelonephritis or chronic obstructive uropathy due to missed ureteropelvic junction obstruction or obstructive stone disease. neither of them had previous abdominal surgeries. functioning of the target kidney was evaluated by pre-operative intravenous urography and technetium-99m dimercaptosuccinic acid scintigraphy. after admitting the patients one night prior to their operation and pre-operative administration of a single intravenous dose underwent less nephrectomy performed by the same surgeon (a.a.). surgical technique adequate padding. through a 3 to 4 cm incision in or lateral to the umbilicus, the peritoneal cavity was entered and the to the wound (figure). three multipurpose ports (instruments accepted: 4.7 to 10 mm) were built on the gelseal cap; then the cap was attached to the wound retractor and pneumoperitoneum was established. a 10-mm, 30º laparoscope and two 5-mm standard laparoscopic scissors and dissector were used. for right side nephrectomy, a needloscopic instrument tion. the procedure was done according to a standard protocol. the duodenum on the right side), the ureter and renal pedicle were found. the renal artery and vein were fully dissected and double-clipped separately with 10-mm hem-o-lok clips (weck closure systems, research triangle park, nc, usa). if severe hydronephrosis was present, the collecting system was drained percutaneously with a chiba needle to achieve via the single port site, which was then closed securely. results the participants consisted of 3 men and 3 women with the median age of 29.5 years. of 6 patients, 4 had poorly functioning kidneys due to missed ureteropelvic junction obstruction (table). in all patients, less nephrectomy was completed successfully without any major complications, such as visceral or great vessel injury (figure). median operation time was 110 minutes (range, 90 to 130 minutes). blood loss was minimal in all procedures. there was no need for blood transfusion in any patient. laparoscopic urology 659vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l laparoendoscopic nephrectomy | aminsharifi et al peri-operative data for patients who underwent laparoendoscopic single-site nephrectomy.* creatinine pre-op/postop, mg/dl hematocrit pre-op/postop, % body mass index, kg/m2 operation time, min target kidneyage, y/ gender patient no. 1.1/1.239.9/38.132100right small sizea (5 cm)35/f1 1.3/1.142.6/42.335110left hnb (15 cm)56/m2 1.6/1.441.4/40.535130right hnc (11 cm)42/m3 0.8/0.944.1/39.330120left hnb (12 cm)25/m4 0.7/0.738.4/332590left small sizea (6 cm)34/f5 0.9/0.937.2/35.425110left hnc (12 cm)17/f6 * f indicates female; m, male; and hn, hydronephrotic. a chronic pyelonephritis b chronic obstructive uropathy due to missed ureteropelvic junction obstruction c chronic obstructive stone disease (a) the gelpoint system consistes of a wound retractor/protector (alexis) and 4 multipurpose ports that accept 4.7 to 10 mm instruments. the trocars can be built on the gelseal cap containing a flexible polymer gel; (b) the wound retractor can be fixed to a 3 to 4-cm incision to provide a 360º atraumatic wound retraction; (c) the gelseal cap is attached to the wound retractor and pneumoperitoneum is established; (d) specimen retrieval from the site of single port; (e) the hydronephrotic kidney due to missed ureteropelvic junction obstruction, which was removed from the site of laparoendoscopic single-site nephrectomy; and (f) the site of laparoendoscopic single-site nephrectomy. 660 | the recovery phase was uncomplicated and all the patients were discharged after a median hospital stay of 2.5 days (range, 2 to 3 days). mean hematocrit drop 6 hours after the surgery was 2.5 (from 40.6 before to 38.1 after the operation). renal function remained stable in all the patients after the operation. the patients were followed up on regular clinical visits. mean follow-up period was 2.7 months (range, 1 to 6 months). the incision site healed well on postoperative follow-up. discussion tomy has become the accepted standard technique at many centers.(5) and colleagues in 2007.(6) this procedure opens new horizons towards improvement in endoscopic surgery in terms of cosmetic outcome and postoperative morbidity. with less nephrectomy, the port sites are located at a single incision, through which the specimen is later retrieved. although multiple comparative studies documented the poremain as whether less is superior to conventional laparoscopic nephrectomy in terms of postoperative morbidity.(7,8) compared to conventional laparoscopic surgery, no advantages in terms of postoperative pain, hospital stay, or return to work have yet be proven. the main disadvantages of less surgery are limited movement of the working instruments and ports, no triangulation, obstacles can be overcome by special articulating or curved instruments in order to prevent instrument collision. this novel platform also poses challenges, such as instrument inversion and crossing over, since the surgeon’s right hand controls the left instrument and vice versa. furthermore, the articulating or prebent instruments currently available can be therefore, the learning curve is a potential challenge.(9) with mini-laparoscopic donor nephrectomy as a more ergonomic and user-friendly procedure compared with less nephrectomy. they performed laparoscopic donor nephrectomy using a 5-mm camera port in the umbilicus, two 3.5mm trocars over the abdomen, and a 10-mm working port on the procedure as a pfannenstiel abdominal incision on a hair while the principles of standard laparoscopy would be appreciated. furthermore, using standard laparoscopic instruments, a smooth learning curve could be anticipated with their novel technique.(10) in the gelpoint system. it can accommodate a 1.7 to 7-cm incision, and due to its 360º atraumatic wound retraction feature, it increases the standpoints of working instruments, which leads in turn to a wider range of motion and thus helps surgeon can adjust the incision size to the size of specimen. polymer gel. since the surgeon can apply 10-mm universal these features facilitate the use of standard laparoscopic instruments to perform the procedure in a familiar manner. as shown in figure, we put the trocars in a triangular fashion. during the major parts of the operation, we used the lowermost trocar for the laparoscope, which remained between and mimics the conventional laparoscopy. with the use of 30º laparoscope, the camera holder was able to visualize the between the laparoscope and instruments would be dramatically reduced. despite these advantages, we, as novice less surgeons, still and dissection of the upper pole of the kidneys. previously, peritoneoscopic less radical nephrectomy using standard laparoscopic instruments. compared with transperitoneal less nephrectomy, they found more limitations in working space, but the distance and the angle of the dissection of the upper pole were much easier in retroperitoneoscopic approach.(11) we found that switching the position of the surgeon and assistant as well as changing the camera port was laparoscopic urology 661vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l references 1. raman jd, bagrodia a, cadeddu ja. single-incision, umbilical laparoscopic versus conventional laparoscopic nephrectomy: a comparison of perioperative outcomes and short-term measures of convalescence. eur urol. 2009;55:1198-204. 2. white wm, goel rk, kaouk jh. single-port laparoscopic retroperitoneal surgery: initial operative experience and comparative outcomes. urology. 2009;73:1279-82. 3. tugcu v, ilbey yo, mutlu b, tasci ai. laparoendoscopic single-site surgery versus standard laparoscopic simple nephrectomy: a prospective randomized study. j endourol. 2010;24:1315-20. 4. brown-clerk b, de laveaga ae, lagrange ca, wirth lm, lowndes br, hallbeck ms. laparoendoscopic single-site (less) surgery versus conventional laparoscopic surgery: comparison of surgical port performance in a surgical simulator with novices. surg endosc. 2011;25:2210-8. 5. clayman rv, kavoussi lr, soper nj, et al. laparoscopic nephrectomy: initial case report. j urol. 1991;146:278-82. 6. rane a, rao p, bonadio f. single port laparoscopic nephrectomy using a novel laparoscopic port (r-port) and evolution of single laparoscopic port procedure (slipp). j endourol. 2007;21:18. 7. kurien a, rajapurkar s, sinha l, et al. first prize: standard laparoscopic donor nephrectomy versus laparoendoscopic single-site donor nephrectomy: a randomized comparative study. j endourol. 2011;25:365-70. 8. greco f, hoda mr, mohammed n, springer c, fischer k, fornara p. laparoendoscopic single-site and conventional laparoscopic radical nephrectomy result in equivalent surgical trauma: preliminary results of a single-centre retrospective controlled study. eur urol. 2012;61:1048-53. 9. raybourn jh, 3rd, rane a, sundaram cp. laparoendoscopic single-site surgery for nephrectomy as a feasible alternative to traditional laparoscopy. urology. 2010;75:100-3. 10. simforoosh n, soltani mh, ahanian a. mini-laparoscopic donor nephrectomy: a novel technique. urol j. 2012;9:3535. 11. chung sd, huang cy, tsai yc, et al. retroperitoneoscopic laparo-endoscopic single-site radical nephrectomy (rlessrn): initial experience with a homemade port. world j surg oncol. 2011;9:138. laparoendoscopic nephrectomy | aminsharifi et al per pole of the kidney or the adrenal gland. our sample (consisting of only 6 cases) is too small to draw termine whether the less technique is superior to traditional laparoscopic nephrectomy in terms of postoperative morbidity. despite these limitations, our report may be helpful to novice less laparoscopists, who wish to become more familiar with this emerging technology. conclusion the gelpoint system offers a suitable platform for singlesite laparoscopic nephrectomy with standard laparoscopic surgeons to overcome the limited range of movement and avoid instrument clashes. acknowledgements this work was supported by shiraz university of medical sciences. we thank k. shashok (authoraid in the eastern mediterranean) for improving the use of english in the manuscript. conflict of interest none declared. u j 03 all-2.pdf 611vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l 1department of oncological and surgical sciences, urology clinic, university of padova, padova, italy 2department of environmental medicine and public health, section of legal medicine and forensic pathology, university of padova, padova, italy 3department of clinical and experimental medicine, university of padova, padova, italy rafael boscolo-berto,1,2 daniela i. raduazzo,3 giovanni cecchetto,2 guido viel2 urethral catheterization in men with artificial urinary sphincter clinical and legal implications corresponding author: rafael boscolo-berto, md department of environmental medicine and public health, institute of legal medicine, university hospital of padova, via falloppio 50, 35121, padova, italy tel: +39 049 827 2200 fax: +39 049 796 9541 e-mail: rafael.boscoloberto @unipd.it received march 2010 accepted april 2010 case report keywords: cal procedures introduction simplanted for the treatment of urinary incontinence in men, mostly in patients affected by post-prostatectomy incontinence.(1) complications. the former are due to a physical failure of the device or to intra-operative errors in rate ranging from 4% to 13%, and may occur also in a late setting.(2,3) the longest time-to-erosion range reported in the literature is of 7 to 10 years after the implantation.(4-6) we report the case of a scrotal extrusion of the pump occurred 22 years after the placement of an tions leading to a major surgical intervention. case report failure. 1): a scrotal control-pump, an abdominal pressure-regulating balloon, and an occlusive bulbous612 | at the department of emergency, an abdominal ultrasonography revealed a severe bilateral hydroureteronephrosis the picture attributed to a mechanical defect of the occluafter 3 months, the patient complained from the scrotal exsurgical removal of the entire device and a perineal urethrossurface immediately caudal to the distal margin of the bulbar figure 1. artificial urinary sphincter ams-800™ consisting of 3 components connected by kink-resistant tubing: a scrotal control pump, an abdominal pressure-regulating balloon, and an occlusive bulbous urethra cuff. note the dotted line showing the normal position of the prostate, in this case previously removed by radical prostatectomy. figure 2. evidence of a partially extruded scrotal pump at the physical examination (arrow). case report 613vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l complicated catheterization of a patient with ams-800 | boscolo-berto discussion tor for urethral erosion. disease, or pre-operative urodynamics, traumas intended as an activated or malfunctioning device are considered as potential causes of urethral lesions, facilitated by the tissutal devascularization due to urethral atrophy.(5,7,9,10) tion, described in the literature as a potential determinant of urethral erosion, as the cause of the damage localized in the bulbar portion of the urethra. we conceive that the amiss vated sphincter due to its malfunctioning and that the scrotal extrusion of the pump, caused by a subsequent urinary opened onto the ventral surface of bulbar urethra, the easiest of a perineal urethrostomy. a complication presented as a consequence of an improper invasive maneuver occurred 22 years after the implantation conclusion led to a major surgical intervention. we do believe that in a because of its possible malfunction or the presence of urethral atrophy associated to tissutal devascularization, a temporary suprapubic cystostomy by ultrasound guidance avoiding damage to the ams components may be advised in place of a urethral stressful catheterization to avoid further comapproach is subtended to a clinical rational, and may avoid malpractice litigations accounting for a medical liability. conflict of interest none declared. references 1. reynolds ws, patel r, msezane l, lucioni a, rapp de, bales gt. current use of artificial urinary sphincters in the united states. j urol. 2007;178:578-83. 2. gousse ae, madjar s, lambert mm, fishman ij. artificial urinary sphincter for post-radical prostatectomy urinary incontinence: long-term subjective results. j urol. 2001;166:17558. 3. elliott ds, barrett dm. mayo clinic long-term analysis of the functional durability of the ams 800 artificial urinary sphincter: a review of 323 cases. j urol. 1998;159:1206-8. 4. castera r, podesta ml, ruarte a, herrera m, medel r. 10-year experience with artificial urinary sphincter in children and adolescents. j urol. 2001;165:2373-6. 5. duncan hj, mcinerney pd, mundy ar. late erosion. a new complication of artificial urinary sphincters. br j urol. 1993;72:597-8. 6. venn sn, greenwell tj, mundy ar. the long-term outcome of artificial urinary sphincters. j urol. 2000;164:702-6; discussion 6-7. 7. kim sp, sarmast z, daignault s, faerber gj, mcguire ej, latini jm. long-term durability and functional outcomes among patients with artificial urinary sphincters: a 10-year retrospective review from the university of michigan. j urol. 2008;179:1912-6. 8. gomha ma, boone tb. artificial urinary sphincter for postprostatectomy incontinence in men who had prior radiotherapy: a risk and outcome analysis. j urol. 2002;167:591-6. 9. martins fe, boyd sd. post-operative risk factors associated with artificial urinary sphincter infection-erosion. br j urol. 1995;75:354-8. 10. kowalczyk jj, spicer dl, mulcahy jj. long-term experience with the double-cuff ams 800 artificial urinary sphincter. urology. 1996;47:895-7. v08_no_2_final.pdf pictorial urology 97urology journal vol 8 no 2 spring 2011 bladder amyloidosis mimicking carcinoma urol j. 2011;8:97. www.uj.unrc.ir an 80-year-old ex-smoker man presented with one episode of gross painless hematuria. his past medical history included hypertension, cerebrovascular accident, and osteoarthritis. physical examination, routine blood tests, and ultrasonography were normal. urine culture, microscopy, and cytology were unremarkable. on cystoscopy, a suspicious looking papillary mass was noted on the bladder roof, which was resected transurethrally. histopathology revealed amyloidosis of the bladder, confirmed with alkaline congo red staining showing apple-green birefringence in polarized light. amyloidosis is characterized by deposition of extracellular, hyaline, amorphous, and proteinaceous material in various organs of the body. it can be classified into (a) primary type, which is associated with an immunocyte dyscrasia; and (b) secondary type, which occurs as a complication of an underlying chronic inflammatory process.(1) although rare, it remains a differential diagnosis in patients with painless hematuria.(2) in elderly, suspicion should be raised in those who have systemic underlying conditions. ashok kumar singh,* michael st j floyd (jr), alan robert de bolla department of urology, wrexham maelor hospital, wrexham, wales, ll13 7tz *e-mail: ashoksingh03@yahoo.co.uk references 1. mitchell r, kumar v. amyloidosis. in: kumar v, cotran rs, robbins sl, eds. robbins basic pathology. 7th ed. philadelphia: elsevier saunders; 2003:158-64. 2. caldamone aa, elbadawi a, moshtagi a, frank in. primary localized amyloidosis of urinary bladder. urology. 1980;15:174-80. female urology 18 urology journal vol 4 no 1 winter 2007 bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al urology journal vol 4 no 1 winter 2007 19 intravesical bacillus calmette-guerin for treatment of refractory interstitial cystitis seyed mohammad kazem aghamir, mohammad ghasem mohseni, saeed arasteh introduction: the aim of this study was to examine the efficacy and safety of intravesical bacillus calmette-guerin (bcg) in the treatment of refractory interstitial cystitis (ic). materials and methods: thirteen patients with refractory ic were enrolled in the study. they were scheduled to receive 6 weekly courses of treatment with intravesical bcg. variables including the frequency, nocturia, urgency, pelvic pain, dyspareunia, dysuria, ic symptom index, ic problem index, and average voided volume were assessed every 6 months after the bcg therapy. results: thirteen patients received the complete course of intravesical bcg therapy. twenty-four months after the treatment a mean improvement of 51.9% was seen in frequency (p = .001), 43.2% in nocturia (p = .002), 28.7% in urgency (p = .004), 43.1% in pelvic pain (p = .001), 58.3% in dyspareunia (p = .003), 6.5% in dysuria (p = .16), 57.7% in the o’leary-sant ic symptom index (p = .001), and 61.8% in the o’leary-sant ic problem index (p = .001) scores. a significant improvement was seen in the mean average voided volume at the 24th follow-up month (89.5%; p = .001). conclusion: intravesical bcg is a relatively effective treatment in patients with refractory ic. its efficacy seems to be modest and lasts for at least 24 months in majority of the patients. it is also safe and well tolerated. urol j (tehran). 2007;4:18-23. www.uj.unrc.ir keywords: bacillus calmette-guerin, interstitial cystitis, urinary tract symptoms, treatment department of urology, sina hospital, tehran university of medical sciences, tehran, iran corresponding author: saeed arasteh, md department of urology, sina hospital, hasanabad sq, tehran, iran tel: +98 912 205 7898 e-mail: s_araste@yahoo.com received august 2005 accepted october 2006 introduction interstitial cystitis (ic) is a chronic pelvic pain syndrome with no specific identifiable cause. its symptoms include variable combinations of referring pain to the bladder, frequency, and urgency.(1) interstitial cystitis is annoying and affects the quality of life in many patients. despite many therapeutic approaches, the improvement remains suboptimal and the efficacy of these treatment modalities are unknown.(2) some evidence suggests that defects in the regulations of the immune system including an imbalance of type 1/type 2 helper t cells may play a role in the pathophysiology of the disease.(3) it has been shown that intravesical bacillus calmette-guerin (bcg) stimulates the type 1 helper t-cell cytokine profile and therefore, alleviate the symptoms of ic.(4,5) we designed this clinical trial to determine the efficacy and safety of intravesical bcg in the treatment of refractory ic. materials and methods between january 2002 and december 2004, patients presented with refractory ic were evaluated in a prospective study at sina hospital in tehran, iran. initial evaluation, including medical history, physical examination, and laboratory studies female urology 18 urology journal vol 4 no 1 winter 2007 bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al urology journal vol 4 no 1 winter 2007 19 (urinalysis, urine culture, urine cytology, purified protein derivative [ppd] skin test, cystoscopy, potassium chloride test, and biopsy), were performed. patients who met the symptom criteria of the national institute of diabetes, digestive, and kidney diseases (niddk) for interstitial cystitis were selected.(6) hunner’s ulcer was reported in none of them, but all had glomerulations after cystoscopic hydrodistension. patients with persistent symptoms for 3 years despite treatment were selected. their symptoms were refractory to hydrodistension, oral treatments (amitriptyline and/or hydroxyzine), and intravesical dimethyl sulfoxide. voiding diaries (for determining the frequency, nocturia, and average voided volume) and a visual analog scale self-administered questionnaire (zero to 5 scores) for assessment of pain, urgency, dyspareunia, and dysuria were recorded before the treatment and during the follow-up.(7) o’leary-sant questionnaire was used for determining the symptom and problem indexes.(8) the quality of life was determined by a global quality of life question on patients’ feeling about their urinary condition scored from zero to 6, corresponding to "delighted" to "terrible," respectively.(9) a total of 15 women were enrolled in the study and intravesical bcg therapy (tice strain, 120 mg) was planned for them. informed consent was obtained from all patients. when the 6-week instillations were completed, the patients returned for follow-up every 6 months, up to the 30th postoperative month. they were asked to rate their symptoms before and after the treatment. clinical responders were defined as those whose symptoms improved 50% or greater.(10) the subjects were instructed to report any adverse event since the first instillation of bcg. differences in scores between the baseline and follow-up times were analyzed using the –wilcoxon signed rank test. results all patients were women and their median age was 27 years (range, 20 to 57 years). of 15 women, 13 received all the courses of intravesical bcg therapy. for 1 patient, bcg was not started initially and for 1 another, bcg therapy was discontinued due to the side effects. the patients’ characteristics are shown in table 1. three patients were followed up for 30 months and the 10 remainders were visited up to the 24th month. table 2 shows the efficacy of the treatment with bcg according to the visual analogue scales, o’leary-sant questionnaire, and the voided volume. table 1. patients’ characteristics before treatment* *values are demonstrated as means ± standard deviations. ic indicates interstitial cystitis. †the median score for quality of life was 5, indicating "unhappy." characteristics values age 31.8 ± 10.8 frequency 14.0 ± 2.7 nocturia 3.8 ± 0.7 urgency score 4.1 ± 0.6 pain score 4.2 ± 0.7 dyspareunia score 2.5 ± 1.4 dysuria score 1.5 ± 1.3 o�leary-sant ic symptom index 13.7 ± 2.3 o�leary-sant ic problem index 12.5 ± 1.7 average voided volume, ml 115.4 ± 15.1 overall quality of life unhappy� table 2. patients’ characteristics after treatment with intravesical bcg* *values are demonstrated as means ± standard deviations. †three patients were assessed at the 30th month. postoperative months characteristics 6 12 18 24 30� frequency 6.1 ± 1.2 5.9 ± 1.1 6.4 ± 1.3 6.7 ± 1.4 7.0 ± 2.0 nocturia 1.9 ± 0.7 1.4 ± 0.7 1.4 ± 0.7 2.1 ± 0.5 2.7 ± 0.6 urgency score 2.7 ± 0.6 2.4 ± 0.7 2.5 ± 0.7 2.9 ± 0.7 2.7 ± 0.6 pain score 2.6 ± 0.8 1.9 ± 0.6 2.1 ± 0.6 2.4 ± 0.7 2.7 ± 0.6 dyspareunia score 1.2 ± 1.0 1.0 ± 1.0 1.1 ± 0.9 1.2 ± 1.0 2.3 ± 0.6 dysuria score 1.2 ± 1.1 1.0 ± 1.0 1.2 ± 1.1 1.3 ± 1.1 2.0 ± 1.0 o�leary-sant ic symptom index 7.7 ± 1.1 6.7 ± 1.3 6.5 ± 1.1 6.8 ± 1.2 7.7 ± 1.5 o�leary-sant ic problem index 5.9 ± 1.1 4.9 ± 1.1 4.7 ± 1.1 5.0 ± 0.9 4.7 ± 0.7 average voided volume, ml 210.8 ± 30.1 233.9 ± 23.6 228.5 ± 28.5 214.6 ± 29.9 246.7 ± 5.8 bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al 20 urology journal vol 4 no 1 winter 2007 bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al urology journal vol 4 no 1 winter 2007 21 at the 12and 24-month follow-ups, the number of patients who responded to the treatments (50% improvement or greater) were 13 (100%) and 11 (84.6%) for frequency, 11 (84.6%) and 8 (61.5%) for nocturia, 6 (46.2%) and 3 (23.1%) for urgency, 11 (84.6%) and 6 (46.2%) for pain, 3 (23.1%) and zero for dysuria, 8 (61.5%) and 8 (61.5%) for dyspareunia, 12 (92.3%) and 12 (92.3%) for average voided volume, 11 (84.6%) and 10 (76.9%) for the o’learysant ic symptom index, and 12 (92.3%) and 12 (92.3%) for the o’leary-sant ic problem index, respectively. table 3 demonstrates the improvement in the scores, and the figure shows the mean scores. the quality of life changed from “unhappy” to “mostly satisfied” in the majority of the patients (median scores 5 in the baseline and 2 in the 12and 24-months follow-ups. patients tolerated the 6 courses of bcg therapy fairly well. self-limited flu-like syndrome, a minor complication of bcg therapy, was reported in 3 patients. one of the patients did not complete the therapy course due to the bcg complications including fatigue, malaise, nausea, arthralgia, and low-grade fever and chills at the 4th week of the treatment. tests for tuberculosis were negative in all patients. discussion intravesical bcg is a novel therapy for the treatment of ic. although this therapy has been used for years in the treatment of bladder cancer, its exact mechanism of action is unknown. bacillus calmetteguerin is a strong stimulus of the immune system in the bladder and it is suggested that in some patients, ic may be an autoimmune disease.(10-12) some evidence has shown ic as a type 2 helper tcell-mediated disease. in addition, it was reported that the urine of these patients had a 5-fold increment in the production of interleukin-6 (il-6).(13) interleukin6 is a known stimulus of the type 2 helper t-cell response and the degree of its elevation correlates with the symptoms of the patient. furthermore, inhibitors of il-2, which stimulate a type 1 helper t-cell response, were found in the urine of these patients.(14) a type 1 t-helper cell response is thought to be beneficial, because it downregulates the inappropriate type 2 t-helper cell-driven responses that may cause immunopathologic problems. bacillus calmette-guerin stimulates the type 1 t-helper cell response causing the remarkable elevation of il-1, il-2, interferon-γ, and tumor necrosis factorα.(15,16) thus, the efficacy of bcg in the treatment of ic may be due to the stimulation of the type 1 t-helper cell response allowing the destruction of stressed immunogenic cells and promoting reparative conditions. correcting the underlying abnormal immunologic problem may be the reason of the effectiveness of intravesical bcg in the treatment of ic and may explain the long-term improvement of the symptoms.(10) additionally, a probable association of ic with a low level of nitric oxide in the urine has been proposed. increasing nitric oxide in the urine was shown to result in an improvement in the symptoms.(17) intravesical bcg is also known to be a potent stimulator for urinary nitric oxide in patients with bladder cancer.(18) morcos and colleagues showed that bcg induced the formation of nitric oxide in the bladder with no evidence of systemic nitric oxide formation.(19) increased production of nitric oxide in the bladder is probably due to the induction of table 3. improvement in scores of symptoms and indicators* *values are percents in proportion to the scores in the baseline and those in parentheses are p values. postoperative months characteristics 12 24 30 frequency 57.9 (.001) 51.9 (.001) 55.9 nocturia 63.1 (.001) 43.2 (.002) 38.3 urgency score 41.5 (.001) 28.7 (.004) 36.7 pain score 55.4 (.001) 43.1 (.001) 43.3 dyspareunia score 65.2 (.003) 58.3 (.003) 36.1 dysuria score 32.4 (.01) 6.5 (.16) 0 o�leary-sant ic symptom index 56.1 (.002) 57.7 (.001) 49.3 o�leary-sant ic problem index 56.9 (.001) 61.8 (.001) 53.6 average voided volume, ml 106.1 (.001) 89.5 (.001) 125.5 bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al 20 urology journal vol 4 no 1 winter 2007 bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al urology journal vol 4 no 1 winter 2007 21 changes in the symptom scores in patients with refractory interstitial cystitis after bcg therapy. 0 2 4 6 8 10 12 14 16 0 6 12 18 24 30 time, mon f re qu en cy 0 0.5 1 1.5 2 2.5 3 3.5 4 0 6 12 18 24 30 tim e, m on n oc tu ria 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 0 6 12 18 24 30 time, mon u rg en cy s co re 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 0 6 12 18 24 30 time, mon p ai n s co re 0 0.5 1 1.5 2 2.5 3 0 6 12 18 24 30 time, mon d ys pa re un ia s co re 0 0.5 1 1.5 2 2.5 0 6 12 18 24 30 time, mon d ys ur ia s co re 0 2 4 6 8 10 12 14 16 0 6 12 18 24 30 time, mon o 'l ea ry -s an t ic s ym pt om i nd e x 0 1 2 3 4 5 6 7 0 6 12 18 24 30 time, mon o 'l ea ry -s an t ic p ro bl em i nd e x bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al 22 urology journal vol 4 no 1 winter 2007 bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al urology journal vol 4 no 1 winter 2007 23 nitric oxide synthase activity in the urothelial cells. this finding is another potential etiology for the effectiveness of intravesical bcg in the treatment of ic.(10) in 1997, a prospective double-blind study on intravesical bcg demonstrated a 60% response rate with bcg in comparison with the response rate of 27% with placebo.(5) in a 24to 33-month follow-up report, 8 of the 9 responders continued to respond favorably and bcg did not worsen the symptoms in nonresponders.(10) these results are in contrast with the study of peeker and coworkers.(20) however, their report has been criticized because of the study design and lack of adequate follow-up for bcg therapy.(21) the study of lane and associates indicated that intravesical tice strain bcg could have a short-term effect on ic patients which was not durable with longer follow-ups. management of these patients usually requires adjuvant therapy after the initial treatment.(22) mayer and colleagues compared intravesical bcg and placebo instillations in patients with refractory ic. the response rates were 21% for bcg and 12% for placebo (p = .06). small improvements were observed in the 24hour voiding diary, pain, urgency, and validated ic symptom indexes; however, these differences were not statistically significant.(23) our study showed that the efficacy of treatment with intravesical bcg in ic patients seems to especially improve the average voided volume. it should be mentioned that this study was performed in a small population of ic patients and the efficacy of this treatment in long-term setting is not clear, either. conclusion intravesical bcg is a relatively effective treatment in refractory ic patients. its efficacy seems to be modest and durable for at least 24 months in the majority of the patients. it is also safe and well tolerated. conflict of interest none declared. references 1. buffington ca. comorbidity of interstitial cystitis with other unexplained clinical conditions. j urol. 2004;172: 1242-8. 2. propert kj, payne c, kusek jw, nyberg lm. pitfalls in the design of clinical trials for interstitial cystitis. urology. 2002;60:742-8. 3. peters km, diokno ac, steinert bw. preliminary study on urinary cytokine levels in interstitial cystitis: does intravesical bacille calmette-guerin treat interstitial cystitis by altering the immune profile in the bladder? urology. 1999;54:450-3. 4. zeidman ej, helfrick b, pollard c, thompson im. bacillus calmette-guerin immunotherapy for refractory interstitial cystitis. urology. 1994;43:121-4. 5. peters k, diokno a, steinert b, et al. the efficacy of intravesical tice strain bacillus calmette-guerin in the treatment of interstitial cystitis: a double-blind, prospective, placebo controlled trial. j urol. 1997;157: 2090-4. 6. gillenwater jy, wein aj. summary of the national institute of arthritis, diabetes, digestive and kidney diseases workshop on interstitial cystitis, national institutes of health, bethesda, maryland, august 2829, 1987. j urol. 1988;140:203-6. 7. parsons cl, greenberger m, gabal l, bidair m, barme g. the role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. j urol. 1998;159:1862-6. 8. o’leary mp, sant gr, fowler fj jr, whitmore ke, spolarich-kroll j. the interstitial cystitis symptom index and problem index. urology. 1997;49:58-63. 9. cockett atk, aso y, denis l, et al. the second international consultation on benign prostatic hyperplasia. in: cockett atk, aso y, chatelain c, et al, editors. the second international consultation on benign prostatic hyperplasia. paris: scientific communication international; 1994. p. 553. 10. peters km, diokno ac, steinert bw, gonzalez ja. the efficacy of intravesical bacillus calmette-guerin in the treatment of interstitial cystitis: long-term follow up. j urol. 1998;159:1483-6. 11. bade jj, deleij l, joustra eb, et al. specific autoantibodies in interstitial cystitis patients suggest an autoimmune etiology. j urol. 1996;155:431a. 12. keay s, zhang co, trifillis al, hebel jr, jacobs sc, warren jw. urine autoantibodies in interstitial cystitis. j urol. 1997;157:1083-7. 13. lotz m, villiger p, hugli t, koziol j, zuraw bl. interleukin-6 and interstitial cystitis. j urol. 1994;152: 869-73. 14. shingleton wb, fleischmann j. urinary interleukin-2 inhibitor and the voiding symptoms in women patients with interstitial cystitis. semin urol. 1991;9:120-3. 15. bohle a, nowc c, ulmer aj, et al. elevations of cytokines interleukin-1, interleukin-2 and tumor necrosis factor in the urine of patients after intravesical bacillus calmette-guerin immunotherapy. j urol. 1990;144:59-64. 16. kaempfer r, gerez l, farbstein h, et al. prediction of response to treatment in superficial bladder carcinoma through pattern of interleukin-2 gene expression. j clin oncol. 1996;14:1778-86. 17. smith sd, wheeler ma, foster he jr, weiss rm. improvement in interstitial cystitis symptom scores during treatment with oral l-arginine. j urol. 1997;158: 703-8. bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al 22 urology journal vol 4 no 1 winter 2007 bacillus calmette-guerin therapy for interstitial cystitis—aghamir et al urology journal vol 4 no 1 winter 2007 23 18. chambers ma, marshall bg, wangoo a, et al. differential responses to challenge with live and dead mycobacterium bovis bacillus calmette-guerin. j immunol. 1997;158:1742-8. 19. morcos e, jansson ot, adolfsson j, ehren i, wiklund np. bacillus calmette-guerin induces long-term local formation of nitric oxide in the bladder via the induction of nitric oxide synthase activity in urothelial cells. j urol. 2001;165:678-82. 20. peeker r, haghsheno ma, holmang s, fall m. intravesical bacillus calmette-guerin and dimethyl sulfoxide for treatment of classic and nonulcer interstitial cystitis: a prospective, randomized doubleblind study. j urol. 2000;164:1912-5. 21. goldman hb. interstitial cystitis--the great enigma. j urol. 2000;164:1921. 22. lane br, abdelmalak j, rackley r, vasavada s, el-azab a. intravesical bacillus calmette-guerin shows limited efficacy in the treatment of interstitial cystitis. j pelvic medicine and surgery. 2004;10:197-203. 23. mayer r, propert kj, peters km, et al. interstitial cystitis clinical trials group. a randomized controlled trial of intravesical bacillus calmette-guerin for treatment of refractory interstitial cystitis. j urol. 2005;173:1186-91. 1353vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l urinary incontinence is a rare complication of memokath® ureteric stent insertion yeng kwang tay,1 scott donnellan,1dan spernat2 keywords: prosthesis implantation; ureter; stents; adverse effects; urinary incontinence. introduction the memokath® ureteric stent is a thermo-expandable titanium-nickel alloy. (1) its use is not recommended in stone formers and patients with functional stenosis.(2) unlike conventional plastic ureteric stents, it is a semi-permanent prosthesis. however, should removal be required simply flushing the stent with cold water returns it to a soft and pliable form. as these stents do not promote tissue ingrowth, removal is atraumatic. the stent should not extend beyond the ureteric orifice into the bladder as this may result in bladder irritability, reflux and associated flank pain.(3) herein we report the unusual case of a 49-year old man who presented with urinary incontinence following insertion of a memokath® ureteric stent three weeks prior. case report the stent was inserted to relieve ureteric compression secondary to retroperitoneal fibrosis in a solitary kidney. the retroperitoneal fibrosis was thought to be secondary to ankylosing spondylitis. our patient had previously undergone a left nephrectomy as an infant for a nonfunctioning kidney, and a proctocolectomy with formation of ileostomy secondary to ulcerative colitis. his obstructed solitary kidney was initially identified due loin pain and a raised serum creatinine. abdominal computed tomography confirmed hydronephrosis and a right nephrostomy was inserted emergently. once the serum creatinine had stabilized antegrade and retrograde pyelograms demonstrated a 60 mm distal right ureteric stenosis. a retrograde ureteric stent was placed with considerable difficulty. due to the patients multiple abdominal surgeries and long segment of ureteric occlusion it corresponding author: dan spernat, md department of urology, the queen elizabeth hospital, 28 woodville rd, woodville south sa 5011, south australia, australia. tel: +61 8 8222 6321 fax: +61 8 8222 7448 e-mail: spernat1@hotmail.com received july 2012 accepted november 2012 1 department of urology, monash medical centre, victoria, australia. 2 university of adelaide, department of urological surgery, the queen elizabeth hospital, south australia, australia. case report 1354 | case report was felt that ureterolysis or ureteric reimplantation would be technically challenging. consequently, a 100 mm singleexpansion memokath® 051 ureteric stent was placed as a long term solution. at the time of insertion the stenotic segment of ureter was dilated without significant difficulty (figure 1). subsequent intra-operative fluoroscopy and cystoscopy demonstrated that the memokath® 051 ureteric stent was successfully deployed across the compressed ureteric segment and not protruding into bladder (figure 2). resolution of hydronephrosis was confirmed on post-operative renal ultrasound and normal serum creatinine. three weeks later the patient felt a “pop” while urinating and developed dysuria and urinary incontinence. there was no macroscopic hematuria. the patient presented to the emergency department at our hospital and abdominal x-ray demonstrated the memokath® ureteric stent had migrated through the prostatic fossa into the anterior urethra (figure 3). cystoscopy and removal of the memokath® ureteric stent was performed with resolution of urinary incontinence. a retrograde pyelogram was performed which demonstrated resolution of the ureteric occlusion. consequently a ureteric stent was not reinserted. he remained well and asymptomatic at his 2, 4, 8 and 16week follow-up. serum creatinine remained normal and serial renal ultrasounds did not demonstrate any evidence of hydronephrosis. discussion spontaneous resolution of ureteric stricture has been associated with the use of memokath® 051 ureteric stents.(4) migration of memokath® ureteral stents occurs in 11%-30% of patients. the rate of migration is similar in benign and malignant strictures, 22% and 20% respectively.(3) migration may occur due to insufficient anchorage and propulsion by antegrade peristalsis.(5) encrustation and obstruction may occur in up to 27% of cases.(3) urinary incontinence secondary to stent migration is a rare event, however it can be easily diagnosed with a simple abdominal x-ray. conflict of interest none declared. figure 1. dilatation of stenotic segment of ureter. figure 2. intra-operative fluoroscopy demonstrates that the memokath® was successfully deployed across the compressed ureteric segment. 1355vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l urinary incontinence with memokath | tay et al figure 3. abdominal x-ray demonstrates that the memokath® had migrated through the prostatic fossa into the anterior urethra. references 1. maan z, patel d, moraitis k, et al. comparison of stent-related symptoms between conventional double-j stents and a new-generation thermoexpandable segmental metallic stent: a validated-questionnaire-based study. j endourol. 2010;24:589-93. 2. klarskov p, nordling j, nielsen jb. experience with memokath® 051 ureteral stent. scan j urol nephrol. 2005;39:169-72. 3. agrawal s, brown ct, bellamy ea, kulkarni r. the thermo-expandable metallic ureteric stent: an 11-year follow-up. bjui. 2009;103:3726. 4. papatsoris ag, buchholz n. a novel thermo-expandable ureteral metal stent for the minimally invasive management of ureteral strictures. j endourol. 2010;24:487-91. 5. siddique ka, zammit p, bafaloukas n, albanis s, buchholz np. repositioning and removal of an intra-renal migrated ureteric memokath® stent. urol int. 2006;77:297-300. letters 187urology journal vol 4 no 3 summer 2007 re: varicocele in brothers of patients with varicocele urol j. 2007;4:187-8. www.uj.unrc.ir sir, in the article "varicocele in brothers of patients with varicocele,(1)" the authors have addressed an interesting clinical question: does having a brother with varicocele exposes a person to a higher risk of having the same disease? nevertheless, this study cannot answer the above question due to the following reasons: first, according to the methods section, this study is case-control. in case-control studies, controls should be disease-free when they are included. the outcome in this study is having varicocele and we see that 10% of controls suffer from this condition. apparently, the authors have excluded infertile persons from control group, while varicocele is the outcome of interest in this research, but not infertility. second, in the exclusion criteria for brothers, it was indicated that those with a positive family history of varicocele were excluded. this is while all of them are brothers of patients with varicocele. third, this study cannot be considered a case-control. in a case-control, subjects are grouped according to having/not having the disease, eg having/not having varicocele (figure). the design seems to be a duplication of the study by raman and colleagues which appears in reference 13 of the above paper and is a retrospective cohort.(2) fourth, the rationale for sample size used is not explained. this can affect the power and interpretation of results. akbar barbarian, mojgan karbakhsh department of community medicine, tehran university of medical sciences, tehran, iran e-mail: mkarbakh@tums.ac.ir references 1. mohammadali beigi f, mehrabi s, javaherforooshzadeh a. varicocele in brothers of patients with varicocele. urol j. 2007;4:33-5. 2. raman jd, walmsley k, goldstein m. inheritance of varicoceles. urology. 2005;65:1186-9. reply barbarian and karbakhsh made comments on a paper by mohammadali beigi and colleagues (urol j. 2007;4:33-5) which reflects a common confusion about the study design. mohammadali beigi and colleagues compared varicocele frequency and its grading in 3 groups: 56 patients with varicocele, 131 brothers of the first group, and 150 control group without a family history of varicocele. in comparison between the patients with and without a family history of varicocele (as defined by varicocele in brothers), grouping was based on the exposure to the risk factor. accordingly, it resembled cohort studies. however there was not a real follow-up or longitudinal evaluation from the exposure time to the outcome. more importantly, in cohort studies, all participants must be disease free in the beginning of the course, whereas this assumption is not met in this study. on the other hand, the study could not be a case-control one, as mentioned by barbarian. therefore, it was a cross-sectional study, comparing 3 groups of the population with respect to the disease frequency. despite this fallacy, the results are still valid and not influenced by the design error. design of a case-control study. 188 urology journal vol 4 no 3 summer 2007 let me clarify the issue by this example that i usually use for my students. a grocery owner complained from cracked eggs. he believed that a kind of eggholder shells (shell a) used by one of the factories was mainly responsible for this problem. he had 3 options to evaluate the subject. firstly, he could count the number of cracked eggs in each box from different factories (a cross-sectional study). secondly, he could alternatively separate damaged eggs from intact ones and assess the frequency of the shell a in each group (case-control). thirdly, he had this option to take identical intact eggs and separate them to the shell a and non-a. then, he had to transport them from the factory to the shop and count the number of damaged eggs in the a and non-a groups (cohort study). now, think again and tell which approach is more compatible to the published study (figure)! ali khoshdel department of epidemiology, school of medicine, artesh university of medical sciences, tehran, iran research approaches to the risk factor-disease relations. kidney transplantation 30 urology journal vol 7 no 1 winter 2010 thyroid hormone changes in early kidney transplantation and its correlation with delayed graft function reza hekmat,1 zahra javadi,1 malihe layghian javan,1 hooshang sanadgol,2 farhad gholami,1 mahmoud mohebbi,1 abbas ali zeraati,3 hassan ahmadnia,4 hamid tabarraiei,5 mahsa baradaran,1 mohammad javad mojahedi1 introduction: thyroid hormones affect kidney function and may alter with changes in kidney function, as well. we evaluated changes in serum levels of triiodothyronine (t3), thyroxin (t4), and thyroid-stimulating hormone (tsh) early after kidney transplantation and their relationship with delayed graft function (dgf). materials and methods: fifty-five consecutive kidney allograft recipients were enrolled in the study. serum levels of t3, t4, and tsh were measured on the day before transplantation, and also on posttransplant days 1, 3, 7, 14, and 21. results were compared between patients with a normal allograft function and those with dgf. results: the mean t3 level decreased from 110.41 ± 49.79 ng/dl before transplantation to 80.78 ± 51.42 ng/dl on the 1st day after transplantation (p = .04), while t4 reduction reached a significant level on the 3rd day after transplantation (8.27 ± 3.27µg/dl to 5.50 ± 2.57 µg/dl, p = .004). patients with dgf experienced a significantly greater decrease in the serum level of t3 at the end of the 1st week after transplantation compared with patients with normal kidney function (p = .02). this significant decrease in t3 continued until the end of the 2nd week. serum levels of t4 reduced comparably in the two groups, until the end of the 1st week, when it showed a significantly more reduction in the patients with dgf (p = .04). conclusion: both t3 and t4 reduced early after kidney transplantation, and this reduction was significantly more prominent in those with dgf. this is compatible with a consequence rather than a cause of dgf, explained in the setting of sick euthyroid syndrome. urol j. 2010;7:30-4. www.uj.unrc.ir keywords: delayed graft function, kidney transplantation, thyroid function tests 1department of nephrology, ghaem hospital, mashhad university of medical sciences, mashhad, iran 2department of nephrology, aliibn abitaleb hospital, zahedan university of medical sciences, zahedan, iran 3department of nephrology, imam reza hospital, mashhad university of medical sciences, mashhad, iran 4department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran 5department of nephrology, hasheminejad hospital, mashhad university of medical sciences, mashhad, iran corresponding author: reza hekmat, md department of nephrology, ghaem hospital, mashhad, iran tel: +98 511 801 2829 e-mail:drhekmatreza@yahoo.com received february 2009 accepted november 2009 introduction thyroid hormones affect the functions of a number of organs, and these may alter the kidney function, as well. on the other hand, the thyroid gland function may be influenced by kidney dysfunction.(1-3) patients with end-stage renal disease may suffer from elevated thyroid-stimulating hormone (tsh) levels, reduced tsh response to thyroid-releasing hormone, and reduced serum total and free triiodothyronine (t3) and thyroxine (t4) values, in the absence of a primary thyroid disease.(1,2) then again, these patients may develop goiter, thyroid nodules, thyroid carcinoma, and hypothyroidism. (2) thyroid hormone changes after kidney transplantation—hekmat et al 31urology journal vol 7 no 1 winter 2010 kidney transplantation alleviates these changes, but it can also affect thyroid function in the presence of different conditions a kidney transplant recipient may experience.(4) in this study, we evaluated t3, t4, and tsh changes early after kidney transplantation, and the relationship of these changes with the occurrence of delayed graft function (dgf). in hope of finding a correlation between dgf and thyroid hormone changes measured by routine and simple thyroid function assessment tests available in all laboratories, we purposefully decided not to perform more complicated thyroid function tests such as reverse t3 and t3 resin uptake. materials and methods fifty-five kidney transplant candidates were consecutively selected to enroll in this crosssectional study. thirty-seven patients were living donor allograft recipients and the remaining 18 received a cadaveric kidney graft. the study was approved by the ethics committee of the university and the patients provided informed consent. before transplantation, all of the patients were on hemodialysis. immunosuppression after transplantation consisted of cyclosporine, mycophenolate mofetil, and prednisone. serum levels of t3, t4, and tsh were measured on the day before transplantation, and also on the 1st and 3rd days and at the end of the 1st, 2nd, and 3rd weeks after transplantation, using radioimmunoassay method. in search of the relationship between kidney allograft function and thyroid hormone changes, serum levels of t3, t4, and tsh on the day before transplantation (baseline) were compared with each consequent posttransplant measurement in all patients. also, t3, t4, and tsh levels were compared between patients with normal immediate kidney function and those with dgf. delayed graft function was defined as a decrease in the serum creatinine level of at least 10% per day for at least 3 consecutive days during the first week after transplantation. we used the paired t test for comparisons of the t3 and t4 levels in patients with and without dgf in each subsequent measurement in relation with before transplantation. due to non-normal distribution of tsh serum levels, the mann whitney u test and the wilcoxon sum rank test were used for comparing its serum level in the two groups and its changes in each measurement after transplantation in comparison with those before transplantation, respectively. general linear model repeated measurement analysis was used for overall significance of t3, t4, and tsh changes in the six measurements. results a total of 55 kidney recipients (34 men and 21 women), with a mean age of 34.41 ± 15.47 years, were included in the study. the kidney allograft resumed normal function in 47 patients (85.5%), while in 8 patients (14.5%), its function was delayed due to acute rejection in 2 and acute tubular necrosis (atn) in 6. baseline thyroid function studies, including serum levels of t3, t4, and tsh, were similar between the two groups of patients with normal graft function and dgf. repeated measurement analysis showed highly significant changes in t3, t4, and tsh through the 6 measurements (p < .001). the mean t3 level decreased from 110.41 ± 49.79 ng/dl on the day before transplantation to 80.78 ± 51.42 ng/dl on the 1st day after transplantation (p = .04). this trend continued until the end of the 2nd week after transplantation. serum level of t4 decreased from 8.27 ± 3.27µg/dl before transplantation to 6.92 ± 3.72 µg/dl on the 1st posttransplant day (p = .09). this trend in t4 concentrations reached a significant level on the 3rd day after transplantation (4.55 ± 2.57 µg/dl, p = .004); however, t4 levels reached the pretransplant levels at the end of the 3rd week after transplantation. patients with dgf experienced a significantly greater decrease in the serum level of t3 at the end of the 1st week after transplantation compared with patients with normal kidney function (p = .02; table 1). this significant decrease in t3 continued until the end of the 2nd week. serum levels of t4 reduced comparably in the two groups, until the end of the 1st week, when it showed a significantly more reduction in the patients with dgf (table 1). thyroid hormone changes after kidney transplantation—hekmat et al 32 urology journal vol 7 no 1 winter 2010 serum levels of tsh began to decrease significantly from the 1st day after transplantation compared with the baseline values (p < .001; table 2). this trend continued to the end of the 3rd week after transplantation when serum tsh level returned to the pretransplantation level. comparing tsh levels in patients with and without dgf, tsh levels decreased on the 1st day after transplantation in both groups, but significantly reduced tsh level continued until the end of the 3rd week after transplantation only in the kidney allograft recipients with normal kidney function, but returned to normal in the patients with dgf on the 3rd day after transplantation (table 3). we compared serum tsh levels between the patients who received antithymocyte globulin (atg) and those with no atg administration; the significant reduction of tsh level in those with atg continued to the end of the 3rd week, while in patients who received atg, tsh returned to the pretransplantation levels after 1 week. there were no associations between donor source, age, gender, and the underlying disease and the thyroid hormones before transplantation and their changes after transplantation. discussion our finding, the moderate reduction of serum t3 and t4 levels on the 1st and 3rd days after transplantation, is compatible with sick euthyroid syndrome (ses). due to the rather shorter t3 half-life in comparison with the half-life of t4, reduction of t3 began earlier than t4.(3) using the same way of reasoning, earlier return of t3 serum level (at the end of the 1st week) compared with t4 can be explained. in the ses (low serum levels of t3, t4, tsh, or all the three), high endogenous catecholamine levels may stimulate preferential tissue conversion of t4 to the nonactive reverse t3 rather than to the active free t3.(4) plasma t3 levels, therefore, drop precipitously. there is evidence that low t3 states occur immediately after kidney transplant due to the stress of the operation, infusion of high-dose intravenous methylprednisolone, and hypothermia. the continuation of significantly reduced t3 in patients with dgf into the second week after transplantation may be regarded as a cause or consequent of failed graft function; regarding the nonsignificant difference in t3 serum level between the two groups before transplantation, we hypothesize that dgf leads to continuation of uremic state, administration of higher doses of methylprednisolone, more severe reperfusion injury, and inflammation, all impairing conversion of t4 to t3. delayed graft function laboratory study no yes p t3, ng/dl baseline 106.2 ± 40.85 121.62 ± 30.99 .33 day 1 90.64 ± 41.64 85.00 ± 43.49 .71 day 3 86.53 ± 35.06 83.05 ± 21.09 .77 day 7 85.18 ± 35.39 57.90 ± 15.86 .02 day 14 82.54 ± 26.44 78.75 ± 23.81 .67 day 21 91.13 ± 28.79 93.79 ± 34.57 .81 t4, µg/dl baseline 8.36 ± 3.06 8.55 ± 3.25 .88 day 1 7.68 ± 2.84 7.24 ± 3.75 .68 day 3 6.80 ± 2.94 5.49 ± 1.90 .16 day 7 6.41 ± 2.32 4.69 ± 2.86 .04 day 14 6.54 ± 2.28 5.03 ± 1.13 .04 day 21 7.88 ± 3.35 6.56 ± 2.72 .23 table 1. changes in triiodothyronine (t3) and thyroxin (t4) after kidney transplantation in recipients with and without delayed graft function tsh measurement tsh, iu/ml p* baseline 1.94 ± 0.89 … day 1 1.09 ± 0.76 < .001 day 3 0.95 ± 0.90 < .001 day 7 1.04 ± 0.79 .01 day 14 1.86 ± 2.89 .02 day 21 1.78 ± 0.40 .15 table 2. thyroid-stimulating hormone (tsh) levels before and after transplantation *p values are related to the comparisons between tsh level of that measurement (the respective row) with the previous one. normal kidney function delayed graft function tsh measurement mean change, iu/ml p mean change, iu/ml p day 1 -3.18 .001 -2.11 .04 day 3 -4.17 < .001 -1.76 .08 day 7 -3.97 < .001 -0.94 .35 day 14 -2.28 .02 -0.92 .36 day 21 -2.96 .003 -0.54 .59 table 3. changes in serum thyroid-stimulating hormone (tsh) levels compared to baseline level before kidney transplantation in recipients with and without delayed graft function thyroid hormone changes after kidney transplantation—hekmat et al 33urology journal vol 7 no 1 winter 2010 lebkowska and colleagues found that the free t3 concentration correlated with function of the kidney allograft.(6) they suggested that in transplant patients, the supplementary thyroid hormone therapy should be considered.(6) in another study, a positive correlation was found between changes in serum concentration of free t4 and changes in serum creatinine (r = 0.73; p < .001).(7) reinhardt and colleagues showed that t3 concentrations reflected kidney allograft function after kidney transplantation. serum t3 was below the normal limit in patients with dgf (acute kidney failure or acute rejection). the postoperative period (up to 3 days after transplantation) was associated with a low t3 syndrome. thyroid-stimulating hormone did not return to the pre-operative values, even in patients with primary graft function.(8) recovery in the hormonal status did not start in the first week of posttransplant period. a significant transient decrease in tsh, free t3, and free t4 concentrations following kidney transplantation has been reported in kidney allograft recipients. (9) however, comparing thyroid hormone changes in donors and recipients immediately after transplantation, t3 changes observed in donors and recipients were similar, indicating that the hormonal changes observed are mostly due to surgical stress.(10) in our study, acute tubular necrosis was the prevalent cause of dgf (in 6 cases). regarding tsh serum level changes, reduced tsh level continued until the end of the 3rd week after transplantation only in the kidney recipients with normal kidney function, but returned to normal in patients with dgf on the 3rd day after transplantation. this cannot be due to relative smallness of the dgf group (type 2 error), regarding the reversed results obtained when comparing t3 in the two groups, also this fact that in all patients, significantly reduced tsh serum level in those who had received no atg continued to the end of the third week, while in atg-administered ones returned to the pretransplantation level after 1 week. we hypothesize this may be a falsely elevated level due to atg administration and the presence of antimouse or antihorse antibodies in the serum of these patients results in falsely elevated tsh values when using radioimmunoassay method for tsh measurement. indeed, 4 patients in the dgf group had received atg. the same reason for falsely elevated tsh serum level in transplanted patients was proposed by seghers and colleagues. (11) we were not able to repeat the tsh determination in the presence of normal horse serum and obtain a true tsh value. fractionation of the serum with protein-a chromatography, to detect the falsely elevated tsh measured by immunoreactivity, was not performed either.(11) conclusion both t3 and t4 levels decreased early after kidney transplantation. when considering the effect of dgf on thyroid hormones changes, t3 and t4 significantly reduced in patients with dgf compared with normal-functioning kidney transplant group. this significantly greater reduction in t3 and t4 in the dgf group, despite no significant difference between the two groups before transplantation, is more compatible with a consequence rather than a cause of dgf occurrence, explained in the setting of ses. continuation of the reduction in tsh level in patients with normal kidney function early after transplantation until the end of the 3rd week in spite of its return to normal level in dgf-inflicted patients can be ascribed a falsely elevated level due to atg administration and the presence of antimouse or antihorse antibodies in the serum of these patients with dgf, resulting in falsely elevated tsh values, when using radioimmunoassay method for tsh measurement. conflict of interest none declared. references 1. kaptein em, feinstein ei, nicoloff jt, massry sg. serum reverse triiodothyronine and thyroxine kinetics in patients with chronic renal failure. j clin endocrinol metab. 1983;57:181-9. 2. kaptein em. thyroid hormone metabolism and thyroid diseases in chronic renal failure. endocr rev. 1996;17:45-63. 3. koller j, wieser c, gottardis m, et al. thyroid hormones and their impact on the hemodynamic and metabolic stability of organ donors and on kidney thyroid hormone changes after kidney transplantation—hekmat et al 34 urology journal vol 7 no 1 winter 2010 graft function after transplantation. transplant proc. 1990;22:355-7. 4. lee pc, tang mj, song cm, chen ej, lee ph, lee cj. thyroid hormone responses in the early kidney transplants. transplant proc. 1994;26:2184-6. 5. hegedus l, andersen jr, poulsen lr, et al. thyroid gland volume and serum concentrations of thyroid hormones in chronic renal failure. nephron. 1985;40:171-4. 6. lebkowska u, malyszko j, lebkowski wj, walecki j, mysliwiec m. is there any relation between thyroid gland function and kidney transplant function? transplant proc. 2003;35:2222-3. 7. lebkowska u, malyszko j, brzosko s, et al. renal artery resistance index, thyroid hormones, and thyroid volume in the early kidney transplants recipients. transplant proc. 2006;38:62-5. 8. reinhardt w, misch c, jockenhovel f, et al. triiodothyronine (t3) reflects renal graft function after renal transplantation. clin endocrinol (oxf). 1997;46:563-9. 9. junik r, wlodarczyk z, masztalerz m, odrowazsypniewska g, jendryczka e, manitius j. function, structure, and volume of thyroid gland following allogenic kidney transplantation. transplant proc. 2003;35:2224-6. 10. rao p, dakshinamurty kv, saibaba kss, murty p, venkataramana g, sreekrishna v. thyroid hormone profile in peritransplant period in live donor kidney transplantation. indian j clin biochem. 1999;14:184-8. 11. seghers j, schrurs f, de nayer p, beckers c. interference in thyrotropin (tsh) determination: falsely elevated tsh values in a transplanted patient. eur j nucl med. 1989;15:194-6. miscellaneous 169urology journal vol 4 no 3 summer 2007 preoperative diagnosis of xanthogranulomatous pyelonephritis farah afgan, seemal mumtaz, m hammad ather introduction: the aim of this study was to evaluate the possibility of differentiating xanthogranulomatous pyelonephritis (xgpn) preoperatively from chronic pyelonephritis on the basis of demographic data, clinical parameters, and biochemical, microbiological, and radiological workups. materials and methods: between 1995 and 2005, a total of 239 patients were diagnosed to have pyelonephritis at our center, of which, 56 underwent nephrectomy. forty-five (80.4%) of the nephrectomy specimens showed diagnosis of chronic pyelonephritis and 11 (19.6%) showed xgpn. results: compared to chronic pyelonephritis, xgpn was more likely to occur in the middle-aged women (91%) with diabetes mellitus (64%) and a history of recurrent uti was more frequently noted. the disease is likely to present with flank pain and tenderness in 100.0% and 90.9% of the patients with xgpn, respectively. anemia (81.8%), hematuria (81.8%), and bacteriuria (90.9%) were more frequent in these patients than in those with chronic pyelonephritis. the mean blood hemoglobin was 7.0 g/dl in the patients with xgpn. proteus mirabilis was detected in 6 patients (55%) of the xgpn group and only 2 of the chronic pyelonephritis group (p < .001). renomegaly and kidney calculus were more frequently noted in the patients with xgpn. finally, xgpn led to a higher rate of postoperative complications. conclusion: demographic data, comorbidities, predisposing factors, and biochemical as well as roentgenological features are significant but nonspecific indicators of preoperative diagnosis of xgpn. urol j. 2007;4:169-73. www.uj.unrc.ir keywords: kidney diseases, pyelonephritis, infection, nephrectomy, xanthogranulomatous pyelonephritis, diagnosis section of urology, department of surgery, aga khan university, karachi, pakistan corresponding author: m hammad ather, md department of surgery, section of urology, aga khan university po box 3500, stadium road, karachi, pakistan tel: +92 21 4859 4761 fax: +92 21 493 4294 e-mail: hammad.ather@aku.edu received april 2007 accepted august 2007 introduction xanthogranulomatous pyelonephritis (xgpn) is a rare chronic inflammatory disorder which was initially described over 90 years ago by schlagenhaufer.(1) it is characterized by diffuse renal parenchymal destruction and its replacement by lipid-laden macrophages (foamy cells) which imparts a yellowish tan to the tissue. these changes were found in 0.6% to 1.4% of patients with kidney inflammation and in 1% to 8% of all inflammatory conditions requiring nephrectomy.(2,3) the disease is classically seen in middle-aged diabetic women in the presence of urolithiasis, nonfunctioning kidneys, and urinary tract infection (uti) especially with proteus mirabilis.(4) it is difficult to make a preoperative differential diagnosis of xgpn from other forms of chronic inflammatory conditions. however, clinically, it is very important to diagnose the disease early and differentiate it from chronic pyelonephritis which has a potentially benign course. early diagnosis helps prevent inevitable loss of kidney diagnosis of xanthogranulomatous pyelonephritis—afgan et al 170 urology journal vol 4 no 3 summer 2007 function.(5) clinical features, imaging, urine cytology, and kidney biopsy are helpful in making a diagnosis.(69) however, urine cytology is nonspecific and followup studies have not supported its accuracy, yet.(7,9) kidney biopsy is invasive and also accompanied by the risk of spreading the tumor through the needle tract in case of malignancy and the risk of sinus formation or spread of infection in xgpn.(10-12) percutaneous biopsy does not generally provide adequate specimen for diagnosis of xgpn or kidney neoplasms in some cases.(13) although difficult to diagnose preoperatively, xgpn can be diagnosed using improved diagnostic tools if there is a high suspicion of the disease. preoperative diagnosis provide the chance of its management by parenteral antibiotic therapy and nephrostomy for drainage of the pus which leads to overall better survival and decreases postoperative morbidities such as bleeding, infection, and fistula.(14) we evaluated the impact of various clinical, laboratory, and radiological parameters in differentiating xgpn from chronic pyelonephritis (cpn). materials and methods in this case-control study between january 1995 and october 2004, a total of 239 patients with the diagnosis of pyelonephritis (based on the international classification of diseases, 9th edition, clinical modification data indexing and coding system) were evaluated.(15) those patients with proven histological diagnosis were included in the study including 11 with xgpn and 45 with cpn (figure). carcinoma and other forms of pyelonephritis such as tuberculous pyelonephritis were excluded. preoperative workup was performed using routine biochemical and hematological tests. radiological evaluations included plain abdominal radiography, ultrasonography, intravenous urography (ivu), computerized tomography (ct), or a combination of these (table 1). nephrectomy was performed under general anesthesia through lumbar, extraperitoneal, or extrapleural approach. the demographic data, comorbidities, etiologic factors, mode of presentation, clinical and radiological features, blood chemistry, and urine cultures were noted. the histological features and postoperative complications were also recorded and reviewed. the data were analyzed using the chi-square test and the t test for nominal and numerical/interval data. a p value of less than .05 was considered statistically significant. results a total of 56 patients underwent nephrectomy for nonfunctioning or poor-functioning kidney with chronic pyelonephritis, of which, 11 had histologically proven xgpn and the remainders had cpn. demographic and clinical characteristics of the schematic representation of patients distribution in various groups is shown. patients with pyelonephritis investigations xgpn cpn plain abdominal radiography number of patients 7 (63.6) 8 (17.8) kidney calculi 7 (100.0) 8 (100.0) intravenous urography number of patients 8 (72.7) 22 (48.9) nonfunctioning kidney 4 (50.0) 8 (36.4) ultrasonography number of patients 7 (63.6) 23 (51.1) renomegaly 6 (85.7) 4 (17.4) kidney calculi 5 (71.4) 14 (60.9) computed tomography number of patients 6 (54.5) 10 (22.2) renomegaly 5 (83.3) 1 (10.0) kidney calculi 5 (83.3) 3 (33.3) table 1. radiological findings of patients with xgpn and cpn* *values in parentheses are percents. xgpn indicates xanthogranulomatous pyelonephritis and cpn, chronic pyelonephritis. diagnosis of xanthogranulomatous pyelonephritis—afgan et al urology journal vol 4 no 3 summer 2007 171 patients are outlined in table 2. the mean age of the patients at the time of diagnosis of xgpn was 48.4 ± 9.7 years (range, 15 to 65 years) and it was 41.6 ± 11.3 (range, 17 to 65 years) in the patients with cpn. male-female ratio was 1:10 and 2:1 in the patients with xgpn and cpn, respectively. all patients had unilateral disease predominantly affecting the left kidney except 1 in the cpn group. seven of 11 patients in xgpn group (63.6%) and 7 of 45 patients in the cpn group (15.6%) had diabetes mellitus (dm). in the patients with xgpn, anemia (hemoglobin of less than 10 g/dl), hematuria, and bacteriuria were more frequent than those in the patients with cpn (table 2). the mean hemoglobin was 7.0 g/dl in the patients with xgpn. proteus mirabilis was detected in 6 patients (54.5%) of the xgpn group and only 2 of the cpn group (p < .001). escherichia coli was found to be the most common affecting organism in the cpn group. finally, the patients in the xgpn group had a higher rate of a positive history of uti (table 2) and they faced a higher rate of postoperative complications. the observed complications are shown in table 3. discussion review of the literature as well as our results revealed xgpn to mostly affect women in their 4th to 5th decades of life.(9) the patients most prone to this disease are those with prior history of dm, urolithiasis, recurrent uti (especially with proteus mirabilis), and urological instrumentation.(4,14) although multiple theories have been proposed to explain the development of this peculiar type of pyelonephritis, the etiology still remains obscure. the probable predisposing factors include recurrent uti, obstruction, malnutrition, abnormal lipid metabolism, altered immunological response, lymphatic blockage, and congenital urinary abnormalities.(16,17) the condition has been described as great imitator due its variant clinical nonspecific symptoms and signs.(9,18) lower urinary tract symptoms, fever and chills, flank pain, tenderness, and palpable mass are the symptoms commonly observed. therefore, a patient presenting with urolithiasis, recurrent uti, and prior urological instrumentation in a poor-functioning kidney has a high index for suspicion of xgpn.(14) in our patients with xgpn, flank tenderness, recurrent uti, dm, fever, and lower urinary tract symptoms were the dominant findings in the primary examinations. to date, imaging modalities such as ct, ultrasonography, and magnetic resonance imaging (mri) have potential ability to identify this fulminant kidney infection preoperatively.(19) it has been stated that xgpn has no specific ultrasonographic features, but is suggested by parenchymal thinning and hydronephrosis, ultrasonographic signs of chronic obstructive uropathy caused by the calculi, echoes in the dilated collecting system, and a perinephric fluid collection. also, ct, needle biopsy, or both are recommended for further evaluations and confirmation of the suspected cases of xgpn. patients with pyelonephritis variables xgpn cpn p mean age, y 48.4 41.6 .03 male/female 1/10 30/15 .001 diabetes mellitus 7 (63.6) 7 (15.6) .001 lower urinary tract symptoms 6 (54.5) 22 (48.9) .73 fever 7 (63.6) 20 (44.4) .32 flank pain 11 (100.0) 40 (88.9) .57 flank tenderness 10 (90.9) 28 (62.2) .08 anemia 9 (81.8) 20 (44.4) .04 leukocytosis 7 (63.6) 17 (37.8) .18 pyuria 10 (90.9) 29 (65.9)† .146 hematuria 9 (81.8) 17 (38.6)† .01 bacteriuria 10 (90.9) 18 (40.9)† .001 proteus mirabilis 6 (54.5) 2 (4.4) < .001 history of uti 8 (72.7) 11 (24.4) .001 history of urologic instrumentation 8 (72.7) 22 (48.9) .19 history of calculus 5 (45.5) 18 (40.0) .74 table 2. demographic and clinical features of patients with xgpn and cpn* *values in parentheses are percents. xgpn indicates xanthogranulomatous pyelonephritis and cpn, chronic pyelonephritis. †these were assessed in 44 patients. patients with pyelonephritis complications xgpn cpn respiratory complications 2 (18.2) 2 (4.4) wound infections 2 (18.2) 6 (13.3) hemorrhage and sepsis 0 1 (2.2) postoperative ileus 0 1 (2.2) overall complications 4 (36.4) 10 (22.2) table 3. postoperative complications in patients with xgpn and cpn* *values in parentheses are percents. xgpn indicates xanthogranulomatous pyelonephritis and cpn, chronic pyelonephritis. diagnosis of xanthogranulomatous pyelonephritis—afgan et al 172 urology journal vol 4 no 3 summer 2007 verswijvel and colleagues reported early findings on the use of diffusion-weighted mri in kidney infections including xgpn.(20) however, nowadays, ct is still considered as the gold standard method in the preoperative radiological evaluation of xgpn. laboratory findings noted leukocytosis in 63.6% and anemia in 81.8% of the patients with xgpn in our series. goodman and associates suggested that anemia might be due to defects in iron reutilization.(21) in our study, no data was available for serum iron and total iron binding capacity, but all of our patients had hypochromic microcytic anemia suggesting iron deficiency. microscopic hematuria normally is not a cause of anemia; however, if prolonged and associated with other risk factors such as nutritional deficiency, it may lead to iron deficiency. urinalysis in patients with xgpn often reveals bacteriuria, pyuria, and hematuria.(12,14) nine out of our 11 patients had hematuria and 10 had bacteriuria, figures that were not that frequent in the patients with cpn. urine culture of 6 patients showed proteus mirabilis which is in agreement with most of the reports.(4, 5) proteus species are implicated as serious causes of infections in humans along with escherichia coli, klebsiella, enterobacter, and serratia species. proteus species are most commonly found in the human intestinal tract as a part of the normal human intestinal flora along with escherichia coli and klebsiella species. patients with recurrent infections, structural abnormalities of the urinary tract, those who have had urethral instrumentation, and those whose infections are acquired in the hospital have an increased frequency of infection caused by proteus species and other organisms such as klebsiella, enterobacter, pseudomonas, enterococcus, and staphylococcus species. bacterial production of urease has also been shown to increase the risk of pyelonephritis in experimental animals. urease production, together with the presence of bacterial motility and fimbriae, may favor the production of upper urinary tract infections by organisms such as proteus mirabilis. the ability of proteus organisms to produce urease and to alkalinize the urine by hydrolyzing urea to ammonia makes it effective in producing an environment to survive. this leads to precipitation of organic and inorganic compounds leading to struvite calculus formation composed of magnesium ammonium phosphate (struvite) and calcium carbonate apatite.(5) ballesteros and associates found presence of xanthoma cells in the urine to be helpful for the primary diagnosis.(7) in our series, data were not available for urine and fine needle aspiration cytologies. however, reports have revealed that urine cytology is nonspecific and has a high false-positive rate. in a study, the investigators detected urine foam cells by serial urine cytology and reported an 80% preoperative accuracy in diagnosing xgpn with this method; however, these results could not be duplicated in later studies.(7,9) kidney biopsy has remote chances of spreading the tumor through the needle tract in case of malignancy as well as being invasive.(10,11) also, percutaneous biopsy increases the risk of sinus formation or spread of infection and does not provide adequate specimen for diagnosis of xgpn or kidney neoplasms in some cases.(12,13) the use of fluoroscopic guidance is also accompanied by an approximately 10% false-negative rate.(18) xanthogranulomatous pyelonephritis has several characteristic features on imaging. plain abdominal radiographies reveal urinary tract calculus and renomegaly with ill-defined outline due to perinephric extension of inflammation which is in agreement to our study (all of our patients who had undergone plain abdominal radiography with xgpn had calculus).(8) poor-functioning or nonfunctioning systems on the ivu are a common finding.(9) ultrasonography reveals renomegaly, typical central echogenic area due to calculi, and multiple parenchymal hypoechogenic areas due to multiple necrotic foci.(18) computed tomography demonstrates an enlarged kidney with calculus and multiple waterdensity areas representing dilated calyxes and abscess cavities filled with varying amounts of pus and debris. although they are prominently enhanced in cpn and tumors, these cavities fail to enhance in xgpn.(2,3) in our study, on kidney ultrasonography, renomegaly and calculus were present in 71.4% and 85.7% of the patients with xgpn with a significant difference from those in the cpn group. on ct scan, 83.3% of the patients had renomegaly and calculus in the xgpn group. data on calculus analyses were inconclusive as the majority had calcium oxalate calculi and 2 of 5 patients in the xgpn and 4 of 14 in the cpn had struvite calculi (table 4). as it has been mentioned before, preoperative diagnosis is difficult, but some characteristic findings can be used for this purpose.(3) in a study by hammadeh and diagnosis of xanthogranulomatous pyelonephritis—afgan et al urology journal vol 4 no 3 summer 2007 173 coworkers, 9 of 11 patients (82%) were diagnosed preoperatively on the basis of clinical and radiological features.(6) imaging is therefore considered the paramount for preoperative diagnosis of xgpn.(22) conclusion demographic data (age, gender distribution), comorbidities, predisposing factors, biochemical analysis, and roentgenological features, in combination, can be highly suggestive of xgpn in the patients with pyelonephritis and are therefore the crucial means for preoperative diagnosis of this disease. conflict of interest none declared. references 1. schlagenhaufer f. uber eigentumliche staphylomykosen der nieren und des pararenalen bindewebes. frankf z pathol. 1916;19:139-48. 2. schaffer aj. infections of the urinary tract. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell’s urology. 6th ed. philadelphia: wb saunders; 1992. p. 731-806. 3. goldman sm, hartman ds, fishman ek, finizio jp, gatewood om, siegelman ss. ct of xanthogranulomatous pyelonephritis: radiologicpathologic correlation. ajr am j roentgenol. 1984;142:963-9. 4. watson ar, marsden hb, lendon m, jones ph. renal pseudotumours caused by xanthogranulomatous pyelonephritis. arch dis child. 1982;57:635-7. 5. petronic v, buturovic j, isvaneski m. xanthogranulomatous pyelonephritis. br j urol. 1989;64:336-8. 6. hammadeh my, nicholls g, calder cj, buick rg, gornall p, corkery jj. xanthogranulomatous pyelonephritis in childhood: pre-operative diagnosis is possible. br j urol. 1994;73:83-6. 7. ballesteros jj, faus r, gironella j. preoperative diagnosis of renal xanthogranulomatosis by serial urinary cytology: preliminary report. j urol. 1980;124:9-11. 8. brown ps jr, dodson m, weintrub ps. xanthogranulomatous pyelonephritis: report of nonsurgical management of a case and review of the literature. clin infect dis. 1996;22:308-14. 9. chuang ck, lai mk, chang pl, et al. xanthogranulomatous pyelonephritis: experience in 36 cases. j urol. 1992;147:333-6. 10. wein aj, ring ej, freiman db, et al. applications of thin needle aspiration biopsy in urology. j urol. 1979;121:626-9. 11. nosher jl, amorosa jk, leiman s, plafker j. fine needle aspiration of the kidney and adrenal gland. j urol. 1982;128:895-9. 12. grainger rg, longstaff aj, parsons ma. xanthogranulomatous pyelonephritis: a reappraisal. lancet. 1982;1:1398-401. 13. papadopoulos i, wirth b, wand h. xanthogranulomatous pyelonephritis associated with renal cell carcinoma. report on two cases and review of the literature. eur urol. 1990;18:74-6. review. 14. malek rs, elder js. xanthogranulomatous pyelonephritis: a critical analysis of 26 cases and of the literature. j urol. 1978;119:589-93. 15. american medical association. physician icd-9-cm 2007: international classification of diseases: clinical modification. american medical association; 2007. 16. klugo rc, anderson ja, reid r, powell i, cerny jc. xanthogranulomatous pyelonephritis in children. j urol. 1977;117:350-2. 17. kural ar, akaydin a, oner a, et al. xanthogranulomatous pyelonephritis in children and adults. br j urol. 1987;59:383-5. 18. hartman ds, davis cj jr, goldman sm, isbister ss, sanders rc. xanthogranulomatous pyelonephritis: sonographic--pathologic correlation of 16 cases. j ultrasound med. 1984;3:481-8. 19. tiu cm, chou yh, chiou hj, et al. sonographic features of xanthogranulomatous pyelonephritis. j clin ultrasound. 2001;29:279-85. 20. verswijvel g, vandecaveye v, gelin g, et al. diffusionweighted mr imaging in the evaluation of renal infection: preliminary results. jbr-btr. 2002;85:100-3. 21. goodman m, curry t, russell t. xanthogranulomatous pyelonephritis (xgp): a local disease with systemic manifestations. report of 23 patients and review of the literature. medicine (baltimore). 1979;58:171-81. 22. takamizawa s, yamataka a, kaneko k, yanai t, yamashiro y, miyano t. xanthogranulomatous pyelonephritis in childhood: a rare but important clinical entity. j pediatr surg. 2000;35:1554-5. patients with pyelonephritis calculus composition xgpn(n = 5) cpn (n = 14) calcium oxalate 2 7 struvite 2 4 uric acid 1 3 table 4. calculi composition in patients with xgpn and cpn* *xgpn indicates xanthogranulomatous pyelonephritis and cpn, chronic pyelonephritis. u j spring 2012.pdf 486 | urological oncology inter/intra-observer reproducibility of gleason scoring in prostate adenocarcinoma in iranian pathologists alireza abdollahi,1 alipasha meysamie,2 sara sheikhbahaei,2 ali ahmadi,1 hedieh moraditabriz,1 mohammadreza bakhshandeh,1 hassan hosseinzadeh1 purpose: to measure the level of inter/intra-observer reproducibility among pathologists as far as gleason scoring of adenocarcinoma of the prostate is concerned. materials and methods: a total of 101 prostate biopsy slides, diagnosed with adwere exposed to gleason scoring. two months later, the slides were re-examined by three of the same pathologists. thereafter, the kappa was calculated for the data pathologists. results: inter-observer reproducibility was inappropriate, but intra-observer diagnostic reproducibility was almost perfect with a corresponding percentage of conclusion: the inter-observer reproducibility was poor. keywords: prostatic neoplasms, neoplasm grading, methods, humans corresponding author: alireza abdollahi, md department of pathology, imam khomeini teaching hospital, tehran university of medical sciences, tehran, iran tel: +98 912 122 0588 fax: +98 21 8826 9844 e-mail: dr_p_abdollahi@ yahoo.com received december 2010 accepted april 2011 1department of pathology, tehran university of medical sciences, tehran, iran 2department of community medicine, tehran university of medical sciences, tehran, iran urological oncology 487vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l reproducibility of gleason grading | abdollahi et al introduction p -cer, is the most prevalent type of cancer in men in the united states. it is also the second leading cause of cancer-related deaths in men, just following lung cancer. the overall prostate cancer detection rate in our community is 3.5%. the gold standard in the diagnosis of the pca is biopsy and making a histological diagnosis of carcinoma. when the tissue sample indicates presence of carcinoma, its gleason scoring is one of the most important elements in reporting. in this method, tumors are graded, based on their pattern of growth and the level of differentiation, from 1 to 5; grade 1 has the lowest and grade 5 the highest level of differentiation. one of the contributing factors to this observed upgrading in gleason scoring is the level of pathologist experience. since gleason score is one of the most important prognostic factors for the outcome of treatment in pca and even determines the treatment of choice for the tumor, a high degree of precision in its reporting and the agreement among the reports of the different pathologists for the same sample are crucial issues. despite the fact that gleason scoring is simple, there is an interobserver variability of the scores. gleason once said that “if i re-score my previously scored samples, in 50% of cases, i report the same scores and scores”. cates the concordance rate of the report varied between 0.16 and 0.836. for example, in a study conducted by rodriguez-urrego and colleagues, the inter-observer agreement was excellent with k good with k = 0.65 and even more. in this study, regarding the crucial importance of the reproducible and concordant reporting of the samples among different pathologists, we want to obtain approximations for these two variables among the pathologists working in iran. materials and methods in this cross-sectional study, 101 tissue samples of the prostate adenocarcinoma obtained through needle biopsy were re-examined to be gleasonscored. thin microscopic sections, and after being stained table 1. gleason’s microscopic grading system of the prostate carcinoma. stage description 1 single, separate, uniform glands in closely packed masses with a definite, usually rounded edge limiting area of tumor. 2 single, separate, slightly less uniform glands, loosely packed (separated by small amounts of stroma), with less sharp edge. 3a single, separate, much more variable glands, may be closely packed, but usually irregularly separated, with ragged, poorly defined edge. 3b like 3a, but very small glands or tiny cell clusters. 3c sharply and smoothly circumscribed rounded masses of papillary or loose cribriform tumor (papillary intraductal tumor). 4a raggedly outlined, raggedly infiltrating, fused glandular tumor. 4b like 4a, with large pale cells (hypernephroid). 5a sharply circumscribed, rounded masses of almost solid cribriform tumor, usually with central necrosis (comedocarcinoma). 5b ragged masses of anaplastic carcinoma with only enough gland formation or vacuoles to identify it as adenocarcinoma. 488 | randomly selected pathologists to be scored using was based on the degree of glandular differentiation and the growth pattern of the tumor compared sections that cannot be scored, those extracted from patients previously treated with anti-androgenic drugs or radiotherapy, and samples containing less than 5 malignant acini were excluded from the study. after selection of the samples, a code was given to each of them. thereafter, the scores given by each sheet. two months later, the same samples with altered code were sent back to three of the pathologists to be re-scored. finally, the concordance rate this research was carried out according to the principles of the declaration of helsinki. the local ethics medical committee of tehran university of medical sciences approved the study protocol. our statistical analysis included calculation of second data report and comparison of kappa between pathologists. kappa varied between 0 and 1; the greater the kappa, the higher the concordtable 2. percentages of agreement and kappa values of all possible pair combination of 5 pathologists’ grading scores.*† o1t1 o2t1 o3t1 o4t1 o5t1 o3t2 o4t2 o5t2 o1t1 40.00% (30.40% to 49.60%) 36.50% (27.06% to 45.94%) 60.00% (50.40% to 69.60%) 35.70% (26.31% to 45.09%) 39.10% (29.54% to 59.10% (49.46% to agreement, % 0.24 0.25 0.19 0.19 0.21 0.47 kappa o2t1 46.60% 34.50% 50.00% (40.20% to 41.40% (31.75% to 51.05%) 31.00% (21.94% to 40.06%) 46.60% agreement, % 0.34 0.19 0.15 0.35 kappa o3t1 37.10% (27.63% to 46.57%) 52.60% 62.39%) 94.29%) 31.00% (21.94% to 40.06%) agreement, % 0.19 0.4 0.12 0.34 kappa o4t1 41.00% (31.36% to 50.64%) 37.60% 47.09%) (70.56% to 40.20% (30.59% to agreement, % 0.25 0.2 0.72 0.24 kappa o5t1 52.10% (42.31% to 95.06%) agreement, % 0.39 0.21 kappa o3t2 (21.75% to agreement, % 0.11 0.35 kappa o4t2 41.00% (31.36% to 50.64%) agreement, % 0.24 kappa * p < .001. † urological oncology 489vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l 0.60 moderate agreement, 0.61 to 0.80 substanperfect agreement. eventually, the data were analyzed both descriptively and analytically using spss (the statistical package for the social sciences, version 15.0, spss inc, chicago, illinois, results percentages of agreement and kappa values of all overall kappa values in different gleason scores using weighted kappa values, there was no sigbetween poorly differentiated and moderately difintra-observer diagnostic reproducibility was almost perfect with a corresponding percentage of discussion today, the gleason system (prostate adenocarcitumor grading, crucial for both patients and doctors. we found an extremely low reproducibility bebility has a good level when the slides were reported lacks an integrated and regular education system in pathology. in addition, there are obvious limitations in the accuracy of grading based on the small amount of tissue available from needle biopsies of the prostate. on the other hand, one should recognize a pathological misinterpretation. differences of opinion are related to different interpretations of tumor grading, which is a qualitative indicator. naturally, this qualitative factor may be interpreted differently by pathologists. therefore, the difference in interpretation should not be construed as an error. in this study, the reproducibility was meaningfully proportionate with gleason score of the samples. it seems that the reproducibility would rise when the ozdamar and colleagues reported an acceptable inter-observer variation for gleason-style grading. furthermore, allsbrook and associates examined were involved. the reproducibility stood at an acceptable level. the reason behind different conclusions from these studies might be related to the pathology education system. holding meetings for exchange of views, conferences, journals, and group studies may bring views and interpretations together. the lack of such programs in our country must explain the differences. with cancer produced an inter-observer reproductraining course for pathologists contributing to lar training to pathologists. table 3. inter-observer reproducibility of gleason’s grading system for prostatic carcinoma.* gleason score kappa prob > z 4 0.0070 0.5939 5 0.0417 6 0.4033 < 0.001 7 < 0.001 < 0.001 9 0.3402 < 0.001 10 0.3964 < 0.001 combined < 0.001 scores 4 and 5 were not significant. reproducibility of gleason grading | abdollahi et al 490 | this study faced restrictions, such as undermanned samples. therefore, studies with more pathologists and samples are recommended for the future. conclusion carcinoma, regular and effective training courses are strongly recommended for pathologists in order to raise intra/inter-observer reproducibility. acknowledgements the authors are sincerely grateful to the vice chancellor for research affairs at tehran university of this study. conflict of interest none declared. references 1. gleason df, mellinger gt. prediction of prognosis for prostatic adenocarcinoma by combined histological grading 2. cancer by measuring free and total serum prostate-specific 3. hosseini sy, moharramzadeh m, ghadian ar, hooshyar h, prostate cancer by measuring total serum prostate-specific 4. bostwick dg. gleason grading of prostatic needle biopsies. correlation with grade in 316 matched prostatectomies. 5. vira ma, tomaszewski je, hwang wt, et al. impact of the percentage of positive biopsy cores on the further stratification of primary grade 3 and grade 4 gleason score 7 tumors in radical prostatectomy patients. urology. 6. d'amico av, renshaw aa, arsenault l, schultz d, richie jp. clinical predictors of upgrading to gleason grade 4 or 5 disease at radical prostatectomy: potential implications for patient selection for radiation and androgen suppression 7. kulkarni gs, lockwood g, evans a, et al. clinical predictors of gleason score upgrading: implications for patients considering watchful waiting, active surveillance, or brachypatel aa, chen mh, renshaw aa, d'amico av. psa failure following definitive treatment of prostate cancer having biopsy gleason score 7 with tertiary grade 5. jama. 9. whittemore de, hick ej, carter mr, moul jw, miranda-sousa aj, sexton wj. significance of tertiary gleason pattern 5 in gleason score 7 radical prostatectomy specimens. j urol. 10. albertsen pc, hanley ja, gleason df, barry mj. competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. 11. gleason df. histologic grading of prostate cancer: a per12. allsbrook wc, jr., mangold ka, johnson mh, lane rb, lane cg, epstein ji. interobserver reproducibility of gleason grading of prostatic carcinoma: general pathologist. hum 13. melia j, moseley r, ball ry, et al. a uk-based investigation of interand intra-observer reproducibility of gleason grad14. lotan tl, epstein ji. clinical implications of changing definitions within the gleason grading system. nat rev urol. 15. brennan p, silman a. statistical methods for assessing ob4. 16. rodriguez-urrego pa, cronin am, al-ahmadie ha, et al. interobserver and intraobserver reproducibility in digital and routine microscopic assessment of prostate needle 17. ozdamar so, sarikaya s, yildiz l, atilla mk, kandemir b, yildiz s. intraobserver and interobserver reproducibility of who and gleason histologic grading systems in prostatic mulay k, swain m, jaiman s, gowrishankar s. gleason scoring of prostatic carcinoma: impact of a web-based tutorial on interand intra-observer variability. indian j pathol urological oncology appendixes 255urology journal vol 4 no 4 autumn 2007 acknowledgement reviewers in volume 4 the editorial team of the urology journal would like to acknowledge a depth of gratitude to the following colleagues who have done us the great favor of peer reviewing of the submitted manuscripts over the past year: abadpour b abbasi a abdi h aghamohamdi h ahmadi asr badr y ahmadnia h akhavizadegan h alamdari h ali asgari m alizadeh a al-zahrani h, saudi arabia ameri a amin-sharifi ar amjadi m arasteh s argani h arshadi h asgari sa azizi f barbaghli g, italy barghi mr beighi f broumand b bruner a, austria calogero ae, italy cheuk dk, china dadfar mr dadkhah f danesh ar darabi mr dolatshahi a einollahi b el assmy a, egypt esmaeili h etemadian m falahatkar s falahian m farshi a fazeli f frimberger d, usa ghacha r, saudi arabia ghadiani m ghanaati h ghavamian r gholamrezaei hr ghorbani a hafez at, egypt hajebi am hajebrahimi s hosseini mm hosseini moghadam smm hosseini sy jaladat h kajbafzadeh am kang kp, republic of korea karami h kavoussi lr, usa kazemi b khalili m kheradmand a khezri aa khorrami h khoshdel a khosropanah i kinebuchi y, japan kohanzad sh madaen sk maghsoudi r mahdavi zafarghandi r makhdomi kh mehraban d mehrabi s mehrsaei ar mirzazadeh a moslemi mk mousavi bahar sh murokami t, japan nahabidian a naseh h nasehi a nikibakhsh a nikoobakht mr nouralizadeh a omrani d orafa m pajouheshi a parvin m perabo fg, germany pourmand g rahmani m rajaei esfahani m razeghi e razi a rostami n safarinejad mr salehi m salem s sedighi gilani ma serefoglu ec, turkey seyedzadeh a shadab a shadpour p shaeer o, egypt shahbazian h shahrazad a shahrokh h shakeri s shakhs salim n shamsa a sharhrazad a sharifian m simforoosh n soleimani m soufi majidpour h marild s, sweden tabibi a tadayyon a taghizadeh afshari a torbati p tousi p tufek i, turkey zand s endourology and stone disease an overnight stay versus three days admission after uncomplicated percutaneous nephrolithotomy: a randomized clinical trial abbas basiri1, davood arab2, hamid pakmanesh3, mehdi abedinzadeh 4, hormoz karami4* purpose: to evaluate the safety and efficacy of discharging patients on the first postoperative day after an uncomplicated percutaneous nephrolithotomy (pcnl). materials and methods: after an uncomplicated successful pcnl without significant residual stone (>5mm) or any complication up to the first postoperative day, we randomly assigned patients into two groups—group 1: overnight surgery, and group 2: routine discharge after three days. patients with significant residual stone on control fluoroscopy were excluded. ninetyeight and 102 patients were assigned to groups 1 and 2, respectively. serum hemoglobin and creatinine were evaluated before the operation as well as the first postoperative day. stone free status was evaluated using ultrasound and kub radiography at the first postoperative day. results: the stone and patient characteristics were not different in two groups. the preoperative change in the hemoglobin and creatinine levels were not significantly different between the two groups. nine patients (9.2%) in group 1 and five (4.9%) in group 2 were readmitted because of complications (mainly hematuria) (p = .23). of the readmitted patients, five in group 1 (55%), and three in group 2 (60%) received blood transfusion (p = .87). in these patients, group 1 received 1.6 ± 0.51 units of blood compared with 1.93 ± 0.25 in group 2 (p = .07). all the readmitted patients did well with conservative therapy with no need for angioembolization. conclusion: in uncomplicated pcnl with no significant residual stone, discharging the patient on the first postoperative day is safe. the outcome is comparable to a routine three-day hospital stay. keywords: cost savings; early discharge; length of stay; percutaneous nephrolithotomy; uncomplicated introduction percutaneous nephrolithotomy (pcnl) is the gold standard for surgical management of large renal stones. since its popularization as an effective and safe modality, several modifications have been made to the original procedure(1,2) including patient positioning , choice of anesthesia(3), modality for access guide(4) or tract dilation method(5). compared to open procedures, pcnl is associated with lower morbidity, lower post operation pain, smaller scars, shorter hospital stay, lower transfusion rate, shorter convalescence, and lower cost (7). pcnl has become a common method and the first line of intervention for patients with a significant stone burden, because of continued improvement in safety, stone-free rate and length of hospitalization (loh) (7,8). the hospital stay after pcnl is much shorter than open kidney surgery; however, it has typically remained 2-5 days. a shorter hospital stay may decrease cost of pcnl, increase patients’ comfort and decrease nosocomial complications. some authors have 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2department of surgery, kowsar hospital, semnan university of medical sciences, semnan, iran. 3department of urology, faculty of medicine, kerman university of medical sciences, kerman, iran. 4department of urology, shahid rahnemoon hospital, sahid sadooghi university of medical sciences, yazd, iran. *correspondence: urology department ,shahid rahnemoon hospital ,sahid sadooghi university of medical sciences,yazd , iran. tel: +989131575705. email: hormozkarami@yahoo.com. received april 2019 & accepted april 2019 addressed this issue by advocating tubeless outpatient pcnl in highly selected patients(9-11). in the other hand, with recent advances in the field of retrograde intrarenal surgery (rirs), patients are treated as outpatient or with a short hospital stay. therefore, with reducing hospital stay in selected uncomplicated patients, pcnl may remain more economical compared with rirs while showing superior stone free rate with a single procedure.(12,13) this is the first randomized clinical trial that compares the safety of overnight stay with three days admission in patients undergoing uncomplicated pcnl. materials and methods study population in a 6-month period from june to december 2015, 210 patients who underwent uncomplicated pcnl were included in the study according to the selection criteria (table 1). urinalysis and culture, cbc and serum creatinine were conducted for all the patients. using urology journal/vol 17 no. 4/ july-august 2020/ pp. 352-357. [doi: 10.22037/uj.v0i0.5314 ] vol 17 no 04 july-august 2020 112 simple randomization method, the patients were categorized into two groups—group 1: overnight stay after surgery, and group 2: routine discharge after three days admission. the surgeon who visited the patients at first postoperative day, allocated patients randomly in two groups. the primary outcome was the re-admission rate. the decision about the readmission was done by another surgeon who was blind regarding the study group. pcnl procedure we administrated prophylactic antibiotics (first generation cephalosporin) to all the patients. in patients receiving general or spinal anesthesia, 5-french ureteral stent was placed on the affected side through cystoscopy. then in prone or supine position, pyelocaliceal system and stones were determined by contrast and fluoroscopy or ultrasonography, and a chiba needle was passed into the selected calyces of the kidney. a guidewire was passed through the needle into the pelvis over the guidewire. the dilatators and then working element (26-30f) were placed, and by using normal saline solution as irrigating solution, 24 french nephroscope was passed inside amplatz sheaths and the stone(s) overnight vs. standard pcnl – basiri et al. endourology and stones diseases 130 were crushed by pneumatic lithotripsy and removed with grasping forceps. finally, a nephrostomy tube was fixed in the kidney. the size of the nephrostomy tube was 20-24f depending on the presence of bleeding during the procedure, extent of manipulation, and surgeon’s preference. if a considerable amount of the stone residue (>5mm) was observed on control fluoroscopy at the end of the procedure, the patient was excluded from the study. post-operative care kidney, ureters and bladder x-ray (kub), renal ultrasonography, hemoglobin (hb) and creatinine (cr), sodium and potassium were checked in all the patients on the first postoperative day. if there was no significant residual stone and laboratory data were in normal range, and there was no fever and chill or underlying diseases such as cardiovascular disease, the patients were classified into two groups based on simple randomization method. patients with considerable complications during or early after the surgery were excluded from the study. the patients in group 1 were discharged after removing the foley catheter, the ureteral stent, and the nephrostomy tube. in group 2, the nephrostomy tube table 1. selection criteria stones larger than 2 cm in the kidney or proximal ureter stones less than 2 cm with failed swl acceptable anesthesia risk (asa class< 3) normal coagulation status two functional kidneys without renal insufficiency no active infection ≤ 2 access sites insignificant residual stone (<5mm) no intra or postoperative complications less than or equal one unit blood transfusion during operation less than three unit hemoglobin decrease in the next morning hemoglobin more than 10mg/dl after surgery informed consent no postoperative complications including fever, urinary leakage, demise, uti and urosepsis, pneumothorax and hemothorax, colonic and gi perforation. normal postoperative chest x-ray (cxr) no fever, gross hematuria or severe pain at the time of discharge figure 1. flow diagram of the study vol 17 no 04 july-august 2020 353 was removed on the second postoperative day. the patient was discharged on the third postoperative day after removing the foley and the ureteral stent if no urine leakage was observed from nephrostomy site and there was no fever. follow-up before discharge, the patients were informed about symptoms such as hematuria, and the probability of having luts, fever and chills. they were told to refer to the emergency department in case of fever, chills, vomiting or worsening back pain. the patients were followed-up with sonography, kub and laboratory tests one week post-operation. the patients with hematuria were readmitted and received iv fluid, and their vital signs were assessed routinely. all the patients had a complete blood count, and electrolytes and serum creatinine levels and coagulation parameters were assessed. parenteral antibiotics were administered. if the bleeding from the nephrostomy site continued or gross hematuria with acute urine retention was observed, then blood transfusion plus fluid resuscitation and foley catheterization with urinary bladder irrigation were administered. statistical methods it was of interest to establish non-inferiority of discharging patients on the first postoperative day after an uncomplicated pcnl (overnight group) as compared to the patients with routine discharge after three days regarding its complications. the primary outcome was the rate of readmission and secondary outcome was the rate of complications like sepsis and sever pain or bleeding. considering a difference of less than 5% is of no clinical importance in calculating the sample size. thus, the non-inferiority margin was selected to be δ=.05. the mean complications rates of the intervention and the control groups were θ1=1% and θ2=0%, respectively. then, by the formula: , the required sample size with equal allocation (r=1) to achieve an 80% power (β=.2) at α=.05 was determined by n1 = n2 = 98. adding seven participants to each group for probable loss to follow up and other reasons, 105 participants were set in each group as the sample size(15). descriptive statistics including means (±sds) were calculated for the numerical variables and count and table 2. pre, intra, and postoperative characteristics of the patients in two groups parameters group1 (overnight) group2 (admitted three days) p-value n=98 n=102 sex male 71.4 (70) 66.7 (68) female 28.6 (28) 33.3 (34) 0.46 age (years) 44.9 ±12.8 45.97±13.49 0.57 laterlity lt kidney 53.1 (52) 52 (53) rt kidney 46.9 (46) 48 (49) 0.87 stone size (cm) 3.62 ± 2.03 3.68 ± 2.12 0.84 stone size <1 cm 8.1 (8) 5.8 (6) >1 cm 91.8 (90) 96 (96) 0.53 anesthesia type spinal 92.8 (91) 90.1 (92) general 7.1 (7) 9.8 (10) 0.76 guide for access fluoroscopy 84.6 (83) 75.4 (77) ultrasonography 15.3 (15) 24.3 (25) 0.17 position prone 100 (98) 98 (100) supine _ _ 1.9 (2) 0.49 preoperative hb 13.85±1.53 13.84 ± 1.62 0.94 postoperative hb 11.8 ± 1.62 11.66 ± 2 0.59 hb drop 2.09 ± 1.17 2.18 ± 1.63 0.69 preoperative cr 1.38 ± 1.71 1.13 ± 0.31 0.16 postoperative cr 0.99 ± 0.24 1.05 ± 0.3 0.1 cr rise -0.41 -0.08 0.72 stone free rate 71.4 (70) 70.5 (72) 0.74 data are presented as mean (±sd) or % (n) group 1 (overnight) 2 (admitted three days) p value readmission 9/98 (9.2%) 5/102 (4.9%) .23 discharged without transfusion 4/9 (45%) 2/5 (40%) .87 blood transfusion 5/9 (55%) 3/5 (60%) .87 transfused blood units (mean±sd) 1.6 ± 0.51 1.93 ± 0.25 .07 readmission duration (mean±sd) 3.8 ± 0.9 4.0 ± 1.0 .84 angioembolization 0 0 table 3. readmission and transfusion rate between two groups overnight vs. standard pcnl – basiri et al. endourology and stones diseases 354 percentage were reported for the categorical or nominal ones. the student’s t-test was used for continuous variables to compare the means of both groups. the chisquared test was used for comparing the categorical variables. the differences were considered statistically significant for p < .05. the data were analyzed using spss-15 software. all procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. informed consent was obtained from all the individual participants included in the study. this study is registered in the iranian registry of clinical trials (www.irct.ir) with the following registration number: irct20171228038115n1. results out of a total of 300 patients who underwent pcnl, 90 patients were excluded because of not meeting the inclusion criteria, incomplete information, consent refusal or other reasons. finally, 200 patients (98 cases in group 1 and 102 cases in group 2) remained in the study, and were analyzed. the consort flow diagram is depicted in figure 1. the patients’ demographic characteristics as well as preoperative and postoperative data are presented in table 2. there were no significant differences in the patients’ characteristics before and during surgery between the two groups (table 2). only one patient in each group needed two accesses for pcnl, and the rest underwent single-access pcnl. in the first group, patients were discharged after 14 to 20 hours. nine patients in group 1 (9.1%) and five patients in group 2 (4.9%) were re-hospitalized due to gross hematuria during the first week after surgery (p = .23). of these patients, five patients in group 1 (55%) and three patients in group 2 (60%) required blood transfusion after surgery (p = .87). bleeding resolved with conservative treatment in all and no patient needed further evaluation and radiologic intervention for the treatment of bleeding. all of them were discharged after three to five days. patients in group 2 received more blood units during admission (table 3). the postoperative results, in terms of stone-free rate and complications, were not statistically different between the two groups. discussion the cost effectiveness of pcnl correlates with stonefree rate, length of hospitalization (loh), and major complications(8). reducing the loh is a key strategy to improve the cost effectiveness of pcnl(9). the hospital stay in uncomplicated pcnl has been three days routinely. during this period, no particular healthcare is provided for these patients except removing the nephrostomy and the ureteral and urethral stents in the consecutive days. further, based on the aua recommendation there is no place for routine intravenous antibiotics after uncomplicated pcnl. meanwhile, previous studies have revealed that most of the fevers after pcnl are not related to bacteremia.(15) on the other hand, we routinely do not observe severe complications during this period. the most common complications is early urine leakage and hemorrhage during and after removal of the tubes, which can be determined and managed at the same time. nonetheless, delayed postoperative bleeding does not have a specific time of occurrence and we showed that 3-day hospital stay dose not reduce its risk. all these data is against routine three days admission in an uncomplicated successful pcnl. in recent years, the idea of performing pcnl as an outpatient procedure or as an overnight pcnl is considered due to the reduced hospital stay, thereby saving of attendant healthcare cost and minimizing potential nosocomial infections as well. few case series described good outcomes with outpatient and overnight pcnl in carefully selected patients(9,16-18). ambulatory tubeless pcnl was first reported by singh et al. in 2005. they reported “ambulatory” pcnl in 10 patients with spinal anesthesia. the patients were kept overnight and had a mean hospital stay of 40 h. the nephrostomy tract was fulgurated with diathermy in their series(19). the first case report of the outpatient pcnl was from canada. they reported a patient with lower pole 11 mm stone who was successfully treated with tubeless pcnl as outpatient. she was discharged home 4 hours after leaving the operating room(17). shahrour and andonian reported a median hospital stay of 1 day(20). in their study median stone size was 2 cm. overnight hospital stay after pcnl was reported as 1.7 days in a study by fahad alyami et al.(9). the latest study by ahmed fahmy et al. described outpatient pcnl and the mean time to discharge home was 8.97 hours. they concluded that outpatient pcnl presented several advantages, including rapid of recovery of the patient, minimizing nosocomial infection , and also decline in healthcare cost with no additional morbidity to the patient and without compromising of the stone-free rate(18). another series of ambulatory pcnl on 10 patients studied by shahrour and andonian reported that all the patients were discharged with ureteral stent, which were removed using flexible cystoscopy one week later(20). although long-term nephrostomy tube improves urinary drainage and prevents urinary extravasation as well as tract tamponade, reduces bleeding, and may facilitate a second look re-intervention as mentioned in all studies, the stone clearance rate is equal to that of conventional pcnl. moreover, the complication rate is similar and tubeless pcnl or early removal of the foley catheters, nephrostomy tube, and ureteral stent make the patients feel more comfortable(21-23). tubeless pcnl, often with postoperative ureteral stent drainage in highly selected patients, has been shown to be a safe modification to limit the need for a long hospital stay(10,11,16). in a report on tubeless pcnl by bell man et al., the median hospital stay was 0.6 day or 14.4 hours. however, a double-j stent was placed at the end of the procedure for all the patients, and they were discharged home with an indwelling foley catheter(18). we inserted the nephrostomy tube in all cases. our data shows that the rate of re-admission due to bleeding was 9% in group one compared with 4% in group two. although this difference is not significant, may be due to early removal of the nephrostomy tube. this is the first published study to access the feasibility of overnight surgery after a conventional pcnl in a randomized clinical trial. we evaluated the safety and outcome of overnight pcnl in selected uncomplicated patients with the placement of ureteral stent and nephrostomy tube during the operation. our patients in the overnight group were discharged without the nephrosovernight vs. standard pcnl – basiri et al. vol 17 no 04 july-august 2020 355 tomy tube, foley catheter or jj stent. the groups were not different in sex, age, site of operation, and stone size. there were no significant differences in residual stone, hemoglobin drop and creatinine rise, transfusion rate during and after surgery, and readmission rate between the two groups. our findings showed efficacy and safety of overnight pcnl in select patients. nevertheless, the limitation of the present study is that the choice of the anesthesia and positioning of the patient as well as the guide for access was not constant during the study; however, these factors were distributed randomly in two groups (table 2) and most of the patients were done in the prone position under spinal anesthesia. nevertheless, in a bigger sample size we could perform subgroup analysis to find out whether overnight pcnl is beneficial for which patient exactly. unfortunately, we did not evaluate the exact cost for each individual separately in the current study. nevertheless, we think with reducing hospital stay without increasing the complications, the cost will decrease significantly. conclusions in highly selected uncomplicated pcnl, to limit the need for hospital stay, early discharge of patients seems to be safe and does not contribute to a higher rate of complication and re-hospitalization compared with three days postoperative admission. this needs to be confirmed by studies with bigger sample size. acknowledgments the authors would like to acknowledge the support of our colleagues in labbafinejad hospital operation room, shahid beheshti university of medical sciences for their leading suggestions on this manuscript. conflict of interest the authors confirm there is no any conflict of interest. references 1. fernström i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. mcdougal ws, wein aj, kavoussi lr, partin aw, peters ca. campbell-walsh urology 11th edition review: elsevier health sciences division; 2015. 3. nouralizadeh a, pakmanesh h, basiri a, et al. solo sonographically guided pcnl under spinal anesthesia: defining predictors of success. scientifica (cairo). 2016;2016:5938514. 4. nouralizadeh a, 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hn, sodha hs, khandkar aa, kharodawala s, hegde ss, bansal mb. a randomized trial evaluating type of nephrostomy drainage after percutaneous nephrolithotomy: small bore v tubeless. j endourol. 2008;22:1433-9. 11. liu m, huang j, lu j, et al. randomized controlled study of selective tubeless minimally invasive percutaneous nephrolithotomy for upper urinary calculi. minerva urol nefrol. 2016. 12. sari s, ozok hu, cakici mc, et al. a comparison of retrograde intrarenal surgery and percutaneous nephrolithotomy for management of renal stones ?2 cm. urol j. 2017;14:2949-54. 13. atis g, culpan m, pelit es, et al. comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery in treating 2040 mm renal stones. urol j. 2017;14:2995-9. 14. chow sc, wang h, shao j. sample size calculations in clinical research, second edition: taylor & francis; 2007. 15. ziaee sa, kazemi b, moghaddam sm, et al. a study of febrile versus afebrile patients after percutaneous nephrolithotomy regarding bacterial etiologic factors through blood and urine cultures and 16s rrna detection in serum. j endourol. 2008;22:2717-21. 16. bellman gc, davidoff r, candela j, gerspach j, kurtz s, stout l. tubeless percutaneous renal surgery. j urol. 1997;157:1578-82. 17. beiko d, samant m, mcgregor tb. totally tubeless outpatient percutaneous nephrolithotomy: initial case report. adv urol. 2009295825. 18. fahmy a, rhashad h, algebaly o, sameh w. can percutaneous nephrolithotomy be performed as an outpatient procedure? arab j urol. 2017;15:1-6. 19. singh i, kumar a, kumar p. "ambulatory pcnl" (tubeless pcnl under regional anesthesia) -a preliminary report of 10 cases. int urol nephrol. 2005;37:35-7. 20. shahrour w, andonian s. ambulatory percutaneous nephrolithotomy: initial series. urology. 2010;76:1288-92. overnight vs. standard pcnl – basiri et al. endourology and stones diseases 356 vol 17 no 04 july-august 2020 357 21. borges cf, fregonesi a, silva dc, sasse ad. systematic review and meta-analysis of nephrostomy placement versus tubeless percutaneous nephrolithotomy. j endourol. 2010. 22. mishra s, sabnis rb, kurien a, ganpule a, muthu v, desai m. questioning the wisdom of tubeless percutaneous nephrolithotomy (pcnl): a prospective randomized controlled study of early tube removal vs tubeless pcnl. bju int. 2010;106:1045-8; discussion 8-9. 23. aghamir smk, salavati a, hamidi m, fallahnejad a. primary report of totally tubeless percutaneous nephrolithotomy despite pelvi-calyceal perforations. urol j. 2017;14:4020-3. overnight vs. standard pcnl – basiri et al. best reviewer of the year 2018 takahiro yasui takahiro yasui september 2019 takahiro yasui, m.d, ph.d., is a professor at the nephrourology department of nagoya city university graduate school of medical sciences. he earned his m.d. degree in 1994 and ph.d. degree in 2000 from the nagoya city university graduate school of medical sciences. dr. yasui mostly specializes in the field of urolithiasis, laparoscopic and robotic surgery, and endourology. he has been a researcher in the field of urology since 1994 and has published more than 160 scientific papers and contributed in clinical guidelines such as the “clinical guideline for urinary stone disease” and “clinical guideline for urolithiasis” prof. yasui is a principle member of several scientific organizations such as the japanese urological association, japanese society of endourology, and japanese society on urolithiasis research in which he is the director and the japanese society of nephrology in which he is the councilor. he is also an active member of the japanese society for endoscopic surgery, japanese society of clinical oncology, japanese association of endocrine surgery, american urological association, european association of urology, and société internationale d'urologie and an editorial board member of the “international journal of urology, urolithiasis”. due to his outstanding scientific contributions, he has been gifted several awards to name some are the sakaguchi prize in 2003 (japanese urological association), first prize for presentation in 2007 (japanese society on urolithiasis research), best presentation in 2010 (japanese society of nephrology), medical research award in 2011 (japan medical association), international journal of urology reviewer of the year in 2012, best poster award in 2014 (european association of urology), and best poster in 2015 (american urological association). “to be the best reviewer of the year 2018 of the “urology journal” is a great honor for me. contributing to high-impact scientific journals is part of my work life. i especially consider the further development of urology in asia to be important. "urology journal" contributes to many advanced and original studies and i am happy to be involved in this journal. i look forward to the dedication of "urology journal” to the improvement of medical and research level and the development of urology.” takahiro yasui was chosen as the “best reviewer of the year 2018” by the editorial board of the urology journal. endourology and stone disease the clinical application of puncture frame in establishing ultrasound guided percutaneous nephrolithotomy access xiang-biao he1* , yang-yang liu2, gui-min huang1, dan du1 purpose: to investigate the clinical efficacy and safety of ultrasound-guided percutaneous nephrolithotomy (pcnl) assisted by a puncture frame. materials and methods: clinical data of 106 patients with nephrolithiasis who underwent ultrasound-guided percutaneous nephrolithotomy from october 2016 to december 2017 in our hospital were analyzed retrospectively. the channels were established by the assistance of the puncture frame. results: the mean puncture time was 35 ± 18 seconds, the puncture was performed 1.3 ± 0.9 times on average. the puncture was successfully performed at first attempt in 73 cases. the mean operation time was 67.3 ± 39.2 min, and the mean intraoperative blood loss was 48 ± 22 ml. the stones were located on the left in 50 (47.2%) cases, and on the right in 56 (52.8%) cases. channels were established through the upper, middle and lower calyces of the kidney in 78 (73.6%), 20 (18.9%), and 8 (7.5%) cases, respectively. the puncture sites were located on the upper and lower of 12th rib in 81 (76.4%) and 25 (23.6%) cases. intraoperative and postoperative blood transfusion was given in four cases. pleural injury occurred in two cases, and hydropneumothorax occurred in one case in whom closed thoracic drainage was performed. the stone free rate after a single surgery was 87.7% (93/106). conclusion: establishing a percutaneous nephrolithotomy access tract under ultrasound guidance using the puncture frame is an efficacious and safe approach. keywords: puncture frame; ultrasound; percutaneous nephrolithotomy; puncture; complications introduction the application of ultrasound-guided percutaneous nephrolithotomy access tract was first reported by karamcheti(1) in 1977. its main utility lies in the establishment of a percutaneous tract before the operation and intraoperative stone localization and postoperative calculus examination. fluoroscopic-guided access percutaneous nephrolithotomy is also widely used. its advantage lies in the accuracy of puncture guidance. however, surgeons, assistants, nurses and patients, all have to endure various levels of radiation exposure. numerous studies have shown that frequent radiation exposure is harmful to the human body, even under the aegis of protective aprons and thyroid shileds(2). establishing the access tract is the most critical step in pcnl and renal puncture(3). it does not only affect the operation time, intraoperative blood loss, surgical complications, but also affects successful stone removal rate of a single operation, postoperative sepsis incidence, mortality, etc. for the surgeons who are not familiar with the surgery, the intraoperative and postoperative complications increase correspondingly. the safe and effective establishment of percutaneous nephroscope channel urgently requires a certain real-time positioning and needle insertion technology to achieve. 1department of urology, the people’s hospital of leshan, leshan city, 614000, china. 2department of gastroenterology, the people’s hospital of leshan, leshan city, 614000, china. *correspondence: department of urology, the people’s hospital of leshan, leshan city, sichuan province, china. tel: +86 15390216944. fax: +86 2119351. e-mail: 546036415@qq.com. received september 2019 & accepted february 2020 as a result, we decided to perform an analysis based on the clinical data of patients who underwent pcnl surgery from october 2016 to december 2017 in our hospital. all operations are performed by the same surgical team, and the establishments of percutaneous renal channels were completed with ultrasound guidance assisted by puncture frame. patients and methods study population all patients from sichuan province were treated with pcnl in our hospital. pcnl is typically done by our team for renal stones ≥ 2 cm, smaller stones refractory to extracorporeal shock wave lithotripsy (eswl), and large upper ureteral stones. the exclusion criteria were ureteral stones which underwent ureteroscopy or flexible ureteroscopic lithotripsy before or after pcnl. the surgical indications conform to the 2014 chinese guidelines for the diagnosis and treatment of urological diseases (4). preoperative blood biochemical examination, electrocardiogram, chest x-ray, echocardiography, pulmonary function and other routine preoperative tests and preparation were completed in advance, excluding surgical contraindications, such as cardiopulmonary and cerebral lesions, coagulation abnormalities, etc. as urology journal/vol 17 no. 4/ july-august 2020/ pp. 358-362. [doi: 10.22037/uj.v0i0.5587 ] for specialist examination, color doppler ultrasound, plain kidney-ureter-bladder x-ray (kub), intravenous pyelography (ivp), and computed tomography (ct) were used to determine the location and size of stones. furthermore, preoperative ct scans were used to design puncture targets for calyces, focusing on the location of calculi and calyces, as well as the relationship between the kidney and surrounding organs, such as lower pleura, liver, spleen, and posterior colon. study design equipment mainly included digital ultrasonic diagnostic imaging system (mindray, dp-30; mindray bio-medical electronic co, ltd, shenzhen, china ), and matching puncture frame (mindray, 18g; mindray bio-medical electronic co, ltd, shenzhen, china) (figure 1), pcnl kits (reborn medical, 18g, f8-f22; hunan reborn medical science and technology development co. ltd, hunan, china), guidewire (zebra™, 0.032in×150cm; boston scientific corporation, usa) and ureteral stent (percuflex™ plus, 4.8fr-6fr×26cm; boston scientific corporation, usa ), ureteroscope (wolf, 9.8 fr. ; richard wolf inc., germany), and nephroscope (wolf, 20 fr. ; richard wolf inc., germany), holmium: yag laser lithotripsy unit (p.s. int-60w holmium laser system; lumenis gmbh, dieburg, germany), and ultrasonic lithotripter (ems; swiss master lithoclast, bern, switzerland). all operations were performed under general anesthesia with endotracheal intubation. the patient was firstly placed in a lithotomy position, routinely sterilized and laid with operation towels, and placed 5f or 6f ureteral catheter on the affected side under cystoscopy and ureteroscopy. the ureteral catheter was retained to fix the ureteral catheter, and the 3-liter bag (3000ml saline) was externally connected for continuous irrigation. the patients’ posture adjustment for the prone position, raise the waist with a cushion, the surgical bed was adjusted for "⁔" to expose the lower back. the ultrasonic probe was firstly positioned, and puncture channel was designed in combination with ct, kub, and ivp to determine the approximate range of puncture points. routine disinfection and towel laying were performed again, preoperative preparation of instruments such as ureteroscope was performed by the assistant simultaneously. a three-way tube was placed in the ureteral catheter, and methylene blue was used as an indicator during the operation. the puncture frame was fixed on the ultrasonic probe, and the puncture angle was adjusted to 23°. the puncture point was determined at the preoperative puncture range, and the puncture path, puncture angle, puncture safe depth interval (and the length between the deepest and shallowest puncture) were emphatically determined. after determining the puncture point, the anesthesiologist adjusted the patient's breathing to the end of expiration, in order to raise the pleura and lower lung lobe to the highest level, and avoid injury to pleura and lung, and help reduce the influence of respiratory activity on the position of the kidney. the assistant then penetrated the puncture needle slowly into the puncture frame, observing the path of the puncture needle. after the tip of the puncture needle entered the target cup, the inner core of the puncture needle was removed, and the scrub nurse injected methylene blue. when the blue urine overflowed from the puncture needle, the urinary guide wire was inserted, and the puncture frame and ultrasonic probe were removed, and the patient was allowed to resume breathing. the remaining steps included expanding the puncture site to f18~f22 by fascial dilatation, and establishing percutaneous nephroscope channels routinely, then a holmium laser or ultrasonic lithotripsy was used. ureteral stent and renal fistula were placed after the operation. (figure 2) surgical technique techniques and precautions for the establishment of percutaneous nephroscope channels included: (1) ct films were read before surgery to preliminarily determine the target calyces, puncture range, puncture route, puncture depth, and puncture angle, so as to facilitate comparison with those before puncture;(2) preoperative ultrasound localization was performed again, and the puncture location was determined again in combination with preoperative estimated puncture parameters. for the target of the shallower water can be marked "+" on the patient's body surface.(3) the puncture frame was fixed on the ultrasonic probe, the distance from the puncture frame for pcnl sono guided access-he et al. variable gender (m/f) 62/44 age (years), mean±sd 45 ± 7 bmi(kg/cm2), mean±sd 23.1 ± 2.5 side of kidney stone (r/l) 56/50 stone surface area (mm2), mean±sd 637 ± 169 table 1. patients’ charchteristics. parameters duration of establising channel (s), mean±sd 35 ± 18 access, n, mean±sd 1.3 ± 0.8 operation time (min), mean±sd 67 ± 39 upper/ middle/ lower pole 78,20,8 upper and lower 12th rib 81,25 intraoperative blood loss (ml), mean±sd 48 ± 22 hounsefiled units(hu), mean±sd 659 ± 315 table 2. operations' characteristics. figure 1. ultrasonic probe and matching puncture frame. vol 17 no 04 july-august 2020 359 skin to the target calyces was measured again and kept stable, and the puncture needle was slowly inserted by the assistant at the "distance plus 4cm" (the distance from the proximal end of the puncture frame to the skin was 4cm). after the needle tip entered the target renal calyces, the inner core was removed and the urinary guidewire was inserted sequentially.(4) during the puncture, the patient's breathing was adjusted to stop at the end of expiration, which was particularly important for the puncture of the upper calyx; (5). methylene blue was routinely used as an indicator; (6) in the process of fascia dilation, the two-step dilation method was mainly adopted. after the depth is determined by 8f, the channel is directly expanded to 18f~22f, however, the one-step expansion method was performed for mild hydrocephalus target calyx, to prevent the displacement of the urinary guide wire and even channel loss in the repeated expansion process. outcome assessment the observation indicators of the research mainly include puncture time and frequency, intraoperative blood loss, puncture site, intraoperative and postoperative complications. data were entered into excel ver. 2017 software. the puncture time is defined as the time when the tip of the puncture needle penetrates the skin until the inner core of the puncture needle flows out from the needle sheath or the syringe draws out bluedyed urine. if the puncture fails or the location is not ideal, the time is up to the puncture satisfaction. the number of punctures is defined as the number of puncture needle penetrating the skin, and the adjustment of puncture depth is not included in the number of punctures. calculation method of intraoperative blood loss: blood loss (ml)= total intraoperative perfusion fluid (ml)* hemoglobin concentration of lavage fluid (g/l)/ preoperative hemoglobin concentration (g/l)(5). results in this study, there were 62 (58.5%) male patients and 44 (41.5%) female patients, aged from 21 to 73 years old, with an average age of (45.3 ± 6.7) years old. the course of disease lasted from 2 weeks to 10 years. the bmis of patients were 19~27 (23.1 ± 2.5). the stones were located in the left side of 50 (47.2%) cases and the right side in 56 (52.8%) cases. other detailed information could be found in table 1. all patients successfully completed the operation and all procedures were performed with a single-channel surgery. 21 (19.8%) patients were treated with 22f channel and 85 (81.2%) patients were treated with 18f channel. the puncture time was 35 ± 18 seconds, the average number of punctures was 1.3 ± 0.9. there were 73 (68.9%) successful cases of single puncture, and the operative time was 67 ± 39 minutes. the operative blood loss was 48 ± 22 ml. the channels were established through the upper, middle and lower calyces of the kidney in 78 (73.6%), 20 (18.9%), and 8 (7.5%) cases, respectively. the puncture sites were located on the upper and lower 12th rib in 81 (76.4%) and 25 (23.6%) cases, respectively (table 2). intraoperative and postoperative blood transfusion was given in four cases, pleural injuries occurred in two patients, and hydropneumothorax occurred in one case and closed thoracic drainage was performed. the stone removal rate after a single surgery was 87.7% (93/106) (table 3). patients were advised to rest in bed for 3 days after the operation, and kub was reexamined 5-7 days postoperatively to determine the removal of calculi. in general, renal fistula and urethral catheter were extracted 6-8 days after the surgery, and ureteral stent tube was removed 1-2 months post-operation. none of the patients in this study required phase ii pcnl surgery. for the patients with residual stones, extracorporeal shock wave lithotripsy was performed after returning to the hospital about one month after the surgery. after one week of follow-up and reexamination, stones were removed after treatment (defined as residual stones with a diameter of less than 0.4cm). the follow-up period was 3-9 months. the patients were in stable condition endourology and stones diseases 360 clavien classification complications cases grade ⅰ residual stones 13 (12.3%) grade ⅱ blood transfusion 4 (3.8%) sepsis 0 perirenal hematuria 0 grade ⅲ-a hemopneumothrax 2 (1.9%) intervention embolization 0 grade ⅳ-a abdominal organs injury 0 table 3. complications of operations. figure 2. patient a, image pre-operation.(2a, 2b,) ct, arrows point to the posterior colon; (2c) kub; post-surgery (2d) kub. puncture frame for pcnl sono guided access-he et al. and did not complain of special discomfort. discussion percutaneous nephrolithotomy is still an important method for the treatment of renal calculi larger than 2 cm and upper ureteral obstructive calculi, especially suitable for the treatment of complex kidney stones such as cast stones, multiple stones in the kidney and recurrent kidney stones. at present, with the continuous progress of technology and update of ideas, treatment methods such as micro-channel and ultramicro-channel percutaneous nephroscopy, visual puncture technology, flexible ureteroscopy, and multi-lens combination have gradually emerged (5-8). however, for most hospitals, it is still particularly important to master the conventional percutaneous nephroscope technology. the key to this technology is the selection and establishment of surgical channels, and the key point of establishing channels is the mastery of puncture technique (9). puncture technique guided by x-ray fluoroscopy, as an important method, is still widely used at present, but cumulative x-ray exposure is harmful to medical personnel. furthermore, due to the unsatisfactory display of important adjacent organs of the human body, such as liver, spleen, intestine, pleura and lung lobe under fluoroscopy, the difficulty and risk of puncture are increased. a real-time ultrasound-guided puncture technique can be used instead allowing synchronous and multi-dimensional dynamic observation (10-12). however, with this technique the optimal target of puncture may be missed, leading to increased blood loss and reduced stone free rate(13). through observation and statistics, we observed and calculated that the use of puncture frame to fix the puncture needle for operation can effectively improve the puncture accuracy, quantify each step in the puncture process, and try to achieve precise puncture, improve the efficiency and effect of the operation, and reduce the incidence of surgical complications. meanwhile, puncture angle, depth, and other indicators can be quantified by fixing a puncture frame, which is easy to learn and master and reduce the difficulty of learning. during the puncture process, the puncture needle is fixed by the frame, which can effectively avoid the deviation of the puncture needle. the needle can be accurately inserted according to the predetermined puncture line of the ultrasonic probe, and the endoscopic puncture of the patient can be temporarily determined, thereby reducing the respiratory activity to the position of the kidney. the effect can also reduce damage to surrounding organs, especially the pleura or lower lobe of the lung. in addition, the ultrasonic probe matched with the puncture frame is generally a small probe, so that the contact area with the patient's body surface is small, the position of the puncture point is adjusted, and the needle insertion on the twelfth rib is more convenient and accurate. through rational design and successful establishment of percutaneous renal access, the single-surgery rate of stone removal reached 87.7% (93/106), and in terms of complications, there were four cases of intraoperative and postoperative blood transfusion, including one case of postoperative cervical cancer with mild-moderate anemia. one patient had multiple renal stones that recurred on the same side. two patients had secondary bleeding due to postoperative pain. none of the above patients underwent renal artery embolization but were improved by blood transfusion, hemostasis, and conservative treatment. pleural injury occurred in two cases: a case of hydropneumothorax underwent closed thoracic drainage, and the other patient recovered by conservative treatment. there were no serious cases of vascular embolism, renal perforation, intestinal injury, septic shock and death, and the overall effect was satisfactory. the main concerns of percutaneous nephrolithotomy include bleeding, infection, and stone clearing rate, and these are closely related to each other. in general, intraoperative bleeding is obvious, the visual field is not good, the irrigation pressure and flushing volume increase correspondingly, and the sinus opening is increased. the bacteria and lavage fluid enter the blood in a short period of time, increasing the risk of serious infection and internal environment disorder. the stone clearing rate is also affected accordingly, so that the second phase, or even multiple stages of surgery, is needed. the key point of the operation lies in the rational selection of the target and the successful establishment of the surgical channel. firstly, the selection of the target calyx needs to take into account the safety and practicability of the establishment of the surgical channel. before the operation, careful reading of angiogram or ct films should be carried out to select the optimal target calyces and cutaneous and renal channels based on the individual differences of patients and the location of calculi and hydronephrosis, so as to reduce the risk of bleeding and peripheral organ injury and improve the stone removal rate(14). however, due to intraoperative changes in vitro and different respiratory activities, corresponding adjustments should be made in time(15). and as the effect of gravity, the stones are generally in the low position, and irrigation is in the high position(16). therefore, in this study, the puncture sputum generally selects the upper part of the upper pole of the kidney with a higher position as the target renal pelvis (98/106). the water is located on the ventral side, so there is no need to deliberately pursue the accumulation of water. the successful establishment of the skin to the target calyx is the key to the surgical process. in combination with the surgical techniques described above, and due to the intraoperative positioning of the ultrasound probe to reduce the skin to the renal pelvis distance, the needle should be as uniform as possible during the needle insertion process, observe the needle tip and needle position change, to ensure that the needle depth lies within security depths(17). the puncture needle fixed by the puncture frame can effectively avoid the angle change caused by human operation and so on, and can make the puncture needle enter the renal pelvis through the vault lamp neck into calyx according to the estimated route (18), which can effectively reduce the renal column and the neck injury leading to bleeding, and it is convenient to place the urinary guide wire into the direction of the renal pelvis, even into the ureteral cavity, and at the same time, it can improve the safety of the fascia expansion, as well as the scope and efficiency of the clear stone(19). for the target renal hydronephrosis is light or filled with stones, the highest point of the curved back of the stone can be used as the puncture needle target, and the puncture accuracy and success rate can be improved by quantifying the depth(20). it can even be used to treat urolithiasis in pregnancy(21). puncture frame for pcnl sono guided access-he et al. vol 17 no 04 july-august 2020 361 conclusions in conclusion, the main function of the puncture frame is to establish an ideal operating channel by restricting the movement of the puncture needle, which can not only improve the surgical effect but also significantly reduce the occurrence of serious complications. acknowledgement the authors would like to thank the people’s hospital of leshan for help and support. conflict of interest the authors report no conflict of interest. references 1. karamcheti a, o'donnell wf. percutaneous nephrolithotomy: an innovative extraction technique. j urol, 1977 ; 118 : 671-2. 2. thomas chi, selma masic, jianxing li, et al. ultrasound guidance for renal tract acccess and dilation reduces radiation exposure during percutaneous nephrolithotomy. adv in urol, 2016;2016:1-8. 3. fang yq, wu jy, li tc,et al. computer tomography urography assisted realtime ultrasound-guided percutaneous nephrolithotomy on renal calculus. medicine(baltimore). 2017;96(24):1-7. 4. na yanqun, ye zhangqun, sun yinghao, et al. guidelines for the diagnosis and treatment of urological diseases in china 2014. beijing: people's medical publishing house, 2014: 169170. 5. xiao longming, yang qiaozhi, chen jianfa, et al. comparison of standard channels for percutaneous nephrolithotomy with balloon and fascia dilatation [j/cd]. chinese journal of endoscopy and urology: electronic edition, 2016, 10(4): 255 -258. 6. dong chuanjiang, xie zonglan, zhang lusheng, et al. comparison of the efficacy of soft ureteroscopy and percutaneous nephrolithotomy in the treatment of renal calculi with a diameter of ≥ 2 cm . journal of minimally invasive urology, 2016, 5(4): 196198. 7. hongshi xu, anna l zisman, fredric l coe, et al. kidney stones: an update on current pharmacological management and future directions. expert opin pharmacother, 2013, 14 (4), 435-447. 8. chau hl, chan hc, li tb, et al. an innovative free-hand puncture technique to reduce radiation in percutaneous nephrolithotomy using ultrasound with navigation system under magnetic field: a single-center experience in hong kong. j endourol. 2016, 30(2): 160-4. 9. jian li, jisheng lin, junchuan xu, et al. a novel approach for percutaneous vertebroplasty based on preoperative computed tomographybased three-dimensional model design. world neurosurg. 2017; 105: 20-26. 10. zheng jianzhong, liang fulu, fan xianming, et al. comparison of multi-channel percutaneous nephrolithotomy and singlechannel percutaneous nephrolithotomy combined with ureteroscopy for the treatment of complex renal calculi[j]. journal of modern urology, 2016, 21(8): 593-596. 11. foo cheong ng, wai loon yam, tze ying benjamin lim, et al. ultrasound-guided percutaneous nephrolithotomy: advantages and limitations. investig clin urol , 2017; 58: 346-352. 12. 10. zhao huacai, jia li, chen yuangang, et al. application of ultrasound localization in percutaneous nephrolithotomy. hainan medical journal, 2016, 27(6): 987-990. 13. long qingzhi, li xiang, he dalin, et al. complications and management of 1584 patients with renal and ureteral calculi treated with percutaneous nephrolithotomy. journal of modern urology, 2016, 21(7): 516-519 . 14. chan cj, srougi v, tanno fy, et al. percutaneous puncture of renal calyxes guided by a novel device coupled with ultrasound. int braz j urol. 2015, 41(5): 953-8. 15. li j, xiao b, hu w, et al. complication and safety of ultrasound guided percutaneous nephrolithotomy in 8,025 cases in china.chin med j (engl). 2014;127(24):4184-9. 16. patel sr, nakada sy. the modern history and evolution of percutaneous nephrolithotomy. j endourol. 2015;29(2):153-7. 17. liu qm, zhan xs, wang yl, et al. the application of two point positioning puncture technique in percutaneous nephrolithotomy. chin j min inv surg, 2013;13:470-1. 18. yu weimin, cao jun, zhai yuan, et al. ultrasound-guided ”percutaneous renal pelvic-neck-two-step puncture method” to establish percutaneous renal channels [j/cd]. chinese journal of endoscopy and urology: electronic edition, 2016 , 10(3): 148-152. 19. amirhassani s, mousavi-bahar sh, iloon kashkouli a, et al. comparison of the safety and eficacy of one-shot and telescopic metal dilatation in percutaneous nephrolithotomy: a randomized controlled trial. urolithiasis, 2014;42:269-73. 20. liu qm, zhan xs, wang yl, et al. the application of two point positioning puncture technique in percutaneous nephrolithotomy. chin j min inv surg, 2013;13:470-1. 21. basiri a, nouralizadeh a, kashi ah, et al. x-ray free minimally invasive surgery for urolithiasis in pregnancy. j urol. 2016;13(1):2496-501. endourology and stones diseases 362 puncture frame for pcnl sono guided access-he et al. uj 35 summer.pdf 541vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l purpose: to determine the role of glutathione s-transferases (gsts; gstm1, gstt1, and gstp1) gene polymorphisms in susceptibility to male factor infertility. materials and methods: we report a pooled analysis of 11 studies on the association of gstm1, gstt1, and gstp1 polymorphisms and male factor infertility, including 1323 cases and 1054 controls. results: p = .003], gstt1 null genotype p p = .26). conclusion: these results demonstrated that amongst populations studied to date, gstm1 and keywords: glutathione s-transferase, single-nucleotide polymorphisms, infertility, male, genetic, 1clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran 2department of urology, shahid modarres hospital, shahid beheshti university of medical sciences, tehran, iran 3department of health and community medicine, shahid beheshti university of medical sciences, tehran, iran mohammad reza safarinejad,1 farid dadkhah,2 majid ali asgari,2 seyed yousef hosseini,2 ali asgar kolahi,3 elham iran-pour1 review glutathione s–transferase polymorphisms (gstm1, gstt1, gstp1) and male factor infertility risk a pooled analysis of studies corresponding author: mohammad reza safarinejad, md p.o. box 19395-1849, tehran, iran tel: +98 21 2245 4499 fax: +98 21 2245 6845 e-mail: info@safarinejad. com received july 2012 accepted july 2012 542 | review introduction wfrom primary or secondary infertility.(1) the cause of infertility is still not determined in infertility.(2) (3) plicated.(4) number of male infertility is due to gene mutations and single-nucleotide polymorphisms (snp). an increasing number of studies are determining the as(9-12) implication. by determining the underlying genetic basis ity and genetic polymorphisms of gst genes. gene and gene function a superfamily of multifunctional enzymes that detoxify products of oxidative stress, environmental substances, and reactive electrophiles.(13,14) glutathione s-transferases also inactivate carcinogens by catalyzing the conjugation of electrophiles to glutathione.(15) dna damage due to endogenously formed lipid peroxidase can be prevented by gsts.(16) gst isoenzymes have been assigned to eight separate classes, including (alpha), μ (mu), (omega), (pi), (sigma), (theta), and encoded by the gsta, gstm, gstk, gsto, gstp, gsts, gstt, and gstz genes, respectively. dition, each class includes several genes and isoenzymes. (19) polymorphisms have been reported in the gstm1, gstt1, and gstp1 genes coding for gsts enzymes in the mu, theta, and pi classes, respectively. on chromosome 1p13.3.(20) gstm1 has a common functional variant (null versus present). the frequency of this ulation studied.(21) of the gstm1 locus have no enzymatic functional activity of the cytosolic enzyme gst-μ.(22) the homozygous dele(23-25) the human theta class of gsts (gstt) is comprised of cated on chromosome 22q11.(26) the polymorphism in the gstt1 gene loci is also caused by a gene deletion and brings about in virtual absence of enzyme activity in per(27) both gstt1 null genotype(23,24) and nondeletion genotype of the gstt1 gene has also been reported. (29) gene. a single-nucleotide polymorphism at position 313 in (30) the resulting isoleucine to valine substitution in codon 105 of 105 105 activity.(31) another snp at codon 114 leads to alanine ference in catalytic activity.(32) (23) but in a study (33) gst and male infertility risk excessive reactive oxygen species (ros) have been suggested to be one of the major contributory factors resulting in male infertility via oxidative dna damages.(34) glutathione s-transferase is one of the human defense mechanisms opposing the deleterious effects of oxidative stress. (35) glutathione s-transferases gene polymorphisms could impair the capability of defense against oxidative stress and result in the development of some cancers.(36) one of the determinant factors of susceptibility of spermatozoa to oxidative damage is gstm1 polymorphism.(25) dna fragmentation in human sperm can be modulated by gstm1 gene polymorphism.(37) objective there have been various studies in the literature regarding the association of gst (m1, t1, and p1) polymorphisms (table 1). there is sig543vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l gst polymorphisms and male factor infertility | safarinejad et al to determine the overall effect of gst (m1, t1, and p1) materials and methods data collection ciation of gst polymorphisms (gstm1, gstt1, and the search terms of “gst or glutathione s-transferase and polymorphism or polymorphisms and variant or variants and infertility or infertile and male”, yielding 11 results. statistical analysis using unconditional logistic regression model, including p ed using ors from the individual included studies. to asresults the results of the pooled analysis are summarized in tap = .003), gstt1 null genotype (or, p = .02), and male infertable 1. summary of published studies on the association between gstm1, gstt1, and gstp1 polymorphisms and male infertility. first author (ref no.) publication year cases controls country ethnicity studied gene(s) tang (33) 2012 65 30 china asian gstm1, gstt1, gstp1 safarinejad(23) 2010 166 166 iran asian gstm1, gstt1, gstp1 tirumala(40) 2010 42 43 india asian gstm1 polonikov(28) 2010 203 227 russia caucasian gstm1, gstt1 ichioka(41) 2009 274 101 japan asian gstm1, gstt1 wu(42) 2009 63 54 china asian gstt1 finotti(24) 2009 128 105 brazil caucasian gstm1, gstt1 aydos(38) 2009 110 105 turkey caucasian gstm1 wu(43) 2008 78 103 china asian gstt1 aydemir(25) 2007 52 60 turkey caucasian gstm1 chen(39) 2002 142 60 china asian gstm1 544 | review p = .007) and gstt1 null genotype (p = .02). no evidence of p = .62) nor for the gstm1 genotype (p = .24). on the other hand, gstp1 polymorphism had overall protective effect against development of male infertility, p p gstp1 (p p = .12). the sensitivity analysis demonstrated that exclusion of (33) sociates(41) from the analysis decreased the evidence of heterogeneity (gstm1: p = .02; gstt1: p = .04; and gstp1: p = 1.0). after performing sensitivity analysis, null genotype (p p = null genotype (p = .04). p = trend p table 2. association between gstm1 and male infertility in the pooled analysis. genotype adjusted odds ratio* trend p overall .003 present 1.00 (ref ) null 2.47 (1.72 to 3.84) never smoker .004 present 1.00 (ref ) null 2.21 (1.52 to 3.57) ever smoker .002 present 1.00 (ref ) null 2.88 (1.91 to 4.16) infertility .002 present 1.00 (ref ) null 2.71 (1.84 to 3.92) *odds ratios are adjusted for study, age, race, and smoking history. table 3. association between gstt1 and male infertility in the pooled analysis. genotype adjusted odds ratio* trend p overall .02 present 1.00 (ref ) null 1.54 (1.43 to 3.47) never smoker .03 present 1.00 (ref ) null 1.36 (1.57 to 3.12) ever smoker .01 present 1.00 (ref ) null 1.72 (1.63 to 3.74) infertility .01 present 1.00 (ref ) null 1.68 (1.57 to 3.69) *odds ratios are adjusted for study, age, race, and smoking history. 545vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l to 3.12; trend p 3.74; trend p types in both the analysis restricted to the homogeneous studies and in the full-pooled analysis. discussion this pooled analysis, containing 1054 controls and 1323 cases from 11 studies, demonstrates an overall association and gstm1 and gstt1 null genotypes. the direction of the interaction is the same to the expected effect. strength of our pooled analysis is that the collection of has advantages over meta-analysis.(44) meta-analysis al(45) (46) and being (47) asian populations(23,33,39-43) table 4. association between gstp1 and male infertility in the pooled analysis. genotype adjusted odds ratio* trend p overall .002 ile/ile 1.00 (ref ) ile/val 0.48 (0.27 to 0.77) val/val 1.81 (0.34 to 7.85) ile/val or val/val 0.52 (0.31 to 0.81) never smoker .03 ile/ile 1.00 (ref ) ile/val 0.52 (0.33 to 0.80) val/val 1.84 (0.37 to 7.42) ile/val or val/val 0.58 (0.38 to 0.87) ever smoker .01 ile/ile 1.00 (ref ) ile/val 0.50 (0.31 to 0.79) val/val 1.82 (0.35 to 37.66) ile/val or val/val 0.54 (0.34 to 0.84) infertility .01 ile/ile 1.00 (ref ) ile/val 0.54 (0.37 to 0.81) val/val 1.80 (0.41 to 7.12) ile/val or val/val 0.57 (0.36 to 0.86) * odds ratios are adjusted for study, age, race, and smoking history. gst polymorphisms and male factor infertility | safarinejad et al 546 | gstp1 polymorphisms and male infertility in ethnicities genotypes and male infertility. conclusion and gstp1 polymorphisms and male factor infertility, and conflict of interest none declared. review references 1. world health organization. in: vayena e, rowe pj, griffin pd, eds. 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71urology journal vol 4 no 2 spring 2007 human amniotic membrane as a suitable matrix for growth of mouse urothelial cells in comparison with human peritoneal and omentum membranes farzaneh sharifiaghdas,1 nahid hamzehiesfahani,1 reza moghadasali,1,2 fatemeh ghaemimanesh,1 hossein baharvand2 introduction: for tissue engineering of the urinary tract system, cell culture requires to be established in vitro and an appropriate matrix acting as cell carrier should be developed. the aim of the present study was to assess the proliferation quality of mouse urothelial cells on 3 natural matrixes of human amniotic membrane (am), peritoneum, and omentum, and to compare them with collagen matrix. materials and methods: mouse urothelial cells were isolated by collagenase iv, and the urothelial cells (105 cells per milliliter) were cultured on the am, peritoneum, omentum, and collagen. the pattern of growth and asymmetric unit membrane formation were analyzed by histologic examination and immunocytochemistry on the detached urothelium with pancytokeratin and uroplakin iii, respectively. electron micrographs were taken and cell layers, organelles, desmosomes, and junctions were studied. results: immunocytochemistry of cultivated cells confirmed the urothelial cells phenotype. up to 4 cell layers were obtained on the am and 1 to 2 layers on the peritoneum. distribution of the urothelial cells on the omentum was not favorable, which was due to its large pores. cell proliferation started later on the am (7th day) compared to collagen (3rd day). also, apoptosis started later on the am (after 14 days) compared to collagen (7 days). conclusion: these results showed that the am can act as a cell carrier for culture of the urothelial cells, and its exceptional properties such as having various growth factors, availability, and cost-effectiveness make it a unique biological matrix for urothelial culture. urol j. 2007;4:71-8. www.uj.unrc.ir keywords: urothelial cells, amniotic membrane, peritoneum, omentum, mouse, bladder, animal model 1urology and nephrology research center & department of urology, shaheed labbafinejad medical center, shaheed beheshti medical university, tehran, iran 2department of stem cells, royan institute, tehran, iran corresponding authors: farzaneh sharifiaghdas, md departement of urology, shaheed labbafinejad medical center, pasdaran, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: fsharifi@yahoo.com hossein baharvand, md department of stem cells, royan institute, po box: 19345-4644, tehran, iran tel: +98 21 2217 2330 fax: +98 21 2241 4532 e-mail: baharvand50@yahoo.com received april 2007 accepted june 2007 introduction surgical repair of several congenital and acquired abnormalities of the urinary tract, such as strictures, traumatic defects, and hypospadias, requires additional tissue for reconstruction.(1) traditionally, the intestinal segment has been used for bladder augmentation or substitution of bladders with abnormalities. however, its benefits are offset by relatively common complications that are potentially serious, including mucus production, calculus formation, metabolic disturbances, and infection.(1,2) numerous synthetic materials have been investigated for reconstruction of functionally deficient bladder.(1,2) furthermore, culture of animal urothelial cells provides useful material, especially when human tissue is not available.(1-8) in the recent years, collagen has been shown to promote in vitro amniotic membrane for growth of urothelial cells—sharifiaghdas et al 72 urology journal vol 4 no 2 spring 2007 growth and stratification of the urothelial cell and has been used to repair urinary tract defects.(1-5) few investigations attempted to use the omentum in urothelial engineering,(6,7) and the peritoneum has also been used for seeding of the urothelial cells by some researchers.(8) reports on using the amniotic membrane (am) as a matrix for culturing of the oral, ophthalmic, and skin cells have been encouraging, and the specific characteristic of the am such as having various growth factors, availability, and cost-effectiveness can make it a valuable biological matrix.(8-12) however, to our knowledge, there is no documented study comparing these biological matrixes, to date. the aim of the present study was to evaluate of the quantity and quality of mouse urothelial cells cultured on the human omentum, peritoneum, and am matrixes, and to compare them with the previously known material that is collagen. materials and methods mouse urothelial cell cultures all animal procedures were carried out in accordance with the institute of laboratory animal research guide for the care and use of laboratory animals.(13) congenic nmri mouse was used and the study was approved by the ethics committees of royan institute and the urology and nephrology research center. mouse bladder was obtained from the dissected animals. the bladder tissue was frequently rinsed with phosphate-buffered saline (pbs). then, the apical two-thirds of the mouse bladder was harvested, cut in half, and immersed, and the epithelial layer was peeled. in the first step, the epithelial cells were isolated from fibroblast cells by a collagenase solution (collagenase type iv, 443 u/ml [gibco-invitrogen, grand island, ny, usa]) in a humidified, 37°c, 95% air/5% carbon dioxide environment within 1 hour. in the next step, the epithelial layer was digested by the use of trypsin/ethylenediamine tetraacetic acid to obtain split epithelial cells in a humidified environment, the same as in the previous process, within 20 minutes. the obtained cell suspension was plated on a tissue culture plate of bovine dermal collagen (vitrogen, cohesion, palo alto, ca, usa), serving as control, and on acellularized the am, peritoneum, and omentum (test groups) at a concentration of approximately 105 cells per milliliter with dulbecco>s modified eagle medium:nutrient mix f-12 medium (gibco-invitrogen, grand island, ny, usa), containing n 2 , 15% fetal bovine serum, hydrocortisone, l-glutamin, and β-mercaptoethanol, and incubated at 37°c and 5% co 2 . acellular membranes the isolated human membranes including amniotic, peritoneum, and omentum membranes were obtained from the patients who underwent operation in shaheed labbafinejad medical center and atiyeh hospital. they were thoroughly washed and placed in phosphate-buffered saline containing penicillin/ streptomycin (gibco-invitrogen, grand island, ny, usa), and ofloxacin (o-8757, sigma-aldrich, st louis, mo, usa). then, to obtain an acellularized membrane, the epithelial cells were isolated from the membranes by trypsinization histology and immunocytochemistry for immunostaining, the urothelial cells were washed twice with pbs and fixed with 4% paraformaldehyde for 24 hours at 4ºc. these cells were permeabilized and blocked in pbs containing 0.2% triton x-100 (sigma-aldrich, st louis, mo, usa) and 10% goat serum for 10 minutes and 30 minutes, respectively. thereafter, the urothelial cells were incubated in primary antibody diluted in 0.5% bovine serum albumin (bsa) at 37ºc for 1 hour. the antibodies used in this study were pancytokeratin (mab1636, chemicon, hofheim, germany) and uroplakin iii (m-17, santa cruz biotechnology, santa cruz, ca, usa). at the end of the incubation time, the cells were washed twice with pbs + 0.05% tween 20 and incubated with the fluorescence isothiocyanateconjugated antimouse igg (f9006, sigma-aldrich, st louis, mo, usa) diluted in 0.5% bsa for 60 minutes at 37ºc. after washing twice with pbs + 0.05% tween 20, the specimens were examined under fluorescence microscope (bx51, olympus, japan) (figure 1). also, for histologic examination, the membranes containing urothelial cells were removed from the medium, washed twice with pbs, and fixed with 4% paraformaldehyde for 24 hours at 4ºc. the samples were then dehydrated in 70% ethanol for 24 hours and embedded in paraffin in a rotary tissue processor. the paraffin-embedded specimens were amniotic membrane for growth of urothelial cells—sharifiaghdas et al urology journal vol 4 no 2 spring 2007 73 sectioned perpendicular to the culture surface at 5-μm thickness. the sections were attached to poly l-lysine-coated glass slides and placed at 60ºc in an oven for 12 hours, dewaxed in xylene, and stained with hematoxylin-eosin. transmission electron microscopy for transmission electron microscopy (tem), the specimens were fixed using 2.5% glutaraldehyde in 0.1 m pbs (ph, 7.4) for 2 hours. after washing with pbs, they were postfixed with 1% osmium tetroxide for 1.5 hour, again washed in pbs, dehydrated in an acetone series, and then embedded in epoxy resin. after resin polymerization, sections of approximately 50 nm were cut and double-stained with uranyl acetate and lead citrate. electron micrographs were taken using a zeiss em 900 transmission electron microscope (carl zeiss, oberkochen, germany). figure 1. morphological examination and immunocytological staining with pancytokeratin and uroplakin iii of the asymmetric unit membrane antibodies were used to confirm urothelial cells phenotype. a, b, and c. pancytokeratin on collagen. d, e, and f. uroplakin iii on collagen with triton. g, h, and i. uroplakin iii on collagen without triton. j, k, and l. uroplakin iii on the amniotic membrane. amniotic membrane for growth of urothelial cells—sharifiaghdas et al 74 urology journal vol 4 no 2 spring 2007 results primary culture of mouse urothelial cells on human am, peritoneum, omentum, and collagen were routinely expanded and passaged (figure 2). there was no incidence of cessation of growth or abnormal changes in morphology. the cells were in culture for about 3 weeks and we followed the growth pattern of cells daily. morphological examination and immunocytological staining with pancytokeratin (a urothelial cell marker) and uroplakin iii of the asymmetric unit membrane (indicating cell differentiation) antibodies were used to confirm urothelial cells phenotype (figure 1). histologic examination revealed a multilayered polarized urothelial sheet structure on the am and 2-layer cells sheet on the peritoneum. but, studies on the omentum confirmed that it has an inappropriate 3-dimentional structure for urothelial cell engineering. hence, we decided to stop more investigation on the omentum followed by tem (figures 2 and 3a). light and immunocytochemistry staining analysis basically the urothelial cells on the peritoneum had a small round and cuboidal structure. after 3 days, the urothelium appeared well found on the collagen matrix with big flat cells and large nuclei, but on the am, the cells had a small round shape with unremarkable nucleus, and we found small cuboidal cells with round nucleus on the peritoneum (figure 1). collagen. growth, colonization, and cell morphology during the first 3 days was superior on the collagen matrix to the am and the peritoneum matrixes. cell migration was remarkable on the collagen during the first week and it was more significant than the on the 2 other matrixes (figure 3b). on the 7th day, the urothelial cells started the process of vacuolization and apoptosis on the collagen matrix, and within the second week, apoptosis was dominant (figure 4). amniotic membrane. in the first week, cell growth on he am was not significant, but on the following figure 2. light microscopy of the urothelial cells on the matrixes (hematoxylin-eosin). left. urothelial cells constituted a dense layer on the amniotic membrane. middle. a dense layer of cells was not formed on the peritoneum. right. cells on the omentum could not form a distinct layer. figure 3. primary culture of mouse urothelial cells. a, omentum. b, collagen. c, amniotic membrane. d, peritoneum. amniotic membrane for growth of urothelial cells—sharifiaghdas et al urology journal vol 4 no 2 spring 2007 75 days (until day 14), cell colonization and morphology on the am became better than those on the peritoneum and collagen. furthermore, after 2 weeks, confluent primary urothelial cells were established on the am (figure 3c). fourteen days after culturing, the urothelial cell proliferated actively and reached their peak on the am. cell apoptosis occurred on the am, since day 15, and it gradually improved within the days 16 and 18 (figure 4). peritoneum. growth and colonization of the cells started on the 7th day. in other words, cell growth pattern, in concert with the am vacuolization, began on the peritoneum within the second week and was completed by the end of the 14th day. cell growth pattern on the omentum was the same as it was on the peritoneum matrix, but as we mentioned before, due to its big pores and high density of fat cells, we could not obtain an intact sheet cell layer (on light microscopy), so we excluded it from the rest of the study (figure 3d). transmission electron microscopy given the poor 3-dimentional condition, we omitted the omentum from the tem studies. surprisingly, the urothelial cells on the am had 3 to 4 layers and the cells were well stratified. the urothelial cells in the basal layer showed various shapes including cuboidal and flat type, but they mostly had remarkable nuclei with all normal cytoplasm organelles. the urothelial cells were tightly attached to each other with desmosomes and microvilli. the cells at the basal layer were tightly adhered to the underlying basement membrane by hemidesmosomes (figure 5). we found desmosomes and junctions among the cells on the peritoneum. also, cell organelles were the same as those of the natural urothelial cell. furthermore, it seemed that the pattern of cell adhesion and attachment to the underlying peritoneum was weak (figure 6). discussion to the present time, acellular collagen matrix derived from donor bladder submucosa has been successfully used both experimentally and clinically for bladder and urothelial replacement in many centers.(1-4) collagen has been described as a useful matrix due to figure 4. left, vacuoles on collagen i on the 7th day. right, vacuoles on the amniotic membrane on the 14th day. amniotic membrane for growth of urothelial cells—sharifiaghdas et al 76 urology journal vol 4 no 2 spring 2007 its proper characteristics and ease of processing.(1-3) nevertheless, it is an expensive matrix, encouraging researchers to look for a cost-benefit medium with the same or even better qualities. collagen sponges support the growth and stratification of the urothelial cells, forming 4 to 8 layers.(5) sabbagh and colleagues reported that cell proliferation was maximum at days 5 to 10, and collagen sponge remained easy to handle after 3 weeks in culture. on the 15th day, the growth rate reached a plateau.(5) in our study, cell growth was remarkable at the 3rd day. cells were flat and big, and finally vacuolization was started at the end of the first week which was more significant by the 14th day. according to our study; the omentum had an inappropriate 3-dimentional structure due to its big pores; thus, it can hardly be used for direct culture of cells. in 2006, atala and colleagues used the peritoneum for seeding of rat urothelial cell and the cultured cells had the same quality as the natural urothelium did.(7) comparing with collagen, we had poor cell growth and colonization on the peritoneum within the first 3 days, but on the following days, we obtained better results. cell apoptosis occurred with delay in the second week; meanwhile, desmosome junctions between the cells did not have features of the normal urothelium, and we just observed up to 2 cell layers in our primary culture which is not desirable. cultured cells on the am enjoyed the features of the normal urothelium. these cells kept growing figure 5. four urothelial cell layers are seen in the culture on the amniotic membrane by transmission electron microscopy. m, indicates mitochondrion; c, cytokeratin; rer, rough endoplasmic reticulum; j, junction; n, nucleus; am, amniotic membrane; mv, microvillus; hd, hemidesmosome; v, vacuole; ly, lysosome; co, collagen; mlb, multilaminar body; and d, desmosome. amniotic membrane for growth of urothelial cells—sharifiaghdas et al urology journal vol 4 no 2 spring 2007 77 and colonization until the 2nd week which gave us a better chance to preserve it for a longer period of time. desmosome junction among cells and hemidesmosomes in the basal layer shared features of the normal urothelial. this finding encourages us to use it for urothelial reconstruction. although there are a few clinical trials on oral, ocular, and skin reconstruction using the am, this study is pioneering in urology. the am contains various growth factors and is easy to obtain in large amounts, making it highly accessible and valuable as a biological matrix. in addition, it is a very cost-effective material.(8) in our study, the toughness of the am was well preserved through out the culture. therefore, it was easy to transfer and secure the cultured urothelial cells. we used a freeze-dried am to cover the urothelial layer. figure 6. urothelial cells are seen in the culture on the peritoneum by transmission electron microscopy. l, indicates lipid; p, peritoneum; rer, rough endoplasmic reticulum; m, mitochondrion; n, nucleus; v, vaculole; j, junction; np, nuclear pore; and up, uroplakin. in this study, the cultured urothelial cells survived for 2 weeks, and development of 3 to 4 cell layers gave us a feature like the natural urothelium. we suggest that comparison with the peritoneum and omentum matrixes, the am has superior results in urothelial engineering. this research can be the first step for future studies concerning urothelial cell culture based on am matrix. conclusion mouse urothelium cultured on freeze-dried human am resulted in multilayer urothelial cells with tight intercellular connections by desmosomes. hemidesmosome junctions between the cells and the am were observed similar to those of the normal amniotic membrane for growth of urothelial cells—sharifiaghdas et al 78 urology journal vol 4 no 2 spring 2007 urothelium. histological and immunohistochemical examinations also confirmed that the cultured cells had a similar structure to normal urothelial cells, while the peritoneum and omentum did not have the same properties. overall, the successful culture of the urothelial cells on the am signifies the possibility of urothelial reconstruction by using this matrix. conflict of interest dr hossein baharvand and reza moghadasali are employed at royan institute. financial support this study was supported by a grant from the urology and nephrology research center and the laboratory facilities of royan institute. refrences 1. atala a. tissue engineering in urologic surgery. urol clin north am. 1998;25:39-50. 2. falke g, caffaratti j, atala a. tissue engineering of the bladder. world j urol. 2000;18:36-43. 3. bisson i, hilborn j, wurm f, meyrat b, frey p. human urothelial cells grown on collagen adsorbed to surfacemodified polymers. urology. 2002;60:176-80. 4. atala a. experimental and clinical experience with tissue engineering techniques for urethral reconstruction. urol clin north am. 2002;29:485-92, ix. 5. sabbagh w, masters jr, duffy pg, herbage d, brown ra. in vitro assessment of a collagen sponge for engineering urothelial grafts. br j urol. 1998;82:88894. 6. baumert h, simon p, hekmati m, et al. development of a seeded scaffold in the great omentum: feasibility of an in vivo bioreactor for bladder tissue engineering. eur urol. in press 2006. 7. atala a, bauer sb, soker s, yoo jj, retik ab. tissueengineered autologous bladders for patients needing cystoplasty. lancet. 2006;367:1241-6. 8. moriya k, kakizaki h, murakumo m, et al. creation of luminal tissue covered with urothelium by implantation of cultured urothelial cells into the peritoneal cavity. j urol. 2003;170:2480-5. 9. ahn km, lee jh, hwang sj, et al. fabrication of myomucosal flap using tissue-engineered bioartificial mucosa constructed with oral keratinocytes cultured on amniotic membrane. artif organs. 2006;30:411-23. 10. nakamura t, endo k, cooper lj, et al. the successful culture and autologous transplantation of rabbit oral mucosal epithelial cells on amniotic membrane. invest ophthalmol vis sci. 2003;44:106-16. 11. yang gf, chen pj, gao yz, et al. forearm free skin flap transplantation: a report of 56 cases. 1981. br j plast surg. 1997;50:162-5. 12. nakamura t, yoshitani m, rigby h, et al. sterilized, freeze-dried amniotic membrane: a useful substrate for ocular surface reconstruction. invest ophthalmol vis sci. 2004;45:93-9. 13. institute of laboratory animal research. guide for the care and use of laboratory animals. washington, dc: national academy press; 1996. urol_v03_no4_001_editorial.indd appendixes 267urology journal vol 3 no 4 autumn 2006 abadpour b, see tabibi a, 145 abdi hr, see tabibi a, 145 abdi hr, see ziaee sam, 92 abedi ar, see mousavi s, 247 aghaie-maybodi f, see khalili ma, 154 ahmadi asr badr y, madaen k, haj ebrahimi s, ehsan nejad ah, koushavar h. prevalence of infertility in tabriz in 2004, 87-91 ahmadnia h, younesi rostami m, yarmohammadi aa, parizadeh smj, esmaeili m, movarekh m. percutaneous treatment of bladder calculi in children: 5 years experience, 20-22 ahmadnia h, see yarmohammadi aa, 175 aliasgari m, ghadian ar. coincidence of angiomyolipoma and pheochromocytoma, 61-64 aliasgari m, see dadkhah f, 184 amjadi m, madaen sk, pour-moazen h. uroflowmetry findings in patients with bladder outlet obstruction symptoms in standing and crouching positions, 49-53 anvari m, see khalili ma, 154 arab d, see darabi mr, 216 arab d, see mahdavi r, 82 asgari sa, mokhtari gr, falahatkar s, mansourghanaei m, roshani a, zare ar, zamani m, khosropanah i, salehi m. diagnostic efficacy of creactive protein and erythrocyte sedimentation rate in patients with acute scrot zare ar um, 103-107 attar k, see omrani md, 38 ayati m, nikfallah ag, jabalameli p, najjaran tousi v, noroozi mr, jamshidian h. extensive surgical management for renal tumors with inferior vena cava thrombus, 212-215 bagheri m, see omrani md, 38 banai m, see zargar shoshtari ma,44 barfi m, see shahbazian h, 234 barghi mr, rahmani mr, haghighatkhah hr. angiography and segmental artery embolization in renal stab wound, 245-246 barghi mr, rahmani mr, hosseini moghaddam smm, jahanbin m. immediate intravesical instillation of mitomycin c after transurethral resection of author index to volume 3 bladder tumor in patients with low-risk superficial transitional cell carcinoma of bladder, 220-224 barghi mr, seehosseini sj, 165 basiri a, parvin m, simaei nr, hajimohammadmehdi-arbab a. the role of surgery for local recurrence of renal ewing’s sarcoma: a case report, 250-252 basiri a, see ziaee sam, 75 canda ae, kirkali z. current management of renal cell carcinoma and targeted therapy, 1-14 dadkhah f, hosseini sy, aliasgari m, lashay ar. urethral tumors: a report of 6 cases, 184-187 daneshmand s, quek ml. adrenal myelolipoma: diagnosis and management, 71-74 darabi mr, tayebi meibodi n, mahdavi r, arab d. p53 protein in serum and urine samples of patients with bladder transitional cell carcinoma and its overexpression in tumoral tissue, 216-219 dibaei a, see shahbazian h, 234 doosti h, see feizzadeh b, 208 ebrahimi r, see pourmand g, 23 ehsan nejad ah, see ahmadi asr badr y, 87 elahian ar, see zomorrodi a, 130 eskandar-shiri d, see ziaee sam, 150 esmaeili m, see ahmadnia h, 20 ezzatnegad mr, see ziaee sam, 92 falahatkar s, see asgari sa, 103 farrokhi f. duplicate publication: justifiable in a different language?, 191-192 farrokhi f, see sadeghi-nejad h, 193 fazel m, see nikibakhsh aa, 139 feizzadeh b, doosti h, movarrekh m. distilled water as an irrigation fluid in percutaneous nephrolithotomy, 208-211 feizzadeh b, see yarmohammadi aa, 175 geavlete p, seyed aghamiri sa, multescu r. retrograde flexible ureteroscopic approach for pyelocaliceal calculi, 15-19 ghadian ar, see aliasgari m, 61 gholamrezaie hr, see mahdavi r, 82 ghorbani n, see zomorrodi a, 130 author index to volume 3 268 urology journal vol 3 no 4 autumn 2006 givi m, see mombini h, 79 haghighatkhah hr, see barghi mr, 245 haj ebrahimi s, see ahmadi asr badr y, 87 haji-mohammadmehdi-arbab a, see basiri a, 250 haji-mohammadmehdi-arbab a, see hosseini sj, 204 hekmat s, see shahrokh h, 97 hosseini ma, see shahbazian h, 225 hosseini moghaddam smm, see barghi, 220 hosseini moghaddam smm, see ziaee sam, 150 hosseini moghaddam smm, see ziaee sam, 92 hosseini moghaddam smm, see hosseini sj, 165 hosseini sj, kaviani a, jabbari m, mohammad hosseini m, haji-mohammadmehdi-arbab a, simaei nr. diagnostic application of flexible cystoscope in pelvic fracture urethral distraction defects, 204-207 hosseini sj, rahmani mr, razzaghi mr, barghi mr, karami h, hosseini moghaddam smm. fournier gangrene: a series of 12 patients, 165-170 hosseini sy, see dadkhah f, 184 iranpour a, see ziaee sam, 75 jabalameli p, see ayati, 212 jabbari m, see hosseini sj, 204 jahanbin m, see barghi, 220 jalaie s, see salsabili n, 32 jalalizadeh b, see salsabili n, 32 jamshidi m, see zargar shoshtari ma,44 jamshidian h, see ayati, 212 jamshidian h, see ziaee sam, 92 jasemi m, see shahbazian h, 225 karami h, seehosseini sj, 165 karamiyar m, see nikibakhsh aa, 139 kaviani a, see hosseini sj, 204 khafri s, see tabibi a, 145 khaji a, see salimi j, 171 khalili ma, aghaie-maybodi f, anvari m, talebi ar. sperm nuclear dna in ejaculates of fertile and infertile men: correlation with semen parameters, 154-159 khanlarpoor t, see mehrsai ar, 240 kharrazi smh, rahmani mr, sakipour m, khoob s. polyorchidism: a case report and review of literature, 180-183 khoob s, see kharrazi smh, 180 khosropanah i, see asgari sa, 103 kirkali z, see canda ae, 1 koushavar h, see ahmadi asr badr y, 87 lashay ar, see dadkhah f, 184 madaen k, see ahmadi asr badr y, 87 madaen sk, see amjadi m,49 mahdavi r, arab d, taghavi r, gholamrezaie hr, yazdani m, simforoosh n, tabibi a. en bloc kidney transplantation from pediatric cadaveric donors to adult recipients, 82-86 mahdavi r, see darabi mr, 216 mahjub h, see zamanian a, 230 mahmoodzadeh h, see nikibakhsh aa, 139 mansour-ghanaei m, see asgari sa, 103 mehralian a, see zamanian a, 230 mehravaran k, see zargar shoshtari ma,44 mehrsai ar, mousavi s, nikoobakht mr, khanlarpoor t, shekarpour l, pourmand g. improvement of erectile dysfunction after kidney transplantation: the role of the associated factors, 240-244 mehrsai ar, see mousavi s, 240 mehrsai ar, see pourmand g, 23 mehrsai ar, see salsabili n, 32 mirzazadeh m, see zargar shoshtari ma,44 mohamadzadeh rezaei ma, see yarmohammadi aa, 175 mohammad hosseini m, see hosseini sj, 204 mohammadzadeh rezaee ma. intravesical explosion during endoscopic transurethral resection of prostate, 108-109 mokhtari gr, see asgari sa, 103 mombini h, givi m, rashidi i. relationship between expression of p53 protein and tumor subtype and grade in renal cell carcinoma, 79-81 mombini h, see shahbazian h, 225 momeni a, see rajaie esfahani m, 54 momtaz he, see seyedzadeh ah, 134 moosavi s, see pourmand g, 23 moradi a, see moradi mr, 160 moradi a, see seyedzadeh ah, 134 moradi mr, moradi a. urethroplasty for long anterior urethral strictures: report of long-term results, 160-164 moradi mr, see seyedzadeh ah, 134 author index to volume 3 urology journal vol 3 no 4 autumn 2006 269 moula sj, see ziaee sam, 150 mousavi s, mehrsai ar, nikoobakht mr, abedi ar, salem s, pourmand g. a giant congenital posterior urethral diverticulum associated with renal dysplasia, 247-249 mousavi s, see mehrsai ar, 240 movahhed m, see shahrokh h, 97 movarekh m, see ahmadnia h, 20 movarrekh m, see feizzadeh b, 208 multescu r, see geavlete p, 15 nadjafi-semnani m, see ziaee sam, 75 najjaran tousi v, see ayati, 212 nikfallah ag, see ayati, 212 nikibakhsh aa, yekta z, mahmoodzadeh h, karamiyar m, fazel m. technetium tc 99m dimercaptosuccinic acid renal scintigraphy in diagnosis of urinary tract infections in children with negative culture, 139-144 nikoobakht mr, see mehrsai ar, 240 nikoobakht mr, see mousavi s, 247 nikoobakht mr, see pourmand g, 23 nikoobakht mr, see salimi j, 171 noroozi mr, see ayati, 212 nowroozi mr, see ziaee sam, 92 omrani md, samadzadae s, bagheri m, attar k. y chromosome microdeletions in idiopathic infertile men from west azarbaijan, 38-43 orafa am, see shahrokh h, 97 parizadeh smj, see ahmadnia h, 20 parvin m, see basiri a, 250 parvin m, see tabibi a, 145 pourmand g, pourmand mr, salem s, mehrsai ar, taheri mahmoudi m, nikoobakht mr, ebrahimi r, saraji a, moosavi s, saboury b. posttransplant infectious complications: a prospective study on 142 kidney allograft recipients, 23-31 pourmand g, see mehrsai ar, 240 pourmand g, see mousavi s, 247 pourmand g, see salsabili n, 32 pourmand mr, see pourmand g, 23 pour-moazen h, see amjadi m,49 quek ml, see daneshmand s, 71 rahmani mr, see barghi mr, 220 rahmani mr, see barghi mr, 245 rahmani mr, see kharrazi smh, 180 rahmani mr, see hosseini sj, 165 rajaie esfahani m, momeni a. comparison of ultrasonography and intravenous urography in the diagnosis of hematuria causes, 54-60 rashidi i, see mombini h, 79 razzaghi mr, see hosseini sj, 165 roshani a, see asgari sa, 103 saboury b, see pourmand g, 23 sadeghi-nejad h, farrokhi f. the genetics of azoospermia: current knowledge, clinical implications and future directions. part i, 193-203 sakipour m, see kharrazi smh, 180 salehi m, see asgari sa, 103 salem s, see mousavi s, 247 salem s, see pourmand g, 23 salimi j, nikoobakht mr, khaji a. epidemiology of urogenital trauma: results of the iranian national trauma project, 171-174 salsabili n, mehrsai ar, jalalizadeh b, pourmand g, jalaie s. correlation of sperm nuclear chromatin condensation staining method with semen parameters and sperm functional tests in patients with spinal cord injury, varicocele, and idiopathic infertility, 32-37 samadzadae s, see omrani md, 38 saraji a, see pourmand g, 23 seyed aghamiri sa, see geavlete p, 15 seyedzadeh ah, momtaz he, moradi mr, moradi a. pediatric cystine calculi in west of iran: a study of 22 cases, 134-138 shadpour p, shiehmorteza m. enuresis persisting into adulthood, 117-129 shahbazian h, dibaei a, barfi m. public attitudes toward cadaveric organ donation: a survey in ahwaz, 234-239 shahbazian h, mombini h, zand moghaddam a, jasemi m, hosseini ma, vaziri p. changes in plamsa concentrations of hypoxanthine and xanthine in renal vein as an index of delayed kidney allograft function, 225-229 shahrokh h, movahhed m, zargar shoshtari ma, orafa am, hekmat s. ethylenedicysteine versus diethylenetriamine pentaacetic acid as the carrier of technetium tc 99m in diuretic renography for patients with upper urinary tract obstruction, 97-102 shekarpour l, see mehrsai ar, 240 shiehmorteza m, see shadpour 117 simaei nr, see basiri a, 250 author index to volume 3 270 urology journal vol 3 no 4 autumn 2006 simaei nr, see hosseini sj, 204 simforoosh n, see mahdavi r, 82 simforoosh n, see tabibi a, 145 tabibi a, simforoosh n, parvin m, abadpour b, abdi hr, khafri s. prediction of prostatic involvement by transitional cell carcinoma of the bladder using pathologic characteristics of the bladder tumor, 145-149 tabibi a, see mahdavi r, 82 taghavi r, see mahdavi r, 82 taheri mahmoudi m, see pourmand g, 23 talebi ar, see khalili ma, 154 tavoosi a, see zomorrodi a, 130 tayebi meibodi n, see darabi mr, 216 vaziri p, see shahbazian h, 225 yarmohammadi aa, mohamadzadeh rezaei ma, feizzadeh b, ahmadnia h. retrocaval ureter: a study of 13 cases, 175-179 yarmohammadi aa, see ahmadnia h, 20 yazdani m, see mahdavi r, 82 yekta z, see nikibakhsh aa, 139 younesi rostami m, see ahmadnia h, 20 zamani m, see asgari sa, 103 zamanian a, mahjub h, mehralian a. skin diseases in kidney transplant recipients, 230-233 zand moghaddam a, see shahbazian h, 225 zand s, see ziaee sam, 75 zare ar, see asgari sa, 103 zargar shoshtari ma, mirzazadeh m, banai m, jamshidi m, mehravaran k. radiofrequency-induced thermotherapy in benign prostatic hyperplasia, 44-48 zargar shoshtari ma, see shahrokh h, 97 ziaee sam, basiri a, nadjafi-semnani m, zand s, iranpour a. extracorporeal shock wave lithotripsy and transureteral lithotripsy in the treatment of impacted lower ureteral calculi, 75-78 ziaee sam, ezzatnegad mr, nowroozi mr, jamshidian h, abdi hr, hosseini moghaddam smm. prediction of successful sperm retrieval in patients with nonobstructive azoospermia, 92-96 ziaee sam, moula sj, hosseini moghaddam smm, eskandar-shiri d. diagnosis of bladder cancer by urine survivin, an inhibitor of apoptosis: a preliminary report, 150-153 zomorrodi a, elahian ar, ghorbani n, tavoosi a. extracorporeal shock wave lithotripsy in prone and supine positions for patients with upper ureteral calculi, 130-133 editorial 129urology journal vol 4 no 3 summer 2007 editorial policy the right to international papers and contributors urol j. 2007;4:129. www.uj.unrc.ir urology journal is an open access online journal that aims to expeditiously publish basic and clinical research studies related to urological issues from different cultural communities. a review of titles of papers in the last 12 months should amply illustrate our international nature. scientific publishing has been revolutionized in the past decade. with the explosive growth of the internet, the introduction of online publishing, and the advent of electronic printing technology, it is decisive that research findings be published from all over the world. the journal welcomes all types of articles related to urological issues. its timely publication and high visibility are the two most important features that make this journal different from other traditional journals in the region. this is only the beginning of a long journey. our principal aim is to increase the number of corresponding editors from different countries and different regions of the world, although we would like to see an increase in peer reviewers who have, like corresponding editors, an understanding of these issues. international participation will also encourage greater opportunities for publications from researchers from different cultures which is itself worthy. some readers of international journals know something about global inequalities but may not fully realize their extent. although prejudice can explain part of the imbalance, there are also specific measures that may increase the likelihood of a paper being accepted in international journals. these include the need to invest in the quality of the written text, and to show empathy with editors and readers, emphasizing the contribution of the manuscript to the international literature. we can go some way towards greater equality of opportunity from different regions; by improved submissions system, careful assessment, detailed recommendations for revision and sympathetic consideration of revised versions. we should increase research capacity and “manuscript development” skills. the worldwide indexing of a journal is potentially a great boon and a leveler, but the top ranking journals could do more to improve regional journals in different part of the world so that their journals can be indexed. medical journal editors have a main endeavor, publishing of a reliable and readable journal, produced with due respect for the stated aims of the journal and for costs. it is interesting that almost all journals like to describe themselves as international. at present, medical journals, tend to pursue excellence rather than fairness and in doing this their eyes are focused far too closely on the impact factor of their journals as the only adequate measure of worth. all editors have the obligation to support the concept of editorial freedom and to draw major transgressions of such freedom to the attention of the international medical community. the rapid growth in the number of contributions from all over the world to the international medical literature shows that editorial prejudice, although often present, can be effectively offset by research with solid methodology and goodquality presentation. academic, clinical, legal, and administrative bodies foist an authoritative role on peer reviewed professional journals. much of this is driven by the opinion that the journals are “impartial.” if a journal wishes to reject this role, then the editors should decline loudly. the committee on publication ethics (cope) launches a new code of conduct for editors (www.publicationethics.org.uk). the code comprises a set of standards for good editorial practice. the two professions most closely allied to medical journal editing, medicine and the press, have well-established systems for self-regulation. however, self-regulation is a privilege not a right. it brings with it responsibilities to establish and enforce standards of good practice. the cope code of conduct is a first step. recent world events have served to emphasize our interdependence and remind us that we cannot escape into separate worlds. perhaps it is this, more than any other perception, which will break down the barriers between the 90% and 10%. mohammad reza safarinejad associate editor, urology journal 1040 | department of urology, istanbul faculty of medicine, istanbul university, istanbul, turkey tayfun oktar, oner sanli, ömer acar, tzevat tefik, serkan karakus, orhan ziylan retroperitoneoscopic ablative renal surgery in children: the feasibility of using three trocars corresponding author: tayfun oktar, md department of urology istanbul faculty of medicine, istanbul university, 34093, capa, istanbul, turkey. tel: +90 212 259 45 20 fax: +90 212 635 19 18 e-mail: tayfuno@istanbul. edu.tr received february 2012 accepted january 2013 purpose: we report the results of pediatric retroperitoneoscopic renal ablative surgeries, which were performed with only three trocars. materials and methods: we retrospectively reviewed the charts of children who underwent laparoscopic urological procedures on the upper urinary tract at our institution between 2006 and 2012. these procedures consisted of nephrectomies, nephroureterectomies and heminephroureterectomies. the operations were performed retroperitoneoscopically with three trocars. the specimens were removed intact through the primary trocar site. results: a total of 30 retroperitoneoscopic ablative surgeries were performed in 13 girls and 17 boys. the mean patient age was 7.8 ± 4.3 years (range, 1-14 years). the interventions consisted of nephrectomy in 10 cases (33.3%), nephroureterectomy in 17 cases (56.6%) and heminephroureterectomy in 3 (10%) cases. the open conversion rate was 3.3% (1/30). the difference between the initial 10 cases and the latter 20 cases, in terms of mean operative time, was statistically significant (144.5 vs. 115.78 minutes, respectively, p = .031). apart from 3 nephroureterectomies, all of the procedures (86.6%) were completed successfully using three trocars only, without the need for a separate extraction incision. the patients were hospitalized for a mean duration of 2.2 days (range, 2-4 days). none of the patients required blood transfusion. we did not encounter any major perioperative or postoperative complication. conclusion: retroperitoneoscopic renal ablative surgery is a safe and effective treatment alternative for a variety of upper urinary tract disorders in children. keywords: laparoscopy; retroperitoneal space; methods; child; surgical procedures. laparoscopic urology laparoscopic urology 1041vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction laparoscopic nephrectomy has progressively in-creased in popularity since its introduction by clay-man and colleagues in 1990.(1) shorter hospitalization period, reduced postoperative analgesic requirement, rapid convalescence and better cosmetic outcome are the most distinguishing advantages of laparoscopic renal surgery. these benefits have been noted in both adult and pediatric populations.(2,3) the first pediatric laparoscopic nephrectomy and nephroureterectomy were reported in the 1990s by figenshau and colleagues and by ehrlich and colleagues, respectively.(4,5) the initial reports dealt mainly with the transabdominal route. throughout the following years, retroperitoneoscopic procedures became popular. currently, the proponents of transperitoneal and retroperitoneal approaches for laparoscopic renal surgery cite the advantages and disadvantages of each approach. laparoscopic renal surgery in children has gained acceptance in our department after having experienced its safety, efficacy and advantages in adults. we prefer the retroperitoneoscopic route and utilize three trocars when dealing with upper urinary tract pathologies in children. the more direct and rapid access to the kidney and renal vasculature and the lower risk of bowel complications are the major reasons for this preference. in this study, we retrospectively reviewed the charts of children who underwent retroperitoneoscopic renal surgery with three trocars at our clinic, due to a variety of upper urinary tract disorders. materials and methods we retrospectively reviewed the charts of children who underwent retroperitoneoscopic urological procedures on the upper urinary tract at our institution between 2006 and 2012. demographic and perioperative data were abstracted from a prospectively structured database. these procedures consisted of renal ablative surgeries, including nephrectomies, nephroureterectomies and heminephroureterectomies. diagnoses were established clinically with ultrasonography and nuclear imaging results. in cases with duplex systems, voiding cystourethrography (vcug) was also performed to rule out vesicoureteral reflux. the indications for laparoscopy were the same as for open surgery. the indications for nephrectomy were a nonfunctioning kidney secondary to obstructive uropathy, ectopic ureteral insertion, urinary stone disease and multicystic dysplasia. heminephroureterectomy was performed in children with a dysplastic upper pole and a corresponding large ureterocele or ectopic ureter. nephroureterectomy was indicated for those patients who had highgrade vesicoureteral reflux and an ipsilateral, nonfunctioning, and dysplastic kidney. all of the patients with nonfunctioning kidneys had recurrent urinary tract infections or pain. surgical technique surgery was performed with the patient in the lateral decubitus position, under general endotracheal anesthesia. the table was flexed to expand the space between the iliac crest and the twelfth rib. a nasogastric tube was placed to decompress the stomach. appropriate padding was placed at all body pressure points. the abdomen and genitalia were prepared and draped in the standard sterile fashion. after making a 10mm incision at the junction of the subcostal margin and the lateral edge of the sacrospinal muscle (figure 1), the fascia was incised with electocautery. the space between gerota’s fascia and the psoas fascia was dissected gently to avoid an inadvertent peritoneal tear. retroperitoneal working space was created using either balloon dilators or foley catheters (with the finger of a rubber glove tied at the tip). hence, the perinephric fat gets freed from the areolar tissue and peritoneal layer becomes mobilized away from the dissection plane. the balloon device or foley catheter was left inflated to develop the retroperitoneal space adequately and to tamponade any bleeding. depending on the age of the patient, retroperitoneal pressure of 10-12 mmhg was maintained. once an adequately distended retroperitoneal space has been created, two additional 5-mm trocars were introduced under laparoscopic guidance, in the posterior and anterior axillary lines, respectively. a camera lens (30 degrees) was inserted through the 10-mm trocar. scissors and grasper were introduced through the other ports. psoas muscle served as the initial landmark during retroperitoneal dissection. then, the ureter and the inferior aspect of the kidney were exposed. next, the ureter was mobilized up to the lower kidney pole. after being transected at the level of the iliac vessels, the ureter was manipulated in order to ease the dissection of reretroperitoneoscopic renal surgery in children | oktar et al 1042 | nal pedicle. then, the renal artery and vein were individually controlled with hem-o-lok clips. two clips were applied on the proximal side of the vessels while the specimen side was controlled with one clip. after their transection, the kidney was completely freed. the ureteral stump was closed using either hem-o-lok clips or a sealing device (ligasuretm, covidien, mansfield, ma, usa). if there was a history of reflux (while performing the nephroureterectomy), the ureter was completely dissected and clipped at the level of ureterovesical junction. in heminephroureterectomy, the vessels from the different poles were dissected and were selectively transected using ligation. the kidney poles were separated using ligasuretm. the data are presented as means and standard deviations (sd), if not otherwise indicated. the level of statistical significance was set at p < .05. the statistical analysis was performed using he statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0. results a total of 30 retroperitoneoscopic ablative surgeries were performed in 13 girls and 17 boys at our clinic between 2006 and 2012. the mean patient age and mean body weight were 7.8 ± 4.3 years (range, 1-14 years) and 23.6 kg (range,10-50 kg) respectively. the interventions consisted of nephrectomy in 10 cases (33.3%), nephroureterectomy in 17 cases (56.6%) and heminephroureterectomy in 3 cases (10%). only one patient undergoing nephrectomy required open conversion due to access problems and suboptimal visualization of the renal pedicle. of the procedures, 11 were on the right side, and 19 were on the left side. the mean operative time was 125.08 min (range = 70-180 min). the mean duration of surgery was 144.5 min for the initial 10 cases. the latter 20 cases lasted 115.78 min on average. the difference between these 2 patient groups (initial vs. latter) in terms of mean operative time was statistically significant (p = .031). the comparison of the operative times between girls and boys (128.3 min vs. 124.5 min, respectively, p > .05) and children below and above 5 years of age (125.2 min vs. 122.14 min, respectively, p > .05) did not reveal any statistically significant difference. overall, 26 out of 30 (86.6%) procedures were completed successfully using three trocars only, without the need for an additional incision to remove the specimens. the excised specimens were removed from the 10-mm trocar site. out of 20 nephroureterectomies and heminephroureterectomies, the procedure was completed by 3-trocars only in 17 cases (17/20, 85%), including the removal of the ureter and the specimen. a separate lower abdominal incision was then made to remove the kidney and ureter in the remaining 3 patients undergoing nephroureterectomy. the patients were hospitalized for a mean duration of 2.2 days (range, 2-4 days). none of the patients required blood transfusion. the perioperative and postoperative courses were devoid of major complications. despite peritoneal violation in one case, the procedure was completed without open conversion. discussion diagnostic laparoscopy for impalpable testes has pioneered the concept of laparoscopic urological surgery in children and since then considerable progress has been achieved in this field.(6) despite this development, laparoscopy has been adopted more slowly in children than in adults as a method for treating urological problems. the high success rates of open procedures, in addition to longer hours of surgery, more challenging learning curve and increased expenditure associated with laparoscopy are the most probable reasons for this delay. however, the ability to treat children effectively in a minimally invasive fashion has been positively influenced by improvements in instrumentation and increasing experience and creativity of minimally invasive surgeons. better cosmetic results, magnified visualization of the operative field, reduced length of hospital stay and diminished postoperative pain are considered as the main advantages of laparoscopic surgery. after clayman and colleagues documented its feasibility in 1991,(1) laparoscopic nephrectomy has been widely accepted as the standard of care in the adult population. thereafter, laparoscopic renal surgery began to gain popularity among pediatric urologists. the initial series of pediatric nephrectomies and nephroureterectomies were reported by figenshau and colleagues and by ehrlich and colleagues, respectively. (4,5) koyle and colleagues reported their experience about laparoscopic nephrectomy in infants.(7) subsequent studies laparoscopic urology 1043vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l have demonstrated the efficacy of laparoscopic nephrectomy, partial nephrectomy, heminephrectomy, and nephroureterectomy in children, for a variety of upper urinary tract disorders. laparoscopic nephrectomies in children have commonly been used to remove non-functional renal units secondary to obstructive uropathy (posterior urethral valves, ureteropelvic junction obstruction), vesicoureteral reflux, or ectopic ureteral insertion. although initially described using a transperitoneal approach, the advantage and disadvantage of both transperitoneal and retroperitoneal access in children have been frequently debated.(8-13) the retroperitoneal route has several potential advantages. this access allows for more rapid and direct access to the kidney and the renal hilum without dissection of intraperitoneal structures. it avoids direct entry into the peritoneal cavity; hence, minimizes the risk of intestinal complications, such as adhesion formation, bowel injury and postoperative ileus although there is still a risk of bowel injury during retroperitoneal approach. also by staying extraperitoneal, any possible postoperative fluid collection (urinoma, hematoma) would be isolated in the retroperitoneal space. retroperitoneal route has been handicapped by the limited area of port placement and reduced working space when compared with the transperitoneal approach. el ghoneimi and colleagues reported their initial experience with retroperitoneal laparoscopic renal procedures. of their 39 patients undergoing laparoscopic nephrectomy and partial nephrectomy, only two required open conversion.(9) in a systematic review of 51 articles, including nearly 689 pediatric patients undergoing retroperitoneal or transperitoneal laparoscopic nephrectomies, nephroureterectomies and partial nephrectomies, kim and colleagues did not found any significant difference in terms of the overall complication rates between the transperitoneal and the retroperitoneal approach, excluding conversion to open surgery as a complication.(14) the differences between the two groups (transperitoneal vs. retroperitoneal) in terms of vascular and bowel complications were also insignificant.(14) in our series, consisting of 30 upper urinary tract interventions, apart from one open conversion, the perioperative and early postoperative courses were uneventful, without any major complications and none of the patients required blood transfusion. in our series, the renal artery and vein were separately controlled with hem-o-lok clips. modi and colleagues evaluated the safety and efficacy of 5 mm hem-o-lok clips while performing retroperitoneoscopic nephrectomies in children. they completed all 24 nephrectomies without any problems attributable to hem-o-lok clip application.(15) we also did not encounter any clip dislodgement or other technical difficulties regarding clip application. the reported mean operative time for retroperitoneoscopic nephrectomy, partial nephrectomy or nephroureterectomy ranges from 68 to 194 min in different series.(14,16,17) in their systematic review, kim and colleagues reported that the average operative time was 129 min for the retroperitoneal approach which was shorter than that of the transperitoneal approach (154 min).(14) pearce and subramaniam compared the retroperitoneal and transperitoneal approaches for laparoscopic nephrectomy and observed a trend towards decreased operative duration over the course of the study period for retroperitoneoscopic nephrectomy while a similar decrease could not be documented for the transperitoneal route.(18) in our study, when all retroperitoneoscopic renal ablative surgeries were considered, the mean operative time was 125 min. when analyzed in detail, mean operative time decreased significantly after the initial 10 cases (144.5 min and 115.78 min, for the initial 10 and later 20 cases, respectively, p = .031). relatively limited working space and limited area for port placement may be accepted as the main disadvantages of pediatric retroperitoneal laparoscopy. therefore, the ability to perform retroperitoneal laparoscopy in children requires a figure 1. the places of three trocars. retroperitoneoscopic renal surgery in children | oktar et al 1044 | laparoscopic urology learning period. in general, the first 20 cases may be considered as the threshold for complex laparoscopic procedures. in our series, as mentioned above, a significant decrease in mean operative time was observed after the initial 10 cases, which also reflects the learning curve and expertise gained over time. relatively faster decline of the operative duration for retroperitoneoscopic procedures may partially be explained by the experience accumulated over 120 retroperitoneal laparoscopic procedures performed in adults in our department. nevertheless, especially in the early phases of the learning curve, manipulating 3 trocars inside a child’s retroperitoneum can be quite challenging. using smaller instruments (3-mm trocars), depending on the child’s age and body habitus, may increase the surgeon’s manual dexterity. in our series, out of 20 nephroureterectomies and heminephroureterectomies, the procedure was completed by 3-trocars only in 17 cases (17/20, 85%), including the removal of the ureter and the specimen and we did not encounter any major technical difficulty worth mentioning while doing that. also, all nephrectomies were completed by 3-trocars, without a separate incision for specimen removal. similarly, kuzgunbay and colleagues performed retroperitoneoscopic nephroureterectomy and complete ureteral excision in a total of 13 children with end-stage reflux nephropathy. all of these operations were carried out using three trocars. they also supported the safety and feasibility of this technique in children.(19) there are several limitations of our study. it is a retrospective review of the data. also, there is a lack of a control open group for comparison of the results. laparoscopic surgery has become a valid alternative in the surgical treatment of certain pediatric urological disorders. we recognize the advantages of the retroperitoneoscopic approach and it has become our choice for excisional upper urinary tract surgery as well as for pyeloplasty, pyelolithotomy and ureterolithotomy. conclusion retroperitoneoscopic renal ablative surgery is a safe and effective treatment alternative for a variety of upper urinary tract disorders in children. we were able to complete the majority of the operations (87%) using three trocars only. also, the operative times decreased with growing expertise and the latter 20 cases were carried out more rapidly than the initial 10 cases. conflict of interest none declared. references 1. clayman rv, kavoussi lr, soper nj et al. laparoscopic nephrectomy: inital case report. j urol. 1991;146:278-82. 2. el-ghoneimi a. pediatric laparoscopic surgery. curr opin urol. 2003;13:329-35. 3. smaldone mc, sweeney dd, ost mc, docimo sg. laparoscopy in pediatric urology: present status. bju int. 2000;100:143-50. 4. figenshau rs, clayman rv, kerbl k, mcdougall em, colberg jw. laparoscopic nephroureterectomy in the child: initial case report. j urol. 1994;151:740-1. 5. ehrlıch rm, gershman a, mee s, fuchs g. laparoscopic nephrectomy in a child: expanding horizons for laparoscopy in pediatric urology. j endourol. 1992;6:463-5. 6. cortesi n, ferrari p, zambarda e, manenti a, baldini a, morano fp. diagnosis of bilateral abdominal cryptorchidism by laparoscopy. endoscopy. 1976;8:33-4. 7. koyle ma, woo hh, kavoussi lr. laparoscopic nephrectomy in the first year of life. j pediatr surg. 1993;28:693-5. 8. ku jh, yeo wg, choi h, kim hh. comparison of retroperitoneal laparoscopic and open nephrectomy for benign renal diseases in children. urology. 2004;63:566-70. 9. el-ghoneimi a, valla js, steyaert h, aigrain y. laparoscopic renal surgery via a retroperitoneal approach in children. j urol. 1998;160:1138-41. 10. shanberg am, sanderson k, rajpoot d, duel b. laparoscopic retroperitoneal renal and adrenal surgery in children. bju int. 2001;87:521-4. 11. yao d, poppas dp. a clinical series of laparoscopic nephrectomy, nephroureterectomy and heminephroureterectomy in the pediatric population. j urol. 2000;163:1531-5. 12. york gb, robertson fm, cofer br, bomalaski md, lynch sc. laparoscopic nephrectomy in children. surg endosc. 2000;14:469-72. 13. hamilton bd, gatti jm, cartwright pc, snow bw. comparison of laparoscopic versus open nephrectomy in the pediatric population. j urol. 2000;163:937-9. 14. kim c, mckay k, docimo s. laparoscopic nephrectomy in children: systematic review of transperitoneal and retroperitoneal approaches. urology. 2009;73:280-4. 1045vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l retroperitoneoscopic renal surgery in children | oktar et al 15. modi p, rizvi sj, gupta r. use of hem-o-lok clips for vascular control during retroperitoneoscopic nephrectomy in children. j endourol. 2009;23. 16. borzi pa. a comparison of the lateral and posterior retroperitoneoscopic approach for complete and partial nephroureterectomy in children. bju int. 2001;87:517-20. 17. lee rs, retik ab, borer jg, diamond da, peters ca. pediatric retroperitoneal laparoscopic partial nephrectomy: comparison with an age matched cohort of open surgery. j urol. 2005;174:708-11. 18. pearce r, subramaniam r. minimally invasive partial or total nephrectomy in children: a comparison between transperitoneal and retroperitoneal approaches. pediatr surg int. 2011;27:1233-7. 19. kuzgunbay b, bayazit y, bayazit ak, satar n. retroperitoneoscopic nephroureterectomy via three trocars in pediatric patients with end-stage reflux nephropathy. j endourol. 2010;24:1795-9. endourology and stone disease introducing the popvesl score for intrarenal vascular complications of percutaneous nephrolithotomy: experience from a single high-volume referral center pejman shadpour1, naser yousefzadeh kandevani2* robab maghsoudi3, masoud etemadian4, nasrollah abian2 purpose: percutaneous-nephrolithotomy (pcnl), is the current modality of choice for large renal stones. delayed post-op bleeding may herald pseudo aneurysm (pa) or arteriovenous fistula (avf) necessitating costly and inconsistently available angioembolization, or prolonged hospitalization. the goal of this study is to identify criteria that may predict response to conservative therapy, for delayed bleeding from post pcnl intrarenal vascular lesions. materials and methods: we reviewed all data on patients re-admitted for post pcnl gross hematuria at our high volume center between 2011 and 2016. perioperative findings, factors related to the stone and management details, were subjected to multifactorial analysis. logistic regression for multivariable analysis and roc curves to find thresholds predicting mandatory angioembolization. results: of 4403 pcnls, 83 (1.9%) with delayed bleeding were diagnosed with intrarenal vascular lesions: arteriovenous fistulas in 54 (avf, 65%) and pseudoaneurysm in 29 (pa, 35%). overall 49 (59%) responded to conservative management but 34 (41%) eventually required angioembolization. on multivariable analysis, predictive factors for poor response to conservative treatment were requiring transfusion beyond initial stabilization, pseudoaneurysm, history of open renal surgery, longer interval-to-second-admission, and size of vascular lesion. the proposed popvesl score (short for post pnl vascular embolization selection) when below 11, correctly predicts success of conservative management with 81.6% sensitivity & 100% specificity. conclusion: our findings including the proposed popvesl score have the potential for clinical application and enhancing practical guidelines on the management of post-pcnl bleeding. keywords: arteriovenous fistula; angioembolization; conservative management; percutaneous nephrolithotomy; postoperative complications; pseudo aneurysm introduction percutaneous nephrolithotomy (pcnl) was intro-duced in the 1970s and withstanding the test of time, it remains the less invasive modality of choice for renal stones above 20mm.(1) streamlined by smaller nephroscope footprint, flexible devices to address residual fragments and more efficient intracorporeal lithotripters; pcnl now affords over 90% success.(2) however, despite these advances and being less invasive compared to open surgery, complications of the initial puncture exacerbated by dilation and maneuvering to clear the kidney, remain inherent to pcnl. even in the most experienced hands, major complications occur in up to 7% of cases.(2) bleeding is the most common complication, requiring transfusion in 1 to 10% of cases.(3) delayed bleeding in the form of hematuria or retroperitoneal hematoma is encountered in less than 1 % of cas1professor of urology, hasheminejad kidney center (hkc), hospital management research center (hmrc), iran university of medical sciences (iums), tehran, iran. email: shadpour.p@iums.ac.ir; 2urology resident, hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. email: naser.y.tums@gmail.com; naabian@gmail.com. 3associate professor of urology, firoozgar general hospital, iran university of medical sciences (iums), tehran, iran. email: rmaghsudy@yahoo.com. 4associate professor of urology, hasheminejad kidney center (hkc), hospital management research center (hmrc), iran university of medical sciences (iums), tehran, iran. email: masoudetemadian@gmail.com *correspondence: naser.y.tums@gmail.com hasheminejad kidney center, vanak sq, tehran 19697 iran. tel + 98 21 88644444. fax +98 21 88644447 received february 2020 & accepted august 2020 es and heralds pseudoaneurysm (pa) or arteriovenous fistula (avf) formation.(3,13) these intrarenal vascular lesions usually manifest within 3 weeks after pcnl and may require endovascular intervention. in patients with unstable hemodynamics, significant hemoglobin drop or prolonged bleeding, the modality of choice is angioembolization with over 95% success in various reports.(4,14,15) although some authors recommend having a lower threshold for angioembolization to avoid blood transfusion,(3) the costs and complications of this modality should also be considered. studies on predictive factors for the success of conservative therapy are limited. possibly because most surgeons rush to early angioembolization for managing all such lesions. in contrast, some centers in the world give conservative management a chance whenever possible. sharing the lessons learned from such large-volume centers can be insightful. urology journal/vol 18 no.3/may-june 2021/ pp.277-283. [doi: 10.22037/uj.v16i7.5997] the aim of this study is to look back at the data from our exceptionally high-volume single center experience, concentrating on demographics, stone related and procedure-specific prognostic factors to look for possible predictive factors of response to conservative therapy. by analyzing these factors, we have searched for sentinel criteria to assist with the decision to switch from watchful waiting and conservative management to vascular intervention. materials and methods after institutional ethical committee approval for studying this historical cohort, we reviewed the records of all patients who were re-admitted for gross hematuria after being discharged following pcnl at our center, and diagnosed with intrarenal vascular lesions, between december 2011 and january 2016. according to the urologic emergency management policy guidelines at our center, all patients with delayed post pcnl bleeding (i.e., presenting with gross bleeding after being discharged from hospital) are seen at the emergency department. after resuscitation and stabilization, search for an underlying cause for the bleeding begins by combined color doppler and greyscale ultrasonography of the kidneys, performed by experienced in-house vascular interventionists. we perform a non-contrast ct scan in all such readmissions to screen for residual fragments and quantify the extent of any retroperitoneal hematoma. cases of isolated hematoma without hematuria were rarely encountered and are self-limited and minimally symptomatic. color doppler ultrasound combined with non-contrast ct usually provides adequate diagnostic information in post pcnl bleeding. those with equivocal findings and all those requiring intervention were then scheduled for digital subtraction angiography as the modality of choice at our center (compared to ct angiography) for its higher accuracy and needing less contrast, while allowing for immediate intervention if required.(12) any persistently unstable hemodynamics would entail emergent angioembolization. otherwise, all stable patients diagnosed with intra-renal vascular lesions on color doppler, undergo a period of watchful management, monitoring vital signs and hemoglobin levels aside bladder irrigation via a three-way foley. the severity of bleeding is assessed by two factors: first, the magnitude of pre-hospital bleeding (judged by comparing the hemoglobin level before pcnl with that upon the second admission). second, is the number of packed cell units required beyond correcting the initial deficit and primary stabilization (i.e., achieving 10 g/ dl). these reflect the severity of bleeding before and after initial management, and were regarded separately figure 1. pseudo aneurysm and avf during dsa. a: avf before embolization (black arrow), b: the same patient after embolization. c: pa before embolization (black arrow), d: the same patient after angioembolization. figure 2. sonographic view of an iatrogenic pseudoaneurysm. popvesl risk score for post pcnl bleeding-shadpour et al. endourology and stones diseases 278 vol 18 no 3 may-june 2021 279endourology and stones diseases 272 in this analysis. patients requiring more than 3-4 units of blood following the initial correction of hemoglobin levels, also those with persistent hematuria into the tenth day of admission are generally scheduled for elective angioembolization. some exceptions to this approach may be expected based on the clinical progress of individual cases as judged by their responsible urologist. those who respond to conservative management are followed up by color doppler ultrasonography to assess the fate of the vascular lesion. patients are discharged if they no longer have hematuria and there is evidence of a shrinking vascular lesion. demographic and operative data were extracted from the records. in addition, further hemoglobin drop, the interval between pcnl and onset of delayed hematuria, number of packed cells required, type and size of vascular lesions, duration of the second admission, etc. were accounted. statistical analysis on ibm spss software version 19, using the fisher exact test for categorical variables, student’s t-test and mann-whitney tests for continuous parametric and non-parametric variables. the p-value cut off for statistical significance was < 0.05 for this report. logistic regression for multivariable analysis and receiver-operating characteristic (roc) curves were utilized to suggest the threshold value for predicting the need for angioembolization. results after obtaining approval from the institutional review board, a search within data pertaining to all 4403 patients who had undergone pcnl at our single referral center between dec 2011 and jan 2016 (50 months) revealed 83(1.9%) individuals who had presented with delayed hematuria necessitating readmission after initial discharge from the hospital, and further diagnosed to have an intrarenal vascular cause, namely avf or pa. data regarding this entire group was subsequently analyzed in depth with no exclusions. mean age was 50.3 +/12.2, and 61 of the 83 were male (73.5%). all patients had achieved negative urine culture leading to pcnl, none had taken aspirin within the 5 days leading to this surgery. also, coagulation panels were normalized perioperatively and therefore not included in further analysis. chronic kidney disease (defined as glomerular filtration rate below 90ml/min/1.73m2 estimated by the cockcroft-gault equation) was noted in 21.7%, diabetes in 12% and hypertension 14.5%. history of ipsilateral open renal surgery (pyelolithotomy in our cases) and swl were 14.5% and 8.4% respectively, and 2.4% had abnormal ipsilateral renal anatomy. mean stone burden as defined by sum of the maximum length of all stones for each renal unit was 67 mm (range 20-140). twenty-one patients had staghorn calculi (25.3%), 49.4% had renal pelvic stones and the remainder were in the calyces. all surgeries were performed by endourology fellows under direct supervision of the attending. all initial punctures were performed under fluoroscopic guidance using an 18-gauge needle initial coaxial dilation to 12f followed by one-shot dilatation to place the amplatz sheath. the initial punctures were not hematuric, but 22 of the 83 patients (26.5%) had required 2 or 3 attempts to achieve access of whom14 (25.9%) and 8 (27.5%) had avf and pa respectively. looking back at the original pcnl records, and as is standard practice for all pcnls at our center, all but three patients had originally been furnished with an expopvesl risk score for post pcnl bleeding-shadpour et al. figure 3. sonographic view of an iatrogenic avf. figure 4. follow up sonographic view of the case of pseudoaneurysm which was managed conservatively. teriorized ureteral catheter or indwelling stent, plus a urethral foley. in the remaining three a nephrostomy tube had been placed at the surgeon’s discretion. in all 83 cases, the initial pcnl had concluded without undue intraoperative bleeding, therefore abortion of the surgery for bleeding was not an issue in any of these. eleven renal units had required two accesses for stone clearance, all other procedures were accomplished through a single subcostal access (86.7%). the mean operation time was 68.6 +/30.3 min. stone free status was assessed 2 weeks from the surgery by ultrasonography, plus plain radiography or non-contrast ct scan in cases of non-opaque renal stones. presence of any residual stone after pcnl before adjuvant therapy was recorded in 28 of these 83 patients (33.7%). overall, the mean size of the vascular lesion was 9.8mm (sd 6.6): for avf 6.7mm (3-38mm) and pa 10.5 mm (4-42 mm). forty-nine patients (59%) responded to conservative treatment and were discharged when gross hematuria ceased and the lesion was seen to shrink on control sonography. these patients were asked to return in case of recurrent hematuria, and once a week for outpatient follow up sonography until the lesion resolved. thirty-four patients (41%) eventually required angioembolization as shown in figure 1. the overall incidence of developing vascular lesions necessitating embolization in 4403 pcnl procedures was 0.77%. one patient required a second embolization after the failure of the first attempt to control hematuria. the final success rate for embolization was hence 100%. clinical findings related to pcnl and the occurrence of an intra-renal lesion are depicted in table 1. sample sonography of pa and avf managed conservatively and follow up imaging of a case of pseudoaneurysm are shown in figures 2, 3 and 4 respectively. there was no recurrence of hematuria after initial successful conservative therapy, which was predictable given serial doppler sonographies suggestive that the lesions were regressing. all cases diagnosed as pa or avf by color doppler sonography were reconfirmed at angiography, so the specificity of color doppler sonography by an experienced uro-radiologist approached 100%. most patients still had a double j at the time of their second admission, and we did not replace any new ureteral catheter to allow the pyelocaliceal system to help tamponade the bleeding. flank pain was managed with narcotics or non-opioid analgesics as required. univariable analysis of factors affecting the need for angioembolization: preadmission hemoglobin drop, units of packed cell transfused post stabilization, presence of a pseudoaneurysm, size of the lesion, history of previous open renal surgery and stone burden were predictive of the need for endovascular intervention. other factors including time between pcnl and re-admission for hematuria, age, sex, past medical history, history of swl, abnormal anatomy, laterality, access size, residual fragments, and stone location did not differ significantly between the two groups as shown in table 1. multivariable analysis: by logistic regression, predictive factors for poor response to conservative treatment and need for endovascular intervention were units transfused packed cell, presence of pseudoaneurysm, history of open renal surgery, longer interval between pcnl and second admission and size of the vascular lesion. details of these findings are summarized in tafigure 5. roc analysis for popvesl score. the area under the curve is 0.958. cut off point for best sensitivity and acceptable specificity is 10 yielding 100% sensitivity and 81.6% specificity. popvesl risk score for post pcnl bleeding-shadpour et al. endourology and stones diseases 280 vol 18 no 3 may-june 2021 281 ble 2. odds ratio was calculated on the spss platform by backward logistic regression for influential factors (those having a suggestive p-value below 0.2 on univariable analysis). in univariable analysis for factors predictive of the need for endovascular intervention, greater hemoglobin drop, need for more packed cell units, presence of pa, larger size of any vascular lesion (regardless of type), history of open renal surgery on the affected kidney and larger stone burden were all found to be significant; whereas age, sex, history of diabetes, ckd, htn, and abnormal renal anatomy were not. finally, in multivariable analysis, five-factors including the need for more packed cell units beyond initial sttabilizaton (beta 1.060 and p-value 0.012), presence of pa (or 0.145 and p-value 0.013), history of open renal surgery (or 31.092 and p-value: 0.008), larger vascular lesion (beta 0.314 and p-value 0.001) were statistically significant; and longer interval between pcnl and second admission (beta: 0.117 and p-value 0.065) was concluded by the researchers to remain included until further corroboration in larger series. these were taken as predictive factors for failure of conservative treatment and the need for angioembolization. among which, history of open renal surgery has the strongest impact with or=31 followed by type of lesion where pa portends conservative treatment failure (or=10). when tested for our series, a popvesl score below 11 was 100% specific and 81.6% sensitive in predicting success with medical management. conversely, the popvesl score above 16 was 100% specific but 52% sensitive for the inevitability of embolization. (positive predictive value=1, negative predictive value=0.75). roc curve analysis to derive a cut-off point with optimal sensitivity and specificity, for the popvesl score, is shown on figure 5. discussion based on the latest guidelines pcnl is the treatment of choice in large renal stones.(1) complications of this modality are inevitable among which delayed hematuria from intrarenal vascular lesions is one of the most table 1. factors predictive of the need for angioembolization, univariable analysis. factor subgroup responding to subgroup requiring p value conservative therapy n=49 angioembolization n=34 preoperative factors age (mean ± sd) 43 ± 10.8 50 ± 12.8 0.1 sex m / f 35(71%) / 14(29%) 26(76%) / 8(24%) 0.6 dm 6(12%) 4(12%) 0.7 ckd 12(24.5%) 6(17.6%) 0.3 htn 7(8.4%) 5(6%) 0.9 hx of swl 2(4%) 5(15%) 0.1 hx of open renal surgery 2(4%) 10(29%) 0.003 laterality r/l 22(44.8%) / 27(55.2%) 16(47%) / 18(53%) 0.8 operative subcostal access 43(88%) 29(85%) 0.8 multiple access 6(7.2%) 5(6%) 0.8 stone location 27(55%) / 22(45%) 14(86%) / 20(14%) 0.3 (pelvis and one calyx / more locations) duration of surgery (min) 50 ± 1.34 60 ± 1.38 0. 4 (median± sd) stone burden (mm) 60 ± 1.60 70 ± 2.29 0.02 (median± sd) presence of any 14(29%) 14 (41%) 0.2 residual fragments post-operative factors interval from pcnl to 5 ± 4.57 8 ± 6.30 0.06 re-admission (days) (median± sd) duration of the second 8.7 ± 5.2 13 ± 6.6 0.02 admission (days) (mean ± sd) type of vascular lesion pa (n=29) 12(24.5%) 17 (50%) 0.02 avf (n=54) 37(75.5%) 17 (50%) size of vascular lesion(mm) 7 ± 4.02 10 ± 7.86 0.000 (median± sd) pre admission hemoglobin drops (g/dl) 2.8 ± 1.69 3.8 ± 2.15 0.04 (median± sd) units of packed cell transfused 2 ± 1.60 5 ± 1.57 0.000 after stabilization (median± sd) m, male; f, female; dm, diabetes mellitus; htn, hypertension; hx, history; ckd: chronic kidney disease, defined as the presence of glomerular filtration rate less than 90 ml/min/1.73m2 estimated by the cockcroft-gault equation. swl, extracorporeal shockwave lithotripsy; l. left; r, right. sd: standard deviation. table 2. predictive factors of the need for angioembolization, multivariable analysis. factor odds ratio 95% c.i.for or p value lower upper history of open renal surgery 31.092 2.491 388.013 .008 number of transfused units after initial stabilization 2.886 1.264 6.590 .012 type of lesion 1.928 .0320 .669 .013 size of lesion(mm) 1.369 1.133 1.654 .001 interval from pcnl to re-admission(days) 1.125 .993 1.274 .065 or, odds ratio; ci, confidence interval popvesl risk score for post pcnl bleeding-shadpour et al. significant.(3) management is based on clinical course, varying from conservative treatment in cases who can be stabilized; to emergent angioembolization in hemodynamically unstable patients; to elective intervention for sustained hemoglobin drop, repeated need for blood transfusion, and prolonged hematuria despite initial improvement. although some authors suggest early angioembolization to prevent blood transfusion,(3) one must consider the significant costs and complications of any intervention too. previous studies did not focus on factors predictive of success or failure with conservative therapy. some have looked into predicting post-pcnl bleeding, and the success rate of angioembolization.(5,6,7) these studies highlighted the effect of multiple tracts, stone burden, baseline hemoglobin level, perforation of the renal pelvis, intraoperative bleeding, history of open surgery on the affected renal unit and operation time, on the need for transfusion or intervention. un et al studied patients who underwent angioablation for post pcnl hematuria and stated the presence of renal anomaly and stone burden as predictors.(8) therefore, searching for more objective and practical clinical criteria for management decision, rather than waiting to be guided by the natural course of symptoms is justifiable. one virtue of the present study is pertaining to a single high-volume referral center for urolithiasis. hkc is an academic center at which over 1000 pcnl cases are performed annually. the stone-free rate on this report is visibly below that of previous reports from our center, in which the stone-free rate after pcnl measured 2 weeks after surgery was historically reported between 89-92%.(9) although this might owe in part to a slightly larger than institutional average stone burden in the present cohort, it is mostly the result of re-defining stone rest as the presence of any (even smaller than 2mm) fragment as residue in the present analysis. in our 4403 patients, the incidence of intrarenal vascular insult following pcnl was 1.8 % and need for angioembolization was 0.7%. these findings are comparable to contemporary series.(10,11) kessaris et al, reported post pcnl vascular lesions in 0.8 % of their patients.(10) el tayeb et al, also published the result of their survey of 2892 pcnls for which angioembolization was required in 0.5%.(11) many centers would embolize post pcnl hemorrhage early-on. this would detract from those left to present with delayed bleeding, and explains the apparently high proportion of embolized cases in our series which is entirely composed of the high risk patients presenting with delayed gross bleeding, and diagnosed with an overt vascular lesion. in our series, there was no significant difference between the avf and pa in terms of demographic data and other preoperative or intraoperative variables, and none were consistently correlated with the type of lesion. however, factors including the magnitude of hemoglobin drop, number of transfused packed cell units, and duration of hospital stay at the second admission were significantly higher in the pa group. conversely, we found a significant dominance of avf over pa among initial responders to conservative treatment. in suggesting a cut-off point for the size of the vascular lesion, pcnl-to-readmission time and number of units transfused after stabilization enhance the practical value of these findings and enables us to counsel patients based on predictive factors and decide between two lines of treatment. to assist with this bedside decision, based on our multivariable analysis, we propose the popvesl score (short for post pnl vascular embolization selection), wherein the risk factors recognized above are included and weighted building upon their calculated odds ratio, and fine-tuned based on expert opinion of the researchers for fidelity and the highest differentiating power, to derive a score as described in table 3. our study suggests that conservative management and prompt intervention do differ in cost. we calculated the direct cost of each modality in our public health care system as an example, confident that the popvesl score can be used equally well at contrasting settings where the index shall help by predicting the odds for each course of action, while local healthcare fees will be factored-in to allow patients and care givers to make an educated choice. in our academic hospital setting in this country, patients are typically covered by public health insurance. the average cost (at the exchange rate in mid-2019) for hospitalized patients managed on conservative therapy in this series was 30 usd per day, and total cost of conservative therapy amounted to 260 usd +/150 usd; of which patients only pay 10% out of pocket. whereas the total hospital cost for cases requiring angioembolization was about seven times this amount, mostly owing to the coils which alone costed 1600 usd, comparable to the us price tag.(16) due to high costs of angioembolization in our setting and its potential complications, usually in case of stable clinical status following initial resuscitation we offer both treatments to our patients. because of the high success rate of conservative therapy and its lower cost and acceptable complications, most of them choose to be managed conservatively at the beginning. although representing one of the largest volumes of data for any single-center, the low overall incidence of this complication nevertheless makes sample size one of the limitations of this study, along with its retrospective nature. future prospective studies with a larger sample size may fine-tune weight allocation to the score criteria. conclusions post pcnl intrarenal vascular lesions usually occur in the form of arteriovenous fistula and pseudoaneurysm. patients with stable hemodynamics and less severe bleeding can be managed conservatively. based on our results in multivariable analysis, more transfusions, presence of pa, history of open renal surgery, larger p o p v e pseudoaneurysm open surgery on the same kidney post-surgery interval (≥8.5 days) vascular lesion diameter (≥7.5mm) extra units of blood beyond initial stabilization 3 points 5 points 2 points 3 points 2 points per unit table 3. popvesl scoring system for calculating the likelihood of requiring vascular intervention for patients with delayed post pnl bleeding. popvesl risk score for post pcnl bleeding-shadpour et al. endourology and stones diseases 282 vol 18 no 3 may-june 2021 283 vascular lesion and protracted interval between pcnl and second admission are independent predictive factors for angioembolization. our findings including the proposed popvesl score have potential implications in updating future guidelines on the management of post-pcnl bleeding. acknowledgments the authors are grateful to the hospital management research center, iums; for administrative and technical support from the staff, notably comments from epidemiologists mojdeh ramezani md ph.d. & mohsen shatti md ph.d. conflict of interest there is no conflict of interest, or any financial agreement with companies whose products may be alluded to in the paper references 1. european association of urology. (2020). guideline of urolithiasis. retrieved from https://uroweb.org/guideline/urolithiasis/ accessed 1/17/2020 2. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur. urol. 2007; 51:899906 3. matlaga br, krambeck ae, lingeman je: surgical management of upper urinary tract calculi. in: wein aj, kavoussi lr, partin aw et al. campbell-walsh urology-eleventh edition. philadelphia: elsevier, 2016, pp 1111282. 4. zabkowski t, piasecki p, zielinski h, et al. superselective renal artery embolization in the treatment of iatrogenic bleeding into the urinary tract. med sci monit. 2015; 21:333-7. 5. demey a, colomb f, pebeyre b, et al. persistent hematuria after embolization for hemorrhagic complication following percutaneous nephrolithotomy: value of the study of red blood cell volume in urine. prog urol. 2003; 13:486-90. 6. li l, zhang y, chen y, et al. a multicentre retrospective study of transcatheter angiographic embolization in the treatment of delayed haemorrhage after percutaneous nephrolithotomy. eur radiol. 2015; 25:11407. 7. el tayeb mm, knoedler jj, krambeck ae, et al. vascular complications after percutaneous nephrolithotomy: 10 years of experience. j.urology. 2015; 85:777-81. 8. un s, cakir v, kara c, et al. risk factors for hemorrhage requiring embolization after percutaneous nephrolithotomy. cuaj-can urol assoc. 2015; 9:e594-8. 9. etemadian m, soleimani mj, haghighi r, et al. does bleeding during percutaneous nephrolithotomy necessitate keeping the nephrostomy tube? a randomized controlled clinical trial. urol j. 2011; 8:21-6. 10. stoller ml, wolf js jr, st lezin ma. estimated blood loss and transfusion rates associated with percutaneous nephrolithotomy. j urol. popvesl risk score for post pcnl bleeding-shadpour et al. 1994; 152:1977-81. 11. srivastava a, singh kj, suri a, et al. vascular complications after percutaneous nephrolithotomy: are there any predictive factors? j.urology. 2005; 66:38-40. 12. seetharama madhusudhan k, ananthashayana venkatesh h, gamanagatti sh, interventional radiology in the management of visceral artery pseudoaneurysms: a review of techniques and embolic materials, korean j radiol. 2016 may-jun; 17: 351–63. 13. ierardi am, floridi c, fontana f, et al. transcatheter embolisation of iatrogenic renal vascular injuries. radiol med 2014;119:2618. 14. jain s, nyirenda t, yates j, et al. incidence of renal artery pseudoaneurysm following open and minimally invasive partial nephrectomy: a systematic review and comparative analysis. j urol 2013;189:1643-8. 15. shapiro ey, hakimi aa, hyams es, et al. renal artery pseudoaneurysm following laparoscopic partial nephrectomy. j.urology 2009;74:819-23. 16. fergus kb, baradaran n, tresh a, use of angioembolization in urology: a review, transl androl urol 2018;7:535-44 1320 | single dose silodosin prior to voiding cystourethrogram: a pharmacological adjunct to enhance visualization of posterior urethra deepak sharanappa nagathan, divakar dalela, satyanarayan sankhwar, apul goel, amod kumar dwivedi, rahul yadav corresponding author: divakar dalela, md department of urology, chhatrapati shahuji maharaj medical university, erstwhile king george medical college, lucknow, up, india. tel: +91 522 2256543 fax: +91 522 2256543 e-mail: drdalela@satyam.net.in received april 2012 accepted october 2012 department of urology, chhatrapati shahuji maharaj medical university, erstwhile king george medical college, lucknow, up, india. brief communication abstract voiding cystourethrogram (vcug) is needed to ascertain the upper end of urethral stricture. occasionally, a patient is unable to open the bladder neck with resultant failure of the test. realizing the strong and prompt alpha antagonistic action of silodosin, we evaluated single 8 mg dose as a pharmacological adjunct prior to vcug to overcome this problem. keywords: voiding cystourethrogram; silodosin; posterior urethra. introduction voiding cystourethrogram (vcug) is a commonly used technique to image the poste-rior urethra. in contrast to the retrograde urethrogram, opening of the bladder outlet and distension of the posterior urethra are achieved during vcug. sometimes patient is unable to void and open the bladder outlet with resultant failure of contrast to reach the upper end of the obliteration. this makes assessment of length of the stricture difficult especially in a case of pelvic fracture urethral distraction defect (pfudd). various methods have been used to overcome this problem such as passing a bougie through the suprapubic route, passing ureteric catheter antegradely under cystoscopic guidance into the posterior urethra followed by instillation of contrast and magnetic resonance imaging (mri). however, these alternative methods are invasive except for mri. silodosin is a highly selective α1a-blocker which acts on α1a receptors on bladder outlet and prostate. silodosin, with rapid onset of action and with its time to peak concentration approxibrief communication 1321vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l silodocin prior to vcug | nagathan et al mately being 2.6 hours,(1) we explored the usefulness of silodosin prior to vcug to improve the opening of bladder outlet and delineate the posterior urethra. materials and methods all men attending the urology clinic with pelvic fracture urethral distraction defect and stricture urethra with complete obliteration of urethral lumen requiring vcug were included in the study. children, men who voided per urethra, men with neurogenic bladder/ vesical calculus or having contraindication to the use of silodosin (severe hepatic or renal impairment) and who refused to give consent were excluded from the study. all men initially underwent vcug in the conventional manner. men who failed to open the bladder outlet during conventional vcug were done repeat vcug the next day with a single dose of silodosin 8 mg administered three hours prior to repeat vcug. vcug was performed by filling the bladder with contrast medium (made by 76% sodium diatrizoate with distilled water in the ratio of 1:4) through an indwelling suprapubic catheter. when the patient felt the normal desire to void, voiding command was given and a conventional x-ray film was taken. the x-ray films were reviewed by a senior urologist to note the opening of bladder outlet and visualize the posterior urethra. baseline demographic characteristics, indication for vcug, duration of suprapubic catheter and amount of contrast used to fill bladder were noted. the results are presented in means (± sd) and proportions with its 95% confidence intervals. results forty men met the inclusion criteria from august 2011 to february 2012. their demographic data are presented in table. the mean age was 41.8 years with an average body mass index of 23.12 kg/m2. the various indications for performing vcug were pfudd 20/40 (50%), post traumatic bulbar urethral stricture 7/40 (17.5%), lichen sclerosis 6/40 (15%) and post catheterization stricture 7/40 (17.5%). all men had a suprapubic catheter (spc) and the mean duration of spc was 3.5 months. on an average 326.5 ml of contrast was used to fill the bladder to initiate voiding. of participants 28/40 [70%, 95% confidence interval (ci): 56%-84%] men were found to have bladder outlet opened. a total of 12 men couldn’t initiate voiding at the first vcug (figures 1, and 2a). after administration of single dose 8 mg silodosin 3 hours prior to vcug, opening of bladder outlet was achieved in 10 out of 12 men (83.3%, 95% ci: 55%-104%) thus helping in assessing the stricture length (figure 2b). all men completed the study. none of the men reported any adverse effect following administration of the drug. the most prevalent adverse effects of silodosin are hypotension and ejaculatory disturbances. we looked at postural hypotension by measuring blood pressure at baseline, 0, 5 and 10 minutes after administration of drug. there was no significant drop in the blood pressure after administration of drug and none of the patients complained of ejaculatory disturbances because they were not sexually active during the study period. discussion it is important to define the length of the stricture before operating a case stricture urethra or pfudd. various methods such as combined retrograde urethrogram and micturition cystourethrogram,(2) passing of curved metal sound,(2) magnetic resonance imaging(3) and antegrade urethrogram(4) have been used to overcome this problem. although combined rgu and vcug is useful, sometimes bladder outlet does not open because of reduced bladder capacity due to long standing spc and inability to tolerate the bladder distension sufficient enough to open the bladder outlet voluntarily.(5) passfigure 1. retrograde urethrogram showing complete obliteration at the junction of bulbo-membranous urethra in a man with pelvic fracture urethral distraction defect. 1322 | ing of curved metal sound may be deleterious in some cases with inadvertent injury to the bladder outlet. antegrade urethrogram is also useful but is an invasive procedure, requires an expertise and a cystoscope which may not be available at the site of radiology suite to pass the ureteral catheter in posterior urethra. although mri is non-invasive, it is costly and urologists are not familiar in interpreting an mri. also, at mr imaging it is not easy for the patients to open their bladder outlet continuously by straining and increasing the abdominal pressure. silodosin is a new α-adrenoreceptor (ar) antagonist and has been approved by the us food and drug administration in 2008 for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia. silodosin with its favorable pharmacological profile having rapid onset of action within 2 hours(6) and higher affinity for α1a adrenergic receptors compared to tamsulosin and alfuzosin(7) is ideal in this circumstance to relax bladder outlet and prostatic urethra to initiate voiding. in the present study 10 out of 12 men who failed to initiate voiding, voided with the use of silodosin thus substantiating the role of a single dose of silodosin prior to vcug. in two patients spc was in situ for more than 10 months and contrast back leaked by the side of spc despite all maneuvers to prevent it. the probable cause for failure to void was the presence of spc for long term which caused a low compliant and overactive bladder which did not allow the bladder to be filled to its normal capacity. the factors which influence the opening of bladder outlet includes amount of urine in the bladder and an intact nervous system facilitating the micturition process. the micturition process is innervated by parasympathetic nerves (detrusor contractility), sympathetic nerves (bladder outlet relaxation) and somatic nerves (urethral sphincter relaxation). the beneficial effects of α1a ar blockers are associated mainly with relaxation prostatic and urethral smooth muscle. however the bladder outlet also consists of bladder neck, prostate, intraprostaitc urethra and external sphincter. these outlet structures contain α1a ar. (8) therefore, blocking these receptors reduces resistance and facilitates voiding. during vcug, few individuals are anxious because of unnatural position and unfamiliar surroundings with resultant increased sympathetic drive which may preclude opening of the bladder outlet and failure of the test. highly selective α1a blockers with short peak onset of action such as silodosin are effective in such circumstances when administered prior to performance figure 2b. voiding cystourethrogram shows opening of bladder outlet and delineation of proximal urethra after administration of silodosin. figure 2a. voiding cystourethrogram shows failure of bladder outlet to open in same patient. brief communication 1323vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l references 1. rossi m, roumeguère t. silodosin in the treatment of benign prostatic hyperplasia. drug des devel ther. 2010;4:291-7. 2. goel mc, kumar m, kapoor r. endoscopic management of traumatic posterior urethral stricture: early results and follow-up. j urol. 1997;157:95-7. 3. sung dj, kim yh, cho sb, et al. obliterative urethral stricture: mr urethrography versus conventional retrograde urethrography with voiding cystourethrography. radiology. 2006;240:842-8. 4. goel a, gupta a, dalela d. antegrade urethrogram: a technique to visualise the proximal bulbous urethral segment in anterior urethral stricture. indian j urol. 2009;25:415-6. 5. sandler cm, mccallum rw. urethral trauma. in: pollack hm, mcclennan bl, editors. clinical urography. 2nd ed. philadelphia: saunders; 2000. p. 1819-37. 6. matsubara y, kanazawa t, kojima y et al. pharmacokinetics and disposition of silodosin (kmd-3213). yakugaku zasshi. 2006;126:24756. 7. cantrell ma, bream-rouwenhorst hr, hemerson p, magera js jr. silodosin for benign prostatic hyperplasia. ann pharmacother. 2010;44:302-10. 8. mattiasson a, andersson ke, elbadawi a, morgan e, sjögren c. interaction between adrenergic and cholinergic nerve terminals in the urinary bladder of rabbits, cats and man. j urol. 1987:137:1017-9. the test. in the study by tsumura and colleagues(9) patients with prostatic cancer who had prostatic implants as part of brachytherapy were prophylactically administered silodosin showed significant improvement in the post void residual urine at 6 months vs. tamsulosin. in another study uchiyama and colleagues(10) have prospectively studied the effect of silodosin on lower urinary tract symptoms in female and have found silodosin to be effective in improving voiding, storage symptoms and quality of life. uroflowmetry parameters improved in most patients along with significant reduction in postvoid residual urine. one of the limitations in the present study was that there was no control group. also, there are no similar studies to the best of our knowledge to compare our results. randomized, placebo controlled trial are required to further confirm our findings. conclusion the use of single dose silodosin (8 mg) to effectively open the bladder outlet and visualize the posterior urethra prior to vcug. conflict of interest none declared. table . demographic data of men undergoing voiding cystourethrogram. variables voiding cystourethrogram, n = 40 age, years (mean) 41.8 (20-70) etiology, no. (%) pelvic fracture urethral distraction defect 20 (50.0) bulbar urethral stricture 20 (50.0) post traumatic 7 (17.5) lichen sclerosis 6 (15.0) post catheterization 7 (17.5) duration of suprapubic catheterization, months (mean) 4 (1-6) volume of contrast instilled into bladder to initiate voiding before voiding cystourethrogram, ml 326.5 (150-450) bladder outlet opened on initiation of voiding 28/40 (70%, 95% ci: 56%-84%) bladder outlet opened on initiation of voiding with silodosin 10/12 (83.3%, 95% ci: 55%-104%) silodocin prior to vcug | nagathan et al 1324 | 9. tsumura h, satoh t, ishiyama h, et al. comparison of prophylactic naftopidil, tamsulosin and silodosin for 125i brachytherapyinduced lower urinary tract symptoms in patients with prostate cancer: randomized control trial. int j radiat oncol biol phys. 2011;81:e385-92. 10. uchiyama t, yamamoto t, sakakibara r, yanagisawa m, knai k, mori m. selective a1a-blocker “silodosin” safety improves female lower urinary tract dysfunctions. available from: www.icsoffice.org/abstracts/publish/106/000722.pdf brief communication v08_no_2_final.pdf pictorial urology 98 urology journal vol 8 no 2 spring 2011 ureteral herniation with intermittent obstructive uropathy in a renal allograft recipient urol j. 2011;8:98. www.uj.unrc.ir a 44-year-old man underwent live related allograft renal transplantation for stage v chronic kidney disease secondary to unknown cause three years earlier. the immunosuppressive regimen consisted of cyclosporine, azathioprine, and prednisolone. the nadir creatinine level of 1.5 mg/dl was reached one week postoperatively. this remained stable for 30 months when the serum level of creatinine began to fluctuate intermittently between 1.5 mg/dl and 2.2 mg/dl. he noticed a reducible swelling in the lower third of the transplant scar that was confirmed to be an incisional hernia. ultrasonography showed graft hydroureteronephrosis. magnetic resonance urography revealed an incisional hernia involving the lower third of the transplant scar, containing the mid-portion of the transplant ureter and compressing the distal ureter at the neck of the hernial sac, causing hydroureteronephrosis. on exploration, the ureter was found to be in the wall of the hernial sac compressed by the adjacent omentum. the ureter was released from the adherent sac and found to be draining freely. the hernia was repaired using a prolene mesh. after surgery, the serum level of creatinine returned to 1.5mg/dl and a follow-up diuretic renography showed free drainage. ureteral obstruction is a known complication following renal transplantation, often resulting in obstructive uropathy. this requires redo reimplantation, percutaneous diversion, or dilatation and stenting. ureteroinguinal hernias are rare, with about 130 subjects reported in the literature.(1) sliding inguinal hernias containing the ureters have been reported in renal allografts with six reports in literature.(2) we report a case of obstructive uropathy secondary to ureteral herniation into an incisional hernial sac following renal allograft transplantation. to the best of our knowledge, this is the first such report in medical literature and illustrates the importance of recognizing common surgical complications in renal allograft recipients. rajiv p mukha,* antony devasia, elsa m thomas departments of urology and radiodiagnosis, christian medical college vellore, tamil nadu, india *e-mail: mukhas@gmail.com references 1. brand me, brooks s, brooks-searle k, esterl r. ureteroinguinal hernia: a rare cause of ureteral obstruction. surgical rounds. 2006;29:128. 2. otani lh, jayanthi sk, chiarantano rs, amaral am, menezes mr, cerri gg. sonographic diagnosis of a ureteral inguinal hernia in a renal transplant. j ultrasound med. 2008;27:1759. 1602 | prevalence of urinary incontinence and lower urinary tract symptoms in school-age children ipek ozunan akil,1 dilek ozmen,2 aynur cakmakci cetinkaya2 corresponding author: ipek ozunan akil, md department of pediatric nephrology, celal bayar university, izmir, turkey. tel: +90 236 44 44 228 3164 fax: +90 236 233 80 40 e-mail: ipekozunan@yahoo.com received november 2012 accepted january 2014 1 department of pediatric nephrology, celal bayar university, izmir, turkey. 2 department of public health nursing, school of health, celal bayar university, izmir, turkey. pediatric urology pediatric urology purpose: to investigate the prevalence of lower urinary tract symptoms (luts) and urinary incontinence (ui) in elementary school aged children in manisa. materials and methods: dysfunctional voiding and incontinence scoring system (dvis) which was developed in turkey is used. a total of 416 children, 216 (51.9%) male and 200 (48.1%) female were recruited in this study. results: mean age of children was 10.35 ± 2.44 years (median10 years). daytime ui frequency was 6.7% (28 child), nocturnal incontinence 16.6% (69 child) and combined daytime and nocturnal incontinence 4.1% (17 child). there was no statistically significant difference in the prevalence of nocturnal and or daytime ui between male and female gender. mean dvis score was 2.65 ± 3.95 and gender did not affect total dvis points. the mean ages of achieving daytime bowel and bladder control were all significantly correlated with dvis points. dvis points were positively correlated with the history of ui of the family. total points were increased when the father was unemployed. conclusion: ui negatively influences health related quality of life of the family and child, so it is important that awareness of the ui and symptoms of lower urinary tract dysfunction. keywords: lower urinary tract symptoms; child; urination disorders; prevalence; urinary incontinence. 1603vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l prevalence of luts in children | akil et al introduction urinary incontinence (ui) is a common and impor-tant health problem in childhood.(1) it may cause considerable impact on health related quality of life of both the affected child and caregivers.(2,3) nocturnal ui also has negative effects on the child’s sleep quality, because they might be anxious about the risk of urination while asleep.(4) international children’s continence society (iccs) classifies ui in the storage symptoms of bladder and it defines ui as uncontrollable leakage of urine. it can be continuous associated such as ectopic ureter or intermittent. nocturnal enuresis (nocturnal incontinence) describes incontinence while sleeping. daytime incontinence is incontinence during the day. the child may have both nocturnal and daytime ui.(1) fewer than half of the patients presenting with incontinence is thought to be really mono-symptomatic nocturnal enuresis.(5) also, there is a prominent differentiation in children between with mono-symptomatic nocturnal enuresis and who have lower urinary tract symptoms (luts) (non-monosymptomatic nocturnal enuresis) according to pathogenesis, clinical findings and treatment modalities.(1) increased/decreased voiding frequency, daytime incontinence, urgency, hesitancy, straining, a weak stream, intermittency, holding maneuvers, a feeling of incomplete emptying, post-micturition dribble and genital or lower urinary tract pain are luts. nevertheless, general knowledge and interest are often based on nocturnal enuresis (nocturnal incontinence). investigations about nocturnal enuresis including pathophysiology, genetics, and prevalence are much frequent than daytime ui.(6-10) there are a lot of data investigating the prevalence and associated factors of mono-symptomatic nocturnal enuresis in general literature and in turkey.(1,5-13) but, lack of adequate epidemiological data on the prevalence of lower urinary tract symptoms and ui in school-aged children in turkey led us conduct a cross-sectional study in a representative population in our region. materials and methods this is a cross-sectional study planned in the center of the province of manisa including children with the age of 7-15 years. according to data from in the center of manisa province of 11 family health center registered by household assessment sheets (forms) in 2010, there were 41648 children aged between 7 and 15 years. the sample size was calculated as 381 in epi info 2000 program with a margin of error of 95% confidence interval (ci) and with 0.05 error share (based on the expected prevalence of 50%). the survey sample of children admitting family health centers were detected with stratified sampling method according to the number registered in 7-15 age children. sampling within each family health center, children were randomly selected from household detection plugs. creating the sample, the plugs were randomly selected from in a row lined up according to the districts. registered 7-15 age children in these randomly selected plugs were included in the study. if the plug does not have registration for children in this age group, by selecting a new chip sampling was completed with 416 children. celal bayar university hospital ethical committee approved the study. written permission for the conduct of the study in family health centers was obtained from the directorate of health in manisa. informed consent was obtained from parents of children participating in the study. the data was collected from home visits using face to face interview technique between 1 march 2011 to 30 may 2011. as the data collection tool two forms were used. the first one was information form developed by researchers and, the second form was dysfunctional voiding and incontinence scoring system (dvis) which was developed by department of pediatric urology unit of hacettepe university.(14) dvis contains 14 questions including daytime symptoms related urination, night symptoms, voiding habits, bowel habits and quality of life of children. high dvis scores indicate increased risk of disease severity. additionally, we used socio-demographic information form that we developed. it has 28 questions that describe some properties of the child and family, family’s socioeconomic, training status and micturition habits. statistical analysis the statistical analysis of data was performed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. to assess the data points and percentage distributions, pearson chi-square test, student’s t test and one way anova variance analysis were used. the cronbach alpha for intrinsic factors of dvis was 0.77 for this study. 1604 | results there were 416 children in the study, 216 (51.9%) of them were boys and 200 (48.1%) were girls. mean age of children was 10.35 ± 2.44 years (median 10 years). the majority (70.4%) of the families were defined themselves as moderate income families and 8.4% of them did not have any social security. in this study, 56.2% (234) of children described at least one symptom of lower urinary tract dysfunction. mean dvis score was 2.65 ± 3.95 (min: 0, max: 27, median: 1). of study families 22.6% stated that luts were negatively affected their quality of life. luts were not found related with gender. cronbach's alpha coefficient of the scale for this study was 0.7401. table 1 shows the prevalence of luts according to the gender in the study group. the mean ages of achieving daytime bowel and bladder control, family history for ui, sleep arousal, age and whether the father has a job or not were all significantly correlated with dvis points (table 2). consanguineous marriage, the age of mother during pregnancy, the age of father, time of birth, birth weight, breastfeeding, labor (vaginal or operational), the order of siblings, family’s education level were not in relation to ui. availability of toilet training, the age of toilet training, punishment during toilet training were not statistically correlated with dvis points. daytime ui frequency was 6.7% (28 child), nocturnal incontinence 16.6% (69 child) and combined daytime and nocturnal incontinence 4.1% (17 child). there was no statistically significant difference between male and female gender according to nocturnal and or daytime incontinence (table 3). the highest prevalence was 7 years for both nocturnal ui and daytime ui (24.3% and 13.5%, respectively) and the prevalence was decreased with increasing age. when total dvis points evaluated according to the age, it was decreased while the age was increased. discussion it is very well known that lower urinary tract dysfunctions are associated with recurrent urinary tract infections (uti), vesicoureteral reflux (vur) and permanent kidney damage.(15) the relationship between the degree of renal scar and detrusor pressures were reported in literature.(16) also, detrusor-sphincter dyssynergia is more associated vur and uti in comparison with only bladder instability.(17) all type of lower urinary tract dysfunctions present some symptoms and findings of luts mainly increased/decreased voiding frequency, daytime incontinence, urgency, and holding maneuvers. among them, nocturnal incontinence has greater emphasis than daytime incontinence and the other symptoms for the families and families generally do not know their child’s voiding and defecation patterns except nocturnal incontinence. sometimes, incontinence is interpreted as resolves with time by both families and health workers. in our country, urological problems comprised the largest group (50.7%) for the underlying etiologies of end stage renal failure in childhood. these were mainly vesicoureteral reflux (18.5%), neurogenic bladder (15.2%) and chronic pyelonephritis (2.2%).(18) many of these children may have luts. unfortunately, lower urinary tract dysfunction is frequently diagnosed following established renal damage. so, we wanted to know the prevalence of luts in children elementary school aged children (7-15 years) in our city. we have used dvis form which has a validation form in turkish.(14) in this scoring system, 8.5 points and higher values have 90% sensitivity and 90% specificity in determining the voiding dysfunction with a ci of 96.2%. mean dvis score was 2.65 ± 3.95 in our study and 38 (9.1%) children received equal or greater than 8.5 points indicating lower urinary tract dysfunction. we informed these children and their families about the importance of their complaints and to apply to a pediatric nephro-urological outpatient clinic for treatment and associatpediatric urology figure. prevalence of nocturnal urinary incontinence (ui), daytime ui and dysfunctional voiding and incontinence scoring system (dvis) points according to ages. 1605vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l prevalence of luts in children | akil et al table 1. description of symptoms in study group and its distribution according to the gender. luts male (n = 216) no. (%)* female (n = 200) no. (%)* total no. (%)** p*** voiding number (more than 7 per day) yes 193 (53.6) 167 (46.4) 360 (86.5) .081 no 23 (41.1) 33 (58.9) 56 (13.5) strain during voiding yes 208 (52.1) 191 (47.9) 399 (95.9) .682 no 8 (47.1) 9 (52.9) 17 (4.1) pain during voiding yes 207 (53.1) 183 (46.9) 390 (93.8) .068 no 9 (34.6) 17 (65.4) 26 (6.3) intermittently voiding yes 209 (52.4) 190 (47.6) 399 (95.9) .365 no 7 (41.2) 10 (58.8) 17 (4.1) needs to go back voiding soon after finishes his/her pee yes 205 (53.2) 180 (46.8) 385 (92.5) .057 no 11 (35.5) 20 (64.5) 31 (7.5) sudden feeling of having to urinate immediately yes 152 (53.3) 133 (46.7) 285 (68.5) .396 no 64 (48.9) 67 (51.1) 131 (31.5) holding manoeuvres yes 179 (53.3) 157 (46.7) 336 (80.8) .258 no 37 (46.3) 43 (53.8) 80 (19.2) wets on the way to the toilet yes 196 (53.4) 171 (46.6) 367 (88.2) .098 no 20 (40.8) 29 (59.2) 49 (11.8) constipation yes 196 (53.6) 170 (46.4) 366 (88.0) .072 no 20 (40.0) 30 (60.0) 50 (12.0) key: luts, lower urinary tract symptoms. *percentage of row. ** percentage of column. ***pearson chi-square test. ed morbidities. as interesting, a large number of children were found to be affected with this scoring system in at least in one question in our study. whereas, vaz and colleagues described as affected children number was 21.8 % children (161 in 739) in their study groups.(19) luts such as urgency, frequent daytime voiding, nocturia and urge-incontinence were found significantly associated with childhood urinary symptoms in adult females.(20) in our study, dvis points were positively correlated with the presence of family history of ui. this finding preoccupied us that the proper diagnosis and treatment of lower urinary tract dysfunctions were very important in childhood. this study also revealed that dvis points were associated with the age of children (figure), father’s job, sleep arousal of the children and the time of urinary and bowel control. it is generally accepted that daytime ui depends more weakly on socioeconomic and stressful events than nocturnal ui, however we found total dvis points were increased when the father was unemployed.(21) delaying in bowel and bladder control may be related with lower urinary tract dysfunction. in this study, increasing of the mean ages of achieving of daytime bladder and bowel control were all associated with increased dvis points. 1606 | pediatric urology in literature, there are several different results for the prevalence of daytime ui in childhood; it varies from 2.1% to 30.7%.(22-25) lee and colleagues reported the prevalence of daytime ui as 2.1% in 7-12 aged 12570 korean children (the boys had 1.3%, girls 0.8%).(23) sureshkumar and colleagues found the prevalence of daytime ui as 19.2% with a slight girl predominance (boys had 16% and girls 21.8%).(22) from our country, toktamis and colleagues reported overall prevalence of daytime ui was 2.6%, with a tendency to decrease with increasing age and with no difference between genders. (19) in another study, prevalence of daytime ui was reported as 8.3%, and there was no statistical difference between the girls and the boys however the girls slightly more had daytime ui (7.2% and 9.5%, respectively).(25) our study revealed that daytime ui was 6.7%, and the gender did not affect the frequency (the boys had 6.9% and girls 6.5%). daytime ui prevalence is decreasing with the child’s age increases as in agreement with the other studies (figure). the overall nocturnal ui prevalence was 16.6%, marked nocturnal ui was 4.3% (more than 2 per week) in our study group. we did not find gender difference for nocturnal ui. nocturnal ui prevalence was decreasing with age as expected (figure). gunes and colleagues reported that overall prevalence of nocturnal ui as 14.9%. they reported that no difference in prevalence of nocturnal ui between boys and girls (14.3% vs. 16.8%).(25) in ozkan and colleagues’ study the prevalence of whole enuresis was 12.9% and the prevalence of prominent enuresis (at least weekly) was 9.8%. they revealed that nocturnal ui is more prevalent in boys (male to female ratio 1.6) and the prevalence rates declined by age without gender bias.(11) our results are consistent with the literature and nocturnal ui is more prevalent health problem in childhood in our country. iccs consensus states that a normal urinary frequency is between four and seven times per day. the numbers out of these values may point the lower urinary tract dysfunction.(1) in our study, frequent voiding (more than 7) prevalence was 13.5%. there was no gender difference for frequent voidtable 2. dysfunctional voiding and incontinence scoring system points and associated factors. variables number mean ± sd p age of children < 10 years 217 3.32 ± 4.41 .000* > 10 years 199 1.92 ± 3.23 unemployed father yes 94 2.51 ± 3.79 .042* unemployed and/or retired 312 3.81 ± 5.07 urinary incontinence in family yes 73 5.46 ± 6.09 .000* no 341 2.06 ± 3.02 sleep arousal sensitive sleep (a) 42 3.21 ± 4.95 .001** normal (b) 309 2.25 ± 3.45 a = b > c deep sleep (c) 65 4.21 ± 4.99 time of urinary control < 2 year 242 2.1 ± 3.23 > 2 year 166 3.27 ± 4.57 .005* time of bowel control < 2 year 228 2.15 ± 3.29 > 2 year 179 3.16 ± 4.5 .012* * student’s t test. ** one way anova test. 1607vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l prevalence of luts in children | akil et al ing. holding maneuver symptoms were detected in %19.2. although we did not observe a difference for holding maneuvers between genders, vaz and colleagues reported same ratios but girl predominance for this symptom.(19) so, urinary frequency and holding maneuvers should paid attention in clinical practice. lower urinary tract dysfunction symptoms were reported more frequent among girls than boys by vaz and colleagues. (19) however, we could not observe difference between genders for luts. we thought that each society may have different characteristic properties so the problems may vary from one to another. loening-baucke has found constipation prevalence as 22.6% in 4-17 aged children.(26) vaz and colleagues were reported constipation prevalence in their group as 30.7%.(19) there was a close relationship between constipation and lower urinary tract dysfunction. treatment of constipation was yielded in dissolution of daytime ui in 89% and nighttime ui in 63% of patients.(27) constipation was detected less from the other studies, as 12% in our study population. we found that constipation was more prevalent in children with nocturnal incontinence, but it was not statistically significant, and we did not found relationship between daytime ui and constipation in our group. conclusion as a result, this study points out that ui and luts are not uncommon in school aged children, especially in younger group, however, gender does not affect incontinence and general luts. when it was thought that ui negatively influences health related quality of life of family, the importance of the awareness of the problem and therapy come forward. table 3. prevalence of urinary incontinence types in children and distribution according to the gender. variables male (n = 216) no. (%) female (n = 200) no. (%) total no. (%)* p* daytime ui yes 15 (6.9) 13 (6.5) 28 (6.7) .857 no 201 (93.1) 187 (93.5) 388 (93.3) nocturnal ui yes 35 (16.2) 34 (17.0) 69 (16.6) .827 no 181 (83.8) 166 (83.0) 347 (83.4) combined daytime and nocturnal ui yes 8 (3.7) 9 (4.5) 17 (4.1) .682 no 208 (86.3) 191(95.5) 399 (95.9) key: ui, urinary incontinence. *pearson chi-square test. references 1. nevéus t, von gontard a, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents: report from the standardization committee of the international children’s continence society. j urol. 2006;176:314-24. 2. hagglof b, andren o, bergstrom e, marklund l, wendelius m. selfesteem in children with nocturnal enuresis and urinary incontinence: improvement of self-esteem after treatment. eur urol. 1998;33:16-9. 3. egemen a, akil i, canda e, ozyurt bc, eser e. an evaluation of quality of life of mothers of children with enuresis nocturna. pediatr nephrol. 2008;23:93-8. 4. gozmen s, keskin s, akil i. enuresis nocturna and sleep quality. pediatr nephrol. 2008;23:1293-6. 5. neveus t, eggert p, evans j, et al. evaluation of and treatment for monosymptomatic enuresis: a standardization document from the international children's continence society. international children's continence society. j urol. 2010;183:441-7. 6. robson lm, leung a, van hoee r. primary and secondary nocturnal enuresis: similarities and presentation. pediatrics. 2005;115:956-9. 7. butler rj, redfern ej, holland p. children's notions about enuresis and the implications for treatment. scand j urol nephrol. 1994; suppl 163:39-47. 8. balat a, alasehirli b, oguzkan s, gungor m. nitric oxide synthetase gene polymorphisms in children with primary nocturnal enuresis: a preliminary study. ren fail. 2007;29:79-83. 9. schaumburg hl, kapilin u, blasvaer c, et al. hereditary phenotypes in nocturnal enuresis. bju int. 2008;102:816-21. 1608 | 10. butler rj, heron j. the prevalence of infrequent bedwetting and nocturnal enuresis in childhood. scand j urol nephrol. 2008;42:25764. 11. ozkan ku, garipardic m, toktamis a, karabiber h, sahinkanat t. enuresis prevalence and accompanying factors in schoolchildren: a questionnaire study from southeast anatolia. urol int. 2004;73:14955. 12. inan m, tokuc b, aydiner cy, aksu b, oner n, basaran un. personal characteristics of enuretic children: an epidemiological study from south-east europe. urol int. 2008;81:47-53. 13. shadpour p, shiehmorteza m. enuresis persisting into adulthood. urol j. 2006;3:117-29. 14. akbal c, genc y, burgu b, ozden e, tekgul s. dysfunctional voiding and incontinence scoring system: quantitative evaluation of incontinence symptoms in pediatric population. j urol. 2005;173:969-73. 15. naseer s, steinhardt gf. new renal scars in children with urinary tract infections, vesicoureteral reflux and voiding dysfunction: a prospective evaluation. j urol. 1997;158:566-8. 16. acar b, arikan fi, germiyanoglu c, dallar y. influence of high pressure on vesicoureteral reflux and its resolution. urol int. 2009;82:7780. 17. rubben i, goepel m, van gool jd. non-neurogenic bladder dysfunction and vesicoureteral reflux in children. urologe a. 2011;50:551-6. 18. bek k, akman s, bilge i, et al. chronic kidney disease in children in turkey. pediatr nephrol. 2009;24:797-806. 19. vaz gt, vasconcelos mm, oliveira ea, et al. prevalence of lower urinary tract symptoms in school-age children. pediatr nephrol. 2012;27:597-603. 20. fitzgerald mp, thom dh, wassel-fyr c, et al. reproductive risks for incontinence study at kaiser research group. childhood urinary symptoms predict adult overactive bladder symptoms. j urol. 2006;175:989-93. 21. toktamis a, demirel y, ozkan ku, garipardiç m, gözüküçük a, nur n. prevalence and associated factors of day wetting and combined day and night wetting. urol int. 2008;81:54-9. 22. sureshkumar p, craig, jc, roy lp, knight jf. daytime urinary incontinence in primary school children: a population-based survey. j pediatr. 2000;137:814-8. 23. lee sd, sohn dw, lee jz, park nc, chung mk. an epidemiological study of enuresis in korean children. bju int. 2000;85:869-73. 24. söderstrom u, hoelcke m, alenius l, soderling ac, hjern a. urinary and fecal incontinence in primary school children: a populationbased survey. acta paediatr. 2004;93:386-9. 25. gunes a, gunes g, acik y, akilli a. the epidemiology and factors associated with nocturnal enuresis among boarding and daytime school children in southeast of turkey: a cross sectional study. bmc public health. 2009;9:357. 26. loening-baucke v. prevalence rates for constipation and faecal and urinary incontinence. arch dis child. 2007;92:486-9. 27. loening-baucke v. urinary incontinence and urinary tract infection and their resolution with treatment of chronic constipation of childhood. pediatrics. 1997;100:228-32. pediatric urology 373vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l renal tumors in young adults a single-center experience from a developing country rehan mohsin,1 altaf hashmi,1 gohar sultan,1 asad shehzad,1 muhammed mubarak,2 nazish ghazanfar,1 mutahir ali tunio,3 syed ali anwer naqvi,1 syed adeeb ul hassan rizvi1 purpose: to determine the pattern and outcome of renal tumors in young adults in a large surgical series in pakistan. materials and methods: we retrospectively analyzed 133 young adults (age: ≥ 16 to ≤ 40 years) with 136 renal tumors, who underwent surgical treatment for suspected renal cancer from 1994 till 2010. the clinical and pathological parameters were determined and their impact on final outcome was analyzed. results: the mean age of the patients was 33.3 ± 6.2 years. of 136, 121 (88.9%) renal tumors were malignant and 15 (11%) were benign. among malignancies, 76 (62.7%) patients had stage i or ii tumors, 22 (18.1%) stage iii, and 23 (19%) stage iv at surgery. the overall cancer-specific survival for malignant tumors at 1, 5, and 10 years was 97%, 83%, and 83%, whereas the cancer-free survival (cfs) was 80%, 63%, and 37%, respectively. patients with age ≤ 35 years had 1 and 5-year cfs of 83% and 71%, respectively, as compared with 76% and 49% for patients > 35 years (p = .02; odds ratio = 2.3; p = .03). regarding tumor size, 1 and 5-year cfs for tumors ≤ 10 cm was 93% and 75%, while tumors > 10 cm showed cfs of 56% and 41%, respectively (p = .0001; odds ratio = 4.2; p = .0001). for stage i tumors, cfs at 1 and 5 years was 98% and 84%; for stage ii, 82% and 63%; and for stage iii, 62% and 50%, respectively. one-year survival for stage iv was 48% only (p = .0001). conclusion: a wide heterogeneity of renal tumors is seen in young adults with delayed presentation. keywords: epidemiology, nephrectomy, outcome, kidney neoplasms, renal cell carcinoma, young adults corresponding author: muhammed mubarak, md department of histopathology, sindh institute of urology and transplantation, karachi, 74200, pakistan tel: +9221 9215752 fax: +9221 2726165 e-mail: drmubaraksiut@ yahoo.com received may 2011 accepted october 2011 1 department of urology, sindh institute of urology and transplantation, (siut), civil hospital, karachi, pakistan 2 department of histopathology, sindh institute of urology and transplantation, (siut), civil hospital, karachi, pakistan 3 department of radiation oncology, sindh institute of urology and transplantation, (siut), civil hospital, karachi, pakistan urological oncology 374 | introduction renal tumors comprise a diverse spectrum of neoplastic lesions with patterns that are relatively distinct for children and adults. adult renal tumors have a predilection to occur in older patients and are infrequent in adults younger than 40 years. a wide variety of both benign and malignant tumors arise from different components of the renal tissue, especially tubular epithelium. renal cell carcinoma (rcc) is the most common renal tumor in adults with the mean age of 62 years at occurrence.(1) only approximately 5% of all the kidney tumors in adults occur below the age of 40 years.(2) the incidence of renal tumors is on the rise throughout the world and across all age groups, particularly during the last few decades.(3,4) it is now believed that renal tumors in young adults differ from their counterparts in older adults in clinical behavior, biology, histology, and the longterm outcome.(5,6) however, the evidence for this, in the few published studies on the subject, is far from conclusive.(5) we have earlier reported, in the first detailed report from pakistan, the pattern of renal tumors in a preliminary report that included all the adults.(7) to the best of our knowledge, there is no data on the pattern of renal tumors and their behavior in young adults in pakistan. the aim of this retrospective study was to analyze different aspects of renal tumors in young adults based on a large surgical series of renal tumors from a single institution in pakistan and to compare them with the previously published literature. materials and methods the study was conducted at the department of adult urology, sindh institute of urology and transplantation (siut), karachi, pakistan over a period of 16 years from november 1994 till july 2010. medical records of 133 patients with 136 renal tumors who underwent surgical treatment for suspected renal cancer and were ≤ 40 years were retrospectively analyzed. data were collected in terms of age, gender, duration of symptoms, tumor size, laterality, and palpability of tumor. laboratory findings, including hemoglobin and renal functions, were also recorded. world health organization (2004) classification of adult renal tumors was employed for the pathological classification of tumors.(8) fuhrman nuclear grading system was used for rcc.(9) robson staging system was applied for assessing the extent of spread of malignant tumors.(10) disease status was also determined in terms of stability or progression of disease at the last follow-up. patients with benign tumors and incomplete follow-up or who were lost to follow-up were excluded from the survival analysis. follow-up duration was calculated from the date of surgery to the date of death or last follow-up. statistical analysis statistical analysis was performed by spss software (the statistical package for the social sciences, version 10.0, spss inc, chicago, illinois, usa). simple descriptive statistics, such as mean ± standard deviation, were used for continuous variables, such as age, while numbers (percentages) were used for categorical variables. the survival analysis was done using the kaplan-meier method, log-rank test, and multiple regression procedure of cox. p values of less than .05 were considered statistically significant. results a total of 1391 adult patients were treated surgically for suspected renal cancer during the study period. among these, 133 (9.50%) patients were ≤ 40 years old and constituted the study population of the present study. their mean age was 33.3 ± 6.2 years (range, 16 to 40 years). majority (66.40%) were > 30 years, while 39 (29.30%) were between 21 and 30 years, and only 5 (3.70%) patients were ≤ 20 years. the male to female ratio was 1.1:1, with 71 (53.30%) men and 62 (46.70%) women. clinical features at the time of presentation are urological oncology 375vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l renal tumors in young adults in pakistan | mohsin et al shown in table 1. it is seen that flank pain was the most common symptom, observed in 99 (72.40%) patients, followed by hematuria in 70 (52.60%). blood hemoglobin was > 10 g/dl in 95 (71.42%) patients, while the remaining 38 (28.60%) had hemoglobin ≤ 10 g/dl. eight (6.0%) patients were in renal failure at the time of presentation, while the remaining 125 (94.0%) patients had normal renal function. on examination, 77 (56.60%) renal tumors were palpable. the mean duration of symptoms, laterality, and size of the tumor along with type of the surgery, robson stage, and follow-up periods are shown in table 2. among malignant tumors, 76 (62.70%) patients had their tumors confined within gerota’s fascia (stage i or ii), 22 (18.10%) had stage iii, and 23 (19.0%) had stage iv at the time of surgery. on pathological examination, 121 (88.90%) renal tumors were malignant, while the remaining 15 (11.0%) were benign. the histopathological diagnoses of these tumors specimens are presented in table 3. outcome analysis we analyzed 94 patients who were on regular follow-up for their cancer-free status after surgery by table 1. clinical features at the time of presentation in 133 young adults with suspected renal cancer. signs/symptoms number (%) flank pain 99 (72.40) hematuria 70 (52.60) abdominal mass 12 (9.00) symptoms triad 30 (22.50) incidental finding 11 (8.20) fever 5 (3.70) weight loss 2 (1.50) table 2. clinicopathological characteristics of 133 young adults with suspected renal cancer. mean duration of symptoms, month 7.0 ± 2.4 site of tumor, n (%) right 67 (49.20%) left 65 (47.90%) bilateral 4 (2.90%) size of tumor, cm, n (%) 1 to 3 4 (2.90%) 4 to 7 22 (16.10%) 8 to 10 54 (39.40%) 11 to 15 40 (29.40%) > 15 16 (11.70%) mean tumor size, cm 10.4 ± 10.2 surgery, n (%) radical or palliative nephrectomy 129 (94.80%) partial nephrectomy 6 (4.40%) robson staging (for malignant cancers only), n (%) i 58 (47.90%) ii 18 (14.80%) iii 22 (18.10%) iv 23 (19.00%) patient status at the last follow-up, n (%) stable 66 (48.20%) disease progressed 20 (14.90%) lost to follow-up 39 (29.80%) expired 8 (5.90%) table 3. histopathological diagnoses of 136 renal tumors specimens from 133 young adults with suspected renal cancer tumor types number (%) malignant tumors 121 (88.90) rcc clear cell variant 84 (69.40) rcc papillary variant 11 (9.00%) rcc chromophobe variant 3 (2.40%) rcc sarcomatoid 2 (1.60%) transitional cell carcinoma 9 (7.40%) primitive neuroectodermal tumor 5 (4.10%) synovial sarcoma 2 (1.60%) non-hodgkin lymphoma 2 (1.60%) squamous cell carcinoma 1 (0.80%) leiomyosarcoma 1 (0.80%) malignant fibrous histiocytoma 1 (0.80%) benign tumors 15 (11.00%) angiomyolipoma 11 (73.30%) oncocytoma 3 (20.00%) schwannoma 1 (6.60%) rcc indicates renal cell carcinoma. 376 | using kaplan-meier method. the minimum follow-up period for inclusion in the outcome analysis was one year. the overall cancer-specific survival rates at 1, 5, and 10 years were 97%, 83%, and 83% whereas the cancer-free survival (cfs) rates were 80%, 63%, and 37%, respectively (figure 1). various clinicopathologic characteristics of these tumors were analyzed to determine their effect on the progression of disease (table 4). patients ≤ 35 years had better outcome with 1 and 5-year cfs rates of 83% and 71%, respectively. the corresponding figures were 76% and 49%, respectively, for patients older than 35 years [p = .02; odds ratio (or) = 2.3; 95% confidence interval (ci) = 1.1 to 4.9; p = .03]. cancer-free survival rates on the basis of tumor palpability were also analyzed, which confirmed the better survival for the group who had nonpalpable tumors. palpable tumors had 1 and 5-year survival rates of 66% and 52%, while non-palpable tumors had cfs rates of 93% and 75% at 1 and 5 years, respectively (p = .008; or = 2.8; 95% ci = 1.2 to 6.4; p = .01; figure 2). regarding tumor size, of 94 patients, 60 (64%) with tumors measuring ≤ 10 cm had good prognosis compared to 34 (36%) who had tumors > 10 cm in size. oneand 5-year cfs rates for tumors of ≤ 10 cm were 93% and 75%, while the tumors > 10 cm showed cfs rates of 56% and 41%, respectively (p = .0001; or = 4.2; 95% ci = 1.97 to 9.1; p = .0001). tumor stage was also analyzed for cfs and it was observed that for stage i tumors, cfs rates at 1 and 5 years were 98% and 84%, for stage ii, 82% and 63%, and for stage iii, 62% and 50%, respectively. on the other hand, 1-year survival for stage iv was 48% only (p = .0001; figure 3). among patients with malignant tumors, prognosis table 4. outcome analysis of 94 young adults with malignant renal tumors and regular follow-up variables 1 year 5 years 10 years p overall cancer-specific survival 97 83 83 overall cancer-free survival 80 63 37 patient age, y .02 ≤ 35 83 71 > 35 76 49 tumor palpability .008 non-palpable tumors 93 75 palpable tumors 66 52 tumor size, cm .0001 ≤ 10 93 75 > 10 56 41 tumor stage (robson) .0001 stage i 98 84 stage ii 82 63 stage iii 62 50 stage iv 48 histological type .03 renal cell carcinoma 86 71 non-renal cell carcinoma 65 42 *all figures are in percentages. urological oncology 377vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l of patients with rcc was better than non-rcc group. among rcc cohort, 86% were disease-free at 1 year and 71% at 5 years compared to non-rcc group, who had 65% and 42% cfs rates at 1 and 5 years, respectively (or for non rcc and rcc = 2.2; 95% ci = 1.0 to 4.8; p = .03). subtypes of rcc were also analyzed for cfs. clear cell variant of rcc (ccrcc) had 89% 1-year survival and 75% 5-year survival. because of small number of patients in other types of rcc, only 1-year survival could be estimated, which was 53% for papillary rcc (prcc) and 100% for the rest of the two types of rcc (p = .01) the majority of patients with rcc had grade 2 nuclear features; therefore, only grade 2 survivals were estimated and found to be 91% at 1 year and 76% at 5 years. discussion this study is one of the largest studies on the spectrum of renal tumors in young adults throughout the world and the first from this region. we, however, acknowledge the fact that this is a single center-based study and not truly representative of the population in pakistan. the study has also inherent selection bias in that only those subjects, in whom surgery was carried out as part of treatment, were included, but it comes from a center of excellence for the kidney and urological diseases in the country and its catchment area extends more or less to the entire country. therefore, we believe that the findings from this study are fairly representative of the prevailing renal tumor types in young adults from this country. approximately, 9% of adults with renal tumors in our study were either 40 years or less at the time of presentation. published literature reports the incidence of 5% to 9% for renal tumors in younger patients (1, 4). the mean age of the patients in our study was 33.3 ± 6.2 years with male to female ratio of 1.1:1. denzinger and colleagues reported the male to female ratio of 3.1:1,(5) while eggener and assorenal tumors in young adults in pakistan | mohsin et al figure 1. cancer-specific and cancer-free survival following surgery for malignant renal tumors in 94 young adults. figure 3. cancer-free survival according to robson stage of malignant renal tumors in 94 young adults following surgery. figure 2. cancer-free survival according to tumor size following surgery for malignant renal tumors in 94 young adults. 378 | ciates reported the ratio of 1.2:1,(11) the later being concordant with our study. symptomatology of renal tumors in these young patients is generally similar to that reported previously. in this study, approximately 8% of the patients were asymptomatic and were incidentally diagnosed during the workup of some other diseases. this incidence is less as compared with western studies, where incidental detection rates vary between 35% and 75%.(5,11-13) the main reason of this appears to be the lack of awareness among the masses and the inaccessibility of medical facilities. the mean duration of symptoms in our study was 7 months, while it was reported to be 84 weeks in another study,(14) which is markedly longer than our finding. anemia is one of the major complications of renal tumors and its incidence has been reported to be up to 30%.(15) it was not infrequent in our study and approximately 29% of the patients had anemia at the time of presentation representing the outcome of hematuria, malignancy, and chronic disease. in our study, only 6% of the patients had renal dysfunction, which is almost the same as that reported in other study.(11) renal function is usually preserved in these patients, especially in young adults who have a healthy contra-lateral kidney and do not have co-morbidities, like diabetes and hypertension, which are prevalent in the elderly population. laterality of the renal tumors is of no clinical importance. eggener and associates reported the occurrence of 54.6% and 45.4% for renal tumors on the right and left sides, respectively,(11) which was not statistically significant and is concordant with our study. overall incidence of bilateral renal tumors is between 2% to 4%, but in young adults and in von hippel-lindau disease, it is more common. (16) however, there is a wide variation, as eggener and coworkers(11) and boykin and colleagues(14) did not report any bilateral renal tumors. on the other hand, abou el fettouh and associates reported that approximately 13% of the patients who were between 20 to 40 years had bilateral renal tumors.(17) we found bilateral renal tumors in 3% of our patients, which is comparable to most of the previous studies.(16) palpability of the tumors depends on the size of the tumors and the contour of the body. it was the size, and not the palpability of the tumor which affected the clinical outcome in these patients. in our study, only 19% of the patients had renal tumors ≤ 7.0 cm. while approximately 70% of the patients in the study by eggener and colleagues had renal tumors < 7.5 cm,(11) indicating early diagnosis and prompt utilization of investigating tools. despite the larger size of the tumors reported in our study, we found that approximately 63% of the patients had organ confined disease. cao and associates reported almost similar percentage of young patients with organ confined disease.(18) however, other studies have reported up to 90% of the patients with early stage disease at the time of presentation.(11,12) the disparity in the rates of early stage disease may partly be due to the lack of proper health services in our country. renal cell carcinoma is undoubtedly the most common renal malignancy worldwide in adult patients. (11,12,14) in our study, ccrcc was the most common variant and constituted 68.5%, followed by prcc, which constituted 9%. the other variants were rare. our results are generally comparable to the previously published literature.(5,12,17) on the other hand, lopez and coworkers reported ccrcc in 51% of patients,(19) while eggener and associates reported its incidence in up to 76%.(11) low incidence of 21% for ccrcc had also been reported,(20) but this study included children as well. incidence of prcc in our study is almost similar to other studies.(11,19) on the other hand, 50% incidence of prcc reported by renshaw and associates(20) may be because of the fact that this study also included children. chromophobe rcc (crcc) was found in 2% of our patients and is almost compatible to urological oncology 379vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l previous studies.(12,17) but there are studies in which crcc has been reported in up to 10% of patients. (11,19) sarcomatoid variant is a rare presentation, substantiated by this study as well as other studies. (17,18) among malignant tumors, early stage disease has better survival as observed in our study and also other studies.(6-8,14,21-23) sanchez-ortiz and colleagues reported that young patients had more unfavorable histology and higher incidence of lymph node metastases, but the survival is better than the older adults.(23) we also observed in the present study that the younger the patient, the better the survival, as also demonstrated by taccoen and associates.(12) the tumor size is also a good predictor of cfs as observed in this study. goetzl and coworkers reported similar findings; the larger the tumor size, the worse the outcome.(13) histopathological types of renal tumors in young adults also affect the cfs, as we observed a better survival in rcc group compared to nonrcc group. renal pelvis tcc accounts for only 5% of renal malignancies.(24,25) it is difficult to determine the exact incidence of the renal pelvic tumors because statistics vary substantially worldwide between different geographical areas and even an incidence as high as 40% had been reported in balkan countries.(22) very limited data are available for transitional cell carcinomas of the renal pelvis in young adults. incidence of 1.7% and 5.5% had been reported in different studies on young adults.(11,14) we report a somewhat higher incidence of transitional cell carcinomas, which is slightly greater than 7%. primitive neuroectodermal tumor (pnet) is rarely localized primarily in the kidney.(26) we found primary renal pnet in approximately 4% of our young adult patients. thyavihally and colleagues reported the mean age of patients with renal pnet as 27 years at the time of presentation(27) reflecting the fact that pnet is a disease of young adults,(23) similar to our findings.(26) in our study, 11% of the patients had benign renal tumors. angiomyolipoma was the most common benign renal tumor in our study and constituted up to 73% of total benign tumors, but overall incidence was 8%. even lower incidence of angiomyolipoma was reported in previous studies.(11,14) we also found a few cases of rare benign renal tumors, such as oncocytoma and schwannoma, which were surgically removed with suspicion of renal cancer. conclusion in conclusion, a wide heterogeneity of renal tumors in young adults is documented in this study with somewhat late presentation as compared with western studies. despite limitations inherent in the study design, the findings are an important contribution from a developing country to the scanty literature on the subject throughout the world. conflict of interest none declared. references 1. bretheau d, koutani a, lechevallier e, coulange c. a french national epidemiologic survey on renal cell carcinoma. oncology committee of the association francaise d'urologie. cancer. 1998;82:538-44. 2. ku jh, moon kc, kwak c, kim hh. disease-specific survival in patients with renal cell carcinoma: an audit of a large series from korea. jpn j clin oncol. 2011;41:110-4. 3. chow wh, devesa ss, warren jl, fraumeni jf, jr. rising incidence of renal cell cancer in the united states. jama. 1999;281:1628-31. 4. kantor al, meigs jw, heston jf, flannery jt. epidemiology of renal cell carcinoma in connecticut, 1935-1973. j natl cancer inst. 1976;57:495-500. 5. denzinger s, otto w, burger m, et al. sporadic renal cell carcinoma in young and elderly patients: are there different clinicopathological features and disease specific survival rates? world j surg oncol. 2007;5:16. 6. thompson rh, ordonez ma, iasonos a, et al. renal cell carcinoma in young and old patients--is there a difference? j urol. 2008;180:1262-6; discussion 6. renal tumors in young adults in pakistan | mohsin et al 380 | 20. renshaw aa, granter sr, fletcher ja, kozakewich hp, corless cl, perez-atayde ar. renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes. am j surg pathol. 1999;23:795-802. 21. schiff m, jr., herter g, lytton b. renal adenocarcinoma in young adults. urology. 1985;25:357-9. 22. rainwater lm, zincke h, farrow gm, gonchoroff nj. renal cell carcinoma in young and old patients. comparison of prognostic pathologic variables (cell type, tumor grade and stage, and dna ploidy pattern) and their impact on disease outcome. urology. 1991;38:1-5. 23. sanchez-ortiz rf, rosser cj, madsen lt, swanson da, wood cg. young age is an independent prognostic factor for survival of sporadic renal cell carcinoma. j urol. 2004;171:2160-5. 24. alpers ce. the kidney. in: kumar v, abbas ak, fausto n, aster jc, eds. robbins and cotran pathologic basis of disease. 8 ed. philadelphia: wb saunders; 2010:905-70. 25. flanigan rc. urothelial tumors of the upper urinary tract. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 2. 9 ed. philadelphia: saunders; 2007:1638-52. 26. mohsin r, hashmi a, mubarak m, et al. primitive neuroectodermal tumor/ewing's sarcoma in adult uro-oncology: a case series from a developing country. urol ann. 2011;3:103-7. 27. thyavihally yb, tongaonkar hb, gupta s, et al. primitive neuroectodermal tumor of the kidney: a single institute series of 16 patients. urology. 2008;71:292-6. 7. latif f, mubarak m, kazi ji. histopathological characteristics of adult renal tumours: a preliminary report. j pak med assoc. 2011;61:224-8. 8. eble jn, sauter g, ebstein j, sesterhenn i. pathology and genetics of tumours of the urinary system and male gential organs. iarc-press, lyon. 2004. 9. fuhrman sa, lasky lc, limas c. prognostic significance of morphologic parameters in renal cell carcinoma. am j surg pathol. 1982;6:655-63. 10. robson cj, churchill bm, anderson w. the results of radical nephrectomy for renal cell carcinoma. j urol. 1969;101:297301. 11. eggener se, rubenstein jn, smith nd, et al. renal tumors in young adults. j urol. 2004;171:106-10. 12. taccoen x, valeri a, descotes jl, et al. renal cell carcinoma in adults 40 years old or less: young age is an independent prognostic factor for cancer-specific survival. eur urol. 2007;51:980-7. 13. goetzl ma, desai m, mansukhani m, et al. natural history and clinical outcome of sporadic renal cortical tumors diagnosed in the young adult. urology. 2004;63:41-5. 14. boykin wh, bright ke, zeidman ej, thompson im. renal tumors in young adults. urology. 1992;40:503-5. 15. konety br, williams rd. renal parenchymal neoplasms. in: tanagho ea, mcaninch jw, eds. smith's general urology. 16 ed. new york (usa): mcgraw-hill medical; 2004:346-66. 16. novick ac, campbell sc. renal tumors. in: walsh pc, retik ab, vaughan ed, wein aj, eds. campbell's urology. vol 4. 8 ed. philadelphia: saunders; 2002:2672-731. 17. abou el fettouh hi, cherullo ee, el-jack m, al maslamani y, novick ac. sporadic renal cell carcinoma in young adults: presentation, treatment, and outcome. urology. 2002;60:806-10. 18. cao y, paner gp, perry kt, flanigan rc, campbell sc, picken mm. renal neoplasms in younger adults: analysis of 112 tumors from a single institution according to the new 2004 world health organization classification and 2002 american joint committee on cancer staging system. arch pathol lab med. 2005;129:487-91. 19. lópez ji, moreno v, garcía h, et al. renal cell carcinoma in young adults: a study of 130 cases and a review of previous series. urol int. 2010;84:292-300. urological oncology 614 | a rare, but life-threatening complication of percutaneous nephrolithotomy massive intra-abdominal extravasation of irrigation fluid masoud etemadian,1 pejman shadpour,1 ramin haghighi,2 mohammad reza mokhtari,1 robab maghsoudi1 keywords: percutaneous nephrolithotomy, lithotripsy, complications introduction nowadays, percutaneous nephrolithotomy (pcnl) is treatment of choice for large or multiple kidney stones and stones in the inferior calyx.(1) percutaneous nephrolithotomy is generally safe and associates with low, but indisputable complication rate.(2) despite rarity, intra-abdominal irrigation fluid extravasation and absorption may occur during pcnl resulting in serious outcome. we present a case of massive intra-abdominal fluid extravasation in an otherwise healthy man who underwent pcnl. case report a 46-year-old man presented with symptomatic multiple left renal stones in a chronic pyelonephritic kidney and was candidate for pcnl (figure). pre-operative laboratory studies were normal. left renal differential function on dimercaptosuccinic acid renal scan was 30%. he had a history of right pcnl two months earlier without any complication. percutaneous nephrolithotomy was performed using standard method. at the end of the procedure, the abdomen was markedly distended. immediate diagnostic peritoneal tap revealed clear fluid. thereafter, a drain was placed, through which 3500 cc was evacuated. portable chest x-ray and left pleural tap revealed no thoracic accumulation. mild acidosis and dilutional hyponatremia occurred, which were managed accordingly. the patient was transferred to the intensive care unit. bloody fluid continued to flow from drains corresponding author: pejman shadpour, md hasheminejad clinical research development center, hasheminejad kidney center, vanak sq, tehran, 19697, iran tel: +98 912 132 6392 fax: +98 21 8864 4441 e-mail: pshadpour@gmail. com received july 2010 accepted august 2010 1hasheminejad kidney center, tehran university of medical sciences (tums), tehran, iran 2north khorasan university of medical sciences, north khorasan, iran case report case report 615vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l and blood pressure dropped steadily. serial lab tests confirmed severe coagulopathy, but there was no evidence to support disseminated intravascular coagulation. multiple units of blood products, packed red blood cells, and fresh frozen plasma were administered to maintain homeostasis. after 4 hours, the patient’s systolic blood pressure dropped to 60 mmhg despite conservative management. the patient was taken to the operating room for open exploration. laparotomy revealed intact intraperitoneal viscera and no vascular injury. in retroperitoneal exploration, the kidney’s thin and atrophic parenchyma had been ruptured at both poles. however, the extent of bleeding was not significant and less than 300 cc of blood was found in the field, which could not explain the patient’s condition. due to continuous oozing despite adequate suturing, nephrectomy was performed. fifteen hours after the surgery, the patient developed respiratory distress, hypotension, continuous bleeding via drains, and metabolic acidosis. his chest x-ray showed bilateral pleural effusion, clinically significant on the left side. a chest tube was inserted producing 700 cc of pink fluid testing negative for urine based on creatinine content. his coagulation, activated partial thromboplastin, and prothrombin times as well as the platelet count were within normal limits. a very significantly prolonged bleeding time responded to the administration of cryoprecipitate. having stabilized the hemodynamic state and curbed the bleeding, we began parenteral nutrition. nonoliguric transient renal failure was managed with a few sessions of hemodialysis. he was improving rapidly until four days later, then, the patient developed abdominal distension and vomiting. x-rays consistent with the small bowel obstruction led to abdominal exploration for early adhesion bands. the patient was ultimately discharged on the 15th postoperative day with serum creatinine of 1.6 mg/dl. the serum creatinine level decreased to 1.18 mg/dl within 3 weeks. discussion extravasation is a common incident during pcnl, which can potentially lead to untoward consequences depending on the rate, volume, and nature of fluid absorbed.(3) the sterile water, used routinely for irrigation, can cause intravascular hemolysis, when absorbed in high volume.(4) there are few reports of such a complication in percutaneous stone surgery.(5,6) pugach and colleagues reported fluid extravasation in a 4-year-old boy who underwent pcnl. elevated ventilation pressure was the first sign of his complication.(7) the intrathoracic collection of fluid in our patient was secondary to redistribution of the abdominal fluid as proven by negative chest radiography and negative pleural tap at the onset in the operating room. peterson and associates reported two cases of extravasation of irrigant fluid. one of them died a few hours after surgery due to disseminated intravascular coagulation.(8) platelet function was seriously impaired in our patient as well, but it was not accompanied with diagnostic criteria supporting disseminated intravascular coagulation, and responded rapidly to the administration of cryoprecipitate to correct platelet dysfunction. in our patient, the kidney with thinned cortex has been ruptured easily with resulting hemorrhage. ghai and coworkers reported intra-abdominal extravasation left kidney with numerous stones. a rare complication of pcnl | etemadian et al 616 | in pcnl. their patient suffered from severe anemia, prolonged hyponatremia, hypokalemia, and abdominal pain persisted for 45 days.(9) in our patient, hyponatremia, hypokalemia, metabolic acidosis, continuous oozing, and blood loss responded well to the interventions and the transient renal failure resolved within 2 weeks. conclusion irrigation fluid extravasation during pcnl can be life-threatening if left untreated. conflict of interest none declared. references 1. wong my. an update on percutaneous nephrolithotomy in the management of urinary calculi. curr opin urol. 2001;11:367-72. 2. rudnick dm, stoller ml. complications of percutaneous nephrostolithotomy. can j urol. 1999;6:872-5. 3. hahn rg. fluid absorption in endoscopic surgery. br j anaesth. 2006;96:8-20. 4. grundy pl, budd dw, england r. a randomized controlled trial evaluating the use of sterile water as an irrigation fluid during transurethral electrovaporization of the prostate. br j urol. 1997;80:894-7. 5. rao pn. fluid absorption during urological endoscopy. br j urol. 1987;60:93-9. 6. dunnick nr, carson cc, 3rd, moore av, jr., et al. percutaneous approach to nephrolithiasis. ajr am j roentgenol. 1985;144:451-5. 7. pugach jl, moore rg, parra ro, steinhardt gf. massive hydrothorax and hydro-abdomen complicating percutaneous nephrolithotomy. j urol. 1999;162:2110; discussion -1. 8. peterson g, krieger j, glauber d. anaesthetic experience with percutaneous lithotripsy. anaesthesia. 1985;40:460-4. 9. ghai b, dureja gp, arvind p. massive intraabdominal extravasation of fluid: a life threatening complication following percutaneous nephrolithotomy. int urol nephrol. 2003;35:3158. case report urol_v03_no4_001_editorial.indd kidney transplantation 234 urology journal vol 3 no 4 autumn 2006 public attitudes toward cadaveric organ donation a survey in ahwaz heshmatollah shahbazian, amir dibaei, maryam barfi introduction: the aim of this study was to evaluate the attitudes of the residents of ahwaz toward organ donation after brain death. materials and methods: a total of 1000 people between 15 and 70 years of age were selected by cluster sampling in ahwaz, south-west of iran. a questionnaire was designed about the attitudes of the interviewees toward organ donation after brain death by themselves and by their family members, demanding compensation for organ donation, and the need for consent or testimony. results: of the participants, 75% were pro organ donation, while 22% were against it and the remaining 3% had no specific idea. age, sex, and occupation did not influence the attitudes; however, the ethnicity, educational level, economic status, and having a loved one in need of organ transplantation significantly increased the willingness of these people for organ donation (p < .05). regarding the issue of demanding compensation for organ donation, 27% of the participants were in favor of the idea and 73% disagreed. a higher proportion of the participants with higher educational levels believed in organ donation without any consent or testimony (p = .02). conclusion: according to our study, many people are pro organ donation after death. it is necessary to have a regular program for these people to give them the opportunity to register and receive a donation card. for the people who do not have the tendency for the matter, we had better try to increase their knowledge by educational programs and provide sufficient information. urol j (tehran). 2006;4:234-9. www.uj.unrc.ir keywords: organ transplantation, brain death, cadaveric transplantation, living donor, survey department of kidney transplantation, golestan hospital, jondishapour university of medical sciences, ahwaz, iran corresponding author: heshmatollah shahbazian, md department of kidney transplant golestan hospital ahwaz, iran tel: +98 916 111 4595 fax: +98 611 338 6257 e-mail: heshmatolahs@yahoo.com received may 2005 accepted june 2006 introduction scarcity of donated cadaveric organs is the first problem in organ procurement. more than 50 000 people are in the waiting list of kidney transplantation in the united states, while less than 9000 cadaveric grafts are usually available.(1) this is especially important in candidates for receiving the vital organs such as the heart, the liver, and the lung. most of these patients die without receiving transplantation. in addition, although there are other replacement therapies such as dialysis for endstage renal disease (esrd), the significantly better outcome of kidney transplantation emerges organ procurement for these patients, too.(2-4) if all available cadaveric donors were accessible for transplantation by organ procurement efforts, the supply of the donated organs would increase only 60% to 80 %.(5,6) for increasing the supply, we should consider all the possibilities such as changes in the criteria of suitable donors and public education. lack of knowledge among people is one of the most important problems in the progression of this planning, especially in developing countries(7); however, most of the islamic, christian, jewish, hindu, and organ donation after brain death—shahbazian et al urology journal vol 3 no 4 autumn 2006 235 buddhist religious leaders support transplantation of the organs.(8) one of the factors that must be regarded for promotion of organ procurement is general education for changing the negative attitudes of people toward organ donation from a dead person. in most of the southeast asian countries, organ donation is understood as a western concept and is not accepted.(7) about half of the organs eligible for donation usually cannot be used due to the disinclination of the deceased patient’s family. some other reasons include inability for making immediate decisions and some religious and ethnical beliefs. even the attitude of the health care personnel needs to be changed.(9) they have an important role and should be aware of organ procurement policies and be educated enough for contacting the family of the dead person.(10) another factor is the appropriate definition of brain death and legal frame works for cadaveric organ donation. most of the developing countries such as pakistan, bangladesh, and malaysia do not have such acts.(11) in 1995, cadaveric organ donation was legally accepted in india.(12) in iran, a regulation was passed in march 6, 2000, and has been put into action since october 13, 2001. finally, the last factors are the financial and medical care supports. organ transplantation from cadaveric donors is more expensive than that from living ones. on the other hand, access to intensive care unit and equipped laboratories for tissue typing plays a decisive role.(13) in our country, the main source of kidney allograft is the living donor (mostly unrelated), and recently, cadaveric donor constitutes a portion, yet very small. the outcome of kidney transplantation from living donor is better(14); however, in our country, most donors have financial interests. thus, there is a high risk of misbehavior and ethical issues are still a matter of concern. accordingly, the national health policy has changed opting for cadaveric transplantation. after resolving legal bans, many kidney transplantation centers in iran have commenced cadaveric transplant, one of which was the center for kidney transplantation of ahwaz (jondishapour) university of medical sciences. in an effort to supply cadaveric transplantation, we have planned to advocate cadaveric donation. as a first step, we designed this study to evaluate the attitude of the people of ahwaz toward organ donation after brain death. materials and methods in this survey, 1000 residents of ahwaz were selected through cluster sampling for interview. the city was firstly divided into 3 zones according to the ethnicity of the residents (arab, persian, and lor). according to the available maps and the population in each zone, the streets, blocks, and houses were randomly selected. by reference to the houses in each zone, the questionnaire was filled out for each person between 15 and 70 years who consented to participate in the study. brain death was explained as definite death of the brain despite other live organs without any hope for improvement and the impending change into complete death (death of the brain and other organs) within few hours, days, or months. a definite death was explained as the traditional and legal concept of death. the interviews were done face to face by a trained person. the questionnaire was comprised of 2 parts: questions about personal information of the interviewee including sex, age, ethnicity, level of education, economic status, and occupation; and questions about having a loved one in need of organ transplantation and the interviewee’s opinions about cadaveric organ donation (table 1). validity and reliability of the questions were assessed by a group of psychologists and sociologists. the economic status of the individuals was categorized based on their monthly income (low, < us$ 400; middle, us$ 400 to us$ 600; high, > us$ 600). table 1. questions about organ donation 1. do you have a loved one in need for organ transplant? 2. do you accept your organs to be donated in case of brain death? 3. if brain death occurs in a member of your family or relatives, will you allow organ donation? 4. in case of your brain death, do you prefer the compensation to be demanded by your family? 5. if brain death occurs in a member of your family or relatives, will you demand compensation for organ donation? 6. which do you think is needed for organ donation? a written testimony of the dead person? written consent of the dead person’s family? none of them? 7. are you in favor of organ donation from definitely dead bodies? organ donation after brain death—shahbazian et al 236 urology journal vol 3 no 4 autumn 2006 the collected data were analyzed using student t test and chi-square test. continuous variables were demonstrated as means ± standard deviations and values for p less than .05 were considered significant. results a total of 1000 people were interviewed (table 2). the mean age of the interviewees was 27.9 years (men, 28.2 years; women, 27 years; range, 15 to 70 years). the answers of the participants to the questions regarding organ donation are summarized in table 3. three-fourths (75%) of the interviewees were pro organ donation by themselves in case of brain death, 22% rejected to donate their own organs , and 3% had no specific idea. age was not significantly different between these 3 groups (mean ages, 30.0 ± 8.2 years, 29.2 ± 11.8 years, and 28.4 ± 10.7 years, respectively; p = .23). of women, 84.8%, 12%, and 3.2% were in favor of, against, and neutral for the matter. in men, these rates were 79.7%, 17.3%, and 3%, respectively. although the rate of acceptance was higher in women, the difference was not significant (p = .63). regarding the ethnicity, 91.2% of the lor people, 85.1% of the persian, and 75.2% of the arabs were against their own organ donation. the difference between the lor and arab people was significant (p = .03). a greater number of interviewees with a high school or higher educational level were pro their organ donation (p = .43). in the low-income families, 61.9% and 32.1% were in favor of and against the process and 7% were neutral. these rates were 84.1%, 13.3%, and 2.6% for the middle-income and 77.7%, 19.3%, and 3% for the high-income families (p = .01). in the low-income families, men were less willing for organ donation compared to women (p = .04). no significant difference was found between the occupational groups (p > .05). twelve percent of the participants had a loved one in need of organ transplantation. of these, 108 (90%) and 12 (10%) were in favor of and against their organ donation, respectively. these rates were 73% and 23.6% among the people who had no one in need of transplantation (p = .003). regarding the issue of demanding compensation for organ donation, 27% of the participants were in favor of the idea and 73% disagreed. the participants against demanding compensation included 66.9% of the men, 66.5% of the women, 67.7% of the arabs, 66.6% of the persians, and 64.1% of the lors. the sex and ethnicity of the interviewees had no influence on their opinions about compensation. the disagreement rates were 58.2%, 79.4%, and table 3. answers of 1000 interviewees to questions about organ donation* *values are percents. † ellipses indicate not applicable. questions yes no † no idea † donate your organs in case of brain death? 75 22 3 donate your family member’s organs in case of brain death? 72 20 8 demand compensation for your organ donation? 27 73 0 demand compensation for family member’s organ donation? 25.3 70 4.7 prerequisite for organ donation: a written testimony? 32 … … written consent of the family? 50 … … none of them? 18 … … are you in favor of organ donation from definitely dead bodies? 73 27 0 table 2. demographic data of interviewed people in ahwaz characteristic number sex male 683 female 317 ethnicity arab 468 lor 148 persian 384 level of education school dropout 266 high school or associate bachelor’s degree 554 bachelor’s or higher degree 170 occupation student 100 employee 330 businessman 410 unemployed or housewife 160 organ donation after brain death—shahbazian et al urology journal vol 3 no 4 autumn 2006 237 80.6% among the participants with school dropout, high school or associate bachelor’s degree, and bachelor’s or higher degrees, respectively (p = .04). of the interviewees in families with low, middle, and high incomes, 59.4%, 81%, and 73% were against demanding compensation (p = .04). no difference was found between the ethnicities with regard to the prerequisites of organ donation (table 4), but a higher proportion of the participants with higher educational levels believed in organ donation without any consent or testimony (p = .02). finally, 73% and 27% of the participants were in favor of and against organ donation from the patients with definite death, which is similar to the results for brain death. discussion organ donation from living unrelated donors is failing to fulfill the demand in our country.(1) on the other hand, there exist a number of disadvantages for the use of living unrelated donors: the increasing financial interests among living donors, early complications of donor nephrectomy, unclear longterm impact of living with one kidney in donors, and impossibility of vital organs transplantation such as heart, liver, pancreas, and lung from living donors. as a result, organ transplantation from the patients with brain death has been encouraged by the health care authorities in iran. by passing the laws in this regard, now there is no official prohibition in most countries.(12) however, lack of organ donation regulations is one of the most important restrictions in some developing countries such as pakistan, bangladesh, and malaysia.(11) another issue which must be considered is the public attitude toward the sources of organ donation. our study showed that 75% and 72% of the people were in favor of organ donation by themselves and by their family members, respectively. these hopeful results have been achieved in spite of no appropriate educational program. in the study by barcellos on 3159 participants, the rate of donation acceptance after the death was 52%.(15) in a study by donmez and colleagues, these rates were reported to be 52.5% and 37.6% for organ donation by the interviewees and by their family members, respectively.(16) bilgel and coworkers reported that 50.5% of the subjects selected from a turkish community agreed organ donation after the death.(17) the higher results of ours indicate that we can have a larger source of potential donors. in a study by cynthia and gurch on the african and the caribbean black people, it was shown that although these populations have an enormous number of patients in need of organ donation, their information about esrd and organ donation is very little.(18) a significant correlation existed between the level of education, economic situation, age, and sex of the participants with their tendency for organ donation.(17,19) however, among selected groups of people with the same conditions contradictory findings have been reported. surveys among the japanese, for instance, showed that 50% of the people were pro donation after their death in 1995 and this rate has increased by 15.2% in 2001.(20,21) however, terada, in a study performed on the nurses, showed that less than half of them agreed with organ donation after brain or cardiac death and more than half of them could not decide about it at the time table 4. participants’ opinions about prerequisites for organ donation* *values are percents. prerequisite for organ donation participants family’s consent written testimony nothing all 50 32 18 ethnicity arab 50 35.6 14.4 lor 54.4 29.3 16.3 persian 54.4 29.3 16.3 level of education school dropout 43.9 39.4 16.5 high school or associate bachelor’s degree 53.9 30 16.1 bachelor’s or higher degree 26.4 38.2 35.2 organ donation after brain death—shahbazian et al 238 urology journal vol 3 no 4 autumn 2006 of study.(22) this means that the education level and information cannot always improve the peoples’ attitudes toward organ donation. among our subjects, those with higher levels of education and better knowledge were more willing for organ donation. also, they believed in organ donation without claiming compensation and providing consent from the deceased patient’s family. people with a loved one in their family or relatives had more tendency for organ donation. this highlights the quality of educational programs; the more we can depict how the patients and their families suffer from the disease, the better feedback we can receive. finally, the diverse acceptance rates among different nations and ethnicities should be considered in plans for organ procurement. our study shows that the arabs have the least tendency for organ donation after the death which can be due to their traditional beliefs. but, educational and economic situation of this group may have influenced the results. differences between the ethnicities and their beliefs need to be evaluated in studies with special attention to the other social factors. conclusion according to our study, many people are pro organ donation after their death. in order to have such a great donor population, it is necessary to have a regular program for these people to give them the opportunity to register and receive a donation card. for the people who do not have the tendency for the matter, we had better try to increase their knowledge by educational programs and provide sufficient information. increasing the level of general public education in a long-term plan is quite useful. in order to get familiar with the problems of the patients in need of organ transplantation and their families, production of some educational programs are advocated. also, it is recommended to financially support families who donate organs. regarding the overall positive attitude of the people toward organ donation in our country, we can easily have a place for cadaveric transplantation. conflict of interests none declared. references 1. cecka jm. donors without a heartbeat. n engl j med. 2002;347:281-3. 2. wolfe ra, ashby vb, milford el, et al. comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. n engl j med. 1999;341:1725-30. 3. port fk, wolfe ra, mauger ea, berling dp, jiang k. comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients. jama. 1993;270:1339-43. 4. shahbazian h, paiami b. comparison of short-term results of kidney transplantation in diabetic and nondiabetic patients. j ahwaz univ med sci. 2002;34:2-5. 5. evans rw, orians ce, ascher nl. the potential supply of organ donors. an assessment of the efficacy of organ procurement efforts in the united states. jama. 1992;267:239-46. 6. spital a. mandated choice for organ donation: time to give it a try. ann intern med. 1996;125:66-9. 7. cheng ik. special issues related to transplantation in hong kong. transplant proc. 1992;24:2423-5. 8. daar as. a survey of religious attitudes towards donation and transplantation. in: collins gm, dubernard jm, land w, persijn gg, editors. procurement and preservation and allocation of vascularized organs. dordecht: kluwer academic publishers; 1997. p. 333-8. 9. rizvi sa, naqvi a. the need to increase transplantation activity in developing countries. transplant proc. 1995;27:2739-40. 10. mckay db, king aj. donor and recipient issues in renal transplantation. in: brenner bm, levine sa, editors. brenner & rector’s the kidney. 7th ed. philadelphia: wb saunders; 2004: p. 2786-99. 11. moosa mr, walele aa, daar as. renal transplantation in developing countries. in: morris pj, editor. kidney transplantation, principles and practice. philadelphia: wb saunders; 2001. p. 659-84. 12. daar as. an emerging transplant force--developing countries: middle east and the indian subcontinent. transplant proc. 1997;29:1577-9. 13. de villa v, alonzo h, tejada f, et al. characterization of kidney allograft donation in the philippines. transplant proc. 1997;29:1584-5. 14. ojo ao, meier-kriesche hu, hanson ja, et al. the impact of simultaneous pancreas-kidney transplantation on long-term patient survival. transplantation. 2001;71:82-90. 15. barcellos fc, araujo cl, da costa jd. organ donation: a population-based study. clin transplant. 2005;19:33-7. 16. donmez l, ozbey c, aydogan s. knowledge, attitudes and behaviors regarding organ transplantation in a primary health care region in turkey. dial transplant. 2003; 32:324-30. 17. bilgel h, bilgel n, okan n, kilicturgay s, ozen y, korun n. public attitudes toward organ donation. organ donation after brain death—shahbazian et al urology journal vol 3 no 4 autumn 2006 239 a survey in a turkish community. transpl int. 1991;4: 243-5. 18. cynthia d, gurch r. awareness and attitudes toward organ donation and transplantation among the black caribbean and black african population in lambeth, southwark, and lewisham, united kingdom. transplantation. 2004;78:420-425. 19. coelho jc, fontan rs, pereira jc, wiederkehr jc, campos ac, zeni neto c. [organ donation: opinion and knowledge of intensive care unit physicians in the city of curitiba]. rev assoc med bras. 1994;40:36-8. portuguese. 20. hasegawa t, maeda y, yamakawa k, tsuchida t, oshima s. donor card registration system in japan: an obstacle to procuring kidneys for transplantation. health policy. 1995;33:169-77. 21. kigawa m, hasegawa t, amemiya h. [knowledge, attitudes and behavior regarding organ transplantation: the impact of the first transplantation from a brain-dead donor under the organ transplantation act]. nippon koshu eisei zasshi. 2001;48:521-33. japanese. 22. terada i, otani a, hiramatsu k, matsuo m, ito h. knowledge of criteria for brain death and attitudes towards organ donation and transplantation of nursing professionals in tottori prefecture, japan. yonago acta medica. 2004;47:53–62. brief communication 188 urology journal vol 5 no 3 summer 2008 percutaneous management of urinary calculi in horseshoe kidneys heshmatollah soufi majidpour,1 vahid yousefinejad2 urolithiasis in horseshoe kidney presents a unique challenge in decision-making and technical aspects of calculus treatment. we present our experience with a group of patients with symptomatic calculi in their horseshoe kidneys. we had 8 patients with 9 horseshoe kidneys bearing calculi. they all underwent percutaneous nephrolithotomy. the median size of the calculi was 21 mm (range, 12 to 45 mm). auxiliary therapeutic procedures were required in 2 patients who had residual calculi on control imaging. the stone-free status was observed in 6 patients (75.0%) at discharge, and in 7 (87.5%) after 3 months of follow-up. surgical complications included bleeding in 2 patients that was controlled with complete bed rest and blood transfusion, and pleural injury in 1 which was managed conservatively. urol j. 2008;5:188-91. www.uj.unrc.ir keywords: kidney abnormalities, kidney calculi, lithotripsy, percutaneous nephrostomy, treatment outcome 1department of urology, tohid hospital, kurdistan university of medical sciences, sanandaj, iran 2research vice-chancellorship, kurdistan university of medical sciences, sanandaj, iran corresponding author: heshmatollah soufi majidpour, md department of urology, tel: +98 871 328 6113 fax: +98 871 666 4649, e-mail: h_majidpour2007@yahoo.com received march 2008 accepted july 2008 occurring at an incidence of 20% to 60%, urolithiasis is the most common complication of horseshoe kidneys.(1,2) calculi in horseshoe and ectopic kidneys present unique challenges in decision-making and technical aspects of treatment.(3) although, adequate fragmentation could be achieved by extracorporeal shock wave lithotripsy (swl), the anatomic abnormality prevents passage of fragments.(2,4) the stone-free rate is only 53% (range, 50% to 79%) for calculi in horseshoe kidneys treated with swl.(5,6) in contrast, percutaneous nephrolithotomy (pcnl) has been shown to be highly successful with an overall stone-free rate of 75% to 100% in a few series.(2,5,7,8) we present our experience with pcnl in a group of patients with symptomatic calculi in a horseshoe kidney. in tohid hospital of sanandaj, a city in the west of iran, we performed pcnl for 8 patients (5 men and 3 women) with horseshoe kidney from 2004 to 2006. one patient had bilateral involvement, and therefore, underwent pcnl in both kidneys. there was at least 1 calculus larger than 2 cm in all of the patients. the indications of performing pcnl were complex multiple calculi in 2 patients, staghorn calculus in 5, and failed swl in 2. laboratory tests included complete blood count, blood urea nitrogen, serum creatinine, fasting blood sugar, serum sodium, serum potassium, and blood group and rh. radiological assessments were done by plain abdominal radiography, intravenous urography (ivu), and ultrasonography in all of the patients. all of the calculi were opaque with different degrees on percutaneous nephrolithotomy in horseshoe kidneys—majidpour and yousefnejad 190 urology journal vol 5 no 3 summer 2008 blood vessels enter the horseshoe kidney through the ventromedial region; however, the possibility of hemorrhage does not necessarily confine percutaneous access to the opposite side of these vessels. on the other hand, the probability of arterial hemorrhage is not more likely than that in a normal kidney, because the dorsal vessels supplying the isthmus are supported with the vertebrae and are far from the nephrostomy tract.(2) in the present study, upper pole access was used in 89% of the kidneys compared to 64% to 81% cited in other studies.(2,5,10) the use of this method provides access to the upper pole, calyxes, renal pelvis, lower calyx, ureteropelvic junction, and proximal ureter. raj and coworkers believed that using upper pole access decreases hemorrhage, because the nephroscopic axis is along with the kidney s longitudinal axis resulting in restriction of nephroscope movement.(5) however, in a study from egypt, upper caliceal puncture was shown as a risk factor of severe bleeding.(14) it is remarkable that although some researchers consider flexible nephroscope for upper pole access essential,(5) we achieved comparable results with a rigid nephroscope (flexible nephroscope was not available at our center).(2,5,7-9) these results are justifiable considering that the majority of our access attempts were from the upper pole, providing the opportunity to observe more calyxes by rigid nephroscope, and also that we used two access sites in case of poor access. another explanation is that we did not have overweight patients in whom access is more difficult. nonetheless, the use of flexible nephroscope seems to be associated with higher overall success rates. in patients with normal kidney anatomy, upper pole access often requires supracostal approach that may cause intrathoracic complications.(15) contrary to normal kidneys, the upper pole access is not supracostal in horseshoe kidneys (due to the different position of the kidney). thus, the risk of pleural injury is not high. in our study, only 1 patient suffered from with pleural injury that was managed conservatively. pneumothorax has been reported to occur in 6% of the patients with horseshoe kidney.(5) the main complication in our study was excessive hemorrhage (25%) which is frequently seen in these patients (12.5% to 42%).(2,5,10) in summary, our experience in pcnl for horseshoe kidneys confirms the results of the previous studies. as a consequence, in our opinion, pcnl can be recommended for the treatment of kidney calculi in patients with horseshoe kidney as a safe and effective procedure. conflict of interest none declared. references 1. yohannes p, smith ad. the endourological management of complications associated with horseshoe kidney. j urol. 2002;168:5-8. 2. shokeir aa, el-nahas ar, shoma am, et al. percutaneous nephrolithotomy in treatment of large stones within horseshoe kidneys. urology. 2004;64:426-9. 3. stein rj, desai mm. management of urolithiasis in the congenitally abnormal kidney (horseshoe and ectopic). curr opin urol. 2007;17:125-31. 4. kirkali z, esen aa, mungan mu. effectiveness of extracorporeal shockwave lithotripsy in the management of stone-bearing horseshoe kidneys. j endourol. 1996;10:13-5. complications study number of patients calcium calculi, % upper pole access, % stone free, % secondary procedure, % minor, % major, % raj et al(5) 24 87.5 64.0 87.5 33.0 16.7 12.5 lingeman and saw(12) 17 … 81.0 84.6 73.0 24.0 5.0 jones et al(13) 15 53.3 na 88.8 13.3 20.0 6.0 al-otaibi and hosking(10) 12 83.0 75.0 75.0 8.3 42.0 0 darabi mahboub et al(11) 9 … … 66.7 33.3 … … present series 8 100.0 88.8 87.5 25.0 12.5 25.0 table 2. published studies on percutaneous management of calculi in horseshoe kidneys* *ellipses indicate that data were not available. percutaneous nephrolithotomy in horseshoe kidneys—majidpour and yousefnejad urology journal vol 5 no 3 summer 2008 191 5. raj gv, auge bk, weizer az, et al. percutaneous management of calculi within horseshoe kidneys. j urol. 2003;170:48-51. 6. al-tawheed ar, al-awadi ka, kehinde eo, abdulhalim h, hanafi am, ali y. treatment of calculi in kidneys with congenital anomalies: an assessment of the efficacy of lithotripsy. urol res. 2006;34:291-8. 7. lojanapiwat b. percutaneous nephrolithotomy (pcnl) in kidneys with fusion and rotation anomalies. j med assoc thai. 2005;88:1426-9. 8. mosavi-bahar sh, amirzargar ma, rahnavardi m, moghaddam sm, babbolhavaeji h, amirhasani s. percutaneous nephrolithotomy in patients with kidney malformations. j endourol. 2007;21:520-4. 9. viola d, anagnostou t, thompson tj, smith g, moussa sa, tolley da. sixteen years of experience with stone management in horseshoe kidneys. urol int. 2007;78:214-8. 10. al-otaibi k, hosking dh. percutaneous stone removal in horseshoe kidneys. j urol. 1999;162:674-7. 11. darabi mahboub mr, zolfaghari m, ahanian a. percutaneous nephrolithotomy of kidney calculi in horseshoe kidney. urol j. 2007;4:147-50. 12. lingeman je, saw kc. percutaneous operative procedure in horseshoe kidneys. j urol. 1999;161 supl:371. 13. jones dj, wickham je, kellett mj. percutaneous nephrolithotomy for calculi in horseshoe kidneys. j urol. 1991;145:481-3. 14. el-nahas ar, shokeir aa, el-assmy am, et al. postpercutaneous nephrolithotomy extensive hemorrhage: a study of risk factors. j urol. 2007;177:576-9. 15. munver r, delvecchio fc, newman ge, preminger gm. critical analysis of supracostal access for percutaneous renal surgery. j urol. 2001;166:1242-6. acr81cb.tmp pages from 53_10.pdf acr81cf.tmp v08_no_2_final.pdf case report 159urology journal vol 8 no 2 spring 2011 endoscopic neo cystolithotripsy for multiple calculi in studer ileal neo bladder a case report venkata ramana murthy kusuma, jayaram reddy, rama krishna prasad divella urol j. 2011;8:159-62. www.uj.unrc.ir keywords: urinary bladder calculi, lithotripsy, continent urinary reservoirs, treatment outcome department of urology, osmania general hospital, india corresponding author: venkata ramana kusuma murthy, ms, mrcs, mch department of urology, osmania general hospital, afzal gunj, hyderabad, 500012, andhra pradesh, india tel: +91 991 274 7789 fax: + 91 402 460 0260 e-mail: murthy.kusuma@rediffmail.com received september 2009 accepted february 2010 introduction radical cystectomy with urinary diversion is the standard treatment for muscle invasive bladder cancer.(1) the ileal conduit has long been considered as the gold standard for urinary diversion. continent urinary diversion with orthotopic neo bladder offers distinct advantages over ileal conduit. orthotopic ileal neo bladder provides large capacity and low pressure reservoir, and is anastomosed to native urethra. it provides the patient with a superior cosmetic appearance, a simple effective alternative for urine storage, upper tract preservation, and efficient voiding.(2) however, various early and late complications have been described.(3) herein, we report an unusual case of multiple calculi occurring in studer orthotopic ileal neo bladder. case report a 45-year-old man had undergone radical cystectomy and orthotopic neo bladder reconstruction with studer ileal neo bladder one year earlier. he was lost to follow-up 3 months after the surgery. after 8 months, he again presented to us with 1-month history of fever, dysuria, and urinary frequency. on physical examination, except mild tenderness in his suprapubic region, nothing abnormal was figure 1. plain kidney, ureter, and bladder x-ray showing multiple radio opaque shadows in the neo bladder area. neo cystolithotripsy—kusma et al 160 urology journal vol 8 no 2 spring 2011 detected; he was afebrile. his renal function tests and urine analysis were normal, and urine culture was sterile. plain kidney, ureter, and bladder x-ray showed multiple radio opaque shadows in the neo bladder area (figure 1). ultrasonography revealed multiple neo bladder calculi; the largest measuring 3 × 2 cm in diameter. cystoscopy revealed multiple calculi with extensive mucus flakes. all the calculi were fragmented by endoscopic neocystolithotripsy via transurethral approach. complete stone clearance was achieved (figures 2 and 3). after 1-year follow-up, he is stone free and voiding by abdominal straining with minimal post-void residual urine. discussion the incidence of calculi in urinary diversion depends on the type of diversion used.(4) neo bladder calculi in orthotopic ileal bladder are very rare. deliveliotis and colleagues reported a stone rate of 5.7% in patients with modified s-shaped ileal neo bladder(5) while abol-enein and ghoneim reported a stone rate of 2.9% in patients with orthotopic w-shaped ileal neo bladder.(6) studer and associates did not report a single case of neo bladder calculi in their twenty-year experience on 482 patients, because all the patients were kept under stringent lifelong follow-up protocol and monitored by computer (personal communication with studer, ue).(3) similarly, other centers using studer pouch reported very low rates of neo bladder calculi.(7) the etiology of neo bladder calculi is multifactorial, including idiopathic, metabolic, infectious, and structural causes. patients with urinary diversion with ileal neo bladder have chronic metabolic acidosis which results in hypercalciuria and hypocitraturia. furthermore, they may have hyperoxaluria, hyperphosphaturia, hypermagnesuria, and supersaturation of urine due to chronic dehydration. all these metabolic derangements will predispose them to stone formation.(4) there is increased colonization of urea-splitting bacteria in orthotopic neo bladder, with prevalence of 12% to 79%.(8) proteus, pseudomonas, and klebsiella species are most commonly involved pathogens. these bacteria produce the figure 2. postoperative plain x-ray showing complete clearance of the stones figure 3. fragmented stones neo cystolithotripsy—kusma et al 161urology journal vol 8 no 2 spring 2011 urease enzyme that promotes the generation of ammonia and hydroxide from urea. the resultant alkaline urinary environment and high ammonia concentration along with abundant phosphate and magnesium in urine promote crystallization of magnesium ammonium phosphate, leading to formation of struvite calculi.(9) since the degree of colonization depends on the amount of residual urine in the bladder, inefficient voiding and non compliance with clean intermittent catheterization are the main reasons for stone formation in patients with neo bladder. increased mucus production, foreign bodies, and use of nonabsorbable staples are other causative factors implicated in the formation of stones. in our patient, multiple neo bladder calculi were due to increased mucus production, increased residual volume due to inefficient voiding, and non compliance of the patient to strict follow-up program. the presentation of neo bladder calculi can be asymptomatic; hence, they are incidentally diagnosed on follow-up or the patient may present with dysuria, frequency, urgency incontinence, suprapubic pain, hematuria, and recurrent urinary tract infection. initial investigation should include complete biochemical profile, serum level of electrolytes as well as urine analysis and urine culture. diagnosis is confirmed by cystoscopy. the number, size, and location of the calculi can be determined by plain kidney, ureter, and bladder x-ray. alternatively, abdominal computed tomography scan provides necessary information. intravenous urography is performed to look for any upper tract dilatation and function of the kidneys. cystoscopic examination confirms the presence of stones and provides information regarding the etiology of stones. furthermore, the cause of calculi, such as staples, sutures, foreign bodies, and mucus flakes can be determined. various treatment modalities have been described, including percutaneous cystolithotripsy, transurethral endoscopic neo cystolithotripsy, and open cystolithotomy. patel and bellman recommended percutaneous approach for management of calculi in continent urinary pouches. although they had no personal experience with orthotopic bladder calculi, they suggested percutaneous approach. because they postulated that aggressive instrumentation per the urethra would lead to the bladder neck contracture.(10) in our patient, we used transurethral approach for treatment of the stones because the patient had good caliber urethra. we could achieve complete clearance of the stones without any complications. as the majority are infected stones, it is imperative to achieve a complete stone clearance, and special care must be taken in removing any foreign bodies. prevention is one of the most effective measures to deal with this complication. maintaining adequate intake of fluids, daily irrigation of the pouch with normal saline, voiding by clock or double voiding, performance of regular clean intermittent catheterization in those who void ineffectively, and antibiotic prophylaxis in those who develop recurrent urinary tract infections are the recommended preventive measures.(4) strict adherence to the above-mentioned measures and lifelong follow-up with biochemical investigations, ultrasonography at least every 6 months for the first four years and annually thereafter as well as annual pouchoscopy after 5 years will definitely eradicate the problem.(11) conflict of interest none declared references 1. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001;19:666-75. 2. hobisch a, tosun k, kinzl j, et al. life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. semin urol oncol. 2001;19:18-23. 3. studer ue, burkhard fc, schumacher m, et al. twenty years experience with an ileal orthotopic low pressure bladder substitute--lessons to be learned. j urol. 2006;176:161-6. 4. beiko dt, razvi h. stones in urinary diversions: update on medical and surgical issues. curr opin urol. 2002;12:297-303. 5. deliveliotis c, alargoff e, skolarikos a, varkarakis i, argyropoulos v, dimopoulos c. modified ileal neobladder for continent urinary diversion: experience and results. urology. 2001;58:712-6. neo cystolithotripsy—kusma et al 162 urology journal vol 8 no 2 spring 2011 6. abol-enein h, ghoneim ma. functional results of orthotopic ileal neobladder with serous-lined extramural ureteral reimplantation: experience with 450 patients. j urol. 2001;165:1427-32. 7. tanaka t, kitamura h, takahashi a, masumori n, itoh n, tsukamoto t. long-term functional outcome and late complications of studer’s ileal neobladder. jpn j clin oncol. 2005;35:391-4. 8. razvi ha, martin tv, sosa re, vaughan jr ed. endourologic management of complications of urinary intestinal diversions. aua update series. 1996;15:174-9. 9. menon m, resnick mi. urinary lithiasis: etiology, diagnosis and medical management in: walsh pc, a.b. r, vaughan ed, et al., eds. campbell’s urology. vol 4. 8 ed. philadelphia: wb saunders 2002:3260-1. 10. patel h, bellman gc. special considerations in the endourologic management of stones in continent urinary reservoirs. j endourol. 1995;9:249-54. 11. venn sn, mundy ar. continent urinary diversion using the mainz-type ureterosigmoidostomy--a valuable salvage procedure. eur urol. 1999;36:247-51. 1204 | department of urology and renal transplant, sgpgims, lucknow-226014, india. saurabh vashishtha, sanjoy kumar sureka, shikhar agarwal, alok srivastava, sandeep prabhakaran, rakesh kapoor, aneesh srivastava, priyadarshi ranjan, md. sulah ansari urethral stricture and stone: their coexistence and management corresponding author: sanjoy kumar sureka, md department of urology and renal transplant, sgpgims, lucknow-226014, india. tel: +91 522 249 4110 fax: +91 522 2668017 email: drsksureka@gmail.com purpose: the aim of the study was to determine whether the coexistence of urethral stricture and stone influence the treatment modality of each other and to ascertain the best treatment modality for these group of patients. we also tried to speculate whether the stone is an effect or a cause of the stricture. materials and methods: retrospective analysis of prospectively collected data of 35 male patients with coexistent urethral stricture and stone were done between january 1998 and december 2011. patients were divided in two groups (1 and 2) limited stone bulk (group 1, n = 30) and extensive stone bulk (group 2, n = 5). the former group was treated with endourologic procedures and the latter group managed with open staged procedures. we used ureteroscope for endourological management which we think eases the management. results: endoscopic management of both stone and stricture were successful in all patients of group 1. patients of group 2 have been managed by open surgery in two stages. all of them are urologically asymptomatic after a mean of 28 months of follow up. the principle determinants of treatment modality were the bulk of stone, its location and characteristics of stricture. conclusion: both stone and stricture can be managed successfully by endoscopic method in most of the patients. bulk, location of the urethral stone and length of stricture is the main limiting factor for the endoscopic management. a stone can be an “effect” as well as the “cause” of strictured urethra. keywords: urethral stricture; etiology; surgical procedures; adverse effects; urinary calculi. endourology and stone disease endourology and stone disease 1205vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l introduction the urethral stricture, particularly common in males, is predisposed by urethritis, perineal trauma, en-dourological treatments or repeated catheterizations.(1,2) the spongiofibrosis as a result of scarring process of spongy erectile tissue of corpus spongiosum leads to anterior urethral strictures. posterior urethral strictures usually result from a fibro-obliterative process secondary to distraction injuries. posterior strictures are associated with dense fibrosis interposed between distracted urethral ends. the main complications associated with urethral strictures, are inflammatory periurethral phlegmon, discharging sinuses and fistula, associated urethral calculi, periurethral abscesses and urethral diverticula. co-existence of urethral stone along with urethral stricture is infrequently known entity. often urethral stones are thought to be result from stasis of urine. it usually occurs in the dilated urethra proximal to the stricture segment. isolated urethral stone account for 2% of the urolithiasis and are common in developing countries,(2) more so in the middleeast.(3) isolated stone in the urethra is often secondary to migrated stone from the upper tract or the bladder.(4) one of the risk factors for urethral stones is urethral stricture, apart from episodes of urethritis, balanitis xerotica obliterans and long-term supra pubic catheter. less often, a primary urethral calculus may be formed proximal to strictured segment. it may be associated with a urethral diverticulum, urethrocele or related to hair ball developed after previous graft urethroplasty. the important determinants of appropriate treatment modality for urethral stricture include the length, location, depth of stricture and degree of spongiofibrosis. various modalities of treatment of urethral strictures include serial co axial dilation in soft partial stricture, optical internal urethrotomy (oiu) with or without local steroid injection in short segment passable strictures of anterior urethra, end to end anastomosis in non-passable dense strictures, lay opening of urethra or augmentation urethroplasty for long segment urethral strictures. (5-8) urethral stones can be treated by retrograde manipulation, milking, forceps extraction, extra corporeal shockwave lithotripsy, transurethral litholapaxy and ultrasonic, laser or pneumatic fragmentation.(9-14) to our knowledge all reports till date about urethral calculi are based on retrospective studies and mostly on few patients as these stones are infrequent. the literature on management of both complexities together is limited and the best treatment option for this dual pathology is still to be determined. the aim of the present study was to describe our experience with technical difficulties encountered and the best treatment modality for these groups of patients when both stricture and stone exist together. materials and methods prospectively collected data of 35 consecutive patients admitted to our hospital having urethral stricture and stone, between january 1998 and december 2011 were reviewed (tables 1 and 2). patients were evaluated with relevant medical history (including any history of urethral trauma or urethral discharge), physical examination (including palpation of the urethra, scrotum, perineum and a digital rectal examination), urine analysis, urine culture when necessary and a plain x-ray of the abdomen including pelvis and entire length of urethra. all patients underwent voiding cystourethrogram and or retrograde urethrography for diagnosis of stricture and the stone in the urethra. confirmation of the stone was done by urethroscopy per-operatively. uroflowmetric assessment was done as objective assessment of lower urinary tract symptoms (luts) preoperatively and in follow up. the spectrum of urethral stone bulk was divided into two groupslimited stone bulk (group 1, n = 30) and extensive stone bulk (group 2, n = 5). the extensive stone bulk group included those patients who had more than one stone. in the former group, the location of stone was defined in relation to the site of stricture as proximal, distal or at the site of stricture. four stones were in distal, 4 at the site of stricture and 22 were in proximal (table 3). there were 5 patients with multiple stones, all associated with pan anterior urethral stricture. one was associated with a proximal urethral diverticulum and concomitant pan anterior urethral stricture. the number, size, shape and location of the urethral calculi were determined. the limited stone bulk group was managed by endoscopic means (table 4). a guide wire was passed if negotiable across the stone and the stricture into urethral stricture and stone | sureka et al 1206 | the urinary bladder, using the ureteroscope. oiu was done using cold knife or holmium laser (200 µ fiber) before managing the stone in cases with stone proximal to the stricture. after dealing with the distal stricture the stones were tried to push back into the bladder followed by litholapaxy. this method was successful in 5 patients. in other patients, it was not possible to manipulate the stone due to its size and the limited space. in those cases, we used an ureteroscope and tried to negotiate a guide wire. if the guide wire was not negotiable, stone was fragmented using a pneumatic lithotripter or by using holmium laser energy via the ureteroscope. once the stone was fragmented repeat attempt was done to pass the guide wire. continuous irrigation under pressure by means of a pathfinder was helped to dislodge the fragments easily and creates space for the passage of the guide wire. the same technique was used for stones located distally to the stricture and across which the guide wire could not be passed without fragmentation. the common difficulties encountered during cystoscopy were limited and obscured vision due to impacted urethral stones and less available working space. hence the use of an ureteroscope and a pathfinder to generate high-pressure irrigation greatly facilitate the procedure. also the use of holmium laser made it easy to fragment the harder stones which were not easily broken by the pneumatic lithotripter. the stone fragments were pushed up into the bladder using the pushback technique as for the posterior urethral stones and then retrieved at the end of the procedure. a foley catheter was put in for 7 days and thereafter the patients were explained for selfcatheterization weekly for three months. all the strictures associated with the limited stone bulk were amenable for oiu except for one which was managed with end to end anastomosis. patients who had extensive stone bulk were managed by staged surgical treatment. standard lay open of the urethra with stone extraction was performed in all patients. these patients underwent staged urethroplasty after 6-8 weeks. three patients underwent buccal mucosal graft reconstruction whereas in 2 patients the neourethra was made from a cutaneous flap. patients were followed up as long as possible during the study with a mean follow up of 28 months. results the mean age of patients presenting with urethral stricture and coexistent urethral stone was 32 years (range 9-64 years) with 1 child (9 years). all 35 patients were males. the chief complaint of all these patients was poor stream (85%), dysuria (80%), straining (68.5%) and interrupted stream (51.4%) and all of them were admitted through the out patients department except 3 patient (8.5%), who was admitted with acute retention in the emergency ward (table 2). all patients in the study had radio opaque calculi confirmed by radiography. the commonest location of the stricture was the posterior urethra following the distraction injury. sixteen patients had anterior urethral stricture whereas nineteen patients had posterior stricture. five patients had a long segment pan urethral stricture. one case was associated with urethrocutaneous fistula along with pan anterior urethral stricture and 1 patient had stone in a diverticulum of the urethra. endourology and stone disease table 1. patient demographic characteristics. no. of patients 35 sex males mean age, years (range) 32 (9-64) mean duration of symptoms, years (range) 1.8 (8 months – 3 years) no. of naïve patients 29 no. of patients with previous history of urethroplasty 6 patients with history of urolithiasis 2 patients with limited stone bulk 30 patients with extensive stone bulk 5 table 2. presenting symptoms and signs. symptoms and signs number dysuria 28 loss of stream 30 straining 24 interruption of stream 18 retention 3 urethral fistula 1 palpable urethral mass 2 1207vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l in the limited stone bulk group 4 patients had urethral stone distal to the site of the stricture in the penile urethra and 22 patients had calculi proximal to the stricture whereas four patients had stone at the site of the stricture. therefore, 30 patients had a single calculus, whereas 5 patients had multiple calculi (figure) and all were associated with pan anterior urethral stricture. the endoscopic technique was successful in all the cases of the limited bulk group except one which was managed by end to end urethroplasty. staged reconstruction was done in all patients of extensive stone bulk. none of the patients treated with staged reconstruction developed urethral fistula or incontinence with excellent healing of the donor sites. spontaneous expulsion methods with no surgery and milking procedures were not successful in any case. three patients had gram negative urosepsis in postoperative period and one had a urethral bleeding which subsided with conservative management. one patient who was managed endoscopically had recurrence at an interval of 8 months and was managed simply by oiu. discussion urethral stone constitute of less than 2% of all urolithiasis and considered as a rare disease in literature.(2,15) but urethral stone is not an uncommon disease in northern part of india as we found in our study. reported literature does not describe any well-defined algorithm for treatment of urethral stone associated with stricture at the same sitting without affecting the ultimate outcome. we subscribe to the common view that treatment is based essentially on the size, shape, location and the bulk of stone present in the strictured urethra. anterior urethral stone can be milking down with instillation of 2% lignocaine jelly or can be removed by ventral meatotomy or urethroscopic extraction method. milking is usually avoided in stones which are spiked or are associated with urethral obstruction.(9) endoscopic forceps extraction should be avoided in such stones. non operative manipulation was tried in some with no positive results. good results are reported in literature for the endoscopic pushback method followed by fragmentation provided that the manipulation was done under direct vision.(9) it is ideal for moderate sized calculi located specially in the prostatic urethra. we stuck to the same principles while trying to manipulate the stones into the bladder after oiu for distal stricture and were successful in 5 patients. in cases of urethral stones associated with stricture or impacted urethral stone open urethrotomy with primary or staged urethroplasty has been preferred.(16) however, good results of in situ holmium laser lithotripsy under cystourethroscopic guidance for impacted stones which could not be pushed back into the bladder have been reported.(17,18) successful management of impacted stones has also been reported with the use of ultrasonic lithotripter. we had satisfactory results in 24 of our patients including those with impacted stones by using lithotripsy (pneumatic or laser). we used an ureteroscope instead of a cystoscope as it gave more space to work with. continuous irrigation under pressure by means of a pathfinder helped to dislodge the fragments easily and create space for the passage of the guide wire. patients with extensive stone bulk have been managed by open surgery. in presence of stricture we used endoscopic modality only in those patients in whom the stone bulk was limited or the stricture length was not long. it is practically impossible to pass the ureteroscope, in patients of extensive stone bulk, as the scarred segment is tight and long. endoscopic intervention is unlikely to be successful and will lead to high rates of re-stricture as the previous stone bulk has caused long-standing inflammation, infection, fibrosis and ischemia of the urethra. patients with extensive bulk of stones and stricture are best managed by staged urethroplasty. there was no female patient with urethral calculus in this current study and is similar to the previous reports that females are infrequently involved,(4) although giant urethral urethral stricture and stone | sureka et al table 3. location of stricture and stone. symptoms and signs number anterior urethra 16 posterior urethra 19 diverticula with anterior urethral stricture 1 stone location distal to stricture 4 proximal to stricture 22 at the site of stricture 4 1208 | calculus in females has been reported in literature.(19) sharfi(10) and selli and colleagues(20) has reported that 56% of patients with urethral stones had anatomical abnormalities in their urethra. hence they have concluded that urethral calculi are mostly associated with anatomical abnormality in the urethra. we also noted similar findings in our study, although kamal and colleagues did not notice any anatomical changes.(9) isolated urethral stones are relatively common in children(4) specially in the developing countries due to higher prevalence of bladder calculi. in contrary to literature, only 1 patient in our study was below 12 years. acute urinary retention was presenting symptoms in patients with urethral stone in 20% to 90% of patients as reported by el-sherif and el-hafi and sharif.(14,21) in our study the most common presentation of these patients was poor stream (85%) followed by dysuria (80%) as compared to acute urinary retention (8.5%) (table 2) described classically for urethral stones. none of the patient had acute retention in 14 male patients as reported by selli and colleagues.(20) urethral stones has been classified as primary and secondary on the basis of the site of origin. primary calculi are usually associated with anatomical abnormality of urethra such as stricture and diverticula. secondary stones are migrated stone from bladder or upper urinary tract.(21) secondary stones are more common than primary stone and secondary stones usually present with acute onset symptoms such as acute retention, dysuria, severe obstructive flow or dribbling of urine. primary stones do not cause acute symptoms and usually associated with long history of lower urinary tract symptoms related to primary urethral abnormality. in our study only 3 patients presented with acute retention which may correlates with the primary nature of stone in association with stricture. the etiology of primary stones is related to the concept of urinary stasis, infection and local inflammation. during initial stages of stone formation, obstructed flow and a dependent location in the pre-stenotic dilated segments of urethra causes the stone to be retained. the commonest location of stricture was posterior urethra (66%) and all of them had stones in the posterior urethra. most urethral stones in our study (65%) were in posterior urethra, as reported previously by others for isolated urethral stones.(2,10,13) all patients in our study had radio opaque calculi confirmed by uroradiography. this contradicts some earlier reports that most urethral calculi are radiolucent.(13,22) kamal and colleagues also reported that 98% of the urethral stones in his study were radio opaque.(9) data on the constituents of urethral calculi are lacking in literature except kamal and colleagues(9) have reported that calcium oxalate was most common type ( 86%) followed by struvite (6%) and uric acid (2%) stone. this is probably a limitation of our study that we did not analyzed the composition of stones in our patients routinely. conclusion urethral stone and stricture disease is not an uncommon association. a stone can be an “effect” as well as the “cause” endourology and stone disease table 4. endoscopic management of limited stone bulk group. management number mean follow up, month endoscopic intervention oiu + pneumatic lithotripsy 7 36 (18-24) oiu + holmium lithotripsy 14 12.2 (8.5-14) pneumatic lithotripsy followed by oiu 2 18.8 (14.6-28.8) holmium lithotripsy followed by oiu 1 13.2 (13.0-15.8) oiu + retrograde manipulation then litholapaxy 5 60.0 (15.0-118.5) 1209vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l urethral stricture and stone | sureka et al of stricture urethra. in these cases of dual pathology the treatment modality is principally guided by the location of stone in relation to the stricture, the bulk of the stone and character of stricture. lithotripsy including lasertripsy is an effective modality in patients with limited stone bulk and the use of an ureteroscope instead of a cystouretherscope can ease the procedure. patients with extensive stone bulk are better managed with open staged procedure. co-existence of both entities may complicate the surgical technique but does not affect the outcome of surgery. conflict of interest none declared. references 1. polo m, cabras m, licheri s, polo f. a case of lithiasis and stenosis of the urethra. diagnostic and therapeutic problems. minerva urol nefrol. 1990;42:235-8. 2. koga s, arakaki y, matsuoka m, ohyama c. urethral calculi. br j urol. 1990;65:288-9. 3. amin ha. urethral calculi. br j urol. 1973;45:192-5. 4. hegele a, olbert p, wille s, heidenreich a, hofmann r. giant calculus of the posterior urethra following recurrent penile urethral stricture. urol int. 2002;69:160-1. 5. tavakkoli tabassi k, yarmohamadi a, mohammadi s. triamcinolone injection following internal urethrotomy for treatment of urethral stricture. urol j. 2011;8:132-6. 6. tavakkoli tabassi k, mansourian e, yarmohamadi a. onestage transperineal repair of pan-urethral stricture with dorsally placed buccal mucosal grafts: results, complications, and surgical technique. urol j. 2011;8:307-12. 7. chiang dt, a dewan p. guide wire-assisted urethral dilation in pediatric urology: experience of a single surgeon. urol j. 2007;4:226-9. 8. saurabh vashishtha, sanjoy sureka kumar, jatinder kumar, sandeep prabhakaran, rakesh kapoor, m.s. ansari. predictors for recurrence after urethroplasty in pediatric and adolescent stricture urethra. j pediatr urol. 2013 (article in press, available online :http://www.sciencedirect.com/science/article/pii/s147751311300226x) 9. kamal ba, anikwe rm, darawani h, hashish m, taha sa. urethral calculi: presentation and management. bju int. 2004;93:549-52. 10. sharfi ar. presentation and management of urethral calculi. br j urol. 199; 68:271-2. 11. durazi mh, samiei mr. ultrasonic fragmentation in the treatment of male urethral calculi. br j urol. 1988;62:443-4. 12. englisch j. uber eigelagere and einges achle stein der hanrohre. arch klin chir. 1904;72:487-93. 13. paulk sc, khan au, makek rs, greene lf. urethral calculi. urology. 1976;16:436-40. 14. el-sherif ac, el-hafi r. proposed new method for non-operative treatment of urethral stones. j urol. 1991;146:1546-50. 15. drach gw. urinary lithiasis etiology, diagnosis and medical management. in walsh pc, retik ab, stamey ta, vaughan ed jr. eds campbell’s urology 6th edition. philadelphia: wb saunders; 1992. p. 2085-156. 1210 | endourology and stone disease 16. suzuki y, ishigooka m, hayami s, nakada t, mitobe ka. case of primary giant calculus in female urethra. int j urol nephrol. 1997;29:237-9. 17. maheshwari pn, shah hn. in-situ holmium laser lithotripsy for impacted urethral calculi. j endourol. 2005;19:1009-11. 18. walker br, hamilton bd. urethral calculi managed with transurethral holmium laser ablation. j pediatr surg. 2001;36:e16. 19. suzuki y, ishigooka m, hayami s, nakada t, mitobe ka. case of primary giant calculus in female urethra. int j urol nephrol. 1997;29:237-9. 20. selli c, barbagli g, carini m, lenzi r, masini g. treatment of male urethral calculi. j urol. 1984;132:37-42. 21. sharfi ar. complicated male urethral strictures: presentation and management. int urol nephrol. 1989;21:491-7. 22. koh cj, de fillipo re, bochner bh, stein jp, skinner dg. extensive bladder and urethral calculus detected with computerized tomography; diagnosis and management. j urol. 1999;162:158-62. 1328 | social shyness stands behind a roll pen in a female bladder: it mimics acute appendicitis ihab a. hekal corresponding author: ihab ahmed hekal, md, phd department of urology, dossary hospital, alkhobar, saudi arabia. tel: +96 65 6677 2693 e-mail: eahekal@yahoo.com received december 2011 accepted february 2012 department of urology, dossary hospital, alkhobar, saudi arabia. keywords: abdomen; acute; etiology; foreign bodies; female; urinary bladder; appendicitis. introduction herein, we reported unique case which had been presented to emergency with picture simulating acute appendicitis. the surprising event; when she underwent the routine investigations, an intact roll pen was seen on her pelvic cavity. later, she claimed self-inflected intravesical trans-urethral roll pen (14 cm) that was inserted for two months prior to her presentation. case report a 38 years old saudi female, married with 4 offspring. she was presented to emergency with right iliac fossa pain and fever of two days duration. she also experienced nausea and vomiting twice. on examination she was febrile (38˚c) with tender right iliac region and guarding. leukocytosis, anemia and high erythrocytes sedimentation rate (esr) were the remarkable findings in her laboratory workup. primary diagnosis was acute appendicitis with shifting to surgical ward. routine preoperative abdominal and pelvic ultrasound revealed minimal right iliac fossa collection (2 × 3 cm) with possible foreign body in the bladder or near the uterus. case report case report 1329vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l a roll pen in a female bladder, it mimics acute appendicitis | hekbal urological consultation was requested. kidney ureter bladder (kub) x-ray was done in which a complete roll pen was obliquely lie inside her pelvic cavity (figure 1). urinalysis showed microscopic hematuria and minimal pyuria. non contrast abdominal and pelvis computerized tomography (ct) was performed; it revealed a roll pen (14 cm) obliquely lie inside the bladder, its tip was piercing the bladder on right side and it has been under the skin (figure 2). retrospective through history taking; the patient claimed that she inserted the roll pen for sexual play and she could not retrieve it when it had been slipped inside her bladder. social shyness prevents her to seek any medical advices and keep silent for 2 months. on next day; cystoscopy was carried out and trial manipulation of the roll pen inside the bladder with a grasping forceps (figure 3a). with hydro-distension of the bladder, the roll pen was mobilized inside the bladder cavity starting by detachment of the blunt posterior end first, once it became free withdrawal of the other end aiming to be on its longitudinal access. intact extraction of the roll pen via the urethra has been done (figure 3b). re-check cystoscopy for possible perforation was negative. fixation of large caliber urethral catheter was done with recommendation of one week catheterization. total procedure time was 30 minutes. the patient stayed in hospital for couple of days with low grade fever. ultrasound follow-up showed a small pelvic free fluid in douglas pouch. she was responded well on intravenous antibiotic and discharged afebrile with normal ultrasound findings. one week later, passive aseptic cystogram was carried out; it showed no leakage with intact bladder walls. discussion although foreign body (fb) inside the adult bladder is not a rare condition, but the aggressiveness of the case by insertion of a complete roll pen as well as the minimal invasive procedure with safely extraction of the whole object as one unit are worth to be demonstrated. in english literature many articles discuss the insertion of pen case, cover or even smaller objects were reported. in most of them cystoscopic extraction was the best treatment modality. however, open surgery is still encountered. most of reported bladder fb cases were presented to the hospital with urinary symptoms. different objects have been reported, majority of them were iatrogenic in nature, intrauterine devices (iud), artificial sphincters, vaginal pessaries, catheter, and beak of resectoscope.(1-9) however, self-inflected objects were encountered aiming for sexual pleasure and gratifications. in rafique and colleagues study,(10) they traced many cases with different objects (wire, thermometers, hair pen, battery and others), all presented with urological symptoms. the radiological diagnosis of radiopaque objects is the corner stone before any intervention. the identification of numbers, length, size, and associated injuries are the main goals. in our case, ct was important to identify the extent of associated figure 1. kub-x ray from abdomen and pelvis. figure 2. serial ct images of the bladder demonstrated the roll pen in bladder; a) the metallic tip of the pen under the skin on right iliac fossa; b) the blunt tip was resting on the bladder wall with thickening of the posterior bladder wall. 1330 | bladder injury. the treatment of choice is surgical extraction. minimal invasive techniques (endoscopic) is the best, however in some complicated cases the open surgical treatment (cystostomy) is warranted. in english literature, we could trace only one case similar to our case (ball pen) in which the open surgery was done(10) and the urinary symptoms were the presentation. in our case, the object is 14 cm long, stiff, rigid and obliquely lies with small perforation. late presentation due to social shyness prevents early intervention. non-familiar presentation; right iliac fossa pain and suspicious of acute appendicitis was the primary diagnosis. all these factors were made difficultly, urological challenge and seldom case presentation. conclusion in community; shyness, social traditions and believes may mask serious surgical conditions. for general surgeons, differential diagnosis of bladder problems should be excluded before any operative intervention. routine investigation, at least ultrasound, kubx-ray, prior to any lower abdominal surgery is mandatory. for urologists, whenever fb in the bladder, minimal invasive techniques should be exhausted before open surgery is threatened. conflict of interest none declared. figure 3. a) cystoscopic view of the pen inside the bladder; b) extraction of the pen intact through urethra. references 1. bartoletti r, gacci m, travaglini f, sarti e, selli c. intravesical migration of ams 800 artificial urinary sphincter and stone formation in a patient who underwent radical prostatectomy. urol int. 2000;64:167-8. 2. tornero j, palou j, prados m, salvador j, vicente j. bladder perforation caused by foreign body migration. int urol nephrol. 2000;32:241-3. 3. nouira y, rakrouki s, gargouri m, fitouri z, horchani a. intravesical migration of an intrauterine contraceptive device complicated by bladder stone: a report of six cases. int urogynecol j pelvic floor dysfunct. 2007;18:575-8. 4. chamary vl. an unusual cause of iatrogenic bladder stone. br j urol. 1995;76:138. 5. cardozo l. recurrent intra-vesical foreign bodies. br j urol. 1997;80:687. 6. grody mh, nyirjesy p, chatwani a. intravesical foreign body and vesicovaginal fistula: a rare complication of a neglected pessary. int urogynecol j pelvic floor dysfunct. 1999;10:407-8. 7. aliabadi h, cass as, gleich p, johnson cf. self inflicted foreign bodies involving lower urinary tract and male genitals. urology. 1985;26:12-6. 8. ohashi h. a case of bladder calculus due to a ruptured balloon fragment of a foley catheter. hinyokika kiyo. 1997;43:227-8. 9. persad ra, paisley a, smith pj. retained catheter tip causing recurrent urinary tract infection in a 91-yearold man. br j urol. 1990;66:664. 10. rafique m. intravesical foreign bodies: review and current management strategies. urol j. 2008;5:223-31. case report case report 524 case report endoscopic dilatation of meatal stenosis of ureterocele in adult patients: an easy and innovative technique with literature review abbas basiri1,2*, milad bonakdar hashemi1, arsalan aslani1 this study presents initial experience in endoscopic meatal dilatation of obstructive ureterocele in adult patients. during cystourethroscopy, we tried to find the orifice of ureterocele, passed a guide wire and introduce an 8 fr ureteroscope in to the ureterocele orifice, going up to the renal pelvis as under vision dilatation of ureterocele meatus. two double-j stent were inserted and remained for six weeks to keep the meatus dilated. adverse effect of endoscopic management was decreased due to minimal anatomic changes. patients’ symptoms were relieved and no evidence of new onset vesico-ureteral reflux and obstruction were seen after up to one-year follow-up. endoscopic meatal dilatation of stenotic ureterocele in adult patients is safe and effective thus, trying to find the orifice of ureterocele is suggested. keywords: meatal dilatation; ureterocele; ureteroscope introduction ureterocele is a cystic dilation of the distal ureter. it is a congenital anomaly, associated with other anomalies such as a duplicated system and other diseases(1). there is no consensus on the management of ureterocele, type of presentation, and function of the affected kidney, and there are issues that should be considered in ureterocele cases. thus, individualized management is expectable (1). the ureterocele in an adult patient is rare and usually asymptomatic. the management of ureterocele mainly have focused on pediatric patients in the literature. endoscopic approach has been accepted as a temporary technique and was introduced as a useful surgical management with minimal postoperative morbidity(2). ureteral re-implantation and/or bladder neck reconstruction is not necessary for all patients especially in adult patients(3). the successful management of ureterocele is associated with relieving the obstruction, and prevention of de novo vesicoureteral reflux (vur)(4). high incidence of acquired vur (up to 35%) in endoscopic approach has been reported and it was associated with endoscopic techniques (transurethral incision (tui), watering can technique) and ureterocele type(3,4). we present successful endoscopic meatal dilatation in adult obstructive ureterocele without adverse impact on outcomes. 1urology nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2erfan hospital, tehran, iran *correspondence: urology nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. e mail: unrc.ir received november 2019 & accepted april 2020 urology journal/vol 18 no. 2/ march-april 2021/ pp. 240-246. [doi: 10.22037/uj.v0i0.5808] figure1. pre-operative intravenous urography (ivu). case presentation and technique a) a forty-year-old man was referred to our clinic with the complaint of vague abdominal pain for years and hydroureteronephrosis on abdominopelvic ultrasonography. the orthotopic single system ureterocele was obsereved in intravenous urography (ivu) (figure 1). during cystourethroscopy, the pinpoint orifice was found at the anterolateral of ureterocele with sharp urine jet through the orifice (figure 2a). the safety wire was inserted, and with 8fr ureteroscope via native orifice we were able to enter into the ureter and continue up to the renal pelvis under vision dilatation procedure (figure 2b). then two double-j stent were inserted to keep the meatus dilated (figure 2c). after 6 weeks, both double-j stents were removed. there was no evidence of de novo vur and obstruction after 12 weeks of follow up (figures 3,4). the urinary stasis after one year follow up was resolved. b) a forty-three-year-old man came to our clinic with left renal colic pain due to a one-centimeter uretero-vesical junction stone (figure 5a). the patient was being prepared for transurethral lithotripsy. during cystoureteroscopy, ureterocele was found incidentally with a pinpoint orifice. 0.038 fr guide wire was inserted, 8 fr ureteroscope was passed through the ureterocele orifice, the stone was extracted and removed with grasper and ureteroscopy was continued up to the renal pelvis (figure 5b). after removing the ureteroscope, the ureterocele meatus remained dilated enough and urine jet was seen. two double-j stent were inserted to keep the meatus dilated. after 6 weeks, both double-j stents were removed. the voiding cystourethrography (vcug) was normal 12 weeks post-operation. there was no evidence of hydronephrosis on abdominopelvic ultrasonography in one-year follow-up. c) a thirty-year-old woman with a complaint meatal dilatation of adult ureterocele-basiri et al. figure2. a. intra-operation urine jet from pin point native orifice of ureterocele, before endoscopic dilatation. b. intra-operation insertion of guide wire. c. insertion of two double-j. figure 3. post-operative dtpa scan after 12. case report 241 vol 18 no 2 march-april 2021 242 of recurrent urinary tract infection was referred to our clinic. the patient had a history of laparoscopic heminephrectomy due to non-functioning lower pole left kidney with complete double collecting system and also history of right side nephrectomy twenty years before referral due to non-functioning kidney with unknown etiology. pre-operative evaluation consisted of serum creatinine (1.7 mg/dl) and normal ultrasound on the remaining part of the left kidney. on the cystourethroscopy, there were two ureteral orifices on the left side of trigone (cephalad one for lower moiety and caudal one on the tip of ureterocele for upper moiety) (figure 6a). a guide wire was inserted to the cephalad orifice to make sure that was for lower moiety with no connection to the upper moiety. the second safety guide wire was inserted into the ureterocele orifice (figure 6b) and 8 fr ureteroscope was passed through the native orifice of the ureterocele up to the renal pelvis. after removing the ureteroscope, the ureterocele orifice was seen to be dilated enough and urine jet was seen. the double-j stent was inserted (figure 7) and removed after six weeks. on one-year follow-up, the patient was asymptomatic and the urine culture was negative. d) a thirty-five-year-old man was referred to our clinic with refractory irritative lower urinary tract symptoms. abdomino-pelvic ultrasonography showed right side moderate hydroureteronephrosis without any apparent causes of obstruction. the single system ureterocele was seen in ivu (figure 8). the patient was scheduled for endoscopic management of ureterocele, during cystourethroscopy native meatus of ureterocele was apparent (figure 9) and guide wire 0.038(fr) was inserted and 8 fr ureteroscope was passed through the native orifice of ureterocele over the guide wire and ureteroscopy continued up to the renal pelvis. after removing the ureteroscope, the ureterocele orifice was seen to be dilated enough and urine jet was seen. the double-j stent was inserted. after limited follow-up (three months) hydroureteronephrosis was relieved in ultrasonography and ivu (figure 10). figure4. post-operative vcug after 12 weeks. figure5. a. pre-operative abdomino-pelvic ct-scan without contrast. b. the large stone located in ureterocele. meatal dilatation of adult ureterocele-basiri et al. discussion most adults ureteroceles are in single system, intravesical, and located on the trigone of bladder. the therapeutic management of ureterocele is controversial, which is related to the type of presentation and postoperative morbidity. short operation time and acceptable outcomes of endoscopic approach have made the endoscopic procedure the first-line therapy at some centers (5), however according to previous studies, there is no consensus on any priority for the type of endoscopic techniques(6) (table 1). the high incidence of vur and the necessity of auxiliary procedures in endoscopic approaches are considered as disadvantages of transurethral incision (tui) or puncturing(4,6). the goals of endoscopic techniques are to decompress the obstructed system while minimizing the incidence of postoperative reflux(7), therefore, less manipulation of anatomic integrity in ureterocele is an important technical point to reach these goals. we went through literature for treatment of adult ureterocele and summarize them in table 1. dutov and colleagues studied 51 patients with true ureterocele in adult patients in which 26 patients underwent endoscopic incision wall of ureterocele. incidence of de novo vur was not reported(8). also sadiki and figure 6. a. insertion of guide wire to lower moiety remnant ureter. b. intra-operation insertion of guide wire. figure 7. post operation kub. meatal dilatation of adult ureterocele-basiri et al. case report 243 with ureterocele who underwent tui and were followed by ultrasonography and micturating cystourethrography (mcu). mcu revealed grade-1 vur in three patients and grade-2 vur in one patient at 3-month follow-up. repeated mcu at six months revealed complete resolution of vur in these patients(6). based on previous reports that were shown in table 1, it seems that there is no consensus for the location, length, and instrument for ureterocele incision and sometimes there is no confidence to cut the full thickness of ureterocele wall. it seems that our technique can offer a uniform procedure for every surgeon by details of the procedure and have the answer for above mentioned unanswered technical questions with acceptable outcomes. conclusions we introduce our initial experience in the endoscopic management of adult ureterocele. it seems that meatal dilatation of stenotic ureterocele without changing anatomic integrity is a safe, feasible, and effective endoscopic technique for relieving obstruction and preventing new-onset vur. figure 10. post-operative intravenous urography. author year of number of endoscopic secondary incidence of. vur occurrence of post study patient technic intervention post op op. obstruction rodriguez(10) 1984 25 smiling mouth incision none 1 (4%) not reported gotoh (11) 2000 1 small incision none nil not reported chtourou (12) 2001 20 endoscopic horizontal none 1 (5%) – resolved not reported ureterocele incision after six months aron (13) 2001 1 holmium laser incision none nil at 3 months not reported jones (14) 2002 2 holmium laser incision none not specified not reported lieb (15) 2003 1 holmium laser incision none not specified not reported dutov (8) 2004 51 incision wall of ureterocele none not specified not reported sadiki (9) 2005 14 endoscopic meatotomy 1 (7%) resection of the 5 (35.7%) resolved after not reported ureterocele and hendren three months ureteric reimplantation 1 (7.14%) persistent after six months spatafora (16) 2006 15 collins knife incision none 3 (20%) not reported singh (17) 2007 2 transverse incision none nil at 6 months not reported shah (6) 2008 16 holmium laser incision none 4 (25%) resolved after not reported six months table 1. literature review on the management of ureterocele. meatal dilatation of adult ureterocele-basiri et al. case report 245 vol 18 no 2 march-april 2021 138 references 1. stephens fd. aetiology of ureteroceles and effects of ureteroceles on the urethra. british journal of urology. 1968;40:483. 2. palmer bw, greger h, mannas db, al. e. comparison of endoscopic ureterocele decompression techniques. preliminary experience--is the watering can puncture superior? the journal of urology. 2011;186(4 suppl):1700-3. 3. plaire jc, pope jct, kropp bp, adams mc, keating ma, rink rc, et al. management of ectopic ureters: experience with the upper tract approach. the journal of urology. 1997;158(3 pt 2):1245-7. 4. park js, lee ys, lee cn, kim sh, kim sw, lee h, et al. transurethral incision as initial option in treatment guidelines for ectopic ureteroceles associated with duplex systems. world journal of urology. 2019. 5. kajbafzadeh a, salmasi ah, payabvash s, arshadi h, akbari hr, moosavi s. evolution of endoscopic management of ectopic ureterocele: a new approach. the journal of urology. 2007;177:1118-23; discussion 23. 6. shah hn, sodha h, khandkar aa, kharodawala s, hegde ss, bansal m. endoscopic management of adult orthotopic ureterocele and associated calculi with holmium laser: experience with 16 patients over 4 years and review of literature. journal of endourology. 2008;22:489-96. 7. marr l, skoog sj. laser incision of ureterocele in the pediatric patient. the journal of urology. 2002;167:280-2. 8. dutov vv, dolgov ag. [ureterocele and urolithiasis]. urologiia (moscow, russia : 1999). 2004(1):43-7. 9. sadiki r, sadiq a, tazi k, koutani a, hachimi m, lakrissa a. [ureterocele in adults based on a series of 14 cases]. progres en urologie : journal de l'association francaise d'urologie et de la societe francaise d'urologie. 2005;15:231-7; discussion 7. 10. rodriguez jv. endoscopic surgery of calculi in ureteroceles. european urology. 1984;10:369. 11. gotoh t, arai h, komori k, satoh e, imazu t, nishimura k, et al. [a case of urinary stone in ureterocele extracted transurethrally after eswl]. hinyokika kiyo acta urologica japonica. 2000;46:467-70. 12. chtourou m, sallami s, rekik h, binous my, kbaier i, horchani a. [ureterocele in adults complicated with calculi: diagnostic and therapeutic features. report of 20 cases]. progres en urologie : journal de l'association francaise d'urologie et de la societe francaise d'urologie. 2002;12:1213-20. 13. aron m, costello aj. case report: holmium laser resection and lasertripsy for intravesical ureterocele with calculus. lasers in surgery and medicine. 2001;29:82-4. 14. jones js. holmium laser for management of ureterocele calculi. lasers in surgery and medicine. 2002;31:297-8. 15. lieb j, abrahams hm, das ak. endoscopic management of milk of calcium-filled ureterocele stump. journal of endourology. 2003;17:917-8. 16. spatafora s, buli p, leoni s. combined percutaneous-transurethral incision for treatment of ureterocele in adults. urology. 2006;68:1333-5. 17. singh i. adult bilateral non-obstructing orthotopic ureteroceles with multiple calculi: endoscopic management with review of literature. international urology and nephrology. 2007;39:71-4. meatal dilatation of adult ureterocele-basiri et al. vol 18 no 2 march-april 2021 246 pictorial urology 15urology journal vol 7 no 1 winter 2010 tricholithobezoar an unusual long-term complication of hypospadias surgery a 16-year-old boy presented with gradually increasing painless swelling between the testes. he had undergone a 2-stage denis-browne repair of congenital proximal hypospadias, second stage performed at the age of 8 years. on examination, a hard lump was felt between the testes. radiography of the pelvis showed a faint oval radiopaque shadow in the scrotal region. cystoscopy revealed a small opening which led to a calculus covered with hair inside a urethral diverticulum near the penoscrotal junction. the patient underwent open surgical removal of the calculus, excision of the diverticulum, and repair of the urethra, all in the same session. diverticulum with calculus formation is a known late complication after hypospadias repair. if the diverticulum develops in a hair-bearing skin, the stone might be “hairy. (1)” open surgical removal of the tricholithobezoar followed by diverticulectomy is the treatment of choice.(2) this case report once again underscores the need for proper examination of a patient who has undergone hypospadias correction earlier. this particular finding is not unusual where patients with hypospadias may present for the first time in late childhood or even adolescence. consequently, the surgical complications of hypospadias repair may manifest up to a later age. vishwajeet singh, krishna murari singh, rahul janak sinha kk hospital and research center and department of urology, chhatrapati shahuji maharaj medical university, lucknow, uttar pradesh, india e-mail: vishwajeeturo@sify.com references 1. hayashi y, yasui t, kojima y, maruyama t, tozawa k, kohri k. management of urethral calculi associated with hairballs after urethroplasty for severe hypospadias. int j urol. 2007;14:161-3. 2. ozgok y, seckin b, demirci s, harmankaya c, erduran d, sinav a. surgical treatment of urethral diverticula in men. scand j urol nephrol.1994;28:207-10. urol j. 2010;7:15. www.uj.unrc.ir endourology and stone disease the clinical efficacy and safety of flexible ureteroscopic treatment for parapelvic renal cyst and secondary renal stone jiaming wen, gang xu, gaofei he, bohan wang, xiawa mao, shigeng zhang* purpose: to explore the efficacy and safety of flexible ureteroscopic incision and drainage and flexible ureteroscopic lithotripsy for treatment of parapelvic renal cyst combined with secondary renal stone. materials and methods: 28 patients with parapelvic renal cyst combined with renal stone were treated with flexible ureteroscopic incision and drainage and flexible ureteroscopic lithotripsy simultaneously from may 2010 to december 2016. the follow-up was made 1, 3, 6ι12 months and 2 years after surgical treatment in our outpatient department. ultrasonic examination and ct were used to detect the residual stone and recurrence of renal cyst. results: the mean age of the patients was 45.3 ± 18.6 years. the average size of the parapelvic renal cysts was 4.3 ± 1.6 cm, including 27 with bosniak category i and 1 patient with bosniak ii renal cysts. the mean size of the renal stones was 14.3 ± 3.9 mm. the mean operative time was 53.4 ± 20.7 minutes and the mean blood loss was 10.8 ± 5.6 ml. the mean hospitalization time was 3.2 ± 0.7 days. no severe complications were encountered. the complications included transient fever ( > 38°c) in 3 patients and significant hemorrhage in 1 patient. the stonefree rates one month and three months after operation were 89.3% and 96.4%, respectively. during the 2 years follow-up, the cyst recurrence rate was 14.3% and the stone recurrence rate was 7.1%. conclusion: in this study, we firstly demonstrated that it is safe and effective to treat both renal stone and parapelvic renal cyst simultaneously by flexible ureteroscopic lithotripsy and flexible ureteroscopic incision and drainage, with satisfactory stone free rate and low cyst recurrence rate. keywords: parapelvic renal cyst; renal stone; flexible ureteroscopy; retrograde intrarenal surgery; holmium laser introduction renal cyst is a very common renal disease with in-creased incidence following by age. it is reported that 33% of people suffer from this disease at the age of 60 years old(1,2). generally, most of the renal cysts are asymptomatic and do not require any treatment(3,4). for the symptomatic renal cyst, the most common symptoms include renal obstruction, hematuria and lumbar discomfort(5). at present, the main therapeutic strategies for symptomatic renal cyst with relatively larger size include laparoscopic unroofing and ultrasound guided percutaneous sclerotherapy. parapelvic renal cyst easily become symptomatic which may cause urinary obstruction, hydronephrosis and hemorrhage, and also vascular compression, renin-mediated hypertension and complicated stone formation as observed in some cases(1,4). the treatments of parapelvic renal cysts with laparoscopic unroofing and ultrasound guided percutaneous sclerotherapy are challenges and with high risk since they are close to the renal pelvis and hilar structures. the recurrence rates are extremely high after surgical treatments(4,6,7). recently, basiri et al. reported the application of ureteroscopic treatment for parapelvic renal cyst. the results indicated that ureteroscopic treatment was feasible and safe in selected patients with simple parapelvic renal cyst(8). mao et al. and 1department of urology, second affiliated hospital, school of medicine, zhejiang university, hangzhou, china. *correspondence: department of urology, second affiliated hospital, school of medicine, zhejiang university. 88# jiefang road, hangzhou, zhejiang, china. 310009. tel: +86 571 87783550. e-mail: zsg710728@zju.edu.cn. received july 2019 & accepted february 2020 yu et al. have confirmed the clinical feasibility of flexible ureteroscopic management for parapelvic renal cyst in a larger number of patients. they found that flexible ureteroscopic incision and drainage with the holmium laser was a safe and effective therapeutic choice for parapelvic renal cyst, with multiple advantages such as minimal trauma, rapid recovery, and a definite curative effect(1,4). urinary obstruction and stone formation are common complications associated with parapelvicrenal cyst. based on the guideline, shock wave lithotripsy (swl), flexible ureteroscopic lithotripsy and percutaneous nephrolithotomy (pcnl) are recommended for the treatment of renal stones. swl is recommended as the first-line treatment option by eau and aua for renal calculi < 20mm(9,10). however, for renal stones associated with parapelvic renal cyst, swl could not generate satisfactory stone-free rate due to the obstruction caused by parapelvic renal cyst. for the same reason, flexible ureteroscopic lithotripsy may also not achieve satisfactory stone free rate without treatment of parapelvic renal cyst and obstruction caused by parapelvic renal cyst may affect the entry of flexible ureteroscopy toward the target calyxes. thus, it is essential to treat the parapelvic renal cyst in order to get better stone free rate for stone treatment. hu et al. reported that pcnl comurology journal/vol 17 no. 3/ may-june 2020/ pp. 243-247. [doi: 10.22037/uj.v0i0.5441] bined with cyst laser intrarenal incision and drainage is a feasible and safe approach for treatment of renal and upper ureteral stones with ipsilateral renal cyst(11). however, very rare study was found to clarify whether it is possible to treat both renal stone and parapelvic renal cyst simultaneously by flexible ureteroscopic lithotripsy and flexible ureteroscopic incision and drainage. to test this possibility, flexible ureteroscopy was used to treat 28 patients with parapelvic renal cysts combined with renal stones in this study. patients were follow-up to determine the clinical safety and efficacy. patients and methods study population from may 2010 to december 2016, 28 patients diagnosed with parapelvic renal cysts combined with renal stones were treated with flexible ureteroscopic incision and drainage and flexible ureteroscopic lithotripsy simultaneously. the diagnosis of parapelvic renal cysts and renal stones was achieved by ultrasonic examination and computerized tomography. retrograde pyelography was performed if necessary. study design we applied surgical treatment for these patients based on the following indications: (a). free renal stones larger than 6 mm; (b). flank pain; (c). parapelvic renal cysts larger than 3cm; (d).urinary obstruction and hydronephrosis caused by parapevic cyst were detected. (e). hemorrhage, vascular compression, renin-mediated hypertension and some other complications caused by parapevic renal cyst. patients suspected as cystic renal cell carcinoma were excluded in our study. the average age of these patients was 45.3 ± 18.6 years old, including 15 men and 13 women. surgical technique before surgical treatment, urinary culture was routinely done and antibiotics treatment was administered to the patients with positive findings. a double j stent was placed two weeks before surgery for the dilation of ureter. the surgery was performed under general anesthesia in lithotomy position. for the flexible ureteroscopy (urf-v, olympus), a ureteral access sheath (flexor 12/14f, cook) was placed through a 0.035-in guidewire to facilitate flexible ureteroscopy. for the fragmentation of the stones, we used holmium laser (power suite 100w plus, lumenis) through a 200 um fiber with the frequency from 20-30 hz and energy from 0.8 to 1.0j based on the stone rigidity. the renal stones were fragmented to less than 4mm and large fragments were removed by a stone basket. the incision and drainage of parapelvic renal cysts was finished by holmium laser (power suite 100w plus, lumenis) through a 200 um fiber under flexible ureteroscopy, the frequency of holmium laser was 20 hz and the energy was 0.8 j. the typical morphological representation of parapelvic renal cyst under flexible ureteroscopy is shown in figure 1. the incision was performed on thin cyst wall and vascular injury avoided. a window was opened by using holmium laser as large as possible. after the surgical procedure, double j stents were placed which were removed 7-14 days later. outcome assessment the follow-up was made at 1, 3, 6 and 12 months and 2 years after surgical treatment in our outpatient department. ultrasonic examination and ct were used to detect the residual stones and recurrence of renal cyst. clinically significant residual stone was defined as > 4 mm in largest diameter. patients without cyst detected by ct scan and ultrasonic examination on 6 months were considered as curative. for the pain evaluation before and after surgery, a pain visual analog scale score was used to identify the severity of the pain. endourology and stones diseases 244 characteristics a value (n=28) age (years) 45.3±18.6 gender male (%) 15(53.6) female (%) 13 (46.4) body mass index (kg/m2) 21.69 ± 3.82 location right kidney (%) 12 (42.9) left kidney (%) 16 (57.1) mean cyst size (cm) 4.3 ± 1.6 bosniak classification of renal cysts bosniak i (%) 27 (96.4) bosniak ii (%) 1 (3.6) stone size (mm) 14.3 ± 3.9 stone ct density (hu) 867.8 ± 209.7 table 1. patients’ clinical characteristics table 2. patients’ clinical characteristics adata are presented as mean ± sd or number (percent) main outcome value (n=28) mean operative time (min) 53.4 ± 20.7 blood loss (ml) 10.8 ± 5.6 hospitalization time (days) 3.2 ± 0.7 flank pain release (%) 26 (92.9) the stone-free rate postoperative first month (%) 25 (89.3) postoperative third month (%) 27 (96.4) the two years cyst recurrence rate (%) 4 (14.3) the two years stone recurrence rate (%) 2 (7.1) adata are presented as mean ± sd or number (percent) complications a value (n=28) clavien classification overall complication rate (%) 4 (14.3) ⅰ-ⅱ splanchnic injury 0 (0) urine leakage 0 (0) significant hemorrhage (%) 1 (3.6) ⅱ transfusion (%) 0 (0) fever > 38 ℃(%) 3 (10.7) ⅱ adata are presented as mean ± sd or number (percent) table 3. patients’ major intraoperative and postoperative complications rirs for parapelvic renal cyst and renal stone-wen et al. statistical analysis for the statistical analysis, we used spss software to calculate the mean, standard deviation and rate for the clinical data. data are presented as mean ± sd or number (percent). results a total of 28 patients with renal stones associated with parapelvic renal cysts were involved in our study, including 13 women and 15 men. the mean age of these patients was 45.3 ± 18.6 years. the diagnosis of renal stones and parapelvic renal cysts was achieved by ultrasonic examination and computerized tomography. the average size of the parapelvic renal cysts was 4.3 ± 1.6 cm, including 27 with bosniak category i and 1 patient with bosniak ii renal cysts(7). the mean size of the renal stones was 14.3 ± 3.9mm. total of 35 calyxes (2 upper calyxes, 5 middle calyxes and 28 lower calyxes) were located with renal stones. the average stone ct density for all of the stones was 867.8 ± 209.7 hu. the clinical characteristics of these patients are shown in table 1. all 28 patients presented with the symptom of different degrees of flank pain, the mean pain score before treatment was 4.5. intermittent gross hematuria was present in 5 patients. hydronephrosis was detected in 11 cases, including 8 mild, 2 moderate and 1 severe. all operations for these patients were successful. the mean operative time was 53.4 ± 20.7 minutes. the mean blood loss was 10.8 ± 5.6 ml, which was determined by measuring mass of hemoglobin in the intraoperative irrigation fluid(12). the mean hospitalization time was 3.2 ± 0.7 days (table 2). typical ct pictures for one patient before and after treatment are shown in figure 2. the perioperative complication rate is low for the treatment. no severe complications were found. the complications included 3 transient fever ( > 38°c), which was sensitive to antibiotic treatment based on urine culture findings. 1 patient showed significant hemorrhage lasting for one day after operation, which did not require blood transfusion. no splanchnic injury or urine leakage was found in our series of patients (table 3). ultrasonic examination and ct were used to determine the stone-free rate and the cyst recurrence rate on each follow-up. 3 months after the operation, the mean pain score after operation was 1.5. 26 patients (92.9%) showed significant relief of flank pain. gross hematuria disappeared in all patients one month after the operation. hydronephrosis was not detected in all 8 patients with mild hydronephrosis and alleviated for patients with moderate or severe hydronephrosis. the stonefree rate one month after operation was 89.3% and three months after operation was 96.4%. only one case with significant residual stones three months after operation was treated with one session of eswl treatment and finally achieved stone free status. during the 2years follow-up, no cyst was found in 24 patients through ultrasonic examination and ct scan. renal cyst was detected in 4 patients. the mean diameter of recurrent cyst was 1.8 cm on the 6 months follow-up and 2.1 cm on the 12 months follow-up and 2.4 cm on the 2 years follow-up. overall, all of the patients felt satisfied with the treatment. discussion both parapelvic renal cysts and renal stones are very common diseases in urological system. urinary obstruction and stone formation are complications of parapelvic renal cyst. in some specific patients, renal stone may be secondary to renal cyst. for some of our previous patients, we firstly treated the renal stone with flexible ureteroscopic lithotripsy and during our follow-up, residual stones were observed in many patients due to the obstruction caused by parapelvic renal cyst. to generate satisfactory stone free rate, a second session of operation was normally required to treat the parapelvic renal cyst, such as laparoscopic unroofing. based on the development of retrograde intrarenal surgery and early experience, it is possible to treat both renal stones and parapelvic renal cysts simultaneously by flexible ureteroscopic lithotripsy and flexible ureteroscopic incision and drainage. after review of the clinical data of 28 patients mentioned in this study, we have firstly demonrirs for parapelvic renal cyst and renal stone-wen et al. figure 1. image of parapelvic renal cyst before and after flexible ureteroscopic incision and drainage. figure 2. the ct images before and after surgical treatment from typical patient. renal stone and parapelvic renal cyst were shown in left kidney (a and b), which disappeared after flexible ureteroscopic treatment (c and d). vol 17 no 03 may-june 2020 245 strated that the transurethral flexible ureteroscopic incision and drainage is safe and effective method to treat parapelvic renal cysts, which could improve the stone free rate of flexible ureteroscopic lithotripsy for the combined renal stones, with less patient discomfort and hospitalization expenses. simple renal cyst is usually asymptomatic. however, parapelvic renal cysts are intimately associated with the vessels of the renal hilum and symptoms of obstruction due to their locations (13). in our study, urinary obstruction and hydronephrosis were detected in 11 patients (39.3%). for patients with renal cyst induced urinary obstruction, it may be a challenge for the flexible ureteroscopy to reach the target calyxes to treat the stones. meanwhile, flexible ureteroscopic lithotripsy could not generate satisfactory stone free rate due to the obstruction and the stone may easily get recurrent. thus, it is meaningful to treat the urinary obstruction and hydronephrosis before the stone treatment. in this study, we generate very satisfactory stone free rate for the 28 patients by performing flexible ureteroscopic incision and drainage simultaneously and the stone recurrence rate is 7.1% during 2 years follow-up. the major treatments for renal cyst include laparoscopic unroofing, sclerotherapy and percutaneous ablation with various clinical outcomes(14,15). nasseh et al. reported that laparoscopic unroofing is an effective treatment option for skilled surgeons with low recurrence rate and complication rate(16). recently, chen et al. reported that modified mini-laparoscopic decortication of renal cyst have more comprehensive advantages and reduces incisional pain compared with conventional laparoscopic surgery. however, laparoscopic unroofing is not feasible and safe for parapelvic cysts unless operators have advanced surgical skills(17). recent studies by bas et al. have compared the laparoscopic decortication to percutaneous aspiration-sclerotherapy for treatment of renal cyst. they found that laparoscopic decortication has high success rates, a low recurrence rate and minimal morbidity and percutaneous aspiration-sclerotherapy is an outpatient procedure with a higher recurrence rate(18). liaconis and basiri firstly reported the application of flexible and semi-rigid ureteroscopy for the management of parapelvic renal cyst(19,20). however, very few cases were reported and the follow-up period is lack. more recently, mao et al. and yu et al. have confirmed the clinical feasibility of flexible ureteroscopic management for parapelvic renal cysts by a larger number of patients, they found that flexible ureteroscopic incision and drainage with the holmium laser was a safe and effective therapeutic choice for parapelvic renal cysts, with multiple advantages such as minimal trauma, rapid recovery, and a definite curative effect(1,4). a big misgiving for the flexible ureteroscopic incision and drainagewith the holmium laser is intraoperative bleeding. identification of renal cyst wall under flexible ureteroscopy is very important. incision should be applied to the thin wall to avoid injuring the renal parenchyma or renal vessels. normally, during the incision, three layers should be presented: the first layer is mucous membrane of renal pelvis; the second layer is connective tissue between cyst wall and mucous membrane of renal pelvis; the third layer is cyst wall. for some cases with thick wall between parapelvic renal cysts and renal pelvis, we firstly made tentative incision for the mucous membrane of renal pelvis based on the ct result and then separated the mucous membrane of renal pelvis from cyst wall by flexible ureteroscopy until the thin and avascular cyst wall was presented for incision. in our center, the incision for all of the patients was performed by a skilled surgeon. only 1 patient displayed significant hemorrhage lasting one day after operation, which did not require specific treatments. however, there are some limitations for this study. this is a single center study with a relatively small series of patients and some data were collected retrospectively without a control group. and also a long time follow-up should be made to determine the long-term reoccurrence rate for the parapelvic renal cysts. conclusions for the parapelvic renal cysts combined with renal stones patients, flexible ureteroscopic lithotripsy may not generate satisfactory stone free rate without treatment of parapelvic renal cysts. in this study, we demonstrated that it is safe and effective to treat both renal stones and parapelvic renal cysts simultaneously by flexible ureteroscopic lithotripsy and flexible ureteroscopic incision and drainage, with satisfactory stone free rate and low cyst recurrence rate. acknowledgement this work was supported by grants from zhejiang provincial natural science foundation of china (no. ly18h040007 to jiaming wen) and national natural science foundation of china (no. 81871153 to jiaming wen) conflict of interest the authors declare no conflict of interest. references 1. kozacioglu z, degirmenci t, gunlusoy b, ceylan y, minareci s. ureterocutaneostomy: for whom and when? turk j urol. 2013;39:1436. 2. hall mc, chang ss, dalbagni g, et al. guideline for the management of nonmuscle invasive bladder cancer (stages ta, t1, and tis): 2007 update. j urol. 2007;178:2314-30. 3. dall'era ma, cheng l, pan cx. contemporary management of muscle-invasive bladder cancer. expert rev anticancer ther. 2012;12:941-50. 4. yates dr, roupret m. contemporary management of patients with high-risk nonmuscle-invasive bladder cancer who fail intravesical bcg therapy. world j urol. 2011;29:415-22. 5. grossman hb, o'donnell ma, cookson ms, greenberg re, keane te. bacillus calmetteguerin failures and beyond: contemporary management of non-muscle-invasive bladder cancer. rev urol. 2008;10:281-9. 6. bricker em. bladder substitution after pelvic evisceration. surg clin north am. 1950;30:1511-21. 7. israel gm, bosniak ma. an update of the endourology and stones diseases 246 rirs for parapelvic renal cyst and renal stone-wen et al. vol 17 no 03 may-june 2020 247 bosniak renal cyst classification system. urology. 2005;66:484-8. 8. perdzynski w, klewar m, rutka j, stembrowicz z, sakson b. [simple renal cysts in children: treatment with ethyl alcohol injection into their lumen]. pol merkur lekarski. 2000;8:246-8. 9. stamatelou kk, francis me, jones ca, nyberg lm, curhan gc. time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003;63:1817-23. 10. xu g, wen j, li z, et al. a comparative study to analyze the efficacy and safety of flexible ureteroscopy combined with holmium laser lithotripsy for residual calculi after percutaneous nephrolithotripsy. int j clin exp med. 2015;8:4501-7. 11. hu x, jiang k, chen h, zhu s, zhao c. simultaneous treatment of renal and upper ureteral stone and cysts with percutaneous nephrolithotomy and cyst laser intrarenal incision and drainage. urol j. 2017;15:6-10. 12. he x, xie d, du c, et al. improved nephrostomy tube can reduce percutaneous nephrolithotomy postoperative bleeding. int j clin exp med. 2015;8:4243-9. 13. umemoto y, okamura t, akita h, yasui t, kohri k. clinical evaluation of parapelvic renal cysts: do these represent latent urological malignant disease? asian pac j cancer prev. 2009;10:1119-20. 14. korets r, mues ac, gupta m. minimally invasive percutaneous ablation of parapelvic renal cysts and caliceal diverticula using bipolar energy. j endourol. 2011;25:769-73. 15. bean wj. renal cysts: treatment with alcohol. radiology. 1981;138:329-31. 16. nasseh h, hamidi madani a, ghanbari a, arfa s. laparoscopic unroofing of symptomatic kidney cysts. a single center experience. minerva urol nefrol. 2013;65:285-9. 17. yu w, zhang d, he x, et al. flexible ureteroscopic management of symptomatic renal cystic diseases. j surg res. 2015;196:11823. 18. bas o, nalbant i, can sener n, et al. management of renal cysts. jsls. 2015;19:e2014 00097. 19. basiri a, hosseini sr, tousi vn, sichani mm. ureteroscopic management of symptomatic, simple parapelvic renal cyst. j endourol. 2010;24:537-40. 20. liaconis h, pautler se, razvi ha. ureteroscopic decompression of an unusual uroepithelial cyst using the holmium:yag laser. j endourol. 2001;15:295-7. rirs for parapelvic renal cyst and renal stone-wen et al. 1140 | point of technique pneumovesicoscopy: an effective technique for urinary bladder foreign body pandey praveen kumar, shukla suruchi, bera malay kumar, sharma pramod kumar, singh jitendra pratap keywords: foreign bodies; urinary bladder; emergency service; cystoscopy; therapy. introduction foreign bodies in urinary bladder could be of various origins but are more commonly noted as an attempt to achieve sexual gratification, in psychiatric patients and as complication of various surgical procedures. here we present a case of retained cut end of foleys catheter in urinary bladder of a patient suffering from lower urinary tract symptoms. case report a 52year old man with benign prostatic hyperplasia presented to us with retained cut end of a foleys catheter with inflated bulb in his urinary bladder. he was catheterized for one month and the bulb could not be deflated as the catheter was due for change. in a hospital, an attempt was made to deflate the bulb. accidentally, foleys catheter was cut and distal end with the inflated bulb was pushed into the urinary bladder. technique on examination urinary bladder was palpable. at first, a suprapubic ultrasound guided approach was attempted to puncture the bulb but failed. subsequently cystoscopic examination was done. the catheter was long due for change and bulb was resistant to puncture by optical internal urethrotomy knife or kollins knife. finally a 10 mm laparoscopy port was introduced in the bladder using cystoscopic guidance and pneumovesicum was created under spinal anesthesia. a laparoscopic hook was used to puncture the balloon (figure) and cut end corresponding author: pandey praveen kumar, md department of urology, ipgme & r and s.s.k.m. hospital, 244, a.j.c. bose road, kolkata-700020, india. tel: +91 995 393 1506 e-mail: drpandeypraveen@gmail. com received october 2011 accepted november 2012 department of urology, ipgme & r, kolkata-700020, india. point of technique 1141vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l pneumovesicoscopy for bladder foreign body | kumar et al of foleys catheter was removed. the 10 mm port facilitated the removal of foreign body using non tooth forceps. a final cystoscopic examination was performed after removal of laparoscopic port. the port site was closed and the patient catheterized per urethra. discussion intravesical foreign body is not an uncommon entity in surgical practice. usually, these foreign bodies may be self introduced, result of a penetrating injury or complication of a surgical procedure.(1) the most common objective for introduction of these foreign bodies is to achieve sexual gratification. it may be complication of an attempt to induce abortion. surgery in anatomical surrounding areas can also lead to migration of some prosthesis or suture materials in urinary bladder.(2) the foreign bodies may include intra uterine devices, artificial urinary sphincter, prosthetic slings, non absorbable sutures used in incontinence surgeries and clips used in laparoscopic urological or gynecological surgeries.(3) fragments of endoscopic instruments are the most common iatrogenic intravesical foreign bodies due to urological procedures.(4) apart from these iatrogenic foreign bodies other objects reported are long wires, glass rods, bottles, batteries, pencils, plastic tubes, thermometers and even passage of a leech into the urinary bladder per urethra during bathing in ponds. these patients may present with acute or chronic symptoms. but there could be complete absence of symptoms in some cases. however, such patients may also present for the first time with a vesical calculus. diagnosis can be made with a kidney ureter bladder (kub) radiograph or else by an ultrasound of kub region. finally a cystoscopic examination may be done. different techniques have been described to retrieve retained catheter tip of an inflated foley catheter’s bulb. these include per urethral removal using urethrotome knife or hypodermic needle to puncture the bulb.(5) there have been reports of pneumovesicoscopy for failed cases.(6) a pneumovesicum is created after placing ports in urinary bladder under cystoscopic guidance which was done in this case. foreign body may be removed in pieces or en mass using laparoscopic forceps. finally, an open surgery may be required in failed cases. in conclusion, pneumovesicoscopy could be a viable option for retrieval of an intravesical foreign body after failure of much advocated transurethral approach. conflict of interest none declared. references 1. pal dk, bag ak. intravesical wire as foreign body in urinary bladder. int braz j urol. 2005;31:472-4. 2. padmanabhan p, hutchinson rc, reynolds ws, kaufman m, scarpero hm, dmochowski rr. approach to management of iatrogenic foreign bodies of the lower urinary tract following reconstructive pelvic surgery. j urol. 2012;187:168590. 3. cardozo l. recurrent intra-vesical foreign bodies. br j urol. 1997;80:687 4. prasad s, smith am, uson a, melicow m, lattimer jk. foreign bodies in urinary bladder. urology. 1973;2:258-64. 5. hemal ak, taneja r, sharma rk, wadhwa sn. unusual foreign body in urinary bladder: points of technique for their retrieval. eastern j med. 1998;3:3031. 6. ko yh, kang sg, kang sh, et al. removal of long, complex foreign bodies from bladder using single laparoscopic port under pneumovesicum. j laparoendosc adv surg tech a. 2010;20:639-42 figure 1. laparoscopic hook being used to puncture the balloon of foleys catheter. female urology evaluation of therapeutic effect of intratrigonal injection of abobotulinumtoxina(dysport) and hydrodistention in refractory interstitial cystitis /bladder pain syndrome mahtab zargham1*, mahdieh mahmoodi1, hamid mazdak1, farhad tadayon2, mansooreh mansori3, maryam kazemi4, mohamad hatef khorami1, narjes saberi1 purpose: there are two brands of botulinumtoxina(btxa) that are commonly used in the treatment of lower urinary tract disease: onabotolinumtoxina(ona-btxa) and abobotulinumtoxina (abo-btxa). the present study was conducted to assess the potential therapeutic and adverse effects of abo-btxa or dysport for interstitial cystitis/bladder pain syndrome (ic/bps). materials and methods: twenty-two out of 52 women diagnosed with ic/bps who were refractory or had a low response to oral treatments of ic/bps after 6 months, were included in the study. the end-point was o'leary-sant score (oss) including “symptoms” and “problem” indexes (icsi and icpi respectively) assessment after 1,3and 6 months after abo-btxa injection. each patient underwent cystoscopy and immediately after hydrodistention received intratrigonal injections of 300 iu of abo-btxa (dysport®) in 30 sites. the effect and side effects of this treatment over time have been investigated. complications including high post void residual urine (pvr), bladder rupture, and urinary tract infections (uti) were also assessed. results: the mean age of patients was 46.2 ± 13.7 years and the median oss was 27.8 ± 5.8.: after a single injection icsi, icpi, and total oss significantly reduced in 1, 3, and 6 months follow up; rate of decreased total oss was 39.5%, 36%, 18%, respectively. its effect lasted up to six months and started to decrease after 1 month (p-value < 0.05). complications included urinary retention (pvr > 200ml), bladder rupture, and uti in 13.5%, 4.3%, and 18% of the patients, respectively. conclusion: intravesical injection of 300iu abo-btx(dysport) could be a useful approach for the treatment of patients with refractory ic/bps in a period of six months. keywords: abobotilinumtoxina; bladder pain syndrome; botulinum toxin ; dysport; refractory interstitial cystitis; intravesicle injection introduction interstitial cystitis/bladder pain syndrome (ic/bps) is characterized by symptoms like urinary urgency, urinary frequency, and nocturia in middle-aged women. due to the lack of a universal concurrence of the diagnostic criteria, it is not possible to estimate the prevalence of ic/bps precisely; however, it has been reported that between 2.7% and 6.5% of the women in the united states suffer from ic.(1) in addition, based on the o'leary-sant score (oss) questionnaire prevalence of ic/bps among women has been reported to be 265 in 100,000 in japan, 450 in 100,000 in finland, and 306 in 100,00 in austria(2-4) although patients usually suffer from dysuria and have urinary urgency in the absence of uti, their conditions rarely (14%) related to urodynamic detrusor overactivity.(5) the exact pathophysiology of ic/bps is unclear; 1isfahan kidney transplantation research center, department of urology, al-zahra research institute, isfahan university of medical science, isfahan, iran 2isfahan kidney transplantation research center, department of urology, noor hospital, isfahan university of medical science, isfahan, iran 3urology department, treata hospital, iran university of medicine science 4pelvic floor research center department of physical therapy faculty of rehabilitation sciences isfahan university of medical sciences isfahan, school of public health, isfahan university of medical sciences. *correspondence: urology department, al-zahra hospital, shohadaye soffeh blvd., isfahan, iran. e mail: mah_zargham@yahoo.com. received december 2019 & accepted november 2020 however, some possible underlying factors are proposed to explain the etiology of the disease including changes in urothelial permeability, mast cell activation, and abnormal sensory nerve stimulation especially in bladder afferent pathways. the interesting point in the last hypothesis is that it includes all other mechanisms and provides a comprehensive explanation; i.e., neuritis.(6) according to this hypothesis, some of the suggested treatments focused on intravesical therapy; e.g., hydraulic distension of the bladder, intravesical instillation of dmso, or chondroitin sulfate.(1) considering the probable neuritis origin of ic/bps, a neuromodulation procedure that directly manipulates the vesical nerves can be a reasonable treatment(7) intravesical injection of botulinum toxin type a (btxa) was suggested as an overactive bladder (oab) and ic/bps treatment for the first time 15 years ago.(8) many studies approved its positive effect in, improvurology journal/vol 18 no. 2/ march-april 2021/ pp. 203-208. [doi: 10.22037/uj.v16i7.5879] ing bladder sensory symptom and pain in association with reduction of the level of urinary ngf levels.(9-11), and interestingly some other studies reported that the response in patients with ic/pbs depends on the phenotype of the disease, i.e., ulcerative or non-ulcerative.(12) to assess the effects of abo-btxa on ic/bps symptoms according to oss questionnaire including urinary urgency, urinary frequency, nocturia, and suprapubic pain, patient’s quality of life, and potential complications of this method, we designed the present study to compare the symptoms and complications related to ic/ bps in female patients before and after intravesical injection of abo-btxa. to our knowledge, there is little evidence about intravesical injection effects of abobtxa versus ona-btxa (botox). materials and methods patients the study was designed as a single-center prospective interventional quasi-experimental study and was conducted between november 2013 and october 2017 in our center. ethical and technical approval was obtained from the urology and transplantation research center of isfahan university of medical sciences. the participants of the present study included women 1880 years old examined at the outpatient clinics affiliated to isfahan university of medical sciences. the participants were diagnosed with ic/bps based on icdb criteria and their symptoms lasted at least 4 months.(13) all these patients received different medical treatments approved in the aua guideline of interstitial cystitis for 1 year.(14) other inclusion criteria were a lack of response to the medical treatment or recurrence of symptoms after at least 6 months. all participants were informed about the therapeutic effects and complications of the treatment including generalized muscle weakness, difficulties in urination, transient urinary retention, clean intermittent catheterization (cic), and uti. informed consent was obtained from all participants. exclusion criteria included any gross pathology in urinary tract, active uti (as documented by urine culture), pregnancy, pelvic radiation, endometriosis, bladder cancer, pelvic reconstructive surgery, anti-incontinence surgery, and any contraindications of btxa injection including a known allergy to dysport, a history of myasthenia gravis, amyotrophic lateral sclerosis or injection of the toxin for any reason in previous 6 months. procedures and technique among 52 women diagnosed with ic/bps, 22 patients who did not respond to conventional medication treatments of ic/bps according to 2017 eua guidelines, developed side effects, or who refused the treatment were enrolled in the study. all patients were admitted to the hospital on the day of the procedure. ic/bps symptom and problem indexes were evaluated before the treatment by the oss questionnaire. the internal consistency of the indices is precisely enhanced by cronbach's alpha, which exceeded 0.85 for the symptom index, and 0.90 for the problem index.(15) all patients received 1g ceftriaxone before the procedure and underwent regional or general anesthesia depending on the choice of the anesthesiologist. injection technique and type of toxin are still controversial issues. we used dysport because it is the only type of btxa approved by the ministry of health in iran. in addition, there are few studies about the intravesical injection of abo-btxa for the treatment of ic/pbs; therefore, the result of evaluating this type of botulinum in this group of women would be interesting. all patients received 300ui of dysport (abobotulinum toxin a, ipsen biopharmaceuticals, pharma, germany, dys-us-001865). after cystoscopy and bladder hydrodistention, each 300u dysport vial was diluted with 3 ml of normal saline (the concentration was 100iu/ml). the amount of toxin is controversial and depends on the type of btxa and indications. we used the lowest doses of abobtxa (300 iu) which has been utilized intravesical successfully in adult patients. dysport 300u in 3 cc saline was injected as 30 trigonal and bladder base of 0.1 ml (every lateral side of trigon triangle 6-8 injections and inside and outside of base or inter orifice ridge of trigon at suburothelium 14-18 injections) using 21ga needle (10 iu/site). we chose intratrigonal injection because trigon contains a prominent parasympathetic plexus, the most concentrated site of sensory and peripheral afferent nerve ending in the bladder. foley catheter was removed after 24 hours. patients were discharged during the first postoperative day if pvr was less than 200 ml. patients had been recommended and taught timed voiding. ciprofloxacin 500mg for 5 days was also prescribed for them. patients were in a stable condition regarding their luts before intervention; therefore, the change of their oss was considered to result from intravesical treatment. patients were examined at 1, 3, and 6 months after the injection. the primary goal of the study was assessing the changes of oss, the voiding diary, brief symptoms inventory, the occurrence of uti, cic, and urethra or bladder perforation. finally, the results of the oss and voiding diary were compared between pre and post intravesical injection. the therapeutic outcome was assessed using the oss demographic variable details age(year),mean ±sd 46.24 ± 13.791 duration of symptoms(m),mean ± sd 111.73 ± 113.653 marriage, n (%) married 20(90.9) single 2(9.1) pelvic surgery n (%) c/s 5(22.72) hysterectomy 4(18.18) tube ligation 3(13.63) cystocele repair 2(9.09) perianal abscess drainage 1 (4.54) none 9(40.9) nvd n (%) none 9(40.9) 2 5(22.72) 4 4(18.18) 3 2(9.09) 5 1(4.54) 1 1(4.54) comorbidity n (%) none 12(54.54) ibs 4(18.18) anemia 2(9.09) discopathy 2(9.09) pud 1(4.54) htn 1(4.54) ibd 1(4.54) nephrolithiasis 1(4.54) hypothyroidism 1(4.54) uti, n (%) 10(45.5) nervosas 18(81.8) table 1. demographic information and medical records. dysport) in refractory ic/bps-zargham et al. vol 18 no 2 march-april 2021 204 changes, every patient's oss was compared with baseline: women with more than 10% improved total oss after treatment were considered to have recovery response, otherwise, patients were considered “non-responder”. statistical analysis was performed using spss version 25.0 and the level of significance was considered 0.05. investigation of changes in oss and symptom indices mean over time were performed by repeated measures analysis of variance (anova) to examine the impact of the intervention over time. the post-hoc test is then performed to find a significant difference at times. in addition, tests of within-subject's contrasts were performed to examine the shape of the mean changes over time. results twenty-two out of 52 women diagnosed with bps enrolled in the interventional phase of the study. the steps are shown in figure 1. the patients aged from 24 to 74 years with a mean of 46.24 ± 13. 71 years. the duration of symptoms was from 6 to 396 months and its mean was 111.73±113.653 months. the majority of patients (90.9%) were married. the most common pelvic surgery was a cesarean section (5 patients, 22.7%), which may be a predisposing factor for pbs. more than half of the patients did not have any comorbidities but the most common one among those who had was ibs (4 patients, 18.18%). positive urine culture in a patient’s medical records was considered as uti. according to this index, 12 patients (54.5%) did not have any infection and 10 (45.5%) had at least one episode of uti. demographic information and medical records of patients are detailed in table 1. the results (table 2) show a total mean of 27.86 ± 5.808 for total oss score before the treatment, the mean rate of its was reduced to 38.99% after 1 month, 36.72% after 3 months, and 18.78% after 6 months (p-value< 0.001). we obtained a mean of 14.82 ± 3.800 for the icsi before the treatment. as presented in table 2, the mean symptom index reduced to 45.38%, 40.18%, and 18.1% after 1, 3, and 6 months, respectively (p-value< 0.001). each of the symptoms evaluated by oss questionnaire including urgency, frequency, nocturia, and suprapubic pain/dysuria had a significant reduction (all p values: < 0.001). the icpi mean was 13.04 ± 2.192 before the treatment that reduced to 36.28%, 33.44%, and 18.49% after 1, 3, and 6 months, respectively(all p values: < 0.001). willing to retreatment was taken into account when the patient asked for the re-injection again. seven patients (31.8%) were willing to receive the treatment again while 15 were not, which of these 15, one patient was completely cured and two experienced a major decrease in their symptoms. only 4 patients did not have a record of nervosis, such as depression, anxiety, chronic tension headache. complications were classified into two major categories: the systemic adverse effects of dysport and vesicle formation after surgery. the systemic adverse effects of dysport (including weakness in all of the muscles in the body, double vision, difficulty breathing, or swallowing) did not happen in any of the patients. the bladder complication happened in 4 patients. in one of them, “bladder rupture” was developed due to neglected urinary retention, which was completely restored. the patient administered an indwelling catheter for 7 days and was advised to take cic for 5 days. this patient finally had completely normal urination and was one of the patients who returned after 1 year for retreatdysport) in refractory ic/bps-zargham et al. table 2. the changes of parameters at baseline, 3 and 6 months after single bont-a injection parametrs baseline 1 months 3 months 6 months p-value oss 27.863 ± 5.808 17.0 ± 9.304 17.636 ± 9.348 22.636 ± 8.742 < 0/001 symptom 14.818 ± 3.800 8.090 ± 5.681 8.863±5.453 12.136 ± 5.148 < 0/001 problem index 13.045 ± 2.192 8.318 ± 4.156 8.681±4.133 10.636 ± 3.885 < 0/001 urgency (s1) 4.22 ± 1.06 2.40 ± 1.62 2.50 ± 1.50 3.27 ± 1.57 < 0/001 frequency (s2) 3.90 ± 1.37 2.04 ± 1.49 2.22 ± 1.44 3.04 ± 1.52 < 0/001 nocturia(s3) 3.00 ± 1.57 2.04 ± 1.98 2.09 ± 1.94 2.68 ± 1.75 < 0/001 suprapubic pain/dysuria (s4) 3.68 ± 1.24 2.04 ± 1.13 2.18 ± 1.29 2.86 ± 1.32 < 0/001 figure 1. flow diagram of enrollment of patients to the study. female urology 205 ment. voiding dysfunction and overflow incontinence due to impaired detrusor contractility happened in 3 patients who needed cic for 1-2 weeks after the intervention. uti developed in 5 of the patients during the first 6-month follow-up. discussion our results suggest that a dose of 300 iu abo-btxa results in the improvement of qol and a decrease in irritative symptoms in ic/bps patients similar to the effect of 100 iu of botox.(16,17) oss and qol improved significantly: the peak effect of the treatment was about 1 month (40% reduction rate in oss) but it could last for six months (20% reduction rate in oss). tests of contrasts showed the decline over the six-month was non-linear. the sharpest decline was observed in the first month, followed by a trend of up to three months and rising in six months. although various botulinum toxin preparations and serotypes have a similar mechanism, which is blocking neurotransmitter release(18), a comparison of ona-btxa (botox) and abo-btxa (dysport) showed that botox tends to have higher efficacy, longer duration, and higher frequency of adverse effects in the treatment of detrusor overactivity.(19) our results show that urine urgency has the highest frequency among patients but the one that makes the biggest effect on the quality of life is suprapubic pain or dysuria. based on the literature, abo-btxa is a chemical neuromodulator affecting the sensory and pain nerves by inhibition of neurotransmitter release in neuromuscular junctions, especially in cholinergic terminals(20) and reduction of some sensory receptors like p2x3 and trpv1(21), and capsaicin expression in axons. in addition, it has central desensitization effects by a decrease in uptake of substance p in cns.(22) the efficacy of abo-btxa in our groups of patients was less than expected compared to botox used in another similar study.(22) our results were different from the results obtained by kuo hc et al.(23) one possible explanation is the use of different questionnaires oss in our study versus vas in kuo’s study. another explanation is that botox is more effective than dysport in blocking of sensory nerve endings. it is expected that patients referred for luts treatment who have a high urinary score on upoint show a better response to intravesical injection. therefore, estimation of the patient’s upoint score before treatment helps in the identification and selection of those who have a high score on urinary or organ-specific domain, which leads to a better rate of successful treatment. btxa has been reported to have an antinociceptive effect on ic/bps.(8) in addition, other studies approved the positive effect of btxa on decreasing the ic/bps symptoms(9,23,24) and increasing the bladder capacity and urodynamic parameters.(10,25,26) some studies reported that the injection of abo-btxa followed by hydrodistention can reduce bladder pain.(27,28) in contrast, other studies that used the injection of btxa without hydrodistention supported the efficacy of injecting btxa without hydrodistention.(11) we decided to use hydrodistention before dysport injection according to the theory that sensory nerve ending necrosis due to hydrodistention may increase toxin absorption and efficacy. it has been reported that this treatment can reduce the irritative symptoms and increase the bladder capacity only in the non-ulcer type of ic/bps, and there is no improvement in symptoms or urodynamic in ulcer type of the disease.(12) in a cohort study by pinto et al. (2014), it was suggested that there is no connection between the presence and absence of “hunner’s ulcer” and response to ona-btxa.(29) studies that injected botox multiple times reported that the therapeutic effects of multiple injections are persistent. (30) in addition in another study, it was suggested that multiple injections provide better outcomes compared to a single injection.(31) there are other studies including a multi-center randomized double-blind study that did not obtain any positive effects reducing or curing the symptoms after treatment.(32,33) there is no study about the therapeutic and adverse effects of abo-btxa or dysport on ic/bps in iran; therefore, this study can be a guide for more sophisticated researches in the future. the follow-up period was 6 months in this study and we observed that the therapeutic effects reduced over time, however, the effects remained after the 6-month follow-up. in one study, the authors reported that the therapeutic effects can persist more than 50% after 9 months.(26) since we excluded any patient with contraindications to btxa including patients with gillen barre, patients using aminoglycoside, or those with any history of dysport hypersensitivity, we did not observe any significant systemic adverse effects related to dysport. it is noteworthy that no other study reported such adverse effects.(20) we had two major bladder-related complications, one was bladder rupture and the other was prolonged urinary retention ( > 4 weeks) which was reported in other studies (10,30,34) and could be related to the dosage of the toxin. in a study that used 100 iu botox, no adverse effects were reported.(26) extraperitoneal bladder rupture was observed in one of the patients 24 hours after injection due to the neglected urinary retention. although the rupture was successfully restored and the patient did not experience any difficulties and returned for retreatment the next year, it is a serious issue that should be investigated further. certainly, it should be kept in mind that the rupture of the bladder is a limitation on the scientific basis of hydrodistention(34) and urinary retention, especially in thin bladder wall of bps patients. we advised routine control of pvr in all the patients because bladder sensation after abo-btxa (dysport) injection is not reliable. post-surgery uti is one of the complications reported in some studies.(10,35) we also observed acute cystitis in 4 (18%) patients during the 6-month follow-up. it may be due to impaired contractility and high pvr after dysport injection. the response rate to intravesical injection of dysport was less than 40%, the matter is why it fails in some of patients and how we must improve patient selection for intravesical treatment? because of heterogeneous nature of pbs, detailed clinical phenotype using upoint (urinary, psychosocial, organ specific, infection, neurological/systemic / tenderness) system may guide therapy for this organ specific and urinary treatment.(36) ic/bps women with less domains of upoint may be have a better response to treatment.(37) due to financial limitations we designed the study without a control group. in addition, we did not include urodynamic test and only asked if patients suffered from voiding dysfunction or urge incontinence. therefore, further investigations using upoint, applying other assessment methods and having a control group provide additional dysport) in refractory ic/bps-zargham et al. vol 18 no 2 march-april 2021 206 female urology 207 information about the treatment options of the patients. conclusions injection of 300 iu abo-btx a has shown to improve symptoms and qol in half of the women with refractory ic/ pbs. in addition, there was a low risk of retention and morbid complications in the patients. conflict of interest none declared. appendix: https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/19 references 1. berry sh, elliott mn, suttorp m, et al. prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the united states. j urol. 2011;186:540-4. 2. inoue y, mita k, kakehashi m, kato m, usui t. prevalence of painful bladder syndrome (pbs) symptoms in adult women in the general population in japan. neurourol urodyn. 2009;28:214-8. 3. leppilahti m, tammela tl, huhtala h, auvinen a. prevalence of symptoms related to interstitial cystitis in women: a population based study in finland. j urol. 2002;168:13943. 4. temml c, wehrberger c, riedl c, ponholzer a, marszalek m, madersbacher s. prevalence and correlates for interstitial cystitis symptoms in women participating in a health screening project. european urology. 2007;51:803-9. 5. hanno pm, landis jr, matthews-cook y, kusek j, nyberg l, jr. the diagnosis of interstitial cystitis revisited: lessons learned from the national institutes of health interstitial cystitis database study. j urol. 1999;161:553-7. 6. elbadawi ae, light jk. distinctive ultrastructural pathology of nonulcerative interstitial cystitis: new observations and their potential significance in pathogenesis. urol int. 1996;56:137-62. 7. karsenty g, altaweel w, hajebrahimi s, corcos j. efficacy of interstitial cystitis treatments: a review. eau-ebu update series. 2006;4:47-61. 8. smith cp, radziszewski p, borkowski a, somogyi gt, boone tb, chancellor mb. botulinum toxin a has antinociceptive effects in treating interstitial cystitis. urology. 2004;64:871-5; discussion 5. 9. gao y, liao l. intravesical injection of botulinum toxin a for treatment of interstitial cystitis/bladder pain syndrome: 10 years of experience at a single center in china. int urogynecol j. 2015;26:1021-6. 10. emami m, shadpour p, kashi ah, choopani m, zeighami m. abobotulinum a toxin injection in patients with refractory idiopathic detrusor overactivity: injections in detrusor, trigone and bladder neck or prostatic urethra, versus detrusor only injections. international braz j urol : official journal of the brazilian society of urology. 2017;43:1122-8. 11. akiyama y, nomiya a, niimi a, et al. botulinum toxin type a injection for refractory interstitial cystitis: a randomized comparative study and predictors of treatment response. int j urol. 2015;22:835-41. 12. lee cl, kuo hc. intravesical botulinum toxin a injections do not benefit patients with ulcer type interstitial cystitis. pain physician. 2013;16:109-16. 13. simon lj, landis jr, erickson dr, nyberg lm. the interstitial cystitis data base study: concepts and preliminary baseline descriptive statistics. urology. 1997;49:64-75. 14. hanno pm, burks da, clemens jq, et al. aua guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. j urol. 2011;185:2162-70. 15. o'leary mp, sant gr, fowler fj, jr., whitmore ke, spolarich-kroll j. the interstitial cystitis symptom index and problem index. urology. 1997;49:58-63. 16. grosse j, kramer g, stöhrer m. success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. eur urol. 2005;47:653-9. 17. ruffion a, capelle o, paparel p, leriche b, leriche a, grise p. what is the optimum dose of type a botulinum toxin for treating neurogenic bladder overactivity? bju int. 2006;97:1030-4. 18. aoki kr. pharmacology and immunology of botulinum toxin serotypes. journal of neurology. 2001;248:i3-i10. 19. rosales rl, bigalke h, dressler d. pharmacology of botulinum toxin: differences between type a preparations. european journal of neurology. 2006;13:2-10. 20. jhang jf, jiang yh, kuo hc. potential therapeutic effect of intravesical botulinum toxin type a on bladder pain syndrome/ interstitial cystitis. int j urol. 2014;21 suppl 1:49-55. 21. apostolidis a, popat r, yiangou y, et al. decreased sensory receptors p2x3 and trpv1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. j urol. 2005;174:977-82; discussion 82-3. 22. apostolidis a, dasgupta p, fowler cj. proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. european urology. 2006;49:644-50. 23. kuo hc, jiang yh, tsai yc, kuo yc. intravesical botulinum toxin-a injections reduce bladder pain of interstitial cystitis/ bladder pain syndrome refractory to conventional treatment a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial. neurourol urodyn. 2016;35:609-14. 24. smith cp, nishiguchi j, o'leary m, dysport) in refractory ic/bps-zargham et al. yoshimura n, chancellor mb. singleinstitution experience in 110 patients with botulinum toxin a injection into bladder or urethra. urology. 2005;65:37-41. 25. giannantoni a, costantini e, di stasi sm, tascini mc, bini v, porena m. botulinum a toxin intravesical injections in the treatment of painful bladder syndrome: a pilot study. eur urol. 2006;49:704-9. 26. pinto r, lopes t, frias b, et al. trigonal injection of botulinum toxin a in patients with refractory bladder pain syndrome/interstitial cystitis. eur urol. 2010;58:360-5. 27. zargham m, abedi s, alizadeh f, et al. is there any relationship between bladder trabeculation and efficacy and safety of intravesical botulinum toxin a injection in refractory idiopathic overactive bladder women? advanced biomedical research. 2017;6:113-. 28. kuo hc, chancellor mb. comparison of intravesical botulinum toxin type a injections plus hydrodistention with hydrodistention alone for the treatment of refractory interstitial cystitis/painful bladder syndrome. bju int. 2009;104:657-61. 29. pinto r, lopes t, costa d, et al. ulcerative and nonulcerative forms of bladder pain syndrome/ interstitial cystitis do not differ in symptom intensity or response to onabotulinum toxin a. urology. 2014;83:1030-4. 30. pinto r, lopes t, silva j, silva c, dinis p, cruz f. persistent therapeutic effect of repeated injections of onabotulinum toxin a in refractory bladder pain syndrome/interstitial cystitis. j urol. 2013;189:548-53. 31. kuo hc. repeated onabotulinumtoxin-a injections provide better results than single injection in treatment of painful bladder syndrome. pain physician. 2013;16:e15-23. 32. kuo hc. preliminary results of suburothelial injection of botulinum a toxin in the treatment of chronic interstitial cystitis. urol int. 2005;75:170-4. 33. manning j, dwyer p, rosamilia a, colyvas k, murray c, fitzgerald e. a multicentre, prospective, randomised, double-blind study to measure the treatment effectiveness of abobotulinum a (abobtxa) among women with refractory interstitial cystitis/bladder pain syndrome. international urogynecology journal. 2014;25:593-9. 34. ham bk, kim jh, oh mm, lee jg, bae jh. effects of combination treatment of intravesical resiniferatoxin instillation and hydrodistention in patients with refractory painful bladder syndrome/interstitial cystitis: a pilot study. international neurourology journal. 2012;16:41-6. 35. kuo h-c. repeated intravesical onabotulinumtoxina injections are effective in treatment of refractory interstitial cystitis/ bladder pain syndrome. international journal of clinical practice. 2013;67:427-34. 36. guan x, zhao c, ou z-y, et al. use of the upoint phenotype system in treating chinese patients with chronic prostatitis/chronic pelvic pain syndrome: a prospective study. asian journal of andrology. 2015;17:120-3. 37. giannantoni a, gubbiotti m, bini v. botulinum neurotoxin a intravesical injections in interstitial cystitis/bladder painful syndrome: a systematic review with meta-analysis. toxins. 2019;11:510. dysport) in refractory ic/bps-zargham et al. vol 18 no 2 march-april 2021 208 v08_no_3_final_last.pdf sexual dysfunction and infertility 214 urology journal vol 8 no 3 summer 2011 prevalence of self-reported erectile dysfunction among urological cases in turkish men zeki bayraktar, ihsan atun purpose: to determine the prevalence of self-reported erectile dysfunction (ed) among urological cases in turkish men. materials and methods: between january 2007 and january 2011, the diagnoses of 9780 men over 18 years old that presented to our urology polyclinic were reviewed. the 10 diseases with the highest frequency, the rate of the disease, and the intra-group ranking were determined in 18 to was considered to be the self-reported ed prevalence. the findings were evaluated using the population-based (turkey) ed prevalence found in the literature. also, the prevalence of benign prostatic hyperplasia (bph) was evaluated in the turkish population. this evaluation compared the ed and bph prevalence. results: the prevalence of ed (self-reported ed) was 1.9%, 8.2%, and intra-group ranking of ed was 8th, 3rd, and 8th in the aforementioned groups, groups. the ratio of patients with bph to ed was 6.1 (bph/ed: 2250/366). the prevalence of ed (self-reported ed) as well as bph significantly increased with age (p < .001 and p < .001, respectively). conclusion: the prevalence of ed in urological cases is relatively lower than expected. there is a discrepancy between the self-reported ed prevalence in urological cases and population-based ed prevalence. urol j. 2011;8:214-21. www.uj.unrc.ir keywords: erectile dysfunction, prevalence, medical records, icd-10 department of urology, private pendik hospital, pendik, istanbul,turkey corresponding author: zeki bayraktar, md dogu mahallesi, bilge sok. no.1, pendik, istanbul,turkey tel: +90 216 491 6262 fax: +90 216 491 6806 e-mail: zekibay@superonline.com received march 2011 accepted july 2011 introduction erectile dysfunction (ed) is defined as the inability to attain or maintain the penile erection required for sufficient sexual performance for at least 6 months.(1) erectile dysfunction is a multi-factorial disease; the vascular, neurogenic, hormonal, psychogenic, cavernosal, iatrogenic, and anatomic causes lie in its pathophysiology.(2) in the world database, the reported ed prevalence for different countries varies between 3% and 71% according to the age.(3-10) there are many factors that affect ed prevalence. poor health in general is likely to concur with a low level of sexual desire or interest and with ed. increased physical activity is associated with a lower risk of ed. erectile dysfunction may be more prevalent in hispanic men after controlling for other factors, and the prevalence of ed increases with age even when controlling for other diseases.(3) hormonal and endocrine disorders, self-reported erectile dysfunction—bayraktar and atun 215urology journal vol 8 no 3 summer 2011 diabetes mellitus, cardiovascular disease, hypertension, and psychiatric diseases are clearly associated with ed and other sexual disorders in men. medication and recreational drugs are also associated with male sexual disorders, particularly disorders that are associated with use of neuroleptics.(3-16) new epidemiological studies show an increase in the prevalence rates for ed in men who smoke as a standalone risk.(2,3) recent literature on obesity and metabolic syndromes shows a clear association with the components of diabetes mellitus, hypertension, and hypogonadism. (3,16) andersen and colleagues reported that both the reduced time spent in rapid eye movement phase and fragmented sleep were significant risk factors for ed complaints. also, obesity, low testosterone levels, poor quality of life, apneahypopnea, and obstructive sleep apnea syndrome were significantly associated with a higher risk of ed complaints.(5) some urological diseases, including lower urinary tract symptoms (luts) and chronic prostatitis, are also associated with ed.(3,17-20) in a review of 20 studies in urology clinics, bouwman and associates reported that many studies have shown a significant positive correlation between luts and ed.(17) surgery in the pelvic region and trauma to this area damage vital neurological and vascular pathways that are necessary for erection and, therefore, serve as risk factors for ed.(3) there have been some epidemiological studies in turkey and neighboring countries. a populationbased study in turkey reported that the prevalence of ed in turkish men was 69.2%.(10) bal and coworkers reported that ed prevalence was 79% in urological cases with metabolic syndrome in turkey.(16) in the west-neighboring country of greece, doumas and colleagues reported that ed prevalence was 35.2% in patients with essential hypertension and 14.1% in normotensive patients.(13) in the east-neighboring country of georgia, hebert and associates reported that the prevalence of ed was 61.7% in patients with systolic heart failure (ejection (15) in another east-neighboring country, iran, mehraban and coworkers reported that ed prevalence was 68.2% in iranian men with luts.(19) the prevalence rates vary considerably because of the study design, the different ages reported, the different age compositions of the studies, the different percentages of responders, the different time periods asked about, the different definitions of ed used, and the different strategies of data collection (eg, telephone interviews, mailed questionnaires, in-office questionnaires, faceto-face interviews, and single questions versus multiple scales).(3) according to these world-wide data, the highest reported population-based ed prevalence was in turkey. despite the high ed prevalence in the turkish population, the prevalence of ed in urological cases is unknown. the aim of this study was to determinate the self-reported ed prevalence in urological cases. materials and methods all procedures and methods of data collection were approved by the local ethics committee before commencement of the study. between january 2007 and january 2011, the diagnoses of 14 232 patients who presented to the urology polyclinic of our hospital were reviewed. the scanning of patients’ records in the electronic environment was conducted with the help of the hospital information management system (hims). the international statistical classification of diseases and related health problems, 10th revision (icd-10) diagnosis codes of 14 232 patients in the hims were listed. the icd-10 code is a standard coding system developed by the world health organization for the purpose of collecting epidemiological data. however, these codes are used as diagnosis codes in turkish medical institutions because the ministry of health adapted the icd-10 coding system into turkish medical institutions and made its use compulsory since july 2005. all the women (3780 patients) and men under the age of 18 years (972 patients) were excluded from data analysis. the remaining 9780 men were classified into two groups according to age. the first group included men in the age range of 18 and 39 years and the second group consisted self-reported erectile dysfunction—bayraktar and atun 216 urology journal vol 8 no 3 summer 2011 icd-10 codes was determined separately for each group and in total. the 10 most frequent diseases for each group were determined, and the diagnoses were ranked in decreasing order. the rate of ed was considered to be the selfreported ed prevalence in urological cases, which was evaluated using the following factors: 1) the population-based ed prevalence (turkey) in the literature; 2) the self-reported ed prevalence in the literature; and 3) the population-based benign prostatic hyperplasia (bph) prevalence (turkey) in the literature, and our findings for bph prevalence in this study. data of bph was evaluated to compare our findings of ed and bph. our aim was to compare the number or ratio of patients that referred to urology clinics to the population-based disease prevalence for ed and bph. some interventions that were harmless for the design of the study were made during the listing of the icd-10 codes. similar diagnoses were collected with the higher group that included the diagnosis. for example, dysuria (r30.0), vesical tenesmus (r30.1), and painful pissing (r30.9) diagnoses were all regarded as dysuria (r30). in addition, there is only one option (n48.8) in the icd-10 list for ed diagnosis, and this code only includes impotencies with organic origins. although there might be different etiological causes for ed, all the patients with ed were given the code n48.8 because there are no other options in the icd-10 list. therefore, this coding includes all ed forms within the scope of this study. patients in this study were limited to those who presented to the clinic because of ed only; therefore, they were considered as self-reported ed. even if they had some urological and nonurological diseases, they were seeking the hospital only because of ed. however, patients with ed were not systematically examined in our clinic routinely during the scanned period, not even with a single verbal questionnaire for some patients. although not all the patients were examined systematically for ed, the patients with ed in this study were routinely questioned using the international index of erectile function (iief) questionnaire in our clinic, which has been a routine procedure for patients with ed in our clinic since 2005. the iief is a 15-item questionnaire that assesses the five domains of sexual function: erectile function (ef) is assessed by the responses to questions 1 to 5 and 15. erectile dysfunction was classified using the iiefef domain score with mild ed characterized by a score of 17 to 25, moderate ed by a score of 11 to 16, and severe ed by a score of 6 to 10. this study employed a large population-based sample of istanbul and turkey because patients were living in istanbul, and they came from all parts of turkey. therefore, the population of istanbul is a large sample population of turkey. data analyses were performed using microsoft excel 2003 and a statistical package software (medcalc v11.5.1.0 incl. keygen crd). the prevalence of ed and other diseases within the different age groups was calculated as a percentage rate. the comparisons of this rate between the different age groups were performed statistically using the comparison of two rates between two independent groups. p values less than .05 were considered significant. results the mean age of the patients was 41.7 ± 12.3 years (range, 18 to 87 years). of 9780 men, 5438 (55.6%) belonged to the age group of 18 to 39 years and 4428 (45.2%) patients were 40 years old or over. the prevalence of ed (self-reported ed) was 1.9%, 8.2%, and 4.8% in the age groups of 18 to group ranking of ed was 8th, 3rd, and 8th in the aforementioned groups, respectively (table 1). the prevalence of bph was 1.6%, 50.8%, and groups, respectively. the most frequent disease the ratio of patients with bph over ed was 6.1 (bph/ed: 2250/366; table 1). the prevalence of ed (self-reported ed) as well as bph significantly increased with age (p < .001 and p < .001, respectively). of the participants, 5141 (52.5%) were married, self-reported erectile dysfunction—bayraktar and atun 217urology journal vol 8 no 3 summer 2011 4376 (44.7%) unmarried, 134 (1.3%) divorced, and 129 (1.3%) unmarried and cohabitating. of 476 patients with ed, 443 (93%) were married, 23 (4.8%) unmarried, 19 (3.9%) divorced, and 7 (1.4%) unmarried and cohabitating. the patients had some diseases or comorbidities, including diabetes mellitus, hypertension, coronary artery disease, cardiac disease, various endocrine diseases, anemia, and gastrointestinal diseases with the prevalence of 11.7%, 14.3%, 6.1%, 6.9%, 7.3%, and 9.3%, respectively. while 54%, 45.3%, 10.9%, 7.7%, 6.5%, and 5.6% of patients with ed suffer from aforementioned conditions, respectively. we could not detect other risk factors or comorbidities, such as cigarette smoking, obesity, apnea-hypopnea, because the study was retrospective. of the 476 patients with ed, 318 (66.8%) had severe, 119 (25%) had moderate, and 39 (8.1%) had mild ed. also, 223 (46.8%) patients had luts, 57 (11.9%) had premature ejaculation, 54 (11.3%) had chronic prostatitis, and 15 (3.1%) had ejaculatory dysfunction. discussion erectile dysfunction is the most frequently encountered form of sexual dysfunction in elderly men and reduces the quality of life.(21) epidemiological studies indicate that ed is a widespread public health concern that affects millions of men around the world. over 140 million men in the world have ed, and it is expected that approximately 200 million men in asia-pacific countries and approximately 300 million men in the world will suffer from ed by the year 2025.(22) millions of men suffer from ed in different countries, including turkey. the ed prevalence reported for turkey, the usa, the uk, australia, japan, and korea are 69.2%, 52%, 32%, 43%, 26%, and 37%, respectively.(10,23-25) in asian countries, self-reported ed varies from 3.0% to 71%.(3,17) khoo and colleagues reported that self-reported ed prevalence is 70.1%, including 32.8% mild, 17.7% mild to moderate, 5.1% moderate, and 14.5% severe ed in malaysia. (26) hao and associates reported that the self-reported ed prevalence is 12% in total and reported that the prevalence of ed among men with chronic prostatitis is 40.5% in total. they rightfully discussed that the differing prevalence of self-reported ed could be attributed to the different populations that were surveyed and other confounding factors, such as the number of participants, the presence of comorbidities, differences in help-seeking behavior, the use of diverse survey methodologies, questionnaires, and different risk factors depending on the age and local area.(18) lewis assessed the reports of nine epidemiological studies on sexual dysfunction published in english that involved asian countries and compared these reports to the rest of the world. he reported that otal (41.7 ± 12.3) 18 to 39 ears old (33.2 ± 6.1) 40 ears old (54.1 ± 7.5) icd-10 diagnosis n % s n % s n % s n40 benign prostatic hyperplasia 2340 23.9 1 90 1.6 9 2250 50.8 1 r30 dysuria 1298 13.2 2 1118 20.5 1 180 4.0 5 n2.0 kidney stone 891 9.1 3 441 8.1 6 450 10.1 2 i86.1 varicocele 887 9.0 4 809 14.8 3 78 1.7 9 n46 infertility 874 8.9 5 840 15.4 2 34 0.7 10 n20.1 ureteral stone 673 6.8 6 475 8.7 4 198 4.4 4 n39 infection 812 6.2 7 472 8.6 5 140 3.1 6 n84.4 impotence 476 4.8 8 106 1.9 8 366 8.2 3 n23 renal colic 312 3.1 9 186 3.4 7 126 2.8 7 n43 hydrocele 73 0.7 10 45 0.8 10 118 2.6 8 other 1344 13.7 856 15.7 488 11.0 total 9780 5438 4428 able 1. prevalence of diseases according to age and intra-group ranking. s indicates sequence, intra-group ranking. self-reported erectile dysfunction—bayraktar and atun 218 urology journal vol 8 no 3 summer 2011 the prevalence rate of ed increased with each decade of life in all studies. (3) asian studies showed a 7% to 15% rate of ed for ages 40 to 49 years and 39% to 49% for ages 60 to 70 years. similarly, australian studies showed the prevalence of 5% to 6% for ages 40 to 49 years and 12% to 13% for ages 50 to 59 years for ed. europeans were hard to compare, but roughly, lower values for the total groups were reported: 3% to 5% for men less than 49 years of age with the widest difference of rates in men aged 50 to 59 years. after 60 to 65 years of age, ed increased to double-digit percentages, and at the age of 70 years and above, it increased to 40% to 50% of the population sampled. latin american reports have varied as well, and by the age of 60 years, the prevalence rate of ed increases to 40% to 50%. north american studies have similar marked increases at the age of 60 years. world studies have shown a trend of higher rates of ed in the usa and asia compared to other regions of the world.(3) in our study, the self-reported ed prevalence among urological cases was 4.8% in total and 8.2% are lower than the results of some studies in the literature. especially, according to the high population-based ed prevalence in turkish men (69.2%),(10) the ed prevalence among urological cases should have been higher than our findings. self-reported ed prevalence in our study is not the real population-based ed prevalence. our data is the number or rate of patients with ed who referred to the urology clinics seeking treatment. however, it may be expected that the self-reported ed prevalence is correlated with the population-based ed prevalence. we observed that turkish men suffering from ed referred to the urology clinics at a lower rate than some of the western countries in europe. for example, in a study by the french urology association partnered with 150 urology clinics, droupy and colleagues reported that male sexual dysfunction, including ed, was the second reason for visiting urologists (14%), following prostatic diseases (62%). this study used a sample that was representative of urology patients in france regarding age, geographical distribution, and the practice of men over 18 years old visiting a urologist to estimate the prevalence of male sexual dysfunction, including ed, and described treatment options. among these patients, 68% had ed (44% severe) and 25% were treated.(27) in our study, the most frequent disease was bph, which is similar to the study by droupy and associates, but male sexual dysfunction, including ed, was not the first reason for visiting the urologist; rather, it was only eighth. we observed a discrepancy between the high prevalence of ed (population-based) and the low rate of patients consulting for this condition (self-reported ed) in our study. nevertheless, droupy and coworkers conclusively commented that “despite declared urologists’ interest in male sexual dysfunction, the discrepancy between the high prevalence of ed and the low rate of patients consulting for this condition probably explains the low rate of patients using treatments.” however, about 60% of these patients had already talked about their ed to a physician, who was a urologist in 44.6% of cases. the perspective of living the rest of their lives with this trouble was “unacceptable” for 21.1% of patients with ed and “fairly acceptable” for 34.4%.(27) in our study, 66.5%, 25%, and 8.1% of patients had severe, moderate, and mild ed, respectively, but 44% of patients with ed in the study by droupy and colleagues had severe ed. therefore, it may be that only turkish men who are suffering from severe ed visit the urology clinics in turkey. the majority of turkish patients with ed who have mild to moderate ed do not visit the urologists or urology clinics. in another study in germany, hoesl and associates reported that office-based urologists were aware of ed in 37.3% of the 8768 patients who presented with luts before the study, and 14.7% of patients were treated for ed. the aim of their study was to determine the prevalence of ed in patients who visited office-based urologists in germany because of luts due to bph and to evaluate the impact of ed on the quality of life in these patients. after the studyrelated assessment, physicians diagnosed ed in 62.1% of these patients and planned treatment in self-reported erectile dysfunction—bayraktar and atun 219urology journal vol 8 no 3 summer 2011 46.9%. the severity of luts and ed prevalence correlated significantly after age stratification, and the incidence of ed increased in patients with established ed risk factors.(20) according to the literature, the population-based prevalence of bph,(28) the prevalence of ed,(10) and the prevalence of moderate to severe ed are 34.9%, 69.2%, and 36%, respectively, in the according to 2011 data, the total male population in turkey is approximately 36 million, and there are 12 million men over 40 years. in this case, there are approximately 10 million turkish men who suffer from ed and approximately 5 million who suffer from moderate to severe ed. there are approximately 5 million turkish men with bph. therefore, subjects with bph and cases with moderate to severe ed are approximately equal to each other, and each number is around 5 million. in our study, the prevalence of bph was 50.8%, years old. although the ratio of prevalence in our findings to the population-based prevalence was 1.45 for bph (50.8/34.9), the same ratio was much lower (only 0.11) for ed (8.2/69.2). therefore, the ratio of bph to ed was 6.1. these results suggest that the turkish men suffering from ed visited urology clinics about 6 times less than subjects with bph (table 2). these results suggest that subjects with bph visited urology clinics in parallel with prevalence of the disease, but this is not the case for turkish patients with ed. the prevalence of ed and bph in the general population of turkey correlated with the literature. also, the prevalence of bph in our study among urology patients correlated with literature. but this was not the same for ed. the prevalence of ed in our study did not correlate with literature. however, the selfreported ed prevalence was lower than expected and was not parallel with similar studies in the literature. the reason for this difference may be because of the behavioral characteristics of turkish men suffering from ed, who may visit urologists at a relatively lower rate than other urological cases. in a retrospective study in turkey, karakose and associates investigated the rate of andrological cases in general urology practice in all urological cases, including female patients, and found similar results. they reported that patients with bph ranked 1st with a 39.9% rate, and ed ranked 13th with a 1.1% rate.(29) in our study, subjects with ed ranked 8th with a 4.8% rate. this difference might be due to multi-factorial causes, such as differences in patient population and study design. however, these results confirmed our findings and showed that, in all cases, patients with ed are lower than expected among urology patients in turkey. the main problem for measuring ed rates in turkish men suffering from ed is the relatively lower rate of visits to urology clinics. since the majority of patients with mild to moderate ed do not visit urologists. this condition may be caused by the behavioral characteristics of turkish men according to some socio-cultural factors. however, in another study, we observed that only 4.2% of turkish patients with ed who had been followed up for some diseases in the internal medicine department had consulted a urologist for ed. of these patients, 95.7% had not consulted a urologist for ed (40.1% mild, 28.8% moderate, and 30.9% severe ed). patients described the reasons for their failure to visit a urologist for ed treatment as follows: 16.6% embarrassment, 13.1% herbal product use, 10.9% considering the problem normal due to aging, 10.8% not finding time because of other chronic diseases, 8.9% oral drug use without physician recommendation, 8.3% not minding the problem, 7.0% supposing that there was not a treatment, 6.4% not being aware of the problem, 5.4% not knowing which doctor to go to, 4.8% not accepting it as a disease or supposing it transient, 2.8% applying to other prevalence (a) prevalence (b) a/b benign prostatic hyperplasia 50.8% 34.9% 1.45 erectile dysfunction 8.2% 69.2% 0.11 able 2. the ratio of prevalence in our findings to the populationbased prevalence (a) : the prevalence rate (b) : population-based prevalence (turkey) of disease in self-reported erectile dysfunction—bayraktar and atun 220 urology journal vol 8 no 3 summer 2011 clinics (psychiatry, etc), and 5.1% not reporting a reason. therefore, the majority of turkish men suffering from ed sought help alone without any consultation with a urologist. the prevalence of these conditions was higher in patients with lower education.(30) we considered the use of some herbal products and medications without physician recommendation as important causes. the rate of use of an oral phosphodiesterase-5 inhibitor without physician recommendation was 26.4% in turkish patients with ed who had not consulted a urologist.(30) unfortunately, these medications can be used without physician prescription because there are no legal obstacles for their use in turkey. the low help seeking rates for turkish men suffering from ed might also be due to the fact that ed is not a terminal disease. although it reduces the quality of life, it does not restrict daily activities. low educational levels and ignorance of ed may be other main factors. therefore, the professional urology and andrology societies must inform the population by organizing educational activities regarding ed. the population must be told that ed is primarily a uroandrological disease, and the societal level of knowledge and awareness must be raised on this issue because a significant portion of turkish men suffering from ed are acting on primarily erroneous information. this condition is mostly seen in patients with lower levels of education. these erroneous behaviors of turkish men must be prevented. there were some limitations in our study. the most important limitation was that the icd-10 codes were used for the diagnosis of diseases. the icd-10 list is advantageous for data collection, but there is only one option for ed diagnosis in the icd-10 list. therefore, an etiological classification of ed could not be done. in addition, our study was a single-center study. however, the patients were a population-based sample of turkey because they were living in istanbul, which contains a large sample of the turkish population. additionally, only selfreported ed prevalence was determined by this study. further prospective studies are needed to determine the ed prevalance in urological cases by iief questionnaire or other examinations. conclusion the prevalence of ed in urological cases is relatively lower than expected. there was a discrepancy between the low self-reported ed prevalence and high population-based ed prevalence in turkish men. these findings suggest that more prospective research is needed to evaluate the prevalence of ed. conflict of interest none declared. references 1. feldman ha, goldstein i, hatzichristou dg, krane rj, mckinlay jb. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994;151:54-61. 2. chew kk, bremner a, stuckey b, earle c, jamrozik k. is the relationship between cigarette smoking and male erectile dysfunction independent of cardiovascular disease? findings from a populationbased cross-sectional study. j sex med. 2009;6: 222-31. 3. lewis rw. epidemiology of sexual dysfunction in asia compared to the rest of the world. asian j androl. 2011;13:152-8. 4. selvin e, burnett al, platz ea. prevalence and risk factors for erectile dysfunction in the us. am j med. 2007;120:151-7. 5. andersen ml, santos-silva r, bittencourt lr, tufik s. prevalence of erectile dysfunction complaints associated with sleep disturbances in sao paulo, brazil: a population-based survey. sleep med. 2010;11:1019-24. 6. giuliano f, chevret-measson m, tsatsaris a, reitz c, murino m, thonneau p. prevalence of erectile dysfunction in france: results of an epidemiological survey of a representative sample of 1004 men. eur urol. 2002;42:382-9. 7. moreira ed, jr., lbo cf, diament a, nicolosi a, glasser db. incidence of erectile dysfunction in men 40 to 69 years old: results from a population-based cohort study in brazil. urology. 2003;61:431-6. 8. nicolosi a, moreira ed, jr., shirai m, bin mohd tambi mi, glasser db. epidemiology of erectile dysfunction in four countries: cross-national study of the prevalence and correlates of erectile dysfunction. urology. 2003;61:201-6. 9. teles ag, carreira m, alarcao v, et al. prevalence, severity, and risk factors for erectile dysfunction in a representative sample of 3,548 portuguese men aged 40 to 69 years attending primary healthcare centers: results of the portuguese erectile dysfunction study. j sex med. 2008;5:1317-24. self-reported erectile dysfunction—bayraktar and atun 221urology journal vol 8 no 3 summer 2011 10. akkus e, kadioglu a, esen a, et al. prevalence and correlates of erectile dysfunction in turkey: a population-based study. eur urol. 2002;41:298-304. 11. kendirci m, trost l, sikka sc, hellstrom wj. the effect of vascular risk factors on penile vascular status in men with erectile dysfunction. j urol. 2007;178:2516-20; discussion 20. 12. blumentals wa, gomez-caminero a, joo s, vannappagari v. should erectile dysfunction be considered as a marker for acute myocardial infarction? results from a retrospective cohort study. int j impot res. 2004;16:350-3. 13. doumas m, tsakiris a, douma s, et al. factors affecting the increased prevalence of erectile dysfunction in greek hypertensive compared with normotensive subjects. j androl. 2006;27:469-77. 14. malavige ls, levy jc. erectile dysfunction in diabetes mellitus. j sex med. 2009;6:1232-47. 15. hebert k, anand j, trahan p, et al. prevalence of erectile dysfunction in systolic heart failure patients in a developing country: tbilisi, georgia, eastern europe. j sex med. 2010;7:3991-6. 16. bal k, oder m, sahin as, et al. prevalence of metabolic syndrome and its association with erectile dysfunction among urologic patients: metabolic backgrounds of erectile dysfunction. urology. 2007;69:356-60. 17. bouwman, ii, van der heide wk, van der meer k, nijman r. correlations between lower urinary tract symptoms, erectile dysfunction, and cardiovascular diseases: are there differences between male populations from primary healthcare and urology clinics? a review of the current knowledge. eur j gen pract. 2009;15:128-35. 18. hao zy, li hj, wang zp, et al. the prevalence of erectile dysfunction and its relation to chronic prostatitis in chinese men. j androl. 2011;32:496-501. 19. mehraban d, naderi gh, yahyazadeh sr, amirchaghmaghi m. sexual dysfunction in aging men with lower urinary tract symptoms. urol j. 2008;5: 260-4. 20. hoesl ce, woll em, burkart m, altwein je. erectile dysfunction (ed) is prevalent, bothersome and underdiagnosed in patients consulting urologists for benign prostatic syndrome (bps). eur urol. 2005;47:511-7. 21. sanchez-cruz jj, cabrera-leon a, martin-morales a, fernandez a, burgos r, rejas j. male erectile dysfunction and health-related quality of life. eur urol. 2003;44:245-53. 22. ayta ia, mckinlay jb, krane rj. the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999;84:50-6. 23. cho bl, kim ys, choi ys, et al. prevalence and risk factors for erectile dysfunction in primary care: results of a korean study. int j impot res. 2003;15:323-8. 24. mckinlay jb. the worldwide prevalence and epidemiology of erectile dysfunction. int j impot res. 2000;12 suppl 4:s6-s11. 25. wong sy, leung jc, woo j. sexual activity, erectile dysfunction and their correlates among 1,566 older chinese men in southern china. j sex med. 2009;6:74-80. 26. khoo em, tan hm, low wy. erectile dysfunction and comorbidities in aging men: an urban cross-sectional study in malaysia. j sex med. 2008;5:2925-34. 27. droupy s, giuliano f, cuzin b, costa p, vicaut e, levrat f. [prevalence of erectile dysfunction in patients consulting urological clinics: the enjeu survey (one day national survey on prevalence of male sexual dysfunction among men consulting urologists)]. prog urol. 2009;19:830-8. 28. uluocak n, sanli o, gul h, et al. a population based epidemiological study on benign prostatic obstruction in a suburban district of istanbul. turkish j urol. 2009;35:170-9. 29. karakose a, alp t, guner nd, citlak mb, aydin s. the place of andrological cases in our general urology practice. turkish j urol. 2010;36:49-54. 30. bayraktar z, atun i. the rate of use of phosphodiesterase-5 (pde5) inhibitor without physician recommendation and the faults of using medication in patients with erectile dysfunction. new j urol. 2011;6:26-31. fall 2012 08.pdf 662 | pre-operative imaging may overestimate the kidney tumor size hamidreza nasseh, siavash falahatkar, atefeh ghanbari, hossein bagheri chenari purpose: to compare the kidney tumor size on radical nephrectomy pathology specimen with size estimated by computed tomography (ct) scan and ultrasonography. materials and methods: the tumor size on pathology specimen of 40 patients who had undergone radical nephrectomy at our center from march 2003 until march 2009 was compared with pre-operat test was used to compare the means. results: the participants included 40 patients, 25 men and 15 women, with the mean age of 64.12 ± 10.75 years (range, 42 to 79 years). all tumors were renal cell carcinoma. mean tumor size on pathology specimen was 6.2 ± 1.1 cm. mean tumor size estimated by pre-operative ct scan and ultrasonography was 7.34 ± 1.83 cm and 7.4 ± 1.96 cm, respectively (p = .001). tumor stage did not affect this scan or ultrasonography (p = .39). conclusion: computed tomography scan and ultrasonography both may overestimate renal tumor size. this point must be considered in clinical staging and treatment selection. multicenter prospective comparison is suggested. keywords: corresponding author: hamidreza nasseh, md urology research center, razi hospital, rasht, guilan, iran tel/fax: +98 131 552 5259 e-mail: nasseh_hamid@ yahoo.com received may 2011 accepted september 2011 urology research center, razi hospital, guilan university of medical sciences, guilan, iran urological oncology urological oncology 663vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l introduction t umor size is an important clinical and pathologic feature for evaluating patients with renal cell carcinoma (rcc). the pt1a, pt1b, and pt2 primary depending just on the tumor size.(1) tumor size has substantial clinical implications for patients with a renal mass. the prediction of prognosis, and helps in choosing the best treatment modality, including observation, partial nephrectomy, or radical nephrectomy.(2) furthermore, size of the kidney tumor and its location enjoin the surgical approach, such as nephron-sparing surgery (nss) for smaller lesions, incision for large upper pole lesions, or a transperitoneal approach for bilateral lesions operated on in one session. recently, tumor size is mostly represented by pathologic size, which is routinely estimated during pathologic sectioning.(2,3) studies reporting the appropriate size cutoff for the use of nss have used the pathologic size of the renal tumor. on the other hand, nss is chosen as a treatment modality based on the radiologic size. novick concluded that the tumor size has gradually gained acceptance for elective nss.(4,5) in addition, the pathologic size is not always available in patients who are treated by percutaneous or laparoscopic ablation procedures(6,7) or laparoscopic nephrectomy with subsequent tumor morcellation. several previous observations suggest that there is an overestimation of pathologic size of renal tumors compared with radiographic size, which may have implications for planning nss.(8-11) radiographic overestimation may diminish the number of patients who would otherwise be candidates for a nephron-sparing approach.(10) computed tomography (ct) depicts more renal masses than (12) due to paucity of studies comparing pathologic kidney tumor size with both ultrasonography and ct scan size, we performed this study to compare the radiographic size of the tumor by ct scanning and ultrasonography prior to the surgery with the pathologic size of the tumor after the surgery. materials and methods the medical records of patients treated by open or laparoscopic radical nephrectomy for localized rcc from march 2003 to march 2009 were retrospectively reviewed. patients with positive surgical margin, multiple tumors, imaging performed more than two months before the surgery, benign or cystic lesions, partial nephrectomy, and incomfinally, 40 patients met the inclusion criteria. patients’ demographic characteristics, including age, gender, histology, type of procedure, and cancer stage, were collected from the records. the radiologic and pathologic reports were also reviewed, and tumors were staged according to the 2002 tnm staging system.(1) all the patients had undergone a helical intravenous contrast-enhanced abdominal ct scan and ultrasonography by solitary renal neoplasm. the largest of diameter measuresize. tumor stage, size, and histologic subtype were determined from the pathology reports. the pathologic tumor size was the mean values of ct scan, ultrasonography, and pathokidney tumor size | nasseh et al table 1. demographic characteristics of the patients. parameters patients mean age (range), y 64.12 (42 to 79) gender, n (%) male 25 (62.5%) female 15 (37.5%) type of procedure, n (%) open radical nephrectomy 33 (82.5%) laparoscopic radical nephrectomy 7 (17.5%) histology, n (%) clear cell 31 (77.5%) non clear cell 9 (22.5%) staging, n (%) t1 25 (62.5%) > t1 15 (37.5%) 664 | logic sizes, and their difference were calculated. paired student’s t test was used to compare the mean values. the correlation between radiological and pathological sizes was statistical testing. statistical analysis was performed using spss software (the statistical package for the social sciences, version 18.0, spss inc, chicago, illinois, usa). results demographic characteristics of patients are shown in table from the study. the average interval from pre-operative ct scan and ultrasonography to surgery was 29.9 days (range, 1 to 60 days). the mean pathologic, ct scan, and ultrasonography sizes are shown in table 2. the mean radiological tumor sizes for 1.14 cm and 1.2 cm larger on the ct scan and ultrasonography assessment versus the pathologic measurement (p = .001 and p = .001, respectively). mean ultrasonographic and ct scan size difference (0.06 cm) was not statistically p = .39). tumor size by ct scan and ultrasonography for both t1 and > t1 stages (table 2), but mean difference was higher in t1 stage. the mean change in size for t1 tumors was 1.61 cm larger on the ct scan assessment versus the pathologic measurement while this difference was 0.35 cm for t2 tumors. the mean size of t1 tumors was 1.63 cm larger on the ultrasonography assessment versus the pathologic measurement, while this difference was 0.52 cm for t2 tumors. scatter plot of radiological sizes (ultrasonography and ct scan sizes) and pathological size are shown in figures 1 and 2, respectively. according to figures, radiological sizes correlated with pathological size. discussion lationship between the radiographic and pathologic tumor figure 1. regression line between pathology and ultrasonography sizes (cm). (r = 0.80, p < .001) (r2 = 0.644, p < .001) figure 2. regression line between pathology and computed tomography scan sizes (cm). (r = 0.94, p < .001) (r2 = 0.89, p < .001) table 2. mean tumor size estimated by ultrasonography, ct scan, and pathology.* ultrasonography ct scan pathology p (ultrasonography and pathology) p (ct scan and pathology) t1 5.6 ± 0.53 5. 58 ± 0.65 3.97 ± 0.31 .001 .001 > t1 10.44 ± 0.66 10.26 ± 0.63 9.92 ± 0.65 .007 .002 overall 7.4 ± 1.96 7.34 ± 1.83 6.2 ± 1.1 .001 .001 *ct indicates computed tomography. urological oncology 665vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l kidney tumor size | nasseh et al sizes.(3,8,9,13,14) herr prospectively reviewed 50 patients who had undergone partial nephrectomy and found that the clinical tumor size (pre-operative ct) was 0.63 cm (range, 2.2 to 0.4 cm) larger than the pathologic size. moreover, he reafter ligation or occlusion of the renal artery. the decrease whole kidney shrank. this helps the surgeon resect larger tumors completely within a safe margin, regardless of the size of the kidney as a whole.(8) in a follow-up study, herr and coworkers found that the greatest difference was seen in clear cell carcinoma and tumors > 3 cm. they concluded that because the shrinkage was consistent, tumors with a radiographic diameter slightly larger than 4 cm could still meet the 4-cm pathologic size criterion after partial nephrectomy.(9) irani and coworkers retrospectively studied 100 patients with renal tumors who had undergone radical nephrectomy. they reported that the average pathologic tumor size was versus 70 mm). they also found that the smaller the tumor, the more the clinical size overestimated the pathologic size. overestimated the tumor size more in smaller tumors, and of the tumor.(15) tumors smaller than 5 cm.(10) similarly, choi and associates stated that pre-operative ct imaging may overestimate tumor size in rccs of smaller than 6 cm.(14) in the present study, we compared both ultrasonography and ct scan sizes with pathologic tumor size in patients previous reports which found that pre-operative ct may overestimate the pathologic size. while radiological sizes correlated with pathological size, renal tumors were on average 1.14 cm and 1.2 cm smaller after nephrectomy than what the ct scan and ultrasonography estimated before the surgery. changes in radiographic and pathologic tumor sizes were more pronounced in patients with smaller tumors (stage t1), which are the best candidates for nss. which suggests that ct imaging estimates renal tumor size in a manner that is compatible with ultrasonography. in our study, the ct scan and ultrasonography estimations of tumors were similar in all sizes, which is compatible with results that jamis-dow and colleagues found in small renal masses. they understood, however, that neither modality is perfect.(12) tumor shows larger view of the tumor, which may result in selecting an inappropriate treatment and a falsely worsened overall prognostic prediction. sign is retrospective; ct scans have been performed elsewhere; the radiologic and pathologic measurements were not done in the same geometric dimensions; and the ct scan apparatus and technicians were not the same for all the patients. conclusion renal tumor sizes comparing ct scan and ultrasonography with pathology. this point must be considered in clinical staging and treatment selection. however, multicenter prospective comparison is suggested. conflict of interest none declared. references 1. greene fl, page dl, flemming id, et al. ajcc cancer staging manual. vol 1. 6 ed. new york: springer-verlag; 2002. 2. kurta jm, thompson rh, kundu s, et al. contemporary imaging of patients with a renal mass: does size on computed tomography equal pathological size? bju int. 2009;103:247. 3. yaycioglu o, rutman mp, balasubramaniam m, peters km, gonzalez ja. clinical and pathologic tumor size in renal cell carcinoma; difference, correlation, and analysis of the influencing factors. urology. 2002;60:33-8. 666 | 4. novick ac. laparoscopic and partial nephrectomy. clin cancer res. 2004;10:6322s-7s. 5. uzzo rg, novick ac. nephron sparing surgery for renal tumors: indications, techniques and outcomes. j urol. 2001;166:6-18. 6. berger a, kamoi k, gill is, aron m. cryoablation for renal tumors: current status. curr opin urol. 2009;19:138-42. 7. krehbiel k, ahmad a, leyendecker j, zagoria r. thermal ablation: update and technique at a high-volume institution. abdom imaging. 2008;33:695-706. 8. herr hw. radiographic vs surgical size of renal tumours after partial nephrectomy. bju int. 2000;85:19-21. 9. herr hw, lee ct, sharma s, hilton s. radiographic versus pathologic size of renal tumors: implications for partial nephrectomy. urology. 2001;58:157-60. 10. schlomer b, figenshau rs, yan y, bhayani sb. how does the radiographic size of a renal mass compare with the pathologic size? urology. 2006;68:292-5. 11. kanofsky ja, phillips ck, stifelman md, taneja ss. impact of discordant radiologic and pathologic tumor size on renal cancer staging. urology. 2006;68:728-31. 12. jamis-dow ca, choyke pl, jennings sb, linehan wm, thakore kn, walther mm. small (< or = 3-cm) renal masses: detection with ct versus us and pathologic correlation. radiology. 1996;198:785-8. 13. ates f, akyol i, sildiroglu o, et al. preoperative imaging in renal masses: does size on computed tomography correlate with actual tumor size? int urol nephrol. 2010;42:8616. 14. choi jy, kim bs, kim th, yoo es, kwon tg. correlation between radiologic and pathologic tumor size in localized renal cell carcinoma. korean j urol. 2010;51:161-4. 15. irani j, humbert m, lecocq b, pires c, lefebvre o, dore b. renal tumor size: comparison between computed tomography and surgical measurements. eur urol. 2001;39:300-3. urological oncology case reports 123urology journal vol 4 no 2 spring 2007 bladder perforation during laparoscopic donor nephrectomy robab maghsoudi, arash azaripour urol j. 2007;4:123-4. www.uj.unrc.ir keywords: laparoscopy, nephrectomy, kidney transplantation, bladder department of urology, tabriz university of medical sciences, tabriz, iran corresponding author: robab maghsoudi, md department of urology, shaheed hasheminejad hospital, vanak sq, tehran, iran tel: +98 914 411 0966 e-mail: rmaghsudy@yahoo.com received january 2007 accepted february 2007 introduction bladder perforation is a rarely reported complication of laparoscopic donor nephrectomy. it was first reported by metcalfe and colleagues.(1) herein, we report a case of bladder perforation that occurred during blunt penetration of the peritoneum for kidney extraction. case report a 25-year-old man underwent laparoscopic donor nephrectomy through intraperitoneal approach in the semiflank position at our center. he had no history of surgery. a foley catheter was placed into the bladder before the operation which was well functioning. the colon was medialized for entrance into the retroperitoneal area and after successful dissection of the kidney and pedicle division, the kidney was extracted through a previously made pfannenstiel incision (figure). during blunt dissection for peritoneal penetration, the surgeon’s finger inadvertently entered the bladder. the resulted perforation had a 1.5-cm width and was extraperitoneal. after kidney extraction, the bladder was repaired in 2 layers. drainage of the bladder was performed using a urethral catheter. the patient did not experience any other complications during the procedure. the catheter was removed after 4 days and due to the small size of the perforation, we did not perform postoperative cystography. discussion laparoscopic donor nephrectomy is less frequently accompanied by blood loss, prolonged hospitalization, postoperative analgesic requirement, long convalescence time, or delayed return to work in comparison with open surgery. postoperative retroperitoneal bleeding and injuries to the epigastric artery and the bowel are among the most important complications of laparoscopic technique.(2-4) in literature review, we found only 1 report of bladder the incision used to extract the kidney. bladder perforation in laparoscopy—maghsoudi and azaripour 124 urology journal vol 4 no 2 spring 2007 perforation during the entrance into the peritoneum for kidney extraction. metcalfe and colleagues described 2 cases with bladder perforation during this procedure.(1) both of these cases were in women with a history of tubal ligation. to our knowledge, our case is the third being reported. we could not find any predisposing factor for bladder perforation in our patient. we should keep in mind that the finger may inadvertently enter the bladder during blunt peritoneal penetration. however, a careful sharp peritoneal incision is safe and thus recommended. a sharp incision after a careful identification of the peritoneum is reasonable to avoid this complication. we also emphasize that a negative abdominopelvic surgical history and appropriate drainage of the bladder, as in our case, do not ultimately protect against this complication. when bladder perforation occurs, the surgeon can simply repair it. references 1. metcalfe pd, hickey l, lawen jg. bladder perforation during laparoscopic donor nephrectomy. can j urol. 2004;11:2456-8. 2. kavoussi lr. laparoscopic donor nephrectomy. kidney int. 2000;57:2175-86. 3. foss a, leivestad t, brekke ib, et al. unrelated living donors in 141 kidney transplantations: a one-center study. transplantation. 1998;66:49-52. 4. simforoosh n, basiri a, tabibi a, shakhssalim n. laparoscopic donor nephrectomy--an iranian model for developing countries: a cost-effective no-rush approach. exp clin transplant. 2004;2:249-53. u j spring 2012.pdf 491vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l is it effective to perform two more prostate biopsies according to prostate-specific antigen level and prostate volume in detecting prostate cancer? prospective study of 10-core and 12-core prostate biopsy byung il yoon, tae seung shin, hyuk jin cho, sung-hoo hong, ji youl lee, tae-kon hwang , sae woong kim purpose: volume. materials and methods: amination and transrectal ultrasonography, received transrectal ultrasound-guided prostate biopsies. the patients were prospectively randomized to undergo 10-core were assessed and compared according to the serum level of psa and prostate volume. results: p = both groups. comparing the cancer detection rates according to the prostate volp conclusion: the overall cancer detection rates showed no differences in both keywords: corresponding author: sae woong kim, md department of urology, the catholic university of korea college of medicine, seoul, korea seoul st mary’s hospital, 505 banpo-dong, seochogu, seoul, 137-701, korea tel: +822 2258 6226 fax: +822 599 7839 e-mail: ksw1227@catholic. ac.kr received april 2011 accepted december 2011 department of urology, the catholic university of korea, college of medicine, seoul, korea urological oncology 492 | introduction ahave become generalized for the screenpatients receiving the prostate biopsy is increasing. since hodge and colleagues proposed trantate biopsy, it has become the standard method for the diagnosis of the pca. but sextant biopsies 30% in the pca detection. in sextant biopsy, several studies have suggested the extended prostate biopsy to improve the cancer detection rates compared to standard sextant prostate biopsy; however, this issue is still under debate. while some authors reported that extended prostate biopsy did not only improve the pca detection rates, but also increased morbidity rates due to increased biopsy samples. recently, many urologists are more labile to perform extended prostate biopsy rather than the conventional sextant biopsy. most of the studies reported previously are on the comparison of sextant with extended biopsies. our aim was to evaluate the pca detection rates of extended biopsy of materials and methods a central ethical committee (catholic medical center, the catholic university of korea college and then by the respective local ethical committees. for the prostate biopsy with elevated serum levels written informed consent was obtained from each participant. core biopsies; 351 patients received 10-core prosbiopsy cores were obtained from the lateral pethe lateral peripheral zone biopsy cores were takbiopsy, apex of the lateral peripheral zone biopsy cores was added to 10-core prostate biopsy. acin starting pre-biopsy and continued twice daily for 5 days. prior to the prostate biopsy, soap-saline enema was performed for the patients, and quinolones antibiotics were injected intravenously. continued for additional 7 days. the patient was discharged the day after the prostate biopsy after hematuria, acute prostatitis, rectal bleeding, vasovagal syncope, and acute urinary retention. prostate volume was measured by the applica× transverse length × vertical length × anteropos we evaluated the pca detection urological oncology figure. b) position of 12-core biopsy. 493vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l two more prostate biopsies for pca diagnosis | yoon et al furthermore, we evaluated the pca detection data were analyzed using spss software (the statistical package for the social sciences, verassess the differences between the groups, independent samples t test and pearson chi-square test were used. p values less than .05 were conresults there were no differences between the two groups (p p respectively (p in table 1. when the cancer detection rates of 10-core and tate cancer detection rates showed no statistically p p when the cancer detection rates of 10-core and p table 1. clinical characteristics and cancer detection rate of the patients. total 10-core prostate biopsy 12-core prostate biopsy p number of patients 474 351 123 age, y 65.9 ± 9.7 66.5 ± 9.5 64.4 ± 10.2 .053 prostate-specific antigen, ng/ml 10.9 ± 15.3 10.5 ± 13.3 12.1 ± 20.1 .411 prostate volume, ml 42.4 ± 20.7 42.6 ± 22.4 42.0 ± 14.9 .723 cancer detection rate, n (%) 93 (26.4) table 2. prostate cancer detection rate according to the serum level of prostate-specific antigen and prostate volume. total 10-core prostate biopsy 12-core prostate biopsy p prostate-specific antigen, ng/ml 2.5 to 4.0 3/19 (15.7%) .540 4.1 to 10.0 66/293 (22.5 %) 16/74 (21.6%) 10.1 to 20.0 54/124 (43.5 %) 16/30 (53.3%) .152 prostate volume, ml < 40 .331 ≥ 40 42/215 (19.5%) 25/152 (16.4%) 17/63 (26.9%) .049 494 | ml (p core biopsy scheme according to psa levels and prostate biopsy-related complications. the most common complication was mild hematuria (30%; treatments. other complications were acute prosble 3. discussion with the increased concern of pca and the wide spread use of serum psa test, performing prostate biopsy for the detection of the pca is increasing. due to the low sensitivity of psa testing, ageindependent markers of the presence, nature, and progression of the pca are needed to facilitate timely diagnosis and treatment. recently, metabolomics or metabonomics have been proposed as a novel method of pca detection. but these methods are still under study and most of countries are using psa as the screening of the pca. the estimated cancer detection rate in korean men 55 years or older is 3.36%. among all cancers, the incidence of pca increased most in ko6-core prostate biopsy, it has been the most widely used method for diagnosing pca. several studies reported that the pca detection rates of tions because of not considering the pv and location of tumor. many studies attempted to improve the pca detection rates by increasing the number of biopsy samples using 8-core, 10-core, biopsy. these extended prostate biopsies improved pca detection rates and the complication rates were comparable to conventional 6-core biopsy. presti and colleagues and moon and associates reported that the 10-core biopsy detection rates up to 19%. rochester and associates reported that pca detection rates improved pared with conventional 6-core biopsy group. in studies that compared the 6-core biopsy group with the extended biopsy group, naughton and coworkers reported that the pca detection rate in bae and chang reported tients who were suspected to have t1c pca. they urological oncology table 3. total 10-core prostate biopsy 12-core prostate biopsy p hematuria 142 (30%) 102 (29.0%) 40 (32.5%) acute prostatitisa 10 (2.0%) 7 (1.9%) 3 (2.4%) rectal bleeding 5 (1.0%) 4 (1.1%) vasovagal syncope 3 (0.6%) 1 (0.2%) 2 (1.6%) .732 acute urinary retentionb 0 (0%) 0 (0%) 0 (0%) a fever > 37.5 ºc and white blood cells/high power field in urine analysis > 4 b residual urine volume > 200 ml 495vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l improve the cancer detection rates in suspicious t1c pca. several recent studies have examined the cancer detection rates with saturation biopsy. lane and rate for saturation biopsy was the same as that found with traditional prostate biopsy. pepe and saturation technique. a retrospective comparison showed comparable detection rates of 39.8% and our study was different from many other previous studies that compared the 6-core biopsy regimen with the extended biopsy protocols. our aim was to evaluate the pca detection rates in extended opsies in pca detection. our results showed that the rate of pca detection rates of the 10-core and tively. performing additional two more biopsies to the 10-core biopsy protocol did not improve pca detection rate. limitation of our study is that we excluded conventional 6-core biopsy and compared its detection rate only with extended prostate biopsy. considered to the standard cutoff value of prosrecommended performing prostate biopsy even tected in these patients. catalona and colleagues might be overlooked. in patients with increased we found that pca detection rates improved with the increase of the psa levels, but no statistical prostate biopsies according to the psa levels. prostate size plays an important role in the diagnosis of pca, because it correlates directly with the relative amount of tissue sampled per biopsy core. prostate cancer detection rate is known to be related to the pv, varying from 39% in small glands to 10% in large prostates. but the impact of pv on the prostate biopsy in detecting pca is still controversial. several researchers have reported that pca detection rates decrease with increasing the pv. uzzo and colleagues considered the pv of 50 ml as cutoff and mariappan cantly higher in the small pv. did not respond to medical treatment. in our results, the pca detection rate of the small pv (< biopsy. in small pv group, pca detection rates detection rates compared with 10-core biopsy in addition to 10-core biopsy can help improve the pca detection rate. in many centers in korea, prostate biopsy is done on outpatient basis, but some centers prefer to practice biopsy with hospitalized patients. two more prostate biopsies for pca diagnosis | yoon et al 496 | the reason why we hospitalized the patients is to check and prevent severe complications after the prostate biopsy. with the increase of the number of biopsy samples, the rates of complications, such as hematuria, rectal bleeding, and infection, may be increased. but complications after the prostate biopsy are usually minor. in our results, mild hematuria was the most common complication after the prostate biopsy, but special treatments were not required in most of the patients. the complication rate of hematuria, acute prostatitis, rectal bleeding, and vasovagal biopsies yielded similar complication rate withmore additional biopsies without worrying about an increase in complication rate with increased samplings. conclusion improve the pca detection rates. with regard to the cutoff of serum levels of psa and the pv for the application of extended prostate biopsy, the more prospective studies with larger number of patients are needed in the future. acknowledgements we are thankful to seol kim and woong-jin bae from the department of urology in our institution for data processing of case materials. conflict of interest none declared. urological oncology references 1. hodge kk, mcneal je, terris mk, stamey ta. random systematic versus directed ultrasound guided transrectal core 4-5. 2. naughton ck, smith ds, humphrey pa, catalona wj, keetch dw. clinical and pathologic tumor characteristics of prostate cancer as a function of the number of biopsy 3. levine ma, ittman m, melamed j, lepor h. two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. j urol. 4. loch t, eppelmann u, lehmann j, wullich b, loch a, stockle m. transrectal ultrasound guided biopsy of the prostate: random sextant versus biopsies of sono-morphologically 5. macmahon pj, kennedy am, murphy dt, maher m, mcnicholas mm. modified prostate volume algorithm improves transrectal us volume estimation in men presenting for 6. song c, ahn h, lee ms, et al. mass screening for prostate cancer in korea: a population based study. j urol. 7. norberg m, egevad l, holmberg l, sparen p, norlen bj, busch c. the sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of ravery v, goldblatt l, royer b, blanc e, toublanc m, boccongibod l. extensive biopsy protocol improves the detection 9. lee sb, kim cs. comparative analysis of sextant and ex10. moon kh, cheon sh, kim cs. systematic 10-site prostate biopsy is superior to sextant method for diagnosing carci11. presti jc, jr., o'dowd gj, miller mc, mattu r, veltri rw. extended peripheral zone biopsy schemes increase cancer detection rates and minimize variance in prostate specific antigen and age related cancer rates: results of a commu12. bae ks, chang sg. comparative analysis between sextant biopsy and 12-samples needle biopsy for detection of 497vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l 13. presti jc, jr., chang jj, bhargava v, shinohara k. the optimal than 6 biopsies: results of a prospective clinical trial. j urol. 14. durkan gc, sheikh n, johnson p, hildreth aj, greene dr. improving prostate cancer detection with an extendedcore transrectal ultrasonography-guided prostate biopsy 15. spective randomised trial of extended core prostate biopsy 9. 16. naughton ck, miller dc, mager de, ornstein dk, catalona wj. a prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. j urol. 17. lane br, zippe cd, abouassaly r, schoenfield l, magi-galluzzi c, jones js. saturation technique does not decrease cancer detection during followup after initial prostate pepe p, aragona f. saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. 19. catalona wj, smith ds, ornstein dk. prostate cancer detection in men with serum psa concentrations of 2.6 to 4.0 ng/ml and benign prostate examination. enhancement of specificity with free psa measurements. jama. 20. karakiewicz pi, bazinet m, aprikian ag, et al. outcome of sextant biopsy according to gland volume. urology. 21. uzzo rg, wei jt, waldbaum rs, perlmutter ap, byrne jc, vaughan ed, jr. the influence of prostate size on cancer 22. mariappan p, chong wl, sundram m, mohamed sr. increasing prostate biopsy cores based on volume vs the sextant biopsy: a prospective randomized controlled clinical study on cancer detection rates and morbidity. bju int. 23. of first and repeat transrectal ultrasound guided prostate needle biopsies: results of a prospective european prostate two more prostate biopsies for pca diagnosis | yoon et al urol_v03_no4_001_editorial.indd errata 261urology journal vol 3 no 4 autumn 2006 errata in volume 3 number 2, page 92 of the urology journal, the fourth author’s name should have been hassan jamshidian. it is erroneously typed as mohammadreza jamshidian. in volume 3, number 3, page 130, the first author’s name should have been afshar zomorrodi. it is erroneously typed as ali afshar zomorrodi. in volume 3 number 3, page 147, there is an error in table 2. the proportions and their percentages should have been as follows in the 2nd and 3rd columns: we regret these errors and express our apology to the authors and readers. urol j (tehran). 2006;4:261. www.uj.unrc.ir table 2. characteristics of patients and bladder tcc in relation to involvement of prostate* *tcc indicates transitional cell carcinoma; ci, confidence interval; td, tumor distance from bladder neck; and cis, carcinoma in situ. †values in parentheses are percents. prostatic involvement † factors positive negative p odds ratio 95% ci age, mean, y 63.2 ± 12.4 64.2 ± 10.8 .79 … -8.37 to 6.46 td, mean, cm 0.46 ± 0.35 1.79 ± 1.10 < .001 … 0.74 to 1.91 tumor stage noninvasive 2 (13.3) 15 (33.3) t2 8 (53.3) 20 (44.4) t3 3 (20.0) 8 (17.8) t4 2 (13.3) 2 (4.4) .37 … … cis 6 (40.0) 16 (35.6) .76 1.21 0.36 to 4.01 vascular invasion 8 (53.3) 8 (17.8) .007 5.29 1.48 to 18.82 perineural invasion 4 (26.7) 7 (15.6) .34 1.97 0.48 to 8.00 multifocal disease 11 (73.3) 21 (46.7) .07 3.14 0.87 to 11.36 high grade disease 9 (60.0) 23 (51.1) .55 1.44 0.44 to 4.70 hydronephrosis 5 (33.3) 17 (37.8) .76 0.82 0.24 to 2.82 tumor diameter ≥ 2 cm 12 (80.0) 38 (84.4) .69 0.74 0.16 to 3.30 v08_no_4_final_new.pdf opposing views 257urology journal vol 8 no 4 autumn 2011 supine percutaneous nephrolithotomy pro siavash falahatkar, aliakbar allahkhah, soheil soltanipour purpose: to share the experience of the authors with the urological family in the world by the review of literature on supine percutaneous nephrolithotomy (pcnl). materials and methods: we have searched all the available databases, including pubmed or medline and embase biomedical database to find any english articles related to supine pcnl from 1998 to 2010. of 17 studies, 11 were case series and 6 were comparative. results: a total of 1914 patients were studied. only the results of mean operation time were significant. supine pcnl offers several advantages, including less operation time, less patient handling, needing only one drape, easier access to the urethra and upper calyces, facilitation of drainage of stone fragment with the amplatz sheath, less anterior kidney displacement due to lying the kidney in its normal anatomical position, less risk of the colon injury, more tolerable for the patients with pulmonary or cardiovascular disease, and better for morbid obese patients. the overlap density of the vertebrae in the semi-supine position can be avoided. furthermore, the fluoroscopy tube is far from the puncture site; thus, the space is open for the surgeon to work and the surgeon can perform the procedure in a more comfortable seated position. conclusion: the study showed that pcnl in the supine position is feasible. although supine pcnl has numerous advantages, it is not routine in many surgical centers throughout the world. the practice of supine pcnl will be popular when the academic centers be encouraged to start it. urol j. 2011;8:257-64. www.uj.unrc.ir keywords: percutaneous nephrolithotomy, supine position, urolithiasis urology research center, razi hospital, rasht, iran corresponding author: aliakbar allahkhah, md urology research center, razi hospital, sardare jangal st., rasht, iran tel/ fax: +98 131 552 5259 e-mail: mallahkhah@yahoo.com received december 2010 accepted may 2011 introduction percutaneous nephrolithotomy (pcnl) has numerous advantages and is the best treatment modality for kidney stones larger than 20 mm. it has been traditionally performed in the prone position, but recently, there have been many reports about pcnl in the supine position and complete supine position.(1) the prone position is not a good option because it needs repositioning the patient and there is probability of injuring the nerves, neck, and limbs. furthermore, some patients, such as those with ankylosing spondylitis, severe lordosis, or kyphosis, can not tolerate this position. the prone position is not also favorable for patients with severe cardiopulmonary disease and morbid obesity.(2-8) supine position has numerous advantages, but it is not familiar by most of the endourologists. although there is a little chance of the colon injury in the supine position comparing to the prone supine percutaneous nephrolithotomy—falahatkar et al 258 urology journal vol 8 no 4 autumn 2011 position, but most urologists are reluctant to perform it.(2-8) some studies reported that pcnl in the supine position was as effective and safe as pcnl in the prone position and is an alternative option for removal of renal calculi with pcnl.(6,7) the purpose of this study was to share the experience of the authors with the urological family in the world by the review of literature on pcnls performed in the supine position. materials and methods we searched all the available databases, including pubmed or medline (us national library of medicine) and embase biomedical database® (elsevier; amsterdam, netherlands) to find any articles related to pcnls performed in the supine position. the keywords of percutaneous nephrolithotomy, supine position, sonography, imaging, body mass index (bmi), tubeless, upper pole access, previous open renal surgery, and tract creation were used in various combinations. articles in which pcnl in supine or complete supine position alone have been discussed and those comparing two methods of pcnl were included in our review. we found 17 articles in english language from 1998 to 2010. of 17 studies, 11 were case series and 6 were comparative. the information regarding the total number of patients, male to female ratio, age, maximum stone diameter, affected side, positive history of extracorporeal shock wave lithotripsy, previous open or percutaneous surgery, bmi, operation time, length of hospital stay, stonefree rate, calyx puncture site, blind access to the calyx, transfusion, extravasation, fever or infection, conversion to open surgery, deep vein thrombosis, pleural effusion, colon injury, and mortality were collected. results the results of the literature review for pcnls performed in the supine position are summarized in table.(1,3,4,7,9-16) a total of 1914 patients in the age range of 32 to 55.9 years were studied. stones with a wide range of sizes were removed by pcnl with the patient being in a supine position. the majority of the studied patients did not have a positive history of extracorporeal shock wave lithotripsy, but most of them had a history of previous open or percutaneous surgery. the operation times ranged from 15 to 300 minutes. the stone-free rate was 70.5% to 95%. the most commonly puncture site was the lower calyx. transfusion was needed in 0% to 20% of the patients. extravasation occurred in 1.09% of the patients. the most common complication was fever that occurred in 10.25% of the patients. conversion to open surgery was seen only in 3 patients. the reports of deep vein thrombosis and pleural effusion were sporadic and rare. no colon injury or mortality was reported. discussion we perform pcnl as a well-known surgical procedure in the complete supine position without any towel under the patient’s flank, and with no change in the leg position.(3) the steps of complete supine pcnl in a 66-year-old woman with multiple stones in the right kidney are illustrated in figure.(8) although the supine position has many benefits compared with the prone position, the traditional prone position is acceptable by many urologists.(8) falahatkar and colleagues compared the outcome of pcnl in the complete supine position with the standard prone position in 80 patients who randomly underwent pcnl.(3) they performed supine pcnl without the use of a rolled towel and without any change in the leg position. they suggested that complete supine pcnl is feasible when the flank was near the edge of operating table. the surgeons must avoid overlapping of the kidney with the metal density of the table. they showed that pcnl in the supine position has numerous advantages, including no need to change the position.(3,8,9) liu and coworkers performed a systematic review and meta-analysis on pcnl in the supine versus prone position. although there was no difference between the positions with regard to success rate, complication, transfusion, and fever, the operation time in the supine pcnl position supine percutaneous nephrolithotomy—falahatkar et al 259urology journal vol 8 no 4 autumn 2011 fi rs t a ut ho r, ye ar p ub lis he d o ut co m e valdiviauria, 1998(31) shoma, 2002(4) ng, 2004(32) steele, 2007(33) manohar, 2007(26) de sio, 2008(17) neto, 2007(1) falahatkar, 2008(3) rana, 2008(5) zhou, 2008(34) basiri, 2010(14) scoffone, 2008(11) falahatkar, 2011(12) falahatkar, 2010(8) falahatkar, 2011(7) falahatkar, 2010(13) falahatkar, 2011(10) to ta l ( n ) 55 7 53 67 32 2 62 39 88 40 18 4 92 19 12 7 18 11 7 20 28 81 g en de r m al e 22 1 34 34 19 8 50 17 30 23 61 12 22 1 90 15 64 11 15 41 f em al e 24 2 19 33 12 4 12 22 58 17 31 7 24 2 37 3 53 9 13 40 a ge ( ye ar s) , m ea n ± s d 55 .1 43 .6 55 .9 58 48 14 .1 6 38 43 .5 13 .3 45 .3 5 32 52 .6 44 49 .9 47 .2 45 .9 ± 1 3. 2 45 .8 44 .7 5 m ax im um s to ne d ia m et er ( m m ), m ea n ± s d /r an ge 29 .2 15 31 6 27 8 34 36 19 40 .6 35 to 1 20 20 to 1 00 29 .2 23 .8 ± 7 .3 31 .2 36 48 .3 46 .5 34 .3 s id e (n ) r ig ht 24 8 27 31 15 2 20 25 40 8 24 8 27 31 65 64 14 13 46 le ft 26 5 26 36 17 0 19 15 38 11 26 5 26 36 62 53 6 15 35 p re vi ou s sh oc kw av e lit ho tr ip sy ( n) 15 9 9 p re vi ou s op en o r pe rc ut an eo us su rg er y (n ) 16 4 55 15 10 33 6 12 28 b od y m as s in de x, m ea n ± s d 24 .2 8 4. 69 28 25 .6 3. 5 26 .9 27 .1 27 .7 o pe ra tio n tim e (m in ut es ), m ea n ± s d /r an ge 85 15 -3 00 73 .6 6 43 16 2. 1 49 .3 74 .7 12 0 68 11 1 80 (2 5 to 2 25 ) 98 10 2. 25 84 .1 99 .2 3 h os pi ta l s ta y (h ou rs ), m ea n ± s d /r an ge 20 9 72 -1 44 10 3 12 9. 6 74 .4 80 .0 2 86 33 12 2. 4 ± 69 .6 64 .8 76 .8 90 .7 2 s to ne -f re e ra te ( % ) 89 76 91 95 88 .7 70 .5 80 84 82 .6 84 87 .4 77 .8 77 .7 7 85 75 72 .4 5 c al yx p un ct ur e si te ( n) u pp er 2 8 5 0 3 6 1 11 6 20 0 m id dl e 23 13 25 7 2 46 3 9 0 6 lo w er 51 7 42 32 32 27 13 2 15 2 0 22 tr an sf us io n (% ) 1 9 3 3. 7 3. 2 0 8 20 4 1. 1 5 3. 15 5. 6 14 .5 5 14 .3 14 .8 e xt ra va sa tio n (n ) 2 3 7 4 5 5 0 0 0 0 0 f ev er o r in fe ct io n (% ) 4 19 .4 18 5 13 .6 2. 5 27 .5 5 5. 6 6. 8 5 10 .7 4. 9 c on ve rs io n to o pe n su rg er y (n ) 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 d ee p ve in th ro m bo si s (n ) 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 p le ur al e ffu si on ( n) 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 c ol on in ju ry ( n) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 m or ta lit y (n ) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 t he r es ul ts o f t he li te ra tu re s ea rc h fo r pe rc ut an eo us n ep hr ol ith ot om y do ne w ith p at ie nt s in th e su pi ne p os iti on . supine percutaneous nephrolithotomy—falahatkar et al 260 urology journal vol 8 no 4 autumn 2011 this figure shows the steps of complete supine percutaneous nephrolithotomy (pcnl) in a 66-year-old woman with multiple stones in the right kidney.(17) a. lateral view of the patient’s supine position for pcnl. b. inferior view of the patient’s supine position for pcnl. c. the patient’s position after preparation and drape for pcnl. d. urine drop after needle entrance to the kidney during pcnl. e. step-1 dilatation of one-shot dilatation during pcnl. f. step-2 dilatation of one-shot dilatation during pcnl. g. amplatz sheath insertion after one-shot dilatation during pcnl. h. the surgeon in seated position during pcnl. i. skin sutures at the end of the pcnl procedure. supine percutaneous nephrolithotomy—falahatkar et al 261urology journal vol 8 no 4 autumn 2011 was significantly shorter than the prone position (p < .00001). they concluded that pcnl in the supine position is as effective and safe as pcnl in the prone position.(6) de sio and colleagues carried out a randomized clinical trial on pcnl with single access in 75 patients (39 patients in supine and 36 in prone position). they found no significant difference between the two groups in terms of stone-free rate (p = .12), mean blood loss (p = .23), and mean hospital stay (p = .18). the only significant difference was for mean operation time, which was shorter in the prone position (p < .001). no blood transfusions or visceral injuries were reported. they concluded that the supine position was safe in uncomplicated stones.(17) another study in 2010 evaluated the safety and efficacy of renal displacement technique in complete supine pcnl in 20 patients. the authors reported that subcostal approach with the lung inflation was feasible in the supine position. this technique helped the surgeon avoid the supracostal puncture.(18) in 2010, falahatkar and associates determined the effects of the previous stone surgery on the results of complete supine pcnl in 81 patients. they reported that complete supine pcnl in patients with a history of stone surgery can be safe and effective.(10) scoffone and coworkers reported that simultaneous performance of pcnl and retrograde ureteroscopy (endoscopic combined intrarenal surgery) provided the most beneficial results in 127 patients. they concluded that this technique is safe and effective for the treatment of upper urinary tract abnormalities.(11) in another study, falahatkar and colleagues evaluated the outcomes of tubeless complete supine pcnl in 117 patients. they demonstrated that complete supine pcnl is a good option for all the patients.(7) in a study performed in 18 patients in 2010, the authors compared the amount of the kidney displacement in the complete supine position. they showed that the amount of the kidney movement was less than the standard prone position. it maybe another benefit of the supine position, reported by falahatkar and associates.(12) benefits of supine pcnl(3,5,7,8) 1) no need to change position; 2) ability to perform ureteroscopy during pcnl; 3) easier air way control by the anesthesiologist; 4) easier pcnl of the upper calyceal stones; 5) evacuation of stone fragments; 6) decreasing operating time; 7) no contact between the patient’s skin and water, which would prevent hypothermia; 8) less kidney displacement; 9) less retrorenal colon injury; 10) more comfortable for corpulent or obese patients, and the patients with respiratory or cardiac problems. there are numerous advantages for the endourologists in performing pcnl in the supine position:(3,5,7,8) 1) the fluoroscopy tube is far from the working space. 2) lack of overlapping of the vertebrae with the kidney. supine percutaneous nephrolithotomy—falahatkar et al 262 urology journal vol 8 no 4 autumn 2011 3) decreasing the total operating time. 4) sitting position for the surgeon. supine pcnl is safe, effective, and suitable for most of the patients, and is feasible for all types of stones, such as calyceal, pelvic, multiple, staghorn, or upper pole calyceal stones.(3,7,8,18) imaging fluoroscopy has been the golden imaging modality standard for pcnl. although numerous novel techniques have been done in pcnl by help of fluoroscopy, many researchers prefer to find an alternative method to reduce radiation exposure.(8,13,14) ultrasound-guided pcnl in the supine position because the endourologists are highly exposed to x-ray irradiation during endourologic surgeries and the procedure poses a potential health risk to the patients and endourologists, falahatkar and coworkers performed the other study on 28 patients in 2009 and compared the results of ultrasound and fluoroscopically-guided pcnl in complete supine position. they showed that totally ultrasound-guided in complete supine pcnl had certain advantages, such as elimination of x-ray exposure to the surgeon and the operating room staff, avoidance of contrast media administration, identification of all the tissues between the skin and kidney, and no need to wear a lead shield. ultrasound-guided pcnl in the supine position is recommended because of being safe and feasible even in re-operative patients.(13) basiri and colleagues in 2009 reported that the efficacy of pcnl with ultrasonography in the supine position was comparable to pcnl in the prone position with fluoroscopy. they suggested that it may be possible for expert surgeons to extend this approach to simple stones in patients with little operation risk.(14) the outcomes of ultrasonic access were similar to fluoroscopic access.(13,19,20) disadvantages 1) sometimes the lubricant gel on the gloves can slide the dilators, which can be resolved by cleaning the hands. 2) the amplatz dilator and amplatz sheath echo do not have good imaging quality. 3) less visibility of the guidewire echo causes the wrong way for the surgeon. it is possible to solve this problem by rigid rouche guidewire.(8,13) computed tomography (ct) although pcnl by the guidance of ct scan is feasible, it has numerous disadvantages, such as producing more x-ray, being expensive, and unavailable to be used in most operating rooms. until now, there has been no report of using ct in the supine pcnl. blind access we believe that with popularity of imaging modality, especially ultrasonography, there is no place for blind pcnl. according to our knowledge, there is no report of using blind access in the supine pcnl. upper pole access in supine pcnl there is only one study about upper pole access in supine pcnl. the authors performed pcnl with a subcostal approach to the upper pole in 20 subjects. the mean operation time was 102.25 ± 41.56 minutes and the stone-free rate was 95%. the authors believed that in the supine position, the kidney is lower than the prone position; hence, the access to the upper pole is easier. upper pole pcnl with a subcostal approach seems to be a new, valuable treatment option for complex stone disease.(8,15,18) the effect of bmi on the results of supine pcnl obesity may play a role in the efficacy of stone treatments, such as shockwave lithotripsy, and increase the risk of morbidity in the patients.(16,21-23) by several reported studies, bmi had no significant effect on the results of pcnl.(16,18,22,24,25) for proximal ureteral and kidney stones, pcnl is done in the supine position.(3,7,8,26) supine pcnl is feasible in obese and morbidly obese patients; however, it may supine percutaneous nephrolithotomy—falahatkar et al 263urology journal vol 8 no 4 autumn 2011 increase the anesthesia time in patients with higher bmi.(8) the effect of previous renal surgery on pcnl previous renal surgery creates scar and fibrosis in the retroperitoneal space. on the other side, prescient infection and surgery would cause scar tissue in the cortex of the kidney. at first, physician may think these factors will affect the outcomes of pcnl in the patient with previous surgery, but some studies have repudiated the idea.(8,27-29) percutaneous nephrolithotomy is feasible and safe in patients who have had previous renal surgery, but falahatkar and colleagues reported that the fibrosis problem would be caused by the previous renal surgery and in the first step, the dilation process would be increased. they have considered the tone of the fascia as the key element of fibrosis problem. the authors have found no differences between outcomes of pcnl in two groups.(8,28) there was only one study that compared supine pcnl in patients with and without a history of stone surgery. eighty-one patients were divided into two groups. renal surgery had been done in 28 (34.6%) patients (group 1) while 53 (65.4%) had no history of pervious renal surgery (group 2). they reported the outcomes of patients were similar in both groups.(10) tubeless pcnl nowadays, many researchers believe that the nephrostomy tube placement is not necessary after uncomplicated pcnl. however, the majority of urologists believe that there are few indications for nephrostomy placement, including severe hemorrhage, significant extravasation, and large stone residue.(3,7,10,13,15,18,30) according to our knowledge, there is no study to compare patients with and without nephrostomy tube after supine pcnl, but there are several studies on tubeless supine pcnl without any major complications.(3,7,10,13,18) falahatkar and associates have accomplished tubeless supine pcnl in 117 patients requiring complete supine pcnl and have demonstrated that it is a safe procedure with no significant complications.(7) we believe that tubeless pcnl is a safe and effective procedure in the supine position like the prone position. conclusion the study showed that pcnl in the supine position is an effective and safe method for urinary stones. there are numerous advantages for pcnl, including decreasing operating time, evacuation of stone fragment, a more tolerable position for high-risk patients, and sitting position for the surgeon. we hope this paper encourage researchers in academic centers to perform pcnl in the supine position. acknowledegments the supine pcnl study was supported and encouraged by professor simforoosh. it is a pleasure to thank all who made this research possible. we also show our gratitude to mrs. nadia rastjou herfeh for english revising. conflict of interest none declared. references 1. neto ea, mitre ai, gomes cm, arap ma, srougi m. percutaneous nephrolithotripsy with the patient in a modified supine position. j urol. 2007;178:165-8; discussion 8. 2. valdivia-uria jg. complete supine percutaneous nephrolithotripsy comparison with the prone standard technique: the time for change from prone to supine position has come. urotoday int j. 2009;2. 3. falahatkar s, moghaddam aa, salehi m, nikpour s, esmaili f, khaki n. complete supine percutaneous nephrolithotripsy comparison with the prone standard technique. j endourol. 2008;22:2513-7. 4. shoma am, eraky i, el-kenawy mr, el-kappany ha. percutaneous nephrolithotomy in the supine position: technical aspects and functional outcome compared with the prone technique. urology. 2002;60:388-92. 5. rana am, bhojwani jp, junejo nn, das bhagia s. tubeless pcnl with patient in supine position: procedure for all seasons?--with comprehensive technique. urology. 2008;71:581-5. 6. liu l, zheng s, xu y, wei q. systematic review and meta-analysis of percutaneous nephrolithotomy for patients in the supine versus prone position. j endourol. 2010;24:1941-6. 7. falahatkar s, farzan a, allahkhah a. is complete supine percutaneous nephrolithotripsy feasible in all patients? urol res. 2011;39:99-104. supine percutaneous nephrolithotomy—falahatkar et al 264 urology journal vol 8 no 4 autumn 2011 8. falahatkar s, allahkhah a. recent developments in percutaneous nephrolithotomy: benefits of the complete supine position. urotoday int j. 2010;3. 9. wu p, wang l, wang k. supine versus prone position in percutaneous nephrolithotomy for kidney calculi: a meta-analysis. int urol nephrol. 2011;43:67-77. 10. falahatkar s, asli mm, emadi sa, enshaei a, pourhadi h, allahkhah a. complete supine percutaneous nephrolithotomy (cspcnl) in patients with and without a history of stone surgery: safety and effectiveness of cspcnl. urol res. 2011;39:295-301. 11. scoffone cm, cracco cm, cossu m, grande s, poggio m, scarpa rm. endoscopic combined intrarenal surgery in galdakao-modified supine valdivia position: a new standard for percutaneous nephrolithotomy? eur urol. 2008;54:1393-403. 12. falahatkar s, asgari sa, nasseh h, et al. kidney displacement in complete supine pcnl is lower than prone pcnl. urol res. 2011;39:159-64. 13. falahatkar s, neiroomand h, enshaei a, kazemzadeh m, allahkhah a, jalili mf. totally ultrasound versus fluoroscopically guided complete supine percutaneous nephrolithotripsy: a first report. j endourol. 2010;24:1421-6. 14. basiri a, mohammadi sichani m, hosseini sr, et al. x-ray-free percutaneous nephrolithotomy in supine position with ultrasound guidance. world j urol. 2010;28:239-44. 15. falahatkar s, khosropanah i, roshan za, golshahi m, emadi sa. decreasing the complications of pcnl with alternative techniques including complete supine pcnl and subcostal approach. pak j med sci. 2009;25:353-8. 16. koo bc, burtt g, burgess na. percutaneous stone surgery in the obese: outcome stratified according to body mass index. bju int. 2004;93:1296-9. 17. de sio m, autorino r, quarto g, et al. modified supine versus prone position in percutaneous nephrolithotomy for renal stones treatable with a single percutaneous access: a prospective randomized trial. eur urol. 2008;54:196-202. 18. falahatkar s, enshaei a, afsharimoghaddam a, emadi sa, allahkhah aa. complete supine percutaneous nephrolithotomy with lung inflation avoids the need for a supracostal puncture. j endourol. 2010;24:213-8. 19. basiri a, ziaee am, kianian hr, mehrabi s, karami h, moghaddam sm. ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2008;22:281-4. 20. hosseini mm, hassanpour a, farzan r, yousefi a, afrasiabi ma. ultrasonography-guided percutaneous nephrolithotomy. j endourol. 2009;23:603-7. 21. sergeyev i, koi pt, jacobs sl, godelman a, hoenig dm. outcome of percutaneous surgery stratified according to body mass index and kidney stone size. surg laparosc endosc percutan tech. 2007;17: 179-83. 22. el-assmy am, shokeir aa, el-nahas ar, et al. outcome of percutaneous nephrolithotomy: effect of body mass index. eur urol. 2007;52:199-204. 23. thomas r, cass as. extracorporeal shock wave lithotripsy in morbidly obese patients. j urol. 1993;150:30-2. 24. bagrodia a, gupta a, raman jd, bensalah k, pearle ms, lotan y. impact of body mass index on cost and clinical outcomes after percutaneous nephrostolithotomy. urology. 2008;72:756-60. 25. pearle ms, nakada sy, womack js, kryger jv. outcomes of contemporary percutaneous nephrostolithotomy in morbidly obese patients. j urol. 1998;160:669-73. 26. manohar t, jain p, desai m. supine percutaneous nephrolithotomy: effective approach to high-risk and morbidly obese patients. j endourol. 2007;21:44-9. 27. clayman rv. supine position is safe and effective for percutaneous nephrolithotomy. j urol. 2005;174: 601-2. 28. falahatkar s, panahandeh z, ashoori e, akbarpour m, khaki n. what is the difference between percutaneous nephrolithotomy in patients with and without previous open renal surgery? j endourol. 2009;23:1107-10. 29. basiri a, karrami h, moghaddam sm, shadpour p. percutaneous nephrolithotomy in patients with or without a history of open nephrolithotomy. j endourol. 2003;17:213-6. 30. falahatkar s, khosropanah i, roshani a, et al. tubeless percutaneous nephrolithotomy for staghorn stones. j endourol. 2008;22:1447-51. 31. valdivia-uria jg, valle gerhold j, lopez lopez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol. 1998;160:1975-8. 32. ng mt, sun wh, cheng cw, chan es. supine position is safe and effective for percutaneous nephrolithotomy. j endourol. 2004;18:469-74. 33. steele d, marshall v. percutaneous nephrolithotomy in the supine position: a neglected approach? j endourol. 2007;21:1433-7. 34. zhou x, gao x, wen j, xiao c. clinical value of minimally invasive percutaneous nephrolithotomy in the supine position under the guidance of real-time ultrasound: report of 92 cases. urol res. 2008;36: 111-4. urology journal vol 4 no 1 winter 2007 41 miscellaneous hydatid cyst of urinary tract eleven cases at a single center mohammadali zargar-shoshtari, pejman shadpour, nader robat-moradi, mohammadkazem moslemi introduction: we retrospectively reviewed clinical records of 11 patients with hydatid cyst of the urinary tract admitted to our institution from 1998 to 2005. materials and methods: hospital and follow-up records of 11 patients with hydatid cyst of the urinary tract were reviewed and data on the patients’ symptoms and signs at presentation, radiological findings, diagnostic tests, pathologic findings, and surgical outcomes were reviewed. results: the chief complaint was flank pain in 7 patients (63.6%). hydaturia was not seen in any of our patients. ten patients had renal involvement and 1 had a retrovesical hydatid cyst. eosinophilia was detected in 2 of 11 patients who were tested. a positive indirect hemagglutination test was seen in 4 of 7 patients and a positive casoni test in 1 of 2. intravenous urography revealed caliceal distortion in 6 patients (54.5%), caliectasis in 3 (27.3%), and nonfunctioning kidney in 2 (18.2%). ultrasonography showed a complex cyst in all of the patients. computed tomography demonstrated multivesicular cystic structure in 4 patients (36.4%), complex cyst in 4 (36.4%), and a simple cyst in 3 (27.3%). definite diagnosis was made only after surgical operation. we performed nephrectomy in 2 patients (18.2%), partial nephrectomy in 2 (18.2%), cystectomy plus marsupialization in 5 (45.4%), and retrovesical surgery in 1 (9.1%). one patient refused surgical treatment. there was no perioperative major complication. conclusion: renal hydatidosis is a rare entity and the main challenge is preoperative diagnosis. radiological and serologic studies, although indicative, cannot confirm the diagnosis, and only pathologic examination after surgical removal can confirm echinococcal infection. urol j (tehran). 2007;4:41-5. www.uj.unrc.ir keywords: hydatid cyst, space occupying lesion, urinary tract, diagnosis department of urology, hasheminejad hospital, iran university of medical sciences, tehran, iran corresponding author: nasser robat-moradi, md hasheminejad hospital, vanak sq, tehran, iran tel: +98 21 8879 6605 e-mail: nadir-robatmoradi@yahoo.com received april 2006 accepted december 2006 introduction echinococcosis is an infection caused by the larval stage of a tapeworm called echinococcus.(1) there are 3 species of echinococcus that cause hydatid disease. echinococcus granulosus is the most common type, whereas echinococcus multilocularis and echinococcus oligartus account for a small number of cases.(1) dog is the definitive host of echinococcus granulosus, in which the adult tapeworm is attached to the villi of the ileum. eggs are passed and deposited within the dog’s feces. sheep is the usual intermediate host, but humans are accidental intermediate hosts. in the human duodenum, the parasitic embryo penetrates the mucosa, allowing access to the blood stream, and enters the liver (most commonly) and the lungs.(1) clinical manifestations result from blood-borne invasion of the liver (50% to 70%) and the lungs (20% to 30%). most infected individuals are asymptomatic and it might take 5 to urinary hydatid cyst—zargar-shoshtari et al 42 urology journal vol 4 no 1 winter 2007 urinary hydatid cyst—zargar-shoshtari et al urology journal vol 4 no 1 winter 2007 43 20 years for a cyst to grow to its symptomatic size (3 cm to 15 cm).(1) the kidneys are the most commonly affected organs in the urogenital tract (2% to 4%),(2) although hydatid cyst of the prostate, the seminal vesicles, and the testes have also been reported.(1) echinococcal larvae may reach the kidney through the blood stream or lymph nodes, and by direct invasion.(1) reports on urogenital hydatid cyst are limited in the literature, and usually there are no specific clinical manifestions or laboratory findings for an accurate diagnosis of renal hydatid cysts. radiological studies might be helpful, but they cannot provide specific findings.(2) we present our 8-year experience in the diagnosis and management of 11 patients with hydatid cyst in their urinary tract. materials and methods a total of 11 patients with urinary hydatidosis were admitted and treated from 1998 to 2005 at hasheminejad hospital. ten patients had renal involvement and 1 had a retrovesical hydatid cyst. investigations included history, physical examination, complete blood count, serum biochemistry, urinalysis, the casoni test (intradermal skin test), and indirect hemagglutination test. all patients underwent ultrasonography, intravenous urography (ivu), and computed tomography (ct) scan. bone scan was carried out in 3 patients and dimercaptosuccinic acid (dmsa) renography in 2, for bone pain and nonfunctioning kidney, respectively. the clinical and laboratory data of the patients were retrospectively collected from the hospital and follow-up records. results of 11 patients, 8 (72.7%) were men and 3 (27.3%) were women. the median age of the patients was 48 years (range, 21 to 72 years). six patients (54.5%) had prior contact to dog. the main clinical symptom was flank pain; 7 patients (63.6%) had only flank pain, 1 (9.1%) had post-ejaculation pain, and 3 (27.3%) were asymptomatic (table 1). two patients (18.2%) had bilateral hydatid cysts and 1 (9.1%) had a palpable mass. eosinophilia was detected in 2 patients (18.2%). indirect hemagglutination test was carried out in 7 patients (63.6%), being positive in 4 (57.1%). of the 2 patients who underwent the casoni test, 1 had a positive result. calcification was seen in 1 patient (figure 1). intravenous urography revealed caliceal distortion in 6 patients (54.5%), caliectasis in 3 (27.3%), and nonfunctioning kidney in 2 (18.2%) (figure 2). ultrasonography was done in all patients and with no exceptions showed a complex cyst. computed tomography was also performed in all patients and demonstrated multivesicular cystic structure in 4 patients (36.4%), complex cyst (bosniac iii) in 4 (36.4%), and a simple cyst in 3 (27.3%) (figures 3 and 4). bone scan and dmsa scan were performed in 3 (27.3%) and 2 (18.2%) patients for bone pain and nonfunctioning kidney, respectively and a spaceoccupying lesion with no parenchymal function was demonstrated in all cases. a definitive diagnosis was not made in any of the patients before the surgery and pathologic examination. the treatment details are listed in table 2. ten patients underwent surgical operation and 1 refused table 1. clinical and demographic data of patients with hydatid cyst of urinary tract* *f indicates female; m, male; p, positive; n, negative; and ellipses, no available data. patient age, y sex chief complaint main sign environmental contact 1 29 f flank pain gross hematuria p 2 55 f none none n 3 58 m bilateral flank pain none p 4 72 f none none � 5 58 m flank pain none p 6 21 m flank pain none � 7 50 m flank pain none p 8 62 m none none p 9 46 m bilateral flank pain none � 10 56 m bilateral flank pain palpable mass p 11 21 m post-ejaculation pain none n urinary hydatid cyst—zargar-shoshtari et al 42 urology journal vol 4 no 1 winter 2007 urinary hydatid cyst—zargar-shoshtari et al urology journal vol 4 no 1 winter 2007 43 surgical treatment. in cystectomy, the outer gelatinous membrane of the cyst and the whole inner germinal membrane were removed after isolation by gauze packs soaked in hypertonic saline solution and sterilization of the cyst content by injection of povidone iodine for 10 minutes. the margins of pericyst remnants were oversewed. a drain was placed in the cyst cavity. one patient was explored due to retrovesical involvement in whom the cyst was approached extraperitoneally (figure 5). no mortality was seen in the perioperative period. overall, complications were seen in 2 patients (18.2%). one patient had a pleural effusion 3 days after the operation that was treated successfully by placing a chest tube. another patient presented a continuous urinary leakage from the operation site. he was treated with a double-j stent that improved leakage within 1 day. all of the patients were treated figure 1. calcification in the lower pole of the right kidney in a 46-year-old man (case 9). figure 2. upper pole of caliectasis in a 55-year-old woman (case 2). figure 3. hydatid cyst of the right kidney in a 58-year-old man with a dense cyst wall (case 5). figure 4. hydatid cyst of the right kidney in a 62-year-old man with complex cyst (case 8). urinary hydatid cyst—zargar-shoshtari et al 44 urology journal vol 4 no 1 winter 2007 urinary hydatid cyst—zargar-shoshtari et al urology journal vol 4 no 1 winter 2007 45 with oral albendazole, 400 mg twice a day, at least for 3 postoperative months. pathologic examination confirmed hydatid cyst in all of our patients. radiological assessment showed improvement in all of the patients after 3 to 6 months. discussion hydatid cyst is a parasitic infection caused by the larval form of echinococcus granulosus. the adult worm of echinococcus is present in the dogs’ small intestine. an intermediate host (human for instance) may ingest echinococcal eggs excreted in the feces of dogs. the eggs penetrate the duodenum and enter the portal system.(3) if not filtered out by the liver, embryos enter the systemic blood circulation and may lodge in any organ. embryos that are not phagocyted and destroyed develop into hydatid cyst.(4) usually, there are no specific signs or symptoms for renal hydatidosis and the disease usually remains asymptomatic for years. the most common symptoms are palpable mass, flank pain, hematuria, malaise, and fever.(5) hydaturia is a pathognomonic sign.(5) its origin is a grape-like material in the urine resulting from the rupture of the cysts into the collecting system. it has been reported in 5% to 25% of all renal hydatidosis cases,(5) but hydaturia was not detected in our patients. there is no serological and immunological test pathognomonic for hydatid disease. eosinophilia, the casoni test, complement fixation test, and indirect hemagglutination test may be helpful for diagnosis of renal hydatidosis.(6) eosinophilia is detected in 20% to 50% of patients with renal hydatidosis, but its detection cannot help much since falsepositive results may develop in the other parasitic diseases.(5) the casoni test produces positive results in about 25% to 50% of patients, while complement fixation test yields about 40% positive results and even indirect hemagglutination test has a higher positive rate of about 75% for hydatid disease.(6) in conclusion, a negative serology result does not exclude hydatid disease and on the other hand, a positive one does not confirm the diagnosis.(5) in table 2. treatment data of patients with urinary tract hydatid cyst *the patient refused surgical treatment. patient hospital stay surgical complication surgery 1 5 none cystectomy and marsupialization 2 6 none nephrectomy 3 4 none partial nephrectomy 4 5 pleural effusion cystectomy and marsupialization 5 15 urinary leakage cystectomy and marsupialization 6 7 none nephrectomy 7 4 none partial nephrectomy 8 6 none cystectomy and marsupialization 9 5 none cystectomy and marsupialization 10 5 none retrovesical surgery 11* 7 � � figure 5. retrovesical hydatid cyst in the cystography of a 21year-old man with post-ejaculation pain (case 10). urinary hydatid cyst—zargar-shoshtari et al 44 urology journal vol 4 no 1 winter 2007 urinary hydatid cyst—zargar-shoshtari et al urology journal vol 4 no 1 winter 2007 45 our series, indirect hemagglutination test was done in 7 patients, which was positive in 4. moreover, eosinophilia was seen in 18.2% of cases. radiological studies have a more important role in the preoperative diagnosis of renal hydatidosis. on plain abdominal radiography, ring-shaped calcification can be visualized.(7) calcifications may be linear, multilaminated, or amorphous. intravenous urography shows distortion of the calixes or caliectasis as a result of a renal mass involving the collecting system. a nonfunctioning kidney or a filling defect in the renal pelvis may be rarely evidenced by ivu.(7) ultrasonography is usually the primary radiological investigation, because of its advantages including cost-effectiveness and noninvasiveness. hydatid cyst on ultrasonography may be unilocular or multivesicular.(7) the determination of daughter cysts, which is characteristic of a hydatid cyst, is also possible on ultrasonography. with its own advantages, ct can detect calcification and daughter cysts much easier; thus, it is more sensitive and accurate than ultrasonography.(7) stable, asymptomatic, and calcified cysts do not require specific therapy, but should be monitored by serial imaging over several years to ensure a benign nature. when technically feasible, expanding, symptomatic, and infected cysts are best removed with surgery and isolation and killing of the cysts with hypertonic saline (25 g/dl to 30 g/dl) or other agents such as ethanol.(1-4) many symptomatic echinococcal cysts are not amenable to resection. in such cases, medical treatment with antihelminthics, either long-term mebendazole or albendazole can be effective.(4) conclusion hydatid disease of the urinary tract is a rare condition and the kidney is the most common site of involvement in the urinary system. primary diagnosis is made by ultrasonography and ct scan. surgery is the choice of treatment. conflict of interest none declared. references 1. white ac jr, weller pf. helminthic infections. cestodes. in: kasper dl, braunwald e, fauci as, hauser sl, longo dl, jameson al, editors. harrison’s principles of internal medicine. 16th ed. new york: mcgrow-hill; 2005. p. 1253-72. 2. kilciler m, bedir s, erdemir f, coban h, sahan b, ozgok y. isolated unilocular renal hydatid cyst: a rare diagnostic difficulty with simple cyst. urol int. 2006;77: 371-4. 3. gogus c, safak m, baltaci s, turkolmez k. isolated renal hydatidosis: experience with 20 cases. j urol. 2003;169:186-9. 4. horchani a, nouira y, kbaier i, attyaoui f, zribi as. hydatid cyst of the kidney. a report of 147 controlled cases. eur urol. 2000;38:461-7. 5. afsar h, yagci f, meto s, aybasti n. hydatid disease of the kidney: evaluation and features of diagnostic procedures. j urol. 1994;151:567-70. 6. shetty sd, al-saigh aa, ibrahim ai, malatani t, patil kp. hydatid disease of the urinary tract: evaluation of diagnostic methods. br j urol. 1992;69:476-80. 7. angulo jc, sanchez-chapado m, diego a, escribano j, tamayo jc, martin l. renal echinococcosis: clinical study of 34 cases. j urol. 1997;157:787-94. endourology and stone disease comparison of two different scoring systems in encrusted ureteral stent management: a single-center experience ekrem guner1*, kamil gokhan seker1 purpose: to report our single-center experience in encrusted ureteral stent management and to compare the utility of two different scoring systems, kub (kidney, ureter, bladder) versus fecal (forgotten, encrusted, calcified), in patient management. materials and methods: we retrospectively analyzed the medical records of all patients who were found to have encrusted/retained ureteral stent and underwent various procedures to remove encrusted ureteral stent in our clinic between may 2014 and december 2018. encrusted stent grading was performed using kub and fecal grading systems. kub system score is the sum of the stone burden scores of 3 different parts of an encrusted stent within the kidney, ureter and bladder determined using a scale from 1 to 5 according to the maximal diameter of encrustation. fecal grading system is based on the stone size, location and degree of stent encrustation and scored from grade 1 to grade 5. results: a total of 39 patients (29 males and 10 females) were included the study. the mean age of the patients was 46.4 ± 14.5 years, ranging from 13 to 71 years. the mean time from ureteral stent insertion to encrustation was 13.7 ± 26.4 months, varying between 2 and 120 months. the mean kub score was 6.4 ± 2.4. according to fecal system, 53.8% of the patients were classified as grade 1 and 15.4% as grade 2. the encrusted ureteral stents of eight patients (20.5%) could be removed with the aid of a foreign body forceps inserted through a cystoscope. fourteen patients (35.9%) underwent cystolithotripsy, seven (17.9%) underwent flexible ureterorenoscopy (urs), six (15.4%) underwent rigid urs, and three (7.7%) underwent combined percutaneous nephrolithotomy and urs beside stent removal. in multivariate regression analysis, largest encrustation diameter, fecal system grade and kub score were found to be significant predictors of stoneand stent-free status (p < 0.001 for all). also, kub score was found to be associated with the number of required procedures (r= .506, p = .001). conclusion: kub encrusted stent scoring system might be useful in predicting the number of required procedures to achieve stoneand stent-free status. pure intracorporeal endourologic procedures, percutaneous interventions or open surgery might be preferred according to the patient’s situation and the surgeon’s experience and preference. keywords: ureteral stent; encrusted; calcified; score; kub; fecal introduction ureteral stent has been a widely and routinely used device in urological procedures since it was first described in 1967. ureteral stent placement is a main part of either open or endoscopic urologic operations performed for ureteral stones, retroperitoneal fibrosis, ureteropelvic junction obstruction, ureteral strictures, etc(1,2). besides being a safe and usually well-tolerated material obtaining urinary drainage from kidney to urinary bladder, ureteral stents are not without complications. these complications include dysuria, hematuria, flank pain, suprapubic discomfort, vesicoureteral reflux, migration, encrustation, urinary tract infection, etc(3,4). encrustation of ureteral stent depends on various factors such as indwelling time, urinary tract infection, stent material, history or presence of concomitant stone disease and metabolic or congenital abnormalities(5). university of health sciences, bakirkoy dr.sadi konuk training and research hospital, department of urology, istanbul /turkey. *correspondence: university of health sciences, bakirkoy dr.sadi konuk training and research hospital department of urology tevfik saglam caddesi no:11 zuhuratbaba/bakirkoy, istanbul/turkey 34147 tel: +90 532 613 89 12. fax: +90 212 414 64 99. e-mail: ekremguner@yahoo.com. received & accepted encrusted ureteral stents might also lead to significant complications like urinary obstruction, persistent urinary infection, stent fracture and even injuries of the urinary tract and renal function loss(6,7). two different scoring systems were proposed for encrusted stent grading: 1. kub score; 2. fecal grading. management of encrusted ureteral stents may be challenging for urologists. several procedures have been suggested such as extracorporeal shock wave lithotripsy, endourological procedures including rigid and flexible ureteroscopy (urs), percutaneous nephrolithotomy (pnl) and open and laparoscopic surgeries(5,8-10). in the present study, we aimed to report our single-center experience in encrusted ureteral stent management and to compare the utility of two different scoring systems in patient management. materials and methods after the approval of the study by the local ethics comurology journal/vol 17 no. 3/ may-june 2020/ pp. 248-251. [doi:10.22037/uj.v0i0.5516] vol 17 no 03 may-june 2020 249 mittee of istanbul bakirkoy dr. sadi konuk training and research hospital (approval number: 2019/40), we retrospectively analyzed the medical records of all patients who had encrusted/retained ureteral stent and underwent various procedures for encrusted ureteral stent removal in our clinic between may 2014 and december 2018. both male and female patients at any age with available data were included the study. patients whose encrusted/retained stent could be removed at first attempt on an outpatient basis were excluded from the study. patients with an encrusted ureteral stent in the transplanted kidney were also excluded. the studied parameters included patient demographics, indication of stent insertion, preoperative and postoperative imaging results, urinalysis results, serum biochemical test results and the type of surgery performed for encrusted stent removal. encrusted stent grading was performed using kub (kidney, ureter, bladder)(11) and fecal (forgotten, encrusted, calcified) (7) grading systems as described previously. kub system score is the sum of the stone burden scores of 3 different parts of an encrusted stent within the kidney, ureter and bladder determined by using a scale from 1 to 5 according to the maximal diameter of encrustation (11). fecal grading system is based on the stone size, location and degree of stent encrustation and scored from grade 1 to grade 5 (7). negative urine culture was obtained prior to each surgery. statistical analysis was performed using ibm spss statistics for mac v.21.0 (ibm corp., armonk, ny). quantitative values are shown as mean ± sd (range), and qualitative values are shown as number and percentage. pearson correlation analysis was used to investigate the linear correlation between two continuous variables. multivariate logistic regression analysis was used to determine the effect of potentially significant variables on stentand stone-free status. the level of statistical significance was set at p < .05. results a total of 39 patients (29 males and 10 females) were included the study. the mean age of the patients was 46.4 ± 14.5 years, ranging from 13 to 71 years. the indwelling ureteral stent insertion indication was ureterorenoscopy (urs) for stone disease in 28 patients, obstruction due to renal stone in four, hydronephrosis in two, pnl in three and pyeloplasty in two. the mean time from ureteral stent insertion to encrustation was 13.7 ± 26.4 months, varying between 2 and 120 months. the mean kub score was 6.4 ± 2.4. according to fecal system, 53.8% of the patients were classified as grade 1 and 15.4% as grade 2. the encrusted ureteral stents of eight patients (20.5%) could be removed with the aid of a foreign body forceps inserted through a cystoscope. fourteen patients (35.9%) underwent cystolithotripsy, seven (17.9%) underwent flexible urs, six (15.4%) underwent rigid urs, and three (7.7%) underwent combined pnl and urs beside stent removal. one patient underwent nephrectomy and stent removal due to massive stone formation and a non-functioning kidney. stoneand stent-free status was achieved in 36 (92.3%) patients (table 1). in multivariate regression analysis, largest encrustation diameter, fecal system grade and kub score were found to be significant predictors of stoneand stent-free status (p < .001 for all) (table 2). gender and ureteral stent insertion indication had no predictive value on stoneand stent-free status (p = .751 and p = .99, respectively). in correlation analysis, fecal system grade and kub score were found to be significantly correlated (r = .652, p < .001). also, kub score was found to be associated with the number of required procedures (r = .482, p = .002). however, fecal grading was not correlated with the number of procedures (r = .239, p = .143). kub score and fecal grade were also found to be positively correlated with stent indwelling time (r = .513, p = .001; r = .456, p = .004, respectively). table 1. patient demographics and characteristics of encrustation. variables number of patients 39 mean age (years) 46.4 ± 14.5 male/female 29/10 indication of stent insertion urs for ureteral stone 28 (71.8%) pnl 3 (7.7%) hydronephrosis 2 (5.1%) pyeloplasty 2 (5.1%) ureteral obstruction 4 (10.3%) stent retaining time (months) 13.7 ± 26.4 grade of encrustation kub score 6.4 ± 2.4 fecal grade grade 1 21 (53.8%) grade 2 6 (15.4%) grade 3 3 (7.7%) grade 4 4 (10.3%) grade 5 5 (12.8%) average number of procedures 1.18 ± 0.45 type of procedures stent removal 8 (20.5%) flexible urs + stent removal 7 (17.9%) rigid urs + stent removal 6 (15.4%) pnl+ urs + stent removal 3 (7.7%) cystolithotripsy + stent removal 14 (35.9%) nephrectomy+ stent removal 1 (2.6%) stoneand stent-free yes 36 (92.3%) no 3 (7.7%) encrusted ureteral stent managemen-guner et al. discussion ureteral stents, especially double-j stents, also named as pigtail stents, are widely used in urological clinical practice. ureteral stents allow urine passage from kidney to bladder in case of a ureteral obstruction due to intrinsic and extrinsic causes like urinary stones, iatrogenic trauma or injuries, strictures, retroperitoneal fibrosis or malignancies. ureteral stents are also utilized in complex abdominal and gynecological procedures to identify and preserve ureters(8). encrustation of ureteral stents may lead serious complications, and the management of this situation might be challenging for urologists. the exact mechanism of encrustation is not well known; however, various etiological factors such as indwelling time, stent material, urinary infection, stone disease and metabolic and congenital abnormalities(5), pregnancy and lack of health insurance have been suggested (11). in a study, el-faqih et al.(12) investigated the relation between stent indwelling time and encrustation. they reported that the encrustation rates of stents that were retrieved before 6 weeks, that were retrieved in 6 to 12 weeks and that were retrieved later than 12 weeks were 9.2%, 47.5% and 76.3%, respectively. they concluded that morbidity related to stent was minimal if stent indwelling time did not exceed 6 weeks. in a study by polat et al., ureteral stent indwelling time was found to be correlated with stone burden and hospital stay during encrusted stent removal(9). in our study, the mean indwelling time was 13.7 months and was significantly associated with kub score and fecal grading. in addition, most of our patients (89.8%) had a history of urinary stone disease that might have constituted the significant factor for encrustation. two scoring systems have been proposed for grading encrustation of stent, kub(11) and fecal(7) scoring systems. a total kub score of ≥ 9 was found to be associated with multiple surgeries, operation time longer than 180 minutes and lower stone-free rates(11). in a study, kub score was found to be associated with indwelling time. also, a kub score ≥ 3 was found to be related with multiple surgery requirements, multi-modal procedure requirement and lower stone-free rates. by using fecal grading system, authors proposed a clear multimodal step-wise approach in encrusted ureteral stent management(7). in the present study, both kub score and fecal grade were found to be correlated with indwelling time. also, both were found to be significant predictors of stoneand stent-free status. however, while kub score was correlated with the number of procedures required to achieve stoneand stent-free status, fecal score was not. this might be due to design of fecal grading system, as it proposes a treatment algorithm besides grading. achieving stentand stone-free status while preserving maximal renal function is the main goal in encrusted stent management. various types of operations have been suggested for encrusted stent removal including endourological, percutaneous and open procedures as well as combined approaches(8-10,13). in a study by thomas et al.(8), authors reported the outcomes of complete retrograde technique with holmium laser in encrusted stent management. they first inserted a safety guide-wire to the ureter beside the retained stent. then, they fragmented the bladder curl encrustations cystoscopically. afterwards, they used rigid urs for the middle part of the stent to reach the renal pelvis. if it was not possible to reach the renal pelvis, they cut the stent as proximal as possible and removed the distal portion of the stent using grasping forceps. then, they inserted a ureteral access sheath and performed flexible urs to fragmentize the proximal end of the encrusted stent. the mean operative time was 110 ± 35.2 minutes, ranging between 42 and 225 minutes. the main postoperative early complication was non-obstructive pyelonephritis, which was not associated with operative time, gender or encrustation degree (8). bostanci et al.(10) proposed a combined endourological approach including cystolithotripsy, retrograde urs with intracorporeal lithotripsy and pnl for removing encrusted stents in a single session. the average number of required interventions was 1.9. the authors concluded that, although it was the most invasive procedure, using pnl in encrusted stent management provided higher stonefree rates and decreased the number of required procedures especially in large encrustations. in the present study, we used multimodal approaches when required. our mean operation number for the complete removal of stents and stones was 1.18, which is relatively smaller than the numbers reported previously. this might be because most patients had encrustation on the distal part of their stent, and we think that bladder is a relatively comfortable space for stone surgery. the main reason for unintentionally retained stents seems to be poor patient compliance. however, it is both the physician’s and patient’s responsibility to ensure the timely removal of the ureteral stent. to overcome the retained/forgotten stent problem, several strategies have been developed such as ureteral stent card registry, e-mail reminder and a letter of reminder based on billing information(14,15). recently, ziemba et al.(15) developed a hipaa (health insurance portability and accountability act) complaint, a cloud based point-of-care application, to track ureteral stents. in the present study, stent indwelling time varied between 2 and 120 months. as two months is not a very long time, we think that clinicians must be alert for early encrustation of stents and might want to schedule an earlier stent removal time, especially in patients with a history of stone disease. conclusions forgotten/retained ureteral stents might lead to challenging problems for urologists. appropriate management of this situation and deciding the feasible technique of operation(s) is vital. kub encrusted stent scoring system might be useful in predicting the number of required procedures to achieve stoneand stent-free status. pure intracorporeal endourologic procedures, variables score p-value age 1.639 .200 gender .101 .751 encrustation diameter 14.589 <.001 fecal classification 22.100 <.001 kub grading system 19.725 <.001 ureteral stent placement indication 7.815 .099 table 2. multivariate logistic regression analysis for predicting stone-free status. encrusted ureteral stent managemen-guner et al. endourology and stones diseases 250 vol 17 no 03 may-june 2020 251 percutaneous interventions or open surgery might be preferred according to the patient’s situation and the surgeon’s experience and preference. as prevention is the best method to struggle with the disease, tracking patients with ureteral stents and providing timely removal of the ureteral stent is highly recommended. conflict of interest the authors report no conflict of interest. references 1. zimskind pd, fetter tr, wilkerson jl. clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically. j urol. 1967; 97:840-4. 2. adanur s, ozkaya f. challenges in treatment and diagnosis of forgotten/encrusted double-j ureteral stents: the largest single-center experience. ren fail. 2016; 38:920-6. 3. niranjan a, agarwal n, agarwal v, srivastava a. enigma of forgotten double j stent. saudi j kidney dis transpl. 2010; 21:157-9. 4. hao p, li w, song c, yan j, song b, li l. clinical evaluation of double-pigtail stent in patients with upper urinary tract diseases: report of 2685 cases. j endourol. 2008; 22:6570. 5. bultitude mf, tiptaft rc, glass jm, dasgupta p. management of encrusted ureteral stents impacted in upper tract. urology. 2003; 62:622-6. 6. barreiro dm, losada jb, montiel fc, lafos n. urinary incontinence and urosepsis due to forgotten ureteral stent. urol case rep. 2016; 8:63-5. 7. acosta-miranda am, milner j, turk tm. the fecal double-j: a simplified approach in the management of encrusted and retained ureteral stents. j endourol. 2009; 23:409-15. 8. thomas a, cloutier j, villa l, letendre j, ploumidis a, traxer o. prospective analysis of a complete retrograde ureteroscopic technique with holmium laser stent cutting for management of encrusted ureteral stents. j endourol. 2017. [epub ahead of print]. 9. polat h, yucel mo, utangac mm, et al. management of forgotten ureteral stents: relationship between indwelling time and required treatment approaches. balkan med j. 2017; 34:301-7. 10. bostanci y, ozden e, atac f, yakupoglu yk, yilmaz af, sarikaya s. single session removal of forgotten encrusted ureteral stents: combined endourological approach. urol res. 2012; 40:523-9. 11. arenas jl, shen jk, keheila m, et al. kidney, ureter, and bladder (kub): a novel grading system for encrusted ureteral stents. urology. 2016; 97:51-5. 12. el-faqih sr, shamsuddin ab, chakrabarti a, et al. polyurethane internal ureteral stents in encrusted ureteral stent managemen-guner et al. treatment of stone patients: morbidity related to indwelling times. j urol. 1991; 146:148791. 13. veltman y, shields jm, ciancio g, bird vg. percutaneous nephrolithotomy and cystolithalapaxy for a "forgotten" stent in a transplant kidney: case report and literature review. clin transplant. 2010; 24:112-7. 14. lynch mf, ghani kr, frost i, anson km. preventing the forgotten ureteral stent: implementation of a web-based stent registry with automatic recall application. urology. 2007; 70:423-6. 15. ziemba jb, ludwig ww, ruiz l, carvalhal e, matlaga br. preventing the forgotten ureteral stent by using a mobile point-ofcare application. j endourol. 2017; 31:71924. comparison of three different enucleation techniques of holmium laser enucleation of prostate (holep) zafer tokatli1, bariş esen2*, önder yaman2, remzi sağlam1 purpose: to evaluate the effect of different enucleation techniques on operation time, enucleation efficacy and postoperative results. materials and methods: 178 holep cases performed by two senior surgeons were evaluated retrospectively. all patients were evaluated for age, ipss, preoperative psa, prostate size, maximum flow rate (qmax) postvoid residual volume (pvr), enucleation time, morcellation time, enucleated tissue weight, enucleation ratio (enucleated tissue weight/prostate volume) and enucleation time efficacy (enucleated weight/enucleation time). patients were categorized into three groups according to performed enucleation techniques; retrograde low tension (rlt) two-lobe, traditional three-lobe, and en bloc techniques. ipss, qmax, pvr and transient urine leakage (tul) were evaluated during postoperative follow up. all preoperative, intraoperative and postoperative results were compared between 3 groups. results: mean age was 70.52 (52-85) years. baseline data were comparable between groups. enucleation time was significantly shorter in rlt two-lobe (median; 50, 60 and 60 min; rlt two-lobe, traditional three-lobe, and en bloc holep techniques, respectively. (p = .031). morcellation time was comparable between groups (p = .532). no significant difference was observed between morcellated prostate weights (p = .916) significant improvements in ipss, qmax, and pvr were noted in all groups (p < .001). tul was significantly increased in en bloc technique (p = .034). postoperative stricture rates were similar between groups. (p = .769) conclusion: shorter enucleation time was observed in the rlt holep technique and increased tul rate was observed in the en bloc technique. keywords: enucleation; holep technique; holmium laser; morcellation; operative time; prostatectomy introduction benign prostate hyperplasia (bph) is a common cause of lower urinary tract symptoms (luts) in aging men. (1) introduction of lasers for the surgical management of benign prostatic obstruction (bpo) has been a revolutionary step and rapidly adopted by many centers worldwide. currently, several laser devices with different energy sources are available, but holmium is by far the most commonly used laser. holmium laser enucleation of prostate (holep) was first introduced into clinical practice by gilling et al. in 1998.(2) many studies have reported the safety and efficacy of holep. lower morbidity, shorter catheterization time, length of hospital stay and fewer blood transfusions were reported in favor of holep compared to conventional methods such as transurethral resection of prostate (turp) and open prostatectomy (op).(3) several enucleation techniques have been described in the literature. the traditional three-lobe technique was first described by gilling and freundorfer.(2) krambeck et al. and baazeem et al. proposed the two-lobe technique which involves a single bladder neck incision with one 1department of urology, medicana international hospital, ankara, turkey. 2department of urology, ankara university school of medicine, ankara, turkey. *correspondence: department of urology, medical faculty, ankara university, ankara, turkey. phone: +905054532337. fax: +903123112167. email: barsesen90@gmail.com. received march 2019 & accepted august 2019 of the lateral lobes excised together with the middle lobe and subsequently the second lateral lobe.(4,5) in our retrograde low tension (rlt) two-lobe holep technique, some alterations were made in the surgical approach to minimize stretching of the external urethral sphincter, to shorten the enucleation time and to fascilitate learning. more recently, scoffone et al. described the en-bloc technique that provides enucleation the prostate in one piece, without separating the lobes using only a single incision to find the cleavage between prostate capsule and the adenoma.(6) studies have reported the safety and efficacy of these techniques however data comparing these three approaches are lacking.(4,6-9) herein we present our results in patients who underwent holep with our rlt twolobe, traditional three-lobe holep and en bloc holep techniques and data were compared between three enucleation techniques. materials and methods medical records of 178 patients who underwent holep between october 2015 and june 2017 were evaluaturology journal/vol 17 no. 4/ july-august 2020/ pp. 408-412. [doi: 10.22037/uj.v0i0.5211 ] unclassified ed retrospectively. all male patients who underwent holep surgery regardless of patient age, prostate size and psa level were evaluated in this study. patients with urethral stricture, neurogenic bladder, prostatic adenocarcinoma, prostatic or pelvic surgeries, and previous pelvic radiotherapy were excluded. all patients were evaluated for baseline characteristics such as age, preoperative psa, prostate size, international prostate symptom score (ipss), maximum flow rate (qmax) and postvoid residual volume (pvr). all operations were performed by two senior surgeons (tokatlı z. and saglam r.), who had an experience with more than 400 cases of holep including traditional three-lobe and en bloc techniques, previously. 100-watt holmium:yttrium -aluminum-garnet (ho-yag) laser device with 550-micron end-firing laser fibers (versapulse, power suite, lumenis medical systems, santa clara, ca) and versacut tissue morcellator (lumenis medical systems, santa clara, ca) were utilized in all operations. the morcellator was equipped with single use-disposable blades in all cases. intraoperative data such as enucleation time, morcellation time, enucleated tissue weight, catheterization time and length of hospital stay were recorded in all patients. patients were categorized into three groups according to performed holep technique; rlt two-lobe, traditional three-lobe, or en-bloc techniques. in the traditional three-lobe technique; median lobe was resected first, followed by lateral lobes. three-lobe enucleation technique was preferred especially in cases with a large median lobe. in our rlt two-lobe technique; an incision is made at 5 or 7 o’clock position and early apical enucleation of one lobe is performed initially. to prevent stretching of the external urethral sphincter (eus); parasphincteric mucosal strip between prostate adenoma and eus was cut early after apical dissection. all of the dissections and enucleation were performed retrogradely. in en-bloc enucleation technique; both lateral lobes and median lobe were enucleated together without separating the right and left lobes. during the enucleation of the complete prostate adenoma, to reach the bladder neck by pressing the highest place of the prostate adenoma, it is unavoidable to stretch the eus. one day after removal of the urinary catheter, patients were asked verbally about any involuntary loss of urine and number of pad use per day and followed at postoperative 1., 3. and 6. months. transient urine leakage (tul) was defined as urine leakage persistent more than 24 hours after catheter removal but less than 3 months. patients who use ≥ 1 pad per day were considered positive for tul. spontaneously resolved urine leakage persistent more 3 months was considered as “prolonged incontinence”. patients were evaluated for ipss, qmax, and pvr at postoperative 6. months. further investigations with cystourethroscopies were performed as deemed necessary. urethral stricture rates and complications were noted. pelvic-floor muscle exercise was recommended to all patients with postoperative tul. in addition, duloxetine was recommended to patients with postoperative stress type ui, and anticholinergic drugs were recommended to patients with urge type ui. statistical analysis was performed using spss software version 21. variables were investigated using visual (histograms, probability plots) and analytic methods (kolmogorov-smirnov/shapiro-wilk’s test) to determine whether or not they were normally distributed. kruskal wallis test was utilized to compare baseline characteristics and intraoperative data among three different enucleation groups. the mann-whitney u test was performed to test the significance of pairwise differences using bonferroni correction to adjust for multiple comparisons. friedman tests were conducted to test whether there is a significant change between preoperative and postoperative results. spearman correlation test was used to evaluate correlations between prostate size and enucleation-morcellation times. chi-square test or fisher exact test was used to compare proportions between different groups. p-value of less than 0.05 was considered to show a statistically significant result. results overall 178 patients who underwent holep between october 2015 to june 2017 were evaluated in the study. mean age was 70.24 ± 7.50 years. baseline data were comparable between groups (table 1). patients with a wide range of prostate volume (30-224) were included in the study and median prostate volumes were comparable between 3 groups. (p = .425) the urethral catheter was routinely removed on postoperative 2. day and the patient was discharged home. significant positive correlation was observed between prostate size and enucleation time (correlation coefficient; 0.449, p ≤ .001) and morcellation time (correlation coefficient; 0.513, p ≤ .001). enucluation time was significantly shorter in rlt two-lobe technique (median 50, 60 and 60 min; rlt two-lobe, en bloc, and three-lobe techniques, respectively, p = .031). statistically significant difference was found only between rlt two-lobe and three-lobe techniques in pairwise comparisons. (p = .012) morcellation time was similar between groups (p = 0.532). enucleated tissue weights were similar between groups. (p = .916) enucleation ratio (median; 0.40, 0.46 and 0.49; rlt two-lobe, three-lobe, en bloc groups respectively, p = .165) and enucleation time efficacy (median; 0.82, 0.57 and 0.77; rlt two-lobe, three-lobe, en bloc groups respectively, p = .516) were also found similar comparison of 3 enucleation techniques of holep-tokatli et al. table 1. baseline data of three groups. parameter rlt two-lobe (n = 60) three-lobe (n = 59) en bloc (n = 59) p value* age (years) (mean ± sd) 70.14 ± 6.21 70.14 ± 6.06 71.38 ± 6.23 0.904 pre-op. psa (ng/dl)[median (iqr) ] 1.69 (0.74-4.12) 2.12 (1.05-3.09) 1.71(0.93-3.03) 0.704 prostate volume (ml) [median (iqr) ] 106 (74-130.5) 90 (69-121) 86 (65-130) 0.425 pre-op qmax (ml/sec) [median (iqr) ] 7 (3-12) 7 (4-11) 6 (4-9) 0.624 preop pvr (ml) [median (iqr) ] 119.5 (69-367.5) 134 (80-185) 141 (94-259) 0.709 ipss [median (iqr) ] 16.5 (13-19) 18 (14-23) 19 (14-22) 0.167 abbreviations: ml: mililiters, sec: second. *kruskal-wallis test vol 17 no 04 july-august 2020 409 between groups. significant improvements in ipss, qmax, and pvr were noted in all groups at postoperative 6. months (p < .001). holep increased qmax by 283% and reduced pvr by 88% when all patients were evaluated together. qmax increase and pvr decrease rates were comparable between 3 enucleation groups. mean follow up duration was 17.9 months. postoperative results were summarized in table 2. tul was observed in 14 (7.9%) patients. tul rate was significantly higher in the en-bloc technique (p = .034). total operation time (median; 72.5 vs 65 mins, p = .033) was significantly longer in patients with tul. postoperative bleeding requiring intervention was observed in 2 patients, one in three-lobe technique and one in en bloc technique. there was only one patient with “prolonged” incontinence in en bloc group which became continent 7 months after the surgery. permanent urinary incontinence was not observed. postoperative stricture rates were similar between the groups. (p = .769) (table 2) discussion holep is a safe and effective treatment for prostates of all sizes, men in retention and those who are anticoagulated or have bleeding disorders.(10) meta-analyses comparing holep with turp found comparable and even superior symptom improvement with holep (3,11,12) shorter catheterization time and hospital stay, reduced blood loss and fewer blood transfusions despite a longer operation time compared with turp were reported by 3 meta-analyses.(11-13) in a meta-analysis comparing holep with open prostatectomy (op), holep was found associated with shorter catheterization duration, shorter hospital stay and lower risk of perioperative blood transfusion.(3) long term complications of holep include retreatment, urinary incontinence, and urethral strictures.(14) a recent retrospective cohort revealed that urinary calculi formation in the prostatic fossa or bladder neck after holep is a rare but possible complication. reintervention, stress incontinence and urethral stricture rates were similar between turp and holep.(11) despite previously reported favorable outcomes and its proven advantages compared to conventional bph surgeries, holep still comprises only 4-5% of all major bph surgeries.(15) three major drawbacks prevent wider adoption of holep; steep learning curve, longer operation time and high transient urinary incontinence rates. the steep learning curve has always been considered as a major limitation of holep which prevents wide diffusion of the technique. in a prospective study, the learning curve of an experienced endourologist was evaluated from data of the first 160 cases and it was shown that morcellation and enucleation efficacy reached a plateau after the first 50 cases.(16) a retrospective trial also reported that morcellation and enucleation efficacy improved significantly after the first 50 cases.(17) seki et al. reported that enucleation efficacy increased during the first 70 cases. gregoire et al. evaluated the learning curve of holep step by step in a multicentric observational trial. of 9 surgeons participated in the trial, only one achieved the main judgment criterion of four consecutive successful holep procedures in 20 consecutive cases. it was concluded that holep has a steep learning curve exceeding 20 cases.(18) in our study, the learning curve was not evaluated since both surgeons had high experience with a total of 400 cases of holep. postoperative tul is a bothersome complication, occurring in 1.3%-16.6% of patients.(19-21) even though most cases recover spontaneously, it was shown to decrease patients’ quality of life significantly.(22) there are few studies investigating the factors to predict tul occurrence. elmansy et al. reported that presence of diabetes mellitus, prostate volume greater than 81 gm, operative time longer than 96 minutes and reduction in prostate-specific antigen higher than 84% were significantly associated with stress urinary incontinence after holep.(23) in another retrospective study with 391 patients who were treated with holep, tul was observed in 16.6% of the patients. increased age and operation time was found the factors significantly associated with the occurrence of postoperative tul.(19) kobayashi et al. also found that enucleation time longer than 100 min and blood loss >2.5 g/dl were significant and independent risk factors for postoperative ui.(24) data related to the effects of different enucleation techniques on postoperative results and operation time is scarce. in our study, tul rate was significantly higher in the enbloc technique. operation time was also significantly longer in patients with tul, consistent with previous studies. we suggest that one of the most important reasons for tul is the stretching of the external urethral sphincter, and it is recommended to avoid external urethral sphincter-stretching to decrease tul rates. in the traditional three-lobe technique described by fraundorfer and gilling, the median lobe is resected table 2. intraoperative and postoperative data of 3 different enucleation groups. rlt two-lobe (n = 60) three-lobe (n = 59) en bloc (n = 59) p value enucleation time (min) [median (iqr) ] 50 (42.5-60) 60 (30-70) 60 (40-60) †0.031* morcellation time (min) [median (iqr) ] 10 (5-12) 10 (5-15) 10 (5-10) †0.532 enucleated prostate weight (g) [median (iqr) ] 40 (26-59) 45 (23-68) 42 (25-51) †0.916 enucleation rate [median (iqr) ] 0.40 (0.31-0.49) 0.46 (0.28-0.55) 0.49 (0.32-.60) †0.165 enucleation time efficacy[median (iqr) ] 0.82 (0.51-1.03) 0.58 (0.42-1.10) 0.77 (0.43-1.00) †0.516 ipss (6. mo)[median (iqr) ] 8 (5.5-13) 12 (6-15) 11 (5-13) †0.202 qmax 6. mo (ml/sec) [median (iqr) ] 26.2 (17.8-31.8) 26.4 (19.3-30.1) 25.6 (19.8-31.7) 0.904 pvr (6. mo) ml [median (iqr) ] 19 (10-23.5) 22 (15-27) 17 (11-26) 0.184 transient urine leakage 2/60 3/59 9/59 ¶0.034 “prolonged” incontinence 0/60 0/60 1/59 na urethral stricture 1/59 2/59 1/59 ¶0.769 *pairwise comparisons: rlt two-lobe vs three lobe p = .012, rlt two-lobe vs en bloc p = .050, two-lobe vs three lobe p = .679 (p < .017; statistically significant due to bonferroni correction) abbreviations: na: not applicable, min: minute, mo:months, g: gram, iqr: interquartile range† kruskal-wallis test, ¶ fisher exact test. comparison of 3 enucleation techniques of holep-tokatli et al. unclassified 410 first, followed by lateral lobes.(25) in rlt two-lobe technique -a modification of two-lobe enucleationone lateral lobe was enucleated initially and the remaining lateral lobe and median lobe was enucleated together afterward. in this technique; early cutting of parasphincteric mucosal strip and retrograde 12 o’clock incision results in less stretching of the external urethral sphincter which is probably the reason for the decreased tul rate in this technique. in 2016, scaffone et al. reported en-bloc no-touch holep technique, in which both lateral lobes and median lobe are enucleated altogether and they suggested that en bloc technique may improve the learning curve of holep.(6) however, in our study increased tul rates were observed in the en bloc group. in the en bloc technique; during the enucleation of the whole prostate gland altogether, stretching of the eus is unavoidable while reaching the bladder neck by pressing the highest place of the prostate adenoma it is more important for larger size prostates. in our en bloc group, median prostate sizes were also larger than the other studies, this may explain higher tul rates. additionally, enucleation time was significantly shorter in the rlt two-lobe technique. in en bloc technique; it takes more time to push the whole prostate gland into the bladder, and in three-lobe technique, enucleation of both lateral lobes and the median lobe separately increases the operation time. late complication rates were similar for all enucleation techniques. our study has some limitations. the main limitation of our study is its retrospective design and lack of information about validated symptom scores to evaluate urinary incontinence. on the other hand; to our knowledge, this is the first clinical trial comparing the results of different enucleation techniques. effect of different enucleation techniques on the learning curve, operation time and postoperative results are issues of great importance and should be investigated with further prospective randomized trials. conclusions rlt two-lobe, three-lobe, and en bloc techniques are all safe and efficient methods to perform holep with similar postoperative results and late complication rates. shorter enucleation time was observed in the rlt twolobe technique and increased tul rate was observed in en bloc technique. conflict of interest the authors report no conflict of interest. references 1. calogero ae, burgio g, condorelli ra, cannarella r, la vignera s. epidemiology and risk factors of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction. aging male. 2019;22:129. 2. gilling pj, fraundorfer mr. holmium laser prostatectomy: a technique in evolution. curr opin urol. 1998;8:11-5. 3. cornu jn, ahyai s, bachmann a, et al. a systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. eur urol. 2015;67:1066-96. 4. krambeck ae, handa se, lingeman je. experience with more than 1,000 holmium laser prostate enucleations for benign prostatic hyperplasia. j urol. 2010;183:1105-9. 5. baazeem as, elmansy hm, elhilali mm. holmium laser enucleation of the prostate: modified technical aspects. bju int. 2010;105:584-5. 6. scoffone cm, cracco cm. the en-bloc no-touch holmium laser enucleation of the prostate (holep) technique. world j urol. 2016;34:1175-81. 7. glybochko pv, rapoport lm, enikeev me, enikeev dv. holmium laser enucleation of the prostate (holep) for small, large and giant prostatic hyperplasia: tips and tricks. urologia. 2017;84:169-73. 8. hurle r, vavassori i, piccinelli a, manzetti a, valenti s, vismara a. holmium laser enucleation of the prostate combined with mechanical morcellation in 155 patients with benign prostatic hyperplasia. urology. 2002;60:449-53. 9. gu m, chen yb, liu c, et al. comparison of holmium laser enucleation and plasmakinetic resection of prostate: a randomized trial with 72-month follow-up. j endourol. 2018;32:139-43. 10. aho tf. holmium laser enucleation of the prostate: a paradigm shift in benign prostatic hyperplasia surgery. ther adv urol. 2013;5:245-53. 11. tan a, liao c, mo z, cao y. meta-analysis of holmium laser enucleation versus transurethral resection of the prostate for symptomatic prostatic obstruction. br j surg. 2007;94:12018. 12. yin l, teng j, huang cj, zhang x, xu d. holmium laser enucleation of the prostate versus transurethral resection of the prostate: a systematic review and meta-analysis of randomized controlled trials. j endourol. 2013;27:604-11. 13. lourenco t, pickard r, vale l, et al. alternative approaches to endoscopic ablation for benign enlargement of the prostate: systematic review of randomised controlled trials. bmj. 2008;337:a449. 14. davydov ds, tsarichenko dg, bezrukov ea, et al. [complications of the holmium laser enucleation of prostate for benign prostatic hyperplasia]. urologiia. 201842-7. 15. anderson bb, heiman j, large t, lingeman j, krambeck a. trends and perioperative outcomes across major benign prostatic hyperplasia procedures from the acs-nsqip 2011-2015. j endourol. 2019;33:62-8. 16. shah hn, mahajan ap, sodha hs, hegde comparison of 3 enucleation techniques of holep-tokatli et al. vol 17 no 04 july-august 2020 411 s, mohile pd, bansal mb. prospective evaluation of the learning curve for holmium laser enucleation of the prostate. j urol. 2007;177:1468-74. 17. placer j, gelabert-mas a, vallmanya f, et al. holmium laser enucleation of prostate: outcome and complications of self-taught learning curve. urology. 2009;73:1042-8. 18. robert g, cornu jn, fourmarier m, et al. multicentre prospective evaluation of the learning curve of holmium laser enucleation of the prostate (holep). bju int. 2016;117:4959. 19. nam jk, kim hw, lee dh, han jy, lee jz, park sw. risk factors for transient urinary incontinence after holmium laser enucleation of the prostate. world j mens health. 2015;33:88-94. 20. shah hn, mahajan ap, hegde ss, bansal mb. peri-operative complications of holmium laser enucleation of the prostate: experience in the first 280 patients, and a review of literature. bju int. 2007;100:94-101. 21. hwang jc, park sm, lee jb. holmium laser enucleation of the prostate for benign prostatic hyperplasia: effectiveness, safety, and overcoming of the learning curve. korean j urol. 2010;51:619-24. 22. vavassori i, valenti s, naspro r, et al. three-year outcome following holmium laser enucleation of the prostate combined with mechanical morcellation in 330 consecutive patients. eur urol. 2008;53:599-604. 23. elmansy hm, kotb a, elhilali mm. is there a way to predict stress urinary incontinence after holmium laser enucleation of the prostate? j urol. 2011;186:1977-81. 24. kobayashi s, yano m, nakayama t, kitahara s. predictive risk factors of postoperative urinary incontinence following holmium laser enucleation of the prostate during the initial learning period. int braz j urol. 2016;42:7406. 25. fraundorfer mr, gilling pj. holmium:yag laser enucleation of the prostate combined with mechanical morcellation: preliminary results. eur urol. 1998;33:69-72. comparison of 3 enucleation techniques of holep-tokatli et al. unclassified 412 point of technique 123urology journal vol 5 no 2 spring 2008 retroperitoneal ureterocyctoplasty in bilaterally functioning kidneys mohammad ali zargar-shoshtari, kaveh mehravaran, hormoz salimi urol j. 2008;5:123-5. www.uj.unrc.ir keywords: bladder diseases, reconstructive surgical procedures, ureter, cystoplasty department of urology, shahid hasheminejad hospital, iran university of medical sciences, tehran, iran corresponding author: mohammad ali zargar-shoshtari, md shaheed hasheminejad hospital, vanak sq, tehran, iran tel: +98 21 8852 6900 fax: +98 21 8852 6901 e-mail: dr.zargarm@gmail.com received october 2007 accepted april 2008 introduction augmentation cystoplasty is an effective method of treatment in bladders with low volume and capacity. various techniques such as enterocystoplasty and gastrocystoplasty are used in order to increase bladder volume and to lower its pressure.(1) given the metabolic disorders due to the use of gastrointestinal segments, on the one hand, and mucus secretion and increasing risk of malignancy, on the other hand, applying other methods have been strongly taken into consideration. one of these methods is using the ureter for augmentation. the ureter is considered as a suitable and ideal option, because it is lined with urothelial cells, does not secrete mucus, and is not accompanied with the risk of malignancy.(2-4) we are present our experience in 3 patients whose ureter was used in their augmentation retroperitoneal ureterocystoplasty. case report three patients, 2 men and 1 woman, with neurogenic bladder and bilaterally functioning kidneys were selected for augmentation ureterocystoplasty. all of the patients had urinary incontinence, a small-capacity noncompliant bladder, and high-grade reflux on voiding cystourethrography. urodynamic study was performed in all of the three patients. their bladder capacities were 100 ml, 70 ml, and 55 ml. detrusor instability was present in 2 patients. technique a lower midline incision was made from the umbilicus to the pubic symphysis. the peritoneum was mobilized cephalad. mobilization of the ureters was done extraperitoneally for 8 cm to 9 cm (both ureters in 2 patients and 1ureter in 1), while taking care to preserve ureteral vascularization. the distal ends of the ureters were incised longitudinally, and the medial borders were sutured together using absorbable suture. the bladder was opened vertically across the bladder dome, and the ureter was sutured as a patch onto the open bladder with a continuous absorbable suture. bilateral reimplantation of the ureters in 2 patients and unilateral reimplantation in 1 was performed using the paquin technique.(5) two double-j stents were inserted in each ureter. a pezzer catheter was placed as a cystostomy. a foley catheter was inserted transurethrally and the bladder was closed with continuous absorbable suture material. retroperitoneal ureterocyctoplasty—zargar-shoshtari et al 124 urology journal vol 5 no 2 spring 2008 results the age range of the patients was 18 to 22 years (table). preoperative serum levels of creatinine were 2.3 mg/dl to 2.7 mg/dl. preoperative voiding cystourethrography showed trabeculated low-capacity bladder and bilateral severe vesicoureteral reflux (figure). the operative time was 2.5 to 3 hours. the median intra-operative blood loss was 280 ml. the postoperative course was uneventful. the patients became ambulated 48 hours after the operation and liquid diet was started the morning after the operation. the median hospital stay was 6.7 days. all of the patients were dry by the day with clean intermittent catheterization. serum creatinine levels were 1.2 mg/dl, 1.6 mg/dl, and 1.9 mg/ dl, 1 month postoperatively. bladder capacities of the patients reached 290 ml to 360 ml from the baseline values of 55 ml to 100 ml. discussion first, eckstein and martin described the extraperitoneal removal of a poorly functioning kidney in a 7-month-old infant.(6) they transversely opened the bladder to facilitate incorporation of the longitudinally incised ureter and showed that the procedure could be performed after ureteral reimplantation. this surgical technique became popular when it was shown to be the most suitable for patients with a dilated ureter draining a poorly functioning kidney.(7,8) ureterocystoplasty is now suggested for a variety of conditions associated with low bladder capacity, poor compliance, and increased intravesical pressure. a segment of the small or large bowel is conventionally used for augmentation of the bladder. complications of this approach, though, are well known, including excessive left, preoperative voiding cystourethrography. right, postoperative voiding cystourethrography. preoperative postoperative patient age, y operative time, h serum creatinine, mg/dl bladder capacity, ml compliance, ml/cm h2o serum creatinine, mg/dl bladder capacity, ml compliance, ml/cm h2o 1 18 3.0 2.3 100 4.5 1.2 290 29.0 2 22 2.5 2.4 90 4.5 1.6 340 22.6 3 21 2.5 2.7 110 4.0 1.9 360 21.1 characteristics of patients before and after augmentation ureterocystoplasty retroperitoneal ureterocyctoplasty—zargar-shoshtari et al urology journal vol 5 no 2 spring 2008 125 mucus formation, calculus formation, dysplasia and malignancy, metabolic acidosis, and abnormalities of calcium metabolism. using the stomach can also lead to hematuria, dysuria, metabolic alkalosis, and hypergastrinemia.(9,10) several other techniques have been suggested to produce a urothelial-lined reservoir; however, none of them has gained worldwide acceptance. urothelial grafting onto denuded bowel muscle, auto-augmentation, diverticulocystoplasty, and demucosalized enterocystoplasty are either not attempted in human or not appropriate enough to be applied in all patients.(7) in contrast, bladder augmentation with the ureter provides a urothelial-lined reservoir with the appropriate histological layers. it seems that ureterocystoplasty is an ideal option for patients with appropriately enlarged ureters. completely extraperitoneal ureterocystoplasty is a recently introduced technique that has several additional benefits. the risk of ventriculoperitoneal shunt infection and adhesive bowel obstruction are reduced by this method, because the integrity of the peritoneal cavity can be maintained. taking the patient-oriented viewpoint into consideration, extraperitoneal approach is accompanied by less postoperative pain and better cosmetic results.(7) previously, ureterocystoplasty had been used only at the time of concurrent nephrectomy, because it was thought that an adequate bladder volume can be achieved only by the use of both the renal pelvis and the megaureter.(11) however, recent studies have shown that the lower two-thirds of a dilated ureter can provide the desired bladder capacity, so that the ipsilateral kidney can be preserved by forming a transureteroureterostomy.(4) also, the lower two-thirds of the divided ureter can be used for bladder augmentation and the transected upper ureter replanted into the bladder, using the lower ureter for augmentation. indeed, both ureters can be used simultaneously, with one to enlarge the bladder and the other to form a continent diversion stoma.(12) we used the distal one-thirds of both ureters for augmentation and reimplanted both into the bladder, separately. a midline incision and transperitoneal approach to the kidney has been advocated if preservation of the kidney and transuretero-ureterostomy is planned.(7) we used the plane between the peritoneum and the great vessels, enabling access to the both ureters. therefore, we enjoyed the benefits of the extraperitoneal approach, too. we believe that the early results of ureterocystoplasty are comparable with those of enterocystoplasty, while the risks of longterm metabolic and neoplastic complications are prevented. division of the ureter and use of its distal part for augmentation is always possible. we can conclude that augmentation ureterocystoplasty performed this way can be done more frequently. conflict of interest none declared. references 1. duel bp, gonzalez r, barthold js. alternative techniques for augmentation cystoplasty. j urol. 1998;159:998-1005. 2. churchill bm, aliabadi h, landau eh, et al. ureteral bladder augmentation. j urol. 1993;150:716-20. 3. cilento bg, jr., diamond da, yeung ck, manzoni g, poppas dp, hensle tw. laparoscopically assisted ureterocystoplasty. bju int. 2003;91:525-7. 4. gosalbez r, jr., kim co, jr. ureterocystoplasty with preservation of ipsilateral renal function. j pediatr surg. 1996;31:970-5. 5. paquin aj jr. ureterovesical anastomosis: the description and evaluation of a technique. j urol. 1959;82:573-83. 6. eckstein hb, martin mrr. uretero-cystoplastik. acta urol. 1973;4:255-7. 7. dewan pa, anderson p. ureterocystoplasty: the latest developments. bju int. 2001;88:744-51. 8. dewan pa, nicholls ea, goh dw. ureterocystoplasty: an extraperitoneal, urothelial bladder augmentation technique. eur urol. 1994;26:85-9. 9. nguyen dh, bain ma, salmonson kl, ganesan gs, burns mw, mitchell me. the syndrome of dysuria and hematuria in pediatric urinary reconstruction with stomach. j urol. 1993;150:707-9. 10. gosalbez r, jr., woodard jr, broecker bh, warshaw b. metabolic complications of the use of stomach for urinary reconstruction. j urol. 1993;150:710-2. 11. churchill bm, jayanthi vr, landau eh, mclorie ga, khoury ae. ureterocystoplasty: importance of the proximal blood supply. j urol. 1995;154:197-8. 12. ahmed s, neel kf, sen s. tandem ureterocystoplasty. aust n z j surg. 1998;68:203-5. female urology 35urology journal vol 7 no 1 winter 2010 urogenital fistulas in women 5-year experience at a single center onkar singh, shilpi singh gupta, raj kumar mathur introduction: urogenital fistula is one of the most devastating complications that can result from labor or urogenital surgeries. it is still a frequent problem in the developing world. urogenital fistulas can lead to devastating medical, social, and psychological problems; thus cause major impact on the lives of girls and women. however, these cases are still largely neglected in the developing world. we aimed to evaluate causative factors and discuss management of urogenital fistulas. materials and methods: forty-two cases of urogenital fistula developing within 5 to 38 days after delivery, pelvic surgery, and obstetric procedures were treated over a period of 5 years from 2003 to 2008. these included 37 vesicovaginal fistulas (88.1%), 4 uterovesical fistulas (9.5%), and 1 pure ureterovaginal fistula (2.4%). all of the patients were catheterized immediately on presentation and the catheter was left in situ for a minimum of 3 weeks before surgical intervention. results: the most common cause of vesicovaginal fistulas was obstructed labor, while other varieties of fistulas were mostly associated with pelvic surgery. spontaneous closure occurred in 3 cases of vesicovaginal fistula. surgical intervention needed in 39 patients. peritoneal flap and martius flap were interposed between suture lines in transabdominal and transvaginal approaches, respectively. thirty-four fistulas (80.1%) were closed at the first attempt. there was no mortality from the surgical procedure. conclusion: vasicovaginal fistula is the most common urogenital fistula. obstructed labor and its complications are still the leading cause of its development. peritoneal flap interposition technique is a successful and effective treatment method for urogenital fistula. urol j. 2010;7:35-9. www.uj.unrc.ir keywords: urinary fistulas, vesicovaginal fistula, female urogenital diseases department of surgery, mgm medical college and my hospital, indore, india corresponding author: onkar singh, ms department of surgery, mgm medical college and my hospital, indore, india, 452001 tel: +91 98 9377 7321 e-mail: dronkarsingh@gmail.com received april 2009 accepted november 2009 introduction “in an unequal world, these women are the most unequal among unequals.(1)” the misfortune that may lead a woman to the development of a urogenital fistula (ugf) has remained one of the difficult challenges to surgical therapy for centuries. fistulas are perhaps the most distressing and feared complications of gynecologic and obstetric procedures.(2) whereas in former years this pitiful condition resulted from obstetrical methods, it is rarely seen after childbirth in countries where modern concepts of obstetrical practice are applied. the principal cause in developed countries has come to be trauma due to gynecological surgeries, chiefly hysterectomy. however, concerning parts of the world which are still in developing urogenital fistulas—singh et al 36 urology journal vol 7 no 1 winter 2010 phase, difficult labor has not left its place as the most common reason for the most frequent type of ugf, ie, vesicovaginal fistula (vvf). the objective of this study was to review our experience in the management of these ugfs over a 5-year period (may 2002 to may 2007), with an emphasis on causes, means of treatment, and outcomes. materials and methods a total of 42 cases of ugf were treated in our hospital between may 2002 and may 2007, including 29 referred cases from other hospitals. among the patients referred from other centers, 6 had already undergone at least one failed surgical intervention for vvf. the mean age of our patients was 28 years (range, 18 to 68 years). all medical records were reviewed, and the etiology of fistula, time of presentation, prior treatment, management, and outcomes were recorded. the follow-up period ranged from 4 to 42 months after discharge from hospital. results the most common variety of ugf was vvf, found in 37 patients (88.1%), and the leading cause of vvf was obstructed labor, which included 22 (59.5%). transabdominal hysterectomy for benign conditions was the second most common cause in 8 patients (21.6%), while vaginal hysterectomy, wertheim radical hysterectomy for malignancy, and laparoscopic hysterectomy were the cause in 4 (10.8%), 2 (5.4%), and 1 (2.7%), respectively (table). associated ureterovaginal fistula was detected in 2 patients with vvf. time for development of vvf due to obstructed labor ranged from 5 to 38 days, while remaining cases of iatrogenic vvf presented with urinary leak within 13 days. eleven among 15 cases of iatrogenic vvf had a history of trauma to the urinary bladder, vaginal stump or ureters during primary surgery. all these injuries were repaired in the same sitting, but fistula still occurred. other than the vvf cases, there were 1 case of pure ureterovaginal fistula following wertheim radical hysterectomy and 4 uterovesical fistulas. of the 4 patients with uterovesical fistulas, 2 had a history of pelvic trauma and 1 had undergone partial cystectomy for bladder tumor. one of the women with uterovesical fistula had been referred from another center after one failed surgical attempt to close the fistula. she underwent fistula repair via transabdominal route, which failed. biopsy of the fistulous tract was reviewed, which came out to be tubercular. she was started on 4-drug antituberculosis therapy and kept catheterized. fistula healed in 6 weeks, and antituberculosis therapy continued for 6 months. diagnostic workup included vaginal examination and cystoscopy in all of the patients, while retrograde cystography was done in 5. intravenous contrast studies were done in all of the 19 patients with a history of surgery (intravenous urography in 16 and computed tomography-intravenous urography in 3), in order to rule out any possible involvement of the ureters. the three-swab test was required in 4 patients to confirm the diagnosis, as cystoscopy and contrast studies could not demonstrate the fistula. initially, antibiotic therapy was started in all of the patients. conservative management with catheterization was successful in 3 patients with vvf, which presented within 7 days after obstructed labor. one spontaneous closure of the fistula was also noted in an undiagnosed tubercular uterovesical fistula, after 2 failed attempts to repair the fistula. in all these cases, the fistula size was less than 1 cm. the foley catheter type and cause of fistula patients (%) vesicovaginal fistula obstructed labor 22 (52.4) transabdomian hysterectomy 7 (16.7) vaginal hysterectomy 4 (9.5) laparoscopic hysterectomy 1 (2.4) radical hysterectomy for malignancy 1 (2.4) vesicovaginal and ureterovaginal fistulas transabdominal hysterectomy 1 (2.4) radical hysterectomy for malignancy 1 (2.4) uterovesical fistula suprapubic resection of blabber tumor 1 (2.4) pelvic trauma 2 (4.8) sponatenous tuberculosis 1 (2.4) ureterovaginal fistula radical hysterectomy for malignancy 1 (2.4) type and frequency of different urogenital fistulas and their causative factors urogenital fistulas—singh et al 37urology journal vol 7 no 1 winter 2010 was kept in situ for a total of 6 weeks. thirty-nine cases (95.1%) were managed surgically, 28 by transabdominal approach and 11 (all of which were vvf) by the transvaginal approach. thus, all ugfs other than vvfs were operated through transabdominal approach. selection of the surgical approach (transabdominal versus transvaginal) in vvfs was made depending on the location and size of the fistula. the transabdominal approach was used in cases where the fistula was located high on the vaginal stump or close to the ureter opening and with more than 2 cm of size. also, all 6 cases which were referred from other centers after failed surgical intervention were managed surgically through transabdominal approach. one patient among these needed 2 surgical repairs. both transvaginal and transabdominal approaches involved complete excision of the fistulous tract. the transvaginal approach also involved labial fat interposition, obtained from one or both sides (martius flap). in all cases of ugf which were repaired via transabdominal approach by the intra-abdominal technique, the peritoneal flap interposition was done. peritoneal flaps were raised, from one or both sides, from the peritoneum overlying the common iliac vessels. there was no mortality following operative procedures. no incontinence was found in any cases after the fistula was repaired. discussion a urogenital fistula is an abnormal opening between the vagina and the urinary bladder (vvf), the vagina and the ureter (ureterovaginal fistula), or the uterus and the bladder (uterovesical fistula), through which urine continually leaks. naturally, ugf makes the patients embarrassed that they are unable to control their bodily functions, that they are constantly soiled and wet, and that they smell. thus, ugfs have a profound effect on the patient’s emotional well-being that results from the social distress because of persistent leakage of urine and feces. this may be further complicated by recurring infections, infertility, and damage to the vaginal tissue that makes sexual activity impossible. the vvf is the most common among ugfs, due to its relationship with various obstetric and gynecologic risk factors. urogenital fistula has remained a hidden condition, because it affects some of the most marginalized members of the population—poor, young, often illiterate girls and women in remote regions of the world. in the developed countries, with the advent of widespread emergency obstetric care, ugfs are rarely seen.(3) however, it is still frequent in the developing world, with the number of new cases annually estimated at 100 000 to 500 000.(4) to point out the exact nature of this problem in the developing countries like india, it is wise to compare incidence rates of these fistulas in the developing countries with those in the developed countries. in the developing world, the true incidence of vvfs is unknown, as many patients with this condition suffer in silence and isolation. in india and pakistan, some 70% to 90% of women with fistula are abandoned or divorced.(5) in the past, obstetric complications like prolonged obstructed labor, coupled with a lack of medical attention, were more common causes of ugf, especially vvf.(1,3,6) in developed countries, with much better obstetric facilities, the causative factors of ugf are mostly associated with gynecologic and pelvic surgery, especially hysterectomy, occurring in 1 in 1800 hysterectomies.(3,5,7) however, prolonged labor still remains a major cause in many underdeveloped countries with a low standard of obstetric care.(2,8) in prolonged labor, the unrelenting pressure of the entrapped fetal head against the mother’s pelvis can cut off the flow of blood to the soft tissues of the bladder, vagina, and rectum. independent of the fetal outcome, prolonged obstructed labor usually leads to sloughing away of the injured pelvic tissue, leaving a fistula between adjacent organs.(9) other rare etiologies of ugfs include urological and gastrointestinal surgery, illegal abortion, cesarean section, and congenital anomalies.(10-12) bai and coworkers reported an overall incidence of 0.33% for urinary tract injury in pelvic surgeries. (13) the bladder is the most common organ to be injured, comprising 76% of the cases. harkki-siren and colleagues reported the urogenital fistulas—singh et al 38 urology journal vol 7 no 1 winter 2010 incidence of vvf formation to be 0.8 in 1000 procedures for all kinds of hysterectomies.(14) in their report of 230 cases of vvf, kochakarn and associates found that more than 70% were caused by hysterectomy.(15) laparoscopic hysterectomy has a higher incidence of urological injury than open surgery.(14) urogenital fistulas other than vvf, are mostly the result of iatrogenic trauma; 4 of 5 cases of ugfs other than vvf among our patients were of nonobstetrical origin. regarding management, the most important factor for successful repair of a fistula is adherence to basic principles, including pre-operative evaluation, adequate exposure of the fistula, good hemostasis, resection of devascularized tissue, excision of surrounding fibrous tissue and removal of foreign body, tension-free closure, and adequate postoperative urinary drainage.(16) our patients were kept catheterized for 14 to 21 days postoperatively. treatment of ugf is surrounded by a number of controversies. the first of those is when to perform the repair, ie, early or late repair, which can be a difficult dilemma for the physician and the patient. according to the literature, it is apparent that there is no consensus as to the definition of late (2 to 4 months) and early (1 to 3 months) repair.(17) experienced surgeons are now operating as soon as the tissues are clean.(18) in our series, repair of fistula was done early, within 3 months. classical opinion of repairing the ugf late, after 3 months, may be more applicable to the iatrogenic ugf, which forms a greater proportion of cases seen in the developed world. moreover, several authors have reported comparable success with early and late surgical repair of iatrogenic ugf.(17,19,20) we found immediate repair to be highly effective in terms of closure and continence, and it prevents progressive downgrading of the patient medically, socially, and mentally. controversies also exist regarding approach and technique of repair. for vvf, transvaginal or transabdominal approach depends on the location of the fistula, relation with the ureteric orifice, and time to repair after fistula formation. (4) many studies have claimed that the transvaginal approach is less invasive than the transabdominal procedure.(21) in our institute, we prefer the vaginal approach when the fistula is low and easily approached vaginally. advantages include lesser blood loss, low complication rate, shorter hospital stay, and early resumption of routine activities. the transabdominal approach is selected in cases where the fistula is high lying and cannot be adequately visualized vaginally, is close to the ureteral orifice, or is a large complex fistula. there are various internationally recognized techniques for fistula repair. the specific method used usually depends on the surgeon’s preferences and the nature of the fistula. successful repair of ugf, especially complex and recurring, necessitates the use of adjunctive measures. (22) these include placement or interposition of some local tissue or graft between the two structures connected by the fistula, after complete excision of the fistula. labial fat pad (martius flap) interposition is a well-known technique performed via transvaginal approach. via transabdominal and intraperitoneal approach, many tissues have been interposed in repair of vvf and other ugfs, including the omentum, peritoneal flap, gracilis muscle, bladder wall flap, or appendix epiploica.(23) the omentum and peritoneal flaps are easy to mobilize and thus are commonly used. khawaja and colleagues found the peritoneum to be equally good as the omentum for the use as interposing tissue in repair of vvf, with a comparable complication rate.(24) our experience also supports khawaja and associates’ observations. also, suture can be applied in such a manner, so that minimum lengths of suture lines come in contact. this can be done by closing the bladder opening vertically and the vaginal opening horizontally in cases of vvf. closing the vaginal opening transversally will also prevent or at least cause minimal vaginal stenosis. this can be followed in other ugfs wherever possible. conclusion large numbers of ugfs have an obstetric origin, and are caused by prolonged obstructed labor and its complications. early repair after clearing the infection is very effective and avoids extra sociomedical and mental trauma. the use of some urogenital fistulas—singh et al 39urology journal vol 7 no 1 winter 2010 interposing tissue is highly recommended. when the basic principles of fistula repairs are adhered to, peritoneal flap repair is successful and very effective. conflict of interest none declared. references 1. zacharin rf. a history of obstetric vesicovaginal fistula. aust n z j surg. 2000;70:851-4. 2. hilton p, ward a. epidemiological and surgical aspects of urogenital fistulae: a review of 25 years’ experience in southeast nigeria. int urogynecol j pelvic floor dysfunct. 1998;9:189-94. 3. kochakarn w, pummangura w. a new dimension in vesicovaginal fistula management: an 8-year experience at ramathibodi hospital. asian j surg. 2007;30:267-71. 4. danso ka, martey jo, wall ll, elkins te. the epidemiology of genitourinary fistulae in kumasi, ghana, 1977-1992. int urogynecol j pelvic floor dysfunct. 1996;7:117-20. 5. cottingham j, royston e. obstetric fistula: a review of available information. geneva: world health organization; 1991. 6. creanga aa, genadry rr. obstetric fistulas: a clinical review. int j gynaecol obstet. 2007;99 suppl 1:s40-6. 7. kumar s, kekre ns, gopalakrishnan g. vesicovaginal fistula: an update. indian j urol. 2007;23:187-91. 8. lawson j. tropical obstetrics and gynaecology. 3. vesico-vaginal fistula--a tropical disease. trans r soc trop med hyg. 1989;83:454-6. 9. wall ll. dead mothers and injured wives: the social context of maternal morbidity and mortality among the hausa of northern nigeria. stud fam plann. 1998;29:341-59. 10. puri m, goyal u, jain s, pasrija s. a rare case of vesicovaginal fistula following illegal abortion. indian j med sci. 2005;59:30-1. 11. ba-thike k, than a, nan o. tuberculous vesicovaginal fistula. int j gynaecol obstet. 1992;37:127-30. 12. dolan lm, easwaran sp, hilton p. congenital vesicovaginal fistula in association with hypoplastic kidney and uterus didelphys. urology. 2004;63:175-7. 13. bai sw, huh eh, jung da j, et al. urinary tract injuries during pelvic surgery: incidence rates and predisposing factors. int urogynecol j pelvic floor dysfunct. 2006;17:360-4. 14. harkki-siren p, sjoberg j, tiitinen a. urinary tract injuries after hysterectomy. obstet gynecol. 1998;92:113-8. 15. kochakarn w, ratana-olarn k, viseshsindh v, muangman v, gojaseni p. vesico-vaginal fistula: experience of 230 cases. j med assoc thai. 2000;83:1129-32. 16. ayed m, el atat r, hassine lb, sfaxi m, chebil m, zmerli s. prognostic factors of recurrence after vesicovaginal fistula repair. int j urol. 2006;13:345-9. 17. blaivas jg, heritz dm, romanzi lj. early versus late repair of vesicovaginal fistulas: vaginal and abdominal approaches. j urol. 1995;153:1110-2; discussion 2-3. 18. waaldijk k. the immediate surgical management of fresh obstetric fistulas with catheter and/or early closure. int j gynaecol obstet. 1994;45:11-6. 19. blandy jp, badenoch df, fowler cg, jenkins bj, thomas nw. early repair of iatrogenic injury to the ureter or bladder after gynecological surgery. j urol. 1991;146:761-5. 20. cruikshank sh. early closure of posthysterectomy vesicovaginal fistulas. south med j. 1988;81:1525-8. 21. dupont mc, raz s. vaginal approach to vesicovaginal fistula repair. urology. 1996;48:7-9. 22. punekar sv, prem ar, kelkar ar, ridhorkar vr. repair of complex vesicovaginal fistulas using peritoneal flap interposition: a different design. indian j urol. 1997;14:24-8. 23. gerber gs, schoenberg hw. female urinary tract fistulas. j urol. 1993;149:229-36. 24. khawaja aa, ahmed r, anjum r. role of peritoneum as interposition tissue in the management of vesicovaginal fistula. j surg pak. 2005; 10:2-4. u j 03 all-2.pdf 617vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l department of urology, brighton and sussex university hospitals nhs trust, the royal sussex county hospital, brighton bn2 5be, united kingdom shawket w alkhayal, fahad a rizvi clinical features and management of methicillin-resistant staphylococcus aureus cystitis corresponding author: fahad rizvi, md department of urology, sussex house, royal sussex county hospital, abbey road, brighton, bn2 5be, uk tel: +44 127 369 6955 e-mail: fahadrizvi@doctors .org.uk received october 2010 accepted october 2010 case report keywords: methicillin-resistant staphylococcus aureus, cystitis introduction since its initial detection in europe in 1960, methicillin-resistant staphylococcus aureus -lin-resistance acquisition and spread are major health care concern. (1,2) (3,4) invasive.(5) case report case 1 complained of suprapubic discomfort, increased frequency of micturition, and dysuria. 618 | outs. this cleared up her mrsa from the bladder, but she case 2 toselective vaporization of his prostate for symptomatic bea large trabeculated bladder and a large occlusive prostate mucosa and an ulcerated necrotic area seen at the bladder a repeat cystoscopy 5 months later revealed a tight scarred serted at later date to treat his incontinence. discussion staphylococcus aureus is responsible for a variety of infecmation and destruction. these range from relatively benign threatening conditions that can affect almost every organ system in the body, including the urinary tract.(6) this bacterium can produce more than 20 different toxins, including cytotox(7) bladders and incontinence that necessitated urinary diverproper antibiotics against mrsa could have prevented this that both patients acquired the infection from hospital as both virus infection, alcohol abusers, and diabetic patients, have tion than the normal population. less frequent predisposing factors encompass chemotactic defects and defects in phagocytosis. dently adds to these predisposing conditions is chronic staphylococcus aureus carriage.(9,10) recent hospitalization for acquiring urinary tract infections. therefore, prevention of this infection in hospitalized patients by changing and immethicillin-resistant staphylococcus aureus cystitis is rare, case report 619vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l mrsa cystitis | alkhayal and rizvi nous vancomycin or linezolid should be initiated to treat the infection and prevent further complications. conflict of interest none declared. references 1. bass je, redwine md, kramer la, huynh pt, harris jh, jr. spectrum of congenital anomalies of the inferior vena cava: cross-sectional imaging findings. radiographics. 2000;20:639-52. 2. gorak ej, yamada sm, brown jd. community-acquired methicillin-resistant staphylococcus aureus in hospitalized adults and children without known risk factors. clin infect dis. 1999;29:797-800. 3. ito t, okuma k, ma xx, yuzawa h, hiramatsu k. insights on antibiotic resistance of staphylococcus aureus from its whole genome: genomic island scc. drug resist updat. 2003;6:41-52. 4. ma xx, ito t, tiensasitorn c, et al. novel type of staphylococcal cassette chromosome mec identified in community-acquired methicillin-resistant staphylococcus aureus strains. antimicrob agents chemother. 2002;46:1147-52. 5. salgado cd, farr bm, calfee dp. community-acquired methicillin-resistant staphylococcus aureus: a meta-analysis of prevalence and risk factors. clin infect dis. 2003;36:131-9. 6. diekema dj, pfaller ma, schmitz fj, et al. survey of infections due to staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the united states, canada, latin america, europe, and the western pacific region for the sentry antimicrobial surveillance program, 1997-1999. clin infect dis. 2001;32 suppl 2:s114-32. 7. lina g, piemont y, godail-gamot f, et al. involvement of panton-valentine leukocidin-producing staphylococcus aureus in primary skin infections and pneumonia. clin infect dis. 1999;29:1128-32. 8. laupland kb, church dl, mucenski m, sutherland lr, davies hd. population-based study of the epidemiology of and the risk factors for invasive staphylococcus aureus infections. j infect dis. 2003;187:1452-9. 9. kluytmans j, van belkum a, verbrugh h. nasal carriage of staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. clin microbiol rev. 1997;10:50520. 10. chiang fy, climo m. staphylococcus aureus carriage and health care-acquired infection. curr infect dis rep. 2002;4:498-504. v08_no_4_final_new.pdf reconstructive surgery 307urology journal vol 8 no 4 autumn 2011 one-stage transperineal repair of pan-urethral stricture with dorsally placed buccal mucosal grafts results, complications, and surgical technique kamyar tavakkoli tabassi,1 ehsan mansourian,2 aliasghar yarmohamadi2 purpose: to report the surgical details and results of one-stage transperineal urethroplasty using dorsal buccal mucosal graft (bmg) in treatment of panurethral stricture. materials and methods: this cohort study was carried out on 17 men with pan-urethral stricture who underwent one-stage transperineal bmg urethroplasty. failure was defined as a need to any intervention during the follow-up period. results: the etiology of stricture was trauma in 4 (23.5%), sexually transmitted diseases in 4 (23.5%), lichen sclerosus in 2 (11.8%), and idiopathic in 7 (41.1%) patients. the mean follow-up period was 8.5 months (range, 3 to 18 months). six (35.3%) patients developed complications; namely wound infection in 2 (11.8%), meatal stenosis in 1 (5.9%), and re-stenosis in 3 (17.6%) (2/8) and 44% (4/9), respectively, which did not reach statistically significant difference (p = .6). the final success rate was 88.2%. none of the patients needed open redo-urethroplasty during the follow-up period. conclusion: reconstruction of pan-urethral strictures may be safely and effectively performed at a simple single operative procedure using a transperineal approach with combinations of dorsal bmg. urol j. 2011;8:307-12. www.uj.unrc.ir keywords: urethra, urethral stricture, urologic surgical procedures, mouth mucosa, tissue and organ harvesting 1department of reconstructive urology, mashhad university of medical sciences, mashhad, iran 2department of urology, mashhad university of medical sciences, mashhad, iran corresponding author: aliasghar yarmohamadi, md department of urology, mashhad university of medical science, mashhad, iran tel: +98 511 854 3031 fax: +98 511 859 1057 e-mail: yarmohamadiaa@mums.ac.ir received june 2010 accepted august 2010 introduction short strictures are most commonly caused by trauma; while in developing countries, sexually transmitted diseases remain an important cause of long urethral strictures.(1) lichen sclerosus, in which external genitalia (the glans of penis and prepuce) is involved, may be accompanied with long urethral strictures as well.(2) different treatments have been described for urethral strictures, including simple dilatation, internal urethrotomy, scar excision, and end-to-end anastomosis. these are all appropriate procedures for short strictures,(3,4) while management of long anterior urethral strictures, especially pan-urethral strictures, still remains a great challenge for urologists. the two-stage urethra-plasties, such as johanson urethroplasty with or without use of free graft, are the conventional techniques used for the treatment of long anterior urethral strictures.(3,4) furthermore, several one-stage techniques using grafts and different flaps have been described for the treatment of this condition.(3) here, we present the results and also surgical details of one-stage transperineal pan-urethral stricture treatment—tavakkoli tabassi et al 308 urology journal vol 8 no 4 autumn 2011 urethroplasty using buccal mucosal graft (bmg) and its outcomes in the treatment of pan-urethral strictures. materials and methods study population this cohort study was carried out on 17 men with pan-urethral stricture (stricture beginning from the proximal of the bulb to the distal of the penile urethra), who underwent one-stage transperineal bmg urethroplasty from december 2006 to december 2009. pre-operative studies included retrograde urethrography, voiding cystography, and urethoscopy. all of the patients underwent onestage transperineal repair of pan-urethral stricture with dorsally placed bmg. follow-up visits were scheduled every 3 months for the first year, every 6 months thereafter, and whenever the patients had a problem. we called the patients if they did not show up for the follow-up. during each follow-up visit, a careful history taking, physical examination, and urine analysis and culture were performed. cystoscopy was done at the end of the third months. if there were symptoms, such as poor urine flow rate, retrograde urethrography was done to rule out a stricture. failure was defined as a need to any intervention during the follow-up period. complications were defined as wound infections, development of meatal stenosis, urethrocutaneous fistula formation, recurrent stricture, erectile dysfunction, penile cordee or deformity, urethral diverticula formation, urinary incontinence or other urinary dysfunctions, lower limb complications due to lithotomy position, and buccal donor site complications. surgical technique patients were placed in lithotomy position under general anesthesia.to prevent injury to lower limbs, they were covered with soft pad. a circumcisional incision was made and the penis was degloved under the dartos fascia. midline of the perinea was incised and the penis was brought to the perineal incision (figure 1). the corpus spongiosum, from beginning at the glans of penis to the sphincter, was separated from the corpora cavernosa with special concern not to traumatize distal blood supply of the corpus spongiosum (the connection between corpus spongiosum and glans penis) (figure 2). a longitudinal incision was made on the dorsal aspect of the urethral stricture (figure 3). a maximal length of the buccal graft, with about 1.5 to 2 cm width, was harvested from each cheek. because of long stricture in 5 patients, we were obligated to extend the graft to the inner mucous of the lower lip in one side for getting 4 to 5 cm more length. after harvesting graft from the cheek, the buccal incision was repaired with 4-0 chromic sutures, but the place of the graft harvesting on the lower lip was left unsutured. after harvesting, grafts were thinned and placed on the dorsal aspect of the urethra, and fixed to the tunica albuginea of the corpora cavernosa by applying several sutures using 5-0 vicryl sutures to prevent dead spaces (figure 4). thereafter, a deep incision was made on the dorsal aspect of the glans (dorsal meatotomy), the graft was advanced on it, and fixed to prevent future meatal stenosis. the urethra was retubularized by suturing figure 1. the penis was brought to the perineal incision pan-urethral stricture treatment—tavakkoli tabassi et al 309urology journal vol 8 no 4 autumn 2011 the edges of incisioned urethra to the rims of the buccal graft over an 18f silicon catheter (figure 5). the penis was replaced in normal anatomy. after placing a drain, the perinea was closed in anatomic layers. the penile skin was placed back in circumsional position. the patients remained bed rest with limited activity for 48 to 72 hours. the perineal pressure dressing was changed after 48 hours and the drain was removed after 2 to 3 days. the patient was discharged on the 5th to 7th postoperative days. the urethral catheter was kept for 21 days. at the end of the 3rd week, retrograde urethrography was figure 2. separation of the corpus spongiosum from the corpora cavernosa figure 3. longitudinal incision on the dorsal aspect of the urethral stricture figure 4. buccal mucosal graft in place figure 5. tubularization of the urethra pan-urethral stricture treatment—tavakkoli tabassi et al 310 urology journal vol 8 no 4 autumn 2011 performed (figure 6). if extravasation was present, which occurred only in 1 patient, the urethral catheter was remained for another 14 days, if not, the catheter was removed at that time. statistical analysis the data were analyzed using spss software (the statistical package for the social sciences, version 11.0, spss inc., chicago, illinois, usa) with chi-square test. p values less than .05 were considered statistically significant. we analyzed the relationship between complication rate and age, history of previous surgery, and etiology of stricture. results the mean age of the patients was 43 years (range, 23 to 68 years). the mean stricture length was 20.7 ± 4.6 cm. the etiology of stricture was trauma in 4 (23.5%), sexually transmitted diseases in 4 (23.5%), lichen sclerosus in 2 (11.8%), and idiopathic in 7 (41.1%) patients. four subjects had a history of previous urethrotomy, 4 had urethral dilatation, and 1 had open urethroplasty. the mean follow-up period was 8.5 months (range, 3 to 18 months). six (35.3%) patients developed complications; wound infection in 2 (11.8%), meatal stenosis in 1 (5.9%), and re-stenosis in 3 (17.6%) subjects. no scrotal hematoma was noted. re-stenosis was ring-shaped at the site of the attachment of bmg, which was treated by simple urethral dilatation in 2 and by internal urethrotomy in another patient, three months after the primary reconstructive surgery. neither of these patients had restenosis again during the follow-up period. in one patient, wound infection was associated with circumcisional dehiscence, which did not respond to antibiotic therapy and needed surgical debridement. meatal stenosis was treated by simple dilatation. five patients suffered from lower limbs pain during the first 24 to 48 hours after the surgery because of lithotomy position; but severe injuries were not seen. other complications, such as erectile dysfunction, penile cordee or deformity, urinary incontinence, urethral diverticula formation, or other urinary dysfunctions were not seen in any patient. years was 25% (2/8) and 44% (4/9), respectively; there was not a statistically significant difference (p = .6). the primary etiology of pan-urethral stricture and history of previous surgery for stricture did not predict postoperative complication rate. the discomfort at the buccal donor site was mild in all of our subjects in the first 1 to 2 days after the operation, and normal diet was started on the 2nd postoperative day. furthermore, there were no aesthetic or functional complications at the oral donor site during the follow-up period. the ultimate success rate was 88.2%. none of the patients needed open redo-urethroplasty during the follow-up period. figure 6. retrograde urethrography before (a) and after (b) the operation a b pan-urethral stricture treatment—tavakkoli tabassi et al 311urology journal vol 8 no 4 autumn 2011 discussion management of pan-urethral strictures is challenging for urologists. several different surgical methods have been described for treatment of urethral strictures, to increase success rate and avoid the stepped procedures. the selected surgical technique depends mainly on the stricture length, but the stricture etiology should be considered as well.(5) formal perineal urethrostomy is a reasonable option for patients who are not good candidate for surgical treatments. several techniques were introduced for urethral reconstruction, using different free grafts and flaps. the traditional two-stage urethroplasties, including johanson and scrotal or penile skin grafts, are used for treatment of complex and extremely narrow pan-urethral strictures or strictures associated with local adverse conditions, such as fistula, abscess, or tumor.(5,6) joseph and colleagues suggested that re-stenosis may occur due to local factors, such as poor tissue condition and compromised blood supply in multi-stage procedures.(7) in 1968, orandi, a new surgical technique was introduced for the repair of urethral strictures, which was a one-stage urethroplasty technique, using the principles of pedicled skin grafting.(8) over time, quartey popularized a new and original one-stage flap urethroplasty, based on orandi’s original suggestions.(9) another recent technique, which is used more frequently and has been the gold standard in the past decade, is using bmg in urethral surgery for hypospadias and urethral strictures.(6) the oral mucosa is architecturally similar to the squamous epithelium of the penile and glanular urethra, making it a suitable subtitute material for the urethra.(5) buccal mucosal graft has several advantages over other grafts. the tissue is tough and resilient, compatible with wet environment, and has a thick epithelium, high potential of tensile strength, rapid healing time, and a higher density of elastic fibers in comparison with the skin. therefore, it provides better revascularization and inosculation.(10-12) furthermore, the process of harvesting is simple and does not create a visible donor site scar.(10) additionally, the tendency of fluid collection, hematoma formation, and lifting the graft from the bed as the result of shear forces can be decreased by quilting of bmg well onto its bed.(11) in 1996, morey and mcaninch described the ventral onlay bmg urethroplasty, and barbagli and colleagues described the dorsal free graft urethroplasty.(13,14) ventral bmg accompanies better visualization of stricture, but carries risk for urethral diverticulum formation while dorsal placement of bmg provides better mechanical support and blood supply to the graft.(6) in 2005, barbagli and associates showed the same success rates (83% to 85%) for using bmg that was placed on the ventral, dorsal, or lateral suface of the urethra; mentioning that the surgical technique does not affect the outcome.(15) on the other hand, patterson and chapple reported that in experienced hands, the outcomes of both dorsal and ventral onlay grafts in bulbar urethroplasty are similar. however, the dorsal onlay technique is less dependent on surgical expertise and therefore is more suitable for surgeons new to the practice of urethroplasty. in general, ventral onlay of bmg and tube graft procedures in the management of penile strictures are associated with much higher rates of recurrence and should therefore be avoided.(16) in our technique, the bmg was placed dorsally to reduce the complication rate. no urethral diverticulum or fistula occurred in our patients. in the study by barbagli and colleagues, the success rate was higher in patients who underwent prior urethroplasty (88.9% versus 88.7%) and there was no relationship between age and success rate. they suggested that one-stage urethroplasty should not be withheld due to the patients’ age.(5) in our study, the success rate was 88.2%, which is comparable with other methods. furthermore, complication rate was higher in older age group, but success rate was the same in older and younger groups of patients. mild lower extremity complications resulting from extended time in the high lithotomy position may occur in 10% of patients, which are time-related.(17) in our study, lower extremity pain occurred in 5 (29.5%) patients, but no severe complication occurred. by decreasing time in the pan-urethral stricture treatment—tavakkoli tabassi et al 312 urology journal vol 8 no 4 autumn 2011 high lithotomy position, related complications may be eliminated. dubey and coworkers reported excellent results in one-stage dorsal onlay buccal mucosal urethroplasty for balanitis xerotica obliteransrelated strictures.(18) langston and associates reported reconstruction of synchronous urethral strictures by scrotal disassembly maneuver. in this technique, the scrotum was completely bisected in midline down to the deep perineum.(19) in this study, by degloving the penis and bringing it to the perineum, anterior urethra was accessible to repair in one stage and there was no need to incise the scrotum. this technique is easy to perform with satisfactory results and low complication rate. the advantages of onestage transperineal urethroplasty method are as follows: a single-stage procedure, no need for incision of the scrotum, direct visualization of the stricture segment, low postoperative resticture rate, no postoperative cordee formation, and low possibility of scare formation in the skin. although a long-term follow-up period was unavailable for all the patients in the present study, the results are expected to be similar to those of other extensive urethral reconstruction procedures. conclusion reconstruction of pan-urethral strictures may be effectively performed in a single operative procedure using a transperineal approach with combinations of dorsal bmg. the results are comparable tothose of published series using the dorsal bmg through the standard dorsal twostage urethroplasties, in which there is a good and direct exposure of the stricture segment. conflict of interest none declared. references 1. lumen n, hoebeke p, willemsen p, de troyer b, pieters r, oosterlinck w. etiology of urethral stricture disease in the 21st century. j urol. 2009;182:983-7. 2. barbagli g, palminteri e, balo s, et al. lichen sclerosus of the male genitalia and urethral stricture diseases. urol int. 2004;73:1-5. 3. berglund rk, angermeier kw. combined buccal mucosa graft and genital skin flap for reconstruction of extensive anterior urethral strictures. urology. 2006;68:707-10; discussion 10. 4. kumar mr, himanshu a, sudarshan o. technique of anterior urethroplasty using the tunica albuginea of the corpora cavernosa. asian j surg. 2008;31:134-9. 5. barbagli g, guazzoni g, lazzeri m. one-stage bulbar urethroplasty: retrospective analysis of the results in 375 patients. eur urol. 2008;53:828-33. 6. pisapati vl, paturi s, bethu s, et al. dorsal buccal mucosal graft urethroplasty for anterior urethral stricture by asopa technique. eur urol. 2009;56:201-5. 7. joseph jv, andrich de, leach cj, mundy ar. urethroplasty for refractory anterior urethral stricture. j urol. 2002;167:127-9. 8. orandi a. one-stage urethroplasty. br j urol. 1968;40:717-9. 9. quartey jk. one-stage penile/preputial cutaneous island flap urethroplasty for urethral stricture: a preliminary report. j urol. 1983;129:284-7. 10. dessanti a, iannuccelli m, ginesu g, feo c. reconstruction of hypospadias and epispadias with buccal mucosa free graft as primary surgery: more than 10 years of experience. j urol. 2003;170:1600-2. 11. snodgrass w, elmore j. initial experience with staged buccal graft (bracka) hypospadias reoperations. j urol. 2004;172:1720-4; discussion 4. 12. yerkes eb, adams mc, miller da, pope jct, rink rc, brock jw, 3rd. y-to-i wrap: use of the distal spongiosum for hypospadias repair. j urol. 2000;163:1536-8; discussion 8-9. 13. morey af, mcaninch jw. when and how to use buccal mucosal grafts in adult bulbar urethroplasty. urology. 1996;48:194-8. 14. barbagli g, selli c, tosto a, palminteri e. dorsal free graft urethroplasty. j urol. 1996;155:123-6. 15. barbagli g, palminteri e, guazzoni g, montorsi f, turini d, lazzeri m. bulbar urethroplasty using buccal mucosa grafts placed on the ventral, dorsal or lateral surface of the urethra: are results affected by the surgical technique? j urol. 2005;174:955-7; discussion 7-8. 16. patterson jm, chapple cr. surgical techniques in substitution urethroplasty using buccal mucosa for the treatment of anterior urethral strictures. eur urol. 2008;53:1162-71. 17. anema jg, morey af, mcaninch jw, mario la, wessells h. complications related to the high lithotomy position during urethral reconstruction. j urol. 2000;164:360-3. 18. dubey d, sehgal a, srivastava a, mandhani a, kapoor r, kumar a. buccal mucosal urethroplasty for balanitis xerotica obliterans related urethral strictures: the outcome of 1 and 2-stage techniques. j urol. 2005;173:463-6. 19. langston jp, robson ch, rice kr, evans la, morey af. synchronous urethral stricture reconstruction via 1-stage ascending approach: rationale and results. j urol. 2009;181:2161-5. v08_no_2_final.pdf case report 163urology journal vol 8 no 2 spring 2011 accidental rupture of hydrocele a case report viroj wiwanitkit urol j. 2011;8:163-4. www.uj.unrc.ir keywords: testicular hydrocele, rupture, cysts wiwanitkit house, bangkhae, bangkok, thailand corresponding author: viroj wiwanitkit, md wiwanitkit house, bangkhae, bangkok, 10160, thailand tel: +66 2413 2436 e-mail: wviroj@yahoo.com received october 2009 accepted november 2009 introduction of several male genital tract disorders that present as a mass, hydrocele is a common pathological condition.(1) the easy way to confirm the diagnosis of hydrocele is the translucent test,(2) and surgery is the recommended modality for its management.(1,3) herein, we report a case of hydrocele that is accidentally ruptured, without subsequent serious complication. case report a 24-year-old man presented with accidental rupture of a mass in his genitalia. he noted that the rupture had occurred about 2 hours before. his past history showed that he had been diagnosed with right side hydrocele for about 4 years. he had been suggested to have a surgery for hydrocele, but he refused. the mass in his genitalia was recorded to be about 2 × 2 × 3 cm. ultrasonography confirmed the nature of hydrocele. the patient reported that he had got accidental attack by a big box during his daily work on that day and he had felt sudden pain as well as decreased size of mass in his genitalia. discussion basically, the hydrocele is a benign cystic mass. in this report, the patient had a clear history of attack by a heavy box, which resulted in the sudden rupture of the hydrocele. in this patient, the indication for surgical management had been already reached before, but the patient refused the surgical procedure. the accidental rupture in this subject led to a sudden decrease in size of the mass, which made the patient refer to the physician. indeed, this condition is not common.(4,5) the clinical presentation of hydrocele may be minimal scrotal discomfort, disappearance of turgescence, late ecchymosis, and localized edema in the penis and scrotum.(5) bleeding can also be expected.(6) the ruptured hydrocele can be a serious condition; however, it might be symptomless. this patient was managed conservatively and there was no serious complication. however, the ruptured hydrocele without any serious complication is very rare. conflict of interest none declared. references 1. ounaies a, halila m, saadani h, el kamel r, jemni m. [abdominoscrotal hydrocele]. ann urol (paris). 2001;35:240-2. 2. junnila j, lassen p. testicular accidental rupture of hydrocele—wiwanitkit 164 urology journal vol 8 no 2 spring 2011 masses. am fam physician. 1998;57:685-92. 3. jordan wp, jr. hydroceles and varicoceles. surg clin north am. 1965;45:1535-46. 4. cuervo pinna c, rodriguez rincon jp, garcia-moreno aa, cabello padial j, murillo mirat j, fernandez de alarcon l. [spontaneous rupture of hydrocele: an unusual complication]. actas urol esp. 1998;22:610-2. 5. quint hj, miller ji, drach gw. rupture of a hydrocele: an unusual event. j urol. 1992;147:1375-7. 6. oeseburg hb. [an unusual cause of testicular hematocele]. ned tijdschr geneeskd. 1976;120: 1739-40. miscellaneous improved long ureteral reconstruction with ileum by longitudinal clipping and mucosal stripping: an animal study hao gu1,#, shulian chen1,#, yubo wu1, lei shen2, yihang luo1, xu li1, houjin huang3*, zeju zhao1** purpose: to investigate the possibility of bridging long ureteral defects by longitudinal clipping and mucosal stripping of the pedicled segment of ileum (cmspi). materials and methods: ten beagle dogs (five males and females aged 2-3 years) were used to model a defect of the entire ureter. an ileal segment was selected, and half of the intestinal segment was longitudinally resected, without mesenteric resection. the intestinal mucosa was removed. then, the ileum was sutured to form a tube connecting the renal pelvis to the bladder. a 5f ureter stent was inserted into the ileum and removed 4 weeks after surgery. intravenous urography (ivu) was used to observe the reconstructed ureters at 6 and 12 weeks after the operation. blood samples were collected before surgery and during each radiological examination to assess electrolyte and renal function. five dogs were randomly euthanized after each ivu. after macroscopic analysis, hematoxylin-eosin (h&e) staining was performed to observe the microscopic changes in the reconstructed ureter. results: all dogs were in good condition after surgery. changes in blood electrolyte and renal function after surgery were not significant. ivu demonstrated no ureteral obstruction or extravasation of the contrast agent; however, mild hydronephrosis were observed in three dogs. macroscopic analysis indicated that the reconstructed ureter was intact without strictures. h&e showed that no mucosal structure was present on the luminal surface. conclusion: cmspi is feasible for bridging long ureteral defects and has shown good efficacy in this preliminary study. keywords: ureteral defect; ureteral reconstruction; ureteral replacement; ileal ureter; reconstructive urology introduction in view of the development of endourologic proce-dures, laparoscopic surgery, and radiation therapy, the incidence of iatrogenic ureteral injury, including long ureteral defect, has increased significantly in the past decades(1). the treatment of severe ureteral defects is a challenge for urologists. therefore, suitable and efficient treatment methods are crucial. ureteral replacement is common when the ureteral defect is longer than 5 cm, especially in cases of full-length ureter defects. the main corrective methods are ileal ureter replacement, autotransplantation, and boari tubularized bladder flap(2). ileal ureter replacement is more common than the other two techniques and is often used as the final solution after the failure of other methods(3,4). ureteral replacement with ileum to correct full-length ureteral defects was first described by schoemaker in 1906 and was later popularized by goodwin et al.(5) in 1956. since then, this technique has improved and has become a useful alternative for reconstructive urology(6). however, the extended use of this technique is 1department of urology, affiliated hospital of zunyi medical university, zunyi, guizhou, p. r. c. 2department of surgical lab, zunyi medical university, zunyi, guizhou, p. r. c. 3department of preventive medicine, zunyi medical university, zunyi, guizhou, p. r. c. **correspondence: department of preventive medicine, zunyi medical university, zunyi, guizhou, 563000, china. tel: +86-183-8503-9532. fax: +86-0851-28608357. e-mail: 1026553087@qq.com. *correspondence: department of urology, affiliated hospital of zunyi medical university, 149 dalian road, zunyi, guizhou, 563000, china. e mail: zhaozeju1969@163.com. received may 2019 & accepted december 2019 limited by surgical complications, including urinary fistula, infection, obstruction, urine reflux, chronic pyelonephritis, electrolyte imbalance, and gradual decline in renal function(7,8). postoperative complications in the ileal ureter are attributable to the large ileum diameter and the presence of the intestinal mucosa. in the past studies which had focused on improvement of ileum ureter and only some complications were addressed(9). to overcome these complications, the traditional technique was modified by using longitudinal clipping and mucosal stripping of the pedicled segment of ileum. this study investigated the feasibility and the initial outcomes of cmspi for reconstructing the full-length ureter in an animal ureteral defect model. materials and methods experimental animals five female and five male healthy adult beagle dogs (aged 2-3 years; weight 10–15 kg) were obtained from the animal experiment center of the third military medical university, china. the level of microbial urology journal/vol 17 no. 2/ march-april 2020/ pp. 198-203. [doi: 10.22037/uj.v0i0.5330] vol 17 no 02 march-april 2020 199 control was standard. surgeries were performed in the surgical laboratory of zunyi medical university. all dogs fasted for 24 hours before undergoing surgery. five dogs were examined at 6 weeks postoperatively and five dogs at 12 weeks postoperatively. materials and equipments surgical bed, shadowless lamp, intestinal resection, and anastomosis bag ( surgical laboratory of zunyi medical university); 3/0 absorbable sutures (huawei brand hy3901 20pcs); 20 ml disposable syringe and 22g disposable indwelling needle (0.9 × 25 mm; condele); 5f double-j ureteral stent tube (huaye medical instruments); metronidazole and ampicillin; specimen fixation (10% formaldehyde); digital radiography machine (shimadzu sonialvision g4); and automatic biochemical analyzer (backman au5821). experimental methods preoperative preparation the dogs were anesthetized with 3% pentobarbital sodium (30 mg/kg) intraperitoneally. hair was removed using a sodium sulfide solution. the dogs were fixed supine. the depth of anesthesia was monitored at a respiratory frequency of 16-20 times/min. femoral venous blood (5 ml) was collected to perform electrolyte and renal function assay. establishing the full-length ureteral defect model a midline abdominal incision was performed. the abdominal cavity was explored to ensure the absence of apparent abnormalities. the left lateral peritoneum was dissected, and the renal pedicle was separated and clamped. after that, the left kidney was removed. then, the right lateral peritoneum was incised. the entire ureter was separated and resected, and the bladder stump was sutured. ileum preparation and mucosal stripping starting at 10 cm proximal to the ileocecal junction, an ileal segment of approximately 10-15 cm in length was sectioned. the stumps of the primary ileum were endto-end anastomosed with 1-0 silk suture in front of the selected ileum to restore ileal continuity, and the mesenteric openning was closed. residues in the selected ileum were washed off with physiological saline. half of the ileum on the contralateral side of the mesentery was clamped with leather forceps and excised, and the remaining half ileum was washed with saline. a 5 ml syringe needle was inserted into the space between the mucosa and the submucosa along the edge. physiological saline was injected into this space to separate the mucosal layer from the submucosal layer, and the mucosal layer was removed. electrocoagulation was used to interrupt bleeding. ureteral reconstruction the pedicled half clipping ileum was sutured into a tubular tract with 3/0 absorbable sutures to serve as the reconstructed ureter, and then a 5f double-j ureteral stent tube was inserted in the tube. the proximal end of the reconstructed ureter was anastomosed to the renal pelvis, and the distal end was anastomosed to the bladder to maintain the direction of intestinal peristalsis. the ureteral stent was fixed to the renal pelvis using 3/0 absorbable sutures to prevent dislocation. the abdominal cavity was checked to confirm the absence of abnormalities. ampicillin 0.5 g and metronidazole 50 ml were injected into the abdominal cavity. the abdominal incision was sutured layer-by-layer. after recovery from anesthesia, the dogs were fasted for 24 hours, but were given water, and then fed normally after enteral feeding. postoperative measurements the dogs’ mental status, food intake, defecation, and emiction were assessed after surgery. a small abdominal incision of approximately 3.0 cm was made at 4 weeks after the operation. the distal end of the double-j stent was located in the bladder and the whole stent was pulled. the bladder wall and abdominal incision were sutured separately. two weeks after removing the double-j stent, all dogs were anesthetized, and venous blood (5 ml) was collected again for analyzing postoperative electrolyte and renal function. five dogs were randomly selected for digital radiography (dr) of the kidney, ureter, and bladder (kub). then intravenous urography (ivu) was performed after injecting iohexol (25 ml) into the lingual vein to perform intravenous urography (ivu). after that, all five dogs were euthanized to assess the morphology of the peritoneum, kidney, and the reconstructed ureter, and obtain tissue specimens. venous blood (5 ml) was collected from the other dogs at12 weeks after surgery, and kub+ivu was performed. after morphological analysis, kidney specimens and the reconstructed ureters were fixed in formalin. this study was performed with the approval of the institutional animal care and use committee of zunyi medical university. all experimental procedures were conducted according to local guidelines on the ethical use of animals and the national institutes of health “guide for the care and use of laboratory animals” (nih publication no. 80-23, revised in 1996). this study did not involve human participants. statistical analysis quantitative data were expressed as means ± standard deviations. the repeated measure anova was used for making comparisons between two groups. data ureteral reconstruction and ileal substitution-gu et al. table 1. electrolyte and renal function before and after ureteral reconstruction (mmol/l) indexa baseline (n=10)b 6 weeks (n=10)c 12 weeks (n=5) f p k+ 4.32 ± 0.72 4.21 ± 0.46 4.39 ± 0.67 0.162 0.851 na+ 145.25 ± 2.02 143.19 ± 5.16 144.88 ± 2.35 0.85 0.441 cl 109.87 ± 2.27 110.97 ± 4.17 111.72 ± 3.94 0.531 0.595 ca+ 2.44 ± 0.20 2.35 ± 0.14 2.43 ± 0.11 0.739 0.489 ur 4.30 ± 1.06 4.10 ± 0.85 4.01± 0.80 0.195 0.824 cr 82.20 ± 11.65 85.3 ± 12.38 82.00 ± 9.77 0.222 0.802 adata are presented as mean ± sd bblood samples were collected before surgery. cblood samples collected at 6 weeks after surgery and five dogs were euthanized after intravenous urography. were analyzed using spss software (spss, inc., chicago, illinois) version 17.0. a p-value < 0.05 was considered statistically significant. results establishment of the model the intraperitoneal injection of 3% pentobarbital sodium (30 mg/kg) achieved a satisfactory anesthetic effect. all surgical procedures were performed by the same urological surgeon using standard protocols (figure 1a). after removing the mucosa from the ileum, the submucosa was dense and smooth and strongly attached to the muscle layer. no significant bleeding occurred. physiological saline (20 ml) was injected into the reconstructed ureter to check for leakage. the diameter of the reconstructed ureter was approximately four times that of the original ureter. intraoperative blood loss was 40-60 ml (average of 50 ml), and operative time was 100-160 min (average of 130 min). blood analysis there were no significant differences in the electrolyte and renal functions of the ten dogs between before and after surgery, and no significant decrease in function between week 6 and week 12 after the operation (table 1). kub and ivu kub and ivu were performed at 6 and 12 weeks after the surgery (figure 2). on the ivu, the kidney was filled with the contrast agent in 5 minutes, the ureter and bladder were filled in 10 minutes. the ureters presented no obstruction or extravasation of the contrast agent. hydronephrosis did not occur in the dogs euthanized at 6 weeks after surgery, however, mild hydronephrosis were observed in three dogs that survived at 12 weeks after surgery. postoperative macroscopic observation of the reconstructed ureters the reconstructed ureters were resected and observed macroscopically (figure 3). there was no significant change in renal volume. the shape of the reconstructed ureters was regular and cylindrical in all dogs. no fistula or scar nodule was observed in the ureters. there was no abnormal hyperplasia or mucous secretion. the ureteral diameter was approximately 10 mm. the shape of the bladder was normal. mild stenosis at the renal pelvis anastomotic site with hydronephrosis was observed in one dog survived at 12 weeks after surgery. hematoxylin-eosin (h&e) staining and microscopic observation figure 1. ileum clipping and removal of the ileal mucosa. (a) half of the ileum on the contralateral side of the mesentery was removed, and the other half of the ileum on the mesenteric side was preserved. (b) a tubular duct was formed after mucosal stripping, and the original ileal stumps were sutured to restore intestinal continuity. figure 2. representative images of intravenous urography (ivu) after surgery. (a) ivu image at 6 weeks postoperatively. (b) ivu image at 12 weeks postoperatively. ureteral reconstruction and ileal substitution-gu et al. miscellaneous 200 vol 17 no 02 march-april 2020 201 the standard ileal segment and the reconstructed ureter specimens were collected and stained with h&e. the structure of the standard ileal wall was intact, and there were several mucous glands. the submucosal and mucosal layers were intact and clear (figure 4a). in contrast, the reconstructed ureter had no mucosal layer, whereas the submucosal and muscle layers were intact. a small amount of inflammatory cell infiltration was observed (figure 4b). discussion long ureteral defect is a challenging condition for urologists when an end-to-end anastomosis is not feasible. currently available methods including boari flap, ileal ureter, and renal autotransplantation(2,10). in clinical practice, ileal substitution is the most used procedure for ureteral defects; nevertheless, urologists have raised concerns about postoperative complications(7,8). the aim of improving ileum ureter replacement is to transport urine from the kidneys to the bladder in the proper lumen with low pressure and decrease electrolyte reabsorption and mucus secretion(11). these objectives can be achieved using several structures, including the appendix, greater omentum, and venous ureters; however, these applications are restricted because of the complexity of these procedures and related postoperative complications(12). based on the traditional method of ileal ureter we constructed cmspi of beagle dogs to substitute the full-length ureter and assess the feasibility and efficacy of this technique. after ureteral reconstruction, all evaluated dogs survived and were in good condition. the filling time of the kidneys and ureter-bladder was adequate, without strictures or leakage of the contrast agent in the urinary tract. the electrolyte and renal function of the dogs after surgery was statistically similar to that at baseline, indicating a satisfactory outcome. one of the strategies used to improve the traditional method of ileal ureter replacement is the yang-monti procedure, which reduces the pressure in the substituted ureter and the diameter of the ureteral lumen. yang (13) described for the first time the transversal tubularization of the ileum for treating bladder carcinoma. monti et al.(14) later described the same technique to form an efferent duct for urinary diversion in dogs, and esmat et al.(15) applied the yang-monti principle to reconfigure ileal segments for ureter substitution. however, a retrospective study found that the major complication was infection caused by integrated intestinal mucosa(16). anatomical defects also need to be considered, and the figure 3. morphological observation of ureter specimens. morphology at 6 weeks (a) and 12 weeks (b) after surgery. the images showed that the reconstructed ureter presented a constant diameter without forming scar nodules and fistulas. the surface of the duct wall was smooth without stenosis. mild hydronephrosis occurred in one specimen with a smooth inner surface of the reconstructed ureter. figure 4. morphological analysis of a normal ileum and the reconstructed ureter wall sections by hematoxylin-eosin staining (×100). (a) the structure of the ileal wall was intact, the mucosal and submucosal layers were clear, and there were several mucous glands in the mucosal layer. (b) the reconstructed ureter did not present a mucosa, but the submucosa and muscle layers were intact. a small amount of inflammatory cell infiltration was found in the interstitium. ureteral reconstruction and ileal substitution-gu et al. retubularization process makes the muscularis move mode of the small intestine uniquely, the inconsistent and variable tension along the duct wall could create lax areas. pouches and leakage could result directly from the formation of a false passage(17). in the modified technique presented in this study, longitudinal clipping can maintain the movement of the muscularis propria and decrease the contractive force of the ileum, reducing the internal pressure of the renal pelvis and ureter. moreover, the intestinal mucosa was completely removed to eliminate its absorptive and secretory functions. after surgery, all dogs survived for 6 weeks, whereas the last euthanized dogs survived for 12 weeks. ivu images confirmed the satisfactory patency of the reconstructed urinary tract. macroscopic observation showed that the inner surface of the constructed ureter was intact and smooth, without strictures or leakage of urine throughout the urinary tract. nevertheless, mild pyelectasis occurred in three of five dogs that survived for 12 weeks postoperatively and one of them had minor stenosis at the renal pelvis anastomotic site. given that cystostomy and the anti-reflux technique were not performed in all the dogs, we believe that reflux hydronephrosis was possibly the primary cause of pyelectasis. the inhibition of intestinal secretion makes the use of the anti-reflux technique feasible in this procedure and ensures that the tube is not blocked by secretions. the effects of anti-reflux techniques on hydronephrosis will be investigated in a follow-up study. ureteral tissue engineering may serve as an alternative approach for decreasing absorption and secretion in the intestinal mucosa. most studies investigating ureteral defects used extracellular matrix(ecm) and synthetic materials; however, the disadvantage of these materials is lack of flexibility and alloimmunization(18). the use of the submucosa of the small intestine (sis) without cellular pre-seeding to construct a tube could solve these problems and expedite the regeneration of the urothelium and smooth muscle(19); however, this technique is limited to treating ureteral defects of less than 5 cm, and fibrosis occurs in some cases(20,21). the complication rates of ureteral tissue engineering can reach 25%(22). the main cause of fibrosis is the lack of effective blood supply. in the procedure described in this study, we removed the ileal mucosa to allow the submucosa to become the inner layer of the reconstructed ureter, and preserved the integrity of the muscularis propria layer and blood supply. during the 12-week study period, there was no sign of mucosal regeneration, and a satisfactory result was achieved without strictures or fibrosis of the submucosal and muscularis layers, which indicates the potential use of the ileal submucosa to replace the ureteral lining. our study focused on investigating the feasibility of longitudinal clipping and mucosa stripping of the pedicled segment of ileum to reconstruct the entire ureter in a beagle dog model. the results showed that cmspi was a novel, feasible, and promising technique for bridging long ureteral defects. the study limitations were the absence of a control group, the small sample size, and the short-term follow-up. moreover, further studies are necessary to assess the effect of anti-reflux techniques and whether the urothelium is regenerated in the inner layer of the reconstructed ureter after a longer period. however, this preliminary study is useful to urologists involved in urinary reconstruction. conclusions cmspi is feasible for replacing the entire ureter and showed good efficacy in this preliminary study. furthermore, this procedure reduces the complications attributable to the large diameter of the ileal tract and mucosa. these initial findings may be helpful to urologists. the anti-reflux technique and whether the urothelium is regenerated will be addressed in the follow-up study. acknowledgement this study was supported by the science and technology department of guizhou province (grant no. 20157501). conflict of interest the authors declare that they have no conflicts of interest. references 1. burks fn, santucci ra. management of iatrogenic ureteral injury. ther adv urol. 2014; 6:115-124. 2. li y, li c, yang s, song c, liao w, xiong y. reconstructing full-length ureteral defects using a spiral bladder muscle flap with vascular pedicles. urology. 2014; 83:11991204. 3. engel o, rink m, fisch m. management of iatrogenic ureteral injury and techniques for ureteral reconstruction. curr opin urol. 2015; 25:331-335. 4. shekarriz b, lu h, duh q, freise ce, stoller ml. laparoscopic nephrectomy and autotransplantation for severe iatrogenic ureteral injuries. urology. 2001; 58:540-543. 5. goodwin we, winter cc, turner rd. replacement of the ureter by small intestine: clinical application and results of the ileal ureter. j urol. 1959; 81:406-418. 6. kim a, nam w, song sh, jeong ig, hong b. use of the ileum for ureteral stricture and obstruction in bilateral, unilateral, and single-kidney cases. urology. 2018; 111:203207. 7. kocot a, kalogirou c, vergho d, riedmiller h. long-term results of ileal ureteric replacement: a-25-year single-center experience. bju int. 2017; 120:273–279. 8. zhong w, hong p, ding g, et al. technical considerations and outcomes for ileal ureter replacement: a retrospective study in china. bmc surgery. 2019; 19:9. 9. ordorica r, wiegand lr, webster jc, lockhart jl. ureteral replacement and onlay repair with reconfigured intestinal segments. j urol. 2014; 191:1301–1306. 10. png jc, chapple cr. principles of ureteric reconstruction. curr opin urol. 2000; 10:207212. 11. takeuchi m, masumori n, tsukamoto t. ureteral reconstruction with bowel segments: ureteral reconstruction and ileal substitution-gu et al. miscellaneous 202 vol 17 no 02 march-april 2020 203 experience with eight patients in a single institute. korean j urol. 2014; 55:742-749. 12. gild p, kluth la, vetterlein mw, engel o, chun fkh, fisch m. adult iatrogenic ureteral injury and stricture–incidence and treatment strategies. asian j urol. 2018; 5: 101–106. 13. yang wh. yang needle tunneling technique in creating antireflux and continent mechanisms. j urol. 1993; 150:830-834. 14. monti pr1, lara rc, dutra ma. new techniques for construction of efferent conduits based on the mitrofanoff principle. urology. 1997; 49:112-115. 15. esmat m, abdelaal a, mostafa d. application of yang-monti principle in ileal ureter substitution: is it a beneficial modification? int braz j urol. 2012; 38:779-785. 16. bao js, he q, li y, shi w, wu g, yue z. yang-monti principle in bridging long ureteral defects: cases report and a systemic review. urol j. 2017; 14:4055–4061. 17. narayanaswamy b, wilcox dt, cuckow pm, et al. the yang-monti ileovesicostomy: a problematic channel?[j]. bju int. 2015; 87:861-865. 18. zou q, fu q. tissue engineering for urinary tract reconstruction and repair: progress and prospect in china. asian j urol. 2018; 5:57– 68. 19. smith tg 3rd, gettman m, lindberg g, et al. ureteral replacement using porcine small intestine submucosa in a porcine model. urology. 2002; 60:931-934. 20. el-assmy a, hafez at, el-sherbiny mt, et al. use of single layer small intestinal submucosa for long segment ureteral replacement: a pilot study. j urol. 2004; 171:1939–1942. 21. paul k. j. d. de jonge, vasileios simaioforidis, paul j. geutjes, et al. recent advances in ureteral tissue engineering. curr urol rep. 2015; 16:465. 22. elliott sp, mcaninch jw. ureteral injuries: external and iatrogenic. urol clin north am. 2006; 33:55-66. ureteral reconstruction and ileal substitution-gu et al. urological oncology 101urology journal vol 4 no 2 spring 2007 relation between her-2 gene expression and gleason score in patients with prostate cancer bahram mofid, mohammadreza jalali nodushan, afshin rakhsha, lida zeinali, hamidreza mirzaei introduction: her-2 is a proto-oncogene of the tyrosine kinase receptor family on chromosome 17. overexpression of this gene affects the growth and prognosis of some tumors. this study was performed to evaluate the expression of the her2 gene in patients with prostate cancer and its relation with the gleason score. materials and methods: pathology specimens of all men with prostate cancer who had undergone radical prostatectomy without any supportive treatment were studied. the gleason scores of the specimens and the expression of her-2 gene were examined. the expression of her-2 was scored between zero and 3+ in accordance with the herceptest method. patients with scores of 2+ and 3+ were considered to be positive for her-2 overexpression. results: of 150 cancerous prostate specimens evaluated, 20 (13.3%) were positive for her-2 gene overexpression. a weakly positive her-2 overexpression (2+) was seen in 15 of them (75%) and the remaining 5 (25%) were strongly positive. the gleason score was not different between the her-2-postitive and her-2negative patients (p = .08). fourteen out of 97 patients (14.4%) with a gleason score less than 7 and 6 out of 53 (11.3%) with scores of 7 or greater were positive for her-2 overexpression. conclusion: the frequency of her-2 gene overexpression is not very high in our patients with prostate cancer, and we failed to show any association of her-2 expression and the gleason score. urol j. 2007;4:101-4. www.uj.unrc.ir keywords: prostate cancer, her-2 gene, gleason score, immunohistochemistry department of radiotherapy, shohada-e-tajrish hospital, shaheed beheshti medical university, tehran, iran corresponding author: bahram mofid, md department of radiotherapy, shohada-e-tajrish hospital, tajrish sq, tehran, iran tel: +98 912 148 2371 fax: +98 21 2271 8082 e-mail: mofid429@yahoo.com received september 2006 accepted february 2007 introduction prostate cancer is the most common malignancy in men and the second cause of death due to cancer.(1) surgery and radiotherapy are promising for tumors limited to the prostate; however, it is seldom useful in advanced tumors, and in such cases, hormone therapy is the only kind of treatment that may result in improvement. many studies have been performed to evaluate factors affecting the prognosis of prostate cancer in order to find treatment options that can improve life expectancy in the patients. one of the newly introduced treatments is the use of a monoclonal antibody named trastuzumab, the effect of which on progressive breast cancer with a positive hairy-related 2 (her-2) proto-oncogene has been proved.(2) her-2 is a proto-oncogene of the tyrosine kinase receptor family on chromosome 17.(3) this protein acts as the site of growth factor; however, its complete structure has not been understood. overexpression of this gene affects the growth and prognosis of some tumors.(3) the studies performed her-2 in prostate cancer—mofid et al 102 urology journal vol 4 no 2 spring 2007 in this regard have shown different results. in an investigation on 150 patients with prostate cancer, 66% of the patients were positive for her-2 and its expression had no relation with the gleason score and the stage of the disease.(4) in another study in spain, 44% of the patients were positive for her-2 and the level of expression was significantly related to the gleason score.(5) the prevalence of this gene had been reported to be very low (8%) in another study.(6) an increase in the prevalence of this cancer is predicted in iran due to the increase in life expectancy. we designed this study to evaluate the frequency of her-2 in the patients with prostate cancer and its relation with the prognosis of the tumor. materials and methods patients with prostate cancer at shohada-e-tajrish hospital and shaheed labbafinejad medical center between 2002 and 2004 were evaluated in this crosssectional study. pathology specimens of all men with prostate cancer who had undergone radical prostatectomy without any supportive treatment were studied. diagnosis had been made according to their clinical course, ultrasonography, and biopsy. a single pathologist examined the archival paraffinembedded tumor tissue of these patients, confirmed the diagnoses of adenocarcinoma of the prostate, and determined the gleason scores using light microscopy. for examination of her-2, 4-μm thick sections were taken and stained using the immunohistochemical methods for the her-2 oncoprotein according to the histostain-plus kit instructions (zymed laboratories, pasching, austria). the pathologist who performed the immunohistochemistry was blind to the gleason scores. the expression of her-2 was scored between zero and 3+ in accordance with the herceptest method.(6) patients with scores of 2+ and 3+ were considered to be positive for her-2 overexpression (table 1).(6) overall, of 165 patients with prostate cancer, 150 were studied. in 6 cases, the patients had received chemotherapy or radiotherapy, and therefore, were excluded. in addition, 9 patients were excluded due to technical problems in immunohistochemical staining of their specimens. data including the gleason scores and immunohistochemistry results were analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). comparison of the gleason scores between the 2 groups with and without her-2 overexpression was done by the mannwhitney u test. a p value less than .05 was considered significant. results one hundred and fifty specimens positive for prostate cancer were evaluated. the mean age of the patients was 70.3 ± 8.9 years (range, 32 to 90 years). her-2 expression was increased in 20 patients (13.3%). a weakly positive result (2+) was seen in 15 patients (10.0%) and a 3+ score in 5 (3.3%). the gleason scores and her-2 expressions are demonstrated in table 2. the gleason score was not different between the her-2-postitive and her2-negative patients (p = .08). fourteen out of 97 patients (14.4%) with gleason scores less than 7 and 6 out of 53 (11.3%) with scores of 7 or greater were positive for her-2 overexpression. table 1. her-2 scoring by immunohistochemical staining(6) her-2 overexpression scoring staining negative 0 less than 10% staining negative 1 weak staining in more than 10% of the cells only in the cell wall weakly positive 2 weak to moderate staining in all parts of the cell wall in more than 10% of the cells strongly positive 3 staining in all parts of the cell wall in more than 10% of the cells table 2. her-2 overexpression in patients with prostate cancer categorized by their gleason scores gleason score number of patients her-2 2+ her-2 3+ 2 11 4 0 3 15 1 2 4 14 1 1 5 29 2 1 6 28 2 0 7 35 4 1 8 11 1 0 9 5 0 0 10 2 0 0 total 150 15 5 her-2 in prostate cancer—mofid et al urology journal vol 4 no 2 spring 2007 103 discussion in our study, only 13.3% of the patients with prostate cancer had overexpression of her-2, which is in accordance with the findings of a study by jorda and associates who had shown a 15% overexpression of her-2 in 220 pathologic blocks.(7) in a similar study performed by lara and colleagues, only 8% of the patients had her-2 overexpression.(6) however, our results completely disagree with the results of 2 other studies that reported a 66% and 44% frequency of her-2 overexpression in their patients.(4,5) also, we found out that overexpression of this gene was not significantly related to the gleason score. fonseca and colleagues had the same result, but their sample size was small.(4) lara and colleagues reported no correlation between her-2 overexpression and the gleason score of 62 patients.(6) in contrast to our findings, san miguel fraile reported a significant association between these 2 factor.(5) in a study on 216 patients, 97% of the her-2-positive tumors had a gleason score of 7 or higher.(7) the differences in the prevalence of her-2 overexpression reported by the above studies might be due to the technical variations in the evaluation methods of the gene expression such as the antigen preservation, antigen retrieval techniques, antibody selection, and sampling for immunohistochemical staining.(8) a standard method of immunochemical staining approved by food and drug administration (fda) was first used by sanchez and colleagues at indiana university.(9) they used 2 different antigenretrieval techniques for evaluation of her-2 expression: the standard fda-approved herceptest assay and a modified herceptest—which employed an alkaline citrate buffer (ph 9.0)—for antigen retrieval and a 1-hour primary antibody incubation time. they found a statistically significant relation between the her-2 expression and the gleason score. it was also noticed that her-2 was positive only in 1 patient with the standard method, but in 19 with the modified technique.(9) lara and colleagues used 2 methods of immunohistochemical staining and evaluation of shed her-2 antigen levels in serum by enzyme-linked immunosorbent assay and discovered that no relation existed between these 2 methods.(6) signoretti and colleagues believed that the differences in the results of her-2 gene studies was due to the different locations of biopsy.(10) biopsy may be taken from the androgen-sensitive cells and a positive her-2 overexpression is reported to be more frequent in these cases. the prevalence of her-2 overexpression in cases with prostate cancer resistant to the hormone therapy was much higher than the localized cancer (78% versus 25%).(10) however, some studies do not confirm such a difference.(6) some researchers have attempted to determine the prevalence of her-2 overexpression in patients with resistant cancer to phase 2 hormone therapy (docetaxel plus trastuzumab). a higher her-2 overexpression rate in the patients resistant to hormone therapy in comparison with the patients with hormone-dependent prostate cancers (40% versus 14%) was reported.(11) conclusion we concluded that the frequency of her-2 gene overexpression in our patients with prostate cancer seemed to be quite low and there was no significant relation between the expression of her-2 and the gleason score. however, our findings might be biased by the small number of patients and research on large samples might lead to different conclusions. conflict of interest none declared. references 1. jemal a, thomas a, murray t, thun m. cancer statistics, 2002. ca cancer j clin. 2002;52:23-47. 2. cobleigh ma, vogel cl, tripathy d, et al. multinational study of the efficacy and safety of humanized antiher2 monoclonal antibody in women who have her2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. j clin oncol. 1999;17:2639-48. 3. king cr, kraus mh, aaronson sa. amplification of a novel v-erbb-related gene in a human mammary carcinoma. science. 1985;229:974-6. 4. fonseca gn, srougi m, leite kr, nesrallah lj, ortiz v. the role of her2/neu, bcl2, p53 genes and proliferating cell nuclear protein as molecular prognostic parameters in localized prostate carcinoma. sao paulo med j. 2004;122:124-7. 5. san miguel fraile p, dos santos je, pelaez boismorand e, et al. [expression of the cerbb-2 (her2/neu) oncoprotein in prostatic adenocarcinoma]. actas urol esp. 2005;29:64-9. spanish. 6. lara pn jr, meyers fj, gray cr, et al. her-2/neu is overexpressed infrequently in patients with prostate carcinoma. results from the california cancer her-2 in prostate cancer—mofid et al 104 urology journal vol 4 no 2 spring 2007 consortium screening trial. cancer. 2002;94:2584-9. 7. jorda m, morales a, ghorab z, fernandez g, nadji m, block n. her2 expression in prostatic cancer: a comparison with mammary carcinoma. j urol. 2002;168:1412-4. 8. sweeney cj, bolton mg, koch mo, sanchezkm, cheng l. evaluation of her-2 in prostate cancer by immunohistochemistry (ihc) with 2 different antigen retrieval techniques and fluorescent in situ hybridization (fish). proc am soc clin oncol. 2001;20:2408. 9. sanchez km, sweeney cj, mass r, et al. evaluation of her-2/neu expression in prostatic adenocarcinoma: a requested for a standardized, organ specific methodology. cancer. 2002;95:1650-5. 10. signoretti s, montironi r, manola j, et al. her-2neu expression and progression toward androgen independence in human prostate cancer. j natl cancer inst. 2000;92:1918-25. 11. morris m, reuter v, kelly w, et al. a phase ii trial of herceptin alone and with taxol for the treatment of prostate cancer. proc am soc clin oncol. 2000;19:1298. urology journal vol 4 no 1 winter 2007 55 urological survey the experimental and clinical transplantation the experimental and clinical transplantation (ect) is the official journal of the middle east society for organ transplantation (mesot). this society was originally founded in 1987 and the ect has been published since july 2003. the ect is a peer-reviewed international publication that accepts manuscripts of full-length original articles, case reports, letters to the editor, and invited reviews. professor mehmet haberal is the editor-in-chief and professor ahad ghods, from iran, is one the associate editors of the ect. medline has listed the papers of the journal since 2003, making the ect one of the most prestigious publications of the region. the ect is published biannually in july and december, and the latest issue (december 2006) is now available on www.ectrx.org. some abstracts of the papers in volume 4, number 2, december 2006 are as follows: urol j (tehran). 2007;4:55-60. www.uj.unrc.ir implications of icu stay after brain death: the saudi experience besher al-attar,1 faissal shaheen,1 mohammed abdul salam,1 abdullah al-sayyari,2 abdulqayoum babiker,1 haroun zakaria,1 ahmed babiker,1 levi saclayan1 1medical department and the 2research and journal department, saudi center for organ transplantation, riyadh, kingdom of saudi arabia objective: the interval from brain death (bd) to organ harvesting is critical to the success of transplantation. we evaluated the time from bd onset to harvesting and analyzed sources of delay. materials and methods: this retrospective study was conducted from january 1999 to december 2003. time intervals analyzed to determine the causes of delay were: time of admission to the intensive care unit (icu), to the report to the saudi center for organ transplantation (scot), to the documentation of bd, to organ retrieval and/or cardiocirculatory cessation without organ retrieval. results: during the 5-year analysis, 1834 people were reported to the scot. of those, more than 1511 (80%) were reported during their first week of treatment in the icu, and the experimental and clinical transplantation 56 urology journal vol 4 no 1 winter 2007 the experimental and clinical transplantation urology journal vol 4 no 1 winter 2007 57 bd was documented in 1099 (59.9%). the mean interval from icu admission to organ retrieval or cardiac arrest was 10.3 days and that from admission to the report to the scot was 5.6 days. in the consensual group, the mean interval from the documentation of bd until harvesting was 2 days, and that from documentation until cardiocirculatory cessation without organ retrieval in the nonconsensual group was 5 days. all subjects demonstrated a significant decrease in systolic blood pressure and a significant increase in plasma sodium and serum creatinine levels. the body temperature, serum plasma levels of sodium, and kidney function (measured by the serum creatinine level) of potential donors were compared, and patients with hypothermia, hypernatremia, or renal failure had a shorter stay in the icu. conclusions: fewer than 30% of the patients could be maintained on mechanical support for more than 1 week after the declaration bd. it is crucial that we increase hospitalstaff awareness about the importance of organ donation and transplantation, improve the identification of bd candidates, and enable the early reporting and documentation of bd. urologic complication rates in kidney transplantation after a novel ureteral reimplantation technique mehmet haberal,1 hamdi karakayali,1 sinasi sevmis,1 gokhan moray,1 gulnaz arslan2 departments of 1general surgery, transplantation and burn units, 2anesthesiology, baskent university faculty of medicine, ankara, turkey our transplantation team has performed 1615 renal transplantations since 1975. after september 2003, we began a corner-saving technique for urinary tract continuity. in this study, we analyzed these 174 renal transplantations retrospectively. the mean recipient age was 31.6 years (range, 7 to 66). the mean donor age was 39.8 years (range, 6 to 67). for ureteral reimplantation, a running suture is started 3 mm ahead of the middle of the posterior wall and is finished 3 mm afterward. after the last stitch, both ends of the suture material are pulled, and the posterior wall of the ureter and bladder are approximated tightly. the anterior wall is sewn either with the same suture or another running suture. since using this technique, we have not employed a double-j or any other stent to prevent ureteral complications at the anastomosis site. we have seen only 4 (2.2%) ureteral complications (2 ureteral stenosis and 2 anastomotic leaks) during a follow-up period of 18.9 months. in conclusion, due to the low complication rate, we believe that our new technique is the safest way to perform a ureteroneocystostomy. plasmapheresis in the treatment of early acute kidney allograft dysfunction mohsen nafar,1 farhat farrokhi,2 keyvan hemati,2 fatemeh pour-reza-gholi,1 ahmad firoozan,1 behzad einollahi1 1department of kidney transplantation, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran 2urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran objective: to evaluate the efficacy of plasmapheresis (pp) in kidney transplant recipients with acute humoral rejection (ahr). patients and methods: a retrospective review was conducted of all kidney allograft recipients who had undergone pp rescue therapy for early acute allograft dysfunction the experimental and clinical transplantation 56 urology journal vol 4 no 1 winter 2007 the experimental and clinical transplantation urology journal vol 4 no 1 winter 2007 57 diagnosed as ahr at shaheed labbafinejad medical center from 1995 to 2002. results: twelve patients (4 men and 8 women; median age, 32 years; age range, 15-68 years) with ahr were treated with pp. the median time from transplantation to ahr was 6 days (range, 2-7 days). pp was performed in 2 to 11 sessions (median, 8.5 sessions) in the patients studied. eight patients responded to that treatment, and their creatinine value normalized. those responders were monitored for a median of 162.5 weeks (range, 69.3484.7 weeks), and all had a functioning allograft during the follow-up period except for 1 patient in whom the graft failed 154 weeks after transplantation. in the 4 remaining patients (nonresponders), the allograft failed within the first posttransplant month. the median time from the acute serum creatinine elevation to the initiation of pp was 6 days in responders and 18.6 days in nonresponders (p = .37). conclusions: we suggest that pp with or without other therapeutic measures may have a role in the salvage of grafts with early acute dysfunction that is resistant to conventional therapy. our findings indicate that graft survival in patients with ahr who respond to pp can be comparable to that in other kidney recipients. impact of mycophenolic acid dose modifications on renal function after kidney transplantation nassim kamar,1 loubna oufroukhi,1 federico sallusto,2 olivier cointault,1 laurence lavayssière,1 marc mouzin,2 joelle guitard,1 dominique durand,1 lionel rostaing1 1department of nephrology, dialysis and multiorgan transplantation, chu rangueil, toulouse, france 2department of urology, chu rangueil, toulouse, france objective: mycophenolic acid dose modifications after renal transplantation seem to adversely affect renal allograft outcome. the aim of this retrospective study was to examine the effect of mycophenolic acid dose modifications on renal function 1 year after transplantation and to determine the factors predictive of those dose modifications within the first year after renal transplantation. patients and methods: all 130 patients at our institution who were treated de novo between january 2002 and april 2003 with either a mycophenolate mofetil-based or an enteric-coated mycophenolate sodium-based therapy and who had a functioning renal allograft 1 month after transplantation were included in this study. results: fifty-seven patients (43.8%) underwent a dose modification during the first year after transplantation. one, 3, 6, and 12 months after transplantation, renal function was significantly improved in the patients who did not receive a dose modification. a mycophenolic acid dose that 1 year after transplantation was less than the initial dose received just after transplantation was an independent factor associated with deteriorating renal function. sirolimus immunosuppression, cytomegalovirus infection, and pretransplant lymphocyte counts were independent factors associated with mycophenolic acid dose modifications within the first year after kidney transplantation. conclusions: modification of the mycophenolic acid dose may adversely affect renal function 1 year after transplantation. the experimental and clinical transplantation 58 urology journal vol 4 no 1 winter 2007 the experimental and clinical transplantation urology journal vol 4 no 1 winter 2007 59 majocchi’s granuloma after kidney transplantation michael burg,1 dagmar jaekel,1 eva kiss,2 volker kliem1 1department of internal medicine and nephrology, nephrologisches zentrum niedersachsen, hann. muenden, germany 2department of cellular and molecular pathology, deutsches krebsforschungsinstitut, heidelberg, germany mycosis may follow an atypical course in an individual undergoing immunosuppressive therapy. we describe a patient with a fungal infection that was manifested as a bilateral inguinal granuloma. owing to suspected inguinal lymphadenopathy characterized by distinct subcutaneous swellings in the groin, a 39-year-old man who had undergone kidney transplantation 14 years earlier was admitted to the nephrologisches zentrum in hann. muenden, germany. the results of a clinical examination revealed bilateral, soft, partly fluctuant, indolent swellings in the groin as well as onychomycosis of the right great toe. an ultrasonographic scan showed bilateral hypoechogenic lesions (<= 1.5 cm) in the groin. the lesions were surgically removed, and the results of histologic examination revealed severe granulating pseudocystic inflammation with a distinct foreign body reaction. dermatophytes of the species trichophyton rubrum were detected microbiologically. after the lesions had been resected, the wound healed without complications. immunosuppressive treatment with tacrolimus 8 mg/d and steroids 7.5 mg/d was not changed. local antimycotic treatment of the onychomycosis with ciclopirox cream was initiated. at the patient’s 2-year followup examination, there was no evidence of recurrence. in transplant recipients, local fungal infections should be treated as a matter of course, because dermatophytosis is present in almost every other such patient. in patients with a suspicious inguinal lesion, an atypical form of dermatophytosis must be considered. t rubrum, the most frequently occurring dermatophyte, causes 80% of the dermatophytosis that develops in immunosuppressed patients. changes in health-related quality of life in greek adult patients 1 year after successful renal transplantation aikaterini balaska, panagiotis moustafellos, stavros gourgiotis, dimitrios pistolas, evangelos hadjiyannakis, vassilis vougas, spiros drakopoulos transplant unit, evangelismos general hospital of athens, greece objectives: this study was undertaken to compare and to evaluate the health-related quality of life (hrqol) in greek adult transplant recipients before and 1 year after successful renal transplantation (rt) and to examine which parameters had the greatest effects on their hrqol. the sf-36 survey score was used. materials and methods: eighty-five greek hemodialysis patients underwent rt at the transplant unit of evangelismos general hospital of athens, including 44 men and 41 women (mean age, 43.8 years; range, 21-59 years). thirty-nine patients had received a kidney from a living-related donor, and 46 from a cadaver. the scale scores of a greek version of the sf-36 survey were compared between the transplant and the hemodialysis patients. we also examined the relationships of the scale scores with the patients’ age and the type of donor. results: according to the sf-36 health survey, transplant recipients had better results for general health perception (p <= .001), role-physical functioning (p <= .01), role-emotional functioning (p <= .01), and vitality (p <= .01). in addition, the scale scores of physical the experimental and clinical transplantation 58 urology journal vol 4 no 1 winter 2007 the experimental and clinical transplantation urology journal vol 4 no 1 winter 2007 59 functioning, general health, and vitality of the patients who were younger than 30 years old at the time of transplantation were significantly higher than those of the patients who were older than 30 years, while the scores of bodily pain, general health, and physical functioning were significantly lower in cadaveric graft recipients compared with living-related graft recipients. conclusions: the sf-36 health survey is a validated and comprehensive instrument for evaluating renal transplant patients’ hrqol. our data demonstrate an improvement in hrqol in renal transplant patients from before to 1 year after successful rt. the data also confirm that the recipients’ age at transplantation and the type of donor were important factors affecting the hrqol. cytokine gene polymorphisms in renal transplant recipients n azarpira, mh aghdaie, b geramizadeh, s behzadi, s nikeghbalian, f sagheb, m rahsaz, a behzad-behbahanie, m ayatollahi, m darai, mr azarpira, m banihashemie, sz tabei organ transplant research center, shiraz university of medical sciences, shiraz, iran objective: acute rejection remains an important cause of graft loss after renal transplantation, and cytokines are key mediators in the induction and effector phases of all immune and inflammatory responses. however, the influence of gene polymorphisms on the functional immune response of transplant recipient outcomes remains controversial. materials and methods: the amplification refractory mutation system polymerase chain reaction was used to detect the interleukin-10 (il-10) (-1082 g/a), tumor necrosis factor-alpha (tnf-alpha) (-308 g/a), and interferon-gamma (ifn-gama) (+874 t/a) single nucleotide polymorphisms in 100 of the first adult kidney recipients at our institution who were receiving cyclosporine-based immunosuppressive therapy. the diagnosis of acute rejection was based on clinical and histologic findings according to the banff criteria. results: the results of multivariate analyses showed no significant association between episodes of acute rejection and single nucleotide polymorphisms in il-10, tnf-alpha genes, or dinucleotide repeat polymorphisms in the ifn-gama gene. conclusions: our results demonstrate that cytokine gene polymorphisms did not influence the early outcome of kidney transplantation. renal function and histology in kidney transplant patients receiving tacrolimus and sirolimus or mycophenolate mofetil nassim kamar, tuan tran van, david ribes, anne modesto, olivier cointault, laurence lavayssière, jean louis ader, dominique durand, lionel rostaing nephrology, dialysis, and transplantation; service d’explorations physiologiques rénales, and pathology, chu rangueil, toulouse, france objective: the aim of this study was to assess the effects of tacrolimus in combination with either sirolimus (n = 10) or mycophenolate mofetil (n = 7) on renal function and renal histopathologic factors 6 and 12 months after kidney transplantation. materials and methods: renal function was assessed by the glomerular filtration rate (as the experimental and clinical transplantation 60 urology journal vol 4 no 1 winter 2007 measured by the inulin clearance rate) and by determining renal functional reserve. a renal allograft biopsy was performed at the time of transplantation and 6 and 12 months later. results: serum creatinine levels tended to be higher in the sirolimus group 12 months after transplantation. in contrast, inulin clearance and renal functional reserve were similar in both groups 6 and 12 months after transplantation. with respect to histopathologic findings, only mononuclear-cell interstitial inflammation was significantly higher in the sirolimus group than in the mycophenolate mofetil group 12 months after transplantation. however, the progression of tubular atrophy, interstitial fibrosis, and vascular fibrous intimal thickening within the first postoperative year was significantly greater in the sirolimus group. conclusions: in the long term, the addition of sirolimus to treatment with tacrolimus in de novo renal transplant patients might more adversely affect renal allograft survival than might the addition of mycophenolate mofetil to tacrolimus therapy. renal autotransplantation for complex renal arterial disease: a case report sinasi sevmis,1 hamdi karakayali,1 fatih boyvat,2 turan colak,3 cem aydogan,1 e arzu gencoglu,4 mehmet haberal1 departments of 1general surgery, transplantation and burn units, 2radiology, 3nephrology, 4nuclear medicine, baþkent university faculty of medicine, ankara, turkey a renal artery aneurysm in a stenotic renal artery is a rare clinical entity with an incidence of 0.015% to 1% in patients with renovascular hypertension. interventional stent placement is the first line of treatment for simple aneurysms of the proximal renal artery. however, renal autotransplantation has been used as an alternative treatment for complex lesions and for lesions originating from the distal renal artery. we present a patient with a renal artery aneurysm, renal artery stenosis of the segmental branches of the left kidney, and occlusion of the right renal artery. the surgical strategy included renal explantation, ex vivo renal preservation, ex vivo reconstruction of the 2 renal artery branches, and renal heterotopic autotransplantation. we conclude that renal autotransplantation is a safe and effective surgical procedure for patients with complex renal arterial disease. case report 66 urology journal vol 7 no 1 winter 2010 asymptomatic giant adrenal myelolipoma samrat mukherjee,1 stephanos pericleous,1 robert r hutchins,1 ps freedman2 urol j. 2010;7:66-8. www.uj.unrc.ir keywords: myelolipoma, adrenal gland, retroperitoneal neoplasms 1department of hepatobiliary and pancreatic surgery, royal london hospital, whitechapel, london, united kingdom 2department of diabetes and metabolism, st bartholomew’s hospital, west smithfield, london, united kingdom corresponding author: mukherjee s, md department of hepatobiliary and pancreatic surgery, the royal london hospital, whitechapel, london, uk e-mail: samrat.mukherjee@rwh-tr.nhs.uk received february 2009 accepted may 2009 introduction adrenal myelolipomas are nonfunctioning benign tumors composed of adipose tissue and hemopoietic elements resembling bone marrow. before the availability of modern imaging, they were detected only at autopsy with an incidence of 0.08% to 0.2%.(1) these tumors are now being picked up more frequently with the availability of computed tomography and ultrasonography, but they are usually small and isolated.(2) the first excision of a myelolipoma was carried out in 1922. since then, more than 100 cases of surgically resected adrenal myelolipomas have been documented. the management of incidentally found tumors and their pre-operative diagnosis is discussed. we describe the largest asymptomatic adrenal myelolipoma weighing 5.5 kg. case report a 56-year-old man with type 2 diabetes mellitus presented to the diabetic clinic with an ulcer in his left foot due to ill-fitting shoes. he had an amputation of his left hallux for diabetic complications 6 years previously. on direct questioning, he denied any significant loss of appetite, abdominal bloating, urinary symptoms, or change of bowel habit. he had lost approximately 25 kg of weight over a 2-year period. on examination, he was thin with a distended abdomen. there was evidence of gynecomastia, but no jaundice or lymphadenopathy. he had a large right upper quadrant mass extending down to his pelvis with a recurrent umbilical hernia. his left leg was affected by cellulitis. he was admitted to hospital for further management of his foot ulcer, control of his diabetes mellitus, and investigation of his abdominal mass. ultrasonography revealed a large predominantly hyperechoic mass within the right retroperitoneum. computed tomography of the abdomen confirmed a massive soft tissue mass containing fatty and soft tissue elements. it was well circumscribed and extended to the anterior, posterior, and right lateral abdominal wall without invasion. it displaced the liver anteriorly and to the left, and the right kidney inferiorly. the mass extended as far as the right pelvic brim. there was no ascites or lymphadenopathy (figures 1 and 2). it suggested the diagnosis of an incidental retroperitoneal tumor, probably a liposarcoma. it was decided that the best option for this patient would be a resection. his pre-operative workup, including complete blood count, biochemistry, and tumor markers, were all within normal limits. he was explored through asymptomatic giant adrenal myelolipoma—mukherjee et al 67urology journal vol 7 no 1 winter 2010 a reverse l incision. a huge heterogeneous retroperitoneal tumor was found in the right upper quadrant of his abdomen. the liver was pushed anteriorly with the gallbladder and hilum stretched over the mass. the inferior vena cava and the right renal vein were grossly stretched and compressed by the mass. there was no bowel involvement. the right kidney was freed from the tumor down to the renal capsule. the tumor was then excised preserving all the other structures. a small nodule was seen superficially in the right lobe of the liver and a nonanatomical wedge resection using the tissuelink ds3. 5c radiofrequency dissector was performed. the umbilical hernial defect was repaired with proceed intraperitoneal mesh, stapled in situ. the procedure took approximately 4 hours and was associated with no transfusion requirement. postoperatively, the patient was extubated immediately and made an uneventful recovery. he was discharged on the 10th postoperative day. the tumor was a large lobulated greyish yellow mass with a pseudocapsule. it weighed 5.5 kg and measured 28 × 26 × 17 cm. on sectioning, there were areas representing well-differentiated fat as well as areas of hemorrhage and infarction. histological examination revealed that the lesion arose from the adrenal gland and consisted of lobules of mature adipocytes in the background of hemorrhage and some sclerosis. extramedullary hematopoiesis was seen. mitotic figures were not seen. these features suggested the diagnosis of a myelolipoma. further immunohistochemistry was positive, confirming the presence of erythroblasts, and cytogenetic analysis was negative for mdm2-cdk4. the latter is present in atypical lipomatous tumors/well-differentiated liposarcoma. the liver lesion turned out to be a sclerosed hemangioma. discussion adrenal myelolipomas are rare, benign, nonfunctioning tumors composed of mature adipose tissue and hemopoietic elements.(1) in 1979, boudreaux and coworkers reported the first case ever of a giant myelolipoma.(3) the tumor, resected en bloc with the kidney and retroperitoneal soft tissues, weighed 5.9 kg. however, the weight of the actual tumor was not reported. the largest adrenal myelolipoma to be resected was reported by akamatsu and colleagues from japan.(4) the tumor measured 31 × 24.5 × 11.5 cm and weighed 6 kg. the only other reported myelolipoma weighing more than 5 kg was reported by wilhelmus and colleagues who described a tumor weighing 5.5 kg.(5) our case represents the 4th largest adrenal myelolipoma, weighing 5.5 kg. however, this represents the largest asymptomatic adrenal myelolipoma. all the previously described adrenal myelolipomas weighing more than 5 kg have been symptomatic at presentation. giant adrenal tumors are quite rare and mostly affect patients in their 4th to 6th decades. the association of myelolipoma with obesity, hypertension, chronic disease, and malignancies have been described.(6) our patient’s mass had figure 1. liver hilum stretched by the huge retroperitoneal tumor. figure 2. huge retroperitoneal tumor displacing the liver. asymptomatic giant adrenal myelolipoma—mukherjee et al 68 urology journal vol 7 no 1 winter 2010 become visible with recent profound weight loss. his only comorbidity was diabetes mellitus. however, due to the frequent association of obesity and hypertension in the affected group of older patients, these are probably incidental associations.(7) the pathogenesis of adrenal myelolipomas is still unclear. various theories have been proposed including autonomous proliferation of bone marrow cells during embryogenesis, degeneration of the epithelial cells of the adrenal cortex, metaplasia of mesenchymal cells, and bone marrow emboli.(5) adrenal myelolipomas are usually asymptomatic. only when the tumor attains an enormous size does it cause symptoms. the most common symptom is abdominal pain, probably due to hemorrhage, tumor necrosis or compression of surrounding structures.(7) they are usually nonfunctioning, though occasional secretion of catecholamines or hormones have been reported.(8) the classic myelolipoma is lucent on plain films, echogenic on ultrasonography, and avascular on angiography. computed tomography is a very sensitive modality for diagnosis, because it can show an adrenal mass with tissue density similar to that of fat. it also has signal intensity similar to that of fat on t-weighted magnetic resonance imaging. however, distinguishing between myelolipoma and liposarcoma is impossible radiologically, as happened in our case. previously, most of the patients with myelolipoma underwent surgical resection for a suspected malignant neoplasm. nowadays, with the frequent detection of these “incidentalomas,” the treatment has been subjected to a lot of debate.(9) when the tumor is 4 cm or smaller and asymptomatic, follow-up with computed tomography is recommended. if symptoms occur, surgery should be carried out promptly, especially in large myelolipomas, as spontaneous rupture of the lesion with hemorrhage is possible.(10) resection of larger lesions due to diagnostic doubt is probably inevitable. conflict of interest none declared. references 1. olsson ca, krane rj, klugo rc, selikowitz sm. adrenal myelolipoma. surgery. 1973;73:665-70. 2. kenney pj, wagner bj, rao p, heffess cs. myelolipoma: ct and pathologic features. radiology. 1998;208:87-95. 3. boudreaux d, waisman j, skinner dg, low r. giant adrenal myelolipoma and testicular interstitial cell tumor in a man with congenital 21-hydroxylase deficiency. am j surg pathol. 1979;3:109-23. 4. akamatsu h, koseki m, nakaba h, et al. giant adrenal myelolipoma: report of a case. surg today. 2004;34:283-5. 5. wilhelmus jl, schrodt gr, alberhasky mt, alcorn mo. giant adrenal myelolipoma: case report and review of the literature. arch pathol lab med. 1981;105:532-5. 6. noble mj, montague dk, levin hs. myelolipoma: an unusual surgical lesion of the adrenal gland. cancer. 1982;49:952-8. 7. dieckmann kp, hamm b, pickartz h, jonas d, bauer hw. adrenal myelolipoma: clinical, radiologic, and histologic features. urology. 1987;29:1-8. 8. tamidari h, mishra ak, gupta s, agarwal a. catecholamine secreting adrenal myelolipoma. indian j med sci. 2006;60:331-3. 9. belldegrun a, dekernion jb. what to do about the incidentally found adrenal mass. world j urol. 1989;7:117. 10. goldman hb, howard rc, patterson al. spontaneous retroperitoneal hemorrhage from a giant adrenal myelolipoma. j urol. 1996;155:639. review comparison of the safety and efficacy between transperitoneal and retroperitoneal approach of laparoscopic ureterolithotomy for the treatment of large (>10mm) and proximal ureteral stones: a systematic review and meta-analysis hualin chen1, gang chen1*, han chen1, yang pan1, yunxiao zhu1, fei gao1, xiaoxiang jin1 purpose: we aimed to compare the safety and efficacy between laparoscopic transperitoneal ureterolithotomy (ltu) and laparoscopic retroperitoneal ureterolithotomy (lru) in the treatment of large (>10mm) and proximal ureteral stones. materials and methods: electronic databases, including pubmed, embase, cochrane library, web of science, and scopus were searched through december 2019. comparative studies comparing the two approaches were included. the primary outcome was a single-procedure success rate; the secondary outcomes included operative time, hospital duration, and complications (according to the clavien-dindo grade). newcastle–ottawa scale (nos) and the modified jadad scale were used to evaluate the quality of the included studies. the egger's test estimated publication bias. the meta-analysis was performed by review manager 5.3 and stata 15.0. results: seven studies, involving 125 participants in ltu group and 128 in lru group, were included in the study. the results suggested that both single-procedure success rate and the rate of postoperative paralytic ileus were significantly higher in the ltu group than in the lru group (95.2% vs 87.5%, 95% ci: .00-.16, rd = .08, p = .04; 10.4% vs 0, 95% ci: .02.19, rd = .10, p = .02, respectively). no publication bias of the primary outcome was observed with the egger’s test (p = .117). no significant differences were noted in terms of operative time and hospital duration (95% ci: -18.95-8.80, md = -5.08, p = .47; 95% ci: -.98.58, md = -.20, p = .61, respectively). additionally, according to clavien-dindo grade, the rates of major complications (>= grade 3a) including open conversion (.8% vs 5.5%, 95%ci: -.11.01, rd = -.05, p = .12), stone migration (8.1% vs 6.7%, 95% ci: -.08.11, rd = .02, p = .76), vascular injury (5.4% vs 0, 95%ci: -.03.14, rd = .05, p = .21) and ureteral stricture (1.3% vs 5.3%, 95% ci: -.11.02, rd = -.04, p = .20), were comparable between the two groups. conclusion: in the treatment of large and proximal ureteral calculi, ltu has a significantly higher single-procedure success rate and a higher rate of postoperative paralytic ileus than lru. however, the complication was well-tolerated. the small sample size and limited, including studies, were the main limitations. keywords: laparoscopy; meta-analysis; retroperitoneal; transperitoneal; ureterolithiasis; ureterolithotomy introduction the treatment of large proximal ureteral stones is complicated.(1) although ureterorenoscopy (urs) and extracorporeal shockwave lithotripsy (swl) are the most common procedures, however, multiple sessions are required.(2) this drawback promotes the usage of laparoscopic ureterolithotomy (lu) due to its high stone-free rate (sfr). traditionally, lu was realized through the retroperitoneal approach. as laparoscopic retroperitoneal ureterolithotomy (lru) is at risk of stone migration to the kidney, the new method of laparoscopic transperitoneal ureterolithotomy (ltu) is attempted(3). however, different opinions have emerged during the exploration of these two approaches. ltu is recommended to the less-experienced surgeons by abat et al.(4) for its broader operation field and familiar anatomy. however, another study reported that ltu and lru were comparable in terms of efficiency and safety and surgeons could perform the procedure dependent on personal preference.(5) due to such controversy, a comprehensive study of this issue was needed. thus, 1department of urology, the first affiliated hospital of chongqing medical university, chongqing, china. *correspondence: youyi# road, yuzhong district, chongqing, 400016, china. e mail: youyi# road, yuzhong district, chongqing, 400016, china. received september 2019 & accepted september 2020 we conducted a meta-analysis with an attempt to understand these two approaches comprehensively. materials and methods this meta-analysis was performed based on the guidelines outlined in the preferred reporting items for systematic reviews and meta-analysis (prisma) statement.(6) search strategy we conducted a systematic search of electronic databases, including pubmed, embase, cochrane library, web of science, and scopus (through december 2019) to identify all relevant studies. the search strategy was combining with following terms without language restriction: (‘laparoscopic ureterolithotomy’ or ‘lu’) and (‘proximal’ or ‘upper’) and (’ureteral stone’ or ‘ureteral stones’ or ‘ureteral calculi’ or ‘ureteral calculus’ or ‘ureteral lithiasis’). and references of included studies were manually identified for relevant records. the titles and abstracts of identified studies were independently screened by two reviewers urology journal/vol 18 no. 1/ january-february 2021/ pp. 11-18. [doi: 10.22037/uj.v16i7.5588] (hualin and han) following deduplication. then, full texts or conference abstracts were obtained for further identification of their eligibility. inclusion and exclusion criteria the including trials met the following requirements: 1) study types: randomized controlled trials (rcts) and non-randomized comparative studies. 2) patients with large (>10mm) and proximal ureteral calculi. 3) comparison between ltu and lru. 4) report on the primary outcome and at least one of the secondary outcome measures mentioned below. 5)reviews, animal studies, case reports, and non-comparative studies were excluded. data extraction and outcome measures two reviewers (hualin, han) extracted data from including literature independently, including baseline char¬acteristics and data of outcome measures. 1) baseline characteristics included first author, time of publication, country, recruitment duration, study design, stone characteristics, number of surgeon(s) and patients, gender proportion, body mass index (bmi) and average age, stone size, and laterality. 2) outcome measures were single-procedure success rate (defined below), operative time, length of hospital duration, and complications. the primary outcome was a single-procedure success rate. it was defined as reaching stone-free status at a single-one procedure without an open conversion relaparoscopy in proximal ureteral calculus-chen et al. table 1. characteristics and quality evaluation of including studies. study preop postop country study study stone no. surgical f/u (mon) quality id imaging imaging period type characteristics surgeon(s) experience score abat 2016 kub, us na turkey nov. 2011 to retroproximal 2 limited 14.84 ± 7.46/ 6 ivu, ncct mar. 2013 35.56 ± 9.11 almeida 2009 kub, us kub brazil jan. 2004 to prolarge(>10mm), 1 limited 1 8 ivu, ct nov. 2007 proximal pierluigi 2009 us, ivu ct na italy 2004 to prolarge(>10mm), 2 limited 12 8 2006 proximal, impacted khalil 2015 ct na egypt jan. 2012 to rct large(>15mm), na na 12 8 sep. 2013 proximal, impacted wisoot 2010 kub na thailand jul. 1997 to retrolarge(>15mm), 3 na 18 7 dec. 2007 impacted vishwajeet 2013 kub, us kub, ivu india jan. 2009 to rct proximal 1 na 14/15 5a ivu us may 2012 chiu 2015 na na china dec. 2009 to retrolarge(>15mm), 1 experienced 3 8 sep. 2014 proximal, impacted abbreviations: preopimaging, preoperative imaging examinations; postopimaging, postoperative imaging examinations; kub, kidney; ureter; and bladder x-ray; us, ultrasound; ivu, intravenous urogram; ncct, non-contrast computed tomography; na, not available; retro-, retrospective comparative study; pro-, prospective comparative study; f/u, follow up. a quality evaluated by the modified jadad scale, the others were evaluated by nos. study id sample age bmi stone stone gender single-procedure operative hospital size(n) (years) (kg/m2) size(mm) side(r:l) (m:f) success rate time(mins) duration(days) abat 2016 25/25 38.96±17.01/ na 16.62±4.78/ 6:19/ 6:19/ 21/20 147±36.54/ 2.94±1.69/ 47.8±14.1 20.12±5.18 11:14 15:10 106.4±38 7.12±4.47 almeida 2009 15/19 43.2±16.7/ na 12.5±2.6/ 10:6/ 8:7/ 15/15 100(70-180)/ 3(2-3)/ 43.8±15.7 13.6±3.8 8:10 12:7 105(90-120) 2(2-3) pierluigi 2009 18/17 42(25-60)/ 22.3(20.6-35.7)/ 23(15-45)/ na na 17/17 68(48-130)/ 4(2-7)/ 40(28-61) 21.6(20.2-31.8) 22(13-35) 103(69-147) 5(2-10) khalil 2015 13/11 37.6±13.2/ 25.9±2.8/ 15.5±3.7/ 5:8/ 9:4/ 13/7 116.2±21.8/ 5.4±1.2/ 44.6±7.9 28.09±4.4 15.8±3.02 5:6 8:3 137.3±17.9 5±0.8 wisoot 2010 11/28 42.1/ na 17.8/ na na 11/27 128.3(75-180)/ 8.8/ 44.2 18.2 125.9(75-270) 4.1 vishwajeet 2013 24/24 37.75±10.61/ na 18±3.6/ 14:10/ 14:10/ 23/22 83.12±8.3/ 3.125±0.74/ 39.16±11.49 17±3.8 8:16 13:11 84.1±6.4 2.67±0.63 chiu 2015 19/4 54.47±10.75/ 25.31±2.82/ 20.2±6.4/ na 15:4/ 19/4 102.3±33.9/ 5±1.76/ 51.5±17.91 28.2±4.19 18±2.2 3:1 111.25±8.3 5.25±1.26 data was presented as “ltu/lru” abbreviations: r, right; l, left; m, male; f, female; na, not available. table 2. demographic and baseline characteristics of included patients. review 12 vol 18 no 1 january-february 2021 13 quirement or auxiliary procedures requirement due to stone migration. secondary outcomes included length of hospital stay, operative time, minor and complications. complications were classified according to the clavien-dindo grade.(7) additionally, complications of more than grade 3a were regarded as major ones. prolonged drainage was defined as urine leakage requiring drainage for more than 72 hours.(4,5,8,9) and paralytic ileus was defined as the absence of bowel sound lasting for over 36 hours.(2,4,8) any disagreements were resolved by discussion or consultation with a third reviewer (gang). evaluation of study quality comparative studies included rcts and non-randomized comparative studies. the modified jadad scale was used to assess the methodological qualities of rcts, while, newcastle–ottawa scale (nos) was used for non-randomized comparative studies. the results were listed in table 1. statistical analysis the risk difference (rd) was used for dichotomous variables, while the mean difference (md) was used for continuous ones. forest plots were used to present the results of our meta-analysis. the z test determined all the pooled effects, and p < 0.05 was considered statistically significant. p values of dichotomous and continuous variables were calculated by mantel–haenszel (mh) test and inverse-variance (iv) weighting, respectively. chi square-based q test and i2 tests were used to assess the quantity of heterogeneity among these studies. when i2 < 50 %, p > 0.1, the pieces of evidence table 3. intraor postoperative complications classified by the modified clavien-dindo grade (p value was calculated by using mh test). grade no. complications (%) p value ltu lru grade 1 8 (6.4%) 9 (7.03%) prolonged drainage retroperitoneal hematoma 6 (4.8%) 2 (1.6%) 7 (5.47%) 2 (1.56%) .95 .74 grade 2 22 (17.6%) 13 (10.16%) uti 12 (9.6%) 12 (9.38%) .87 transfusion 3 (2.4%) 1 (.78%) .49 paralytic ileus 7 (5.6%) 0 .02 grade 3a grade 3b 10 (8%) 16 (12.5%) open conversion 1 (.8%) 7 (5.47%) .12 stone migration 5 (4%) 4 (3.13%) .76 vascular injury 3 (2.4%) 0 .21 ureteral stricture 1 (.8%) 5 (3.91%) .20 grade 4a 1 (.8%) 0 pulmonary embolus 1 (.8%) 0 .45 total complications 41 (32.8%) 39 (30.47%) figure 1. flow diagram of included studies. laparoscopy in proximal ureteral calculus-chen et al. were thought to be acceptable heterogeneity, we used the fixed-effects model. otherwise, the random-effects model was applied. publication bias was evaluated with the egger’s regression asymmetry test. review manager 5.3 (cochrane collaboration, oxford, uk) was used to analyze the aggregate data. stata 15.0 (college station, texas, usa) was used to identify publication bias and generate eggers plot. results search process and study characteristics the systematic search identified 1172 relevant studies. after further screening, seven studies (2 rcts and five non-randomized comparative studies),(2,4,5,8-11) involving 125 participants in ltu group and 128 in lru group, satisfied our inclusion criteria. the process of study identification is detailed in figure 1. except for one conference abstract,(11) the full texts of the left six studies were obtained. overall, the quality of non-randomized comparative studies was very high, with only one study(4) having a nos of 6, and two rcts(8,10) had a modified jadad scale of 5. the characteristics of included studies were listed in table 1. demographic and baseline characteristics of enrolled patients were presented in table 2. primary outcomes single-procedure success rate patients in ltu group had significantly higher single-procedure success rate than those in lru group (95.2% vs 87.5%, 95% ci: .00-.16, rd = .08, p = .04, figure 2). for the primary outcome, the publication bias was not observed with the egger’s test (p = .117; figure 3). secondary outcomes according to the clavien-dindo grade, complications were listed in table 3. no significant differences were observed in terms of operative time (95% ci: -18.958.80, md = -5.08, p = .47, figure 4) and length of hospital stay (95% ci: -.98.58, md = -.20, p = .61, figure 4). however, significant heterogeneity was reported (i² = 87%, i² = 90%, respectively, figure 4). additionally, according to the clavien-dindo grade, major complications between two groups were similar in terms of open conversion (.8% vs 5.5%, 95%ci: -.11.01, rd = -.05, p = .12, figure 5), stone migration (8.1% vs 6.7%, 95% ci: -.08.11, rd = .02, p = .76, figure 5), vascular injury (5.4% vs 0, 95%ci: -.03.14, rd = .05, p = .21, figure 5) and ureteral stricture (1.3% vs 5.3%, 95% figure 2. forest plot of comparison: single-one procedure success rate. figure 3. eggers plot for the single-one procedure success rate. laparoscopy in proximal ureteral calculus-chen et al. review 14 vol 18 no 1 january-february 2021 15 ci: -.11.02, rd = -.04, p = .20, figure 5). one case in ltu group with grade 4a complication (pulmonary embolus) was recorded in the study by abat et al.(4) the patient was admitted to intensive care unit (icu) for further treatment. considering minor complications, except for paralytic ileus of which the morbidity was significantly higher in ltu group (10.4% vs 0, 95% ci: .02.19, rd = .10, p = .02, figure 6), no statistical differences were noted between two groups in terms of urinary tract infection (uti) (21.8% vs 23.1%, 95% ci: -.17.14, rd = -.01, p = .87, figure 6), transfusion (4.2% vs 1.4%, 95% ci: -.04.09, rd = .02, p = .49, figure 4. forest plot of comparison: operative time and hospital duration. figure 5. forest plot of comparison: major complications. laparoscopy in proximal ureteral calculus-chen et al. figure 6), prolonged drainage (8% vs 7.3%, 95% ci: -.08.09, rd = .00, p = .95, figure 6), and retroperitoneal hematoma (2.4% vs 3.5%, 95% ci: -.07.05, rd = -.01, p = .74, figure 6). discussion for large(>10mm) and proximal ureteral stones, lu shows significantly higher sfr than urs.(8) it is still unclear which approach, transperitoneal or retro-peritoneal, is better in terms of efficacy and safety. our results revealed that patients in the ltu group had a significantly higher single-procedure success rate than those in the lru group. they suffered from a substantially higher proportion of postoperative paralytic ileus. however, it had to be admitted that the overall sample size and number of included studies were small, which was the main drawback of the study. thus, theoretical significance may be clinically insignificant. the significantly higher single-procedure success rate in ltu group may be explained by the advantages of transperitoneal approach and drawbacks of retro-peritoneal approach, as well as open conversion rate. as we know, ltu owns advantages including a wider operating field, clear anatomical landmarks, and easy identification of the ureter. contrarily, lru has drawbacks including limited working space, lacking anatomic landmarks, and difficulty in suturing the ureter. moreover, periureteral inflammatory adhesions because of long impaction time by large stones could contribute to relatively difficult identification of ureter in retroperitoneal approach.(8,10) thus, open conversion rate was relatively higher in the lru group (5.5% vs 0.8%) due to these drawbacks, although the difference was not significant. moreover, şahin et al(12) also reported one case in the lru group who was converted to open surgery. with respect to postoperative complications, the rate of paralytic ileus was significantly higher in the ltu group. surprisingly, only patients who had received ltu suffered from the complication.(2,4,8) the result was consistent with that of the study of şahin et al.(12) moreover, khalil et al(10) described in their report that the average time to oral intake was significantly longer in the ltu group than in the lru group (15.5 ± 2.8h vs 21.2 ± 4.9h, p = .002). this could be explained by the fact that ltu has disadvantages including intestine mobilization, peritoneal contamination with blood or urine leakage, and dissection or retraction of viscera. in lru, lost blood does not come into the bowel and urine leakage would be contained within the retroperitoneal space and for cases with previous abdominal surgery, bowel injury could be prevented.(4) however, the complication was well-tolerated, and did not need surgical intervention. it seemed that vascular injury only developed in the ltu group (table 3). the outcome, however, revealed no significant difference between the two groups. in fact, patients in the lru group still could suffer from the complication.(12) among patients with vascular injury, two suffered from inferior vena cava injuries, who were managed by laparoscopy and open access,(2,4) respectively. of note, surgeons in each study had limited laparoscopic experience. they just completed a laparoscopic training programme or were during their learning curve in laparoscopy. besides, pierluigi et al(2) reported 10 cases in the lru group who developed peritoneal tearing when the surgeon tied to make pneumoperitofigure 6. forest plot of comparison: minor complications. laparoscopy in proximal ureteral calculus-chen et al. review 16 vol 18 no 1 january-february 2021 17 neum, resulting in prolonged operative time. we also noticed that the outcomes of operative time and hospital duration revealed significant heterogeneity (i² = 87%, i² = 90%, respectively, figure 4). the experience of the surgeon, which differed in studies included, may explain it. because a surgeon who has initial experience in laparoscopy is unfamiliar with surgical procedures and the anatomy around ureter, resulting in being slow, and careful and needing more dissection and a prolonged operative time which causes an increase postoperative pain and dose of analgesic prescribed. therefore, longer hospital stay is required due to pain management.(10) in brief, it was noteworthy that experience in laparoscopy mattered with respect to operative time and hospital stay, as well as morbidity of complications. three included studies reported their experience in the management of migrated stones.(4,8,10) urs, percutaneous nephrolithotomy (pcnl) and lu were adopted and these patients achieved complete sfr. totally 5 stone migrations were reported in the study by şahin et al(12) and were managed by swl and ureteroscope successfully. for migrated stones, a combination of lu with endourologic lithotripsy through the laparoscopic ports (urs) may be better for that urs needs no laparoscopic ports(13), indicating that no more puncture was needed. in this study, the incidences of prolonged drainage and ureteral stricture were similar between two groups. some urologists believed that ureteral stent placement following lu could prevent urine leakage and stricture, while others opposed the opinion because stenting may add cost and discomfort to the patient.(8) one meta-analysis(14) in 2017 concluded that no significant difference was found in the rate of prolonged drainage between stented and stentless lu. however, ureteral stricture was not pooled in the analysis due to limited data. future studies are needed to address this topic. other minor complications including uti and retroperitoneal hematoma were well-tolerated and were managed with conservative treatment. although blood transfusion was needed for some cases, the overall rate (2.8%) was low. overall, both two approaches were safe and efficient in the management of large and proximal ureteral stones. interestingly, nouralizadeh et al.(13) reported their experience in synchronous or metachronous bilateral laparoscopic stone surgery and the result revealed that this procedure was feasible for laparoscopic expertise. o'kelly and colleagues(15) found that lu was safe in the management of partial duplex ureteric collecting system. even though this is the first meta-analysis to evaluate the efficacy and safety of two approaches in the management of large and proximal ureteral calculi, some limitations should be clarified. firstly, the number of included studies and the sample sizes was relatively small. secondly, the number and experience of surgeons varied among these studies, in addition to different study designs, contributing to certain biases. thirdly, subgroup analysis was not applied due to limited data. conclusions ltu has a significantly higher single-procedure success rate and paralytic ileus rate than lru, but the complication is well-tolerated. acknowledgments this work was supported by chongqing science and technology commission (cstc2015shmszx120067). conflicts of interest the authors report no conflicts of interest. references 1. zumstein v, betschart p, abt d, schmid h-p, panje cm, putora pm. surgical management of urolithiasis–a systematic analysis of available guidelines. bmc urol. 2018;18:25. 2. bove p, micali s, miano r, et al. laparoscopic ureterolithotomy: a comparison between the transperitoneal and the retroperitoneal approach during the learning curve. j endourol. 2009;23:953-7. 3. raboy a, ferzli gs, ioffreda r, alber ps. laparoscopic ureterolithotomy. urology. 1992;39:223-5. 4. abat d, altunkol a, kuyucu f, demirci da, vuruskan e, bayazit y. after a urological laparoscopic training programme, which laparoscopic method is safer and more feasible in the management of proximal ureteral stones: transperitoneal or retroperitoneal? jpma. 2016;66:971-6. 5. kongchareonsombat w, atichoksakun s, kitvikai k, patcharatrakul s, chaimuengraj s. extraperitoneal versus transperitoneal approach of laparoscopic ureterolithotomy in selected patients. j med assoc thai. 2010;93:794-8. 6. shamseer l, moher d, clarke m, et al. preferred reporting items for systematic review and meta-analysis protocols (prisma-p) 2015: elaboration and explanation. bmj (clinical research ed.). 2015;350:g7647-g. 7. dindo d. the clavien–dindo classification of surgical complications. treatment of postoperative complications after digestive surgery: springer; 2014:13-7. 8. singh v, sinha rj, gupta dk, kumar m, akhtar a. transperitoneal versus retroperitoneal laparoscopic ureterolithotomy: a prospective randomized comparison study. j urol. 2013;189:940‐5. 9. almeida g, heldwein fl, graziotin tm, schmitt cs, teloken c. a prospective trial comparing laparoscopic and open surgery for the treatment of impacted ureteral stones. actas urol esp. 2009;33:1108-14. 10. khalil m, omar r, abdel-baky s, mohey a, sebaey a. laparoscopic ureterolithotomy; which is better: transperitoneal or retroperitoneal approach? turk j urol. 2015;41:185-90. 11. chiu hc, chang ch, wu hc, huang cp. the comparison of peritoneal, retro-peritoneal and transperitoneal robotic assisted laparoscopic ureterolithotomy for large proximal ureteral stone. eur urol suppl. 2015;14:e982-ea. 12. şahin s, aras b, ekşi m, şener nc, tugču v. laparoscopic ureterolithotomy. jsls. 2016;20. laparoscopy in proximal ureteral calculus-chen et al. 13. nouralizadeh a, kashi ah, valipour r, nasiri kopaee mr, zeinali m, sarhangnejad r. bilateral laparoscopic stone surgery for renal stonesa case series. urol j. 2017;14:5043-6. 14. soltani mh, shemshaki h. stented versus stentless laparoscopic ureterolithotomy: a systematic review and meta-analysis. j laparoendosc adv surg tech a. 2017;27:1269-74. 15. o'kelly f, nicholson p, brennan j, carroll a, skehan s, mulvin dw. a novel case of laparoscopic ureterolithotomy in a partial duplex ureteric collecting system: can open procedures still be justified in the minimally invasive era? irish j med sci. 2013;182:51922. laparoscopy in proximal ureteral calculus-chen et al. review 18 urol_v03_no4_001_editorial.indd urological oncology 212 urology journal vol 3 no 4 autumn 2006 extensive surgical management for renal tumors with inferior vena cava thrombus mohsen ayati, abolghasem nikfallah, parviz jabalameli, vahid najjaran tousi, mohammadreza noroozi, hasan jamshidian introduction: the aim of this study was to evaluate the outcome in patients with renal cell carcinoma (rcc) and the inferior vena cava (ivc) or the right atrium tumor thrombus that were treated with radical nephrectomy and thrombectomy. materials and methods: eleven of a total of 105 patients who underwent radical nephrectomy due to rcc had tumor thrombus extended to the ivc and/or the right atrium. we evaluated the surgical techniques used and the perioperative mortality and morbidity in these patients. results: the median age of the patients was 47 years (range, 16 to 59 years). they all underwent radical nephrectomy with cavotomy, tumor thrombus removal, and lymphadenectomy. eight patients underwent extracorporeal circulation and hypothermic circulatory arrest; 2, temporary venovenous bypass by chevron incision and median sternotomy; and 1, only chevron incision with mobilization of the right lobe of the liver and cross-clamping proximal to the tumor thrombus and cavotomy. in 1 case, a solitary liver metastasis was excised and the patient died within 30 days postoperatively because of massive hemorrhage due to liver metastatectomy. two patients had invasion to the ivc wall and 7 had pathological lymph node involvement. four patients were tumor free (follow-up range, 9 to 18 months) and 7 died due to multiple metastases during the follow-up. conclusion: this study supports the role of extensive surgical treatment as the best initial management of patients with renal cancer extended to the ivc only in highly selected cases. urol j (tehran). 2006;4:212-5. www.uj.unrc.ir keywords: renal tumor, thrombus, vena cava, right atrium department of uro-oncology, imam khomeini hospital, tehran university of medical sciences, tehran, iran corresponding author: vahid najjaran tousi, md department of urology, imam khomeini hospital tohid sq, tehran, iran tel: +98 912 380 1237 e-mail: najjaran_vahid@yahoo.com received june 2006 accepted september 2006 introduction extensive management of renal cell carcinoma (rcc) with venous thrombus has been supported by corroborative evidence.(1–5) tumor thrombus extension into the renal vein or the inferior vena cava (ivc) occurs in up to 10% of patients with rcc and the involvement of the right atrium is seen in 1%. factors influencing the outcome of these patients include the clinical staging, completeness of the resection, and biological characteristics of the primary tumor.(1) survival may be significant in patients with organconfined tumors.(6–9) the 5-year survival is about 60% for the most favorable tumors.(4–6) in nonmetastatic patients with ivc involvement, the 5-year survival rate is reported to be between 18% and 68% with a perioperative mortality rate of 2.7% to 13% after complete surgical resection.(1,4,5) however, intravenous tumor extension will not be associated with an adverse prognosis provided that a complete resection is possible.(10–12) we report the operative strategies and outcomes in our renal tumors with inferior vena cava thrombus—ayati et al urology journal vol 3 no 4 autumn 2006 213 patients with rcc extending into the ivc and/or the right atrium. materials and methods patients between 1999 and 2005, a total of 105 patients with rcc underwent radical nephrectomy at our center. venous tumor thrombus was reported in 11 patients. according to the classification used by blute and colleagues (table 1),(1) there were 1 patient with inferahepatic ivc tumor thrombus (level 2), 2 with retrohepatic ivc tumor extension (level 3), 7 with suprahepatic ivc extension (level 4), and 1 with extension into the right atrium (level 4). all of the patients underwent abdominal, pelvic, and chest computed tomography (ct). magnetic resonance imaging (mri) was performed in cases suspected to have tumor thrombus. based on the findings of ct scan and mri, all tumors were confined to the gerota’s fascia. four of the patients had suspected lymph node involvement and 1 had a solitary metastasis in the right lobe of the liver (table 2). surgical strategy we applied the following approaches depending on the disease condition: in cases with thrombus extension into the infrahepatic ivc, a chevron incision with mobilization of the right lobe of the liver was made and cross-clamping of ivc above and below the tumor thrombus and then cavotomy were performed. if cross-clamping of the ivc was necessary and venous return to the heart was impaired, a chevron incision was made and median sternotomy with temporary venovenous bypass from the ivc below the cross-clamping site to the right atrium was done. for level 4 tumor extensions, a chevron incision was made and median sternotomy with extracorporeal circulation and hypothermic circulatory arrest were performed. the median follow-up of the patients was 11 months (range, 0 to 36 months). none of the patients received postoperative immunotherapy. only 1 patient with wilms tumor received adjuvant chemotherapy. results the clinical characteristics and outcomes are listed in table 2. the median age of the patients was 47 years (range, 16 to 59 years). eight patients were men and 3 were women. they all underwent radical nephrectomy with concomitant cavotomy, tumor thrombus removal, and lymphadenectomy. eight patients underwent extracorporeal circulation and pathology tumor extension level stage surgical technique follow-up, mo outcome rcc 4 t3c n2 m0 hypothermic circulatory arrest 10 died of metastases rcc 4 t3c n2 m0 hypothermic circulatory arrest 13 died of metastases rcc 4 t3c n2 m0 hypothermic circulatory arrest 10 died of metastases rcc 4 t3c n2 m1 hypothermic circulatory arrest 0 died of bleeding rcc 4 t3c n1 m0 hypothermic circulatory arrest 12 died of metastases rcc 4 t3c n1 m0 hypothermic circulatory arrest 9 died of metastases rcc 4 t3c n0 m0 hypothermic circulatory arrest 14 alive without tumor rcc 3 t3b n0 m0 venovenous bypass 18 alive without tumor rcc 3 t3b n0 m0 venovenous bypass 15 alive without tumor rcc 2 t3b n0 m0 elevation of liver and cross-clamping of ivc 9 alive without tumor wilms tumor 4 t3 n+ hypothermic circulatory arrest 36 died of metastases table2. clinical characteristics, surgical managements, and outcomes* *rcc indicates renal cell carcinoma and ivc, the inferior vena cava. table 1. levels of tumor thrombosis* levels definition 1 tumor extending up to 2 cm above the renal vein 2 tumor extending more than 2 cm above the renal vein but limited to the infrahepatic ivc 3 tumor extending into the ivc up to the diaphragm 4 tumor extending into supradiaphragmatic ivc or the right atrium *based on a classification used by blute and colleagues.(1) ivc indicates the inferior vena cava. renal tumors with inferior vena cava thrombus—ayati et al 214 urology journal vol 3 no 4 autumn 2006 hypothermic circulatory arrest and 2 were managed with temporary venovenous bypass by chevron incision and median sternotomy. in 1 patient, we used only chevron incision with mobilization of the right lobe of the liver and cross-clamping proximal to the tumor thrombus and cavotomy. a solitary liver metastasis was excised by a general surgeon, but the patient died within 30 days postoperatively because of massive hemorrhage due to liver metastatectomy. the median estimated blood loss was 2 l (range, 350 ml to 12 l). two patients had invasion to the ivc wall and 7 had pathological lymph node involvement. four patients were alive at the end of the follow-up without evidence of local tumor recurrence or distant organ metastases (follow-up range, 9 to 18 months). finally, 7 patients died due to multiple metastases. discussion outcome predictors in rcc with tumor thrombus extending into the ivc or the right atrium are variably discussed. the most common factors influencing the prognosis are local infiltration to perinephric tissue, lymph node involvement, distant metastases, pathological stage of the tumor, and invasion to the vena cava regardless of the level of tumor extension.(1) therefore, complete staging should be performed for these patients.(13) the role of mri in the evaluation of the renal vein and ivc for detection of the thrombus extension is crucial.(14) another good technique for detection of the thrombus extension into the right atrium is preoperative and intraoperative transesophageal echocardiography.(4,9) the role of proximal extension of tumor thrombus as a prognostic factor in the absence of lymph node involvement or metastatic disease is controversial. libertino and colleagues detected no differences in the prognosis regarding the level of ivc involvement.(15) in contrast, sosa and associates reported a poor outcome in patients with tumor thrombus.(16) outcome of the surgery in the presence of synchronous metastatic disease is also a matter of debate. some authors have reported grave survival rate, while others have advocated surgery with satisfactory results.(9,17) overall, 1-year survival in the patients with ivc and lymph node involvement supports the role of surgery only in patients with rcc and venous thrombus without any concomitant lymphadenopathy or metastases. ficarra and coworkers reported that the best chance of cure and long-term survival is achieved by a combination of radical surgery and adjuvant immunotherapy.(13) the surgical approach should be individualized according to the level of the tumor thrombus and decision should be made by both cardiovascular surgeon and urologist. the choice of incision, caval control method, and venous return provision are important factors in surgical approach. according to our experience, a combined chevron incision with median sternotomy is the most appropriate method for adequate access to the kidneys, the ivc, and the heart. side-clamping or cross-clamping of the ivc may be sufficient if the involvement of the ivc is limited to the level of the renal vein. however, patients with partially obstructed ivc and inadequate collaterals may not permit caval cross-clamping. in these cases, venous blood flow from the ivc has to be provided.(18,19) in some patients, an intraluminal shunt may be applicable, but may be accompanied by the risk of tumor embolization. therefore, we prefer a temporary venovenous bypass from the ivc to the right atrium if cross-clamping of the ivc significantly impairs the venous return.(20) when the tumor thrombus reaches the intrapericardial ivc or the right heart, hypothermic circulatory arrest is the approach of choice. this technique allows complete resection of the tumor in a virtually bloodless operation field without the risk of leaving tumor cells or tumor thrombus embolization, in contrast to cardiopulmonary bypass alone or blind mobilization of the tumor thrombus via the right atrium. also, the risk of uncontrollable massive bleeding is nearly eliminated which provides a safer operation.(21) furthermore, the ivc may be inspected thoroughly and an appropriate resection may be performed. if resection of the intrapericardial ivc or the right atrium is necessary, it can also be done more easily by this approach.(22) conclusion surgical removal of rcc tumors through a chevron incision and median sternotomy is possible. we believe that patients with lymph node and ivc involvement do not benefit from this aggressive surgical management. therefore, accurate clinical renal tumors with inferior vena cava thrombus—ayati et al urology journal vol 3 no 4 autumn 2006 215 staging is mandatory and surgery is recommended only for highly selected patients. conflict of interest none declared. references 1. blute ml, leibovich bc, lohse cm, cheville jc, zincke h. the mayo clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumour thrombus. bju int. 2004;94:33-41. 2. kaplan s, ekici s, dogan r, demircin m, ozen h, pasaoglu i. surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. am j surg. 2002;183:292-9. 3. belis ja, levinson me, pae we jr. complete radical nephrectomy and vena caval thrombectomy during circulatory arrest. j urol. 2000;163:434-6. 4. marshall ff, dietrick dd, baumgartner wa, reitz ba. surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. j urol. 1988;139:1166-72. 5. novick ac, kaye mc, cosgrove dm, et al. experience with cardiopulmonary bypass and deep hypothermic circulatory arrest in the management of retroperitoneal tumors with large vena caval thrombi. ann surg. 1990;212:472-6. 6. gettman mt, boelter cw, cheville jc, zincke h, bryant sc, blute ml. charlson co-morbidity index as a predictor of outcome after surgery for renal cell carcinoma with renal vein, vena cava or right atrium extension. j urol. 2003;169:1282-6. 7. quek ml, stein jp, skinner dg. surgical approaches to venous tumor thrombus. semin urol oncol. 2001;19:88-97. 8. bissada nk, yakout hh, babanouri a, et al. long-term experience with management of renal cell carcinoma involving the inferior vena cava. urology. 2003;61:89-92. 9. staehler g, brkovic d. the role of radical surgery for renal cell carcinoma with extension into the vena cava. j urol. 2000;163:1671-5. 10. neves rj, zincke h. surgical treatment of renal cancer with vena cava extension. br j urol. 1987;59: 390-5. 11. baumgartner f, scott r, zane r, et al. modified venovenous bypass technique for resection of renal and adrenal carcinomas with involvement of the inferior vena cava. eur j surg. 1996;162:59-62. 12. chiappini b, savini c, marinelli g, et al. cavoatrial tumor thrombus: single-stage surgical approach with profound hypothermia and circulatory arrest, including a review of the literature. j thorac cardiovasc surg. 2002;124:684-8. 13. ficarra v, righetti r, d’amico a, et al. renal vein and vena cava involvement does not affect prognosis in patients with renal cell carcinoma. oncology. 2001;61: 10-5. 14. oto a, herts br, remer em, novick ac. inferior vena cava tumor thrombus in renal cell carcinoma: staging by mr imaging and impact on surgical treatment. ajr am j roentgenol. 1998;171:1619-24. 15. libertino ja, zinman l, watkins e jr. long-term results of resection of renal cell cancer with extension into inferior vena cava. j urol. 1987;137:21-4. 16. sosa re, muecke ec, vaughan ed jr, mccarron jp jr. renal cell carcinoma extending into the inferior vena cava: the prognostic significance of the level of vena caval involvement. j urol. 1984;132:1097-100. 17. zisman a, wieder ja, pantuck aj, et al. renal cell carcinoma with tumor thrombus extension: biology, role of nephrectomy and response to immunotherapy. j urol. 2003;169:909-16. 18. janosko eo, powell cs, spence pa, hodges we, lust rm. surgical management of renal cell carcinoma with extensive intracaval involvement using a venous bypass system suitable for rapid conversion to total cardiopulmonary bypass. j urol. 1991;145: 555-7. 19. attwood s, lang dm, goiti j, grant j. venous bypass for surgical resection of renal carcinoma invading the vena cava: a new approach. br j urol. 1988;66:402-5. 20. rotker j, schmid c, oberpennig f, et al. surgery of the inferior vena cava for tumor-related obstruction. int j angiol. 1998;7:173-6. 21. laas j, schmid c, allhoff e, borst hg. tumor-related obstruction of the inferior vena cava extending into the right heart--a plea for surgery in deep hypothermic circulatory arrest. eur j cardiothorac surg. 1991;5: 653-6. 22. skinner dg, pritchett tr, lieskovsky g, boyd sd, stiles qr. vena caval involvement by renal cell carcinoma. surgical resection provides meaningful long-term survival. ann surg. 1989;210:387-92. case report 197urology journal vol 5 no 3 summer 2008 mucinous cystadenoma arising from renal pelvis a report of 2 cases nitin gangane, anshu, nitin shende, satish m sharma urol j. 2008;5:197-9. www.uj.unrc.ir keywords: renal pelvis, mucinous cystadenoma, pelvic neoplasms department of pathology, mahatma gandhi institute of medical sciences, sevagram, maharashtra, india corresponding author: nitin gangane, md department of pathology, mahatma gandhi institute of medical sciences, sevagram 442102, wardha, maharashtra, india tel: +91 7152 284 955 fax: +91 7152 284 333 email: nitingangane@rediffmail.com received july 2007 accepted april 2008 introduction epithelial tumors originating from the renal pelvis are uncommon, and adenocarcinomas account for less than 1% of malignancies which arise from renal pelvic epithelium.(1) primary mucinous epithelial tumors occurring in the kidney are presumed to originate from the multipotential renal pelvic epithelium. most reported cases are malignant.(2) only isolated cases have been reported where the epithelial lining of the tumor was benign.(3) we report 2 cases of mucinous cystadenoma arising from the renal pelvis and discuss the histogenesis of this rare lesion. case reports case 1 a 35-year-old woman presented with complaints of a lump of 2 years duration in the left upper abdomen and intermittent pain in the abdomen. an irregular lump was palpable in the left hypogastrium. the clinical diagnosis was hydronephrosis. left nephrectomy was done and the specimen showed grossly distorted kidney and pelvis. the kidney was thick walled and showed areas of hemorrhage and necrosis, and a smooth-walled unilocular cyst was seen in the pelvis (figure 1). copious amount of thick viscid mucinous fluid extruded out on cutting open the kidney. the cyst wall and the renal pelvis were in apposition. the calyxes were dilated. no calculi could be found either in the kidney or in the pelvis. on histology, the cyst wall showed a single-layered tall columnar mucinous epithelium that resembled endocervical cells. there was focal pseudostratification (figure 2). however, there were figure 1. unilocular cyst in the pelvic region with glistening mucoid cyst wall. figure 2. papillary projections and marked stratification of the epithelium lining the cyst wall (hematoxylin-eosin, × 100). mucinous cystadenoma of renal pelvis—gangane et al 198 urology journal vol 5 no 3 summer 2008 no areas of nuclear atypia, multilayering, or stromal invasion. sections from the adjacent areas of transitional epithelium failed to reveal any inflammatory or metaplastic changes. a diagnosis of mucinous cystadenoma arising from the renal pelvis was made. during the 2-year follow-up, the patient was well and no recurrence of the neoplasm occurred. case 2 a 65-year-old man presented with pain in the abdomen, weakness and loss of appetite of 8 days duration. on physical examination, a tender lump was palpable in his left lumbar region, extending up to the left iliac fossa. the lump was firm and ballottable. he was found to have prostatomegaly on rectal examination. the primary clinical diagnosis was left renal mass with prostatic hyperplasia. ultrasonographic examination of the abdomen revealed an enlarged left kidney, which was labeled as pyonephrosis. a calculus was present in his left lower calyx, and the proximal left ureter was dilated. peripheral smear examination revealed anemia (hemoglobin, 5.4 g/dl) and neutrophil leukocytosis with presence of toxic granules. urine microscopy showed pyuria. urine culture showed growth of escherichia coli and klebsiella pneumoniae. the patient was operated on and a grossly dilated left kidney measuring 13 × 9 × 4 cm3 was extracted. the renal capsule could not be stripped off. on the cut section, the pyelocaliceal system was extensively dilated and distorted. the cortex was thinned out to a fibrous rim. there were multiple smooth-walled dilated cystic areas, some of which were filled with grey opaque gelatinous clots. no distinct mass could be outlined. on pathology examination, only occasional glomeruli were seen. the pelvic lining epithelium showed dense fibrocollagenous tissue and infiltration by lymphocytes and plasma cells. there were some foci where the lining was made of transitional epithelium, but largely, the cystically dilated areas were lined by single layers of mucin secreting cells with basally located nuclei. there was minimal architectural complexity. at places, these cells showed pseudostratification and were thrown into delicate papillary folds. the epithelium was reminiscent of the lining epithelium of mucinous cystadenoma of the ovary. the nuclei were bland looking, and foci of stromal invasion were absent. a transition from nonneoplastic urothelium to mucinous epithelium was demonstrable (figure 3). a diagnosis of mucinous cystadenoma arising from the renal pelvis with changes of pyonephrosis was made. the patient did well postoperatively and was symptom free during the 8-month follow-up period. discussion adenocarcinomas arising from the renal pelvic epithelium are rare, accounting for less than 1% of all epithelial malignancies found in the renal pelvis.(1) the existence of a benign counterpart of mucinous adenocarcinoma is an unsettled issue.(3) auferderheide and streitz(2) reviewed 32 cases of glandular neoplasm occurring in the renal pelvis. of the 31 cases with adequate information, only 3 showed no malignant changes. thus, the majority of the cases were interpreted as malignant. ross and d’amato(3) reported a case of papillary mucinous cystadenoma of probable renal pelvic origin in a horseshoe kidney. they suggested that the same criteria used for evaluating mucinous ovarian tumors might also be appropriate for mucinous tumors of the kidney. similarly, the striking resemblance of this lesion to mucinous cystadenoma of the ovary suggests the possibility of a similar histogenesis, ie, either mesodermal coelomic epithelium or teratomatous in derivation. the normal transitional epithelium is capable of metaplasia into squamous, columnar, or cuboidal form.(4) transitional or squamous carcinomas are figure 3. pseudostratified epithelium with mucinous metaplasia (hematoxylin-eosin, × 100). mucinous cystadenoma of renal pelvis—gangane et al urology journal vol 5 no 3 summer 2008 199 more frequently seen, as squamous metaplasia is relatively more common. protoplastic conversion of transitional epithelium to colonic type of epithelium is exceedingly rare, and by that logic, mucin producing adenocarcinoma should be exceedingly uncommon. we believe that mucinous cystadenoma, like its malignant counterpart, arises in foci of intestinal metaplasia, as we were able to demonstrate histological transition from transitional epithelium to metaplastic mucinous areas in the same lesion. toyoda and colleagues(5) and mardi and colleagues(6) reported a case of mucinous cystadenoma arising from the renal pelvis which showed malignant transformation. they suggested the possibility that adenomacarcinoma sequence might exist among the glandular neoplasms arising from the renal pelvis. however, we are documenting cases of mucinous metaplasia progressing to adenoma which may progress to malignancy. urothelial glandular metaplasia often develops nonspecifically in response to injury.(4) glandular metaplasia and chronic inflammation with or without obstruction frequently coexist with carcinoma, leading to speculation by many authors that intestinal metaplasia is the precursor lesion for adenocarcinoma.(4) this is supported by compelling reports of a high incidence of associated adenocarcinoma (30%) in cases of significant grossly identifiable intestinal metaplasia followed up for more than 2 years.(2) long-standing chronic infection and kidney calculi have been invoked as possible etiologic factors in mucinous adenocarcinoma of the pelvis.(7) it is not clear if the same hypothesis holds true for adenomas as well. while one of our patients had a long-standing infection and calculus, the other one had no such preceding lesion. however, liwnicz and associates(8) postulated that formation of the calculi might be initiated by the abundant glycoproteins secreted by the tumor. these glycoproteins can bind to cations such as sodium, calcium, and magnesium, forming larger calculi. thus, calculi may be the result, and not the cause of the neoplasm. in most of the previously reported cases of adenocarcinoma, however, the kidneys were chronically infected.(2,7) it is noteworthy that the literature from india(9-11) indicates a greater incidence of adenocarcinoma of the renal pelvis than data published from other geographical areas. the predisposing factors leading to this apparent increased incidence needs to be evaluated. there have been series of adenocarcinomas that show lower frequencies of calculi.(12) epidemiological studies in specific geographic locations like india are essential if the etiology and progression of this rare neoplasm is to be unraveled. conflict of interest none declared. references 1. ward am. glandular neoplasia within the urinary tract. the aetiology of adenocarcinoma of the urothelium with a review of the literature. i. introduction: the origin of glandular epithelium in the renal pelvis, ureter and bladder. virchows arch a pathol pathol anat. 1971;352:296-311. 2. aufderheide ac, streitz jm. mucinous adenocarcinoma of the renal pelvis. report of two cases. cancer. 1974;33:167-73. 3. ross dg, d’amato na. papillary mucinous cystadenoma of probable renal pelvic origin in a horseshoe kidney. arch pathol lab med. 1985;109:954-5. 4. mostofi fk. potentialities of bladder epithelium. j urol. 1954;71:705-14. 5. toyoda h, mabuchi t, fukuda k. mucinous cystadenoma with malignant transformation arising in the renal pelvis. pathol int. 1997;47:174-8. 6. mardi k, sharma j, mahajan p. mucinous cystadenoma of the renal pelvis with malignant transformation: a case report. indian j pathol microbiol. 2006;49:595-6. 7. kobayashi s, ohmori m, akaeda t, ohmori h, miyaji y. primary adenocarcinoma of the renal pelvis. report of two cases and brief review of literature. acta pathol jpn. 1983;33:589-97. 8. liwnicz bh, lepow h, schutte h, fernandez r, caberwal d. mucinous adenocarcinoma of the renal pelvis: discussion of possible pathogenesis. j urol. 1975;114:306-10. 9. ranadive nu, vaze am, abhyankar sc, bapat sd, deodhar kp. primary carcinomas of renal pelvis. (a follow up study). indian j pathol microbiol. 1984;27:11-7. 10. solanki rl, ramdeo in, gupta dp, mahawal bs. primary tumours of renal pelvis. indian j cancer. 1980;17:230-6. 11. guha t, datta bn, aikat bk, kataria pn. neoplasms of the kidney, renal pelvis and ureter. a study of 92 primary and 44 metastic tumours. indian j cancer. 1974;11:60-8. 12. spires se, banks er, cibull ml, munch l, delworth m, alexander nj. adenocarcinoma of renal pelvis. arch pathol lab med. 1993;117:1156-60. case report 200 urology journal vol 5 no 3 summer 2008 high-grade vesicoureteral reflux in pfeiffer syndrome abolhassan seyedzadeh, farshid kompani, ebrahim esmailie, sara samadzadeh, bohaire farshchi urol j. 2008;5:200-2. www.uj.unrc.ir keywords: pfeiffer syndrome, cleft lip, cleft palate, craniosynostoses, vesicoureteral reflux urology-nephrology research center, kermanshah university of medical sciences, kermanshah, iran corresponding author: abolhassan seyedzadeh, md emam reza hospital, zakaria blvd, kremanshah, iran tel: +98 918 131 2529 e-mail: asayedzadeh@kums.ac.ir received november 2007 accepted march 2008 introduction in 1964, pfeiffer described an acrocephalosyndactyly syndrome consisting of bicoronal craniosynostosis, midface hypoplasia, broad thumbs, broad big toes, and partial and variable soft-tissue syndactyly of the hands and feet.(1) autosomal dominant inheritance with complete penetrance is the main characteristic despite variable expressivity related to the presence or absence of syndactyly and its degree of severity. based on the severity of the phenotype, cohen proposed a classification of pfeiffer syndrome into 3 clinical subtypes.(2) we report, a case of pfeiffer syndrome type 2 with high-grade bilateral vesicoureteral reflux (vur), and discuss the importance of surveillance for urogenital problems in patients with this syndrome. case report a 4-month-old male infant was admitted to our hospital because of fever since 3 days earlier and generalized tonic-clonic seizure. he was a product of term normal vaginal delivery. he had 3 normal siblings. there was a history of abortion at the third month of gestation in the first maternal pregnancy. the parents had a normal phenotype and were not consanguineous. the mother was 34 years and the father was 36 years old. the child had failure to thrive with a birth weight of 3.8 kg. his present weight was 4.5 kg. developmental delay was also noticed. on physical examination, the patient had a cloverleaf skull, cleft palate, cleft lip, flat nasal bridge, broad toes, and low-set ears. proptosis and some degree of strabismus were also noticed (figure 1). on cardiac examination, a grade 2/6 systolic murmur was auscultated at the pulmonary area. mild valvular pulmonary stenosis was documented by echocardiography. skull radiography showed acrocephaly and the prominence of temporal bones (cloverleaf skull). computed tomography of the skull and brain showed bicoronal craniosynostosis and enlargement of lateral ventricles suggestive of moderate hydrocephalus. electroencephalography showed paroxysmal discharge. according to the abovementioned findings, diagnosis of pfeiffer syndrome was made clinically. ultrasonography of the urogenital january–february 2019 best reviewer of the issue – fazil marickar fazil marickar february 2019 dr. ym fazil marickar, ms, mams, phd (urology), fams, fas,fimsa, femsi is the vice chancellor of the mount zion international university of rwanda, east africa and dean, mount zion medical college, adoor, india. he has been a medical teacher for 47 years in surgery and urology and has been a guide for twenty students pursuing phd degree. he has authored eight text books, various chapters in medical books and over 300 publications in medical journals. he has done extensive research on urinary stone disease. he has completed 48 funded research projects of the icmr, csir, ksst, sbmr, asikc and university of kerala. his main interest in research is urinary stone disease concentrating on the aetiology and preventive aspects of stone disease. he has evolved fool proof prophylaxis against the common idiopathic calcium oxalate urinary stone. he has attended 29 international conferences, presented 140 guest lectures and scientific papers and chaired scientific sessions. he has presented over 1100 papers in scientific medical conferences in national and international level. he is currently the chief editor of kerala surgical journal, member of the editorial board of urolithiasis and reviewer for over twenty international medical and educational journals. he has been examiner for various undergraduate and post graduate medical examinations and adjudicator for phd from various universities in india and abroad. he has been member of the international consulting committee on urolithiasis for the last thirty years. he is an active member of the international urolithiasis society, british association of urological surgeons, society international de urology and various national associations. he is presently president of the association of genito urinary surgeons of india and governing council member of the association of surgeons of india 2013 – 2018. he has delivered various prestigious orations and guest lectures in india and abroad. he was awarded the best doctor award of the kerala state in 2000. reviewing and editing thesis submissions and papers for publication have been of ardent interest to dr. marickar. being a reviewer for urology journal has been a very fruitful experience. many submissions have grammatical errors; hence the correction at basic levels takes the prime focus of reviewing papers. the reviewer has to feel himself to be a layman in the subject and try to see whether the publication will benefit the lay reader. papers are primarily meant for the ordinary reader interested in learning the topic and not just meant for experts in the field. the introduction of any paper should clarify the intention of the paper and make it understandable to the basic reader. too much of statistical jargons should be avoided for the sake of the common reader. the formatting of the paper and the references should be done based on the requirements of the journal to which the paper is submitted for publication. plagiarism has to be screened by the reviewer, if not done at the journal office level. reviewers should not be harsh in rejecting papers. authors should be given opportunity to correct errors and explain their stand. peer review should help in increasing the quality of the paper. this responsibility lies with the reviewer. last but not the least, the reviewer has to accept all the invitations and return the reviewed article at the earliest and not wait for the last date for submission. many reviewers are lost due to procrastination. dr. marickar was chosen as the best reviewer(s) of the issue by the editorial board of the urology journal for his valuable and timely review of manuscript. v08_no_2_final.pdf urology for people 168 urology journal vol 8 no 2 spring 2011 what’s up in urology journal, spring 2011? urol j. 2011;8:168. www.uj.unrc.ir urethral stricture the urethra is a conduit that allows urine to leave the bladder. in men, the urethra is a thin tube-like structure that starts from the bladder neck and traverses the entire length of the penis. urethral stricture is a narrowing of the urethra caused by injuries or diseases such as urinary tract infections or sexually transmitted diseases. any instrument inserted into the urethra (such as a catheter) can also cause urethral stricture. any section of the urethra may be affected. during the early phase of the condition, the patient may experience pain during urination and the inability to fully empty the bladder. it is not uncommon for the bladder’s capacity to significantly increase due to this inability to completely void. however, the following symptoms may occur, which are likely to worsen with time: spraying of urine or a ‘double stream’ and dribbling of urine for a while after going to the toilet to pass urine. a look into the urethra by a special thin urethroscope will be needed to assess the stricture. there are various treatment options which aim to widen the narrowed section of the urethra. the urethra may be widened (dilated) during cystoscopy by inserting a thin instrument to stretch the urethra while you are under local anesthesia. you may be able to treat your stricture by learning to dilate the urethra at home (self intermittent catheterization). see page 132 for full-text article renal colic renal colic is a common condition in which a person experiences severe pain due to a kidney stone. the pain typically begins in the loin region and often radiates to the hypochondrium or the groin. the pain is often colicky (comes in waves), but may be constant. acute renal colic is often described as one of the strongest pain sensations felt by humans (being worse than childbirth, gunshot wounds, broken bones, burns, or stab wound). this severe pain usually accompanies with nausea and vomiting. the chance of kidney stone formation is most eminent when there is a richly concentration of dissolved substances in the urine. poor consumption of fluid increases the chance of developing kidney stones. if you are having a renal colic, it is best to seek always professional medical advice about any treatment or change in treatment plans. fortunately, surgery is not always necessary. most kidney stones (usually smaller than 5 mm) can pass through the urinary system with plenty of water (2 to 3 quarts a day) to help move the stone along. often, it is very important during this process to drink fluids and take pain medication as needed. recommendations for prevention: maintain fluid intake > 2.5 liters per day, ingest 8 to 12 ounces fluid at bedtime, maintain urine volume > 2 liters per day, and periodically measure urine output in a 2-liter bottle. restrictions: limit animal protein to 8 ounces per day, limit sodium intake to 2 grams per day, limit oxalate containing foods and beverages, such as cola, avoid excessive vitamin c, and increase dietary cereal fiber. see page 137 for full-text article urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. 1106 | effect of voiding position on uroflowmetric parameters in healthy and obstructed male patients cenk murat yazici, polat turker, cagri dogan corresponding author: cenk murat yazici, md department of urology, namik kemal univercity, tekirdag, 59100, turkey. tel: +90 506 855 2687 fax: +90 282 262 4625 e-mail: drcenkyazici@yahoo.com received february 2012 accepted april 2012 department of urology, namik kemal univercity, tekirdag, turkey miscellaneous purpose: uroflowmetry is frequently used and simple urodynamic test, but it may be affected by various factors. voiding position is one of the factors that can change the results. we tried to compare the uroflowmetric parameters in sitting and standing positions during urination. material and methods: a total of 198 patients were enrolled to the study. all patients underwent an uroflowmetry in standing and sitting position at late afternoon (2-4 pm) of two corresponding days with a gravimetric uroflowmeter (uroscan, aymed, turkey). a transabdominal ultrasonography was used to evaluate post voiding residue (pvr). all uroflowmetric parameters and pvr were compared with paired t test or wilcoxon signed rank test. results: the median age of study population was 58.0 (36-69) years. there was no statistically significant difference at voided volume of patients in standing and sitting position as it was 271.5 ± 81.8 ml and 274.8 ± 82.4 ml, respectively (p = .505). mean maximum flow rate (qmax) during urination at standing position was 15.3 ± 6.7 ml/s while it was 15.0 ± 7.0 ml/s at sitting position (p = .29). mean average flow rate in standing position was 8.60 ± 4.0 ml/s and 8.25 ± 3.8 ml/s in sitting position (p = .054). there was a statistically significant difference between the median post-voiding residues in standing and sitting urination which was 29.5 (0-257) ml in standing and 47.5 (2-209) ml in sitting position (p < .0001). other uroflowmetric parameters (time to maximum flow and voiding time) was not statistically different between groups. conclusion: there are no clinically important uroflowmetric differences between voiding in sitting and standing positions so voiding position may be left to personal preferences during uroflowmetric evaluation. keywords: urination disorders; urodynamics; predictive value of tests; posture; male. miscellaneous 1107vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction uroflowmetry is a frequently used and simple urodynamic test for both diagnosis and follow-up of obstructive lower urinary tract symptoms (luts). although it is a non-specific test, it can give valuable objective data. on the other hand, uroflowmetry may be affected by various internal and external factors such as age, sex, ethnicity, voided volume (vv) and psychological status of patients.(1) voiding position may be another factor affecting uroflowmetric results which is related with patients’ health status, social and cultural characteristics. there are some studies investigating the effect of voiding position on uroflowmetric parameters. these studies reported inconsistent results, some indicating voiding position affects uroflowmetric parameters, whereas some does not.(2-4) authors who reported supportive data about this relation concluded that positional changes of pelvic floor and thigh muscles might be effective on their results. as sitting and squatting position is the most common way of voiding habit of eastern and middle eastern countries, ritual or religious causes were proposed to be another explanation for those positional differences. but these theories need to be proven with more interventions because there are also some studies opposing these results.(5-7) daily preferred urination position may also affect uroflowmetric parameters. positions other than patients’ usual habit may change results causing misdiagnosis for patients. this theory also needs verification because there are very limited studies about this subject. in our study, we tried to compare the uroflowmetric parameters in different voiding positions and to discriminate the better voiding position for elimination of misdiagnosis. as sitting and standing positions during urination was the most preferred voiding positions in the western part of our country, we designed a study evaluating the uroflowmetric differences between these two positions. secondary objective of this study was to evaluate the uroflowmetric differences at patients voiding in a different position other than their natural voiding habit. the tertiary aim of this study was to investigate the effect of urination position on patients with low maximum flow rate values suggestive of bladder outlet obstruction (boo). material and methods study population a total of 250 male patients, between 35 to 70 years old, admitted to urology outpatient clinic with unilateral or bilateral flank pain, from april 2011 to november 2011, were prospectively enrolled to the study. for the homogeneity of the study population, we excluded female patients. the study was approved by institutional ethic committee. patients with a history of neurological disease, diabetes mellitus, urinary tract infection, prostate surgery, bladder and ureter stone, prostate cancer, bladder cancer, meatal stenosis, recent prostate biopsy and patients with ongoing medical treatment interfering lower urinary system function (like anticholinergics, alpha-blockers, 5-alpha reductase inhibitors, alpha stimulants, antibiotics etc.) were excluded. all patients underwent complete medical history, physical examination, digital rectal examination, urine analysis, urine culture, serum prostate specific antigen (psa) (in patients over 40 years) and urinary system ultrasonography. specific blood tests and radiological examination were performed according to symptoms by the choice of the clinician. natural voiding position and the duration was asked to the patients before uroflowmetric evaluation. natural voiding position was defined as the voiding position of patients that was used at more than 80% of their daily life micturations for a minimum of 15 years. as we evaluated sitting and standing positions, patients who had urination habit other than these positions (like squatting) were also excluded from the survey. study design all participants were cooperative and able to urinate in both sitting and standing position. as all patients were informed about study and given a written informed consent, an uroflowmetry in standing and sitting position was performed at late afternoon (2-4 pm) of two corresponding days with a gravimetric uroflowmeter (uroscan, aymed, turkey). patients were randomized according to voiding position for the first and second day evaluation. for the privacy and comfort of patients, uroflowmetric study was performed in a private room. the entire study group was informed to urivoiding parameters in positional changes | yazici et al 1108 | nate as their usual way of urination without any straining in both sitting and standing positions. uroflowmetries with a voided volume less than 150 ml were disregarded and patients recalled for a new measurement at the same time of the corresponding day. post voiding residue (pvr) was evaluated by transabdominal ultrasonography (accuson x 300, siemens ag, munich, germany). for this measurement, we used prolate ellipsoid method (volume = lenght × width × heigth × 0.52) which was shown to be effective for evaluation of bladder volumes.(8) patients were enrolled to uroflowmetry at the same time of the next day with a similar desire for urination, at a position other than the first day evaluation. bladder capacity before voiding was the most important parameter that may change the results of uroflowmetric evaluation. we calculated the exact bladder capacity by adding pvr to voided volume during the test. the difference between the bladder capacities of corresponding days over 20% was thought to be a bias for the results. study was repeated for the patients who had minimum 20% differences between the sum of voided volumes and pvr of corresponding days. all of the uroflowmetric parameters and pvr were compared in standing and sitting position. in order to evaluate the effect of urinary position on uroflowmetric parameters at different maximum flow rate (qmax) values, we also subdivided the patients into three groups; as patients with qmax < 10 ml/s, qmax 10-15 ml/s and qmax > 15 ml/s. statistical analysis as we had 2 dependent groups in our study, we evaluated the normalcy of data by using one sample kolmogorov-smirnov test. statistical analysis for normal data was performed by parametric test (paired t-test) and non-parametric test (wilcoxon signed rank test) was performed for non-normal data. the statistical package for social science (spss inc, chicago, illinois, usa) version 16.0 was used for statistical analysis. differences were stated as statistically significant as p < .05. results after the exclusion of 52 patients, a total of 198 patients were enrolled to study (figure). the mean age of study population was 57.1 ± 11.6 years. all patients were able to urinate in both standing and sitting positions. only 13 patients urinate less than 150 ml during second uroflowmetric evaluation and re-evaluated in the subsequent day. there was no statistically significant difference at voided volume of patients in standing and sitting position as it was 271.5 ± 81.8 ml and 274.8 ± 82.4 ml, respectively (p = .505). mean qmax during urination at standing position was 15.3 ± 6.7 ml/s while it was 15.0 ± 7.0 ml/s at sitting position (p = .29). mean average flow rate in standing position was 8.60 ± 4.0 ml/s and 8.25 ± 3.8 ml/s in sitting position (p = .054). there was a statistically significant difference between the median post-voiding residues in standing and sitting urination which was 29.5 (0-257) ml in standing and 47.5 (2-209) ml in sitting position (p < .0001). other uroflowmetric parameters (time to qmax and voiding time) was not statistically different between groups (table 1). as qmax values was shown to be related with the degree of bladder outlet obstruction, we sub-classified the patients as qmax at standing position > 15 ml/s, 10-15 ml/s and < 10 ml/s.(9) we evaluated the change of uroflowmetric parameters at different qmax values of each group in standing and sitting position. there were 96 (48.5%) patients with qmax > 15 ml/s, 64 (32.3%) patients with qmax 10-15 ml/s and 38 (19.2%) patients with qmax < 10 ml/s. voided volumes of all groups were similar in both sitting and standing positions and there was no statistically significant difference. maximum flow rates in sitting and standing position were not significantly different in patients with different qmax values (as subgroups are qmax > 15 ml/s, qmax 10-15 ml/s and qmax < 15 ml/s) whereas average flow rate presented a statistical difference in patients whose qmax < 10 ml/s. the mean average flow rate increased 0.5ml/s in sitting position and this difference was found to be significant (p = .022). it was not surprising that mean time to peak flow and voiding time increased as mean maximum flow rates decreased, but there was no statistically significant difference between groups for those parameters. as it was documented in whole groups, pvr was significantly higher in sitting position of all subgroups (p < .001) (table 2). our study population was composed of patients who use sitting or standing position for voiding in their daily life. miscellaneous 1109vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l there were 114 (57.6%) patients voiding at standing and 84 (42.4%) patients voiding in sitting position. we used patients’ natural voiding position as control group and evaluated the uroflowmetric parameter and pvr differences according to their natural voiding habit. the mean age of patients voiding in standing position was 56.4 ± 12.6 years. the mean age of patients voiding in sitting position was 58.2 ± 10.2 years (p = .062). although it was not statistically significant, patients who were voiding in sitting position in their daily life had better qmax values in sitting position. patients who void in standing position in their daily life had significantly better uroflowmetric parameters at standing position. nearly all uroflowmetric parameters except time to peak flow were significantly better when these patients performed uroflowmetry at their natural voiding position (standing position). on the other hand pvr was still significantly higher in sitting position unrelated to natural voiding position of patients (table 3). discussion uroflowmetry with pvr determination is an important and widely used urodynamic testing for evaluation of voiding dysfunction. although it does not discriminate bladder outlet obstruction from detrusor insufficiency, it can give valuable objective data about both degree of obstruction and affectivity of the treatment. as micturition is a dynamic event, various external and internal factors may influence this event. external factors are generally related with patients like; age, sex and psychological characteristics, whereas internal factors are mainly composed of the anatomical properties of lower urinary tract and corresponding tissues. neurological innervations of bladder and urethra and the biomechanical properties of detrusor muscle, urethra and urethral meatus are supposed to be the main determinants of micturition in all voiding models.(10,11) at myocybernetic model defined by bastiaanssen and colleagues, normal activity of sphincter was also supposed to be one of the factors related to micturition. according to this model, voiding position may affect striated muscle activity and geometrical properties of urethra and meatus.(10) rad and colleagues found that, average angle between rectum and anal canal was 92◦ while sitting and becomes 132◦ when the patient gets to squatting position and concluded that this may cause relaxation of puborectalis muscles leading more easier bladder and bowel evacuation.(12) in another study, bockus and colleagues reported that sitting position stretches the puborectalis muscle which slightly close urogenital hiatus.(13) although there were no significant difference at qmax and q average values of patients in standing and sitting position, we found statistically significant higher pvr values at voiding in sitting position. this data also shows a slight obstruction at urogenital hiatus during micturition at sitting position independent to presence or absence of bladder outlet obstruction. changes in parameters in healthy males there are some studies reporting controversial results about this subject. yamanishi and colleagues, evaluated 21 healthy male patients in 5 different voiding positions (standing, sitting, lateral, supine and prone) and reported no difference between standing and sitting position in terms of uroflowmetric parameters.(5) in another study, aghamir and colleagues evaluated 10 healthy males’ uroflowmetric parameters in standing and sitting position. they also found no difference and concluded that different voiding positions in healthy people did not influence uroflowmetric findings and pvr.(6) confirming these findings, unsal and colleagues found no difference in uroflowmetric parameters and pvr in standing and sitting position of 44 healthy table 1. comparison of uroflowmetric parameters in standing and sitting position of whole study group. standing position sitting position p qmax (ml/s) 15.3 ± 6.7 15.0 ± 7.0 p = .112** time to peak flow, s 8.0 (1.6-48.2) 8.3 (3.0-50.8) p = .247* average flow rate, ml/s 8.60 ± 4.0 8.25 ± 3.8 p = .054** voiding time, s 37.2 ± 19.3 38.9 ± 18.9 p = .124** voided volume, ml 271.5 ± 81.8 274.8 ± 82.4 p = .505** post voiding residue, ml 29.5 (0-257) 47.5 (2-209) p < .0001* key: qmax, maximum flow rate. *data were distributed non-normally according to kolmogorov-smirrov test so wilcoxon signed rank test was performed for statistical analysis and p value was calculated using the median data values. **data were distributed normally according to kolmogorov-smirrov test so paired t test was performed for statistical analysis and p value was calculated using the mean data values. voiding parameters in positional changes | yazici et al 1110 | males and concluded that patients might be asked for their preference voiding position during uroflowmetric evaluation.(7) in contrast, eryildirim and colleagues reported that maximum and average flow rates were significantly higher in sitting position at their 30 healthy males series, but there was no difference in pvr values between these positions.(1) in another study with 61 young male participants, choudhury and colleagues found significant lower flow rates at sitting position than standing position, but pvr was still not different between the groups.(2) we also did not find any significant difference in uroflowmetric parameters at standing and sitting position. although it was not statistically significant, patients who had qmax > 10 ml/s was able to void with higher flow rates and lower voiding time at standing position. it was not surprising that pvr increased as qmax decreased. according to statistical analysis pvr was significantly higher in sitting position in all groups, but this difference was not over 25 ml and had no clinical imtable 2. changes in uroflowmetric parameters in standing and sitting position according to maximum flow rates (qmax). qmax > 15 ml/s (n = 96) qmax < 15 ml/s (n = 102) standing sitting p standing sitting p qmax (ml/s) 20.7 ± 5.5 19.9 ± 6.4 .155** 10.3 ± 2.7 10.3 ± 3.5 .880** time to peak flow, s 7.4 (1.6-25.8) 7.4 (3.2-45.2) .944* 8.5 (2.6-48.2) 9.6 (3-50.8) .149* average flow rate, ml/s 11.5 ± 3.6 11.2 ± 3.6 .11** 5.7 ± 1.7 5.7 ± 1.8 .698** voiding time, s 28.5 ± 11.1 29.1 ± 11.7 .083** 47.3 ± 20.1 48.4 ± 19.7 .572** voided volume, ml 288.7 ± 80.2 291.0 ± 81.4 .737** 254 ± 80.6 258 ± 80.9 .554** post voiding residue, ml 19 (0-100.0) 35.5 (0-128) < .001* 44.0 (0-257) 66.5 (4-209) < .001* qmax 10-15 ml/s (n = 64) qmax < 10 ml/s (n = 38) standing sitting p standing sitting p qmax, ml/s 12.0 ± 1.5 11.6 ± 3.1 .335** 7.4 ± 1.5 8.1 ± 3.0 .072** time to peak flow, s 8.1 (2.6-38.0) 9.4 (3.0-50.8) .120* 14.7 ± 12.3 13.7 ± 10.1 .687** average flow rate, ml/s 6.7 ± 1.5 6.2 ± 1.7 .068** 4.2 ± 0.8 4.7 ± 1.4 .022** voiding time, s 41.7 ± 1.9 44.1 ± 13.0 .092** 55.5 (27.8-113.2) 47.3 (18.8-118.2) .231** voided volume, ml 258.7 ± 76.3 266.7 ± 77.5 .381** 247 ± 88.1 245 ± 85.8 .844** post voiding residue, ml 49.1 ± 41.3 69.9 ± 47.9 < .001◊ 49.5 ± 44.2 75.0 ± 38.9 < .001◊ key: qmax, maximum flow rate. *data were distributed non-normally according to kolmogorov-smirrov test so wilcoxon signed rank test was performed for statistical analysis and p value was calculated using the median data values. **data were distributed normally according to kolmogorov-smirrov test so paired t test was performed for statistical analysis and p value was calculated using the mean data values. table 3. comparison of uroflowmetric parameters in standing and sitting position according to preferred voiding position in daily life. patients preferring standing position for micturition patients preferring sitting position for micturition standing sitting p sitting standing p qmax, ml/sec 15.0 ± 6.6 14.1 ± 7.0 .033** 16.16 ± 6.9 15.7 ± 6.8 .251** time to peak flow, s 8.4 (1.6-48.2) 9.2 (3.0-45.2) .257* 7.4 (3.2-50.8) 7.5 (2.6-43.4) .653* average flow rate, ml/s 8.4 ± 3.9 7.8 ± 3.7 .015** 8.7 ± 3.8 8.7 ± 4.1 .830** voiding time, s 37.5 ± 19.4 40.5 ± 19.7 .031** 37.0 ± 17.8 36.9 ± 19.5 .963** voided volume, ml 270 ± 78.8 271 ± 87.9 .761** 277.8 ± 74.9 272.8 ± 86.6 .505** post voiding residue, ml 32.0 (0-257) 48 (2-209) < .001* 45.5 (2.198) 25.0 (0-166) < .001* key: qmax, maximum flow rate. *data were distributed non-normally according to kolmogorov-smirrov test so wilcoxon signed rank test was performed for statistical analysis and p value was calculated using the median data values. **data were distributed normally according to kolmogorov-smirrov test so paired t test was performed for statistical analysis and p value was calculated using the mean data values. miscellaneous 1111vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l portance in terms of treatment opportunities. according to our results patients who had high qmax values were able to void better at standing position with significant lower pvr values. changes of parameters in patients with lower qmax values there are also limited numbers of studies evaluating the effect of voiding position on uroflowmetric parameters in patients with obstructive luts. unsal and colleagues, reported the results of uroflowmetric parameters of 44 bph and 44 healthy patients in both sitting and standing positions. they used maximum flow rate of 15 ml/s as cut-off point and did not find any difference in uroflowmetric parameters and pvr between the groups.(7) in another study with 10 bph patients, authors found no difference in uroflowmetric parameters in standing and sitting position while pvr was significantly lower in sitting position.(6) we evaluated 102 patients with qmax < 15 ml/s and did not find any difference in uroflowmetric parameters including qmax, q average and voided volume, but there was a significant difference in pvr. same relation was also observed in patients with qmax > 15 ml/s that pvr was significantly higher in sitting position while qmax, q average and voided volume was not statistically different in those patients. opposing to unsal and colleagues results, our study did not show any significant difference that qmax value of 15 ml/s was a cut-off point for uroflowmetric parameters in standing and sitting position. we also did not find any difference at uroflowmetric parameters of patients who had borderline obstruction with qmax 10-15 ml/s. but, as obstruction became severe (qmax < 10 ml/s), sitting position was seem to be more advantageous for flow rates that average flow rate was significantly higher in sitting position. this was the only significant difference of uroflowmetric parameters in our study. so the patients with qmax values < 10 ml/s may be advised to urinate in sitting position to have higher qmax values. post voiding residue of patients with lower qmax values was also significantly higher in sitting position, but like patients with high qmax values, the difference was not over 25 ml and did not change treatment protocol for those patients. changes in parameters according to natural voiding position there are very limited studies evaluating the changes of uroflowmetric parameters related to voiding position other than patients’ daily life habit. in a study designed in saudi arabia, where participants void in sitting position because of religious traditions, authors found no difference in uroflowmetric parameters, whereas patients had significantly higher pvr values at standing position. but this difference between the mean pvr was not over 15 ml (73 ± 80.2 in sitting and 86.1 ± 77 in standing position). although authors did not find any statistically significant difference at their series, they concluded that obliging the patients to void in a position to which they are not familiar may alter micturition act and might produce higher cerebellar inhibitory effect during voiding.(3) in our study, we had nearly equal number of patients who use standing or sitting position in their daily life (57.4% vs. 42.6%, respectively). in both group, patients had higher qmax values when they performed uroflowmetric evaluation in their natural position and this relation was significant in patients who use standing position in their daily life. patients, who were voiding in standing position, had 6% decrease in qmax and 7% decrease in q average values when they performed uroflowmetry at sitting posifigure. the study flow chart. voiding parameters in positional changes | yazici et al 1112 | tion. this decrease was lower and statistically insignificant in patients who use sitting position in their daily life as; 2.5% worsening in qmax and no change on q average. on the other hand, post voiding residue was significantly higher in sitting position in both groups, unrelated to natural voiding position. so, the uroflowmetric parameters were not affected by the natural voiding habit of patients in our study. different voiding positions other than sitting and standing were also evaluated by some authors. aghamir and colleagues, also evaluated crouching position and report no difference in uroflowmetric parameters.(6) similar conclusion was also reported by unsal and colleagues that crouching position did not alter uroflowmetric parameters in healthy males.(7) although sitting position was seem to be advantageous than standing position, eryildirim and colleagues reported no difference between sitting and squatting position.(1) on the other hand, amjadi and colleagues reported a significant improvement of uroflowmetric parameters of obstructed patients as they micturate in crouching position. (4) in our study we were not able to analyze uroflowmetric differences in other voiding positions like crouching, squatting, recombinant or supine. but our entire study group was using standing or sitting position in their daily life. different theories had been proposed to define the effect of voiding position on uroflowmetric parameters. according to their results, el-bahnasawy and colleagues proposed that patients who void in the sitting position throughout their life will have micturitional reflexes modified and conditioned to this position.(3) but in our study we were able to observe that patients who void at sitting position in their whole life was able to void in standing position without any change in uroflowmetric parameters. amjadi and colleagues, propose another theory according to their results and proposed that relaxation of pelvic floor musculature may be a reason for decrease in bladder outlet resistance and abdominal musculature may help to increase intra-abdominal pressure helping micturition in crouching position.(4) this may be true for crouching position but it does not seem to work in sitting position according to our results. although we did not find significant uroflowmetric differences among voiding positions, we have similar results with choudhury and colleagues and uluocak and colleagues who demonstrated a decrease in uroflowmetric parameters in sitting position. (2,14) as it was shown at uluocak’s study, patients may have lower voiding detrusor pressure in sitting position. on the other hand gravity, slower detrusor contractions and altered geometry of bladder may be an advantage for voiding in standing position. uroflowmetric evaluation is a popular and frequently used test that has been performed by many centers in all around the world. although we had large number of patients in our study, this may not be enough to make a direct conclusion for general population. in order to understand the exact effect of voiding position on uroflowmetric parameters, more well-organized, prospective studies with higher number of participants are needed. conclusion as a conclusion, the preferred voiding positions may differ among people because of several factors like social, cultural and medical reasons. as there are no clinically important uroflowmetric differences between voiding in sitting and standing positions, voiding position may be left to personal preferences during uroflowmetric evaluation. according to our results it seems that the best voiding position is the position in which patient feels most comfortable. conflict of interest none declared. references 1. eryildirim b, tarhan f, kuyumcuoğlu u, erbay e, pembegül n. position-related changes in uroflowmetric parameters in healthy young men. neurourol urodyn. 2006;25:249-51. 2. choudhury s, agarwal mm, mandal ak et al. which voiding position is associated with lowest flow rates in healthy adult men? role of natural voiding position. neurourol urodyn. 2010;29:413-7. 3. el-bahnasawy ms, fadl fa. uroflowmetric differences between standing and sitting positions for men used to void in the sitting position. urology. 2008;71:465-8. 4. amjadi m, madaen sk, pour-moazen h. uroflowmetry findings in patients with bladder outlet obstruction symptoms in standing and crouching positions. urol j. 2006;3:49-53. miscellaneous 1113vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l voiding parameters in positional changes | yazici et al 5. yamanishi t, yasuda k, sakakibara r et al. variation in urinary flow according to voiding position in normal males. neurourol urodyn. 1999;18:553-7. 6. aghamir sm, mohseni m, arasteh s. the effect of voiding position on uroflowmetry findings of healthy men and patients with benign prostatic hyperplasia. urol j. 2005;2:21621. 7. unsal a, cimentepe e. effect of voiding position on uroflowmetric parameters and post-void residual urine volume in patients with benign prostatic hyperplasia. scand j urol nephrol. 2004;38:240-2. 8. dicuio m, pomara g, menchini fabris f, ales v, dahlstrand c, morelli g. measurements of urinary bladder volume: comparison of five ultrasound calculation methods in volunteers. arch ital urol androl. 2005;77:60-2. 9. j. de la rosette, g. alivizatos, s. madersbacher et al. eau guidelines 2006. benign prostatic hyperplasia; p. 23 10. bastiaanssen eh, van leeuwen jl, vanderschoot j, redert pa. a myocybernetic model of the lower urinary tract. j theor biol. 1996;178:113-33. 11. valentini fa, besson gr, nelson pp, zimmern pe. a mathematical micturition model to restore simple flow recordings in healthy and symptomatic individuals and enhance uroflow interpretation. neurourol urodyn. 2000;19:153-76. 12. rad s. impact of ethnic habits on defecographic measurements. arch iranian med 2002;5:115-7 13. bockus hl. gastroenterology. philadelphia: saunders co; vol 2, 1994. p. 469. 14. uluocak n, oktar t, acar o, incesu o, ziylan o, erkorkmaz u. positional changes in voiding dynamics of children with non-neurogenic bladder dysfunction. urology. 2008;72:53034. 1264 | holmium laser endourethrotomy for the treatment of long-segment urethral strictures: a retrospective study of 190 patients qigui liu,1 weiqing ma,2 xin li,1 wentao zhang,1 wei cao,1 qingyu zhou,1 juan duan1 purpose: long-segment urethral strictures (lsus) are refractory to urethrotomy and urethroplasty. holmium laser urethrotomy has shown favorable therapeutic outcomes in short-segment urethral stricture. we therefore evaluated the therapeutic effectiveness and safety of holmium laser endourethrotomy in the treatment of lsus. materials and methods: holmium laser endourethrotomy was used to treat 190 consecutive male patients with lsus. a urethrocystoscopic poking maneuver incorporating holmium laser ablation was used to eliminate the urethral strictures completely. maximum flow rate (qmax) on retrograde uroflowmetry, international prostate symptom score (ipss) and the expanded prostate cancer index composite (epic) quality of life (qol) index were assessed at baseline and at 1-, 3and 6-months postoperatively. results: holmium laser urethrotomy was successfully completed in all 190 patients. the mean operation time was 25 ± 17.8 min (range, 6-69 min). no significant intraoperative complications occurred, except that 23 patients (12.1%) experienced controllable scrotal and penile edema. none of these lsus patients experienced recurrent strictures during a follow-up period of 6-36 months. from baseline to 6 months postoperatively, the mean qmax increased significantly, from 1.4 ± 2.7 ml/sec to 19.7 ± 4.1 ml/sec (p < .001); mean ipss decreased significantly, from 31.3 ± 7.2 points to 9.3 ± 3.1 points (p < .001); and mean qol score showed significant improvement, from 5.7 ± 1.6 points to 1.8 ± 0.4 points (p < .001). conclusion: holmium laser endourethrotomy with the poking maneuver is a therapeutically effective and minimally invasive treatment for lsus. keywords: lasers; therapeutic use; treatment outcome; urethral stricture; surgery. corresponding author: qigui liu, md department of urology, kunming general hospital of chengdu military command, 212 daguan road, kunming city, yunnan province 650032, china. tel: +86 139 8768 0497 fax: +871 6477 4425 e-mail: 572155713@qq.com received december 2012 accepted december 2013 1 the department of urology, kunming general hospital of chengdu military command, kunming city, yunnan province, china. 2 the department of anesthesia, kunming general hospital of chengdu military command, kunming city, yunnan province, china. reconstructive urology reconstructive urology 1265vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l introduction long-segment urethral stricture (lsus) is defined as a narrowing of a urethra longer than 1 cm.(1) etiolog-ically, lsus is due primarily to urinary tract trauma, surgery or infection. the symptoms and signs of lsus vary in severity and manifest primarily as dysuria, urinary retention, urinary incontinence, and urinary obstruction. as a refractory urologic condition, lsus usually requires surgical intervention, consisting of urethrotomy and urethroplasty.(1) many surgical methods have been used to treat urethral strictures, with the choice of method depending primarily on the location and length of the stricture as well as on the experience of the urologist.(1) current urological surgical techniques include visual internal urethrotomy,(2) oneor two-stage urethroplasty with skin flap(3) or mucosal onlay(4) and temporary or permanent urethral stenting.(5) treatment outcomes, however, have been unsatisfactory due to high rates of iatrogenic urogenital injuries, urinary calculosis, urinary fistula, septic infection, and stricture recurrence.(6) these morbidities and complications are more likely to occur in patients with a history of previous urethrotomy and/or urethroplasty.(7) endourethrotomy with the holmium laser is an endourologic technique incorporating laser ablation for the management of urological stricture diseases.(8) this treatment is minimally invasive, with similar or even superior effectiveness and safety compared with conventional urethrotomy and urethroplasty.(9) compared with other ablation methods, such as cold-knife and electrical resection, laser incision can efficiently eliminate scarred tissues through vaporization but with minimal thermal damage to adjacent urogenital tissues. the major benefit of laser ablation is small extent of scarring following urethrotomy.(10) although this technique has rarely been used to treat complicating lsus, we have utilized it to treat this condition since 2001, obtaining good treatment outcomes. we have retrospectively assessed the effectiveness and safety of endourethrotomy with holmium laser ablation in 208 males with complicating lsus at our institution. to our knowledge, this report is the first to describe the use of laser endourethrotomy to treat lsus. materials and methods study participants we assessed 190 consecutive male patients, aged 10-65 years, diagnosed with lsus (> 1.0 cm) on urethroscopy and/ or urethrography and hospitalized for elective endourethrotomy with holmium laser between august 2001 and july 2011. indications included a urethral stricture length > 1.0 cm; history of urethral stricture for more than 3 months; and undergoing urinary diversion 3 months prior to admission. contraindications included active urinary tract infection; upper urinary tract stricture; being unable to complete outpatient follow-up of at least 6 months; or refusal to participate in this study. chief patient complaints included narrow or interrupted urine stream, urinary incontinence, and progressively prolonged voiding time. the duration of lsus ranged from 3 months to 7 years following the onset of stricture disease. during preoperative endoscopic examination in all patients, a 17.5-19.5 french (f) urethrocystoscope or an 8-10f urethral sound probe could not be advanced into the bladder; the stricture manifested as an oval-, radiatingor irregularlyshaped scarred obliteration. the urethral strictures ranged in size from 2.6 cm to 4.5 cm and were located in the pendulous urethra (n = 14, 7.4%), bulbous urethra (n = 142, 74.7%), and membranous urethra (n = 34, 17.9%). the causes of lsus were determined to be trauma in 126 patients (66.3%), iatrogenic (instrumental or surgical) injury in 30 (15.8%), and urinary tract infection in 34 (17.9%). of these 190 patients, 60 (31.6%) underwent suprapubic cystostomy due to complete or near complete urethral atresia, whereas 127 (66.8%) had a previous history of urethrotomy and/or urethroplasty. the study protocol was approved by the institutional review board at the people's liberation army kunmin general hospital in accordance with the declaration of helsinki, and all patients provided written informed consent prior to surgery. endourethrotomy with holmium laser ablation all procedures were performed by a single surgeon (q.l.), who had extensive experience with endourethrotomy for the treatment of simple urethral strictures and with holmium laser enucleation of the prostate. patients were started on intravenous prophylactic fluoroquinolones, beginning two days prior to surgery. following spinal anesthesia, each patient was placed in the lithotomy position. a 26f water-circulating lateral emission laser cystoscope (olympus, tokyo, jaholmium laser endourethrotomy in urethral strictures | liu et al 1266 | pan) equipped with a high-definition video monitoring and display system (stryker, kalamazoo, mi 49002, usa) was inserted into the urethra to visualize the urethral mucosae. if cystoscope insertion failed, urethrotomy was performed throughout the entire anterior urethra using an endourological cold-knife. following clear visualization of the strictures, the cystoscope was used to poke the strictures and establish an artificial lumen. a holmium laser optical-fiber knife (coherent, inc., santa clara, ca, usa), at a series of calibers (200 μm, 365 μm and 550 μm), was inserted through the endoscope working channel to completely eliminate the scarred tissues from the distal to the proximal direction. the power and frequency of the holmium laser emission were set at 2.5-30.0 w and 5.0-20.0 hz, respectively. the scarred tissues were incised more frequently using cystoscopic poking than using laser ablation. multiple incisions were made at the 0300, 0900 and 0600 counterclockwise positions for pendulous strictures and at the 1200, 0300 and 0900 clockwise positions for membranous strictures. in patients with complete urethral atresia or refractory urethral stricture, a metallic urethral sound was induced via the suprapubic cystostomy opening into the posterior urethra to guide the advance of cystoscope; the assistant's index finger was inserted into the rectum to assist the advance of the instrument into the bladder. postoperative care and follow-up patients were maintained on intravenous broad-spectrum antibiotics for one week after surgery and switched to oral medication for 4-6 weeks afterwards. the 18-24f double or triple-lumen urethral catheter was allowed to remain for 4-6 postoperative weeks, and all patients underwent routine urethral dilation for 4-8 postoperative weeks. all patients were followed up at the outpatient clinic at 3 and 6 months after endourethrotomy. the main outcome measures were improvements from baseline in maximum flow rate (qmax), international prostate symptom score (ipss), and quality of life (qol) index. treatment success was defined as complete or near complete restoration of a normal urinary stream and micturition distance without requiring urethral dilation within 6 months of urethrotomy. statistical analysis all data were expressed as mean ± sd. mean improvements from baseline in qmax, ipss, and qol index were analyzed using one-sample student’s t tests. a p value less than .05 was considered statistically significant. results following the incision of scarred tissues, the retrograde 26f lateral emission holmium laser cystoscopy could be successfully advanced through the strictured urethra into the bladder of all 190 patients. the mean operating time (the interval between the insertion and the withdrawal of the urethroscope) was 25 ± 17.8 min (range, 6-69 min). none of these patients experienced any intraoperative complications, such as massive urethral bleeding, rectal or corpus cavernosum penis injuries, urethral false passage, or urethral perforation. however, 23 patients (12.1%) experienced marked scrotal and penile edema suggesting urinary extravasation. these complications occurred mainly in the first 50 patients (11/50, 22.0%), but all of these complications resolved completely 2-3 days following symptomatic treatment, such as pressure dressing, scrotal elevation, and scrotal incision and drainage. during the postoperative period, none of these patients developed urinary tract infection, urethral fistula, false urethral passage, urinary incontinence, or erectile dysfunction. lsus treatment with a single endourethrotomy using the holmium laser was determined to be successful in all 190 patients (100.0%), with all having a normal urinary stream and micturition distance. the follow-up period ranged from 6-36 months (mean, 14.1 ± 7.2 months). no patient was lost to follow-up within the first six months. none of these patients experienced any types of recurrent strictures; therefore, none required second-look instrumental, endoscopic or surgical interventions during follow-up. the improvements from baseline in main outcome measures are shown in figure 2. at baseline, the qmax on uroflowmetry was 1.4 ± 2.7 ml/sec (range, 0.05.3 ml/sec), increasing to 23.2 ± 6.5 ml/sec following the removal of the urethral catheter (p < .001), to 21.4 ± 3.2 ml/ sec after 3 months (p < .001), and to 19.7 ± 4.1 ml/sec after 6 months (p < .001). the ipss, which has a maximum of 35 points,(11) was 31.3 ± 7.2 points (severely symptomatic) at baseline, decreasing to 10.4 ± 3.1 points after catheter removal (p < .001), to 8.8 ± 2.3 points after 3 months (p < .001), reconstructive urology 1267vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l and to 9.5 ± 1.8 points after 6 months (p < .001). the mean expanded prostate cancer index composite (epic)(12) qol index, which was 5.7 ± 1.6 points at the baseline, showed similar improvements, to 2.4 ± 1.1 points after catheter removal (p < .001), 1.8 ± 0.9 points after 3 months (p < .001), and 1.6 ± 0.7 points after 6 months (p < .001). discussion the goal of urethral stricture treatment is to reconstruct the anatomical continuity and patency of the urethra without significantly impairing urogenital functions.(16) urethrotomy and urethroplasty are thought to be the definitive treatment modalities for urethral strictures; the latter is more frequently used in patients with lsus due to the high recurrence rate following urethrotomy alone.(13) however, urethroplasty incorporating a skin graft/flap or mucosal onlay has been associated with technical complications, including patch graft failure, urinary tract infection, hair growth and urinary stone formation.(14,15) therefore, urethrotomy with an end-to-end anastomosis is still recommended as the first-line treatment option of choice in patient with lsus.(16) conventional open urethrotomy is regarded as massively invasive in male patients and has been associated with high risks of urinary fistula and erectile dysfunction.(17) endourethrotomy, also called endoscopic urethrotomy, is a minimally invasive urological technique.(18) that has shown therapeutic benefits, including good technical reproducibility, precise incision of the scarred tissue, minimal intraoperative bleeding, accelerated postoperative recovery, and, importantly, controlled tissue scarring following wound healing.(19) in this technique, a retrograde urethral incision is performed using a guidewire or ureteral catheter to pass through the stricture. this pass-through, however, is not always possible, especially in patients with lsus or multiple strictures. in the absence of a guidewire, the retrograde incision using the urethrocystoscope is technically difficult and associated with urethral perforation. we have therefore modified the advancement technique of conventional urethrocystoscopy by combining it with a 'poking' maneuver. in the latter, the urethrocystoscope, or ureteroscope for a small-caliber urethra, is advanced in proximity to the stricture, and the scarred tissues are simultaneously poked, contralaterally to the normal mucosal tissue, to create a lumen-like passage. this maneuver is repeated until the normal mucosal lining appears upwards to the bladder. the endoscope is subsequently withdrawn to the distal end of the stricture to completely eliminate the scarred tissues. if the urethra exhibits complete obliteration, laser ablation is used to incise the scarred tissues through the predefined urethral passage, and the advancement-poking-advancement maneuver is again performed as above. this modified technique was successful in all 208 of our patients with complicating lsus. the operation time was shorter than that of conventional endoscopic laser urethrotomy, while the shortand long-term safety outcomes were also favorable. the use of this modified technique requires some expertise and experience with endourological procedures, such as holmium laser enucleation of the prostate. our results suggest that prior experience with at least 20 patients undergoing endourethrotomy for the treatment of simple urethral strictures is required before performing holmium laser endourethrotomy with the poking maneuver for the treatment of long-segment urethral strictures. moreover, some technical measures should be considered when using this endoscopic figure 1. schematic diagram of endourethrotomy using the poking technique: a) the urethrocystoscope or ureteroscope is advanced in proximity to the stricture; b) the scarred tissues are poked contralaterally to the normal mucosal tissue; and c) the advancement of urethrocystoscope is oriented to parallel the median plane. holmium laser endourethrotomy in urethral strictures | liu et al 1268 | maneuver. first, the operator should avoid poking normal mucosal tissues, while poking scarred tissues along their median line or along the interface between the scarred tissues and the normal mucosae. even if iatrogenic injuries occur to the urethral mucosal lining, the urethral epithelia can proliferate and cover the wound with minimal squeal following the indwelling of the urethral catheter. second, the urethrocystoscope should be advanced parallel to the median plane between the pubis and the rectum; this orientation is essential for surgical success and safety. third, the urologist must be acquainted with advanced urogenital anatomy, including the urethral flexure, bulbous urethra, membranous urethra, external urethral sphincter, prostatic urethra, bladder neck and internal urethral orifice, as well as with neighboring structures, including the external urethral sphincter, pubis, rectum and pelvic vessels and nerves. incidental damage to the external urethral sphincter and rectum are associated with high rates of urinary incontinence and rectal fistulae.(9) endourologic ablation methods include the cold-knife, electric resection, and laser incision. the cold-knife was the first ablation technology to be described.(18) this technique has a short patency time and a high recurrence rate, of up to 69% within 6 months of urethrotomy.(20) our 'poking' maneuver was similar to the cold-knife but was more effective. electrical resection can result in the complete elimination of scarred tissues and rapid urethral re-epithelialization via the electrothermal effect.(21) however, the resulting tissue coalization can cause fibrovascular proliferation, leading to high rates of stricture recurrence. several laser technologies have been widely used to treat urinary calculi, benign prostate hyperplasia, and urethral stricture.(8) the laser sources available for urologic practice include the neodymium,(22) argon,(23) thulium(10) and holmium(8) lasers. the holmium laser is a solid-state laser with a wavelength of 2140 mm and pulse-like emission. tissue absorption of the holmium laser is nonselective but uniform, with a penetration depth of only 0.4 mm. the emission time is as short as 0.25 msec, with a transient power of up to 10 kw. the laser energy vaporizes its target, such as calculi and scars, in a very short time with minimal thermal release.(24) no tissue coalization or scarring occurs following laser ablation; vaporization, dissection and hemostasis can be achieved simultaneously, resulting in minimal intraoperative bleeding and allowing a precise incision in a clear operative field. no electric current or electric field emerges following holmium laser emission; and iatrogenic injuries, such as the formation of a false urethral passage and external urethral sphincter injury, do not occur incidentally due to the absence of the obturator nerve reflex. our follow-up results indicate that holmium laser urethrotomy results in favorable therapeutic efficacy, as shown by the reduction in patient symptoms and improvements in urodynamics and overall life of qualreconstructive urology figure 2. figure 2. improvements in maximum flow rate (a), international prostate symptom score (b) and quality of life (c) in patients with long segment urethral strictures following holmium laser endourethrotomy. 1269vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l ity. holmium laser treatment is also associated with minimal invasiveness, less pain, and rapid postoperative recovery.(25) the elimination of scarred tissues using holmium laser treatment can be completed in either a radiating or an annular manner. this elimination is superior to that achieved with the cold-knife or electric resection, advantages attributed to the high degree of spatial and temporal coherence of the laser. annular strictures are more common, and usually include a small-size cracked at their center. laser incision should be started from the center, without requiring any guidance. however, the 0500, 0600 and 0700 o'clock positions cannot be used as the starting points for laser incision of irregularlyshaped strictures. guidewire is usually needed to eliminate scarred tissues, with a metallic urethral sound used for patients who undergo cystostomy and treatment with a light source, urethral dilator, and ureteral catheter following the poking of scarred tissues. as an alternative to guidewire, optical fibers 200-550 μm in diameter can be advanced into a strictured urethra. most lsus patients have a complex history of treatment with several types of urethral instrumentation and/or surgery. stricture recurrence is the primary complication following urethrotomy, especially in patients with irregularly-shaped or valve-like residual scarring.(26) the complete elimination of scarred tissues is essential for the reconstruction of urethral continuity and patency. caution is required during the process of laser urethrotomy to increase the treatment success rate and decrease the restenosis rate. the location, length and severity of strictures should be fully characterized, and a proper guidewire, metallic sound or optical fiber should be inserted to orientate the endoscopic maneuver and prevent the formation of false urethral pathways. in patients with anterior urethral strictures, massive incision of scarred tissues located at the 1200 o'clock position should be avoided to minimize the risk of urethral perforation or fistula. in patients with lsus following prostate surgery, the external urethral sphincter should be protected to reduce the occurrence of urinary incontinence. careful wound finishing is critical to minimize postoperative recurrent strictures, and fibrotic scarred tissues should be removed completely. false urethral passages in patients with posterior lsus should be incised, allowing the passage to communicate with the posterior urethra and to expand the urethral lumen. scarred tissue projecting into the urethral lumen should be incised thoroughly, but care should be taken to avoid incising the normal urethral mucosae to eliminate the formation of new strictures. lsus patients undergoing urethrotomy usually require postoperative urethral dilation. this benefits patients, by minimizing mucosal fibrosis while maximizing urethral re-epithelialization.(27) the duration of urethral catheter placement following holmium laser urethrotomy is relatively shorter, with the duration of catheter indwelling depending primarily on the length of the stricture. for example, catheter indwelling is not required for patients with strictures < 0.5 cm in length, whereas catheter placement should be maintained for one week in patients with 1-cm long and one or two weeks in patients with 1-2 cm long strictures. following the removal of scarred tissues, mucosal re-epithelialization sufficient to cover the wound normally takes up to 4 weeks, suggesting that the urethral catheter be maintained for at least 4 weeks in patients with complicating lsus. most lsus patients require prophylactic treatment with broad-spectrum antibiotics, as urinary tract infection is a risk factor for recurrent stricture. we have utilized these urethral catheter placement and antibiotic prophylaxis protocols in our patients with lsus, with none of our patients experiencing stricture recurrence after midto long-term follow-up. although the recurrence rate following holmium laser urethrotomy has been reported to be 18.7% in patients with short-segment urethral stricture, the recurrence rate in our lsus patients following holmium laser endourethrotomy incorporating the poking maneuver was 0%. conclusions holmium endourethrotomy using the poking maneuver is a technically feasible and therapeutically effective urologic modality with minimal invasiveness for the treatment of lsus. a long-term (>1 year) prospective, blinded, randomized, controlled study is currently ongoing at our institute to further evaluate the clinical usefulness and safety of holmium laser endourethrotomy for the treatment of lsus. acknowledgment we thank medjaden bioscience limited for assisting in the holmium laser endourethrotomy in urethral strictures | liu et al 1270 | reconstructive urology references 1. benet ae, abarbanel j, lask dm, kimche d. surgical management of long urethral strictures. j urol. 1990;143:917-9. 2. dubey d. the current role of direct vision internal urethrotomy and self-catheterization for anterior urethral strictures. indian j urol. 2011;27:392-6. 3. hussein mm, moursy e, gamal w, zaki m, rashed a, abozaid a. the use of penile skin graft versus penile skin flap in the repair of long bulbo-penile urethral stricture: a prospective randomized study. urology. 2011;77:1232-7. 4. fransis k, vander eeckt k, van poppel h, joniau s. results of buccal mucosa grafts for repairing long bulbar urethral strictures. bju int. 2010;105:1170-2. 5. sertcelik mn, bozkurt ih, yalcinkaya f, zengin k. long-term results of permanent urethral stent memotherm implantation in the management of recurrent bulbar urethral stenosis. bju int. 2011;108:1839-42. 6. meeks 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in a malaysian population. int j urol. 2005;12:39-45. 12. chang p, szymanski km, dunn rl, et al. expanded prostate cancer index composite for clinical practice: development and validation of a practical health related quality of life instrument for use in the routine clinical care of patients with prostate cancer. j urol. 2011;186:865-72. 13. erickson ba, breyer bn, mcaninch jw. single-stage segmental urethral replacement using combined ventral onlay fasciocutaneous flap with dorsal onlay buccal grafting for long segment strictures. bju int. 2012;109:1392-6. preparation of this manuscript. conflict of interest none declared. 14. olajide ao, salako aa, aremu aa, eziyi ak, olajide fo, banjo oo. complications of transverse distal penile island flap: urethroplasty of complex anterior urethral stricture. urol j. 2010;7:178-82. 15. tavakkoli tabassi k, mansourian e, yarmohamadi a. one-stage transperineal repair of pan-urethral stricture with dorsally placed buccal mucosal grafts: results, 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j endourol. 2003;17:791-4. 23. becker hc, miller j, nöske hd, klask jp, weidner w. transurethral laser urethrotomy with argon laser: experience with 900 urethrotomies in 450 patients from 1978 to 1993. urol int. 1995;55:150-3. 24. atak m, tokgöz h, akduman b, et al. low-power holmium:yag laser urethrotomy for urethral stricture disease: comparison of outcomes with the cold-knife technique. kaohsiung j med sci. 2011;27:503-7. 25. futao s, wentong z, yan z, qingyu d, aiwu l. application of endoscopic ho:yag laser incision technique treating urethral strictures and urethral atresias in pediatric patients. pediatr surg int. 2006;22:514-8. 26. micheli e, ranieri a, peracchia g, lembo a. end-to-end urethroplasty: long-term results. bju int. 2002;90:68-71. 27. gelman j, liss ma, cinman nm. direct vision balloon dilation for the management of urethral strictures. j endourol. 2011;25:1249-51. fall 2012 08.pdf 667vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l prostate cancer predicting factors a preliminary report from tehran gholamreza pourmand,1 farzad allameh,1 kazem mohammad,2 sanaz dehghani,1 bita pourmand,3 abdolrasoul mehrsai,1 seyed hamed hosseini1 purpose: to determine the probability of having prostate cancer (pca) using the combination materials and methods: a total of 160 patients and 190 controls were enrolled in this hospital-based case-control study. using a logistic regression model and the odds ratio of age and psa level, the probability of pca was estimated based on serum level of psa and age of the participants. results: the mean age of patients with pca and benign prostatic hyperplasia (bph) was 67.75 ± 8.81 and 62.07 ± 8.71 years, respectively (p < .000). using univariate analysis, we found that increase in life decades of the cases almost doubles the risk of having pca (odds ratio = 1.95; p = .00), and the probability of developing cancer may increase by 74% in ketchup consumers. after multiple variable regressions, it was revealed that the odds of developing pca increase pca. conclusion: in clinical practice, psa level combined with the age at presentation can be used as predictors of pca probability and the necessity of biopsy. keywords: corresponding author: sanaz dehghani, md urology research center, sina hospital, imam khomeini st., hassan abad square, tehran, iran tel: +98 21 6634 8560 fax: +9821 6634 8561 e-mail: sanaz_dehghani2002@yahoo.com received august 2011 accepted january 2012 1urology research center, sina hospital, tehran university of medical sciences, tehran, iran 2epidemiology & biostatistics department, tehran university of medical sciences, tehran, iran 3research development center, sina hospital, tehran university of medical sciences, tehran, iran urological oncology 668 | introduction p rostate cancer (pca) is the third most commonly diagnosed cancer in many countries and the second cause of cancer death among men.(1) in iran, pca is reportedly the 3rd most commonly diagnosed visceral cancer, accounting for almost 7.75% of new cancer cases, and is the 7th most common cause of cancer death.(2) the overall detection rate of pca in iran is 3.5%.(3,4) according to the ministry of health cancer registry report in 2004 and 2005 to 2006, the age-standardized rate of incidence of pca in iran are respectively 7.24 and 9.22 men per 100 000.(5,6) this rate is apparently less than the rate reported for western countries, especially for the us (49.4 per 100 000 and 158.2 per 100 000, respectively), but it is still considerable in comparison to the rate in eastern asian countries (1.6 per 100 000).(3) among various important determinants of pca development,(4) age are considered to be the most important factors. the annual pca screening is rootinely performed using serum screening for assessing tumor control and its impact on pros(7) a serum psa level of 4 ng/ml is usually considered the cutoff threshold, above which further evaluations (prostate biopsy) are required. but recently, there have been many which psa levels are below 10 ng/ml and in the range of 4 to 10 ng/ml. it is evident that in epidemiologic studies, sometimes diagnoses are made higher or lower in frequency compared to the real-life situation in the society. in case of pca, underdiagnosis of the disease is rather common.(8,9) accepting a lower threshold for higher detection rate of pca will result in many unnecessary biopsies and their complications, such as bleeding, hematuria, urinary tract infection, and sepsis.(10) as schroder and colleagues have discussed, no single thresh(4) to increase the predictive value for psa and improve its positive predictive value in screening tests, several methods have evolved recently for earlier detection of pca and avoidtime (psadt), psa velocity, percent free psa, and age-speregarding the above-mentioned facts, an individual with an elevated level of psa may ask his urologist about the probability of having cancer. the primary study objective was to help urologists decide whether or not a patient needs a transrectal ultrasonography (trus)-guided biopsy to rule out pca. in the current study, we provided a model analyzed by the logistic regression to predict the risk of pca based on age and the serum psa level in iranian population. materials and methods the study population comprised patients referred to our clinic for trus-guided biopsy from april 2009 to september 2009. the study protocol was approved by medical ethics committee of tehran university of medical sciences. guided biopsy served as the case group and individuals with any pathologic diagnosis other than pca as controls. accordingly, 160 patients were included in the case group and 190 patients entered the control group. both groups had same socio-economic status. the same urologist performed 12-core trus-guided biopsy for all the patients. using an unconditional logistic regression model and the odds ratio (or) regarding psa and age, the probability of pca was estimated based on age at presentation and serum psa level. the results are presented as mean ± standard deviation. in univariate analysis, or was calculated for evaluating the strength of association. the appropriate variables hosmer-lemeshow test. the accuracy of the diagnostic tests was studied by receiver operating characteristic (roc) curve considered at p < .05. results the mean age of patients with and without pca was 67.75 ± 8.81 and 62.07 ± 8.71 years, respectively (p < .00). other demographic and clinical characteristics are presented in taurological oncology 669vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l prostate cancer predicting factors | pourmand et al ble 1. the increase in life decades of the cases almost doubled the risk of developing pca (or = 1.95; p < .00). furthermore, the probability of developing pca reached 74% in ketchup cept red meat that showed a protective effect against developing pca; or = 0.75; p relationship with developing pca (table 1). age was the only pca predicting variable that remained unchanged after multivariate logistic regression analysis. we found that the probability of developing pca increased by 90% for every decade after adjustment (or adj = 1.90; p < .00). between free, total, and free/total psa in both groups. the difference between patients with pca and bph is presented in figures 1 to 3 according to various age groups. in addition, using free/total psa provided a more precise means of differentiating patients with bph (table 3 and figure 4). discussion findings of the present study showed that the probability of developing pca almost doubles for every life decade. furother risk factors, including ketchup, red meat, garlic, and fatty diet, and developing pca. the rate of cancer detection varies in different countries with regard to psa level. a study on 297 male us residents with either high psa or abnormal dre reported the pca detection rate of 44% following prostate biopsy.(9,11) however, the data are not compatible with the studies performed in similar countries. the study accomplished by catalona and colleagues reported the cancer detection rate of about 4.6%.(12) with a cutoff level of 2 ng/ml for serum total psa, the detection rate is 3.8% in iran.(4) table 1. basic characteristics of patients in pca and bph groups.* variables pca bph odds ratio crude (p) age, y ≤ 50 50 to 59 60 to 69 ≥ 70 6 (1.6%) 80 (21.4%) 135 (36.1%) 153 (40.9%) 16 (8.4%) 70 (36.8%) 69 (36.3%) 35 (18.4%) 1.95 ( .00) marriage 157 (98.1%) 188 (98.9%) 0.56 ( .52) family history 23(14.4%) 19 (10%) 1.51 ( .21) vasectomy 4 (2.1%) 1 (0.6%) 0.29 ( .27) smoking 27 (16.9%) 44 (23.2%) 0.67 ( .15) diabetes mellitus 12 (7.5%) 17 (8.9%) 0.83 ( .63) garlic consumption never low moderate high 35 (21.9%) 78 (48.8%) 31 (19.4%) 16 (10%) 43 (22.6%) 94 (49.5%) 37 (19.5%) 16 (18.4%) 1.05 ( .68) ketchup consumption low moderate high 36 (22.9%) 77 (48.1%) 72 (29.4%) 70 (36.8%) 90 (47.4%) 30 (15.8%) 1.74 ( .00) red meat consumption low moderate high 69 (43.1%) 68 (42.5%) 23 (14.4%) 59 (31.4%) 99 (52.7%) 30 (16.0%) 0.75 ( .07) fatty diet low moderate high 123 (76.9%) 23 (14.4%) 14 (8.8%) 132 (69.8%) 43 (22.8%) 14 (7.4%) 0.86 ( .40) *pca indicates prostate cancer; and bph, benign prostatic hyperplasia. 670 | need for regional models to estimate the pretest probability of psa in different parts of the world. prostate cancer prediction trial (pcpt), conducted by national cancer institute, was a seven-year study of us men with psa < 3 ng/ml and normal dre. several risk factors, such as race, dre, family history, annual biopsies, and age, were considered along with psa level. this study evaluated the risk of cancer detection in us low-risk population.(13) the european randomized study of screening for prostate cancer (erspc) was also performed to develop a statistical model for pca prediction in the european population. in this study, the prostate volume was added to assess factors in pcpt study in order to enhance the accuracy of pca risk assessment model.(8) in our study, the factors, including ketchup, red meat, garlic, and fatty diet, were also studied. some studies have shown urological oncology table 2. comparing lab criteria in pca and bph groups.* pca bph mean difference (95% confidence interval) total psa, ng/ml 28.04 ± 60.82 6.08 ± 5.99 -21.95 (-28.19 to -15.71) free psa, ng/ml 2.97 ± 9.32 1.30 ± 1.59 -1.67 (-2.77 to -0.57) total/free psa 11.63 ± 6.40 19.60 ± 18.01 7.97 (4.52 to 11.42) prostate volume, ml 48.84 ± 25.21 57.49 ± 35.91 8.65 (2.81 to 14.48) *pca indicates prostate cancer; bph, benign prostatic hyperplasia; and psa, prostate-specific antigen. figure 3. mean (95% confidence interval) serum level of free psa in different age groups of patients with prostate cancer and benign prostatic hyperplasia. figure 1. mean (95% confidence interval) serum level of free/ total psa in different age groups of patients with prostate cancer and benign prostatic hyperplasia. figure 2. mean (95% confidence interval) of total psa in different age groups of patients with prostate cancer and benign prostatic hyperplasia. 671vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l a relationship between the aforementioned risk factors and relationship was found between age and pca. the predictive value of psa test increases with age.(14) studies show that positive predictive value for psa > 4 ng/ml is about 5.6% and the cancer detection rate by simple psa test is 4.6%. these odds differ when psa values are interpreted with regard to the age of patients. the rate of cancer detection in people aged between 40 and 49 years is 1.4% while it is 1.6% in 50 to 59 years. this rate is over 4.9% in 60 to 69 years and reaches 12.9% for men older than 70 years.(15) as a result, age was included in our analytic model as an important determinant for the risk of pca. our results cannot be generalized to other counties and populations. conclusion considering the obtained results, it seems that age of the patients as well as free/total psa results are the best predicting factors of pca in hospital-based urology clinic patients. acknowledgements this study was supported by grants from tehran university of medical sciences research fund. we would like to thank ms heidari for her cooperation and assistance as well as the patients who participated in this study. conflict of interest none declared. table 3. lab tests accuracy in diagnosing patients with pca and bph. * area under curve 95% confidence interval p total psa, ng/ml 0.798 0.757 to 0.839 .000 free psa, ng/ml 0.623 0.570 to 0.675 .000 total/free psa 0.817 0.776 to 0.858 .000 *pca indicates prostate cancer; bph, benign prostatic hyperplasia; and psa prostate-specific antigen. figure 4. receiver operating characteristic curve, comparing total psa, free psa, free/total psa sensitivity and specificity. references 1. jemal a, siegel r, ward e, hao y, xu j, thun mj. cancer statistics, 2009. ca: a cancer journal for clinicians. 2009;59:22549. 2. mousavi sm. toward prostate cancer early detection in iran. asian pac j cancer prev. 2009;10:413-8. 3. parkin dm, pisani p, ferlay j. global cancer statistics. ca cancer j clin. 1999;49:33-64, 1. 4. schröder fh, gosselaar c, roemeling s, postma r, roobol mj, bangma ch. psa and the detection of prostate cancer after 2005. part i. eau-ebu update series. 2006;4:2-12. 5. center for disease control, noncommunicable deputy, cancer control office: iranian annual of national cancer registration report 2004. 2 ed: iran ministry of health and medical education, health deputy; 2006. 6. center for disease control and prevention, noncommunicable deputy cancer office. iranian annual national cancer registration report 2005 – 2006: tehran (iran): ministry of health and medical education; 2007. 7. andriole gl, crawford ed, grubb rl, 3rd, et al. mortality results from a randomized prostate-cancer screening trial. n engl j med. 2009;360:1310-9. 8. van den bergh rc, roobol mj, wolters t, van leeuwen pj, schroder fh. the prostate cancer prevention trial and european randomized study of screening for prostate cancer risk calculators indicating a positive prostate biopsy: a comparison. bju int. 2008;102:1068-73. prostate cancer predicting factors | pourmand et al 672 | urological oncology 9. hernandez dj, han m, humphreys eb, et al. predicting the outcome of prostate biopsy: comparison of a novel logistic regression-based model, the prostate cancer risk calculator, and prostate-specific antigen level alone. bju int. 2009;103:609-14. 10. rodriguez lv, terris mk. risks and complications of transrectal ultrasound guided prostate needle biopsy: a prospective study and review of the literature. j urol. 1998;160:2115-20. 11. sadjadi a, nooraie m, ghorbani a, et al. the incidence of prostate cancer in iran: results of a population-based cancer registry. arch iran med. 2007;10:481-5. 12. catalona wj, smith ds, ratliff tl, basler jw. detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. jama. 1993;270:948-54. 13. thompson im, ankerst dp, chi c, et al. assessing prostate cancer risk: results from the prostate cancer prevention trial. j natl cancer inst. 2006;98:529-34. 14. moul jw, sun l, hotaling jm, et al. age adjusted prostate specific antigen and prostate specific antigen velocity cut points in prostate cancer screening. j urol. 2007;177:499503; discussion -4. 15. ishidoya s, ito a, orikasa k, et al. the outcome of prostate cancer screening in a normal japanese population with psa of 2-4 ng/ml and the free/total psa under 12%. jpn j clin oncol. 2008;38:844-8. pdf-957.pdf 381vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l expression of bcl-2 and bax in advanced or metastatic prostate carcinoma kazem anvari,1 mehdi seilanian toussi,1 mahmoud kalantari,2 shahram naseri,1mahdi karimi shahri,1 hassan ahmadnia,3 mehrdad katebi,4 abdolazim sedighi pashaki,1 mahdieh dayani,1 maryam broumand5 purpose: to evaluate the correlation of bcl-2 and bax protein expressions with biochemical failure-free survival in patients with advanced or metastatic prostate materials and methods: this retrospective study was performed on patients with therapy. samples were analyzed immunohistochemically for bax and bcl-2 expression. the h-score was calculated for each sample based on intensity and perresults: thirty-seven patients (13 metastatic and 24 locally advanced) were eligitween bax expression and gleason score, high bcl-2 expression (h-score > 85) p months and 16 (range, 9 to 26) months, respectively. high bcl-2 expression (p = p of lower biochemical progression-free survival. conclusion: high bcl-2 expression was associated with higher gleason scores androgen deprivation therapy. keywords: prostatic neoplasms, bax protein, bcl-2, disease progression, survival corresponding author: mehdi seilanian toussi, md department of oncology, omid hospital, kohsangi st., alandasht square, mashhad, iran tell/fax: +98 511 842 6936 e-mail: silanianm@mums. ac.ir received april 2011 accepted september 2011 1 cancer research center, department of radiotherapy oncology, mashhad university of medical sciences, mashhad, iran 2 department of pathology, mashhad university of medical sciences, mashhad, iran 3 department of urology, mashhad university of medical sciences, mashhad, iran 4 department of pathology, bentolhoda hospital, mashhad, iran 5mashhad university of medical sciences, mashhad, iran urological oncology 382 | introduction p -cal behavior from indolent tumors to agfactors, which predict recurrence after treatment, include clinical stage, grade, and pretreatment se(1) however, the above-mentioned prognostic factors are unable to predict the outcome in all subjects. the genetic factors play an essential role in tumor progression and in governing whether a prostate cancer is aggressive or indolent.(2-4) almost all tissues have a system to remove damaged cell through programmed cell death or apoptosis.(5) disturbance of programmed cell death can lead to accumulation of cells with impaired genome and eventually cancer. a number of genes regulate apoptosis, which include bcl-2 family and tumor suppressor p53 gene.(6) bcl-2 family proteins include both anti-apoptotic (eg, bcl-2 and bcl-xl) and pro-apoptotic (eg, bax, bak, duce permeabilization of outer mitochondrial chrome c into the cytosol, which in turn activates a group of cysteine protease called caspases leading to cell death. meanwhile, anti-apoptotic proteins prevent cell death program through preserving mitochondrial membrane integrity and releasing cytochrome c.(7,8) a study by tolonen and colleagues showed that normal epithelium of cancerous prostates contain multiple foci with high expression of bax and bcl-2.(9) 2 expression and ki-67 index indicating higher proliferating rates in bcl-2 positive tumors. ly associated with high gleason score tumors.(11,12) these results suggest a potential role for altered apoptosis in carcinogenesis. androgen deprivation, which is the mainstay of mediated apoptosis in androgen dependant cells and regression of tumor. however, androgen independent cancer eventually develops in all cases of metastatic disease, which is accompanied with bcl-2, bcl-xl, and mcl-1 overexpression in most cases.(13,14) the results of some studies suggest an association between apoptotic pathway dysfunction and worse outcome.(15-17) according to the result of a population–based cancer registry, the age-standardized incidence rate of son per year,(18) which is much lower than western countries. meanwhile, in comparison with westwhich can be explained partly by lack of national study was to investigate the association between bax and bcl-2 expression and time to progression undergoing androgen deprivation therapy. materials and methods eligible subjects were patients with distant metastasis and/or lymph node metastasis (metastatic who were referred to our department between were not followed up properly and those without required clinicopathological information. the usual imaging procedures were chest x-ray, abdominopelvic computed tomography scan, and bone scintigraphy. thirty-seven eligible patients with retrievable pathological specimens and adequate clinical information were selected. the specimens were re-evaluated for determining their gleason score by our pathologists. the gleason urological oncology 383vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l bcl-2 and bax protein expression in prostate carcinoma | anvari et al scores above 7 were considered as poorly differentiated (high gleason score). our samples consisted of 14 low and 23 high gleason scores. treatment and follow-up the diagnosis was based on histologic evaluation of the prostate biopsy specimens. all non-metastatic cases underwent local and regional external beam radiotherapy. all the patients received androgen deprivation therapy, which included luteinizing hormone-releasing hormone (lhrh) agotwenty-eight subjects received anti-androgen plus medical or surgical castration. all the patients were followed up every 3 months for the evidence of biochemical progression. three consecutive rises in psa was considered as biochemical progression.(19) immunostaining for bax and bcl-2 multiple 4-μm-thick sections of representative cut for immunohistochemical studies. a polymerbased (envision™) immunohistochemical method was used for the detection of bax (polyclonal rabbit anti-human, dako) and bcl-2 (monoclotive lymph node with follicular hyperplasia was adding antibody was used as the negative control. all immunostained sections were examined by for evaluating bax and bcl-2 expression. bax and bcl-2 staining was cytoplasmic. protein expression was scored as negative, weak; faint cytoplasmic staining, moderate; diffuse cytoplasmic stain, and strong; diffuse intense cytoplasmic stain. furthermore, proportion of malignant cells which had positive staining was considered in reporting. mild, moderate, and strong staining was considered as positive. which considers both the intensity and percentage of cells stained in each intensity. h-score was calculated as follows: (% of cells stained at intensity 1 × 1) + (% of cells stained at intensity 2 × 2) + (% of cells stained at intensity 3 × 3). a hconsidered as positive for bax or bcl-2 expression (figures 1 and 2). the median h-score values were selected for distinction between the groups of high and low bax or bcl-2 expression. figure 1. positive bax immunostaining (h-score = 240) in a prostate cancer with the gleason score of 7. figure 2. positive bcl-2 reaction (h-score = 200) in a prostate cancer with the gleason score of 9. 384 | statistical analysis progression-free survival was determined from the time of diagnosis to the time of biochemical failure or the last visit using kaplan-meier method. we used log-rank test for univariate comparsion model with backward stepwise selection of co-variates was used for multivariate analysis. tion between the bax and bcl-2 expression and the gleason score. results the participants included 13 patients with metastasis (9 distant and 4 lymph node metastasis) and 24 with locally advanced tumors. the median age of the patients was 73 years (range, 52 to 87 years). the median pretreatment psa value was 17 ng/ ml (range, 7.5 to 96 ng/ml) for high-risk adof metastatic cases. for all the subjects. we recorded gleason scores > 7 in 23 (62.7%) patients, including 16 (66.6%) of high-risk advanced and 7 (53.8%) of metastatic cases. treatment results with a median follow-up period of 32 months biochemical progression, including 13 out of 13 (58.3%) in the locally advanced group. the median time to the biochemical progression was 22 advanced group and 16 months (range, 9 to 26 months) in the metastatic group. the median biochemical recurrence-free survival rates for locally advanced and metastatic groups 21.87), respectively. bax and bcl-2 expression of 37 samples, 36 (97.3%) were positive for bax figure 3. association between bcl-2 expression and biochemical recurrencefree survival in patients with advanced or metastatic prostatic carcinoma. figure 4. association between pretreatment prostate-specific antigen and biochemical recurrent-free survival in patients with advanced or metastatic prostatic carcinoma. urological oncology 385vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l bax expression and gleason score (p = .28), high high gleason score (p table 2 shows the effect of different parameters on biochemical failure-free survival. gleason score and bax expression did not affect biochemical progression-free survival. meanwhile, as shown in figures 3 and 4, patients with high bcl-2 expression (p p ated with lower biochemical progression-free surwas associated with relatively higher biochemical failure-free survival, the difference did not reach bcl-2 expression (p (p chemical progression-free survival. discussion ing androgen deprivation therapy. about 41.6% of high-risk locally advanced group had pretreatsubjects that could not be found via our imaging methods, such as bone scintigraphy and computed tomography scan. hormonal treatment was the main treatment modality for prolongation of survival in most of our patients. we used the median h-score for the distinction between high and low expression of each ical progression-free survival was shown for subng/ml) and those with high bcl-2 expression. the contribution of bcl-2 to prostate carcinotable 1. correlation between gleason score and bax or bcl-2 expression high bax expression, n (%) high bcl-2 expression, n (%) gleason score: g 2 to 7, n = 14 g 8 to 10, n = 23 8 (57.1%) 9 (39.1%) 3 (21.4%) 16 (69.6%) p = .28 p = .004* *statistically significant. bcl-2 and bax protein expression in prostate carcinoma | anvari et al table 2. the pathological features and progression-free survival rate median biochemical failure-free survival (95% confidence interval), months p bax .45high expression 24 (14.59 to 33.41) low expression 20 (09.60 to 39.41) bcl-2 .01*high expression 16 (09.60 to 22.30) low expression 32 (22.35 to 41.03) gleason score .54high (g 8 to 10) 18 (07.8 to 35.22) low ( g 2 to 7 ) 24 (15.54 to 32.46) pretreatment prostate-specific antigen, ng/ml .01*> 20 18 (14.11 to 21.88) ≤ 20 35 (23.02 to 36.98) *statistically significant. 386 | genesis and hormone independence has been documented.(21) as the bcl-2 family modulates apoptosis, altered expression of bcl-2 might affect response to genotoxic stresses, including radiotherapy, hormone deprivation, or cytotoxic agents. expression of bcl-2 was shown to be associated with higher failure rate after radiotherapy in localized prostate cancer.(22-25) bcl-2 expression has also been associated with higher biochemical recurrence after radical prostatectomy.(26) predicting factors for time to progression included gleason score, pretreatment psa value, and nadir psa value after treatment initiation.(27-29) tissue biomarkers might also be helpful in prediction of response duration in metastatic or advanced diseases. following androgen ablation therapy, increased expression of bcl-2 develops in tumor cells, which eventually leads to an androgen independent state. zhou and colleagues used in-vivo model of anmolecular biology of progression from a hormone sensitive to hormone resistant state following castration. hormone resistant tumors had decreased apoptosis accompanied with augmented expression of p53, p21/waf1, bcl-2, bax, and the bcl-2/ bax ratio compared to androgen-sensitive tumors. (31) bcl-2 expression in newly diagnosed metastatic patients might be less responsive to hormone manipulation.(13) as bax is a pro-apoptotic agent, its expression is expected to be associated with increased tumor sensitivity to radiotherapy or systemic therapy. however, the results of studies have been inconreported worse prognosis for patients with bax expression.(17) meanwhile, in a group of patients undergoing external beam radiotherapy, lower bax expression was associated with worse prognosis; however; the difference was not statistically significant. patients with increased bcl-2/bax ratio had higher risk of failure following radiotherapy.(22) a study by amirghofran and colleagues, bax expression was not correlated with apoptosis index suggesting presence of nonfunctional bax protein. mutated or dysfunctional bax may appear overexpressed, while negatively affect apoptotic bax expression in a tumor specimen was considered as underor overexpression relative to the pollack and associates showed that higher bcl-2 expression and altered bax expression were associated with higher biochemical failure rates.(16) a group of patients with locally advanced prostate cancer who underwent radiotherapy, more favorable outcome were associated with negative bcl-2 and normal bax, especially in those who received short-term androgen ablation therapy plus radiotherapy.(15) altered bax expression seems to be a more reliable predictor of outcome compared to bax overexpression. as the role of apoptotic modulator, especially bcl2, has been documented in development of hormone independent prostate cancer, these genes were considered as a target for development of novel treatments. bcl-2 antisense oligonucleotides might counteract anti-apoptotic survival mechanisms and enhance hormone and chemotherapy sensitivity.(32-36) conclusion we concluded that high bcl-2 expression is associated with worse biochemical progression-free tients undergoing hormone manipulation therapy. acknowledgements urological oncology 387vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l this study was supported by a grant from the vicechancellorship for research, mashhad university of medical sciences. conflict of interest none declared. references 1. kattan mw, eastham ja, stapleton am, wheeler tm, scardino pt. a preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. j natl cancer inst. 1998;90:766-71. 2. qian j, jenkins rb, bostwick dg. determination of gene and chromosome dosage in prostatic intraepithelial neoplasia and carcinoma. anal quant cytol histol. 1998;20:37380. 3. xu j, zheng sl, isaacs sd, et al. inherited genetic variant predisposes to aggressive but not indolent prostate cancer. proc natl acad sci u s a. 2010;107:2136-40. 4. kehinde eo, maghrebi ma, anim jt. the importance of determining the aggressiveness of prostate cancer using serum and tissue molecular markers. can j urol. 2008;15:3967-74. 5. hartwell lh, 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androgen-independent prostate cancer. cancer res. 1992;52:6940-4. 31. zhou jr, yu l, zerbini lf, libermann ta, blackburn gl. progression to androgen-independent lncap human prostate tumors: cellular and molecular alterations. int j cancer. 2004;110:800-6. 32. gleave me, zellweger t, chi k, et al. targeting anti-apoptotic genes upregulated by androgen withdrawal using antisense oligonucleotides to enhance androgenand chemo-sensitivity in prostate cancer. invest new drugs. 2002;20:145-58. 33. yamanaka k, rocchi p, miyake h, et al. induction of apoptosis and enhancement of chemosensitivity in human prostate cancer lncap cells using bispecific antisense oligonucleotide targeting bcl-2 and bcl-xl genes. bju int. 2006;97:1300-8. 34. rubenstein m, guinan p. bispecific antisense oligonucleotides have activity comparable to monospecifics in inhibiting expression of bcl-2 in lncap cells. in vivo. 2010;24:489-93. 35. rubenstein m, tsui p, guinan p. treatment of prostate and breast tumors employing monoand bi-specific antisense oligonucleotides targeting apoptosis inhibitory proteins clusterin and bcl-2. med oncol. 2010;27:592-9. 36. karnak d, xu l. chemosensitization of prostate cancer by modulating bcl-2 family proteins. curr drug targets. 2010;11:699-707. urological oncology u j 03 all-2.pdf 620 | keywords: adrenal gland diseases, cysts, surgery introduction ectopic adrenal tissue detected in 20% of autopsies is relatively a common lesion. the site of its appearance is closely related to the migration of primordial adrenal cells in the course of organogenesis. ectopic intrarenal adrenal tissue can be found in 6% of general population. they are usually discovered incidentally in autopsies, and surgical specimens are of no to be differentiated from neoplastic lesions.(1) been reported in the literature. case report abbas basiri, nadali moosanejad, shahram shabaninia, alireza mir intrarenal adrenal cyst presenting as a renal mass corresponding author: nadali moosanejad, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: moosanejad@ gmail.com received december 2010 accepted february 2011 urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran case report case report 621vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l limits. intra-operatively. of normal adrenal cortical tissue. differentiation, such as inhibin and synaptophysin, and negadiscussion ectopic adrenal tissues usually consist of small clusters of cells identical to adrenal cortex, and are found in various locations. adrenal rest is most commonly located in the retropfigure 1. the computed tomography scan showed a hyperdense mass in the upper pole of the left kidney. figure 2. (a) renal tissue cohesive to adrenal gland tissue with infiltration of benign looking cortical adrenal cells into the renal parenchyma. (b) the adrenal tissue surrounds a cyst with flat lining. adrenal cyst presenting as a renal mass | basiri et al 622 | of the spermatic or gonadal vein, in the path of the testicular descent, near the tail of the epididymis, in the female gonadal ture, distant unusual location of adrenal rest, such as the lung, liver, and central nervous system, has also been reported.(2) nine cases of intrarenal adrenal tissue and renal-adrenal fuinto the renal parenchyma. seven cases have been inciden(3) operative diagnosis.(4) tures on imaging studies.(5) and therefore, unique. on computed tomography scan, this renal. (6) edge, this is the only reported case of ectopic intrarenal adreconflict of interest none declared. references 1. brodsky g, garnick mb. renal pathology with clinical and functional correlations. in: tisher cc, brenner bm, eds. renal tumors in adult patients. vol 2. philadelphia lippincott williams & wilkins;1989:1945. 2. rosai j. adrenal gland and other paraganglia. in: rosai j, ed. ackerman's surgical pathology: mosby-year book, st. louis, mo;1996:1015-40. 3. ye h, yoon gs, epstein ji. intrarenal ectopic adrenal tissue and renal-adrenal fusion: a report of nine cases. mod pathol. 2009;22:175-81. 4. fan f, pietrow p, wilson la, romanas m, tawfik ow. adrenal pseudocyst: a unique case with adrenal renal fusion, mimicking a cystic renal mass. ann diagn pathol. 2004;8:87-90. 5. tajima t, funakoshi a, ikeda y, et al. nonfunctioning adrenal rest tumor of the liver: radiologic appearance. j comput assist tomogr. 2001;25:98-101. 6. colberg jw, cai x, humphrey pa. unilateral adrenal heterotopia with renal-adrenal fusion. j urol. 1998;160:116. case report v08_no_3_final_last.pdf miscellaneous 222 urology journal vol 8 no 3 summer 2011 peri-ictal urinary dysfunction in patients with epilepsy a cross-sectional study mahmoud motamedi,1 mohammad reza nikoobakht,2 mehdi aloosh,1,3 sara ebrahimi nasrabady,4 azadeh afshin,3 amirhossein orandi,3 fatemeh talei khatibi3 purpose: to evaluate the prevalence of peri-ictal urinary symptoms and their association with seizure type in patients with epilepsy. materials and methods: a total of 115 patients with epilepsy were recruited consecutively from neurology clinic between january 2006 and january 2008. peri-ictal period was defined as the period ranging from 2 minutes prior to seizure attack up to 48 hours after it, and post-ictal period was the time up to 48 hours after regaining consciousness. peri-ictal urinary complaints were gathered with interview and data were analyzed using pearson’s chi-square, fisher’s exact test, and independent sample t test. results: the study population consisted of 57 (49.5%) men and 58 (50.4%) women, with the mean age of 26.83 ± 10.01 years. the frequency of at least one urinary symptom in studied patients was 39.1%. incontinence, frequency, urgency, retention, and hesitancy were reported by 28 (24.3%), 14 (12.2%), 19 (16.5%), 10 (8.7%), and 8 (7%) patients, respectively. women expressed more symptoms than men and a higher frequency of peri-ictal retention. although overall urinary complaints were more frequent in patients with partial seizures, there was a higher frequency of urgency in patients with partial seizure (p = .037). furthermore, apart from retention, there was no significant correlation between peri-ictal urinary symptoms and the patients’ age. conclusion: our findings suggest that peri-ictal urologic dysfunction is a common problem among patients with epilepsy and post-ictal urinary retention might also be considered as a post-ictal deficit (todd’s deficit). urol j. 2011;8:222-6. www.uj.unrc.ir keywords: epilepsy, complications, urination disorders, cross-sectional studies 1iranian center of neurological research, sina hospital, tehran university of medical sciences, tehran, iran 2urology research center, sina hospital, tehran university of medical sciences, tehran, iran 3research development center of sina hospital, tehran university of medical sciences, tehran, iran 4neurobiology sector, international school for advanced studies, trieste, italy corresponding author: mohammad reza nikoobakht, md sina hospital, emam khomeini st., tehran, iran tel/fax: 98 21 6671 6546 e-mail: nikoobakht_r@live.com received july 2010 accepted january 2011 introduction seizures that arise from or spread to areas in the central autonomic network can mimic the stimulation of autonomic afferents or modify autonomic expressions. as a result, different types of seizures, especially tonic-clonic and complex partial ones originating from the temporal or extratemporal areas often lead to sympathetic activation at different ages.(1,2) activation or inhibition of areas in the central autonomic network can lead to cardiovascular, gastrointestinal, cutaneous, and genitourinary manifestations.(2-5) genitourinary complications, including urgency, frequency, hesitancy, dribbling, and overt incontinence, reflect alterations in the bladder function, mediated by the parasympathetic nervous system.(2,6) while these urinary symptoms influence the life style greatly, few studies have evaluated the frequency of these peri-ictal peri-ictal urinary dysfunction and epilepsy—motamedi et al 223urology journal vol 8 no 3 summer 2011 complaints in patients with epilepsy.(1,2,4) even the number of studies that have been carried out examining the brain control of the bladder function is relatively limited. the purpose of this study was to evaluate the frequency of peri-ictal urinary symptoms in patients with epilepsy in order to achieve a better health care for this public health problem. materials and methods a cross-sectional study design was used to determine the peri-ictal urinary dysfunction among all the patients with epilepsy referred to the neurology clinic of sina hospital in tehran, iran from january 2006 to january 2008. this study was approved by the ethics committee of tehran university of medical sciences. epilepsy was diagnosed and classified based on the international league against epilepsy criteria(7) and the neurologist’s perspective. patients in the age range of 12 to 50 years were recruited. those with a positive history of urogenital diseases, such as urinary tract infection, urolithiasis, malignancies, benign prostatic hyperplasia, and anatomic disorders (prolapsed of the uterus or bladder) were excluded from the study. furthermore, patients in whom the urinary disorder was secondary to other neurologic diseases, such as dementia or multiple sclerosis, were also excluded. of 206 patients with epilepsy, 115 eligible subjects with urologic complaints enrolled in the study, consecutively. all of the subjects gave written informed consent. thereafter, they were interviewed and a data sheet was completed. eligible subjects that were able to answer questions were questioned directly and in case of mental retardation or any inability to answer questions, patient’s family was approached. peri-ictal period was defined as the period ranging from 2 minutes before occurrence of seizure until 48 hours following the attack. post-ictal period was the time up to 48 hours after regaining consciousness.(8-11) the data were analyzed by spss software (the statistical package for the social sciences, version 13, spss inc., chicago, illinois, usa), using pearson’s chi-square, fisher’s exact test, and t test, when appropriate. a p value < .05 was considered statistically significant. results participants consisted of 57 (49.5%) men and 58 (50.4%) women, with the mean age of 26.83 ± 10.01 years. there was no significant difference between the mean age of the men and women. forty-five (39.1%) patients reported at least one urinary symptom during the periictal phase. urinary incontinence was the main complaint of participants (24.3%). frequency, urgency, urinary retention, and hesitancy were reported by 14 (12.2%), 19 (16.5%), 10 (8.7%), and 8 (7%) patients, respectively. all the subjects with urinary retention reported it as a post-ictal problem. table 1 demonstrates the peri-ictal urinary symptoms reported by patients with respect to the subjects’ gender. women expressed more symptoms than men (49 versus 30) and a higher frequency of retention (p = .049). generalized, partial, and unclassified seizures were noted in 76 (66.1%), 37 (32.2%), and 2 (1.7%) patients, respectively. all of the patients were taking antiepileptic drugs; 76 (66.1%) patients were using single drug, 31 (26.9%) two drugs, and 8 (6.9%) more than two drugs. table 2 variables male female otal p incontinence 15 13 28 (24.3%) .63 urgency 6 13 19 (16.5%) .09 frequency 5 9 14 (12.2%) .27 hesitancy 2 6 8 (7%) .14 retention 2 8 10 (8.7%) .049 able 1. peri-ictal urinary symptoms considering the subjects’ gender variables ps ± s (%) s (%) unclassified p incontinence 11 (29.7) 17 (21.8) 0 .24 frequency 5 (13.5) 8 (10.2) 1 .42 urgency 10 (27) 9 (11.5) 0 .03 hesitancy 4 (10.8) 4 (5.1) 0 .43 retention 6 (16.2) 4 (5.1) 0 .07 overall urinary symptoms 18 (48.6) 26 (33.3) 1 .10 able 2. peri-ictal urinary symptoms according to type of seizure ps ± sg indicates partial onset seizures with or without secondary generalization; and gs, generalized seizures. peri-ictal urinary dysfunction and epilepsy—motamedi et al 224 urology journal vol 8 no 3 summer 2011 demonstrates the frequency of different urinary symptoms regarding the type of seizure. periictal urinary complaints were more frequent in patients with partial seizures; however, the difference was not statistically significant (p = .109). peri-ictal urinary urgency was more frequent in patients with partial seizure than those with generalized seizure (p = .037) and in p = .014). apart from urgency, there was no significant correlation between the peri-ictal urinary symptoms and the patients’ seizure type. discussion different aspects of autonomic function, including the parasympathetic, sympathetic, and adrenal medullary systems, may be affected during ictal, post-ictal, and inter-ictal stages of partial or generalized epilepsies.(6) seizures typically activate the sympathetic nervous system and increase the heart rate and blood pressure as a result. on the other hand, parasympathetic activation or sympathetic inhibition may predominate during partial seizures.(2) while postictal focal neurologic deficits, such as hemiparesis, aphasia, and visual field disturbances, are wellknown, post-ictal urinary disorders are not clearly reported. furthermore, there are large varieties in defining peri-ictal period.(4,12-14) todd described the regional loss of function of the brain after seizure attack (todd’s paralysis) as a condition usually lasting for a few minutes; however, it may persist for 48 hours in certain cases.(11) therefore, urinary symptoms may appear before (seconds to minutes) or after (few minutes to 48 hours) a lucid inter-ictal period of seizure. among urinary dysfunctions, incontinence is a frequent symptom in generalized tonic-clonic seizure. urinary incontinence is not secondary to increased bladder pressure, but it occurs due to the bladder sphincter relaxation during the muscular recovery phase of the seizure.(2,15) while urinary incontinence occasionally complicates the partial seizure, it possibly results from a combination of increased bladder pressure and loss of cortical inhibition of the micturation reflex.(6) oliva and colleagues reported 84 consecutive patients with at least one convulsive event during video electroencephalography monitoring. incontinence occurred in 23% (15/66) of patients. they could not find any relationship between type of epilepsy, lateralization, and the prevalence of incontinence.(16) in another study on 28 subjects with epilepsy, 78.6% reported incontinence.(17) in our study, in line with other studies, incontinence was the main urologic complaint (24.3%). discrepancy in reported rates could have various reasons, such as interaction between central and peripheral effects, ictal autonomic discharges, and side effects of antiepileptic drugs. therefore, more studies are necessary to elucidate the mechanisms of autonomic changes in epilepsy. ictal “desire to void” is an autonomic manifestation of temporal lobe epilepsy (tle) reported in 0.3% to 8% of the cases. aura of a “desire to void” and increased bladder pressure are infrequent manifestations of focal seizures. (18) janszky and associates reported peri-ictal vegetative symptoms (pivs) in 141 patients with tle, and assessed frequency, gender effect, and lateralizing value of peri-ictal autonomic signs. peri-ictal vegetative symptoms were present in 93% of women and 77% of men.(4) they found urge to void in 3 patients, which was contradictory to previous studies.(3,19,20) the presence of pivs had no lateralizing value, which may be linked to a low frequency of occurrence of pivs.(4) ictal urinary urgency appears to occur in patients with non-dominant hemispheric focal epilepsy, most notably, tle.(19) urge to void and incontinence have been described in patients with right hemispheric strokes.(18) in the current study, 19 (16.5%) patients had urinary urgency. furthermore, compared with generalized seizure, partial seizures were accompanied by a higher frequency of peri-ictal urgency. however, as this study was only based on clinical presentations, it was impossible to distinguish frontal and tle in these subjects. acute urinary retention is well-documented in patients with acute destructive lesions in various parts of the brain, including the frontal lobe, paraventricular white matter, internal capsule, basal ganglia, and pontine tegmentum.(21) metaanalysis of positron emission tomography and peri-ictal urinary dysfunction and epilepsy—motamedi et al 225urology journal vol 8 no 3 summer 2011 functional magnetic resonance imaging studies have shown that the thalamus, insula, prefrontal cortex, anterior cingulate, periaqueductal gray matter, pons, medulla, and supplementary motor area are activated during urinary storage(22) and connections between the forebrain and brainstem structures are involved in the control of the bladder and sphincter in the human. pontine micturation center is the final common pathway from the brain to the spinal cord. (23) periaqueductal gray matter has multiple connections that enable it to coordinate and control voiding, and appear to perform much of the required signal processing. however, pontine micturation center acts as a switch between the storage and voiding phases. for voiding, the pontine micturation center requires both an excitatory signal from the periaqueductal gray matter and a safe signal from the hypothalamus.(24) following focal seizure, there may be a localized paralysis, todd’s paralysis, which may last from minutes to hours, in the previously involved region.(8,11) this category refers to transient paralysis that may occur following some partial epileptic seizures with focal motor components or somatosensory symptoms. wieser and colleagues showed that aura can be long-lasting, continuous, or recurrent(25) and engel defined post-ictal symptoms as “manifestations of seizure induced by reversible alterations in neuronal function, but not structure”.(10) vander and ifergane reported 3 cases of transient postictal urinary retention, which were all men with different types of seizure.(26) on the contrary, of the 10 subjects presented with post-ictal urinary retention in our study, 8 were women. janszky and associates also found that pivs were more common in women,(4) which is compatible with our study. conclusion post-ictal urinary retention should be kept in mind and asked during history taking; and if present, the patient should be referred to urologists for further treatment. further studies are necessary to better elucidate the mechanisms of peri-ictal autonomic changes in epilepsy and prevent their undesirable effects. acknowledgements we are indebted to the iranian center of neurological research as well as research development center of sina hospital for their support. conflict of interest none declared. references 1. devinsky o. effects of seizures on autonomic and cardiovascular function. epilepsy curr. 2004;4:43-6. 2. baumgartner c, lurger s, leutmezer f. autonomic symptoms during epileptic seizures. epileptic disord. 2001;3:103-16. 3. horvath r, kalmar z, feher n, fogarasi a, gyimesi c, janszky j. [brain lateralization and seizure semiology: ictal clinical lateralizing signs]. ideggyogy sz. 2008;61:231-7. 4. janszky j, fogarasi a, toth v, et al. peri-ictal vegetative symptoms in temporal lobe epilepsy. epilepsy behav. 2007;11:125-9. 5. nikoobakht m, motamedi m, orandi a, meysamie a, emamzadeh a. sexual dysfunction in epileptic men. urol j. 2007;4:111-7. 6. blok bf. central pathways controlling micturition and urinary continence. urology. 2002;59:13-7. 7. mazzoni p, pearson t, rowland lp, merritt hh. merritt’s neurology handbook. 2 ed. philadelphia: lippincott williams & wilkins; 2006:585-90. 8. so n. epileptic auras. in: wyllie e, ed. the treatment of epilepsy: principles and practice. 3 ed. philadelphia: williams & wilkins; 2001:297-340. 9. dreifuss fe, penry jk, bancaud j, henriksen o, rubio-donnadieu f, seino m. proposal for revised clinical and electroencephalographic classification of epileptic seizures. epilepsia. 1998;22:489-501. 10. engel j. seizures and epilepsy: fa davis co.; 1989:346. 11. todd rb. clinical lectures on paralysis, certain diseases of the brain, and other affections of the nervous system. 2 ed. london: churchill; 1856:291302. 12. badawy r, macdonell r, jackson g, berkovic s. the peri-ictal state: cortical excitability changes within 24 h of a seizure. brain. 2009;132:1013-21. 13. boylan ls. peri-ictal behavioral and cognitive changes. epilepsy behav. 2002;3:16-26. 14. surges r, scott ca, walker mc. enhanced qt shortening and persistent tachycardia after generalized seizures. neurology. 2010;74:421-6. 15. gastaut h, orfanos a, lob h. polygraphic study of enuresis during grand mal attacks. electroencephalogr clin neurophysiol. 1964;16:626-7. 16. oliva m, pattison c, carino j, roten a, matkovic z, peri-ictal urinary dysfunction and epilepsy—motamedi et al 226 urology journal vol 8 no 3 summer 2011 o’brien tj. the diagnostic value of oral lacerations and incontinence during convulsive “seizures”. epilepsia. 2008;49:962-7. 17. imam i, talabi oa, sanya eo, ogunniyi a. the determinants of seizure severity in nigerian epileptics. niger j clin pract. 2005;8:94-6. 18. kuroiwa y, tohgi h, ono s, itoh m. frequency and urgency of micturition in hemiplegic patients: relationship to hemisphere laterality of lesions. j neurol. 1987;234:100-2. 19. loddenkemper t, foldvary n, raja s, neme s, luders ho. ictal urinary urge: further evidence for lateralization to the nondominant hemisphere. epilepsia. 2003;44:124-6. 20. baumgartner c, groppel g, leutmezer f, et al. ictal urinary urge indicates seizure onset in the nondominant temporal lobe. neurology. 2000;55: 432-4. 21. sakakibara r, hattori t, yasuda k, yamanishi t. micturitional disturbance after acute hemispheric stroke: analysis of the lesion site by ct and mri. j neurol sci. 1996;137:47-56. 22. dasgupta r, kavia rb, fowler cj. cerebral mechanisms and voiding function. bju int. 2007;99:731-4. 23. tadic sd, griffiths d, schaefer w, resnick nm. abnormal connections in the supraspinal bladder control network in women with urge urinary incontinence. neuroimage. 2008;39:1647-53. 24. blok bf, sturms lm, holstege g. a pet study on cortical and subcortical control of pelvic floor musculature in women. j comp neurol. 1997;389: 535-44. 25. wieser hg, hailemariam s, regard m, landis t. unilateral limbic epileptic status activity: stereo eeg, behavioral, and cognitive data. epilepsia. 1985;26: 19-29. 26. vander t, ifergane g. transient postictal urinary retention: presentation of three cases. eur j neurol. 2004;11:207-8. sexual dysfunction and infertility 164 urology journal vol 4 no 3 summer 2007 orchidopexy for retractile testes in infertile men a prospective clinical study mohammad reza dadfar introduction: retractile testis may affect testicular parenchyma and spermatogenesis, and surgical treatment has been recommended for infertile men with retractile testes. we evaluated outcomes of orchidopexy in men with idiopathic infertility who suffered from bilateral retractile testes. materials and methods: we performed dartos pouch orchidopexy on 22 men with idiopathic infertility and bilateral retractile testes. the patients were subsequently followed up for 1 year and sperm parameters were assessed at 3month intervals. testicular volume was determined by ultrasonography 1 year postoperatively and compared with that before orchidopexy. satisfaction with the appearance of the external genitalia, sexual desire, and the ability to have successful intercourse were assessed through a likert-scale questionnaire. results: before the operation, the mean testicular volume was 12.2 ± 5.0% lower than the lower normal limit of the testis volume in adults, and no clinically significant change was observed 1 year after the operation. sperm density showed no significant changes postoperatively, but the mean proportion of sperms with high-grade motility witnessed a significant increase 1 year after the operation (p = .007). the mean percentage of sperms with normal morphology had a significant decrease at 1 postoperative year. significant improvements were reported in satisfaction with the appearance of the external genitalia, sexual desire, and successful intercourse 1 year after the operation. conclusion: retractile testes might be at risk of growth retardation. we found that orchidopexy in retractile testes may improve sperm motility and increase fertility potential of the patients. we recommend orchidopexy in infertile men with bilateral retractile testes. urol j. 2007;4:164-8. www.uj.unrc.ir keywords: cryptorchidism, retractile testes, male infertility, orchidopexy department of urology, ahwaz jundishapur university of medical sciences, ahwaz, iran corresponding author: mohammad reza dadfar, md department of urology, imam hospital, ahwaz, iran tel: +98 611 222 2114 e-mail: mdadfar@yahoo.com introduction retractile testes have been a controversial subject in male infertility. they used to be considered without clinical importance in past years, but recently scrotal orchidopexy has been recommended for these testes by some authors, since they believe that this procedure may increase fertility profile of patients by correction of testicular metabolic environment and better spermatogenesis.(1) hereby, we report the results of clinical and paraclinical evaluations of 26 infertile men with bilateral retractile testes who underwent dartos pouch orchidopexy. materials and methods a total of 3241 men were referred to our male infertility clinic during a period from march 2002 through february 2005. in 26 of these patients, bilateral retractile testes was diagnosed according to caucci and colleagues’ definition as “a testis which can be drawn to the scrotal orchidopexy for retractile testes—dadfar urology journal vol 4 no 3 summer 2007 165 base on physical examination by manual traction, but in other times, it is palpable in the upper inguinal or abdominal positions.(2)” four of the patients were excluded from the study according to our exclusion criteria (table 1), and only men with a final diagnosis of idiopathic oligoasthenospermia entered the study. in all of these patients, complete clinical and sexual history was obtained and a questionnaire was designed to assess satisfaction with the appearance of the external genitalia, sexual desire, and intercourse based on likert scales before and 1 year after orchidopexy (appendix). informed consent was obtained from all selected patients and bilateral inguinal exploration and standard dartos pouch orchidopexy was performed under general anesthesia by a single urologist using redman and barthold’s method.(3) the patients were followed up for at least 1 year according to a unified protocol: physical examination and computer-aided semen analysis at 3-month periods, and scrotal ultrasonography and sexuality assessment using the previously used questionnaire 1 year after the procedure. semen parameters were compared with the world health organization criteria,(4) and a highgrade sperm motility (sum of motility grades a and b) was considered. the recorded clinical and surgical data were collected and analyzed by the spss software (statistical package for the social sciences, version 11.0, spss inc, chicago, ill, usa) to evaluate the effects of orchidopexy on testicular volume and semen parameters of the retractile testis. the mcnemar test was used to evaluate changes in the scores of the questionnaire postoperatively. normal distribution of sperm parameters and testicular volumes were evaluated by kolmogorov-smirnov test and the preoperative-postoperative changes were assessed by the paired t test. results a total of 22 patients with a diagnosis of nonobstructive idiopathic oligoasthenospermia were enrolled in the study. their mean age was 37.5 ± 8.7 years (range, 26 to 49 years). bilateral retractile testes were found on primary physical examination in all of the patients, and in postoperative examinations it was confirmed that all testes were fixed successfully in the lower scrotal area. table 2 depicts the mean values for the sperm and testicular parameters measured before and 1 year after orchidopexy. preoperative ultrasonography revealed that the mean testicular volume was 12.2 ± 5.0% lower than the lower normal limit of the testis volume in adults. on postoperative examinations, done 1 year after orchidopexy, there was a significant change in testicular volumes, but it was not clinically considerable. sperm density assessments before and after the operation showed no significant changes (figure 1), but the mean proportion of sperms with high-grade motility witnessed a significant increase 1 year after the operation (figure 2). this parameter was significantly higher than its normal ranges (p = .046).(5) the mean percentage of sperms with normal morphology had a significant decrease at 1 postoperative year, but it was not clinically of importance. regarding the sexuality questionnaire, significant improvements were obtained in satisfaction with the appearance of the external genitalia, sexual desire, exclusion criteria disagreement of patient absence of true bilateral retractile testes atrophic testes past history of endocrine diseases or hormone therapy past history of other testicular diseases past history of clinical varicocele past history of any testicular surgery other proved etiologies for male infertility table 1. study exclusion criteria values parameters preoperative postoperative p testicular volume, ml 23.63 ± 1.17 (21.2 to 25.2) 24.19 ± 1.25 (21.2 to 25.7) .02 sperm density, × 106/ml 34.18 ± 1.50 (31.3 to 36.4) 34.56 ± 2.53 (25.2 to 36.8) .51 high-grade sperm motility, % 15.34 ± 1.87 (12.2 to 18.2) 31.00 ± 9.85 (13.3 to 45.2) < .001 sperm morphology, % 18.12 ± 3.60 (12.2 to 24.1) 17.69 ± 3.73 (12.1 to 24.1) .007 table 2. sperm and testicular parameters before orchidopexy and 1 year postoperatively* *values in parentheses are the minimums and maximums. orchidopexy for retractile testes—dadfar 166 urology journal vol 4 no 3 summer 2007 and successful intercourse (table 3). preoperative responses of the patients to the question about satisfaction with appearance of their external genitalia showed that 9 (40.9%) were not satisfied at all, while 1 year after orchidopexy no satisfaction was mentioned by only 2 patients (9.1%), and 9 (40.9%) stated the level of “very good” (p = .001). sexual desire was “very low” or “a little” in 13 patients (59.1%), and 1 year postoperatively, 17 (72.3%) mentioned “moderate” or “very good” for this factor (p = .003). the physical ability of successful intercourse had moderate improvement and 17 patients (72.3%) responded to have a “moderate” or “strong” status (p = .046). successful induction of clinical pregnancy was reported in 2 patients (9.1%) in our series during follow-up period. discussion clinical significance of retractile testis and its effect on male infertility has been a matter of debate since many years ago.(6) puri and nixon reported no detrimental effect of retractile testes on the patient fertility and other investigators such as la scala and ein recommended no surgical intervention for these gonads.(7,8) in contrast, some other investigators have defended hormonal or surgical therapy,(9) and raboch and pondelickova reported low sperm values in adolescents with unilateral or bilateral retractile testes that were ameliorated in a small portion of the patients.(10) ito and colleagues also recommended early treatment of retractile testes to prevent future severe histologic damages.(11) patients responses questionnaire preoperative postoperative p satisfaction with appearance of external genitalia .001 not at all 9 (40.9 ) 2 (9.1) a little 4 (18.2) 2 (9.1) can be better 7 (31.8) 9 (40.9) very good 2 (9.1) 9 (40.9) sexual desire .003 very low 2 (9.1) 1 (4.5) a little 11 (50.0) 4 (18.2) moderate 6 (27.3) 9 (40.9) very good 3 (13.6) 8 (36.4) ability of successful intercourse .046 very weak 2 (9.1) 1 (4.5) weak 6 (27.3) 4 (18.2) moderate 12 (54.6) 11 (50.0) strong 2 (9.1) 6 (27.3) *values in parentheses are percents. table 3. responses of patients to questions on their genitalia and sexuality before orchidopexy and 1 year postoperatively* figure 1. sperm density in the patients with retractile testes before orchidopexy and during the follow-up period. s pe rm d en si ty , × 1 06 /m l figure 2. high-grade sperm motility in the patients with retractile testes before orchidopexy and during the follow-up period. orchidopexy for retractile testes—dadfar urology journal vol 4 no 3 summer 2007 167 microscopic parenchymal lesions have also been proved in long-term follow-up of retractile testes.(12) during the recent years, a new trend towards dartos pouch orchidopexy for these organs has been aroused and many investigators have recommended this procedure not only for improving testicular sperm production,(13) but also for preventing from spermatic cord torsion.(14) despite the small sample of cases in our prospective study, we had some interesting findings; preoperative mean testicular volume in our patients was less than the normal values for adults. this finding may be related to two probable hypotheses: growth retardation may be due to testicular retraction and secondary deranged internal metabolic milieu of the organ. the other explanation is that the primary maldeveloped testes may become more prone and finally present as retractile organs. these theories both need more investigation and maldevelopment of gubernaculum testis as a fixation anchor may be of pivotal importance in these matters. in this study, we failed to find significant improvement in the mean sperm density in contrast to the experiment by caucci and colleagues.(2) this finding along with the relatively stable testicular volumes during the follow-up period may be a sign of permanent damages in function and quantity of spermatogenetic cells of the retractile testes. we speculate that retractile testes may be at risk of growth retardation and orchidopexy in childhood may provide better spermatogenesis and fertility profile in the upcoming years of their adulthood. the main finding of our study was the significant improvement in sperm motility which was recorded steadily in prolonged follow-up period of orchidopexy. multiple factors may be responsible for enhanced sperm motility; more favorable scrotal environment for spermatogenesis, decreased hydrostatic pressure on the testes, and lower intrascrotal temperature, all may have a role here.(15) more extended and better planned national or international studies with larger patient populations may produce more information on this controversial subject. another interesting finding in our study was improvement in sexual desire and function in postoperative visits. these changes were proved through a questionnaire with direct questions on sexual life and potency status of the patient. we linked these findings with increased self-esteem of the patients secondary to favorable changes in the appearance of the external genitalia after the operation and stable decent of the testes to the intrascrotal position. this outcome may also encourage patients to better follow their infertility therapeutic plans. conclusion retractile testes are at risk of growth retardation. although we were unable to show improvement in sperm density, increased sperm motility, satisfactory sexuality, and increased self-esteem of the patient are all in favor of recommending scrotal orchidopexy in infertile men with retractile testis. conflict of interest none declared. appendix sexuality questionnaire 1. how much do you like or is satisfied with appearance and shape of your external genitalia in present status? (a) not at all (b) a little (c) it can be better (d) it is very good 2. how is your present level of sexual desire? (a) very low (b) a little (c) moderate (d) very good 3. how is your ability of successful sexual intercourse now? (a) very weak (b) weak (c) moderate (d) strong references 1. okuyama a, nonomura n, nakamura m, et al. surgical management of undescended testis: orchidopexy for retractile testes—dadfar 168 urology journal vol 4 no 3 summer 2007 retrospective study of potential fertility in 274 cases. j urol. 1989;142:749-51. 2. caucci m, barbatelli g, cinti s. the retractile testis can be a cause of adult infertility. fertil steril. 1997;68:1051-8. 3. redman jf, barthold js. a technique for atraumatic scrotal pouch orchiopexy in the management of testicular torsion. j urol. 1995;154:1511-2. 4. world health organization. who laboratory manual for the examination of human semen and spermcervical mucus interaction. 4th ed. cambridge (uk): cambridge university press; 1999. 5. bonde jp, ernst e, jensen tk, et al. [semen quality and fertility in a population-based follow-up study]. ugeskr laeger. 1999;161:6485-9. 6. lee pa. fertility in cryptorchidism. does treatment make a difference? endocrinol metab clin north am. 1993;22:479-90. 7. puri p, nixon hh. bilateral retractile testes-subsequent effects on fertility. j pediatr surg. 1977;12:563-6. 8. la scala gc, ein sh. retractile testes: an outcome analysis on 150 patients. j pediatr surg. 2004;39:1014-7. 9. abyholm t, oian p, gordeladze jo. true cryptorchidism and retractile testes in infertile men. acta eur fertil. 1986;17:15-8. 10. raboch j, pondelickova j. [andrological findings in adolescents with retractile testis]. andrologia. 1988;20:417-21. 11. ito h, kataumi z, yanagi s, et al. changes in the volume and histology of retractile testes in prepubertal boys. int j androl. 1986;9:161-9. 12. nistal m, paniagua r. infertility in adult males with retractile testes. fertil steril. 1984;41:395-403. 13. zini a, abitbol j, schulsinger d, goldstein m, schlegel pn. restoration of spermatogenesis after scrotal replacement of experimentally cryptorchid rat testis: assessment of germ cell apoptosis and enos expression. urology. 1999;53:223-7. 14. cendron m, keating ma, huff ds, koop ce, snyder hm, 3rd, duckett jw. cryptorchidism, orchiopexy and infertility: a critical long-term retrospective analysis. j urol. 1989;142:559-62; discussion 72. 15. thonneau p, marchand s, tallec a, et al. incidence and main causes of infertility in a resident population (1,850,000) of three french regions (1988-1989). hum reprod. 1991;6:811-6. review 130 urology journal vol 4 no 3 summer 2007 minimally invasive approaches to prostate cancer a review of the current literature abraham ari hakimi, marc feder, reza ghavamian introduction: while radical retropubic prostatectomy has been the gold standard surgical approach, the explosion of minimally invasive methods has led to the search for less invasive treatment options. we offer an overview of the evolution of laparoscopic radical prostatectomy (lrp) and robot-assisted laparoscopic prostatectomy (ralp) in terms of the landmark publications and recent head-tohead comparisons, and we review our own experience. materials and methods: a medline search was performed using the keywords prostate cancer, prostatectomy, laparoscopic, and robotic. all pertinent articles concerning localized prostate cancer were reviewed. the montefiore experience consisted of a retrospective review of a prospectively maintained confidential database. results: several laparoscopic and robotic series were identified including review articles of each modality as well as studies directly comparing the two. both lrp and ralp compare very favorably with conventional open surgery in terms of safety and oncologic efficacy. both minimally invasive approaches offer decreased blood loss, transfusion rate, and length of hospital stay when contrasted with open surgery. when compared directly, lrp and ralp offer similar surgical, oncologic, and functional outcomes. however, ralp likely requires a shorter learning curve. conclusion: the use of minimally invasive techniques has revolutionized the surgical treatment of prostate cancer. pure lrp has been shown to be feasible and reproducible. however, it has a steep learning curve and is difficult to learn. in contrast, ralp is easier to learn and is now the surgical treatment of choice in most centers of excellence in the united states. the superior optics with respect to visualization and magnification translates into a procedure that is equivalent, if not superior, with respect to perioperative parameters, oncologic outcomes, and functional outcomes to its open counterpart. urol j. 2007;4:130-7. www.uj.unrc.ir keywords: prostatic neoplasms, surgical procedures, laparoscopy, robotics department of urology, montefiore medical center, albert einstein college of medicine, bronx, new york, usa corresponding author: reza ghavamian, md department of urology, montefiore medical center, bronx, new york, united states e-mail: rghavami@montefiore.org introduction prostate cancer is the second most common diagnosed cancer in men in the united states trailing only nonmelanoma skin cancer. it is also the second leading cause of cancerrelated mortality after lung cancer.(1) the two mainstays of treatment for localized prostate cancer are radiation and surgical excision. radical retropubic prostatectomy (rrp) has been the gold standard for the surgical approach, although the perineal approach has been shown to be equally efficacious surgical option.(2) the explosion of minimally invasive surgery and the inherent morbidity associated with conventional open radical prostatectomy has led to the search for less invasive treatment options. schuessler and colleagues(3) attempted minimally invasive approaches to prostate cancer—hakimi et al urology journal vol 4 no 3 summer 2007 131 the first laparoscopic radical prostatectomy (lrp) in 1992 and published a series comprised of 9 prostatectomies. the operation was cumbersome and difficult with unacceptably prolonged operative time. the authors concluded that the procedure offered no advantage compared to rrp. after substantially improving the techniques at montsouris in france, guillonneau and associates published their series demonstrating substantial improvements in postoperative convalescence.(4) the operation was shown to be feasible, but more importantly, reproducible. the expansion of lrp in the united state has been limited, however, secondary to the steep learning curve.(5,6) recently, robot-assisted laparoscopic prostatectomy (ralp) has introduced several new theoretical advantages to accelerate learning for the laparoscopically naive surgeon. the da vinci surgical system’s (intuitive surgical, sunnyvale, california, usa) magnified 3-dimensional view and intuitive surgical capabilities has allowed surgeons to master the laparoscopic extirpation of the prostate with optimal visualization and dexterity (figure). additionally, it has been hypothesized that the development of robotic laparoscopic equipment with 6 degrees of freedom has shortened the lrp learning curve. in 2000, menon and colleagues spear-headed and described the technique of robotic prostatectomy at henry ford hospital.(7) since then, numerous studies have evaluated ralp in terms of its learning curve as well as direct comparisons of surgical and oncologic outcomes to both the open and pure laparoscopic approaches. herein, we offer an overview of evolution of lrp and ralp in terms of the landmark publications and recent head-tohead comparisons. laparoscopic radical prostatectomy laparoscopy was introduced to urology in the early 1990s,(8) with the first series of lrp reported by schuessler and colleagues in 1991.(3) guillonneau and colleagues described their early experience in published in 1997.(4) several large subsequent studies have evaluated the risks and benefits of lrp. the driving force has been an attempt to minimize the patient’s overall pain, length of hospital stay, and hasten return to normal activities, while at the same time, duplicate the overall surgical and oncologic outcomes of rrp. laparoscopic radical prostatectomy has been shown to offer improved visualization of the pelvic anatomy, thereby optimizing preservation of anatomical structures, namely the neurovascular bundles and the external striated sphincter, which could lead to improvements in potency and urinary continence. guillonneau and colleagues’ early data, along with numerous other series have consistently described lower blood loss and decreased postoperative need for analgesia, while achieving comparable negative surgical margins and disease-free follow up.(4,9,10) operative results most studies indicate longer operative time for lrp when compared to rrp, but lrp seems to offer consistently more significant decrease in estimated blood loss (ebl), and transfusion rates. rassweiler and coworkers found a more significant reduction in postoperative pain following the lrp compared to the rrp.(9) in this study, 55% of patients undergoing rrp still required analgesics compared to only 9% in the lrp group. in their excellent recent review of 10 lrp series, tooher and colleagues(10) found the mean operative time of 288 minutes for lrp versus 168 minutes for rrp. the ebl decreased from a mean of 1400 ml to 800 ml and the transfusion rate, from 26% to 2%. the length of hospital stay varied significantly in terms of countries of origin (european versus united states), but seemed to be significantly less for lrp.(11,12) at our institution, a single surgeon (rg) has performed over 300 pure laparoscopic prostatectomies. a review of our last magnified view of the prostatic apex after a bilateral nervesparing robotic prostatectomy prior to urethral transection. minimally invasive approaches to prostate cancer—hakimi et al 132 urology journal vol 4 no 3 summer 2007 135 patients, which comprises our experience well after the learning curve was overcome, revealed comparable outcomes. the average operative time was 280 minutes, ebl was 298 ml, and the average length of hospital stay was 2.6 days. complications the incidence of conversion of lrp to an open procedure ranges in the literature from zero to 14% in several studies.(13-15) most studies cite similar complication rates between rrp and lrp.(9),(10) rassweiler and colleagues(9) found that the complication rate significantly improved when trending their experience of lrp over time. in their group of 438 patients, the first third had a similar complication rate to that of rrp, but the last third a significantly decreased rate. they also found differences in the types of complications. in the early laparoscopic group there were more rectal injuries compared to those in the late laparoscopic and open groups (3.2% versus 1.8% and 1.8%, respectively) and more urinary leakages (2.3% versus 0.5% and 0.9%, respectively). on the other hand, compared to early and late laparoscopic groups, the incidences of lymphocele (6.9% versus zero and zero), wound infection (2.3% versus 0.5% and zero), and embolism/pneumonia (2.3% versus 0.5% and 0.5%) were higher after open surgery. oncologic outcomes in the 5 studies reviewed by tooher and colleagues, the positive margin rates for lrp and rrp were similar.(13-17) importantly, stage for stage, there did not appear to be any differences in the positive margin rate between laparoscopic and open prostatectomy. biochemical recurrence-free survival, defined as prostate-specific antigen greater than 0.2 ng/ml on more than 1 occasion, was poorly reported, but it did not appear to differ between laparoscopic and open approaches in 4 studies.(14,15,18,19) quality-of-life outcomes the two major factors that directly impact quality of life are urinary incontinence and erectile dysfunction. the definition of continence and potency are variable in the literature and therefore, there is great variability in their reporting noted in the literature. rassweiler and coworkers reviewed the literature concerning continence range at 12 months for both rrp and lrp.(9) both rates were similar (81% to 92% for rrp and 84% to 97%) for lrp. rogers and colleagues looked at age and return continence and potency after lrp using the expanded prostate cancer index composite.(20) they found that younger men (less than 50 years) treated with nerve-sparing laparoscopic radical prostatectomy regain urinary control and potency earlier than older men. however, validated questionnaire subscale analyses demonstrated that the return to preoperative baseline urinary continence and sexual function was similar in all age groups (< 59, 50 to 59, and > 60 years) by the end of the first postoperative year. jacobsen and associates found no differences in continence 1 year after open radical retropubic prostatectomy or laparoscopic radical prostatectomy.(21) urinary incontinence was found to affect a similar proportion of patients who underwent open (13%) and laparoscopic (17%) radical prostatectomies 12 months postoperatively. learning curve tooher and colleagues cited 6 studies dealing with the learning curve in lrp. they found that most clinical parameters improved with time, including estimated blood loss, length of procedure, and complications.(10) of note, length of catheter time and hospital stay did not seem to improve. our experience at montefiore medical center with respect to the learning curve showed that the use of intensive laparoscopic skills training at a minimally invasive surgery center helped overcome the steep learning curve.(22) more importantly, all operations were video recorded. by reviewing operative footage, the surgeon was able to assess outcomes by comparing cases in which the optimal outcome was not achieved to cases in which it was indeed achieved to modify his surgical technique. using these criteria, the operative aspects of the learning curve were reasonably overcome by the 35th case. we have published our experience comparing pure lrp and rrp performed by a single surgeon (rg).(23) a total of 70 lrp patients operated on between 2001 and 2002 with at least 18 months of follow-up were compared with a matched cohort of 70 patients who had undergone rrp from 1999 to 2001. the baseline patient characteristics, perioperative and histologic parameters, recovery time, complications, minimally invasive approaches to prostate cancer—hakimi et al urology journal vol 4 no 3 summer 2007 133 and 18-month functional data were compared. no significant differences were found in the preoperative characteristics. the mean operative time was 181.8 ± 18.7 minutes for rrp and 246.4 ± 46.1 minutes for lrp (p < .001). the mean estimated blood loss was 563.2 ml for rrp and 275.8 ml for lrp (p < .001). the positive margin rates were not significantly different between the rrp and lrp groups (20% and 15.7%, respectively). the mean pain score on the postoperative day 1 was 4.5 in the lrp group and 7.8 in the rrp group on an analog pain score of zero to 10 (p = .02). full recovery was achieved at 33 ± 17 days and 45 ± 20 days for the lrp and rrp groups, respectively (p < .001). the total perioperative complication rates for lrp and rrp were comparable at 18.5% and 15.7%, respectively. the diurnal continence rate (no pads) for the lrp and rrp groups was 70.0%, 90.0%, and 92.8% and 71.4%, 87.6%, and 92.0% at 6, 12, and 18 months, respectively. the potency rate after bilateral neurovascular preservation with or without sildenafil for the lrp and rrp group was 55.0%, 72.6%, and 79.5% and 43.0%, 58.0%, and 72.4% at 6, 12, and 18 months, respectively, with no significant differences. we concluded that lrp is well tolerated and provides short-term oncologic and functional results comparable to those of rrp. at our institution we have performed over 300 pure laparoscopic prostatectomies. a review of 135 patients was conducted towards the end of our experience in whom complete data and follow-up was available. this comprised our experience well after the learning curve was overcome and has revealed comparable outcomes. the average operative time was 280 minutes, ebl was 298 ml and the average length of stay was 2.6 days in this cohort. this compares well with our previous experience and with other reports in the literature(4,10) (table 1). robot-assisted laparoscopic prostatectomy the use of a robotic technology offers many advantages over conventional lrp, including 3-dimensional visualization, magnification, increased degrees of freedom, absence of the fulcrum effect, and robotic-wrist instrumentation. the hypothesis is that ralp can successfully reduce the learning curve that even experienced surgeons face while performing lrp. the steep learning curve for lrp is often cited as a major impediment for the widespread implementation of lrp. any improvement that is gained by the use of robotic technology would help circumvent this issue and favor the use of a laparoscopic approach compared to the traditional open technique. menon, guillonneau, and vallancien at henry ford hospital developed the robotic prostatectomy in 2000.(24) since that time, an explosion of case series have surfaced in the literature looking at the surgical and oncologic outcomes. we have currently performed over 160 robotic prostatectomies. our learning curve for this procedure has been low due to our relatively adequate and prior experience with pure lrp. we believe there are inherent advantages to the robotic technique. herein, we review the different aspects of ralp by citing appropriate references and present our current experience with each parameter discussed. operative results as with any new surgical procedure, the initial reports of operative time with ralp varied greatly. in a recent review of the literature, patel and coworkers found the operative time to range from 141 minutes to 540 minutes.(25) however, most published reports from major centers find a marked decrease in time with patel and associates reporting operative time of approximately 90 minutes after a series of 1000 patients.(25) aherling and colleagues outcome large series(guillonneau et al(4); n = 550)* review of series (tooher et al(10))† montefiore experience (n = 135)* operative time, min 200 288 (180 to 400) 280 estimated blood loss, ml 380 800 (317 to 1100) 298 length of hospital stay, d 4.2 5 (2 to 12) 2.6 positive margin rate, % 16.7 23 (11 to 50) 17.0 overall complication rate, % 3.6 17 (0 to 25) 17.0 table 1. outcomes of laparoscopic radical prostatectomy at our center and in the literature *values for the first 3 rows are means. †values for the first 3 rows are medians (ranges). minimally invasive approaches to prostate cancer—hakimi et al 134 urology journal vol 4 no 3 summer 2007 reported a direct comparison of their experience with open and robotic approaches and found no significant difference in operative time between the two modalities.(26) in a subsequent study, the same authors showed that the conversion of skills from rrp can be successfully transferred to laparoscopy using a robotic interface with the da vinci surgical system.(27) a retrospective study by hu and coworkers comparing ralp to lrp showed a mean operative time of 4.1 hours and 3.1 hours, respectively, using a sample size of over 300 cases for each group.(28) with respect to blood loss, many reported series report transfusion rate approaching nil.(24) tewari and colleagues described a 67% transfusion rate in rrp compared to zero in ralp.(29) hu and colleagues also reported a decrease in the ebl for ralp, 200 ml compared to 250 ml in rrp.(28) other studies have shown even lower values for ebl in their ralp case series, such as patel and associates(30) who report an ebl of 75 ml (with an average of only 43 ml in the last 100 patients), and ahlering and colleagues who report an average ebl of 145 ml.(27) our mean ebl in our initial 131 patients was 242 ml. complications hu and colleagues reviewed the intraoperative complication rates in their and menon’s series of 1100 patients.(28,31) both series had a major intraoperative complications rate of less than 1% including ureteral, rectal, and epigastric vessel injury. in a recent review of the literature, ficarra and associates cited an overall postoperative complication rate ranging from 1.5% to 17%, with the major complications consisting of rectal and ureteral injuries, ileus, and urinary leakage.(32) our overall complication rate was 13% for our initial 131 patients. oncologic outcomes the literature has a wide range of positive margin rates, largely correlating with clinical and pathologic stage. ficarra and colleagues’ review article(32) stratified the literature on pathologic stage and found the positive surgical margin rate to vary from 5.7% to 27% in stage t2 disease to 26% to 40% in t3a and 27% to 67% in t3b. the overall positive margin rate varied from 2% to 36%. with regards to positive margins, most series report a lower positive margin rate in pathologic t2 disease as opposed to pathologic t3 disease, with t2 positive margin rate quoted as low as 5% in some series. the most common positive margin site in our experience is the apex, even though visualization and dissection are greatly aided and enhanced by the robotic optics. the prostate-specific antigen recurrence rates are still premature with the majority of studies, as it is in our experience. functional outcomes in terms of continence, the range is from 76% to 95% of patients who are fully continent, defined as the use of no pads at 3 months time.(25,29) patel and colleagues,(30) who have the longest period of follow-up, report that all patients were continent at 18 months after surgery. these values are similar to those seen in both rrp and lrp. data are sparse regarding potency following ralp. in a recent series, a 78% potency rate was reported at one 1 year with or without the use of oral medications, with only 15% of patients being unable to sustain erections sufficient for intercourse, and another 7% requiring injection therapy.(30) tewari and colleagues(29) reported 82% of preoperatively potent patients younger than 60 years returned to some sexual activity and 64% having sexual intercourse at 6 months. in patients older than 60 years, 75% had some return of sexual activity and 38% having intercourse at 6 months postoperative. learning curve the greatest advantage of ralp compared to lrp may lie in the significantly decreased learning curve. a laparoscopically naive surgeon may require as many as 80 to 100 cases before reaching the peak the leaning curve for lrp. in a prospective study of 200 patients in a community setting, patel and colleagues reported a learning curve of 20 to 25 cases using ralp. a second study performed by ahlering and coworkers(27) reported even shorter learning curve of only 8 to 12 cases, although this series only included 45 patients. this study also delineated the individual steps of the operation. the surgeon was laparoscopically naive and only received a 1-day training course, in addition to performing 2 cadaveric cases, prior to the 45 cases in the series. this is in contrast to patel and colleagues’ study where the surgeon was a fellowship-trained laparoscopist.(30) minimally invasive approaches to prostate cancer—hakimi et al urology journal vol 4 no 3 summer 2007 135 our learning curve with the ralp was abbreviated due to our prior lrp experience. this is only with regard to perioperative parameters such as blood loss, operative time, and anastomosis time. there are different definitions of learning curve. just being able to complete the robotic operation fast does not translate into proficiency and overcoming the learning curve. proficiency has to be defined also by the return of functional outcomes after surgery. the learning curve continues to evolve and continues well into one’s experience. this has been shown with rrp and is most probably true for ralp as well.(33) costs the overall costs of these new technologies complicate their recommendation for widespread use, despite favorable surgical outcomes compared to conventional rrp. using an economic model with data from several peer-reviewed articles, lotan and associates evaluated the current cost components for rrp, lrp, and ralp.(34) they reported that rrp remains the most cost-effective approach and has a cost advantage of us$ 487 and us$ 1726 over lrp and ralp, respectively. this study mentioned that the main factors responsible for the increased cost burden for ralp are the purchase and maintenance costs of the robot (us$ 857 per case) and the equipment costs (us$ 1705). even if the robot (approximate cost us$ 1 200 000) was donated through philanthropic efforts, there is still a us$ 1155 added cost for ralp versus rrp. equipment costs for lrp (us$ 533 per case) accounts for the major cost burden over rrp. this is the case since cost advantage for the shorter length of hospital stay in lrp cases is mitigated by the longer operative time. of note, lotan and colleagues mentioned that at current costs for the da vinci robot, no singlefactor change could make ralp cost equivalent to rrp.(34) the robotic equipments costs would have to decrease to us$ 550 per case for a donated robot to reach economic equivalence. conversely, the robot cost would have to decrease to us$ 500 000, the maintenance contract to us$ 34 000 per year, and the equipment cost to us$ 500 per case for ralp to have an advantage to rrp. on the other hand, menon and coworkers estimated that an institution must perform 75 cases per year with an average operative time of 3 hours per case to be cost-effective in the united states.(35) table 2 details our initial experience with ralp in 131 patients along with comparisons to the current literature.(32,36) laparoscopic radical prostatectomy versus robot-assisted laparoscopic prostatectomy a few recent papers have reviewed direct comparisons between the two modalities. rozet and colleagues(37) from france reviewed their series consisting of 4 surgeons. the ralp series was matched to a retrospective series of equivalent lrp patients. the authors found no statistical differences regarding operative time, ebl, hospital stay, or bladder catheterization between the two groups. the overall rate of complications was higher in the ralp group (9.1% versus 19.4%), but the overall rate of major complications was not significantly different (6.0% versus 6.8%). the positive margin rate was 26% and 21% for the ralp and lrp cases, respectively, across all pathological stages (p = .42). both menon and colleagues(35) and joseph and colleagues(36) did find significant decrease in blood loss when comparing the to groups in favor of ralp. our comparative experience can be seen in table 3. the most striking difference in our experience is the operative time that is significantly decreased with ralp as opposed to lrp. the ebl outcome large series(joseph et al(36); n = 325) review of series (ficarra et al(32)) montefiore experience (n = 131) operative time, min 130 168 (130 to 250) 191 estimated blood loss, ml 196 174 (75 to 500) 242 length of hospital stay, d 1 1.8 (1.2 to 5) 1.8 positive margin rate, % 13.0 15.1 (2 to 59) 15.2 overall complication rate, % 9.6 11.3 (1.5 to 17.2) 13.0 table 2. outcomes of robot-assisted laparoscopic prostatectomy at our center and in the literature* *values for the first 3 rows are means (ranges). minimally invasive approaches to prostate cancer—hakimi et al 136 urology journal vol 4 no 3 summer 2007 which is significantly less with lrp as compared to rrp, based on our previous report, is even further reduced in ralp. of course there are other variables that are difficult to assess and prove with regard to ergonomics and surgeon fatigue, but our anecdotal experience is that robotics does significantly enhance the surgeon’s ability to perform a precise and accurate operation that is much less taxing and ergonomically easier than pure laparoscopy. conclusion the use of minimally invasive techniques has revolutionized the surgical treatment of prostate cancer. pure lrp has been shown to be feasible and reproducible. however, it has a steep learning curve and is difficult to learn. in contrast, ralp is easier to learn and is now the surgical treatment of choice in most centers of excellence in the united states. traditional rrp has set the bar very high for the surgical treatment of prostate cancer. experiencing the robotic capabilities, it is not difficult to envision why it is a superb modality for prostate cancer surgery. the superior optics with respect to visualization and magnification translates into a procedure that is equivalent, if not superior, with respect to perioperative parameters, oncologic outcomes, and functional outcomes to its open counterpart. conflict of interest none declared. references 1. surveillance, epidemiology, and end results (seer) program. seer*stat database: incidence seer 9 regs limited-use, nov 2006 sub (1973-2004). national cancer institute, dccps, surveillance research program, cancer statistics branch, released april 2007, based on the november 2006 submission. available from: http://www.seer.cancer. gov 2. janoff dm, parra ro. contemporary appraisal of radical perineal prostatectomy. j urol. 2005;173:186370. 3. schuessler ww, schulam pg, clayman rv, kavoussi lr. laparoscopic radical prostatectomy: initial shortterm experience. urology. 1997;50:854-7. 4. guillonneau b, cathelineau x, barret e, rozet f, vallancien g. laparoscopic radical prostatectomy: technical and early oncological assessment of 40 operations. eur urol. 1999;36:14-20. 5. dahl dm, l’esperance j o, trainer af, et al. laparoscopic radical prostatectomy: initial 70 cases at a u.s. university medical center. urology. 2002;60:859-63. 6. farouk a, gill i, kaouk j, et al. 100 laparoscopic radical prostatectomies (lrp): learning curve in the united states. j urol. 2002;167(suppl 1):390. 7. menon m, tewari a, peabody j. vattikuti institute prostatectomy: technique. j urol. 2003;169:2289-92. 8. mcdougall em, clayman rv. advances in laparoscopic urology, part i. history and development of procedures. urology. 1994;43:420-6. 9. rassweiler j, seemann o, schulze m, teber d, hatzinger m, frede t. laparoscopic versus open radical prostatectomy: a comparative study at a single institution. j urol. 2003;169:1689-93. 10. tooher r, swindle p, woo h, miller j, maddern g. laparoscopic radical prostatectomy for localized prostate cancer: a systematic review of comparative studies. j urol. 2006;175:2011-7. 11. mitka m. laparascopic prostate surgery suggested. jama. 2001;286:2224. 12. namiki s, egawa s, baba s, et al. recovery of quality of life following laparoscopic or open radical prostatectomy. bju int. 2004;94(suppl 2):104. 13. bhayani sb, pavlovich cp, hsu ts, sullivan w, su lm. prospective comparison of short-term convalescence: laparoscopic radical prostatectomy demographics laparoscopy robotic surgery p patients 135 131 age, y 60.3 ± 7.0 60.1 ± 6.9 .78 positive/negative margins 23/109 20/97 .19 psa, ng/ml 7.68 ± 5.01 8.36 ± 6.19 .33 specimen weight, g 48.27 ± 24.05 53.62 ± 23.74 .07 postoperative gleason 6.4 ± 0.6 6.5 ± 0.9 .36 length of hospital stay, d 2.6 ± 1.6 1.8 ± 1.2 < .001 estimated blood loss, ml 298.33 ± 114.69 242.33 ± 227.98 .01 operative time, min† 279.2 ± 62.6 191.3 ± 43.7 < .001 complication rate, % 17 13 .49 table 3. laparoscopic versus robotic prostatectomy at montefiore center* *values of continues variables are shown as mean ± standard deviation. †operative time was determined as the total operative room time, from time in to time out of room. minimally invasive approaches to prostate cancer—hakimi et al urology journal vol 4 no 3 summer 2007 137 versus open radical retropubic prostatectomy. urology. 2003;61:612-6. 14. brown ja, garlitz c, gomella lg, mcginnis de, diamond sm, strup se. perioperative morbidity of laparoscopic radical prostatectomy compared with open radical retropubic prostatectomy. urol oncol. 2004;22:102-6. 15. roumeguere t, bollens r, vanden bossche m, et al. radical prostatectomy: a prospective comparison of oncological and functional results between open and laparoscopic approaches. world j urol. 2003;20:3606. 16. khedis m, huyghe e, soulie m, seguin p, mouly p, plante p. comparison of carcinological results between laparoscopic and retropubic radical prostatectomy. bju int. 2004;94(suppl 2):222. 17. martorana g, manferrari f, bertaccini a, et al. laparoscopic radical prostatectomy: oncological evaluation in the early phase of the learning curve comparing to retropubic approach. arch ital urol androl. 2004;76:1-5. 18. salomon l, anastasiadis ag, levrel o, et al. location of positive surgical margins after retropubic, perineal, and laparoscopic radical prostatectomy for organconfined prostate cancer. urology. 2003;61:386-90. 19. artibani w, grosso g, novara g, et al. is laparoscopic radical prostatectomy better than traditional retropubic radical prostatectomy? an analysis of peri-operative morbidity in two contemporary series in italy. eur urol. 2003;44:401-6. 20. rogers cg, su lm, link re, sullivan w, wagner a, pavlovich cp. age stratified functional outcomes after laparoscopic radical prostatectomy. j urol. 2006;176:2448-52. 21. jacobsen ne, moore kn, estey e, voaklander d. open versus laparoscopic radical prostatectomy: a prospective comparison of postoperative urinary incontinence rates. j urol. 2007;177:615-9. 22. ghavamian r, schenk g, hoenig dm, williot p, melman a. overcoming the steep learning curve of laparoscopic radical prostatectomy: single-surgeon experience. j endourol. 2004;18:567-71. 23. ghavamian r, knoll a, boczko j, melman a. comparison of operative and functional outcomes of laparoscopic radical prostatectomy and radical retropubic prostatectomy: single surgeon experience. urology. 2006;67:1241-6. 24. pasticier g, rietbergen jb, guillonneau b, fromont g, menon m, vallancien g. robotically assisted laparoscopic radical prostatectomy: feasibility study in men. eur urol. 2001;40:70-4. 25. patel vr, chammas mf, jr., shah s. robotic assisted laparoscopic radical prostatectomy: a review of the current state of affairs. int j clin pract. 2007;61:30914. 26. ahlering te, woo d, eichel l, lee di, edwards r, skarecky dw. robot-assisted versus open radical prostatectomy: a comparison of one surgeon’s outcomes. urology. 2004;63:819-22. 27. ahlering te, skarecky d, lee d, clayman rv. successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. j urol. 2003;170:1738-41. 28. hu jc, nelson ra, wilson tg, et al. perioperative complications of laparoscopic and robotic assisted laparoscopic radical prostatectomy. j urol. 2006;175:541-6; discussion 6. 29. tewari a, srivasatava a, menon m. a prospective comparison of radical retropubic and robot-assisted prostatectomy: experience in one institution. bju int. 2003;92:205-10. 30. patel vr, thaly r, shah k. robotic radical prostatectomy: outcomes of 500 cases. bju int. 2007;99:1109-12. 31. menon m, tewari a, peabody jo, et al. vattikuti institute prostatectomy, a technique of robotic radical prostatectomy for management of localized carcinoma of the prostate: experience of over 1100 cases. urol clin north am. 2004;31:701-17. 32. ficarra v, cavalleri s, novara g, aragona m, artibani w. evidence from robot-assisted laparoscopic radical prostatectomy: a systematic review. eur urol. 2007;51:45-55; discussion 6. 33. vickers aj, bianco fj, serio am, et al. the surgical learning curve for prostate cancer control after radical prostatectomy. j natl cancer inst. 2007;99:1171-7. 34. lotan y, cadeddu ja, gettman mt. the new economics of radical prostatectomy: cost comparison of open, laparoscopic and robot assisted techniques. j urol. 2004;172:1431-5. 35. menon m, shrivastava a, tewari a. laparoscopic radical prostatectomy: conventional and robotic. urology. 2005;66:101-4. 36. joseph jv, vicente i, madeb r, erturk e, patel hr. robot-assisted vs pure laparoscopic radical prostatectomy: are there any differences? bju int. 2005;96:39-42. 37. rozet f, jaffe j, braud g, et al. a direct comparison of robotic assisted versus pure laparoscopic radical prostatectomy: a single institution experience. j urol. 2007;178:478-82. 1406 | 1 department of urology, haydarpasa numune training hospital, istanbul, turkey. 2 department of pediatric hematology and oncology, cerrahpaşa medical school and oncology institute, istanbul university, istanbul, turkey. 3 the hemophilia society of turkey, istanbul, turkey. corresponding author: orhan koca, md department of urology, haydarpasa numune training and research hospital, tıbbiye cad. no. 2 üsküdar zip: 34718, istanbul, turkey. tel: +90 216 414 4502 fax: +90 216 345 5982 e-mail: drorhankoca@hotmail. com received december 2012 accepted may 2013 purpose:circumcisionisaverycommonsurgicalprocedurethathasbeenperformedforthousandsofyears.inthispaper,wereportthelong-termresultsofcircumcisionperformedbyusing diathermicknifeonpatientswithbleedingdiathesisandtheamountofbloodfactorsused. materials and methods:atotalof147patientswithbleedingdiathesiscircumcisedunderlocal anesthesiabyusingdiathermicknifebetween1996and2010wererecruitedintothisstudy.age ofthepatients,typeofthebleedingdiathesisandthetreatmentprotocolswererecorded.postsurgicalinfectionandbleedingratesof2differentfactorreplacementprotocolswererecorded. results:meanageofthepatientswas11.5years(range,1.5-37years).inthegroupofprotocol 1appliedpatients,3patients(4%)hadbleedingandonepatienthadinfectionwhereasingroup ofprotocol2,4patients(5.4%)hadbleeding.thebleedingcasesweretakenundercontrolafter thefactorreplacementandelasticbandage. conclusion:wheneveritisnecessaryforanindividualtobecircumcisedforanyreasonwhatsoever,wethinkthatcircumcisioncanbeperformedinthepatientswithbleedingdiathesiswith lowercostsandcomplicationratesbyusingdiathermicknifeandtheprotocolthatweused. keywords:circumcision;male;adverseeffects;hemorrhage;prevention&control;electrocoagulation;hemophiliaa;complications. muhammet ihsan karaman,1 bülent zulfikar,2 metin ishak özturk,1 orhan koca,1 mehmet akyüz,1 fikret bezgal3 circumcision in bleeding disorders: improvement of our cost effective method with diathermic knife pediatric urology pediatric urology 1407vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l circumcision in bleeding disorders | karaman et al introduction circumcisionisaverycommonsurgicalprocedurethathasbeenperformedforthousandsofyears.itisperformedasareligiousobligationincertainsocieties,asatraditioninsomeofthemandduetomedical reasons in the others.(1,2) all people with bleeding diathesis includingthehemophiliapatientsareundertheriskofexcessivebleedingduringandafterthesurgicalinterventions. although the circumcision is a relatively minor surgical intervention,thesepatientscanalsohaveprolongedbleedingevenafterthecircumcisionprocedure.(3)however,althoughmanyparentsknowthisrisk,theyinsistoncircumcisionduetoreligiousandculturalreasons.themeasures taken to perform circumcision in children with bleeding diathesisbringaseriouseconomicburdenduetothehigh costoffactorreplacement.itwillbemoreappropriateto performcircumcisiontopreventthesechildrenfromfeelingexcludedfromthesocietyandwithlowercomplication ratesandcosts.inturkey,88%ofparentsreportedthatitis notacceptabletobeuncircumcised,yetagainanotherstudy showedthatthehemophilicchildrenandtheirparentshave inferioritycomplexduetobeinguncircumcised.(4,5) the methods that increase hemostasis on the wound site reducetheriskofbleedinganddiminishthefactorrequirementbuthightreatmentcoststillremainsasaproblem.(6) we alreadyshowedthatcircumcisioncanbeperformedinthe patientswithbleedingdiathesisbyusingthediathermicknife withrelativelylowercostandcomplicationratios.(4)wehave aimedtoreducethecostfurtherbyimprovingourfactorreplacementprotocolsforthelast6years.thepurposeofthis studyistocomparethesuccess,costandcomplicationrates obtainedaftercircumcisionsperformedusingthediathermic knifeinpatientswithbleedingdiathesisbyadministratingof twodifferentfactorreplacementprotocols.atthesametime, weherebyreportthelongtermresultsofcircumcisionperformedbyusingthediathermicknife,whichisanoriginal technique,withalargernumberofpatients. materials and methods atotalof147patientswithbleedingdiathesiscircumcised under local anesthesia by using diathermic knife between 1996and2010wereenrolledintothisstudy.ageofthepatients,typeofthebleedingdiathesisandthetreatmentprotocolswererecorded.thebleedingandinfectionrateswere recordedaftertheprocedure.ifthewoundwasstillbleeding aftercircumcisionandtherewasaneedforanadditionalintervention,thiswasdefinedas"bleeding". between1996and2004thefactorreplacementwasapplied accordingtoprotocol1,whereasbetween2005and2010 thefactorreplacementwasappliedaccordingtotheprotocol 2.allthepatientswerehospitalizedforminimum4hours before the procedure and their informed consent for surgerywasobtainedandtherequiredfactorreplacementwas applied.forthepurposeoflocalanesthesia,2-4ml2%lidocainehydrochloridewasinjectedaroundthebaseofthe penis to obtain a ring blockage. following the necessary cleaningandcoverage,thestretchedforeskinwasalignedto thecoronalsulcusandclampedusingapersonallymodified clamp(figure1),andthentheforeskinonthedistalsideof theclampwasexcisedusingthediathermicknifedeveloped inourcountryforbloodlesscircumcision(figure2).the skinandmucosaweresuturedwith5-0absorbablesutures. theantibioticcreamwaslocallyadministered,dressingor systematicantibioticwasnotadministered.the15mg/kg/ doseofparacetamolwasadministeredorallyforanalgesic purposes when necessary. statisticalanalysiswasperformedbythettestusingthestatisticalpackageforthesocialscience(spssinc,chicago, illinois,usa)version13.0.apvalue<.05wasconsidered statisticallysignificant. results inprotocol1groupthemeanageofthe75patientswas11 years(range,1.5-25years),whileinprotocol2groupthe meanageof72patientswas12years(range,4.5-37years) (table1).forthepatientsinwhomthefactorreplacement wasadministeredaccordingtotheprotocol1,hospitalizationtimewas2-3daysandthedurationoffactoradministrationwas9-18dayswhileforpatientsingroupofprotocol2 hospitalizationtimewas1-2daysandthedurationoffactor administrationwas9-13days(table2).twenty-fourpatients requiringsurgicalinterventionforanotherreasonwerecircumcisedusingdiathermicknifeundergeneralanesthesia. bleedingwasobservedin3(4%)ofthepatientsforwhom theprotocol1wasadministered,infectionwasobservedin onepatientandbleedingwasobservedin4(5.4%)ofthe patients for whom the protocol 2 was administered. the bleedingcasesweretakenundercontrolafterthefactorre1408 | placementandapplyingelasticbandage.amildedemawas detectedonthelineofthecircumcisioninallpatientsbutit spontaneouslyrecoveredwithin3-4days.seriousscartissueswerenotfoundinthebiopsiestakenfromthecasesfollowingthecircumcisionperformedwiththediathermicknife anditwaspreviouslydemonstratedthatitdidnothaveany negativeimpactonthevesselsandnerves.(4)thecostofboth protocolaregivenintable3.staticallythereisasignificant differencebetweenprotocol1andprotocol2,inwhichprotocol 1 has higher cost (p<.001). discussion themodernhemophiliatreatmentaimstoachieveafullsocialandculturalintegrationofthehemophilicchildwiththe society.(7)forthisreason,ifthehemophilicpatientsliveina societyinwhichthecircumcisionhasasocio-culturalimportanceandmostimportantlyifthepatientwantstobecircumtable 2. factor replacement protocol 1 (between 1996-2004) and protocol 2 (between 2005-2010). variables severe moderate mild day 1, preoperative 25 20 20 postoperative 25 20 20 days 2-3 40 25 15 days 4-7 30 20 10*** days 8-10 20 10* 10 (day 9 only) days 12 and 14 15 10 ----days 16 and 18 10 ----total 360 u/kg 220 u/kg 120 u/kg factor replacement protocol 2 (u/kg)*,** variables severe moderate/mild day 1, preoperative 25 15 postoperative 15 10 days 2-7 15 10*** days 9, 11 and 13 15 10 (day 9 only) total 175 u/kg 95 u/kg * double doses for hemophilia b, vasopressin not used. ** tranexamic acid 25 mg/kg/day for 7 days + 10 mg/kg during surgery. *** plus vasopressin 0.3 µg/kg/day for 3 days. figure 1. the personally modified clamp for the diathermic knife and diathermic knife device. figure 2. clamped foreskin and excision with the diathermic knife and after the circumcision (small picture). table 1. characteristics of study patients. variables years 1996-2004 (period 1) years 2005-2010 (period 2) protocol method 1 2 total patients, no. 75 72 hemophilia-a 65 57 hemophilia-b 6 6 von willebrand disease 1 8 glanzmann's thrombasthenia 1 ----factor vii deficiency 1 ----factor xiii deficiency 1 -----factor v deficiency ----1 age, years-median (range) 11 (1.5-25) 12 (4.5-37) body weight, kg-median (range) 30 (9-74) 34 (18-102) pediatric urology 1409vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l cised,webelievethatitshouldbeperformedbycreatingthe appropriate conditions. asthemeasuresaretakenforthepatientwithbleedingdiathesis,itisaprioritytochoosethesurgicalmethodthatcause lessbleedingasmuchaspossible.(4)thesemethodsinclude bipolar scissors and laser.(8,9) however, information about theuseofthesemethodsonthepatientswithbleedingdiathesisislimited.wethinkthatthediathermicknifedevice thatweuseasanalternativetotheabovementionedmethods causessignificantlylessbleeding.inthefirstseriesthatwe publishedbefore,weshowedthatcircumcisioncanbeperformedonthepatientswithbleedingdiathesiswithminimal complicationratesbyusingdiathermicknife.(4)thefindings ofourstudyshowsthatthediathermicknifeisreliablein longtermandcanbeusedwiththeupdatedfactorreplacementprotocolwithalowercostandapproximatelythesame complicationrates. theothermeasuresthatcanbetakenforthepatientswith bleedingdiathesisincludethefactorreplacement,1-deamino-8-d-argininevasopressin(ddavp)infusion,fibrinolysis inhibitors,localfibringlueapplication,andtheuseofankaferd blood stopper.(7,10)someauthorsclaimedthatthelocal fibringlueapplicationisareliableandinexpensivesolution forthehemophilicpatients.(5,11)avanoğluandcolleaguesreportedthattheyreducethecostofcircumcisionbyusingthe fibringlueonthehemophilicpatients.(6)however,thecost theyreportedismuchhigherthanthecostwefoundinour studyforbothprotocols.eventhoughwedidnotuseany agentstopreventlocalbleedingfollowingthecircumcision, thebleedingratesaretremendouslylow.thisindicatesthe reliabilityofourmethod.theuseoftheclassicelectrocauteryonpenisisavoidedasanundesireddamagemayoccur onthepenisasaresultofuncontrolledtransmissionofelectric current.(12)however,ourdeviceisnotanelectrocautery and the electric current is not conducted to the tissue. as a matteroffact,onlyalimiteddamageonthetissuewasdemonstrated in the histopathology test.(4) thepositiveresultsofthepatients,whogotcircumcisedby protocol1,encouragedustoreducefactorlevels.protocol2 wascreatedafterconsultationwithhematology.whenever itisnecessaryforanindividualtobecircumcisedforany reasonwhatsoever,wethinkthatcircumcisioncanbeperformedinthepatientswhohavebleedingdiathesiswithlow costsandcomplicationratesbyusingdiathermicknifeand protocol2thatweapplied.stillthereisnoneedtorushfor performingcircumcisionandwhenthereisanobligationfor anothersurgicalprocedureperformingcircumcisionat the samesessionwiththissurgeryseemstobeamoreeconomic andlessmorbidway.also,toavoidthedevelopmentofinhibitorsduetofactorusagewhichcanbeaproblemforsuch asurgicalintervention,itisappropriatetodelaycircumcision after12monthsoflife.(13) thelimitationsofourstudyarewiderangeofpatient'sages andnotallproceduresweremadebythesamesurgeon.also thecostfactordiffersfromonecountrytoanother. conclusion inourstudywefoundthatthecostofprotocol1ishigher thanprotocol2.thissituationshowsus,thecostofthecircumcisionsperformedwiththe"diathermicknife"inthepatients with bleeding diathesis is lower. conflicts of interest none declared. table 3. total cost (us$) of the circumcision in hemophilia.* protocol 1 protocol 2 variables severe moderate mild severe moderate mild concentrate 216/kg 120/kg 72/kg 105/kg 57/kg 57/kg other medications 10 10 + 0.3/kg 10 + 0.3/kg 10 10 + 0.3/kg 10 + 0.3/kg hospitalization 170 140 140 170 140 140 total 225/kg 127.8/kg 79.8/kg 114/kg 64.3/kg 64.3/kg * total cost includes factor replacement + other medications + hospitalization. circumcision in bleeding disorders | karaman et al 1410 | references 1. massry sg. history of circumcision: a religious obligation or a medical necessity. j nephrol. 2011;24 (suppl 17):100-2. 2. shittu ob, shokunbi wa. circumcision in haemophiliacs: the nigerian experience. haemophilia. 2001;7:534-6. 3. sasmaz i, antmen b, leblebisatan g, şahin karagün b, kilinç y, tuncer r. circumcision and complications in patients with haemophilia in southern part of turkey: çukurova experience. haemophilia. 2012;18:426-30. 4. karaman mi, zulfikar b, caskurlu t, ergenekon e. circumcision in hemophilia: a cost-effective method using a novel device. j pediatr surg. 2004;39:1562-4. 5. avanoglu a, celik a, ulman i, et al. safer circumcision in patients with hemophilia: the use of fibrin glue for local hemostasis. bju int. 1999;83:91-4. 6. tazi i. fibrin glue, hemophilia, and circumcision in low-income countries. j pediatr surg. 2011;46:428-9. 7. kavakli k, aledort m. circumcision and haemophilia: a perspective. haemophilia. 1998;4:1-3. 8. méndez-gallart r, estévez e, bautista a, et al. bipolar scissors circumcision is a safe, fast, and bloodless procedure in children. j pediatr surg. 2009;44:2048-53. 9. how ac1, ong cc, jacobsen a, joseph vt. carbon dioxide laser circumcisions for children. pediatr surg int. 2003;19:11-3. 10. öner af, doğan m, kaya a, et al. new coagulant agent (ankaferd blood stopper) for open hemorrhages in hemophilia with inhibitor. clin appl thromb hemost. 2010;16:705-7. 11. yilmaz d, akin m, ay y, et al. a single centre experience in circumcision of haemophilia patients: izmir protocol. haemophilia. 2010;16:88-91. 12. gearhart jp, rock ja. total ablation of the penis after circumcision with electrocautery: a method of management and long-term followup. j urol. 1989;142:799-801. 13. lloyd jm, wight j, paisley s, knight c. control of bleeding in patients with haemophilia a with inhibitors: a systematic review. haemophilia. 2003;9:464-520. pediatric urology u j spring 2012.pdf 498 | female urology sexual function of primiparous women after elective cesarean section and normal vaginal delivery ladan hosseini,1 elham iran-pour,2 2 purpose: to compare sexual function between two groups of women who had materials and methods: in this cross-sectional study, two groups of healthy women, with antenatally normal singleton pregnancies at term, who underwent nvd function of participants was assessed using physician-administered female sexual questionnaire. secondary outcome measures included the remaining items. results: function, including desire (p p p gasm (p p p eighty percent of women who had undergone vaginal delivery complained from conclusion: we believe that pcs is not preferred to nvd in regard to preserving normal sexual functioning. keywords: women’s health, cesarean section, postpartum period, sexual dysfunction, sexual behavior corresponding author: mohammad reza safarinejad, md p.o. box 19395-1849, tehran, iran tel: +98 21 2245 4499 fax: +98 21 2245 6845 e-mail: info@safarinejad. com received june 2011 accepted november 2011 1school of nursing and midwifery, tehran university of medical sciences, tehran, iran 2private practice of urology and andrology, tehran, iran female urology 499vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l mode of delivery and sexual function | hosseini et al introduction sinability to achieve or enjoy orgasm. the accurate prevalence of female sexual dysfunction is unknown; however, in our community 31.5% of women suffer from some types of fsd. tal, and social aspects of individuals’ lives; hence, nowadays more attention is given to the sexual health. some studies have reported that sexual health may be affected by the mode of delivery. the pudendal nerve which innervates the clitoris, vulva, and perineum, may be damaged during vaginal delivery by infant’s head pressure and/or forceps. furthermore, hypotonic muscles of the vagina due to vaginal prolapse can lead to decreased ability to achieve orgasm. adverse effects of vaginal delivery on sexual function have been reported previously. these studies have demonstrated that undergoing cesarnormal sexual function, and maintains anatomical intrapelvic organs. accordingly, cs has high popularity and attitudes of women, midwives, and obstetricians have changed towards cs. a recent english survey found that 33% of obstetriner. about 80% to 93% of women restart their sexual ery. during this period, about two-thirds of women experience at least one sexual dysfunction, such as vaginal dryness, pain, decreased libido, and lack of orgasm. many researchers believe that problems, such as dyspareunia, low back pain, and sexual dysfunction, are due to the pelor pudendal nerve damage during normal vaginal dyspareunia after cs. other studies have shown a relationship between dyspareunia and nvd. ual dysfunction six months after delivery, which may be due to conditions like reduced serum level of progestin, emotional factors, breastfeeding, or changes in body image after childbirth. there are limited studies about long-term effects of two types of deliveries on sexual function with different results being reported. dean and colleagues showed that six years after delivery, sexual satisfaction and vaginal muscles tone are significantly less in women with nvd than the women who had undergone a cs. on the other hand, lationship in sexual function among women with different types of delivery six months to two years after delivery. function after the nvd and cs, we aimed to compare sexual function in women after the nvd and pcs. materials and methods in this cross-sectional study, we compared sexual ethics committee of tehran university of medireferred to the health clinics at tehran university of medical sciences were recruited consecutively. the participants were informed of the purpose of the study and gave their informed consent. furinclusion criteria were being in the age range of 19 to tehran university of medical sciences with live children, no history of stillbirth or miscarriage, and living with the husband. the exclusion criteria 500 | included having a child with anomalies, preterm delivery, previous pelvic surgery, history of previous marriage, history of subfertility, body mass index > 30, consuming medications with adverse effects on sexual function (eg, blood pressure lowering drugs, anti-arrhythmia drugs, sedative drugs, mental problems, presence of relationship problem with husband, mental retardation, smoking and alcohol consumption, and having a critical incident, such as the death of relatives in the past year. all of the subjects should have normal sexual functioning before pregnancy according to female teria and recruited into the study. data were collected using a physician-administered questiondemographic characteristics and fsfi questions. the demographic characteristics included age, educational level, spouse’s educational level, occupational status, spouse’s employment, duration of marriage, monthly income, type of delivery, infant’s gender, weight and head circumference at birth, contraceptive methods used, and history of breastfeeding. the sexual function of women were assessed using fsfi in six domains including: 1. sexual orision of the questionnaire as follows: the items 1 ual items that comprise the domain and multiplying the sum by domain factor obtained individual domain score. factors were 0.6 for desire, 0.3 for and satisfaction. the full-scale score range was pleted in a private setting. statistical analysis unless otherwise stated. differences in variables between groups were determined with the student’s two tailed t test and one-way anova for dichotomous and normally distributed continuous variables, respectively. proportions were compared using chi-square test. analysis of variance between means in groups. for obtaining adjusted p values, a multivariable regression model was used to adjust for potential confounding factors. statistical analysis was performed using the spss software (the statistical package for the social sciences, version 17.0, spss inc, chicago, illip values less than .05 were considp values are adjusted for confounding factors, namely, age, duration of marriage, educational level, contraception methods, and occupational status. results the baseline characteristics of the patients who completed the study protocol are shown in table in both groups. a majority of the participants had at least high school education, were housewives, and used natural method for contraception. most of the women had breastfed their children. the majority of the participants had duration of less (p ferent domains of sexual function, including sexufemale urology 501vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l al desire (p p nal lubrication (p (p p disorder (p tween the overall sexual function scores between the two groups of women (p regarding the question that asked whether the nvd had any adverse effect on their sexual function and the reproductive tract, of patients in nvd adversely affected their sexual function. we also examined whether breastfeeding confounded the observed associations. the correlation between breastfeeding and total fsfi scores with mode of p p discussion tween childbirth to six weeks later. postpartum period health is prospectively divided into three from six weeks to six months after delivery (shortwe studied the effect of mode of delivery on sexual functioning during long-term postpartum period. in this study, the subjects either had nvd with a mediolateral episiotomy or underwent pcs. the results of this study showed that women in the nvd group and the women with cs had no function, including sexual desire, sexual arousal, vaginal lubrication, sexual satisfaction, pain, and orgasm. in a study by hannah and colleagues, the results of sexual function three months to two years postpartum among women who had undergone nvd and cs. furthermore, other studies showed that mode of delivery was not an affecting factor on sexual function after one year of delivmode of delivery and sexual function | hosseini et al table 1. demographic characteristics. variables normal vaginal delivery (n = 114) planned cesarean section (n = 99) p mean age, y 25 ± 3.2 25 ± 3.4 .92 duration of marriage, y 3 ± 1.7 3 ± 1.5 education level, n (%) primary school 0 (0.0) 0 (0.0) -----high school .74 graduate 20 (17.5) 16 (16.2) .073 contraception methods, n (%) condom 26 (26.3) .067 ocp 13 (11.4) .072 iud 25 (21.9) 27 (27.3) .032 withdrawal 35 (35.4) .43 others 3 (3.0) .054 occupational status, n (%) unemployed 72 (72.7) .71 employed 29 (25.4) 27(27.3) .43 502 | ery. safarinejad and associates evaluated the effect of the mode of delivery on the quality of life, sexual function, and sexual satisfaction in primiparous women and their husbands. they concluded that women with vaginal delivery and emergency cs tionship between the type of delivery and sexual function six months after delivery. ings differ from the results of the present study. this may be due to small number of subjects, different type of study population, a restricted age range of the population, and differences in study design. our study assessed the sexual function up to two years after delivery; however, the mentioned studies were carried out during six months to one year postpartum. therefore, the decreased sexual function may be due to the reduced progesterone as a result of breastfeeding or emotional factors, such as changes in self-image, the relationship between the partners, and altered body image early in childbirth. it is also reported that the fear of women after nvd results in increasing frustration and pain and decreasing sexual desire and vaginal lubrication, which usually disappear within the women who had undergone nvd were not satisimpact on sexual satisfaction was low. it is clear cia and nerves are unavoidable consequences of pressure of fetal head. these forces cause functional changes in nerves, muscles, and connective tissues and result in relaxation of the vagina and inability to achieve orgasm in women. the orgasm is described as the most gratifying sexual feeling. this feeling require answers from smooth and skeletal muscles during the sexual stage of motivation. during orgasm, rhythmic contractions tor ani and anus. accordingly, the reduced tone can result in inability to reach orgasm. according to the study by signorello and colleagues, the degree of perineal injury during assisted vaginal delivery was correlated with the ability to have orgasm. we excluded the women who had assisted vaginal deliveries and who had 3rd th-degree lacerations from our study. furthermore, we did not measure the muscle tone. table 2. domain scoring of fsfi in 24-month follow-up.† fsfi domains normal vaginal delivery planned cesarean section p* desire 6.09 ± 1.31 .55 arousal 9.57 ± 2.05 .39 orgasm 10.05 ± 2.13 9.79 ± 1.96 .36 pain 9.42 ± 2.4 9.54 ± 2.59 .74 lubrication 12.11 ± 2.16 .45 satisfaction .39 sexual function 21.39 ± 3.13 21.34 ± 2.70 .91 † fsfi indicates female sexual function index. * p methods, and occupational status. female urology 503vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l between the women with nvd and women who had undergone pcs. baytur and associates reportreduced in women with nvd; however, there was muscle tone and sexual dysfunction. dean and coworkers also reported that six years after delivery, sexual satisfaction and vaginal muscle tone comparing to those with cs. one advantage of this study was using valid persian version of the fsfi questionnaire. furthermore, we controlled the impact of age by limitalso tried to control other confounding factors on sexual function, such as employment status, educational level, and monthly income. this study has some limitations. first, it was a self-reported survey. we made every effort to explain all the questionnaire items to the participants to obtain valid responses. the second limitation of the study is that we did not address the husbands’ views. the third drawback is that we had no equipments to measure the muscle tone exactly. finally, we did not study the sexual function across different parities. conclusion we concluded that women with nvd were less to the women who had pcs. however, there was delivery and the six domains of sexual function between the two groups. therefore, it can be suggested that nvd has little impact on the sexual function of the women two years after delivery. hence, undergoing pcs in order to preserve sexual function is not recommended. conflict of interest none declared. references 1. buhling kj, schmidt s, robinson jn, klapp c, siebert g, dudenhausen jw. rate of dyspareunia after delivery in primiparae according to mode of delivery. eur j obstet 2. based study in iran: prevalence and associated risk factors. 3. mode of delivery on the quality of life, sexual function, and sexual satisfaction in primiparous women and their 4. pollack j, nordenstam j, brismar s, lopez a, altman d, zetterstrom j. anal incontinence after vaginal delivery: a five-year prospective cohort study. obstet gynecol. 5. gungor s, baser i, ceyhan t, karasahin e, kilic s. does mode of delivery affect sexual functioning of the man partner? j 6. wagner m. choosing caesarean section. lancet. 7. lavender t, kingdon c, hart a, gyte g, gabbay m, neilson jp. could a randomised trial answer the controversy relating to elective caesarean section? national survey of consultant obstetricians and heads of midwifery. bmj. abraham s. recovery after childbirth. med j aust. 9. clark mh, scott m, vogt v, benson jt. monitoring pudendal 9. 10. abraham s, child a, ferry j, vizzard j, mira m. recovery after childbirth: a preliminary prospective study. med j 11. klein mc, gauthier rj, robbins jm, et al. relationship of episiotomy to perineal trauma and morbidity, sexual dysfunction, and pelvic floor relaxation. am j obstet gynecol. 12. barrett g, pendry e, peacock j, victor c, thakar r, manyonda i. women's sexuality after childbirth: a pilot study. arch sex mode of delivery and sexual function | hosseini et al 504 | female urology 13. dean n, wilson d, herbison p, glazener c, aung t, macarthur c. sexual function, delivery mode history, pelvic floor muscle exercises and incontinence: a cross-sectional study six years post-partum. aust n z j obstet gynaecol. 14. baytur yb, deveci a, uyar y, ozcakir ht, kizilkaya s, caglar h. mode of delivery and pelvic floor muscle strength and sexual function after childbirth. int j gynaecol obstet. 15. rosen r, brown c, heiman j, et al. the female sexual function index (fsfi): a multidimensional self-report instrument for the assessment of female sexual function. j sex marital 16. a comparison of sexual outcomes in primiparous women experiencing vaginal and caesarean births. indian j com17. hannah me, whyte h, hannah wj, et al. maternal outcomes at 2 years after planned cesarean section versus planned vaginal birth for breech presentation at term: the international randomized term breech trial. am j obstet gynecol. van brummen hj, bruinse hw, van de pol g, heintz ap, van der vaart ch. which factors determine the sexual function 19. baksu b, davas i, agar e, akyol a, varolan a. the effect of mode of delivery on postpartum sexual functioning in primiparous women. int urogynecol j pelvic floor dysfunct. 20. signorello lb, harlow bl, chekos ak, repke jt. postpartum sexual functioning and its relationship to perineal trauma: a retrospective cohort study of primiparous women. am j letter re: zhaohui he, fucai tang, zechao lu, ye he, genggeng wei , fangling zhong, guohua zeng, weizhou wu, lemin yan5, zhibiao li. “comparison of supracostal and infracostal access for percutaneous nephrolithotomy: a systematic review and meta-analysis” urology journal 2019 junbo liu, guo jiang, tao wu* department of urology, affiliated hospital of north sichuan medical college, nanchong 637000, sichuan, p.r. china. *correspondence: department of urology, affiliated hospital of north sichuan medical college, wenhua road 57, shunqing district, nanchong, 637000, sichuan, p.r. china. tel: 2282023-0817; fax: 2282023-0817; e-mail: alhawking@163.com dear editors, we read the article in your journal titled “comparison of supracostal and infracostal access for percutaneous nephrolithotomy: a systematic review and meta-analysis” by zhaohui h. et al (1). the article conducts a comprehensive meta-analysis of existing evidence to quantify and compare the safety and efficacy of supracostal and infracostal access for percutaneous nephrolithotomy. this question is clear and important in clinical practice. this is a meaningful article. however, we would like to raise our concerns about the correct quotation of references in the article. firstly, in the second paragraph of discussion, the authors mentioned that “fan et al(2). previously reviewed the results of 98 mpcnls and their results revealed that there was no negative effect on any intraoperative and postoperative parameters, or any increase complication rates when comparing supracostal and infracostal access”. however, after we read the article of fan et al(2), we find there is something wrong. there are only 83 patients in the study of fan et al(2), and the conclusion of fan et al(2) is that “there were several advantages of infracostal access. these included accuracy in establishing a percutaneous tract, safety, quickness, convenience and flexibility in moving the patented sheath, and higher renal and upper ureteral stone clearance rate by one surgery.” that seems to be quite different from the description in the article of zhaohui h et al(1). secondly, in the second paragraph of discussion, the authors mentioned that “however, ozgor et al (3). reviewed 83 cases involving treatment with mpcnl and found that there were several advantages of infracostal access, including increased accuracy in establishing a percutaneous tract, safety, speed, convenience and flexibility in moving the patented sheath”. however, after we read the article of ozgor et al(3), we find there is also something wrong. there are 98 cases in the study of ozgor et al(3), and the conclusion of ozgor et al.(3) is that “our study demonstrated that mpnl resulted in acceptable stone-free rates whether accessed through either the supracostal or subcostal areas. moreover, the supracostal approach with mpnl had no negative effect on any intraoperative and postoperative parameters, nor did it increase complication rates”. that seems to be quite different from the description in the article of zhaohui h et al(1). in other words, the description about fan et al(2) and ozgor et al(3) is reversed in the discussion of the article of zhaohui h et al(1). finally, in the second paragraph of discussion, the authors mentioned that “sinha et al(4). performed a retrospective review of 777 patients who underwent pcnl and suggested that the avoidance of the supracostal approach was unnecessary, although there was an increase in thoracic complications when the supra 11th approach (between the 10th and 11th ribs) was used, compared with the infracostal approach.” however, after we read the article of sinha et al(4). we find there is something wrong. there is only 700 patients who underwent pcnl in the study of sinha et al(4). this article is very meaningful, but the authors of this article seem to be a little careless. and if the researchers can revise these points that we mentioned. the article will be a higher quality paper. conflict of interests the authors declare that there are no conflict of interests references 1 .he z, tang f, lu z, et al. comparison of supracostal and infracostal access for percutaneous nephrolithotomy: a systematic review and meta-analysis. urol j. 2019; 16:107–114. 2. fan d, song l, xie d, et al. a comparison of supracostal and infracostal access approaches intreating renal and upper ureteral stones using mpcnl with the aid of a patented system. bmc urol. 2015; 15:102. 3. ozgor f, tepeler a, basibuyuk i, et al. supracostal access for miniaturized percutaneous nephrolithotomy: comparison of supracostal and infracostal approaches. urolithiasis. 2018; 46:279-283. 4. sinha m, krishnappa p, subudhi sk, krishnamoorthy v. supracostal percutaneous nephrolithotomy: a prospective comparative study. indian j urol. 2016; 32:45-9. urology journal/vol 19 no. 2/ march-april 2022/ pp. 160-160. [doi: 10.22037/uj.v18i.5811] v08_no_2_final.pdf endourology and stone disease 99urology journal vol 8 no 2 spring 2011 the most important metabolic risk factors in recurrent urinary stone formers mahmoud parvin,1 nasser shakhssalim,1 abbas basiri,1 amir hossein miladipour,2 banafsheh golestan,3 peyman mohammadi torbati,1 mohaddeseh azadvari,4 sanaz eftekhari4 purpose: to evaluate different urinary factors contributing to idiopathic calcium stone disease for determining appropriate medical treatments. materials and methods: two 24-hour urine samples were collected from 106 male recurrent idiopathic calcium stone formers and another 109 randomly selected men as the control group matching for age. results: cases had significantly higher mean urine oxalate, calcium, uric acid, and chloride in comparison with the healthy controls (p < .001). after necessary adjustment, only mean urine levels of oxalate and uric acid were higher in stone formers than those in controls. the mean value of supersaturation for calcium oxalate was significantly higher in patients than the controls (p = .001); whereas supersaturation for calcium phosphate and uric acid did not reach statistical significe (p = .675 and p = .675, respectively). hyperoxaluria and hypercalciuria were among the most frequent abnormalities. after categorizing urine parameter values into four quartiles, the risk of stone formation was found to increase as the urine calcium, oxalate, uric acid, chloride, and citrate rise. in contrast, the risk of stone formation decreased with the increase of urine potassium. conclusion: oxalate seems to play the most important role as urinary stone risk factor in our population followed by calcium and uric acid. in addition to the risk factors, it seems that supersaturation as the sum of all risk factors probably has a high predictive value. urol j. 2011;8:99-106. www.uj.unrc.ir keywords: kidney calculi, risk factors, calcium oxalate, hypercalciuria, hyperoxaluria 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2urology and nephrology research center, shohada-e-tajrish medical center, shahid beheshti university of medical sciences, tehran, iran 3department of epidemiology and biostatistics, school of public health, tehran university of medical sciences, tehran, iran 4urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran corresponding author: nasser shakhssalim, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., 1666677951, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: slim456@yahoo,com received june 2010 accepted december 2010 introduction nephrolithiasis is a common disorder with the estimated prevalence of up to 15% in lifetime, influenced by many factors, such as age, gender, race, and geographical location resulting in various incidence rates in different countries.(1,2) the reported incidence rate of urolithiasis varies between 68 to 720 per 1 000 000 population depending on the countries or regions in which the studies were performed.(3) in a population-based study in iran, the pooled yearly incidence of urolithiasis was 136/100 000.(3) calcium is a principal component of urinary calculi, forming nearly 80% of all stones.(4) stones containing calcium are mainly in the form of calcium oxalate with the relative occurrence rate of 60% followed by hydroxyapatite (20%) and brushite (2%).(5) not only genetic and environmental factors, but also metabolic ones are implicated in the pathogenesis of stone formation.(6-9) therefore, metabolic evaluation of recurrent stone formers might risk factors for urinary stone formers—parvin et al 100 urology journal vol 8 no 2 spring 2011 recognize urolithiasis risk factors,(10,11) leading to proper medical and dietary therapies to prevent stone formation.(12) it has been shown that lifestyle, diet, race, environment, climate, drinking water quantity, and soil factors can affect stone formation; therefore, the risk factors for iranian stone formers might be different from that of other ethnicities or races. in this study, we evaluated the contributory urinary factors to the idiopathic calcium stone disease in male stone formers. materials and methods in this case-control study, 106 men with recurrent urinary calcium stones were recruited. they were selected from our outpatient stone clinic and were in the age range of 30 to 55 years. the study was approved by the medical ethics committee, and all of the subjects gave their informed consents. the participants had no documented metabolic, gastrointestinal, liver, renal, cardiovascular, or endocrinological disorders. we excluded all the patients with urinary tract anomalies, urinary tract infection, first single stone presentation, obesity (body mass index > 30), and those who were on medication that may affect calcium metabolism. furthermore, those patients with the excretion of cystine crystals in their urine were also excluded from this study. “recurrent stone former” was defined as either a recurrent stone event or an increase in the stone size during the past five years confirmed by imaging modalities. the type of stones was documented either by stone analysis (69 patients) or by disappearance of the opaque material on conventional radiography after stone passage or intervention for stone removal (37 patients). two 24-hour urine samples with one week to one month apart were collected from all the subjects. moreover, the patients were requested to collect their urine at least 30 days after the last stone episode, which was defined either by an intervention for stone removal or spontaneous stone passage. furthermore, we asked the patients to be on their normal diets and avoid taking any medication that could influence urinary excretion rates of the stone forming materials two weeks prior to the urine collections. the control group consisted of 109 healthy men with the age range of 30 to 55 years. they volunteered to participate in this study. all the control subjects had no renal or urinary stone disease confirmed by ultrasonography. they were instructed to collect two 24-hour urine samples similar to the case group. the 24-hour urine samples were collected in polyethylene containers with hydrochloric acid 6n or boric acid as preservative and were stored at -20o c until analysis. urine volume, urine specific gravity, creatinine, urea, phosphate, calcium, oxalate, citrate, sodium, potassium, chloride, magnesium, uric acid, ph (in fresh urine), urinary supersaturation of calcium oxalate, calcium phosphate, and uric acid were measured using standard methods as indicated in brackets: sodium (flame photometry; constant velocity (cv) 1.9%), potassium (flame photometry; cv 1.5%), chloride (colorimetric assay; cv 2.1%), ph (reflectance photometry), specific gravity (refractometry), protein (sulfosalicylic acid, quantitative; cv 2.1%), creatinine (jaffe’s kinetic, cv 1.8%), calcium (arsenazo, colorimetric, cv 2.4%), oxalate (enzymatic colorimetric, lta, milano, italy, cv 3.57%), uric acid (enzymatic uricase; cv 4.2%), citrate (enzymatic colorimetric, lta, milano, italy, cv 3.18%), magnesium (calmagite, colorimetric; cv 2.9%), urea (urease, gldh; cv 2.6%), chloride (colorimetric assay; cv 2.3%), and inorganic phosphate (phosphomolybdate; cv 2.5%). lithorisk software was utilized to calculate the supersaturation. we measured calcium, phosphate, magnesium, and oxalate in the hydrochloric acid 6n containing urine, and the other parameters in the boric acid containing urine, according to national committee for clinical laboratory standards.(13) we further categorized 24-hour urine chemistries into four quartiles, and class intervals were defined by combining both groups. thereafter, these new categorical variables were compared between the two groups using the chi-square test as well as multivariate logistic regression to obtain age-adjusted odds ratios (for each categorical risk factors for urinary stone formers—parvin et al 101urology journal vol 8 no 2 spring 2011 variable, the first quartile served as the reference category). we adjusted the urine chemical values for body weights and urine creatinine levels in all the analyses. the mean of two 24-hour urine chemistries was calculated and applied. a p value of less than .05 was considered statistically significant. results the characteristics of the cases and controls are summarized in table 1. although the controls were selected matching for age, the difference between two groups was statistically significant. to overcome this mismatch, the 24-hour urine chemistries were compared by covariances analysis in which “age” was the covariate. in the case group that the linear age relationship was important, the adjusted means and their confidence intervals were reported. of 69 patients who had stone analysis, 64 were calcium oxalate stone formers, while 1 had calcium phosphate stone, and the remaining 4 patients were mixed calcium stone formers. stone formers had significantly higher urine oxalate, calcium, uric acid, chloride in comparison to the healthy controls (p < .001). tendencies towards statistical significance were observed with higher values of creatinine and lower values of urine potassium when the cases were compared with the healthy controls (p = .064 and p = .075, respectively). citrate, however, had strong linear correlation with age and did not differ between the two groups after the adjustment made for age (p = .892). the mean value of calcium oxalate supersaturation was significantly higher in the patients compared to the controls (p = .001) (table 2). the mean 24-hour urine values were further adjusted according to the measured body weights and urine creatinine (tables 3 and 4). excretion of oxalate, chloride, and uric acid variable case (n = 106) control (n =109) p urine ph (first morning) 5.9525 (sd:0.48195) 5.9817 (sd:0.47957) .88 volume (ml/24hr) 1842.1 (sd: 771.09) 1338.2 (sd: 448.67) .026* phosphorus (g/24hr) 0.63 (sd:0.26) 0.59 (sd: 0.23) .218 creatinine (g/24hr) 1.78 (sd:0.55) 1.65 (sd: 0.55) .064 calcium (mg/24hr) 221.46 (sd: 109.89) 156.26 (sd: 73.30) <.001 oxalate (mmol/24hrs)† 0.4584 (sd:0.1860) 0.3366 (sd: 0.1284) <.001 sodium (meq/24hr) 220.83 (sd: 88.66) 211.73 (sd: 69.53) .235 uric acid (mg/24hr) 464.43 (sd: 239.00) 352.1 (sd: 205.86) <.001 magnesium (mg/24hr) 97.88 (sd:48.80) 91.03 (sd: 43.59) .275 urea (mg/24hr) 19.83 (sd:6.62) 18.96 (sd: 6.25) .354 chloride (mmol/24hr) 196.82 (sd: 73.67) 167.96 (sd: 52.04) <.001 citrate (mg/24hr) 487.55§ (se: 23.646) 461.20§ (se: 23.298) .892* potassium (meq/24hr) 47.69 (sd: 20.27) 53.90 (sd: 21.59) .075 calcium oxalate supersaturation 7.52 (sd: 4.69) 5.80 (sd: 2.68) .001 calcium phosphate supersaturation 1.63 (sd: 1.78) 1.59 (sd: 1.56) .675 uric acid supersaturation 0.56 (sd: 0.61) 0.48 (sd:0.40) .273 table 2. comparison of the mean values of urinary parameters in the cases and the controls *adjusted for age †oxalate (mg/24hr): case: 41.30 (sd:16.76), control: 30.32 (sd: 11.57) §adjusted mean variable case control p age (y) mean 43.42 (sd: 6.925) 38.36 (sd: 6.907) <.001 median 44.00 36.00 range 30 to 55 30 to 55 weight (kg) mean 78.44 (sd: 9.861) 78.53 (sd: 10.540) .950 median 79.50 78.00 range 50 to 104 54 to 104 height (cm) mean 172.59 (sd:6.606) 174.38 (sd: 7.536) .066 median 173.00 175.00 range 160 to 190 155 to 190 body mass index (kg/m2) mean 26.3115 (sd: 2.74583) 25.8258 (sd: 3.00603) .218 median 26.7946 26.4463 range 18.41 to 29.94 17.83 to 29.98 table 1. characteristics of the participants risk factors for urinary stone formers—parvin et al 102 urology journal vol 8 no 2 spring 2011 were significantly higher in the case group when the mean 24-hour urine values were compared adjusted for body weights (p < .001, p < .004, and p < .001, respectively). all other 24-hour urine parameters did not show any significant differences between the patients and the controls, except for potassium that was marginally higher in the control group (p = .051) (table 3). when we adjusted the results for the urine creatinine, the cases had significantly higher urine oxalate and uric acid, and lower potassium excretion than the controls (p < .001, p = .011, and p < .001, respectively). no other significant differences were observed (table 4). in terms of concentration, the mean value of urea was higher in the control group (p = .002), yet other parameters did not differ significantly when the two groups were compared (table 5). hyperoxaluria and hypercalciuria were the most frequent abnormalities. since there is a lack of data in our country regarding the normal values for the urine parameters, we examined the risk of stone formation according to the categories of absolute amounts of 24-hour urinary excretion (table 6). to determine the odds ratio of recurrent urinary stone formation due to variables with significant effect, logistic regression model was used, in which presence or absence of urolithiasis (dependent variable) as well as risk factors, including calcium, oxalate, uric acid, chloride, and citrate (independent variables) were assessed. we found that the risk of stone formation would increase with rising urine calcium [p = .026; or (95%ci):1.471 (0.971 to 1.632)], oxalate [p = .015; or (95%ci): 2.061 (1.543 to 2.753)], uric acid [p = .028; or (95%ci): 1.668 (1.269 to 2.193)], chloride [p = .034; or (95%ci): 1.407 (1.083 to 1.829)], and citrate [ p = .026; or (95%ci): 1.660 (1.265 to 2.178)]. in contrast, stone formation risk would decrease with an increase in urine potassium [or (95%ci): 0.766 (0.592 to 0.990)]. for other urine parameters, no significant association was found. since the risk of stone formation in a patient is the consequent of inhibitory as well as variable case (n = 106) control (n = 109) p phosphorus (g/kg) 8.08 (sd: 3.28) 7.55 (sd: 3.06) .323 calcium (mg/kg) 2.88 (sd: 1.54) 2.02 (sd: 1.00477) .296* oxalate (mmol/kg) 0.0059 (sd: 0.002391) 0.00436 (sd: 0.001740) <.001 sodium (meq/kg) 2.84 (sd: 1.16) 2.74 (sd: 0.96) .336 uric acid (mg/kg) 5.95 (sd: 3.02) 4.54 (sd: 2.65) <.001 magnesium (mg/kg) 1.26 (sd: 0.64) 1.18 (sd: 0.6) .401 urea (mg/kg) 0.25 (sd: 0.086) 0.24 (sd: 0.08) .491 chloride (mmol/kg) 2.54 (sd: 0.98) 2.17 (sd: 0.71) .004 citrate (mg/kg) 6.95 (sd: 3.77) 5.28 (sd: 2.32) .918 potassium (meq/kg) 0.61 (sd: 0.26) 0.69 (sd: 0.28) .051 *adjusted for age table 3. comparison of the mean values of the urine parameters adjusted for weight in the case and control groups variable case (n = 106) control (n = 109) p phosphorus (g/mg cr) 0.35 (sd: 0.09) 0.36 (sd: 0.10) .219 calcium (mg/mg cr) 0.13 (sd: 0.06) 0.10 (sd: 0.05) .432† oxalate (mmol/mg cr) 0.0003 (sd: 0.00012) 0.0002 (sd: 0.00009) <.001 sodium (meq/mg cr) 0.13 (sd: 0.05) 0.14 (sd: 0.04) .566 uric acid (mg/mg cr) 0.27 (sd: 0.13) 0.22 (sd: 0.11) .011 magnesium (mg/mg cr) 0.05 (sd: 0.02) 0.06 (sd: 0.02) .539 urea (mg/mg cr) 0.01 (sd: 0.002) 0.01 (sd: 0.002) .057 chloride (mmol/mg cr) 0.11 (sd: 0.04701) 0.11 (sd: 0.04152) .335 citrate (mg/mg cr) 0.34 (sd: 0.21) 0.28 (sd: 0.14) .658 potassium (meq/mg cr) 0.03 (sd: 0.01) 0.03 (sd: 0.01) <.001 table 4. comparison of the mean values of the urine parameters adjusted for urine creatinine in the case and control groups *cr indicates creatinine. †adjusted for age risk factors for urinary stone formers—parvin et al 103urology journal vol 8 no 2 spring 2011 variable case (n = 106) control (n = 109) p calcium (mg/dl) 13.62 (sd: 9.74) 12.12 (sd: 5.25) .287 oxalate (mmol/dl) 0.09 (sd: 0.01) 0.027 (sd: 0.01) .99* sodium (meq/dl) 13.24 (sd: 5.36) 16.74 (sd: 5.19) .940 uric acid (mg/dl) 27.07 (sd: 14.58) 27.08 (sd: 14.82) .618 magnesium (mg/dl) 6.04 (sd: 3.62) 7.13 (sd: 3.40) .095 urea (mg/dl) 1.21 (sd: 0.54) 1.49 (sd: 0.48) .002 chloride (mmol/dl) 11.50 (sd: 3.82) 12.95 (sd: 2.84) .839 citrate (mg/dl) 32.76 (sd: 19.25) 32.85 (sd: 15.95) .794 potassium (meq/dl) 2.89 (sd: 1.42) 4.29 (sd: 1.89) .117* table 5. concentration of parameters in 24-hour urine of cases and controls *adjusted for age variable number ofcases number of controls odds ratio odds ratio for trend (95%ci) creatinine (g/24hr) q1, cr < 1.340 25 31 ref 1.471 (0.971 to 1.632) q2, cr: 1.34 to 1.700 24 31 1.048 (0.468 to 2.346) q3, cr: 1.701 to 2.050 28 25 1.442 (0.645 to 3.226) q4, cr > 2.050 29 22 1.945 (0.854 to 4.427) calcium (mg/24hr) q1, ca < 110 18 36 ref 1.682 (1.277 to 2.216) q2, ca: 110 to 174 20 34 1.004 (0.435 to 2.318) q3, ca: 174 to 245.5 29 26 1.954 (0.862 to 4.428) q4, ca > 245.5 39 13 4.587 (1.893 to 11.115) oxalate (mmol/24hr) q1, ox < 0.265 14 40 ref 2.061 (1.543 to 2.753) q2, ox: 0.266 to 0.364 20 34 1.587 (0.661 to 3.810) q3, ox: 0.365 to 0.497 34 20 5.273 (2.173 to 12.793) q4, ox > 0.497 38 15 7.266 (2.927 to 18.039) sodium (meq/24hr) q1, na < 163 28 28 ref 1.087 (0.840 to 1.405) q2 na: 163 to 207.5 26 26 0.883 (0.393 to 1.986) q3 na: 207.5 to 262 21 21 0.697 (0.307 to 1.582) q4 na > 262 31 31 1.415 (0.627 to 3.197) uric acid (mg/24hr) q1 ua < 214.5 18 36 ref 1.668 (1.269 to 2.193) q2 ua: 214.5 to 353 22 32 1.134 (0.489 to 2.630) q3 ua: 353 to 572 29 25 2.197 (0.959 to 5.032) q4 ua > 572 37 16 4.401 (1.846 to 10.489) magnesium (mg/24hr) q1 mg < 55.5 26 28 ref 1.039 (0.804 to 1.341) q2 mg: 55.5 to 92.5 26 29 0.890 (0.397 to 1.994) q3 mg: 92.5 to 123.5 28 26 1.070 (0.479 to 2.391) q4 mg > 123.5 26 26 1.067 (0.475 to 2.396) urea (mg/24hr) q1 urea < 15 27 27 ref 1.193 (0.923 to 1.541) q2 urea: 15 to 19.55 22 36 0.542 (0.242 to 1.214) q3 urea:19.55 to 23.5 25 25 0.969 (0.425 to 2.209) q4 urea > 23.5 32 21 1.480 (0.657 to 3.338) chloride (mmol/24hr) q1 cl < 134.5 21 34 ref 1.407 (1.083 to 1.829) q2 cl: 134.5 to 170 23 30 1.407 (0.619 to 3.202) q3 cl: 170 to 214.5 26 28 1.524 (0.679 to 3.422) q4 cl > 214.5 36 17 3.081 (1.333 to 7.120) citrate (mg/24hr) q1 cit < 336.5 16 38 ref 1.660 (1.265 to 2.178) q2 cit: 336.5 to 410 20 34 1.194 (0.514 to 2.773) q3 cit: 410 to 584.5 35 19 3.784 (1.624 to 8.820) q4 cit > 584.5 35 18 3.603 (1.536 to 8.453) potassium (meq/24hr) q1 k < 36 32 24 ref 0.766 (0.592 to 0.990) q2 k: 36 to 48 28 26 0.582 (0.257 to 1.318) q3 k: 48 to 61.5 27 25 0.710 (0.314 to 1.6050 q4 k > 61.5 19 34 0.383 (0.168 to .872) q indicates quartile; and 95% ci, 95% confidence interval. table 6. stone formation trend according to the categories of 24-hour urinary excretion risk factors for urinary stone formers—parvin et al 104 urology journal vol 8 no 2 spring 2011 provoking factors, it could be shown better by supersaturation; thus, the result about the citrate is not conflicting with its inhibitory role. discussion in this study, the stone formers had significantly higher urine oxalate excretion not only in terms of absolute amount, but also after adjustments for body weight and urine creatinine. in addition, hyperoxaluria was one of the most frequent abnormalities in our study. after categorizing the absolute amounts of oxalate into 4 quartiles (table 6), the risk of stone formation increased from the third quartile (ie, ox > 32.80 mg/24hr or ox > 0.365 mmol/24hr). these findings indicate the very important role of oxalate as a risk factor for stone formation in our population. robertson and hughes re-examined the hypothesis of the superior role of mild hyperoxaluria over hypercalciuria in stone formation pathogenesis. the result of their study in arabian peninsula indicated that the prevalence of calcium containing stones was higher in that area than the western countries. of note, none of their subjects had hypercalciuria, and hyperoxaluria was strongly associated with urolithiasis.(14) some other studies have also reported higher mean urinary excretion of oxalate in stone formers compared with the individuals who are not stone formers.(15-17) although curhan and colleagues first reported no significant differences in the mean values of urine oxalate in their cases and controls,(18) in the second cycle of urine collection after increasing their sample size, they found that the mean urine oxalate was significantly higher in the cases than the controls, and that the risk of stone formation escalated with increasing urine oxalate.(19) however, netelenbos and associates reported that hyperoxaluria did not influence the risk for active stone formation.(20) although hyperoxaluria was one of the most common risk factors in the studies by serra and coworkers(6) and curhan and colleagues,(18) it was the second most common risk factor in the study by hess and associates,(21) but not very common in the thai stone formers.(15) hess and colleagues included both men and women in their study and this might have influenced the frequency of hyperoxaluria in their study compared to ours that was carried out in men only.(21) this justification could further be supported by the results of the study by curhan and coworkers, where they reported that hyperoxaluria was not the most frequent abnormality among their female cohorts.(18) as a result, differences in oxalate and calcium intake as well as genetic factors could be in part responsible for different values in various populations. in our study, the mean calcium excretion (only absolute amount) was significantly higher in the stone formers than the controls, which is consistent with other studies.(6,16,18,19,22) furthermore, hypercalciuria was one of the most common risk factors that is in agreement with studies carried out by other researchers.(12,18,21,23) in addition, when categorizing the urine calcium amounts into 4 quartiles (table 6), risk of stone formation increased in the fourth quartile (with ca > 245.5mg/24hr). curhan and colleagues reported that the relative risk of stone formation significantly increased for urine calcium values of over 250mg/24hr in the male cohort,(18) which is very similar to the results of the present study. mean urine uric acid was significantly higher among our cases that is in accordance with some studies.(16,24,25) after adjusting the uric acid value for body weight and urine creatinine, we reached approximately the same results. in addition, after categorizing uric acid absolute amounts into four quartiles, the risk of stone formation increased in the fourth quartile, supporting the existing belief that uric acid increases the risk of calcium oxalate stone formation.(20,26) the mean values of magnesium did not differ between the groups that is compatible with the study by deshmukh and khan.(16) in the study by curhan and coworkers,(18,19) although male cases had higher urine magnesium than the controls, the differences did not seem to be clinically significant. in our study, the risk of stone formation increased unexpectedly with the rise in urine citrate levels from the third quartile (cit > 410 mg/24hr) that is inconsistent with the studies of netelenbos and colleagues(20) and curhan and taylor.(19) in risk factors for urinary stone formers—parvin et al 105urology journal vol 8 no 2 spring 2011 curhan and associates’ first study,(18) lower urine citrate was not associated with the increased risk of stone formation in the male cohort. generally, hypocitraturia has happened to be an isolated abnormality in up to 10% of the patients with calcium stones and has been associated with other risk factors in 20% to 60% of the patients. (12,27-29) in our study, 13.2% of the patients were hypocitratuic. one possible explanation for this discrepancy with the inhibitory role of citrate is that its effect as stone formation inhibitor could be overcome by calcium, and especially oxalate promotive effect in our study. furthermore, although khan and hackett reported that urine magnesium decreases urinary saturation of calcium oxalate through increasing urinary ph and citrate,(30) two randomized trials did not show any clinical advantages in stone formers who were taking magnesium oxide compared with those who took placebo or received no treatment at all.(31,32) this leaves us with the unclear role of magnesium in stone formation. based on our findings, the cases found to have a tendency toward showing a statistical significance in lower mean urine potassium over the controls and it is in accordance with the literature.(16,18,19,22) this was also true even after adjusting the value of potassium for body weight and urine creatinine (tables 3 and 4). furthermore, after categorizing potassium absolute amounts into four quartiles, we observed that potassium was inversely associated with the risk of stone formation beginning from the fourth quartile (k > 61.501 meq/24hr). all these could demonstrate the role of potassium in preventing stone formation. although not statistically significant, our patients had higher mean urine sodium and phosphate excretion in agreement with the study of curhan and taylor (male cohort.)(19) according to our results, it seems that absolute amounts of urinary risks are more important than adjustment of these urinary measurements with urine creatinine levels and body weights. the mean values of calcium oxalate supersaturation were significantly higher in the case group than the controls in our study. higher calcium oxalate supersaturation in calcium stone formers were also reported in several studies.(15,17,33,34) according to the study by coe and associates, supersaturation is a useful index to follow the treatment response in stone formers.(35) siener and coworkers also reported that after medical treatment for calcium oxalate in stone formers, those who remained stonefree had significant decrease in calcium oxalate supersaturation.(17) conclusion in our study, oxalate was realized to play the most important role as a urinary stone risk factor in our population followed by calcium and uric acid. it seems that the absolute amount of parameters is a stronger and more determinant factor in stone formation than their concentration and the adjusted values for body weight and urine creatinine. in comparison to other studies, some discrepancies were observed in our results that could be justified due to the fact that our sample group was very homogeneous in terms of gender, age range, and exclusion of primarily stone formers. furthermore, the differences in lifestyle, environment, and races are believed to be other explanatory factors to this issue. according to our findings, since supersaturation is not influenced by geographical, environmental, and nutritional factors, it could be considered as the final and aggregative index for the evaluation of the stone formers. it seems that seeking an index that could accommodate all involving elements in stone formation is necessary, and supersaturation by definition could be one of them. as our studied population was highly selective, the results cannot be generalized to other groups of patients. conflict of interest none declared. references 1. soucie jm, coates rj, mcclellan w, austin h, thun m. relation between geographic variability in kidney stones prevalence and risk factors for stones. am j epidemiol. 1996;143:487-95. risk factors for urinary stone formers—parvin et al 106 urology journal vol 8 no 2 spring 2011 2. basiri a, shakhssalim n, khoshdel ar, ghahestani sm, basiri h. the demographic profile of urolithiasis in iran: a nationwide epidemiologic study. int urol nephrol. 2010;42:119-26. 3. basiri a, shakhssalim n, khoshdel ar, naghavi m. regional and seasonal variation in the incidence of urolithiasis in iran: a place for obsession in case finding and statistical approach. urol res. 2009;37:197-204. 4. wilson dm. clinical and laboratory approaches for evaluation of nephrolithiasis. j urol. 1989;141:770-4. 5. pearle ms, pak yc. renal calculi: a practical approach to medical evaluation and management. in: andreucci ve, fine lg, eds. international yearbook of nephrology. new york: oxford university press; 1996:69-80. 6. serra a, domingos f, salgueiro c, prata mm. [metabolic evaluation of recurrent idiopathic calcium stone disease in portugal]. acta med port. 2004;17: 27-34. 7. shakhssalim n, kazemi b, basiri a, et al. association between calcium-sensing receptor gene polymorphisms and recurrent calcium kidney stone disease: a comprehensive gene analysis. scand j urol nephrol. 2010;44:406-12. 8. basiri a, shakhssalim n, khoshdel ar, et al. familial relations and recurrence pattern in nephrolithiasis: new words about old subjects. urol j. 2010;7:81-6. 9. shakhssalim n, gilani kr, parvin m, et al. an assessment of parathyroid hormone, calcitonin, 1,25 (oh)2 vitamin d3, estradiol and testosterone in men with active calcium stone disease and evaluation of its biochemical risk factors. urol res. 2011;39:1-7. 10. tomson cr. prevention of recurrent calcium stones: a rational approach. br j urol. 1995;76:419-24. 11. yagisawa t, chandhoke ps, fan j. comparison of comprehensive and limited metabolic evaluations in the treatment of patients with recurrent calcium urolithiasis. j urol. 1999;161:1449-52. 12. levy fl, adams-huet b, pak cy. ambulatory evaluation of nephrolithiasis: an update of a 1980 protocol. am j med. 1995;98:50-9. 13. jeffers dm, carter jh, graham ga, highsmith ak. preparation and testing of reagent water in the clinical laboratory. in: gibbs el, ed. a critique of national committee for clinical laboratory standards guideline c3-a3. vol 17. 3 ed; 2002. 14. robertson wg, hughes h. importance of mild hyperoxaluria in the pathogenesis of urolithiasis-new evidence from studies in the arabian peninsula. scanning microsc. 1993;7:391-401; discussion -2. 15. stitchantrakul w, kochakarn w, ruangraksa c, domrongkitchaiporn s. urinary risk factors for recurrent calcium stone formation in thai stone formers. j med assoc thai. 2007;90:688-98. 16. deshmukh sr, khan zh. evaluation of urinary abnormalities in nephrolithiasis patients from marathwada region. indian journal of clinical biochemistry. 2006;21:177-80. 17. siener r, glatz s, nicolay c, hesse a. prospective study on the efficacy of a selective treatment and risk factors for relapse in recurrent calcium oxalate stone patients. eur urol. 2003;44:467-74. 18. curhan gc, willett wc, speizer fe, stampfer mj. twenty-four-hour urine chemistries and the risk of kidney stones among women and men. kidney int. 2001;59:2290-8. 19. curhan gc, taylor en. 24-h uric acid excretion and the risk of kidney stones. kidney int. 2008;73:489-96. 20. netelenbos jc, zwijnenburg pj, ter wee pm. risk factors determining active urinary stone formation in patients with urolithiasis. clin nephrol. 2005;63: 188-92. 21. hess b, hasler-strub u, ackermann d, jaeger p. metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasis. nephrol dial transplant. 1997;12:1362-8. 22. babic-ivancic v, avdagic sc, seric v, et al. metabolic evaluation of urolithiasis patients from eastern croatia. coll antropol. 2004;28:655-66. 23. del valle e, spivacow r, zanchetta jr. [metabolic changes in 2612 patients with nephrolithiasis]. medicina (b aires). 1999;59:417-22. 24. coe fl. hyperuricosuric calcium oxalate nephrolithiasis. kidney int. 1978;13:418-26. 25. ettinger b, tang a, citron jt, livermore b, williams t. randomized trial of allopurinol in the prevention of calcium oxalate calculi. n engl j med. 1986;315:1386-9. 26. coe fl, evan a, worcester e. kidney stone disease. j clin invest. 2005;115:2598-608. 27. menon m, mahle cj. urinary citrate excretion in patients with renal calculi. j urol. 1983;129:1158-60. 28. pak cy, fuller c. idiopathic hypocitraturic calciumoxalate nephrolithiasis successfully treated with potassium citrate. ann intern med. 1986;104:33-7. 29. pak cy, fuller c, sakhaee k, preminger gm, britton f. long-term treatment of calcium nephrolithiasis with potassium citrate. j urol. 1985;134:11-9. 30. khan sr, hackett rl. hyperoxaluria, enzymuria and nephrolithiasis. contrib nephrol. 1993;101:190-3. 31. wilson dr, strauss al, manuel ma. comparison of medical treatments for the prevention of recurrent calcium nephrolithiasis. urol res. 1984;12:39-40. 32. ettinger b, citron jt, livermore b, dolman li. chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. j urol. 1988;139:679-84. 33. ogawa y, yonou h, hokama s, oda m, morozumi m, sugaya k. urinary saturation and risk factors for calcium oxalate stone disease based on spot and 24hour urine specimens. front biosci. 2003;8:a167-76. 34. marangella m, daniele pg, ronzani m, sonego s, linari f. urine saturation with calcium salts in normal subjects and idiopathic calcium stone-formers estimated by an improved computer model system. urol res. 1985;13:189-93. 35. coe fl, wise h, parks jh, asplin jr. proportional reduction of urine supersaturation during nephrolithiasis treatment. j urol. 2001;166:1247-51. 1301vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l percutaneous nerve evaluation (pne) for treatment of non-obstructive urinary retention: urodynamic changes, placebo effects, and response rates farzaneh sharifiaghdas, mahboubeh mirzaei, babak ahadi corresponding author: mahboubeh mirzaee, md department of urology, urology and nephrology research center, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran , iran. tel: +98 21 22567222 fax: +98 21 22567282 email: mirzaeimahboubeh@yahoo. com received january 2013 accepted december 2013 department of urology, shaheed labbafinejad medical center, urology and nephrology research center, shaheed beheshti university of medical sciences tehran, iran. miscellaneous purpose: to evaluate the results of percutaneous nerve evaluation (pne) implantation in the treatment of non-obstructive urinary retention and report the changes in the urodynamic parameters. materials and methods: patients with non-obstructive urinary retention or incomplete bladder emptying were included. all patients filled a 7 days voiding diary chart and underwent pne for one week, and the patient was asked to record the second voiding diary chart and repeat urodynamic study in this period. then the pne lead was removed from the s3 foramen, but the connections remained fixed in place for another 3 days to exclude the placebo effects and the third voiding diary chart was completed by the patient. the patient wasn’t aware of lead removal. success was defined as, more than 50% improvement in at least one of the urinary tract symptoms. results: forty five patients with a mean age of 37.1 years (ranged 9-83 years) were treated with pne for refractory, non-obstructive urinary retention. of study subjects 28 complained from complete urinary retention, and 17 had incomplete emptying. of participants, 28 (62.2%) demonstrated greater than 50% improvement in the urinary symptoms. urodynamic data, showed a statistically significant increase in maximum flow rate (8 ± 2.2 ml/sec to 16 ± 3.6 ml/sec, p = .06) and voided volume (35 ml to 187 ml, p = .032) in the responders. any placebo effects in pne have not been seen. conclusion: patients with complete non obstructive urinary retention were good responders to pne. the placebo effect in sacral nerve stimulation was negligible. keywords: electric stimulation therapy; humans; urinary incontinence; urination disorders; therapy. 1302 | introduction non obstructive urinary retention is one of the most difficult diseases to manage. these patients not only have some degrees of urinary incontinence but also they suffer from recurrent (urinary tract infection uti) and decrease of renal function.(1,2,3) medical treatment and urethral dilation are usually unsuccessful and patients ultimately have to do intermittent catheterization or to use permanent catheter.(4) neuromodulation has been approved by the us food and drug administration (fda) since 1997 to treat idiopathic overactive bladder (i-oab) and non-obstructive urinary retention.(5-10) the relative ease of the technique, hopeful results and low complication rate make this therapy a superior alternative to the standard treatment of idiopathic non obstructive urinary retention. candidates for neuromodulation first should undergo a trial known as the percutaneous nerve evaluation (pne). more than 50% improvement in at least one of the urinary tract symptoms is considered success; this is currently the only proven predictive factor in determining long-term prognosis.(6,7) if the patient is considered a suitable candidate for sacral nerve modulation (snm), an implantable nerve stimulator (ins) is inserted at the second stage. in this study we assess efficacy and complications of temporary simple lead pne in non-obstructive urinary retention. materials and methods patients with complete or incomplete urinary retention who were refractory to medical treatment (full dose of bethanechol and baclofen and α-blocker administration) were included. all of the participants underwent physical examination and filled a 7 days voiding diary chart. urine analysis and culture, ultrasound imaging, urodynamic study including filling cystometry with electromyography (emg) patch and cystoscopy was performed to rule out obstruction, infection and malignancy. residual urine was measured by ultrasound, urodynamic study and cystoscopy. medical and surgical history were recorded. exclusion criteria were, morbid obesity (body mass index > 40, for high risk of lead displacement), active urinary tract infection, urinary tract obstruction, and uncorrected coagulation disorders. patients who might need to be evaluated by magnetic resonance imaging in the future or to be treated by radiation therapy or high-frequency diathermy and pregnancy were also excluded. pne lead (conventional pne-test with thin wire electrodes) was implanted under fluoroscopic guide with local anesthesia in the left or right s3 foramen, on an outpatient basis. the nerve was tested for the appropriate motor responses, plantar flexion of the great toe and anal sphincter contraction (bellows reflex) which represented the contraction of the levator muscles. simultaneous sensory responses at the time of lead placement helped to optimize positioning. the lead was connected to an external pulse generator and fixed with adhesive dressings. the patient and his/her caregiver were taught how to replace the battery and regulate voltage. test period was 1-week, and the patient was being asked to record another 7 days voiding diary chart and urodynamic study was repeated at this period. the pne lead was removed from the s3 foramen, but the connections and external pulse generator remained fixed in place for another 3 days and the third voiding diary chart was completed by the patient. the patient wasn’t aware of lead removal. more than 50% improvement in at least one of the following parameters was considered positive response: reduction in the number of catheterization times, increase in the voided volume and the number of voids per day, and decrease in postvoid residual urine volume. multichannel urodynamic study was performed in all patients with medium-fill water cystometry (50 ml per minute) and dual-lumen 6 french catheter. the patients were allowed to void in the sitting position and all the events of filling and voiding phases were recorded. the study was approved by the local research ethics committee (urology and nephrology research center) and the trial was independent of any industry support and involvement. statistical analysis data were analyzed using paired-samples t test with the statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. a p value of < .05 was considered statistically significant, confidence interval was set at 95%. results the study results are summarized in tables 1-4. of study miscellaneous 1303vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l percutaneous nerve evaluation (pne) in non-obstructive urinary retention | sharifiaghdas et al subjects 31 (68.9%) were female, 28 had complete urinary retention and were dependent on clean intermittent catheterization or permanent catheter, and 17 had incomplete bladder emptying (evaluated by post void residual urine volume). the mean duration of emptying disorders was three years. twenty seven patients had idiopathic urinary retention (60%), and 18 patients (40%) had the past history of spinal cord trauma or tumor, previous pelvic surgery and neurogenic disease. of the 45 patients, 28 (62.2%) demonstrated greater than 50% improvement in urinary symptoms. response rate was higher in the complete urinary retention group versus incomplete emptying (75% vs. 41.1%, p = .023). the details are summarized in table 1. patient with idiopathic urinary retention demonstrated better response rate compared to those with a history of neurogenic disease (70.3% vs. 50%, p = .167). the patients were divided into four groups according to their age range: 1-18 years, 19-50 years, 51-70 years and > 70 years. the response rate in female and male was 67.7% and 50%, respectively (p = .256). the mean age of men who responded to the test was 30.8 years (41.7 years in non-responders) and 57% of them were neurologic. the patients were categorized into two subgroups groups, responders and non-responders. comparison between prestimulation and during stimulation data on uroflowmetry showed significant increase in the maximum flow rate in responders (from 6.1 ml/sec to 17.6 ml/sec, p < .05). mean voided volume increase was significant in responders (from 35 ml to 187 ml, p = .032). bladder contractibility index increased in the responders which was statistically significant (from 78.1 to 108.1). post-void residual urine decreased from 125 ml to 17 ml in voiding diary and from 197.3 ml to 40.2 ml in urodynamic study that was not statistically significant. mean maximum cystometric capacity on standard cystometry increased from 325 ml to 359 ml from the preoperational to post operation time. the post operation pattern of voiding was interrupted flow. the complications were as follow, lead migration in 2 (4.4%), infection in 1 (2.2%), pain at lead site in 2 (4.4%), sensation of electrical shock in 1 (2.2%). according to the permission of ethics committee, the pne lead was removed from the s3 foramen, but the connections and external pulse generator remained fixed in place for another 3 days and the third voiding diary chart was completed by the patient. the patient was not aware of lead removal. none of the responders in the first 7 days observed greater than 50% improvement in the third voiding diary, so it seems that the placebo effect in sacral nerve stimulation is neglitable 1. response rate in different study groups with percutaneous nerve evaluation. variables patients (no.) responder (no.) rate (%) p total patients 45 28 62.2 retention complete 28 21 75.0 .023 incomplete 17 7 41.1 gender male 14 7 50.0 .256 female 31 21 67.7 type secondary 18 9 50 .167 idiopathic 27 19 70.3 age range (year) 1-18 7 4 57 .076 19-50 27 20 74 51-70 7 4 57 > 70 5 0 0 1304 | gible .in both responder and non-responder groups voiding dairy chart returned to the base-line. discussion neuromodulation was approved by the fda since 1997 to i-oab and non-obstructive urinary retention.(5-10) in patients with non-obstructive urinary retention, snm offers a superior therapeutic alternative to intermittent self-catheterization or indwelling catheters, which significantly influences the quality of life.(11) long-term results for snm in patients with chronic urinary retention are better than overactive bladder.(12) in reports, with at least 40 months follow up, success rate was between 55%-86%.(12-16) the best long-term results for snm have been achieved in patients with non-obstructive urinary retention.(13,2) side effects are low and/or uncommon. infection, leg discomfort, pain at the lead site are the main complications, the less common adverse events are, bowel dysfunction, technical problems and nerve irritation.(14,17-19) although the mechanism of action of snm is not clear, it is told that it affects brain networks, as well as modulation of spinal cord reflexes and afferent peripheral nerves. candidates for neuromodulation must first undergo a screen test. there are two methods for screening, two-stage implantation technique with tined lead test, and the standard one-stage procedure following a positive pne. the test duration is rather restricted in pne due to the risk of lead migration, the success rate is between 33%-66% in different reports.(17,20-22) the risk with tined lead is lower, duration of the test is longer (about 4 weeks) and response rate is higher (about 60%-70%).(22-23) the cost of tined lead and the more difficult process of removal, compared to simple wire, are the drawbacks. datta and colleagues reported equal results for both techniques in the women with urinary retention (one stage versus two stages) (about 70%).(14) according to the literature, evaluation of the results in the test period is based on more than 50% improvement in subjective and objective measures reported by the voiding diary chart. this is currently the only proven predictive factor in determining long-term prognosis.(7) in this study we evaluated the table 2. urodynamic parameters (preand postoperative) with percutaneous nerve evaluation. baseline postoperative p group 1* pdet at maximum flow rate 19 (10-21) 31 (14-39) .107 bladder contractility index 78.1 (60-115) 108.1 (86-197) .048 bladder capacity (ml) 325 (226-450) 359 (317-524) .165 residual urine (ml) 197.3 (110-450) 40.2 (5-145) .059 maximum flow rate (ml/sec) 6.1 (0-12) 17.6 (15-22) .018 bladder outlet obstruction index 16.5 (-9-27) -1.1 (-12-23) .096 time to maximum flow rate (sec) 10.7 (2.6-19.4) 7.7 (2.1-13.9) .185 voided volume (ml) 35 (0-150) 187 (90-340) .032 group 2** pdet at maximum flow rate 18 (12-23) 21 (15-29) .176 bladder contractibility index 78.4 (61-105) 79.1 (76-98) .436 bladder capacity (ml) 315 (225-450) 335 (315-470) .175 residual urine (ml) 179 (120-446) 182 (103-435) .269 maximum flow rate (ml/sec) 9 (0-12) 9.6 (0-14) .509 bladder outlet obstruction index 16 (-5-29) 8 (-4-23) .108 time to maximum flow rate (sec) 10.8 (6-18) 10 (7-30) .285 voided volume (ml) 37 (0-140) 45 (0-120) .845 key: pdet, detrusor pressure. * patients which responded > 50% to percutaneous nerve evaluation according to voiding diary. ** patients which didn’t response < 50% to percutaneous nerve evaluation according to voiding diary. the numbers in the pirates are range. miscellaneous 1305vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l pre and posttest urodynamic results, to look for another probable objective predictive factor. there are few reports in the literature about urodynamic outcomes after neuromodulation. in 2004, sgupta and colleagues reported changes in the urodynamic parameters in 30 women with urinary retention (fowler’s syndrome) who were able to void following neuromodulation. twenty one underwent a permanent implant and nine had pne. the results of snm in this study was attributed to the rise in the detrusor voiding pressure, they concluded that snm does not relax the external sphincter directly.(24) in our study, 33.3% of patients which responded to pne were male as detrusor voiding pressure is usually higher in men, although there was an increase in maximum detrusor pressure (from 19 cmh2o to 31 cmh2o), but it was not statistically significant (p = .107). the mechanism of action of snm is unclear, although it seems both relaxant effect on the sphincter and increase in detrusor pressure are involved. bannowsky and colleagues performed bilateral pne in 42 patients (25 retention, 9 hypersensitive urinary bladder and 8 detrusor hyperactivity). the mean age of participants was 49.2 years (14 male, 28 female). twenty (47.9%) had positive test results (9 with retention, 7 with overactive bladder and 4 with pelvic pain syndrome). they concluded that tined lead, leads to significantly higher response rate. the criticism over their conclusion is the rather low number of patients in the second group (11 patients).(25) in our study with unilateral pne in the retention group, response rate was higher (62.2%). in their study in the group with urinary retention the pne led to an average increase of the maximum detrusor pressure from 19 cmh2o (± 5 cmh2o) to 32 cmh2o (± 9.7 cmh2o) and a mean reduction of residual urine by 71%; none of them was significant (p = .068). there were 9 patients with retention that had responded to pne. in their study an average increase in maximum flow rate from 8 ± 2.2 ml/sec to 16 ± 3.6 ml/sec also was not statistically significant (p = .06). however, as they included three different groups (retention, overactive bladder and pelvic pain syndrome), the results have not been mentioned each group separately. our study was focused on the retention group and according to results they were divided into two groups, responders and non-responders. jonas and colleagues reported the results of 68 patients with non-obstructive urinary retention which responded to pne, 31 individuals were randomly assigned to a group with delayed implanted pulse generator implantation after 6 months, in this interval 9% of these patients (only 2 of 22) had more than 50% improvement in their symptoms, compared to the 83% in group with immediate implanted pulse generator implantation.(2) demographic and clinical characteristics of these two patients were not mentioned in this study. a clinical trial in new onset (less than 2 years) idiopathic complete urinary retention with only percutaneous nerve evaluation may be useful. conclusion table 3. preoperative urodynamic parameters in responder and non-responder to percutaneous nerve evaluation. variables group 1 (responders) group 2 (non responders) p pdet at maximum flow rate 19 (10-21) 18 (12-23) .543 bladder contractibility index 78.1 (60-115) 78.4 (61-105) .508 bladder capacity (ml) 325 (226-450) 315 (225-450) .487 residual urine (ml) 197.3 (110-450) 179 (120-446) .309 maximum flow rate (ml/sec) 6.1 (0-12) 9 (0-12) .415 bladder outlet obstruction index 16.5 (-9-27) 16 (-5-29) .567 time to maximum flow rate (sec) 10.7 (2.6-19.4) 10.8 (6-18) .576 voided volume (ml) 35 (0-150) 37 (0-140) .498 key: pdet, detrusor pressure. the numbers in the pirates are range. percutaneous nerve evaluation (pne) in non-obstructive urinary retention | sharifiaghdas et al 1306 | in selected patients with non-obstructive urinary retention, snm offers an effective, minimally invasive treatment option. patients with complete non-obstructive retention are good responder to pne. there was not any predictive parameter of failure of pne according to urodynamic parameters. none of pre-operative urodynamic parameters could predict the success rate of pne. efforts should continue to further optimize patient selection and improvement of the testing technique. the placebo effect in sacral nerve stimulation is negligible. conflict of interest none declared. table 4. findings demonstrating no placebo effect. responders (n = 28) pre-stimulation pne period* post pne** mean voided volume (ml) 35 187 39 cic time per day (mean) 8 1 8 post void residual urine (ml) 125 17 127 key: pen, percutaneous nerve evaluation; cic, clean intermittent catheterization. *seven days voiding diary ** the third voiding diary miscellaneous references 1. white wm, dobmeyer-dittrich c, klein fa, wallace ls. sacral nerve stimulation for treatment of refractory urinary retention: long-term efficacy and durability. urology. 2008;71:71-4. 2. jonas u, fowler cj, chancellor mb. efficacy of sacral nerve stimulation for urinary retention: results 18 months after implantation. j urol. 2001;165:15-9. 3. powell cr and kreder kj. long-term outcomes of urgency-frequency syndrome due to painful bladder syndrome treated with sacral neuromodulation and analysis of failures. j urol. 2010;183:173-6. 4. comiter cv. sacral nerve stimulation to treat nonobstructive urinary retention in women. curr urol rep. 2008;9:405-11. 5. botlero r, urquhart dm, davis sr, bell rj. prevalence and incidence of urinary incontinence in women: review of the literature and investigation of methodological issues. int j urol. 2008;15:230-4. 6. scheepens wa , jongen mm , nieman fh. predictive factors for sacral neuromodulation in chronic lower urinary tract dysfunction. urology. 2002;60:598-602. 7. carmel me, vasavada sp, goldman hb. troubleshooting sacral neuromodulation issues. curr urol rep. 2012;13:363-9. 8. schmidt ra, jonas u, oleson ka, et al. sacral nerve stimulation for treatment of refractory urinary urge incontinence. sacral nerve stimulation study group. j urol. 1999;162:352-7. 9. hassouna mm, siegel sw, nyeholt aa, et al. sacral neuromodulation in the treatment of urgency-frequency symptoms: a multicenter study on efficacy and safety. j urol. 2000;163:1849-54. 10. malaguti s, spinelli m, giardiello g, lazzeri m, van den hombergh u. neurophysiological evidence may predict the outcome of sacral neuromodulation. j urol. 2003;170:3-6. 11. kessler tm, fowler cj. sacral neuromodulation for urinary retention. nat clin pract urol. 2008; 5: 657-66. 12. de ridder d, ost d, bruyninckx f. the presence of fowler’s syndrome predicts successful long-term outcome of sacral nerve stimulation in women with urinary retention. eur urol. 2007;51:229-33. 13. elhilali mm, khaled sm, kashiwabara t, elzayat e, corcos j. sacral neuromodulation : long-term experience of one center. urology. 2005;65:1114-7. 14. datta sn, chaliha c, singh a, et al. sacral neurostimulation for urinary retention: 10-year experience from one uk centre. bju int. 2008;101:192-6. 15. van kerrebroeck pe, van voskuilen ac, heesakkers jp, et al. results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. j urol. 2007;178:2029-34. 16. van voskuilen ac, oerlemans dj, weil eh, de bie ra, van kerrebroeck pe. long term results of neuromodulation by sacral nerve stimulation for lower urinary tract symptoms: a retrospective single center study. eur urol. 2006;49:366-72. 17. kessler tm, buchser e, meyer ,s et al. sacral neuromodulation for refractory lower urinary tract dysfunction: results of a nationwide registry in switzerland. eur urol. 2007;51:1357-63. 18. swinn mj, schott gd, oliver se, kitchen nd, fowler cj. leg pain after sacral neuromodulation: anatomical considerations. bju int. 1999;84:1113-5. 19. brazzelli m, murray a, fraser c. efficacy and safety of sacral nerve stimulation for urinary urge incontinence: a systematic review. j urol. 2006;175:835-41. 1307vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l percutaneous nerve evaluation (pne) in non-obstructive urinary retention | sharifiaghdas et al 20. janknegt ra, weil eh, eerdmans ph. improving neuromodulation technique for refractory voiding dysfunctions: two-stage implant. urology. 1997;49:358-62. 21. swinn mj, kitchen nd, goodwin rj, fowler cj. sacral neuromodulation for women with fowler’s syndrome. eur urol. 2000;38:439-443. 22. spinelli m, giardiello g, gerber m. new sacral neuromodulation lead for percutaneous implantation using local anesthesia: description and first experience. j urol. 2003;170:1905-7. 23. kessler tm, burkhard fc, madersbacher h. safety of prolonged sacral neuromodulation tined lead testing. curr med res opin. 2008;24:343-7. 24. dasgupta r, fowler cj. urodynamic study of women in urinary retention treated with sacral neuromodulation. j urol. 2004;171:1161-4. 25. bannowsky a, wefer b, braun pm, jünemann kp. urodynamic changes and response rates in patients treated with permanent electrodes compared to conventional wire electrodes in the peripheral nerve evaluation test. world j urol. 2008;26:623-6. u j 03 all-2.pdf 549vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l department of urology, osaka medical college, osaka, japan kiyoshi takahara, naokazu ibuki, teruo inamoto, hayahito nomi, takanobu ubai, haruhito azuma predictors of success for stone fragmentation and stone-free rate after extracorporeal shockwave lithotripsy in the treatment of upper urinary tract stones corresponding author: kiyoshi takahara, md department of urology, osaka medical college, 2-7 daigaku-machi, takatsuki city, osaka, 569-8686, japan tel: +72 683 1221 fax: +72 684 6546 e-mail: uro037@poh. osaka-med.ac.jp received december 2011 accepted january 2012 purpose: to evaluate factors affecting the success rate of stone fragmentation and stone-free rate materials and methods: treatment. results: p p the stone-free rate (middle: p = .0229). conclusion: our study suggests that stone fragmentation and stone-free rate after swl treatment for upper urinary tract stones can be predicted. keywords: ment outcome brief communication 550 | introduction renal and ureteral stones are common urological for treatment of upper urinary tract stones. several factors swl treatment for renal(1,2) and ureteral stones,(3,4) includgender, and stone features, such as stone site and size. predict stone fragmentation after swl for upper urinary selected for assessment. materials and methods 2), respectively. and 45, respectively. p results tation. the success of stone fragmentation for each factor is cess rate (p p brief communication table 1. factors affecting stone fragmentation. variable success, n (%) p odds ratio body mass index, kg/m2 25 < 25 18/30 (60%) 71/91 (78%) .04 2.745 stone size, mm small (0 to 15) medium (16 to 25) large (> 25) 59/80 (73.8%) 22/31 (71.0%) 8/10 (80.0%) .3556 .5225 0.611 0.553 stone position r2 r3 u1 42/48 (87.5%) 9/11 (81.8%) 38/62 (61.3%) .5054 .0108 0.517 0.167 hydronephrosis yes no 52/76 (68.4%) 37/45 (82.2%) .8731 1.109 r2 indicates renal pelvis and calices; r3, ureteropelvic junction; and u1, upper ureter. 551vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l on the stone-free rate (middle: p = .0229). discussion as the preferred method for treating upper urinary tract (1-4) an ideal method for stone therapy should provide high ef(5) ple, immediate stone-free rate can not be achieved after swl, and some patients may need repeated treatment due to stone recurrence.(6) therefore, determining the patients and colleagues constructed pre-operative nomograms for predicting stone-free rates after single swl treatment, and (7) cess of stone fragmentation and stone-free rate. pendent predictors of stone-free rate after swl. a successful p < .01). clinical outcome of swl treatment. stone size has been nal stones.(1,2) prognostic factors that affect the success rate after swl p < .001).(1) p < .05).(2) predicting stone fragmentation in swl | takahara et al table 2. factors affecting stone-free rate. variable success, n (%) p odds ratio body mass index, kg/m2 ≥ 25 < 25 10/15 (66.7%) 41/56 (73.2%) .5297 1.549 stone size, mm small (0 to 15) medium (16 to 25) large (> 25) 39/49 (79.6%) 7/16 (43.8%) 5/6 (83.3%) .0229 .5923 0.205 1.881 stone position r2 r3 u1 20/32 (62.5%) 6/9 (66.7%) 25/30 (83.3%) .8269 .4326 0.517 0.167 hydronephrosis yes no 32/42 (76.2%) 19/29 (65.5%) .5496 1.611 swl treatment times 1 > 2 47/61 (77%) 4/10 (40%) .06745 0.705 r2 indicates renal pelvis and calices; r3, ureteropelvic junction; u1, upper ureter; and swl, extracorporeal shockwave lithotripsy. 552 | strongest independent predictors of failure for swl treat(3) the clinical outcome of swl treatment [success: 1.00 cm (0.90 to 1.10) and failure: 1.30 cm (1.10 to 1.60); p < .001]. (4) cated that after successful stone fragmentation, only stone higher for pelvic and upper calyceal stones compared to (1,9-11) erally considered to be the reason for the superior success rates, but the multivariate analyses indicated that ureteral clinical outcome.(4,12) stone fragmentation and stone-free rate. stone location sigprevious research has indicated that hydronephrosis has a (13) cess for both stone fragmentation and stone-free status after swl treatment. conclusion success for stone fragmentation and stone-free rate, separately. our analysis indicated that different factors affect stone fragmentation and stone-free rate. conflict of interest none declared. references 1. abdel-khalek m, sheir kz, mokhtar aa, eraky i, kenawy m, bazeed m. prediction of success rate after extracorporeal shock-wave lithotripsy of renal stones--a multivariate analysis model. scand j urol nephrol. 2004;38:161-7. 2. al-ansari a, as-sadiq k, al-said s, younis n, jaleel oa, shokeir aa. prognostic factors of success of extracorporeal shock wave lithotripsy (eswl) in the treatment of renal stones. int urol nephrol. 2006;38:63-7. 3. delakas d, karyotis i, daskalopoulos g, lianos e, mavromanolakis e. independent predictors of failure of shockwave lithotripsy for ureteral stones employing a secondgeneration lithotripter. j endourol. 2003;17:201-5. 4. wang m, shi q, wang x, yang k, yang r. prediction of outcome of extracorporeal shock wave lithotripsy in the management of ureteric calculi. urol res. 2011;39:51-7. 5. augustin h. prediction of stone-free rate after eswl. eur urol. 2007;52:318-20. 6. sun by, lee yh, jiaan bp, chen kk, chang ls, chen kt. recurrence rate and risk factors for urinary calculi after extracorporeal shock wave lithotripsy. j urol. 1996;156:9035; discussion 6. 7. kanao k, nakashima j, nakagawa k, et al. preoperative nomograms for predicting stone-free rate after extracorporeal shock wave lithotripsy. j urol. 2006;176:1453-6; discussion 6-7. 8. pareek g, armenakas na, panagopoulos g, bruno jj, fracchia ja. extracorporeal shock wave lithotripsy success based on body mass index and hounsfield units. urology. 2005;65:33-6. 9. zanetti g, montanari e, mandressi a, et al. long-term results of extracorporeal shock wave lithotripsy in renal stone treatment. j endourol. 1991;5:61-4. 10. rassweiler j, köhrmann ku, alken p. eswl, including imaging. curr opin urol. 1992;2:291-9. 11. tolon m, miroglu c, erol h, et al. a report on extracorporeal shock wave lithotripsy results on 1,569 renal units in an outpatient clinic. j urol. 1991;145:695-8. 12. gnanapragasam vj, ramsden pd, murthy ls, thomas dj. primary in situ extracorporeal shock wave lithotripsy in the management of ureteric calculi: results with a third-generation lithotripter. bju int. 1999;84:770-4. 13. turna b, akbay k, ekren f, et al. comparative study of extracorporeal shock wave lithotripsy outcomes for proximal and distal ureteric stones. int urol nephrol. 2008;40:23-9. brief communication 553vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l urology and nephrology research center, shohadae-tajrish medical center, shahid beheshti university of medical sciences, tehran, iran hossein karami, alireza rezaei, mohammad mohsen mazloomfard, babak javanmard, behzad lotfi, amir haji-mohammadmehdi-arbab effects of surgical position on patients’ arterial blood gases during percutaneous nephrolithotomy corresponding author: mohammad mohsen mazloomfard, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2277 0954 e-mail: mazloomfard@ yahoo.com received august 2010 accepted january 2012 endourology and stone disease purpose: materials and methods: repositioning. results : and supine positions, respectively (p 2 p = .21). arterial oxygen pressure (pao2 p = .01) and p p 2 3 prone, and supine groups. conclusion: keywords: percutaneous nephrolithotomy, blood gas analysis, prone position special feature 144 urology journal vol 5 no 3 summer 2008 lymphocele after kidney transplantation where are we standing now? mohammad reza ebadzadeh,1 mahmood tavakkoli2 urol j. 2008;5:144-8. www.uj.unrc.ir 1department of urology, shafa hospital, kerman medical university, kerman, iran 2department of urology, shahid labbafinejad medical center, shahid beheshti university (mc), tehran, iran corresponding author: mohammad reza ebadzadeh, md department of urology and kidney transplantation, shafa hospital, shafa st, kerman, po box: 7619836495, iran tel: +98 341 272 0578 fax: +98 341 211 5780 e-mail: m_ebadzadeh@kmu.ac.ir received october 2008 accepted march 2008 introduction lymphocele is a lymphatic collection around a transplanted kidney. diagnosis is made when there is a pelvic collection with similar properties to the plasma. this can be confirmed with biochemical analysis of the fluid that shows similar electrolyte content compared with the plasma with low protein level. on microscopic evaluation, presence of lymphocytes can be a useful clue.(1) lymphocele occurs 2 weeks to 6 months after transplantation with its peak incidence being at 6 weeks. on the other hand, its development following trauma to the kidney and delayed formation 8 years after transplantation has been reported, too.(2) the incidence of clinically significant lymphocele is about 20%, but it may develop in 12% to 40% of transplant recipients.(3,4) since the introduction of ultrasonography, in about half of transplanted kidneys, collections smaller than 50 cm3 can be detected, most of which are less than 3 cm in diameter and resolve spontaneously. indeed, most of the lymphatic collections are subclinical.(3) etiology radioisotope studies suggest that most lymphoceles originate from leakage of lymph from unligated iliac vessel lymphatics of the recipient. the drainage route of the lower limb lymphatic vessels is along the iliac vessels. as a consequence, when the iliac vessels are mobilized for anastomosis, some lymphatic vessels are unavoidably divided. lymphocele can also originate from transplanted kidney lymphatic vessels.(1) in a study by sansalone and colleagues, cephalad implantation of the kidney in the ipsilateral iliac fossa to the common iliac vessels in comparison with standard operation (in the contralateral iliac fossa and anastomosis to the external iliac vessels) was accompanied by a significant lower rate of lymphocele formation (2.1% versus 8.5%), and it was assumed that this was due to less lymphatic manipulation in the former operative technique.(5) hamza and colleagues demonstrated that there was no relationship between the extent of iliac vessel preparation and lymphocele occurrence(6); however, they recommended that to prevent lymphocele formation, transplanted bed be restricted to the least possible and lymphatic vessels be ligated precisely at the hilum of the kidney allograft. because the lymph does not have any clotting factor, all of lymphatic vessels must lymphocele after kidney transplantation—ebadzadeh and tavakkoli urology journal vol 5 no 3 summer 2008 145 be tied or clipped, but diathermy is not suggested. it is unexplained why the lymph from the transplanted kidney has a small role in lymphocele formation. probably, the inflammatory process associated with allograft presence increases the flow of lymph from lymphatic vessels around the iliac vessels.(1) ligation of the lymphatic vessels during preparation of either the graft or the site of transplantation and appropriate external drainage thereafter can reduce the incidence of lymphocele.(7) it has been shown that limitation of vessel dissection does not increase the major vessel complications or pulmonary emboli after kidney transplantation.(8) there is some evidence that incidence of lymphocele has decreased since introduction of low-steroid regimens for immunosuppression. however, there are controversies in literature about this matter.(9-11) in a study by goel and colleagues, combination of sirolimus, mycophenolate mofetil, and prednisone was an independent factor for lymphocele occurrence by a mechanism of delayed healing of wound and injured lymphatic vessels.(9) also, langer and kahan suggested the impact of sirolimus on the risk of lymphocele.(10) tondolo and colleagues, however, questioned this mechanism and showed that the incidence of lymphocele is similar in multiple immunosuppressive regimens.(11) there are also other factors associated with lymphocele in kidney transplant recipients. it has been reported that that obese patients have a longer operative time and more frequently suffer from wound infection, perinephric hematoma, and lymphocele.(12) along with this finding, it should be noted that obesity (body mass index greater than 30 kg/m2) is an independent risk factor for lymphocele formation.(9) there is evidence that although prophylaxis with highmolecular weight heparin can reduce graft losses secondary to thrombosis or vascular rejection, it can increase the incidence of lymphocele; lundin and colleagues reported a higher frequency of lymphocele with heparin prophylaxis (43% versus 20%) in a group of 130 kidney allograft recipients. such an increase was not associated with hemorrhagic events.(13) finally, rejection episodes may have a role in lymphocele formation. in a study by lipay and colleagues, high frequency of cellular rejection in patients with lymphocele was indicative of a possible cause-effect relationship.(14) in another study on 115 patients, multivariate analysis of possible lymphocele risk factors showed that only rejection was accompanied by high risk of lymphocele formation. the authors concluded that allograft rejection was most important contributing factor in lymphocele formation.(15) clinical manifestations most lymphoceles are clinically silent, but the most common manifestation is impaired graft function in the presence of perigraft collection and unilateral leg edema. many other presentations have been recognized including: hypertension, pain, fever, frequency, ipsilateral thrombophlebitis, palpable mass, and lymphatic fistula.(1) even, a case of urinary retention due to compressive effect of lymphocele on the bladder neck has been reported.(16) diagnosis ultrasonography is the key to diagnosis of lymphocele. given its homogeneity and specific shape and position, lymphocele is distinct from blood clot. most lymphoceles are inferior to the lower pole of the transplanted kidney, but are obviously separate from the bladder. repeated ultrasonography after bladder drainage can differentiate the presence of lymphocele from a full bladder. ultrasonography can show obstruction in the urinary tract that produces hydronephrosis. furthermore, ultrasonographyguided aspiration allows biochemical and cytologic analysis. infective lymphoceles are characterized by the presence of complex echo pattern inside the kidney.(1) most lymphoceles are routinely followed up with dynamic renal scintigraphy using technetium tc 99m diethylenetriamine pentaacetic acid.(17) in a study on 14 patients by kumar and colleagues, 3 patterns for lymphoceles were described: (1) an initial photopenic area that progressively fills with tracer activity with an equal level to the background activity in delayed films, (2) initial lymphocele after kidney transplantation—ebadzadeh and tavakkoli 146 urology journal vol 5 no 3 summer 2008 photopenic areas with an activity more than the background activity in delayed films, (3) persistent photopenic areas in early and delayed films. in addition, they found that there is a rim of increased activity of tracer around the initial photopenic area in some patients.(17) the most common pattern of radiotracer activity in this study was an early photopenic area that is filled with tracer in delayed films. presence of rim was in favor of lymphocele diagnosis.(17) additional radiological imagings such as intravenous urography and computed tomography are not necessary in typical cases, but they are required in complicated or equivocal ones.(1) management conservative management. small asymptomatic collections are common and usually resolve spontaneously. therefore, conservative management can be satisfactory. simple aspiration. ultrasonography-guided aspiration is not only diagnostic, but also therapeutic in selected cases. it can be the initial treatment modality that allows relief of urinary obstruction, recovery of kidney function, and prevention of emergency situation. although simple aspiration is sometimes therapeutic, it may be necessary to perform multiple sessions of aspiration and the rate of spontaneous recovery reduces after 3 recurrences. in addition, each aspiration brings about a low risk of infection.(1) sclerotherapy. prolonged external drainage via percutaneous catheter and administration of a sclerosing agent (instillation) is also used. recurrences have been reported in up to 20% of cases following sclerotherapy. agents like ethanol, povidone iodine, and tetracycline have been used for this purpose.(1) in a study by tasar and colleagues, ethanol was used in 18 patients with symptomatic lymphoceles. the mean duration of therapy and mean alcohol volume in each session were 17 days and 30 cm3, respectively. there was 1 case of recurrence, 1 graft loss, and 10 cases of minor complications including local discomfort and low grade fever. in their opinion, this method of sclerotherapy was safe and cost-effective.(18) in another study on 30 patients with lymphocele, alcohol injection was found to be safe and costeffective, with a success rate of 94%. the authors reported 2 cases of recurrence. all complications were minor, including catheter-induced infection and catheter displacement.(19) povidone iodine, as a sclerotherapy agent, has a failure rate of less than 11%, but it lasts about 20 to 30 days to cease the leakage. iodine-induced nephrotoxic acute kidney failure following the use of povidone iodine has also been reported.(20) tetracycline seems not to be effective as a sclerosing agent.(1) surgery. surgery for lymphocele is needed in the presence of local symptoms, graft dysfunction, or both. surgical treatment is named incorrectly as marsupialization, but unroofing or fenestration is more precise.(1) this therapy is an intraperitoneal drainage of lymphocele. because of its effectiveness and safety, surgery should be the first line of the treatment.(21) laparoscopy is the procedure of choice for surgical management of lymphocele. the most susceptible organ to injury during laparoscopy is the transplanted ureter. in addition, bulging induced by extraperitoneal kidney might be sometimes mistaken by lymphocele.(1) organ injury during laparoscopy can be avoided by the use of intra-operative ultrasonography. in a study by schips and colleagues, a method of laparoscopic fenestration of lymphocele with diaphanoscopic guidance was described. in their method, after puncture and ultrasonographyguided dilation, it was possible to determine the exact site of incision by detecting the light of cystoscope.(22) tie and colleagues introduced a method of replacement of a guide wire or drainage catheter under ultrasonography or computed tomography guidance. they used this marker as a guide for laparoscopic marsupialization of lymphocele.(23) in different series, the rate of recurrence following laparoscopic marsupialization has been reported between 5% to 13%, and it has been noted that there is a risk of injury to other organs such as the bladder.(21,24) in a study on laparoscopic lymphocele after kidney transplantation—ebadzadeh and tavakkoli urology journal vol 5 no 3 summer 2008 147 treatment of lymphocele, the mean operative time was 123 minutes and the mean blood loss was 43 ml. the authors reported an average duration of hospitalization of 1.5 days. only minor complications were seen. they concluded that laparoscopy is an effective minimally invasive treatment and an excellent alternative for open surgery.(25) open surgery may be required in patients with a previous abdominal surgery, for lymphoceles with inappropriate characteristics or location, or when other simultaneous procedures should be done. for deep lymphoceles around the lower pole of the kidney, it seems that open surgery is safer. in other unusual cases, including thick wall of lymphocele or bladder rupture during laparoscopy, open surgery may be necessary.(1) in a study by fuller and colleagues, the most common indication for open drainage was uninfected wound complication and high probability of injury to the ureter or the vessels because of proximity to the hillar structures.(26) open surgery can be done by re-opening of the transplant incision, or preferably through a lower midline abdominal incision and transperitoneal approach. intraoperatively, lymphocele can be seen in the form of a bulge into the peritoneal cavity, and it is possible to make a 5-cm opening between these two cavities. it must be noted that according to the variable anatomy of the transplanted structures, several vital organs may be present between these two cavities that makes avoidance of injury to these organs a crucial point. when a simple incision is made in the wall between the lymphocele and the peritoneum, a low but significant rate of recurrence is anticipated. for prevention of recurrence, it is recommended to perform techniques such as oversewing of the edges and mobilization of the peritoneum with omentopexy.(1) in children, prophylactic fenestration between the two cavities at the end of the operation is recommended by some authors.(27) nghiem and colleagues introduced a new method named intraperitoneal catheter drainage of lymphocele as an outpatient procedure in 14 patients with local anesthesia and seledinger method. under ultrasonography guidance, a 13-f hickman catheter was introduced to the lymphocele, and it was connected to a small window of the peritoneum via subcutaneous tissue.(24) in a period of 8 years, this procedure has been done with success. one case of wound infection led to catheter removal and 1 case of lymphocele recurrence due to retraction of the catheter beneath the peritoneum was reported in this study. it was mentioned by the authors that this was an effective outpatient procedure that obviated the need for anesthesia. however, they emphasized that further conclusions require a multicenter study.(24) complications most lymphoceles are managed without complication, but infections, especially with organisms like yeasts, in an immunocompromised recipient may be a problem. in addition to impaired graft function, lymphoceles that put pressure on the renal vein or iliac veins may predispose the patient to venous thrombosis.(1) conflict of interest none declared. references 1. gray dwr. vascular and lymphatic complications after renal transplantation in: morris pj, editor. kidney transplantation, principles and practice. 5th ed. philadelphia: wb saunders; 2001. p. 424-6. 2. thompson tj, neale tj. acute perirenal lymphocele formation 8 years after renal transplantation. aust n z j surg. 1989;59:583-5. 3. adani gl, baccarani u, bresadola v, et al. graft loss due to percutaneous sclerotherapy of a lymphocele using acetic acid after renal transplantation. cardiovasc intervent radiol. 2005;28:836-8. 4. zietek z, sulikowski t, tejchman k, et al. lymphocele after kidney transplantation. transplant proc. 2007;39:2744-7. 5. sansalone cv, aseni p, minetti e, et al. is lymphocele in renal transplantation an avoidable complication? am j surg. 2000;179:182-5. 6. hamza a, fischer k, koch e, et al. diagnostics and therapy of lymphoceles after kidney transplantation. transplant proc. 2006;38:701-6. 7. dubeaux vt, oliveira rm, moura vj, pereira jm, henriques fp. assessment of lymphocele incidence following 450 renal transplantations. int braz j urol. 2004;30:18-21. 8. burleson rl, marbarger pd. prevention of lymphocele formation following renal allotransplantation. j urol. 1982;127:18-9. lymphocele after kidney transplantation—ebadzadeh and tavakkoli 148 urology journal vol 5 no 3 summer 2008 9. goel m, flechner sm, zhou l, et al. the influence of various maintenance immunosuppressive drugs on lymphocele formation and treatment after kidney transplantation. j urol. 2004;171:1788-92. 10. langer rm, kahan bd. incidence, therapy, and consequences of lymphocele after sirolimuscyclosporine-prednisone immunosuppression in renal transplant recipients. transplantation. 2002;74:804-8. 11. tondolo v, citterio f, massa a, et al. lymphocele after renal transplantation: the influence of the immunosuppressive therapy. transplant proc. 2006;38:1051-2. 12. singh d, lawen j, alkhudair w. does pretransplant obesity affect the outcome in kidney transplant recipients? transplant proc. 2005;37:717-20. 13. lundin c, bersztel a, wahlberg j, wadström j. low molecular weight heparin prophylaxis increases the incidence of lymphocele after kidney transplantation. ups j med sci. 2002;107:9-15. 14. lipay ma, noronha ide l, vidonho júnior a, romão júnior je, campagnari jc, srougi m. lymphocele: a possible relationship with acute cellular rejection in kidney transplantation. sao paulo med j. 1999;117:238-42. 15. khauli rb, stoff js, lovewell t, ghavamian r, baker s. post-transplant lymphoceles: a critical look into the risk factors, pathophysiology and management. j urol. 1993;150:22-6. 16. hwang ec, kang tw, koh ys, et al. post-transplant lymphocele: an unusual cause of acute urinary retention mimicking urethral injury. int j urol. 2006;13:468-70. 17. kumar r, bharathi dasan j, choudhury s, guleria s, padhy ak, malhotra a. scintigraphic patterns of lymphocele in post-renal transplant. nucl med commun. 2003;24:531-5. 18. tasar m, gulec b, saglam m, yavuz i, bozlar u, ugurel s. posttransplant symptomatic lymphocele treatment with percutaneous drainage and ethanol sclerosis: long-term follow-up. clin imaging. 2005;29:109-16. 19. zuckerman da, yeager td. percutaneous ethanol sclerotherapy of postoperative lymphoceles. ajr am j roentgenol. 1997;169:433-7. 20. manfro rc, comerlato l, berdichevski rh, et al. nephrotoxic acute renal failure in a renal transplant patient with recurrent lymphocele treated with povidone-iodine irrigation. am j kidney dis. 2002;40:655-7. 21. bailey sh, mone mc, holman jm, nelson ew. laparoscopic treatment of post renal transplant lymphoceles. surg endosc. 2003;17:1896-9. 22. schips l, lipsky k, hebel p, et al. laparoscopic fenestration of lymphoceles after kidney transplantation with diaphanoscopic guidance. urology. 2005;66:185-7. 23. tie ml, rao mm, russell c, burapa k. transperitoneal guide-wire or drainage catheter placement for guidance of laparoscopic marsupialization of lymphocoeles post renal transplantation. nephrol dial transplant. 2001;16:1038-41. 24. nghiem dd, beckman i. intraperitoneal catheter drainage of lymphocele: an outpatient procedure. transpl int. 2005;18:721-3. 25. hsu th, gill is, grune mt, et al. laparoscopic lymphocelectomy: a multi-institutional analysis. j urol. 2000;163:1096-8; discussion 8-9. 26. fuller tf, kang sm, hirose r, feng s, stock pg, freise ce. management of lymphoceles after renal transplantation: laparoscopic versus open drainage. j urol. 2003;169:2022-5. 27. zaontz mr, firlit cf. pelvic lymphocele after pediatric renal transplantation: a successful technique for prevention. j urol. 1988;139:557-9. best reviewer of the july-august 2018 issue mohammed s. elsheemy mohammed s. elsheemy february 2019 mohammed s. elsheemy is currently an associate professor of urology at cairo university, egypt. after obtaining his medical degree from cairo university in 1999, dr. mohammed elsheemy earned a master of science then doctor of medicine in urology in 2008. his research includes endourology and urolithiasis, swl, pediatric urology, pediatric renal transplantation, female urology, pelvic floor dysfunctions and urodynamics. based on dr. elsheemy research, a surgeon tailored ordinary polypropylene mesh was inserted as a mid-urethral tape for treatment of sui using his own-designed (with his team) helical passers with marked decrease in the cost of treatment. additionally, an important part of his research was on calcular anuria in children and infants which resulted; for the 1st time, in a protocol for management depending on severity of obstruction, size and site of stones, and renal functions. furthermore, he has several publications on mini-pnl in adults and children. his publications on the use of mini-pnl for the management stones in patients with renal congenital anomalies or the use of single-stage bilateral mini-pnl for bilateral renal stones may be the first studies in this field. he has published several scientific papers and book chapters and serve as an editor and reviewer in several international peer-reviewed scientific journals. these research activities was supported by several courses in scientific writing and advanced statistical analysis. he was selected as one of the top 10% of reviewers in the field of medicine for 2016 in the peer review week (2016) through (sentinels of science awards) that is provided by (publon) which is an international web site concerned with peer review activities (with its verification) for international scientific journals. then, he was selected as one of the top 1% of reviewers in the next 2 years (2017) and (2018). additionally, his researches were selected as the best poster/abstract in many international conferences including espu and eau. dr. elsheemy is a member of several societies in urology including european association of urology (eau), european society for pediatric urology (espu) and societe internationale urologie (siu). he has served as assistant-secretary of peditric urology section of egyptian urological association (eua). being a reviewer for urology journal is an honor, as you are allowed to contribute to the scientific level of this journal. careful and fair-minded evaluation of scientific articles is an important scholarly contribution and a gratifying duty in academics. unclassified validation of the persian version of the national institute of health chronic prostatitis symptom index farzad allameh1, mohammad mersad mansouri tehrani2, mohammad ali tasharrofi2, mohammad ali ganji jameshouran3* objectives: to compose a comprehensible and fluent persian translation of the national institute of health chronic prostatitis symptom index (nih-cpsi), and to determine its linguistic validity in a persian sample population. methods: the standard double-back translation method, provided by the previous studies were utilized by three professional linguists to translate the english version of the nih-cpsi to persian, and a group of 10 urologists further reviewed and translated questionnaire. the questionnaire was then presented to the sample study, comprised of 60 men with cp/cpps and 60 controls with adverse urological history, and the collected data was analyzed through ibm-spss software to test its validity, evaluative, and discriminatory power, psychometric qualities and internal consistency. results: a total of 80 subjects (42 cp/cpps patients and 38 healthy controls) were considered eligible for this study. the total persian nih-cpsi scores and each subdomain showed significant difference (p < 0.001) between the two study groups, indicating a satisfactory discriminant validity for the index. psychometric analysis established the index to benefit from a high internal consistency. the translation was also considered by both the subjects and the physicians to be easily comprehensible. conclusion: the persian nih-cpsi is a reliable and valid instrument for evaluating cp/cpps symptoms in general population, while also benefitting from high discriminatory power, and can be utilized with ease in both clinical practice and laboratory studies. keywords: asymptomatic inflammatory prostatitis; asymptomatic inflammatory prostatitides; chronic prostatitis with chronic pelvic pain syndrome; national institute of health chronic prostatitis symptom index; prostatitis; prostatitides introduction chronic non-bacterial prostatitis (cp) or chronic pelvic pain syndrome (cpps) is a frequent disorder in general population, with a prevalence ranging from 5% to 14.2%(1,2), and accounting for about 90% of the subject admissions with prostatitis-like symptoms to general physicians and urologists(3,4). the national institute of health defines cp/cpps as a primary urological pain in the absence of any secondary etiology, with or without present urethral inflammation(3). moreover, cp/cpps is a poorly-defined clinical entity, and therefore is prone to misdiagnosis, mistreatment, and mismanagement(5). furthermore, the lack of a systematized and universally accepted outcome measure has caused inconsistent and vague results in cp/cpps studies while making patient evaluation a challenge, as well as hindering researches and clinical endeavors in aiding cp/cpps patients(6,7). accordingly, the national institutes of health (nih) chronic prostatitis collaborative research network de1laser application in medical science research center, shahid beheshti university of medical sciences, tehran, iran 2student research committee, department and faculty of medicine, shahid beheshti university of medical sciences, tehran, iran 3urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran *correspondence: urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. tel: +98 912 0713 765. fax: +98 21 22 56 72 82. e-mail: mohammadali.ganji@sbmu.ac.ir. received july 2019 & accepted february 2020 vised the national institute of health chronic prostatitis symptom index (nih-cpsi) to effectively evaluate both the symptoms of cp/cpps and the impact they impose on the subject’s quality of life. the index consists of nine questions divided into three subsections, each providing measurement for the three most essential fields in cp/cpps patients’ experience; pain, urinary symptoms and the patient’s quality of life(6). the nih-cpsi has been widely recognized as a standard and authentic outcome measure for cp/cpps patients, providing a primary endpoint in both clinical practices, in addition to clinical trials(7). moreover, it has been acknowledged by the international prostatitis collaborative network as the standard evaluation instrument for males with cp/cpps symptoms(8). while primarily published to measure the extent, previous history, and treatment outcomes of cp/cpps, the nih-cpsi is shown to benefit from a high discriminatory value, being able to detect chronic prostatitis symptoms in the general population and thus proving to be valuable in epidemiologic studies(9). urology journal/vol 18 no. 1/ january-february 2021/ pp. 117-121. [doi: 10.22037/uj.v0i0.5444] recently, the translation-validation of the nih-cpsi questionnaire has been performed into german, italian, spanish, finnish, japanese, malay, estonian, and arabic(10-17). however, as of yet, no standardized evaluative tool for cp/cpps exists in persian. the current study aims to present a coherent and comprehensive persian version of the nih-cpsi and validate it in a persian sample population. materials and methods translation procedure we followed the double translation method, as suggested and utilized by prior studies(10-17). the original nih-cpsi questionnaire was translated into persian by two independent iranian translators, each unaware of the goals of the study. the translators then compared the versions to each other and the author (f.a.), resolving any inconsistencies and revising several phrases and words to ensure comprehensibility. the revised version was then back-translated into english by a native australian, fully bilingual (english, persian) translator. the translated version was then compared to the original nih-cpsi form by the translators and the authors, finding little to none inconsistencies between the versions, with the idiomatic content being practically identical. we then forwarded the back-translated version to the corresponding author of the original nih-cpsi, professor m. s. litwin, who reviewed the back-translation alongside the original english validation and found it to be a very close approximation. after being assessed on the accounts of proper vocabulary and grammar usage as well as ease of understanding by an iranian english literature professor, a finalized persian questionnaire was then harmonized and presented to a committee of ten iranian urologists. validation process the sample population for this study was composed of 60 patients afflicted with cp/cpps and 60 healthy controls, collected in a span of 3 months, from november 2018 to january 2019. those patients were included whose diagnosis was under the nih definition of cp/ cpps type iii(3), attending shohada-e-tajrish hospital urology clinic. all the patients had consecutive referrals across iran with specific symptoms of cp/cpss for a time span of at least one year, with the majority of them giving an unsatisfactory history of treatment through conventional methods, including antibiotics, anti-inflammatory drugs, and alpha-blockers. according to the study protocol, those males were excluded, who were designated with chronic bacterial prostatitis (nih type ii)(3,18), and reported a previous history of urethritis, malignancies, recurrent urolithiasis, inflammatory bowel disease, benign prostatic hyperplasia, major psychiatric disorders, and neurological diseases; meaning those with a secondary etiology for cp/cpps were excluded. we selected the control group among healthy personnel of shohada-e-tajrish hospital and shahid beheshti university of medical sciences, who had no previous urological history, or any other disease capable of presenting with prostatitis-like symptoms. all the participants were fully briefed about their role in a symptom evaluation with a specific questionnaire and signed written consent. furthermore, any ethical issues concerning the study, subjects, and the authors were discussed and resolved if necessary. at the first visit, all the patients underwent a clinical examination to solidify the clinical diagnosis of cp/cpps further. both the patients and controls then completed a short questionnaire regarding their personal information, with the data provided in table 1. afterward, both the cp/cpps patients and the healthy controls self-completed the persian version of the nih-cpsi, and then were asked to fill out the index again in 1 week, to evaluate the test-retest reliability. two of the authors (f.a. and m.m.m.t.) supervised the process, noted the time of completion for each individual, determined whether any question was deemed too difficult or irrelevant for the subjects, and considered their subjective opinions in case of any rearrangement in the questionnaire. statistical analysis the questionnaires were analyzed through the software statistical package for social sciences (spss version 21). mann-whitney u test was utilized to compare distributary differences between the two groups. test-retest reliability, item associations, and data validity were studied through the intraclass correlation coefficient (icc) and pearson product-moment. p-values < 0.001 table 1. basic data of the sample populations, nih-cpsi and the subdomains scores for each of the subject groups (cp/cpps patients and healthy controls). characteristicsa cp/cpps controls number of patients 42 38 mean age (years) 45.6 ± 3.4 42.7 ± 3.9 education primary school 18 (30) 14 (23) high school 26 (43) 25 (42) university graduate 16 (27) 21 (35) mean duration of symptoms (years) 3.8 ± 2.3 mean duration of index completion (minutes) 8 ± 2 7 ± 2 mean nih-cpsi scores ± (sd)* total (0-43) 22.47 ± (6.9)* 2.1 ± (2.7)* pain domain (0-21) 10.35 ± (3.7)* 0.3 ± (0.2)* urinary symptoms domain (0-10) 4.73 ± (1.98)* 0.5 ± (0.4)* quality of life domain (0-12) 7.38 ± (2.7)* 0.8 ± (0.4)* abbreviations: cp/cpps, chronic prostatitis/chronic pelvic pain syndrome; nih-cpsi, national institute of health chronic prostatitis symptom index. a data are presented as mean ± sd or number (percent). * p < 0.001 with mann-whitney u-test. persian version of the nih-cpsi – allameh et al. unclassified 118 vol 18 no 1 january-february 2021 119 were deemed statistically significant. finally, the overall internal consistency for the persian nih-cpsi and each of its subdomains was assessed by cronbach’s coefficient α(19). face validity was utilized in composing the questionnaire, whereas content validity was used in designing the literature. results of the 120 enrolled subjects, a sum of 80 (42 cp/cpps patients and 38 healthy controls) were considered eligible for our study. forty (18 of the cp/cpps patients and 12 of the controls) subjects were excluded on the accounts of only partially filling the questionnaire. as mentioned above, table 1 depicts the subjects’ general information. the mean age for both of the groups was relatively equivalent, with cp/cpps patients’ mean age (sd) being 45.6(3.4), and the control group’s mean age (sd) being 42.7 (3.9). similarly, both groups completed the questionnaire in a relatively same amount of time. the general compliance of both groups in filling the questionnaire was satisfactory. the mean duration (sd) of cp/cpps symptoms among the patients was 3.8 (2.3) years. the persian nih-cpsi scores significantly differed between the two groups (p < 0.001), with the total mean (sd) score being 22.47 (6.9) for the cp/cpps patients and 2.1 (2.7) for the control subjects. mean and iqr for the total nph-cpsi scores among patients was reported as 20.21 and q1-q3 (14.23 – 32.68), respectively. notable differences were seen (p < 0.001) between the resulted scores of all the three subdomains. table 1 presents the performance result for each domain and the total questionnaire, as well as the differences studied with mann-whitney u test. pearson’s test was utilized to analyze the association between the sections of the persian nih-cpsi, demonstrating that the domains correlated positively with one another. the highest associations were witnessed between the total nih-cpsi scores, and the pain (0.889) and the qol (0.846) domains. the urinary symptoms domain also positively correlated with the other subdomains and the total score, albeit not quite as high. table 2 shows the cross-tabulations of the correlations in-between the three domains and the total nih-cpsi score. test-retest reliability, performed on the previous sample of 80 subjects, showed little to no disparity between the score distributions for each of the subdomains and the overall persian nih-cpsi. the correlation between the total scores was 0.901 for cp/ cpps patients, 0.912 for the controls, and 0.908 for all 80 subjects. psychometric analysis dictated a satisfactory internal consistency with α coefficient of 0.865 for the index in general (table 3). discussion despite the high worldwide prevalence of cp/cpps among the global population and patient visits to general practitioners and urologists alike, there has not been any effort to establish a standardized outcome measure for the persian population; absence of such an instrument not only hinders the clinical judgment of iranian physicians regarding cp/cpps, but also contributes to a lack of epidemiologic research regarding cp/cpps among the persian population. what this study provided was the translation-validation process of the nih-cpsi in an iranian sample population. the double translation method, as previously accepted and utilized(10-16), was diligently performed in a methodology similar to the german study(10). the persian nih-cpsi scores among cp/cpps patients were notably similar to the values provided by the previous studies. the mean nih-cpsi scores across all the subdomains (22.47 total, 10.35 pain, 4.73 voiding symptoms, and 7.38 qol) were higher when compared to the corresponding values in the english article(6). such disparity, however, has also been present in other validation studies, with the scores from the italian study(11) being similar to our own, and the two years of trial with the german nih-cpsi resulting in scores higher than our current data(10). these discrepancies are expected, with the implications behind them table 2. correlation of nih-cpsi and its subclasses among the cp/cpps patients through icc pain urinary symptoms quality of life nih-cpsi pain 1.000 urinary symptoms 0.389 1.000 quality of life 0.612 0.433 1.000 nih-cpsi 0.889 0.666 0.846 1.000 abbreviations: cp/cpps, chronic prostatitis/chronic pelvic pain syndrome; nih-cpsi, national institute of health chronic prostatitis symptom index. p < 0.001 with mann-whitney u-test. characteristicsa alpha cp/cpps controls number of patients 42 38 mean age (years) 45.6 ± 3.4 42.7 ± 3.9 domain (range) test re-test correlation test re-test correlation overall nih-cpsi 0.865 22.47 22.21 0.901 2.1 2.2 0.912 pain 0.853 10.37 10.46 0.894 0.3 0.3 0.900 urinary symptoms 0.652 4.73 4.62 0.912 0.5 0.4 0.895 quality of life 0.726 7.38 7.25 0.846 0.8 0.7 0.887 abbreviations: cp/cpps, chronic prostatitis/chronic pelvic pain syndrome; nih-cpsi, national institute of health chronic prostatitis symptom index. a data are presented as mean ± sd. table 3. test-retest reliability analysis (icc) and internal consistency (cronbach) of the study. persian version of the nih-cpsi – allameh et al. ranging from differences in sample qualities to unique characteristics of lingual expressions. nonetheless, the persian version of the nih-cpsi demonstrated content validity and discriminatory viability in distinguishing cp/cpps patients from the healthy individuals; as the scores in each three of the subdomains in addition to the total score of the two study groups were widely different (p < 0,001 u-test). the association between the pain scores and the total index scores among the prostatitis patients was demonstrated to be significant (0.889), with the score corresponding to those reported in the italian (0.89) and the finnish (0.91) studies. the correlation between the total score and the quality of life domain also followed suit (0.846), again comparable to the scores reported by the italian (0.88) and the finnish (0.85) studies. the correlation reported between the total nih-cpsi scores and the urinary symptom subdomain, although statistically significant (0.666), was not as remarkable as the previous domains. however, this trend is also seen in the previous studies, with the correlation score reported as 0.67 and 0.56 in the finnish and the italian studies, respectively. nonetheless, the correspondence between the correlation scores across the board and the results described by the other studies, including the original english supports the construct validity of the current instrument(6,11,13). our results confirmed a high internal consistency of the persian nih-cpsi (0.865 with cronbach). an internal consistency greater than 0.7 for the overall translated index demonstrated acceptable reliability(10). while in our study, the internal consistency of the pain domain (0.853) and the total index (0.856) were similar to those of the english version, the cronbach alpha of the voiding symptoms and qol domains were slightly decreased, compared to the original study. among other validation studies, internal consistency was presented in the german(10), italian(11), spanish(12), japanese(14), and the arabic(16) versions, which all demonstrated a cronbach’s alpha comparable to that of the original version; except for the german two-year trial, which presented slightly decreased values compared to the study conducted by litwin et al. across all the domains. in discussing the attributing factors for this discrepancy, as schneider et al. describe, differences in patient selection and sample qualities may be crucial since the original north american study sample included subjects with a lower quality of life and pain, but higher urinary symptom scores. although our study demonstrates a higher internal consistency for the overall questionnaire in comparison to the german study (0.74), the discussion as mentioned above is nonetheless significant in clarifying the slight discrepancy(6,10). furthermore, reevaluating the translation procedure may also be noteworthy; albeit as stated before, we performed this method carefully following the previously conducted studies. as stated, the nih-cpsi was initially designed with an evaluative goal, rather than a discriminatory one. however, subsequent translation-validations(10-16) and several epidemiologic studies(9,20,21) have all determined the significant discriminatory power of this questionnaire in differentiating between the cp/cpps patients and healthy individuals in the general population. nih-cpsi is to optimally function if adopted widely as a routine tool of evaluating cp/cpps(6,7) and thus will benefit from the constant translation-validation studies to yield the prime of its use. the study limitations are concerned mostly with the socioeconomic demographics of its subjects, since a sample population of this proportion may not be a proper presentation of the persian-speaking population. a better demonstration of the discriminatory power of this index may be available if tested by other physicians in different geographical and socioeconomic settings of persian speaking populations. our other limitation concerned the sample-pool of our subjects; shohada-e-tajrish hospital is a primary/secondary healthcare center with a broad spectrum of urological patients and therefore provides limited access to cp/cpps patients when compared with more specialized, tertiary care centers with focus on prostate diseases. conclusions to conclude, our study presented and recognized the persian translated nih-cpsi as an easily comprehensible and standard instrument in evaluating cp/cpps symptoms, with significant discriminatory value and construct validity, making it reliable and viable as a primary outcome measure in both clinical practice and sub-clinical studies, in the iranian population. acknowledgments this research was approved by laser application in medical sciences research center, shahid beheshti university of medical sciences, and conducted in the urology ward of shohada-e-tajrish hospital, tehran, iran. the authors would like to thank dr. mohammad javad nasiri and dr. nasrin borumandnia, for their aid in composing this article. conflict of interest the authors report no conflict of interest. appendix:https://journals.sbmu.ac.ir/urolj/index.php/ uj/libraryfiles/downloadpublic/17 references 1. moon td, hagen l, heisey dm. urinary symptomatology in younger men. 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13. leskinen mj, mehik a, sarpola a, tammela tl, jarvelin mr. the finnish version of the national institutes of health chronic prostatitis symptom index correlates well with the visual pain scale: translation and results of a modified linguistic validation study. bju int. 2003;92:251-6. 14. kunishima y, matsukawa m, takahashi s, et al. national institutes of health chronic prostatitis symptom index for japanese men. urology. 2002;60:74-7. 15. cheah py, liong ml, yuen kh, et al. reliability and validity of the national institutes of health: chronic prostatitis symptom index in a malaysian population. world j urol. 2006;24:79-87. 16. el-nashaar a, fathy a, zeedan a, al-ahwany a, shamloul r. validity and reliability of the arabic version of the national institutes of health chronic prostatitis symptom index. urol int. 2006;77:227-31. 17. korrovits p, punab m, mehik a, mandar r. the estonian version of the national institutes of health chronic prostatitis symptom index. andrologia. 2006;38:106-9. 18. ludwig m, schroeder-printzen i, ludecke g, weidner w. comparison of expressed prostatic secretions with urine after prostatic massage--a means to diagnose chronic prostatitis/inflammatory chronic pelvic pain syndrome. urology. 2000;55:175-7. 19. cronbach lj. coefficient alpha and the internal structure of tests. psychometrika. 1951;16:297-334. 20. nickel jc. recommendations for the evaluation of patients with prostatitis. world j urol. 2003;21:75-81. 21. nickel jc, nyberg lm, hennenfent m. research guidelines for chronic prostatitis: consensus report from the first persian version of the nih-cpsi – allameh et al. national institutes of health international prostatitis collaborative network. urology. 1999;54:229-33. vol 18 no 1 january-february 2021 121 sexual dysfunction and infertility 40 urology journal vol 7 no 1 winter 2010 salvage use of citalopram for treatment of fluoxetine-resistant premature ejaculation in recently married men a prospective clinical trial mohammad reza dadfar,1 mahmood reza baghinia2 introduction: a wide variety of therapeutic modalities have been tried for treatment of premature ejaculation. selective serotonin reuptake inhibitors are from the latest and most effective medical agents. among these drugs, fluoxetine hydrochloride has been used for some years in our institutions with considerable drug untoward effects and significant failure rates. we tried to salvage treatment process by using citalopram in fluoxetine-resistant patients. materials and methods: in a prospective clinical trial, we used citalopram hydrobromide as a salvage agent in 16 newly married men with premature ejaculation who experienced a history of unsuccessful treatment with fluoxetine hydrochloride. intravaginal ejaculation latency time (ivelt) was recorded by a stopwatch before and after the treatment, and a 5-stage visual scale was designed and used to compare patients’ sexual satisfaction levels during the 1-month treatment period. results: the ivelt and sexual satisfaction levels both significantly improved after citalopram prescription. the mean measured ivelt was 0.388 ± 0.212 minutes before the treatment, which increased to 4.313 ± 2.886 minutes after the treatment. the reported drug untoward effects were mild. citalopram was ineffective only in 1 patient, which was discontinued after 4 weeks. conclusion: our study showed that citalopram is effective and safe in the treatment of premature ejaculation in newly married men after failed treatment with fluoxetine. urol j. 2010;7:40-4. www.uj.unrc.ir keywords: ejaculation, serotonin uptake inhibitors, sexual dysfunction, male 1department of urology, imam khomeiny hospital, ahwaz jundishapoor medical university, ahwaz, iran 2arak university of medical sciences, arak, iran corresponding author: mohammad reza dadfar, md department of urology, imam khomeiny hospital, ahwaz jundishapoor medical university, ahwaz, iran tel: +98 611 222 2114 e-mail: mdadfar@yahoo.com received march 2009 accepted august 2009 introduction premature ejaculation (pe) has been defined as “ejaculation before or very soon after the beginning of intercourse.(1)” others have stated an ejaculation time of 2 minutes after vaginal intromission as a definition of normal intravaginal ejaculation latency time (ivelt). (2) premature ejaculation in recently married men has been reported by many authors. lack of sexual experience and performance stress have been presumed as the contributing factors of temporary pe in newly married men.(3) probably due to cultural differences and earlier sexual activity, pe in newly married men may be less frequent in western countries.(4) during the past decades and based on different theories, multiple citalopram for premature ejaculation—dadfar et al 41urology journal vol 7 no 1 winter 2010 therapeutic modalities have been used to treat this annoying disorder, including pharmacologic therapy and intercourse maneuvers like “stop-start method.(5,6)” during the recent years, new detailed studies on the pathophysiology of pe have been carried out,(3) and a more precise treatment strategy based on a better defined neurohormonal explanation has been introduced to lengthen the ivelt through affecting cerebral serotonin reuptake system.(7) a relatively common drug in selective serotonin reuptake inhibitors (ssris) family, fluoxetine hydrochloride, has been used for a decade by urologists with a remarkable efficacy and of course a relatively severe side effects profile. (8) considering the relatively high incidence of pe in recently married men in our region and considerable failure rate and drug untoward effects of fluoxetine treatment in these patients, more research is warranted to evaluate alternative therapeutic agents with better safety margin and/ or more efficacy. citalopram hydrobromide, another agent of the ssris family, has been introduced as an antidepressant, which has proved its efficacy during clinical use as an ejaculation retarder agent. also, due to less drug untoward effects and better tolerance of citalopram in patients with depression,(9,10) we hypothesized that it could be a better tolerated drug for treatment of pe, as well. thus, we designed a prospective clinical trial on citalopram as a salvage agent in newly married men with a history of pe who failed to respond to fluoxetine hydrochloride. we evaluated the drug in terms of alterations in ivelt, sexual satisfaction rate, and adverse effects. materials and methods during a 2-year period from december 2006 till october 2008, we selected a total of 16 newly married potent men being married for less than 1 year through direct clinical interviews. they all had a chief compliant of primary pe and a history of failed treatment with fluoxetine hydrochloride. our inclusion and exclusion criteria are shown in table 1. all of the patients underwent a full medical interview and physical examination. after filling a detailed informed consent form, they were enrolled in the study. primarily, the mean ivelt was recorded by the patients using a stopwatch technique after detailed training during a 2-week period with at least 3 consecutive sexual intercourse sessions. in addition, a 5-stage analogue scale was designed to check and record the level of sexual satisfaction after each intercourse (table 2). furthermore, the patients were asked to record their sexual satisfaction level precisely before and after drug administration. an ivelt of less than 1 minute after at least a 4-week period of treatment with fluoxetine hydrochloride was presumed as an unsatisfying result and fluoxetine failure. citalopram hydrobromide (pharma chemie co, tehran, iran) was prescribed for all of the patients with a primary dosage of 20 mg every night. then, the patients were asked to write down their ivelt and sexual satisfaction level after each sexual encounter. all of the patients were patient selection criteria inclusion age between 20 and 35 years married for the first time for less than 1 year history of primary premature ejaculation intravaginal ejaculation latency time less than 1 minute history of fluoxetine use for premature ejaculation for at least 1 month with a dose of at least 10 mg, twice a day, with unsatisfactory results history of no prescribed drug use for at least 1 month exclusion past history of psychological problems any past history of long-term medical treatment history of diabetes mellitus or smoking drug noncompliance history of impotency history of marital conflicts past history of pelvic or central nervous system trauma, fracture, or operations table 1. inclusion and exclusion criteria score condition 4 very satisfied with present sexual activities 3 moderately satisfied with present sexual activities 2 sexual satisfaction is not good 1 often unsatisfied with present level of sexual activity 0 unsatisfied at all table 2. sexual satisfaction analogue visual scale citalopram for premature ejaculation—dadfar et al 42 urology journal vol 7 no 1 winter 2010 visited by the researchers 2 weeks later and the changes in the ivelt, sexual satisfaction level, and drug complications were recorded. a second visit of the patients was planned for 2 weeks later, and treatment continued for at least 6 months by the same dose if it was reported as successful by the patients. in 3 patients, we doubled the primary dose due to unsatisfactory results and in 1, we discontinued it after 4 weeks due to ineffectiveness. the latter patient later reported severe interpersonal and marital problems with his partner. the final results after 4 weeks of treatment were recorded and analyzed using the spss software (statistical package for the social sciences, version 14.0, spss inc, chicago, illinois, usa). we used the nonparametric wilcoxon signed rank test to compare ivelts and sexual satisfaction scores of each patient before and after the treatment. p values less than .05 were considered significant. results the measured ivelt and sexual satisfaction level results before and after the 1-month treatment with citalopram hydrobromide in newly married patients with pe and fluoxetine resistance are listed in table 3. the median age of the patients was 28.5 years and the mean calculated ivelt was 0.388 ± 0.212 minutes before the treatment, which increased to 4.313 ± 2.886 minutes after the treatment. the mean calculated primary sexual satisfaction level was 0.63 ± 0.81 which rose to a mean of 3.75 ± 1.44 after treatment, both of these findings were statistically significant (p = .001). the observed adverse effects were dizziness, dry mouth, and lowered libido which were reported in 7 patients (43%), but they did not lead to discontinuation of treatment in none of the patients. one of the participants reported no satisfaction with citalopram and his ivelt remained unchanged after 4 weeks of drug administration. we considered him a case of drug failure and discontinued the drug. on the final assessment after 4 weeks of treatment, 15 patients (93.75%) were treated successfully with citalopram after fluoxetine failure. discussion premature ejaculation is a worldwide sexual disorder that may be seen by every urologist in a daily basis. it has a strong negative impact on patients’ self-esteem, sexual satisfaction, and libido and may be a major factor in marital sex conflicts.(8) some theories have been proposed to define the cause of pe; two more widely accepted theories which may explain the occurrence of fast uncontrolled ejaculation are penile hypersensitivity and 5-hydroxytryptamine intravaginal ejaculation latency time sexual satisfaction score patient age, y before treatment after treatment drug dose, mg before treatment after treatment complications 1 28 0.3 to 0.5 5 to 6 20 1 5 dizziness 2 25 0.5 4 20 0 5 no 3 32 0.3 4 20 1 4 no 4 20 0.1 7 to 8 20 1 5 no 5 22 0.5 4 20 1 4 dizziness 6 27 0.1 2 to 5 40 0 4 dizziness 7 29 < 0.1 2 to 5 40 0 5 no 8 32 < 0.1 10 20 0 4 dry mouth 9 35 0.6 0.5 20 2 1 no 10 30 0.6 > 10 20 2 5 no 11 27 0.3 to 0.5 1 to 2 20 2 3 dizziness 12 29 < 0.1 5 to 10 20 0 3 low libido 13 32 0.5 4 40 0 4 no 14 31 0.6 0.5 40 0 0 dry mouth 15 23 0.6 5 20 0 4 no 16 24 0.5 to 0.6 5 20 0 4 no table 3. characteristics of patients with premature ejaculation, outcome of treatment with citalopram, and complications citalopram for premature ejaculation—dadfar et al 43urology journal vol 7 no 1 winter 2010 receptor sensitivity.(7) the first theory proposes that men with pe have a hypersensitive penis,(11) lower penile vibration perception threshold, and shorter somatosensory evoked potential latency times in the glans and penile shaft.(12) the second theory proposes that disorders in 5-hydroxytryptamine type c receptors in the hypothalamus and brain medulla will facilitate ejaculation and may directly lead to pe, and pharmaceutical agents with potent effects on these receptors may be able to affect ejaculation latency time.(13) a vast array of different therapeutic modalities has been used for treatment of pe. psychological/ behavioral treatment has been advocated by masters and johnson and used for years by psychologists and sex therapists with varying results.(6) other therapeutic means such as extracorporeal functional magnetic stimulation have been discussed by morales and coworkers in 2009 which showed to be as efficacious as ssris. (10) injection of hyaluronic acid in the penis glans by kwak and colleagues in 2008 showed also a moderate long-term positive effect,(14) and also, acupuncture was reported by chen in 2009 to be of variable effects.(15) in another study, shi and associates performed selective dorsal penile nerve resection in 2008 to control pe and introduced it as a safe and effective measure.(16) pharmacotherapy for pe has also a long history. in the recent years and after better understanding of erection and ejaculation physiology, pharmacologic agents have been selected as the first treatment modalities.(17) among pharmaceutical agents which have been suggested to treat this disorder, the ssris family which includes fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram, have been used in many clinical studies during the past decade and proved their propensity to delay ejaculation.(18) this drug family, being used as antidepressants, can activate 5-hydroxytryptamine type c receptors, adjust ejaculatory threshold set point, and delay ejaculation.(19) as their prototype, fluoxetine has been used extensively by urologists to treat pe in the recent years. unfortunately, some drug reactions such as intolerable fatigue or dizziness have been reported by many patients as reasons to discontinue treatment. drug ineffectiveness has also been reported by other patients which had the therapists search for better tolerable and more effective therapeutic agents.(20) another member of the ssris family, citalopram, has shown less frequent adverse effects and more considerable ejaculation retarding ability,(9) and has been used as an effective agent in men with pe. another agent in the ssris family, dapoxetine, which has a short acting time and less untoward effects, has been introduced recently by hellstrom.(21) dapoxetine showed a good ejaculation retardation activity. in addition, it can be used in an as-needed manner and is awaiting more detailed studies now. in our study, we tried citalopram as a salvage agent in young newly married men resistant to fluoxetine, and according to the results, we achieved a statistically significant therapeutic effect in this difficult group of patients. the stopwatch time measurement of the ivelt recorded a considerable ejaculation retardation effect, a mean improvement of more than 4 minutes. sexual satisfaction level also increased with a mean increase of 3 units. in addition, we did not detect any significant clinical adverse effects with this drug regimen. in another placebo-controlled study by safarinejad and hosseini in 2006, beneficial effects of citalopram and little side effects were reported.(22) in a study carried out by atmaca and colleagues, similar results were acquired.(23) all these studies were conducted in potent middle-aged men and all showed an increase in sexual satisfaction and performance after drug administration. in our literature search, we could not find any studies on the use of citalopram after a failed treatment with fluoxetine, and it seems that this drug can be used as a salvage agent in this group of men. conclusion in this prospective clinical trial, we used citalopram as a salvage agent to treat pe in newly married men with a history of fluoxetine resistance. according to our results, after 4 weeks of continuous drug administration, ivelt and sexual satisfaction both improved significantly. citalopram had some mild untoward effects, citalopram for premature ejaculation—dadfar et al 44 urology journal vol 7 no 1 winter 2010 and nearly all patients were satisfied with this treatment. therefore, it seems that this agent can be used as a powerful choice to treat patients with pe, especially in newly married men in whom other medical therapies have failed. acknowledgement we would like to thank mr bahman cheraghian, msc, for his kind assistance in statistical data analysis. conflict of interest none declared. references 1. world health organization. international statistical classification of diseases and related health problems. 10th ed. geneva: world health organization; 1994. 2. kaplan h. the evaluation of sexual disorders: the urologic evaluation of ejaculatory disorders, new york: brunner/mazel; 1983. 3. strassberg ds, mahoney jm, schaugaard m, hale ve. the role of anxiety in premature ejaculation: a psychophysiological model. arch sex behav. 1990;19:251-7. 4. grenier g, byers es. rapid ejaculation: a review of conceptual, etiological, and treatment issues. arch sex behav. 1995;24:447-72. 5. rowland dl, cooper se, slob ak. the treatment of premature ejaculation: psychological and biological strategies. drugs today (barc). 1998;34:879-99. 6. masters wh, johnson ve. human sexual inadequacy. boston: little, brown; 1970. 7. waldinger md, hengeveld mw, zwinderman ah, olivier b. effect of ssri antidepressants on ejaculation: a double-blind, randomized, placebocontrolled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. j clin psychopharmacol. 1998;18:274-81. 8. metz me, pryor jl, nesvacil lj, abuzzahab f, sr., koznar j. premature ejaculation: a psychophysiological review. j sex marital ther. 1997;23:3-23. 9. waldinger md, zwinderman ah, olivier b. ssris and ejaculation: a double-blind, randomized, fixeddose study with paroxetine and citalopram. j clin psychopharmacol. 2001;21:556-60. 10. morales a, black a, clark-pereira j, emerson l. a novel approach to premature ejaculation: extracorporeal functional magnetic stimulation. can j urol. 2009;16:4458-62. 11. rowland dl, greenleaf w, mas m, myers l, davidson jm. penile and finger sensory thresholds in young, aging, and diabetic males. arch sex behav. 1989;18: 1-12. 12. xin zc, choi yd, rha kh, choi hk. somatosensory evoked potentials in patients with primary premature ejaculation. j urol. 1997;158:451-5. 13. coolen lm, olivier b, peters hj, veening jg. demonstration of ejaculation-induced neural activity in the male rat brain using 5-ht1a agonist 8-oh-dpat. physiol behav. 1997;62:881-91. 14. kwak ti, jin mh, kim jj, moon dg. long-term effects of glans penis augmentation using injectable hyaluronic acid gel for premature ejaculation. int j impot res. 2008;20:425-8. 15. chen zx. [control study on acupuncture and medication for treatment of primary simple premature ejaculation]. zhongguo zhen jiu. 2009;29:13-5. chinese. 16. shi wg, wang xj, liang xq, et al. [selective resection of the branches of the two dorsal penile nerves for primary premature ejaculation]. zhonghua nan ke xue. 2008;14:436-8. 17. montague dk, jarow j, broderick ga, et al. aua guideline on the pharmacologic management of premature ejaculation. j urol. 2004;172:290-4. 18. waldinger md, berendsen hh, blok bf, olivier b, holstege g. premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of the serotonergic system. behav brain res. 1998;92:111-8. 19. coolen lm, peters hj, veening jg. anatomical interrelationships of the medial preoptic area and other brain regions activated following male sexual behavior: a combined fos and tract-tracing study. j comp neurol. 1998;397:421-35. 20. kim sc, seo kk. efficacy and safety of fluoxetine, sertraline and clomipramine in patients with premature ejaculation: a double-blind, placebo controlled study. j urol. 1998;159:425-7. 21. hellstrom wj. emerging treatments for premature ejaculation: focus on dapoxetine. neuropsychiatr dis treat. 2009;5:37-46. 22. safarinejad mr, hosseini sy. safety and efficacy of citalopram in the treatment of premature ejaculation: a double-blind placebo-controlled, fixed dose, randomized study. int j impot res. 2006;18:164-9. 23. atmaca m, kuloglu m, tezcan e, semercioz a. the efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study. int j impot res. 2002;14:502-5. reconstructive surgery 184 urology journal vol 5 no 3 summer 2008 internal urethrotomy combined with antegrade flexible cystoscopy for management of obliterative urethral stricture seyed jalil hosseini, ali kaviani, ali reza vazirnia introduction: we studied the safety and efficacy of flexible cystoscopyguided internal urethrotomy in the management of obliterative urethral strictures. materials and methods: forty-three flexible cystoscopy-guided internal urethrotomies were performed between 1999 and 2005. the indication for the procedure was nearly blinded bulbar or membranous urethral strictures not longer than 1 cm that would not allow passage of guide wire. candidates were those who refused or were unable to undergo urtheroplasty. by monitoring any impression of the urethrotome on the monitor through the flexible cystoscope, we were able to do under-vision urethrotomy. all of the patients were started clean intermittent catheterization afterwards which was tapered over the following 6 months. follow-up continued for 24 months after the last internal urethrotomy. results: seventeen patients were younger than 65 years with a history of failed posterior urethroplasty, and 26 were older than 65 with poor cardiopulmonary conditions who had bulbar urethral stricture following straddle or iatrogenic injuries. urethral stricture stabilized in 16 patients (37.2%) with a single session of urethrotomy and in 17 (39.5%) with 2 urethrotomies. overall, urethral stricture stabilized in 76.7% of patients with 1 or 2 internal urethrotomies within 24 months of follow-up. no severe complication was reported. conclusion: flexible cystoscopy-guided internal urethrotomy is a simple, safe, and under-vision procedure in obliterative urethral strictures shorter than 1 cm. it can be an ideal option for patients who do not accept posterior urethroplasty or are in a poor cardiopulmonary condition that precludes general anesthesia. urol j. 2008;5:184-7. www.uj.unrc.ir keywords: urethral injuries, urethral stricture, male, cystoscopy, treatment outcome reconstructive urology section, department of urology, shohada-etajrish hospital and reproductive health research center, shahid beheshti university (mc), tehran , iran corresponding author: seyed jalil hosseini, md department of urology, shohada-etajrish hospital, tehran, iran tel: +98 21 2271 8001 fax: +98 21 8852 6901 e-mail: jhosseinee@gmail.com received december 2007 accepted june 2008 introduction traumatic and iatrogenic obliterative urethral strictures shorter than 1 centimeter constitute a significant number of diagnoses among patients with urethral stricture. conventionally, their repair is done through a perineal approach. there are some groups of patients, however, who do not consent to undergo urethroplasty or are in very poor cardiac or pulmonary conditions that preclude general or spinal anesthesia. cutto-the-light technique has been used by leonard and colleagues(1) as a less-invasive procedure, but turner-warwick and others have combined flexible cystoscopy and internal urethrotomy—hosseini et al urology journal vol 5 no 3 summer 2008 185 disputed this procedure because of its blind nature and high complication rates.(2,3) we are reporting our experience with flexible cystoscope to guide retrograde internal urethrotomy as an alternative method to the cut-to-the-light procedure in selected patients. materials and methods we reviewed flexible cystoscopy-guided internal urethrotomies we had performed between 1999 and 2005. this technique would be used in patients who had denied primary or secondary urethroplasty or had been in a very poor cardiac or pulmonary condition precluding general or spinal anesthesia. our planned indication for the procedure was nearly blinded bulbar or membranous urethral strictures not longer than 1 cm shown on simultaneous voiding cystourethrography and retrograde urethrography (figure 1) that did not allow passage of guide wire. in case of a positive history of transurethral resection of the prostate (turp) or open prostatectomy, our inclusion criteria would be intact external urethral sphincter and appropriate distance of the external urethral sphincter from the bulbar urethral stricture, documented by antegrade flexible cystoscopy. we excluded patients with membranous urethral stricture who had a history of turp or open prostatectomy. all of the patients had a suprapubic catheter because of obliterative urethral stricture and their inability to void. the procedure was done electively. a flexible cystoscope was introduced through a mature cystostomy tract to the posterior urethra up to the nearly blinded point. the bladder, bladder neck, and prostatic urethra were examined, and in cases of bulbar urethral stricture, the external urethral sphincter and the distance of the stricture from the sphincter were evaluated. then, the urethrotome was passed retrogradely through the urethra to the stricture point (figure 2). monitoring any impression of urethrotome on the monitor through the flexible cystoscope, we were able to do under-vision urethrotomy in our patients. after providing a wide open urethra that allows easily introduction of a 21-f resectoscope to the bladder, a 18-f urethral catheter was placed. the urethral catheter was left in place for 7 days. thereafter, clean intermittent catheterization (cic) by the patient was started with 18-f urethral catheters. the cic regime was planned to be tapered over a 6-month period. the patients were instructed for performing cic, and the probable complications or problems were described. the follow-up visits were planned as monthly clinical visits for 12 months, and then, every 3 months for a maximum of 24 months. all of the patients were followed up for 24 months after their last urethrotomy. retrograde figure 1. simultaneous voiding cystourethrography and retrograde urethrography in a patient with obliterative urethral stricture. figure 2. schematic view of a flexible cystoscopy-guided internal urethrotomy procedure. combined flexible cystoscopy and internal urethrotomy—hosseini et al 186 urology journal vol 5 no 3 summer 2008 urethrography was done 6 and 12 months postoperatively, and urethrocystoscopy was done 6, 12, and 24 months, postoperatively. semiurgent urethrocystoscopy was done in patients who had any difficulty in voiding or had any problem in passing the urethral catheter. our indication for additional urethrotomies was stricture recurrence shown on retrograde urethrography and confirmed by urethrocystoscopy. we defined urethral stricture stabilization for our patients as remaining without stricture recurrence for 24 months after the last urethrotomy. the patients were observed for any complications. severe complications considered as the following: severe bleeding that needed packing or any other intervention and rectal injury or a newly built false passage in the urethra determined at end of the operation by physical examination and antegrade or retrograde cystoscopy. results a total of 43 patients underwent flexible cystoscopy-guided internal urethrotomy at our center. their mean age was 55.2 years (range, 20 to 81 years). seventeen patients (39.5%) were younger than 65 years and had stricture recurrence following posterior urethroplasty done for pelvic fracture urethral distraction. all of them denied repeat urethroplasty. the remaining 26 patients (60.5%) were older than 65 years with bulbar stricture disease. twelve of them had a history of turp and 5, a history of open prostatectomy. the external urethral sphincter was intact and away from the stricture site in all of these patients. straddle injury and catheterization trauma were the cause of disease in 2 and 7 patients, respectively. all of the 26 patients older than 65 years had severe cardiac or pulmonary disease and as a result were not able to undergo general or spinal anesthesia. local anesthesia was used in all of the patients together with intravenous administration of sedative drugs. urethral stricture stabilized in 16 patients (37.2%) with a single session of urethrotomy and 17 (39.5%) underwent 2 urethrotomies to achieve stabilization. overall, urethral stricture stabilized in 76.7% of patients with 1 or 2 internal urethrotomies within 24 months of follow-up. all second internal urethrotomies in these patients were done during the first 12 months after the first internal urethrotomy, and 12 (70.6%) of them were during the first 3 months. ten patients (23.3%) had several recurrences and needed multiple repeat internal urethrotomies, of whom 7 were younger than 65 years old. the patients did not experience any severe complications. discussion traumatic and iatrogenic obliterative urethral strictures shorter than 1 centimeter constitute a significant number of urethral strictures. visual internal urethrotomy has been used for management of short (usually less than 1 cm) urethral strictures.(4-6) some authors believe that the most cost-effective strategy for the management of short bulbar urethral strictures is to reserve urethroplasty for patients in whom a single endoscopic attempt fails.(7) however, if the guide wire cannot be passed, this procedure cannot be done safely. classically the repair of obliterative urethral strictures has been performed using perineal urethroplasty. in 1990, leonard and colleagues believed that cut-to-the-light technique could be performed easily and carried a very low morbidity rate.(1) on the other hand, cut-to-thelight technique has been condemned by some other authors because of the blind nature of the procedure and also the high complication rates.(2,3,8) dogra and colleagues believe that core through urethrotomy with contact neodymiumdoped yttrium aluminum garnet laser seems to be a safe and effective treatment option for selected strictures.(9) in their experience, the urethrotomy was guided by metal sound introduced through the suprapubic tract. thomas and associates believe that using a laser fiber as a guide wire can be a viable and effective option for gaining access through strictures when alternative methods fail. (10) nonetheless, there is no consensus on any of the above techniques and obliterative urethral stricture is still a challenge for the urologist. flexible cystoscope has been widely used for early realignment after pelvic fracture urethral distraction.(3) also, flexible cystoscopy-guided combined flexible cystoscopy and internal urethrotomy—hosseini et al urology journal vol 5 no 3 summer 2008 187 valve ablation has been reported by some authors.(11,12) although there are different papers regarding the use of flexible cystoscopy for early realignment and valve ablation, there is not much information regarding its use during internal urethrotomy. in fact, it is also completely different from the somehow old-fashioned cutto-the-light technique, because it does not have the disadvantage of blind context in the former procedures. in other words, flexible cystoscopyguided internal urethrotomy helps to perform an under-vision urethrotomy in obliterative urethral strictures shorter than 1 cm in patients who do not consent to urethroplasty or are in very poor cardiac or pulmonary conditions and as a result, are not able to stand general or spinal anesthesia. the principal surgeon can check the impression caused by the urethrotome on the monitor, while performing internal urethrotomy, so that creating false passage can be avoided. we had a good experience in flexible cystoscopyguided urethrotomy. we would stop the procedure if we could not see the impression of the uretrotome antegradely in order to avoid blind urethrotomy. its advantage over cutto-the-light method is that one can monitor the procedure from both sides and avoid creating a false passage. its advantage over putting antegrade urethral sound as a guide for internal urethrotomy is again the visual access of the surgical team to what is happening in the posterior site of the blinded urethra. our study bears no contradiction to thomas and colleagues’ study(10) and can be used when in such procedures, the laser fiber cannot be passed. in fact, this technique lets us perform a safe internal urethrotomy in suitable candidates and help us to avoid the serous complications related to the cutto-the-light procedure. conclusion flexible cystoscopy-guided internal urethrotomy is a simple, safe, and under-vision procedure for the treatment of obliterative urethral strictures shorter than 1 cm in patients who refuse to or cannot undergo posterior urethroplasty. conflict of interest none declared. references 1. leonard mp, emtage j, perez r, morales a. endoscopic management of urethral stricture: “cut to the light” procedure. urology. 1990;35:117-20. 2. turner-warwick r. prevention of complications resulting from pelvic fracture urethral injuries--and from their surgical management. urol clin north am. 1989;16:335-58. 3. husmann da, rathbun sr. long-term followup of visual internal urethrotomy for management of short (less than 1 cm) penile urethral strictures following hypospadias repair. j urol. 2006;176:1738-41. 4. hafez at, el-assmy a, dawaba ms, sarhan o, bazeed m. long-term outcome of visual internal urethrotomy for the management of pediatric urethral strictures. j urol. 2005;173:595-7. 5. hsiao kc, baez-trinidad l, lendvay t, et al. direct vision internal urethrotomy for the treatment of pediatric urethral strictures: analysis of 50 patients. j urol. 2003;170:952-5. 6. wright jl, wessells h, nathens ab, hollingworth w. what is the most cost-effective treatment for 1 to 2-cm bulbar urethral strictures: societal approach using decision analysis. urology. 2006;67:889-93. 7. mcaninch jw, santucci ra. genitourinary trauma. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 313-48. 8. tollefson mk, ashley ra, routh jc, husmann da. traumatic obliterative urethral strictures in pediatric patients: failure of the cut to light technique at longterm followup. j urol. 2007;178:1656-8; discussion 8. 9. dogra pn, aron m, rajeev tp. core through urethrotomy with the neodymium:yag laser for posttraumatic obliterative strictures of the bulbomembranous urethra. j urol. 1999;161:81-4. 10. thomas ma, ong am, pinto pa, rha kh, jarrett tw. management of obliterated urinary segments using a laser fiber for access. j urol. 2003;169:2284-6. 11. kawasaki t, takeda m, katayama y, et al. [endoscopic operation of congenital anterior urethral valve. application of flexible renoureteroscope for antegrade urethroscopy]. nippon hinyokika gakkai zasshi. 1992;83:1709-12. japanese 12. takeda m, katayama y, kawasaki t, et al. application of flexible renoureteroscope for antegrade urethroscopy in the treatment of congenital anterior urethral valve. eur urol. 1992;22:190-3. 1508 | suspected ketamine-associated lower urinary tract symptoms tzu-rong peng,1 ming-chia lee,1 ta-wei wu,1 chou-chin lan2,3 keywords: ketamine;urinationdisorders;lowerurinarytractsymptoms;etiology. introduction anincreasingnumberofcasereportsofketamineinvolvinginurinarysystemcom-plications,suchaslowerurinarytractsymptoms(luts)orulcerativecystitis,havebeencitedfromthechronicabuseofketamine.(1-7)manyhealthcareprofessionals, however,arenotawareoftheseunder-diagnosedadverseeffects.thus,wereportonacaseof suspectedketamineassociatedcontractedbladderandhydronephrosisandconductareview oftherelatedliterature. case report a45-year-oldmalewasadmittedtoouremergencydepartmentduetochangedconsciousness andrenalfunction.hehada3-yearhistoryofintranasalketamineuseandincreasedurinary frequencyandurethralpainsineoneyearago.thesymptomsbeganonlyaftertheonsetof ketamineuseandresolvedwithtreatmentoforalpropiverine15mgtwicedailyandoraltamsulosin0.2mgoncedailyandcessationofketamineuse.aftertwoyearsthen,however,the symptomsrecurredafterinhaledketaminereused.inthisadmission,urineanalysisshowed hematuriaandproteinuria.urineculturesweresterile.thebloodtestsrevealedwhiteblood corresponding author: chou-chin lan, md division of pulmonary medicine, buddhist tzu-chi general hospital, taipei branch, taiwan. tel: +886 2 6628 9779 fax: +886 2 6628 9009 e-mail: bluescopy@yahoo.com.tw received november 2012 accepted december 2012 1 department of pharmacy, buddhist tzu chi general hospital, taipei branch, taiwan. 2 department of internal medicine, buddhist tzu chi general hospital, taipei branch, taiwan. 3 school of medicine, tzu chi university, hualien, taiwan. case report case report 1509vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l ketamine and luts | peng et al cell20,200/µl,neutrophilbands3%,neutrophilsegments 88%, c-reaction protein 21.25 mg/dl, serum creatinine 11.8mg/dl,bloodureanitrogen106mg/dl,sodium104 mmol/l,potassium6.6mmol/l,alkalinephosphatase944 iu/l,gamma-glutamyltransferase1998iu/l,totalbilirubin 2.46mg/dl,directbilirubin2.25mg/dl,lipase1,165iu/l, andamylase212iu/l.thecomputedtomographyimaging oftheabdomenshowedbilateralhydronephrosisandsmall bladdercapacityandnosignofpancreatitis.besides, the echoimagingofabdomenrevealedgallbladdersludge.afull screeningconfirmedtheexclusionofothercausesofliver disease.ketamineassociatedlowerurinarytractsyndrome wasdiagnosedandketamineassociatedgallbladdersludge wassuspected(figure).thehemodialysisandureteraldouble-jplacementwereperformedforpoorrenalfunctionand bilateralhydronephrosis.oralsilymarinwasgivenforpoor liverfunction.intravenouslevofloxacin750mgsingledose and500mgeveryotherdaywasadministratedfortreating infection.aftersevendays,hisrenalandliverfunctionimproved,serumcreatinine1.7mg/dl,bloodureanitrogen38 mg/dl,totalbilirubin0.54mg/dl,directbilirubin0.52mg/ dl, gamma-glutamyltransferase 1,617 iu/l, lipase 1,405 iu/l,andamylase328iu/l,butnosignofpancreatitis,so hewasdischargedhomeduetostablecondition.healso wasreferredtodrugrehabilitationcenterfortheproblemof ketamineabuse. discussion ketamine,ann-methyl-d-asparticacid(nmda)receptor antagonist,hasbeenusedinveterinarymedicineandforanesthesiapurposesmorethan30years.ithasbeenabusedas arecreationaldruginnightclubsduetotheeffectsofhallucination and “near-death experiences”.(8) however, the detrimentaleffectsofketaminearenotunderstoodbymany recreationalusers,inparticularonthecentralnervoussystem, respiratory and cardiovascular systems. since 2007, severalcasereportsofketamineassociatedlutshavebeen described,(1-7) all patients had a history of ketamine use. the clinical presentations of luts include dysuria, frequenturination,smallvolumevoidsandpainfulhematuria. (1,8)inaddition,somereportsindicatedthatthecomputed tomographyimagingoftheabdomenshowedasmallbladder capacity and unilateral or bilateral hydronephrosis.(1,4,8) ourpatient’sluts,asmallbladdercapacityandbilateral hydronephrosisareconsistentwithpreviousreports.cystoscopyandbiopsywerebothrefusedbythepatient.however thelutsofourpatientresolvedaftercessationofketamine and recurred when he re-inhaled ketamine. the naranjo probabilityscale (7 points) indicateda probable relationshipbetweenketamineandlutsinthispatient.(10)tsaiand colleaguesdemonstratedthatthetimeofonsetoflutsafterketamineabuserangedfrom1monthtoafewyears.(5) inourpatient,theonsetofsymptomswasabout1-2years andthedosesofketamineareunknown.themechanismof ketamineassociatedlutsisstillnotclear.highconcentrationsofketamineanditsmetabolitescanbedetectedinthe urineofpatientsusingketamine.(11)thedirecttoxicityof ketamineanditsmetabolitesmaycausesignificantbladder irritationandkidneydamage.(4,12)attheearlystageofthe disease,ketaminecessationmayresolvetheluts.cheung andcolleagueshaveindicatedthesubjectswhohadceased ketamineuseforlessthan3monthshadsignificantlymore urinarysymptomsthanthosewhohadstoppedfor3months ormore.however,thosepersonswhoabusedketaminefor 2yearsormoreandceasedforlessthan3months,endured significantlypoorerqualityoflife.(13) in addition, pentosan polysulfatesodium,antihistamine,andcorticosteroidmay helpalleviate theirritablevoidingsymptoms.asthediseasebecomesmoresevere,suchaspainfulhematuria,or impairedrenalfunction,enterocystoplastymayberequired. itisimportanttonotethatdelayeddiagnosisandintervenfigure . the computed tomography imaging of the abdomen showed bilateral hydronephrosis (a), small bladder capacity (b) and gallbladder sludge (c). 1510 | tionwilleventuallyleadtoirreversiblerenaldamage.(4,12) thebiliaryabnormalityduetochronicketamineuseisfully reversible,soloandcolleaguessuggestthatbiliarystentingshouldbeavoidedunlessabsolutelynecessary.(13) accordingtoourpatient,ketamineassociatedurinarytractand biliaryabnormalitycouldappearsimultaneously.therefore, ketamineabuseshouldbeconsideredasapotentialcauseif patientshaveunexplainedcholestaticliverfunctiontestsand urinarytractsyndrome.healthcareworkersshouldbealert tothisdiseaseandatriskpatientsshouldbeinformedabout thesepossiblesideeffects. conflict of interest none declared. references 1. shahani r, streutker c, dickson b, stewart rj. ketamine-associated ulcerative cystitis: a new clinical entity. urology. 2007;69:810-2. 2. chu ps, ma wk, wong sc, et al. the destruction of the lower urinary tract by ketamine abuse: a new syndrome? bju int. 2008;102:161622. 3. chen ly, chen kp, huang mc. cystitis associated with chronic ketamine abuse. psychiatry clin neurosci. 2009;63:591. 4. chiew yw, yang cs. disabling frequent urination in a young adult. ketamine-associated ulcerative cystitis. kidney int. 2009;76:123-4. 5. tsai th, cha tl, lin cm, et al. ketamine-associated bladder dysfunction. int j urol. 2009;16:826-9. 6. middela s, pearce i. ketamine-induced vesicopathy: a literature review. int j clin pract. 2011;65:27-30. 7. nomiya a, nishimatsu h, homma y. interstitial cystitis symptoms associated with ketamine abuse: the first japanese case. int j urol. 2011;18:735. 8. mason k, cottrell am, corrigan ag, gillatt da, mitchelmore ae. ketamine-associated lower urinary tract destruction: a new radiological challenge. clin radiol. 2010;65:795-800. 9. naranjo ca, busto u, sellers em, et al. a method for estimating the probability of adverse drug reactions. clin pharmacol ther. 1981;30:239-45. 10. moore ka, sklerov j, levine b, jacobs aj. urine concentrations of ketamine and norketamine following illegal consumption. j anal toxicol. 2001;25:583-8. 11. shahani r, stewart rj. reply to letter-to-the-editor, re: shahani r, streutker c, dickson b, et al: ketamine-associated ulcerative cystitis: a new clinical entity. urology 69: 810-812, 2007. urology. 2008;71:987. 12. cheung ry, chan ss, lee jh, pang aw, choy kw, chung tk. urinary symptoms and impaired quality of life in female ketamine users: persistence after cessation of use. hong kong med j. 2011;17:26773. 13. lo rs, krishnamoorthy r, freeman jg, austin as. cholestasis and biliary dilatation associated with chronic ketamine abuse: a case series. singapore med j. 2011; 52:e52-5. case report urological oncology the association between gelsolin-like actin-capping protein (capg) overexpression and bladder cancer prognosis samira bahrami1, ali gheysarzadeh2, mehdi sotoudeh3, mojgan bandehpour4, reza khabazian3, hakimeh zali5, mehdi hedayti6, abbas basiri3*, bahram kazemi1,4* purpose: muscle-invasive bladder cancer (mibc) is associated with disease progression and metastasis leading to poor prognosis. current chemotherapy approaches have not adequately increased patient survival. therefore, in this study, tissue proteome of patients with mibc was performed to introduce possible protein candidates for bladder cancer prognosis as well as targeted therapy. materials and methods: after obtaining tumoral and non-tumoral tissues of mibc patients, and normal bladder tissue of non-bladder cancer patients, two-dimensional gel electrophoresis (2-de) and liquid chromatography-mass spectrometry (lc-ms/ms) were used to analyze tissue proteome. gelsolin-like actin-capping (capg) protein was further examined using real-time pcr and western blot analysis. results: the 2-de analysis and lc-ms/ms identified capg protein as differentially expressed protein in tumor and non-tumor tissues of bladder cancer compared with normal tissues. western blot analysis showed the capg overexpression in tumor tissues compared with normal tissues in a stage-dependent manner. correspondingly, realtime pcr showed a higher mrna expression in tumoral bladder tissues than normal ones. capg mrna overexpression had significantly a positive relation with tumor size (p = 0.019), the tnm staging (p = 0.001), and tumor differentiation (grade) (p = 0.006). patients with lower levels of capg had higher recurrence-free survival in comparison with patients with higher levels (p = .027). conclusion: capg overexpression was correlated with size, stage, grade, and shorter time to recurrence of bladder cancer. therefore, capg overexpression could be related to poor prognosis of bladder cancer. these results suggest that capg may be considered as a prognostic factor and also for targeted therapy in bladder cancer. moreover, it could be concluded that cancerous and noncancerous tissues of mibc have the same protein expression because 2-de results showed the capg expression in cancer and adjacent cancer tissues of bladder while capg was not detectable in normal tissues of bladder. keywords: bladder cancer; capg; prognosis; proteome; targeted therapy introduction bladder cancer is the ninth most common malignant cancer and the second most frequent cause of death in genitourinary malignancies(1). worldwide, it is the fourth most common cancer in men and its incidence rate is remarkably increasing in women(2). in 2018, it lead to the diagnosis of approximately 81,190 new cases and it is the cause of 17,240 deaths in usa(3). the 1biotechnology department, school of advanced technologies in medicine, shahid beheshti university of medical sciences, tehran, iran. 2clinical microbiology research center, ilam university of medical sciences, ilam, iran. 3department of urology, urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 4cellular and molecular biology research center, shahid beheshti university of medical sciences, tehran, iran. 5medical nanotechnology and tissue engineering research center, school of advanced technologies in medicine, shahid beheshti university of medical sciences, tehran, iran. 6cellular and molecular endocrine research center, institute for endocrine sciences, shahid beheshti university of medical sciences, tehran, iran. 7department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: department of urology, urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. tel: +98 (21) 22567222, email: basiri@unrc.ir ** cellular and molecular biology research center, shahid beheshti university of medical sciences, tehran, iran.tel: +98-21-22439957, fax: (+98)21 89784665, email: bahram.kazemi.demneh@gmail.com. received october 2019 & accepted april 2020 5-year bladder cancer survival is 77%, but it reduces based on the stage and type of bladder cancer (3). more than 90% of bladder cancers are urothelial carcinomas. approximately 75% of these are the non-muscle-invasive bladder cancers (nmibc) and 25% are the muscle-invasive bladder cancers (mibc)(4). bladder cancer diagnosis is based on urine cytology and cystoscopy procedures. however, urine cytology has a low sensiurology journal/vol 18 no. 2/ march-april 2021/ pp. 186-193. [doi: 10.22037/uj.v0i0.5664] tivity to discriminate between mibc and nmibc and cystoscopy is an expensive and invasive procedure(5). recurrence is the most prominent feature of bladder cancer. 50-70% of nmibcs recur, 10-35% progress to mibcs, and 50% of mibcs relapse(6). therefore, bladder cancer is one of the cancers with the most expensive treatment cost(7). radical cystectomy is the gold standard treatment for mibc patients with administration of chemotherapy following metastasis or recurrence. however, chemotherapy does not adequately increase patient survival(8), hence it is of great clinical importance to find new and efficient markers to improve bladder cancer prognosis and efficacy of treatment. proteins reflect cell behavior better than genes and rna transcripts, are the functional state of molecular alteration during development of the disease, and are final targets for pharmaceutical industries(9). therefore, tissue proteomic profiling of human clinical samples can be a simple alternative approach to determine biomarker candidates. changes in these tissue proteins are directly associated with cancer development(10). today, the number of studies investigating tissue proteome of bladder cancer and capg overexpression-bahrami et al. parameter capg mrna expression1 p value 2 no. of cases ≤mean >mean age (year) .51 ≥ 70 29 (47.5%) 20 (32.8%) 9 (14.75%) <70 32 (52.5%) 16 (26.2%) 16 (26.2%) sex .93 male 39 (64%) 24 (39.3%) 15 (24.6%) female 22 (36%) 12 (19.67%) 10 (16.4%) tumor size (cm) .009 ≥ 2 31 (50.8%) 14 (31.37%) 17 (27.86%) < 2 30 (49.2%) 22 (36%) 8 (13.1%) tnm stage .001 0 14 (22.9%) 13 (21.3%) 1 (1.64%) i 12 (19.6%) 7 (11.47%) 5 (8.2%) ii 10 (16.3%) 7 (11.47%) 3 (4.9%) iii 13 (21.3%) 6 (9.83%) 7 (11.47%) iv 12 (19.6%) 3 (4.9%) 9 (14.7%) tumor differentiation3 .006 well 24 (39.3%) 20 (39.3%) 4 (6.55%) moderate 23 (37.7%) 11 (18%) 12 (19.7%) poor 14 (22.9%) 5 (8.2%) 9 (14.7%) table 1. the relationship between the capg mrna level in the tumor tissues and the demographic features 1: the mrna expression was quantified based on gapdh in tumor and adjacent normal tissues using 2-∆∆ct from at least 2 experiments. the level of capg mrna expression had normal distribustion using kolmogrov-smirnov test and we used mean as the cut-off 2: p-value was calculated from independentsamples t test and one-way anova. the comparison was between two groups of each parameter such as age (older and younger than 70), sex (male and female), etc… 3: tukey’s post hoc showed that there was also a significant difference in capg mrna level between grade1 with grade 2 and 3” figure 1. flow chart of the current study. urological oncology 187 vol 18 no 2 march-april 2021 188 bladder cancer is increasing(10-17). the results of these studies introduced novel diagnostic markers like transgelin 2 (tagln2), stathmin 1 (stmn1)(10) or potential therapeutic targets like phosphoglycerate mutase 1 (pgam1)(11). besides, multiple cellular alterations appear to be involved in the development of bladder cancer. these alterations possess various frequencies in a specific geographic location because of genomic and proteomic heterogeneity of bladder cancer in a various geographical pattern(18). in this study, a proteomic approach was used to detect the possible prognostic marker in patients with bladder cancer. our results showed that gelsolin-like actin-capping (capg) protein overexpression is related to the poor prognosis of bladder cancer. therefore, capg has the potential to apply as a prognostic marker and therapeutic target for bladder cancer. materials and methods study design the current study was designed in three steps; a, tissue proteomic of normal bladder and patients with bladder. b, validation of capg expression in mrna and protein level c, recurrence-free survival analysis the flow chart of this study is depicted in figure 1. tissue proteomic study sample collection the patients signed informed consent for study participation. the tumor and non-tumoral samples were obtained from 9 mibc patients who underwent radical cystectomies at labbafinezhad hospital (tehran, iran) and normal samples were obtained from patients with benign prostatic hyperplasia (bph). the pathological features of tumor samples based on the tumor node metastasis (tnm) staging system were shown in supplementary table 1. in the validation process, real-time pcr and western blotting were performed on samples from 61 patients who were managed by transurethral resection bladder (turbt) or radical cystectomy at labbafinezhad hospital (june 2014march 2016). the pathologic features of patients including the histology, grade, tumor size, and tnm staging were confirmed by 2 pathologists of the labbafinezhad hospital. these 61 patients had no chronic or acute inflammatory diseases or other malignancies. moreover, they did not previously receive any chemotherapy or radiotherapy. patient demographic features were displayed in table 1. samples were immediately placed in liquid nitrogen and frozen at -70°c. all procedures performed in this study involving human participants were in accordance with the ethical standards of the local ethics committee of urology and nephrology research center (ethic number: 94040401-08) and with institutional and/or national research committee of the 2013 helsinki declaration. figure 2. the second sentence should be correct as following, the representative 2-de commassie brilliant blue-stained gel images of bladder tissues. normal (a), non-tumoral tissue (b), and mibc tissue (c). figure 3. western blotting analysis for capg protein expression. (a) bands of western blotting in bladder cancer tissues in comparison with adjacent normal bladder tissue. (b) capg protein level was evaluated by identifying intensities of capg bands in relation to β tubulin bands using imagej software. * and ** stand for the statistical difference with normal tissues using t-test (*p < 0.05, and **p < 0.005). tukey’s post hoc also showed that there were significant differences between stage 0 with sage 3 and 4 (p < 0.05). bladder cancer and capg overexpression-bahrami et al. two-dimensional polyacrylamide gel electrophoresis (2-de) each sample was placed in a mortar and ground with a pestle under liquid nitrogen. approximately 100 mg of the ground sample was lysed in 700 μl lysis buffer [7m urea, 2m thiourea, 4% chaps, 50 mm dtt, 40 mm tris, .2% bio-lyte (ph 3-10), 1 mm pmsf, .1% anti-protease cocktail, dnase 1 unit/μl (fermentas, 5 μl per 1 ml of lysis buffer), and 10 mg/ml rnase (fermentas, 5 μl per 1 ml of lysis buffer)]. the samples were incubated for 1 h at room temperature with gentle vortexing each 15 min. subsequently, the samples were sonicated for 3 cycles (20 khz, 30 s/cycle). the mixture was then centrifuged at 18000 × g for 20 min at 4°c to remove any debris. the protein extracts were collected, aliquoted, and stored at -70°c until further analysis. we used the bradford assay with bovine serum albumin (bsa) as the standard to determine the protein concentrations(19). isoelectric focusing (ief) was performed on 17 cm immobilized ph gradient (ipg) strips with a nonlinear range of ph 3-10 (bio-rad, usa). ipg strips were passively rehydrated overnight by loading approximately 1 mg of protein extracts to a 300 μl total volume of rehydration buffer that included 7 m urea, 2 m thiourea, 4% chaps, 0.2% bio-lyte (ph 3-10), 50 mm dtt, and a trace amount of bromophenol blue. the focused program for the protean ief cell (bio-rad) consisted of a linear voltage increase from 0 to 250 v for 20 min, followed by an additional linear increase to 10000 v, and maintenance at 10000 v for a total of 50000 vh. next, the ipg strips were equilibrated for 15 min in equilibration buffer [50 mm tris–hcl (ph 8.8), 6 m urea, 20% glycerol, 2% sds, .01% bromophenol blue, and 2% dtt], alkylated for an additional 15 min in equilibration buffer devoid of dtt, and supplemented with 2.5% iodoacetamide. in the second dimension, electrophoresis of the reduced and alkylated protein samples was performed by placing the equilibrated strips on top of the home-made 12% sds-page gel slabs and sealed with 1% agarose. the standard laemmli buffer system was used for electrophoresis at the following running conditions: 16 ma/gel for 30 min and 24 ma/gel for approximately 5 h at 18°c until the bromophenol blue located 1 cm above the bottom of the gel. the gels were stained by a sensitive colloidal coomassie brilliant blue g 250 (ccb) method (20). image analysis of the 2-de results and protein identification the gel images were prepared using a densitometer gs-800 scanner (bio-rad, usa) at a resolution of 300 dpi. the images were stored as tif files. spot detection and matching were carried out using progenesis pg200 software (nonlinear dynamics, newcastle-upon-tyne, uk). the spots were automatically detected by the software and visually inspected. statistical analysis of protein variations was performed in 2-de gels prepared from each group using the student’s t-test on vol% of matched spots with more than 1.5-fold expression changes. each of favorite spots was isolated and digested with trypsin then proteins were identified using electrospray lc-ms/ms (proteomics international laboratories ltd company, australia). validation in mrna and protein level western blot analysis protein samples (70 μg) were diluted in 2x sample buffer (50 mm tris-base, 2% sds, 10% glycerol, .1% bromophenol blue, and 5% β-mercaptoethanol), heated for 5 min at 95°c, and electrophoresed on 12% sds-page at 100 v. the separated proteins were transferred to pvdf membranes using transfer buffer (25 mm trisbase, 190 mm glycine, 20% methanol, ph 8.3). the membranes were blocked overnight in blocking buffer (5% skim milk, 5% glycerol, and .05% tween 20 in tbs) at 4°c. they were rinsed with ttbs buffer (100 mm tris-hcl, .9% nacl, .05% tween-20, ph 7.5) for 10 min, then probed with the following primary antibodies: mouse monoclonal antibody for capg; sc-1664208 and mouse monoclonal antibody for β tubulin; sc-166428 for 2 h at 4°c. the membranes were washed 3 times with ttbs, followed by incubation with the following hrp-conjugated secondary antibody: goat anti-mouse igg h&l (ab-6789) at 25°c for 2 h. the proteins were detected using dab as the chromogen substrate. once we visualized proteins on the membranes, they were scanned and processed with imagej software. then, the results were graphed with prism7 software. quantitative real-time polymerase chain reaction (qrt-pcr) total rna from surgically resected tissues was extracted using the trizol extraction reagent (gibco, life technologies) according to the manufacturer's instruction. synthesis of cdna was performed using the takara cdna synthesis kit (takara inc., kyoto, japan) based on the instruction provided by the manufacturer. the conditions to generate cdna were as follows: incubation of the reaction at 85°c for 1 min and 37°c for 15 min. the cdnas were subjected to sybr green (qiagen, hilden, germany) according to the standard quantitative real-time rt-pcr analysis using an abi 7500 sequence detection system (applied biosystems). all reactions were carried out in triplicates. the conditions of real-time pcr were as follows: one cycle at 50˚c for 2 min, and 95˚c for 10 min, followed by 40 cycles of denaturation at 95˚c for 15 sec and annealing extension at 55˚c for 1 min. the sequence of primers was shown in supplementary table 2. according to the instruction provided by the manufacturer, the melting curve was produced at the end of each examination to check the specificity of amplification. relative gene expression was calculated using the 2-∆∆ct method and resulted data was normalized using gapdh as an internal control. ultimately values were presented as mean ± sem. statistical analysis statistical analysis was carried out using the statistical software package spss version 20.0 (spss inc., chicago, il). the t-test was performed to estimate the significant differences between the tumor and normal bladder tissues for western blotting and qrt-pcr. the anova test for analysis of variance followed by a tukey’s post hoc test was performed to evaluate differences between the capg expression and stages and grades of bladder cancer. normality assumption was done by kolmogorov-smirnov test. the kaplan–meier analysis and cox proportional hazards model was used to evaluate the survival data; p values <.05 were considered statistically significant. the proportional hazard assumption was tested. bladder cancer and capg overexpression-bahrami et al. urological oncology 189 vol 18 no 2 march-april 2021 190 results tissue proteome according to 2-de, image analysis, and lc-ms/ms the proteins extracted from the tumoral, non-tumoral tissues of mibc patients, and normal tissues of the bladder and then were analyzed using 2-de examination. 2-de commassie brilliant blue-stained gel of bladder tissues were represented in figure 2. progenesis pg200 software gel image analysis recognized several differentially expressed proteins among these three different types of samples. we selected proteins which were not detectable in the normal tissues. these spots were excised, digested, and then identified using lcms/ms. one of the favorite proteins at approximately pi 5 to 9 mw 38 kda in the 2-de of tumor tissue was identified by lc-ms/ms as capg protein. based on the 2-de analysis, western blotting and real time pcr urological oncology 70 were only performed between two groups of mibc tissues and normal tissue samples. expression pattern of capg protein by western blot analysis western blotting was performed to compare capg protein expression between tumor and normal tissues in all 61 samples and also to confirm the expressional pattern of capg obtaining from 2-de analysis. the results showed that capg protein was significantly overexpressed in tumoral tissues, while 2-de analysis showed the lack of capg expression in normal tissues. it might be due to the low sensitivity of the 2-de method. the relative protein expression of capg (capg expression values were divided to β tubulin values) in bladder cancer tissues was significantly higher than that in normal bladder tissues (p < 0.05). capg protein level was 1.09 ± 0.1 for stage 0 (ta or tis), 1.72 ± 0.31 for stage 1, 1.86 ± 0.15 for stage 2, 2.21 ± 0.62 for stage 3, and 2.53 ± 0.38 for stage 4. furthermore, tukey’s post hoc analysis indicated that capg protein level was significantly different between stage 0 with stage 3 and stage 4 (p < 0.05; figure 3). evaluation and validation of mrna expression level of capg in bladder cancer tissues and their normal adjacent tissues western blot analysis indicated that capg overexpressed in mibc tumor in comparison with normal tissues. further investigation using qrt-pcr was performed on 61 bladder cancer samples. the relative mrna expression of capg also showed that mrna level of capg significantly correlated with tnm staging (p < .05). for example, the mrna level increased from 1.37 ± 1.24 to 2.43 ± 1.31, 2.66 ± 2.11, 3.33 ± 2.40, 4.35 ± 1.78 for stage 0 (ta or tis), 1, 2, 3, and 4 respectively. in addition, tukey’s post hoc analysis showed that there were significant differences between stage 0 with sage 3 and 4 as well as stage 1 with stage 4. (p < 0.05, figure 4). the association between mrna level of capg and clinicopathological characteristics the relationship between capg mrna level and clinicopathological characteristics of patients with bladder cancer was presented in table 1. the high expression of figure 4. relative expression of capg mrna in different stages of bladder cancer using qrt-pcr in 61 bladder cancer cases. the results displayed that capg level was remarkably stage dependent. mrna level of each sample was evaluated through 2 −∆∆ct and normalization according to gapdh as the internal control. ** and *** stand for the statistical difference with normal tissues using paired t test (**p < .005, and ***p < .001). tukey’s post hoc also showed that there were significant differences between stage 0 with sage 3 and 4 as well as stage 1 with stage 4. (p < 0.05). figure 5. kaplan-meier survival curve by capg expression. high level of capg expression is significantly correlated with poor recurrence free survival in patients with bladder cancer (n = 41, log-rank test: p = .027). the hazard ratio=2.21, 95% ci: 1.1-4.48 and p value = 0.038, reference group: capg greater than mean. bladder cancer and capg overexpression-bahrami et al. capg was remarkably related to tumor size (p = .009), the tnm staging (p = .001), and tumor differentiation (p = .006), whereas capg expression level of bladder cancer tumors had no significant association with age and gender. the relationship between the capg mrna expression and survival time we retrieved data of recurrence of patients for survival analysis, necessary data were available for 41 out of 61 patients (20 patients of this study were not visited again and their information was not obtained). tumor recurrence were considered as any disease observation through following-up evaluation every 3 months. recurrence definition is dependent on the type of bladder cancer. in non-muscle invasive or local recurrence, cancer progresses only in the inner layer of bladder (turbt post-management). but in muscle invasive and distant recurrence, cancer progresses within the muscle layer of bladder and other parts of body, respectively (radical cystectomy, radiotherapy, or chemotherapy post-management). patients with recurrence bladder cancer were classified into two groups (n=41), based on the mean of the capg mrna level. kaplan-meier analysis showed that high expression of capg was significantly correlated with shorter recurrence-free survival time (p = .027) (figure 5). patients with low expression (n=18) of capg had a higher recurrence-free survival (24.26± 1.05 months) than patients with high expression (n=23) of capg (21 ± 1.6 months). the hazard ratio for capg expression was 2.21, 95% ci: 1.1-4.48 and p value was 0.038. discussion bladder cancer as a highly frequent disease is associated with significant morbidity and mortality(3). although in recent years there is substantial progress in the knowledge of molecular alteration occurring in bladder cancer, but mibc still is accompanied by poor prognosis(21). therefore, determining markers is critical to improve prognosis, diagnosis, and treatment of mibc. in this study, we aimed at comparing the tissue proteome of mibc patients with non-tumor and normal tissues to discover possible prognostic protein candidates. our results showed that capg overexpression is associated with a poor prognosis of bladder cancer. capg is a member of the gelsolin/villin family which binds to actin and regulates the structure of cytoplasm and the nucleus in a calcium-dependent manner. it has been determined that cytoplasmic capg affects cell motility. under normal situations, it is presumed that capg has a redundancy effect on cells and inactivation of this protein displays only mild defects over cell function. under the pathologic conditions, capg controls cell invasion by modulating turnover of actin filaments (22). therefore, our study in line with previous studies has shed some light on capg as a novel target for bladder cancer therapy. in our study, the 2-de analysis showed that capg expression was too low to be detectable in normal samples while capg expression was identified in cancer and non-cancerous tissues of mibc. it confirms the results that cancerous tissue affects the normal adjacent tissue (nat) and nat is an intermediate state between tumor and normal(23). western blot analysis indicated that capg under-expressed in normal samples compared to the mibc samples. this could be attributed to the higher sensitivity of western blot compared to 2-de analysis in the identification of small amounts of protein. our results also showed that capg increased in a stage-dependent manner in mrna level in patients with bladder cancer. we demonstrated that capg overexpression is related to shorter recurrence survival (p = .027). although three months difference in recurrence-free survival between patients with low and high expression of capg has not significant clinical value currently, but the 21 months recurrence survival time can provide a vision that patients with higher capg expression should be controlled with more severe surveillance schedule and close follow up because it was shown that the high recurrence rate during the first two years of diagnosis necessitates an intense surveillance program(24). previously it has been shown that capg acts as an oncogene and is overexpressed in several types of cancers including breast cancer(25), hepatocellular carcinoma (26), colorectal cancer, gastric cancer, lung cancer, pancreatic cancer(27), glioblastoma(22), and ovarian cancer(25). this overexpression is associated with dissemination and invasion of these tumors. therefore, capg could be considered as a diagnostic and prognostic marker in these cancers. it is important to mention that when we started this study, there was no literature about the capg expression in bladder cancer in spite of capg importance in other cancers. however, in parallel with our results, one report was published about the oncogenic function and signaling pathway of capg in bladder cancer. zhaojie et al. demonstrated that capg has an oncogenic function in bladder cancer. they showed that capg promote tumor development and emt in vitro and in vivo through inactivating the hippo tumor suppressor signal pathway(28). these results strongly confirm our findings that capg is related to poor prognosis of bladder cancer. other investigations have shown that capg inhibition and disruption of the capg interaction with actin decreased invasiveness of breast tumor cells in an immune-deficient mouse(29). moreover, repression of capg gene activity in pancreatic and prostate cancer cell lines has been shown to lead to a remarkable decrease in cell motility and metastasis(30). therefore, capg could also be examined as a possible target for the treatment of bladder cancer. conclusions in conclusion, the present study clearly revealed the capg overexpression in tumor and non-tumor tissues of bladder cancer compared with normal tissues. it could be concluded that cancerous tissues possibly affect the adjacent tissues of bladder or this overexpression is the urothelial tendency of the affected patients. moreover, capg mrna expression was significantly stage-dependent and in a negative correlation with recurrence-free survival time. this overexpression was related to the poor prognosis of bladder cancer. this study introduced capg as a possible prognostic marker and therapeutic target for bladder cancer. however, more samples and functional tests would be needed to apply capg in clinics and in treatment of bladder cancer. acknowledgment this study was adapted from a thesis for ph.d. degree of samira bahrami. it was conducted in cellular and molecular biology research center, shahid beheshbladder cancer and capg overexpression-bahrami et al. urological oncology 191 vol 18 no 2 march-april 2021 192 ti university of medical sciences, tehran, iran. this study was financially supported by urology nephrology research center [grant no. 940041] from the national institute for medical research development, iran. conflict on interest the authors declare no conflict of interest. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2017. ca: ca cancer j. clin. 2017;67:7-30. 2. scosyrev e, noyes k, feng c, messing e. sex and racial differences in bladder cancer presentation and mortality in the us. cancer. 2009;115:68-74. 3. cumberbatch mg, noon ap. epidemiology, aetiology and screening of bladder cancer. transl. androl. urol. 2019;8:5. 4. edge sb, compton cc. the american joint committee on cancer: the 7th edition of the ajcc cancer staging manual and the future of tnm. ann. surg. oncol. 2010;17:1471-4. 5. zhou y, song r, ma c, et al. discovery and validation of 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and promotes tumorigenesis and epithelialmesenchymal transition via the hippo signaling bladder cancer and capg overexpression-bahrami et al. pathway in human bladder cancer. ther. adv. med oncol. 2019;11:1758835919841235. 29. van impe k, bethuyne j, cool s. a nanobody targeting the f-actin capping protein capg restrains breast cancer metastasis. breast cancer rese. 2013;15:r116. 30. li b, guo k, li c. influence of suppression of capg gene expression by sirna on the growth and metastasis of human prostate cancer cells. genet. mol. res. 2015;14:1576978. bladder cancer and capg overexpression-bahrami et al. urological oncology 193 1081vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l evaluation of sexual function in women with rheumatoid arthritis burhan coskun,1 belkis nihan coskun,2 gokhan atis,3 erbil ergenekon,4 kamil dilek5 purpose: to evaluate the link between rheumatoid arthritis (ra) and female sexual functioning. material and methods: a total of 32 women with ra and 20 healthy age matched controls were enrolled in this study. the participations are asked to complete female sexual function index (fsfi), the short form 36 (sf-36) health survey and beck depression inventory (bdi) questionnaires. results: the groups were comparable in terms of demographic characteristics. the women with ra represented significantly worse sexual functioning in category of desire, arousal, lubrication, orgasm, satisfaction domain and total fsfi score compared with healthy women (p = .0001, p = .0001, p = .0001, p = .0001, p = .022 and p = .0001, respectively). the mean bdi scores for the patients with ra were greater than control group (p = .036). women with ra also had significantly lower quality of life (qol) parameters: physical functioning, limitations due to physical health, pain, general health, vitality and limitations due to emotional problems compared with healthy women (p = .0001, p = .0001, p = .028, p = .002, p = .001 and p = .0001, respectively). conclusion: the present study shows that a significant percent of patients with ra had sexual dysfunction and also deterioration in qol. keywords: arthritis; rheumatoid; female; sexual dysfunction; quality of life. corresponding author: burhan coskun, md doburca cad, başak sitesi, c blok no 4, bursa, turkey. tel: +90 533 646 0323 fax: +90 216 521 8608 e-mail: drburhancoskun@ yahoo.co.uk received july 2012 accepted january 2013 1department of urology, inegöl hospital, bursa, turkey. 2department of internal medicine, school of medicine, uludag university, bursa, turkey. 3department of urology, göztepe training and research hospital, istanbul, turkey. 4department of urology, şişli training and research hospital, istanbul, turkey. 5department of rheumatology, school of medicine, uludag university, bursa, turkey. sexual disfunction and infertility 1082 | introduction the rheumatoid arthritis (ra) is a prevalent, idi-opathic, autoimmune disease, which is more com-mon in women with a prevalence of about %1 worldwide.(1) the characteristic feature of ra is persistent inflammatory synovitis in peripheral joints, which usually distributes symmetrically. the synovial inflammation may lead to cartilage damage, bone erosions and changes in joint integrity. finally, all these pathologies may cause various degrees of disability.(2,3) ra has deleterious effects on social, economic, psychological and sexual aspects of the patient’s life.(3) female sexual dysfunction (fsd) is a common health problem affecting 20% to 50% of population and prevalence of this condition correlates with age. it has a profound impact on quality of life (qol) and interpersonal relationships.(4-7) several factors such as endocrine, social, anatomical and psychological diseases may cause fsd and some specific causes like pain, fatigue, stiffness, functional impairment, depression, negative body image, reduced libido and drug treatment are also responsible in patients with rheumatic diseases.(8,9) in this study we aimed to evaluate sexual functions and qol of female subjects with ra and to compare them with voluntary healthy controls. materials and methods a total of 50 sexually active women with diagnosis of ra for more than one years and 20 age matched voluntary healthy women (controls) were included in the study. all of the subjects in both groups were married and patients were followed and treated at outpatient department of rheumatology clinic of uludağ university. the patients with ra were diagnosed according to the 1987 revised criteria for classification of ra of american college of rheumatology. (10) the local ethical committee approved the study. an informed consent was obtained from all subjects with ra and control group. demographic characteristics including age, educational attainment level, and occupational status were assessed in all women. participants who had coexisting diseases or condition resulting in sexual dysfunction (cardiovascular disease, neurological disease, major psychiatric disease, diabetes, previous pelvic surgery, menopause, hysterectomy, premature ovarian failure etc.) and had no sexual disfunction and infertility table 1. demographic characteristics of the patients with rheumatoid arthritis and control group. variables patients with ra (n = 32) control group (n = 20) p age* 38.43 ± 6.94 39.30 ± 5.52 .630 number of pregnancy* 1.93 ± 1.18 1.75 ± 1.25 .603 education status n (%) .383 primaryhigh school 12 (37.5) 5 (25) university 20 (62.5) 15 (75) occupational status n (%) .276 employment 29 (90.625) 20 (100) unemployment 3 (9.375) 0 (0) smoking history n (%) .747 current 8 (25) 4 (20) neverex-smoker 24 (75) 16 (80) alcohol consumption n (%) 1.000 yes 3 (9.375) 2 (10) no 29 (90.625) 18 (90) physical activity n (%) .754 daily-several times in a week 8 (25) 6 (30) once in a week –rarelynever 24 (75) 14 (70) data are presented as number/total (%), fisher’s exact test or *student’s t-test. key: sd, standard deviation; ra, rheumatoid arthritis. 1083vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l sexual activity within the past month were not included in the study. all women recruited into the study had a stable, heterosexual relationship, and were sexually active. five patients found to have coexisting disease, 6 patients did not have sexual intercourse in past one month, 4 patients did not want to reply the questions because of embarrassment, 3 of the responders did not reply the questions properly and 18 patients are excluded from study. turkish version of fsfi, which has been previously validated in the turkish language by turkish society of andrology(5,6) was used for evaluation of fsd. fsfi includes 19-item questionnaires, which assesses sexual functioning during the last 4 weeks. the specific subdomains including quality of desire, arousal, lubrication, orgasm, satisfaction and degree of pain is evaluated in fsfi. each domain scores and overall fsfi scores of the women were compared between two groups. the overall fsfi score was 2-36. sexual dysfunction were considered in a total score of less than 26.55.(11) beck depression inventory (bdi), a 21-item self-reported inventory, was previously adapted for the turkish population.(12,13) each of 21 questions is scoring between 0 and 3 (absent to severe), and the highest possible total score for the whole test is 63. psychiatric assessment was performed by the bdi and depression was diagnosed when the bdi score was 17 or greater. the qol in both groups was assessed with sf-36 questionnaire, which has been previously validated in turkish population by koçyiğit and colleagues. sf-36 questionnaire has been designed to evaluate following these concerns in global health: physical function, physical role, body pain, general health, vitality, social function, emotional role and mental health. the scores of the eight subscales range from 0 to 100. higher scores indicate less limitations or distress in the different dimensions.(14,15) the statistical analyses were performed using a computer with medcalc software version 11.4.3. data analyses were performed with the kolmogorov-smirnov test that was used for documenting the normal distribution. data were given as mean ± sd and median (minimummaximum). the mann-whitney u test and student’s t test were used for comparison of scores within the groups. categorical variables are presented as frequencies and percentages and were compared using fisher’s exact test. statistical significance was considered at p ≤ .05. results table 1 lists demographic characteristics of the patients with ra and control group. there was not any significant difference in age, educational level, occupational status, smoking history, alcohol consumption and physical activity between both groups. table 2 shows mean total and domain fsfi and bdi scores between the patients with ra and control group. the dofemale sexual function and rheumatoid arthritis | coskun et al table 2. the mean± sd, median (min-max) total and domain scores of fsfi with bdi scores in study groups. variables ra (n = 32) control (n = 20) p mean ± sd median (min-max) mean ± sd median (min-max) desire 3.47 ± 0.96 3.60 (1.20-4.80) 5.16 ± 0.74 5.40 (3.60-6.0) .0001* arousal 3.750 ± 1.44 3.75 (0.0-6.0) 5.37 ± 0.80 5.7 (3.30-6.0) .0001* lubrication 3.90 ± 1.34 4.05 (0.0-6.0) 5.40 ± 0.52 5.70 (4.206.0) .0001* orgasm 3.95 ± 1.34 4.0 (0.0-6.0) 5.46 ± 0.51 5.60 (4.0-6.0) .0001* satisfaction 4.41 ± 1.49 4.60 (0.0-6.0) 5.40 ± 0.54 5.60 (4.0-6.0) .022* pain 4.26 ± 1.77 4.80 (0.0-6.0) 5.50 ± 0.56 5.60 (4.0-6.0) .104 total 24.49 ± 6.00 25.0 (10.40-36.0) 32.31 ± 3.50 33.90 (24.50-35.0) .0001* bdi score 12.90 ± 8.87 11.50 (0.0-38.0) 7.82 ± 5.20 6.0 (2.0-21.0) .036** *mann–whitney u-test, **student’s t test. key: sd, standard deviation; (min-max), minimum and maximum values; ra, rheumatoid arthritis; bdi, beck depression inventory; fsfi, female sexual function index. 1084 | main scores of fsfi including desire, arousal, lubrication, orgasm, and satisfaction, in patients with ra were significantly lower than control group (p = .0001, p = .0001, p = .0001, p = .0001, p = .022 and p = .0001, respectively). the domain score of pain were not statistically significant (p = .104). the mean bdi scores for the patients with ra were greater than control group (p < .05). fsd was diagnosed in 22 out of 32 (68.75%) patients with ra and 3 out of 20 (15%) (p = .0001). table 3 shows mean total and domain fsfi scores of patients with ra according to they have morning stiffness more than one hour or not. the domain scores of fsfi including, satisfaction and total domain scores in patients who have morning stiffness more than one hour were significantly lower than the patients who do not have morning stiffness more than one hour (p = .05 and p = .026, respectively). the domain scores of fsfi including desire, arousal, lubrication, orgasm and pain were not statistically significant in both groups (p = .626, p = .182, p = .548, p = .097, and p = .609, respectively). table 4 shows mean scores of sf-36 questionnaire between patients with ra and control group. the scores of physical function, physical role, body pain, general health, vitality, emotional role were significantly lower in patient group than the control group (p = .0001, p = .0001, p = .028, p = .002, p = .001 and p = .0001, respectively). the scores of social function and mental health were not statistically significant (p = .4954 and p = .1192, respectively). discussion assessment of sexual functioning and qol in the present study revealed that women with ra had lower scores of total fsfi and also lower scores in all of the fsfi subdomains except pain subdomain, when compared with healthy women. women with ra also had lower scores of qol parameters except social function and mental health, when compared with healthy women. the impact of chronic disabling conditions like ra, on qol of the patients has been investigated in many studies; however sexual functioning in these patients remains a neglected area of qol.(16) therefore, we evaluated the link between ra and female sexual functioning by using fsfi, which is a validated and reliable self-report measurement. recently frikha and colleagues assessed sexual functioning in 10 women with ra by using fsfi.(17) they reported 7 women with fsd out of 10 and all subscales of fsfi were affected. in our study fsd rate was 68%, 75 out of 32 women with ra and 15% out of 20 women belonging to control group. to our knowledge, this is the first study comparing fsfi scores of patients with ra with healthy controls. fsfi is essential in evaluating different components sexual activity (like desire, arousal, lubrication, pain, orgasm, satisfaction and total disorders) rather than determination of sexual dysfunction.(5) therefore, we used cutoff score for sexual disfunction and infertility table 3. the mean ± sd, median (min-max) total and domain fsfi scores of patients with ra according to they have morning stiffness more than one hour or not. variables patients without morning stiffness (n = 23) patients with morning stiffness (n = 9) p mean ± sd median (min-max) mean ± sd median (min-max) desire 3.52 ± 0.91 3.60 (1.20-4.80) 3.33 ± 1.12 3.60 (1.20-4.80) .626 arousal 3.69 ± 1.51 4.2 (0.00-6.0) 2.93 ± 1.13 3.30 (1.20-4.50) .182 lubrication 3.99 ± 1.50 4.2 (0.00-6.0) 3.66 ± 0.80 3.60 (1.80-4.50) .548 orgasm 4.23 ± 1.57 4.40 (0.00-6.0) 3.24 ± 1.12 3.60 (1.20-4.40) .097 satisfaction 4.73 ± 1.50 4.80 (0.00-6.0) 3.60 ± 1.18 4.0 (1.20-4.80) .05* pain 4.36 ± 1.90 5.20 (0.00-6.0) 4.00 ± 1.45 4.0 (2.0-6.0) .609 total 25.94 ± 5.69 26.40 (11.90-36.0) 20.77 ± 5.37 22.20 (10.40-26.40) .026* *student’s t test. key: sd, standard deviation; (min-max), minimum and maximum values; fsfi, female sexual function index; ra, rheumatoid arthritis. 1085vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l the turkish population to evaluate fsd.(18) although the total score and all of the domain scores were lower in patients with ra control group, the domain score of ‘pain’ were not statistically significant. these results suggest, all domains of fsfi may contribute the fsd in patients with ra. interestingly pain domain of fsfi is found to be less effective on fsd when compared to healthy age matched controls in our study. the pain domain of fsfi is about the pain during vaginal penetration and it is apart from the pain that patients have routinely. sexual act may positively affect patients mood and most of them denote ease of their pain after sexual relation.(19) the percentage of patients with ra who experience sexual problems ranged in previous studies from 31 to 76% and these studies highlighted two main problems: difficulties in sexual performance and diminution of sexual desire and satisfaction.(16,20-26) in a study which hill and colleagues. investigated effects of ra on sexual activity they found that 56% limitations on sexual intercourse, 50-60% decrease in desire, 73% reduction of frequency of intercourse.(27) in the study of abdel-nasser and colleagues, it has been reported that women with ra had impaired sexual function with a prevalence of 60%.(28) in our study similar results observed with previous papers in terms of fsd. fsd is a common disorder, which has serious effects on women’s qol. aslan and colleagues evaluated the prevalence of and risk factors for fsd using the turkish version of fsfi in 1009 turkish women and found that fsd occurs in 43.4% of women.(29) similarly, in the study of cayan and colleagues it has been reported that 46.9% of women in turkey had fsd, which has been associated with increased age, lower education level, unemployment status, chronic diseases, multiparity and menopause status as important risk factors for fsd.(6) another important factor that effect female sexual functioning is depression and other mood disorders.(30) the present study revealed, the rate of depression in women with ra was significantly higher than healthy controls (p = .036). monga and colleagues assessed the relationship between sexual function and physiological measures in 70 patients with chronic pain and found that sexual problems are common in patients with chronic pain and in those with symptoms of distress and depression.(31) in our study we also evaluated fsfi in women with ra whether they have morning stiffness for a period more than one hour. the total score and the category of and satisfaction domain of fsfi in women who had morning stiffness more than one hour were significantly lower than the women who had morning stiffness less than one hour (p = .026 and p = .05, respectively). similarly gutweniger and colleagues reported that morning stiffness in women with ra plays an important in their feelings of being a handicap. female sexual function and rheumatoid arthritis | coskun et al table 4. the mean ± sd and median (min-max) scores of sf-36 questionnaire between patients with rheumatoid arthritis and control group. variables patients with ra (n = 32) control group (n = 20) p mean ± sd median (min-max) mean ± sd median (min-max) physical function 54.53 ± 23.08 45.0 (45.0-100.0) 86.75 ± 15.58 92.50 (45.0-100.0) .0001* physical role 32.03 ± 39.26 12.50 (0.0-100.0) 76.25 ± 30.85 87.50 (0.0-100.0) .0001* body pain 54.65 ± 18.28 52.0 (21.0-84.0) 68.80 ± 26.67 73.00 (12.0-100.0) .028* general health 44.93 ± 22.95 40.0 (15.0-97.0) 65.85 ± 20.96 74.50 (20.0-97.0) .002* vitality 39.21 ± 21.74 35.0 (0.0-80.0) 64.00 ± 26.08 65.0 (15.0-100.0) .001* social function 71.87 ± 23.54 68.75 (12.50-100.0) 76.25 ± 20.23 87.50 (37.50-100.0) .4954 emotional role 31.23 ± 41.42 0.0 (0.0-100.0) 74.95 ± 35.72 100.0 (0.0-100.0) .0001* mental health 54.25 ± 19.27 54.0 (8.0-100.0) 63.60 ± 22.80 62.0 (24.0-96.0) .1192 *student’s t test. key: sd, standard deviation; (min-max), minimum and maximum values; ra, rheumatoid arthritis; sf-36, the short form 36. 1086 | sexual disfunction and infertility they declared, women with substantial degree of morning stiffness had significantly more worries about their body image and lived more sexual dissatisfaction than females with lower degrees of morning stiffness.(32) the factors like physical disability, fatigue, altered body image and worries about partner interest are also reported to effect sexuality of the patients.(3,21,26) sf-36 has been used in several studies including the patients with ra and has been found to be reliable, valid, and responsive. the major advantage of this survey is its ability to compare the physical and mental status of ra patients with the overall population.(33) in a study, birtane and colleagues assessed the qol of patients with fibromyalgia, ra and healthy controls by using sf-36. the patients with ra and fibromyalgia syndrome had lower scores of all sf-36 subdomains except social function than the control subjects.(34) similarly we found scores of physical functioning, physical role, bodily pain, general health, vitality and emotional role significantly lower in patients with ra than healthy controls (p = .0001, p = .0001, p = .028, p = .002, p = .001 and p = .0001, respectively). although the scores of social functioning and mental health were also lower in patient group the results were not statistically significant (p = .4954 and p = .1192, respectively). our findings are relevant for patient communication, as physicians should be advised to address the sensitive subject of sexual dysfunction in women with ra. there are several limitations of the present study. first of all, the sample size was small and the results may not reflect general population. secondly, we conducted our study in cross-sectional method, which is less valuable than prospective cohort studies. thirdly, depression was not clinically diagnosed in patients and defined based on a self-rating questionnaire .also, we did not investigate whether the fsd was distressful or not for the enrolled women. this would bring more information regarding the relationship between depression and fsd. the last limitation was, lack of evaluation whether the treatment of ra has any effect on fsd. conclusion the present study shows that a significant percent of patients with ra had sexual dysfunction and also deterioration in qol. all domains of fsfi were affected except from the “pain” domain and this may reflect the pathophysiology of fsd in this group of patients. however, more studies in larger population comparing sexual functioning between the patients with ra and healthy controls is necessary to understand this relation. conflict of interest none declared. references 1. gabriel se. the epidemiology of rheumatoid arthritis. rheum dis clin north am. 2001;27:269-81. 2. lipsky pe. rheumatoid arthritis. in: braunwald e (ed) harrison’s 16th edition principles of i̇nternal medicine. new york: mc graw hill; 2005. p. 1968-76. 3. erlich ge. social, economic, psychologic, and sexual outcomes in rheumatoid arthritis. am j med. 1983;75:27-34. 4. laumann e, paik a, rosen rc. sexual dysfunction in the united states: prevalence and predictors. jama1999;281:537-44. 5. rosen r, brown c, heiman j, et al. the female sexual function index (fsfi): a multidimensional self-report instrument for the assessment of female sexual function. j sex marital ther. 2000;26:191-208. 6. cayan s, akbay e, bozlu m, canpolat b, acar d, ulusoy e. the prevalence of female sexual dysfunction and potentional risk factors that may impair sexual function in turkish women. urol int. 2004;72:5257. 7. basson r, berman j, burnett a, et al. report of the international consensus development conference on female sexual dysfunction: definitions and classifications. j urol. 2000;163:888-93. 8. salonia a, munarriz rm, naspro r, et al. women’s sexual dysfunction: a pathophysiologiacal review. bju int. 2004;93:1156-64. 9. østensen m. new insights into sexual functioning and fertility in rheumatic diseases. best pract res clin rheumatol. 2004;18:219-32. 10. arnett fc, edworthy sm, bloch da, et al. the american rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. arthritis rheum. 1988;31:315-24. 11. wiegel m, meston c, rosen r. the female sexual function index (fsfi): cross-validation and development of clinical cutoff scores. j sex marital ther. 2005:31:1-20. 12. onem k, erol b, sanli o, et al. is sexual dysfunction in women with obstructive sleep apneahypopnea syndrome associated with the severity of the disease? a pilot study. j sex med. 2008;5:2600-609. 1087vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l female sexual function and rheumatoid arthritis | coskun et al 30. berman jr, bassuk j. physiology and pathophysiology of female sexual function and dysfunction. world j urol. 2002;2:111-8. 31. monga tn, tan g, ostermann hj, monga u, grabois m. sexuality and sexual adjustment of patients with chronic pain. disabil rehabil. 1998;20:317-29. 32. gutweniger s, kopp m, mur e, günther v. body image of women with rheumatoid arthritis. clin exp rheumatol. 1999;17:413-7. 33. tugwell p, idzerda l, wells ga. generic quality-of-life assessment in rheumatoid arthritis. am j manag care. 2007;13:s224-36. 34. birtane m, uzunca k, taştekin n, tuna h. the evaluation of qol in fibromyalgia syndrome: a comparison with rheumatoid arthritis by using sf-36 health survey. clin rheumatol. 2007;26:679-84. 13. beck at, ward ch, mendelson m, mock j, erbaugh j. an inventory for measuring depression. arch gen psychiatry. 1961;4:561-71. 14. ware je jr, kosinski m, bayliss ms, mchorney ca, rogers wh, raczek a. comparison of methods for the scoring and statistical analysis of sf-36 health profile and summary measures: summary of results from the medical outcomes study. med care. 1995;33:as264-79. 15. koçyiğit h, aydemir ö, fişek g, ölmez n, memiş a. kısa form–36 (kf-36)’nın türkçe versiyonunun güvenilirliği ve geçerliliği. i̇laç ve tedavi dergisi. 1999;12:102-106. 16. tristano ag. the impact of rheumatic diseases on sexual function. rheumatol int. 2009;29:853-60. 17. frikha f, maazoun f, ben salah r, et al. sexual function in married women with rheumatoid arthritis. presse med. 2011;40:e521-7. 18. oksuz e, malhan s. reliability and validity of the female sexual function index in turkish population. sendrom. 2005;17:54-62. 19. katz wa. sexuality and arthritis. katz wa (ed). rheumatic diseases: diagnosis and management. philadelphia, toronto: jb lippincott co; 1973. p. 1011-20. 20. baldursson h, brattstrom h. sexual difficulties and total hip replacement in rheumatoid arthritis. scand j rheumatol. 1979;8:214-16. 21. blake dj, maisiak r, koplan a, alarcón gs, brown s. sexual dysfunction among patients with arthritis. clin rheumato 1988;l7:50-60. 22. brown gm, dare cm, smith pr, meyers ol. important problems identified by patients with chronic arthritis. s afr med j. 1987;72:126-8. 23. ferguson k, figley b. sexuality and rheumatic disease: a prospective study. sex disabil. 1979;2:130-38. 24. gordon d, beastall gh, thomson ja, sturrock rd. androgenic status and sexual function in males with rheumatoid arthritis and ankylosing spondylitis. q j med. 1986;60:671-9. 25. hill rh, herstein a, walters k. juvenile rheumatoid arthritis: followup into adulthood-medical, sexual and social status. can med assoc j. 1976;114:790-6. 26. kraaimaat fw, bakker ah, janssen e, bijlsma jw. intrusiveness of rheumatoid arthritis on sexuality in male and female patients living with a spouse. arthritis care res. 1996;9:120-5. 27. hill j, bird h, thorpe r. effects of rheumatoid arthritis on sexual activity and relationships. rheumatology (oxford). 2003;42:280-6. 28. abdel-nasser am, ali ei. determinants of sexual disability and dissatisfaction in female patients with rheumatoid arthritis. clin rheumatol. 2006;25:822-30. 29. aslan e, beji nk, gungor i, kadioglu a, dikencik bk. prevalence and risk factors for low sexual function in women: a study of 1,009 women in an outpatient clinic of a university hospital in istanbul. j sex med. 2008;5:2044-52. 1238 | 1department of pathology, university college of medical sciences and guru teg bahadur hospital, delhi, india. 2department of surgery, university college of medical sciences and guru teg bahadur hospital, delhi, india. corresponding author: surbhi goyal, md department of pathology, university college of medical sciences and guru teg bahadur hospital, dilshad garden, delhi 110095, india. tel: +91 9873 896416 email: dr.surbhi4you@gmail.com received june 2012 accepted november 2012 purpose: to evaluate the mutual inter-relationship of mitotic indices, argyrophilic nuclear organizer regions (agnor) count, ki-67 and b-cell lymphoma 2 protein (bcl-2) in papillary urothelial bladder cancer (pubc), and their correlation with grade and stage. to establish the cut-off values of these markers to detect high grade and muscle invasive bladder cancer. materials and methods: fifty-four patients with primary pubc who underwent transurethral resection / radical cystectomy were analyzed retrospectively. cell proliferation was assessed by ki-67 labelling index, mean agnor count, mitotic count, mitotic activity index and mitosis/ volume index. immunohistochemistry was done to see bcl-2 and ki-67 expression. correlation of these indices with tumor grade and stage and amongst themselves was assessed. the receiver operating characteristic (roc) curves were drawn to establish the cut-off values. results: we found a strong positive correlation of mitotic indices and ki-67 with tumor grade (p = .000), stage (p < .05) and bcl-2 (p = .000). agnor count correlated positively with the grade (p = .006), mitotic indices and ki-67 (p = .032) but not with tumor stage and bcl-2. cytoplasmic bcl-2 immunopositivity was seen in 42.3% of low grade pubc and 85.7% of high grade pubc cases (p = .001). bcl-2 positivity was seen in 85% of muscle invasive pubc as compared to only 52.9% of superficial cases. ki-67 ≥ 32.5%, ≥ 14 mitoses/10 high power fields (hpf), ≥ 11.20 mitoses/mm2, ≥ 0.75 mitoses/100 tumor cells and agnor ≥ 11.55 are 100% specific for high grade bladder carcinoma. ki-67 ≥ 59% and mitoses ≥ 36.50 per 10 hpf can indicate muscle invasion with 100% specificity. conclusion: cut-off values for ki-67, mitotic indices and agnor can confirm high grade bladder carcinoma in equivocal cases. ki-67 and mitotic count can serve as potential and reliable indicators of muscle invasion. keywords: ki-67 antigen; mitotic index; predictive value of tests; urinary bladder neoplasms; diagnosis. surbhi goyal,1 usha rani singh,1 sonal sharma,1 navneet kaur2 correlation of mitotic indices, agnor count, ki-67 and bcl-2 with grade and stage in papillary urothelial bladder cancer urological oncology urological oncology 1239vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l proliferative markers and bcl-2 in bladder cancer | goyal et al introduction bladder cancer is the fourth most common cancer in men and ninth most common in women worldwide, leading to significant morbidity and mortality which poses a major economic burden on global health care systems. (1) bladder cancer is one of the costliest diseases to treat due to long term survival associated with non-muscle-invasive disease.(2) conventional parameters like tumor size, grade and stage alone have limited role in specifying the risk of progression, recurrence or response to treatment for an individual patient, as bladder cancer patients with the same grade and stage often show markedly different clinical outcome.(3) despite their imperfections presently, there are no prognostic markers for bladder cancer which are superior to conventional grading and staging.(4) overall 5 year survival drops to 38.5% for stage t2 as compared to 70% in stage t0 and t1 bladder cancer patients.(5) newer reproducible markers which can detect muscle invasion and are confirmatory for high grade bladder cancer may serve as a better guide for patient management and clinical outcome, than conventional grade and stage alone.. evolution of bladder cancer comprises a multistep process involving various alterations in the activity of genes regulating the cell division and apoptosis. b-cell lymphoma 2 protein (bcl2) family, a group of closely related proteins and several other genes including c-myc, h ras, abl, apo-1, and p53 play a major regulatory role in apoptosis. bcl-2 overexpression has been associated with reduced tumor sensitivity to chemotherapy and radiotherapy.(6) bcl-2 expression in different malignancies is variable and depends on cell lineage.(7) bcl-2 overexpression is a poor prognostic factor in high grade lymphomas, leukemia, neuroblastoma and prostatic cancer, while lung and breast cancer patients with bcl-2 expression have a better chance of survival.(8) overexpression of bcl-2 is therefore, of potential relevance to the pathogenesis and progression of bladder cancer and its response to therapeutic interventions. proliferative activity is currently being evaluated as an indicator of biological aggressiveness in bladder cancer. mitotic count is apparently the most convenient marker to assess the proliferative status of a tumor. mitotic indices especially mitosis/volume (m/v index) has been shown to be an independent prognostic indicator of survival in papillary urothelial bladder cancer (pubc), although most of the studies regarding this largely come from one group of researchers.(9-11) nuclear organizer regions (nor) are loops of ribosomal dna (rdna) in cell nucleoli which are visible in interphase on silver staining.(12) argyrophilic nors (agnors) are nonhistone proteins associated with the synthetic activity localized to the nors and provide an estimate of cellular proliferation.(13) in bladder cancer, correlation between agnors and the tumor behavior remains still disputatious.(14,15) tumor growth fraction can be assessed by using a monoclonal antibody ki-67 reacting with a nuclear antigen, which is expressed in the s, g2 and m phases of the cell cycle. proportion of ki-67 labelled cells in a given cell population (ki-67 labelling index) has been found to be related to bladder tumor recurrence, grade and stage in various studies.(16) however, absolute cutoff values to confirm high grade and invasive pubc have not been reported yet. to the best of our knowledge, very few studies in literature have studied the diagnostic role of these three proliferative markers and bcl-2, in combination, and cut-off values to detect high grade and muscle invasive pubc (which is known to have a poor clinical outcome) have never been proposed in literature before. current literature is confounding regarding the utility of bcl-2 in bladder cancer. therefore, the present study was conducted with the aims: 1) to compare and determine the correlation of proliferative markers (mitotic indices, agnor count and ki-67 labelling index) and bcl-2 with grade and stage in pubc: 2) to establish the cut-off values which can reliably distinguish high grade from low grade and, invasive from superficial papillary bladder cancer. materials and methods subject population this was a single-institution retrospective study approved by the institutional ethics committee and the need to obtain informed consent was waived. fifty four patients (45 males, 9 females) of primary bladder cancer presenting in the urology outpatient department from october 2008 to april 2011, who were treated with trans-urethral resection of bladder tumor (turbt) or cystectomy and found to have primary histologically confirmed pubc, were included in the study. clinical details, radiological findings and adequate tissue material were available in all these cases for tumor grading and staging. radical cystectomy specimen was available in ten cases; turbt material was evaluated for the rest of the 44 cases. the tissue was fixed in 10% buffered formalin, routinely processed and embedded in paraffin blocks. the 5 µm thick sec1240 | urological oncology tions were taken for hematoxylin and eosin and agnor staining. twenty turbt samples reported as non-neoplastic (inflammatory) in patients suspected to have bladder malignancy, in the study period were taken as controls. histological grading and staging hematoxylin and eosin stained sections were examined and graded in the worst differentiated area. grading and tnm staging was done according to world health organization/international society of urological pathology (who/isup) 2004 and the american joint committee on cancer (ajcc) classification system.(17,18) clinico-radiological correlation was done to assign stage in cases of advanced tumors (beyond pt2). mitotic indices the most cellular tumor areas were selected for mitotic counts, avoiding the necrotic areas, at × 400 magnification. mitotic counts were counted per 10 high power fields (hpf) on hematoxylin and eosin sections. mitoses/volume (m/v) index is defined as number of mitotic figures per square millimeter of tumor (in motic microscope, 10 consecutive hpf correspond to 1.25 mm2). the mitotic activity index (mai) was calculated as number of mitotic figures per 100 tumor cells counted under × 400 magnification. agnor staining for agnor staining, working solution was made of two parts of 50% aqueous silver nitrate solution, made in distilled water and one part of 2% gelatin in 1% aqueous formic acid. deparaffinized sections were incubated at room temperature for half an hour in dark after adding freshly prepared working solution. slides were washed, air dried and mounted using dpx. number of agnors in 100 randomly selected tumor cells were counted under oil immersion lens. agnors in clusters were counted separately wherever possible and the mean agnor count/nucleus was calculated. bcl-2 and ki-67 immunoanalysis streptavidin-biotinylated immunoperoxidase method was used for demonstration of bcl-2 and ki-67 antigen. four µm thick serial sections on poly-l-lysine coated slides were deparaffinized in xylene, rehydrated using graded alcohol and washed with tris buffer (ph 7.4). for antigen retrieval sections were placed in 0.01 m citrate buffer (ph 6.0) for 10 min at 980c in ez retriever system (v.2.1, biogenex, fremont, california, usa). sections were cooled to room temperature, and washed with tris buffer. endogenous peroxide was blocked by 4% h2o2 for 15 min. sections were incubated overnight at 4-80c with the ready to use primary mouse monoclonal antibody (bcl-2: 226m-98 cell marque, rocklin, california, usa; ki-67: pm375 aa biocare medical, concord, california, usa). sections were treated with biotinylated antimouse link antibody, followed by preformed streptavidin conjugated horseradish peroxidise complex for 30min. diaminobenzidine tetrahydrochloride (dab) (0.6 mg/ml in tris buffer saline, ph 7.6 containing 0.04% hydrogen peroxide) was used to develop brown color. harris hematoxylin was used to counterstain the slides. for positive controls of bcl-2 and ki-67 follicular lymphoma and normal tonsil were stained respectively. a negative control (with primary antibody omitted) was taken along with each batch. immunohistochemical analysis was performed by two pathologists in consensus, blinded to tumor grade and stage. fraction of positively stained tumor cells was scored semiquantatively after examining at least 5 hpf (×400) for each case. at least moderate cytoplasmic or perinuclear staining in 10% table 1. grade and stage wise distribution of cases. stage low grade high grade total, no (%) pta 15 3 18 (33.3) pt1 8 8 16 (29.6) pt2 1 10 11 (20.4) pt3 2 5 7 (12.9) pt4 0 2 2 (3.8) total, no (%) 26 (48.1) 28 (51.9) 54 (100) figure 1. high mitotic count with atypical mitoses in high grade papillary bladder cancer (hematoxylin and eosin, ×400). 1241vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l of tumor cells was required to define bcl-2 positivity. staining intensity of bcl-2 immunopositivity was determined as mild/ moderate/high by comparison with the staining of lymphocytes (positive internal control). mean bcl-2 immunopositivity was scored according to the percentage of tumor area showing bcl-2 staining. for assessing tumor growth fraction, random fields were selected in well preserved areas in each section. proportion of tumor cells showing nuclear staining was counted and expressed as percentage (ki-67 labelling index). at least 1000 tumor cells were assessed for each case, unless the section was smaller, in which case all the cells were counted. statistical analysis the statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0 was used for analysis. for comparison between two groups, student’s t test was employed and one way analysis of variance (anova) was used in case of more than two groups. spearman’s coefficient of correlation (rho) was calculated to assess the association of the proliferative indices and bcl-2 with tumor stage and grade. contingency table 2. correlation of mitotic indices, mean agnor count, ki-67 labelling index and bcl-2 with tumor grade. variables controls low grade high grade correlation coefficient p mean mitotic count 0.32 ± 0.45 3.30 ± 2.54 15.30 ± 20.04 0.679 .0001 mitoses/volume index 0.04 ± 0.07 2.64 ± 2.03 12.55 ± 16.3 0.581 .001 mitotic activity index 0.0 0.20 ± 0.07 92. ± 0.96 0.458 .000 mean agnor count 1.7 ± 4.2 1.86 ± 6.39 4.04 ± 8.86 0.312 .006 ki-67 labelling index 4.5 ± 2.68 11.88 ± 8.23 35.86 ± 17.55 0.711 .000 proportion of bcl-2 positive cases 0.0 42.3% 85.7% 0.454 .001 mean bcl-2 immunopositivity* 0.0 19.35 ± 23.16 49.57 ± 3.49 0.486 .000 key: bcl-2, b-cell lymphoma 2 protein; agnor, argyrophilic nuclear organizer regions. *percentage area positive for bcl-2. figure 2. a) low agnor count in low grade papillary bladder cancer (agnor, ×1000). b) high agnor count in high grade papillary bladder cancer (agnor, ×1000). proliferative markers and bcl-2 in bladder cancer | goyal et al 1242 | tables were drawn and fischer’s exact test or pearson’s chi square test of proportions were used to assess grade and stage significance for bcl-2 positivity. pearson’s correlation coefficient was used to assess the mutual correlation between the proliferative indices and bcl-2 immunopositivity. all p values < .05 were considered statistically significant. receiver operating characteristic (roc) curves were drawn to determine the cut-off values (with highest average sensitivity and specificity) for distinction between two groups. results demographic profile mean age of 54 pubc patients (45 men, 9 women) was 58.4 years, age range 35-95 years. control group comprised of twenty non-neoplastic cases with mean age of 54.5 years (17 males, 3 females), age range 30-75 years. distribution of cases according to histological grade and stage is shown in table 1. keeping in view the small number of cases in each stage, and considering the fact that invasion into lamina propria is associated with sharp decrease in patient survival, we divided our cases into prognostically significant groups: superficial (pta and pt1, n = 34) and invasive (stage pt2 and beyond, n = 20). mitotic indices a significant difference was noted in the mean mitotic count, table 3. correlation of mitotic indices, mean agnor count, ki-67 labelling index and bcl-2 with tumor stage. stage pta pt1 pt2 pt3 pt4 p correlation coefficient mitotic count 10.43 ± 5.0 11.59 ± 11.56 17.8 ± 24.6 7.28 ± 9.76 15.0 ± 16.9 .004 0.517 mitoses/volume index 9.54 ± 4.36 9.27 ± 9.25 14.2 ± 19.7 5.83 ± 7.80 12.0 ± 13.5 .008 0.509 mitotic activity index 0.56 ± 0.23 0.69 ± 0.50 1.04 ± 1.26 0.23 ± 0.60 0.75 ± 1.06 .009 0.238 mean agnor count 2.44 ± 7.17 3.63 ± 8.51 4.65 ± 8.10 5.66 ± 2.33 10.1 ± 1.4 .285 ns ki-67 labelling index 13.78 ± 14.16 24.31 ± 14.91 36.1 ± 18.0 29.0 ± 21.2 37.5 ± 31.8 .000 0.490 bcl-2 positive cases, (%)* 5/18 (27.7) 13/16 (81.2) 9/11 (81.8) 6/7 (85.7) 2/2 (100) .002 0.492 mean bcl-2 positivity** 11.39 ± 17.18 36.63 ± 28.05 55.9 ± 31.2 55.0 ± 29.7 50.0 ± 49.4 .000 0.580 key: ns, not significant ; bcl-2, b-cell lymphoma 2 protein; agnor, argyrophilic nuclear organizer regions . *proportion of bcl-2 positive cases, ** percentage area positive for bcl-2. urological oncology figure 3. a) very faint cytoplasmic bcl-2 positivity in low grade papillary bladder cancer with lymphocytes serving as strong internal positive controls (bcl-2 immunostain x 400) b) strong cytoplasmic staining of bcl-2 in high grade papillary bladder cancer (bcl-2 immunostain x 100). 1243vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l mai and m/v index of the low and high grade pubc (table 2) as well as between the various stages of the tumor (tables 3 and 4). spearman’s correlation coefficient showed a significant positive correlation of the mitotic indices with the tumor grade and stage. atypical mitoses includingtri/quadripolar and multipolar mitoses, ring mitoses, asymmetrical mitoses were easily identified in high grade tumors (figure 1). agnor counts the mean agnor count in pubc cases ranged from 3.2-18.8 with a mean of 8.7 ± 3.3 as compared to 4.2 ± 1.7 in controls. the mean agnor count was significantly lower in low grade pubc as compared to high grade tumors (figure 2), however, the difference between the superficial and muscle invasive groups was not statistically significant and no correlation was observed between mean agnor count and tumor stage (tables 2 and 3). bcl-2 and ki-67 labelling index in the control group, cytoplasmic bcl-2 immunopositivity was seen in one to two basal cell layers of transitional epithelium. stromal lymphocytes were strongly positive for bcl-2, thereby acting as internal controls (figure 3). in pubc cases, expression of bcl-2 was seen mainly in superficial and non-basal layers of urothelium. bcl-2 positivity was mainly cytoplasmic (figure 3). bcl-2 expression was seen in 35/54 (64.8%) cases of pubc. not only the proportion of bcl-2 immunopositive cases was significantly higher in high grade group, but also the percentage tumor area positive for bcl-2 was significantly higher in high grade as compared to low grade (fisher’s exact test, p = .001) (table 2). we observed an increase in the proportion of bcl-2 immunopositive cases with increasing tumor stage and this difference was found to be statistically significant (p = .002, spearman’s correlation coefficient, r = 0.492). mean bcl-2 immunopositivity was significantly higher in invasive cases as compared to superficial ones (table 4). no significant correlation was found between the staining intensity and the tumor grade or stage. ki-67 immunostaining showed variable intense nuclear positivity (figure 4) in all pubc cases, which was significantly higher than in control group. mean ki-67 labelling index (ki-67 li) was significantly higher in high grade and invasive pubc as compared to low grade and superficial cases (tables 3 and 4). box and whisker plots depicting the median and distribution range of bcl-2 and ki-67 percentage immunopositivity in low vs. high grade and superficial vs. invasive pubc cases are shown in figure 5. mutual correlation between proliferative indices and bcl-2 expression we found a strong positive correlation of the proliferative markers (mitotic count, ki-67) with bcl-2 immunopositivity (p = .000, r = 0.596). however, no correlation was found between mean agnor count and bcl-2 expression. mitotic count and ki-67 li showed a significant positive correlation with mean agnor count (p = .032, r = 0.292). mean mitotic count of bcl-2 positive cases was 14.97 ± 14.39/10 hpf and of bcl-2 negative cases was 5.42 ± 11.93/10 hpf, and this difference was found to be statistically significant (p = .017). mean ki-67 li (29.37 ± 17.23) in bcl-2 positive table 4. mitotic indices, mean agnor count, ki-67 labelling index and bcl-2 in superficial (pta and pt1) and invasive (pt2 and beyond) papillary urothelial bladder cancer. variables superficial invasive p mean mitotic count 8.09 ± 11.32 17.60 ± 16.78 .016 mitoses/volume index 6.66 ± 9.56 14.08 ± 13.43 .022 mitotic activity index 0.36 ± 0.63 0.85 ± 0.94 .029 mean agnor count 7.80 ± 3.08 7.44 ± 3.92 .714 ki-67 labelling index 18.74 ± 15.26 33.80 ± 19.49 .003 proportion of bcl-2 positive cases 52.9% 85.0% .021 mean bcl-2 immunopositivity* 23.26±25.94 55.00 ± 30.43 .000 * percentage area positive for bcl-2. key: bcl-2, b-cell lymphoma 2 protein; agnor, argyrophilic nuclear organizer regions. proliferative markers and bcl-2 in bladder cancer | goyal et al 1244 | urological oncology cases was significantly higher than in bcl-2 negative cases (15 ± 16.86), p = .005. so bcl-2 immunopositivity was associated with higher mitotic count and ki-67 li. roc analysis roc curves were drawn to calculate area under the curve (figure 6) and cut-off values with highest average sensitivity and specificity for all the parameters to distinguish high grade from low grade (table 5). in addition to cut-off value shown in the table, roc analysis also showed ki-67 li ≥ 32.5%, mitotic count ≥ 14/10 hpf, m/v index ≥ 11.20 mitoses/mm2, mai ≥ 0.75 and agnor count ≥ 11.55 were found exclusively in high grade pubc (specificity = 100%). none of the high grade tumors had ki-67 li < 9%. similar roc analysis for tumor stage revealed, 100% specificity of ki-67 ≥ 59% and mitotic count ≥ 36.50/10 hpf for invasive bladder cancer. however, agnor and bcl-2 did not show significant specific or sensitive cut-off values to detect invasive bladder cancer cases. discussion we assessed the relationship of mitotic indices, agnor count, ki-67 li and anti apoptotic bcl-2 immunopositivity with the well established prognostic parameters, that is, tumor grade and stage. we found a significant strong positive correlation of mitotic indices and ki-67 li with bladder cancer grade and stage, which is explained by the significant increase in proliferative activity of tumor cells with muscle invasion. ki-67 is a more accurate protable 5. receiver operating characteristic analysis for distinction of high grade papillary bladder cancer. variables auc cut-off value sensitivity (%) specificity (%) 95% ci se p mitotic count 0.890 5.5 75.0 88.5 0.800-0.981 0.046 .000 mitoses/volume index 0.890 2.0 92.9 76.9 0.800-0.981 0.046 .000 mitotic activity index 0.793 0.75 57.1 100.0 0.669-0.916 0.063 .000 mean agnor count 0.680 8.70 53.6 92.3 0.531-0.829 0.076 .023 ki-67 labelling index 0.910 21.5 75.0 84.6 0.837-0.983 0.037 .000 mean bcl-2 positivity 0.780 32.5 64.3 84.6 0.656-0.905 0.064 .000 key: ci, confidence interval; se, standard error; auc, area under the curve; bcl-2, b-cell lymphoma 2 protein; agnor, argyrophilic nuclear organizer regions. figure 4. a) low ki-67 labelling index in low grade papillary bladder cancer (ki-67 immunostain, ×100) insethigher magnification (×400). b) high ki-67 labelling index in high grade papillary bladder cancer (ki-67 immunostain, ×100) insethigher magnification (×400). 1245vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l liferating index because it stains all the phases of cell cycle except g0. however, it requires standardized immunohistochemistry setup for valid results. mitosis has long been employed as a simple way to measure proliferation on routine sections, but is limited to a phase of cell cycle with substantial inter-observer variability in its identification. since area of a single high power field may vary up to 3-5 folds in different microscopes, m/v index is a more reliable and reproducible marker to assess proliferation. lipponen and colleagues have also documented m/v index as a better independent prognostic indicator.(9) we found ki-67 li ≥ 32.5%, mitoses ≥ 14/10 hpf, ≥ 11.20 mitoses/mm2 and ≥ 0.75 mitoses/100 tumor cells confirmatory for high grade bladder cancer (specificity = 100%). gontero and colleagues have reported ki-67 li > 20% as predictor of recurrence in superficial low grade bladder cancer cases.(19) we found ki-67 ≥ 59% and mitoses ≥ 36.50 /10 hpf 100% specific for invasive bladder cancer, which can have practical implications in tumor staging and management in situations where morphological evidence of muscle invasion is equivocal. very limited studies done worldwide on ki-67 in pubc have reported the cut-off values, which have not yet been validated, nevertheless are practically useful in diagnosis, reflective of the relative trends (with their specificities and sensitivities) and serve as a guide in newer research. review of existing literature on agnors in bladder cancer yields confounding results regarding their correlation with grade, stage and prognosis.(13-5,20-22) we found a statistically significant positive correlation of mean agnor count with tumor grade, mitotic indices and ki-67 li. roc analysis revealed mean agnor count ≥ 11.55 as 100% specific for diagnosis of high grade pubc cases. however, no correlation was found with tumor stage or bcl-2 confirming the findings of previous researchers.(15,21,22) small number of cases, aggregation of agnors leading to erroneous counts and technical factors related to staining and fixation may limit the practical utility of agnor in evaluation of an individual case. measurement of agnor area per nucleus by quantitative image analyzer is a more accurate and objective method to reflect tumor behavior as it provides indirect measurement (ratio) of agnor proteins amount close to 3d evaluation.(23) bcl-2 cytoplasmic positivity in superficial urothelium was a hallmark of pubc cases while basal layer expression of bcl2 was seen in normal urothelium and cystitis. previous studies have reported bcl-2 positivity ranging from 2 % to 69% in bladder tumors. we found bcl-2 expression in 64.8% of pubc cases. we found significantly higher non basal bcl-2 expression in high grade and muscle invasive tumors as compared to low grade and superficial pubc, highlighting the role of bcl-2 upregulation in pathogenesis and progression of bladder cancer. (7,24-28) shift in bcl-2 expression from basal cells of non-neofigure 5. a) box and whisker plot of bcl-2 and ki-67 percentage immunopositivity with grade of pubc showing higher values associated with high grade ubc. b) box and whisker plot of bcl-2 and ki-67 percentage immunopositivity in invasive (stage pt2 and beyond) and superficial (stage pta and pt1) pubc cases. the lines within boxes represent median value. the top and bottom of boxes (hinges) represent 25th and 75th percentiles of the data values. the t bars that extend from the boxes (whiskers) are expected to include 95% of the data (assuming normal distribution). the points represent outliers. proliferative markers and bcl-2 in bladder cancer | goyal et al 1246 | plastic urothelium to superficial layers of bladder cancer, reflect deregulation of the control mechanisms, conferring a prolonged survival advantage and when superimposed by uncontrolled cell proliferation, leads to definite tumor progression. higher incidence of ki-67 and mitotic indices in bcl-2 positive tumors suggest that aggressive high grade bladder cancer cells with higher proliferative activity also have longer survival. in contrast, few studies in literature have reported inverse(16,30,32) and no significant correlation(29,31,33) of bcl-2 with grade, stage and survival of bladder cancer. controversial relationship of bcl-2 with clinicopathological parameters and survival in bladder cancer noted in these studies raises the need for further studies regarding the role of genes involved in the regulation of apoptosis in bladder cancer. there were few limitations of our study. first, the sample size was small for uniform grade and stage wise distribution of cases. second, the mitotic and agnor count are subjective, and we did not evaluate inter-observer variability in their interpretation. third, since we retrospectively analyzed the archival blocks, follow up of the patients was not possible in our study. there is a need to apply these cut-off values in equivocal cases and follow them up in larger prospective studies to validate our results. in conclusion, the three proliferative markers studied here correlated strongly with tumor grade. mitotic indices and ki-67 correlated with tumor stage, while agnor was not useful in evaluating muscle invasive bladder tumor cases. bcl-2 was found to correlate positively with both tumor grade and stage. all the proliferative markers correlated strongly with each other. ki-67 and mitotic indices showed a positive correlation with bcl-2, but agnor did not show any correlation with bcl2. ki-67 ≥ 59% and mitotic count ≥ 36.50 per 10 hpf, if proven seem to be promising and reliable indicators to assess muscle invasion in superficial bladder biopsies and turbt samples where muscle is not resected. keeping in view, the cost, time and workload constraints, this may be of practical utility in developing countries, as of ours, where it is not feasible to do multiple repeat biopsies and patients are often lost to follow up. we suggest that such cases should be considered muscle-invasive, for all practical purposes. also, absolute values of ki-67 li ≥ 32.5% , mitoses ≥ 14/10 hpf, ≥ 11.20 mitoses/mm2, ≥ 0.75 mitoses/100 tumor cells and agnor ≥ 11.55 can increase the diagnostic confidence (specificity = 100%) for high grade bladder carcinoma situations where clear distinction between low and high grade is not possible on morphology alone. thus, addition of these markers to the existing protocols may increase the objectivity and reliability for accurate diagnosis, patient management and tumor progression than the conventional grade and stage alone. acknowledgements technical assistance in immunohistochemistry was provided by mr. dilvar dutt. conflict of interest none declared. figure 6. roc curve of mitotic indices, agnor count, bcl-2 and ki-67 labelling index for bladder cancer grade. references 1. parkin dm. the global burden of urinary bladder cancer. scand j urol 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gonzalez-campora r, davalos-casanova g, beato-moreno a et al. bcl-2, tp53 and bax protein expression in superficial urothelial bladder carcinoma. cancer lett. 2007;250:292-9. 33. touloupidis s, fatles g, kalaitzis c et al. the significance of p53 and bcl-2 overexpression and other prognostic factors in transitional cell carcinoma of the bladder. int urol nephrol. 2006;38:231-6. proliferative markers and bcl-2 in bladder cancer | goyal et al pediatric urology safety and efficiency of pyeloplasty in the first six weeks of infants' life serdar moralıoğlu*, aysenur cerrah celayir, oktav bosnalı, osman zeki pektas purpose: the aim of this study was to assess the safety and the efficiency of pyeloplasty in infants with ureteropelvic junction obstruction (upjo) in the first six weeks of their life. materials and methods: clinical records of the patients who had surgery during first six weeks of life for upjo between june 2009 and june 2014 were analysed retrospectively. results: in this period, twenty-six dismembered pyeloplasties were performed in twenty-four patients on mean operation age of 27.3 ± 10.2 days (range 8-42 days). on the first postnatal ultrasound all twenty-six renal units had sfu-4 hydronephrosis. mean preoperative and postoperative anterior-posterior pelvic diameter and parenchymal thickness were 33.1 ± 8.9mm (range 14-49mm), 3.2 ± 1mm (range 1-4,6mm) and 14.7 ± 6.6mm (range 6-27mm) and 7.8 ± 1.9mm (range 3.0-10.4mm), respectively. the differences between preoperative and postoperative parenchymal thickness and anterior-posterior pelvic diameter were statistically significant (p ˂ 0.0001). preoperative mag3 dynamic renal scintigraphy showed obstructive pattern on the diuretic renogram in 26 units. mean preoperative and postoperative differential renal function on dynamic renal scintigraphy of the affected renal units were 46 ± 15 and 44 ± 15, respectively. postoperative drainage was normal on dynamic renal scintigraphy in 25 (96.2%) of the 26 units, redo-pyeloplasty was needed in only one unit (3.8%). conclusion: in conclusion, patient selection and timing of surgery are very important in the protection of renal function in newborn with upjo. in our opinion, if there is indication for surgery, early surgical intervention should not postpone in this period. surgical treatment of upjo during first six weeks of life is safe and effective. keywords: newborn; pyeloplasty; ureteropelvic junction obstruction introduction ureteropelvic junction obstruction (upjo) is still the most common antenatally diagnosed surgical anomaly in pediatric urology. antenatal hydronephrosis is detected on prenatal ultrasonography in 1-5% of all pregnancies.(1) the reasons of antenatal hydronephrosis are transient hydronephrosis, ureteropelvic junction obstruction, vesicoureteral reflux, megaureters, multicystic dysplastic kidney, posterior urethral valve and other less common diseases. typical ultrasonographic findings of upjo are commonly unilateral pelvicalyceal dilatation without ureteral dilatation. in the postnatal management of these patients, non-operative follow-up is widely accepted, especially unilateral mild to moderate hydronephrosis. most of these patients’ hydronephrosis resolve spontaneously, this benign situation is named as transient hydronephrosis. surgical treatment is indicated when progression of hydronephrosis and/or deterioration of renal function are detected, on the follow-up period. although, vast majority of the cases with antenatally detected hydronephrosis resolve spontaneously, some of these required early intervention during early infancy. in the patients with severe hydronephrosis, indications of early surgical intervention, type and the timing of the intervention are still controversy. in here, indications and experiences of surgical treatment in patients with severe hydronephrosis with upjo in the first six weeks of life were reported. the aim of this study was to assess the safety and efficiency of pyeloplasty in infants with upjo in this period. materials and methods study population this retrospective study was carried out at university of health sciences, zeynep kamil maternity and children’s diseases health training and research center, department of the pediatric surgery, istanbul. clinical records of the patients who had surgery during first six weeks of life for upjo between june 2009 and june 2014 were analysed retrospectively. demographic, diagnostic, operative findings and outcomes were analysed. age, gender, side of hydronephrosis, type of presentations, results of the preoperative imaging studies, additional urological anomalies, indications of surgery, details of operations, and status on the follow-ups were recorded. the patients who had less than 1 year follow-up period were excluded from the study. preoperative evaluation in all patients with antenatally diagnosed hydronephrosis, detailed ultrasounds of the urinary system were done in the first week of life. on ultrasound examination, hydronephrosis was graded according to the society of fetal urology (sfu) guidelines, and antero-posuniversity of health sciences, zeynep kamil maternity and children’s diseases health training and research center, department of the pediatric surgery, istanbul, turkey. *correspondence: zeynep kamil mah. op.dr.burhanettin üstünel cad. no:4/3 34668 üsküdar, istanbul,turkey. tel:+90 216 3910680. fax:+90 216 3439251. key, e-mail: serdarmoralioglu@gmail.com received august 2019 & accepted february 2020 urology journal/vol 18 no. 1/ january-february 2021/ pp. 81-85. [doi: 10.22037/uj.v0i0.5531] terior diameter of renal pelvis, parenchymal thickness and caliectasis existence were determined.(2) if severe hydronephrosis (sfu-4) was present with thinning of the parenchyma, serial ultrasonography and dynamic renal scintigraphy were done. dynamic renal scintigraphy was done as well-tempered diuretic mercaptoacetyltriglycine (mag3) renogram. in this procedure, intravenous hydration and urethral catheterisation before the procedure and diuretic administration at the point of maximal uptake were done in all patients. voiding cystourethrography was done in all patients. when progressive hydronephrosis and severe parenchymal thinning were detected on ultrasonography and the obstructive pattern was present on mag3 dynamic renal scintigraphy, pyeloplasty was performed. the obstructive pattern was defined as completely non-responsiveness to diuretic administration on the renography and completely persistence of pelvic accumulation on the 2 hours delayed images. in the patients who had not obstructive pattern or severe parenchymal thinning, non-operative follow-up were continued. in case of bilateral disease simultaneous operation was not done, worst side was operated first. operative technique in the operating theater, urethral catheter was inserted and affected side was slightly elevated with towels in supine position. in all patients’ operations, approximately 2cm length anterior subcostal incision was used and kidney was exposed via extraperitoneal approach. anderson-hynes dismembered pyeloplasty with pelvic reduction were done in all patients. ureteropelvic anastomoses were done with 6-0 or 7-0 polydioxanone absorbable monofilament separated sutures. antegrade placement of double-j stent or insertion of pyelostomy catheter was done during ureteropelvic anastomosis. at the end of the all procedures a penrose drain was inserted to the perinephric area through the same incision (figure 1). post-operative evaluation enteral feeding was started 4 hours after operation. antibiotic treatment (ampicillin/sulbactam) was started preoperatively and this was continued until the patient was discharged from the hospital. urethral catheter was removed in the first postoperative day. penrose drain was removed when drainage ceased. thereafter, patient was discharged with antibiotic prophylaxis (amoxicillin, 20 mg/kg/day) until the double-j stent was removed on the 6th week after the operation. postoperative follow-up consisted of serial ultrasonography and mag3 dynamic renal scintigraphy. statistical analysis descriptive statistics were used and results were expressed as mean ± standard deviation, and median. a paired t-test was used to determine whether a statistically significant difference between preoperative and postoperative results of the patients. statistical significance was considered at p < 0.05. statistical analyses were performed with the spss statistics for windows version 15 package software (spss inc., chicago, il, usa). institutional ethical board approval was obtained for this study (5.09.2014-150). results in this five-year period, a total of 603 renal units in 499 newborns with antenatally diagnosed isolated hydronephrosis were followed and treated. 526 renal units (87.2%) were followed conservatively. in the 26 units (4.3%) early pyeloplasty were done before six-week of age. afterward, 51 units (8.5%) which were initially treated conservatively eventually required pyeloplasty. of the 24 patients whom had early pyeloplasty done before six-week of age, consisted of 16 male and 8 female. twenty-three patients presented with antenatally detected hydronephrosis. diagnosis was made incidentally in one patient following workup for etiology of simian line. upjo was found in the left kidney in 21 patients (87.5%) and in the right in one patient. two patients had bilateral disease. two patients had (8.3%) additional urological anomalies. one patient had multicystic dysplastic kidney in contralateral kidney and the other patient had bilateral ureterovesical junction obstruction. on the first postnatal ultrasound all twenty-six renal units had sfu-4 hydronephrosis. mean preoperative anterior-posterior pelvic diameter and parenchymal thickness were 33.1 ± 8.9 mm (range 14-49 mm, median 32 mm) and 3.2 ± 1 mm (range 1-4,6 mm, median 3.3 mm), respectively. mag3 dynamic renal scintigraphy showed obstructive pattern on the diuretic renogram in 26 units. mean preoperative differential renal function on dynamic renal scintigraphy of the affected 19 renal units (2 bilateral upjo, 1 multicystic dysplastic kidney, 2 differential functions unavailable) was 46 ± 15% (range 4-64%, median 48%). voiding cystourethrography results were normal in all patients. twenty-six dismembered pyeloplasties were performed on mean operation age of 27.3 ± 10.2 days (range 8-42 days, median 30 days). the mean operative time was 84 minutes (range 60-100 minutes, median 90 minutes). double-j ureteral stent was used as internal drainage in 20 patients (22 units). in three patients, ureteral stent was used as pyelostomy tube. in one patient, operation was done without stent. there was no anesthesia related complication. mean time of the penrose drain removal was 2.3 ± 0.4 days (range 2-3 days). average length of stay was 3.2 ± 0.7 days (range 2-5 days). in the intraoperative and postoperative period, double-j stent related events occurred in the 8 of 26 renal units. in the one patient, double-j stent did not pass through the ureterovesical junction and the operation was performed without internal and external stent. in the two girl patients double-j stents passed out through the urethra spontaneously in the early postoperative period. in these three patients no complication such as urinoma or pyeloplasty in the six weeks of life-moralıoğlu et al. table 1. classification of double-j stent related events according to clavien classification system.(3) total renal units grade 1, n (%) grade 2, n (%) grade 3, n (%) grade 4, n (%) grade 5, n (%) 26 8 (31) 0 (0) 0 (0) 0 (0) 0 (0) pediatric urology 82 vol 18 no 1 january-february 2021 83 table 2. comparison of preoperative and postoperative anterior-posterior pelvic diameter, parenchymal thickness and differential renal function on mag3. variables preoperative postoperative p-value anterior-posterior pelvic diameter (mean ± sd) 33.1 ± 8.9 mm (range 14-49) 14.7 ± 6.6 mm (range 6-27) ˂ 0.0001 parenchymal thickness (mean ± sd) 3.2 ± 1 mm (range 1-4,6) 7.8 ± 1.9 mm (range 3.0-10.4) ˂ 0.0001 differential renal function on mag3 (mean ± sd) 46 ± 15% (range 4-64%) 44 ± 15% (range 5-59%) ˃ 0.05 recurrent upjo occurred. in the one renal unit, ureteroscopic intervention was required for ureteral migration of the double-j stent. in the last two renal units, double-j stents were removed during politano-leadbetter ureteroneocystostomy which was performed due to bilateral ureterovesical junction obstruction. when these events were classified according to clavien classification system stage 1, 2, 3, 4, 5, complication rate was observed in 31%, 0%, 0%, 0%, and 0% of renal units, respectively (table 1).(3) mean time of the follow-up period after the operation was 81.2 ± 17.4 months (range 53-110 months, median 84 months). mean postoperative anterior-posterior pelvic diameter and parenchymal thickness on the third postoperative month were 14.7 ± 6.6 mm (range 6-27 mm, median 13 mm) and 7.8 ± 1.9 mm (range 3.0-10.4 mm, median 8.1 mm), respectively. the differences between preoperative and postoperative parenchymal thickness and anterior-posterior pelvic diameter were statistically significant (p ˂ 0.0001). mean postoperative differential renal function on dynamic renal scintigraphy of the affected 21 renal units (2 bilateral upjo, 1 multicystic dysplastic kidney) was 44 ± 15% (range 5-59%, median 51%).(table 2) postoperative drainage was normal on dynamic renal scintigraphy in 25 of the 26 units (96.2%), redo-pyeloplasty was needed in only one unit (3.8%). in this patient, operation was performed for recurrent upjo at 2-year old. early and late postoperative period was uneventful. in the postoperative mag3 dynamic renal scintigraphy, drainage was normal. in the 71st month of follow up after the reoperation, the patient had no symptoms and hydronephrosis had improved. discussion by the routine usage of prenatal ultrasonography, detection of asymptomatic severe upjo is increased and these patients catch the early treatment of chance before the renal dysfunction and the failure. the main goal in the treatment of the upjo is to preserve or to improve renal function. although, antenatal hydronephrosis is common, severe hydronephrosis is relatively rare. in the literature, sfu grade 3 and 4 hydronephrosis rate in all hydronephrosis varies 21-25% and 15-21%, respectively.(4,5) in order to assess severity of antenatal and postnatal hydronephrosis many grading system is being used. the anteroposterior diameter of the renal pelvis and society for fetal urology grading systems most commonly used methods in the literature and practice. in 1993, society for fetal urology proposed a grading system based on the postnatal ultrasonographic appearance of the renal pelvis, calyces and parenchyma. in this system sfu grade 4 is presence of distention of renal pelvis and calyces with parenchymal thinning. severity of parenchymal thinning was not graded in sfu grading system. by this grading system standardisation was aimed, there was no treatment algorithm.(2) in onen’s alternative grading system parenchymal thinning was graded as less than half and more than half parenchymal thinning and named in the alternative grading system as grade 3 and 4, respectively. in this grading system, early intervention was recommended for the patients with grade 4.(4) in our series, all patients fell into grade 4 hydronephrosis according to both sfu and onen’s alternative grading system. in 1990 ransley et al. advocated a conservative approach based on isotope imaging findings and surgery was reserved presence of significant loss of renal function.(6) later, several publications have supported this approach even in patients with severe (sfu grade 3-4) hydronephrosis.(7-10) in that series, early pyeloplasty rate varies from 10% to 38% and final pyeloplasty rate when added the patients with operated after initially conservative treatment varies from 22% to 68% in the severe hydronephrosis.(7-10) on the other hand, criticisms of this conservative approach have been done in the literature. subramaniam et al. concluded that conservative management of some patients with antenatally detected upjo probably results in irreversible loss of function.(11) hanna, in an editorial review paper, emphasised inaccuracy of diagnostic tests for the diagnosis of obstruction, sensitive nature of the infant kidneys and more significant improvement than older pyeloplasties of the renal function after surgery in all infants(12) thus, he advocated early intervention in patients with increased pelvic dilation on ultrasound and prolongation of the diuretic nuclear renogram washout half-time. in their prospective study, babu et al. found significant loss of renal function in patients; with sfu grade 3-4 hydronephrosis with obstructive renogram; who had been initially treated conservatively.(13) defi-fig1. postoperative view of the pyeloplasty incision. pyeloplasty in the six weeks of life-moralıoğlu et al. nition of obstructive renogram in this study was type 2 o'reilly curve with hold up at 2 hours delayed graphy.(14) in the literature, early and total pyeloplasty rates in all hydronephrosis grades varies from 0-10.1% and 11.8-15.2%, respectively.(4-6,9) in our series, early and total pyeloplasty rates in all hydronephrosis grades were 4.3% and 12.8%, respectively. actually, still there is no absolute indicator of accurate obstruction or early predictor of renal injury in the newborn hydronephrosis. current methods are not sensitive or specific enough yet to differentiate an obstruction which has potential lead to renal deterioration. for that reason, indications and timing of surgery in newborns with severe hydronephrosis are still controversial. previously, on the mag3 dynamic renal scintigraphy, postdiuretic renal pelvis clearance half-time (t1/2) greater than 20 minutes is thought to indicate obstruction.(14) afterward, eskild-jensen et al. stated that it could be affected by hydration, renal function, diuretic injection time, gravity, status of bladder filling and volume of renal pelvis.(16) in our practice, in the patients with half-time shorter than 20 minutes, non-operative follow-up was continued by intervals depending on severity of hydronephrosis. prolonged half-time (˃ 20 minutes) was not used for indicator of obstruction in our series. obstructive pattern was defined as completely non-responsiveness to diuretic administration on the renography and completely persistence of pelvic accumulation on the late images. in the literature, there are many algorithms about management of antenatal hydronephrosis. the cornerstone of vast majority of these algorithms is estimated differential renal function on mag3 dynamic renography. (5,9,10,17) eskild-jensen et al. stated that estimated differential renal function is not influenced by degree of hydronephrosis, status of hydration and bladder filling, gravity, diuretic usage and the level of renal function. (16) on the other hand, estimation of differential renal function is influenced by age, size of the affected kidney, time period of the calculation of differential renal function and size of the region of interest.(18,19). in small children with severe hydronephrosis difficulties may arise in interpreting. age-related disparity of differential renal function estimation in children with unilateral hydronephrosis is more common under 1 year of age. especially, disagreement rate is much higher in the children age under 3 months.(18) in our series, mean preoperative and postoperative differential renal function on mag3 dynamic renography was 46% and 43%, respectively. we think that, postoperative estimation of differential renal function is more realistic than preoperative differential renal function estimation because of higher age and normalised kidney size in postoperative period. in the literature, surgical indications generally described as existence of urinary obstruction, renal deterioration, urinary tract infection and abdominal mass. definitions of urinary obstruction and renal deterioration were specified as impaired differential renal function (<30-40%), worsening hydronephrosis on ultrasonography and parenchymal loss or reduction in differential renal function of more than 10% on follow up.(9,10,20,21) onen recommends early intervention after a short period of follow up in patients with severe hydronephrosis plus severe parenchymal loss (more than half).(4) babu et al. have operated patients with sfu grade 3-4 hydronephrosis with type 2 o'reilly curve with hold up at 2 hours delayed graphy.(13,14) in our series, all renal units had severe hydronephrosis (sfu-4) and also they had severe parenchymal loss or progression of hydronephrosis or both. in our series, indication for surgery was, in the patients with initially grade 4 hydronephrosis, increased hydronephrosis with severe parenchymal thinning and obstructive pattern on the diuretic renogram. we think that, this kind of investigation and follow-up of the patients with severe hydronephrosis is helpful for the individualized decision-making process. in this instance each case should be evaluated individually and parents should be informed on the advantages and disadvantages of both early surgery and conservative approach. when intervention required in the six-week of life, treatment options could be definitive (i.e.pyeloplasty) or temporary (i.e.nephrostomy, double-j stent insertion). in the literature, there is no data about these methods’ safety or efficiency for this period. in our series, we preferred open dismembered pyeloplasty through the approximately 2cm length anterior subcostal incision. this approach with that kind of a small incision is proper and suitable for newborns and small infants. also, it has satisfactory cosmetic results. in pediatric age group, using diversion in dismembered pyeloplasty is still controversial. surgeon does make diversion or not according to clinical preferences. in the newborn period, diversion is usually recommended. in open dismembered pyeloplasty, diversion options are external drainage by nephrostomy, pyelostomy, ureteropyelostomy or internal drainage by double-j stent. each of these has unique advantages and disadvantages; and none of these methods are free of complication. in our series, primarily, diversion by double-j stent was preferred. in three cases, pyelostomy was used due to surgeon preference and difficulties with antegrade passing of the stent. pyelostomies were removed in 7 to 15 days the operation. in our series, no perioperative and early postoperative complication was encountered and postoperative recovery was uneventful. in the literature, even though age groups and details of operative techniques are heterogeneous, failure and reoperation rates after open dismembered pyeloplasty varies from 0% and 12,5%.(20,22-26) in our series, which is the homogeneous age group of patients in the first six-week of life, recurrence rate was 3.8%. our study has some limitations. these were retrospective design of the study, the lack of comparison group in the study design and the low number of patients in the study group. conclusions patient selection and timing of surgery are very important in the protection of renal function in newborn with upjo. in our opinion, if there is indication for surgery, early surgical intervention should not postpone in this period. surgical treatment of upjo during first six weeks of life is safe and effective. conflict of interest the authors declare no conflict of interest references 1. nguyen ht, herndon cd, cooper c, et al. the society for fetal urology consensus pyeloplasty in the six weeks of life-moralıoğlu et al. pediatric urology 84 vol 18 no 1 january-february 2021 85 statement on the evaluation and management of antenatal hydronephrosis. j pediatr urol 2010; 6: 212-31. 2. fernbach sk, maizels m, conway jj. ultrasound grading of hydronephrosis: introduction to the system used by the society for fetal urology. pediatr radiol 1993; 23: 47880. 3. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg 2004; 240: 205–13. 4. onen a. an alternative grading system to refine the criteria for severity of hydronephrosis and optimal treatment guidelines in neonates with primary upj-type hydronephrosis. j pediatr urol 2007; 3: 200-5. 5. karnak i, woo ll, shah sn, sirajuddin a, ross jh. results of a practical protocol for management of prenatally detected hydronephrosis due to ureteropelvic junction obstruction. pediatr surg int 2009; 25: 61-7. 6. ransley pg, dhillon hk, gordon i, duffy pg, dillon mj, barratt tm. the postnatal management of hydronephrosis diagnosed by prenatal ultrasound. j urol 1990; 144: 584-7. 7. arnold aj, rickwood am. natural history of pelviureteric obstruction detected by prenatal sonography. br j urol 1990; 65: 91-6. 8. madden np, thomas df, gordon ac, arthur rj, irving hc, smith se. antenatally detected pelviureteric junction obstruction. is nonoperation safe? br j urol 1991; 68: 305-10. 9. ulman i, jayanthi vr, koff sa. the longterm followup of newborns with severe unilateral hydronephrosis initially treated nonoperatively. j urol 2000; 164: 1101-5. 10. heinlen je, manatt cs, bright bc, kropp bp, campbell jb, frimberger d. operative versus nonoperative management of ureteropelvic junction obstruction in children. urology 2009; 73: 521-5. 11. subramaniam r, kouriefs c, dickson ap. antenatally detected pelvi-ureteric junction obstruction: concerns about conservative management. bju int 1999; 84: 335-8. 12. hanna mk. antenatal hydronephrosis and ureteropelvic junction obstruction: the case for early intervention. urology 2000; 55: 612-5. 13. babu r, rathish vr, sai v. functional outcomes of early versus delayed pyeloplasty in prenatally diagnosed pelvi-ureteric junction obstruction. j pediatr urol 2015; 11: 63.e1-5. 14. o’reilly ph, consensus committee of the society of radionuclides in nephrourology. standardization of the renogram technique for investigating the dilated upper urinary tract and assessing the results of surgery. bju int 2003; 91: 239-43. 15. lupton ew, testa hj, o'reilly ph, et al. diuresis renography and morphology in upper urinary tract obstruction. br j urol 1979; 51: 10-14. 16. eskild-jensen a, gordon i, piepsz a, frøkiaer j. interpretation of the renogram: problems pyeloplasty in the six weeks of life-moralıoğlu et al. and pitfalls in hydronephrosis in children. bju int 2004; 94: 887-92. 17. palmer ls, maizels m, cartwright pc, fernbach sk, conway jj. surgery versus observation for managing obstructive grade 3 to 4 unilateral hydronephrosis: a report from the society for fetal urology. j urol 1998; 159: 222-8. 18. ozcan z, anderson pj, gordon i. robustness of estimation of differential renal function in infants and children with unilateral prenatal diagnosis of a hydronephrotic kidney on dynamic renography: how real is the supranormal kidney? eur j nucl med mol imaging 2006; 33: 738-44. 19. gungor f, anderson p, gordon i. effect of the size of regions of interest on the estimation of differential renal function in children with congenital hydronephrosis. nucl med commun 2002; 23: 147-51. 20. kajbafzadeh am, tourchi a, nezami bg, khakpour m, mousavian aa, talab ss. miniature pyeloplasty as a minimally invasive surgery with less than 1 day admission in infants. j pediatr urol 2011; 7: 283-8. 21. turner rm 2nd, fox ja, tomaszewski jj, schneck fx, docimo sg, ost mc. laparoscopic pyeloplasty for ureteropelvic junction obstruction in infants. j urol 2013; 189: 1503-7. 22. braga lh, lorenzo aj, bägli dj, et al. risk factors for recurrent ureteropelvic junction obstruction after open pyeloplasty in a large pediatric cohort. j urol 2008; 180: 1684-7. 23. morsi ha, mursi k, abdelaziz ay, elsheemy ms, salah m, eissa ma. renal pelvis reduction during dismembered pyeloplasty: is it necessary? j pediatr urol 2013; 9: 303-6. 24. almodhen f, jednak r, capolicchio jp, eassa w, brzezinski a, el-sherbiny m. is routine renography required after pyeloplasty? j urol 2010; 184: 1128-33. 25. scuderi mg, arena s, di benedetto v. onetrocar-assisted pyeloplasty. j laparoendosc adv surg tech a. 2011; 21: 651-4. 26. masieri l, sforza s, cini c, et al. minilaparoscopic versus open pyeloplasty in children less than 1 year. j laparoendosc adv surg tech a. 2019; 29: 970-5. v08_no_4_final_new.pdf miscellaneous 313urology journal vol 8 no 4 autumn 2011 protective effects of zofenopril on testicular torsion and detorsion injury in rats bülent altunoluk,1 haluk söylemez,2 vedat bakan,3 harun ciralik,4 fatma inanc tolun5 purpose: to investigate the protective effect of zofenopril on torsion/ detorsion-induced biochemical and histopathological changes in experimental testicular ischemia or reperfusion injury in rats. materials and methods: a total of 35 prepubertal male wistar-albino rats were divided into five groups, including 7 rats in each group: group i (sham, s), sham operation; group ii (torsion/detorsion-early orchiectomy, t/d-e), 2 hours ischemia and 4 hours reperfusion; group iii (torsion/detorsion-late orchiectomy), t/d-l), 2 hours ischemia and 5 days reperfusion; group iv (zofenopril-early orchiectomy, z-e), 2 hours ischemia, 4 hours reperfusion, and a single dose of zofenopril; and group v (zofenopril-late orchiectomy, z-l), 2 hours ischemia, 5 days reperfusion, and 5 doses of zofenopril. we determined the tissue levels of malondialdehyde, nitric oxide, glutathione peroxidase, and superoxide dismutase enzyme activities. histopathologically, mean seminiferous tubule diameter measurements were used. results: malondialdehyde (3.490 ± 0.89 versus 1.729 ± 0.25 in early period; 3.837 ± 1.694 versus 1.694 ± 0.47 in late period) and nitric oxide levels (3.507 ± 0.44 versus 2.853 ± 0.54 in early period; 4.010 ± 0.72 versus 2.446 ± 0.29 in late period) significantly reduced and glutathione peroxidase (0.012 ± 0.001 versus 0.017 ± 0.001 in early period; 0.013 ± 0.002 versus 0.018 ± 0.001 in late period) and superoxide dismutase enzyme activities (58.030 ± 5.97 versus 70.773 ± 3.85 in early period; 57.421 ± 7.81 versus 76.329 ± 4.09 in late period) significantly increased in the testis tissue in zofenopril pretreated groups compared to group t/d both in early and late period (p < .05). the mean seminiferous tubule diameter was significantly better in pretreated group (210.33 ± 17.32) than group t/d (185.02 ± 22.45) only in late period (p < .05), but not in early period (209.38 ± 30.40 versus 208.21 ± 13.57; p > .05). conclusion: treatment with zofenopril decreased damage in ipsilateral testis caused by ischemia/reperfusion, and clinical application of zofenopril might be a new approach for the treatment of testicular torsion in addition to conventional detorsion. urol j. 2011;8:313-9. www.uj.unrc.ir keywords: zofenopril, antioxidants, oxidative stress, testis, ischemia, reperfusion 1department of urology, medical 2department of urology, dicle 3department of pediatric surgery, 4department of pathology, medical 5department of biochemistry, corresponding author: altunoluk bülent, md department of urology, medical yörükselim mah, hastane cad, tel: +90 505 952 3622 fax: +90 344 221 2371 e-mail: drbulenta@yahoo.com received december 2010 accepted april 2011 introduction testicular torsion is a common urologic emergency condition usually affecting newborns, children, and adolescent boys. early diagnosis and immediate treatment are crucial for the preservation of the sperm production and fertility. it seems that the main pathophysiology of testicular torsion/detorsion is ischemia/reperfusion (i/r) injury of the testis.(1,2) zofenopril and testicular torsion—altunoluk et al 314 urology journal vol 8 no 4 autumn 2011 these i/r injuries are associated with the overproduction of reactive oxygen species (ros) and reactive nitrogen species (rns), with the return of blood flow following a period of ischemia, as shown in other organs, such as the brain, myocardium, kidneys, and testes.(3) it has been demonstrated that ros increase in the areas of ischemia and reperfusion, and is thought to play a crucial role in the loss of ipsilateral testicular spermatogenesis.(4) zofenopril, a derivative of the proline amino acid and an inhibitor of angiotensin-converting enzyme and angiotensin ii,(5) ameliorates experimental cardiac and renal i/r injury or doxorubicininduced cardiac injury in animal models(6,7) and has beneficial cardiovascular effects in patients with myocardial infarction.(8) mak and colleagues demonstrated that angiotensin-converting enzyme inhibitor agents, including zofenopril, can protect endothelial cells against free radical-induced lipid peroxidation and cell injury.(9) the successful result of zofenopril in different organs led us to the use of this treatment in the model of testicular torsion. the aim of this study was to investigate the protective effect of zofenopril, on torsion/detorsion-induced biochemical and histopathological changes in experimental testicular i/r injury. materials and methods animals and reagents the experimental protocol was approved by the ethics committee. this study was carried out on 35 prepubertal male wistar-albino rats (170 to 220 g). the experimental animals were housed at room temperature under a 12 h light/12 h dark cycle and had free access to both tap water and standard pellet diet for rats. zofenopril (zoprotec, menarini group, italy) was given orally (15 mg/ kg/day). experimental groups a total of 35 rats were randomly divided into five groups (n = 7). group i (sham, s), sham operation; group ii (torsion/detorsion-early orchiectomy, t/d-e), 2 hours ischemia and 4 hours reperfusion; group iii (torsion/detorsionlate orchiectomy), t/d-l), 2 hours ischemia and 5 days reperfusion; group iv (zofenopril-early orchiectomy, z-e), 2 hours ischemia, 4 hours reperfusion, and a single dose of zofenopril; and group v (zofenopril-late orchiectomy, z-l), 2 hours ischemia, 5 days reperfusion, and 5 doses of zofenopril. surgical procedure the rats were anesthetized with intraperitoneal ketamine injection (50 mg/kg). all operations were performed under sterile conditions. the scrotum was entered through a scrotal midline incision. the tunica vaginalis was opened, and the left testis was delivered to the surgical field. the left testis was rotated 720° in a clockwise direction and then left in the same position by fixing it to the scrotum with a 4–0 silk suture.(10-13) the ischemia period was 2 hours and orchiectomy was performed after 4 hours of detorsion in the early orchiectomy model. in the late orchiectomy model, the ischemia period was 2 hours and orchiectomy was performed after 5 days of detorsion. in the early orchiectomy groups, zofenopril (15 mg/kg/day, po) was administered only once, 30 minutes prior to detorsion. in the late orchiectomy groups, zofenopril (15 mg/ kg/day, po) was administered 30 minutes before detorsion, once daily for 5 days. in order to be consistent, all the control animals (both the early and late orchiectomy models) were gavaged with pro-rated volumes of normal saline. at the end of the study, ipsilateral orchiectomy was performed to determine biochemical and histopathological changes in all groups. biochemical analysis all testes tissue specimens were washed with 0.9% nacl to remove hematoma and then air dried. they were stored in plastic bottles individually at -20°c until biochemical analyses were carried out. the testicular tissue was homogenized with 1.5% potassium chloride to make a 10% homogenate using a glass homogenizer. testicular malondialdehyde (mda) in tissue homogenate was measured using the thiobarbituric acid reactive substance assay, as described by ohkawa and associates.(14) the principle of the method is based zofenopril and testicular torsion—altunoluk et al 315urology journal vol 8 no 4 autumn 2011 on measurement of the concentration of the pink chromogen compound that forms when mda reacts with thiobarbituric acid. the mda level is expressed as nanomoles per milligram protein. nitric oxide (no) measurement was performed using the griess method for detection of nitrite levels.(15) nitric oxide is unstable and has a short lifetime; in the presence of oxygen, it reacts rapidly to form nitrite or nitrates. since the direct determination of no radicals is difficult, and since nitric oxide synthase (nos) activity can only be determined in tissue or cell homogenates, the determination of nitrite, the stable end product of no radicals, is most often used as a measure of no production. superoxide dismutase activity in the tissue was measured according to the method described by fridovich.(16) this method employs xanthine and xanthine oxidase to produce superoxide radicals that react with p-iodonitrotetrazolium violet to form a red formazon dye, which was measured at 505 nm. superoxide dismutase activity was expressed in units per milligram of protein (units/mg). glutathione peroxidase (gpx) activity was measured by the method of paglia and valentine.(17) the enzymatic reaction in the tube, which contained nicotinamide adenine dinucleotide phosphate, reduced glutathione, sodium azide, and glutathione reductase, was initiated by addition of h2o2, and the change in absorbance at 340 nm was monitored by a spectrophotometer. histopathological evaluation the testicular tissue was fixed in bouin’s solution, post fixed in 70% alcohol, and embedded in a paraffin block. a 5-μm section was obtained, deparaffinized, and stained with hematoxylin and eosin. histological evaluation using the light microscope was done by an observer in a blind, randomly numbered fashion without any knowledge of which testis had or had not undergone torsion. the mean seminiferous tubular diameter (mstd) was estimated by measuring ten separate roundest seminiferous tubules with a microscope-adaptable micrometer for each testis. statistical analysis statistical analyses were accomplished using the spss software (the statistical package for the social sciences, version 15.0, spss inc, chicago, illinois, usa). all results were reported as mean ± sd. differences between groups of continuous data were compared by mann– whitney u test. p values less than .05 were considered statistically significant. results biochemical results malondialdehyde and no levels, and sod and gpx activities from the testicular tissue samples are demonstrated in table. the mda and no levels were significantly higher in the t/d-e and t/d-l groups compared to the sham group (p < .01). mda (nmol/mg protein) sod (units/mg protein) gpx (units/mg protein), μm no (units/mg protein) mstd s 1.327 ± 0.30 76.359 ± 7.05 0.018 ± 0.001 2.353 ± 0.29 205.17 ± 11.21 t/d-e 3.490 ± 0.89a 58.030 ± 5.97a 0.012 ± 0.001a 3.507 ± 0.44a 208.21 ± 13.57 t/d-l 3.837 ± 1.52b 57.421 ± 7.81b 0.013 ± 0.002b 4.010 ± 0.72b 185.02 ± 22.45b z/e 1.729 ± 0.25c 70.773 ± 3.85c 0.017 ± 0.001c 2.853 ± 0.54c 209.38 ± 30.40 z/l 1.694 ± 0.47d 76.329 ± 4.09d 0.018 ± 0.001d 2.446 ± 0.29d 210.33 ± 17.32d *mda indicates malondialdehyde; sod, superoxide dismutase; gpx, glutathion peroxidase; no, nitric oxide; mstd, mean seminiferous tubular diameter; group s, sham operation; group t/d-e, 2 hours ischemia and 4 hours reperfusion; group t/d-l, 2 hours ischemia and 5 days reperfusion; group z-e, 2 hours ischemia, 4 hours reperfusion, and a single dose of zofenopril; and group z-l, 2 hours ischemia, 5 days reperfusion, and 5 doses of zofenopril. £ the values are expressed as mean ± sd, n = 7 for each group. a p < .01 when t/d-e compared with s b p < .01 when t/d-l compared with s c p < .05 when z/e compared with t/d-e d p < .05 when z/l compared with t/d-l tissue mda, sod, gpx, and no levels and mstd values of all groups* zofenopril and testicular torsion—altunoluk et al 316 urology journal vol 8 no 4 autumn 2011 in groups z-e and z-l, there was significant reduction of the ipsilateral testicular mda and no levels after zofenopril treatment both in early and late period (p < .05). the gpx and sod activities of ipsilateral testes in groups t/d-e and t/d-l reduced in comparison with group s (p < .01). in the treatment groups, groups z-e and z-l, the sod and gpx activities increased after treatment with zofenopril (p < .05). histopathological results the values of mstd of each group are listed in table. after testicular i/r, the mstd from the group t/d-l significantly decreased in the ipsilateral testes when compared with the group s (p < .01). but in the group t/d-e, the value of mstd did not reduce. the findings of the histopathological evaluation for each group are shown in figures 1 to 5. the testes of rats in group s indicated the presence of normal testicular structure and uniform seminiferous tubular morphology with normal spermatogenesis and the presence of primary and secondary spermatocytes, spermatids, and spermatozoa (figure 1). in the i/r group, there was a significant reduction in the seminiferous tubular diameter. furthermore, there were severe distortion of tubules and presence of peritubular fibrosis. these findings were observed only in the late orchiectomy model (figure 2), but not in the early orchiectomy model (figure 3). zofenopril-treated animals showed an improved histological appearance in the left testis in the z-l group compared with t/d-l group (p < .05). figure 4. histologic findings of ipsilateral testes in zofenopril pretreatment-late orchiectomy (hematoxylin and eosin, 100×) figure 3. histologic findings of ipsilateral testes in torsion/ detorsion-early orchiectomy figure 2. histologic findings of ipsilateral testes in torsion/ detorsion-late orchiectomy figure 1. histologic findings of ipsilateral testes in shamoperation zofenopril and testicular torsion—altunoluk et al 317urology journal vol 8 no 4 autumn 2011 administration of zofenopril caused significant rescue of testicular function by preserving the intact seminiferous tubular morphology in the left testis (figure 4). on the other hand, in z-e group, treatment with zofenopril led to findings similar to those of the t/d-e group (figure 5). discussion testicular torsion is a surgical emergency that needs prompt intervention to torsioned gonad. late presentation or failures in diagnose or inadequate management will lead to testicular injury.(18) ischemia-reperfusion injury to the testes is associated with overgeneration of ros, such as hypochlorous acid, nitric oxide, hydrogen peroxide, superoxide anion, hydroxyl radicals, and so forth.(19) mammalian testes are highly susceptible to oxidative stress.(1,12) high concentrations of ros play an important role in the pathophysiology of damage to human spermatozoa.(19) the ros are difficult to quantify directly in tissue because of their high reactivity and short half-life. (12,20) malondialdehyde is used widely as an oxidative stress indicator in tissues induced by i/r.(20) malondialdehyde is the stable final product of lipid peroxidation produced by ros and is a well-known parameter for determining the increased free radical formation in reperfused tissue.(21) many studies showed that mda levels in testicular tissue increase after testicular injury.(10-13,22) the level of mda significantly increased in the t/d group when compared to the sham group. our findings agree with these testicular torsion studies. furthermore, pretreatment with zofenopril (15 mg/kg/ day) prevented lipid peroxidation, resulting in decreased mda accumulation. nitric oxide is an important mediator of cell death either through apoptosis or necrosis, depending on the duration and severity of injury.(23) our study showed that i/r injury due to testicular torsion/detorsion increased no production in ipsilateral testicular tissue. treatment with zofenopril before reperfusion prominently decreased the concentration of testicular no level when compared with the sham group. enzymatic antioxidant defense systems, such as sod and gpx, protect tissues from ros and oxidative damage.(11) superoxide dismutase and gpx are major enzymes that scavenge harmful ros in male reproductive organs. superoxide dismutase, one of the major intracellular antioxidant enzymes, is a potent protective enzyme that can selectively and rapidly reduces o2 to h2o2. the gpx system constitute the first step of antioxidant defense system in i/r injury in the testis tissue, among the antioxidant defense enzymes.(22) glutathione peroxidase catalyzes the conversion of h2o2 to h2o. this balance is disrupted under high oxidative stress, such as reperfusion injury. in our study, we observed that the level of sod and gpx activities significantly decreased by i/r injury due to testicular torsion/detorsion in testicular tissue. previous studies have shown the same findings that i/r leads to inactivation of antioxidant enzymes in rat testes.(24,25) pretreatment with zofenopril significantly increased sod and gpx activity after testicular torsion. mogilner and colleagues concluded that ischemia leads to histological damage in the ipsilateral testis.(26) in this study, we evaluated testicular damage by observing changes in tubular architecture. using a rat model, it has been demonstrated that testicular torsion/detorsion caused a prominent reduction in mstd. in our experiment, we observed morphologic changes in ipsilateral testis following unilateral testicular torsion/detorsion. figure 5. histologic findings of ipsilateral testes in zofenopril pretreatment-early orchiectomy zofenopril and testicular torsion—altunoluk et al 318 urology journal vol 8 no 4 autumn 2011 according to our biochemical and histological results, treatment with zofenopril decreased damage in ipsilateral testis caused by i/r. it can be explained that zofenopril had protective effects against i/r injury by reducing the production of free radicals, scavenging free radicals, and preventing inflammation. various antioxidants and free radical scavengers have been proposed in recent years for treatment of testicular torsion-induced male infertility. moreover, application of some antioxidants and ros scavengers, such as sod, catalase, allopurinol,(27) caffeic acid phenethyl ester,(28) melatonin,(29) selenium,(10) resveratrol,(30) and n-acetylcysteine(11) have been shown to prevent i/r injury in testes. however, none have been tested and confirmed the efficacy in clinical trials. zofenopril has been used as an antihypertensive drug in humans, and it may have the clinical applicability in patients with testicular torsion. the use of this drug in cardiac patients clinically without significant side effects and successfully in previous experimental i/r injury in the heart and kidney can make its use in testicular torsion more attractive. according to the results presented in this study, it is reasonable to propose that clinical application of zofenopril might be a new approach for the treatment of testicular torsion in addition to conventional detorsion. conclusion in conclusion, exogenous administration of zofenopril reduced oxidative damage biochemically in the early and late stage and histopathologically only in the late stage of testicular torsion/detorsion in our rat model. antioxidant treatment with compounds, such as zofenopril, may contribute to the salvage of surgically untwisted testis, and zofenopril might play a role in the treatment of testicular torsion in the future. further studies should be performed in the models comparable to clinical testicular t/d cases, both from the point of timing of administration and the dosage needed. conflict of interest none declared. references 1. akgur fm, kilinc k, aktug t. reperfusion injury after detorsion of unilateral testicular torsion. urol res. 1993;21:395-9. 2. akcora b, altug me, kontas t, atik e. the protective effect of darbepoetin alfa on experimental testicular torsion and detorsion injury. int j urol. 2007;14: 846-50. 3. power re, scanlon r, kay ew, creagh ta, bouchierhayes dj. long-term protective effects of hypothermia on reperfusion injury post-testicular torsion. scand j urol nephrol. 2003;37:456-60. 4. turner tt, tung ks, tomomasa h, wilson lw. acute testicular ischemia results in germ cell-specific apoptosis in the rat. biol reprod. 1997;57:1267-74. 5. de nigris f, d’armiento fp, somma p, et al. chronic treatment with sulfhydryl angiotensin-converting enzyme inhibitors reduce susceptibility of plasma ldl to in vitro oxidation, formation of oxidation-specific epitopes in the arterial wall, and atherogenesis in apolipoprotein e knockout mice. int j cardiol. 2001;81:107-15; discusssion 15-6. 6. sacco g, bigioni m, evangelista s, goso c, manzini s, maggi ca. cardioprotective effects of zofenopril, a new angiotensin-converting enzyme inhibitor, on doxorubicin-induced cardiotoxicity in the rat. eur j pharmacol. 2001;414:71-8. 7. altunoluk b, soylemez h, oguz f, turkmen e, fadillioglu e. an angiotensin-converting enzyme inhibitor, zofenopril, prevents renal ischemia/ reperfusion injury in rats. ann clin lab sci. 2006;36:326-32. 8. borghi c, bacchelli s, degli esposti d, ambrosioni e. a review of the angiotensin-converting enzyme inhibitor, zofenopril, in the treatment of cardiovascular diseases. expert opin pharmacother. 2004;5:1965-77. 9. mak it, freedman am, dickens bf, weglicki wb. protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells. biochem pharmacol. 1990;40:2169-75. 10. avlan d, erdougan k, cimen b, dusmez apa d, cinel i, aksoyek s. the protective effect of selenium on ipsilateral and contralateral testes in testicular reperfusion injury. pediatr surg int. 2005;21:274-8. 11. cay a, alver a, kucuk m, et al. the effects of n-acetylcysteine on antioxidant enzyme activities in experimental testicular torsion. j surg res. 2006;131:199-203. 12. dokmeci d, inan m, basaran un, et al. protective effect of l-carnitine on testicular ischaemia-reperfusion injury in rats. cell biochem funct. 2007;25:611-8. 13. unsal a, eroglu m, avci a, et al. protective role of natural antioxidant supplementation on testicular tissue after testicular torsion and detorsion. scand j urol nephrol. 2006;40:17-22. 14. ohkawa h, ohishi n, yagi k. assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. anal biochem. 1979;95:351-8. zofenopril and testicular torsion—altunoluk et al 319urology journal vol 8 no 4 autumn 2011 15. cortas nk, wakid nw. determination of inorganic nitrate in serum and urine by a kinetic cadmiumreduction method. clin chem. 1990;36:1440-3. 16. fridovich i. superoxide dismutases. adv enzymol relat areas mol biol. 1974;41:35-97. 17. paglia de, valentine wn. studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. j lab clin med. 1967;70: 158-69. 18. visser aj, heyns cf. testicular function after torsion of the spermatic cord. bju int. 2003;92:200-3. 19. wei sm, yan zz, zhou j. beneficial effect of taurine on testicular ischemia-reperfusion injury in rats. urology. 2007;70:1237-42. 20. etensel b, ozkisacik s, ozkara e, et al. dexpanthenol attenuates lipid peroxidation and testicular damage at experimental ischemia and reperfusion injury. pediatr surg int. 2007;23:177-81. 21. zimmerman bj, granger dn. reperfusion injury. surg clin north am. 1992;72:65-83. 22. filho dw, torres ma, bordin al, crezcynski-pasa tb, boveris a. spermatic cord torsion, reactive oxygen and nitrogen species and ischemia-reperfusion injury. mol aspects med. 2004;25:199-210. 23. bonfoco e, krainc d, ankarcrona m, nicotera p, lipton sa. apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with n-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures. proc natl acad sci u s a. 1995;92:7162-6. 24. gezici a, ozturk h, buyukbayram h, okur h. effects of gabexate mesilate on ischemia-reperfusion-induced testicular injury in rats. pediatr surg int. 2006;22: 435-41. 25. salmasi ah, beheshtian a, payabvash s, et al. effect of morphine on ischemia-reperfusion injury: experimental study in testicular torsion rat model. urology. 2005;66:1338-42. 26. mogilner jg, lurie m, coran ag, nativ o, shiloni e, sukhotnik i. effect of diclofenac on germ cell apoptosis following testicular ischemia-reperfusion injury in a rat. pediatr surg int. 2006;22:99-105. 27. prillaman hm, turner tt. rescue of testicular function after acute experimental torsion. j urol. 1997;157: 340-5. 28. koltuksuz u, irmak mk, karaman a, et al. testicular nitric oxide levels after unilateral testicular torsion/ detorsion in rats pretreated with caffeic acid phenethyl ester. urol res. 2000;28:360-3. 29. abasiyanik a, dagdonderen l. beneficial effects of melatonin compared with allopurinol in experimental testicular torsion. j pediatr surg. 2004;39:1238-41. 30. uguralp s, mizrak b, bay karabulut a. resveratrol reduces ischemia reperfusion injury after experimental testicular torsion. eur j pediatr surg. 2005;15:114-9. best author of the year 2018 siavash falahatkar siavash falahatkar september 2019 siavash falahatkar is professor of urology at guilan university of medical science. he is the pioneer of complete supine pcnl (cspcnl) in the world. since 2007 he performed cspcnl and introduce the technique with many benefits in several scientific papers. as an innovation, the cspcnl has absorbed the attention of many authors throughout the world, so many of them cited his technique in their published articles. professor falahatkar was chosen by editorial board of iranian text book of urology to write a new chapter entitled innovative techniques in pcnl. he has published more than 70 scientific papers in international peer reviewed journals. he had also written three books on urology in persian: practical urology, urology questions and answers, uroradiology. he set up the pcnl and advanced urolaparoscopic surgeries for the first time in guilan province, in iran. he is director of urology research center, guilan university of medical science since 2005. now he works in razi research & educational hospital, rasht, iran. dr. falahatkar was chosen as the best author of the year 2018 by the editorial board of the urology journal for authoring a review article with highest citation in the jcr 2018 report of the urology journal. administration of nicotine exacerbates the quinine-induced structural and functional alterations of testicular tissue in adult rats: an experimental study davoud kianifard1*, seyyed maysam mousavi shoar2, ahmed aly3, leila kianifard3, farhad rezaee4,5 purpose: in this study the role of nicotine (nct) administration on the intensity of rat testicular tissue alterations induced by quinine (qu) was evaluated. materials and methods: forty adult wistar rats were divided into four groups. control (con), nct administrated (4 mg/kg) (nct), qu treated (25 mg/kg for 7 days) (qu), and nicotine with quinine received (nct+qu). after 28 days, serum testosterone and malondialdehyde (mda) levels were measured. testes and epididymides samples were prepared for determining tissue mda levels, histomorphometry, microscopic indices of spermatogenesis, immunohistochemistry of p53 and sperm analysis. results: testosterone levels were decreased significantly (p = .0004) in treated groups compared to con group. serum mda levels were increased significantly (p = .0004) in nct and qu groups compared to con group. tissue mda levels were increased significantly (p = .0012) in nct+qu group in comparison to con group. these parameters were changed significantly in nct+qu group compared to qu group. seminiferous tubules diameter decreased significantly (p < .0001) in treated groups compared to con group and in nct+qu group compared to qu group. the height of germinal epithelium decreased significantly (p = .0001) in nct and nct+qu groups compared to con and qu groups. the number of sertoli cells, spermatocytes, and spermatids decreased significantly in treated groups compared to con group. the number of spermatogonia decreased significantly (p = .0017) in nct and nct+qu groups compared to con group. the number of sertoli cells, spermatogonia, and spermatocytes decreased significantly in nct+qu group compared to qu group. all indices of spermatogenesis decreased in treated groups compared to con group. the lowest mean of these indices was observed in nct+qu group. the sperm viability decreased significantly (p < .0001) in treated groups compared to con group. sperm count and motility decreased significantly in nct and nct+qu groups compared to con group. all experimental groups showed the over-expression of p53 compared to con group. conclusion: the administration of nicotine could be involved in the exacerbation of testicular tissue alterations related to quinine therapy. keywords: nicotine; quinine; male infertility; testicular tissue; toxicity introduction complex cellular and endocrine/paracrine proce-dures regulate the process of spermatogenesis(1). this process and likewise the androgen synthesis which is completed in testes are susceptible to a wide range of environmental stresses. in this regard, the endogenous and exogenous factors could induce various types of alterations in this process(2). testicular toxicity has become a serious concern due to the industrialization of societies and the ever-increasing use of chemicals and drugs(3,4). moreover, exposure to different xenobiotics can affect the male reproductive system by making structural and functional changes in testicular tissue. malaria is one of the most common parasitic diseases seen worldwide. a wide range of medications is used to 1division of histology and microscopic anatomy, department of basic sciences, faculty of veterinary medicine, university of tabriz, tabriz, iran 2department of basic sciences, faculty of veterinary medicine, shahid chamran university, ahvaz, iran 3beykoz institute of life sciences and biotechnology, bezmialem vakif university, istanbul 34820, turkey 4department of gastroenterology-hepatology, erasmus medical center, rotterdam, the netherlands 5department of cell biology, university medical center groningen, university of groningen, groningen, the netherlands. *correspondence: faculty of veterinary medicine, university of tabriz, tabriz, iran. tel: +98 41 36378743. fax: +98 41 36378743. email: davoudkianifard@gmail.com. kianifard@tabrizu.ac.ir. received december 2019 & accepted july 2020 treat malaria disease. quinine (qu) is one of the most common medications used for the treatment of malaria disease. the quinine treatment is associated with side effects such as irreversible deafness, amblyopia, and cinchonism syndrome(5). some studies have reported the quinine-induced toxicity including neurotoxicity, cardiotoxicity, and testicular toxicity(6,7). histological alterations of the seminiferous tubules, reduction of testosterone levels, a decrease of sperm count and motility, and the changes in lipid peroxidation indices were reported following the administration of qu in experimental animal studies(6,7). the abuse of narcotics such as opioids and nicotine is common in some regions of the world. it has been well established that these narcotics have side effects on the andrology urology journal/vol 18 no. 1/ january-february 2021/ pp. 103-110. [doi: 10.22037/uj.v16i7.5884] structure and the function of the male reproductive system(2,4,8). cigarette smoking a common public health problem, leads to exposure of nicotine (as the important toxic chemical compounds) to various body organs. as well, human and experimental studies revealed the negative effects of nicotine on the male reproductive system(2, 4,9-12). nicotine (nct) is an alkaloid compound that is exposed through different routes including tobacco products and insecticides(9). the alteration of sexual function and spermatogenesis, reduction of semen quality, and malfunction of the pituitary-testis axis have been reported following the administration of nct or smoking in experimental and clinical studies(10-12). it is believed that following the administration of nct or qu, an increase of lipid peroxidation could induce ros over production which can interact with cellular lipids and inducing cellular damage(2,6,9,10). both nicotine and quinine have gonadotoxic effects on testicular tissue(4,6,7). consequently, in this study, the potential role of nicotine administration, as a model of high-risk lifestyle (exposure to gonadotoxic compounds), was evaluated on the proportion of quinine-induced alterations of testicular tissue through an experimental study. materials and methods chemicals nicotine, quinine hydrochloride, embryomax human tubal fluid (htf medium) and tris hydrochloride (tris-hcl) were purchased from sigma-aldrich (st louis, mo 63178, usa). enzyme immunoassay kit for measurement of serum testosterone was obtained from (monobind inc. usa). primary antibody (rabbit polyclonal anti p53 antibody) was purchased from st john's laboratory ltd, uk. secondary antibody (goat anti-rabbit igg) was purchased from agrisera antibodies, se-911 21 vännäs, sweden. animals forty adult male wistar rats weighing 180-200 grams were used in this study. the animals were placed in standard cages under controlled temperature (22 ± 2 ºc) and 12 h light/dark cycle. during the period of the experiment, the standard laboratory chow and water were available ad-libitum to animals. all animals' procedures used in this study were approved by the university of tabriz standards for care and use of laboratory animals (ethical code: ir.tabrizu.rec.1398.034), in accordance with the animal ethical committee (aec) of the ministry of health and medical education of iran (adopted on april 17, 2006) based on the national institutes of health guide for the care and use of laboratory animals (nih publications no. 8023, revised 1978) based on the helsinki protocol (helsinki, finland, 1975). study design the animals were randomly divided into four experimental groups (10 animals per group): control (con), nicotine-received (nct), quinine-received (qu), nicotine and quinine received (nct+qu). in nct+qu group, the 28-days period of study were divided into two time sections consisted of day 0 to day 21 which only nct was administrated, and day 22 to day 28 which both the nct and qu were administrated (figure 1). quinine hydrochloride was solubilized in distilled water (20 mg/ml as stock treatment solution) and was administered orally (gavage) at a dose of 25 mg/kg once a day for a period of seven days(6). nicotine was administrated at a dose of 4 mg/kg intraperitoneally once daily for 28 days(13). biochemical analysis twenty four hours after the final treatment, the animals were anesthetized with xylazine hydrochloride (10 mg/ kg i.p.) and ketamine hydrochloride (100 mg/kg i.p.). the blood samples were collected through cardiac puncture. serum testosterone the assessment of the serum testosterone levels was carried out through the standard elisa method with a commercial assay kit (monobind inc. usa)(7). sampling and preparation the animals were euthanized through sodium thiopental (100 mg/kg i.p.). the left and right testicles were separated and dissected from their epididymis and were table 1. the effect of nct and qu on testes weight, organ relative weight, serum testosterone and the lipid peroxidation levels. variablesa control nicotine quinine nicotine+quinine testes weight (g) 2.28 ± 0.23 1.65 ± 0.36b 1.92 ± 0.21 1.43 ± 0.24bc organ relative weight (%) 0.98 ± 0.12 0.83 ± 0.21 0.90 ± 0.13 0.73 ± 0.11b testosterone (ng/ml) 0.66 ± 0.039 0.50 ± 0.054b 0.56 ± 0.053b 0.48 ± 0.044bc serum mda (nmol/mg protein) 0.67 ± 0.103 1.01 ± 0.151b 0.79 ± 0.144 1.19 ± 0.355bc tissue mda (nmol/mg protein) 0.73 ± 0.067 1.04 ± 0.130 0.98 ± 0.275 1.33 ± 0.388bc abbreviations: mda, malondialdehyde. a. data are expressed as means ± sd. b. p < .05 compared to the control group. c. p < .05 compared to the quinine group. figure 1. diagram of animal grouping and time schedule of the administration of nicotine and quinine. nicotine and quinine related infertility-kianifard et al. andrology 104 vol 18 no 1 january-february 2021 105 weighed as total testes weight. moreover, the organ relative weight (organ relative weight = organ weight/ body weight × 100) was recorded. the left testicles were used for histologic studies, and the right testicles were prepared for tissue lipid peroxidation measurement and immunohistochemistry. the sperm analysis was prepared on the left epididymides. serum and tissue lipid peroxidation levels the quantification of the serum and tissue lipid peroxidation was completed by the determination of thiobarbituric acid levels(14). testicles samples were homogenized in 50 mm tris/hcl, ph 7.5 (1/10, w/v) and centrifuged at 3000g for 10 minutes. an aliquot of serum or tissue samples were incubated (95 ºc) for two hours with thiobarbituric acid. the sample coated microplates were analyzed by a microplate reader and the absorbance was measured at 532 nm. histology the testicular tissues were immediately fixed in 10% formaldehyde in buffered solution containing 54 mm nah2po4 and 28 mm na 2 hpo 4 (ph 7.4) and kept at 4°c. after 48 hours, the transverse section was made on the middle part of each testis and kept immersed in the fixative solution for the completion of tissue fixation. then, formaldehyde-fixed samples were embedded in paraffin and sliced with thickness of 6-7 micrometer and were mounted onto albumin-pre-coated glass slides. the mounted tissue samples were deparaffinized with xylene and stained by the hematoxylin and eosin method for histological observations by light microscopy (olympus cx22, tokyo, japan). histomorphometry of seminiferous tubules for performing morphometric assessments, 10 microscopic fields (200×) and at least 20 seminiferous tubules (sts) were studied in each section. the measurement of the height of germinal epithelium (geh) and the diameter of seminiferous tubules (std) was performed on the images obtained via amscope digital camera (amscope md500). the images were processed by the table 2. the effect of nct and qu on testicular tissue morphometry and the germinal epithelium population. variablesa control nicotine quinine nicotine+quinine st diameter (μm) 276.4 ± 18.11 200.3 ± 27.77b 226.0 ± 25.37b 177.5 ± 27.18bc ge height (μm ) 124.4 ± 9.81 86.63 ± 16.04bc 108.4 ± 13.79 76.88 ± 14.94bc sertoli cells(# / 20 tubules) 26.33 ± 4.38 17.00 ± 3.00b 21.22 ± 3.83b 15.67 ± 2.95bc spermatogonia (# / 20 tubules) 58.63 ± 7.23 43.50 ± 8.40b 51.50 ± 4.81 42.13 ± 6.46bc spermatocyte (# / 20 tubules) 65.88 ± 6.33 47.25 ± 7.18b 55.63 ± 5.29b 45.00 ± 7.13bc spermatids (# / 20 tubules) 230.5 ± 26.37 145.6 ± 31.11b 164.4 ± 23.78b 132.6 ± 20.38b abbreviations: st, seminiferous tubule; ge, germinal epithelium. a. data are expressed as means ± sd. b. p < .05 compared to the control group. c. p < .05 compared to the quinine group. figure 2. cross-sections of seminiferous tubules in experimental groups. (a) control group: normal architecture of seminiferous tubules (st) with consistent arrangement of spermatogenic cells is visible. narrow interstitial connective tissue (squares) has been situated between seminiferous tubules. (b) nct-administrated group: atrophied seminiferous tubules (ast) and depletion in height of germinal epithelium (black arrow) are visible. the normal arrangement of germ cells is demolished (square). (c) qu-treated group: ast with a decline in the germinal cell population (squares) are evident. (d) nct+qu-treated group: tubular atrophy and disruption with a prominent reduction of the cellular population (squares) were the noticeable changes. h&e staining. magnification: ×200 figure 3. immunohistochemical staining for p53 expression in testicular tissue. (a) control group: faint positive reaction immunostaining to p53 expression is visible in seminiferous tubules. (b) nct-administrated group: the positive reactions increased compare to the control group. (c) qu-treated group: an increase in areas with a positive reaction is visible compare to the control group. the positive reaction is less than nct-administrated group. (d) nct+qu-treated group: the positive reaction to p53 expression is higher in comparison to other groups. magnification: ×200 nicotine and quinine related infertility-kianifard et al. image analysis software (amscope 3.7). the population of spermatogenic cells lineage for quantitative calculating of the populations of the cells, the number of sertoli cells, the spermatogonia, the spermatocyte, and the round spermatids was counted in every tubule and this process repeated for at least 20 tubules. then the whole number of counted cells for 20 tubules presented as the mean of the cell population. microscopic indices of spermatogenesis the quantitative investigation of spermatogenesis in testicular tissue was completed by the measurement of three indices: tubular differentiation index (tdi, the number of seminiferous tubules with more than three layers of germinal cells derived from type-a spermatogonia), spermiogenesis index (spi, the ratio of seminiferous tubules with spermatozoids to the empty tubules) and repopulation index (ri, the ratio of active spermatogonia to inactive cells)(15). immunohistochemistry of p53 paraffin-embedded testicular tissue sections were prepared for immunostaining of p53 protein. briefly, antigen retrieval was conducted on deparaffinized and rehydrated slides kept in 10 mm sodium citrate solution (ph 6.0) at 95 ºc in a water bath for 40 minutes. immunohistochemical staining was performed in terms of the manufacturer's protocol (st john's laboratory ltd, uk). briefly, endogenous peroxidase activity was blocked with 0.3% h 2 o 2 . tissue slides were washed with phosphate buffered saline solution (pbs) (ph 7.2) and then incubated with rabbit polyclonal anti p53 antibody (as primary antibody) (1:500) at 4 ºc overnight. sections were treated with horseradish peroxidase (hrp) conjugated goat anti-rabbit igg (as secondary antibody) (agrisera antibodies, se-911 21 vännäs, sweden) in 37 ºc incubator humidified chamber container with a wet paper towel for 1 hour. diaminobenzidine (dab) chromogen was added to the tissue sections and incubated for 5 minutes. also, the tissue slides were dehydrated and cover-slipped after hematoxylin counterstaining. epididymal sperm analysis sperm count the cauda epididymis was cut into small pieces. the contents of epididymis were diluted by the htf medium (1:20 v:v). approximately 10 microliters of the specimen were transferred to a haemocytometer, and were placed for five minutes in the humidified chamber. the number of cells was counted with a light microscope at 400× magnification and was expressed as the sperm concentration (×106/ml)(16). sperm motility percentage one drop of the specimen was placed on an incubated glass slide (37 ºc) and covered with a lamella. the percentage of motile cells was recorded in four different microscopic fields at 400× magnification(17). sperm viability percentage the evaluation of sperm viability was carried out by adding 20 μl of eosin y-1% solution and nigrosin 10% solution into an equal volume of the specimen. the examination was done on the slides were incubated for two minutes at room temperature. the head of dead sperm cells was stained with pink while the head of live cells appeared pale(18). statistical analysis non-parametric (kruskal wallis test) and parametric (one-way anova analysis of variance followed by tukey's multiple comparison test) methods were performed for the evaluation of differences between experimental groups. all data were expressed as the mean ± sd. statistical analyses were performed using graphpad prism software (version 5.04; graphpad inc., ca, usa). the p values < .05 were considered significant statistically between experimental groups. results weight of testicles the mean of testicular weight was altered in all treated groups compared to the control group (table 1). the reduction of testes weight was significant between the control group with the nct and nct+qu groups (p = .0003). as well, the weight of testes was reduced significantly in nct+qu group compared to the qu group. in this regard, the organ relative weight was changed in treated groups in comparison to con group. the reduction of organ relative weight was observed significantly in nct+qu group (p = .0222). moreover, the administration of the nct prior and during to the qu therapy led to more decrement of the organ relative weight compared to qu group. serum testosterone levels the blood concentration of testosterone was reduced significantly (p = .0004) in all treated groups in comparison to con group (table 1). also, this parameter was reduced significantly in nct+qu group compared to qu group. lipid peroxidation the levels of serum malondialdehyde (mda) were increased in all treated groups compared to control group (table 1). this increase of mda levels was observed significantly in nct and nct+qu groups (p = .0004). in this regard, the serum mda levels were increased significantly in nct+qu group compared to qu group. accordingly, the most increase in serum mda levels was observed in nct+qu group (table 1). the table 3. the effect of nct and qu on the microscopic indices of spermatogenesis and epididymal sperm analysis. variablesa control nicotine quinine nicotine+quinine tubular differentiation index (%) 71.63 ± 8.81 56.88 ± 6.05b 60.25 ± 9.45 50.75 ± 10.50b spermiogenesis index (%) 74.75 ± 8.067 49.75 ± 7.83bc 62.38 ± 9.63b 50.38 ± 8.94bc repopulation index (%) 70.13 ± 7.60 57.25 ± 8.82b 60.63 ± 6.25 46.25 ± 6.69bcd sperm count (106/ml) 16.63 ± 2.32 12.88 ± 1.72b 14.25 ± 2.12 11.50 ± 2.44b sperm viability (%) 78.50 ± 7.85 58.38 ± 9.53b 65.13 ± 5.35b 51.75 ± 6.01bc sperm motility (%) 76.00 ± 7.502 60.25 ± 8.031b 66.13 ± 9.387 55.38 ± 5.069bc a. data are expressed as means ± sd. b. p < .05 compared to the control group. c. p < .05 compared to the quinine group. d. p < .05 compared to the nicotine group. nicotine and quinine related infertility-kianifard et al. andrology 106 vol 18 no 1 january-february 2021 107 measurement of mda levels in testicular tissue showed the increase of this parameter in all treated groups in comparison to con group (table 1). however, this increase of tissue mda levels was significant between nct+qu group and control group (p = .0012). in this way, the mda levels in testicular tissue were increased significantly in nct+qu group compared to qu group. testicular tissue morphometry the mean diameter of the seminiferous tubules was reduced significantly (p < .0001) in treated groups compared to con group (table 2). accordingly, tubular diameter was reduced significantly in nct+qu group in comparison to qu group. in this regard, the height of the germinal epithelium was decreased in treated groups compared to the control group. this reduction was observed significantly (p = .0001) between con group with nct and nct+qu groups as well. moreover, this index was reduced significantly in nct and nct+qu groups compared to quinine treated group. the population of spermatogenic cells the mean of the germ cells population was changed in all treated groups in comparison to the control group (table 2). in this regard, the population of the sertoli cells, spermatocytes and round spermatids was decreased significantly in treated groups (p = .0001, p = .0002 and p = .0002 respectively). the population of spermatogonia was reduced significantly in nct and nct+qu groups compared to con group (p = .0017). the administration of nct before and during the qu therapy led to a significant reduction in the population of the sertoli cells, spermatocytes and spermatogonia compared to qu group however, the mean of round spermatids was not reduced significantly. microscopic indices of spermatogenesis the mean of all indices of spermatogenesis was reduced in treated groups in comparison to con group (table 3). this reduction was significant between nct and nct+qu groups with con group for tdi and ri indices (p = .0016 and p = .0003, respectively) and between all experimental groups with the control group for spi index (p = .0002). the microscopic indices of spermatogenesis were reduced in nct+qu group compared to qu group. this decrement was observed significantly for spi and ri and was observed non-significantly for tdi (table 3). sperm analysis the results obtained from epididymal sperm analysis showed that all parameters of sperm analysis were declined in treated groups in comparison to the control group (table 3). this reduction was observed significantly in all treated groups for sperm viability (p < .0001) while, sperm count and sperm motility parameters were reduced significantly in nct and nct+qu groups compared to con group (p = .0024 and p = .0010, respectively). moreover, treatment of animals with qu after the administration of nct induced more reduction in sperm analysis parameters compared to qu group. this reduction was recorded significantly for sperm motility and viability between above mentioned groups (table 3). histology of testicular tissue the histologic study showed various alterations in testicular tissue of treated groups in comparison to the control group (figure 2). the atrophy of seminiferous tubules and the loss of tubular architecture, a decrease of the germ cells population, impaired cellular arrangement, and the increase of interstitial connective tissue were the most prominent alterations observed in treated groups. the most prominent changes were observed in nct and nct+qu groups as well. the structural changes of testicular tissue were observed in lower degrees in qu group in comparison to nct+qu group. immunohistochemistry of p53 immunostaining of testicular tissue for detection of the p53 expression showed an increase of the positive reaction areas to p53 expression in treated groups in comparison to the control group (figure 3). in this regard, the expression of p53 was higher in nct+qu group compared to nct and qu groups. discussion the results of this study showed that, the administration of nicotine exacerbates the structural and functional alterations of testicular tissue induced by quinine therapy. in the present study, the existence of significant difference in most quantitative and qualitative evaluated parameters between the qu-treated group and the nct+qu treated group indicates that nicotine could involve in exacerbating of testicular tissue changes following quinine therapy in adult rats. based on the results of previous studies and the results of this experiment, it can be established that the main mechanism for tissue alterations following nicotine or quinine administration is increased oxidative stress. so, it can be suggested that the administration of nicotine before and during quinine therapy increases the structural and functional changes in testicular tissue through increasing the amount of ros and its related cellular and tissue alterations. both nicotine and quinine have toxic effects on the male reproductive system(7,13). it has been known that the administration of nicotine or quinine leads to the over-production of reactive oxygen species (ros) in the male reproductive system(6,19). in this regard, oxidative stress-related cellular and tissue damages play a major role in male infertility problems(20). over production of ros could induce various damages in the cellular membrane of spermatozoa which lead to peroxidation of plasma membrane lipids and subsequently cellular structural abnormalities(21). the results of this study showed the increase of serum and tissue mda levels (as one of the final products of lipid peroxidation) in all treated groups. our results are in parallel to the previous reports indicating the increase of ros in testicular tissue following the administration of nicotine or quinine (2,4,6,7). in this study, it was also found that the most increase in mda levels occurs in the nct+qu group. this result indicates that the administration of the nct prior to qu therapy can induce more tissue damage related to lipid peroxidation compared to individual quinine therapy. various studies demonstrated the cellular and tissue alterations of the seminiferous tubules following the administration of nicotine or quinine(6,10,22). in this study, the results obtained by the histologic and morphometric evaluations showed different changes in the seminiferous tubules in treated groups. these changes included varieties of cellular destruction, impaired tubular architecture and the spermatogenic alterations which are closely related to cell population decline. testicular tisnicotine and quinine related infertility-kianifard et al. sue and spermatozoa due to theirs considerable amount of lipids are susceptible to cellular lipid peroxidation (7,19). in the present study the alterations of testicular histomorphometry and the germ cells population were observed in parallel to the changes of mda levels as a marker of cell and tissue lipid peroxidation and its related cellular damage and cell loss. these results demonstrated that the administration of nicotine before and during the period of quinine therapy could involve in exacerbation of the qu-related changes of the structure and the function of testicular tissue. this study showed a decrease of the serum testosterone levels in all treated groups compared to control group. also, this reduction was significant in the nct+qu group in comparison to the qu-received animals. testosterone through interaction with the sertoli cells has an essential role in progressing of the spermatogenesis(23,24). the reduction of testosterone levels has been noted following the administration of nicotine or quinine(6,22-24). decreased testosterone levels may be due to seminiferous tubular damage and subsequently decrease in diameter of tubules(7). moreover, one of the possible mechanisms which is involved in the reduction of testosterone levels following the administration of nct or qu is the raise in the activity of testosterone hydroxylases which result in increased hepatic metabolism of testosterone(25). however, it has been documented that the elevation of testosterone levels leads to improvement of the function of the reproductive system in metabolic diseases such as diabetes which indicates the positive role of testosterone in the process of spermatogenesis(26). according to the significant decrease of the sertoli cells population and testosterone levels in the nct+qu received group compared to the qu received group, it could be proposed that the administration of the nct before or during the qu therapy could involve in exacerbation of the structural changes of testicular tissue through diminished spermatogenesis process and subsequent decrease of tubular cellularity. in this way, the microscopic indices of spermatogenesis were reduced more in the nct+qu received group in comparison to the qu treated group. reactive oxygen species (ros) play a critical role in the normal function of spermatozoa through the stimulation of sperm capacitation, acrosome reaction, and oocyte fusion(27). moreover, the functions of sperm due to its high levels of fatty acids and limited dna repair ability are highly dependent on ros(28). in this study, we verified a decrease in the sperm analysis indices in all treated groups. our results are consistent with the previous studies that have reported a reduction of sperm analysis indices following the administration of quinine or nicotine(6,9). moreover, the results of the present study showed a significant decrease in sperm count, sperm viability and sperm motility in the nct+qu received group. these sperm alterations are in parallel to the changes observed in the serum and tissue mda levels. tumor protein p53 is one of the regulatory proteins involved in the cell cycle through the activation of dna repair proteins or initiation of apoptosis after severe dna damage. the p53 is often up-regulated after dna damage resulting in the initiation of apoptosis(29). in physiological conditions, apoptosis occurs in 20% of developing germ cells. however, the increase of apoptosis could induce some alterations in germ cell lineage and sperm parameters(30). consequently, the expression level of this protein may indicate the amount of oxidative stress-induced cellular damage. in this study, the immunostaining of testicular tissue showed that the administration of the nct before the qu treatment induced more up-regulation of p53 compared to individual quinine therapy. accordingly, the consistency of the immunohistochemical results with the histomorphometric results indicates that the increase of dna damage of the germ cells related to oxidative stress induces the cell loss of the germinal epithelium through the induction of p53 up-regulation and the initiation of the apoptotic pathways. the negative effects of common chemotherapeutic medications and xenobiotic toxicants have been reported on the structure and function of the male reproductive system(9-11,13,19, 22,31). according to the results of these studies, oxidative stress and dna damage are the main factors which are involved in the structural and functional alterations of the male reproductive system organs. so, the synergistic effects of these gonadotoxic agents in conditions of simultaneous administration should be taken into consideration. in this study, the mean testicular weight was decreased in the experimental groups compared to the control group. this reduction was observed in more degrees in the nct-treated and the nct+qu treated groups. moreover, this index was reduced significantly in the nct+qu received group compared to the qu received group. the measurement of absolute and relative organ weight is the important indices in toxicological studies(32). moreover, it has been demonstrated that the weight of testes depends on the mass of differentiated spermatogenic cells(33). according to the results of testicular weight, testes relative weight and histomorphometry, we can suggest that compared to the individual qu therapy, the administration of the nct prior to the qu therapy could induce more reduction of testicular weight through the exacerbation of the cellular depletion and structural alterations. conclusions the effects of nicotine on the structure and function of testicular tissue have been demonstrated in various human and animal studies(2,4,9,10). moreover, in recent years, experimental studies in animal models have shown the negative effects of quinine on the male reproductive system(6,7). our study showed that treatment of rats with quinine hydrochloride in its common therapeutic dose induces structural and functional alterations in testicular tissue. also, nicotine administration before and during quinine therapy exacerbates these changes. this study is the first report about the effect of nicotine administration on the intensity of testicular tissue alterations induced by quinine. based on the results of this study, it can be proposed that nicotine may affect the level of quinine associated structural and functional changes of testicular tissue and could be involved in the exacerbation of these alterations. finally, this subject should be given more attention that the use of xenobiotic gonadotoxic compounds such as nicotine at the time of quinine therapy can exacerbate the adverse effects of this antimalarial drug on the male reproductive system. acknowledgment parts of this work have been carried out at beykoz institute of life sciences and biotechnology, bezmialem vakif university. the authors would like to thank mr. nicotine and quinine related infertility-kianifard et al. andrology 108 vol 18 no 1 january-february 2021 109 ali haghi for the preparing of histologic slides. conflicts of interest the authors report no conflict of interest. references 1. guerriero g, trocchia s, abdel-gawad fk, ciarcia g. roles of reactive oxygen species in the spermatogenesis regulation. front endocrinol (lausanne). 2014; 5:56. 2. zenzes mt. smoking 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protective effect of melatonin on sperm parameters, epididymis and seminal vesicle morphology in adult mouse treated with busulfan. j iran anatomic sci. 2010; 8:25-36. 32. crissman jw, goodman dg, hildebrandt pk, et al. best practices guideline: toxicologic histopathology. toxicol pathol. 2004, 32:12631. 33. katoh c, kitajima s, saga y, kanno j, horii i, inoue t. assessment of quantitative dual-parameter flowcytometric analysis for the evaluation of testicular toxicity using cyclophosphamideand ethinylestradioltreated rats. j toxicol sci. 2002; 27:87-96. nicotine and quinine related infertility-kianifard et al. andrology 110 reconstructive surgery appendicovesicostomy as an alternative procedure for patients with complex urethral distraction defects amir reza abedi1, saleh ghiasy2*, morteza fallah-karkan3, seyyed ali hojjati2, jalil hosseini4 purpose: surgical repair of post-traumatic complex urethral stricture poses a major challenge to urologists. here, we report six patients with irreparable urethral strictures who were successfully treated by using the appendix as conduit for urinary diversion. materials and methods: six patients who had underwent urinary diversion using an appendix during 2015 to 2019 were included in our study. all patients had a history of one or more failed attempts of urethral reconstruction in the past. mean follow-up for patients was 29 months. continency was defined as being completely dry for at least 3 hours. results: mean age of patients was 40.1 years old (range: 20-70 years). intermittent catheterization through the conduit was easily performed for every patient without any stomal stenosis. mild stomal incontinence only occurred in one case which was resolved after a few months. all patients were continent during day and night. conclusion: based on the results of our study, mitrofanoff’s technique is a valuable procedure for managing patients with serious complicated urethral strictures who cannot be treated with common standard approaches. keywords: appendix diversion; mitrofanoff’s appendicovesicostomy; urethral stricture; urinary diversion introduction urethral stricture and posterior urethral defects are an important clinical problem in male patients(1,2). road traffic accidents, iatrogenic injuries, and inflammatory disorders are common causes of urethral strictures. in previous studies, the incidence of posterior urethral stricture after pelvic fracture was predicted to be %5-10(3,4). the surgical management of urethral stenosis varies based on etiology, position, length, and thickness of the lesion in addition to the extent of fibrosis involving the surrounding tissues(5,6). treatment of stenosis of the bulbar part of the urethra includes excision and end-to-end urethroplasty or a short patch onlay substitution anastomosis(7,8). however, in some patients the urethral defect is so long that it cannot be managed with extensive releasing of urethra from the surrounding fibrosis, inferior pubectomy, and even re-routing maneuvers(9,10). various approach have been used to overcome this problem depending on the location and length of the stenosis including oral mucosa graft, enterourethroplasty, and the combination of dorsal graft with ventral penile flap . however, many complications have been related to these techniques(11-13). in patients with severe and complicated urethral injury, salvage procedures such as perineostomy or suprapubic tube could be performed(14,15). patients with a history of past surgical procedures, stenosis longer than 3 cm, accompanying perineal and gi fistulas, presence of diverticulitis adjacent to the duct, and a non-competent bladder 1department of urology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 2men’s health and reproductive health research center, shahid beheshti medical science university, tehran, iran. 3laser application in medical science research center, shahid beheshti university of medical sciences, tehran, iran. 4reconstructive urology department, shohada e tajrish hospital, shahid beheshti medical science university, tehran, iran. *correspondence: men’s health and reproductive health research center, shahid beheshti medical science university, tehran, iran. telfax +98 2122712234, mob +98 9128198037. email;saleh.ghiasy@sbmu.ac.ir. received september 2019 & accepted april 2020 neck are defined as complex cases and are not suitable candidates for urethroplasty(13,16). although the design of a concealed and easily catheterizable stoma in cases with unreconstructable urethral disease was considered a good practical method, the clinical management of these patients still remains to be a dilemma(17). in 1980, mitrofanoff introduced an alternative procedure for continent diversion in which one end of the appendix was brought to the skin surface as a catheterizable stoma and the other end was tunneled into the bladder wall (17-20). here, we have reported our experience with this surgical procedure in terms of safety and efficacy. materials and methods patient inclusion five male and one female patient aged 20 to 70 years old (mean age= 40.1) who had underwent urinary diversion using the appendix during 2015 to 2019 at shohada-e-tajrish hospital, tehran, iran were included in the study. all patients had a history of one or more previously failed surgical attempts of urethral reconstruction and had an long urethral defect involving different anatomic segments of the urethra, or were at risk of urinary incontinence after urethroplasty of membranous urethra because of insufficient proximal sphincteric mechanism or patient’s denial to undergo surgery (figure 1). due to the reasons mentioned above, patients became candidates of mitrofanoff urinary diversion. prior to enrollment, male patients were informed that urology journal/vol 17 no. 4/ july-august 2020/ pp. 386-390. [doi: 10.22037/uj.v0i0.5592 ] vol 17 no 04 july-august 2020 387 they would need art (assistance reproductive technology) in case of plans for paternity in the future and then informed consent were obtained from all patients. this study was approved by the ethics committee of shohadae-tajrish hospital. surgical technique a lower midline incision was performed to allow simultaneous access to the bladder, ileocecal junction, and the appendix. after locating the appendix, it was cut separate from the cecum while preserving its mesentery. then, an opening was created as the blind end and washed. after passing a 14f catheter down the appendix to check for patency, it was implanted into the bladder through a submucosal tunnel of at least 4 cm length to achieve an anti-reflux effect (figure 2). during surgery, the appendix was dilated with a 14f catheter and the catheter was left in-situ for three weeks. the appendix was then secured with absorbable sutures to the bladder muscle and mucosa. the stomal site was prepared based on pre-operative counselling for site selection and the stoma was placed at a level proximal to the bladder so that gravity would assist in achieving continence (figure 3). also, a cystostomy tube was inserted for all cases to increase safety measures. patients were usually discharged 3-5 days after surgery, as soon as they could tolerate solid food. after about 3 weeks, the mitrofanoff or pouch catheter was removed and the supra pubic catheter was left clamped-off. the patient was taught how to catheterize his pouch/mitrofanoff (clean intermittent catheterization) every 3 hours by using a 12 or 14f nelaton catheter. occurrence of urinary leakage throughout the period was considered as the patient being incontinent. as for the night, a catheter was inserted and secured in place to allow for free urine drainage. if there was no difficulty in catheterization, the suprapubic catheter was removed after 3 days. after that, cases were frequently followed-up at 3, 6, 18 and 24 months, with special consideration given to patients having difficulties with catheterization and incontinence. follow-up plan included: stoma evaluation, upper urinary tract ultrasonography, measurement of post-catheterization urine residue, serum creatinine level, and catheter size. table 1. patients’ characteristics and procedure outcome. no age (year) defect length (cm) follow up, month cause of injury previous surgical reason for appendix outcome intervention diversion candidacy 1 70 6 24 long urethral stenosis one attempt of urinary incontinency, no residual, post radical prostatectomy cystolithotomy, several long urethral defect no stenosis failed attempts of urethral (from bladder neck to dilation membranous part) 2 36 7 27 pelvic fracture due to laparotomy cystography history of twice failed no residual, entrapment under rubble and cystostomy, twice end urethroplasty, no stenosis to end urethroplasty, long urethral defect several urethral dilation attempts,one attempt of stent insertion 3 45 8 36 pelvic fracture due to laparotomy and long posterior no residual, motor vehicle injury cystostomy, non urethral defect no stenosis competent bladder neck, internal urethrotomy, pubectomy, failed end to end urethroplasty 4 41 10 30 fournier gangrene extensive debridement, history of two failed no residual, several plastic surgeries attempts of urethroplasty no stenosis for scrotal and penile defect 5 60 6 24 pelvic fracture due cystostomy insertion, history of twice failed no residual, to motor vehicle injury twice failed urethroplasty,, urethroplasty, incontinency no stenosis orthopedic surgery and long urethral defect 6 20 3 33 pelvic fracture due to laparotomy, history of history of once failed no residual, motor vehicle injury once failed urethroplasty, urethroplasty, no stenosis in childhood bladder neck closure risk of incontinence and cystostomy figure 1. contrast imaging of all of the included patients. appendicovesicostomy for urethral distraction-abedi et al. results etiology of urethral defect in our cases included pelvic fracture, post radical prostatectomy urethral stenosis, and necrotic perineal infection (table 1). the time gap between trauma and mitrofanoff’s procedure ranged from 18 to 120 months (mean ± sd= 49.3 ± 37.2). patients’ characteristics and procedure outcome are presented in table 1. sonographic evaluation of upper urinary tract during follow-up did not reveal any pathologic findings. mean serum creatinine level before surgery was 1.2 mg/dl. mean surgical time was 2 hours (range= 1-3). average predicted blood loss was around 150 cc (ranged 50 to 600). there was no need for blood transfusion or adjacent organ injury. all cases were discharged 3-5 days after surgery. follow-up duration ranged from 24 to 36 months (mean= 29). post-operative complica¬tions consisting of dehiscence, wound infection, hematoma, necrosis, or perforations of the appendix tube were not detected in any cases during the fol¬low-up period. catheter size of patients ranged from 12 to 14f. in five of the patients, catheterization was easily performed through the conduit every 2 hours. over time, the pouch was expanded to hold more urine and the patient needed to catheterize every four to six hours. the only patient who could not easily catheterize underwent flexible cystoscopy and dilation with a 14f catheter. none of the patients had stomal stenosis during the follow-up period. mild stomal incontinence occurred in only one case who became continent after a few months. discussion the potentiality of the appendix to be used as a concealed stoma capable of catheterization was discovered in 1980 by mitrofanoff(21) in an attempt to achieve urinary continence and maintenance of a low-pressure urinary storage reservoir(17). later variations of this technique were developed such as the monti technique in which a short part of the ileum was used according to the same principle(13,22). the benefit of using the appendix instead of an ileum segment is that intestinal anastomosis is not required in appendicular diversion, thereby the risk of intestinal anastomotic leakage is reduced. also post-operative fasting period is minimized. on the other hand, the physiologic function of the appendix is unknown in adults; therefore, the removal of appendix does not bring a serious harm to the body and does not lead to any impairment in the body’s function. another disadvantage of the ileum compared to the appendix is the need for tapering and tabularization which increases the likelihood of urinary leakage. finally, the most important advantage of using an appendix is shortening of operative time since time-consuming procedures such as ileum-ileum anastomosis and tabularizations are not necessary. the reasons for deciding to create a mitrofanoff stoma are irreparable loss of the urethra, continence problems, neurogenic bladder with incontinence, unreconstructable bladder (e.g. exstrophy), unreconstructable urethral disease, and congenital anomalies like urogenital sinus (23). the mitrofanoff principle can also be performed in combination with a bladder augmentation technique.(24) appendicular diversion can be used in cases who have complicated urethral trauma after accidents(25). the benefits of appendix diversion include maintaining complete continence; easy catheterization; excellent body image; and rarity of post-surgical complications such as dermatitis and urinary tract infection(26). regarding the length of appendix ,the cutaneous stoma can be placed in the umbilicus or the lower right abdominal quadrant(27). yang et al.(28) demonstrated that the submucosal tunnel and abdominal wall muscles are critical factors in the success rate of continence. however, like any other surgery, the mitrofanoff procedure is associated with some complications such as leakage from the stoma and non-catheterizable channel. recent reports showed an overall complication rate of figure 2. passing a 14f catheter down the isolated appendix to check for patency. figure 3. the stoma was created at a level relative to the bladder so that gravity would assist in achieving continence. figure 4. urethral stricture shown in retrograde urethrogram (rug) appendicovesicostomy for urethral distraction-abedi et al. reconstructive surgery 388 vol 17 no 04 july-august 2020 389 6.2%(18). the incidence of stomal stenosis was 10-23%, incontinence 2-7%(29,30) and stoma revision was required in 16-20% of cases (29,30). adherence to the technique which provides ease of catheterization intraoperatively, wide reflection of the cecum to preserve vascularity, and fixation of the bladder to the anterior abdominal wall guarantees a durable achievement (30). the downside is that the prevalence of catheterization and stomal problems increases with the length of follow-up(24). our study enrolled patients with long urethral strictures who had failed attempts of urethroplasty. thus, the only alternative method that would make them catheter-free and continent was appendix diversion using mitrofanoff principle. although these patients need to perform cic to empty their bladder, it does not interfere with their daily activities. the patients enrolled in our study suffered from complicated urethral stricture and were dependent on suprapubic catheter for emptying their bladder ever since. after performing appendicular urinary diversion, these patients became catheter-free and did not have any difficulties with intermittent catheterization for over two years. our study reports a continence rate of 100% with good satisfactory results, consistent with the reports of previous articles(29-32). in our study, none of the six patients had stomal stenosis during the fol¬low-up period. this means that our results were more satisfying than other studies.(17,24,33). the reason for a lower rate of stomal stenosis in our study might be the preservation of the mesenteric base of the appendix through wide reflection of the cecum with minimal manipulation which helped attain vascularity to decrease inflammation and mucosal dysfunction. also, a minimum tension was placed on the appendix between the bladder and the skin due to the appropriate selection of the location of the ostoma and, if necessary, the bladder was sutured to the rectus sheath. using a suitable catheter size for insertion and then catheterization, appendix end speculation at the stoma site, as well as careful training of the catheterization technique could be other reasons. although the results of appendix diversion are desirable, sometimes the appendix is not usable because of insufficient length or quality, short mesentery, or histopathologic changes consistent with chronic inflammation or fibrous lumen obstruction(34). regarding these situations, techniques such as the monti method, or using a bladder or cecal flap to partially span the distance between the bladder and abdominal wall are good alternative methods.(13,35) conclusions based on the results of our study, mitrofanoff technique is a valuable procedure with low incontinence and complication rates and should be considered in cases with unreconstructable urethral damage who cannot be treated with other routine methods to achieve urinary continence and low-pressure reservoir. acknowledgements the authors are thankful for the assistance of the urology ward staff due to their invaluable help throughout this study. we thank the medical librarians at shohada-e-tajrish hospital who helped us with data collection. conflict of interest the authors report no conflict of interest in this work. references 1. webster gd, ramon j . repair of pelvic fracture posterior urethral defects using an elaborated perineal approach: experience with 74 cases. j urol. 1991;145:744-8. 2. mirzazadeh m, fallahkarkan m, hosseini j. penile fracture epidemiology, diagnosis and management in iran: a narrative review. transl androl urol. 2017;6:158. 3. gibson gr . urological management and complications of fractured pelvis and ruptured urethra. j urol. 1974;111:353-5. 4. hosseini j, tabassi kt. surgical repair of posterior urethral defects: review of literature and presentation of experiences. urol j. 2008;5:215-22. 5. hampson la, mcaninch jw, breyer bn . male urethral strictures and their management. nat rev urol. 2014;11:43. 6. mathur r, nayak d, aggarwal g, et al. a retrospective analysis of urethral strictures and their management at a tertiary care center.nephro-urol mon. online ahead of print.2011;3:109-113. 7. andrich d, mundy a . substitution urethroplasty with buccal mucosal-free grafts. j urol. 2001;165:1131-4. 8. barbagli g, de angelis m, romano g, lazzeri m. long-term followup of bulbar end-to-end anastomosis: a retrospective analysis of 153 patients in a single center experience. j urol. 2007;178:2470-3. 9. wu d-l, jin s-b, zhang j, chen y, jin c-r, xu y-m. staged pendulous-prostatic anastomotic urethroplasty followed by reconstruction of the anterior urethra: an effective treatment for long-segment bulbar and membranous urethral stricture. eur urol. 2007;51:504-11. 10. kinnaird as, levine ma, ambati d, zorn jd, rourke kf. stricture length and etiology as preoperative independent predictors of recurrence after urethroplasty: a multivariate analysis of 604 urethroplasties. can urol assoc j. 2014;8:e296. 11. chapple c, barbagli g, jordan g, et al. consensus statement on urethral trauma. bju int. 2004;93:1195-202. 12. xu y-m, qiao y, sa y-l, et al. substitution urethroplasty of complex and long-segment urethral strictures: a rationale for procedure selection. eur urol. 2007;51:1093-9. 13. hosseini j, kaviani a, mazloomfard mm, golshan ar. monti’s procedure as an alternative technique in complex urethral distraction defect. int braz j urol. 2010;36:31726. 14. scorer c. the suprapubic catheter a method appendicovesicostomy for urethral distraction-abedi et al. of treating urinary retention. lancet. 1953;262:1222-5. 15. myers jb, mcaninch jw. perineal urethrostomy. bju int. 2011;107:856-65. 16. santucci ra, mcaninch jw, mario la, et al. urethroplasty in patients older than 65 years: indications, results, outcomes and suggested treatment modifications. j urol. 2004;172:201-3. 17. freitas filho lgd, carnevale j, melo filho a, vicente n, heinisch a, martins jl. posterior urethral injuries and the mitrofanoff principle in children. bju int. 2003;91:402-5. 18. lemelle j, simo ak, schmitt m. comparative study of the yang-monti channel and appendix for continent diversion in the mitrofanoff and malone principles. j urol. 2004;172:1907-10. 19. gerharz ew, köhl un, melekos md, bonfig r, weingärtner k, riedmiller h. ten years’ experience with the submucosally embedded in situ appendix in continent cutaneous diversion. eur urol. 2001;40:625-31. 20. simforoosh n, razzaghi m, danesh a, sharifi f, gholamrezaie h, mousavi h. continent ileocecal diversion with an unaltered in situ appendix conduit. j urol. 1998;159:1176-8. 21. mitrofanoff p. cystostomie continente transappendiculaire dans le traitement des vessies neurologiques. chir. pediatr. 1993;150:830-4. 22. turner-warwick r. prevention of complications resulting from pelvic fracture urethral injuries--and from their surgical management. urol clin north am. 1989;16:335-58. 23. filipas d, fisch m, leissner j, stein r, hohenfellner r, thüroff j. urinary diversion in childhood: indications for different techniques. bju int. 1999;84:897. 24. gowda bd, agrawal v, harrison sc. the continent, catheterizable abdominal conduit in adult urological practice. bju int. 2008;102:1688-92. 25. mohr am, pham am, lavery rf, sifri z, bargman v, livingston dh. management of trauma to the male external genitalia: the usefulness of american association for the surgery of trauma organ injury scales. j urol. 2003;170:2311-5. 26. kobayashi m, nomura m, yamada y, fujimoto n, matsumoto t. bladder‐sparing surgery and continent urinary diversion using the appendix (mitrofanoff procedure) for urethral cancer. int j urol. 2005;12:581-4. 27. hakenberg ow, ebermayer j, manseck a, wirth mp. application of the mitrofanoff principle for intermittent self-catheterization in quadriplegic patients. urology. 2001;58:3842. 28. yang w-h. yang needle tunneling technique in creating antireflux and continent mechanisms. j urol. 1993;150:830-4. 29. harris cf, cooper cs, hutcheson jc, snyder hm. appendicovesicostomy: the mitrofanoff procedure—a 15-year perspective. j urol. 2000;163:1922-6. 30. cain mp, casale aj, king sj, rink rc. appendicovesicostomy and newer alternatives for the mitrofanoff procedure: results in the last 100 patients at riley children′ s hospital. j urol. 1999;162:1749-52. 31. okada y, ogura k, ueda t, et al. urinary reconstruction using appendix as a urinary and catheterizable conduit in 12 patients. int j urol. 1997;4:17-20. 32. chen k-c, lai w-m, chen y-k, chiang h-s. the use of the appendix or tapered ileal segment as a continent cathererizable efferent limb of urinary reservior. fu jen journal of medicine. 2005;3:69-74. 33. aggarwal sk, goel d, gupta cr, ghosh s, ojha h. the use of pedicled appendix graft for substitution of urethra in recurrent urethral stricture. j pediatr surg. 2002;37:246-50. 34. sgourakis g, sotiropoulos gc, molmenti ep, et al. are acute exacerbations of chronic inflammatory appendicitis triggered by coprostasis and/or coproliths? world j gastroenterol: wjg. 2008;14:3179. 35. tsuji i, kuroda k, ishida h. a new method for the reconstruction of the urinary tract: bladder flap tube. j urol. 1959;81:282-6. appendicovesicostomy for urethral distraction-abedi et al. reconstructive surgery 390 1386 | 1urology and nephrology research center, shohadae tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 2 department of urology, medical laser application research center, shohadae tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 3 infertility and reproductive health research center, shahid beheshti university of medical sciences, tehran, iran. hossein karami,1 mohammad mohsen mazloomfard,2 aida moeini,3 mojtaba mohammadhosseini,1 alireza rezaei,1 behzad lotfi2 blind versus fluoroscopy-guided percutaneous nephrolithotomy: a randomized clinical trial corresponding author: mohammad mohsen mazloomfard, md urology and nephrology research center, no.103, boostan 9th st., pasdaran ave., tehran, iran. tel: +98 21 22567222 fax: +98 21 22567282 e-mail: mazloomfard@yahoo. com received february 2012 accepted january 2014 purpose:duetothenegativeimpactofradiationonthepatientandthesurgicalteamduring percutaneousnephrolithotomy(pcnl),weaimedtoevaluatesuccessrateandcomplications ofblindaccessforpcnlusinglumbarnotchlandmarkandcomparewithconventionalfluoroscopy-guided access. materials and methods:inaclinicaltrial,100patientswhowerecandidateforpcnl,were randomlyassignedintoblindgroup(1)andfluoroscopy-guidedgroup(2).ingroup1thelumbarnotchwasusedtoguidepercutaneousaccessandingroup2fluoroscopyperformedafter needleinsertion,amplatzplacementandattheendofsurgery.iftheaccessfailed,wewould repeatpuncturingupto5times.ingroup2,accesswasachievedusingfullfluoroscopyguidance.allpatientsunderwentpostoperativeassessmentincludingkidney-ureter-bladderx-ray and ultrasonography. results:bothmeanaccesstimeandmeanoperationtimewerestaticallysimilaringroup1 andgroup2(3.3±0.5vs.3.6±0.7minand35.2±4.6vs.38.9±4.1min,respectively).asuccessfulpuncturewasachievedin86%and94%ofthepatientsingroups1and2,respectively (p=.18).totalsuccessrateofprocedurewas80%and88%ofthepatientsingroups1and2, respectively(p=.27). conclusion:accordingtothisstudy,itseemsthatblindaccessisasafeandeffectivepcnl method,andwerecommendemploymentofthistechniquebyskilledendourologistinurology centersespeciallyforpatientwithlargehydronephrotickidney. keywords:kidneycalculi;surgery;nephrostomy;percutaneous;methods;endoscopy;lithotripsy;adverseeffects;postoperativecomplications;treatmentoutcome;fluoroscopy;prospectivestudies. endourology and stone disease endourology and stone disease 1387vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l introduction percutaneous nephrolithotomy (pcnl) has im-provedthetreatmentofkidneycalculisinceitsin-troductioninlate1970s.(1)becauseofitssafetyand lowincidenceofcomplications,nowpcnlisthetreatment ofchoiceinpatientswithkidneycalculi>2cmindiameter andinwhomextracorporealshockwavelithotripsy(swl) hasfailed.(2) althoughpcnlunderfluoroscopyguidanceistheroutine approachforaccessingthepyelocalicealsystem,othermethodssuchascomputedtomography-guided(ct-guided)accessandespeciallyx-rayfreeapproacheslikeultrasonography-guidedmethodhavebeenemployedrecentlyinsome studies.(3-7)becausetheadverseeffectsofradiationarenot dosedependentandshieldprotectionisnotcomplete,x-ray shouldbeusedcarefullyinmedicalproceduresandeliminate in unnecessary protocols. all occupational personnel should ‘achieveaslowasreasonablyachievable’(alara)doseof radiation.(8) accordingtoourknowledge,thereareonlyfewstudiesreportingblindaccesstopyelocalicealsystemwithacceptable safetyandefficacyandlowradiationhazardstothepatient andthesurgicalteamduringpcnl.(9-12)thisclinicaltrialis afirststudythatcomparestheresultsandcomplicationsof pcnlwithblindaccessunderfullfluoroscopyevaluation withconventionalfluoroscopy-guidedapproach. materials and methods study population betweenjanuary2005andoctober2010,atotalnumberof 100patientswhowerecandidateforpcnlenrolledinthe studyafteraroutinepreoperativeevaluation.theinclusion criteriawereeitherpelvic/pyelocalicealstoneslargerthan2 cmindiameterorimpactedproximalureteralstoneslarger than1cm.thepatientswithkidneyanomalies,uncontrolled coagulopathies, single caliceal stones without hydronephrosisandprevioushistoriesofpcnloropenrenalstonesurgerieswereexcluded.thestudyprotocolwasexplainedto eachpatientandinformedconsentwasobtained.thestudy wasapprovedbytheethicscommitteeoftheurologyand nephrologyresearchcenter.preoperativeevaluationconsistedoftestssuchasurineanalysis,urinecultureandrenal functiontests.beforepcnl,urinecultureswereobtained, and ifpositive,antibioticswereadministered. intravenous urographywastheprimaryimagingmodalitytodetermine thesizeandlocationofcalculi,theanatomyoftheupperurinarytract,thedegreeofhydronephrosis,andthetargetedcalyx.prophylacticintravenousantibioticswereadministered beforesurgery.allprocedureswereperformedbyasingle surgeonwhowasexperiencedinpcnl. study design thiswasasinglecenter[withbalancedrandomization(1:1)], parallel-groupstudyconductedintheurologydepartmentof shohadaetajrishhospitalintehran,iran.patientswererandomlyassignedtooneoftwogroupsaccordingtothemethod oftreatment:blind(group1,n =50)andfluoroscopy-guided (group 2, n =50)pcnlgroups.simplerandomizationwas carried out using computerized random numbers. sample sizewasdeterminedafterconsiderationoftype1statistical error<5%;andtype2statisticalerror<20%. surgical technique afterinductionofgeneralanesthesia,anopenended5french (f)ureteralcatheterwasinsertedinthelithotomicposition, and then patient was repositioned into prone position with all pressure points padded. forpatientsingroup1,thelumbarnotchwasusedtoguide percutaneous access(13)whichisboundedbythelatissimus dorsimuscleandthe12th rib in the superior, by the sacrospinalisand thequadratus lumborummuscles in themedial, andbythetransversesabdominisandtheexternaloblique muscleslaterally.(9) an 18-gauge access needle was inserted intothelumbarnotchwithanangleof30°to45°pointed cephalad,andadvancedtoadepthofnearly4to6cmunder the 12th rib.correctentrance to thecollectingsystem was assured when urine is withdrawn spontaneously or by syringeaspiration.forpatientswithalargepelvisandstaghornstones,accesswasaccomplishedbytouchingthestones bytheneedle.fluoroscopywasusedinthissteptoassess thepositionandlocationofneedlein thecalyx,andthen aguidewirewasplaced.thedepthofinsertionmeasured preciselybyrulerfornextstepsdilatation.thetractdilated bytelescopicdilatorsandthenamplatzsheath(28to30f) inserted.duringthesesteps,sterilewaterornormalsaline was injected into the ureteral catheter to increase the grade ofhydronephrosisinordertooutflowingoffluidfromthe endofdilatorsoramplatzsheathtopreventover-advanceblind access percutaneous nephrolithotomy | karami et al 1388 | mentofthem.otherfluoroscopyperformedtoestimatethe placementofamplatzsheath.byusingrigidnephroscope and swiss pneumatic lithotripsy (swiss lithoclast; ems, angiomed,gmbh&co.,karlsruhe,germany),stoneswere fragmentedandextractedbygraspingforceps.attheend, nephroscopyfollowedbyacontrolfluoroscopywerecarried outforanyresidualstonedetectionandthenamplatzsheets wereremovedandskinweresutured(tubelessprocedure). maximumof5timespuncturingwasappliedincaseofno urinedrainage,andifitfailed,theproperaccesswasperformedunderfluoroscopicguidance.ingroup2,allstandard pcnlstepsmentionedaboveincludingaccesstothecollectingsystemperformedunderfluoroscopyguidance. outcome assessment duetothedifferencebetweentwomethods,itwasnotpossibletoblindthesurgicalteamfromknowledgeofwhichprocedureaparticipantreceived;however,afterpcnloperation thepatients’evaluatorwasblindtothemethodofsurgery. stonefreestatusastheprimaryoutcomemeasurewasused toevaluatetheefficacyandresidualstoneburdenwasdeterminedbyplainabdominalradiographsandrenalultrasound studiesroutinelyobtained48hoursaftertreatment.theprocedureconsideredasafailureeitherinanystoneresidual fragmentsdetectedbythesestudiesorunsuccessfulaccess. demographicandstonescharacteristics,degreeofhydronephrosis,timetoaccess(fromthestartofpuncturingtocompletedilation),numberofpuncturingattempts,locationof accesstothesystem,timeofoperation(fromtheinduction ofanesthesiatolastskinsuture),hospitalizationtime,change inhemoglobinlevel(preoperativeand1dayaftersurgery) andcomplicationssuchasbleeding,uro-sepsisandcollectingsystemperforationwerecomparedbetweenthe2groups. statistical analysis dataanalysiswasperformedusingstudent’sttestandchisquare test. the statistical package for the social science (spssinc,chicago,illinois,usa)version16wasusedfor analysis and pvalueslowerthan.05wereacceptedassignificant. results afteraroutinepreoperativeevaluation,50patientsineach groupwereenrolledinthisstudy.demographicandclinical characteristicsofpatientsineachgroupareshownintable 1.asuccessfulaccessachievedin43(86%)and47(94%) endourology and stone disease table 1. demographic and clinical characteristics of study patients. variables blind fluoroscopy-guided p mean age (years) 30.3 ± 6.5 30.4 ± 7.8 .95 male, no. (%) 31 (62) 32 (64) .84 body mass index (kg/m2) 26.1 ± 4.3 26.7 ± 4.1 .48 stone diameter (mm) 26.4 ± 5.1 25.8 ± 4.1 .52 number of stones 1.3 ± 0.7 1.3 ± 0.6 .99 stone location, no. (%) superior ureter pyelocalix pelvic 9 (18) 14 (28) 27 (54) 8 (16) 18 (36) 24 (48) .69 hydronephrosis, no. (%) mild moderate severe 9 (18) 16 (32) 25 (50) 17 (34) 14 (28) 19 (38) .18 left side stone, no. (%) 25 (50) 23 (46) 1389vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l patients (94%) ingroups1and2, respectively(p= .18). allsevenpatientsinblindgroupwithunsuccessfulaccess underwentfluoroscopyguidedpcnlatthesameoperation time.also,thethreepatientswithfailedaccessingroup2 successfullymanagedwithfluoroscopicguidedpcnlinanothersessionofoperation.theaveragenumberofpercutaneouspunctures±sdneededtofindthecollectingsystem was1.8±0.9/caseingroup1and1.5±0.7/caseingroup2 (p=.11).bothmeanaccesstimeandmeanoperationtime werestaticallysimilaringroup1andgroup2.successrate ofprocedurewas80%ingroup1and88%ingroup2(p = .275).whenmoderatetoseverehydronephrosiswaspresent, optimalexposuretoureteropelvicjunctionwaspossibleeven fromthelowerpolebygentlyturningthenephroscopeand amplatzsheath. intraoperativebleedingoccurredin2patients(4%)ingroup 1andonepatient(2%)ingroup2,whichwerecontrolledby tractdilationwithballoondilator.noneofthepatientsexperiencedpostoperativebleeding.urinarycollectiondevelopedinonepatientingroup1,sotheureteralstentremained for4daysandthepatientdischargedwithoutcomplication. one(2%)patientineachgroupexperiencedsepsiswhich weretreatedwithbroadspectrumantibiotics.detailsofthe treatmentsineachgrouparesummarizedintable2.ofpatientswithfailedpcnl,12patientsunderwentclassicpcnl andswlperformedin4patients. discussion recently,pcnlconsideredasasafeandefficientmodalityformanagementofvarioustypesofrenalstonedisease. (14)thefirststepinpcnlisaccesstothecollectingsystem whichisusuallyachievedusingfluoroscopy.(5)insertionof anephrostomytubeunderfluoroscopyaccompanieswitha successrateof90-98%.(5,15) blind access percutaneous nephrolithotomy | karami et al table 2. intraoperative and postoperative data of study subjects. variables blind fluoroscopy-guided p access, no. (%) direct middle calyx inferior calyx 2 (4) 37 (74) 11 (22) 0 41 (82) 9 (18) .30 mean hemoglobin level (mg/dl) before operation after operation change 12.8 ± 1.3 11.8 ± 1.2 -0.96 ± 0.3 12.6 ± 1.1 11.9 ± 1.0 -0.82 ± 0.3 .40 .65 .20 intraoperative bleeding, no. (%) 2 (4) 1 (2) ns postoperative sepsis, no. (%) 1 (2) 1 (2) ns postoperative bleeding, no. (%) 0.0 0.0 ns injury to adjacent organs, no. (%) 0.0 0 ns pyelocalyceal system disruption, no. (%) 1 (2) 0.0 ns mean access time (minutes) 3.3 ± 0.5 3.6 ± 0.7 .15 unsuccessful access, no. (%) 7 (14) 3 (6) .18 mean operation time (minutes) 35.2 ± 4.6 38.9 ± 4.1 .10 mean hospital staying (days) 2.7 ± 0.3 2.9 ± 0.3 .14 success rate, no. (%) 40 (80) 44 (88) .275 key: ns, not significant. 1390 | manystudieshaveinvestigatedmethodsforloweringthedose ofx-rayusedinpcnl,suchaspcnlunderultrasonography guidance(15,16)andblindpcnl.(9-12).thisisbecauseof adverseeffectsofradiationtohumantissues.previousstudieshavebeenshownoperatingroompersonnelarewithinsafe radiationdoselimitsduringpcnl.(8,17,18) in order to the deleteriouseffectsofradiationontissueisnotdosedependent, surgicalteamshouldalaradoseofradiation.(8) chienandbellman(9)performedblindaccessnephrostomy in26patientswithhydronephrosiswithoutanysignificant complication.inthisstudynephrostomieswereperformed onhydronephrotickidneys,butthedegreeofhydronephrosis whichcouldaffectthesuccessrate,hadnotbeendetermined. theyreported98%successratewiththemeanpuncturing attemptsof2.5perpatient.directaccesstotherenalpelvis wasachievedin75%ofthecases. mcdougall and colleagues(19) suggested blind access in cases withobstructionorstrictureoftheureter,abnormalanatomy oftheureteralorifice,orwhentherequiredequipmentforthe standardapproachisnotavailable.intheirexperience,blind accessachievedbyinsertionofa22fchibaneedlewitha 90°angle,1cmto1.5cmlateraltolumbar1vertebra,for antegradeproceduresorcontrastmediuminjection. inoursurgicalteam’sexperienceontreatmentofimpacted upperureteralcalculi>1cmwithblindaccesspcnl,both successrateofachievingaccessandprocedurewere100% withoutanymajorcomplication.(11)itmeansthatinexperiencedhand,blindaccesspcnlcouldbeperformedwithno needtospecialinstruments,andachievedahighsuccessrate inashortperiodwithminimalmorbidityespeciallyinthe presenceofmoderatetoseverehydronephrosis.inanother study(12)weusedblindaccessforpcnlin128patientswith staghornorpyelocalicealstonewithmoderatetoseverehydronephrosiswhichresultedinnearlysuccessrateof90%. accesswasaccomplishedbytouchingthestoneswiththe needle,incaseswithalargepelvisandstaghornstone. inaclinicaltrialstudy,basiriandcolleagues(10)compared blindaccesswithclassicfluoroscopicpcnl.thesuccess rateofbothachievingaccessandprocedureinblindaccess groupwere62%and100%,respectively;withnocomplicationsoftheinitialaccesstothesystem.thenumberofpuncturingattemptswasnotdifferentbetweenthe2groups. mousavi-baharandcolleagues(20) reportedsuccessrateof 87%in62casesofkidneycalculuswhounderwentblindaccesspcnl. inthisstudy,successratewas80%and88%andsuccessful accesswas86%and94%inblindandfluoroscopicpcnl, respectively.allsevenpatientswithfailedaccessinblind pcnlgroupunderwentfluoroscopiconeatthesameoperatingsessionwithstoneclearanceof100%.ourstonefreerate wassimilartochienandbellman’sstudy(9)butitwasmore thanbasiriandcolleagues’report.(10)theaccessratewas comparableinthesestudies.however,inabilitytodesigna doubleblindclinicaltrialandlownumberofcaseswerethe majorlimitationsofourstudy. conclusion itseemsthatblindaccessisasafeandeffectivepcnlmethodthatcouldbeperformedbyskilledendourologist,especiallyforpatientwithlargehydronephrotickidney. conflict of interest none declared. endourology and stone disease references 1. fenstrom i, johannson b. percutaneous pyelolithotomy: a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. kader ak, finelli a, honey rj. nephroureterostomy drained percutaneous nephrolithotomy: modification combining safety with decreased morbidity. j endourol. 2004;18:29-32. 3. montanari e, serrago m, esposito n, et al. ultrasound fluoroscopy guided access to the intrarenal excretory system. ann urol (paris). 1999;33:168-81. 4. delavierre d, fournier g, mangin p. percutaneous drainage nephrostomy guided by ultrasound. apropos of 80 adult cases. j urol (paris). 1989;95:319-29. 5. patel u, hussain ff. percutaneous nephrostomy of nondilated renal collecting systems with fluoroscopic guidance: technique and results. radiology. 2004;233:226-33. 6. matlaga br, shah od, zagoria rj, dyer rb, streem sb, assimos dg. computerized tomography guided access for percutaneous nephrostolithotomy. j urol. 2003;170:45-7. 7. karami h, arbab am, rezaei a, mohammadhoseini m, rezaei i. percutaneous nephrolithotomy with ultrasonography-guided renal access in the lateral decubitus flank position. j endourol. 2009;23:33-5. 1391vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l 8. kumari g, kumar p, wadhwa p, aron m, gupta np, dogra pn. radiation exposure to the patient and operating room personnel during percutaneous nephrolithotomy. int urol nephrol. 2006;38:207-10. 9. chien gw, bellman gc. blind percutaneous renal access. j endourol. 2002;16:93-6. 10. basiri a, mehrabi s, kianian h, javaherforooshzadeh a, kamranmanesh mr. blind puncture in comparison with fluoroscopic guidance in percutaneous nephrolithotomy a randomized controlled trial. urol j. 2007;4:79-83. 11. karami h, arbab ah, hosseini sj, razzaghi mr, simaei nr. impacted upper-ureteral calculi >1 cm: blind access and totally tubeless percutaneous antegrade removal or retrograde approach? j endourol. 2006;20:616-9. 12. karami h, jabbari m, arbab ah. tubeless percutaneous nephrolithotomy: 5 years of experience in 201 patients. j endourol. 2007;21:1411-3. 13. bellman gc, huang s, tebyani n, et al. lumbar notch: a technique in percutaneous renal access. presented at the 16th world congress on endourology and swl. new york, september 1998. 14. consensus conference. prevention and treatment of kidney stones. jama. 1998;260:977-81. 15. basiri a, ziaee am, kianian hr, mehrabi s, karami h, moghaddam sm. ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2008;22:281-4. 16. gupta s, gulati m, uday shankar k, rungta u, suri s. percutaneous nephrostomy with real-time sonographic guidance. acta radiol. 1997;38:454-7. 17. rao pn, faulkner k, sweeney jk, asbury dl, sambrook p, blacklock nj. radiation dose to patient and staff during percutaneous nephrostolithotomy. br j urol. 1987;59:508-12. 18. inglis ja, tolley da, law j. radiation safety during percutaneous nephrolithotomy. br j urol. 1989;63:591-3. 19. mcdougall em, liatsikos en, dinlenc cz, smith ad. percutaneous approaches to the upper urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3320-45. 20. mousavi-bahar sh, minaei ma. [results of pcnl for renal and upper ureteral stones without fluoroscopy]. sci j hamadan univ med sci. 2003;10:35-8. blind access percutaneous nephrolithotomy | karami et al pl steinberg md department of surgery, dartmouth hitchcock medical center , lebanon, new hampshire, usa. comment on blind versus fluoroscopyguided percutaneous nephrolithotomy: a randomized clinical trial i applaud the randomized design, but the au-thorsshouldincludeapoweranalysisofwhyfiftypatientsperarmwereused.whatlevelof differencedidtheywanttodetectandwhatisthe primaryendpoint?fluoroscopyaccesswasmore successful,andthereasonitmaynotbesignificant isasmallsamplesize.stone-freeratesarebestassessedonpost-operativecomputedtomography,not kidney-ureter-bladder x-ray. the stone free rates maynotbeasgoodassuggested.interpolaraccess isusuallyonlydesirableforureteropelvicjunction proceduresandoftenisnotagoodangleforother stone burdens. in addition these patients had a low bodymassindexandasmallstoneburdenandi wonderhowwellthiswouldworkwithlargerpatients and a larger stone burden. u j all final for web.pdf 780 | 1 division of pediatric urology, children’s medical center of dallas and university of texas southwestern medical center, dallas, texas 2 division of urologic oncology, university of texas southwestern medical center, dallas, texas 3 division of pediatric hematology and oncology, children’s medical center of dallas and university of texas southwestern medical center, dallas, texas 4 department of pathology, children’s medical center and university of texas southwestern medical center, dallas, texas nicholas g. cost,1,2 candace f. granberg,1 bruce j. schlomer,1 jonathan e. wickiser,3 patricio c. gargollo,1 linda a. baker,1 dinesh rakheja4 single institution experience with tru-cut renal mass biopsy for diagnosing wilms tumor corresponding author: nicholas g. cost, md division of pediatric urology, cincinnati children’s hospital medical center, 3333 burnet avenue, mlc 5037, cincinnati, ohio 45229, usa tel: +513 363 0773 fax: +513 636 6753 e-mail: nicholas.cost@sbcglobal.net received january 2012 accepted october 2012 purpose: chemotherapy. materials and methods: pathology. results: no patients have had local or regional recurrence. conclusion: keywords: pediatrics, wilms tumor, nephroblastoma, kidney neoplasms, diagnosis urological oncology urological oncology 781vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l tru-cut renal mass biopsy for wilms tumor | cost et al introduction wilms tumor (wt) is the most common renal ma-lignancy in children and the fourth most com-mon childhood cancer. in north america, strategy is used by the international society of pediatric onchemotherapy, after radiographic diagnosis. protocol, chemotherapy includes over-treating benign, non-wt renal cyclines), and the reduced need for radiation. furthermore, advocates of minimally-invasive surgery and nephronsparing surgery(7) recognize that pre-surgical chemotherapy could increase the percentage of children eligible for these approaches. csg) has recently investigated the timing of chemotherapy ly diagnosed, unilateral, and non-metastatic renal tumors to their solution to paradigm is not routinely used in north america and current cog recommendations mandate upstaging in unilateral cases undergoing biopsy. given the various risks and potential cutaneous biopsy for pediatric renal masses to evaluate its diagnostic ability and safety. case review resection of the renal mass. the biopsy and surgical resection months). one patient had a prior liver transplant, and imaging done for elevated transaminases demonstrated a renal mass suspicious lymphoproliferative disorder (ptld), the patient underptld, saving them from un-necessary nephrectomy. another patient had a percutaneous biopsy performed for a possible renal abscess versus tumor. after the pathology demsame operative session as needle biopsy due to inconclusive patient did not undergo nephrectomy due to disease progression during the time from biopsy to planned nephrectomy. the remaining 6 patients had bilateral renal masses. section after percutaneous biopsy in order to correlate the read as wt versus hyperplastic nephrogenic rests. no biopsy to produce a median of 3 (2 to 6) evaluable specimens for after the biopsy and no patients have had a local or regional 782 | months) post-biopsy. discussion despite the potential advantages of pre-surgical chemotherapy for wt, the concern for inappropriately treating paradigm. previous investigators have studied pre-therapy non-wt pathology. therefore, they propose that a predates for pre-surgical chemotherapy. risks of tumor spillage and possible biopsy-tract seeding. for these reasons, the current cog protocols mandate upstaging of cases undergoing percutaneous biopsy. thus, despite using biopsy to achieve a goal of decreased morplications. to investigate this, the ukccsg has studied a masses suspected to be wt. their results indicate that percutaneous biopsy of such masses is safe and effective. ous needle biopsy of suspicious renal masses to assess both its safety and diagnostic ability. safe and accurate in our small series. to determine the accuresection. in each case, the diagnosis of wt from the biopsy tion. ever, there are risks and these must be highlighted. the immediate risks include bleeding, infection, and pain. the more dreaded long-term complications are needle-tract tumor seeding or tumor spillage and increased local disease recurrence. ture of needle tract recurrence, the risk must not be ignored. to put this into perspective, the rate of intra-operative tumor rupture in the immediate surgery arm of the same study in event-free or overall survival. furthermore, they achieved immediate surgery group. perience may not be applicable to a generalized population conclusion in our series, tru-cut renal mass biopsy reliably and safely diagnosed wt. using such a pre-therapy biopsy paradigm may aid in the appropriate selection of candidates for prethis aim to assess its ultimate utility and safety. conflict of interest none declared. references 1. gurney jg, severson rk, davis s, robison ll. incidence of cancer in children in the united states. sex-, race-, and 1-year age-specific rates by histologic type. cancer. 1995;75:2186-95. 2. grovas a, fremgen a, rauck a, et al. the national cancer data base report on patterns of childhood cancers in the united states. cancer. 1997;80:2321-32. urological oncology 783vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l tru-cut renal mass biopsy for wilms tumor | cost et al 3. kaste sc, dome js, babyn ps, et al. wilms tumour: prognostic factors, staging, therapy and late effects. pediatr radiol. 2008;38:2-17. 4. nakamura l, ritchey m. current management of wilms' tumor. curr urol rep. 2010;11:58-65. 5. barber td, wickiser je, wilcox dt, baker la. prechemotherapy laparoscopic nephrectomy for wilms' tumor. j pediatr urol. 2009;5:416-9. 6. duarte rj, denes ft, cristofani lm, odone-filho v, srougi m. further experience with laparoscopic nephrectomy for wilms' tumour after chemotherapy. bju int. 2006;98:155-9. 7. cost ng, lubahn jd, granberg cf, et al. oncologic outcomes of partial versus radical nephrectomy for unilateral wilms tumor. pediatr blood cancer. 2012;58:898-904. 8. mitchell c, pritchard-jones k, shannon r, et al. immediate nephrectomy versus preoperative chemotherapy in the management of non-metastatic wilms' tumour: results of a randomised trial (ukw3) by the uk children's cancer study group. eur j cancer. 2006;42:2554-62. 9. cheng e, fustino n, klesse l, chinnakotla s, sanghavi r. post-transplant lymphoproliferative disorder resembling wilms tumor. diagnostic dilemma: renal biopsy or nephrectomy? pediatr transplant. 2011;15:e187-91. 10. vujanic gm, kelsey a, mitchell c, shannon rs, gornall p. the role of biopsy in the diagnosis of renal tumors of childhood: results of the ukccsg wilms tumor study 3. med pediatr oncol. 2003;40:18-22. 11. lee is, nguyen s, shanberg am. needle tract seeding after percutaneous biopsy of wilms tumor. j urol. 1995;153:1074-6. 12. shet t, viswanathan s. the cytological diagnosis of paediatric renal tumours. j clin pathol. 2009;62:961-9. 13. aslam a, foot a, spicer r. needle track recurrence after biopsy of non-metastatic wilms tumour. pediatr surg int. 1996;11:416-7. v08_no_2_final.pdf case report 165urology journal vol 8 no 2 spring 2011 extragastrointestinal stromal tumor of the urinary bladder a case report hong-seok shin,1 chang-ho cho,2 yoon-seup kum2 urol j. 2011;8:165-7. www.uj.unrc.ir keywords: gastrointestinal stromal tumor, urinary bladder, cystoscopy 1department of urology, school of medicine, catholic university of daegu, korea 2department of pathology, school of medicine, catholic university of daegu, korea corresponding author: yoon-seup kum, md department of pathology, school of medicine, catholic university of daegu, 3056-6, daemyung-dong, nam-gu, daegu, 705-718, korea tel: +82 536 504 159 fax: +82 536 503 050 e-mail: yskum@cu.ac.kr received october 2009 accepted november 2009 introduction a gastrointestinal stromal tumor (gist) is primarily located in the gastrointestinal tract. it is classified as a mesenchymal tumor that shows a cd117 (c-kit)-positive mesenchymal spindle or epithelioid neoplasm. tumors outside the gastrointestinal tract that were histologically similar to gists and showed immunopositivity for cd117 were classified as extragastrointestinal stromal tumors. although there were several reports of tumors outside the gastrointestinal tract, only a case of extragastrointestinal stromal tumor in the urinary bladder was reported.(1,2) herein, we report another case arising in the urinary bladder presenting with submucosal polypoid mass. case report a 42-year-old man presented with hematuria since three weeks ago. he had no irritative or obstructive urinary symptoms. urine analysis was normal and other laboratory studies were within normal limits. computed tomography scan revealed an intravesical solid polypoid mass measuring 2.6 × 2.4 cm and multiple small calcified spots in the bladder base (figure 1). no no evidence of an intra or extraluminal mass was observed in the gastrointestinal tract. the patient was taken to the operating room for a cystoscopic examination. a thumb tip-adult size polypoid submucosal mass with a smooth surface mucosa and a broad base was detected in the bladder dome. thereafter, the mass was cystoscopically removed. the cystoscopically resected specimen consisted of multiple chips of yellow, pink, and gray, soft rubbery tissue, measuring 3.0 × 2.0 × 2.0 cm in aggregate. tumor cells were found to be scattered in figure 1. computed tomography scan revealed an intravesical polypoid mass with small multiple calcified spots within the contrast-filled urinary bladder lumen. extragastrointestinal stromal tumor—shin et al 166 urology journal vol 8 no 2 spring 2011 the submucosa, and the overlying transitional epithelium was intact without ulceration. it was composed of sheets or nests of eosinophilic cells without any organoid features and loose edematous well-vascularized stroma, and with varied cellularity (figure 2). in some areas, the tumor cells proliferated along the abundant vascular structures, and were arranged in a perithelial pattern. occasionally, individuallyscattered tumor cells were noted in the edematous stroma. the tumor cells were chiefly composed of polygonal epithelioid cells and were rarely composed of little spindle cells. the nuclei were ovoid or round and often centrally located. some had bland or hyperchromatic nuclei. occasionally, intranuclear inclusion bodies were noted. the cytoplasms were bright plump eosinophilic with relatively distinct cytoplasmic margins; occasionally, irregular margins were observed. furthermore, eosinophilic cytoplasms were not stained by periodic acid-schiff staining. neither mitosis nor necrosis was observed. the stroma had a loose edematous myxoid or a focally liquefied appearance with high vascularity. immunohistochemically, the tumor cells strongly expressed cd117 (figure 3) and weakly expressed cd34, but they were negative for smooth muscle actin, pan-cytokeratin, and s-100 protein. during 20-month follow-up, using transabdominal ultrasonography and cystoscopic examination, no recurrence of tumor growth was noted. discussion most of the gists were previously classified as leiomyoma or neurogenic tumors because of similar histologic and immunophenotypic features of smooth muscle or neurogenic differentiation.(3) recently, however, they expressed a growth factor receptor with tyrosine kinase activity, known as kit, which appeared to play a key role in committing primitive mesenchymal cells towards interstitial cells of cajal differentiation.(3,4) true neural and smooth muscle neoplasms of the gastrointestinal tract entirely lack kit mutations. some gists contain activating mutations in the kit proto-oncogene, which appears to be a strong candidate for the molecular pathogenesis of gists.(5) therefore, kit expression was proposed to be both the most sensitive and specific phenotypic marker of gists showing differentiation towards the interstitial cell of cajal.(4) extragastrointestinal stromal tumors are relatively rare compared with their gastrointestinal counterpart. approximately, 7% of the tumors occurred in the soft tissues of the peritoneum, omentum, and mesentery.(6) extragastrointestinal stromal tumors usually present during adult life in the form of enlarging masses with variable duration. unlike their gastrointestinal counterparts, these lesions tend to be large when are first detected. most of them are firm, fleshy, grey, and red masses with occasionally cystic change. figure 2. the tumor shows sheet or nests of polygonal epithelioid cells having bland or hyperchromatic nuclei and bright eosinophilic cytoplasms with relatively distinct cytoplasmic margins (hematoxylin and eosin stain ×100). figure 3. the stain-positive tumor cells for cd117 (immunohistochemical stain, × 200). extragastrointestinal stromal tumor—shin et al 167urology journal vol 8 no 2 spring 2011 histologically, there are two types; epithelioid and spindle cells. the former is noted where the tumor is composed of round cells with varying pleomorphic cell size and an eosinophilic or clear cytoplasm. the nuclei are uniform and round to ovoid, and have a vesicular chromatin. occasionally, hyperchromatism, multinucleation, a prominent cytoplasmic vacuole, and a peripherally located nucleus are also seen. the epithelioid type was previously classified as leiomyoblastoma. the spindle pattern more closely resembles the conventional smooth muscle tumors, which are short and fusiform in contrast to the smooth muscle cells that show short fascicles and whorls, and their nuclei tend to be uniform and round.(3) in addition to the fact that the cells were consistent positive for kit (cd117), some gists showed immunopositivity for cd34 and s-100 protein and were rarely positive for smooth muscle actin and desmin. the clinical behavior of an extragastrointestinal stromal tumor is difficult to predict. however, it is well-accepted that the malignant behavior of gists is strongly correlated with tumor size (> 5 cm in greatest diameter) and mitotic count on this rule, our case is benign. however, it should be noted that the lesions that are very small (even < 2 cm) and have low mitotic rates (even < 5 per 50 high-power field) occasionally metastasize.(3) therefore, a prolonged follow-up period is necessary for almost any gist that exhibits the potential to behave in a malignant fashion. it was known that there was no effective therapy except complete surgical resection until the recent development of the kit inhibitor imatinib mesylate. this inhibitor attacks a specific molecular target in gists, by employing tyrosine kinase of kit inhibition as well as disrupting signal transduction at mitosis. it induces growth arrest and apoptosis of tumor cells.(7) conflict of interest none declared. references 1. kobayashi t, teruya m, shimizu s, et al. giant extragastrointestinal stromal tumor. am j surg. 2004;188:191-2. 2. mekni a, chelly i, azzouz h, et al. extragastrointestinal stromal tumor of the urinary wall bladder: case report and review of the literature. pathologica. 2008;100:173-5. 3. fletcher cd, berman jj, corless c, et al. diagnosis of gastrointestinal stromal tumors: a consensus approach. hum pathol. 2002;33:459-65. 4. hirota s, isozaki k, moriyama y, et al. gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. science. 1998;279:577-80. 5. nasu k, ueda t, kai s, et al. gastrointestinal stromal tumor arising in the rectovaginal septum. int j gynecol cancer. 2004;14:373-7. 6. emory ts, sobin lh, lukes l, lee dh, o’leary tj. prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site. am j surg pathol. 1999;23:82-7. 7. dematteo rp, heinrich mc, el-rifai wm, demetri g. clinical management of gastrointestinal stromal tumors: before and after sti-571. hum pathol. 2002;33:466-77. endourology and stone disease effect of different musical types on patient’s relaxation, anxiety and pain perception during shock wave lithotripsy: a randomized controlled study ali çift*, can benlioğlu purpose: the aim of this study was to investigate the effects of listening to different music types during extracorporeal shock wave lithotripsy (swl) on the patients’ pain control, anxiety level, and satisfaction. materials and methods: this study was a prospective single-blinded, paral¬lel-group randomized clinical trial with balanced ran¬domization [1:1]. a total of 150 patients who underwent first-session swl were included in the study. the patients were randomly divided in to five groups (30 participants in each group) as follows: headphones were not put on and no music was played in group 1 (control group); headphones were put on but no music was played in group 2; turkish art music was listened to with headphones in group 3; western classical music was listened to with headphones in group 4; thetype of music the patient liked was listened to with headphones in group 5. demographic data related to patients and procedure, state-trait anxiety inventory-state anxiety (stai-sa), visual analog scale (vas) scores, willingness to repeat procedure (0: never 4: happily), and patient satisfaction rates (0: poor 4: excellent) were recorded immediately after the procedure. results: there was a statistically significant difference between groups in terms of median vas scores (7, 6, 4.5, 5, and 4, respectively, p < .001), whereas the vas scores in groups 3, 4, and 5 were significantly lower than those in group 1 and 2 (p < .001). the median stai-sa scores between the groups were significantly different (45, 45, 42, 45, and 40, respectively, p < .001), while the anxiety levels in groups 3, 4, and 5 were significantly lower than those in group 1 (p = .008, p = .018, and p < .001, respectively). moreover, there were statistically significant differences between the groups in terms of willingness to repeat the procedure and patient satisfaction rates (p < .001). conclusion: music therapy during swl reduced the patients' pain and anxiety scores, moreover listening to the patient’s preferred music type provided greater satisfaction. listening to the patient’s preferred music type could be standardized and routinely used during swl. keywords: anxiety; music; nephrolithiasis; pain; shockwave lithotripsy introduction extracorporeal shock wave lithotripsy (swl) has been used extensively in the treatment of urinary tract stones since the 1980s due to its low morbidity and high efficacy.(1) the most common complaints of the patients undergoing swl are pain and anxiety. despite pain reduction with new generation swl devices, severe pain was still reported in 30% of all patients when treated without undergoing analgesia.(2) it is important that patients are kept at the lowest levels of pain and anxiety to ensure their compliance with the swl procedure. therefore, many complementary therapies have been reported.(3) one of these therapies is music which is a non-pharmacological and non-chemical method and used in addition to traditional care and medical treatment for postoperative pain treatment.(4) moreover, it is a source of pleasure for many people and has been used throughout history to alleviate sickness and pain.(5) in the literature, there are several studies related to listening to music during swl.(6-12) these studies have shown that music has positive effects on pain and anxiety during swl. individuals' musical preferences are influenced by age, gender, culture, mood, and previous department of urology, faculty of medicine, adıyaman university, adıyaman, turkey. *correspondence: adiyaman university, faculty of medicine, department of urology, adiyaman, turkey phone:+90 5325701602. email: dr.alicift@gmail.com. received may 2019 & accepted september 2019 musical experience. different types of music have been shown to affect heart rate, blood pressure, and the frequency and depth of breathing.(13) it is important to consider the musical preferences of individuals, as these preferences contribute to the therapeutic effect.(14) in this study, patients with upper urinary tract stones undergoing swl without any medication were assessed for their pain and anxiety scores after listening to different music types during the procedure. to our knowledge, this is the first study in the literature investigating the effect of different music types on the pain and anxiety scores of patients during swl. materials and methods study population this prospective randomized study was completed with the permission of the presidency clinical research ethics committee in adiyaman university (2016/5-5) between july 2016 and november 2017. informed consent was obtained, and the patients participated voluntarily in the study. inclusion criteria were presence of a radiopaque stone 10-20 mm in diameter localized in the renal pelvis or ureteropelvic (up) junction, not having a ureteral stent, urology journal/vol 17 no. 1/ january-february2020/ pp. 19-23. [doi: 10.22037/uj.v0i0.5333] age over 18 years, and absence of renal colic before the procedure. exclusion criteria were previous swl history, presence of ureteral stent, hearing deficit, uncontrolled hypertension and antidepressant drug usage. patients’ en¬rollment algorithm has been illustrated in figure 1. before swl, the size and localization of the kidney stones were evaluated by plain films (kub radiography), ultrasonography and computed tomography. study design this study was a prospective single-blinded, paral¬lelgroup randomized clinical trial with balanced ran¬domization [1:1]. sample size was calculated considering a .30 effect size with one-way anova expected difference among study groups in the primary outcome of interest. considering type i error of .05 and type ii error of .20, at least 28 cases were needed for eac harm. therefore 30 cases were decided to be enrolled in eac harm of the study. sample size estimation was performed using g*power 3.0.10. (franz faul, universität kiel, kiel, germany) statistical package. patients were randomly assigned to one of the five study groups (30 pa¬tients in each group). randomization was carried out using computerized random numbers. the allocated treatment for each patient was recorded in concealed envelopes. all study personel were blinded to treatment assignment. the procedure of simple randomization was followed therefore no restriction we had such as stratifying or blocking. after achieving eligibility criteria and pa-tient’s agreement on participation, the concealed envelopes were opened by one of the staff who was working at the clinic and unaware of the study. the study was completed by a senior urologist and a staff lithotripsy technician. the patients were randomly divided into five groups as follows: headphones were not put on and no music was played in group 1 (control group); headphones were put on but no music was played in group 2; turkish art music was listened to with headphones in group 3; western classical music was listened to with headphones in group 4; the type of music the patient liked was listened to with headphones in group 5. the headphones were sony mdr zx100. medication was not administered to any patient in any group before or during the procedure. a total of 150 patients (30 in each group) who underwent first-session swl were included in the study. the demographic data related to the patient and procedure, pain and anxiety scores, willingness to repeat procedure (0: never 4: happily), and patient satisfaction rates (0: poor 4: excellent) were recorded. hemodynamic parameters were also recorded before and after the swl procedure. outcome assessment anxiety assessment was performed by using the statetrait anxiety inventory-state anxiety scores (staisa) form.(15the anxiety score was calculated as follows: questions 1, 2, 5, 8, 10, 11, 15, 16, 19, and 20 of the 20 questions on the form had opposite statement. the total scores obtained from the reverse statements were subtracted from those of the remaining direct statements. 50 points were added in order to calcueffect of different musical types during swl-çift et al. table 1. demographic and clinical characteristics group 1 (n=30) group 2 (n=30) group 3 (n=30) group 4 (n=30) group 5 (n=30) p-value age (years) 38.4 ± 13.9 39.2 ± 12.1 37.7 ± 10.9 36.3 ± 10.6 36.4 ± 10.2 .883† gender .081‡ male 16 (53.3%) 17 (56.7%) 25 (83.3%) 21 (70.0%) 22 (73.3%) female 14 (46.7%) 13 (43.3%) 5 (16.7%) 9 (30.0%) 8 (26.7%) body mass index (kg/m2) 26.3 ± 3.3 26.1 ± 2.3 25.6 ± 2.7 26.0±2.3 26.4 ± 1.4 .748† stone location .963‡ pelvis 21 (70.0%) 19 (63.3%) 20 (66.7%) 21 (70.0%) 19 (63.3%) ureteropelvic (up) junction 9 (30.0%) 11 (36.7%) 10 (33.3%) 9 (30.0%) 11 (36.7%) stone laterality .983‡ right 11 (36.7%) 12 (40.0%) 11 (36.7%) 12 (40.0%) 10 (33.3%) left 19 (63.3%) 18 (60.0%) 19 (63.3%) 18 (60.0%) 20 (66.7%) stone size (mm) 11.5 (10.0-13.0) 12.0 (11.0-14.0)a,b 10.0 (10.0-12.0)a 10.0 (10.0-12.0)b 12.0 (10.0-12.25) .007¶ swl duration (min) 30.0 (25.0-30.0) 28.5 (25.0-30.0) 30.0 (28.75-30.0) 25.0 (25.0-30.0) 27.5 (25.0-30.0) .185¶ swl total energy (joule) 80.0 (74.75-92.5) 85.0 (65.0-93.25) 92.0 (82.0-101.25) 90.0 (64.25-103.5) 94.0 (79.75-96.25) .159¶ total number of shockwaves 2700 (2500-2900) 2725 (2500-2900) 2851.5 (2685.7-3000.0) 2842.5 (2437.2-2958.7) 2800 (2500-2925) .473¶ † one-way anova, data shown as mean ± sd, ‡ pearson's chi-square test, data presented as number of cases and percentages, ¶ kruskal–wallis test, descriptive statistics given as median (q1 – q3), a: group 2 vs group 3 (p < .001), b: group 2 vs group 4 (p = .002). figure 1. patients’ enrollment algorithm. endourology and stones diseases 20 vol 17 no 01 january-february 2020 21 late the anxiety score (constant value). this score was a minimum value of 20 and a maximum value of 80. higher scores indicate greater anxiety. visual analog scale (vas pain: 0-10) was used to evaluate pain.(16) the zero value was defined as "no pain", while the value 10 was defined as "unbearable pain". the patient was asked to indicate the degree of pain. in all patients, vas and stai scores were recorded immediately after the swl procedure. treatment success defined as the absence of stone fragments or the presence of clinically insignificant fragments smaller than 4 mm in diameter and being stone-free was assessed by kub radiography and ultrasonography on the 15th day of swl. all recorded parameters were compared between the five groups. swl technique swl was performed using a modularisvario lithotripter (modularisvario; siemens, ag healthcare, munich, germany). modularisvario is a mobile, fully integrated, next-generation lithotripter with an electromagnetic shock wave source and fully integrated fluoroscopic guided device. the energy levels start with e0.1 and progressively increase to a maximum of e8.0 in 38 steps. the average energy level, the maximum energy level, and the total energy delivered were automatically displayed at the end of each session. the patients were treated in the supine position. fluoroscopy was used to localize the stone. lubricating gel was applied to the area where swl was to be administered in all patients. for the kidney: number of shock waves = 3000-3500, energy level (max) = 3-4, starting: 100 shock waves with level 0.1-1 afterwards, maximal level: pelvis: 4.0 with frequency sw/min = 60. the number of shock waves, their intensity, and their energy were recorded for patients in all groups. statistical analysis normality of continuous variables was determined using kolmogorov–smirnov test. levene test was used for the evaluation of homogeneity of variances. descriptive statistics for continuous variables were shown as mean±sd or median (q1-q3), as appropriate. number of cases and percentages were used for categorical data. the mean differences among groups for normally distributed data were compared by one-way anova, while kruskal–wallis test was applied for the comparisons of variables that were not normally distributed or the variance homogeneity assumption was not met. when the p-values from kruskal–wallis test statistics were statistically significant, conover’s multiple comparison testwas used to determine which group(s) differed from the others. categorical data were analyzed using pearson's chisquare test. data analysis was performed by using ibm spss statistics version 17.0 software (ibm corporation, armonk, ny, usa). a p-value less than 0.05 was consideredas statistically significant. results there were no statistically significant differences between the groups in terms of age, mean body mass index, stone localization (p = .883, p = .748, p = .963, respectively). there were no statistically significant differences between groups in terms of swl duration, total swl energy, or total number of shock waves among the groups (p > .05 for all comparison). demographic and clinical characteristics and swl variables for the study groups are presented in table 1. there was a statistically significant difference between the groups in terms of median vas scores (7, 6, 4.5, 5, and 4, respectively), p < .001), while the vas scores in groups 3, 4, and 5 were significantly lower than those in groups 1 and 2 (p < .001). there was not a statistically significant difference between groups 1 and 2, groups 3 and 4, groups 3 and 5, or groups 4 and 5 in terms of vas scores (p = .386, p = .956, p = .112 and p = .100, respectively) (table 2). there was a statistically significant difference between groups in terms of median stai scores (45, 45, 42, 45, and 40, respectively, p < .001), while the anxiety levels in groups 3, 4 and 5 were statistically lower than that in group 1 (p = .008, p = .018 and p < .001, respectively). in addition, the anxiety level in group 5 was statistically lower than group 2 (p < .001). there was not a statistically significant difference between groups 1 and 2, groups 2 and 3, groups 2 and 4, groups 3 and 4, groups 3 and 5, or groups 4 and 5 in terms of anxiety levels (p = .442, p = .059, p = .107, p = .780, p = .145 and p = .083, respectively) (table 2). in addition, there were statistically significant differences between the groups in terms of willingness to repeat the procedure and patient satisfaction rates (p < .001), whereas these parameters were significantly higher in groups 3, 4, and 5 than in group 1 (p < .001). in addition, the willingness to repeat the procedure and patient satisfaction rates in group 5 were significantly higher than those in groups 3 and 4 ((p = .005 and p < .001), (p = .007 and p = .003), respectively) (table 2). the stone-free rates were statistically similar between the groups (p = .992) (table 2). table 2. clinical outcomes group 1 (n=30) group 2 (n=30) group 3 (n=30) group 4 (n=30) group 5 (n=30) p-value patient satisfaction rate 1 (1 2)a,b,c 2 (1 2)d,e,f 2 (1 3)a,d,g 2 (1 3)b,e,h 3 (2.75 3)c,f,g,h <.001† 0=poor to 4=excellent willingness to repeat procedure 1 (1 2)a,b,c 2 (1 2)d,e,f 2.5 (1 3)a,d,g 2 (2 3)b,e,h 3 (3 3.25)c,f,g,h <.001† 0=never to 4 happily visual analog scale (vas) 7 (6 7.25)a,b,c 6 (5 7.25)d,e,f 4.5 (4 6)a,d 5 (3 5.25)b,e 4 (3 5)c,f <.001† 0=no pain to 10=unbearable pain stai-state anxiety score 45 (42 54)a,b,c 45 (40 48.25)f 42 (37.75 45)a 45 (32.75 45.5)b 40 (31.75 45)c,f <.001† min=20 to max=80 stone-free rate 15 (50.0%) 16 (53.3%) 16 (53.3%) 16 (53.3%) 17 (56.7%) .992‡ † kruskal–wallis test, descriptive statistics given as median (q1 – q3), ‡ pearson's chi-square test, data presented as number of cases and percentages, a: group 1 vs group 3 (p < .01), b: group 1 vs group 4 (p < .05), c: group 1 vs group 5 (p < .001), d: group 2 vs group 3 (p < .05), e: group 2 vs group 4 (p < .05), f: group 2 vs group 5 (p < .001), g: group 3 vs group 5 (p < .05), h: group 4 vs group 5 (p < .01). effect of different musical types during swl-çift et al. endourology and stones diseases 22 discussion there are many interventions that can be performed in outpatients without anesthesia. one of them is swl therapy, which has revolutionized the treatment of urinary tract calculi because of its cost effectiveness and low morbidity. for these reasons, it remains one of the first choice in the treatment of renal stones up to 20 mm.(17) patients should be immobile for a while in certain procedures like swl, magnetic resonance imaging (mri), and colonoscopy. disturbing noise and beats from the swl device can cause the patient to feel pain and anxiety, and to move.(6) both pain and anxiety can reduce the patient’s tolerance, which can lead to difficulty in targeting the stone, preventing maximal energy delivery. therefore, fragmentation of the stone may fail during the procedure, and patients may refuse additional swl sessions due to pain and anxiety.(7) the success of swl is closely related to factors such as the patient's compliance with the procedure, the experience of the person using the device, the localization of the stone, urinary system anatomy, and composition of the stone.(18) the patient's pain and anxiety should be kept to a minimal level to provide compliance with the swl procedure and achieve the highest possible success rates. local anesthetic drugs such as emla (2.5% lidocaine and 2.5% prilocaine), nsaids (diclofenac, ketorolac, and piroxicam), opioids (morphine, fentanyl, and pethidine), and anxiolytics (midazolam) can be used before the swl procedure for these purposes. according to the urolithiasis guideline prepared by the european urology association, the recommendation level for pain control is c and the level of evidence is 4.(19) however, side effects such as respiratory depression, hypotension, tachycardia, bradycardia, transient cognitive dysfunction, nausea-vomiting, and allergic reactions may occur due to these drugs.(13) therefore, complementary treatments are becoming increasingly popular in order to reduce pain and anxiety during swl. these treatments include music, transcutaneous electrical nerve stimulation, acupuncture, and auricular acupressure. music therapy has been shown to reduce pain by activating the cingulofrontal cortex.(20,21) it is also suggested that music has anxiolytic effects and should be used as therapy in stressful interventions. in the literature, there are a few studies about the approach of listening to music during swl. koch et al. reported that listening to music during swl significantly reduced the requirement for alfentanil. (22) moreover, cepeda et al. argued that music did not reduce the requirement for alfentanil when using patient-controlled analgesia during swl. limitations of this study include the limited number of patients and the use of morphine and ketorolac in addition to pre-procedural alfentanil.(23) in another study using music or midazolam during swl, music was found to be at least as effective as midazolam and had similar stai-sa and vas scores.(9) in addition, the common feature of these three studies was the administration of analgesics and anxiolytics to the control group. patients in our study did not any receive medication. therefore, our study differs from these studies. in these studies, patients completed swl sessions by using nsaids or drugs such as alfentanil and midazolam before the procedure; as a result anxiety scores were found to be lower. since we did not use any analgesics or anxiolytics in our study, our pain and anxiety scores may be slightly higher than those reported in the literature. akbaş et al. reported in their prospective study that there were lower anxiety and pain scores during swl sessions in which the patient listened to music. in addition, patients were asked to complete more swl therapy while listening to music, and patients were more satisfied.(6) one of the limitations of this study was that the stone-free rates were not compared between the first and second sessions, while the other limitation was that there was not a third group using only noise-canceling headphones. in a prospective randomized trial by karalar et al., it was reported that music therapy during swl reduced pain and anxiety, and that music therapy with active noise-canceling headphones (nchs) was more effective for pain and anxiety reduction.(7) in the present study, we used active non-noise canceling headphones. patients receiving music therapy (groups 3, 4, 5) were found to have lower pain scores than those who did not (groups 1, 2). when we compared groups 3, 4, and 5 in terms of music types, there was not a statistically significant difference in terms of vas scores. in addition, when we compared groups 1 and 2, there was not a statistically significant difference in terms of vas scores. the anxiety scores of the patients who received music therapy in our study (groups 3, 4, 5) were lower than those who did not receive music therapy (groups 1, 2). we found that anxiety scores were lower in group 5 than those in groups 1 and 2. in addition, when the groups that listened to music were evaluated among themselves in this study, we also found that the approach in which the patient listened to his/her favorite music during swl had more positive results than the patients listening to other types of music in terms of the willingness to repeat the procedure and satisfaction rates. one limitation in this study was the absence of analgesic groups. conclusions our results suggest that music therapy during swl reduces the level of pain and anxiety. when we compared the groups in terms of music types, it was determined that willingness to repeat the procedure and patient satisfaction rates were better when the patients listened to the music types they liked. music therapy during swl is a noninvasive, inexpensive, simple, and non-pharmacological method. allowing the patients to listen to the music they like using headphones allows swl to be better tolerated. thus, patients are protected from unwanted side effects of drugs. furthermore during the swl procedures, listening to the patient’s preferred music type could become standardised. acknowledgement this study was approved in university of adıyaman institutional ethics committee. the authors would like to thank dr. alper gök, dr. mehmet özgür yücel and appreciate her support for the preparing of this manuscript. effect of different musical types during swl-çift et al. vol 17 no 01 january-february 2020 23 conflict on interest the authors report no conflict of interest. trial registration: isctrn85279715, 29/07/2018 references 1. kim ch, shin ds, kim tb, jung h. the efficacy of early extracorporeal shockwave lithotripsy for the treatment of ureteral stones. urol j. 2019 2. bach c, zaman f, kachrilas s, kumar p, buchholz n, masood j. drugs for pain management in shock wave lithotripsy. pain res treat. 2011;259426. 3. ngee-ming g, tamsin d, rai bp, somani bk. complementary approaches to decreasing discomfort during shockwave lithotripsy (swl). urolithiasis 2014;42(3):189-93. 4. shang ab, gan tj. optimising postoperative pain management in the ambulatory patient. drugs 2003;63(9):855-67 5. heiser rm, chiles k, fudge m, gray se. the use of music during the immediate postoperative recovery period. aorn j. 1997;65(4):777-85 6. akbas a, gulpinar mt, sancak eb, at al. the effect of music therapy during shockwave lithotripsy on patient relaxation, anxiety, and pain perception. ren fail. 2016;38(1):46-9. 7. karalar m, keles i, dogantekin e, kahveci ok, sarici h. reduced pain and 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efficacy of taxotere, thalidomide, and prednisolone in patients with hormoneresistant metastatic prostate cancer hamid rezvani, shirin haghighi, mojtaba ghadyani, hamid attarian purpose: materials and methods: this clinical trial was performed on 16 patients with hormoneresistant prostate cancer. results: mean age of the participants was 72.7 ± 5.39 years (range, 65 to 85 years). in more than 50%. the mean time to progression was 15 months and mean survival time was 23 months. this combination therapy had some adverse events. conclusion: addition of anti-angiogenic agents, such as thalidomide, can improve therapeutic outcome in this group of patients. keywords: prostatic neoplasms, treatment failure, antineoplastic agents, drug resistance corresponding author: hamid attarian, md taleghani hospital, shahid beheshti university of medical sciences, tehran, iran tel: +98 21 2243 2560 fax: +98 21 2243 2570 e-mail: hattarian@hotmail.com received march 2012 accepted march 2012 taleghani hospital, shahid beheshti university of medical sciences, tehran, iran urological oncology 674 | introduction p -cer in both genders and the second most common cancer in men. an estimated 900 000 men worldwide were diagnosed with pca in 2008, accounting for almost one in seven (14%) cancers diagnosed in men (7% of the total in men and women).(1) there have been large increases in the incidence of pca in many countries worldwide, coupled with little change or small declines in mortality.(2) report from tehran population-based cancer registry showed that pca is the second most common cancer in tehran only after gastric cancer with age-standardized rate (asr) of 15.6.(3) based on another report of cancer registry in 5 provinces in iran, during 5-year follow-up from 1996 to 2000, the asr of pca was 5.1 per 100 000 people in a year.(4) the asr of pca in iran shows a slow rise with increasing age. hormone therapy in patients with metastatic pca usually over the time, most patients will develop progressive disease, which is resistant to hormone therapy. the appropriate therapy for patients with hormone-resistant (5,6) the combination with prednisolone was 19.2 months, compared prednisolone.(7) several studies have showed that thalidofactor.(8,9) cations with different mechanism of action in treatment of hormone-resistant pca. materials and methods all recruited patients (16) had advanced metastatic pca and were symptomatic despite orchiectomy or treatment with gnrh agonists alone or in combination with antiandrogens. as follows: 1. constant bone pain; 2. 50% increase in serial psa level more than nadir in association with 2 ng/cc increase in psa in patients who had 50% decrease in serial psa level after initial therapy, which occurred despite suppressed level of testosterone (50 ng/dl); 3. 25% increase of nadir level in patients who did not have 50% decrease in serial psa level after initial therapy, which occurred despite suppressed levels of testosterone (50 ng/dl); 4. appearance of new lesions in bone scan or increased distant metastasis in imaging studies. the inclusion criteria were age > 18 years, eastern cooperative oncology group performance status (ps) = 0 to 1, 3, platelet count at uln, alkaline phosphatase < 2.5 uln, serum creatinine < 1.5 mg/dl, or creatinine clearance at least 40 cc/ml. patients should have no history of myocardial infarction within recent 6 months, no evidence of congestive heart failure or unstable angina, no history of previous chemotherapy for metastatic with history of neuropathy, thrombophlebitis, brain metastathe study. a written informed consent was obtained from all the patients. the primary objective was to observe if there is any re-measurement of psa level two weeks later.(7) secondary objectives were time to progression of the disease, overall survival rate, and adverse effects. water, nj) 75 mg/m2 day, which was repeated every 3 weeks. they also received thalidomide (celgene corporation; warren, nj) 50 mg/day and prednisolone 10 mg/day orally. aspirin 80 mg/day was essary. in patients who did not undergo bilateral orchiectomy, medical castration with gnrh analogs was continued. patients were evaluated every 3 weeks before undergoing chemotherapy and their symptoms, signs, and psa levels urological oncology 675vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l were documented. all the patients had basal serum psa levabdomen, and pelvic. these evaluations were repeated every 3 cycles. all responses were evaluated based on psawg criteria and response evaluation criteria in solid tumor (recist). the pain was evaluated by visual analogue scaling (vas) from 0 to 10; as mild (0 to 2), moderate (3 to 5), severe (6 to 8), and very severe (9 to 10). adverse effects were evaluated based on national cancer institute (nci) common (10,11) developed grade iv febrile neutropenia after receiving pegceiving thalidomide or if grade ii peripheral neuropathy was developed, thalidomide was discontinued. in patients that statistical analysis the percentage of difference in psa level from baseline to nadir level was calculated and reported as waterfall plot (figure 1).(12) was reported. lesion at baseline. considering secondary objectives, progression-free survival (pfs) was calculated at the recruitment time until appearfollow-up. progressive disease was considered if each of the following items occurred: 1. 25% increase in the size of all soft tissue masses or presentation of new lesions. the partial response based on bone scan was considered when 2 or more new lesions disap2. need to do radiotherapy; 3. two times increase in psa level more than 50% of nadir in patients who had psa response and more than 25% increase from nadir or baseline psa (either that was less), and also increase in absolute level of psa at least 5 ng/ml that is sponsive for psa. in patients that psa level decreased, but did not reach the nadir that should increase at least 5 ngr/cc. the time of overall survival rate was determined from refigure 1. the percentage of difference in prostate-specific antigen level from baseline. taxotere in pca | rezvani et al 676 | cruitment time to death date (for any cause). patients who remained in the study or were alive at the time of analysis were followed-up on the last day. the probability of pfs was estimated by kaplan-meier method (figure 2). results mean age of the patients was 72.7 ± 5.39 years (range, 65 to 85 years). mean gleason score of the patients was 8 ± 0.71 (range, 6 to 8). the performance status was zero in 15 patients and 1 in one patient. twelve patients had undergone prostatectomy and 4 had received radiotherapy. fourteen patients only had bone metastasis and 3 only had soft tissue metastasis, while 2 patients had both soft tissue and bone metastases. mean serum level of psa before treatment was 221.4 ± 165.3 ng/ml. percentage of difference in psa level from baseline to nadir was reported as waterfall plot. ninety-four percent of 3 months of therapy. (100%) adverse events were noted in 16 study subjects. adverse effects were grade ii fatigue in 10 (62%) patients, grade ii weight loss in 3 (18%), peripheral neuropathy in 1 (6.2%), and grade i neutropenia in 2 (12%) patients. the pfs was 15 months and mean overall survival rate was 23 months. discussion (6,13) resistant pca. prostate tumors should have angiogenic phenotype for progression to aggressive form.(14,15) without angiogenesis, primary tumors of the prostate will remain indolent and their agent that inhibits angiogenesis, induces apoptosis in vitro, and reduces higher levels of angiogenic factors, such as vegf and bfgf in patients with pca.(9) 40% in 27% of patients, and clinical symptoms disappeared in most of them.(16) in another phase ii study on 75 patients with hormone-resistant pca, patients were divided into two respectively (p = .32). after 18 months, rate of overall surgroup. in a randomized phase ii trial on patients with hormonelidomide or placebo in two groups of patients. patients who psa reduction (53% versus 37%) and also higher mean progression-free survival (5.9 versus 3.7 months; p = .32). the months versus 15 months in other group.(7) the combination therapy was tolerated by most of the patients, but thromboembolic events occurred in 28% of patients who did not rein our study, in 94% of patients who received the combination therapy, psa decreased more than 50%. mean time to progression was 15 months and mean survival rate was 23 months. the response rate of psa and mean time to progression of disease were considerably raised. in a phase ii cliniand prednisone were used in patients with hormone-resistant urological oncology figure 2. kaplan-meier plots of prostate-specific antigen nonprogressive survival. 677vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l pca, high response rate of 50% reduction in psa was 88% and pfs was 18.2 months.(17) conclusion prednisolone regimen was an effective combination therapy verse effects. conflict of interest none declared. taxotere in pca | rezvani et al references 1. ferlay j, shin hr, bray f, forman d, mathers c, parkin dm. globocan 2008 v1.2, cancer incidence and mortality worldwide: iarc cancer base no. 10 [internet]. lyon, france: international agency for research on cancer; 2010. 2. boyle p, levin b. world cancer report 2008: iarc press, international agency for research on cancer; 2008. 3. mohagheghi ma, mosavi-jarrahi a, malekzadeh r, parkin m. cancer incidence in tehran metropolis: the first report from the tehran population-based cancer registry, 19982001. arch iran med. 2009;12:15-23. 4. sadjadi a, nooraie m, ghorbani a, et al. the incidence of prostate cancer in iran: results of a population-based cancer registry. arch iran med. 2007;10:481-5. 5. tannock if, de wit r, berry wr, et al. docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. n engl j med. 2004;351:1502-12. 6. bissery mc, vrignaud p, bayssas m. preclinical in vivo activity of docetaxel containing combinations. proc am soc clin oncol. 1995;489. 7. berthold dr, pond gr, soban f, de wit r, eisenberger m, tannock if. docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the tax 327 study. j clin oncol. 2008;26:242-5. 8. dahut wl, gulley jl, arlen pm, et al. randomized phase ii trial of docetaxel plus thalidomide in androgen-independent prostate cancer. j clin oncol. 2004;22:2532-9. 9. d'amato rj, loughnan ms, flynn e, folkman j. thalidomide is an inhibitor of angiogenesis. proc natl acad sci u s a. 1994;91:4082-5. 10. bubley gj, carducci m, dahut w, et al. eligibility and response guidelines for phase ii clinical trials in androgenindependent prostate cancer: recommendations from the prostate-specific antigen working group. j clin oncol. 1999;17:3461-7. 11. therasse p, arbuck sg, eisenhauer ea, et al. new guidelines to evaluate the response to treatment in solid tumors. european organization for research and treatment of cancer, national cancer institute of the united states, national cancer institute of canada. j natl cancer inst. 2000;92:20516. 12. scher hi, halabi s, tannock i, et al. design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. j clin oncol. 2008;26:1148-59. 13. petrylak dp, tangen cm, hussain mh, et al. docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. n engl j med. 2004;351:1513-20. 14. jones a, fujiyama c. angiogenesis in urological malignancy: prognostic indicator and therapeutic target. bju int. 1999;83:535-55; quiz 55-6. 15. lissbrant if, lissbrant e, damber je, bergh a. blood vessels are regulators of growth, diagnostic markers and therapeutic targets in prostate cancer. scand j urol nephrol. 2001;35:437-52. 16. figg wd, dahut w, duray p, et al. a randomized phase ii trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. clin cancer res. 2001;7:1888-93. 17. ning ym, gulley jl, arlen pm, et al. phase ii trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. j clin oncol. 2010;28:2070-6. 1046 | 1department of urology, xiangya hospital, central south university, changsha, hunan province, china. 2department of general surgery, xiangya hospital, central south university corresponding author: xiang chen, md department of urology, xiangya hospital, central south university, changsh, hunan province. china. tel: +86 138 7480 8998 fax: +73 184 327354 email: cxiang1007@126.com received may 2012 accepted january 2013 purpose: to describe our technique and experience with retroperitoneoscopic upper pole nephroureterectomy in duplex kidney, focusing on the role of dilated upper ureter. materials and methods: from november 2004 to august 2011, retroperitoneoscopic upper pole nephroureterectomy was performed in 31 patients with a duplex kidney by a single, experienced laparoscopic surgeon. we developed our own surgical technique to suit this technically challenging procedure. follow-up studies were performed using renal ultrasonography, intravenous urography (ivu) and/or dimercaptosuccinic acid (dmsa) renal scan in all patients at 3 months postoperatively and annually thereafter. results: all procedures were completed laparoscopically without conversion to open surgery and blood transfusion. the mean operative time was 106 (90-157) min. the estimated blood loss was < 50 ml in all cases. the mean postoperative hospital stay was 4.2 (3-7) days. perioperative complications were limited to 1 case of peritoneal tear during a procedure and 1 case of transient postoperative fever. no major intraoperative and postoperative complication occurred. with the mean follow-up period of 41 months (range 3 to 80), no case was observed to have functional loss of the remaining lower moiety on postoperative ivu or dmsa renal scan. conclusion: retroperitoneoscopic upper pole nephroureterectomy using our technique is safe and effective. keywords: laparoscopy; retroperitoneal space; postoperative complications; kidney abnormalities; treatment outcome. zhi chen,1 zheng-yan tang,1 ben-yi fan,1 xiang chen,1 peng zhou,2 yan-cheng luo,1 yao he,1 chao-qun xie,1 chen lai,1 xiao-long fang1 retroperitoneoscopic upper pole nephroureterectomy in duplex kidney: focus on the role of dilated upper pole ureter laparoscopic urology laparoscopic urology 1047vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction duplex kidney is a common congenital anomalies of the urinary tract. heminephrectomy, either by an open or a laparoscopic approach, is a wellestablished option for the management of nonfunctioning or symptomatic renal moieties in duplex kidneys. several reports have demonstrated that laparoscopic heminephrectomy was a safe and technically feasible with the advantages of less morbidity, decreased postoperative pain, improved cosmetic result and significantly shorter hospital stays compared with open surgery.(1-10) however, laparoscopic heminephrectomy, especially for upper pole heminephrectomy, may be a much more complex operation and more technically challenging than total nephrectomy,(10,11) because it is usually difficult to control upper pole vessels and excise upper pole parenchyma. that may lead to inadvertent injury to the vessels and parenchyma of lower pole moiety, thus offering a higher risk of bleeding responsible for hematoma, urine leakage responsible for urinoma and pedicle lesions responsible for lower pole deterioration.(2-7,9,10) this explains why minimally invasive techniques have remained confined to the hands of experienced teams, with a limited number of reports including relatively few cases.(10,11) in this study, we developed our own surgical technique to suit this technically challenging procedure. the aim of the present study is to describe our technique and experience with retroperitoneoscopic upper pole nephroureterectomy in duplex kidney, focusing on the role of dilated upper ureter. material and methods patients from november 2004 to august 2011, 31 patients with a duplex kidney (10 men and 21 women) underwent retroperitoneoscopic upper pole nephroureterectomy. the mean age is 30.4 years (range, 13-47). the all procedures were performed by a single, experienced laparoscopic surgeon (xiang chen). of the 31 patients, 11 had a duplicated collecting system on the right side, 18 on the left side, and 2 on both sides. of the procedures, 18 were on the left and 13 on the right side. the presenting symptoms included flank pain in 19 patients, recurrent urinary tract infection in 10, and hematuria in 2. no patient had undergone previous renal surgery. ultrasonography, intravenous urography (ivu) and/or computed tomography urography (ctu) and dimercaptosuccinic acid (dmsa) renal scan were routinely used to evaluate the patients preoperatively. voiding cystourethrography (vcug) was used to demonstrate vesicoureteral reflux and the presence of an ureterocele. the indications for upper pole heminephrectomy were ectopic ureter with a non-functioning upper pole moiety or ureterocele with a non-functioning upper pole moiety. follow-up studies were performed with ultrasonography and ivu or dmsa renal scan at 3 months postoperatively and annually thereafter. laparoscopic technique all procedures were performed with the patient in the lateral decubitus position under general anesthesia. a 3or 4-port, fingerand balloon-dissecting, retroperitoneoscopic approach was used, as described in previous series.(21) the retroperitoneal fat and adjacent tissues were first dissected sufficiently with a harmonic scalpel and removed to create a larger working space. then gerota’s fascia was incised longitudinally. the upper pole moiety and part of the lower pole moiety was dissected free from the peri-renal fat and tissue. after clear identification of the ureters of both moieties (figure 1a), the dilated upper pole ureter was dissected free to the closest edge of the pelvis. with traction on the dilated upper pole ureter, the renal artery was identified and carefully dissected. the branch for the upper and lower pole vessels could be easily identified, because the upper pole vessels often located behind and above the dilated upper pole ureter and the lower pole vessels located beneath that. the polar vessels to the upper pole moiety were mobilized carefully and were clipped using two titanium or hem-o-lok clips at the proximal end and one on the kidney side, and divided (figure 1b). if there were any concerns regarding the polar vessels to the upper pole moiety, the potential branch to upper pole moiety could be temporarily clamped with atraumatic forceps to confirm the ischemic color change of the upper pole moiety. the dilated upper pole ureter was then transected close to the renal pelvis using a harmonic scalpel. after the proximal ureteral stump was drawn towards the diaphragm by forceps, dissection proceeded in the plane between the urothelium of the upper pole moiety and the renal parenchymal surface retroperitoneoscopic approach in duplex kidney | chen et al 1048 | of the lower pole moiety to most closely expose the edge of parenchymal section (figure 1c). excision of the upper pole moiety was performed using a harmonic scalpel along a border between the upper and lower pole moiety, which corresponded to the level of vascular demarcation (figure 1d). the edge of the parenchymal section was approximated with intracorporeally interrupted sutures using 2-0 vicryl suture to achieve complete hemostasis. the remnant upper pole ureter was mobilized toward the bladder level to allow as complete an ureterectomy as possible. the distal dilated ureter was left open. great care should be taken to avoid possible injury to the blood supply of the lower pole ureter. finally, a drain was left in place. results preoperative imaging demonstrated that all patients had a complete pelvic and ureter duplication and a dilated and nonfunctioning upper-pole moiety due to ectopic ureter. no vesicoureteral reflux or ureterocele was found in all patients using preoperative vcug. the outcomes of our series and the similar published studies were summarized in table. all procedures were completed laparoscopically without conversion to open surgery and blood transfusion. the mean operative time was 106 (90-157) min. the estimated blood loss was < 50 ml in all cases. the mean postoperative hospital stay was 4.2 (3-7) days. preoperative complications were limited to 1 case of peritoneal tear during a procedure and 1 case of transient postoperative fever. no major intraoperative and postoperative complication occurred. with the mean follow-up period of 41 months (range 3 to 80), no case was observed to have functional loss of the remaining lower moiety on postoperative ivu or dmsa renal scan. discussion non-functioning or symptomatic upper pole moieties are the most common clinical indication for heminephrectomy in duplex kidneys.(10) although laparoscopic heminephrectomy has been demonstrated to be a technically feasible and minimally invasive procedure to treat this morbidity, to date, this procedure remains limited to few centers with advanced laparoscopic experience. laparoscopic heminephrectomy, especially upper pole heminephrectomy, may be very technical challenging,(10) because it offers the higher risk of bleeding, urine leakage and lower pole deterioration. jayram and colleagues(9) reported that they combined data from 4 highvolume international teaching centers to evaluate outcomes following laparoscopic heminephrectomy, and found that 7 children (4.9%) had a significantly functional loss in the refigure 1a. the upper (a) and lower (b) ureters were clearly identified. figure 1b. the upper pole vessels (a) often located above the dilated upper pole ureter and the lower pole vessels (b) located beneath that. the upper pole vessels were mobilized carefully and were clipped using two titanium clips at the proximal end and one on the kidney side (arrow pointing to the dilated upper ureter that was drawn towards the diaphragm). laparoscopic urology 1049vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l maining moiety with a median follow-up of 4.5 years, 11 patients (7.7%) required open conversion and 7 patients (4.9%) developed a postoperative urinoma. major technical difficulties in laparoscopic upper pole heminephrectomy are related to control upper pole vessels and excise upper pole parenchyma. in the present study, we developed our own surgical technique to suit this technically challenging procedure via retroperitoneal approach, in which the role of dilated upper ureter was emphasized on. the most technically challenging portion of retroperitoneoscopic upper pole heminephrectomy may be the renal hilar dissection, because vascular injuries may lead to severe bleeding and a functional loss of the lower pole moiety. in our experience, to obtain vascular control, the dilated upper pole ureter was drawn towards the diaphragm, which facilitated the mobilization of the polar vessels to the upper pole moiety. simultaneously, excessive traction on the polar vessels to the lower pole moiety, which may be detrimental to postoperative renal outcome,(9) should be avoided. furthermore, because the polar vessels to the upper pole moiety often located behind and above the dilated upper pole ureter and the polar vessels to the lower pole moiety located beneath that, the identification of upper and lower pole vessels could be relatively easy using the dilated upper pole ureter as a landmark. in addition, if there were any concerns regarding the upper pole vessels, in order to confirm the ischemic color change of the upper pole moiety, we can temporarily clamp the branch using atraumatic forceps.(12) section of upper pole parenchyma could be another technically challenging portion of retroperitoneoscopic upper pole heminephrectomy, because inappropriate section of renal parenchyma could result in postoperative urine leakage from the functioning remnant upper pole moiety or the opening of the remaining lower pole calices. in our experience, there is often a lax plane between the urothelium of upper pole moiety and the renal parenchymal surface of lower pole moiety. whereas the dilated upper ureter was drawn towards the diaphragm by forceps, constant traction maintained adequate exposure and dissection along that plane could be easy and safe, in our experience, almost with no bleeding. furthermore, the exactly control of upper pole vessels could contribute to successful identification of the border between upper and lower pole using the ischemic color change of the parenchyma. with traction on the dilated upper pole ureter, section of upper pole parenchyma could be also easily performed. therefore, the risk of inadvertent injury to the lower pole moiety could be reduced as far as possible. li and colleagues(12) reported that in their procedure the upper pole renal parenchyma was difigure 1c. after the proximal ureteral stump (a) was drawn towards the diaphragm by forceps, dissection proceeded in the plane (arrow pointing) between the urothelium of the upper pole moiety and the renal parenchymal surface of the lower pole moiety to most closely expose the edge of parenchymal section. figure 1d. excision of the upper pole moiety was performed using a harmonic scalpel along a border (arrow pointing) between the upper and lower pole moiety, which corresponded to the level of vascular demarcation. retroperitoneoscopic approach in duplex kidney | chen et al 1050 | vided circumferentially between the upper and lower poles using a harmonic scalpel before the urothelium of the remnant upper pole parenchyma was stripped off. however, with no adequate mobilization of urothelium of the upper pole parenchyma, resection circumferentially between the upper and lower poles could lead to inadvertent injury to the lower pole moiety.(12) although in their study they maintained a margin around the upper pole parenchyma, incomplete removal of the diseased moiety could lead to renal cyst formation. recently, the endoloop technique have been an alternative to reduce the level of technical difficulty of the parenchymal section,(13) however, this variant may also be responsible for a higher incidence of cyst formation at the resection margin.(10) although it is more difficult to perform by laparoscopy, intracorporeally interrupted sutures using 2-0 vicryl suture of the parenchymal section is recommended to achieve complete hemostasis, as performed in open surgery. valla and colleagues(11) reported that in their study the cut surface was not routinely sutured in their first 19 cases, leading to postoperative residual effusion in 5 cases.(11) in contrast, with our present surgical techniques, no postoperative bleeding and urine leakage was found in our series. in our technique, the dilated upper pole ureter was transected close to the renal pelvis using a harmonic scalpel just after the vessels supplying the upper pole moiety was clipped. that has two roles. first, when clipping the vessels supplying the upper pole moiety, the dilated upper moiety could be helpful to confirm the ischemic color change of the upper pole moiety; in contrast, laparoscopic urology table. outcomes of patients treated with laparoscopic upper pole heminephrectomy.* series patients (no.) tp/rp (no.) ot (min) ebl (ml) conversion to open surgery (no.) mean hospital stay (days) follow-up (months) complications (no.) janetschek et al.14 (1997) 9 9/0 222 (180-330) 10-30 none 4.4 (3-6) na none horowitz et al.19 (2001) 14 14/0 100 (70-135) < 30 none 2.6 (2-4) na none valla et al.29 (2003) 24 0/24 180 na 3 3.4 32 (6-60) urinoma (5) wang et al.20 (2004) 3 3/0 198 (165-244) 63 (40-100) none 3 (1-6) 5.3 (3-9) urinoma (1) olsen et al.30 (2005)** 14 0/14 176 (120-360) minimal (< 10 ml) 2 1 (1-4) 8 (1-24) uti (1) abouassaly et al.21 (2007) 5 5/0 189 (150-225) 120 (100-200) none 2.8 (2-4) 42 (11-72) urinoma (1) denes et al.15 (2007) 17 0/17 147 < 50 none 3.2 (2-6) 57.1 uti (5), ureteral stump empyema (3) breda et al.22 (2007) 3 3/0 138 (120, 135, 160) negligible none 2 (1-4) na none miranda et al. 23 (2007) 7 7/0 135 (120-160) na none 1.7 (1-2) 18 none seibold et al.24 (2008) 5 5/0 190 (170-210) minimal (< 50) none 5.6 (4-7) 42.4 none leclair et al.4 (2009) 36 0/36 120 (70-215) na 6 3 (2-13) 14 (3-125) functional loss of remaining moiety (1), schneider et al.25 (2010) 7 7/0 130 (90-195) na none 3 (2-6) 14.4 (1.2-38.5) diminution of renal function with pyelic dilation (1) li et al.31 (2011) 32 0/32 83 (55-110) 18 (10-50) none 7 (5-9) na none mason et al. 26 (2012)** 4 4/0 310 (240-400) 395 (80-1200) none 2.2 (2-3) 13 (9-19) none abedinzadeh et al. 27 (2012) 14 14/0 203 (95-360) negligible none 4.1 (2-7) 32 atrophy of remaining moiety (1) our series 31 0/31 106 (90-157) < 50 none 4.2 (3-7) 41 (3-80) none keys: tp, transperitoneal; rp, retroperitoneal; ot, operative time; ebl, estimated blood loss; na, information not available. * only reports of 3 or more cases and reports that had available data of laparoscopic upper pole heminephrectomy are included. ** robot-assisted laparoscopic upper pole heminephrectomy. 1051vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l when stripping off the urothelium of the upper pole moiety and dividing upper pole parenchyma, decompression of the dilated pelvis and upper moiety could increase the working space, thus facilitating the manipulation; second, traction on the shorter proximal ureteral stump could present a good surgical exposure without the interference of a redundant ureteral stump. laparoscopic heminephroureterectomy can be performed either through a transperitoneal (tp)(14-27) or a retroperitoneal (rp)(2,4, 9,10,12,15,28-31) approach. the later included lateral (lrp) and prone (prp) approaches. there are several advantages and disadvantages to each approach. castellan and colleagues(6) compared tp and rp approaches in a total of 48 laparoscopic heminephrectomies and they investigated five complications, which was not depending on the surgical approach but related to patient age. kieran and colleagues(32) compared the intraoperative parameters and perioperative complications of retroperitoneal and transperitoneal approaches to laparoscopic partial nephrectomy. they found that the incidence of perioperative complications was similar in the 2 groups but the operative time and length of stay were shorter and the estimated blood loss was lower in rp group. the outcomes of our series and the similar published studies were summarized in table 1. horowitz and colleagues(19) described their experience with laparoscopic upper pole heminephrectomy in 13 pediatric patients through a transperitoneal approach. mean operative time was 104 min, estimated blood loss was less than 30 ml, and mean hospital stay of 2.6 days. similarly, and colleagues(31) demonstrates the effectiveness and low morbidity of the retroperitoneal approach for laparoscopic upper pole heminephrectomy. mean operative time was 83 min, mean estimated blood loss was 18 ml, and mean hospital stay of 7 days. our study has also confirmed the efficacy and low morbidity of the retroperitoneoscopic approach in terms of the operative time, minimal blood loss, minimal complications, hospital stay, and recuperation (table). we believe that the choice of surgical approach, whether tp or lrp or prp, could be depend on the surgeon comfort and experience. the lrp approach was preferred in our centre because of our previously extensive experience with this approach.(33, 34) the lrp approach, although more technically challenging, provides a direct and rapid access to the kidney and renal hilum and effectively exposes the renal pedicle without having to mobilize the colon, thus reducing the possibility of intraperitoneal organ injury intraoperatively and organ adhesions postoperatively.(10) furthermore, lrp approach allows the vessels supplying the upper pole moiety to be treated prior to parenchymal section, thereby limiting blood loss.(11) moreover, it could facilitate the vascular control of the upper pole moiety because the renal artery was first encountered before the vein, and dissection of the hilum vessels could be facilitated because it was not hindered by the presence of the ureters through the lrp approach, as in the case of the tp approach.(11) in addition, a completely dry field should be maintained intraoperatively, which was very important because of the limited working space through a lrp approach. the data in the published reviews demonstrates remaining moiety loss rates of 1-9% in laparoscopic heminephroureterectomy series.(2,5-7,9,10) various factors (i.e. pneumoperitoneum, patient age, and injury to the remaining pole vessels) have been thought to be possibly responsible for remaining moiety loss. however, to date, only patient age has been established to have a strong correlation to renal loss.(2) in our series, with the mean follow-up period of 41 months, no case was observed to have functional loss of the remaining lower moiety on postoperative ivu or dmsa renal scan. that could be explained in part by the fact that in our series the majority of patients were adults. therefore, these adult patients could provide a relatively bigger retroperitoneal working space, thus facilitating the surgical difficulties. furthermore, in our technique, we emphasized on the role of dilated upper ureter and kept a high awareness of risk of vascular damage to lower moiety, which could be another reason for no functional loss of the remaining lower moiety in our series. in published reviews, the most conversions to open surgery occurred at the beginning of the experience for the reasons of poor visualization, bleeding, opening of upperor lower-pole calyces, injury to unaffected ureter or peritoneal tear.(10,35-38) in our series, no conversion to open surgery occurred. two reasons may explain that. first, we had significantly improved surgical capabilities and accumulated extensive experience with retroperitoneoscopic kidney surgery (i.e. live donor nephrectomy, simple or radical nephrectomy) before retroperitoneoscopic approach in duplex kidney | chen et al 1052 | we started the practice of retroperitoneoscopic upper pole heminephrectomy. second, because we highly emphasized the role of dilated upper ureter to reduce the injury to the vessels and parenchyma of lower pole moiety, surgical complications was significantly reduced. although peritoneal tear was found in one case intraoperatively, a fourth trocar was introduced to provide additional retraction and the procedure was completed successfully. conclusions retroperitoneoscopic upper pole nephroureterectomy using our technique was safe and effective. the possibility of vascular damage to the lower pole moiety warranted a very cautious dissection of the renal pedicle and section of the renal parenchyma. acknowledgment zhi chen and zheng-yang tang contributed equally to this work. conflict of interest none declared. 7. goyal a, hennayake s. prone retroperitoneoscopic approach for heminephrectomy: specific advantages relating to access to vascular pedicle. journal of pediatric urology. 2010;6:153-56. 8. lee rs, retik ab, borer jg, diamond da, peters ca. pediatric retroperitoneal laparoscopic partial nephrectomy: comparison with an age matched cohort of open surgery. j urol. 2005;174:708-11. 9. jayram g, roberts j, hernandez a, et al. outcomes and fate of the remnant moiety following laparoscopic heminephrectomy for duplex kidney: a multicenter review. j pediatr urol. 2011;7:272-75. 10. leclair m-d, vidal i, suply e, podevin g, héloury y. retroperitoneal laparoscopic heminephrectomy in duplex kidney in infants and children: a 15-year experience. eur urol. 2009;56:385-91. 11. valla j. treatment of ureterocele on duplex ureter: upper pole nephrectomy by retroperitoneoscopy in children based on a series of 24 cases. eur urol. 2003;43:426-29. 12. li h-z, ma x, zhang j, et al. retroperitoneal laparoscopic upperpole nephroureterectomy for duplex kidney anomalies in adult patients. urology. 2011;77:1122-25. 13. mushtaq i, haleblian g. laparoscopic heminephrectomy in infants and children: first 54 cases. j pediatr urol. 2007;3:100-103. 14. janetschek g, seibold j, radmayr c, bartsch g. laparoscopic heminephroureterectomy in pediatric patients. j urol. 1997;158:1928-30. 15. denes ft, danilovic a, srougi m. outcome of laparoscopic upperpole nephrectomy in children with duplex systems. j endourol. 2007;21:162-68. 16. kurokawa y, kanayama ho, anwar a, et al. laparoscopic nephroureterectomy for dysplastic kidney in children: an initial experience. int j urol. 2002;9:613-17. 17. gao z, wu j, lin c, men c. transperitoneal laparoscopic heminephrectomy in duplex kidney: our initial experience. urology. 2011;77:231-36. 18. seibold j, schilling d, nagele u, et al. laparoscopic heminephroureterectomy for duplex kidney anomalies in the pediatric population. journal of pediatric urology. 2008;4:345-47. 19. horowitz m, shah sm, ferzli g, syad pi, glassberg ki. laparoscopic partial upper pole nephrectomy in infants and children. bju int. 2001;87:514-16. 20. wang ds, bird vg, cooper cs, austin jc, winfield hn. laparoscopic upper pole heminephrectomy for ectopic ureter: initial experience. can j urol. 2004;11:2141-45. 21. abouassaly r, gill is, kaouk jh. laparoscopic upper pole partial nephrectomy for duplicated renal collecting systems in adult patients. urology. 2007;69:1202-5. 22. breda a, lam js, veale j, lerman s, schulam pg. laparoscopic heminephrectomy for upper-pole moiety in children using a 3-mm laparoscope and instruments. j endourol. 2007;21:883-85. laparoscopic urology references 1. yao d, poppas dp. a clinical series of laparoscopic nephrectomy, nephroureterectomy and heminephroureterectomy in the pediatric population. j urol. 2000;163:1531-35. 2. wallis mc, khoury ae, lorenzo aj, pippi-salle jl, bagli dj, farhat wa. outcome analysis of retroperitoneal laparoscopic heminephrectomy in children. j urol. 2006;175:2277-80. 3. schneider a, ripepi m, henry-florence c, geiss s. laparoscopic transperitoneal partial nephrectomy in children under 2 years old: a single-centre experience. j pediatr urol. 2010;6:166-70. 4. leclair md, vidal i, suply e, podevin g, heloury y. retroperitoneal laparoscopic heminephrectomy in duplex kidney in infants and children: a 15-year experience. eur urol. 2009;56:385-89. 5. singh rr, wagener s, chandran h. laparoscopic management and outcomes in non-functioning moieties of duplex kidneys in children. j pediatr urol. 2010;6:66-69. 6. castellan m, gosalbez r, carmack aj, prieto jc, perez-brayfield m, labbie a. transperitoneal and retroperitoneal laparoscopic heminephrectomy--what approach for which patient? j urol. 2006;176:2636-39. 1053vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l retroperitoneoscopic approach in duplex kidney | chen et al 23. miranda ml, oliveira-filho ag, carvalho pt, ungersbock e, olimpio h, bustorff-silva jm. laparoscopic upper-pole nephroureterectomy in infants. int braz j urol. 2007;33:87-91. 24. seibold j, schilling d, nagele u, et al. laparoscopic heminephroureterectomy for duplex kidney anomalies in the pediatric population. journal of pediatric urology. 2008;4:345-47. 25. schneider a, ripepi m, henry-florence c, geiss s. laparoscopic transperitoneal partial nephrectomy in children under 2 years old: a single-centre experience. j pediatr urol. 2010;6:166-70. 26. mason md, peters ca, schenkman ns. robot-assisted upper pole nephrectomy in adult patients with duplicated renal collecting systems. j endourol. 2012;26:838-42. 27. abedinzadeh m, nouralizadeh a, radfar mh, moslemi mk. transperitoneal laparoscopic heminephrectomy in duplex kidneys: a one center experience. ger med sci. 2012;10:doc05. 28. kawauchi a, fujito a, naito y, et al. retroperitoneoscopic heminephroureterectomy for children with duplex anomaly: initial experience. int j urol. 2004;11:7-10. 29. valla js, breaud j, carfagna l, tursini s, steyaert h. treatment of ureterocele on duplex ureter: upper pole nephrectomy by retroperitoneoscopy in children based on a series of 24 cases. eur urol. 2003;43:426-29. 30. olsen lh, jørgensen tm. robotically assisted retroperitoneoscopic heminephrectomy in children: initial clinical results. journal of pediatric urology. 2005;1:101-104. 31. li hz, ma x, zhang j, et al. retroperitoneal laparoscopic upper-pole nephroureterectomy for duplex kidney anomalies in adult patients. urology. 2011;77:1122-25. 32. kieran k, montgomery js, daignault s, roberts ww, wolf js, jr. comparison of intraoperative parameters and perioperative complications of retroperitoneal and transperitoneal approaches to laparoscopic partial nephrectomy: support for a retroperitoneal approach in selected patients. j endourol. 2007;21:754-59. 33. chen z, chen x, luo yc, he y, li nn, wu zh. retroperitoneoscopic decortication of symptomatic peripelvic renal cysts: chinese experience. urology. 2011;78:803-807. 34. chen z, chen x, luo yc. technical modifications of double-j stenting for retroperitoneal laparoscopic dismembered pyeloplasty in children under 5 years old. plos one. 2011;6:e23073. 35. chertin b, ben-chaim j, landau eh, et al. pediatric transperitoneal laparoscopic partial nephrectomy: comparison with an age-matched group undergoing open surgery. pediatr surg int. 2007;23:1233-36. 36. el-ghoneimi a, farhat w, bolduc s, bagli d, mclorie g, khoury a. retroperitoneal laparoscopic vs open partial nephroureterectomy in children. bju int. 2003;91:532-35. 37. robinson bc, snow bw, cartwright pc, de vries cr, hamilton bd, anderson jb. comparison of laparoscopic versus open partial nephrectomy in a pediatric series. j urol. 2003;169:638-40. 38. borzi pa. a comparison of the lateral and posterior retroperitoneoscopic approach for complete and partial nephroureterectomy in children. bju int. 2001;87:517-20. v08_no_3_final.pdf miscellaneous 227urology journal vol 8 no 3 summer 2011 international prostate symptom score really appreciated by all patients or not? purpose: to investigate the relationship between the accuracy of the answers provided by the patients to the international prostate symptom score (ipss) questionnaire and age and level of education. materials and methods: two hundred and thirty-eight men were given self-administered ipss questionnaires. after 48 to 96 hours, the ipss form was completed again with the assistance of a physician. the relationship of the difference between the self-administered ipss and forms completed with assistance with age and level of education was evaluated through wilcoxon test. p values less than .05 were considered significant. results: there was not a significant difference between the two ipss among the high school or university graduates (p = .480). however, the difference was significant among the primary and secondary school graduates (p = .042 and p = 0.34, respectively). of values obtained from self-administered ipss forms and those completed with the assistance of a years of age. conclusion: are factors lowering the comprehension of the ipss by the patients. older patients and those with lower education could benefit from the assistance of a physician while completing this questionnaire. urol j. 2011;8:227-30. www.uj.unrc.ir keywords: questionnaires, education, prostatic hyperplasia, predictive value of tests department of urology, haydarpasa numune training and research hospital, istanbul, turkey corresponding author: orhan koca, md department of urology, haydarpasa numune training and research tel: +90 216 414 4502 fax: +90 216 345 5982 e-mail: drorhankoca@hotmail.com received september 2010 accepted april 2011 introduction a patient’s perception of his health is very important in terms of quality of life; however, it is based on personal and subjective knowledge. it is important to make this information objective for the use of standard algorithms in treatment and follow-up. numerous forms have been designed for this purpose.(1) the international prostate symptom score (ipss), which is one of the most frequently used questionnaires in urology practices, was developed by the american urological association.(2,3) despite undeniable benefits of ipss questionnaires, the information that is provided can be affected by level of perception and the present mood of the subject, as well as the age and the level of education that may indirectly affect the abovementioned parameters.(4) in the present study, we investigated the relationship between the accuracy of the answers given to the ipss questionnaires and the level of education and age. 228 urology journal vol 8 no 3 summer 2011 materials and methods two hundred and forty-seven men between 20 and 83 years of age who presented to the urology outpatient clinic for any reason and who had not previously completed the ipss form were evaluated in our study. patients were questioned regarding their age, level of education, and whether or not they had any neurologic diseases, such as alzheimer’s disease. thereafter, patients were grouped according to their age and level of education. international prostate symptom score forms, validated by the turkish urological association, were given to the patients, and they were asked to complete the ipss forms without any assistance. (5) forty-eight to 96 hours later, 238 (96.4%) patients were re-evaluated on the control visit and the ipss form was completed with the assistance of the physician. all the treatment plans and recommendations concerning the changes on lifestyle were given on the control visit in order not to cause any differences between the symptoms of both visits. it was evaluated whether the difference between the self-administered ipss and scores obtained with the assistance of the physician was related to the age and level of education. all the gathered data were analyzed using spss software (the statistical package for the social sciences, version 13.0, spss inc., chicago, illinois, usa) through wilcoxon test. p values less than .05 were considered significant. results the mean ipss answered with and without the assistance of the physician are reported in table 1. there was not a significant difference between the two ipss among the high school or university graduates (p = .480). however, the difference was significant among the primary and secondary school graduates (p = .042 and p = 0.34, respectively). of values obtained from self-administered ipss forms and those completed with the assistance of a physician, there was a statistically significant (table 2). discussion recently, many questionnaires prepared on different subjects have been used in urology practices. the ipss has become quite popular in a short time, and was validated after being translated into various languages.(6) it was reported that the ipss was a reliable and simple evaluating method, which was not affected by the level of education and socio-demographic variables.(1,7) however, our clinical observations have demonstrated that most of the patients were having difficulties in completing the ipss form. studies show that 60% of the urologists in the usa and 70% of the urologists in france use the ipss.(1,8) these results can be interpreted as there are similar findings to our clinical observations on ipss in other countries as well. the questionnaires were prepared in a way that the patient could complete it by himself; thus, obviating the potential effect of a person assisting them to complete the form.(1) nonetheless, illiterates or visually impaired subjects inevitably have to complete the forms with assistance. studies on this subject have shown that unless the assistant contributes to the answers, the approximate scores are obtained when the questionnaires are completed by the patient independently or with the assistance of a health worker.(5,9,10) in the present study, no significant education level number (%) patient’s ipss, mean ipss, mean p primary school 128 (53.8%) 12.16 15.80 .042 secondary school 29 (12.1%) 10.21 7.13 .034 high school or above 82 (34.4%) 7.65 6.98 .480 education level and ipss of the patients and the physician ipss indicates international prostate symptom score. patient’s ipss, mean 8.21 10.15 physician’s ipss, mean 7.10 17.38 p .48 .015 . comparison of the age and ipss of the patients and the physician ipss indicates international prostate symptom score. 229urology journal vol 8 no 3 summer 2011 difference was demonstrated between the selfadministered ipss and the scores obtained in presence of an assistant physician among young patients and patients with a high level of education. in a study conducted in spain involving 666 patients with benign prostatic hyperplasia, the effect of several socio-demographic variables, including the level of education, on the symptom score was investigated. although the effect of a low level of education on the symptom score was limited, it was shown that it might have a significant effect if associated together with pain and depression or anxiety.(4) in the present study, when patients younger than 60 years of age were was found that the rate of accurate completion of the ipss forms for the younger patients was significantly better. however, within our study group, the mean level of education of the younger group was higher. the reason for the difference between these two groups may be the level of education as well as the mental alterations due to age, and we think that this needs to be studied further in larger studies. netto junior and de lima showed that the level of education had no effect on ipss. however, they reported that an orientation was given about how to complete these questionnaires at the beginning of their study.(2) such an approach might affect the outcomes, particularly in favor of the patients with low level of education. bozlu and colleagues also showed that the level of education had no impact on their study.(5) in other studies conducted in brazil via the validated portuguese version of the ipss and in argentina via the spanish version of the ipss, patients were divided into two groups according to their level of education, and the rate of accurate completion of the questionnaire was found to be low in the group with low level of education in both countries, especially in argentina. however, only the difference in the argentina group was significant.(11) in the present study, a statistically significant difference was found when the forms were completed with or without the assistance of the physician in primary and secondary schools’ graduates. it is very important to know the language of the questionnaire in order to be able to understand and fill it in accurately. in many countries, although the native language of a considerable number of people is different from the official language and they have a limited command of the language, the validated questionnaire can only be obtained in the official language. naturally, the outcomes of these forms completed by such people alone are suspicious. the words that are used in the original ipss form are not frequently encountered and routinely used words for many people until they reach an advanced level of education.(12) the reading levels of 28% of the subjects who participated in the mentioned study were significantly lower than what they declared, and it was emphasized that the high level of education declared by the patient might not be sufficient alone to understand the ipss form. in the present study, similar results were obtained. although the subjects with high levels of education completed the questionnaire significantly more accurately, this does not always guarantee accurate completion. in order to complete the ipss form accurately, correct understanding is necessary. although the parameters, such as age and level of education, are effective in understanding the questionnaire accurately, they are not sufficient alone, and the understanding capacity of a person at that moment must be evaluated. unfortunately, most of the neurocognitive tests used in neurology and psychiatry are time-consuming and not practical. the development of an easily applicable “reading and comprehension” test could be very useful for this purpose. conclusion or secondary school graduate are factors lowering the comprehension of the ipss by the patients. older patients and those with lower education could significantly benefit from the assistance of a physician while completing this questionnaire. conflict of interest none declared. 230 urology journal vol 8 no 3 summer 2011 references 1. barry mj. evaluation of symptoms and quality of life in men with benign prostatic hyperplasia. urology. 2001;58:25-32; discussion 2. netto junior nr, de lima ml. the influence of patient education level on the international prostatic symptom score. j urol. 1995;154:97-9. 3. stage ac, hairston jc. symptom scores: mumbo jumbo or meaningful measures? curr urol rep. 2005;6:251-6. 4. badia x, rodriguez f, carballido j, et al. influence of sociodemographic and health status variables on the american urological association symptom scores in patients with lower urinary tract symptoms. urology. 2001;57:71-7. 5. bozlu m, doruk e, akbay e, et al. effect of administration mode (patient vs physician) and patient’s educational level on the turkish version of the international prostate symptom score. int j urol. 2002;9:417-21. 6. badia x, garcia-losa m, dal-re r. ten-language translation and harmonization of the international prostate symptom score: developing a methodology for multinational clinical trials. eur urol. 1997;31: 129-40. 7. moon td, brannan w, stone nn, et al. effect of age, educational status, ethnicity and geographic location on prostate symptom scores. j urol. 1994;152: 1498-500. 8. duclos a, touzet s, perrin p, colin c. [follow-up of ipss scoring in teaching hospitals]. prog urol. 2007;17:65-8. 9. plante m, corcos j, gregoire i, belanger mf, brock g, rossingol m. the international prostate symptom score: physician versus self-administration in the quantification of symptomatology. urology. 1996;47:326-8. 10. cam k, akman y, cicekci b, senel f, erol a. mode of administration of international prostate symptom score in patients with lower urinary tract symptoms: physician vs self. prostate cancer prostatic dis. 2004;7:41-4. 11. rodrigues netto n, jr., de lima ml, de andrade ef, et al. latin american study on patient acceptance of the international prostate symptom score (ipss) in the evaluation of symptomatic benign prostatic hyperplasia. urology. 1997;49:46-9. 12. macdiarmid sa, goodson tc, holmes tm, martin pr, doyle rb. an assessment of the comprehension of the american urological association symptom index. j urol. 1998;159:873-4. urol_v3_no2_001_editorial.qxd introduction the most common mutated gene in human malignancies is tp53. the mutation of this gene is reported in most of human malignancies such as astrocytoma, mesothelioma, sarcoma, leukemia, and colon, bladder, lung, and breast carcinomas.(1,2,3) wild-type protein product of this gene, called p53, weighs 53 000 d and has a short half-life (6 to 30 minutes). this normal protein product does not accumulate in cells enough to be detected by immunohistochemical methods(4); however, the mutated protein has a longer halflife, accumulates in the tissues, and can be easily detected in cell nucleus.(1) the relationship between the increased expression of this protein and urogenital cancers (bladder and prostate carcinomas) has been well demonstrated(3,5-7); while its relationship with renal cell carcinoma (rcc) is still a matter of debate. increased expression of tp53 has been reported to be 20% to 32% in different studies.(8-14) also, in some studies, a relationship has been demonstrated between the expression of p53 and the tumor subtype (increased p53 expression in papillary tumors comparing with other tumor types),(8) while in other studies, such a relation has not been detected.(13,14) the same controversy exists about the association of p53 expression and the tumor grade; while some investigators have found urological oncology relationship between expression of p53 protein and tumor subtype and grade in renal cell carcinoma hayat mombini,* majid givi, iran rashidi department of urology, jundishapour university of medical sciences, golestan hospital, ahwaz, iran abstract introduction: our aim was to evaluate the overexpression of p53 protein, product of mutated tp53 gene, in histologic sections of the kidneys with renal cell carcinoma (rcc) and its association with tumor grade and subtype. materials and methods: a total of 66 histologic sections of the kidneys of patients with the diagnosis of rcc were re-evaluated and tumor grade, tumor subtype, and p53 expression were determined. results: of the total 66 histologic sections with the diagnosis of rcc, 34 (51.5%), 27 (41%), and 5 (7.5%) were conventional, papillary, and chromophobe subtypes, respectively. fifty-one (77.3%), 14 (21.2%), and 1 (1.5%) of tumors were grade 2, 3, and 4, respectively. thirty (45.4%) sections were positive for p53 immunohistochemical staining. in 7 cases (20.6%) of the conventional tumors, p53 staining was positive, while 18 papillary (66.6%) and 5 chromophobe tumors (100%) had a positive staining for p53 (p < .001). seventeen out of 51 grade 2 tumors (33.4%) and 12 out of 14 grade 3 tumors (85.7%) were positive for p53. the single case of grade 4 tumor was positive for p53 protein, too (p = .001). conclusion: increased expression of p53 protein is rather prevalent in rcc. this factor is associated with tumor grade and subtype. according to our findings, it is generally accompanied by nonconventional subtypes and higher tumor grades. key words: renal cell carcinoma, p53 protein, tumor grade, tumor subtype 79 urology journal unrc/iua vol. 3, no. 2, 79-81 spring 2006 printed in iran received november 2005 accepted may 2006 *corresponding author: department of urology, jundishapour university of medical sciences, golestan hospital, ahwaz, iran. tel: +98 611 334 9293, fax: +98 611 334 9293 e-mail: moombeni_h@yahoo.com. p53 protein in renal cell carcinoma no association,(14) a strong relationship has been demonstrated between them by some others and it has been regarded as a potential marker in determining the prognosis of patients with rcc.(11) we conducted this study to evaluate the relationship between the overexpression of p53 tumor suppressor protein and the grade and subtype of rcc. materials and methods in a retrospective study, all cases of radical nephrectomy due to rcc between 1995 and 2005 in golestan and imam khomeini hospitals in ahwaz were reviewed. a total of 66 patients were selected. the paraffin-embedded blocks of their tumor specimens were available. after their reblockage, 2-µm-thick sections were stained again by hematoxylin-eosin and were evaluated regarding the latest tumor subtype classification(15,16) and fuhrman's grading system.(17) immunohistochemical staining was performed to evaluate increased p53 protein expression. catalyzed signal amplification (csa) system (dako, carpinteria, ca) was used for immunohistochemical visualization; skin squamous cell carcinoma specimens were used as controls. sections of rcc with 10% or more of the tumor cell nuclei stained were considered positive for p53. chi-square test was used to analyze the relationship between p53 protein expression and pathological variables of rcc. values for p less than .05 were considered significant. results of the total 66 histologic sections with the diagnosis of rcc, 34 (51.5%), 27 (41%), and 5 (7.5%) were conventional, papillary, and chromophobe subtypes, respectively. none of the specimens was reported to be collecting duct, medullary cell, or oncocytoma subtypes. there was no grade 1 tumor, while 51 (77.3%), 14 (21.2%), and 1 (1.5%) were reported to be grade 2, 3, and 4. thirty (45.4%) sections were positive for p53 immunohistochemical staining (table 1). in 7 cases (20.6%) of the conventional tumors, p53 staining was positive, while 18 papillary (66.6%) and 5 chromophobe tumors (100%) had a positive staining for p53 (p < .001). seventeen out of 51 grade 2 tumors (33.4%) and 12 out of 14 grade 3 tumors (85.7%) were positive for p53. the single case of grade 4 tumor was positive for p53 protein, too (p = .001). discussion the relationship between p53 protein overexpression and tumor subtype and grade has not been well known in rcc. in our study, the overexpression of this protein was seen in 45.4% of the histologic sections with the diagnosis of rcc. zigeuner and coworkers studied 184 sections with the diagnosis of primary rcc and 56 sections with the diagnosis of metastatic rcc. overexpression of p53 protein was detected in 22.8% and 51.8% of primary and metastatic tumors, respectively.(8) other studies have reported this rate to be 20% to 32%.(9,13,14) in our study, the increased p53 protein expression was relatively high. we found that p53 overexpression was more frequent in nonconventional tumor 80 table 1. immunohistochemical staining results for p53 protein in histologic sections of renal cell carcinoma cases* renal cell carcinoma p53 positive p53 negative total p value subtypes conventional 7 (20.6) 27 (79.4) 34 (51.5) papillary 18 (66.6) 9 (33.4) 27 (40.9) chromophobe 5 (100) 5 (7.6) < .001 grades 1 2 17 (33.4) 34 (66.6) 51 (77.3) 3 12 (85.7) 2 (14.3) 14 (21.2) 4 1 (100) 1 (1.5) .001 total 30 (45.4) 36 (54.6) 66 (100) *values in parentheses are percents. mombini et al subtypes. thus, our higher rate of p53 positive tumors is, probably, due to our higher frequency of nonconventional subtypes. it has been shown in different studies that p53 overexpression is higher in nonconventional tumor subtypes. zigeuner and colleagues detected p53 overexpression in 70%, 27.3%, and 11.9% of papillary, chromophobe, and conventional subtypes of rcc.(8) however, in some studies, no correlation has been found between the increased protein expression and the tumor subtype.(13,14) increased p53 protein expression was accompanied by higher grades of the tumor in our study which is in agreement with other studies. leonardi and colleagues have suggested that the strong relation between the p53 expression and the tumor grade, stage, and size found in their study can affect the prognosis of the patients with rcc.(11) in a study by uhlman and colleagues, it has been also demonstrated that increased p53 expression is seen in higher tumor grades and stages.(13) however, in a study by bot and coworkers, no relation was found between the tumor grade and the increased p53 protein expression.(14) although we could find the above associations of p53 with pathologic characteristics of rcc, our study lacked a multivariate analysis. furthermore, we could not investigate all grades and subtypes of these tumors due to the relatively small sample size. however, this limited data mandates more investigation to elucidate the role of tp53 and p53 protein in rcc. conclusion increased p53 protein expression seems to be rather prevalent in rcc as it was seen in half of the histologic sections of our patients. also, there is a significant association of p53 overexpression with the tumor subtype and grade. we found that p53 overexpression is more prevalent in nonconventional subtypes and higher grades. however, to date controversial findings have been reported warranting more investigation. references 1. cote rj, jhanwar sc, novick s, pellicer a. genetic alterations of the p53 gene are a feature of malignant mesotheliomas. cancer res. 1991;51:5410-6 2. messing em. urothelial tumors of urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 2737-41. 3. fujimoto k, yamada y, okajima e, et al. frequent association of p53 gene mutation in invasive bladder cancer. cancer res. 1992;52:1393-8. 4. reich nc, oren m, levine aj. two distinct mechanisms regulate the levels of a cellular tumor antigen, p53. mol cell biol. 1983;3:2143-50. 5. sidransky d, von eschenbach a, tsai yc, et al. identification of p53 gene mutations in bladder cancers and urine samples. science. 1991;252:706-9. 6. isaacs wb, carter bs, ewing cm. wild-type p53 suppresses growth of human prostate cancer cells containing mutant p53 alleles. cancer res. 1991;51:4716-20. 7. chi sg, devere white rw, meyers fj, siders db, lee f, gumerlock ph. p53 in prostate cancer: frequent expressed transition mutations. j natl cancer inst. 1994;86:926-33. 8. zigeuner r, ratschek m, rehak p, schips l, langner c. value of p53 as a prognostic marker in histologic subtypes of renal cell carcinoma: a systematic analysis of primary and metastatic tumor tissue. urology. 2004;63:651-5. 9. girgin c, tarhan h, hekimgil m, sezer a, gurel g. p53 mutations and other prognostic factors of renal cell carcinoma. urol int. 2001;66:78-83. 10. gotoh a, shirakawa t, hanioka k, et al. relation to pulmonary metastasis of alterations in p53 and proliferating cell nuclear antigen in renal cell carcinoma. j of urol pathol. 2000;13: 73-84. 11. leonardi e, luciani l, reich a, luciani lg, dalla palma p. bivariate flow cytometric analysis of cytokeratin 19/dna content in renal cell carcinoma (rcc). correlation with clinico-pathological features (t and g) and p53 expression. a prospective study on 84 cases. wiley cytometry web site-isac 2000 international congress. available from: http://www.wiley.com/legacy/products/ subject/life/cytometry/isac2000/6349.htm. 12. reiter re, anglard p, liu s, gnarra jr, linehan wm. chromosome 17p deletions and p53 mutations in renal cell carcinoma. cancer res. 1993;53:3092-7. 13. uhlman dl, nguyen pl, manivel jc, et al. association of immunohistochemical staining for p53 with metastatic progression and poor survival in patients with renal cell carcinoma. j natl cancer inst. 1994;86:1470-5. 14. bot fj, godschalk jc, krishnadath kk, van der kwast th, bosman ft. prognostic factors in renal-cell carcinoma: immunohistochemical detection of p53 protein versus clinico-pathological parameters. int j cancer. 1994;57:634-7. 15. oyasu r. renal cancer: histologic classification update. int j clin oncol. 1998;3:125. 16. storkel s. classification of renal cancer: correlation of morphology and cytogenetics. in: vogelzang nj, scardino pt, shipley wu, coffey ds, editors. comprehensive textbook of genitourinary oncology. 2nd ed. baltimore: williams & wilkins; 1996. p. 179-86. 17. fuhrman sa, lasky lc, limas c. prognostic significance of morphologic parameters in renal cell carcinoma. am j surg pathol. 1982;6:655-63. 81 v08_no_4_final_new.pdf opposing views 265urology journal vol 8 no 4 autumn 2011 con alireza lashay, erfan amini, ali ahanian, ardalan ozhand, mohammad masoud nikkar, seyed hossein hosseini sharifi advocates of supine percutaneous nephrolithotomy (pcnl) consider several theoretical advantages for this procedure. despite the potential advantages of the supine pcnl, the majority of urologists have remained reluctant to perform this technique. this reluctance may be related to successful outcomes of prone pcnl and technical difficulties associated with supine pcnl. feasibility of supine pcnl has been shown in different series and the current evidence, although limited and not fully organized, implies the application of this technique for patients with simple stones who are at high anesthesiological risk. however, there is no convincing evidence to support performing supine pcnl in morbidly obese patients and those with complex and multiple stones. further randomized clinical trials of large sample size with high methodological quality are required to recommend extensive application of supine pcnl as an alternative to prone pcnl. urol j. 2011;8:265-8. www.uj.unrc.ir keywords: percutaneous nephrolithotomy, supine position, urolithiasis urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran corresponding author: alireza lashay, md urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: alireza_lashay @ yahoo.com received july 2011 accepted july 2011 introduction anesthesiological disadvantages associated with prone position in percutaneous nephrolithotomy (pcnl) are absent in supine position. this advantage is of particular importance in morbid obese patients and those with skeletal deformities. a comfortable sitting position is provided for the surgeons during the whole procedure with their hands outside of the fluoroscopic field. retrograde access to the urinary tract is possible while the surgical field remains sterile and the patient position is unchanged. since the bowels lie away from the puncture site in supine position, the risk of the bowel injury is comparable to that in prone position. furthermore, supine position has been postulated to reduce the possibility of stone migration into the ureter due to horizontal percutaneous tract and the low intrarenal pressure.(1,2) percutaneous nephrolithotomy in supine position was introduced by valdivia uría and colleagues 12 years earlier(3) and the aforesaid advantages for this technique have been elucidated in different studies. despite the potential advantages of the supine position, it has not become popular among urologists, and pcnl in prone position is being considered as the preferred method worldwide. plausible explanations to this low acceptability may be fear of the colon injury and lack of experience.(4) however, supine position does not seem to increase the risk of the colon injury.(5) in a review of supine and prone pcnls, duty and colleagues supine percutaneous nephrolithotomy—lashay et al 266 urology journal vol 8 no 4 autumn 2011 indicated that none of the 1494 patients in a total of 8 supine pcnls experienced the colon injury. (6) this may have been related to more anterior displacement of the colon in supine position. although the concerns regarding the risk of the colon injury have been resolved to a certain extent, the majority of urologists have remained reluctant to either utilize supine position as a safe technique with several potential advantages or improve their knowledge and experience in this regard. a possible reason may be related to the availability of highly effective and safe conventional prone pcnl.(7) moreover, one has to consider that pcnl in supine position despite its irrefutable benefits is associated with several technical disadvantages. prone pcnl as a safe and effective procedure prone pcnl has been performed successfully during the past 30 years and still represents the standard for percutaneous access to the kidney. (8) stone-free rate in prone pcnl ranges from 76% to 91% in different large scale series and complication rates have been reported to be within the acceptable limits.(5,6,9) several disadvantages have been claimed for prone pcnl, including patient’s discomfort, circulatory and respiratory complications, increased intraocular pressure, risk of the cervical spine injury, tracheal tube displacement, and prolonged surgical duration due to need for patient repositioning. however, the majority of these position-related complications have been reported in the neurosurgical and orthopedic literature, and in most patients who experienced adverse events attributable to the prone position, operation time has been much longer than the average time for performing prone pcnl.(6) two large studies on pcnl, each including more than 1000 patients, reported no complications attributable to prone position during pcnl.(10,11) technical difficulties of pcnl in supine position despite some technical advantages, such as spontaneous stone drainage during the procedure and more comfortable position of the surgeon, supine pcnl is associated with several important technical difficulties: 1in case of anterior caliceal stone, lateral deflection of the rigid nephroscope into an anterior calyx is restricted by the side of the bed. in these conditions, either applying flexible nephroscope or forming a tract directly through the anterior calyx could be considered as practical alternatives. nevertheless, applying flexible nephroscope is associated with relatively limited visual field and subsequently lower success rates. (12) furthermore, forming a tract directly through the anterior calyx does not pass through the area of brodel’s avascular line and is associated with higher bleeding complications.(13) 2since the upper pole is more medial and posterior, and located deeply in the rib cage, upper pole caliceal puncture in supine position is more difficult and associated with a higher risk of hydrothorax or pulmonary injury.(14) studying 20 patients, falahatkar and associates performed renal displacement technique (lung inflation) to access the superior calyx subcostally.(15) using this technique, they were able to avoid intrathoracic complications. however, this finding requires further confirmation and may not be applicable for patients with prior history of renal surgery and more superiorly located calices. 3the distance between 12th rib and the superior edge of the iliac crest is greater in prone than supine position. since the puncture site lies between these two landmarks, supine pcnl may be associated with a limited field, which restricts nephroscopic maneuvers and may interfere with execution of further tracts in the case of multipleaccess pcnl.(6) 4in supine position, the kidney is positioned more medially and is more floating in the retroperitoneum. in case of a floating kidney, wide kinking of the metallic guidewire may occur. consequently, execution of the nephrostomy tract and dilator progression may be more challenging in the supine position. (13) greater mobility of the kidney may also be associated with longer tract, which subsequently decreases nephroscope mobility. therefore, greater force must be exerted on the renal parenchyma to maneuver the nephroscope, which supine percutaneous nephrolithotomy—lashay et al 267urology journal vol 8 no 4 autumn 2011 may increase the chance of parenchymal damage and bleeding.(6) 5supine pcnl is associated with decreased filling of the pyelocaliceal system. collapsed collecting system restricts the surgical field and even a moderate amount of bleeding obscure vision and may lead to early termination of the surgery. some authors advocate supine pcnl as it provides a comfortable sitting position for the surgeons during the whole procedure with their hands outside of the fluoroscopic field. nevertheless, surgeon’s comfort is not only limited to the sitting position, but also depends on the better vision and possibility of greater maneuver of the nephroscope. therefore, supine pcnl is not necessarily associated with surgeon’s comfort. radiation exposure in supine pcnl may also be more due to technical difficulties, ie, kinking of the guidewire may interfere with easy execution of the nephrostomy tract. however, these theoretical comparisons require confirmation by well-controlled trials. review of the current evidence low acceptability of the supine pcnl may be attributable to the lack of level i data. only few studies have been performed so far to compare different positions for pcnl. two randomized clinical trials(4,13) and two case control analyses(16,17) have evaluated pcnl in 182 and 207 patients with supine and prone positions, respectively. stone burden was approximately similar between different study groups and all the studies revealed similar technical success and complication rates. operation time was significantly longer in prone pcnl, which included time for repositioning. however, neither of these studies comprised morbidly obese patients and some studies have excluded patients with complex stones. in one of the aforesaid randomized trials, de sio and colleagues excluded patients with complex stones, ie, stones in more than one calyx or complete staghorn calculi. furthermore, no access was performed through the upper calyx or with supracostal approach in their study.(13) falahatkar and associates also reported few subjects with staghorn calculi.(4) therefore, the results are not representative of the entire population with urolithiasis. different case series have also compared supine and prone pcnls and revealed similar stonefree rates and slightly lower bleeding in favor of supine pcnl. however, analysis has shown larger proportion of staghorn and multiple calculi treated in prone position.(5) to address outcomes in obese patients and those with staghorn calculi in a comprehensive review, de la rosette and coworkers compared weighted means presenting outcomes in supine and prone positions on operation time, success rate, and bleeding needing transfusion.(18) this comparison revealed significantly less operation time for the prone against supine pcnl, with similar bleeding and slightly better success rates. in the second analysis, they included studies with similar proportions of staghorn calculi to compare supine and prone pcnls and noted that prone position provides better stone-free rates among patients with complex renal calculi. however, the number of studies meeting these criteria is very limited at present and conclusions should be carefully interpreted. conclusion current data support the feasibility of pcnl in supine position and this technique can be considered as a promising alternative in treating patients with uncomplicated stones and those with high anesthesiologic risk. however, there is no convincing evidence to support performing supine pcnl in patients with complex stones, staghorn calculi, multiple stones, upper caliceal stones, morbidly obese patients, and those with coexisting renal anomalies. further randomized clinical trials with larger sample size and high methodological quality are required to add valuable information to the totality of the currently available evidence. acknowledgements the authors are thankful to professor basiri for his valuable guidance and comments. supine percutaneous nephrolithotomy—lashay et al 268 urology journal vol 8 no 4 autumn 2011 conflict of interest none declared. references 1. cracco cm, scoffone cm, scarpa rm. new developments in percutaneous techniques for simple and complex branched renal stones. curr opin urol. 2011;21:154-60. 2. basiri a, mohammadi sichani m, hosseini sr, et al. x-ray-free percutaneous nephrolithotomy in supine position with ultrasound guidance. world j urol. 2010;28:239-44. 3. valdivia uria jg, valle gerhold j, lopez lopez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol. 1998;160:1975-8. 4. falahatkar s, moghaddam aa, salehi m, nikpour s, esmaili f, khaki n. complete supine percutaneous nephrolithotripsy comparison with the prone standard technique. j endourol. 2008;22:2513-7. 5. wu p, wang l, wang k. supine versus prone position in percutaneous nephrolithotomy for kidney calculi: a meta-analysis. int urol nephrol. 2011;43:67-77. 6. duty b, okhunov z, smith a, okeke z. the debate over percutaneous nephrolithotomy positioning: a comprehensive review. j urol. 2011;186:20-5. 7. autorino r, giannarini g. prone or supine: is this the question? eur urol. 2008;54:1216-8. 8. miano r, scoffone c, de nunzio c, et al. position: prone or supine is the issue of percutaneous nephrolithotomy. j endourol. 2010;24:931-8. 9. el-nahas ar, shokeir aa, el-assmy am, et al. colonic perforation during percutaneous nephrolithotomy: study of risk factors. urology. 2006;67:937-41. 10. duvdevani m, razvi h, sofer m, et al. third prize: contemporary percutaneous nephrolithotripsy: 1585 procedures in 1338 consecutive patients. j endourol. 2007;21:824-9. 11. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899906; discussion 12. basiri a, mohammadi sichani m. supine percutaneous nephrolithotomy, is it really effective? a systematic review of literature. urol j. 2009;6:73-7. 13. de sio m, autorino r, quarto g, et al. modified supine versus prone position in percutaneous nephrolithotomy for renal stones treatable with a single percutaneous access: a prospective randomized trial. eur urol. 2008;54:196-202. 14. ng mt, sun wh, cheng cw, chan es. supine position is safe and effective for percutaneous nephrolithotomy. j endourol. 2004;18:469-74. 15. falahatkar s, enshaei a, afsharimoghaddam a, emadi sa, allahkhah aa. complete supine percutaneous nephrolithotomy with lung inflation avoids the need for a supracostal puncture. j endourol. 2010;24:213-8. 16. amon sesmero jh, del valle gonzalez n, conde redondo c, rodriguez toves a, cepeda delgado m, martinez-sagarra oceja jm. [comparison between valdivia position and prone position in percutaneous nephrolithotomy]. actas urol esp. 2008;32:424-9. 17. shoma am, eraky i, el-kenawy mr, el-kappany ha. percutaneous nephrolithotomy in the supine position: technical aspects and functional outcome compared with the prone technique. urology. 2002;60:388-92. 18. de la rosette jj, tsakiris p, ferrandino mn, elsakka am, rioja j, preminger gm. beyond prone position in percutaneous nephrolithotomy: a comprehensive review. eur urol. 2008;54:1262-9. uj 35 summer.pdf 553vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l urology and nephrology research center, shohadae-tajrish medical center, shahid beheshti university of medical sciences, tehran, iran hossein karami, alireza rezaei, mohammad mohsen mazloomfard, babak javanmard, behzad lotfi, amir haji-mohammadmehdi-arbab effects of surgical position on patients’ arterial blood gases during percutaneous nephrolithotomy corresponding author: mohammad mohsen mazloomfard, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2277 0954 e-mail: mazloomfard@ yahoo.com received august 2010 accepted january 2012 endourology and stone disease purpose: materials and methods: repositioning. results : and supine positions, respectively (p 2 p = .21). arterial oxygen pressure (pao2 p = .01) and p p 2 3 prone, and supine groups. conclusion: keywords: percutaneous nephrolithotomy, blood gas analysis, prone position 554 | endourology and stone disease introduction pulmonary ventilation and perfusion. atelectasis of the dependent areas of the lung due to general arterial oxygen tension.(1) tion and ventilation. patients undergoing surgery in prone space to tidal volume ratio.(2) this position has been reporttory distress syndrome.(3) alternating the positions could also improve arterial oxygen pressure in these patients.(4) an improvement in both oxygenation and carbon dioxide tion.(5) (abg) changes after repositioning patients to prone, sumaterials and methods groups using pseudorandomization method (30 patients in supine positions, respectively. anomalies, uncontrolled coagulopathies, previous history of or respiratory disease, and children younger than 15 years ing to their groups. all the patients received balanced anesthroughout the study, the ventilator settings (tidal volume, 2 and 20 minutes after repositioning using abl 330® blood demographic characteristics, operation duration, hemop values results spectively (p 2 supine positions, respectively (p = .21). demographic and p = .56). respectively (p p and complications, such as sepsis in the three groups. 555vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l effects of surgical positions on patients’ abg during pcnl | karami et al table 2 summarizes the abg analyses data of patients in the three groups. after positioning, pao2 p = p < p = .23). the changes of pao2 icantly different from that in supine group (p =.035). with 2 p p = .2), p = .3). 3 from each other. discussion percutaneous nephrolithotomy can be carried out in different positions; the three common positions are prone, lateral, and supine. we demonstrated that oxygenation improves alterations in distribution of pulmonary ventilation and studies.(6,7) the combined effect of position and general anof oxygenation and carbon dioxide elimination. mentzelomechanically ventilated chronic obstructed pulmonary disease, repositioning to prone could facilitate oxygenation recumbent position. have found that in anesthetized and paralyzed obese subjects, the prone position improves pulmonary function and increases functional residual capacity, lung compliance, and oxygenation.(7) the prone position does not change oxygen consumption; author concluded that changes in alveolar ventilation could possibly be the result of circulatory changes caused by the prone position.(9) papazian and colleagues have indicated that the prone position increases oxygenation and reduces syndrome.(10) that the prone position increases the homogeneity of the ventilation perfusion distribution.(11) ventilation-perfusion matching.(12,13) mechanically ventilated patients, regional ventilation-perthe prone position. prone position diminishes the percentage of the lung volume in the dependent zones and as a result, the volume of potentially collapsible lung. during mechanical ventilation, the tidal volume is preferentially distributed to the nondependent areas of the lung that have a proportionately larger volume in the prone position positioning in both pulmonary alveolar proteinosis patients and the healthy controls.(14) soro and colleagues found that in the prone position and pao2 2 patients undergoing surgery in prone position under general the tidal volume.(2) the effect of lateral position on arterial oxygenation under anesthesia is still under debate. kerbl and colleagues compression of the patients.(15) gofrit and associates recto avoid severe hypoxemia and hypercarbia.(16) although 556 | elimination.(5) 2. we demonstrated that pao2 increases after repositioning 2. we also found that 2 3 supine positions in this percutaneous procedure. history of cardiovascular or respiratory disease, abnormal tion. conclusion and ventilation, serial arterial blood gases analyses during longer operations could be helpful. conflict of interest none declared. endourology and stone disease 4. kim mj, hwang hj, song hh. a randomized trial on the effects of body positions on lung function with acute respiratory failure patients. int j nurs stud. 2002;39:549-55. 5. manikandan s, rao g. effect of surgical position on pulmonary gas exchange in neurosurgical patients. indian j anaesth. 2002;46:356-9. 6. lumb ab, nunn jf. respiratory function and ribcage contribution to ventilation in body positions commonly used during anesthesia. anesth analg. 1991;73:422-6. 7. pelosi p, croci m, calappi e, et al. prone positioning improves pulmonary function in obese patients during general anesthesia. anesth analg. 1996;83:578-83. 8. mentzelopoulos sd, zakynthinos sg, roussos c, tzoufi mj, michalopoulos as. prone position improves lung mechanical behavior and enhances gas exchange efficiency in mechanically ventilated chronic obstructive pulmonary disease patients. anesth analg. 2003;96:1756-67, table of contents. 9. radstrom m, loswick ac, bengtsson jp. respiratory effects of the kneeling prone position for low back surgery. eur j anaesthesiol. 2004;21:279-83. 10. papazian l, gainnier m, marin v, et al. comparison of prone positioning and high-frequency oscillatory ventilation in patients with acute respiratory distress syndrome. crit care med. 2005;33:2162-71. 11. mure m, domino kb, lindahl sg, hlastala mp, altemeier wa, glenny rw. regional ventilation-perfusion distribution is more uniform in the prone position. j appl physiol. 2000;88:1076-83. 12. flaatten h, aardal s, hevroy o. improved oxygenation using the prone position in patients with ards. acta anaesthesiol scand. 1998;42:329-34. 13. klingstedt c, hedenstierna g, lundquist h, strandberg a, tokics l, brismar b. the influence of body position and differential ventilation on lung dimensions and atelectasis formation in anaesthetized man. acta anaesthesiol scand. 1990;34:315-22. 14. lin fc, chen yc, chang hi, chang sc. effect of body position on gas exchange in patients with idiopathic pulmonary alveolar proteinosis: no benefit of prone positioning. chest. 2005;127:1058-64. 15. kerbl k, clayman rv, chandhoke ps, urban da, de leo bc, carbone jm. percutaneous stone removal with the patient in a flank position. j urol. 1994;151:686-8. 16. gofrit on, shapiro a, donchin y, et al. lateral decubitus position for percutaneous nephrolithotripsy in the morbidly obese or kyphotic patient. j endourol. 2002;16:383-6. references 1. bendixen hh, hedley-whyte j, laver mb. impaired oxygenation in surgical patients during general anesthesia with controlled ventilation. a concept of atelectasis. n engl j med. 1963;269:991-6. 2. soro m, garcia-perez ml, belda fj, et al. effects of prone position on alveolar dead space and gas exchange during general anaesthesia in surgery of long duration. eur j anaesthesiol. 2007;24:431-7. 3. fridrich p, krafft p, hochleuthner h, mauritz w. the effects of long-term prone positioning in patients with traumainduced adult respiratory distress syndrome. anesth analg. 1996;83:1206-11. pictorial urology 16 urology journal vol 7 no 1 winter 2010 giant cystic pheochromocytoma a 53-year-old man presented with a 1-month history of pain and a palpable mass in the left side of the abdomen. physical examination revealed a mass on the left half of the abdomen crossing the midline. laboratory data were unremarkable, except for an upper limit of reference range for urinary cathecholamine metabolites. computed tomography and magnetic resonance imaging revealed a huge complex cyst in the left side of the abdominal cavity, extending superiorly to the level of the pancreas and caudally to the iliac crest, displacing the kidney downward. the mass was surgically removed en bloc through a thoracoabdominal incision. the histopathological examination revealed pheochromocytoma of the adrenal gland, weighed 3150 g. while magnetic resonance imaging and metaiodobenzylguanidine scintigraphy were negative for metastasis, the patient had a urinary normetanephrine level, slightly upper than normal. giant prominently cystic pheochromocytomas are extremely rare tumors.(1) patients with giant pheochromocytomas may not display typical clinical or laboratory manifestations.(2) abdominal computed tomography and magnetic resonance imaging may not determine the origin of mass.(3) pheochromocytoma should be considered in differential diagnosis of abdominal cysts. the presented case is one of the largest reported cystic pheochromocytomas with a benign course and no recurrence or complications on follow-up. abbas basiri, mohammad hadi radfar urology and nephrology research center, shahid beheshti university of medical sciences and erfan hospital, tehran, iran e-mail: mhadirad@yahoo.com references 1. pan z, repertinger s, deng c, sharma p. a giant cystic pheochromocytoma of the adrenal gland. endocr pathol. 2008;19:133-8. 2. melegh z, rényi-vámos f, tanyay z, köves i, orosz z. giant cystic pheochromocytoma located in the renal hilus. pathol res pract. 2002;198:103-6. 3. antedommenico e, wascher ra. a case of mistaken identity: giant cystic pheochromocytoma. curr surg. 2005;62:193-8. urol j. 2010;7:16. www.uj.unrc.ir 1248 | zeki tuncel tekgül,1 rauf taner divrik,2 murat turan,1 ersin konyalioğlu,2 esen şimşek,1 mustafa gönüllü1 impact of obturator nerve block on the short-term recurrence of superficial bladder tumors on the lateral wall corresponding author: nicholas g. cost, md division of pediatric urology, cincinnati children’s hospital medical center, 3333 burnet avenue, mlc 5037, cincinnati, ohio 45229, usa tel: +513 363 0773 fax: +513 636 6753 e-mail: nicholas.cost@sbcglobal.net received january 2012 accepted october 2012 corresponding author: zeki tuncel tekgül, md department of anesthesiology and reanimation, izmir tepecik research and training hospital, gaziler st. no 468 yenişehir 35120, izmir, turkey. tel: +90 232 469 6969 fax: +90 232 469 6969 e-mail: zekittekgul@yahoo.com received december 2012 accepted july 2013 purpose: the aim of this study was to compare the recurrence rates of patients with bladder tumors on the lateral wall undergoing transurethral resection of bladder tumor(tur-bt) with or without obturator nerve block (onb) and to investigate the impact of onb on the effective tumor resection on the lateral bladder wall. materials and methods: all patients who underwent tur-bt under spinal anesthesia within the three-year study period in the study center were reviewed retrospectively. among these, 68 patients who had been diagnosed with de novo lateral bladder wall tumor and included in low risk group 1n accord with european organization for research and treatment of cancer (eortc) classification, undergone complete resection were enrolled into the study. group 1 (36 patients who underwent tur-bt with only spinal anesthesia) and group 2 (32 patients who underwent tur-bt with spinal anesthesia plus onb) were evaluated with respect to tumor recurrence rates and disease-free time to recurrence, if any. results: follow-up periods (range, 19 to 41 months for group 1 and 19 to 39 months for group 2) and overall recurrence rates (group 1, 27.8% and group 2, 18.8%) were also found to be similar. mean time to recurrence was significantly higher in group 2 (15 ± 5.5 months) than in group 1 (7.8 ± 4.5 months) (p = .009) conclusion: onb employed in addition to spinal anesthesia in tur-bt involving the lateral wall can prolong time to recurrence and increase the chance to lengthen disease-free survival in low-risk superficial bladder tumors. keywords: urinary bladder neoplasms; anesthetic; methods; nerve block; obturator nerve; anesthesia. urological oncology urological oncology 1 department of anesthesiology and reanimation, izmir tepecik research and training hospital, izmir, turkey. 2 department of urology, izmir tepecik research and training hospital, izmir, turkey. 1249vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l obturator nerve block and recurrence of superficial bladder tumors | tekgül et al introduction transurethral resection for bladder tumors (tur-bt) is the standard method of diagnosis, staging and treat-ment. one of the most important problems with the procedure is high rates of tumor recurrence and progression. there are multiple factors affecting recurrence. of note, residual tumor tissue of the bladder tumor can be detected, even when "complete resection” is performed.(1-3) resection of tumor tissues completely as necessary, including detrusor muscle has been shown to eliminate residual tumor and prevent short-term recurrence in the tur-bt procedure.(2-4) superficial bladder tumors comprise up to 75% to 85% of all bladder tumors at the time of diagnosis and of these, nearly 70% are in the stage of ta (noninvasive papillary carcinoma ).(5) rodriguez and colleagues demonstrated that the lateral wall harbors 46.8% of all bladder tumors.(6) adductor muscle spasm is reported to occur in 55.3% to 100% of resections of lateral wall bladder tumors, with untoward effects on surgery and complications.(6-9) this phenomenon results from proximity of the obturator nerve to the lateral wall of the bladder as it originates from the 2nd and 4th lumbar nerve roots that course towards the adductor muscles. sudden spasms in the adductor muscles ensue with direct stimulation of the obturator nerve with electrocautery during surgery. to prevent adductor muscle spasm, many methods including administration of muscle relaxants under general anesthesia, obturator nerve block (onb) in conjunction with spinal anesthesia, incomplete filling of the bladder, diminishing the power of the electrical current, using a 90-degree conventional loop, bipolar plasma kinetic energy, relocating the cautery pad and resection of the tumor by smaller steps have been employed. (10-13) this study is designed to investigate the impact of onb employed with spinal anesthesia on the recurrence rates and recurrence times in patients with superficial bladder tumors on the lateral wall in patients undergoing tur-bt in a mean follow-up period of 32 months. materials and methods helsinki declaration principles were followed in this study. following the approval of the study by the institutional review board, all patients who underwent tur-bt under spinal anesthesia within the three-year study period (2009-2011) in the study center were reviewed retrospectively. among these, 68 patients who had been diagnosed with de novo bladder tumor nested in the lateral wall as noted in the surgery reports and included in a low-risk group 1n accord with european organization for research and treatment of cancer (eortc) classification (smaller than 3 cm, solitary and documented as ta g1 papillary urothelial carcinoma by the pathological examination) and who had undergone complete resection were enrolled into the study.(4) group 1 (36 patients who underwent tur-bt with only spinal anesthesia) and group 2 (32 patients who underwent tur-bt with spinal anesthesia plus onb) were evaluated with respect to tumor recurrence rates and disease-free time to recurrence, if any. onb was performed following verification of the level of spinal anesthesia with the patient in lithotomy position. a 21 gauge 100 mm long stimuplex a (b. braun melsungen ag. 34209 melsungen, germany) was inserted perpendicularly at the point 2 cm inferior and 2 cm lateral to the pubic tubercle. in accord with the 'traditional approach', the current power of the nerve stimulator was adjusted to 1.5-2 ma and current period as 0.1 ms, the needle was inserted through the skin to the inferior rami of the pubic bone. then, it was slightly pulled back and redirected anterolaterally, contacting the nerve in a depth of 2 to 4 cm(14) and 10 ml 0.25% levobupivacaine were administered with current at 0.3-0.5 ma when contraction was observed at the adductor muscle groups and after aspiration was negative. surgery was initiated 10 min following injection. the same anesthesia staff performed the onbs and the same urologists operated on the patients in both groups and no additional techniques were used to prevent adductor muscle contractions during surgery other than onb. all patients underwent complete tur-bt. a 26 french resectoscope with 30 degree optics were utilized for resection. the whole bulk of the tumor tissue was resected using monopolar cautery while sampling muscle tissue. the patients were administered single-dose intravesical epirubicin (80 mg) in 4 to 6 hours after the operation. patients suspected to have intraoperative bladder perforation or those with postoperative hematuria did not receive this treatment. all patients were followed up with flexible cystoscopy under local anesthesia every three months for the first year, and then every six months. demographic and clinical data were obtained and recorded with respect to age, sex, weight, american so1250 | urological oncology ciety of anesthesiologists (asa) classification, tumor size, follow-up period and recurrence time, if any. statistical analysis was performed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0. descriptive data were given as mean ± standard deviation. student’s t test was performed for comparisons of age, weight, tumor size, recurrence time and follow-up period. recurrence rates and one-year recurrence rates were compared via chi-square, while bladder perforation, sex and asa scores were compared using fisher's exact chi-square test. statistical significance was interpreted when p values were below .05. results the differences between the groups regarding age, sex, weight and asa classification scores were not statistically significant (p > 0.05) (table 1). mean tumor size was 1.7 ± 0.8 cm in group 1 and 2.0 ± 0.7 cm in group 2 (p = .227). there were two bladder perforations in group 1 whereas no perforations in group 2 (p = .494). intravesical chemotherapy was withheld in two patient in group 1 due to suspected bladder perforation, and another one because of hematuria; and in one patient in group 2 for hematuria. no recurrences were detected in these four patients who did not receive intravesical chemotherapy. no side effects related to onb were reported. tumor progression was not noted in the follow-up period in any patient recruited in the study. recurrence rates of the patients in the one-year follow-up were 25% in group 1 and 9.4% in group 2 (table 2). follow-up periods (range, 19 to 41 months for group 1 and 19 to 39 months for group 2) and recurrence rates (27.8% in group 1 and 18.8% group 2) were found to be similar in both groups (table 2). on the other hand, mean recurrence time in group 1 (7.8 ± 4.5 months) was significantly shorter than that in group 2 (15.5 ± 5.5 months) (p = .009) (table 2). discussion sudden contractions of adductor muscles during tur-bt situated in the lateral wall result in leg movements which hamper the procedure and result in a myriad of complications.(6-13) strong contractions of the adductor muscle may lead to partial or complete bladder perforations and resultant extravesical spread of tumor.(8-13) the severity of the potential consequences makes the operator pursue maneuvers such as filling the bladder less than completely, diminishing the power of the electrical current for the electrocautery, or resecting the tumor on thinner slices. these maneuvers may help reduce the rates of complications at the expense of tumor resection performed more often. the present study is originated from the idea to compare the recurrence rates and times in patients undergoing resections of bladder tumors on the lateral wall with or without onb, thus highlighting the efficacy of onb on the outcome of the procedure. in the present study, mean time to tumor recurrence is found to be 7.8 ± 4.5 months in group 1, while 15.5 ± 5.5 in group 2 (p = .009). recurrences were identified in nine patients in group 1 (25%) and three patients in group 2 (9.4%) during one-year follow-up. disease-free interval in patients who had undergone onb was significantly longer than others, which is considered to result from the effect of onb on tumor retable 1. demographic data (mean ± standard deviation) of study participants. variables group 1 (n = 36) group 2 (n = 32) p age (years) 65.8 ± 7.8 67,1 ± 7,8 .477 weight (kg) 72.8 ± 6 74,8 ± 9,7 .326 sex male/female 34/2 30/2 1.000 asa i/ii/iii 4/25/7 2/24/6 .767 key: asa, american society of anesthesiologists physical status classification. 1251vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l section on the lateral bladder wall. residual tumor tissue following the tur-bt procedure increase recurrence rates and thus shorten tumor-free interval. jancke and colleagues pointed out that 26% of patients had residual tumor tissue following complete resection of superficial bladder tumors (ta/t1) and that these patients suffered from significantly higher recurrence rates when compared to the others.(1) tumor recurrence rates noted in the groups in the present study (group 1, 27.8% and group 2, 18.8%) were not found to be significantly different which may be attributed to small sample size and especially small number of patients with recurrence. future studies with a greater sample size may be expected to reach statistical significance. six factors with the greatest impact on the tumor recurrence and progression are; the number and size of tumors, previous recurrence time, tnm classification, presence of carcinoma in situ (cis) and grade of the tumor.(4) one-year expectancy of recurrence rate in bladder tumors smaller than 3 cm, solitary, newly diagnosed, categorized as ta, without cis and low-grade is 10% to 19% and progression rate is 0% to 0.7%. (4) the recurrence rates of tumors which possess the same features in five-year follow-up are between 24% and 36% with a progression rate between 0% and 1.7%.(4) these figures are similar to the rates found in the present study. both groups of patients received single-dose intravesical epirubicin which was well proven to be effective in low-risk superficial bladder tumors following the tur-bt procedure. (15,16) the relatively high recurrence rate (25%) compared to expected recurrence rate (10% to 19%) in the one-year follow-up period in the group who were not treated with onb can be attributed to relative difficulty in complete resection of bladder lateral wall tumors. literature search yields many studies indicating the efficiency of onb to prevent complications of the resection procedure in the bladder tumors on the lateral wall.(6-9,11-13,17) onb can be performed with various approaches producing success rates in prevention of adductor muscle spasm between 84% and 96%.(17-19) more recent studies cite that introduction of ultrasound in the practice of regional anesthesia is associated with higher success rates in ultrasound-guided onb procedures (93% to 97.2%).(20-22) similar to the present study, most reports favored onb as a safe procedure. however, there are also reports in the literature of complications related to onb such as serious bleeding and seizures.(23-24) on the contrary, literature lacks data supporting the beneficial effect of onb on tumor recurrence rates and recurrence time following resection of lateral wall bladder tumors. the major limitation of this study is the small sample size in both groups. limited numbers of patients were enrolled into the study in an effort to standardize the factors affecting tumor recurrence rate and recurrence time in both groups. another limitation is that the patients to be blocked with onb were chosen by surgeon (patients with a high adductor muscle spasm probability) preoperatively. this situation may have caused a difference in aspect of tumor size (group 1, 1.7 ± 0.8 cm and group 2, 2.0 ± 0.7 cm) between the two groups. well-designed multi-centered studies will help test the present findings with greater samples. the patients in the present study are still under follow-up in order to investigate table 2. data regarding the follow up period, number of recurrences and mean time to recurrence (mean ± standard deviation) in both group of patients. variables group 1 (n = 36) group 2 (n = 32) p patients with recurrence at 1 year, no. (%) 9 (25) 3 (9.4) .092 follow up period (month) 31.6 ± 5.9 31.7 ± 6.8 .930 patients with recurrence, no. (%) 10 (27.8) 6 (18.8) .381 mean time to recurrence (month) 7.8 ± 4.5 15.5 ± 5.5 .009 obturator nerve block and recurrence of superficial bladder tumors | tekgül et al 1252 | urological oncology long-term efficacy of onb on the recurrence rate, recurrence time and progression of lateral wall bladder tumors. conclusion onb performed in addition to spinal anesthesia in tur-bt procedures for tumors involving the lateral wall can prolong time to recurrence and increase the chance to lengthen the disease-free survival in low-risk superficial bladder tumors. conflict of interest none declared. references 1. jancke g, rosell j, jahnson s. residual tumor in the marginal resection after a complete transurethral resection is associated with local recurrence in ta/t1 urinary bladder cancer. scand j urol nephrol. 2012;46:343-7. 2. mariappan p, zachou a, grigor km. detrusor muscle in the first, apparently complete transurethral resection of bladder tumor specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. eur urol. 2010;57:843-9. 3. divrik rt, yildirim ü, zorlu f, ozen h. the effect of repeat transurethral resection on recurrence and progression rates in patients with t1 tumors of the bladder who received intravesical mitomycin: a prospective, randomised clinical trial. j urol. 2006;175:1641-4. 4. babjuk m, oosterlinck w, sylvester r, et al. eau guidelines on nonmuscle-invasive urothelial carcinoma of the bladder, the 2011 update. eur urol. 2011;59:997-1008. 5. anastasiadis a, reijke tm. best practice in the treatment of nonmuscle invasive bladder cancer. ther adv urol. 2012;4:13-32. 6. rodríguez jg, monzón aj, alvarez rcg, et al. an alternative technique to prevent of obturator nerve stimulation during lateral bladder tumors transurethral resection. actas urol esp. 2005;29:445-7. 7. kuo jy. prevention of obturator jerk during transurethral resection of bladder tumor. jtua. 2008;19:27-31. 8. patel d, shah b, patel bm. contribution of obturator nerve block in the transüretral resection of bladder tumors. indian j anaesth. 2004;48:47-9. 9. tatlisen a, sofikerim m. obturator nerve block and transurethral surgery for bladder cancer. minerva urol nefrol. 2007;59:137-41. 10. chen wm, cheng cl, yang cr, chung v. surgical tip to prevent bladder perforation during transurethral resection of bladder tumors. urology. 2008;72:667-8. 11. yıldırım i, basal s, irkilata hc. safe resection of bladder tumors with plasma kinetic energy. int j hematol oncol. 2009;19:232-6. 12. kihl b, nilson ae, pettersson s. thigh adductor contraction during transurethral resection of bladder tumors: evaluation of inactive electrode placement and obturator nerve topography. scand j urol nephrol. 1981;15:121-5. 13. deliveliotis c, alexopoulou k, picramenos d. the contribution of obturator nerve block in transurethral resection of bladder tumors. acta urology belg. 1995;63:51-4. 14. parks cr, kennedy wf jr. obturator nerve block: a simplified approach. anesthesiology. 1967;28:775-778. 15. shin ys, kim jy, ko os, et al. the direct anti-cancer effect of a single instillation of epirubicin after transurethral resection of bladder tumor for non-muscle-invasive bladder cancer. korean j urol. 2012;53:78-81. 16. gudjónsson s, adell l, merdasa f, et al. should all patients with nonmuscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? the results of a prospective randomised multicentre study. eur urol. 2009;55:773-80. 17. naseem a, syed mzh, faizan a, shahid mr, arshad m, muhammad sa. obturator nerve block; transurethral resection of lateral bladder wall tumors (tur-btt). professional med j. 2009;16:48-52. 18. youn yi jo yy, choi e, kil hk. comparison of the success rate of inguinal approach with classical pubic approach for obturator nerve block in patients undergoing turb. korean j anesthesiol. 2011;61:143-7. 19. kakinohana m, taira y, saitoh t, hasegawa a, gakiya m, sugahara k. interadductor approach to obturator nerve block for transurethral resection procedure: comparison with traditional approach. j anesth. 2002;16:123-6. 20. thallaj a, rabah d. efficacy of ultrasound-guided obturator nerve block in transurethral surgery. saudi j anaesth. 2011;5:42-4. 21. akkaya t, ozturk e, comert a, et al. ultrasound-guided obturator nerve block: a sonoanatomic study of a new methodologic approach. anesth analg. 2009;108:1037-41. 22. lee sh, jeong cw, lee hj, yoon mh, kim wm. ultrasound guided obturator nerve block: a single interfascial injection technique. j anesth. 2011;5:923-6. 23. takeuchi m, hirabayashi y, hotta k, inoue s, seo n. ropivacaineinduced grand mal convulsion after obturator nerve block. masui. 2005;54:1309-12. 24. akata t, murakami j, yoshinaga a. life-threatening haemorrhage following obturator artery injury during transurethral bladder surgery: a sequel of an unsuccessful obturator nerve block. acta anaesthesiol scand. 1999;43:784-8. 1511vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l digital tomosynthesis: an innovative tool for challenging diagnoses in urology alexis lacout,1 pierre yves marcy2 corresponding author: alexis lacout, md centre d’imagerie médicale 47, boulevard du pont rouge, 15000 aurillac, france. tel: +33 471 480050 fax: +33 471 485348 e-mail: lacout.alexis@wanadoo.fr received december 2012 accepted november 2012 1 centre d’imagerie médicale 47, boulevard du pont rouge, 15000 aurillac, france. 2 polyclinique les fleurs, service imagerie médicale, 332 avenue frederic mistral, 83190 ollioule, france. case report keywords:nephrolithiasis;radiography;tomography,x-raycomputed;methods;radiographic imageenhancement introduction digitaltomosynthesis(dts)allowsthevisualizationofdilatedrenalcavitieswith-outneedofcontrastmediuminjectionandbettershowsureteralandkidneystonesthanstandardabdominalx-ray.fromnowon,digitaltomosynthesisisindeedrevivaloftheold‘conventional’’tomographytechniquethatprogressivelyhasbecomeobsolete.thestronggrowthanddevelopmentofdigitalradiologyandplanesensorshasledto givebirthtothisinnovativeimagingtechnique,whichmaysoonbepartofthestandardinitial workupandfollow-upofpatientswithureteralandkidneystone. case report a60year-oldmanwasreferredtoourinstitutionforleftflankpainassessmentoccurringafter aleftrenalstonelithotripsy(figure1).ultrasonography(us)examinationrevealedthepresenceofbilateralintra-renalstonesaswellasadilationoftheleftrenalpyelocalycealcavities. however,noobstaclewasshownontheurinarytract.conventionalx-rayexamination(figure 1512 | 2)suggestedthepresenceofkidneystones.dts(sonialvisionsafire;shimadzuco.,kyoto,japan)(figure3)examinationoftheabdomenconfirmedtheintra-renallocationof thestonesthatwerealreadyshownonusandalsoformally disclosedthepresenceofthreeotherobstructivestonesinto the left ureter lumen.although dts has been performed withoutcontrastmediuminjection,thisinnovativetechnique waspronetodemonstratethedilationoftheleftpyelocalycealcavities. discussion dtsisatechnicalevolutionofconventionalgeometrictomography.itallowstheproductionofasmanyhighspatial resolutionslice-images(200μmintheacquisitionplane)as necessary following a single low-dose acquisition.(1) this technique uses a flat-panel detector and a computer-controlledmovingx-raytube.thepatientislayingonthetable, inthedesiredposition(supineorpronepositionwhenfrontal viewsarerequired,lateralpositionifsagittalviewsareneeded).breathholdisrequiredtoavoidmotionartifactsofthe patient.duringacquisition,thex-raytubemovesthrougha 40-degree(-20to+20degrees)circulararcsymmetricover thepatient.atthesametime,theplanesensorsynchronously movesinsidethetable.severalparameterscanbemodified: kv,ma,thenumberofpulsespersecond(x-rayemissionis discontinuousor‘‘pulsed’’),theduration(2.5to5s),center andtotalthicknessofthevolumeacquisition.medianslice thicknessisnotpreciselyquantifiable(abouttenmillimeter) butcanberoughlymodified(++,+,±,-,--).interestingly, specificalgorithmsallowreconstructionofslice-imagesparalleltothecentralprojectionthroughouttheentirevolumeof thepatient.aposterioripost-processingreformationscanbe producedatdifferentplacesintheacquisitionvolume,decreasingorincreasingthenumberofslicesatwill. dtsallowsanaccurateexplorationwithlowradiationdose exposurei.e. lowerthanwithcomputedtomography(ct) scan,(2)equivalenttotwostandardx-rayprocedures.(3) accordingtotheliteraturedata,aneffectivedoseisintheorder of0.85millisieverts(msv),tobecomparedto0.5msvwith digitalradiography,and2.5msvwithlow-dosectscan,and 12.6msvwithhigh-dosectscan.(4) however,majordrawbacksincludelowresolutionindensity oftomosynthesiscomparedtoctscan,andinabilitytoproducemultiplanar(planetoplane)reformations.indeed,the case report figure 1. computed tomography scan, frontal 11 mm thick maximum intensity projection reformation performed before lithotripsy, showing bilateral renal stones (arrows). figure 2. supine abdominal radiograph performed after lithotripsy of the left renal stone showing renal stones (arrows). note the anatomical superimpositions of colonic gas and faces. 1513vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l digital tomosynthesis in urology | lacout et al higherperformancesofdtscomparedtostandardx-ray intheevaluationofrenalstonesincludeitsveryhighspatial resolutionandtheabsenceofanatomicalsuperimpositions offeces.(3)inthenearfuture,dtsmaythusreplaceconventionalx-ray,atinitialworkupandinsomecasesatfollowup,thuslimitingexcessiveirradiationexposure.inaddition, dtsmaybemoreadvantageousthanctscanexamination fromamedico-economicpointofview. conflict of interest none declared. figure 3. abdominal digital tomosynthesis performed after left renal stone lithotripsy; (a) showing intrarenal stones (arrows) and the dilation of the left pyelocalyceal cavities (double arrow), (b) magnification shows three persistent obstructive ureteral stones despite previous left renal stone lithotripsy fragmentation (arrows). references 1. dobbins jt 3rd, mcadams hp. chest tomosynthesis: technical principles and clinical update. eur j radiol. 2009;72 :244-51. 2. koyama s, aoyama t, oda n, yamauchi-kawaura c. radiation dose evaluation in tomosynthesis and c-arm cone-beam ct examinations with an anthropomorphic phantom. med phys. 2010;37:4298306. 3. mermuys k, de geeter f, bacher k, et al. digital tomosynthesis in the detection of urolithiasis: diagnostic performance and dosimetry compared with digital radiography with mdct as the reference standard. ajr am j roentgenol. 2010;195:161-7. 4. mermuys k, de geeter f, bacher k, et al. digital tomosynthesis in the detection of urolithiasis: diagnostic performance and dosimetry compared with digital radiography with mdct as the reference standard. ajr am j roentgenol. 2010;195:161-7. urol_v03_no3_001_editorial.indd review articles urology journal vol 3 no 3 summer 2006 117 enuresis persisting into adulthood pejman shadpour, masoud shiehmorteza introduction: nocturnal enuresis is a very common finding in children to the extent that many families and caregivers, alike, may dismiss it as a developmental stage rather than a disease. persistence of nocturnal enuresis into adulthood, however, has received little discussion and is surrounded by fallacies. materials and methods: all existing literature cited in pubmed between 1970 and 2005 were reviewed using the search entries “nocturnal enuresis and adult*”. result: of the 220 papers reviewed, enuresis persisting into adulthood was covered in only 87. those aspects pertinent to this subset of patients were placed in focus. conclusion: in contrast to the numerous researches on childhood enuresis, persistent adulthood enuresis is an underdiscussed subject, distinct in a few aspects of its etiology and management described herein. urol j (tehran). 2006;3:117-29. www.uj.unrc.irkeywords: enuresis, adult, nocturia department of urology, hasheminejad kidney center, iran university of medical sciences, tehran, iran corresponding author: pejman shadpour, md department of urology, shaheed hasheminejad kidney center, vanak sq, tehran, iran tel: +98 21 8888 5028 fax: +98 21 8879 6540 e-mail: pshadpour@hkc.ir introduction nocturnal enuresis (ne) is a very common finding in children, to the extent that many families and caregivers, alike, may dismiss it as a developmental stage rather than a disease. currently, an estimated 5 to 7 million children in the united states have primary ne. a similar rate has been reported in other countries.(1) despite the spontaneous resolution rate of 15% per year, enuresis persists in 1.5% to 3% of the adult population.(2) this article reviews current information on primary ne persisting into adulthood, describes various aspects of its etiology and management, and provides an updated and comprehensive review of this disorder. definition according to the international children’s continence society (iccs), urinary incontinence denotes involuntary loss of urine that happens both day and night or in either portion.(3) nocturnal enuresis or common enuresis is defined as involuntary loss of urine that occurs only at night, specifically during sleep. based on the presence of a period of dryness, nocturnal enuresis is categorized as primary—a child who has never had a dry period for at least 6 months; and secondary—a child who has experienced at least 6 months of nighttime dryness. the criterion for the period required to meet this definition varies in the literature between 6 months and 1 year. based on the diagnostic and statistical manual of mental disorders-fourth edition (dsm-iv), a primary nocturnal enuretic patient is defined as an individual who has never established urinary continence, and secondary nocturnal enuresis is enuresis in adulthood—shadpour and shiehmorteza 118 urology journal vol 3 no 3 summer 2006 defined as a disturbance developed after a period of established urinary continence. in this paper, primary ne is defined as bed-wetting since birth. table 1 lists typical classification schemes for enuresis. epidemiology the prevalence of primary nocturnal enuresis (pne) in adults varies from 0.19% to 3.8% in different studies.(4-9) it is suggested that bias in reporting might have played a role in epidemiological surveys on the adolescent and adult population, for such patients may be reluctant to report that they suffer from ne. in 1943, levine(4) first reported that 1.2% of the army recruits were still bed-wetters at 18. between 1944 and 1954, additional prevalence studies were conducted on the recruits and estimated the prevalence of pne from 0.19% to 2.5%.(5-8) these variations result from applying different definitions for ne by the investigators. in addition, they have not included women in their studies; thus, it is of limited value to generalize the results beyond their study population. to clarify these issues, cushing and baller(9) performed a prevalence study among graduates and undergraduates. of 398 students participating in this study, 3.8% had pne. moreover, two prospective cohort studies were initiated focusing on ne persisting into adulthood. one swedish cohort study(10) was based on a questionnaire mailed to 1034 teenagers in 1995 who had previously been evaluated at age 7. the prevalence of pne was 0.7% in men and 0.6% in women at 17 years of age among the 736 respondents. the second cohort study was designed to determine the prevalence and natural history of incontinence among healthy adolescent school children.(11) beginning in 1994, urinary symptoms were obtained from 1176 school children at ages 11 to 12 years and again at 15 to 16 years. nocturnal enuresis was reported by 4.7% of children at 11 to 12 (3.5% in girls and 6.25% in boys) and 1.1% at 15 to 16 years old (0.8% and 1.6%, respectively). nocturnal enuresis was more frequent among boys in both age groups and day-wetting was more frequent in girls. more recently, two large population-based crosssectional studies have been performed to identify the characteristics of the pne in adults. in the netherlands, 13081 non-institutionalized adults (18 to 64 years old) were asked to participate in a study in january through march 1996.(12) of those approached, 11406 (87%) agreed to complete a personal questionnaire. the definition was based on bed-wetting once a month or more. their overall prevalence of ne was 0.5%. half of the enuretic men and 19% of the women had pne. there was no significant difference in the prevalence of ne between the age groups and sexes. the second study was a survey in hong kong.(13) in this study, 13086 people were contacted randomly and data were obtained by telephone interview. the response rate was 65%. the overall prevalence of pne was 2.35% (2.7% in men and 2% in women). fifty percent of the patients wetted their bed more than 3 nights per week and 26% every night. in addition, 18.4% of the enuretics also complained of daytime incontinence. in both reports, there was no significant difference in the prevalence of pne between the age groups. the authors concluded that in adults, ne showed no trend to spontaneous improvement as age increases. in addition, finding a high prevalence of severe ne, they suggested that pne persisting into adulthood represents a more pronounced and refractory form of the condition. the studies on the prevalence of pne in adults are summarized in table 2. table 1. classification schemes for enuresis basis of classification classes time of enuresis nocturnal enuresis: passing urine while asleep diurnal enuresis or incontinence: leakage of urine during the day other symptoms monosymptomatic or uncomplicated nocturnal enuresis: normal voiding occurring at night in bed in the absence of other symptoms referable to the urogenital or gastrointestinal tract polysymptomatic or complicated nocturnal enuresis: bed-wetting associated with daytime symptoms such as urgency, frequency, chronic constipation, or encopresis previous periods of dryness primary enuresis: bed-wetting in a child who has never been dry secondary enuresis: bed-wetting in a child who has had at least six months of nighttime dryness enuresis in adulthood—shadpour and shiehmorteza urology journal vol 3 no 3 summer 2006 119 in summary, depending on whether data have been accumulated by direct interview or hand-in questionnaire, women have been included or not, etc, results on the prevalence of the adulthood enuresis have varied, ranging from 0.5% to 2.7%. etiology from an etiologic standpoint, ne is a heterogeneous disorder and several pathophysiological mechanisms contribute to its initiation, severity, and degree of associated symptoms. numerous etiologic factors have been investigated and various theories have been proposed. the most likely explanation for ne is a complicated interplay among the nocturnal urine production, the nocturnal functional bladder capacity, and the sleep patterns. all adults are at risk of ne if nocturnal diuresis exceeds the functional bladder capacity, provided that they are not awakened by imminent bladder contraction or the strong desire to void. evidence suggests that the pne persisting into adulthood may differ from that of children in its underlying pathophysiological mechanisms. a higher incidence of severe forms of ne plus a very low rate of spontaneous cure support the notion of a more complex pathology in adults. genetics nocturnal enuresis is a complex disorder in which both genetic and environmental factors (somatic and psychosocial) play a role, although at proportionally different contributions. in addition to genetic/ environmental interactions, enuresis appears to be under the influence of multiple genes.(14) enuresis has been suspected of having a genetic component at least since 1935, when frary found a higher incidence of enuresis in affected relatives than the general population.(15) frary’s statement was confirmed by studies demonstrating an increased prevalence of enuresis among the first-degree relatives of the enuretic subjects.(16,17) in one review, it was found that the risk for ne was 77% if both parents were affected. the risk declined to 43% when only one parent had a history of enuresis, and to 15% when neither parent was enuretic.(18) in 1997, von gontard and colleagues found a positive family history in 63.2% of patients, with 22.2% of fathers, 23.9% of the mothers, and 16.5% of the siblings being affected.(19) in a cross-sectional epidemiological study, yeung and colleagues evaluated characteristics of adults with pne in hong kong and found a positive family history in 13.1% of subjects.(13) another study by nappo and associates on 107 enuretic adolescents (mean age, 15.3 years; range, 13 to 23 years) identified up to 80% of adolescents with ne to have a positive family history of ne.(20) there was no difference in the prevalence of positive family history between primary and secondary enuretics, as in von gontard’s study.(19) the exact mechanisms underlying this family aggregation are unknown. according to a study by arnell and coworkers in 1997, about 45% of the ne cases are compatible with an autosomal dominant mode of inheritance.(21) in 1995, birch and miller evaluated the bladder function over 3 generations in a family of which two members had undergone clam enterocystoplasty for refractory pne.(22) eight members had the history of pne persisting into adolescence and 4 members (age range, 20 to 39 years) had pne with urodynamically proved detrusor table 2. studies on prevalence of primary nocturnal enuresis* authors year of publication patients’ age, y prevalence levine (4) 1943 18 1.2% wadsworth (5) 1944 na 0.7% to 2.0% turner and taylor (6) 1974 na 0.7% to 2.0% thorne (7) 1944 18 1.0% to 2.5% bieger (8) 1954 na 0.2% cushing and baller (9) 1975 na 1.6% to 3.8% hellstrom and colleagues (10) 1995 17 0.7% swithinbank and colleagues (11) 1998 15 to 16 1.1% hirasing and colleagues (12) 1997 18 to 64 0.5% yeung and colleagues (13) 2004 16 to 40 2.3% *na indicates not available. enuresis in adulthood—shadpour and shiehmorteza 120 urology journal vol 3 no 3 summer 2006 instability. the authors concluded that detrusor instability had, at least in part, a genetic basis with autosomal dominant mode of transmission in family members with a history of current or past pne. this finding was in agreement with previous studies that had suggested the most common mode to be an autosomal dominant transmission.(23) in summary, adulthood enuresis is a hereditary disease like its childhood counterpart, and it may follow an autosomal dominant genetic pattern with a strong environmental influence. bladder physiology debate is ongoing about the role of abnormalities of bladder function in ne. the results of urodynamic studies suggest that ne is different in adults and children. however, the incidence of anatomical and functional bladder abnormalities in enuretic children is similar to that in the normal population.(24,25) in 1994, robertson and colleagues assessed the bladder function in 17 healthy volunteers and detrusor instability was found in 17% on filling cystometry, filling at a rate of 50 ml/min.(26) wyndaele reported an incidence of 11% among 38 volunteers with a negative urologic history, as well.(27) on the contrary, the incidence of urodynamic abnormalities on conventional assessment in adults with pne lies between 28.8% and 93% in different studies, much higher that that in normal volunteers. in one filling cystometric analysis of 39 adults with enuresis, the rate of urodynamic abnormalities was found to be 28.2%, and the most common abnormality was detrusor instability.(28) in another study, yeung and coworkers reported a greater rate of urodynamic abnormalities in the adults with pne.(29) again, detrusor overactivity was the most common finding in 93% of the patients, more often moderate to severe. the high rate of detrusor instability in this study was in part due to the evaluation of the selected patients with moderate or severe enuretic symptoms and mild cases were not included in this study. of the 30 patients with moderate or severe pne, 16 (53%) had also significantly reduced bladder capacity (less that 300 ml). in addition, 73% of patients had urodynamic evidence of functional bladder outflow obstruction including dysfunctional voiding and detrusor sphincter or detrusor pelvic discoordination. the authors concluded that pne in adults is not only a psychologically disturbing condition, but also a urological disorder with a significant underlying bladder dysfunction that warrants special attention. these results and the work of preceding investigators suggest that pne in adults is a cause rather than the result of psychological disturbance. detrusor instability has its impact on both filling properties of the bladder as well as symptoms. wadie reported the urodynamic evaluation of 52 enuretic adults.(30) detrusor instability was recognized in 20 (38.5%) of those enrolled in the study. interestingly, the author found a significant effect of detrusor instability on both bladder capacity and compliance. the average capacity value was approximately 140 ml lower in the patients with detrusor instability compared with the patients with a stable bladder. similarly, in another urodynamic study performed by yucel and associates, differences in the maximal bladder capacity and compliance between the patients with and without instability were statistically significant and all hypocompliant cases had detrusor instability.(31) interestingly, however, in both studies the overall cystometric capacity and compliance in patients with persistent pne had fallen to the reference range for adults as depicted by wyndaele.(27) in addition, voiding pressure had been normal in the patients. nighttime and daytime bladder capacities are not equal and reduction in the nighttime bladder capacity may be an important cause of ne.(32) a study on the overnight natural filling cystometries in 26 patients (age range, 8 to 36 years) with resistant pne supported this statement.(33) of 16 patients who were healthy on conventional urodynamic assessment, 10 showed involuntary detrusor contraction during the night. in conclusion, urodynamic analysis of the bladder function and coordination in enuretic adults has been in stark contrast to children. in adults, we may expect a 38.5% instability on conventional urodynamics which can grow to 77% if sleep urodynamics are included. nocturnal urine production a circadian rhythm of urine production is developed from early childhood with a marked nocturnal reduction in diuresis to about 50% of the daytime levels.(34) it has been postulated that normal enuresis in adulthood—shadpour and shiehmorteza urology journal vol 3 no 3 summer 2006 121 development may include the establishment of a circadian rhythm in release of the hormones that regulate free water or solute excretion.(35,36) such a normal circadian variation in urine production is absent in a significant proportion of the patients with monosymptomatic pne (mpne). these patients produce large quantities of dilute urine at nights which exceed the bladder capacity. failure of such a child to wake up results in an enuretic episode.(37) in 1951, mills first provided evidence of nocturnal polyuria in some children with ne and suggested that nocturnal urine production exceeding the bladder capacity might play a role in the pathophysiology of ne.(38) this finding led to many more studies in the following decades documenting nocturnal polyuria and its underlying causes. the circadian rhythm of various urine output modulating hormones has been investigated. most hormone levels have proved to be normal except for arginine vasopressin (avp). abnormal diurnal rhythm of avp with lack of the normal nocturnal rise has been reported in children with ne,(39,40) and seems to correlate with nocturnal polyuria as well as response to the avp analogue (desmopressin).(41,42) a subgroup of the patients with ne who respond to desmopressin generally has normal functional bladder capacity and increased nocturnal urine output.(43) in healthy adults, urine production is roughly 70 ml/h to 80 ml/h while awake and 30 ml/h to 40 ml/h while asleep. similar to enuretic children, adults with pne have an increased production of urine relative to the functional bladder capacity which plays an important role in the pathophysiology of enuresis. however, the underlying mechanism for this abnormal diurnal rhythm of urine production seems to be different in adults. with aging, the rate of nocturnal urine production increases while total daily urine production remains constant. in addition, concentrating ability of the kidney and activity of the renin-angiotensin axis both decrease.(44) it seems that the circadian rhythm of avp declines with age, leading to similar hormone levels during day and night.(45) in 1998, hunsballe and colleagues reported the results of a study comparing nocturnal urine output in 24 patients (mean age, 21.5 years; range, 15 to 37 years) who had mpne with a control group of 9 healthy subjects.(46) patients were subdivided into desmopressin responders and nonresponders. urine outputs demonstrated an abolished circadian rhythm only in the desmopressin responding group with nocturnal polyuria and poorly concentrated urine at night. in contrast, desmopressin nonresponders had a significant variation in urine production similar to healthy controls with a decrease in urine output from day to night. interestingly, avp did not increase in either controls or desmopressin nonresponding enuretics at night, which further confirmed the result of previous studies pointing to the lack of diurnal variation in avp in older healthy adults. on the other hand, no evidence of oscillation in avp was encountered in desmopressin responders, either, and nocturnal avp levels were again similar to healthy adults. in another study, hunsballe and coworkers compared urine volume and plasma avp levels before and during a 24-hour water deprivation test in adults with pne.(47) a significant decrease in urine output was noted after water deprivation in enuretic patients. again, plasma avp levels were normal in enuretic adolescents and adults regardless of response to desmopressin. moreover, magnetic resonance imaging characteristics of the pituitary gland in 8 adults suffering from pne have demonstrated no detectable pathology.(48) these findings led to the conclusion that unlike enuresis in children, nocturnal polyuria in adults has not been related to nocturnal hyposecretion of avp, and nocturnal polyuria in adults may result from reduced renal tubular sensitivity to endogenous avp or abnormal excretion of solutes. in summary, the normal circadian rhythm of avp production fades with age, and nocturnal polyuria, still an important factor in adult enuresis, seems to result from non-avp–mediated mechanisms in this group of patients. sleep and central nervous system function neither nocturnal polyuria nor diminished functional bladder capacity adequately explains why patients with ne do not wake up to void. a problem with arousal is therefore a prerequisite for enuresis to occur. controversy has existed about the role of sleep disturbance in bringing about the enuretic enuresis in adulthood—shadpour and shiehmorteza 122 urology journal vol 3 no 3 summer 2006 event. over the past three decades, sleep investigation among nocturnal enuretic patients has evolved steadily. it is still believed that enuretics are deep sleepers. results of the large survey in hong kong showed significantly higher incidence of sleep disturbances in adults with pne compared to healthy subjects.(13) difficulty in entering the sleep state and staying asleep, and early awakening were all more frequent in enuretic adults than in normal controls. in other studies, however, abnormality in the sleep pattern of enuretic patients has not been noted.(49) it has also been showed that bed-wetting can occur during all sleep stages.(49) these findings suggest that pne may be associated with a problem of arousal from any stage of sleep rather than the depth of sleep. lack of success in finding any abnormalities of sleep pattern in some previous studies could be in part due to inaccurate measurement of sleep staging. currently, a classic polysomnographic scoring technique according to the criteria defined by rechtschaffen and kales(50) is being used in sleep studies. in 2000, hunsballe compared sleep patterns in 11 patients with pne (mean age, 23.0 years; range, 15 to 49 year) with 10 healthy age-matched controls.(51) conventional polysomnography and a computerized electroencephalographic power analysis were used. an increased delta-wave energy was found among enuretic patients compared to healthy controls, reflecting abnormally deep sleep in adolescents and adults with mpne. they concluded that “manual sleep scoring might inadequately reflect the sleep process.” moreover, no sleep-modulating effect of desmopressin was found in this study. this finding was in contrast to the results of previous studies suggesting the sleep-modulating effect of avp.(52,53) in summary, sleep factors are the common pathway in translating production/storage discord into enuresis, and difficulty in arousing from any stage of sleep is disputably influenced by avp. management primary care awareness “in most european countries, primary nocturnal enuresis is not necessarily considered as a disease per se, particularly by the medical community; as a consequence, there is no specific education at medical school, and a poor involvement from the practitioners.(32)” a study conducted among adolescents and young adults (mean age, 15.3 years; range, 13 to 23 years) has shown 20% of enuretic adolescents to have never consulted a doctor about their problem.(20) among enuretic adolescents consulting a specialist, more than 40% received no therapy. most consulted caregivers were pediatricians. in the study of yeung and associates, the percentage of adults with pne who had never sought medical attention or therapy in hong kong was found to be 37% among 47 patients with pne (mean age, 20 years; range, 16 to 43 years).(29) in addition, the incidence of depression and lowered self-esteem was significantly higher in enuretic adults. about one-third of the patients believed that this condition had negatively affected their job choice, work performance, and social activities; and 23% felt it had an impact on their family life and making friends for either sex. similarly, results of the survey preformed by hirasing and colleagues showed that ne was associated with a great psychosocial impact.(12) of 57 patients with ne, one-third were concerned about bed-wetting and one-third were depressed. due to bed-wetting, 33% of the patients were reluctant to go on holidays and 23% said it complicated their relationships. despite such a negative impact on their life, 40% of the patients in this study had never consulted a care provider. in summary, evidence attests to the great impact of adult enuresis on people’s lives, and at the same time, it points to the need for enhancing awareness about the problem and treatment options among the public and health care providers, alike. evaluation a similar assessment as for children is justifiable as the initial step in evaluating adults with pne. initial assessment should focus on distinguishing between the possible definable and perhaps treatable causes of complex bed-wetting in enuretic adults. in such patients, the age of onset, length and circumstances of dry spells, number and timing of episodes of ne, sleep habits, and psychosocial situation should all be elicited. the patient should also be asked about any history of urinary tract infection, presence of daytime enuresis in adulthood—shadpour and shiehmorteza urology journal vol 3 no 3 summer 2006 123 voiding symptoms, and frequency and consistency of bowel movements. the physician should consider pne as a diagnosis of exclusion, and all other causes of bed-wetting must be ruled out. a list of urological causes for nonmonosymptomatic bed-wetting and clues to their diagnosis is provided in table 3. physical examination in a patient suffering from ne might provide clues to a structural problem as the cause. it may reveal tell-tales of neurological abnormality. a thorough genital examination should be performed in all patients for possible anatomical abnormalities such as epispadias and ectopic ureter. the main utility of physical examination lies in guiding further workup by excluding or suggesting underlying bladder dysfunction. in children, a carefully obtained history, physical examination, and a routine urinalysis are often sufficient for establishing the correct diagnosis and determine whether nocturnal polyuria or reduced functional bladder capacity are present. further urodynamic investigation and imaging are indicated only for patients in whom day symptoms present or when conventional treatment fails.(32) however, in enuretic adults, whether having daytime symptoms or not, additional urodynamic evaluation seems necessary at an early stage. in urodynamic evaluation of 30 patients with pne, yeung and colleagues found more than 90% of the patients to have detrusor overactivity, while only 38% had daytime urinary symptoms.(29) in addition, 6.7% of patients had a previously undiagnosed lesion causing some form of anatomical bladder outflow obstruction, 1 with congenital obstruction from posterior urethral membrane, and 1 with moormann’s ring. in the study performed by wadie, 35% of patients with detrusor instability had neither diurnal urgency nor incontinence.(30) these urodynamic studies, together with the fact that pne of adults represents a more pronounced and refractory form of enuresis, suggest that urodynamic evaluation and contrast imaging of voiding function should be performed as a part of the initial workup in all adults with pne. treatment the treatment approach to enuresis is controversial in large part due to the lack of consensus on the exact cause of enuresis, because so many factors either alone or together may contribute to this condition. generally, treatment can be divided into two broad categories: nonpharmacologic and pharmacologic. nonpharmacologic treatment of enuresis includes motivational therapy, behavior modification (conditioning therapy), bladder-training exercises, table 3. urologic causes for nonmonosymptomatic bed-wetting* *didmoad indicates diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. disorder clues for diagnosis causes storage dysfunction overactive bladder increased frequency, urgency, urge incontinence, history of wetting during the afternoon nap, history of wetting more than once per night idiopathic detrusor overactivity, neurogenic detrusor overactivity (eg, myelomeningocele, tethered cord syndrome, or spinal cord injury), urinary tract infection, polyuria (eg, diabetes mellitus, diabetes insipidus, or polyuric renal failure), didmoad syndrome sphincter bypass continuous dribbling between voids ectopic ureter sphincter incompetence continuous dribbling between voids, stress incontinence, observed on physical examination urethral anomaly (epispadias or extrophy), spina bifida, sacralagenesis, iatrogenic( eg, post prostatectomy) voiding dysfunction sphincter-active voiding overflow incontinence, voiding with a poor stream or strain, staccato voiding primary sphincter overactivity, previous urinary infection poorly contracting bladder overflow incontinence, voiding with a poor stream or strain, staccato voiding, infrequent voiding autonomic neuropathy (eg, diabetes mellitus, meningo-myelocele), lazy bladder urethral stricture overflow incontinence, voiding with a poor stream, or straining, observed on physical examination congenital (eg, posterior urethral valves, cobb’s collar), acquired (eg, postcircumcision, balanoposthitis, traumatic) elimination dysfunction constipation, encopresis spinal cord abnormality enuresis in adulthood—shadpour and shiehmorteza 124 urology journal vol 3 no 3 summer 2006 psychotherapy, diet therapy, and hypnotherapy. based on the fact that ne may result from nocturnal polyuria, small functional bladder capacity, and decreased arousal response to the full bladder, pharmacologic treatment modalities can be defined under 3 subsets. to regulate the sleep-awake center in the brain, amphetamine, imipramine, and diazepam are used. calcium channel blockers, prostaglandin inhibitors, and α-adrenoreceptor inhibitors are utilized for pathological conditions of bladdersphincter complex, and desmopressin is meant to induce antidiuretic effect at the kidney level. recent studies have shown that many of these drugs have different mechanisms of action, and division into these subgroups may therefore be inaccurate. these drugs have been used with varying degrees of success, and many studies provide supporting evidence for each approach. however, much of these data comes from enuretic children, and evidence for or against the use of different treatment modalities in the enuretic adult is limited. alarm therapy alarm therapy is currently recommended as the first choice for children suffering from ne.(32) there is a good deal of evidence to support alarm therapy as the most effective treatment with reproducible rate and durable results in enuretic children, achieving dryness in more than 50% of patients.(54,55) moreover, on the long run, alarm therapy would appear to be the most clinically effective and cost-effective intervention.(56,57) unfortunately, treatment with bed-wetting alarms has a dropout rate of 10% to 30%.(58) to achieve optimal results, alarm therapy requires a motivated patient and family and significant commitment of effort and time.(32) these considerations make alarm therapy a less favorable choice in enuretic adolescents and adults. studies have shown that most enuretic adults prefer not to use alarm therapy or discontinue it very soon. in a large survey involving 11 406 noninstitutionalized adults (age range, 18 to 64 years), the number of patients who had ever tried the alarm was very low (about 7%) among 57 adults with ne.(12) similarly, nappo and colleagues reported on characteristics of enuretic adults in italy(20); of 107 patients suffering from ne, only 8 had tried alarm therapy after desmopressin failure. two discontinued therapy and stopped it very soon, one due to discomfort and not awakening and the other (an obese patient) due to frequent false alarm caused by perspiration. the main reason for low compliance with alarm therapy in adolescents and young adults seems to be the time it is required for alarm therapy to take effect. many patients request for a treatment modality with a rapid action. in addition, they believe that alarm therapy would disrupt others’ sleep and/or make their private problem public. it has been shown that adults who use the alarm (even those who are cured) recall the treatment period as the worst time of their life.(34,59) despite the high dropout rate in adults, evidence still suggests that alarm therapy enjoys a comparable success rate in compliant patients. an uncontrolled trial of patients with mpne was conducted by vandersteen and husmann to determine the efficacy of alarm therapy versus medical therapy.(60) in this study, 29 patients (median age, 20 years; range, 18 to 33 years) were treated with desmopressin, alarm therapy, and imipramine, consecutively. patients who remained incontinent with the maximum dose of desmopressin or whose ne returned after weaning desmopressin were treated with an enuretic alarm system. two-thirds of the patients were continent on desmopressin for 6 months, of those only 7% remained continent when weaned from the medication. on the other hand, in another study, alarm therapy had much lower initial success rate (33%), but this response was durable and all patients remained continent at 18 months’ follow-up. although the patients were informed about the importance of perseverance, 56% had discontinued therapy within 6 weeks. the investigators attributed the low success rate to noncompliance. in the complier group, success was 75%, very similar to the 79% rate observed in the compliant children.(61) it was concluded that children and adults respond equally well to alarm therapy if they adhere to the treatment protocol. the effect of alarm therapy can be enhanced by adding behavioral components such as arousal training, overlearning, full spectrum home treatment, and dry-bed training (dbt). enuresis in adulthood—shadpour and shiehmorteza urology journal vol 3 no 3 summer 2006 125 dry-bed training refers to regimens that include enuresis alarm, waking routines, positive practice, cleanliness training, bladder training, and rewarding, in various combinations. developed by azrin and associates,(62,63) it is probably the most successful therapy for children of different ages and is usually tried as the last resort for resistant patients after failing on simple alarm and pharmacotherapy.(64) in 2 studies by von son and colleagues on 9 patients treated with dbt, continence (dry during for consecutive weeks) was achieved between 4 and 21 weeks after the first treatment. relapse occurred in 3 patients after complete response and in 4 during the 6-year follow-up. of the patents with recurrence, 1 received a booster training to achieve continence and 1 became continent after using desmopressin.(65,66) the success and relapse rates were not significantly different between primary and secondary enuretics. no relapse during dbt was the only predictor of further relapses. age, gender, type of ne (primary versus secondary), and reported lighted or deep sleep were not identified as predictors of relapse. in summary, conditioning by the alarm and behavioral modification suffer from great dropout due to being effort intensive and time consuming. nevertheless, these methods retain their high efficacy and durability in enuretic adults, too. desmopressin desmopressin, a synthetic analogue of avp, results in increased reabsorption of water by the kidney, forwarding a smaller volume of more concentrated urine to the bladder and reducing 2-hour urine production.(67) desmopressin is 2000 to 3000 times more potent than avp and its duration of effect is also 5 times longer.(68) the antidiuretic effect of desmopressin is mediated through the v2 receptor acting on collecting ducts of the kidney.(69) by a yet unknown mechanism, desmopressin triggers the redistribution of water channel (aquaporin-2) into the apical membrane.(70) it has been suggested that its beneficial effect on enuresis is not entirely due to its antidiuretic activity, but this needs further proof. in a human study performed by born and colleagues, intravenous infusion of avp caused significant decrease in rapid eye movements at sleep and subjects woke up easier.(52) the authors concluded that enuretic patients may benefit from this effect of desmopressin on the sleep-awake center. in addition, it has been shown that desmopressin might interact with the serotonergic system.(71,72) desmopressin has been utilized in adults in both forms of nasal spray (20 µg/spray) and oral tablet (0.2 mg). the usual dose is 20 µg to 40 µg, intranasal, or 0.2 mg to 0.4 mg, oral, at bedtime regardless of age or weight.(67) it has no vasopressor or smooth muscle activity in the therapeutic dose range, and its effect lasts for 7 to 12 hours.(69) desmopressin is the first-line pharmacotherapy agent for ne in children,(73) with a partial (50% to 90% reduction in wet night) and full (at least 90% reduction) response rate ranging from 10% to 90%.(74,75) it produces a more rapid improvement than alarm therapy (reduction of urine output on the first night of therapy). however, these benefits are temporary, with a high relapse rate ranging from 50% to 100% once the treatment is discontinued.(76,77) trials in adults with pne have yielded comparable outcomes with studies in children. in a randomized, double-blind, cross-over trial of 25 patients resistant to alarm therapy (age range, 11 to 21 years) on desmopressin 200 µg/day to 400 µg/day for 24 weeks, stenberg and lackgren found that a titrated dose of oral desmopressin in comparison with placebo was associated with a reduction in the number of wet nights per week.(78) in addition, 400µg tablets were found to be more effective than 200µg ones in ne. the reported efficacy of this drug in the treatment of ne persisting into adulthood varies partly, because the study population is not always homogenous, and the prevalence of voiding disorders is not always reported. monosymptomatic pne is a different clinical entity from enuresis associated with diurnal voiding disturbance, and the study population should therefore be distinct to correctly evaluate drug efficacy. in 1996, janknegt and coworkers reported the results of a randomized multicenter trial in 66 patients with pmne (mean age, 19.4 years; range, 12 to 45 years) who received either desmopressin, 200 µg or 400 µg, for 4 weeks followed by 12 weeks of open-labeled treatment with desmopressin, 400 µg.(79) fifty-seven percent of the patients responded completely to desmopressin. the difference between the 4 weeks’ treatments with 200 µg and 400 µg enuresis in adulthood—shadpour and shiehmorteza 126 urology journal vol 3 no 3 summer 2006 of desmopressin was not significant. however, patients who initially received 200 µg experienced an additional decease in the number of wet nights after receiving 400 µg of desmopressin. similarly, vandersteen and husmann, treating 29 patients with pne (median age, 20 years; range 18 to 33 years), reported a 66% full response rate (no or one wet night per month) under desmopressin therapy.(60) however, the benefit of desmopressin was temporary with 93% relapse from 3 days to 6 weeks after discontinuation of desmopressin. nocturnal polyuria and a low nocturnal urine osmolality are characteristic of children with enuresis that respond favorably to the treatment with desmopressin.(46) similarly, the response to desmopressin in enuretic adults has been shown to be related to nocturnal polyuria. in 1998, hunsballe and colleagues evaluated the treatment response to desmopressin in 24 patients (age range, 15 to 37 years) with mpne and compared them with 9 healthy subjects (age range, 24 to 31 years).(46) the results demonstrated a significantly high pretreatment nocturnal urine volume in desmopressin responders in comparison with nonresponders and controls. the urine osmolality was also significantly lower in desmopressin responders. daytime values of urine output and urine osmolality did not differ significantly among the groups. in children, a better response to desmopressin has been found in patients with larger bladder capacities.(80) a study of 20 pne adult patients (mean age, 27.1 years; range, 20 to 42 years) revealed that response to desmopressin was not related to the urodynamic profile. of 10 patients responding to desmopressin, 6 (60%) had normal urodynamic profiles and 4 (40%) had detrusor instability and/ or hypocompliance.(31) in addition, the relapse rate was also not related to the urodynamic profile. a study of 107 pne adults demonstrated no association between response to desmopressin and age, gender, family history, or severity of ne in adults.(20) some controversy exists as to whether a family history of ne is a positive predictor for good response to desmopressin or not.(81) the results of numerous clinical trials have shown desmopressin to be generally well tolerated even during long-term treatment (1 year or more) and associated with a low incidence of adverse events.(32) side effects appear to be dose related, and temporary cessation of the drug commonly leads to their resolution.(82,83) in a study involving 7 patients with pne (mean age, 17.7 years; range, 10 to 26 years) long-term desmopressin therapy (mean duration, 13 months; range, 4 to 24 months) was not associated with any abnormalities in hematological, biochemical, and hormonal parameters examined in the study.(84) adverse effects of desmopressin include headache, tinnitus, sore throat, dizziness, nausea, abdominal pain, elevated blood pressure, and local irritation by using intranasal administration such as rhinorrhea, nasal congestion, epistaxis, and ulceration. the major but rare adverse effect of desmopressin is water intoxication with severe hyponatremia which occurs mostly in children. only 5 cases have been reported in adults with pne under therapy with desmopressin.(85) their desmopressin dose ranged from 20 µg to 80 µg, daily, and serum levels of sodium ranged from 114 mmol/l to 124 mmol/l. seizures developed in most patients. the common history leading to this serious side effect is a considerable intake of water while taking desmopressin.(85) to minimize this risk, it has been recommended that daily fluid intake should be limited to 1 liter in a healthy 70-kg adult taking desmopressin.(86) it is suggested that the intake of all fluids be restricted to the minimum tolerable amount within the 12 hours following administration, because the effect of desmopressin usually lasts 6 to 12 hours. serum sodium levels should be measured in patients taking the drug 24 to 48 hours, 1 week, and 1 month after beginning treatment. in addition, it should be used cautiously in disease states in which rapid increase in extracellular fluid may impose risks (eg, in angina, hypertension, and heart failure). the drug is likewise prohibited in patients with acute renal failure.(69) in summary, desmopressin remains the most rapidly acting tool for symptomatic control of adult enuresis and has a reasonable safety profile in this group; however, it is notorious for posttreatment recurrence. lastly, those patients in whom urodynamic study and imaging suggest significant bladder dysfunction deserve specific medical treatment tailored to their specific type of aberration (including antimuscarinics, smooth muscle relaxants, botulinum toxoid, and enuresis in adulthood—shadpour and shiehmorteza urology journal vol 3 no 3 summer 2006 127 clean intermittent catheterization as required). nonresponders would naturally be considered for augmentation cystoplasy. discussion of these subjects is beyond the scope of this article. references 1. miller k. concomitant nonpharmacologic therapy in the treatment of 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221urology journal vol 4 no 4 autumn 2007 ureteroscopic and extracorporeal shock wave lithotripsy for rather large renal pelvis calculi kamyar tavakkoli tabasi, mehri baghban haghighi introduction: the aim of this study was to compare the results and complications of extracorporeal shock wave lithotripsy (swl) plus retrograde ureteroscopic lithotripsy using laser and pneumatic lithotriptors with swl monotherapy for renal pelvic calculi between 2 cm and 3 cm. materials and methods: a total of 55 patients with 2to 3-cm pelvic calculi were assigned into groups 1 and 2, including 22 and 33 patients, respectively. patients in group 1 first underwent laser or pneumatic lithotripsy and insertion of a double-j ureteral catheter and then underwent swl 2 to 4 weeks thereafter. in group 2, the patients underwent swl after double-j ureteral catheter insertion. the stone-free rate, complications, and cost effectiveness were evaluated 3 months postoperatively. results: five patients (22.7%) in group 1, had their calculi completely fragmented after ureteroscopy and retrograde lithotripsy without any need for further swl. in 9 patients (40.9%), after a single session of swl, and in 3 (13.6%), after 2 sessions, fragmentation was completed. in group 2, successful treatment was achieved after 1 and 2 swl sessions in 6 (18.2%) and 8 (24.2%) patients, respectively. the stone-free rate was significantly higher in the patients of group1 than those in group 2 (77.3% versus 42.4%, respectively; p = .01). the period of anesthesia was 23.1 minutes (during ureteroscopy) in group 1 and 13.2 minutes in group 2 (during cystoscopy or ureteroscopy and insertion of ureteral catheter). no significant complication was reported in neither of the groups. the mean costs of the treatment were us $ 400 and us $ 370 in groups 1 and 2, respectively. conclusion: ureteroscopic lithotripsy before swl is a rational method for the treatment of the rather large renal pelvic calculi with fairly acceptable costs. urol j. 2007;4:221-5. www.uj.unrc.ir keywords: urinary calculi, lithotripsy, ureteroscopy department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran corresponding author: kamyar tavakkoli tabasi, md department of urology, imam reza hospital, mashhad, iran tel: +98 915 311 6149 fax: +98 511 8591057 e-mail: kamiartt@yahoo.com received september 2006 accepted september 2007 introduction kidney calculi with pain, infection, or urinary outflow obstruction usually need complete calculus removal. however, many calculi without any of these problems are nowadays treated thanks to the availability of minimally invasive methods and instruments.(1) kidney calculi are commonly treated by extracorporeal shock wave lithotripsy (swl) or percutaneous nephrolithotomy (pcnl).(1-4) size, location, and composition of the calculi are of the critical factors affecting the method of treatment.(1) although most authors prefer pcnl for the calculi greater than 2 cm, swl is another accepted method for these calculi subject to insertion of a ureteral catheter.(5,6) another optional method is ureteroscopic lithotripsy using a rigid or flexible ureteroscope. the energy for lithotripsy in this case may be supplied by ultrasound, ureteroscopic and shock wave lithotripsy for renal pelvis calculi—tavakkoli tabasi and baghban haghighi 222 urology journal vol 4 no 4 autumn 2007 pneumatic or laser sources. however, ureteroscopic lithotripsy is not as common as the previously mentioned methods.(7) using a combination of this method with swl has already been suggested by some authors as an alternative for pcnl with encouraging results.(8,9) the aim of our study was to compare ureteroscopic lithotripsy plus swl with swl monotherapy for the treatment of the 2to 3-cm pelvic calculi. materias and methods in a clinical trial carried out between september 2003 and september 2005, we evaluated 124 patients referred to our center with 2to 3-cm renal pelvic calculi. patients who were not willing to or could not undergo pcnl due to their preferences or medical contraindications were selected to enroll in the study. medical limitations for performing pcnl included cardiovascular or respiratory problems which did not let a prone position or prolonged general anesthesia. kidney calculus was diagnosed by ultrasonography, plain abdominal radiography, and intravenous urography. also, urinalysis, urine culture, and renal function tests were performed before the procedure. patients with a surgical history or a history of a previous swl, active urinary infection, anatomic abnormalities such as horseshoe kidney or duplicate renal system, and previous metabolic problems were excluded. finally, 66 patients entered the study and provided written consent. the patients were assigned into groups 1 (31 patients) and 2 (35 patients) based on their preferences. in group 1, the patients underwent general anesthesia with propofol after 8 hours of fasting. in the lithotomy position, a 5-f semirigid or flexible ureteroscope (henke-sass wolf gmbh, tuttlingen, germany) was passed into the ureter and after visualizing the pelvic calculus, pneumatic or laser lithotripsy (ems, dallas, usa and deka, italy; respectively) was used to fragment the calculus (figure). then, a ureteral catheter was inserted and swl (mpl 9000, dornier, munich, germany) was performed if there were residual calculi greater than 7 mm. in group 2, a ureteral catheter was inserted under general anesthesia, while the patient was secured in the lithotomy position. two weeks later, swl was performed once for these patients. both groups were followed up 2 to 4 weeks postoperatively using ultrasonography and plain abdominal radiography. the procedures were considered to be completely successful if there were no calculi or calculi smaller than 5 mm. otherwise, left, a 3-mm calculus is shown in the pelvis. right, the calculus is shown in the pelvis after ureteroscopy and 1 session of shock wave lithotripsy. ureteroscopic and shock wave lithotripsy for renal pelvis calculi—tavakkoli tabasi and baghban haghighi urology journal vol 4 no 4 autumn 2007 223 swl was repeated for the patients of both groups and follow-up by ultrasonography and abdominal radiography was done 2 to 4 weeks thereafter. the costs of the procedures were calculated and compared between the two groups. results of the 66 patients, 9 in group 1 and 2 in group 2 were lost to follow-up. overall, records of 22 and 33 patients in groups 1 and 2 were analyzed, respectively. the mean ages of the patients in groups 1 and 2 were 28.7 ± 12.9 years (range, 14 to 59 years) and 29.4 ± 9.1 years (range, 17 to 60 years), respectively. the mean size of the calculi was 2.73 cm (range, 2.53 cm to 2.98 cm) and 2.76 cm (range, 2.54 cm to 2.99 cm) in the patients of groups 1 and 2, respectively. no significant difference was noted between the patients’ ages. in group 1, entering the pelvis and visualizing the calculus by ureteroscope was unsuccessful in 2 patients (9.1%). in 5 patients (22.7%), the calculi were completely fragmented after ureteroscopy and retrograde lithotripsy without any need for further swl. in 9 patients (40.9%), after a single session of swl, and in 3 (13.6%), after 2 sessions, fragmentation was completed. in the remainder, even after 2 swl sessions, large residues were still left. the total success rate of the procedure was 77.3% (17 of 22 patients). three patients experienced allergy to the anesthetic drugs, severe flank pain, and fever and chills (suspicion of sepsis) and were hospitalized for 1 night after the procedure. in group 2, successful treatment was achieved after 1 and 2 swl sessions in 6 (18.2%) and 8 (24.2%) patients, respectively, and in the other patients, residues remained even after 2 sessions of swl. the total success rate was 42.4% (14 of 33 patients). consequently, the stone-free rate was significantly higher in the patients of group1 than those in group 2 (p = .01). the period of anesthesia was 23.1 minutes (during ureteroscopy) in group 1 and 13.2 minutes in group 2 (during cystoscopy or ureteroscopy and insertion of ureteral catheter). no significant complication was observed in neither of the groups. the mean costs of the treatment were us $ 400 and us $ 370 in groups 1 and 2, respectively. discussion invention of swl and other technologic advances in endourology have made us able to treat most of the kidney calculi with the least complications.(1) nowadays, most kidney calculi are treated by swl.(10,11) however, the problem of this technique is its less success rate in larger calculi. percutaneous nephrolithotomy is an effective technique for the treatment of such large kidney calculi and it is preferred to open surgery because of low complications and favorable outcomes.(12,13) however, there is still controversy in the treatment of the pelvic and kidney calculi between 2 cm to 3 cm. lingeman and colleagues believe that calculi sized 2 cm to 3 cm require more surgical approaches after swl when compared with calculi sized 1 cm to 2 cm. also, the stone-free rate is only 34% after swl, while this rate has been reported to be 90% after pcnl.(14) in another study by psihramis and associates, the complete success rate of swl for the kidney calculi larger than 2 cm was only 33%.(15) in their study, swl was just used once and the location of the calculus was variable including the inferior calyx. in our study, the success rate for swl per se was 42.4% for the 2 to 3-cm calculi, which is a bit higher than those in the previous studies. it should be mentioned that in most of our patients, swl was performed twice and all the calculi were located in the pelvis. regarding the need for extra treatment in most of the cases and low rate of successful removal of the calculi after swl, in the national institutes of health consensus development conference in 1988, it was recommended that pcnl be used as the first choice for removal of the kidney calculi larger than 2 cm.(5) however, some authors still consider swl for the treatment of these calculi. they believe that it is necessary to insert ureteral catheter before swl in these patients to reduce the need for unwanted surgical interventions.(6) we, therefore, inserted a double-j catheter before the procedure for all patients. for the treatment of kidney calculi, retrograde intrarenal surgery has also been considered by some authors. grasso and bagley reported the results of this method in 22 patients. in one-third of these patients, ureteroscopy was again needed and the total success rate was 91% after 2 sessions of flexible ureteroscopy and laser lithotripsy.(7) the problem ureteroscopic and shock wave lithotripsy for renal pelvis calculi—tavakkoli tabasi and baghban haghighi 224 urology journal vol 4 no 4 autumn 2007 with this technique is the long period of the surgery and frequent failures in long-term stone-free rates. a combination of outpatient ureteroscopic lithotripsy with swl has been considered as an alternative for pcnl. in a recent study by hafron and colleagues, 14 patients with a mean calculus size of 847 mm2 were treated by a combination of flexible ureterorenoscopy with holmium laser lithotripsy and swl.(8) thirteen patients (93%) were successfully treated; 2 of them remained stone-free with the first intervention and 10 needed a second intervention (ureterorenoscopy in 7, ureterorenoscopy and swl in 1, swl in 1, and alkalizing medications in 1) to become stone-free. one patient died due to an irrelevant disease. two patients needed a third session of swl, of whom 1 underwent pcnl due to urosepsis. the success rate was 84.6% (residues smaller than 4 mm). thus, in comparison with the conventional pcnl method, this technique could have the same treatment results and less morbidity. retrograde intraenal surgery has been considered a great substitute for swl monotherapy.(9) the indications for endourological swl include the presence of coagulopathies, intrarenal strictures, concurrent calculus of the kidney and ureters, kidney anomalies, and swl failure.(8,9) in our study, the use of ureteroscopy and swl resulted in a success rate of 77% which is less than the mentioned outcome reported by hafron and colleagues,(8) but higher than that of swl monotherapy. in our study, the number of the patients was more and in contrast with the pervious studies which had used flexible ureteroscope, rigid ureteroscope was used, too. therefore, due to the more difficult access to all calculi, the success rate seems to be less with this method. concerning the costs, although our proposed technique is slightly more expensive, it is worth due to the higher success rate. our study had some limitations; the number of patients who did not return for follow-up was relatively high, and therefore, we could not evaluate them. another factor which could make a bias in the procedure was performance of swl by 2 surgeons. however, the considerably higher success rate in one group can allow us to make our preliminary conclusion that ureteroscopy with lithotripsy prior to swl would provide a higher chance of successful treatment. conclusion since in some patients, pcnl is not possible due to medical problems or lack of facilities in some regions, it is rational to consider alternative methods for pcnl. furthermore, some of the urologists do not have enough acquaintance with pcnl and prefer other choices. in our experience, ureteroscopic lithotripsy plus swl was a safe method for the treatment of rather large calculi in the renal pelvis. notwithstanding that the authors still believe that pcnl is the treatment of choice in these cases, a combination of endourological approaches and swl can always be a favorable alternative since it eliminates the skin tracts and its complications. besides, this approach does not need a prone position which could be troublesome in some patients. conflict of interest none declared. references 1. lingeman je, lifshitz da, eval ap. surgical management of urinary lithiasis. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3361-78. 2. lam hs, lingeman je, barron m, et al. staghorn calculi: analysis of treatment results between initial percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy monotherapy with reference to surface area. j urol. 1992;147:1219-25. 3. streem sb, lammert g. long-term efficacy of combination therapy for struvite staghorn calculi. j urol. 1992;147:563-6. 4. lam hs, lingeman je, mosbaugh pg, et al. evolution of the technique of combination therapy for staghorn calculi: a decreasing role for extracorporeal shock wave lithotripsy. j urol. 1992;148:1058-62. 5. [no authors listed]. consensus conference. prevention and treatment of kidney stones. jama. 1988;260:977-81. 6. renner c, rassweiler j. treatment of renal stones by extracorporeal shock wave lithotripsy. nephron. 1999;81:71-81. 7. grasso m, bagley d. small diameter, actively deflectable, flexible ureteropyeloscopy. j urol. 1998;160:1648-53. 8. hafron j, fogarty jd, boczko j, hoenig dm. combined ureterorenoscopy and shockwave lithotripsy for large renal stone burden: an alternative to percutaneous nephrolithotomy? j endourol. 2005;19:464-8. 9. patel a, fuchs gj. expanding the horizons of swl through adjunctive use of retrograde intrarenal surgery: new techniques and indications. j endourol. 1997;11:33-6. ureteroscopic and shock wave lithotripsy for renal pelvis calculi—tavakkoli tabasi and baghban haghighi urology journal vol 4 no 4 autumn 2007 225 10. krings f, tuerk c, steinkogler i, marberger m. extracorporeal shock wave lithotripsy retreatment («stir-up») promotes discharge of persistent caliceal stone fragments after primary extracorporeal shock wave lithotripsy. j urol. 1992;148:1040-1. 11. wickham je. treatment of urinary tract stones. bmj. 1993;307:1414-7. 12. snyder ja, smith ad. staghorn calculi: percutaneous extraction versus anatrophic nephrolithotomy. j urol. 1986;136:351-4. 13. kahnoski rj, lingeman je, coury ta, steele re, mosbaugh pg. combined percutaneous and extracorporeal shock wave lithotripsy for staghorn calculi: an alternative to anatrophic nephrolithotomy. j urol. 1986;135:679-81. 14. lingeman je. non-staghorn renal calculi. in: lingeman je, smith lh, woods jr, newman dm, editors. urinary calculi. philadelphia: lea and febiger; 1989. p. 149-62. 15. psihramis ke, jewett ma, bombardier c, caron d, ryan m. lithostar extracorporeal shock wave lithotripsy: the first 1,000 patients. toronto lithotripsy associates. j urol. 1992;147:1006-9. 1278 | miscellaneous is there a relationship between acute coronary syndrome and prostate specific antigen level? tahir durmaz,1 hüseyin ayhan,1 telat keleş,1 emine bilen,2 murat akçay,1 nihal akar bayram,2 engin bozkurt1 purpose: interestingly, prostate-specific antigen (psa), which is used to monitor prostate disorders, has been suggested to be beneficial in estimating prognosis associated with coronary artery disease (cad). the aim of the present study was to investigate the relationship of serum levels of psa and free psa (fpsa) with prognosis of acute coronary syndromes (acs), extent of cad and major adverse cardiac events in patients with acute coronary syndromes. materials and methods: sixty-seven male patients who were diagnosed with acute coronary syndromes were included. all patients were assessed according to the thrombolysis in myocardial infarction (timi) classification [st elevation myocardial infarction (stemi) and non-st elevation (nste)-acs groups, separately], the global registry of acute cardiac events (grace) (difference between psa and fpsa) risk score and the killip classification. all patients underwent angiography. the degree of stenosis was scored using the gensini score to assess the extent of cad. results: serum psa, fpsa, fpsa/psa levels, and alpha 1-antichymotrypsin-psa (act-psa) (difference between psa and fpsa) results were found to be moderately correlated with the timi and grace risk scores, which are predictors of shortand mid-term prognosis. while there was no correlation between the gensini score and psa and act-psa, the gensini score was moderately correlated with fpsa and fpsa/psa. there were no significant differences between patients with major adverse cardiovascular events (maces) and those without maces at the 6-month follow-up in terms of psa, fpsa, fpsa/psa, and act-psa results. conclusion: there may be a relationship between serum psa and fpsa levels and prognosis of acs and extent of cad. it should be kept in mind that additional biomarkers could be used together with current scoring systems in risk classification in cases for which clinical decisionmaking is challenging. moreover, psa and fpsa results should be approached with caution in patients to be screened for prostate cancer as their serum levels may be influenced from several factors (acs, infection, etc.). keywords: acute coronary syndrome; predictive value of tests; male; prostate-specific antigen; blood. corresponding author: hüseyin ayhan, md department of cardiology, faculty of medicine, yıldırım beyazıt university, ankara, turkey. tel: +90 312 2912525 fax: +90 312 2912745 e-mail: huseyinayhan44@ yahoo.com received september 2012 accepted march 2013 1 department of cardiology, faculty of medicine, yıldırım beyazıt university, ankara, turkey. 2 department of cardiology, ankara ataturk education and research hospital, ankara, turkey. miscellaneous 1279vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l acute coronary syndrome and serum psa level | durmaz et al introduction ischemic heart disease is the leading cause of mortality and morbidity in adults worldwide. although coronary atherosclerosis mostly results in chronic coronary artery disease (cad), obstructive lesions in the coronary vessels, plaque erosion and rupture, and atherosclerotic plaques may also lead to acute myocardial ischemia. rapidly progressing ischemic lesions threatening myocardial tissue are currently defined as acute coronary syndrome (acs). acs is mainly classified in the following three groups: 1) st elevation myocardial infarction (stemi), troponin-positive, 2) nonst elevation myocardial infarction (nstemi), troponinpositive, 3) unstable angina pectoris (uap), non-st elevation, troponin-negative; the latter two being also named as nste-acs. every year, more than one million people suffer from acute myocardial infarction (mi) in the usa. registry data consistently show that nste-acs is more frequent than ste-acs. the annual incidence is 3 per 1000 inhabitants, but varies between countries.(1) although there has been a reduction in mortality due to the increase in the number of coronary intensive care units and advances in fibrinolytic and catheter-based reperfusion treatments, overall mortality rate associated with acute mi including deaths before admission to hospital is greater than 30%.(2) although several markers have been identified in order to predict mortality, determine prognosis, and demonstrate the extent of cad in acs, novel markers are still being investigated. recent case reports have suggested that there might be an association between prostate-specific antigen (psa) and cad and that this marker may be helpful in predicting prognosis. being responsible for the liquefaction of semen, psa is a 33000 da single chain glycoprotein comprised of 237 amino acids and 4 carbohydrate side chains. the gene encoding the psa molecule is located on the 19th chromosome. based on gene location, and amino acid composition and function, psa is identified as a member of the human kallikrein (hk3) family of the serine proteases.(3) inactive form of psa, pro-psa, is rapidly converted to active psa by hk2; hk2 also activates single-chain urokinase-type plasminogen activator and plasminogen activator inhibitor-1 (pai-1). psa induces apoptosis and inhibits negative growth factor and angiogenesis. psa increases the release of insulin like growth factor-1 (igf-1), which has been shown to increase all-cause mortality and risk of development of heart failure, by binding to insulin-like growth factor binding protein-3. it has been determined that psa exhibits antiangiogenic activity through inhibition of endothelial cell proliferation induced by fibroblast growth factor–2 and vascular endothelial growth factor.(4) it has also been shown that psa levels are reduced by statin treatment and psa production is regulated by angiotensin receptor blockers through a peroxisome proliferator-activated receptor gamma like effect.(5) psa levels have been demonstrated to be increased in cases of cardiogenic shock due to prolonged cardiopulmonary resuscitation, cardiac surgery, on-pump bypass, and acute mi.(6,7) in a controlled study, serum psa and fpsa levels was found to be higher in patients after elective stent implantation compared to those who were not treated with stent implantation, whereas no significant difference was found between these groups in terms of fpsa/psa ratio.(8) in a study comparing nste-acs and control groups, no significant difference was found between these two groups in terms of psa level. psa was determined to be correlated with high-sensitivity c-reactive protein (hscrp) and increased in heart failure in 14 days of follow-up. although there have been no large randomized studies, it has been observed in several case reports that coronary lesions is more common, extensive and severe and that major adverse cardiac events (maces) is more frequent within the initial 8 days after acute mi in cases with elevated psa. these reports have suggested that large randomized studies were needed to confirm this association.(9-11) the aim of the present study is to investigate the relationship of serum psa, fpsa, complex psa (act-psa; difference between psa and fpsa) levels and fpsa/psa ratio with prognosis of acs, extent of cad, development of arrhythmias, troponin and hscrp levels, and maces (death, mi, reinfarction, re-revascularization, hospitalization, stroke). materials and methods sixty-seven male patients who were hospitalized in the coronary intensive care unit with the diagnosis of acs between november 2009 and april 2010 were included in this prospective study. patients with a history of lower urinary tract symptoms (luts), prostate cancer and benign prostatic hy1280 | table 1. baseline clinical, laboratory, and procedural characteristics of the patients. characteristics study patients (n=67) age (years) 58.4 ± 11.4 bmi (kg/m2) 27.34 ± 2.7 time before hospital admission (hours) 6.4 ± 5.1 dm (%) 16.4 ht (%) 41.8 smoking (%) 67.2 family history (%) 9 functional capacity (nyha class) (%) i 68.6 ii 23.9 iii 7.5 iv 0 stemi (%) 47.7 nstemi (%) 46.3 uap (%) 6 lvef (%) 47.8 ± 11.2 heart rate (beats/min) 77.9 ± 18 systolic bp (mmhg) 129.25 ± 22.6 diastolic bp (mmhg) 77.08 ± 12.4 total cholesterol (mg/dl) 190.08 ± 35.94 triglyceride (mg/dl) 179.08 ± 122.45 ldl (mg/dl) 117.9 ± 36.01 hdl (mg/dl) 36.18 ± 9.33 peak troponin i (ng/ml) 2.16 ± 27.9 peak ck-mb (ng/ml) 71.59 ± 100.9 hscrp (mg/l) 6.6 ± 7.1 timi risk score 3.3 ± 1.9 grace risk score (inhospital) 119 ± 26.2 grace risk score (6 months) 100 ± 29.1 gensini score 61.2 ± 46.4 psa (0-4 ng/ml) 1.1 ± 0.9 fpsa (0-3.7 ng/ml) 0.49 ± 0.55 psafpsa 0.61±0.65 fpsa/psa ratio 0.46 ± 0.23 percutaneous coronary intervention (%) 67.16 fibrinolytic treatment (%) 17.9 infarction releated artery (%) lad 37.3 rca 38.8 lcx 23.9 key: bmi, body mass index; dm, diabetes mellitus, ht, hypertension, nyha, new york heart association; stemi, st elevation myocardial infarction; nstemi, non-st elevation myocardial infarction; uap, unstable angina pektoris; lvef, left ventricular ejection fraction; bp, blood pressure; ldl, lowdensity lipoprotein; hdl, high-density lipoprotein; ck, creatinine kinase; hscrp, high sensitivity c-reactive protein; timi, thrombolysis in myocardial infarction; psa, prostate-specific antigen; fpsa, free prostate-specific antigen; lad, left anterior descending artery; rca, right coronary artery, lcx, circumflex coronary artery. miscellaneous 1281vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l perplasia (bph), those who underwent urinary catheterization, those with a recent history of prostate biopsy, prostatitis or urinary tract infection, those who had a survival expectancy of less than one year due to non-cardiac pathologies, and those who did not provide informed consent were excluded. these were 30 patients. routine follow-up and treatment were performed on study patients in accordance with the recommendations in the current guidelines. blood samples were obtained from all patients diagnosed with acute coronary syndromes on admission for routine laboratory investigations, creatinine kinase (ck)-mb, troponin i, and hscrp levels in addition to serum psa and fpsa levels. fpsa/psa ratio and act-psa levels were calculated. information regarding risk factors including age, gender, type ii diabetes mellitus, hypertension, hyperlipidemia, and smoking were recorded. all patients were assessed according to the thrombolysis in myocardial infarction (timi) classification (stemi and nste-acs groups, separately), the global registry of acute cardiac events (grace) risk score (during inpatient period and 6 months after discharge), and the killip classification. left ventricular ejection fraction (lvef) was measured by transthoracic echocardiography (vivid 3 pro, ge vingmed, milwaukee, wi, usa) using the modified biplane simpson’s method. st-segment resolution (str) was assessed by electrocardiography that was performed 60 min after the procedure; a str of > 70% was defined as successful reperfusion. all patients underwent angiography. coronary angiographies were performed by experienced cardiologists via femoral arterial route using standard techniques. lesions were assessed from at least two angles and at end-diastolic phase. according to the recommendations of current guidelines, primary percutaneous coronary intervention (pci), early invasive intervention, medical treatment, and bypass treatments were performed. following the procedure, coronary angiographies of all patients were evaluated in order to assess the extent of cad, and stenosis was scored using the gensini score. (12) the degree of angiographic stenosis was scored between 1 and 32, this score was then multiplied by a factor defined for each main coronary artery and each segment, and finally summed up. maces (death, mi, re-revascularization, stroke) during inpatient period, one month and 6 months after discharge were recorded for all patients. informed consent was obtained from all patients at the time of admission, and the study was approved by the hospital local ethics committee. measurement of prostate-specific antigen blood samples for psa and fpsa measurements were obtained from the antecubital veins of all patients in a single puncture before the procedure. samples were immediately frozen in citrate tubes at -20°c, and measurements were performed by electrochemiluminescence immunoassay (eclia) method using cobas 6000 device (roche diagnostic). fpsa/psa ratio and act-psa were calculated for all samples. statistical analysis the statistical package for the social science (spss inc, chicago, illinois, usa) version 14.0. numerical variables were expressed as mean ± standard deviation (sd), whereas categorical variables were expressed as percentage. groups were compared using the student’s t test for normally distribtable 2. psa, fpsa, fpsa/psa and psafpsa results and their correlation with the timi and grace risk scores. timi risk score grace score inhospital period grace score at 6-month follow-up r p r p r p psa 0.30 .01 0.08 .50 0.17 .15 fpsa 0.41 .001 0.23 .05 0.31 .01 fpsa/psa -0.25 .04 -0.23 .05 -0.26 .03 psa-fpsa 0.08 .48 0.09 .46 0.04 .74 key: timi, thrombolysis in myocardial infarction; grace, global registry of acute cardiac events; psa, prostate-specific antigen; fpsa, free prostatespecific antigen. acute coronary syndrome and serum psa level | durmaz et al 1282 | uted variables and using the mann-whitney u test for nonnormally distributed variables. the pearson correlation test was used for normally distributed variables, and the spearman correlation test was used for non-normally distributed variables. a p value of < .05 was considered statistically significant. results sixty-seven male patients with acs were included in the present study. their mean age was 58.4 ± 11.4 years (range, 29-86 years). thirty-two patients had stemi, 31 patients had nstemi, and four patients had uap. fibrinolytic treatment was administered in 18% of stemi patients, and successful reperfusion was observed in half of these cases. coronary angiography was performed in all patients, and revascularization through pci was performed in 67% of the patients. coronary arteries were noted to be normal in two patients. general features of the study patients are presented in (table 1). no significant difference was found between stemi and nste-acs groups in terms of psa and fpsa levels, fpsa/ psa ratio and act-psa (p = .58). correlation analysis of psa, fpsa, fpsa/psa, and act-psa with other laboratory and clinical variables revealed no significant correlation with lvef, killip class, peak ck-mb, peak troponin i, and hscrp levels. however, moderate correlation was noted with the timi and grace risk scores, which are predictors of shortand mid-term prognosis (table 2). correlation analysis between the gensini score, which is an indicator of the extent of cad, and psa, fpsa, fpsa/psa, and act-psa revealed no significant correlation with psa and act-psa, whereas a moderate correlation was noted with fpsa and fpsa/psa ratio (table 3). multivariate regression analysis between the gensini score, which is an indicator of the extent of cad, and psa, fpsa, fpsa/psa, and act-psa revealed significant correlation with fpsa, fpsa/psa (table 4). during inpatient follow-up, atrial fibrillation was noted in 3%, atrioventricular complete block was noted in 1.5%, ventricular tachycardia in 4.5%, and maces (death in 2 patients, re-revascularization in 1 patient) was noted in 4.5% of the patients. at the 1-month follow-up, mi was noted in 4 (6%) patients and death was noted in 3 (4.5%) patients, which did not reach statistical significance. maces were noted in 23.5% of the patients at the 6-month follow-up. there were no significant differences between patients with maces and those without maces at the 6-month follow-up in terms of psa, fpsa, fpsa/psa, and act-psa results (p = .60). discussion the relationship of serum psa, fpsa, fpsa/psa levels and act-psa on admission and prognosis of acs, extent of cad, and other biomarkers in patients diagnosed with acs was investigated in the present study. a significant moderate correlation was found with the timi and grace risk scores and the gensini score was not found to be correlated with psa and act-psa; however, it was found to be significantly moderately correlated with fpsa and fpsa/psa. gensini score was found to be correlated with fpsa and fpsa/psa by multivariate regression analysis. no significant difference was found between stemi and nste-acs groups in terms of psa and fpsa levels, fpsa/psa ratio and act-psa. table 3. correlation of psa, fpsa, fpsa/psa, and psa-fpsa results with gensini score. gensini score variables r p psa 0.10 .42 fpsa 0.35 .003 fpsa/psa -0.42 .001 psa-fpsa -0.18 .13 key: psa, prostate-specific antigen; fpsa, free prostate-specific antigen. table 4. multivariate regression analysis for gensini score; including age, psa, act-psa, fpsa, fpsa/psa.* gensini score variables coefficient β p age 0.051 > .05 psa 0.082 > .05 act-psa 0.056 > .05 fpsa 0.418 < .001 psa/fpsa 0.483 < .001 * a p value < .05 was considered to be significant. f ratio = 41.2, r 2 = 0.776. key: psa, prostate-specific antigen; fpsa, free prostate-specific antigen; act-psa, alpha 1-antichymotrypsin-psa. miscellaneous 1283vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l there were no significant differences between patients with maces and those without maces at the 6-month follow-up in terms of psa, fpsa, fpsa/psa, and act-psa results. atherosclerosis and acute mi as its complication are still the leading cause of mortality and morbidity worldwide. similar to atherosclerosis, prevalence of prostate cancer increases with age, and it is one of the most common cancers in males. biochemical markers indicating myocardial damage in acute coronary syndromes patients play a vital role both in establishing diagnosis and in making treatment decisions. cardiac troponins that are markers for myocardial necrosis are found to be elevated only in 1/3 of acute coronary syndromes patients and are associated with increased short-term mortality and nonfatal mi risk in these patients.(13) although this risk is significantly lower in troponin-negative patients as compared to troponin-positive ones, a relatively high number of troponin-negative acute coronary syndromes makes risk assessment and treatment selection rather challenging. thus, simultaneous measurement of several biomarkers defining different stages of acute coronary syndromes pathophysiology may enable a better risk assessment in patients with negative myocardial necrosis markers.(14) a sensitive and specific biomarker, which can indicate plaque instability and can be measured in systemic circulation independent from myocardial necrosis, can provide improvement in diagnosis and treatment decision-making. in this context, several novel biomarkers such as hscrp, fibrinogen, pai-1, pregnancy-associated plasma protein a (papp-a), and myeloperoxidase have been introduced, and some have indeed been implemented into clinical practice, whereas others remain at an experimental level.(15-17) detection of unstable or potentially unstable coronary lesions, in which particularly early interventional and medical treatments provide considerable benefit, is an important clinical goal. it is clear that inflammatory markers have a significant role in the detection of these unstable lesions. it has been increasingly emphasized in recent years that inflammation, which is one of the most significant steps in the pathogenesis of atherosclerosis, has an important role in clinical diagnosis and treatment. the role of psa also appears in this context. it has been suggested that psa may assist in the diagnosis and treatment of acute coronary syndromes as acute phase reactants, which are markers of inflammation. psa is secreted into the lumen of the prostatic duct by exocytosis and transferred into the seminal fluid. the concentration of psa is 0.5-2.0 g/l in semen.(18) its concentration in the semen is approximately a million times of its concentration in the serum (0.1-4 ng/ml). psa in serum is found predominantly in three distinct molecular forms: 1) free psa (fpsa, molecular weight of 30 kda), 2) alpha-2 macroglobfigure 1. correlation between gensini score and free prostatespecific antigen (fpsa) (r = 0.35, p = .003). figure 2. correlation between gensini score and fpsa/psa ratio (r = -0.42, p = .001). psa, prostate-specific antigen, fpsa, free prostate-specific antigen. acute coronary syndrome and serum psa level | durmaz et al 1284 | ulin-bound psa (a2m-psa; molecular weight of 780 kda) and 3) alpha 1-antichymotrypsin-psa (act-psa); molecular weight of 90 kda). malignant tissues such as adrenal neoplasms (neuroblastoma), renal cell carcinoma, and breast cancer can also synthesize psa in low concentrations.(19,20) the mean half-life of total psa (free + bound forms) is 2.6 days.(21) as fpsa has a relatively lower molecular weight, it can be eliminated through renal clearance. having a half-life of 1.5 hours, fpsa constitutes 5% of serum psa, and fpsa/ psa ratio reduces in patients with prostate cancer. measurement of fpsa is used to increase sensitivity during screening for cancer in patients with normal total psa levels and to increase specificity and reduce the number of unnecessary prostate biopsies in patients with high total psa levels (> 4-10 ng/ml). prostate manipulations (firm rectal examination), prostate biopsy, and urethral instrumentations lead to increase in fpsa component of total psa. therefore, any kind of manipulations should be avoided 48-72 hours before fpsa measurement. impairment of normal structure of prostate, which enables the diffusion of psa into the prostate tissue, leads to the elevation of serum psa levels. major causes of elevated psa include bph, prostate cancer, prostate inflammation or infection, and trauma to the prostatic or perineal region. serum psa level increases with age and accompanying increase in prostate volume. this is due to psa-producing bph tissue.(22) significant portion of serum psa is found as a complex with act. in patients with prostate cancer, act-psa or complex psa levels increases more than that in patients with bph. act-psa is directly associated with total psa and calculated by subtracting fpsa from total psa.(22-24) although it was shown in a study that psa is correlated with hscrp during a 14-day of follow-up and increased in heart failure,(25) in the present study, psa, fpsa, act-psa levels, and fpsa/psa ratio was not found to be correlated with lvef, killip class, peak ck-mb, peak troponin i, and hscrp levels. however, a significant moderate correlation was found with the timi and grace risk scores, which are predictors of shortand mid-term prognosis. in certain case reports, coronary lesions were reported to be more severe and extensive in cases with elevated psa.(11,26) in the present study, the gensini score, which is calculated from coronary angiography findings and is an indicator of the extent of cad, was not found to be correlated with psa and actpsa; however, it was found to be significantly moderately correlated with fpsa and fpsa/psa. also gensini score was found to be correlated with fpsa and fpsa/psa by multivariate regression analysis with there was no difference in age. due to low number of arrhythmias and maces occuring during hospitalization and one month after discharge, statistical analysis could not be performed. furthermore, there were no significant differences between patients with maces and those without maces at the 6-month follow-up in terms of psa, fpsa, fpsa/psa, and act-psa results. recent studies have suggested that there might be a relationship between cardiovascular disorders and psa levels.(27) psa levels have been demonstrated to be increased in cases of cardiogenic shock due to prolonged cardiopulmonary resuscitation, cardiac surgery, on-pump bypass, and acute mi.(7,2730) although the precise mechanism of increase in psa levels in such conditions is unclear, it has been suggested that it might be caused by pelvic ischemia due to aortic clamp or cardiogenic shock. therefore, psa results should be interpreted with caution when screening for prostate cancer in patients who have sustained such events within previous weeks. moreover, to our knowledge, there have been no previous randomized studies investigating the relationship between psa and prognosis and the extent of cad following acute coronary syndromes. recently, several case reports suggested that coronary lesions was more common and extensive, presenting with more severe clinical manifestations and that number of maces within the 8 days following acute mi was higher in cases with elevated psa.(10,26) however, it was also reported in these case reports that psa level was low on the 1st and 3rd days, while it was high on the 2nd day. in the present study, we measured the psa levels of the patients on admission. monitorization of psa levels with 12-hour intervals may be more valuable in detecting the significance of psa in acute coronary syndromes. in another case report, a low psa level was emphasized in a case of coronary spasm without a significant coronary stenosis.(28) in a controlled study, psa and fpsa levels was found to be higher in patients following elective stent implantation compared to those who were not treated with stent implantation, while no significant differmiscellaneous 1285vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l ence was reported between these groups in terms of fpsa/ psa ratio.(8) in another controlled study comparing nsteacs and control groups, no significant difference was found between psa levels of these two groups.(31) supporting some of the previous studies, we also found a significant moderate correlation of psa and fpsa with acute coronary syndromes. large, randomized controlled studies are needed to confirm this relationship. conclusion in conclusion, psa, fpsa and fpsa/psa were found to be correlated with the timi and grace risk scores, which are prognosis markers in acute coronary syndromes, and the gensini scores, which are markers for the extent of cad, in the present study. moreover, psa and fpsa results should be approached with caution in patients to be screened for prostate cancer as their serum levels may be influenced from various other cardiovascular disorders commonly seen in the elderly population. conflict of interest none declared. 1. hamm cw, bassand jp, agewall s, et al. esc guidelines for the management of acute coronary syndromes in patients presenting without persistent st-segment elevation. eur heart j. 2011;32:29993054. 2. griffin p te, editor. manual of cardiovascular medicine. third ed: philadelphia pa: lippincott williams & wilkins; 2009. p. 563-70. 3. armitage tg, cooper eh, newling dw, robinson mr, appleyard i. the value of the measurement of serum prostate specific antigen in patients with benign prostatic hyperplasia and untreated prostate cancer. br j urol. 1988;62:584-9. 4. cohen p, graves hc, peehl dm, kamarei m, giudice lc, rosenfeld rg. prostate-specific antigen (psa) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. j clin endocrinol metab. 1992;75:1046-53. 5. crook m, preston k, lancaster i. serum prostatic specific-antigen concentrations in acute myocardial infarction. clin chem. 1997;43:1670. 6. rittenhouse hg, finlay ja, mikolajczyk sd, partin aw. human kallikrein 2 (hk2) and prostate-specific antigen (psa): two closely related, but distinct, kallikreins in the prostate. crit rev clin lab sci. 1998;35:275-368. 7. hagood pg, parra ro, rauscher ja. nontraumatic elevation of prostate specific antigen following cardiac surgery and extracorporeal cardiopulmonary bypass. j urol. 199;152:2043-5. 8. ozcan t, bozlu m, muslu n, gozukara kh, seyis s, akcay b. elevation of the serum total and free prostate specific antigen levels after stent implantation in patients with coronary artery disease. swiss med wkly. 2009;139:672-5. 9. patane s, marte f. prostate-specific antigen kallikrein and acute myocardial infarction: where we are. where are we going? int j cardiol. 2011;146:e20-2. 10. patane s, marte f, sturiale m, grassi r, patane f. significant coronary artery disease associated with coronary artery aneurysm and elevation of prostate-specific antigen during acute myocardial infarction. int j cardiol. 2010;141:e39-42. 11. patane s, marte f. prostate-specific antigen kallikrein: from prostate cancer to cardiovascular system. eur heart j. 2009;30:1169-70. 12. gensini gg. coronary arteriogaphy. mount kisco, new york: futura publishing co; 1975. 13. hamm cw, goldmann bu, heeschen c, kreymann g, berger j, meinertz t. emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin t or troponin i. n engl j med. 1997;337:1648-53. 14. fernandez-berges d, bertomeu-gonzalez v, sanchez pl, et al. clinical scores and patient risk stratification in non-st elevation acute coronary syndrome. int j cardiol. 2011;146:219-24. 15. bayes-genis a, conover ca, overgaard mt, et al. pregnancy-associated plasma protein a as a marker of acute coronary syndromes. n engl j med. 2001;345:1022-9. 16. liuzzo g, biasucci lm, gallimore jr, et al. the prognostic value of c-reactive protein and serum amyloid a protein in severe unstable angina. n engl j med. 1994;331:417-24. 17. libby p. inflammation in atherosclerosis. nature. 2002;420:868-74. 18. lilja h, abrahamsson pa. three predominant proteins secreted by the human prostate gland. prostate. 1988;12:29-38. 19. yu h, diamandis ep. measurement of serum prostate specific antigen levels in women and in prostatectomized men with an ultrasensitive immunoassay technique. j urol. 1995;153:1004-8. 20. levesque m, hu h, d'costa m, diamandis ep. prostate-specific antigen expression by various tumors. j clin lab anal. 1995;9:123-8. 21. pruthi rs. the dynamics of prostate-specific antigen in benign and malignant diseases of the prostate. bju int. 2000;86:652-8. references acute coronary syndrome and serum psa level | durmaz et al 1286 | 22. özorak a. prostate biopsy prostate cancer detection rates and prostate cancer 6-10-12 dial biopsies to be taken to determine the optimal investigation part number. isparta: süleyman demirel university, faculty of medicine 2007. 23. stenman uh, leinonen j, alfthan h, rannikko s, tuhkanen k, alfthan o. a complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. cancer res. 1991;51:222-6. 24. okihara k, fritsche ha, ayala a, johnston da, allard wj, babaian rj. can complexed prostate specific antigen and prostatic volume enhance prostate cancer detection in men with total prostate specific antigen between 2.5 and 4.0 ng./ml. j urol. 2001;165:1930-6. 25. baldus s, heeschen c, meinertz t, et al. myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. circulation. 2003;108:1440-5. 26. patane s, marte f, sturiale m, dattilo g. st-segment elevation and diminution of prostate-specific antigen in a patient with coronary spasm and without significant coronary stenoses. int j cardiol. 2011;148:e31-3. 27. patane s, marte f. prostate-specific antigen and acute myocardial infarction: a possible new intriguing scenario. int j cardiol. 2009;134:e147-9. 28. koller-strametz j, fritzer m, gwechenberger m, et al. elevation of prostate-specific markers after cardiopulmonary resuscitation. circulation. 2000;102:290-3. 29. berent r, auer j, porodko m, et al. influence of cardiopulmonary resuscitation on levels of tumour markers. eur j cancer care (engl). 2006;15:252-6. 30. koreny m, koller-strametz j, geppert a, delle karth g, heinz g, maurer g, et al. elevation of prostatic markers following cardiogenic shock. intensive care med. 2001;27:447. 31. dominguez-rodriguez a, abreu-gonzalez p, avanzas p, hernandez-garcia c, tome mc, lara-padron a. prostate-specific antigen kallikrein is not a marker of non-st elevation acute coronary syndrome. int j cardiol. 2011;149:141-2. miscellaneous 1350 | case report salmonella typyhi isolated from urine culture before percutaneous nephrolithotomy: a case report tansu değirmenci,1alpay arı,2 zafer kozacıoğlu,1bumin örs,1bülent günlüsoy1 keywords: nephrostomy, percutaneous; urinary tract infections; microbiology; salmonella typhimurium; salmonella infections. introduction typhoid fever is the most common illness caused by salmonella typhi (s. typhi). (1) s. typhi bacteriuria can be seen following a recent episode of typhoid fever, or in chronic carrier state involving the urinary system, especially with local abnormalities of urinary tract.(2) however, s. typhi bacteriuria with renal stone disease has rarely been reported.(2) we presented a rare case of a kidney stone with salmonella infection and discussed the treatment approaches in the light of literature. case report a 58 years old man with right flank pain and frequent urination was presented to our outpatient clinic. there was hematuria and leukocyturia in dipstick urinalysis. intravenous urography findings were 25 mm stone located in the right pelvis with multiple lower calyx stones and severe hydronephrosis of the right kidney (figure 1). noncontrast computed tomography revealed severe hydronephrosis, parenchymal loss and in the renal pelvis and lower pole hyper dense appearance of 25 mm millimeter stones (figure 2). in technetium-99m-diethylenetriaminepentacetic acid (99mtc-dtpa) renal scintigraphy, renal functions for the right and left kidneys were measured as 29% and 71%, respectively. serogroup d salmonella was isolated from the first midstream urine culture. findings of the vital signs were normal but erythrocyte sedimentation rate was 44 mm/h (0-20 mm) and c-recorresponding author: tansu değirmenci, md izmir bozyaka eğitim ve arastirma hastanesi, uroloji klinigi, bozyaka, 35360, izmir, turkey. tel: + 90 532 3631611 fax: + 90 232 250 29 97 e-mail: tansudegirmenci@hotmail. com received june 2012 accepted august 2011 1 i̇zmir bozyaka education and research hospital, urology department, izmir, turkey. 2 i̇zmir bozyaka education and research hospital, infectious disease and clinical microbiology department, izmir, turkey. case report 1351vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l salmonella typyhi in urine culture | değirmenci et al active protein was 14.18 mg/dl (0-5 mg/dl). microbiological workup resulted positive for s. typhi h antigen (1/100) and s. serogroup d. there was no significant infection according to the stool culture. ceftriaxone (2g every 12 hours, intravenously) was administered thereafter. on the third day of the antibiotic therapy the patient underwent percutaneous nephrolithotomy. we obtained pyuric urine samples from the renal pelvis. the obstructive pelvis and lower calyx stones were cleared. stone culture samples were taken. the urinary catheter and the nephrostomy tube were retrieved on the first and third postoperative day, respectively. on the first and the second postoperative day, 38.5°c fever was measured. s. typhi was isolated from the intraoperative pelvic urine and stone culture. preoperative antibiotic treatment was continued for 7 days and the patient was discharged with oral ciprofloxacin therapy (750 mg twice daily) after 11 days of hospitalization. ciprofloxacin was discontinued after 3 months of use. outpatient evaluation of third months was negative for urine culture. at six months, 99mtc-dtpa renal scintigraphy revealed the percentages of distribution of the total renal function as 31% and 69% for the right and left kidney, respectively. discussion salmonellae are facultative anaerobic, non-spore-forming, gram-negative bacilli.(1) the bacilli have been classified into 2541 serotype by the kaufmann-white scheme based on the o and h antigens.(1) the laboratories perform a few simple agglutination reactions that define specific o antigens into serogroups, designated as groups a, b, c1, c2, d and e salmonella.(1) s. enteritidis and s. typhi are both group d. our patient’s midstream urine, pelvic urine and stone culture yielded salmonella group d. isolation of s. typhi from urine is rare even where this infection is endemic.(1) it is believed that the bacilli are shed in urine following a recent typhoid fever as part of the natural history of this disease or in chronic carrier states.(3,4) during asymptomatic bacteriuria, cystitis or pyelonephritis can be seen clinically.(1,2,5) but interstitial nephritis and renal micro abscesses can develop as important complications in the course of the disease.(1) the incidence of bacteriuria is reported as 0.6%.(1) this condition occurs in patients both with and without local abnormalities of the urinary tract. up to 50% of patients with s. typhi urinary tract infection figure 1. the stone located in right kidney pelvis on intravenous urography. figure 2. noncontrast computed tomography shows a stone in the renal pelvis with severe hydronephrosis and parenchymal loss. 1352 | case report (uti) had urinary calculi.(3) this bacteriuria was related with predisposing factors such as urinary tract abnormalities or immunosuppression.(4) in case of a uti associated with anatomic obstructive abnormalities, surgical correction may be required in addition to prolonged antimicrobial therapy (≥ 6 weeks) to eradicate infection.(1) s. typhi bacteriuria is asymptomatic in the majority of patients and probably is associated with a recent typhoid fever in patients. although s. typhi bacteriuria is rare even where it’s endemic, this specific infection should be kept in mind in patients who have an unidentified chronic uti. conflict of interest none declared. references 1. pegues da, miller si. salmonella species, including salmonella typhi. mandell, douglas, and bennett's principles and practice of infectious diseases, editors: gerard mendel, johhn bennett, raphael dolin. seven edition, philadelphia, churchill livingstone; 2009. p. 2887-903. 2. mathai e, john tj, rani m, et al. significance of salmonella typhi bacteriuria. j clin microbiol. 1995;33:1791-2. 3. kapoor r, tewari a, dhole tn, ayyagiri a. salmonella typhi urinary tract infection: a report of two cases. indian j urol. 1992;8:94-95. 4. gagnon j, labbe r, laroche b. salmonella urinary tract infection: a vascular emergency. can j surg. 2007;50:221-2. 5. ramos jm, aguado jm, garcía-corbeira p, alés jm, soriano f. clinical spectrum of urinary tract infection due to nontyphoidal salmonella species. clin infect dis. 1996;23:388-90. 389vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l effect of low dose dopamine on early graft function in living unrelated kidney donors hamzeh hosseinzadeh, samad golzari, mohammad abravesh, ata mahmoodpoor, davood aghamohammadi, afshar zomorrodi, parisa hosseinzadeh purpose: to evaluate the effect of low-dose dopamine administration on the early function of the kidney in unrelated kidney donors after transplantation. materials and methods: in this double-blinded clinical trial, 60 adult kidney donors and 60 recipients, younger than 50 years old, were studied. donors and recipients were randomly divided into two groups; group 1 received dopamine 3 µg/ kg/min and group 2 received similar regimen of placebo. during the first 3 days postoperatively, serum levels of urea and creatinine as well as urine output and early kidney function were compared between two groups. results: serum levels of creatinine and urea and urine output during the first three days after the operation did not differ statistically significantly between two groups (p = .549, p = .306 and p = .375, respectively). early kidney function was better significantly in group 1 (5.3 ± 3.2 versus 8.6 ± 8.0 hours; p = .048). conclusion: premedication of the kidney transplant donors with low-dose dopamine accelerates early kidney function after transplantation, but has no effect on the hemodynamic status and serum levels of creatinine and urea in the donors. keywords: kidney transplantation, kidney function tests, dopamine, tissue donors corresponding author: ata mahmoodpoor, md; fccm general icu, shohada hospital, el-goli st., tabriz, iran tel: +98 914 116 0888 e-mail: amahmoodpoor@ yahoo.com received january 2011 accepted july 2011 department of anesthesiology, imam khomeini hospital, faculty of medicine, tabriz university of medical sciences, tabriz, iran kidney transplantation 390 | kidney transplantation introduction kidney transplantation is the treatment of choice for patients with end-stage renal disease. delay in achieving transplanted kidney function after transplantation is a serious problem.(1) although immunosuppressive medications have been able to prevent acute transplant rejection, chronic nephropathy still exists and disturbs the function of transplanted kidneys. there are numerous non-immunologic factors which can affect transplanted kidney function, including hemodynamic instability, manipulations during donor nephrectomy, renal vessels spasm in the donor and recipient, duration of cold ischemia, and ischemia and reperfusion-induced injuries. these conditions can lead to pro-inflammatory state and increase immunogenicity of graft, which in turn results in graft dysfunction and rejection.(2-4) therefore, decreasing organ injury with medical pretreatment of donors may lead to better outcome of the kidney transplantation. instant urine production has been reported in 90% of the living donor transplantations and 40% to 70% of the cadaveric transplantations.(5) some studies demonstrated that catecholamine administration could have protective effects on the transplanted kidney, reducing acute transplant rejection and increasing long-term survival after transplantation.(6-9) among catecholamines, dopamine has the best effect on survival of transplanted kidneys. dopamine induces heat shock protein heme oxygenase enzyme-1,(10) which plays an important role in preventing vascular damage in the transplanted kidney in animal models.(11) dopamine can protect endothelial cells from oxidative stress with its dihydroxy-phenolic structure.(12) although catecholamines protect against the increase of inflammatory molecules, such as intracellular adhesion molecule-1, and cold storage-induced endothelial cell damage,(13,14) there is controversy over protective effects of dopamine in kidney recipients by reviewing current strategies for renal transplantation.(15) the majority of transplantations which are performed in imam khomeini hospital in tabriz are from the unrelated living donors, and delay in achieving kidney function reduces graft survival. this study was aimed to evaluate the effect of lowdose dopamine administration in the living donors on early function of the transplanted kidney. materials and methods from may 2008 to october 2009, 120 subjects were studied. sixty kidney donors were randomized into two groups, group 1 (n = 30) received 3 µg/kg/min dopamine and group 2 (n = 30) received similar regimen of placebo. sixty recipients were allocated in respected groups. randomization was done by random block. there were 60 sealed envelopes for each group with the name of dopamine (30) or control (30) inside them. patients and anesthesiologist were blind to the study. this study was reviewed and approved by the medical ethics committee of tabriz university of medical sciences. written informed consent was obtained from each participant. power calculations indicated that a sample of 60 patients and 60 controls would detect a proportion difference of at least 15% between two groups, with a significance (α = 0.05) and a power of 80%. the kidney donors’ conditions and short-term survival after kidney transplantation were compared between the two groups. blood pressure, central venous pressure, body temperature, end-tidal co2, and urine output were measured. furthermore, pulse oximetry and electrocardiography were performed. intravenous anesthesia was performed using remifentanil, propofol, cisatracurium, and a gas mixture of n2o + o2 6 l/min. the administered gas was reduced by 50% every 10 minutes until reaching the flow of 2 l/min. central venous pressure of the patients was maintained between 10 and 12 mmhg. 391vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l effect of dopamine on early graft function | hosseinzadeh et al subjects in group 1 received dopamine drip with 3 µg/kg throughout the operation with infusion pump and those in control group received normal saline with the same volume/hour as drip through infusion pump. all donors received manitol 1 g/kg before nephrectomy. all kidney recipients received manitol 1 g/kg plus furosemide 1.5 mg/kg before removing arterial clamp. during reperfusing, bicarbonate 1 meq/ kg was administered intravenously. time to diuresis after removing vascular clamp was recorded. diuresis below 60 minutes was considered early. all the subjects were followed up for 6 hours after diuresis. the follow-up period was 3 days after the operation. subjects in each group received the same immunosuppressive regimen. demographic parameters and cold and warm ischemia duration were recorded. serum levels of blood urea nitrogen and creatinine as well as urine volume were recorded before the operation and 12, 24, 36, 40, 60, and 72 hours postoperatively. data were presented as mean ± standard deviation, frequency, and percentage. data were analyzed with spss software (the statistical package for the social sciences, version 15.0, spss inc, chicago, illinois, usa). quantitative variables were compared using independent samples t test, and categorical variables were compared using contingency tables and chi-square or fisher’s exact test. to compare the changes in the quantitative parameters between two groups, repeated measures analysis was used. p values less than .05 were considered statistically significant. results kidney donors demographic characteristics of kidney donors are shown in table 1. no statistically significant difference was observed between two groups. as shown in table 2, there were no significant differences regarding systolic blood pressure (p = .100), mean arterial pressure (p = .547), heart rate (p = .618), spo2 (p = .413), and body temperature (p = .866) between two groups. kidney recipients general quantitative variables in both groups are summarized in table 1. no statistically significant difference was observed between two groups. again, there was no significant difference regarding systolic blood pressure (p = .299), mean artetable 1. comparing demographic characteristics in kidney donors and recipients donors recipients variables intervention group control group p intervention group control group p mean ± sd mean ± sd mean ± sd mean ± sd age, y 28.9 ± 5.0 26.9 ± 4.2 .093 37.6 ± 11.7 35.6 ± 9.7 .480 weight, kg 70 ± 12.3 68.4 ± 11.6 .602 62.4 ± 10.1 62.3 ± 14.4 .983 duration of anesthesia, h 3.7 ± 0.6 3.6 ± 0.4 .316 5.0 ± 0.8 4.9 ± 0.7 .427 duration of surgery, h 2.9 ± 0.5 2.9 ± 0.5 .682 4.2 ± 0.7 4.2 ± 0.6 .780 liquid volume, l 4.6 ± 0.9 4.3 ± 0.7 .056 4.7 ± 1.0 4.9 ± 0.9 .486 urine , l 0.8 ± 0.4 0.9 ± 0.4 .772 0.3 ± 0.2 0.3 ± 0.2 .480 bleeding, l 0.3 ± 0.1 0.3 ± 0.1 .184 0.6 ± 0.2 0.6 ± 0.1 .084 hematocrit, % 43.3 ± 4.4 4 5 ± 4.3 .094 32.4 ± 2.3 33.3 ± 3.8 .118 body mass index 22.7 ± 2.4 22.2 ± 2.4 .389 duration of dialysis, month 17 ± 11.2 19.9 ± 0.6 .560 warm ischemia duration, min 1.3 ± 0.5 1.2 ± 0.5 .552 cold ischemia duration, min 94 ± 21.6 88.2 ± 17.9 .262 sd indicates standard deviation. 392 | kidney transplantation table 2. comparing quantities of general variables between two recipient groups variables time intervention group control group p mean ± sd mean ± sd systolic blood pressure before surgery 89.8 ± 9.5 88.9 ± 13.8 .761 after induction 84.7 ± 13.1 90.9 ± 12.2 .062 after intubation 96.3 ± 18.7 94.6 ± 15.2 .821 during surgery 92.6 ± 9.0 91.9 ± 11.2 .771 heart rate before surgery 80.6 ± 13.5 82.4 ± 10.3 .564 after induction 80.5 ± 12.5 85.1 ± 9.7 .116 after intubation 87.4 ± 16.0 89.7 ± 18.6 .615 during surgery 83.3 ± 9.6 79.4 ± 11.4 .157 spo2 before surgery 95.3 ± 1.3 97.9 ± 1.1 .382 after induction 98.6 ± 1.2 98. 8 ± 0.7 .508 after intubation 98.9 ± 1.2 99.1 ±1.0 .561 during surgery 99.4 ± 0.7 99.0 ± 1.2 .115 body temperature before surgery 35.9 ± 0.7 35.7 ± 0.6 .239 during surgery 34.6 ± 5.5 35.5 ± 0.5 .350 end-tidal co2 31.7 ± 4.3 30.1 ± 2.7 .096 sd indicates standard deviation. table 3. comparing hemodynamic parameters and vital signs in recipients variables time intervention group control group p mean ± sd mean ± sd mean arterial pressure before surgery 102.3 ± 18.1 102.3 ± 12.5 .993 after induction 96.8 ± 17.5 95.1 ± 13.9 .684 after intubation 95.9 ± 20.0 101.4 ± 23.9 .327 during surgery 88.4 ± 12.4 92.5 ± 12.9 .218 heart rate before surgery 88.9 ± 17.0 85.8 ± 14.1 .450 after induction 88.5 ± 15.4 86.0 ± 18.1 .561 after intubation 90.2 ± 18.5 86.5 ± 17.3 .418 during surgery 75.8 ± 15.0 73.4 ± 12.3 .502 spo2 before surgery 96.7 ± 1.7 96.4 ± 1.5 .373 after induction 97.9 ± 1.0 98.4 ± 1.3 .150 after intubation 98.2 ± 1.1 98.7 ± 0.8 .048 during surgery 98.2 ± 1.3 98.9 ± 0.9 .035 body temperature before surgery 36.4 ± 0.5 36.2 ± 0.9 .206 after induction 35.4 ± 5.4 36.2 ± 0.7 .469 during surgery 35.8 ± 1.8 35.9 ± 0.8 .975 central venous pressure before surgery 12.6 ± 3.8 11.8 ± 2.9 .387 after induction 13.2 ± 3.2 12.7 ± 3.5 .587 after intubation 13.6 ± 3.3 13.7 ± 3.8 .914 during surgery 13.7 ± 3.1 13.6 ±2 .3 .816 end-tidal co2 31.9 ± 3.4 31.7 ± 3.0 .810 sd indicates standard deviation. 393vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l rial pressure (p = .538), heart rate (p = .429), spo2 (p = .179), body temperature (p = .973), and central venous pressure (p = .667) (table 3). changes in serum levels of creatinine and urea and urine volume during the study in both groups are presented in table 4. mean serum level of urea and mean urine volume after 24 hours were significantly higher in group 1 (p = .367 and p = .480, respectively). there was no statistically significant difference regarding other variables. studying the variables mentioned above revealed no statistically significant difference between two groups regarding serum creatinine (p = .549), serum urea (p = .306), and urine volume (p = .375). the mean time for initiation of diuresis after clamp removal was 5.3 ± 3.2 hours (range, 1 to 13 hours) in group 1 and 8.6 ± 8.0 hours (range, 1 to 29 hours) in group 2 (p = .048). instant delay function was observed in 1 subject (3.3%) in the intervention group and in 2 subjects (6.7%) in the control group. there was no statistically significant difference between two groups in this regard (p = .500). discussion there are few studies about the effect of lowdose dopamine on transplanted kidney function. schnuelle and colleagues reported that low-dose dopamine administration in intensive-care unit significantly reduced the probability of acute transplant rejection and increased transplanted organ survival.(16) in another study, they also concluded that low-dose dopamine administration in the kidney donors reduced the need for hemodialysis after transplantation.(17) in a randomized controlled trial, grundmann and associates showed a higher urine output in the immediate post transplant period with the use of low dosage of dopamine, without any effect on creatinine clearance.(18) in another study, the effect of low-dose dopamine (5 µ/kg/min) on the kidney donors’ status before transplantation was evaluated. in a 3-year follow-up period, transplant rejection rate was significantly lower in the intervention group. although dopamine administration significantly increased systolic blood pressure in the donors, it was not clinically significant or influential.(19) low-dose dopamine administration in donors has a positive effect on the recipient status and transplanted organ survival in all the above-mentioned conditions. however, the method of results evaluation and follow-up duration after transplantation are different in our study compared to others. the core objective of the above-mentioned studies was the evaluation of hemodialysis need after transplantation. while in our study, we focused on the changes of serum levels of urea and creatinine after transplantation for 3 days, which can directly reflect status of the kidney recipients as core parameters. the study by schnuelle and colleagues, which has been still the most comprehensive study on the living kidney donors,(19) had several limitations. the most important drawback in their study is that the researchers and evaluating staff were not blind to the study and the results were obtained according to the patients’ grouping (epinephrine or placebo). in comparison, our study has been carried out as a double-blind study, which can be considered a major advantage. on the other hand, the study by schnuelle and associates was carried out on brain death donors whereas the present study was carried out on healthy donors in the age range of 20 to 30 years. considering the intervention and controlled status of brain death cases, generalizing the obtained results to the non-brain death living donors might be inaccurate. furthermore, the status of dopamine administration during kidney transplantation surgery in the recipients and status of receiving other common medications related to kidney transplantation by donors, such as thyroxin, corticosteroid, vasopressin, insulin, iron chelator, etc, have not been studied.(20-22) gottmann and coworkers evaluated the effect of low-dose dopamine (5µ//kg/min) in the kidney effect of dopamine on early graft function | hosseinzadeh et al 394 | donors in rat models. they demonstrated that dopamine administration in kidney donors improved both short-term and long-term prognoses.(23) as it was mentioned, early kidney function was significantly better in the intervention group in our study, but no significant effect was observed regarding serum levels of creatinine and urea within three days after transplantation. novitzky and colleagues and wood and associates concluded that dopamine administration in the kidney donors only increased systolic blood pressure whereas it had no significant effect on transplant rejection rates within 30 days and on allograft and patient survival until 36 months after transplantation.(24,25) de los angeles and colleagues reported that lowdose dopamine administration (3µg/kg/min) in combination with furosemide in kidney donors had no significant effect on urine output or creatinine clearance in the recipients after transplantation compared to the placebo.(26) spicer and associates using doppler ultrasonography in their study showed that dopamine administration in the kidney donors had no significant effect on speed and degree of blood stream in the transplanted tissue.(27) as it can be seen, the results obtained in this field differ greatly. one of the reasons can be the effect of confounding factors on final results, such as the age of donors, the weight of recipients, and cold ischemia duration.(24) in our study, all the abovementioned factors were matched between two groups. to the best of our knowledge, this study is the first study carried out on non-brain death donors. limitations of our study were the short duration of study, monitoring of kidney function based kidney transplantation table 4. serum levels of creatinine and urea, and urine volume after transplantation in recipients variables time intervention group control group p mean ± sd mean ± sd serum creatinine basic 7.2 ± 3.6 13.8 ± 36.3 .322 after 12 hours 6.5 ± 3.5 5.4 ± 2.0 .139 after 24 hours 4.7 ± 3.2 4.5 ± 2.5 .701 after 36 hours 4.1 ± 2.9 3.5 ± 2.1 .338 after 48 hours 3.3 ± 2.7 2.9 ± 1.9 .605 after 60 hours 2.8 ± 2.4 2.6 ± 1.8 .666 after 72 hours 2.0 ± 2.0 2.6 ± 1.9 .272 serum urea basic 84.0 ± 32.6 66.4 ± 26.8 .026 after 12 hours 81.0 ± 27.9 75.8 ± 27.2 .468 after 24 hours 78.0 ± 4.7 70.0 ± 26.2 .367 after 36 hours 80.8 ± 49.3 70.3 ± 27.4 .309 after 48 hours 78.9 ± 52.8 68.4 ± 30.7 .349 after 60 hours 77.3 ± 57.1 68.1 ± 34.4 .450 after 72 hours 68.2 ± 50.3 72.4 ± 35.4 .706 urine volume, l basic 0.9 ± 0.9 0.7 ± 0.9 .470 after 12 hours 2.4 ± 2.2 2.9 ±1.9 .359 after 24 hours 2.2 ± 1.8 3.9 ± 2.4 .004 after 36 hours 1.8 ± 1.6 2.2 ± 1.0 .274 after 48 hours 1.8 ± 1.7 2.3 ± 1.6 .306 after 60 hours 3.0 ± 7.6 1.7 ± 1.1 .355 after 72 hours 1.4 ± 0.9 1.9 ± 1.1 .072 sd indicates standard deviation. 395vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l on early diuresis and urea/creatinine, and shortterm patients’ follow-up. conclusion we concluded that low-dose dopamine in the unrelated kidney donors, compared to the placebo, significantly increases the speed of diuresis initiation in the recipients after transplantation. furthermore, it has no statistically significant effect on reducing serum level of creatinine and/or urea in the kidney recipients after transplantation. conflict of interest none declared. references 1. wolfe ra, ashby vb, milford el, et al. comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. n engl j med. 1999;341:1725-30. 2. pratschke j, wilhelm mj, kusaka m, et al. brain death and its influence on donor organ quality and outcome after transplantation. transplantation. 1999;67:343-8. 3. matzinger p. tolerance, danger, and the extended family. annu rev immunol. 1994;12:991-1045. 4. van der woude fj. graft immunogenicity revisited: relevance of tissue-specific immunity, brain death and donor pretreatment. nephron. 2002;91:181-7. 5. qureshi f, rabb h, kasiske bl. silent acute rejection during prolonged delayed graft function reduces kidney allograft survival. transplantation. 2002;74:1400-4. 6. schnuelle p, lorenz d, mueller a, trede m, van der woude fj. donor catecholamine use reduces acute allograft rejection and improves graft survival after cadaveric renal transplantation1. kidney int. 1999;56:738-46. 7. wagner m, cadetg p, ruf r, mazzucchelli l, ferrari p, redaelli ca. heme oxygenase-1 attenuates ischemia/ reperfusion-induced apoptosis and improves survival in rat renal allografts. kidney int. 2003;63:1564-73. 8. perdue pw, balser jr, lipsett pa, breslow mj. "renal dose" dopamine in surgical patients: dogma or science? ann surg. 1998;227:470-3. 9. stephan h, sonntag h, henning h, yoshimine k. cardiovascular and renal haemodynamic effects of dopexamine: comparison with dopamine. br j anaesth. 1990;65:380-7. 10. berger sp, hunger m, yard ba, schnuelle p, van der woude fj. dopamine induces the expression of heme oxygenase-1 by human endothelial cells in vitro. kidney int. 2000;58:2314-9. 11. dragun d, hoff u, park jk, et al. prolonged cold preservation augments vascular injury independent of renal transplant immunogenicity and function. kidney int. 2001;60:1173-81. 12. brinkkoetter pt, beck gc, gottmann u, et al. hypothermiainduced loss of endothelial barrier function is restored after dopamine pretreatment: role of p42/p44 activation. transplantation. 2006;82:534-42. 13. kapper s, beck g, riedel s, et al. modulation of chemokine production and expression of adhesion molecules in renal tubular epithelial and endothelial cells by catecholamines. transplantation. 2002;74:253-60. 14. yard b, beck g, schnuelle p, et al. prevention of cold-preservation injury of cultured endothelial cells by catecholamines and related compounds. am j transplant. 2004;4:2230. 15. schnuelle p, berger s, de boer j, persijn g, van der woude fj. effects of catecholamine application to brain-dead donors on graft survival in solid organ transplantation. transplantation. 2001;72:455-63. 16. schnuelle p, lorenz d, mueller a, trede m, van der woude fj. donor catecholamine use reduces acute allograft rejection and improves graft survival after cadaveric renal transplantation. kidney int. 1999;56:738-46. 17. schnuelle p, yard b, braun c, et al. impact of donor dopamine on immediate graft function after kidney transplantation. am j transplant 2004;4:419-26. 18. grundmann r, kindler j, meider g, stowe h, sieberth hg, pichlmaier h. dopamine treatment of human cadaver kidney graft recipients: a prospectively randomized trial. klin wochenschr. 1982;60:193-7. 19. schnuelle p, gottmann u, hoeger s, et al. effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. jama. 2009;302:1067-75. 20. silverstein jh. donor dopamine pretreatment and graft function after kidney transplantation. jama. 2010;303:230; author reply 1-2. effect of dopamine on early graft function | hosseinzadeh et al 396 | 21. wood ke, mccartney j. management of the potential organ donor. transplant rev 2007;21:204-18. 22. salahudeen ak. cold ischemic injury of transplanted kidneys: new insights from experimental studies. am j physiol renal physiol. 2004;287:f181-7. 23. gottmann u, notheisen a, brinkkoetter pt, et al. influence of donor pretreatment with dopamine on allogeneic kidney transplantation after prolonged cold storage in rats. transplantation. 2005;79:1344-50. 24. wood ke, becker bn, mccartney jg, d'alessandro am, coursin db. care of the potential organ donor. n engl j med. 2004;351:2730-9. 25. novitzky d, cooper dk, rosendale jd, kauffman hm. hormonal therapy of the brain-dead organ donor: experimental and clinical studies. transplantation. 2006;82:1396-401. 26. de los angeles a, banquero a, bannett a, raja r. dopamine and furosemide infusion for prevention of post-transplant oliguric renal failure. kidney int. 1985;27:339-45. 27. spicer st, gruenewald s, o'connell pj, chapman jr, nankivell bj. low-dose dopamine after kidney transplantation: assessment by doppler ultrasound. clin transplant. 1999;13:479-83. kidney transplantation 1636 | the α 1 adrenoceptor antagonist tamsulosin for the treatment of voiding symptoms improves nocturia and sleep quality in women sun-ouck kim, hyang sik choi, dongdeuk kwon corresponding author: sun-ouck kim, md, phd department of urology, chonnam national university hospital and medical school 8, hak-dong, dong-ku, gwangju #501-757, south korea. tel: +82 62 220 6705 fax: +82 62 227 1643 e-mail: seinsena@hanmail.net received february 2013 accepted march 2014 department of urology, chonnam national university medical school, gwangju, south korea. female urology female urology purpose: nocturia is the main cause of disturbance of sleep maintenance and negatively impacts quality of life (qol). we assessed the effects of the α1-adrenoceptor antagonist, tamsulosin, on nocturia and quality of sleep, for the treatment of lower urinary tract symptoms (luts) in women with a maximal flow rate (qmax) less than 15 ml/sec. materials and methods: from january 2008 to december 2009, women with luts [qmax ≤ 15 ml/s, international prostate symptom score (ipss) ≥ 8] and nocturia (void/night ≥ 1) were selected for this study. two hundred ninety six patients completed voiding diary, a questionnaire on the medical outcomes study (mos) sleep scale and underwent follow-up evaluation after 4 weeks of treatment (tamsulosin, 0.2 mg, once daily). effectiveness was assessed by analysis of the ipss, the bother score, the qmax, and postvoid residual urine (pvr). results: the mean number of voids per night was 2.66 ± 1.3, and the total ipss and bother scores were 15.2 ± 8.9 and 3.4 ± 1.2, respectively. clinical parameters, including the ipss, the bother score, the qmax and the pvr, improved significantly from baseline after treatment (p < .05). the change in nocturia was -1.12 (p < .05). concerning sleep quality, the sleep problem index showed a significant decrease. among the items on the sleep subscale, sleep disturbance, somnolence, and sleep adequacy were significantly changed (p < .05). conclusion: the α1-adrenoceptor antagonist tamsulosin significantly improved nocturia and sleep quality as well as luts in women with low qmax. keywords: adrenergic alpha-1 receptor antagonists; therapeutic use; lower urinary tract symptoms; drug therapy; urination disorders; female; quality of life; treatment outcome. 1637vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l tamsulosin for the treatment of voiding symptoms in women | kim et al introduction nocturia is a common symptom in adult women and has a pronounced impact on sleep, quality of life (qol) and general health.(1) according to the definition of the international continence society, “nocturia” is the complaint that an individual wakes one or more times during the night to void urine.(2) due to the presumed correlation between nocturia and bladder outlet obstruction (boo), most published studies have tended to focus on nocturia in men(3) even though nocturia is also common in women. (4) a large number of studies have demonstrated that a high proportion of patients with nocturia, estimated from 63% to 75%, complain of nocturia as a troublesome symptom.(4,5) the fragmented and disturbed sleep patterns observed in patients with nocturia can result in daytime sleepiness and can lead to serious health risks.(6) boo is known to cause irritative and obstructive symptoms. although boo in women has traditionally been considered uncommon, recent studies have shown that it is an underdiagnosed cause of female lower urinary tract symptoms (luts). (7) boo may induce secondary changes in the bladder, such as bladder overactivity, that can result in decreased bladder capacity and storage symptoms, including nocturia. some reports have shown that the real incidence of voiding difficulty in women is between 6.5% and 24%.(8) use of α-blockers has been reported in women with obstructed urine flow.(9-11) athanasopoulas and colleagues reported that alfuzosin significantly improved urodynamic parameters and alleviated bothersome symptoms in women with boo.(11) interest has focused on the α1d-adrenoceptor subtype in the bladder as an important target in the treatment of luts.(12) tamsulosin is a potent, specific and selective α1-adrenoceptor antagonist that is known to have greater specificity for α1a and α1d receptors than for α1b (13) and that thus might have a role in the management of both voiding symptoms and storage symptoms in women. however, little research has been conducted on the efficacy of α-blockers in female patients with a low maximal flow rate (qmax) who are suspected of having functional boo and nocturia. in the present study, therefore, we aimed to determine the effect of tamsulosin on luts and nocturia in women with low qmax. we also attempted to evaluate the related impact of nocturia on sleep quality. materials and methods participants and study design in this prospective observational study conducted from january 2008 to december 2009, 324 women aged > 20 years who had moderate to severe luts [international prostate symptom score (ipss) ≥ 8, qmax ≤ 15 ml/s at voided volume over 150 ml] and nocturia of at least once per night (ipss nocturia score of question 7) were included. all patients underwent urological evaluation before treatment, including a medical history, physical and neurologic examinations, urine analysis, urine culture and urethrocystoscopy. participants completed three day voiding diary and a questionnaire on the medical outcomes study (mos) sleep scale. the effectiveness of tamsulosin (0.2 mg/day) was assessed by analysis of the ipss, the bother score, the qmax, and postvoid residual urine (pvr). data for these parameters were acquired at baseline and after 4 weeks of treatment. all participants provided written informed consent with data collection and the study received approval from the local ethics committee and the institutional review board. the study procedures complied with the guidelines provided by the declaration of helsinki. exclusion criteria subjects with confused or depressed mental status; taking medications such as sedatives or tranquilizers that may alter or control bladder symptoms; with a history of previous surgery for luts; any implication of detrusor dysfunction, detrusor sphincter dyssynergia or neurogenic bladder; with symptomatic urinary tract infection; with uropathologic conditions, such as urinary stones and urogenital cancer; with pelvic organ prolapse of higher than stage 2; or with a history of insomnia or a sleep disorder were excluded. we also excluded any patients with iatrogenic, anatomic, or neurogenic causes of boo. patients with nocturnal polyuria from the voiding diary, severe symptoms of stress urinary incontinence of stamey grade 3, patients with restricted mobility, and patients who worked at night were also excluded from this analysis. patients who had received an α-blocker during the 3 months before enrollment and patients with contraindications to the use of α-adrenergic receptor antagonists were also excluded. medical outcome study sleep scale the mos sleep measure yields a sleep problems index and six scale scores: sleep disturbance (have trouble falling 1638 | asleep, how long to fall asleep, sleep was not quiet, awaken during sleep time, and have trouble falling asleep again), sleep adequacy (get enough sleep to feel rested upon waking in the morning, get the amount of sleep needed), daytime somnolence (drowsy during the day, have trouble staying awake during the day, take naps), snoring, awaken short of breath or with headache, and quantity of sleep.(14) quantity of sleep is scored as the average number of hours slept per night. the other scales and problems index are scored on a possible range of 0-100, with higher scores indicating more of the concept being measured. statistical analysis the statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0 was used for statistical analyses. data were analyzed by student’s t test. p values < .05 were deemed statistically significant. results the women’s mean age was 58.3 ± 11.2 years (range, 4168 years) and the mean nocturnal frequency during the night was 2.66 ± 1.3. the mean duration of symptoms was 20.3 ± 36.6 months. the incidence of hypertension, diabetes mellitus, and cardiovascular disease was 27.0%, 18.9%, and 5.4%, respectively. among the subject 28 women discontinued because of lost to follow-up for personal reason (18) and lack of efficacy (10), the remainder 296 women who completed data were selected as subjects for final analysis. after treatment, there was no reported significant treatment related complications. however, 7 reported mild dizziness or fatigue and 3 reported incontinence without discontinuation of α-blocker therapy. concerning uroflowmetric parameters, the baseline qmax and pvr were 13.3 ± 7.8 ml/s and 75.3 ± 23.7 ml, respectively. at 4 weeks after tamsulosin treatment, the ipss total (p = .03), voiding symptoms (p = .01), storage symptoms (p = .05), the bother score (p = .01), qmax (p = .001) and pvr (p = .001) showed significant improvement from baseline (table 1). the overall mean change in nocturnal frequency after tamsulosin treatment was -1.12 times per night (p = .001). concerning sleep quality, the sleep problem index (p = .012) showed a significant decrease. on the mos sleep scale, the subcategories of sleep disturbance (p = .004), somnolence (p = .001), and sleep adequacy (from p = .001) changed significantly after treatment (table 2). the subcategories of hours of sleep, shortness of breath, and snoring, however, were not significantly changed after treatment. discussion luts resulting from boo are commonly associated with detrusor overactivity and storage symptoms. the efficacy of α-blockers for relief of the symptoms of boo has been well demonstrated; however, less information is available on how this treatment affects the increased nocturia and sleep quality. in the present study, we found that treatment with tamsulosin resulted in significant improvement of both voiding symptoms and storage symptoms in female patients with low qmax and significant improvement of qmax and pvr. furthermore, nocturia was significantly reduced after tamsulosin treatment. thereby, sleep quality was also improved. tamsulosin treatment appears to be effective in female patients with a low qmax with respect to reducing both storage symptoms including nocturia and voiding symptoms. therefore, female urology table 1. changes in ipss and uroflowmetry parameters after treatment with tamsulosin. voiding baseline 4 weeks after treatment p ipss total 15.2 ± 8.9 13.6 ± 3.4 .003 voiding symptoms 9.0 ± 6.2 7.7 ± 3.1 .001 storage symptoms 6.7 ± 3.9 5.8 ± 0.9 .005 bother symptom 3.4 ± 1.2 2.9 ± 1.6 .001 uroflowmetric parameters maximal flow rate (ml/s) 13.3 ± 7.8 20.4 ± 8.2 .001 residual urine (ml) 75.3 ± 23.7 54.8 ± 27.5 .001 key: ipss, international prostate symptom score. 1639vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l therapy could be an initial treatment option for the patients with luts associated with low qmax who do not have other distinct factors causing boo. the adrenergic receptors found at the bladder neck are α1adrenergic receptors, and three subtypes have been identified: α1a, α1b, and α1d (15) the α1-adrenergic blocking agents with subselectivity for α1a and α1d might be the most useful in the management of lower urinary tract dysfunction. accordingly, it was speculated that the α1d receptor might mediate overactive symptoms and luts, whereas the α1a receptor subtype would mediate obstructive symptoms.(16) tamsulosin is a potent, specific, and selective α1-adrenoceptor antagonist that is known to have greater specificity for α1a and α1d receptors than for α1b (13) and that thus might have a role in the management of luts in women. currently, there is little objective evidence to support the efficacy of tamsulosin for the treatment of storage symptoms. alpha-blocker therapy is an established treatment for boo related to benign prostatic enlargement in men. the use of α-blockers in women with obstructed urine flow has also been reported.(9-11) kessler and colleagues examined the effect of terazosin on functional boo in women and concluded that terazosin had significant symptomatic and urodynamic effects in two-thirds of patients.(10) athanasopoulos and colleagues reported that alfuzosin induced significant improvement of urodynamic parameters and alleviated the bothersome symptoms of patients with boo.(11) in the present study, we also observed a significant improvement in uroflowmetric parameters and subjective symptom scores after tamsulosin treatment in patients with a low urine flow rate. nocturia is common in women and its prevalence increases with age.(17) although nocturia is not a life-threatening symptom, it is known to have a significant effect on qol, including sleep quality. fragmented and disturbed sleep patterns are observed in patients with nocturia and can result in daytime sleepiness and lead to serious health risks.(4) middelkoop and colleagues suggested that nocturia is a main factor of disturbance of sleep maintenance in adults aged 50 years or older.(5) su and colleagues reported that nocturia increases the risk of insomnia by 20.6-fold.(6) in our previous study, we already found that nocturia appeared to be associated with further negative effects on sleep quality, health-related qol and symptom bother in men.(18) for this reason, it is important to determine the impact of nocturia on sleep quality and related qol and how they are correlated. in the present study, we found consistent result with the above-mentioned report showing clear correlation between nocturia and sleep quality. even though men and women share a common micturition character, the definitions used to describe boo in men do not apply to women. diagnosis of boo in women is still controversial; however, obstruction is characterized by a decreased flow rate and a high detrusor pressure, both of which are due to increased bladder outlet resistance. urodynamic study currently remains the gold standard for assessing the presence of boo by measurement of qmax and detrusor pressure at qmax.(7) during urodynamic study, an obstruction is highly suspected when the study results show a low urine flow rate despite a detrusor contraction of adequate power.(19,20) blaivas and groutz suggested the usefulness of the free flow rate, and they reported that boo can be diagnosed if the free flow qmax is ≤ 12 ml/s with normal detrusor power.(21) however, abnormal uroflowmetry has been used as a surrogate tamsulosin for the treatment of voiding symptoms in women | kim et al table 2. changes in nocturia and medical outcome study sleep scale after tamsulosin treatment. voiding baseline 4 week after treatment p no. of nocturia 2.66 ± 1.2 1.54 ± 1.1 .001 sleep problem index i 40.3 ± 16.7 35.9 ± 15.7 .012 hours of sleep 6.1 ± 1.8 6.2 ± 1.5 .58 sleep disturbance 39.7 ± 23.0 34.9 ± 21.5 .004 somnolence 33.2 ± 25.7 28.7 ± 25.9 .001 shortness of breath 28.4 ± 57.5 27.3 ± 30.6 .68 sleep adequacy 46.1 ± 22.1 40.7 ± 23.4 .001 snoring 40.3 ± 16.7 38.3 ± 18.8 .167 1640 | marker for voiding dysfunction.(22) some authors have suggested that an abnormal flow rate of 15 ≤ ml/s can be used for reliable prediction of patients who are more likely to have voiding disturbance.(23) in the present study, considering the invasiveness of urodynamic study and on the basis of a clinical diagnosis of suspected boo, we included patients with a low qmax of less than 15 ml/s on free uroflowmetry and a complaint of voiding symptoms on the ipss. in the present study, we clearly found an effect of tamsulosin on both voiding symptoms and storage symptoms for the patients with female luts associated with low qmax. therefore, it would be logical to expect that α-blocker therapy in patients with a low maximal flow rate and mixed urinary tract symptoms of voiding and storage symptoms. we suggest that clinicians consider α-blocker treatment as an initial medical treatment of choice for these patients. clinicians should expect improvement of nocturia and related quality of sleep with α-blocker treatment. this study has a few limitations. this small scale study does not have placebo control group. we could not fully evaluate the exact reason of follow-up loss with personal issues from the study. thus, considering the low number of female patients with low qmax, a multicenter, double-blind, placebocontrolled trial would be ideal for further determination of the efficacy and safety of α-blocker treatment in these patients. nocturia is associated with various conditions and circumstances. the major causes of nocturia fall into three categories: diurnal polyuria, nocturnal polyuria, and low nocturnal bladder capacity. nocturia may represent nocturnal frequency from the symptoms of frequent voiding of small volumes, possibly secondary to bladder overactivity and decreased nocturnal bladder capacity, or nocturnal polyuria due to large amounts of urine production during the night that may suggest pathology other than from the lower urinary tract.(24) another limitation of this study was that we could not evaluate the individual cause of nocturia, neither could we consider the effect of treatment with tamsulosin by the exact cause of nocturia. conclusion the α1-adrenoceptor antagonist tamsulosin significantly improved nocturia and sleep quality as well as voiding symptoms in women with a qmax of less than 15 ml/s. these improvements were confirmed by measurement of clinical parameters and administration of a sleep-related questionnaire in this study, warranting further study well designed and large sampled. conflict of interest none declared. female urology references 1. lose g, alling-moller l, jennum p. nocturia in women. am j obstet gynecol. 2001;185:514-21. 2. van kerrebroeck p, abrams p, chaikin d, et al. the standardization of terminology in nocturia: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002;21:179-83. 3. asplund r, aberg h. health of the elderly with regard to sleep and nocturnal micturition. scand. j prim health care. 1992;10:98-104. 4. weiss jp, blaivas jg. nocturia. j urol. 2000;163:5-12. 5. middelkoop ha, smilde-van den doel da, neven ak, kamphuisen ha, springer cp. subjective sleep characteristics of 1,485 males and females aged 50-93: effects of sex and age, and factors related to self-evaluated quality of sleep. j gerontol a biol sci med sci. 1996;51:m108-15. 6. su tp, huang sr, chou p. prevalence and risk factors of insomnia in community-dwelling chinese elderly: a taiwanese urban area survey. aust n z j psychiatry. 2004;38:706-13. 7. nitti vw, tu lm, gitlin j. diagnosing bladder outlet obstruction in women. j urol. 1999:161:1535-40. 8. stanton sl, ozsoy c, hilton p. voiding difficulties in the female: prevalence, clinical and urodynamic review. obstet gynecol. 1983;61:144-7. 9. pischedda a, pirozzi farina f, madonia m, cimino s, morqia g. use of alpha1-blockers in female functional bladder neck obstruction. urol int. 2005;74:256-61. 10. kessler tm, studer ue, burkhard fc. the effect of terazosin on functional bladder outlet obstruction in women: a pilot study. j urol. 2006;176:1487-92. 11. athanasopoulos a, gyftopoulos k, giannitsas k, perimenis p. effect of alfuzosin on female primary bladder neck obstruction. int urogynecol j pelvic floor dysfunct. 2009;20:217-22. 12. dreikorn k. the role of phytotherapy in treating lower urinary tract symptoms and benign prostatic hyperplasia. world j urol. 2002;19:426-35. 13. chapple cr. α1-adrenergic blocking drugs in bladder outflow obstruction: what potential has α1-adrenoceptor selectivity? br j urol. 1995;76 (suppl. 1):47-55. 14. hays rd, stewart al. sleep measures. in: stewart al, ware je, eds. measuring functioning and well-being: the medical outcomes study approach. durham, nc: duke university press; 1992. p. 235-59. 1641vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l 15. malloy bj, price dt, price rr, et al. alpha1-adrenergic receptor subtypes in human detrusor. j urol. 1998;160:937-43. 16. schwinn da. novel role for alpha 1-adrenergic receptor sub-types in lower urinary tract symptoms. bju int. 2000;86(suppl. 2):11-20. 17. robinson d. nocturia in women. int j clin pract suppl. 2007;155:2331. 18. kim so, choi hs, kim yj, et al. impact of nocturia on health-related quality of life and medical outcomes study sleep score in men. int neurourol j. 2011;15:82-6. 19. farrar dj, osborne jl, stephenson tp, et al. a urodynamic view of bladder outflow obstruction in the female: factors influencing the results of treatment. br j urol. 1975;47:815-22. 20. diokno ac, hollander jb, bennett cj. bladder neck obstruction in women: a real entity. j urol. 1984;132:294-8. 21. blaivas jg, groutz a. bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. neurourol urodyn. 2000;19:553-64. 22. dietz hp, haylen bt. symptoms of voiding dysfunction: what do they really mean? int urogynecol j pelvic floor dysfunct. 2005;16:52-5. 23. costantini e, mearini e, pajoncini c, biscotto s, bini v, porena m. uroflowmetry in female voiding disturbances. neurourol urodyn. 2003;22:569-73. 24. matthiesen tb, rittig s, nørgaard jp, pedersen eb, djurhuus jc. nocturnal polyuria and natriuresis in male patients with nocturia and lower urinary tract symptoms. j urol. 1996;156:1292-9. tamsulosin for the treatment of voiding symptoms in women | kim et al 1706 | epidermoid cyst of the scrotum: a clinical case tomasz ząbkowski, marcin wajszczuk corresponding author: tomasz ząbkowski, md szaserów 128, 00-909, warsaw, poland. tel: +48 791 533 555 e-mail: urodent@wp.pl received april 2013 accepted april 2014 urology clinic of the military medical institute, szaserow 128, 00-909 warsaw, poland. case report keywords: epidermoid cyst; scrotum; diagnosis; differential. introduction epidermoid cysts are the most common epithelial cysts. they are well encapsulated cysts and histologically characterized by a cystic lining of stratified squamous epi-thelial cells and no cutaneous adnexal structures in the stromal tissue.(1) they are within the skin slowly growing benign tumors of the retention cyst’s character filled with sebaceous and keratinous masses and containing elements of hair follicles. these are single or multifocal spherical nodules of size from a few millimeters to a few centimeters mostly occurring on the scalp, the face, the trunk and in the genitals’ area. their content is dense and resembles the porridge and the cottage cheese. they are covered with the unchanged, slightly red skin. the epidermoid cyst’s multiplex of the scrotum forming multisegmental and multifocal tumors of long term course are often hereditary. the diagnosis is based on appearance of the change. the treatment consists in a surgical removal of the tumor along with the capsule. the prognosis is favorable. when only the content of the cyst is evacuated and the cyst’s capsule is not removed the recurrence can occur. as follicular disruption is important in the pathogenesis of many epidermoid cysts, multiple epidermoid cysts may occur in individuals with a history of significant acne vulgaris. multicase report 1707vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l epidermoid cyst of the scrotum | ząbkowski et al ple cysts may also occur in the setting of gardner syndrome (familial adenomatous polyposis) and in nevoid basal cell carcinoma (bcc) syndrome.(1) multiple scrotal cysts may lead to scrotal calcinosis via dystrophic calcification.(1) non-inflamed epidermoid cysts are usually asymptomatic, but, with pressure, cyst contents may be expressed that may have an objectionable odor. rupture of the cyst wall can result in an intensely painful inflammatory reaction, and this is a common reason for presentation to a physician. development of a bcc or squamous cell carcinoma (scc) within an epidermoid cyst is a very rare event.(1) histologic examination shows a cystic cavity filled with laminated keratin lined by a stratified squamous epithelium including a granular layer. a surrounding inflammatory response with both acute and chronic granulomatous inflammation may be seen as evidence of prior rupture. in individuals with gardner syndrome, some cysts show, as a characteristic feature, columns of pilomatricoma-like shadow cells projecting into the cyst cavity.(1) scrotal nodules without any connection with the testis, the epididymis or the spermatic cord occur rarely. their etiology and histogenesis are not sufficiently explained. the first cases of figure 1. the epidermoid cyst’s multiplex of the scrotum. figure 2. the epidermoid cyst’s multiplex removed separately and as a segment of nodules (left). little, satellite changes about one millimeter in diameter (right). 1708 | the epidermoid cyst were presented by dockerty and prestly in 1942. according to rauschmeier 50% of all benign neoplasms of testes are epidermoid cysts. these are cysts of a sharply limited wall of the connective tissue lined with the cornifying squamous epithelium containing the desquamated epithelium. they differ from the dermoid cyst because they arise only from one germ layer.(2,3) case report a forty years old male patient (his medical history–50533/2011) was admitted to the clinic of urology in warsaw because of numerous fusing nodules of the scrotum. according to the patient interview, it was concluded that the first skin changes occurred about ten years ago. their sizes as well as the quantity were gradually increasing what inclined the patient to the medical consultation. the skin changes occurred only in the scrotum area, no remote metastasizes was observed. the patient has not visited the urologist till now because he was ashamed of his disease. he also denied similar complaints in members of his family. the general condition of the patient was good. the numerous, hard and fusing nodules on the skin of the scrotum were shown during the clinical examination, in diameter from 2 millimeters to about 2.5 centimeters. inguinal lymph nodes were impalpable. no abnormality was observed during the physical examination. no deviation in the area of testes and epididymis were revealed according to us in course of the hospitalization (figure 1). based on a medical history and a physical examination, the steatocystoma multiplex of the scrotum was shown. the patient was qualified for the surgery. the nodules were removed under spinal anesthesia. because of a focal accumulation of the changes and their dissemination they were removed both separately and in several blocks. little, satellite changes about one millimeter in diameter were revealed intraoperatively on the rims of larger nodules. when the lesions were surgically removed, they were given to a histopathological examination. during the histopathological examination the cyst of a sharply limited wall of the connective tissue lined with the cornifying squamous epithelium was characterized. inside the cyst there were desquamated, keratinized cells of the squamous epithelium with multifocal calcifications. the intraand postoperative course showed no complications. the patient was discharged on the second day after the surgery. during the consultations 2 weeks after the surgery, apart from the scar, no other pathological symptoms were observed. discussion an epidermoid cyst is the most common benign simple epithelial cyst without malignant potential, mostly found on the scalp, the face and the back, however, in the urological spectrum it often occurs in testes or on the skin of the scrotum.(4) it is characterized histologically by the cyst lining of stratified squamous cells and loosely packed lamellae of keratin debris, cholesterol and water without teratomatous elements or skin appendages in the stromal tissue.(4) the pathogenesis of the epidermoid cyst is not precisely known, but there are different theories about the embryonic origin of this lesion:(5) they arise from the ectopic cutaneous tissue due to dislocation of this tissue into the neighboring area. they are the end results of the monolayer teratoma from germ cells. they occur due to a traumatic implantation of the epidermal tissue into the dermis and the subcutis. however, in the case of the extratesticular scrotal epidermoid cyst, they are believed to be an abnormal closure or the associated degenerative process of the median raphe and the urethral groove.(6,7) the deeply located scrotal steatocystomas can suggest tumors of the testes, however, well performed ultrasonography excludes their presence unequivocally. a characteristic, ultrasonographic picture of the scrotum is the echoless area arising from tissues of the thin wall’s cyst, sharply limited with enhancement of the ultrasound wave. irregular dispersed reflections of the ultrasound wave inside the cyst occur more rarely or the areas of enhanced and reduced laminated repercussions of the ultrasound wave and in case of capsule calcification, with acoustic shadows.(8) initially scrotal cysts were felt to be true sebaceous cysts, perhaps because of their clinical similarity to steatocystoma multiplex, but histologic examination does not reveal sebaceous glands. some investigators have suggested that scrotal cysts represent primary calcifications without a precase report 1709vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l references 1. bolognia jl, jorizzo jl, schaffer jv, et al, eds.dermatology. 3rd ed. philadelphia, pa: mosby elsevier; 2012. chap 37. p. 1817-27. 2. yang wt, whitman gj, tse gm. extratesticular epidermal cyst of the scrotum. ajr am j roentgenol. 2004;183:1084. 3. bassler r., bocker w.: pathologic, tom 3. springer, berlin, heidelberg, new york, 1984. 4. dambro tj, stewart rr, carroll ba. the scrotum. in: rumack cm, wilson sr, charboneau jw, eds. diagnostic ultrasound. 2nd ed. st louis, mo: mosby; 1997. p. 791-821. 5. tanaka t, yasumoto r, kawano m. epidermoid cyst arising from the spermatic cord area. int j urol. 2000;7:277-9. 6. katergiannakis v, lagoudianakis ee, markogiannakis h, manouras a. huge epidermoid cyst of the spermatic cord in an adult patient. int j urol. 2006;13:95-7. 7. picanco-neto jm, lipay ma, d’avila cl, verona cb, zerati-filho m. intrascrotal epidermoid cyst with extension to the rectum wall: a case report. j pediatr surg. 1997;32:766-7. 8. lee hs, joo kb, song ht, et al. relationship between sonographic and pathologic findings in epidermal inclusion cysts. j clin ultrasound. 2001;29:374-83. 9. braun-falco o, plewig g, wolff hh, et al. dermatology. springer berlin heidelberg; 2000. p. 1428. cursor cyst or other structure. when noninflamed scrotal cysts are evaluated, they show the typical features of an epidermoid cyst. mixed cysts may be slightly more common on the scrotum.(9) a complete removal of the cyst is the only choice of treatment because no neoplastic malignant lesion or remote metastases were reported in the literature contrary to the proper skin’s cysts which can be malignant. conflict of interest none declared. epidermoid cyst of the scrotum | ząbkowski et al urology for people 69urology journal vol 7 no 1 winter 2010 what’s up in urology journal, winter 2010? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. the persian translation of this article is available from www.uj.unrc.ir. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2010;7:69. www.uj.unrc.ir elderly with kidney stone can choose their treatment there are many surgical treatment options for removal of a stone from a kidney, but not all of them can be used for all patients. for example, the stone can be removed through the instrument inserted into the kidney from the flank of the patient. but, this surgery accompanies with risks in older patients. extracorporal shock wave lithotripsy, fraction of the stone by shock waves sent to the body, is another option. however, sometimes this does not work for the older patients either. in such a situation, the surgeon may have no choice but to take the risk! the first treatment, which is called percutaneous surgery, was attempted in patients older than 65 years by dr karami and his colleagues in shohada-etajrish hospital, in tehran. they compared the outcome with that in patients younger than 40 years. and now they can reassure their elderly patients that percutaneous approach would be safe and effective. risky operations are sometimes inevitable, but in the hands of an experienced surgeon, the patient fills safe, especially when the surgeon has done research on its safety issues! see page 17 for full-text article kidney transplant and a remote organ: thyroid when the kidneys fail to work properly, almost all organs in the body will be affected. the same happens when the patient receives a kidney transplant. the thyroid gland was the subject of a group of kidney transplant in mashhad. they measured thyroid hormones before and then during the first days after a kidney transplantation. they observed a decrease in the levels of thyroid hormones, and the interesting finding was that such a decrease was greater in those who faced a delayed function of their new kidneys. kidney transplant is a very sophisticated surgery, and the patient needs extensive care after the surgery by a team of experts. endocrinologists should also be involved in this process. the thyroid gland is one of the organs that have its own reactions to changes in kidney function and its substitution. researchers have to pursue all these detailed alteration in the body, in order to provide the best care for the patients. see page 30 for full-text article antideppressants are not only for your depression … fluoxetine is now a worldwide famous drug, especially among depressed people. but another group of patients may know it very well. fluoxetine can also help men with premature ejaculation. these men suffer from early ejaculation before they can have a complete intercourse. this sexual problem usually needs medical treatment with fluoxetine. however, it fails sometimes. dr dadfar and his colleagues offered another drug from the same antidepressant family to their patients who did not benefit from fluoxetine. the opponent’s name is citalopram, and indeed, it did well. dr dadfar and his colleague followed their patients and reported the results in an article in urology journal. see page 40 for full-text article u j spring 2012.pdf 505vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l effects of varicocele repair on spontaneous first trimester miscarriage a randomized clinical trial mandana mansour ghanaie,1 seyyed alaeddin asgari,1 nassrin dadrass,1 aliakbar allahkhah,1 elham iran-pour,2 2 purpose: to evaluate the effects of varicocelectomy on semen parameters, pregmaterials and methods: one hundred and thirty-six women with recurrent miscarriage were recruited into this study. all of the husbands had normal semen parameters according to world health organization criteria and clinical varicocele. in order to evaluate the causes of recurrent pregnancy loss, we looked for diseases. both groups were well matched according to male/female age, varicocele grade, and smoking history. these couples were assigned randomly into two followed up until delivery. in each 3-month follow-up visits, two semen analyses were performed. results: mean sperm concentration, sperm progressive motility, and sperm with p p p p p p factors to pregnancy rate by multiple regression analysis. conclusion: varicocelectomy improves semen quality, increases pregnancy rate, our results seem warranted. keywords: varicocele, pregnancy trimesters, abortion, randomized controlled trial corresponding author: mohammad reza safarinejad, md p.o. box 19395-1849, tehran, iran tel: +98 21 2245 4499 fax: +98 21 2245 6845 e-mail: info@safarinejad. com received june 2011 accepted september 2011 1urology research center, guilan university of medical sciences, rasht, iran 2private practice of urology and andrology, tehran, iran sexual dysfunction and infertility 506 | sexual dysfunction and infertility introduction the incidence of varicocele in both men and adolescent boys varies between 10% and the association of a varicocele with infertility has been well documented. it has been demonstrated that testicular development is compromised in teenagers with varicocele; this impairment can adversely affect sperm quality. it is also important to note that varicocele can result in sperm dna damage, and elevated reactive oxygen species when ros are in excess, they can cause pathological impairment by inducing oxidative changes in cellular lipids, proteins, and dna. men whose semen contains increased levels of ros may have diminished fertility for both invitro and invivo procedures, and there may be adverse effects on embryo development. in some cases, apoptosis may commence, but terminate prematurely, in a process known as abortive apoptosis, leading to ejaculation of mature sperm with apoptotic traits, such as fragmented dna. chen and colleagues reported that patients with varicocele have elevated levels of 8-hydroxydeoxyguanosine, a marker of oxidative dna damage. excessive levels of dna damage have been associated with a decrease in several fertility indices, including embryo cleavage rate, implantation rate, pregnancy rate, and live birth rate. furthermore, examination of biopsies obtained from varicocele-affected testes by atomic force microscopy reveals structural and morphological well as changes in head dimensions. surgical varicocelectomy improves seminal parameters and is associated with decreased ros production and increased levels of seminal plasma antioxidants. loss of three or more consecutive pregnancies in it affects about 1% of all fertile couples trying to conceive. despite extensive investigations, no clear cause is found in more than half of cases and they are categorized as idiopathic rm. there is an interaction between the male and female genomes during the time of both natural and assisted conception. the paternal genome plays its role during early embryonic development by sion. measures increased sperm chromatin susceptibility in the time from unprotected intercourse to conception in men with high scsa values. in a study by evenson and associates, higher values of the scsa were able to predict 39% of the miscarriages. furthermore, correlations exist between sperm dna integrity and outcomes of invitro fertilization treatment cycles. another study, investigating sperm chromosome anomalies, demonstrated a we therefore designed a prospective randomized, double blind study to determine pregnancy outcome after varicocele repair in normozoospermic men. materials and methods study population in a randomized clinical trial, consecutive women were recruited from alzahra hospital’s gynecologynecology clinic due to recurrent pregnancy loss riages were included in this study. in order to evaluate the causes of rpl, we looked for chromosomal tory, and infectious diseases. when these women 507vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l varicocelectomy and miscarriage | mansour ghanaie et al to them for consideration of their participation in this study. couples were excluded if their husband had abnormal semen analysis according to the tive antisperm antibody assay. evaluations women willing to participate were encouraged to ring for an appointment. at this appointment, a full history was taken and the results of previous investigations were noted to make certain that there no cause was found for rpl. in all the cases, the wives had undergone gynecologic workups and were found to be fertile. the trial was then explained further and a written informed consent was obtained. all the patients underwent karyotype analysis in order to determine chromosomal abnormalities, such as balanced translocations. the anatomy of the uterus was evaluated by transvaginal ultrasound scan and hysterosalpingography and/or hysteroscopy in order to diagnose mullerian malformations all men underwent a basic infertility evaluation, including history taking, complete physical examiof varicocele was diagnosed by physical examinaparameters, at least two semen analyses were performed at 1 month interval to remove inadvertent and possible adverse effects of various issues on spermatogenesis. the normal who values in6/ml concentration with grade a of spermatozoa and normal morphology in at least 30% of the spermatozoa. exclusion criteria includon physical examination, total testicular volume of or substance abuse, severe general diseases, and endocrinopathies. informed consent and local medical ethics committee approved the study protocol. randomization women meeting the inclusion criteria were visited 508 | after a negative pregnancy test. if the consent was obtained, couples were given consecutive study numbers and sent to department of urology. a number. we used minimization to ensure comparability between women with respect to parity, type of miscarriage, and gestation. both groups were well matched according to male/female age, varicocele grade, and smoking history. inguinal standard varicocelectomy was performed using a loupe magnioutcome measures the primary endpoint was clinical pregnancy and live birth. the secondary outcome was to deterpatients and their husbands were visited every month during the whole study period. since besexual dysfunction and infertility table 1. baseline demographic and clinical characteristics of study groups.* characteristics group 1 (n = 68) group 2 (n = 68) p age, y male 36.1 ± 4.2 .67 female 29.1 ± 3.7 .46 infertility duration, y 5.4 ± 2.6 .52 prior miscarriage, no. 3.7 ± 1.3 .72 body mass index, kg/m2 male 27.3 ± 2.4 27.6 ± 2.2 .72 female 24.1 ± 2.7 24.3 ± 2.6 .64 varicocele grade, no. (%) grade i 17 (25.0) 15 (22.1) grade ii 41 (60.3) 42 (61.7) .24 grade iii 10 (14.7) 11 (16.2) .09 testis volume, ml 23.7 ± 2.6 23.6 ± 2.7 .12 serum hormones male testosterone, nmol/l 16.4 ± 4.7 16.2 ± 4.6 .27 fsh, iu/l 12.2 ± 3.6 12.6 ± 4.1 .34 female shbg, nmol/l 63.2 ± 14.4 .47 lh, iu/l .62 fsh, iu/l 9.7 ± 2.4 9.4 ± 2.3 .46 estradiol, pmol/l 91.2 ± 47.1 .26 estrone, pmol/l 102 ± 25 .52 prl, pmol/l prolactin. 509vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l ginning of the study, to assess fertility outcome, women were visited every month to complete a questionnaire. we collected data regarding pregnancy, including date of last normal menstrual period, serum level mation of clinical pregnancy. pregnancy testing was performed by the quantitative measurement of serum level of hcg in the absence of menstruation. for every 3-month visit, two semen samples were time to pregnancy since the start of the trial. all of the clinical pregnancies were followed up until delivery. statistical analysis univariate analyses were carried out using student’s t test for continuous variables and the chisquare or fischer’s exact test for dichotomous variables. a two-sided independent-sample t test was used for comparison. the pearson correlation r was used to determine any potential associations. cox proportional hazards regression analysis was performed to determine which groups of varicocelectomy and miscarriage | mansour ghanaie et al table 2. semen parameters and pregnancy data at various assessment points.£ assessment points after varicocelectomy assessment points during expectant therapy variables baseline 3 months 6 months 9 months 12 months baseline 3 months 6 months 9 months 12 months semen parameters, (mean ± sd) total sperm count, ×106 110.6 ± 15.3 114.2 ± 14.4d 159.4 ± b 176.2 ± 15.1c c 113.4 ± 12.2 115.2 ± 14.2d 14.2d 114.2 ± 14.7d 115.5 ± 16.7d sperm density, ×106/ml 32.2 ± 6.4 33.2 ± 4.4d 55.2 ± 5.2c 56.2 ± c 62.6 ± 5.7c 32.4 ± 6.4 36.6 ± 5.3d 6.1d 36.6 ± 6.2d 36.7 ± 6.1b sperm motility, % 2.2 41.4 ± 2.5d 4.4a b 54.2 ± 5.7c 37.2 ± 2.1 2.6d 40.4 ± 2.2d 39.6 ± 2.6d 40.6 ± 2.5 d normal morphology, % 56.7 ± 2.6 59.7 ± 2.6d 64.4 ± 3.4a 67.6 ± 4.6c 66.4 ± 4.2c 2.4 67.7 ± 3.4d 3.5d 3.5 d d pregnancy data, no. (%)* clinical pregnancy rate na 0 (0) 20 (29.4) 7 (10.3) 3 (4.4) na 5 (7.3) 4 (2.6) 3 (2.6) live birth rate na 0 (0) 3 (100.0) na 0 (0.0) 1 (20.0) 1 (25.0) 2 (66.7) miscarriage rate na 0 (0) 3 (15.0) 1 (14.3) 0 (0.0) na 1 (100.0) 3 (75.0) 1 (33.3) ap = .02 to .05, bp = .01, cp = .001 to .005, and dp = not significant. all p values are versus baseline. *new cases between previous assessment point and current assessment point. £ 510 | pregnancy rates. the spss software (the statistical package for the social sciences, version 17.0, statistical analyses and a p value < .05 was considresults baseline demographics and clinical characteristics of study groups are shown in table 1. mean total sperm count, sperm concentration, sperm motility, in sperm parameters were observed during the baseline mean sperm concentration in groups 1 ml, respectively (p period, the mean sperm concentration increased by (p celectomy, the increases in total sperm counts from improved sperm motility. mean sperm motility months postoperatively (p underwent varicocelectomy, the normal morphological sperm level increased from a mean of 56.7 (p when studying the correlations between the time elapsed after the varicocelectomy and the semen analysis parameters, strong positive correlations were found between elapsed time and sperm conp p phology (r = 0.37; p forty-three of 138 couples conceived clinically nancies were after the varicocelectomy and 13 p = .003; table (p varicocelectomy group, respectively. these rates respectively (p tively (p table 3. summary of multiple regression analysis of factors affecting live birth rates in couples. variables univariate multivariate coefficient p odds ratio (95% ci)* coefficient p odds ratio (95% ci) male age, y -0.024 .03 -0.026 .03 female age, y -0.062 .002 -0.064 .002 varicoceletomy .001 .001 total sperm count, ×106 0.061 .001 3.6 (2.5 to 5.6) 0.067 .001 sperm density, ×106/ml 0.072 .001 3.7 (2.7 to 6.4) 0.073 .001 3.2 (2.5 to 5.2) normal morphology, % 0.064 .001 2.7 (1.7 to 4.7) 0.061 .01 2.7 (1.7 to 4.7) *ci indicates confidence interval. sexual dysfunction and infertility 511vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l ended with miscarriage in the expectant group. correlations we also addressed the correlations between some variables and live birth. we put them in multivarilated to outcome were the sperm density followed chance of pregnancy increased with an increase in p = .001] and decreased with rising age of to 0.90; p the time elapsed from varicocelectomy was a continuous variable that was categorized into two difp nancy within the statistical model. with sperm mowas almost 3.5 times more than the chance with to 5.8; p ogy was > 60%, the chance of achieving pregnancy p discussion celectomy and the rate of clinical pregnancy and miscarriage. the risk of child loss decreased sigmained after correction for male/female age and study for comparison. our data indicate that even in healthy men with varicocele, without overt oligoasthenoteratozoospermia, there is an increased risk of miscarriage in their wives. in the present study, varicocelectomy in normozoospermic men resulted in improved live birth rate in their wives. we could not explain this completely. men with varicocele have increased oxidative dna damage. seminal antioxidant capacity increased oxidative stress production in seminal membrane and the sperm dna integrity. excessive sperm dna damage is associated with a reduction in some fertility indices, such as fertilization, embryo cleavage, implantation, and clinical pregnancy rates. o’brien and coworkers studied the outcomes in infertile men with varicocele who had female partners older than 35 years. they reported that surgical and nonsurgical approaches resulted in similar pregnancy rates. in this study, we included men with normal semen parameters. tion and excessive ros production. it has been shown that oxidative stress plays a key role in sperm dysfunction in patients with varicocele. spermatozoa are vulnerable to oxidative damage in men with varicocele, sperm ros levels are greater than those in normal healthy men. it has been demonstrated that varicocelectomy decreases ros levels and increases the antioxidant capacity of seminal plasma from infertile men with varicocele. increased level of ros in the reproductive tract disrupts the integrity of dna in the sperm nucleus. spermatozoa containing damaged dna may result in paternal transmission of defective genetic material with adverse outcomes for embryonic development. it has been reported that infertile men demonstrate improved sperm dna integrity six months after varicocele repair. varicocele is characterized by increased temperature of the scrotum. according to one theory, invaricocelectomy and miscarriage | mansour ghanaie et al 512 | creased temperature can result in thermal damage of the dna and proteins in the nucleus of spermatic tubules’ cells and/or leydig cells. furthermore, it has been shown that in men with varicocele, germ cell apoptosis is a very common phenomenon. indeed, germ cell apoptosis can lead to subsequent oligozoospermia. varicocele grades in the treated and untreated groups were well matched. our study is not without limitations. the main limitation is the small sample size. the sample was graphical area, limiting the generalizability of the al sperm parameters, such as seminal antioxidant capacity, sperm acrosomal reaction, and sperm dna integrity. conclusion our results demonstrate that varicocele repair increases the chance for spontaneous pregnancy and live birth. varicocelectomy may be offered to couples who suffer from recurrent miscarriage. nonetheless, further studies with a large number of subconflict of interest none declared. 6. sakkas d, moffatt o, manicardi gc, mariethoz e, tarozzi n, bimatozoa and the possible involvement of apoptosis. biol 7. saleh ra, agarwal a, sharma rk, said tm, sikka sc, thomas aj, jr. evaluation of nuclear dna damage in spermatozoa 6. griveau jf, le lannou d. reactive oxygen species and human spermatozoa: physiology and pathology. int j androl. 9. aitken rj, irvine ds, wu fc. prospective analysis of spermoocyte fusion and reactive oxygen species generation as criteria for the diagnosis of infertility. am j obstet gynecol. 10. sakkas d, mariethoz e, st john jc. abnormal sperm parameters in humans are indicative of an abortive apoptotic mechanism linked to the fas-mediated pathway. exp cell 11. gorczyca w, traganos f, jesionowska h, darzynkiewicz z. presence of dna strand breaks and increased sensitivity of dna in situ to denaturation in abnormal human sperm cells: analogy to apoptosis of somatic cells. exp cell res. 12. yguanosine in leukocyte dna of spermatic vein as a biomarker of oxidative stress in patients with varicocele. j urol. 13. cocuzza m, cocuzza ma, bragais fm, agarwal a. the role of varicocele repair in the new era of assisted reproductive 14. joshi nv, medina h, osuna ja. ultrastructural pathology of varicocele spermatozoa by using atomic force microscopy 15. mostafa t, anis th, el-nashar a, imam h, othman ia. varicocelectomy reduces reactive oxygen species levels and increases antioxidant activity of seminal plasma from infertile 16. 11. 17. li tc, makris m, tomsu m, tuckerman e, laird s. recurrent miscarriage: aetiology, management and prognosis. hum references 1. oster j. varicocele in children and adolescents. an investigation of the incidence among danish school children. scand 2. niedzielski j, paduch d, raczynski p. assessment of adoles3. diamond da. adolescent varicocele: emerging understand4. world health organisation. the influence of varicocele on parameters of fertility in a large group of men presenting to 5. hadziselimovic f, herzog b, jenny p. the chance for fertility in adolescent boys after corrective surgery for varicocele. j sexual dysfunction and infertility 513vol. 9 | no. 2 | spring 2012 |u r o lo g y j o u r n a l 19. palermo g, munne s, cohen j. the human zygote inherits its mitotic potential from the male gamete. hum reprod. 20. evenson dp, jost lk, marshall d, et al. utility of the sperm chromatin structure assay as a diagnostic and prognostic 49. 21. g. sperm chromatin damage impairs human fertility. the danish first pregnancy planner study team. fertil steril. 22. sakkas d, urner f, bizzaro d, et al. sperm nuclear dna damage and altered chromatin structure: effect on fertilization 4:11-9. 23. lopes s, sun jg, jurisicova a, meriano j, casper rf. sperm deoxyribonucleic acid fragmentation is increased in poorquality semen samples and correlates with failed fertili24. rubio c, simon c, blanco j, et al. implications of sperm chromosome abnormalities in recurrent miscarriage. j assist re25. agarwal a, prabakaran s, allamaneni ss. relationship between oxidative stress, varicocele and infertility: a meta26. o'brien jh, bowles b, kamal km, jarvi k, zini a. microsurgical varicocelectomy for infertile couples with advanced female 43. 27. pasqualotto ff, sharma rk, nelson dr, thomas aj, agarwal a. relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing infertility nallella kp, allamaneni ss, pasqualotto ff, sharma rk, thomas aj, jr., agarwal a. relationship of interleukin-6 with semen characteristics and oxidative stress in patients with 29. hendin bn, kolettis pn, sharma rk, thomas aj, jr., agarwal a. varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal 30. zini a, buckspan m, jamal m, jarvi k. effect of varicocelectomy on the abnormal retention of residual cytoplasm by 31. zini a, blumenfeld a, libman j, willis j. beneficial effect of microsurgical varicocelectomy on human sperm dna in32. naughton ck, nangia ak, agarwal a. varicocele and male infertility: part ii: pathophysiology of varicoceles in male in33. 59. varicocelectomy and miscarriage | mansour ghanaie et al non-invasive stent removal after ureteroneocystostomy in pediatric patients: long-term results yasar issi purpose: among the more serious problems in urological interventions among the pediatric age group is the requirement of general anesthesia. the advantages of removing a double-j stent (djs) without anesthesia in ureteroneocystostomy (unc) operations among children were investigated in this study. patients and methods: in all, 25 patients who underwent unc surgery between november 2016 and november 2018 were retrospectively divided into two groups according to the method used for the removal of the djs. in group 1, the stent was tied to the urethral catheter by a suture and retrieved postoperatively on the fourth day without anesthesia and cystoscopy. in group 2, we inserted the stent according to the classical method with no suturing to the catheter and removed it 3 to 4 weeks after the first operation, with cystoscopy under anesthesia. results: a total of 16 girls and 9 boys were included in the study. the mean age was 4.3 and 6.3 years in groups 1 and 2, respectively. we did not observe statistically significant difference between the groups in long-term renal function or hydronephrosis regression. conclusion: we consider that the removal of a stent placed in pediatric intravesical unc operations without anesthesia and cystoscopy is less invasive and affords safety and long-term results comparable to the standard method. keywords: catheter; vesico-ureteral reflux; stent; pediatrics introduction in anastomotic urological surgeries performed in pediatric patients, double-j stent (djs) application is the most common procedure and is almost routine. stents play an important role in preventing postoperative obstruction or leakage of urine through anastomosis. there are controversies in the literature regarding whether ureteral stenting in patients undergoing transtrigonal ureter reimplantation is required and how long it should remain in patients in whom it have been applied. in general, surgeons tend to leave the stent for an extended time (approximately 1 month) because of safety, while others prefer to remove the stent after a short time (3-7 days), and yet others do not prefer stenting.(1,2) however, unlike with adults, stent removal requires anesthesia and a new operation. in addition, due to dysuria and hematuria complaints, antibiotic treatment may be given unnecessarily, with the assumption that there is a urinary tract infection. apart from these concerns, if the stent is left in place for a lengthy period, stent migration and encrustation are additional complications that can be seen. considering that all these complications are corrected under anesthesia in pediatric patients, it may be seen how difficult the process can be. therefore, to avoid further interference, new methods have been presented in the literature. in this study, the benefits and results of removing a djs without anesthesia in ureteroneocystostomy (unc) operations on children were investigated. *cengiz gokcek maternity and children hospital, department of pediatric urology, gaziantep, turkey. email: yasarissi@yahoo.com. received february 2020 & accepted august 2020 patients and methods this cross-sectional retrospective study was performed between november 2016 and december 2018. in all, 25 patients, regardless of age or sex, who underwent intravesical unc surgery due to vesicoureteral reflux in south-eastern turkey were included to the study. ureteral tailoring was not performed on any of the patients. patients were divided into two groups according to the method of djs removal performed during surgery (unilateral/bilateral) for intravesical technical procedures in a pediatric urology department. one end of the djs of 14 patients in the first group was connected to the trans-urethrally inserted catheter with the help of its own thread or a suture (figures 1 and 2). patients in this group were hospitalized for 3 days with probes. at the end of the fourth day, when the catheter was removed, the djs was removed spontaneously, and no anesthesia was required. the stents of the 11 patients in group 2 were taken as standard and removed under anesthesia 3 to 4 weeks after surgery. all patients in group 2 received antibiotic prophylaxis until the stents were removed. patients in group 1 did not receive additional treatment after discharge. patients in both groups were called for follow-up on the 15th day, first month, third month, sixth month, twelfth month, and eighteenth month after the operation. all patients underwent tc99m dimercaptosuccinic acid (dmsa) scintigraphy 6 months and 1 year after the operation. ultrasonography was performed during all follow-ups to monitor for hydronephrosis. at all follow-ups, the two groups pediatric urology urology journal/vol 18 no. 3/ may-june 2021/ pp. 322-325. [doi: 10.22037/uj.v16i7.6023] vol 18 no 3 may-june 2021 138vol 18 no 3 may-june 2021 323 were compared for the presence of infection, operation success, the need for additional treatment, and whether complications occurred. exclusion criteria of the study were any previous antireflux surgery for vesicoureteral reflux, performance of any extravesical surgical technique of ureteral reimplantation, and patients who could not be followed properly. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. results a total of 16 girls and 9 boys were included in the study. the mean age was 4.3 and 6.3 years in groups 1 and 2, respectively. the mean follow-up period for group 1 was 10.1 months (range 3–18 months), while in group 2 it was 9.8 months (range 3–18 months). two of the patients in group 2 had cystitis-like symptoms, and no evidence of urinary tract infection was detected. complaints were due to djs irritation, and anticholinergic treatment was started. both patients experienced regression of these complaints, and treatment continued until the stents were removed. none of the patients had postoperative pyelonephritis. although the stents of patients in group 1 were withdrawn early, no progress was observed in any of the patients’ hydronephrosis, noninvasive stent removal in pediatric ureteroneocystostomyissi figure 1. intraoperative image of connecting the stent to the urethrally inserted catheter with a suture. figure 2. intraoperative view of the ureteral stent attached to the catheter. and no new hydronephrosis occurred. we observed regression in dilatation of all patients with hydronephrosis. postoperative scintigraphic features of all patients were similar to those in the preoperative period. none of the patients required a second operation. discussion most surgeons perform stenting of the ureter in terms of anastomosis safety during intravesical unc operations performed to treat vesicoureteral reflux or ureterovesical stenosis disease in pediatric patients. removal of the ureteral stent requires anesthesia in pediatric patients. every administration of anesthesia carries a natural risk. in addition, the patient must be hospitalized again, and therefore labor, time, and financial costs are incurred. to prevent the administration of anesthesia again within a short period, the patient waits 3–4 weeks for the second operation and lives with a stent during this time. most clinics continue prophylactic antibiotic treatment during this time; however, in some patients, secondary to the foreign body reaction, urine burning, difficult urination, urinary tract infection, stent petrification—named “stent syndrome”(3)—can develop, which may require hospitalization(4,5). considerable research has been done on the treatment of stent-related symptoms in adults. in treatment, anticholinergics or alpha blockers alone and their combinations have yielded successful results(6-8). in children, although no specific study related to this syndrome has been reported, in one study patients were given combinations of painkillers, oxybutynin, and phenazopyridine for stent-related complaints after robotic pyeloplasty(9). in addition, stent encrustation and stone formation are among the most difficult complications of djs. these complications can be addressed with operations ranging from endoscopic minimally invasive methods to open surgery(10,11). while some of these methods can be applied under local anesthesia in adults, all procedures are under general anesthesia in children. djs migration is not common but is a well-known complication that extends the duration of the second session. managing stent migration in pediatric patients is a more challenging process than adults. several methods for resolving this problem have been reported(12,13). the most common, and most disturbing, complication is ureteral stent-dependent complaints. modification of stent removal methods in pediatric patients has been studied inadequately, and related data about it are limited. another preferred method is to place a thin feeding catheter to the anastomosed ureter. then, the catheters are removed from lateral sides of the lower abdominal wall. however, in these patients, an additional surgical scar is formed after the catheter is removed. this scarring may cause cosmetic distress for patients, who are children. in addition, cases of infection can also be observed in this application because it involves exposure to the external environment. for all these reasons, we believe that the removal of the stent without anesthesia and before the discharge of the patient has numerous benefits and avoids the long-term use of antibiotics. there are few studies in the literature, and we could not find any stent removal method which can be performed easily and effortlessly(14). this study has some limitations. our sample was small since it was at a single center, and a single surgeon and the same surgical method were preferred. the other limitation was the retrospective design of the study. conclusions in conclusion, since it is not possible to remove ureteral stents without anesthesia in childhood, the attachment of a djs to the urethral catheter and removal with the catheter eliminates the need for any additional intervention or anesthesia. in this study, we did not observe any difference in terms of complications or surgical success in long-term observation of both methods. for these reasons, we consider that the removal of a stent placed during intravesical unc operation without anesthesia and without cystoscopy is the less invasive method, with safety and long-term results comparable to the standard method. references 1. so ep, brock wa, kaplan gw. ureteral reimplantation without catheters. j urol. 1981;125:551‐553. 2. miller of, bloom tl, smith lj, mcaleer im, kaplan gw, kolon tf. early hospital discharge for intravesical ureteroneocystostomy. j urol. 2002;167:2556‐59. 3. lawrentschuk n, russell jm (2004) ureteric stenting 25 years on: routine or risky? anz j surg 74:243–7. 4. al-kandari am, al-shaiji tf, shaaban h, ibrahim hm, elshebiny yh, shokeir aa. effects of proximal and distal ends of double-j ureteral stent position on postprocedural symptoms and quality of life: a randomized clinical trial. j endourol 2007 ;21:698-702. 5. giannarini g, keeley fx jr, valent f, manassero f, mogorovich a, autorino r, et al. predictors of morbidity in patients with indwelling ureteric stents: results of a prospective study using the validated ureteric stent symptoms questionnaire. bju int 2011 feb; 107:648–54. 6. yan h, wang y, sun r, cui y. the efficacy of antimuscarinics alone or in combination with alpha-blockers for the treatment of ureteral stent-related symptoms: a systematic review and meta-analysis. urol int. 2017;99:6-13. 7. wang j, zhang x, zhang t, mu j, bai b, lei y. the role of solifenacin, as monotherapy or combination with tamsulosin in ureteral stentrelated symptoms: a systematic review and meta-analysis. world j urol. 2017;35:16691680. 8. chen yb, gao l, jiang q, ran k, luo rt. tamsulosin monotherapy is effective in reducing ureteral stent-related symptoms: a meta-analysis of randomized controlled studies. curr med sci. 2019;39:707-718. 9. finkelstein jb, van batavia jp, casale p. is outpatient robotic pyeloplasty feasible? j robot surg. 2016;10:233-237. 10. bultitude mf, tiptaft rc, glass jm, dasgupta p. management of encrusted ureteral stents impacted in upper tract. urology. 2003;62:622626. 11. dakkak, y, janane, a, ismail, t, ghadouane, m, ameur, a, abbar, m. management of encrusted ureteral stents. african journal of urology. 2012;18. 131–134. 12. jayakumar s, marjan m, wong k, bolia a, pediatric urology 324 noninvasive stent removal in pediatric ureteroneocystostomyissi ninan gk. retrieval of proximally migrated double j ureteric stents in children using goose neck snare. j indian assoc pediatr surg. 2012 jan;17:6-8. 13. low rk, kogan ba, stoller ml. intraluminal wire retrieval of a proximally migrated pediatric double-j ureteral stent. j urol. 1995;154:223–224. 14. nabavizadeh b, keihani s, hosseini sharifi sh, kajbafzadeh am. insertion of a single double j stent for bilateral open ureteral reimplantation: introducing a novel technique and assessment of feasibility. int urol nephrol. 2016 ;48:1015-9. vol 18 no 3 may-june 2021 325 noninvasive stent removal in pediatric ureteroneocystostomyissi v08_no_4_final_new.pdf point of technique 320 urology journal vol 8 no 4 autumn 2011 assessment of increased desquamation of epididymal epithelial cells in semen of men as a predictor of acute epididymitis fernando tadeu andrade-rocha urol j. 2011;8:320-2. www.uj.unrc.ir keywords: epididymis, epididymitis, semen, semen analysis, epithelial cells cipslab – center for advanced semen analysis, dom bosco laboratory, niterói, rj, brazil corresponding author: fernando tadeu andrade-rocha, bs cipslab – center for advanced semen analysis, dom bosco laboratory avenida ernani do amaral peixoto 178 sala 609, 24.020-075, niterói, rj, brazil tel/fax: + 55 021 212 719 9670 e-mail: ftarocha@yahoo.com.br received december 2010 accepted march 2011 introduction acute epididymitis is an inflammation of the epididymis sometimes diagnosed in urological practice, in men mainly aged between 18 to 50 years.(1) usually, the sexually transmitted pathogens chlamydia trachomatis and neisseria gonorrhoeae are causes of acute epididymitis in men under 35 years old, whereas in men older than the age 35, the infection is generally caused by common urinary tract pathogens, such as escherichia coli.(2) acute epididymitis is also caused by noninfectious factors, such as behçet’s disease, urethral manipulation, epididymal injury after vasectomy, and urinary reflux in the epididymis.(1) clinically, the diagnosis of acute epididymitis is based on careful history taking, physical examination, urine and/or semen cultures, and ultrasonography findings. semen analysis has been infrequently used in diagnosing acute epididymitis. in few cases in which semen specimens were explored, it has been given emphasis to the quantification of seminal leukocytes and the investigation of causative pathogen (semen culture).(2) sometimes, the evaluation of the incidence of sperm abnormalities after the treatment has also been of particular concern, to investigate the deleterious effects of the infection on male fertility.(3) on the other hand, semen analysis does not provide any data about negative impacts of the infection on the epididymal epithelium. this study reports a case of 24-yearold man with acute epididymitis causing exceeding desquamation of epithelial cells of the epididymis in seminal fluid. implications of this finding are discussed. case report a 24-year-old man was referred to the center for advanced semen analysis (cipslab) to do semen analysis with a diagnosis of acute epididymitis made by his family urologist, based on complaints of testicular pain and swollen, somewhat tenderness of the left testis and findings in ultrasonography evaluation. the patient had no history of genital trauma, including testicular torsion, and genital infections, such as urinary tract infections. the semen specimen was collected in the laboratory by masturbation, after four days of sexual abstinence. epididymal cells in semen in acute epididymitis—andrade-rocha 321urology journal vol 8 no 4 autumn 2011 technique physical properties of the ejaculate were evaluated according to methodologies reported previously,(4) whereas sperm characteristics and the leukocyte count were assessed following recommendations of the world health organization (2010) laboratory manual for the examination and processing human semen.(5) in cipslab, the assessment of squamous epithelial cells from the urethra, prostate, seminal vesicles, and transitional epithelium is part of the semen analysis routinely, which are assessed according to methodology described elsewhere.(6) increased desquamation of these cells is commonly found in disorders affecting epithelia of the accessory genital glands, including those caused by infections. recently, the assessment of epididymal epithelial cells was also introduced in semen analysis routinely in the laboratory using the same methodology, which was assessed in semen of this patient. results table demonstrates evaluated semen parameters. apart from the pronounced leukocytospermia, seminal phagocytes were also found increased at a ratio of 15 leukocytes per phagocyte. in the assessment of the squamous epithelial cells of the accessory sex glands, no cells were found from the seminal vesicles, the transitional epithelium, and a normal concentration of the prostatic epithelial cells (6% of total of squamous epithelial cells) was found. on the other hand, an increased incidence of epididymal epithelial cells (20% of total of squamous epithelial cells) was found, usually forming clusters (figure). this finding was considered uncommon in the routine of the laboratory, as these cells are usually found in percentage of less than 5%. like other examinations, squamous epithelial cells were abundant in the sample (74% of total). parameter results reference value coagulation moderate moderate† liquefaction 40 min 10 to 60 min† volume 6.3 ml 2.0 to 5.0 ml† viscosity hyperviscosity normoviscosity† ph 8.4 7.3 to 7.8† sperm concentration/ml 4.75 × 106/ml 6/ml vitality 62% > 58% total motility 47% > 40% progressive motility 46% > 32% non-progressive motility 1% 1 to 18% immotile 53% 22 to 59% hypoosmotic swelling test 52% > 58% normal morphology 4% > 4% small head 18% large head pyriform 2% amorphous 36% round-headed pin-headed 5% tapered cytoplasmic droplet abnormal mid-piece 2% abnormal tail combined anomalies 33% leukocytes/ml 15.2 × 106/ml < 1 × 106/ml urethral cells 74% ‡ > 70% § prostate cells 6% ‡ 17% ¶ seminal vesicles cells < 10% § epididymal cells 20% ‡ § transitional cells seminal parameters of a man with acute epididymitis and increased desquamation of epididymal epithelial cells † reference values published previously(4) ‡ percentage of the total of squamous epithelial cells § unpublished reference values ¶ reference value published previously(6) other reference values – world health organization manual for semen analysis(5) microscopic examination of human semen showing increased desquamation of non-germinal epithelial cells and leukocytes (×1000). the arrows show epididymal cells. semen smear stained by a modified leishman’s blood staining method(6) epididymal cells in semen in acute epididymitis—andrade-rocha 322 urology journal vol 8 no 4 autumn 2011 discussion to the best of my knowledge, this is the first report on the increased desquamation of the epididymal cells in semen in acute epididymitis. semen analysis is infrequently performed in investigating this infection in urological practice. if any, the presence and increase of epididymal cells are not investigated routinely, because no suitable methodology is available. since acute epididymitis produces well-defined symptoms, the treatment is usually performed promptly, taking into account the patient’s age, without using this laboratory procedure to the protocol considers that the infection disease is probably caused by neisseria gonorrhoeae or chlamydia trachomatis. on the other hand, if the patient is > 35 years, it is assumed that the infection is probably caused by gram-negative bacilli, such as escherichia coli.(7) indeed, semen analysis is mostly indicated in investigating male infertility. therefore, this examination mainly focuses on the evaluation of sperm characteristics and function. as a consequence, there is a plethora of information about physiological and pathological properties of the spermatozoa in the literature on male infertility. on the other hand, few data are available about the presence of squamous cells of the accessory sex glands in semen, including epididymal cells, which are only reported in studies about the composition of the epididymal epithelium.(8) even the presence of the prostate cells in semen has been poorly explored; however, there are a plethora of studies reporting damage in the prostate epithelium, chiefly in patients with the prostate cancer. ultimately, squamous epithelial cells of the genital glands are not usually investigated in laboratory practice of the semen analysis. i could not determine whether the increase of epididymal cells in the semen is indicative of damage to the epididymal epithelium caused by the infection. however, it is thought that it will open up a new way for studying the pathophysiology of the epididymis, since it is now technically feasible to detect epididymal cells in the semen routinely, as reported herein. it is also expected that the increased desquamation of the epididymal cells in the semen may be a marker of damage to the epididymal epithelium; however, no solid proof was found. therefore, further studies are needed to more consistently evaluate the clinical significance of this finding. conflict of interest none declared. references 1. luzzi ga, o’brien ts. acute epididymitis. bju int. 2001;87:747-55. 2. trojian th, lishnak ts, heiman d. epididymitis and orchitis: an overview. am fam physician. 2009;79:583-7. 3. weidner w, garbe c, weissbach l, et al. [initial therapy of acute unilateral epididymitis using ofloxacin. ii. andrological findings]. urologe a. 1990;29:277-80. 4. andrade-rocha ft. physical analysis of ejaculate to evaluate the secretory activity of the seminal vesicles and prostate. clin chem lab med. 2005;43:1203-10. 5. world health organization. who laboratory manual for the examination and processing of human semen. 5 ed. geneva: world health organization press; 2010. 6. andrade-rocha ft. assessment of exfoliated prostate cells in semen: relationship with the secretory function of the prostate. am j clin pathol. 2007;128:788-93. 7. centers for disease control and prevention. sexually transmitted diseases treatment guidelines 2006: epididymitis. available at: http://www.cdc.gov/std/ treatment/2006/epididymitis.htm. accessed january 23, 2009. 8. cornwall ga. new insights into epididymal biology and function. hum reprod update. 2009;15:213-27. miscellaneous the therapeutic effect of intravesical instillation of platelet rich plasma on recurrent bacterial cystitis in women: a randomized clinical trial mahboubeh mirzaei1, azar daneshpajooh1, alireza farsinezhad2, zeinab jafarian3, mohammad reza ebadzadeh1, narjes saberi4, mohammad teimorian1* purpose: recurrent bacterial cystitis is a common infection in women and there are concerns about its antibiotic therapy. platelet rich plasma has antimicrobial and tissue repairing effects. we investigated the effect of platelet rich plasma as an intravesical therapy to prevent recurrence of bacterial cystitis. materials and methods: thirty women with a history of recurrent bacterial cystitis were randomly assigned into two groups: 1) platelet rich plasma and 2) control groups. the first group received 10 ml of platelet rich plasma with intravesical instillation plus 40 ml of normal saline. the control group only received 50 ml of normal saline. we did the instillation once a week for four weeks in both groups. we followed up the participants two and 12 months after the last instillation with a questionnaire (the international consultation on incontinence questionnaire in overactive bladder) and result of their urine culture. results: a significant decrease was observed in the number of bacterial cystitis recurrences in the platelet rich plasma group compared to the control group 12 months after the instillation (4 vs. 1, p = 0.004). also, there was a significant improvement in the questionnaire’s score two (3.6 ± 2.58 vs. 0.66 ± 1.63, p = 0.002) and 12 months (3.4 ± 2.77 vs. 0.006 ± 1.83, p < 0.001) after instillation in the platelet rich plasma group compared to control group. there was no adverse effect 12 months after instillation. conclusion: platelet rich plasma can significantly decrease the recurrence of bacterial cystitis up to a year after instillation without any side effect. keywords: platelet rich plasma; recurrent cystitis; bacterial cystitis; intravesical instillation introduction urinary tract infection is the most common bacterial infection. the acute cystitis occurs about 0.5 episodes per person per year in young women(1). approximately 25% of women involved in the first episode of cystitis experience recurrent urinary tract infections in the next six months. some of them experience this infection six or more times per year. also, recurrence of cystitis which follows an acute cystitis is a major complaint that can affect their quality of life(2). bacterial urinary tract infection occurs with various symptoms, and many organisms can be responsible for it. escherichia coli is the most common pathogen of acute cystitis(2). although its current antibiotic therapy is effective, it cannot prevent the recurrence of bacterial cystitis(2). prophylactic antibiotic regimes cannot prevent infection completely(3). according to the rising uropathogens’ antibiotic resistance, we will soon need new treatments for this urinary tract infectious disease(4,5). there is a strong relationship between lower urinary tract symptoms such as frequency, urgency, suprapubic 1department of urology, kerman university of medical sciences, kerman, iran. 2cell therapy and regenerative medicine center, kerman university of medical sciences, kerman, iran. 3department of internal medicine, kerman university of medical sciences, kerman, iran. 4isfahan kidney transplantation research center, isfahan university of medical sciences, isfahan, iran. *correspondence: department of urology, shahid bahonar hospital, gharani ave, kerman, iran. postal code: 7613747181 tel: 3422235011 98+. fax: 3432239188 98+. mobile: 9111002128 98+. email: teimorianm@gmail.com received march 2019 & accepted august 2019 pain with or without hematuria and positive urine culture(6,7). a symptomatic cystitis depends on a reaction between a uropathogen and the host cells(8). uropathogens can continue to expose immature urothelial cells and form quiescent intracellular reservoirs to protect themselves from the immune system and antibiotics(9-11). platelet rich plasma (prp) is the concentrated autologous platelet in a small amount of plasma. also, factors such as factor 7, tgf（1, tgfβ2, pdgfαβ, pdgfββ, pdgfαα, egf and vegf and three blood proteins (fibrin, fibronectin and vitronectin which repair lesions) can be found in prp(12). some studies suggest the antimicrobial role of platelet with releasing antimicrobial peptides from its alpha granules. these peptides have a broad-spectrum action against gram-positive and gram-negative bacteria and fungi(13-16). in our study, we sought to return the bladder to a normal state in which it would be sterile for a longer period. this therapeutic idea had been suggested before(17). thus, we investigated the effect of prp as an intravesical therapy to prevent recurrence of bacterial cystitis. urology journal/vol 16 no. 6/ november-december2019/ pp. 609-613. [doi: 10.22037/uj.v0i0.5239] patients and methods study design and population this was a double-blinded clinical trial with available sampling method. in this sense, 30 women older than 18 years old participated in our study. they had referred to our center with a history of recurrent cystitis in 2016. they were randomly assigned into two groups based on random table numbers (15 women in each group): 1) prp and 2) control groups. the first group received 10 ml of prp with intravesical instillation plus 40 ml of normal saline. the control group only received 50 ml of normal saline. the inclusion criteria were having: 1) at least four episodes of bacterial cystitis during the previous year; and 2) positive urine culture with more than 1000 cfu/ml. the exclusion criteria were having: 1) any urologic disease history (such as ureterocele, vesicoureteral reflux, urinary stone, urethral stenosis, pyelonephritis history); 2) any history of urological surgery (such as cystocele); 3) any measurable post-void urine residue, constipation, vaginal prolapse; 4) an active infection at the time of entering the study; 5) not using any drugs and addiction history; and 6) not using spermicidal and intrauterine devices during the study. one woman in each group was single. the rest were married and sexually active. we instilled the treatment for each participant based on her group once a week for four weeks, that is if she cooperated and based on her therapeutic responses. then we followed them up at two and 12 months after the last instillation. they filled a questionnaire and we took their urine culture before the first instillation and in each follow-up session. the questionnaire was the persian (farsi) version of international consultation on incontinence questionnaire in overactive bladder (iciq-oab)(18). this questionnaire has five questions and each question has a score of 1 to 4 according to severity of symptoms. if at any time after treatment the participants had symptoms of acute cystitis, we did urine culture and they underwent a three-day antibiotic therapy with ciprofloxacin. informed consent was obtained from the participants before entering the study. this study was approved by the ethics committee of our university (ir.kmu. ah.rec.1396.110). instillation method the instillation was done with a 10 french nelaton catheter insertion in both groups. it was done in a sterile method and under local anesthesia with xylocain 2% gel. the participants did not void until two hours after instillation. the instillation’s position was changed every 30 minutes to the sides, back and abdomen to make sure it reaches the entire bladder. platelet rich plasma preparation the first 20 ml of participants’ blood was collected in a dexterous citrate acid contained tube. then it was centrifuged 10 minutes with 2400 rmp at room temperature to be divided into three layers: red blood cells, buffy coat and platelet poor plasma. buffy coat and platelet poor plasma were carefully transferred to another tube with micropipette. platelet poor plasma was centrifuged 10 minutes at 3500 rmp at room temperature. prp was extracted from it and used for instillation immediately (figure 1). statistical analysis mann-whitney u test was used to compare the demographic characteristics and number of bacterial cystitis episodes. we used wilcoxon test for comparing the bacterial cystitis episodes between patients before and after intervention. the repeated measure analysis was used to compare iciq-oab scores within groups during follow up (before treatment, two and 12 mounts after treatment), respectively. the data were analyzed with statistical package for social sciences (spss) software version 18. results the means of age were 46.2 ± 10.62 and 45.06 ± 11.93 years old (p = 0.78) in the prp and control groups, respectively. there was no significant difference between the two groups in the number of deliveries 2.46 ± 1.24 vs 3 ± 1.77 (p = 0.34) before the study. there was no significant difference in the number of bacterial cystitis episodes between the two groups (p = 0.13; table 1) a year after the intervention, a significant reduction was observed in the number of cystitis recurrences in both groups (5.53 ± 1.92 vs 1.88 ± 1.59, p = 0.001 in prp group and 6.46 ± 1.64 vs 5 ± 1.6, p = 0.003 in the control group). this reduction was significantly more in the prp group compared to the control group (3.66 ± 2.16 vs. 1.46 ± 1.59, p = 0.004). there was a little reduction in the control group that could be due to placebo effect (table 2). the result of the repeated measure analysis showed that iciq-oab score decreased significantly in prp group table 1. comparison of bacterial cystitis episodes in the prp and control groups bacterial cystitis episodes prp group control group p-value* before treatment (mean) 5.53 ± 1.92 6.46 ± 1.64 0.13 12 months after treatment (mean) 1.88±1.59 5 ± 1.64 < 0.001 * mann-whitney u bacterial cystitis episodes before treatment (mean) 12 months after treatment (mean) p-value† the reduction of bacterial cystitis episodes p-value* prp group 5.53 ± 1.92 1.88 ± 1.59 < 0.001 3.66 ± 2.16 0.004 control group 6.46 ± 1.64 5 ± 1.64 0.003 1.46 ± 1.59 † wilcoxon test * mann-whitney u table 2. comparison of bacterial cystitis episodes and the reductions before and after treatment in prp and control groups prp preventing bacterial cystitis-mirzaei et al. miscellaneous 610 vol 16 no 06 november-december2019 611 during follow up (p ≤ 0.001). but there was no significant change in this score in the control group during the same period (p = 0.89; table 3) discussion the recurrent bacterial cystitis is a common infection in women(1). its current antimicrobial therapies have problems such as increased antibiotic resistance and recurrence after discontinued treatment(2,4,5). therefore, we need to find new treatments for it. platelet has an antimicrobial role with releasing antimicrobial peptides from its alpha granules(13-16). there are studies on using prp for tissue repair(19,20) which can be used to repair the damaged bladder mucosa in recurrent cystitis. dönmez and colleagues investigated the effect of prp intravesical instillation in interstitial cystitis in rabbits. they divided the rabbits into four groups: 1) serum physiologic, 2) serum physiologic + prp, 3) hydrochloride acid and 4) hydrochloride acid + prp. they observed that mitotic activity increases in serum physiologic + prp and hydrochloride acid + prp groups compared to serum physiologic and hydrochloride acid groups(21). they did instillation only once. they gave a 96-hour time to the agents to act on the bladder. although the results were significant, doing more instillations and spending more time could have had better results. two years later, the same authors studied the effects of prp on rabbits’ bladders. this time they instilled saline, saline + prp, hydrochloride acid, hydrochloride acid+prp, cyclophosphamide, cyclophosphamide+prp in six groups with six rabbits in each group. the bladder of rabbits in hydrochloride acid and saline groups were surgically removed 96 hours after the instillation. in cyclophosphamide group, they were removed 72 hours after administration. they saw that the instillation of prp significantly increases mitotic index and significantly decreases macroscopic bleeding in these groups(22). these results support the repairing role of prp on bladder mucosa. so, we theoretically accepted and used it to improve the symptoms of humans with recurrent bacterial cystitis. in another study, lara paro dias and colleagues used prp to treat the non-muscular invasive bladder cancer in rats. they divided the animals into four groups: 1) control, 2) bacillus calmette–guérin, 3) prp and 4) bacillus calmette–guérin+prp. they reported that animals treated with bacillus calmette–guérin+prp had less neoplastic lesion progression compared to the other groups (23). these studies are promising, but have been done on animals. to our knowledge, there is no study on prp intravesical instillation on humans. however, there are studies that have examined intravesical instillation therapies for recurrent bacterial cystitis with hyaluronic acid with or without chondroitin sulfate. they show the significant effect of intravesical instillation with few side effects(24-27). in a recent study, dutta and lane treated 39 women with recurrent urinary tract infection by heparin intravesical instillation in six sessions, one per week. they reported that 12 patients (30.8%) had recurrence of urinary tract infection in the treatment phase. 46.2% of patients had at least one urinary tract infection and seven (17.9%) met the criteria of recurrent urinary tract infections in the six months follow up period(28). their study had no control group and their follow-up period was only six months. if they had a longer follow-up period or a control group, the results could have been more useful. their study had no strong exclusion criterion that could lead to a difference in participants because of the small sample size, causing an error in the conclusion. we examined the effect of intravesical instillation of prp in women who suffered from recurrent bacterial cystitis. this is important because to our knowledge, it is the first study of intravesical instillation of prp on humans. so, we should be cautious about the possible adverse effects. although we had a small sample size, we observed a significant therapeutic effect in administering intravesical instillation of prp. this seems promising. although recurrence happened in all of our participants, the number of occurrences had decreased compared to the year before doing the intervention. we observed a partial improvement in the control group, which was the placebo effect in our study. conclusions prp seems to have a therapeutic effect. fortunately, we have not seen any adverse effect up to 12 months after instillation. prp can significantly improve the symptoms and decrease recurrence of cystitis up to a year after instillation. more studies with larger sample sizes should be done until we can present the intra-vesical instillation of prp as an available non-antibiotic therapy for recurrent cystitis. table 3. the comparison of iciq-oab scores before, two and 12 months after treatment in prp and control groups iciq-oab score before treatment 2 months after treatment 12 months after treatment p-value* prp group 12.06 ± 2.25 8.46 ± 3.22 8.66 ± 3.61 0.001 control group 13.06 ± 5.78 12.4 ± 2.61 13.13 ± 2.92 0.89 *repeated measure analysis figure 1. platelet rich plasma prp preventing bacterial cystitis-mirzaei et al. miscellaneous 612 acknowledgement the authors thank muhammed hussein mousavinasab for editing this text. this study was funded by kerman university of medical sciences. conflict of interest the authors report no conflict of interest. references 1. tm h. a prospective study for risk factors for symptomatic urinary tract infection in young women. n engl j med. 1996;335:468. 2. foxman b. urinary tract infection syndromes: ocuurrence, recurrence, bacteriology, risk factors, and disease burden. infect dis clin north am. 2014;28:1-13. 3. hoberman aea. antimicrobial prophilaxis for childeren with vesicoureteral reflux. n engl j med. 2014;370:2367-76. 4. kudinha tea. escherichia coli sequence type 131 as a prominent cause of antibiotic resistance among urinary escherichia coli isolates from reproductive-age women. j clin microbiol. 2013;51:3270-6. 5. spellberg bea. novel approaches are needed to develop tomorrows antibacterial therapies. am j respir crit care med. 2015;191:135-40. 6. bent s nb, simel dl, et al. dose this woman have an acute urinary tract infection? jama. 2002;287:2701-10. 7. gupta k ht, roberts pl, et al. patient-initiated treatment of recurrent urinary tract infection in women. ann intern med. 2001;135:9-16. 8. hannan tjea. host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic escherichia coli bladder infection. fems microbiol rev. 2012;36:616-48. 9. mysorekar iuah, s.j. mechanisms of uropathogenic escherichia coli persistence and eradication from the urinary tract. proc natl acad sci usa. 2006;103:14170-5. 10. mulvey maea. establishment of a persistent escherichia coli reservoir during the acute phase of a bladder infection. infect immun. 2001;69:4572-9. 11. schilling jdea. effect of trimethoprimsulfamethoxazole on recurrent bacteriuria and bacterial persistence in mice infected with uropathogenic escherichia coli. infect immun. 2002;70(7042-7049):7042. 12. chan ky tw. growth factors concentrate and the use there of. us patent. 2015;20:300. 13. mr. y. the role of platelets in antimicrobial host defense. clinical infectious diseases. 1997(951-68):951. 14. o. l. antimicrobial proteins and peptides of blood: templates for novel antimicrobial agents. blood. 2000;96:2664-72. 15. yeaman mr ps, norman d, bayer a. prp preventing bacterial cystitis-mirzaei et al. partial characterization and staphylocidal activity of thrombin-induced platelet microbicidal protein. infection and immunity. 1992;60:1202-9. 16. yeaman mr ia, edwards j, bayer a, ghannoum m. thrombin-induced rabbit platelet microbicidal protein is fungicidal in vitro. antimicrobial agents and chemotherapy. 1993;37:546-53. 17. brubaker law, a. the urinary microbiota: a paradigm shift for bladder disorders? cuee opin obstet gynecol. 2016;28(407-412):407. 18. reza sari motlagh sh, homayoun sadeghi-bazargani, and javad joodi tutunsaz. reliability and validation of the international consultation on incontinence questionnaire in over active bladder to persian language. luts. 2014;7:99-101. 19. re m. platelet rich plasma: evidence to support its use. j oral maxillofac surg. 2004;62:48996. 20. man d ph, winland-brown je. the use of autologous platelet-rich plasma (platele gel) and autologous platelet poor plasma (fibrin glue) in cosmetic surgery. plast reconstr surg. 2001;107:229-37. 21. dönmez m.i̇. inci k zn, dogan h.s, ergen a. the effect of intravesical instillation of platelet rich plasma (prp) in interstitial cystitis model. eur urol suppl. 2014;13:461. 22. donmez mi ik, zeybek nd, dogan hs, ergen a. the early histological effects of intravesical instillation of platelet-rich plasma in cystitis models int neurourol j. 2016;20:188-96. 23. lara paro dias acml, bruno b. volpe, marcela duran, sofia e.m. galdames , luiz a.ab. ferreira, nelson duran, wagner j.favaro. effect of intravesical therapy with plateletrich plasma (prp) and bacillus calmetteguerin (bcg) in non-muscle invasive bladder cancer. tissue and cell. 2018;52:17-27. 24. constantinides c mt, nikolopoulos p, stanitsas a, haritopoulos k, giannopoulos a. prevention of recurrent bacterial cystitis by intravesical administration of hyaluronic acid: a pilot study. bju int. 2004;93:1262-6. 25. lipovac m kc, reithmayr f, verhoever hc, huber jc, imhof m. prevention of recurrent bacterial urinary tract infections by intravesical instillation of hyaluronic acid. int j genaecol obstet. 2007;96:192-5. 26. damiano r qg, bava i. prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. eur urol. 2011;59:645-51. 27. davide de vita sg. effectiveness of intravesical hyaluronic acid/chondroitin sulfate in recurrent bacterial cystitis: a randomized study. int urogynecol j. 2012;23:1707-13. 28. dutta s lf. intravesical instillations for the vol 16 no 06 november-december2019 613 treatment of refractory recurrent urinary tract infections. ther adv urol. 2018;10:157-63. prp preventing bacterial cystitis-mirzaei et al. pic.pdf 847vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l department of urology, aintree university hospital, lower lane, liverpool, l9 7al, united kingdom * e-mail: jmac@doctors.org.uk a 42-year-old man presented with a three-day history of acute following his initial presentation, he required an exploratory laparotomy, gastric oversew, and transverse colon repair, but was still known to have multiple remaining intra-abdominal pellets (figure 1). he had no previous urological history, but urinalysis on admission revealed microscopic hematuria. renal function was normal, but his c-reactive protein was increased at 38 mg/l (normal value <10 mg/l). a non-contrast computed tomography revealed one pellet had migrated into the left ureter causing ureteral obstruction and hydronephrosis (figure 1). initial management involved decompression of an infected system with a percutaneous nephrostomy followed by an antegrade pyleand involved delayed ureteroscopy and extraction of the pellet under general anesthesia. the pellet was extracted with forceps, and a ureteral stent was inserted for a period of four weeks due to the nature of the foreign body and to permit ureteral healing. there were no complications during the procedure or during the urological follow-up of the patient. ureteral obstruction caused by a foreign body is uncommon.(1,2) when suspected, it is usually an indwelling ureteral stent;(1) however, rarer causes, such as shotgun pellets and bullets, have been described.(2) in previous reports of shotgun pellets causing ureteral obstruction, the pellets have passed spontaneously without the need for further intervention.(1-3) this case highlights the multidisciplinary approach to the management of ureteral foreign bodies due to gunshot injuries, and the fact that migration of embedded pellets can involve the urological tract several months after the initial injury. jessica louise macwilliam, rahul mistry, michael st john floyd jr delayed ureteral obstruction following gunshot pellet migration references 1. bulut k, kukul e, ogus m, guntekin e. an unusual case of ureteric colic. br j urol. 1998;82:148-9. 2. gawande as, kinnard pd, stanley eh. ureteric colic due to migrating shotgun pellet. br j urol. 1982;54:191. 3. kumar pal d. spontaneous passage of shotgun pellets during voiding. br j urol. 1998;81:498. pictorial urology a b c figure 1. computed tomography scan showing multiple intraabdominal radioopaque pellets and a proximal ureteral pellet causing obstruction with periureteral and renal fat stranding (a). figure 2. plain abdominal x-ray showing radioopaque pellets and indwelling left nephrostomy (b). figure 3. antegrade pyelogram showing a proximal obstructing left ureteral pellet (c). point of technique 120 urology journal vol 5 no 2 spring 2008 laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal ureteral tumor abbas basiri,1 hossein karami,1 sadrollah mehrabi,2 ahmad javaherforooshzadeh1 urol j. 2008;5:120-2. www.uj.unrc.ir keywords: laparoscopy, ureteral neoplasms, reconstructive surgical procedures, surgical flaps 1urology and nephrology research center and department of urology, shahid labbafinejad hospital, shahid beheshti university (mc), tehran, iran 2department of urology, yasuj university of medical sciences, yasuj, iran corresponding author: abbas basiri, md urology and nephrology research center, no 44, 9th boustan, pasdaran, tehran 1666668111, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir received october 2007 accepted march 2008 introduction boari flap construction and ureteroneocystostomy is an appropriate technique for repairing the injuries in the distal ureter that result in shortening of the ureter.(1) we report the use of laparoscopic distal ureterectomy consisting resection of the bladder cuff and boari flap construction in a patient with low-grade transitional cell carcinoma of the distal ureter. case report a 52-year-old man was referred to our center with 4-month left flank pain and gross hematuria. physical examination and urine and blood tests revealed no abnormality. on ultrasonography, left hydroureteronephrosis and a hyperechoic mass in the left distal ureter were detected. a solid mass was also seen on computed tomography and magnetic resonance urography (figure 1). urine cytology was reported positive for malignancy. ureteroscopy revealed an obstructive nodular mass 3 cm above the left ureteral orifice. cold-cup biopsy was done and pathology examination showed a low-grade transitional cell carcinoma. metastatic workup was also uneventful. due to impossibility of endoscopic resection, the patient was selected for laparoscopic ureterectomy. technique in the flank position, 4 ports (a 10-mm umbilical trocar, two 5-mm trocars, and one 10-mm working trocar) were inserted in a diamond-shaped area in the left lower quadrant. after releasing the ureter, 2 hemolocks were figure 1. magnetic resonance urography showed marked narrowing of the distalsegment of the left ureter due to tumor (arrow). laparoscopic boari flap ureteroneocystostomy—basiri et al urology journal vol 5 no 2 spring 2008 121 used in the proximal and 1 in the distal parts of the mass to prevent the spillage of the tumor (figure 2). the ureteral defect was repaired by a boari flap. the bladder was cut from the anterior surface towards the left orifice, and the ureter was separated from the bladder with 1-cm margins. the ureter was then cut from 2 cm above the proximal part of the tumor, and the sample containing a tumoral ureter and bladder cuff was removed (figure 3). the flap was fixed to the ventral surface of the psoas muscle by a 2-0 vicryl suture. the frozen section was negative for tumor. the ureter was anastomosed end to end to the bladder flap using a 4-0 vicryl suture on a 10-f catheter (figure 4). the bladder was also repaired by 2-0 vicryl suture. a drain was inserted and the operation was ended after 406 minutes without complications. results the amount of bleeding was about 300 ml and the hospitalization period was 5 days. the pathology report showed a low-grade tumor with the staging of t1nxmx and tumor-free margins (figure 5). three months postoperatively, intravenous urography showed palliation of the hydroureteronephrosis with negative urine cytology (figure 6). figure 4. intra-operative picture shows bladder flap with the anastomosed ureter and ureteral stent. u indicates ureter and bf, bladder flap. figure 5. low-grade and low-stage transitional cell carcinoma was reported (t1nxmx) on pathologic examination of the ureteral specimen (hematoxylin-eosin, × 10). figure 2. intra-operative picture shows distal segment of the ureter containing tumor. pu, indicates proximal ureter; du, distal ureter; and b, bladder. figure 3. tumoral segment of the ureter. t indicates tumor. laparoscopic boari flap ureteroneocystostomy—basiri et al 122 urology journal vol 5 no 2 spring 2008 discussion minimally invasive methods have been properly used for treatment of tumors of the distal ureter. in patients with low-grade tumors, recurrence rates and disease-specific survival rates are 26% to 28% and 96% to 100%, respectively.(2) the use of laparoscopy has been reported by gerber and colleagues as distal ureterectomy and ureteoneocystostomy.(3) also there are some reports addressing laparoscopic boari flap for treatment of benign ureteral lesions. in a retrospective study by simmons and colleagues,(4) the results of laparoscopic and open ureterectomy, ureteroneocystostomy, and boari flap reconstruction were compared between 12 laparoscopic and 34 open surgeries for ureteral stricture. patients with open surgery had greater operative blood loss (258 ml versus 86 ml) and longer hospital stay (mean, 5 days versus 3 days) compared with the laparoscopic group. the overall complication rate in the open and laparoscopic groups were 15% and 8%, respectively (p = 0.22). ureteral patency was successfully reestablished in all the 12 patients in the laparoscopic group compared to 96% in the open group at a mean follow-up of 23 months.(4) in the our case, as boari flap construction was planned preoperatively, we cut the bladder up to the ureteral orifice to make a flap; therefore this incision helped us to have excellent intravesical exposure for incising 1 cm of the bladder wall as a bladder cuff. to our best knowledge, laparoscopic ureterectomy and boari flap construction has not been used for the treatment of ureteral tumors. according to our findings, laparoscopic ureterectomy and boari flap construction promises ease in the operation, less morbidity, and enough exposure for cutting the distal ureter and bladder cuff. conflict of interest none declared. references 1. fergany a, gill is, abdel-samee a, kaouk j, meraney a, sung g. laparoscopic bladder flap ureteral reimplantation: survival porcine study. j urol. 2001;166:1920-3. 2. soderdahl dw, fabrizio md, rahman nu, jarrett tw, bagley dh. endoscopic treatment of upper tract transitional cell carcinoma. urol oncol. 2005;23:11422. 3. gerber e, dinlenc cz, wagner jr. laparoscopic distal ureterectomy for low grade transitional cell carcinoma. j urol. 2003;169:2295. 4. simmons mn, gill is, fergany af, kaouk jh, desai mm. laparoscopic ureteral reconstruction for benign stricture disease. urology. 2007; 69:280-4. figure 6. intravenous urography 3 months after the operation. 959 edited1.pdf 912 | bladder calcification secondary to ketamine thomas jenyon,1 graham sole2 keywords: introduction k(1) (3,4) case report corresponding author: thomas jenyon, mrcp; mbbs; bsc; pcme hereford county hospital, hereford, hr1 2er, uk tel: +44 143 235 5444 fax: +44 014 323 44061 e-mail: tomjenyon@hotmail.com received april 2011 accepted may 2011 1 birmingham university, west midlands deanary, uk 2 hereford county hospital, uk case report case report 913vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l bladder calcification secondary to ketamine | jenyon and sole discussion figure 1. computed tomography scan showing bladder calcification. figure 2. bladder calcification at cystoscopy. figure 3. histology showing focal calcification and total ulceration of urothelium (×20). 914 | case report lief (11) acknowledgements conflict of interest references 1. sinner b, graf bm. ketamine. handb exp pharmacol. 2008;313-33. 2. statistics on drug misuse: england, 2009. england: the health and social care information centre; 2009:8. 3. chu ps, kwok sc, lam km, et al. 'street ketamine'-associated bladder dysfunction: a report of ten cases. hong kong med j. 2007;13:311-3. 4. shahani r, streutker c, dickson b, stewart rj. ketamineassociated ulcerative cystitis: a new clinical entity. urology. 2007;69:810-2. 5. colebunders b, van erps p. cystitis due to the use of ketamine as a recreational drug: a case report. j med case rep. 2008;2:219. 6. chu ps, ma wk, wong sc, et al. the destruction of the lower urinary tract by ketamine abuse: a new syndrome? bju int. 2008;102:1616-22. 7. oxley jd, cottrell am, adams s, gillatt d. ketamine cystitis as a mimic of carcinoma in situ. histopathology. 2009;55:705-8. 8. lo rs, krishnamoorthy r, freeman jg, austin as. cholestasis and biliary dilatation associated with chronic ketamine abuse: a case series. singapore med j. 2011;52:e52-5. 9. wong sw, lee kf, wong j, ng ww, cheung ys, lai pb. dilated common bile ducts mimicking choledochal cysts in ketamine abusers. hong kong med j. 2009;15:53-6. 10. sigtermans mj, van hilten jj, bauer mc, et al. ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. pain. 2009;145:304-11. 11. agarwal a, gupta d, kumar m, dhiraaj s, tandon m, singh pk. ketamine for treatment of catheter related bladder discomfort: a prospective, randomized, placebo controlled and double blind study. br j anaesth. 2006;96:587-9. 1271vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l department of urology, university of istanbul, cerrahpasa medical faculty, istanbul, turkey. sinharib citgez, oktay demirkesen, fatih ozdemir, fetullah gevher, cetin demirdag, bulent onal, bulent cetinel transvaginal repair using acellular collagen biomesh for the treatment of anterior prolapse correspondence author: sinharib citgez, md kartaltepe mahaleesi, yavuklular sokak, gul apartmani, no:1/3 bakirkoy, istanbul, turkey. tel: + 90 532 312 2377 fax: + 90 212 571 3570 e-mail: drsinharib@yahoo.com received january 2013 accepted december 2013 purpose: to determine the results and satisfaction of the patients underwent transvaginal repair of cystocele in our clinic. materials and methods: from january 2006 to october 2010, 15 patients with a mean age of 64 years (ranged 47-85 years) underwent transvaginal cystocele repair using acellular collagen biomesh. the patients were presented with vaginal mass in 10, dyspareunia and urge incontinence in 5 while 4 of them had both stress and urge incontinence. grade 4 cystocele was determined in 2 patients, grade 3 in 9 and grade 2 in 4. concomitant transobturator tape (tot) was performed in 4 patients. patient satisfactions were determined after the operation. results: the mean follow-up time was 23.5 (12-60) months. there was no postoperative complication in early followup period. cystocele was recurrent in 1 patient. the success rate was 93.4%. urinary incontinence was continued in 1 patient after tot. nearly all of the patients (14/15) were satisfied from the operation. conclusion: transvaginal cystocele repair with using acellular collagen biomesh appears to be a safe and effective method. further prospective and randomized controlled studies including large series of patients are needed. keywords: urinary bladder diseases; surgery; cystocele; vagina; treatment outcome; urinary incontinence; surgical mesh. reconstructive urology 1272 | introduction pelvic organ prolapse (pop) is accepted as the hernia-tion of the pelvic organs from the vagina. internation-al continence society (ics) describes this condition as downward displacement of the reproductive organs during valsalva maneuver.(1) pop is a condition that can affect women at any age. according to epidemiological studies, life-long risk in women to be operated due to prolapse or urinary incontinence is between 7% to 19%.(2,3) in a study from the usa, the number of women having pop is expected to increase by 46% in 2050.(4) treatment of pop aims to eliminate the symptoms, repair the anatomy, protect or improve the functions, prevent new problems related to the other compartments and to protect the quality of life in long term. surgical treatment of pop can be made with methods performed through vaginal or abdominal routes. the studies demonstrated that vaginal route is preferred more for treatment of pop.(2,5,6) in fact, recurrence rates are high following anterior colporrhaphy performed especially because of anterior vaginal pop, and this rate is given as 40% in a recent randomized controlled trial.(7) thus, use of synthetic or biological grafts can be argued in order to strengthen pop repair. in fact, international consultation on incontinence (ici) emphasizes as a first level of evidence that the repairs carried out by vaginal route using synthetic polypropylene meshes yield more excellent anatomic outcomes in the first-year follow-ups than anterior colporrhaphy, while it reports an acceptable efficiency and lower risk of complications in the repairs alternatively performed with biological grafts.(8) in this study, we investigated the success, complication rates and patients satisfaction in patients undergone cystocele repair by vaginal route using acellular collagen bio mesh. materials and methods between january 2006 and october 2010, 15 patients having anterior prolapse were investigated. repair of anterior wall prolapse through vaginal route using acellular collagen bio mesh (pelvisoft biomesh, cr bard, cranston, r.i., usa) was performed to all patients. ten of the patients presented with a palpable mass and 5 with pain during sexual intercourse and urge urinary incontinence. the mean number of pregnancies was 4.5 (1-9), and the mean number of births was 2.8 (1-7) (table 1). none of the patients had a history of prolapse surgery. two of the patients had diabetes mellitus while no any other comorbidity was detected in any of the patients preoperatively. the grade of prolapse was preoperatively assessed according to baden-walker system and/or pelvic organ prolapse quantification system (pop-q) classification.(1) grade 4 cystocele was found in 2, grade 3 in 9 and grade 2 in 4 patients. four of the patients complained of mixed (stress + urge) incontinence. these patients were asked to fill turkish validated international consultation on incontinence questionnaire short form (iciq-sf).(9) patients scheduled for concurrent surgery for stress urinary incontinence had undergone urodynamic study. transobturator midurethral sling (transobturator tape, tot) was planned for patients who defined to have urodynamic stress urinary incontinence (usui). the operation was performed at lithotomy position under general anesthesia. all the patients were administered 1 g cefazolin preoperatively. following insertion of the urethral catheter, an incision was made in the anterior vaginal wall from the level of the bladder neck towards to the vaginal apex. the incision was expanded to the sideways from inferior and superior, providing a horizontal ‘h’ shape (figure). thus, a wider area of dissection was obtained. the dissection plane was defined with the bright, white pubocervical fascia and expanded until infralevator obturator fascia was palpated. two anchoring sutures were placed through the fascia as to be at 1 and 11 o’clock positions, and the other two sutures were inserted through the cardinal ligament as to be at 5 and 7 o’clock positions. in the meantime, acellular collagen biomesh of 4 × 7 cm in size was cropped and tailored to the size of the defect, and the sutures were crossed from the proper pore openings in the mesh and tied. after the mesh was inserted, excess of the vaginal wall was properly cut and the process was ended by closure of the anterior wall. in 4 patients who were found to have usui, a separate suburethral and longitudinal incision was made, and tot was properly placed. the urethral catheters were withdrawn immediately after or at the night of the operation. postoperative follow-up of the patients were carried out in the first, 3rd and 6th weeks of the operation and then annureconstructive urology 1273vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l acellular collagen biomesh for anterior prolapse | citgez et al ally. the follow-up procedure was planned as questioning in terms of urinary incontinence (iciq-sf) and prolapse recurrence (palpable mass), full urine test, vaginal examination and determination of post void residual urine. in the followup, patients having not complaints of prolapse or those with anterior wall prolapse under grade 2 at the vaginal examination were considered as cure, while patients with complaints or those having a recurrence of grade 2 and above were considered as failed. patient to be dry was accepted as success for the treatment of stress urinary incontinence. in addition, patient satisfaction was evaluated by asking them whether they would recommend this operation to a relative, and if they would want to be operated again if it is necessary, in order to learn their reviews for the operation. results mean age of the patients was 64 years (ranged 47-85 years). body mass index (bmi) was calculated as 26.5 (range, 24.228.4) for the patients. there was no any obese patient according to bmi while 5 of them were overweight. mean operation time was 57.2 minutes (range, 30-75), while mean hospitalization stay was 18.4 hours (range, 12-36) (table 2). there were no postoperative complications for the patients in early period. mean follow up time was 23.5 months (range, 12-60). in one patient the palpable mass observed to persist. in this patient the examination revealed recurrence of grade 2 anterior prolapse. the patient did not want to be re-operated and was taken to follow-up. the success rate for repair of prolapse was found as 93.4%. none of the patients developed de novo dyspareunia or sui. two of the 4 patients who had urgency at the preoperative period were improved after the operation. de novo urgency was detected in 2 patients. a total of 4 patients, including those having urge urinary incontinence preoperatively and continued postoperatively, responded to anticholinergic therapy. combination treatment (prolapse repair + anti-incontinence surgery) was performed in 4 of our patients. although decreasing, urinary incontinence was observed to continue in one of 4 patients in whom tot was inserted and the rate of success for stress urinary incontinence was 75%. in patients with urinary incontinence, the mean preoperative and postoperative iciq-sf values were 14.33 (8-21) and 2.3 (0-11) respectively. of 15 patients evaluated for satisfaction, 14 (93.4%) stated that they were completely well; they could be re-operated if necessary and would recommend the operation to their relatives. in one patient the palpable mass observed to persist and dissatisfaction was observed because of the failure and unnecessary anesthesia. discussion rates of recurrence are reported between 3% and 70% following anterior colporrhaphy and between 5% and 50% after paravaginal repair by vaginal route in the treatment of anterior wall prolapse.(7,10-12) this is because the classical anterior colporrhaphy primarily focuses on central defects, while paravaginal repair targets lateral defects.(12) since the central defects alone are rare,(13) the dissection should be expanded toward the lateral to provide adequate support both for lateral and central defects in all anterior prolapse repairs. by the technique and incision form we used and by expanding the dissection area toward the lateral, we aimed to realize an anterior wall repair supporting not only central but also lateral defects and to reduce the rates of recurrence. besides the surgical method, use of support material is proposed in the literature in order to achieve a higher anatomic success compared to traditional anterior colporrhaphy.(8) indeed, increased rates of anatomic success were demonstrated in the repair of central and lateral defects using additional support material.(14) govier and colleagues also suggested a method similar to above mentioned using mesh.(15) polypropylene figure 2. a) type of incision, b) appearance after dissection, c) insertion of the prepared biomesh, and d) appearance after operation. 1274 | type 1 synthetic meshes have priority as support material, while despite their low rate of success, biological grafts are also reported and can be preferred due to their lower risk of complications.(8,15) in addition to repair of the anterior wall through vaginal route with synthetic meshes,(16,17) there are several studies in the literature about posterior wall,(18) vaginal stump(19) and total genital prolapse treatment.(20) however, as it is reported by ici, there is no sufficient scientific evidence showing that support material in the posterior wall repair or use of any specific technique in apical wall repair through vaginal route is superior to native tissues.(8) in a study by flood and colleagues, in the mean follow-up duration of 3.2 years following use of synthetic meshes for treatment of anterior wall prolapse, none of 142 patients developed recurrent prolapse and, only in 3 patients meshes had to be removed due to vaginal erosion.(21) in a prospective, randomized controlled trial with 161 women recurrence rates of anterior wall prolapse was found to be statistically significantly decreased with use of mesh.(22) in a study by sand and colleagues, a higher rate of success was reported in the patients undergone repair of anterior wall prolapse using mesh compared to the traditional colporrhaphy methods.(22) in this study, rate of success was found as 75% in mesh group and 57% in the anterior colporrhaphy group. according to the cochrane database regarding to the treatment of anterior wall prolapse, the anatomic failure rate is reported to be lower in the repair of anterior wall prolapse through vaginal route using mesh.(23,24) biomesh is another support material described in the literature and the rates of success using biomesh for the treatment of anterior wall prolapse are reported between 81%-93%. (25,26) ici reports that, there is only one randomized controlled study with a high level of evidence demonstrating anterior repair using porcine dermis to be superior to traditional vaginal plication,(27) but although with low level of evidence, there are also several studies giving conflicting results, thus use of biomesh in anterior repair can be recommended at the level of c.(8) although it is not recommended by ics, high efficiency was found in a study with 35 patients undergone surgery for posterior wall prolapse surgery using acellular collagen biomesh.(28) in our study we also found the rate of success and patients satisfaction very high (93.4%) with acellular collagen biomesh we used for the repair of anterior wall prolapse through vaginal route. however, as mentioned earlier, since use of biological mesh is recommended by ici at the level of c,(8) better designed studies with extensive series should be conducted in order to define its efficiency and to obtain higher levels of recommendations.(15) on the other hand, it should be noted that the anatomic success is not always compatible with subjective results.(29) in fact, before the surgery to be performed using mesh, the patients should be informed in details about functional results such as sexual function, continence, detrusor over activity and about the operation. de novo dyspareunia was reported between 2% and 15% in patients undergone repair of the anterior wall with recently described transobturator four arms mesh which is inserted using trocar.(30-33) in this method, dyspareunia may be both due to the mesh,(34) and the tool used to insert the mesh.(35) on the other hand, a randomized controlled study comparing porcine dermis with standard repair anterior colporrhaphy without using graft reported that insertion of biomesh does not increase the risk for dyspareunia.(27) in another randomized, controlled study, synthetic table 1. patients characteristics. number of patients 15 mean age, years (range) 64 (47-85) body mass index (mean) 26.5 (24.2-28.4) underweight (< 18.5) 0 normal weight (18.5-24.9) 10 (66.7%) overweight (25-29.9) 5 (33.3%) obesity (≥ 30) 0 mean pregnancy, no. (range) 4.5 (1-9) mean delivery, no. (range) 2.8 (1-7) sexual activity, no. (%) yes 9 (60.0) no 6 (40.0) presentation of the patient palpable mass 10 (66.7) dyspareunia, urinary incontinence 5 (33.3) pop-q classification (no.) grade 2 4 grade 3 9 grade 4 2 key: pop-q, pelvic organ prolapse quantification. reconstructive urology 1275vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l polypropylene mesh gynemesh ps (ethicon, inc, somerville, nj,usa) and pelvicol (c.r. bard, mol, belgium) were compared, and sexual functions were found to be better in biomesh group, and this was attributed to propylene mesh to impair vaginal flexibility.(36) in accordance with the literature, in this study with biomesh, none of the sexually active patients developed dyspareunia. development of de novo sui in anterior repairs through vaginal route using mesh is reported between 12% and 17% in the literature.(33,37,38) in a randomized controlled trial, this rate was stated as 12.3% following insertion of mesh using trocar, and it was reported to be statistically more frequent than anterior colporrhaphy.(37) in another randomized controlled study, no statistically significant difference was found between the mesh group and standard methods.(39) in our study, de novo sui was not found in any patient. in addition, following the repairs with biological mesh, rate of detrusor overactivity was found as 17.4%, but this was not found statistically significant compared to the standard techniques. (36) in the present study, 13% of the patients developed complaints of de novo urgency, and responded to anticholinergic therapy. in the reviews of cochrane's database, conflicting data are mentioned about the prophylactic surgery for concurrent incontinence during the repair of anterior wall prolapse.(23,24) in our study, we simultaneously inserted tot in 4 patients who was found to have usui. none of these patients developed peror postoperative additional complications. tot was failed in one patient, although the patient was satisfied with the operation. the mean iciq-sf value was declined to 2.3 (0-11) postoperatively which was 14.33 (8-21) preoperatively. use of mesh leads to additional complications requiring special treatment. the most common ones are mesh exposition or extrusion, and the complications related to the mesh shrinkage.(40) in fact, rates of vaginal exposition or extrusion may show an increase up to 11.9% according to the type of mesh used.(41) however, these types of complications are rare when using biological mesh because of the lower tissue rejection and less risk of infection.(27) nevertheless, these complications should be considered in follow-up in the patients with complaints such as vaginal bleeding, vaginal discharge, vaginal or pelvic pain and dyspareunia. in this study, none of the patients developed such a biomesh specific complication. in addition, it should be remembered that despite they are prepared with aseptic techniques, all the allografts like biomeshes are under the risk for transmission of diseases such as human immunodeficiency virus (hiv) and hepatitis b. there are several limitations to our study. one weakness of our study is that our data were collected retrospectively. second, our series is small and not a long term study. although it was not a randomized controlled study, this technique seems to be an alternative treatment in pop surgery. further prospective, randomized and comparative studies with a high level of evidence are needed. in conclusion, in this study outcomes and complication rates seem to be acceptable in the anterior repair through vaginal route using acellular collagen biomesh. conflict of interest none declared. table 2. results and complications after surgery. mean follow up, month (range) 23.5 (12-60) mean operation time, min (range) 57.2 (30-75) mean hospitalization stay, hour (range) 18.4 (12-36) success rate, no. (%) 14/15 (93.4) complications, no. (%) major (bleeding, organ injury) 0 de novo dyspareunia 0 de novo sui 0 de novo urgency 2 (13.3) key: sui, stress urinary incontinence. references 1. bump rc, mattiason a, bo k et al. the standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. am j obstet gynecol. 1996;175:10-17. 2. olsen al, smith vj, bergstrom jo, colling jc, clark al. epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. obstet gynecol. 1997;89:501-6. 3. smith fj, holman cd, moorin re, tsokos n. lifetime risk of undergoing surgery for pelvic organ prolapse. obstet gynecol. 2010;116:1096-1100. acellular collagen biomesh for anterior prolapse | citgez et al 1276 | 4. wu jm, hundley af, fulton rg, myers er. forecasting the prevalence of pelvic floor disorders in u.s. women: 2010 to 2050. obstet gynecol. 2009;114:1278-83. 5. boyles sh, weber am, meyn l. procedures for pelvic organ prolapse in the united states 1979-1997. am j obstet gynecol. 2003;188:10815. 6. brown js, waetjen le, subak ll, thom dh, van den eeden s, vittinghoff e. pelvic organ prolapse surgery in the united states, 1997. am j obstet gynecol. 2002;186:712-6. 7. nguyen j, burchette rj. outcome after anterior vaginal prolapse repair: a randomized controlled trial. obstet gynecol. 2008;111:891-8. 8. brubaker l. surgery for pelvic organ prolapse. committee 15. incontinence. editors: paul abrams, linda cardozo, saad khoury, alan wein. 4th international consultation on incontinence, paris july 5-8, 2008. 9. cetinel b, ozkan b, can g. the validation study of iciq-sf turkish version. turk j urol. 2004;30:332-8. 10. porges rf, smilen sw. long-term analysis of the surgical management of pelvic support defects. am j obstet gynecol. 1994;171:1518-26. 11. flood cg, drutz hp, waja l. anterior colporrhaphy reinforced with marlex mesh for the treatment of cystoceles. int urogynecol j pelvic floor dysfunct. 1998;9:200-4. 12. weber am, walters md, piedmonte mr, ballard la. anterior colporrhaphy: a randomized trial of three surgical techniques. am j obstet gynecol. 2001;185:1299-304. 13. shull b, baden w. a six-year experience with paravaginal defect repair for stress urinary incontinence. am j obstet gynecol. 1989;160:1432-9. 14. de ridder d. the use of biomaterials in reconstructive urology. eur urol. 2002;1 (suppl):7-11. 15. govier fe, kobashi kc, hsiao k. use of synthetics and biomaterials in vaginal reconstructive surgery. female urology (raz s and rodriguez lv) third edition. philadelphia, saunders; ch59, 2008. p. 609623. 16. julian tm. the efficacy of marlex mesh in the repair of severe, recurrent vaginal prolapse of the anterior midvaginal wall. am j obstet gynecol. 1996;175:1472-5. 17. salomon lj, detchev r, barranger e, cortez a, callard p, darai e. treatment of anterior vaginal wall prolapse with porcine skin collagen implant by transobturator route: preliminary results. eur urol. 2004;45:219-25. 18. kohli n, miklos jr. dermal graft-augmented rectocele repair. int urogynecol j pelvic floor dysfunct. 2003;14:146-9. 19. fox sd, stanton sl. vault prolapse and rectocele: assessment of repair using sacrocolpopexy with mesh interposition. bjog. 2000;107:1371-5. 20. nicita g. a new operation for genitourinary prolapse. j urol. 1998;160:741-5. 21. flood cg, drutz hp, waja l. anterior colporrhaphy reinforced with marlex mesh for the treatment of cystoceles. int urogynecol j pelvic floor dysfunct. 1998;9:200-4. 22. sand pk, koduri s, lobel rw, winkler ha, tomezsko j, culligan pj goldberg r. prospective randomized trial of polyglactin 910 mesh to prevent recurrence of cystoceles and rectoceles. am j obstet gynecol. 2001;184:1357-62. 23. maher c, feiner b, baessler k, adams ej, hagen s, glazener cm. surgical management of pelvic organ prolapse in women. cochrane database syst rev. 2010;:cd004014. 24. maher cm, feiner b, baessler k, glazener cm. surgical management of pelvic organ prolapse in women: the updated summary version cochrane review. int urogynecol j. 2011;22:1445-57. 25. leboeuf l, miles ra, kim ss, gousse ae. grade 4 cystocele repair using four-defect repair and porcine xenograft acellular matrix (pelvicol): outcome measures using seapi. urology. 2004;64:282-6. 26. salomon lj, detchev r, barranger e, cortez a, callard p, darai e. treatment of anterior vaginal wall prolapse with porcine skin collagen implant by the transobturator route: preliminary results. eur urol. 2004;45:219-25. 27. meschia m, pifarotti p, bernasconi f, magatti f, riva d, kocjancic e. porcine skin collagen implants to prevent anterior vaginal wall prolapse recurrence: a multicenter, randomized study. j urol. 2007;177:192-195. 28. dell jr, o’kelley kr. pelvisoft biomesh augmentation of rectocele repair: the initial clinical experience in 35 patients. int urogynecol j pelvic floor dysfunct. 2005;16:44-7. 29. haylen bt, sand pk, swift se, maher c, moran pa, freeman rm. freeman transvaginal placement of surgical mesh for pelvic organ prolapse: more fda concerns-positive reactions are possible. int urogynecol j. 2012;23:11-3. 30. milani al, hinoul p, gauld jm, sikirica v, van drie d, cosson m; prolift+m investigators. trocar-guided mesh repair of vaginal prolapse using partially absorbable mesh: 1 year outcomes. am j obstet gynecol. 2011;204:74.e1-8. 31. zyczynski hm, carey mp, smith ar, et al. one-year clinical outcomes after prolapse surgery with nonanchored mesh and vaginal support device. am j obstet gynecol. 2010;203:587.e1-8. reconstructive urology 1277vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l 32. moore rd, beyer rd, jacoby k, freedman sj, mccammon ka, gambla mt. prospective multicenter trial assessing type i, polypropylene mesh placed via transobturator route for the treatment of anterior vaginal prolapse with 2-year follow-up. int urogynecol j. 2010;21:545-552. 33. jacquetin b, fatton b, rosenthal c, et al. total transvaginal mesh (tvm) technique for treatment of pelvic organ prolapse: a 3-year prospective followup study. int urogynecol j. 2010;21:1455-62. 34. feiner b, gietelink l, maher c. anterior vaginal mesh sacrospinous hysteropexy and posterior fascial plication for anterior compartment dominated uterovaginal prolapse. int urogynecol j. 2010;21:203-8. 35. alcalay m, cosson m, livneh m, lucot jp, von theobald p. trocarless system for mesh attachment in pelvic organ prolapse repair–1-year evaluation. int urogynecol j. 2010;22:551-6. 36. natale f, la penna c, padoa a, agostini m, de simone e, cervigni m. a prospective, randomized, controlled study comparing gynemesh, a synthetic mesh, and pelvicol, a biologic graft, in the surgical treatment of recurrent cystocele. int urogynecol j pelvic floor dysfunct. 2009;20:75-81. 37. altman d, vayrynen t, engh me, axelsen s, falconer c. anterior colporrhaphy versus transvaginal mesh for pelvic-organ prolapse. n engl j med. 2011;364:1826-36. 38. fayyad am, north c, reid fm, smith ar. prospective study of anterior transobturator mesh kit (prolift) for the management of recurrent anterior vaginal wall prolapse. int urogynecol j. 2010;22:15763. 39. hiltunen r, nieminen k, takala t, et al. low-weight polypropylene mesh for anterior vaginal wall prolapse: a randomized controlled trial. obstet gynecol. 2007;110:455-62. 40. chermansky cj, winters jc. complications of vaginal mesh surgery. curr opin urol. 2012;22:287-91. 41. foon r, smith p. the effectiveness and complications of graft materials used in vaginal prolapse surgery. curr opin obstet gynecol. 2009;21:424-7. acellular collagen biomesh for anterior prolapse | citgez et al case report 206 urology journal vol 5 no 3 summer 2008 spermatocele presenting as acute scrotum atsuya hikosaka, yutaka iwase urol j. 2008;5:206-8. www.uj.unrc.ir keywords: spermatocele, epididymis, acute scrotum, torsion abnormality department of urology, toyota kosei hospital, toyota, japan corresponding author: atsuya hikosaka, md department of urology, toyota kosei hospital, 500-1, ibobara, josui-cho, toyota, aichi 470-0396, japan tel: +81 565 43 5000 fax: +81 565 43 5100 e-mail: uropatho@ybb.ne.jp introduction spermatocele, a retention cyst of the scrotum which is or has been in communication with the semen-carrying system,(1) is a relatively common clinical entity. it presents typically as an intrascrotal paratesticular mass, but it usually has few subjective symptoms. here, we report a case of spermatocele manifested with acute scrotum due to its unique feature. case report a 25-year-old man presented to our hospital complaining of persistent left scrotal pain with a sudden onset 12 hours earlier. he had no history of scrotal injury or vasectomy. physical examination noticed a thumb-head-sized soft subcutaneous ovoid mass with severe tenderness above the left testicle, but bilateral testes were normally palpable. laboratory findings were unremarkable. doppler ultrasonography showed a simple cystic mass adjacent to the upper pole of the left testis and normal appearance of the both testes. however, slight decrease of blood flow in the left testis was suggested (figure 1). due to these confusing findings and perpetual pain, immediate surgical exploration was performed, which revealed a cystic lesion with a short stalk arising from the head of the left epididymis (figure 2). the cyst was filled with yellowish turbid fluid and was twisted about 180 degrees. histologically, the inner surface of the cyst wall was lined with columnar epithelial cells with cilia (figure 3, left). on cytological examination, the fluid in the cyst included spermatozoa (figure 3, figure 1. left, scrotal ultrasonography demonstrates a cystic lesion adjacent to the left testicle. right, doppler ultrasonography suggests slight decrease in the blood flow of the left testis compared with the right one. spermatocele presenting as acute scrotum—hikosaka and iwase urology journal vol 5 no 3 summer 2008 207 right). these findings led to the pathological diagnosis of spermatocele. the convalescence period was uneventful with cease of scrotal pain, and the patient was discharged 5 days postoperatively. discussion the first 2 cases of spermatocele presenting as acute scrotum were reported in 1985,(2) followed only by 3 other cases.(3-5) therefore, the present case is the 6th in the literature to our knowledge. they have occurred mostly in young patients (age range, 13 to 44 years; mean, 24.5 years) who may suffer from other common causes of acute scrotum such as torsion of the spermatic cord or the appendix. hence, its diagnosis may be difficult even though normal blood flow would be proved by doppler ultrasonography. figure 3. left, histological findings of the resected cystic mass. the cyst wall consists of connective tissue lined inside with cuboid or columnar epithelial cells with microvilli (hematoxylin-eosin, × 200). right, cytological appearance of the fluid in the cyst. a number of spermatozoa are evident among many erythrocytes and some histiocytes (papanicolaou, × 400). figure 2. macroscopic findings on the surgical exploration. an ovoid cystic tumor (asterisk) arising from the head of the epididymis is shown. the testis appears normal. the tumor is connected with the epididymis by a distinct stalk. the photos were taken after release of torsion (left, medial side and right, lateral side). t indicates testis and e, epididymis. spermatocele presenting as acute scrotum—hikosaka and iwase 208 urology journal vol 5 no 3 summer 2008 interestingly, all spermatoceles with torsion had arisen from the head of the epididymis, while some anatomical evaluations suggest the spermatocele originates most frequently from the ductuli efferentes testis, and less commonly from the superior vas afferens, canal of the epididymis, and the appendix testis.(1) in addition, they all had distinct pedicles with torsion, resulting in acute scrotum. the pedunculated hydatid (appendix of the epididymis) has vesicular structure lined inside with epithelial cells similar to those of the spermatic tract, attachment to the head of the epididymis by a stalk, and connection with the canal of the epididymis.(1) considering these findings, it is suggested that the origin of spermatocele which can be the cause of acute scrotum is the appendix of the epididymis in connection with the canal of the epididymis. this kind of spermatocele may arise secondarily as a result of cystic transformation of the hydatid, contrary to a primary spermatocele which arises from the ductuli efferentes. although rare, urologists should keep in mind that the torsion of spermatocele can be a differential diagnosis of acute scrotum. conflict of interest none declared. references 1. crossan et. spermatocele. ann surg. 1920;72:500-7. 2. jassie mp, mahmood p. torsion of spermatocele: a newly described entity with 2 case reports. j urol. 1985;133:683-4. 3. kaye ri, cromie wj. torsion of a spermatocele: a case report and review of the literature. j urol. 1990;143:786. 4. odabas o, aydin s, yilmaz y. torsion of a spermatocele. j urol. 1995;154:2143. 5. takimoto k, okamoto k, wakabayashi y, okada y. torsion of spermatocele: a rare manifestation. urol int. 2002;69:164-5. case report 524 case report ectopic prostatic tissue in the right paracolic gutter: a case report bokyung ahn1, youngseok lee1, ki choon sim2, jeong hyeon lee1* ectopic prostatic tissue (ept) is fairly uncommon; however, when reported, it is most often found in the male genitourinary tract. since extragenitourinary ept is very rare, it is extremely difficult to properly diagnose preoperatively.(1-3) this article describes a unique case of ept found in the right paracolic gutter. keywords: ectopic prostatic tissue; extragenitourinary tract; paracolic gutter introduction ectopic prostatic tissue (ept) is fairly uncommon; however, when reported, it is most often found in the male genitourinary tract. since extragenitourinary ept is very rare, it is extremely difficult to properly diagnose preoperatively.(1-3) this article describes a unique case of ept found in the right paracolic gutter. case report a 73-year old man with a 6-year history of hepatocellular carcinoma (hcc) showed a 1.7-cm-sized hyperenhancing mass in the right paracolic gutter in follow-up abdominal computed tomography (ct) (figure 1). he had been treated with transarterial chemoembolization and radiofrequency ablation without surgery. follow-up abdominal ct revealed a newly noted mass in the right paracolic gutter, which was suspicious of metastatic hcc and necessitated surgical resection. gross examination showed a relatively well-demarcated nodule with partly cystic appearance (figure 2). microscopic examination showed a nodule full of simple, dilated glandular structures with corpora amylacea present in several of the glandular lumina. the background stroma showed a fibrous to partly loose appearance with bland, spindled cells (figure 3a). the glands had both a luminal and a basal layer of cuboidal to columnar cells, reminiscent of a benign hyperplastic prostatic epithelium. prostatic-specific antigen immunostaining showed strong, diffuse positivity in the luminal cells that further confirmed the prostatic nature of the nodule (figure 3b). discussion review of the literature revealed few reports of ept outside the genitourinary tract including the rectum, presacral or perirectal fat, anal canal, spleen, and cervix.(4-7) ept within or near the gastrointestinal (gi) tract has a left-side preference, especially in the anorectal region. to the best of our knowledge, there are no published reports describing an ept on the right colon. 1department of pathology, korea university anam hospital, korea university college of medicine, seoul, korea 2department of radiology, korea university anam hospital, korea university college of medicine, seoul, korea *correspondence: department of pathology, korea university anam hospital, korea university college of medicine, 73, inchon-ro, seongbuk-gu, seoul 02841, korea tel: 82-10-5919-5753. fax: 82-2-920-6576. e-mail: jhleepath@gmail.com. received october 2019 & accepted december 2019 urology journal/vol 18 no. 1/ january-february 2021/ pp. 134-135. [doi: 10.22037/uj.v0i0.5593] figure 1. axial contrast-enhanced ct of the abdomen and pelvis (portal phase). an incidental lesion was found in the right paracolic gutter area during follow-up after hcc treatment. in the next follow-up examination, the size was slightly increased, and the operation was performed under suspicion of hcc metastasis. figure 2. after serial section of the fibroadipose tissue, the cut surface shows a relatively well-demarcated white-colored mass with multiloculated cystic spaces, measuring 1.6 x 1.4 cm. vol 18 no 1 january-february 2021 20 there are three hypotheses regarding the pathogenesis of ept.(8) one is faulty embryogenesis, as both the rectum and bladder originate from the endodermal cloaca. when morphogenetic organization fails in the dorsal cloacal compartment, which is destined to become the rectum, the tissue retains the ability to produce anterior cloacal structures, which later forms the bladder, urethra, and prostate. a second hypothesis is aberrant location of prostatic stromal tissue, which is thought to induce the local epithelium to differentiate into prostatic epithelium.(9) the third hypothesis is based on seeding of viable prostatic tissue during surgery or biopsy of the prostate, which is mostly conducted in a transurethral or transrectal manner. no single hypothesis has been confirmed or explains the location of ept in the right paracolic region with no previous history of biopsy or surgery of the prostate. in our case, pathologic confirmation of ept was important in determining further treatment and prognosis. preoperative diagnosis of ept outside the urinary tract is extremely difficult; however, correct diagnosis is crucial to avoid malignant transformation.(5) although halat et al. reported similar pathologic findings of 80% of ept cases to those of the central zone of the prostate,(1) our case showed features reminiscent of the peripheral zone of the prostatic gland. there were no signs of dysplastic or malignant change in our case. since there is no explanation for the location of ept in our case, more cases should be collected, and further studies should be conducted. in conclusion, misdiagnosis of ept may lead to unneeded treatment and patient anxiety; therefore, proper suspicion and correct diagnosis are important. acknowledgement this study was approved by the institutional review board of korea university anam hospital (irb no. 2018an0171). conflict of interest no potential conflicts of interest relevant to this article are reported. references 1. halat s, eble jn, grignon dj, et al. ectopic prostatic tissue: histogenesis and histopathological characteristics. histopathology. 2011;58:750-8. 2. fulton rs, rouse rv, ranheim ea. ectopic prostate. arch pathol lab med. 2001;125:2868. 3. seol mj, noh kh, jeon ds, lee km. ectopic prostatic tissue in the rectum: a case report. j korean soc radiol. 2017;76:91. 4. dai s, huang x, mao w. a novel submucosa nodule of the rectum: a case of the ectopic prostatic tissue outside the urinary tract. pak j med sci. 2013;29. 5. gardner jm, khurana h, leach fs, ayala ag, zhai j, ro jy. adenocarcinoma in ectopic prostatic tissue at dome of bladder: a case report of a patient with urothelial carcinoma of the bladder and adenocarcinoma of the prostate. arch pathol lab med. 2010;134:1271-5. 6. nucci mr, ferry ja, young rh. ectopic prostatic tissue in the uterine cervix: a report of four cases and review of ectopic prostatic tissue. am j surg pathol. 2000;24:1224-30. 7. vogel u, bültmann b, negri g. ectopic prostatic tissue in the spleen. virchows archiv. 1996;427:543-5. 8. xin-lin w, lin s, li-zhen z, jing-yuan w, pei-de d, yang-zhi x. prostatic tissue ectopia in the rectum. chin med j 2010;123:3372-4. 9. marker pc, donjacour aa, dahiya r, cunha gr. hormonal, cellular, and molecular control of prostatic development. developmental biology. 2003;253:165-74. 10. bostwick dg, cheng l. urologic surgical pathology. 3rd ed. saunders-elsevier; 2014. ectopic prostatic tissue in paracolic gutter-ahn et al. figure 3. prostate glands are composed of a distinct luminal epithelial cell layer and a basal cell layer (h&e, x40) (a). prostate glands show strong, diffuse, immunopositive staining for prostate-specific antigen (psa) (h&e, x40) (b). vol 18 no 1 january-february 2021 135 u j all final for web.pdf 784 | urological oncology takahiro osawa,1 nobuo shinohara,1 satoru maruyama,1 koji oba,2 takashige abe,1 shintaro maru,1 norikata takada,1 ataru sazawa,1 katsuya nonomura1 long-term renal function outcomes in bladder cancer after radical cystectomy corresponding author: nicholas g. cost, md division of pediatric urology, cincinnati children’s hospital medical center, 3333 burnet avenue, mlc 5037, cincinnati, ohio 45229, usa tel: +513 363 0773 fax: +513 636 6753 e-mail: nicholas.cost@sbcglobal.net received january 2012 accepted october 2012 urological oncology corresponding author: nicholas g. cost, md division of pediatric urology, cinci nati children’s hospital medical center, 3333 burnet avenue, mlc 5037, cincinnati, ohio 45229, usa tel: +513 363 0773 fax: +513 636 6753 e-mail: nicholas.cost@sbcglobal.n received january 2012 accepted october 2012 1department of urology, hokkaido university graduate school of medicine, sapporo, japan 2translational research and clinical trial center, hokkaido university hospital, sapporo, japan corresponding author: takahiro osawa, md department of renal and genitourinary surgery, hokkaido university graduate school of medicine, north-15, west-7, north ward, sapporo, 060-8638, japan tel: +81 117 161 161 (ext.) 5949 fax: +81 117 067 853 e-mail: taka0573@gmail. com received march 2012 accepted october 2012 purpose: to evaluate postoperative renal function and risk factors for the loss of renal function in materials and methods: tion, type of urinary diversion, the postoperative occurrence of acute pyelonephritis, and the presence of chemotherapy. results: 2 before surgery and 63.6 2 p p conclusion: keywords: cystectomy 785vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l introduction urinary diversion is inevitable during radical cys-and high-grade non-muscle invasive bladder cantion of the bladder is that it should not jeopardize the function of the upper urinary tract. to achieve long-term upper urinary discussed. considered to be the better measure of overall kidney funcfunction after partial nephrectomy and renal transplantation. (2,3) tion and the risk factors for the loss of renal function in pamaterials and methods before the selection of the urinary diversion, a thorough evalcontinent urinary diversions as it leads to an inability to compensate for metabolic disturbances. the indications for the ileocecal reservoir are its large initial volume and its ilprocedure has not been performed in our institution since vitamin b m2 nese society of nephrology.(6) pre-operative renal function. hypertension or diabetes mellitus, pre-operative renal function, type of urinary diversion, the presence of chemotherapy, and the repeated postoperative episode of acute pyelonephri colony-forming units) and the presrenal function after radical cystectomy | osawa et al 786 | glycemic control. estimated using the kaplan-meier method, and distribucary, north carolina, usa). p results 2 2 2 2 ing to the type of diversion. both cutaneous diversion and furthermore, surgical intervention, including balloon urep (p 2 patients from three apn, and 2 patients from more than urinary diversion. the peri-operative chemotherapy regimens used in the cururological oncology figure 1. kaplan–meier curve of the renal deterioration-free interval of all the patients. the 10-year renal deterioration-free interval was 63.8%. figure 2. kaplan–meier curve of the renal deterioration-free interval by the repeated acute pyelonephritis episode in univariate log-rank analysis. p ro p o rt io n ( % ) months months p ro p o rt io n ( % ) 787vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l of 3 in the other chemotherapy group. on the other hand, among chemotherapy courses. p p pre-operative egfr, the type of urinary diversion, diabetes function outcomes (table 2). discussion urinary diversion is mandatory for patients undergoing is critical for evaluating urologic reconstructive procedures. this result is comparable to the results of a previous study in general, renal function is favorably preserved after conurinary diversion, and the incidence of renal deterioration after continent urinary diversion has been reported to range concentrated on serial serum creatinine measurements as an indicator of early renal impairment. fontaine and colleagues evaluated gfr pre-operatively in therefore, the upreport. cant predictor of renal deterioration in our series. the mvac table 1. characteristics of patients stratified according to the type of urinary diversion that they underwent. variables cutaneous ureterostomy ileal conduit ileal neobladder ileocecal neobladder p patients, n 9 25 24 12 age, >75/<75 y 5/4 5/20 1/23 0/12 <.01 gender, male/female 6/3 20/5 19/5 9/3 .86 pre-operative egfr,* >60/<60 ml/min/1.73 m2 3/6 21/4 21/3 12/0 .01 chemotherapy, +/3/6 8/17 6/18 5/7 .78 acute pyelonephritis, >2/<2 times 2/7 2/23 7/17 1/11 .19 ureteral obstruction,+/1/8 5/20 0/24 1/11 .14 diabetes mellitus,+/3/6 3/22 3/21 0/12 .16 hypertension, +/4/5 9/16 2/22 1/11 .03 *egfr indicates estimated serum creatinine-based glomerular filtration rate. renal function after radical cystectomy | osawa et al 788 | is the standard chemotherapy regimen for metastatic urothelial cancer. verse effects compared to the mvac. we use the pin, standard cisplatin-based chemotherapy. cisplatin is a potent chemotherapy agent that is used to treat a broad spectrum of malignancies, but it causes renal tubular dysfunction and a cumulative impairment of renal function, as manifested by a decline in the gfr. py. in cases involving relapse or metastasis, patients often multimodal treatment strategies incorporating peri-operative when chemotherapy is employed, it is necessary to take the icity by forced hydration and diuresis. lent risk factor for renal deterioration. samuel and associates our peri-operative episode of apn might be prevented by antibiperi-operative use of antibiotics. on the other hand, apn in p diversions. of urinary diversion. the limitations of this study include its retrospective design, small patient population in each type sions. furthermore, different surgeons performed the proconclusion table 2. results of multivariate analysis.* variable hazard ratio (95% ci) p age, every 10 years 1.17 (0.78 to 1.76) .44 gender, female 1.40 (0.45 to 4.29) .56 pre-operative egfr,< 60 ml/min/1.73 m2 0.77 (0.24 to 2.44) .66 urinary diversion (compared to ileal neobladder) .39 cutaneous ureterostomy 0.30 (0.05 to 1.78) ileal conduit 1.00 (0.32 to 3.15) ileocecal neobladder 0.45 (0.10 to 2.01) chemotherapy 3.27 (1.33 to 8.01) .01 acute pyelonephritis,>2 times 3.21 (1.14 to 9.02) .03 diabetes mellitus 1.78 (0.48 to 6.57) .39 hypertension 0.40 (0.10 to 1.59) .19 *ci indicates confidence interval; and egfr estimated serum creatinine-based glomerular filtration rate. urological oncology 789vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l renal function after radical cystectomy | osawa et al references 1 hautmann re, abol-enein h, hafez k, et al. urinary diversion. urology. 2007;69:17-49. 2 lane br, poggio ed, herts br, et al. renal function assessment in the era of chronic kidney disease: renewed emphasis on renal function centered patient care. j urol. 2009;182:435-43; discussion 443. 3 gera m, slezak jm, rule ad, et al. assessment of changes in kidney allograft function using creatinine-based estimates of glomerular filtration rate. am j transplant. 2007;7:880-7. 4 koch mo, mcdougal ws, thompson co mechanisms of solute transport following urinary diversion through intestinal segments: an experimental study with rats. j urol. 1991;146:1390-4. 5 koch mo, mcdougal ws, flora md urease and the acidosis of urinary intestinal diversion. j urol. 1991;146:458-62. 6 matsuo s, imai e, horio m, et al. revised equations for estimated gfr from serum creatinine in japan. am j kidney dis. 2009;53:982-92. 7 hautmann re urinary diversion: ileal conduit to neobladder. j urol. 2003;169:834-42. 8 samuel jd, bhatt ri, montague rj, et al. the natural history of postoperative renal function in patients undergoing ileal conduit diversion for cancer measured using serial isotopic glomerular filtration rate and 99m technetium-mercaptoacetyltriglycine renography. j urol. 2006;176:2518-22; discussion 2522. 9 akerlund s, delin k, kock ng, et al. renal function and upper urinary tract configuration following urinary diversion to a continent ileal reservoir (kock pouch): a prospective 5 to 11-year followup after reservoir construction. j urol. 1989;142:964-8. 10 kristjansson a, bajc m, wallin l, et al. renal function up to 16 years after conduit (refluxing or anti-reflux anastomosis) or continent urinary diversion. 2. renal scarring and location of bacteriuria. br j urol. 1995;76:546-50. 11 thoeny hc, sonnenschein mj, madersbacher s, et al. is ileal orthotopic bladder substitution with an afferent tubular segment detrimental to the upper urinary tract in the long term? j urol. 2002;168:2030-4; discussion 2034. 12 wiesner c, pahernik s, stein r, et al. long-term follow-up of submucosal tunnel and serosa-lined extramural tunnel ureter implantation in ileocaecal continent cutaneous urinary diversion (mainz pouch i). bju int. 2007;100:633-7. 13 kristjansson a, mansson w renal function in the setting of urinary diversion. world j urol. 2004;22:172-7. 14 fontaine e, leaver r, woodhouse cr the effect of intestinal urinary reservoirs on renal function: a 10-year follow-up. bju int. 2000;86:195-8. 15 sternberg cn, yagoda a, scher hi, et al. m-vac (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. j urol. 1988;139:461-9. 16 sternberg cn the treatment of advanced bladder cancer. ann oncol. 1995;6:113-26. 17 kuroda m, kotake t, akaza h, et al. efficacy of dose-intensified mec (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing mec and m-vac (methotrexate, vinblastine, doxorubicin and cisplatin). japanese urothelial cancer research group. jpn j clin oncol. 1998;28:497-501. 18 shinohara n, harabayashi t, suzuki s, et al. salvage chemotherapy with paclitaxel, ifosfamide, and nedaplatin in patients with urothelial cancer who had received prior cisplatin-based therapy. cancer chemother pharmacol. 2006;58:402-7. 19 gonzales-vitale jc, hayes dm, cvitkovic e, et al. the renal pathology in clinical trials of cis-platinum (ii) diamminedichloride. cancer. 1977;39:1362-71. 20 cvitkovic e, spaulding j, bethune v, et al. improvement of cis-dichlorodiammineplatinum (nsc 119875): therapeutic index in an animal model. cancer. 1977;39:1357-61. ence in renal deterioration among the four types of urinary urinary diversion, ie, the postoperative episode of repeated function. conflict of interest none declared. 1028 | 1department of urology, koru hospital, ankara, turkey 2department of urology, university of gazi, ankara, turkey mustafa kiraç,1 mehmet sinan atkin,2 hasan biri,2 nuri deniz1 ureteroscopy: the first-line treatment for distally located ureteral stones smaller than 10 mm corresponding author: mustafa kirac, md. umit mah. yeni çağın sitesi, a blok no:38, yenimahalle ankara-turkey. tel: +90 533 357 2617 fax: +90 312 287 9898 e mail: mkirac@gmail.com received july 2012 accepted november 2012 purpose: to compare the efficacy of different treatment strategies for distal ureteral stones smaller than 10 mm. material and methods: a total 127 patient were included in the study. based on the treatment modality, patients were divided into three groups. patients in group 1 only received conventional treatment including daily hydration of 2500 ml, ciprofloxacin, diclofenac sodium and a spasmolytic agent; group 2 patients received conventional treatment (daily hydration of 2500 ml, ciprofloxacin, diclofenac sodium and a spasmolytic agent) and tamsulosin 0.4 mg orally daily for 4 weeks; and group 3 patients underwent ureteroscopy. patients were further subdivided into 2 categories based on maximum stone diameter: category a (less than 5 mm) and category b (5.0-9.9 mm). following treatment, all groups were compared in terms of stone-free rate and time to expulsion. results: following treatment, the stone-free rates for groups 1, 2 and 3 were 48.7%, 59.5% and 95.6%, respectively (p < .0001). the mean expulsion times for groups 1, 2 and 3 were 15.3 ± 5.33, 15.1 ± 5.5 and 1.95 ± 2.2 days, respectively (p < .001). compared to the other treatments, the stone-free rate and mean expulsion time in the ureteroscopy group were significantly increased and decreased, respectively. conclusion: there are several treatment options for distal ureteral stones. based on our data, we conclude that ureterorenoscopy should be the standard of care for distal ureteral stones smaller than 10 mm. key words: drug therapy; lithotripsy; treatment options; ureteroscopy; ureteral calculi. endourology and stone disease endourology and stone disease 1029vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction ureteral stones account for roughly 20% of all uri-nary calculi, and 70% of these stones are located in the distal third of the ureter. management of ureteral stones includes observation, medical expulsive treatment, extracorporeal shock wave lithotripsy (swl), percutaneous antegrade ureteroscopy, retrograde ureteroscopy (especially for distal ureteral stones), and open/laparoscopic ureterolithotomy.(1) although current therapeutic options for ureteral stones include both active intervention and conservative watch and wait approaches, the endoscopic treatment of ureteral stones has a high success rate and reliably results in immediate stone removal.(2,3) furthermore, developments in ureteroscopic instrumentation has increased operational success while decreasing severe complications.(4,5) currently, ureteroscopy is often used as a first choice treatment option for distal ureteral stones and as an alternative method to swl or medical treatment modalities. in the present study, we evaluated the efficacy, feasibility and success rate of endoscopy for the treatment of distal ureteral stones smaller than 10 mm. we compared this treatment modality to observation and tamsulosin therapy. material and methods the study was approved by the local ethic committee. this study was conducted randomized and prospectively. patients a total 127 patients with distal ureteral stones that were less than 10 mm were included in the study from february 2009 to july 2011. all of the patients had been admitted to and were managed by the gazi university and koru hospitals’ department of urology due to distal ureteral stones. all patients were diagnosed with distal ureteral stones with smaller than 10 mm based on plain abdominal x-rays and urinary tract ultrasonography as well as with helical computed tomography when necessary. a case history was obtained from all patients; additionally, they underwent a physical examination and a series of measurements, including a complete blood cell count, blood electrolyte analysis, routine urinalysis, and serum urea and creatinine analyses. patients who were pregnant or had severe hydronephrosis, a solitary kidney, a urinary tract infection, renal failure, stones greater than 10 mm, bilateral ureteral stones, multiple ureteral stones or previous urinary tract surgery were excluded from the study. all the patients′ plain abdominal x-rays and urinary ultrasonography results were reviewed and confirmed by two experienced radiologists, and the stone diameters were measured using x-rays, computed tomography and ultrasonography. all patients signed a written informed consent, and we discussed with them in detail the potential side effects and complications prior to treatment. grouping patients were divided into three groups based on treatment (see below). they were further subdivided into 2 categories based on maximum stone diameter: category a (less than 5 mm) and category b (5.0-9.9 mm). group-1 (observation)-thirty-nine patients were included in this group. treatment included daily hydration of 2500 ml and ciprofloxacin (500 mg orally, twice a day) for the first 7 days. during the 4-week treatment period, diclofenac sodium (50 mg orally, twice a day) and a spasmolytic agent (hyoscine butylbromide, 10 mg orally, three times a day) were given. group-2 (tamsulosin)-forty-two patients were included in this group and were given tamsulosin 0.4 mg daily orally for 4 weeks. additionally, these patients received conventional treatment with daily hydration of 2500 ml and ciprofloxacin (500 mg orally, twice a day) for the first 7 days. diclofenac sodium (50 mg orally, twice a day) and spasmolytic (hyoscine butylbromide, 10 mg orally, three times a day) were also given to the patients in this group. group-3 (ureteroscopy)-forty-six patients were included in this group. ureteroscopy was performed under general anesthesia using a 9.5 fr (karl storz gmbh & co kg, tuttlingen, germany) semi-rigid ureteroscope and a 0.035 mm safety guide wire. patients were covered with antibiotics prior to instrumentation. all stones were located in the distal ureter and fragmented with a swiss lithoclast (2.4 fr long probe; 0.8 mm thick). stone fragmentation was continued until all fragments were < 2 mm in diameter. in the event that fragments were larger than 2 mm, extraction was performed. fragments < 2 mm were left for spontaneous ureteroscopy in ureteral stones | kiraç et al 1030 | passage. ureteral stenting was left to the discretion of the treating surgeon. however, in the event of proximal stone migration with ureteral extravasation, a stent was placed. post-operative treatment of this patient population included daily hydration of 2500 ml, ciprofloxacin (500 mg orally, twice a day) and an analgesic agent for the first 7 days. group 1 and 2 patients were followed weekly for 4 weeks, or until alternative treatment (ureteroscopy) was undertaken. follow-up visits included plain abdominal x-rays, urinary tract ultrasonography, urinalysis, serum urea creatinine and computed tomography if needed. during each visit, stone-free condition, analgesic dose, side effects and complications were recorded. stone-free condition was defined as the absence of stones on plain abdominal x-rays and computed tomography. following ureteroscopy, group 3 patients were followed with routine biochemical analysis, blood counts and urinalysis. preoperative aerobic urine cultures were routinely performed. in the event of a urinary tract infection, the patient was treated, and urine cultures were repeated to confirm sterility. the stone-free rate was determined by plain abdominal radiography and computed tomography on postoperative days 1 and 7. if inserted, the double-j ureteral stent was removed during postoperative week 3. statistical analysis all groups were compared in terms of stone-free rate and time to expulsion. all data were recorded with spss (statistical program for social science) statistical analyses were performed using pearson chi-square test, t test and fisher′s exact test using the statistical package for the social science (spss inc, chicago, illinois, usa) version 11.0. the efficiency quotient rate (eq) was calculated using the following formula: eq = percentage of stone-free patients/100% + percentage of re-treatment patients rate + ancillary procedures rate.(6) p < .05 was considered as statistically significant. results of the 127 patients included the study, 71 were male and 56 were female. the mean patient age was 30.27 ± 6.7 (range, 19-44). four patients in group 1 (2 included category a and 2 included category b) and five patients in group 2 (1 included category a and 4 included category b) withdrew from the study due to severe renal colic, infection or fever. these patients underwent immediate ureteroscopy. in the group 3, ureteroscopy was not successful in two category a patients. in one patient, the stone was inadvertently pushed up the ureter into the upper urinary system, and in the second patient, the stone was impacted in the ureteral wall. in postoperatively, re-ureterorenoscopy were applied to two patients (in category b) for residual fragment. ancillary procedures was not need required any patient. re-treatment rate was 4.34 and ancillary procedures rate 0.0 for group 3. there were no minor and major complications in group 1 and 2 during treatment. in the ureteroscopy group, there were no intraoperative and major postoperative complications; however there were two postoperative minor complications. of these patients, one (included category a) had appeared acute pyelonephritis in postoperative second days. the patient treated with antibiotic including cephalosporin. in the other patient (included category b), the ureteral stent was spontaneously fallen in postoperative five days. additionally, no statistical difference was found for patients’ age, sex distribution or stone size between groups 1, 2 and 3 (table 1). the stone-free rates for groups 1, 2 and 3 were 48.7%, 59.5% and 95.6%, respectively. the efficiency quotient rate for group 3 was 0.91. across treatment groups, uretendourology and stone disease table 1. patients’ characteristics in the three treatment groups and in the two stone-diameter categories. characteristics patients treatment groups (n = 127) p 1 2 3 patient, n 127 39 42 46 age, years 30.27 ± 6.7 29.3 ± 7.1 30.7 ± 6.4 30.6 ± 6.4 .38 sex, n (%) male 71(55.9) 23 (59.0) 25 (59.5) 23 (50.0) .60 female 56 (44.1) 16 (41.0) 17 (40.5) 23 (50.0) .61 stone location, n (%) left 61(48.1) 21 (53.8) 18 (42.9) 22 (47.8) .78 right 66 (51.9) 18 (46.2) 24 (57.1) 24 (52.2) .80 stone diameter, mm 6.79 ± 2.8 6.98 ± 2.1 6.46 ± 2.1 6.92 ± 2.0 .85 1031vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l eroscopy was significantly more effective in terms of the stone-free rate (p < .0001) (table 2). in both the patients with stones smaller than 5 mm and in those with stones larger than 5 mm, surgical treatment was also significantly more effective in terms of the stone-free rate (p = .011 and p < .001 for category a and category b, respectively). in groups 1 and 2 (groups treated non-surgically), there was no significant difference in terms of the stone-free rate (p = .29); furthermore, there was no significant difference between category a and b patients in either group 1 or 2. the mean expulsion times for groups 1, 2 and 3 were 15.3 ± 5.33, 15.1 ± 5.5 and 1.95 ± 2.2 days, respectively. compared to groups 1 and 2, the expulsion time for the ureteroscopy group (group 3) was statistically different. ureteroscopy was also significantly more effective than other treatment modalities (p < .001). in group 3, no difference was observed between category a and b patients (p = .69). discussion due to recent technological advances, there are many options for the treatment of ureteral stones. the factors that determine suitable treatment choices include stone location, number of stones, renal function, surgical experience, additional patient health factors, technological qualification, cost and the patient’s decision.(1,7) in our study, we compared three different options for the treatment of distal ureteral stones smaller than 10 mm. observation remains an alternative to treatment. to increase the likelihood of stone passage, patients are encouraged to increase fluid intake, and these patients are followed with regular visits to assess for spontaneous passage. location and stone size should always be considered before deciding on observation. small stones that are distally located are more suited to spontaneous passage. analgesics overuse, debility, frequent doctor visits and emergent urinary diversion may be required in such cases.(8) in clinical trials, stones smaller than 4 mm usually pass spontaneously. spontaneous passage rate falls significantly for stones larger than 5 mm.(1,9-11) morse and colleagues found that distal ureteral stones pass spontaneous 71% of the time, whereas hübner and colleagues reported an expulsion rate of distal ureteral stones of 45%.(12) in our study, the stone expulsion rate in the observational group was 48.7%. this rate was higher in individuals with stones smaller than 5 mm (52.9%), but this rate was not significantly higher than that for stones larger than 5 mm. therefore, our results are compatible with those reported in the literature. both observation and treatment of distal ureteral stones have advantages and disadvantages. for observation, the disadvantages are persistent renal colic and frequent physician visits. furthermore, urinary diversion or urgent intervention is sometimes required. therefore, observation as the first choice remains controversial. another treatment for distal stones is medical expulsive therapy (met). the presence of a ureteral stone often causes ureteral spasm, edema, pain and infection. the purpose of met is to relax the smooth muscle, relieve pain and decrease edema without impeding peristalsis. drugs used for met include non-steroidal anti-inflammatory drugs (nsaids), antimuscarinics, steroids, calcium channel blockers and alpha-blockers. of these drugs, alpha-blockers are the most effective and the most widely used. blockage table 2. the comparison of patient’s stone-free rates and expulsion times. condition group 1 group 2 group 3 p category a category b total category a category b total category a category b total stone-free rate, n (%) 52.9 (9/17) 45.5 (10/22) 48.7 (19/39) 60.8 (14/23) 57.8 (11/19) 59.5 (25/42) 95.0 (19/20) 96.1 (25/26) 95.6 (44/46) < .0001 expulsion time, day 12.9 ± 5.4 16.0 ± 3.8 15.3 ± 5.3 13.5 ± 3.2 16.7 ± 7.0 15.1 ± 5.5 1.65 ± 2.7 1.97 ± 2.4 1.95 ± 2.2 < .001 category a: stone size < 5 mm, category b: stone size between 5.0-9.9 mm. p values are for total stone-free rates. ureteroscopy in ureteral stones | kiraç et al 1032 | of alpha-receptors, which are located throughout the ureter but are concentrated distally, causes propulsive contractions without blocking physiologic peristalsis.(13) various studies have shown that alpha-blockers accelerate the passage of the distal ureteral stones.(14-16) in a meta-analysis on the treatment of ureteral stones with alpha-blockers, it was shown that the use of alpha-blockers increases the rate of spontaneous passage to as high as 44 %.10 additionally, in a study by küpeli and colleagues, it was shown that the addition of tamsulosin increased the rate of distal stone clearance.(15) in a study by erturhan and colleagues, the stone-free rate in individuals with distal ureteral stones was 73.3% following treatment with tamsulosin alone.16 on the other hand, hermanns and colleagues showed that tamsulosin treatment does not improve stone expulsion rates in patients with distal ureteral stones ≤ 7 mm.(17) in our study, the stone-free rate was 59.5% in the tamsulosin group (group 2). in patients with stones smaller than 5 mm, the stone-free rate was 60.8%, and in individuals with stones larger than 5 mm, it was 57.8%. ureterorenoscopy was performed in 41.5% of these patients due to the failure of medical treatment. in contrast to the literature, we found no significant difference between the tamsulosin and observational groups. however, tamsulosin does accelerate the expulsion of distal ureteral stones. thus, if the stone is likely to pass, tamsulosin accelerates this process. as mentioned above, the addition of tamsulosin to the medical treatment of distal ureteral stones has been shown to increase expulsion rates. however, there are two parameters that remain controversial: the duration of treatment and problems such as uncontrollable pain, the development of hydronephrosis, and surgical intervention. although tamsulosin increases the expulsion of distal ureteral stones, we think that the use of alpha-blockers should not be the standard of care due to the controversial treatment duration and the high need of surgical intervention. because of improvements in instrumentation coupled with ureteroscopy’s quick learning curve, ureteroscopy is the best treatment for ureteral stones. although extra swl was historically the first choice treatment for ureteral stones, the 2010 european association of urology (eau) urolithiasis guidelines now list ureteroscopy as the best choice.(18,19) additionally, in the guidelines published by preminger and colleagues, urs is the treatment of choice for mid and distal ureteral stones smaller than 10 mm.(1) the ureteroscopy is the treatment with the highest stone-free rate after a single procedure for distal ureteral stones.(1,18) thus, patients with ureteral stones also prefer urs over other treatments due to immediate cessation of pain and disability. in fact, perchel and colleagues reported patient satisfaction in 100% of ureteroscopy cases.(20) differing energy sources coupled with ureteroscopy have produced successful results. ultrasonic, electrohydrolic, laser and pneumatic lithotripters are widely used methods of lithotripsy. the effectiveness of ureteroscopy is well known in the treatment of distal ureteral stones when pneumatic lithotripters are used.(1,18,21) in our study, we also used a pneumatic lithotripter that is a widely used and comparatively inexpensive. in a study by ceylan and colleagues, they reported a 95.0% success rate for 209 distal ureteral stones (average size of 8.7 mm) treated with urs.(22) tuğcu and colleagues reported a success rate of 96.7% in their group of patients with distal ureteral stones (average size of 9 mm).(23) in our study, the average stone size was 6.9 mm, and our success rate for ureteroscopy was 95.6%. the stone-free rate was 95.3% for cases where the stone was smaller than 5 mm and 96.1% in cases where the stone was larger than 5 mm. this result shows that ureteroscopy is more effective than observation and alpha-blockers for the treatment of distal ureteral stones smaller than 10 mm. stone size and localization affect ureteroscopy success.(1,24) if the location of the stones is near the distal proportion of the ureter, ureteroscopy success is more likely.(1,18,24,25) thus, distally located stones smaller than 10 mm are more suitable for ureteroscopy. the ureteroscopy also has a lower complication rate, morbidity and mortality compared to other treatments. in addition, it is much more effective. factors included male sex, proximal ureteral stone, large stone size, surgical inexperience and symptoms for more than three months may increase the complication rate.(26,27) in our study, there were no major or minor complications in patients treated with urs. thus, we think that it is unnecessary to treat patients with alpha-blockers for distal ureteral stones of any size, unless the patient cannot tolerate ureterendourology and stone disease 1033vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l 10. parsons jk, hergan la, sakamato k, lakin c. efficacy of alpha-blockers for the treatment of ureteral stones. j urol. 2007;177:983-7. 11. segura jw, preminger gm, assimos dg, et al. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. the american urological association. j urol. 1997;158:1915-21. 12. morse rm, resnick mi. ureteral calculi: natural history and treatment in an era of advanced technology. j urol. 1991;145:263-5. 13. itoh y, kojima y, yasui t, tozawa k, sasaki s, kohri k. examination of alpha 1 adrenoceptor subtypes in the human ureter. int j urol. 2007;14:749-3. 14. singh a, alter hj, littlepage a. a systematic review of medical therapy to facilitate passage of ureteral calculi. ann emerg med. 2007;50:552-63. 15. küpeli b, irkilata l, gürocak s, et al. does tamsulosin enhance lower ureteral stone ̀ clearance with or without shock wave lithotripsy? urology. 2004 ;64:1111-5. 16. erturhan s, erbagci a, yagci fr, celik m, solakhan m, sarica k. comparative evaluation of efficacy of use of tamsulosin and/or tolterodine for medical treatment of distal ureteral stones. urology. 2007;69:633-6. 17. hermanns t, sauermann p, rufibach k, frauenfelder t, sulser t, strebel rt. is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? results of a randomised, double-blind, placebo-controlled trial. eur urol. 2009;56:407-12. 18. tiselius hg, ackermann d, alken p, buck c, conort p, gallucci m. working party on lithiasis, european association of urology. guidelines on urolithiasis. eur urol. 2001;40:362-1. 19. türk c, knoll t, petrik a et al. guidelines on urolithiasis. european association of urology 2010. available at http://www. uroweb.org/guidelines/online-guidelines 20. peschel r, janetschek g, bartsch g. extracorporeal shock wave lithotripsy versus ureteroscopy for distal ureteral calculi: a prospective randomized study. j urol. 1999;162:190912. 21. pearle ms, nadler r, bercowsky e, et al. prospective randomized trial comparing shock wave lithotripsy and ureteroscopy for management of distal ureteral calculi. j urol. 2001;166:1255-60. 22. ceylan k, sünbül o, sahin a, güneş m. ureteroscopic treatment of ureteral lithiasis with pneumatic litho-tripsy: analysis of 287 procedures in a public hospital. urol res. 2005;33:422-5. references 1. preminger gm, tiselius hg, assimos dg, et al. guideline for the management of ureteral calculi. eur urol. 2007;52:161031. 2. strohmaier wl, schubert g, rosenkranz t, weigl a. comparison of extracorporeal shock wave lithotripsy and ureteroscopy in the treatment of ureteral calculi: a prospective study. eur urol. 1999;36:376-9. 3. osorio l, lima e, soares j, et al. emergency ureteroscopic management of ureteral stones: why not? urology. 2007;69:27-31. 4. geavlete p, georgescu d, nita g, mirciulescu v, cauni v. complications of 2735 retrograde semirigid ureteroscopy procedures: a single-center experience. j endourol. 2006;20:17985. 5. chow gk, patterson de, blute ml, segura jw. ureteroscopy: effect of technology and technique on clinical practice. j urol. 2003;170:99-102. 6. denstedt jd, clayman rv, preminger gm. efficiency quotient as a means of comparing lithotripters. j endourol. 1990;4:100-3. 7. bensalah k, pearle m, lotan y. cost-effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones. eur urol. 2008;53:411-8. 8. hollingsworth jm, rogers ma, kaufman sr, et al. medical therapy to facilitate urinary stone passage: a meta-analysis. lancet. 2006;368:1171-9. 9. hübner wa, irby p, stoller ml. natural history and current concepts for the treatment of small ureteral calculi. eur urol. 1993;24:172-6. oscopy. conclusion we concluded that ureteroscopy was shown to be the most effective in our study. the advantages of ureteroscopy are its low complication rate, short expulsion time, and high stone-free rate after a single application and high patient satisfaction. therefore, we believe that ureteroscopy should be the standard of care for distal ureteral stones smaller than 10 mm. conflict of interset none declared. ureteroscopy in ureteral stones | kiraç et al 1034 | 23. tuğcu v, gürbüz g, aras b, gürkan l, otunctemur a, tasci ai. primary ureteroscopy for distal ureteral stones compared with ureteroscopy after failed extracorporeal lithotripsy. j endourol. 2006;20:1025-9. 24. tunc l, kupeli b, senocak c et al. pneumatic lithotripsy for large ureteral stones: is it the first line treatment? int urol nephrol. 2007;39:759-64. 25. ather mh, nazim sm, sulaiman mn. efficacy of semirigid ureteroscopy with pneumatic lithotripsy for ureteral stone surface area of greater than 30 mm2. j endourol. 2009;23:619-22. 26. fuganti pe, pires s, branco r, porto j. predictive factors for intraoperative complications in semirigid ureteroscopy: analysis of 1235 ballistic ureterolithotripsies. urology. 2008;72:770-4. 27. abdelrahim af, abdelmaguid a, abuzeid h, amin m, mousa el-s, abdelrahim fr. rigid ureteroscopy for ureteral stones: factors associated with intraoperative adverse events. j endourol. 2008;22:277-80. endourology and stone disease uj 35 summer.pdf 557vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l 1private medicabil hospital, bursa, turkey 2department of urology, acibadem university school of medicine, bursa, turkey 3department of urology, afyon kocatepe university school of medicine, afyonkarahisar, turkey 4ack urotas shock wave lithotripsy center, bursa, turkey murat demirbas,1 murat samli,2 mustafa karalar,3 ahmet c. kose4 extracorporeal shockwave lithotripsy for ureteral stones twelve years of experience with 2836 patients at a single center corresponding author: murat demirbas, md fsm bulvari aksel sitesi a blok d.10 i̇hsaniyenilüfer, bursa, turkey tel: +90 532 236 4838 fax: +90 224 247 6630 e-mail: muratdemirbas@ doctor.com received september 2011 accepted february 2012 purpose: materials and methods: spontaneous passage of the stone. results: p = .257). the success rates for individuals respectively (p p = .09). conclusion: our retrospective evaluation of this large patient series reveals that swl is effective for treating stones in the proximal, mid, and distal ureter. keywords: endourology and stone disease 558 | introduction the prevalence of urolithiasis is estimated to range -nary system stones are in the ureters.(1) the various treatment options for ureteral stones include extracorporeal copy, and open surgical ureterolithotomy. laparoscopy and open ureterolithotomy are rarely used to remove these stones, (2) have made it an important treatment modality for urinary tract (3) materials and methods derlying infection. cluded age, gender, stone location, stone size, number of culated rates of swl success (stone-free status after swl tation after three swl sessions or no spontaneous passage of patients overall and for various subgroups. not used routinely to detect the presence of minute stone fragments, due to concerns about the amount of radiation dose ment of the patient.(4) by spontaneous passage.(5) peridine). (6) (7) the endourology and stone disease 559vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l reached. sessions or retained fragmented stones after one month of gery. stone location (proximal, mid, and distal ureter) and stone t and subgroups. p results (range, 15 to 74 years). the mean maximum stone length and mm (range, 2 to 14 mm), respectively. eight hundred and than in the right ureter (1530 versus 1306, respectively; p = (range, 110 to 13500). became stone-free after a maximum of three swl treatments. categorized according to demographic characteristics and stone parameters. maximum stone dimension, mean number the failure group (p < .001 for all). self-limiting hematuria, dysuria, and pain that responded to oral analgesics. p = .257). the success rate for patients p p = .371). p tively (p = .09). spectively; p p discussion since the initial attempt at extracorporeal lithotripsy by the optimal approach for managing ureteral stones remains shockwave lithotripsy for ureteral stones | demirbas et al 560 | controversial. guideline published by the european assoureterolithotomy are rarely used in these cases. such tech(2) according to the guideline mentioned above, there is no ureteral stones.(2) (2) the distal ureter, and several have documented success rates above 90% for this patients group.(9,10) (9) proximal, mid, and distal ureteral stones, respectively.(2) associates documented for proximal, mid, and distal ureteral used for treating mid and distal ureteral stones.(10) the moditor in our success.(6) a common problem during swl, particularly in patients imaging due to intestinal gas. when such gas is present, it is mg four times a day before the procedure to ensure clear imendourology and stone disease results for the successful and failed shockwave lithotripsy groups with the 2836 total patients categorized according to demographic characteristics and various stone parameters. successful (stone-free) failed (surgery) p gender male 1842 (74.7%) 268 (72.4%) .371 female 624 (25.3%) 102 (27.6%) mean age, y 40.4 ± 12.5 42.66 ± 12.13 .003 stone location proximal ureter 742 (85.1%) 129 (14.8%) .257mid-ureter 262 (83.9%) 50 (16%) distal ureter 1462 (88.4%) 191 (11.5%) side affected right 1117 (85.5%) 189 (14.4%) .039 left 1349 (88.1%) 181 (11.8%) stone size and location in ureter proximal stones ≤ 10 mm 526 (90%) 58 (10%) < .001 proximal stones > 10 mm 216 (75.3%) 71 (24.7%) mid-ureter stones ≤ 10 mm 158 (85.8%) 26 (14.2%) mid-ureter stones > 10 mm 104 (81.3%) 24 (18.7%) distal stones ≤ 10 mm 1160 (90.4%) 123 (9.6%) distal stones > 10 mm 302 (81.6%) 68 (18.4%) mean maximum stone dimension (range), mm 9.5 ± 2.66 (5 to 15) 10.86 ± 2.56 (5 to 15) < .001 mean no. of shockwaves (range) 3084.06 ± 1866.46 (110 to 13400) 5186.92 ± 2404.22 (800 to 13700) < .001 561vol. 9 | no. 3 | summer 2012 |u r o lo g y j o u r n a l the other main problem during swl is that many patients administered diclofenac 75 mg orally or intramuscularly diclofenac analgesia. previous reports have indicated that an(11-13) of swl success in older patients. larger stones, higher numbers of swl sessions, and larger (2) conclusion our retrospective evaluation of this large patient series reveals that swl is effective for treating stones in the proximal, mid, and distal ureter. we believe that experience of the sition, effective analgesia during swl, and administration of simethicone before each session are all important factors in the success of this therapy. although advances continue to be made in endourologic surgery, swl remains an appropriate treatment option for stones of 5to 15-mm diameter in any location along the ureter, and yields good success. conflict of interest none declared. references 1. resit-goren m, dirim a, ilteris-tekin m, ozkardes h. time to stone clearance for ureteral stones treated with extracorporeal shock wave lithotripsy. urology. 2011;78:26-30. 2. türk c, knoll t, petrik a, sarika k, straub m, seitz c. guidelines on urolithiasis eau. http://www.uroweb.org/gls/ pdf/18_urolithiasis.pdf; 2011. 3. chaussy c, brendel w, schmiedt e. extracorporeally induced destruction of kidney stones by shock waves. lancet. 1980;2:1265-8. 4. smith-bindman r. is computed tomography safe? n engl j med. 2010;363:1-4. 5. smith rd, shah m, patel a. recent advances in management of ureteral calculi. f1000 med rep. 2009;1:1-53. 6. kose ac, demirbas m. the 'modified prone position': a new approach for treating pre-vesical stones with extracorporeal shock wave lithotripsy. bju int. 2004;93:369-73. 7. rassweiler jj, knoll t, kohrmann ku, et al. shock wave technology and application: an update. eur urol. 2011;59:78496. 8. chaussy c, eisenberger f, forssmann b. extracorporeal shockwave lithotripsy (eswl): a chronology. j endourol. 2007;21:1249-53. 9. demirbas m, kose ac, samli m, guler c, kara t, karalar m. extracorporeal shockwave lithotripsy for solitary distal ureteral stones: does the degree of urinary obstruction affect success? j endourol. 2004;18:237-40. 10. hara n, koike h, bilim v, takahashi k, nishiyama t. efficacy of extracorporeal shockwave lithotripsy with patients rotated supine or rotated prone for treating ureteral stones: a case-control study. j endourol. 2006;20:170-4. 11. ng cf, thompson t, tolley d. characteristics and treatment outcome of patients requiring additional intravenous analgesia during extracorporeal shockwave lithotripsy with dornier compact delta lithotriptor. int urol nephrol. 2007;39:731-5. 12. tokgoz h, yurtlu s, hanci v, et al. comparison of the analgesic effects of dexketoprofen and diclofenac during shockwave lithotripsy: a randomized, double-blind clinical trial. j endourol. 2010;24:1031-5. 13. tiselius hg. anesthesia-free extracorporeal shock wave lithotripsy of distal ureteral stones without a ureteral catheter. j endourol. 1993;7:285-7. shockwave lithotripsy for ureteral stones | demirbas et al 942 | 1department of urologic surgery, henan provincial people's hospital, 7 weiwu road, zhengzhou, henan, china 2yun-jiang zang, department of urologic surgery, weifang people's hospital, 151 guangwen street, kuiwen district, weifang, shandong, china jianjun liu,1 yun-jiang zang2 comparative study between three analgesic agents for the pain management during extracorporeal shock wave lithotripsy corresponding author: yun-jiang zang, md department of urologic surgery, weifang people's hospital, 151 guangwen street, kuiwen district, weifang, shandong, china tel: +13869652099 e-mail: yunshanzang@ gmail.com received june 2012 accepted january 2013 purpose: to compare the clinical efficacy between locally applied diclofenac diethylamine gel, emla cream and systemically given diclofenac sodium for the pain relief during extracorporeal shock wave lithotripsy (swl) using dornier delta compact lithotripter. material and methods: one hundred five patients with renal stones were randomly divided in to 3 groups. group a was given intramuscular diclofenac sodium (1 mg/kg), 45 minutes before the procedure. in group b, 10 gm of eutectic mixture of local anesthetic (emla) cream and in group c, 15 gm of diclofenac diethylamine gel was applied locally 45 minutes before the procedure. ten-score linear and visual analogue scale (vas) was used to assess the severity of pain during the procedure. analysis of variance (anova) test was used to compare various parameters and analyzed statistically. results: all the three groups were not statistically different with respect to age, weight, stone size, number of shock wave delivered and maximum voltage used (p > .05). the mean pain score in group a was 4.48, in group b was 3.60 and in group c was 3.95, which were not significantly different (p = 1.34). complication like skin lesion was found only in injection diclofenac sodium group whereas cold sensation at the local site was typically found in diclofenac diethylamine gel group. conclusion: although not statistically significant, the mean pain score in locally applied analgesic agents (emla and diclofenac diethylamine gel) is lower as compared to intramuscularly given diclofenac sodium. among these two locally acting drugs, diclofenac diethylamine gel is an equally effective alternative to emla. endourology and stone disease endourology and stone disease 943vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l introduction extracorporeal shock wave lithotripsy (swl) is well known for its noninvasiveness, effectiveness and minimal morbidity for the management of renal and ureteric stones.(1,2) older lithotripter were associated with more pain as compared to modern day lithotripter and it was impossible to carry out stone fragmentation without the need of anesthesia, now with the advent of modern lithotripters we can break the stones even on outpatient basis. although the pain intensity and severity has been decreased from original hm3 lithotripter to present day modern lithotripter, still most of the patients require some form of analgesic agents to decrease their pain during swl. various analgesics and anesthetics agent has been tried to decrease pain, still we don’t have any guidelines for the pain management.(3,4) the present study aimed to compare the clinical efficacy between the three drugs, two of which are applied locally at the site of the entry of shock wave like eutectic mixture of local anesthetic agents (emla) cream and diclofenac diethylamine gel, third drug is diclofenac sodium which is given intramuscularly. this study is using locally applied diclofenac diethylamine gel for the first time and compared its clinical efficacy with that of emla and injection diclofenac sodium. materials and methods this was a prospective and randomized study conducted in our institute from january 2011 to august 2011 after obtaining ethical clearance from the institute and written consent from the patients. these patients were recruited from the urology department outpatient clinic. our institute being a secondary referral center, we get frequent cases of renal stones and so more cases of those undergoing an intervention for this disorder. following inclusion criteria were used: renal stone of size less than 2cm, no previous surgery and no previous exposure of swl. exclusion criteria used in the study were: stone size more than 2cm, pregnancy, bleeding disorders, active urinary tract infection, age less than 18 years and allergy to one of the study medications. we recruited 105 patients out of 156 patients with renal stones fulfilling the inclusion and exclusion criteria. enrolled patients were evaluated in detailed with clinical examination, family history, baseline biological and hematological tests, urine microscopy with culture and sensitivity. an intravenous urogram (ivu) was done in all the cases to assess the anatomical and functional aspects of the urinary system along with stone characteristics like stone size and position. recruited 105 outpatients of renal stones were randomly divided in to three groups. right sided renal stone was found in 54 patients and 51patient had stone on the left side. randomization was done by simple randomization using the random number generator. procedure was conducted using third generation lithotripter (dornier delta compact, germany). group a (n=35) were given diclofenac sodium at the dose of 1 mg/kg, intramuscularly 45 minutes before the procedure. in group b (n=34), 10 gm of eutectic mixture of local anaesthetic (emla) cream (2.5% lignocaine and 2.5% prilocaine) was applied locally at the site of the entry of shock wave, 60 minutes before the procedure. in group c (n=36), 15 gm of diclofenac diethylamine gel was applied locally at the site of the entry of shock wave, 45 minutes before the procedure. pain assessment was done with the 10-score linear visual analogue pain scale and was compared between the three groups. age, sex, weight, stone size, total shock waves given and voltage used for each patient were recorded. statistical analysis was done using one way anova and results were compared between the three groups. a p value of less than .05 was considered to be statistically significant. results the patients mean age, sex distribution in each group, weight (kg), stone size (mm), number of shock wave delivered and voltage level used in each group was recorded and presented in table 1. mean vas score in group a was 4.48 ± 2.01, in group b was 3.60 ± 2.21 and in group c was 3.95 ± 2.5, and the p-value was 1.34 (table 2). thus the difference was insignificant and each drug was equally effective in decreasing the pain during swl. if we see complication then cold sensation at the site of the entry of shock wave was the most common complication associated with pain management during swl | liu et al 944 | diclofenac diethylamine gel. it was present in 20 out of 36 patients. whereas skin lesion was present only in 2 out of 35 patient’s injection diclofenac sodium group, it was not seen in other two locally applied agents. discussion extracorporeal shock wave lithotripsy (swl) is a noninvasive and effective mode of treatment for the urinary stones. as it is associated with minimum morbidity, it can be perform in an outpatient setting. earlier first generation lithotripter were associated with severe pain during the procedure so general or regional anesthesia was considered essential, but with the advent of modern third generation lithotripter now it is possible to complete the procedure without the need of anesthesia. this general or regional anesthesia has been replaced by opioids, sedatives, nonsteroidal anti-inflammatory drugs (nsiads) and topical anesthetics. various analgesic agents that has been tried are opioids (morphine, fentanyl, and pethidine), nsaids (diclofenac, ketorolac and piroxicam), local anesthetic agents like emla (eutectic mixture of lignocaine 2.5% and prilocaine 2.5%) and dimethyl sulfoxide (dmso) in combination with lignocaine and various other combination drugs. still we don’t have any guidelines regarding the use of analgesic agents during swl. opioids like fentanyl, morphine and pethidine are well established for the management of pain during swl but they are associated with dose related profound decrease in breathing rate, tidal volume, nausea, vomiting, broncospasm and respiratory depression.(5) so to prevent these side effects various centers started using other alternatives like nsaid and topical anesthetic agents. non steroidal anti inflammatory drugs like diclofenac sodium and ketorolac have been proven as effective analgesics for the pain relief during the swl.(6) its main action is by anti inflammatory effect secondary to prostaglandin synthesis inhibition. various routes has been tried for diclofenac like oral, intramuscular and rectal, but in this study it was used as a locally applied gel for the first time.(7) in our study we used diclofenac as intramuscular injection as well as locally applied gel and comparison was made among them as well as with topical emla cream. kumar et al used oral diclofenac in their study to compare it with emla and combination of oral diclofenac sodium and emla. they suggested combination of oral diclofenac and occlusive dressing of emla provides adequate analgesia for swl. (8) eryidilium et al. compared the efficacy of emla cream, diclofenac sodium and emla+ diclofenac sodium for the pain management during swl. their study showed that diclofenac sodium was more effective than emla cream, but in our study we find both are equally effective in reducing the pain of swl.(9) emla cream is a eutectic mixture of lignocaine (2.5%) and prilocaine (2.5%), and has been used as topical anesthetic agent for venous catheterization, condyloma acuminatum excision, phimosis and preparation of skin grafts in various studies.(10,11) to achieve its maximum anesthetic effect, it should be applied 45-60 minutes before the procedure,(8) and this property of emla cream made it, an effective agent for pain reduction during swl in various studies. bierkens and associates reported reduced opoid requirement when emla was used as a supplement during swl. (12) tritrakarn and associates also reported in their study that emla is a safe, effective and economical method to reduce pain during swl.(13) mcdonald and berry found emla cream as an ineffective agent for the pain management durendourology and stone disease table 1. demographic characteristics variables group a (diclofenac injection) group b (emla) group c (diclofenac gel) p value age 38.5±12.0 37.5±13.5 37.5±14.5 5.5 sex (m:f) 21:14 18:16 21:15 .99 weight 61.0±8.2 58.6±9.4 58.3±9.9 .8 stone size 10.3±3.3 10.4±2.8 10.9±2.3 .4 no. of shock waves 1580±408 1682±301 1800±322 3.5 used voltage 1-2 1-2 1-2 .07 table 1. demographic characteristics variables group a (diclofenac injection) group b (emla) group c (diclofenac gel) p value vas score 4.48 3.60 3.90 1.34 945vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l ing swl as compared to placebo.(14) in our study we found emla cream equally effective to intramuscular diclofenac sodium and locally applied diclofenac diethylamine gel in controlling pain of the intervention conclusion the emla cream, diclofenac gel and intramuscular diclofenac sodium produce similar results for pain scores during swl. further studies with larger sample sizes are needed to extrapolate these results. conflict of interest none declared. pain management during swl | liu et al references 1. chaussy c, brendel w, schmiedt e. extracorporeal induced destruction of kidney stones by shock waves. lancet. 1980;2:1265–8. 2. chaussy gc, fuchs gj. current state and future developments of noninvasive treatment of urinary stones with extracorporeal shock wave lithotripsy. j urol. 1989;141:782–9. 3. wickham je. treatment of urinary tract stones. bmj. 1993;307:1414–7. 4. hosking mp, morris sa, klein fa, dobmeyer-dittrich c. anesthetic management of patients receiving calculus therapy with a third-generation extracorporeal lithotripsy machine. j endourol. 1997;11:309–11. 5. notcutt wg, knowles p, kaldas r. overdose of opoid from patient controlled analgesia pumps. br j anaesth 1992;69:95-97. 6. cohen e, hafner r, rotenberg g, fadilla m, garty m. comparison of ketorolac and diclofenac in the treatment of renal colic. eur j clin pharmacol 1998;54:455-458 7. dawson c, vale ja, corry da, et al. choosing the correct pain relief for extracorporeal lithotripsy. br j urol. 1994;74:302307 8. anup kumar, narmada p. gupta, ashok k. hemal, pankaj wadhwa. comparison of three analgesic regimens for pain control during shockwave lithotripsy using dornier delta compact lithotripter: a randomized clinical trial. j endourol. 2007;21: 578-582. 9. eryildirim b, kuyumcuoğlu u, tarhan f, faydaci g, uruç f. comparison of three analgesic treatment protocols for pain management during extracorporeal shock wave lithotripsy. urol int. 2009;82:276-9. 10. xavier b, caffaratti j, orsola a, garat jm, vicente gj. topical anesthesia with the emla cream: application in pediatric urology. actas urol esp. 1996;20:883–5. 11. aldret-neilson l, bjerring p, nielson j. regional variations in analgesic efficacy of emla cream. acta dermatol scand. 1999;70:314–8. 12. bierkens af, maes rm, hendrikx jm, erdos af, de vries jd, debruyne fm. the use of local anesthesia in second generation extra corporeal shock wave lithotripsy; eutectic mixture of local anesthetics. j urol. 1991;146:287-289. 13. tritrakarn t, lertakyamanee j, koompong p, et al. both emla and placebo cream reduced pain during extracorporeal piezoelectric shock wave lithotripsy with the piezolith 2300. anesthesiology. 2000;92:1049–54. 14. mcdonald pf, berry am. topical anesthesia for extracorporeal shock wave lithotripsy. br j anaesth. 1992;69:399-400. 941vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l urology department, san cecilio university hospital, granada, spain * e-mail: arrabalp@ono.com a 39-year-old man with a medical history of hypertension, type i diabetes mellitus (hba1c: 7%) and 3 components penile prosthesis for erectile dysfunction refrac-tory to medical treatment implanted 9 years before, presented at the urology department. he reported an extrusion of the prosthesis through the urethral meatus avoiding spontaneous urination (figure). three months before during an intense sexual intercourse (“cowboy sex” syndrome), the patient had pain in the penis and latter the prosthesis started to appear through the meatus. the function of the prosthesis had been successful during these years. a physical examination showed one cylinder through the meatus without inflammation or infection signs (no pus collection). a longitudinal peno-scrotal incision checking the extrusion of left cylinder through the left side of the urethra was performed and the cylinder was removed keeping the patient without a bladder catheter. two months after surgery the patient had a normal urination and sexual intercourse with the use of a single cylinder of the penile prosthesis. penile prosthesis extrusion is a rare complication produced by infection, trauma, intense sexual activity(1) and in relation with diabetes mellitus, radiotherapy or neurological problems. (2) once the extrusion has been produced, treatment depends on the type of perforation. some authors repair the erosion with good results(3) and others prefer to remove the prosthesis.(2) miguel ángel arrabal-polo, fernando lópez-carmona pintado, samuel gonzález-torres transurethral extrusion of penile prosthesis references 1. salama m, kishimoto t, kanayama ho, kagawa s. unusual trivial trauma may end with extrusion of a well-functioning penile prosthesis: a case report. j med case rep. 2007;1:34. 2. shaeer o. management of distal extrusion of penile prosthesis: partial disassembly and tip reinforcement by double breasting or grafting. j sex med. 2008;5:1257-62. 3. shindel aw, brant wo, mwamukonda k, bella aj, lue tf. transglanular repair of impending penile prosthesis cylinder extrusion. j sex med. 2010;72884-90 pictorial urology figure. extruded penile prosthesis through the urethral meatus urol_v3_no1_001_editorial.qxd o r i g i n a l a r t i c l e s endourology and stone diseases retrograde flexible ureteroscopic approach for pyelocaliceal calculi petrisor geavlete, seyed abdulah seyed aghamiri,* razvan multescu department of urology, st john clinical emergency hospital, bucharest, romania abstract introduction: our goal was to investigate the efficacy of flexible ureteroscopy (fu) in the treatment of pyelocaliceal calculi. materials and methods: between september 2002 and december 2004, a total of 41 patients with multiple (23 cases), pelvic (7 cases), and inferior caliceal (11 cases) swl-resistant calculi underwent fu. we used a 7.5-f flexible ureteroscope with pressure irrigation and electro-hydraulic lithotripsy. the fragments were retrieved with triradiate graspers or tipless baskets. results: a double j stent had been previously placed in 34% of the patients. dilation of the ureteral orifice was necessary in 9.8%. the location of the calculi was renal pelvis, inferior calyx, and pelvis and calyxes in 7, 11, and 23 patients, respectively. the median operative time was 64 minutes for pyelocaliceal, 46 minutes for pelvic, and 39 minutes for inferior caliceal calculi. complete stone clearance or good fragmentation (fragments less than 3 mm) was obtained in 71% of patients (57% for pyelocaliceal, 87% for pelvic, and 71% for inferior caliceal calculi). a successful outcome was achieved in 78%, 72%, and 49% for calculi sized 10 mm or smaller, 11 mm to 20 mm, and greater than 20 mm, respectively. two or more procedures were required in 11 patients (27%). the complication rate was 7.3% (hematuria, persistent renal colic, and hyperthermia). conclusion: our experience shows that fu can be an effective approach in selected patients, especially those with kidney calculi that are resistant to swl. however, percutaneous approach is a better alternative for calculi greater than 20 mm. key words: flexible ureteroscopy, kidney calculus, shock wave lithotripsy 15 urology journal unrc/iua vol. 3, no. 1, 15-19 winter 2006 printed in iran introduction the first flexible ureteroscopy (fu) was performed for diagnostic purposes in 1964 by marshall.(1) he used a 9-f endoscope produced by an american cystoscope manufacturer, without a working channel or active deflection facilities. at the beginning of the 1980s, bagley and colleagues(2,3) contributed significantly to the development of fu by adding three essential technical characteristics: the working channel, an active deflection, and--by reducing the rigidity in the distal portion of the sheath--a passive deflection. by miniaturization of the endoscopes and development of the optical system, ureteroscopes became very useful tools in the diagnosis and treatment of upper urinary tract lesions.(4) although shock wave lithotripsy (swl) represents the first-line treatment of pyelocaliceal received november 2005 accepted february 2006 *corresponding author: tel: +40 722 402 887, fax: +40 21 321 0507, e-mail: seyedag@yahoo.com calculi smaller than 20 mm, other alternatives of endourologic techniques for swl-resistant calculi are necessary. since 2002, the use of fu in the diagnostic and therapeutic arsenal at st john clinical emergency hospital in bucharest has substantially improved the diagnosis and treatment of the upper urinary tract diseases, especially kidney calculi. the purpose of this study was to evaluate the efficacy, limits, and complications of the fu in swl-resistant pyelocaliceal calculi. materials and methods between september 2002 and december 2004, a total of 41 patients with swl-resistant pyelocaliceal calculi underwent fu in our department. the investigational protocol included physical examination, routine blood tests, abdominal ultrasonography, plain abdominal radiography (kidney, ureter, and bladder), intravenous urography (ivu), and, in selected cases, retrograde ureteropyelography and ct scan. the characteristics of the calculi are summarized in table 1. in the patients with multiple calculi, the location of calculi was either concomitant pelvic and caliceal (inferior, middle, or superior) or multiple caliceal. the maximum dimensions were 25 mm for pelvic calculi and 12 mm for caliceal ones; the mean area was 328 mm2 (range, 175 mm2 to 610 mm2). in 14 patients (34%) with obstructive pelvic calculi and hydronephrosis, double j stenting had been previously performed and the stent maintained for 14 days before fu. in all patients, swl had been attempted and the mean number of procedures was 2.9 (range, 1 to 4). they were treated using a 7.5-f storz flexible ureteroscope (karl storz, tuttlingen, germany) with an active deflection, a secondary passive deflection, and a 3.6-f working channel. as an energy source, we used an electrohydraulic lithotripter (calcutript, karl storz, tuttlingen, germany) with 1.6-f and 1.9-f flexible probes. for irrigation, saline (0.9% nacl) solution was used. for retrieval of calculi fragments, we used flexible triradiate graspers or nitinol tipless baskets. all interventions were performed under fluoroscopic guidance using a mobile radiological unit (siemens, erlangen, germany). ureteral orifice dilation was necessary in 4 patients (9.8%). the insertion of the fu was fluoroscopically controlled by sliding on a nitinol guide wire (figure 1); no access ureteral sheath was used. in 33 patients (80.4%), ureteral stenting after the procedure was not necessary. stents were used only in patients who needed meatal dilation (4 cases) and those with significant renal bleeding during lithotripsy (4 cases), which were left in place for 14 days. the procedure was considered successful if all the calculi were extracted (figures 2 to 4) or if the resulted fragments were smaller than 3 mm, small enough not to be considered as obstructive. the follow-up protocol included abdominal ultrasonography, plain abdominal radiography (in patients with radio-opaque calculi), and in selected cases (6 patients), ivu. flexible ureteroscopy for pyelocaliceal calculi16 table 1. size and location of the kidney calculi fig. 1. flexible uretroscopic approach to the middle caliceal calculi (fluoroscopic aspect) number of calculi (%) size of the calculi < 10 mm 45 (51.7) 10 mm to 20 mm 25 (28.7) > 20 mm 17 (19.5) location of the calculi number of patients (%) pelvic 7 (17) inferior calyx 11 (26.8) pyelocaliceal 23 (56.1) geavlete et al results the median operative time was 64 minutes (range, 41 to 215 minutes) for pyelocaliceal, 46 minutes (range, 28 to 89 minutes) for pelvic, and 39 minutes (range, 27 to 70 minutes) for inferior caliceal calculi. the mean follow-up period was 7 months (range, 3 to 22 months). eleven patients (26.8%) required to repeat the procedure. in 6 of them (54.5%), the initial procedure was interrupted due to a low visibility (bleeding in 5 and pyuria in 1) and lithotripsy was performed in a secondary procedure. in the other 5 patients (45.5%), the inferior caliceal calculi could not be approached by flexible retrograde ureteroscopy, requiring a second procedure. the overall success rate was 71%; it was 57% for pyelocaliceal, 87% for pelvic, and 71% for inferior caliceal calculi. considering the calculi dimensions, the success rate was 78% for calculi sized 10 mm or smaller, 72% for calculi between 11 mm and 20 mm, and 49% for calculi larger than 20 mm. the causes of fu failure were the impossibility of calculi approach (only in inferior caliceal calculi), impossibility of fragmentation, or the necessity of procedure interruption. in all cases, percutaneous nephrolithotripsy (pcnl) was performed thereafter. there were no major complications or deaths. complication rate was 7.3% (3 patients) presented as minor complications including hematuria, persistent lumbar pain, and pyelonephritis. discussion the therapeutic options for pyelocaliceal calculi are represented by swl, fu, and pcnl, selected according to the therapeutic strategy for each patient. developed in the 1980s, swl became the first line treatment of calculi smaller than 20 mm. although the success rate of this method reaches 92% in selected patients, it is 33% to 65% for calculi larger than 20 mm,(5,6) and only 41% for inferior caliceal calculi.(7) in all swl-resistant calculi, other methods of fragmentation and/or extraction are necessary. although it has very good results (90% stone-free rate), pcnl is an invasive method with a high morbidity rate.(8) allowing, at least theoretically, the access to any upper urinary tract region, fu represents a valuable alternative in the therapeutic arsenal for kidney calculi. flexible ureteroscopy offers the advantages of direct visualization and extraction of the calculi, followed by inspection of the pyelocaliceal system for potential remnant fragments.(7) parameters such as dimension, composition, and multiplicity of the calculi influence the success rate of the lithotripsy methods. the success rate of swl in lower caliceal calculi is low (41% to 79%).(7,9,10) large dimensions of the calculi, higher concentration of cystine or calcium monohydrate oxalate,(11) or anatomical particularities of intrarenal ducts (inferior caliceal infundibular length of more than 3 mm and/or a diameter smaller than 5 mm, acute infundibulopelvic angle) are associated with a poor swl success rate.(12) in the presence of these negative factors, the fu could be a superior alternative. 17 fig. 3. a stone-free inferior calyx (endoscopic and fluoroscopic intra-operative aspect) fig. 4. middle caliceal calculi (endoscopic and fluoroscopic intra-operative aspect) fig. 2. multiple caliceal calculi (endoscopic and fluoroscopic intra-operative aspect) flexible ureteroscopy for pyelocaliceal calculi grasso and ficazzola have treated 90 cases of lower pole calculi with a small diameter, actively deflectable, flexible ureteropyeloscope and reported a 94% success rate using fu for inferior caliceal calculi smaller than 10 mm and a 95% rate for those between 11 mm and 20 mm.(13) hollenbeck and colleagues have reported a 79 % stone-free rate after one attempt, raised to 88% after the second procedure.(14) the 71 % stonefree rate for inferior caliceal calculi in our study— lower than that in other reports—can be explained by the patient selection (with swl-resistant calculi) and by the type of energy used to fragment calculi (electrohydraulic lithotripter). in a study on 81 patients with swl-resistant kidney calculi, stav and associates have reported a 67 % success rate.(7) hallenbeck have suggested that anatomical particularities of intrarenal ducts associated with a poor swl success rate also makes the endoscopic approach difficult.(14) likewise, grasso and ficazzola have indicated that hydronephrosis, inferior caliceal duct stenosis, and infundibular length of more than 3 mm are most frequently associated with the failure of intrarenal lithotripsy using fu.(13) oxalate calcium monohydrate calculi associated with a low swl success rate are frequently electrohydraulic lithotripsy-resistant. the use of a holmium laser energy source would probably improve the stone-free rate.(15) the success rate of fu in patients with pyelocaliceal calculi larger than 20 mm is less than 50%; grasso and ficazzola have reported the complete fragmentation of calculi of such dimensions in 45% of patients,(13) and robert and colleagues have reported it in 47 %.(16) shock wave lithotripsy is also associated with poor results for this type of calculi (average success rate of 63%). the best therapeutic alternative for this type of calculi remains pcnl.(5,6,17) in 14 patients (35%) of our series with obstructive pelvic calculi and hydronephrosis, a double j stent was placed and fu was performed 14 days thereafter. the double j stent reduces the hydronephrosis, enhancing the performances of fu by offering the possibility of obtaining the secondary passive deflection, which allows the access to the inferior caliceal group. the complication rate reported in literature is between 0% and 13%--mostly due to minor complications.(11) only one major complication was cited: retroperitoneal hematoma in a patient with uncontrolled hemorrhagic diathesis.(18) stav and colleagues have reported a 10% rate of minor complications and no major ones.(7) because of the reduced dimensions of the flexible ureteroscope, the injury to the upper urinary tract is minimal(19); this technical particularity associated with an adequate preoperative assessment makes fu a safe method with a lower morbidity and practically no mortality. conclusion flexible ureteroscopy can be an efficient treatment alternative in kidney calculi, especially in swl-resistant calculi smaller than 20 mm. this method provides a good approach for inferior caliceal calculi (with a success rate higher in selected cases than that obtained by swl). for calculi larger than 20 mm, the most efficient method remains pcnl, despite its higher morbidity rate. overall, respecting the anatomical urinary tract, fu is a minimally invasive method with a low morbidity rate. references 1. marshall vf. fiber optics in urology. j urol. 1964;91:110-4. 2. bagley dh, huffman jl, lyon es. combined rigid and flexible ureteropyeloscopy. j urol. 1983;130:243-4. 3. bagley dh, huffman jl, lyon es. flexible ureteropyeloscopy: diagnosis and treatment in the upper urinary tract. j urol. 1987;138:280-5. 4. grasso m. ureteroscopy. emedicine [cited 2002 may 29]. available from: http://www.emedicine.com/med/topic3079.htm 5. tiselius hg, ackermann d, alken p, buck c, conort p, gallucci m; working party on lithiasis, european association of urology. guidelines on urolithiasis. eur urol. 2001;40:362-71. 6. lingeman je, lifshitz da, evan ap. surgical management of urinary lithiasis. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 3361-436. 7. stav k, cooper a, zisman a, leibovici d, lindner a, siegel yi. retrograde intrarenal lithotripsy outcome after failure of shock wave lithotripsy. j urol. 2003;170:2198-201. 8. kerbl k, rehman j, landman j, lee d, sundaram c, clayman rv. current management of urolithiasis: progress or regress? j endourol. 2002;16:281-8. 9. lingeman je, siegel yi, steele b, nyhuis aw, woods jr. management of lower pole nephrolithiasis: a critical analysis. j urol. 1994;151:663-7. 10. netto nr jr, claro jf, lemos gc, cortado pl. renal 18 geavlete et al calculi in lower pole calices: what is the best method of treatment? j urol. 1991;146:721-3. 11. busby je, low rk. ureteroscopic treatment of renal calculi. urol clin north am. 2004;31:89-98. 12. elbahnasy am, shalhav al, hoenig dm, et al. lower caliceal stone clearance after shock wave lithotripsy or ureteroscopy: the impact of lower pole radiographic anatomy. j urol. 1998;159:676-82. 13. grasso m, ficazzola m. retrograde ureteropyeloscopy for lower pole caliceal calculi. j urol. 1999;162:1904-8. 14. hollenbeck bk, schuster tg, faerber gj, wolf js. flexible ureteroscopy in conjunction with in situ lithotripsy for lower pole calculi. urology. 2001;58:859-63. 15. sofer m, watterson jd, wollin ta, nott l, razvi h, denstedt jd. holmium:yag laser lithotripsy for upper urinary tract calculi in 598 patients. j urol. 2002;167:31-4. 16. robert m, drianno n, marotta j, delbos o, guiter j, grasset d. [the value of retrograde ureterorenoscopy in the treatment of bulky kidney calculi]. prog urol. 1997;7:35-41. french. 17. conort p, dore b, saussine c; comite lithiase de l'association francaise d'urologie. [guidelines for the urological management of renal and ureteric stones in adults]. prog urol. 2004;14:1095-102. french. 18. watterson jd, girvan ar, cook aj, et al. safety and efficacy of holmium: yag laser lithotripsy in patients with bleeding diatheses. j urol. 2002;168:442-5. 19. bagley dh. ureteroscopic surgery: changing times and perspectives. urol clin north am. 2004;31:1-4, vii. editorial comment consistent with other reports, the success rate of ureteroscopy in the treatment of calculi greater than 2 cm and multiple pyelocaliceal calculi was lower in this study. however, it should be noted that the patients with such calculi constituted a very smaller proportion of the patients in this report. thus, with a larger sample size and increasing the surgeons' experience, a different outcome may be achieved. moreover, the relatively low success rate in patients with multiple calculi could be related to the total size of the calculi. the authors have mentioned that the energy source was provided by an electrohydraulic lithotripter. nonetheless, using holmium laser is nowadays a more recommended method as electrohydraulic lithotripsy can lead to injuries to the ureteral mucosa and damage to the ureteroscope lens. this can explain the cause of intra-operative bleeding in 5 out of 41 patients, resulting in lithotripsy failure. abbas basiri department of urology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran reply by author indeed, the electrohydraulic lithotripsy has some disadvantages comparing with laser lithotripsy: lower success rate in stone fragmentation, higher risk of damaging the pyelocaliceal mucosa, and the ureteroscope's optical system. nonetheless, electrohydraulic lithotripsy presents some advantages: lower costs and also a higher flexibility of the thin 1.6-f electrohydraulic probes, in comparison with the 200-µm laser fiber. these flexible probes inserted through the working channel have a reduced influence on the maximum deflection angle of the flexible ureteroscope, important when the access to the inferior calyx is difficult. seyed abdulah seyed aghamiri department of urology, st john clinical emergency hospital, bucharest, romania 19 v08_no_3_final.pdf point of technique 231urology journal vol 8 no 3 summer 2011 laparoscopic dismembered pyeloplasty and pyelolithotomy in a patient with a retrocaval ureter our experience and review of literature vishwajeet singh, rahul janak sinha urol j. 2011;8:231-5. www.uj.unrc.ir keywords: ureter, congenital abnormalities, laparoscopy, reconstructive surgical procedures department of urology, chhatrapati shahuji maharaj medical university (csmmu, formerly kgmu), lucknow, 226003, india corresponding author: rahul janak sinha, ms (surgery), mch (urology) department of urology, csmmu (formerly kgmu), lucknow, 226003, india tel: +91 941 500 3051 e-mail: rahuljanaksinha@rediffmail.com received june 2010 accepted december 2010 introduction the incidence of retrocaval ureter is reported as 1 in 1100, with male to female predominance of 2.8:1. (1) the cause of this anomaly is persistence of posterior cardinal vein as infrarenal vena cava during the embryologic development. (2) the symptoms usually start in 3rd to 4th decade of life, and the common presentation is recurrent flank pain, recurrent urinary tract infection, or hypertension due to hydronephrosis.(3,4) retrocaval ureter is diagnosed by the appearance of s-shaped curve of the upper ureter, which may be confirmed by spiral contrast-enhanced computerized tomography (cect) scan.(5) this vascular anomaly is not usually associated with the ureteral obstruction.(6) any functional urinary obstruction may be diagnosed by nuclear scan.(7) open dismembered pyeloplasty has been the traditional treatment for retrocaval ureter.(7-9) recently, few papers have focused on the laparoscopic dismembered pyeloplasty and reported acceptable results.(10-14) the laparoscopic technique has advantage of decreased convalescence and analgesic requirement.(8,9,15) laparoscopy is challenging as extensive caval dissection in the medial and lateral regions of the vena cava are performed.(15-19) herein, we discuss the laparoscopic management of retrocaval ureter presenting with renal calculus, which was managed by pyelolithotomy and dismembered pyeloplasty in the same session. case report an 18-year-old man presented with recurrent right flank pain for 6 months. he did not report other urological symptoms. his abdominal examination was unremarkable. his renal function tests were within the normal limits. the ultrasonography of the kidney, ureter, and bladder (kub) region showed right hydronephrotic kidney with a 2-cm renal calculus. his plain kub x-ray depicted a 2 cm × 1 cm radiopaque shadow in the right renal area (figure 1). intravenous urogram (ivu) showed right moderate hydronephrosis with a j-shaped ureter and a renal stone (figure 2). the spiral cect scan of the abdomen revealed right hydronephrosis with the ureter passing posterior to the inferior vena cava (ivc) (figure 3). his nuclear scan depicted right kidney split renal function of 45% with subrenal obstruction. laparoscopic repair of a retrocaval ureter—singh et al 232 urology journal vol 8 no 3 summer 2011 he was managed by transperitoneal laparoscopic pyelolithotomy and dismembered pyeloplasty. technique cystoscopy and right retrograde pyelography were performed, which showed findings suggestive of the right retrocaval ureter. a 6-f ureteric catheter was negotiated in the right ureter, but it got stuck a few centimeters below the right pelviureteric junction (puj). a guidewire (0.035” terumo glidewire) could enter the pelvicalyceal system. the patient was placed in left lateral position with slight tilt to the left side and 4 ports were placed. the right colon was reflected and the right ureter was identified above the pelvic brim and traced till the point where it was passing in front of and behind the ivc (figure 4). the ivc was lifted with dissecting forceps and the ureter was mobilized in the interaortocaval region, where it was passing posterior to the ivc. the proximal ureter, lateral to the ivc, was dissected free till the puj level. the ureter at the puj was transected and the atretic unhealthy portion (approximately 2 cm in length) was excised; following which the ureter was spatulated for 2 cm. a vertical incision in the pelvis was made and the stone was retrieved with the help of a grasper (figure 5). the double-j stent was inserted in figure 1. plain kidney, ureter, and bladder x-ray showing radiopaque shadow in the right renal area. figure 2. intravenous urogram showing typical j-shaped proximal ureter with an inferior calyceal calculus. figure 3. contrast-enhanced computerized tomography scan of the abdomen showing dilated right renal pelvis with the proximal ureter passing postero-medial to the inferior vena cava. laparoscopic repair of a retrocaval ureter—singh et al 233urology journal vol 8 no 3 summer 2011 the ureter by antegrade technique. uretropelvic anastomosis was performed with 4-0 polyglactin suture in continuous fashion (figure 6). a 16-f continuous suction drain was placed in the right renal area at the end of the laparoscopic surgery. results the operation and the intracorporeal suturing time were approximately 180 and 60 minutes, respectively. the blood loss was approximately 50 ml. the postoperative course was uneventful. suction drain was removed after 48 hours and the patient was discharged on the 3rd postoperative day. double-j stent was removed after 6 weeks. after 2 weeks following stent removal, nuclear scan showed no evidence of subrenal obstruction. the patient is doing well at 6 months of followup period. discussion retrocaval ureter may be asymptomatic or discovered during radiologic imaging for some other problems.(6) spiral cect scan of the abdomen is said to be the gold standard investigation.(5) however, ivu shows the typical appearance of the ureter. two types of retrocaval ureter have been described; type i is typical s-shaped or fish hook pattern (j-shaped) while type ii has a more horizontal shape that gives it the appearance of sickle shape. if the patient is symptomatic with documented subrenal functional obstruction, dismembered pyeloplasty is the gold standard treatment.(8,9) if the retrocaval portion is atretic, then it may be left in situ. uretropelvic or uretroureterostomy is the recommended treatment in this situation.(19,20) over the past decade, few case reports and case series describing transperitoneal or retroperitoneal laparoscopic dismembered pyeloplasty with intracorporeal suturing have appeared in literature (table). till date, approximately 50 cases have been reported in literature using laparoscopic technique. in this patient, there was an associated renal stone, which was changing position. ultrasonography of the kub suggested it as a pelvic stone, ivu showed it as inferior calyceal stone, while we located it in the renal pelvis during the procedure. pyelolithotomy was done prior to the uretropelvic anastomosis. figure 4. laparoscopic view of the ureter passing posteromedial to the inferior vena cava. figure 6. laparoscopic view of uretropelvic anastomosis by intracorporeal suturing over a stent. figure 5. laparoscopic view while extracting the renal calculus. laparoscopic repair of a retrocaval ureter—singh et al 234 urology journal vol 8 no 3 summer 2011 simforoosh and colleagues have reported simultaneous treatment of renal stone and retrocaval ureter with laparoscopic technique earlier.(19) similarly, mugiya and associates reported a case, in which retrocaval ureter and upper ureteric calculus were managed during the same procedure.(21) even with our limited experience, we believe that laparoscopic technique should be kept as the first option for the management of retrocaval ureter even if it is complicated by the presence of a renal calculus. conflict of interest none declared. references 1. lautin em, haramati n, frager d, et al. ct diagnosis of circumcaval ureter. ajr am j roentgenol. 1988;150:591-4. 2. considine j. retrocaval ureter. a review of the literature with a report on two new cases followed for fifteen years and two years respectively. br j urol. 1966;38:412-23. 3. zhang xd, hou sk, zhu jh, wang xf, meng gd, qu xk. diagnosis and treatment of retrocaval ureter. eur urol. 1990;18:207-10. 4. pais vm, strandhoy jw, assimos dg. pathophysiology first author ye ar o f pu bl ic at io n n um be r of pa tie nt s a cc es s n um be r of po rt s o pe ra tio n du ra tio n, m in o pe n co nv er si on a na st om ot ic tim e, m in b lo od lo ss , m l baba(10) 1994 1 tp 5 560 150 nr matsuda(11) 1996 1 tp 5 450 nr <30 ishitoya(12) 1996 1 tp 4 365 1 nr nr gaur(21) 1997 1 rp 4 300 1 nr nr polascik(13) 1998 1 tp 3 225 anastomosis done by automatic suture device nr salomon(14) 1999 1 rp 4 270 nr <20 mugiya(20) 1999 1 rp 4 300 anastomosis done by automatic suture device 50 ameda(15) 2001 2 tp rp 4 4 450 400 nr nr 20 nr gupta(16) 2001 1 rp 3 210 nr nr miyazato(22) 2002 1 rp 3 180 nr <50 bhandarkar(23) 2003 1 tp 3 240 nr nr ramalingam(17) 2003 2 tp tp 6 6 240 210 nr minimal nr tobias-machado(18) 2005 1 rp 3 130 40 extracorporeal anastomosis 50 simforoosh(19) 2006 6 tp 4 180 nr <50 gundeti(24) 2006 1 tp 3 210 robot assisted nr chung(25) 2008 1 tp 4 210 30 minimal fernandez fernandez(26) 2008 1 tp 3 60 nr, extracorporeal anastomosis nr xu(27) 2009 7 rp 3 128 20 (mean) smith(28) 2009 1 tp 3 294 robot assisted nr li(29) 2010 10 rp 3 82 <10 autorino(30) 2010 1 tp 1 180 minimal hemal(31) 2010 4 tp 3 138 robot assisted 98 dogan(32) 2010 4 tp 4 210 nr nr published literature on laparoscopic surgical management of the retrocaval ureter. tp indicates transperitoneal laparoscopic dismembered pyeloplasty; rp, retroperitoneal laparoscopic dismembered pyeloplasty; and nr, not reported. laparoscopic repair of a retrocaval ureter—singh et al 235urology journal vol 8 no 3 summer 2011 of urinary tract obstruction. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbellwalsh urology. vol 2. 9th ed. philadelphia: saunders elsevier 2007:1223. 5. pienkny aj, herts b, streem sb. contemporary diagnosis of retrocaval ureter. j endourol. 1999;13:721-2. 6. crosse je, soderdahl dw, teplick sk, clark re. nonobstructive circumcaval (retrocaval) ureter. a report of 2 cases. radiology. 1975;116:69-71. 7. hsu ths, streem sb, nakada sy. management of upper urinary tract obstruction. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campell-walsh urology. vol 2. 9 ed. philadelphia saunders elsevier 2007:1253. 8. bauer jj, bishoff jt, moore rg, chen rn, iverson aj, kavoussi lr. laparoscopic versus open pyeloplasty: assessment of objective and subjective outcome. j urol. 1999;162:692-5. 9. baldwin dd, dunbar ja, wells n, mcdougall em. single-center comparison of laparoscopic pyeloplasty, acucise endopyelotomy, and open pyeloplasty. j endourol. 2003;17:155-60. 10. baba s, oya m, miyahara m, deguchi n, tazaki h. laparoscopic surgical correction of circumcaval ureter. urology. 1994;44:122-6. 11. matsuda t, yasumoto r, tsujino t. laparoscopic treatment of a retrocaval ureter. eur urol. 1996;29: 115-8. 12. ishitoya s, okubo k, arai y. laparoscopic ureterolysis for retrocaval ureter. br j urol. 1996;77:162-3. 13. polascik tj, chen rn. laparoscopic ureteroureterostomy for retrocaval ureter. j urol. 1998;160:121-2. 14. salomon l, hoznek a, balian c, gasman d, chopin dk, abbou cc. retroperitoneal laparoscopy of a retrocaval ureter. bju international. 1999;84:181-2. 15. ameda k, kakizaki h, harabayashi t, watarai y, nonomura k, koyanagi t. laparsocopic ureteroureterostomy for retrocaval ureter. int j urol. 2001;8:71-4. 16. gupta np, hemal ak, singh i, khaitan a. retroperitoneoscopic ureterolysis and reconstruction of retrocaval ureter. j endourol. 2001;15:291-3. 17. ramalingam m, selvarajan k. laparoscopic transperitoneal repair of retrocaval ureter: report of two cases. j endourol. 2003;17:85-7. 18. tobias-machado m, lasmar mt, wroclawski er. retroperitoneoscopic surgery with extracorporeal uretero-ureteral anastomosis for treating retrocaval ureter. int braz j urol. 2005;31:147-50. 19. simforoosh n, nouri-mahdavi k, tabibi a. laparoscopic pyelopyelostomy for retrocaval ureter without excision of the retrocaval segment: first report of 6 cases. j urol. 2006;175:2166-9; discussion 9. 20. mugiya s, suzuki k, ohhira t, un-no t, takayama t, fujita k. retroperitoneoscopic treatment of a retrocaval ureter. int j urol. 1999;6:419-22. 21. gaur dd. laparoscopic operative retroperitoneoscopy: use of a new device. j urol. 1992;148:1137-9. 22. miyazato m, kimura t, ohyama c, hatano t, miyazato t, ogawa y. retroperitoneoscopic ureteroureterostomy for retrocaval ureter. hinyokika kiyo. 2002;48:25-8. 23. bhandarkar ds, lalmalani jg, shivde s. laparoscopic ureterolysis and reconstruction of a retrocaval ureter. surg endosc. 2003;17:1851-2. 24. gundeti ms, duffy pg, mushtaq i. robotic-assisted laparoscopic correction of pediatric retrocaval ureter. j laparoendosc adv surg tech a. 2006;16:422-4. 25. chung bi, gill is. laparoscopic dismembered pyeloplasty of a retrocaval ureter: case report and review of the literature. eur urol. 2008;54:1433-6. 26. fernandez-fernandez ja, pachano-arenas fe. laparoscopic-assisted correction of a retrocaval ureter. j pediatr surg. 2008;43:1560-2. 27. xu df, yao yc, ren jz, et al. retroperitoneal laparoscopic ureteroureterostomy for retrocaval ureter: report of 7 cases. urology. 2009;74:1242-5. 28. smith km, shrivastava d, ravish ir, nerli rb, shukla ar. robot-assisted laparoscopic ureteroureterostomy for proximal ureteral obstructions in children. j pediatr urol. 2009;5:475-9. 29. li hz, ma x, qi l, shi tp, wang bj, zhang x. retroperitoneal laparoscopic ureteroureterostomy for retrocaval ureter: report of 10 cases and literature review. urology. 2010;76:873-6. 30. autorino r, khanna r, white ma, et al. laparoendoscopic single-site repair of retrocaval ureter: first case report. urology. 2010;76:1501-5. 31. hemal ak, nayyar r, gupta np, dorairajan ln. experience with robot assisted laparoscopic surgery for upper and lower benign and malignant ureteral pathologies. urology. 2010;76:1387-93. 32. dogan hs, oktay b, vuruskan h, yavascaoglu i. treatment of retrocaval ureter by pure laparoscopic pyelopyelostomy: experience on 4 patients. urology. 2010;75:1343-7. correlation between protamine-2 and mirna-122 in sperm from heroin-addicted men: a case-control study zohreh nazmara1, mohammad najafi2,3, mansoureh movahedin4, zahara zandieh1,5, peymaneh shirinbayan6, hamid reza asgari1, mohsen roshanpajouh7, chad b. maki8, zahra bashiri1,2, morteza koruji1,2* purpose: recreational use of illicit drugs is one of the main factors affecting male fertility. however, the mechanisms of heroin smoke-associated damage to mature spermatozoa are still completely unknown. the aim of this study was to concomitantly examine the levels of protamine-2 gene and protein concentrations, the amount of mirna-122 in seminal plasma and semen analysis findings in heroin-addicted men. materials and methods: in a case control study, twenty-four fertile men that lacked any recreational drug abuse were considered as the healthy group, and 24 addicted men who used only heroin for at least four months were selected as the addicted group. semen samples were gathered by masturbation after 2 5 days of sexual abstinence. following the preparation of a semen analysis by computer-assisted sperm analysis according to who (2010), the level of protamine-2 gene expression in sperm and mirna-122 in seminal plasma was measured using real-time sqpcr. also, protamine-2 protein concentrations were quantified by nuclear protein extraction, sds-page and western blotting. results: among the studied variables, body mass index (27.75 ± 0.88 vs. 22.30 ± 0.36, p = 0.001), seminal ph (7.79 ± 0.06 vs. 7.58 ± 0.06, p = 0.003), white blood cell count in semen (1.69 ± 0.41 vs. 8.61 ± 1.73, p = 0.001), motility (65.51 ± 2.57 vs. 41.96 ± 3.58, p = 0.001) and survival rate (87.41 ± 1.00 vs. 71.50 ± 4.59, p = 0.002) of sperm cells was significantly different between the healthy and addicted groups. in addition, the levels of protamine-2 gene and protein expression in the addicted group (0.05 ± 0.02 and 0.10 ± 0.02, respectively) were significantly lower than the healthy group (3.59 ± 0.94 and 0.27 ± 0.06, respectively) (p = 0.002 and p = 0.017, respectively). seminal mirna-122 levels in addicted men (3.51 ± 0.73) were statistically higher than in healthy men (1.52 ± 0.54) (p = 0.034). conclusion: this is one study on human infertility that evaluates the effects of heroin on protamine deficiency and seminal small rnas expression levels. heroin abuse may lead to male infertility by causing leukocytospermia, asthenozoospermia, protamine deficiency, and seminal plasma mirna profile alteration. keywords: protamine-2; mirna-122; sperm; male infertility; heroin; illicit drugs; addiction introduction infertility is one of the major medical challenges that affects over 15% of couples worldwide. approximately 50% of the infertile cases are due to male factors(1). semen abnormalities are one of the most common types of infertility due to multiple potential causes including inheritance, hormonal defects, drug abuse, (especially illicit drugs), and infection(2,3), but alarmingly, 60 to 75% of causes are still unknown or idiopathic(4,5). it has been explored that drug abuse affects the hormonal 1department of anatomy, school of medicine, iran university of medical sciences, tehran, iran. 2iran university of medical sciences, tehran, iran. 3department of biochemistry, school of medicine, iran university of medical sciences, tehran, iran. 4department of anatomical sciences, school of medicine, tarbiat modares university, tehran, iran. 5shahid akbar-abadi ivf center, iran university of medical sciences, tehran, iran 6pediatric neuro-rehabilitation research center, university of social welfare and rehabilitation sciences, tehran, iran. 7department, school of behavioral sciences and mental health(tehran institute of psychiatry) iran university of medical sciences, tehran, iran. 8vetcell therapeutics, santa ana, california, usa. *correspondence: cellular and molecular research center & department of anatomy, iran university of medical sciences (iums), hemmat highway, p. o. box 14155-5983, tehran, iran tel & fax: +98 21 88622689, email: koruji.m@iums.ac.ir. received november 2019 & accepted june 2020 balance and quality of semen, which leads to increased dna fragmentation in sperm cells(6). although close scrutiny of the patient's history along with semen analysis to diagnose idiopathic infertility is necessary, it is not enough(7,8). in recent years, alongside with conventional sperm parameters, the attention to molecular details, especially the seminal rna content, has significantly grown. micro rnas (mirna) are a class of non-coding small rnas which exist in serum and plasma, semen and other body fluids. however, their production paturology journal/vol 17 no. 6/ november-december 2020/ pp. 638-644. [doi: 10.22037/uj.v16i7.5747] andrology terns differ in different disease(9). the seminal plasma mirnas are implicated in the regulation of spermatogenesis and gene expression in spermatozoa and the zygote during fertilization. these molecules were used as a novel, non-invasive biomarkers for the diagnosis of infertility and the classification of the types of them(1012). mirna-122 is one of the high-expressing seminal mirnas which alters in patients with azoospermia and asthenozoospermia(10,13). however, the role of mirnas, and more specifically, mirna-122 in infertility are not yet clear(14,15). likely, recognizing this role will make mirnas more reliable indicators for identifying and treating infertility. recognizing the role of mirnas in semen comes down to this: mirnas are bound to be used as more reliable biomarkers for diagnosing different types of infertility, and subsequently dictating their treatment protocol (14). the health of the head and more specifically the nucleus of the sperm depends on the correct expression of the proteins and protamine genes. one of the issues raised in idiopathic infertility is protamination abnormalities(16). in human, there are two types of protamine: protamine-1 (p1) and protamine-2 (p2) and they are expressed equally in the sperm cells(17). the protamine mrna (prm) is expressed in round spermatids, whereas the translation is postponed until spermatid elongation(18,19). according to this time interval, protamines play an important role in post-transcription and epigenetics. in addition, a subset of protamine mrnas are never translated and remain in mature sperm cells, which is inherited in the zygote after fertilization (20). previous studies have shown that mirna-122a, through binding to its complementary sequences in the 3’ untranslated regions (utrs) of the transition protein 2 (tnp2) mrna, decreases the target transcription(21). p1, p2 and tnps have the same promoter thus, their transcription occurs simultaneously(22,23). on the other hand, mirna-122 is likely to have similar effects on the protamine genes based on mirna base data. although the effect of the drug on infertility has been reported, its mechanism and molecular changes remain unclear. in this study, the correlation among mirna-122 and protamine gene and protein expression levels were studied alongside semen analysis, and mirna-122’s association with protamine and seminal parameters were investigated. patients and methods study population the medical ethics committee of iran university of medical science approved this study (code: ir.iums. rec.1394.9211313202). in case control study, 24 men with normal semen analysis [according to world health organization (who) 2010 criteria] and 24 heroin-addicted men whose addiction were confirmed by a psychiatrist and experiments, were considered as the control and addiction groups, respectively. all volunteers executed the written informed consent which was conducted according to the declaration of helsinki and a questionnaire containing exact demographic information. inclusion and exclusion criteria all participants were 20-50-year-old men with normal body mass index (bmi). other criteria included normozoospermia, in the control group, and only heroin consumption for at least four months and collecting samples before initiating drug-tapering treatment protocols, in the addiction ones. subjects with infertility, aids and hepatitis, and alcohol consumption were excluded from the study. also, if addicted men consumed other narcotics in the last four months, they would be excluded from the study. sampling and preparation semen samples were collected by masturbation in sterile containers after 2 to 5 days of sexual abstinence and immediately sent off for processing according to who (2010) guidelines. a part of the samples was cryopreserved for nuclear protein evaluation. the rest of the samples were incubated to liquefy at 37 °c for 30 minutes. gradient-swim up technique was used to precisely separate spermatozoa from seminal plasma. the pellet protamine-2 and mirna-122 in sperm-nazmara et al. andrology 639 table 1. gene primers. gene forward primer reverse primer prm-2 5'-cacgcacgaggtgtacagg-3' 5'-cagtgtctgcgcctaaagtga-3' β-actin 5′-tccctggagaagagctacg-3′ 5′-gtagtttcgtggatgccaca-3′ mirna-122 5′tggagtgtgacaatgg-3′ parameter control group mean ± sd (n) addicted group mean ± sd (n) p-value demographic data age (year) 34.41 ± 1.25 34.87±1.80 0.836 bmi (kg/m2) 27.75 ± 0.88 22.30 ± 0.36 0.001 seminal parameters semen physical parameters volume (ml) 3.90 ± 0.35 3.22±0.35 0.136 semen ph 7.79 ± 0.06 7.58±0.06 0.003 wbc 1.69 ± 0.41 8.61±1.73 0.001 sperm concentration (×106/ml) 136.18 ± 25.23 146.22±37.32 0.823 sperm motility (%) 65.51±2.57 41.96 ± 3.58 0.001 sperm viability (%) 87.41±1.00 71.50 ± 4.59 0.002 normal morphology (%) 16.98±3.97 12.48±1.49 0.300 molecular data protamine-2 expression 3.59 ± 0.94 0.05 ± 0.02 0.002 level (2-δδct) relative density of protamine-2 protein 0.27 ± 0.06 0.10 ± 0.02 0.017 mir-122 expression levels (2-δδct) 1.52 ± 0.54 3.51 ± 0.73 0.034 table 2. demographic, semen analysis, and molecular data in the participants. and supernatant of each sample were also subsequently used for total rna extraction and mirna assessment. rna extraction and cdna synthesis the spermatozoa rna was prepared using rneasy mini kit (qiagen, germany). rna 260/280 od ratio and concentration were evaluated by nanodrop. cdna was synthesized with rt primers according to the manufacturer's instructions (quantitect reverse transcription kit, qiagen, germany). real-time semi-quantitative pcr technique the prm-2 (nm_001286356.1) expression level was determined by quantinova sybr green pcr kit (qiagen, germany) and were normalized with beta-actin gene. the primers for target genes are presented in table 1. the temperature cycles (n = 45) were generally performed at 95 °c for 5 s and 59 °c for 30 s. total rna isolation from seminal plasma after thawing, seminal plasma aliquots were centrifuged twice (1,600 g for 10 min, then 16,000 g for 10 min) at 4 °c to harvest cell-free seminal plasma. the supernatant was carefully collected for subsequent assays. for purification of cell-free total rna, (primarily mirnas and other small rnas), from seminal plasma, we used mirneasy serum/plasma kit (qiagen, germany) according to the manufacturer’s recommendations. the purity and integrity of rna were checked by a 260/280 nm ratio measurement. cdna synthesis and real-time semi-quantitative pcr for mirna the miscript pcr system (qiagen, germany) was used for cdna synthesis and determination of mirna-122 expression levels. this system consists of the miscript ii rt kit for cdna synthesis with oligo-dt primers, ce_mir-39_1 miscript primer assay to monitor mirna purification and amplification, and miscript sybr green pcr kit to enable quantification of mirna-122 by real-time sqpcr. expression values were normalized with c. elegans mir-39 mimic as a reference gene. nuclear protein extraction 10 million spermatozoa from each sample were individually centrifuged at 3000 g for 5 minutes at room temperature (rt), and the pellet was washed three times with pbs (500 µl each time). the pellet was finally resuspended in 300 µl pbs and was sonicated for 5 minutes under these circumstances: 80 % strength, pulse on 15 seconds and pulse off 5 seconds. then the samples were boiled for 30 minutes at 95 °c. after centrifugation at 15294 ×g for 20 minutes at 4 °c, and discarding of supernatant, 200 µl lysis buffer (0.2 m tris-hcl, ph 7.5, containing 1 % sds, and 10 % glycerol) was added and pipetted. finally, after freezing and thawing of the specimens in liquid nitrogen five times, samples were centrifuged at 15294 ×g for 20 minutes at 4 ºc and the table 3. partial correlation between study variables. addiction seminal ph seminal wbc sperm motility sperm viability prm-2 p2 mirna-122 -0.362 0.391 -0.416 -0.315 -0.562 -0.382 0.440 addiction correlation 0.020 0.011 0.007 0.045 0.002 0.144 0.019 p value seminal correlation -0.350 0.234 0.043 0.190 0.008 -0.302 ph p value 0.025 0.141 0.790 0.343 0.975 0.118 seminal correlation -0.467 -0.097 -0.267 -0.225 0.471 wbc p value 0.012 0.547 0.179 0.402 0.011 sperm correlation 0.832 0.437 0.457 -0.404 motility p value 0.001 0.023 0.075 0.033 sperm correlation 0.288 0.378 -0.533 viability p value 0.145 0.149 0.004 prm-2 correlation 0.772 -0.391 p value 0.001 0.050 p2 correlation -0.309 p value 0.244 mirna correlation 122 p value this correlation was adjusted for cigarette smoking in the addicted group. parameters unstandardized coefficients standardized coefficients p-value b std. error beta age (year) 0.137 0.395 0.052 0.731 bmi (kg/m2) -0.772 0.756 -0.175 0.314 cigarette smoking -5.929 6.954 -0.158 0.400 heroin addiction (yes or no) -24.794 11.148 -0.672 0.033 duration of opioid dependence (year) -0.478 0.410 -0.224 0.252 duration of heroin dependence (year) 0.259 0.662 0.070 0.699 amounts of heroin consumed (mg/day) 4.168 4.394 0.185 0.349 table 4. simple linear regression analysis for sperm motility. protamine-2 and mirna-122 in sperm-nazmara et al. vol 17 no 06 november-december 2020 640 supernatant was collected. extracted protein was concentrated by a concentrator machine and protein content of each sample was calculated by the bca method (thermo scientific™ pierce™ bca™ protein assay kit, usa). western blotting an extracted nuclear protein from each sample was separated by 15 % polyacrylamide sds-page. after electrotransfer onto a pvdf membrane, blocking was performed in buffer containing 5 % non-fat dry milk in 4 ºc overnight and the membranes were washed with 0.05 % tween 20 in pbs. proteins were detected using anti-protamine 2 antibody (erp15738, abcam; mv= 17 kda) and anti-beta-actin antibody (ab8227, abcam, mw=41.7 kda) as primary antibodies, and goat anti-rabbit igg h&l (hrp) (ab6721, abcam) as the secondary antibody and were visualized with the ecl reagent (amersham, canada) according to the manufacturer’s instructions. the primary antibodies were diluted 1:1,000 in 2 % non-fat dry milk (biolife) in pbs. the level of protamine was quantified via densitometry and normalized to beta-actin protein levels. statistical analysis statistical analysis was performed using a statistical software package spss (ver. 16.0, chicago, spss inc.). the parametric distribution was evaluated with kolmogorovsmirnov test. the differences between groups were statistically determined by chi-square, independent t-test, and mann-whitney test. the binary and multiple regression analyses were performed among gene and protein expression levels and other parameters. 2-δδct values were used to compare the target gene expression levels. p-value < 0.05 was proposed to be significant. the alphaeassefc software was also used to determine the protamine-2 density versus β-actin. results demographic and semen analysis information of all participants is shown in table 2. there was no significant difference in the mean age between the 2 groups (34.41 ± 1.25 vs. 34.87 ± 1.80). although bmi was in the normal range in both groups, this parameter in the addicted men (22.30 ± 0.36 kg/m2) was significantly lower than the healthy men (27.75 ± 0.88 kg/m2) (p ≤ 0.01). all subjects in the addicted group smoked cigarettes, so this factor was statistically different between the two groups (p ≤ 0.01). there was no significant difference in semen volume (3.90 ± 0.35 vs. 3.22 ± 0.35), sperm concentration (136.18 ± 25.23 vs. 146.22 ± 37.32) or normal morphology (16.98 ± 3.97 vs. 12.48 ± 1.49) between healthy and addicted men. however, seminal ph (7.79 ± 0.06 vs. 7.58 ± 0.06), white blood cells (wbcs) in semen (1.69 ± 0.41 vs. 8.61 ± 1.73), and sperm viability (87.41 ± 1.00 vs. 71.50 ± 4.59) and motility (65.51 ± 2.57 vs. 41.96 ± 3.58) were significantly altered in the heroin consumption group. protamine-2 gene and protein content and mirna-122 expression prm-2 concentrations that was given by real-time sqpcr were significantly decreased in addicted men versus healthy ones (3.59±0.94 and 0.05±0.02, respectively; p ≤ 0.01). in western blots of sperm nuclear proteins separated by sds–page (fig 1 a, b), increased density in p2 content was also observed in the addicted group (0.27 ± 0.06) as compared to the healthy group (0.10 ± 0.02) (p ≤ 0.05) (table 2). in addition, the real-time sqpcr analysis revealed that mirna-122 expression levels were increased in addicted men as compared to the healthy group (3.51 ± 0.73 versus 1.52 ± 0.54) (p ≤ 0.05). correlation analysis figure 1. analysis of protamine 2 (p2), beta actin (β-act). (a) western blot, using an antibody specific for p2 and an antibody specific for (β-act). (b) nuclear proteins extracted from spermatozoa, separated on a polyacrylamide gel and stained with coomassie blue. protamine-2 and mirna-122 in sperm-nazmara et al. andrology 641 cigarettes were smoked by all participants in the addicted group, but not by participants in the healthy group, so partial correlation was used to eliminate that variable. the correlation results have been presented in table 3. wbc count in seminal plasma was negatively correlated with seminal acidity and sperm motility. however, there was a positive correlation between the presence of wbc and mirna-122 expression levels in seminal fluid. the increase in mirna-122 is associated with a decrease in motility and survival rate of spermatozoa and a reduction in the amount of prm-2. among the groups, a positive significant relationship between sperm cell motility and spermatozoa survival rate, and prm-2 expression levels was demonstrated. the number of copies of prm-2 was directly correlated with the p2 content. simultaneous analysis of demographic variables on sperm motility by simple linear regression among the age, bmi, cigarette smoking, heroin addiction, duration of opioid and heroin dependence, and amounts of heroin consumed, only heroin addiction parameter affects sperm motility (p < 0.05, table 4). discussion to the best of our knowledge, no study has been conducted to addiction science that simultaneously evaluates the conventional and molecular parameters associated with infertility. main obstacles on the way of human studies can be legislation and ethical considerations as well as simultaneous polydrug abuse. our findings can contribute to increase our knowledge about the seminal molecular changes in the addicted men. although bmi of heroin-addicted men was in the normal range, the mean of this variable in that group was statistically lower than the healthy one. based on demographic data, the economic and educational condition of heroin consumers were different from healthy men. based on the previous many human and animal studies, we conclude that a decrease in bmi in addiction cases (3,5,24,25). yilmaz et al. (1999) determined morphine reduced body weight with decreased metabolism caused by inhibition of androgen production along with the reduction of gastrointestinal activity(25). illicit drugs can compete with food for brain reward sites, and decrease appetite(26,27). based on these results, it would be expected bmi is a heroin-dependent variable and is considered as a physiological change in the drug users. it seems that one of the possible pathways for heroin effects on gametogenesis is with bmi reduction. ph and wbc count are some of the seminal quality criteria, which decreased and increased in the addiction group, respectively. the results of partial correlations and previous studies suggests that the presence of wbc changes seminal ph leads to acidification of seminal fluid(28) and reduced survival rate and motility of sperm cells(29). similar to the link between heroin addiction and bmi reduction, leukocytospermia, which refers to the presence of leukocytes in semen, is one of the inherent heroin-related clinical manifestations. leukocytes produce reactive oxygen species (ros) in semen and contribute to male infertility (7,8,30). few studies have investigated sperm microenvironment in addicted cases. however, our finding is in line with agrawal et al. (2014) and nazmara et al. (2019) who reported leukocytospermia in addicted cases (5,8). in this study, protamine-2 content (gene and protein) in ejaculated spermatozoa and mirna-122 levels in seminal fluid showed that addiction could lead to protamine deficiency and alter the functionality of cell-free seminal rnas. it seems that insufficiency of protamine-2 in the addicted group is dependent on epigenetic regulators. data on the copy number of protamine-2 mrna confirms this conclusion in three ways. first: the significant positive correlation between protamine-2 protein and mrna levels could support the idea that diminished p2 content was due to the low levels of prm2. second: the negative correlation between prm2 and mirna-122 levels suggests that abnormally high levels of mirna-122 may lead to protamine-2 transcripts would be inaccessible or non-functional ones. third: an abnormally high level of mirna-122 and its association with seminal acidification and leukocytospermia, along with the correlation of these factors with addiction, suggests that the increase of mirna-122 may be affected by heroin-dependent seminal changes. protamine-2 is the most important protein involved in spermatozoa chromosome condensation(31). it is said that a defect in protamine gene expression is not due to gene mutations and may reflect new transcription regulations or incomplete post-translational processes (32). as previously mentioned, protamine transcription and translation is temporally uncoupled during spermiogenesis(33). although this time-separation is critical to the sperm development and is transcriptionally gene silent, it can make protamine mrnas sensitive to intraand extra-cellular alterations which result in protamine deficiency. the most important hypothesis for reducing protein in a condition where the level of gene expression is low, (as in the present study), or normal is summarized: (a)abnormalities in the post-translational process of p2: defective protein kinases and their activating pathways were reported in patients with diminished p2 concentration by aoki and carrell (2003)(34) and wu et al. (2000)(35). (b) reduction in prm2 levels: in mice, mirna-469 binds to the coding regions of tnp2 and prm2, and hence represses those protein expressions at the translation level with minor effects on mrna degradation(23). furthermore, inhibition of tnp2 transcription, (one of the most widely studied genes in humans), was achieved by binding mirna-122 to 3'-utr of tnp2 and its endonucleolytic cleavage activity in sperm-like cells(22). these are two examples of post-transcriptional regulation by mirnas and our findings were consistent with the reports by the aforementioned investigators. the presence of protamine-2 transcripts in mature spermatozoa rna profiles and its transfer to the oocyte during fertilization(36) indicates the importance of the protamine-2 mrna as a gene expression regulator in those cells. in other words, prm2 not only contributes to toroidal structure, but also can be considered as one of the biomarkers which guarantees successful fertilization. motility was another modified parameter in the addiction group which was measured and reported by computer-assisted sperm analysis (casa). considering that prm2 and mirna-122 levels had significant correlations with sperm motility, it is legitimate to speculate that heroin abuse affects chromatin packaging, expression of motility-related genes, and sperm viability, resulting in asthenospermia. up-regulation of protamine-2 and mirna-122 in sperm-nazmara et al. vol 17 no 06 november-december 2020 642 mirna-122 in patients with asthenozoospermia(14) decreased motility with increased % dfi (dna fragmentation index) in opiate users, especially heroin-addicted men(37), depression of sperm motility along with movement-related gene impairment, including catsperes, in mice that were addicted to iranian kerack(24), are part of the studies which have similarities with our study. semen and sperm cells are a major source of endorphins and enkephalins(38), and their defined activity levels are required to regulate sperm motility(39). however, heroin as a µ-agonist decreased sperm motility(40). in view of cigarette smoking is the most confounding factor affecting sperm mobility(41), and all participants in addicted group smoking cigarettes, simple linear regression was used to explore the most important demographic factors affecting mobility. our findings showed that among the studied demographic variables, heroin addiction has the most deleterious effect on sperm motility. our recommendations for further research are: evaluation of other factors associated with nuclear condensation; in vitro assessment of the impact of heroin on ejaculated semen; the study of sperm surface receptors which are necessary in sperm-oocyte attachment. acknowledgements the research team would like to thank the individuals who participated in this study. this study was supported by iran university of medical sciences (iums), (number: 94-02-30-25973) and insf (number: 94017358). funding this study was funded by a grant from 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impaired in male germ cells lacking camk4. nat genet. 2000;25:448-52. 36. ostermeier gc, miller d, huntriss jd, diamond mp, krawetz sa. delivering spermatozoan rna to the oocyte. nature. 2004;429:154-. 37. safarinejad mr, asgari sa, farshi a, et al. the effects of opiate consumption on serum reproductive hormone levels, sperm parameters, seminal plasma antioxidant capacity and sperm dna integrity. reprod toxicol. 2013;36:18-23. 38. kew d, muffly ke, kilpatrick dl. proenkephalin products are stored in the sperm acrosome and may function in fertilization. proc natl acad sci u s a. 1990;87:9143-7. 39. subiran n, agirregoitia e, valdivia a, ochoa c, casis l, irazusta j. expression of enkephalin-degrading enzymes in human semen and implications for sperm motility. fertil steril. 2008;89:1571-7. 40. rezaei-mojaz s, nazmara z, najafi m, et al. evaluation of enkephalin-degrading enzymes in sperm from heroin-addicted men. international journal of fertility & sterility. 2020;13:301. 41. hammadeh me, hamad mf, montenarh m, fischer-hammadeh c. protamine contents and p1/p2 ratio in human spermatozoa from smokers and non-smokers. hum reprod. 2010;25:2708-20. vol 17 no 06 november-december 2020 644 urol_v3_no1_001_editorial.qxd 65 urology journal unrc/iua vol. 3, no. 1, 65-69 winter 2006 printed in iran urological survey african journal of urology objective: to evaluate the clinical, etiological and therapeutical aspects of priapism. patients and methods: sixty-three patients were retrospectively studied regarding their age, the time elapsed between onset of the condition and presentation at the hospital, their medical and surgical history, additional examinations such as blood count and hemoglobin electrophoresis, treatment modalities and outcome of treatment. results: the mean age of the patients was 22.4 years (range: 3-68 years). the time elapsed between onset of the condition and presentation at the hospital ranged from 4 hours to 41 days. two patients (3.2%) presented about 6 hours after the onset of priapism, while 80.9% presented more than 24 hours later. hemoglobin electrophoresis revealed sickle-cell disease in 29 (46%) patients. in two patients, priapism occurred after intracavernous injection of vasoactive drugs. the patients were treated medically and/or surgically. immediate penile flaccidity after treatment was obtained in 53 cases (84.1%). at a mean follow-up of 8 months 51 patients could be evaluated; 23 of them (45.1%) reported a satisfactory erection. fibrosis of the corpora cavernosa occurred in 24 (38.1%) patients. conclusion: priapism represents a urologic emergency which in africa is commonly associated with sickle-cell disease. a timely and adequate treatment in our environment is rendered difficult due to the fact that most patients present very late. this situation can only be changed by an improvement of the socioeconomic situation and a large-scale education of the population as well as the establishment of a larger number of specialized medical and health centers. the african journal of urology is the official journal of the pan african urological surgeons' association (pausa). this journal is a bilingual publication, accepting articles in english and french. the editor-in-chief of the african journal of urology is professor ismail m khalaf from egypt. you can find the website of this journal in the african journals online available from: http://www.ajol.info/index.php. here are the abstracts of the original articles in its current issue (2005, volume 11, number 3): priapism: clinical aspects and etiology fall pa, diao b, ndoye ak, ndiaye diop e, sylla c, gueye sm, diagne ba dantec and general grand yoff hospitals, dakar, senegal urological survey66 objective: the aim of this study was the evaluation of the histological characteristics of testicular cancer in ivory coast. patients and methods: in this retrospective study, the medical charts of 54 patients with testicular tumors (mean age: 23.41 years; range: 13 months 68 years) seen over a period of 25 years at the anatomy/pathology units of the universities of côte d'ivoire were evaluated with emphasis on the following data: patient age, geographical origin and clinical tumor characteristics, such as location, features, histological type. tumor markers and staging of the disease were not included in the study. results: on average, two tumors per year were diagnosed. histologically, 87% were primary tumors, 46.3% of them being germinal neoplasms (22.22% seminomas and 24.07% of the nonseminomatous type) and 40.74% being nongerminal neoplasms including 18.5% of rhabdomyosarcomas. secondary testicular tumors comprise 13.9% of the cases of our study; most of them are metastases from burkitt lymphoma (5/7 cases). the rate of bilateral tumors in our study is high with 31%. conclusion: our study shows that testicular tumors are a rare entity in ivory coast with an average incidence of 2 cases per year. the disease affects young males at an average age of 23 years, and the prognosis is often unfavorable due to the high incidence of bilateral disease which was found in 31% of our cases. malignant testicular tumors in ivory coast-anatomopathologic observations on 54 cases konan pg, dekou a, kouame b, manzan k, djedje mady a, honde m, d'horpock af, kassanyou s university hospital of cocody and university hospital of treichville, abidjan, ivory coast objective: complications may be encountered during pelvic and inguinal hernia surgery, among them iatrogenic urogenital lesions. the objective of this study is to report on our experience in the management of genitourinary complications of pelvic and inguinal hernia surgery. patients and methods: this retrospective study evaluates the genitourinary complications encountered in 15 patients (10 males and 5 females with a mean age of 35.5 years) operated on at our institution between january 1, 1997 and december 31, 2001. they had undergone the following operations: laparotomy for inguinal hernia repair (n=8), volvulus of the sigmoid colon (n=1), rectal occlusive cancer (n=1), uterine rupture (n=1), tubo-ovarian abscess (n=1) and uterine fibroma (n=3). results: the urinary complications encountered were the following: ureteral injuries (n=7), bladder injuries (n=6) and testicular atrophy (n=2). six urinary lesions were recognized preoperatively while seven were misdiagnosed and generated postoperative peritonitis. testicular atrophy occurred after inguinal hernia repair. the treatment modalities applied were uretero-ureteric anastomosis (n=6), ureteric reimplantation (n=1), cystorrhaphy (n=6) and orchidectomy (n=2). there was no morbidity from re-operation. the patient who had undergone emergency laparotomy for occlusion of rectal cancer died on the 12th postoperative day. conclusion: prevention of genito-urinary complications of pelvic and inguinal hernia surgery can be best achieved by well-trained surgeons using well-tried operative techniques. genitourinary complications of pelvic and inguinal hernia surgery djè k, lebeau r university hospital of bouaké, abidjan, ivory coast african journal of urology 67 objective: due to the numerous economic and social benefits associated with the practice of daycare surgery, it is gaining widespread acceptance worldwide and across all specialties. we therefore determined the spectrum of procedures and the difficulties faced during implementation of daycare urologic surgery in a tertiary-care center in nigeria. patients and methods: this was a prospective study of all consecutive urologic day cases seen at the urology unit of jos university teaching hospital, nigeria, from january 2003 to december 2004. a total of 270 patients aged between 2 weeks and 100 years (median 55 years) with a male to female ratio of 14:1 were seen during the study period. the parameters studied were the presenting symptoms, diagnosis, treatment modalities, anesthesia, complications and whether or not the patients were converted to be in-patients or readmitted after discharge as well as the reasons for such conversion or readmission. the statistical analysis was done using the epi-info 2004 system, version 3.2.2. results: the main conditions seen were urethral stricture in 89 (32.5%) patients, benign prostatic hyperplasia in 86 (31.8%), carcinoma of the prostate in 26 (9.6%), carcinoma of bladder in 15 (5.6%) and male infertility in 10 (3.7%) patients. the procedures carried out were mainly urethroscopy/ urethrocystoscopy in 103 (38.2%) patients, visual internal urethrotomy in 48 (17.8%) and trucut prostatic biopsy in 33 (12.2%) patients. sedation was used in 142 (52.9%), sedation and local anesthesia in 53 (19.7%), local anesthesia alone in 9 (3.3%), general anesthesia in 22 (8.1%) and other combinations or omissions in entry in 41 (15.2%) patients. circumcision was performed on 3 neonates (1.1%) without anesthesia. there was a cancellation rate of 15.6% (n=42) mainly due to the inability of the patients to come (24 patients, 57.1%), inadequate materials in the theatre (9 patients, 21.4%), power failure (4 patients, 9.5%), strike action (3 patients, 7.1%) and financial difficulties (2 patients, 4.8%). we had a conversion rate to inpatients of 1.9% (n=5) for various reasons. no further complications or readmissions after discharge were encountered. conclusion: urethrocystoscopy is the most frequently performed procedure and urethral stricture the most common diagnosis in our day practice. cancellation of cases and conversion to in-patients remain our major challenges. the education of patients and physicians, as well as the provision of adequate material and infrastructure are recommended in order to provide the maximum benefit from urologic daysurgery practice. urologic day-care surgery: scope and problems in a developing country dakum nk, ramyil vm, misaouno ma, ojo eo, ogwuche ei, sani aa jos university teaching hospital, jos, nigeria objective: evaluation of the transobturator tape (tot), the newest tension-free technique for the treatment of female stress urinary incontinence (sui) and its early results with 6 months follow up. patients and methods: this study was conducted at king saud hospital, saudi arabia, between september 2002 and march 2004. fourteen cases with pure sui were treated with uratape, a lowelasticity polypropylene tape, according to the technique described by delorme. preoperative assessment included full history, transobturator tape (tot) for treatment of female stress incontinence: early experience el sheikh ah menoufeya university, menoufeya, egypt urological survey68 objective: to evaluate the role of partial prostatectomy in the management of bladder outlet obstruction due to benign prostatic hyperplasia (bph) and to illustrate the indications and results with regard to micturition and preservation of antegrade ejaculation. patients and methods: sixty-nine patients with a mean age of 53 years (range: 40 85 years) who had undergone partial prostatectomy for bph were followed up between january 1997 and december 2002. details on the quality of micturition and ejaculation of each patient were obtained via telephone calls after a period of at least 6 months following surgery. results: as for micturition, good results were reported by 75.36% (52/69) of the patients, while 23.19% (16/69) and 1.45% (1/69) of the patients reported satisfactory and unsatisfactory results, respectively. antegrade ejaculation could be achieved in 97.1% (67/69) patients. conclusion: we conclude that partial prostatectomy as suggested by hermabessière is a technique which allows for the preservation of antegrade ejaculation. it is of special interest in the young patient, but can also be applied in the elder man. preservation of ejaculation during transurethral resection of the prostate coulibaly n, zarour h, sangare is university hospital of treichville, abidjan, ivory coast objective: the majority of vesical calculi in adults can now be treated transurethrally with the use of different lithotriptors. the aim of this article was to study the effectiveness of the egyptian pneumatic lithotriptor through a rigid cystoscope in the treatment of vesical calculi. patients and methods: fourteen adult patients (12 males and 2 females) had single urinary bladder stones. mean stone diameter was 20 mm. through a cystoscopic sheath, a modified ureteric catheter was introduced into the bladder. using the egyptian pneumatic lithotriptor-kh. yg2, the pneumatic probes (rigid or flexible) were passed through the catheter for stone disintegration. results: successful stone disintegration was efficacy of the egyptian pneumatic lithotriptor using cystoscopy in vesical calculi treatment azooz ma student's hospital, cairo university, cairo, egypt urogynecological examination, cough stress test, q-tip test, cystogram and urodynamic studies. perioperative cystoscopy was also done. results: no intraoperative complications were recorded. postoperative complications included transient incisional pain in 2 (14.3%), transient voiding difficulty in 5 (35.7%) and urgency and frequency with mild pyuria in 3 cases (21.4%). mild groin ecchymosis was seen in 5 cases (35.7%). vaginal wound infection and wound dehiscence with subsequent tape removal occurred in one case only (7.1%) twelve cases (85.7%) achieved full continence and one patient (7.1%) had minimal leak with extreme stress but was fully satisfied. conclusion: from the promising results of our early experience we conclude that the tot procedure is a simple, safe, fast and minimally invasive technique for the treatment of sui in women with few minor complications and a high success rate. further studies on a larger number of patients will however be needed to confirm these results. african journal of urology 69 recorded in 13 patients (92.9%) where the patients were stone-free at the end of the procedure. failure of stone fragmentation occurred in one case (7.1%). the stone was removed surgically. its chemical composition was found to be calcium oxalate monohydrate. the average time of cystolithotripsy was 35 minutes. hospitalization ranged from 12 to 24 hours which was longer (2 to 4 days) for those patients who had undergone other procedures. minor complications such as mild hematuria (100%) and cystitis (21.4%) were observed. no major complications were noted. conclusion: the use of the egyptian lithotriptor during cytoscopy has been found to be an effective, easy, safe and economical method for the treatment of vesical stones. re: intra-operative oxycodone reduced postoperative catheter-related bladder discomfort undergoing transurethral resection prostate. a prospective, double blind randomized study a ram doo1,2, yu seob shin2,3, myung kim kim2,3 1department of anesthesiology and pain medicine, chonbuk national university medical school, jeonju, republic of korea. 2research institute of clinical medicine of chonbuk national university-biomedical research institute of chonbuk national university hospital, jeonju, republic of korea 3department of urology, chonbuk national university medical school, jeonju, republic of korea *correspondence: yu seob shin, m.d., ph.d. (http://orcid.org/0000-0002-1126-3821) department of urology, chonbuk national university, medical school, 560-180, jeonju, south korea. tel: 82-63-250-1560. fax: 82-63-250-1564. e-mail: ball1210@hanmail.net. the catheter-related bladder discomfort (crbd) to an indwelling urinary catheter is defined as a painful ure-thral discomfort, resistant to conventional opioid therapy, decreasing the quality of postoperative recovery(1). the indwelling urinary catheter during lower urinary tract surgeries, especially transurethral resection of prostate (turp), frequently leads to crbd in the immediate postoperative period. the mechanism of crbd is mediated by type 3 muscarinic receptor activation, which increases acetylcholine release and then causes the detrusor muscles of the bladder to contract involuntarily(2). therefore, agents with anticholinergic, analgesics including tramadol and paracetamol, antiepileptics such as gabapentin and pregabalin, anesthetics including ketamine and dexmedetomidine have been successfully studied for the prevention and treatment of crbd(2). nevertheless, these drugs when administered, generally can cause some side effects such as facial flushing, dry mouth, blurred vision and sedation. i have carefully read the article published in urology journal by juncheng et al., and his findings and conclusions are indeed interesting(3). this article is one of the few reports which addresses the issue of crbd. we have encountered few papers regarding this medical condition because, to the best of our knowledge, most of the studies address crbd using drugs. their study including 91 patients with turp has shown that the incidence of crbd was significantly lower in the oxycodone group. oxycodone can effectively prevent patients with crbd after turp without incurring serious adverse effects. similar to the authors above, we are working on ways to reduce crbd after turp. for a long time, urethral catheter traction has been accepted as the most effective way to control postoperative bleeding after turp. in our opinion, the patients who received turp suffer from more pain probably due to urethral catheter traction. we felt that spinal anesthesia has a crbd-reductive effect compared to general anesthesia during the early postoperative hours. because spinal anesthesia has longer duration of analgesic effect on perineal region compared to general anesthesia. in conclusion, we designed new trial with the hypothesis that spinal anesthesia has a crbd-reductive effect in early postoperative hours compared to general anesthesia. references 1. zugail as , pinar u, irani j. evaluation of pain and catheter-related bladder discomfort relative to balloon volumes of indwelling urinary catheters: a prospective study. investig clin urol 2019;60:35-9. 2. wilson m. causes and management of indwelling urinary catheter-related pain. br j nurs 2008;17:232– 9. 3. juncheng x, xiang c, chengwei w, shuqun l, jian l. intra-operative oxycodone reduced postoperative catheter-related bladder discomfort undergoing transurethral resection prostate. a prospective, double blind randomized study. urol j. 2019;16:392-6. letter urology journal/vol 17 no. 2/ march-april 2020/ pp. 216-216. [doi: 10.22037/uj.v0i0.5242] 1228 | shahid labbafinejad medical center , urology and nephrology research center , shahid beheshti university of medical sciences, tehran, iran. corresponding author: mohammad hossein soltani, md shahid labbafinejad medical centre, urology and nephrology research centre, shahid beheshti university of medical sciences, tehran, iran. tel: +98 21 22588016 fax: +98 21 22588016 e-mail: mhsoltani@iurtc.org.ir received june 2012 accepted november 2012 purpose: laparoscopy is the gold standard approach for management of some adrenal masses in adult cases. still there have not been many findings in case of children. we present our experience with clipless laparoscopic adrenalectomy in pediatric cases for the first time. materials and methods: from january 2007 to january 2011, thirteen laparoscopic adrenalectomy were performed in patients 5-18 years old. the first port (10 mm) was inserted using open approach above the umbilicus and three 5 mm trocars were inserted under direct vision. on the left side, the colon was mobilized medially, then the renal vein exposed. adrenal vein was coagulated using bipolar cautery after separating from renal vein. no endoscopic clips were used. results: eight girls and five boys with the mean age of 14.4 years old (ranging from 5 to 18 years old) underwent laparoscopic adrenalectomy. the mean operative time was 151 ± 47 (80240) minutes. the mean size of adrenal lesions in greatest diameter was 6.9 ± 2.4 cm (3.5 to 10). the mean hospital stay was 3.7 days (2-5) and average follow-up time was 21 months (6-27). conclusion: laparoscopic adrenalectomy in children and young adults is effective and safe if the cases are selected appropriately. clipless laparoscopic approach by an expert surgeon has acceptable outcomes. keywords: adrenalectomy; laparoscopy; child; postoperative complications; treatment outcome. nasser simforoosh, ali ahanian, amin mirsadeghi, alireza lashay, seyed hossein hosseini sharifi, mohammad hossein soltani clipless laparoscopic adrenalectomy in children and young patients: a single center experience with 12 cases laparoscopic urology laparoscopic urology 1229vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l clipless laparoscopic adrenalectomy in children | simforoosh et al introduction the early experiences of laparoscopic adrenalectomy were reported in 1992.(1,2) nowadays, it is widely performed in adult patients and is accepted as a gold standard surgery for adrenal tumor up to 8-11 cm.(3,4) the advantages of laparoscopic adrenalectomy compared to open surgery are, less post-operative pain and discomfort, shorter hospital stay and better cosmetic results. only a few percent of pediatric adrenal lesions are benign. the most common pediatric adrenal tumor is neuroblastoma; this type of adrenal tumor is the most common extra cranial solid tumor in children. saad and colleagues and iwanaka and colleagues have described the effectiveness of laparoscopic biopsy and excision of abdominal neuroblastoma even in children with advanced neuroblastoma.(5,6) some previous reports with different number of cases (from 8 to 140 patients) about laparoscopic adrenalectomy in children have revealed that this approach should be considered in the majority of adrenal lesions in children.(7-10) few studies have been published about clipless laparoscopic adrenalectomy in adult cases where adrenal vessels were controlled by different modalities including ligasure vessel-sealing system(11,13) and bipolar coagulator, but we found no reports of clipless laparoscopic adrenalectomy in paediatric patients. the present study describes our experiences of thirteen laparoscopic clipless adrenalectomy cases in children and young adolescents with adrenal tumors during their four-year treatment. materials and methods from january 2007 to january 2011, thirteen cases of laparoscopic adrenalectomy were performed in patients 5-18 years old. preoperative evaluation of patients included metabolic and hormonal assessment, plus imaging studies such as computed tomography (ct), magnetic resonance imaging (mri) and metaiodobenzylguanidine (mibg) scan according to the circumstances of each case. selected patients who were suspicious of pheochromocytoma were treated with phenoxybenzamine for a period of one week before operation. general anesthesia was used in all patients. each patient was positioned in a 45 degree lateral decubitus. first 10 french urethral catheter was fixed and then transperitoneal approach was carried out in all cases. the first port (10 mm) was fixed using open access technique above the umbilicus and three 5 mm trocars (and additional trocar in the right-sided adrenal tumor for retracting the liver) were inserted under direct vision. on the left side, the colon was mobilized medially and the renal vein was exposed. adrenal vein was coagulated using only bipolar cautery. no endoscopic clips or other energy sources such as ultrasonic or vessels sealing system were used. also, no other energy sources were used for controlling the vessels such as harmonic scalpels. on the right side, duodenum was mobilized medially, then adrenal vein was coagulated using bipolar cautery and finally the adrenal was freed from the surrounding tissues. the specimen was extracted from abdominal cavity using endobag and depending its size, it was brought out via the umbilical port or using a pfannenstiel incision. results thirteen laparoscopic adrenalectomies were performed. eight girls and five boys with the mean age of 14.4 years old (ranging from 5 to 18 years old) were included in this study. only one patient underwent two sessions of laparoscopic surgery. the mean operation time was 151 ± 47 (80-240) minutes. perioperative blood loss was negligible for all patients except a 17-year-old patient who had 10 cm retro-peritoneal mass with some adhesions to the surrounding tissues that received one unit packed red blood cell after operation. the mean size of adrenal lesions in greatest diameter was 6.9 ± 2.4 cm (3.5 to 10). the mean hospital stay was 3.7 days (2-5 days). average follow-up time was 21 months (6-27 months). there were no intra-operative complications and no conversion to open was required. final pathology of these tumors were ganglioneuroma (n = 2), adrenocortical hyperplasia (n = 5), adrenal adenomas (n = 2), pheochromocytoma (n = 1), adrenocortical carcinoma (n = 2), and cushing syndrome (n = 1) (table). the youngest patient was a 5-year-old girl presented with hirsutism, clitoromegaly and hyperandrogenemia. she had an equivocal pathology, adrenocortical tumor with undetermined clinical behavior. capsular and intra-tumoral vascular 1230 | invasion were in favor of carcinomatous change of this neoplasm but lack of pleomorphism and necrosis were against it. her operative time was 140 minutes and she revealed complete resolution during the follow up. in another case, a 12-year-old girl underwent two sessions of laparoscopic surgery for bilateral adrenalectomy. she had adrenal hyperplasia (refractory to medical management). no significant improvement of symptoms happened after one side laparoscopic adrenalectomy; hence she underwent laparoscopic adrenalectomy in the other side and follow-up visiting revealed noticeable symptom improvement. final pathology of adrenal mass in a 15-year-old girl, who underwent complete laparoscopic enbloc tumor resection, was adrenocortical carcinoma. she was symptom free and no recurrences were detected during a 16 months follow up. lastly, a 17-year-old girl with right adrenal mass and retroperitoneal mass underwent laparoscopic tumorectomy. the pathology of adrenal and retro-peritoneal mass was ganglioneuroma and benign nerve sheath tumor, respectively and short-term follow-up imaging revealed no residual tumors. 10 months later, she was readmitted with relapsing of hypertension after temporary resolution of her signs and symptoms. she had no abnormal laboratory test results. considering local recurrence, she underwent open surgery and the pathology of lesion at the location of right adrenal was adrenocortical adenoma consistent with cushing and the pathology of para-vertebral and para-caval mass was ganglioneuroma. disscusion laparoscopic adrenalectomy is the standard treatment of benign adult adrenal tumors.(3) however, it is less common for pediatric adrenal lesions. some surgeons believe that pediatric adrenal tumors do not require laparoscopic surgery because most of them are malignant and malignant tumors trend to grow and become huge, invading the other organs. thus, learning curve is an important subject in laparoscopic adrenalectomy in children.(14) there are some controversies about the maximum size of the adrenal lesions in children which can be treated by a laparoscopic approach. macgillivray and colleagues have recommended an upper size limit of 12 cm for laparoscopic adrenalectomy in adult adrenal lesions.(15) still, there is no obvious limitation for the tumor size in children and it should be decided individually according to the ratio of the tumor size to the body size. heloury and colleagues have considered the laparoscopic approach for removing small adrenal masses in children.(14) however, it seems that there is no limitation in respect to tumor size and patient age for expert surgeons. in our experience, the maximum diameter of adrenal mass was 10 cm. a multicenter experience of laparoscopic adrenalectomy in 140 pediatric cases from 10 institutions during 10 years has revealed noticeable findings about this issue in children. the mean operation time was 130.2 ± 63.5 (43-406) minutes in this study. they had a 9.9% conversion to open (the most table . pathology and side of the adrenal tumors in study subjects. pathology of adrenal tumor number left right ganglioneuroma 2 1 1 adrenal adenoma 2 1 1 adrenocortical hyperplasia 5 3 2 pheochromocytoma 1 0 1 adrenocortical carcinoma 2 1 1 cushing 1 0 1 laparoscopic urology 1231vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l common reason was adhesion of the tumor to the surrounding tissues) and there was only one local recurrence in a patient with pheochromocytoma. this report had emphasized that tumor size is not a risk factor for open conversion.(9) some previous reports have assessed the efficacy and safety of laparoscopic adrenalectomy in children and young patients with different number of cases, follow-up periods and tumor sizes. to our knowledge, no report of clipless laparoscopic adrenalectomy using bipolar cautery in children and young patients has been published. in one report, 10 patients with adrenal tumor in adult cases (mean size of 6.2 cm) underwent laparoscopic adrenalectomy using ligasure vessel-sealing device instead of clip and suture. the authors demonstrate that using this modality is concomitant with shorter operation time, less blood-loss, and lower conversion rates.(12) in another study, chueh and colleagues performed laparoscopic adrenalectomy in 12 adult cases using bipolar coagulation cautery for vessels control and found acceptable results.(13) this study introduced the first experience of clipless laparoscopic adrenalectomy in 12 cases of pediatric and young patients in this study. it seems that using bipolar instead of clip has comparable results and is applicable even in large adrenal masses (i.e. 10 cm). displacement of clips by instrument manipulation or spontaneously is an issue of concern, so there will be no fear of clip displacement by using bipolar cautery. the authors accept that larger group of cases and longer follow-up time is necessary to evaluate this approach more properly in pediatric patients. conclusion laparoscopic adrenalectomy in children and young adults is effective and safe if the cases are selected appropriately. taking a clipless laparoscopic approach by an expert surgeon is preferred to open surgery and has acceptable outcomes. conflict of interest none declared. clipless laparoscopic adrenalectomy in children | simforoosh et al references 1. gagner m, lacroix a, bolté e. laparoscopic adrenalectomy in cushing's syndrome and pheochromocytoma. n engl j med. 1992;327:1033. 2. higashihara e, tanaka y, horie s, et al. a case report of laparoscopic adrenalectomy. nihon hinyokika gakkai zasshi. 1992;83:1130-3. 3. ramacciato g, nigri g, di santo v, et al. minimally invasive adrenalectomy: transperitoneal vs. retroperitoneal approach. chir ital. 2008;60:15-22. 4. goitein d, mintz y, gross d, reissman p. laparoscopic adrenalectomy: ascending the learning curve. surg endosc. 2004;18:771-3. 5. saad df, gow kw, milas z, wulkan ml. laparoscopic adrenalectomy for neuroblastoma in children: a report of 6 cases. j pediatr surg. 2005;40:1948-50. 6. iwanaka t, arai m, ito m, et al. surgical treatment for abdominal neuroblastoma in the laparoscopic era. surg endosc. 2001;15:751-4. 7. laje p, mattei pa. laparoscopic adrenalectomy for adrenal tumors in children: a case series. j laparoendosc adv surg tech a. 2009;19 suppl 1:s27-9. 8. nerli rb, reddy mn, guntaka a, patil s, hiremath m. laparoscopic adrenalectomy for adrenal masses in children. j pediatr urol. 2011;7:182-6. 9. st peter sd, valusek pa, hill s, et al. laparoscopic adrenalectomy in children: a multicenter experience. j laparoendosc adv surg tech a. 2011;21:647-9. 10. castilho ln, castillo oa, dénes ft, mitre ai, arap s. laparoscopic adrenal surgery in children. j urol 2002;168:221-4. 11. surgit o. clipless and sutureless laparoscopic adrenalectomy carried out with the ligasure device in 32 patients. surg laparosc endosc percutan tech. 2010;20:109-13. 12. misra mc, aggarwal s, guleria s, seenu v, bhalla ap. clipless and sutureless laparoscopic surgery for adrenal and extra-adrenal tumours. jsls. 2008;12:252-5. 13. chueh sc, chen j, chen sc, liao ch, lai mk. clipless laparoscopic adrenalectomy with needlescopic instruments. chueh scj urol. 2002;167:39-42. 14. heloury y, muthucumaru m, panabokke g, cheng w, kimber c, leclair md. minimally invasive adrenalectomy in children. j pediatr surg. 2012;47:415-21. 15. macgillivray dc, whalen gf, malchoff cd, oppenheim ds, shichman sj. laparoscopic resection of large adrenal tumours. ann surg oncol. 2002;9:480-5. comparison of the diagnostic performance of pi-rads v1 and pi-rads v2 for the detection of prostate cancer: a meta-analysis ying he1, ruochen cong2, jie zhou2, zhenyu xu3, jushun yang2, lin wang2, jing xiao 4, bosheng he 2,5* purpose: in order to comprehensively determine the diagnostic accuracy of the prostate imaging reporting and data system version 1 (pi-rads v1) and pi-rads version 2 (pi-rads v2) in prostate cancer (pca) diagnosis. materials and methods: the literatures were screened from the databases, including the pubmed, embase, web of science and cochrane library up to january 20th, 2020. the meta-analysis was conducted by meta-disc and quality assessment was performed by using the quadas. furthermore, the sensitivity, specificity, likelihood ratio (lr), diagnostic odds ratio (dor), as well as receiver operating curve (roc) related to diagnostic accuracy were pooled. results: a total of 6 articles containing 814 participants (379 patients) were included in the study. for pi-rads v1, the combined sensitivity, specificity, plr, nlr and dor were 0.82 (95% ci: 0.77-0.85), 0.81 (95% ci: 0.770.85), 4.58 (95% ci: 2.55-8.22), 0.24 (95% ci: 0.18-0.34) and 24.00 (95% ci: 10.38-55.51). with regard to pirads v2, the combined sensitivity, specificity, plr, nlr and dor were 0.88 (95% ci: 0.84-0.91), 0.81 (95% ci: 0.77-0.84), 4.34 (95% ci: 1.98-9.49), 0.16 (95% ci: 0.08-0.32) and 33.39 (95% ci: 15.05-74.05), respectively. furthermore, except that the sensitivity of pi-rads v2 was significantly greater than that of pi-rads v1 (p = 0.027), there was no remarkably difference in other indicators for the diagnosis of pca between the two versions. conclusion: both pi-rads v1 and pi-rads v2 showed good diagnostic performance for pca diagnosis; moreover, there was no difference in the diagnostic effect between them. keywords: pi-rads v1; pi-rads v2; prostate cancer; multiparametric mri introduction prostate cancer (pca), accounting for 20% of all can-cers diagnosed, has been the second most common cancer with more than 1.1 million new cancer cases annually(1,2). usually, due to the some symptoms of pca with similar to those of other diseases, such as prostatitis, benign prostatic hyperplasia, cystitis and urinary tract infection, the rate of the early detection and resection rate of pca is only approximately 10–20% (3). currently, method for pca detection includes prostate-specific antigen test, digital rectal examination (dre), and biopsies. specifically, the elevated serum prostate-specific antigen (psa) level is the most frequently used biomarker for pca detection (4), but it has been criticized because of the lack of specificity diagnostic accuracy (5,6). multi-parametric magnetic resonance imaging (mpmri), including anatomic t2-weighted imaging (t2 1department of ultrasound, the tumor hospital of nantong university, nantong 226361, china. 2department of radiology, affiliated hospital 2 of nantong university, nantong 226001, china. 3department of ultrasound, the second people’s hospital of nantong, nantong 226002, china. 4department of epidemiology and medical statistics, school of public health, nantong university, nantong 226019, china 5clinical medicine research center, affiliated hospital 2 of nantong university, nantong 226001, china *correspondence: department of radiology, affiliated hospital 2 of nantong university, no.6 hai er xiang north road, nantong, jiangsu 226001, china. tel: +86-0513-85061220. fax: +86-0513-85061220. e-mail: boshenghe@126.com. received august 2019 & accepted april 2020 w) with functional diffusion-weighted imaging (dwi) and dynamic contrast-enhanced (dce), is characterized by noninvasive, multi-parameter, high soft tissue resolution, as well as the high subject tolerance. hence, it has been widely used in clinical localization, qualitative and staging diagnosis, as well as risk and prognosis evaluation of pca (7-9). mp-mri can provide the better diagnostic accuracy in the detection of pca, and accordingly, the standardized reporting system for it has been published. in 2012, the first version (v1) of the prostate imaging reporting and data system (pi-rads) was published by the european society of urogenital radiology (esur)(10). generally, pi-rads v1 scores showed high diagnostic accuracy for pca diagnosis (11,12); however, the clear instructions on how to integrate the overall score were lacking. hence, the updated pirads version 2 (v2) was established by the american college of radiology, which has improved some of the urological oncology urology journal/vol 18 no. 1/ january-february 2021/ pp. 51-57. [doi: 10.22037/uj.v16i7.5532 limitations of pi-rads v1. due to the differences between pi-rads v1 and pi-rads v2 scoring methods, many literatures have studied the diagnostic efficacy of the two methods in pca, but the results are not completely consistent(13-15). hence, the aim of the present study was to comprehensively analyze the diagnostic value of pi-rads v1 and pi-rads v2 in pca detection by using a meta-analysis, which will provide a basis for pca screening. author public country study gold n/n* prostate control age group tp fp fntn tn year year standard zone characteristics (years) (pz/tz) auer t 2016 austria na histo103/32 89/14 bph 63.0 ± 8.0 pi-rads v1 84 1 19 31 pathological pi-rads v2 82 4 21 28 feng 2016 china 2013.6radiography 150/251 95/55 non-pca 64.4(34-88) pi-rads v1 127 48 23 203 zy 2015.7 pi-rads v2 144 40 6 211 kasel2016 germany 2013.7 histo31/51 na benign 65(48-81) pi-rads v1 22 17 9 34 seibert m 2015.3 pathological pi-rads v2 24 10 7 41 polanec 2016 austria 2011.6radio 33/32 25/8 benign 65.3 pi-rads v1 31 21 2 11 s 2015.9 graphy,histopathological (62.3-87.4) pi-rads v2 32 12 1 20 tewes 2016 germany 2012.12histo31/23 26/5 non-pca 69.6 ± 9.6 pi-rads v1 24 2 7 21 s 2014.12 pathological pi-rads v2 28 4 3 19 wang 2018 china 2015.9histo31/46 0/31 bph 72.3±7.5 pi-rads v1 21 2 10 44 xm 2016.7 pathological pi-rads v2 23 3 8 41 table 1. characteristics of the included literatures. *: prostate cancer/ control; tp: true positives; tn: true negatives; fp: false positives; fn: false negatives; quadas: quality assessment tool of diagnostic accuracy studies; pi-rads: prostate imaging reporting and data system; pz, peripheral zone; tz, transition zone; na: not available; bph: benign prostatic hyperplasia. figure1. flow diagram of the articles included in this systematic review. pi-rads v1 and pi-rads v2 for prostate cancer-he et al. urological oncology 52 materials and methods literature search the literature searches were conducted on the basis of the databases, including pubmed (http://www.ncbi. nlm.nih.gov/pubmed), embase (http://www.embase. com), web of science (http://webofknowledge.com) and cochrane library (http://www.cochranelibrary. com/) up to january 20th, 2020. the keywords were as follows: (“prostate cancer” or “prostatic carcinoma” or “carcinoma of prostate” or (prostatic neoplasms)) and (“prostate imaging reporting and data system” or “pi-rads v1” or “pi-rads v2”) and (diagnostic or diagnose or sensitivity or specificity). the language was restricted to english. inclusion and exclusion criteria inclusion criteria was as follows: 1) patients with pca (p); 2) english literature published on pi-rads v2; 3) pi-rads v1 diagnostic effect in patients with pca; 4) can provide true positive number, false positive number, false negative number and true negative number of participants; 5) diagnostic test for the diagnostic value of pca. exclusion criteria was as following: 1) the study with incomplete data that cannot be used for statistical analysis; 2) review, letters, and other non-treatises of literature. in addition, for the literature with repeated publication or the same population data used in multiple studies, only the latest study or the one with the most complete information was included. data extraction and quality assessment all data from included studies was retrieved by two independent researchers: first author, year of publication, study year, country, the gold standard in the diagnosis of pca, age composition of included participants, the number of true positive (tp), false positive (fp), true negative (tn), and false negative (fn) results for either pi-rads v1 and pi-rads v2 analysis. quality assessment of the included studies was performed by using the quality assessment of diagnostic accuracy studies tool (quadas)(16). 11 items were evaluated according to the three criteria of "yes" (meeting this standard), "no" (not meeting or not being mentioned), and "unclear" (partly meeting or not getting enough information from the literature). specifically, once there was a difference of opinion in the process of literature data extraction and quality evaluation, a consensus will be reached after a group discussion with the third researcher. pi-rads v1 and pi-rads v2 for prostate cancer-he et al. table 2. results of diagnostic analysis. indicators pi-rads v1(95%ci) pi-rads v2(95%ci) z p sensitivity 0.82(0.77-0.85) 0.88(0.84-0.91) 2.321 0.027 specificity 0.81(0.77-0.85) 0.81(0.77-0.84) 0.074 0.941 plr 4.58(2.55-18.22) 4.34(1.98-9.49) 0.100 0.920 nlr 0.24(0.18-0.34) 0.16(0.08-0.32) 1.087 0.277 dor 24.00(10.38-55.51) 33.39(15.05-74.05) 0.496 0.620 figure 2. the pooled sensitivity (a) and specificity (b), plr (c), nlr (d), dor (e), and sroc (f) estimates for pi-rads v1 detection of pca patients. uj.v16i7.5532/10.22037 vol 18 no 1 january-february 2021 53 urological oncology 54 statistical analysis meta-analysis was conducted with meta-disc (version 1.4), and the effect indicators, including sensitivity, specificity, positive likelihood ratio (plr), negative likelihood ratio (nlr), and diagnostic odds ratio (dor). the threshold effect was evaluated by the spearman correlation coefficient of the sensitivity logarithm and the (1-specificity) logarithm. and the heterogeneity was determined based on the cochran’s q test and the i2 index(17): if significant heterogeneity was detected (p < 0.05, i2 > 50%), the combined effect value was calculated by the random effect model (dersimonian-laird); otherwise, fixed-effect model was used (mantel-haenszel) (18). the differences between pi-rads v1 and v2 in diagnostic indicators were determined with z test, and the publication bias of egger's test was conducted by using stata software. results characteristics of the included literatures according to the flow diagram for literature selection (figure 1), a total of 652 studies were preliminarily screened from pubmed (n = 323), embase (n=307) and cochrane library (n=22), including 234 duplicated articles. after title and abstract screen, 345 unrelated researches were excluded. next, through the full text reading, finally 6 articles with 814 participants (379 patients) were included in the study (13,14,19-22). as illustrated in table 1, the characteristics of 6 studies were summarized. the data showed that all included articles were published between 2016 and 2018, and the location included the australia, china and germany. additionally, the basic characteristics of demography revealed average age of all participants was 63-72, among which the elderly were the majority. furthermore, pi-rads v1 ≥ 10 or ≥ 4 and pi-rads v2 ≥ 4 or ≥ 3 had been regarded as the cut-off values in the diagnosis of pca. as shown in supplementary table 1, the quality of included articles was evaluated according to 11 items of quadas. the results showed that the bias of the included studies was small, indicating that the methodological quality was high. the combination of quantitative data . spearman correlation coefficient for v1 and v2 were 0.429 (p = 0.397) and 0.600 (p = 0.428), respectively, indicating there was no threshold effect and other statistics should be combined. the results with random effects model (dersimonian-laird) revealed that the combined sensitivity was 0.82 (95% ci: 0.773-0.853), specificity was 0.81 (95% ci: 0.77-0.85), plr was 4.58 (95% ci: 2.55-8.22), nlr was 0.24 (95% ci: 0.18-0.34) and dor was 24.00 (95%ci: 10.38-55.51) for pi-rads v1 (figure 2a-2e). similarly, based on the random effects model, the combined sensitivity, specificity, plr, nlr and dor for pi-rads v2 were 0.88 (95% ci: 0.84-0.91), 0.81(95% ci: 0.77-0.84), 4.34 (95% ci: 1.98-9.49), 0.16 (95% ci: 0.08-0.32) and 33.39 (95%ci: 15.05-74.05) (figure 3a-3e), respectively. the sroc curve was symmetric and random effect model (dersimonian-laird) was adopted. the area under curves of sroc for v1 and v2 were 0.8938 (q = 0.8244) and 0.9154 (q = 0.8482) (figure 2f and figure 3f). after the z test, the data revealed that there was no statistical difference between pi-rads v1 and v2 in the diagnosis of pca (auc, z = 0.557, p = 0.577).q, z = 0.568, p = 0.570). taken together, sensitivity of pi-rads v2 for the detection of pca was obviously higher than that of pi-rads v1 (z = 2.213, p = 0.027; table 2), suggesting the diagnostic effect of pi-rads v2 was superior to v1. however, the diffigure 3. the pooled sensitivity (a) and specificity (b), plr (c), nlr (d), dor (e), and sroc (f) estimates for pi-rads v2 detection of pca patients. pi-rads v1 and pi-rads v2 for prostate cancer-he et al. ference of specificity, plr, nlr or dor between pirads v1 and v2 was not significant, respectively (all, p > 0.05). publication bias the egger's test indicated that there was no publication bias in the diagnosis of pca in pi-rads v1 and v2 (t = 0.22, p = 0.823; t = 0.85, p = 0.428), which proves that our results are reliable. discussion in the present study, we for the first time compared the diagnostic performance of mpmri with pi-rads v1 and v2 in the pca detection. the results of meta-analysis demonstrated that both pi-rads v1 and v2 both presented high diagnostic value. furthermore, in addition to the fact that pi-rads v2 was more sensitive than v1, there was no difference in the other indicators between the two versions. therefore, in general, there was no difference in the diagnostic effect between the two versions. till now, although several studies have been reported to conduct the meta-analyses of pi-rads, the difference of diagnostic effect between pi-rads v1 and v2 has not been reported till now. for example, maggi(23) and zhai(24) et al only separately investigate the diagnostic performance of pi-rads 3; moreover, barkovich et al(25) only quantitatively and qualitatively assesses the methodologic heterogeneity of the pi-radsv2 literature and estimate the proportions of gleason scores (gss) diagnosed across piradsv2 categories. because of the high diagnostic accuracy for pca detection and reproducible interpretation, mpmri has been widely used by urologists. hence, comprehensible and clearly defined criteria for standardized analysis of mri for pca should be urgent. as the initial version, pi-rads v1 has been reported to have a good inter-observer agreement and high diagnostic accuracy (26,27). compared with the sequence of t2-wi, dwi, and dce in pi-rads v1 was considered to have equal discriminatory power, pi-rads v2 introduces the concept of "dominant sequence", which believes that dwi is the key sequence of pz and t2-wi is the dominant sequence in tz (28,29). and if there is no evidence of invasive behavior, the main difference between a finding with a score of 4 and that with a score of 5 on t2-w and dwi is a diameter less than 1.5 cm or equal /greater than 1.5 cm(30,31). in recent years, numerous studies have validated the value of pi-rads v2 but, as expected, have also identified a number of ambiguities and limitations, some of which have been documented in the literature with potential solutions offered(32). it has been reported pi-rads v2 in clinical practice retains higher accuracy over systematic trus biopsies for pca diagnosis(33). till now, a series of studies have reported some key differences between pi-rads v1 and v2, but the comparisons between the two versions have been controversial. for instance, thomas et al(13) revealed that pi-rads v1 showed a significantly larger discriminative ability for the detection of pca, due to the more false negative results in pi-rads v2. inversely, moritz(14) has demonstrated pi-rads v2 could be a reliable reporting system for pca assessment. and hoffmann et al(34) reports pi-rads v2 is reproducible between radiologists but does not have improved accuracy for diagnosing anterior tumors of the prostate when compared to pi-rads v1. in the present study, the results of a comprehensive comparison with meta-analysis suggested that there was no statistical difference between pi-rads v1 and v2 in the diagnosis of pca. furthermore, the sensitivity of pi-rads v2 for pca diagnosis in our study was significantly higher than that of pi-rads v1, but there was no significant difference in specificity, plr, nlr and dor between pi-rads v1 and pi-rads v2. actually, the summed pi-rads v2 outperformed v1 in the assessments of pca has been understood as a consequence of cancer location. briefly, pi-rads v2 has been reported to be the preferable method to evaluate the transitional zone (tz) due to a higher sensitivity, whereas pi-rads v1 performed better in (peripheral zone) pz(35). hence, in the process of mpmri, the versions of pi-rads should be selected based on the tumor site. usually, the inter-reader agreement has been regarded as one of the most important limitations in the use of mprmi. a previous study reports that the low inter-user agreement of mpmri may reduce the overall applicability of this methodology in all centers(36). in the present study, the results of the inter-reader agreement analysis (supplementary table 2) showed that inter-reader agreement of pi-rads v2 and pi-rads v1 were different in the included studies. in fact, based on the the heterogeneity of the sensitivity or specificity the included literature, we can also find that the diagnostic accuracy of pi-rads v2 and pi-rads v1 varies in different studies. heterogeneity has been regarded as a critical element in meta-analysis(37). in this study, we discussed the diagnostic value of pi-rads v1 and v2 in pca detection, and significant heterogeneity was detected among the overall pooled analyses mainly due to the following aspects: 1) differences in race, country and region; 2) differences in living habits, cultural exchanges and living environment; 3) differences caused by age, sample size and other factors. furthermore, there were no significant publication bias between the included studies, which suggested that the data of our meta-analysis are reliable. however, this study still had limitations; for example, due to the relatively small number of literatures and incomplete stratification information, the study was unable to obtain the source of its heterogeneity. conclusions in summary, the results with meta-analysis showed the differences of diagnostic accuracy of pi-rads v1 and v2 were not significant for detection of pca. however, to further verify the results, a larger cohort from multi-center institutions are still needed. acknowledgement this work was supported by the social development fund of nantong(program no. ms12018086 and no.ms22019013) and research topics of teaching reform of nantong university(program no. 2016b103). conflict of interest the authors declare that they have no competing interests. appendix: https://journals.sbmu.ac.ir/urolj/index.php/uj/library pi-rads v1 and pi-rads v2 for prostate cancer-he et al. vol 18 no 1 january-february 2021 55 urological oncology 56 files/downloadpublic/16 references 1. 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prostate imaging reporting and data system version 2. eur urol. 2019;76:340-351. 33. padhani ar, weinreb j, rosenkrantz ab, villeirs g, turkbey b, barentsz j. prostate imaging-reporting and data system steering committee: pi-rads v2 status update and future directions. eur urol. 2019;75:385-96. 34. hoffmann r, logan c, o’callaghan m, gormly k, chan k, foreman d. does the prostate imaging-reporting and data system (pi-rads) version 2 improve accuracy in reporting anterior lesions on multiparametric magnetic resonance imaging (mpmri)? int urology nephrol. 2018;50:13-9. 35. polanec s, helbich th, bickel h, et al. headto-head comparison of pi-rads v2 and pirads v1. eur j radiol. 2016;85:1125-31. 36. cormio l, cindolo l, troiano f, et al. development and internal validation of novel nomograms based on benign prostatic obstruction-related parameters to predict the risk of prostate cancer at first prostate biopsy. front oncol. 2018;8:438. 37. turner rm, jonathan d, clarke mj, thompson sg, julian pt h. predicting the extent of heterogeneity in meta-analysis, using empirical data from the cochrane database of systematic reviews. int j epidemiol. 2012;41:818-27. pi-rads v1 and pi-rads v2 for prostate cancer-he et al. 1423vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l departments of urology, sisli etfal training and research hospital, istanbul, turkey. goksel bayar, orhan tanriverdi, mehmet taskiran, umut sariogullari, huseyin acinikli, elshad abdullayev, kaya horasanli, cengiz miroglu comparison of laparoscopic and open ureterolithotomy in impacted and very large ureteral stones corresponding author: goksel bayar, md sisli etfal egitim ve arastirma hastanesi, uroloji klinigi, 19 may st., istanbul, turkey. tel: + 90 212 3735171 fax: + 90 212 2339876 e-mail: goxelle@gmail.com received february 2013 accepted february 2014 purpose:tocomparetheefficacyoflaparoscopicandopenureterolithotomyinpatientswith ureteral stones. materials and methods:patientswhohadundergoneopenorlaparoscopicureterolithotomy between2001and2013inourclinicwereenrolledinthestudy.ureterolithotomywasperformed duetothefollowingreasons:failuretopositionthepatientforureteroscopy,unreachablestone withureteroscopyalsouseofballoondilatation,highstonevolume,andtheneedforremoval ofkidneystonesatthesamesession..thepatients’demographicdata,thevolumeofthestones, thedurationoftheoperationandthehospitalstay,theamountofanalgesicsadministeredafter theoperation,andtheneedforanotherprocedurewerecompared. results:ofstudysubjects32patientshadundergoneopenand20patientshadundergonelaparoscopicureterolithotomy.whenthetwogroupswerecompared,therewasnostatisticallysignificantdifferencewithregardtothemeanage(44.5-44years),thebodymassindex(26-24.7kg/m²), thestonevolume(420-580mm³),thedurationofoperation(122-123min),theneedforanother procedureandcomplications.themeanamountofanalgesicsadministeredaftertheoperation (3.6and1.81doses,p=.02)andthemeanhospitalstay(6.1and2.9days,p =.01)weresignificantlylowerinthelaparoscopicureterolithotomygroup. conclusion:laparoscopicureterolithotomyisagoodalternativewithlessneedforanalgesia andashorterhospitalstaywhencomparedwithopenureterolithotomy. keywords:laparoscopy;methods;ureteralcalculi;surgery;treatmentoutcome. laparoscopic urology 1424 | introduction in recent years, with development of extracorporealshockwavelithotripsy(swl),percutaneousnephroli-thotomy(pnl)andwiththeadvancesinthetechnologyofureteroscopy(urs),theratesofinvasivesurgeryfor stonesintheurinarytracthasdroppedtolevelsof1-5.4%. therateofopensurgeryproceduresisabout1.5%inall procedures,withtheremainingsurgicalprocedurescomprising laparoscopic procedures.(1-5) forpatientswhoareunsuitableforswlandursandirresponsivetothesetreatmentmodalities,invasivetreatment modalitiesareputforth.fortheupperpartoftheureter,antegradepercutaneousureteroscopyisagoodalternative.if thepatientisnotsuitableforantegradepercutaneousureteroscopyandforstonesoftheotherpartsoftheureter,theonly alternativetreatmentisureterolithotomy.radiofrequencyincisionofintramuralureterandtheextractionofthestoneisa newalternativetechniquefordistalimpactedureteralstone. (6)butthisisnotgoldstandardtechniqueanddescribedissue on urology guidelines. intheeuropeanurologyguidelineonurolithiasis,itisaccepted that if laparoscopic ureterolithotomy is performed withtherightindications,itissuperiortoswlandureteroscopywithanevidencelevelof“1a”.andforpatientswith impactedlargeureteralstoneswhocannotbetreatedwith swlandendoscopicprocedures,theevidencelevelforlaparoscopicureterolithotomyhasbeenreportedtobe“2”witha recommendationlevelof“b”.(7) impactedstonesaredefinedasstonesremainingatthesame localizationforatleastfor2months.theminimaltimeperiodforthediagnosisofanimpactedstonemaybeunclear foreachpatient.definitionsforimpactedstonesincludethe following:ifthecontrastmediaisradiologicalobservednot tohavepassedtothedistalofthestone;andpreoperatively,if theguidewiredoesnotpasstotheproximalofthestone,and whenthestoneremainsatthesameanatomicalpositionfor2 months.(8-10)beingofstateofimpactedisveryimportantfor postoperativelong-termcomplications.becauseafterureteroscopy,forimpactedstones,stricturesmaydevelopwith ratesashighas24%.(11)wecanrefereetotheeuropeanurologyguidelineonurolithiasisforthedefinitionof“verylarge stone”,alargeureterstoneis>10mm,whereasverylarge stonesaredescribedtobelargerthan15mmindiameter.(7) so,forthesereasons,wehaveaimedtocomparisonofopen andlaparoscopicapproachforureterolithotomyintermsof postoperativeureteralstricture,amountoftheanalgesicdrug needingandhospitalizationintervalinpatientswhohadwe cantakeoutthispartofsentenceimpactedverylargeureteral stones. materials and methods thirty-twopatientswhohadundergoneopenureterolithotomyand20patientswhohadundergonelaparoscopicureterolithotomybetween2001and2013wereretrospectivelyanalyzed.ureterolithotomywasperformedduetothefollowing reasons:failuretopositionthepatientforureteroscopy(1 patient);unreachablestonewithureteroscopyalsouseofballoondilatation(17patients);highstoneload(31patients), andtheneedforremovalofkidneystonesatthesamesession(3patients).allofpatient’sstonesareverylargeand impacted.openureterolithotomywaspreferredbetweenthe yearsof2001-2008,andwiththeadvancesinlaparoscopic surgeryinourclinic,laparoscopicureterolithotomywaspreferredbetween2008-2013.onepatientunderwentopenureterolithotomyin2011andanotherpatientunderwentopen ureterolithotomyin2012,bothduetothefactthattheywere unsuitableforlaparoscopicsurgery.twopatientsunderwent openureterolithotomyat2013duetopatients’request. inopenprocedures, lombotomyforsuperiorandmid-part ureteralstonesandthegibsonincisionfordistalpartureteral stoneswereused.afterpalpationoftheureterforstones,the ureterwasopenedthroughaverticalincisionandthestone wasextracted.thenadoublejureteralstentwasplacedin ureter and ureter was closed with absorbable sutures. an abdominaldrainwasthenplacedattheoperationsite.fifteen patientshadbeenoperatedforupper,3midand14distalureteralsegmentstones. laparoscopic procedures were performed trans and retroperitoneally.havingpalpatedthestonewiththelaparoscopic instrument,withthetechniquethatwehavedevelopedinour clinictoincreasesafety,theureterwasverticallyincisedusingano.11orano.15scalpelandthestonewasextracted. laparoscopic urology 1425vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l ureterolithotomy for impacted stones | bayar et al a double j ureteral stent was then placed and the ureter was closed using absorbable sutures.an abdominal drain was thenplacedattheoperationsite.fifteenpatientshadbeenoperatedforupper,4midand1distalureteralsegmentstones. allofoperations,openandlaparoscopic,wereperformedby samesurgeon. thedemographicdataofthepatients,theage,sexandthe bodymassindexwererecorded.theanalgesicmedications thathadbeenadministeredpostoperativelywereanalyzed. amountofanalgesicdrugneededwastakenintoaccountfor first24hours.oneanalgesicdoseisacceptedtobe50mg pethidine,50mgdiclofenac,and500mgparacetamol.the stonevolumewascalculatedwiththeformula:(stonewidth ×stonelength×π×0.25)^1.27×0.6. thepatientsweredividedintotwogroupsaccordingtothe surgerybeingopenorlaparoscopic,andtheirdemographic data,stonevolumes,durationsofoperationandhospitalization,amountofanalgesicsadministeredaftertheoperation andtheneedforanotherprocedurewerecompared.finishing ofoperationlaparoscopicallyandreachingstone-freewere consideredsuccesscriteria.complicationswereclassifiedby clavien-dindosystem. mann whitney uandfisher’sexacttestwereusedforthe statistical analyses and pvalueof<.05wasconsideredas significant. results alloftheopenprocedureswereretroperitoneal,while5of thelaparoscopicproceduresweretransperitonealand15of the laparoscopic procedures were retroperitoneal. in the open proceduregroup,7patientswerewomenand25weremen, withameanageof44.5years.inthelaparoscopygroup,4 patientswerewomenand16weremen,withameanageof 44years.whenthebodymassindexesofthetwogroups werecompared,therewasnostatisticallysignificantdifference(table1). forthestonevolumes,althoughthevolumesinthelaparoscopygroupwerehigher,thedifferencebetweentwogroups wasnotstatisticallysignificant.wethinkthatitwasbecause ofthesmallnumberofpatients.whenwecomparedtheoperationtimes,interestingly,themeanoperationtimeswere veryclosetoeachotherforthetwogroups.operationtimes are similar between trans and retroperitoneal laparoscopy groups(114vs.126min,p=.45).theneedforanalgesia wassignificantlylowerinthelaparoscopygroupinthepostoperativeperiod.furthermore,thepostoperativehospitalizationtimewassignificantlyshorterinthelaparoscopygroup (table1). intheopenureterolithotomygroup,3patientshadpainand hydronephrosisafterthedoublejstentwasremovedatthe fourthpostoperativeweek.theyunderwentdiagnosticurettable 1. demographic and clinical characteristics of study subjects. variables open laparoscopic p female/male ratio 7/25 4/16 .72 mean age (years) 44.5 ± 17 44 ± 12 .9 mean bmi (kg/m²) 26 ± 3 24.7 ± 3 .41 mean stones volume (mm³) 420 ± 280 580 ± 325 .085 operation time (minutes) 122 ± 38 123 ± 40 .9 hospitalization time (days) 6 ± 2.6 2.9 ± 1.4 .01* analgesic drug needing (doses) 3.6 ± 2.7 1.81 ± 1.2 .02* additional treatment 3 1 .12 complication 1 2 .4 key: bmi, body mass index. * statistically significant. 1426 | eroscopy,andtheremainingstonesintheureterweretreated endoscopically.thatpatientsstonesmaybebrokenduring openureterolithotomy.intheopenureterolithotomygroup,1 patienthaddevelopedureterovesicalobstruction.then,with opensurgery,theobstructedsegmentwasexcisedandureteroneocystostomywasperformed.onthefollow-up,itwas seenthattheobstructionhadbeenalleviated.furthermore, intheopenureterolithotomygroup,1patienthadpermanent obstructioninalongsegmentofthemid-partoftheureter.as theotherkidneywashypoplasticandtheobstructionwasin thelongsegment,hewasonfollow-upfor91monthswithoutanyfurthercomplicationsbychangingthedoublejstent every6months.allofpatientswerefollowedmean15,minimum3monthsinopengroup. in the laparoscopy group, in the one and only patient in whomadoublejstenthadnotbeenplaced,thedrainrevealedover1000mldaydrainagewithurinecontentpostoperatively.hence,weperformedendoscopyafter2days, andtheremainingstonewastreatedendoscopically.wehave recoveredtoopenprocedureatonepatientduetobleeding. postoperativeileusoccurredinnoneofthepatients.allof patientswerefollowedmean30,minimum6monthsinlaparoscopygroup.therewerenodifferencesbetweenthetwo groupswithregardtotherequirementforanextraprocedure. discussion thesuccessoftheoperationisdefinedasfinishingthesurgerylaparoscopicallyandreachingastonefreestateforlaparoscopicureterolithotomy.thesuccessrateforthisprocedure is usually reported as 90%; however, there are reports of 100%success,too.(15,18,21) in our study, the success rate was 90%,alltheprocedureswerecompletedlaparoscopicallyand withacompletestonefreestateexceptonepatient(table1). simforooshandcolleaguesreported96.7%successrateand theirserieswas123patients.(22) nasseh and colleagues reported94%successrate.alsothisstudywaspublishedat2013 years and operations were done between 2008-2011 years.(23) thatistosay,wethinkrealsuccessrateoflaparoscopicureterolithotomyisabout95%. intheliterature,thecomplicationratesarelowandthehighlaparoscopic urology table 2. our and other studies’ databases about laparoscopic ureterolithotomy in current literature. studies patients no. success rate (%) complication rate (%) additional treatment rate (%) operation time (min) hospitalization time (day) our study, 2014 20 90 10 5 123 2.9 el moula et al. 2008(12) 74 94.6 0 1.4 58.7 6.4 ko hy et al. 2011(13) 71 93.8 12.5 4.2 118 5.9 flasko et al. 2005(14) 75 98.7 0 0 45 3 skrepetis et al. 2001(15) 18 100 0 0 130 3 kijvikai et al. 2006 (16) 30 96 13.3 3.3 121.38 3.86 gaur et al. 2002(17) 101 92 11 0 79 3.5 fang et al. 2012(18) 25 100 0 0 41.8 2.9 huri et al. 2010(19) 41 97.5 12.5 12.5 124 4.8 wang et al. 2010(20) 36 94.5 17.6 0 131.5 5.8 keeley et al. 1999(21) 14 100 0 14 105 5.6 simforoosh et al. 2007(22) 123 96.7 11.4 10.5 143 5.86 1427vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l estreportedrateis17.6%.(24)thereareseveralstudiesreportingthecomplicationrateof0%.(12,14,15,18,21) in our study, the complicationratewas10%(table2).ureteralstrictureisthe maincomplicationconcernaftertheoperation.inareviewof theliterature,nouiraandcolleaguesreportedthiscomplicationrateas2.5%.(25)topreventthestrictures,itisimportant nottodisturbthevasculatureoftheincisedpartoftheureter duringtheoperation.gaurandcolleaguesreportedthatitis safetousethehookdeviceinthecuttingmodeoftheelectrocauterydevicefortheureterincision.theyreportedthat inthe10-yearfollow-upof75patients,only3hadstrictures inthepartthatthestonehadbeenimpacted,buttheydidnot mentionanythingabouttheincisiontechniqueinthepatients whohaddevelopedstrictures.twoofthose3patientswere treated with balloon dilatation and 1 underwent double j stent placementfor3monthsandnorecurrencewasobserved.(17) weusedthescalpelforincisionwithasafetechniquethat wehaddevelopedinourclinic,andinthemeanfollow-up timeof30months(range,7-42months),noneofthepatients experiencedureteralstricture. theextraprocedureswereureteroscopy,percutaneousnephrolithotomyanddoublejstentplacementforpatientswith prolongedurinaryleakageorpatientswhocouldnotberenderedstonefree.thisratehasbeenreportedtobeashighas 14%intheliterature,(20) but there are studies reporting the rateas0%(table2).(14,15,17,18,21) in our study, the one and onlypatientinwhomwedidnotplaceadoublejureteral stent,developedurineleakageof1000ml/day,andhence, weperformedureteroscopyonthesecondpostoperativeday andplacedadoublejureteralstent(table1).urinaryleakageforaprolongeddurationshouldbeavoided,sinceitmust bekeptinmindthatprolongedretroperitonealurinaryleakagecancauseretroperitonealfibrosis.(26) theoperationtimeintheavailableliteratureshowsawide rangefrom41.8to132minutes(table2).fanandcolleagues demonstratedthataftercompletionofa20caseseriescomprisingtheteachingcurve,theoperationtimedecreasedfrom 120minutesto65minutesinthesecond20cases.(26)gaur andcolleaguesreportedthatclosingtheureterwithprimary suturesprolongstheoperationbyabout26minutes.(17) in our study,weclosedtheureterwithprimarysutures,anddueto thefactthattheteachingcurveforlaparoscopicureterolithotomywasnotcompleted,theoperationtimewaslonger(table1).itisexpectedthatwhenwehaveasufficientnumber ofcases,theoperationtimewilldecrease. thedurationofhospitalstayhasbeenreportedtobebetween 2.9-6.4days(table2),(16,25)andinourstudyitisestimatedto be2.9days(table1).sincethepreviousstudieshadbeencarriedoutwithregardtolaparoscopicureterolithotomyexperiencesanditscomparisonwithureteroscopy,thereishardly anymentionaboutthedurationofhospitalstay.skrepetisand colleaguesreportedthedurationofhospitalstayforthelaparoscopygroupas3daysandthatfortheopensurgerygroup as 8 days.(15)gaurandcolleaguesdemonstratedthatwith uretersuturingandplacementofadoublejureteralstent,the urinaryleakagetimeinpatientsdecreasedfrom5.5daysto 3.2days.(17)inourstudy,whenwecomparedthegroups,the timedurationwasdeterminedtobesignificantlylowerinthe laparoscopygroup.wethinkthat,exceptforone,wesutured the ureter and placed double j ureteral stent in all the other operationsandthisdecreasedthedurationofhospitalstay.in thatoneparticularpatient,thedurationofhospitalstaywas 7days.manyofopenureterolithotomypatientshavestayed prolongedtimeduetopain.apatient,oneofopenureterolithotomyhasstayed16daysinhospitalonlyduetopain. unfortunately,theneedforanalgesiahasnotbeendefined withacommondrugoraunit.everyclinichasreportedthe drugsforitsownpracticaluseandanalgesiaunitoftheir own.thenumberofstudiesabouttheneedofanalgesiafor openandlaparoscopicureterolithotomygroupsisverylimited.skrepetisandcolleaguesreportedthedailyrequirement ofanalgesicsinthelaparoscopicgroupas1,andthatinthe opensurgerygroupas4wecantakeouttihspart.(15) in our study,theneedforanalgesiawasexpressedasunitanalgesia, andthiswas1.8unitsinthelaparoscopygroupand3.5units intheopengroup,whichissignificantlylowerinthelaparoscopygroup(table1). smallsamplesizeandretrospectivedesignarelimitationsof our study. conclusion laparoscopicureterolithotomyhassimilarsuccessandcomplicationratestoopenureterolithotomy.inthetreatmentof largeimpactedureteralstones,laparoscopicureterolithotomy ureterolithotomy for impacted stones | bayar et al 1428 | maybepreferredtoopenureterolithotomyduetolowamount ofanalgesicdrugneededandhospitalizationtime. acknowledgements wethankourclinicalsecretary,ayferguzel,forhereffortsin reachingthepatients’data. conflict of interest none declared. references 1. assimos dg, boyce wh, harrison lh, mccullough dl, kroovand rl, sweat kr. the role of open stone surgery since extracorporeal shock wave lithotripsy. j urol. 1989;142:263-7. 2. segura jw. current surgical approaches to nephrolithiasis. endocrinol metab clin north am. 1990;19:919-35. 3. honeck p, wendt-nordahl g, krombach p, et al. does open stone surgery still play a role in the treatment of urolithiasis? data of a primary urolithiasis center. j endourol. 2009;23:1209-12. 4. bichler kh, lahme s, strohmaier wl. indications for open stone removal of urinary calculi. urol int. 1997;59:102-8. 5. paik ml, resnick mi. is there a role for open stone surgery? urol clin north am. 2000;27:323-31. 6. guner b, gurbuz c, caskurlu t. a novel technique for treatment of distal ureteral calculi: early results. urol j. 2013;10: 807-10. 7. türk c, knoll t, petrik a, sarica k, seitz c, straub m. eau. guidelines on urolithiasis 2012 available at http://www.uroweb.org/gls/ pdf/20_urolithiasis_lr%20march%2013%202012.pdf. 8. goel r, aron m, kesarwani pk, dogra pn, hemal ak, gupta np. percutaneous antegrade removal of impacted upper-ureteral calculi: still the treatment of choice in developing countries. j endourol. 2005;19:54-7. 9. erhard m, salwen j, bagley dh. ureteroscopic removal of mid and proximal ureteral calculi. j urol. 1996;155:38-42. 10. morgentaler a, bridge ss, dretler sp. management of the impacted ureteral calculus. j urol. 1990;143:263-6. 11. roberts ww, cadeddu ja, micali s, kavoussi lr, moore rg. ureteral stricture formation after removal of impacted calculi. j urol. 1998;159:723-6. 12. el-moula mg, abdallah a, el-anany f, et al. laparoscopic ureterolithotomy: our experience with 74 cases. int j urol. 2008;15:593-7. 13. ko yh, kang sg, park jy, et al. laparoscopic ureterolithotomy as a primary modality for large proximal ureteral calculi: comparison to rigid ureteroscopic pneumatic lithotripsy. j laparoendosc adv surg tech a. 2011;21:7-13. 14. flasko t, holman e, kovacs g, tallai b, toth c, salah ma. laparoscopic ureterolithotomy: the method of choice in selected cases. j laparoendosc adv surg tech a. 2005;15:149-52. 15. skrepetis k, doumas k, siafakas i, lykourinas m. laparoscopic versus open ureterolithotomy. a comparative study. eur urol. 2001;40:32-6. 16. kijvikai k, patcharatrakul s. laparoscopic ureterolithotomy: its role and some controversial technical considerations. int j urol. 2006;13:206-10. 17. gaur dd, trivedi s, prabhudesai mr, madhusudhana hr, gopichand m. laparoscopic ureterolithotomy: technical considerations long term follow-up. bju int. 2002;89:339-43. 18. fang yq, qiu jg, wang dj, zhan hi, situ j. comparative study on ureteroscopic lithotripsy and laparoscopic ureterolithotomy for treatment of unilateral upper ureteral stones. acta cir bras. 2012;27:266-70. 19. huri e, basok ek, uğurlu o, et al. experiences in laparoscopic removal of upper ureteral stones: multicenter analysis of cases, based on the turkurolap group. j endourol. 2010;24:1279-82. 20. wang y, hou j, wen d, ouyang j, meng j, zhuang h. comparative analysis of upper ureteral stones (> 15 mm) treated with retroperitoneoscopic ureterolithotomy and ureteroscopic pneumatic lithotripsy. int urol nephrol. 2010;42:897-901. 21. keeley fx, gialas i, pillai m, chrisofos m, tolley da. laparoscopic ureterolithotomy: the edinburgh experience. bju int. 1999;84:765-9. 22. simforoosh n, basiri a, danesh ak, et al. laparoscopic management of ureteral calculi: a report of 123 cases. urol j. 2007;4:138-41. 23. nasseh h, pourreza f, kazemnejad leyli e, zohari nobijari t, baghani aval h. laparoscopic transperitoneal ureterolithotomy: a singlecenter experience. j laparoendosc adv surg tech a. 2013;23:495-9. 24. mitchinson mj, bird dr. urinary leakage and retroperitoneal fibrosis. j urol. 1971;105:56-8. 25. nouira y, kallel y, binous my, dahmoul h, horchani a. laparoscopic retroperitoneal ureterolithotomy initial experience and review of literature. j endourol. 2004;18:557-61. 26. fan t, xian p, yang l, liu y, wei q, li h. experience and learning curve of retroperitoneal laparoscopic ureterolithotomy for upper ureteral calculi. j endourol. 2009;23:1867-70. laparoscopic urology v08_no_4_final_new.pdf answer to clinical pathology case 323urology journal vol 8 no 4 autumn 2011 an unusual presentation of an uncommon renal disease farzaneh sharifiaghdas,* hossein kilani, seyed amin mirsadeghi urol j. 2011;8:323-4. www.uj.unrc.ir brief history a 59-year-old man with a history of right nephrolithotomy for staghorn stone presented with right flank pain and recurrent pyelonephritis. he was planned for right simple nephrectomy because of suspicious xanthogranulomatous pyelonephritis. quiz 1. do you agree with the approach chosen for the diagnosis or do you recommend other imaging studies post-chemotherapy computed tomography scan with contrast 2 months after the operation showing multiple hepatic metastases. urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran corresponding author: farzaneh sharifi aghdas, md department of urology, shahid labbafinejad medical center, 9th boustan st., pasdaran ave., 16666-94516, tehran, iran tel/fax: +98 21 2258 8016 e-mail: fsharifiaghdas@yahoo.com answer to clinical pathology case 324 urology journal vol 8 no 4 autumn 2011 or procedures? 2. what do you think the final pathology report of the specimen might be? the recommended approach in this patient, the ultrasonography revealed pyonephrosis. therefore, the first step is adequate kidney drainage via nephrostomy tube or double-j stents insertion. the next step is to determine the location and etiology of obstruction. currently, the most appropriate radiologic modality for the diagnosis of obstruction is computed tomography scan. ureteroscopy can be complementary to radiologic evaluation to evaluate intramural and mural pathologies. in case of urinary tract obstruction, in addition to common etiologies, like stone and benign strictures, one should also be suspicious of external pressure and obstruction due to neoplastic lesions. therefore, evaluation with other imaging studies, such as retrograde pyelography or nephrostography and urine cytology might be indicated. retrograde pyelography or nephrostography not only can demonstrate intra-calyceal and intra-pelvic lesions perfectly, but also is able to diagnose the presence and level of obstruction in poor functioning kidneys because nuclear scans, such as diethylene triamine pentaacetic acid, are ineffective in this situation. operative findings during operation, severe adhesion of the gerota fascia and renal capsule to surrounding tissues, including the psoas, diaphragm muscles, and peritoneum, was noted. there was a yellow, fibrotic mass over the hilum, which had engulfed the whole of the renal pelvis and main vessels and had resulted in severe obstruction. this mass, which has firmly adhered to the posterior abdominal wall, was removed with renal specimen. final pathology report high-grade urothelial carcinoma of the pelvis with invasion into the renal parenchyma and perirenal fat was reported. surgical margins were positive for tumor and pyelocalyceal carcinoma in situ was also present. pathologic stage was pt3 nx mx. short-term follow-up back to the patient, he was referred to an oncologist for adjuvant chemotherapy, but in spite of chemotherapy, he developed hepatic metastases (figure). urol_v03_no4_001_editorial.indd sexual dysfunction and infertility 240 urology journal vol 3 no 4 autumn 2006 improvement of erectile dysfunction after kidney transplantation the role of the associated factors abdolrasoul mehrsai, shahram mousavi, mohammadreza nikoobakht, tina khanlarpoor, leila shekarpour, gholamreza pourmand introduction: the aim of this study was to evaluate erectile dysfunction (ed) in hemodialysis patients and the factors influencing ed after a successful kidney transplantation. materials and methods: a total of 64 patients on hemodialysis were evaluated before and 6 months after the kidney transplantation. they were all recipients of their first kidney allografts from living unrelated donors and had a functional kidney allograft during the follow-up. the 5-item version of the international index of erectile function (iief-5) was used to assess their erectile function. a group of age-matched controls were compared with them before transplantation. the effects of pretransplant iief-5 score, age at transplantation, the artery used for anastomosis, and duration of the dialysis prior to transplantation on ed were also studied. results: fifty-six of the patients (87.5%) and 23 of the controls (35.9%) had ed (p < .001). the prevalence of ed was 87.5% in the hemodialysis patients. there was no relationship between the duration of dialysis and the severity of ed. successful transplantation improved iief-5 score significantly (13.6 ± 5.2 before and 19.2 ± 5.0 after transplantation; p < .001). based on the iief-5 scores, the severity of ed increased in 6 (9.4%) patients; 8 (12.5%) experienced no change in their erectile function; and 50 (78.1%) reported an improved erectile function. preoperative iief-5 score and age at transplantation had statistically significant associations with ed improvement (p < .001; p = .02). conclusion: erectile dysfunction is highly prevalent in hemodialysis patients and significantly improves after successful kidney transplantation. younger patients with a less severe ed have the most improvement after transplantation. urol j (tehran). 2006;4:240-4. www.uj.unrc.ir keywords: impotence, kidney transplantation, erectile dysfunction, hemodialysis department of urology, sina hospital, tehran university of medical sciences, tehran, iran corresponding author: shahram mousavi, md urology research center, sina hospital, hasan-abad sq, tehran, iran tel: +98 21 6671 7447 fax: +98 21 6671 7447 e-mail: shahram_moosavi1353@yahoo.com received july 2006 accepted september 2006 introduction erectile dysfunction (ed) is a major health issue in modern life and is often underdiagnosed and underestimated due to the patient’s embarrassment and the physician’s unawareness about its high prevalence and impact on the quality of life.(1,2) the prevalence of ed in 40to 70-year-old men was about 52% in massachusetts male aging study.(1) end-stage renal disease (esrd) is a chronic disease which is frequently associated with ed. the high prevalence of ed in esrd is multifactorial; it is due to the comorbid conditions that frequently accompany esrd (eg, diabetes mellitus, hypertension, atherosclerosis, erectile dysfunction and kidney transplantation—mehrsai et al urology journal vol 3 no 4 autumn 2006 241 heart disease, etc), neurogenic disorders, hormonal imbalance, metabolic abnormalities, drugs side effects, and psychogenic factors.(1-14) the prevalence of ed in hemodialysis patients is reported to be up to 82%.(5) although several studies have shown significant improvement in ed after a successful kidney transplantation,(3,4,7,15,16) some other studies reported minimal effect of transplantation on the status of ed.(12,17-19) the present study was planned to assess the effect of kidney transplantation on ed in esrd patients and determine the influential factors on ed improvement after transplantation. materials and methods this prospective study was conducted between september 2002 and november 2005. during this period, 270 patients who were on hemodialysis for at least 6 months underwent kidney transplantation. we selected 80 patients and excluded the others (group 1). the exclusion criteria were age less than 20 years, diabetes mellitus, history of ischemic heart disease, hypercholesterolemia, history of pelvic trauma or prostate surgery, presence of penile deformities, cigarette smoking, an uncontrolled major medical illness, previous kidney transplantation, and the use of medications with significant adverse effects on erectile function. the ethics committee of tehran university of medical sciences approved our study. a written consent was taken from all patients. all patients received the kidneys from living unrelated donors and were on a same regimen of immunosuppressive drugs. renal arteries of the graft were anastomosed to the internal and external iliac arteries and common iliac artery in 45 (56.3%), 11 (13.7%), and 8 (10%) patients, respectively. they were followed for 6 months. of 80 eligible kidney recipients, 64 (80%) completed the study protocol. during the study, 4 cases of death (5%) and 5 cases of suboptimal graft function (6.3%) were reported. seven patients (8.7%) did not return for follow-up. erectile function of the patients was assessed by the 5-item version of the international index of erectile function (iief-5) before and 6 months after kidney transplantation.(20) according to the iief-5 scores, ed was classified into 4 groups of mild (17 to 21), mild to moderate (12 to 16), moderate (8 to 11), and severe (5 to 7).(20) iief-5 in detail available from: http://www.uj.unrc.ir see the electronic version of article a control group was selected (group 2), consisting of age-matched patients who referred to the outpatient clinics for neither ed nor kidney function impairment (none of them had any of the exclusion criteria). they were assessed using iief-5. all questionnaires were completed by a single physician. the iief-5 scores of the patients before transplantation were compared with the scores after transplantation and with those of the control group, using paired t test and t test, respectively. also, the effect of the pretransplant iief-5 score, age at transplantation, the artery used for anastomosis, and duration of the dialysis prior to transplantation on ed was assessed using chi-square test and mannwhitney test. a p value less than .05 was considered significant. results a total of 64 esrd patients (group 1) and 64 controls (group 2) were studied. the mean age of the patients in group 1 was 42.3 ± 10.4 years (range, 23 to 63 years). they had been on hemodialysis for a mean time of 16.8 ± 18.7 months (range, 6 to 120 months). the mean age of the patients in group 2 was 42.7 ± 11.2 years (range, 24 to 64 years). fifty-six of the patients in group 1 (87.5%) and 23 in group 2 (35.9%) had ed (p < .001). the mean iief-5 score was 13.6 ± 5.2 (range, 5 to 25) in group 1 before transplantation and 22.0 ± 2.8 (range, 8 to 25) in group 2 (p < .001). in group 1, mild to severe ed was present in 41 out of 49 men aged 50 years or younger (83.7%) and in all of the 15 patients older than 50 years (100%). there was no significant correlation between the score of iief-5 and the age in group 1 (p = .10). also, duration of hemodialysis was not associated with the pretransplant iief scores (p = .18). six months after the successful kidney transplantation, the mean iief-5 score of the patients in group 1 increased to 19.2 ± 5.0 which was significantly higher than that before transplantation (p < .001). the degrees of ed before and after the operation are shown in table. based on the iief-5 erectile dysfunction and kidney transplantation—mehrsai et al 242 urology journal vol 3 no 4 autumn 2006 scores, the severity of ed increased in 6 (9.4%) patients; 8 (12.5%) experienced no change in their erectile function; and 50 (78.1%) reported an improved erectile function. in an attempt to find the predictors of ed improvement after transplantation, factors including pretransplant iief-5 score, age at transplantation, the artery used for anastomosis, and duration of the dialysis prior to transplantation were evaluated. pretransplant iief-5 score had a significant inverse association with improvement of erectile function (p < .001). also, younger patients had a more significant ed improvement (p = .02). the artery used for anastomosis and duration of the dialysis prior to transplantation were not associated with ed improvement (p = .93; p = .71). discussion the effect of kidney transplantation on ed has been evaluated in several studies. in this prospective study, we assessed the effect of kidney transplantation on ed by evaluating a group of hemodialysis men before and after a successful transplantation. in different studies, the reported prevalence of ed in hemodialysis patients has been different. in a study by rosas and colleagues, the prevalence of ed in hemodialysis patients was estimated to be 82%.(5) other investigators have found the prevalence of ed to be even lower in this group of patients.(21,22) we observed a higher prevalence (87.5%). a total of 11% and 30% of the hemodialysis patients had severe and moderate ed while these numbers were reported to be 45% and 8% in the study of rosas and colleagues.(5) this may be due to the higher mean age of the participants in comparison with that in our study (59.5 years versus 42.3 years). compared to the pretransplant status, erectile function after the transplantation deteriorated, remained without change, or improved in 9.41%, 12.5%, and 78.1% of the patients, respectively. there was a higher percentage of improvement in erectile function of our patients compared to the other studies. for example, in the study by el-bahnasawy and associates, erectile function deteriorated, had no change, and improved in 12.5%, 43.5% and, 44% of the patients, respectively.(12) in another study by the same author, these rates were 18%, 42%, and 40%, respectively.(22) the effect of the associated factors was also assessed. as anticipated, the lower was the pretransplant iief-5 score, the higher was the difference between the pretransplant and posttransplant scores. also, the present study showed a significant association between the age and the probability of ed improvement in kidney transplant recipients. although in some studies there was an association between the duration of the dialysis and the probability of the recovery from erectile dysfunction after the kidney transplantation,(11-17) no significant relationship was found between these two variables in our study. the esrd patients in our country usually can enjoy transplantation before being on dialysis for a long time; thus, the duration of hemodialysis was relatively shorter in our study (16.8 months). there are different opinions about the effect of the type of the artery used for anastomosis on the ed improvement. the major blood supply of the penis is derived from 2 penile arteries which are branches of the internal iliac arteries. most surgeons prefer the internal iliac artery for anastomosis.(23) a crucial question is that how much is the risk of vasculogenic ed following end-to-end anastomosis of the internal iliac artery to the graft respecting the basic problems in hemodialysis patients such as severe atherosclerosis and vascular insufficiency? its reported risk is 10%.(24) an interesting study by el-bahnasawy and coworkers degree of ed in controls and in patients before and after kidney transplantation* *values in parentheses are percents. ed indicates erectile dysfunction. kidney transplant patients degree of ed before kidney transplantation after kidney transplantation controls no ed 8 (12.5) 26 (40.6) 41 (64.1) mild 11 (17.2) 18 (28.1) 22 (34.4) mild to moderate 19 (29.7) 13 (20.3) 0 moderate 19 (29.7) 5 (7.8) 1 (1.6) severe 7 (10.9) 2 (3.1) 0 erectile dysfunction and kidney transplantation—mehrsai et al urology journal vol 3 no 4 autumn 2006 243 demonstrated that after excluding most major vascular factors, interruption of the hypogastric artery had led to a significant decrease in arterial blood flow in the 2 cavernous arteries. however, none of the evaluated patients had penile arterial insufficiency (peak systolic velocity less than 30 cm/ s). unilateral ligation of the internal iliac artery is not harmful to erectile function if the contralateral artery is normal. they recommended the use of end-to-side anastomosis of the graft to the external iliac artery in patients with impaired pelvic blood flow to reduce the risk of vasculogenic ed.(22) after a second kidney transplant to the other internal iliac artery, the risk of vasculogenic ed is between 25% and 65%.(23,25) therefore, in contrast to nghiem and colleagues who stated that the ligation of both internal iliac arteries does not necessarily mean pelvic devascularization (due to reestablishment of the collateral vessels within a few months),(26) we believe that it is better to use an artery other than the internal iliac artery in the second kidney transplantation. although in our study, the best ed improvement was obtained with anastomosis to the external iliac artery, the results were not significantly different between the types of anastomosis. conclusion erectile dysfunction is an extremely common problem in hemodialysis patients and has a major negative effect on the quality of life in these patients. also, many patients with ed will not seek treatment themselves. thus, respecting the development of effective oral therapies for ed, discussions about this problem should be a part of the routine management of the patients on hemodialysis. finally, ed improvement seems to be higher when the kidney transplantation is performed at lower ages. acknowledgment the authors thank the staff of the urology operation room and the hemodialysis unit of sina hospital. the secretarial assistance of mrs leila shekarpour and mrs fariba heidari are gratefully appreciated. we also thank mr benik horsepian for his kind assistance. conflict of interest none declared. references 1. feldman ha, goldstein i, hatzichristou dg, krane rj, mckinlay jb. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994;151:54-61. 2. rosas se, joffe m, franklin e, et al. association of decreased quality of life and erectile dysfunction in hemodialysis patients. kidney int. 2003;64:232-8. 3. saha mt, saha hh, niskanen lk, salmela kt, pasternack ai. time course of serum prolactin and sex hormones following successful renal transplantation. nephron. 2002;92:735-7. 4. akbari f, alavi m, esteghamati a, et al.effect of renal transplantation on sperm quality and sex hormone levels. bju int. 2003;92:281-3. 5. rosas se, joffe m, franklin e, et al. prevalence and determinants of erectile dysfunction in hemodialysis patients. kidney int. 2001;59:2259-66. 6. milne jf, golden js, fibus l. sexual dysfunction in renal failure: a survey of chronic hemodialysis patients. int j psychiatry med. 1977-1978;8:335-45. 7. holdsworth sr, de kretser dm, atkins rc. a comparison of hemodialysis and transplantation in reversing the uremic disturbance of male reproductive function. clin nephrol. 1978;10:146-50. 8. mahajan sk, abbasi aa, prasad as, rabbani p, briggs wa, mcdonald fd. effect of oral zinc therapy on gonadal function in hemodialysis patients. a double-blind study. ann intern med. 1982;97:357-61. 9. grimm rh jr, grandits ga, prineas rj, et al. longterm effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. treatment of mild hypertension study (tomhs) hypertension. 1997;29: 8-14. 10. palmer bf. sexual dysfunction in uremia. j am soc nephrol. 1999;10:1381-8. review. 11. rebollo p, ortega f, valdes c, et al. factors associated with erectile dysfunction in male kidney transplant recipients. int j impot res. 2003;15:433-8. 12. el-bahnasawy ms, el-assmy a, el-sawy e, et al. critical evaluation of the factors influencing erectile function after renal transplantation. int j impot res. 2004;16:521-6. 13. wuerth d, finkelstein sh, ciarcia j, peterson r, kliger as, finkelstein fo. identification and treatment of depression in a cohort of patients maintained on chronic peritoneal dialysis. am j kidney dis. 2001;37: 1011-7. 14. rodger rs, fletcher k, dewar jh, et al. prevalence and pathogenesis of impotence in one hundred uremic men. uremia invest. 19841985;8:89-96. 15. salvatierra o jr, fortmann jl, belzer fo. sexual function of males before and after renal transplantation. urology. 1975;5:64-6. 16. flechner sm, novick ac, braun we, popowniak kl, steinmuller d. functional capacity and rehabilitation of recipients with a functioning renal allograft for ten years or more. transplantation. 1983;35:572-6. erectile dysfunction and kidney transplantation—mehrsai et al 244 urology journal vol 3 no 4 autumn 2006 17. malavaud b, rostaing l, rischmann p, sarramon jp, durand d. high prevalence of erectile dysfunction after renal transplantation. transplantation. 2000;69: 2121-4. 18. diemont wl, vruggink pa, meuleman ej, doesburg wh, lemmens wa, berden jh. sexual dysfunction after renal replacement therapy. am j kidney dis. 2000;35:845-51. 19. peskircioglu l, tekin mi, demirag a, karakayali h, ozkardes h. evaluation of erectile function in renal transplant recipients. transplant proc. 1998;30:747-9. 20. rosen rc, cappelleri jc, smith md, lipsky j, pena bm. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 1999;11:319-26. 21. ali me, abdel-hafez hz, mahran am, et al. erectile dysfunction in chronic renal failure patients undergoing hemodialysis in egypt. int j impot res. 2005;17:180-5. 22. el-bahnasawy ms, el-assmy a, dawood a, et al. effect of the use of internal iliac artery for renal transplantation on penile vascularity and erectile function: a prospective study. j urol. 2004;172:2335-9. 23. taylor rm. impotence and the use of the internal iliac artery in renal transplantation: a survey of surgeons’ attitudes in the united kingdom and ireland. transplantation. 1998;65:745-6. 24. hefty t. complications of renal transplantation: the practicing urologist’s role. aua update series. lesson 8, vol x. linthicum, md: american urological association; 1991. 25. gittes rf, waters wb. sexual impotence: the overlooked complication of a second renal transplant. j urol. 1979;121:719-20. 26. nghiem dd, corry rj, picon-mendez g, lee hm. factors influencing male sexual impotence after renal transplantation. urology. 1983;21:49-52. fall 2012 08.pdf 678 | urological oncology overall survival and functional results of prostate-sparing cystectomy a matched case-control study abbas basiri,1 hamid pakmanesh,1 ali tabibi,1 mohammad hadi radfar,1 farzam tajalli,1 babak ahadi,1 nazanin eslami2 purpose: to compare two matched groups of men with bladder transitional cell carcinoma (tcc) who underwent prostate-sparing cystectomy (psc) or conventional radical cystoprostatectomy (crc). materials and methods: twenty-three men who have undergone psc with the diagnosis of perimental group. the control group composed of 27 men with comparable tumor characteristics and age range, who had non-nerve-sparing radical cystoprostatectomy and orthotopic ileal w pouch reconstruction in the same center. all the procedures were performed by the same surgical group under the supervision of different attending staff. results: mean follow-up period was 39 months in psc and 35 months in crc group. the 5-year overall survival was 47% and 30% in psc and crc groups, respectively. median survival was 48 months in psc and 36 months in crc group, using kaplan-meier survival analysis (p > .05). impotence was observed in 16.6% in psc and in 83.3% in crc group (p 19.8 compared with 5.7 in the crc group (p = .003). only one patient in each group was completely incontinent. urethral anastomosis stricture occurred in 2 patients in crc group. conclusion: patients who underwent psc did not show decreased overall survival compared to crc, which provided better functional results. keywords: urinary bladder neoplasms, transitional cell carcinoma, cystectomy, male, prognosis, adverse effects corresponding author: hamid pakmanesh, md urology and nephrology research center, no.103, boustan 9th st., pasdaran ave., tehran, iran tel: +98 21 2360 2220 fax: +98 21 2256 7282 e-mail: h_pakmanesh@yahoo.com received september 2012 accepted november 2012 1 urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2 kerman medical university, kerman, iran urological oncology 679vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l prostate-sparing cystectomy | basiri et al introduction f ormerly, radical cystoprostatectomy and urethrectomy were proposed for all men with bladder transitional cell carcinoma (tcc) indicated for cystectomy.(1,2) but to achieve better functional results with acceptable tumor control, conventional radical cystoprostatectomy (crc) and orthotopic reconstruction are usually performed for invasive bladder cancer. however, this radical surgery potentially carries important inherent functional consequences that affect quality of life, especially in younger patients. with muscle-invasive bladder tumor; the delay imposes an increased mortality rate.(3) this encourages some surgeons perform prostate-sparing cystectomy (psc), which has better (4-6) in 1990s, schilling and friesen described transprostatic cystectomy to preserve the neurotency results.(4) although there is serious concern about the recurrence of tcc in the prostate,(6-8) some factors have been proposed which can help determine patients at high risk for the prostate involvement with tcc.(9) on the other hand, the incidence of incidental prostate adenocarcinoma has been shown to be low in a group of selected iranian men who underwent crc for the bladder tcc.(10) this study aimed to compare two matched groups of iranian men with bladder tcc who underwent crc or psc, in terms of functional and tumor control results with especial focus on survival. materials and methods indication for radical cystectomy was a history of muscleinvasive, recurrent, or unresectable bladder tcc. all the nation. patients with tcc involvement of the prostatic urethra or bladder neck on the pre-operative cystoscopy or any the study. the low incidence of incidental prostate adenocarcinoma in iran,(10) pre-operative prostate biopsy was not performed in this study. on pre-operative imaging studies, including abdominopelvic spiral computed tomography (ct) scan with intravenous and oral contrast, all the patients had organ-condata of pre-operative renal function and kidney ultrasonic cystectomy was done through a lower midline incision or laparoscopically. prostate adenoma was enucleated in continuity with the bladder specimen while urethral catheter was in place to prevent urine spillage. intra-operative frozen section of distal surgical margin was negative in all the patients. in the intra-operative observations, no lymphadenopathy was detected. an orthotopic ileal w neobladder was reconstructed for all the patients. pathological results of surgical specimens were collected. patients were followed up with abdominopelvic ct scan, chest radiography, liver function tests, and serum level of psa. if there was a higher serum level of alkaline phosphatase or calcium, radionuclide whole body bone scan was performed. none of the patients underwent pre-operative radiotherapy or neoadjuvant chemotherapy, but adjuvant chemotherapy was given to patients with pathological stage all the patients were questioned about their continence and ter the operation. potency status was evaluated before and after the surgical procedure using a simple presented scale 5) questionnaire. patients who used any pad during the day were marked as incontinent. statistical analysis all the data were analyzed by spss software (the statistical package for the social sciences, version 16.0, spss inc, chicago, illinois, usa). data were presented as mean ± standard between two groups was analyzed using chi-square test for categorical variables and independent sample t test for nup value was less than .05. kaplan-meier estimate of survival was used for survival analysis. results a total of 50 patients, 23 in psc group and 27 in crc group, 680 | ference between two groups in terms of age, pre-operative serum level of creatinine, presence of hydronephrosis, or tumor stage and grade on transurethral resection of the prostate (turp) (p > .05; table 1). men in two groups are presented in table 2. the pathologigroup, 2 cases of the adenocarcinoma with gleason score of 6 and 3 were detected. while in the psc group, one patient with adenocarcinoma with gleason score of 5 was detected in the enucleated prostate adenoma. they underwent watchstudy. only one patient in crc group showed prostate stromal involvement with tcc, who was a 65-year-old man with history of a high-grade bladder tumor and pre-operative bilateral hydronephrosis. he was alive at 4-year follow-up with cystectomy specimen. mean follow-up period was 39 months in psc group and 35 months in crc group (p = .65). mean follow-up for patients who were alive in the last follow-up was 53 months (range, 23 to 90 months) and 57 months (range, 17 to 110 months) in psc and crc groups, respectively. mean survival time in the psc and crc groups was 27 months (range, 2 to 74 months) and 22 months (range, 1 to 52 months), respectively. twenty-nine (58%) patients, including 12 (52%) patients in the psc group and 17 (63%) in the crc group, died during follow-up (p = .39). in 25 patients, the death cause was apparent; 22 deaths were caused by tumor or chemotherapy complications and 3 were due to myocardial infarction. the overall 5-year survival was 47% and 30% in psc and crc groups, respectively. median overall survival was estimated to be 48 months in psc and 36 months in crc group, using kaplan-meier survival analysis (p > .05; figure). twodifferent between two groups (55% versus 52%; table 3). the 5-year disease-free survival was estimated to be 35% in psc and 13% in crc group. table 1. pre-operative characteristics of patients in two groups.*§ variable radical cystoprostatectomy prostate-sparing cystectomy p age, y 61 ± 12.0 59 ± 14.0 .59 serum creatinine, mg/dl 1.2 ± 0.4 1 ± 0.3 .25 hydronephrosis, n (%) no 11 (47.8) 11 (64.7) yes 12 (52.5) 6 (35.3) .28 turp stage, n (%) recurrent ta 1 (4.5) 0 (0.0) recurrent t1 4 (18.2) 2 (10.5) t2 16 (72.5) 13 (68.4) unresectable£ 1 (4.5) 4 (21.1) .31 turp grade, n (%) i 4 (20) 1 (7.7) ii 5 (25) 3 (23.1) iii 11 (55) 9 (69.2) .58 *data are presented as mean ± standard deviation or count (column percent). percents were calculated excluding missing data. §turp indicates transurethral resection of the prostate. £tumor was not resectable via turp, thus the real stage could not be evaluated. urological oncology 681vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l the recurrence data were available for 38 patients, including 18 patients in psc and 20 patients in crc group. twentytwo (57.9%) patients developed tumor recurrence at followup (61.1% in psc and 55% in crc group; p > .05). twenty-four patients, including 12 patients in each group who were completely potent and able to have intercourse pretable 2. results of pathological evaluation of cystectomy specimen in two groups.*§ variable radical cystoprostatectomy prostate-sparing cystectomy p tumor stage,£ n (%) t0 0 (0.0) 1 (4.3) t1 6 (22.2) 7 (30.4) .51 t2a 6 (22.2) 5 (21.7) t2b 6 (22.2) 4 (17.4) t3a 2 (7.4) 4 (17.4) t3b 5 (18.5) 2 (8.7) t4 2 (7.4) 0 (0.0) tumor grade, n (%) i 4 (14.8) 1 (5.3) ii 5 (18.5) 3 (15.8) .54 iii 18 (66.7) 15 (78.9) prostate, n (%) normal 18 (78.3) 12 (85.7) pi-tcc 1 (4.3) 0 (0.0) adenocarcinoma 2 (8.7) 1 (7.1) .86 hgpin 2 (8.7) 1 (7.1) *percents were calculated excluding missing data. § pi-tcc indicates prostate involvement with transitional cell carcinoma; and hgpin, high-grade prostate intra-epithelial neoplasia. £tumor stage was based on tnm tumor staging system; sobin, l. h. and i. d. fleming:"tnm classification of malignant tumors, fifth edition (1997)". table 3. two-year survival data divided by final pathological stage. prostate-sparing cystectomy radical cystoprostatectomy stage no. 2-year survival no. 2-year survival t1 7 53% 6 67% t2 9 71% 12 55% t3 6 33% 7 29% all patients* 23 55% 27 52% *including one patient with stage t0 and two with t4. kaplan-meier survival rate plot by surgery type. psc indicates prostate-sparing cystectomy; and crc, conventional radical cystectomy. prostate-sparing cystectomy | basiri et al % 682 | operatively (iief score >20), cooperated for potency status interview. of twelve patients in the crc group, 10 (83.3%) showed severe erectile dysfunction (no erection), but in the psc group, only 2 (16.6%) patients had no erection (p = .002; table 4). regarding the iief-5 questionnaire results, mean score of the psc group was 19.8 compared with 5.7 in the crc group (p = .003). data regarding postoperative continence status were collected in 29 patients (16 in psc and 13 in crc group). as table 4 shows, only one patient in each group was completely incontinent. eight (50%) patients in psc and 7 (53.8%) patients in crc group did not need to do clean intermittent catheterization (cic) to become continent (p > .05). bed wetting was seen more frequently in crc group, but the difcluding patients with any evidence of local or urethral tumor recurrence, only 2 (15.3%) patients in crc group showed stricture at the urethral anastomosis (p > .05). discussion kaplan-meier analysis has not shown lower overall and disease-free survival rates for the patients who underwent psc in comparison with the crc group. overall 5-year survival rate of patients after radical cystectomy reportedly is 50% to 66%.(11-14) in a research by rozet and colleagues, this rate was 67% in 107 patients selected for psc. they reported long-term follow-up period of the largest group of psc patients, and compared the survival results of their cohort with the literature data on the 5-year survival after crc. they concluded that the results were comparable and “prostatesparing cystectomy is an additional option for treating hightable 4. functional results of available patients in two groups. variable radical cystoprostatectomy prostate-sparing cystectomy p potency, n (%) impotent 10/12 (83.3) 2/12 (16.6) .002 potent 2/12 (16.6) 10/12 (83.3) erection, no penetrationa 2/12 (16.6) 3/12 (25.0) penetration, no ejaculationb 0/12 (0) 3/12 (25.0) penetration and ejaculationc 0/12 (0) 4/12 (33.3) continence, n (%) totally incontinent 1/13 (7.6) 1/16 (6.2) ns continent but bed wettingd 4/13 (30.7) 2/16 (12.5) continent with cice 1/13 (7.6) 5/16 (31.2) continent, no cic 7/13 (53.8) 8/16 (50.0) stricturef, n (%) no 11/13 (84.6) 16/16 (100) ns yes 2/13 (15.3) 0/16 (0) a there was erection, but not enough for intercourse. b strong enough erection and ability for penetration, but dry ejaculation. c as b, also complete normal ejaculation. d no pad and no cic in the daytime, but only bed wetting. e these patients were dependent on cic. f patients with any evidence of local or urethral tumor recurrence were excluded. *cic indicates clean intermittent catheterization. urological oncology 683vol. 9 | no. 4 | fall 2012 |u r o lo g y j o u r n a l ly selected patients who want to be offered curative therapy with minimal side effects.”(15) in a recently published study, de vries and associates evaluated the long-term survival of 63 men who underwent psc. with 64% in the crc group. they concluded that this procedure is safe and could be offered to selected patients.(16) in our study, the overall 5-year survival rate was 30% in the crc group and 47% in the psc group. the lower survival of our patients compared with the survival rate in the literature may be due to delayed diagnosis and treatment of the patients better functional recovery in selected patients, the tumor conin long-term follow-up (mean of 54 months) of 108 patients after psc by rozet and coworkers, they found only 6 paof turp specimen, and 3 patients out of 102 during later follow-up. all of them had a gleason score of 6 and were treated effectively by brachytherapy, high-intensity focused ultrasound, or androgen deprivation therapy. the authors concluded that concomitant prostate carcinoma does not have tcc.(15) furthermore, the risk of prostate adenocarcinoma (17) and the amount of this risk should be regarded while considering prostatesparing for the treatment of the bladder tcc. de veries and colleagues showed an incidence of 18% for incidental prostate adenocarcinoma in cystoprostatectomy specimens. they reported two patients with adenocarcinoma out of 63 patients who had undergone psc; one died due to tcc recurrence and the other was alive at 50-month followup.(16) in our study, only one (4.3%) patient in the psc group and 2 (7.4%) patients in the crc group had prostate adegrade of more than 3; all of them selected watchful waiting. one of them died due to the recurrence of bladder tumor and others were alive with no evidence of prostate adenocarcinoma recurrence. furthermore, none of other patients in psc group was suspicious for the prostate cancer during the postoperative follow-up. our data show that in selected patients of iranian population, prostate adenocarcinoma is not a sigit is accepted that psc has better functional results than crc. (5,8,15,18,19) function in patients in psc group while continence results tients in psc group showed lower rate of bed wetting than crc group, while their need to cic for the bladder emptying was a little more. similarly, some authors have indicated that in spite of lower rate of bed wetting, overcontinence may be an imperfection for psc.(7) we think this shortcoming is not nique. finally, urethral anastomosis stricture occurred in 2 patients in crc group without tumor recurrence. this complication did not take place in psc group, which may be due to a wider anastomosis with the neobladder, limitations although the patients in the crc group were matched by are aware that it is a retrospective study and selection bias may be present. furthermore, because some patients did not cooperate tensely in the follow-up, they died without a distinct diagnosis of the site of recurrence or functional status. however, the vast majority of missed follow-up for functional evaluation seems to be related to patients’ death due to the proven fatal nature of the disease and its low 5-year overall survival. finally, it would be better to compare functional results of patients who had undergone psc with a group of nerve-sparing conventional cystectomy patients. conclusion when selected patients are included, patients who underwent psc did not show decreased overall and disease-free survival rates compared to crc. tumor recurrence rate was not associated with the type of surgery. potency results were sigresults were not different. a randomized clinical trial is needed to disclose the truth about the safety of this functional preserving modality. conflict of interest none declared. prostate-sparing cystectomy | basiri et al 684 | references 1. stams uk, gursel eo, veenema rj. prophylactic urethrectomy in male patients with bladder cancer. j urol. 1974;111:177-9. 2. schellhammer pf, whitmore wf, jr. transitional cell carcinoma of the urethra in men having cystectomy for bladder cancer. j urol. 1976;115:56-60. 3. gore jl, lai j, setodji cm, litwin ms, saigal cs. mortality increases when radical cystectomy is delayed more than 12 weeks: results from a surveillance, epidemiology, and end results-medicare analysis. cancer. 2009;115:988-96. 4. schilling a, friesen a. transprostatic selective cystectomy with an ileal bladder. eur urol. 1990;18:253-7. 5. vallancien g, abou el fettouh h, cathelineau x, baumert h, fromont g, guillonneau b. cystectomy with prostate sparing for bladder cancer in 100 patients: 10-year experience. j urol. 2002;168:2413-7. 6. botto h, sebe p, molinie v, herve jm, yonneau l, lebret t. prostatic capsuleand seminal-sparing cystectomy for bladder carcinoma: initial results for selected patients. bju int. 2004;94:1021-5. 7. hautmann re, stein jp. neobladder with prostatic capsule and seminal-sparing cystectomy for bladder cancer: a step in the wrong direction. urol clin north am. 2005;32:177-85. 8. stein jp, hautmann re, penson d, skinner dg. prostatesparing cystectomy: a review of the oncologic and functional outcomes. contraindicated in patients with bladder cancer. urol oncol. 2009;27:466-72. 9. tabibi a, simforoosh n, parvin m, abadpour b, abdi h, khafri s. prediction of prostatic involvement by transitional cell carcinoma of the bladder using pathologic characteristics of the bladder tumor. urol j. 2006;3:145-9. 10. hosseini sy, danesh ak, parvin m, et al. incidental prostatic adenocarcinoma in patients with psa less than 4 ng/ml undergoing radical cystoprostatectomy for bladder cancer in iranian men. int braz j urol. 2007;33:167-73; discussion 73-5. 11. may m, helke c, nitzke t, vogler h, hoschke b. survival rates after radical cystectomy according to tumor stage of bladder carcinoma at first presentation. urol int. 2004;72:10311. 12. hautmann re, gschwend je, de petriconi rc, kron m, volkmer bg. cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. j urol. 2006;176:486-92; discussion 91-2. 13. madersbacher s, hochreiter w, burkhard f, et al. radical cystectomy for bladder cancer today--a homogeneous series without neoadjuvant therapy. j clin oncol. 2003;21:690-6. 14. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001;19:666-75. 15. rozet f, lesur g, cathelineau x, et al. oncological evaluation of prostate sparing cystectomy: the montsouris longterm results. j urol. 2008;179:2170-4; discussion 4-5. 16. de vries rr, nieuwenhuijzen ja, van tinteren h, et al. prostate-sparing cystectomy: long-term oncological results. bju int. 2009;104:1239-43. 17. cook ls, goldoft m, schwartz sm, weiss ns. incidence of adenocarcinoma of the prostate in asian immigrants to the united states and their descendants. j urol. 1999;161:1525. 18. thorstenson a, o'connor r c, ahonen r, et al. clinical outcome following prostatic capsuleand seminal-sparing cystectomy for bladder cancer in 25 men. scand j urol nephrol. 2009;43:127-32. 19. simone g, papalia r, leonardo c, et al. prostatic capsule and seminal vesicle-sparing cystectomy: improved functional results, inferior oncologic outcome. urology. 2008;72:162-6. urological oncology pdf-843.pdf 397 ??? vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l mri in stress urinary incontinence endovaginal mri with an intracavitary coil and dynamic pelvic mri nuri tasali,1 rahmi cubuk,1 orhun sinanoğlu,2 kemal sahin,1 bulent saydam3 purpose: to evaluate both morphology of the urethra and its supporting strucmaterials and methods: cording to the different layers of the urethra, the degree of distortion in the periurethral, paraurethral, and pubourethral ligaments, the vesicourethral angle, the also evaluated according to the number of deliveries and degree of the bladder neck prolapsus. results: the urethra between the two groups (p ourethral ligament distortion (p p the number of deliveries and the degree of the bladder neck prolapsus (p conclusion: dysfunction, such as vesicourethral angle increase and pubourethral ligament diskeywords: urethra, stress urinary incontinence, magnetic resonance imaging, women corresponding author: orhun sinanoglu, md department of urology, maltepe university, feyzullah caddesi, no.39, maltepe, 34843, istanbul, turkey tel: +90 533 658 6922 fax: +90 216 383 0270 e-mail: orhundr@hotmail. com received january 2011 accepted july 2011 1 department of radiology, maltepe university, istanbul, turkey 2 department of urology, maltepe university, istanbul, turkey 3 department of radiology, fatih sultan mehmet teaching hospital, istanbul, turkey female urology 398 | female urology introduction sinvoluntary voiding, which results in social and hygienic problems.(1) obesity, pregnancy, and vaginal delivery can lead to urinary incontinence by weakening the support on the urethra.(2-4) stability and restoring the functions of urethral supporting structures. the treatment options vary from niques, depending on the severity of structural abnormalities. stress urinary incontinence has been linked to unequal urethral walls mobility, urethral instability,(5) and weakness in the pelvic supporting structures.(6,7) the comprehension of the normal disposition of the ligaments and anatomic defects in the suspensory system is essential because these are the surgically treatable factors in patients with (8) the urethra in women remains unclear as this area mists and surgeons. continence mechanism considered the urethra and underlying structures to function as a combined mechanism.(6,7) furthermore, precise imaging of the urethra and its supporting structures is very important for treatment selection.(6) both diagnosis and treatment decision.(11) among imaging modalities, with its soft tissue resolution alization of the pelvic structural alteration. moreover, endoluminal coils provide higher resolution and signal to noise ratio and can assess very small anatomical structures in detail.(6,12-15) several studies have reported that endovaginal structures at rest and during valsalva maneuver using ultrafast sequences.(7,14,16-18) the aim of this study was to assess the convenience identify certain structural and functional abnormalities, such as vesicourethral angle increase and pumaterials and methods study population tinent controls who had never undergone surgery cruited through urology and gynecology clinics. study patients who met the above criteria were selected in a consecutive manner. patients who were not married or did not accept the procedure were excluded. stress urinary incontinence was diagnosed by a ments during cough and valsalva maneuver. the caused by a sudden increase in intra-abdominal pressure during measurement with multi-channel urodynamic testing through an 8f micro-tip dual the control group were sent to department of radiology with suspicion of other gynecological benign diseases, including bartholin cyst, diffuse vaginal the number of vaginal deliveries was documented informed consent was obtained from each partici399vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l mri in stress urinary incontinence | sinanoğlu et al mri technique magnetic resonance imaging was performed following at least four hours of fasting. the subjects were requested not to void at least for two hours by 1.5 tesla magnet (25 mt/m: magnetom vision plus; siemens, erlangen, germany) using connection between the urethra and coil, the coil nal imaging planes using t2-weighted turbo spinthe bladder neck and extended to the external meatus level in planes perpendicular and parallel to the long axis of the urethra. therefore, it was possible to visualize the entire length of the urethra. sagittal and coronal planes with true fast imaging ed both at rest and during valsalva maneuver. examinations were performed in supine position using body coil and water resistant padding. prior to the procedure, the subjects were informed about participants who were unable to produce enough strain, the sessions were repeated several times in order to achieve similar level of strain among subjects. during the sessions with 9-second duration, we obtained 6 slices in each plane. measurements performed the assessments based on predetermined levels. these levels were determined based on the reference points reported by kim and colleagues.(7) the straight and smooth muscle of the mucosa and submucosa layers were separately measured using predetermined levels. the supporting ligaments of the urethra were considered normal if they preserved their continuity throughout their entire length. the bending of the ligaments, the changes in signal intensity, and focal defects were considered as the distortion of the ligament. the vesicourethral angle was assessed using sagthrough the long axis of the urethra and one parallel to the bladder base, and the intersection of these lines determined the vesicourethral angle. we also used the sagittal images to measure the dimension of the retropubic space from the posterior wall of the symphysis pubis to the anterior urethral wall. the thickness of the two branches of the puborecimages. the mean muscle thickness was calculated from the thickness of the branches of the puborectal muscle measured at 4 and 8 o’clock radiuses using axial images. the degree of the bladder neck prolapsus in cases diagnosis of the bladder neck prolapsus was made bis. the pubococcygeal line that determines the nects the lower corner of symphysis pubis and left obtained during rest (figure 1). the degree of prodistance between the pubococcygeal line and inferiorly extending bladder neck (mild to moderate: 1 pendent radiologists (n.t. and k.s.), who were gists had different interpretations of an image, the 400 | statistical analysis group, we used student’s t test to assess the differences in the thickness of each layer of the urethra, vesicourethral angle, dimension of the retropubic space, and thickness of the puborectal muscle. tion in periurethral, paraurethral, and pubourethral between the number of deliveries and degree of the bladder neck prolapsus was determined by fischer’s exact’s test. p results was 49 years (range, 33 to 66 years) and 43.5 years (range, 38 to 53 years), respectively. the mean number of vaginal deliveries was 3.5 in patients table 1 shows the mean thickness of each layer of group. the thickness of three layers of the urethra particularly in the striated muscle layer of patients p table 1; figure 2). more distortion of the pubourethral ligament was trol group (p differences in the distortion of the periurethral and paraurethral ligaments between the two groups (p p = garding the dimension of the retropubic space and thickness of the puborectal muscle (p 3; figure 4). bladder prolapsus was observed in all the subjects female urology figure 1. the bladder neck is visualized on top of the pubocoxygeal line in a patient with stress urinary incontinence at rest. figure 2. thinning of the striated muscle of the urethra in a patient with stress urinary incontinence at t2-weighted image in axial plane, which was obtained by using endovaginal coil. figure 3. normal urethral supporting ligaments. 401vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l in 19 patients and advanced in 6 patients (figure the degree of the bladder prolapsus and number of p table 4). discussion lection.(15) patient management.(19) magnetic resonance imagchanged clinical management in 41.6% of patients bles visualization of the urethra and its supporting during valsalva maneuver using fast sequences. (6,7,14,16,18) sic muscles and supporting ligaments between pa(7,12,17) these studies also reported that in patients with layers could be thin. the endovaginal coil was not only able to visualize the urethra throughout its whole length, but to evaluate the striated, smooth muscle, mucosa, and submucosa as well.(7,12,17) our study, the striated urethral muscles were sigcontrol group. association between the urethral sphincter anatoreported that a smaller striated urogenital sphincter (21) thickness of the urethral smooth muscle, mucosa, and submucosa layers between the two groups. urethra participate in the mechanism of incontinence. position or location of the urethral suporting ligaas detailed understanding of the normal continence mri in stress urinary incontinence | sinanoğlu et al figure 4. asymmetrical thinning of the left puborectal sling in a patient with stress urinary incontinence. figure 5. during valsalva maneuver, the bladder neck can be identified below the puborectal line and the urethra becomes horizontally oriented distal to the pubic bone in a patient with stress urinary incontinence (t2-weighted sagittal image). 402 | underlying incontinence process.(19) our study shows that distortion of pubourethral the urethral supporting ligaments, the pubourethral ligament distortion plays an important role in the tion of the periurethral and paraurethral ligaments between two groups. the vesicourethral angle and dimension of retropubic space are closely related to the urethral (22) the mean dimension of the retropubic space was larger in our might be the expansion of endovaginal coil balloon with air that caused smaller measurements for the dimension of retropubic space. a defect in hammock structure consisting of anterior vaginal wall and pubourethral ligaments was shown in several studies. reports, as the grade of distortion in the pubouremean thickness of the puborectal muscle and numthe control group. the two groups did not differ for the degree of the bladder prolapsus determined by the number of vaginal deliveries and thickness of puborectal muscle are not individual determinants demonstrate that the most determining parameter layers, particularly in the striated muscle layer. one of the limitations of our study is the fact that the assessments were performed in the supine pofemale urology table 1. the thickness of the urethral layers in patients with stress urinary incontinence compared to controls urethral layers thickness (mean ± sd)†, mm patients with stress urinary incontinence (n = 25) control group (n = 8) 95% confidence interval p* striated muscle 1.7 ± 0.2 2.3 + 0.2 0.80 to 0.40 .000 smooth muscle 3.1 ± 0.2 3.3 + 0.2 0.56 to 0.06 .024 mucosa and submucosa 2.5 ± 0.2 2.7 + 0.1 0.31 to 0.05 .009 †sd indicates standard deviation. *p < .05 is significant. table 2. distribution of the distortion in the urethral supporting ligaments; comparison of patients with urinary incontinence and asymptomatic controls. distortion in the supporting ligaments of the urethra, n (%) patients with stress urinary incontinence (n = 25) control group (n = 8) p* periurethral ligaments 14 (56.0) 3 (37.5) > .05 paraurethral ligaments 25 (100) 6 (75.0) > .05 pubourethral ligaments 15 (60.0) 1 (12.5) .024 *p < .05 is significant. 403vol. 9 | no. 1 | winter 2012 |u r o lo g y j o u r n a l sition. as compared to normal anatomical position, the investigations performed in supine position do not allow to assess the dynamic changes in the urethra and its supporting structures resulting from the changes of intra-abdominal pressure. due to gravity and increased intra-abdominal pressure in vertical or standing positions during cept posterior urethrovesical angle were reported to be stable between supine and sitting positions. (24) other investigators showed that assessments in supine position after maximum strain were more reliable.(25) another limitation of our study comes from the use of endovaginal coil technique, which supports the anterior wall of the vagina. the use of this coil technique can displace the vaginal walls laterally and visualize rather small defects in these assess the fascia and muscle structures accurately with high spatial resolution still presents as an advantage. conclusion provides complementary information and allows functions. however, we accept that the utility of cordance with comprehensive studies, which may assess the structural abnormalities directly related conflict of interest none declared. mri in stress urinary incontinence | sinanoğlu et al table 3. comparison of the patients with urinary incontinence and asymptomatic controls regarding the mean values of vesicourethral angle, retropubic space, and puborectal muscle thickness patients with stress urinary incontinence (n = 25) control group (n = 8) 95% confidence interval p* vesicourethral angle (mean ± sd)† 146 ± 5.05 136 ± 3.84 5.26 to 13.23 .000 retropubic space (mean ± sd), mm 4.46 ± 0.79 3.28 ± 0.83 0.43 to 1.909 > .05 puborectal muscle thickness (mean ± sd), mm 3.676 ± 0.63 3.688 ± 0.65 0.53 to 0.51 > .05 †sd indicates standard deviation. *p < .05 is significant. table 4. comparison of the degree of the bladder prolapsus and number of deliveries in patients with stress urinary incontinence. number of deliveries degree of the bladder prolapsus mild to moderate, n (%) advanced, n (%) total p* 1 to 3 11 (78.6) 3 (21.4) 14 (100) > .05≥ 4 8 (72.7) 3 (27.3) 11 (100) total 19 (76.0) 6 (24.0) 25 (100) *p < .05 is significant. 404 | references 1. abrams p, blaivas jg, stanton sl, andersen jt. the standardisation of terminology of lower urinary tract function. the international continence society committee on standardisation of terminology. scand j urol nephrol suppl. 1988;114:5-19. 2. herzog ar, fultz nh. prevalence and incidence of urinary incontinence in community-dwelling populations. j am geriatr soc. 1990;38:273-81. 3. diokno ac, brock bm, brown mb, herzog ar. prevalence of urinary incontinence and other urological symptoms in the noninstitutionalized elderly. j urol. 1986;136:1022-5. 4. herzog ar, diokno ac, fultz nh. urinary incontinence: medical and psychosocial aspects. annu rev gerontol geriatr. 1989;9:74-119. 5. mostwin jl, yang a, sanders r, genadry r. radiography, sonography, and magnetic resonance imaging for stress incontinence. contributions, uses, and limitations. urol clin north am. 1995;22:539-49. 6. stoker j, rociu e, bosch jl, et al. high-resolution endovaginal mr imaging in stress urinary incontinence. eur radiol. 2003;13:2031-7. 7. kim jk, kim yj, choo ms, cho ks. the urethra and its supporting structures in women with stress urinary incontinence: mr imaging using an endovaginal coil. ajr am j roentgenol. 2003;180:1037-44. 8. klutke c, golomb j, barbaric z, raz s. the anatomy of stress incontinence: magnetic resonance imaging of the female bladder neck and urethra. j urol. 1990;143:563-6. 9. vazzoler n, soulie m, escourrou g, et al. pubourethral ligaments in women: anatomical and clinical aspects. surg radiol anat. 2002;24:33-7. 10. fauconnier a, delmas v, lassau jp, boccon-gibod l. ventral tethering of the vagina and its role in the kinetics of urethra and bladder-neck straining. surg radiol anat. 1996;18:81-7. 11. delancey jo, trowbridge er, miller jm, et al. stress urinary incontinence: relative importance of urethral support and urethral closure pressure. j urol. 2008;179:2286-90; discussion 90. 12. tan il, stoker j, zwamborn aw, entius ka, calame jj, lameris js. female pelvic floor: endovaginal mr imaging of normal anatomy. radiology. 1998;206:777-83. 13. goh v, halligan s, kaplan g, healy jc, bartram ci. dynamic mr imaging of the pelvic floor in asymptomatic subjects. ajr am j roentgenol. 2000;174:661-6. female urology 14. macura kj, genadry rr. female urinary incontinence: pathophysiology, methods of evaluation and role of mr imaging. abdom imaging. 2008;33:371-80. 15. tunn r, delancey jo, quint ee. visibility of pelvic organ support system structures in magnetic resonance images without an endovaginal coil. am j obstet gynecol. 2001;184:1156-63. 16. prando a. the urethra and its supporting structures in women with stress urinary incontinence: mr imaging using an endovaginal coil. int braz j urol. 2003;29:174-5. 17. aronson mp, bates sm, jacoby af, chelmow d, sant gr. periurethral and paravaginal anatomy: an endovaginal magnetic resonance imaging study. am j obstet gynecol. 1995;173:1702-8; discussion 8-10. 18. unterweger m, marincek b, gottstein-aalame n, et al. ultrafast mr imaging of the pelvic floor. ajr am j roentgenol. 2001;176:959-63. 19. el-sayed rf, morsy mm, el-mashed sm, abdel-azim ms. anatomy of the urethral supporting ligaments defined by dissection, histology, and mri of female cadavers and mri of healthy nulliparous women. ajr am j roentgenol. 2007;189:1145-57. 20. el sayed r, fielding j, el mashed s, morsy m, el azim m. preoperative and postoperative magnetic resonance imaging of female pelvic floor dysfunction: correlation with clinical findings. j women’s imaging 2005;7:163-80. 21. morgan dm, umek w, guire k, morgan hk, garabrant a, delancey jo. urethral sphincter morphology and function with and without stress incontinence. j urol. 2009;182:2039. 22. macura kj, genadry rr, bluemke da. mr imaging of the female urethra and supporting ligaments in assessment of urinary incontinence: spectrum of abnormalities. radiographics. 2006;26:1135-49. 23. el sayed rf, el mashed s, farag a, morsy mm, abdel azim ms. pelvic floor dysfunction: assessment with combined analysis of static and dynamic mr imaging findings. radiology. 2008;248:518-30. 24. fielding jr. practical mr imaging of female pelvic floor weakness. radiographics. 2002;22:295-304. 25. bertschinger km, hetzer fh, roos je, treiber k, marincek b, hilfiker pr. dynamic mr imaging of the pelvic floor performed with patient sitting in an open-magnet unit versus with patient supine in a closed-magnet unit. radiology. 2002;223:501-8. 1699vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l transumbilical laparoendoscopic singlesite decortication of peripelvic renal cyst: a case report yao he, zhi chen, xiao-long fang, yan-cheng luo, peng-yang dai, miao-long lu, xiang chen corresponding author: xiang chen, md department of urology, xiangya hospital, central south university, no. 87 xiangya road changsha 410008,china. tel: +86 013874808998 e-mail: cxiang1007@126.com received march 2013 accepted february 2014 department of urology, xiangya hospital, central south university, changsha 410008, china. case report keywords: kidney; cyst; laparoscopy; methods; umbilicus; kidney diseases; cystic. introduction recently, laparoendoscopic single-site surgery (less) has been introduced and rep-resents the latest evolution in minimally invasive therapeutic techniques.(1) several studies have demonstrated that it is a safe and effective therapy for many urological diseases.(2-4) however, less decortication for peripelvic cyst is still an infrequently described technique. in this report, we describe a case of peripelvic cyst that was successfully managed by transumbilical less decortication. case report a 31-year-old female presented with recurrent left flank pain. abdominal ultrasonography detected a left renal cyst. a computed tomography (ct) scan, with delayed views, identified a left peripelvic cyst measuring 7.5×7.0×6.8 cm, which was not communicating with the collecting system (figure 1a). retrograde pyelography (rp) also demonstrated the cyst was not in communication with the collecting system. she was managed by transumbilical less decortication. informed consent was obtained before the surgery. surgical technique after induction of general anesthesia, a 5 french (f) open-ended ureteral catheter was placed by cystoscope for instillation of methylene blue. subsequently, the patient was placed in a 45° lateral decubitus position. a triport access system was introduced through a 2 cm semi1700 | circular periumbilical incision (figure 2a). harmonic scalpel was used for incising the line of toldt and the descending colon was mobilized and reflected medially to expose the kidney. after carefully clearing away the perinephric fat to expose the renal pelvis, the renal vessels were isolated and the peripelvic cyst was exposed. the cyst was incised, and fluid was carefully aspirated for cytologic examination. most of the cyst wall was excised and sent for histopathological examination (figure 2b). fulguration was not performed to reduce the chance of fistula formation with the collecting system and major renal vessels. a drain was not placed. the operative time was 122 min and the estimated blood loss was 20 ml. no intraoperative or postoperative complications occurred. the postoperative analgesia was not needed. the patient resumed oral food intake on day 2 and was discharged on day 3, postoperatively. all cytology and cyst wall pathologic findings were negative for malignancy. at 3-month follow-up, a ct scan demonstrated no cyst recurrence (figure 1b). the patient was very satisfied because she remained symptom free and the umbilical scar was barely visible (figure 2c). discussion currently, laparoscopic decortication has substituted for open technique and is admitted as a standard treatment of symptomatic peripelvic cysts. a number of reports have also been published, documenting successful results of laparoscopic decortications using either a transperitoneal or retroperitoneal route.(5-9) nevertheless, with increasing experience in the laparoscopic environment, surgeons are still working on ways to further improve cosmetic outcomes and minimize surgical morbidity. this trend has led to the development of new techniques such as mini-laparoscopic case report figure 1. preoperative and postoperative computed tomography scans; (a) preoperative computed tomography scan demonstrates a left peripelvic renal cyst, (b) postoperative computed tomography scan at the 3-month follow-up demonstrated no cyst recurrence. figure 2. (a) triport access system was introduced through a 2 cm semicircular periumbilical incision, (b) neither additional cysts nor any areas suspicious for carcinoma were detected in the interior of the cavity, (c) the umbilical scar is barely visible at postoperative day 30. 1701vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l less decortication of peripelvic cyst | he et al surgery and less. however despite widespread reports of less for simple renal cyst decortication, less decortication for peripelvic cyst is still an infrequently described technique. compared with less decortication of simple renal cyst, less peripelvic cyst decortication faces more technical challenges due to its complexity and multilobulated feature of cyst and the intimate association to the renal hilar structures. thus, the surgeon should not only be familiar with the procedure of less but also have experience in less urinary tract reconstruction in response to the inadvertent collecting system injury. we had completed over 200 cases of less procedures including over 50 cases of less urinary tract reconstruction such as dismembered pyeloplasty, ureterolithotomy and ureteroureterostomy before beginning less peripelvic cyst decortication. moreover, using a combination of the high-quality ct imaging and retrograde pyelography preoperatively is essential to determine the possible number and configuration of cysts and to rule out collecting system communications. it is also necessary to inject methylene blue through an open-ended retrograde ureteral catheter intraoperatively that can help surgeons distinguish the collecting system from cysts, and make an early diagnosis and timely treatment of unsuspected collecting system injury. conclusion in conclusion, the transumbilical less decortication is technically feasible, and can be considered as potential alternative for conventional laparoscopic surgery. acknowledgments yao he and zhi chen contributed equally to this work. conflict of interest none declared. references 1. kaouk jh, autorino r, kim fj, et al. laparoendoscopic single-site surgery in urology: worldwide multi-institutional analysis of 1076 cases. eur urol. 2011;60:998-1005. 2. cindolo l, gidaro s, tamburro fr, schips l. laparo-endoscopic single-site left transperitoneal adrenalectomy. eur urol. 2010;57:911-4. 3. fadahunsi at, sanford t, linehan wm, pinto pa, bratslavsky g. feasibility and outcomes of partial nephrectomy for resection of at least 20 tumors in a single renal unit. j urol. 2011;185:49-53. 4. dasgupta p. laparoendoscopic single-site pyeloplasty: a comparison with the standard laparoscopic technique. bju int. 2011;107:816. 5. yoder bm, wolf js jr. long-term outcome of laparoscopic decortication of peripheral and peripelvic renal and adrenal cysts. j urol. 2004;171:583-7. 6. doumas k, skrepetis k, lykourinas m. laparoscopic ablation of symptomatic peripelvic renal cysts. j endourol. 2004;18:45-8. 7. rassweiler j, frede t, henkel to, stock c, alken p. nephrectomy: a comparative study between the transperitoneal and retroperitoneal laparoscopic versus the open approach. eur urol. 1998;33:48996. 8. camargo ah, cooperberg mr, ershoff bd, rubenstein jn, meng mv, stoller ml. laparoscopic management of peripelvic renal cysts: university of california, san francisco, experience and review of literature. urology. 2005;65:882-7. 9. micali s, pini g, sighinolfi mc, de stefani s, annino f, bianchi g. laparoscopic simultaneous treatment of peripelvic renal cysts and stones: case series. j endourol. 2009;23:1851-6. andrology stem cell factor receptor immunoexpression in adolescent varicocele arena salvatore1*, impellizzeri pietro1, fazzari carmine2, peri flora maria1, antonelli enrica1, calabrese ugo1, centorrino antonio1, alibrandi angela3, romeo carmelo1 purpose: stem cell factor receptor (c-kit) plays a crucial role in regulating proliferation and survival of germ cells. the aim of this study was to find the correlation between the number of c-kit positive germ cells, testicular asymmetry and histological grade in varicocele affected testis samples of adolescents. materials and methods: twenty testicular biopsy samples of adolescents affected by varicocele and eight normal control testes were included. the relationship between percentage of testicular asymmetry, number of tubular c-kit positive germ cells and severity of spermatogenic failure was assessed. results: the mean (sd; median) histological grade for spermatogenic failure in controls was 1.37(0.52; 1), while in the varicocele group, it was 2.70(1.08; 3) (p = .0052). mean(sd; median) number c-kit positive germ cells in the control group were 20.1(2.52; 20), while in the varicocele group it was 12.35(7.16; 12.5) (p = .0059). spearman test documented a significant positive correlation between percentage of hypotrophy and histological grade of spermatogenic failure (r = 0.5544 , 95% ci: 0.1345 to 0.8055, p = .0112) but a negative correlation with the number of c-kit positive cells (r = 0.5871, 95% ci: 0.8219 to -0.1817, p = .0065). moreover, a significant negative correlation was found between grade of histological changes and number of c-kit positive germ cells (p < .0001). conclusion: a significant correlation between hypotrophy, histological lesions and c-kit positive germ cells exists in varicocele testes. this finding suggests a possible role for c-kit in the pathogenesis of germ cell impairment in varicocele. histological changes and lack of c-kit germ cells were also noted in testes not displaying hypotrophy. we believe that reliable markers should be found as better predictors of testicular function in adolescent with varicocele. keywords: c-kit; histology; male infertility; testicular hypotrophy; varicocele introduction varicocele affects testicular function and is consid-ered a main but corrigible cause of male infertility(1-2). even if medical management promises a potential solution (3-9), surgery is considered the mainstay of varicocele treatment(10). the pathogenesis of testicular damage remains controversial and no mechanism has exclusively explained the exact way in which varicocele impairs spermatogenesis. multifactorial pathogenesis of testicular damage includes hypoxia by small vessel occlusion and venous stasis and(11), enhancement of scrotal and testicular temperature(12), retrograde blood flow of renal and adrenal metabolites in the spermatic vein(13), reduction of gonadotrophins and androgens(14), testicular aquaporin 9 down-regulation(15), and oxidative stress (16). it has been reported that the expression of c-kit receptor plays a pivotal role in the survival and proliferation of type a spermatogonia(17), mature germ cells, and regulation of gametogenesis(18-19). moreover, its expression in testicular tubular cells has also been 1unit of pediatric surgery, department of human pathology of adult and childhood “gaetano barresi”, university of messina, messina, italy. 2department of human pathology, ospedale umberto i, siracusa, italy. 3unit of statistical and mathematical sciences, department of economics, university of messina, messina, italy. *correspondence: unit of pediatric surgery, department of human pathology of adult and childhood “gaetano barresi”, university of messina, messina, italy, tel: +390902213014. email: salarena@unime.it. received may 2019 & accepted february 2020 reported to be inversely related to germ cell apoptosis and hypoplasia(20-22). of note, alteration of transcription levels or deregulated actions of the c-kit signaling system have been associated with reproductive disorders and male infertility(21-23). in this regard, w (dominant white spotting) and sl (steel) loci mutations in mice which encode the c-kit receptor, cause sterility, as they are necessary for the migration and proliferation of primordial germ cells(24). to the best of our knowledge, the immunoexpression of c-kit in adolescent human testicular samples affected by varicocele has not yet been investigated. the aim of the present study was to immunolocalize c-kit and to correlate it with the number of c-kit positive germ cells per tubule. testicular volumetric asymmetry and grade of histological changes were also assessed. materials and methods ethical approval for this study was received from the local ethics committee (ethics code: 90/19). we retrospectively evaluated testicular incisional biopsies of urology journal/vol 17 no. 4/ july-august 2020/ pp. 391-396. [doi: 10.22037/uj.v0i0.5351 ] 20 post-pubertal adolescents (mean age (sd):14.3 (1.4) years old, range 13–18) with grade ii or iii idiopathic left varicocele which were obtained during inguinal varicocelectomy before the ligation of spermatic veins. post-mortem tissue samples from eight age-matched subjects with normal lesion-free adolescent testes were also processed by employing archival blocks. diagnosis of varicocele was made after performing physical examination and was confirmed by echo color doppler ultrasonography. the percentage of volume difference between the right (unaffected) and left testis was calculated according to medical records and decreased volume of the left testis compared with the right was considered as testicular hypotrophy. histological grading histological spermatogenesis was graded according to the johnsen score. as previously described, samples were assigned to the following groups: (26) • normal spermatogenesis: a majority (>50%) of the spermatogenic tubules have a johnsen’s score of 10 (normal) or 9 (disorganized architecture, but with ≥ 10 sperm cells). • spermatogenic impairment: <50% of the spermatogenic tubules exhibit a johnsen’s score of 10 or 9. to investigate the severity of the spermatogenic impairment, this group was further divided into the following histological subgroups: (i) moderate hypospermatogenesis: < 50% of the seminiferous tubules have a johnsen’s score of 9 or 10 but >10% of the seminiferous tubules have a johnsen’s score of 8 (<10 sperm cells); (ii) severe hypospermatogenesis with few sperm cells: no seminiferous tubules have a johnsen’s score of 9 or 10, and ≤ 10% of the seminiferous tubules have a johnsen’s score of 8 (<10 sperm cells). (iii) severe hypospermatogenesis without sperm cells: no mature sperm cells found but at least one seminiferous tubule has a johnsen’s score between 7 and 3 (presence of immature germ cells). (iv) sertoli cell-only syndrome: the seminiferous tubules have a johnsen’s score ≤ to 2 (no germ cells). immunohistochemical evaluation immunostaining was carried out using a 1:50 dilution of the rabbit polyclonal anti-human c-kit (cd117) antibody (dakocytomation a/s,glostrup, denmark) after microwave treatment. the streptavidin-biotin method (lsab, dako), with diaminobenzidine development (vector vip substrate, vector lab, burlingame, ca), and methylgreen or toluidine blue nuclear counter-staining was performed. positive controls were carried out using specimens from lung small cell carcinoma for c-kit labelling. negative controls were obtained by omitting incubation with the primary antibody. statistical analysis in our study, we focused on the primary variable which was the immunoexpression of c-kit in human testicular samples. secondary variables were the histology of the testis, the grade of histological spermatogenesis and the volume of testis. for a quantitative analysis, the percentage of intratubular positive cells in each tubule was counted in five tubules of each specimen. as the number of observations in each group was not enough to assess the normality of the distributions, the results of each group were compared by the non-parametric mann–whitney u test. the relationship between the quantitative parameters (percentage of left testicular hypotrophy, number of c-kit positive germ cells per tubule) and the histological grade of spermatogenesis according to modified johnsen’s score(26) was studied by the non-parametric spearman’s rank correlation test between the parametric values and values 1 (normal spermatogenesis), 2 (moderate hypospermatogenesis), 3 (severe hypospermatogenesis with few sperm cells), 4 (severe hyvariables left control testes left testes with varicocele p value mean ± sd median q1-q3 mean ± sd median q1-q3 histological grade 1.37 ± 0.52 1 1-2 2.70 ± 1.08 3 2-4 .0052 c-kit+ germ cells 20.1 ± 2.52 20 17.5-22 12.35 ± 7.16 12.5 6.5-18 .0059 table 1. mean (sd) of histological grade and number of c-kit positive cells in each group and the relative p-value. figure 1. a-c: light microscopy: a) normal control testis (johnsen's score 9-10, h&h, original magnification 200x); b) varicocele affected testis showing detachment and sloughing of basal germ cells and a depletion of sperm cells (jonhsen's score 5, h&h, original magnification 200x); c) severe grade of histological lesion of a varicocele affected testis, with intra and extratubular edema, venular ectasia, peritubular ectasia and marked depletion of germ cells (johnsen's score 3, h&h, original magnification 200x). c-kit expression in adolescent varicocelesalvatore et al. andrology 392 vol 17 no 04 july-august 2020 393 pospermatogenesis without sperm cells) and 5 (sertoli cell only syndrome) regarding the histologic subgroups (26). p < .05 was considered as statistically significant. results changes in tubular and extra-tubular compartments were seen in the studied varicocele testes, displaying more or less disarranged tubular compartments. sloughing and detachment of basal germ cells occurred with a varying degree of germ and sertoli cell impairment, up to spermiogenesis failure. unlike normal testes (figure 1a), varicocele testes showed dilated microvessels, more or less expanded extra-tubule fluid and extracellular matrix, and many extracellular vesicles inside the seminiferous tubules. leydig cell clusters were constantly observed. a varying degree of interstitial edema prevailed, with notable peritubular and extratubular fibrosis (figure 1b & c). mean (sd) histological grade of spermatogenesis in the control group was 1.37 (0.52), while in the varicocele group, this figure was 2.70 (1.08), indicating a statistically significant difference (p = .0052). specifically, in the control group, 5 testes had value 1 and 3 testes demonstrated value 2. on the other hand, in the varicocele group, 3 testes had value 1, 6 had value 2, 5 demonstrated value 3, and 6 samples were value 4. mean (sd) of c-kit positive germ cells in the control group was 20.1 (2.52) and 12.35 (7.16) in the varicocele group (p = .0059) (figure 2ac) (table 1). the mean percentage (sd) of testicular volume discrepancy between right (unaffected) and figure 2. a-c: c-kit immunohistochimestry: a) control testis: about 20% of c-kit positive germ cells are shown in a control testis (original magnification 200x); b) varicocele testis with moderate hypospermatogenesis: about 10% of c-kit positive cells are present in sloughed germ cells (original magnification 200x); c) varicocele testis with severe hypospermatogenesis without sperm cells: no positive cells are present (original magnification 200x) figure 3. distribution of percentage of left testicular asymmetry and histological grade of spermatogenesis in varicocele group figure 4. distribution of percentage of left testicular asymmetry and number of c-kit positive germ cells in the varicocele group. c-kit expression in adolescent varicocelesalvatore et al. left (varicocele affected) testes was %14.1 (%22.5), median %12.5, q1 = 0, and q3 = 29.7. spearman test documented a significant positive correlation between percentage of testicular volumetric discrepancy and histological grade of spermatogenesis (r = .5544, 95% confidence interval (ci): 0.1345 to 0.8055, p = .0112) (figure 3) but a negative correlation with number of c-kit positive cells (r = 0.5871, 95% ci: 0.8219 to -0.1817, p = .0065) (figure 4). moreover, a significant negative correlation was found between histological grade of spermatogenesis and number of c-kit positive germ cells (p <.0001, r = 0.7621, 95% ci: 0.9035 to -0.4714) (figure 5). discussion although surgical correction of varicocele in adolescents before onset of infertility may be advantageous, it has been reported that fertility problems will arise later in about 20% of adolescents with varicocele(26). as sperm analysis is not obtained worldwide from pediatric patients, both for legal and ethical reasons and because patients' hormonal profiles are not fully developed, establishing the potential existence of prognostic markers that would make it possible to decide for surgery and to determine, when necessary, the appropriate time of surgery is still a controversial issue. while waiting for a reliable marker to be identified for early detection of testicular impairment in adolescents affected by varicocele, current international guidelines recommended treatment of clinical varicocele in adolescents only in selected cases such as objective evidence of reduced ipsilateral testicular size(9). however, recently, it has been reported that 100% of adolescent patients varicocele affected with a testicular volumetric discrepancy > 20% calculated by ultrasonography fail to fulfill the world health organisation adult criteria for normal spermatogenesis in comparison with 50% of those with symmetrical testis(27). not only is it suggested that a positive correlation between testicular hypotrophy and spermatogenic impairment exists but also that a symmetrical testis affected by varicocele does not always reflect normal semen parameters(28). in our study, we found that there is a significant positive correlation between the percentage of testicular volumetric discrepancy and the histological grade of spermatogenesis and that testicular symmetry does not exclude the probability of an even severe testicular impairment, triggering a potential subsequent infertility. this data suggests that testicular volume should not be considered as an early, reliable marker of testicular impairment in adolescent varicocele. moreover, in this study, a lack of c-kit positive germ cells was found in varicocele affected testes, with a significant positive correlation with histological changes. c-kit is closely associated with developing germ cells contributing to germ-cell homoeostasis(29). a diminished expression of c-kit has been found in the testis of infertile men(30), particularly in sertoli-cell-only syndrome(31, 32). these observations highlight the importance of c-kit signaling for germ-cell survival and successful spermatogenesis, implying crucial participation of c-kit in the onset and maintenance of spermatogenesis(29,33,34). a reduced expression of c-kit in the tubular compartment of damaged varicocele-affected testes substantiates the role of this proto-oncogene in the pathogenesis of infertility. moreover, unexpected data which emerged from our study was that there is a significant difference in histological grade of spermatogenesis between the subgroup of varicocele affected testes with a hypotrophy ≤ 10% and control testes. in this regard, 9 out of 20 varicocele-affected testes showed a volumetric testicular discrepancy ≤ 10% and in this subgroup, the histological grade of spermatogenesis was 2.33 ± 1.00 which was significantly higher compared to the control group (p = .0495). furthermore, a lower but not significant reduction of c-kit cells was recorded in varicocele group compared with control group (14.89 ± 6.918 versus 20.13 ± 2.532, p = .1193). it suggests that testes affected by varicocele during adolescence can display a significant impairment of the tubular testicular function irrespective of testicular volume, and that left testicular volumetric loss is strictly correlated with histological changes, which based on our experience, is the rule. even if current international guidelines, which provide a framework of standardized care, restrict the surgical management of idiopathic monolateral asymptomatic varicocele to conditions such as the presence of ipsilateral testicular hypotrophy, at times when sperm analysis is not available, our study suggests that a reliable and more sensitive indicator of testicular damage should be identified to avoid progressive impairment of future fertility in adolescents with varicocele. on this basis, we believe that the effort of both basic and clinical research should be focused on the identification of a reliable predictor of future infertility of adolescent affected by varicocele even when volumetric testicular discrepancy is not present. on the other hand, until a highly sensitive, specific and non-invasive indicator is found, it is at least questionable to correct all varicoceles in adolescents, since only few adolescents with varicocele will show infertility impairment in adulthood. the main limitations of this study were its retrospective nature, small sample size and the unavailability of access to testicular volume in the control group figure 5. distribution of percentage of histological grade of spermatogenesis and number of c-kit positive germ cells in the varicocele group. c-kit expression in adolescent varicocelesalvatore et al. andrology 394 vol 17 no 04 july-august 2020 395 conclusions our study showed a significant correlation between the percentage of left testicular asymmetry, histological grade of spermatogenesis and c-kit positive germ cells in varicocele affected testes. it suggests a role of c-kit in the pathogenesis of germ cell impairment in testes of adolescents affected by varicocele. however, histological changes and a lack of c-kit germ cells have also been noted in testes not displaying a significant left hypotrophy. this suggests that testicular hypotrophy is a specific but not sensitive-enough indicator of testicular damage. we believe that other markers should be investigated as better and more reliable predictors of testicular function in adolescents with varicocele. acknowledgement the authors would like to thank miss piscilla haass for the linguistic revision. conflict of interest none declared by the authors. references 1. haddad ng, houk cp, lee pa. varicocele: a dilemma in adolescent males. pediatr endocrinol rev 2014; 11:274-83 2. pasqualotto ff, lucon am, de góes pm et al. testicular growth, sperm concentration, percent motility, and pregnancy outcome after varicocelectomy based on testicular histology. fertil steril 2005; 83:362-6 3. oliva a, dotta a, multigner l. pentoxifylline and antioxidants improve sperm quality in male patients with varicocele. fertil steril 2009; 91:1536–9 4. practice committee of the american society for reproductive medicine; society for male reproduction and urology. report on varicocele and infertility: a committee opinion. fertil steril 2014; 102:1556–60 5. minutoli l, arena s, antonuccio p et al. role of inhibitors of apoptosis proteins in testicular function and male fertility: effects of polydeoxyribonucleotide administration in experimental varicocele. biomed res int 2015; 2015:248976 6. arena s, minutoli l, arena f et al. polydeoxyribonucleotide administration improves the intra-testicular vascularization in rat experimental varicocele. fertil steril 2012; 97: 165-8 7. minutoli l, antonuccio p, squadrito f et al. effects of polydeoxyribonucleotide on the histological damage and the altered spermatogenesis induced by testicular ischaemia and reperfusion in rats. int j androl 2012; 35:133-44 8. minutoli l, arena s, bonvissuto g et al. activation of adenosine a2a receptors by polydeoxyribonucleotide increases vascular endothelial growth factor and protects against testicular damage induced by experimental c-kit expression in adolescent varicocelesalvatore et al. varicocele in rats. fertil steril 2011; 95:15103 9. roque m, esteves sc. a systematic review of clinical practice guidelines and best practice statements for the diagnosis and management of varicocele in children and adolescents. asian j androl 2016; 18:262-8 10. borruto fa, impellizzeri p, antonuccio p et al. laparoscopic vs open varicocelectomy in children and adolescents: review of the recent literature and meta-analysis. j pediatr surg. 2010 ;45(12):2464-9 11. chakraborty j, hikim ap, jhunjhunwala js stagnation of blood in the microcirculatory vessels in the testes of men with varicocele. j androl 1985; 6:117-26 12. goldstein m, eid jf. elevation of intratesticular and scrotal skin surface temperature in men with varicocele. j urol 1989; 142:743-5 13. hudson rw . the endocrinology of varicoceles. fertil steril 1988; 49:199-208 14. swerdloff rs, walsh pc. pituitary and gonadal hormones in patients with varicocele. fertil steril 1975: 26:1006-12 15. arena s, arena f, maisano d et al. aquaporin-9 immunohistochemistry in varicocele testes as a consequence of hypoxia in the sperm production site. andrologia 2011; 43:34-7 16. romeo c, santoro g free radicals in adolescent varicocele testis. oxid med cell longev 2014; 2014:912878 17. vigodner m, lewin lm, shochat l et. spermatogenesis in the golden hamster: the role of ckit. mol reprod dev 2001; 60:562–8 18. feng hl, sandlow ji, sparks ae et al. decreased expression of the c-kit receptor is associated with increased apoptosis in subfertile human testes. fertil steril 1999; 71:85–89 19. jin g, liu j, qin q, gao s, zhang f, ma y, ding c, dong l, yin h, wang y. increased level of c-kit in semen of infertile patients with varicocele. urol j. 2017 mar 16;14(2): 3023-3027 20. tsuchida j, dohmae k, kitamura y, nishimune y. the role of the c-kit receptor in the regenerative differentiation of rat leydig cells. int j androl 2003; 26:121–5 21. sandlow ji, feng hl, cohen mb et al. expression of c-kit and its ligand, stem cell factor, in normal and subfertile human testicular tissue. j androl 1996; 17:403–8 22. mauduit c, hamamah s, benahmed m stem cell factor/ c-kit system in spermatogenesis. hum reprod update 1999; 5:535–545 23. figueira mi, cardoso hj, correia s, maia cj, socorro s. hormonal regulation of c-kit receptor and its ligand: implications for human infertility? prog histochem cytochem. 2014 ;49(1-3):1-19) 24. sette c, dolci s, geremia r et al. the role of stem cell factor and of alternative c-kit gene products in the establishment, maintenance and function of germ cells. int j dev biol 2000; 44:599-608. 25. plotton i, sanchez p, durand p et al. decrease of both stem cell factor and clusterin mrnalevels in testicular biopsies of azoospermic patients with constitutive or idiopathic but not acquired spermatogenic failure. hum reprod 2006; 21:2340-5. 26. world health organization. the influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. fertil steril 1992; 57:1289–93 27. keene dj, sajad y, rakoczy g et al. testicular volume and semen parameters in patients aged 12 to 17 years with idiopathic varicocele. j pediatr surg 2012; 47:383-5 28. romeo c, arrigo t, impellizzeri p et al. altered serum inhibin b levels in adolescents with varicocele. j pediatr surg 2007; 42:3904. 29. cardoso hj, figueira mi, correia s et al. the scf/c-kit system in the male: survival strategies in fertility and cancer. mol reprod dev 2014; 81:1064-79 30. feng hl, sandlow ji, sparks ae et al. decreased expression of the c-kit receptor is associated with increased apoptosis in subfertile human testes. fertil steril 1999; 71:8589 31. malcher a, rozwadowska n, stokowy t et al. the gene expression analysis of paracrine/autocrine factors in patients with spermatogenetic failure compared with normal spermatogenesis. am j reprod immunol 2013; 70:522-8 32. bialas m, borczynska a, rozwadowska n et al. scf and c-kit expression profiles in male individuals with normal and impaired spermatogenesis. andrologia 2010; 42:83-91 33. guerif f, cadoret v, rahal-perola v et al. apoptosis, onset and maintenance of spermatogenesis: evidence for the involvement of kit in kit-haplodeficient mice. biol reprod 2002; 67:7079. 34. raucci f, di fiore mm. the c-kit receptor protein in the testis of green frog rana esculenta: seasonal changes in relationship to testosterone titres and spermatogonial proliferation. reproduction 2007; 133:5160. c-kit expression in adolescent varicocelesalvatore et al. andrology 396 915.pdf 915vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l hair-thread tourniquet syndrome in an adult penis case report and review of literature sataa sallami, sami ben rhouma, karim cherif, yassine noura keywords: penis, hair, tourniquets, complications, reconstructive surgical procedures introduction hair-thread tourniquet syndrome (htts) is an unusual entity occurring mainly in young age. it is due to a hair-strangulation of an appendage, such as the penis, caus-ing obstruction to circulation.(1) we report a new case in an adult patient. case report a 37-year-old man presented to the urology outpatient’s clinic with a 10-year history of postcoital pain. he had no history of trauma, foreign body, or allergy. he has been circumcised 32 years before. clinical examination revealed a constrictive ring scar at the distal penis (figure 1). there was neither any change in the skin color or texture nor in sensation distal to the scar. he had minimal granulation tissue on the ventral aspect of the scar (figure 2). there was a palpable dense trolytes, and serum creatinine levels were normal. findings on urinalysis were negative. he reported that in his childhood and during 3 years his mother used to put a hair around the distal part of his penis to increase his future sexual function. this hair had caused infection; thus, it was removed long time ago. corresponding author: sataa sallami, md department of urology, la rabta hospital-university, tunis, tunisia tel: + 216 2338 7359 fax: + 216 7179 6602 e-mail: sataa_sallami@yahoo.fr received april 2011 accepted august 2011 department of urology, la rabta hospital-university, tunis, tunisia case report 916 | keywords: penis, hair, tourniquets, complications, reconstructive surgical procedures introduction hair-thread tourniquet syndrome (htts) is an unu-sual entity occurring mainly in young age. it is due to a hair-strangulation of an appendage, such as the penis, causes obstruction to circulation.(1) we report a new case in an adult patient. case report a 37-year-old man presented to the urology outpatient’s clinic with a 10-year history of post-coital pain. he had no history of trauma, foreign body, or allergy. he has been circumcised 32 years before. clinical examination revealed a constrictive ring scar at the distal penis (figure 1). there was neither any change in the skin color or texture nor in sensation distal to the scar. he had minimal granulation tissue on the ventral aspect of the scar below the scar. the bladder did not distend. his blood urea nitrogen, electrolytes, and serum creatinine levels were normal. findings on urinalysis were negative. he reported that in his childhood and during 3 years his mother used to put a hair around the distal part of his penis to increase his future sexual function. this hair had caused infection, thus it was removed long time ago. at surgery, under general anesthesia, the penile skin was discircumferentially excised. fibrous tissue was excised and removed (figure 3), and the cutaneous incision was repaired (figures 4 and 5). pre-operatively, the urethra was intact at inspection. the patient was discharged from the hospital on months. he has been voiding well with no sexual dysfunction (figure 6). discussion hair coil strangulation of the penis, also known as the penile tourniquet syndrome, is a rare event.(1) it is a serious complication, usually contested in north africa.(2) it is considered as a circumferential constriction of an appendage (digit or case report figures 1 and 2. the ring scar (circumferential fibrosis) on the penis (coronal sulcus) (arrow) and the exuberant granulation on the ventral aspect. figure 3. specimen: ring-shaped excised skin. 917vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l hair-thread tourniquet syndrome in adults | sallami et al genitalia) by human hairs or occasionally a piece of thread or (3) hair remains the most common causative agent. its physical characteristics make it an ideal tourniquet. it is thin, elastic, and expansible when wet, but constricts as it dries off without losing its strength.(4) according to mat saad and colleagues who reviewed a total of 210 reported htts, penile involvement occurred in nile tourniquet was more common in patients around 2 years old.(4) the oldest reported subject was 12 years.(2) hair-thread tourniquet syndrome in young age is presumed to be accidental.(5-7) however, barton and colleagues reported a case of criminal abuse.(3) in the present case, the reason why this patient had the hair around his penis was not immediately apparent. this backs-up to his childhood, based on popular believes to increase sexual capability. the penile strangulation etiologies have been divided by haddad into accidental, incidental, intentional, and undetermined causes. the circumcision has been considered to be a major risk factor of strangulation; the hair or other agents seem to constrict more easily a circumcised penis than one with a normal prepuce.(8) compression of the penis will cause blood and lymon the force and duration of the compression.(9) are often delayed. swelling, erythema, circumferential constriction, and distal oedema resume the early clinical presen-figures 4 and 5. operative and immediate postoperative aspect. figure 6. postoperative aspect after 2 months. 918 | case report 4. mat saad az, purcell em, mccann jj. hair-thread tourniquet syndrome in an infant with bony erosion: a case report, literature review, and meta-analysis. ann plast surg. 2006;57:447-52. 5. miller rr, baker we, brandeis gh. hair-thread tourniquet syndrome in a cognitively impaired nursing home resident. adv skin wound care. 2004;17:351-2. 6. vazquez rueda f, nunez nunez r, gomez meleno p, blesa sanchez e. [the hair-thread tourniquet syndrome of the toes and penis]. an esp pediatr. 1996;44:17-20. 7. thomas aj, jr., timmons jw, perlmutter ad. progressive penile amputation. tourniquet injury secondary to hair. urology. 1977;9:42-4. 8. haddad fs. penile strangulation by human hair. report of three cases and review of the literature. urol int. 1982;37:375-88. 9. de silva-gutiérrez a, osorio-campos j, arcos-marcín m, morales-díaz j, martínez-méndez m. glans autoamputation secondary to penile strangulation causing ischemic necrosis. rev mex urol. 2008;68:341-3. 10. singh b, kim h, wax sh. strangulation of glans penis by hair. urology. 1978;11:170-2. 11. jezior jr, brady jd, schlossberg sm. management of penile amputation injuries. world j surg. 2001;25:1602-9. 12. nazir z, rasheed k, moazam f. penile constrictive band injury. j pak med assoc. 1993;43:135-7. 13. harouchi a, el-andaloussi me, benhayoun n. [les strangulations du gland par cheveu]. inf magh medical. 1980;2:1926. 14. okeke li. thread embedded into penile tissue over time as an unusual hair thread tourniquet injury to the penis: a case report. j med case rep. 2008;2:230. tation.(6) early recognition and removal are usually followed by complete recovery. if the tourniquet is not removed early, there may be progression to skin infection and ulceration. therefore, it is of utmost importance for the physician to act quickly in order to prevent irreversible damage and necrosis of the penis.(9) when diagnosed very late, the dorsal neurovascular bundle may be transected, leading to the loss of sensation over the distal part of the penis with a high risk of partial or total amputation of the penis distal to the tourniquet.(10-12) four grades of injury were described by harouchi and associates,(13) the loss of the glans (grade iv). an unexplained pain and swelling of the penis should suspect this rare entity.(1) in our patient, there were no ischemic skin changes, no loss of sensation over the glans penis, and tourniquet was not too tightly applied. the ischemia might be partial and chronic, thus causing minimal tissue damage.(14) limited to the skin and did not reach the urethra. hair-thread tourniquet syndrome of the penis in adult is a very rare and poorly recognized condition that needs to be known. early diagnosis and rapid and adequate treatment can prevent from serious complications. non-accidental causes should be considered carefully in these subjects. furthermore, patient's history should be taken very carefully with meticulous enquiry on popular believes and practices in the society he originates from. conflict of interest none declared. references 1. silver ri, docimo sg. hair coil strangulation of the penis. urology. 1997;49:773. 2. mhiri mn, midassi h, mezghanni m, smida ml. [strangulation of glans penis by hair or "penis tourniquet syndrome"]. pediatrie. 1987;42:351-3. 3. barton dj, sloan gm, nichter ls, reinisch jf. hair-thread tourniquet syndrome. pediatrics. 1988;82:925-8. urological oncology 10 urology journal vol 4 no 1 winter 2007 histological subtype of the kidney tumor and its grade and stage—tabibi et al urology journal vol 4 no 1 winter 2007 11 correlation between size of renal cell carcinoma and its grade, stage, and histological subtype ali tabibi,1 mahmoud parvin,2 hamidreza abdi,1 reza bashtar,1 nasim zamani,3 behrang abadpour1 introduction: the aim of this study was to determine the correlation between histological subtype, size, grade, and stage of the kidney tumors and to investigate whether a correlation exists between the size of the kidney tumor and its behavior. materials and methods: between 1996 and 2004, we had 212 patients with radical or partial nephrectomy due to a kidney tumor at shaheed labbafinejad medical center. their pathologic blocks were re-evaluated with consideration of their tumor size and pathologic features. results: of 212 pathologic blocks, 17 (8%) were benign and 195 (92%) were malignant masses including 179 renal cell carcinoma (rcc) tumors. malignant tumors were slightly greater compared with the benign ones (p = .10). there was no significant relation between the size of tumor and the histological subtype. significant relations between the size of the kidney tumor and the nuclear grade (p = .007), clinical symptoms (p = .02), and extracapsular extension (p < .001) were observed. in smaller rcc tumors (< 4 cm), extracapsular extension (stages t3 and t4) was rare (1 in 29). however, smaller rcc tumors were not significantly different from those larger than 4 cm regarding the nuclear grade, symptoms, and histological subtypes. conclusions: tumor size is not an independent predictor for the histological subtype of the tumors; however, larger malignant tumors may have higher grades, higher stages, and clinical symptoms. urol j (tehran). 2007;4:10-3. www.uj.unrc.ir keywords: kidney neoplasms, tumor size, pathologic grade, stage, renal cell carcinoma 1department of urology, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran 2department of pathology, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran 3urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: hamidreza abdi, md department of urology, shaheed labbafinejad medical center, pasdaran, tehran, iran tel: +98 21 258 8016 e-mail: hamidrezaabdi@hotmail.com received march 2006 accepted september 2006 introduction with the advent of the new imaging technologies, more cases of kidney neoplams are diagnosed at earlier stages.(1-3) since biopsy is not routinely performed for the diagnosis and evaluation of the kidney tumors, size of the tumor and radiographic features can be important in surgeon’s decision making.(4) renal cell carcinoma (rcc) tumors tend to be spherical and their radiologic and pathologic measurement is easy.(5) although the association between pathologic tumor size and the outcome of the rcc is well understood, evidence about the relationship between the pathologic tumor size and other features is lacking. reviewing the literature, there is only one paper that studies the relationship between the size of the kidney tumor and histological features in a large number of patients.(4) therefore, we designed a study to investigate the relationship between the size of the kidney tumor and its histological subtype and pathologic stage and grade in our hospital. urological oncology 10 urology journal vol 4 no 1 winter 2007 histological subtype of the kidney tumor and its grade and stage—tabibi et al urology journal vol 4 no 1 winter 2007 11 materials and methods between 1996 and 2004, a total of 212 patients with clinical diagnosis of kidney neoplasm underwent radical or partial nephrectomy at our center. physical examination, laboratory examination, ultrasonography, and abdominal ct scan were performed for all cases. the patients were also evaluated for flank pain, hematuria, and palpable mass. partial nephrectomy was performed for tumors smaller than 4 cm and those in the solitary kidneys. all pathologic blocks were reviewed by a single expert pathologist. histological diagnosis was made as rcc according to the classification of the union internationale contre le cancer and american joint committee on cancer workshop.(6) nuclear grade was assessed using fuhrman table.(7) tumor stage was assessed using the tnm classification of rcc, version 1997.(8) sizes of the tumors were categorized into less than 4 cm, between 4 cm and 7 cm, and greater than 7 cm. the relationship between the size of the tumor and the dichotomous or categorical variables was analyzed by the t test and kruskalwallis test. the chi-square test was used to evaluate categorical variables. a p value less than .05 was considered significant. results there were 138 men (65.1%) and 74 women (34.9%) who underwent nephrectomy. the mean age of the patients was 55.3 ± 13.9 years (range, 5 to 82 years). there were 195 patients (92%) with a malignant tumor and 17 (8%) with a benign one (table 1). the mean ages of the patients with benign tumors and malignant tumors were 47.0 ± 18.6 years and 55.9 ± 13.2 years, respectively (p = .01). size of the tumors varied from 1 cm to 19 cm and benign tumors were not significantly smaller than the malignant ones (p = .10; table 1). according to the available hospital records of 210 patients, the tumor had been incidentally discovered in 53 cases (25.2%), and it had been manifested by flank pain, hematuria, and mass feeling in 157 (74.8%). the presence of symptoms at presentation did not have a relation with the type of tumor (benign versus malignant; p = .55). one hundred and eighteen patients with rcc (65.9%) were men and 61 (34.1%) were women. their mean age was 56.5 ± 12.3 years. a total of 58.6% of the rcc tumors were right-sided. the mean size of the rcc tumors was 6.98 ± 3.09 cm. the rcc tumor sizes were greater in the symptomatic patients (p = .02; table 2), and the grade of tumor increased with the increment in tumor size (p = .007; table 3). but, grade was not higher in symptomatic patients (p = .19). the most frequent rcc tumor types were clear cell in 97 (54.2%) and papillary cell in 49 (27.4%) patients. the mean size of the papillary tumors did not significantly differ from clear cell tumors (6.95 ± 3.14 cm versus 7.00 ± 3.02 cm; p = .67). of the clear cell tumors, 16.5%, 43.3%, and 40.2% and of the papillary tumors, 14.3%, 51.0%, and 34.7% were smaller than 4 cm, 4 cm to 7 cm, and larger than 7 cm, respectively. the other tumor types in the rcc patients were mixed cell, chromophobe, scarcomatoid, and collecting duct tumors in 16 (8.9%), 6 (3.4%), 8 (4.5%), and 1 (0.6%). finally, the stage increased by increasing the size of the rcc tumors (p < .001; table 4), but it was not higher in symptomatic patients (p = .22). with greater tumor sizes, extracapsular extension (stages t3 and t4) was more frequent (p < .001), and there was only 1 patient with a small tumor (< 4 cm) and table 1. pathologic classification and size of kidney tumors* type number (%) size, cm� malignant tumors rcc 179 (84.4) 6.98 ± 3.09 (1.00 to 17.00) tcc of pelvis 10 (4.7) 7.45 ± 4.62 (3.00 to 19.50) wilms tumor 3 (1.4) 9.83 ± 3.62 (7.00 to 14.50) metastatic scc 2 (0.9) 9.00 ± 1.41 (8.50 to 10.00) sarcoma 1 (0.5) 6.00 benign tumors adenoma 6 (2.8) 4.45 ± 2.04 (1.20 to 7.00) oncocytoma 5 (2.4) 7.60 ± 2.10 (5.50 to 10.50) angiomyolipoma 5 (2.4) 5.60 ± 0.89 (5.50 to 7.00) leiomyoma 1 (0.5) 5.50 total 212 (100.0) 6.96 ± 3.11 (1.00 to 19.00) *rcc indicates renal cell carcinoma; tcc, transitional cell carcinoma; and scc, squamous cell carcinoma. †values are demonstrated as means ± standard deviations (ranges), except for tumors which are found only in 1 patient. table 2. size of tumor and symptoms in rcc patients* *values in parentheses are percents. tumor size manifestation < 4 cm 4 cm to 7 cm > 7 cm total asymptomatic 12 (25.0) 24 (50.0) 12 (25.0) 48 (26.8) symptomatic 17 (13.0) 59 (45.0) 55 (42.0) 131 (73.2) total 29 (16.2) 83 (46.4) 67 (37.4) 179 (100.0) histological subtype of the kidney tumor and its grade and stage—tabibi et al 12 urology journal vol 4 no 1 winter 2007 histological subtype of the kidney tumor and its grade and stage—tabibi et al urology journal vol 4 no 1 winter 2007 13 a high stage (p = .009). however, regarding the 4 cm as the cutoff, no significant difference was noted in nuclear grade (p = .06), clinical symptoms (p = .15), and histological subtype (p = .67). discussion according to our findings, size of the tumor is not a precise criterion for differentiation of benign kidney tumors from malignant ones. this data is in contrast with the findings of frank and colleagues,(4) which may be due to our small sample size and also the differences in the genetic characteristics of the two groups of patients. however, in our study, the incidence of benign tumors was 8% that is in agreement with the literature (6.1 % to 16.9%).(4) a similar distribution of the tumors is seen in most studies and further studies are warranted to reveal the possible association of the tumor size and malignancy. nowadays, there are little documented information about the association of size with clinical and pathological features of the kidney solid masses. in our study, the number of patients with clinical symptoms increased with increment in the size of the tumor, but not with grade or stage. furthermore, size of the tumor did not have a relation with the pathological subtype. on the other hand, smaller tumors (< 4 cm) were not statistically different from larger ones in nuclear grade (p = .06), symptoms (p = .15), and histological subtypes (p = .67); however, the rate of extracapsular extension (stages t3 and t4) was 3.4% for tumors smaller than 4 cm, 20.5% for those between 4 cm and 7 cm, and 32.8% for those larger than 7 cm. it is believed that the size of 4 cm seems to be a significant cutoff point for extracapsular extension and nephron-sparing surgery for tumors under this point seems to be safe.(9,10) further prospective studies are warranted to determine the relation between the tumor size and the histological subtype or the tumor size and the nuclear grade. conclusion although malignant tumors were larger in our study, tumor size was not a predicting factor for differentiation between benign and malignant tumors. in rcc tumors, size of the lesion had a relation with symptoms, nuclear grade, and tumor stage, but not with the histological subtype. conflict of interest none declared. references 1. lau wk, cheville jc, blute ml, weaver al, zincke h. prognostic features of pathologic stage t1 renal cell carcinoma after radical nephrectomy. urology. 2002;59:532-7. 2. luciani lg, cestari r, tallarigo c. incidental renal cell carcinoma-age and stage characterization and clinical implications: study of 1092 patients (1982-1997). urology. 2000;56:58-62. table 3. nuclear grade and size of tumors in rcc patients* *values in parentheses are percents. tumor size grade < 4 cm 4 cm to 7 cm > 7 cm total 1 3 (25.0) 9 (75.0) 0 12 (6.7) 2 22 (21.2) 48 (46.2) 34 (32.7) 104 (58.1) 3 4 (4.7) 22 (40.7) 28 (51.9) 54 (30.2) 4 0 4 (44.4) 5 (55.6) 9 (5.0) total 29 (16.2) 83 (46.4) 67 (37.4) 179 (100.0) *values in parentheses are percents. table 4. size of tumor and stage in rcc patients* tumor size stage < 4 cm 4 cm to 7 cm > 7 cm total t1 25 (32.5) 51 (66.2) 1 (1.3) 77 (43.0) t2 3 (4.80 15 (24.2) 44 (71.0) 62 (34.6) t3 1 (2.7) 17 (45.9) 19 (51.4) 37 (20.7) t4 0 0 3 (100.0) 3 (1.7) total 29 (16.2) 83 (46.4) 67 (7.4) 179 (100.0) histological subtype of the kidney tumor and its grade and stage—tabibi et al 12 urology journal vol 4 no 1 winter 2007 histological subtype of the kidney tumor and its grade and stage—tabibi et al urology journal vol 4 no 1 winter 2007 13 3. patard jj, rodriguez a, rioux-leclercq n, guille f, lobel b. prognostic significance of the mode of detection in renal tumours. bju int. 2002;90:358-63. 4. frank i, blute ml, cheville jc, lohse cm, weaver al, zincke h. solid renal tumors: an analysis of pathological features related to tumor size. j urol. 2003;170:2217-20. 5. guinan pd, vogelzang nj, fremgen am, et al. renal cell carcinoma: tumor size, stage and survival. members of the cancer incidence and end results committee. j urol. 1995;153:901-3. 6. storkel s, eble jn, adlakha k, et al. classification of renal cell carcinoma: workgroup no. 1. union internationale contre le cancer (uicc) and the american joint committee on cancer (ajcc). cancer. 1997;80:987-9. 7. fuhrman sa, lasky lc, limas c. prognostic significance of morphologic parameters in renal cell carcinoma. am j surg pathol. 1982;6:655-63. 8. sobin lh, fleming id. tnm classification of malignant tumors, fifth edition (1997). union internationale contre le cancer and the american joint committee on cancer. cancer. 1997;80:1803-4. 9. lau wk, blute ml, weaver al, torres ve, zincke h. matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. mayo clin proc. 2000;75:1236-42. 10. fergany af, hafez ks, novick ac. long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year follow up. j urol. 2000;163:442-5. urol_v3_no2_001_editorial.qxd urology journal unrc/iua vol. 3, no. 2, 104-105 spring 2006 printed in iran 104 introduction acute scrotum is defined as a painful inflammation of the scrotum or its components presenting with local signs and systemic symptoms.(1) its differential diagnoses include spermatic cord torsion, acute epididymitis, hydrocele, varicocele, trauma, testicular tumors, etc. the most common cause of acute scrotum is epididymitis.(2) in practice, early differentiation of spermatic cord torsion from acute epididymitis is of utmost importance. differentiation of these two conditions is sometimes challenging; diagnosis of spermatic cord torsion must be made diagnostic accuracy of c-reactive protein and erythrocyte sedimentation rate in patients with acute scrotum seyyed alaeddin asgari,1* gholamreza mokhtari,1 siavash falahatkar,1 mandana mansour-ghanaei,2 ali roshani,1 alireza zare,1 mehrangiz zamani,3 iradj khosropanah,1 mohammad salehi1 1department of urology, razi hospital, gilan university of medical sciences, rasht, iran 2department of obstetrics and gynecology, al-zahra hospital, gilan university of medical sciences, rasht, iran 3department of obstetrics and gynecology, ekbatan hospital, hamedan university of medical sciences, hamedan, iran abstract introduction: our aim was to investigate the diagnostic accuracy of c-reactive protein (crp) and erythrocyte sedimentation rate (esr) in patients with acute scrotum. materials and methods: one hundred and twenty patients with acute scrotum were evaluated and divided into 3 groups: 46 with acute epididymitis (group 1), 23 with spermatic cord torsion (group 2), and 51 with other noninflammatory causes of acute scrotum (group 3). serum levels crp and esr were measured at the time of admission. results: of the patients in group 1, 44 (95.6%) had elevated serum levels of crp (mean, 67.77 ± 47.80 mg/l). in contrast, only 1 patient in group 2 had a significant increase in the serum level of crp (mean, 9.0 ± 4.90 mg/l), and the patients in group 3 did not have any significant increase in the crp levels (mean, 7.0 ± 2.2 mg/l) (p < .001). the mean esr values were 45.9 ± 21.4 mm/h, 14.2 ± 11.2 mm/h, and 8.8 ± 7.5 mm/h, in groups 1 to 3, respectively (p < .001). the cutoff points for distinguishing between epididymitis and noninflammatory causes of acute scrotum were 24 mg/l for crp and 15.5 mm/h for esr. the sensitivity and specificity values were 93.4% and 100% for crp and 95.6% and 85.1% for esr, respectively. conclusion: based on our findings, serum levels of crp and esr can provide helpful information for differentiation between epididymitis and other causes of acute scrotum. we recommend crp and esr measurements before making a decision of surgical intervention. keywords: acute-phase proteins, acute scrotum, c-reactive protein, erythrocyte sedimentation rate, epididymitis, spermatic cord torsion, diagnosis received january 2005 accepted september 2005 *corresponding author: razi hospital, rasht, iran. tel: +98 131 669 0006, e-mail: s-a-asgari@gums.ac.ir asgari et al 105 within the first 4 to 6 hours, otherwise it can lead to an irreversible ischemic injury to the testis and loss of gonads,(1-3) especially if a complete spermatic cord torsion, ie, a 720-degree rotation, is present.(4) physical examination and history can make the diagnosis in two-thirds, but in onethird of patients with acute scrotum, further assessments such as laboratory studies and imaging would be required. current diagnostic methods are nonspecific, time consuming, and not always available, resulting in loss of the golden diagnostic time. an infectious or inflammatory process can alter the serum levels of acute-phase proteins and erythrocyte sedimentation rate (esr), and so do the inflammatory causes of acute scrotum. this may help early diagnosis; however, the value of these nonspecific inflammatory parameters has not been elucidated yet. in a retrospective study on 104 patients with acute scrotum, it was shown that serum level of c-reactive protein (crp) is helpful in differentiating epididymitis from noninflammatory conditions like spermatic cord torsion or tumor.(1) however, the literature lacks ample prospective evaluation. we designed a study to investigate the diagnostic efficacy of crp and esr in patients with acute scrotum. materials and methods in a cross-sectional study, we enrolled 120 consecutive patients with an acute scrotum who referred to our emergency clinic from march 2003 to march 2004. all men with an acute scrotum visited within the first 24 hours of pain initiation were enrolled. the exclusion criteria were the existence of one of the following conditions: immunocompromised diseases, administration of immunosuppressives or nonsteroid anti-inflammatory drugs, rheumatoid arthritis, inflammatory bowel diseases, recent surgical operation, acute myocardial infarction, allograft rejection, malignancy, burns, infectious diseases with origins other than the scrotum, anemia, congestive heart failure, multiple myeloma, renal insufficiency, hyperchlostrolemia, hyperfibrinogenemia, tuberculosis, and endocarditis. the patients were treated according to history, physical examination, laboratory tests, scrotal ultrasonography, respond to manual detorsion maneuver, and surgical exploration (if required). the final diagnoses were made after appropriate follow-up to evaluate the outcome. in patients with spermatic cord torsion, preceded by taking serum samples, manual detorsion was attempted and if successful, bilateral orchidopexy was performed immediately. if manual detorsion was not possible or in case of suspicion between epididymitis and spermatic cord torsion, surgical exploration would be carried out. patients with acute epididymitis were recommended to rest, decrease scrotal temperature, and elevate testes. in addition, appropriate antibiotics and sedatives were started on. other causes of acute scrotum were treated appropriately. patients were divided into 3 groups: 46 with acute epididymitis (group 1), 23 with spermatic cord torsion (group 2), and the remaining 51 had other noninflammatory causes of acute scrotum (group 3; testicular appendix torsion, trauma, tumor, hydrocele, varicocele, etc). serum levels of crp and esr were measured at the time of admission. erythrocyte sedimentation rate. as an indirect measurement of an acute-phase plasma protein in serum (fibrinogen), esr was determined in all patients before therapeutic interventions using modified westergren method. the westergren pipet was filled to the "0" mark (+1 mm) with the blood sample which was anticoagulated with tripotassium ethylenediaminetetraacetic acid and diluted by 0.85% nacl solution. in 1 hour, the distance between the meniscus of the plasma and the top of the sedimented erythrocyte column was recorded in millimeters.(5-8) c-reactive protein. turbidimetric analysis was used to measure serum levels of crp. the blood sample was centrifuged at 4000 rpm for 10 minutes. the turbidity resulted from the reaction between serum and the specific antibody for crp was measured using photometrical method.(1,7,8,9) the reference ranges were less than 8 mg/l for adults and less than 10 mg/l for children. statistical analyses. the results of esr and crp tests were compared between the 3 groups of patients using 1-way analysis of variance (anova) and tukey test. differential diagnosis between acute epididymitis and noninflammatory causes of acute scrotum (including spermatic cord torsion) was considered to determine a cutoff point for esr and crp using receiver operating characteristic (roc) curves. diagnostic parameters were calculated using routine equations. continuous variables were demonstrated as means ± standard deviations running head: acute-phase proteins in acute scrotum106 and a p value less than .05 was considered significant. results a total of 120 patients with acute scrotum were investigated and divided into 3 groups based on the final diagnoses (table 1). of 46 men with epididymitis, 20 (43.5%) were older than 35 years, and 15 (65.2%) of those with spermatic cord torsion were younger than 20 years. in addition, 1 patient (4.3%) with torsion was older than 35 years (42 years old), while 8 (17.4%) with acute epididymitis were younger than 20 years. fever (> 38.5°c) was present in 30 men with acute epididymitis (65%; group 1) and in 1 of those with spermatic cord torsion (4.3%; group 2). irritative urinary symptoms and pyuria were seen in 37 (80.4%) and 31 (67.4%) patients in group 1, respectively, but in none of those in group 2. leukocytosis was present in 20 (43.5%) and 6 (26%) patients in groups 1 and 2, respectively. the cremasteric reflex was absent in all of the patients in group 2 and in 37 (80%) and 33 (64.7%) of those in groups 1 and 3, respectively. a horizontal position of the testis was found in 19 (82.6%) of the patients in group 2 and 9 (1.9%) of those in group 1. prehn sign was positive in 10 (21.7%) and 21 (91.3%) patients in groups 1 and 2, respectively. an at least 4-fold increase in the serum crp levels was seen in 44 patients (95.6%) in group 1 (mean, 67.77 ± 47.80 mg/l). in contrast, only 1 patient in group 2 had a significant increase in the serum crp level (mean, 9.0 ± 4.90 mg/l). the patients in group 3 did not have any significant increase of the crp levels (mean, 7.0 ± 2.2 mg/l). the mean serum levels of crp and esr in the patients are shown in table 1. using the 1-way anova and tukey test, significant differences were seen in the esr and the crp levels between groups 1 and 2 and groups 1 and 3 (p < .001; p < .001), but not between groups 2 and 3 (crp, p = .96; esr, p = .32). overall, the patients with epididymitis (group 1) had higher crp and esr values than others (p < .001; p < .001). according to roc curves, the best cutoff points for differentiation between epididymitis and noninflammatory causes of acute scrotum (mainly spermatic cord torsion) were 24 mg/l for crp and 15.5 mm/h for esr. the values of diagnostic parameters for crp and esr are demonstrated in table 2. discussion differential diagnosis of acute scrotum by history and physical examination is difficult in one-third of patients, mandating a rapid and accurate diagnostic tool.(9) in the present study, we evaluated the diagnostic accuracy of crp and table 1. demographic and clinical characteristics of the patients with acute scrotum *values in parentheses are percents. table 2. diagnostic parameters of crp and esr for differentiation of acute epididymitis from other noninflammatory causes of acute scrotum* *values are percents. group 1 (epididymitis) group 2 (torsion) group 3 (others) number of the patients * 46 (38.3) 23 (19.2) 51 (42.5) mean age (year) 36.3 16.7 24.4 age range 1 to 86 9 to 42 5 to 85 mean esr (mm/h) 45.9 ± 21.4 14.2 ± 11.2 8.8 ± 7.5 mean crp (mg/l) 67.7 ± 47.8 9.0 ± 4.9 7.0 ± 2.2 sensitivity specificity positive predictive value negative predictive value esr 93.4 100 100 96.1 crp 95.6 85.1 80 96.9 asgari et al 107 esr in patients with acute scrotal conditions. acute-phase proteins comprise a large heterogeneous group of proteins, mainly synthesized in the liver, and their serum concentrations usually increase or decrease by at least 25% in acute conditions. several stimuli can lead to an acute phase such as infections, physical or chemical traumas, surgical operations, tissue ischemia, and advanced carcinomas. sophisticated mechanisms including the release of a series of mediators are behind this acute response. acute-phase proteins are capable of direct neutralization of inflammatory factors, reduction of tissue damage, and contribution to reconstruction of tissue.(1,10) serum levels of some proteins such as albumin, pre-albumin, and transferrin (negative group), decrease while some others such as crp, haptoglobin, and fibrinogen (positive group) increase. in 1991, young and associates suggested that the serum levels of crp are helpful in 6 clinical conditions: monitoring the response to antibiotic treatment; in obstetric patients with premature rupture of membranes, a rise in crp can give early warning of intrauterine infections; differentiation between active disease and infections in patients with systemic lupus and ulcerative colitis where the level of response to active disease has been previously established; as a measure of disease activity and response to disease-modifying drugs in rheumatoid arthritis; early detection of complications in postoperative patients; and in differentiating between infection and graft-versushost disease in bone marrow transplant patients.(11) acute-phase proteins and their indicators such as crp and esr were then considered in the differential diagnoses of acute scrotum including epididymitis, spermatic cord torsion and other noninflammatory causes. acute scrotum is most often diagnosed by history, physical examination, laboratory studies, and imaging. age is a major parameter as spermatic cord torsion usually occurs during adolescence, often in men younger than 20 year, whereas epididymitis is mostly seen in men older than 35 years.(2) in our study, 43.5% of men with epididymitis were older than 35 years and 65.2% of those with spermatic cord torsion were younger than 20 years. acute epididymitis is accompanied by fever in 18% to 33%, pyuria in 24% to 74%, and leukocytosis in 17% to 72% of cases.(2,3) the above factors, albeit strongly indicative of epididymitis, are not pathognomonic. pyuria and bacteriuria are rarely seen in cases of torsion, but since they are nonspecific signs, even by a positive urine culture for infection one cannot rule out spermatic cord torsion. in our study, fever and leukocytosis were present in 4.3% and 26% of men with spermatic cord torsion, respectively. thus, it seems that such classic indicators of inflammation are less accurate diagnostic parameters than crp and esr. of 46 men with epididymitis, 20 (43.5%) were older than 35 years, and 15 (65.2%) of those with spermatic cord torsion were younger than 20 years. in addition, 1 patient (4.3%) with torsion was older than 35 years (42 years old), while 8 (17.4%) with acute epididymitis were younger than 20 years. a severely tender testis is typically seen in spermatic cord torsion, and on physical examination, the horizontal position of the testis is a common finding. the cremasteric reflex is absent, spermatic cord is thick, and epididymis may be palpable at initial stages. however, progression of inflammation and the subsequent enlargement of scrotum preclude palpation of epididymis. moreover, if a 360-degree torsion occurs, epididymis is placed posteriorly. the cremasteric reflex was absent in all of our patients with spermatic cord torsion and in 80% with epididymitis. a horizontal position of the testis was found in 82.6% of the patients with torsion and only 1.9% with acute epididymitis. prehn sign is another diagnostic factor in the differential diagnoses of spermatic cord torsion and epididymitis. a positive prehn sign is in favor of epididymitis, but it is not reliable in most of cases. a positive result was seen in 21.7% and 91.3% of our patients with epididymitis and spermatic cord torsion, respectively. doppler ultrasonography is usually used to assess blood circulation in the spermatic cord and the testis, reported to have a 89% sensitivity and a 100% specificity for diagnosis of spermatic cord torsion. however, it is operator dependent; not always available; and not reliable in incomplete torsions, pediatric cases, and torsions in their initial stages.(1,12,13) radionuclide imaging reveals a photopenic feature in torsion and an increased flow and infiltration of radioactive substance in epididymitis. it is the study of choice in the diagnosis of acute scrotum, yet even with more limitations than ultrasonography(2); anatomic assessment is not possible and an inflammation and hyperemia in the scrotal wall can result in running head: acute-phase proteins in acute scrotum108 false-positive findings for spermatic cord torsion. a definite diagnosis of spermatic cord torsion is ultimately made by operative exploration, and prompt exploration is necessary when torsion is suspected. we considered surgical operation as the gold standard and assessed the crp and esr values obtained preoperatively in association with the final diagnoses. based on our findings, esr and especially crp have high sensitivities, specificities, and predictive values for differentiation between epididymitis and noninflammatory causes of acute scrotum including spermatic cord torsion. of 46 patients with acute epididymitis, only 2 had a crp value less than the cutoff point (24 mg/l) and 2 had an esr less than 15.5 mm/h. consonant with the only similar study performed worldwide,(9) a 4-fold increase in serum crp levels was seen in 2 patients with epididymitis, while a significant increase was seen in only 1 patient with torsion and no one with other causes. both crp and esr had high diagnostic values (table 2). conclusion while most diagnostic tests are not precise enough or otherwise not practicable in the limited golden time for the diagnosis of acute scrotum causes, serum levels of crp and esr can provide helpful information easily and rapidly. our findings revealed that with high sensitivity and specificity, these tests can differentiate acute epididymitis from noninflammatory causes, especially spermatic cord torsion. we suggest crp and esr be measured before making a decision of surgical exploration. however, further study is warranted to prove their value and rely on them without a concern of missing spermatic cord torsion. references 1. doehn c, fornara p, kausch i, buttner h, friedrich hj, jocham d. value of acute-phase proteins in the differential diagnosis of acute scrotum. eur urol. 2001;39:215-21. 2. schneck fx, bellinger mf. abnormalities of the testes and scrotum and their surgical management. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 2379-82. 3. gerber gs, brendler cb. evaluation of the urologic patient: history, physical examination, and urinalysis. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 95-7. 4. kogan sj, hadziselimovic f, howards ss, huff d, snyler iii hm. pediatric andrology. in: gillenwater jy, grayhack jt, howards ss, mitchell m, editors. adult and pediatric urology. 4th ed. philadelphia: lippincott williams & wilkins; 2002. p. 2572-81. 5. dinarello ca, wolff sm. the role of interleukin-1 in disease. n engl j med. 1993;328:106-13. 6. gabay c, kushner i. acute-phase proteins and other systemic responses to inflammation. n engl j med. 1999;340:448-54. 7. kushner i, gewurz h, benson md. c-reactive protein and the acute-phase response. j lab clin med. 1981;97:739-49. 8. pepys mb, baltz ml. acute phase proteins with special reference to c-reactive protein and related proteins (pentaxins) and serum amyloid a protein. adv immunol. 1983;34:141-212. 9. pakzad p. principles and interpretation of clinical serologic tests. 1st ed. tehran: nour-e-danesh; 2001. p. 178. 10. feingold kr, soued m, serio mk, moser ah, dinarello ca, grunfeld c. multiple cytokines stimulate hepatic lipid synthesis in vivo. endocrinology. 1989;125:267-74. 11. young b, gleeson m, cripps aw. c-reactive protein: a critical review. pathology. 1991;23:118-24. 12. pepys mb, baltz ml. acute phase proteins with special reference to c-reactive protein and related proteins (pentaxins) and serum amyloid a protein. adv immunol. 1983;34:141-212. 13. baker la, sigman d, mathews ri, benson j, docimo sg. an analysis of clinical outcomes using color doppler spermatic cord ultrasound for spermatic cord torsion. pediatrics. 2000;105:604-7. urol_v03_no4_001_editorial.indd urological oncology 216 urology journal vol 3 no 4 autumn 2006 p53 protein in serum and urine samples of patients with bladder transitional cell carcinoma and its overexpression in tumoral tissue mohammadreza darabi, nasser tayebi meibodi, reza mahdavi, davood arab introduction: the aim of this study was to evaluate the levels of p53 protein in serum and urine samples of patients with bladder transitional cell carcinoma (tcc) and their relation with the overexpression of p53 in the tumoral tissue. materials and methods: a total of 39 patients with bladder tcc were evaluated for p53 protein in their serum and urine samples and the overexpression of this marker in their tumoral tissue. results: of 39 patients with bladder tcc, 29 (74.4%) had tissue specimens positive for p53 protein overexpression, 20 (51.3%) had p53 protein in their serum samples, and 27 (69.2%) had this protein in their urine samples. a positive immunohistochemical finding was more common in higher grades of the bladder tumor (p = .03), but not in higher stages (p = .07). eighteen of 20 patients (90%) with a positive serum for p53 showed protein overexpression in the tumoral tissue of the bladder (p = .03). of 27 patients with a positive urine sample, 25 (92.6%) had p53 overexpression in their bladder tissue, and of the remainder 12 patients with a negative p53 protein in their urine samples, 8 (66.7%) had no evidence of p53 protein overexpression in their tumoral tissue (p < .001). the grade and stage of tumor had no correlation with serum or urinary p53. conclusion: according to our findings, a positive serum or urine sample for p53 protein is highly associated with the overexpression of p53 protein in the tumoral tissue of patients with bladder tcc. urol j (tehran). 2006;4:216-9. www.uj.unrc.ir keywords: p53 protein, tp53, bladder cancers, enzymelinked immunosorbent assay, immunohistochemistry department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran corresponding author: mohammadreza darabi, md department of urology imam reza hospital, mashhad, iran tel: +98 511 854 3031 e-mail: j_darabi@yahoo.com received may 2006 accepted september 2006 introduction bladder carcinoma is one of the most common malignancies in urology. the most common type of the bladder cancer is transitional cell carcinoma (tcc) that is the fourth most common cancer in men and the eighth in women.(1) molecular genetic studies have revealed that mutations in the suppressor genes are responsible for the formation of bladder cancer. one of these suppressor genes is tp53 which is the most common mutated gene in human beings.(2) the p53 protein has been shown as a valuable tumor marker in most of the tumors especially bladder tumors.(1,3) the half-life of a normal p53 protein is short (20 to 60 minutes), but with some mutations, it increases and reaches up to 6 hours.(4) the mutated p53 protein prevents formation of the normal type of this protein due to the negative feedback caused by its long half-life.(5) this will result in the accumulation of p53 protein in the nucleus of the cell which can be determined using immunohistochemical methods.(4) bladder cancer and p53 protein—darabi et al urology journal vol 3 no 4 autumn 2006 217 however, very few tumors with mutated tp53 will not show the nuclear accumulation of p53 protein by the abovementioned methods.(6) it should be noted that in some cases, immunohistochemical staining may be more sensitive than the molecular methods in the diagnosis of tp53 mutations and may also reveal the main functional changes of the protein, as well.(6) in the recent years, several studies have been performed for finding more precise methods to determine p53 protein.(7-9) it has been demonstrated that abnormal p53 protein accumulation in the cells may increase its level in extracellular fluids such as serum and urine by an unknown mechanism which can be measured using enzyme-linked immunosorbent assay (elisa).(9) several reports have shown different views about the levels of p53 in the serum and urine and their relation with overexpression of p53 protein.(9-14) in this prospective study, we evaluated the relation between the level of p53 protein in the serum and urine samples of the patients with bladder tcc and the pathological and clinical parameters of the disease. materials and methods between march 2005 and may 2006, 45 patients with tcc referred to the clinics of imam reza hospital in mashhad were selected. the patients provided informed consent and the study was approved by the ethics committee of mashhad university of medical sciences. none of them had the history of previous intravesical bacillus calmette-guerin (bcg) instillation, radiotherapy, chemotherapy, or immunocomprising conditions. pathology specimens of the bladder were obtained by transurethral resection, cold-cut biopsy, or cystectomy. tissue passage was performed on the specimens and paraffin blocks were obtained. fourmicrometer tissue cuts were prepared and evaluated by a single pathologist according to the definitions of the world health organization.(15) of 45 samples taken, 39 with tcc were selected for further study. the specimens were then stained by biotin avidin immunoenzymatic technique. those with at least 10% of the tumoral cells stained were considered positive for overexpression of p53 protein and those with less than 10% were considered negative.(16) according to the pathologic stage and radiologic findings, the tumors were categorized into two groups of superficial and deep regarding the invasion of the tumor to the detrusor muscles. concurrently, a 2-ml peripheral blood sample and a 2-ml urine sample were also taken. after separation of the serum, they were kept in a temperature of 20°c. thirty-nine samples with positive pathologic report of tcc were evaluated regarding the presence of p53 protein using elisa method (bender medsystem, vienna, austria). serum and urine samples of 6 healthy ageand sex-matched people without the history of malignancy were also evaluated by elisa method. statistical analyses were done using chi-square test and fisher exact test for comparison of dichotomous variables and a value for p less than .05 was considered significant. results of 39 patients with bladder tcc, 29 (74.4%) had tissue specimens positive for p53 protein overexpression. a positive immunohistochemical finding was more common in high-grade tumors; 4 (44.4%), 10 (71.4%), and 15 (91.8%) patients with grades 1, 2, and 3 had positive results (p = .03). higher stages of the tumors were slightly associated with overexpression of p53 protein (p = .07). twenty (51.3%) patients showed p53 protein in their serum samples. the grade of tumor had no correlation with serum p53 (table 1). eighteen of these patients (90%) showed protein overexpression in the tumoral tissue of the bladder that was indicative of a significant relationship between the serum positivity and protein overexpression (p = .03; table 2). table 1. positive p53 protein and grade of tumor* *values in parentheses are percents. p53 protein grade 1 (n = 9) grade 2 (n = 14) grade 3 (n = 16) total (n = 39) p tissue specimen 4 (44.4) 10 (71.4) 15 (91.8) 29 (74.4) .03 serum sample 4 (44.4) 9 (64.3) 7 (43.8) 20 (51.3) .51 urine sample 5 (55.6) 9 (64.3) 13 (81.3) 27 (69.2) .38 bladder cancer and p53 protein—darabi et al 218 urology journal vol 3 no 4 autumn 2006 twenty-seven patients (69.2%) had p53 protein in their urine samples. although the frequency of p53 positivity was higher in grade 3 compared with grades 1 and 2, there was no significant relation between the tumor grade and p53 protein in the urine (table 1). of 27 patients with a positive urine sample, 25 (92.6%) had p53 overexpression in their bladder tissue, and of 12 patients with a negative p53 protein in their urine samples, 8 (66.7%) had no evidence of p53 protein overexpression in their tumoral tissue (table 2). thus, a significant relationship was found between the overexpression of the p53 protein in the tissues and the existence of p53 in urine specimens (p < .001). also, in spite of higher frequency of p53 protein detection in serum and urine of the patients with higher tumor invasiveness (63% and 68.4%, respectively), this difference was not significant, either (p = .07 and p = .63, respectively). the mean serum level of p53 protein in the patients who were considered to be serum-positive for p53 was 1.17 ± 1.37 u/ml. mean serum level of p53 in the patients with positive tissue specimens for p53 was 1.46 ± 1.42 u/ml (range, 0 to 5.3 u/ml). in those with tissue-negative specimens, the mean serum level of p53 was 0.32 ± 0.77 u/ml (range, 0 to 2.4 u/ml). the mean urine level of p53 protein in the patients who were considered to be urine-positive was 1.78 ± 1.67 u/ml. the mean urine level of p53 in the patients with tissue-positive specimens was 2.27 ± 1.6 u/ml (range, 0 to 5.3 u/ml). this was 0.35 ± 0.8 u/ml (range, 0 to 2.4 u/ml) in the patients with negative tissue specimens. discussion mutations of tp53 have been reported in human tumors such as bladder carcinoma.(2) several studies have shown that mutation of this gene is common in bladder tumors and has a relation with the grade and stage of the disease.(1,2) the rate of overexpression of p53 in bladder tumors is reported to be 29% to 78% in different studies.(9,17) in our study, 74.4% patients with bladder tcc showed accumulation of p53 protein in the tumoral tissue. the diversity of these results may be due to the differences in the pathologic stages and grades of the tumors, the process of tissue preparation for the evaluation or antigen retrieval techniques, and finally the definition of positive p53 specimen in the tissues in these studies (cut-off point may be considered 5%, 10%, or 20%).(16) one of the limitations of this study was the lack of a control group, the cut-off value for positive immunohistochemical staining was obtained from previous reports. a positive p53 protein in serum samples of the patients with bladder tcc has been reported to be 3% to 68% in different studies.(9-12) also, a positive urine sample for p53 protein has been reported in 60% of these patients by elisa test.(13) in our study, 51.3% of the patients with tcc had a positive elisa test for p53 protein in their serum and 69.2% had it in their urine; our relatively high rates may be due to the higher pathologic grades in our patients. in the previous studies a relation had been reported between the p53 protein and pathologic grade.(9-13) in our study, a statistically significant relation was found between the expression of p53 in the tissues and the pathology grade of the bladder tcc. however, such a relation was not found between p53 protein in the urine and serum samples and the tumor stage. also, although the prevalence of p53 protein was higher in the serum and urine samples of the patients with higher stages, this rate was not statistically significant. more studies in this regard are warranted. in a study in india, of 18 patients with positive tissues for p53 protein, 17 (94.4%) had positive sera.(9) in another study in argentina, this rate was reported to be 83.3%.(3) in these studies, the existence of p53 protein was always an indicator of table 2. overexpression of p53 in tumoral tissue and p53 protein in serum and urine* *values in parentheses are percents. serum p53 protein urinary p53 protein p53 protein overexpression positive negative positive negative total positive 18 (62.1) 11 (37.9) 25 (86.2) 4 (13.8) 29 negative 2 (20.0) 8 (80.0) 2 (20.0) 8 (80.0) 10 total 20 19 20 19 39 bladder cancer and p53 protein—darabi et al urology journal vol 3 no 4 autumn 2006 219 p53 overexpression in the tumoral tissue; however, this relation was one-way.(9) our study agrees with the previous studies in this regard. of 20 patients with a positive serum for p53 protein, 18 showed p53 protein overexpression in their bladder tissue, but of 29 patients with overexpression of p53, 11 did not show the protein in their serum samples. in our study, the relation between the p53 protein in the urine samples, and the tumoral tissues of the patients with tcc was also evaluated. in 29 patients who had overexpression of p53 in their tumoral tissue of the bladder, 25 showed positive urine samples using elisa method (86%). this relation had also been reported in a similar study by indulski and colleagues.(13) conclusion it seems that serologic evaluation of p53 protein in serum and urine samples is a very sensitive tool for the prediction of p53 overexpression in the patients with bladder tcc. however, negative serologic result does not rule out the p53 overexpression. according to the findings of this study, a positive result of elisa for p53 protein in urine and serum samples can be considered as p53 protein overexpression in tumoral tissue. this test is cost-effective and simple; thus, performing complicated and expensive immunohistochemical tests can be avoided in the future. conflict of interest none declared. references 1. messing em. urothelial tumors of the urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 2733-6. 2. kibel as, nelson jb. molecular genetics and cancer biology. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 2637. 3. balogh ga, mailo da, corte mm, et al. mutant p53 protein in serum could be used as a molecular marker in human breast cancer. int j oncol. 2006;28:9951002. 4. levine aj, momand j, finlay ca. the p53 tumour suppressor gene. nature. 1991;351:453-6. 5. fontanini g, fiore l, bigini d, et al. levels of p53 antigen in the serum of non-small cell lung cancer patients correlate with positive p53 immunohistochemistry on tumor sections, tumor necrosis and nodal involvement. int j oncol. 1994;5: 553-8. 6. esrig d, spruck ch 3rd, nichols pw, et al. p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. am j pathol. 1993;143:1389-97. 7. dahse r, utting m, werner w, schimmel b, claussen u, junker k. tp53 alterations as a potential diagnostic marker in superficial bladder carcinoma and in patients serum, plasma and urine samples. int j oncol. 2002;20:107-15. 8. evans cp. p53 immunodetection in urine samples successful and predictive of bladder tumor progression. br j cancer. 2005;93:242-7. 9. gopi kishore m, hamid a, dwivedi us, et al. the correlation of tissue p53 protein overexpression and p53 antigen in serum of patients with bladder cancer. urooncol. 2003; 2:121-8. 10. hollstein m, sidransky d, vogelstein b, harris cc. p53 mutations in human cancers. science. 1991;253: 49-53. 11. luo jc, neugut ai, garbowski g, et al. levels of p53 antigen in the plasma of patients with adenomas and carcinomas of the colon. cancer lett. 1995;91:235-40. 12. suwa h, ohshio g, okada n, et al. clinical significance of serum p53 antigen in patients with pancreatic carcinomas. gut. 1997;40:647-53. 13. indulski ja, lutz w, krajewska b. serum and urine p53 protein in bladder cancer patients and in workers occupationally exposed to genotoxic and mutagenic dyes. cejoem. 1999;5:17-25. 14. lipponen pk. over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. int j cancer. 1993;53:365-70. 15. epstein ji, amin mb, reuter vr, mostofi fk. the bladder consensus conference committee. the world health organization/international society of urologic pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. am j surg pathol. 1998;22:1435-48. 16. kay ew, barry walsh cj, whelan d, o’grady a, leader mb. inter-observer variation of p53 immunohistochemistry--an assessment of a practical problem and comparison with other studies. br j biomed sci. 1996;53:101-7. 17. esrig d, elmajian d, groshen s, et al. accumulation of nuclear p53 and tumor progression in bladder cancer. n engl j med. 1994;331:1259-64. review association of endothelial nitric oxide synthase gene polymorphisms with susceptibility to prostate cancer: a comprehensive systematic review and meta-analysis mehdi abedinzadeh1, seyed alireza dastgheib2*, hadi maleki1, naeimeh heiranizadeh3, mohammad zare3, jamal jafari-nedooshan3, saeed kargar3, hossein neamatzadeh4,5 purpose: a variety of studies have evaluated the association of polymorphisms at endothelial nitric oxide synthase (enos) gene with risk of prostate cancer. however, the results remain inconclusive. this meta-analysis was performed to derive a more precise estimation between enos polymorphisms and prostate cancer risk. materials and methods: a comprehensive literature search was conducted using pubmed, embase, wed of science, elsevier, cochrane library, scielo, sid, wanfang, vip, cbd and cnki database up to march 20, 2020. odds ratios with 95% confidence intervals were used to assess the strength of the associations. results: a total of 22 case-control studies including 12 studies with 4,464 cases and 4,347 controls on +894g>t, five studies with 589 cases and 789 controls on vntr 4a/b, and five studies with 588 cases and 692 controls on -786t > c were selected. overall, pooled data showed a significant association between enos 894g>t, vntr 4a/b, and -786t > c polymorphisms and an increased risk of prostate cancer in the global population. when stratified by ethnicity, a significant association was found between enos +894g>t and -786t>c polymorphisms and risk of prostate cancer in caucasians. conclusion: our results indicated that enos 894g>t, vntr 4a/b, and -786t>c polymorphisms were associated with risk of prostate cancer in the global population as well as caucasian population. keywords: prostate cancer; nitric oxide synthase; polymorphism; meta-analysis introduction prostate cancer is the second most common cancer and the third leading cause of cancer death in men in united states(1). it is suggested that approximately 161,360 men will have been diagnosed with prostate cancer and 26,000 men will have died of the disease in 2017 in the united states(2). although, african-american males have the highest mortality and morbidity rates of prostate cancer in the world, the global burden of this disease is raising globally(3,4). although the occurrence rate of prostate cancer is rare in men younger than 40 years, but its morbidity increases with age more rapidly than any other malignancies in men(5,6). the exact etiology of prostate cancer is poorly understood(4). however, with the remarkable advances in high-throughput technologies of molecular biology of cancer, genetic risk factors of prostate cancer have been intensively investigated(7,8), and polymorphisms of endothelial nitric oxide synthase (enos) gene were on focus(9,10). nitric oxide (no) is mainly produced by the catalyzing action of the 3 nitric oxide synthase (nos3) 1department of urology, shahid rahnamoun hospital, shahid sadoughi university of medical sciences, yazd, iran 2department of medical genetics, school of medicine, shiraz university of medical sciences, shiraz, iran 3department of general surgery, shahid sadoughi university of medical sciences, yazd, iran 4department of medical genetics, shahid sadoughi university of medical sciences, yazd, iran 5mother and newborn health research center, shahid sadoughi university of medical sciences, yazd, iran *correspondence: department of medical genetics, school of medicine, shiraz university of medical sciences , shiraz, iran tel: +989177148573, fax: +983518248382, e-mail: dastgheibsa@gmail.com. received july 2019 2019 & accepted april 2020 family enzymes via the conversion of l-arginine(11,12). no is an intracellular messenger that plays a vital role in vascular system, homoeostasis, and bone turnover (13). low no release can cause several cardiovascular diseases, such as atherosclerosis, hypertension and thrombosis, while high circulating no concentration is generally toxic(14,15). moreover, no has been suggested plays an effective role in different cancer related processes including angiogenesis, apoptosis, invasion, and metastasis(10,11,16). the human enos gene is located on chromosome 7q3536, comprises 26 exons and spanning 21 kb of genomic dna(10). the 894g>t (rs1799983, glu298asp), intron vntr 4a/b (a-deletion allele with 27 bp vntr in intron 4), and -786t>c (rs2070744) are the most clinically relevant polymorphisms in the enos gene so far described(9). several studies have evaluated the association of the enos 894g>t, vntr 4a/b, and -786t>c polymorphisms with risk of prostate cancer in different populations(17–29). however, those studies results are inconsistent and inconclusive, might be due to small sample size, different characteristics of populations, urology journal/vol 17 no. 4/ july-august 2020/ pp. 329-337. [doi: 10.22037/uj.v0i0.5445 ] low statistical power, different genotyping methods and clinical heterogeneity of the patients. therefore, we have performed this systematic review and meta-analysis to clarify the association of 894g>t, vntr 4a/b, and -786t>c polymorphisms at enos gene with susceptibility to prostate cancer. materials and methods literature search the ethical approval was not required for this study, as it is a systematic review and meta-analysis. this work was conducted according to the prisma (preferred reporting items for systematic reviews and meta-analyses) guidelines. we conducted a comprehensive literature search on electronic databases including pubmed, embase, wed of science, elsevier, google scholar, cochrane library, scielo, sid, wanfang, vip, chinese biomedical database (cbd) and chinese national knowledge infrastructure (cnki) databases to identifying all relevant studies on association of enos 894g>t, vntr 4a/b, and -786t>c polymorphisms with prostate cancer risk up to march 20, 2020. terms used for the research were (“prostate cancer” or “prostate carcinoma”) and (“endothelial nitric oxide synthase” or ‘’enos'’ or ‘’nitric oxide synthase 3’’ or ‘’nos3’’ or ‘’constitutive nos’’ or ‘’endothelial nos’’) and (‘’894g>t’’ or ‘’rs1799983’’ or ‘’glu298asp’’) and (‘’27-bp repeat insertion (b)/deletion (a) in intron 4’’ or ‘’intron 4 b/a vntr’’ ‘’ intron 4a/4b’’ or ‘’rs61722009’’) and (‘’-786t>c’’ or ‘’rs2070744’’) and (‘’gene’’ or ‘’allele’’ or ‘’genotype’’ or ‘‘polymorphism’’ or ‘‘mutation’’ or ‘‘variation’’ or ‘‘variant’’). we also identified additional studies with the “related articles” option and list of references. in the current meta-analysis, publications written in english, farsi, portuguese and chinese were eligible. the search was limited to human studies. inclusion and exclusion criteria studies included in this meta-analysis had to meet the following criteria: 1) studies with case-control design; 2) studies evaluating the association between 894g>t, vntr 4a/b, and -786t>c polymorphisms of enos gene and prostate cancer risk; 3) having detailed data to calculate the odds ratio (or) and 95% confidence interval (ci). accordingly, the following exclusion criteria were also used: 1) studies did not provide adequate data to estimate the association between enos polymorphisms and prostate cancer risk; 2) case only studies or studies without controls; 3) in vitro and animal studies; 4) linkage studies and family based studies such as twins and sibling studies; 5) case reports, abstracts, reviews, posters, commentaries, editorials, conference articles, proceedings and previous meta-analyses; and 6) repeating or overlapping studies. we defined overlapping data to studies that used the same published case-control studies to generate the same results with the exact same population sample size as well. thus, if more than one study was published by the same author(s) using repeated or overlapped data, the most complete one or more recently published study was selected. data extraction all the data was collected independently by two authors according to the inclusion criteria. then, in order to guarantee the veracity of collected data, two authors checked the collected data achieved an agreement. if there was a dispute regarding inclusion data, a third author was invited to resolve the issue. the following data were collected from each study: first author, year of publication, country of origin, ethnicity, source of healthy controls (hospital based or population based), genotyping methods, sample size, genotype and allele frequencies of cases and controls, genotype distribution in cases and controls, minor allele frequencies (mafs) and p value for hardy-weinberg equilibrium (hwe) in healthy controls. the patient ethnicities were categorized as caucasian, asian, african, and mixed. the ‘‘mixed’’ group means mixed or unknown populations. disagreements about eligibility were resolved through a discussion between the two investigators. quality assessment the quality of the case-control studies included in the current meta-analysis was evaluated by two authors using newcastle-ottawa scale (nos). primary contents to be assessed include selection of study subjects (4 scores in total); inter-group comparability (2 scores in total); exposure factors or outcomes (3 scores in total). low-quality studies: 0 to 4 points; high-quality studies: 5 to 9 points. statistical analysis the strength of association between the enos 894g>t, vntr 4a/b, and -786t>c polymorphisms and risk of prostate cancer was measured by odds ratios (ors) with 95% confidence intervals (cis). the z-test was used to assess the pooled or, in which p-value less than 0.05 was considered as statistically significant. the association was estimated under all five genetic models, i.e., allele (b vs. a), homozygous model (bb vs. aa), heterozygous model (ba vs. aa), dominant model (bb+ba vs. aa), and recessive model (bb vs. ba+aa), which ‘’a’’ represent the ‘’wild allele’’ and ‘’b‘’ represent ‘’mutant allele’’, respectively. in this meta-analysis the cochran’s χ2 based q-statistic test was used to appraise the between-studies heterogeneity, where test result was p < 0.1 indicated the presence of heterogeneity. moreover, the i2 value was used to quantify the effect of heterogeneity, with the range of 0 to 100% (0%-40% meant no risk of heterogeneity, 30%-50% meant a low risk of heterogeneity, 60%-90% meant substantial heterogeneity, and 75%-100% meant considerable heterogeneity). if obvious heterogeneity was observed among the studies, the random-effects model (the dersimonian and laird method) was used to calculate the pooled or and 95% ci. otherwise, the fixed-effects model (the mantel-haenszel method) was adopted for the meta-analysis. hardy-weinberg equilibrium (hwe) in the healthy subjects was assessed using fisher’s exact test, which a p-value < 0.05 was considered significant. subgroup analyses according to the ethnicity were also performed to evaluate the association and heterogeneity. to check the stability of the results, a sensitivity analysis was performed by omitting each individual study in turn from the all selected studies and reanalyzing the pooled or for the remainder. moreover, the sensitivity analysis was performed by excluding hwe-violating studies. publication bias was assessed by the funnel plots and the egger’s linear regression test. additionally, if publication bias was seen, the “trim and fill” method which conservatively imputes hypothetical negative unpublished studies to enos snps and prostate cancer-abedinzadeh et al. review 330 vol 17 no 04 july-august 2020 331 mirror the positive studies that cause funnel plot asymmetry was used to further analyses the possible effect of publication bias. all statistical analyses were performed using comprehensive meta-analysis (cma) software version 2.0 (biostat, englewood, usa). all tests were two-sided, and the p < 0.05 was considered statistically significant. results characteristics of included studies a flow diagram summarizing the process of study selection was shown in figure 1. searches of the electronic databases and manually searching references returned 186 studies. among them, 78 studies were extable 1. characteristics of the studies included in the meta-analysis. first author/year country (ethnicity) soc genotyping methods case/control cases controls nos mafs hwe genotype allele genotype 894g>t gg tt tt g t gg gt tt g t medeiros portugal hb pcr-rflp 125/153 49 61 15 159 91 70 65 18 205 101 7 0.330 0.623 2002 (caucasian) marangoni 2006 brazil(mixed) hb pcr-rflp 84/76 30 50 4 110 58 35 34 7 104 48 6 0.315 0.751 jacobs 2008 usa(caucasian) pb taqman 1420/1446 659 632 129 1950 890 682 600 164 1964 928 9 0.320 0.065 lee 2009a usa(caucasian) pb taqman 1088/1293 517 468 103 502 674 607 557 129 1771 815 9 0.315 0.947 lee 2009b usa(caucasian) pb taqman 97/373 77 20 0 174 20 280 88 5 648 98 6 0.131 0.510 chen 2011 china(asian) ns pcr-rflp 78/88 64 12 2 140 16 66 21 1 153 23 6 0.130 0.633 ziaei 2012 iran(caucasian) mixed sequencing 78/87 44 23 11 111 45 48 33 6 129 45 6 0.258 0.912 safarinejad 2013 iran(caucasian) hb pcr-rflp 170/340 120 48 2 288 52 248 89 3 585 95 7 0.139 0.101 brankovic 2013 serbia(caucasian) hb pcr-rflp 150/250 76 65 9 217 83 132 99 19 363 137 7 0.274 0.945 polat 2016 turkey(caucasian) hb pcr-rflp 50/50 1 22 27 24 76 29 17 4 75 25 6 0.250 0.502 ceylan 2016 turkey(caucasian) hb pcr-rflp 40/75 20 17 3 57 23 47 23 5 117 33 6 0.220 0.358 diler 2016 turkey(caucasian) hb pcr-rflp 84/116 6 55 23 67 101 65 41 10 171 61 7 0.262 0.342 vntr 4a/b bb ab aa b a bb ab aa b a medeiros 2002 portugal(caucasian) hb pcr-rflp 125/153 87 32 6 206 44 121 29 3 271 35 7 0.114 0.434 safarinejad 2013 iran(caucasian) hb pcr-rflp 170/340 101 54 15 256 84 249 88 3 586 94 7 0.138 0.112 sanli 2011 turkey(caucasian) pb pcr-rflp 137/158 92 40 5 114 50 104 48 6 256 60 7 0.189 0.885 polat 2016 turkey(caucasian) hb pcr-rflp 50/50 41 7 2 89 11 36 12 2 84 16 6 0.160 0.442 diler 2016 turkey(caucasian) hb pcr-rflp 84/116 65 16 3 146 22 83 31 2 197 35 6 0.150 0.646 -786t>c tt tc cc t c tt tc cc t c safarinejad 2013 iran(caucasian) hb pcr-rflp 170/340 52 93 25 197 143 150 159 31 459 221 7 0.325 0.223 brankovic 2013 serbia(caucasian) hb pcr-rflp 150/100 54 68 28 176 124 34 51 15 119 81 7 0.405 0.562 polat 2016 turkey(caucasian) hb pcr-rflp 50/50 32 11 7 75 25 21 24 5 66 34 6 0.340 0.623 diler 2016 turkey(caucasian) hb pcr-rflp 84/116 30 30 24 90 78 47 56 13 150 82 6 0.353 0.542 sugie 2016 japan(asian) ns pcr-rflp 134/86 65 48 21 178 90 54 27 5 135 37 7 0.215 0.514 abbreviations: soc: source of controls; hb: hospital-based; pb: population-based; ns: not stated; pcr: polymerase chain reaction; rflp: restriction fragment length polymorphism; nos: newcastle-ottawa scale; maf: minor allele frequency; hwe: hardy-weinberg equilibrium. figure 1. flow diagram for inclusion of the studies in the meta-analysis. enos snps and prostate cancer-abedinzadeh et al. cluded because they were duplications, review articles, case reports, meta-analyses, irrelevant to enos polymorphisms and prostate cancer risk, and did not provide enough genotype information. finally, a total of 22 case-control studies in 13 publications(17–29) with 4,618 cases with prostate cancer and 5,856 healthy subjects were included in this meta-analysis. detailed characteristics and genotype distribution of eligible studies are listed in table 1. the relevant research was published between august 2002 and april 2016. prostate cancer cases in the selected studies ranged from 50 to 1420. of those 22 case-control studies, 12 studies with 3,464 cases and 4,347 controls were on enos 894g>t, five studies with 566 cases and 817 controls were on enos vntr 4a/b, and five studies with 588 cases and 692 controls were on enos -786t>c polymorphism. in terms of ethnicity, eleven were performed on a caucasian population, one on a mixed and two on an asian population. the studies were carried out in portugal (n=2), brazil (n=1), usa (n=3), china (n=1), iran (n=4), serbia (n=2), turkey (n=8) and japan (n=1). the control sources of the 15 studies were hospital‐based (hb), four studies were population‐based (pb), one study was mixed (hb and pb), and one study did not state. three molecular techniques including rflppcr, taqman and direct sequencing were used to genotype the enos polymorphisms. the genotypes and minor allele frequency (maf) distributions for enos polymorphisms in cases and controls were presented in table 1. the distribution of genotypes in the healthy controls was consistent with the hardy-weinberg equilibrium (table 1). quantitative data synthesis enos 894g>t table 2 listed the main results of the meta-analysis for association between enos 894g>t polymorphism and prostate cancer risk. when all the eligible studies were pooled into the meta-analysis of enos 894g>t polymorphism, significantly increased risk of prostate cancer was observed under two genetic models, i.e., allele (t vs. g: or = 1.340, 95% c = 1.039-1.727, p = 0.024) and dominant (tt+gt vs. gg: or = 1.323, 95% ci 1.004-1.745, p = 0.047). moreover, we performed subgroup analysis based on ethnicity among caucasians. assessment of stratified analysis by ethnicity in other populations is not meaningful due to limited number of studies included in this study (table 1). when stratified by ethnicity, there was a significant association between enos 894g>t polymorphism and an increased risk of prostate cancer in caucasians under three genetic models, i.e., allele (t vs. g: or = 1.421, 95% c = 1.071-1.885, p = 0.015, figure 2a), heterozygote (gt vs. gg: or = 1.345, 95% ci 1.003-1.803, p = 0.048) and dominant (tt+gt vs. gg: or = 1.387, 95% ci 1.023-1.880, p = 0.035). enos vntr 4a/b the summary results for the association between enos vntr 4a/b polymorphism and prostate cancer risk are shown in table 2. when all the eligible studies were pooled into the meta-analysis of enos vntr 4a/b polymorphism, significantly an increased risk of prostate cancer was observed under the recessive genetic model (aa vs. ab+bb: or = 2.504, 95% ci 1.309-4.788, p = 0.006, fig 2b). assessment of stratified analysis by ethnicity is not meaningful due to limited number of studies included in this study (table 1). enos -786t>c table 2 also listed the main results for the association between enos -786t>c polymorphism and prostate cancer risk. overall, the pooled data indicated a significant association between the enos 894g>t polymortable 2. summary risk estimates for association between enos polymorphisms and risk of prostate cancer. polymorphism genetic model type of model heterogeneity odds ratio publication bias i2 (%) p h or 95% ci zor por pbeggs peggers +894g>t overall t vs. g random 88.25 ≤0.001 1.340 1.039-1.727 2.256 0.024 0.086 0.102 tt vs. gg random 81.37 ≤0.001 1.679 0.966-2.918 1.836 0.066 0.450 0.106 tg vs. gg random 78.17 ≤0.001 1.299 0.991-1.702 1.894 0.058 0.114 0.106 tt+tg vs. gg random 81.15 ≤0.001 1.323 1.004-1.745 1.987 0.047 0.023 0.062 tt vs. tg+gg random 72.17 ≤0.001 1.357 0.886-2.077 1.405 0.160 0.537 0.154 ethnicity caucasian t vs. g random 90.28 ≤0.001 1.421 1.071-1.885 2.437 0.015 0.020 0.076 tt vs. gg random 84.57 ≤0.001 1.825 0.998-3.337 1.953 0.051 0.283 0.100 tg vs. gg random 80.52 ≤0.001 1.345 1.003-1.803 1.982 0.048 0.049 0.077 tt+tg vs. gg random 83.78 ≤0.001 1.387 1.023-1.880 2.105 0.035 0.020 0.047 tt vs. tg+gg random 76.26 ≤0.001 1.447 0.917-2.281 1.589 0.112 0.474 0.124 vntr 4a/b overall a vs. b random 73.45 0.005 1.193 0.783-1.825 0.825 0.409 0.462 0.136 aa vs. bb random 58.97 0.045 2.393 0.840-6.814 1.634 0.102 0.806 0.577 ab vs. bb fixed 44.18 0.127 1.160 0.903-1.490 1.161 0.246 0.226 0.129 aa+ab vs. bb random 65.67 0.020 1.130 0.735-1.738 0.558 0.577 0.220 0.117 aa vs. ab+bb fixed 53.07 0.074 2.504 1.309-4.788 2.775 0.006 0.806 0.659 -786t>c overall c vs. t random 65.33 0.021 1.387 0.954-2.016 1,715 0.086 0.086 0.018 cc vs. tt fixed 26.35 0.246 2.019 1.399-2.913 3.752 ≤0.001 0.806 0.737 ct vs. tt random 73.26 0.005 0.946 0.567-1.579 -0.212 0.832 0.220 0.038 cc+ct vs. tt random 83.18 ≤0.001 0.860 0.417-1.776 -0.407 0.684 0.086 0.045 cc vs. ct+tt fixed 0.00 0.398 1.915 1.365-2.686 3.759 ≤0.001 1.000 0.596 ethnicity caucasian c vs. t random 76.70 0.005 1.265 0.845-1.895 1.141 0.254 0.734 0.481 cc vs. tt fixed 33.26 0.213 1.843 1.222-2.779 2.916 0.004 1.000 0.748 ct vs. tt random 78.21 0.003 0.970 0.519-1.814 -0.095 0.924 0.308 0.110 cc+ct vs. tt random 77.81 0.004 1.118 0.626-1.996 0.376 0.707 0.308 0.164 cc vs. ct+tt fixed 0.00 0.603 1.680 1.149-2.457 2.676 0.007 1.000 0.679 enos snps and prostate cancer-abedinzadeh et al. review 332 vol 17 no 04 july-august 2020 333 phism and an increased risk of prostate cancer under two genetic models, i.e., homozygote (cc vs. tt: or = 2.019, 95% ci 1.399-2.913, p ≤ 0.001) and recessive (cc vs. ct+tt: or = 1.915, 95% ci 1.365-2.686, p ≤ 0.001, figure 2c). moreover, we performed subgroup analysis based on ethnicity among caucasians. assessment of stratified analysis by ethnicity in other populations is not meaningful due to limited number of studies included in this study (table 1). stratified analysis showed an increased risk of prostate cancer in caucasian population under two genetic models, i.e., homozygote (cc vs. tt; or = 1.843, 95% ci 1.2222.779, p = 0.004) and recessive (cc vs. ct+tt; or = 1.680, 95% ci 1.149-2.457, p = 0.007). between-study heterogeneity we found significant between-study heterogeneity for enos 894g>t, vntr 4a/b, and -786t>c polymorphisms in overall population under almost genetic models and thus the random-effect model was applied to calculate their combined or (table 2). therefore, a subgroup analysis by ethnicity was performed to explain the potential source of heterogeneity. as shown in table 2, when subgroup analyses were performed, the between-study heterogeneity did not change considerably. the results revealed that ethnicity might not be the major source of heterogeneity in the current meta-analysis. sensitivity analysis sensitivity analysis was performed to identify the influence of each study on the pooled or by consecutively omitting one study each time in the overall population. the sensitivity analysis for enos 894g>t, vntr 4a/b, and -786t>c polymorphisms revealed that no individual study did not significantly affect the pooled data. hence, results of the sensitivity analysis indicated that our results are statistically stable and reliable. publication bias the begg’s and egger’s linear regression tests were used to investigate the potential publication bias for association between enos polymorphisms and prostate cancer risk in the overall population. table 2 lists the publication bias assessment method with its respective p-value for each test. the shapes of the funnel plots did not show any evidence of publication bias under all five genetic models in the overall population for enos 894g>t and vntr 4a/b polymorphisms. for example, figure 3 showed funnel plot of publication bias test for association of enos 894g>t (allele model: t vs. g), vntr 4a/b (homozygote model: aa vs. bb) and -786t>c (recessive model: cc+ct vs. tt) polymorphisms with prostate cancer risk. however, the shapes of the funnel plots revealed obvious asymmetry for -786t>c polymorphism under the dominant model (tt+tg vs. gg: pbeggs = 0.023; peggers = 0.062). moreover, egger’s test found a publication bias under the genetic model, suggesting that there was an obvious publication bias for association between enos -786t>c polymorphism and prostate cancer. thus, we used the duval and tweedie nonparametric ‘‘trim and fill’’ method to adjust the pooled risk for association between enos -786t>c polymorphism and prostate cancer under the dominant model (figure 4). however, the “trim and fill” method did not significantly change conclusions, indicating that our results were statistically robust. discussion although several case-control studies have been conducted to assess the roles of enos gene polymorphisms to the prostate cancer susceptibility in different populations, contradictory results were reported due to the relatively small sample size of individual studies and sampling effects. for example; ziaei et al. did not observe an association between enos 894g>t polyfigure 2. forest plots for association of enos 894g>t, vntr 4a/b, and -786t>c polymorphisms with prostate cancer risk. a: +894g>t (allele model: t vs. g); b: vntr 4a/b (recessive model: aa vs. ab+bb); and c: -786t>c (recessive model: cc vs. ct+tt).risk. a: +894g>t (allele model: t vs. g); b: vntr 4a/b (recessive model: aa vs. ab+bb); and c: -786t>c (recessive model: cc vs. ct+tt). enos snps and prostate cancer-abedinzadeh et al. morphism and prostate cancer risk in 95 prostate cancer patients and 111 benign prostate hyperplasia in an iranian population(25). similarly, two studies by polat et al., and ceylan et al., also found no association between enos 894g>t and the 4 vntr polymorphism and prostate cancer risk, respectively(30,31). however, in a case-control study with 125 prostate cancer patients and 153 controls, medeiros et al., reported that the enos 894g>t polymorphism was associated with an increased risk of prostate cancer risk in a caucasian population(17). safarinejad et al. also showed that two enos -786t>c and vntr 4a/b polymorphisms might modify the individual susceptibility to prostate cancer in an iranian population(26). therefore, the current meta-analysis based on 22 case-control studies was performed to provide a more precise estimation of the association between enos 894g>t, vntr 4a/b, and -786t>c polymorphisms and prostate cancer risk. our pooled results showed that enos −786t>c, vntr 4a/b, and -786t>c polymorphisms were significantly associated with risk of prostate cancer. the 894g>t polymorphism is one of the most important identified functional polymorphisms on the enos gene. as this polymorphism is located in a coding region, it might be in relation to altered enos protein and functional changes of the endothelium by an amino acidic substitution at position 298 (glu298asp)(30). our pooled results support the role of 894g>t polymorphism in pathogenesis of prostate cancer. in addition, epidemiological studies have showed that the -786t>c polymorphism, a 5’ flanking region polymorphism of the enos gene, is associated with different disease. in the present meta-analysis, the overall analysis showed a significant association between the enos -786t>c polymorphism and prostate cancer risk in the homozygote and recessive models, identifying that the c allele of enos -786t>c polymorphism had a statistically significant increased prostate cancer risk. as this polymorphism located in promoter region of enos gene, it may affect enos expression and then lowers enos mrna and serum no levels. our pooled results were inconsistent with two previous meta-analysis by nikolić et al., and gao et al. on 894g>t polymorphism(10,31). nikolić et al., included nine case-control studies and one case-only study on enos 894g>t and four studies on -786t>c. their results suggested that -786t>c polymorphism were associated with increased prostate cancer risk, while the 894g>t polymorphism did not associated with risk and progression of prostate cancer. however, the previous meta-analyses results regarding the enos 894g>t polymorphism and prostate cancer risk essentially remains an open field, as the number of studies included was considerably smaller than that needed to achieve robust and conclusive results. moreover, nikolić et al., and gao et al. did not perform subgroup analysis. in the present meta-analysis, by including only 12 case-control studies for quantitative synthesis, we found that both enos 894g>t and -786t>c polymorphisms were associated with susceptibility to prostate cancer. moreover, stratified analysis indicated that the caucasians carriers of the minor alleles of enos 894g>t and -786t>c polymorphisms might have high risk of prostate cancer. the polymorphism of enos vntr 4a/b (vntr 4a/4b) gene consists of the two alleles of enos 4a with 4 tandem 27-repeats and enos 4b with 5 repeats in the intron 4. the polymorphism of enos vntr 4a/b gene has been associated with many vascular diseases including hypertension, diabetic retinopathy, and diabetic nephropathy in various populations. in 2002, medeiros et al., first reported that the enos vntr 4a/b polymorphism is associated with threefold increase risk of prostate cancer risk in a portuguese population(17). in 2015, in a meta-analysis of three case-control studies an increased risk of prostate cancer was observed for enos vntr 4a/b polymorphism(31). the present meta-analysis based on five case-control studies found a significantly increased risk of prostate cancer for enos vntr 4a/b polymorphism, which was partially consistent with the previous meta-analysis. however, the larger number of studies included leading to an increased statistical power. between-study heterogeneity is common in meta-analysis for genetic association studies(32–34). therefore, exploring the potential sources of between-study heterogeneity is an essential component of meta-analysis (35–37). the between-study heterogeneity might arise from study quality, characteristics such as study design, sample size, inclusion criteria, ethnicity, clinical heterogeneity, and different genotyping methods and lifestyle factors(38–41). in the case of prostate cancer, the screening policy also varies between countries. these different screening policies might also be responsible for the between study heterogeneity. in this study, there was a significant heterogeneity for enos gene polyfigure 3. begg's funnel plot of publication bias test for association of enos 894g>t, vntr 4a/b, and -786t>c polymorphisms with prostate cancer risk. a: 894g>t (allele model: t vs. g); b: vntr 4a/b (homozygote model: aa vs. bb); and c: 786t>c (recessive model: cc+ct vs. tt). enos snps and prostate cancer-abedinzadeh et al. review 334 vol 17 no 04 july-august 2020 335 morphisms. therefore, meta-regression and subgroup analyses were performed to explore the sources of between-study heterogeneity. however, the results indicated that ethnicity was not the source of heterogeneity in the current meta-analysis some limitations of our meta-analysis should be considered when interpreting the results. first, although we collected all the eligible studies, sample size of the included studies was small, especially for stratified analyses by ethnicity, which may have limited the statistical power to find conclusions. second, we included only published study in english in this meta-analysis, published studies in other languages, ongoing studies and unpublished data were not included, which may cause publication bias. third, among those 22 studies included in this meta-analysis, most of studies were conducted in caucasians, only two studies were in asians and one study in mixed. thus, the findings from this meta-analysis might be applicable to caucasians. future studies containing the full range of possible ethnic differences are required to avoid selection bias. fourth, in this meta-analysis evidence of heterogeneity and publication bias was observed, which both might distort the conclusion of our results. fifth, due to the unavailability of other detailed information our results were based on single-factor estimates without adjustments for other risk factors such as age, gender, life style, environmental factors and other variables. finally, further evaluation of prostate cancer risk should pay more attention to the potential interactions among gene-gene, gene-environment, and even different polymorphisms of the enos gene. conclusions the current meta-analysis indicates that enos 894g>t, vntr 4a/b and -786t>c polymorphisms were 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(1) overexpression of bmi1 was roughly associated with advanced pathological stage and higher tumor grade of bladder cancer.(1) although the major limitation of this study is a weakness in the number of patients, the finding that bmi expression intensity correlates with cancer stage, suggests bmi1 may be a potential molecular target in patients with bladder cancer. statistical evaluations will reveal whether bmi1 overexpression is associated with an increased probability of bladder cancer-specific survival and recurrence-free survival. we hope that this article leads to additional studies. teruo inamoto haruhito azuma yoji katsuoka department of urology, osaka medical college, osaka, japan e-mail: tinamoto@poh.osaka-med.ac.jp references 1. malekzadeh shafaroudi a, mowla sj, ziaee sam, bahrami ar, atlasi y, malakootian m. overexpression of bmi1, a polycomb group repressor protein, in bladder tumors: a preliminary report. urol j. 2008;5:99-105. 2. cookson ms. the surgical management of muscle invasive bladder cancer: a contemporary review. semin radiat oncol. 2005;15:10-8. 3. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001;19:666-75. 4. baumgart e, cohen ms, silva neto b, et al. identification and prognostic significance of an epithelial-mesenchymal transition expression profile in human bladder tumors. clin cancer res. 2007;13:1685-94. 5. yamada y, naruse k, nakamura k, et al. potential for molecular targeted therapy of her-2/neu for invasive bladder cancer: examination of gene amplification by fluorescence in situ hybridization. oncol rep. 2007;18:1183-7. v08_no_2_final.pdf laparoscopic urology 107urology journal vol 8 no 2 spring 2011 laparoscopic extraperitoneal simple prostatectomy for benign prostate hyperplasia a two-year experience bulent oktay,1 gokhan koc,2 hakan vuruskan,1 mahmut esad danisoglu,1 yakup kordan1 purpose: to evaluate the feasibility of laparoscopic simple prostatectomy for large volume prostates. materials and methods: between october 2007 and july 2009, laparoscopic simple prostatectomy was performed on 16 patients with the prostates over 80 ml. all the patients were operated with transvesical method. peri-operative and 3rd postoperative month data were recorded and evaluated. results: the mean prostate volume was 147 ml (range, 80 to 200 ml). the mean operation time, blood loss, duration of hospitalization, and duration of drain placement was 133 minutes (range, 75 to 210 minutes), 134 cc (range, 50 to 300 cc), 3.9 days (range, 2 to 7 days), and 2.1 days (range, 2 to 3 days), respectively. only one patient required blood transfusion due to postoperative bleeding and clot obstruction in the catheter lumen. postoperative infection was not seen and recatheterization was not needed in any of the patients. all the patients’ pathology reports were noted as benign. pre-operative and postoperative international prostate symptom score were 9.2 and 25.4, respectively. maximum urinary flow rate was 4.0 ml/sec pre-operatively, but 24.7 ml/sec postoperatively. conclusion: laparoscopic simple prostatectomy is a feasible method with low morbidity and improved postoperative outcomes. urol j. 2011;8:107-12. www.uj.unrc.ir keywords: prostatic hyperplasia, laparoscopy, prostatectomy 1uludag university medical faculty, department of urology, gorukle, bursa 16059, turkey 2tepecik teaching and research hospital, izmir 35121, turkey corresponding author: gokhan koc, md tepecik teaching and research hospital, izmir, 35121, turkey tel: +90 232 324 3264 fax: +90 232 433 0756 e-mail: gokfekoc@gmail.com received april 2010 accepted october 2010 introduction benign prostatic hyperplasia (bph) is one of the serious health problems of the aging men. around 60% of men manifest clinical symptoms of the disease by the 60 years of age(1) and nearly 3 out of every 10 men may undergo surgery.(2) prostate volume is principally considered in determination of the operation technique. for the prostates smaller than 30 ml, transurethral incision of the prostate (tuip) technique is found to be as effective as transurethral resection of the prostate (turp).(3,4) although an upper limit for the turp technique is not reported, it is recommended for the prostates smaller than 80 to 100 ml; however, for the larger volumes, open prostatectomy is the preferred operational technique.(5,6) on the other hand, with the successful results achieved recently, bipolar turp technique has become an alternative to the standard technique.(7) holmium laser enucleation of the prostate laparoscopic prostatectomy for bph—oktay et al 108 urology journal vol 8 no 2 spring 2011 (holep)(8,9) and photoselective vaporization of the prostate (pvp) using potassium titanyl phosphate (ktp)(10,11) are also successfully used techniques as alternatives to the open prostatectomy of the large volume prostates. similarly, laparoscopic simple prostatectomy (adenomectomy) is also in successful use since its very first introduction and a steady therapy alternative for the enlarged prostates today.(12) in this study, we evaluated the consequences of the extraperitoneal laparoscopic adenomectomy performed with transvesical approach. materials and methods between october 2007 and july 2009, laparoscopic adenomectomy was performed on 16 patients having symptomatic bladder outlet obstruction as well as 80 ml or more enlarged prostates that had been detected by transrectal ultrasonography. all of the procedures were performed by the same urologist (b.o.). duration of operation, total amount of blood loss during operation, duration of hospitalization, duration of catheter placement, blood transfusion needs, and other complications were all noted. international prostate symptom score (ipss) and maximum urinary flow rate (qmax) of all the operated patients were reassessed at the 3rd postoperative month. surgical technique operations were performed via extraperitoneal and transvesical approach using 5 ports. as a standard pre-operative management, rectal enema was applied just one night before the surgery to prepare the intestines. furthermore, antibioprophylaxis and also anticoagulant therapy to prevent venous thromboembolism were both administered to all the patients. on the operating table, in the modified trendelenburg position of the patient, a 20-f foley catheter was inserted. approximately, a 2-cm long transverse incision was made just under the umbilicus for the camera port placement. preperitoneal space was exposed by gentle blunt finger dissection and dilated with approximately 700 ml air, using a balloon dissector. subsequently, other ports were inserted under direct view. second and third ports, 10 mm each, were placed at mcburney point and on the left symmetry. forth and fifth ports, 5 mm each, were inserted at around 2 fingers long superomedial of the spina iliaca anterior superior, both on the right and on the left sides (figure 1). using a harmonic scalpel, a transverse incision was made at the vesicoprostatic junction of the bladder (figure 2). after the bladder was opened and the prostate was approached, a mucosal incision was performed between surgical capsule and adenoma. adenoma was enucleated with the assistance of a harmonic scalpel, an aspiration cannula, and a claw grasper (figure 3). following a 2-0 polyglactin trigonisation application, three-way 22 f foley catheter was inserted and the bladder figure 1. the prepared extraperitoneal space and replaced trocars. figure 2. transverse cystostomy near the vesicoprostatic junction. laparoscopic prostatectomy for bph—oktay et al 109urology journal vol 8 no 2 spring 2011 was closed with a 2-0 polyglactin ct-1 needle in one layer suture, in a running continuous fashion (figure 4). operation was finalized after the retropubic placement of one hemovac drain. results the mean prostate volume was 147 ml (range, 80 to 200 ml). the mean operation duration, blood loss, duration of hospitalization, and duration of drain placement was 133 minutes (range, 75 to 210 minutes), 134 cc (range, 50 to 300 cc), 3.9 days (range, 2 to 7 days), and 2.1 days (range, 2 to 3 days), respectively. only one patient required blood transfusion due to postoperative bleeding and clot obstruction in the catheter lumen (table). postoperative infection was not seen and recatheterization was not needed in any of the patients. all the patients’ pathology reports were noted as benign. preoperative and postoperative ipss were 9.2 and 25.4, respectively. maximum urinary flow rate was 4.0 ml/sec pre-operatively, but 24.7 ml/sec postoperatively. discussion despite decreased surgical therapy rates and improved medical therapy methods,(13) extraperitoneal laparoscopic adenomectomy is still the second major operation technique widely performed in the elderly men.(14) for the patients with symptomatic bph who are decided to be operated, the prostate volume is the most important factor in determining the operation method. transurethral incision of the prostate is the recommended method for the prostates smaller than 30 ml,(3,4) while turp is recommended for more enlarged prostates. however, when operation lasts more than 90 minutes, morbidity risk increases for the patients with acute urinary retention history and for the elderly patients over the age of 80 years. for the patients with the prostates greater than 80 to 100 ml with accompanying inguinal hernia, big bladder diverticulum, or bladder stones, open prostatectomy is the recommended operation method.(5,6) open prostatectomy accounts for 14% to 32% of all invasive procedures performed for bhp today in all european countries.(6,15) however, transfusion rate of 0% to 57% has been reported due to excessive bleeding.(5,6,16) therefore, even for the big prostates, minimal invasive procedures gain more importance today. recently, holep, pvp performed with ktp, and laparoscopic simple prostatectomy are the subjects that are highly concentrated on. kuntz and colleagues compared holep and open figure 3. adenoma dissection with harmonic scalpel and suction-irrigation cannula. figure 4. one-layer closing of the bladder. mean range age, y 63 52 to 73 prostatic weight, ml 147 80 to 220 operation time, mins 133 75 to 210 blood loss, cc 134 50 to 300 foley catheter duration, d 6.3 6 to 7 hospital stay, d 2.11 2 to 3 demographic characteristics and clinical data of the patients. laparoscopic prostatectomy for bph—oktay et al 110 urology journal vol 8 no 2 spring 2011 prostatectomy in patients with 100 gr or more enlarged prostates during the 5-year followup period. they reported that almost similar results were obtained with holep as open prostatectomy, and holep is a confident method to be performed.(8) in another study comparing holep and open prostatectomy in patients with enlarged prostates over 70 gr, naspro and associates found that operation duration was shorter in the open prostatectomy group while hospitalization and catheterization duration as well as blood loss were significantly less in the holep method. the overall operation success was almost similar to open prostatectomy method in the 2-year follow-up period.(9) skolarikos and coworkers compared pvp and open prostatectomy in patients with 80 gr or more enlarged prostates and detected shorter operation duration in the open prostatectomy group; however, catheterization period, hospital stay, and transfusion need were all much less in the pvp group. after 18-month follow-up, the similar operation success rates were reported in both groups.(17) it has been reported that laparoscopic prostatectomy requires shorter hospital stay, less amount of blood transfusion, and less analgesia, and yields better cosmetic results.(18) according to the less operational trauma, shorter time is required by the patient to return to the normal social life. despite hopeful results in the recent literature dealing with both robot-assisted transvesical(19) and transcapsular (millin)(20) operations as well as single port adenomectomy,(21,22) because of the limited number of subjects, extraperitoneal approach with five ports is the preferred method in use today. transvesical and the millin are two different techniques of the open adenomectomy operation. in the literature, there is one single study comparing these two techniques. in that study, transvesical and the millin techniques were not fround predominant to each other in terms of pre-operative data and postoperative results.(23) therefore, practical habits and preferences of the surgeon gain importance in this respect for the operation technique to be perceived. furthermore, duration of the open prostatectomy was evaluated shorter than laparoscopic method and total blood loss, irrigation, and catheterization duration as well as hospital stay were found considerably less in the laporoscopic group. in another study comparing laparoscopic millin method and open prostatectomy, porpiglia and colleagues reported that total amount of blood loss was considerably less in the laparoscopy group, but operation duration, analgesia need, catheterization duration, and hospital stay were almost the same in these two groups.(24) they also compared the first ten laparoscopic operations with the next ten in terms of operation duration and found it significantly shorter, but did not observe any differences in terms of other parameters. mccullough and associates compared laparoscopic millin technique with open prostatectomy. they reported significantly longer operation duration, but shorter catheterization and hospitalization duration in the laparoscopy group. they did not find any difference between bleeding and irrigation periods.(25) similarly, successful consequences of the laparoscopic adenomectomy with millin technique was reported in many diffent studies.(26,28) data regarding transvesical adenomectomy are scarce. sotelo and coworkers reported a significant improvement in the postoperative ipss and qmax values of the 17 patients, but five (29%) of their patients needed blood transfusion.(29) in present study, ipss and qmax values significantly improved in the 3rd postoperative month. despite the long learning curve in the laparoscopic surgery praxis, the operation duration of 133 minutes in our study is compatible with the literature. in addition, duration of catheterization and hospital stay were also similar to literature. our mean blood loss was 134 cc, which was reasonably less. sotelo and colleagues reported the blood loss of approximately 660 cc in their first five patients, which decreased to 165 cc in their last 12 subjects, in parallel to the learning curve. in our study, only 1 patient needed transfusion due to the obstruction of the catheter with laparoscopic prostatectomy for bph—oktay et al 111urology journal vol 8 no 2 spring 2011 bleeding. we achieved optimal minimum risk of transfusion with the effective utilization of harmonic scalpel in adenomectomy procedures. the most important drawback of laparoscopic adenomectomy seems to be the long duration of the operation. however, the number of subjects studied in the literature is very few. we believe that if the number of patients studied increased, operation duration would be shorter and possibe complications faced in the operations would also decrease. conclusion laparoscopic adenomectomy is an appropriate operation method for the big prostates. in our study, with our low rate of morbidity and considerably successful operation results, we showed that laparoscopic adenomectomy is a reasonable alternative to the open prostatectomy, which has been widely accepted as the major procedure. however, it seems that laser prostatectomy procedures, like holep and pvp, are also suitable alternative methods to the open prostatectomy, especially for the enlarged prostates. however, the most effecive way to decide on the operation method is to compare laser prostatectomy and laparoscopic adenomectomy with more subjects in various studies. conflict of interest none declared. references 1. arrighi hm, metter ej, guess ha, fozzard jl. natural history of benign prostatic hyperplasia and risk of prostatectomy. the baltimore longitudinal study of aging. urology. 1991;38:4-8. 2. boyle p. epidemiology of benign prostatic hyperplasia: risk factors and concomitance with hypertension. br j clin pract suppl. 1994;74:18-22. 3. yang q, peters tj, donovan jl, wilt tj, abrams p. transurethral incision compared with transurethral resection of the prostate for bladder outlet obstruction: a systematic review and meta-analysis of randomized controlled trials. j urol. 2001;165:1526-32. 4. tkocz m, prajsner a. comparison of long-term results of transurethral incision of the prostate with transurethral resection of the prostate, in patients with benign prostatic hypertrophy. neurourol urodyn. 2002;21:112-6. 5. tubaro a, carter s, hind a, vicentini c, miano l. a prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. j urol. 2001;166:172-6. 6. serretta v, morgia g, fondacaro l, et al. open prostatectomy for benign prostatic enlargement in southern europe in the late 1990s: a contemporary series of 1800 interventions. urology. 2002;60:623-7. 7. ho hs, cheng cw. bipolar transurethral resection of prostate: a new reference standard? curr opin urol. 2008;18:50-5. 8. kuntz rm, lehrich k, ahyai sa. holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-year followup results of a randomised clinical trial. eur urol. 2008;53:160-6. 9. naspro r, suardi n, salonia a, et al. holmium laser enucleation of the prostate versus open prostatectomy for prostates >70 g: 24-month follow-up. eur urol. 2006;50:563-8. 10. rajbabu k, chandrasekara sk, barber nj, walsh k, muir gh. photoselective vaporization of the prostate with the potassium-titanyl-phosphate laser in men with prostates of >100 ml. bju int. 2007;100:593-8; discussion 8. 11. alivizatos g, skolarikos a, chalikopoulos d, et al. transurethral photoselective vaporization versus transvesical open enucleation for prostatic adenomas >80ml: 12-mo results of a randomized prospective study. eur urol. 2008;54:427-37. 12. mariano mb, graziottin tm, tefilli mv. laparoscopic prostatectomy with vascular control for benign prostatic hyperplasia. j urol. 2002;167:2528-9. 13. holtgrewe hl, ackermann r, bay-nielsen h, et al. report from the committee on the economics of bph. in: cockett atk, ed. third international consultation on benign prostatic hyperplasia (bph). jersey: scientific communication international; 1996:51-70. 14. meigs j, barry m. natural history of benign prostatic hyperplasia. in: kirby r, ed. textbook of benign prostatic hyperplasia. oxford: isis medical media; 1996:125–35. 15. tubaro a, montanari e. management of symptomatic bph in italy: who is treated and how? eur urol. 1999;36 suppl 3:28-32. 16. debruyne fmj, djavan b, de la rosette j. interventional therapy for benign prostatic hyperplasia. in: chatelain c, denis l, foo kt, khoury s, mcconnell j, eds. benign prostatic hyperplasia. plymouth: plymbridge distributors; 2001:399–421. 17. skolarikos a, papachristou c, athanasiadis g, chalikopoulos d, deliveliotis c, alivizatos g. eighteen-month results of a randomized prospective study comparing transurethral photoselective vaporization with transvesical open enucleation for prostatic adenomas greater than 80 cc. j endourol. 2008;22:2333-40. 18. tooher r, swindle p, woo h, miller j, maddern g. laparoscopic radical prostatectomy for localized prostate cancer: a systematic review of comparative studies. j urol. 2006;175:2011-7. laparoscopic prostatectomy for bph—oktay et al 112 urology journal vol 8 no 2 spring 2011 19. sotelo r, clavijo r, carmona o, et al. robotic simple prostatectomy. j urol. 2008;179:513-5. 20. yuh b, laungani r, perlmutter a, et al. robot-assisted millin’s retropubic prostatectomy: case series. can j urol. 2008;15:4101-5. 21. desai mm, aron m, canes d, et al. single-port transvesical simple prostatectomy: initial clinical report. urology. 2008;72:960-5. 22. sotelo rj, astigueta jc, desai mm, et al. laparoendoscopic single-site surgery simple prostatectomy: initial report. urology. 2009;74:626-30. 23. baumert h, ballaro a, dugardin f, kaisary av. laparoscopic versus open simple prostatectomy: a comparative study. j urol. 2006;175:1691-4. 24. porpiglia f, terrone c, renard j, et al. transcapsular adenomectomy (millin): a comparative study, extraperitoneal laparoscopy versus open surgery. eur urol. 2006;49:120-6. 25. mccullough tc, heldwein fl, soon sj, et al. laparoscopic versus open simple prostatectomy: an evaluation of morbidity. j endourol. 2009;23:129-33. 26. van velthoven r, peltier a, laguna mp, piechaud t. laparoscopic extraperitoneal adenomectomy (millin): pilot study on feasibility. eur urol. 2004;45:103-9; discussion 9. 27. mariano mb, tefilli mv, graziottin tm, morales cm, goldraich ih. laparoscopic prostatectomy for benign prostatic hyperplasia--a six-year experience. eur urol. 2006;49:127-31; discussion 31-2. 28. zhou ly, xiao j, chen h, zhu yp, sun yw, xuan q. extraperitoneal laparoscopic adenomectomy for benign prostatic hyperplasia. world j urol. 2009;27:385-7. 29. sotelo r, spaliviero m, garcia-segui a, et al. laparoscopic retropubic simple prostatectomy. j urol. 2005;173:757-60. urological oncology interobserver variability in assessment of renal mass biopsies łukasz nyk1, wojciech malewski1, krystian kaczmarek2, piotr kryst3, michał pyźlak4, aneta andrychowicz5, tomasz ząbkowski6* purpose: the main goal of this study was to assess the histopathological efficacy of renal mass biopsy and to check the concordance between pathological results and biopsy of the final specimen, as well as interobserver variability in the assessment of biopsy cores. materials and methods: a hundred sets of core biopsies of postoperative specimens (renal masses) have been performed. three core biopsies of the intact specimen had been performed once the kidney with the tumor, or the tumor alone were resected. the urologist aimed to obtain two cores from the peripheral sides of the tumor and one core from its center. the surgical specimen was evaluated by a single pathologist, whereas biopsy samples were referred to three independent pathologists who were blinded to the final results of the renal mass biopsy. results: nondiagnostic biopsy rates ranged from 13% to 22%. sensitivity and specificity ranged 83-97% and 97-99% by excluding nondiagnostic results. the concordance between assessment of surgical specimen and biopsy in the fuhrman grading system ranged 36.5-77.0%, respectively. interobserver agreement between the three pathologists was substantial or moderate, depending on the tumor subtype. the krippendorff's alpha coefficient, calculated by excluding the nondiagnostic results, was 0.28 (moderate agreement) for the fuhrman grading system. conclusion: the agreement regarding grading of biopsies between three pathologists ranged from moderate to substantial. therefore, a team of dedicated uropathologists should be engaged in final diagnosis of renal mass biopsy rather than single one before implementing the proper treatment. keywords: renal mass biopsy; interobserver variability; assessment; efficacy; treatment introduction over the past decades, the detection rate of renal cell carcinoma (rcc) has increased. availability of ultrasound diagnostics has contributed to frequent diagnoses of small renal masses (srms) as well as larger asymptomatic tumors(1). because up to 33% of srms present as benign lesions on the final pathological examination, preoperative diagnosis is of significant value(2). currently, only angiomyolipomas (amls) can be confirmed with cross-sectional imaging without histopathological examination(3). although techniques of partial nephrectomy have been refined through robotic assistance, nephron-sparing surgery still carries a risk of complications(4). consequently, srm surveillance poses an interesting management modality, especially in the elderly and/or comorbid patients(5). moreover, a large multi-institutional study by pierorazio confirmed the safety and uncompromised cancer-specific survival of patients with srm managed with active surveillance 1department of urology, european health center, otwock, poland, ii urology clinic, centre of postgraduate medical education, warsaw, poland. 2department of urology and urological oncology, pomeranian medical university, szczecin, poland. 3department of urology, bielański hospital, warsaw, poland, ii urology clinic, centre of postgraduate medical education, warsaw, poland. 4department of pathology and laboratory medicine. maria sklodowska-curie institute cancer center. roentgena 5, 02-781 warsaw, poland. 5urological clinic, warsaw, poland. 6department o urology, military institute of medicine, warsaw, poland. *correspondence: department o urology, military institute of medicine, warsaw, poland, e mail: urodent@wp.pl, phone number: 0048 791 533 555 received february 2020 & accepted october 2020 (as). renal mass biopsy, pathological proof of benignancy or relatively low-risk pathology, with regular radiological follow-up, are essential parts of such management(6). eau guidelines recommend performing biopsies with at least two cores, avoiding necrotic areas in the tumor. biopsy of cystic masses is questionable. on the other hand, obtaining reliable pathology from bosniak iii lesions preoperatively would be valuable as most of them are benign or have low malignant potential(7). the present metanalysis confirmed high sensitivity and specificity of renal mass biopsy in the diagnosis of malignancy. concordance of biopsy results and final specimen for histotype is lower. correct assessment of tumor grade seems to be the most challenging(6). as the diagnosis of malignancy is of the highest importance for active surveillance, variability of assessments between different pathologists is intriguing. this study focuses on the accuracy and interobserver variability of histopathourology journal/vol 18 no. 4/ july-august 2021/ pp. 400-403. [doi: 10.22037/uj.v16i7.6024] logical results of renal mass biopsy performed in ideal non-real life conditions. even computerized tomography guidance may result in insufficient material for analysis(8). as biopsies were performed “in-bench” postoperatively, samples were most representative for this kind of study as the tumor was sampled directly without imaging guidance. to the best of our knowledge, this is the second study assessing histopathological interobserver variability of renal mass biopsies performed “in-bench” with a large number of cases. materials and methods a hundred sets of core biopsies of postoperative specimens (renal masses) have been performed. all patients provided written informed consent before the procedure, to allow the use of the specimen for this study. it was used an 18-g core needle for each biopsy. the urologist aimed to obtain two cores from the peripheral sides of the tumor and one core from its center. after the biopsy, the surgical specimen was processed as previously described. biopsy samples were fixed in formalin, embedded in paraffin, and stained with hematoxylin and eosin dye. the surgical specimen was evaluated by a single pathologist, whereas biopsy samples were referred to three independent pathologists who were blinded to the final results of the renal mass biopsy. all three pathologists are trained in genitourinary pathology with at least ten years of work experience. their task was to subclassify biopsy samples into one of the following tumor types: clear cell rcc (ccrcc), chromophobe rcc (chrcc), papillary rcc (prcc), urothelial carcinoma, collecting duct carcinoma, neuroendocrine tumor, renal oncocytoma, and angiomyolipoma. furthermore, they were asked to identify the ccrcc grade according to the fuhrman grading system. samples without tumor patterns were classified as non-diagnostic, whereas samples in which the pathologist could not decide between malignant or benign were classified as nonconclusive. statistical analysis the diagnostic accuracy was calculated for each pathologist. the results obtained with the index test were compared with those of the reference standard, which was the complete surgical specimen. analysis of the diagnostic accuracy included assessment of the following measures: sensitivity/specificity, positive predictive value (ppv), and negative predictive value. for each measure, 95% confidence intervals (cis) were calculated. additionally, overall accuracy was calculated by the sum of correctly scored core biopsies. since there were four possible results of the index test (nondiagnostic, nonconclusive, malignant tumor, and benign tumor), diagnostic accuracy was calculated in two different ways: with and without exclusion of nondiagnostic results from the index test. the diagnostic accuracy to classify a malignant or benign tumor was calculated by excluding nondiagnostic samples. the generalized kappa was calculated to measure the agreement between the three pathologists in the classification of subtypes of renal tumors, and krippendorff's alpha coefficient was used to measure agreement in the ccrcc grade (interobserver variability). the generalized kappa and krippendorff's alpha coefficients were calculated by excluding the nondiagnostic results. the following interpretation of agreement was used: fair, 0.00-0.20; moderate, 0.21-0.45; substantial, 0.46-0.75; almost perfect, 0.76-0.99; and perfect, 1.00(9). a negative value indicates nonstoichastic agreement. an unpaired (two-sample) t-test was performed to evaluate differences between means. statistica software, version 13.5 (statsoft, inc., tulsa, ok) was used for all statistical analyses. a p-value < 0.05 was considered significant and all p-values were two-sided. results nondiagnostic biopsy rates ranged from 13% to 22%. seven sets of cores were recognized as nondiagnostic by all pathologists, of which, six were derived from nephrectomy specimens and one from nephron-sparing surgery of multi-cystic rcc lesions. the mean tumor urological oncology 401 diagnostic accuracy of renal core biopsies for the individual pathologists, calculated by excluding nondiagnostic results and nonconclusive results 1 – pathologist 1 td – pathologist 2 mp – pathologist 3 estimated value lower limit upper limit estimated value lower limit upper limit estimated value lower limit upper limit sensitivity (%) 97.7% 91.1% 99.6% 83.3% 72.8% 90.5% 85.5% 75.7% 92.0% specificity (%) 99.7% 98.7% 99.9% 97.6% 95.6% 98.7% 97.8% 96.0% 98.8% ppv (%) 97.7% 91.1% 99.6% 85.5% 75.1% 92.2% 86.6% 76.8% 92.8% npv (%) 99.7% 98.7% 99.9% 97.2% 95.1% 98.4% 97.6% 95.7% 98.7% table 1. diagnostic accuracy of renal core biopsies for the individual pathologists, calculated by excluding nondiagnostic results and nonconclusive results table 2. diagnostic accuracy of renal core biopsies to classify a malignant tumor for the individual pathologists, calculated by including the nondiagnostic results diagnostic accuracy of renal core biopsies to classify a malignant tumor for the individual pathologists, calculated by including the nondiagnostic results 1 – pathologist 1 td – pathologist 2 mp – pathologist 3 estimated value lower limit upper limit estimated value lower limit upper limit estimated value lower limit upper limit sensitivity (%) 86.2% 77.1% 92.1% 74.5% 64.2% 82.6% 79.8% 70.0% 87.1% specificity (%) 100.0% 51.7% 100.0% 100.0% 51.7% 100.0% 100.0% 51.7% 100.0% ppv (%) 100.0% 94.4% 100.0% 100.0% 93.5% 100.0% 100.0% 93.9% 100.0% npv (%) 31.6% 13.6% 56.5% 20.0% 8.4% 39.1% 24.0% 10.2% 45.5% variability in renal mass biopsies-nyk et al. size of diagnostic and nondiagnostic cbs (for at least one pathologist) was 44.6 mm (sd ± 22.5) and 40.6 mm (sd ± 17.5), respectively. no differences between the groups were observed (p = 0.380). there were no nonconclusive samples. the summary of the scoring results of nondiagnostic, nonconclusive, correctly and incorrectly scored cbs, and overall accuracy of the three pathologists is presented in table 1. the diagnostic accuracy of renal core biopsies, calculated by excluding nondiagnostic results, was high in the assessments performed by all pathologists. sensitivity and specificity ranged 83-97% and 97-99%, respectively. high diagnostic accuracy was also estimated for malignant tumors (sensitivity 74-86%, and specificity 100%). all the above-mentioned measures had narrow 95% cis. the lowest diagnostic accuracy was calculated for benign tumors, with sensitivity ranging 66.783.3% and specificity ranging 88.5-100% and wide 95%cis. correspondingly, ppv for benign tumors varied across pathologists and the estimated 95%cls were wide (table 2,3). malignant tumors dominated in the analyzed populations (93%). in addition, ccrcc was the most representative group (74 cases). the concordance between surgical specimen and biopsy for ccrcc ranged between 75% and 87%. in two cases, ccrcc was mistaken as a benign tumor in biopsy. further, 100% concordance with biopsy results was found for ro and ucc. perfect interobserver agreement was estimated for aml and ucc, whereas only fair agreement was estimated for cdc and crcc (table 4,5). the distribution of the ccrcc grade in the fuhrman grading system was 23% (grade 1), 66.2% (grade 2), 5.4% (grade 3), and 5.4% (grade 4). the concordance between assessment of surgical specimen and biopsy in the fuhrman grading system ranged 36.5-77.0%, respectively. interobserver agreement between the three pathologists was substantial or moderate, depending on the subtype (table 5). the krippendorff's alpha coefficient, calculated by excluding the nondiagnostic results, was 0.28 for the fuhrman grading system. discussion rmb plays a pivotal role in the active surveillance of renal tumors. proper assessment of biopsy cores is crucial in the final decision making. the main goal of this study was to assess the histopathological efficacy of rmb and to check the concordance between pathological results and biopsy of the final specimen, as well as interobserver variability in the assessment of biopsy cores. the number of nondiagnostic biopsy results (13-22%) in the current study is comparable with other series (1020%)(10). meta-analysis provided the highest level of evidence available on rmb performance(11,12). although the biopsies were performed after the resection of the specimen, we expected a higher diagnostic yield. in a similar study with a lower number of cases by kummerlin et al., nondiagnostic biopsy rate ranged from 8-16% (13). the reason for this might be the performance of biopsies by a few different surgeons. inconclusive results of the biopsies do not exclude further repeat rmbs. diagnostic yield of secondary rmb may reach up to 83%(14). the most significant role of rmb is to differentiate malignant tumors from benign lesions. including only diagnostic cores, sensitivity and specificity in diagnosing malignancy were similar to those reported in a large meta-analysis by marconi et al. in which sensitivity and specificity reached 99.1% and 99.7%, respectively. however, direct comparison of these two studies is not possible as that meta-analysis mentioned excluded studies with ex vivo biopsies(12). currently, the largest study on diagnostic accuracy of “in bench” biopsies was published in 2007. sensitivity ranged between 79-91% and specificity was 100% in malignancy diagnosis. this analysis focused on interobserver variability in tumor subtyping, which ranged from substantial to almost perfect. however, it did not include assessment of interobserver variability in tumor grade based on biopsy cores. to our knowledge, our study is the first to evaluate this issue. in real life situations, decisions regarding introducing active surconcordance between the surgical specimen and renal core biopsies for the individual pathologists (%) 1 – pathologist 1 td – pathologist 2 mp – pathologist 3 rcc (74) 87.7 75.7 81.1 prcc (10) 60.0 30.0 40.0 crcc (5) 80.0 0.0 0.0 ro (3) 100.0 100,0 100.0 xgo (1) 0.0 0.0 0.0 aml (2) 50.0 50.0 50.0 ucc (2) 100.0 100.0 100.0 cdc (1) 100.0 0.0 0.0 net (2) 100.0 0.0 50.0 table 4. concordance between the surgical specimen and renal core biopsies for the individual pathologists (%) variability in renal mass biopsies-nyk et al. table 3. diagnostic accuracy of renal core biopsies to classify a benign tumor for the individual pathologists, calculated by including the nondiagnostic results diagnostic accuracy of renal core biopsies to classify a benign tumor for the individual pathologists, calculated by including the nondiagnostic results 1 – pathologist 1 td – pathologist 2 mp – pathologist 3 estimated value lower limit upper limit estimated value lower limit upper limit estimated value lower limit upper limit sensitivity (%) 83.3% 36.5% 99.1% 66.7% 24.1% 94.0% 66.7% 24.1% 94.0% specificity (%) 100.0% 95.1% 100.0% 96.8% 90.3% 99.2% 95.7% 88.8% 98.6% ppv (%) 100.0% 46.3% 100.0% 57.1% 20.2% 88.2% 50.0% 17.4% 82.5% npv (%) 98.9% 93.4% 99.9% 97.8% 91.7% 99.6% 97.8% 91.6% 99.6% vol 18 no 4 july-august 2021 402 veillance are not only based on diagnosing malignancy. the crucial issue is also the proper assessment of the tumor grade. interobserver agreement in tumor grade was moderate and substantial. therefore, in our opinion, the final diagnosis should be provided by a team of pathologists rather than an individual one(13). in our study, three cases of chromophobe carcinoma were erroneously diagnosed by two pathologists as oncocytoma based on biopsy cores. the diagnostic challenge of differentiating low grade chromophobe and hybrid oncocytoma-chromophobe rccs from oncocytic lesions is well known. however, using additional immunohistochemical staining limits this problem. moreover, the course of disease in low grade chromophobe and hybrid oncocytoma-chromophobe rccs is rather benign. study limitations first of all, the biopsies were performed “in bench” therefore the study does not reflect real life conditions. the study material was collected prospectively irrespective of tumor size and imaging suspicion of tumor type. consequently, it does not reflect the biopsy potential within active surveillance setting. moreover, operations and postoperative biopsies were performed by several different surgeons, which may justify lower than expected diagnostic yield. conclusions the agreement regarding grading of biopsies between three pathologists ranged from moderate to substantial. therefore, a team of dedicated uropathologists should be engaged in the final diagnosis of renal mass biopsy rather than a single one before implementing the proper treatment, especially active surveillance. further analysis of a larger cohort of cases should be performed to confirm our results. conflict of interest the authors declared no conflict of interest. references 1. ljungberg b, campbell sc, choi hy, jacqmin d, lee je, weikert s, et al. the epidemiology of renal cell carcinoma. eur urol. 2011;60:615-21. 2. corcoran at, russo p, lowrance wt, asnisalibozek a, libertino ja, pryma da, et al. a review of contemporary data on surgically resected renal masses-benign or malignant? urology. 2013;81:707-13. 3. flum as, hamoui n, said ma, yang xj, casalino dd, mcguire bb, et al. update on the diagnosis and management of renal angiomyolipoma. j urol. 2016;195:834-46. 4. choi je, you jh, kim dk, rha kh, lee sh. comparison of perioperative outcomes between robotic and laparoscopic partial nephrectomy: a systematic review and metaanalysis. eur urol. 2015;67:891-01. 5. ljungberg b, bensalah k, canfield s, dabestani s, hofmann f, kuczyk ma, et al. eau guidelines on renal cell carcinoma: 2014 update. eur urol. 2015;67:913–24. 6. pierorazio pm, johnson mh, ball mw, gorin ma, trock bj, chang p, et al. five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the dissrm registry. eur urol. 2015;68:408-15. 7. schoots ig, zaccai k, hunink mg, verhagen pcms. bosniak classification for complex renal cysts reevaluated: a systematic review. j urol. 2017;198:12-21. 8. neuzillet y, lechevallier e, andre m, daniel l, coulange c. accuracy and clinical role of fine needle percutaneous biopsy with computerized tomography guidance of small (less than 4.0 cm) renal masses. j urol. 2014;171:1802-05. 9. munoz sr, bangdiwala si. interpretation of kappa and b statistics measures of agreement. j appl statistics. 1997;24:105-11. 10. patel hd, johnson mh, pierorazio pm, sozio sm, sharma r, iyoha e, et al. diagnostic accuracy and risks of biopsy in the diagnosis of a renal mass suspicious for localized renal cell carcinoma: systematic review of the literature. j urol. 2016;195:1340-7. 11. richard po, jewett ma, tanguay s, saarela o, liu za, pouliot f, et al. safety, reliability and accuracy of small renal tumour biopsies: results from a multi-institution registry. bju int. 2016;119:543-9. 12. marconi l, dabestani s, lam tb, hofmann f, stewart f, norrie j, et al. systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. eur urol. 2016;69:660-73. 13. kummerlin i, ten kate f, smedts f, horn t, algaba f, trias i, et al. core biopsies of renal tumors: a study on diagnostic accuracy, interobserver, and intraobserver variability. eur urol. 2008; 53:1219-27. 14. leveridge mj, finelli a, kachura jr, evans r, chung h, shiff da, et al. outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. eur urol. 2011;60:578-84. table 5. interobserver variability for the renal subtypes interobserver variability for the renal subtypes rcc 0.6 .prcc 0.5 crcc 0.1 ro 0.7 unrcc 0.5 aml 1.0 ucc 1.0 cdc 0.0 net 0.3 variability in renal mass biopsies-nyk et al. urological oncology 403 u j all final for web.pdf 790 | urology and nephrology research center; department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran farzaneh sharifiaghdas, mehdi kardoust parizi, babak ahadi efficacy of transurethral bladder neck incision with 2-micron continuous wave laser (revolix) for the management of bladder outlet stricture in women corresponding author: mehdi kardoust parizi, md urology and nephrology research center, no. 103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2265 7222 fax: +98 21 2256 7282 e-mail: m.kardoust@ yahoo.com received september 2012 accepted november 2012 purpose: materials and methods: results: p p p conclusion: term clinical outcomes. keywords: female, laser, urinary incontinence, urodynamics, prospective studies female urology female urology 791vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l introduction although bladder neck obstruction is prevalent in its manage-ment has been addressed more among men in (2) various treatment modalities are reported for bladder neck obstruction in literature, including medical therapy, clean intermittent catheterization (cic), urethral dilator, and endoscopic incision. management of refractory bladder neck stenosis (bns) by transurethral bladder neck incision using 2-micron continumaterials and methods blockers) for more than 3 months and had undergone at least sponse. fore the surgery according to international continence soci and cystourethroscopic aptients had previously received medical treatment, such as satisfactory results. all the patients had a negative urine culture before the procedure. international prostate symptom recorded. (pvr) urine using post void urethral catheterization. urodyoperation technique lisa laser products, katlenburg, germany) under general the results. a p results transurethral bladder neck incision with revolix laser | sharifiaghdas et al 792 | the procedure. the mean times of bladder neck dilation beto severe trabeculation of the bladder. mean operation time novo stress incontinence after the surgery. median ipss imp p one month after the procedure. p in pvr urine volume (p p gross hematuria, febrile urinary tract infection, urinary sepsis, bladder perforation, deep venous thrombosis, or pulmonary emboli. discussion symptoms during their practice, mostly caused by bns, neuis not as common as men. furthermore, due to lack of univer2 in another study, zhang and associates performed transurethral incision of the bladder neck for the management of female bladder outlet obstruction. using video-urodynamic study, radio2 bladder outlet obstruction. bladder outlet obstruction. mended that a full video-urodynamic evaluation is essential for correct diagnosis and selection of appropriate treatment plan.(3) score, multichannel urodynamic parameters, and cystourerefractory cases to conservative therapy can be considered as indication for surgical intervention. after making decision for surgical intervention, patients should be informed about possible urinary incontinence. endoscopic managemodalities include cold-knife incision, electrocautery of the bladder neck, and mechanical dilation of the stenosis. bladder neck incision has been reported to improve voiding neykov and associates evaluated late results of transurethral bladder neck in another study, urodynamic characteristics of patients before and one month after the procedure. variable pre-operative postoperative p median peak flow rate (range), ml/s 8 (2.7 to 12) 11 (9.1 to 16) .005 median maximum voiding pressure (range), cm h 2 o 67.5 (13.3 to 155.5) 55 (33 to 81.9) .59 median post void residual urine (range), ml 101 (30 to 300) 17 (0 to 100) .003 female urology 793vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l transurethral bladder neck incision with revolix laser | sharifiaghdas et al primary bladder neck obstruction. improvements in ipss, patients. reported de-novo stress urinary incontinence rate modality in the management of female primary bladder neck obstruction.(7) recently, laser energy has been evaluated as a promising utility in management of bladder neck obstruction. fu and xu bns. they reported clinical and urodynamic improvement, of female bns.(2) ous cutting and coagulation of perfused, avascular, and either hardly vascularized tissues, such as scars. in another study, cedure in the treatment of recurrent bladder neck sclerosis. detrusor pressure before and after the surgery. there are several limitations to the present study. first, due to used combination of diagnostic modalities, including ipss, prevent possible postoperative incontinence. this strategy perhaps, a deeper bladder neck incision can be performed coclusion conflict of interest none declared. references 1. el-baz ma, yousef aa, moustafa h. transurethral incision of the bladder neck: an objective and subjective evaluation of its efficacy. int urol nephrol. 1995;27:717-21. 2. fu q, xu ym. transurethral incision of the bladder neck using ktp in the treatment of bladder neck obstruction in women. urol int. 2009;82:61-4. 3. peng ch, kuo hc. transurethral incision of bladder neck in treatment of bladder neck obstruction in women. urology. 2005;65:275-8. 4. klijer r, bar k, bialek w. bladder outlet obstruction in women: difficulties in the diagnosis. urol int. 2004;73:6-10. 5. kumar a, mandhani a, gogoi s, srivastava a. management of functional bladder neck obstruction in women: use of α-blockers and pediatric resectoscope for bladder neck incision. j urol. 1999;162:2061-5. 6. athanasopoulos a, gyftopoulos k, giannitsas k, perimenis p. effect of alfuzosin on female primary bladder neck obstruction. int urogynecol j pelvic floor dysfunct. 2009;20:217-22. 7. jin xb, qu hw, liu h, li b, wang j, zhang yd. modified transurethral incision for primary bladder neck obstruction in women: a method to improve voiding function without urinary incontinence. urology. 2012;79:310-3. 794 | 8. yee ch, ho ly, hung hh, chan wh. the effect of urethral calibration on female primary bladder outlet obstruction. int urogynecol j. 2012;23:217-21. 9. chassagne s, bernier pa, haab f, roehrborn cg, reisch js, zimmern pe. proposed cutoff values to define bladder outlet obstruction in women. urology. 1998;51:408-11. 10. akikwala tv, fleischman n, nitti vw. comparison of diagnostic criteria for female bladder outlet obstruction. j urol. 2006;176:2093-7. 11. zhang p, yang y, wu zj, zhang xd, zhang ch. videourodynamics study on female patients with bladder neck obstruction. chin med j (engl). 2012;125:1425-8. 12. farrar dj, osborne jl, stephenson tp, et al. a urodynamic view of bladder outflow obstruction in the female: factors influencing the results of treatment. br j urol. 1975;47:81522. 13. gronbaek k, struckmann jr, frimodt-moller c. the treatment of female bladder neck dysfunction. scand j urol nephrol. 1992;26:113-8. 14. jenkins jd, allen nh. bladder neck incision--a treatment for retention with overflow in the absence of adenoma. br j urol. 1978;50:395-7. 15. waymont b, ward jp, perry kc. long-term assessment of 107 patients undergoing bladder neck incision. br j urol. 1989;64:280-2. 16. soonawalla pf, pardanani ds. transurethral incision versus transurethral resection of the prostate. a subjective and objective analysis. br j urol. 1992;70:174-7. 17. neykov kg, panchev p, georgiev m. late results after transurethral bladder neck incision. eur urol. 1998;33:73-8. 18. bach t, herrmann tr, cellarius c, gross aj. bladder neck incision using a 70 w 2 micron continuous wave laser (revolix). world j urol. 2007;25:263-7. female urology endourology and stone disease ultra-mini-percutaneous nephrolithotomy for the treatment of upper urinary tract stones sized between 10-20 mm in children younger than 8 years old heshmatollah sofimajidpour1,2, bushra zareie2,3, mohammad aziz rasouli2,3*, masoumeh hoseini4 purpose: with the invention of miniature devices, it has been advised to apply less aggressive methods for the management of upper urinary tract stones, especially in children. in the recent years, ultra-mini percutaneous nephrolithotomy (ump) has been used for the treatment of upper urinary tract stones in order to perform surgeries with less complications and more acceptable outcomes. results reported from different medical centers have been promising. materials and methods: twenty-two children aged less than 8 years old with upper urinary stones sized between 10-20 mm underwent ump. inclusion criteria was solitary unilateral kidney stone, stone size between 10-20 mm, normal renal function tests, absence of any congenital malformations, and history of previous eswl failure. data including age, sex, side of kidney involvement, size of stone, location of stone, duration of surgery, duration of hospitalization, stone composition, need for blood transfusion, damage to adjacent organs, postoperative fever, septicemia after surgery, need for narcotics, further need for a complementary method, stone-free rate, pre and post-operative hemoglobin levels, and urinary leakage from the access tract were extracted from patients' medical files and were recorded. results: the mean age (± standard deviation) of children was 5.22 (±1.57) years. fourteen (63.6%) patients were male. fifteen (68.2%) renal stones were located in the right kidney, and 82% of patients had pelvis stones. 13 (59%) patients’ stones were composed of calcium oxalate. stone-free rate was 95.5%. in none of the cases urinary leakage, septicemia after surgery, injury to adjacent organs, and need for blood transfusions was reported. conclusion: ultra-mini percutaneous nephrolithotomy is an efficient and safe method for treating urinary stones sized between 10-20 mm in children. keywords: children; iran; nephrolithiasis; percutaneous nephrolithotomy; ultra-mini-percutaneous nephrolithotomy introduction kidney and urinary tract stones are one of the most common problems in pediatrics and due to factors such as sanitary lifestyle, malnutrition, anatomical abnormalities, genetics, poor fluid consumption, and inappropriate medication use, its prevalence is increasing (1,2). urinary tract stones are more common in males than females with men being three times more likely than women to acquire this disease(3). although the male predominance is maintained, this ratio is slightly different in children and the odds of having a urinary stone is 1.5-2 times more likely in boys(3). in 2010, the incidence of kidney stones in children was estimated to be 50 cases per 100,000 people, showing a dramatic increase(4). due to the high prevalence and recurrence rate of urinary stones, a less invasive, cost-effective approach which can also be easily repeated is necessary for the management of urinary stones (5). the majority of pediatric urinary stones can be effectively managed 1department of urology, faculty of medicine, kurdistan university of medical sciences, sanandaj, iran 2clinical research development center, kowsar hospital, kurdistan university of medical sciences, sanandaj, iran 3department of epidemiology and biostatistics, faculty of medicine, kurdistan university of medical sciences, sanandaj , iran. 4student research committee, kurdistan university of medical sciences, sanandaj, iran *correspondence: m.sc epidemiology, vice chancellor for educational and research, kowsar hospital, kurdistan university of medical sciences, pasdaran ave, sanandaj, iran. tel: +988733131366. email: rasouli1010@gmail.com. received january 2020 & accepted march 2020 with less invasive procedures such as eswl, pcnl, and rirs (6). in 2013, desai and colleagues introduced the ultra-mini percutaneous nephrolithotomy (ump) which has shown to be an effective method for treating medium-sized urinary stones(7,8). since there are limited studies investigating this approach in the pediatric population, the aim of this study was to evaluate ultra-mini percutaneous nephrolithotomy (ump) for the treatment of upper urinary tract stones sized between 10-20 mm in children younger than 8 years in terms of safety and efficacy. materials and methods study design this study was performed between 20172019 on children younger than 8 years old with upper urinary tract stones sized between 10-20 mm admitted to tohid and kowsar hospitals in sanandaj, iran. during this period, 22 children who met the inclusion criteria were inurology journal/vol 17 no. 2/ march-april 2020/ pp. 139-142. [doi: 10.22037/uj.v0i0.5903] cluded in the study and subsequently underwent ump. inclusion criteria were single unilateral kidney stone measuring between 10-20 mm, normal renal function tests, absence of any congenital malformations, history of previous eswl failure, and finally guardian permission for participation in this study. patients' clinical data including age, sex, kidney involvement, location of stone, duration of surgery, size of stone, duration of hospitalization, type and number of stones and surgical data such as need for blood transfusion, damage to adjacent organs, postoperative fever, septicemia after surgery, need for narcotics, further need for a complementary method (double-j stent, ureteroscopy, re-pcnl, etc), stone-free rate, pre and post-operative hemoglobin levels, and urinary leakage from the access tract were extracted from their medical files and recorded in a separate check list. prior to study recruitment, written informed consent was obtained from patients’ parents after a verbal interview between the doctor, the patient and the legal guardian. the surgical tool used in this study was the ump device (lut, germany) which consists of a 1 mm (3f) telescope, 7.5 f nephroscope, inner sheath with three ports (one each for the telescope, saline irrigation inlet, and laser fiber), and a 11-13f metallic outer cannula which served as the amplatz sheath. after general anesthesia, while the patient was placed in lithotomy position, a 4f ureteric catheter was inserted into the kidney in a retrograde manner. then the patient was switched to prone position and with the help of c-arm (fluoroscopy) image intensifier, the desired calyx was determined. under fluoroscopic guidance, an 18-gauge chiba needle, which was most suitable according to the size and position of the stone, was used for entering the kidney calyx. the needle insertion site was dilated 1 mm. then a 0.035-inch j-tip guide wire was passed through the needle. dilatation was performed using a 7.5f nephroscope and an 11-13f sized amplatz cannula. under direct visualization of the nephroscope provided by holmium:yag laser, the stone was broken and then washed-out. the presence of residual stones was evaluated by kidney urinary bladder (kub) radiography and ultrasonography, and a stonefree result was defined as residual stone fragments of less than 4 mm. nephrostomy was not routinely performed in any patient. since no significant residual stone was seen in fluoroscopic control, the pyelocaliceal system was unaffected and no contrast extravasation was observed. in two patients, the leakage of the access tract lasttable 1. patient demographic data and stone characteristics. variable number % age (year) 5.22 ±1.57 mean ± sd sex male 14 63.6 female 8 36.4 kidney left 7 31.8 right 15 68.2 stone location pelvis 18 82 upper ureter 1 4.5 pelvis and upper ureter 3 13.5 stone composition calcium oxalate 13 59.1 cystine 5 27.7 calcium oxalate and cystine 1 4.5 uric acid and calcium oxalate 2 9 uric acid , calcium oxalate, calcium phosphate 1 4.5 number of stones 1 19 86.5 2 (pelvis and upper ureter) 3 13.5 blood transfusion no 22 100 yes 0 0 damage to adjacent no 22 100 organs yes 0 0 fever after surgery no 18 81.8 yes 4 18.2 septicemia after no 22 100 surgery yes 0 0 need for narcotics no 22 100 yes 0 0 need for further no 19 86.5 complementary yes 3 13.5 method (jj stent, ureteroscopy, etc) stone -free status no 1 4.5 yes 21 95.5 perirenal urinary no 22 100 collection yes 0 0 urinary leakage no 20 91 from access tract yes 2 9 duration of surgery (min) mean ± sd 58.6 ± 5.68 size of kidney stone 15.5 ± 2.81 (mm) mean ± sd duration of 44.7 ± 15.3 hospitalization (hour) mean ± sd hemoglobin level mean ± sd before 13.32 ± 0.52 p-value after 12.18 ± 0.67 < .001 ultra pcnl in children-sofimajidpour et al. endourology and stones diseases 140 vol 17 no 02 march-april 2020 141 ed for 2–5 days. the presence of an inferior ureteral stone in control kub and ultrasound implied the need for performing tul and jj insertion. on day 6 after ump, jj was inserted and leakage was discontinued the following day. after 4 weeks, ultrasound examination was performed and due to the absence of stone in the system and ureteral tract, doublej was removed. this study was approved by the ethics committee of kurdistan university of medical sciences (ir.muk. rec.1397.369). statistical analysis descriptive statistics are reported as frequencies and percentages. in addition, continuous variables with normal distribution are expressed as mean ± standard deviation (sd). data was analyzed using stata 14 software. results the mean age (± sd) of patients was 5.22 ( ±1.57( years old. out of 22 patients, 14 (63.6%) were male. in 15 patients (68.2%), the stone was located in the right kidney and 82% of patients had a pelvis stone. 59% of the stones had a calcium oxalate composition. the average size of stones was 15.5 mm. mean surgical time was 58.6 minutes and mean hospital stay was 44.7 hours. in 4 cases (18.2%), postoperative fever was reported and 3 (13.5%) cases required further complementary operations (e.g. ureteroscopy or double-j stent insertion). stone-free rate was 95.5%. urinary leakage, septicemia after surgery, injury to nearby organs, and need for blood transfusion were not reported in any cases. however, the results of our study showed a significant drop in the level of serum hemoglobin after surgery (p < .001). results are summarized in table 1. discussion the location of the stone in the urinary system and the anatomy of the pyelocaliceal system are important factors in choosing the appropriate treatment approach (12). ultra-mini-percutaneous nephrolithotomy (ump) has been shown to be a safe and effective method for treating small-size urinary stones. the advantages of this method are rapid performance, high stone clearance, and minimal complications(9,10). in this study, the average stone size was 15.5 mm. in a study by desai et al. the average stone size was (14.9 ± 4.1 mm) in adults(11–13). in another study, the average stone size was 8 20 mm(14). a systematic review of 7 studies with 262 patients who underwent ump reported a mean stone size of 18.6 mm and an average stone-free rate of 88.2% from. also, in 5 of the studies, jj stent was used in 44.5% of cases(15). according to the findings of the present study, 68.2% of the stones were located in the right kidney. also, the mean surgical time was 58.6 minutes and mean hospital stay was 44.7 hours. in a study by tepeler et al., the ratio of right kidney to left kidney stone was 2.125 and the mean time of surgery and hospital stay were 65.4 minutes and 1.4 days, respectively (16). desai and colleagues reported a mean time of surgery of 59.8 (± 15.9) minutes and a mean hospital stay of (± 0.9 days) in their study(12). the results of another study showed that the mean duration of surgery was 39.7 minutes and mean hospital stay was 22.3 hours(14). in a systematic review study conducted in 2017, the mean surgery time and hospital stay was estimated as 89 minutes and 1.8 days, respectively(15). the reason for the variations in results could be due to differences in age groups, type of stone, and location of the stone. although pcnl is still the standard choice for treating stones larger than 20 mm, but due to the size of the device, its access site, and complications, it is not considered a safe method for kidney stones of less than 20 mm, especially in the pediatric population. despite the efficacy of pcnl in stone removal, it has serious side effects, the most important of which is bleeding (17,18). in this study, all stones were opaque. in five patients with cysteine stones, the stones were seen with kub and fluoroscopy. in several studies, it has been suggested that the presence of non-opaque stones is associated with longer operative times and increased complications(19,20). it is assumed that ump reduces the risk of trauma and serious complications, especially bleeding, in children. in the present study, significant bleeding requiring blood transfusion was not reported in any study, which is consistent with the study of jones and colleagues(15). the limitations associated with our study were a small sample size, and the lack of a control group for comparison of ump with other treatment modalities. conclusions according to the findings of this study, it can be concluded that ump is an appropriate and safe method for treating medium-sized urinary stones (between 10-20 mm) in children younger than 8 years old. acknowledgments the study was sponsored by the deputy of research and technology of kurdistan university of medical sciences, sanandaj, iran. the authors wish to thank the clinical research development center at kowsar hospital, sanandaj, iran for their collaboration. conflict of interest the authors declare that there is no conflict of interest. references 1. geary df, schaefer f. comprehensive pediatric nephrology e-book: text with cdrom: elsevier health sciences; 2008. 2. tasian ge, copelovitch l. evaluation and medical management of kidney stones in children. the j urol. 2014;192:1329-36. 3. vandervoort k, wiesen j, frank r, vento s, crosby v, chandra m, et al. urolithiasis in pediatric patients: a single center study of incidence, clinical presentation and outcome. j urol. 2007;177:2300-5. 4. sas dj, hulsey tc, shatat if, orak jk. increasing incidence of kidney stones in children evaluated in the emergency department. j pediat. 2010;157:132-7. 5. wein aj, kavoussi lr, novick ac, partin aw, peters ca. campbell-walsh urology: expert consult premium edition: enhanced online features and print, 4-volume set: elsevier health sciences; 2011. 6. tekgül s. ureteroscopy versus shock wave ultra pcnl in children-sofimajidpour et al. lithotripsy for renal calculi in children. j urol. 2011;185:1188-9. 7. desai j, solanki r. ultra-mini percutaneous nephrolithotomy (ump): one more armamentarium. bju int. 2013;112:1046-9. 8. datta s, solanki r, desai j. 582 prospective outcomes of ultra-mini percutaneous nephrolithotomy (ump): a consecutive cohort study. eur urol suppl. 2015 ;14: e582e582b. 9. lingeman j. prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for lower pole nephrolithiasis; initial long-term follow up. j endourol. 1997;11:2-5. 10. sabnis rb, jagtap j, mishra s, desai m. treating renal calculi 1–2 cm in diameter with minipercutaneous or retrograde intrarenal surgery: a prospective comparative study. bju int. 2012;110:e346-e9. 11. bader mj, gratzke c, seitz m, sharma r, stief cg, desai m. the “all-seeing needle”: initial results of an optical puncture system confirming access in percutaneous nephrolithotomy. eur urol. 2011;59:1054-9. 12. desai j, zeng g, zhao z, zhong w, chen w, wu w. a novel technique of ultra-minipercutaneous nephrolithotomy: introduction and an initial experience for treatment of upper urinary calculi less than 2 cm. biomed res int. 2013;2013:490793. 13. desai mr, sharma r, mishra s, sabnis rb, stief c, bader m. single-step percutaneous nephrolithotomy (microperc): the initial clinical report. j urol. 2011;186:140-5. 14. agrawal ms, agarwal k, jindal t, sharma m. ultra-mini-percutaneous nephrolithotomy: a minimally-invasive option for percutaneous stone removal. ind j urol. 2016;32:132. 15. jones p, bennett g, aboumarzouk o, griffin s, somani b. role of minimally invasive pcnl techniques: micro and ultra-mini pcnl (< 15fr) in the paediatric population—a systematic review. j endourol. 2017;10:81624. 16. tepeler a, başıbüyük i̇, tosun m, armağan a. the role of ultra-mini percutaneous nephrolithotomy in the treatment of kidney stones. turk j urol. 2016;42:261. 17. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899-906. 18. skolarikos a, de la rosette j. prevention and treatment of complications following percutaneous nephrolithotomy. curr opin urol. 2008;18:229-34. 19. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016 ;13:2899-902. 20. taheri m, basiri a, taheri f, khoshdel ar, fallah ma. the agreement between current stone analysis techniques and sem-edax in urolithiasis. urol j. 2019 ;16:6-11. ultra pcnl in children-sofimajidpour et al. endourology and stones diseases 142 unclassified a randomized crossover pilot study examining the effect of carvedilol and terazosin plus enalapril on urinary symptoms of patients with hypertension and benign prostatic hyperplasia alireza farshi1, nooriyeh dalirakbari2*, afshar zomorrodi3, mohammad khalili4**, mahsa mahmoudinezhad5 purpose: the present study aims to assess and compare the effects of carvedilol and terazosin plus enalapril on lower urinary tract symptoms (luts), urine flow, and blood pressure (bp) in patients with moderate hypertension (htn) and benign prostatic hyperplasia (bph). materials and methods: in this randomized crossover trial, a total of 40 men with htn and luts symptoms were enrolled. the first group was treated with carvedilol, and the second group received terazosin plus enalapril. after eight weeks of treatment, the patients experienced a one-month washout period, and the treatments changed and were continued for eight weeks. to diagnose bph in the study, the international prostate symptom score (ipss) questionnaire was used. moreover, the prostate-specific antigen (psa), the post-void residual (pvr) urine volume, and the maximum urinary flow rate (q-max using the uroflowmetry test) were measured. results: effect assessment results in this crossover trial illustrated neither carryover effects nor significant treatment effects on all primary outcomes (p > 0.05). moreover, the results for the period effect indicated a significant reduction in bp (systolic and diastolic), pvr, and ipss, yet a significant raise in qmax. conclusion: the effects of carvedilol are similar to those of the combination of terazosin and enalapril in patients with moderate htn and bph in controlling luts. carvedilol could be used as an appropriative drug in patients with moderate htn and cardiac problems with luts of bph. further studies are recommended to be conducted to investigate and compare the efficacy of carvedilol with that of other alpha-blockers with a larger sample size and over a longer period of time. keywords: benign prostatic hyperplasia; blood pressure; carvedilol; ipss; qmax introduction benign prostatic hypertrophy (bph), as a common disease in middle-aged and elderly men, imposes a large economic burden on the society every year(1), thereby affecting 50% of men over 60 years old. in addition, it is a progressive disease associated with lower urinary tract symptoms (luts), including frequent urination, post-void dribbling, prolonged micturition, urinary hesitancy, and incomplete urinary excretion(2-4). moreover, as this disease is supposed to be associated with bladder outlet obstruction (boo) and urinary retention(3), it has a significant impact on the patient’s quality of life(5). hypertension (htn) causes many life-threatening complications, such as heart failure that affects more than half of the population in many countries, and like bph, its prevalence grows with age. research shows 1assocaite professor of urology, department of urology, tabriz university of medical sciences, tabriz, iran. 2urology resident, department of urology, tabriz university of medical sciences, tabriz, iran. 3professor of urology, department of urology, tabriz university of medical sciences, tabriz, iran 4ph.d. in nutrition, multiple sclerosis research center, neuroscience institute, tabriz university of medical sciences, tabriz, iran 5department of community nutrition, faculty of nutrition & food technology, tabriz university of medical sciences, tabriz, iran. *correspondence: faculty of medicine, tabriz university of medical sciences, daneshgah street, tabriz, iran. tel: +989143039769. email:dr.neda67@gmail.com. **multiple sclerosis research center, neuroscience institute, tabriz university of medical sciences, tabriz, iran tel: +989127773382. email:nutrifoodkhalili@gmail.com. received november 2019 & accepted january 2021 that 20-40% of people with high blood pressure (bp) suffer from bph as well(6). an epidemiologic study reported an age-independent association between bph and htn(7). bph treatment involves modifications in the patient’s lifestyle and administration of smooth muscle relaxant medications (alpha-1 blockers), which in turn reduce urinary retention and luts symptoms(8). however, several studies have indicated that administration of alpha-blockers alone for the treatment of bph increases the risk of heart failure(9,10), which is not recommended for the control of blood pressure and an improvement in cardiovascular complications(10). carvedilol is a non-selective beta-blocker, has an alpha-1 receptor-blocking property, has an effect on α1 and β receptors, and can be an effective medical therapy in heart failure and bph(10). the ability of carvedilol to block α1-adrenoceptors results in vasodilatation, urology journal/vol 18 no. 3/ may-june 2021/ pp. 337-342. [doi: 10.22037/uj.v18i.5678] thereby reducing urinary disorders caused by bph. in a study conducted in the netherlands in 2013 on 49 patients with bph and htn, the positive effects of carvedilol on the maximum urinary flow rate (q-max) and other parameters, including the international prostate symptom score (ipss), the post-void residual (pvr) urine volume, and the prostate-specific antigen (psa) within three months of treatment were reported(6). terazosin is a long-acting alpha-blocker that causes a significant increase in q-max at doses 5 and 10 mg per day, with its effects lasting for two weeks. however, it is not recommended for controlling blood pressure(11), so other drugs, such as enalapril should be taken. past research shows that carvedilol could be effective in improving administrative symptoms of prostate enlargement. however, effectiveness of this drug in treating bph has not been studied yet, in contrast to other common drugs. accordingly, this article aims to compare effects of carvedilol with those of common alpha blockers, such as terazosin, on the treatment of bph. due to the simultaneous alpha-blocking and beta-blocking effects of carvedilol, the present study aims to determine effects of carvedilol as well as terazosin plus enalapril on q-max, pvr, psa, and ipss in patients with moderate htn and bph. materials and methods study population the present randomized, blind, crossover clinical trial was conducted in tabriz, iran, using the convenience random sampling procedure, on 46 eligible male patients aged over 40, who referred to a urology clinic with moderate luts and htn symptoms from march to august 2019 and were recruited for this study. written informed consent forms were obtained from all patients at the beginning of the study. in addition, the study protocol was approved by the ethics committee of tabriz university of medical sciences (ir.tbzmed.rec.1397.604). sample size calculation in an equivalence test of means using a two-period crossover design on pvr as the primary outcome of the study, a total sample size of 37 was achieved with 80% power and a 5% significance level. accordingly, the true difference between the means and the root mean square error was considered to be 0 and 4.5, respectively. the information on the primary outcome was obtained through a pilot of 5 participants as the trial started. to consider a dropout rate of about 10%, the total sample size increased to 40 participants (20 per sequence). the sample size was estimated by pass15 (pass 15 power analysis and sample size software (2017), ncss, llc, kaysville, utah, usa, ncss.com/ software/pass) inclusion and exclusion criteria six patients who did not meet the inclusion criteria were excluded from the trial. accordingly, two patients having an increased psa level, one patient touching the nodule, two patients receiving medication therapy during the study, as well as one patient not willing to continue the study were dropped out of the study. in the end, 20 patients in each group participated in this study. accordingly, 40 eligible patients suffering from benign prostatic hyperplasia, who aged over 40, with moderate blood pressure, systolic blood pressure (sbp) between 140-150 mmhg and/or diastolic blood pressure (dbp) between 90–99 mmhg specified according to the european society of hypertension guidelines, those having sustained symptoms of luts over the past six months as diagnosed by physical examinations and ultrasonography tests, as well as patients with ipss > 8 and qmax > 5 ml were recruited in the study. in addition, patients with a history of prostate surgery, urinary symptoms caused by other diseases, the psa level > 4 ng/ml, the persistent pvr volume > 200 ml, hepatic or renal dysfunction, diabetes mellitus, and cardiovascular complications caused by hypertensive diseases were excluded from the study. finally, the patients' eligibility was confirmed by performing medical examinations, clinical laboratory tests, and urological evaluations during clinical visits. following the eligibility assessment, the patients experienced a four-week washout period. procedure the first assignment of the patients to the groups treated with carvedilol as well as terazosin plus enalapril was performed. next, the patients experienced a four-week washout period to get prepared for switching the groups (crossover) and beginning the second active intervention period. clinical evaluations were carried out at the baseline, after eight weeks of the first active interventable 1. participants’ baseline characteristics variables terazosin + enalapril (n=20) carvedilol (n=20) p value age, year; mean ± sd 61.25 ± 8.86 60.62 ± 9.31 0.15 bmi, kg/m2; mean ± sd 0.66 hypertension history (mo.); mean ± sd 80.5 ± 7.1 87.2 ± 5.3 0.23 bph history (mo.); mean ± sd 39 ± 4.2 36 ± 6.1 0.46 the last dose of study drug(mg); mean ± sd 11.2 ± 3.1 14.6 ± 5.3 0.32 first laboratory tests creatinine (mg/ld.); mean ± sd 1.28 ±0.1 1.19 ± 0.2 0.58 psa (µg/ml); mean ± sd 2.39 ± 2.86 2.63 ± 2.12 0.64 first ipss; mean ± sd 16.0 ± 2.86 15.80 ± 3.25 0.07 first pvr (ml), mean ± sd 35.55 ± 16.85 37.30 ± 26.52 0.34 first qmax (ml/s), mean ± sd 10.18 ± 3.45 10.08 ± 3.25 0.85 first systolic bp (mmhg), mean ± sd 149.75 ± 8.95 148.5 ± 9.47 0.75 first diastolic bp (mmhg); mean ± sd 92.50 ± 5.50 93.75 ± 5.82 0.17 bph: benign prostatic hyperplasia, psa; prostate-specific antigen, ipss; international prostate symptom score, pvr; post void residual urine volume, qmax; maximum urinary flow rate p-values were not significant for all comparisons made between groups. carvedilol and terazosin plus enalapril in bph-farshi et al. unclassified 338 vol 18 no 3 may-june 2021 339 tion period, at the end of the second washout period, and after the second active intervention period. drugs were adjusted from the initial doses of 12.5 mg for carvedilol as well as 10 mg for terazosin plus 2.5 mg for enalapril to the doses of up to 25 mg for carvedilol as well as 20 mg for terazosin plus 20 mg for enalapril to ensure normal bp control. however, due to the orthostatic effects of all drugs, they were prescribed with dinner. in addition, bph symptoms were assessed using the ipss questionnaire. moreover, the ipss questionnaire was completed, and psa, pvr, as well as q-max (using the uroflowmetry test) were measured. systolic blood pressure and diastolic blood pressure (sbp and dbp) were assessed twice in a relaxed position after a 15-minute rest, and the mean values were recorded. in addition, sbp, dbp, pvr, ipss, psa, and q-max were considered the main primary outcomes of this study and assessed at the beginning and after eight weeks. registration number and name of trial registry: ir.tbzmed.rec.1397.604 where the full trial protocol can be accessed: irct20181128041777n1 (www.irct.ir) statistical analysis all analyses were performed using data and expressed using mean and standard deviation (sd) for numeric variables and using frequency (percentages) for categorical variables. in this 2x2 crossover trial, we defined two sequences, with the first of which being 'te_car' in which 20 patients received 'terazosin + enalapril' in the first period, and then they received 'carvedilol' in the second period; the second sequence was 'car_te' in which 20 patients received 'carvedilol' during the first period, and then they received 'terazosin + enalapril' in the second period. measuring effects of both treatments on the same participants allowed us to reduce the rate of variations caused by differences between the participants. in addition, the repeated measures anova was used to analyze results of data comparison between the two groups at the baseline and after treatments. statistical analyses were performed using spss software version 22. in addition, mean ± standard error of mean (sem) was reported for all collected data. an independent samples t-test was used to compare the results of the quantitative data. moreover, a paired sample t-test was used to determine mean differences before and after the treatment. in addition, a chi-square test and the fisher's exact test were used to analyze the qualitative data. p values less than 0.05 were considered statistically significant. the three aforementioned effects were assessed using a single model and represented by both tests at a significant level of 5% and a 95% confidence interval (ci) for the effects. results table 1 shows the patients' baseline characteristics. a total of 20 patients in each group received the treatment, and the mean age of terazosin plus enalapril and carvedilol groups was 61.25 ± 8.86 and 60.62 ± 9.31 years, respectively, which indicates no significant difference between the two intervention groups in age. moreover, there were no statistically significant differences between the two intervention groups in terms of demographic variables (p > 0.05). table 2 shows the number of adverse events and dropouts from the treatment. interestingly, a significant reduction was observed in sbp values compared to the baseline values in both carvedilol and terazosin plus enalapril intervention groups (p < 0.05) as shown in table 3. table 4 shows comparison results for the mean and standard deviation of sbp, dbp, pvr, psa, q-max, and ipss between the two intervention groups. however, dbp values significantly decreased compared to the baseline values in table 2. withdrawals from the treatment and the number of adverse events terazosin + enalapril carvedilol withdrawals all causes 0 0 due to adverse events 0 0 dizziness 2 0 symptoms of hypo tony 2 0 asthenia/ fatigue 0 0 headaches 2 0 impotence 0 0 bradycardia 0 0 variables period 1 period 2 p value sequence mean sd mean sd sq. vs. time sbp (mmhg) te_car 149.75 2.06 132 2.13 0.29 car_te 148.5 2.06 133.25 2.13 dbp (mmhg) te_car 92.50 1.27 85.75 3.35 0.16 car_te 93.75 1.27 80 3.35 pvr (ml) te_car 35.55 4.97 15.45 2.78 0.29 car_te 37.30 4.97 11.10 2.78 ipss (points) te_car 16.00 0.69 9.10 0.84 0.99 car_te 15.80 0.69 8.90 0.84 qmax (ml/s) te_car 12 2.85 17.50 2.57 0.29 car_te 13.50 2.85 20 2.57 sbp: systolic blood pressure; dbp: diastolic blood pressure; pvr: post-void residual; ipss: international prostate symptom score; psa: prostate-specific antigen; qmax: maximum urinary flow rate; ci: confidence interval; sd: standard deviation sequences: “te_car”: wherein first period, 20 patients received “terazosin + enalapril” and then in the second period these patients received “carvedilol” “car_te”: wherein first period, 20 patients received “carvedilol” and then in the second period these patients received “terazosin + enalapril”. table 3. the results of period and treatment effects for urologic markers and systolic and diastolic blood pressures after 8 weeks of treatment carvedilol and terazosin plus enalapril in bph-farshi et al. both intervention groups (p < 0.05). moreover, carvedilol therapy was more effective than terazosin plus enalapril therapy in lowering dbp values during the eight-week period (p < 0.05). in addition, in contrast to baseline values, pvr and ipss scores indicate a remarkable decline in both carvedilol and terazosin plus enalapril groups (p < 0.05). in contrast, psa values did not decrease significantly in comparison to baseline values in any of the intervention groups and had a large amount of data loss, which made the calculation of this parameter became impossible. furthermore, treatments with carvedilol and terazosin plus enalapril significantly increased q-max values compared to the baseline values (p < 0.05). as the last column of table 3 shows, the interactions between sequence and time were not significant for all parameters; thus, one could conclude that the time effect was equal on both groups. as comparisons show in table 4, the mean and standard deviation of the variables between the two groups were just divided by time. accordingly, the presented mean values for time 2 decreased for all variables except for q-max. discussion htn and bph are both chronic disorders that commonly coexist; therefore, it is better to consider an effective therapy for both of these disorders to improve patients’ quality of life. the present study was conducted to show efficacy of carvedilol as against terazosin plus enalapril in patients with moderate htn and bph. the original dataset of this study confirmed that carvedilol, at hypotensive doses, might improve urological indices and reduce bph-related annoying symptoms; thus, it could improve quality of life in patients with luts due to bph. a bph treatment based on lifestyle modifications and administration of smooth muscle relaxants (α1 blockers)(11) has been proved to reduce high bp (12) ; however, its efficacy in optimal management of htn has not been verified. patients with bph and concomitant htn may require a distinctive treatment for high bp(12). therefore, carvedilol, a β-blocker (β1 and β2 blockers) with selective α-adrenoceptor antagonist activity, was used in treating hypertension and heart failure, which seemed to be a reasonable alternative(6). the results of the current investigation revealed that carvedilol effectively improved bph symptoms (luts). to the best of our knowledge, this is the first randomized study to have evaluated efficacy of carvedilol (α and β blockers) as against terazosin plus enalapril in patients with bph and htn. in 2013, in a double-blind randomized crossover study, lewandowski et al evaluated effects of carvedilol on urologic indices in patients with htn and bph. they prescribed 12.5 mg/d carvedilol or 10 mg/d enalapril for three months and found out that carvedilol, as against enalapril, had a positive effect on luts associated with bph in patients with htn(6). our study had some similarities to this trial, yet terazosin was used along with enalapril as a treatment for high bp in the present study. the results of this study indicated no significant difference in the treatment effect between terazosin and carvedilol in terms of bp, but a significant period effect was observed for bp. in the same vein, ayashi reported table4. mean and standard deviation comparisons of sbp, dbp, pvr, psa, q-max, and ipss between two groups variables period 1 period 2 mean sd ci mean sd ci sbp 149.13 1.46 (146.18, 152.08) 132.63 1.5 (129.58, 135.67) dbp 93.13 0.90 (91.31, 94.34) 82.88 2.37 (78.08, 87.67) pvr 36.43 3.51 (29.32, 43.53) 13.28 1.96 (9.3, 17.25) ipss 15.9 0.49 (14.92, 16.88) 9 0.60 (7.79, 10.21) qmax 12.75 2.02 (4.08, 21.42) 18.75 1.82 (10.92, 26.58) figure 1. diagram of the patients’ enrollment carvedilol and terazosin plus enalapril in bph-farshi et al. unclassified 340 vol 18 no 3 may-june 2021 341 that treatment with carvedilol reduced systolic and diastolic bp in patients with mild to moderate htn (40 and 160mmhg)(13). in lewandowski’s study, the mean difference between systolic and diastolic bp was not significantly different(6). in addition, ostergren et al showed that the mean value of diastolic bp was similar in both groups after five months of maintenance treatment with carvedilol and enalapril(14). lewandowski et al.’s study showed a significant reduction in pvr after carvedilol therapy as against enalapril therapy. in contrast, no significant treatment effect was shown on the pvr value in both treatments as against a significant reduction in the pvr value in terms of the time effect in the present study. similarly, no significant treatment effect was observed on the q-max value in patients receiving terazosin plus enalapril and carvedilol in the present study. considering the mentioned findings, it is implied that findings about alpha-blocking effects are consistent with the results obtained in the present study. lewandowski et al reported that q-max values increased significantly after treatment in the carvedilol group. based on the results of this study, no significant treatment effects were observed on the psa variable in both groups. similarly, lewandowski’s study(6) reported that there were no significant changes or differences in the psa levels between the two groups in the study. the results of the present study indicated no significant differences between the two groups in terms of ipss. accordingly, the percentage of the ipss reduction in patients with luts using alpha-1 blockers was between 35-40% in a randomized clinical trial(15). in another study, it was reported that both terazosin and tamsulosin could lead to statistically significant improvements in subjective and objective variables of symptomatic benign prostatic hyperplasia in japanese patients(16). in addition, lewandowski reported that the percentage of the reduction in prostate symptoms (ipss) was 32% in the carvedilol group, which led to a significant difference between the mean values of the ipss reduction in the two intervention groups as against the placebo group(6). our study shows that treatment with carvedilol reduced the values of sbp, dbp, pvr, and ipss, but it increased the value of qmax. in addition, treatment with carvedilol in patients of this study was safe and well-tolerated, and no major adverse effects were reported by the patients. however, tolerance to carvedilol in normotensive patients with bph requires further investigations. a crossover design was used to reduce the number of patients required for performing the study. as the crossover design necessitates a larger number of observations and higher estimation precision with less number of patients, it can be considered more advantageous than a parallel group design. one of the major limitations of the present study was its smaller number of patients with hypertension and bph, who were preselected according to inclusion and exclusion criteria. hence, the obtained findings could not be easily generalized to other groups of patients, such as those with congestive heart failure or severe hypertension treated with multidrug regimens. furthermore, the short period of treatment with carvedilol could be regarded as another limitation of the present study. conclusions the obtained results indicated that carvedilol, similar to terazosin plus enalapril was effective in treating urinary tract symptoms in patients with hypertension and benign prostatic hyperplasia . however, further studies are required to investigate efficacy of carvedilol treatment compared to that of other alfa blockers with larger sample sizes to propose carvedilol as a single-drug treatment for patients with bph and htn to prevent polypharmacy. acknowledgment the present study was financially supported by the vice-chancellor for research, tabriz university of medical sciences, tabriz, iran. conflict on interest all authors declared that they have no conflict of interest. references 1. vuichoud c, loughlin kr. benign prostatic hyperplasia: epidemiology, economics and evaluation. can j urol. 2015;22 suppl 1:1-6. 2. shrivastava a, gupta vb. various treatment options for benign prostatic hyperplasia: a current update. jmh. 2012;3:10-9. 3. alan c, kirilmaz b, kocoglu h, ersay ar, ertung y, eren ae. comparison of effects of alpha receptor blockers on endothelial functions and coagulation parameters in patients with benign prostatic hyperplasia. uro. 2011;77:1439-43. 4. chiu g, li s, connolly pj, pulito v, liu j, middleton sa. (arylpiperazinyl) cyclohexyl sufonamides: discovery of α1a/1d-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/ lower urinary tract symptoms (bph/luts). bioorg med chem lett. 2007;18:640-4. 5. reijke tm, klarskov p. comparative efficacy of two alpha-adrenoreceptor antagonists, doxazosin and alfuzosin, in patients with lower urinary tract symptoms from benign prostatic enlargement. bjui. 2004;93:757-62. 6. lewandowski j, sinski m, symonides b, et al. beneficial influence of carvedilol on urologic indices in patients with hypertension and benign prostatic hyperplasia: results of a randomized, crossover study. uro. 2013;82:660-5. 7. michel mc, heemann u, schumacher h, mehlburger l, goepel m. association of hypertension with symptoms of benign prostatic hyperplasia. j urol. 2004;172:1390-3. 8. kapoor a. benign prostatic hyperplasia (bph) management in the primary care setting. can j urol. 2012;19 suppl 1:10-7. 9. rohrer ck, page rl 2nd, shakar sf, lindenfeld j. carvedilol for the treatment of benign prostatic hypertrophy in patients with heart failure? j card fail. 2011;17:875-7. 10. dhaliwal as, habib g, deswal a, et al. impact of alpha 1-adrenergic antagonist use for benign carvedilol and terazosin plus enalapril in bph-farshi et al. prostatic hypertrophy on outcomes in patients with heart failure. am j.2009;104:270-5. 11. yuan jq, mao c, wong sy, et al. comparative effectiveness and safety of monodrug therapies for lower urinary tract symptoms associated with benign prostatic hyperplasia: a network meta-analysis. medicine. 2015;94:e974. 12. williams b, mancia g, spiering w, et al. esc/ esh guidelines for the management of arterial hypertension. eur heart j. 2018;39:3021-104. 13. ayashi s, assareh ar, jalali mt, olapour s, yaghooti h. role of antioxidant property of carvedilol in mild to moderate hypertensive patients: a prospective open-label study. indian j pharmacol. 2016;48:372-6. 14. ostergren j, storstein l, karlberg be, tibblin. quality of life in hypertensive patients treated with either carvedilol or enalapril. journal blood pressure. 2009;5:41-9. 15. oelke m, bachmann a, descazeaud a, et al. eau guidelines on the treatment and followup of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur. 2013;64:118-40. 16. okada h, kamidono s, yoshioka t, et al. a comparative study of terazosin and tamsulosin for symptomatic benign prostatic hyperplasia in japanese patients. bjui. 2000;85:676-81. carvedilol and terazosin plus enalapril in bph-farshi et al. unclassified 342 case report 46 urology journal vol 4 no 1 winter 2007 malignancy in a horseshoe kidney—jones et al urology journal vol 4 no 1 winter 2007 47 malignant tumor in a horseshoe kidney lori jones, mallory reeves, scott wingo, agha babanoury urol j (tehran). 2007;4:46-8. www.uj.unrc.ir keywords: horseshoe kidney, kidney neoplasms, renal cell carcinoma, diagnosis department of urology, medical university of south carolina, charleston, sc, usa corresponding author: agha babanoury, md department of urology, medical university of south carolina, charleston, sc, usa fax: +1 843 937 6001 e-mail: noury@bellsouth.net received july 2006 accepted october 2006 introduction horseshoe kidney, first recognized at autopsy by decarpi in 1521, is a renal fusion anomaly found in about 0.25% of the population.(1) malignancies are associated with this anomaly and adenocarcinoma comprises about 50% of tumors arising in the horseshoe kidney.(1) we report a case of renal cell carcinoma in a 66-yearold man and depict our experience in its management. case report a 66-year-old caucasian man presented with intermittent epigastric discomfort of several days’ duration. review of systems was negative for cardiac or pulmonary symptoms and the patient denied any unexplained weight loss. he was afebrile and physical examination revealed no abnormalities. basic hematological and biochemical investigations were unremarkable. urinalysis, urine cytology, and urine cultures were negative. the patient’s eastern cooperative oncology group performance status was zero. computed tomography (ct) of the abdomen and pelvis revealed benign hepatic cysts, a benign lesion in the pancreas, and a horseshoe kidney. to the right of the isthmus was a 5.4 × 4.4-cm enhancing mass. it measured 24 hu in the noncontrast phase, 75 hu in the corticomedullary phase, and 96 hu in the excretory phase. the ct angiography demonstrated unremarkable celiac axis and superior mesenteric artery origins and single renal arteries to the left and right portions of the kidney. of note, the inferior mesenteric artery draped over the left side of the lesion and the right ureter passed close to its right side (figures 1 and 2). figure 1. corticomedullary phase of renal dedicated ct reconstruction. asterisk indicates mass; solid white arrow, inferior mesenteric artery; and broken white arrow, right ureter. figure 2. computed tomography reconstruction. asterisk indicates mass and black arrow, inferior mesenteric artery. case report 46 urology journal vol 4 no 1 winter 2007 malignancy in a horseshoe kidney—jones et al urology journal vol 4 no 1 winter 2007 47 after appropriate preoperative testing was completed, the patient was taken to the operating room for a right open partial nephrectomy of the right renal unit of the horseshoe kidney. a double-j right ureteral stent was placed cystoscopically. a midline abdominal incision was then made, the posterior peritoneum was incised from the ileocecal junction to the ligament of treitz, and the horseshoe kidney was exposed. the right ureter was dissected off the mass and identified with a vessel loop. the right renal hilum was exposed, umbilical tapes were placed around the right renal artery and vein, and a rumel tourniquet was prepared for the artery. the inferior mesenteric artery was dissected free of the mass as well (figure 3). intravenous mannitol was given and the kidney was immersed in ice slush. the renal capsule around the mass was scored with bovie electrocautery and the tumor was then removed with several millimeters of normal parenchyma, while the right renal artery was occluded. the defect was closed over a surgicel bolster with 0-0 chromic and fat bolsters. excellent hemostasis was obtained. the total ischemic time was 13 minutes. a closed suction drain was placed and the wound was closed after copious irrigation. the patient was discharged home after a speedy recovery with a normal serum creatinine level, adequate pain control, and good ambulatory status. pathology revealed a grade 4 clear cell renal cell carcinoma with sarcomatoid features. vascular invasion was present, but the surgical margins were negative for malignancy (figure 4). the patient continued under diligent surveillance, and to date has shown no evidence of disease recurrence. discussion horseshoe kidney is a renal fusion anomaly found in about 0.25% of the population.(1) virtually, every urologic disease process has been described in the horseshoe kidney, including malignancy. adenocarcinoma comprises about 50% of tumors arising in the horseshoe kidney, followed by transitional cell carcinoma and wilms tumor.(1) while prognosis is dependant on the same factors as in nonfused kidneys, careful attention must be paid to highly variable vascular supply and anomalies of the collecting system when planning surgical intervention. in a review of the literature up to 1998, rubio briones reported 144 cases of tumorous pathology in horseshoe kidney.(2) we searched the literature and found 43 other cases by july 2006, 22 of which were rcc.(3,4) transitional cell carcinoma accounts for 28% to 40% of these malignancies, with an increased incidence over the general population, possibly related to an increase in calculus pathology, frequent urinary obstruction, and chronic infection leading to prolonged exposure to carcinogens in horseshoe kidneys.(2) the incidence of wilms tumor is twice as that expected in the general population, perhaps related to abnormal migration of nephrogenic cells which form the isthmus and subsequently undergo malignant changes. as mentioned, renal cell carcinoma is the most common neoplasm described in horseshoe kidneys, accounting for about 50% of figure 3. gross intraoperative photograph. solid white arrow indicates right ureter; broken white arrow, rumel tourniquet around the right renal artery; asterisk, mass; and black arrow, inferior mesenteric artery. figure 4. low-power photomicrograph shows granular clear cell renal cell carcinoma with a spindle pattern and grade 3 anaplasia (hematoxylin-eosin, × 40). malignancy in a horseshoe kidney—jones et al 48 urology journal vol 4 no 1 winter 2007 cases, and occurs no more often than in the general population.(2) prognosis is unaffected by the anomaly and is dependant on tumor pathology and stage at diagnosis just as in normal kidneys.(1,2) conflict of interest none declared. references 1. stuart bb. anomalies of the upper urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 1885-924. 2. rubio briones j, regalado pareja r, sanchez martin f, et al. incidence of tumoural pathology in horseshoe kidneys. eur urol. 1998;33:175-9. 3. mochizuki k, ohno y, tokai y, et al. congenital intrarenal teratoma arising from a horseshoe kidney. j pediatr surg. 2006;41:1313-5. 4. kim th. renal cell carcinoma in a horseshoe kidney and preoperative superselective renal artery embolization: a case report. korean j radiol. 2005;6: 200-3. urol_v03_no3_001_editorial.indd sexual dysfunction and infertility 154 urology journal vol 3 no 3 summer 2006 sperm nuclear dna in ejaculates of fertile and infertile men correlation with semen parameters mohammad ali khalili,1 fatima aghaie-maybodi,2 morteza anvari,2 ali reza talebi2 introduction: our aim was to compare the nuclear dna integrity of the spermatozoa from infertile men with abnormal semen parameters with that from normospermic fertile men, and to evaluate the relationship between the sperm dna integrity and semen parameters. materials and methods: thirty ejaculate samples with abnormal semen analysis and 30 ejaculates with normal semen parameters were randomly collected from infertile and fertile men, respectively. the acridine orange test was used to assess the integrity of sperm dna. results: the number of ejaculates with a dna fragmentation index (dfi) above 30% were 16 (53.3%) and 22 (73.3%) in fertile and infertile subjects, respectively (p = .10). the mean dfi was 37.7 ± 19.6% and 46.1 ± 16.7% in the fertile and infertile subjects, respectively (p = .24). the dfi of the fertile men with normal sperm morphology (12 patients) ranged from 1% to 80%. in the samples with oligoasthenospermia, mean dfi was 52.7 ± 17.9%. there were 2 samples with severe teratospermia (normal morphology less than 4%) and dfis of 70% and 87%. there were no significant correlations between the dna integrity and the 3 parameters of semen quality in our 60 subjects. conclusion: our results failed to show any significant difference in the dna integrity of the spermatozoa between infertile and fertile men. also, no correlation was noticed between the dna abnormality and the semen parameters in the studied samples. urol j (tehran). 2006;3:154-9. www.uj.unrc.ir keywords: dna, spermatozoa, acridine orange, semen analysis 1fertility and infertility research center, isfahan university of medical sciences, isfahan, iran 2research and clinical center for infertility, yazd university of medical sciences, yazd, iran corresponding author: mohammad ali khalili, phd fertility & infertility research center, dr beheshti hospital, felezi bridge, isfahan, iran tel: +98 913 311 3358 e-mail: khalili59@hotmail.com received july 2005 accepted may 2006 introduction conventional semen analysis is still one of the most popular tests for the evaluation of male fertility. however, in many circumstances, semen analysis per se is unable to predict the fertilizing capacity of ejaculated spermatozoa, because it does not assess some factors such as the integrity of sperm nuclear dna.(1-3) it has been reported that some of the infertile men are normospermic; while fertilization has occurred in others with an abnormal semen parameters.(4) therefore, sperm function tests like sperm nuclear maturation assay have been developed to assess the fertility capacity of individuals in assisted reproductive technologies (art). it is now well understood that the integrity of sperm dna is an essential factor for normal transmission of genetic materials during the process of fertilization as well as embryo development.(1,3,4) therefore, it is essential to develop accurate diagnostic tests that provide better prognostic capabilities than the conventional sperm assessments. at present, several assays are available for sperm nuclear dna in ejaculates of infertile men—khalili et al urology journal vol 3 no 3 summer 2006 155 the evaluation of the nuclear chromatin integrity or the maturity of human spermatozoa.(4,5) one of these tests which was first introduced by evenson and colleagues in 1980 is acridine orange test (aot).(6) in human testis, the histone nucleoprotein is replaced by protamine during spermiogenesis. protamine is rich in cysteine and also other basic amino acids. the structure of the sperm nuclear chromatin becomes stable following transformation to dna-protamine complex.(2,3,7) during the epididymal passage, the thiols of cysteines in protamine are oxidized to disulfide bonds (s-s). this process will make the spermatozoa more stable than testicular sperm. at ejaculation, sperms are matured enough for the next step to occur—fertilization. the maturity of sperm nuclei (rich in s-s) can be determined by the use of aot. the acridine orange molecules are intercalated into double-stranded dna and green fluorescence is emitted from the sperm nuclei. however, with immature nuclei (poor s-s), sperm dna is easily denatured into single strands. consequently, the acridine orange molecules aggregate in the nuclei and the color of the fluorescence changes into orangered.(8) it has previously been demonstrated that significant differences exist in the proportion of the spermatozoa with impaired dna integrity between fertile and infertile populations.(3,9) also, it has been demonstrated that human spermatozoa with impaired chromatin structure, detected by aot, are not able to penetrate the zona pellucida and fuse with the oolemma of the hamster oocytes.(10) this indicates that a sperm chromatin abnormality seems more likely to affect the fertilization process. also, in another clinical study, it has been shown that in individuals with immature sperm nuclei, dna is easily denatured into single strands, thus reducing the chance of a successful in vitro fertilization (ivf).(1) a correlation between the staining of sperms by acridine orange and sperm morphology has also been found.(11) although most studies have supported the significant correlation between the acridine orange fluorescence capability and the in vitro fertilizing ability of human spermatozoa, a negative correlation has also been reported.(12) in addition, there have been controversial issues in terms of the relationship between the integrity of sperm dna and semen parameters and whether measurements of dna integrity can differentiate the spermatozoa of fertile and infertile men.(1,3) it is still unclear whether the widely used dna integrity tests are sensitive enough to reveal the differences in baseline sperm dna integrity between the semen collected from fertile and infertile populations. the purpose of this cross-sectional study was first, to compare the nuclear dna integrity of spermatozoa using aot in ejaculates of infertile patients with abnormal semen parameters with that of normospermic fertile people, and second, to evaluate the correlation between the integrity of sperm dna and semen parameters (sperm concentration, motility, and morphology) in both groups of fertile and infertile men. materials and methods patients this cross-sectional study included a randomly selected group of 30 iranian men with a history of infertility presented to our clinics. they were diagnosed with male factor infertility, and their wives were reported to have normal reproductive function following gynecological and endocrinological examinations. infertile patients with normospermia were excluded. also, 30 randomly selected married fertile men were served as controls. they had normal semen parameters and presented with other complaints. all subjects provided informed consent and the study was approved by our university’s research and ethics committees. every single patient was asked to collect a fresh ejaculated semen sample into a sterile wide-mouth container. semen analysis all semen analyses were performed after the liquefaction of the semen samples within 15 to 20 minutes. using the who criteria (sperm count, > 20 106/ml; normal sperm motility, ≥ 50%; and normal sperm morphology, ≥ 30%), the samples were categorized into normospermic and those with single, double, and triple defects in spermatozoa.(13) following macroscopic evaluation of each specimen, sperm count and motility were evaluated using makler chamber and light microscopy at × 200 magnification. motility was expressed as the percentage of progressive and nonprogressive spermatozoa. sperm morphology was assessed on sperm nuclear dna in ejaculates of infertile men—khalili et al 156 urology journal vol 3 no 3 summer 2006 smears with the giemsa staining (merck chemical co, darmstadt, germany). the percentage of spermatozoa with a normal morphology was determined by assessing 100 sperms under oil immersion with magnification of × 1000 under bright-field illumination.(2,14) acridine orange staining for assessment of sperm dna integrity, the smears were air-dried for 1 hour and then fixed overnight in freshly made carnoy’s solution (one part glacial acetic acid, three parts methanol) at 4ºc. the slides were rinsed 2 times with distilled water and dipped in mcilvaine phosphate-citrate buffer (ph = 4) for 5 minutes. each sample was then stained with freshly prepared acridine orange (0.19 mg/ml; sigma chemical co, st louis, usa) in mciivaine phosphatecitrate buffer for 10 minutes in the darkness.(15) the preparations were washed with distilled water, covered with glass cover slips, and assessed on the same day using fluorescent microscope (zeiss, oberkochen, germany) with a 460-nm filter. the duration of illumination was limited to 40 seconds per field. the percentage of green (normal dna integrity) and orange-red (abnormal dna integrity) spermatozoa per 100 spermatozoa in each sample was calculated by a same single person. an abnormal integrity of sperm nuclear dna was considered as more than 30% denaturation (orange-red spermatozoa on acridine orange staining).(16) the dna fragmentation index (dfi), which is the ratio of the orange-red to the total (orange-red + green) fluorescence intensities of spermatozoa, was also calculated for the samples. statistical analyses for statistical analyses, spss software (statistical package for the social sciences, version 9, spss inc, chicago, ill, usa) was used. the chi-square test and the fisher exact test were used to compare the frequencies and student t test to compare quantitative values. the pearson correlation test was used to evaluate the relationship between sperm dna integrity and sperm parameters. a p value less than .05 was considered significant. results overall, semen samples of 30 infertile and 30 fertile men were assessed. the mean sperm concentration, motility, and normal morphology were significantly higher in the fertile subjects. the mean values of semen parameters are presented in table 1. also, the viscosity of the seminal specimens were abnormally high in 4 (13.3%) and 2 (6.7%) patients in the fertile and infertile groups, respectively (p = .67). nineteen men (63.3%) in the infertile group had asthenoteratospermia, 7 (23.3%) had asthenospermia, and 4 (13.4%) had oligoasthenoteratospermia. therefore, the majority of our patients suffered from abnormal progressive motility. the number of ejaculates with denatured sperm dna (dfi) above the normal value of 30% were 16 (53.3%) and 22 (73.3%) in fertile and infertile subjects, respectively (p = .10). the mean dfi was 37.7 ± 19.6% and 46.1 ± 16.7% in the fertile and infertile subjects, respectively (p = .24). the mean percentage of green fluorescent sperm in aot was 62.4 ± 28.8% and 53.8 ± 24.3% in the fertile and infertile subjects, respectively (p = .22). a total of 4 (13.3%) and 1 (3.3%) ejaculates were presented with over 97% double-stranded-dna sperms (green staining) in the fertile and infertile groups, respectively (p = .35). interestingly, the mean dfi of the fertile men with a normal sperm morphology (12 patients) was 32.2 ± 8.3% (range, 1% to 80%), and 6 of them had a dfi greater than 30%. table 1. semen parameters and sperm dna integrity for 60 ejaculates of fertile and infertile men* *values are demonstrated as means ± standard deviations (ranges). semen parameters fertile group infertile group p volume, ml 3.8 ± 1.6 (1 to 8) 3.5 ± 1.8 (1 to 7) .46 sperm concentration, × 10 6 81.5 ± 36.0 (38 to 180) 55.1 ± 36.3 (3 to 170) .006 progressive motility, % 60.3 ± 7.5 (50 to 73) 19.3 ± 16.4 (2 to 47) < .001 nonprogressive motility, % 10.3 ± 2.6 (5 to 17) 16.3 ± 7.1 (7 to 38) < .001 normal morphology, % 52.5 ± 11.7 (38 to 78) 22.6 ± 12.4 (2 to 48) < .001 round cells, × 10 6 0.3 ± 0.1 (0 to 0.4) 0.52 ± 0.9 (0 to 0.3) .36 normal dna integrity, % 62.4 ± 28.0 (19 to 100) 53.8 ± 24.3 (12 to 98) .22 sperm nuclear dna in ejaculates of infertile men—khalili et al urology journal vol 3 no 3 summer 2006 157 in the samples with oligoasthenospermia, the mean percentage of green sperms was 48.25 ± 6.8% (range, 28% to 71%) and the mean dfi was 52.7 ± 17.9%. in addition, there were 2 samples with severe teratospermia (normal morphology less than 4%) and dfis of 70% and 87%. there were no significant correlations between the dna integrity (demonstrated by the green staining of the sperm nucleus in aot) and the 3 parameters of semen quality in our 60 subjects (table 2). discussion in clinical practice, the conventional subjective semen analysis using light microscopy still plays the central role in the assessment of fertility in men. however, a definitive diagnosis of infertility cannot often be made solely on the basis of semen analysis results. although in many circumstances the sperm parameters are impaired in infertile population, there is a significant overlap between the semen parameters of infertile and fertile men.(3,16) thus, to upgrade the prognostic and diagnostic ability of semen analysis, an sperm function assay should be included. nowadays, there are several assays available to assess the sperm nuclear integrity in clinical setting. however, the efficacy or prognostic value of each assay for prediction of fertilization or pregnancy outcome following art is still a matter of controversy. one of the standard assays is aot, which is quick and easy to be performed at clinical andrology laboratories. application of acridine orange fluorescent staining allows the nuclear chromatin integrity of the human spermatozoa to be analyzed under either fluorescent microscope or by flowcytometry. this can be used for testing the sperm maturity and predicting the fertilization capacity of ejaculated spermatozoa.(16) hoshi and colleagues showed that men who had ejaculates with more than 50% green sperms in aot (doublestranded dna) had a significantly higher fertilization capacity for ivf compared with men with immature sperms.(17) therefore, it seems that sperm chromatin abnormality affects the fertilization process in clinical setting. it has been previously reported that a significant difference exists between the proportions of the sperms with impaired dna integrity in the fertile and the infertile populations.(9,16,18) zini and coworkers studied the prevalence of sperm dna denaturation by aot among 13 fertile and 88 infertile men. they observed that the rate of dna denaturation was significantly lower among infertile men with normospermia compared with infertile patients with abnormal spermatozoal parameters (11.1% versus 23.1%, respectively). thus, a negative correlation was reported between the dna integrity and semen parameters.(16) however, our results disagree with the aforementioned studies; the proportion of sperms with a normal dna integrity in our fertile (normospermic) subjects was slightly higher than that in infertile subjects with impaired semen parameters, but the difference was not significant. neither could we find any correlation between the status of sperm dna integrity and the sperm parameters in our patients. the rate of sperm dna integrity was not consistent among the fertile men with normal semen parameters. for example, 54% of the fertile men had a sperm dfi over 30%. in addition, samples with normal sperm morphology revealed a 32.2% dfi which is above the normal range. evaluation of sperm nuclear integrity with aot and fluorescent microscopy, as used in our study, is a routine procedure in andrology units; however, usage of flowcytometry is more efficient as stated by erenpreiss and coworkers.(9) but, flowcytometry is an expensive technique and also time consuming, thus, less practical for daily evaluation of sperm dna in art. in our previous studies, we noticed that the sperm parameters were more defective in samples extracted from the testis comparing with the ones extracted from the ejaculates. this is due to the fact that sperms are immature in the testis and should reach the epididymis to achieve the maturity. also, the fertilization rates were lower with sperms retrieved from testis than either epididymal or table 2. correlations between dfi and sperm parameters in fertile and infertile men* * values are correlation coefficient (p). dfi indicates dna fragmentation index. dfi semen parameters fertile group infertile group sperm concentration -0.23 (.21) -0.29 (.12) progressive motility -0.02 (.91) -0.05 (.80) normal morphology -0.06 (.74) -0.15 (.44) sperm nuclear dna in ejaculates of infertile men—khalili et al 158 urology journal vol 3 no 3 summer 2006 seminal spermatozoa. in addition, the fertilization and pregnancy rates were higher in samples with normospermia compared with the abnormal samples with 2 or 3 defects in the sperm parameters.(3,19) therefore, it can be concluded that mature sperms from ejaculates of infertile patients are capable of fertilizing oocytes at higher rates comparing with the immature spermatozoa that are retrieved from the testis of infertile subjects, and also, the seminal samples with normal sperm parameters have higher levels of fertilizing potentials than abnormal samples regardless of the source of collection. it should be emphasized that normal dna integrity of spermatozoa is very important in intracytoplasmic sperm injection (icsi), because the sperm selection is performed by the embryologist on the basis of the motility and morphology status. bungum and colleagues observed significantly higher dfi levels in successful icsi cases compared with those in successful ivf or intrauterine insemination cases.(20) therefore, the highest level of sperm dna damage was detected in men with the poorest semen quality (icsi candidates). the authors concerned the safety of the icsi procedure since damaged dna is often observed more frequently among icsi candidates. developing assays for detecting and selecting spermatozoa with intact dna for microinjection during icsi procedure will be the future challenge. our results showed that none of the sperm parameters correlated with dna integrity of the spermatozoa;(18) therefore, we cannot predict the outcome of the icsi cycles solely on the basis of sperm parameters such as sperm motility and nonstained sperm morphology. acridine orange test has been successfully used by some laboratories in an attempt to improve the male fertility evaluations; however, the predictive value of aot is still controversial.(1,12,16,20-22) most investigators have noticed a significant relationship between the aot and the sperm parameters or sperm fertilizing ability, while a negative correlation has also been reported.(12) as our results showed, aot may be associated with severe teratospermia or oligoastheno teratospermia. therefore, we do not recommend the application of aot as a part of the routine fertility workup. on the other hand, it should only be used in selected infertile men with severely abnormal sperm parameters. it should be emphasized that the application of other chromatin integrity assays may reveal the precise quality of the spermatozoa.(23) thus, it may be necessary to apply several chromatin or dna integrity assays for the elucidation of the precise pathophysiology of male infertility. in addition, as katayose and associates stated, acridine orange fluorescent staining is very useful in cases with unexplained infertility.(11) we, however, have not investigated the dna integrity of such cases so far. conclusion our study showed that the relationship between dna integrity status and the sperm quality is a rather complex issue. although more dna abnormalities were detected among infertile cases with abnormal sperm parameters, the difference was not significant when compared with ejaculates of fertile controls. however, defects in sperm dna integrity were associated with severe cases such as oligoasthenospermia or severe teratospermia. additional large-scale trials are needed to confirm the predictive value of sperm chromatin integrity using aot for the outcome of art cycles. acknowledgement the authors would like to thank mr hossain fazli and mrs habibeh ghaisari for their technical assistance during the course of this research study. authors are also grateful to mr ahmedieh, msc, for the statistical analysis. conflict of interest none declared. references 1. fraser l. structural damage to nuclear dna in mammalian spermatozoa: its evaluation techniques and relationship with male infertility. pol j vet sci. 2004;7:311-21. 2. aitken rj. sperm function tests and fertility. int j androl. 2006 ;29:69-75. 3. khalili ma, vahidi s, aflatonian a, amir-arjmand m. intracytoplasmic sperm injection for the treatment of male factor infertility. med j islam repub iran. 1997;11:181-5. 4. chohan kr, griffin jt, lafromboise m, de jonge cj, carrell dt. comparison of chromatin assays for dna fragmentation evaluation in human sperm. j androl. 2006;27:53-9. 5. evenson dp, larson kl, jost lk. sperm chromatin 1453.pdf 848 | sindh institute of urology and transplantation (siut), civil hospital, karachi, pakistan manzoor hussain, altaf h. hashmi, syed adeebul hassan rizvi problems and prospects of neglected renal calculi in pakistan can this tragedy be averted? corresponding author: manzoor hussain, mbbs; ms department of urology, sindh institute of urology and transplantation, civil hospital, karachi, 74200, pakistan tel: +92 219 498 9172 fax: +92 213 272 6165 e-mail: info@siut.org received may 2012 accepted november 2012 purpose: to report our recent experience of treating patients with stones associated with renal failure, some of the factors underlying this problem, and few suggestions to avert this tragedy. materials and methods: from january 2010 to december 2010, a total of 2838 new patients with stone disease and renal failure were reviewed and compared with a cohort of 878 patients with normal renal functions. their demographic and clinicopathological parameters were noted and analyzed. results: of 2838 patients, 278 presented with acute and chronic renal failure, 40 (1.4%) with unilateral non-functioning kidneys, and 25 (0.8%) with pyonephrosis and perinephric abscess. management in 278 (9.7%) subjects was divided into initial relief of obstruction by percutaneous gery, percutaneous nephrolithotomy, extracorporeal shockwave lithotripsy, and ureterorenoscopy to make these patients stone-free. results of treatment showed that 72% of patients either recovered their renal functions or became dialysis-free at the end of the follow-up period. conclusion: complications of renal calculi in the era of modern treatment can be prevented by public education and organizing courses for family physicians as well as opening new stone clinics in the rural areas of the country equipped with modern treatment facilities and strategies for prevention of renal calculi. keywords: kidney calculi, renal failure, anuria, pakistan endourology and stone disease endourology and stone disease 849vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l introduction stone disease is one of the common causes of obstruc-tive uropathy and nephropathy in pakistan, which affects all age groups, including children, adults, and elderly.(1) the impact of the obstruction due to stone is line condition of the kidneys, the potential for recovery, and the presence of infection.(2) stone disease is not only the cause of pain and infection, (3) renal failure (rf) due to stone disease could be caused by long standing obstruction, infection, and irritation due to crystals in the renal tubules, or associated medical conditions like diabetes and hypertension, or previous procedures done on the kidney for removal of stones.(4) neglected renal calculi is a different entity in pakistan, because on one hand, there is increasing incidence of stone disease and on the other hand, the inadequate facilities for treatment result in very late presentation with large and multiple calculi with rf or any other complication. in the last 30 years, advances in the management of stone disease in the form of extracorporeal shockwave lithotripsy (eswl), percutaneous nephrolithotomy (pcnl), ureterorenoscopy (urs), retrograde intrarenal surgery (rirs), and laparoscopy have diminished the role of open stone surgery all over the world.(5) unfortunately, in spite of advances, the number of patients with stone presenting with complications is on rise in the public sector hospitals in pakistan.(6) the reported life-threatening complication rate due to stone disease is about 12%.(7) the management of this group of the patients is a challenge and multi-disciplinary. although various endourologic methods can be applied to make these patients stone-free,(8) open surgery remains cost-effective. (3) previous report from our institute showed that the frequency of rf in patients with renal calculi was about 8% and frequency of end-stage renal disease due to stone disease was 7.3 %.(1) similarly, 5.3% of acute rf was due to ureteral and renal calculi.(6) other investigators have also reported the problems of both acute and chronic rf due to stone disease from other parts of the country.(9,10) literature review shows that the problem of rf due to stone disease also exists in other developing countries, such as india(8) and china,(11) but rarely in western countries.(12) herein, we report our recent experience of treating patients with stones associated with rf, some of the factors underlying this problem, and few suggestions to avert this tragedy. materials and methods were registered for treatment at this institute from january 2010 to december 2010. this descriptive study was carried out on 278 patients who presented with rf and were admitted in the ward for treatment. a group of 878 patients with stone with normal renal functions, who were admitted in the ward for management, was taken as control group to study co-morbidities and site of stones in these groups. rest of the patients (1682) were managed as outpatients in the stone clinic and lithotripsy departments. at the time of admission, full history taking, physical examination, ultrasonography of the kidneys, and the kidney, ureter, and bladder (kub) x-ray were performed in every subject. blood chemistry, complete hemogram, and serum urea, creatinine, and electrolytes were evaluated. urine analysis and culture/sensitivity were done if patients were not anuric. after investigations, the patients were evaluated jointly by a nephrologist, urologist, and radiologist. if urea and creatinine were >200 mg/dl and >10 mg/dl, respectively, serum potassium would be >5.5 meq/l and hco3 <15 meq/l or if acidosis was present on arterial blood gas analysis, then hemodialysis would be done as an initial treatment. if renal functions were within acceptable level for anesthesia and patients were afebrile, then double-j (dj) stents with or without urs were used to relieve the obstruction. oes, pcnl would be done under local anesthesia to relieve the obstruction and to drain the infection. in some patients, bilateral pcnl was done. once patients were stabilized were done in the form of eswl, urs, pcnl, and open surgery depending on the indications. neglected nephrolithiasis in pakistan | hussain et al 850 | were followed up in stone clinic with ultrasonography, renal function tests, urine for culture/sensitivity, and kub x-ray after discharge from the ward. preand postoperative serum were compared to study the effect of relief of obstruction. if they would be prepared for live-related renal transplantation. during hospitalization in the ward, these patients were managed jointly by nephrologists, urologists, infectious disease team, and anesthetists. who present very late with complications, such as rf, pyonephrosis, and perinephric abscess. we hypothesized that velopment of rf in patients with stone. results two hundred and seventy-eight (9.7%) patients presented with pyonephrosis or perinephric abscess and 40 (1.4%) with unilateral non-functioning kidneys, while remaining 2560 (90.2%) had normal renal functions (serum creatinine <1.5 mg/dl). of 278 patients with rf, 200 (72.3%) were from rural areas, while 78 (27.7%) were from urban areas of the country. two hundred and fourteen (77.6%) subjects belonged to poor socioeconomic class. there were 193 (69.4%) men and 85 (30.5%) women with male-to-female ratio of 2.2:1. similarly, 878 patients with renal stones with normal renal functions (control group) were evaluated for male-tofemale ratio, which was found to be 1.4:1. the duration of symptoms of renal calculi and rf ranged from <1 month to >4 years. ninety patients presented early with duration of <1 month; these patients had symptoms of acute rf with duration of anuria ranging from 2 to 8 days. the causes of delay in diagnosis and neglect were analyzed in 278 patients. it showed that 12% of patients had silent causes included family physicians (19%), hakims, homeopaths and quacks (24%), and dentists (45%). the site of stones in 278 patients with rf was bilateral renal or ureteral in 158 (55.6%) patients. similarly, of 878 control patients, 197 (21.6%) had bilateral disease (table 1). analysis of co-morbid conditions in 278 patients with rf showed that 35 (12.5%) were diabetics, 55 (21%) were hypertensive, and 4 (1.4%) were both diabetic and hypertensive. seventeen (6.1%) had radiolucent stones. comparison of co-morbidities in the patient and control groups is shown in table 2. management in 278 patients with stone with rf was di113 (40.6%) subjects, pcnl was done to relieve obstrucendourology and stone disease table 1. comparison of site of stones in the study and the control groups. site of stones study group (n = 278) control group (n = 878) p number (%) number (%) bilateral renal 108 (38.8) 152 (17.3) .0001 bilateral ureteral 33 (11.8) 39 (4.4) .0001 bilateral renal + bilateral ureteral 8 (2.8) 1 (0.1) .0001 bilateral renal + unilateral ureteral 9 (3.2) 5 (0.56) .001 unilateral ureteral 29 (10.4) 153 (17.4) .005 unilateral renal 49 (17.6) 437 (49.7) .0001 uniteral renal + ureteral 31 (11.1) 45 (5.1) .0001 unilateral renal + bladder 5 (1.8) 8 (0.9) .22 ureteral + vesical 6 (0.6) .16 bilateral renal + bladder 1 (0.3) 24 (2.7) .18 851vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l tion and in 19 (6.8%), urs and dj stent were successful, but 103 (37%) patients presented with severe uremic symptoms; therefore, hemodialysis was needed, while in 43 (15.4%), conservative medical treatment consisting of hydration, antibiotics, and correction of electrolyte imbalance was done. in 278 patients. in 158 (56.8%) subjects, open surgery was performed while pcnl was done in 18 (6.4%) and eswl ureteral calculi included urs in 33 and urs + dj stent + eswl in 15 patients; the rest were treated by open surgery (table 3). preand postoperative serum creatinine levels were available in 220 patients; remaining patients either died or underwent renal transplantation. pre-operative serum creatinine ranged from 1.6 to 28 mg/dl with mean serum creatinine of 10.7 mg/dl, while at 3 months postoperative follow-up, serum creatinine ranged from 0.6 to 8.0 mg/dl with mean value of 2.76 mg/dl. the overall results of surgery in 278 patients showed that 72.3% of patients were dialysis-free at the end of the follow-up, 14% received renal transplantation, and 10.4% died till 2010 (table 4). stone analysis in 207 samples analyzed by infrared spectroscopy showed that 62.5% stones contained calcium oxalate or calcium phosphate either in pure (16%) or mixed (43.5%) form. similarly, uric acid stones were seen in 11.1% in pure form and in 17.3% in mixed with other compounds constituting 28.3% of samples. struvite stones were present in 5.6% samples with ammonium hydrogen urate in 3.3% and 2,8-dihydroxyadenine in 0.4% patients (table 5). discussion renal stones presenting very late with complications are quite common in pakistan and have been very well reported in the past(13) and present literature.(14) there are many reasons for this tragedy; one is the silent stones not causing any pain, presenting very late with rf or pyonephrosis. other is treatment of renal calculi by hakims, homeopaths, and alternative medicines leading to delay in the diagnosis and treatment, and family physicians, who deliberately treat these patients with pain killer drugs and do not try to investigate is the poverty and poor health facilities in rural areas of the country. there are 24 urology centers in public and private sectors with 24 lithotripters, but they are functional only in few centers. the incidence of renal calculi is increasing worldwide and pakistan is not an execption, but treatment modalities are not increasing in parallel resulting in delay and neglect in the treatment of renal calculi in this country. at sindh institute of urology and transplantation, a tertiary care center table 2. comparison of co-morbids, congenital anomalies, and radiolucency in the study and the control groups. co-morbids study group (n = 278) control group (n = 878) p number (%) number (%) dm 35 (12.5) 19 (2.1) .0001 hypertension 22 (7.9) 16 (1.8) .0001 dm + hypertension 4 (1.4) 3 (0.3) .04 adult polycystic kidneys 2 (0.7) .012 crossed fused ectopia 2 (0.2) .42 horseshoe kidney 1 (0.3) 3 (0.3) .96 stones with upjo 7 (0.7) .44 radiolucent stones 17 (6.1) 21 (2.3) .002 pelvic kidney with stones 2 (0.2) .42 dm, indicates diabetes mellitus; and upjo, ureteropelvic junction obstruction. neglected nephrolithiasis in pakistan | hussain et al 852 | for renal and urologic diseases, about 9.8% of all patients with stone present with rf, which is probably the highest number ever reported in the world literature.(8,15) obviousshows that in spite of minimally-invasive and non-invasive methods, this complication has not reduced in our recent practice. we can avert this tragedy by opening more comprehensive stone centers in the country equipped with lithotripsy machines, facilities for pcnl, ureteroscopy, and facilities for open and laparoscopic surgery, as has happened in developed countries. comparison of site of stones in rf and control groups showed that rf was more common in patients with bilateral stone disease and stones in solitary kidney. it means that patients with bilateral renal calculi need thorough investigations to prevent this tragedy and should be treated on priority basis before they go into complications. in 6 patients, large bladder calculi presented with rf; stones were occupying almost all the capacity of the bladder. neglected bladder calculus presenting with rf has also been reported from china.(16) co-morbidities, such as diabetes mellitus, hypertension, and congenital anomalies, were compared between the study and control groups. patients with rf had slightly higher numbers in co-morbidities, which shows that a minor contributing factor may be a co-morbidity leading to rf. associated obstruction and stasis caused by congenital anomalies were not a contributing factor in rf. radiolucent stones were more commonly seen in patients with rf compared to the control group, which shows that uric acid nephropathy may be a contributing factor in this population. this was supported by the stone analysis reports in this group of patients. computed tomography scan played a vital role in diagnosis of these patients. management of patients with stone and rf is different from the patients with stone and normal renal function. they to drain the infection, but in 19 (6.8%) patients, the ureteroscopy was directly performed, stones were fragmented, and dj stents were passed without doing pcnl and hemodialysis. this group of patients was selected carefully due to possibility of septicemia. careful selection included afebrile patients, normal or near normal electrolytes, and preferably a negative urine culture. acute renal failure due to ureteral calculi can be treated directly by ureteroscopy, lithoclast fragmentation, and dj stents, as has been recently reported from china.(11) in 37% of our patients, hemodialysis was done as an initial treatment, which showed severe leading to uremia. initial mode of drainage of obstructed kidneys with rf is controversial; there are advantages and disadvantages of pcnl and dj stents. double-j stenting obviates the need for external collection device, but is associated with bothersome lower tract symptoms and a higher incidence of urinary tract infection, and requires general anesthesia in many cases. however, if the patient has uncorrectable coagulopathy or platelet abnormality, ureteral stenting is inendourology and stone disease table 3. management of stones with renal failure in 278 patients. initial management number (%) percutaneous nephrostomy 113 (40.6) dj stents 19 (6.8) hemodialysis 103 (37) conservative 43 (15.4) definitive management extended pyelolithotomy 65 (23.3) pyelolithotomy + dj + eswl 9 (3.2) pyelolithotomy + urs + dj 20 (7.1) anatrophic nephrolithotomy 21 (7.2) anatrophic nephrolithotomy + urs + dj 2 (0.7) pyeloureterolithotomy 4 (1.4) nephrectomy 31 (11.1) pcnl 26 (9.3) pcnl + urs 2 (0.7 ) eswl + dj 13 (4.6) urs + dj 33 (11.8) urs + dj + eswl 15 (5.3) ureterolithotomy 25 (8.9) ureterolithotomy + dj + eswl 2 (0.7) cystolithotomy 6 (2.1) cystolithoclast 2 (0.7) eswl bladder stone 2 (0.7) dj indicates double-j; eswl, extracorporeal shockwave lithotripsy; urs, ureterorenoscopy; and pcnl, percutaneous nephrolithotomy. 853vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l dicated. internal stenting requires x-ray exposure; hence, should be avoided in pregnancy. on the other hand, pcnl should be strongly considered in pyonephrosis and in case of dj stenting failure.(2) model therapy ranging from open surgery to endourology (pcnl, urs, or eswl). because of multiple and very large staghorn calculi, these patients are best treated with open surgery due to the following reasons. open surgery provides higher chances of making these patients stone-free in one sitting, and also drainage of pus with excellent stonefree rates like in our patients. recently, many studies from india have shown pcnl as the (17,18) we have done pcnl in 18 subjects with renal calculi. in our experience, the rate of redo pcnl was high in cases of multiple renal calculi, which needs multiple general anesthesia and multiple admissions, and is not cost-effective. multiple anesthesia and procedures can affect the recovery of renal functions. furthermore, many patients do not prefer to undergo multiple procedures. the aim of surgery in these patients is to make them stoneand dialysis-free if possible and to get maximum mileage from these chronically obstructed kidneys to save the cost of dialysis. in our experience, open surgery provides the best chance in experienced hands as compared to pcnl. overall stone clearance rate after eswl in these patients was observed to be poor in our study and others.(19) an analysis of the outcome of management at the end of the follow-up showed that 57% of patients either had complete tive treatment. another group of 41 (14.7%) remained dialysis-free after management with overall 72% of the patients a good achievement in a developing country like pakistan to save the cost of dialysis in these patients and give them better life with joint management by urologists, nephrologists, and anesthetists at our center. recovery of renal functions after relief of obstruction provides human model for study of recovery potential as most of the studies reported in the literature are animal-based.(2) since our center is a public sector renal transplant center in the country, 39 (14%) of the patients received renal transplantation in this group, which is an achievement to rehabilitate these patients back to normal life. recovery of renal table 4. results of treatment (n = 278 patients). outcomes number (%) complete recovery (serum creatinine 0.6 to 1.5 mg/100 ml) 64 (23) improvement of renal functions (serum creatinine 1.6 to 3 mg/100 ml) 96 (34.5) renal functions remained stable (dialysis-free) (serum creatinine 3 to 6 mg/100 ml) 41 (14.7) no recovery (dialysis dependent) 9 (3.2) renal transplantation 39 (14) mortality 29 (10.4) table 5. stone analysis in the study group (n = 207). number (%) caox (m) + cap 84 (40.5) caox (m) 28 (13.5) cap 5 (2.4) cap + fat + proteins 2 (0.9) caox (d) + caox (m) 4 (1.9) cod + cap 7 (3.3) ua 23 (11.1) ua + caox (m) + cap 16 (7.7) ua + com + ahu 1 (0.4) ua + caox (m) 15 (7.2) ua + nah-urate 2 (0.9) ua + cod 2 (0.9) struvite + cap 16 (4.7) struvite 2 (0.9) ahu 2 (0.9) ahu + ua 5 (2.4) 2, 8-dihydroxyadenine 1 (0.4) caox indicates calcium oxalate; m, monohydrate; cap, calcium phosphate; d, dihydrate; cod, calcium oxalate dehydrate; ua, uric acid; com, calcium oxalate monohydrate; ahu, ammonium hydrogen urate; and nah, sodium hydrogen. neglected nephrolithiasis in pakistan | hussain et al 854 | functions after removal of stones with open surgery has also been reported by other researchers.(20) the mortality in neglected renal stones with rf was seen and irreversible damage due to renal stones. the common causes of mortality in these patients are sepsis and other complications of dialysis and end-stage renal disease.(3) all subjects who recovered their renal functions were regularly followed up in stone clinic with advice on hydration, diet, and treatment of urinary tract infection and hypertension. this strategy helps in stabilizing renal functions and prevention of future recurrence.(5) conclusion our recent data show the increasing number of neglected renal calculi presenting very late for management, which on one hand, is a challenge and on the other hand, a tragedy, which should have been averted in the modern era of shockwave therapy and endourology. unfortunately, we have not yet succeeded in averting this tragedy. this tragedy can be avoided by organizing public awareness programs in print and electronic media to educate the patients to seek early consultation. furthermore, education programs should be organized for family physicians for early diagnosis, treatment, and referral to tertiary care urologic centers. as most of the patients are coming from rural areas and belong to poor socioeconomic class, there is a need to open new stone clinics in these areas equipped ureteroscopy facilities. acknowledgements we acknowledge with gratitude the efforts of professor dr. muhammed mubarak, associate professor, department of pathology, siut, for his critical review of the manuscript and help in the preparation of this paper for publication. conflict of interest none declared. references 1. rizvi sa, manzoor k. causes of chronic renal failure in pakistan: a single large center experience. saudi j kidney dis transpl. 2002;13:376-9. 2. wilson dr. pathophysiology of obstructive nephropathy. kidney int. 1980;18:281-92. 3. hussain m, lal m, ali b, et al. management of urinary calculi associated with renal failure. j pak med assoc. 1995;45:2058. 4. worcester e, parks jh, josephson ma, thisted ra, coe fl. causes and consequences of kidney loss in patients with nephrolithiasis. kidney int. 2003;64:2204-13. 5. alivizatos g, skolarikos a. is there still a role for open surgery in the management of renal stones? curr opin urol. 2006;16:106-11. 6. naqvi r, ahmed e, akhtar f, yazdani i, naqvi nz, rizvi a. analysis of factors causing acute renal failure. j pak med assoc. 1996;46:29-30. 7. hussain m, rizvi sa, askari h, et al. management of stone disease: 17 years experience of a stone clinic in a developing country. j pak med assoc. 2009;59:843-6. 8. gopalakrishnan g, prasad gs. management of urolithiasis with chronic renal failure. curr opin urol. 2007;17:132-5. 9. amanullah gk, lal s, soomro mi, jalbani mh. calculus anuria and its remedy. j ayub med coll abbottabad. 2010;22:112-4. 10. khan fa. calculous anuria. j pak med assoc. 1979;29:25662. 11. yang s, qian h, song c, xia y, cheng f, zhang c. emergency ureteroscopic treatment for upper urinary tract calculi obstruction associated with acute renal failure: feasible or not? j endourol. 2010;24:1721-4. 12. rule ad, bergstralh ej, melton lj, 3rd, li x, weaver al, lieske jc. kidney stones and the risk for chronic kidney disease. clin j am soc nephrol. 2009;4:804-11. 13. khan fa. calculus renal failure. lahore new fine printing press; 1981. 14. rizvi sa, naqvi sa, hussain z, et al. the management of stone disease. bju int. 2002;89 suppl 1:62-8. 15. kukreja r, desai m, patel sh, desai mr. nephrolithiasis associated with renal insufficiency: factors predicting outcome. j endourol. 2003;17:875-9. 16. wei w, wang j. a huge bladder calculus causing acute renal failure. urol res. 2010;38:231-2. endourology and stone disease 855vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l 17. kumar s, ganesamoni r, mandal a. efficacy and outcome of percutaneous nephrolithotomy in patients with calculus nephropathy. urol res. 2011;39:111-5. 18. agrawal ms, aron m, asopa hs. endourological renal salvage in patients with calculus nephropathy and advanced uraemia. bju int. 1999;84:252-6. 19. hung sf, chung sd, wang sm, yu hj, huang hs. chronic kidney disease affects the stone-free rate after extracorporeal shock wave lithotripsy for proximal ureteric stones. bju int. 2010;105:1162-7. 20. singh i, gupta np, hemal ak, aron m, dogra pn, seth a. efficacy and outcome of surgical intervention in patients with nephrolithiasis and chronic renal failure. int urol nephrol. 2001;33:293-8. neglected nephrolithiasis in pakistan | hussain et al 1532 | laparoscopic redo-pyeloplasty using vertical flap technique akbar nouralizadeh, alireza lashay, mohammad hadi radfar corresponding author: alireza lashay, md urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. tel: +98 912 1549076 fax: +98 22074101 e-mail: alireza_lashay@yahoo.com urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. video iintroduction wehaveperformedmorethan20laparoscopicpyeloplastiesbetween2007and2012,herewepresentoneofthiscases.a46yearsoldmanwithhistoryofbilaterallaparoscopicdismemberedpyeloplasty,presentedwithleftflankpain. intravenousurography(ivu)andisotopescanwasinconclusiveduetoseveredilationof pyelocalycealsystem.ureteroscopyrevealednarrowingandtighteningoftheleftureteropelvicjunction(upj)whiletherightupjwasrelativelynormal. keywords:laparoscopy;methods;reconstructivesurgicalprocedures;ureteralobstruction; surgery. surgical technique thepatientunderwentleftsidelaparoscopicredopyeloplastyusingverticalflaptechnique. laparoscopicdissectionthroughfibroustissuewasdemanding,howevertherewasnointra video 1533vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l laparoscopic redo-pyeloplasty | nouralizadeh et al operativeandpost-operativecomplication.operativetime was192minutesandintraoperativebloodlosswasabout 300ml.thepatientdischargedafter5days.after6months hewassymptomfreeandtheupjwaspatentinfollow-up ureteroscopy. discussion laparoscopic pyeloplasty seems to be the new standard methodforthetreatmentofupjobstruction(upjo)and secondaryupjoisincreasinglybeenmanagedbylaparoscopy.(1)bothdismemberedtechniqueandflappyeloplasty havebeenreportedforthesespecialcases.(2-4)flappyeloplastyjeopardizetissuevascularitylessthandismembered techniquethereforethistechniquemaybemoresuitablefor patientswithhistoryofpreviousfailedsurgery. conclusion laparoscopicmanagementofsecondaryupjoisafeasible andsafeprocedureespeciallywhenflappyeloplastytechniqueisused. conflict of interest none declared. references 1. moon da, el-shazly ma, chang cm, gianduzzo tr, eden cg. laparoscopic pyeloplasty: evolution of a new gold standard. urology. 2006;67:932-6. 2. basiri a, behjati s, zand s, moghaddam sm. laparoscopic pyeloplasty in secondary ureteropelvic junction obstruction after failed open surgery. j endourol. 2007;21:1045-51. 3. shadpour p, haghighi r, maghsoudi r, etemedian m. laparoscopic redo pyeloplasty after failed open surgery. urol j. 2011;8:31-7. 4. shapiro ey, cho js, srinivasan a, et al. long-term follow-up for salvage laparoscopic pyeloplasty after failed open pyeloplasty. urology. 2009 ;73:115-8. urological oncology characteristics and prognostic value of papillary histologic subtype in nonmetastatic renal cell carcinoma in korea: a multicenter study won ki lee,1 sang eun lee,2 sung kyu hong,2 chang wook jeong,2 yong hyun park,2 seok ho kang,3 yong-june kim,4 sung-hoo hong,5 won suk choi,6 seok-soo byun2* purpose: to analyze the characteristics of nonmetastatic papillary renal cell carcinomas (rcc) and the prognostic value of rcc histologic subtyping, based on a large multicenter experience in korea. materials and methods: a total of 2,905 patients with nonmetastatic rcc (txn0m0) at the time of surgery were retrospectively enrolled from five institutions between 1999 and 2011 in korea. among these, patients with clear cell subtype (n = 2,488, 85.6%) and papillary subtype (n = 192, 6.6%) were included in our study. results: patients with papillary subtype did not differ significantly from those with clear cell subtype on the following parameters: age (p = .694), gender (p = .511), body mass index (p = .136), patient performance status (p = .419), symptoms at presentation (p = .419), tumor size (p = .778) and pathologic stage (p = .367). however, high fuhrman’s grades were more common in papillary subtypes compared with clear cell subtypes (p = .001). the 5-year recurrence-free survival rates in patients with clear cell subtype and papillary subtype were 84.9% and 86.7%, respectively (p = .167). the 5-year cancer-specific survival rates in patients with clear cell subtype and papillary subtype were 92.0% and 93.1%, respectively (p = .931). histologic subtype was not an independent prognostic factor of recurrence-free and cancer-specific survival (p = .107 and p = .998, respectively). conclusion: our study suggests that the characteristics and prognosis of papillary subtype might be comparable to those of clear cell subtype in non-metastatic rcc, especially in asia. keywords: kidney neoplasms; carcinoma; renal cell; papillary; pathology; follow-up studies; retrospective studies; prognosis. introduction it is well known that renal cell carcinoma (rcc) is a heterogeneous and complex disease, and its natu-ral history is greatly variable.(1) prediction of disease progression is, therefore, critical in optimal clinical decision making with and counseling of patients. a variety of findings have been considered as prognostic factors for rcc. however, only a few prognostic factors including tumor-node-metastasis (tnm) stage, fuhrman’s grade and tumor size are almost undisputed prognostics factor for rcc, especially non-metastatic rcc.(2) the histologic subtypes of rccs, according to the 2004 world health organization (who) classification, include clear cell, papillary, chromophobe, collecting duct and unclassified.(3) histologic subtype has been traditionally considered as a prognostic factor for rcc, based on molecular and genetic studies which have shown that rccs have genetic and pathologic differences among the histologic subtypes.(4) however, the tumor characteristics and prognostic value of the histologic subtypes have not been verified, and remain debated.(2) it is also remarkable that almost all studies involving the prognostic value of histologic subtypes have focused on the western population. differences in characteristics of cancer among different races have well been established in other urologic cancers, such as prostate cancer.(5) also, because many previous studies have reported the existence of racial/ ethnic disparities in incidence and survival of rcc,(6-8) the prognostic value of histologic subtypes in asians may differ from that in westerners. in the current study, we analyzed the characteristics and prognostic values of papillary rcc (prcc) compared with clear cell rcc (crcc) in nonmetastatic rcc, based on a large, multicenter experience in korea. materials and methods study subjects our study was a clinical case series with retrospective design based on a large, multicenter experience in korea. a total of 2,905 patients with nonmetastatic rcc (txn0m0), which was determined by imaging modalities at the time of surgery, were enrolled from five institutions 1department of urology, college of medicine, hallym university, chun cheon, korea. 2department of urology, college of medicine, seoul national university, seoul, korea. 3department of urology, college of medicine, korea university, seoul, korea. 4department of urology, college of medicine, chungbuk national university, cheongju, korea. 5department of urology, college of medicine, catholic university, seoul, korea. 6department of urology, choi won suk urology clinic, yongin, korea. * correspondence: department of urology, seoul national university bundang hospital, 166, gumi-ro, bundang-gu, seongnam, kyunggi-do, 463-707, korea. tel: +82 31787 7342; fax: +82 31787 4057. e-mail: ssbyun@snubh.org. received august 2013 & accepted march 2014 urological oncology 1884 between 1999 and 2011. all patients had undergone surgery with curative intent. patients with hereditary syndrome were excluded. of the 2,905 patients identified, the 2,680 who were diagnosed with crcc or prcc, which are the 2 major histologic variants, were finally included in our study. one hundred thirteen patients underwent lymph node dissection, because of suspicious malignant lymph node lesions during the operation. however, all patients had pathologically n0. thirty patients had positive surgical margins, and any of them did not receive any adjuvant treatments. after receiving approval from the relevant institutional review board (approval no. b-1202-145-102), patients’ clinical and pathologic data were reviewed. variables the following variables were noted in all patients: follow-up duration including recurrence-free survival (rfs) and cancer-specific survival (css), age, gender, body mass index (bmi), eastern cooperative oncology group performance status (ecog ps), symptoms at presentation, tumor size and laterality, type and method of surgery, pathologic stage, fuhrman’s grade and histologic subtype. the follow-up consisted of a history, physical examination, comprehensive metabolic panel, abdominal computed tomography and chest radiography performed every 3 months for 6 months, every 6 months for 3 years and yearly after surgery for most of the patients. bone or brain scan was performed only when clinically indicated. rfs and css were determined from the date of surgery to the date of recurrence and cancer-specific death, respectively, and identified using the imaging studies. tumor size was determined from the pathologic specimen by recording the greatest diameter. pathologic stage was determined according to the 2002 tnm classification system. tumor grade was determined according to the fuhrman’s nuclear grade. histologic subtyping was performed according to the 2004 who classification. to assess pathologic features, urological pathologists reviewed all specimens at variables prcc crcc p value number of subjects 192 2488 ----follow up duration, mean ± sd, months 38.0 ± 26.8 37.8 ± 29.7 .950 age, mean ± sd, years 56.4 ± 13.5 56.1 ± 12.4 .694 gender, no (%) male 142 (74.0) 1785 (71.7) female 50 (26.0) 703 (28.3) .511 bmi, mean ± sd, kg/m2 24.2 ± 3.4 24.5 ± 3.3 .136 ecog ps ≥ 1, no (%) 114 (59.4) 1515 (60.9) .678 symptoms at presentation, no (%) .419 no symptoms 156 (81.3) 2074 (83.4) hematuria 16 (8.3) 235 (9.4) flank pain 15 (7.8) 135 (5.4) others 5 (2.6) 44 (1.8) tumor size continuous, mean ± sd, cm 4.3 ± 3.1 4.2 ± 2.9 .778 category, no (%) .225 < 4 112 (58.3) 1410 (56.7) 4-7 43 (22.4) 682 (27.4) > 7 37 (19.3) 396 (15.9) side, no (%) left 105 (54.7) 1270 (51.0) right 86 (44.8) 1207 (48.5) bilateral 1 (0.5) 11 (0.4) type of surgery, no (%) .01 radical nephrectomy 97 (50.5) 95 (49.5) partial nephrectomy 1492 (60.0) 996 (40.0) method of surgery, no (%) 0.067 laparoscopic 127 (66.1) 1799 (72.3) open 65 (33.9) 689 (27.7) t stage (tnm 2002), no (%) .367 pt1 151 (78.6) 1994 (80.1) pt2 20 (10.4) 203 (8.2) pt3 18 (9.4) 273 (11.0) pt4 3 (1.6) 18 (0.7) fuhrman’s grade, no (%) .001 g1 7 (3.6) 166 (6.7) g2 86 (44.8) 1385 (55.7) g3 91 (47.4) 840 (33.8) g4 8 (4.2) 97 (3.9) table 1. association of different clinical and pathological variables with histologic subtype in non-metastatic renal cell carcinoma. abbreviations: prcc, papillary renal cell carcinoma; crcc, clear cell renal cell carcinoma; sd, standard deviation; no, number of subjects; bmi, body mass index; ecog ps, eastern cooperative oncology group performance status. nonmetastatic papillary rcc in korea-lee et al vol 11. no 05 sept-oct 2014 1885 each institution. statistical analysis to compare the relationship between clinical and pathologic characteristics of patients with crcc and prcc, independent t-test and pearson’s chi-square or fisher’s exact test were used in the comparison of continuous and categorical variables, respectively. the rfs and css rates were calculated using the kaplan-meier method, and the log-rank test was used to examine the difference in survival rate between two groups. the prognostic values of variables for survival were evaluated using cox proportional hazards models. all tests were two-sided, and p < .05 was considered to be statistically significant. statistical package for the social sciences, version 17.0 (spss, chicago, il, usa) was used for all statistical assessments. results histologic subtypes of all patients included the following; 2,488 (85.6%) with crcc, 192 (6.6%) with prcc, 158 (5.4%) with chromophobe rcc, 14 (0.5%) with collecting duct rcc and 53 (1.8%) with unclassified rcc. mean age at surgery for all patients was 55.9 ± 12.6 years, and there were 2,040 males (70.2%) and 865 females (29.8%). mean tumor size was 4.3 ± 3.0 cm, and the pathologic stage was t1a in 1,659 (57.1%), t1b in 628 (21.6%), t2 in 256 (8.8%), t3a in 306 (10.5%), t3b in 26 (0.9%), t3c in 5 (0.2%) and t4 in 25 patients (0.9%). fuhrman’s grade was grade 1 in 183 (6.3%), grade 2 in 1,548 (53.3%), grade 3 in 1.039 (35.8%) and grade 4 in 135 patients (4.6%). table 1 shows the association of different clinical and pathological variables between patients with crcc and prcc. patients with prcc did not differ significantly from those with crcc for most variables. however, high fuhrman’s grades were more common in prccs than in crccs (p = .001). during the follow-up period, among 2,488 patients with crcc, 258 (10.4%) had recurrence and among 192 patients with prcc, 14 (7.3%) had recurrence. the 5-year rfs rates were 84.9 ± 1.0% in patients with crcc and 86.7 ± 4.0% in patients with prcc, and there was no significant difference between the two groups (p = .167, figure 1). when patients were stratified according to pathologic stage, the 5-year rfs rates for crcc and prcc with t1 were 91.4 ± 0.9% and 94.1 ± 3.2% (p = .095), with t2 were 73.6 ± 4.1% and 87.7 ± 8.2% (p = .321), and with t3-4 were 47.5 ± 4.3% and 23.3 ± 19.3% (p = .553), respectively. when patients were stratified according to fuhrman’s grade, the 5-year rfs rates for crcc and prcc with grade 1 were 94.1 ± 2.8% and 100% (p = .674), with grade 2 were 92.9 ± 1.0% and 88.3 ± 6.3% (p = .810) and with grades 3-4 were 70.6 ± 2.2% and 84.6 ± 5.3% (p = .020), respectively. a significant rfs difference was only present among the two groups for fuhrman’s grade 3-4. during the follow-up period, 129 patients (5.2%) with crccs and 10 patients (5.2%) with prcc died of cancer-specific causes. the 5-year css rates were 92.0 ± 0.8% in patients with crcc and 93.1 ± 2.6% in patients with prcc, and there was no significant difference between two groups (p = .931, figure 2). when patients were stratified according to pathologic stage, the 5-year css rates for crcc and prcc with t1 were 96.8 ± 0.6% and 97.8 ± 2.2% (p = .209), with t2 were 88.6 ± 2.9% and 84.6 ± 10.0% (p = .764) and with t3-4 were 62.5 ± 4.3% and 60.5 ± 16.0% (p = .100), respectively. when patients were stratified according to fuhrman’s grade, the 5-year css rates for crcc and prcc with grade 1 were 100% and 100% (p = .850), with grade 2 were 96.5 ± 0.7% and 100% (p = .608), and with grades 3-4 were 83.2 ± 1.9% and 87.5 ± 4.8% (p = .357), respectively. no significant css difference remained among the two groups stratified according to pathologic stage or fuhrman’s grade. independent prognostic factors of rfs in multivariate analysis were age, bmi, symptoms at presentation, tumor size, pathologic stage and fuhrman’s grade. however, the histologic subtype was not an independent prognostic factor of rfs in univariate and multivariate analysis (p = .170 and 0.107; hazard ratio (hr) = 0.686 and 0.642; 95% confidence interval (ci) = 0.401-1.175 and 0.374 univariate analysis multivariate analysis variables hr 95% ci p value hr 95% ci p value age 1.019 1.009-1.030 < .001 1.013 1.002-1.023 .020 gender: female vs. male 0.935 0.715-1.222 . 621 0.976 0.742-1.282 . 859 bmi (kg/m2) 0.932 0.896-0.969 < .001 0.941 0.903-0.980 .004 ecog ps: ≥ 1 vs. 0 1.291 1.004-1.661 .047 0.816 0.624-1.067 .137 symptoms at presentation 4.774 3.763-6.057 < .001 2.027 1.531-2.682 < .001 tumor size 1.300 1.268-1.334 < .001 1.172 1.128-1.218 < .001 side: bilateral vs. unilateral 1.584 0.394-6.369 .517 1.911 0.471-7.755 .365 t stage (2002 tnm) < .001 < .001 t2 vs. t1 3.606 2.551-5.096 < .001 0.883 0.582-1.340 .558 t3 and 4 vs. t1 9.084 6.995-11.798 < .001 2.571 1.798-3.676 < .001 fuhrman’s grade < .001 < .001 g2 vs. g1 1.948 0.788-4.813 .149 1.630 0.658-4.040 .291 g3 and 4 vs. g1 7.997 3.287-19.453 < .001 4.106 1.666-10.120 .002 histology: prcc vs. crcc 0.686 0.401-1.175 .170 0.642 0.374-1.101 .107 table 2. univariate and multivariate analyses predicting the probability of recurrence in non-metastatic renal cell carcinoma. abbreviations: hr, hazard ratio; ci, confidence interval; bmi, body mass index; ecog ps, eastern cooperative oncology group performance status; prcc, papillary renal cell carcinoma; crcc, clear cell renal cell carcinoma. nonmetastatic papillary rcc in korea-lee et al urological oncology 1886 1.101, respectively (table 2). similar to those of rfs, independent prognostic factors of css in multivariate analysis were age, bmi, symptoms at presentation, tumor size, pathologic stage and fuhrman’s grade. the histologic subtype did not remain an independent prognostic factor of css in univariate or multivariate analysis (p = .931 and .998; hr = 1.029 and 1.001; 95% ci = 0.5401.958 and 0.522-1.917, respectively (table 3). discussion it is well known that histologic subtypes of rcc show differences in genetic and morphologic parameters.(4) nevertheless, the characteristics and prognostic value of these histologic subtypes remain controversial.(2) deng and colleagues(2) recently analyzed the data from large cohort studies including more than 20,000 patients. they figure 1. kaplan-meier curve for recurrence-free survival for patients with non-metastatic renal cell carcinoma according to histologic subtype. abbreviations: crcc, clear cell renal cell carcinoma; prcc, papillary renal cell carcinoma. figure 2. kaplan-meier curve for cancer-specific survival for patients with non-metastatic renal cell carcinoma according to histologic subtype. abbreviations: crcc, clear cell renal cell carcinoma; prcc, papillary renal cell carcinoma. nonmetastatic papillary rcc in korea-lee et al vol 11. no 05 sept-oct 2014 1887 reported that the independent prognostic value of the histologic subtype is not yet widely accepted. therefore, far more studies are needed to prove the prognostic value of histologic subtype. another important point is that almost all studies in this field have focused on western populations. differences in characteristics of cancer among different races have well been established in other urologic cancers, such as prostate cancer.(5) racial disparities in rcc have also been reported in many studies. using the national surveillance, epidemiology, and end results (seer) database, vaishampayan and colleagues(6) reported that young blacks with localized renal cancer appeared to have had a greater rise in incidence and a poorer outcome than whites of the same age and pathologic stage. tripathi and colleagues(9) also reported that race was a significant predictor of overall survival in metastatic rcc. recently, stafford and colleagues(7) published a large population-based study comparing racial/ethnic groups using 39,434 cases of rcc. they concluded that higher incidence rates and lower survival rates were identified among blacks when compared to their counterparts, whereas asian/pacific islanders showed the opposite trend. rcc subtypes have also been reported to differ by race. recently, sankin and colleagues(8) reported that prcc had a much higher occurrence among blacks compared to non-blacks. more recently, purdue and colleagues(10) analyzed data from two large case-control studies of rcc, and observed a significant difference across rcc subtypes with respect to their distribution by race. although the issue of race has not fully been established yet in rcc, the characteristics and prognostic value of histologic subtypes in asians may differ from those in westerners. viewed in this light, our study is remarkable, because it is one of the largest population-based studies, especially in asia. prcc generally accounts for approximately 10% of all rccs, and is historically associated with smaller tumor size and presentation at an earlier stage and grade when compared with crcc.(2,15,16) in our study, the distributions of crcc and prcc were 2,488 (85.6%) and 192 (6.6%) patients, respectively. the proportion of prcc was slightly lower than that reported in previous studies performed on western populations,(2) but it was similar to those performed on the asian population.(11-14) in two studies of japanese patients, the incidence of prcc was 5.4 and 5.6%, respectively.(11,12) in a study of chinese patients, the incidence of prcc was 4.1%.(13) in a large multicenter study analyzing 2,981 korean patients, the incidence of prcc was also 5.6%.(14) previous results including ours suggest that the proportion of prcc in asia might be lower than that in the west. from the viewpoint of tumor characteristics, opposite of our expectations, our results showed that there were no significant differences in the distribution of age, gender, tumor size, and stage between prcc and crcc. on the contrary, high fuhrman’s grades were even more common in prcc. these trends are also similar to those in studies which were performed on the asian population.(17-19) rcc is a heterogeneous and complex disease, and has genetic and molecular differences among the histologic subtypes.(1,4) therefore, our results might reflect the characteristics of prcc not in the west but in asia. our results show that independent prognostic factors of rfs and css are age, bmi, symptoms at presentation, tumor size, stage and fuhrman’s grade. of these factors, the most powerful predictors are stage and fuhrman’s grade. these results are similar to those reported in previous studies.(2,5) stage represents the major prognostic factor used routinely in localized rcc.(2) the role of the fuhrman’s grade for prcc is not widely accepted. however, recent studies have shown the prognostic value of fuhrman’s grade in prcc. klatte and colleagues(20) reported that fuhrman’s grade should be the standard grading system for prcc. zucchi and colleagues(21) also suggested that the use of fuhrman’s grade had prognostic relevance for prcc. our results also support the suggestion that fuhrman’s grade has the prognostic value for prcc. the independent prognostic value of the histologic subtypes has not yet been verified. although most previous studies have shown the prognostic value of histologic subtypes by univariate analysis, only a few studies have shown prognostic significance on multivariate analysis. (2) teloken and colleagues(22) in a study of 1,863 patients with localized rccs, showed that histologic subtype remained significantly associated with metastasis and css on multivariate analysis. however, the difference between prcc and crcc did not reach statistical significance. recently, in a study of 3,062 patients, leibovich and colleagues(23) reported that histologic subtype was an independent predictor of progression to distant metastasis and css. however, because these authors only analyzed the prognostic difference between crcc and non-crcc, the prognostic value of prcc compared with crcc is unclear. all of these large single center series have not proved that prcc has a more favorable outcome than crcc, when adjusted for covariates. results from multicenter and international studies have also been similar to those from single center series. patard and colleagues(15) analyzed 4,063 patients across the united states and europe. they concluded that histologic subtype was not an independent prognostic factor of rccs. in another multicenter study which included 2,530 patients in europe, karakiewicz and colleagues(24) reported that histologic subtype was not associated with outcome on multivariate analysis. recently, keegan and colleagues(25) published a very large multicenter study analyzing 17,605 patients using the seer database. they reported that the effects of histologic subtype were decreased substantially after accounting for covariates. particularly, the prognostic value of prcc was not significantly different from that of crcc. similar to previous studies, our study has shown that the rfs and css of prcc are not significantly different compared with those of crcc. both groups also have comparable rfs and css when stratified by pathologic stage and fuhrman’s grade except for grade 3-4. based on univariate and multivariate analyses, histologic subtype is likewise not an independent prognostic factor. more recently, steffens and colleagues(26) published a multicenter study in germany. they reported that non-metastatic prcc had a better prognosis compared with non-metastatic crcc. however, it should be known that age, gender, stage and grade were only considered as a covariate. two distinct subtypes of prcc were introduced in 1997, and are generally known to be associated with different clinical outcomes.(27) we could not assess the subtypes nonmetastatic papillary rcc in korea-lee et al urological oncology 1888 of prcc in our retrospective study. prcc is heterogeneous,(28,29) and can show features characteristic of type 1 and 2.(30) furthermore, many recent studies have not identified subtype as an independent prognostic factor. (30) therefore, the prognostic value of subtype of prcc is yet controversial. nevertheless, it is a weak point that subtype of prcc was not assessed in our study. patients with lymph node and/or distant metastasis at the time of surgery were excluded, because natural history and treatments, such as targeted therapy of metastatic rccs may be different from those of non-metastatic rccs. nevertheless, to our knowledge, our study is the largest asian population-based study of the value of histologic subtype. our results are noteworthy, because racial disparities in rcc have been reported in many studies,(6-10) and almost all previous studies have focused on the western population. there are a few limitations to our study. first, our data are retrospective in nature. second, our study lacks a centralized pathologic review. although most of the multicenter studies including ours have lacked centralized pathologic review, it is likely that this limitation has resulted in misclassifications or misdiagnoses. however, the proportion of prcc in our study was similar to that reported previous studies performed on the asian population, in which urological pathologists reviewed all specimens at each institution. third, we could not assess potential prognostic factors, such as molecular markers, sarcomatoid features and tumor necrosis in all patients. these factors may better allow the identification of patients at high risk and affect the clinical outcomes. however, our study includes the most widely accepted independent prognostic factors of non-metastatic rcc, including stage, fuhrman’s grade, and tumor size,(2) and had one of the largest scale studies, especially in asia. conclusion our results show that non-metastatic prcc is not significantly different from non-metastatic crcc in various clinical and pathologic parameters. rfs and css of nonmetastatic prcc are not significantly different compared with those of non-metastatic crccs, even when stratified by pathologic stage and fuhrman’s grade. in addition, histologic subtype is not an independent prognostic factor of non-metastatic rcc. our study suggests that tumor characteristics and prognosis of prccs might be comparable to that of crccs, especially in asia. conflict of interest none declared. references 1. sun m, shariat sf, karakiewicz pi. factors af fecting outcome in renal cell carcinoma. curr opin urol. 2010;20:355-60. 2. deng fm, melamed j. histologic variants of renal cell carcinoma: does tumor type influence outcome? urol clin n am. 2012;39:119-32. 3. kovacs g, akhtar m, beckwith bj, et al. the heidelberg classification of renal cell tumours. j pathol. 1997;183:131-3. 4. cohen ht, mcgovern fj. renal-cell carcino ma. n engl j med. 2005;353:2477-90. 5. klein ea, platz ea, thompson im. epidemiol ogy, etiology, and prevention of prostate cancer. in: campbell-walsh urology, 9th ed. elsevier saunders, st. louis, 2007. 6. vaishampayan un, do h, hussain m, et al. racial disparity in incidence patterns and out come of kidney cancer. urology. 2003;62:1012 7. 7. stafford hs, saltzstein sl, shimasaki s, sand ers c, downs tm, sadler gr. racial/ethnic and gender disparities in renal cell carcinoma inci dence and survival. j urol. 2008;179:1704-8. 8. sankin a, cohen j, wang h, macchia rj, ka ranikolas n. rate of renal cell carcinoma sub types in different races. int braz j urol. 2011;37:29-32. 9. tripathi rt, heilbrun lk, jain v, vaishampay an un. racial disparity in outcomes of a clinical trial population with metastatic renal cell carci noma. urology. 2006;68:296-301. 10. purdue mp, moore le, merino mj, et al. an investigation of risk factors for renal cell carci noma by histologic subtype in two case-control studies. int j cancer. 2013;132:2640-7. 11. yamashita s, ioritani n, oikawa k, aizawa m, endoh m, arai y. morphological subtyping of papillary renal cell carcinoma: clinicopathologi al characteristics and prognosis. int j urol. 2007;14:679-83. 12. onishi t, ohishi y, goto h, suzuki m, miyaza wa y. papillary renal cell carcinoma: clinico pathological characteristics and evaluation of prognosis in 42 patients. bju int. 1999;83:937 43. 13. chen j, shi b, zhang d, jiang x, xu z. the clinical characteristics of renal cell carcinoma in female patients. int j urol. 2009;16:554-7. 14. lee wk, byun ss, kim hh, et al. character istics and prognosis of chromophobe non-meta static renal cell carcinoma: a multicenter study. int j urol. 2010;17:898-904. 15. patard jj, leray e, rioux-leclercq n, et al. prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. j clin oncol. 2005;23:2763–71. 16. vikram r, ng cs, tamboli p, et al. papillary re nal cell carcinoma: radiologic-pathologic cor relation and spectrum of disease. radiograph ics. 2009;29:741-54. 17. tabibi a, parvin m, abdi h, bashtar r, zamani n, abadpour b. correlation between size of re nal cell carcinoma and its grade, stage, and his tological subtype. urol j. 2007;4:10-3. 18. kim h, cho nh, kim ds, et al. renal cell car cinoma in south korea: a multicenter study. hum pathol. 2004;35:1556-63. 19. süer e, baltaci s, burgu b, aydoğdu ö, göğüş ç. significance of tumor size in renal cell can cer with perinephric fat infiltration: is tnm staging system adequate for predicting progno sis? urol j. 2013;10:774-9. 20. klatte t, anterasian c, said jw, et al. fuhrman nonmetastatic papillary rcc in korea-lee et al vol 11. no 05 sept-oct 2014 1889 grade provides higher prognostic accuracy than nucleolar grade for papillary renal cell carcino ma. j urol. 2010;183:2143-7. 21. zucchi a, novara g, costantini e, et al. prognostic factors in a large multi-institution al series of papillary renal cell carcinoma. bju int. 2012;109:1140-6. 22. teloken pe, thompson rh, tickoo sk, et al. prognostic impact of histological subtype on surgically treated localized renal cell carcino ma. j urol. 2009;182:2132-6. 23. leibovich bc, lohse cm, crispen pl, et al. histological subtype is an independent predictor of outcome for patients with renal cell carcino ma. j urol. 2010;183:1309-16. 24. karakiewicz pi, briganti a, chun fk, et al. multi-institutional validation of a new renal cancer-specific survival nomogram. j clin on col. 2007;25:1316-22. 25. keegan ka, schupp cw, chamie k, hellenthal nj, evans cp, koppie tm. histopathology of surgically treated renal cell carcinoma: survival differences by subtype and stage. j urol. 2012;188:391-7. 26. steffens s, janssen m, roos fc, et al. incidence and long-term prognosis of papillary compared to clear cell renal cell carcinoma-a multicentre study. eur j cancer. 2012;48:2347-52. 27. delahunt b, eble jn. papillary renal cell carci noma: a clinicopathologic and immuno histochemical study of 105 tumors. mod pathol. 1997;10:537-544. 28. arora p, rao s, khurana n, ramteke vk. re nal replacement lipomatosis with coexistent papillary renal cell carcinoma, renal tubulopap illary adenomatosis, and xanthogranulomatous pyelonephritis: an extremely rare association and possible pathogenetic correlation. urol j. 2013;10:906-8. 29. atilgan d, uluocak n, erdemir f, parlaktas bs, koseoglu rd, boztepe o. multicystic renal cell carcinoma: a rare kidney tumor in children. urol j. 2013;10:811-4. 30. sukov wr, lohse cm, leibovich bc, thomp son rh, cheville jc. clinical and pathological features associated with prognosis in patients with papillary renal cell carcinoma. j urol. 2012;187:54-9. nonmetastatic papillary rcc in korea-lee et al urological oncology 1890 reconstructive surgery the effect of preoperative gabapentin on pain severity after posterior urethral surgery: a randomized, double-blind, placebo-controlled study saleh ghiasy1, ali tayebi-azar2, amin alinezhad4 , morteza fallah-karkan1, hojat salimi1, seyyed ali hojjati1, jalil hosseini3* purpose: prevention and treatment of postoperative pain is a major challenge in posterior urethroplasty surgery. gabapentin can control postoperative pain by preventing excessive sensitivity of the central nervous system. in this study, we aimed to evalate the effect of gabapentin compared with placebo on reducing patients’ pain following posterior urethroplasty. material and methods: this prospective, randomized, double-blind study was performed in shohada-e-tajrish hospital. a total of 100 patients who were candidates of posterior urethral stricture were included. patients were then randomly assigned into two groups (n=50 in each group) and received either single-dose gabapentin or placebo, preoperatively. then, all patients underwent posterior urethroplasty. using the visual analog scale (vas), the level of patients’ postoperative pain was assessed at two hours,four hours, six hours,eight hours, 12 hours, and 24 hours after surgery. results: there was a significant difference in the vas pain scores after two hours, four hours, six hours, eight hours, 12 hours, and 24 hours post-surgery (p <0.001). this resulted in a significant decrease in morphine consumption in the gabapentin group compared with the placebo group (p <0.001). furthermore, post-surgery adverse events such as vomiting, nausea, drowsiness, and pruritus were significantly less frequent in the gabapentin group versus the placebo group. conclusion: the results of our study revealed that gabapentin can control postoperative pain after posterior urethroplasty, decrease the need for opioid consumption, an reduce the occurrence of post-surgery adverse events such as nausea, vomiting, drowsiness, and pruritus. keywords: gabapentin; pain; urethroplasty introduction the management and treatment of urethral tract strictures remains a major challenge in the field of urology.(1,2) on the other hand, the rate of posterior urethral damage is also increasing in developing countries.(3) a traumatic urethral tract can occur due to blunt trauma to the perineum, penetrating trauma, iatrogenic trauma, or pelvic fracture. factors such as urbanization and industrial life have increased the incidence of urethral tract injury and pelvic fracture urethral disruption defects (pfudd) due to the increased occurrence of vehicle crash accidents(4,5). generally, urethroplasty is divided into anterior and posterior repair, based on the site of the urethral tract damage.(4) prevention and managment of postoperative pain following urethroplasty is a main challenge in postoperative care. although opioid drugs are potentially capable of decreasing postoperative pain, their use is restricted due to side effects such as nausea, vomiting, itching, drowsiness, and urinary retention.(6-7) epidural analgesics are also used for pain control, although they are less effective and are associated with serious complications. non-steroidal anti-inflammatory drugs (nsaids) are also prescribed for postoperative pain but they can increase the risk of injury to the digestive system, nephropathy, allergic reflex, and heart failure. nsaid selective cyclooxygenase-2 has prothrombotic effects and increases the possibility of brain stroke and heart ischemia. therefore, a multi-therapy method for post-operative pain relief is suggested(8). surgery leads to pain by stimulating the central and peripheral nervous systems. anti-hyperalgesic drugs can manage post-surgical pain by preventing excessive sensitivity of the central nervous system(9). gabapentin and pregabalin are examples in this regard, having anticonvulsant, analgesic, and anti-anxiety properties. gabapentin and pregabalin act by binding to the α2δ-1 subunit of voltage-dependent calcium channels 1men’s health and reproductive health research center , shahid beheshti university of medical sciences, tehran, iran. 2nephrology and kidney transplant research center, urmia university of medical sciences, urmia , iran. 3professor of urology, reconstructive urology department, shohada-e -tajrish hospital, shahid beheshti medical science university, iran. 4department of clinical pharmacy , school of pharmacy , tehran university of medical sciences , tehran , iran. *correspondence: reconstructive urology department, shohada e tajrish hospital, shahid beheshti medical science university, iran. email; jhosseinee@gmail.com. telfax +98 2122712234, mob +98 9123279844 received september 2019 & accepted may 2020 urology journal/vol 17 no. 6/ november-december 2020/ pp. 626-630. [doi: 10.22037/uj.v0i0.5598] available in the central nervous system. in addition to calcium channel blockage, other proposed mechanisms of gabapentin include interaction with nmda receptors or monoaminergic systems. it is well-established that the use of gabapentin reduces the irritability of the central nervous system and subsequently. neuropathic pain, and can result in the control of postoperative pain (10,11,12-14). shohada-e-tajrish hospital in tehran, iran, is a referral center for reconstructive urology. anually, many patients from across the nation and also neighboring countries are admitted to this center for this purpose. here, we aimed to compare the effect of gabapentin with placebo on reducing the pain following posterior urethroplasty in patients admitted to this center. we hope that the results of this study will provide a better overview of the long-term outcome of the treatment of these patients and provide a more accurate decision about the best treatment option for controlling postoperative pain in these patients. material and methods ethics approval this study was approved by the ethics committee of shahid beheshti university of medical sciences (ethics code: ir.sbmu.retech.rec.1398.231). written informed consent was obtained from all patients prior to enrollment in the study. study population this prospective, randomized, double-blind study was conducted in shohada-e-tajrish hospital. in this study, 100 patients with posterior urethral stricture (age range= 30-60 years old) who were admitted to our hospital during 2018-2019 for urethroplastic surgery were included. patients were randomly assigned to two groups (n=50 in each group) and received either single dose gabapentin or placebo, preoperatively. the same surgeon performed posterior end-to-end urethroplasty for all patients by using the same technique. then, an 18f lubricated silicon urethral catheter was inserted for all patients and was fixed to the skin using adhesive tapes. inclusion criteria were as follows: 1) age > 18 years old and 2) confirmed diagnosis of posterior urethral stricture by retrograde urethrogram (rug) and flexible cystoscopy. cases with concurrent consumption of anti-epileptic or antidepressant drugs, presence of malfunction kidney disease, diabetes, history of chronic pain, history of substance abuse, any allergy to drugs, and an american society of anesthesia (asa) physical status ≥ iii were excluded from the study. procedures based on a random technique, patients were divided into two equal groups. randomization was performed by a resident physician who was not participating in the survey by using sealed envelopes labeled as gabapentin (group a) or placebo (group b). all patients underwent general anesthesia using the same technique by the same surgeon. after blinding of patients, an hour prior to administration of general anesthesia for posterior urethroplasty, patients in group a recieved a single dose of gabapentin 600 mg (neuroleptin®, soha), whereas in group b, a single dose of placebo was given. in order to minimize bias during the completion of the visual analog scale (vas) questionnaire, the researchers that filled in the questionnaire were made blind to patients’ study group. gathered information was then extracted by another colleague who was not involved in the study. evaluations before surgery, participants were educated regarding the vas questionnaire. then, the pain level was assessed and evaluated by the vas at two hours,four hours, six hours,eight hours, twelve hours, and 24 hours post-surgery and based on the level of pain, a score gabapentin for catheter pain-ghiasy et al. reconstructive surgery 627 table 1. demographic and clinical data of patients undergoing posterior urethropelasty. characteristic gabapentin (n = 46) placebo(n = 47) p-value age (years) 43.4 ± 8.9 44.2 ± 8.2 0.6 bmi (kg/m2) 25.7 ± 3.2 26.8 ± 3.1 0.1 duration ofsurgery(minute) 242.5 ± 36.4 249.7 ± 25.6 0.2 duration of anesthesia(minute) 266.5 ± 36.4 273.7 ± 25.6 0.2 sbp(mmhg) 138 ± 12.6 139.5 ± 12.9 0.5 dbp(mmhg) 76.9 ± 8.4 77.6 ± 6.7 0.6 hr(beats per minute) 76.7 ± 8.6 78.3 ± 7.5 0.3 type of posterior urethropelasty simple 37 40 0.3 complex 9 7 0.3 qualitative data was analyzed by chi-square test and quantitative data was analyzed by independent t-test and mann-whitney u test. abbreviations: bmi, body mass index; sbp, systolic blood pressure;dbp, diastolic blood pressure;hr, heart rate characteristic gabapentin (n =46) placebo(n =47) p-value pain score by vas (mean ±sd) 2 hrs after intervention 4.7±0.7 7.4±0.6 < 0.001 4 hrs after intervention 3.8±0.7 6.9±0.6 < 0.001 6 hrs after intervention 3±0.5 5.3±0.7 < 0.001 8 hrs after intervention 3±0.5 4.4±0.7 < 0.001 12 hrs after intervention 1.9±0.6 2.9±0.5 < 0.001 24 hrs after intervention 0.6±0.4 1.6±0.6 < 0.001 morphine consumption (mg) 14.2±4.3 30.9±6.1 < 0.001 table 2. severity of postoperative pain (vas score) and amount of opioid consumption (morphine) across the two groups (gabapentine vs placebo). quantitative data was analyzed by independent t-test and mann-whitney u test ranging from 1 to10 was given. any patient with a vas score of more than three was given 5mg morphine infusion as needed. in this study, more than three points difference in the vas score was considered as a clinically significant outcome. time since general anesthesia to the first dose of analgesic, total analgesic dose during hospital stay and usage of analgesics after discharge was recorded. furthermore, posterior urethroplasty procedure was categorized into two subgroups of simple and complex urethroplasty. patients who had undergone reoperation and those who had stenosis longer than 3 cm, accompanying perineal and gi fistulas, presence of diverticulitis adjacent to the duct, and non-competent bladder neck were defined as complex cases. complex cases are more likely to need prolonged surgery, manipulation and partial pubectomy. this likely leads to more pain in these cases in comparison with simple urethroplasty. statistical analysis data was analyzed using spss version 21 (ibm, illinois, usa). two sample paired t-test was used to compare vas before and after administration of gabapentine or placebo. data is reported as mean value ±s.d. a p-value of < 0.05 was considered statistically significant. for evaluation of pain, patients were categorized as follows based on pain intensity score at different assessment points: 1) mild pain: score < 4 or 2) moderate to severe pain: score ≥ 4. qualitative data was analyzed by chi-square test and quantitative data was analyzed by independent t-test and mann-whitney-u test. results patients’ allocation flowchart is shown in figure 1. one-hundred and thirty patients were initially enrolled of which 30 were excluded from the study: six because of asa physical status ≥ iii, two due to diabetes, two due to malfunction kidney disease, nine due to analgesic drug abuse and 11 due to antiepileptics or antidepressant consumption. finally, a total of 100 cases were included and were equally divided into two groups of 50 patients. there was no significant difference regrading patients’ demographic data, blood pressure, heart rate, number of complex posterior urethropelasty, duration of anesthesia and surgery between the study groups (table 1). however, we observed a significant difference in the pain level as evaluated by the visual analog scale at two hours, four hours, six hours, eight hours, twelve hours, and 24 hours after surgery (p < 0.001). we also found a significant decrease in morphine consumption in the gabapentin group as compared with the placebo group table 3. frequency of adverse effects across the two groups characteristic gabapentin (n =46) placebo(n =47) p-value vomiting 6(13%) 18(38.2%) 0.008 nausea 7(15.2%) 19(40.4%) 0.01 headache 5(10.8%) 8(17%) 0.5 dizziness 10(21.7%) 17(36.1%) 0.1 shivering sensation 11(23.9%) 15(31.9%) 0.4 drowsiness 2(4.3%) 18(38.2%) < 0.001 pruritus 9(19.5%) 19(30.4%) 0.04 figure 1. patients’ allocation flowchart. gabapentin for catheter pain-ghiasy et al. vol 17 no 06 november-december 2020 628 qualitative data was analyzed by chi-square. (p < 0.001) (table 2). furthermore, post-surgery assessments showed significantly lower adverse events such as vomiting, nausea, drowsiness, and pruritus in the gabapentin group than the placebo group (table 3). discussion treatment of postoperative pain following posterior urethroplasty is a major challenge in post-surgery care. although opioid drugs are routinely prescribed to manage post surgical pain, their use is restricted due to occurrence of side effects such as nausea, vomiting, itching, drowsiness and urinary retention. therefore, a multimodel analgesic approach has been attempted (6,7). for instance, gabapentin has been introduced as an alternative option for the treatment of postoperative pain. gabapentin is approved as an anti-epileptic medication but it is also used as an off-label analgesic drug (15,16). the purpose of this study was to elobarote whether gabapentin could possibly have a role in the improvement of postoperative pain. although no definite dosage of gabapentin has been recommended to be optimal, we decided to administer 600 mg single-dose gabapentin, preoperatively. the results of our study showed that prescribing preoperative gabapentin (600 mg) has a significant correlation with decreased postoperative pain and less need for opioid consumption after end-to-end urethroplasty. the outcomes of this study support our hypothesis, demonstrating ameliorated vas pain scores in patients who recieve gabapentin preoperatively as compared with patients in the placebo group. these results are consistent with that of previous studies.(17,18) previous studies have also reported decreased postoperative pain and less need for opioid consumption after preoperative administration of gabapentin.(3,19) in a meta-analysis study performed by fabritius et al., it was demonstrated that, regardless of type of surgery, there is marked reduction in morphine consumption after pre or postoperative gabapentin adminstration(20). moreover, doleman et al. concluded that gabapentin is the most successful treatment for reducing vas postoperative pain scores at 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after surgery compared with other analgesics ( p-value < 0.001)(21). gabapentin has the ability to reduce the irritability of the central nervous system (from other regions of the brain) by binding to α2-δ-1 subunit of voltage-dependent calcium channels in the posterior horn of the spinal cord and inhibiting its regulatory pathway.(13,14) however, further research is warranted in order to estimate the efficacy of gabapentin on preventing and decreasing postoperative pain after posterior urethroplasty. nausea and vomiting are common postoperative side effect of prolonged anesthesia after urethroplasty surgery. in this study, post-operative nausea, vomiting, drowsiness, and pruritus occured significantly less in the gabapentin group compared with the placebo group; no significant difference existed regarding other complications such as headache, dizziness, and shivering sensation between the two groups.(6) a meta-analysis by seib et al. showed that gabapentin reduces postoperative nausea and vomiting.(22) irwin and kong also reported that nausea, vomiting, and pruritus occur less in cases who recieve gabapentin.(23) the mechanism of gabapentin on postoperative nausea and vomiting remains unidentified; however, it could possibly be due to the indirect effect of decreased opioid consumption or possibly decreased neurotransmitter activity of tachykinin.(24) the results of this randomized placebo-controlled study showed that gabapentin is efficient in treating postoperative pain following posterior urethroplasty and can reduce the need for opioid consumption. furthermore, adverse events such as nausea, vomiting, drowsiness, and pruritus seem to occur significantly less in patients who receive gabapentine, preoperatively. conclusions gabapentin is efficient in treating postoperative pain following posterior urethroplasty and can reduce the need for opioid consumption. furthermore, adverse events such as nausea, vomiting, drowsiness, and pruritus seem to occur significantly less in patients who receive gabapentine, preoperatively. acknowledgements we thankthe staff at shohada-e-tajrish hospital operation room and urology ward who helped in data collection. conflict on interest the authors declare that they have no conflict of interest. references 1. koraitim mm. pelvic fracture urethral injuries: the unresolved controversy. j urol. 1999;161:1433-41. 2. xu ym, song lj, wang kj, et al. changing trends in the causes and management of male urethral stricture disease in china: an observational descriptive study from 13 centres. bju int. 2015;116:938-44. 3. brogly n, wattier j-m, andrieu g, et al. gabapentin attenuates late but not early postoperative pain after thyroidectomy with superficial cervical plexus block. eur j anesthesiol. 2008;107:1720-5. 4. cooperberg mr, mcaninch jw, alsikafi nf, elliott sp. urethral reconstruction for traumatic posterior urethral disruption: outcomes of a 25-year experience. j urol. 2007;178:2006-10. 5. waterhouse k, laungani g, patil u. the surgical repair of membranous urethral strictures: experience with 105 consecutive cases. j urol. 1980;123:500-4. 6. lo p-h, chiou c-s, tsou m-y, chan k-h, chang k-y. factors associated with vomiting in orthopedic patients receiving patient-controlled epidural analgesia. acta anaesthesiol taiwan. 2008;46:25-9. 7. dolin s, cashman j, bland j. effectiveness of acute postoperative pain management: i. evidence from published data. br j anaesth. 2002;89:409-23. 8. haas da. an update on analgesics for the management of acute postoperative dental pain. j can det assoc. 2002;68:476-84. gabapentin for catheter pain-ghiasy et al. reconstructive surgery 629 vol 17 no 06 november-december 2020 630 9. kissin i. preemptive analgesia. anesthesiology: j am anesthesiol. 2000;93:1138-43. 10. rai as, clarke h, dhaliwal j, et al. preoperative pregabalin or gabapentin for postoperative acute and chronic pain among patients undergoing breast cancer surgery: a systematic review and meta-analysis of randomized controlled trials. j plast reconstr aesthet surg. 2015;136:171-2. 11. rorarius mg, mennander s, suominen p, et al. gabapentin for the prevention of postoperative pain after vaginal hysterectomy. pain. 2004;110:175-81. 12. tiippana em, hamunen k, kontinen vk, kalso e. do surgical patients benefit from perioperative gabapentin/pregabalin? a systematic review of efficacy and safety. anesth analg. 2007;104:1545-56. 13. rose m, kam p. gabapentin: pharmacology and its use in pain management. anaesthesia. 2002;57:451-62. 14. sills gj. the mechanisms of action of gabapentin and pregabalin. current opinion in pharmacology. 2006;6:108-13. 15. gidal b. new and emerging treatment options for neuropathic pain. am j manag care. 2006;12:s269-78. 16. lichtinger a, purcell tl, schanzlin dj, chayet as. gabapentin for postoperative pain after photorefractive keratectomy: a prospective, randomized, double-blind, placebo-controlled trial. j refract surg. 2011;27:613-7. 17. fabritius ml, wetterslev j, mathiesen o, dahl jb. dose-related beneficial and harmful effects of gabapentin in postoperative pain management–post hoc analyses from a systematic review with meta-analyses and trial sequential analyses. j pain res. 2017;10:2547. 18. maghsoudi r, farhadi-niaki s, etemadian m, et al. comparing the efficacy of tolterodine and gabapentin versus placebo in catheter related bladder discomfort after percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2018;32:168-74. 19. montazeri k, kashefi p, honarmand a. preemptive gabapentin significantly reduces postoperative pain and morphine demand following lower extremity orthopaedic surgery. singapore med j. 2007;48:748. 20. fabritius ml, geisler a, petersen pl, et al. gabapentin in procedure-specific postoperative pain management – preplanned subgroup analyses from a systematic review with meta-analyses and trial sequential analyses. bmc anesthesiol. 2017;17:85. 21. doleman b, heinink t, read d, faleiro r, lund j, williams j. a systematic review and meta‐regression analysis of prophylactic gabapentin for postoperative pain. anaesthesia. 2015;70:1186-204. 22. seib rk, paul je. preoperative gabapentin for postoperative analgesia: a meta-analysis. can janesthes. 2006;53:461. 23. kong v, irwin m. gabapentin: a multimodal perioperative drug? bri j anaesthes. 2007;99:775-86. 24. guttuso jr t, roscoe j, griggs j. effect of gabapentin on nausea induced by chemotherapy in patients with breast cancer. the lancet. 2003;361:1703-5. gabapentin for catheter pain-ghiasy et al. 1692 | laparoscopic repair of a rare case of bladder rupture due to intravesical explosion during transurethral resection of the prostate kishore thekke adiyat, abijit shetty, jayakrishnan t corresponding author: kishore ta, md medical trust hospital, mg road, cochin, kerala 682016, india tel: + 91 984 603 3119 fax: +91 484 235 8031 e-mail: kishoreta@yahoo.com received december 2012 accepted june 2013 medical trust hospital, cochin, kerala, india. case report keywords: urinary bladder; injuries; laparoscopy; surgery; rupture; diseases. introduction intravesical explosion is an extremely rare event during turp. (1) though previously reported , all the cases were dealt by immediate laparotomy and bladder repair.(1) to our knowledge this is the first case where laparoscopy has been offered as a treatment option. case report a 72 years old man presented with refractory urinary retention. the ultrasound evaluation showed 65 grams prostate, bladder was normal. all other preoperative parameters were within normal limits. the patient was administered a spinal anesthesia. transurethral resection of the prostate (turp) was performed using electrocautery (erbe usa inc., marietta, ga, usa) at 75 watts cutting and coagulation current, a 26 french (f) resectoscope (karl storz gmbh & co. kg, tuttlingen, germany) and sterile water was used as an irrigant. initial 55 minutes of the procedure were uneventful, while resecting the lateral lobes of the prostate a loud snap was heard. subsequent to that intestinal loops were seen in the bladder. turp was immediately aborted. foley catheter was inserted. the patient was intubated and converted to general anesthesia. pneumoperitoneum was initiated using veress needle, a 10 mm supraumblical port was placed. two 5 mm ports were placed radially on both sides at about 10 cm distance. another 5 mm port was placed midway between the pubic symphysis and the midline 10 mm port. the case report 1693vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l laparoscopic repair of bladder rupture during turp | adiyat et al extravasated irrigant and prostate chips were suctioned out. then patient position was switched to trendelenburg position, to allow the bowels to gravitate away from the field. there was a large laceration at the dome adjoining the posterior wall and foley catheter was easily visible through the rent (figure, a). a small portion of the unhealthy bladder was excised and the rest of the bladder was sutured with continuous 2.0 vicryl suture (polyglycolic acid suture; ethicon, inc, somerville, new jersey, usa) (figure, b). this was reinforced with few interrupted sutures (figure, c). at the end of the procedure the integrity of the bladder was confirmed using methylene blue instilled in the bladder and a 22f three way foley catheter was placed. a peritoneal drain was left behind which was removed after 48 hours. the patient was discharged the 4th postoperative day. a cystogram was performed on the 14th day before catheter removal (figure, d). patient had a successful voiding following that. the histopathology of the prostate was benign prostatic hyperplasia and unhealthy segment of bladder excised was found to be normal. discussion traditionally bladder repair subsequent to intravesical explosion has been dealt with open surgery.(1) laparoscopy avoids the big incision, pain and subsequent wound complications associated with open surgery. with laparoscopy it is possible to remove the fluid accumulated in the abdomen more efficiently, especially in subphrenic, perisplenic and interbowel areas. under high definition magnification it is very easy to deliver out the prostatic chips dispersed in the abdomen. laparoscopy also offers an option for achieving hemostasis in the prostatic fossa as it offers good access deep into the pelvis. the incriminating factor for intravesical explosion is the formation of explosive gases in the bladder during turp and its admixture with air or oxygen.(1) the explosive gases when combined with air triggers explosion when it comes in contact with the resectoscope loop.(2) hydrogen constitutes about 40 to 50% of gas which emits from the cautery followed by oxygen (3%).(3) according to them the majority of hydrogen was derived from the electrolysis of intracellular water. davis and colleagues reproduced similar results in in vitro experiments.(2) the best method to avoid this dreaded complication is to take precautionary measures. in patients with diseased bladder due to radiation, cystitis, tuberculosis and etc., extra caution is to be taken to avoid hyper distension. a continuous flow resectoscope would decrease the chances of over distension of the bladder and avoid air bubble entering the bladder by reducing the frequency of manual irrigation. extreme caution should be exercised to avoid activation of the loop within the air bubble. precise use of the ellick’s evacuator bulb, reducing the frequency of manual irrigations of the bladder would help prevent.(4) while resecting near the dome air may be aspirated using a ureteral catheter or a suprapubic catheter. suprapubic pressure can be used to dislodge the air bubble away from the area of resection. constantly changing the position during resection will also dislodge the air bubble.(5) other preventive measures that have been recommended include decreasing the duration of resection with judicious coagulating of tissue, avoiding a high-temperature cautery during turp, decreasing the mean time of resection. newer technologies like bipolar resection and advanced electro cautery machines might reduce the incidence intravesical explosion. conflict of interest none declared. figure . photographs demonstrating; a: ruptured bladder with foley catheter visible through the rent; b: partially sutured bladder; c: bladder filled with methylene blue to check the integrity of bladder wall and d: post-operative cystogram showing well healed bladder. 1694 | case report references 1. seitz m, soljanik i, stanislaus p, sroka r, stief c. explosive gas formation during transurethral resection of the prostate (turp). eur j med res. 2008;13:399-400. 2. davis tr. the composition and origin of the gas produced during urological endoscopic resections. br j urol. 1983;55:294-7. 3. ning tc jr, atkins dm, murphy rc. bladder explosions during transurethral surgery. j urol. 1975;114:536-9. 4. khan a, masood j, ghei m, kasmani z, ball aj, miller r. intravesical explosions during transurethral endoscopic procedures. int urol nephrol. 2007;39:179-83. 5. horger dc, babanoury a. intravesical explosion during transurethral resection of bladder tumors. j urol. 2004;172:1813. ufp.pdf 919vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l testis cancer the testes are 2 egg-shaped organs located inside the scrotal sac. the testicular cancer had 3 distinct fea-tures: it predominantly involves young adults, has rapidly progressive nature, and responds very well to chemotherapy. the diagnosis of testis cancer in early stage has outmost importance. however, most patients do not visit a physician due to embarrassment. the common early symptom of testicular cancer is a painless mass inside the testis. every solid mass in the testis is tumor unless otherwise noted. although testicular cancer accounts for only 1% of cancers in men, it is the most common cancer in men in their 20s and 30s. fortunately, it has become one of the most amenable of all cancers for cure. about 95% of all men diagnosed with testis cancer survive their disease. the testicular cancers have two main types: cancers which originate from testis germ cells (eg, seminoma) and cancers which originate from testis non-germ cells (eg, embryonal cell carcinoma and choriocarcinoma). non-germ cell testicular tumors are more malignant than germ cell testicular tumors. the original treatment for testicular cancer is removal of related testis by surgery. the surgical specimen is being sent for pathologic examination. then, according to pathologic diagnosis and the extend of involvement of the body with tumor (tumor stage), necessary treatment is done. the main stem treatment for germ cell testicular tumor is radiotherapy, and the main stem treatment for non-germ cell testicular tumor is surgery for removal of involved lymph nodes and chemotherapy. testicular cancers have excellent tumor markers. tumor markers are substances produced by cancer cells and can be measured in the blood. the tumor markers for testicular cancer are: alpha fetoprotein (afp), beta human chorionic gonadotropin (beta-hcg), and lactate dehydrogenase (ldh). not all treatment modalities mine the most appropriate treatment option based upon patient’s condition. some men with testicular cancer need only surveillance (watchful waiting). see page 873 for full-text article. what’s up in urology journal, spring 2013? urology for people urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. 1054 | urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran. nasser simforoosh, mohammad hossein soltani, seyed hossein hosseini sharif i, ali ahanian, alireza lashay, davood arab, samad zare mini-laparoscopic live donor nephrectomy: initial series corresponding author: nasser simforoosh, md urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran. tel: +98 21 2259 4204 e-mail: simforoosh@iurtc.org.ir received october 2013 accepted october 2013 purpose: to present the safety and surgical outcomes of the initial series of mini-laparoscopic live donor nephrectomy and graft outcomes in related recipients. materials and methods: from january 2012 through july 2012, fifty patients underwent minilaparoscopic live donor nephrectomy. two 3.5 mm trocars were inserted above and lateral to the umbilicus for grasping and scissoring. one 5 mm trocar with a camera was inserted in the umbilicus and an 11 mm trocar was inserted through fascia from a 6-8 cm pfannenstiel incision for bipolar coagulation, kidney extraction, and vascular clip applier. results: mean age of donors was 28 ± 4.2 (range, 21-39) years. mean operative time from trocar insertion was 145.8 (range, 85-210) minutes. no major perioperative or postoperative complications occurred. the average decrease in hemoglobin level was 1.14 (range, 0.32-1.8) mg/dl and no one required blood transfusion. mean warm ischemia time was 4.41 (range, 2.359) minutes. mean hospital stay was 2.2 (range, 2-5) days. mean follow-up time of the recipients was 215 (range, 130-270) days. the mean serum creatinine level of the recipients at discharge time and the last follow-up visit was 1.38 mg/dl and 1.22 mg/dl, respectively. conclusions: while the primary purpose of this technique is to make donor nephrectomy less invasive and more cosmetic, it is also comfortable for the laparoscopist surgeons because it is nearly similar to standard laparoscopy. a randomized controlled trial with a large sample size, long-term follow-up, and comparison with standard laparoscopy are necessary to present more definitive data about this technique. keywords: laparoscopy; methods; surgical procedures; minimally invasive; kidney transplantation; nephrectomy; living donors. laparoscopic urology laparoscopic urology 1055vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l introduction laparoscopy has brought changes to various ad-vanced urologic surgeries, and donor nephrec-tomy is no exception. the first laparoscopic donor nephrectomy(ldn) was performed by ratner and colleagues.(1) afterward, some reports revealed that laparoscopy is concomitant with less bleeding, shorter convalescence, and better cosmesis compared with open donor nephrectomy (odn). a review of the literature shows that ldn is now accepted as a standard procedure for donor nephrectomy.(2) a randomized clinical trial with a sufficient number of cases revealed the safety of ldn, which had similar graft outcomes as odn.(3) a later follow-up study of the aforementioned cases confirmed the short-term findings.(4) recently, efforts were made to improve the technical aspects, cosmesis, and surgical outcomes of laparoscopy. pure natural orifice transluminal endoscopic surgery (notes) and laparoendoscopic single-site surgery (less) using umbilical or pfannenstiel incision are new modifications employed in donor nephrectomy.(5-7) although the cosmetic outcomes are better compared to standard laparoscopy; these procedures seem to be less ergonomic and more costly. previously, mini-laparoscopy was performed in general surgery with good results.(8) this study reveals our experience with mini-laparoscopic donor nephrectomy, comprising fifty cases, and evaluates the safety of this approach and graft outcomes. likewise, it seems that this technique is easier to master for surgeons already skilled at standard laparoscopy. materials and methods we previously report a successful technique, mini-laparoscopic donor nephrectomy that had an excellent graft outcome in the recipient and excellent cosmetic outcome in the donor.(9) afterward, from january 2012 through july 2012, fifty mini-laparoscopic left donor nephrectomies were performed with the same technique. multiple vessels and right donor nephrectomies were excluded. weight of the donor was not considered an excluding factor. donors underwent general anesthesia in modified left flank position, and nasogastric tube was fixed. a 5 mm trocar was used as a camera port and placed transumbilically using open access technique. two 3.5 mm trocars were placed above and lateral to the umbilicus and were used for grasping and scissoring, respectively. an 11 mm trocar was fixed through fascia from a 6-8 cm pfannenstiel incision, to be used for kidney extraction. vascular clipping, suctioning, and bipolar coagulating can all be performed through this trocar. a vascular stapler was not used, because large series have recently shown that vascular clips are safe and very cost-effective.(10) the colon was mobilized medially and splenorenal and renocolic ligaments were dissected. the left ureter together with the gonadal vein was dissected free and upward while preserving peri-ureteral tissues. the renal vein was dissected distal to the gonadal vein and bipolar coagulation and division of lumbar and adrenal veins were performed. the adrenal gland was separated from the kidney using bipolar coagulation of small adrenal arteries under the adrenal gland. the rest of the kidney was dissected free from surrounding tissues. the renal artery and vein and the ureter were clipped through the suprapubic trocar using a hem-o-lok clip applier and titanium clip applier, as we previously described in a report of 1834 nephrectomy cases.(10) the renal artery and vein and the ureter were divided and the kidney was hand extracted through the prepared suprapubic opening.(9) only the 5 mm camera port was closed, using monocryl sutures. the two 3.5 mm miniports were left unsutured according to novitsky and colleagues experience.(8) figures 1 and 2 demonstrate the appearance of the skin at the site of miniport insertion at operation time and 2 months later. results forty three cases were men and the others were women, and their mean age was 28 ± 4.2 (range, 21-39) years. mean body mass index (bmi) was 22.6 (range, 18.1-29.8) kg/m². mean operative time from trocar insertion to skin closure was 145.8 (range, 85-210) min. according to clavien grading system, grade i and ii happened in three and two donors, respectively and no major perioperative or postoperative complications occurred. the average decrease in hemoglobin level was 1.14 (range, 0.32-1.8) mg/dl and no one required blood transfusion. mean warm ischemia time was 4.41 (range, 2.35-9) minutes. average opium requirement from recovery room to discharge was 33 mg mepridine (intramuscular injection). mean hospital stay was 2.2 (range, 2-5) days. harvested kidmini laparoscopic donor nephrectomy | simforoosh et al 1056 | neys started diuresis immediately after transplantation in all cases except one case who had delayed graft function (dgf) and diuresis started after one week and discharged with normal serum creatinine. no arterial or venous thrombosis was happened in the recipients. there were two cases of ureteral leak that were managed successfully by repeat ureteral reimplantation. mean follow-up time of the recipients was 215 (range, 130-270) days. the mean serum creatinine level of the recipients at discharge time (average discharge time of the recipients was 17 days) and the last follow-up visit was 1.38 mg/dl and 1.22 mg/dl, respectively. discussion definitive management of end-stage renal disease (esrd) is kidney transplantation.(11) graft outcome is usually better when it comes from a living donor, and the waiting list for kidneys from cadavers is too long.(12) the introduction of laparoscopic donor nephrectomy, with acceptable cosmetic outcomes, shorter hospital stay, and lower pain score, has encouraged kidney donation.(2) simforoosh and colleagues reported a randomized clinical trial comparing short-term and long-term graft outcomes between two groups of 100 donors (laparoscopic and open), and concluded that graft outcomes are similar for these groups.(3,4) a long-term follow-up study by dols and colleagues comparing ldn with mini-incision open live donor nephrectomy confirmed these results.(13) improvement of surgical outcomes, cosmetic appearance, and perioperative morbidity led to the introduction of new modifications to laparoscopic surgery. gill and colleagues performed donor nephrectomy using less technique with an umbilical r-port and extracted the specimen from this incision.(5) kurien and colleagues compared some variables between two groups (25 cases in each arm) of donors who had undergone standard laparoscopy (sl) and less surgery for kidney donation and reported notable findings. dissection of the upper pole, division of the renal artery and vein, and specimen extraction were more difficult in the less group. warm ischemia time (7.5 min in less) was significantly longer than in the standard group (p < .0001), but this difference did not negatively affect graft outcome or quality of life. body image was similar between the two groups.(14) in another report, andonian and colleagues performed less donor nephrectomy with three trocars fixed in a pfannenstiel incision 5 cm long.(7) afterward, they compared surgical outcomes between six sl donor nephrectomies and six pfannenstiel less donor nephrectomies. warm ischemia time, hospital stay, morbidity, and pain score were similar in the aforementioned groups. they concluded that less has only a cosmetic advantage over sl, and the major limitation of this approach is that it requires a flexible telescope and more figure 1. configuration of trocars for mini-laparoscopic donor nephrectomy. figure 2. skin appearance two months after operation. laparoscopic urology 1057vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l expensive instruments.(15) mini-laparoscopy is a modification of sl. some reports in this field focus on general surgery, and especially cholecystectomy. cheah and colleagues reported that using three 2 mm ports instead of three 5 mm ports will be lead to decreased analgesic consumption and postoperative pain.(16) novitsky and colleagues compared 33 sl cholecystectomies with 34 mini-laparoscopies. eight (twenty-four percent) patients in the mini-laparoscopy arm were converted to standard technique. mean operative time was similar between the two groups, cosmetic result was significantly better with mini-laparoscopy, and visual analog scale on the first postoperative day was significantly lower in the mini-laparoscopy group than in the sl group. this last item was not different on the third or seventh postoperative days.(8) we previously reported that mini-laparoscopic donor nephrectomy using unique trocar insertion has outcomes similar to sl.(9) we used only two 3 mm trocars instead of three or four trocars, thereby improving the cosmetic outcome. the renal pedicle was divided using vascular clips, not endo-gia stapler; using these clips considerably reduced the total cost of surgery.(10) we present the first case series of mini-laparoscopic donor nephrectomy, with initial outcomes and short-term follow-up of the donors and their recipients, in this study. robotic single-site surgery is a notable alternative for donor nephrectomy and has improved cosmetic outcomes; but the high cost is a drawback. the less technique has some limitations, including the lack of triangulation and rolls over of the instruments, a less ergonomic experience for the surgeon, additional training requirement for laparoscopic surgeons, and expensive equipment, such as flexible videoscope and instruments. mini-laparoscopy is performed with one 5 mm camera port and two 3.5 mm ports that are not closed and leave nearly invisible scars after a few weeks.(8) an 11 mm trocar is placed through the pfannenstiel incision. this approach is ergonomic and similar to standard sl and requires no additional expensive instruments. cosmetic outcomes seem better than in sl and especially better than in transumbilical less, since a smaller incision is made in the umbilicus (5 mm). warm ischemia time, hospital stay, analgesic requirement, perioperative morbidity, and short-term graft outcome were acceptable and comparable to previous report of sl outcomes.(3) in a retrospective study, tisdale et al revealed that extraction of the specimen through a pfannenstiel incision is concomitant with lower incisional hernia and morbidity and shorter hospital stay, compared with less surgery, which requires which requires large umbilical incision.(17) precise assessment of mini-laparoscopic donor nephrectomy requires a randomized clinical trial with a sufficient number of cases and long-term follow-up comparing this modification with sl. we accept that subjective assessment of cosmetic appearance of scars is a drawback of our study and we will use a validated questionnaire for objective evaluation of cosmesis in future randomized clinical trial. conclusion mini-laparoscopic donor nephrectomy as one of the less invasive approach for donor nephrectomy was performed using 3.5 mm trocars in usually visible parts of the abdomen. it is comfortable for the laparoscopist surgeons because it is nearly similar to standard laparoscopy. perioperative outcomes and short-term follow-up in donors and recipients revealed acceptable findings. a randomized controlled trial with a large sample and long-term follow-up seems to be necessary. conflict of interest none declared. references 1. ratner le, ciseck lj, moore rg, cigarroa fg, kaufman hs, kavoussi lr. laparoscopic live donor nephrectomy. transplantation. 1995;60:1047-9. 2. duchene da, winfield hn. laparoscopic donor nephrectomy. urol clin north am. 2008; 35:415-24. 3. simforoosh n, basiri a, tabibi a, shakhssalim n, hosseini moghaddam sm. comparison of laparoscopic and open donor nephrectomy: a randomized controlled trial. bju int. 2005;95:851-5. 4. simforoosh n, basiri a, shakhssalim n, et al. long term graft function in a randomized clinical trial comparing laparoscopic versus open donor nephrectomy. exp clin transplant. 2012;10:428-32. 5. gill is, canes d, aron m, et al. single port transumbilical (e-notes) donor nephrectomy. j urol. 2008;180:637-41. mini laparoscopic donor nephrectomy | simforoosh et al 1058 | 6. alcaraz a, musquera m, peri l, et al. feasibility of transvaginal natural orifice transluminal endoscopic surgery–assisted living donor nephrectomy: is kidney vaginal delivery the approach of the future? eur urol. 2011;59:1019-25. 7. andonian s, rais-bahrami s, atalla ma, herati as, richstone l, kavoussi lr. laparoendoscopic single-site pfannenstiel donor nephrectomy. urology. 2010;75:9-12. 8. novitsky yw, kercher kw, et al. advantages of minilaparoscopic vs conventional laparoscopic cholecystectomy: results of a prospective randomized trial. arch surg. 2005;140:1178-83. 9. simforoosh n, soltani mh, ahanian a. mini-laparoscopic donor nephrectomy: a novel technique. urol j. 2012; 9:353-5. 10. simforoosh n, sarhangnejad r, basiri a, et al. vascular clips are safe and a great cost-effective technique for arterial and venous control in laparoscopic nephrectomy: single-center experience with 1834 laparoscopic nephrectomies. j endourol. 2012;26:1009-12. 11. doyle am, lechler ri, turka la. organ transplantation: halfway through the first century. j am soc nephrol. 2004;15:2965-71. 12. park yh, min sk, lee jn, et al. comparison of survival probabilities for living-unrelated versus cadaveric renal transplant recipients. transplant proc. 2004;36:2020-2. 13. dols lf, ijzermans jn, wentink n, et al. long-term follow-up of a randomized trial comparing aparoscopic and mini-incision open live donor nephrectomy. am j transplant. 2010;10:2481-7. 14. kurien a, rajapurkar s, sinha l, et al. first prize: standard laparoscopic donor nephrectomy versus laparoendoscopic single-site donor nephrectomy: a randomized comparative study. j endourol. 2011;25:365-70. 15andonian s, rais-bahrami s, atalla ma, herati as, richstone l, kavoussi lr. laparoendoscopic single-site pfannenstiel versus standard laparoscopic donor nephrectomy. j endourol. 2010;24:429-32. 16. cheah wk, lenzi je, so jb, kum ck, goh pm. randomized trial of needlescopic versus laparoscopic cholecystectomy. br j surg. 2001;88:45-7. 17. isdale be, kapoor a, hussain a, piercey k, whelan jp. intact specimen extraction in laparoscopic nephrectomy procedures: pfannenstiel versus expanded port site incision. urology. 2007;69:241-4. laparoscopic urology urology journal unrc/iua 120 transitional cell carcinoma in children: report of a case and review of the literature aliasghar yarmohammad, hassan ahmadnia,* mohammad asl zare department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran key words: bladder, transitional cell carcinoma, hematuria, children vol. 2, no. 2, 120-121 spring 2005 printed in iran introduction transitional cell carcinoma (tcc) of the bladder is a rare condition in the first 2 decades of life, and it occurs nearly 9 times more frequently in males as it does in females. since 1950, only 100 cases of tcc of the bladder have been reported in patients younger than 21 years.(1) tcc of the bladder in children under 10 years is extremely rare, and by 1983, it was reported in only 17 cases.(2) the aim of this study is to report tcc of the bladder in a 9-year-old girl, who was referred to our institution with a chief complaint of gross hematuria. case report a 9-year-old girl from shahrood (semnan province, iran) who had gross hematuria of 2 weeks' duration was referred to our institution. her hematuria was painless and intermittent and was accompanied by clotting in the urine. the patient had a history of urinary retention. results of her laboratory tests were normal, and numerous red blood cells were seen on urinalysis. the patient had no history of urinary tract infection, and her family history was also unremarkable. on sonography, the kidneys were normal, and a papillary mass measuring 9 × 11 mm was reported in the trigon (figure 1). on intravenous pyelography, no pathologic finding was seen. cystoscopy, performed under general anesthesia, revealed a solitary and pedunculated papillary mass at the trigon. ureteral orifices and other parts of the bladder were normal. the mass was resected using a resectoscope. pathologic report confirmed a grade 1 tcc tumor (figures 2 and 3). the patient was discharged on the second postoperative day in good general condition. she was followed using cystoscopy and ultrasonography of the kidneys and bladder, which showed no recurrence in 6 postoperative years. discussion malignancies of the bladder in children are received may 2004 accepted january 2005 *corresponding author: 136 farhang ln, tehran st, mashhad 91366, iran. tel: ++98 511 859 5880, fax: ++98 511 841 7404 e-mail: ahmadnia2001@yahoo.com fig. 1. ultrasonography revealed a bladder tumor in a 9-year-old girl. fig. 2. pathologic feature of the bladder tumor (× 10) yarmohammadi et al 121 mainly of nonepithelial origin, and tumors with epithelial origin are extremely rare.(3) benson and coworkers reported only 3 cases of tcc of the bladder in patients under 10 years at a large referral center during a 30-year period.(1) the mean age of tcc occurrence in children is 11.8 years.(2) the male-to-female ratio is 9:1,(4) and it is 39 times more common among white children than among black ones.(2) its major symptom in children is painless hematuria. therefore, although it is a rare condition in children, it should always be considered in the differential diagnosis of hematuria during the first 2 decades of life.(1) some children may be referred with urinary tract infection and irritative voiding symptoms.(2,5) our patient had a history of urinary retention, and to the best of our knowledge, this has not been reported in any prior articles. in the cystographic phase of an intravenous pyelogram, a filling defect is generally seen, but in some patients, this defect is revealed only by cystoscopy.(2) hoenig and colleagues have reported a 100% sensitivity of ultrasonography in detecting bladder tumors, while pyelography can reveal tumors in only 75% of cases.(5,6) in our patient, the defect was first detected on sonography, while results of the intravenous pyelography were normal. although urine cytology has shown positive results in a few cases, it is not an appropriate method for tcc diagnosis in children(2) because the tumors are often low-grade.(5) most bladder epithelial tumors in children are low-stage and low-grade solitary tumors.(3,7) most authors believe that tcc of the bladder is obviously more benign in children than it is in adults.(8) however, some authors believe that the natural history of tcc in children is the same as it is in adults.(9) currently, the ideal treatment of tcc in children is transurethral resection of the bladder tumor with subsequent follow-up. in cases with several or invasive tumors, treatment is similar to that in adults. data to determine the appropriate method for follow-up are insufficient owing to the extremely low prevalence of the disease. some believe that tcc in children should be followed by the same protocols as those used for adults, while others believe that follow-up could be performed using ultrasonography (a sensitive and noninvasive method) and that intervals between cystoscopic evaluation should be lengthened owing to the possibility of urethral injury during cystoscopy and the need for general anesthesia. references 1. benson rc jr, tomera km, kelalis pp. transitional cell carcinoma of the bladder in children and adolescents. j urol. 1983;130:54-5. 2. khasidy lr, khashu b, mallett ec, kaplan gw, brock wa. transitional cell carcinoma of bladder in children. urology. 1990;35:142-4. 3. yanase m, tsukamoto t, kumamoto y, et al. transitional cell carcinoma of the bladder or renal pelvis in children. eur urol. 1991;19:312-4. 4. aboutaieb r, dakir m, sarrf i, et al. [bladder tumors in young patients]. prog urol. 1998;8:43-6. french. 5. hoenig dm, mcrae s, chen sc, diamond da, rabinowitz r, caldamone aa. transitional cell carcinoma of the bladder in the pediatric patient. j urol. 1996;156:203-5. 6. uemura m, inoue h, nishimura k, mizutani s, miyoshi s. [transitional cell carcinoma of the bladder in a young patient: a case report]. hinyokika kiyo. 2001;47:277-9. japanese. 7. kawaguchi t, hashimoto y, kobayashi h, et al. [a clinical study of bladder cancer in adolescent patients]. nippon hinyokika gakkai zasshi. 1999;90:614-8. japanese. 8. mottola a, daniele g, de benedetto a, bianchi s. [transitional cell carcinoma of the bladder in the first four decades of life]. minerva urol nefrol. 1998 jun;50:139-41. italian. 9. ozbey i, aksoy y, bicgi o, polat o, okyar g. transitional cell carcinoma of the bladder in patients under 40 years of age. int urol nephrol. 1999;31:655-9. fig. 3. pathologic feature of the bladder tumor (× 40) 1222 | department of urology, gaziantep university, gaziantep, turkey. corresponding author: omer bayrak, md university of gaziantep, school of medicine, department of urology, 27310 gaziantep, turkey. tel: +90 532 6428800 fax: +90 342 3603998 e-mail: dromerbayrak@yahoo. com received june 2012 accepted november 2012 purpose: to compare the complications and the cost analysis of open radical nephrectomy (orn) versus laparoscopic radical nephrectomy (lrn) in patients with renal tumors larger than 7 centimeters (cm). materials and methods: a retrospective analysis was performed in 173 patients (orn group, n = 140; lrn group, n = 33) who underwent surgery for kidney tumors between 2008 and 2011. patients' age, tumor size, pre-operative surgical risk score (american society of anesthesiologists score), duration of hospitalization, complications and the costs of hospitalization were recorded. the complications in orn group and lrn group were specified with modified clavien system in five grades. results: the mean age was found 58.52 ± 13.74 years in orn group, and 58.15 ± 12.81 years in lrn group (p = .847). post-operative pain necessitating analgesics was observed in all patients (100%) after early post-operative period in both groups (grade 1 complications). blood transfusions were required in 51 patients (36.42%) in the orn group, and 7 (21.21%) patients in the lrn group (grade 2 complications) (p = .185). grade 3 complication was not observed in each groups. grade 4 complications were occurred in 6 (4.28%) patients [aortic injury, acute tubular necrosis, the need for dialysis, respiratory arrest (2), atrial fibrillation] in the orn group, and in 1 (3.03%) patient (pulmonary embolism) in the lrn group. grade 5 complication was occurred in 1 (0.71%) patient (death) in the orn group. by the cost analysis, the average cost of orn group was €1328, whereas €1508 in lrn group (p < .05). conclusion: laparoscopy is used in many clinics with an increasing frequency because of the improved patient comfort, better cosmetic results, less post-operative pain, lower transfusion rates, and early return to the daily activities. besides these advantages, the negligible difference in the costs compared to the open surgery (mean difference = €180 per case) makes it even more attractive. keywords: kidney neoplasms; surgery; laparoscopy; nephrectomy; methods. omer bayrak, ilker seckiner, sakip erturhan, gokhan cil, ahmet erbagci, faruk yagci comparison of the complications and the cost of open and laparoscopic radical nephrectomy in renal tumors larger than 7 centimeters laparoscopic urology laparoscopic urology 1223vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l introduction renal cell carcinoma (rcc) is a common malignant tumor of the genitourinary tract, accounting for 2% 3% of all adult malignant tumors. the increase in the incidence rates of the renal tumors all over the world in recent years is undoubtedly, the widely use of the ultrasound and the computerized tomography. although the incidental diagnosis of the kidney tumors has become more frequent, the treatment policy is usually based on the clinical stage of the disease.(1) partial or radical nephrectomy, is the mainly applied current method in the treatment of renal cell cancer. laparoscopic radical nephrectomy (lrn) has been routine practice for localized rcc for indicated patients.(2,3) most of studies about lrn were performed in small tumors. but few recent publications have showed that, lrn could be also performed for large renal tumors. ritchie and colleagues emphasized that patients with stage t2 rcc were operated with lrn safely although more challenging procedure.(4) in addition to these; compared to open radical nephrectomy (orn), lrn has advantages as decreased blood loss, less postoperative pain, improved cosmetics, and quicker return to daily activities.(5,6) in our country, which is among the developing countries, there is rapidly increase in series of lrn. there is an increase in costs due to the instruments used during surgery, and this situation leads to financial problems in most centers. in our study, we aimed to compare complications and to make a cost analysis of orn vs. lrn in patients underwent surgery due to large renal tumors larger than 7 centimeters (cm). materials and methods a retrospective analysis was performed in 173 patients (orn group, n = 140; lrn group, n = 33) who underwent surgery for kidney tumors between 2008 and 2011. patients with t1 and t4 tumors were excluded from the study, because of they were treated with partial nephrectomy and orn, respectively. tumor staging was performed according to the 2009 american joint committee on cancer (ajcc) tnm classification. pre-operatively all patients were evaluated with posterior-anterior chest radiography, abdominal computerized tomography and/or magnetic resonance imaging. of study subjects 140 patients underwent orn and in 33 patients lrn was performed. recommendations and surgeon experience were affected the choice of surgical method. patients with tumor invasion of the renal vein and the inferior vena were included in the orn group. orn was performed through hemi-chevron incision. after the dissection and division of subcutaneous tissues and abdominal muscles; the peritoneum was incised and colon was medialized. then retroperitoneal space was entered from posterior peritoneum. after the hilar area was reached, first renal artery, then the renal vein and ureter were sutured and cut, respectively. the kidney was extracted en-bloc with perinephric fat and gerota’s fascia, and a 20 french foley drain was left at the renal space. when an enlarged lymph node (hilar, para-aortic, paracaval) was detected radiologically before surgery or largish during the operation; lymph node dissection was also performed. the transperitoneal approach was preferred in all patients who underwent lrn. after pneumoperitoneum was performed with a veress needle, 3 or 4 laparoscopic trocars were sited under direct vision. laterocolic tissue was dissected and colon was medialized. then approaching the renal hilum, the renal vein and artery was isolated. first renal artery, subsequent renal vein were separately ligated with hem-o-lok clips. three or 4 clips or vascular stapler were used to control the renal vein. we performed nephrectomy, with surrounded by the perinephric fat and gerota’s fascia, with or without a simultaneous adrenalectomy. the specimens were extracted with endo catch bag and a 20 french foley drain was left in the retroperitoneal area. in all patients receiving transperitoneal laparoscopic procedure, two 10-11 mm trocars for the camera, the endobag and the clip applicator, and for the non-dominant hand one 5 mm trocar to suspend ureter , where necessary one 5 mm trocar for the retraction of the liver or the spleen were used during the procedure. in all cases, three clips were placed on the renal artery and vein, and one on the ureter (hem-o-lok, weck closure systems, research triangle park, nc, usa). for minimizing the operation time and to ensure adequate hemostasis, ligasure™ (valleylab, tyco healthcare group lp, longbow drive boulder colorado, usa) was used. for each patient, monopolar scissors, bipolar dissector and gear holder were used. to reduce the costs, ligasure™, the monopolar open vs. laparoscopic radical nephrectomy in renal tumors | bayrak et al 1224 | scissors, the bipolar dissector, the gear holder, and the trocars were re-sterilized in solution and used at least for four laparoscopic interventions. all the transperitoneal or laparoscopic procedures were performed using surgical techniques as described in other publications.(7) patients' age, tumor size, pre-operative surgical risk score (american society of anesthesiologists score: asa score), duration of hospitalization, complications and the costs of hospitalization were recorded. the complications in both groups were specified with modified clavien system in five grades (table 1).(8) the cost analysis was performed by scanning the hospital bills in the automation system and the calculations were made in euro’s. all the expenses starting from the patient's hospitalization until the discharge [consumables used during surgery, laboratory, radiologic imaging, drugs, intravenous (iv) fluids, analgesics, bed costs, surgeons, and anesthesia] were included in this bill. comparison of two independent groups was performed with mann whitney u-test. for the categorical data chi-square test was used. the statistical package for the social science (spss inc, chicago, illinois, usa) version 11.5 was used for analysis and p values lower than .05 were accepted as significant. results the mean age was found 58.52 ± 13.74 years in orn group, and 58.15 ±12.81 years in lrn group (p = .847). in orn group, 103 (73.5%) patients had asa ii scores, and 37 (26.4%) patients had asa iii scores. in lrn group, 22 (66.6%) patients had asa ii scores, and 11 (33.3%) patients had asa iii scores (p = .432). tumor size was calculated 9.90 ± 2.04 (7-15) cm in orn group, and 9.54 ± 1.43 (7-12) cm in lrn group (p = .692). in the orn group, t2 tumors were found in 106 (75.71%) patients, and t3 tumors in 34 (24.28%) patients. in the lrn group, t2 tumors were identified in 28 (84.84%) patients, and t3 tumors in 5 (15.15%) patients (p = .242). there was no significant difference between the two groups in terms of mean age, asa score, mean tumor size, and the tumor stages (p > .05) (table 2). post-operative pain necessitating analgesics was observed in all patients (100%) after early post-operative period in both groups (grade 1 complications). blood transfusion were required in 51 patients (36.42%) in the orn group, and 7 (21.21%) patients in the lrn group (grade 2 complications) (p = .185). grade 3 complication was not observed in each groups. grade 4 complications were occurred in 6 (4.28%) patients [aortic injury, acute tubular necrosis, the need for dialysis, respiratory arrest (2), atrial fibrillation] in the orn group, and in 1 (3.03%) patient (pulmonary embolism) in the lrn group. grade 5 complication was occurred in 1 (0.71%) patient (death) in the orn group (table 3). the mean hospital stay was 3.75 ± 2.26 days in orn group, and 3.27 ± 1.39 days in lrn group (p = .601). the total cost per patient for open surgery was calculated €1328, whereas the total cost per patient for laparoscopic surgery was €1508 (p = .011) (table 2). the mean follow up period was calculated 33 months for the laparoscopic urology table 1. classification of surgical complications according to the modified clavien grading system. grade 1. any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological interventions. allowed therapeutic regimens are as follows: drugs as antiemetics, antipyretics, analgesics, diuretics, electrolytes, and physiotherapy. this grade also includes wound infections opened at the bedside. grade 2. requiring pharmacological treatment with drugs other than such allowed for grade 1. complications. blood transfusions and total parenteral nutrition are also included. grade 3. requiring surgical, endoscopic, or radiological intervention. 3a. intervention not under general anesthesia. 3b. intervention under general anesthesia. grade 4. life-threatening complication (including central nervous system) requiring intensive care unit stay. 4a. single organ dysfunction (including dialysis). 4b. multi organ dysfunction. grade 5. death of a patient. 1225vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l orn group, and the 23 months for the lrn group. local recurrence was occurred in 2 (1.4%) patients in the orn group. two patients in orn group and 2 patients in lrn group were died during follow-up period. discussion the laparoscopic dissection of large tumors highly depends on the experience of the laparoscopic surgeon. although the limitation of the working space, more bleeding, and the neovascularization of the larger tumors constitute a disadvantage for the laparoscopic technique, today lrn is often performed for t2 tumors. after gill and colleagues(9) have reported in 2000 that they have successfully implemented lrn in tumors larger than 12 cm (mean 14.6 cm), dunn and colleagues(10) have published the results of laparoscopic radical nephrectomy in a series of 61 patients with kidney tumors larger than 10 cm. in these studies, the authors have found more advantageous results in the laparoscopy group than the open surgery group, such as less pain, faster recovery and similar efficacy. these results have encouraged the urologists to perform laparoscopic surgery, to all stage t2 tumors, regardless of tumor size. steinberg and colleagues have compared a series of 62 patients with stage t2 tumors (mean diameter 9.2 cm) treated with lrn; with a series of 32 patients treated with orn. in this study, laparoscopic intervention was found to be associated with a shorter hospital stay, less blood loss compared to the open group.(11) hemal and colleagues retrospectively compared 41 patients performed lrn with 71 patients performed orn between 1998 and 2006 with tumor stage t2 . the average tumor size was about 10 cm in both groups. the transfusion rate was 15% and 32%, and the hospital stay was 3.6 days and 6.6 days for lrn and for orn groups respectively. the postoperative complications were similar (12% and 15% in lrn and orn groups, respectively). the lrn was thus found to be more advantageous than the orn.(6) these results were in concordance with the results obtained in our study. although the difference was not statistically significant, the transfusion rates in orn (36.42% vs. 21.21%) was higher and the hospitalization time (3.75 days vs. 3.27 days) in orn was also longer. in their study comparing the orn and lrn for masses larger than 7 cm, jeon and colleagues have not found significant differences in complication (pre-operative; vascular/hemorrhage, bowel, spleen, liver complications, post-operative; delayed bleeding, ileus, respiratory, and cardiac complications) rates between the groups.(12) similar to our study, major complications were occurred in 6 (4.28%) patients (aortic injury, acute tubular necrosis, the need for dialysis, respiratory arrest, and atrial fibrillation) in the orn group, and in 1 (3.03%) patient (pulmonary embolism) in the lrn group. unfortunately, 1 (0.71%) patient was died in the orn group due to respiratory arrest. although the difference between orn and lrn groups in terms of complications was not statistically significant, due to the high costs and the payments done according to the package standard prices, most centers have to deal with the financial aspects when they decide to switch to laparoscopic table 2. demographic data of patients in study groups. orn (n = 140) lrn (n = 33) p age (years) 58.52 ± 13.74 58.15 ± 12.81 p = .847 tumor size, cm (range) 9.90 ± 2.04 (7-15) 9.54 ± 1.43 (7-12) p = .692 tumor stage, n (%) t2: 106 (75.71) t3: 34 (24.28) t2: 28 (84.84) t3: 5 (15.15) p = .242 hospitalization (days) 3.75 ± 2.26 3.27 ± 1.39 p = .601 key: orn, open radical nephrectomy; lrn, laparoscopic radical nephrectomy. open vs. laparoscopic radical nephrectomy in renal tumors | bayrak et al 1226 | surgery, in our country. postoperative complications result in high costs due to the extended the duration of hospital stay and additional treatment. when the published data are analyzed, the complication rates are similar in open and laparoscopic kidney surgery. for this reason, we think that the complication rates do not have any effect on the cost calculation. today, the factors determining the costs of the open and the laparoscopic kidney surgery are the operating time, the number of transfusions, the medications, the hospital stay and the additional costs resulting from the complications. however, the main factor that increases the costs of the laparoscopic procedures are the high prices of the instruments. although the use of ligasure™ results in additional costs, it has a number of advantages such as the user-friendliness, the possibility of blunt dissection with the tip, the effective bleeding control and ability to reduce the duration of the surgery. furthermore, the possibility of sterilization and the repeated usage of the ligasure™ reduces the additional cost. in our procedures, we have used each ligasure™ device in about four cases after sterilization. the hem-o-lok polymer clips are preferred by many urologists due to the lower in price compared to the endovasculargia stapler, and higher reliability than the titanium clips with a comparable price. guazzoni and colleagues have reported a cost reduction of €805 per patient after 2003 by using the hem-o-lok clip instead of the endovascular-gia stapler.(13) we have used the endovascular-gia stapler only in three cases in our procedures. we have tried to minimize the costs by placing three clips on the renal artery and vein; and one polymer clip on the ureter (hem-o-lok, weck closure systems, research triangle park, nc, usa), in all cases. the studies comparing the costs of the open and laparoscopic procedures, performed outside our country, holligsworth and colleagues have reported $5808 for orn and $5157 for lrn.(14) in another study, lotan and colleagues reported that the cost of lrn is $1211 cheaper than orn. (15) in the publications showing the financial burden brought by the laparoscopic renal interventions in our country, basok and colleagues have calculated that the costs of lrn to be 20% higher than orn.(16) in our study, the costs of orn was €1328, whereas lrn was calculated to cost €1508, with a difference of 13.5% (p < .05). this study has certain limitations. our study was retrospective nature, and because of this, we could not perform randomization. we compare the expenses starting from the patient's hospitalization until the discharge. only intra-operative cost may be more important to assess cost effectiveness of these two techniques. conclusion laparoscopy is used in many clinics with an increasing frequency because of the improved patient comfort, cosmetic display, post-operative pain reduction, lower transfusion rates, and early return to the daily life. besides these advantages, similar complication rates even in larger renal masses and the negligible difference in the costs compared to the laparoscopic urology table 3. comparing complications of orn and lrn by clavien classification. orn, n (%) lrn n (%) p grade 1 140 (100) 33 (100) ns grade 2 51 (36.4) 7 (21.2) 185 grade 3 0 0 grade 4 6 (4.28) 1 (3.03) ns grade 5 1 (0.71) 0 ns key: orn, open radical nephrectomy; lrn, laparoscopic radical nephrectomy; ns, not significant. 1227vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l references 1. chow wh, devesa ss, warren jl, fraumeni jr jf. rising incidence of renal cell carcinoma in the united states. jama. 1999;281:1628-31. 2. ono y, kinukawa t, hattori r, gotoh m, kamihira o, ohshimas. the long-term outcome of laparoscopic radical nephrectomy for small renal cell carcinoma. j urol. 2001;165:1867-70. 3. gill is, meraney am, schweizer dk, et al. laparoscopic radical nephrectomy in 100 patients: a single center experience from the united states. cancer. 2001;92:1843-55. 4. ritchie rw, sullivan me, jones a. laparoscopic radical nephrectomy for t2 renal cell carcinoma. bjmsu. 2009;2:117-23. 5. luo jh , zhou fj , xie d, et al . analysis of long-term survival in patients with localized renal cell carcinoma: laparoscopic versus open radical nephrectomy. world j urol. 2010;28:289-93. 6. hemal ak, kumar a, kumar r, wadhwa p, seth a, gupta np. laparoscopic versus open radical nephrectomy for large renal tumors: a long-term prospective comparison. j urol. 2007;177:862-6. 7. rassweiler j, coptcoat mj. laparoscopic surgery of the kidney and adrenal gland. in: janetschek g, rassweiler j, griffith d, editors. laparoscopic surgery in urology. thieme stuttgart-new york; 1996. p. 139-155. 8. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of a 6336 patients and results of a survey. ann surg. 2004;240:205-13. 9. gill is, schweizer d, hobart mg, sung gt, klein ea, novick ac. retroperitoneal laparoscopic radical nephrectomy: the cleveland clinic experience. j urol. 2000;163:1665-70. 10. dunn md, portis aj, shalhav al, et al. laparoscopic versus open radical nephrectomy: a 9-year experience. j urol. 2000;164:1153-9. 11. steinberg ap, finelli a, desai mm, et al. laparoscopic radical nephrectomy for large (greater than 7 cm, t2) renal tumors. j urol. 2004;172:2172-6. 12. jeon sh, kwon tg, rha kh, et al. comparison of laparoscopic versus open radical nephrectomy for large renal tumors: a retrospective analysis of multi-center results. bju int. 2011;107:817-21. 13. guazzoni g, cestari a, naspro r, riva m, rigatti p. cost containment in laparoscopic radical nephrectomy: feasibility and advantages over open radical nephrectomy. j endourol. 2006;20:509-13. open surgery (mean difference = €180 per case) makes laparoscopy even more attractive. conflict of interest none declared. 14. hollingsworth jm, miller dc, dunn rl, montgomery js, wolf js jr. cost trends for oncologic renal surgery: support for a laparoscopic standard of care. j urol. 2006;176:1097-101. 15. lotan y, cadeddu ja. a cost comparison of nephron sparing surgical techniques for renal tumor. bju int. 2005;95:1039-42. 16. basok ek, yıldırım a, basaran a, rifaioglu m, tokuç r. cost analysis of laparoscopic and open renal surgery. turk j urol. 2008;34:100-7. open vs. laparoscopic radical nephrectomy in renal tumors | bayrak et al endourology and stone disease 88 urology journal vol 6 no 2 spring 2009 accuracy of radiological features for predicting extracorporeal shock wave lithotripsy success for treatment of kidney calculi hamid arshadi,1 seyed saied dianat,2 leila ganjehei2 introduction: our aim was to assess the accuracy of radiological characteristics observed by the urologist in estimating the success rate of extracorporeal shock wave lithotripsy (swl) in patients with kidney calculi. materials and methods: patients with kidney calculi sized 10 mm to 15 mm who underwent swl in our center were enrolled. one urologist estimated the success chance of swl based on plain abdominal radiography. accordingly, the patients were categorized into 2 groups with more than 75% chance of fragmentation (group 1) and with 50% to 75% estimated chance of fragmentation (group 2). factors used for estimation included calculus shape, homogeneity, and density as compared with the adjacent 12th rib. the estimations were compared with the resulted stone-free rate after a 3-month follow-up. results: a total of 137 patients were studied, of whom, 92 (67.2%) were categorized in group 1 and 45 (32.8%) in group 2, before the lithotripsy. successful treatment was recorded in 101 patients (73.7%). eighty-five patients with favorable estimated chance of successful lithotripsy (92.4%) had successful swl, and 29 with less favorable estimate (64.4%) did not have successful fragmentation following 2 sessions of swl (p < .001). the sensitivity and specificity of radiological parameters for prediction of treatment success were 84.2% and 80.6%, respectively. conclusion: we found that certain radiographic features of urinary calculi such as calculus density, as compared with the adjacent bone, and calculus shape could have predictive impression for the success rate of swl. urol j. 2009;6:88-91. www.uj.unrc.ir keywords: urinary calculi, abdominal radiography, lithotripsy, treatment outcome 1department of urology, children’s medical center, tehran university of medical sciences, tehran, iran 2school of medicine, tehran university of medical sciences, tehran, iran corresponding author: hamid arshadi, md department of urology, children’s medical center, keshavarz blvd, dr gharib st, tehran, iran tel: +98 21 6691 7646 e-mail: drhamidarshadi@yahoo.com received october 2008 accepted april 2009 introduction extracorporeal shock wave lithotripsy (swl) was first introduced into clinical practice as a treatment of ureteral calculi in the early 1980s.(1) despite of the recent advances in endourologic methods for calculus removal, such as ureteroscopy and percutaneous nephrolithotomy, swl still remains the primary treatment of most uncomplicated upper urinary tract calculi. however, the location, size, and composition of the calculus might affect the outcome of swl.(2,3) certain radiographic features of calculi and the urinary tract could have an impact on calculus clearance after therapy with swl. it has been proposed that calculi with certain characteristics such as smooth shape, higher density than bone, lower calyx location, and predicting shock wave lithotripsy success—arshadi et al urology journal vol 6 no 2 spring 2009 89 larger than 15 mm in diameter have less favorable success rate with swl. (4) considering radiological features that could predict swl success, it would be possible to select this type of treatment only for calculi that are more likely to respond to this modality. alternatives such as percutaneous nephrolithotomy, ureteroscopy, and open surgery can be used in other situations. however, studies on the predictive role of radiological features are conflicting. bon and colleagues studied the predictive value of shape and radiologic density of urinary calculi for swl success and showed that smooth dense calculi had less success rate than rough and less dense calculi.(5) in another study by aebreli and colleagues, no correlation was reported between radiographic appearance of the calculus and swl treatment outcome.(6) to address some of these controversies, we designed the present study to assess the accuracy of radiological characteristics in estimating the success rate of swl in patients with kidney calculi. materials and methods a total of 143 consecutive patients (101 men and 36 women) were enrolled in the present study. they had kidney calculi sized 10 mm to 15 mm who were treated in our lithotripsy center between january and november 2007. pregnancy, calculi smaller than 10 mm or larger than 15 mm, body weight more than 90 kg, large abdominal aortic aneurysm, and uncorrectable bleeding disorders were the exclusion criteria. the patients were diagnosed based on plain radiography, ultrasonography, and intravenous urography in suspected cases such as residual calculi in the ureter. written informed consent was obtained from all of the patients for registering their imaging data and outcome of lithotripsy in our study. lithotripsy was performed by edap technomed lto2x (vaulx-en-velin, france) with ultrasound wave as the source of energy emitted to the calculus. pretreatment plain abdominal radiographies of the kidneys, ureters, and bladder were evaluated by one urologist in order to categorize the patients into 2 predictive groups based on certain radiological criteria (shape, size, and density of the calculus). the 1st group was estimated to have more than 75% chance of fragmentation (more favorable response to swl), and the 2nd group constituted those with 50% to 75% estimated chance of fragmentation (less favorable response to swl). factors used for estimation included calculus shape, homogeneity, and density as compared with the adjacent 12th rib. it has been proposed that calculi with higher density compared with the adjacent bone and smooth surface are more difficult to be successfully treated with swl.(5) accordingly, the patients were categorized in either group 1 or group 2. the patients were followed up for the outcome of lithotripsy, and a stone-free status within 3 months after lithotripsy was considered as successful treatment. the follow-up was performed by plain abdominal radiography and ultrasonography. statistical analysis for the relationship between success rate and estimated chance of fragmentation was performed by the chi-square test, using the graphpad prism software (version 3.0, graphpad software inc, la jolla, california, usa). p values less than .05 were considered significant. results six of the enrolled patients did not return for follow-up, finally, 137 patients were studied and considered in the analyses. of those, 92 patients (67.2%) were categorized in group 1 and 45 (32.8%) in group 2, before the lithotripsy (table). the maximum calculus diameter in both groups was 15 mm. successful treatment was recorded in 101 patients (73.7%). eightyfive patients with favorable estimated chance of successful lithotripsy (92.4%) had successful swl, estimation of success patients and outcome > 75% 50% to 75% p number of patients 92 45 … sex male 70 (69.3) 31 (30.7) female 22 (56.5) 14 (43.5) .37 stone-free patients 85 (92.4) 16 (35.6) < .001 estimate of shock wave lithotripsy success using radiological parameters* *values in parentheses are percents. ellipsis indicates not applicable. predicting shock wave lithotripsy success—arshadi et al 90 urology journal vol 6 no 2 spring 2009 and 29 with less favorable estimate (64.4%) did not have successful fragmentation following 2 sessions of swl (table; p < .001). accordingly, the sensitivity and specificity of radiological parameters for prediction of treatment success were 84.2% and 80.6%, respectively. the positive predictive value and the negative predictive value were 92.4% and 64.4%, respectively. discussion shock wave lithotripsy was introduced to clinical practice as a treatment for urinary calculi in the early 1980s.(1) currently, even with the refinement of endourologic methods for calculus removal such as ureteroscopy and percutaneous nephrolithotomy, swl keeps its position through the therapeutic options for most of the urinary calculi sized less than 20 mm. several factors might influence the success rate of swl, including the size, location, and composition of calculi, as well as the type of energy used for lithotripsy. although swl is considered the treatment of choice for calculi less than 20 mm, certain calculus compositions are not considered favorable to fragmentation using this modality. however, it is not yet practical to identify the exact composition of most of the urinary calculi before the treatment in order to predict the chance of fragmentation. some investigators have studied the correlation of calculus composition with radiographic features. dretler and polykoff investigated the correlation of calculus composition of a calcium oxalate calculus crystallographically with radiographic parameters observed on plain radiography, in order to predict the success rate of lithotripsy for this type of calculi. they showed that shape and calculus radiodensity correlated with calculus composition. therefore, smooth highly radiodense calculi were usually composed of calcium oxalate monohydrate which were less likely to be fragmented by swl.(7) to our knowledge, 3 clinical studies have been performed to determine the radiographic correlations with calculus fragmentation rate. in a study by bon and coworkers, success rate for rough and less radiodense calculi was considerably higher than that of smooth and more radiodense ones (79.4% and 33.6%, respectively).(5) in another study by aeberli and associates, no correlation was observed between calculus radiodensity and fragmentation using a dornier hm-3 machine.(5) the most recent study was conducted by krishnamurthy and colleagues to identify the proposed correlation between radiodensity of solitary renal pelvic calculi sized less than 2 cm and the outcome of lithotripsy. no correlation was found between calculus radiodensity and calculus composition. calculi with the size of less than 10 mm were similarly fragmented regardless of radiodensity differences. however, higher success rate in calculi sized 10 mm to 20 mm with lower radiodensity was reported as compared to the adjacent rib (71% versus 60%).(4) in the present study, we investigated the accuracy of the estimation of lithotripsy success rate with plain radiography by considering the success rate of lithotripsy after a 3-month follow-up. the overall success rate in our sample was 73.7%. we found that calculi with certain favorable radiographic features including size of less than 15 mm in diameter, lower radiodensity as compared to the adjacent rib, and smooth surface could be predicted to have also high success rate after treatment with swl. estimation of the success rate based on radiographic features could predict calculus fragmentation in our sample with sensitivity and specificity of 84.2% and 80.6%, respectively. accordingly, it is suggested that several radiographic parameters observed by the urologist could predict the success rate of urinary calculi treatment using swl. also the present study shows that the urologist can predict successful treatment more reliably than failure to fragmentation. the limitation of our study was the lack of adjustment for calculus size to detect the independent predictive radiographic factor as well as using an inaccurate method to quantitatively assess calculus radiodensity. however, in order to overcome the interindividual bias on estimation of fragmentation, all of the radiography images were evaluated by a single urologist. conclusion we found that certain radiographic features of urinary calculi could have predictive impression predicting shock wave lithotripsy success—arshadi et al urology journal vol 6 no 2 spring 2009 91 for the success rate of treatment by lithotripsy. considering several calculus radiographic features might be useful to recommend swl for patients with more favorable estimate of response to treatment, and in another way, to recommend other therapeutic options such as endourologic treatments. this may be save time and reduce the costs in the treatment of this common urologic disease. future studies in large samples are needed to confirm the results of the present study. conflict of interest none declared. references 1. schmiedt e, chaussy c. extracorporeal shock-wave lithotripsy (eswl) of kidney and ureteric stones. int urol nephrol. 1984;16:273-83. 2. stroller ml. urinary stone disease. tanagho ea and mcanineh jw. smith’s general urology, 17th ed. new york: lange medical books/mcgraw-hill; 2008. p. 24677. 3. atala a, steinbock gs. extracorporeal shock-wave lithotripsy of renal calculi. am j surg. 1989;157:350-8. 4. krishnamurthy ms, ferucci pg, sankey n, chandhoke ps. is stone radiodensity a useful parameter for predicting outcome of extracorporeal shockwave lithotripsy for stones < or = 2 cm? int braz j urol. 2005;31:3-8. 5. bon d, dore b, irani j, marroncle m, aubert j. radiographic prognostic criteria for extracorporeal shock-wave lithotripsy: a study of 485 patients. urology. 1996;48:556-60; discussion 60-1. 6. aeberli d, muller s, schmutz r, schmid hp. predictive value of radiological criteria for disintegration rates of extracorporeal shock wave lithotripsy. urol int. 2001;66:127-30. 7. dretler sp, polykoff g. calcium oxalate stone morphology: fine tuning our therapeutic distinctions. j urol. 1996;155:828-33. case report an adrenal hepatoid adenocarcinoma with left renal vein thrombosis extending into the inferior vena cava xiaokai deng, yuting jin, wenxue yang, shuaibin wang, haiqi mu, kaiyuan yu, youhua he* keywords: hepatoid adenocarcinoma; adrenal gland; inferior vena cava thrombosis department of urology, the second affiliated hospital and yuying chindren’s hospital of wenzhou medical university, zhejiang, china. *correspondence: department of urology, the second affiliated hospital and yuying chindren’s hospital of wenzhou medical university, zhejiang , china. tel: +8613566242737. e-mail: heyouhua304@163.com. received march 2019 & accepted july 2019 hepatoid adenocarcinoma (hac) is an uncommon tumor with morphological resemblance to hepatocellular carcinoma. hac of the adrenal glands is extremely rare. here, we report the case of an 83-year-old man with adrenal hac who presented with a greatly increased preoperative serum alpha-fetoprotein level (> 24,200 ng/ml). the findings of magnetic resonance imaging and contrast-enhanced abdominal computed tomography revealed a large mass occupying the left adrenal gland region as well as thrombosis of the renal vein extending into the inferior vena cava. subsequently, the adrenal hac was treated by surgical resection and targeted sorafenib therapy. however, the patient died 9 months later because of systemic metastasis of the tumor. in conclusion, adrenal hac with inferior vena cava tumor thrombosis is extremely rare and challenging to diagnose and treat. pathological and immunohistochemical examination are helpful for diagnosis and surgical excision is the main strategy for treating the tumor. introduction hepatoid adenocarcinoma (hac) is an extremely rare neoplasm which has a similar tissue morphology to hepa-tocellular carcinoma (hcc) and is associated with frequent expression alpha-fetoprotein (afp). hac generally originates from the stomach, ovaries, lungs, gallbladder, pancreas, and uterus(1). however, to date, only sporadic cases of hac have been reported in the literature to originate from the adrenal glands. in this report, we present figure 1. (a) abdominal magnetic resonance imaging (mri) revealed a large mass (13.1× 8.7 × 11.5 cm) in the left adrenal gland region with compression of the surrounding tissues and organs (yellow arrow). (b) enlarged retroperitoneal lymph nodes (yellow arrow). (c) ct scan showing a tumor thrombosis in the left renal vein extending into the inferior vena cava (red arrow). figure 2. a well-encapsulated tumor with partially necrotic tissue. no infiltration to the left kidney was observed. urology journal/vol 16 no. 5/ september-october 2019/ pp. 511-514. [doi: 10.22037/uj.v0i0.5250] information regarding a rare adrenal hac with tumor thrombosis of the renal vein extending into the inferior vena cava. case report an 83-year-old chinese man with a medical history of herpes zoster, diabetes, and hypertension was admitted to our hospital because of dizziness and fatigue. his cranial magnetic resonance imaging (mri) showed multiple ischemic demyelination lesions in the brain and senile cerebral atrophy which could not fully justify the occurrence of his dizziness and fatigue. laboratory investigations showed that the serum afp level was exceedingly high (> 24,200 ng/ml). however, except for an elevated serum neuron-specific enolase level of 61.11 ng/ml (normal range, 0.00 – 16.30 nmol/l), the serum levels of other tumor markers, including carcinoembryonic antigen (cea) and carbohydrate antigens(ca) 72 4 and ca 19 9 were completely normal. the patient then underwent abdominal ultrasonography, the results of which revealed a large hypoechoic mass in the left upper abdomen. the findings of mri and contrast-enhanced abdominal computed tomography (ct) revealed a large mass (13.1 × 8.7 × 11.5 cm) occupying the region of the left adrenal gland, associated with a renal vein and inferior vena cava thrombosis (mayo i) and enlarged retroperitoneal lymph nodes (figure 1). the liver and lungs showed no significant tumors, and there was no evidence of metastasis. the levels of serological markers for hepatitis b and c viruses were within normal limits. the levels of adrenal function indicators such as corticotrophin, cortisol, serum catecholamine, urinary vanillin-amygdalic acid, and recumbent renin, angiotensin, and aldosterone were also normal on admission. on the basis of these findings, we diagnosed the tumor as a malignant non-functional adrenal tumor with a clinical stage of t3n1m0. subsequently, the patient underwent surgical resection including left adrenal tumor resection, left nephrectomy, and left renal vein tumor thrombectomy. the pathological specimen showed an encapsulated tumor with partial ischemic necrotic tissue inside. the surrounding adipose tissue showed no tumor involvement (figure 2). the para-aortic lymph nodes and peripheral vessels showed metastasis (1/1) and tumor thrombus, respectively, while the surrounding nerve plexus showed cancer involvement. histopathological findings revealed poorly differentiated cells with round atypical nuclei resembling hcc cells under a light microscope. the cells were arranged in irregular lamellar and cordlike structures (figure 3). immunohistochemical findings showed the cells to be focally positive for hepatocyte paraffin-1 (hep-1) antigen (figure 4.a) and approximately 50% positive for antigen ki-67 (figure 4.b) and glypican-3 (gpc-3) (figure 4.c). the tumor cells were also positive for afp and arginase-1 (arg-1). after surgery, the serum afp level of the patient decreased to 2897 ng/ml. on the basis of these findings, the patient was diagnosed with adrenal hac. he was then administered targeted treatment with sorafenib. at two months after surgery, the serum afp level of the patient had increased to 8998 ng/ml, and the results of repeated imaging showed multiple nodules in both lungs (figure 5.b) which were considered to be metastatic tumors according to the insignificance observation of tumor in both lungs before surgery (figure 5.a). eight months after surgery, ct findings revealed further progression of the pulmonary nodules (figure 5.c) as well as metastatic tumors in the liver (figure 5.d). the patient eventually died due to systemic metastasis of the tumor in 2018. adrenal hepatoid adenocarcinoma with renal vein thrombosis-deng et al. case report 413 figure 3. histopathological features of hepatoid adenocarcinoma of the adrenal gland. the tumor was composed of polygonal cells with atypical nuclei arranged in irregular lamellar and cordlike structures ((a) he × 400, (b) he × 400). figure 4. immunohistochemical staining of adrenal hepatoid adenocarcinoma. (a) hep1 positivity of tumor cells (× 200). (b) ki-67 positivity of tumor cells (× 100). (c) glypican-3 positivity of tumor cells (× 200). case report 512 discussion hac is a very rare type of extrahepatic adenocarcinoma with pathological and morphological similarity to hcc(1,3). in 1985, ishikura et al. reported the first case of an afp-producing gastric carcinoma with features of hepatic differentiation, which they termed “gastric hepatic adenocarcinoma”(4). since then, hac has been identified in various organs of the abdominal cavity with the stomach being the most common location. here, we have reported an hac of the adrenal glands. to date, only seven cases of adrenal hac have been reported in the literature(5), with the first one being reported by yoshioka et al. in japan in 1994(6). serum afp level is generally considered to be an effective marker for diagnosing hcc and hac. in the present case, our patient showed an extremely elevated serum afp level. however, afp, a well-known marker of hcc, is usually produced by hcc and gonadal tumors, and tissues of these tumors can be positive for this marker (7). moreover, adrenal cortex cancer can also cause elevated afp levels(2). therefore, histopathological results are necessary for diagnosing hac. in most cases, diagnosis of hac is straightforward if the patient shows increased serum afp levels, positive tumor tissue afp expression upon immunohistochemical analysis, and hepatocyte differentiation upon histological analysis. however, lin et al. recently encountered a case of non-afp-producing adrenal hac(5) and they used next-generation sequencing to establish the diagnosis. there is currently no conclusive evidence for differentiating between hac and hcc during clinical diagnosis. su et al. performed a literature review of the clinicopathological characteristics used for differential diagnosis of hac over a 10-year period (2001–2011) (7). they identified 98 eligible studies (involving 217 patients) and found that immunohistochemical markers can help clearly differentiate hac from hcc. hcc should be diagnosed based on the results of dynamic imaging (such as ct or mri) and/or liver tumor biopsy. a typical dynamic image of hcc shows intense arterial uptake followed by contrast washout in the venous and/or delayed phases(7). in contrast, hac can be definitively diagnosed on the basis of pathological and immunohistochemical findings. hacs are composed of polygonal cells with nuclei at the centre of sheet-like or trabecular portions, and they occasionally show bile production and/or bile canaliculi formation(3). generally, afp, arg-1, gpc-3, ki-67, and hep-1 antigen are positive indicators of hcc. in the present case, the tumor cells were positive for afp, arg-1, gpc-3, and hep-1 antigen. recently, several studies have suggested that pet/ct might play a role in the diagnosis of this individual disease. wang et al. reported a case of hac revealed by fdg pet/ct whose primary tumor and metastases showed a moderate fdg uptake(8). hu et al. also reported positive findings in patients with hac (9). however, another study reported a case without any uptake on pet-ct(10). surgical resection is the main treatment for hac in combination with adjuvant chemotherapy and radiotherapy. adrenal hac with inferior vena cava tumor thrombosis has not been previously reported. the safety and efficacy of radical adrenal tumor resection and inferior vena cava tumor thrombectomy have not been fully studied. complete resection with negative margins represents the best chance of cure for the patient(11). a research by danuel et al.(12) compared 65 patients undergoing resection of adrenocortical carcinoma with and without inferior vena cava (ivc) tumor thrombosis which indicated that the median survival for patients with ivc involvement was 14.8 months compared to 43 months for patients without ivc thrombosis. the short-term safety and survival were similar to two groups while survival beyond 36-months was limited in patients with inferior vena cava tumor thrombosis. because of its high malignancy rate, hac generally has a worse prognosis than common adenocarcinoma. in addition, hac is usually metastatic at initial presvol 16 no 04 july-august 2019 414 figure 5. (a) chest ct did not show any significant mass before surgery (b) two months after surgery multiple high-density nodules were seen (c) at eight months after surgery the tumor had progressed. (d) as shown by the arrows, liver metastasis occurred eight months after surgery. adrenal hepatoid adenocarcinoma with renal vein thrombosis-deng et al. vol 16 no 04 september-october 2019 513 entation(13). the most common sites of metastasis are the lymph nodes, liver, and lungs(7). in the present case, the patient first presented with lymph node metastasis, followed by lung and liver metastasis, which suggested that the tumor cells are extremely aggressive. furthermore, most cases of adrenal hac have been reported from asian countries, especially japan and china(5-6). whether this trend is consistent with the incidence area of hcc remains to be studied. conclusions having in mind this rare pathological type of adenocarcinoma which manifests as a non-uniformly enhanced soft-tissue mass on imaging and is accompanied by an increase in afp level is important for timely diagnosis and treatment. despite the lack of literature regarding adrenal hac, radical surgery is still the preferred treatment for cases associated with inferior vena cava tumor thrombosis. acknowledgement we thank international science editing (http://www. internationalscienceediting.com) for editing this manuscript. conflict of interest the authors report no conflict of interest. references 1. mtzgeroth g, strobel p, baumbusch t, reiter a, hastka j. hepatoid adenocarcinoma review of the literature illustrated by a rare case originating in the peritoneal cavity. onkologie. 2010; 33: 263-9. 2. malya fu, bozkurt s, hasbahceci m, et al. a rare tumor in a patient with hepatic hydatic cyst: adrenal hepatoid adenocarcinoma. case rep med. 2014; 2014: 824574. 3. kuo pc, chen sc, shyr ym, kuo yj, lee rc, wang se. hepatoid carcinoma of the pancreas. world j surg oncol. 2015; 13: 185. 4. ishikura h, fukasawa y, ogasawara k, natori t, tsukada y, aizawa m. an afp-producing gastric carcinoma with features of hepatic differentiation. a case report. cancer. 1985; 56: 840-8. 5. lin j, cao y, yu l, lin l. non-α-fetoproteinproducing adrenal hepatoid adenocarcinoma: a case report and literature review. medicine. 2018; 97: e12336. 6. yoshioka m, ihara h, shima h, et.al. adrenal hepatoid carcinoma producing alphafetoprotein: a case report. hinyokika kiyo. 1994; 40: 411-4. 7. su js, chen yt, wang rc, wu cy, lee sw, lee ty. clinicopathological characteristics in the differential diagnosis of hepatoid adenocarcinoma: a literature review. world j gastroenterol. 2013; 19: 321-7. 8. wang xy, bao wq, hua fc, et al. afpproducing hepatoid adenocarcinoma of appendix: a case report of 18f-fdg pet/ct. clin imaging. 2014; 38: 526-8. 9. hu n, tan y, luo j, cheng z, wang y. 18f-fdg pet/ct of primary mediastinal hepatoid adenocarcinoma. clin nucl med. 2016; 41: 321-2. 10. søreide ja, greve oj, gudlaugsson e, størset s. hepatoid adenocarcinoma of the stomach-proper identification and treatment remain a challenge. scand j gastroenterol. 2016; 51:646-53. 11. haghdani s, kafash nayeri r, zargar h, zargar ma. adrenocortical carcinoma with renal vein tumor thrombus extension. urol j. 2015; 12: 2037-9. 12. laan dv, thiels ca, glasgow a, et al. adrenocortical carcinoma with inferior vena cava tumor thrombus. surgery. 2017; 161: 240-8. 13. cong q, li g, jiang w, et.al. ectopic choriocarcinoma masquerading as a persisting pregnancy of unknown location: case report and review of the literature. j clin oncol. 2011; 29: e845-8. adrenal hepatoid adenocarcinoma with renal vein thrombosis-deng et al. case report 514 urology journal unrc/iua vol. 2, no. 1, 28-31 winter 2005 printed in iran 28 comparison of snodgrass and mathieu surgical techniques in anterior distal shaft hypospadias repair mahmoudreza moradi*, as'ad moradi, farzin ghaderpanah urology-nephrology research center, 4th shaheed mehrab hospital, kermanshah uuniversity of medical sciences, kermanshah, iran abstract purpose: to compare the outcomes of mathieu and snodgrass techniques in the repair of anterior distal shaft hypospadias. materials and methods: from 2001 to 2003, 33 patients with the mean age of 7.06 ± 3.44 (range 2 to 12) years suffering from anterior distal shaft hypospadias, were assessed. inclusion criteria were anterior distal shaft hypospadias, and exclusion criteria were association with chordee, circumcision, and surgical repair history. fifteen patients underwent surgical repair using snodgrass technique and 18 patients, using mathieu technique. surgeries were performed by one single surgeon, acquainted with both techniques. patients were examined 1 week, 1 month, and 6 months after discharge. data including duration of the surgery, stenting time, duration of hospitalization, and any kind of complications such as break down, meatal stenosis, and fistula formation were collected. also, success rate was calculated for every single patient and accordingly, the two groups were compared. results: mean operative time, stenting duration, and hospital stay were 94 ± 26.06 minutes, 5.06 ± 1.31 days, and 3.93 ± 1.86 days in mathieu group and 106.11 ± 23.04 minutes, 5.11 ± 1.56 days, and 4.55 ± 1.29 days in snodgrass group, respectively (p >0.05). the rate of break down, meatal stenosis, and fistula formation were 0%, 0%, and 5.55% in mathieu group and 0%, 6.66%, and 13.32% in snodgrass group, respectively (p >0.05). success rate was 80.02% in snodgrass group and 94.45% in mathieu group (p >0.05). conclusion: in spite of some reports about preference for snodgrass technique, we concluded that these techniques are as acceptable and as effective as each other for hypospodias repairing, regardless of cosmetic outcomes; however, we need further studies and larger sample sizes to determine which is the superior technique. key words: hypospadias, snodgrass technique, mathieu technique, urethroplasty introduction hypospadias is a congenital abnormality caused by incomplete development of urinary meatus, in which the meatus is opened on the ventral side of penis instead of apex of glans. its incidence rate is reported to be about 1 in 300 male live births.(1) hypospadias is divided into three types of posterior, middle, and anterior, regarding the position of meatus. in anterior type, meatal orifice opens either on distal penile shaft, on corona, or under the glans.(2) anterior hypospadias is the most common form and several surgical methods have been suggested for its repairing, among which mathieu and snodgrass are the most common techniques.(1,2) snodgrass technique has been more welcomed by urological circles in recent years. regarding the high incidence of this anomaly and need for choosing appropriate treatment, the received december 2004 accepted march 2005 *corresponding author: department of urology, 4th shaheed-e-mehrab hospital, doalatabad blvd. kermanshah, iran. e-mail: drmrmoradi@yahoo.com moradi et al 29 results and postoperative complications of mathieu and snodgrass techniques in patients with anterior distal shaft hypospadias were compared in this study. materials and methods in a randomized clinical trial from 2001 to 2003, 33 boys with the mean age of 7.06 ± 3.44 (range 2 to 12) years with anterior hypospadias, were assigned into two groups to undergo either snodgrss or mathieu surgical repair. inclusion criteria were anterior and distal shaft hypospadias and age of 12 years or less, and exclusion criteria were association with chordee, history of circumcision, and surgical repair history. on a random basis, 18 patients underwent surgical repair using mathieu technique and 15 patients using snodgrass technique. all surgeries were performed by one single surgeon who was experienced enough to do both surgeries. surgical instruments, suture materials (6-0 vicryl) and urinary diversion (nelaton 6 f to 8 f) were the same for all patients. the protective pedicle layer from dartos muscle covered the suture line in all patients and cautery would not be used, unless it was necessary. all of the patients were examined 1 week, 1 month, and 6 months after discharge. data including duration of the surgery, stenting time, duration of hospitalization, and any kind of complications such as break down, meatal stenosis, and fistula formation were collected. also, success rate was calculated for every single patient. the information related to operation along with findings in follow-ups were recorded in forms and they were compared between the two groups. data were analyzed using spss software. mannwhitney and t tests were used for quantitative data comparison and fisher's exact test for comparison of qualitative data. results mean operative time was 94 ± 26.06 minutes and 106.11 ± 23.04 minutes in mathieu and snodgrass groups, respectively. mean stenting duration was 5.06 ± 1.31 days and 5.11 ± 1.56 days in mathieu and snodgrass groups, respectively. hospital stay was 3.93 ± 1.86 days in mathieu group and 4.55 ± 1.29 days in snodgrass group. statistical analysis showed no differences between the two groups. complication rates were as follows: break down was seen in none of the patients, meatal stenosis occurred in 0 (0%) and 1 (6.66%) cases in mathieu and snodgrass groups, respectively, and fistula formation was seen in 1 (5.55%) patient in mathieu group and 2 (13.32%) patients in snodgrass group, respectively (p >0.05). success rate was 80.02% in snodgrass group and 94.45% in mathieu group (p >0.05) (table 1). discussion hypospadias is a congenital anomaly in which meatal orifice opens to anterior part of penis instead of the glans apex, because of a defect in urethral development. its incidence rate is about 1 in 300 male live births.(1) about 50% to 70% of hypospadias cases are the anterior types.(1,2) several surgical techniques have been advocated for repairing anterior hypospadias. some of these techniques are magpi, mathieu, arap, snodgrass, mustard, and barcat, among which mathieu and snodgrass are the most commonly used techniques.(1,2) in a study by hakim et al, mathieu technique results with and without urethral stenting were compared in 336 cases of anterior hypospadias. no significant difference was seen in fistula formation (2.63% vs. 2.7%) and total surgical complications rate (2.63% vs. 3.6%) between these two groups. they concluded that hypospadias repairing success rate using mathieu technique, does not depend on stenting.(3) retik and colleagues used dartos muscle flap to cover neourethra in 204 patients who were operated on table 1. comparison of the patients' characteristics and the outcomes of surgical techniques snodgrass mathieu p values number of patients 15 18 mean age (years) 6.88 ± 2.16 7.26 ± 3.01 0.75 mean operative time (minutes) 106.11 ± 23.04 94 ± 26.06 0.16 mean hospital stay (days) 4.55 ± 1.29 3.93 ± 1.86 0.13 mean stenting duration (days) 5.11 ± 1.56 5.06 ± 1.31 0.72 break down (%) 0 0 meatal stricture (%) 6.66 0 0.28 fistula (%) 13.32 5.55 0.45 success rate (%) 80.02 94.45 0.20 snodgrass and mathieu techniques in hypospadias repair30 by mathieu technique. using this method, no fistula formation was seen and success rate was 98%.(4) in sariyuce and coworkers' study on 52 patients who were operated on using modified mathieu technique, they used delicate instruments and surgical materials and a 2.5-fold magnification. complication rate was 5.8% (3 patients) and fistula formation rate was 1.9% (1 patient). hence, they concluded that anterior hypospadias repairing, using mathieu technique and delicate instruments, is completely successful.(5) uygur and colleagues repaired hypospadias in 197 patients using mathieu technique in a period of 15 years and evaluated factors resulting in undesirable consequences. previous surgical history, presence of chordee or torsion, circumcision, flap length, suture material type, and suturing technique were analyzed as prognostic factors. they divided the 15-year period into three 5-year periods and success rate was compared among these three groups. flap length (less than 20 mm or more), suture material (monofilament or multifilament), suture material size (6-0 or 5-0) were recognized as the most effective factors on surgical success (p <0.05). fistula formation rate was 52%, 28%, and 11% in these three periods, respectively (p <0.01). however, in multivariate analysis, only time period difference was significant. consequently, this study suggests that surgeon's experience is a very important factor in success rate of hypospadias repairing, and they recommend to the surgeons not to change their technique unless they are familiar enough with another technique.(6) holland et al performed a study on 59 patients with a mean age of 13 months, using snodgrass technique, and followed them for 9 months. glandular meatus, conic form of glans, steady urinary outflow, fistula, and meatal stenosis were reported in 97%, 98%, 89%, 10%, and 5% of cases, respectively. appearance and functional results were reported to be acceptable.(7) decter et al performed a study on 197 patients and reported that fistula was seen in 6.4% of patients for whom adjacent tissue had been used to cover urethroplasty, and it was seen in 0.8% of those for whom pediculated tissue had been used. they concluded that in case of using snodgrass technique, fistula formation is very rare if we use vascularized pedicle to cover neourethra, and snodgrass method is the best technique for hypospadias repairing.(8) in a study by gurdal et al, they analyzed longterm functional and cosmetic results of snodgrass technique in anterior and mid-penile hypospadias repairing in 70 patients. mean follow-up period was 3.1 years and uroflometry was performed in all patients. all of the patients had a normal appearance of penis after operation and proportional meatal stenosis was seen in just 1 patient in whom meatomy was done. they concluded that snodgrass is a successful technique with acceptable cosmetic results.(9) in some studies, these two techniques were compared with each other. for example, in the study by imamoglu et al, 56 patients were operated on using snodgrass technique (32 patients experienced primary repairing and 24 experienced secondary repairing) and 54 patients were operated on using mathieu technique (33 primary repairing and 21 as secondary repairing). they were followed for 24 months. these two groups had no significant difference demographically. meatal stenosis, fistula formation, wound dehiscence, and flap necrosis were reported in 2, 4, 2, and 2 patients with mathieu method, and 5, 4, 3, and 0 patients with snodgrass method, respectively. wound dehiscence and flap necrosis were the rarest complications and meatal stricture was the most common complication in patients who were operated on using snodgrass technique and a significant statistical difference was seen. no significant difference was seen between these two groups in fistula formation rate. mean hospitalization period, stent removing time, and catheterization time were significantly lower in patients who had been operated on using mathieu technique. success rate was reported the same (78.6% in snodgrass and 77.8% in mathieu), but cosmetic appearance was obviously better in snodgrass technique. they concluded that if the urethral plate is intact, snodgrass technique will be preferable and if not, mathieu technique will be much better.(10) in the study by oswald j et al, these two techniques were compared regarding fistula formation, appearance, and duration of surgery in patients with anterior hypospadias. sixty children were divided into two groups of 30 patients. operative time was much shorter in snodgrass technique (75 minutes vs. 110 minutes) (p <0.05). three patients experienced complications in mathieu technique group moradi et al 31 (2 cases of fistulas and 1 meatal stenosis); whereas, only one patient experienced glandular dehiscence in snodgrass technique group. in all patients who had been operated on using snodgrass technique, meatal appearance was slit like; whereas, in patients who had been operated on using mathieu technique, meatus was rounded and horizontal. they concluded that snodgrass technique is accompanied by better results and more natural meatal appearance.(11) as it was shown in the above studies, the success of hypospadias repairing operation depends on flap circulation, type and quality of suture, instruments used, neourethral protecting cover, and the surgeons' experience, and both methods have had acceptable results. general agreement about glans appearance is in favor of snodgrass technique. in our study, regarding the surgeon's enough experience in both techniques, using delicate instruments and sutures (6-0 vicryl), not using cautery in order to avoid circulation defect, and hypospadias repairing basics consideration, no significant difference between these two groups was observed; however, there were two suture lines in mathieu technique. in our study, duration of surgery was a little more than that in other studies, which is maybe because of not using cautery during the operation. in the present study, penile appearance was not considered as a parameter, and as a result it was not compared between the two groups. conclusion in spite of some reports about snodgrass preference, we concluded that these techniques are as acceptable and as effective as each other for hypospodias repairing, regardless of cosmetic results; however, we need further studies and larger sample sizes to determine which is the superior technique. references 1. retik ab, borer jg. hypospadias. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.2284-333. 2. duckett jw. hypospadias. in: walsh pc, retik ab, stamey ta, vaughn ed jr, et al, editors. campbellõ's urology. 7th ed. philadelphia: wb saunders; 1998. p.2093-116. 3. hakim s, merguerian pa, rabinowitz r, shortliffe ld, mckenna ph. outcome analysis of the modified mathieu hypospadias repair: comparison of stented and unstented repairs. j urol. 1996;156:836-8. 4. retik ab, mandell j, bauer sb, atala a. meatal based hypospadias repair with the use of a dorsal subcutaneous flap to prevent urethrocutaneous fistula. j urol. 1994;152:1229-31. 5. sariyuce o, roth dr, gonzales et jr. distal hypospadias repair with meatal-based flaps on an outpatient basis. int urol nephrol. 1997;29:241-4. 6. uygur mc, erol d, germiyanoglu c. lessons from 197 mathieu hypospadias repairs performed at a single institution. pediatr surg int. 1998;14:192-4. 7. holland aj, smith gh, cass dt. clinical review of the 'snodgrass' hypospadias repair. aust n z j surg. 2000;70:597-600. 8. decter rm, franzoni df. distal hypospadias repair by the modified thiersch-duplay technique with or without hinging the urethral plate: a near ideal way to correct distal hypospadias. j urol. 1999;162:1156-8. 9. gurdal m, tekin a, kirecci s, sengor f. intermediateterm functional and cosmetic results of the snodgrass procedure in distal and midpenile hypospadias. pediatr surg int. 2004;20:197-9. 10. imamoglu ma, bakirtas h. comparison of two methods-mmathieu and snodgrass--in hypospadias repair. urol int. 2003;71:251-4. 11. oswald j, korner i, riccabona m. comparison of the perimeatal-based flap (mathieu) and the tubularized incised-plate urethroplasty (snodgrass) in primary distal hypospadias. bju int. 2000;85:725-7. editorial comment accomplished urologists, who perform hypospadias repair frequently, decide on the technique they use in each case, according to their experience with different surgical methods and also to the anatomical condition and associating factors in each case. for instance, the type of urethral plate or its dept and width, especially on glans site is decisive; in cases with shorter width, snodgrss technique is more helpful. eventually, regarding the prevalence of hypospadias, a larger sample is needed to justify the success of this surgical repair method. hamid arshadi department of urology, tehran university of medical sciences vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2032 sexual dysfunction and infertility changing concepts in microsurgical pediatric varicocelectomy: is retroperitoneal approach better than subinguinal one? massimiliano silveri,* francesca bassani, ottavio adorisio purpose: to compare and to assess two different microsurgical “lymphatic-sparing” techniques (subinguinal/inguinal vs. retroperitoneal) used for the treatment of a pediatric and adolescent varicocele in terms of success rate, complications and mean operative time. materials and methods: a retrospective study included 54 consecutive patients affected by a varicocele and treated with a microsurgical (loupes – operating microscope) magnification. thirty-four out of 54 (group 1) underwent subinguinal ligation with the help of loupes magnification (× 3); 20 out of 54 (group 2) underwent retroperitoneal (palomo like) ligation with preservation of lymphatics and with the help of an operating microscope (× 6 to 10). the two groups were homogeneous in terms of mean age, clinical and color doppler ultrasound grade of disease. preand post-operative testicular volume was measured in all cases. all the procedures were performed under general anesthesia and in an outpatient basis. results: mean post-operative follow-up time was 23.6 months. in group 1 we observed 3 (8.8%) early complications (wound’s infection, transient hydrocele), 2 (5.8%) recurrences and 1 (2.9%) major complication (atrophy of the testis). mean operative time was 45 ± 6 min. in group 2 we did not observe complications and/or varicocele recurrence and mean operative time was 38 ± 7 min. comparison of mean operative time between the two groups resulted statistically significant differences (p < .05) such as the difference in testicular “catch-up” growth volume between preand post-operative evaluations. conclusion: retroperitoneal microsurgical “lymphatic-sparing” varicocelectomy is safe and effective method. in our experience, it is preferable, in the pediatric and adolescent patient, to the subinguinal/inguinal approach in terms of success rate, complications and operative time duration. keywords: pediatrics; varicocele; therapy; physician's practice patterns; lymphatic vessels; postoperative complications; retrospective studies. introduction whilst there is general agreement in considering varicocele as a major cause of male infertility, there is still no consensus on what might be the best treatment method. published studies(1-5) comparing more than a technique applied (laparoscopy, microsurgery, interventional radiology) have definitively shown that microsurgical subinguinal or microsurgical inguinal procedures offer the best outcome in terms of increased fertility, decreased postoperative complications and recovery time. furthermore, microscopic varicocelectomy is safe and effective even in pediatric age.(6-8) friedman and colleagues reported(9) a simple modification of the classical palomo technique in which a successful alternative method to correct a varicocele was obtained using the magnification of an operating microscope in the retroperitoneum, and so sparing the lymphatics. in this retrospective study, we compared two different microsurgical techniques employed in a pediatric population (the subinguinal microscopic varicocelectomy and the retroperitoneal microscopic one) in order to assess, respectively, success rate, complications and mean operative time. materials and methods we retrospectively reviewed the medical records of 54 consecutive patients (mean age 14.3 years, range 8-18 years) with clinical grade ii/iii varicocele who underwent microsurgical varicocelectomy performed by the same surgeon. thirty-four patients (group 1) underwent subinguinal microsurgical ligation with the help of loupes magnification (× 3) whilst 20 patients (group 2) underwent retroperitoneal microsurgical ligation with an operating microscope (× 6 to 10). the two groups were homogeneous in terms of mean age, clinical and ultrasonographic grade of disease according to sarteschi and colleagues.(10) all the procedures were performed under general anesthesia and in an outpatient basis. indication for surgery was testicular hypotrophy. all patients with a difference in testicular volume greater than 2 ml or ≥ 15% on the affected side were included in this study. we did not obtained semen data because our patients were too young to be assessed using a semen analysis. department of surgery, bambino gesù children’s research hospital, via torre di palidoro 00050, palidoro, rome, italy. *correspondence: department of surgery and transplantation, center bambino gesù children’s research hospital, via torre di palidoro 00050, palidoro, rome, italy. tel: +39 668 593358. fax: +39 668 593373. e-mail: massimiliano.silveri@gmail.com. received august 2014 & accepted december 2014 operative technique group 1. the surgical approach consisted of a small subinguinal incision without opening the external oblique aponeurosis using loupes magnification (× 3). the gonadal vessels were identified and a vessel loop passed around the gonadal bundle, then all the identifiable spermatic veins were ligated while the spermatic artery and deferential vessels spared. subcutaneous and cutaneous layers approximated using absorbable stitches. group 2. twenty patients underwent a microscopic retroperitoneal varicocelectomy according to the technique described by friedman with a modification that we introduced, that is a selective ligation of spermatic veins and artery with preservation of the entire remaining bundle instead of a selective sparing of the lymphatics, as suggested by friedman, with “en bloc” ligations of the remaining bundle. all patients were under general anesthesia. through a transverse incision at the level of the anterosuperior iliac spine, the external fascia incised and internal oblique and transversalis muscles split, the gonadal bundle was easily identified and externalized at the level of the skin incision (figure 1). with the aid of an operating microscope (figure 2) and under high magnification (× 6 to 10), spermatic veins and artery were identified, dissected and the entire remaining bundle repositioned. muscles and skin approximated using a running 4.0 absorbable stitch. all the procedures were on an outpatient basis. statistical analysis description of population and parameters has been reported as mean values with standard deviation (sd). a comparison among the two study groups regarding the preoperative and postoperative parameters was done using the student’s t-test. statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0 was used for statistical analysis. values of p < .05 were considered significant. results mean postoperative follow-up time was 23.6 months. in group 1, we observed 3 (8.8%) early complications (wound’s infection in 2 cases and transient hydrocele in 1 case). in one case (2.9%), we observed a persistence of varicocele, that needed a redo varicocelectomy and in another one a major complication (testicular atrophy) occurred (table 1). mean operative time was 45 ± 6 min in group 1 while in group 2 was 38 ± 7 min. this difference was statistically significant (p < .05). in the “retroperitoneal” group we did not observe early, late complications and/or recurrence. in both group no cases of postoperative scrotal hematoma was detected. the difference in terms of early and late complications was not significant (p < .05). the preoperative volume of left testis was 5.1 ± 3.2 ml in group 1 and 5.4 ± 3.1 ml in group 2. this difference was not statistically significant (p > .05). postoperative volume of the affected testis between the two groups was respectively 7.6 ± 3.4 and 9.6 ± 4.5 ml. this difference was statistically significant (p < .05). the difference in testicular volume between preand post-operative in both groups resulted statistically significant too (p < .05) (table 2). discussion the increasing rate of varicoceles diagnosed in pediatric patients and the clear benefit of the early intervention in terms of semen quality justify the increasing number of surgical procedures performed in prepubertal age. (3,11) varicocele has an adverse effect on the histologic, endocrine and biochemical testis function(12) and is considered as a major cause of male infertility. however, not all men with varicocele are infertile and require a treatment. operative treatment should be reserved to those cases in which a decreased testicular size and/or altered semen quality are observed even considering the fact that varicocele may decrease the potential for fertility in the affected men in the future.(13) the effects of varicocele are, indeed, long term and progressive, leading to alterations figure 1. the small incision at the left flank with exteriorization of the gonadal bundle. variables group 1 group 2 p value mean operative time (min) 45 ± 6 2 38 ± 7 < .05 mean testicular volume (ml) preoperative 5.1 ± 3.2 5.4 ± 3.1 > .05 postoperative 7.6 ± 3.4 9.6 ± 4.5 < .05 table 2. clinical data in study groups. complications group 1 group 2 wound infection 2 0 hydrocele 1 0 testicular atrophy 1 0 persistence 1 0 table 1. complications in study groups. figure 2. the operating microscope is essential in the retroperitoneal lymphatic-sparing procedure. microsurgical pediatric varicocelectomy-silveri et al sexual dysfunction and infertility 2033 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2034 in semen quality and decrease in testicular volume.(1416) current guidelines state that adolescent varicoceles should be treated when reduced ipsilateral testicular size is observed or upon detection of testicular or semen abnormalities.(17) most studies regarding varicocelectomy in adolescents demonstrate either an improvement in testicular size or semen quality following the surgery. (13,18) noteworthy is the fact that varicocele has been associated with a damaged dna indicating important spermatogenic alterations and suggesting that early treatment is mandatory.(13) as we know, many surgical and non-surgical challenges are proposed as a therapeutic option. nowadays, the most popular varicocelectomy methods include the ivanissevich technique, the palomo one, the microsurgical, the laparoscopic and the embolization techniques. postoperative hydrocele formation and recurrence are the most frequent complications. between the various surgical options the subinguinal approach seems to offer the best outcome in terms of hydrocele formation and recurrence but the duration of the operation is usually longer.(19) microscopic inguinal or subinguinal approach has to be considered as a viable option for adolescent varicocele treatment. the microsurgical low inguinal or subinguinal approach was reported in the adult infertility literature as the method with the highest success rate (99%) and the lowest morbidity (no hydrocele). laparoscopic varicocelectomy is a good option in experienced hands. transvenous percutaneous varicocele treatment has the advantages of a quick recovery and minimal pain. the success rate changes from 89% to 95% with approximately 6 % of complications, in addition to the issue of radiologic exposure of the testes. alkandari and colleagues(19) studied 120 patients with 147 varicocelectomies performed using three different techniques. the recurrence rate was 2% (1 patient) with microscopic subinguinal varicocelectomy and 13% (7 patients) and 18% (9 patients) with open inguinal and laparoscopic methods, respectively. this report was statistically significant in favor of microscopic subinguinal varicocelectomy. in our study, both techniques have proven to be successful in terms of effectiveness. in the “subinguinal” group a major complication occurred, consisting of testicular atrophy and probably caused by a ligation of the spermatic artery. in the same group a case of recurrence occurred. this patient underwent a successful redo microsurgical procedure, with retroperitoneal approach, after performing a diagnostic venography. in group 1, three minor complications (2 wound infections and 1 transient hydrocele) occurred. no major or minor complications occurred in group 2. conclusion so, both by a careful review of the literature that according to our experience, microsurgical open techniques appear to be safe and effective. in the context of the microsurgical lymphatic sparing techniques and in our experience in the pediatric and adolescent patient, the retroperitoneal approach with the aid of an operating microscope seems to be safer and more effective in respect to subinguinal microsurgical especially in terms of both postoperative volume increase and mean operative time. moreover, despite the difference was not statistically significant, retroperitoneal approach appears to be burdened by a lower complications rate. conflict of interest none declared. references 1. abdulmaaboud mr, shokeir aa. treatment of varicocele: a comparative study of conventional open surgery, percutaneous retrograde sclerotherapy, and laparoscopy. urology. 1998;52:294-300. 2. pintus c, rodriguez matas mj, manzoni c, nanni l, perrelli l. varicocele in pediatric patients: comparative assessment of different therapeutic approaches. j urol. 2001;57:154-7. 3. kass e, marcol b. results of varicocele surgery in adolescents: a comparison of techniques. j urol. 1992;148:694-6. 4. riccabona m, oswald j, koen m, lusuardi l, radmayr c, bartsch g. optimizing the operative treatment of boys with varicocele: sequential comparison of 4 techniques. j urol. 2003;169:666-8. 5. bansal d, riachy e, defoor wr, et al. pediatric varicocelectomy: a comparative study of conventional laparoscopic and laparoendoscopic single-site approaches. j endourol. 2014;28:5136. 6. minevich e, wacksman j. inguinal microsurgical varicocelectomy in the adolescent: technique and preliminary results. j urol. 1998;159:10224 7. silveri m, adorisio o, pane a, colajacomo m, de gennaro m. subinguinal microsurgical ligation. its effectiveness in pediatric and adolescent varicocele. scand j urol nephrol. 2003;37:53-4. 8. schiff j, kelly c, goldstein m, schlegel p, schelgel p, poppas d. managing varicoceles in children: results with microsurgical varicocelectomy. bju int. 2005;95:399-402. 9. wong j, chan s, pagala m, friedman s. lymphatic sparing microscopic retroperitoneal varicocelectomy: a preliminary experience. j urol. 2009;182:2460-3. 10. sarteschi lm, bertozzi a, chiechi a, et al. tridimensional ultrasonography in andrology. arch ital urol androl. 2000;72:168-73. 11. parick fr, kamat sa. computer-assisted semen analysis parameters in men with varicocele: is surgery helpful? fertil steril. 1996;66:440-5. 12. borruto fa, impellizzeri p, antonuccio p, et al. laparoscopic vs open varicocelectomy in children and adolescents: review of the recent literature and meta-analysis. j pediatr surg. 2010;45:2464-9. 13. lacerda ji, del giudice pt, da silva bf, et al. adolescent varicocele: improved sperm function after varicocelectomy. fertil steril. 2011;95:994-9. 14. macleod j. seminal cytology in the presence of microsurgical pediatric varicocelectomy-silveri et al varicocele. fertil steril. 1965;16:735-57. 15. lipshultz li, corriere jn jr. progressive testicular atrophy in the varicocele patient. j urol. 1977;117:175-6. 16. salem hk, mostafa t. preserved testicular artery at varicocele repair. andrologia. 2009;41:241-5. 17. practice committee of the american society for reproductive medicine. report on varicocele and infertility. fertil steril. 2006;86(5 suppl 1):s93-5. 18. steeno o, knops j, declerck l, adimoelja a, van de voorde h. prevention of fertility disorders by detection and treatment of varicocele at school and college age. andrologia. 1976;8:47-53. 19. al-kandari a, shabaan h, ibrahim hm, elshebiny yh, shokeir aa. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology. 2007;69:41720. microsurgical pediatric varicocelectomy-silveri et al sexual dysfunction and infertility 2035 reconstructive surgery boomerang technique, the buccal mucosal grafting harvesting model for long urethral stricture urethroplasty: a case series jalil hosseini1, morteza fallahkarkan2,3, hojjat salimi4*, saleh ghiasy5 introduction urethral stricture disease is a complicated condi-tion representing a challenging management(1-4). during the past two decades, buccal mucosal grafting (bmg) has gained worldwide attention for urethroplasty(5-7). for the first time in 1894, sapezhko performed urethroplasty for four patients by using mucosal grafts from the lip and mouth(8). however, the first study describing mucosal grafts in adult patients with urethral strictures was published in 1993 by el-kasaby et al(9). in the aforementioned articles, the oral mucosa was harvested from the mucosal membrane of the lower lip(10). purpose: currently, three methods are implicated in cases of long urethral stricture including harvesting buccal mucosa of inner cheeks, harvesting lip mucosa and finally lingual mucosal graft. this study evaluated the feasibility, safety and morbidity of our “boomerang shape” technique used for graft retrieval from the inner cheeks to repair long urethral defect cases which are usually 12-15 cm in length and 2.5 cm in width. materials and methods: the kilner-doughty mouth retractor is inserted to give access to the donor site. initially, the internal surface of the right/left cheek is cleaned with a solution containing 10% povidone-iodine. then, stensen’s duct, located at the level of the second molar is identified and the desired size of the graft is measured and marked in a boomerang shape, 1.5 cm from the stensen’s duct and 1.5 cm from the edge of the cheek. to decrease submucosal bleeding from the harvest site, 1% lidocaine combined with a 1:100,000 epinephrine solution is injected using a 25-gauge long needle. the outlines of the graft are drawn by using a scalpel through the mucosa. then, the outlined graft is sharply dissected and removed, leaving the muscle intact. a 5-0 polyglactin continuous suture is used for the closure of the harvest site. the standard graft harvested from the cheek should be 12-15 cm in length and 2.5 cm in width. results: between 2017-2019, five adults have had their mucosal grafts harvested by the “boomerang shape” technique in our center. no donor site complications were observed. moreover, no urethral strictures or diverticulum occurred and the functional outcomes were satisfactory in all patients. conclusion: our routine technique of harvesting the buccal mucosa from the cheek is secure and easily performable by any surgeon. it has minimal incidence of intra and post-operative complications. keywords: urethral stricture; urethral reconstruction; buccal mucosa graft; boomerang technique; lingual mucosal graft 1professor of urology. infertility and reproductive health research center (irhrc), shahid beheshti medical science university, iran. 2resident of urology. laser application in medical science research center, shahid beheshti university of medical sciences, tehran, iran. 3resident of urology. urology and nephrology research center (unrc), department of urology. shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 4fellowship of reconstructive urology. infertility and reproductive health research center (irhrc), shahid beheshti medical science university, iran 5resident of urology. shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: fellowship of reconstructive urology. infertility and reproductive health research center (irhrc), shahid beheshti medical science university, iran. . tel & fax: +98 2122736386, mobile +98 9133135266. e mail: salimi_hojat@yahoo.com. received august 2019 & accepted february 2020 in 1996, morey and his colleague developed a novel approach in applying bmg for urethral reconstruction by harvesting graft from the cheek. they recommended the use of a steinhauser mucosal retractor to improve access to the donor site and mark the desired area for graft retrieval which usually measured to 2.5 cm wide and 5-7 cm long(11). this technique was later completed and updated in 2014 by barbagli et al(12). currently, three approaches are implicated in cases with long urethral strictures: harvesting the buccal mucosa from both inner cheeks, from lip mucosa, and lingual mucosal graft (lmg)(13). however, there are limitations urology journal/vol 17 no. 3/ may-june 2020/ pp. 289-293. [doi: 10.22037/uj.v0i0.5534] associated with harvesting grafts from lip and lingual mucosa including tightness of the mouth, motor deficits, limited size of the graft, lip vermilion eversion (14,15), scarring and lip retraction(16), numbness in the operative area of tongue, parageusia, slurred speech, and difficulty in tongue protrusion(17,18). on the other side, the thick, elastin-rich, non-keratinized epithelium and highly vascularized lamina propia of the buccal mucosa and the hands of a urologist familiar with bmg harvesting procedures offers a superb setting for reconstructive surgery(19). the advantage of long bmg harvesting for treating long urethral strictures includes fewer complications of bilateral donor site, reciprocal preservation for probable future surgeries, and also reduced urethral complications such as fistula and stenosis due to graft gap removal between the two separate mucosae. the present study aimed to evaluate the feasibility, safety and morbidity of our “boomerang shape” technique for graft retrieval from the inner cheeks in patients with long urethral defects. materials and methods three days prior to surgery, the patient undergoes oral cleansing with chlorhexidine mouth wash and then normal saline serum irrigation is performed until three days after surgery. a day before surgery, antibiotics are administered to patients and are continued for three days after surgery. the patient is intubated through the nose, allowing the mouth to be completely free. before the start of graft harvest, an oropharyngeal pack is placed in order to prevent aspiration of blood from bleeding mucosal edges. surgical technique after stabilizing the donor site with the kilner-doughty mouth retractor, the internal surface of the left/right cheek is prepared and cleaned with a solution containing 10% povidone-iodine. then the bobcok forceps are placed along the outer edge of the cheek to stretch the buccal mucosa. after recognizing the stensen’s duct which is placed at the level of the second molar, the desired graft size is measured and marked in a boomerang shape; 1.5 cm from the stensen’s duct and 1.5 cm from the edge of the cheek (figure 1. a, b &c). to decrease bleeding from the submucosa, 1% lidocaine combined with 1:100000 diluted epinephrine solution is injected using a 25-gauge long needle. after allowing 10 minutes for homeostasis, the outline of the graft is marked with a scalpel through the mucosa. subsequently, the outlined graft is sharply dissected and removed, leaving the muscle and fat intact. after carefully inspecting the donor site for bleeding, a 5-0 polyglactin continuous suture is used for closure (figure1. c). then the oropharyngeal pack is removed at the end of the surgery and an ice bag is placed on the cheek for 24 hours to decrease pain and hematoma formation. patients are treated with cold clear liquid diet on the first day post-surgery before advancing to a regular diet on the next day. the graft is stabilized on a silicone board using insulin needles. after watchful defatting, the graft is tailored according to the site, length, and characteristics of the stricture. the standard graft harvested from the cheek (in minimal stretch) is 12-15 cm in length and 2.5 cm wide (figure 2. a, b & c). ethical considerations boomerang technique, buccal mucosal grafting for urethroplasty-hosseini et al. figure 1.a. schematic boomerang shape graft. b. boomerang shape graft. c. harvesting site closure. figure 2. a and b. defatted buccal mucosa graft (bmg). c. buccal mucosa grafted as ventral onlay. reconstructive surgery 290 this study was reviewed and approved by the research ethics committee of shahid beheshti university of medical sciences. full written informed consent were obtained from every patient before inclusion into the study. results during a period of two years (from june 2017 to june 2019), boomerang shape bmg urethroplasty was performed for five adults with complex long urethral defects. table 1 shows the baseline characteristics of patients. to date, no donor site complications including postoperative hemorrhage, hematoma, infection, undue discomfort, and lip or cheek malformation have been reported. moreover, in all patients, the open posterior regions of the donor site entirely healed within 2 weeks after surgery (figure. 3). also, no urethral strictures or diverticulum were noted and the functional outcomes were satisfactory in all patients. discussion the utilization of buccal mucosa grafts for urethral reconstruction is becoming more and more popular in the clinical setting(6,11,20-22). however, despite its many theoretical advantages, the lining of the oral cavity is limited. thus, careful selection of the intra-oral donor site and applying a well-conceived harvesting technique is gaining more importance in order to acquire grafts with adequate dimension, decrease the number of circumferential suture lines, and reduce oral complications(15,23). the two most frequent sites of oral mucosa (om) harvest for urethral repair are the mucosa from the inner cheek and the mandibular labial alveolar region(24). the prevalence of postoperative oral complications following om harvest is still a controversial and challenging issue since most of the studies in literature do not report complications associated with each harvesting method individually and also do not provide details about the graft shape and size. nevertheless, in a few studies, om harvest was related to oral complications such as numbness, tension of the mouth, and motor deficits(25-27). an overview of published data revealed no significant difference between the two donor sites, cheek or lip, in terms of complications and a morbidity rate of 3% to 4% for both sites. harvest from the cheek is more commonly related to scarring and contracture due to the buccinator muscle underlying this site(25). however, labial harvest can affect mental nerve function leading to perioral numbness and other complications(27). in case of outsized urethral defects exceeding six cm, due to the limited size of buccal mucosa graft, other methods should be applied. in this regard, tissue-engineered buccal mucosa might seem a promising alternative (28,29). nonetheless, clinical data on the first human series showed that this approach was not without complications, specially fibrosis, infection and contraction (30). also, inconclusive results were observed in a number of studies(31). lingual mucosa (lmg) is another type of graft used for urethral reconstruction(32). lmg is readily available, easy to harvest, and can adapt well to a wet environment. these features make it suitable for substitution urethroplasty(33). the downside is that the graft harvested from the tongue is thinner, more fragile, and more delicate to handle compared to a graft from the cheek (34). also, since the series of patients treated by lmg is limited with a short follow-up time, it is not possible to draw any conclusions regarding the long-term outcomes of urethroplasty using lmg(32). limited studies with inconclusive outcomes reported as case series suggested combined tissue transfer techniques such as fasciocutaneous flap combined with buccal mucosa, bladder epithelium or skin grafts to repair long and multi segmented urethral strictures(35-37). in our technique, the buccal mucosa harvest is not initially tubular, however, it transforms into a tube-shape appearance through an indwelling catheter left in place table 1. patients’ characteristics. age stricture cause stricture previous donor site urethroplasty length(cm) intervention complications*** outcome*** case 1 34 bxo* 11 dilatation none**** satisfactory***** case 2 28 std** 9 internal none satisfactory uretrotomy, dilatation case 3 41 std 10 dilatation none satisfactory case 4 58 instrumentation 9 dilatation none satisfactory case 5 21 failed hypospadias 10 failed skin none satisfactory repair flap repair *balanitis xerotica obliterans; **sexually transmitted disease; ***mean 11 month follow up; **** numbness, tightness of the mouth, salivator ychanges, motor deficits, scarring and lip deviation; ***** patent without stricture and diverticulae figure 3. the donor sites entirely healed within 2 weeks after surgery. boomerang technique, buccal mucosal grafting for urethroplasty-hosseini et al. vol 17 no 03 may-june 2020 291 for an adequate period of time. moreover, the graft is evenly expanded so that when tubularizing the spongy tissue, the lumen’s caliber is not reduced by folding the graft on itself. in our initial experience, patients who underwent bmg had no oral-related complications, although the duration of follow-up was short. the benefits of this method after ensuring stensen’s duct is not damaged includes intact oral mucosa on the contralateral side for possible future surgeries, availability of the appropriate length of graft for the treatment of long stenosis, and fewer side effects in the donor site and the urethra. the ideal surgical technique should be simple, safe, reliable, easily repeatable by any surgeon, and should be readily performed with currently available surgical instruments. we believe that the technique introduced in this article meets all of these criteria. conclusions to retrieve grafts with satisfactory dimensions, decrease number of circumferential suture lines (required for a neourethra) and reduce oral complications, careful selection of the intra-oral donor site and a well-conceived harvesting technique is essential. our routine technique of harvesting the buccal mucosa from the cheek in a boomerang-shape is secure and easily repeatable by any surgeon. it is also associated with insignificant rates of intraand post-operative complications and good patient satisfaction. however, larger cohort studies with more prolonged follow-up periods are required to confirm these findings. references 1. fallahkarkan m, razzaghi mr, karami h, ghiasy s, tayyebiazar a, javanmard b. experience of 138 transurethral urethrotomy with holmium: yag laser. j lasers med sci.. 2019;10:104-7. 2. razzaghi mr, karkan mf, ghiasy s, javanmard b. laser application in iran urology: a narrative review. j lasers med sci.. 2018;9:1. 3. santucci ra, joyce gf, wise m. male urethral stricture disease. j urol.. 2007;177:1667-74. 4. fallah-karkan m, hosseini ma, azad bk, heidarzadeh a, hosseini j. persian version of patient-reported outcome measure for urethral stricture surgery (uss-prom) questionnaire, validation and adaptation study. urol j. 2020;17: 61-7. 5. hosseini j, kaviani a, mohammadhosseini m, rezaei a, rezaei i, javanmard b. fistula repair after hypospadias surgery using buccal mucosal graft. urol j. 2009;6:19-22. 6. hosseini j, kaviani a, hosseini m, mazloomfard mm, razi a. dorsal versus ventral oral mucosal graft urethroplasty. urol j. 2011;8:48-53. 7. wessells h, mcaninch jw. use of free grafts in urethral stricture reconstruction. j urol. 1996;155:1912-15. 8. korneyev i, ilyin d, schultheiss d, chapple c. the first oral mucosal graft urethroplasty was carried out in the 19th century: the pioneering experience of kirill sapezhko (1857–1928). eur urol. 2012;62:624-7. 9. el-kasaby a, fath-alla m, noweir a, elhalaby m, zakaria w, el-beialy m. the use of buccal mucosa patch graft in the management of anterior urethral strictures. j urol.. 1993;149:276-8. 10. barbagli g, balo s, montorsi f, sansalone s, lazzeri m. history and evolution of the use of oral mucosa for urethral reconstruction. asian j urol. 2017;4:96-101. 11. morey af, mcaninch jw. technique of harvesting buccal mucosa for urethral reconstruction. j urol. 1996;155:1696-7. 12. barbagli g, fossati n, sansalone s, et al. prediction of early and late complications after oral mucosal graft harvesting: multivariable analysis from a cohort of 553 consecutive patients. j urol. 2014;191:688-93. 13. maarouf a, elsayed e, ragab a, et al. buccal versus lingual mucosal graft urethroplasty for complex hypospadias repair. j pediatr urol. 2013;9:754-8. 14. dublin n, stewart lh. oral complications after buccal mucosal graft harvest for urethroplasty. bju int. 2004;94:867-9. 15. eppley bl, keating m, rink r. a buccal mucosal harvesting technique for urethral reconstruction. j urol. 1997;157:1268-70. 16. castagnetti m, ghirardo v, capizzi a, andretta m, rigamonti w. donor site outcome after oral mucosa harvest for urethroplasty in children and adults. j urol. 2008;180:2624-8. 17. kumar a, goyal nk, das sk, trivedi s, dwivedi us, singh pb. oral complications after lingual mucosal graft harvest for urethroplasty. anz j surg. 2007;77:970-73. 18. xu ym, xu qk, fu q, et al. oral complications after lingual mucosal graft harvesting for urethroplasty in 110 cases. bju int. 2011;108:140-5. 19. markiewicz mr, margarone iii je, barbagli g, scannapieco fa. oral mucosa harvest: an overview of anatomic and biologic considerations. eau-ebu update series. 2007;5:179-87. 20. hosseini j, soltanzadeh k. a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran. urol j. 2009;1:94-8. 21. mirzazadeh m, fallahkarkan m, hosseini j. penile fracture epidemiology, diagnosis and management in iran: a narrative review. transl androl urol. 2017;6:158. 22. hosseini j, fallah-karkan m, rahavian a, et al. feasibility, complication and long-term follow-up of the newly nelaton based urethral dilation method, retrospective study. am j boomerang technique, buccal mucosal grafting for urethroplasty-hosseini et al. reconstructive surgery 292 clin exp urol. 2019;7:378-83. 23. andrich d, mundy a. substitution urethroplasty with buccal mucosal-free grafts. j urol. 2001;165:1131-4. 24. markiewicz mr, lukose ma, margarone je, barbagli g, miller ks, chuang s-k. the oral mucosa graft: a systematic review. j urol. 2007;178:387-94. 25. markiewicz mr, desantis jl, margarone iii je, pogrel ma, chuang s-k. morbidity associated with oral mucosa harvest for urological reconstruction: an overview. j oral maxillofac surg. 2008;66:739-44. 26. jang tl, erickson b, medendorp a, gonzalez cm. comparison of donor site intraoral morbidity after mucosal graft harvesting for urethral reconstruction. urology. 2005;66:71620. 27. barbagli g, vallasciani s, romano g, fabbri f, guazzoni g, lazzeri m. morbidity of oral mucosa graft harvesting from a single cheek. eur urol.2010;58:33-41. 28. bhargava s, chapple c, bullock a, layton c, macneil s. tissue‐engineered buccal mucosa for substitution urethroplasty. bju int.2004;93:807-11. 29. morey af. tissue-engineered buccal mucosa for substitution urethroplasty. j urol. 2005;174:1858. 30. bhargava s, patterson jm, inman rd, macneil s, chapple cr. tissue-engineered buccal mucosa urethroplasty—clinical outcomes. eur urol. 2008;53:1263-71. 31. orabi h, safwat as, shahat a, hammouda hm. the use of small intestinal submucosa graft for hypospadias repair: pilot study. arab j urol. 2013;11:415-20. 32. barbagli g, de angelis m, romano g, ciabatti pg, lazzeri m. the use of lingual mucosal graft in adult anterior urethroplasty: surgical steps and short-term outcome. eur urol.2008;54:671-6. 33. xu y-m, sa y-l, fu q, zhang j, si j-m, liu z-s. oral mucosal grafts urethroplasty for the treatment of long segmented anterior urethral strictures. world j urol. 2009;27:565-71. 34. singh o, gupta ss, arvind nk. anterior urethral strictures: a brief review of the current surgical treatment. urol int. 2011;86:1-10. 35. wessells h, morey af, mcaninch jw. single stage reconstruction of complex anterior urethral strictures: combined tissue transfer techniques. j urol. 1997;157:1271-4. 36. elliott sp, metro mj, mcaninch jw. long-term followup of the ventrally placed buccal mucosa onlay graft in bulbar urethral reconstruction. j urol. 2003;169(5):1754-7. 37. berglund rk, angermeier kw. combined buccal mucosa graft and genital skin flap for reconstruction of extensive anterior urethral boomerang technique, buccal mucosal grafting for urethroplasty-hosseini et al. strictures. urology. 2006;68:707-10. vol 17 no 03 may-june 2020 293 1629vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l long-term follow-up on the effects of sigmoid-rectal pouch for urinary diversion bin sun, jing-min yan, jian-ye li, he-qing guo, quan hong, zhi-yong yao, gao-biao zhou, guang-xin pan, xianchu li corresponding author: heqing guo, md department of urology, the general air force hospital of people's liberation army, no. 30 fucheng road haidian district, beijing 100142, china. tel: +86 1561 116 1132 fax: +86 1068 482 380 e-mail: heqingguocn@126.com received october 2013 accepted april 2014 department of urology, the general air force hospital of people's liberation army, beijing 100142, china. urological oncology purpose: the aim of this study was to investigate the long-term clinical effects of sigmoidrectal pouch for urinary diversion. materials and methods: a total of 45 patients, including 40 males and 5 females, underwent sigmoid-rectal pouch procedure. the patients aged from 38 to 70 years with a mean age of 59 years. the postoperative follow-up ranged from 6 months to 19 years with an average of 6 years. postoperative continence and voiding were analyzed, urinary reservoir pressure was measured and the complications of upper urinary tract were determined. the index of quality of life (qol) in the international prostate symptom score (ipss) was used to evaluate the degree of satisfaction to urinate. results: forty patients had slight incontinence in the early postoperative stage and could control urination well 30 days postoperatively. the volume of pouch was 270-600 ml with an average of 375 ml. the basic pressure during filling period was 6-20 cmh2o with an average 15 cmh2o, the maximum filling pressure was 15-30 cmh2o with an average 26 cmh2o. the compliance of sigmoid-rectal pouch was fine with an average of 30 (range 18-40) ml/ cmh2o. there were no severe complications such as hyperchloremic acidosis or retrograde pyelonephritis. six patients had slight hydronephrosis. the index of qol were 0-2 in 20 patients, 3 in five patients and 4 in two patients. conclusion: the sigmoid-rectal pouch operation was simple and acceptable by surgeons and patients. it may be an ideal urinary diversion for patients with muscle-invasive bladder cancer, especially for patients on whom urethrectomy should be done. keywords: reconstructive surgical procedures; urinary diversion; methods; urinary reservoirs; surgery; continent; carcinoma; transitional cell; urinary bladder neoplasms. 1630 | introduction the incidence of bladder cancer ranks 11 th among all malignant tumors in the world and ranks 7th in men, out of place in the top 10 in women.(1) in urinary tract malignant tumors, the incidence of bladder cancer ranks second, while transitional cell carcinoma accounts for 90%.(2) although most bladder cancers are non-muscle invasive, about 30% still manifest or develop into invasive cancers, requiring radical cystectomy, pelvic lymphadenectomy and urinary diversion (ud), which can improve the survival rates and reduce the chance of local recurrence and distant metastasis in patients. there are many methods of ud and mainly be categorized into noncontinent diversion, continent diversion. among those methods, orthotopic neobladder and bricker operation are most widely performed on the patients. the former could make patients to urinate near to physiological. moreover, the recurrence of cancer in residual urethra is also a concern. bricker operation is simple and more endurable, but patients have to carry urine collection bag due to abdominal colostomy. continence preserved with anus is another choice. in early operations, ureters were connected to sigmoid flexure or rectum directly and this kind of operations tends to lead to retrograde infection, hyperchloremic acidosis and hydronephrosis. in 1993, fisch reported urinary diversion in which sigmoid colon and rectum were folded to form a pouch and ureterosigmoidostomy was performed to control defecation and urination by anus (mainz pouch ii). relative to early operations, this improved operation reduces the complications and can get reasonable compliance of urinary reservoir. the continence and life quality of patients greatly improved. for summarizing the long-term clinical effects of sigmoid-rectal pouch for urinary diversion, we analyzed the clinical data of 45 patients who were performed sigmoid-rectal pouch for ud. materials and methods clinical data forty-five patients were included in our study treated by radical cystectomy for invasive bladder cancer with the urinary diversion of sigmoid-rectal pouch between june 1993 to june 2012 at the air force general hospital. data of the patients are summarized in table 1. all the cases were muscle invasive bladder cancer, which were mainly multiple bladder tumors or/and invaded bladder trigon and posterior urethra. in preoperative preparation, the sense of perianal skin was checked; digital rectal examination was conducted; barium enema was carried out to diagnose problems with rectum and sigmoid colon; at the same time, 500 ml of saline was utilized for retention enema for 1 hour to confirm that anal sphincter functioned well. this study was conducted in accordance with the declaration of helsinki and with approval from the ethics committee of the general hospital of air force. written informed consent was obtained from all participants. indications and contraindications of sigmoid-rectal pouch the indications are bladder malignancy, bladder exstrophy/ epispadias, trauma and sinus urogenitalis. the contraindications are colon cancer and polyps, and deteriorated anal sphincter function. in this study, all the patients had bladder cancers. surgical procedure after resection of bladder, prostate and urinary tract, anal canal was cannulated into anus, through which 200 ml diluted iodophor was installed into rectum and sustained for 10 min. the boundary spot between sigmoidal colon and rectum was taken as midpoint, where to fold and suture seromuscular layer adjacent to sigmoidal colon and rectum. intestinal canal was split over 20-24 cm along antimesenteric border in an inverted "v" shape. the wall of adjacent sigmoid colon and rectum was all sutured with catgut continuously till the nadir. the left and right ureters were dissociated and pulled out of the incision, and then derived to the paries medialis and posterior of sigma neobladder. ureters were pulled out of two selected entrances on the neighboring intestinal wall. from these two entrances a 2-3 cm submucosal tunnel was built downwardly. a small circular incision was built on the mucosa of lower tunnel. the ureter could go through the tunnel and the mucosa of ureteral end was connected with the intestinal mucosa. an 8 french (f) supportive silicone catheter was implanted in the ureters till the pelvis, fixed and marked, and driven out of the anus. the ends from left or right ureter were marked correspondingly to observe the urine output from left and right kidney (figure). the paries anterior of neobladder was sutured to construct the urinary reservoir, which was placed in the abdominal cavity and was fastened to the longitudinal ligaments of sacral promontory.(3) after urological oncology 1631vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l follow-up of sigmoid-rectal pouch for urinary diversion | sun et al the surgery the patient should perform ambrosia and intravenous injection with high nutrient for 5-7 days, and sustaining gastro-intestinal decompression 3-5 days. the anal tube was removed 5-7 days postoperatively and the two ureter supportive catheters were removed or self-released 10-14 days postoperatively. follow-up postoperatively, patients were evaluated at 3-month intervals for the first year, with 6-month intervals for the years 2 and 3, and annually thereafter. urodynamic tests of urinary reservoir and ultrasound of upper urinary tract were performed at six month, one, five, ten and fifteen years, postoperatively. intravenous urography (ivu) examination was conducted on the patients with hydronephrosis. hydronephrosis, as well as vesicoureteral reflux and urinary tract infections were recorded. interviews and frequency-volume charts were used to determine voiding behavior, daytime and nighttime continence. we defined daytime continence as completely dry without use of a pad and nighttime continence as completely dry with 2 or fewer voids per night. a satisfactory continence result was defined if no more than 1 pad was required during the day or night. all other cases were defined as incontinent. the european organization for research and treatment of cancer quality of life questionnaire (eortc qlq-c30) survey was utilized to estimate the general health state of the patients. in this survey, two subjective answers from the patients were referred as the most characteristic of their health state and life quality results follow-up all operations were performed successfully and there was no serious complication. the postoperative follow-up ranged from 6 months to 19 years with an average of 6 years. fourteen patients died from tumor recurrence and metastasis, and 4 patients died from cardiovascular and cerebrovascular diseases. the patients survived more than 15 years in 2 cases, 10-15 years in 4 cases, 5-10 years in 10 cases an 6 months to 5 years in 11 cases. continence and voiding after removal of anal tube, 45 patients had different degrees of daytime and nighttime incontinence in the early days. they passed urine and stools 6 to 10 times (mean 8 times) in the daytime, while 4 to 8 times (mean 5 times) at night. three months after the surgery, all the patients well controlled defecation and urination; they passed urine and stools 4 to 6 times (mean 5 times) in the daytime and 1 to 4 times (mean 2 times) at night. from 6 months on, all the patients satisfied with urinary control. good urinary control in the daytime was observed in 27 cases from six months to 15 years in follow-up. three patients required urinal pad. urinating and stools separately were achieved in 80% cases. urinary incontinence occurred in six patients when they had diarrhea and cough. table 2 demonstrates patient voiding patterns during follow-up. urodynamic testing maximum storage capacity was 270-600 ml with an average figure . a: reconfiguration of 20 to 24 cm of rectosigmoid into u shape to construct mainz ii pouch. b: submucosal tunnel technique for bilateral normal caliber ureter, bilateral ureteral stents and anal tube are drawn out extracorporeally through the anus. table 1. clinical and demographic characteristics of participants. variables values sex, no. (%) male 40 (88.9) female 5 (11.1) age (years), mean (range) 59 (38-70) histopathology, no. (%) transitional cell carcinoma 40 (88.9) adenocarcinoma 3 (6.7) squamous carcinoma 2 (4.4) radical urethrectomy, no. (%) male 32 (80) female 0.0 (0.0) 1632 | urological oncology of 375 ml (more than 500 ml was considered as reverse flow in sigmoid colon); the average filling pressure in neobladder was 26 cmh2o. the compliance of sigmoid-rectal pouch was fine with an average of 30 (range 18-40) ml/cmh2o. the maximum pressure in neobladder at urination [15-30 cmh2o (average, 26 cmh2o)] was equal to abdominal pressure at micturition. upper urinary tract there was one case of high fever complicated with unilateral hydronephrosis in the early days, which was cured by pyelostomy. in long-term follow-up, five patients had waist pain with fever and were relieved by anti-inflammatory therapy. unilateral hydronephrosis was indicated by ultrasound and ivu in six cases. early metabolic acidosis was observed in two patients who were recovered three months later. in the long-term follow-up, there was no metabolic acidosis, retrograde infection of the kidney or renal failure. qol evaluation the index of qol and general health state of the patients were evaluated by eortc qlq c-30 survey at 1 year postoperatively (table 3). secondary tumors there was no colorectal cancer in the 45 sigmoid-rectal pouch patients during follow up but one 64-year old patient was diagnosed as benign polyps of colon at the 2nd year postoperatively. the polyps were resected via a wire loop using colonoscopy. discussion the options of surgical procedures for ud are according to specific conditions of patients, such as age, complications, life expectancy and the history of pelvic operation, as well as the requirements of patients and the experience of surgeons. the ultimate goal of treatment is protecting renal function and improving qol in patients.(4) moreover, ud has not only achieved simple urine shunt and the protection of upper urinary tract, but also has reconstructed the lower urinary tract, which provides a safe, controllable method to storage and discharge urine, improves the patient's qol. currently, the most common procedure is orthotopic neobladder. however, only non-continent ud, such as bricker operation, can be applied to most patients who simultaneously underwent total urethrectomy. the patients have to carry urine collection bag lifelong due to abdominal colostomy in bricker operation, and the incidence of stoma complication is up to 24%.(5) neobladder, allowing micturition through urethra, is most mimicking physiological state, but not suitable for the patients who have urethrostenosis or undergo urethrectomy. in addition, the surgery is complex, and the incidence of early and late operation complications is up to 12-37%.(6) mainz pouch ii is confluence of urine and feces improved by fisch, which allows patients to control urination by anus. this operation could approve urinary continence, improve the quality of patients’ life and the incidence of complications is acceptable. because of the resection of all posterior urethra, the recurrence of cancer is the same as bricker operation theoretically. from 1993, we performed this operation on 45 selective bladder cancer patients and the inclusion criteria mainly included cancers in trigone of bladder, bladder-neck and men’s posterior urethra and patients expected without good compliance. for investigating the long-term effect of mainz pouch ii, we follow-up visited all patients. mainz pouch ii controls urination by anus. therefore, the function of anal sphincter was assessed in the patients before table 2. daytime and nighttime voiding patterns of 45 patients with sigmoid-rectal pouch. voiding < 3-month (mean) 3-6 month (mean) ≥ 6 month (mean) daytime times 6-10 (8) 4-6 (5) 4-6 (5) pad use (piece) 2.0 1.0 0.0 continence (%) 0.0 95.6 93.3 nighttime times 4-8 (5) 1-4 (2) 1-4 (2) pad use (piece) 2.0 1.0 0.1 continence (%) 0.0 88.9 91.1 1633vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l surgery.(2,6) all the patients in our study underwent digital rectal examination and urodynamic examination to exclude patients with dysfunction of anal sphincter. after ordinary enema and defecation, 500 ml saline with diodone was used for retention enema and imaging. we observed the shape and pathological changes of rectum and sigmoid colon, estimated rectal bladder capacity and calculated urination time controlled by anus. the pressure of anal sphincter was measured with urodynamic device after enema. although all the patients had different degrees of urinary incontinence in early time, especially at night, they could well control urination 6 months after the surgery. the longer the postoperative time lasted, the better the effect of urinary control was achieved, which was speculated to correlated with that long retention of anal tube damaged the function of anal sphincter,(6) and colonic mucosal did not adapt to the stimulation of urine, as well as anastomotic edema in the early days after surgery. the stimulation from urine reduced over time, and the function of anal sphincter gradually increased. six patients lived more than ten years and had no incontinence in the day time; mild urinary incontinence occurred only when they had diarrhea and cough. moreover, most patients passed clear urine and stools separately, which was consistent with previous reports.(7-9) the common complications of various neobladder are urinary incontinence induced by inadequate urinary control and dysuria resulted from excessive urinary control, which turns better 6 to 12 months after surgery when the capacity and compliance of neobladder apparently improve. bedwetting rate is especially high at night, which shows a huge difference in reports (0-67%). however, bedwetting rate of most orthotopic bladder at night is 20-30%.(10) possible influencing factors are, detrusor-sphincter dyssynergia; the lack of feedback between neobladder and brain arousal system when the new bladder is filling at night; the deficiency of urethra sensory controlling branch, belonging to the basin plexus of pudendal nerve, could lead to the protective reflection deficiency of external sphincter when the near-end urethra is stimulated by urine; reduced muscle tension of pelvic floor at night; nocturia (due to osmotic diuresis of neobladder at night); the neobladder filling increases the occurrence of peristaltic wave.(11,12) mainz pouch ii allows patients to control urination by anus; uriesthesis is from awareness of defecation; urinary control depends on the function of anal sphincter. all the patients in our study controlled urination well, which was probably associated with evaluation of the function of anal sphincter before surgery and the training of contraction of anal sphincter after operation. there was no dysuria or residual urine in all cases. dysuria is one of the common complications of neobladder. it is reported that 4-25% of patients need intermittent clean self-catheterization to void, which results from several reasons, including urethral angle; the opening of new bladder is not in the lowest position; allantoic wall blocks urethra opening; the patients are unable to urinate by using abdominal pressure or relaxing pelvic floor and etc.(13) the incidence of intermittent clean self-catheterization in female patients is 21-61%(14,15) due to chronic urine retention and urethral angle. moreover, constipation is avoided because urine flushes rectum. female patients do not change their habit of crouch a micturition. secondary colorectal cancer is always a concern in sigmoidrectal pouch patients. the total ileo colon tumor risk in ureterosigmoidostomy (2.58%) was significantly higher than in other continent forms of ud. (16) because the sample is small in the present study, we could not draw any conclusion on colorectal cancer rate in the 45 sigmoid-rectal pouch patients. the ideal urinary reservoir should have large capacity, low pressure and good compliance. the capacity of sigmoid-recfollow-up of sigmoid-rectal pouch for urinary diversion | sun et al table 3. qlq c-30 survey: life quality, health status and number of patients. qlq c-30 scale 1 2 3 4 5 6 7 very bad excellent no. of patients health status 1 2 14 15 11 1 1 life quality 2 2 13 15 11 1 1 key: eortc qlq-c30, european organization for research and treatment of cancer quality of life questionnaire. 1634 | tal pouch is equal to capacity of folded urinary reservoir plus rectum, and colon that has reverse flow can also be used as urinary reservoir with full bladder. however, the patients are not recommended to hold urine because it might increase the chance of retrograde acute pyelonephritis, and subsequent increase the risk of renal function deterioration.(17) micturition depends on abdominal strain instead of strong contraction of urinary reservoir. in addition, the awareness of defecation from rectal can replace bladder sensation, which is missing for orthotopic neobladder. some patients pass clear urine at most time. urinary reservoir is established by folding sigmoid-colon rectum, which is separated from the cavity of sigmoid colon and rectum after fixation upwards and backwards, and mimic colonic diverticula. the urine continuously flushes downwards, stools form in sigmoid colon and are passed after arriving rectum, which rarely retrogrades to urinary reservoir. in addition, low pressure and good compliance of neobladder comply with resistance to reverse flow of sigmoid colon, which reduces the chance of retrograde infection. in long-term follow-up, five patients had flank pain with fever caused by retrograde infection and were treated by antibiotics. due to the confluence of urine and excrement, urine and stool routine tests are not available. therefore, the diagnosis of retrograde infection stands on the symptoms, such as fever with flank pain, and sometimes nephrostomy drainage is performed as early as possible if the efficacy is not satisfying. hydronephrosis is one of the complications of ud. various anti-reflux techniques always might result in anastomotic stenosis between ureter and urinary reservoir. it is controversial with respect to ureterocystic anti reflux replantation, which includes submucosal tunneling, ureteral papilla implantation and etc. some people believe neobladder without high pressure and urinary catheterization rarely has reflex and infection, and anti-reflux techniques are not necessary to be performed. all the patients had submucosal tunneling, in which the tunnel was wide enough at anastomosis. emphasis on anti-reflux increases the chance of obstruction. there were six cases of mild unilateral hydronephrosis during the follow up interval of 3 to 6 months. the temporary hydronephrosis might be correlated to the edema of anastomotic stoma mucosa. no special therapy was applied and the hydronephrosis disappeared gradually. recently, jin and colleagues(18) has demonstrated that ureteral obstruction is the first and independent risk factor of renal function damage in the patients who survive more than 10 years after ileal conduit ud and ileal orthotopic bladder. in ileal, colonic neobladder and all kinds of intestinal bladder substitution, the incidences of pure metabolic acidosis are 5.5%, 13.3% and 11.1%, and the incidence with concomitant hyperchloremia are 5.5%, 8.9% and 7.9%, respectively. oral sodium bicarbonate is usually administered for acidosis.(19) mainz pouch ii involves less and lower intestinal canal, thus the complications occur less, which is one of the advantages. there were two cases of metabolic acidosis and hypokalemia who discontinued the 1.5 g postoperative bicarbonate daily protocol, and were corrected with oral intake of bicarbonate and potassium tablets. the incidence of metabolic acidosis and hypokalemia was lower than previous report which described high incidence of acidosis and even lethal acidosis. (7,20) this was considered to correlate with long segment of intestine and inadequate compensatory renal function. the surgery is simple and easy for surgeons to perform and for patients to accept. the procedure involves folding and suture of seromuscular layer adjacent to sigmoid colon and rectum, as well as simple submucosal tunneling for anastomosis. there is no need to intercept large segment of intestine canal and perform complex anti reflex techniques. the index of qol were high in patients.(21-23) except some male patients were not used to crouch a micturition, most patients satisfied qol in our research. the ideal ud should meet the following conditions: neobladder can independently control urination, enough capacity, low pressure, resistant to retrograde infection, without metabolic disorders, simple procedures, easy to learn and low incidence of surgical complications.(24) most pristine urochesia diversions were abandoned because of lack of aforementioned characteristics, but some improved operations can also reach satisfied effect and improve the patients’ qol. according to our follow-up, mainz pouch ii basically meets the above requirements. it may be an ideal ud technique for patients who need total urethrectomy due to tumor in urinary tract, have normal function of anal sphincter, and are unable to pass urine through urethra because of urethrostenosis. one of the most important objective of ud is to improve patients’ qol. orthotopic neobladder is the main method urological oncology 1635vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l follow-up of sigmoid-rectal pouch for urinary diversion | sun et al selected by many medical centers because it could make patients to recover physiological urination as possible. it’s long-term complications includes, urinary incontinence (2030%), ureter-intestines anastomotic stenosis (3-18%), retention of urine (4-12%), metabolic disease and etc.(25,26) some urologists think the reasonable urinary reservoir and qol improving of mainz pouch ii may be superior to orthotopic neobladder, so patients should be told the advantages and disadvantages of both operations and return the options to patients themselves if the pathogenic conditions permit. conflict of interest none declared. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics 2008. ca cancer j clin. 2011;61:69-70. 2. fleshner ne, herr hw, stewart ak, murphy gp, mettlin c, menck hr. the national cancer data base report on bladder carcinoma. cancer. 1996;78:1505-13. 3. lampel a, fisch m, stein r, et al. continent diversion with the mainz pouch. world j urol. 1996;14:85-91. 4. elmar wg, alexander r, wiking m. complications and quality of life following urinary diversion after cystectomy. eau update series. 2005;:156-68. 5. madersbacher s, schmidt j, ebele jm, et al. long-term outcome of ileal conduit diversion. j urol. 2003;169:985-90. 6. szűcs m, keszthelyi a, szendrői a, et al. investigation of anal sphincter function following mainz pouch type ii urinary diversion after radical cystectomy. int urol nephrol. 2012;44:1013-20. 7. zhvania g, mshvildadze sh, managadze g, khvadagiani g. results of radical cystectomy with mainz pouch ii diversion (single institution experience). georgian med news. 2012;211:7-13. 8. alemu mh: mainz ii pouch: continent urinary diversion, for bladder extrophy epispadia complex and irreparable vvf: a 5 year comprehensive retrospective analysis. ethiop med j. 2010;48:57-62. 9. sherwani afak y, wazir bs, hamid a, wani ms, aziz r. comparative study of various forms of urinary diversion after radical cystectomy in muscle invasive carcinoma urinary bladder. int j health sci. 2009;3:3-11. 10. hautmann re, abol-eneinh, hafez k, et al. urinary diversion. urology. 2007;69 (1 suppl):17-49. 11. ghoneim ma, shaaban aa, mahran mr, kock ng. further experience with the urethral kock pouch. j urol. 1992;147:361-5. 12. el bahnasawy ms, osman y, gomha ma, shaaban aa, ashamallah a, ghoneim ma. nocturnal enuresis in men with an orthotopic ileal reservoir: urodynamic evaluation. j urol. 2000;164:10-3. 13. steers wd. voiding dysfunction in the orthotopic neobladder. world j urol. 2000;18:330-7. 14. anderson cb, cookson ms, chang ss, clark pe, smith ja jr, kaufman mr. voiding function in women with orthotopic neobladder urinary diversion. j urol. 2012;188:200-4. 15. finley ds, lee u, mcdonough d, raz s, dekernion j. urinary retention after orthotopic neobladder substitution in females. j urol. 2011;186:1364-9. 16. hautmann re, abol-enein h, davidsson t, et al. icud-eau international consultation on bladder cancer 2012: urinary diversion. eur urol. 2013; 63:67-80 17. osawa t, shinohara n, maruyama s, et al. long-term renal function outcomes in bladder cancer after radical cystectomy. urol j. 2013;10:784-9. 18. jin xd, roethlisberger s, burkhard fc, birkhaeuser f, thoeny hc, studer ue. long-term renal function after urinary diversion by ileal conduit or orthotopic ileal bladder substitution. eur urol. 2012;61:491-7. 19. varol c, studer ue. managing patients after an ileal orthotopic bladder substitution. j br urol. 2004;93:266-70. 20. ignjatovic i, basic d. modified mainz pouch ii (sigma rectum pouch) urinary diversion: 12 years experience. acta chir iugosl. 2007;54:735. 21. dzamic z, hadzi djokic j, acimovic m, et al. modified mainz pouch ii urinary diversion and quality of life. acta chir iugosl. 2007;54:57-62. 22. romics i, riesz p, keszthelyi a, pánovics j. experiences with radical cystectomy combined with urinary diversion by ureteral sigma pouch (mainz-pouch ii) in bladder cancer patients. orv hetil. 2006;147:1691-6. 23. patrick jb, peter a, herbert h, et al. health-related quality-of-life following modified ureterosigmoidostomy (mainz pouch ii) as continent urinary diversion. eur urol. 2004;46:591-7. 24. ardelt pu, woodhouse cr, riedmiller h, gerharz ew. the efferent segment in continent cutaneous urinary diversion: a comprehensive review of the literature. bju int. 2012;109:288-97. 25. stein jp, dunn md, quek ml, miranda g, skinner dg. the orthotopic t pouch ileal neobladder: experience with 209 patients. j urol. 2004;172:584-7. 26. abol-enein h, ghoneim ma. functional results of orthotopic ileal neobladder with serous-lined extramural ureteral reimplantation: experience with 450 patients. j urol. 2001;165:1427-32. urological oncology 109urology journal vol 6 no 2 spring 2009 frequency and outcome of metaplasia in needle biopsies of prostate and its relation with clinical findings alireza abdollahi,1 mohsen ayati2 introduction: metaplasia is a reversible change in which one adult cell type is replaced by another adult cell type. our aim was to determine the frequency and outcome of metaplasia in specimens from needle biopsies of the prostate and its relation with clinical findings. materials and methods: among 1566 prostate specimens referred to 2 pathology centers of tehran, we studied on cases with a diagnosis of metaplasia, during a 2-year period. the clinical and laboratory data of the patients with metaplasia were collected, and they were followed-up for 2 years. age, serum total and free prostate-specific antigen levels, ultrasonography findings, and results of digital rectal examination were recorded at baseline and the followup period. results: ten prostate specimens (0.6%) had metaplasia, of which 6 were transitional and 4 were squamous metaplasia. serum total psa levels ranged from 0.7 ng/ml to 14.5 ng/ml, and free psa levels ranged from 0.1 ng/ml to 1.3 ng/ml in the patients with metaplasia. none of the patients developed carcinoma of the prostate during the 2-year follow-up, and no significant changes were seen in the follow-up studies. conclusion: metaplasia of the prostate are often associated with bph. clinical findings on dre and trus resemble those found in benign lesions of the prostate, such as bph. we found no sign of developing malignancy in our 2-year follow-up. however, in the differential diagnosis of this benign lesion, malignant lesions, such as squamous cell carcinoma or urothelial transitional cell carcinoma, should also be taken into consideration. urol j. 2009;6:109-13. www.uj.unrc.ir keywords: prostate neoplasms, metaplasia, needle biopsy 1department of pathology, tehran university of medical sciences, tehran, iran 2department of urology, tehran university of medical sciences, tehran, iran corresponding author: alireza abdollahi, md imam khomaini hospitals complex, keshavarz blvd, tehran, iran tel: +98 21 6119 2337 e-mail: dr_p_abdollahi@yahoo.com received september 2008 accepted april 2009 introduction during the past decade, there was a sudden increase of interest in research on diseases of the prostate. this is largely due to the recently perceived high incidence of prostatic carcinoma in different geographical areas. attention has naturally focused on premalignant, as well as malignant, lesions of the prostate. an example is the necessity of periodically evaluation of benign lesions such as metaplasia.(1) squamous and transitional epithelial metaplasia are relatively common in the prostate. they can occur as a result of infections, traumatic lesions, or infarcts. squamous metaplasia is frequently observed in men under estrogen therapy. while the squamous metaplasia is seen in the areas of the acinar and ductal epithelium, metaplasia in needle biopsies of prostate—abdollahi and ayati 110 urology journal vol 6 no 2 spring 2009 transitional cell metaplasia is characteristically found in the ductal epithelium.(1,2) metaplasia is a reversible change, in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.(3) this is cellular adaptation whereby cells sensitive to a particular stress are replaced by other cell types which are better able to withstand the adverse environment.(3) metaplasia is thought to arise by genetic reprogramming of epithelial stem cells or of undifferentiated mesenchymal cells in connective tissue.(2,3) this study was performed to determine the frequency and outcome of metaplasia in needle biopsies of the prostate, and its connection with the clinical findings, including digital rectal examination (dre), transrectal ultrasonography (trus), and serum levels of total prostate-specific antigen (psa) and free psa. materials and methods in a cross-sectional study, all prostate samples that had been sent to one of the largest pathology centers (danesh pathology laboratory) in tehran, iran and imam khomeini hospital (tehran, iran) were examined. the study was carried out for 2 years, from 2004 to 2005. all of the received needle biopsy specimens taken from the prostate were studied without any restrictions. the hematoxylin-eosin-stained histological slides were reviewed by 2 pathologists and the specimens with a diagnosis of metaplasia were determined according to the defined microscopic properties.(2) all of the patients were informed of the study protocol and provided written consent. they were examined with dre and their serum levels of total and free psa were measured. transrectal ultrasonography was carried out in the axial and sagital planes using a 7.5-mhz multiplaner transducer. sextant biopsies from the prostate were obtained using an 18-gauge biopsy gun. nineteen to 22 tissue specimens of each patient (depending on ultrasonographic observations and suspected zones) were taken, and a total of 6 to 7 cut sections from each specimen were prepared for microscopic examination. patients with metaplasia were followed up for 2 years. on a regular basis (every 6 months), they were assessed for signs and symptoms of prostate diseases and serum levels of total and free psa. they also underwent dre and trus at each follow-up visit. in case of increased psa levels or abnormal findings on examinations, biopsy of the prostate would be repeated. results of the total number of 1566 prostate specimens, 10 (0.6%) were diagnosed with benign prostatic hyperplasia (bph) with metaplasia (6 cases of transitional metaplasia and 4 cases of squamous metaplasia; figures 1 and 2). the age range of the patients with transitional metaplasia was 51 to 75 years, and the age range of patients with squamous metaplasia was 57 to 68 years (table). digital rectal examination revealed symmetric figure 1. microscopic features of prostatic epithelial transitional metaplasia (hematoxylin-eosin, × 800). metaplasia in needle biopsies of prostate—abdollahi and ayati urology journal vol 6 no 2 spring 2009 111 enlargement in all of the 10 patients. other baseline clinical findings of the patients are summarized in the table. serum total psa levels ranged from 5.5 ng/ml to 14.5 ng/ml in the patients with transitional metaplasia and from 0.7 ng/ml to 6.2 ng/ml in those with squamous metaplasia. free psa levels ranged from 0.1 ng/ml to 1.3 ng/ml in patients with transitional metaplasia and from 0.3 ng/ml to 0.7 ng/ml in those with squamous metaplasia. all prostate specimens showed mild to moderate chronic inflammation and 1 cases of the transitional metaplasia was associated with atrophy. all of the patients completed the study up to the end of the follow-up period. none of the patients developed carcinoma of the prostate during the 2-year follow-up, and no significant increases were seen in the total and free psa levels and the trus and dre findings were the same as they were at the beginning of the study. since no indication was determined, repeat biopsy of the prostate was not performed during this period. discussion given the increasing trend in the prevalence of prostate carcinoma and bph, it can be of help to detect any potential link between metaplasia and such diseases. the reason is that the development of metaplasia, followed by predictive measures and more screening, could prevent progress of carcinoma in a bid for minimizing consequences. squamous metaplasia is usually an adaptive response of marginally viable epithelial cells to infarcts.(3,4) there are no specific gross features.(4,5) since metaplastic change is a microscopic finding associated with bph, the gross feature will be that of bph. on microscopic appearance, the normal ductal and glandular epithelial cells of the prostate are transformed to squamous cells. the cells are no longer cuboidal or columnar, but flattened. these cells may show keratinization and squamous pearl formation.(5,6) squamous metaplasia in the prostate can be seen adjacent to infarcts. an infarct of the prostate is rare and is usually reported in transurethral resections of the prostate or in prostatectomy specimens.(6) in animals, such as canine, squamous metaplasia of prostatic epithelial cells results from excessive estrogenic stimulation. the most common endogenous cause of this is a functional sertoli cell tumor. exogenous administration of estrogenic compounds is another cause, but it has not been confirmed in human.(7) although rare, patients with metaplasia of the patients age, y metaplasia total psa, ng/ml free psa, ng/ml trus findings 1 68.0 squamous 6.2 0.6 symmetric enlargement 2 57.0 squamous 0.7 0.3 symmetric enlargement 3 61.5 squamous 6.0 0.4 symmetric enlargement 4 63.5 squamous 2.1 0.7 symmetric enlargement 5 73.0 transitional 11.3 0.1 symmetric enlargement 6 70.0 transitional 14.5 0.9 symmetric enlargement 7 51.0 transitional 10.2 0.9 symmetric enlargement 8 64.0 transitional 7.9 0.6 symmetric enlargement 9 75.0 transitional 5.5 0.5 symmetric enlargement with focal calcification 10 69.0 transitional 6.4 1.3 symmetric enlargement summary of baseline clinical findings in patients with prostatic metaplasia* *psa indicates prostate-specific antigen and trus, transrectal ultrasonography. figure 2. microscopic features of prostatic epithelial squamous metaplasia: islands of squamous epithelial cell replace normal cuboidal prostatic epithelial cell (hematoxylin-eosin, × 800). metaplasia in needle biopsies of prostate—abdollahi and ayati 112 urology journal vol 6 no 2 spring 2009 prostate tissue may present with acute urinary retention, consistent with a history of prostatic hypertrophy. other patients may have hematuria. also, infarct of the prostate occurs predominantly in large prostates that exhibit bph. its incidence is probably dependent on the thoroughness of the microscopic examination. in different studies on prostatic metaplasia, it has been found to be present in 0.07% of needle biopsies to 18% to 25% of cases. the size and number of the lesion are directly related to the degree of prostatic hyperplasia.(6-9) in our study, 0.6% of the samples taken from the prostate by needle biopsy were metaplasic. this wide discrepancy in the frequency of metaplasia may be a result of the method of biopsy and patient selection for biopsy. for instance, age of the patients can be an influential factor. in different studies, age range of patients with metaplasia were 57 to 84 years.(4,5) in our study, the age range was 51 to 75 years (mean, 65.2 years). in our study, metaplasia was seen in lower ages than in others, maybe due to the incidence of bph at lower ages in iran than in developed countries.(10) it is noteworthy that 2 of the our patients had hypertension, but no definite correlation could be found between this sign and metaplasia in the prostate. our patients had acute urinary retention, with markedly enlarged prostates (90 ml to 110 ml)— as in the patients of other studies. two of them had hematuria. ranges of serum total psa level in the patients were 0.7ng/ml to 14.5 ng/ml. while other studies have even reported serum psa level increases up to 287 ng/ml,(9) our measured values were below 4 ng/ml in 2 patients, between 4 ng/ ml and 10 ng/ml in 6, and above 10 ng/ml only in 2. this indicates well that in metaplastic lesions of the prostate, serum psa does not increase like in malignant lesions, and that serum total and free psa levels might be similar to those in cases of bph.(11-13) also on trus, the prostate has been seen enlarged and no sign of malignancy such as hypoechoic nodules has been observed.(14,15) nor has been seen any trace of malignancy, and we merely found the symmetric enlargement of the prostate core without any nodularity on dre. immunohistochemistry can help differentiate squamous metaplasia from squamous cell carcinoma.(16) in the differential diagnosis, squamous cell carcinoma should be taken into account; cellular properties could help us discriminate them. in our 2-year follow-up of patients with metaplasia of the prostate, no increase in the serum psa level or development of malignancy was found. a larger and longer study is required in order to be able to conclude whether metaplasia in the prostate could result in carcinoma. we recommend a prospective multicenter project with larger sample volumes be carried out with 5to 10-year follow-up to reach conclusion. conclusion metaplasia of the prostate is often accompanied by bph, and there is a direct relation between the enlargement of the gland and the incidence of metaplasia. clinical findings in association with prostatic metaplasia on dre and trus resemble those of benign lesions of the prostate, such as bph. no malignancy was detected in our series, but a larger study is needed to confirm whether or not this lesion is premalignant. when conducting differential diagnosis of this benign lesion, malignant lesions, such as squamous cell carcinoma or urothelial transitional cell carcinoma, should also be taken into consideration. conflict of interest none declared. references 1. anim jt, ebrahim bh, sathar sa. benign disorders of the prostate: a histopathological study. ann saudi med. 1998;18:22-7. 2. rosai j. prostate gland. in: rosai j, editor. ackerman’s surgical pathology. 8th ed. st louis: mosby-year book inc; 1996. p. 1221-318. 3. kumar v, abbas ak, fausto n. cell injury, adaptation, and death. in: kumar v, cotran rs, robbins sj, editors. robbins basic pathology. 7th ed. philadelphia: wb saunders; 2003. p. 3-33. 4. hu jc, palapattu gs, kattan mw, scardino pt, wheeler tm. the association of selected pathological features with prostate cancer in a single-needle biopsy accession. hum pathol. 1998;29:1536-8. 5. risbridger g, wang h, young p, et al. evidence that epithelial and mesenchymal estrogen receptor-alpha mediates effects of estrogen on prostatic epithelium. metaplasia in needle biopsies of prostate—abdollahi and ayati urology journal vol 6 no 2 spring 2009 113 dev biol. 2001;229:432-42. 6. orihuela e, pow-sang m, motamedi m, cowan df, warren mm. mechanism of healing of the human prostatic urethra following thermal injury. urology. 1996;48:600-8. 7. lasnitzki i, lucy ja. amino acid metabolism and arginase activity in mouse prostate glands grown in vitro with and without 20-methylcholanthrene. exp cell res. 1961;24:379-92. 8. chan ym, ka-leung cheng d, nga-yin cheung a, yuen-sheung ngan h, wong lc. female urethral adenocarcinoma arising from urethritis glandularis. gynecol oncol. 2000;79:511-4. 9. yang xj, lecksell k, short k, et al. does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy? pless study group. proscar long-term efficacy and safety study. urology. 1999;53:696-700. 10. safarinejad mr. prevalence of benign prostatic hyperplasia in a population-based study in iranian men 40 years old or older. int urol nephrol. 2008;40:92131. 11. namimoto t, morishita s, saitoh r, kudoh j, yamashita y, takahashi m. the value of dynamic mr imaging for hypointensity lesions of the peripheral zone of the prostate. comput med imaging graph. 1998;22:239-45. 12. cariou g, vuong-ngog p, merran s, le duc a, plainfosse mc. correlations between radiography, ultrasonography, computed tomography and pathologic findings in prostatic disease. urology. 1985;26:599-602. 13. sperandeo g, sperandeo m, morcaldi m, caturelli e, dimitri l, camagna a. transrectal ultrasonography for the early diagnosis of adenocarcinoma of the prostate: a new maneuver designed to improve the differentiation of malignant and benign lesions. j urol. 2003;169:607-10. 14. samaratunga h, yaxley j, kerr k, mcclymont k, duffy d. significance of minute focus of adenocarcinoma on prostate needle biopsy. urology. 2007;70:299-302. 15. van dieijen-visser mp, delaere kp, gijzen ah, brombacher pj. a comparative study on the diagnostic value of prostatic acid phosphatase (pap) and prostatic specific antigen (psa) in patients with carcinoma of the prostate gland. clin chim acta. 1988;174:131-40. 16. lager dj, goeken ja, kemp jd, robinson ra. squamous metaplasia of the prostate. an immunohistochemical study. am j clin pathol. 1988;90:597-601. 1471vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l vitrificationhasbroughtaboutimportantchangesincryopreservationandhumanfer-tilitypreservation.easinessandspeedandnoneedforcostlyfreezingtechnologiesarereasonsforitsrapiddevelopment.vitrificationisthesolidificationofaliquid withoutcrystallization.ascoolingcontinues,however,themolecularwavesintheliquidpermeatingthetissuedecline.finally,an"arrestedliquid"stateknownasaglassisattained.vitrificationhasbeendemonstratedtoaffordhigherpreservationforanumberofcells,including monocytes,ovaandearlyembryosandpancreaticislets.(1) thereareanumberofmajorcontestsforperformingofvitrificationfortissueengineered medicalproducts.withoutadheringtothesestandards,certainlytheprocessofvitrification willfail.thefirstoneisvitreousstate.thereisnoexplanationaboutvitreousstateinthis study.stabilityofthevitreousstateiscriticalforthemaintenanceofvitrifiedtissueintegrity andviability.inpresentstudythemethodofvitrificationhasnotbeenexplainedindetailsand itseemsmostofstandardsforvitrificationhavenotbeenconsidered.vitrificationmethodsto preservationhavesomeofthelimitationsassociatedwithconventionalfreezingmethods.(2) first,bothmethodsentaillowtemperaturestorageandtransportationconditions.neithercan bestoredabovetheirglasstransitiontemperatureforlongwithoutsignificantriskofproduct damageduetoinherentinstabilitiesresultingtoiceformationandgrowth.bothmethodsuse cryoprotectantswiththeirassociatedproblemsandnecessitateexperiencedtechnicalsupport duringrewarmingandcryoprotectantelutionphases.theveryhighconcentrationsofcryoprotectantsneededtofacilitatevitrificationarepotentiallytoxicsincethecellsmaybeexposedto thesehighconcentrationsathighertemperaturesthaninfreezingmethodsofcryopreservation. cryoprotectantscankillcellsbydirectchemicaltoxicity,orindirectlybyosmotically-induced stressesduringsuboptimaladditionorremoval.(3)uponcompleteachievementofwarming, thecellsshouldnotbeexposedtotemperaturesabove0ocformorethanafewminutesbefore theglass-formingcryoprotectantsareremoved.itispossibletoemployvitrifiedproductsin highlycontrolledenvironments,suchasacommercialmanufacturingfacilityoranoperating theater,butnotinanoutpatientoffice.thereisn’tanydataaboutabovementionedpointsin this study.(4)anotherissueisheattransfer.heattransferissuesaretheprimaryproblemfor scalingupthesuccessesinsomewhatsmalltissuespecimenstolargertissuesandorgans.the limitsofheatandmasstransferinbulkysystemsresultinnon-uniformcoolingandleadsto stressesthatmightbegincracking.infact,thehighercoolingratesthatfacilitatevitrification willtypicallyleadtohighermechanicalstresses.(5)inpresentstudythereisnoinformationon theusedmaterialpropertiesofvitreousaqueoussolutions.materialpropertiessuchasthermal conductivityandfracturestrengthofvitreousaqueoussolutionshavemanyconnectionswith theirinorganicanaloguesthathappenatnormaltemperatures.anymaterialthatisunrestricted willundergoachangeinsize(thermalstrain)whensubjectedtoachangeintemperature. additionalimportantissuethathasnotbeenaddressed,isthestressesthatarisetobilletthe differentialshrinkage.thermalstresscandefinitelyreachtheproducedstrengthofthefrozen tissueresultinginplasticdeformationsorfractures.(6)onemoremajorobstacleforperforming editorial comment on: vitrification of neat semen alters sperm parameters and dna integrity mohammad reza safarinejad m.d clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com 1472 | ofvitrificationisthetechniqueusedforwarming.thisissuealsohasbeenignoredinpresent study.thewarmingtechniqueshouldbehighlyeffectivetopreventdevitrificationandice growth by recrystallization. therationalforvitrificationofneatsemenhasnotbeenmentioned.whataretheadvantages ofvitrificationofsemeninsteadofsperm?isthereanyscientificbackgroundforthisprocedure?forvitrification,itisrecommendedthat,eventheplasmaofspermshouldberemoved. forvitrificationthespermplasmaisremoved,itmeansthatbyusingthistechniquemany infectingagentssuchashiv,hepatitisandotherviruseswillberemovedfromthesperm,and thereforetheseinfectiousmicroorganismcannotbetransmittedviasperm.hencehiv+men willhavethechancetofatherchildrenwithouttheriskofpassinginfectiousorganismstobaby andmother.afterseparationofplasmafromthesperm,thevitrifiedspermshouldbestoredin anultra-colddeepfreezeat-86ºcenvironment.thismethodhasseveraladvantagescompared toothermethods,firstthemotilityofrethawedspermincreasessignificantly(75%usingthis methodvs.31%usingconventionalmethods)secondahighernumberofviablespermcanbe achievedandthiscanresultinhigherchanceoffertilizationinarts,suchasivfandicsi.(7) however,twodecadespastthefirstlive-birthfromvitrifiedembryos,therearestillsome uncertaintiesonthesafetyofthesetechniquesanditspossibletoxiceffectsonthehealthof childrenbornfromvitrifiedembryosoroocytes.thereisfearthatuseofhighconcentrations ofcryoprotectantsmayresultingeneticorepigeneticabnormalitieswithensuinginbornmalformations.therefore,thereisnoagreementorscientificrecommendationsforthereplacementofslowfreezingmethodwithvitrificationuniversally. thetechniquesforperformingvitrificationareevolving.recentlyvitrificationofmetaphase iioocyteshasbeendescribedtoholdabilityforoocytepreservation,whichcanbevitalin countrieswherealimitednumberofoocytescanbeinseminatedandembryocryopreservation isillegal,aswellasinoocytedonationandfertilitypreservationpriortocancertreatment.(8) thetwomostcommonlyusedteststodeterminespermdnadamagearethetunelassayandthespermchromatinstructureassay(scsa).(9)thetunelassayhasneverbeen adjustedforusewithhumanspermatozoaandlowernormalthresholdvalueshavenotbeen obviouslyrecognized.dnatestingbyscsahasbeenwidelystandardized.tuneltesthas notbeenstandardizedtothesamelevelasscsa.tunelassaycannotselectivelydifferentiateclinicallysignificantdnafragmentationfromclinicallyinsignificantfragmentation.the assayalsocannotdifferentiatenormaldnagroovesfrompathologicgrooves.moreover,the tuneltestdoesnotgiveanyinformationconcerningtheparticulargenesthatmaybeaffectedbydnafragmentation.thisassaycanonlydeterminetheamountofdnafragmentationthatensues,withthehypothesisthathigherlevelsofdnafragmentationarepathologic. (10)nowadays,theonlyreliabletesttodeterminespermdnafragmentationisscsa.this testhasvalidatedclinicalreferencerangeandcriteriatointerprettheyieldedresultsprecisely. usingthescsatestonecantest5,000individualspermwithahigh-precisionflowcytometer. tointerprettheresultsofscsatestdnafragmentationindex(dfi)isused,whichrepresents thepopulationofcellswithdnadamage.(11,12) finallyamajorlimitationofpresentstudyisabsenceofpicturesbothfromtunelresults andvitrifiedsperms. sexual dysfunction and infertility 1473vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l references 1. arav a, natan y. vitrification of oocytes: from basic science to clinical application. adv exp med biol. 2013;761:69-83. 2. aerts jm, de clercq jb, andries s, leroy jl, van aelst s, bols pe. follicle survival and growth to antral stages in short-term murine ovarian cortical transplants after cryologic solid surface vitrification or slow-rate freezing. cryobiology. 2008;57:163-9. 3. merino o, aguagüiña we, esponda p, et al. protective effect of butylated hydroxytoluene on sperm function in human spermatozoa cryopreserved by vitrification technique. andrologia. 2014 feb 24. doi: 10.1111/and.12246. [epub ahead of print] 4. imaizumi k, nishishita n, muramatsu m, et al. a simple and highly effective method for slow-freezing human pluripotent stem cells using dimethyl sulfoxide, hydroxyethyl starch and ethylene glycol. plos one. 2014;9:e88696. 5. steif ps, palastro m, wan cr, baicu s, taylor mj, rabin y. cryomacroscopy of vitrification, part ii: experimental observations and analysis of fracture formation in vitrified vs55 and dp6. cell preserv technol. 2005;3:184-200. 6. rabin y, podbilewicz b. temperature-controlled microscopy for imaging of living cells: apparatus, thermal analysis, and temperature dependency of embryonic elongation in caenorhabditis elegans. j microsc. 2000;199:214-23. 7. steif ps, palastro mc, rabin y. the effect of temperature gradients on stress development during cryopreservation via vitrification. cell preserv technol. 2007;5:104-15. 8. baicu s, taylor mj, chen z, rabin y. cryopreservation of carotid artery segments via vitrification subject to marginal thermal conditions: correlation of freezing visualization with functional recovery. cryobiology. 2008;57:1-8. 9. zini a, boman jm, belzile e, et al. sperm dna damage is associated with an increased risk of pregnancy loss after ivf and icsi: systematic review and meta-analysis. hum reprod. 2008;23:2663-8. 10. mitchell la, de iuliis gn, aitken rj. the tunel assay consistently underestimates dna damage in human spermatozoa and is influenced by dna compaction and cell vitality: development of an improved methodology. int j androl. 2011;34:2-13. 11. safarinejad mr. sperm dna damage and semen quality impairment after treatment with selective serotonin reuptake inhibitors detected using semen analysis and sperm chromatin structure assay. j urol. 2008;180:2124-8. 12. safarinejad mr. sperm chromatin structure assay analysis of iranian mustard gas casualties: a long-term outlook. curr urol. 2010;4:71-80. neat semen vitrification and sperm parameters | khalili et al endourology and stone disease 17urology journal vol 7 no 1 winter 2010 does age affect outcomes of percutaneous nephrolithotomy? hossein karami, mohammad mohsen mazloomfard, alireza golshan, taban rahjoo, babak javanmard introduction: the present study aimed to assess the efficacy and safety of percutaneous nephrolithotomy (pcnl) in elderly patients. materials and methods: we retrospectively reviewed 50 pcnls performed in the elderly patients (age > 65 years) carried out in our clinic from 2001 through 2007 and compared those with 248 pcnls performed in younger patients (age < 40 years) during the same period. results: no significant difference was seen in calculus burden between the two groups. the success rates (stone-free patients and patients with residual calculi < 4 mm) were 85% for the elderly patients and 90% for the younger patients (p = .45). the major composition of calculi was calcium oxalate in 58% and 66.5% of the elderly and younger groups, respectively. no significant complication was observed in the elderly group. fever without sign and symptoms of bacteremia was seen in 3 patients of each group (8.0% versus 1.2%, p = .004). the operative time was 75.0 ± 6.4 minutes and 76.0 ± 5.1 minutes (p = .25), and the mean hospital stay was 3.7 ± 0.3 days and 3.8 ± 0.9 days (p = .80) in the elderly and younger patients, respectively. conclusion: we found that pcnl in patients over 65 years was a safe and reliable technique with a stone-free rate of 85% for all types of calculi. wellcontrolled comorbidities do not increase the risk of operation. it seems that despite the higher medical risk in the elderly patients, pcnl could be safe and yields a high stone-free rate. urol j. 2010;7:17-21. www.uj.unrc.ir keywords: urinary calculi, percutaneous nephrolithotomy, aged department of urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran corresponding author: mohammad mohsen mazloomfard, md department of urology, shohada-etajrish hospital, tajrish sq, tehran, iran tel: +98 21 2271 28001-9 fax: +98 21 2271 9017 e-mail: mazloomfard@yahoo.com received april 2009 accepted august 2009 introduction extracorporeal shock wave lithotripsy (swl) and conservative management can treat efficiently most of elderly patients with urinary calculi,(1) while percutaneous nephrolithotomy (pcnl) is considered to be associated with a higher risk in elderly patients compared with swl. however, this technique is sometimes necessary for very large or complex calculi in patients with several comorbidities.(2) the number of elderly patients with urinary calculi has been growing along with the increasing life expectancy.(3) because of high-risk complications of these calculi, observation and medical therapies are no longer recommended and pcnl is inevitable.(4) the changes in cardiorespiratory reserve of elderly patients make the patients less tolerant to certain stressors such as increase in demand during the peri-operative period, bleeding or septic complications, etc. in particular, the usual prone position of pcnl may be a challenge age and percutaneous nephrolithotomy—karami et al 18 urology journal vol 7 no 1 winter 2010 to both the patient and the anesthesiologist. decrease in body reserve and comorbidities are always a concern in applying invasive treatment modalities, such as pcnl, in elderly patients.(5) in this study, we reviewed our pcnl experience in patients older than 65 years, and compared their operative and postoperative complications with those of patients younger than 40 years. materials and methods we retrospectively evaluated the records of 476 pcnls over a 7-year period from 2001 to 2007 in our referral center for the treatment of urinary calculi. fifty of the participants were in patients older than 65 years (mean, 69.2 years). we compared these patients with 248 patients younger than 40 years (mean, 31.4 years). intravenous urography was the primary imaging modality in the diagnostic approach of all the patients. the calculus burden was determined by multiplying the calculus largest length by its width in centimeters, as measured on the pre-operative plain abdominal radiography, or on the intravenous urography in cases of radiolucent calculi. the study was approved by the ethics committee of the hospital. the pcnl indications were swl failures and pelvic or caliceal calculi larger than 2.5 cm in diameter, which were the same in both the elderly patients and the younger group. patients with kidney anomalies and uncontrolled coagulopathies had been excluded. all of the pcnls were done under general anesthesia. after ureteral catheterization and securing the patient in the prone position, contrast material was injected through the ureteral catheter. then, percutaneous access was achieved under fluoroscopy guidance using an 18-gauge needle and a 0.038-inch guide wire (j tailed) by one surgeon. the nephrostomy tract was first dilated by an 8-f polyurethane dilator. after the dilator was removed, an alken guide was replaced, and then, a 30-f amplatz dilator was passed into the calyx. nephroscopy was performed to localize the fragments and extract the calculi. after extraction of all fragments of calculi, a 14-f or 16-f reentry nephrostomy tube was inserted, and the operation was terminated. an antegrade pyelography was obtained at 48 hours postoperatively, and the nephrostomy tube was clamped if no extravasation was seen. the tube was removed the next day unless there was pain or fever. the patient was discharged the same day following the removal of the tube. the two groups of the elderly and young patients were compared in terms of demographic characteristics, operative time, location of calculi, hospital stay, body mass index, changes in hemoglobin level and serum level of creatinine (3 days postoperatively compared to pre-operative value), and complications, including peri-operative bleeding (need for transfusion), adjacent organ damage, respiratory disorders (postoperative respiratory distress), and laceration of the ureter. stone-free status and residual calculus burden were determined by plain abdominal radiography and renal ultrasonography studies routinely obtained 3 months after the treatment. success rate was defined as the proportion of patients who were stone free or those who had residual calculi smaller than 4 mm. statistical analyses were performed using the independent t test, the mannwhitney test, the chi-square test, and the fisher exact, where appropriate. a p value less than .05 was considered significant. results a total of 298 patients were included in this analysis (50 in the elderly group and 248 in the younger group). the elderly group constituted 10.5% of our patients who had undergone pcnl during the study period. demographic and clinical characteristics of the patients are shown in table 1. the calculi diameter and number were not significantly different between the groups of older and younger patients (p = .71 and p = .30, respectively). eight patients (16.0%) in the elderly group and 37 (14.9%) in the younger group had previously undergone open surgery for treatment of the kidney calculus (p = .85), and 9 (18.0%) and 54 (21.8%) had undergone swl, respectively (p = .55). twenty-one (42%) of the elderly patients and 31 (12.5%) of the younger patients had comorbid conditions as noted in table 1 (p < .001). all of these conditions were age and percutaneous nephrolithotomy—karami et al 19urology journal vol 7 no 1 winter 2010 controlled and we performed pcnl with normal anesthetic conditions. the major composition of the calculi removed was calcium oxalate in 58.0% and 66.5% of the elderly and younger groups, respectively. calculus analysis results in 20.0% of the elderly and 18.5% of the younger group were not available (table 2). in terms of complications, the elderly and younger patient groups were not significantly different (table 3). in the elderly group, 2 patients received 2 units of packed cell postoperatively, one due to hypotension and hematocrit depletion and the other one based on the surgeon decision because of the intra-operative bleeding. in both groups, there were no differences between characteristic elderly patients younger patients p age, y 69.2 ± 4.1 31.4 ± 8.5 … sex male 29 (58.0) 160 (64.5) female 21 (42.0) 88 (35.5) .38 body mass index 26.7 ± 2.3 27.1 ± 1.8 .06 medical history hypertension 12 (24.0) 6 (2.4) < .001 diabetes mellitus 10 (20.0) 12 (4.8) < .001 coronary artery disease 8 (16.0) 2 (0.8) < .001 respiratory disorders 6 (12.0) 5 (2.0) .004 peptic ulcer 4 (8.0) 18 (7.3) .85 cerebrovascular disease 2 (4.0) 0 .03 calculus location superior calyx 6 (12.0) 26 (10.4) middle calyx 12 (24.0) 69 (27.8) inferior calyx 24 (48.0) 128 (51.6) renal pelvis 8 (16.0) 25 (10.0) .11 number of calculi 2.0 ± 1.1 2.1 ± 1.5 .30 calculus diameter 28.1 ± 3.3 27.4 ± 3.2 .71 hydronephrosis mild 16 (32.0) 82 (33.0) moderate 26 (52.0) 132 (53.2) severe 8 (16.0) 34 (13.7) .89 *values in parentheses are percents. table 1. demographic and clinical characteristics of older and younger patients who underwent percutaneous nephrolithotomy* calculus composition elderly patients younger patients p calcium oxalate 29 (58.0) 165 (66.5) .24 uric acid 8 (16.0) 22 (8.8) .13 calcium phosphate 2 (4.0) 10 (4.0) .90 cystine 1 (2.0) 5 (2.0) .90 unknown 10 (20.0) 46 (18.5) .80 *values in parentheses are percents. table 2. kidney calculi analysis of patients* outcome elderly patients younger patients p access superior calyx 2 (4.0) 9 (3.6) middle calyx 8 (16.0) 25 (10.0) inferior calyx 40 (80.0) 214 (86.2) .56 successful treatment 43 (86) 224 (90) .45 operative time, min 75 ± 6.4 76 ± 5.1 .25 hospital stay, d 3.7 ± 0.3 3.8 ± 0.9 .80 hemoglobin level, mg/dl before operation 12.8 ± 2.1 13.2 ± 1.1 .60 after operation 12.1± 1.9 12.5 ± 1.5 .70 change -0.65 ± 0.30 -0.58 ± 0.35 .65 creatinine level, mg/dl before operation 1.10 ± 0.30 1.04 ± 0.20 .35 after operation 1.10 ± 0.30 1.07 ± 0.20 .40 range of change -0.1 to 0.1 -0.3 to 0.5 .23 complications peri-operative bleeding 2 (4.0) 4 (1.6) .30 perirenal hematoma 0 0 … adjacent organ damage 0 1 (0.4) .60 respiratory complications 1 (2) 2 (0.8) .40 laceration of ureter 0 1 (0.4) .60 post operation fever 4 (8) 3 (1.2) .004 delay bleeding 0 0 … table 3. intraoperative and postoperative data of patients* *values in parentheses are percents. age and percutaneous nephrolithotomy—karami et al 20 urology journal vol 7 no 1 winter 2010 pre-operative and postoperative serum creatinine and hemoglobin levels (p = .23 and p = .65, respectively). peri-operative bleeding was not significantly different between the two groups, either (p = .30). in addition, the frequency of respiratory complications was not different between the two groups (p = .40). in the early postoperative period, fever without sign and symptoms of bacteremia was seen in 4 patients (8.0%) of the elderly group and 3 (1.2%) of the younger group (p = .004), who were treated with an antibiotic and conservative measures. the success rates (stone-free patients and patients with residual calculi < 4 mm) were comparable; 85% for the elderly patients and 90% for the younger patients had a successful treatment (p = .45). in both groups, the operative time (75.0 ± 6.4 minutes versus 76.0 ± 5.1 minutes, p = .25) and the mean hospital stay days (3.7 ± 0.3 days and 3.8 ± 0.9 days, p = .8) were not significantly different. discussion careful consideration must be given to the most appropriate treatment for any urinary calculus in an elderly patient. when serious medical conditions such as pulmonary or heart disease present, a high risk of potential anesthetic complications, minimally invasive therapy or observation should be done.(1) for elderly patients, swl may actually have a less satisfactory result than the other treatment modalities.(5) considering pcnl, anagnostou and coworkers suggest that a high age and its associate morbidities would not be a major concern if the surgeon is experienced enough.(6) like most previous studies on geriatric kidney calculus formers, there was a male predominance in our study.(1,2,7) however, sahin and colleagues in turkey demonstrated female predominance in their elderly pcnl candidates.(3) it was reported that the first calculus episode in patients over 65 years was significantly later than in younger patients.(5) therefore, it is reasonable to conclude that the pathogenesis of urinary calculi may be different in elderly patients.(3) stoller and colleagues found a high incidence of uric acid calculus in the elderly compared with that in the younger cohort.(1) likewise, gentle and associates reported the high rate of uric acid calculi in older patients, after retrospective review of more than 6000 patients.(8) sahin and colleagues showed the most calculus composition was calcium oxalate in 79% of patients.(3) calculi analyses were available in 80% of our patients, with the following results: calcium oxalate in 58%, uric acid in 16%, calcium phosphate in 4%, and cystine in 2% of the elderly group with insignificant differences from those in the younger patients. a long surgical procedure can impose risks to the elderly patients. the previously reported mean duration of pcnl in elderly was 60 to 130 minutes.(3,9,10) in our study, the mean operative time was 75.0 ± 6.4 minutes. this time is similar to that in younger patients or children with pcnl (89 minutes).(11) renal scintigraphy for evaluation of kidney function detected no significant harmful effects of pcnl on the kidneys.(9,10) we could not perform these studies, because of their cost, but our patients did not show any complications that could be a sign of impaired kidney function. even for the expert urologists, major complications can still occur in 1.1% to 7% of patients undergoing pcnl, and minor complications may be encountered in 11% to 25% of patients. hemorrhage is the most significant complication which has given rise to a transfusion rate reported from 1% to 10%.(12-14) although the anesthetic risks for elderly patient is more than younger patients,(15) anesthetic complications in our study were not more frequent in the elderly than in the younger patients. the overall complication rate, in the previous studies was 6% with pyrexia as the most common complication,(16,17) fairly comparable with our study results. our 86% rate of stone-free status, as stoller and associates pointed out, is certainly an acceptable outcome, especially because no long-term complications were seen in elderly populations. (1) comparing with the normal adult patients, the structural and physiological difference in the elderly populations certainly affect our management for calculus diseases. with the advance in endoscopy design and experience, age and percutaneous nephrolithotomy—karami et al 21urology journal vol 7 no 1 winter 2010 pcnl in these ages seem to be providing the same efficacy and safety as the standard adult population. conclusion the decrease in body reserve and comorbidities are always a concern in applying invasive treatment, such as pcnl, in elderly patients. regarding the low overall complication rate of pcnl in our elderly cohort and the acceptable success rate of the treatment, we can imply that this procedure is a safe and effective method in the treatment of the urinary calculi in elderly patients even when they are assumed to be high risk. conflict of interest none declared. references 1. stoller ml, bolton d, st lezin m, lawrence m. percutaneous nephrolithotomy in the elderly. urology. 1994;44:651-4. 2. dore b, conort p, irani j, et al. [percutaneous nephrolithotomy (pcnl) in subjects over the age of 70: a multicentre retrospective study of 210 cases]. prog urol. 2004;14:1140-5. french. 3. sahin a, atsu n, erdem e, et al. percutaneous nephrolithotomy in patients aged 60 years or older. j endourol. 2001;15:489-91. 4. gupta m, bolton dm, gupta pn, stoller ml. improved renal function following aggressive treatment of urolithiasis and concurrent mild to moderate renal insufficiency. j urol. 1994;152:1086-90. 5. ng cf. the effect of age on outcomes in patients undergoing treatment for renal stones. curr opin urol. 2009;19:211-4. 6. anagnostou t, thompson t, ng cf, moussa s, smith g, tolley da. safety and outcome of percutaneous nephrolithotomy in the elderly: retrospective comparison to a younger patient group. j endourol. 2008;22:2139-45. 7. serio a, fraioli a. epidemiology of nephrolithiasis. nephron. 1999;81 suppl 1:26-30. 8. gentle dl, stoller ml, bruce je, leslie sw. geriatric urolithiasis. j urol. 1997;158:2221-4. 9. wilson wt, husmann da, morris js, miller gl, alexander m, preminger gm. a comparison of the bioeffects of four different modes of stone therapy on renal function and morphology. j urol. 1993;150: 1267-70. 10. thomas r, frentz jm, harmon e, frentz gd. effect of extracorporeal shock wave lithotripsy on renal function and body height in pediatric patients. j urol. 1992;148:1064-6. 11. mahmud m, zaidi z. percutaneous nephrolithotomy in children before school age: experience of a pakistani centre. bju int. 2004;94:1352-4. 12. lang ek. percutaneous nephrostolithotomy and lithotripsy: a multi-institutional survey of complications. radiology. 1987;162:25-30. 13. lee wj, smith ad, cubelli v, et al. complications of percutaneous nephrolithotomy. ajr am j roentgenol. 1987;148:177-80. 14. matlaga br, hodges sj, shah od, passmore l, hart lj, assimos dg. percutaneous nephrostolithotomy: predictors of length of stay. j urol. 2004;172:1351-4. 15. ryall dm, dodds c. anaesthesia for urological surgery in the elderly. churchill livingstone; 1992. p. 200. 16. troxel sa, low rk. renal intrapelvic pressure during percutaneous nephrolithotomy and its correlation with the development of postoperative fever. j urol. 2002;168:1348-51. 17. rao pn, dube da, weightman nc, oppenheim ba, morris j. prediction of septicemia following endourological manipulation for stones in the upper urinary tract. j urol. 1991;146:955-60. reconstructive surgery 45urology journal vol 7 no 1 winter 2010 does tobacco consumption influence outcome of oral mucosa graft urethroplasty? rahul janak sinha, vishwajeet singh, sn sankhwar introduction: in a prospective study, outcome of oral mucosa graft urethroplasty (omgu) was assessed in patients suffering from stricture of the urethra. materials and methods: patients who underwent omgu between july 2005 and december 2007 were included in this prospective study. forty-eight patients with stricture of the urethra were divided into 2 groups of those who consumed tobacco and had poor oral hygiene and those who did not consume tobacco and had satisfactory oral hygiene. the oral cavity was inspected. the type of tobacco consumption and the duration of exposure to tobacco were noted. the mean follow-up was 18.2 months (range, 6 to 36 months). the patients were evaluated to assess the outcome of omgu. results: the final outcome was analyzed in 42 patients. thirty-one patients were asymptomatic and/or satisfied with their urinary flow rate, who were considered to have a successful outcome (73.8 %). successful outcome in patients who consumed tobacco was significantly less (58.3%) compared to that in the tobacco nonusers (94.4%; p = .008). conclusion: failure rate of omgu was higher in patients who consumed tobacco and had a poor oral hygiene, which might be due to adverse effects of these substances on the oral mucosa, leading to a poor graft quality. urol j. 2010;7:45-50. www.uj.unrc.ir keywords: urethral stricture, tobacco, smoking, lime-piper betel quid, treatment outcome, oral mucosa department of urology, chhatrapati shahuji maharaj medical university, lucknow, uttar pradesh, india corresponding author: rahul janak sinha, ms (gen surgery), mch (urology) department of urology, chhatrapati shahuji maharaj medical university, lucknow-226003, uttar pradesh, india tel: +91 941 500 3051 e-mail: rahuljanaksinha@rediffmail.com received april 2009 accepted october 2009 introduction chewing and smoking tobacco and consumption of paan (betel leaves) or paan masala (dried mixture of betel leaves with areca nut and slaked lime, consumed with or without tobacco along with other condiments) are popular in india. (1,2) the consumption of tobacco (in any form) results in poor oral hygiene and has an adverse effect on the oral mucosa.(1-4) thus, patients suffering from stricture of the urethra who consume tobacco in any form might have an unsatisfactory outcome following oral mucosa graft urethroplasty (omgu) due to poor quality of the oral graft.(1-4) we carried out a prospective study of patients suffering from stricture of the urethra to assess the impact of the quality of oral mucosa on the outcome of omgu. materials and methods patients forty-eight patients with stricture of the urethra of more than 2 cm in length underwent omgu between july 2005 and december 2007. they were included in this prospective study and their last follow-up was in june 2008. patients with a short stricture influence of tobacco on oral mucosa graft urethroplasty—sinha et al 46 urology journal vol 7 no 1 winter 2010 (< 2 cm) were excluded from the study. written informed consent was obtained from all the eligible patients. ethical clearance for this study was obtained from the institutional ethics committee and was in accordance with the declaration of helsinki. general data of all the patients e.g. name, age, sex, address and phone number were recorded for the purpose of identification and correspondence. routine laboratory and specific radiological evaluations were performed prior to surgery. oral hygiene was inspected and those with doubtful oral hygiene were referred to the dental department for further opinion. graft from these patients was only harvested if the dental department cleared these patients for omgu. of the patients, 28 were consumers of tobacco, paan, or paan masala (group 1) and 20 were not users of these substances (group 2). distribution of the patients according to the type of tobacco, paan, or paan masala consumption and the total duration of exposure are summarized in table 1. procedure ventral onlay urethroplasty was done for all the bulbar or bulbopenile urethral strictures, while dorsal onlay and modified dorsal onlay urethroplasty were done for all the strictures in the penile urethra.(5-7) in case of pananterior urethral strictures or 2 separate strictures, dorsal or modified dorsal onlay was done in the penile portion, while ventral onlay was carried out for the bulbar portion. the oral mucosa graft was harvested under general anesthesia (nasal or oral intubation) in 12 patients (7 in group 1 and 5 in group 2) and under local anesthesia in 36 patients (21 in group 1 and 15 in group 2) based on our technique. (8,9) the tongue mucosa was supplemented along with the cheek mucosa in 3 patients of group 1 and 2 of group 2, and the lower lip mucosa was supplemented in 3 patients of group 1 and 1 of group 2, due to the long length of the stricture. two surgical teams worked simultaneously with separate instruments. the penile urethra was exposed by degloving the penis with a circumcoronal incision. for proximal penile and bulbar urethral dissection, a midline perineal incision was made. the scrotum was not bivalved; a tunnel was created between penile and perineal exposure, if needed. a 16-f perurethral catheter was placed prior to closure. we do not insert a drain or suprapubic catheter on routine basis. in the postoperative phase, the patients were put on anti-erection drugs (eg, diazepam) with dosages modified according to body weight. the patients were discharged 1 week after the operation with catheters and visited after 2 to 3 weeks in the clinic, where pericatheter study was done. if no extravasation was visible, the perurethral catheter was removed and the patient was given voiding trial. if urine flow was satisfactory, the suprapubic catheter, if any, was removed later. the patients were then visited every 3 months for the rest of the study period. in case they were unable to present, then they were contacted by phone or letters. irrespective of the phone calls and letters, the majority of the patients came to the clinic for follow-up. a proforma which was prepared at the time of admission was used to document all the raw data. follow-up data was collected by an interviewer. the interviewer understood the significance and meaning of the questions and asked the questions in hindi language, which is the spoken language in the northern india. uroflowmetry with postvoid residual urine exposure to tobacco or paan type of substance number of patients < 5 years 5 to 10 years > 10 years paan masala 3 1 1 1 tobacco chewing 3 1 1 1 tobacco smoking 3 1 1 1 paan masala with tobacco chewing 6 3 2 1 paan masala with tobacco smoking 4 2 1 1 tobacco chewing and smoking 3 1 1 1 paan masala with tobacco chewing and smoking 6 4 1 1 table 1. type of tobacco or paan and duration of exposure in patients who underwent oral mucosa graft urethroplasty influence of tobacco on oral mucosa graft urethroplasty—sinha et al 47urology journal vol 7 no 1 winter 2010 measurement was done and repeated at regular intervals during the follow-up period. if the patient complained of poor flow or if his flow was less than 14 ml/sec, additional investigations including retrograde urethrography and/or cystoscopy were done. the definition of failure of urethroplasty is not consistent in the literature; for this study, failure was defined as the need to carry out any intervention or invasive procedure in the urethra following the complaint of decreased urinary flow by the patient. statistical analyses the data were analyzed using the spss software (statistical package for the social sciences, version 15.0, spss inc, chicago, illinois, usa). the mean ± standard deviations were calculated for continuous variables (age and different stricture lengths variables), and proportions (percentages) were calculated for dichotomous variables. the chi-square test was used to compare dichotomous and categorical variables, and the paired t test was used to detect significance from baseline value to follow-up time in case of continuous variables. a p value less than .05 was considered significant. results all of the 48 patients were followed up 1 month postoperatively. thereafter, 6 patients with pananterior urethral strictures were lost to followup or died of nonsurgical causes (4 in group 1 and 2 in group 2). therefore, the final outcome was analyzed in 42 patients. the mean age of the patients was 40.2 ± 14.7 years (range, 22 to 72 years) in group 1 and 32.0 ± 18.2 years (range, 12 to 68 years) in group 2. the mean age of all the patients (n = 48) was 36.6 ± 16.9 years (range, 12 to 72 years). the mean follow-up of the patients was 18.2 months (range, 6 to 36 months). the mean duration of disease in all the patients (n = 48) was 5.8 ± 4.9 years (range, 4 months to 15 years) and was comparable between the two groups. etiology was unknown in the majority of the patients (56.3%), while it was trauma in 22.9%, inflammatory disease in 10.4%, prior urethral catheterization in 6.3%, and lichen sclerosis in 4.2%, distributed comparably between the two groups. six patients in group 1 and 5 in group 2 had comorbidities, including diabetes mellitus, hypertension, hepatitis b-positive status, and ischemic heart disease at the time of admission. these comorbidities did not have any impact on the final outcome of this study. twenty patients in group 1 and 14 in group 2 had undergone one or multiple prior procedures like dilation of the urethra and optical internal urethrotomy and 7 of whom (4 in group 1 and 3 in group 2) were admitted with a suprapubic catheter in place. the mean stricture length in the patients was 9.88 ± 5.21 cm (range, 2.0 to 17.8 cm). the graft length was 10.42 ± 5.12 cm (range, 2.5 to 18.0 cm) and the graft width was 2.62 ± 0.18 cm (range, 2.3 to 3.1 cm). these measurements were similar between the patients in groups 1 and 2. the operative time was comparable between the two groups and had no significant impact on the success rate. intra-operative complications occurred in 3 patients of group 1 (increased bleeding from the recipient site, hypotension for a short duration, and tooth dislodgement, each in 1 patient) and had no impact on postoperative recovery or the success rate. thirty-one patients were asymptomatic and/ or satisfied with their urinary flow rate, which were considered to have a successful outcome (73.8%). the overall success rate was 58.3% in the patients of group 1 and 94.4% in those of group 2 (p = .008). the final outcomes based on the site of stricture and the technique of urethroplasty are outlined in tables 2 and 3, respectively. uroflowmetry at the beginning of the study could be done in 36 patients only (22 in group 1 and 14 in group 2) who were not catheterized at the time of admission and could void with a reasonable flow (patients on catheter or those with poor flow were excluded). uroflowmetry at the end of the study was done in the 31 patients (14 in group 1 and 17 in group 2) who had a successful outcome (table 4). postoperative complications were observed in12 patients (10 in group 1 and 2 in group 2). two patients in group 2 had extravasation at the time of postoperative pericatheter study, which influence of tobacco on oral mucosa graft urethroplasty—sinha et al 48 urology journal vol 7 no 1 winter 2010 healed when the perurethral catheter was kept for 2 weeks more. in group 1, stenosis of the urethra and fistula was observed each in 3 patients and decreased urinary flow was observed in 4 patients (2 had objective complaints while 2 were diagnosed following uroflowmetry). all of the patients in group 1 were declared failures as they had to undergo further intervention. in 1 patient, the stenosis was at the site of distal anastomosis; in 1, it was at the site of the proximal anastomosis and 1 patient had narrowing of the entire urethral segment. two patients required optical internal urethrotomy and 1 patient was subjected to co-axial dilation, and then all the 3 were put on clean intermittent self-catheterization. patients with fistula were kept on prolonged perurethral catheter, and then, repeat omgu at the fistula site was attempted. only 2 of the 4 patients with poor flow opted for further treatment, and they underwent co-axial dilation followed by clean intermittent self-catheterization. discussion oral mucosa urethroplasty is a well-established procedure for long strictures of the urethra, where excision and anastomotic urethroplasty is not feasible.(10-12) to date, no study has focused on the impact of tobacco or oral hygiene on the final outcome of omgu. our center is one of the largest tertiary-level referral government centers in northern india where all the urethroplasties are performed by qualified urologists with extensive training and experience in reconstructive urology. majority of the expense is borne by the hospital (government) and the patient has to spend a small amount of money. this study focused primarily on the outcome at recipient site. hence, we did not go into the details of the oral hygiene or dental history apart from judging whether the patient is an appropriate candidate for oral graft harvest or not. we asked the patient to open his mouth and assessed the oral cavity. if we thought it was unhealthy (inadequate opening probably due to sub-mucous fibrosis, whitish plaque probably due to leukoplakia, etc) or if the patient gave a history of tobacco consumption for a long period, then the patient was referred to the dentistry department and the oral graft was only taken if he was treated by the dentist. in our study, tobacco users with poor oral tobacco users tobacco nonusers stricture site number of patients successful outcome number of patients successful outcome overall successful outcome penile 3 1 (33.3) 2 2 (100) 3 (60.0) bulbar 7 5 (71.4) 5 5 (100) 10 (83.3) bulbopenile† 10 7 (70.0%) 8 8 (100) 15 (83.3) pananterior 3 0 2 1 (50.0) 1 (20.0) two separate strictures 1 1 (100) 1 1 (100) 2 (100) all 24 14 (58.3) 18 17 (94.4) 31 (73.8) table 2. final outcome of oral mucosa graft urethroplasty based on the site of stricture in users and nonusers of tobacco, paan, and paan masala* *values in parentheses are percents. †strictures mainly involved the bulbar urethra, but extended slightly into the adjacent proximal penile urethra, too. tobacco users tobacco nonusers technique number of patients successful outcome number of patients successful outcome overall successful outcome ventral onlay 17 12 (70.6) 13 13 (100) 25 (83.3) dorsal onlay 7 2 (28.6) 5 4 (80.0) 6 (50.0) all 24 14 (58.3) 18 17 (94.4) 31 (73.8) table 3. final outcome of oral mucosa graft urethroplasty based on the technique of urethroplasty in users and nonusers of tobacco, paan, and paan masala uroflowmetry tobacco users tobacco nonusers preoperative 5.14 ± 2.58 6.28 ± 3.86 postoperative 14.44 ± 3.86 21.63 ± 6.06 mean improvement* 14.49 ± 6.42 15.32 ± 3.28 table 4. pre-operative and postoperative uroflowmetry outcomes *p < .001 (paired t test) influence of tobacco on oral mucosa graft urethroplasty—sinha et al 49urology journal vol 7 no 1 winter 2010 hygiene had worst outcomes even though the patients were evenly distributed between the two groups. they had poorer outcomes even when compared in terms of site of stricture and technique of urethroplasty. this finding did not reach statistical significance due to the small number of patients and is one of the limitations of this study. also, no significant relationship was observed between the etiology of stricture and the success rate. a large number of patients (56.3%) were unaware of the cause of stricture. many of the patients had undergone multiple minimally invasive methods in the peripheral hospitals before coming to our hospital. in our study, patients with pananterior urethral strictures had a poor outcome, which is supported by the studies of morey and coworkers,(10,12) who have stated that long strictures were associated with poorer outcomes. several authors have reported higher success rates with ventral onlay(13-15); however, morey and mcaninch(16) and andrich and mundy(17) have reported a higher success rate with dorsal onlay technique, while pansadoro and coworkers(18) and markiewicz and colleagues(19) have stated that both dorsal and ventral onlay have similar outcomes. in our study, we used both of the techniques, dorsal onlay for stricture in the penile urethra and ventral onlay for bulbar strictures. the outcome according to the site of stricture or technique of urethroplasty could not be compared due to uneven distribution of the patients. dubey and colleagues(20) concluded in a randomized trial that technique is not influenced by the site of stricture. postoperative uroflowmetry confirmed that the difference in improvement was statistically significant (p = .001), which is consistent with the findings of kane and associates(13) who noted that the peak urinary flow rates improved postoperatively. in our study, the patients who underwent uroflowmetry in the pre-operative phase and those in the postoperative period were exactly not the same, and this is another limitation of this study. in this study, a statistically significant correlation was observed between the length of the stricture and success rate. on statistical analysis, patients who had a stricture length of more than 8 cm had a poor outcome when compared to those with strictures shorter than 8 cm irrespective of their tobacco consumption status and oral hygiene. the overall outcomes of our omgus were inferior to that mentioned in the literature. this may be due to the fact that patients in our study had long strictures for a longer duration and had poor oral hygiene. the outcome in the tobacco user group with poor oral hygiene was dismal (58.3%), but the outcome in the nonuser group with good oral hygiene was comparable to that in the world literature (94.4%).(21) even though the duration of study was only 3 years and it is a limitation of this study, it did bring out the difference in outcome between the tobacco users and nonusers. tobacco use is known to have systemic effect on the microvasculature and that in turn may hamper the graft take at the recipient site. this may be a confounding factor in this study since it might be difficult to distinguish between failures due to microvasculature or graft quality. even if this is taken as a limitation, it may still help us forewarn tobacco users regarding poorer outcome following omgu. we have presumed that all tobacco users had a poor oral hygiene and all nonusers had a good oral hygiene. there may be that rare patient who consumes tobacco and still has a good oral hygiene and there may be a nonuser with bad oral hygiene; such substratification was not possible in this study due to limited number of patients. we tried to overcome this bias by referring our patients to the dentistry department. it is already known that long-term use of tobacco denudes the epithelium of the oral mucosa and makes it prone to colonization by the pathogenic bacteria. this has an adverse impact on the oral hygiene. nonetheless, we accept this as a limitation of this study. the strength of this study is that it was a prospective study in a homogenous group of patients who were followed regularly for almost 3 years. this is probably the first study to focus on the impact of the quality of graft (related to tobacco consumption or oral hygiene) on the final outcome of omgu and adds a new dimension to the existing literature on omgu. influence of tobacco on oral mucosa graft urethroplasty—sinha et al 50 urology journal vol 7 no 1 winter 2010 conclusion oral mucosa graft urethroplasty remains a good option for patients with stricture of the urethra, but careful thought must go into selecting the appropriate patient based on the oral hygiene and the site and length of the stricture. if the quality of oral mucosa is unsatisfactory due to poor oral hygiene or tobacco consumption, then the patient should be forewarned regarding poorer outcome. in the near future, histopathological evaluation of the oral graft could be a new line of investigation which may provide information at the cellular and molecular level and may help us in predicting the success of omgu. further study with larger number of patients and longer follow-up is needed to validate the findings of this study. conflict of interest none declared. references 1. balaram p, sridhar h, rajkumar t, et al. oral cancer in southern india: the influence of smoking, drinking, paan-chewing and oral hygiene. int j cancer. 2002;98:440-5. 2. mathew al, pai km, sholapurkar aa, vengal m. the prevalence of oral mucosal lesions in patients visiting a dental school in southern india. indian j dent res. 2008;19:99-103. 3. tan d, goerlitz ds, dumitrescu rg, et al. associations between cigarette smoking and mitochondrial dna abnormalities in buccal cells. carcinogenesis. 2008;29:1170-7. 4. proia nk, paszkiewicz gm, nasca ma, franke ge, pauly jl. smoking and smokeless tobacco-associated human buccal cell mutations and their association with oral cancer--a review. cancer epidemiol biomarkers prev. 2006;15:1061-77. 5. wessells h. ventral onlay graft techniques for urethroplasty. urol clin north am. 2002;29:381-7, vii. 6. asopa hs, garg m, singhal gg, singh l, asopa j, nischal a. dorsal free graft urethroplasty for urethral stricture by ventral sagittal urethrotomy approach. urology. 2001;58:657-9. 7. barbagli g, palminteri e, lazzeri m. dorsal onlay techniques for urethroplasty. urol clin north am. 2002;29:389-95, vii. 8. goel a, dalela d, sinha rj, sankhwar sn. harvesting buccal mucosa graft under local infiltration analgesia-mitigating need for general anesthesia. urology. 2008;72:675-6. 9. sinha rj, singh v, sankhwar sn, dalela d. donor site morbidity in oral mucosa graft urethroplasty: implications of tobacco consumption. bmc urol. 2009;9:15. 10. morey a. urethral stricture is now an open surgical disease. j urol. 2009;181:953-4. 11. fichtner j, filipas d, fisch m, hohenfellner r, thuroff jw. long-term outcome of ventral buccal mucosa onlay graft urethroplasty for urethral stricture repair. urology. 2004;64:648-50. 12. morey af, duckett cp, mcaninch jw. failed anterior urethroplasty: guidelines for reconstruction. j urol. 1997;158:1383-7. 13. kane cj, tarman gj, summerton dj, et al. multiinstitutional experience with buccal mucosa onlay urethroplasty for bulbar urethral reconstruction. j urol. 2002;167:1314-7. 14. heinke t, gerharz ew, bonfig r, riedmiller h. ventral onlay urethroplasty using buccal mucosa for complex stricture repair. urology. 2003;61:1004-7. 15. elliott sp, metro mj, mcaninch jw. long-term followup of the ventrally placed buccal mucosa onlay graft in bulbar urethral reconstruction. j urol. 2003;169:1754-7. 16. morey af, mcaninch jw. technique of harvesting buccal mucosa for urethral reconstruction. j urol. 1996;155:1696-7. 17. andrich de, mundy ar. substitution urethroplasty with buccal mucosal-free grafts. j urol. 2001;165:1131-3. 18. pansadoro v, emiliozzi p, gaffi m, scarpone p. buccal mucosa urethroplasty for the treatment of bulbar urethral strictures. j urol. 1999;161:1501-3. 19. markiewicz mr, lukose ma, margarone je, 3rd, barbagli g, miller ks, chuang sk. the oral mucosa graft: a systematic review. j urol. 2007;178:387-94. 20. dubey d, vijjan v, kapoor r, et al. dorsal onlay buccal mucosa versus penile skin flap urethroplasty for anterior urethral strictures: results from a randomized prospective trial. j urol. 2007;178:2466-9. 21. barbagli g, guazzoni g, lazzeri m. one-stage bulbar urethroplasty: retrospective analysis of the results in 375 patients. eur urol. 2008;53:828-33. 1660 | reconstruction of urethral strictures in patients with a long history of blind urethral dilatation ivan ignjatovic, ivica stojkovic, dragoslav basic, jablan stankovic, milan potic, ljubomir dinic corresponding author: ivan ignjatovic, md, phd professor of urology, clinical center nis/clinic of urology, zorana djindjica 46, 18000 nis, serbia. tel: +381 64 1810907 e-mail: ivanig@live.com received march 2013 accepted january 2014 clinical center nis/clinic of urology, zorana djindjica 46, 18000 nis, serbia. reconstructive surgery reconstructive surgery purpose: to compare urethral reconstructions in patients after several years with or without blind urethral dilatation. materials and methods: a retrospective study of 107 patients with urethral reconstructions was performed. sixty patients with a long history of blind urethral dilatation (group 1) were compared with 47 patients without prior dilatations (group 2). results: the type of surgery planned according to urethrography and endoscopy findings was appropriate in 37/60 (61.6%) patients in group 1 and in 39/47 (83%) patients in group 2 (p < .03). anastomotic repairs were more frequent among the patients in group 2 (p < .001). eighty five out of 107 patients were available for the 24 months follow-up. the success rate was higher in group 2 (91.4%) than patients in group 1 (70%) (p < .04). the greatest improvement in symptoms and quality of life occurred three months after the surgery (p < .05). postoperative infection was persistent in 20/107 (18.7%) patients. conclusion: urethral strictures with a long history of blind dilatation are separate entity. they are more difficult to image, require more augmentation and staged procedures and have a lower success rate. keywords: dilatation; intermittent urethral catheterization; adverse effects; recurrence; urethral stricture; therapy; surgery; treatment outcome. 1661vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l urethral reconstructions after long term blind dilatations | ignjatovic et al introduction reconstructive urethral surgery is traditionally con-sidered as a demanding discipline due to different etiology and variety of surgical options. the reliability of preoperative radiological evaluation is lower in cases with spongiofibrosis(1) and requires a surgeon with adequate experience and the ability to change operative strategy during the surgery.(2,3) urethral dilatation (especially a blind one) was a preferable type of treatment during previous decades due to its simplicity and immediate results. dilatations are rarely curative but are performed anyway by 31-33% of the urologists in the usa, even though failure is predictable.(4) another reason is that 57.8% of urological surgeons never perform urethral reconstruction and only 4.2% perform buccal graft surgery,(4) which is currently the most frequent augmentation procedure. the increasing frequency of urethral reconstructive procedures means that numerous patients are looking for more durable solution after many years of prior dilatations. the aim of this study is to analyze the difference between urethral reconstructions in patients with long history of blind urethral dilatations and patients without it. materials and methods a retrospective study of 107 patients with urethral stricture disease, operated between 2003 and 2010 was performed. surgery was done in all patients by a single well trained surgeon (i.i.). standard diagnostic procedures in all patients included urethrography (retrograde and voiding), ultrasound evaluation of the kidneys, bladder, residual urine and endoscopic evaluation of the urethra. repeated blind urethral dilatations were performed in 60 patients (group 1) at least two years before the surgery, with or without direct visual internal urethrotomies (iu). the other 47 patients had neither previous dilatations nor iu (group 2). absence of infection was confirmed in 78/107 (72.9%) patients before the surgery. in 29/107 (27.1%) patients with persistent positive urine culture, targeted antibiotic therapy was initiated three days before the surgery and continued for at least seven days. the type of surgery was planned according to urethrography and endoscopy findings. in patients with ≥ 3 cm length of the stricture and well defined endoscopic distinction, anastomotic repair was performed. in longer strictures and non-distinct appearance of the healthy mucosa, augmentation ventral buccal graft was planned. in cases with the long complete obliteration of the urethra staged procedure was planned. plan of the surgery was considered as “appropriate” in patients when the surgery planned according to the preoperative evaluation was possible. in “inappropriate” patients the plan of surgery was changed due to length of the stricture (longer than expected) or long “grey urethra” augmentation instead of the anastomotic repair. staged procedures were required in cases with the absent urethral plate or unexpected pus in the urethral lumen. success was defined as: no need for additional instrumentation during the follow up, absent residual urine and maximum flow rate (qmax) > 15 ml/s. symptoms and quality of life (qol) in successfully repaired patients were evaluated with the international prostate symptom score (ipss) and ipss quality of life score (ipss-qol) before and after the surgery . the nonparametric yates corrected chi square test was used for statistical analysis. results the mean age of the patients was 66.4 ± 7.4 years (range, 2181 years). etiology and position of the strictures are shown in table. there was no significant difference between groups regarding etiology and location of the strictures. preoperative decision regarding the type of surgery was appropriate in 37/60 (61.6%) patients in group 1 and in 39/47 (83%) patients in group 2 (p < .03). acquired bladder diverticula were found in 12 patients. eighty five out of 107 (79.4%) patients (35 from group 2 and 50 from group 1), were available for the evaluation 24 months after the surgery. the success was confirmed in 32/35 patients in group 2 (91.4%) and in 35/50 (70%) patients in group 1 (p < .04). six out of the 107 patients (5.6%) had a primary failure (graft necrosis). deterioration occurred during the follow up in 18/85 (21%) patients. total number of patients who were lost from the follow-up was almost equal in both groups; 9 (8.4%) in group 2 and 7 (6.5%) in group 1, totally 16 (14.9%) in both groups. the drop-out of patients occurred one year after the surgery without complications (figure 1). figure 2 shows the combined data for the stricture length and the type of surgery. strictures longer than 5 cm were more frequent in group 1 (p < .01). anastomotic repairs were performed in 32/47 (68%) patients in group 2 and in 16/60 1662 | (26.7%) patients in group 1 (p < .001). augmentation procedures were performed in 33/60 (55%) patients in group 1, and in 14/47 (29.8%) patients in group 2 (p < .02). improvement of symptoms and qol was significant in both groups (figures 3 and 4). the highest improvement occurred three months after the surgery (p < .05). ipss was better three months after the surgery in the group 2 than in group 1, but without statistical significance. the most frequent postoperative bothersome symptom was urgency. infection was persistent after the surgery in 20/107 (18.7%) patients without statistical significance between 2 groups. discussion the etiology of urethral strictures has changed over the recent decades. today, infective etiology is less important, but traffic accident, trauma, iatrogenic and idiopathic causes became more frequent.(5) the most important recognizable cause of urethral injury, according to our results, was iatrogenic trauma. investigations of avoidable iatrogenic complications showed that educational support regarding urethral catheterization was generally poor, even in highly developed medical systems.(6) an figure 1. follow-up and complications of surgery. figure 2. type of surgery and length of the strictures. * significantly more frequent strictures longer than 5 cm (p < .01) ** anastomotic repair was more frequently possible among no previous dilatation strictures 0-5 cm (p < .001). figure 3. mean values of international prostate symptom score before and after the urethral reconstruction. keys: ipss, international prostate symptom score; nd, no previous dilatation; pd, previous dilatation. *significant difference (p < .05). figure 4. mean values of international prostate symptom score quality of life score before and after the urethral reconstruction. keys: ipss, international prostate symptom score; ipssqol, ipss quality of life score; nd, no previous dilatation; pd, previous dilatation. *significant difference (p < .05). reconstructive surgery 1663vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l overuse of urinary catheters was evident, with only 47% of the physician orders for catheters documented in hospital departments. urinary catheter related morbidity resulted from interns performing catheterization in 74% of case.(6,7) iatrogenic injury, in our series, occurred more frequently in nonurological departments (traumatology, neurosurgery, cardiac surgery and neurology). preoperative evaluation was significantly less reliable with respect to operating strategy in the group 1. other reports have demonstrated the relatively high reliability of urethrography in cases without spongiofibrosis.(1) in our series of patients, reliability was less than reported in the group 1, which can be attributed to the repeated trauma (spongiofibrosis). urethral dilatation and iu are rarely curative and associated with progressive deterioration and frequent inflammatory complications.(8) these procedures are frequently abused in the developing world,(8) such as in our series in the group 1. it should be recommended only in selected patients, who are recurrence free after 3 months.(9) considerable evidence is accumulating that, patient undergoing more than two iu have a lower probability of success and negative effect on the length of the stricture.(10) because of that numerous alternative techniques are developed.(11) the mean number of repeated urethrotomies suggests that iu contributed to the length of the stricture and decreased probability of success.(12,13) no uniform approach exists among the urologists worldwide regarding the treatment of urethral strictures. one reliable study from netherlands suggests that almost all urologists perform iu, and 49% of them will suggest it even for 3.5 cm long strictures and consider urethroplasty only after failure of iu.(14) another step forward is uncritically forced blind urethral dilatation (tunneling), which resulted in completely false passage in 13 patients in both the anterior and bulbar urethra, followed by monthly subsequent dilatations and virtually no chance of success (figure 5). these tunnels remained visible for more than four weeks, regardless of cystostomy placed before the surgery (figure 3). urethral dilatations, although ineffective, are highly accepted among the “non-reconstructive” urological surgeons,(15,16) with a “soft” border between allowed and non-allowed manipulation. anastomotic urethroplasty was performed in 47 patients. in 20 patients, strictures measuring 3-5 cm were excised from the bulbar urethra (mean 3.5 cm) and anastomotically repaired using extensive preparation, diversion of the corporeal bodies, and urethral mobilization.(17) anastomotic urethroplasty is usually performed for strictures ≤ 2 cm.(8) there are rare, anecdotal reports regarding anastomotic urethroplasty for strictures up to 5 cm.(18) anastomotic repairs were used less restrictively in our series, due to the age of the patients and the primary importance of complication-free voiding after the surgery and the less importance of sexual activity. buccal graft augmentation has improved dramatically outcome of the surgery of long strictures, however, residual symptoms, as well as, complications are more frequent and numerous improvement are still under way.(19) our results confirmed that augmentation surgery is initially as successful as reported in the series of other authors.(2,3,20) deterioration subsequently occurred in a considerable number of patients with the special impact on success in group 1. we were aware of the impaired durability and worse longterm outcome of an inflammatory stricture repair.(22) persistent urinary infection (12%) is a common problem during the first postoperative months in other reports.(23) in our subjects, infection was present in 14.9% patients in the group urethral reconstructions after long term blind dilatations | ignjatovic et al figure 5. multiple dilatation “channels” performed after several years of “blind” dilatation in the bulbar urethra four weeks after cystostomy. 1664 | references 1. gupta n, dubey d, mandhani a, srivastava a, kapoor r, kumar a. urethral stricture assessment: a prospective study evaluating urethral ultrasonography and conventional radiological studies. bju int. 2006;98:149-53. 2. barbagli g, lazzeri m. urethral reconstruction. curr opin urol. 2006;16:391-5. 3. barbagli g, lazzeri m. surgical treatment of anterior urethral stricture diseases: brief overview. int braz j urol. 2007;33:461-9. 4. bullock tl, brandes sb. adult anterior urethral strictures: a national practice patterns survey of board certified urologists in the united states. j urol. 2007;177:685-90. 5. lumen n, hoebeke p, willemsen p, de troyer b, pieters r, oosterlinck w. etiology of urethral stricture disease in the 21st century. j urol. 2009;182:983-7. 2 and 21.6 % of patients in the group 1 (p > .05). this could be partially explained by the chronically infected bladder diverticula, which appeared in 12 cases (all in group 1) due to long-acting subvesical obstruction. residual symptoms were not the same in all cases, regardless the anastomosis was clinically patent. the highest symptomatic as well as qol improvement, occurred three months after the surgery in group 2, probably due to less frequent infection and more frequent anastomotic repairs. the main complaint after the surgery was urgency. symptoms declined together with infection and the mean ipss remained between 6.8 and 11.1. the ipss and ipss-qol are simple and reliable, although not disease specific. they were previously used for the evaluation of the outcome of surgery. patients in our series had higher values of ipss than some that have been reported,(25) which could be explained by the advanced age of our patients, as well as coexisting morbidity (prostate hyperplasia, bladder diverticula and etc.). a patient reported outcome measurement tool has recently become available.(26) there is confirmed evidence that the ipss-qol questionnaire also has a moderate to high correlation with the outcome of surgery.(27) clearly, although anatomical patency is a “must” for the successful reconstruction, residual symptoms could not be neglected. the strength of the present study is sufficient number of patients, single operating surgeon and enough follow-up period. however, its weaknesses are the retrospective nature, certain number of patients was lost from the follow-up and the lack of data about sexual life. conclusion repeated dilatations are not a good treatment, although commonly performed, due to relative ease of the procedure and a lack of awareness in the medical community. they are correlated with the less reliable preoperative decision making, more frequent augmentation procedures and worse outcome of the surgery. surgeon must be flexible in their approach as the type, location and degree of spongiofibrosis can affect the type of the surgery chosen for the repair. acknowledgement this work has been supported by the serbian ministry of education and science, grant no. 175092. conflict of interest none declared. table . etiology and location of the strictures. voiding previous dilatation group no dilatation group total no. (%) etiology of the stricture* infection 7 2 9 (8.4) accident 8 5 13 (12.1) iatrogenic 28 20 48 (44.8) idiopathic 25 12 37 (35.5) location of the stricture* pendular 14 8 23 (21.5) bulbar 37 30 67 (62.6) membranous 11 6 17 (15.9) * there were no significant differences regarding the etiology and position of the strictures in the study groups. reconstructive surgery 1665vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l 6. thomas az, giri sk, meagher d, creagh t. avoidable iatrogenic complications of urethral catheterization and inadequate intern training in a tertiary-care teaching hospital. bju int. 2009;104:110912. 7. fakih mg, pena me, shemes s, et al. effect of establishing guidelines on appropriate urinary catheter placement. acad emerg med. 2010;17:337-40. 8. mundy, ar and andrich, de. urethral strictures. bju int. 2011;107:626. 9. heyns cf, steenkamp jw, de kock ml, whitaker p. treatment of male urethral strictures: is repeated dilation or internal urethrotomy useful? j urol. 1998;160:356-8. 10. singh bp, andankar mg, swain sk, et al. impact of prior urethral manipulation on outcome of anastomotic urethroplasty for posttraumatic urethral stricture. urology. 2010;75:179-82. 11. hosseini sj, kaviani a, vazirnia ar. internal urethrotomy combined with antegrade flexible cystoscopy for management of obliterative urethral stricture. urol j. 2008;5:184-7. 12. pansadoro v, emiliozzi p. internal urethrotomy in the management of anterior urethral strictures: long-term followup. j urol. 1996;156:73-5. 13. santucci r, eisenberg l. urethrotomy has a much lower success rate than previously reported. j urol. 2010;183:1859-62. 14. van leeuwen ma, brandenburg jj, kok et, vijverberg pl, bosch jl. management of adult anterior urethral stricture disease: nationwide survey among urologists in the netherlands. eur urol. 2011;60:159-66. 15. greenwell tj, castle c, andrich de, macdonald jt, nicol dl, mundy ar. repeat urethrotomy and dilation for the treatment of urethral stricture are neither clinically effective nor cost-effective. j urol. 2004;172:275-7. 16. ferguson gg, bullock tl, anderson re, blalock re, brandes sb. minimally invasive methods for bulbar urethral strictures: a survey of members of the american urological association. urology. 2010;78:701-6. 17. mundy ar. anastomotic urethroplasty. bju int. 2005;96:921-44. 18. morey af, kizer ws. proximal bulbar urethroplasty via extended anastomotic approach--what are the limits? j urol. 2006;175:2145-9. 19. dalela d, sinha rj, sankhwar sn, singh v. ventral bulbar augmentation: a new technical modification of oral mucosa graft urethroplasty for stricture of the proximal bulbar urethra. urol j. 2010;7:115-9. 20. barbagli g, palminteri e, guazzoni g, montorsi f, turini d, lazzeri m. bulbar urethroplasty using buccal mucosa grafts placed on the ventral, dorsal or lateral surface of the urethra: are results affected by the surgical technique? j urol. 2005;174:955-7. 21. erickson ba, breyer bn, mcaninch jw. single-stage segmental urethral replacement using combined ventral onlay fasciocutaneous flap with dorsal onlay buccal grafting for long segment strictures. bju int. 2012;109:1392-6. urethral reconstructions after long term blind dilatations | ignjatovic et al 22. mathur r, aggarwal g, satsangi b, khan f, odiya s. comprehensive analysis of etiology on the prognosis of urethral strictures. int braz j urol. 2011;37:362-9. 23. mathur r, aggarwal g, satsangi b. a retrospective analysis of delayed complications of urethroplasty at a tertiary care centre. updates surg. 2011;63:185-90. 24. raber m, naspro r, scapaticci e, et al. dorsal onlay graft urethroplasty using penile skin or buccal mucosa for repair of bulbar urethral stricture: results of a prospective single center study. eur urol. 2005;48:1013-7. 25. jackson mj, sciberras j, mangera a, et al. defining a patient-reported outcome measure for urethral stricture surgery. eur urol. 2011;60:60-8. 26. kessler tm, fisch m, heitz m, olianas r, schreiter f. patient satisfaction with the outcome of surgery for urethral stricture. j urol. 2002;167:2507-11. 27. frie gk, van der meulen j, black n. single item on patients’ satisfaction with condition provided additional insight into impact of surgery. j clin epidemiol. 2012;65:619-26. 1609vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l comparison of 12and 16-core prostate biopsy in japanese patients with serum prostatespecific antigen level of 4.0-20.0 ng/ml yasuhide miyoshi, masahiro furuya, jun-ichi teranishi, kazumi noguchi, hiroji uemura, yumiko yokomizo, shinpei sugiura, yoshinobu kubota corresponding author: yasuhide miyoshi, md 4-57 urafune-cho, minami-ku, yokohama 232-0024, japan. tel: +81 45 261 5656 fax: +81 45 253 1962 e-mail: miyoyasu@med.yokohamacu.ac.jp received march 2013 accepted december 2013 department of urology, yokohama city medical center, yokohama, japan. purpose: in the present study, we compared 12with 16-core biopsy in patients with prostate-specific antigen (psa) levels of 4.0-20.0 ng/ml. materials and methods: between 2003 and 2010, 332 patients whose serum psa level was between 4.0 and 20.0 ng/ml underwent initial transrectal ultrasound (trus)-guided needle biopsy. of those patients, 195 underwent 12-core biopsy and 137 underwent 16-core biopsy. results: in the 12-core prostate biopsy group, 66 (33.8%) patients were found to have prostate cancer. on the other hand, in the 16-core prostate biopsy group of 137 patients, 61 (44.5%) were found to have prostate cancer. among all patients, the prostate cancer detection rate was slightly higher in the 16-core biopsy group than in the 12-core biopsy group. moreover, in patients with prostate volume > 30 ml or psa density (psad) < 0.2, the prostate cancer detection rate was significantly higher in the 16-core biopsy group than in the 12-core biopsy group. there was no significant difference in pathological tumor grade, indolent cancer probability, or biopsy complication rate between the two groups. conclusion: in order to detect prostate cancer, 16-core prostate biopsy is safe and feasible for japanese patients with serum psa level of 4.0-20.0 ng/ml. keywords: prostate-specific antigen; prostatic neoplasms; sensitivity and specificity; biopsy; large-core needle; predictive value of tests. urological oncology 27. loening-baucke v. urinary incontinence and urinary tract infection and their resolution with treatment of chronic constipation of childhood. pediatrics. 1997;100:228-32. 1610 | introduction there were 679,000 new cases of prostate cancer worldwide in 2002, making it the fifth most com-mon cancer in the world and the second most common cancer in men. estimated age-standardized incidence rates were 119.9, 61.6 and 12.6 per 100,000 male population in the united states, western europe and japan.(1) in japan, despite the lower incidence of prostate cancer than in western countries, diagnosis of the disease has been gradually increasing in recent years owing to widespread use of the serum prostate-specific antigen (psa) test in japanese men. for prostate cancer detection, hodge and colleagues first proposed sextant systematic biopsy of the prostate under transrectal ultrasound (trus) in 1989.(2) since then, many investigators have reported the usefulness of trus-guided systematic prostate biopsy. as originally described, 6 biopsies were obtained in the parasagittal line halfway between the lateral border and midline of the prostate on the left and right sides from the base, mid-gland and apex. later, stamey recommended shifting biopsies more laterally to better sample the anterior horn of the peripheral zone.(3) although trus-guided systematic prostate biopsy has been established as the standard, it is recognized that 6-core biopsy is inadequate for cancer detection. the standard sextant procedure misses 10% to 30% of cancers.(4,5) recently, many investigators have indicated that extended prostate biopsy sampling with 8 or more cores might improve the prostate cancer detection rate.(6,7) in spite of the increased likelihood of prostate cancer detection by extended biopsy, the appropriate number of cores remains unclear. it is expected that increasing the number of biopsy cores would lead to improved cancer detection; however, the risk of detection of latent or insignificant prostate cancer may also be elevated. for accurate diagnosis with avoidance of overdiagnosis and overtreatment of latent cancer, a strategy for prostate cancer detection is important. in our study, we analyzed the data by comparing 12with 16-core biopsy in patients with serum psa level of 4.0-20.0 ng/ml. we evaluated extended 16-core prostate biopsy and defined the optimal number of biopsy cores. materials and methods between january 2003 and march 2010, 332 patients whose serum psa concentration was between 4.0 and 20.0 ng/ ml underwent initial transrectal ultrasound (trus)-guided needle biopsy at yokohama city university hospital and yokohama city medical center. between january 2003 and march 2005, 195 patients underwent 12-core biopsy (8 cores from the peripheral zone and 4 cores from the transition zone) at yokohama city university hospital, and between april 2005 and march 2010, 137 patients underwent 16-core biopsy (8 cores from the peripheral zone and 8 cores from the transition zone) at yokohama city medical center, retrospectively. sampling sites are shown in figure 1. patient characteristics of the 12and 16-core biopsy groups are listed in table 1. serum psa free/total ratio was significantly higher and patient age was significantly younger in the 16-core biopsy group than in the 12-core group. all procedures were performed using diagnostic ultrasound machines, and core biopsies were obtained transperineally under ultrasound guidance, using a 18-gauge needle with a spring-loaded biopsy gun. all procedures were performed under local anesthesia (1% xylocaine). before biopsy, all patients underwent trus and the prostate volume was measured. total psa as well as free psa levels were determined with a dpc imrise third generation psa assay kit. pathological tumor grade was classified according to the japanese general rules for clinical and pathological studies on prostate cancer. statistical analyses were performed by mannwhitney u test, chi-squared test, or logistic regression test using the statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0. results a total of 195 patients with serum psa level ranging from 4.0 to 20.0 ng/ml underwent 12-core trus-guided prostate biopsy. of those patients, 66 (33.8%) were found to have prostate cancer. on the other hand, a total of 137 patients with serum psa level ranging from 4.0 to 20.0 ng/ml underwent 16-core trus-guided prostate biopsy. of these 137 patients, 61 (44.5%) were found to have prostate cancer. among all patients, the prostate cancer detection rate was slightly higher in the 16-core biopsy group than in the 12core biopsy group, but the difference was not statistically significant (p = .068). figure 2 shows positive core sites in 12and 16-core biopsies. there were 15 cases (23.0%) of urological oncology 1611vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l comparison of 12and 16-core prostate biopsy | miyoshi et al detection in transition zone (tz) biopsy, 31 (47.7%) in the peripheral zone (pz) and tz, and 19 (29.3%) in pz in the 12-core biopsy group. on the other hand, in the 16-core biopsy group, there were 22 cases (36.7%) of detection in tz, 27 (45.0%) in pz and tz and 11 (18.3%) in pz. there was no significant difference in positive core sites between the groups. among patients with prostate volume > 30 ml, 17 (15.5%) cancer patients were detected in the 12-core biopsy group and 25 (29.4%) in the 16-core biopsy group. among patients with prostate volume > 30 ml, the prostate cancer detection rate was significantly higher in the 16-core biopsy group than in the 12-core biopsy group (p = .023). similarly, among patients with psa density (psad) < 0.2, four cancer patients (6.3%) were detected in the 12-core biopsy group and 18 (34.0%) in the 16-core biopsy group. among patients with psad < 0.2, the prostate cancer detection rate was significantly higher in the 16-core biopsy group than in the 12-core biopsy group (p < .0001). we compared the pathological tumor grade obtained by 12core biopsy with that obtained by 16-core biopsy. median gleason score of detected cancer was 7 [95% confidential interval (ci): 6.55-7.00] in the 12-core biopsy group and 7 (95% ci: 6.42-6.73) in the 16-core biopsy group. there was no significant difference in pathological tumor grade between the two groups (p = .083). we predicted the possibility of insignificant prostate cancer in this study using epstein criteria, and compared the insignificant cancer detection rate in the 12-core biopsy group with that in the 16-core biopsy group. only one patient (0.5%) was detected as insignificant cancer in the 12-core biopsy group and 2 (1.5%) in the 16-core biopsy group. our data showed that the insignificant cancer detection rate was not higher in the 16-core biopsy group than in the 12-core biopsy group (p = .31). significant independent variables for positive biopsies were age, prostatic-specific antigen level, prostate volume and vbr (volume biopsies ratio)(8) which means the prostate volume divided by the number of biopsies (p < .001). vbr had the strongest correlation coefficient out of all significant variables. we examined the predictive factors for prostate cancer patients with psa of 4.0-20.0 ng/ml by multivariate analysis. significant independent variables for positive biopsies were age, psa, psa f/t ratio, prostate volume, prostate tz volume, psad and vbr. vbr had the strongest correlation coefficient out of all significant variables (table 2). the detection rates for vbr of < 2.0, 2.0-2.9, 3.0-3.9 and > 4 were 68.0%, 34.1%, 20.0% and 7.7%, respectively. the risks and complications of prostate cancer biopsy were compared between the 12-core and 16-core biopsy groups (table 3). adverse events were graded by national cancer institute common toxicity criteria (nci ctc) version 4.0. none of the patients in either group developed urinary tract infection. the occurrence rate of grade 3 hematuria and grade 2 urinary retention was similar in each group. discussion although the optimum number of cores that should be obfigure 1. sampling sites in 12and 16-core prostate biopsy are shown. figure 2. positive core sites in 12and 16-core biopsies are demonstrated (for explanation see text). 1612 | tained at prostate biopsy remains unclear, many studies have shown that extended prostate biopsies are superior to sextant protocols for detecting prostate cancer.(9) in the present study, we compared the prostate cancer detection rate and clinicopathological findings in the 12-core biopsy group and 16-core biopsy group. the total detection rate of prostate cancer in patients with psa of 4.0-20.0 ng/ml was 66 of 195 patients (33.8%) in the 12-core biopsy group. these results were similar to those in previous reports.(10,11) in the 16-core biopsy group, the prostate cancer detection rate was 61 of 137 patients (44.5%), which was superior to that in the 12-core biopsy group although the difference was not statistically significant. among the patients with prostate volume > 30 ml, 17 (15.5%) cancer patients were detected in the 12-core biopsy group and 25 (29.4%) in the 16-core biopsy group. among patients with prostate volume > 30 ml, the prostate cancer detection rate was significantly higher in the 16-core biopsy group than in the 12-core biopsy group (p = .023). similarly, among patients with psad < 0.2, four cancer patients (6.3%) were detected in the 12-core biopsy group and 18 (34.0%) in the 16-core biopsy group. among patients with psa density < 0.2, the prostate cancer detection rate was significantly higher in the 16-core biopsy group than in the 12-core biopsy group (p < .0001). our results indicate that 12-core prostate biopsy might be inadequate in patients with large prostate volume or low psad. in patients with prostate volume > 30 ml or psad < 0.2, 16-core biopsy improved the prostate cancer detection rate over that with 12-core biopsy. various efforts to improve prostate cancer detection have been reported such as increasing the number of cores, laterally focused biopsy, changing access, biopsy corresponding to diffusion-weighted magnetic resonance images before biopsy or saturation biopsy using a template.(12-14) the second consideration is the location of cores. from repeat prostate biopsy studies, it emerges that prostate cancer tends to locate more frequently in the lateral and anterior apical regions than in the transition zone.(15,16) although it is not surprising that taking more cores enhances the cancer detection rate and diagnostic ability, the possibility of increasing the detection of clinically insignificant cancer should be considered. a lower threshold for serum psa and extended biopsy might lead to a marked increase in detection of small, low-grade prostate cancers.(17,18) in an attempt to identify clinically insignificant prostate cancer, epstein and colleagues examined preoperative clinical and pathological features in 157 men with clinical stage t1c prostate cancer who underwent radical prostatectomy, to find features that could predict insignificant tumors (organconfined tumors less than 0.2 ml, pathological gleason sum table 1. patient characteristics of 12and 16-core biopsy groups. variables 12-core 16-core p no. of patients 195 137 --age (years) (median, 95% ci) 69 (66.9-68.6) 67 (64.8-67.3) .029 psa (ng/ml) (median, 95% ci) 7.82 (8.34-9.42) 8.51 (8.65-10.15) .234 psa f/t ratio (median, 95% ci) 0.12 (.12-.14) 0.17 (.16-.19) < .001 prostate volume (ml) (median, 95% ci) 32.0 (33.1-38.1) 35.6 (35.6-43.2) .192 tz volume (ml) (median, 95% ci) 15.9 (16.2-19.3) 14.5 (16.4-21.5) .708 psa density (ng/ml/g) (median, 95% ci) 0.24 (.26-.31) 0.22 (.25-.32) .575 keys: psa, prostate-specific antigen; f, free; t, total; tz, transition zone. table 2. predictive value for cancer detection in patients with serum psa levels of 4-20 ng/ml. variables p exp (b) age .066 1.043 psa .409 1.076 psa f/t ratio .068 0.011 prostate volume .070 1.074 tz volume .120 0.945 psa density .659 2.762 vbr .002 0.264 keys: psa, prostate-specific antigen; f, free; t, total; tz, transition zone. exp(b) = this is the exponentiation of the b coefficient, which is an odds ratio. urological oncology 1613vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l 6 or lower).(19) their model for predicting an insignificant tumor was no gleason grade of 4 or 5 in the biopsy specimen and either (1) psad of 0.1 ng/ml per gram or less, two or one biopsy cores involved with cancer (minimum of six cores obtained) and no core with more than 50% involvement or (2) psad ≤ 0.15 ng/ml per gram and cancer smaller than 3 mm in only one prostate biopsy sample (minimum of six cores). this model had a positive predictive value of 95% and a negative predictive value of 66% in their own dataset. these investigators predicted that 73% of their cases were insignificant tumors. we predicted the possibility of insignificant prostate cancer in this study using epstein criteria,(19) and compared the insignificant cancer detection rate in the 12-core biopsy group with that in the 16-core biopsy group. our data showed that the insignificant cancer detection rate was not higher in the 16-core biopsy group than in the 12core biopsy group. there was no evidence that 16-core biopsy elevated clinically insignificant cancer detection. pepe and colleagues(20) reported that prostate cancer diagnosed by saturation biopsy with a median of 30 cores showed a significant cancer in 48/22 (87.3%) patients. only 12.7% of cases showed insignificant cancer, but the detection rate of more aggressive disease with a risk of non-organ-confined cancer in their series was 27.3%. epstein and colleagues reported that overall, only 7/274 (2.6%) men had an “insignificant” tumor in the prostatectomy specimen, and a model including gleason grade, psad, and number of positive biopsy cores did not provide an accurate means of selecting patients for active monitoring in their patient cohort.(21) the risks and complications of prostate cancer biopsy were compared in the 12-core and 16-core biopsy groups. none of the patients developed urinary tract infection. the occurrence rate of grade 3 hematuria and grade 2 urinary retention was similar in each group. these results were consistent with previous reports.(22,23) there are some limitations about this study. in particular, it is a major weakness that this study is retrospective. for obtain the optimum number of cores, prospective randomized clinical trial may be warranted conclusion we concluded that 16-core prostate biopsy is safe and feasible for japanese patients with serum psa level of 4.0-20.0 ng/ml. further studies in different population with greater sample size are needed to draw final conclusion. acknoweldgement this work was supported by a mext/jsps kakenhi grant. conflict of interest none declared. comparison of 12and 16-core prostate biopsy | miyoshi et al table 3. comparison of complication grades between 12-core and 16-core biopsy. variables 12-core (n = 75) 16-core (n = 126) p urinary retention (g2) 7 (6.55-7.00) 7 (6.42-6.73) .546 hematuria (g3) 7 (6.55-7.00) 7 (6.42-6.73) .996 references 1. parkin dm, bray f, ferlay j, pisani p. global cancer statistics, 2002. ca cancer j clin. 2005;55:74-108. 2. hodge kk, mcneal je, terris mk, stamey ta. random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. j urol. 1989;142:71-4. 3. stamey ta. making the most out of six systematic sextant biopsies. urology. 1995;45:2-12. 4. norberg m, egevad l, holmberg l, sparen p, norlen bj, busch c. the sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. urology. 1997;50:562-6. 5. presti jc jr, chang jj, bhargava v, shinohara k. the optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. j urol. 2000;163:163-6. 6. guichard g, larre s, gallina a, et al. extended 21-sample needle biopsy protocol for diagnosis of prostate cancer in 1000 consecutive patients. eur urol. 2007;52:430-5. 7. yokomizo y, miyoshi y, nakaigawa n, et al. free psa/total psa ratio increases the detection rate of prostate cancer in twelve-core biopsy. urol int. 2009;82:280-5. 1614 | 8. jiang j, colli j, el-galley r. a simple method for estimating the optimum number of prostate biopsy cores needed to maintain high cancer detection rates while minimizing unnecessary biopsy sampling. j endourol. 2010; 24: 143-7. 9. ahyai sa, isbarn h, karakiewicz pi, et al. the presence of prostate cancer on saturation biopsy can be accurately predicted. bju int. 2010;105:636-41. 10. abd tt, goodman m, hall j, et al. comparison of 12-core versus 8-core prostate biopsy: multivariate analysis of large series of us veterans. urology. 2011;77:541-7. 11. rochester ma, griffin s, chappell b, mcloughlin j. a prospective randomised trial of extended core prostate biopsy protocols utilizing 12 versus 15 cores. urol int. 2009;83:155-9. 12. jeong ig, kim jk, cho ks, et al. diffusion-weighted magnetic resonance imaging in patients with unilateral prostate cancer on extended prostate biopsy: predictive accuracy of laterality and implications for hemi-ablative therapy. j urol. 2010;184:1963-9. 13. kawakami s, yamamoto s, numao n, ishikawa y, kihara k, fukui i. direct comparison between transrectal and transperineal extended prostate biopsy for the detection of cancer. int j urol. 2007;14:71924. 14. taira av, merrick gs, galbreath rw, et al. performance of transperineal template-guided mapping biopsy in detecting prostate cancer in the initial and repeat biopsy setting. prostate cancer prostatic dis. 2010;13:71-7. 15. jones js. saturation biopsy for detecting and characterizing prostate cancer. bju int. 2007;99:1340-4. 16. jones js. prostate cancer: are we over-diagnosing-or under-thinking? eur urol. 2008;53:10-2. 17. chan ty, chan dy, stutzman kl, epstein ji. does increased needle biopsy sampling of the prostate detect a higher number of potentially insignificant tumors? j urol. 2001;166:2181-4. 18. loeb s, roehl ka, thaxton cs, catalona wj. combined prostatespecific antigen density and biopsy features to predict "clinically insignificant" prostate cancer. urology. 2008;72:143-7. 19. epstein ji, walsh pc, carmichael m, brendler cb. pathologic and clinical findings to predict tumor extent of nonpalpable (stage t1c) prostate cancer. jama. 1994;271:368-74. 20. pepe p, fraggetta f, galia a, candiano g, grasso g, aragona f. is a single focus of low-grade prostate cancer diagnosed on saturation biopsy predictive of clinically insignificant cancer? urol int. 2010;84:440-4. 21. epstein ji, walsh pc, carter hb. importance of posterolateral needle biopsies in the detection of prostate cancer. urology. 2001;57:1112-6. 22. kakehi y, naito s, japanese urological a. complication rates of ultrasound-guided prostate biopsy: a nation-wide survey in japan. int j urol. 2008;15:319-21. urological oncology 23. tuncel a, aslan y, sezgin t, aydin o, tekdogan u, atan a. does disposable needle guide minimize infectious complications after transrectal prostate needle biopsy? urology. 2008;71:1024-7. urological oncology periprostatic adiposity measured on magnetic resonance imaging correlates with prostate cancer aggressiveness zhang qiang,1 sun li-jiang,1 qi jun,2 yang zhi-gang,3 huang tao,2 huo ri-cha3 1department of urology, the affiliated hospital of qingdao university, qingdao, shandong 266003, china. 2 department of urology, xinhua hospital affiliated to shanghai jiao tong university, s c h o o l o f m e d i c i n e , s h a n g h a i 200092, china. 3department of urology, baotou city central hospital, botou 014040, inner mongolia, china. corresponding author: zhang qiang, md department of urology, the affili ated hospital of qingdao university medical college, qingdao, shandong 266003, china. tel: +86 474 6955387 fax: +86 474 6955387 e-mail: zq19825@163.com received july 2013 accepted march 2014 purpose: to evaluate the correlation between aggressiveness of prostate cancer (pca) and obesity measuring the periprostatic fat on magnetic resonance imaging (mri). materials and methods: one hundred eighty-four patients who had undergone radical retropubic prostatectomy (rrp) were analyzed retrospectively. the different fat measurements (periprostatic fat area (pfa), the subcutaneous fat thickness, the anterior and posterior abdominal fat thicknesses and anteroposterior diameter) were performed on the slices of mri and then compared with the clinical and pathologic characteristics. results: the pfa and ratio showed a statistically significant differences (p = .019 and p = .025, respectively) among three groups, that is to say, more adipose were distributed in periprostatic area of the high risk patients. seventy-one patients in clinical stage and 82 patients in gleason score have the significant differences between pre-operation and post-operation values. in the clinical stage, the pfa and ratio showed a statistically significant differences (p = .014 and p = .037, respectively). the difference group had more periprostatic adipose than the other one (65.26 ± 9.03 vs. 64.44 ± 9.62; 87.52 ± 3.97 vs. 87.30 ± 3.96). nothing but the “pfa” was significantly different between two groups (p = .017). logistic regression analysis adjusted for age revealed a statistically significant association between the pfa, the ratio and the risk of having high-risk disease (p = .031 and p = .024, respectively). conclusion: the periprostatic adiposity not only affects the pca aggressiveness, but also has effect in accurate assessment of the tumor stage and grade. we should predict the prognosis of patient with rrp by measuring periprostatic adiposity on pre-operative mri. keywords: adipose tissue; body mass index; magnetic resonance imaging; obesity; prostatic neoplasms. 1793 urological oncology urology journal vol. 11 no. 04 july august 2014 1794 periprostatic adiposity on mri and prostate cancer aggressiveness-qiang et al figure 2. the anterior abdominal fat thicknesses, posterior abdominal fat thicknesses and anteroposterior diameter on the slices of magnetic resonance imaging (t2 weighted) at the midline section. calculated as the anterior plus posterior abdominal wall fat thickness subtracted from the apd divided by the apd and expressed as percentage. all measurements were performed in a blinded manner by a single observer (figure 1). the sft and the (pfa) were obtained from the images of mri (t2 weighted) at the transverse section at the level of the femoral head and greater trochanter of the femur (figure 2). the localization image is on the slice of mri (t2 weighted) at the midline section. the anterior and posterior abdominal fat thicknesses, and apd were measured in 3 images around the midline and the results were averaged. statistical analysis association between fat measurements and clinical/pathological characteristics were analyzed by chi-square test in case of categorical variables and kruskal-wallis test in case of continuous variables. logistic regression analysis was applied with adjustment of age to evaluate the independent effect of each variable on the risk of higher-risk disease. introduction prostate cancer (pca) is the second most common malignant tumor of men worldwide, the incidence of which has also ris-en gradually in china during recent decades.(1,2) obesity has became a worldwide challenge in the 21st century. many epidemiological studies have found that higher body mass index (bmi) and abdominal obesity were associated with increased risk of several cancers (kidney, colon, endometrium and breast) including prostate.(3-5) however, the relationship between obesity and pca aggressiveness is still in controversial. some studies have found positive correlation,(6-8) whereas others have drawn adverse results.(9,10) the difference of results is considered to be due to the method of measurement. the bmi doesn’t effectively reflect the most metabolic active fat in body, whereas the visceral adipose is a more sophisticated measurement of abdominal obesity than bmi, because it is metabolically active and can produce a large number of hormones and cytokines such as tumor necrosis factor-α, interleukin-6, leptin and adiponectin.(11,12) magnetic resonance imaging (mri) is a direct, quantitative measurement method to characterize the distribution of abdominal adipose tissue in normal status or in pathologic conditions.(13) the aim of this study is to evaluate the correlation between aggressiveness of pca and obesity by measuring the visceral fat (periprostatic fat) using mri. materials and methods from march 2006 to october 2012, one hundred eighty-four patients were histologically diagnosed as localized pca by prostate needle biopsy at xin hua hospital affiliated to shanghai jiao tong university school of medicine before being given radical retropubic prostatectomy (rrp). in preoperative phase, all patients were evaluated with digital rectal examination (dre), serum prostate-specific antigen (psa), transrectal ultrasonography, radionuclide bone scan and x-ray chest film. magnetic resonance imaging (mri) was also performed to evaluate the local extent of disease and the possibility of nodal involvement for clinical staging. pathologic stage is determined by histologic analysis of surgical samples including prostate, seminal vesicles and pelvic lymph nodes. measurements height and weight data were recorded before rrp. bmi (kg/m2) was calculated and categorized according to the national institutes of health classification of normal weight (< 25 kg/m2), overweight (2529 kg/m2) and obese (≥ 30 kg/m2). only two patients who had a bmi value of < 18.5 kg/m2 were included in the normal weight group. the periprostatic fat area (pfa) (cm2) and the subcutaneous fat thickness (sft) measurements were performed on the slices of mri at the transverse section, at the level of the femoral head and greater trochanter of the femur (figure 1); the anterior abdominal fat thicknesses (aat), posterior abdominal fat thicknesses (pat) and anteroposterior diameter (apd) were measured on the slices of mri (t2 weighted) of the midline section (figure 2). the umbilicus, bladder, prostate and urethra were identified at the midline section. the ratio of visceral fat was figure 1. the periprostatic fat area and the subcutaneous fat thickness on the slices of magnetic resonance imaging at the transverse section, at the level of the femoral head and greater trochanter of the femur. .015, p = .041 and p = .042, respectively). logistic regression analysis which adjusted for age (table 4) revealed a statistically significant association between the pfa, the ratio and the risk of having higher-risk disease (p = 0.031 and p = 0.024, respectively). discussion in recent years, the relationship between obesity and cancer has drawn significant academic interests. epidemiological studies have demonstrated that obesity is a risk factor of breast, endometrium, kidney and gallbladder cancers, but its role in pca etiology remains elusive. (3,5,15). obesity is often assessed by bmi, which comes from physical measurement or self-reported height and weight. however, the bmi, which is a marker for overall obesity, cannot distinguish between adiposity and lean body mass, particularly in men with greater muscle mass, nor does it reflect fat distribution. therefore, the link between bmi and pca is controversial in many studies.(16-19) in our research, no association between bmi and pca risk was revealed, and bmi was not an independent risk factor for pca aggressiveness. abdominal adiposity or periprostatic adiposity has been found to precisely reflect the association between obesity and pca in recent years. (20-22) although abdominal fat make up only 10% of total body fat, it is metabolically more active than subcutaneous or peripheral fat. furthermore, periprostatic fat is associated with fluctuation in levels of several hormones, including insulin, testosterone, estrogen, sex hormone binding globulin, and leptin which play a significant role in the biology of pca.(23,24) the leptin, a cytokine produced by white adipose tissue, plays a critical role in the regulation of body weight by inhibitall statistic were performed by the statistical package for the social science (spss inc, chicago, illinois, usa) version 13.0 with statistical significance being defined as p values < .05. results baseline clinical characteristics and different fat measurements according to kattan(14) we stratified the patients into three groups. the clinical and pathologic characteristics were summarizes in table 1. the median age, prostate volume, t-zone volume, bleeding volume and duration of operation had no significant differences among three groups (p > .05). bmi at the time of rrp was 25.51 ± 2.46, 25.83 ± 2.16 and 25.74 ± 2.29 kg/m2, respectively (p = .142). the pfa and the ratio showed statistically significant difference between three groups (p = .019 and p = .025, respectively). table 2 demonstrates the difference of clinical stage and gleason score between preoperative and postoperative phase. in clinical stage, the pfa and ratio showed a statistically significant difference (p = .014 and p = .037, respectively). in terms of gleason score, nothing but pfa was found to have significant difference between two groups (p = .017). moreover, the prostate volume and t-zone volume have statistically significant difference (p = .049 and p = .020, respectively). the difference in bleeding volume and duration of operation are shown in table 3. during operation, patients with bleeding volume over 450 ml were significantly older (p = .022) and had more dispose in periprostatic area (ratio: 88.46 ± 3.00 vs. 86.95 ± 4.36, p = .013). the pat, anteroposterior abdominal fat thickness (apt) and ratio was significantly higher in the group with operation time > 210 min (p = table 1. clinical characteristic of study subjects.* risk groups variables low intermediate high p value no. of patients 47 80 57 age, years 70.10 ± 6.04 69.68 ± 6.39 68.07 ± 5.53 .177 prostate volume, cm3 40.40 ± 24.22 42.29 ± 22.55 48.02 ± 28.33 .250 t-zone volume, cm3 18.76 ± 15.27 21.49 ± 19.10 25.02 ± 21.46 .242 initial psa, ng/ml 6.91 ± 2.87 12.47 ± 4.25 25.15 ± 11.49 .242 bmi, kg/m2 25.51 ± 2.46 25.83 ± 2.16 25.74 ± 2.29 .142 sft, cm 2.69 ± 0.83 2.78 ± 1.05 2.83 ± 1.03 .773 pfa, cm2 64.44 ± 8.06 64.96 ± 9.75 65.69 ± 9.42 .019 aat, cm 1.46 ± 0.55 1.42 ± 0.56 1.53 ± 0.67 .533 pat, cm 0.98 ± 0.48 1.03 ± 0.43 1.03 ± 0.49 .800 apt, cm 19.54 ± 1.67 19.45 ± 1.76 19.87 ± 1.88 .387 ratio (%) 87.31 ± 4.23 87.52 ± 3.84 87.65 ± 3.99 .025 bleeding volume, ml 470.85 ± 289.64 452.62 ± 356.57 492.86 ± 463.92 .830 duration of operation, min 214.77 ± 41.62 215.75 ± 40.09 219.65 ± 62.06 .853 the groups according to kattan:(14) low risk, ≤ t2a, gleason score ≤ 6, ipsa < 10 ng/ml; intermediate risk, t2b, gleason score = 7, ipsa = 10-20 ng/ml; high risk, ≥ t2c, gleason score ≥ 8, ipsa > 20 ng/ml. abbreviations: bmi, body mass index; sft, subcutaneous fat thickness; pfa, periprostatic fat area; aat, anterior abdominal fat thicknesses; pat, posterior abdominal fat thicknesses; apt, anteroposterior diameter abdominal fat thicknesses; ipsa, initial prostate specific antigen. ratio was calculated as: the anterior plus posterior abdominal wall fat thickness subtracted from the anteroposterior diameter divided by the anteroposterior diameter. * data are presented as mean ± sd. 1795 urological oncology urology journal vol. 11 no. 04 july august 2014 1796 clinical stage gleason score difference no difference p value difference no difference p value no. of patients (%) 71 (38.59) 113 (61.41) ns 82 (44.57) 102 (55.43) ns age, years 68.39 ± 6.37 69.84 ± 5.77 .116 68.96 ± 6.37 68.55 ± 5.84 517 prostate volume, cm3 44.47 ± 27.02 43.69 ± 23.81 .839 46.83 ± 27.33 39.56 ± 21.08 .049 t-zone volume, cm3 22.09 ± 17.40 22.20 ± 20.31 .971 24.81 ± 22.08 18.25 ± 13.69 .020 initial psa, ng/ml 15.22 ± 8.59 14.83 ± 10.97 .800 13.98 ± 9.41 15.78 ± 10.57 .231 bmi, kg/m2 25.13 ± 2.62 24.92 ± 2.37 .451 25.36 ± 3.12 25.41 ± 2.78 .576 sft, cm 2.77 ± 1.05 2.77 ± 0.96 .997 2.71 ± 0.99 2.82 ± 0.99 .46 pfa, cm2 65.26 ± 9.03 64.44 ± 9.62 .014 65.29 ± 9.57 63.75 ± 8.78 .017 aat, cm 1.50 ± 0.59 1.43 ± 0.60 .387 1.44 ± 0.58 1.48 ± 0.60 .626 pat, cm 1.03 ± 0.51 1.03 ± 0.43 .951 0.99 ± 0.46 1.04 ± 0.46 .497 apt, cm 19.73 ± 1.69 19.36 ± 1.89 .169 19.39 ± 1.72 19.77 ± 1.81 .145 ratio (%) 87.52 ± 3.97 87.30 ± 3.96 .037 87.59 ± 4.15 87.40 ± 3.86 .150 table 2. the difference in clinical stage and gleason score between preoperation and postoperation.* abbreviations: bmi, body mass index; sft, subcutaneous fat thickness; pfa, periprostatic fat area; aat, anterior abdominal fat thicknesses; pat, posterior abdominal fat thicknesses; apt, anteroposterior diameter abdominal fat thicknesses. ratio was calculated as: the anterior plus posterior abdominal wall fat thickness subtracted from the anteroposterior diameter divided by the anteroposterior diameter. * data are presented as mean ± sd. ing food intake and stimulating energy expenditure. in addition, leptin influences cellular differentiation and progression in pca cells, further increasing pca risk and stage.(25) the waist circumference (wc) and waist-to-hip ratio (whr) are commonly used to define the extent of abdominal obesity.(26,27) in a large cohort study among 129,502 men(28) waist circumference and waist-to-hip ratio were positively association with advanced disease among men with a lower bmi. although wc can be measured easily, it estimates abdominal adipose tissue imprecisely. mri is an excellent technique to distinguish and quantify subcutaneous and periprostatic fat. the benefits of mri over other adipose imaging methods are accelerated acquisition, quantitative reconstruction and physiologically based threshold, all of which are required for accurate adipose tissue measurements.(13,29) in addition, the patient with pca should be undergo mri before surgery in order to assess tumor stage, so fat measurement by mri cannot increase the economic burden of patients. in our study, mri is proved to be a precise way to measure the periprostatic adiposity. we could clearly distinguish the fat, muscle and bone. by measurement of abdominal adipose distribution, reflecting the periprostatic fat, we have found a close association between periprostatic adiposity (the pfa and ratio) and pca aggressiveness as well as pca risk. however, the sft, pat periprostatic adiposity on mri and prostate cancer aggressiveness-qiang et al and aat, reflecting the peripheral fat, have showed no statistically significant differences. it is important to assess tumor stage and grade more accurately in the preoperative phase, because it would affect the selection of treatment of the localized pca and evaluation of the patient’s prognosis. the incidence of under staging was 38.6% in our study, which lies between 24% and 60% previously reported in large single institution studies. (30) the incidence of discordance in gleason score between biopsy and rrp was 44.6%, which was similar to that reported by several researchers.(31) previous studies have shown that preoperative serum psa level, the percent of positive systematic prostate biopsies and the interval between biopsy and rrp are the most important predictors of under staging and under grading. in our study, the tumor volume affects the concordance in gleason score between biopsy and rrp, probably owing to the association between the percentage of positive systematic biopsies and tumor volume.(30,32) our study is to date only one that analyzed association between periprostatic adiposity and the discordance of staging or grading before and after surgery. these findings might be important and may indicate that obese patients require different treatment considerations. several explanations could be given for the reason. first, the periprostatic fat tissue could affect the table 3. the difference in bleeding volume and duration of operation.* bleeding volume duration of operation ≤ 450 ml > 450 ml p value ≤ 210 min > 210 min p value no. of patients 118 66 ns 102 82 ns age, years 68.53 ± 6.31 70.65 ± 5.39 .022 69.29 ± 6.14 69.28 ± 6.02 .988 prostate volume, cm3 42.35 ± 24.09 45.80 ± 26.43 .368 42.23 ± 26.13 45.27 ± 23.44 .412 t-zone volume, cm3 20.43 ± 17.67 24.50 ± 21.16 .165 20.03 ± 18.60 24.19 ± 19.45 .142 initial psa, ng/ml 15.22 ± 10.39 14.55 ± 9.56 .670 14.45 ± 9.62 15.63 ± 10.65 .432 bmi, kg/m2 24.87 ± 2.61 25.08 ± 2.41 .098 25.28 ± 2.26 25.17 ± 2.19 .127 sft, cm 2.80 ± 1.08 2.73 ± 0.79 .668 2.69 ± 0.91 2.87 ± 1.07 .214 pfa, cm2 65.04 ± 9.61 65.06 ± 8.51 .998 65.12 ± 9.39 64.97 ± 9.03 .916 aat, cm 1.51 ± 0.67 1.38 ± 0.41 .163 1.40 ± 0.50 1.53 ± 0.68 .125 pat, cm 1.07 ± 0.48 0.93 ± 0.40 .055 0.94 ± 0.42 1.11 ± 0.50 .015 apt, cm 19.43 ± 1.80 19.90 ± 1.70 .085 19.36 ± 1.77 19.89 ± 1.75 .041 ratio (%) 86.95 ± 4.36 88.46 ± 3.00 .013 86.82 ± 4.54 88.02 ± 3.40 .042 abbreviations: bmi, body mass index; sft, subcutaneous fat thickness; pfa, periprostatic fat area; aat, anterior abdominal fat thicknesses; pat, posterior abdominal fat thicknesses; apt, anteroposterior diameter abdominal fat thicknesses; ns, not significant. ratio was calculated as: the anterior plus posterior abdominal wall fat thickness subtracted from the anteroposterior diameter divided by the anteroposterior diameter. * data are presented as mean ± sd. table 4. logistic regression analysis of factors predicting high-risk disease.* variables odds ratio (95% ci) p value prostate volume, cm3 1.01 (0.97-1.05) .599 t-zone volume, cm3 1.01 (0.96-1.06) .800 bmi, kg/m2 0.98 (0.63-1.58) .485 sft, cm 0.74 (0.44-1.22) .234 pfa, cm2 1.00 (0.96-1.04) .024 aat, cm 1.06 (0.96-1.15) .287 pat, cm 1.08 (1.02-1.21) .261 apt, cm 1.14 (1.02-1.24) .091 ratio (%) 1.05 (1.03-1.08) .031 abbreviations: bmi, body mass index; sft, subcutaneous fat thickness; pfa, periprostatic fat area; aat, anterior abdominal fat thicknesses; pat, posterior abdominal fat thicknesses; apt, anteroposterior diameter abdominal fat thicknesses; ci, confidence interval. ratio was calculated as: the anterior plus posterior abdominal wall fat thickness subtracted from the anteroposterior diameter divided by the anteroposterior diameter. * data are presented as mean (interquartile range). judgment of extracapsular disease extension, seminal vesicle in vasion or lymph node metastasis on mri. second, the periprostatic fat tissue could influence the positive outcome of systematic prostate biopsies. finally, the periprostatic fat tissue producing cytokine might change the level of preoperative serum psa, which has been proved to be associated with under staging and under grading in preoperative phase. in addition, our study has showed that the periprostatic fat could increase the difficulty and risk of operation (bleeding volume and duration of operation), probably because the periprostatic fat is rich in vascular. the limitations of our study are as follow: first, this is a retrospective review of prospectively maintained database, secondly, our study did not perform other anthropometric measurements such as waist circumference, waist-to-hip ratio and percentage of body fat. thirdly, different risk group definition could lead to different outcome. the reason why we choose the kattan,(14) is the treatment and prognosis of the localized pca assessed according to it in china. finally, the direct measurement of fat area and thickness on preoperative mri could result in the very small observed difference in the percentage of periprostate fat, because it includes muscle, spinal fluid and bowel as well as periprostatic fat within the calculation. despite these limitations, 1797 urological oncology urology journal vol. 11 no. 04 july august 2014 1798 the result still remained significance. in further study, we should apply quantitative method of mri to measure the periprostatic fat, in order to precisely reveal the association between periprostatic adiposity and aggressiveness of pca. in addition, we should perform animal experiment, in order to find the mechanism that the periprostate adiposity can influence aggressiveness of pca. conclusion the periprostatic adiposity can not only affects the aggressiveness, but also has effect in accurate evaluation of stage and grade of pca. in addition, the periprostate fat could increase the difficulty and risk of rrp. conflict of interest none declared. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global can cer statistics. ca cancer j clin. 2011;61:69-90. 2. zl tang, j bai, ln gu, l li, d xue. a systematic review: epidemic status of prostate cancer and breast cancer from 2000 to 2010 in china. china cancer. 2013,4:260-5. 3. tobias p, ute n, heiner b. obesity and cancer. proc nutr soc. 2008;67:128-45. 4. buschemeyer wc. 3rd, freedland sj. obesity and prostate cancer: epi demiology and clinical implications. eur urol. 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world j urol. 2010;28:699 704. 21. von hafe p, pina f, pérez a, tavares m, barros h. visceral fat accumu lation as a risk factor for prostate cancer. obes res. 2004;12:1930-5. 22. van roermund jg, hinnen ka, tolman cj, et al. periprostatic fat cor relates with tumour aggressiveness in prostate cancer patients. bju int. 2011;107:1775-9. 23. hsing aw, sakoda lc, chua s jr. obesity, metabolic syndrome, and prostate cancer. am j clin nutr. 2007;86:s843-57. 24. baillargeon j, rose dp. obesity, adipokines, and prostate cancer. int j oncol. 2006;28:737-45. 25. saglam k, aydur e, yilmaz m, göktaş s.bottom of form leptin inf luences cellular differentiation and progression in prostate cancer. j urol. 2003;169:1308-11. 26. oka r, miura k, sakurai m, et al. comparison of wcf with body mass index for predicting abdominal adipose tissue. diabetes res clin pract. 2009;83:100-5. 27. zilli t, chagnon m, nguyen tv, et al. influence of abdominal adiposity, waist circumference, and body mass index on clinical and pathologic findings in patients treated with radiotherapy for localized prostate can cer. cancer. 2010;116:5650-8. 28. pischon t, boeing h, weikert s, et al. body size and risk of prostate cancer in the european prospective investigation into cancer and nutriti on. cancer epidemiol biomarkers prev. 2008;17:3252-61. 29. ludescher b, machann j, eschweiler gw, et al. correlation of fat dist ribution in whole body mri with generally used anthropometric data. invest radiol. 2009;44:712-9. 30. grossfeld gd, chang jj, broering jm, et al. under staging and under grading in a contemporary series of patients undergoing radical prosta tectomy: result from the cancer of the prostate strategic urologic research endeavor database. j urol. 2001;165:851-6. periprostatic adiposity on mri and prostate cancer aggressiveness-qiang et al 31. fine sw, epstein ji. a contemporary study correlating prostate needle biopsy and radical prostatectomy gleason score. j urol. 2008;179:1335 8. 32. peller pa, young dc, marmaduke dp, marsh wl, badalament ra. sextant prostate biopsies. a histopathologic correlation with radical prostatectomy specimens. cancer. 1995:75:530-8. 1799 urological oncology pediatric urology possible impact of comorbid conditions on the persistence of nocturnal enuresis: results of a long-term follow-up study pietro ferrara,1 maria chiara de angelis,2 olga caporale,2 monica malamisura,2 valentina del volgo,2 flaminia vena,2 antonio gatto,1 antonio chiaretti1 1institute of pediatric, catholic university of sacred heart, rome, italy. 2campus bio-medico uni versity, rome, italy. corresponding author: pietro ferrara, md institute of pediatric, catholic university of sacred heart, rome, italy. tel: +39 06 30154348 fax: +39 06 3383211 e-mail: pferrara@rm.unicatt.it received january 2014 accepted june 2014 purpose: to describe the natural history of patients with nocturnal enuresis (ne) during a 10-year period and to evaluate possible impact of comorbid conditions on the persistence of ne. materials and methods: ninety-five children (male to female ratio [m:f] 65:30), aged at first visit between 6 and 21 years were included in this study. of study subjects 75 had primary monosymptomatic nocturnal enuresis (pmne), 3 had secondary monosymptomatic nocturnal enuresis (smne) and 17 had non-monosymptomatic nocturnal enuresis (nmne). demographic and ne-related details were assessed from electronic medical records and by telephone interview at the times 3, 6, 12 months and 3, 5, 10 years after the first examination. sixty-seven of 95 patients were enrolled, of whom 57 had pmne (m:f ratio 39:18, mean age 9.35 ± 2.81 years, mean age at improvement 11.5 ± 4.08 years), 8 had nmne (m:f ratio 4:4, mean age 10.1 ± 2.64 years, mean age at improvement 12.6 ± 1.68 years) and 2 had smne (m:f ratio 1:1, mean age 12 years, mean age at improvement 13.5 ± 2.12 years). results: the mean duration of follow up was 7.2 ± 2.5 years. all of the 67 children had 5 years follow up. only 29 of 67 patients (19 with pmne, 8 with nmne and 2 with smne) had 10 years follow up and 4 of 19 with pmne were still affected by ne. out of 57 patients with pmne 12 (2/12 with language disorders, 1/12 varicocele and 1/12 cryptorchidism) and out of 8 patients with nmne 1 were still enuretic while all patients with smne were in remission. conclusion: we observed that language disorders and testicular pathology in ne children could be comorbidities associated with persistence of ne and treatment resistance. keywords: nocturnal enuresis; risk factors; comorbidity; epidemiology; urination disorders. 1777 pediatric urology urology journal vol. 11 no. 04 july august 2014 1778 comorbid conditions and persistence of nocturnal enuresis-ferrara et al therapy with a chart for dries nights. active treatment should be avoided in children < 6 years of age. the first line therapy for the subgroup of patients with pmne associated with nocturnal polyuria and normal bladder function is desmopressin (ddavp) and/or the ne alarm (both level 1 grade a recommendations).(1,14,15) ddavp is an effective treatment for pmne, it rapidly reduces the number of wet nights per week compared with placebo and with homotoxicological remedies.(16) recent guidelines recommend an individualized treatment based on parameters obtained using a voiding diary.(17) therefore, it is important to identify effective interventions because successful treatment of ne can result in improvement in health, self-esteem and quality of life.(11) the aim of this study is to evaluate the natural history of patients with ne investigating a 5 and 10-year follow up period to increase the knowledge on these conditions in particular the possible impact of comorbid conditions on the persistence of ne. materials and methods study subjects children with ne and/or luts who referred to the pediatric nephrology clinic of “a. gemelli” university hospital of rome between january 2000 and december 2008 were eligible for inclusion in the study. exclusion criteria were, urogenital malformations, renal failure and chronic disease such as diabetes. we analyzed retrospectively data on medical records to identify signs and symptoms of voiding disorders and to evaluate behavioral characteristics of the child during the first examination and then by telephone interview which were performed at follow up periods of 3, 6 12 months and 3, 5 10 years. demographic details (sex, age) at first observation, family history of ne, age at attaining diurnal continence, and characteristics related to bedwetting, e.g. frequency of wetting, daytime incontinence, urgency, wetting during the early hours of sleep (before 12 pm) and early hours of morning (after 12 pm), deep sleep, snoring, left-handedness,(18) previous surgery, lumbosacral region trauma, allergies, constipation, encopresis, urinary tract infection (uti), previous therapy, presence of stress and worrying events including socialization and school performance, polythelia and signs of spinal dysraphism,(19) were extracted from patients’ records. to diagnose constipation, we used the rome iii criteria. at least two of the following criteria must be met for ≥ 2 months before diagnosis (patients should not have a diagnosis of irritable bowel syndrome), ≤ 2 defecations in the toilet per week, ≥ 1 episode of fecal incontinence per week, history of retentive posturing or excessive volitional stool retention, history of painful or hard bowel movements, presence of a large fecal mass in the rectum and history of large diameter stools that may obstruct the toilet.of the 95 eligible patients, 67 (male to female ratio [m:f] of 44:23, mean age at first visit 10 ± 2.78 years) participated in the telephone interview and were included in the study. age of imintroduction according to international children’s continence society (iccs), nocturnal enuresis (ne) is defined as intermit-tent incontinence while asleep in children older than 5 years age in which the sphincters control is acquired.(1) night wetting is dichotomized into monosymptomatic ne (mne) and non-monosymptomatic ne (nmne).(2) mne means bedwetting without any other lower urinary tract symptom (luts), and without a history of bladder dysfunction. ne in children with any other luts and with a history of bladder dysfunction is defined as non-monosymptomatic nocturnal enuresis (nmne).(1,2) there are different types of mne including primary monosymptomatic nocturnal enuresis (pmne) diagnosed in child who has never achieve nocturnal urinary continence (ui) and has never been dry at night.(3) it is considered related to impaired sleep arousal, to nocturnal polyuria, to a small nocturnal bladder capacity, or to a combination of these factors. secondary monosymptomatic nocturnal enuresis (smne) describes children who acquired urinary continence for at least 6 months and it is usually secondary to psychological stress or organic causes.(4) categorization into mne and non-mne, based on the absence or presence of bladder dysfunction, respectively, is important in clinical practice.(5) the estimated prevalence of ne are highly variable(6) because there is a heterogeneity in diagnostic criteria with few studies using iccs standardization.(1) the study of nevéus and sillén described the prevalence of ne and ui as approximately 10-15% at 5-year old, 5-10% at 7-year old, 3-8% at 10-year old children and 1-4% in adolescents with 0.5-2% in the untreated adults.(7) bedwetting is more common in boys than girls until the teenage years.(8) most studies show decreasing prevalence with increasing age, until about 1-2% in adulthood.(9) ne is a multifactorial disorder with a genetic underpinning. butler described a conceptual model that ne occurs when there is poor arousal from sleep in response to a sensation of a full bladder associated with overactivity of bladder function or with an excessive overnight urine production, or both.(10) other risk factors and correlates of ne include, delay in attaining bladder control, physiological factors such as constipation, fecal incontinence, daytime ui, caffeine consumption, sleep apnea, upper airway obstructive symptoms, lower socioeconomic status and black race.(6,11,12) family history of ne, is positive in 50% of cases. in particular pmne may be polygenetic, candidate genes have been localized to chromosomes 13, 12 and 8.(4,13) although different treatments (pharmacological, psychological/behavioral and alternative interventions) have been tried for ne, the relative effectiveness of each one remains uncertain. simple behavioral interventions are often the first line treatment tried by parents or caregivers at home with minimal professional involvement, including the reduction fluid intake after 6 or 7 pm and motivational (68.4%); constipation 3/57 (5.2%); left-handedness 12/57 (21%); deep sleep 53/57 (92.9%); utis 3/57 (5.2%) and polythelia 6/57 (10.5%). thirty of 57 (52.6%) children were treated with ddavp; 10/30 (33.3%) with nasal spray, 13/30 (43.3%) oral tablets 0.2 mg and 7/30 (23.3%) oral ddavp lyophilisate 120 µg (melt). the characteristics of these patients group were m:f ratio of 23:7; mean age at first examination 9.6 ± 2.6 years and mean age at remission 11.8 ± 3.73 years. at the different follow-up times the percentages of remission in children with drug therapy were 16/30 (53.3%) at 3 months; 18/30 (60.0%) at 6 months; 18/30 (60.0%) at 1 year; 19/30 (63.3%) at 3 years and 23/30 (76.7%) at 5 years. at 10 years we had data only for 12/30 children; 9/12 (75.0%) were in remission and 3/12 (25.0%) had pmne (table 1). of these patients, 2/12 (16.7%) were affected by language disturbances, 1/12 (8.3%) had dyslexia, 1/12 (8.3%) had delayed language development, 1/12 (8.3%) child had varicocele and another 1/12 (8.3%) had cryptorchidism. among 3 patients still bedwetting, 1 was affected by dyslexia, 1 had delayed language development and cryptorchidism and 1 was affected by varicocele. twenty-seven of 57 (47.4%) children were never treated with pharmacologic therapy, m:f ratio of 16:11, mean age at first examination 9.0 ± 2.9 years and mean age at remission 11.6 ± 4.47 years. at the different follow up time the percentage of remission in untreated children were 3/27 (11.1%) at 3 months; 4/27 (14.8%) at 6 months; 8/27 (29.6%) at 1 year; 19/27 (70.4%) at 3 years and 22/27 (81.5%) at 5 years. at 10 years we had data only for 7/27 children; 6/7 (85.7%) were in remission and 1/7 (14.3%) had pmne. the rate of remission in 39/57 (68.4%) children with pmne and positive family history was 12/39 (30.8%) at 3 months, 15/39 (38.5%) at 6 months; 21/39 (53.9%) at 1 year; 27/39 (69.2%) at 3 years and 32/39 (82.1%) at 5 years. at 10 years we had data only for 12 patients and rate of remission not considered. the rate of remission in children without family history of ne 18/57 (31.6%) was 4/18 (22.2%) at 3 months; 5/18 (27.8%) at 6 months; 7/18 (38.9%) at 1 year; 11/18 (61.1%) at 3 years and 13/18 (72.2%) at 5 provement, compliance to treatment and length of treatment were assessed by telephone interview at the follow up times of 3, 6 12 months and 3, 5 10 years after the first visit. using iccs definitions of pmne (child who has never achieve nocturnal urinary continence and has never been dry at night), smne (child who has acquired control for at least 6 months and it is usually secondary to psychological stress or organic causes) and nmne patients were included in 3 groups. of the 67 eligible patients there were 57 children with pmne, 39 (68.4%) male and 18 (31.6%) female with mean age at first examination 9.35 ± 2.81 years; 2 with smne, 1 (50%) male and 1 (50%) female, they were both 12 years old at first observation and 8 children with nmne, 4 (50%) male and 4 (50%) female with mean age at first observation 10.12 ± 2.64 years. data referring to the treatment response were classified as follows: “partial response” as a reduction of wet nights of 50-90%, and “full response” as a reduction of at least 90%. statistical analysis data are presented as frequency, percentage and standard deviation. comparison of remission in patients who received and didn’t receive special treatments is analyzed using chi-square test and p < 0.05 was considered statistically significant. the same statistical method is used to analyze data on positive family history. results ninety-five children were eligible for the study, 75/95 (78.9%) with pmne, 17/95 (17.9%) with nmne and 3/95 (3.2%) with smne. of the 75 eligible children with pmne, 57 (76.0%) had completed interviews and agreed to give information, while 13 (17.3%) did not participate due to disconnected telephone number and 5 (6.7%) didn’t participate due to parental refusal, parents affirmed that their children had never suffered from ne. eight of 17 (47.0%) patients with nmne and 2/3 (66.7%) with smne participated in the telephone interview. the characteristic of the 57 patients with pmne were: mean age at remission 11.5 ± 4,08 years; positive family history for ne 39/57 table 1. characteristics of treated and untreated children with primary monosymptomatic nocturnal enuresis. variables therapy no therapy p value patients (no.) 30 27 ---- male 23 16 ---- female 7 11 ----mean age at first visit (years) 9.6 9.0 ----mean age at remission (years) 11.8 11.6 ----remission at (%) ---- 3 months 53.3 11.1 .0007 6 months 60.0 14.8 .0005 1 year 60.0 29.6 .02 3 years 63.3 70.4 .57 5 years 76.7 81.5 .65 10 years 75.0 85.7 .58 1779 pediatric urology urology journal vol. 11 no. 04 july august 2014 1780 with pmne, in particular, children with familial aggregation pne are more likely to be severe symptoms and bladder dysfunction.(20,21) our study instead showed that at 5 years of follow up 82% of children with family history for ne were in remission vs. 72.2% of whom without family history of ne and the same trend was also observed in all previous follow up. these data could be analyze considering the association between genotype and phenotype to evaluate eventually genotype associated with the persistence of enuresis. in our study we observed that the highest percentage of remission (33.3%) occurred in the age group of 9-11 years and that, also among children who had never received pharmacologic therapy, 48.2% achieve spontaneous remission between 9-11 ages. however, details on reasons of this age distribution of remissions remain unknown. we observed that only 5.2% of children with pmne presented constipation, despite of previous studies which showed that prevalence of constipation in children affected by ne was significantly higher (12.6%).(22-24) furthermore, in our study, none of the children who were still affected by ne at 5 and 10 years had constipation. our study also showed an interesting relationship between oral language disorders and ne; 2/12 children who, after 10 years from the first visit, were still affected by ne, presented oral language disorders, dyslexia in one case and delayed language development in the other case. according to several studies the frequency of language disorders in the general population varied from 10-15% at 2 years old to 3% at 5 years old. this association at 10 years follow up was very strong so also considering the limit of small size of our study population this data is very significant. these data indicate that enuretic children present a higher percentage of oral language disorders when compared to non-enuretic children.(25) previous researches have instead suggested the association between ne and attention deficit hyperactivity disorder (adhd), probably related to delays in central nervous system maturation.(26) comorbidity between ne and adhd could either be due to common etiologic pathways underlying these two conditions or due to “causal” relations in which the non-resolution or treatment of one disorder increases the risk for the other disorder.(27) there aren’t data that showed a correlation between ne and testicular pathology, while we had observed that 2 children with long-term ne presented this kind of problems: cryptorchidism in a case and varicocele in another one. years. at 10 years we had data only for 7 patients and rate of remission was not considered (table 2). of the 17 children affected by nmne, 8 had completed telephone interview: 4/8 (50%) had positive family history, 6/8 (75%) had deep sleep and none had uti or left-handedness. mean age at recovery was 12.6 ± 1.68 years. pharmacological treatment was administered for 4/8 children (50%). the characteristics of this group were: m:f ratio of 3:1; mean age at first examination 9.7 ± 2.21 years and mean age at remission 12.7 ± 0.95 years. at the different follow up points the percentage of remission were 1/4 (25%) at 3, 6 and 12 months; 3/4 (75%) at 3 and 5 years and 4/4 (100%) at 10 years. at 10 years follow up, all the patients were in remission. one had a complete remission after 1 month of therapy, 2 had a partial response until the complete remission after 3 years, 1 child didn’t respond to therapy but he had a complete remission after 6 years spontaneously. four of 8 children, m:f ratio of 1:3, with nmne were never treated with drug therapy, mean age at first visit was 10.25 ± 3.31 years; mean age at recovery was 12.5 ± 2.38 years. at the follow-up after 3, 6 and 12 months and after 3, 5 and 10 years from the first visit, the percentage of remission were at 3 months 1/4 (25%); at 6 months 1/4 (25%); at 1 year 2/4 (50%); at 3 years ¾ (75%); at 5 years 4/4 (100%) at 10 years 4/4 (100%). of the 3 children with smne, 2 completed telephone interview, 1 was male, who was never treated with pharmacologic therapy and had a complete remission after 3 years spontaneously; the other 1 was female, she was treated with melt with a full response and complete remission after 1 month of therapy. at the follow up after 5 and 10 years, both of them were in remission. discussion according to other studies, our results confirm the recurrence of positive family history for ne. approximately 32% of cases are sporadic and 68% seems to follow a genetic predisposition. many authors had identified some associated genetic loci on different chromosomes, mainly a gene on chromosome 13 responsible for the dominant inheritance of ne and a gene on chromosome 12, on 22 and probably on 8.(4,13) thus, molecular genetics have shown that ne is a genetically complex disorder with locus heterogeneity and presumed gene-environment interactions. von gontard and colleagues and wang and colleagues demonstrated that a positive family history had significant effects on the children table 2. rate of remission in children with and without family history of nocturnal enuresis.* follow up periods children with positive family history children without family history p value 3 months 30.8 22.2 .50 6 months 38.5 27.8 .43 1 year 53.9 38.9 .29 3 years 69.2 61.1 .54 5 years 82.1 72.2 .39 10 years 75 85.7 .58 * data are presented as percentage. comorbid conditions and persistence of nocturnal enuresi-ferrara et al case report 1471 13. wei cc, wan l, lin wy, tsai fj. rs 6313 polymorphism in 5‐hydroxy tryptamine receptor 2a gene association with polysymptomatic primary nocturnal enuresis. j clin lab anal. 2010;24:371-5. 14. o’flynn n. nocturnal enuresis in children and young people: nice clin ical guideline. br j gen pract. 2011;61:360-2. 15. ferrara p, romano v, cortina i, ianniello f, fabrizio gc, chiaretti a. oral desmopressin lyophilisate (melt) for monosymptomatic enuresis: structured versus abrupt withdrawal. j pediatr urol. 2014;10:52-5. 16. ferrara p, marrone g, emmanuele v, et al. homotoxicological reme dies versus desmopressin versus placebo in the treatment of enuresis: a randomised, double-blind, controlled trial. pediatr nephrol. 2008;23:26974. 17. walle jv, rittig s, bauer s, eggert p, marschall-kehrel d, tekgul s. practical consensus guidelines for the management of enuresis. eur j ped. 2012;171:971-83. 18. ferrara p, ruggiero a, diociaiuti l, paoletti fp, chiozza m, caione p. primary nocturnal enuresis and left-handedness. scand j urol nephrol. 2001;35:184-5. 19. ferrara p, costa s, rigante d, et al. intramedullary epidermoid cyst pre senting with abnormal urological manifestations. spinal cord. 2003;41:645-8. 20. von gontard a, heron j, joinson c. family history of nocturnal enuresis and urinary incontinence: results from a large epidemiological study. j urol. 2011;185:2303-6. 21. wang qw, wen jg, song dk, su j, zhu qh, liu k. bed-wetting in chinese children: epidemiology and predictive factors. neurourol uro dyn. 2007;26:512-7. 22. loening-baucke v. prevalence rates for constipation and faecal and uri nary incontinence. arch dis child. 2007;92:486-9. 23. shadpour p, shiehmorteza m. enuresis persisting into adulthood. urol j. 2006;3:117-29. 24. barghi m. the relation of enuresis and irritable bowel syndrome with premature ejaculation: a preliminary report. urol j. 2005;2:201-5. 25. birenbaum tk, cunha mc. oral language disorders and enuresis in chil dren. pro fono. 2010;22:459-64. 26. park s, kim b-n, kim jw, et al. nocturnal enuresis is associated with attention deficit hyperactivity disorder and conduct problems. psychi atry investig. 2013;10:253-8. 27. merikangas kr, angst j, isler h. migraine and psychopathology: re sults of the zurich cohort study of young adults. arch gen psychiatry. 1990 ; 47:849 -53. conclusion considering the possible correlation between language disorders, testicular pathology and long term ne, it could be suggested that pediatricians, when dealing with this kind of diseases in enuretic children, pay more attention to the ne treatment, in a bio-psychical approach. future investigations on larger sample are useful to clarify this hypothesis. if this association will be confirmed the treatment in this children could be more strong both in drug and motivational therapy. conflict of interest none declared. references 1. nevéus t, von gontard a, hoebeke p, et al. the standardization of ter minology of lower urinary tract function in children and adolescents: report from the standardisation committee of the international chil dren’s continence society. j urol. 2006;176:314-24. 2. rittig n, hagstroem s, mahler b, et al. outcome of a standardized ap proach to childhood urinary symptoms-long‐term follow‐up of 720 patients. neurourol urodyn. 2014;33:475-81. 3. djurhuus jc. definitions of subtypes of enuresis. scand j urol nephrol. 1999;33:5-7. 4. ferrara p, ianniello f, romani l, fabrizio g, gatto a, chiaretti a. five years of experience in nocturnal enuresis and urinary incontinence in children: where we are and where we are going. urol int. 2014; 92:223-9. 5. butler rj, heron j. the prevalence of infrequent bedwetting and noc turnal enuresis in childhood: a large british cohort. scand j urol nephrol. 2008;42:257-64. 6. chiozza m, bernardinelli l, caione p, et al. an italian epidemiological multicentre study of nocturnal enuresis. br j urol. 1998;81:86-9. 7. nevéus t, sillén u. lower urinary tract function in childhood; normal development and common functional disturbances. acta physiologica. 2013; 207:85-92. 8. yeung ck, sreedhar b, sihoe jd, sit fk, lau j. differences in char acteristics of nocturnal enuresis between children and adolescents: a crit ical appraisal from a large epidemiological study. bju int. 2006;97:1069 73. 9. yeung ck, sihoe j, sit f, bower w, sreedhar b, lau j. characteristics of primary nocturnal enuresis in adults: an epidemiological study. bju int. 2004;93:341-5. 10. butler rj, holland p. the three systems: a conceptual way of under standing nocturnal enuresis. scand j urol nephrol. 2000;34:270-7. 11. caldwell ph, nankivell g, sureshkumar p. simple behavioural inter ventions for nocturnal enuresis in children. cochrane database syst rev. 2013;7:cd003637. 12. ferrara p, rigante d, lambert-gardini s, et al. urinary excretion of gly cosaminoglycans in patients with isolated nocturnal enuresis or com bined with diurnal incontinence. bju int. 2000;86:824-5. 1781 pediatric urology urological oncology multıparametric prostate magnetic resonance imaging before radical prostatectomy: can it predict histopathology? mehmet sahin1*, fuat kizilay1, ezgi guler2, banu sarsik3, mustafa harman2, serdar kalemci1, adnan simsir1, ibrahim cureklibatir1 purpose: we aimed to investigate the histopathological correlation of the suspected prostate malignancy detected in multiparametric prostate magnetic resonance imaging (mpmri). materials and methods: the data of 93 patients who underwent radical prostatectomy and had preoperative mpmri were examined. age and pre-operative prostate-specific antigen values were retrospectively collected from patient files. the pathology specimens were examined again and post-operative isup grade group, other pathological findings (seminal vesicle invasion, lymph node involvement, and extraprostatic extension), pre-operative mpmri were re-examined and pirads score, extracapsular extension, seminal vesicle invasion, neurovascular bundle invasion, lymph node involvement, and adc values were recorded. results: 151 (92,07%) of 164 lesions detected in mpmri were histopathologically correlated. 80% of patients with seminal vesicle invasion (p < 0.001), 28.8% of patients with extracapsular extension (p < 0.052) and 42.9% of patients with lymph node involvement (p = .001) in mpmri were histopathologically correlated. a significant relationship was found between pirads scores and isup grade groups (p < 0.001). there was a negative correlation between adc values and isup grade groups (p < 0.001). conclusion: our study showed that the lesions detected by mpmri showed a high histopathological correlation. keywords: correlation; diagnosis; histopathology; prostate cancer; multiparametric prostate mri introduction prostate cancer (pca) is considered as one of the most important health problems encountered in male population. in europe, pca, which exceeds the number of colorectal and lung cancer, has been the most common solid neoplasm(1). however, pca is the second most common cause of cancer death in men(2). since pca has a heterogeneous structure, two or more graded tumors may coexist in the same disease. therefore, the gleason grading system, defined by donald gleason in 1966 and later modified, is used for the grading of prostate adenocarcinoma(3). in 2014, the international society of urological pathology (isup) prostate carcinoma gleason grading conference brought a new interpretation to the gleason score. the isup grading system has been introduced to describe in detail the clinically important distinction between gleason score 7 (4+3) and 7 (3+4) prostate adenocarcinoma(4). magnetic resonance imaging (mri) has been used for the non-invasive assessment of the prostate gland and surrounding structures since the 1980s. initially, prostate mri was based solely on morphological evaluation using t1-weighted and t2-weighted sequences, and its primary role was local staging in the patients with pca proven by biopsy. advances in technology have led to the development of multiparametric mri (mpmri) 1departmentof urology, ege university hospital, izmir 35100, turkey. 2department of radiology, ege university hospital, izmir 35100, turkey. 3department of pathology, ege university hospital, izmir 35100, turkey. *correspondence: department of urology, ege university school of medicine, izmir 35100, turkey. tel: +90 505 900 57 02 fax: + 90 (232) 374 65 52 e-mail: dr.mehmetsahin@hotmail.com. received february 2020 & accepted october 2020 which combines t2 weighted imaging with functional and physicological evaluation through techniques such as diffusion weighted imaging (dwi), and its variations like diffusion coefficient (adc) and dynamic contrast-enhanced imaging (dci). in 2012, prostate imaging and reporting and data system (pirads) version 1 (v1) was released by the european society of urogenital radiology (esur). as a result of the increase in experience and rapid progress in this field, some limitations of this scoring system have emerged. pirads v2 has been published in 2014 to make the standardization more acceptable(5). however, further efforts are underway to improve it and overcome its shortcomings. the pirads v2 uses a 5-point scale based on the combination of mpmri findings in t2w, dwi, and dci which is associated with the presence of a clinically significant cancer for each lesion in the prostate gland(5). pirads v2 segmentation model is adapted from the european consensus meeting and the esur 2012 prostate mri guidelines(5). the use of this map; enables radiologists, urologists, and pathologists to localize the findings described in mri, and is a valuable visual aid for discussions with patients about biopsy and treatment options. mpmri has recently become more widely used in the urology journal/vol 18 no. 4/ july-august 2021/ pp. 417-421. [doi: 10.22037/uj.v16i7.6025] diagnosis and staging of pca, and its importance has increased with increasing experience and device quality. in this study, we aimed to investigate the histopathological correlation of malignant suspected foci detected in mpmri. materials and methods study population 919 patients who underwent radical prostatectomy at a third step urology department between january 2012 and june 2018 were included. retropubic radical prostatectomy or transperitoneal robot-assisted laparoscopic radical prostatectomy (da vinci si system, intuitivesurgical®) was performed. patients who had not undergone mpmri and had not been recorded according to pirads v2 and those who had previously received radiotherapy and/or hormonotherapy for pca were excluded. procedures gleason scores, lesion localization, capsule invasion, extraprostatic extension, peripheral surgical margin status, seminal vesicle invasion, lymph node involvement, and isup grade were evaluated by an experienced uropathologist. pirads scores, lesion localization, lymph node involvement, capsule invasion, seminal vesicle invasion, and adc scores of lesions were evaluated by an experienced uroradiologist. age and pre-operative psa data were collected retrospectively from patient files. the gleason score and isup grading were assigned according to the decisions of the international urological pathology consensus conference on the gleason grading of pca in 2014. pirads scores were assigned acmpmri and prostate histopathology-sahin et al. figure 1. distribution of average adc values by grade group figure 2. distribution of gleason scores according to pirads scores of lesions vol 18 no 4 july-august 2021 418 cording to piradsv2. permission was obtained from all patients for the availability of preoperative data. ethics committee approval was received (decision number: 18-10.1/7). during the study, the principles of the declaration of helsinki were followed and confidentiality of the data was ensured. evaluations histopathological correlation of suspicious foci detected in mpmri and radiological correlation of foci detected in pathology was analyzed. histopathological confirmation of seminal vesicle invasion, capsule invasion, and lymph node involvement detected in mpmri was analyzed. the relationship between adc value and isup grade group was analyzed. the relationship between pirads score with gleason score and pirads score with isup grade group was analyzed. statistical analysis statistical analysis was performed using spss for windows 22.0. chi-square, anova, mcnemar, kappa, mann-whitney-u, kruskal-wallis, and logistic regression tests were used for statistical analysis. p < 0.05 was considered statistically significant. results the mean age of patients was 65.38 ± 6,814, and the median pre-op psa value was 8 ng/ml and the interquartile range of pre-op psa was 10.935 ng/ml. mpmri and histopathologic data of the patients are shown in table 1. one hundred and fifty one (92.07%) of 164 lesions detected in mpmris of 93 patients were confirmed with radical prostatectomy specimens. 151 (60.88%) of 248 lesions detected by a pathologist were confirmed by a radiologist. we investigated the histopathological correlation of patients with seminal vesicle invasion, capsule invasion, and lymph node involvement in mpmri. both methods were shown to be significantly similar in detecting seminal vesicle invasion and lymph node involvement. histopathological correlation of patients with seminal vesicle invasion, capsule invasion, and lymph node involvement in mpmri is shown in table 2. we found a negative correlation between adc value and isup 2014 groups using anova test. we determined that the adc value decreased as the isup grade group increased. (p < 0.001) spearman's rho correlation coefficient was 0.432. the relationship between adc value and isup 2014 grade group is shown in figure 1. a positive correlation was found between pirads score and gleason score with kruskal wallis test. (p < 0.001) spearman's rho correlation coefficient was 0.449. we showed that with using bonferroni correction for multiple comparisons, the difference between pirads 3 and 4 was not significant (p .073), while the difference between pirads 3 and 5 (p < 0.001), and pirads 4 and 5 (p < 0.001) were statistically significant. figure 2 shows the distribution of gleason score according to pirads scores of lesions. discussion there are studies investigating the rate of accurate diagnosis of pca by taking random transrectal ultrasound (trus) guided biopsy, transperineal template prostate mapping biopsy, mri-targeted trus biopsy, and radical prostatectomy specimen histopathology as the standard reference diagnostic method(8-10,15). the general opinion is that radical prostatectomy histopathology is the most valid reference standard. in our study, the radical prostatectomy specimen was accepted as the reference. with the emerging role of mpmri, the current paradigm of pca staging is changing, with greater emphasis on the inclusion of mpmri in clinical staging(6). before definitive treatment, staging can be performed with mpmri. significant staging data may be obtained with mpmri to guide definitive treatment. using mpmri may improve surgical, oncological, and functional management(7). loggitsi et al. reported 53% sensitivity and 90.3% specificity for mpmri by taking radical prostatectomy hisurological oncology 419 table 1. demographic, preoperative, perioperative, and histopathologic data for groups 1 and 2 variables (n = 93) number (%) seminal vesicle invasion (pathology) positive 14 (15.1%) negative 79 (84.9%) seminal vesicle invasion (mpmri) positive 15 (16.1%) negative 78 (83.9%) capsule invasion (pathology) positive 20 (21.5%) negative 73 (78.5%) capsule invasion (mpmri) positive 52 (55.9%) negative 41 (44.1%) lymph node involvement (pathology) positive 8 (8.6%) negative 85 (91.4%) lymph node involvement (mpmri) positive 7 (7.5%) negative 86 (92.5%) neurovascular bundle invasion (mpmri) positive 46 (49.5%) negative 47 (50.5%) extraprostatic extension (pathology) positive 40 (43%) negative 53 (57%) peripheral surgical margin (pathology) positive 20 (21.5%) negative 73 (78.5%) operation type rrp 43 (46.2%) ralrp 50 (53.8%) gleason score n = 248 (3 + 3) 6/10 22 (8.8%) (3 + 4) 7/10 94 (37.9%) (4 + 3) 7/10 63 (25.4%) (4 + 3,5) 7/10 4 (1.6%) (4 + 4) 8/10 28 (11.2%) (4 + 4,5) 8/10 5 (2%) (4 + 5) 9/10 26 (10.4%) (5 + 4) 9/10 6 (2.4%) grade group (isup 2014) n = 248 1 22 (8.4%) 2 95 (36.4%) 3 66 (25.3%) 4 33 (12.6%) 5 32 (12.3%) pirads score n = 161 3 7 (4.3%) 4 66 (41%) 5 88 (54.7%) abbreviations: mpmri, multiparametric prostate magnetic resonance imaging; rrp, retropubic radical prostatectomy; ralrp, robot assisted laparoscopic radical prostatectomy; psa, prostate spesific antigen; isup, international society of urological pathology. mpmri and prostate histopathology-sahin et al. topathology as a reference(8). lee et al. reported 46% sensitivity for mpmri and 77.7% specificity for index lesions using radical prostatectomy histopathology as a reference for detecting clinically significant pca(9). in our study, pirads score ≥ 3 lesions in mpmri were reported in 151 (60.9%) of a total of 248 foci with cancer detected by pathology. this may be due to the smaller size of these foci or the presence of well differentiated tumors. the diagnostic value of mri decreases in lesions < 5 ml and poorly differentiated tumors are more easily detected by mri. in the study of radtke et al., the cancer detection rate of mpmri was significantly increased in lesions with a gleason score ≥ 3+4 7/10 and tumor volume of ≥ 0.55 ml(10). tumor was confirmed histopathologically in 151 (92.07%) of 164 foci with pirads score ≥ 3 lesions reported in mpmri. since our study was a correlation study, there were no false positive results of pathology. therefore, specificity could not be calculated. the sensitivity was 60.9%. bonekamp et al. reported that clinically significant cancer was detected in 97% of the foci with a pirads score ≥ 3 in mpmri by mpmri targeted biopsy(11). they also reported that only 18% of foci detected by mpmri were false. in our study, the rate of cancer in foci indicated by mpmri was 92.07%. in addition, 97 of 248 foci (39.1%) reported by pathology could not be detected by mpmri. the difference may be due to the use of mri biopsy like in the study of bonekamp et al. ruprecht et al. reported 77.78% sensitivity and 92.86% specificity for histopathological confirmation of seminal vesicle invasion in mpmri(12). in our study, 85% sensitivity and 96% specificity were detected. this difference may be due to the fact that radiologist interpreting mpmris in our study is experienced and 3 tesla mri was used in our study. for the confirmation of extraprostatic extension in mpmri by pathology, in a meta-analysis conducted by salerno et al, 50% sensitivity and 85% specificity have been reported for extraprostatic extension in mpmri(13). similar to these meta-analysis data, we found 49.3% sensitivity and 75% specificity in our study. in the study of vonbelow et al. on confirmation of lymph node invasion detected by mpmri, they reported 55% sensitivity, 90% specificity, and 75% accuracy for lymph node involvement in mpmri(14). in our study, 37.5% sensitivity and 95% specificity were detected. the difference may be fact that all patients have undergone extended lymph node dissection and included patients with moderate to high-risk pca only by vonbelow. in our study, extended lymph node dissection was not performed in all patients and low-risk patients were also included. in the study of gaur et al., a negative correlation was found between adc values and isup grade group. in the same study, a negative correlation was also found between pirads scores and adc values(15). in our study, a negative correlation was found between adc values and isup grade groups in accordance with the literature. in the study of john et al. on the probability of detecting clinically significant pca with increasing pirads score; 11.1% of patients with pirads 3 lesions, 42.9% of patients with pirads 4 lesions, and 35.6% of patients with pirads 5 lesions were clinically significant (isup grade group ≥ 2)(16). in our study, clinically significant pca was detected in 42.3% of pirads 3 lesions, 91.8% of pirads 4 lesions, and 98.8% of pirads 5 lesions. the difference was due to the fact that the patients in our study were previously diagnosed with trus biopsy and radical prostatectomy was performed and trus/mri cognitive fusion biopsy was performed in patients without a previous diagnosis in the study of john et al. similar results have been obtained in other studies; mpmri findings were correlated with biopsy results and pirads score was correlated with isup grade group and gleason score(17,18). the limitations of our study are its retrospective manner and the low number of patients because of recent utilization of mpmri in our institute. conclusions based on these results, we concluded that the rate of malignancy diagnosis was found to be very high in the lesions reported as mpmri was likely malignant (pirads score ≥ 3). on the other hand, almost 40% of the malign foci could not be detected by mpmri. as the experience and knowledge of radiologists and mpmri technique, equipment, pirads scoring system improve, the diagnostic ability and objectivity of the test will increase. as the staging accuracy in mpmri improves, treatment planning or the priority of the patients may change. there may also be decision changes including the operating methods and techniques. the role of mpmri in the diagnosis of pca can be better demonstrated with prospective studies including larger patient populations. acknowledgement this study was approved in the ethics comitte of ege university medical faculty, as a research project. the authors would like to thank dr. timur kose and appreciate his support for the statistical analysis of this study. conflict of interest the authors report no conflict of interest. references 1. boyle p, ferlay j. cancer incidence and mortality in europe 2004. ann oncol 2005 mar;16:481-8. 2. jemal a, siegel r, ward e et al. cancer table 2. histopathological correlation of patients with seminal vesicle invasion, capsule invasion and lymph node involvement in mpmri. variablesa histopathologic correlation kappa value p-value seminal vesicle invasion 12 of 15 (80%) .796 < 0.01 capsule invasion 15 of 52 (28.8%) .154 .052 lymph node involvement 3 of 7 (42.9%) .348 .001 a variables were compared by mc nemar test mpmri and prostate histopathology-sahin et al. vol 18 no 4 july-august 2021 420 statistics, 2008. ca cancer j clin 2008 marapr;58:71-96. 3. gleason df: classification of prostatic carcinomas. cancer chemother rep 1966, 50:125-8 4. epstein ji, egevad l, amin mb, et al. the 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. am j surg pathol. 2016 feb;40:244-52. 5. weinreb jc, barentsz jo, choyke pl, et al. pi-rads prostate imaging reporting and data system: 2015, version 2. eur urol. 2016 jan;69:16-40. 6. gupta rt, faridi kf, singh aa, et al. comparing 3-t multiparametric mr imaging and the partin tables to predict organ-confined prostate cancer after radical prostatectomy. urol oncol 2014 nov;32:1292-9. 7. sciarra a, barentsz j, bjartell a, et al. advances in magnetic resonance imaging: how they are changing the management of prostate cancer. eur urol. 2011 jun;59:96277. 8. loggitsi d, gyftopoulos a, economopoulos n et al. multiparametric magnetic resonance imaging of the prostate for tumour detection and local staging: imaging in 1.5t and histopathologic correlation. can assoc radiol j. 2017 nov;68:379-86. 9. chan ho lee, ja yoon ku, won young park, nam kyung lee, hong koo ha. comparison of the accuracy of multiparametric magnetic resonance imaging (mpmri) results with the final pathology findings for radical prostatectomy specimens in the detection of prostate cancer. asia pac j clin oncol. 2019 apr; 15:20-7. 10. radtke jp, schwab c, wolf mb, et al. multiparametric magnetic resonance imaging (mri) and mri-transrectal ultrasound fusion biopsy for index tumor detection: correlation with radical prostatectomy specimen. eur urol. 2016 nov;70:846-53. 11. bonekamp d, schelb p, wiesenfarth m, et al. histopathological to multiparametric mri spatial mapping of extended systematic sextant and mr/trus-fusion-targeted biopsy of the prostate. eur radiol. 2019 apr;29:182030. 12. oliver ruprecht, philipp weisser, boris bodelle, hanns ackermann, thomas j vogl. mri of the prostate: interobserver agreement compared with histopathologic outcome after radical prostatectomy. eur j radiol. 2012 mar;81:456-60. 13. salerno j, finelli a, morash c, et al. multiparametric magnetic resonance imaging for pre-treatment local staging of prostate cancer: a cancer care ontario clinical practice guideline. can urol assoc j. 2016 sep-oct;10:332-9. 14. von below c, daouacher g, wassberg c et al. validation of 3 t mri including diffusionweighted imaging for nodal staging of newly diagnosed intermediateand high-risk prostate cancer. clin radiol 2016 apr;71:328-34. 15. gaur s, harmon s, rosenblum l, et al. can apparent diffusion coefficient values assist pi-rads version 2 dwi scoring? a correlation study using the pi-radsv2 and international society of urological pathology systems. ajr am j roentgenol. 2018 jul;211:33-41. 16. john s, cooper s, breau rh, et al. multiparametric magnetic resonance imaging transrectal ultrasound-guided cognitive fusion biopsy of the prostate: clinically significant cancer detection rates stratified by the prostate imaging and data reporting system version 2 assessment category. can urol assoc j. 2018 jun 19;12:401-6. 17. hofbauer sl, maxeiner a, kittner b, et al. validation of prostate imaging reporting and data system version 2 for the detection of prostate cancer. j urol. 2018 oct;200:76773. 18. mehralivand s, bednarova s, shih jh, et al. prospective evaluation of pi-rads™ version 2 using the international society of urological pathology prostate cancer grade group system. j urol. 2017 sep;198:583-90. urological oncology 421 mpmri and prostate histopathology-sahin et al. v08_no_2_final.pdf urological oncology 113urology journal vol 8 no 2 spring 2011 bowel preparation and peri-operative management for radical cystectomy in turkey turkish urooncology association multicenter survey guven aslan,1 sumer baltaci,2 cag cal,3 levent turkeri,4 bulent gunlusoy,5 oztug adsan,6 and member participants* purpose: to investigate the preferences and practice patterns of urooncologic surgeons in turkey on bowel preparation and peri-operative management for radical cystectomy. materials and methods: this study was conducted by turkish urooncology association as a multicenter survey. participants were asked to fill in questionnaires dispensed at annual oncologic meeting or using internet access to the website of urooncology association. the questionnaire consisted of multiple choice or open-ended questions related to frequency of cystectomy, surgical technique and type of diversion, bowel preparation protocol, nasogastric tube applications, antibiotic prophylaxis, and deep vein thrombosis prophylaxis. collected data from the survey were presented descriptively. results: forty-four questionnaires from 44 surgeons of different centers were evaluated. all participants answered that they always perform bowel preparation before cystectomy. four participants reported that they had an experience of cystectomy without bowel preparation. bowel preparation methods included long conservative methods, short enema protocols, and golytely, but there were significant differences in application of each method. of participants, 88.6% perform diversion by themselves whereas others ask help from a general surgeon. antibiotic prophylaxis is preferred mostly by 2 agents using third-generation cephalosporins and metronidazole for a period of 5 days or more in the majority. type, duration, and dosage of deep vein thrombosis prophylaxis differed among participants. conclusion: there are significant individual differences in peri-operative management of radical cystectomy, which render deficient and sometimes inadequate patient care. there is a need to establish standard protocols for bowel preparation and adequate peri-operative management for radical cystectomy. urol j. 2011;8:113-9. www.uj.unrc.ir keywords: urinary bladder neoplasm, urinary diversion, perioperative care, postoperative complications 1department of urology, dokuz eylul university, izmir, turkey 2department of urology, ankara university, ankara, turkey 3department of urology, ege university, izmir, turkey 4department of urology, marmara university, istanbul, turkey 5department of urology, izmir education hospital, izmir, turkey 6department of urology, ankara numune hospital, ankara, turkey *member participants: oner sanli: istanbul university urology department, istanbul, turkey zuhtu tansug: çukurova university urology department, adana, turkey urology department, istanbul, turkey cemil uygur: ankara oncology hospital urology department, ankara,turkey haluk ozen: hacettepe university urology department, ankara, turkey corresponding author: guven aslan, md department of urology, dokuz eylul university school of medicine, inciralti, 35340, izmir, turkey tel: +90 232 412 3456 fax: +90 232 412 3479 e-mail: aslang@deu.edu.tr received january 2010 accepted august 2010 introduction radical cystectomy (rc) represents the standard treatment for muscle and non muscle invasive bladder cancer not controlled by conventional treatment options.(1,2) despite improvements in perioperative care, rc is still associated with greater morbidity and mortality than any other urological procedures.(1-4) radical cystectomy is an invasive procedure, with an early complication rate of approximately 30% and median hospital stay of 7 days in specialist centers, which has significant peri-operative management for radical cystectomy—aslan et al 114 urology journal vol 8 no 2 spring 2011 implications for peri-operative management and healthcare as a whole.(4) bladder cancer is predominantly a disease of the aging population, when comorbid conditions commonly exist, further emphasizing the importance of peri-operative care and surgical management.(5) bowel preparation, nutritional support, antibiotic prophylaxis, risk of venous thrombosis, etc are well-known measures for rc. however, there are wide variations in treatment protocols, and different peri-operative regimens are recommended by several authors, specifically for bowel preparation.(5-9) in recent years, few reports have been published to attempt standardization of preand postoperative measures of rc, including bowel preparation and nutritional support.(5,10-15) however, a guideline statement for standard peri-operative management of rc has not been published yet. there is no consensus on the best peri-operative regimen for rc mostly due to a lack of evidence from large randomized clinical trials. we sought to investigate the current peri-operative management strategies adopted by turkish urologists specific to urooncology, to determine the discrepancies of their clinical practice and to evaluate the need for directory of guidelines for cystectomy. the questions posed were specifically designed to include controversial issues in perioperative management of rc. materials and methods this study was conducted by turkish urooncology association as a multicenter survey. all participants were certified active members of urooncology association and they were all experienced surgeons and specific to urooncology in their surgical practice. a questionnaire was designed to assess patterns of practice across the country regarding perioperative regimens and bowel preparation at cystectomy and dispatched to urologists (appendix). the questionnaire consisted of multiple choice or open-ended questions related to frequency of cystectomy, surgical technique and type of diversion, bowel preparation protocol, nasogastric tube applications, antibiotic prophylaxis, and deep vein thrombosis (dvt) prophylaxis. participants were asked to fill in the questionnaire dispensed at annual urooncologic meeting or using internet access to the website of urooncology association. subjects’ opinions were also asked about cystectomy without any bowel preparation as well as need for a standard protocol of rc preparation and early recovery period management. returned questionnaires were analyzed and collected data from the survey were presented descriptively. no statistical analyses were performed. results forty-four questionnaires from 35 centers (either university hospital or state hospital) were evaluated. response rate was 76% considering 46 member centers registered to urooncology asccociation. data from selected questions are shown in table 1. all participants answered that they always perform bowel preparation before cystectomy, but 4 participants reported an experience of cystectomy without bowel preparation. bowel preparation includes long conservative method combined with diet restriction plus enema and oral laxatives or one-day protocol using laxatives and/or enema with sodium phosphate and polyethylene glycol administered the day before the surgery, but significant differences were encountered in application of each method. several authors apply 3-day oral restrictive diet with antibiotics for enteric flora whereas some do not use antibiotics. some use enemas on the 2nd and 3rd day whereas some use both oral laxative and enema on the 3rd day of preparation. considering short form of bowel preparation, some use one laxative with enema, other use two consecutive oral laxatives only. some use 2 laxatives and enema in the evening and early morning while others use only enema at midnight or in the early morning before the operation. almost 30% of the participants reported that they would consider doing cystectomy without bowel peri-operative management for radical cystectomy—aslan et al 115urology journal vol 8 no 2 spring 2011 preparation when the ileum was used. however, they are all used to doing bowel preparation in their daily practice, which may reflect traditional conservative manner. when participants were asked why they were opposite to no bowel preparation, the reasons were no strong evidence in urology literature, potentially increased risk of complications, and no attempt at their center before, respectively. nineteen of the participants reported that they would add their patients to such a clinical trial without bowel preparation if requested. antibiotic prophylaxis is preferred mostly by 2 agents, including both third-generation cephalosporins and metronidazole for a period of 5 days or more in the majority. type, duration, and dosage of dvt prophylaxis differed among participants. some commence low molecular weight heparin at midnight before the surgery and continue until mobilization while some continue its use 3 days; some use it once a day and others twice a day. low molecular weight heparin combined with elastic bandages is reported in few. interestingly, 4 participants reported that they never use any form of prophylaxis. of participants, 88.6% perform diversion by themselves whereas remained surgeons ask a general surgeon for help. the ileum is the most preferred bowel segment for diversion. a substantial number of participants (75%) rinse the isolated ileum segment with antiseptic solutions. a significant number of participants reported that there is a need for preparation of standard protocols for rc. nearly all participants reported that they would clearly apply these protocols as their routine when they were recommended at guidelines. discussion peri-operative care impacts substantially on the postoperative course of rc. antibiotic and dvt prophylaxis as well as bowel preparation are key issues in decreasing morbidity and mortality as much as surgical technique and anesthetic procedures. this study expectedly has shown that number of cystectomy per year (n) <5 5 to 10 10 to 20 >20 3 11 19 11 deep venous thrombosis prophylaxis (n) elastic bandage compression only low molecular weight heparin only low molecular weight heparin + elastic bandage compression none 4 23 9 4 distribution of diversion type, % ileal conduit orthotopic bladder catheterized pouch 69, 7 33, 2 8, 5 pre-operative diet restriction (n) yes no 23 21 mostly used bowel segment for diversion,% ileum colon 95, 5 4, 5 agree to consider ileal diversion without bowel preparation (n) yes no uncertain 13 21 10 antibiotic prophylaxis for bowel flora (n) erythromycin neomycin both none 15 6 1 19 time to nasogastric tube out (n) 1st postoperative day 2nd postoperative day 3rd postoperative day after flatulence no nasogastric tube 6 8 1 25 2 antibiotic prophylaxis (n) metronidazol + 3rd generation cephalosporin 5 to 7 days single dose metronidazol + 3rd generation cephalosporin ampicillin/sulbactam + gentamicin cephalosporin monotherapy 31 9 1 2 time to start first oral intake (n) 2nd postoperative day 3rd postoperative day 4th postoperative day after flatulence others 3 7 1 32 1 bowel anastomosis technique, % primer suture stapler both 31, 8 47, 7 20, 5 necessity for standard protocols, % yes no uncertain 93,2 4, 5 2, 3 table 1. descriptive data of selected questions from 44 urologists. peri-operative management for radical cystectomy—aslan et al 116 urology journal vol 8 no 2 spring 2011 there were great discrepancies between physicians’ preferences in implementation of antibiotic prophylaxis, dvt prophylaxis, and bowel preparation regimens for rc. we have found that every participant uses bowel preparation before the surgery. almost half of them prefer long conservative bowel preparation methods with diet restricted 2 to 3 days. currently, there is a raising trend towards fast tract surgery, and thus short form of bowel preparation or abandoning bowel preparation are highlighted in few reports.(5,13,14,16-19) however, bowel preparation acceptance seems to be low among urologists. there is no uniformity in the literature for bowel preparation, and it is not addressed in american urological association (aua) and european association of urology (eau) guidelines in detail. high volume cystectomy centers have different protocols for bowel preparation.(6-8) few data advocate no bowel preparation for cystectomy when the ileum is to be used in current practice among our survey urologists and probably worldwide is in favor of some form of bowel preparation. although our study group specifically addresses turkish urologists, one could infer that heterogeneity in the practice patterns would be similar in most of the countries. in our survey, most urologists use antibiotic prophylaxis with 2 types of antibiotics, but few prefer one. most of the participants in our survey use antibiotics longer than advised duration in eau guidelines.(20) although eau guideline recommends maximum 3-day antibiotic usage, our survey has shown that the majority of surgeons prefer antibiotic administration for at least 5 days or more (table 2). our results demonstrated that the majority of urologists wait for flatulence both for nasogastric tube removal and for commencing oral intake. although there are several reports in favor of early removal of nasogastric tube and early oral intake, there is low acceptability among our urologists.(5,14,19,21) in our survey, oral intake was strictly dependent on flatulence reported by the patient. the limitations of our study are evident inherent to all surveys, including the wording and order of questions and the potential bias of the interviewer. our results are clearly limited to practicing turkish urologists and can not be generalized to any practice in any country. in addition, only descriptive data are presented; statistical comparisons were not performed. some of other key important questions, including nutrition preferences, catheter care, use of alkalizing agent, etc are overlooked in our survey. despite these limitations, this is one of the first surveys of practice patterns in rc among urologists. this study can perhaps be looked on as providing a baseline reference assessment of practice preferences for cystectomy to which future assessments of guideline implementation, impact, and compliance can be compared. in the present study, our main aim was to describe the current situation and controversies about peri-operative management of cystectomy. although our study sample represents turkish urology, we strongly believe, based on the current literature, that differences in practice patterns are similar worldwide. more flexible and freely adopted protocols are sometimes inappropriate and may increase morbidity because there is no written standard guideline current study eau guideline aua guideline reference 10 reference 5 bowel preparation short form long conservative diet no bowel preparation 50% 50% none not addressed not addressed no bowel preparation cleansing enema before surgery antibiotic prophylaxis at least 5 days maximum 3 days not addressed not addressed not addressed nasogastric tube usually after flatulence not addressed not addressed not addressed 2 to 8 hours deep venous thrombosis prophylaxis heterogeneous not addressed not addressed low molecular weight heparin + stocking not addressed *eau indicates european association of urology; and aua, american urological association. table 2. comparison of current approaches in the peri-operative management of cystectomy.* peri-operative management for radical cystectomy—aslan et al 117urology journal vol 8 no 2 spring 2011 or consensus report about bowel preparation and early postoperative management of rc. hence, our study may take attention of urology community into set up of standard approaches in peri-operative management of rc. we believe our results clearly demonstrate a lack of uniformity and an overall low acceptance of the few urologic guidelines or recommendations, which cause concern and should lead to further investigations. our findings highlight the importance of adequate standard peri-operative regimens for rc. conclusion the majority of urologists use their own experience alone to direct peri-operative period, given the lack of evidence to support specific protocol. due to lack of standard recommendations, more liberate bowel preparation and peri-operative regimens have been performed currently, which seem to be inadequate in many forms. an evidence-based protocol of peri-operative management could contribute to reduce discrepancies and thus prevent or reduce complications associated with radical cystectomy and intestinal urinary diversion. we have clearly shown the rationale of such a protocol. acknowledgements the authors are thankful to all participative members of turkish urooncology association. conflict of interest none declared. references 1. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001;19:666-75. 2. dalbagni g, genega e, hashibe m, et al. cystectomy for bladder cancer: a contemporary series. j urol. 2001;165:1111-6. 3. novotny v, hakenberg ow, wiessner d, et al. perioperative complications of radical cystectomy in a contemporary series. eur urol. 2007;51:397-401; discussion -2. 4. chang ss, cookson ms, baumgartner rg, wells n, smith ja, jr. analysis of early complications after radical cystectomy: results of a collaborative care pathway. j urol. 2002;167:2012-6. 5. maffezzini m, gerbi g, campodonico f, parodi d. multimodal perioperative plan for radical cystectomy and intestinal urinary diversion. i. effect on recovery of intestinal function and occurrence of complications. urology. 2007;69:1107-11. 6. stein jp, skinner dg. surgical atlas: the orthotopic t-pouch ileal neobladder. bju int. 2006;98:469-82. 7. bhatta dhar n, kessler tm, mills rd, burkhard f, studer ue. nerve-sparing radical cystectomy and orthotopic bladder replacement in female patients. eur urol. 2007;52:1006-14. 8. ghoneim ma. surgical atlas: orthotopic bladder substitution in women after cystectomy for bladder cancer. bju int. 2004;93:891-908. 9. irwin bh, gill is, haber gp, campbell sc. laparoscopic radical cystectomy: current status, outcomes, and patient selection. curr treat options oncol. 2009;10:243-55. 10. arumainayagam n, mcgrath j, jefferson kp, gillatt da. introduction of an enhanced recovery protocol for radical cystectomy. bju int. 2008;101:698-701. 11. maffezzini m, gerbi g, campodonico f, parodi d. a multimodal perioperative plan for radical cystectomy and urinary intestinal diversion: effects, limits and complications of early artificial nutrition. j urol. 2006;176:945-8; discussion 8-9. 12. slim k, vicaut e, panis y, chipponi j. meta-analysis of randomized clinical trials of colorectal surgery with or without mechanical bowel preparation. br j surg. 2004;91:1125-30. 13. tabibi a, simforoosh n, basiri a, ezzatnejad m, abdi h, farrokhi f. bowel preparation versus no preparation before ileal urinary diversion. urology. 2007;70:654-8. 14. maffezzini m, campodonico f, canepa g, gerbi g, parodi d. current perioperative management of radical cystectomy with intestinal urinary reconstruction for muscle-invasive bladder cancer and reduction of the incidence of postoperative ileus. surg oncol. 2008;17:41-8. 15. pruthi rs, chun j, richman m. reducing time to oral diet and hospital discharge in patients undergoing radical cystectomy using a perioperative care plan. urology. 2003;62:661-5; discussion 5-6. 16. olbert pj, baumann l, hegele a, schrader aj, hofmann r. [fast-track concepts in the perioperative management of patients undergoing radical cystectomy and urinary diversion: review of the literature and research results]. urologe a. 2009;48:137-42. 17. shafii m, murphy dm, donovan mg, hickey dp. is mechanical bowel preparation necessary in patients undergoing cystectomy and urinary diversion? bju international. 2002;89:879-81. 18. morey af, evans la, mcdonough rc, 3rd, et al. evaluation of mechanical bowel preparation methods in urinary diversion surgery. can j urol. 2006;13: 3250-4. peri-operative management for radical cystectomy—aslan et al 118 urology journal vol 8 no 2 spring 2011 19. jain s, simms ms, mellon jk. management of the gastrointestinal tract at the time of cystectomy. urol int. 2006;77:1-5. 20. grabe m, bishop mc, bjerklund-johansen te, et al. guidelines on urological infections. european association of urology. 2009. 21. inman ba, harel f, tiguert r, lacombe l, fradet y. routine nasogastric tubes are not required following cystectomy with urinary diversion: a comparative analysis of 430 patients. j urol. 2003;170:1888-91. appendix questionnaire dispensed to participants in order to assess practice patterns of bowel preparation and peri-operative management protocols. 1) how often do you perform cystectomy in a year? <5 5 to 10 10 to 20 >20 2) are you doing urinary diversion yourself or with help of a general surgeon? myself help by a general surgeon 3) what is the distribution of diversion type you are doing in your current practice? please rank in percentage for each. ileal conduit catheterized pouch orthotopic bladder 4) which segment of the bowel do you mostly use for diversion? ileum colon 5) which bowel anastomosis technique do you prefer? primer suture stapler both 6) do you rinse bowel segment isolated at surgery with antiseptic solutions? yes no 7) do you always recommend bowel preparation before cystectomy for your patients? yes no 8) do you have any experience of doing cystectomy without bowel preparation? yes no 9) do you agree to consider doing cystectomy without bowel preparation when the ileum is to be used? yes no (explain why) uncertain 10) when do you take nasogastric tube out? 1st postoperative day 2nd postoperative day 3rd postoperative day after flatulence no nasogastric tube 11) when do you start first oral intake? 2nd postoperative day 3rd postoperative day 4th postoperative day after flatulence other 12) which antibiotic do you commence for prophylaxis of the bowel flora? erythromycin neomycin both none 13) what is your antibiotic prophylaxis regimen for cystectomy? 14) what is your bowel preparation regimen before cystectomy? 15) what is your preference for dvt prophylaxis? elastic bandage compression only low molecular weight heparin only low molecular weight heparin + elastic bandage compression none peri-operative management for radical cystectomy—aslan et al 119urology journal vol 8 no 2 spring 2011 16) do you think diet restriction is required before surgery for better bowel preparation? 2 to 3-day diet restriction is required. no need to restrict diet until midnight before the surgery. 17) do you consider enrolling your patients in a cystectomy clinical trial with no bowel preparation? yes, i do. no, i do not. uncertain 18) do you think there is a need for standard bowel preparation and peri-operative management protocol? yes no uncertain 19) would you use any standard bowel preparation or peri-operative management protocol for cystectomy if recommended by eau or aua guidelines at your routine? yes no uncertain 1415vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l department of urology, graduate school of medicine and pharmaceutical sciences for research, university of toyama, 2630 sugitani, toyama 9300194, japan. tetsuo nozaki, akihiro morii, yasuyoshi fujiuchi, hideki fuse the effect of selective renal parenchymal clamping during laparoscopic partial nephrectomy on early postoperative renal function: a preliminary report corresponding author: tetsuo nozaki, md department of urology, graduate school of medicine and pharmaceutical sciences for research, university of toyama, 2630 sugitani, toyama 9300194, japan. tel: +81 76 434 2281 fax: +81 76 434 5039 e-mail: nozaki0921@yahoo. co.jp received april 2013 accepted october 2013 purpose:amajorconcernwhenperforminglaparoscopicpartialnephrectomy(lpn)ispotentialpostoperativerenaldysfunction.theobjectiveofthisstudywastocomparetheeffectsof lpnwithselectiverenalparenchymalclamping(srpc)(lpnsrpc)andlpnusingmicrowavetissuecoagulation(mtc)(lpnmtc)onpostoperativerenalfunction. materials and methods:thisstudyincluded12patients(5menand7women)whounderwentlpnsrpc(n=6)orlpnmtc(n=6)forexophytictumors.renalscanningwithtechnetium-99mdiethylenetriaminepentaaceticacid(tc-99mdtpa)wasperformedpreoperatively andpostoperativelyat1monthinallpatients. results:themeantumorsize,surgicalduration,andintraoperativebloodlossweresimilar inbothgroups.inthelpnmtcgroup,althoughnotsignificant,themeanpostoperativeglomerularfiltrationrate(gfr)valuesintheaffectedkidneysweredecreasedcomparedtothe preoperativevalues.whenevaluatingtheaffectedrenalfunctionbysplitfunction(sf),the meanpostoperativesfintheaffectedkidneyswassignificantlydecreasedcomparedtothe preoperativevalue.inthelpnsrpcgroup,themeanpostoperativegfrandsfintheaffected kidneyswerenotsignificantlychangedcomparedwiththepreoperativevalues conclusion: our preliminary experience demonstrates that lpnsrpc facilitates maximal nephron-sparingsurgerywithoutcollateralthermaldamagecausingrenalimpairment. keywords:nephrectomy;methods;laparoscopy;bloodloss;pilotprojects;carcinoma;renal cell;kidneyneoplasms;surgery;treatmentoutcome. laparoscopic urology 1416 | introduction partialnephrectomy(pn)isrecognizedasastand-ardofcareforlocalizedsmallrenalmasses.(1)re-cently,laparoscopicpartialnephrectomy(lpn)has beenshowntohaveequivalentoncologicaloutcomesand improvedmorbiditycomparedtotheopentechnique.(2) as apromisingminimallyinvasivenephron-sparingsurgery, lpnisgainingpopularityinthetreatmentofselectrenal tumors.furthermore,renalfunctionappearstohaveahigh effectonnon-cancer-relatedmortality,andanothermajor concernoflpnismaximumpreservationofresidualrenal function.(3)inparticular,whenapplyinglpntoagrowing numberofpatientsinanagingcohortwithahighprevalenceofpreoperativelatentorapparentchronicrenalinsufficiency,postoperativerenalfunctionshouldbeconsidered inalltreatmentdecisions.(4)however,todate,nolpnsatisfiesallthecriteriaforclinicalpractice. recently,simonandcolleaguesreportedanoveltechnique ofselectiveclampingtoestablishregionalischemiainlpn, usingthelaparoscopicsimonclamp(aesculapag,tuttlingen,germany).(5)thelaparoscopicsimonclampisnewly developedandincludesastandardlockingratchethandleand anopenjawdiameterof70mm.theclampcanbeplaced alongtherenalparenchymaimmediatelysurroundingtherenalmass,thuscreatingregionalischemiaandlimitinginjury tothepreservedportionofthekidney.lpnwithselective renal parenchymal clamping (lpnsrpc) using the laparoscopicsimonclampmaythusminimizepotentialinjury totheunaffectedportionofthekidney.however,itseffect onrenalfunctionremainsunknown.themainobjectiveof thisstudywastoevaluatetheeffectoflpnsrpconpostoperative renal function using technetium-99m diethylenetriaminepentaaceticacid(tc-99mdtpa)scanning.asthe majorityofpatientswhoundergolpnhaveafunctioning contralateralkidney,assessmentofpostoperativecreatinine levelstodeterminetheeffectoflpnonrenalfunctionis equivocal, since serum creatinine conveys the total renal function,whichwouldbeaffectedbythecontralateralkidney.toevaluatethepostoperativefunctionoftheaffected kidneyseparatelyfromthenon-affectedkidneyisimportant toexaminethespecificutilityoflpn.thetc-99mdtpa renographyisacommonlyacceptedandsimplemethodfor measurementofindividualrenalfunction.itprovidesnotableinformationsuchasquantitativeindividualrenalfunction and pathophysiologic changes of the kidney.(6) moreover, calculationofsfonthebasisofrenalscanshowsthefunctionsofeachkidneyseparatelyandthusmoreaccuratelyreflectstheinfluenceofsurgeryontheaffectedkidney.(7)tothe bestofourknowledge,thisisthefirstreporttoevaluatethe effectoflpnsrpconrenalfunction.wealsocomparedthe changesinrenalfunctionbetweenlpnsrpcandlpnusing microwavetissuecoagulation(mtc)(lpnmtc). materials and methods study subjects fromoctober2010,12consecutivepatients(5menand7 women;meanage62.8±13.6years;range36-77years)were enrolledinthisstudy.sixpatientswhowereundergoinglpnsrpcwerecomparedwith6patientswhowereundergoing lpnmtc. all patients had undergone preoperative spiral computedtomography(ct)with3-dimensionalreconstructionormagneticresonanceimaging(mri)topreciselydelineatetherenalmass.thecomplexityoftherenaltumorwas classifiedusingther.e.n.a.l.nephrometryscoringsystem. (8)thepresenceofperipherallylocated,solitary,smallrenal tumorswastheoperativeindicationforlpnsrpc.inlpnmtc,inordertoavoidunexpectedthermaldamagetothecollectingsystem,operativeindicationswereexophyticrenaltumorswithadequateinterveningrenalparenchymaasfarasthe renalcollectingsystem(<10mm).table1showsthepreoperativepatientcharacteristicsandrenaltumordata.lpnsrpc patientsweregenerallyyoungerthanlpnmtcpatients,but thedifferencewasnotstatisticallysignificant(p=.200).there wasnosignificantdifferenceintumordiameterandnephrometryscoreseenbetweenthelpnsrpcandlpnmtcgroups (p=.878and.614,respectively).inthelpnsrpcgroup, therewas1caseoftheimperativecase. weprospectivelyevaluatedtheeffectsonrenalfunctionusing tc-99mdtpascanningpreoperativelyandpostoperativelyat 1monthinallpatients.splitfunction(sf)wascalculatedfrom renograms.allresultsareexpressedasmeanandsd.statisticalsignificancewasdeterminedusingthewilcoxonsignedranktestbetweenpreoperativeandpostoperativerenalvalues. a pvalueof<.05wasconsideredstatisticallysignificant. lpnsrpc surgical technique afteradministrationofgeneralanesthesia,thepatientwas placedinthelateraldecubitusposition.bothtransperitoneal and retroperitoneal approaches were used according to the laparoscopic urology 1417vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l surgeon’sdiscretion.atfirst,thekidneywasdissectedcircumferentiallyandfullymobilized.therenalpediclewas not routinely dissected.after incising the gerota’s fascia toexposetherenalmass,thelaparoscopicultrasonography usinga5-10mhzflexiblelaparoscopictransducer(aloka, wallingford,ct,usa) wasperformed to identify the tumorlocationandthesurgicalmargins.then,12-mmports wereplacedintheidealsitetoclamptherenalparenchyma. usingelectrocauteryscissors,theincisionlinewasmarked circumferentiallyapproximately1cmfromthetumormargins on the renalcapsule.the laparoscopicsimonclamp wasintroducedthroughthe12-mmporttoallowforclosure, anditwaslockedinplacealongthetumormargininorder tocreateregionalischemia(figure1).becausethekidney wasfullymobilized,oncethesimonclampwasclosed,it allowedforrotationofthekidney,thusprovidingoptimal tumorvisualizationandfacilitatingtumorexcision.thepreservedportionofthekidneywasperfusednormally;therefore,thetumorcouldberemovedwithoutanyhurryorfear ofrenalischemia.thesimonclampprovidedauniformand constantpressureoverthelengthofthejaws,permittingcold excisiontobeperformedinanearlybloodlessfield(figure 2).aftercompletetumorexcision,biopsyspecimensfrom thetumorbedweresentforfrozen-sectionstudy.thejaw pressurewasthentemporarilyreducedtobettervisualizethe bleeding site, which was then cauterized by bipolar electrocautery.ifnecessary,ongoingbleedingfromtheinjuredvesselswasrepairedusingfigure-of-8sutureswith4-0vicryl. afterachievinggoodhemostasis,thesimonclampwasremoved.thepresenceofurineleakagewasinvestigatedby injectingindigotindisulfonatesodiumintravenously.ifentry intothecollectingsystemwasnoted,intracorporealfreehand suturerepairofthepelvicalycealsystemwasperformed.parenchymalsuturesusing2-0vicrylsuturesonasmallhalfcircle(sh)needlewereplacedforcross-compressionalong thedefect.rolledsurgicelbolsterswerethenappliedtothe tumorbed,andthepledgetedparenchymalsuturesweretied downacrossthebolsterstoprovideadditionalcompressive hemostasis.thetumorwasplacedinanendoscopic-bagdeviceandremoved.adrainwassubsequentlyplaced,andthe portsiteswereclosedintheroutinefashion. lpnmtc surgical technique both transperitoneal and retroperitoneal approaches were usedaccordingtothesurgeon’sdiscretion.afterobtaining tumorexposure,througha5-mmport,alaparoscopicmtc probe(microtazeot-110m,aswellco.,osaka,japan)was introduced.themtcbendsatitsdistalnear-objectendand causesthermalcoagulationoftissuesusingmicrowaveenergy(2,459mhz).thisenergyistransmittedfromagenerator throughacoaxialcabletoaprobe,whichconsistsofahand pieceandaneedle-likeelectrode.therapidoscillationof waterparticlescausedbymicrowavesresultsinahightemperature, inducing cone-shaped tissue coagulation around the needlethatis7-10mminwidthwithoutanycarbonization.in lpn,mtcwasappliedperipherallytothehealthyparenchymasurrounding the tumorwithcircumferentialpunctures, producingcoagulationofaconical-shapedportionoftissue. subsequently, thebaseof the tumorwasresectedusinga renal parenchymal clamping during laparoscopic partial nephrectomy | nozaki et al figure 1. the laparoscopic simon clamp was placed at a distance from the tumor edge. figure 2. the resection of the tumor could easily be performed in a nearly bloodless operative field. 1418 | laparoscopic urology combinationofconventional5-mmlaparoscopicscissorsand bluntdissectionwithalaparoscopicaspiratorwithoutclampingtherenalpedicle.aftercompletetumorexcision,biopsiesfromthetumorbedweresentforfrozen-sectionstudy. thepresenceofurineleakagewasinvestigatedbyinjecting indigotindisulfonate sodium intravenously. after confirming complete hemostasis and clear margins, the specimen wasplacedinthelaparoscopicbagandretrievedthroughthe abdominalincision.inlpnmtc,theapplicationofbolster, sealant,orparenchymalstitcheswasnotnecessary. results table2showssurgicaloutcomesforpatientswhounderwent lpnsrpcandlpnmtc.bothlpnsrpcandlpnmtc weresuccessfulinallpatients,andconversiontoopensurgeryorischemiclpnwasnotrequired.therewerenosignificantdifferencesinthemeanoperativetime,meanblood lossandmeanhbdecrease.inthelpnsrpcgroup,themean selectiveclampingtimewas48.8±11.3min(44-59min).all patientshadnegativesurgicalmargins.postoperativecomplicationssuchasdelayedhemorrhage,arteriovenousfistula, andurinaryleaksdidnotdevelopinanyofthepatients. table3showstheperioperativerenalfunctiondata.inboth groups,themeanpostoperativecreatininedidnotsignificantlydifferfromthepreoperativevalues.noneofthepatients developedacuterenalfailureduringthepostoperativeperiod. inbothgroups,themeanpostoperativeglomerularfiltration rate(gfr)ofbothkidneyscalculatedfromtherenalscan wasnotsignificantlychangedcomparedtothepreoperative values. inthelpnsrpcgroup,themeanpostoperativegfrvalues intheaffectedkidneysdidnotsignificantlydifferfromthe preoperativevalues(41.4±18.5ml/minvs.38.7±17.7ml/ min,p=.562).whenevaluatingeachkidneyseparatelyusingtherenalscan,sfmoreaccuratelyreflectedtheeffect ofsurgeryontheaffectedkidney.(7)themeanpostoperative sf in the affected kidney was not significantly decreased comparedtothepreoperativevalue(48.8±9.8%vs.51.9± 5.3%,p=.312).inaddition,meanpostoperativesfinthe non-affectedkidneywasnotsignificantlychangedcompared withthepreoperativevalue(48.0±5.3%vs.51.2±9.8%, p=.311).inthelpnmtcgroup,althoughnotsignificant, themeanpostoperativegfrvaluesintheaffectedkidneys calculatedfromtherenalscanswerereducedascomparedto thepreoperativevalues(29.6±8.8ml/minvs.36.8±10.8 ml/min,p=.093).intheaffectedkidneys,meanpostoperatable 1. preoperative patient characteristics and renal tumor data. age sex side tumor size (mm) nephrometry score approach pathology lpnmtc 1 79 m lt 20 4 t ccc 2 81 m lt 25 6 r ccc 3 59 m rt 18 7 t ccc 4 49 m rt 25 5 t chromophobe rcc 5 68 m rt 23 6 r ccc mean ± sd 68.0 ± 12.2 21.8 ± 0.2 5.83±1.16 lpnsrpc 6 49 f lt 25 6 r hemorrhagic renal cyst 7 36 f lt 20 7 t ccc 8 62 m lt 23 5 t ccc 9 77 f lt 26 4 t ccc 10 62 f lt 21 6 t papillary rcc 11 60 f lt 14 5 t ccc mean ± sd 57.7 ± 13.9 21.5 ± 4.3 5.60 ± 1.14 keys: lpnmtc, laparoscopic partial nephrectomy using microwave tissue coagulation; lpnsrpc, laparoscopic partial nephrectomy with selective renal parenchymal clamping; t, transperitoneal; r, retroperitoneal; ccc, clear cell carcinoma; rcc, renal cell carcinoma; lt, left; rt, right; m, male; f, female. 1419vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l tivesfvaluesweresignificantlydecreasedcomparedtothe preoperativevalues(39.7±6.5%vs.48.4±4.9%,p<.05). ontheotherhand,meanpostoperativesfinthenon-affected kidneywassignificantlyincreasedcomparedwiththepreoperativevalue(60.3±6.5%vs.51.3±4.5%,p<.05). meanfollow-upsforlpnsrpcandlpnmtcwere14.5± 9.3and17.2±4.8months,respectively(p =.568).postoperativectwasperformedtoscreenforanyrecurrenceevery 6 months. however, no patient demonstrated local recurrenceordistantmetastasisduringthefollow-upperiod.inthe lpnsrpcgroup,postoperativectdidnotshowthebands of non-enhancing renal tissue along the surgical margins. however,inthelpnmtcgroup,postoperativectshowed bandsofnon-enhancingheat-damagedrenaltissuemeasuring5to10mminwidthalongthesurgicalmargins. discussion aslpngainswidespreadacceptance,thereisagreatneed foranovelsurgicaltechniquethatisreliableandprovides bloodlessresectionoftherenalparenchymawithoutdamagingtheresidualrenaltissue.therehavetraditionallybeen3 differenttechnicalstrategiesforlpn. thecompleterenal ischemictechniqueinvolvesclamping therenalvessels.however,amajorconcernisthedurationof renalischemiaafterhilarclamping,whichgenerallyrequires 20-30min.sincethistechniqueisverycomplex,including completetumorresection,ensuringhemostasisintherenal parenchymaandintracorporealfreehandsuturerepairofthe pelvicalycealsystemandapproximationoftherenalparenchyma,itmaynotalwaysbeeasytoperformlpnwithinthe limitedwarmischemiatime.ithasbeenreportedthatifthe warmischemiatimeisprolongedduringlpn,thefunctional damagetotheaffectedkidneyisprogressiveandcanbeirreversible.(9) inthenon-ischemictechnique,avarietyofenergysources maybeusedasanadjunctivemeasuretominimizehemorrhage, including ultrasonic shears,(10) water-jet dissector,(11) diode laser,(12)floating-ballradiofrequencydissector(13)and radiofrequencycoagulation.(14)resectionofthetumorwithoutinducingischemiaisfeasibleinsmallandperipherally locatedrenalmasses.however,itcanbedifficulttoobtain adequatehemostasisandanotherpossiblemajordrawback iscollateralthermaldamagetosurroundingstructuresdueto excessiveburningorcharringofthetissue. lpnsrpcpermitsnormalbloodperfusionoftheunclamped kidneyduringlpn.thus,amajorportionofthekidneyis sparedfromischemia,whichtheoreticallypreventstheinherentproblemofischemicdamage.however,lpnsrpc’seffectonrenalfunctionisnotwellknownandrequiresfurther studies.(5,15,16) inthelpnsrpcgroup,gfrandsfintheaffectedkidney werenotsignificantlydifferentpostoperativelyaccordingto renal scanning. postoperative ct in the lpnsrpc group did not show bands of non-enhancing renal tissue along thesurgicalmargins,asopposedtointhelpnmtcgroup. furthermore,coldexcisioncanbeperformedinabloodless operativefieldusingthistechnique.coldexcisionmayminimizecollateralthermaldamagetothesurroundingstructures. moreover,duringhemostasis,thejawpressurecanbetemporarilyreducedtobettervisualizethebleedingsite,which mightpreventexcessiveburningorcharringofthetissue. thesimonclampprovidesuniformandconstantpressure overthelengthofthejawsandisthereforeunlikelytocrush therenalparenchyma.althoughtheclinicalsignificanceof frozen-sectionanalysistoevaluateresectionmarginsduring pniscontroversial,weroutinelyperformedintraoperative pathologicalconsultationtoensurethatweachievednegativemargins.therefore,themeanselectiveclampingtime, renal parenchymal clamping during laparoscopic partial nephrectomy | nozaki et al table 2. the surgical outcomes. lpnmtc (n = 6) pnsrpc (n = 6) p mean operative time (min) 209.1 ± 73.3 (105-326) 230.6 ± 38.9 (179-270) .540 mean blood loss (ml) 26.6 ± 60.5 (0-150) 50.0 ± 45.1 (0-100) .84 mean hb decrease (g/dl) 0.5 ± 1.7 (0.1-2.6) 1.3 ± 0.7 (0.1-2.0) .48 keys: lpnmtc, laparoscopic partial nephrectomy using microwave tissue coagulation; lpnsrpc, laparoscopic partial nephrectomy with selective renal parenchymal clamping; hb, hemoglobin. 1420 | laparoscopic urology whichincludedpathologicalconsultationofabiopsytaken fromthetumorbed,wasrelativelyprolongedincomparison to other clinical reports of lpnsrpc.(16) our study findings indicated that prolonged parenchymal clamping does notimpairthepostoperativerenalfunctionoftheaffected kidney.therefore,ourpreliminaryresultsdemonstratedthat lpnsrpcpreservedthemaximumrenalfunctionoftheaffectedkidney.inparticular,lpnsrpcwouldbepreferable forpatientswithpre-existingrenalimpairmentandelderly patients. additional studies, including larger cohorts, are needed to support our results. injapan,mtciswidelyusedinnon-ischemiclpn.(17,18) inourseries,sfintheaffectedkidneysofthelpnmtc groupweresignificantlydecreasedpostoperatively,accordingtotherenalscan.inaddition,postoperativectshowed bandsofnon-enhancingheat-damagedrenaltissuemeasurtable 3. preoperative and postoperative renal function data of lpnsrpc and lpnmtc. variables lpnmtc (n = 6) p lpnsrpc (n = 6) p mean serum creatinine (mg/dl) .732* preoperative 0.88 ± 0.16 (0.7-1.1) 0.96 ± 0.91 (0.5-2.8) .750** .250** postoperative 0.92 ± 0.21 (0.8-1.3) .676* renal scan data total kidney .984* mean preoperative gfr 77.0 ± 25.7 (48.3-111.8) 77.3 ± 37.9 (14.5-124.3) .843** .062** mean postoperative gfr 74.9 ± 21.0 (50.7-102.8) 90.6 ± 55.7 (17.7-137.5) .424* the affected kidney mean preoperative gfr 36.8 ± 10.8 (25.2-51.8) 38.7 ± 17.7 (8.9-9.0) .093** .562** mean postoperative gfr 29.6 ± 8.8 (16.5-40.2) 41.4 ± 18.5 (11.9-61.1) .191* .268* mean preoperative sf 48.4 ± 4.9 (38.8-52.1) 51.9 ± 5.3 (47.5-61.4) < .05** .312 mean postoperative sf 39.7 ± 6.5 (31.8-47.8) 48.8 ± 9.8 (43.4-67.1) .089* the non-affected kidney .891* mean preoperative gfr 40.1 ± 16.3 (23.1-16.3) 38.6 ± 20.4 (5.6-65.3) .218** < .05 mean postoperative gfr 45.2 ± 13.9 (29.8-62.6) 48.3 ± 23.7 (5.8-77.8) .793* .274* mean preoperative sf 51.3 ± 4.5 (47.9-60.2) 48.0 ± 5.3 (38.6-53.2) < .05** .311 mean postoperative sf 60.3 ± 6.5 (52.2-68.2) 51.2 ± 9.8 (32.9-61.1) .089* keys: lpnmtc, laparoscopic partial nephrectomy using microwave tissue coagulation; lpnsrpc, laparoscopic partial nephrectomy with selective renal parenchymal clamping; gfr, glomerular filtration rate; sf, split function. * lpnmtc vs. lpnsrpc. ** preoperative vs. postoperative. 1421vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l references 1. uzzo rg, novick ac. nephron sparing surgery for renal tumors: indications, techniques and outcomes. j urol. 2001;166:6-18. 2. abukora f, nambirajan t, albqami n, et al. laparoscopic nephron sparing surgery: evolution in a decade. eur urol. 2005;47:488-93. 3. zini l, patard jj, capitanio u, et al. cancer-specific and non-cancerrelated mortality rates in european patients with t1a and t1b renal cell carcinoma. bju int. 2009;103:894-8. renal parenchymal clamping during laparoscopic partial nephrectomy | nozaki et al ing5to10mminwidthalongthesurgicalmargins.nanri andcolleaguessuggestedthatrenaldamageinducedbymtc comprises not only necrosis but also apoptotic changes. whenperformingthelpnmtc,itmustbeconsideredthat renalthermaldamagecausedbymtcmayspreadbeyond thesurgeon’sexpectations.(19)ontheotherhand,sfinthe non-affectedkidneywassignificantlyincreased.therefore, therenalfunctionofthenon-affectedkidneymightcompensatefordysfunctionontheaffectedkidney,postoperatively. furthermore,atumorincontactwiththecollectingsystem wouldbeunresectableusingthistechnique,becausesuturingtherenalpelvicmucosacanbedifficultaftercoagulation usingthemtc.lpnmtccanbeoneoftheusefulmodalitiesforthetreatmentofrenaltumorbecauseofitstechnical feasibilityandadequatehemostasis.however,thesurgeon mustbearinmindthatthemtccouldcauseheat-induced apoptosisoverunexpectedlywidearea. withtheexceptionofclampingtherenalartery,theremaining surgicalprocedureofthelpnsrpcissimilartolpnwithischemia,includingcompleteresectionoftherenaltumor,hemostasisfromtherenalparenchyma,andintracorporealfreehand suturerepairofthepelvicalycealsystemandapproximationof therenalparenchyma.werecommendthatlpnsrpcshould beperformedbyhighlyexperiencesurgeonswithskillsinlaparoscopicsuture.incomparisonwithlpnwithischemia,the simonclampgraspstheentirekidney,andtherefore,itisnecessarytofullymobilizethekidneyevenwithintheconfinesof thelimitedspace.thedirectionandangleofthekidneycould beeasilychangedinatimelymanner,thusfacilitatingprecise tumorexcisionandintracorporealfreehandsuturewithoutany hurryorfearofrenalischemia. lpnsrpc has several limitations. first, this technique cannotbeappliedtocentralorhilartumorsbecauseofthe impossibilityofplacingtheclamp.thistechniqueisbetter suitedforpolartumorsorsmallexophytictumorslocatedon thelateralconvexityofthekidneywheresomedegreeofischemiaoccursinthenormaltissuealso.second,incomplete regionalischemiamaycauseexcessivebleedingduringlpn. therefore,specialconsiderationshouldbegiventotheideal trocarlocationforclampplacementtominimizeischemic damageduringlpn.viprakasitandcolleaguesreportedthat incompleteclampcompressionatthedistalaspectin3cases resultedinexcessivebleedinganddecreasedvisualization, necessitatingparenchymalclampremovalandplacementofa centralhilarclamptocompletetheprocedure.(16)keepingthe renalpediclewithvesseltapeisrecommendedforsafecompletionoflpnsrpc,especiallyduringthelearningcurve. itallowsrapidapplicationoflaparoscopicbulldogclamps ifbleedingshouldprecludesafelpnsrpc.flexibilitywith regardtotheconversiontolpnwithischemiaisnecessary incaseswithdifficultyincompleteclampcompressionor unmanageable bleeding. careful anatomical evaluation of thelesionisessentialforoperativesuccess.third,ourstudy hasasmallnumberofpatients,andthisisalimitationfor thisstudy.thepresentstudywouldhavebeenenhancedbya largerseriesofpatientstodemonstrablyprovetheefficacyof thistechniqueanditsadvantages,includingreducedbleeding,maximumpreservationofrenalfunctionintheaffected kidney,andreducedoperativetime.althoughweareencouragedbythepreliminaryfindingsofourexperience,itwas onlyassessedthesuperiorityoflpnsrpcwhencompared withlpnmtcinearlypostoperativeperiod.recently,offclamp,(20)orzero-ischemiaapproachtolpn(21) has been a proposedmeansofpreservingglobalrenalfunctionbypreventingischemiatonormalrenalparenchyma.furtherstudies,inadditiontoacomparisonofotherlpntechnique,such aszero-ischemiaapproachtolpn,arenecessarytodelineate what,ifanyspecificadvantagesmayliewiththelpnsrpc. conclusion inthisstudy,wedescribeourexperiencewithlpnusing thelaparoscopicsimonclamptoinduceselectiveregional ischemia,withoutrenalhilarclamping,andtc-99mdtpa scanning to compare preoperative and postoperative renal function.incarefullyselectedpatientswithtumorsinideal locationsforlpnsrpc,werecommendthisnon-ischemic techniqueformaximumnephron-sparingsurgery. conflict of interest none declared. 1422 | 4. hollingsworth jm, miller dc, daignault s, hollenbeck bk. rising incidence of small renal masses: a need to reassess treatment effect. j natl cancer inst. 2006;98:1331-4. 5. simon j, bartsch g, finter f, hautmann r, de petriconi r. laparoscopic partial nephrectomy with selective control of the renal parenchyma: initial experience with a novel laparoscopic clamp. bju int. 2008;103:8805-8. 6. assadi m, eftekhari m, hozhabrosadati m, et al. comparison of methods for determination of glomerular filtration rate: low and high-dose tc-99m-dtpa renography, predicted creatinine clearance method, and plasma sample method. int urol nephrol. 2008;40:1059-65. 7. yasui t, itoh y, kojima y, et al. impact of microwave tissue coagulation during laparoscopic partial nephrectomy on postoperative renal function. int urol nephrol. 2008;40:277-82. 8. kutikov a, uzzo rg. the r.e.n.a.l. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. j urol. 2009;182:844-53. 9. choi jd, park jw, lee sy, et al. does prolonged warm ischemia after partial nephrectomy under pneumoperitoneum cause irreversible damage to the affected kidney? j urol. 2012;187:802-6. 10. harmon wj, kavoussi lr, bishoff jt. laparoscopic nephron-sparing surgery for solid renal masses using the ultrasonic shears. urology. 2000;56:754-9. 11. moinzadeh a, hasan w, spaliviero m, et al. water jet assisted laparoscopic partial nephrectomy without hilar clamping in the calf model. j urol. 2005;174:317-21. 12. ogan k, jacomides l, saboorian h, et al. sutureless laparoscopic heminephrectomy using laser tissue soldering. j endourol. 2003;17:295-300. 13. sundaram cp, rehman j, venkatesh r, et al. hemostatic laparoscopic partial nephrectomy assisted by a water-cooled, high-density, monopolar device without renal vascular control. urology. 2003;61:906-9. 14. zeltser is, moonat s, park s, anderson jk, cadeddu ja. intermediateterm prospective results of radiofrequency-assisted laparoscopic partial nephrectomy: a non-ischaemic coagulative technique. bju int. 2008;101:36-8. 15. viprakasit dp, altamar ho, miller nl, herrell sd. selective renal parenchymal clamping in robotic partial nephrectomy: initial experience. urology. 2010;76:750-3. 16. viprakasit dp, derweesh i, wong c, et al. selective renal parenchymal clamping in robot-assisted laparoscopic partial nephrectomy: a multi-institutional experience. j endourol. 2011;25:1487-91. 17. terai a, ito n, yoshimura k, et al. laparoscopic partial nephrectomy using microwave tissue coagulator for small renal tumors: usefulness and complications. eur urol. 2004;45:744-8. 18. furuya y, tsuchida t, takihana y, et al. retroperitoneoscopic nephron-sparing surgery of renal tumor using a microwave tissue coagulator without renal ischemia: comparison with open procedure. j endourol. 2003;17:53-8. 19. nanri m, udo k, kawasaki m, et al. microwave tissue coagulator induces renal apoptotic damage to preserved normal renal tissue following partial nephrectomy. clin exp nephrol. 2009;13:424-9. 20. rais-bahrami s, george ak, herati as, srinivasan ak, richstone l, kavoussi lr. off-clamp versus complete hilar control laparoscopic partial nephrectomy: comparison by clinical stage. bju int. 2012;109:1376-81. 21. rizkala er, khalifeh a, autorino r, samarasekera d, laydner h, kaouk jh. zero ischemia robotic partial nephrectomy: sequential preplaced suture renorrhaphy technique. urology. 2013;82:100-4. laparoscopic urology u j all final for web.pdf 795vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l optimal number of biopsies and impact of testicular histology on the outcome of testicular sperm extraction farid dadkhah,1,2 seyed jalil hosseini,1 mohamad ali sadighi gilani,1 faramarz farrahi,1 erfan amini,2 behrang kazeminejad3 purpose: on outcome. materials and methods: a single biopsy of the contralateral testis. results: cess rate did not increase considerably after the third sampling. performing contralateral testicular conclusion: keywords: azoospermia, infertility, histology, sperm retrieval corresponding author: erfan amini, md urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran tel: +98 21 8800 2337 fax: +98 21 2207 4101 e-mail: amini.erfan@gmail. com received july 2012 accepted december 2012 1department of andrology, reproductive biomedicine research center, royan institute, tehran, iran 2department of urology, shahid modarress hospital, shahid beheshti university of medical sciences, tehran, iran 3department of pathology, shahid modarress hospital, shahid beheshti university of medical sciences, tehran, iran sexual dysfunction and infertility 796 | introduction mhave long been considered irrevocably infersperm injection (icsi), these patients have the opportunity to active spermatogenesis, sperm can be retrieved in some inferdifferent prognostic factors have been recommended to topathological pattern is more accurate. although various patterns of testicular histology can be treated applying matogenesis. in addition to the histologic pattern, presence of sperm in prior biopsies also predicts the success conventional tese, including sampling a larger testicular tissue through a single incision and multiple biopsies through different small incisions in tunica albuginea. there is inconsistency in the literature concerning the optimal of testicular tissue, an impaired testosterone synthesis, rate. histological pattern and success or failure of previous biopsies may also affect the optimal number of biopsies. we conducted this study to determine the optimal number of success and avoid multiple unnecessary biopsies. we also evaluated the impact of testicular histology and the success sperm retrieval procedure. materials and methods tese in our institution. to assess the optimal number of cised. the number of biopsies varied according to the presthe contralateral testis. oratory in bouin solution. we also reevaluated the histosmall or atrophied testes, and such patients have not been included in the analysis. (the statistical package for the social sciences, version p cant. results sexual dysfunction and infertility 797vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l sperm retrieval and histopathology | dadkhah et al esis, germ cell maturation arrest, sco appearance, and hygenesis, early maturation arrest, late maturation arrest, sco ond, third, fourth, and contralateral sampling, respectively. pling. ferent histopathological patterns and noted a considerable esis. although contralateral testicular biopsy yielded no success rate of tese in different histopathological patterns according to the number of biopsies. ence or absence of spermatozoa in their testicular biopsy tozoa (sp+ negative biopsies (sp-). sertoli cell only and hypospermatosp+ subgroups, respectively (table 2). successful sperm retrieval irrespective of histopathologi+ patients of the result of prior biopsy, performing more than three biopsies, including contralateral testicular biopsy, did not outcome of prior biopsy and histopathology of the testis p ever, routine postoperative ultrasonography and testosterand hypoandrogenism, respectively. discussion ously considered infertile may father children. isolated foci table 1. cumulative incidence of positive testicular sperm extraction according to the number of biopsies in different histopathological patterns. histopathological pattern number of biopsies contralateral biopsy 1 2 3 4 uniform hypospermatogenesis 114 (73.5%) 132 (85.2%) 141 (91.0%) 147 (94.8%) 151 (97.4%) early maturation arrest 64 (46.4%) 75 (54.3%) 81 (58.7%) 83 (60.1%) 83 (60.1%) late maturation arrest 22 (20.6%) 26 (24.3%) 29 (27.1%) 29 (27.1%) 29 (27.1%) sertoli cell only 29 (17.8%) 35 (21.5%) 41 (25.1%) 41 (25.1%) 41 (25.1%) hypospermatogenesis with mixed pattern 101 (56.7%) 113 (63.5%) 124 (69.7%) 133 (74.7%) 137 (77.0%) 798 | men. there is no consensus regarding the optimal number thors hypothesize that multifocal distribution of the spermatogenesis is present throughout the entire testis and accordingly, advocate a single testicular biopsy production and recommend multiple samples from different sites. comparing multiple and single sampling, amer and associates revealed a nevertheless, multiple sampling has been postulated to be tion of the number of biopsies and avoiding unnecessary multiple samplings may prevent the potential hazards of biopsy. terns and accordingly performing multiple biopsies from different sites may be of greater importance in these hisin our study, multiple testicular sampling, including conalso evident in adverse histopathological patterns, includin case of sco and late maturation arrest, further biopsies table 2. frequency of different histopathological patterns in patients with positive and negative prior testicular biopsy.* histopathological pattern from tese specimens patients with sp + patients with sp total uniform hypospermatogenesis 63 (64.9%) 34 (35.1%) 97 (100%) early maturation arrest 27 (37.5%) 45 (62.5%) 72 (100%) late maturation arrest 4 (8.9%) 41 (91.1%) 45 (100%) sertoli cell only 12 (11.3%) 94 (88.7%) 106 (100%) hypospermatogenesis with mixed pattern 48 (39.7%) 73 (60.3%) 121 (100%) *tese indicates testicular sperm extraction; sp+, patients with positive prior biopsy; and sp-, patients with negative prior biopsy. table 3. cumulative incidence of positive testicular sperm extraction according to the number of biopsies and the result of prior biopsy in different histopathological patterns. histopathological pattern number of biopsies contralateral biopsy 1 2 3 4 uniform hypospermatogenesis sp+ 55 (87.3%) 60 (95.2%) 63 (100%) sp25 (73.5%) 31 (91.2%) 34 (100%) early maturation arrest sp+ 18 (66.7%) 22 (81.5%) 25 (92.6%) 27(100%) sp22 (48.9%) 25 (55.5%) 27 (60.0%) 27 (60.0%) 27(60.0%) late maturation arrest sp+ 2 (50%) 4(100%) 4 (100%) 4 (100%) sp9 (21.9%) 11 (26.7%) 12 (29.3%) 12 (29.3%) 12 (29.3%) sertoli cell only sp+ 6 (50.0%) 8 (66.7%) 10 (83.3%) 10 (83.3%) 10 (83.3%) sp16 (17.0%) 18 (19.1%) 20 (21.3%) 20 (21.3%) 20 (21.3%) hypospermatogenesis with mixed pattern sp+ 32 (66.7%) 36 (75.0%) 41 (85.4%) 46 (95.8%) 48 (100%) sp43 (58.9%) 46 (63.0%) 48 (65.7%) 50 (68.5%) 50 (68.5%) sp+ indicates patients with positive prior biopsy; and sp-, patients with negative prior biopsy. sexual dysfunction and infertility 799vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l sperm retrieval and histopathology | dadkhah et al opsies in each histopathology category. nevertheless, the importance of performing multiple biopsies cannot be unform hypospermatogenesis. patchy distribution of spermatogenesis. this term has reand has changed prior methods of interpretation of historeported.(22) spermatogenesis precludes the diagnosis of sco.(22) both prior successful tese and biopsy have been associ(23) a ret in the +), and the success rate -) varied from the likelihood of sp+ + no germ cells are found. therefore, the sperm retrieval rate is present in the literature. this overestimation may be related to the absence of germ cells in the biopsied specimen, tissue and considering that only a small specimen from a cerning testicular histology. histopathology is not applicahistopathological diagnosis, it may be helpful in planning prior to tese procedure. in the case of hypospermatogenpresence of spermatozoa is relatively high and performing further biopsies may improve the outcome. fine needle aspiration biopsy is a simple and less invasive no complication. despite high success rate in some studcessful more often than aspiration biopsy.(26,27) nevertheless, it should be considered that prior history of successful pre-operatively, can provide an opportunity to apply aspiration biopsy prior to open surgery. in these conditions, there conventional tese to minimize the testicular tissue loss and enhance retrieval success rate. some investigators have rate. theretern(2,32) 800 | references 1. vernaeve v, verheyen g, goossens a, van steirteghem a, devroey p, tournaye h. how successful is repeat testicular sperm extraction in patients with azoospermia? hum reprod. 2006;21:1551-4. 2. okada h, dobashi m, yamazaki t, et al. conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia. j urol. 2002;168:1063-7. 3. tsujimura a, matsumiya k, miyagawa y, et al. conventional multiple or microdissection testicular sperm extraction: a comparative study. hum reprod. 2002;17:2924-9. trieval rate in cases of hypospermatogenesis.(33) hypospermatogenesis may be considered as having sco syndrome or maturation arrest. this misinterpretation overeither sco syndrome or maturation arrest. conventional tese has been replaced by microdissection tese in many centers, including our institution. never this cessible to all centers. furthermore, operation time is significantly longer in microdissection tese. therefore, tese conclusion volume testes, conventional tese can be an alternative in ered to perform conventional tese, including sampling a larger testicular tissue through a single incision and multiple biopsies through different small incisions in tunica albuglatter approach is applied. further biopsies are also reasonpattern or uniform hypospermatogenesis prior to procedure. conflict of interest none declared. 4. amer m, ateyah a, hany r, zohdy w. prospective comparative study between microsurgical and conventional testicular sperm extraction in non-obstructive azoospermia: follow-up by serial ultrasound examinations. hum reprod. 2000;15:653-6. 5. schlegel pn, su lm. physiological consequences of testicular sperm extraction. hum reprod. 1997;12:1688-92. 6. ramasamy r, lin k, gosden lv, rosenwaks z, palermo gd, schlegel pn. high serum fsh levels in men with nonobstructive azoospermia does not affect success of microdissection testicular sperm extraction. fertil steril. 2009;92:590-3. 7. mitchell v, boitrelle f, pigny p, et al. seminal plasma levels of anti-mullerian hormone and inhibin b are not predictive of testicular sperm retrieval in nonobstructive azoospermia: a study of 139 men. fertil steril. 2010;94:2147-50. 8. seo jt, ko wj. predictive factors of successful testicular sperm recovery in non-obstructive azoospermia patients. int j androl. 2001;24:306-10. 9. sousa m, cremades n, silva j, et al. predictive value of testicular histology in secretory azoospermic subgroups and clinical outcome after microinjection of fresh and frozen-thawed sperm and spermatids. hum reprod. 2002;17:1800-10. 10. ramasamy r, schlegel pn. microdissection testicular sperm extraction: effect of prior biopsy on success of sperm retrieval. j urol. 2007;177:1447-9. 11. borges e, jr., braga dp, bonetti tc, pasqualotto ff, iaconelli a, jr. predictive factors of repeat sperm aspiration success. urology. 2010;75:87-91. 12. carpi a, sabanegh e, mechanick j. controversies in the management of nonobstructive azoospermia. fertil steril. 2009;91:963-70. 13. takada s, tsujimura a, ueda t, et al. androgen decline in patients with nonobstructive azoospemia after microdissection testicular sperm extraction. urology. 2008;72:114-8. 14. akbal c, mangir n, tavukcu hh, ozgur o, simsek f. effect of testicular sperm extraction outcome on sexual function in patients with male factor infertility. urology. 2010;75:598601. 15. silber sj, van steirteghem ac, liu j, nagy z, tournaye h, devroey p. high fertilization and pregnancy rate after intracytoplasmic sperm injection with spermatozoa obtained from testicle biopsy. hum reprod. 1995;10:148-52. sexual dysfunction and infertility 801vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l sperm retrieval and histopathology | dadkhah et al 16. verheyen g, de croo i, tournaye h, pletincx i, devroey p, van steirteghem ac. comparison of four mechanical methods to retrieve spermatozoa from testicular tissue. hum reprod. 1995;10:2956-9. 17. tournaye h, liu j, nagy pz, et al. correlation between testicular histology and outcome after intracytoplasmic sperm injection using testicular spermatozoa. hum reprod. 1996;11:127-32. 18. tournaye h, verheyen g, nagy p, et al. are there any predictive factors for successful testicular sperm recovery in azoospermic patients? hum reprod. 1997;12:80-6. 19. hauser r, botchan a, amit a, et al. multiple testicular sampling in non-obstructive azoospermia--is it necessary? hum reprod. 1998;13:3081-5. 20. ostad m, liotta d, ye z, schlegel pn. testicular sperm extraction for nonobstructive azoospermia: results of a multibiopsy approach with optimized tissue dispersion. urology. 1998;52:692-6. 21. amer m, haggar se, moustafa t, abd el-naser t, zohdy w. testicular sperm extraction: impact of testicular histology on outcome, number of biopsies to be performed and optimal time for repetition. hum reprod. 1999;14:3030-4. 22. cerilli la, kuang w, rogers d. a practical approach to testicular biopsy interpretation for male infertility. arch pathol lab med. 2010;134:1197-204. 23. haimov-kochman r, lossos f, nefesh i, et al. the value of repeat testicular sperm retrieval in azoospermic men. fertil steril. 2009;91:1401-3. 24. lewin a, reubinoff b, porat-katz a, et al. testicular fine needle aspiration: the alternative method for sperm retrieval in non-obstructive azoospermia. hum reprod. 1999;14:178590. 25. levine la, dimitriou rj, fakouri b. testicular and epididymal percutaneous sperm aspiration in men with either obstructive or nonobstructive azoospermia. urology. 2003;62:328-32. 26. westlander g, hamberger l, hanson c, et al. diagnostic epididymal and testicular sperm recovery and genetic aspects in azoospermic men. hum reprod. 1999;14:118-22. 27. khadra aa, abdulhadi i, ghunain s, kilani z. efficiency of percutaneous testicular sperm aspiration as a mode of sperm collection for intracytoplasmic sperm injection in nonobstructive azoospermia. j urol. 2003;169:603-5. 28. turunc t, gul u, haydardedeoglu b, et al. conventional testicular sperm extraction combined with the microdissection technique in nonobstructive azoospermic patients: a prospective comparative study. fertil steril. 2010;94:215760. 29. vicari e, grazioso c, burrello n, cannizzaro m, d'agata r, calogero ae. epididymal and testicular sperm retrieval in azoospermic patients and the outcome of intracytoplasmic sperm injection in relation to the etiology of azoospermia. fertil steril. 2001;75:215-6. 30. ezeh ui, moore hd, cooke id. a prospective study of multiple needle biopsies versus a single open biopsy for testicular sperm extraction in men with non-obstructive azoospermia. hum reprod. 1998;13:3075-80. 31. schlegel pn. testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. hum reprod. 1999;14:131-5. 32. donoso p, tournaye h, devroey p. which is the best sperm retrieval technique for non-obstructive azoospermia? a systematic review. hum reprod update. 2007;13:539-49. 33. ramasamy r, yagan n, schlegel pn. structural and functional changes to the testis after conventional versus microdissection testicular sperm extraction. urology. 2005;65:1190-4. 34. ishikawa t, nose r, yamaguchi k, chiba k, fujisawa m. learning curves of microdissection testicular sperm extraction for nonobstructive azoospermia. fertil steril. 2010;94:1008-11. pseudocapsule of small renal cell tumors: ct imaging spectrum and correlated histopathological features gang li1#, xianqi lu2#, yunshen ding3, qiang luo4, liang xu5, dongsheng zhu6*, changyi quan1** purpose: to systematically analyze histopathologic features of pseudocapsule in small renal cell tumor (diameter ≤ 4cm), assess the integrity of pseudocapsules by computed tomography (ct), and provide theoretical basis for the safety of nephron sparing surgery. materials and methods: the pathological data of 116 patients who underwent surgery with clear cell renal cell carcinoma admitted from may 2010 to october 2017 were retrospectively analyzed. all patients underwent a ct scan of the abdomen including an unenhanced and three-phase (arterial, nephrographic and excretory) post contrast series. thorough gross examination and histological sections were used to determine the integrity of the pseudocapsule by two uropathologists. the consistency between pathological findings and ct imaging were evaluated by kappa consistency test. results: the mean diameter of tumor was 3.0cm, range (2.6 ± 0.8) cm. on ct the pseudocapsule can present with one of the three following feathers:1) a regular and distinct halo; 2) lobulated clear margins;3) blurred margins. on histopathology, complete psuedocapsule was found in 85 tumors, incomplete psuedocapsule in 25 and no psuedocapsule was found in 6 tumors; ct scan findings demonstrated a regular halo in 82 tumors, lobulated clear margins in 26 and blurred margins in 8 tumors(kappa = 0.833, p = 0.000). conclusion: most small renal cell tumors have an obvious psuedocapsule. preoperative determination of the psuedocapsule’s integrity is particularly important. ct scan can reliably evaluate the tumor margins and demonstrate the psuedocapsule when present. the imaging results are well correlated with the pathologic findings. keywords: pseudocapsule; small renal carcinoma; pathology; ct; surgery introduction renal cell carcinoma is the most common malig-nant tumor of the kidney in adults.(1) it accounts for 3% of all adult malignancies and the incidence of the young is increasing.(2,3) in recent years, with the development and widespread use of imaging diagnostic technology, detection rate of early asymptomatic small renal masses (srms) is significantly improved, therefore, the incidence of early-stage renal cell carcinoma increased steadily year by year.(4-6) clear cell renal cell carcinoma (ccrcc) is the most common histological subtype. most renal cancer is low degree of malignancy 1department of urology, the second hospital of tianjin medical university, tianjin institute of urology, tianjin city, 300211, china. 2department of urology, tianjin wuqing hospital , tianjin city, 300000,china 3department of urology, tianjin baodi hospital,baodi clinical college of tianjin medical university, tianjin city, 301800,china 4department of urology, the people’s hospital of jiangyin,wuxi city,214000,china. 5department of urology, china medical university aviation general hospital, beijing city, 100012, china. 6department of surgery, the first people’s hospital of lianyungang, affiliated to xuzhou medical university, lianyungang, china. #these authors contribute equally to the article *correspondence: department of surgery, the first people’s hospital of lianyungang, affiliated to xuzhou medical university, 182 tongguan north road, lianyungang 222000, p.r. china. tel:+86 18961321672,email:zhudongsheng@tmu.edu.cn. **tianjin medical university, no. 22, qixiangtai road, tianjin, 300211, p.r. china. tel: +86 16600380083, e-mail: zhudongsheng@tum.edu.cn received january 2020 & accepted may 2020 and grows slowly,(7) and squeezes the renal parenchyma or surrounding tissue to form the pseudocapsule, which is the protective response of the body to limit the growth and proliferation of tumor. it was initially described in the early 1900s and was commonly identified in ccrcc. however, high degrees of malignant tumors are invasive with no obvious pseudocapsule. for patients with small renal cell carcinoma, under the premise of no distant metastasis, partial nephrectomy is the general choice.(8) nephron sparing surgery(nss) maximizes the preservation of renal function, it has shown oncological efficacy and favorable outcomes in urological oncology urology journal/vol 18 no. 3/ may-june 2021/ pp. 301-306. [doi: 10.22037/uj.v16i7.5907] carefully selected patients with t1a tumors, also offers an equally effective form of local control as well as 5year disease-specific survival rates.(9) the integrity of the pseudocapsule determines the safety and feasibility of partial nephrectomy. additional, regardless of the presence or absence of pseudocapsule, there is no difference in surgical approach. hence, preoperative determination of pseudocapsule integrity is particularly important. as far as we know, the literature on preoperative judgments of pseudocapsule integrity is less reported in english to date. therefore, we evaluate the integrity of the pseudo-capsule by computer tomography (ct), and systematically analyze the histopathological characteristics of the pseudo-capsule of renal cell tumor (diameter ≤ 4cm) to provide a theoretical basis for the safety of nss. materials and methods study population a retrospective study was conducted to value the relationships between ct imaging spectrum and histopathological features of 116 patients who underwent nss in our hospital with clear cell of renal cell carcinoma admitted from may 2000 to october 2016. all patients had received preoperative ct examination included unenhanced and three-phase (arterial, portal, and nephrographic-excretory) contrast-enhanced and signed informed consent. the study included 116 patients (65 men, 51 women; mean age, 56 years; range, 33–78 years). based on the tumor growth pattern, small renal cell carcinoma is divided into single nodular type, infiltration type (nodular boundary uncertainty) and multi-nodular fusion. all tumors were single nodular and less than 4 in diameter. 114 of the 116 patients had no symptoms and were referred because of a small renal mass found incidentally at physical examination. a renal tumor was detected at ct examination in 12 patients. no patient had distant metastases. only 2 cases were referred with clinical symptoms which is slight pain. procedures thorough gross examination of the pseudocapsule including pseudocapsular invasion and completeness of pc was performed by the uropathologist. if the pseudocapsules existed, but some were infiltrated, it is defined as incomplete psuedocapsule. we striped the pseudocapsule completely to do pathological sections. entire sections including the tumor-pc-parenchyma interface and representative sections from the largest plane of the tumor were submitted. all specimens were step-sectioned at 5-mm intervals, entirely embedded in paraffin blocks, stained with hematoxylin and eosin. tumor grade was according to the fuhrman criteria. all ct examinations were performed using a 64mdct scanner. unenhanced scans and contrast-enhanced scans were reconstructed at 3-mm intervals. the margins of the tumor were recorded and classified on the ct. ct and pathological findings were compared by case analysis. sample size based on our pilot data, the sample size was estimated on a power of 80 % at the 5 % significance level. it has been suggested that at least 22 patients per group were required. these study protocols were approved by the medical ethics committee of the second hospital of tianjin medical university, tianjin institute of urology. this work was supported by tianjin municipal natural science foundation (grant 17jcybjc26000) pseudocapsule of small renal cell tumors -li et al. table 1. comparing ct scan and pathological results ct scan(n) pathological results(n) total kappa coefficient p-value positive negative positive 107 1 108 0.833 .000 negative 3 5 8 total 110 6 116 figure 1. microscopically, integrated psuedocapsule of ccrcc. the pathological components of pseudocapsule include compressed renal parenchyma, hyperplastic fibers, and inflammatory cells. (hematoxylin and eosin staining, ×40). urological oncology 302 statistical analysis spss statistics 20.0 was used for statistical analysis. the pathological results as gold standard, using kappa test analysis to judge consistency with the ct detecting results. kappa coefficient > 0.7 and < 0.4 indicates a high or low consistency between the two results respectively; p < .05 was considered statistically significant. results the mean diameter of tumor was 3.0 cm, range (2.6 ± 0.8) cm. pathological results showed 7 cases were of fuhrmanⅰgrade, 39 cases were of grade ⅰ-ⅱ, 55 cases were of grade ⅱ, 12 cases were of grade ⅱ-ⅲ, 3 cases were of grade ⅲ and 0 cases were of grade ⅳamong the 116 cases of clear cell carcinoma. integrated psuedocapsule (figure 1) were found in 85 (73.3%) tumors with the thickness ranged from 0.2 to 1 mm, 25 (21.6%) without integrated psuedocapsule (figure 2) and 6 (5.2%) cases had no obvious psuedocapsule (figure 3). tumor infiltrated while not penetrated into the psuedocapsule were found in 16 cases (13.8%), while tumors penetrated into the psuedocapsule were found in 7 cases (6.0%). the pathological components of pseudocapsule include compressed renal parenchyma, hyperplastic fibers, and inflammatory cells. in mdct, the presence of pseudocapsule on ct had three kinds. 82(70.7%) cases of rcc were confirmed with a regular halo surrounding a renal neoplasm (figure 4). 26 (22.4%) had clear margin but not continuous or lobulated (figure 5), 8 (6.70%) were found presenting blurred margin (figure 6) surrounding the tumor. the pathological results as gold standard, the sensitivity, specificity, positive predictive value and negative predictive value of ct detecting psuedocapsule was 97.3% (107/110), 83.3% (5/6), 99.1% (107/108), 62.5% (5/8), respectively and the consistency between ct and pathological results were high by kappa test analysis in which the kappa value was 0.833 (table1). the presence of a regular and distinct halo surrounding a renal neoplasm presented the completeness of pseudocapsule. clear margin but not continuous or lobulated was regards as incomplete capsule while blur margin presented no capsule. discussion at present, small renal cancer is well differentiated, the clinical stage is low, the natural growth rate is slow and the prognosis is better. nephron sparing surgery (nss) is safe and reliable in the treatment of small renal cell carcinoma, with a low rate of recurrence and mortalifigure 2. microscopically, incomplete psuedocapsule of ccrcc. tumor infiltrated and penetrated into the psuedocapsule resulting in pseudocapsule discontinuity (hematoxylin and eosin staining, ×100). figure 3. microscopically, no psuedocapsule of ccrcc. the neoplastic cells directly interfaced with normal renal parenchyma without any fibrous band (hematoxylin and eosin staining, ×100). pseudocapsule of small renal cell tumors -li et al. vol 18 no 3 may-june 2021 303 ty. (10,11) a meta-analysis confirms that nss can reduce the incidence of postoperative chronic kidney disease relative to radical nephrectomy 61%, 19% reduction in mortality. rccs usually have no true histologic capsule but are surrounded by pseudocapsule.(12)pseudocapsule is an important feature which is helpful to evaluate the differentiation of renal cell carcinoma.(13) pseudocapsule formation is the result of tumor growth, which causes compression, ischemia, and necrosis of the adjacent renal parenchyma.(14) this is a protective response that the body limits the growth and spread of the tumor. in early stage of small and low-grade rccs, the presence of pseudocapsule is often seen,(15) which is a good indicator of renal cancer prognosis.(6) complete pseudocapsule predicts higher degree of differentiation and the lesion is still early; the other hand, the incomplete pseudocapsule herald higher diffusion and metastasis rate. (16) joseph m et al. found clear cell rcc exhibits the most consistent pc, a complete pc was found in 77% of 60 cases with t1 stage clear cell tumors.(17) nss can only be performed if the tumor is confined to the renal parenchyma and there is a significant pseudocapsule around it.(18) wei xi et al. findings suggest that pseudocapsule status is of good prognostic implications in rcc and lack of pseudocapsule certainly had remarkable adverse impact on patient outcome.(19) thus, we discuss the judgment of its completeness preoperatively to ensure pathology margin postoperative. there are different reports about detecting pseudocapsules in small kidneys, such as ultrasound and mri and ct. hricak et al.(20) reported that a pseudocapsule was observed on mri firstly in 1985, both of which showed a low signal band between tumor and normal renal parenchyma in both t1wi and t2wi. yamashita et al. showed that t2wi is the most sensitive through different sequences of mr pseudocapsules display study.(15) moreover, mri has been reported to be more reliable imaging modality, the accuracy ranging from 74% to 93%, the sensitivity was 87.5% and the specificity was 80.8% respectively. preoperative mri showed complete pseudocapsule around the tumor which sugfigure 4. abdominal ct shows a regular halo surrounding a renal neoplasm. figure 5. abdominal ct shows the renal mass had clear margin but not continuous or lobulated. pseudocapsule of small renal cell tumors -li et al. urological oncology 304 vol 18 no 3 may-june 2021 305 gesting the feasibility of enucleation. ultrasound has a higher veracity up to 89.29% in diagnosis of small renal cell cancer, it can detect more than 1cm mass. conventional ultrasound in detecting rcc pseudocapsules can manifest as two types of echogenicity: hypoechoic halo or slightly hyperechoic bands around the tumor. ultrasound contrast showed enhanced echo around the tumor and enhancing time is longer, the sensitivity was 85.7%, much higher than conventional ultrasound. (13) there are few studies on the performance of rcc pseudocapsules by ct. yamashita et al.(15) studied 52 cases of renal cell carcinoma and compared the ability of detecting pseudocapsules between enhanced ct and mri, they concluded the mri t2-weighted image showing the most accurate. tsili et al.(21) retrospectively studied 29 histologically proven rccs which examinations were performed with a 16-mdct scanner preoperatively. they finally concluded that multiphase mdct with multiplanar reformations had satisfactory results in detecting renal pseudocapsule in rcc and imaging in the portal and nephrographic phases with coronal and sagittal reformations proved more accurate. in our studies, among 116 cases, integrated psuedocapsule were found in 85 (73.3%) tumors with the thickness ranged from 0.2 to 0.8 mm, 25 (21.6%) without integrated psuedocapsule and 6 (5.2%) cases had no obvious psuedocapsule. wang et al. concluded clear cell renal carcinomas showed the thickest pseudocapsule (average 0.23 mm) among 178 renal tumors.(22) this is similar to our findings. in mdct, the presence of pseudocapsule on ct had three kinds. 82 (70.7%) cases of rcc were confirmed with a regular halo surrounding a renal neoplasm. 26 (22.4%) had clear margin but not continuous or lobulated, 8 (6.70%) were found presenting blurred margin surrounding the tumor. the consistency between ct and pathological results were high by kappa test analysis. this provides a certain basis for determining the integrity of the pseudocapsule by ct preoperatively. the current study has a number of limitations: (1) the study design is retrospective; (2) this study was conducted at a single institution; (3) the number of samples is relatively small and remains a significant limitation; (4) there are some limitations on the determination of tumor margin on ct. conclusions most small renal tumors have obvious psuedocapsule. ct can demonstrate psuedocapsule of tumor margin, and is well correlated with the pathologic findings in ccrcc. this provides a theoretical basis for the safety of nephron sparing surgery. further studies are necessarily needed to verify the accuracy of detecting pseudocapsules. conflict of interest the authors declare that they have no competing interests. references 1. novara g, ficarra v, antonelli a, artibani w, bertini r, carini m, et al. validation of the 2009 tnm version in a large multiinstitutional cohort of patients treated for renal cell carcinoma: are further improvements needed? eur urol, 2010. 58: 588-95. 2. sheth s, scatarige j c, horton k m, corl f m, fishman e k. current concepts in the diagnosis and management of renal cell carcinoma: role of multidetector ct and three-dimensional ct. radiographics, 2001. 21 spec no: s237-54. 3. chow w h, devesa s s. contemporary epidemiology of renal cell cancer. cancer j, 2008. 14: 288-301. 4. curry n s. imaging the small solid renal mass. abdom imaging, 2002. 27: 629-36. 5. chow w h, devesa s s, warren j l, fraumeni j j. rising incidence of renal cell cancer in the united states. jama, 1999. 281: 1628-31. 6. reddan d n, raj g v, polascik t j. management of small renal tumors: an overview. am j med, 2001. 110: 558-62. 7. abouassaly r, lane b r, novick a c. active surveillance of renal masses in elderly patients. j urol, 2008. 180: 505-8. 8. ljungberg b, bensalah k, canfield s, dabestani s, hofmann f, hora m, et al. eau figure 6. abdominal ct shows blurred margin surrounding the tumor. pseudocapsule of small renal cell tumors -li et al. guidelines on renal cell carcinoma: 2014 update. eur urol, 2015. 67: 913-24. 9. capitanio u, terrone c, antonelli a, minervini a, volpe a, furlan m,et al. nephron-sparing techniques independently decrease the risk of cardiovascular events relative to radical nephrectomy in patients with a t1a-t1b renal mass and normal preoperative renal function. eur urol, 2015. 67: 683-9. 10. minervini a, di cristofano c, lapini a, marchi m, lanzi f, giubilei g, et al. histopathologic analysis of peritumoral pseudocapsule and surgical margin status after tumor enucleation for renal cell carcinoma. eur urol, 2009. 55: 1410-8. 11. krejci k g, blute m l, cheville j c, sebo t j, lohse c m, zincke h. nephronsparing surgery for renal cell carcinoma: clinicopathologic features predictive of patient outcome. urology, 2003. 62: 641-6. 12. roy c s, el g s, buy x, lindner v, lang h, saussine c, et al. significance of the pseudocapsule on mri of renal neoplasms and its potential application for local staging: a retrospective study. ajr am j roentgenol, 2005. 184: 113-20. 13. ascenti g, gaeta m, magno c, mazziotti s, blandino a, melloni d, et al. contrastenhanced second-harmonic sonography in the detection of pseudocapsule in renal cell carcinoma. ajr am j roentgenol, 2004. 182: 1525-30. 14. hedgire s s, elmi a, nadkarni n d, cao k, mcdermott s, harisinghani m g. preoperative evaluation of perinephric fat invasion in patients with renal cell carcinoma: correlation with pathological findings. clin imaging, 2013. 37: 91-6. 15. yamashita y, honda s, nishiharu t, urata j, takahashi m. detection of pseudocapsule of renal cell carcinoma with mr imaging and ct. ajr am j roentgenol, 1996. 166: 11515. 16. park b k, kim s h, choi h j. characterization of renal cell carcinoma using agent detection imaging: comparison with gray-scale us. korean j radiol, 2005. 6: 173-8. 17. jacob j m, williamson s r, gondim d d, leese j a, terry c, grignon d j, et al. characteristics of the peritumoral pseudocapsule vary predictably with histologic subtype of t1 renal neoplasms. urology, 2015. 86: 956-61. 18. frank i, blute m l, cheville j c, lohse c m, weaver a l, leibovich b c, et al. a multifactorial postoperative surveillance model for patients with surgically treated clear cell renal cell carcinoma. j urol, 2003. 170(6 pt 1): 2225-32. 19. xi w, wang j, liu l, xiong y, qu y, lin z, et al. evaluation of tumor pseudocapsule status and its prognostic significance in renal cell carcinoma. j urol, 2017. 20. hricak h, demas b e, williams r d, mcnamara m t, hedgcock m w, amparo e g, et al. magnetic resonance imaging in the diagnosis and staging of renal and perirenal neoplasms. radiology, 1985. 154: 709-15. 21. tsili a c, argyropoulou m i, gousia a, kalefezra j, sofikitis n, malamou-mitsi v, et al. renal cell carcinoma: value of multiphase mdct with multiplanar reformations in the detection of pseudocapsule. ajr am j roentgenol, 2012. 199: 379-86. 22. wang l, feng j, alvarez h, snarskis c, gupta g, picken m m. critical histologic appraisal of the pseudocapsule of small renal tumors. virchows arch, 2015. 467: 311-7. pseudocapsule of small renal cell tumors -li et al. urological oncology 306 1735vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l pictorial renal angiomyolipoma embolization with flexible microcatheter konstantinos stamatiou,1 hippocrates moschouris,1 katerina malagari2 corresponding author: stamatiou konstantinos, md 2 salepoula street, 18536 piraeus, greece. tel: +30 210 452 6651 fax: +30 210 429 6987 e-mail: stamatiouk@gmail.com received december 2012 accepted december 2013 1 general hospital “tzanio”, piraeus, greece. 2 2nd department of radiology, university of athens, athens, greece. a 35-year-old woman with a history of multiple angiomyolipomas (amls) of the right kidney presented with severe right flank pain and hypotension after a fall. the patient’s hematocrit on admission was 26%. emergency contrast-enhanced computed tomography (ct) scan showed a perirenal hematoma and findings indicative of rupture of at least one of the amls (figure 1, arrow). the patient was referred to the interventional radiology services for emergency angiography. after selective catheterization of a lower polar artery of the right kidney using a 5 french (f) cobra-1 catheter, a thin branch was considered as a potential feeder of the aml on the basis of its location and course (figure 2, arrows). however, no tumor vasculature could be detected on angiography through the cobra-1 catheter. super selective catheterization of this thin branch was achieved using a 2.7 f fathom microcatheter (early phase, figure 3, arrow). angiography through this microcatheter revealed several branches which were considered as tumor-feeding (late phase, figure 4, arrows). to facilitate catheterization of the origin of the lower polar artery branch, the guidewire of the microcatheter was shaped in the form of a shepherd’s hook, according to a previously described technique.(1) embolization of aml feeders was performed through the fathom microcatheter using embozene microspheres (embozene; celonova biosciences, peachtree city, georgia, usa) with a diameter of 250 and 400 μm. a post-embolization angiogram confirmed occlusion of the tumor feeders (figure 5). the patient’s recovery was uneventful and no recurrence of the hemorrhage occurred. figure 1. emergency contrastenhanced computed tomography scan shows a perirenal hematoma (arrow). figure 2. selective catheterization of a lower polar artery of the right kidney demonstrates a thin branch (arrows). figure 4. angiography through microcatheter revealed several branches which were considered as tumor-feeding (late phase, arrows). figure 5. post-embolization angiogram shows occlusion of the tumor feeders. figure 3. super selective catheterization of thin branch using a 2.7 f fathom microcatheter (early phase, arrow). reference 1. jee hyun baek, jin wook chung, hwan jun jae, whal lee, jae hyung park. a new technique for superselective catheterization of arteries: preshaping of a micro-guide wire into a shepherd's hook form. korean j radiol. 2007;8:225-30. urology journal unrc/iua vol. 2, no. 4, 222-223 autumn 2005 printed in iran 222 case reports crossed testicular ectopia: a case report behzad feizzadeh kerigh,* mohamadali mohamadzadeh rezaei department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran key words: testis, ectopia, inguinal hernia introduction crossed testicular ectopia or transverse testicular ectopia is an extremely rare anomaly in which both testes descend through a single inguinal canal.(1) it is characterized by symptomatic inguinal hernia on one side and cryptorchism on the contralateral side. crossed testicular ectopia is often not diagnosed until surgical exploration.(2) we report a case of crossed testicular ectopia in a 22-month-old boy. case report a 22-month-old boy with a large mass that had been present on the left groin since birth was referred to our institution for treatment. on physical examination, a large left inguinal hernia was revealed, and the right testis was not palpable. no other genitourinary abnormality was noted. the patient underwent herniorrhaphy through an inguinal incision on the left side. both testes were detected intraoperatively in the hernial sac of the left side (figure 1). each testis had its own vas deferens, and the separation of spermatic cords was not possible. the scrotum was subsequently opened through a midline incision, and after the removal of hernial sac, the testes were fixed separately in their respective hemiscrotum. postoperative ultrasonography showed a normal genitourinary system and pelvis, and no complications were noted at the patient's 2-month postsurgical followup examination. discussion crossed testicular ectopia is a rare but well known congenital anomaly that was first reported by von lenhossek(3) in 1886. it is usually associated with other abnormalities such as persistent mullerian duct syndrome,(4) true hermaphroditism,(5) inguinal hernia, hypospadias, pseudohermaphroditism, and scrotal anomalies. in 2% to 97% of patients with crossed testicular ectopia, disorders of the upper and lower urinary tract system have been reported.(6) the development of malignancy is also relatively common in patients with crossed testicular ectopia.(2) although the cause of crossed testicular ectopia is unknown, local factors (such as gubernaculum mechanism) in the absence of endocrine disorders have been suggested. some experts(7) have proposed the following classification of crossed testicular ectopia: type 1, accompanied received may 2005 accepted september 2005 *corresponding author: department of urology, ghaem hospital, mashhad, iran. fax: ++98 511 8417404 e-mail: behzadfeizzadeh@yahoo.com fig. 1. crossed testicular ectopia in a 22-month-old boy detected at herniotomy. vas deferens were separate, but the spermatic cords were fused. feizzadeh kerigh and mohamadzadeh rezaei 223 only by hernia; type 2, accompanied by persistent mullerian duct; and type 3, associated with disorders other than persistent mullerian remnants. according to that classification, our patient exhibited a type 1 crossed testicular ectopia. clinical presentations in patients with that type of testicular ectopia generally include an inguinal hernia on one side and cryptorchidism on the contralateral side. the patients are usually 1 to 2 years old at presentation, and diagnosis is not made before surgical operation. the use of computed tomographic scan, magnetic resonance imaging, arteriography, and venography has yielded different results. if crossed testicular ectopia is suspected, ultrasonography and subsequent magnetic resonance imaging have been recommended for diagnosis.(2) the therapy for testicular ectopia is either transseptal or extraperitoneal transposition orchidopexy.(7) a case of successful laparoscopicassisted orchidopexy has been reported by dean and shah.(1) in conclusion, it can be said that crossed testicular ectopia should be a diagnosis considered when unilateral inguinal hernia and concurrent cryptorchidism of the contralateral side are present. an appropriate preoperative assessment and careful differential diagnosis to rule out other potential abnormalities are needed. clinicians should be cautioned that patients with a history of crossed testicular ectopia require long-term follow-up for the development of malignancy. references 1. dean ge, shah sk. laparoscopically assisted correction of transverse testicular ectopia. j urol. 2002;167:1817. 2. lam ww, le sd, chan kl, chan fl, tam pk. transverse testicular ectopia detected by mr imaging and mr venography. pediatr radiol. 2002;32:126-9. 3. von lenhossek mn. ectopia testis transversa. anta anz. 1886;1:376. 4. avolio l, belville c, bragheri r. persistent mullerian duct syndrome with crossed testicular ectopia. urology. 2003;62:350. 5. d'agostino s, pesce c, donadio p, spata f, cimaglia ml. [true hermaphroditism in crossed testicular ectopy: report of a case]. pediatr med chir. 1993;15:513-5. italian. 6. tolete-velcek f, bernstein mo, hansbrough f. crossed testicular ectopia with bilateral duplication of the vasa deferentia: an unusual finding in cryptorchism. j pediatr surg. 1988;23:641-3. 7. esteves e, pinus j, maranhao rf, abib sde c, pinus j. crossed testicular ectopia. sao paulo med j. 1995;113:935-40. final-1497.pdf 856 | 1hasheminejad clinical research development center (hcrdc), iran university of medical sciences, tehran, iran 2departmentof urology, tabriz university of medical sciences, tabriz, iran masoud etemadian,1 robab maghsoudi,1 vafa abdollahpour,1 mohsen amjadi2 percutaneous nephrolithotomy in horseshoe kidney our 5-year experience corresponding author: robab maghsoudi, md department of endourology, hasheminejad clinical research development center (hcrdc), valiasr ave, vanak sq, valinejad st, tehran, iran tel: +98 914 411 0966 fax: +98 21 8864 4497 e-mail: rmaghsudy@ yahoo.com received may 2012 accepted october 2012 purpose: to review our 5-year experience in percutaneous nephrolithotomy (pcnl) for horseshoe kidney with large stone burden or failed shockwave lithotripsy (swl). materials and methods: during 5 years (2006 to 2011), pcnl was performed on 21 patients with horseshoe kidney stone. we evaluated patients (age, gender), stones characteristics (size, number, side, and site), surgical technique, and outcomes. results: sixteen (76.16%) subjects were man and 5 (23.80%) were women, with the mean age of 35 ± 12 years. mean stone size was 37.2 ± 16.6 mm. percutaneous nephrolithotomy was performed because of the stone size (over 20 mm) in 18 (85.68%) and failed swl in 3 (14.28%). stone numbers were more than one in 18 (85.68%) subjects, and were in the pelvis and at least one calyx. the most common access site was superior posterior calyx (66.64%). stone-free rate with single session and rigid nephroscope was 71.40%. no major complication occurred during the surgery or in post surgical period. postoperative minor complications occurred in 3 (14.28%) patients, including transfusion in one (4.76%), fever in one (4.76%), and ileus in one (4.76%) subject. conclusion: percutaneous nephrolithotomy has acceptable results in horseshoe kidney stone and kidney in our study. keywords: kidney calculi, percutaneous nephrolithotomy, treatment outcome endourology and stone disease endourology and stone disease 857vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l introduction one of the most common renal fusion anomalies berengario da carpi in 1522,(1) with the prevalence of 0.25% in general population. fusion of lower poles during embryogenesis prevents normal kidney ascent and consequently leads to anterior malrotation of the collecting system.(2) anatomical position of the pelvis and calyces and high insertion of the ureter in comparison with normal kidney cause more prevalence of complications in horseshoe kidney. the incidence of nephrolithiasis has been reported to be approximately 20%.(2) percutaneous nephrolithotomy (pcnl) is one of the recommended modalities for horseshoe kidney stone disease treatment. fletcher and ketin 1973.(3) percutaneous nephrolithotomy has been advised for stones larger than 20 mm or failed shockwave lithotripsy (swl). it has been reported that performing pcnl in success and complications rates were both in the acceptable range.(4,5) our center is a referral endourological center in iran and approximately 130 pcnls are being performed monthly since several years ago. our center is a referral center for stone fer to us. horseshoe kidney stone is one of the challenging issues in endourology and multiple treatment modalities exist for its management. in this case series, we reviewed our 5-year experience in pcnl of horseshoe kidney in our center. materials and methods twenty-one patients with horseshoe kidney stone, who have undergone pcnl from april 2006 until april 2011 in our center, were enrolled in this case series study. digital recording system was the source of patients’ information in our center. patients were visited in outpatient clinic and became candidate for pcnl if their stone size was greater than 20 mm or had history of failed swl with smaller stone size. the recorded variables were patients’ age, gender, stonerelated factors (side, size on kidney, ureter, and bladder xray or computed tomography, stone number and location, access site, and tract number), serum hemoglobin and creatinine level before and after procedure, duration of hospital stay, and complications during and after the operation. preoperative intravenous urography had been obtained from all the patients (figure 1), but computed tomography scan had been performed in 10 patients without any retrorenal colon (figure 2). percutaneous nephrolithotomy was performed in prone position with a subcostal access to the collecting system. in all the patients, only one tract was created. access site was based on stone burden, stone location, and colpcnl in horseshoe kidney | etemadian et al figure 1. intravenous urography in a horseshoe kidney with left renal stone. figure 2. computed tomography scan of horseshoe kidney with nephrolithiasis. 858 | used, and lithotripsy was performed by pneumatic lithotripter alone or in combination with ultrasonic swiss lithoclast master lithotripter. large stone fragments (up to 10 mm) were extracted with grasping forceps. at the end of the procedure, nephrostomy tube, double-j (dj) stent, or both were used if fluoroscopy was not used for stone-free rate (sfr) evaluation because of low density of stones in some patients and low resolution of images, especially in the presence of extravasated contrast media. stone-free rate was evaluated by kidney, ureter, and bladder x-ray or ultrasonography (in cases with non-opaque stones) 48 hours postoperatively. routinely, patients were discharged on the 2nd postoperative day if they had clear urine, returned bowel habit, and no fever or urine leakage. corded complications, such as blood transfusion, visceral injury during or after surgery, fever, urinary leakage, etc, were noticed. follow-up visits were done at 2 weeks, 2 months, and 4 months postoperatively. patients were evaluated with serum creatinine level and ultrasonography in each visit. data were analyzed using spss software (the statistical package for the social sciences, version 19.0, spss inc, chicago, illinois, usa). results stone >20 mm was seen in 18 (85.68%) patients and failed jects. microscopic hematuria was detected in urinalysis of 17 (80.92%) patients. three (14.28%) patients had a history of previous open stone surgery on the same kidney. table 1 shows characteristics of the patients. mean stone size was 37.2 ± 16.67 mm in the largest dimension. eighteen (85.68%) patients had more than one stone, of which 10 (47.60%) were staghorn stone with involvement of the pelvis and at least 2 calyces simultaneously and 13 (61.88%) had stone in the pelvis and one calyx simultaneously. in 7 (33.33%) subjects, stone was either in the calyx or in the pelvis alone. access site was subcostal in all the patients. in 14 (66.64%) subjects, access site was posterior superior calyx. posterior middle and inferior calyx were the entrance site in 2 and 4 patients, respectively. in a patient with diverticulum-in stone, direct puncture of the diverticulum has been done. after endourology and stone disease table 1. characteristics of patients with stone in horseshoe kidney. mean age (range), y 35 (15 to 63) mean stone size (range), mm 37.2 (15 to 90) location, n (%) right side left side 52.36 (11) 47.60 (10) gender, n (%) male female 76.16 (16) 23.80 (5) stone number, n (%) 1 >1 (multiple or staghorn) 14.28 (3) 85.68 (18) indication of pcnl, n (%) stone size failure of swl 85.68 (18) 14.28 (3) pcnl indicates percutaneous nephrolithotomy; and swl, shockwave lithotripsy. table 2. percutaneous nephrolithotomy results in horseshoe kidney. stone site, n (%) lower calyx 14.28 (3) pelvis 19.04 (4) mixed 61.88 (13) lower calyx diverticulum 4.76 (1) access site, n (%) superior calyx 66.64 (14) middle calyx 9.52 (2) lower calyx 19.04 (4) calyceal diverticulum 4.76 (1) double-j insertion, n (%) 4.76 (1) nephrostomy, n (%) 14.28 (3) complications, n (%) urine leak 0 (0) fever 4.76 (1) transfusion 4.76 (1) stone-free rate, n (%) 71.40 (15) 859vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l stone extraction, the diverticular ostium has been dilated and a nephrostomy tube was inserted through the dilated ostium into the pelvis. in other two patients, a nephrostomy tube was used. double-j stent was used in only one (4.76%) subject with previous open surgery and ureteropelvic junction severe edema. percutaneous nephrolithotomy was tubeless in 17 (80.92%) patients. in order to lower the costs, access was achieved only by an in all the subjects. furthermore, no patient was scheduled for only for homeostasis or good drainage of pyelocalyceal system. there was neither operation cessation (due to severe intraoperative bleeding) nor urinary leakage in our subjects. transfusion was required in one (4.76%) patient. mean hemoglobin level was 14.14 ± 1.72 g/dl and 12.84 ± 1.83 g/ dl before and after the operation, respectively. drop in postp < .001). mean serum creatinine level was 1.07 ± 0. 25 mg/dl before the operation and 1.21 ± 0.26 mg/dl after the operap < .007). no acute tubular necrosis occurred. only one (4.76%) patient with a history of previous surgery on the same kidney and positive urine culture before the operation developed fever postoperatively, which was controlled by antibiotics. mean hospital stay was 3.4 ± 0.7 days. longer hospitalization in horseshoe kidney pcnl was due to delay in resolution of gross hematuria. no major intestinal complications occurred. ileus was detected only in one (4.76%) patient postoperatively, which was treated with conservative management. because of subcostal access, no pulmonary complication occurred (table 2). stone-free rate, stone residual fragments less than 4 mm, was 71.40%, which seems to be acceptable due to multiple stone numbers in 18 (85.68%) patients. since our center is pioneer this study as well. discussion stone management in horseshoe kidney is a challenge in endourology. altered pyelocalyceal system anatomy and high ureteropelvic junction position lead to relatively poor results of swl and retrograde intrarenal surgery. percutaneous nephrolithotomy is the routine treatment of large renal stones in a kidney with normal anatomy. it has also been reported as a treatment modality for horseshoe kidney stone as well.(6-10) in our study, acceptable results were achieved with respect to patients’ number. with one session operation using one sfr seems to be ideal and comparable with other studies leagues’ study on 21 renal units, 52% had one pelvic stone and only 14% had staghorn calculi.(11) lower stone burden in their study explains higher sfr (85.70%). stone-free rate in darabi mahboub and associates’ study on 9 patients with horseshoe kidney stone is lower than our study (66.70% versus 71.40%).(12) viola and colleagues reported 75% sfr.(13) stone size in their study was less than ours (25.4 mm versus 37.2 mm).(14) additional intervention or prolonged hospitalization was required. minor complications in our patients included postoperative transfusion, fever that was controlled by antibiotics, and ileus, which was managed with conservative treatment. colon perforation and pelvis rupture did not occur in our patients, while they have been reported by others.(11,15) major table 3. published comparative data on percutaneous management of calculi in horseshoe kidney. first author number of patients complications (minor/major), % initial stone-free rate, % al-otaibi(4) 12 42 (42/0) 75 jones(6) 15 26 (20/6) 72.3 lampel(8) 4 25 (25/0) 75 el ghoneimy(11) 17 19 (14/5) 87.5 darabi mahboub(12) 9 11 (11/0) 66.7 viola(13) 44 20 (20/0) 75 aghamir(14) 30 7 (7/0) 83.3 present series 21 14 (14/0) 71.4 pcnl in horseshoe kidney | etemadian et al 860 | endourology and stone disease complications reported by raj and coworkers were 12.5%.(2) in our study, computed tomography scan was only performed for patients with a history of previous surgery. we believe that it is not necessary to perform computed tomography routinely in all the patients with horseshoe kidney who are planned for pcnl unless they have a history of previous open renal stone surgery. we had 6 patients with stone remanaged conservatively. three other patients became stonefree with swl in 4 months after pcnl. in our study, mean stone size was larger than other studies. horseshoe kidney stone with rigid nephroscope alone. it is not necessary to refer these subjects to a referral center anymore. any endourology center with experienced surgeon can manage stone in this group of patients. conclusion percutaneous nephrolithotomy is a safe and effective treatment modality in horseshoe kidney stones with acceptable results. in skilled hands, pcnl complications in horseshoe kidney are similar to normal anatomy kidney. however, furthis. conflict of interest none declared. references 1. benjamin ja, schullian dm. observations on fused kidneys with horseshoe configuration: the contribution of leonardo botallo (1564). j hist med allied sci. 1950;5:315-26. 2. raj gv, auge bk, weizer az, et al. percutaneous management of calculi within horseshoe kidneys. j urol. 2003;170:48-51. 3. fletcher ew, kettlewell mg. antegrade pyelography in a horseshoe kidney. am j roentgenol radium ther nucl med. 1973;119:720-2. 4. al-otaibi k, hosking dh. percutaneous stone removal in horseshoe kidneys. j urol. 1999;162:674-7. 5. janetschek g, kunzel kh. percutaneous nephrolithotomy in horseshoe kidneys. applied anatomy and clinical experience. br j urol. 1988;62:117-22. 6. jones dj, wickham je, kellett mj. percutaneous nephrolithotomy for calculi in horseshoe kidneys. j urol. 1991;145:481-3. 7. salas m, gelet a, martin x, sanseverino r, viguier jl, dubernard jm. horseshoe kidney: the impact of percutaneous surgery. eur urol. 1992;21:134-7. 8. lampel a, hohenfellner m, schultz-lampel d, lazica m, bohnen k, thurof jw. urolithiasis in horseshoe kidneys: therapeutic management. urology. 1996;47:182-6. 9. stening sg, bourne s. supracostal percutaneous nephrolithotomy for upper pole caliceal calculi. j endourol. 1998;12:359-62. 10. skolarikos a, binbay m, bisas a, et al. percutaneous nephrolithotomy in horseshoe kidneys: factors affecting stonefree rate. j urol. 2011;186:1894-8. 11. el ghoneimy mn, kodera as, emran am, orban tz, shaban am, el gammal mm. percutaneous nephrolithotomy in horseshoe kidneys: is rigid nephroscopy sufficient tool for complete clearance? a case series study. bmc urol. 2009;9:17. 12. darabi mahboub mr, zolfaghari m, ahanian a. percutaneous nephrolithotomy of kidney calculi in horseshoe kidney. urol j. 2007;4:147-50. 13. viola d, anagnostou t, thompson tj, smith g, moussa sa, tolley da. sixteen years of experience with stone management in horseshoe kidneys. urol int. 2007;78:214-8. 14. aghamir sm, mohammadi a, mosavibahar sh, meysamie ap. totally tubeless percutaneous nephrolithotomy in renal anomalies. j endourol. 2008;22:2131-4. 15. shokeir aa, el-nahas ar, shoma am, et al. percutaneous nephrolithotomy in treatment of large stones within horseshoe kidneys. urology. 2004;64:426-9. 1583vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l evaluation of safety and efficacy of open mini-access ureterolithotomy in the era of minimally invasive surgery sholay kangjam meitei, bijit lodh, somarendra khumukcham, sandeep gupta, kaku akoijam singh, rajendra singh sinam purpose: to evaluate the effectiveness and safety evaluation of mini-access ureterolithotomy in the management of ureteric calculus. materials and methods: this was a cross-sectional study conducted at department of urology, regional institute of medical sciences, imphal. a total number of one hundred and forty three patients with radiologically confirmed ureteral calculus (size > 1 cm) were enrolled in this study. results: the mean age of male and female patients was 44.97 ± 11.24 and 43.89 ± 14.49 years, respectively. in the majority of cases stone was in the upper ureter irrespective of the side. the stone size ranged from 10 to 30 mm in diameter. the most common indication for open mini-access ureterolithotomy in the present study was impacted large stone (45%). the mean operation duration was 25.39 ± 5.11 min, with an incision length of 4.78 ± 0.25 mm; the estimated blood loss was 50.55 ± 8 ml and none of the patient’s required post-operative blood transfusion. the overall complication rate was 5.6%. conclusion: open mini-access ureterolithotomy is a safe procedure with fewer complications and cosmetically acceptable results. although in this minimally invasive era, the specific indications for open stone surgery are a few, but when the situation mandates, an open mini-access ureterolithotomy might be considered the best option. keywords: ureteral calculi; surgery; treatment outcome; pain; postoperative; length of stay. corresponding author: bijit lodh, md department of urology, regional institute of medical sciences, lamphelpat, imphal, manipur, india, pin-795004. tel: +91 89 7450 4215 e-mail: drblodh@yahoo.co.in received may 2013 accepted april 2014 department of urology, regional institute of medical sciences (rims), imphal, manipur, india. endourology and stone disease 1584 | introduction for centuries, "cutting for stone" was synonymous with urology, and just over a decade ago, it still made up at least one-fourth of the surgical activity in the field. open stone surgery (oss) was the standard of care for treating urinary stones until the early 1980s. presently, in the developed countries, it has been replaced by minimally invasive techniques like extracorporeal shock wave lithotripsy (swl), ureterorenoscopic lithotripsy and percutaneous nephrolithotomy.(1) however, oss still plays a significant role for management of stone disease refractory to these armamentarium of modern era.(2,3) it is likely to achieve highest stone clearance at single sitting and may be the only option for treating urinary stones in many parts of the developing world. mini-access ureterolithotomy (mau), is a refined percutaneous open surgical procedure that is associated with better cosmesis and a more cost-effective outcomes. here, our study was aimed to determine the efficacy and safety of mau in the management of ureteric calculus in our institution. materials and methods study design this was a cross sectional study conducted at our urology department from september 2010 to february 2012. ethical approval was obtained from the research and ethics committee of the institute. inclusion and exclusion criteria a total number of 143 patients admitted in our urology ward, with radiologically confirmed ureteral calculus (size > 1 cm) and fit to undergo surgery were included in this study. informed written consent was taken from the participants. exclusion criteria were: patients with stone size ≤ 1cm, multiple ureteral or associated renal calculi, patients with renal insufficiency and pregnancy and body mass index (bmi) more than 25 kg/m2. data collection and surgical procedure an eligibility criterion was based on history and physical examination, ultrasound, kidney-ureter-bladder (kub) xray and intravenous urography (ivu). details of various parameters including operative indication, age and sex of patients, size and location of stone were recorded. the operation is performed with the patient under general/spinal anesthesia after proper positioning and determining the surgical approach based on the stone location on preoperative plain films. a subcostal flank incision, modified gibson incision and a midline suprapubic incision is made in approaching the upper, middle and lower ureteric stones, respectively. a 5 cm skin incision (figure 1) is made with a muscle cutting approach for the upper ureter and musclesplitting approach for the mid and lower ureter. during an approach for the upper ureteric stone, after mobilizing the peritoneum anteriorly the ureter is usually found either on the psoas muscle or embedded to the peritoneum. the stone is located by palpating the ureter between thumb and index finger, and then it is clamped with two allis tissue forceps proximal and distal to the stone to prevent migration (figure 2). keeping stay sutures on either side of the proposed ureterotomy incision, it is opened longitudinally onto the stone and then the stone is retrieved (figure 3). proximal and distal patency of the ureter is checked by inserting feeding tube no. 6 through the ureterotomy wound. following insertion of 6 french (f) double j stent, ureterotomy is closed with 3-0 chromic catgut (figure 4). after placement of 22f abdominal drain tube into the retroperitoneal space, muscle and aponeurotic layers are closed with no.1 polydioxanone or polyglactin suture and skin with 2-0 silk suture or skin stapler (figure 5 and 6). patients are discharged on the 3rd5th post-operative day after removing the drain tube. the skin sutures or staples are removed on the 7th post-operative day in the ward review. to see the stone clearance patients are reviewed with kub x-ray after 3 weeks and double j stent are removed cystoscopically. all data were analyzed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. results pre-operative characteristics of the patients are shown in table 1. the mean age of male and female patients was 44.97 ± 11.24 and 43.89 ± 14.49 years, respectively. the number of female patients (79) was more in comparison to male. mean bmi of the patients was 20.79 ± 2.73 kg/m2 (range 16-25 kg/m2). in the present study the stone was mostly located in the upper ureter (72.72%) followed by middle and lower ureter in 15.39% and 11.89%, respectively. the stone size ranged from > 10 to < 30 mm, of which size 15 to < 20 endourology and stone disease 1585vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l mm (36.36%) was the most common occurrence followed by 20 to < 25 mm (27.27%). the mean size of the stone in the present study was 18.35 ± 4.54 (10.50-28.00). chart 1 represents the indications of open mini-access ureterolithotomy. the most common indication for open miniaccess ureterolithotomy in the present study was impacted large stone (45%) and the second most common indication was failure of ureterorenoscopic lithotripsy (ursl). only 12% of patients had anatomical abnormalities which favored open mini-access ureterolithotomy as the preferred modality of treatment. table 2 shows operative features of open mini-access ureterolithotomy. the mean operative duration was 25.39 ± 5.11 min, with an incision length of 4.78 ± 0.25 mm; the estimated blood loss was 50.55 ± 8 ml with none of the patient’s required post-operative blood transfusion. the pain score in the post-operative period of 24 hours 48 hours and 72 hours are shown in chart 3 using the visual analogue scale (vas). although severe post-operative pain (vas score 8-10) has been noted in 35% of cases at 24 hours, it was reduced to 10% and 5% of patients at 48 hours and 72 hours respectively. the post-operative complications were few and minor in all cases as shown in chart 3. the overall complication rate was 5.6%. hematuria and fever resolved with conservative management. the mild ileus resolved with nil oral for another day and laxative suppository. wound infections were mild with minimal subcutaneous collections which resolved with drainage and dressing. the success rate and complications of mini-access ureterolithotomy among the various indicated subgroups are shown in table 3. the success rate was 100% in most all the cases except in patients with prior failed ursl where a success rate of 98% was noticed. complication rate was more in patients with impacted large calculus and patients with prior ursl, and it was 7.93% and 6.12% respectively. however, the overall complication rate in the present study was 5.60%. discussion the last three decades have brought revolutionary changes in the management of urolithiasis. due to recent advances in endourology, there is hardly any role of open stone surgery. according to european association of urology (eau) guidelines, open ureterolithotomy might be conmini-access ureterolithotomy in the modern era | meitei et al chart 1. the indications of open mini-access ureterolithotomy. keys: eswl, extracorporeal shockwave lithotripsy; ursl, ureterorenoscopic lithotripsy. chart 2. evaluation of pain score in the post-operative period using visual analogue scale. keys: vas, visual analogue scale. chart 3. the post-operative complications. 1586 | sidered for treating an impacted large calculus, multiple ureteral stones or in the event of any coexistence disease requiring surgery.(4) despite of a high stone-free rate of 97%, open ureterolithotomy has not been recommended as a first-line of treatment secondary to prolonged hospitalization and greater procedure related morbidity.(5) however, mau is a modified and technically more precise in comparison to conventional ureterolithotomy. it requires a small skin incision (≤ 5 cm) and the muscles are cut minimal for upper ureterolithotomy or split along the fibers in case of mid and lower ureterolithotomy. in this present study, the most common indications for mau were impacted large stone and failure of ursl which is in accordance with the findings of ather and colleagues.(6) swl is a non-invasive method can be performed on an outpatient basis without regional or general anesthesia, but the stone free rate depends on the study, the type of the lithotripter used, the size of the stone and location with respect to the ureter. for proximal endourology and stone disease figure 1. showing skin incision for minimally access ureterolithotomy. figure 2. showing clamping of the proximal and distal stone bearing segment of the ureter with allis forceps. figure 3. showing longitudinal opening of the ureter onto the stone. figure 4. showing placement of double j stent with closure of ureterotomy incision. 1587vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l ureteric stone, swl is associated with a mean stone free rate of 77.4% with a re-treatment rate of 10%, whereas the figure is 80.3% and 8.2% for mid ureteric and 77.9% and 9.4% for distal ureteric stones.(1) the effectiveness of swl is increasingly limited because certain stones are resistant to fragment, leading to high re-treatment rate with an overall increase in cost and lost from work. ursl has become a formidable method for treating ureteric stones. the literature review revealed a stone free rate of 90-100% for the distal and up to 74% for proximal ureteric calculus using a semi rigid or flexible ureteroscopy.(7) however, certain conditions, including ureteric stricture, inflamed and or obliterated ureterovesical junction, extensive urothelial carcinoma in situ and intravesical prostatic protrusion may limit the ureterorenoscopic access into the ureter.(8) moreover, use of flexible ureteroscope is limited by the high purchase and maintenance cost to the surgeon and associated operating cost to the patient. wickham in 1979 first described the laparoscopic ureterolithotomy. gaur and colleagues have described the largest series of retroperitoneal lap ureterolithotomy more than 100 cases over 10 years using a balloon dissector.(9) although these results are admirable, the present study showed that mau is a quicker and costeffective technique requiring only ordinary equipment. major disadvantages of laparoscopy ureterolithotomy included prolonged operating time, expensive instruments and more operative skilled. hossein and colleagues(10) observed a mean operation time of 82.15 min (73-180 min) for the laparoscopic management of the large upper ureteric calculus. the mean operative time of mau in this study was 25.39 ± 5.11 min that is in accordance with findings of sharma and colleagues.(11) laparoscopic ureterolithotomy is usually favorable over conventional open ureterolithotomy based on the data from small non-randomized studies.(12) however, the above finding has little bearing on the mini-access ureterolithotomy, which ranks superior with respect to outcome and morbidity compared to conventional approaches. the cosmetic results are definitely outweighed with a ≤ 5 cm incision and a small puncture site for the drain. in our study bmi of patients was less than < 25 kg/m2. therefore, certainly we will recommend not to perform open mini access ureterolithotomy in patients with bmi > 25 kg/m2. percutaneous open mini-access ureteric approach have also been described earlier, but those techniques require specialized instruments, endourological intervention, and mostly preferred for mid-ureteric calculus.(13,14,15) is also recommended.(12,13) the present technique is comparatively simple and easy to acquire without extra expenses. the majority of the patients had low pain scores and required a few days of postoperative analgesia. this is largely because of the minimal tissue dissection. in the present study, all patients were discharged stone-free and were free of complications apart mini-access ureterolithotomy in the modern era | meitei et al figure 5. showing closure of muscle and aponeurotic layer with 1-0 polydiaxonone. figure 6. showing stapled skin incision measuring < 5 cm. 1588 | from those eight patients with minor complications which responded to conservative management that is comparable with the observation of sharma and colleagues.(11) conclusion open mini-access ureterolithotomy is a safe procedure, which causes minor post-operative complications with early return to work. it is highly effective in the management of ureteric calculus as the calculus can be removed successfully in a single sitting with cosmetically acceptable scar. in this minimally invasive era, the specific indications for open stone surgery are a few. but, when the situation mandates, an open mini-access ureterolithotomy might be considered the best option. in future, randomized comparative study can be carried out between laparoscopy and mau in the management of large ureteric calculus. conflict of interest none declared. references 1. tiselius hg, ackermann d, alken p, buck c, conort p, gallucci m. working party on lithiasis. eau guidelines on urolithiasis. eur urol. 2001;40:362-71. 2. matlaga br, assimos dg. changing indications of open stone surgery. urol. 2002;59:490-3. 3. sy fy, wong my, foo kt. current indications for open stone surgery in singapore. ann acad med singapore. 1999;28:241-4. 4. preminger gm, tiselius hg, assimos dg, et al. 2007 guideline for the management of ureteral calculi. j urol. 2007;178:2418-34. 5. segura jw, preminger gm, assimos dg, et al. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. the american urological association. j urol. 1997;158:1915-21. 6. ather mh, paryani j, memon a, sulaiman mn. a 10-year experience of managing ureteric calculi: changing trends towards endourological intervention – is there a role for open surgery? bju int. 2001;88:173-7. 7. osti ah, hofmockel g, frohmüller h. ureteroscopic treatment of ureteral stones: only an auxiliary measure of extracorporeal shock wave lithotripsy or a primary therapeutic option? urol int. 1997;59:177-81. 8. tligui m, el khadime mr, tchala k, et al. emergency extracorporeal shock wave lithotripsy (swl) for obstructing ureteral stones. eur urol. 2003;43:552-5. endourology and stone disease 9. gaur dd, trivedi s, prabhudesai mr, madhusudhana hr, gopichand m. laparoscopic ureterolithotomy: technical considerations and long-term follow-up. bju int. 2002;89:339-43. 10. hossein k, mohammad mm, behzad l, asghar a, babak j. ultrasonography-guided pnl in comparison with laparoscopic ureterolithotomy in the management of large proximal ureteral stone. braz j urol. 2013;39:22-8. 11. sharma dm, maharaj d, naraynsingh v. open mini-access ureterolithotomy:the treatment of choice for the refractory ureteric stone? bju int. 2003;92:614-6. 12. goel a, hemal ak. upper and mid-ureteric stones: a prospective unrandomized comparison of retroperitoneoscopic and open ureterolithotomy. bju int. 2001;88:679-82. 13. toth cs, varga a, flasko t, tallai b, salah ma, kocsis i. percutaneous ureterolithotomy: direct method for removal of impacted ureteral stones. j endourol. 2001;15:285-90. 14. frang d, jako gj, repassy dl. minimal access ureterolithotomy. int urol nephrol. 1996;28:305-8. 15. repassy d, frang d, jako gj. minimal and direct access ureterolithotomy. acta chir hung. 1995;35:361-8. introduction the incidence rate of diabetic nephropathy, the most common cause of end-stage renal disease (esrd) in most developed countries, is 30% to 35% in both types of diabetes mellitus (dm).(1,2) although, it is more common in type 1 dm, because of the higher prevalence of type 2 dm in general population, the average age of diabetic patients with esrd is approximately 60 years.(3) end-stage renal disease is the cause of death among about 60% of diabetic patients(4); but, they can benefit from kidney and pancreas transplantations. in the united states, 7.1%, 75.4%, and 17.5% of diabetic esrd patients are under the treatment of peritoneal dialysis, hemodialysis, and kidney transplantation, respectively.(2) the patient and kidney allograft survival has improved during the recent years.(5) in a study in the united states, published in 1991, survival rates of patient and kidney allograft at 10 years were 40% and 32% in short-term and long-term outcomes of kidney transplantation in diabetic and nondiabetic patients heshmatollah shahbazian,* hajieh shahbazian department of kidney transplantation, golestan hospital, jondishapour university of medical sciences, ahwaz, iran abstract introduction: the purpose of this study was to compare the short-term and longterm kidney transplant outcomes in diabetic and nondiabetic patients. materials and methods: we studied all kidney recipients in golestan hospital, ahwaz, from 1995 to 2003. the patients were divided into two groups of diabetic and nondiabetic, and 1-year, 2-year, and 5-year survival rates of the patient and the kidney were evaluated. we also evaluated and compared the causes of death between these two groups. results: there were 50 diabetic patients with a mean age of 51 years, and 350 nondiabetic patients with the mean age of 29 years old (p = .03). one-year, 2-year, and 5-year graft survival rates were 90% versus 91.5%, 86% versus 89%, and 76% versus 83% in diabetic and nondiabetic patients, respectively (p = .19). the patient survival rates were 92% versus 93%, 88% versus 91%, and 76% versus 84% in diabetic and nondiabetic patients, respectively. the most common cause of death was myocardial infarction in diabetic patients (50%), and septicemia among the nondiabetic ones (50%). the most common cause of kidney allograft loss was patient's death (75%) in diabetic patients and kidney rejection (40%) in nondiabetics. conclusion: long-term kidney transplantation results have been significantly improved comparing with other studies. thus, kidney transplantation is recommended as the treatment of choice in diabetic patients with end-stage renal disease. however, a complete evaluation of cardiac problems for these patients is recommended before the surgery. key words: diabetes, nephropathy, kidney transplantation, kidney allograft survival 197 urology journal unrc/iua vol. 2, no. 4, 197-200 autumn 2005 printed in iran received february 2005 accepted june 2005 *corresponding author: department of kidney transplantation, golestan hospital, ahwaz, iran. tel: ++98 611 338 6258 e-mail: heshmatolahs@yahoo.ca kidney transplantation in diabetic and nondiabetic patients diabetic patients, and 61% and 51% in nondiabetic patients, respectively.(6) in another study, the 10year allograft survival rate in diabetic patients with matched hla typing has been reported to be 62%, while it has been 89% in nondiabetic patients.(7) also, it has been shown that 1-year survival rate of diabetic and nondiabetic patients are the same (90%), but the allograft survival is 10% less in diabetic patients.(8) overall, diabetic esrd patients have significantly improved following kidney transplantation regarding the survival and quality of life, compared to those maintaining on dialysis.(9) however, diabetic patients have a poorer outcome when compared with nondiabetics, and a strenuous effort is warranted to improve kidney transplantation outcome in these patients. to take the first steps, we reviewed the short-term and long-term outcomes of diabetic and nondiabetic kidney recipients in our transplant center. materials and methods the records of all kidney transplant recipients in golestan hospital, ahwaz, from 1995 to 2003, were reviewed to compare the outcomes in patients with and without diabetes. patients with new-onset diabetes mellitus after kidney transplantation were excluded. all of the patients had been completely assessed for cardiovascular disorders. electrocardiography, echocardiography, stress test or thallium scan, and coronary arteries angiography had been performed in diabetic recipients preoperatively. coronary artery bypass had been done, if necessary. nondiabetic candidates had been examined by electrocardiography, chest radiography, and echocardiography, and other assessments would have been done in case of the presence of vascular involvement in other parts of the body or clinical evidence of ischemic heart disease. all the patients were under triple immunosuppressive regimen of cyclosporine (4 mg/kg to 5 mg/kg), azathioprine (2 mg/kg) and prednisolone (12.5 mg). since 2001, all patients received mycophenolate mofetil (cellcept) with the dose of 2 g instead of azathioprine. all diabetic patients (with types 1 or 2) were under the treatment with insulin. all of the patients were examined monthly in the first posttransplant year and every 2 months thereafter. reviewing the patients' records, data including age, sex, history of diabetes mellitus, duration of diabetes before transplantation, type of diabetes, history of hemodialysis, donor type, graft loss and its cause, death and its cause, serum creatinine level, and follow-up duration were collected and analysed. statistical analysis of the data was performed using spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa) and s-plus software (s-plus 7, insightful corporation, seattle, usa). the chisquare test, kaplan-meier method, and log-rank test were performed for comparisons and analyses of survival. graft loss (death-censored) was considered the graft survival endpoint, and patient's death of any cause was considered the patient survival endpoint. a p value less than 0.05 was considered significant. results the mean follow-up of the patients was 17 ± 13.4 months in diabetic and 21.5 ± 19 months in nondiabetic patients (p = .23). four hundred patients were assessed, of whom 50 were diabetic and 350 were nondiabetic. in diabetic patients group, 35 (70%) were males and 15 (30%) were females. the mean age of them was 51.0 ± 15.2 years (range, 16 to 63 years). diabetes had been diagnosed for a mean duration of 17 ± 2.3 years (range, 12 to 24 years). diabetic patients had been treated by hemodialysis for a mean 10 ± 3.3 conservative months (range, 4 to 18 months) before transplantation. twenty patients had type 1 diabetes, and 30 had type 2 diabetes. in the group of nondiabetic patients, 232 (66.3%) were males and 118 (33.7%) were females. the mean age of these patients was 29 ± 2.3 years (range, 6 to 67 years), which was significantly lower than the age of diabetic patients (p = .03), and they had been treated by conservative hemodialysis for 12 ± 7.5 months (range, 5 to 19 months). kidney donors were alive in both groups. ten kidney donors (20%) in diabetic group and 109 (31%) in the nondiabetic group were living-related and others were living-unrelated (p = .002) one-year graft survival rate was 90% and 91.5% in diabetic and nondiabetic patients, respectively, and the 2-year survival rate was 86% and 89%, respectively (p = .50 and p = .37). the 5-year graft survival rate was 76% and 83% in diabetic and nondiabetic groups (p = .19). 198 shahbazian and shahbazian the 1-, 2-, and 5-year patient survival rates for diabetic kidney recipients were 92%, 88%, and 76%, respectively, while they were 93%, 91%, and 84% for nondiabetic patients (p = .14; p = .09; p = .08). of diabetic patients, 4 (8%) and 2 (4%) died during the first and second posttransplant years, and totally, 12 (24%) died within 5 years after transplantation. causes of death among these patients included myocardial infarction (in 6 patients), septicemia (in 4 patients), lung kaposi's sarcoma (in 1 patient), and liver failure (in 1 patient). of nondiabetic patients, 25 (7.1%) and 6 (1.7%) died during the first and second posttransplant years, and totally, 56 (16%) died within 5 years after transplantation. causes of death were septicemia (in 28 patients), myocardial infarction (in 14 patients), liver failure (in 6 patients), malignancies (in 4 patients), and other diseases (in 4 patients). of diabetic patients, 5 lost their kidney allograft function during the first year, 2 during the second year, and 12 within the first five years. in 9 out of 12 mortality cases in this group, the patients had a normal kidney function at death, while allograft renal artery thrombosis, acute kidney rejection, and extensive ureteral necrosis had developed at death in 3 patients (25%). of nondiabetic patients, 30 lost their kidney function within the first year, 10 within the second year, and 60 within the first 5 years. in 14 (25%) mortality cases, the patients died with a normal kidney function, while in 42 (75%), acute kidney rejection (in 22 patients), allograft renal artery thrombosis (in 11 patients), urine leakage (3 patients), recurrence of primary disease in transplanted kidney (in 3 patients), and other involvements of kidney (in 2 patients) had developed at death. the remainder in both groups had a normal kidney function, 90% of whom had a serum creatinine level lower than 2 mg/dl, and 10% had a creatinine level higher than 2 mg/dl but did not require dialysis. discussion our diabetic kidney recipients had comparable patient and graft survivals with nondiabetic patients, being over 75% at 5 years. life expectancy of diabetic patients on hemodialysis has improved during recent years. the 5-year survival rate of these patients in germany has been reported less than 10% for type 2 diabetes mellitus in early 1990s,(10) but it has been reported to be 30% to 50% in eastern asian countries during the recent years.(2) peritoneal dialysis is the treatment of choice in diabetic patients; however, it mostly increases the 2-year survival.(11) there is a consensus these days that medical rehabilitation of diabetic kidney recipients is preferred to dialysis.(9) survival rate of diabetic patients with a transplanted kidney is lower than nondiabetic kidney recipients.(5-7,12) however, diabetic patients benefit from kidney transplantation more than dialysis, because survival rate of diabetic patients under treatment of hemodialysis is very low. rimmer and colleagues have reported the poor results of kidney transplantation in diabetic patients in 1985. the 1and 2-year graft survival was 37% and 13%, and patient survival was 48% and 24% in 30 patients.(12) this may be resulted from poor surgical techniques and the absence of potent immunosuppressive drugs in 1980s, and performing transplantation in patients with cardiovascular problems. fischel and coworkers have evaluated 10-year results of kidney transplantation in diabetic patients in 1991.(6) they concluded that patient and graft survival rates are poorer in diabetic patients in long run. the results of our 5-year study on diabetic recipients did not differ from those of nondiabetic patients; however, the 10-year survival may be influenced by several vascular defects in different organs in diabetic patients. douzdjian and colleagues(5) have studied the patient and graft survival rates in diabetic kidney recipients in 1995. the graft survival rates in 63 diabetic patients were 76% and 49% at 1 and 5 years, while they were 89% and 63% in 80 nondiabetic patients, respectively. it seems that short-time survival rates of diabetic patients and their transplanted kidneys are improving; however, the long-time survival rate is still lower in these patients comparing with nondiabetic patients.(8,9) the most important cause of poor long-term results of transplantation among these patients is their death because of coronary artery disease, left ventricular hypertrophy, and hypertension after the transplantation.(13) despite the higher mean age (by about 22 years) of diabetic patients and the lower percent of living-related donors in this group of our 199 kidney transplantation in diabetic and nondiabetic patients study, the short-term survival rate of graft was good in these patients. acceptable short-term results may be because of accurate and complete evaluation of diabetic patients before transplantation, especially complete cardiovascular evaluation and elimination of diabetic patients with advanced cardiovascular complications from the transplantation program. another effective factor in our study is the difference between the donors. in addition, all of our patients had received kidneys from living donors, while in other studies cadaveric kidney transplantation is dominant(14,15); transplantation results are much better with living donors. on the other hand, our national program for kidney transplantation, which is based on livingunrelated donors, has minimized the period of dialysis required in esrd patients, leading to less associated cardiovascular complications. finally, long-term results of transplantation in our center were slightly poorer in diabetic patients comparing with nondiabetic patients, but this difference was not significant. conclusion the treatment of choice in diabetic patients with esrd is kidney transplantation or combined transplantation of kidney and pancreas, and the results of hemodialysis and peritoneal dialysis are drastically poorer. complete preoperative cardiovascular evaluation of these patients including coronary arteries angiography and coronary bypass (if needed) is recommended to improve the outcome of transplantation. references 1. ritz e, rychlik i, locatelli f, halimi s. end-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. am j kidney dis. 1999;34:795808. 2. parving hh, mauer m, ritz e. diabetic nephropathy. in: brenner bm, levine sa, editors. brenner & rector's the kidney. 7th ed. philadelphia: wb saunders; 2004: p. 1777-818. 3. cowie cc, port fk, wolfe ra, savage pj, moll pp, hawthorne vm. disparities in incidence of diabetic endstage renal disease according to race and type of diabetes. n engl j med. 1989;321:1074-9. 4. borch-johnsen k. the prognosis of insulin-dependent diabetes mellitus. an epidemiological approach. dan med bull. 1989;36:336-48. 5. douzdjian v, rice jc, gugliuzza kk, fish jc, carson rw. renal allograft and patient outcome after transplantation: pancreas-kidney versus kidney-alone transplants in type 1 diabetic patients versus kidneyalone transplants in nondiabetic patients. am j kidney dis. 1996;27:106-16. 6. fischel rj, matas aj, payne wd, et al. long-term outcome in 1-year graft survivors: comparison of diabetic and nondiabetic populations. transplant proc. 1991;23(1 pt 2):1337. 7. el-gebely s, hathaway dk, elmer ds, gaber lw, acchiardo s, gaber ao. an analysis of renal function in pancreas-kidney and diabetic kidney-alone recipients at two years following transplantation. transplantation. 1995;59:1410-5. 8. zimmerman sw, glass n, sollinger h, miller d, belzer f. treatment of end-stage diabetic nephropathy: over a decade of experience at one institution. medicine (baltimore). 1984;63:311-7. 9. wolfe ra, ashby vb, milford el, et al. comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. n engl j med. 1999;341:1725-30. 10. koch m, kutkuhn b, grabensee b, ritz e. apolipoprotein a, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. nephrol dial transplant. 1997;12:2603-11. 11. heaf jg, lokkegaard h, madsen m. initial survival advantage of peritoneal dialysis relative to haemodialysis. nephrol dial transplant. 2002;17:112-7. 12. rimmer jm, sussman m, foster r, gennari fj. renal transplantation in diabetes mellitus. influence of preexisting vascular disease on outcome. nephron. 1986;42:304-10. 13. hypolite io, bucci j, hshieh p, et al. acute coronary syndromes after renal transplantation in patients with end-stage renal disease resulting from diabetes. am j transplant. 2002;2:274-81. 14. ojo ao, meier-kriesche hu, hanson ja, et al . the impact of simultaneous pancreas-kidney transplantation on long-term patient survival. transplantation. 2001;71:82-90. 15. najarian js, canafax dm, sutherland de. renal transplantation in diabetic patients is confirmed therapy while pancreas transplantation should be performed only in an investigational setting. j diabet complications. 1988;2:158-61. 200 1435vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l postoperative nomogram for disease recurrence and cancer-specific death for upper tract urothelial carcinoma: comparison to american joint committee on cancer staging classification behfar ehdaie,1,3 shahrokh f. shariat,2 caroline savage,3 jonathan coleman,1 guido dalbagni1 purpose:wesoughttodevelopprognosticmodelstopredictdiseaserecurrenceandcancerspecificmortalityinpatientswithuppertracturothelialcarcinoma(utuc)whounderwent radicalnephroureterectomy(rnu). materials and methods:dataon253patientstreatedwithrnubetween1995and2008ata singlehigh-volumetertiaryreferralcenterwereanalyzed.statisticallyandclinicallysignificant patientandtumorcharacteristicswereidentifiedinaunivariateanalysisandincorporatedinto amultivariablecoxregressionmodel.themodelwascomparedtothe2010americanjoint committeeoncancer(ajcc)stagingclassificationusingtheconcordanceindex(c-index), correctedforstatisticaloptimismusingbootstrapmethods. results:five-yearrecurrence-freesurvival(rfs)andcancer-specificsurvival(css)rates were73%[95%confidenceinterval(ci):66-79%)]and78%(95%ci:71-84%),respectively. onmultivariateanalysis,higherpreoperativeglomerularfiltrationrate(gfr)wasassociated withbettercss[hazardratio(hr)per1ml/min/m2increaseingfrforcss:0.74;p=.002)], whilehigherpathologicstage(hrforpt2:2.99andfor≥pt3:7.34;p<.001)andlymph nodeinvolvement(hr:3.75;p<.001)wereassociatedwithworsecss;resultsweresimilar forrfs.theabilityofthefinalmodels,whichincludedpreoperativegfr,lymphnodestatus, pathologicgrade,andstage,topredictrfsandcss(c-index0.82and0.83,respectively)was similartothatofthe2010ajccstagingclassification(c-index0.80and0.81,respectively). conclusion:giventhedata-dependentselectionofvariablesinthissingleinstitutioncohort, itisunlikelythatthemarginalimprovementfoundwiththesepredictionmodelswouldimportantlyimpactclinicaldecision-makingorimprovepatientcare.the2010ajccstagingclassificationaloneisveryaccurateandshouldcontinuetoguidefollow-upafterrnu. keywords: nomograms; prognosis; survival; urologic neoplasms; urothelium; carcinoma; transitionalcell;retrospectivestudies. corresponding author: behfar ehdaie, md urology service, department of surgery, memorial sloankettering cancer center, 1275 york ave., new york, ny 10065, usa. tel: +1 646 422 4406 fax: +1 212 988 0759. e-mail: ehdaieb@mskcc.org received january 2013 accepted july 2013 1urology service, sidney kimmel center for prostate and urologic cancers, memorial sloan-kettering cancer center, new york, ny, usa. 2 department of urology and division of medical oncology, weill cornell medical center, new york-presbyterian, new york, ny, usa. 3 health outcomes research group, department of epidemiology and biostatistics, memorial sloan-kettering cancer center, new york, ny, usa. urological oncology 1436 | introduction uppertracturothelialcarcinoma(utuc)isarela-tivelyrareneoplasmandaccountsfor5-6%ofallurothelial tumors.(1) radical nephroureterectomy (rnu)withbladdercuffremovalisthemosteffectivetreatmentforinvasiveutuc.approximately20-40%ofpatients initially present with locally advanced disease and lymph nodemetastasesatthetimeofdiagnosis.(2)despiteadvances insurgicaltechnique,5-yearcancer-specificmortalityrates are15%,45%and88%forpatientswithpt2n0,pt3n0and pt4n0disease,respectively.(3)therarityofthediseasehas limitedtheuseofprospectivestudiestoevaluatetheroleofa multimodalitytreatmentapproach,andexistingdataindicate thatthesurvivalratesinthesepatientshavenotimproved.(4) accuratepredictionofpostoperativecancerrecurrenceand survivaloutcomescouldhelpguidedecisionsregardingadministrationofadjuvantchemotherapyandselectiveenrollmentintoclinicaltrialsofnoveltherapies.currently,useof adjuvantchemotherapyislimitedbythelackofproofofefficacyandpotentialsideeffects.moreover,physiciansare hesitanttoadministerneoadjuvantchemotherapybecauseof thelimitedaccuracyofpreoperativestagingbasedonhistopathology.thepathologicalstagingcriteriadefinedbythe americanjointcommitteeoncancer(ajcc)incorporate tumorstage,nodalstage,andmetastasesinformationtopredict prognosis.(5)however,applicationof the2010ajcc stagingclassificationtoutucislimitedforseveralreasons. first,lymphnodestatusisnotconsistentinutucasthere isnoconsensusdefiningananatomictemplateforalymph nodedissectionandnearly60%ofpatientsdonothaveadequatelymphnodestaging.(6)second,tumorgrade,which isanimportantpredictorofprognosisforutuc,isnotincludedinthe2010ajccclassification.(7,8) giventheseputativelimitationsofthe2010ajccstaging classification, our objective was to develop multivariable models topredictfive-yearrecurrence-freesurvival(rfs) andcancer-specificsurvival(css)afterrnubasedonpatientandtumorcharacteristicsandtocompareitsprognostic accuracytothatofthe2010ajccstagingclassification. materials and methods patient cohort in this institutional review board-approved study, we reviewedalltheprospectivelycollecteddataon324consecutivepatientswithuppertracttumorstreatedwithrnuatmemorial sloan-kettering cancer center (mskcc) between 1995and2008.weexcludedpatientswhounderwentpreviousorconcurrentradicalcystectomy(n=46),hadpriorcontralateralutuc(n=4),orreceivedpreoperativechemotherapy(n=21).theremaining253patientswerethesubjectsof thepresentanalysis.rnuwasperformedbygenitourinary surgeonsatmskccusingastandardizedapproach,includingtheremovalofthekidneywiththeentirelengthofthe ureterandtheadjacentsegmentofthebladdercuff.thehilarandregionallymphnodesadjacenttotheipsilateralgreat vesselgenerallywereresected.allpatientswereenrolledin standardized post-operative clinical pathways. the preoperativeevaluationwassimilaramongallpatients,including computedtomography(ct)scan,chestx-ray,cysto-ureteroscopy,andurinecytology.nopatientreceivedpreoperative chemotherapyandpost-operativechemotherapyconsistedof platinum-basedtreatmentforevidenceofmetastaticdisease. outcome evaluation todeterminerfs,wedefineddiseaserecurrenceasanyradiographicdocumentationofdiseaseorpathologicallyprovenfailureinoperativesite,regionallymphnodes,ordistant metastasis.recurrenceswithinthebladderandthecontralateralcollectingsystemwerenotconsideredintheanalysisof rfsrate.todeterminecss,causeofdeathwasdetermined bychartreviewcorroboratedbydeathcertificate. statistical analysis ourfirstaimwastoidentifypostoperativepredictorsofoncologicoutcomeafterrnu.weusedunivariatecoxproportional-hazardsregressionmodelstopredictrfsandcss. predictorsinouranalysesincludedgender,age,american societyofanesthesiologists(asa)classificationscore,preoperativeglomerularfiltrationrate(gfr),smokinghistory, carcinomainsitu,multifocaldisease,pathologicgrade(≥2 or<2),pathologicstage(≤pt1,pt2,or≥pt3)andnodestatus(nx,n0,orn1).fortheoutcomesofrfsandcss,we createdtwomultivariablemodelsthatincludedcarcinomain situ,grade,pathologicstage,andnodestatus.predictorsfor themultivariablemodelswerechosenfromthosefoundto besignificantonunivariateanalyses;duetothelimitednumberofevents,wefocusedourselectiononthosethatwere deemedthemostclinicallyrelevant.weevaluatedthepredictiveaccuracyofourmultivariablemodelsusingconcordance index(c-index)withbootstrappingtocorrectforstatistical urological oncology 1437vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l optimism.allstatisticalanalyseswereconductedusingstata11.0(statacorp,collegestation,tx,usa). results patient characteristics are shown in table 1. the median age of patients was 72 years; approximately two-thirds (62%;n =158)ofpatientsweremaleandthree-quartersreportedahistoryofsmoking(74%).themedianfollow-upfor patients without disease recurrence or death was 4.2 years. ofthe58patientswhoexperiencedrecurrence,48diedfrom utucincluding1patientwhodiedfromdiseasewithout priorevidenceofarecurrenceandwasconsideredtohave experienced recurrence at the time of death. overall, the 5-yearprobabilityofrfsandcsswere73%[(95%confidenceinterval(ci):66-79%)]and78%(95%ci:71-84%), respectively(figures1and2).intotal,96patientsdied;the 5-yearsurvivalprobabilitywas65%(95%ci:58-72%). table2showstheresultsfromtheunivariatecoxproportional-hazards(hr)regressionmodels.age,asascore,and preoperativegfrweresignificantlyassociatedwithcss. additionally, grade, pathologic stage, and node status were significantlyassociatedwithrfsandcss.wedidnotfind anyevidencethatgender(allp≥.2),orsmokinghistory(all p≥ .4)weresignificantlyassociatedwithanyof theoutcomes.therewasnoevidenceofnon-linearitywithrespect toageandpreoperativegfr. themultivariableresultsareshownintable3.higherpreoperativegfrwasassociatedwithbetteroutcomes,while highergrade,pathologicstage,andlymphnodeinvolvement weresignificantlyassociatedwithworseoutcomes. wewereconcernedthatgiventhehighrateofdeathfrom othercauses(halfthedeathswereduetocausesotherthan utuc), a competing-risks regression model would have beenmoreappropriate.werepeatedallofouranalysesusingacompetingriskregressionmodelsandfoundverysimilarresults.forexample,thesubhazardratiofortheeffectof gfronrecurrencewas0.74(95%ci:0.61-0.90)compared tohrof0.73(95%ci:0.61-0.88)usingthecoxproportional-hazardsmodel;boththesubhazardratioandhrestimate forpathologicstagept3anddeathfromdiseasewere7.34. giventhesimilarityinestimatesandtheabilitytocompare concordanceindices,wechosetopresentourresultsfromthe coxproportional-hazardsmodels. theoveralldiscriminatoryabilityofourtwomultivariable modelstopredictrfsandcsswashigh(bootstrap-correctedc-index:0.82and0.83,respectively).incomparison,the discriminatoryabilityofajccstagealonetopredictrfs andcssasmeasuredbythebootstrap-correctedc-indexwas 0.80and0.81,respectively. discussion inthisstudy,wecombinedpatientandtumorcharacteristics withpathologicstageandgradetopredictrfsandcss. additional patient characteristics and histology grade only postoperative nomogram for upper tract urothelial carcinoma | ehdaie et al figure 1. recurrence-free survival in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy and bladder cuff excision. figure 2. cancer-specific survival in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy and bladder cuff excision. 1438 | marginallyenhancedthediscriminatoryabilityofthe2010 ajcc staging classification to predict disease recurrence andcancer-specificmortalityinutucpatientstreatedwith rnu.giventhatthecohortwasderivedfromasingleinstitutionandthatvariableswereselectedforthemultivariable modelsinadata-dependentmanner,wearecautioustorecommendtheimplementationofourmodelsandreplacingthe standardajccstageclassification.assuch,theincorporationofgfr,pathologicgrade,andnodalstatusinaformal prognosticmodelisunlikelytoimportantlyimpactclinical decision-makingorimprovepatientcare. predictionmodelshavebeendevelopedforvarioustumors toassistphysicians,providepatientswithestimatesofclinicaloutcomes,andaidindecisionmaking.thereisevidence thatincorporatingmultiplevariablesintoapredictionmodel providesmoreaccurateriskpredictionthanclassifyingpatients based on tumor stage alone. in urologic oncology, multivariablemodelshavebeenshowntobemoreaccurate thanclinicalstaginginpredictingcancer-specificmortality forrenalcellcarcinoma,urothelialcarcinomaofthebladder, prostate cancer, and penile cancer.(9-12)itisimportantto evaluatetheclinicalvalueofanewpredictionmodelbefore itisimplementedintoclinicalpractice.oneoftheprimary stepsistocompareitsdiscriminatoryabilitywiththatofwhat iscurrentlyused.then,adirectcomparisonshouldbeconductedinanexternalcohortusingcalibrationanddecision curveanalytictechniquestodetermineifthenewpredictive outperformsothermodels.(13) recently,jeldresandcolleaguesdevelopedamultivariable predictivemodelinutucincorporatingage,pathological stage,andtumorgradeusingthesurveillance,epidemiology,andendresults(seer)database.(6)theirmodel’saccuracytopredictcancer-specificmortalityafterrnuwasgood (75.4%)anddemonstratedstatisticallysuperiordiscriminatoryabilitycomparedtotheajccandunionforinternationalcancercontrol(uicc)stagingclassification(64.8%). jeldresandcolleaguesacknowledgedthelimitationsinherent withintheseerdatabaseincludinglackofcentralpathologyreview,incompletesurgicalresectionofabladdercuff in31-35%ofpatientsandabsenceofalymphnodedissectioninapproximately60%ofpatients.theincompleteness ofsurgicaltreatmentdefinedbythelackofbladdercuffexcisioncannegativelyimpacttheaccuracyofpathologicalstagingandmaylimitthegeneralizabilityoftheresults. usingacontemporarycohortofpatients,wedevelopedprognosticmodelstopredictdiseaserecurrenceandcancer-specificmortalityincorporatingpathologicstage,lymphnodestatus,tumorgrade,andpreoperativegfr.preoperativegfr isaneffectivesurrogateforoverallhealthasmultiplestudtable 1. patient characteristics. all values are median (iqr) or frequency (proportion). variables no. = 253 age at surgery (years) 72 (63-77) body mass index (n = 246) (kg/m2) 27 (24-30) male gender 158 (62%) preoperative gfr (n = 248) (ml/min/m2) 54 (44-68) preoperative high grade (n = 161) 110 (68%) hematuria, no. (%) none 64 (25) micro 28 (11) gross 161 (64) parenchymal invasion on ct (n = 248) 36 (15%) hydronephrosis on ct (n = 251) 125 (50%) cytology, no. (%) negative 52 (21) positive 190 (75) not done 11 (4) smoking history* (n = 252) 185 (73%) asa score (n = 252), no. (%) 1 7 (3) 2 127 (50) 3 118 (47) pathologic stage, no. (%) ≤ pt1 132 (52) pt2 56 (22) ≥ pt3 65 (26) lymph node status, no. (%) nx 93 (37) n0 137 (54) n1 23 (9) pathologic grade (n = 252), no. (%) high 193 (77) low 59 (23) previous nmibc 86 (34) cis 70 (28) multifocal disease (n = 250) 65 (26%) keys: nmibc, non-muscle invasive bladder cancer; cis, carcinoma in situ; gfr, glomerular filtration rate; iqr, interquartile range; ct, computed tomography; asa, american joint committee on cancer. *smoking history reported at time of surgery (current/former vs. never). urological oncology 1439vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l ieshavedemonstratedthatrenalfunctionimpactsmortality andreducedrenalfunctionleads tohypertension,anemia, malnutrition,cardiovasculardisease,andreducedqualityof life.(14)inutuc,assessmentofrenalfunctionisimportant forprognosisbecausernuisthemosteffectivetreatment forinvasivediseasewhileadjuvantchemotherapyislimited byanincreasedriskofrenaldysfunction.furthermore,and incontrasttotheseerstudy,weevaluatedaconsecutive, prospectivelycollectedcohortofpatientsinasingle,highvolumetertiaryreferralcenter.inaddition,thec-indexforthe ajccstagingclassificationintheseerdatabasewaslow (rfs:64.8%)andinourmodel,the2010ajccstagingclassificationwashighlypredictiveofsurvivaloutcomes(rfs: 80%,css:81%).theseresultsmightbeexplainedbythe heterogeneityinbladdercuffexcisionandlymphadenectomy withintheseerdatabase. wefailedtofindevidencethattheadditionofgrade,gfr,and lymphnodestatusimportantlyimprovedpredictionofoncologicoutcomesinutuc.despiteamarginalimprovementin thediscriminatoryabilityofourpredictivemodelscompared withthe2010ajccstagingclassification,wearecautious withtheinterpretationofourresults.inthissingleinstitution studythatinvolveddata-dependentvariableselection,asmall changeineffectsizeisunlikelytowithstandacomparative analysiswiththestandardajccstagingclassificationinan externalcohortusingcalibrationanddecisioncurveanalytic techniquesasbenchmarks.alternatively,ifwehadachieved theseresultsusingalarge,multi-institutionaldatabase,thena smallimprovementinthec-indexwouldbemoreclinically dependableandworthyoffurtherinvestigation. thereareseveralimportantlimitationsofourstudy.first, utucisararemalignancy,whichmakesevaluationoflarge table 2. univariate cox proportional-hazards models for recurrence-free survival and upper tract urothelial carcinoma-specific survival. variables recurrence-free survival disease-specific survival hr 95% ci p hr 95% ci p male 1.11 0.65-1.89 .7 1.21 .5 age 1.22 0.97-1534 .097 1.44 .014 asa score .074 .037 < 3 ref ref ref ≥ 3 1.60 0.96-2.67 1.84 preoperative gfr 0.76 0.64-0.89 < .001 0.74 .002 (per 10 ml/min/m2) smoking 0.77 0.44-1.35 .4 0.77 .4 cis 1.63 0.96-2.79 .072 1.66 .094 multifocal disease 0.91 0.50-1.66 .8 0.88 .7 grade .005 .014 low ref ref ref high 3.36 1.44-7.83 2.92 pathologic stage < .001 < .001 ≤ pt1 ref ref ref pt2 2.72 1.22-6.05 4.21 ≥ pt3 8.91 4.61-17.2 11.7 node status < .001 < .001 n0 ref ref ref n1 8.01 4.26-15.1 7.99 nx 0.78 0.42-1.46 0.76 keys: hr, hazard ratio; ci, confidence interval; ref, reference; nmibc, non-muscle invasive bladder cancer; cis, carcinoma in situ; smoking, smoking status at time of surgery; gfr, glomerular filtration rate, asa, american joint committee on cancer. postoperative nomogram for upper tract urothelial carcinoma | ehdaie et al 1440 | patientpopulationsdifficult.however,inspiteofthelimited sizeofourcohort,wewereabletoidentifyseveralclinically relevantpredictors.critically,despiteidentifyingseveralvariablesthatwereindependentlyandstatisticallysignificanton multivariableanalysis,incorporationofthesefactorsintoa predictionmodeldidnotimportantlyimprovethepredictive accuracyabovethatofthe2010ajccstagingalone.second, tumorgradeandpathologyweredeterminedbyinstitutional pathologyreport,as therewasnosystematicre-reviewof thepathologicmaterial.third,despitethestandardizationof surgicaltechniqueandroutineexcisionofabladdercuffduringrnu,37%ofthepatientsinourcohortdidnotreceive alymphadenectomy.therefore,webelieveit is important toemphasizetheneedforastandardizationoftheextentof lymphnodedissectionanditsindicationsinutucpatients treated with rnu. webelieveourstudyisnovelandemphasizestheimportanceofconsidering the impactofapredictionmodelon clinicaldecisionmakingrather thanfocusingonmarginal statistical significance. furthermore, our study will help investigatorsdevelopanimprovedpredictionmodelbyincorporatingnovelbiomarkersfordiseaseprogressionsuch astumorarchitecture.(15)inthefuture,theevaluationofa largermulti-institutionaldatabasewithadditionalpatientand tumorcharacteristicsmayimprovethediscriminatoryability ofapredictivemodelforutuc.however,wedemonstrated thatinthiscontemporarycohortofutucpatientstreated withrnutheincorporationofmultipleclinicallysignificant predictorsdoesnotprovidemoreaccurateprognosticinformationthanpathologicstage. conclusion themultivariateprognosticmodelwedevelopedincorporatinggfr,tumorgrade,stageandlymphnodestatusdidnot meaningfullyimprovethediscriminatoryabilityofthe2010 ajccstagingclassificationforutuc.inthispatientcohort, the2010ajccstagingclassificationalonewasveryaccurate.the2010ajccstagingclassificationshouldbeusedto guidefollow-upafterrnuandtoassistphysiciansinprovidingestimatesofcancer-specificoutcomestotheirpatients. acknowledgment thisstudywassupportedbythesidneykimmelcenterfor prostateandurologiccancers. conflict of interest none declared. table 3. multivariate cox proportional-hazards models for recurrence-free survival and cancer-specific survival in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy and bladder cuff excision. variables recurrence-free survival disease-specific survival hr 95% ci p hr 95% ci p preoperative gfr 0.73 0.61-0.88 < .001 0.74 0.61-0.90 .002 (per 10 ml/min/m2) tumor grade .2 .3 low ref ref ref ref high 1.77 0.72-4.38 1.69 0.69-4.17 pathologic stage < .001 < .001 ≤ pt1 ref ref ref ref pt2 1.67 0.71-3.94 2.99 1.12-7.97 ≥ pt3 5.71 2.77-1.7 7.34 2.98-18.1 node status < .001 .002 n0 ref ref ref ref n1 3.95 1.98-7.86 3.75 1.78-7.89 nx 1.16 0.59-2.29 1.31 0.61-2.81 keys: hr, hazard ratio; ci, confidence interval; ref, reference; gfr, glomerular filtration rate. urological oncology 1441vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l references 1. jemal a, siegel r, xu j, ward e. cancer statistics, 2010. ca cancer j clin. 2010;60:277-300. 2. munoz jj, ellison lm. upper tract urothelial neoplasms: incidence and survival during the last 2 decades. j urol. 2000;164:1523-5. 3. margulis v, shariat sf, matin sf, et al. outcomes of radical nephroureterectomy: a series from the upper tract urothelial carcinoma collaboration. cancer. 2009;115:1224-33. 4. lughezzani g, jeldres c, isbarn h, et al. nephroureterectomy and segmental ureterectomy in the treatment of invasive upper tract urothelial carcinoma: a population-based study of 2299 patients. eur j cancer. 2009;45:3291-7. 5. edge sb, david; compton, carolyn; fritz, april; greene, frederick; trotti iii, andy. ajcc cancer staging manual. springer, new york, ny. 2010; 7th edition. 6. jeldres c, sun m, lughezzani g, et al. highly predictive survival nomogram after upper urinary tract urothelial carcinoma. cancer. 2010;116:3774-84. 7. brown ga, matin sf, busby je, et al. ability of clinical grade to predict final pathologic stage in upper urinary tract transitional cell carcinoma: implications for therapy. urology. 2007;70:252-6. 8. hall mc, womack s, sagalowsky ai, carmody t, erickstad md, roehrborn cg. prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. urology. 1998;52:594-601. 9. karakiewicz pi, briganti a, chun fk, et al. multi-institutional validation of a new renal cancer-specific survival nomogram. j clin oncol. 2007;25316-22. 10. shariat sf, karakiewicz pi, palapattu gs, et al. nomograms provide improved accuracy for predicting survival after radical cystectomy. clin cancer res. 2006;12:6663-76. 11. zini l, cloutier v, isbarn h, perrotte p, et al. a simple and accurate model for prediction of cancer-specific mortality in patients treated with surgery for primary penile squamous cell carcinoma. clin cancer res. 2009;15:1013-8. 12. stephenson aj, scardino pt, eastham ja, et al. postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. j clin oncol. 2005;23:7005-12. 13. lughezzani g, budaus l, isbarn h, et al. head-to-head comparison of the three most commonly used preoperative models for prediction of biochemical recurrence after radical prostatectomy. eur urol. 2010;57:562-8. 14. go as, chertow gm, fan d, mcculloch ce, hsu cy. chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. n engl j med. 2004;351:1296-305. 15. fritsche hm, novara g, burger m, et al. macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma. urol oncol. 2012;30:666-72. postoperative nomogram for upper tract urothelial carcinoma | ehdaie et al kidney transplantation comparison of removing double-j stent with and without cystoscopy in kidney transplant patients: a randomized clinical trial mohammad nadjafi-semnani1*, nasser simforoosh1, abbas basiri1, ali tabibi1, ali nadjafi-semnani2 purpose: the ureteric stent can be attached to the foley catheter in kidney transplantation to exclude cystoscopy for its removal. it is rarely practiced in renal transplantation. there has been no randomized trial to evaluate the outcome of this procedure on major urologic complications. materials and methods: one hundred sixty-three kidney transplant patients were randomized into an intervention group in which the stent was attached to the foley catheter and removed together and a control group in which stent was removed by cystoscopy. in both groups, stents were removed around the 8th post-operative day. results: from march 2016 to june 2017, out of 234 kidney transplants performed in our center, one hundred sixty-three (69.6%) patients met the study inclusion criteria. 91patients (55.8%) were allocated to the intervention group. mean days before jj removal for intervention and control groups (“per-protocol” group) were 8.08 ± 1.52 and 8.57 ± 1.58, respectively (p = .09). there was no difference between groups regarding major urologic complications (p = .679). visual analog scale pain scores were significantly higher in the control group (p = .001). the procedure reduced 63-120 usd from the cost of operation in the intervention group. conclusion: in selected kidney transplant patients, attaching stent to the foley catheter and removing both of them early may be a safe maneuver regarding major urological complications, reduces pain, and eliminates the cost of cystoscopy. keywords: cystoscopy; double-j-stent; kidney transplantation; stent; ureteric stenting introduction with the current adequate immunosuppression, the surgical complications are the significant cause of graft loss after kidney transplants(1). urologic complications are associated with significant morbidity, graft loss, and mortality(2). the urinary anastomosis technique evolution occurred gradually during more than half a century from uretero-ureteral to the ureteroneocystostomy anastomosis, and from leadbetter-politano to the lich-grégoire(3). the lich-gregoire extravesical technique has reduced these complications(4), has stood the test of time,(5), and it is technically less demanding(6). stents which mostly are used in the lich-gregoire ureteroneocystostomy(6) technique are still a controversial issue(6). the benefits of stents are still debated(6) but may include making watertight ureteroneocystostomy anastomosis procedure easier and lowering the chance of kinking(6). the optimal stent caliber, length, design(6), duration(7), and methods to remove it remain to be determined(6). there is a considerable amount of research about the stents to address their cost-effectiveness(8,9), their disadvantages regarding urinary tract infections(6), encrustation, reflux(10), obstruction(11), irritation, migrations, a dread complication of “forgotten stents” and the last but not the least, the need for the cystoscopy for 1shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. urology and nephrology research centre, shahid beheshti university of medical sciences, tehran, iran. 2resident in general surgery, shiraz, iran. *correspondence: shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. urology and nephrology research centre, shahid beheshti university of medical sciences, tehran, iran. received july 2019 & accepted january 2020 their removal(12-16). attaching ureteral stent to the foley catheter and excluding cystoscopic removal of the stent, was first reported in 1988(17). although it has not adopted widely, we think that it is a good maneuver making transplant a more comfortable experience for patients. to the best of our knowledge, our study is the first randomized controlled trial which evaluates the major urologic complications (muc), pain, and costs between regular stent removal through cystoscopy with stent removal through attachment to foley catheter. materials and methods study design we did a randomized controlled trial in patients transplanted at shahid labbafinejad medical center, tehran, iran (a quaternary referral hospital) from march 2016 to june 2017. the ethics committee of the urology and nephrology research center of shahid beheshti university of medical sciences approved the study protocol (ir.sbmu.unrc.1395.13). the study has been registered in the iranian registry of clinical trials (irct20100313003547n6). written informed consent obtained from all participants. the stent of all participants proposed to be removed around the seventh postop day. in the intervention group, the stent was attached to the foley catheter by a nylon suture and removed urology journal/vol 17 no. 2/ march-april 2020/ pp. 173-179. [doi: 10.22037/uj.v0i0.5448] together. in the control group, the stent was removed by flexible or rigid cystoscopy in the operating room. participants eligible participants were patients 16 years and older listed for renal transplantation in the renal transplant department, which had given written informed consent. the exclusion criteria were benign prostatic hyperplasia causing bladder outlet obstruction, neurogenic bladder, history of urinary diversion, history of surgery in urethra or bladder, repeat transplanations, patients who had a high risk of bleeding after reperfusion and before performing ureteroneocystostomy anastomosis, double kidney transplantation 174 table 1. etiology of the 71 patients excluded from the study. exclusion criteria number (%) age less than 16 years 23 (32.3) history of bph and bladder outlet obstruction 10 (14.0) multiple arteries in allograft 6 (8.45) neurogenic bladder 6 (8.45) surgeon preferred not to included after reperfusion 3 (4.22) up-side-down transplant of the right-sided living donor nephrectomy 3 (4.22) sever iliac vein adhesion found during surgery 3 (4.22) third transplant 3 (4.22) history of cystoplasty 2 (2.86) double ureter in allograft 2 (2.86) double ureter and multiple arteries in the allograft 2 (2.86) transplant in continent urinary diversion 1 (1.40) iatrogenic trauma to the allograft ureter leading to boari flap procedure 1 (1.40) history of vesicostomy and mitrofannoff procedure 1 (1.40) others 3 (4.22) variablesa modified intention-to-treat group (%) per-protocol group (%) intervention group control group p value intervention group control group p value randomiza-tion per-protocol 73 (80.2) 50 (69.4) .016 na na na as-treated 6 (6.6) 1 (1.4) na na na intention-to-treat 12 (13.2) 21 (29.2) na na na age 43.85 (±15.09) 41.42 (±14.25) .311 44.66 (±14.39) 37.91 (±13.95) .013 sex male 53 (58.9) 45 (63.4) .562 46 (63.0) 32 (64.0) 1 female 37 (41.1) 26 (36.6) 27 (37.0) 18 (36.0) bmi 24.83 (±4.56) 25.0 (±4.15) .821 24.93 (±4.07) 24.02 (±4.21) .505 etiology dm 18 (19.8) 11 (15.3) .108 15 (20.5) 6 (12) .219 hpt 19 (20.9) 12 (16.7) 14 (19.2) 8 (16) unknown 15 (16.5) 10 (13.9) 13 (17.8) 8 (16) preemptive 20 (25.3) 15 (22.7) .717 18 (27.3) 9 (19.1) .375 dialysis dura-tion 16.57 ((±22.5) 15.61 (20.17) .787 14.71 (±20.2) 17.06 (±22.15) .557 positive histo-ry of diabetes 21 (25.9) 12 (17.1) .238 17 (27) 6 (12.5) .097 donor live 44 (48.4) 31 (43.7) .332 38 (52.1) 24 (48.0) .398 cadaveric 47 (51.6) 40 (56.3) 35 (47.9) 26 (52.0) previous his-tory of trans-plant no 67 (87.0) 58 (90.5) .345 54 (87.1) 44 (95.7) .117 yes 10 (13.0) 6 (9.4) 8 (1209) 2 (4.3) donor age 34.1 ((±11.89) 33.91 ((±11.03) .920 33.83 (±11044) 31.35 (±9.69) .220 donor sex male 65 (78.3) 44 (64.7) .175 54 (80.6) 32 (66.7) .234 female 17 (20.5) 23 (33.8) 12 (17.9) 15 (66.7) left or right right kidney 24 (27.3) 22 (32.4) .596 15 (21.4) 13 (27.1) .311 left kidney 64 (72.7) 46 (67.6) 55 (78.6) 35 (72.9) warm ische-mia time 2.62 ((±3.09) 2.80 ((±3.34) .799 2.87 (±3.07) 3.33 (±3.45) .571 cold ischemia time 117.04 ((±79.07) 112.33 ((±66.01) .781 103.58 (±69.81) 97.70 (±66.77) .758 surgeon’s ex-pertise level senior cosultatn 35 (39.3) 19(27.5) .272 27 (37.5) 13 (27.11) .237 (ns, ab, at) jonior consultant (mns) 12 (13.5) 13 (18.8) 10 (13.9) 12 (25) surgical fellow 42 (47.2) 37 (53.6) 35 (48.6) 23 (4709) day double j removed 8.93±3.87 11.79±6.69 .001 8.08 (±1.52) 8.57 (±1.58) .094 immunosuppression cyclospor-ine+mycophenolic 33 (53.2) 29 (46.8) .767 27 (56.3) 21 (43.8) .745 acid + corticoster-oids tacro +mycophenolic acid 24 (58.5) 17 (41.5) 19 (63.3) 11 (36.7) + corticosteroids cyclosporine + si-rolimus 7 (43.8) 9 (56.3) 6 (54.5) 5 (45.5) + cortico-steroids tacro + sirolimus + corticosteroids 12 (50) 12 (50) 9 (47.4) 10 (56.3) table 2. demographic characteristics and immunosuppression regimens. double-j stent in kidney transplant-nadjafi-semnani et al. ureter, or multiple arteries in the allograft, and any injuries to the vessels or ureter during retrieval (table 1). randomization the patients were randomly allocated (1:1) to either attaching the stent to the foley catheter or not attaching them during transplant. a computerized randomization list in blocks of five in random order was created. numbered dark pockets containing the study groups (attached or not attached) were prepared and sealed accordingly. after reperfusion, if the surgeon did not have any contraindication for allocating the patients, randomization to the intervention or the control groups was done. there was no blinding. procedures the technique of lich-gregoire extravesical anastomosis has been described elsewhere(12,18). the anastomosis was done using 5/0 polyglactin suture. the foley catheter was attached to the stent with 3/0 nylon stitch, which was passed through the distal end of the stent and the distal drainage eye of the catheter. all patients received cotrimoxazole for six months. outcomes the primary outcome was a urinary leak or a ureteric obstruction treated with intervention and was defined as major urologic complications (muc). secondary outcomes were pain experienced by the patients during stent removal and the reduction of the cost of kidney transplantation. the data were collected by completing a questionnaire. statistical analysis the primary analysis was targeted to the “modified intention-to-treat” group, although we did the “per-protocol” analysis for cases with no significant protocol violations as well. pearson's chi-squared test, fisher’s exact test, independent-samples t-test, one-way anova were used for analysis. non-parametric mannwhitney u test was used for visual analog score analysis. throughout, we reported two-sided p values. a p value of less than 0.05 was considered significant. we used spss software (version 22.0) for the statistical analysis. results from march 2016 to june 2017, two hundred thirty-four patients, mean age 40.11 ± 17.06 (6-77) years; 121 (51.7%) from deceased donors, were transplanted in our department; seventy-one patients did not meet the inclusion criteria (table 1). one hundred sixty-three patients were randomly allocated to either an intervention group (n = 91) or control group (n = 72) (figure 1). there were no differences in demographic characteristics between the two groups (table 2). mean time to stent removal in the intervention and control groups were 8.93±3.87(ci95%: 8.09-9.77), and 11.79 ± 6.69 (ci95%: 10.07-13.50), respectively (p = .001). one hundred twenty-three patients whose stent were removed early from six to fifteen post-op days were considered as protocol cases and analyzed as a “per-protocol” group. thirty-three patients violated the protocol significantly and were analyzed as an “intention-to-treat” group (table 3). in 16/163 (9.8%) patients, the catheter was removed after 15th post-op day by the decision of the in-charge surgeon because of their post-op condition such as delay graft function. in 33 patients who substantially broke the protocol, the mean ureteric stent removal day in intervention and control groups was 12.75 and 22.38 days (p = .008), respectively. seven randomized patients were considered “as-treated” group because they should not have been included in the study (table 4). the sum of “intention-to-treat,” “as-treated,” and “per-protocol” groups were defined as 163 cases of the “modified intention-to-treat” group. because from march 2016 to january 2017, attaching the stent to catheter was satisfactory in adults, from january 2017, ns and mns were attaching the ureteric stent to the foley catheter in all of their pediatric transplantations. these caused the residents in our department to consider three children as included in the study by mistake, and the parents of three pediatric patients aged 8, 14, and 15 years, were asked to give the informed consent and were randomized inadvertently to the intervention group. one of these three cases, an eight years old girl, developed urinary leakage after stent removal on the 7th post-op day and underwent ureteroneocystostomy three days later. six patients in the “per-protocol” group had their catheter removed on the six post-op day. 3/91 (3.2%) patients had accidental stent dislodgement due to malfunction of the balloon of the foley catheter, (two on the third and one case on the fifth post-op day), and none of them developed muc, although one of them developed lymphocele. 5/163 (3%) cases, including 3/91 (3.2%) in the intervention and 2/72 (2.81%) in the control group underwent ureteroneocystostomy after transplant. 4/163 (2.4%) cases had a urinary leakage, which was resolved by short term percutaneous drainage. one of these four cases was treated by both a percutaneous nephrostomy along with percutaneous drainage. there was no significant difference between the intervention and control reason for meeting the exclusion criteria number age less than 16 years 3 multiple arteries in allograft 3 neurogenic bladder 1 table 3. description of the patients included in the “as-treated” group reasons for violation of the protocol numbers foley catheter came out accidentally before the six post-op day 3 the in-charge surgeon preferred to delay removal for a reason like a delay graft function, rejection, 16 arterial/venous thrombosis or severe rejection leading to graft nephrectomy 5 postoperative hemorrhage and exploration for hematoma evacuation 4 high output drain due to urinary leak and lymphocele 2 severe hyponatremia and convulsion 1 the patient expired before removing the catheter 1 nonfunctioning graft due to arterial thrombosis 1 total 33 table 4. description of the patients analyzed as “intention-to-treat” group. double-j stent in kidney transplant-nadjafi-semnani et al. vol 17 no 02 march-april 2020 175 groups regarding the muc (table 5). the cost of cystoscopy with and without general anesthesia was 120 and 63 usds respectively, which was eliminated in the intervention group. discussion to our knowledge, this is the only randomized study in which the attachment of the ureteric stents to foley catheters versus cystoscopy removal of ureteral catheters were compared in early stent removal groups. 5/163 (3%) patients had ureteroneocystostomy, and 4/163 (2.4%) patients had leakage which was resolved by insertion of a percutaneous drain with or without a nephrostomy. muc in our previous study of 100 kt patients in whom urethral catheter was attached to ureteral stent and removed together three weeks after transplantation was 4% (one stenosis and three fistulas)(12). patel et al.(19), in a randomized trial conducted at six transplant centers in the uk, studied 205 patients aged 2 to 57 years old. cases were randomized to early removal arm, in which stent was attached to the foley catheter and were both removed at the 5th post-op day and a late removal arm, in which stent was removed at six weeks with cystoscopy. 3/80 cases (3.75%) in early removal group and 1/126 (0.79%) in late removal group; (p = 0.36) had ureteroneocystostomy(19). stent complications occurred in 27.3% and 10% in late and early stent removal groups, respectively; (p = .387). urinary tract infection in the early and late groups occurred in 7.6% kidney transplantation 176 table 5. outcomes comparison between intervention and control group. modified intention-to-treat group per-protocol group vairablesa intervention group control group p value intervention group control group p value stent dislodgement 3 (3.8) 0 .252 0 0 urinary leak 6 (8.0) 2 (4.1) .477 4 (4.1) 2 (4.8) 1 lymphocele 1 (1.3) 1 (1.7) 1 0 0 ureteroneocystostomy 3 (3.3) 2 (2.8) .849 2 (2.7) 1 (2.0) 1 drain for collection 3 (3.4) 1 (1.4) .627 3 (4.1) 1 (2.0) 0.645 nephrostomy for hydronephrosis 1 (1.1) 0 1 1 (1.4) 0 1 major urologic complications 5 (5.5) 3 (4.2) .679 5 (6.8) 2 (4.0) 0.7 visual analoge scaleb score .35 (iqr.6 ) 4 (iqr 6.35) .000 4 (iqr .7) 3 (iqr 6.2) .001 follow up 283 ± 132 296 ± 131 .545 299.7 (±126.8) 319.9 (±124.3) 0.393 mean creatinine one year after 1.30 ± .46 1.22 ± .37 .247 1.29 (±.44) 1.22 (±.38) 0.411 transplant a continuous variables were compared by independent samples t-test b continuous variables were compared by mann whitney u test figure 1. trial profile. double-j stent in kidney transplant-nadjafi-semnani et al. and 24.6%, respectively; (p = .004). 37 (18%) patients were ≤ 16 years, and there was no ureteroneocystostomy in any(19) patient. in 11 patients, the surgeon was not able to attach the stent to the urethral catheter because it was a little bit challenging task(19). we also acknowledge that finding the catheter and extracting it through a small incision of bladder mucosa is challenging. one of the authors’ recommendations (ns) for this issue is to push the bladder downward so that the superior bladder wall approaches to the floor of the bladder. by this maneuver, the tip of the foley catheter could be grabbed quickly and smoothly by the surgeon. in a retrospective study (2007-2009 ) in the uk(20) on 127 transplantation comparison was made between 48 cases, which their ureteric stents were removed on the 5th post-op day with 79 cases in which their stents removed 6-8 weeks postoperatively by flexible cystoscopy. uti occurred in early and late removal groups in 25% and 44% (p = .03), respectively. muc in early and late removal groups were 4% and 7% (p = 1), respectively. the preliminary result of an ongoing randomized trial comparing early with late stent removal in adults (isrctn51276329) has revealed that muc has not increased in the early group (mr. kourosh saeb-parsy. addenbrooke's hospital (uk), november 2018, email response). sansalone et al.(21), in 590 consecutive transplanted patients, attached the 7 or 8 fr silicone ureteral stent to the foley catheter and removed both together at mean duration of ten days(8-14). urinary leakage and stenosis occurred in 0.3% and 1.5% respectively(21). in 1998, the simple technique of attaching the ureteric stent to the foley catheter was reported for the first time by morris-stiff (a surgical research fellow) et al.(22) in fifteen (eight men) patients, mean age 48 years, they have attached the stent to a foley catheter and removed both at the mean eight post-op day. none of them developed muc or sepsis. the authors conclude the method as a useful maneuver to be used in renal transplantation. authors state that they had not invented, but they have reported this technique in the surgical literature(22). baxbi, k.(23) (a consultant urological surgeon) wrote a remarkable letter to the journal and criticized the authors’ conclusion as follow: “ authors describe a method of suturing the distal end of a ureteric stent to the tip of the urethral catheter at the time of ureteric anastomosis and say that they cannot find this technique described in the surgical literature. perhaps the reason for the latter is that orthodox urological teaching has long been that this is bad practice. the reason is that if the urethral catheter is, or has to be, removed very early in the postoperative period, the ureteric stent inevitably comes with it. the catheter may block with clots (admittedly rare after transplantation) and have to be changed; a faulty balloon may deflate so that the catheter 'falls out while the bed is being changed,' and it is not unknown for a confused patient to remove the urethral catheter with the balloon intact(23).” the comments by bixbi are a real and annoying concern for every transplant surgeon. in 3/92 (3.26%) of our patients, the catheter came out for the faulty balloon, and none of them developed muc. all of them were re-catheterized, and the catheter removed from 7th to 10th post-op day, although one of them developed lymphocele. patel et al(19). reported catheter and the ureteric stent attached to it were dropped out before the fifth post-op day in 2/79 (2.53%) cases, which is in concordance to our study. parapiboon et al.(24), in a randomized study of 74 patients, assessed the muc and uti in two groups in which the stents were removed either on the median of 8 or 15 days. uti and muc in the eight days and 15 days were 40.5% vs. 72.9%; (p = .004) and 2 cases vs. 4 case; (p = .39) respectively(24). taghizadeh et al.(25) reported the result of a prospective study randomizing 43 cases to a cystoscopic stent removal group at four post-op week and another 43 patients to the attachment of foley to the ureteric stent group removed at seventh post-op day. the uti and urinary leak in early and late removal groups were not significantly different(25). impressing innovations in kt have reported for omitting the cystoscopy, the unwanted procedure imposed by the use of the stent(26,27). as an exciting innovation, the magnetic-tipped stent was first introduced by macaluso et al. in 1989(28) and was developed mainly to decrease additional costs associated with stent removal. pain measurement by visual analog scale method in our study showed that cystoscopic stent removal was significantly more painful than removal by pulling the foley catheter, which is attached to the stent. in a study of the pain at stent removal in the usa, 68 patients who underwent ureteroscopy for urolithiasis were randomized to stent removal by office cystoscopy or the removal by pulling an attached string. the pain score was lower in the cystoscopic removal as compared to removing it by pulling the string, although the difference was not significant(29). there are some shortcomings in our research. first, the data provided is from a single center with center-specific patients, treatment protocol, and a financial perspective. we have excluded 23 children from our study, although no evidence shows a younger age of the recipient is a more significant risk factor for mucs. we did not study the uti in our trial. although both groups in our study had an equal indwelling stent time, i.e., eight days, but its measurement could reveal the effect of cystoscopy on the occurrence of uti in transplanted patients. insertion of the stent is easy but will add a procedure of cystoscopy to the kt, for its removal. cystoscopy after kidney transplant unquestionably increases the risk of uti. there are reports of urosepsis in the transplanted immunocompromised patients after cystoscopy(30). our study has an insufficient sample size. however, ours is the most extensive reported series of its sort. moreover, the study was not able to blind the surgeons or patients regarding the allocation. notwithstanding the previously mentioned shortcomings, we could analyze the primary outcome in the intention-to-treat subgroup and compare it with the per-protocol group. our randomized clinical study presents a shred of clear evidence regarding the rate of mucs occurring with the early stent removal strategy in 163 patients. muc is the critical concerns of surgeons wishing to remove the stent early by attaching the ureteric stent to the foley catheter. the attaching ureteric stent to the foley catheter is not practiced widely and not a well-acknowledged strategy in kt, although it is an easy-to-do maneuver. it is clear from our trial that this is a safe and economical procedure with less pain for the patients in regards to omitting the cystoscopy for the stent removal. double-j stent in kidney transplant-nadjafi-semnani et al. vol 17 no 02 march-april 2020 177 conclusions in selected kidney transplant patients, attaching the foley catheter to the stent and removing both of them early may be a safe maneuver regarding the major urological complications, reduces pain, and eliminates the cost of cystoscopy. references 1. phelan pj, o’kelly p, tarazi m, et al. renal allograft loss in the first post‐operative month: causes and consequences. clinical transplantation. 2012;26:544-9. 2. hau h, tautenhahn h-m, schmelzle m, et al. management of urologic complications in renal transplantation: a single-center experience. paper presented at: transplantation proceedings, 2014. 3. bessede t, hammoudi y, bedretdinova d, et al. preoperative risk factors associated with urinary complications after kidney transplantation. paper presented at: transplantation proceedings, 2017. 4. davari hr, yarmohammadi h, malekhosseini sa, salahi h, bahador a, salehipour m. urological complications in 980 consecutive patients with renal transplantation. international journal of urology. 2006;13:1271-5. 5. alberts vp, idu mm, legemate da, laguna pes mp, minnee rc. ureterovesical anastomotic techniques for kidney transplantation: a systematic review and metaanalysis. transpl int. 2014;27:593-605. 6. wilson ch, rix da, manas dm. routine intraoperative ureteric stenting for kidney transplant recipients. cochrane database syst rev. 2013;6:cd004925. 7. thompson er, hosgood sa, nicholson ml, wilson ch. early versus late ureteric stent removal after kidney transplantation. cochrane database syst rev. 2018;1:cd011455. 8. dubay da, lynch r, cohn j, et al. is routine ureteral stenting cost-effective in renal transplantation? the journal of urology. 2007;178:2509-13. 9. tavakoli a, surange rs, pearson rc, parrott nr, augustine t, riad hn. impact of stents on urological complications and health care expenditure in renal transplant recipients: results of a prospective, randomized clinical trial. j urol. 2007;177:2260-4; discussion 4. 10. waters sl, heaton k, siggers jh, et al. ureteric stents: investigating flow and encrustation. proc inst mech eng h. 2008;222:551-61. 11. simpson cm, sterne ja, walker rg, francis dm, robertson aj, jones cljpn. stentrelated ureteric obstruction in paediatric renal transplantation. 2006;21:79-85. 12. simforoosh n, obeid k, javanmard b, rezaeetalab gh, razmjoo s, soltani mh. stent removal in 200 kidney transplant recipients: nonoperative versus endoscopic removal. experimental and clinical transplantation: official journal of the middle east society for organ transplantation. 2016;14:385-8. 13. kim dj, son jh, jang sh, lee jw, cho ds, lim ch. rethinking of ureteral stent removal using an extraction string; what patients feel and what is patients' preference? : a randomized controlled study. bmc urology. 2015;15:121. 14. rassweiler mc, michel ms, ritter m, honeck p. magnetic ureteral stent removal without cystoscopy: a randomized controlled trial. journal of endourology. 2017;31:762-6. 15. kajbafzadeh am, zeinoddini a, ebadi m, heidari r, tajalli a. external extension of double-j ureteral stent during pyeloplasty: inexpensive stent and non-cystoscopic removal. int urol nephrol. 2014;46:671-6. 16. dong j, lu j, zu q, et al. routine shortterm ureteral stent in living donor renal transplantation: introduction of a simple stent removal technique without using anesthesia and cystoscope. paper presented at: transplantation proceedings, 2011. 17. morris-stiff g, balaji v, lord rh. simple technique for non-operative removal of ureteric stents after renal transplantation. annals of the royal college of surgeons of england. 1998;80:370. 18. kayler l, kang d, molmenti e, howard r. kidney transplant ureteroneocystostomy techniques and complications: review of the literature. paper presented at: transplantation proceedings, 2010. 19. patel p, rebollo-mesa i, ryan e, et al. prophylactic ureteric stents in renal transplant recipients: a multicenter randomized controlled trial of early versus late removal. am j transplant. 2017;17:2129-38. 20. thiyagarajan um, thiyagarajan p, bagul a, nicholson mjijos. early removal of ureteric stents and its impact on reducing the urinary infection in renal transplantation–a single centre experience. international journal of surgery. 2012;10:s84. 21. sansalone cv, maione g, aseni p, et al. advantages of short-time ureteric stenting for prevention of urological complications in kidney transplantation: an 18-year experience. transplant proc. 2005;37:2511-5. 22. morris-stiff g, balaji v, lord rh. simple technique for non-operative removal of ureteric stents after renal transplantation. ann r coll surg engl. 1998;80:370-1. 23. baxby k. simple technique for nonoperative removal of ureteric stents after renal transplantation. ann r coll surg engl. 1999;81:142-3. 24. parapiboon w, wiengpon k, kitiyakara c, et kidney transplantation 178 double-j stent in kidney transplant-nadjafi-semnani et al. vol 17 no 02 march-april 2020 179 al. early ureteric stent removal reduces urinary tract infection in kidney transplant recipients: a randomized controlled trial. 2017;2:0. 25. taghizadeh-afshari a, alizadeh m, farshid s. comparison of complications and short term results of conventional technique versus new technique during graft ureteral stent insertion in bari technique at emam khomeini hospital, urmia. global journal of health science. 2014;6. 26. macaluso jn, deutsch js, goodman jr, appell ra, prats lj, wahl p. the use of the magnetip double-j ureteral stent in urological practice. journal of urology. 1989;142:701-3. 27. robertson ir, edwards rd, harden p. radiological retrieval of transplant ureteric stents. nephrol dial transplant. 1993;8:8778. 28. mosayyebi a, manes c, carugo d, somani bk. advances in ureteral stent design and materials. curr urol rep. 2018;19:35. 29. barnes kt, bing mt, tracy cr. do ureteric stent extraction strings affect stentrelated quality of life or complications after ureteroscopy for urolithiasis: a prospective randomised control trial. bju international. 2014;113:605-9. 30. prabowo s, aditianingsih d. early continuous renal replacement therapy and antibiotic management in shock patients due to urosepsis with immunocompromised post renal transplantation. international journal of medical research & health sciences. 2018;7:58-69. double-j stent in kidney transplant-nadjafi-semnani et al. urology journal vol. 11 no. 04 july august 2014 2472 figure 1. staples are located adjacent to the left ureteric orifice. north eastern indira gandhi regional institute of health and medical sciences, shillong, india. corresponding author: stephen lalfakzuala sailo, md north eastern indira gandhi regional institute of health and medical sciences, shillong, india. e-mail: stephensailo@gmail.com received march 2014 accepted june 2014 spontaneous puerperal bladder perforation presenting with urinary retention pictorial stephen lalfakzuala sailo, laltanpuii sailo a 22-years old woman presented to our hospital on the 9 th postpartum day with history of difficulty in passing urine, pain and distension of abdomen for 2 days. she had anemia and tachycardia. lower abdomen was distended with mild tenderness and sluggish bowel sound. ultrasonography showed distended urinary bladder, bilateral mild hydronephrosis and minimal ascites (figure 1). catheterization drained 1500 ml of mildly blood stained urine. serum creatinine was 1.6 mg/dl. total leucocyte count was 16000/cu mm with 80% neutrophils. abdominal x-ray showed dilated bowel loops (figure 2). she was diagnosed as “puerperal sepsis with paralytic ileus” and treated conservatively for 5 days. repeat ultrasonography showed worsening of ascites with septations and urinary bladder perforation was then suspected. emergency laparotomy showed a 3 cm perforation of the bladder dome, sealed by omentum with signs of peritonitis and purulent urine (figure 3). the perforation was closed after a suprapubic cystostomy and peritoneal toilet and abdomen closed with a drain. she died of urosepsis on the 3rd postoperative day. spontaneous puerperal bladder perforation is a rare and life-threatening condition. very few cases have been reported.(1,2) png and colleagues reported 2 cases and reviewed 2 other published cases.(1) out of the 4 cases, two cases were diagnosed only during laparotomy. this case illustrates the importance of keeping bladder perforation as one of the differential diagnoses in puerperal patients presenting with sepsis and ileus, even in patients who present with urinary retention to avoid untimely death. figure 1. abdominal x-ray shows distended bowel loops. figure 2. ultrasonography demonstrates distended urinary bladder, bilateral mild hydronephrosis and minimal ascites. figure 3. emergency laparotomy showed a 3 cm perforation of the bladder dome, sealed by omentum. references 1. png ks, chong yl, ng ck. two cases of intraperitoneal bladder rupture following vaginal delivery. singapore med j. 2008;49:e327-9. 2. wandabwa j, otim t, kiondo p. spontaneous rupture of bladder in puerperium. afr health sci. 2004;4:138-9. urology journal vol. 11 no. 04 july august 2014 1854 unclassified the obturator nerve reflex after thulium laser vs. monopolar transurethral resection of bladder tumors: a randomized clinical trial vahid abedi yarandi1, fatemeh khatami1, seyed mohammad kazem aghamir1* purpose: obturator nerve reflex is the surgery treatment side effect in patients with bladder cancers. this study was run to determine the obturator nerve reflex by thulium laser versus monopolar transurethral resection of bladder tumors (turbt). materials and methods: after receiving the approval code irct20190624043991n4, one hundred and eightynine patients with bladder tumors from 2010 to 2016 were assessed, and among them, 35 patients were randomly assigned into two groups in a blinded manner; the first group (16 patients) received thulium laser and the second group (19 patients) were patients undergoing monopolar transurethral resection of bladder tumor after spinal analgesia. clinical data, including different variables such as; age, tumor characteristics, gender, operation duration, types of leg jerking, and intraoperative complications, were recorded. the site of the obturator nerve was determined by nerve stimulation, anatomical landmarks, and ultrasonography. leg jerking was compared in both groups. results: of the 35 patients, 28 cases were male, and 7 points were female. the mean ± sd (range) of age was 62.0 ± 6.9 (40-75) years in the thulium laser group and 64.0 ± 7.1 (41-77) years in the monopolar turbt group. the mean operation time was not different between the two groups significantly (p > 0.05). leg jerking was reported in 25% and 63.1% of the patients in thulium laser and monopolar turbt groups, respectively (p < 0.05). conclusion: thulium laser is a more feasible and effective method to prevent leg jerking in patients with bladder cancer; so, it is recommended more than monopolar transurethral. keywords: monopolar turbt; thulium laser; non-muscle-invasive bladder tumor; leg jerking introduction bladder cancer is one of the most common can-cers worldwide, and about 430000 new cases of bladder cancer were reported in 2012 (1). one of the treatment strategies for bladder cancer is transurethral resection of the bladder tumor (tur-bt), resulting in long-term survival rates of 40%-60% (2). however, tur-bt is unfortunately associated with some essential substantial morbidities and complications such as obturator nerve reflex (onr) and consequently adductor muscles contraction that we call "leg jerking"(3, 4). it happens because the obturator nerve extends through the lateral wall of the bladder(5,6). it may result in bladder perforation that is a risky event in these patients(4, 5). general anesthesia and local muscle relaxant injections are the suggested preferred methods of anesthesia in these patients. different laser types are recommended for bladder cancers or upper urinary tract urothelial tumors(7). holmium yttrium aluminum garnet laser (ho: yag) is ef1department of urology, the affiliated changzhou no. 2 people’s hospital of nanjing medical university, changzhou 213003, jiangsu, china. 2dalian medical university, dalian, liaoning, china. *correspondence: lifeng zhang, department of urology, the affiliated changzhou no. 2 people’s hospital of nanjing medical university, changzhou 213003, jiangsu, china. tel:+86 519 88123501. e-mail: nj-likky@163.com. **department of urology, the affiliated changzhou no. 2 people’s hospital of nanjing medical university, changzhou 213003, jiangsu, china. phone:+86 519 88123501. e-mail: zuoli1978@hotmail.com. received september 2019 & accepted july 2021 fective but has disadvantages, including limited tissue collection for pathological studies(8,9). in 2005, the new technique of thulium laser (tm: yag) was suggested surgically generating a wavelength of 2 μm, which is much more helpful for resection in an aqueous medium (10). the use of thulium laser came to be the appropriate option in reducing leg jerking(11,12). this study was performed to compare the obturator nerve reflex by thulium laser versus monopolar transurethral resection of bladder tumor. materials and methods the ethics committee approved the study of the school of medicinetehran university of medical sciences (ir. tums.medicine.rec.1396.4657) and the iranian registry of clinical trials (irct20190624043991n4). this study was designed based on clinical trial policies, and two groups of patients were blindly randomized into the two different intervention groups. after completing informed consent forms by patients, 189 patients with bladder tumors were referred to the study from 2010 urology journal/vol 18 no. 6/ november-december 2021/ pp. 688-692. [doi: 10.22037/uj.v0i0.5599] to 2016. inclusion criteria were filling out the consent form, high risk of general anesthesia for surgery, and bladder tumor presence at the obturator nerve site, which included posterior-lateral, trigone area (figure 1). patients in their clinical examination and their previous clinical records had no history of neurologic disease (such as multiple sclerosis, stroke, and parkinson's disease, diabetes, or discopathy that can affect spinal reflexes. the patients were excluded if there were muscle invasion, tumor recurrence, metastasis, present neurologic disease or history of neurologic disease, patient death, and failure to cooperate and follow-up for treatment. but the grade of leg jerking (a novel grade that we describe bettering comparison in different categories) effect was not significant (table 1). the site of the obturator nerve was determined by nerve stimulation, anatomical landmarks, and ultrasonography. the obturator nerve is found by probing through the known location of the nerve(4). inside a box were two similar folded papers (a and b), each patient took one of them. the nurse has written it down, and all have been done blindly and randomly. when the operating room was reached, standard anesthesia monitors were used, and the patients were preloaded intravenously with 500 ml 0.9% normal saline. spinal anesthesia was performed in both groups with a 25 g quincke needle in the space l3-4 or l4-5 in a sitting position. after confirming the presence of clear flowing cerebrospinal fluid in the syringe barrel, 10 mg of 0.5% bupivacaine was administered. the patients were in trendelenburg position for 5 or 10 minutes at an angle of 15 °. if the block of the sensory level was above the t10 level, the patients were placed in the lithotomy position, and the thulium laser or monopolar turbt was performed. the thulium laser was used in the first group (16 patients), while monopolar turbt was performed in a blinded manner in the second group (19 patients). clinical data, including age, gender, tumor features, operation duration, types of leg jerking, and some intraoperative complications, were recorded. leg jerking and period of the procedures were compared. thulium laser was eradicated by the recruited device (siemens company, germany) with extension and power of 5 mm and 200j/sec. the bladder was half-filled during the procedure, and turbt was started. the same surgeon did all procedures. data analysis was performed among 35 cases, including 16 in laser and 19 in the standard group. data analysis was performed by spss (version 22.0) software [statistical procedures for social sciences; chicago, illinois, usa]. inter-group comparisons were performed using the one-way analysis test of variance or independent-sample-t test for continuous variables and chi-square and fisher tests for categorical variables. p-values less than 0.05 were considered to be statistically significant. results all 35 patients were randomized to receive the thulium laser (n = 16) or the monopolar turbt (n = 19). patient and tumor features before surgeries were alike in both groups and are reported in table 2. there were 28 male and seven female patients. all patients had sufficient specimens for making an accurate diagnosis, including tumor grading and staging. of the 35 patients, 25 had low-grade tumors, and 10 had high-grade tumors (table 2). the mean operation time was no difference between the two groups significantly (p > 0.05; table 3). in four patients in the thulium, the laser group experienced intraoperative leg jerking, including 3 with horizontal leg jerking at the site without movement (grade 1), 1 with horizontal and vertical leg jerking with movement (grade 2), and no patient with horizontal and vertical leg jerking with movement from the location. in the monopolar turbt group, 12 patients experienced intraoperative leg jerking, including 5 with horizontal leg jerking at the site without movement (grade 1), 3 with horizontal and vertical leg jerking with movement (grade 2), and 4 with horizontal and vertical leg jerking with movement from location (p < 0.05; table 3). there was no complication of bladder perforation and severe bleeding in the thulium laser group, but one patient had bladder perforation, and one patient had severe bleeding during the monopolar turbt (p > 0.05; table 3). no mortality was reported during the operations. discussion obturator nerve stimulation during turbt under spinal anesthesia may lead to obturator reflex, adductor table 1. grade of leg jerking grade 1 horizontal leg jerking at site without movement grade 2 horizontal and vertical leg jerking with movement grade 3 horizontal and vertical leg jerking with movement from location variable thulium laser (n =16) monopolar turbt (n =19) male 13 (81.3) 15 (78.9) female 3 (18.8) 4 (21.1) age, years 62.0 ± 6.9 (40-75) 64.0±7.1 (41-77) tumor size, cm 3.3 ± 1.6 (1.5-5.0) 3.5 ± 1.1 (1.7-5.0) tumor location right side 9 (56.3) 10 (52.6) left side 7 (43.8) 9 (47.4) tumor grade low grade 11 (68.8) 14 (73.7) high grade 5 (31.2) 5 (26.3) data reported as n (percent) or mean±sd (range). table 2. demographic and tumor features in patients with non muscle-invasive bladder tumor, treated with thulium laser or monopolar turbt. obturator reflex in laser vs. conventional turt-abediyarvandi et al. vol 18 no 6 november-december 2021 689 contraction, and leg jerking with complications such as bladder perforation, bleeding more than incomplete tumor resection(4,8). some studies report that the thulium laser is superior to turbt(13). however, none of the turbt side effects were seen in our patients in the laser group. our result confirmed that the use of thulium laser would lead to higher efficacy than the monopolar turbt method. different modalities, such as partial filling of the bladder during turbt, reduction of resectoscope current intensity, resecting the tumor on the thinner slices, utilization of bipolar or laser resectoscopes, and using general anesthesia and muscle relaxants together, are used to avoid different complications during surgery to reduce the rate of jerking legs(14-16). migliari et al. reported that thulium laser could be the potential alternative to turbt and nowadays is considered the standard for diagnosis and treatment of non-muscle invasive bladder cancer (nmbic)(17). in his study, the thullium laser provided a detailed report of neoplastic depth contamination, indicating the possibility of a second resection within 90 days. before delivery, all different parts of bladder cancer can be combined with thulium lasers, which has the advantage of monopolar energy, especially when the tumor is in the lateral wall of the bladder, the bladder dome, or the perimeatal region(17,18). the nd: yag does not significantly affect the treatment of lower urinary tract transitional cell carcinoma. ho: yag and tm: yag seem to offer alternatives in the treatment of bladder cancer, but to prove their potential effects in more significant prospective, randomized controlled studies with long-term follow-up should be done(19,20). ozer et al.(21) showed that bipolar bladder tumor resection was not superior to monopolar resection significantly than an obstructive reflex and bladder perforation. however, we found a significant difference was also demonstrated by balci et al.(22), stating that efficacy and safety of monopolar and bipolar methods are comparable in patients with bladder tumors. venkatramani and his colleagues reported that bipolar turbt is not superior to monopolar resection in leg jerking, bladder perforation, and bleeding(23). this same result was also found in our research study. in our tertiary care center, a large number of patients are operated on for bladder malignancies. most of these patients are elderly with various comorbidities. spinal anesthesia is preferred over general anesthesia in these patients. however, the on stimulation during the procedure with subsequent obturator jerk makes spinal anesthesia less popular among our surgeons. h liu has shown that the 2-micron laser resection method effectively reduces operative and postoperative complications compared to turbt but has no other benefits in tumor recurrence. however, patients with multiple non-muscle-invasive bladder tumors were randomized to receive the turbt or the 2-μm laser in a non-blind clinical trial. at the same time, our study was designed as a blind randomized clinical trial(7). moreover, yunjin performed a systematic meta-analysis review and stated that laser techniques are practical, safe, and effective and provide an alternative treatment for non-muscle-invasive bladder tumors. because some limitations cannot be met, well-designed rcts are needed to confirm their results(20). mario w. kramer, in a systematic review, concluded that lasers are potentially useful options for conventional turbts, but systematic evaluation using standard classification systems and well-designed rcts are needed to compare results meaningfully(24). conclusions totally, according to the obtained results in the current study, the use of thulium laser is a more feasible and effective method to prevent leg jerking in patients with a bladder tumor, and the use of this method is suggested. however, further studies with a larger sample size variable thulium laser (n=16) monopolar turbt (n=19) p-value operation duration 32.0 ± 13.5 (25-80) 34.0 ± 11.8 (28-82) p =. 64 leg jerking grade grade 1 3 (18.8) 5 (26.3) p = *.007 grade 2 1 (6.2) 3 (15.8) grade 3 0 (0) 4 (21.1) total 4 (25) 12 (63.1) complications severe bleeding 0 (0) 1 (0.1) p =. 36 bladder perforation 0 (0) 1 (0.1) p = .36 incomplete surgery 0 (0) 0 (0) p > 0.05 table 3. operative features of patients with non-muscle-invasive bladder tumor, treated with thulium laser or monopolar turbt data reported as n (percent) or mean ± sd (range). * p-value less than 0.05 is considered as the significantly meaningful one. unclassified 690 figure1. ct scan of a patient with a non muscle-invasive bladder tumor obturator reflex in laser vs. conventional turt-abediyarvandi et al. are required to attain more definite results. acknowledgments special thanks to urology research center (urc), tehran university of medical sciences (tums). thanks to mrs. bita pourmand as well. conflict of interest all authors declare that there is not any conflict of interest. references 1. antoni s, ferlay j, soerjomataram i, znaor a, jemal a, bray f. bladder cancer incidence and mortality: a global overview and recent trends. eur urol. 2017;71:96-108. 2. ibrahim sm, mohamed e, elsharawy i, kamal k. transurethral resection of bladder tumor (tur-bt) then concomitant radiation and cisplatin followed by adjuvant gemcitabine and cisplatin in muscle invasive transitional cell carcinoma (tcc) of the urinary bladder. j egypt natl canc inst. 2007;19:77-86. 3. golan s, baniel j, lask d, livne pm, yossepowitch o. transurethral resection 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wolters m, imkamp f, gross aj, kuczyk ma, et al. current evidence for transurethral laser therapy of non-muscle invasive bladder cancer. world j. urol. 2011;29:433-42. 9. soler-martínez j, vozmediano-chicharro r, morales-jiménez p, hernández-alcaraz d, vivas-vargas e, garcía-vaquero is, et al. holmium laser treatment for low grade, low stage, noninvasive bladder cancer with local anesthesia and early instillation of mitomycin c. the jou of urol. 2007;178:2337-9. 10. bach t, xia s, yang y, mattioli s, watson g, gross a, et al. thulium: yag 2 μm cw laser prostatectomy: where do we stand? world j. urol. 2010;28:163-8. 11. bolat d, aydogdu o, tekgul zt, polat s, yonguc t, bozkurt ih, et al. impact of nerve stimulator-guided obturator nerve block on the short-term outcomes and complications of transurethral resection of bladder tumour: a prospective randomized controlled study. can urol assoc j. 2015;9:e780. 12. shah nf, sofi kp, nengroo sh. obturator nerve block in transurethral resection of bladder tumor: a comparison of ultrasoundguided technique versus ultrasound with nerve stimulation technique. anesth. essays res. 2017;11:411. 13. kati b, izgi m. a nightmare during endoscopic bladder tumor resection: obturator reflex. j turgut ozal med cent. 2017;24:371-4. 14. ploussard g, daneshmand s, efstathiou ja, herr hw, james nd, roedel cm, et al. critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. eur urol. 2014;66:120-37. 15. smith zl, christodouleas jp, keefe sm, malkowicz sb, guzzo tj. bladder preservation in the treatment of muscle‐ invasive bladder cancer (mibc): a review of the literature and a practical approach to therapy. bju international. 2013;112:13-25. 16. russell cm, lebastchi ah, borza t, spratt de, morgan tm. the role of transurethral resection in trimodal therapy for muscleinvasive bladder cancer. bladder cancer. 2016;2:381-94. 17. migliari r, buffardi a, ghabin h. thulium laser endoscopic en bloc enucleation of nonmuscle-invasive bladder cancer. j. endourol. 2015;29:1258-62. 18. xu h, ma j, chen z, yang j, yuan h, wang t, et al. safety and efficacy of en bloc transurethral resection with 1.9 μm vela laser for treatment of non–muscle-invasive bladder cancer. urol. 2018;113:246-50. 19. teng j-f, kai w, lei y, qu f-j, zhang d-x, cui x-g, et al. holmium laser versus conventional transurethral resection of the bladder tumor. lww; 2013. 20. bai y, liu l, yuan h, li j, tang y, pu c, et al. safety and efficacy of transurethral laser therapy for bladder cancer: a systematic review and meta-analysis. world j. surg. oncol 2014;12:301. 21. ozer k, horsanali mo, gorgel sn, ozbek e. bladder injury secondary to obturator reflex is more common with plasmakinetic transurethral resection than monopolar transurethral resection of bladder cancer. cent eur j urol. 2015;68:284. 22. balci m, tuncel a, keten t, guzel o, lokman u, koseoglu e, et al. comparison of monopolar and bipolar transurethral resection of non-muscle invasive bladder cancer. urol. int. 2018;100:100-4. 23. venkatramani v, panda a, manojkumar r, kekre ns. monopolar versus bipolar transurethral resection of bladder tumors: a single center, parallel arm, randomized, controlled trial. the jou of urol. obturator reflex in laser vs. conventional turt-abediyarvandi et al. vol 18 no 6 november-december 2021 691 2014;191:1703-7. 24. kramer mw, wolters m, cash h, jutzi s, imkamp f, kuczyk ma, et al. current evidence of transurethral ho: yag and tm: yag treatment of bladder cancer: update 2014. world j. urol. 2015;33:571-9. unclassified 692 obturator reflex in laser vs. conventional turt-abediyarvandi et al. 1400 | department of pediatrics and nephrology, medical university of bialystok, białystok, poland. corresponding author: agata korzeniecka-kozerska, md department of pediatrics and nephrology, medical university of białystok, 15-274 białystok, 17 waszyngtona street, poland. tel: +48 85 7450 663 fax: +48 85 7421 838 e-mail: agatakozerska@poczta. onet.pl received december 2012 accepted december 2013 purpose: oxidativestresscancausetissuedamageinmanydiseases.oxidativestatusdepends onthebalancebetweentotaloxygenradicalabsorbancecapacityandantioxidants.neurogenic bladder(nb)isaspecialstatewhereoxidativestatuscaninfluenceurinarytractfunction.we decidedtomeasureantioxidant(thiol)statusinpatientswithnbandassesstheeffectofnbon theurinaryantioxidantstatusandtocorrelateitwithurodynamicfindings. materials and methods:theinvestigationwasconductedontwogroups.thefirstgroup, constitutedof41childrenwithnb.thesecondgroup,consistedof20healthychildrenwithno abnormalityinurinaryandnervoussystems.theantioxidantstatuswasassessedbasedonthe enzyme-linkedimmunosorbentassayofthiols. results:themedianvalueofurinaryproteinthiollevelwassignificantlylowerinnbpatients thaninreferencegroup[median48(0.0-633.33)and221.55(0.17-1293]µmol/gprotein,respectively(p<.01).wefoundoutthestatisticallysignificantdifferencesinurinarythiollevel betweenpatientswithandwithoutoveractivity(p=.017)andbetweencatheterizedandnoncatheterized patients (p=.048). conclusion:thisstudydemonstratesthatantioxidantstatusinpatientswithnbdecreasedand thelevelofthiolstatusdependsonthegradeofbladderoveractivity.oxidativestressmaybe involvedinthepathophysiologyofbladderdysfunctionrelatedtoneurogenicdamage. keywords:urinarybladder,neurogenic,overactive;spinaldysraphism,complications;meningomyelocele;pyrroles. agata korzeniecka kozerska, bożena okurowska zawada, joanna michaluk skutnik, anna wasilewska the assessment of thiol status in children with neurogenic bladder caused by meningomyelocele pediatric urology pediatric urology 1401vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l introduction oxidative stress can cause tissue damage in manychildrenandadultsdiseases.hyperglycemiaindia-beticadultpatientscanincreasethelevelsoffree radicals.(1)otherauthorshavedescribedanincreaseinoxidativestressinpregnantwoman,patientswithrheumatoid arthritisandbladdercarcinomaandinchildrenwithcerebral palsy.(2-5)oxidativestatusdependsonthebalancebetween totaloxygenradicalabsorbancecapacityandantioxidantsas acompensatoryreactionofthebody.amongmanyantioxidants,thiols(sulfhydrylgroups)mayplayanimportantrole. therearesomenotificationsaboutplasmaorurinarythiol statusinpediatricnephrologicalproblems.animpairedantioxidativesystemhasalsobeenobservedinpatientswith nephroticsyndrome,primaryglomerulardisease,andinpatientswithproteinuriaorrenalfailure.(6-10) neurogenicbladder(nb)isanexceptional,incurablestate, dependedontherangeofnervoussystemdamage.toassess thebladderfunction,theurodynamicstudyshouldbeperformed.inthisprocedurewecanmeasureintravesicalpressureduringstorageandvoidingphase.mostofthepatients withnbhavedysfunctionalvoidingsoourmeasurementis basedonlyonstoragephase.thetimeofobservationinthis procedureisquiteshortandtheoutcomescannotbeaccurate. wedon’tknowwhatisgoingonwithbladderfunctionduringwholedayand/ornighttime?therearemanyfactorsinvolvedinthecontrolofbladderfunction.inhealthychildren, firstlyitstayedundercentralnervoussystem(cns)control. eachlevelsofcns(brain,spinalcords,andperipheralganglia)areinvolvedinthiscontrol.therearesomesuggestions demonstratingthatoxidativestatusinfluencesurinarytract function. most of them demonstrate destroyed balance in plasmareactiveoxygenspecies(ros)andantioxidants(e.g. ascorbicacid,α-tocopherol,uricacidandbilirubin)which mayminimizetissuedamagemostlyinadultsandmainlyin anexperimentaldata.(11-15) patientswithnbarestillsignificantgroupamongdialyzed patients.thereisaneedtolookforthereliableexaminations forearlydetectionoflowerurinarytractdeterioration.we havenodoubtsthatearlyidentificationoftheriskfactorsof chronicrenalfailuredevelopmentshouldhavepriority,from thehealthyandtheeconomicalpointofviewtoo. tillnow,therewereonlyafewstudieswhichexaminedurinaryantioxidantstatusinpatientswithnb.mostofthem were concentrated on the adult patients.(16,17)noneofthem assessedthethiolstatus.hence,wedecidedtomeasureantioxidantstatusintheurineofchildrenwithnbbasedonthe assessmentofurinarythiolstatusandcompareitwithhealthy subjects.theaimofourstudywastoinvestigatetheurinary antioxidantstatusinpatientswithnbduetomeningomyelocele(mmc)andtocorrelateitwithbladderfunction. material and methods thestudywascarriedoutinthedepartmentofpediatricsand nephrology,medicaluniversityofbialystok,poland.patients withurodynamicallyconfirmeddiagnosisofnbwereincludedinthestudy.finally,41nbpatientsagedmedian9.0(0.717.5)yearsoldwereenrolledinthestudy(group1).twenty healthyindividualsagedmedian9.5(3-17)yearsoldwithout anynephrologicalandcnsdiseaseshistorywereenrolledas areferencegroup(group2).thisgroupwasrecruitedfrom healthyelementary,middleandsecondaryschoolpupils,obtainedfrom2007to2009intheolafstudy:“elaborationof referencebloodpressurerangesforpolishchildrenandadolescents”pl0080olaf.thematerialfromtheyoungercontrolsubjects(aged3-6yearsold)wasobtainedfromhealthy childrenattendingtodaycareornurseryschool.thehealthy subjectswereonnormaldietwithoutanyvitamins,drugsor dietsupplements. theeligiblecases(group1)weremaleandfemalepatients aged1-18yearsoldwithnbduetommcandwithvoiding dysfunctionforatleastoneyearpriortoscreening.patients inmmcgroupunderwentcystometryandpatientsinnoncatheterizedgroupunderwenturoflowmetry.allofthemhad normalrenalfunction[glomerularfiltrationrate(gfr)of> 90ml/min/1.73m2]andnormalserumcreatininelevels.accordingtothefindingsofurodynamicstudyoxybutyninwas administeredifnecessary. patientswithurinarytractinfection(uti)inthepast4weeks orotherinfectionswereexcludedfromthestudy.thenoncatheterizedpatientswithnbandchildrenfromthecontrol groupallunderwenturoflowmetrystudy3timesandtoincrease precision, the results were averaged and compared with the urinary thiols concentrations. mostofnbpatientscannotemptytheirbladdersbythemselvessowewereterminatingtheinfusionduringcystometry whenthevolumeofsolutionwasthesameasobtainfrom everydaycleanintermittentcatheterization(cic).itwasour intentiontoimitatebladderfunctionasinnaturalenvironment. nb children received medications according to the urodynamicstudyresults.theurodynamicwork-upincluded thiol status in children with neurogenic bladder | kozerska et al 1402 | themeasurementsoffollowingparameters:detrusorpressure at overactivity (pdet overact), detrusor pressure at maximumcystometriccapacity(pdetcc),bladderwallcompliance,andelectromyography(emg)ofsphincteratbeginning(emg1)andattheend(emg2)ofthefillingphase. anticholinergicdrugswereadministeredifthepatienthad detrusoroveractivity.informedconsentwasobtainedfrom allsubjectsandtheirparentsforallproceduresconnectedto obtainingbiologicalmaterial. the first daytime urine samples were collected from all examinedpatientsandurinarytotalprotein,creatinine,microalbuminandosmolalityweredetermined.urinarythiol (sulfhydryl)statuswasmeasuredbyenzyme-linkedimmunosorbentassay(elisa)accordingtomanualinstruction,(immundiagnostikagstubenwald-allee8a,64625bensheim, germany).urinaryproteinandcreatininelevelswerealso measuredin24-hoururinesamplesbyanautomatedclinical analyzer.urinarythiollevelswerecalculatedfromthetotal thiollevelsadjustedforproteinconcentrationinurineand expressedinµmol/gprotein.serumproteins,albuminand creatinineconcentrationsweredeterminedinbothgroups. thegfrwascalculatedusingschwartzformula.thestudy was approved by the ethics committee of medical universityofbialystokinaccordancewiththedeclarationof helsinki.theolafstudywasapprovedbythechildren’s memorialhealthinstituteethicscommittee. statistical analysis thedemographicandbiochemicaldataofnbpatientswas statisticallyanalyzedandexpressedasmedianwithminimum andmaximumrangecomparedwithreferencegroup.since theantioxidantparameterswerenotasperthegaussiandistribution, mann-whitney utestwasusedforthecomparisons between2groups.spearman’scoefficientofcorrelations(r) werecalculatedtolookatthepossibleassociationbetween thiolparametersandbiochemicalandurodynamicone.allstatisticalanalyseswereperformedusingstatistica10.0(statsoft inc.,tulsa,ok,usa).apvalueoflessthan.05wasconsideredstatisticallysignificant. results characteristics of studied subjects are shown in table 1. therewerenostatisticallysignificantdifferencesindemographiccharacteristicsofstudiedgroupssuchasage,gender andbodymassindex.thereweredifferencesinthephysical developmentparametersresultedfromtheprincipaldisease. thechildrenwithmmchadlowermuscularmass(dueto paralysisofthelimbs)orexcessbodyweightresultingfrom the lackofactivityduringthe lifespan(thechildrenwere wheelchair dependent). moreover, the differences in the heightareoftencausedbydistortionandmalformationsof thebonestructure.themediantimeoffollowupofthenb patientswas6(0.5-15)years.ninefrom41patientswere non-catheterized.thecatheterizedsubjectswereemptying their bladder with median urination frequency of 4 (3-5) timesperdaywithnightbrake. inpresentstudywecomparedtheparametersofthekidneys figure 1. the comparison of urine thiol levels between patients with neurogenic bladder (nb) and reference group. figure 2. the data of median urine thiols in patients with neurogenic bladder in various urodynamic conditions. pediatric urology 1403vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l function(urinaryandserumcreatinine,urinaryexcretionof theprotein,urineosmolality,gfrandmicroalbuminuria) andserumalbuminandproteinlevels.laboratoryfindings andcomparisonsareshownintable1.weobservedstatisticallysignificantdifferencesintheserumcreatinine,gfrand creatinineandproteinexcretion(inmorningsampleand24hoururinecollection).thereweredifferencesbetweenstudy groupsintheserumalbuminconcentrationsvaluesbutthe resultswerenotstatisticallysignificant.wedidnotfinddifferencesinpresenceofmicroalbuminuriaandserumprotein levelsbetweenstudygroups(p = .47 and p = .12, respectively). asithasbeenshowninfigure1,theurinarythiollevelwas significantlydecreasedinnbpatientscomparedtothecontrolgroupandtherelatednumericaldatawere,median48 (0.0-633.33)and221.55(0.17-1293)µmol/gprotein,respectively(p<.001).thisreductionwasnotrelatedtoutiinthe past,thefollow-updurationandbladderwallthickness,or thedoseofadministeredtreatment. urodynamic findings are shown in table 2. we revealed statistically significant differences in most uroflowmetry parametersbetweenstudygroups.urinarythiollevelcorrelatednegativelywithvoidedvolume(r=-0.450,p<.05) andpositivelywithresidualurine(r=0.25,p<.05).the thiolstatuslevelsinvariousurodynamicconditionsinnb patientsareshowninfigure2.wefoundstatisticallysignificantdifferencesinurinarythiollevelsbetweenpatients withandwithoutbladderoveractivity(p =.017)andbetween catheterized and non-catheterized patients (p = .048).we alsofounddifferencesbetweenurinarythiolsconcentrations betweenpatientswithnormalandlowbladdercompliance (p=.33)andbetweenpatientswithlow(<10cmh2o)and high(>10cmh2o)detrusorpressureduringfillingphase(p =.48),butthedifferenceswerenotstatisticallysignificant. therewerenocorrelationsbetweenurinarythiolandcystometriccapacity,emgactivityatthebeginningandatthe endoffillingphase.apartofoutcomesmentionedabovewe foundpositivecorrelationbetweenurinarythiolstatusand theageofnbpatients(r=0.33,p<.05)andserumprotein concentration (r=.355,p<.05). table 1. the characteristics of study groups and comparison between patients with neurogenic bladder and reference group.* variables group 1 group 2 p age (years) 9.0 (0.7-17.5) 9.5 (3-17) .32 gender male 19 8 na female 22 12 na height (cm) 134 (70-170) 152 (89-176) .004 weight (kg) 29 (6.2-92) 43 (16-70) .021 body mass index (kg/m2) 17.01 (8.83-17) 18.13 (12-24) .75 oxybutynin administration mg/day 3.75 (1.25-10) ----na mg/kg body weight 0.17 (0.1-0.42) ----na oab treatment/none treatment 16/41 ----na serum creatinine (mg/dl) 0.32 (0.19-0.77) 0.51 (0.2-083) .00 urine creatinine (mg/dl) 53.17 (14.58-149) 100.17 (63-244) .000 gfr ml/min/1.73m2 body surface 233 (102-303) 162.91 (110-330) .017 urine osmolality 715 (314-1177) 685 (391-1130) .85 microalbuminuria 5.5 (0.1-386.9) 1.4 (0.3-51.8) .47 serum protein (g/l) 7.08 (5.8-8.13) 7.55 (6.62-8.14) .12 serum albumin (g/dl) 4.63 (3.61-5.47) 4.79 (4.41-5.23) .067 urine protein (mg/dl) 10 (0-128) 0 (0-2) .000 urine protein (mg/24-hour) 60 (0-560) 5.11 (1.06-10.05) .02 keys: oab, overactive bladder; gfr, glomerular filtration rate; na, not applicable. * data are presented as median (range). thiol status in children with neurogenic bladder | kozerska et al 1404 | discussion thepurposeofthisstudywastoevaluatetheantioxidantstatusinurineofpatientswithmmcandtoanswerwhether oxidative status has an influence on the bladder function. theresults demonstrated that thedecreasedconcentration of sulfhydryl groups (-sh) or groups existing as protein boundthiolsintheurineofpatientswithnbiscausedbyincreasedoxidation.ourfindingsarecomparabletothedatain theliteratureinvariouspathologicalconditionsinchildren. kazunari and colleagues(18) assessed urinary 8-hydroxy2-deoxyguanosine(8-ohdg)inpatientswithidiopathicnephroticsyndromeandreportedincreasedlevelsofrosand decreasedlevelsofantioxidantsintheactivephaseofthe diseaseswhichwerenormalizedinremissionphase.these findingsareinagreementwithmishraandschaefer’sstudy. (19)thesefindingssuggestanimportantroleofoxidativestatusinthepathogenesisofidiopathicnephroticsyndromein children.chienandcolleagues(20)inanexperimentalstudy revealedthatsubstancepinfluencesnbfunctionbyitsabilitytostimulaterosgeneration.otherexperimentalstudies havedemonstratedimbalancebetweenrosandantioxidant ability (as a positive reaction of our body) in neurogenic damage.wedidnotfindanystudyconcerningwithmeasuringofurinarythiol(sulfhydryl)groupsinpatientswithnb. decreasedurinaryproteinthiolsinpatientswithoveractive bladderletustosuspectthatoxidativestressisinvolvedin thedisturbedbladderfunction.thus,couldwetrytonormalizefunctionofthebladderbytakingantioxidants?couldwe influencethedetrusorpressurebyantioxidants?couldwe changethemuscarinicreceptorfunctionbydecreasedoxidativestress?(13)whatcouldbetheadministrationmethod? answertothisquestionsrequiredfurther,verywell-planned andgood-organizedstudieswhichweareplanning.tillnow, theliteraturereviewshowsthattherearesometherapeutic interventionsandnumerousbioactivecompoundsthathave antioxidantstatusbenefitsbutunfortunatelystillinclinical trialsoronanimalmodels.(16) ourresults,focusedonpositivecorrelationbetweenurinary proteinthiollevelandserumproteinconcentration,raisean interestingquestionwhetherhigherserumproteinconcentrationcanincreaseurinaryproteinexcretionandinthisway affecttheoxidativestatusinnb? summarizing, received from uroflowmetry results let us speculatethat,althoughthepatientsemptyingtheirbladders bythemselves(urodynamicfindingsletthemtodothat),the bladdersdonotworkcorrectly.itconfirmsthatnon-catheterizednbpatientsrequiregreaterattentionorverifyrecommendations. thekidneyfunctiondeteriorationisconnectedwiththehigherfrequencyofdetrusoroveractivitydiagnosedinchildhood. (21)thus,themeticulousestimationbasedontheurodynamic findingsinconnectionwiththeassessmentofoxidativestatusinchildhoodcanbeaveryimportantpredictiontolater kidneyimpairment,itisthepotentialclinicalapplicationof our finding.this condition must be fulfilled especially in suchexceptionalstateasnbis,whentheprognosisofbladtable 2. urodynamic findings and comparison between study groups.* cystometry pdet, cmh2o pdet cc, cmh2o bladder wall compliance, ml emg 1, microvolts emg 2, microvolts nb patients (4-100) 25 (2-75) 14 (3-70) 10 4.5 (0-25) 7 (0-47) uroflowmetry time to max flow, s delay time, s flow time, s voiding time, s maximum flow rate, ml/s average flow rate, ml/s voided volume, ml residual urine, ml nb patients 7 (7.0-23.4) 15.6 (3.4-280) 20 (2-129) 28 (3-427) 6.3 (1.4-15) 4.25 (0.5-13) 111.4 (5-275) 80 (5-117.5) control group 7 (4-12) 2 (1-3) 17 (10-38) 19.5 (11-41) 22.9 (13.3-41) 18.1 (6-31) 219.5 (104-456) 0 (0-5) p .835 < .001 .340 .061 < .001 < .001 .004 < .001 keys: pdet, detrusor pressure at overactivity; pdet cc, detrusor pressure at cystometric capacity; emg 1electromyography of sphincter at the beginning of filling phase; emg 2, at the end of filling phase; nb, neurogenic bladder. * data are presented as median (range). pediatric urology 1405vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l references 1. awanti s, baruah ps, prakash m. serum and urine protein thiols in type 2 diabetes mellitus patients. indian j physiol pharmacol. 2009;53:185-8. 2. umeshchandra s, umeshchandra dg, awanti s. serum protein thiol status in pregnant women with malaria. rjpbcs. 2012;3:114-9. 3. pedersen-lane jh, zurier rb, lawrence da. analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients. j leukoc biol. 2007;81:934-41. 4. badjatia n, satyam a, singh p, seth a, sharma a. altered antioxidant status and lipid peroxydation in indian patients with urothelial bladder carcinoma. urol oncol. 2010;28:360-7. 5. kulak w, sobaniec w, solowej e, sobaniec h. antioxidant enzymes and lipid peroxides in children with cerebral palsy. life sci. 200;77:3031-6. 6. karthikeyan k, sinha i, prabhu k, bhaskaranand n, rao a. plasma protein thiols and total antioxidant power in perdiatricnephrotic syndrome. nephron clin pract. 2008;110: 10-4. 7. markan s, kohli hs, sud k, et al. oxidative stress in primary glomerular diseases: a comparative study. mol cell biochem. 2008;311:10510. 8. prakash m, shetty jk, dash s, et al. urinary protein thiols in different grades of proteinuria. indian j clin biochem. 2008;23:404-6. 9. mallikarjunappa s, prakash m. urine protein thiols in chronic renal failure patients. indian j nephrol. 2007;17:7-9. 10. nakai k, yoneda k, maeda r, et al. urinary biomarker of oxidative stress in patients with psoriasis vulgaris and atopic dermatitis. j eur acad dermatol venereol. 2009;23:1405-8. 11. goulart m, batoréu mc, rodrigues as, laires a, rueff j. lipoperoxidation products and thiol antioxidants in chromium exposed workers. mutagenesis. 2005;20:311-5. 12. masuda h, kihara k, saito k, et al. reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anesthetized rats. bju int. 2008;101:775-80. 13. de jongh r, haenen gr, van koeveringe ga, dambros m, de mey jg, van kerrebroeck pe. oxidative stress reduces the muscarinic receptor function in the urinary bladder. neurourol urodyn. 2007;26:302-8. 14. azadzoi km, yalla sv, siroky mb. oxidative stress and neurodegeneration in the ischemic overactive bladder. j urol. 2007;178:710-5. 15. kawada n, moriyama t, ando a, et al. increased oxidative stress in mouse kidneys with unilateral obstruction. kidney int. 1999;56:1004-13. 16. jia z, zhu h, li j, wang x, misra h, li y. oxidative stress in spinal cord injury and antioxidant-based intervention. spinal cord. 2012;50:264-74. 17. barrington jw, jones a, james d, smith s, stephenson tp. antioxidant deficiency following clam entrerocystoplasty. br j urol. 1997;80:238-42. 18. kaneko k, kimata t, takahashi m, shimo t, tanaka s, tsuji s. change in urinary 8-hydroxydeoxyguanosine in idiopathic nephrotic syndrome. pediatr nephrol. 2012;27:155-6. 19. mishra op1, gupta ak, prasad r, et al. antioxidant status of children with idiopathic nephrotic syndrome. pediatr nephrol. 2011;26:2516. 20. chien ct, yu hj, lin tb, lai mk, hsu sm. substance p via nk1 receptor facilitates hyperactive bladder afferent signaling. am j physiol renal physiol. 2003;283:840-51. 21. thorup j, biering-sorensen f, cortes d. urological outcome after myelomeningocele: 20 years of follow-up. bju int. 2011;107:994-9. derfunctioninnbchildrenmostlyremainsunclear. ourstudyhassomelimitations.mostofthemmcpatients weretreatingwithoxybutyninindifferentdosesandthere wasnopossibilitytointerrupttherapy.thenon-treatedgroup wastoosmallanddidnotallowustodrawanunequivocal conclusion.anotherlimitationofthisstudywasaone-time thiolstatusevaluationinspecificpatients,whichmaynotaccuratelyreflectnbfunction.thus,furtherstudiesarenecessarytobetterclarifycorrelationsbetweenbladderfunction andoxidativestatusinmmcpatients. conclusion weconcludedthatantioxidantstatusinpatientswithnbdecreasedinpatientswithoveractivebladderandthelevelof thiolstatusdependsonthegradeofdetrusoroveractivity.in addition,oxidativestressmaybeinvolvedinthepathophysiologyofbladderdysfunctionrelatedtoneurogenicdamage. acknowledgements thisstudyissupportedbyagrantfromthemedicaluniversityofbialystok,poland.authorshavenoconflictofinterest to disclose. conflict of interest none declared thiol status in children with neurogenic bladder | kozerska et al urology journal vol. 11 no. 04 july august 2014 1768 laparoscopic urology comparison between hand suture and carter-thomason needle closure of port sites in laparoscopy abijit shetty, kishore thekke adiyat medical trust hospital, cochin, kerala 682016, india. corresponding author: abijit shetty, ms, dnb medical trust hospital, cochin, kerala 682016, india. tel: +91 889 112 5025 e-mail: shettyabijit@ gmail.com received june 2013 acceptedfebruary 2014 purpose: to compare between hand closure and carter-thomason technique with respect to following parameters, time taken for port site closure, wound infection, wound dehiscence, seroma formation, port site herniation, and ascitic fluid leak. materials and methods: in this study, 200 cases who underwent laparoscopic donor nephrectomy were selected and divided into two groups based on closure technique. first 100 cases underwent port closure by the standard hand closure technique and next 100 cases by carter-thomson needle technique. subjects included in this group are healthy individuals with no co morbid illness. this might help to reduce the bias of complications arising from other than technical issue. results: in our study carter-thomason serves as a better mode of port site closure with respect to time reduced, wound and bowel related complications compared to hand closure technique. conclusion: in this study closure of trocar site is better with the carter-thomason method when compared to hand closure technique. keywords: sutures; treatment outcome; suture techniques; abdominal wound closure techniques; fascia; laparoscopy. 3-0 vicryl. skin was closed using 4-0 interrupted monocryl stitches. hand closure was done after deflating abdomen and other technique utilized laparoscopic visualization retaining pneumoperitoneum. in carter-thomson needle technique, pilot guide (figure 2) was inserted with holes aligned perpendicular to the trocar wound. the suture passer is used to push suture material through the pilot guide, fascia, muscle and peritoneum into the abdomen then drop the suture and remove the suture passer. on the opposite side of the pilot guide, push the suture passer through all of the layers and pick up the suture with the hinged jaw. pull the suture up through the peritoneum, muscle, fascia and pilot guide. remove the pilot guide and tie off the suture. once the surgery is finished, all the instruments were removed carefully under vision. all the accessory ports were removed after deflating the abdomen. the camera port was taken out at last, with telescope introduced in and the cannula is pulled over telescope to prevent herniation of omentum or bowel. the trocar site was cleaned with 10% povidone iodine solution before closure. closure of the fascial defect and skin were performed for all 10 mm ports and skin in 5 mm ports. port site infection information's were taken from patients who developed a port site hernia, witness of pus inside the wound indicate infection, information about seroma collection, ascitic fluid leak and wound dehiscence. patients were followed-up to 2 years. post-operative follow-up was 1, 3, 6, 12 and 24 months with serum creatinine report. the following parameters were observed, time taken for port site closure, wound infection (requires opening up of stich for pus drainage introduction the importance of closing port sites has been well established.(1) portsite hernias in laparoscopic surgeries have been frequently reported and complications related to port site closure have been reported in 0.23% to 6.3% of patients.(2) these complications include wound infection, dehiscence, herniation of the small bowel, entrapment of omentum and incarcerated richter’s hernia.(1,2) a significant complication like hernia for the patient results in a second surgical procedure to fix the defect. it’s a financial burden and impairs quality of life. the benefits of laparoscopic surgery in terms of quick and rapid recovery are questioned. main complication is bowel herniation and obstruction.(3,4) fear was first to report port site herniation.(5,2) trocar related complication is seen in 1% to 6% of patients.(6) to prevent these complications, 10 mm port or more should be closed in adults and 5 mm or more in children.(7) port site herniation for 10 mm is 0.23% and for 12 mm is 1.9%. its incidence is increased to 6.3% for body mass index (bmi) greater than 30 kg/m2.(8) for trocar diameter 10 mm or more the incidence of hernia was around 86.0%.(8) various types of port closure are available. they are usually divided into two groups. first group where closure is done using laparoscopic visualization. the second group includes methods involving direct visualization. carter-thomason device, maciol needles, grice needle, auto stitch, modified veress needle, gore-tex® device, reverdin and deschamps needles, semms emergency needle with a distal eyelet, endoclose device, exit disposable puncture closure, tahoe surgical device and long 14-gauge angiocatheter with looped polypropylene suture mainly in the first group. lowsley retractor with hand-sutured closure, fish hook needle, dual hemostat technique, port plug technique and hand-sutured closure requires direct visualization of the surgeon, and tactile feedback plays an important role in the closure. materials and methods after ethical committee clearance and standard work-up protocol for donor nephrectomy, 200 donors underwent laparoscopic procedure with no open conversion. donors with a history of diabetes mellitus, coronary artery disease and hypertension were excluded from the study. first 100 cases underwent port closure by the standard hand closure technique and next 100 cases by carter-thomson needle technique. none of the cases had an open conversion all donors had two 10 mm ports and three 5 mm ports and the organ extraction site was pfannenstiel incision as shown in figure 1. all patients underwent left laparoscopic donor nephrectomy. bladeless trocars (endopath xcel, ethicon; ethicon endo-surgery, cincinnati, ohio, usa) was used. after organ extraction pfannenstiel incision was closed by standard technique. pneumoperitonum introduced, kidney bed and extraction site examined. drain kept in flank 5 mm port. port closure was done at the end of procedure by operating surgeon. its time taken from fascial closure of two 10 mm port to port site skin closure. ten mm port site closed with 2-0 vicryl by carter-thomason. subcutaneous tissue with figure 1. representing port sites in left laparoscopic donor nephrectomy. figure 2. carter-thomason needle. 1769 laparoscopic urology urology journal vol. 11 no. 04 july august 2014 1770 carter-thomason needle closure in laparoscopy-shetty et al fascia closure of trocar sites more than 10 mm has led to reduced herniation and significantly reduced and postoperative morbidity. (11,15,16) some also advocate that 5 mm port sites subjected to extensive manipulation should have closure of the fascia as well.(17) removal of ports after deflation of pneumoperitoneum and proper fascial closure reduce the chances of port site herniations.(7,18,19) lower incidence of hernias with the non-bladed trocars has not been proven yet.(20-22) the preperitoneal space can be closed incorporating the peritoneum into the fascial closure to reduce the chances of port site herniation.(7,23,25) z-tract or inserting port in oblique fashion will reduce incidence of hernia.(26,27) blunt conical trocar–cannula systems resulted in smaller fascial defects when compared to pyramidal and two cutting-dilating trocar-cannula systems.(28) trocar site hernia in closed laparoscopy was lower than in open first access technique.(15) forced dilation of the fascial layer and the effects of pneumoperitoneum might push abdominal contents through the port site by creating a partial vacuum when the port is withdrawn.(29-31) the abdominal contents like omentum or bowel loops might then be trapped by contractions of abdominal muscle. substantially pannus and high intra-abdominal pressure in obese patients leads to increased chances of hernia.(32) conclusion in this study closure of trocar site is better with the carter-thomason method when compared to hand closure technique in terms of faster closure, wound infection and port site herniation. conflict of interest none declared. and antibiotics), wound dehiscence, wound collection (requiring aspiration, which shows clear fluid or subsiding without treatment), port site herniation and ascitic fluid leak. statistical analysis was done by chi-square test. results in hand port closure group 10 and 21 subjects were obese (bmi between 30-35 kg/m2) and overweight (bmi between 25-29 kg/m2), respectively, rest 69 had normal bmi. similarly in other group 9 and 19 were obese and overweight, respectively, rest 72 had normal bmi. carter-thomason method resulted in less incidence of wound infection, wound dehiscence, wound collection, port site herniation and ascitic fluid leak. in obese patients the closure was technically challenging in hand port technique, whereas in carter-thomason there was no much technical issue. there was lot of tissue handling in case of hand port technique. there was no incidence of vascular or bowel injuries during use of carter-thomason needle (table). patient with wound infection and collection underwent incision and drainage in the outpatient department and treated with oral antibiotics. it resolved within a week. the cases of wound dehiscence underwent secondary suturing in the outpatient department. ascitic fluid leak was from umbilical port. with local dressing and antibiotic it resolved within four days. a case of port site herniation underwent explorative laparotomy and bowel anastomosis to correct bowel obstruction. ascitic fluid or gas leakage was not seen in the carter-thomason technique (table). discussion since the early days of laparoscopy, port site hernias have been reported.(9-11) cause of trocar site hernias mainly attributed to large trocar size, incomplete fascia closure at the trocar site, midline trocars, trocar site stretching, suction effect while port withdrawal, being overweight, malnutrition and vitamin and mineral deficiencies are known factors contributing to these hernias.(11-16) other factors that could play a role in the formation of trocar-site hernias in addition to the trocar site and trocar diameter including its design, existing defect in fascia and operations and patient-related factors like age, wound infection rate, diabetes mellitus and other co-morbidities, such as smoking and greater bmi. variables hand closure technique carter-thomason p value total case 100 100 ----time taken (min) 15 (9-25) 8 (7-12) .02 wound collection 10 1 .005 wound infection 2 1 .56 wound dehiscence 2 none .45 port site herniation 1 none .003 ascitic fluid leak 6 none .012 body mass index 24.28 25.96 .475 male to female ratio 58:42 47:53 ----table. representing compared values. 19. leibl bj, schmedt cg, schwarz j, kraft k, bittner r. laparoscopic sur gery complications associated with trocar tip design: review of literature and own results. j laparoendosc adv surg tech a. 1999;9:135-40. 20. liu cd, mcfadden dw. laparoscopic port sites do not require fascial closure when nonbladed trocars are used. am surg. 2000;66:853-4. 21. shaher z. port closure techniques. surg endosc. 2007;21:1264-74. 22. moreno-sanz c, picazo-yeste js, manzanera-díaz m, herrero-bogajo ml, cortina-oliva j, tadeo-ruiz g. prevention of trocar site hernias: de scription of the safe port plug technique and preliminary results. surg innov. 2008;15:100-4. 23. jorge c, carlos m, alejandro w. a simple and safe technique for closure of trocar wounds using a new instrument. surg laparosc endosc. 1996,6:392-3. 24. chapman wh 3rd. trocar-site closure: a new and easy technique. j lap aroendosc adv surg tech a. 1999;9:499-502. 25. conlon kc, curtin j. a simple technique for the closure of laparoscopic trocar wounds. j am coll surg. 1995;181:565-6. 26. fear r. laparoscopy, a valuable aid in gynecologic diagnosis. obstet gynecol. 1968;31:297-309. 27. hellinger md, larach sw, ferrara a, blake tb. effective peritoneal and fascial closure of abdominal trocar sites utilizing the endo-judge. j laparoendosc surg. 1996;6:329-32. 28. tarnay cm, glass kb, munro mg. incision characteristics associated with six laparoscopic trocar–cannula systems: a randomized, observ er-blinded comparison. obstet gynecol. 1999;94:89-93. 29. de giuli m, festa v, denoye gc, morino m. large postoperative um bilical hernia following laparoscopic cholecystectomy: a case report. surg endosc. 1994;8:904-5. 30. duron jj, hay jm, msika s, et al. prevalence and mechanisms of small intestinal obstruction following laparoscopic abdominal surgery: a retro spective multicenter study. arch surg. 2000;135:208-12. 31. bowrey dj, blom d, crookes pf, et al. risk factors and the prevalence of trocar-site herniation after laparoscopic fundoplication. surg endosc. 2001;15:663-6. 32. cottam dr, gorecki pj, curvelo m, weltman d, angus ld, shaftan g. preperitoneal herniation into a laparoscopic port site without a fascial defect. obes surg. 2002;12:121-3. references 1. rastogi v, dy v. simple technique for proper approximation and clo sure of peritoneal and rectus sheath defects at port site after laparoscopic surgery. j laparoendosc adv surg tech a. 2001;11:13-6. 2. elashry om, nakada sy, wolf js jr, figenshau rs, mcdougall em, clayman rv. comparative clinical study of port-closure techniques fol lowing laparoscopic surgery. j am coll surg. 1996;183:335-44. 3. brody f, rehm j, ponsky j, holzman m. a reliable and efficient tech nique for laparoscopic needle positioning. surg endosc. 1999;13:1053-4. 4. felix el, harbertson n, vartanian s. laparoscopic hernioplasty: signif icant complications. surg endosc. 1999;13:328-31. 5. contarini o. complication of trocar wounds. in: meinero m, melotti g, mouret ph (eds). laparoscopic surgery. masson sp. a, milano, italy. 1994. p. 38-44. 6. eltabbakh gh. small bowel obstruction secondary to herniation through a 5 mm laparoscopic trocar site following laparoscopic lymphadenecto my. eur j gynaecol oncol. 1999;20:275-6. 7. di lorenzo n, coscarella g, lirosi f, gaspari a. port-site closure: a new problem, an old device. jsls. 2002;6:181-3. 8. tonouchi h, ohmori y, kobayashi m, kusunoki m. trocar site hernia. arch surg. 2004;139:1248-56. 9. schiff i, nattolin f. small bowel incarceration after uncomplicated lap aroscopy. obstet gynaecol. 1974;43:674-5. 10. bourke jb. small intestinal obstruction from a richter’s hernia at the site of insertion of a laparoscope. br med j. 1977;2:1393-4. 11. montz fj, holschneider ch, munro mg. incisional hernias following laparoscopy: a survey of the american association of gynecologic lap aroscopists. obstet gynecol. 1994;84:881-4. 12. sanz-lópez r, martínez-ramos c, núñez-peña jr, ruiz de gopegui m, pastor-sirera l, tamames-escobar s. incisional hernias after laparo scopic vs open cholecystectomy. surg endosc. 1999;13:922-4. 13. lee jh, kim w. strangulated small bowel hernia through the port site: a case report. world j gastroenterol. 2008;14:6881-3. 14. ashwin rammohan, r.m. naidu. laparoscopic port site richter's hernia an important lesson learnt. int j surg case rep. 2011;2:9-11. 15. mayol j, garcia-aguilar j, ortiz-oshiro e, de-diego carmona ja, fer ` nandez-represa ja. risks of the minimal access approach for laparo scopic surgery: multivariate analysis of morbidity related to umbilical trocar insertion. world j surg. 1997;21:529-33. 16. crist dw, gadacz tr. complications of laparoscopic surgery. surg clin north am. 1993;73:265-89 . 17. neshat c, nezhat f, seidman ds, neshat c. incisional hernias after op erative laparoscopy. j laparoendosc adv surg tech a. 1997;2:111-5. 18. susmallian s, ezri t, charuzi i. laparoscopic repair of access port site hernia after lap-band system implantation. obes surg. 2002;12:682-4. 1771 laparoscopic urology review partial versus radical nephrectomy in patients with renal cell carcinoma: a systematic review and meta-analysis yong yang* purpose: radical nephrectomy (rn) and partial nephrectomy (pn) are widely used for early-stage renal cell carcinoma (rcc). however, the results were inconsistent while comparing the efficiency of rn and pn. this study aimed to assess the perioperative effectiveness of rn and pn for treating rcc. material and methods: pubmed, embase, and the cochrane library electronic database were searched for studies on adults with rcc comparing rn and pn published until september 2019. the perioperative efficacy and safety outcomes were calculated using odds ratio (or) and standard mean difference (smd) with 95% confidence intervals (cis) for dichotomous and continuous data, respectively. subgroup analysis were conducted based on tumor stage and surgery methods for evaluation of the treatment effect on specific subsets. results: a total of 23 studies involving 30,018 patients with rcc were included in this meta-analysis. notably, rcc treated with pn was associated with low incidences of hospital mortality (or: 0.58; 95% ci: 0.38–0.89; p = 0.013) and reoperation rate (or: 0.74; 95% ci: 0.58–0.95; p = 0.016) as compared to rn. however, pn was associated with an increased risk of overall postoperative complications (or: 1.40; 95% ci: 1.17–1.68, p < 0.001), postoperative hemorrhagic complications (or: 1.92; 95% ci: 1.28–2.87, p = 0.002), and urinary fistula (or: 17.65; 95% ci: 5.35–58.30, p < 0.001) as compared to rn. conclusion: these findings suggested that pn was associated with lower incidences of hospital mortality and reoperation rate, whereas rn was associated with fewer complications. keywords: radical nephrectomy; partial nephrectomy; renal cell carcinoma; perioperative; meta-analysis introduction renal cell carcinoma (rcc) is the third most com-mon urological cancer, accounting for 2–3% of cancer-related deaths in adults(1,2). the incidence of rcc increases with age, maximal at 70 years of age, and 2-fold more prevalent in men than women(3,4). the predisposing factors of rcc include age, gender, smoke, excessive weight, long-term dialysis, hereditary factor, and exposure to hazardous materials (cadmium, benzene, trichloroethylene, and asbestos)(5-7). surgical removal is regarded as the standard treatment for patients with rcc, as the tumor is resistant to chemotherapy and radiotherapy(8,9). radical nephrectomy (rn) removes the affected kidney within gerota’s fascia, including the ipsilateral adrenal gland and regional lymph nodes, which is still the gold standard for treating rcc (10,11). however, whether nephron-sparing surgery, termed as partial nephrectomy (pn), is an ideal alternative to rn is yet a controversy. pn is a feasible organ-preserving approach that avoids unnecessary loss of a viable kidney, especially in the case of small renal tumors with diameter ≤ 4 cm (stage t1a) and normal contralateral kidney(12,13). rn and pn were both recommended according to the nccn guidelines for patients with rcc in the t1b stage(14). therefore, selection of the surgical technique is yet controversial, especially in patients with rcc in the t1b stage(15,16). although various treatment guidelines were available on rcc, a majority were based on personal exdepartment of urology, the ninth hospital of xi'an, xi'an, 710016, shanxi, china *correspondence: department of urology, the ninth hospital of xi'an, xi'an, 710054, china. tel: +86-13571976611. fax: +86-21-57643271. email: yangyong_2016@sina.com. received may 2019 & accepted december 2019 perience(17,18). previous meta-analyses analyzed the differences in clinical outcomes between rn and pn, including overall mortality, cancer-related mortality, and incidence of renal failure(19-24). nevertheless, potential limitations are also presented. first, previous meta-analyses discussed several surgical methods or provided a qualitative comparison between rn and pn; however, the direct quantitative comparison of rn with pn was not included. second, the impact of tumor stage on clinical outcomes was neglected. third, previous studies primarily focused on mortality, while the perioperative side-effects were not summarized. thus, the present study aimed to provide comprehensive results for the treatment strategies of rn and pn in patients with rcc. materials and methods search strategy and selection criteria this review was conducted and reported according to the preferred reporting items for systematic reviews and meta-analysis statement issued in 2009(25) (checklist s1). pubmed, embase, and cochrane library electronic database were systematically searched for studies published until september 2019. “nephrectomy,” “kidney neoplasms,” “renal cell carcinoma*,” “renal mass*,” “renal tumor*,” and “renal cancer*” were used as core search terms. the reference lists of all relevant original and review articles were searched manually to identify additional eligible studies. urology journal/vol 17 no. 2/ march-april 2020/ pp. 109-117. [doi: 10.22037/uj.v0i0.5358] table 1. characteristics of included studies. author design region study no. of mean age male (%) criteria for tnm compared operation perioperative jadad or nos (year) period patients (years) kidney lesions surgical arms outcomes butler (1995) [36] retrospective usa 1975–1992 88 62 61 solitary (<4 cm) t1a open pn open los, it, oc, po severe unilateral rccs (n = 46) hemorrhage, incidence of 5 vs. open rn urinary fistula, spleen (n = 42) damage, reoperation, arf, scr levels indudhara (1997) [37] retrospective uk 1989–1995 106 45 65 solitary (<5 cm) t1 open pn open blood loss, los, mean 6 rccs (n = 35) po scr levels, incidence of vs. open rn urinary fistula, po (n = 71) severe hemorrhage, cc, arf uzzo (1999) [38] retrospective usa 1991–1995 80 median: 65 solitary (<4 cm) t1a open pn open oc, los 6 67.1 (rn) unilateral rccs (n = 52) vs. vs. 61.5 (nss) open rn (n = 28) corman (2000) [39] prospective usa 1991–1998 1885 62 98 heterogeneous na open pn open 30-day mortality, 8 rccs (n = 512) vs. oc, arf, po open rn (n = 1373) severe hemorrhage, los, mean po scr levels shekarrizet al. (2002) retrospective usa 1991–1997 120 64 na solitary (<7 cm) t1 open pn open los, oc, incidence 7 [40] unilateral rccs (n = 60) of urinary fistula, vs. open rn (n = 60) it, blood loss kim (2003) [41] retrospective usa 1998–2002 114 58 65 solitary (<4.5 cm) t1 lpn (n = 79) ) mipn it, arf, spleen damage, 6 unilateral rccs vs. lrn (n = 35 oc, los, mean po scr levels stephenson (2004) retrospective usa 1995–2002 1049 62 na renal cortical na open pn open oc, 30-day mortality, 7 [42] neoplasm (n = 361) incidence of urinary fistula, vs. open rn (n = 688) arf, po severe hemorrhage, los, reoperation, mean po scr levels, cc van poppel (2007) rct multicenter 1992–2003 541 na 67 solitary t1 open pn open po severe hemorrhage, 3^ [43] (<5 cm) (n = 268) incidence of urinary fistula, t1–t2n0m0 rccs vs. open rn (n = 273) pleural damage, spleen damage, reoperation miller (2008) [44] retrospective usa 1991–2002 10123 75 62 rccs na open pn open cc 7 (n = 763) vs. open rn (n = 10123) gratzke (2009) [45] prospective switzerland january– 81 61 64 t1–t2 rccs na open pn open los, 30-day mortality, 7 december 2005 (n = 44) vs. arf, it, po severe open rn (n = 37) hemorrhage, reoperation simmons (2009) retrospective usa 2001–2005 110 63 59 t1b–t3n0m0 na lrn (n = 75) mipn oc, po mean scr levels 5 [46] rccs vs lpn (n = 35) roos (2010) [47] retrospective germany 1981–2007 166 range: 57 > 4 cm rccs t1a open pn open oc, cc, incidence 6 23-84 (n = 69) of urinary fistula, vs. open rn it, spleen damage (n = 97) lowrance (2010) retrospective usa 2000–2008 1712 na 62 <7 cm rccs t1 mixed pn mix oc, in-hospital mortality 6 [48] (n = 1061) vs. mixed rn (n = 651) sun (2012) [49] retrospective canada 1988–2005 1680 72 59 t1an0m0 rccs t1a open pn open arf 8 matched (n = 840) vs. open rn (n = 840) becker (2014)*[50] retrospective canada 1992–2005 1223 >66 53 t1n0m0 rccs t1 lrn mipn po severe hemorrhage, 7 (n = 1066) arf, cc, 30-day mortality vs. lpn liu (2014) [51] retrospective usa 2005–2011 8361 61 na rccs na (n = 157) mix it, arf, cc, 30-day 7 mirn (n = 3014) mortality, reoperation vs. mipn (n = 1439); open rn (n = 2445) vs. open pn (n = 1463) hadjipavlou (2015) prospective uk january– 1768 62 61 t1 rccs t1 mixed rn mix oc, it 8 [52] december 2012 (n = 1082) vs. mixed pn (n = 686) cai (2018) [53] retrospective china 2005-2012 199 54 64 solitary tumor t1b lrn (n = 160) mipn overall survival 6 with a maximum vs. lpn (n = 39) diameter of 4.0 to 7.0 cm rinott mizrahi (2018) retrospective israel 2012-2017 29 65 83 t2 rcc t2 lrn (n = 16) mipn oc 5 [54] vs. lpn (n = 13) reix (2018) [55] retrospective france 2000-2014 267 60 67 localized rcc t2a mixed rn mix overall survival 6 stage ct2a (7.1—10 cm) (n = 176) vs. mixed pn (n = 91) janssen (2018) [56] retrospective germany 1980-2010 123 61 65 large (>7cm) t1b-t3 open rn open overall survival 6 clear cell rcc (n = 105) vs. open pn (n = 18) de saint aubert retrospective france 2000-2013 130 58 63 large (>7cm) t2 mixed rn mix oc, hemorrhage, 7 (2018) [57] rcc (n = 81) hospital stay, arf vs. mixed pn (n = 49) yang (2018) [58] retrospective china 2014-2017 63 58 54 clinical t1 t1 lrn (n = 38) mipn oc 5 renal hilar tumor vs. lpn (n = 25) abbreviations: arf, acute renal failure; cc, cardiovascular complications; it, intraoperative transfusion; los, length of stay; mipn, minimally invasive pn; nss, nephron-sparing surgery; oc, overall complications; pn, partial nephrectomy; po, postoperative; rcc, renal cell carcinoma; rn, radical nephrectomy; scr, serum creatinine *data on open pn vs laparoscopic rn were discarded ^using jadad scale partial vs. radical nephrectomy for rcc-yang et al. review 110 vol 17 no 02 march-april 2020 111 the literature search was undertaken by two reviewers independently, and any inconsistencies were settled by the primary author (yong yang) until a consensus was reached. the study was eligible for inclusion if the following criteria were fulfilled: (1) study with retrospective/prospective cohort or randomized/non-randomized controlled design; (2) study investigating rn versus pn in patients with rcc; (3) outcomes including one of the following: hospital mortality, overall postoperative complications, postoperative hemorrhagic complications, cardiovascular complications, acute renal failure (arf), spleen damage, reoperation, urinary fistula, intraoperative blood transfusion, hospital stay, and mean postoperative scr. all studies describing patients with other diseases or lacking the direct comparison of rn and pn were excluded. data collection and quality assessment two reviewers independently extracted all data; the discrepancies were resolved after consulting with the primary author (yong yang). the following items were extracted from the included studies: first author’s name, design, region, study period, number of patients, mean age, the percentage of males, criteria for kidney lesions, tnm stages, compared surgical arms, operation types, and perioperative outcomes. the following outcomes were evaluated: hospital mortality, overall table 2. subgroup analyses according to tumor stage and surgery methods outcome subgroup no. of studies or or smd and 95% ci p value heterogeneity (%) p for heterogeneity hospital mortality t1 6 1.11 (0.52-2.33) 0.792 0.0 0.558 other 5 0.46 (0.29-0.73) 0.001 28.3 0.223 open 6 0.45 (0.26-0.78) 0.005 24.7 0.249 mipn 3 0.91 (0.37-2.24) 0.844 37.3 0.203 mixed 3 0.69 (0.30-1.59) 0.378 3.8 0.354 overall postoperative t1 9 1.46 (1.19-1.79) < 0.001 25.6 0.200 complications other 5 1.38 (0.95-2.00) 0.094 50.7 0.088 open 6 1.20 (0.99-1.47) 0.066 0.0 0.706 mipn 5 1.17 (0.72-1.89) 0.536 53.2 0.058 mixed 3 1.73 (1.29-2.33) < 0.001 48.6 0.143 postoperative t1 4 2.25 (1.44-3.50) < 0.001 0.0 0.555 hemorrhagic complications other 4 1.73 (0.65-4.60) 0.275 27.0 0.250 open 6 1.71 (1.00-2.90) 0.048 14.1 0.324 mipn 1 2.20 (1.15-4.20) 0.017 mixed 1 12.27 (0.62-242.79) 0.100 cardiovascular t1 3 0.48 (0.07-3.20) 0.450 76.2 0.015 complications other 3 1.02 (0.92-1.12) 0.766 0.0 0.773 open 5 1.00 (0.82-1.22) 0.968 46.2 0.098 mipn 2 0.89 (0.43-1.84) 0.746 8.7 0.295 mixed 0 acute renal failure t1 5 1.25 (0.55-2.86) 0.596 49.8 0.093 other 5 0.78 (0.36-1.66) 0.518 58.2 0.035 open 7 0.87 (0.58-1.32) 0.510 34.4 0.165 mipn 3 0.72 (0.10-4.96) 0.737 80.9 0.005 mixed 1 0.51 (0.05-5.16) 0.568 spleen damage t1 4 0.41 (0.10-1.72) 0.224 0.0 0.769 other 0 open 3 0.31 (0.06-1.52) 0.148 0.0 0.783 mipn 1 1.36 (0.05-35.53) 0.853 mixed 0 reoperation t1 2 1.50 (0.59-3.85) 0.396 0.0 0.320 other 3 0.71 (0.55-0.91) 0.006 0.0 0.657 open 5 0.85 (0.49-1.47) 0.568 18.6 0.296 mipn 1 0.74 (0.49-1.13) 0.162 mixed 0 urinary fistula t1 5 12.55 (3.35-47.00) < 0.001 0.0 0.981 other 1 82.66 (4.98-1371.41) 0.002 open 6 17.65 (5.35-58.30) <0.001 0.0 0.871 mipn 0 mixed 0 hospital stay t1 2 0.06 (-0.21 to 0.33) 0.671 0.0 0.620 other 3 0.04 (-0.05 to 0.13) 0.411 0.0 0.805 open 4 0.05 (-0.04 to 0.14) 0.316 0.0 0.923 mipn 0 mixed 1 -0.04 (-0.39 to 0.31) 0.825 intraoperative t1 4 1.05 (0.60-1.82) 0.866 31.1 0.214 blood transfusion other 3 0.75 (0.46-1.25) 0.272 86.8 < 0.001 open 5 1.04 (0.55-1.99) 0.895 84.0 < 0.001 mipn 2 0.70 (0.53-0.94) 0.017 0.0 0.801 mixed 1 0.81 (0.45-1.44) 0.475 mean t1 2 -0.41 (-2.00 to 1.18) 0.613 96.4 < 0.001 postoperative scr other 2 -0.01 (-0.11 to 0.09) 0.849 0.0 0.962 open 2 0.14 (-0.25 to 0.53) 0.476 70.5 0.066 mipn 2 -0.61 (-1.80 to 0.59) 0.319 94.0 < 0.001 mixed 0 partial vs. radical nephrectomy for rcc-yang et al. postoperative complications, postoperative hemorrhagic complications, cardiovascular complications, arf, spleen damage, reoperation, urinary fistula, intraoperative blood transfusion, hospital stay, and mean postoperative scr. the quality of randomized controlled trial was assessed using jadad scale, which was based on randomization, blinding, allocation concealment, withdrawals and dropouts, and use of intention-to-treat analysis(26). then, the quality of prospective or retrospective observational studies was evaluated using the newcastle–ottawa scale (nos), which was based on the following three subscales: selection (4 items), comparability (1 item), and outcome (3 items)(27). statistical analysis an inverse variance method was used to pool the continuous data, and the results were presented as standard mean difference (smd) with 95% confidence intervals (cis). the results were presented as the odds ratio (or) with 95% cis for dichotomous data as most of the included studies consisted of retrospective cohorts. given the lower prevalence of investigated outcomes, the relative risk could be considered as equivalent to or. the pooled results were further evaluated using the random-effects model(28,29). the statistical heterogeneity was assessed with the i2 test, and i2 > 50% was considered as significant heterogeneity(30). a sensitivity analysis assessed the influence of a single study on overall ors and smds(31). the subgroup analysis for the investigated outcomes was performed according to the tumor tnm stage (t1 stage or other) and surgical procedures (open, minimally invasive pn procedure, or mixed). funnel plots were used for assessing the publication bias; the begg–mazumdar(32) and egger tests (33,34) evaluated the publication bias quantitatively. the trimand-fill method was used to correct the publication bias if necessary(35). all tests were two-tailed, and a p-value < 0.05 was considered as statistically significant. stata software (version 12.0; statacorp, tx, usa) was used to analyze the data. results this meta-analysis yielded 1,561 studies after removing duplications, of which, 23 assessing 30,018 patients were included in the systematic review (figure 1)(36-58). 1/23 was a randomized controlled trial (rct) design (43), 3/23 had a prospective study design(39,45,52), and the remaining had a retrospective design. the rct was a multicenter clinical study; however, blinding was not employed to conceal the intervener and/or the assessor(43) (table 1). moreover, the quality of remaining observational studies were assessed using the nos; 3 studies had 8 stars, 7 had 7 stars, 8 had 6 stars, and the remaining 4 had 5 stars. the summary results of the treatment effects between rn and pn are presented in figures 2–5. the meta-analysis revealed that pn had a significantly lower hospital mortality (or: 0.58; 95% ci: 0.38–0.89; p = 0.013; unimportant heterogeneity) and reoperation rate (or: 0.74; 95% ci: 0.58–0.95; p = 0.016; no evidence of heterogeneity) as compared to rn after pooling the results. however, patients treated with pn were associated with a greater risk of overall postoperative complications (or: 1.40; 95% ci: 1.17–1.68, p < 0.001; moderate heterogeneity), postoperative hemorrhagic complications (or: 1.92; 95% ci: 1.28–2.87, p = 0.002; unimportant heterogeneity), and urinary fistula (or: 17.65; 95% ci: 5.35–58.30, p < 0.001; no evidence of heterogeneity) as compared to rn. finally, no significant differences were detected between pn and rn with respect to the outcomes of cardiovascular complications (or: 0.99; 95% ci: 0.83–1.19, p = 0.932; moderate heterogeneity), arf (or: 0.91; 95% ci: 0.57–1.43, p = 0.675; significant heterogeneity), spleen damage (or: 0.41; 95% ci: 0.10–1.72, p = 0.224; no evidence of heterogeneity), intraoperative blood transfusion (or: 0.87; 95% ci: 0.59–1.28, p = 0.475; significant heterogeneity), hospital stay (smd: 0.04; 95% ci: -0.05 to 0.13; p = 0.360; no evidence of heterogeneity), and mean postoperative scr (smd: figure 1. schematic representation. preferred reporting items for systematic reviews and meta-analysis flow diagram. figure 2. a:pn vs. rn on the risk of in-hospital mortality; b: pn vs. rn on the risk of overall postoperative complications; c: pn vs. rn on the risk of postoperative hemorrhagic complications partial vs. radical nephrectomy for rcc-yang et al. review 112 vol 17 no 02 march-april 2020 113 -0.20; 95% ci: -0.72 to 0.33, p = 0.462; significant heterogeneity). the results of sensitivity analysis indicated that the overall pooled ors and smds were not affected by sequential exclusion of individual study except hospital mortality and reoperation rate (supplemental figure 1). the summary results for subgroup analyses are shown in table 2. first, we noted that pn was associated with a reduced risk of hospital mortality if the included patients exhibited other stage of tumor and underwent an open procedure. second, the risk of overall postoperative complications was significantly increased in t1 stage tumor patients or received mixed pn. third, pn was associated with an increased risk of postoperative hemorrhagic complications than rn when patients with t1 stage tumor used open or minimally invasive pn procedure. fourth, stratified results for cardiovascular complications, arf, spleen damage, urinary fistula, hospital stay, and mean postoperative scr were consistent with the overall analyses. fifth, the rate of reoperation in pn was significantly lower than rn in patients with the other tumor stage. finally, the incidence of intraoperative blood transfusion in the pn group was lower than that in the rn group when minimally invasive pn procedure was carried out. the putative publication bias was examined in various results and was found only in the results of urinary fistula (begg test, p = 0.060; egger test, p = 0.034; supplemental figure 2). these results remained unaltered after trim-and-fill correction (or: 2.87; 95% ci: 1.68– 4.07; p < 0.001). discussion rn and pn used for treating rcc were analyzed in this study; 23 articles that fulfilled the inclusion criteria, comprising of 30,018 patients, were included. the present findings of this study demonstrated relatively fewer overall and hemorrhagic complications in rn, while pn had a lower hospital mortality, and reoperation. in a previous meta-analysis, manikandan et al. first figure 3. a: pn vs. rn on the risk of cardiovascular complications; b: pn vs. rn on the risk of acute renal failure figure 4. pn vs. rn on the risk of spleen damage, reoperation, and urinary fistula figure 5. a: pn vs. rn on the incidence of intraoperative blood transfusion; b:. pn vs. rn on hospital stay and mean postoperative scr partial vs. radical nephrectomy for rcc-yang et al. compared the pn and rn in patients with rcc with clinical outcomes including survival rate, recurrence, and metastasis. the disease-specific survival rate (p = 0.001) and incidence of metastasis (p < 0.050) were found to be significantly enhanced in the pn group; however, no significant difference was found regarding recurrence (p = 0.220). they also demonstrated that the efficacy of pn was similar to that of rn in patients with renal cell tumors up to 4 cm in diameter. however, this study did not discuss the perioperative complications and analyze the differences among variances of patients in the tnm stage(24). a meta-analysis conducted by deng et al. contained 13 retrospective studies encompassing 2,906 patients with large (> 7 cm) renal tumors. the study speculated that pn was associated with improved os and preserved renal function, and was also accompanied by high risk of surgical complications than rn(59). maclennan et al. comprehensively analyzed the laparoscopic approach, open surgery, robot-assisted surgery, and radiofrequency surgery for rcc treatment. the study considered that pn either showed an equivalent or better survival of rcc patients with tumors < 4 cm in diameter, while open surgery and laparoscopic approach achieved an equivalent survival for either rn or pn. therefore, localized pn would be ideally managed in patients with rcc in the t1a stage, which was better in the preservation of renal function and quality of life (qol) as compared to rn. however, these studies primarily focused on the qualitative comparison of rn and pn, while the quantitative results were not illustrated. furthermore, the summary results of perioperative complications were less described in this study (20,21) kim et al. compared rn and pn with respect to the overall and cancer-related mortality as primary outcomes, and severe renal failure as a secondary outcome. their study indicated that pn was associated with a 19% reduced risk in all-cause mortality (hr: 0.81; p < 0.001), a 29% reduced risk in cancer-specific mortality (hr: 0.71, p < 0.001), and a 61% reduced risk in severe chronic kidney disease (hr: 0.39, p < 0.001). however, the estimation of cancer-specific mortality was limited by the lack of robust significant heterogeneity across studies (19). tobert et al. analyzed the overall mortality as the primary outcome measure between rn and pn in 2014 (22); the study confirmed that pn had a 19% reduction in the all-cause mortality (p < 0.001) and 29% reduction in cancer-specific mortality (p < 0.001). although the study did not discuss the postoperative renal function, perioperative complications, and qol, the current study arrived at a similar conclusion on overall mortality. intriguingly, pn had an advantage regarding reoperation, while rn had an advantage in terms of overall and hemorrhagic complications. a multicenter prospective rct included patients in the t1-2n0m0 stage and found that the rate of perioperative blood loss was slightly high after rn and the rate of severe hemorrhage was slightly high after pn (43). this rct further demonstrated that 4.4% patients developed urinary fistulas after pn; the incidences of pleural damage and spleen damage were similar in both groups. therefore, not only mortality but improved qol and reduced perioperative complications were evaluated in surgery modalities. (43) the present study also demonstrated a relatively low mortality in pn and fewer complications in rn. the detection rate of a tumor ≤ 4 cm in diameter would promote advanced iconography, and pn would be the ideal method for this kind of disease. the protection of normal renal function would be further strengthened with developed anatomical structure and function of kidneys as well as improved pn technology. thus, implementation of pn would be more advantageous, avoiding inconsequential trauma in patients with rcc in the t1a stage. however, the conclusions might be variable because as a small number of studies were included in such subsets. hence, a relative result and a synthetic and comprehensive review have been conferred. the subgroup analysis suggested that rn had a low incidence of overall complications, hemorrhagic complications, and incidence of urinary fistula in patients in the t1 stage (maximum tumor diameter ≤ 7 cm). nevertheless, in the patients in t1a stage (tumor ≤ 4 cm), the number of included studies was not sufficient to yield robust results. in the surgical subgroup analysis, the mortality reduced by pn was primarily based on open surgery, and minimally invasive surgery did not show any difference between rn and pn. presently, the minimally invasive surgery is less utilized as compared to open surgery for patients with rcc. however, minimally invasive surgery, such as laparoscopy, exhibited advantages of fewer traumas, less bleeding, reduced infection probability, and reduced perioperative complications post-surgery (60). the perioperative complications may be reduced with an increase in the application of minimally invasive surgery in the future, suggesting the applicability of pn in patients with rcc (61-63). nonetheless, the present study had some limitations as follows: (1) specific individual data were unavailable for all trials, thereby restricting the analysis; (2) although the subgroup analysis was conducted, the heterogeneity continued 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rcc-yang et al. review 116 vol 17 no 02 march-april 2020 117 al. nephron sparing surgery in tumours greater than 7cm. prog urol. 2018;28:336-43. 58. yang c, wang z, huang s, xue l, fu d, chong t. retroperitoneal laparoscopic partial nephrectomy versus radical nephrectomy for clinical t1 renal hilar tumor: comparison of perioperative characteristics and short-term functional and oncologic outcomes. j laparoendosc adv surg tech a. 2018;28:1183-7. 59. deng w, chen l, wang y, liu x, wang g, fu b. partial nephrectomy versus radical nephrectomy for large (>/= 7 cm) renal tumors: a systematic review and meta-analysis. urol oncol. 2019;37:263-72. 60. nouralizadeh a, ziaee sa, basiri a, et al. transperitoneal laparoscopic partial nephrectomy using a new technique. urol j. 2009;6:176-81. 61. hasan wa, abreu sc, gill is. laparoscopic surgery for renal cell carcinoma. expert rev anticancer ther. 2003;3:830-6. 62. breda a, finelli a, janetschek g, porpiglia f, montorsi f. complications of laparoscopic surgery for renal masses: prevention, management, and comparison with the open experience. eur urol. 2009;55:836-50. 63. ghoneim ia, fergany af. minimally invasive surgery for renal cell carcinoma. expert rev anticancer ther. 2009;9:989-97. partial vs. radical nephrectomy for rcc-yang et al. pediatric urology our experience in chordee without hypospadias: results of 102 cases emre can polat,1 mehmet remzi erdem,2 ramazan topaktas,3 cevper ersoz,4 sinasi yavuz onol5 1department of urology, istanbul medipol university, istanbul, turkey. 2department of urology, haydarpasa numune research and training hospital, istanbul, turkey. 3urology clinic, diyarbakir, research and training hospital, diyarbakir, turkey. 4urology clinic, idil government hospital, sirnak, turkey. 5department of urology, bezmialem va kif university, istanbul, turkey. corresponding author: mehmet remzi erdem, md department of urology, hay darpasa numune research and training hospital, istanbul, turkey. tel: +90 505 7981199 e-mail: remzierdem@gmail.com received february 2014 accepted may 2014 purpose: we present long-term surgical experience of 102 chordee without hypospadias cases. materials and methods: this retrospective study included 102 chordee without hypospadias cases who were surgically treated between 1999 and 2012. range of patients’ age was from 1 month to 31 years. seventy-two patients were adult, and 30 were children. mean duration of follow up was 49.3 months. the patients were categorized into 4 groups including skin tethering (group 1), fibrotic dartos and buck’s fasciae ( group 2), corporeal disproportion ( group 3) and urethral tethering (group 4) with the aid of intraoperative artificial erection, according to the structural defect. results: forty patients (group 1) were successfully treated with penile degloving. except 3 (10%) of 31 (group 2) cases, extensive resection of the fibrotic dartos and buck’s fascia was needed to straighten the penis. corporeal disproportion was identified in 27 patients of whom 2 cases (7%) had complications. one of them developed urethrocutaneous fistula, and he was treated with buccal mucosal graft urethroplasty successfully. in other one, chordee persisted after two years, and we had to do nesbit wedge resection after tunica albuginea plication to achieve penile straightening at the same session; otherwise we avoid tunica albuginea excision or incision. overall 96 (94%) of 102 patients were successfully treated at first operation. conclusion: we concluded that tunica albuginea plication is very effective for both prepubertal and postpubertal period and also in management of recurrence. we believe that, in experienced hands, early surgical correction can be done successfully in this condition. keywords: penis; abnormalities; urologic surgical procedures; hypospadias; male; methods. 1783 pediatric urology urology journal vol. 11 no. 04 july august 2014 1784 oughly resolved, the urethra and corpora cavernosa were checked for the cause of the curvature. although no significant urethral tethering was shown if the penis was still ventrally curved under artificial erection, the cause was corporal disproportion (group 3) (figure 3) and patients were treated with dorsal midline plication as reported by baskin and colleagues.(5) we frequently performed tunica albuginea plication and when it was unnecessary we stood aside tunica albuginea excision and incision in this condition. two of group 3 patients had small penis so we made corporal graft augmentation (inguinal dermal and rectus facial graft) and urethroplasty. patients who had tethered urethra after complete urethral mobilization underwent urethral division and creation of a tubularized preputial or buccal mucosa graft (group 4) (figure 4). in all patients an artificial erection test was performed at the end of procedure to confirm the penile straightening. postoperative dressing and stenting varied according to procedure. for patients who did not undergo urethroplasty, the urethral stent was removed next day after surgery and dressing removed at 3 days. for those who underwent urethroplasty, the urethral stent was removed at 7 postoperative days with dressing. for those in whom we did not perform urethroplasty we left a stent for one day because of spinal anesthesia in postpubertal patients and difficulty in urination due to pain in prepubertal patients. during the of follow up period, successful release of chordee was con introduction chordee without hypospadias or congenital penile curvature is a comparatively rare condition. in 1937 young proposed that, chordee without hypospadias was due to a congenitally short urethra.(1) at the present time; it has become well acknowledged that urethral tethering is not always the cause of penile curvature, and this has led to more urethra-preserving urethroplasty procedures. devine and horton classified chordee without hypospadias into three types.(2) type 1 represents the deficiency of corpus spongiosum and buck’s and dartos fascia from the site of chordee to the glans. in type 2 the spongiosum is normal, while the dartos and buck’s fasciae are dysgenetic. in type 3 corpus spongiosum and buck’s fascia are normal but dartos fascia is deficient. kramer and colleagues(3) added type 4, which results from corporeal disproportion and type 5 which is termed congenital short urethra.(2) we review our experience about the congenital chordee without hypospadias in a large series of turkish prepubertal and adolescents/adult patients. materials and methods study patients from july 1991 to december 2009, 102 patients 1 month to 31 years old (median age 19.2 years) who were treated for the congenital chordee without hypospadias retrospectively reviewed. seventy-two of the cases were adolescents/adult age and all patients in this age group were previously circumcised. only 22 of 30 children could be followed until adolescent age. of these patients 8, 6, 5 and 3 were in groups 1, 2, 3 and 4, respectively (figures 1-4). cases of a paper-thin hypoplastic distal urethra were excluded from the study and managed with excision and reconstruction of the abnormal urethral segment. patients with previous surgical corrections were excluded. indications for surgery included abnormalities in the prepuce, parental complaint of penile curvature at erection or a penile angle greater than 30° on examination under natural erection. some author proposed that the correction age of chordee should be after puberty,(4) but others advocate that if diagnosed in childhood correction should be at that time(6) we follow the same principle of managing the patient whenever he presents. surgical technique in all cases, a circumcision incision was made, and the skin was degloved down to the base of penis. then an artificial erection was induced to assess the degree of curvature. patients whose penis straightened after degloving were considered to have skin chordee due to abnormal dartos facial tethering of the skin to the underlying buck’s fascia (group 1) (figure 1). when chordee persisted, any abnormal dense fibrous tissue was excised over the urethra. patients in whom chordee was corrected at this point were considered to have fibrotic buck’s and dartos fasciae as the etiology of chordee (group 2) (figure 2). for patients in whom 2 steps failed and curvature was not thorfigure 1. group 1, skin chordee. figure 2. group 2, fibrotic buck’s and dartos fascia. experience in chordee without hypospadias-polat et al in 1937 young proposed that it was due to a congenitally short urethra and should be managed by transection and reconstruction of hypoplastic urethra.(1) devine and horton in 1973 proposed that chordee without hypospadias was due to abnormal development of fascial layers surrounding the urethra and majority of these patients could be treated with resection of fibrous tissue for chordee correction, transection of urethra being rarely required.(2) kramer and colleagues in 1982 found that corporal disproportion was another principal cause of chordee. (3) they recommended that dorsal corporeal plication should be performed according to the nesbit principle to correct this type of chordee without hypospadias. however, others suggested that elongation of the ventral corporeal bodies with graft material was superior to plication of the dorsal corporeal bodies in severe penile curvature.(7-9) in 1992 hendren and caesar reported disappointing results and significant recurrence of chordee after long-term follow up by nesbit himself,(10) though chertin and colleagues reported that dorsal tunica albuginea plication is a simple and efficient method with good long-term results for correction of chordee without any damage to neurovascular bundles.(11) in our series of 102 patients the etiology of isolated chordee was evenly distributed among skin tethering (39%), fibrotic buck’s and dartos fascia (30%), corporeal disproportion (27%) and a congen firmed by physical examination and patient or parental observation of erection. results forty patients (39%) were categorized as group 1 chordee, 31 patients (30%) as group 2, 27 patients (27%) as group 3 and 4 patients (4%) as group 4 (table 1). mean duration of follow-up was 49.3 months. only 30 of 102 cases were children and 22 patients could be followed until adolescent age. artificial erection test was performed in all patients at the beginning to assess the degree of curvature and at the end of the procedure to confirm the penile straightening (figures 5-7). except 8 patients in group 1, all had a chordee more than 30° (94%). ninety-six (94%) of the 102 cases were cured after first operation. management of patients according to age groups is shown in tables 2 and 3. all group 1 patients were successfully treated at first operation. in 3 (10%) of group 2 patients chordee recurred and managed with tunica albuginea plication and one was operated in infantile age and dorsal penile curvature more than 30° was found in control at adolescent age and straight penis was gained with dorsal midline plication. one of group 3 patients who underwent corporal graft augmentation (inguinal dermal and rectus facial graft) and urethroplasty, developed urethrocutaneous fistula and treated with buccal mucosa graft urethroplasty successfully. in one of group 3 patients who were operated at child age, right 40° lateral penile curvature was found in control at adolescent age. we had to elevate dorsal vessels and nerves after penile degloving and performed nesbit wedge resection after tunica albuginea plication to achieve penile straightening at the same session; otherwise we stood aside tunica albuginea excision or incision. urethrocutaneous fistula occurred in 1 (25%) child of group 4 patients and successfully treated with longitudinal island flap urethroplasty. discussion there are no definitive guidelines for management of chordee without hypospadias, and controversy still continues on etiology or surgical management of this entity. groups definition complications 1 skin chordee 40 (39) 0 2 fibrotic buck’s 31 (30) 3 (10) and dartos fascia 3 corporeal disproportion 27 (27) 2 (7) 4 congenitally short urethra 4 (4) 1 (25) total 102 (100) 6 (6) table 1. classification of study patients.* * data are presented as no. (%). figure 3. group 3, corporeal disproportion. figure 4. group 4, congenitally short urethra. 1785 pediatric urology urology journal vol. 11 no. 04 july august 2014 1786 itally short urethra (4%). paper-thin hypoplastic urethral cases (type 1) were excluded from the study, since they were considered hypospadiac variants, and were managed with excision and reconstruction of the abnormal urethral segment. patients with skin chordee had the best outcome in our series with no complications or recurrence. only 3 (10%) of fibrotic dartos and buck’s fascia patients required repeat surgery for recurrent chordee and tunica albuginea plication was adequate in this condition. patients with corporeal disproportion had also good outcome except 2 (7%) cases who one of them had small penis and underwent corporal graft augmentation and urethroplasty, developed urethral fistula. buccal mucosa graft urethroplasty was sufficient and did not require repeat surgery, in the other patient curvature was recurred in adult age and nesbit plication was needed to correct the lateral curvature. only in one patient as a management of curvature recurrence we had to do nesbit otherwise we did not need to excise or incise tunica albuginea. cases of urethral tethering had the worst prognosis although we had only four patients in this group. urethrocutaneous fistula occurred 1 (25%) of 4 patients and treated with longitudinal island flap urethroplasty (table 4). overall 96 of the 102 patients (94%) were successfully treated at first operation. in cases of corporeal disproportion and urethral tethering there is an increased risk of fistula formation. we did not see meatal stenosis, urethral stricture and urethral diverticulum in our patients. this may be due to limited number of patients in group 4 and excluding the hypoplastic distal urethra cases from the study. groups no. procedure performed no./type of complication management methods of complications 1 16 penile degloving ---- ---- 2 6 chordectomy 1/penile curvature dorsal midline plication 3 5 dorsal midline plication 1/penile curvature tunica albuginea plication and nesbit 4 3 urethral division and 1/fistula longitudinal island flap urethroplasty tubularized preputial ---- ---- graft urethroplasty ---- ---- table 2. management methods in prepubertal patients. groups no. procedure performed no./type of complication management methods of complications 1 24 penile degloving ---- ---- 2 25 chordectomy 2/penile curvature tunica albuginea plication 3 20 dorsal midline plication ---- ---- 2 corporal graft augmentation 1/fistula and urethroplasty 4 1 urethral division and ---- ---- buccal mucosal graft urethroplasty table 3. management methods in postpubertal patients. table 4. types and number of complications. groups type complications no. 1 ---- ----2 persistent chordee 3 3 persistent chordee 1 fistula 1 4 fistula 1 total 6 figure 5. artificial erection test. experience in chordee without hypospadias-polat et al figure 7. artificial erection test at the end of the procedure confirms the penile straightening. conclusion in our experience of correction of chordee without hypospadias, tunica albuginea plication is very effective for both prepubertal, postpubertal period and also management of recurrence. we suggest that, in experienced hands, early surgical correction performed successfully in cases with chordee without hypospadias. conflict of interest none declared. references 1. young hh. genital abnormalities, hermaphroditism and related adre nal diseases. baltimore: wilkins & wilkins; 1937. p. 119. 2. devine jr cj, horton ce. chordee without hypospadias. j urol. 1973;110:264-71. 3. kramer sa, aydin g, kellis pp. chordee without hypospadias in child ren. j urol. 1982;128:559-61. 4. cendron j, melin y. congenital curvatures of penis without hypospadi as. urol clin north am. 1981;8:389-93. 5. baskin ls, erol a, li yw, liu w. anatomy of the neurovascular bund le: is safe mobilization possible? j urol. 2000;164:977-80. 6. devine cj jr, blackley sk, horton ce, gilbert da. the surgical treat ment of chordee without hypospadias in men. j urol. 1991;146:325-9. 7. vine cj jr, horton ce. use of dermal graft to correct chordee. j urol. 1975;113:56-8. 8. kogan sj, reda ef, smey pl, levitt sb. dermal graft correction of extraordinary chordee. j urol. 1983;130:952-4. 9. perlmutter ad, montgomery bt, steinhardt gf. tunica vaginalis free graft for the correction of chordee. j urol. 1985;134:311-3. figure 6. artificial erection test at the end of the procedure. 10. hendren wh, caesar re. chordee without hypospadias: experience with 33 cases. j urol. 1992;147:107-9. 11. chertin b, koulikov d, fridmans a, farkas a. dorsal tunica albuginea plication to correct congenital and acquired penile curvature: a long-term follow-up. br j urol. 2004;93:379-81. 1787 pediatric urology 1524 | intracerebral hemorrhage after sildenafil citrate use: an incidental association? giyas ayberk,1 mehmet faik ozveren,1 mesut emre yaman,2 hakan tosun1 corresponding author: gıyas ayberk, md department of neurosurgery, ataturk training and research hospital, 06800 bilkent, ankara, türkiye. tel: +90 312 291 2525 fax: +9 312 291 2705 e-mail: giyas67@hotmail.com received march 2013 accepted june 2013 1 department of neurosurgery, ataturk training and research hospital, 06800 bilkent, ankara, türkiye. 2 department of neurosurgery, kecioren state hospital, ankara, türkiye. keywords:cerebralhemorrhage;disabilityevaluation;sildenafil;incidentalfindings. introduction themostcommoncausesofintracerebralhemorrhage(ich)arestructuralvascularanomaliesanddysfunctionalcoagulation.ichcausedbysildenafilisrarelyreportedintheliterature.sildenafilisaselectivephosphodiesterase-5(pde-5)enzymeinhibitor,andcausesanincreaseincyclicguanosinemonophosphate(cgmp)inthevascular smoothmuscleofthecorpuscavernosum,leadingtomusclerelaxationandvasodilation. sildenafilhassameeffectsonintracranialvasculaturebywayofpde-1and2enzymes. overdoseofsildenafiloruseoveranextendedperiodoftimeincreasesthelikelihoodof intracerebralhemorrhage. case report a35-year-oldmalewasadmittedtotheemergencydepartmentinadisorientedstateandwith aseriousheadache.hiswifereportedthathehadnoticedaseriousheadachetwohoursafter taking50mgofsildenafilwithouthavingsexualactivity.hehadusedthedrugfornearlya month,twotothreetimesinadaywithoutsupervisionofanurologist.hehadnohypertension,familyhistoryofcerebralarteriovenousmalformation,cerebralaneurysms,orich.on case report case report 1525vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l sildenafil and stroke | ayberk et al admission,bloodpressurewas120/90mmhg,andpulse rate was 90 beats/minute. the glasgow coma score was 12.theneurologicalexaminationwasnormal,withtheexceptionofmildneckstiffness.routinebloodexamination, plateletcountandcoagulationfactorswerenormal.cranial computed tomography(ct)scanrevealedhemorrhage in the right nucleus caudatus, which opened in the lateral and third ventricles (figure 1). ct scan angiography and the cerebraldigitalsubtractionangiography(dsa)revealedno vascularpathology(figure2).thepatientwasconsultedby acardiologydepartmenttoruleoutcardiaccauses,andreportedasnormalfindings.headmittedtotheintensivecare unitforobservation,anddischargedafterfivedayswithnormalneurologicexamination. discussion sildenafilisapde-5enzymeinhibitor,andcausesanincreaseincgmpinthevascularsmoothmuscleofthecorpus cavernosum.thenitricoxide(no)-cgmppathwaymaybe responsibleforcerebralvasodilationbysimilarmechanisms in the brain.(3)ithasbeensuggestedthatsildenafilalsoacts onthepde-1andpde-2enzymes,whichareinvolvedin thecontrolofcerebralvasculature.(4)therearemanyreportedsideeffectsofsildenafil in theliteratureincluding headache, visual and retinal disturbances, dizziness, and apupil-sparingthirdnervepalsy,whichexplainsystemic distributionintothemicrovasculature.(5) hypertension and sexualactivityareknownriskfactorsforich.(6) theingestionofsildenafilandonsetsymptomsafterthree hourswithoutsexualactivitysuggeststhatsildenafilmaybe relatedtotheichinthispatient.thecranialctangiographyanddsadidnotrevealanyvascularanomaliesexplainingthecauseofich.therelationshipbetweentheich andsildenafilingestionisspeculativeintheliterature.(7) it isknownthatsildenafilincreasestheresponseofcerebral vasculaturetoc02andcausesincreasedcerebralbloodflow andcerebralbloodvolumeintracranially.(8) altered cerebrovascularreactivitycausesavasodilatoryresponseandblood flowmodifications.theeffectsofsildenafiloncerebralarterialdiameterarenothemodynamicallysignificantatrest, buthypercapniadecreasesthemeanarterialpressure5to15 mmhg.(2)inhypertensivepatients,theseeffectsaremuch moreprominentanddosedependent.(9)increasedbloodc02 tensionwasnotconsideredasacauseofich,duetothepatient’slackofstrenuousactivity.itwasshownthatsildenafil modulatesno-cgmppathwaysintheratbrain,andendogfigure 1. cranial computed tomography scan demonstrates hemorrhage in the right nucleus caudatus. figure 2. computed tomography scan angiography and the cerebral digital subtraction angiography show no vascular pathology. 1526 | case report enousnoreleasingispotentiatedbysildenafil.(10,4) modulationoftheno-cgmppathwaymaypotentiatetheeffectof sildenafilandcausebleedingincerebralbloodvessels. conclusion to conclude, taking sildenafil for an unusually extended periodoftime,andatahighdosemaycausepersistentvasodilatationoncerebralvasculaturewhichmayincreasethe probabilityofich.additionally,itmaybeanincidentalside effectaspresentedcase. conflict of interest none declared. references 1. johnston kc. effect of sildenafil (viagra) on cerebral blood vessels. neurology. 2005;65:785. 2. diomedi m, sallustio f, rizzato b, ferrante f. sildenafil increases cerebrovascular reactivity: a transcranial doppler study. neurology. 2005;65:919-21. 3. mchugh j, cheek dj. nitric oxide and regulation of vascular tone; pharmacological and physiological consideration. am j crit care. 1998;7:131-40. 4. ballard sa, gingell cj, tang k, turner la, price me, naylor am. effect of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isoenzymes. j urol. 1998;159:2164-71. 5. donahue sp, taylor rj. pupil sparing third nerve palsy associated with sildenafil citrate (viagra). am j ophthalmol. 1998;126:476-7. 6. monastero r, pipia c, camarda lkc, camarda r. intracerebral hemorrhage associated with sildenafil citrate. j neurol. 2001;248:141-2. 7. buxton n, flannery t, wild d, bassi s. sildenafil (viagra)-induced spontaneous intracerebral haemorrhage. br j neurosurg. 2001;15:347-9. 8. jimenez-caballereo pe, segura t. normal values of cerebral vasomotor reactivity using the breath-holding test. rev neurol. 2006;43:598-602. 9. stanopoulos i, hatzichristou d, tryfon s, tzortzis v, apostolidis a, argyropoulou p. effects of sildenafil on cardiopulmonary responses during stres. j urol. 2003;169:1417-21. 10. kruuse c, thomsen ll, jacobsen tb, olesen j. the phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. j cereb blood flow metab. 2002;22:1124-31. monograph causes and risk factors of urinary incontinence: avicenna’s point of view vs. contemporary findings fatemeh nojavan,1 hossein sharifi,2 zinat ghanbari,3* mohammad kamalinejad,4 roshanak mokaberinejad,5 maryam emami6 purpose: to extract the causes and risk factors of urinary incontinence from an old medical text by avicenna entitled “canon of medicine” and comparing it with contemporary studies. materials and methods: in this study, etiology and risk factors of urinary incontinence were extracted from avicenna's “canon of medicine”. commentaries written on this book and other old reliable medical texts about bladder and its diseases were also studied. then the achieved information was compared with contemporary findings of published articles. results: urinary incontinence results from bladder dysfunction in reservoir phase. bladder’s involuntary muscles and voluntary external sphincter are two main components which are involved in this process. urinary incontinence can exist without obvious structural and neuronal etiologies. according to avicenna, distemperment of muscular tissue of bladder and external sphincter is the cause for urinary incontinence in such cases. distemperment is the result of bothering qualities in tissue, i.e.: “wet” and “cold”. they are the two bothering qualities which are caused by extracorporeal and intracorporeal factors. interestingly, the positive associations of some of these factors with urinary incontinence have been shown in recent researches. conclusion: “cold” and “wet” distemperment of bladder and external sphincter can be independent etiologies of urinary incontinence which should be investigated. keywords: urinary incontinence; manuscripts as topic; history; persia; medieval; reference books; avicenna. introduction urinary incontinence, i.e. any involuntary leakage of urine,(1) is a worldwide public health problem with adverse effects on quality of life of affected people.(2) there are various ways to treat this pathological condition. conservative and behavioral therapy,(3) drug therapy and surgery all have their own limitations and complications. (4) urinary incontinence is not a new disease. throughout history mankind has struggled with it and looked for its treatment. so reviewing old medical texts about this morbid symptom is necessary for a deeper understanding of it. involuntary loss of urine with its old terminology has been mentioned as a symptom of lower urinary tract’s dysfunction in old scientific medical books such as canon of medicine written in about 1000 years ago by the great scientist “avicenna”. examining the approach of this great scientist and his followers regarding this bothersome symptom can provide new and different views to urinary incontinence, resulting in new options of prevention and even treatment with natural and herbal medicine. avicenna was a pioneer of a school of traditional persian medicine. this school has a unique approach to health and disease. it believes that an organ of body does well when it is in balance quantitatively and qualitatively. the number, shape and position of each organ are unique. this is balance of quantity. the balance in quality is presence of “hot”, “cold”, “wet” and “dry” qualities to the extent which is necessary for each organ’s function. the outcome of the four qualities is called ‘temperament’ which is specific for every organ. exacerbation or alleviation of each of these qualities that lead to dysfunction of an organ is called “distemperment”. this paper reviewed the etiologies and risk factors of urinary incontinence in a traditional medical text entitled canon of medicine with focus on identifying its predisposing factors. it also compared the achieved results with contemporary findings. this can be the first step to offer a documented and effective preventive strategy for urinary incontinence based on traditional medical texts. materials and methods the contents relevant to urinary incontinence and its etiologies were selected from avicenna’s canon of medicine. the original version of this book in arabic was used for this study.(5) although avicenna was a persian 1 research institute for islamic and complementary medicine, iran university of medical sciences, tehran, iran. 2 school of traditional medicine, tehran university of medical sciences, tehran, iran. 3 department of pelvic floor, imam khomeini hospital complex, tehran university of medical sciences, tehran, iran. 4 school of pharmacy, shahid beheshti university of medical sciences, tehran, iran. 5 school of traditional medicine, shahid beheshti university of medical sciences, tehran, iran. 6 department of urology, hasheminejad hospital, iran university of medical sciences, tehran, iran. *correspondence: department of pelvic floor, imam khomeini hospital complex, end of keshavarz blv., tehran, iran. tel: +98 21 61190. fax: +98 21 66581615. e-mail: drz_ghanbari@yahoo.com. received december 2014 & accepted january 2015. monograph 1995 vol 12. no 01 jan-feb 2015 1995 physician and scholar, his book was written in arabic since the language of science in that time was arabic not persian. diseases of the bladder and lower urinary tract symptoms were described in detail in separate chapters in the third volume of this four-volume version of the book. in addition, two other reference text-books in traditional persian medicine were also used to compare and verify the findings.(6,7) the accumulated contents were then classified and listed. afterwards, databases such as pubmed central and scopus were searched based on two keywords (i.e. urinary incontinence and predisposing factors) in order to find articles with relevant evidences which could support the achieved findings of the studied old medical texts regarding urinary incontinence. results in traditional persian medicine, lower urinary tract consisted of bladder and external voluntary sphincter. nature, shape, location and other unique characteristics of bladder made it suitable for its function which was reserving large amount of urine to keep human being voiding continuously and letting him/her void in proper time and place willfully. in old persian medical texts, factors which oppose bladder’s reservoir function due to their type and severity can cause symptoms including urinary frequency, urgency, nocturnal incontinency and diurnal incontinency.(6) these factors are divided into two extracorporeal and intracorporeal groups.(5-7) extracorporeal factors which affect bladder from the outside of body include: 1.direct trauma to perineal region like falling from a height on perinea which weakens bladder by causing injury to its tissue or its innervations. 2. dislocation of lower lumbar and pelvic vertebras which interfere with innervations of bladder and external sphincter. 3. living in geographical areas with cold and moisturized weather. 4. being in cold seasons like autumn and winter. 5. nutritional habits like drinking much liquid, especially cold with ice. eating sour foods, eating many watery fruits like watermelon, grape, etc. 6. behavioral habits like going to bathroom frequently and using too much cold water for washing the external genitalia due to obsession. 7. having jobs like fishing in the traditional form. in this regard, galen has expressed a fisher man in his era who suffered from urinary and fecal incontinence simultaneously due to standing for a long time in water.(8) they believed that sea with salt water is less harmful than sea with fresh water! 8. using herbal drugs can be another factor. the old texts have mentioned a list of materia medica which is harmful to bladder if used in high dosage and without peacemakers. numbers 3 to 7 are factors which affect bladder’s original healthy temperament and cause it to become cold and wet, i.e. two oppose qualities which interfere with bladder’s function. intracorporeal factors which affect bladder from the inside of body are in two categories: a) factors which influence total body initially and then involve bladder secondarily. gender: according to traditional persian medicine woman due to their temperament are generally colder and wetter than men and are more prone to urinary incontinency age: children and elderly are two at risk groups for urinary incontinency. wet is the predominant temperament in them. obesity: obese people especially who have fatty non-muscular obesity are wetter than slim people. whole body temperament: people with cold and wet temperament are more prone to urinary incontinency. a symptom which indicates the presence of such temperament on body is white color of skin. b) factors which influence bladder and external sphincter primarily. b-1: bladder’s tissue and urine any kind of distemperment which occurs to bladder’s muscles can cause bladder weakness. the term “bladder weakness” in traditional persian medical texts is a condition in which bladder cannot tolerate urine and is eager to lose the urine as soon as possible.(5) weakened bladder is more vulnerable to urine if the urine is not in a standard quality and quantity. so in addition to high volume of urine, any change in quality of urine can cause urinary incontinence especially in a bladder weakness. urine can be converted to a hot and burning material which is not tolerable by bladder, so bladder ejects the urine as soon as possible even if there is no will to void. infection, doing sports, fatigue, having intercourse, taking some sorts of foods and drinks are examples of factors which affect the quality of urine. b-2: adjacent organs to bladder another internal factor that causes urinary incontinence by bothering the bladder indirectly is the pressure effect of adjacent organs on bladder like uterine during pregnancy and rectum in case of chronic constipation and fecal impaction which interfere with augmentation of bladder during reservation phase. b-3: sphincter in traditional persian medical texts, external sphincter is a volunteer muscle on bladder’s neck which closes bladder’s outflow by its forceful contraction. sensory and motor neurons from brain and spine innervate it and let it to relax during voiding phase. two factors cause the sphincter not to work ideally: first are injuries to nerves supplying the sphincter’s innervations: innervations to sphincter can be interrupted structurally by total or near total dissection of nerves. they can also be interrupted functionally by distemperment of nerve tissues, especially “wet” and “cold”. second are injuries to muscular tissue of sphincter which cause it to become weak and loose. so it cannot contract well and let urine to leak. “cold” and especially “wet” distemperment of muscular tissue (sphincter) are of those injuries. exposure of perinea to cold environment by sitting on cold surfaces like ceramics too often, washing this area too much with cold water, and inadequate clothing in cold weather are some examples which gradually result in distemperment of tissues of perinea and subsequently external sphincter, making it so weak that it cannot act perfectly. discussion continence is the result of correct function of bladder and external sphincter. bladder stores urine in proper amount during the phase of reservation and external sphincter does not let urine to leak by its powerful contraction on bladder’s neck during this phase.(9) any impairment to these two structures causes them not to do their roles completely. by reviewing old medical texts, especially avicenna’s canon of medicine, causes and risk factors of urinary incontinence were extracted and listed. most of these avicenna’s point of view vs. contemporary findings-nojavan et al vol 12. no 01 jan-feb 2015 1996 vol 12. no 01 jan-feb 2015 1997 factors attenuate the power of involuntary muscles of bladder and voluntary muscle of sphincter by causing distemperment, especially of wet and cold. it seems that the persian physicians of the past believed that there is a special internal power in bladder resulting in intact holding of urine. beside bladder, this power is in the external sphincter’s muscle which lets it contract completely. when some qualities occur to muscles’ tissue of bladder and sphincter, they cannot do their role correctly during the phase of reservation. depending on the severity and chronicity of attenuator quality, different degrees of incontinency occur from occasional to total urinary incontinence. in fact cold and wet distemperments are the harmful described qualities. nowadays apart from detectable and gross clinical pathologies, like trauma, cord injuries, vertebral fractures, dislocation of bladder, etc., there are undetectable pathologies which cause urinary incontinence. they cannot be recognized even by rigorous and detailed laboratory studies. in such cases treatments are somewhat blind and symptomatically without real cure, eradicating the etiology. in traditional reliable medical texts, distemperment of bladder and external sphincter can be an etiology of urinary incontinence. “wet” and “cold” distemperments are the main reason why bladder and external sphincter do not to work well during the phase of reservation. distemperment is a cause of urinary incontinence and its predisposing factors have been listed. interestingly, the relationship between some of these factors and urinary incontinence has been shown in recent studies. nowadays age is considered as a risk factor for urinary incontinence in both women and men.(10) prevalence of incontinence which is increased with aging has been shown in many contemporary researches.(11-13) in addition to other etiologies like functional impairment, traditional persian medicine’s explanation for this relationship is predominant temperament in adult age which is “cold” and “wet”. obesity is another factor that is primarily associated with urinary incontinence. it has been shown that excessive weight is an established and potent risk factor for urinary incontinence among women of all ages.(14-16) the reduction effect of decreasing obesity especially in women on burden of urinary incontinence has been studied.(17) the association of body mass index (bmi) with higher risk of urinary incontinence has been shown. however, recently different mechanisms for urinary incontinence other than purely mechanical stress on the bladder in obesity has been suggested.(18) traditionally, wet and cold temperaments have more association with fatty obesity than muscular obesity. the elderly, women and obese have established risk factors for urinary incontinence because of their cold and wet temperament. the prevalence of urinary incontinence by race or ethnicity in women has been variable. some studies did not show differences between racial or ethnic groups,(9,23) but others have shown higher prevalence of urinary incontinence in white women compared to black women.(19-22,24) the finding that white women are more prone to urinary incontinence than black women is consistent with traditional persian medicine’s view about different temperaments in different races and genders. some temperaments are more likely to cause some diseases according to traditional persian medicine. in this sense, white people have “colder” temperaments compared to black people. nutrition, drugs, sports and intercourse affect the quality and quantity of urine. this effect is sometimes intolerable for the bladder, leading to urinary incontinence. some of these factors have been studied in recent researches. constipation and high fluid intake are factors which have been mentioned in traditional medical texts as risk factors for urinary incontinence. the positive association of constipation with dysfunction of lower urinary tract including urinary incontinence has been shown.(25) constipation prevention methods and less fluid intake in the evenings especially for elderly women has been shown to be useful for preventing urinary incontinence in recent studies.(26) conclusion it seems that traditional persian physicians’ belief about the relationship between distemperment of bladder and external sphincter and urinary incontinence is not out of date and can be reviewed today. also, the concept of temperament might become clearer with more clinical research on disease etiologies of the traditional persian medical texts. urinary incontinence can be prevented by controlling its traditional predisposing factors, if distemperment is found to be associated with it by more studies. this can be the first step to offer a documented and effective preventive strategy for urinary incontinence based on traditional persian medical texts. acknowledgements the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. this article is based on two phd dissertations, one about urinary incontinence in women by fatemeh nojavan and the other about urinary incontinence in children by hossein sharifi. conflict of interest none declared. references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002;21:167-78. 2. maserejian nn, minassian va, chen s, hall sa, mckinlay jb, tennstedt sl. treatment status and risk factors for incidence and persistence of urinary incontinence in women. int urogynecol j. 2014;25:775-82. 3. wyman jf, fantl a, mcclish dk, bump rc. comparative efficacy of behavioral interventions in the management of female urinary incontinence. am j obstet gynecol. 1998;179:999-1007. 4. epstein bj, gums jg, molina e. newer agents for the management of overactive bladder. am fam physician. 2006;74:2061-8. 5. avicenna. canon of medicine. 1st edition. vol 3. lebanon: darelhilal institute; 2009:435-7. 6. kirmani, n. sharh al asbab va al alamat [describing the reasons and symptoms]. vol avicenna’s point of view vs. contemporary findings-nojavan et al monograph 1997 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 1998 2. correction and research by the institute of natural medicine. qom: jalal al-din; 2009:1735. 7. ibn nafis. commentary on the canon of avicenna. vol 3. tehran: library of parliament; 1993;520-30 8. arzani, ma. tebe akbari. vol 1. by the efforts of ehyaye tebe tabiei institude. qom: jalal aldin; 2009:114. 9. madineh ma. avicenna’s canon of medicine and modern urology, part iv: normal voiding, dysuria, and oliguria. urol j. 2009;6:228-33. 10. nygaard i, barber md, burgio kl, et al. prevalence of symptomatic pelvic floor disorders in us women. jama. 2008;300:1311-6. 11. mcgrother c, resnick m, yalla sv, et al. epidemiology and etiology of urinary incontinence in the elderly. world j urol. 1998;16(suppl 1):s3-9. 12. lee ys, lee ks, jung jh, et al. prevalence of overactive bladder, urinary incontinence, and lower urinary tract symptoms: results of korean epic study. world j urol. 2011;29:185-90. 13. liu b, wang l, huang ss, wu q, wu dl. prevalence and risk factors of urinary incontinence among chinese women in shanghai. int j clin exp med. 2014;7:686-96. 14. matthews ca. risk factors for urinary, fecal, or double incontinence in women. curr opin obstet gynecol. 2014;26:393-7. 15. wesnes sl. weight and urinary incontinence: the missing links. int urogynecol j. 2014;25:725-9. 16. lasserre a, pelat c, guéroult v, et al. urinary incontinence in french women: prevalence, risk factors, and impact on quality of life. eur urol. 2009;56:177-83. 17. markland ad, richter he, fwu cw, eggers p, kusek jw. prevalence and trends of urinary incontinence in adults in the united states, 2001 to 2008. j urol. 2011;186:589-93. 18. khullar v, sexton cc, thompson cl, milsom i, bitoun ce, coyne ks. the relationship between bmi and urinary incontinence subgroups: results from epiluts. neurourol urodyn. 2014;33:392-9. 19. jackson ra, vittinghoff e, kanaya am, et al. urinary incontinence in elderly women: findings from the health, aging, and body composition study. obstet gynecol. 2004;104:301-7. 20. brown js, nyberg lm, kusek jw, et al. proceedings of the national institute of diabetes and digestive and kidney diseases international symposium on epidemiologic issues in urinary incontinence in women. am j obstet gynecol. 2003;188:s77-88. 21. tennstedt sl, link cl, steers wd, mckinlay jb. prevalence of and risk factors for urine leakage in a racially and ethnically diverse population of adults: the boston area community health (bach) survey. am j epidemiol. 2008;167:390-9. 22. dooley y, kenton k, cao g, et al. urinary incontinence prevalence: results from the national health and nutrition examination survey. j urol. 2008;179:656-61. 23. goode ps, burgio kl, redden dt, et al. population based study of incidence and predictors of urinary incontinence in black and white older adults. j urol. 2008;179:1449-53. 24. bump rc. racial comparisons and contrasts in urinary incontinence and pelvic organ prolapse. obstet gynecol. 1993;81:421-5. 25. moller la, lose g, jorgenson t. risk factors for lower urinary tract symptoms in women 40-60 years of age. obstet gynecol. 2000;96:446-51. 26. gungor i, beji nk. lifestyle changes for the prevention and management of lower urinary tract symptoms in women. int j urol nurs. 2011;5:3-13. avicenna’s point of view vs. contemporary findings-nojavan et al urology journal unrc/iua vol. 2, no. 1, 32-35 winter 2005 printed in iran 32 kidney transplantation effect of antibiotic therapy on asymptomatic bacteriuria in kidney transplant recipients mahmoudreza moradi*, mohammadreza abbasi, as'ad moradi, ali boskabadi, amir jalali urology and nephrology research center, kermanshah university of medical sciences, kermanshah, iran abstract purpose: asymptomatic bacteriuria is a very common complication after kidney transplantation and the need for antibiotic therapy is controversial. the aim of this study was to evaluate the effect of antibiotic therapy on the clinical course of asymptomatic bacteriuria in renal transplant recipients. materials and methods: in the present study, 88 kidney transplant recipients with asymptomatic bacteriuria were divided into two groups of cases and controls. the patients had been selected from among those with at least 1 year follow-up. in the case group, asymptomatic bacteriuric episodes were treated with antibiotics, and in control group, they were followed without antibiotic therapy. the follow-up period was 9 to 12 months. bacteriuric episodes, symptomatic urinary tract infection (uti) episodes, and changes in plasma creatinine level were recorded and compared between the two groups. results: the rate of bacteriuric episodes and symptomatic utis were not significantly different between the two groups (p >0.05). in addition, level of plasma creatinine did not increase significantly in neither of the groups during the study (p >0.05). conclusion: it seems that treatment of asymptomatic bacteriuria in kidney recipients does not decrease the rate of uti episodes afterwards. asymptomatic bacteriuria does not affect renal function in short term. thus, we can abandon antibiotic therapy, subject to careful follow-up. key words: antibiotic therapy, asymptomatic bacteriuria, kidney transplant introduction urinary tract infection (uti) is the most common infection after renal transplantation.(1) if left untreated, it has proved harmful effect on allograft function and survival, in addition to infectious complications.(2) asymptomatic bacteriuria is also very common in these patients; however, its negative effect on patient and transplanted kidney has not been proved, yet.(3) in general, treatment of asymptomatic bacteriuria is not useful in non-pregnant patients with normal immune system,(4) and has no positive effect on later incidence of uti. in kidney recipient patients, however, it can be of benefit if antibiotic therapy of asymptomatic bacteriuria can decrease later symptomatic infections. otherwise, if we cannot change the incidence of infections by medication, it will received september 2003 accepted january 2005 *corresponding author: department of urology, 4th shaheed-e-mehrab hospital, doalatabad blvd. kermanshah, iran. e-mail: drmrmoradi@yahoo.com moradi et al 33 impose a burden of potential side effects as well as the excessive costs on these patients. this study was performed to evaluate the short-term effects of antibiotic therapy in asymptomatic bacteriuria on subsequent incidence of uti and also on graft function in kidney recipients. materials and methods in a clinical trial, 50 male and 50 female renal transplant recipients with asymptomatic bacteriuria entered the study, from march 2002 to february 2003. asymptomatic bacteriuria was defined as pyuria and bacteriuria in urine analysis, positive culture with colony count greater than 100000 of one organism, and the absence of irritative voiding symptoms, fever, and chills. all of the selected patients were older than 18 years old and had at least one year posttransplantation follow-up. none of the patients had indwelling urethral catheter or ureteral stent. etiologies of renal failure in these patients were hypertension, diabetes mellitus, urinary stones, and glomerulonephritis (table 1). all of the patients underwent urinalysis, urine culture, colony count, and plasma creatinine level tests. patients with proteus infection were excluded from the study because of high risk of stone formation and emphasis on their treatment. according to the order of patients' transplant code, they were divided into two groups of case and control, in every other one manner. afterwards, they were informed about the study, in detail, and informed written consent was taken. in case group, a 10-day oral antibiotic therapy (according to antibiogram) was administered and the patients were asked to return two weeks later (3 to 4 days after antibiotic therapy period). after resolving bacteriuria, confirmed by urine culture, the patients were asked to return for follow-up one month later. the patients in control group were left untreated and followed one month later with urinalysis and urine culture. in each group, monthly visits continued, assessing urinalysis, urine culture, creatinine serum level, and bun in addition to history and physical examination. in case of bacteriuria and positive culture in case group, treatment would be repeated. standard treatment for symptomatic urinary tract infection would be done in both groups, if any, and when eradication of infectious organism was confirmed by repeat culture, the patients would return to their respective group. all of the patients were followed for 9 to 12 months. the patients with lost follow-up visits, acute rejection, and pyelonephritis leading to hospitalization during the study were excluded. collected data were analysed using spss 9.0 software. chi-square test was used to compare categorical variables and t test to compare normally distributed continuous variables, considering p value less than 0.05 as significant. results twelve patients were excluded of the study, 11 because of lost follow-up visits and 1 because of acute pyelonephritis, and eventually, data from 88 patients were analyzed. there were 43 patients in the case group (20 males and 23 females) and 45 ones in control group (20 males and 25 females). mean ages of case and control groups were 44.2 ± 12.7 (range 19 to 62) years and 40.9 ± 13.2 (range 20 to 70) years (p >0.05). table 1. etiologies of renal failure in case and control groups table 2. pathogen organisms isolated at the first bacteriuria episode etiology case group (%) control group (%) total (%) hypertension 20 (46.5) 18 (40) 38 (43.1) diabetes mellitus 6 (13.9) 7 (15.6) 13 (14.8) glomerulonephritis 3 (6.9) 8 (17.8) 11 (12.5) urolithiasis 4 (9.3) 5 (11.1) 9 (10.2) polycystic kidney 1 (2.3) 4 (8.9) 5 (5.7) chronic pyelonephritis 2 (4.6) 3 (6.7) 5 (5.7) gout 2 (4.6) 2 (4.5) 4 (4.6) tuberculosis 2 (4.5) 2 (2.3) kidney hypoplasia 1 (2.3) 1 (2.2) 2 (2.3) lupus erythematosus 1 (2.3) 1 (1.1) pathogen case group (%) control group (%) e. coli 30 (69.7) 27 (60) klebsiella 3 (6.9) 6 (13.4) pseudomonas 4 (9.3) 3 (6.7) streptococcus-beta 2 (4.6) 1 (2.2) coagulase negative staphylococcus 2 (4.6) 3 (6.7) enterobacter 1 (2.3) 2 (4.5) gram positive cocci 1 (2.3) 3 (6.7) total 43 45 antibiotic therapy in kidney transplant recipients with asymptomatic bacteriuria34 the most common organisms in the patients at the first episode of bacteriuria were escherichia coli in 57 patients, klebsiella in 9, and pseudomonas in 6 (table 2). recurrence of bacteriuria developed in 25 cases (58.1%) and 33 controls (73.3%) (p >0.05). among these patients, mean number of bacteriuria episodes were 2.15 (range 1 to 6) and 1.58, respectively (range 1 to 9) (p >0.05, table 3). nine patients in case group and 14 patients in control group were affected with symptomatic urinary infection (21% vs. 31%, p >0.05). in case group symptomatic infection occurred once, twice, and three times in 5, 3, and 1 patients, respectively; while in the control group, it was seen once, twice, three times, and four times in 7, 4, 2, and 1 patients, respectively (p >0.05). mean plasma creatinine level was 1.16 ± 0.27 mg/dl and 1.42 ± 0.67 mg/dl in case and control groups, respectively (p >0.05), which changed to 1.2 ± 0.55 mg/dl and 1.43 ± 0.56 mg/dl at the end of the study (t and paired t tests, p >0.05). discussion to preserve renal function and prevent or treat acute allograft rejection, kidney transplant recipients require immunosuppressive therapy. however, any kind of immunosuppressive therapy can lead to the development of infections. among renal transplant recipients, uti is the most common type of infection and the most common cause of septicemia.(1,5,6) uti can present as asymptomatic bacteriuria, acute cystitis, pyelonephritis, and septicemia. goya et al detected uti in 20.8% of hospitalized patients and 4.2% of outpatients, of whom 40% were symptomatic and the remainder were asymptomatic.(3) two aspects of the effect of bacteriuria on transplant recipients should be considered: first, morbidity and mortality caused by the infection; and second, potential effects of infection on developing rejection and its clinical course. risk of bacteremia accompanying uti in these patients is nearly 12% and gram negative bacteria are the most common pathogens; however, gram positive bacteria such as enterococcus and staphylococcus are also the potential causes.(5) in a study by muller et al, they evaluated the relationship between uti and biopsy proven chronic rejection. the patients were followed for 5 years and it was found that patients with chronic rejection had had more episodes of uti comparing to those without rejection. microbial antibodies can result in tnf-α, if-δ, and il-6 production, which have important roles in chronic rejection process.(1) morbidity accompanying uti depends on the time of its occurrence after transplantation.(6) uti is very common in the first weeks after transplantation and is usually diagnosed faster in this period. mean interval between the beginning of infection and clinical manifestations is about 4 to 7 days.(7) if left untreated with a standard antibiotic therapy course in the first month, it often results in pyelonephritis, bacteremia, and recurrence.(8) thus, treatment for all nosocomial urinary infections or infections accompanying bacteremia or pyelonephritis should be started with parenteral antibiotic therapy and be continued until the culture is negative. thereafter, depending on the sensitivity of organism, the oral antibiotic therapy should be administered for 2 to 6 weeks. urinary infection in outpatients during the first three months after operation should be also treated with oral antibiotic therapy for 6 weeks. a shorter treatment period of 10 to 14 days is usually accompanied by higher risk of recurrence.(6) urinary infections are usually more benign after the first 3 to 6 post-transplant months and, not differing from urinary infection in general population, they could easily be treated with a standard 10to 14-day antibiotic therapy. however, increasing urinary infection episodes is associated with a higher risk of chronic rejection.(9) but, takai did not find any significant difference between kidney recipients with and those without urinary infection in a 3year follow-up.(10) due to high prevalence of urinary infection within the first post-transplant weeks and table 3. comparison of the number of bacteriuric episodes between the two groups number of episodes case group (%) control group (%) total 1 11 (25.6) 17 (37.8) 28 2 7 (16.3) 10 (22.3) 17 3 2 (4.6) 1 (2.2) 3 4 3 (6.9) 1 (2.2) 4 5 1 (2.3) 1 (2.2) 2 6 1 (2.3) 2 (2.5) 3 9 1 (2.2) 1 total 25 (58.1) 33 (73.3) 58 moradi et al 35 months, high risk of urinary infections leading to bacteremia and sepsis, and high susceptibility of kidney allograft to parenchymal infection, in most centers, they use prophylactic oral antibiotic therapy continuously during the first months. duration of prophylaxis may alter; it continues at least 3 to 4 months, but in some centers, it may last up to 1 year.(11) asymptomatic bacteriuria is commonly seen in kidney transplant recipients. there is a direct relation between bacterial accumulation, diuresis, and renal function. colony count decreases by increasing urine outflow and subsequent bacterial dilution.(3) most of the authors recommend antibiotic therapy for asymptomatic bacteriuria in the first months after transplantation. there is no consensus about the period of therapy and also it is not clear yet whether to treat every episode of asymptomatic bacteriuria after the first months or not. stein and funfstruck recommend treating every episode of bacteriuria with or without symptoms.(12) sayegh has also recommended antibiotic therapy for a period of 10 to 14 days in these cases.(6) on the other hand, some authorities recommend that asymptomatic bacteriuria, occurring after the first posttransplant months, must be carefully followed and we should warn patients of symptoms and begin antibiotic therapy when clinical manifestations are present.(1) in our study, we studied only the patients who had undergone transplantation at least one year before. the two case and control groups were matched for sex in order to eliminate the intruding effect of this factor. the recurrence rate of bacteriuria and symptomatic urinary infection were slightly higher in the case group, but the differences between the two groups were not statistically significant. in other words, antibiotic therapy in asymptomatic bacteriuria did not decrease recurrence of bacteriuria and incidence of symptomatic infection. in addition, there was not a significant difference in the number of bacteriuria or symptomatic infection episodes. analyzing serum creatinine level at the beginning and at the end of the study showed increase in neither of the groups. thus, it seems that asymptomatic bacteriuria does not affect kidney allograft function in a short-time period. conclusion asymptomatic bacteriuria after transplantation is a benign condition which commonly recurs; although most of the patients will have symptomatic urinary infection in the future, antibiotic therapy cannot decrease the rate of bacteriuria recurrence or impending urinary infections. furthermore, asymptomatic bacteriuria and its recurrence do not adversely affect allograft function in short-time. thus, it seems that if asymptomatic bacteriuria is carefully followed after the first year of transplantation, we can abandon antibiotic therapy. references 1. abbott kc, oliver jd 3rd, hypolite i, et al. hospitalizations for bacterial septicemia after renal transplantation in the united states. am j nephrol. 2001;21:120-7. 2. muller v, becker g, delfs m, albrecht kh, philipp t, heemann u. do urinary tract infections trigger chronic kidney transplant rejection in man? j urol. 1998;159:1826-9. 3. goya n, tanabe k, iguchi y, et al. prevalence of urinary tract infection during outpatient follow-up after renal transplantation. infection. 1997;25:101-5. 4. gleckman r. the controversy of treatment of asymptomatic bacteriuria in non-pregnant women-resolved. j urol. 1976;116:776-7. 5. burgos revilla fj, pascual santos j, marcen letosa r, et al. [renal transplantation and urinary infection. review]. actas urol esp. 1999;23:95-104. spanish. 6. mohammad hs. urinary tract infection in renal transplant recipients. in: rose bd, editor. uptodate. wellesley: 2001;9(3). [cd-rom]. 7. kentouni-noly jc, cloix p, martin x, rabodonirina m, lefrancois n, sepetjan m. analysis of nosocomial infections in renal transplant and pancreas transplant recipients. transplant proc. 1994;26:284. 8. tolkoff-rubin ne, rubin rh. urinary tract infection in the immunocompromised host. lessons from kidney transplantation and the aids epidemic. infect dis clin north am. 1997;11:707-17. 9. tolkoff-rubin ne, cosimi ab, russell ps, rubin rh. a controlled study of trimethoprim-sulfamethoxazole prophylaxis of urinary tract infection in renal transplant recipients. rev infect dis. 1982;4:614-8. 10. takai k, tollemar j, wilczek he, groth cg. urinary tract infections following renal transplantation. clin transplant. 1998;12:19-23. 11. barry jm. renal transplantation. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.345-76. 12. stein g, funfstuck r. [asymptomatic bacteriuria]. med klin (munich). 2000;95:195-200. german. 1 short title: ureterocele double-puncture technique a step-by-step guide to double-puncture technique for endoscopic management of ureterocele authors: behnam nabavizadeh1, reza nabavizadeh2, abdol-mohammad kajbafzadeh1* affiliations: 1 pediatric urology and regenerative medicine research center, children's medical center, tehran university of medical sciences, tehran, iran 2 department of urology, emory university school of medicine, atlanta, georgia, usa * corresponding author: a m. kajbafzadeh pediatric urology and regenerative medicine research center, children's medical center, tehran university of medical sciences, no.62, dr. gharib street, keshavarz boulevard, tehran, iran p.o. box: 1419733151 email: kajbafzd@sina.tums.ac.ir tel: + 98-21-66565400 fax: + 98-21-66565400 mailto:kajbafzd@sina.tums.ac.ir 2 summary to date, the optimal surgical technique for treatment of ureterocele remains unclear and the available options are variable. the endoscopic techniques that are gaining popularity mostly share major drawbacks including low success rate, high probability of mandatory secondary surgery and de novo vesicoureteral reflux to the ureterocele moiety. the double-puncture technique is shown to have promising outcomes in terms of long-term success and low rate of complications. in this video, a step-by-step guide to this technique is presented. background: optimal management of ureterocele is still a challenging topic in pediatric urology [1]. over the past two decades, treatment approaches have shifted towards more minimally invasive endoscopic techniques [2]. however, these techniques have common drawbacks such as low success rate, high probability of reoperation, de novo vesicoureteral reflux (vur), and high rates of urinary tract infections. herein, we aim to present a step-by-step guide to the doublepuncture technique for endoscopic management of ectopic and large orthotopic ureteroceles in children; which is shown to have a higher success rate [3]. material: initially in this technique (video 1), the stylet of a 3 fr ureteral stent and the pusher is passed through the working channel of cystoscope. the distal puncture is created in the most distal part of the ureterocele. afterwards, the stylet is passed upward through the ureterocele to meet the roof of the ureterocele and the proximal puncture is made at the most proximal part of the ureterocele. while the pusher remains in the current position, the stylet is removed and guidewire is inserted. then, a double-j stent is passed over the guidewire through the both punctured sites. next, the cystoscope is passed next to the double-j stent through the distal puncture site. using an electrode (3 fr bugbee set at low coagulation current [15 w]), the collapsed walls of the 3 ureterocele is fulgurated at multiple sites under direct visualization. urine channel continuity is preserved by the double-j stent. results: immediate decompression of ureterocele is achieved by making the two puncture sites. long-term decompression is achieved with fulguration and adhesion of ureterocele walls at multiple points. the urine channel inside the ureterocele is formed by maintaining a double-j stent through the two punctured sites and intraureterocele fulguration (similar to tailoring of dilated ureters in open surgery). double-j stent is retrieved about 2 weeks post-operatively using extraction string. the channel with a diameter comparable to double-j stent will remain patent after stent removal. conclusion: long-term outcomes in patients treated with the double puncture technique, shows development of de novo vur in 3.9% of the patients which is considerably lower compared to other endoscopic techniques [3]. this can be explained by the fulguration of ureterocele epithelial walls that provides wall adhesion and subsequent muscular backing to minimize the risk of de novo vur to the ureterocele moiety. additionally, the new intramural channel with patent orifices at each end allows urine drainage from the upper puncture during bladder contraction, which can reduce vur due to outlet obstruction and ureterocele bulging [4]. in conclusion, double-puncture technique is a successful endoscopic technique for management of ureterocele with lower postoperative complications and more favorable long-term outcomes. keywords: ureterocele; endoscopic management; double-puncture conflicts of interest: none. 4 references [1] gander r, asensio m, royo gf, lloret j. evaluation of the initial treatment of ureteroceles. urology 2016;89:113-7. [2] haddad j, meenakshi-sundaram b, rademaker n, greger h, aston c, palmer bw, et al. "watering can" ureterocele puncture technique leads to decreased rates of de novo vesicoureteral reflux and subsequent surgery with durable results. urology 2017;108:161-5. [3] nabavizadeh b, nabavizadeh r, kajbafzadeh am. a novel approach for an old debate in management of ureterocele: long-term outcomes of double-puncture technique. j pediatr urol 2019. [4] kajbafzadeh a, salmasi ah, payabvash s, arshadi h, akbari hr, moosavi s. evolution of endoscopic management of ectopic ureterocele: a new approach. j urol 2007;177:1118-23; discussion 23. letters 210 urology journal vol 5 no 3 summer 2008 re: laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal ureteral tumor sir, the article by basiri and coworkers details their experience with a patient with low-grade ureteral cancer on whom they performed laparoscopic distal ureterectomy with a subsequent reconstruction using the boari flap.(1) the present article helps to add evidence regarding feasibility and safety (technical and functional) of pure laparoscopic partial ureterectomy. although it is evident that open nephroureterectomy has been standardized and can, to date, guarantee acceptable perioperative morbidity, allowing reproducible long-term oncologic results for ureteral cancer, it appears from their experience that when the candidates for surgery are appropriately selected and there is a dedicated surgical team for laparoscopy, these goals are achievable. roupret and colleagues retrospectively reviewed 6 patients with lowgrade upper urinary tract transitional cell carcinoma treated laparoscopically, concluding that laparoscopic distal ureterectomy with reimplantation is technically possible for low-risk low-grade upper urinary tract transitional cell carcinoma.(2) at this point, the exact role of laparoscopic partial ureterectomy is still under careful evaluation, as data from the literature are limited, especially regarding important issues such as long-term results and the feasibility of urinary reconstruction, which remains technically challenging.(3) their report is noteworthy since they give us information about subsequent laparoscopic boari flap, detailing important surgical steps. apparently, initial goal will be to provide the same outcome as in a standard open procedure with the hope that in the future, as we gain more experience, learning curve will provide an improvement in terms of less blood loss and a decrease in length of hospital stay. teruo inamoto haruhito azuma yoji katsuoka department of urology, osaka medical college, osaka, japan e-mail: tinamoto@poh.osaka-med.ac.jp references 1. basiri a, karami h, mehrabi s, javaherforooshzadeh. laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal ureteral tumor. urol j. 2008;5:120-2. 2. roupret m, harmon jd, sanderson km, et al. laparoscopic distal ureterectomy and anastomosis for management of low-risk upper urinary tract transitional cell carcinoma: preliminary results. bju int. 2007;99:623-7. 3. uberoi j, harnisch b, sethi as, babayan rk, wang ds. robot-assisted laparoscopic distal ureterectomy and ureteral reimplantation with psoas hitch. j endourol. 2007;21:368-73. 171 urology journal unrc/iua vol. 2, no. 3, 171-173 summer 2005 printed in iran introduction it is well documented that patients with renal failure suffer from some degree of cardiovascular illnesses.(1) in chronic uremia, cardiovascular disease manifests as concentric left ventricular hypertrophy, left ventricular dilatation, systolic dysfunction, or diastolic dysfunction.(2) these conditions create a predisposition for developing heart failure, arrhythmias, and sudden death,(3) which can be prevented with renal transplantation.(4,5) we report 2 patients with end-stage renal disease (esrd) and severe systolic dysfunction with multivalvular dysfunction whose cardiac indexes improved considerably after kidney transplantation. case reports two girls (20 and 15 years old) with esrd, the first due to an unknown etiology and the other due to a suicide attempt with nephrotoxic drugs, presented with severe dyspnea, high blood pressure, and anemia. both had been on hemodialysis for about 2 years. on admission, because of massive pericardial effusion, pericardiotomy was performed for the first patient. both patients were candidates for heart transplantation because of severe refractory congestive heart failure (chf). echocardiographic findings were left ventricular ejection fractions (lvef) of 15% to 20%, mitral regurgitation (mr), aortic insufficiency (ai), tricuspid regurgitation (tr), and severe cardiomegaly, for both of them. after medical management of chf for 1 month, the best achieved lvefs were 20% to 25%. both patients underwent kidney transplantation. the operations were successful with functional allografts. three months after transplantations, patients' cardiovascular conditions were assessed. both patients were asymptomatic, and echocardiographic findings were suggestive of a considerable increase in lvef, improvement of mr, ai, and tr, and moderate cardiomegaly. laboratory and echocardiographic findings before and after transplantation are presented in table 1. after 1 year's follow-up, both patients' lvef values reached acceptable levels (about 65%), and their valvular disorders have improved considerably. there was no need for any medication other than maintenance immunosuppressive triple-therapy. chest radiographs of the first patient, before and after surgery, are presented in figures 1a and 1b. discussion kidney transplantation has a beneficial impact on the uremic patient's cardiomyopathy, whether it manifests as left ventricular hypertrophy, left ventricular dilatation, or systolic dysfunction.(2) left ventricular dilatation is significantly reduced following transplantation.(2,4) four types of valvular dysfunctions may be observed in patients with chronic renal failure: calcification due to polycystic kidney disease or secondary improvement of severe heart failure with multivalvular dysfunction after kidney transplantation majid aliasgari,1 farid dadkhah,1 ahmad tara,1 hamid noshad,1 hamed akhavizadegan,2* gity birashk1 1department of urology, shaheed modarres hospital, shaheed beheshti university of medical sciences, tehran, iran 2department of urology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran key words: end-stage renal disease, heart failure, valvular dysfunction, kidney transplantation received february 2005 accepted may 2005 *corresponding author: shaheed labbafinejad medical center, 9th boustan st, pasdaran ave, tehran, iran. tel: ++98 21 2254 9010-16 e-mail: hamed_akhavizadegan@yahoo.com heart failure with multivalvular dysfunction and kidney transplantation172 hyperparathyroidism, dilated cardiomyopathy, primary valvular heart disease, and valvular diseases due to systemic disorders (anemia, overload, hyperadrenergism, and arteriovenous fistula). only the first two groups need valve replacements.(6) there have been reports on cardiovascular outcomes in chf after kidney transplantation.(4,5) many researchers have studied the effects of kidney transplantation on heart pathology due to esrd, but none of their cases had been with lvefs below 50%.(2,4,5) although patients with lower ejection fractions have been reported,(7-9) none of them demonstrated significant multivalvular dysfunction. it is known that some degree of left ventricular hypertrophy and probably heart failure improve after successful kidney transplantation.(2) both of our patients had severe chf, with marked multivalvular dysfunction and neither responded to medical treatment. some have used angiography to rule out coronary artery disease or cardiac biopsy.(10) we did not do so, because no heart-related risk factors (other than uremia) were present. both of our patients were candidates for cardiac transplantation owing to severe heart failure. in conclusion, patients with esrd, heart failure, and multivalvular dysfunction, should not be offered early cardiac transplantation, even if cardiovascular complications are severe. both overt heart failure and multivalvular dysfunction are reversible with kidney transplantation. presence of multivalvular dysfunction seems not to be necessarily an alarmingly poor prognosis for cardiac outcome after kidney transplantation. young patients with multivalvular dysfunction and with no primary cardiogenic dysfunction or risk factors of coronary artery disease are especially good candidates, even without invasive cardiac workup. references 1. levin a, foley rn. cardiovascular disease in chronic renal insufficiency. am j kidney dis. 2000;36(6 suppl 3):s24-30. 2. ferreira sr, moises va, tavares a, pacheco-silva a. cardiovascular effects of successful renal transplantation: a 1-year sequential study of left fig. 1. a. chest radiograph before transplantation, b. chest radiograph 1 month after transplantation table 1. laboratory and echocardiographic findings before and after transplantation ef: ejection fraction, mr: mitral regurgitation, ai: aortic insufficiency, tr: tricuspid regurgitation hemoglobin blood pressure ef mr ai tr preoperative 7 mg/dl 180/90 mm hg 20% 3+ 3+ 2+ case 1 (20 years old) postoperative 50% 2+ 1+ 1+ preoperative 6 mg/dl 180/100 mm hg 25% 2+ 1+ 3+ case 2 (15 years old) postoperative 50% 1+ 1+ 1+ aliasgari et al 173 ventricular morphology and function, and 24-hour blood pressure profile. transplantation. 2002;74:1580-7. 3. levey as. controlling the epidemic of cardiovascular disease in chronic renal disease: where do we start? am j kidney dis. 1998;32(5 suppl 3):s5-13. 4. kobori g, moroi s, yoshida h, et al. [marked improvement of cardiac function following renal transplantation: a case report]. hinyokika kiyo. 2003;49:17-9. japanese. 5. rigatto c, foley rn, kent gm, guttmann r, parfrey ps. long-term changes in left ventricular hypertrophy after renal transplantation. transplantation. 2000;70:570-5. 6. straumann e, meyer b, misteli m, blumberg a, jenzer hr. aortic and mitral valve disease in patients with end stage renal failure on long-term haemodialysis. br heart j. 1992;67:236-9. 7. harnett jd, foley rn, kent gm, barre pe, murray d, parfrey ps. congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. kidney int. 1995;47:884-90. 8. fleming sj, caplin jl, banim so, baker lr. improved cardiac function after renal transplantation. postgrad med j. 1985;61:525-8. 9. van den broek jh, boxall ja, thomson nm. improved left ventricular function after renal transplantation. med j aust. 1991;154:279-80. 10. burt rk, gupta-burt s, suki wn, barcenas cg, ferguson jj, van buren ct. reversal of left ventricular dysfunction after renal transplantation. ann intern med. 1989;111:635-40. 1736 | pictorial remission of a renal artery stenosis after laparoscopic removal of an extra adrenal paraganglioma augustin pirvu, sebastien guigard, philippe chaffanjon corresponding author: augustin pirvu, md département de chirurgie thoracique et endocrinienne, chu de grenoble, bp 217, grenoble cedex 09, 38043 france. tel: +33 476 7693 11 fax: +33 476 7651 08 e-mail: pb_augustin@yahoo. com;apirvu@chu-grenoble.fr received may 2013 accepted april 2014 department of thoracic and endocrine surgery, university hospital of grenoble, grenoble, france. a 44-year-old hypertensive man was referred to our department for an infradiaphragmatic right-sided suprarenal mass. biological examinations were compatible with a pheochromocytoma. a computed tomography (ct) scan revealed a 28 × 23 mm mass located upper an ipsilateral renal artery stenosis (figure 1). the tumor was resected by a laparoscopic transperitoneal approach. on histopathological examination the diagnosis of extra adrenal paraganglioma was confirmed. the postoperative course was uneventful. one month later, the control ct scan demonstrated complete restoration of the diameter of the right renal artery (figure 2). the association between pheochromocytoma and a renal artery stenosis is a rare condition.(1,2) if stenosis is mainly due to a local compression by the tumor, in a few cases it can only be explained by the mechanism of an arterial vasospasm due to the local catecholamine secretion. in the treatment sequences, in order to avoid the therapeutic pitfalls, a high degree of suspicion is necessary.(1-3) in the case of simultaneous occurrence of pheochrocytoma and renal artery stenosis, the surgical resection of the tumor must be performed in the first step because the renal artery stenosis may regress spontaneously after surgery. endovascular or open surgical revascularization for the renal artery stenosis is reserved only for persistent or recurrent stenosis.(3) pictorial figure 1. a computed tomography scan shows a 28 × 23 mm mass located upper an ipsilateral renal artery stenosis. figure 2. one month later, the control computed tomography scan demonstrates complete restoration of the diameter of the right renal artery references 1. vaze d, trehan a, saxena a, joshi k, narasimhan kl. extraadrenal pheochromocytoma with renal artery "pseudostenosis"-an important pitfall. urology. 2012;80:925-7. 2. gill is, meraney am, bravo el, novick ac. pheochromocytoma coexisting with renal artery lesions. j urol. 2000;164:296-301. 3. chandra v, thompson gb, bower tc, taler sj. renal artery stenosis and a functioning hilar paraganglioma: a rare cause of renovascular hypertension--a case report. vasc endovascular surg. 2004;38:385-90. giant urethral caruncle presenting as genital prolapse fatih hizli,1 kadir çetinkaya,2 gülay bilir,3 halil başar1 departments of urology,1 obstet rics and gynecology2 and pathol ogy,3 oncology training and re search hospital , ankara, turkey. corresponding author: fatih hizli, md. department of urology, oncology training and research hospital, 06530 demetevler, ankara, turkey. tel: +90 312 336 0909/5607 fax: +90 312 345 4979 e-mail: fatihhizli33@yahoo.com received july 2013 accepted december 2013 keywords: urethral diseases; diagnosis; diverticulum; female; differential; diagnostic errors. introduction urethral caruncles usually arise from the posterior lip of the urethral meatus. although the etiology of urethral caruncles is still undetermined, they are the most common benign tumors of the female urethra.(1) most cases are frequently asymptomatic, but, sometimes patients feel a lump or bleeding at the urethral meatus. symptoms are dysuria, dyspareunia, hematuria and rarely asensation of pressure in the perineal region. in this report we present a case of urethral caruncle mimicking a genital prolapse. case report a 56-year-old woman was referred to the urology clinic with hematuria and a feeling of a lump in her genital region. complaints of dysuria and dyspareunia were also emphasized by the patient. there was no stress or urge incontinence. when she became aware of the mass, she visited a gynecology clinic and was referred to our clinic. our patient entered the menopausal period 7 years ago. on pelvic examination, there was a 6 × 3 cm lump protruding circumferentially from the urethra and suggesting urethral caruncle macroscopically at the external urethral meatus looking like a genital prolapse (figure 1). there was no cystocele view observed. the lesion was reddish, raspberry-like and a bloody leakage occurred upon touching. the patient was placed in the dorsolithotomy position under regional anesthesia. initially, we performed urethrocystoscopy, which revealed no abnormal lesions in either the bladder or urethra. the vulvar skin, vaginal mucosa and cervical region had normal appearance. rectal examination was non-revealing. the lesion was totally resected and an 18 french (f) foley silicon catheter was placed for urine drainage. the postoperative period was uneventful and no signs of residual complaints were ob1841 case report case report urology journal vol. 11 no. 04 july august 2014 1842 urethral caruncle-hizli et al treatment modalities including steroid and estrogen creams for a few years, but in the end the lesion did not regress. finally, the lesion was totally resected circumferentially and the patient was cured. in this case, a giant urethral caruncle affected the patient’s quality of life. the urethral caruncle caused an obstruction by its mass effect. urethral caruncles are the most common lesions of the urethra among elderly and middle aged women. a urethral caruncle resembling a genital prolapse has been reported in the literature.(11) conclusion to the best of our knowledge, our patient is the second reported case of urethral caruncle resembling a genital prolapse in the english literature. thus, a patient’s situation should be carefully observed when conservative therapy is selected. great or persistent caruncles and those with an abnormal view should be surgically treated aggressively and carefully evaluated and pursued for the presence of any potential malignancy. conflict of interest none declared. references 1. cimentepe e, bayrak o, unsal a, koç a, ataoğlu o, balbay md. ure thral adenocarcinoma mimicking urethral caruncle. int urogynecol j pel vic floor dysfunct. 2006;17:96-8. 2. pugh rc. the kidneys: the urinary tract. systemic pathology. 3rd edition. philadelphia, pa: w.b. saunders company; 1992. p. 745. 3. conces mr, williamson sr, montironi r, lopez-beltran a, scarpelli m, cheng l. urethral caruncle: clinicopathologic features of 41 cases. hum pathol. 2012;43:1400-4. 4. türkeri l, simšek f, akdaş a. urethral caruncle in an unusual location occurring in prepubertal girl. eur urol. 1989;16:153-4. served. the patient was discharged on the second postoperative day, and the urethral catheter was removed on the seventh day. microscopic examination of the specimen revealed a transitional epithelium covering the stroma with inflammation and extravasated red blood cells and prominent vascularity observed (figure 2). histopathologic examination of the urethral lesion was reported as a urethral caruncle. discussion urethral caruncles are the most common lesions of the urethra among females. they occur commonly in middle aged and elderly women. they are inflammatory nodules arising at the posterior lip of the external meatus, present as solitary, soft, raspberry-like pedunculated tumors and are commonly seen after menopause.(1) grossly, caruncles are nodular or pedunculated erythematous lesions that may bleed easily.(2) caruncles microscopically involve dense polymorphous infiltrate rich in lymphocytes, which is common to all types, but other reactive patterns may predominate. these include fibrocapillary proliferation (granulomatous), epithelial hyperplasia (papillomatous), hypervascularity (angiomatous) and also intestinal metaplasia (mucinous). urethral caruncles in 32% of cases are asymptomatic and usually are found in postmenopausal women.(3) when present, the most common symptoms are dysuria, pain or discomfort, dyspareunia and rarely bleeding. the mass is quite swollen and bleeds easily.(4) although the caruncles are considered as benign tumors, they need to be treated with surgical intervention; pathologic specimens should carefully be evaluated for having any malignancy and treatment plans established based on the results. when the lesion is atypical in view or behavior, surgical excision may be required to exclude other entities. malignant melanoma, non-hodgkin’s lymphoma, tuberculosis, intestinal metaplasia and ovarian tumor have been reported either to coexist with or to mimic urethral caruncles.(5-9) the management of a urethral caruncle consists of local surgical excision, cryotherapeutic ablation or, conservatively, local application of estrogen and steroid creams.(10) the patient in this case had various figure 1. (a) intraoperative appearance of the lesion, (b) view of excised lesion. figure 2. histopathologic appearance of the urethral caruncle (hematoxylin & eosin, × 40). 5. indudhara r, vaidyanathan s, radotra bd. urethral tuberculosis. urol int. 1992;48:436-8. 6. khatib ra, khalil am, tawil an, shamseddine ai, kaspar hg, suidan fj. non-hodgkin’s lymphoma presenting as a urethral caruncle. gynecol oncol. 1993;50:389-93. 7. lopez ji, angulo jc, ibanez t. primary malignant melanoma mimicking urethral caruncle. case report. scand j urol nephrol. 1993;27:125-6. 8. willett gd, lack ee. periurethral colonic-type polyp simulating urethral caruncle. a case report. j reprod med. 1990;35:1017-8. 9. atalay ac, karaman mi, basak t, utkan g, ergenekon e. non-hod gkin’s lymphoma of the female urethra presenting as a caruncle. int urol nephrol. 1998;30:609-10. 10. singh i, hemal ak. primary urethral tuberculosis masquerading as a ure thral caruncle: a diagnostic curiosity! int urol nephrol. 2002;34:101-3. 11. lammes fb. [diagnostic image (110). an elderly woman with micturiti on problems. caruncle urethrae in genital prolapse]. ned tijdschr gene eskd. 2002;146:1984. 1843 case report urological oncology comparative evaluation of urinary bladder cancer antigen and urine cytology in the diagnosis of bladder cancer mohammad ali zargar shoshtari,1 mohammadjavad soleimani,1 mohammadkazem moslemi2* 1department of urology, shaheed hasheminejad hospital, iran university of medical sciences, tehran, iran 2department of urology, kamkar hospital, qom university of medical sciences, qom, iran abstract introduction: the diagnostic value of the urinary bladder cancer (ubc) antigen as a tumor marker is not clear yet. we designed this study to compare the accuracy of the ubc antigen and voided urine cytology in patients with bladder cancer. materials and methods: fifty-four consecutive patients admitted for a diagnostic workup for bladder cancer were enrolled. two voided urine samples were taken for urinalysis, both before performing cystoscopy. the samples were examined for urinary urine cytology and ubc antigen. cystoscopy was done. resection of pathologic lesion, if any, or random biopsies of multiple foci of the bladder was performed. the results of the diagnostic tests were compared with the pathology examination results. results: of 54 patients, 31 had histologically confirmed transitional cell carcinoma. results were positive for ubc antigen in 28 and for urine cytology in 16 patients. sensitivities and specificities were 74.2% and 78.3% for ubc antigen, 48.4% and 95.7% for urine cytology, and 87.1% and 73.9% for combined ubc antigen and cytology, respectively. positive and negative likelihood ratios were 3.42 and 3.03 for ubc antigen, 11.3 and 1.85 for urine cytology, and 3.34 and 5.73 for combined ubc antigen and cytology, respectively. conclusion: the ubc antigen test had acceptable sensitivity and specificity in our study. however, results of voided urine cytology are significantly more reliable. a combination of tumor markers may help diagnose new tumors and lower the requirements for cystoscopy during follow-up. further studies are warranted to find a more accurate noninvasive test or a complex of tests comparable with cystoscopy for diagnosis of bladder cancer. key words: bladder cancer, diagnosis, tumor marker, urine cytology, urinary bladder cancer antigens 137 urology journal unrc/iua vol. 2, no. 3, 137-140 summer 2005 printed in iran introduction bladder cancer is more prevalent in men, being the second most common malignancy in older men, following prostate cancer.(1) painless gross hematuria is a hallmark, but nonspecific symptoms such as frequency, urgency, and dysuria may be seen, especially in association with carcinoma in situ or invasive bladder cancer. however, microscopic or macroscopic hematuria is almost always present. we speculate that tumors with microscopic hematuria are smaller than those with gross hematuria, and consequently, the diagnostic tests are a less sensitive. given the difficulty of diagnosis in such cases and also the short preclinical latency of bladder tumors, special attention must be paid to received february 2004 accepted june 2005 *corresponding author: kmakar hospital, qom, iran. fax: ++98 251 771 3473 e-mail: mkmoslemi_urologist@yahoo.com urinary bladder cancer antigen in the diagnosis of bladder cancer introduction of an accurate noninvasive test for early diagnosis. recent studies have shown the diagnostic values of some urinary tumor markers.(2-8) however, their clinical role has not yet been confirmed. although cytokeratins are seen in all normal epithelial cells, an association between their concentrations and malignancy has been shown. as most malignant tumors originate from epithelial cells, cytokines could be a valuable marker. degenerative changes of bladder cells can lead to release of cytokeratins or their fragments in urine, mostly cytokeratins 8 and 18. using urinary bladder cancer (ubc) antigen, we can measure these urinary cytokines.(4,6) using an enzyme-linked immunosorbent assay (elisa), the cytokines are traced with an anti-ubc monoclonal antibody and a labeled antibody.(2) diagnostic value of the ubc antigen is a matter of controversy. we designed this study to compare the accuracy of ubc antigen and voided urine cytology in patients with bladder cancer. materials and methods this study was done at the shaheed hasheminejad hospital, iran university of medical sciences, in tehran, iran, between 2001 and 2002. fifty-four consecutive patients (44 men, 10 women; mean age, 59.5 ± 8.4 years; range, 29 to 87 years) admitted for a diagnostic workup for bladder cancer were enrolled. informed consent was obtained from all patients. physical examination was performed and history was taken in all patients. two separate morning midstream voided urine samples were taken for urinalysis, both before performing cystoscopy. the samples were examined for urinary creatinine level, urine cytology, and ubc antigen. all of the patients underwent cystoscopy by a single experienced urologist. resection was performed in the presence of an apparent pathologic lesion, and if there were no lesions, random biopsies of multiple foci of the bladder were taken. the specimens were examined histologically, based on the ash grading system.(9) voided urine specimens were centrifuged for 10 minutes, and the supernatant was frozen at -20°c and used for monoclonal elisa and creatinine level measurements. the ideal ubc rapid elisa is a 2.5-hour test specifically designed to determine antigens in urine. specimens were incubated with a monoclonal anti-ubc catcher antibody. during incubation, the immobilized antibody and horseradish-peroxidase-labeled antibody bind to the ubc antigen, forming a sandwich. the wells were washed and a substrate solution was added. the resultant color was an indicator of cytokeratin-8 and cytokeratin-18 concentrations.(2,4) creatinine was measured in urine samples, and the ubc results were corrected for creatinine concentration in urine by dividing their values by milligrams of urinary creatinine. sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios were calculated for the diagnostic tests, according to standard statistical methods, using spss software (statistical package for the social sciences, version 11.5, ssps inc, chicago, ill, usa). results forty patients (74.1%) had tumoral lesions in cystoscopy, and random biopsies were performed in 14 (25.9%). on pathologic examination, transitional cell carcinoma (tcc) was confirmed in 31 patients (57.4%), of whom 27 had tcc grade 2/4 and 4 had tcc grade 3/4. results of the biopsy specimens of the 23 remaining patients were normal or otherwise contained benign tumoral cells. details of the results of ubc antigen and urine cytology in association with histologic results are shown in table 1. ubc antigen tests were positive in 28 patients (51.9%), while urine cytology was positive for tcc in 16 (29.6%). the sensitivity of ubc antigen was significantly higher than that of urine cytology (74.2% versus 48.4%), while urine cytology had a higher specificity (95.7% versus 78.3%). considering the positive results of both tests, the combined sensitivity and specificity of the ubc antigen test and of cytology were 87.1% and 73.9%. of 28 patients with a positive ubc antigen, 11 had positive urine cytology, and 21 out of 26 with a negative ubc antigen test had negative urine cytology too. likelihood ratios and other characteristics for urine cytology, ubc antigen, and both are listed in table 2. discussion a noninvasive method for diagnosing bladder cancer has yet to be established. several immunohistochemical assessments of urine have been proposed as tumor markers for bladder 138 zargar et al cancer, such as urinary concentrations of cytokines, fibronectin, matrix protein-22, and cytokeratin fragments 21-1. the ubc elisa is a recently advocated method; however, the results remain a matter of controversy. in this study, we compared ubc elisa with urine cytology, a current diagnostic tool, and considered histologic examination as the standard reference. our results indicate that the ubc test was superior to urine cytology when the sensitivity of the test was of importance, but the specificity of cytology is significantly higher. however, a combination of the two tests (a positive result of either ubc antigen or cytology) may bring about an acceptable sensitivity of 87.1%. when considering positive likelihood ratios, a ubc antigen positive result is less reliable than a positive urine cytology (3.41 versus 11.2); however, to achieve a better negative likelihood ratio, a combination of the two tests is superior to either cytology or ubc alone (4.7 versus 1.8 and 3.04, respectively). eissa and colleagues(2) have evaluated the ubc antigen test, urine cytology, fibronectin, and nuclear matrix protein-22 in 168 patients of whom 100 had been histologically diagnosed with bladder cancer. they found that the sensitivity of the ubc antigen test was higher than that of cytology (67% versus 55%), while the specificity of cytology was significantly higher (100% versus 80.8%). they showed that fibronectin and nuclear matrix protein-22 are more accurate markers, and that a combination of cytology with other markers can increase the sensitivity to as much as 95%. ubc antigen and urine cytology had an 82.8% sensitivity. our results agree with the eissa and coworkers study. the sensitivity of the ubc antigen test has been reported to be as low as 20.7% in one study by mungan and colleagues(8) and as high as 82.0% in another study by sumi and coworkers.(10) however, in most studies, it has been over 60% and superior to urine cytology.(2,3,5,7,10-12) concerning the specificity, urine cytology has proven to be a better test with a rate of 86.9% to 100%(2,3,10); while specificity ranges for the ubc antigen test range from 79.3% to 92%,(3,8,11,12) which are higher than our results. it appears, then, that although the ubc antigen test can provide relatively valuable information, cystoscopy cannot be replaced by this test. boman and colleagues(5) have shown that tumor size, grade, and stage have a strong impact on the diagnostic power of tumor markers. they concluded that these tests may be more appropriate for the follow-up of the patients with bladder cancer, as recurrent tumors are usually 139 table 1. the results of biopsy and diagnostic tests table 2. sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv), and positive and negative likelihood ratios of ubc, urine cytology, and cystoscopy sensitivity (%) specificity (%) ppv (%) npv (%) positive likelihood ratio negative likelihood ratio ubc 74.2 78.3 82.1 69.2 3.42 3.03 urine cytology 48.4 95.7 93.8 57.9 11.3 1.85 ubc + cytology 87.1 73.9 81.8 81.0 3.34 5.73 cystoscopy 100 60.9 77.5 100 2.55 biopsy results patients with positive for tcc patients with negative for malignancy total number of patients positive 23 5 28 ubc negative 8 18 26 positive 15 1 16 urine cytology negative 16 22 38 positive 27 6 33 combined ubc and cytology negative 4 17 21 positive 31 9 40 cystoscopy negative 0 14 14 total 31 23 54 urinary bladder cancer antigen in the diagnosis of bladder cancer smaller. in their study, the sensitivity of the ubc antigen test was 72% for recurrent and 60% for new tumors. mian and colleagues evaluated tumor markers during follow-up of patients with transurethral resected urothelial cell carcinoma and reported the sensitivity and specificity of the ubc test to be 66% and 90%.(11) sanchez-carbayo and colleagues followed 232 patients with a previous bladder carcinoma and found that monitoring the disease with the ubc test was able to detect recurrence sooner than scheduled cystoscopies in 87% of the patients.(4) in another study, they also showed that monitoring patients with urinary tumor markers, including the ubc antigen, could detect early recurrence in bacillus calmettegurein nonresponders.(6) however, none of the researchers advocate substitution of the ubc test or other tumor markers over cystoscopy. they simply suggest that these tests could lower the number of cystoscopies needed or individualize the intervals between cystoscopies during followup of patients with bladder carcinoma.(4,11) even mungan and coworkers found no diagnostic value for the ubc antigen test during follow-up of patients with superficial bladder cancer.(8) cystoscopy remains the preferred standard, provided that random biopsies are considered in cases of no apparent lesion. our study showed its sensitivity to be 100%. still, further investigation of urinary tumor markers is warranted. some tumor markers other than ubc antigen have been shown to be more accurate in some studies. for instance, it has been shown that the nuclear matrix protein (nmp22) assay surpasses the ubc antigen test.(2,5) the results yielded by bta stat and cytokeratin fragments are also comparable.(35,11) it seems that an appropriate combination of these tests may offer a favorable noninvasive diagnostic tool. conclusion the diagnostic value of urinary tumor markers is not yet clear. the ubc antigen test demonstrated acceptable sensitivity and specificity in our study. however, positive results of voided urine cytology are significantly more reliable. further studies are warranted to find a more accurate noninvasive test or a combination of tests comparable with cystoscopy. references 1. messing em. urothelial tumors of the renal pelvis and ureter. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.2737-41. 2. eissa s, swellam m, sadek m, mourad ms, ahmady oe, khalifa a. comparative evaluation of the nuclear matrix protein, fibronectin, urinary bladder cancer antigen and voided urine cytology in the detection of bladder tumors. j urol. 2002;168:465-9. 3. babjuk m, kostirova m, mudra k, et al. qualitative and quantitative detection of urinary human complement factor h-related protein (bta stat and bta trak) and fragments of cytokeratins 8, 18 (ubc rapid and ubc irma) as markers for transitional cell carcinoma of the bladder. eur urol. 2002;41:34-9. 4. sanchez-carbayo m, urrutia m, gonzalez de buitrago jm, navajo ja. utility of serial urinary tumor markers to individualize intervals between cystoscopies in the monitoring of patients with bladder carcinoma. cancer. 2001;92:2820-8. 5. boman h, hedelin h, holmang s. four bladder tumor markers have a disappointingly low sensitivity for small size and low grade recurrence. j urol. 2002;167:80-3. 6. sanchez-carbayo m, urrutia m, romani r, herrero m, gonzalez de buitrago jm, navajo ja. serial urinary il2, il-6, il-8, tnfalpha, ubc, cyfra 21-1 and nmp22 during follow-up of patients with bladder cancer receiving intravesical bcg. anticancer res. 2001;21(4b):3041-7. 7. giannopoulos a, manousakas t, gounari a, constantinides c, choremi-papadopoulou h, dimopoulos c. comparative evaluation of the diagnostic performance of the bta stat test, nmp22 and urinary bladder cancer antigen for primary and recurrent bladder tumors. j urol. 2001;166:470-5. 8. mungan na, vriesema jl, thomas cm, kiemeney la, witjes ja. urinary bladder cancer test: a new urinary tumor marker in the follow-up of superficial bladder cancer. urology. 2000;56:787-92. 9. ash je. epithelial tumors of the bladder. j urol. 1940;44:135-45. 10. sumi s, arai k, kitahara s, yoshida ki. preliminary report of the clinical performance of a new urinary bladder cancer antigen test: comparison to voided urine cytology in the detection of transitional cell carcinoma of the bladder. clin chim acta. 2000;296:111-20. 11. mian c, lodde m, haitel a, egarter vigl e, marberger m, pycha a. comparison of two qualitative assays, the ubc rapid test and the bta stat test, in the diagnosis of urothelial cell carcinoma of the bladder. urology. 2000 aug 1;56(2):228-31. 12. mian c, lodde m, haitel a, vigl ee, marberger m, pycha a. comparison of the monoclonal ubc-elisa test and the nmp22 elisa test for the detection of urothelial cell carcinoma of the bladder. urology. 2000;55:223-6. 140 review a systematic review and meta-analysis of three gene variants association with risk of prostate cancer: an update yu chen, huan zhong, jian-guo gao, jian-er tang, rongjiang wang* purpose: prostate cancer (pca) is one of the most commonly diagnosed male malignancies. numerous studies have investigated the role of genetic variants in pca risk. however, the results remain unclear. the purpose of this study was to evaluate the relationship between single-nucleotide polymorphism (snp) rs2228001 in xeroderma pigmentosum group c (xpc), snp rs4073 in interleukin 8 (il8), and snp rs2279744 in mouse double minute 2 (mdm2) homolog gene with pca susceptibility. materials and methods: electronic database of pubmed, medline, and embase were searched for eligible articles published between january 2000 and april 2014. the odd ratio (or) with its 95% confidence interval (ci) were calculated to estimate the strength of association. results: a total 18 case-control studies, including 5725 pca cases and 5900 healthy controls, were screened out. six studies were eligible for each snp. for xpc 939a/c polymorphism, no significant association was found with pca risk in the whole population (p > .05). no relationship in subgroup analysis was found by ethnicity. for il8 -251t/a variant, the a allele was not related with pca risk in any genetic models when compared with those individuals without a allele. for mdm2 -309t/g mutation, the g allele was not associated with the increased risk of pca in total population and subgroup analysis by ethnicity as well. conclusion: our study demonstrated that all these three genetic polymorphisms were not associated with an increased risk of developing pca, which might also provide an insight into the future research. further large-scale studies with concerning the gene-gene and gene-environment interactions are needed to elucidate final conclusion. keywords: prostatic neoplasms; genetics; risk factors; gene expression regulation; humans; tumor marker; biological. introduction prostate cancer (pca) is the common malignan-cies among men in the world. it is also the second and third cause of cancer-related death in the usa and europe, respectively.(1,2) every year, a total of 238,590 new cases are emerging and 29,720 death are occurring according to cancer statistics, 2013.(3) multiple risk factors such as hormones, family history and lifestyle are associated with pca. due to extreme heterogeneity in pca incidences worldwide, major determining factors have not been detected yet,(4) and the pathogenesis mechanism is still unclear. furthermore, the prevention and treatment of pca remain complicated for treatment options depending on disease stage and patient choice.(5) thus, there is an urgent need to explore the molecular mechanism underlying this disease and develop novel target therapies. during the last two decades, genetic factors are considered to contribute substantially in the development of pca. for example, increased b-cell lymphoma 2 (bcl-2) expression was associated with lower biochemical-free survival in patients with advanced pca.(6) polymorphisms of drug-metabolizing genes cytochrome p4501a1 (cyplal)(7) and prostate-specific antigen (psa)(8) genes were shown to be related with increase the risk of sporadic pca, and they might be predisposdepartment of urology, affiliated hospital of huzhou teachers› college, the first people›s hospital of hu zhou, hu zhou, 313000, china. *correspondence: department of urology, affiliated hospital of huzhou teachers› college, the first people›s hospital of huzhou, huzhou, 313000, china. tel: +86 572 2575091. fax: +86 572 2023728. e-mail: rongjiangwang_r@163.com. received november 2014 & accepted may 2015 ing factors for pca. several genes were shown to be involved in the pathogenicity of pca. the xeroderma pigmentosum group c (xpc) gene is located on chromosome 3p25 and is a 940-residue dna binding protein. it serves as the primary initiating factor in the global genome nucleotide excision repair (gg-ner) in human, and plays a vital role in the early steps, especially in damage recognition, open complex formation and reparation.(9) recent reports suggest that xpc also stimulates repair of oxidative lesions by ner. in cells, xpc binds to human homolog of reticulum-associated degradation b (rad) 23 (hhr23b) to form the xpc-hhr23b complex,(10) which is involved in the dna damage recognition and dna repair initiation in the ner pathway, and is necessary to support ner activity in vitro.(11) sequence variants of the xpc gene may alter ner capacity and modulate cancer risk. one single-nucleotide polymorphism (snp) lys939gln (an a to c substitution) in exon 15 of xpc has been identified and is the most studied. interleukin-8 (il8) gene, located on chromosome 4q1221 in humans, is composed of four exons, three introns, and a proximal promoter region. it is an important member of cxc chemokine family(12) and is produced by a wide range of normal cells to initiate and amplify acute inflammatory reactions.(13) il8 is well known for its leukocyte chemotactic properties. many studies have review 2138 demonstrated that il8 may play a vital role in tumorigenesis, including angiogenesis, adhesion, invasion and metastasis.(14) in the promoter region of the il8 gene251 base pairs upstream of the transcriptional start sit, a t/a snp has been identified, and studies have shown that it influences the production of il8 and affects the transcriptional activity of the il8 promoter.(15) mouse double-minute 2 (mdm2) is an e3-ubiquitin ligase which could bind to p53 with high affinity. it inhibits and promotes the degradation of the tumor suppressor protein, p53.(16,17) overexpression of mdm2 is associated with tumor proliferation, and an early onset of tumorigenesis.(18) studies have demonstrated that a mutation in the promoter region of the mdm2 gene (-309 t/g; snp309) could result in increasing the expression of mdm2, leading to the attenuation of p53.(19) although independent study has identified the association between these polymorphisms and pca risk, the results remained inconsistent rather than conclusive. hirata and colleagues showed that xpc lys939gln polymorphism might be a risk factor for pca in japanese population;(20) however, liu and colleagues did not found a significant association between this polymorphism and pca in chinese population.(21) mccarron and colleagues firstly demonstrated that il8 variant might have a significant effect on development of pca;(22) whereas michaud and colleagues identified that il8 variant did not play a role in the risk of pca. (23) xu and colleagues suggested that mdm2 309g allele is significantly related with pca risk;(24) while jerry and colleagues found no association between mdm2 snp 309 and disease recurrence risk, clinicopathologic variables and overall survival outcome in pca. (25) therefore, the objective of this study was to systematically evaluate the prevalence of the above mentioned genetic polymorphisms in patients diagnosed with pca, and comprehensive and reliable assessment of correlations of these polymorphisms with pca risk. materials and methods identification and eligibility of relevant studies we conducted a comprehensive literature search using the electronic database of pubmed, medline, and embase for relevant articles published between january 2000 and april 2014. the following terms «prostate cancer or prostatic cancer», «xeroderma pigmentosum complementation group c or xpc», «interleukin-8 or il8», «murine double minute 2 or mdm2», and «polymorphisms or variants or mutations» as well as their combinations were used to retrieve the related articles. references of retrieved articles were restricted with english language. our research fotable 1. characteristics of the included studies in the meta-analysis. first author year country ethnicity cases no. control no. genotyping method xpc 939a/c hirata27 2007 japan asian 165 165 pcr-rflp agalloi32 2010 usa caucasians 1308 1266 pcr-rflp agalloi32 2010 usa african-americans 149 85 pcr liu21 2012 china asian 202 221 pcr-rflp mittal28 2012 india caucasians 195 250 pcr sorour29 2013 egypt african 50 50 pcr-rflp zhang30 2014 china asian 229 238 pcr, maldi-tof ms il8 -251t /a mccarron22 2002 uk caucasians 247 263 pcr michaud23 2006 usa caucasians 503 652 taqman-pcr yang38 2006 finland caucasians 520 418 taqman wang37 2009 usa caucasians 254 252 taqman zhang35 2010 usa caucasians 193 197 pcr dluzeniewski36 2012 usa caucasians 484 484 taqman-pcr mdm2 -309t/g kibei44 2008 usa caucasians 186 222 pyrosequencing stoehr43 2008 germany caucasians 145 124 pcr-rflp hirata39 2009 japan asian 140 167 pcr-rflp xub42 2010 china asian 209 268 pcr-rflp knappskog41 2012 norway caucasians 666 675 pcr manda40 2012 indian caucasians 192 224 pcr-rflp abbreviations: pcr, polymerase chain reaction; rflp, restriction fragment length polymorphism; maldi-tof ms, matrix-assisted laser desorption ionisation mass spectrometry – time of flight. association of three gene variants with risk of pca-chen et al. vol 12 no 03 may-june 2015 2139 cused on studies that had been conducted in human. criteria for inclusion the included studies must meet the following criteria: 1) the paper should be case-control or cohort association studies; 2) pca cases were diagnosed and histopathologically confirmed; 3) controls were cancer free, unrelated, ageand sex-matched healthy individuals of similar ethnicity; 4) each study included at least one of the three polymorphisms, rs2228001 in xpc (939a/c), rs4073 in il8 (-251t/a), and rs2279744 in mdm2 (-309t/g); 5) genotype distribution information in cases and controls were available to extract, and 5) genotype distribution of control for a certain polymorphism must be in hardy-weinberg equilibrium (hwe). data extraction two investigators independently assessed the quality of the included studies according to the data extracted from each study. any disagreement was solved by consulting with a third author. the following information was extracted from each article: first author, year of publication, country, ethnicity, total numbers, and genotype distributions in pca cases and controls. statistical analysis the overall association between genetic polymorphisms and pca risk was measured by odds ratio (or) and its 95% confidence interval (ci). the z test was employed to determine the significance of the pooled ors with a p value less than .05 considered statistically significant. the allelic model (c vs. a for xpc 939a/c; a vs. t for il8-251a/t; g vs. t for mdm2 -309t/g) and genotype genetic models (co-dominant effects: cc vs. aa xpc 939a/c; aa vs. tt il8 -251a/t; gg vs. tt mdm2309t/g; dominant effect: cc+ac vs. aaxpc 939a/c; table 2. distribution of genotypes and alleles in the individual studies. first author cases controls xpc aa ac cc a c aa ac cc a c hirata27 77 78 10 232 98 72 70 23 214 116 agalloi32 457 595 205 1509 1005 461 600 190 1522 980 agalloi32 70 61 16 201 93 36 38 9 110 56 liu21 86 85 31 257 147 102 100 19 304 138 mittal28 94 73 28 261 129 127 104 19 358 142 sorour29 16 25 9 57 43 18 27 5 63 37 zhang30 58 38 33 354 104 170 37 31 377 99 il8 aa at tt a t aa at tt a t mccarron22 59 122 57 240 236 54 105 76 213 257 michaud23 112 225 147 449 519 151 310 152 612 614 yang38 103 236 181 442 598 66 217 135 349 487 wang37 69 127 58 265 243 62 138 52 262 242 zhang35 60 102 80 93 dluzeniewski36 107 218 121 432 460 106 207 133 419 473 mdm2 tt gt gg t g tt gt gg t g kibei44 85 88 13 258 114 90 98 32 278 162 stoehr43 61 66 18 188 102 41 64 19 146 102 hirata39 58 56 26 172 108 56 79 32 191 143 xu b42 44 118 47 206 212 68 143 57 279 257 knappskog41 297 277 92 871 461 305 295 75 905 445 manda40 67 71 54 205 179 53 98 73 204 244 figure 1. flow chart diagram of literature review. association of three gene variants with risk of pca-chen et al. review 2140 aa+at vs. tt il8 -251a/t; gg+gt vs. tt mdm2 -309t/g; and recessive effect: cc vs. ac+aa xpc 939a/c; aa vs. at+tt il8 -251a/t; gg vs. gt+tt mdm2 -309t/g) were examined. the i2 test and the q test were used to assess the between-study heterogeneity. the fixed-effects model is used when the effects are assumed to be homogenous (less than 50% for the i2 test and p value more than .01 for the q test), while the random effects model is used when they are heterogeneous. the evidence of publication bias was assessed by visual funnel plot inspection. statistical analyses were conducted using review manager (revman) software (version 5.2, the cochrane collaboration, oxford, uk), and followed the program described by collaboration and colleagues.(26) all the tests were two-sided. results study selection and characteristics the electronic database search identified 323 references. after applying the inclusion criteria, 32 full-text articles comprehensively assessed against inclusion criteria. removing duplicate documents, 18 articles were ultimately included in the systematic review and meta-analysis. the study selection process is shown in figure 1. for xpc 939a/c, 6 studies(27-32) consisted three ethnicity (asian, caucasians and african) reporting 2245 cases and 2258 controls were selected. among them, the research conducted by agalliu and colleagues(32) consisted two ethnicities. for il8 -251t/a, 6 studies(33-38) included 1942 cases and 1964 controls were enrolled, all of which had caucasians ethnicity. for mdm2 -309t/g, 6 studies(39-44) contained 1538 cases and 1678 controls including asian and caucasians ethnicities were selected. the main characteristics of the included studies are listed in table 1. the distributions of genotypes in the individual studies are presented in table 2. association between xpc 939a/c variant and pca risk the results of allele and genotypes of xpc polymorphism in this meta-analysis are shown in table 3. the heterogeneity between studies was calculated, and the table 3. meta-analysis of xeroderma pigmentosum group c 939a/c polymorphism in prostate cancer. variables comparison no. or (95% ci) p value* z ph** i2 (%) model overall c vs. a 7 1.06 (0.97-1.15) .22 1.22 0.29 18 f cc vs. aa 7 1.19 (0.85-1.68) .32 1.00 0.04 54 r cc + ac vs. aa 7 1.03 (0.92-1.17) .59 0.54 0.94 0 f cc vs. ac + aa 7 1.20 (0.85-1.70) .30 1.04 0.03 58 r asian c vs. a 3 1.04 (0.79-0.37) .78 0.28 0.09 59 r cc vs. aa 3 1.00 (0.45-2.22) .99 0.01 0.01 77 r cc + ac vs. aa 3 1.06 (0.84-1.34) .62 0.49 0.62 0.0 f cc vs. ac + aa 3 0.99 (0.44-2.21) .97 0.03 0.007 80 r caucasians c vs. a 2 1.06 (0.95-1.18) .27 1.09 0.24 29 f cc vs. aa 2 1.36 (0.77-2.42) .29 1.06 0.08 67 r cc + ac vs. aa 2 1.03 (0.89-1.20) .65 0.45 0.69 0.0 f cc vs. ac + aa 2 1.39 (0.76-2.53) .28 1.08 0.06 72 r african c vs. a 2 1.02 (0.74-1.42) .90 0.13 0.33 0.0 f cc vs. aa 2 1.20 (0.57-2.52) .63 0.48 0.32 0.0 f cc+ac vs. aa 2 0.94 (0.60-1.47) .77 0.29 0.49 0.0 f cc vs. ac + aa 2 1.28 (0.64-2.57) .48 0.70 0.36 0.0 f abbreviations: or, odds ratio; ci, confidence interval. no, number of included studies. * p value for overall effect. ** p value for heterogeneity among studies. comparison no. or (95% cl) p value* z ph** i2 (%) model a vs. t 5 1.01 (0.92-1.10) .88 0.15 0.23 29 f aa vs. tt 5 1.03 (0.86-1.23) .75 0.32 0.25 26 f aa + at vs. tt 5 0.99 (0.79-1.24) .90 0.12 0.04 59 r aa vs. at + tt 6 1.02 (0.88-1.17) .80 0.25 0.27 21 f abbreviations: or, odds ratio; ci, confidence interval. no, number of included studies. * p value for overall effect. ** p value for heterogeneity among studies. table 4. meta-analysis of interleukin 8 -251t/a polymorphism in prostate cancer. association of three gene variants with risk of pca-chen et al. vol 12 no 03 may-june 2015 2141 fixed effect model or random effect model was performed for assessing the pooled or. overall, the frequency of c allele is a little bit higher in pca cases than that in the healthy controls (36.1% vs. 34.7%). however, there was no evidence for a significant association between xpc gene 939a/c polymorphism and pca risk in the whole population (c vs. a, 0r = l.06, 95% ci: 97-1.15, p = .22; cc vs. aa, 0r = l.19, 95% ci: 0.85-1.68, p = .32; cc + ac vs. aa, or = l.03, 95% ci: 0.92-1.17, p = .59; cc vs. ac + aa, or = l.20, 95% ci: 0.85-1.70, p = .30) (figure 2). we also evaluated the effect of the polymorphism by ethnicity. we did not detect a significant association between xpc gene 939a/c polymorphism and pca risk in asians, caucasians, or african population (p > .05). association between il8 -251 t/a polymorphism and pca risk table 4 demonstrates the summary of all genetic comparisons between il8 -251 t/a polymorphism and pca risk. as shown in figure 3, the result demonstrated that the variant a allele did not have a significant increased risk of pca compared with those individuals without a allele (a vs. c; or = l.0l, 95% ci: 0.92-1.10, p = .88). no significant association was found in other genetic models (aa vs. tt, or = l.03, 95% ci: 0.86-1.23, p = .75; table 5. meta-analysis of mouse double minute 2 (mdm2) homolog gene -309t/g polymorphism in prostate cancer. variables comparison no. or (95% ci) p value* z ph** i2 (%) model overall g vs. t 6 0.89 (0.76-1.05) .17 1.37 0.04 56 r gg vs. tt 6 0.81 (0.56-1.17) .25 1.14 0.02 62 r gg + gt vs. tt 6 0.84 (0.67-1.06) .14 1.47 0.07 52 r gg vs. gt + tt 6 0.96 (0.80-1.16) .69 0.40 0.10 46 f asian g vs. t 2 1.00 (0.82-1.22) .00 0.00 0.17 46 f gg vs. tt 2 1.04 (0.69-1.56) .86 0.18 0.25 23 f gg + gt vs. tt 2 0.96 (0.54-1.70) .89 0.14 0.07 69 r gg vs. gt + tt 2 1.03 (0.73-1.46) .86 0.17 0.77 0.0 f caucasians g vs. t 4 0.85 (0.68-1.06) .14 1.47 0.03 67 r gg vs. tt 4 0.71 (0.41-1.20) .20 1.29 0.01 73 r gg + gt vs. tt 4 0.80 (0.60-1.05) .10 1.62 0.08 55 r gg vs. gt + tt 4 0.83 (0.54-1.27) .39 0.87 0.03 67 r abbreviations: or, odds ratio; ci, confidence interval. no, number of included studies. * p value for overall effect. ** p value for heterogeneity among studies. figure 2. forest plot on the association between c allele in xeroderma pigmentosum group c gene and risk of prostate cancer. association of three gene variants with risk of pca-chen et al. review 2142 aa + at vs. tt, or = 0.99, 95% ci: 0.79-1.24, p = .90; aa vs. at + tt, or = l.02, 95% ci: 0.88-1.17, p = .80). association between mdm2 -309t/g polymorphism and pca risk the overall analysis of the studies concerning mdm2 polymorphism and pca risk is shown in table 5, which revealed no significant association between mdm2 309t/g polymorphism with pca risk in any genetic models (g vs. t, or = 0.89, 95% ci: 0.76-1.05, p = .17; gg vs. tt, or = 0.81, 95% ci: 0.56-1.17, p = .25; gg + gt vs. tt, or = 0.84, 95% ci: 0.67-1.06, p = .14; gg vs. gt + tt, or = 0.96, 95% ci: 0.80-1.16, p = .69) as shown in figure 4. in subgroup analysis based on ethnicity, we found that mdm2 309t/g variant did not significantly increase the risk of pca neither in asian (p > .05) nor in caucasians (p > .05) population, no matter what kind of genetic model was used. sensitivity analyses and publication bias each included study was deleted every time to verify whether the individual data influenced the ors. figure 3. meta-analysis of the association between interleukin 8 -251t/a polymorphism and risk of prostate cancer. our results showed that the pooled ors were not significantly changed, confirming the stability of our overall result. the funnel plots did not show any obvious asymmetry, further indicating that there was no publication bias in our meta-analysis (figure 5). discussion the present meta-analysis examined the association between three commonly studied gene polymorphisms xpc 939aic, il8 -251t/a, and mdm2 -309t/g with pca risk. eighteen separate articles including 5725 pca cases and 5900 healthy controls were retrieved in the final analysis. overall we did not detect a significant association between these three gene polymorphisms with pca in any genetic models. similar results were found in stratification analyses by ethnicity. the xpc gene contains 16 exons and 15 introns. it can interact with rad23b to form a xpc-rad23b complex, specifically involving in global genome repair and works as the earliest damage detector to initiate the ner pathway.(45) studies have proved that xpc is figure 4. forest plot of mouse double minute 2 (mdm2) homolog gene -309t/g polymorphism with risk of prostate cancer under each genetic models. association of three gene variants with risk of pca-chen et al. vol 12 no 03 may-june 2015 2143 a key component of the ner pathway that participates in dna damage repair.(46) mutations in this gene, result in xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight and the development of skin cancer at an early age.(47) xpc polymorphisms have been associated with increased risk of many human cancers such as bladder cancer,(48) and digestive system cancers.(49) our results was consistent with previous meta-analysis conducted by zou and colleagues in which screened out five studies including 1966 cases and 1970 controls, demonstrated that this variant was not associated with pca risk.(50) il8 is one of key members of the human a-chemokine subfamily, and acts as a potent chemoattractant and activator of neutrophils.(51) it is produced by normal cells including monocytes, neutrophils, fibroblasts, and endothelial cells. il8 is involved in thrombophilia and angiogenesis, and highly expressed in various human cancers. it also plays an important role in chronic infection, inflammation, and cancer development, and its overexpression may implicate the increased susceptibility or the modulated clinicopathological features for different cancers.(52) the corresponding gene polymorphisms may lead to the aberrant expression of il8 and accordingly increase the risk of cancers. the -251t/a polymorphism is a t-to-a substitution that occurs at nucleotide -251, and the less a allele can lead to the increased expression of il8. xue and colleagues found that il8 -251 aa genotype is associated with the overall risk of developing gastric cancer and may seem to cause more susceptibility to gastric cancer in asian populations.(14) andia and colleagues demonstrated that il8 gene promoter polymorphism (rs4073) may contribute to chronic periodontitis.(53) wang and colleagues reported that il8 -251t/a polymorphism is associated with a significantly increased risk of cancers and may provide evidence-based medical certificate to study the cancer susceptibility.(54) however, no connection was found with pca risk in our meta-analysis. mdm2 is a major regulator of p53 function. it is well known that the functional role of mdm2 is related to the negative regulation of tumor suppressor p53. it acts with p53 in a feedback loop where p53 activates mdm2 at the transcriptional levels while mdm2 binds, inhibits and degrades the p53 protein through e3 ligase activity.(55) studies have shown that mdm2 antagonists-activated wild-type p53 in combination with androgen depletion may provide an efficacious approach to pca therapy.(56) the functional importance of this interaction is illustrated by the findings that reduction of the mdm2 expression level inhibits tumor formation in mice while depletion of the mdm2 gene leads to embryonic lethality, an effect rescued by concomitant p53 deletion.(57) mdm2 amplification and/ or protein over expression has been observed in many human cancers harboring wild-type tp53, the gene coding for the p53 protein,(58) and mdm2 over expression has been suggested to act as an alternative mechanism to p53 inactivation, promoting tumor growth.(59) the mdm2 gene plays a key role in the p53 pathway, and the snp 309t/g in the promoter region of mdm2 has been shown to be associated with increased risk of cancer. however, we did not find a relationship between this polymorphism and pca risk. previous meta-analysis covering 4 independent studies showed no significant association between mdm2 309t/g polymorphism and pca risk in whole analysis as well.(60) several limitations in this meta-analysis should be acknowledged. firstly, the subgroups may have a relatively lower power based on a small number of studies. secondly, other covariates such as age, sex and smoking status should be included to get a more precise result. thirdly, other genes which may interact with these genes should be considered. conclusion in conclusion, our results demonstrated that xpc, il8, and mdm2 variants were not associated with increased risk of pca. further large scale studies with different populations and ethnicities are needed to confirm our results. moreover studies addressing gene–gene and gene-environment interactions and polymorphisms in these 3 genes and the risk of pca should also be performed and considered. conflict of interest none declared. references figure 5. funnel plot analysis 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prostate cancer. cancer res. 2006;66:4525-30. 24. xu z, wei b. editorial comment from dr xu and dr wei to murine double minute 2 promoter snp309 polymorphism and prostate cancer risk: a meta-analysis. int j urol. 2012;19:922. 25. jaboin jj, hwang m, perez ca, et al. no evidence for association of the mdm2-309 t/g promoter polymorphism with prostate cancer outcomes. urol oncol. 2011;29:31923. 26. review manager (revman) [computer program]. version 5.3. copenhagen: the nordic cochrane centre, the cochrane collaboration, 2014. 27. hirata h, hinoda y, tanaka y, et al. polymorphisms of dna repair genes are risk factors for prostate cancer. eur j cancer. 2007;43:231-7. 28. mittal rd, mandal rk. genetic variation in nucleotide excision repair pathway genes influence prostate and bladder cancer susceptibility in north indian population indian j hum genet. 2012;18:47-55. association of three gene variants with risk of pca-chen et al. vol 12 no 03 may-june 2015 2145 29. sorour af, talaat im, 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res. 2002;62:3369-72. 35. zhang j, dhakal ib, lang np, kadlubar ff. polymorphisms in inflammatory genes, plasma antioxidants, and prostate cancer risk. cancer causes control. 2010;21:1437-44. 36. dluzeniewski pj, wang mh, zheng sl, et al. variation in il10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence. cancer epidemiol biomarkers prev. 2012;21:1774-82. 37. wang mh, helzlsouer kj, smith mw, et al. association of il10 and other immune responseand obesity-related genes with prostate cancer in clue ii. prostate. 2009;69:874-85. 38. yang hp, woodson k, taylor pr, et al. genetic variation in interleukin 8 and its receptor genes and its influence on the risk and prognosis of prostate cancer among finnish men in a large cancer prevention trial. eur j cancer prev. 2006;15:249-53. 39. hirata h1, hinoda y, kikuno n, et al. bcl2 -938c/a polymorphism carries increased risk of biochemical recurrence after radical prostatectomy. j urol. 2009;181:1907-12. 40. mandal rk, mittal rd. are cell cycle and apoptosis genes associated with prostate cancer risk in north indian population? urol oncol. 2012;30:555-61. 41. knappskog s, trovik j, marcickiewicz j, et al. snp285c modulates oestrogen receptor/sp1 binding to the mdm2 promoter and reduces the risk of endometrial but not prostatic cancer. eur j cancer. 2012;48:1988-96. 42. xu b, xu z, cheng g, et al. association between polymorphisms of tp53 and mdm2 and prostate cancer risk in southern chinese. cancer genet cytogenet. 2010;202:76-81. 43. stoehr r, hitzenbichler f, kneitz b, et al. mdm2-snp309 polymorphism in prostate cancer: no evidence for association with increased risk or histopathological tumour characteristics. br j cancer. 2008;99:78-82. 44. kibei as, jin ch, klim a, et al. association between polymorphisms in cell cycle genes and advanced prostate carcinoma. prostate. 2008;68:1179-86. 45. bergink s, toussaint w, luijsterburg ms, et al. recognition of dna damage by xpc coincides with disruption of the xpc-rad23 complex. j cell biol. 2012;196:681-8. 46. fleming nd, agadjanian h, nassanian h, et al. xeroderma pigmentosum complementation group c single-nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression-free survival in advanced ovarian cancer. cancer. 2012;118:689-97. 47. kraemer kh, lee mm, andrews ad, lambert wc. the role of sunlight and dna repair in melanoma and nonmelanoma skin cancer. the xeroderma pigmentosum paradigm. arch dermatol. 1994;130:1018-21. 48. li wq, pfeiffer rm, hyland pl, et al. genetic polymorphisms in the 9p21 region associated with risk of multiple cancers. carcinogenesis. 2014;35:2698-705. 49. jiang x, zhou lt, zhang sc, chen k. xpc polymorphism increases risk of digestive system cancers: current evidence from a meta-analysis. chin j cancer res. 2012;24:181-9. 50. zou yf, tao jh, ye ql, et al. association of xpc gene polymorphisms with susceptibility to prostate cancer: evidence from 3,936 subjects. genet test mol biomarkers. 2013;17:926-31. 51. matsushima k, baldwin et, mukaida n. interleukin-8 and mcaf: novel leukocyte recruitment and activating cytokines. chem immunol. 1992;51:236-65. 52. cacev t, radosević s, krizanac s, kapitanović s. influence of interleukin-8 and interleukin-10 on sporadic colon cancer development and progression. carcinogenesis. 2008;29:1572-80. 53. andia dc, de oliveira nf, letra am, nociti fh jr, line sr, de souza ap. interleukin-8 gene promoter polymorphism (rs4073) may contribute to chronic periodontitis. j periodontol. 2011;82:893-9. 54. wang z, liu y, yang l, yin s, zang r, yang g. the polymorphism interleukin-8 -251a/t is associated with a significantly increased risk of cancers from a meta-analysis. tumour biol. 2014;35:7115-23. 55. kubbutat mh, jones sn, vousden kh. regulation of p53 stability by mdm2. nature. association of three gene variants with risk of pca-chen et al. review 2146 1997;387:299-303. 56. tovar c, higgins b, kolinsky k, et al. mdm2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer. mol cancer. 2011;10:49. 57. toledo f, wahl gm. regulating the p53 pathway: in vitro hypotheses, in vivo veritas. nat rev cancer. 2006;6:909-23. 58. momand j, jung d, wilczynski s, niland j. the mdm2 gene amplification database. nucleic acids res. 1998;26:3453-9. 59. bartel f1, meye a, würl p, et al. amplification of the mdm2 gene, but not expression of splice variants of mdm2 mrna, is associated with prognosis in soft tissue sarcoma. int j cancer. 2001;95:168-75. 60. chen t, yi sh, liu xy, liu zg. metaanalysis of associations between the mdm2t309g polymorphism and prostate cancer risk. asian pac j cancer prev. 2012;13:432730. association of three gene variants with risk of pca-chen et al. vol 12 no 03 may-june 2015 2147 u j all final for web.pdf 802 | adjustable male sling our experiences with placement of adjustable male sling, including a case of exstrophy-epispadias initial report abbas basiri, hossein kilani purpose: materials and methods: results: conclusion: argus is a simple and good device to control incontinence in men. it may also be keywords: urinary stress incontinence, suburethral slings, treatment outcome corresponding author: abbas basiri, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir received august 2012 accepted december 2012 urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran miscellaneous miscellaneous 803vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l introduction male stress urinary incontinence (sui) is mostly due to iatrogenic causes, particularly prostate surgeries. plantation has long been accepted as the gold standard for the treatment of male patients suffering from stress incontinence. in recent years, several adjustable and non-adjustable devices have been introduced to treat male incontinence, from adjustable device, has been used in several centers, and its tions and the possibility of medical treatment of prosthesis infection. materials and methods radical prostatectomy, adenomectomy, transurethral resection of the prostate, neurogenic bladder secondary to mypre-operative evaluations included history taking, physithereafter, those patients affected by sui due to sphincteric argus device is actually a synthetic silicone sling for males indirectly measured via reverse leak point pressure (rlpp). reverse leak point pressure is measured by the height of norsaline through the urethra is begun. 2 2o, regardless of pre-operative rlpp. in 2o 2 mainly because rlpp changed disproportionately during ar2 2o in myelomeninsymptoms, irritative symptoms, and complications, such as prosthesis infection, perineal pain, and device erosion. results to non-prostatectomy surgeries (one patient had neurogenic 2 and 3. urodynamic study could not be implemented in one figure 1. argus device containing silicon pad, silicone columns, and washers. adjustable male sling | basiri and kilani 804 | patient due to urethral pathology. 2o. clean intermittent catheterization), 6 had mild urinary inconbecause of irritative urinary symptoms and perineal pain. after argus implantation, 6 became dry (including one pamild urinary incontinence. totally incontinent before argus implantation. although this undergone ileocystoplasty, bladder neck reconstruction, and fascial sling. this patient had continuous incontinence before argus placement, but regained complete daily urinary contiance of incontinence. at the second procedure, the device at the point of the crossing to keep the columns crossed (figure 2). this patient is currently completely dry using clean intermittent catheterization three months after the procedure. 2 cmh2o postoperatively. in one patient, rlpp had actually 2 2o in spite of reappearance of incontinence symptoms. cmh2 2o, and in both patients rlpp had into raise rlpp. miscellaneous table 1. incontinence etiologies. etiology number radical prostatectomy 6 adenomectomy 5 transurethral resection of the prostate 4 neurogenic bladder 1 exstrophy-epispadiasis 1 total 17 table 2. urodynamic findings of post prostatectomy incontinent patients. nparameter filling phase capacity 1 low 13 normal compliance 1 low 13 normal voiding phase contractility 3 hypocontractile 11 stable normocontractile 805vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l figure 2. silicone columns crossed using hem-o-lok. adjustable male sling | basiri and kilani patient. after complete response to antibiotic and infection up accordingly. discussion (7) but high costs, complicated surgical procedure, and the need for patient manipulation for an acceptable void have prompted manufacturers to are either adjustable or non-adjustable. adjustable devices have the advantage of making surgeon able to change the in most of the studies on argus device, the improvement rate in 2o). alized. reverse leak point pressure measurement before and after crease or decrease in time. this change in rlpp might be bulbar urethra. assessment of the impact of the pelvic and prostatectomy incontinence. stress urinary incontinence in men might be due to other causes, such as neurogenic bladtable 3. urodynamic findings of non-post prostatectomy incontinent patients. nparameter filling phase capacity 0 low 2 normal compliance 0 low 2 normal voiding phase contractility 0 hypocontractile 2 stable normocontractile 806 | der and some congenital anomalies affecting the bladder bulbourethral sling procedure on incontinent patients suffering from neurogenic bladder has been evaluated. it has achieved after argus readjustment in the second procedure. wound and prosthesis infection occurred in 2 patients in our the device in this complication. naires. conclusion using adjustable sling in men results in acceptable continence rates in spite of the need for readjustments. our study debridement. conflict of interest none declared. references 1. steiner ms, morton ra, walsh pc. impact of anatomical radical prostatectomy on urinary continence. j urol. 1991;145:512-4; discussion 4-5. miscellaneous 2. kao tc, cruess df, garner d, et al. multicenter patient selfreporting questionnaire on impotence, incontinence and stricture after radical prostatectomy. j urol. 2000;163:85864. 3. kim sp, sarmast z, daignault s, faerber gj, mcguire ej, latini jm. long-term durability and functional outcomes among patients with artificial urinary sphincters: a 10-year retrospective review from the university of michigan. j urol. 2008;179:1912-6. 4. bauer rm, bastian pj, gozzi c, stief cg. postprostatectomy incontinence: all about diagnosis and management. eur urol. 2009;55:322-33. 5. romano sv, metrebian se, vaz f, et al. an adjustable male sling for treating urinary incontinence after prostatectomy: a phase iii multicentre trial. bju int. 2006;97:533-9. 6. romano sv, metrebian se, vaz f, et al. [long-term results of a phase iii multicentre trial of the adjustable male sling for treating urinary incontinence after prostatectomy: minimum 3 years]. actas urol esp. 2009;33:309-14. 7. tse v, stone ar. incontinence after prostatectomy: the artificial urinary sphincter. bju int. 2003;92:886-9. 8. hubner wa, gallistl h, rutkowski m, huber er. adjustable bulbourethral male sling: experience after 101 cases of moderate-to-severe male stress urinary incontinence. bju int. 2011;107:777-82. 9. dalpiaz o, knopf hj, orth s, griese k, aboulsorour s, truss m. mid-term complications after placement of the male adjustable suburethral sling: a single center experience. j urol. 2011;186:604-9. 10. bochove-overgaauw dm, schrier bp. an adjustable sling for the treatment of all degrees of male stress urinary incontinence: retrospective evaluation of efficacy and complications after a minimal followup of 14 months. j urol. 2011;185:1363-8. 11. athanasopoulos a, mcguire ej. efficacy of the bulbourethral autologous sling in treating male stress urinary incontinence: a three-year experience from a single center. int urol nephrol. 2010;42:921-7. 12. winters jc. male slings in the treatment of sphincteric incompetence. urol clin north am. 2011;38:73-81, vi-vii. urol_v03_no3_001_editorial.indd case report 184 urology journal vol 3 no 3 summer 2006 urethral tumors a report of 6 cases farid dadkhah, seyed yousef hosseini, majid aliasgari, alireza lashay urol j (tehran). 2006;3:184-7. www.uj.unrc.ir keywords: urethral tumors, subtotal urethrectomy, radical cystectomy department of urology, shaheed modarres hospital, shaheed beheshti university of medical sciences, tehran, iran corresponding author: farid dadkhah, md department of urology, shaheed modarres hospital, sa’adatabad, tehran, iran tel: +98 21 2207 4090 fax: +98 21 2207 4101 e-mail: dr_fdadkhah@yahoo.com received january 2006 accepted june 2006 introduction primary urethral carcinoma is a very rare cancer in men and generally occurs at the 5th decade of life.(1) its most common types are squamous cell carcinoma (scc), transitional cell carcinoma (tcc), and adenocarcinoma, in order of prevalence. the incidence of different histologic subtypes of these tumors vary at each part of the urethra.(2) the incidence rate of urethral tcc after radical cystectomy is 8% to 10% and its standard treatment is total urethrectomy.(1-3) some cases of late recurrence in the meatus have been reported following subtotal urethrectomy. this has put the value of this technique into question during the recent years.(3-5) between march 2005 and november 2005, 3 cases of primary urethral tumors were treated at modarres hospital. also, during this period, 3 cases of tumor recurrence in the urethra after radical cystectomy were diagnosed, in 2 of which, the patients had previously undergone subtotal urethrectomy and the recurrence occurred in the glandular part of the urethra. we report these 6 cases in our study. case report case 1 an 82-year-old man presented with obstructive urinary tract symptoms and bloody discharge from the urethra. on physical examination, a pedunculated tumor sized 1 × 1 cm was seen in the fossa navicularis which could be protruded by pressure. the distal part of the penis was completely figure 2. partial penectomy in case 1.figure 1. in case 1, a pedunculated tumor was found in the fossa navicularis which could be protruded by pressure. the distal part of the penis was completely indurated. urethral tumors—dadkhah et al urology journal vol 3 no 3 summer 2006 185 indurated and inguinal lymphadenopathy was not detected (figure 1). urine cytology revealed atypical and inflammatory cells. biopsy revealed a grade 3 tcc. metastatic workup was unremarkable. also, on cystoscopy, tumoral lesion was not seen in other parts of the urethra. the patient underwent partial penectomy (figure 2). the pathologic evaluation of the specimen revealed a grade 2/3 tcc with the involvement of the submucosa but with free margins. three months postoperatively, the patient was symptom-free. on cystoscopy, meatus was completely open and no recurrence was detected in the urethra and the bladder. urine cytology result was negative for malignancy. case 2 a 44-year-old man was referred with perception of a mass in penoscrotal junction of the urethra since 1 year earlier. the patient also complained of swelling and pain in the external genitalia during the previous 3 months. ulcerative gangrenous necrotic lesions were found on the penis and the scrotal skin, with a malodorous purulent discharge due to bacterial superinfection. the penile shaft was attached to the body only by a few skin bridges, and the penis was actually auto-amputated. bilateral firm inguinal lymph nodes were detected, fistulated to the skin on the left side (figure 3). a biopsy had been taken from the urethral mass and the pathology report was moderately differentiated invasive scc. after releasing the skin bridges, total penectomy was performed. biopsies from lymph nodes revealed invasive scc. case 3 an 83-year-old diabetic man with irritative lower urinary tract symptoms and obstruction was referred to our clinic. on urethroscopy, papillary and sessile lesions were seen in the penile, bulbous, and prostatic urethra. no tumors were found in the bladder and the intravenous urography did not show any abnormality. biopsy of the tumoral lesions revealed a grade 2 tcc with invasion to the fibrous stroma. radical surgery was not performed due to the poor general condition of the patient, and bilateral orchiectomy was performed. case 4 a 52-year-old man presented with a history of radical cystectomy and bilateral cutaneous ureterostomy in 2000. the patient had experienced bloody discharge from the urethra 2 years after the surgical operation. following the recurrence of the tumor in 2003, subtotal urethrectomy (with sparing the glandular urethra) had been performed. pathologic report was grade 2 tcc. in 2004, the patient had undergone left nephroureterectomy due to several tumoral lesions. the patient returned in 2005 with bloody discharge and clot passage. on physical examination, a 0.5 × 0.5-cm papillary tumor was seen in the fossa navicularis (figure 4). incisional biopsy was figure 4. a papillary tumor was detected in the fossa navicularis in case 4. figure 3. a bilateral firm inguinal lymphadenopathy fistulated to the skin was detected in case 2. urethral tumors—dadkhah et al 186 urology journal vol 3 no 3 summer 2006 performed on the lesion and a papillary tcc was reported. the lesion and a part of the glans of penis were excised. case 5 an 81-year-old man presented with bloody discharge from the meatus. the patient had a history of radical cystectomy and ileal pouch due to muscle-invasive bladder tumor (grade 2 tcc) about 9 years earlier. on urethroscopy, multiple papillary tumors were seen in the proximal bulbar and membranous urethra. total urethrectomy was performed and a grade 3 tcc was reported. case 6 a 46-year-old man had undergone radical cystectomy and urethrectomy due to bladder cancer (tcc). one year afterwards, the patient referred with pain and purulent discharge from the ulcerated and necrotic lesions on the penile glans. on physical examination, tender, firm, bilateral lymph nodes were detected in the groins. pathologic examination of the lesions revealed tcc. discussion primary urethral carcinoma urethral carcinoma is a rare condition especially in men,(1) and the most common presentations are bloody discharge from the meatus, urinary obstructive symptoms, and palpable masses in the anterior urethra. these tumors are usually detected in the bulbomembranous, penile, and prostatic urethra (60%, 30%, and 10%, respectively).(1-3) in men, 80% of the tumors are scc, while only 15% and 5% of these tumors are tcc and adenocarcinoma, respectively.(1-3) the histologic characteristics of a tumor is different depending on its anatomic location. in the posterior urethra, most detected tumors are tcc, while in the anterior part they are mostly scc.(2) transitional cell carcinoma is a panurothelial disease. thus, before regarding it as a primary urethral tumor, it is necessary to rule out the involvement of other parts of the urothelium (especially by carcinoma in situ). most of the tumors present in advanced stages as changes in voiding habits. therefore, attention to the possibility of urethral tumor in all patients with urinary tract symptoms is crucial. a complete history (focusing on hematuria, bloody discharge from the urethra, or perception of a mass in the urethra), physical examination (palpation of penis and corpus cavernosum up to the perineum), and paraclinical studies should be performed in all of these patients. in our first case, despite all diagnostic efforts, we could not detect any finding indicative of the involvement of the other urothelial parts. it could be concluded that the glandular urethral tcc of this patient was most probably isolated. this tumor is noticeable and very rare among the primary urethral tumors, because only 3% of all urethral tumors in men are tcc of the penis.(1-3) large tumors in the ventral part of the urethra can cause a periurethral mass or fistula. of other manifestations of urethral tumors are penile erosion, induration, and penile swelling.(2) but, auto-amputation of the penis due to the urethral cancer, as seen in our second case, is an extraordinary presentation, and we could not find any similar report in the literature. urethral tcc after radical cystectomy the incidence of urethral tcc after radical cystectomy is 8% to 10% and occurs 1.5 to 2.5 years therafter. most of the tumors manifest within 5 years.(3) risk factors associated with the tumor recurrence are multifocal primary tumor, carcinoma in situ, upper tract tcc, and the involvement of the bladder neck and prostatic urethra.(5) none of these factors are absolute contraindications for urethral preservation during radical cystectomy. it has been shown that taking frozen sections from the urethral margin during the operation is the most sensitive method for prediction of the tumor recurrence.(6,7) in some studies, it has been recommended to perform transurethral biopsy to evaluate the involvement of the prostate before radical cystectomy,(5,8) while in others, it has been emphasized that even prostate involvement cannot be a preclusion for orthotopic diversion if the margins are negative in frozen sections.(6,7,9) in the management of the patients who are candidates for radical cystectomy, a correct selection for functional or dry urethral preservation is of urethral tumors—dadkhah et al urology journal vol 3 no 3 summer 2006 187 utmost importance. also, it is essential to monitor the urethra for the rest of the patients’ life. physical examination, washing cytology, and urethroscopy are recommended at least annually. attention to the symptoms of tumor recurrence such as bloody discharge from the urethra, hematuria, and changes in voiding habits are necessary.(3) the ideal treatment for tumor recurrence in the urethra is total urethrectomy. attempts for subtotal urethrectomy (with meatal sparing) for facilitating the use of prosthesis has been accompanied by a high rate of tumor recurrence in glandular part of the urethra.(3,4,10,11) schellhammer and whitmore observed involvement of this part of the urethra in 27% of the patients who had undergone subtotal urethrectomy following the recurrence of the tumor after cystectomy.(12) in a cohort study on 1054 subjects with a follow-up more than 10 years, 2 patients have been diagnosed with late recurrence of the tumor in the meatus (3 and 11 years later), both with a history of subtotal urethrectomy.(3) endoscopic management with or without intraurethral treatments has been attempted in some cases of superficial tcc that recur after orthotopic diversion.(3,13,14) cases 4 and 6 were recurrences of tumor in the preserved urethras 2 and 1 years after the urethrectomy. in case 6, the recurrence was extensive and the corpus cavernosum and the penis were also involved, which made curative treatments impossible. in case 5, late recurrence of tcc (9 years after radical cystectomy) was observed in the posterior urethra. by reviewing the biologic models of oncogenesis, it can be concluded that late recurrences are mostly because of field changes in the whole urothelium rather than derivatives of primary tumor cloning. in summary, it seems that subtotal urethrectomy following radical cystectomy for facilitating the later use of prosthesis is accompanied by a higher recurrence rate in the glandular part of the urethra. the authors recommend total urethrectomy as the standard treatment in these patients, especially in iran where prosthesis is not commonly used. references 1. dalbagni g, zhang zf, lacombe l, herr hw. male urethral carcinoma: analysis of treatment outcome. urology. 1999;53:1126-32. 2. mostofi fk, davis cj jr, sesterhenn ia. carcinoma of the male and female urethra. urol clin north am. 1992;19:347-58. 3. clark pe, hall mc. contemporary management of the urethra in patients after radical cystectomy for bladder cancer. urol clin north am. 2005;32:199-206. 4. baron jc, gibod lb, steg a. management of the urethra in patients undergoing radical cystectomy for bladder carcinoma. eur urol. 1989;16:283-5. 5. faysal mh. urethrectomy in men with transitional cell carcinoma of bladder. urology. 1980;16:23-6. 6. lebret t, herve jm, barre p, et al. urethral recurrence of transitional cell carcinoma of the bladder. predictive value of preoperative latero-montanal biopsies and urethral frozen sections during prostatocystectomy. eur urol. 1998;33:170-4. 7. stein jp, clark p, miranda g, cai j, groshen s, skinner dg. urethral tumor recurrence following cystectomy and urinary diversion: clinical and pathological characteristics in 768 male patients. j urol. 2005;173:1163-8. 8. sevin g, soyupek s, armagan a, hoscan mb, dilmen c, tukel o. what is the ratio of urethral recurrence risk after radical ystoprostatectomy for bladder cancer? int urol nephrol. 2004;36:523-7. 9. liedberg f, chebil g, davidsson t, malmstrom pu, sherif a, mansson w. [transitional cell carcinoma of the prostate in cystoprostatectomy specimens]. aktuelle urol. 2003;34:333-6. german. 10. sarosdy mf. management of the male urethra after cystectomy for bladder cancer. urol clin north am. 1992;19:391-6. 11. clark pe, stein jp, groshen sg, et al. the management of urethral transitional cell carcinoma after radical cystectomy for invasive bladder cancer. j urol. 2004;172:1342-7. 12. schellhammer pf, whitmore wf jr. urethral meatal carcinoma following cystourethrectomy for bladder carcinoma. j urol. 1976;115:61-4. 13. varol c, thalmann gn, burkhard fc, studer ue. treatment of urethral recurrence following radical cystectomy and ileal bladder substitution. j urol. 2004;172:937-42. 14. huguet j, palou j, serrallach m, sole balcells fj, salvador j, villavicencio h. management of urethral recurrence in patients with studer ileal neobladder. eur urol. 2003;43:495-8. 97 urology journal unrc/iua vol. 2, no. 2, 97-101 spring 2005 printed in iran female urology measurable changes in hydronephrosis during pregnancy induced by positional changes: ultrasonic assessment and its diagnostic implication mohammad rajaei isfahani,* mehdi haghighat department of urology, kashani hospital, shahrecord university of medical sciences, shahrecord, iran abstract introduction: unilateral or bilateral dilation of the ureters occurs commonly during pregnancy. ultrasonography is a suitable diagnostic method in hydronephrosis; however, it cannot differentiate obstructive from nonobstructive hydronephrosis. our aim was to evaluate measurable changes in hydronephrosis induced by a mother's positional changes using ultrasonography to differentiate hydronephrosis during pregnancy from pathologic etiologies. materials and methods: pregnant women presenting for routine ultrasonography were enrolled in this study. history taking, and physical examination were done. ultrasonography was performed to determine gestational age, parity, fetal presentation, presence or absence of hydramnios, and hydronephrosis and its severity. thirty minutes after changing position (flank position or on all fours), patients were reevaluated by ultrasonography to determine the severity of hydronephrosis. results: of 59 pregnant women with an average age of 25.4 years, 33 (55.9%) had no urinary complaint during pregnancy. forty-one women (69.5%) had hydronephrosis, 24 (58.5%) of whom only in right kidney. the severity of hydronephrosis in one kidney was related with the severity of hydronephrosis in the other kidney (p = 0.007). fetal presentation and gestational age were not associated with hydronephrosis. risk of hydronephrosis was higher in the first pregnancy (likelihood ratio = 6.8, p = 0.009). thirty minutes after changing positions, the anteroposterior pelvis diameter significantly decreased in the right and left kidneys (p = 0.004, p = 0.001). conclusion: ultraonography in two steps with positional change (dynamic ultrasonography) may be used to differentiate hydronephrosis of pregnancy from other pathologies. key words: hydronephrosis, pregnancy, ultrasonography, diagnosis introduction one hundred and fifty years ago, cruveilhier noted that pregnancy can induce obstruction of the upper urinary tract. imaging studies including intravenous pyelography and ultrasonography have shown that dilation of the upper urinary tract develops in most pregnant women.(1,2) one study from italy has demonstrated that asymptomatic, unilateral or bilateral hydronephrosis during pregnancy can be received september 2004 accepted april 2005 *corresponding author: department of urology, kashani hospital, shariati st., shahrecord, iran. e-mail: dr_mrajaei@yahoo.com ultrasonic assessment of hydronephrosis during pregnancy98 seen in 80% to 90% of pregnant women in the third trimester, with the right side being the most frequently affected side.(3) mechanical pressure of an enlarged uterus is presumed to be the main cause of hydronephrosis and stasis during pregnancy. acute renal failure during pregnancy due to ureteral obstruction in patients with a single kidney has been reported (4), although acute renal failure due to bilateral obstruction is rare.(5) although obstruction is regarded as the main cause of hydronephrosis, several researchers also have emphasized the role of progesterone and gonadotropins in ureteral stasis and its subsequent complications in pregnancy.(6,7) physiologic changes during pregnancy may obscure the manifestations of ureteral obstruction. nausea, vomiting, back pain, urinary frequency, and dysuria could be symptoms of ureteral obstruction or of the pregnancy itself. a definite diagnosis based on these symptoms, and their association with hydronephrosis during pregnancy, is a pivotal challenge to urologists. the progression of signs or localization of flank pain suggests non—pregnancy-induced ureteral obstruction; particularly, if it is associated with fever or urinary tract infection.(8 p422-3) however, more precise paraclinical assessment is needed. since exposure to 1 rad of x-ray leads to a 2.4-fold increased risk of developing malignancies in infants, it would seem prudent to avoid radiographic assessment.(9) furthermore, radiographs can increase the risk of fetal anomalies in the first and second trimesters of pregnancy. in the clinic, ultrasonography is considered of the imaging modality of choice to evaluate the kidney.(10) accordingly, we studied ultrasonic methods, and hereby present a simple and innovative method of using ultrasonography to differentiate hydronephrosis during pregnancy from hydronephrosis caused by ureteral obstruction due to nonpregnancy pathologies such as stone, tumor, and others. materials and methods in a cross-sectional study, we evaluated the ultrasonographic results of consecutive pregnant women with various ages, parity, and gestational ages who had been referred to hajar hospital in shahrekord, iran, for routine follow-up. history was taken regarding frequency, dysuria, flank pain, past history, and previous surgery. ultrasonography was performed, and fetal age, number of fetuses, presentation of fetus, and presence of hydramnios were assessed by a single radiologist. the presence of hydronephrosis and its severity in the left and right kidney were evaluated separately. hydronephrosis of the pelvis with a maximal diameter of less than 15 mm was regarded as mild. a maximal diameter between 15 mm and 20 mm was defined as moderate, and maximal diameters greater than 20 mm were considered severe. patients with hydronephrosis were positioned for 20 to 30 minutes in such a way that the uterus and fetus were away from the hydronephrosis side (they were asked to lie on the opposite side of the hydronephrosis or to bend over on their hands and knees). then, ultrasonography was performed from the unit with hydronephrosis in this position to detect any changes in hydronephrosis, pelvis, and calyx sizes. spss software (statistical package for the social sciences, version 9.05, ssps inc, chicago, ill, usa) was used for statistical analyses. measured sizes before and after positional changes were compared using a paired t test. analyses of the data regarding the frequency and severity of left-side and right-sided hydronephrosis, fetal presentation, parity, mother's age, and gestational age were done with a chi-square test. results of 59 pregnant women with a mean age of 25.4 years (range, 17 to 38 years), 41 (69.5%) had unilateral or bilateral hydronephrosis. thirtythree patients (56%) had no urinary complaint during pregnancy. of the 41 patients with hydronephrosis, 16 (39%) had flank pain, 11 (26.8%) had dysuria and frequency, and 2 (4.9%) had incontinence. unilateral right-side hydronephrosis was present in 24 (58.5%) patients with hydronephrosis, while 6 (14.6%) patients had unilateral left-sided hydronephrosis (table 1). the severity of hydronephrosis in one kidney was related with the severity in the other kidney (p = 0.007). forty of 58 pregnant women had fetuses with cephalic presentation, 30 (75%) of whom developed hydronephrosis; 18 had fetuses with a breech presentation, 10 (55.6%) of which developed hydronephrosis (p = 0.13). twenty-two of 25 (88%) women with no previous delivery, 13 of 25 (52%) with 1 previous rajaei isfahani and haghighat 99 delivery, and 6 of 8 (75%) with more than 1 previous deliveries had hydronephrosis. accordingly, the likelihood ratio of hydronephrosis in the first pregnancy compared with that of subsequent pregnancies was 6.8 (p = 0.009). however, there was no association of parity with the severity of hydronephrosis. of 23 patients under 25 years old, 18 had hydronephrosis; of 17 with the age range of 25 to 30 years, 11 had hydronephrosis; and of 17 patients older than 30 years, 10 had hydronephrosis. prevalence and severity of hydronephrosis were not significantly related with maternal age. table 2 shows the frequencies of hydronephrosis in the subgroups of different gestational ages. gestational age was not associated with hydronephrosis (p = 0.54). table 3 shows the anteroposterior diameters of the pelvis and changes in its ultrasonic measurements before and 30 minutes after positional change in the left and right kidneys. a significant decrease was found in the right and the left kidneys 30 minutes after changing the patient's position (p = 0.004, p = 0.001). discussion in many clinical situations, ultrasonography remains the modality of choice for evaluation of the kidney.(10) this is an inexpensive and readily available diagnostic instrument for use in at-risk patients whose kidneys should be regularly monitored. ultrasonography is the first diagnostic step in evaluating kidneys in patients with azotemia, those who are sensitive to contrast media, pregnant women, and children. however, false negative and false positive results for hydronephrosis are possible. on sonography, hydronephrosis appears as an anechoic or hypoechoic region of fluid collection that splits the white central echo of the renal sinus. it has a shape of the calyces and renal pelvis (pyelocaliectasis). since ultrasonography cannot assess the function of the kidneys, we are not able to distinguish obstructive from nonobstructive hydronephrosis. some authors have attempted to diagnose acute and chronic obstructions by measuring the resistive index of the intrarenal arteries.(8 p134,11,12) the diagnostic value of ultrasonography in pregnant patients may be enhanced by distinguishing hydronephrosis during pregnancy from other ureteral obstruction pathologies (eg, by monitoring the increase in hydronephrosis during pregnancy, defining the normal sizes of hydronephrosis at different gestational weeks,(13) or studying the ureteral jet by color doppler ultrasonography in normal pregnancy and in pathologic obstruction(14)). the purpose of this survey was to explore the accuracy of ultrasonography for differentiating table 1. frequency of hydronephrosis and the classification according to its severity in the right and left kidneys. the prevalence and severity of hydronephrosis was higher in the right kidney than in the left one. the severity of hydronephrosis in the units was related (p = 0.007). table 2. the frequency of hydronephrosis at different gestational weeks. there were no statistically significant relationships between hydronephrosis and gestational week (p = 0.54). severity of hydronephrosis in the right kidney number (%) no mild moderate severe total no 0 (0.0) 17 (41.5) 6 (14.6) 1 (2.4) 24 (58.5) mild 6 (14.6) 2 (4.9) 6 (14.6) 1 (2.4) 15 (4.9) moderate 0 (0.0) 1 (2.4) 1(2.4) 0 (0.0) 0 (0.0) severe 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) s e v e r ity o f h y d r o n e p h r o sis in th e le ft k id n e y total 6 (14.6) 20 (48.8) 13 (31.7) 2 (4.8) 41 (100) number (%) less than 25 weeks between 25 and 30 weeks more than 30 weeks total no hydronephrosis 4 (44.4) 10 (33.3) 4 (23.5) 18 hydronephrosis 5 (55.6) 20 (66.7) 13 (76.5) 38 total 9 (100) 30 (100) 17 (100) 56 ultrasonic assessment of hydronephrosis during pregnancy100 hydronephrosis during pregnancy from other pathologies. by changing patient position, we were able to measure any positive or negative changes in hydronephrosis severity. hydronephrosis was observed in 69.5% of 59 patients, 85.3% of whom had developed hydronephrosis in the right kidney and 41.5% in the left. in 1998, faundes and colleagues performed serial ultrasonography in 1506 pregnant women and in 181 women after delivery. they found that 50% of pregnant women had urinary system dilation during the second and third trimesters of pregnancy.(13) in 1979, erickson and coworkers noted that 60% to 65% of 449 pregnant women presented with hydronephrosis.(15) another study showed that hydronephrosis developed on the right side in 90% of patients and in the left in 67%.(16) thus, our results were similar to those of the mentioned studies. since left and right hydronephrosis have a common etiology in pregnancy, it is probable that the severity of hydronephrosis in one kidney is related to that of the other, as indicated in table 1. our study showed that pressure of the fetus's head on the pelvis in those with cephalic presentation could be an additional factor in hydronephrosis during pregnancy. however, the difference in the rate of hydronephrosis in cephalic presentation compared with breech presentation (75% vs 55.6%), was not statistically significant. further studies are recommended to determine the relationship between fetal presentation and hydronephrosis during pregnancy. in this study, hydronephrosis during pregnancy was inversely related with parity, as its frequency was higher in first pregnancies. this is in agreement with other studies.(8 p422-3) however, some researchers have not confirmed this finding.(3,16) in some studies, the incidence of hydronephrosis has been shown to increase with gestational age, which may be the result of fetal growth (ie, an increase in uterus size and pressure on the ureters). erickson and colleagues have reported an increase in the severity of hydronephrosis from the 21st week up to the 30th gestational week in 449 pregnant women. they have shown that the degree of hydronephrosis remains stable for the next 10 weeks.(15) however, the incidence of hydronephrosis in our patients was not associated with this factor (table 2). no multiple pregnancy or hydramnios was found in this study, so that we could not evaluate the severity of hydronephrosis in these conditions. in 1979, roberts(17) emphasized some findings in this regard, some of which have been shown in other studies: 1. an increase in the basal pressure of the ureters and obstructive changes over the pelvic brim occur in pregnancy. the resultant pressure decreases with positional changes, by which the uterus is kept away from the ureter.(18) 2. it has been reported that the contraction of a normal ureter is preserved during pregnancy, which contrasts the hypothesis of ureteral dilation in pregnancy as a result of atony caused by hormonal factors. 3. hydronephrosis during pregnancy does not develop in those whose ureter does not pass by the pelvic margin (such as those with pelvic kidney or ileal conduit). 4. hydronephrosis during pregnancy does not occur in animals whose ureters are not adjacent to the uterus, as they stand on all fours.(19) 5. in pregnant monkeys, when the uterine pressure is removed from ureter during laparotomy or when the fetus and placenta are removed from uterus, the ureteral pressure returns to normal levels. regarding the above-mentioned findings, it seems reasonable to observe a significant decrease in the anteroposterior diameter of pelvis when comparing the measurements before and 30 minutes after positional changes in ultrasonography. table 3. the size (mean ± standard deviation) of the anteroposterior diameter of the pelvis and its changes before and after positional change (mm) in patients with hydronephrosis. anteroposterior diameter of the pelvis (mm) number of patients before positional change after positional change difference p value right-side hydronephrosis 36 15.4 ± 3.6 10.8 ± 3.8 4.7 ± 2.5 0.004 left-side hydronephrosis 17 12.8 ± 1.7 8.5 ± 3.4 3.4 ± 2.6 0.001 rajaei isfahani and haghighat 101 conclusion positional changes in pregnant women with hydronephrosis can alter the severity of mechanical obstruction caused by the enlarged uterus. thus, comparing the measurements of the pelvis with ultrasonography before and after a positional change (during which the uterus moves away from the ureters). while acknowledging the limitations of this study and the need for further investigation, we can conclude that the size of the anteroposterior diameter of the pelvis (and calices to a lesser extent) in different positions could be helpful in the differential diagnosis of hydronephrosis of pregnancy and other pathologies. references 1. cietak ka, newton jr. serial qualitative maternal nephrosonography in pregnancy. br j radiol. 1985;58:399-404. 2. fried am, woodring jh, thompson dj. hydronephrosis of pregnancy: a prospective sequential study of the course of dilatation. j ultrasound med. 1983;2:255-9. 3. croce p, signorelli p, chiapparini i, dede a. [hydronephrosis in pregnancy. ultrasonographic study]. minerva ginecol. 1994;46:147-53. italian. 4. homans dc, blake gd, harrington jt, cetrulo cl. acute renal failure caused by ureteral obstruction by a gravid uterus. jama. 1981;246:1230-1. 5. d'elia fl, brennan re, brownstein pk. acute renal failure secondary to ureteral obstruction by a gravid uterus. j urol. 1982;128:803-4. 6. guyer pb, delany d. urinary tract dilatation and oral contraceptives. br med j. 1970;4:588-90. 7. fainstat t. ureteral dilatation in pregnancy: a review. obstet gynecol surv. 1963;18:845-60. 8. gulmi fa, felsen d, vaughan jr ed. pathophysiology of urinary tract obstruction. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 134,422-3. 9. loughlin kr. management of urologic problems in the pregnant patients. aua update series. 1997;16:10-15. 10. caskey ci. ultrasound techniques for evaluating renal masses, renal obstruction, and other upper urinary tract pathologies. ultrasound q. 2000;16:10-5. 11. platt jf, rubin jm, ellis jh. acute renal obstruction: evaluation with intrarenal duplex doppler and conventional us. radiology. 1993;186:685-8. 12. hata t, hata k, aoki s, takamiya o, murao f, kitao m. renal arterial blood flow velocity waveforms in pregnant women. am j obstet gynecol. 1987;157:1269-71. 13. faundes a, bricola-filho m, pinto e silva jl. dilatation of the urinary tract during pregnancy: proposal of a curve of maximal caliceal diameter by gestational age. am j obstet gynecol. 1998;178:1082-6. 14. asrat t, roossin mc, miller ei. ultrasonographic detection of ureteral jets in normal pregnancy. am j obstet gynecol. 1998;178:1194-8. 15. erickson lm, nicholson sf, lewall db, frischke l. ultrasound evaluation of hydronephrosis of pregnancy. j clin ultrasound. 1979;7:128-32. 16. peake sl, roxburgh hb, langlois sl. ultrasonic assessment of hydronephrosis of pregnancy. radiology. 1983;146:167-70. 17. roberts ja. hydronephrosis of pregnancy. urology. 1976;8:1-4. 18. sala nl, rubi ra. ureteral function in pregnant women. ii. ureteral contractility during normal pregnancy. am j obstet gynecol. 1967;99:228-36. 19. traut hf. inflammation of the upper urinary tract complication the reproductive period of woman: collective review. int abstr surg. 1938;67:568. percutaneous no-scalpel vasectomy via one puncture in china liping li,1,2 jialiang shao,1 xiang wang1 corresponding author: xiang wang, md department of urology, huashan hospital of fudan university, 12 wulumuqi middle road, shanghai 200040, china. tel: +86 21 5288 7080 fax: +86 21 5288 8279 e-mail: seanw@medmail.com.cn received april 2013 accepted december 2013 1 department of urology, huashan hospital of fudan university, shanghai 200040, china. 2 department of urology, zhongshan hospital of fudan university, shanghai, 200032, china. purpose: toevaluatetheefficacyandpostoperativemorbidityofpercutaneousno-scalpel vasectomy(nsv)viaonepunctureinchina. materials and methods:atotalof150menvisitingoutpatientclinicofthesurgerydepartmentofurology,huashanhospitalanditsbaoshanbranchoffudanuniversity,optedfor percutaneousnsvwithlocalanesthesia.theclinicaldataof150whounderwentmodified nsv(mnsv)wereretrospectivelycomparedwiththoseof120patientswhounderwent standardnsv(snsv).theresultsandfollow-upwererecorded. results:thereviewedaverageoperativetimewas9.8min(range8to20min).averageincisionallengthwas5mm(range4to8mm).patientsreportedcompleterecoveryinanaverage of8.5days(range4to14days).thecomplicationrateswereextremelylowwiththismodifiedtechnique.onlyonecaseoflatehealedincisionwasobserved(0.67%). conclusion:percutaneousnsvviaonepuncturewasprovedtobeapainlessandeffective formofpermanentcontraceptionwithanextremelylowcomplicationrate. keywords: vasectomy;adverseeffects;methods;prospectivestudies;follow-upstudies;surgicalprocedures;minimallyinvasive. 1452 | sexual dysfunction and infertility sexual dysfunction and infertility 1453vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l no-scalpel vasectomy | li et al introduction vasectomyisasimpleandreliablemethodofmalepermanentcontraceptionthathasachievedwide-spreadacceptanceintheworld.varioussurgicalapproachestooccludethevashavebeenrecommendedoverthe years,includingtheconventionalincisionvasectomy(civ) througha2to3cmincisionandthestandardno-scalpelvasectomy(snsv)madethrougha2to3mmpuncturewound onthescrotum,bothofwhichwerefirstintroducedfromchina and used in other countries.(1,2)nsvhasbeenprovedtobe aminimallyinvasiveapproach,whichreducestheincision size,proceduretime,pain,bleedingandpostoperativecomplicationscomparedwithciv.(3-8)yearly16millionchinese menundergothisprocedure,whichistraditionallyperformed through 1 or 2 standard scrotal incisions.(9)somesurgeons havecomplainedthatthesnsvtechniqueis,infact,more difficulttoperformthanthecivtechnique.(10)therefore,in thisstudy,wereportedamnsvwithonlyonetinypuncture inscrotum. materials and methods atotalof150menwhohavebeenundergonemnsvinour center were analyzed retrospectively compared with those 120menwhohavehadsnsv.therewerenosignificantdifferencesbetweenthese2groupsintermsofageandmean numberofchildren(p >.05).thecharacteristicsofsubjects areshownintable.thosewhoagreedforvasectomymust sign an informed consent form and ensure the following: shouldhavehadatleastoneormorechildren,shouldhaverealizedtheriskofthepossiblecomplicationsandshouldhave obtainedtheconsentoftheirspousestoundergothesterilizationmethod.theexclusioncriteriaweresubjectswithtesticularcancer,activescrotalskininfections,epididymitis,orchitis,balanitisandsomeothersurgicalcontraindication.all vasectomieswereperformedbytheresponsibleauthorand hisassistant.mainoutcomemeasureswerethepatients’characteristics, hospital stay, incisional length, recurrence rate, complicationrate,operatingdurationandcomplicationrate. thesurgicalprocedurewassimilartopercutaneoussnsv asreportedbyliandcolleagues.(1)themethodforsnsvis illustratedinfigures1-5.afewmodificationsweremadeas thefollowing:thepointofpuncturewassingletocomplete bilateralvasectomyandlocatedonthescrotalsurfaceatthe medianrapheapproachingtherootsegmentofpenis;after puncturingthroughthescrotalskin,adissectingforcepsand twono-scalpelhemostatswereusedtoisolatethevasscrupulouslyandthewoundwasclosedbymedicaladhesive. results inthegroupofmnsv,theaverageoperativetimewas9.2 minfromsterilizingtheskintoclosingtheskin.averageincisionallengthwas5mm.patientsreportedcompleterecovery figure 1. fixing one vas to the scrotal surface at the median raphe using the three-finger technique to stabilize the vas. performing a local vasal nerve block using a needle injection with 1-2% lidocaine without epinephrine. figure 2. sharpened no-scalpel hemostat pierces skin. 1454 | inanaverageof8.0days.themeandurationoffollow-upwas 6.5months.completeazoospermiawasachievedin100%of men3monthspostoperativelybyatleasttwosemenanalyses. mostofthemen(92%)resumedworkonthesamedayandall (100%)resumedworkwithinaweek.thecomplicationrates wereextremelylow:therewasonediabeticpatientwithlate healedincisionwithoutinfection(0.67%).thewounddidnot healwithintendayspostoperatively.bycontrollinghisblood sugarwithinsulin,thewoundhealedlater(table). discussion nsvwerefirstintroducedfromchinaandthenusedinother countries.(1,2)ithasbeendemonstratedthatitresultsina smallerwoundandshorteroperationtimecomparedtothe civprocedure,beingthemostreliableandthesafestmethod currentlyavailableformalecontraception.(11)becauseofits minimallyinvasivenaturemoreandmorefamiliesinchina alsoselectnsvforcontraceptionrecently. withtwentyyearspassingaway,therewerenumerousmethods improving nsv. owing to the initial needle puncture thatisusuallythecommonestvoicedconcernsforthepatient,arevolutionofapplicationofnovelandactuallypainlessanesthesiahasmadetheproceduremorecomfortable.it wascalledno-needlejetinjectionorno-needlevasectomy. thistechniqueusedaspecialinstrumentthatdeliveredvia highpressureinjectorthroughtinyheadtobeneathskinand throughouttissuearoundvasachievingcompleteanesthetic blockofthevas.(12)asaresultofeconomyandtechnique aspectinchina,thisadvancedandgreatanestheticmethod hasnotbeenusedinourstudy.attheaspectofsurgicalprocedure,therewerealsosomemodificationsofnsv. chendividednsvintoinstrument-dependentno-scalpelvasectomy(idnsv)whichispubliclyknownandinstrumentindependent no-scalpel vasectomy (iinsv).(13) the main differencebetweenthemistwospecializedinstruments(an extracutaneousfixation-ringclampandadissectingclamp) whicharerequiredintheformer.theiinsvtechniqueoffers analternativeoptionforvasectomistswheneverthespecific instrumentsofstandardnsvareunavailable.jonessuggested apercutaneousvasectomy,whichtoavoidthemostdifficult stepwhichisfixationofthevastoskinusingtheringclamp. (10)thesteeplearningcurveofnsviswellknown.itwas statedthat15to20casesarerequiredtodevelopproficiency figure 3. spreading scrotal wall to expose vas. figure 4. ringed clamp is placed into incision to isolate and extract vas. figure 5. an 1 cm piece of vas is excised and the occlusion is accomplished by ligation and cautery of the lumen of both vasal ends. sexual dysfunction and infertility 1455vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l no-scalpel vasectomy | li et al withtheprocedureevenforexperiencedvasectomists.(1)this describedsimplemodificationmaneuversaremasteredeven bymostjuniorresidentswithinfewerthan10cases.numeroustechniquesforvasalocclusionhavebeendevelopedand wereusedallovertheworld.theseconsistedofexcisionof asegmentofvasofvariouslengths,ligationofthevaswith eithersutureorclips,foldingbacktheendofthevasonto itself,fascialinterpositionbetweenthecutendsofthevas, andcauteryofthelumenofthevas(electricorthermal).(8) becauseoftheheterogeneityofstudydesigns,surgicaltechniqueused,andassessmentofresults,therewasnoevidence thatsomeocclusionmethodwasmoreeffectiveintermsof contraceptionandassociatedwithalowerriskofcomplicationscomparedwithanyotherocclusionmethod.(8) as a result,percutaneousidnsvwithsomemodificationwasused in our study. thecomplicationrateswerelowwithnsv.themostcommoncomplicationswereinfectionandhematoma.infection wasveryrarewhennsvwasperformedundersterileconditionsandwasusuallycoexistentwithanunderlyinghematoma.(3)itwaswelldocumentedthatincidenceofcomplicationswascloselyrelatedtotheexperienceofthephysician. (4)themeanincidenceofhematomaislessthan0.5%.(3,14) inourstudytherewasone(0.67%)diabeticpatientwithalate healedincision.thispatienthadpoordiabetesmellituscontrol.fastingbloodsugarwas9mmol/l.inordertocontrol theglycemia,insulinwasadministered.thelatehealedincisionwasfullyrecoveredlater.inbrief,diabetesmellitusand uncontrolledglycemiawerethemainreasonforthesecomplications.itwarnedthatdespiteofasmallincision,thosewho areinpoorhealthconditioncouldbeawareofthem.some measuresshouldbetakentoimproveit.comparedwithother studies,theeffectivenessandmainoutcomewereaccordant andseemedevenbetter(table). inouropinion,thisresultwasprofitedfromsomemodificationsofpercutaneousnsv.asinglepunctureinscrotumto completebilateralvasectomycanreducethetotalincisional length.thepointofpuncturechosenonthescrotalsurface atthemedianrapheapproachingtherootsegmentofpenis canreservealongervasnext totheepididymalend.this improvementcandecrease tensionof theepididymisafter ligation. it can increase the contraception rate and relieve postoperativepain.adissectingforcepsandtwono-scalpel hemostatswereusedtoisolatethevasscrupulously.itcan isolatethevaspreciselywithoutinjuringthevesselsofthevas andreducetheincidenceofhematomaformation.thewound was closed by medical adhesive to prevent contamination withwaterandmicroorganisms.ithelpedtoprotecttheincitable. outcome measures of studies comparing our study with others. effectiveness complications no. (%) study sample size operation time (min) incisional length (mm) post-vasectomy semen analysis hematoma infection others total timing failure rate no. (%) kumar et al. 1999(7) 4253 9.5 not reported 3 months not reported 2 (0.047) 3 (0.07) 3 painful nodules (0.07) 2 vasal fistulae (0.047) 10 (0.2) labrecque et al. 2002(8) 3761 not reported not reported 112 days 104 (2.8) 24 (0.64) 7 (0.19) 90 vasitis/orchiepididymitis (2.4) 20 granuloma (0.53) 2 other unspecified (0.05) 143 (3.8) jones, 2003(13) 573 9.3 8.4 2 to 4 weeks 1 (0.17) not reported not reported not reported not reported chen, 2004(12) 215 15.2 7.8 not reported 1 (0.4) 6 (2.4) 1 (0.4) 4 granuloma (1.6) 11 (5) our study 150 9.2 5.0 3 months 0 (0.00) 0 (0.00) 0 (0.00) 1 late healed incision (0.67) 1 (0.67) 1456 | sionagainstinfection.patientscaneventakeshoweronthe dayofoperation. conclusion weconcludedthatpercutaneousnsvviaonepunctureisa virtuallypainlessandextremelyeffectiveformofpermanent contraceptionwithanextremelylowcomplicationrate. references 1. li sq, goldstein m, zhu j, huber d. the no-scalpel vasectomy. j urol. 1991;145:341-4. 2. huber d. no-scalpel vasectomy: the transfer of a refined surgical technique from china to other countries. adv contracept. 1989;5:217-8. 3. schlegel pn agm. vasectomy. in: m g, m g.m gs. surgery of male infertility: new york, wb saunders; 1995. p. 35-45. 4. goldstein m. surgical management of male infertility and other scrotal disorders. in: walsh pc rave, walsh pc rave. walsh pc raves. campbell’s urology. 8thed: new york, wb saunders; 2002. p. 1541-7. 5. viladoms jm, li ps. vasectomia sin bisturi. arch esp urol. 1994;47:695-701. 6. skriver m, skovsgaard f, miskowiak j. conventional or li vasectomy: a questionnaire study. br j urol. 1997;79:596-8. 7. kumar v, kaza rm, singh i, singhal s, kumaran v. an evaluation of the no-scalpel vasectomy technique. bju int. 1999;83:283-4. 8. labrecque m, dufresne c, barone ma, st-hilaire k. vasectomy surgical techniques: a systematic review. bmc med. 2004;2:21. 9. nian c, xiaozhang l, xiaofang p, qing y, minxiang l. factors influencing the declining trend of vasectomy in sichuan, china. southeast asian j trop med public health. 2010;41:1008-20. 10. jones js. percutaneous vasectomy: a simple modification eliminates the steep learning curve of no-scalpel vasectomy. j urol. 2003;169:1434-6. 11. liu x, li s. vasal sterilization in china. contraception. 1993;48:25565. 12. weiss rs, li ps. no-needle jet anesthetic technique for no-scalpel vasectomy. j urol. 2005;173:1677-80. 13. chen kc. a novel instrument-independent no-scalpel vasectomy a comparative study against the standard instrument-dependent no-scalpel vasectomy. int j androl. 2004;27:222-7. 14. kendrick js, gonzales b, huber dh, grubb gs, rubin gl. complications of vasectomies in the united states. j fam pract. 1987;25:2458. sexual dysfunction and infertility 1656 | in present study the authors aimed to transplant spermatogonial stem cell (ssc) after tes-ticular torsion and ischemia. the rational for the study has not been mentioned clearly. in mammalian testes, sscs are located at the basement membrane of seminiferous tubules. they produce the spermatogenic family, guaranteeing lifelong fertility. an important concern in young prepubertal boys at risk for stem cell loss, i.e. patients undergoing radiotherapy and/ or chemotherapy for malignancy, is fertility preservation in the future. the cryopreservation and transplantation of ssc has been proposed as a fertility preservation strategy for these patients.(1) like other stem cells, sscs are undifferentiated and have the capacity of selfrenewal. the studies of sscs are complicated because these cells are rare and no distinctive recognizing characteristics have been described to date. spermatogonial stem cells contribute only 0.03% of the total germ cell population in rodent and human testis.(2) thus, their few numbers and the absence of specific markers are the main problems to their determination characterization. careful isolation of germ cells, including stem cells, is mandatory prior to transplantation. therefore the validation of surface markers for the isolation of germ cells is required. to address this issue surface markers should be used. isolated germ cells must contain spermatogonial stem cells that can undertake spermatogenesis after transplantation. mhc class i, c-kit, and thy-1.2 are surface markers for spermatogonial stem cells. in addition, fluorescence-activated cell sorting (facs), combined with ssc transplantation is a prevailing modality that can help researchers to scientifically detect cell surface molecules of sscs. it is not clear how sscs have been isolated from other cells in present study. this step is vital. what if there is a risk that the biopsy contains malignant cells? it is clear that this is an experimental study, but the main implication is generalization the results for humans. in addition, editorial comment to: recruiting testicular torsion introduces an azoospermic mouse model for spermatogonial stem cell transplantation mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com sexual dysfunction and infertility 1657vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l testicular torsion as candidate model for sscs transplantation | azizollahi et al due to very scarce number of sscs, accurate isolation of sscs without using specific markers or other related tools, are impossible. jahnukainen and colleagues reported that transplantation of testicular cells from leukemic rats induces transmission of leukemia.(3) therefore, it has outmost importance to detect even the slightest contamination of the testicular tissue. another drawback of present study is defining the successfulness of ssc transplantation procedure. the best method to confirm that transplanted sscs yield functional sperm is to show their ability to fertilize oocytes. the autologous transplant approach used in this study is not amenable to fertilization studies. therefore, an allogeneic transplant model where donor testis cells from unrelated individual animals are transplanted into recipient testes is needed to draw accurate conclusion. it is important to document that transplanted sscs can produce sperm in higher primate prototypes that have the greatest applicability to human testis anatomy and physiology. likewise it is important to document in primates that the testicular environment is perfect to maintain spermatogenesis from transplanted sscs following depletion. another potential source of bias in ssc investigation is the differentiation between proliferation and self-renewal. the differentiation between sscs and progenitor cells is especially vital in the analysis of in vitro data. because the definition of a stem cell is based on functional criteria, it is awkward to define cultured cells as stem cells merely because they proliferate. detecting the number of colonies in a recipient testis seems easy, but there are some potential problems. when sscs are transplanted, donor cells yield colonies of various sizes. because a single ssc results in a single colony, this difference in size demonstrates that the proliferative potential of individual sscs vary. on the contrary, individual stem cells might not result in single colonies under other experimental conditions. the clonal origin of a germ cell colony can be documented only via transplantation experiments and cannot be pragmatic to other cases. although germ cell transplantation has also been tried in large animal species and higher primates, low transplantation competence and complicated recipient preparation make it improbable for practical and clinical applications. the best-case scenario would be to recover sscs from a piece of testis for germ line stem (gs) cell establishment and direct the cells in vitro for sperm production after required genetic manipulations. it would be worthwhile to quote the clinical implication of this study. steady progress regarding ssc transplantation techniques is continuing and this is why many investigators and clinicians are becoming gradually assured that ssc transplantation is applicable method to restore fertility in young boy with malignancy. currently, ssc transplantation is considered the most encouraging modality for fertility restoration in prepubertal cancer patients. this technique comprises the injection of a testicular cell suspension from a fertile donor into the testis of an infertile recipient. before this technique can be bring into a clinical scenery, it is imperative to assess the effectiveness and the safety of the procedure. references 1. bahadur g, ralph d. gonadal tissue cryopreservation in boys with paediatric cancers. hum reprod. 1999;14:11-7. 2. tegelenbosch ra, de rooij dg. a quantitative study of spermatogonial multiplication and stem cell renewal in the c3h/101 f1 hybrid mouse. mutat res. 1993;290:193-200. 3. jahnukainen k, hou m, petersen c, setchell b, söder o. intratesticular transplantation of testicular cells from leukemic rats causes transmission of leukemia. cancer res. 2001;61:706-10. 1658 | reply by author male germ cell (gc) transplantation via injection from a fertile donor to the testis seminiferous tubules of an infertile recipient is unique approach that can re-sult in donor-derived sperm production by recipient animals. transplantation of spermatogonial stem cells (sscs) has been widely used to investigate the spermatogenesis recovery in various species.(1) testicular torsion is a serious urological emergency in newborn and adolescent males that can lead to potential serious infertility and sub-fertility in affected testis. to date, various drugs and chemicals have been used to protect testes against ischemic reperfusion injury(2) in torsion status but sscs transplantation into testicular torsion/detorsion has not been performed for functional assessment of sscs yet. an increase in the efficiency of donor engraftment has been shown following ablative treatments that remove endogenous stem cells and increase niche accessibility. an alternative as a recipient model is removal of endogenous germ cells by torsion/detorsion approach, so we investigated long term assessment of the testes for providing a new azoospermic recipient model. our purpose was to investigate long-term effect of testicular torsion and detorsion on sperm parameters and testis structure in order to introduce a novel mice azoospermic model for spermatogonial stem cell transplantation. as you mentioned, sscs similar to other stem cells are generally rare. it has been demonstrated that the approximate number of sscs in mice and rats (but not human!) is 0.03% of all germ cells, therefore, we predict that human sscs may be rare and similar to rodent sscs. proliferation of sscs in vitro enhances ssc numbers and successful transplantation. in addition, it provides large numbers of stem cells for biochemical or molecular analysis. sscs functionality can be evaluated by two procedures: 1) cluster-forming assay in vitro(3) and 2) sscs transplantation into a recipient testis.(4) recent studies have definitely shown that each sexual dysfunction and infertility 1659vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l colony arises from a single stem cell. since germ cell clusters have a distinct three-dimensional structure, sscs might be possibly analyzed quantitatively in vitro by counting clusters, a procedure analogous to the neurosphere assay for neuronal stem cells. therefore, by counting the number of colonies, the number of functional sscs can be determined. the cluster-forming assay based on two important stem cell characteristics including clonogenicity and long-term self-renewal ability. as there are no specific biochemicals or morphological markers for sscs in clusters and only the stem cells are able to colonize and repopulate in testes 4, transplantation is performed as a functional assay to determine the presence of sscs in a cell population. there is no doubt that contamination of donor samples by leukemic cells may result in relapse, which is an unsolved problem for patient with cancer by now. however various studies have showed donor germ cells (including spermatogonial stem cells without sorting), can be injected into the seminiferous tubules of recipient testis. then these transplanted stem cells undergo spermatogenesis,(1) and recipient testis transmit the donor haplotype to their progeny. transplantation of germ cells has been successful even in primates. in our study, we transplanted cultured-germ cells from neonate 3-6-day-old mice into adult testicular ischemia 2 weeks after reperfusion via rete testis (homologous transplantation). also, to date, no ssc-specific marker has been identified for any species but the combination of expression of multiple markers can provide important information about spermatogonial cell types in rodents and other species. although molecular characterizations of spermatogonial cells in culture have not been mentioned in this project, we have checked them here and before. we have recently reported isolated and cultured spermatogonial cells and the presence of spermatogonial cells in the culture. we determined spermatogonial markers [oct4, gfrα-1, plzf, mvh (vasa),itgα6, and itgβ1] by a reverse transcriptase polymerase chain reaction (rt_pcr) followed by a confirmation via immunocytochemistry (for itgα6, itgβ1, oct4 and thy-1 markers). we have also reported the results of our ultrastructural study of cell clusters and sscs transplantation to a recipient azoospermic mouse. our finding showed that testicular and cultured cells expressed spermatogonial cells-specific genes (including plzf, oct4, gfrα-1, vasa, itgα6, and itgβ1) and c-kit as a differentiated germ cell gene.(5) the present study mainly demonstrated that torsion/detorsion may result in an irreversible azoospermia in mouse, and emphasized on the possibility of recruiting this technique in recipient preparation for sscs transplantation in mouse. to investigate and assess the exact efficiency of gc transplantation following this particular technique is recommended. testicular torsion as candidate model for sscs transplantation | azizollahi et al references 1. brinster cj, ryu by, avarbock mr, karagenc l, brinster rl, orwig ke. restoration of fertility by germ cell transplantation requires effective recipient preparation. biol reprod. 2003;69:412-420. 2. parlaktas bs, atilgan d, ozyurt h, et al. the biochemical effects of ischemia-reperfusion injury in the ipsilateral and contralateral testes of rats and the protective role of melatonin. asian j androl. 2014;16:314-8. 3. yeh jr, zhang x, nagano mc. establishment of a short-term in vitro assay for mouse spermatogonial stem cells. biol reprod. 2007;77:897-904. 4. shinohara t, orwig ke, avarbock mr, brinster rl. spermatogonial stem cell enrichment by multiparameter selection of mouse testis cells. proc natl acad sci u s a. 2000;97:8346-51. 5. eslahi n, hadjighassem mr, joghataei mt, et al. the effects of poly l-lactic acid nanofiber scaffold on mouse spermatogonial stem cell culture. int j nanomedicine. 2013;8:4563-76. endourology and stone disease evaluation of nephrolithometric scoring systems to predict outcomes of retrograde intrarenal surgery nejdet karsiyakali1, emre karabay2*, erkan erkan3, mustafa kadıhasanoglu3 purpose: the aim of the study was to evaluate the predictive value of nephrolithometric scoring systems used to predict the complexity of renal stones for the outcomes of retrograde intrarenal surgery (rirs). materials and methods: a total of 81 patients who underwent rirs for nephrolithiasis between january 2013 and october 2017 were reviewed in this retrospective study. guy’s stone score (gss), the s.t.o.n.e., clinical research office of the endourologic society (croes), and seoul national university renal stone complexity (s-resc) nephrolithometry scores were assessed by same researcher for each patient from preoperative non-contrast enhanced computed tomography scans. these nephrolithometric scores, stone characteristics and complications were compared in patients with/without residual stone. results: the median (iqr) age of patients (37 female/44 male) was 45 (20) years. the median (iqr) stone burden was 139.4 (125.4) mm2 and the mean hounsfield unit (hu) value was 1034.46 ± 239.56. the stone burden, s.t.o.n.e. and s-resc scores were statistically significantly higher and the croes score was significantly lower in patients with a residual stone (p < 0.001, for all). the incidence of residual stones was statistically significantly higher in patients with grade 3 gss (p = 0.018). while s.t.o.n.e., s-resc and croes were significantly correlated with stone-free rates, gss failed to correlate with stone-free status. according to the receiver operating characteristic (roc) curve analysis, the predictive value of stone burden was higher for residual stones, compared to s-resc scoring (p < 0.05). conclusion: nephrolithometric scoring systems nomograms used to predict the pcnl success were not superior to stone burden in predicting the rirs success. keywords: percutaneous nephrolithotomy; kidney stone; nephrolithiasis; retrograde intrarenal surgery; flexible ureteroscopy introduction urinary system stone disease is the third most com-mon disorder following urinary tract infections and prostate diseases in urological complaints. its incidence varies between 2 and 20% with a lifelong risk of 12% in men and 6% in women.(1) with the technological advances in the field of medicine, urinary system stone disease can be treated using non-invasive or minimally invasive methods. according to the european association of urology (eau) guidelines, extracorporeal shock wave lithotripsy (swl), ureteroscopic lithotripsy (urs-l), retrograde intrarenal surgery (rirs), and percutaneous nephrolithotomy (pcnl) are the first-line treatment methods for the removal of kidney stones with varying sizes and localization.(2) the eua guidelines state that stones smaller than 2 cm can be effectively treated using rirs, although there are several studies reporting favorable results for stones larger than 2 cm, as well.(3,4) over the past few decades, rirs has become widespread thanks to sophisticated flexible ureterorenoscopes and other instruments and increased experience. 1cukurca state hospital, department of urology, hakkari, turkey. e-mail: nkarsiyakali@hotmail.com 2haydarpasa numune training and research hospital, department of urology, istanbul, turkey. 3istanbul training and research hospital, department of urology, istanbul, turkey. *correspondence: haydarpasa numune training and research hospital, department of urology, telephone number: +905053858965. e-mail: emrekarabay@gmail.com. adress: tibbiye street. no: 23 34668 uskudar / istanbul tr received april 2019 & accepted december 2019 currently, rirs is an alternative to swl and pcnl with high stone-free status and low morbidity rates in the treatment of urinary system stone disease.(5) in addition, rirs has been shown to be a safe method with minimal complication rates.(6,7) the stone-free rate is the most significant factor of successful nephrolithotomy. to date, several scoring systems have been developed to predict the success of pcnl and to minimize procedure-related complications including guy’s stone score (gss), the s.t.o.n.e. nephrolithometry score, clinical research office of the endourologic society (croes) nephrolithometric nomogram, and seoul national university renal stone complexity (s-resc) score.(8-11) the resorlu-unsal stone score (ruus) is the first scoring system described in the literature for predicting the stone-free rate after rirs.(12) moreover, the s-resc scoring system has been modified for predicting rirs success.(13) in this context, the xiao et al. developed the r.i.r.s. scoring system to estimate the stone-free rate after rirs.(14) however, these scoring systems has not been externally validated. urology journal/vol 17 no. 4/ july-august 2020/ pp. 346-351. [doi: 10.22037/uj.v0i0.5256 ] to the best of our knowledge, there is no study or headto-head comparison evaluating the predictive value of common nephrolithometric scoring systems for rirs success. in the present study, therefore, we aimed to evaluate the predictive value of nephrolithometric scoring systems which are commonly used in pcnl for rirs success. patients and methods study population in this retrospective study, a total of 102 patients who underwent rirs for kidney stones between january 2013 and october 2017 were analyzed. all steps of the study were planned and performed according to the world medical association declaration of helsinki. all patients signed the informed consent demonstrating the permission of the patients to usage of their clinical data in future clinical studies. patients with urinary system anomalies and bleeding diatheses, need for anticoagulants, pregnant patients and patients under 18 years old were excluded from the study. twenty-one patients whose preoperative computed tomography (ct) scans were not available were excluded. finally, a total of 81 patients were included in the study. preoperative evaluation and calculation of scoring systems when the preoperative urine culture of the patients was positive, the patients were treated preoperatively with appropriate antibiotic on the basis of antimicrobial susceptibility test for no less than 7 days. the patients whose control urine cultures were found to be sterile were scheduled for rirs. data including preoperative routine biochemistry analysis, complete blood count, coagulation tests, urine culture, and non-contrast ct scans were retrospectively analyzed. non-contrast ct scans were reviewed by the same researcher who was blind to the patients’ characteristics. he analyzed the stone volume, hounsfield units (hu), and location of the stones. in case of multiple stones, total stone volume was the sum of each stone volume. the mean hu value was calculated from non-contrast enhanced ct scans showing maximum axial diameter of the stone on bone window using maximum diameter in the elliptic plane.(15) the gss, s.t.o.n.e. nephrolithometry score, croes nephrolithometric nomogram, and s-resc scores were also calculated using preoperative non-contrast ct scans described by their authors. surgical procedure all patients received prophylactic single-dose intravenous antibiotherapy (cefazolin sodium 1 g) preoperatively. surgery was performed under general anesthesia. the patient was placed in the semi-lithotomy position on the operating table with a fluoroscope depending on the affected side. the operation was initiated in a standard fashion using semi-rigid ureteroscopy (urs) and a 0.038-inch polytetrafluoroethylene-coated guidewire was advanced through the upper urinary system under the visual and fluoroscopic guidance. a ureteral access sheath compatible with the ureter diameter was placed over the guidewire (10/12-fr or 12/14-fr, re-trace ureteral access sheath, coloplast, humlebaek, denmark). the 7.5-fr flexible urs device (karl storz endoskope, flex-x2, tuttlingen, germany) was used in all patients. during lithotomy, holmium-yttrium aluminum rirs outcomes with nephrolithometry scores-karsiyakali et al. variable n (%) age (year) median (iqr) 45 (20) sex female 37 (45.7) male 44 (54.3) stone features and scoring systems side right 48 (59.3) left 33 (40.7) stone localizations upper pole 7 (8.6) middle pole 5 (6.2) lower pole 10 (12.3) renal pelvis 17 (21.0) kidney + proximal ureter 20 (24.7) multiple calyces 22 (27.2) stone burden (mm2) median (iqr) 139.4 (125.4) hounsfield unit mean ± sd 1034.46 ± 239.56 residual stone yes 21 (25.9) no 60 (74.1) gss grade 1 42 (51.9) grade 2 36 (44.4) grade 3 3 (3.7) s.t.o.n.e. score mean±sd 6.48 ± 1.00 s-resc score median (iqr) 1 (1) s-resc risk group low 73 (90.1) middle 7 (8.6) high 1 (1.2) croes score mean ± sd 194.64 ± 49.71 croes probability of stone-free status (%) mean ± sd 82.23 ± 10.38 complication no 78 (96.3) pyelonephritis 2 (2.5) djs migration to bladder 1 (1.2) table 1. demographic characteristics of patients, baseline stone status, and scores of scoring systems. abbreviations: min, minimum; max, maximum; sd, standard deviation; gss, guy’s stone score; s.t.o.n.e. stone size (s), tract length (t), obstruction (o), number of involved calices (n), and essence or stone density (e); croes, clinical research office of the endourologic society; s-resc, seoul national university renal stone complexity; djs, double j stent. vol 17 no 04 july-august 2020 347 garnet (yag) laser using 270 µm or 365 µm fiber at an energy of 0.6 to 0.8 joule and frequency of 8-10 hertz was applied. pieces of stones were removed using stone basket, if applicable. surgery was terminated, once the absence of opacity was confirmed through fluoroscopy. a 4.8-fr double-j stent was inserted in all patients at the end of surgery. postoperative period on the next day of surgery, all patients underwent ultrasonography (usg) and kidneyureterbladder graphy (kub). double j-stent was retrieved under local anesthesia one month after surgery in all patients. the stone-free status was defined as no evidence of opacity on kub or stones or the presence of clinically insignificant residual fragment stones <4 mm on ct.(16) the treatment success was evaluated using kub at one month postoperatively. the presence of hydronephrosis was assessed using non-contrast enhanced ct, if kub showed no opacity but hydronephrosis in usg. statistical analysis statistical analysis was performed using the number cruncher statistical system (ncss) 2007 statistics software (ncss, llc, kaysville, ut, usa). the kolmogorov-smirnov test was used to analyze the normality of the distribution of variables. the student’s t-test was used to compare normally distributed quantitative data, while the mann-whitney u test was used to compare non-normally distributed quantitative data between the groups. the pearson chi-square test, fisher-freeman-halton exact test, and fisher’s exact test were used to compare qualitative data between the groups. the spearman correlation analysis was performed to evaluate relationships between the variables. the receiver operating characteristic (roc) curve analysis was conducted to estimate optimal cut-off values including sensitivity, specificity, positive predictive value, and negative predictive value. the roc curve analysis was used to predict the presence of residual stones and the results were compared using binomial exact test. chi-sqaure test was performed to evaluate the consistency between the presence of residual stones and stone-free status according to the croes. a p value of <0.05 was considered statistically significant. results of the patients, 37 were females and 44 were males with a median (iqr) age of 45 (20) years. right-sided operation was performed in 48 patients (59.3%) and left-sided operation in 33 patients (40.7%). the median (iqr) stone burden was 139.4 (125.4) mm2 and the mean hounsfield unit (hu) value was 1034.46 ± 239.56. demographic characteristics of the patients, baseline stone status, and scores of the scoring systems are shown in table 1. the incidence of residual stones was statistically significantly higher in the patients with increased stone burden (p < 0.05). however, there was no significant relationship between the presence of residual stones and hu (p > 0.05) (table 2). the incidence of residual stones was statistically significantly higher in patients with grade 3 gss (p < 0.05). the stone burden, s.t.o.n.e. and s-resc scores were statistically significantly higher and the croes score was significantly endourology and stones diseases 348 table 2. relationship of stone types and scoring systems with residual stones. residual stone p-value no (n,%=60, 74.1%) yes (n,%=21, 25.9%) stone burden (mm2) median (iqr) 97.02 (104.77) 266.35 (232.41) c0.001** hounsfield units mean ± sd 1013.58 ± 229.28 1094.10 ± 263.51 c0.099 gss (n,%) grade 1 34 (56.7) 8 (38.1) d0.018* grade 2 26 (43.3) 10 (47.6) grade 3 0 (0) 3 (14.3) s.t.o.n.e. score mean ± sd 6.17 ± 0.83 7.38 ± 0.92 c0.001** s-resc score median (iqr) 1 (1) 2 (2) c0.004** s-resc risk group (n,%) low 58 (96.7) 15 (71.4) e0.003** middle/high 2 (3.3) 6 (28.6) croes score mean ± sd 207.13 ± 43.76 158.95 ± 49.30 c0.001** croes probability of stone-free status (%) median (iqr) 90 (9) 72 (22) c0.001** cmann-whitney u test, dfisher-freeman-halton exact test, efisher’s exact test. *p < 0.05, **p < 0.01 abbreviations: min, minimum; max, maximum; sd, standard deviation; gss, guy’s stone score; s.t.o.n.e. stone size (s), tract length (t), obstruction (o), number of involved calices (n), and essence or stone density (e); croes, clinical research office of the endourologic society; s-resc, seoul national university renal stone complexity. diagnostic screening roc curve ap cut-off sensitivity specificity positive predictive value negative predictive value stone burden (mm2) ≥166.2 80.95 71.67 50.00 91.49 0.866 0.783-0.949 0.001** s.t.o.n.e. score ≥ 7 95.24 70.00 52.63 97.67 0.837 0.737-0.937 0.001** s-resc score ≥ 2 61.90 68.33 40.63 83.67 0.687 0.544-0.829 0.011* croes score ≤ 191 76.19 70.00 47.06 89.36 0.767 0.640-0.894 0.001** acomparisons of cut-off values of each nomograms and stone-burden separately, *p < 0.05, **p < 0.01 abbreviations: roc, receiver operating characteristic; auc, area under the curve; ci, confidence interval; s.t.o.n.e. stone size (s), tract length (t), obstruction (o), number of involved calices (n), and essence or stone density (e); croes, clinical research office of the endourologic society; s-resc, seoul national university renal stone complexity. table 3. diagnostic screening tests and roc curve analysis for stone burden, s.t.o.n.e., s-resc, and croes scoring systems. rirs outcomes with nephrolithometry scores-karsiyakali et al. lower in patients with a residual stone (p < 0.05, for all). the incidence of residual stones was also statistically significantly higher in patients with an intermediate/ high s-resc risk and a low croes stone-free rate (p < 0.05, for both) (table 2). no residual stone was observed in 60 patients (74.1%) with ≥ 90% stone-free rate according to the croes, while 21 patients (25.9%) with <90% stone-free rate had residual stones. according to the croes stone-free rate estimation, 31 patients were at no risk for residual stone development with ≥ 90% probability and no residual stone was observed in 28 of these patients while residual stone was present in three patients. according to the croes stone-free rate estimation, 50 patients were at risk for residual stone development with < 90% probability; however, residual stones were observed in only 18 patients, while no residual stone was observed in 32 of these patients. these findings revealed no statistically significant consistency between the actual residual stone rate and croes stone-free rate (p < 0.05). stone burden and s.t.o.n.e., s-resc and croes scoring systems according to the roc curve analysis are presented in figure 1. a cut-off value of ≥ 166.2 mm2 was calculated for the stone burden according to the presence of residual stones. the odds ratio (or) for residual stones was 10.75 (95% ci 3.15 to 36.61) in patients with a stone burden of ≥ 166.2 mm2 (table 3). a cut-off value of ≥ 7 was calculated for the s.t.o.n.e. scoring system according to the presence of residual stones. the or for residual stones was 46.66 (95% ci 5.81 to 374.62) in patients with ≥ 7 s.t.o.n.e. scores (table 3). a cut-off value of ≥ 2 was calculated for the s-resc scoring system according to the presence of residual stones. the or for residual stones was 3.50 (95% ci 1.24 to 9.87) in patients with ≥ 2 s-resc scores (table 3). a cut-off value of ≤ 191 was calculated for the croes scoring system according to the presence of residual stones. the or for residual stones was 7.46 (95% ci 2.374 to 23.486) in patients with ≤ 191 croes scores (table 3). the roc curve analysis revealed that the predictive value of stone burden was higher for residual stones, compared to s-resc scoring (p < 0.05). there was no statistically significant difference between the other variables (p > 0.05) (table 4). discussion in our study, we found a statistically significant relationship between the scoring systems used to predict the pcnl success and stone-free status following rirs. however, roc curve analysis revealed that these nomograms were not superior to stone burden in predicting the rirs success and that even the predictive value of s-resc was lower than stone burden for the postoperative stone-free status. in the present study, we evaluated the predictive value of percutaneous nephrolithotomy scoring systems which are commonly used in pcnl for rirs success. the pcnl is the gold standard treatment for complex kidney stones and stones larger than 2 cm; however, it is associated with certain minor and major complications including intraor postoperative urinary extravasation, bleeding requiring transfusion, postoperative fever, sepsis, or colon or pleural injury.(17,18) the addition of new ports to the new-generation flexible urs devices with thinner device size and sophisticated optical systems allows clearer visualization and rirs, therefore, has become an alternative to pcnl for the treatment of kidney stones larger than 2 cm.(19) on the other hand, compared to pcnl, the main disadvantage of rirs is the requirement for a additional sessions. in recent years, predicting stone-free rate and possible complications before surgery has generated great interest in endourology and several nomograms have been developed to predict the success rate of swl, urs, pcnl, and rirs.(8-14,20,21) the gss which is a simple and reliable tool for predicting success rate considers location of the stone and renal anatomy. higher scores indicate low stone-free rates. the stone-free rate is also independent on the stone burden, experience of the surgeon, age, body weight and comorbidities of the patient.(8) in a review including pcnl scoring systems, the stone-free rate ranged from 0 to 100% for gss.(22) in our study, the incidence of residual stones was higher in patients with grade 3 gss. however, we believe that gss is not useful to predict the success rates following rirs. using the gss, it is likely to classify a stone as grade 1 in the lower pole and as grade 2 in the upper pole of the kidney. during rirs, it is more difficult to reach the stone localized in the lower pole using a flexible urs due to the deflection angle. in addition, rirs is not a feasible alternative for grade 4 staghorn stones. pairwise comparison of auc auc p stone burden s.t.o.n.e. 0.866 – 0.837 0.594 stone burden s-resc 0.866 – 0.687 0.008** stone burden croes 0.866 – 0.767 0.099 s.t.o.n.e. s-resc 0.837 – 0.687 0.057 s.t.o.n.e.croes 0.837 – 0.767 0.335 s-resc croes 0.687 – 0.767 0.117 table 4. pairwise comparisons of auc of roc curve and stone burden. binomial exact test. **p < 0.01 abbreviations: roc, receiver operating characteristic; auc, area under the curve; s.t.o.n.e. stone size (s), tract length (t), obstruction (o), number of involved calices (n), and essence or stone density (e); croes, clinical research office of the endourologic society; s-resc, seoul national university renal stone complexity. figure 1. roc curve analysis of stone burden and nomograms according to residual stone. rirs outcomes with nephrolithometry scores-karsiyakali et al. vol 17 no 04 july-august 2020 349 the significant relationship found in our study can be attributed to the small sample size with grade 3 gss. the s.t.o.n.e. nephrolithometry score, which is a simple tool for predicting the success rate of pcnl, considers stone size (s), tract length (t), obstruction (o), number of involved calices (n), and essence or stone density (e).(11) the scores vary from 5 to 13 and lower scores indicate less complex stone, while higher scores indicate more complex scenario. in the present study, we found a statistically significant relationship between the s.t.o.n.e. scores and stone-free status. however, we observed no significant relationship between the hu, one of the parameters used in this scoring system, and stone-free status. in addition, tract length is not a helpful measure to predict the success rate of rirs. nonetheless, the area under the roc curve for the s.t.o.n.e. scoring system in terms of the stone burden was the closest compared to the area under the roc curve for other scoring systems. thus, this finding suggests that the s.t.o.n.e. scoring system is superior to the other scoring systems in predicting stone-free status following rirs and that modified version of the system can be used for this purpose. the croes nephrolithometric nomogram in predicting pcnl outcomes is an also reliable tool which incorporates several variables such as stone burden, location of the stone, the presence of staghorn stones, previous surgery due to urolithiasis, and case volume per year of the center. higher scores indicate higher stone-free rates.(9) in our study, we considered that all these variables were helpful in predicting rirs outcomes and found statistically significantly lower croes scores in patients with residual stones. however, we found no statistically significant consistency between the actual residual stone rate and croes stone-free rate. this can be attributed to the fact that our sample size is small and that scoring based on the location of the stone using croes system is not feasible for rirs. the s-resc scoring system, which is also useful in predicting the post-pcnl stone-free rate, is solely based on stone distribution as assessed by the cumulative number of calyces involved.(10) it is a 9-point system with 1 point assigned to 9specific locations. a score of 1 to 2 is considered low, 3 to 4 is medium, and ≥ 5 is high. in a study involving 327 patients undergoing pcnl, the stone-free rate was found to be 65.4%, indicating that the s-resc scoring system is useful in predicting the post-pcnl outcomes.(23) in our study, the incidence of residual stones was also statistically significantly higher in patients with an intermediate/high or high s-resc risk compared to low-risk patients. however, the roc curve analysis revealed that the s-resc is the least sensitive scoring system in predicting stonefree status, compared to other nomograms. this can be explained by the fact that the s-resc nomogram considers equal scoring for all calyces and lacks higher scores for hard-to-reach calyces in the lower pole during rirs. nonetheless, this study has some limitations, which have to be pointed out. first, it was a retrospective study with a relatively small sample size and the inherent retrospective and non-randomized nature might have led to selection bias. second, non-contrast ct scan was not used in all patients to detect the clinically insignificant residual stones and to evaluate the outcomes of rirs. third, all nomograms evaluated in this study were originally designed to predict the pcnl success. hence, these nomograms may not be useful in predicting rirs outcomes. despite all these limitations, the present study is the first study in the literature which demonstrates that all these nomograms may be helpful in predicting rirs success with established cut-off values, although stone burden is still the most significant predictor. further, well-designed, large scale, prospective studies are required to confirm the results of this study and to establish definite conclusion. conclusions nomograms which are used to predict the pcnl success are not superior to stone burden in predicting the rirs success. of note, the deflection angle of the flexible urs should be given particular consideration. in addition to the stone burden, nomograms used to predict the rirs success should also encompass lower pole stones and lower 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imamura y, kawamura k, sazuka t, sakamoto s, imamoto t, nihei n, et al. development of a nomogram for predicting the stone-free rate after transurethral ureterolithotripsy using semi-rigid ureteroscope. int j urol. 2013;20:616-21. 21. kanao k, nakashima j, nakagawa k, asakura h, miyajima a, oya m, et al. preoperative nomograms for predicting stone-free rate after extracorporeal shock wave lithotripsy. j urol. 2006;176:1453-6; discussion 6-7. 22. wu wj, okeke z. current clinical scoring systems of percutaneous nephrolithotomy outcomes. nat rev urol. 2017;14:459-69. 23. choo ms, jeong cw, jung jh, lee sb, jeong h, son h, et al. external validation and evaluation of reliability and validity of the s-resc scoring system to predict stone-free status after percutaneous nephrolithotomy. plos one. 2014;9:e83628. 24. ito h, sakamaki k, kawahara t, terao h, yasuda k, kuroda s, et al. development and internal validation of a nomogram for predicting stone-free status after flexible ureteroscopy for renal stones. bju int. 2015;115:446-51. review diagnostic evaluation of 18f-fdg pet/ct imaging in recurrent or residual urinary bladder cancer: a meta-analysis minmin xue, mm, liping liu, mb, guanghui du, mm, zhigang fu, mm* purpose: to assess the diagnostic accuracy of fluorine-18 fluorodeoxyglucose positron emission tomography combined with the computed tomography (18f-fdg pet/ct) in the detection of recurrent or residual urinary bladder cancer with meta-analysis. methods: we searched pubmed/medline, embase, web of science, cbm, cnki, vip, and wanfang databases through october 2019. two reviewers independently screened the full articles. the imaging findings were confirmed by either histopathology or clinical follow-up. sensitivity, specificity likelihood ratio and diagnostic odds ratio were pooled with 95 % confidence intervals (ci). overall test performance was summarized by a summary receiver operating characteristic (roc) curve. the meta-disc software (version 1.4) was used to perform the meta-analysis. results: the meta-analysis included 7 studies. the pooled sensitivity and specificity of pet/ct for the detection of recurrent or residual urinary bladder cancer was 94.0% (95% ci: 91.0%–96.0%) and 92.0% (95% ci: 88.0%– 95.0%), respectively. positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 9.77 (95% ci: 4.91–19.41), 0.99(95% ci: 0.06–0.13) and 95.09 (95% ci: 47.96–188.53), respectively. when residual urinary bladder cancer was excluded, sensitivity changed slightly. conclusion: this meta-analysis suggested that the diagnostic accuracy of pet/ct was good in detecting recurrent or residual urinary bladder cancer. keywords: bladder cancer; fdg pet/ct; sensitivity; specificity; meta-analysis introduction bladder cancer is the most common urinary tract cancer with a high mortality rate in worldwide, in 2012 the estimated diagnosed new cases were about 430 000(1). despite continuing advances in surgical and nonsurgical therapeutic strategies, the patients with urinary bladder cancer have higher risk of recurrence and residue. cystoscopy is still the gold standard for the diagnosis of bladder cancer, but can still miss 10% of papillary tumors(2). contrast-enhanced computed tomography and mri are the commonly used imaging techniques for bladder cancer diagnosis, but these methods are not highly diagnostic with an accuracy rate ranged from 35% to 55% in ct and 62% to 85% in mri(3,4). 18f-fdg pet/ct has been reported as non-invasive imaging methods for many malignancies, but it’s using is limited due to the high urinary excretion activity of the bladder and ureters(5). recently, several studies have assessed the application value of 18f-fdg pet/ ct in detection recurrence and residue of bladder carcinoma. however, the population of bladder cancer patients was small and results were inconclusive. the aim of our study was to explore the diagnostic accuracy of 18f-fdg pet/ct in the detection of recurrent or residual bladder cancer by a meta-analysis. department of health management center, 983 hospital of joint logistics support force, tianjin, 300142, china. *correspondence: health management center, 983 hospital of joint logistics support force, 60 huangwei road, hebei district, tianjin, china. tel: (022)84683128, fax: (022)84683128, email: fuzhigang983@126.com. received august 2019 & accepted december 2019 methods literature search strategy we performed a comprehensive search from the electronic literature databases of pubmed/medline, embase, web of science, and chinese databases (cbm, cnki, vip, and wanfang database). the search was performed from the earliest available date of indexing to october 2019. our search strategy included terms of “pet, positron emission tomography”, “fdg, fluorodeoxyglucose” and “bladder cancer”. two authors independently screened articles. we also scanned references of articles which were included in the study. data collection and analysis all included studies based on the following criteria: (i) adult patients with primary bladder cancer; (ii) using 18f-fdg pet/ct for detecting the recurrence and residue of bladder lesions; (iii) definite histological or follow-up outcome; (iv) studies providing the number of true-positive, true-negative, false-positive, and false-negative. the exclusion criteria were as follows: (i) the total number of true positives, false positives, true negatives, and false negatives was not provided; (ii) abstracts, reviews, editorials, comments and letters. urology journal/vol 17 no. 6/ november-december 2020/ pp. 562-567. [doi: 10.22037/uj.v0i0.5538 ] data extraction and quality assessment the following information: first author’s name, publication year, country of the study population, patients’ characteristics (number of patients, mean age, gender), study design (retrospective or perspective), doses of 18f-fdg and furosemide, reference test (histopathology or clinical follow-up was ascertained as the golden standard, all imaging findings were confirmed by either histopathology or clinical follow-up.), imaging time, sensitivity and specificity data were retrieved. two reviewers independently reviewed articles and disagreements were resolved by consensus after re-evaluation 18f-fdg pet/ct for bladder cancer-xue et al. review 563 study year country patients, sex age image reference design furosemide fdg dose n (m/f) (years) time test s harkirat (13) 2010 india 22 dual phase: 1 h after pa or fu r 0.5 mg/kg of 370 mbq fdg injection; 60-90 furosemide (10 mci) min after furosemide yang z (14) 2012 china 35 28/7 mean:56 1 h after fdg pa or fu r 7.4 mbq/kg 35-96 injection; additional pelvic images: unknown yildirim2013 turkey 51 42/9 mean:63.6 dual phase: 1 h pa or fu r 0.5 mg/kg of 0.15 mci/kg poyraz n (15) 32-78 after fdg furosemide injection; 30-45 min after furosemide li h (16) 2014 china 84 dual phase: 1 h pa or fu r furosemide 270-350 mbq after fdg 40 mg injection; 2 h after furosemide kitajima k (17) 2016 japan 83 66/17 mean:69.7 1 h after fdg pa, fu or ri r 4.0 mbq/kg 36-88 injection alongi p (18) 2016 italy 41 36/5 mean± sd dual phase: 1 h pa or fu r 3.7mbq/kg 67 ± 10 and 90–120 min after fdg injection zattoni f (19) 2017 italy 287 223/64 mean± sd 1 h after fdg pa or fu r 3-3.8 mbq/kg 69 ± 10 injection table 1. characteristics of the selected studies r: retrospective; pa: pathology; fu: follow-up including physical examination, laboratory tests, and serial imaging, such as ct or mri. figure 1. flow chart showed detail information for eligible studies selection. vol 17 no 06 november-december 2020 564 of the references. research quality was assessed using the standards of the quadas-2 tool(6), which was developed as a validated tool for diagnostic studies. the quadas-2 consists of four domains: (1) patient selection, (2) index test, (3) reference standard and (4) flow and timing. those indexes describe the quality of the included studies and heterogeneity. the egger test was not conducted as included studies were less than 10. statistical analysis we reported data based on the guidelines of meta-analysis evaluating diagnostic tests. sensitivity, specificity, positive likelihood ratio (lr+), negative likelihood ratio (lr–) and diagnostic odds ratio (dor) had been presented. it is commonly used to add 0.5 to all counts in the table automatically when zero values exist(7). pooled sensitivity and specificity also displayed with 95% confidence intervals. i2 index was used to evaluate heterogeneity between included studies. a summary receiving operator characteristics (roc) curve and area under the curve (auc) were used to testify the overall accuracy of 18f-fdg pet/ct based on selected studies. all meta-analyses were performed using the meta-disc software (version 1.4)(8). results literature review a total of 316 publications about fdg pet/ct for recurrent or residual urinary bladder cancer was eligible for inclusion. after reviewing the titles, abstracts and full texts, 305 studies were removed (figure 1). of the remaining 11 studies, 1 study was excluded by reviewing the full text because of unclear classification(9), 2 studies were excluded since the test was conducted only in the patients who were confirmed recurrent or residual urinary bladder cancer (10,11). besides 1 study(12) was excluded from our meta –analysis because 2 studies were from the same team, one in english and one in chinese. although the sample quantities of the two articles were different, the final valid data were the same, and we finally chose the english article. therefore, 7 studies(13-19) finally met the inclusion criteria. the information of the included studies was listed in table 1 and table 2. qualitative analysis (systematic review) among the 7 included publications, 6 studies were published in english and 1 study in chinese. those included studies were conducted in five different counties. the sample size ranged from 22 to 287. all the studies were retrospective, included a valid reference test, and the imaging time was 1 hour after the fdg injection. furosemide was used in 3 of the selected studies, and 5 studies used additional pelvic delayed imaging to better show bladder lesions. the graph of quadas-2 displays the evaluation of the risk of the bias and concerns regarding applicability of those selected study (figure 2). in current study, no obviously bias was observed. quantitative analysis (meta-analysis) 603 patients included in the 7 studies had bladder lesions. pooled sensitivity and specificity were calculated by a random effects model. the sensitivity was 0.94 (95 % ci, 0.91 to 0.96, q=7.73, p = 0.2588), and specificity was 0.92 (95 % ci, 0.88 to 0.95, q=25.13, p = 0.0003) (figures 3 and 4). the overall lr+, lr– and dor were 9.77 (95% ci: 4.91–19.41), 0.09 (95% ci: 0.06–0.13) and 95.09 (95% ci: 47.96–188.53), with the q value of 12.20, 3.94 and 5.53 respectively (all p > 0.05). the sroc curve represents a global test performance which is based on the combination of sensitivity and specificity. the q* index is defined as the maximum joint sensitivity and specificity, where the probabilities are equal for sensitivity and specificity. figure table 2. diagnostic accuracy data of 18f-fdg pet/ct imaging in recurrent or residual urinary bladder cancer author year recurrence or residue recurrence tp fp tn fn tp fp tn fn s harkirat (13) 2010 13 0 7 2 13 0 7 2 yang z (14) 2012 11 3 20 1 11 3 20 1 yildirim-poyraz n (15) 2013 30 2 19 0 li h (16) 2014 22 3 57 2 22 3 57 2 kitajima k (17) 2016 8 0 75 0 8 0 75 0 alongi p (18) 2016 20 1 17 3 20 1 17 3 zattoni f (19) 2017 189 11 38 11 189 11 38 11 figure 2. methodological evaluation according to quadas-2 of the included studies. 18f-fdg pet/ct for bladder cancer-xue et al. review 565 5 showed the sroc curves of 18f-fdg pet/ct for recurrent or residual urinary bladder cancer. the q* index was 0.9197. the auc was 0.9699, indicating that the overall accuracy was relatively high. subgroup analysis when residual urinary bladder cancer was excluded, sensitivity changed slightly while there was no change in specificity. the pooled sensitivity of pet/ct for the detection of recurrent urinary bladder cancer was 93.0% (95% ci: 90.0–96.0%). positive likelihood ratio was 10.66. discussion medical imaging technologies played a critical role in clinical oncology. clinicians could locate where a tumor is with the help of molecular imaging that can visualize the expression and activity of specific molecules which are very important to the future of patients(20,21). accurate assessment of the recurrence and/or residue of bladder lesions is critical for follow-up treatment of bladder cancer patients. usually, ct and mri are widely used in the disease surveillance after bladder preservation therapy(22). residual or recurrent lesions are difficult to be identified morphologically due to the shape change of the bladder wall after treatment(23). pet/ct plays an important role in the diagnosis, staging and therapy monitoring of malignant diseases(24), and can generally detect the activity of biological tumors (11). in urinary tumors, fdg-pet/ct has been used to accurately assess lymph nodes or distant metastases, but is rarely used to image recurrent or residual lesions (25-27), primarily due to the high concentration of fdg in the urine(28). in order to improve 18f-fdg pet/ct imaging, several strategies such as adequate hydration, bladder irrigation and forced diuresis with furosemide have been used to delay pet/ct imaging of bladder tumors(29,30). we identified 7 studies comprising 603 patients and the pooled sensitivity and specificity of 18f-fdg pet/ct vol 17 no 05 september-october 2020 437 figure 3. sensitivity for 18 f-fdg pet/ct in detection of recurrent or residual urinary bladder cancer. figure 4. specificity for 18 f-fdg pet/ct in detection of recurrent or residual urinary bladder cancer. 18f-fdg pet/ct for bladder cancer-xue et al. vol 17 no 06 november-december 2020 112 for the detection of recurrent or residual urinary bladder cancer was 94.0% and 92.0%, respectively. among those studies, 5 of 7 studies used additional pelvic delayed imaging in order to better show bladder lesions (13-16,18). the results showed a relatively high sensitivity and specificity. the q value (0.9197) which represents the highest common value of sensitivity and specificity and the auc (0.9699) which is the area under roc curve demonstrate that 18f-fdg pet/ct is accurate diagnostic methods for the detection of recurrent or residual urinary bladder cancer. thus, 18f-fdg pet/ct has an accurate and effective diagnostic performance for recurrent or residual urinary bladder cancer. our meta-analysis has some limitations. all forms of meta-analyses cannot avoid publication bias. for example, non-significant or negative studies are often rejected and conference abstracts, letters to journal studies were excluded in our meta-analysis. we rechecked all documents in the search stage, including conference papers, and find that no conference abstracts, letters meet the inclusion criteria. considering the methodological evaluation according to quadas-2, publication bias was not obviously in current analysis. besides, language existed because the studies which we searched were published in english or chinese only, so studies published in other languages would be omitted. second, several studies had small sample size. furthermore, heterogeneity in elements such as study design, imaging techniques and quality of the selected studies existed. conclusions overall, we observed that 18 f-fdg pet/ct is an effective means for the detection of recurrent or residual urinary bladder cancer. a large randomized trial is needed to demonstrate the diagnostic capability of 18f-fdg pet/ct in detection of urinary bladder lesions. conflict of interest all authors declare that they have no conflicts of interest. references 1. antoni s, ferlay j, soerjomataram i, znaor a, jemal a, bray f. bladder cancer incidence and mortality: a global overview and recent trends. eur urol. 2017;71:96-108. 2. loidl w, schmidbauer j, susani m, marberger m. flexible cystoscopy assisted by hexaminolevulinate induced fluorescence: a new approach for bladder cancer detection and surveillance? eur urol. 2005;47:323-6. 3. paik ml, scolieri mj, brown sl, spirnak jp, resnick mi. limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. j urol. 2000;163:1693-6. 4. lawrentschuk n, lee st, scott am. current role of pet, ct, mr for invasive bladder cancer. curr urol rep. 2013;14:84-9. 5. bouchelouche k, oehr p. positron emission tomography and positron emission tomography/computerized tomography of urological malignancies: an update review. j urol. 2008;179:34-45. 6. whiting p, rutjes aw, reitsma jb, bossuyt pm, kleijnen j. the development of quadas: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. bmc med res methodol. 2003;3:25. 7. glas as, lijmer jg, prins mh, bonsel gj, bossuyt pm. the diagnostic odds ratio: a single indicator of test performance. j clin epidemiol. 2003;56:1129-35. 8. zamora j, abraira v, muriel a, khan k, coomarasamy a. meta-disc: a software for meta-analysis of test accuracy data. bmc med res methodol. 2006;6:31. 9. mertens ls, fioole-bruining a, vegt e, vogel wv, van rhijn bw, horenblas s. detecting primary bladder cancer using delayed (18)f-2-fluoro-2-deoxy-d-glucosepositron emission tomography/computed tomography imaging after forced diuresis. indian j nucl med. 2012;27:145-50. 10. kosuda s, kison pv, greenough r, grossman review 438 figure 5. sroc curves for 18f-fdg pet/ct for recurrent or residual urinary bladder cancer. 18f-fdg pet/ct for bladder cancer-xue et al. vol 17 no 06 november-december 2020 566 hb, wahl rl. preliminary assessment of fluorine-18 fluorodeoxyglucose positron emission tomography in patients with bladder cancer. eur j nucl med. 1997;24:615-20. 11. higashiyama a, komori t, juri h, inada y, azuma h, narumi y. detectability of residual invasive bladder cancer in delayed (18)f-fdg pet imaging with oral hydration using 500 ml of water and voidingrefilling. ann nucl med. 2018;32:561-7. 12. cheng j, yang z, zhang y, et al. application of whole body 18f-fdg pet/ct plus additional delayed pelvic scan after oral hydration in the diagnosis of the bladder malignant lesions. china oncology. 2014;24:540-4. 13. harkirat s, anand s, jacob m. forced diuresis and dual-phase f-fluorodeoxyglucose-pet/ct scan for restaging of urinary bladder cancers. indian j radiol imaging. 2010;20:13-9. 14. yang z, cheng j, pan l, et al. is whole-body fluorine-18 fluorodeoxyglucose pet/ct plus additional pelvic images (oral hydrationvoiding-refilling) useful for detecting recurrent bladder cancer? ann nucl med. 2012;26:571-7. 15. yildirim-poyraz n, ozdemir e, uzun b, turkolmez s. dual phase 18f-fluorodeoxyglucose positron emission tomography/computed tomography with forced diuresis in diagnostic imaging evaluation of bladder cancer. rev esp med nucl imagen mol. 2013;32:214-21. 16. li h, wu h, wang q, han y, wang q. value of the dual phase 18f-fdg pet/ ct in the diagnosis of recurrent and metastatic bladder cancer after surgery. china academic journal. 2014;30:1450-3. 17. kitajima k, yamamoto s, fukushima k, et al. fdg-pet/ct as a post-treatment restaging tool in urothelial carcinoma: comparison with contrast-enhanced ct. eur j radiol. 2016;85:593-8. 18. alongi p, caobelli f, gentile r, et al. recurrent bladder carcinoma: clinical and prognostic role of 18 f-fdg pet/ct. eur j nucl med mol imaging. 2017;44:224-33. 19. zattoni f, incerti e, colicchia m, et al. comparison between the diagnostic accuracies of 18f-fluorodeoxyglucose positron emission tomography/computed tomography and conventional imaging in recurrent urothelial carcinomas: a retrospective, multicenter study. abdom radiol (ny). 2018;43:2391-9. 20. weissleder r. molecular imaging in cancer. science. 2006;312:1168-71. 21. hoffman jm, gambhir ss. molecular imaging: the vision and opportunity for radiology in the future. radiology. 2007;244:39-47. 22. alfred witjes j, lebret t, comperat em, et al. updated 2016 eau guidelines on muscle-invasive and metastatic bladder cancer. eur urol. 2017;71:462-75. 23. zhang j, gerst s, lefkowitz ra, bach a. imaging of bladder cancer. radiol clin north am. 2007;45:183-205. 24. lawrence j, rohren e, provenzale j. pet/ ct today and tomorrow in veterinary cancer diagnosis and monitoring: fundamentals, early results and future perspectives. vet comp oncol. 2010;8:163-87. 25. apolo ab, riches j, schoder h, et al. clinical value of fluorine-18 2-fluoro2-deoxy-d-glucose positron emission tomography/computed tomography in bladder cancer. j clin oncol. 2010;28:3973-8. 26. chakraborty d, mittal br, kashyap r, et al. role of fluorodeoxyglucose positron emission tomography/computed tomography in diagnostic evaluation of carcinoma urinary bladder: comparison with computed tomography. world j nucl med. 2014;13:34-9. 27. goodfellow h, viney z, hughes p, et al. role of fluorodeoxyglucose positron emission tomography (fdg pet)computed tomography (ct) in the staging of bladder cancer. bju int. 2014;114:389-95. 28. zouhair a, ozsahin m, schaffer m, et al. positron emission tomography and computer tomography (pet/ct) in prostate, bladder, and testicular cancers. curr med chem. 2010;17:2492-502. 29. anjos da, etchebehere ec, ramos cd, santos ao, albertotti c, camargo ee. 18f-fdg pet/ct delayed images after diuretic for restaging invasive bladder cancer. j nucl med. 2007;48:764-70. 30. koyama k, okamura t, kawabe j, et al. evaluation of 18f-fdg pet with bladder irrigation in patients with uterine and ovarian tumors. j nucl med. 2003;44:353-8. 18f-fdg pet/ct for bladder cancer-xue et al. review 567 efficacy of extracorporeal shock wave lithotripsy monotherapy in complex urolithiasis in the era of advanced endourologic procedures dariush irani*, ramin eshratkhah, alireza amin-sharifi department of surgery, shaheed faghihi hospital, shiraz university of medical sciences, shiraz, iran abstract purpose: it is believed that extracorporeal shock wave lithotripsy (eswl) may be less effective than other modalities for treating stones in complex calculi. in this study, we investigated the efficacy of eswl for treatment of complex stones. materials and methods: between september 2002 and october 2003, 250 complex cases of urolithiasis, including ureteral stones, staghorn stones, and stones in children, high risk patients, single kidneys, steinstrasse, and horseshoe kidneys were selected to be treated with siemens lithostar (siemens ag, munich, germany) on an outpatient basis. data were collected prospectively and the results of eswl monotherapy on these complex patients were reviewed. results: the overall success rate was 91.2% for children and 77.7% for patients with single kidneys. also, eswl was efficient in the treatment of ureteral stones at the rate of 70.5% to 83.3%, depending on the location of the stone in the ureter and its size. the success rate of eswl for patients with horseshoe kidneys, staghorn stones, and steinstrasse were marginal (66.6%, 66.0% and 33.3%, respectively). all of the cases were managed on outpatient basis and hospital admission was not required. conclusion: outpatient eswl can be safely performed as a minimally invasive treatment after proper patient selection, even for complex patients. its successfulness in children, patients with solitary kidney, and for almost all of ureteral stones is quite acceptable. however, its usage in patients with horseshoe kidneys or steinstrasse, and those with staghorn stones is questionable and should be done only in carefully selected cases. thus, with appropriate patient selection, significant improvements in stone-free rates may also be achieved in these cases. key words: extracorporeal shock wave lithotripsy, monotherapy, complex, urolithiasis 13 urology journal unrc/iua vol. 2, no. 1, 13-19 winter 2005 printed in iran introduction for a long period of time, stone treatment in some patients has been a matter of controversy for urologists. traditionally, complex stones were removed by surgical intervention, with results appearing satisfactory. with the advancements made in this field, new surgical methods were introduced and complete removal of the stones was the main therapeutic strategy for many years. the use of endourological methods, especially those assisted with percutaneous nephrolithotomy (pcnl), has facilitated the treatment of stones. with the rapid developments in endourology and with the clinical use of extracorporeal shock wave lithotripsy (eswl), the need for surgery has enormously decreased over the past decade. as a less traumatic and more effective method, eswl surpassed open received april 2004 accepted december 2004 *corresponding author: office of surgery, shaheed faghihi hospital, shiraz university of medical sciences, zand blv., shiraz, iran. tel: 0098 917 112 3899, fax: 0098 711 233 1006, e-mail: iranid@sums.ac.ir extracorporeal shock wave lithotripsy monotherapy in complex urolithiasis surgery and pcnl. on the other hand, severe complications occurred less often than before the eswl era. the indications for eswl have changed over time in order to treat urolithiasis, but its usage in the treatment of some situations is the subject of controversy. the purpose of this study was to investigate whether eswl could be recommended for complex cases including ureteral stones, staghorn stones, and stones in children, high risk patients, single kidneys, steinstrasse, and horseshoe kidneys or not. materials and methods between september 2002 and october 2003, 250 complex cases of urolithiasis, including ureteral stones, staghorn stones, and stones in children, high risk patients, single kidneys, steinstrasse, and horseshoe kidneys were selected to be treated with eswl on an outpatient basis. overall, 268 stones in 256 urinary units were treated using siemens lithostar (siemens ag, munich, germany) lithotripter apparatus. the standard treatment protocol consisted of giving the recommended number of shocks per session, with retreatment protocols, if necessary. double j stent was inserted in cases of single kidneys and those with high probability of steinstrasse (e.g. staghorn stones). routinely, all patients undergoing eswl were followed the day after the procedure and two weeks later. they were followed similarly by a regular assessment of kidney function, the degree of fragmentation of the stones, and stone clearance, assessed by kub, ultrasonography or ivp as needed. median follow-up was 6 months. successful treatment was defined as complete clearance or residual stones smaller than 4 mm on kub performed 3 months later. the patients were categorized as: children, surgically high risk patients, and those with horseshoe kidney, staghorn stones, single kidney, and steinstrasse. the data were collected prospectively from september 2002. the results of eswl monotherapy on these complex cases were reviewed. results of 250 patients with complex stones, 174 were male (69.6%). mean age of the patients was 42.5 (range 1.5 to 80) years. table 1 shows the distribution of each category of cases among these 250 patients. the results of eswl monotherapy applying on each category are as follows: children. a total of 26 treatment sessions were performed in 23 patients with 25 stones (mean stone burden = 10.5 mm). ten children underwent general anesthesia and the others were only sedated. no percutaneous intervention or jj insertion was done. transureteral lithotripsy (tul) or open surgery was not required. dmsa scan was performed in10 patients postoperatively that revealed no significant change in kidney function. no loss of kidney, nor any perirenal hematoma formation or hypertention (htn) was recorded after treatment. all of the patients were followed after eswl. imaging study revealed an overall success rate of 91.2% after 3 months. of the patients, 73.9% became completely stone-free (table 2). 14 table 1. patients' characteristics table 2. results of eswl treatment number of patients 250 male/female 2.2 patients age 1.5 to 80 years (42.5) clinical condition children 23 staghorn stone 59 single kidney 9 horseshoe kidney 6 steinestrasse 3 high risk patient 2 ureteral stone 148 total 250 (100%) non-stone-free mean sessions stone-free patients clinically significant clinically insignificant overall success rate staghorn stone 3.9 33.8% 33.8% 32.2% 66% horseshoe kidney 1.33 50% 23.2% 16.6% 66.6% single kidney 1.33 55.5% 22.2% 22.2% 77.7% high risk groups 1 50% 50% 0% 50% children 1.13 73.9% 8.6% 17.3% 91.2% irani et al horseshoe kidneys. ten stones were treated in 6 horseshoe kidneys (mean stone burden = 11.7 mm). three patients had multiple stones. there were not any serious complications such as perirenal hematoma or steinstrasse. no adjunctive procedures, such as pcnl or jj stent placement were required. none of the patients presented with htn during follow-up. overall stone-free rate was 66.6% with complete stone clearance of 50%. steinstrasse. three eswl sessions were required in 3 patients with steinstrasse (mean stone burden = 10 mm). the calculi in these patients were lodged in lower ureter in 1 and in upper ureter in 2. in one of the patients, the impacted leading stone was completely fragmented by eswl and steinstrasse resolved spontaneously. in another one (with stone in the upper ureter) eswl was not effective and ureterolithotomy was done, subsequently. in the third patient (with stone in the lower ureter) fragmentation was only 30% and stone particles did not passed with conservative therapy, so that tul was attempted. none of the patients presented with major complications after eswl. median fragmentation was 43.3% (complete in 1 and incomplete in 2). single kidney. nine patients with solitary kidney underwent 12 sessions of eswl to treat 10 stones (mean stone burden = 13.6 mm). three of them had stones in transplanted kidney. in 1 patient steinstrasse formation occurred (giving an overall incidence of 11.1%), which was managed by percutaneous nephrostomy (pcn) placement. all of the stones were passed in 2 weeks and no adjunctive procedure was required. neither pathological laboratory findings nor renal insufficiency was recorded during the follow-up. overall success rate was 77.7% three months after the treatment, with a mean fragmentation rate of 82.5%. surgically high risk patients. two surgically high risk patients were treated with eswl (mean stone burden = 19.5 mm). no adjunctive procedure, such as pcn or jj stent placement was required. none of the patients had hematoma at the treatment site and no perirenal hematoma was noted on postoperative ultrasonography. overall success rate was 50%. staghorn stones. a total of 230 treatment sessions were required in 59 patients with 67 stones (mean stone burden = 23.4 mm). in 1 patient steinstrasse was formed (1.6%), and the stones were not passed with observation, so that ureterolithotomy was done. no serious complication was seen. none of the patients presented with htn during the follow-up. overall success rate was 66% and complete stone clearance achieved in 33.8% of cases. mean number of treatment sessions was 3.9. ureteral stone. overall, 149 ureteral stones in 148 patients were treated through 184 eswl sessions. one hundred and twenty six stones were in the upper ureter and 23 were in the lower ureter. pcn was not placed in any of our patients and all of the stones were treated as in situ (i.e. no stone was pushed back into the pelvis). two patients with mean stone burden of 13 mm developed steinstrasse in upper ureter. in one of them, stones were passed with watchful waiting and in another one, tul was performed. in the remainders no major complication occurred during and after the treatment. results of this category are summarized in table 3. discussion nowadays, with the advent of modern endourologic procedures such as pcnl, tul, and retrograde intrarenal surgery (rirs), many authors believe that the role of eswl has been waned especially in the so called "complex" patients. in the present study we investigated the efficacy of eswl in such complicated settings and focused on benefits and disadvantages of eswl as a noninvasive tool in each complex subcategory. eswl in children. there is controversy regarding the optimal management of stones in pediatric population. experience at our hospital, especially with staghorn calculi, showed that eswl is safe in children with desirable results and minimal morbidity. in our series there was a low complication rate similar to that in the literature. previously, others have noted that the passage of stone fragments in younger children is less difficult and is associated with significantly less pain than in older children and adults.(1) 15 table 3. results of eswl in ureteral calculi proximal ureteral stones distal ureteral stones >1cm ≤1cm >1cm ≤1cm complete fragmentation 36% 65.7% 40% 29.4% overall success rate 79.3% 74.4% 83.3% 70.5% extracorporeal shock wave lithotripsy monotherapy in complex urolithiasis obstruction is rare and trends to resolve spontaneously. because of these observations, stenting before eswl is not routinely required even for staghorn calculi. eswl provides good results and is minimally invasive and a nearly complication-free treatment method for children.(2) in our series, the stone-free rate of 73.9% was achieved by eswl monotherapy with minimum morbidity. these findings are consistent with the study of garat in paris that achieved a 70% success rate.(3) meanwhile, when orsola et al used eswl monotherapy for staghorn stones in children, they obtained a stone-free rate of 73.3% after an average of 2 eswl sessions with siemens lithostar apparatus.(4) notwithstanding, there have always been some worries regarding the effects of eswl on growing kidneys. traxer et al investigated this problem by evaluating post-eswl renal parenchymal damage using dmsa-tc99 scintigraphy; albeit short-term follow-up, they confirmed the innocuousness of eswl for renal parenchyma even in infants.(5) alternative treatment options, such as pcnl or open surgery, are more invasive. they have more potential negative impact on renal function and are associated with high morbidity and a high incidence of residual and recurrent stones. it seems that the interaction of eswl with stones and/or urinary tract in children is somewhat different with that in adults. for example, as mentioned before, the chance of stone passage is much higher in children. thus, the standards of therapy with eswl should be changed when it is used in pediatrics. we recommend that eswl monotherapy is currently the best treatment available for children with stone and should be the first choice even for staghorn calculi. horseshoe kidneys. results of eswl in horseshoe kidneys are greatly different in multiple series and stone-free rate has been reported to be 27% to 87%.(6-8) this wide variation may be due to the variability of stones size and location. renal stones in horseshoe kidneys necessitate higher number of shock waves per session, as seen in our study. because of particular anatomy and urinary stasis, all of the fragmented stones could not be passed, so that the probability of stone recurrence and need for retreatment is higher. overall, stone-free rate of 66.6% was achieved in our study. in a study including 24 patients with malformed kidney, theiss et al reported 61% stone-free rate. however, they mentioned the higher frequency of stone recurrence and regrowth, necessitating careful monitoring of these patients.(6) similar results are confirmed by other authors.(7-8) it is noteworthy to say that all of the authors have stressed on careful selection of these patients and the best results were seen in patients with a mean stone burden of less than 1 cm. if properly selected, eswl has satisfactory results in horseshoe kidneys.(9) when the stone is small and urinary drainage is proper, eswl as a first-line treatment is reasonable, but with greater stone burden, the efficacy of eswl would be reduced. for larger stones, pcnl is recommended. results of pcnl and open surgery are superior to eswl and stone-free rate of 78% to 100% will be expected.(10) if eswl fails or is not possible because of anatomical reasons, we recommend pcnl and/or open surgery. single kidney. in patients with solitary kidney, open surgery will provide better results than eswl therapy and particularly for some forms of staghorn calculi, open surgery and pcnl have proved more successful than eswl.(11) nowadays, eswl appears to be the most useful therapeutic modality for stones in solitary kidneys, except for these cases.(11) the less invasiveness and the satisfactory results have encouraged urologists, so that eswl has become the therapy of choice for these patients too. our experience demonstrated that eswl should be accepted as the therapy of choice for stones in patients with solitary kidney. we had 77.7% overall success rate, with 11.1% incidence of steinstrasse and anuria. these results are comparable with series of vuksanovic and that of jimenez where they had a success rate of 89% and 82.1%, respectively.(12,13) to determine the potential long-term side effects of eswl on renal function in patients with solitary kidney, chandhoke et al compared long-term effects of eswl and pcnl monotherapy on 31 patients with a solitary kidney and/or chronic renal insufficiency whose follow-ups were all more than 2 years; they concluded that there is no evidence to suggest that eswl results in long-term renal function deterioration in patients with solitary kidney.(14) therefore, this treatment modality prevents the harmful effect of open surgery, while enhancing the preservation of kidney tissue. urinary lithiasis after renal transplantation is a relatively uncommon complication. the predisposing factors and composition of the 16 irani et al calculi are similar to those of non-transplant patients. the least invasive treatment modality should be utilized according to the stone burden and the need to preserve renal function. three of our cases had stones in transplanted kidneys that all became stone free with eswl. although we had limited cases, the results were in agreement with those of rodrigo aliaga et al who found eswl a non-invasive tool, quite successful for the management of their 16 transplant patients suffering from stone in their allografts.(15) surgically high risk patients. to our knowledge there is no reported data about the effectiveness and complications of eswl in surgically high risk patients. some authors have studied the efficacy of eswl on biliary stones. in these series, overall fragmentation has been 69% that is somewhat low.(16) this low rate could be due to the different composition of billiary and urinary stones. however, according to its noninvasiveness, eswl is a reasonable modality in surgically high risk groups. however, we had few patients in our study and further studies should be taken. staghorn stones. untreated staghorn stones may cause infection, obstruction, and secondary injury to kidney, which may eventually lead to chronic renal insufficiency, especially in bilateral cases. due to these serious morbidities, treatment should not be delayed. in adults, the clearance rate of staghorn stones treated with eswl has ranged from 31% to 85 %, depending on stone burden.(17) it is quite acceptable that eswl monotherapy has marginal results in the management of adults with staghorn renal stones. lam et al, in their series, compared the treatment results of eswl monotherapy with pcnl in adult patients with staghorn renal stones. they found that even for staghorn calculi smaller than 50 mm, stone-free rate of eswl is much lower than that of pcnl (63.2% versus 94.4%). they also condemned eswl in these patients when found the 30.5% rate of post-eswl obstruction in them.(17) in our series, although we had only a 1.6% rate of steinstrasse, the stonefree rate was disappointing (33.8%). it seems that this low rate of success is due to relatively large stone burden in our patients (23.4 mm). thus, most urologists do not recommend eswl as the primary treatment of staghorn stones and they insist on the better results of pcnl. the use of eswl monotherapy in treating struvite stones may be particularly problematic, because residual fragments would prevent sterilization of the urine, increasing the risk of stone regrowth.(18) as a guideline, pcnl followed by eswl should be used for most patients. open surgery is appropriate in unusual situations, when a staghorn stone is not expected to be removed by a reasonable numbers of pcnls and/or eswls. nephrectomy is also a proper option for a poorly functioning kidney having staghorn stone. steinstrasse. eswl is one of the common modalities used in the management of steinstrasse and in previous studies it has had high success and low complication rates. but it was not seen in our study, perhaps because of our limited patients. in our study, only 3 patients with steinstrasse were treated by eswl, which was successful in only one of them. in this concept, we are in agreement with fernandez et al for the use of ureteroscopy as a safe and highly effective approach for the management of steinstrasse following eswl.(19) madbouly et al, in an interesting study, developed a statistical model based on risk factors for the formation of steinstrasse after eswl to predict this phenomenon. they found that stone size (more than 2cm), renal morphology, and shock wave energy are the significant predictive factors controlling steinstrasse formation. they also recommended prophylactic pre-eswl ureteral stenting, if a patient has a high probability of steinstrasse formation.(20) it is surprising that although the use of j stenting before lithotripsy lowers the incidence of steinstrasse in patients with large stone burden, j stenting has no apparent effect on the mode of presentation or the subsequent management of steinstrasse and the incidence of steinstrasse will increase with the stone size, whether or not a j stent is present.(21) ureteral stones. eswl is one of the common treatment modalities in the management of the ureteral stones, but with appearance of tul and ureteroscopy its indications have been greatly restricted. we achieved stone-free rates of 79.3% and 74.4% for stones greater and less than 1 cm, respectively (table 3). double j stent was inserted in none of our patients, although it is recommended for single kidneys containing stone, relief of pain, and stones that could not be well localized. excellent results for tul using holmium:yag laser has been achieved for proximal as well as distal ureteral stones with a 17 extracorporeal shock wave lithotripsy monotherapy in complex urolithiasis mean stone-free rate of 94.9%, associated with a complication rate of 1%.(22) these results are superior to the results achieved by eswl for proximal ureteral stones. meanwhile, when we used eswl for 23 patients with distal ureteral stones of variable sizes, we observed the overall success rates of 83.3% and 70.5%, for stones greater and lesser than 1cm, respectively. strohmaier et al through a prospective study, compared the results of eswl and ureteroscopy in the treatment of ureteral calculi. after randomizing their 146 patients with ureteral stones into two groups (eswl and ureteroscopy), stone-free rate of 70.1% for eswl was achieved, versus 94.9% after ureterscopy. success rate of eswl for ureteral stone was highly dependent on stone size and composition as well as the location of calculi, i.e. stone-free rate after eswl was higher in distal ureteral stones in comparison with proximal ones.(22) therefore, for all of the ureteral calculi, success rate of tul is higher than that of eswl with the expense of its more invasive nature and its need for general anesthesia. lamotte et al also defined a therapeutic approach to ureteral stones, studying 152 ureteral calculi treatment: while eswl eliminated 82% of all ureteral stones, tul on the other hand, was successful for 100% of ureteral stones. finally, they came into the conclusion that eswl is the reference treatment for proximal ureteral stones and ureteroscopy gives excellent results for eswl failures and for distal ureteral stones as the initial therapy.(23) fernandez et al also found ureteroscopy as a safe and effective treatment modality for the management of calculi debris following eswl of ureteral stones.(19) despite the improved results of tul, we still favor eswl as the initial approach for proximal ureteral stones, and ureteroscopy reserves as the initial treatment approach for distal ureteral stones and for eswl failures. however, as discussed above, the relatively high success rate of eswl for distal ureteral stone guarantees its application for surgically high risk patients. conclusion shock wave lithotripsy has been considered a mainstay of therapy in renal calculi for the last 20 years. shock wave lithotripsy is noninvasive and requires the least anesthesia among the treatment modalities and therein lays its popularity. in the last decade, however, there have been changes in thinking regarding methods of patient selection for shock wave lithotripsy, changes in the technique of the existing shock wave lithotripters, and new technologies designed to increase the efficacy of shock wave lithotripters especially for "complex" patients. in this study, we specifically evaluated the role of eswl in these patients. in brief, we can say that although success rates in some of these circumstances are acceptable, there is room for improvement. with appropriate patient selection, significant improvements in stone-free rates may be achieved. it is anticipated that improvements in lithotripter design will result in higher treatment success rates with reduced renal trauma and improved patient comfort. references 1. renner c, rassweiler j. treatment of renal stones by extracorporeal shock wave lithotripsy. nephron. 1999;81 suppl 1:71-81. 2. krichene a, fontaine e, quenneville v, sauty l, beurton d. [extracorporeal lithotripsy in children. report of 30 cases]. prog urol. 2002;12:651-3. french. 3. garat jm. [treatment of staghorn calculi by extracorporeal shock-wave lithotripsy in children]. ann urol (paris). 1999;33:315-9. 4. orsola a, diaz i, caffaratti j, izquierdo f, alberola j, garat jm. staghorn calculi in children: treatment with monotherapy extracorporeal shock wave lithotripsy. j urol. 1999;162:1229-33. 5. traxer o, lottmann h, archambaud f, helal b, mercierpageyral b. traxer o, lohmann h, archambaud herald b. [extracorporeal lithotripsy in children. study of its efficacy and evaluation of renal parenchymal damage by dmsa-tc 99m scintigraphy: a series of 39 children]. arch pediatr. 1999;6:251-8. french. 6. theiss m, wirth mp, frohmuller hg. extracorporeal shock wave lithotripsy in patients with renal malformations. br j urol. 1993;72:534-8. 7. torrecilla ortiz c, ponce campuzano a, contreras garcia j, et al. [treatment of lithiasis in horseshoe kidney with extracorporeal shock-wave lithotripsy]. actas urol esp. 2001;25:50-4. spanish. 8. collado serra a, parada moreno r, rousaud baron f, monreal garcia de vicuna f, rousaud baron a, rodriguez jv. current management of calculi in horseshoe kidneys. scand j urol nephrol. 2000;34:114-8. 9. kupeli b, isen k, biri h, et al. extracorporeal shockwave lithotripsy in anomalous kidneys. j endourol. 1999;13:349-52. 10. torrecilla ortiz c, colom feixas s, contreras garcia j, trilla herrera e, arbelaez arango s, serrallach mila n. [current treatment of lithiasis in congenital renoureteral malformations]. arch esp urol. 2001;54:926-36. spanish. 18 irani et al 11. sarica k, kohle r, kunit g, frick j. experiences with extracorporeal shock wave lithotripsy in patients with a solitary kidney. urol int. 1992;48:200-2. 12. vuksanovic a, micic s, petronic v, bojanic n. solitary kidney stone treatment by extracorporeal shock wave lithotripsy. eur urol. 1997;31:305-10. 13. jimenez verdejo a, arrabal martin m, mijan ortiz j, sanchez tamayo j, lopez-carmona pintado f, zuluaga gomez a. [treatment of lithiasis in patients with one kidney by extracorporeal shock wave lithotripsy]. arch esp urol. 1998;51:709-15. spanish. 14. chandhoke ps, albala dm, clayman rv. long-term comparison of renal function in patients with solitary kidneys and/or moderate renal insufficiency undergoing extracorporeal shock wave lithotripsy or percutaneous nephrolithotomy. j urol. 1992;147:1226-30. 15. rodrigo aliaga m, morera martinez j, lopez alcina e, et al. [lithiasis of the transplanted kidney: therapeutical potential]. arch esp urol. 1996;49:1063-70. spanish. 16. van der hul rl, plaisier pw, van blankenstein m, terpstra ot, den toom r, bruining ha. extracorporeal shock wave lithotripsy of common bile duct stones in patients with increased operative risk. eur j surg. 1994;160:31-5. 17. lam hs, lingeman je, barron m, et al. staghorn calculi: analysis of treatment results between initial percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy monotherapy with reference to surface area. j urol. 1992;147:1219-25. 18. candau c, saussine c, lang h, roy c, faure f, jacqmin d. natural history of residual renal stone fragments after eswl. eur urol. 2000;37:18-22. 19. fernandez de la maza s, noldus j, huland h. [ureterorenoscopy (urs) in treatment of ureteral calculi. ii. ureteroscopic treatment of calculus debris after eswl]. urologe a. 1999;38:133-7. german. 20. madbouly k, sheir kz, elsobky e, eraky i, kenawy m. risk factors for the formation of a steinstrasse after extracorporeal shock wave lithotripsy: a statistical model. j urol. 2002;167:1239-42. 21. al-awadi ka, abdul halim h, kehinde eo, al-tawheed a. steinstrasse: a comparison of incidence with and without j stenting and the effect of j stenting on subsequent management. bju int. 1999;84:618-21. 22. strohmaier wl, schubert g, rosenkranz t, weigl a. comparison of extracorporeal shock wave lithotripsy and ureteroscopy in the treatment of ureteral calculi: a prospective study. eur urol. 1999;36:376-9. 23. lamotte f, izadifar v, fontaine e, barthelemy y, beurton d. [treatment of ureteral calculi: report of 152 calculi]. prog urol. 2000;10:24-8. french. 19 urology journal unrc/iua vol. 1, no. 4, 246-249 autumn 2004 printed in iran 246 o r i g i n a l a r t i c l e s urological oncology correlation between prostate needle biopsy and radical prostatectomy gleason gradings of 111 cases with prostatic adenocarcinoma tavangar sm1*, razi a2, mashayekhi r1 1department of pathology, shariati hospital, tehran university of medical sciences, tehran, iran 2department of urology, shariati hospital, tehran university of medical sciences, tehran, iran abstract purpose: there are conflicting reports in the literature about correlation of biopsy and prostatectomy gleason scores in prostate carcinoma. the goal of this study was to determine the correlation of grading in these two types of pathologic materials. materials and methods: the coupled hematoxylin and eosin slides of 111 patients with prostate carcinoma were collected. gleason scores were determined. patients who had undergone any therapy except surgery were excluded from the study. correlation between grades was calculated by determination of correlation coefficient. accuracy of biopsy grading in prediction of final grade was also determined by measuring the sensitivity, specificity, and positive and negative predictive values. results: in 50 cases (45%), grade was underestimated in the biopsy. after dividing the cases into gleason scores of 2 to 4, 5 to 6, 7, and 8 to 10, the most of undergraded cases (84.2%) were in the first group (gleason score 2 to 4) and this rate reached 5% in the fourth group (gleason score 8 to 10). the correlation coefficient measured was 0.535 in grade to grade comparing and 0.514 in group to group comparison of the specimens. in low-grade tumors, grading in biopsy, in spite of high sensitivity (90.9%), had low positive predictive value (26.3%). conclusion: there is a moderate direct linear relationship between scores in biopsy and prostatectomy specimens. but there is a high probability of underestimation of real gleason score of the radical prostatectomy specimen in low-grade tumors. pathologists and urologists must consider the phenomenon of undergrading in reporting prostate specimens and managing patients. key words: gleason grading, needle biopsy, adenocarcinoma of prostate introduction the grading system for prostatic adenocarcinoma, developed by gleason, has a strong prognostic value. the primary and secondary patterns are combined to give a gleason score or sum. when only a minute focus of tumor is present in the specimen, the score is determined by doubling the number of gleason pattern.(1) it has been claimed that gleason score in biopsy specimen correlates with prostatectomy gleason score and in combination with pretreatment received june 2004 accepted november 2004 *corresponding author: department of pathology, shariati hospital, tehran university of medical sciences, tehran, iran. tel: ++98 21 8490-2159. e-mail: tavangar@ams.ac.ir tavangar et al 247 serum prostate-specific antigen (psa) and digital rectal examination results, it can predict tumor stage and lymph node metastasis.(2) there are studies in the literature that have specifically correlated needle biopsy and prostatectomy gleason scores.(3-6) in many of these studies it has been noted that when in biopsy specimen, one encounters a low-grade tumor, in a notable percent of cases the gleason score will be higher in prostatectomy specimen. thus, gleason grading of a seemingly low-grade tumor in biopsy specimens may have unwanted effects on management of such patients. the aim of this study was to investigate the correlation between gleason score of biopsy and prostatectomy specimens. materials and methods between 2000 and 2003, consecutive paired biopsy and prostatectomy specimens from 111 cases of prostatic adenocarcinoma, which were diagnosed by prostatic needle biopsy and had undergone radical prostatectomy in follow-up, were selected. patients who had undergone neoadjuvant therapy as radiotherapy or androgendeprivation therapy were excluded from the study. all biopsy specimens had been taken by 18gauge needle, mostly under the guide of ultrasonography, but the number of cores was varying between 4 and 10, because of different clinical experience of the urologists. the primary and secondary gleason patterns and final gleason scores of paired biopsy and prostatectomy (minimum of three slides per patient) were determined separately, blindly and without matching of paired samples. the analysis of agreement between biopsy and prostatectomy gleason scores was based on individual scores and after assignment to one of the four groups defined as gleason scores of 2 to 4, 5 to 6, 7 and 8 to 10. correlation between gleason scores of biopsy and prostatectomy specimens was analyzed by calculating the coefficient of agreement (kappa) and pearson's correlation coefficient using spss 11.5 software. accuracy of biopsy was also evaluated by determination of sensitivity, specificity, and positive and negative predictive values. results median age of the patients was 62 ± 10.6 (range 39 to 89) years. the most prevalent score was 6 (20.7%) in biopsy specimens and 7 (23.4%) in prostatectomy specimens (tables 1, 2). there was no score 10 tumor in any of biopsy or surgical specimens. most of the tumors in biopsy specimens were in the first grading group (low-grade, gleason score 2 to 4) and most of the tumors in prostatectomy specimens were in the second group (medium-grade, gleason score 5 to 6). the correlation between the gleason scores of biopsy and prostatectomy is shown in table 1. the gleason scores were similar in 47.7%, and differed by 1 point in 18% of cases. overall, 45% were undergraded and 7.2% overgraded. considering a maximal difference of one number as a desirable correlation, in 65.7% of the cases correlation was seen between biopsy and prostatectomy specimens. the most undergrading cases (84.2%) was observed in first group (gleason score 2 to 4) and the most overgrading cases was seen in the last group (gleason score 8 to 10). kappa analysis yielded a value of 0.392 and pearson's r was measured as 0.535 (table 1), corresponding to a moderate agreement beyond chance and relative direct correlation between the biopsy and prostatectomy specimens. after grouping, the same analysis was done for the gleason score group assignments (table 2). in this instance 55.8% of cases remained within the same group, 37.8% were undergraded and 6.3% were overgraded. kappa and pearson's r yielded values of 0.419 and 0.514 respectively. the accuracy based on these group assignments is given in table 3. the sensitivity and positive predictive value for a biopsy gleason score of 2 to 4 (lowgrade carcinoma in biopsy specimen) was 90.9% and 26.3%, respectively, while for gleason score table 1. correlation of biopsy and prostatectomy gleason scores pearson's r = 0.535, kappa = 0.392 (p <0.0001) � ����� � �� �� �� �� �� �� �� ��� ����� � �� �� �� �� �� �� �� �� �� �� �� �� �� �� �� �� �� �� �� �� ��� �� �� �� �� �� �� �� �� �� �� ��� �� �� �� �� �� �� �� �� �� �� ��� �� �� �� �� �� � � �� �� �� �� ��� �� �� �� �� �� �� ��� �� �� �� ��� �� �� �� �� �� �� �� �� �� �� ��� �� �� �� �� �� �� �� �� �� �� � � �� � �� � ��� �� �� �� �� �� �� �� �� �� �� � ������ �� �� �� ��� � � ��� ��� ��� �� ���� table 2. correlation of biopsy and prostatectomy gleason scores by group assignment pearson's r = 0.514, kappa = 0.419 (p <0.0001) � � ����������� � � � ������ �� � �� �� ������ �� ��� ��� � � � � � �� ��� �� � ��� �� �� �� ��� �� ��� � �� � �� � �� �� �� �� ��� ��� � ������ ��� ��� ��� � � ���� prostate needle biopsy and radical prostatectomy gleason gradings248 of 8 to 10 (high-grade carcinoma in biopsy) was 48.6% and 85%, respectively. there is clear evidence that more well-differentiated cancers have a higher frequency of being underscored and the poorly differentiated cancers being overscored in biopsy specimens. the correlation between the biopsy gleason score and surgical gleason score is shown in figure 1. the relationship between these, in the sense that well-differentiated cancers are consistently undergraded and poorly differentiated cancers are consistently overgraded, is well fit by a linear regression (r2 = 0.29, p = 0.0001). discussion gleason grading system is important in determination of prognosis and management of prostatic adenocarcinoma.(7) gleason score in association with pretreatment serum psa level and result of digital rectal examination predicts tumor stage and existence of lymph node metastasis.(8) consequently, it is necessary to determine the accuracy of needle biopsy scoring and correlation of this score with the one assigned to radical prostatectomy specimens. there are some studies in the literature comparing gleason scores of biopsy and prostatectomy, in most of which it has been indicated that in some cases, especially when one encounters a low-grade tumor in biopsy, the assigned score underestimates the final score in the prostatectomy specimen and contrarily needle biopsy scoring overestimates prostatectomy scores to some extent in high-grade tumors.(3-6,8-13) pearson's correlation coefficient and kappa coefficient of agreement were calculated as 0.535 and 0.392, respectively, implying a moderate direct relationship between biopsy and prostatectomy gleason scores (tables 1,2). the relationship between the biopsy gleason score, in the sense that well-differentiated cancers are consistently undergraded and poorly-differentiated cancers overgraded is well shown in figure 1. in low-grade tumors (gleason grade 2 to 4) 84.2% of cases were undergraded. in comparison, only 5% undergrading was found in highgrade tumors. on the other hand, needle biopsy gleason scores of 20% of high-grade tumors were overestimated, while no overgrading was observed in low-grade tumors. as an index of accuracy, the positive predictive value of gleason scoring in biopsy was only 26.3% in low-grade tumors and reached to 85% in high-grade tumors, implying insufficient accuracy in low-grade tumors (table 3). different factors have been suggested as the reasons of this significant undergrading of lowgrade tumors in biopsy specimens. its consistency in different studies implies that it is more a systematic bias toward undergrading, rather than an error in pathologic interpretation. gleason has proposed that the undergrading may be due to several sources including reluctance of pathologists to characterize a small amount of highgrade tumor in an otherwise low-grade background.(4) other factors may contribute to the discrepancies between gleason score of biopsies and surgical specimens as the amount of cancerous tissue present within biopsy material and sampling effects.(4) to determine whether the amount of cancerous tissue in the biopsy specimen is responsible for the gleason score difference between the prostatectomy and biopsy, a correlation analysis has been performed by king,(4) bostwick,(9) and steinberg;(3) none of them have found any significant correlation. since prostate cancer is often multifocal, with a table 3. accuracy of biopsy gleason score in predicting final surgical gleason group ���������� � ������������������������� ���������� � !� "��#����� $� !� "��#������ $� ��� ��� ������ ���� ���� � ����� �� ��� ������ ���� ������ ����� �� ������ ���� ������ ����� �� ���� ���� � � �� ������ ��� fig. 1. relationship between the biopsy gleason score and surgical gleason score. error bars represent the 95% confidence interval about the mean. the number of cases in different groups is indicated above error bars. regression is indicated by the solid line (r2 = 0.29, p = 0.0001). the dashed line represents perfect correlation. � �� �� � �� �� � �� ����������� � �� � �� �� �� �� �� �� �� �� � ����� � ������ � ������ � ��� � � ������ � ������ � ������ � ������ � � � �� � �� � ��� � � �� �� � � � � tavangar et al 249 heterogeneous population of tumor cells, a certain degree of sampling error is inevitable. this may result in sampling an area that consists of more high-grade or low-grade tumor samples than the actual tumor. it has been suggested that to overcome sampling error one must either perform a directed biopsy (if there is an ultrasound-visible lesion) or increase the number of biopsies obtained. some studies suggest that sampling error might be significantly reduced by obtaining more biopsies.(12,14) some authors propose a modification to the gleason system to include "tertiary" or the third most prevalent pattern in the scoring,(15) but king(4) argues that this modification may even increase the error of sampling. also a routine consensus approach to pathologic evaluation of prostate adenocarcinoma seems useful. conclusion according to our findings, there is a moderate direct linear relationship between scores in biopsy and prostatectomy specimens. but there is a high probability of underestimation of real gleason score of the radical prostatectomy specimen in low-grade tumors. pathologists and urologists must consider the phenomenon of undergrading in reporting prostate specimens and managing patients. it must be emphasized that radical therapies for localized prostate adenocarcinoma are sometimes determined or excluded from consideration on the basis of the biopsy gleason score. now the differences between the histological grade in biopsies and surgical specimens are being understood. therefore, staging of organ confined prostate cancer, when based on biopsy grading, should include the likelihood of histological overestimation in the surgical specimen. references 1. deshmukh n, foster cs. grading prostate cancer. in: foster cs, bostwick dg, editors. pathology of prostate.1st ed. philadelphia: wb saunders; 1998. p.191-227. 2. epstein ji, partin aw, sauvageot j, walsh pc. prediction of progression following radical prostatectomy: a multivariate analysis of 721 men with long-term follow-up. am j surg pathol. 1996;20:.286-92. 3. steinberg dm, sauvageot j, piantadosi s, epstein ji. correlation of prostate needle biopsy and radical prostatectomy gleason grade in academic and community settings. am j surg pathol 1997;21:566-76. 4. king cr. patterns of prostate cancer biopsy grading, trends and implications. int j cancer. 2000;90:305-11. 5. ruijter e, van leenders g, miller g, debruyne f, van de kaa c. erros in histological grading by prostatic needle biopsy specimens: frequency and predisposing factors. j pathol. 2000;192:229-33. 6. prost j, gros n, bastide c, bladou f, serment g, rossi d. correlation between gleason score of prostatic biopsies and one of the radical prostatectomy specimens. prog urol. 2000;11:45-8. 7. gleason d. classification of prostate carcinoma. cancer chemother rep. 1996;50:125-8. 8. rubin ma, dunn r, kambham n, misick cp, o'toole km. should a gleason grade be assigned to a minute focus of carcinoma on needle biopsy? am j surg pathol. 2000;24:1634-40. 9. bostwick dg. gleason grading of prostate needle biopsies. correlation with grade in 316 matched prostatectomies. am j surg pathol. 1994;18:796-803. 10. epstein ji. gleason score 2-4 adenocarcinoma of prostate on needle biopsy. am j surg pathol. 2000;24:477-8. 11. de la taille a, viellefond a, berger n, et al. evaluation of interobserver reproducibility of gleason grading of prostatic adenocarcinoma using tissue microarrays. hum pathol. 2003;34:444-9. 12. san francisco if, de wolf wc, rosen s, upton m, olumi af. extended prostate needle biopsy improves concordance of gleason grading between prostate needle biopsy and radical prostatectomy. urology. 2003;169:136-40. 13. djavan b, kadesky k, klopukh b, marberger m, roehrborn cg. gleason scores from prostatic biopsies obtained with 18-gauge biopsy needles poorly predict gleason scores of radical prostatectomy specimens. eur urol. 1998;33:261-70. 14. thickman d, speers wc, philpott pj, shapiro h. effect of the number of core biopsies of the prostate on predicting gleason score of prostate cancer. j urol. 1996;156:110-3. 15. pan cc, potter sr, partin aw, epstein ji. the prognostic significance of tertiary gleason patterns of higher grade in radical prostatectomy specimens: a proposal to modify the gleason grading system. am j surg pathol. 2000;24:563-9. 914 edited1.pdf 909vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l persistent mullerian duct syndrome with transverse testicular ectopia rare presentation of inguinal hernia ashish gupta,1 nilanjan panda,1 makhan lal saha,2 shuvro ganguly,2 samik kumar bandyopadhyay,1 ruchira das3 keywords: persistent mullerian duct syndrome, testis, male pseudohermaphroditism introduction persistent mullerian duct syndrome (pmds) is a rare type of pseudohermaphroditism in genotypically and phenotypically males. they have a uterus, fallopian tubes, and upper part of the vagina; but mullerian duct fails to regress. in transverse testicular ectopia (tte), one of the testis moves to the opposite side and both testes pass the same inguinal canal. we report a case of pmds with tte presented with a left-sided inguinal hernia and right undescended testis. case report a 23-year-old man presented with a left-sided reducible inguinal hernia and undescended testis in an empty ill-developed right hemiscrotum. left scrotum revealed two separate contents, a small 3 × 2 cm oval structure (clinically testis) and another larger structure (clinically the hernia sac with its content) (figure 1). on taxis, the sac and the left testis both reduced into the abdomen together. ultrasonography revealed left-sided normal testis, bulky left epididymis, thickened spermatic cord, and a heterogeneous mass 2.8 × 1.7 × 1.7 mm with minimal vascularity. partial herniation of the small bowel loops was seen through the internal ring on the left side. right-sided corresponding author: nilanjan panda, ms; mrcs ed; dnb 318 b, cit road, scheme 6m, kankurgachi, kolkata 700054, west bengal, india tel: +91 974 877 4942 e-mail: drnilanjanpanda2002@ yahoo.co.in received april 2011 accepted july 2011 1 department of surgery, r.g kar medical college, kolkata, india 2 department of surgery, ipgmer and sskm, kolkata, india 3 department of surgery, b.s medical college, bankura, india case report 910 | testis was not seen either in the scrotal sac, inguinal canal, or in any other possible ectopic sites. in semen analysis, volume was 2 ml and there were no spermatozoa. serum testosterone level was 862.20 ng/dl (normal range, 280 to 800 ng/dl). karyotyping showed male xy pattern. on diagnostic laparoscopy, well-developed uterus, round ligament, fallopian tubes, and the left testis were seen. the left testis was entering the left internal inguinal ring and the right testis migrated to left and was in the left internal inguinal ring. we reduced the hernia and took a biopsy from the right testis to prove tte (figure 2). the histopathology revealed seminiferous tubules containing sertoli cell with no germ cells. the patient was counseled and re-explored. total hysterectomy with bilateral salpingectomy followed by bilateral orchidopexy and repair of left-sided hernia were performed (proliferative phase), fallopian tube, and vaginal tissue. discussion until now.(1) mullerian inhibiting substance (mis), secreted by the sertoli cells from seven weeks of gestation, causes the regression of the mullerian duct in the male fetus.(2) in pmds, there is presence of mullerian derivatives, ie, the uterus, fallopian tube, and upper part of the vagina in otherwise normally virilized xy male. it results from a failure or mistiming in the synthesis and release, or end organ resistance to mis.(3) the subjects have normal levels of testosterone with normal male secondary sexual characters. the a normal male pattern. more than 100 cases of tte have been reported; however, the presence of pmds and tte together is rare. persistent mullerian duct syndrome is mostly found out during surgery for inguinal hernia or cryptorchidism. transverse patient. persistent mullerian duct syndrome has two clinical variants. commoner is unilateral cryptorchidism and contralateral inguinal hernia. the term “hernia uteri inguinalis” is used when the uterus is found in the hernia sac. sometimes the contralateral testis is found in the sac due to the abnormal mobility of the mullerian derivatives, known as tte. (6) in another variant, bilateral cryptorchidism is seen with the uterus in the pelvis and the testis embedded in the broad ligament. the undescended testes are at increased risk for malignant transformations into seminoma, embryonal carcinoma, yolk sac tumors, and rarely clear cell adenocarcinoma of the mullerian duct in pmds.(7) infertility is common with figure 1. showing normal penis with inguinal hernia on the left side and empty right scrotum. figure 2. laparoscopic view showing the right and left gonads with the uterus in between them. case report 911vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l transverse testicular ectopia | gupta et al absence of spermatozoa in semen analysis. surgical management is done in stages. diagnostic laparosbiopsy and karyotyping are available; it aims at preserving the testes. orchidopexy and hysterectomy are done after dissecting the vas deferens from the mullerian structures. orchidectomy is indicated if the testis cannot be brought to the scrotum. orchidectomy should be followed by a lifelong testosterone supplement. patients with pmds and tte are usually infertile. orchidopexy should be done to prevent malignancy. conflict of interest none declared. references 1. acikalin m, pasaoglu o, tokar b, ilgici d, ilhan h. persistent mullerian duct syndrome with transverse testicular ectopia: a case report with literature review. turk j med sci. 2004;34:333-6. 2. gujar nn, choudhari rk, choudhari gr, et al. male form of persistent mullerian duct syndrome type i (hernia uteri inguinalis) presenting as an obstructed inguinal hernia: a case report. j med case rep. 2011;5:586. 3. josso n, belville c, di clemente n, picard jy. amh and amh receptor defects in persistent mullerian duct syndrome. hum reprod update. 2005;11:351-6. figure 3. operative picture showing the uterus with both the testes and normally developed penis. 4. mouli k, mccarthy p, ray p, ray v, rosenthal im. persistent mullerian duct syndrome in a man with transverse testicular ectopia. j urol. 1988;139:373-5. 5. fourcroy jl, belman ab. transverse testicular ectopia with persistent mullerian duct. urology. 1982;19:536-8. 6. karnak i, tanyel fc, akcoren z, hicsonmez a. transverse testicular ectopia with persistent mullerian duct syndrome. j pediatr surg. 1997;32:1362-4. 7. shinmura y, yokoi t, tsutsui y. a case of clear cell adenocarcinoma of the mullerian duct in persistent mullerian duct syndrome: the first reported case? am j surg pathol. 2002;26:1231-4. urol_v3_no1_001_editorial.qxd urology journal unrc/iua 70 errata in volume 1, number 2, pages 222 to 223 of the urology journal, the editorial comment and the reply by author for "crossed testicular ectopia: a case report" were not published. we regret this error. the following is the editorial comment and the reply by the author: vol. 3, no. 1, 70 winter 2006 printed in iran editorial comment the report of a crossed ectopia of testis was of my interest as it is a rare and attractive case. however, given the information provided in the case report and the figure, polyorchidism of the involved site could not be ruled out. accordingly, the patient may have had an intra-abdominal testis in the contralateral side. thus, a search by imaging and even laparoscopic exploration was a requisite. hamid arshadi department of pediatric urology, children's medical center, tehran university of medical sciences, tehran, iran reply by author the authors would like to thank dr arshadi for mentioning this crucial point. we performed ultrasonography of the pelvis and groins meticulously and found no evidence of a crypt orchid. behzad feizzadeh kerigh department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran in volume 2, number 4, the following error was published on the cover, the left upper figure and on page 228, the same figure: cyctitois should have read cystitis. we apologize for this error. urological oncology in the era of shared decision making, how would an iranian urologist screen himself for prostate cancer? majid ali asgari, mohammad soleimani,* farid dadkhah, alireza lashay, erfan amini, maryam baikpour, razie amraei purpose: prostate cancer (pca) poses a significant health problem in developed countries. prostate specific antigen (psa) based screening for pca is controversial and large trials have failed to show a significant reduction in prostate-specific mortality and all-cause mortality. considering the contradictory data on pca screening, current guidelines emphasize shared decision making. physicians are the ones in charge of helping patients with informed decision making, so we conducted this study to find out what urologists would do for themselves as patients. materials and methods: urologists attending the 15th congress of iranian urological association were invited to participate in a questionnaire-based survey on pca screening. a total of 184 physicians completed the questionnaire. results: of participants 76.8% declared that they would like to be screened. 69.3% of those in favor of screening did not consider digital rectal examination (dre) as part of their screening program. 62.8% of the urologists willing to be screened chose serial psa as their follow up method in case their psa level came above normal ranges, and 35.8% preferred to be biopsied. conclusion: urologists tend to prefer psa screening despite the current controversy about its usefulness. most of the urologists practicing in iran do not choose dre as part of their screening program. large high quality studies conducted in other countries are needed to look into urologist’s attitudes towards pca screening, and to investigate their preferences in order to understand the rationale behind their decisions. keywords: practice guidelines as topic; prostate; prostate-specific antigen; prostatic neoplasms; diagnosis; health knowledge; attitudes; practice. introduction prostate cancer (pca) is the most frequently diag-nosed cancer and a major cause of death among men in developed countries.(1,2) although the majority of men older than 50 years in these countries have been screened for pca with the prostate-specific antigen (psa) blood test,(3,4) pca screening is controversial because there is no convincing evidence that screening reduces disease-specific morbidity and mortality. the european randomized study of screening for prostate cancer (erspc) showed an absolute reduction of 0.09% in pca deaths in men aged 55 to 70 after 11 years of follow up, suggesting a negligible survival benefit for screening.(5) meanwhile, the simultaneously published results from the american prostate, lung, colorectal, and ovarian cancer (plco) screening trial found a slightly increased risk of pca mortality in screened men after 13 years, which was reported to be statistically insignificant.(6) both plco and erspc failed to demonstrate a reduction in all-cause mortality perhaps due to the fact that most men with pca die of competing causes in this age group. there are considerable data suggesting that treatments for early stage cancersthe targets for screening-may lead to important complications(7) and are only marginally beneficial, especially for men 65 years and older.(8) the recommendations of available guidelines on pca screening vary as a result of the emerging new evidence. some guidelines, namely the 2012 us preventive services task force (uspstf), are now recommending against psa based screening,(9-11) while others still advocate its use in men with a life expectancy of greater than 10 years.(12-14) considering these contradictory data about pca screening, most professional organizations recommend that the first step in screening should be a discussion between health care providers (hcps) and patients about the potential harms and benefits of early detection and treatment to help patients make informed department of urology, clinical research development center, shahid modarres hospital, shahid beheshti university of medical science, tehran, iran. *correspondence: department of urology, clinical research development center, shahid modarres hospital, shahid beheshti university of medical science, tehran, iran. tel: +98 9125954970. fax: +98 21 22074101. e-mail: mohamad.soleimani.md@gmail.com. received january 2015 & accepted october 2015 vol 12 no 06 november-december 2015 2404 decisions regarding pca screening.(15) unfortunately unlike many other preventive services, discussion about pca screening is relatively complicated and not all the necessary information can be conveyed to the patient in a single office visit.(16) also, lack of patient health literacy is an important barrier to shared decision making.(17) consequently, true informed decision making about psa testing rarely occurs in practice.(18) an ideal thoroughly-informed patient is the one that has as much knowledge on the subject as a physician. in other words, doctors can be considered as fully informed patients. among the health care providers who are responsible for informing patients about risks and benefits of pca screening and treatment, urologists are the ones with the most accurate knowledge on this subject. so we decided to conduct a survey among urologists to discover what they would choose for themselves as patients. materials and methods in april 2012, through a convenience non-random sampling method, board certified urologists attending the 15th congress of iranian urological association, were invited to participate in a questionnaire-based survey on pca screening. participants were asked to answer questions on what screening methods and treatment measures they would choose for themselves. 184 physicians were willing to participate and completed the questionnaire. there were missing data on some of the questions (table1); for every question only the valid data were included, but the missing data would comprise the sample for the remainder of the questions. data analysis was performed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. descriptive statistics of the variables were calculated. to evaluate the correlations between variables, chi-square test and independent samples t-test were used for qualitative and quantitative variables respectively. anova test, spearman and kendall’s tau correlations were also utilized as needed. results the mean age of the participants was 46.3 ± 9.08 years with the minimum and maximum being 30 and 65 years respectively (figure 1). of participants 100 (69%) were under the age of 50, and 45 (31%) were over fifty years old. 36 questionnaires lacked information on age of the participant. the mean value of years of experience was 12.37 ± 8.19 years, with a minimum of zero and a maximum of 31 years. fifty-nine (33.5%) responders were attending-urologists in academic centers, 69 (39.2%) provided health care services in public hospitals, and 48 (27.3%) were in private practice. urologists' attitude towards prostate cancer screening-asgari et al. table 1. valid and missing data regarding each question. variables age graduation year type of fellowship fellowship previous plan of method of follow up (years of experience) medical course screening screening screening methods practice valid 145 165 176 176 169 181 181 179 177 missing 36 16 5 5 12 0 0 2 4 variables age (years) p value years of p value type of p value mean ± sd experience medical practice academic public private no. % no. % no. % plan of screening yes 46.63 ± 9.14 .449 12.72 ± 8.00 .333 43 72.9 54 78.3 38 79.2 .695 no 45.29 ± 8.94 11.28 ± 8.78 16 27.1 15 21.7 10 20.8 method of screening psa and dre 43.72 ± 8.43 .052 11.03 ± 7.56 .136 12 28.6 20 37.0 8 21.6 .280 psa alone 47.58 ± 9.25 13.37 ± 8.11 30 71.4 34 63.0 29 78.4 follow up methods biopsy 45.03 ± 9.51 .478 10.48 ± 7.58 .081 18 45.0 20 36.4 10 26.3 .318 serial psa 46.70 ± 8.76 13.42 ± 7.69 21 52.5 35 63.6 27 71.1 no follow up 42.00 ± .00 9.00 ± 2.83 1 2.5 0 .0 1 2.6 abbreviations: sd, standard deviation; psa, prostate specific antigen, dre, digital rectal examination. table 2. correlations between all the evaluated variables. urological oncology 2405 with regard to training, 53 (30.1%) participants had completed fellowship training in urology subspecialties: 25 in endourology, 5 in urologic-oncology, 15 in transplant, and 1 in reconstructive urology (7 respondents didn't specify their fellowship field). one hundred twenty-three (69.9%) of the urologists didn't have a fellowship degree. previous screening seventy one (39.2%) of the respondents stated that they had undergone previous psa screening, 12 of whom were less than 50 years old. among urologists over the age of fifty 84.4% had undergone previous psa screening. plan of screening when asked whether they had a plan of screening for themselves, 139 (76.8%) urologists answered yes. forty-two (23.2%) preferred not to undergo screening for pca. among the 71 urologists who had undergone previous psa screening, 9 (12.6%) mentioned no further plans for pca screening. the mean age of the participants with a positive answer to this question was slightly higher than the subjects who declared no plans for screening (46.63 ± 9.14 years vs. 45.29 ± 8.94 years), but the differences were not statistically significant (p = .449). similarly, the average years of experience was also higher in the first group (12.72 ± 8.00 years vs. 11.28 ± 8.77 years) but the differences were not found to be significant with a p = .333 (table 2). surprisingly the lowest percentage of positive answers to this question was found among the urologists working in academic centers with 72.9%. following that, 78.3% of the subjects in public practice and 79.2% of the ones working in private section had claimed to have screening plans. however, the differences were found to be insignificant (p = .695) (table 2). method of screening of those who had a plan of being screened, 69.3% (n = 95) preferred psa alone, while 30.7% (n = 42) considered dre along with psa as their method of choice. the mean age of the participants who mentioned psa alone as their preferred screening method was higher than the subjects who chose psa and dre together (47.58 ± 9.25 years vs. 43.72 ± 8.43 years) but the differences were insignificant (p = .052). the average years of experience also followed a similar pattern with 13.37 ± 8.11 years among the ones who chose psa alone and 11.03 ± 7.56 years in subjects who chose both methods (p = .136) (table 2). psa alone was most commonly selected by the urologists working in private section with 78.4%. participants from academic hospitals were in the second place with 71.4% and the lowest percentage was found among the subjects in public practice with 63.0% (p = .280) (table 2). follow up method urologists that were willing to be screened were asked about their method of choice for follow-up, in case their psa levels came above normal ranges. 84 (62.2%) chose serial psas, 49 (36.3%) preferred to be biopsied, and 2 (1.5%) stated that they wouldn't go through any follow-ups. the mean age of the subjects who chose serial psa as follow-up method was 46.93 ± 8.78 years. this figure was 45.03 ± 9.50 among the participants who chose biopsy and 42 in the subjects who preferred no follow-ups. the differences were evaluated via anova test and were found to be insignificant (p = .478) (table 2). urologists who chose serial psa as their follow-up method of choice had the highest average years figure 1. distribution of participant's age. figure 2. urologists' preferred follow up method relative to their type of practice. blue: prostate biopsy. green: serum prostate specific antigen measurement. urologists' attitude towards prostate cancer screening-asgari et al. vol 12 no 06 november-december 2015 2406 of experience with 13.59 ± 7.72 years. the second highest figure was 10.48 ± 7.57 among subjects who selected biopsy. the mean for the two participants who preferred no follow-ups was 9 ± 2.82 years (p = .081) (table 2). the highest preference rate for biopsy as the method of choice for follow-up was 46.2% among the subjects working in academic centers compared to 37% in participants from public practice and 26.3% among the ones from private section. on the other hand, 71.1% of the private section urologists selected serial psa as their method of choice. the differences between follow up methods regarding the participants’ type of medical practice were insignificant (p = .318) (table 2) (figure 2). discussion no matter what the final recommendations of different guidelines on pca screening are, a general emphasis on shared decision making prevails. to guide patients in their decision, doctors are supposed to provide them with all the available information on screening harms and benefits. but even with the advent of prewritten pamphlets, this concept is practically unachievable in clinical settings. a study by pollack and colleagues(19) on health care provider's perspective towards discontinuing pca screening, found that the two most important factors in cessation of psa screening were patient expectation (74.4%) and time constraints (66.4%). but even if these obstacles were overcome, and informed decision making actually put into practice, physicians will not limit guiding patients to evidence alone. they will share their own perspective with patients and influence their decisions to a great extent. of course doctors have the added advantage of having experience as well as knowledge, but as a downside, physicians are likely to stick to a previous practice despite strong evidence against it. this will definitely translate into what they will be recommending to patients. so if informed decision making happened as completely as theoretically desired, we can expect patients to think like doctors, and to have quite the same attitudes towards screening. therefore we conducted this survey to find out what urologists or rather "fully-informed patients" would choose to do for themselves (provided that they are aware of almost all the available evidence on harms and benefits of screening). our study showed that despite the controversy on psa-based screening,(9-14) most urologists prefer to be screened for pca. this choice was irrespective of physician's age, years of experience, type of medical practice, and fellowship status, meaning that a great number of urologist with different backgrounds are still in favor of pca screening. in a recent survey by pollack and colleagues, health care providers in a university-affiliated practice (johns hopkins community physician) who attended an annual organizational retreat were asked about their opinion on latest usptf draft on pca screening. 92.7% of the 123 practitioners had heard about the uspstf recommendations. approximately 50% of them agreed that the recommendations were appropriate, while 36.0% disagreed. only a few providers (2%) said that they would no longer order routine psa testing; about 60% said that they would be less likely to do so; and 38% said that they would not change their screening practices. even among those clinicians who agreed with the draft recommendations, fewer than half stated that they would no longer order routine psa screening or be much less likely to do so.(20) our study demonstrated that 69.3% of those in favor of screening did not consider dre as part of their screening program. physicians 50 years and older were twice more like to refuse dre compared to those under 50 (p = .06). even among the five urologic-oncologists who participated in our study, only three chose dre along with psa. in their prospective study on 450 men, romero and colleagues looked into the reasons why patients reject digital rectal examination.(21) according to their results, among the 8.2% who rejected dre despite an initial educational program on pca screening and a second consultation to orient participants on the importance of dre, 84.4% still had misconceptions about screening. 43.7% were concerned about severe discomfort during the procedure, and 53.1% regarded dre as a reason for shame. the latter might be even more pronounced in some cultures especially those with strict religious beliefs. conducting similar studies on other populations can show the impact of cultural values on patient's attitudes towards dre and might stress the significance of developing culture-specific guidelines. studies show that cancers with higher stages and grades have shorter psa doubling times.(22) therefore following the pattern of psa increase can be an effective follow up method to substitute the more invasive prostate biopsy. harms of prostate biopsy include persistent hematospermia, hematuria, fever, urinary retention, prostatitis and urosepsis.(23) according to the results of protect study, about 19.6% of men who undergo biopsy, consider these as moderate to major problem.(24) our results show that 62.8% of the urologists willing to be screened chose serial psa as their follow up method, and 35.8% preferred to be biopsied. participants who had spent more years in medical practice, were more urologists' attitude towards prostate cancer screening-asgari et al. urological oncology 2407 likely to choose serial psa but the correlation was not statistically significant (p = .42). compared to faculty members, physicians who were in private practice were 1.5 times more likely to follow an abnormal test result with serial psa (p = .38). the major limitation of this survey was the method of sampling. since accessibility to a large number of urologists working in different parts of the country is extensively limited, we decided to conduct this study on a sample of participants gathered from all around the nation for a congress being held in tehran. therefore we inevitably executed a convenience non-random sampling method which might cause selection and volunteer bias. the lost data in the questionnaires brought about another limitation for this study. since the missing data could be most likely classified as “missing at random”, the analyses were not majorly affected and the estimated parameters were not biased by the absence of data. therefore the simplest approach of listwise deletions was used for this matter. conclusions our study demonstrated that urologists continue to favor psa screening despite the current controversy on its usefulness. most of the urologists practicing in iran do not choose dre as part of their screening program. large high quality studies are needed to look into urologist’s attitudes towards pca screening, and to investigate their preferences in order to understand the rationale behind their decisions. conflicts of interest none declared. references 1. hsing aw, tsao l, devesa ss. international trends and patterns of prostate cancer incidence and mortality. int j cancer. 2000;85:60-7. 2. jemal a, siegel r, ward e, et al. cancer statistics, 2008. ca cancer j clin. 2008;58:7196. 3. ross le, coates rj, breen n, uhler rj, potosky al, blackman d. prostate-specific antigen test use reported in the 2000 national health interview survey. prev med. 2004;38:732-44. 4. jemal a, ward e, wu x, martin hj, mclaughlin cc, thun mj. geographic patterns of prostate cancer mortality and variations in access to medical care in the united states. cancer epidemiol biomarkers prev. 2005;14:590-95. 5. moyer va. screening for prostate cancer: us preventive services task force recommendation statement. annals of internal medicine. 2012;157:120-34.. 6. andriole gl, crawford ed, grubb rl, et al. prostate cancer screening in the randomized prostate, lung, colorectal, and ovarian cancer screening trial: mortality results after 13 years of follow-up. j natl cancer inst. 2012;104:125-32. 7. wilt tj, macdonald r, rutks i, shamliyan ta, taylor bc, kane rl. systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. annals ann intern med. 2008;148:435-48. 8. bill-axelson a, holmberg l, ruutu m, et al. radical prostatectomy versus watchful waiting in early prostate cancer. n engl j med. 2011;364:1708-17. 9. moyer va. screening for prostate cancer: us preventive services task force recommendation statement. ann intern med. 2012;157:120-34. 10. heidenreich a, bellmunt j, bolla m, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and treatment of clinically localised disease. eur urol. 2011;59:61-71. 11. lim ls, sherin k. screening for prostate cancer in us men acpm position statement on preventive practice. am j prev med. 2008;34:164-70. 12. greene kl, albertsen pc, babaian rj, et al. prostate specific antigen best practice statement: 2009 update. j urol. 2013;189:s2s11. 13. wolf a, wender rc, etzioni rb, et al. american cancer society guideline for the early detection of prostate cancer: update 2010. ca cancer j clin. 2010;60:70-98. 14. horwich a, parker c, bangma c, kataja v. prostate cancer: esmo clinical practice guidelines for diagnosis, treatment and followup. ann oncol. 2010;21(suppl 5):v129-v33. 15. volk rj, hawley st, kneuper s, et al. trials of decision aids for prostate cancer screening: a systematic review. am j prev med. 2007;33:428-34. 16. wilbur j. prostate cancer screening: the continuing controversy. am fam physician. 2008;78:1377-84. 17. guerra ce, jacobs se. are physicians discussing prostate cancer screening with their patients and why or why not? a pilot study. j gen intern med. 2007;22:901-07. 18. chan ec, vernon sw, haynes mc, o'donnell ft, ahn c. physician perspectives on the importance of facts men ought to know about prostate‐specific antigen testing. j gen intern med. 2003;18:350-6. 19. pollack ce, platz ea, bhavsar na, et al. primary care providers' perspectives on discontinuing prostate cancer screening. urologists' attitude towards prostate cancer screening-asgari et al. vol 12 no 06 november-december 2015 2408 cancer. 2012;118:5518-24. 20. pollack ce, noronha g, green ge, bhavsar na, carter hb. primary care providers' response to the us preventive services task force draft recommendations on screening for prostate cancer. arch intern med. 2012;172:668-70. 21. romero fr, romero k, brenny f, pilati r, kulysz d, de oliveira júnior fc. reasons why patients reject digital rectal examination when screening for prostate cancer. arch esp urol. 2008;61:759-65. 22. schmid hp, mcneal je, stamey ta. observations on the doubling time of prostate cancer. the use of serial prostate‐specific antigen in patients with untreated disease as a measure of increasing cancer volume. cancer. 1993;71:2031-40. 23. raaijmakers r, kirkels wj, roobol mj, wildhagen mf, schrder fh. complication rates and risk factors of 5802 transrectal ultrasound-guided sextant biopsies of the prostate within a population-based screening program. urology. 2002;60:826-30. 24. rosario dj, lane ja, metcalfe c, et al. short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within protect study. bmj. 2012;344-55. urologists' attitude towards prostate cancer screening-asgari et al. urological oncology 2409 1514.pdf 861vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l 1urology & nephrology research center, department of urology, hamadan university of medical sciences, hamadan, iran 2department of general surgery, hamadan university of medical sciences, hamadan, iran 3endometr & endometriosis research center, department of gynecology, hamadan university of medical sciences, hamadan, iran 4department of community medicine, school of medicine, hamadan university of medical sciences, hamadan, iran 5islamic azad university, tehran medical branch, tehran, iran hamid shayani-nasab,1 mohammad ali amir-zargar,1 seyed habibollah mousavi-bahar,1 abdolmajid iloon kashkouli,1 manoochehr ghorban-poor,2 marzieh farimani,3 saadat torabian,4 amir ali tavabi5 complications of entry using direct trocar and/or veress needle compared with modified open approach entry in laparoscopy six-year experience corresponding author: abdolmajid iloon kashkouli, md; mph urology & nephrology research center, beheshti hospital, eram blvd, hamadan, 6516757666, iran tel: +98 811 838 0704 fax: +98 811 838 0098 e-mail: ilounmajid@yahoo.com received june 2012 accepted june 2013 purpose: to compare the results obtained from three routine laparoscopic entry techniques, including direct trocar (dt), veress needle (vn), and open approach (oa). materials and methods: were evaluated prospectively in 453 consecutive patients who had undergone laparoscopy results: of 453 patients, 105 (23.2%) were operated on with the dt, 168 (37.1%) with the among the groups in terms of mean age (p = .003), male-to-female ratio (p < .001), indications for the operation (p < .001), and mean trocar insertion time (p < .001). three major complications (1 colon perforation and 2 iliac artery injuries) occurred in dt and one (iliac p = .04). four major complications required laparotomy. minor complications were seen in 6 (5.8%), 9 (5.4%), and 17 (9.4%) patients (p = .274) and gas leakage in 4 (3.8%), 16 (9.5%), and 27 (15%) patients (p conclusion: although dt and vn are rapid and relatively safe, they can be associated with able due to less major complications. keywords: laparoscopy, pneumoperitoneum, complications laparoscopic urology 862 | introduction establishing an acceptable pneumoperitoneum is the best entry technique into the abdominal cavity is always a dilemma, and may result in complications and severe morbidity.(1-3) major vascular and bowel injuries are rare, but serious complications of laparoscopic surgery. generally, the insertion technique is done with direct trocar (dt), which has the potential for injury.(4) although veress needle (vn) is widely used as another popular technique, life-threatening complications.(4) the open approach (oa) is relatively more safe; hence, is a good alternative to dt and vn techniques, even if it is considered cumbersome by many surgeons. although oa is credited with reducing the incidence of vascular and visceral complications to nil, a 0.2% incidence of complications among 10 840 open gynecologic laparoscopies and a 0.06% incidence of bowel injuries have been reported.(5) some surgeons use a new version of oa as modi(6,7) furthermore, some surgeons use oa for percutaneous nephrolithotomy.(8) to compare and designed this prospective, nonrandomized, clinical study and discussed the results. materials and methods this study was approved by urology & nephrology research center, hamadan university of medical sciences as well as chancellor of research and technology of hamadan university of medical sciences, hamadan, iran. after ethic committee approval was obtained based on declaration of helsinki, this observational study was conducted prospectively at shahid beheshti, ekbatan, besat, and fatemieh acacal sciences in hamadan, iran from january 2005 to january 2011.these hospitals are the main centers for laparoscopic surgery in hamadan province with a population of more than 1 700 000 people in the west of iran. during the period of six years, all patients with any age who had undergone laparoscopic surgery were enrolled in the study. the only criterion for the technique selection was the surgeon’s preference. exclusion criteria were any contraindication for laparoscopy, such as uncorrectable coagulopathy, massive hemoperitoneum or hemoretroperitoneum, generalized peritonitis, and suspected malignant ascites. furthermore, 34 patients were excluded from the study due to previous abdominopelvic surgery, body mass index more than 40 kg/m2, and refusal of surgery. finally, 453 patients were evaluated as: group 1, dt (n = entry technique (n = 180). various surgeons with different specialty, who have been employees of hamadan university of medical sciences with at least assistant professor degree, learning curve, performed the operations. after full pre-operative assessment, including history taking, general physical examination, laboratory evaluation, and diagnostic studies, patients were admitted to the hospital on the day of the procedure or one day prior for some major operations. data, such as gender, age, body weight, surgery indications, intra and postoperative complications, and mortality and morbidity rates, were compared among the groups. compliconversion to an open procedure or re-intervention (mesenteric or iliac vessels, the bowel, or solid organ injury) and encing the length of hospital stay (subcutaneous emphysema, injury). statistical analysis data were analyzed by spss software (the statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa) and expressed as mean ± standard deviation. independent t test was used for quantitative parameters and chi-square for others. a p value of less than .05 was considsurgical procedure laparoscopic urology 863vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l ing the patients in appropriate position, in group 1, a 12-mm incision was made just below the umbilicus. first, a 5-mm incision was made on the rectus muscle sheath. then, a 10 to 12-mm disposable shielded trocar was passed vertically into the peritoneal cavity. entry into the abdominal cavity was the obturator was removed, and carbon dioxide gas was inof 12 to 14 mmhg. subsequently, other trocars were inserted. (9) in the vn group, a pneumoperitoneum was created with disposable or metal vn (70 or 120 mm, 14 gauge, and 2 mm outer diameter). the vn was inserted through a created supraumbilical incision in supine or lateral decubitus position. mm trocar was inserted in a similar manner to group 1.(8) midclavicular incision in obese patients, incision medial edge was held with a blunt homeostasis, and metzen was used for dissection onto the fascia. after elevation of the abdominal cavity with the towel clips, followed by an under vision small incision by surgical blade, the fascia was dilated about 10 to peritoneal cavity was performed downwardly by closed metzen and with empty bladder. metzen was set back in open manner to prevent solid or hollow organ injury. after visual clips to prevent instability and probable gas leakage if need. (6,10) results of 453 patients, 105 (23.2%) were operated on by dt, 168 are presented in table. the main indications for the operation were urologic (renal cyst, undescended testes, inguinal hernia, and ureteral stone), appendicitis), and gynecologic diseases (diagnostic laparoscopy, tubal ligation, and infertility). no mortality was observed in each group. there were statistical differences among the groups in terms of mean age (p = .003), male-to-female ratio (p < .001), indications for the operation (p < .001), and mean trocar insertion time (p < .001). complications were not associated with the surgeons’ experience. there were three major complications (1 colon perforation and 2 iliac artery injuries) in group 1 and one (iliac artery injury) in group 2 whereas no major complication was detected in group 3 (p = .04). these four major complications required a re-intervention, such as laparotomy. one patient with iliac artery injury in the vn group improved after one-week intensive care unit admission. as table shows, 32 minor complications occurred during insertion technique. these complications were seen in 6 (5.8%), 9 (5.4%), and 17 (9.4%) patients in the dt, vn, and oa groups, respectively (p = .274). there was no other for any unrecognized intra-abdominal injury. gas leakage occurred in 4 (3.8%), 16 (9.5%), and 27 (15%) patients in the dt, vn, and oa groups, respectively (p = .01). about 5% of the vn patients needed more than one try for successful trocar insertion. discussion although some studies have been carried out to compare laparoscopy entry techniques, adequate data are not yet available. vilos and colleagues in 2007 concluded that optical trocar was better than other techniques. they also stated that the visual entry cannula system may represent an advantage over traditional trocars, since it allows a clear optical trocar entry, but this advantage has not been fully explored and they suggested more investigation.(9) altun and associates compared dt and vn techniques and reported 2.2% major complication for vn, but nothing for dt. they also reported 6.7% minor complication for vn and 2.05% for dt. they concluded that surgeon’s preference, skill, anatomic knowledge, and experience are determining factors in the selection of technique.(5) simforoosh and colleagues described outcome of 3000 patients that underwent entry techniques in laparoscopy | shayani-nasab et al 864 | medical center. they concluded that a new version of oa as (6,7,10) bemelman and associates compared dt, vn, and oa techmean trocar insertion time between groups (p < .001), but not for morbidity and gas leakage.(11) some other studies did rates between the vn and the dt entry techniques.(2,12,13) mainly used by gynecologists, general surgeons, and urologists, respectively. because of more incidences of some diseases, such as undescended testes and varicocele, in young than other groups (p < .05). furthermore, most patients in dt group were women (p < .001). mean trocar insertion technique group (p < .001 and p = .01, respectively), which were expected based on the technique. more occurrence of major life-threatening complications were seen in dt than other groups (p = .04). although minor complications were p = .274). our study was not without limitations. to eliminate possible confounding factors, such as morbid obesity and previous abdominopelvic surgery, we suggest enrolling more patients and designing a randomized study to enhance the power of the investigation and decrease biases. furthermore, since various surgeons were involved, surgeon’s experience can conclusion acceptable due to less life-threatening major complications. acknowledgements the authors are grateful to drs amir derakhshanfar (general laparoscopic urology data of different entry techniques in 450 patients who had undergone laparoscopy. variable direct trocar group group (n = 105) veress needle group (n = 168) open approach group (n = 180) p mean age ± sd, y 41.37 ± 1.27 35.13 ± 1.61 30.49 ± 1.23 vn/dt: .003 vn/oa<.001 dt/oa: .023 female, n (%) 86 (81.9%) 91 (54.2%) 35 (19.4%) < .001 male, n (%) 19 (18.1%) 77 (45.8%) 145 (80.6%) < .001 mean bmi ± sd, kg/m2 25.2 ± 6.3 26.8 ± 13.1 24.4 ± 5.8 .615 mean trocar insertion time ± sd, sec 176.94 ± 96.426 331.02 ± 64.405 375.36 ± 63.808 < .001 urologic cases, n (%) 11 (10.5%) 15 (8.9%) 131 (72.8%) < .001 gynecologic cases, n (%) 78 (74.3%) 25 (14.9%) 27 (15%) < .001 general surgery cases, n (%) 16 (15.2%) 128 (76.2%) 22 (12.2%) < .001 minor complications, n (%) 6 (5.8%) 9 (5.4%) 17 (9.4%) .274 subcutaneous emphysema, n (%) 1 (1.0%) 5 (3.0%) 6 (3.3%) .314 abdominal wall vessel injury, n (%) 5 (4.8%) 2 (1.2%) 9 (5.0%) .314 omental hernia, n (%) 0 (.0%) 2(1.2%) 2 (1.1%) .314 major complications, n (%) 3 (2.9%) 1 (0.6%) 0 .04 mesenteric vessel laceration 0 0 0 intestinal injury, n (%) 1 (1%) 0 0 .085 solid organ injury 0 0 0 major vessel injury, n (%) 2 (1.9%) 1 (0.6%) 0 .085 gas leakage, n (%) 4 (3.8%) 16 (9.5%) 27 (15%) .01 sd indicates standard deviation; bmi, body mass index; vn, veress needle; dt, direct trocar; and oa, open approach. 865vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l entry techniques in laparoscopy | shayani-nasab et al surgeon), abbas moeini (general surgeon), soghra rabiei (gynecologist), mehrangiz zamani (gynecologist), and adel eslami (urology resident) for the use, analysis, and interpretation of their laparoscopy data. we are also thankful to the staff of the records section of shahid beheshti, ekbatan, besat, and fatemieh hospitals for their help with data collection. conflict of interest none declared. references 1. philips pa, amaral jf. abdominal access complications in laparoscopic surgery. j am coll surg. 2001;192:525-36. 2. agresta f, de simone p, ciardo lf, bedin n. direct trocar insertion vs veress needle in nonobese patients undergoing laparoscopic procedures: a randomized prospective single-center study. surg endosc. 2004;18:1778-81. 3. agarwala n, liu cy. safe entry techniques during laparoscopy: left upper quadrant entry using the ninth intercostal space--a review of 918 procedures. j minim invasive gynecol. 2005;12:55-61. 4. vilos ga, ternamian a, dempster j. laparoscopic entry: a review of techniques, technologies, complications. society of obstetricians, gynecologists (sogc) clinical practice guideline no.1993. j obstet gynecol can. 2007;29:433–47. 5. altun h, banli o, kavlakoglu b, kucukkayikci b, kelesoglu c, erez n. comparison between direct trocar and veress needle insertion in laparoscopic cholecystectomy. j laparoendosc adv surg tech a. 2007;17:709-12. 6. simforoosh n, basiri a, ziaee sam, tabibi a, noralizadeh a. complications of laparoscopic access techniques in urology: open access versus blind access. 30th world congress of endourology & swl; wce 2012. istanbul, turkey; 2012:mp 11-14. 7. simforoosh n, soltani mh, ahanian a, lashay a. initial series of minilaparoscopic live donor nephrectomy using a novel technique. complications of laparoscopic access techniques in urology: open access versus blind access. 30th world congress of endourology & swl; wce 2012. istanbul, turkey; 2012:mp 18-04. 8. mousavi-bahar sh, amir-zargar ma, gholamrezaie hr. laparoscopic assisted percutaneous nephrolithotomy in ectopic pelvic kidneys. int j urol. 2008;15:276-8. 9. vilos ga, ternamian a, dempster j, laberge py, the society of o, gynaecologists of c. laparoscopic entry: a review of techniques, technologies, and complications. j obstet gynaecol can. 2007;29:433-65. 10. simforoosh n, nouralizadeh a. iranian text book of urology. tehran: behineh; 2007;744-50. 11. bemelman wa, dunker ms, busch or, den boer kt, de wit lt, gouma dj. efficacy of establishment of pneumoperitoneum with the veress needle, hasson trocar, and modified blunt trocar (trocdoc): a randomized study. j laparoendosc adv surg tech. 2000;10:325–30. 12. jaime l, elspeth mm, indiber s. adult laparoscopic urology in: gillenwater jy, grayhaek jt, howards ss, eds. adult and pediatric urology; 2002:667-90. 13. inan a, sen m, dener c, bozer m. comparison of direct trocar and veress needle insertion in the performance of pneumoperitoneum in laparoscopic cholecystectomy. acta chir belg. 2005;105:515-8. review impact of diabetes mellitus on urinary continence recovery after radical prostatectomy: a systematic review and meta-analysis jianlin huang, yu wang, yu an, yong liao*, mingxing qiu purpose: to evaluate the impact of diabetes mellitus (dm) on the recovery of urinary continence (uc) after radical prostatectomy (rp). materials and methods: a systematic review of english articles was performed in august 2019, following the preferred reporting items for systematic reviews and meta-analyses (prisma) statement. trials were identified in a literature search of pubmed, embase, cochrane library and web of science using appropriate search terms. all comparative studies reporting diabetes mellitus, study characteristics, and outcome data including the relationship between diabetes mellitus and urinary continence data were included. continence rates at different time after rp were compared. odds ratio (or) was used for the comparison and all the results were presented with 95% confidence intervals (cis). results: seven cohort studies comprising with 5944 participants were included, the percentage of dm patients was 8.7%. the results showed that dm decreased urinary continence rates at 12 months after rp (or 0.54, 95%ci 0.36 to 0.81, p = 0.003). the continence rates were not significantly different between dm and non-dm groups at short-term (catheter removal, 3 months, 6 months) and long-term (>12 months). when stratified by the surgical approaches, the pooled results in patients who underwent robot -assisted radical prostatectomy (rarp) were similar to results of the overall analysis. conclusion: dm has an adverse impact on the recovery of uc during the intermediate-term after rp. well-designed trials with strict control of confounders are needed to make results more comparable. keywords: urinary continence; diabetes mellitus; radical prostatectomy; prostate cancer; meta-analysis introduction urinary incontinence (ui) is still the most impor-tant complication of radical prostatectomy (rp) with a negative impact on the quality of life(1). the prevalence of postprostatectomy ui varies according to the definition applied(2). various factors that affect urinary continence (uc) recovery have been reported. in addition to surgeon experience and different surgical techniques, age, membranous urethral length, and some comorbidities might impact on continence recovery(3,4). diabetes mellitus (dm) is a chronic disease associated with some genitourinary complications(5). uropathy due to dm may cause voiding disorders by impairing the storage and outlet functions of the urinary tract(6). dm is a very common comorbidity in prostate cancer patients who receive treatment of rp. however, there is a lack of evidence in terms of the relationship between dm and uc recovery after rp for prostate cancer patients. our study was aimed to systematically review and meta-analyze studies reporting the impact of dm on the recovery of uc following rp. department of urology, sichuan academy of medical science & sichuan provincial people’s hospital, chengdu, china. *correspondence: department of urology, sichuan academy of medical science & sichuan provincial people’s hospital, no. 32, west section 2, 1st ring road, chengdu 610072, china. tel: +86 28 87393691 fax: +86 28 87393687. e-mail: liaoyong616@sina.com. received november 2019 & accepted may 2020 materials and methods search strategy a literature search was performed in august 15, 2019 using pubmed, embase, cochrane library, and web of science databases. medical subject headings (mesh) and related keywords were used in searching. a combination of search terms was used including [title/ abstract] or [topic (ts)]: “diabetes mellitus or diabetes”, “prostatectomy or prostatectomies or radical prostatectomy” and “urinary incontinence or incontinence or urinary continence or continence”. the search was conducted with a language restricted to english publication. references for all of the original studies were also identified. inclusion criteria and exclusion criteria inclusion criteria: (1) men undergoing radical prostatectomy; (2) postoperative continence assessment completed; (3) original articles in english publication; (4) full journal article published in a peer-reviewed journal; (5) dm was described; (6) a report of the relationship between dm and postoperative continence status. urology journal/vol 18 no. 2/march-april 2021/ pp. 136-143. [doi: 10.22037/uj.v16i7.5750] exclusion criteria: (1) review articles and descriptive commentaries; (2) animal studies; (3) conference abstracts or poster publications; (4) publication in a language other than english. data extraction and quality assessment after the removal of duplicates, two authors (huang and wang) screened all titles and abstracts independently to identify potentially relevant articles for eligibility. subsequent full-text record screening was fulfilled independently by two authors (huang and an). any disagreements were resolved by a third reviewer by discussion (liao). all included trials in our meta-analysis contained data as follows: (1)first author’s name, published year, country; (2)sample size, age, prostate-specific antigen, gleason score, type of surgical approach; (3)the proportion of patients with dm; (4)the definition, method of assessment, and the time points used for uc assessment. authors of the studies identified in our search were also contacted by email to provide clarification and/ or additional data where necessary. some studies have shown the or and 95% ci but not the numbers of continence of each group, which could be calculated with the total continence rates and numbers of each group. the quality of each included study was assessed by the newcastle-ottawa scale (nos), which is widely used and recommended by the cochrane collaboration(7). the scale instrument evaluates cohort studies based on three aspects: participant selection, comparability of study groups, and assessment of outcome. a maximum of four, two, and three stars can be awarded for each category, respectively. statistical methods review manager 5.3 (cochrane collaboration, oxford, uk) was used to perform this meta-analysis. odds ratio (or) was used for the comparison of dichotomous variables, and all the results were presented with 95% confidence intervals (cis). chi-square and i-square tests were employed to test the heterogeneity of different trials. a fixed-effects model (mantel–haenszel method) was applied to pool the trial results since no significant heterogeneity existed when p > 0.1 and i2 < 50%. significant heterogeneity was identified if p < 0.1 and i2 > 50%, and a random-effects model which considered both withinand between-study variability was employed. publication bias was assessed by funnel plots. a p < 0.05 was considered statistically significant. results workflow of literature research figure 1 presents the flow diagram for the study selection process. after primary literature search, 156 potentially relevant studies were found and 56 duplicate studies were excluded. then, after screening the title and abstract, 65 studies were further excluded. finally, 28 additional studies were removed by two authors accessing the full text independently. therefore, 7 studies were included in this meta-analysis(8-14). dm and continence after rp-huang et al. review 137 table 1. demographic and clinical data of dm and non-dm patients in different studies. wille et al. teber et al. nilsson et al. mao et al. song et al. cakmak et al. manfredi et al. 2006 2010 2011 2015 2017 2019 2019 country germany turkey sweden china korea turkey italy study period 1989~ 2003 1999~ 2008 2002~ 2006 2010~ 2013 2008~ 2013 2009~ 2014 2013 ~ 2017 patients 742 2071 1179 446 186 312 1008 dm cases (%) 74(10) 135(6.5) 71(6.2) 34(7.6) 31(16.7) 99(31.7) 71(7.04) type of dm both type 2 na na na type 2 na age (years) 66 ± 6.5 na 63 (36–77) 66.9 (41-82) 64.5 ± 7.6 63.3 ± 6.5 (dm), 64.8 ± 6.8 61.3 ± 6.8 (non-dm) preoperative psa, na na 6.9 (0.4–117) 18.5 (0.17-150.4) 8.25 ± 9.11 9.8 ± 9.3 (dm), 9.7 ± 8.2 10.31± 11.61 mean (non) gleason score ≤6 na na 822(71.2) na 33 (17.7) 198(63.5) 97 (9.6) 7 na na 276(23.9) na 137 (73.7) 69(22.1) 763(75.7) 8-10 na na 57(4.9) na 16 (8.6) 45(14.4) 148 (14.7) clinical stage t1 28(3.8) na 702 (60) 135 (30.3) na 192(61.5) 0a t2 395(53) na 422 (36) 301 (67.5) na 120(38.5) 549 (54.5) t3 306(41) na 55 (5) 10 (2.2) na 0 458 (45.5) surgical approach rrp lrp rrp+rarp rrp+lrp rarp rarp rarp operation time(min) na 221 (134–395), na na 294.5 ± 88.9 na 117.28± 26.05 212 (138–394) ebl (ml) na 560 (200–2400), na na 304.9 ± 217.5 133.3± 89.2 156.3± 158.3 250.75± 64.44 600 (200–2500) nerve sparing(%) 129(17.4) none, unilateral or bilateral na 0 104 (55.9) 270(86.5) bilateral full 102(10.1) partial 408 (40.5) other techniques na bns na na na pr tar catheterization(days) na 7 (4–25) (dm)7 (7–25) na na na 9.6 ± 5.0 (dm) 9.7 ± 5.3 3.5 (3–6) hospital stay (days) na 10 (6–25) (dm)10 (5–30) na na na 3.8 ± 1.8 (dm) 3.8± 2.7 6 (4–8) definition of ≤1 pad in 24 h ≤1 pad in 24 h ≤1 pad in 24 h ≤1 pad in 24 h 0 pad in 24 h ≤1 pad in 24 h ≤1 pad in 24 h continence study quality ***** ******** ***** **** ***** ****** ****** (stars rating) abbreviations: dm, diabetes mellitus; na, not available; rrp, retropubic radical prostatectomy; lrp, laparoscopic radical prostatectomy; rarp, robot-assisted radical prostatectomy; ebl, estimated blood loss; bns, bladder neck sparing; pr, posterior reconstruction; tar, total anatomical reconstruction. a pathological stage was used. study characteristics seven included studies recruited 5944 participants. the percentage of dm patients was 8.7% (515/5944), from 6.2% to 31.7% in different studies. the demographics of enrolled patients and tumor characteristics are presented in table 1. all seven studies were cohort studies (one prospective and six historical) representing seven different institutions from seven different countries. all studies were rated at 4-8 stars (of a maximum of 9 stars), according to the newcastle-ottawa scale grading system (table 1). assessment and definition of uc or ui all studies reported a definition of continence and the method of assessment used. seven studies reported similar methods for the assessment of postoperative uc via direct patient questioning and/or the use of questionnaires about the perceived degree of ui, the absence of involuntary leakage and/or the use of pads. continence status was additionally evaluated by physical examination with valsalva or cough test at 3 months postoperatively in one study(9). there was only one study that used both the 24-h pad weight test and the standard 1-h pad test for patients who were still incontinent at 12 and 24 weeks(14). continence was defined as the use of no or one safety pad per day, or incontinence was defined as the use of two or more pads per day in six studies. one study defined continence as no pad or protection(12). continence outcomes three trials reporting the uc data after catheter removal consisted of 1766 participants. the overall pooled or indicated that there was no significant association between dm and uc in patients who underwent radical prostatectomy (rp) (odds ratio [or] 0.27, 95% confidence interval [ci] 0.02 to 4.64, p =0.37) (figure 2(a)). four trials reporting the uc data at 3 months consisted of 2036 participants. the overall pooled or indicated that there was no significant association between dm and uc in patients who underwent rp (or 0.46, 95% ci 0.19 to 1.11, p =0.08) (figure 2(b)). three trials reporting the uc data at 6 months consisted of 1506 participants. all 3 trials were about robot-assisted radical prostatectomy (rarp). the overall pooled or indicated that there was no significant association between dm and uc in patients who underwent rp (or 0.38, 95% ci 0.13 to 1.08, p = 0.07) (figure 2(c)). four trials reporting the uc data at 12 months consisted of 1776 participants. no significant heterogeneity existed (i2= 47% and p = 0.13) and a fixed-effects model was used. the overall pooled or indicated that there was a significant association between dm and uc in patients who underwent rp (or 0.54, 95% ci 0.36 to 0.81, p =0.003) (figure 2(d)). same result was obtained while a random-effects model was used (or 0.49, 95% ci 0.25 to 0.97, p = 0.04). four trials reporting the uc data at long-term (>12 months) consisted of 2474 participants. the time of assessment was not completely the same in each study, two were at 24 months (teber et al. 2010 and cakmak et al. 2019), one was at average 45 months (12~143 months) (wille et al. 2006) and the other one was at average 2.2 years (1~5 years) (nilsson et al. 2011). the figure 1. flow diagram for selection of the included trials reviewed. dm and continence after rp-huang et al. vol 18 no 2 march-april 2021 138 review 139 figure 2. forest plots comparing urinary continence rates between dm and non-dm men at catheter removal(a), 3 months (b), 6 months (c), 12 months (d) and long-term (>12 months) (e). dm and continence after rp-huang et al. vol 18 no 2 march-april 2021 138review 438 figure 3. funnel plots of urinary continence rates at 3 months (a), 12 months (b) and long-term (>12 months) (c). se standard error, or odds ratio. dm and continence after rp-huang et al. vol 18 no 2 march-april 2021 140 overall pooled or indicated that there was no significant association between dm and uc in patients who underwent rp (or 0.85, 95% ci 0.57 to 1.26, p = 0.41) (figure 2(e)). subgroup analysis when stratified by the surgical methods including radical retropubic prostatectomy (rrp), laparoscopic radical prostatectomy (lrp), and rarp. there were three studies of rarp, one study of rrp, and one study of lrp. two studies included 2 types of surgical approach (rrp+rarp, rrp+lrp), in which subgroup analysis was not performed. because only one trial was included in each subgroup, so subgroup analysis was not performed at long-term (>12 months). in rarp subgroup, there was also a significant association between dm and uc at 12 months after rp (or 0.33, 95% ci 0.18 to 0.60, p =0.0003), and no significant association at catheter removal (or 0.10, 95% ci 0.00 to 5.06, p = 0.25), 3 months(or 0.18, 95% ci 0.01 to 3.24, p = 0.24), 6 months(or 0.38, 95% ci 0.13 to 1.08, p = 0.07). in the lrp subgroup, there was a significant association between dm and uc at 3 months after lrp. in other subgroups, there were no significant associations between dm and uc after surgery. publication bias the publication bias of our meta-analysis was assessed using funnel plots (figure 3). no evidence of significant publication bias was found. discussion at present, diabetes mellitus (dm) is a major public health problem worldwide because of its frequency and the complications. with the rapid lifestyle changes, the prevalence of type 2 dm is steadily increasing in many countries(15). as a result, the number of patients with both dm and prostate cancer is increasing, too. in addition to receiving curative therapy, patients with prostate cancer also need to maintain their quality of life (qol). urinary incontinence remains an important factor influencing the qol after surgery(16). several studies have investigated the effect of factors on incontinence. patient age, body mass index (bmi), comorbidity index, lower urinary tract symptoms, and prostate volume were considered as the factors that affect the occurrence of incontinence(3,17). however, the results obtained in these studies do not always support each other(18). currently, there is still a lack of data in terms of predictors of continence recovery after rp for prostate cancer patients. to the best of our knowledge, this study is the first meta-analysis with a focus on the relationship between dm and uc recovery after rp. our results showed that patients with dm had lower continence rates than patients without dm at 12 months following rp, while there was no difference at short-term (≤ 6 months) and long-term (>12 months). it could be understood that dm delayed continence recovery during the intermediate-term after rp. postprostatectomy incontinence mainly depends on sphincter deficiency caused by operation and leads to stress type incontinence(19). the persistent incontinence of patients that is seen within the first year may be related to the anatomic dysfunction related to the operation. many patients continue to recover urinary function after 12 months(20), which might be delayed by dm. while in the short-term after rp, dm might not be the predominant factor which influences the recovery of uc. in most studies included, other factors such as age, bmi, prostate volume, and surgical techniques had not been controlled, so it’s hard to find the difference of continence between the two groups. furthermore, some non-significant differences (non-significant p-value) might be due to the small sample size and the small number of studies. considering the efficacy of operative technology, subgroup analysis stratified by rrp, lrp, and rarp was performed. in subgroups, similar results showed that patients with dm had lower continence rates than patients without dm at 12 months following rarp. in other subgroups, the difference was not significant except patients with dm had lower continence rates than patients without dm at 3 months following lrp. it’s possible that other main factors such as surgical techniques have a bigger impact(4). in recent years, rarp has been the predominant surgical approach of rp, especially in some developed countries. robotic technology allows surgeons to perform meticulous, precise, and accurate movements that are fundamental to preserve the key anatomic structures for urinary continence and potency. basiri et al. performed a meta-analysis regarding ui between rlrp and lrp groups. the results revealed that the rate of ui was significantly lower after rlrp than lrp(21). ficarra et al. also found a better 12mo urinary continence recovery after rarp in comparison with rrp or lrp(22). there are 3 studies in which the only surgical approach was rarp, while other subgroups only include one study in each category. results of rarp subgroup analysis were similar to results of the overall pooled analysis, which further strengthened the conclusion of the impact of dm on continence recovery, regardless of the surgical approach used. various surgical steps of the procedure can influence the recovery of urinary continence. it was also showed that more techniques were used in later studies especially in rarp, including nerve sparing, posterior rhabdosphincter reconstruction, bladder neck sparing, etc. posterior reconstruction for example, was popularized by rocco for use in radical retropubic prostatectomy to support recovery of continence(23), which was also later used in laparoscopic and robotic prostatectomy (24). this procedure was recommended as a simple and fast technique to improve the recovery of continence in rarp. furthermore, total anatomical reconstruction, a ‘tension-free’ anastomosis technique that aims to restore the anterior and posterior supports to the sphincter, conferred excellent results in the early recovery of urinary continence(14). there were different opinions about whether the duration of diabetes has an impact on continence. teber et al. found that rates of continence in patients with dm for 5 or more years were significantly less than those in patients with dm for less than 5 years at 3, 12 and 24 months postoperatively(9). however, another study showed that patients with a longer duration of diabetes (≥ 5 years vs < 5 years) had significantly more incontinence at the urethral catheter removal time, whereas no differences were detected in terms of urinary continence outcomes during the 1st, 3rd, 6th, 12th, 18th, and 24th months of follow-up times(13). there are several limitations of our study. firstly, we did not include data from conference proceedings because generally this type of publication does not report a complete set of data, which is required for a meta-analreview 141 dm and continence after rp-huang et al. ysis. this choice might be considered a limitation of the study. secondly, it is possible that other potential confounding factors were not adequately evaluated and could have influenced the reported outcomes, which included the participant preoperative parameters, the experience of surgeons, different kinds of techniques used by surgeons, and data collected and reported using different methods. only one study used 1:1 randomly matched control for age, bmi, preoperative prostate specific antigen, clinical stage, presence of neoadjuvant hormonal therapy, measured prostate volume, and presence of previous abdominal surgeries(9). thirdly, with the development of society, rp techniques have changed and improved over time. the publication year of 7 studies included in this meta-analysis varied from 2006 to 2019, and the study periods ranged from 1989 to 2017. it is difficult to assess the potential difference in techniques in statistical models because the same surgical step can be performed using different techniques by various surgeons. fourthly, in terms of the small sample size and the limited number of studies enrolled, the results may lack statistical power. further studies need to be done. fifthly, two different definitions of continence have been given in the literature and several ways of assessing continence have been used. the outcome could be affected by some degree of subjectivity. moreover, preoperative urinary continence status was not reported in most studies, and continence recovery is not evaluated in all treated cases because some patients are lost at follow-up. conclusions in conclusion, this study indicated that dm had an adverse impact on the recovery of uc at 12 months (intermediate-term) in patients who underwent rp or rarp. however, there was no significant association between dm and uc at short-term (0~6 months) and long-term (>12 months) in patients with rp. the results should be confirmed by well-designed trials with strict control of confounders to make results more comparable. acknowledgements the authors would like to thank dr. matteo manfredi and appreciate his support for providing additional data. conflict of interest the authors report no conflict of 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for early postoperative urinary continence recovery after non-nerve-sparing radical prostatectomy in chinese patients: a single institute retrospective analysis. int j clin exp med. 2015;8:14105-9. 12. song w, kim ck, park bk, et al. impact of preoperative and postoperative membranous urethral length measured by 3 tesla magnetic resonance imaging on urinary continence recovery after robotic-assisted radical prostatectomy. cuaj. 2017;11:e93-e99. 13. cakmak s, canda ae, ener k, atmaca af, altinova s, balbay md. does type 2 diabetes mellitus have an impact on postoperative early, mid-term and late-term urinary continence after robot-assisted radical prostatectomy? j endourol. 2019;33:201-6. 14. manfredi m, checcucci e, fiori c, et al. total anatomical reconstruction during robot-assisted radical prostatectomy: focus on urinary continence recovery and related complications after 1000 procedures. bju int. 2019. 15. ginter e, simko v. global prevalence and future of diabetes mellitus. in: ahmad si, ed. diabetes: an old disease, a new insight. new york, ny: springer new york; 2013:3541. 16. haga n, yanagida t, yabe m, et al. timing of urinary pad exchanges was the most important factor affecting quality of life in the early postoperative period after robotdm and continence after rp-huang et al. vol 18 no 2 march-april 2021 142 assisted laparoscopic radical prostatectomy. j endourol. 2015;29:1044-51. 17. kim jj, ha ys, kim jh, et al. independent predictors of recovery of continence 3 months after robot-assisted laparoscopic radical prostatectomy. j endourol. 2012;26:1290-5. 18. kumar a, samavedi s, bates as, et al. continence outcomes of robot-assisted radical prostatectomy in patients with adverse urinary continence risk factors. bju int. 2015;116: 764-70. 19. walz j, epstein ji, ganzer r, et al. a critical analysis of the current knowledge of surgical anatomy of the prostate related to optimisation of cancer control and preservation of continence and erection in candidates for radical prostatectomy: an update. eur urol. 2016;70:301-11. 20. lee jk, assel m, thong ae, et al. unexpected long-term improvements in urinary and erectile function in a large cohort of men with self-reported outcomes following radical prostatectomy. eur urol. 2015;68:899-905. 21. basiri a, de la rosette jj, tabatabaei s, woo hh, laguna mp, shemshaki h. comparison of retropubic, laparoscopic and robotic radical prostatectomy: who is the winner? world j urol. 2018;36:609-621. 22. ficarra v, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012;62:405-17. 23. rocco f, carmignani l, acquati p, et al. restoration of posterior aspect of rhabdosphincter shortens continence time after radical retropubic prostatectomy. j urol. 2006;175:2201-6. 24. coelho rf, chauhan s, orvieto ma, et al. influence of modified posterior reconstruction of the rhabdosphincter on early recovery of continence and anastomotic leakage rates after robot-assisted radical prostatectomy. eur urol. 2011;59:72-80. review 143 dm and continence after rp-huang et al. urological oncology diagnostic utility of lutetium-177 (lu 177) prostate-specific membrane antigen (psma) scintigraphy in prostate cancer patients with psa rise and negative conventional imaging mohammad ali ghodsirad1*, elaheh pirayesh1, ramin akbarian1,babak javanmard2, fatemeh kaghazchi1, mehrdad tavakoli1, kourosh fattahi.1 purpose: prostate cancer is a major worldwide health concern with up to 60% of patients experiencing biochemical relapse after radical treatment. introduction of prostate-specific membrane antigen (psma)-based radiotracers for imaging and therapy had gained increasing attention in recent years. positron emission tomography (pet) imaging with ga68 psma is the most promising technique, but psma-based radiotracers spect imaging with low dose of 177lu-psma when pet imaging is not available may also be considered. the goal of the study is to evaluate the sensitivity of 177lu_psma for detection of metastatic sites in patients with biochemical relapse and negative conventional (mri, mrs, ct scan and bone scintigraphy) imaging. materials & methods: 26 patients with biochemical recurrence after curative (surgery and/or radiotherapy) therapy, which had previous negative imaging as pelvic ct scan, pelvic mri, mrs and bone scan, were enrolled in this clinical imaging approach between 2015 and 2017.after injection of 5 mci (185mbq)177lu-psma-617, diagnostic planar whole body scan and spect study was obtained after 3 hours, 24 hours and 72 hours. the images were analyzed visually by an expert nuclear medicine physician for the presence of active regional or distant lesions. results were then prospectively checked by new ct scan images as a control. result: a total of 26 patients, with a mean age of 70 years (range: 46 to 89 years) were included in this study. the overall detection rates were 38.5% (10 out of 26 patients). most common site of detected lesions was lung in 6 patients, abdominal lymph nodes in 2 and mediastinum in another 2 patients. conclusion: 177lu-psma spect scan can help detecting metastatic lesions in more than one third of patients with biochemical recurrence and negative conventional investigations, when 68gapsma pet is not available. keywords: 177lutetium; psma; scintigraphy; prostate cancer; psa introduction prostate cancer is universally the most common ma-lignant tumor in male gender (1),causing 19% of all diagnosed cancer cases in american men and estimated number of 26,730 deaths in the united states alone in 2017(2). in spite of the fact that more than 80% of cases are diagnosed in a form of localized disease and are usually treated by radical prostatectomy , postoperative recurrence happens in about 15% of patients within 5 years and up to 40% within 10 years(3). once biochemical recurrence is detected, it is vital to find whether this signifies local recurrence or metastatic disease, or both and follow best treatment strategies(4).different modalities like ct scan, mri and choline pet have been introduced to detect possible sites of recurrence but each of them comes with special shortcomings(5). prostate-specific membrane antigen psma, is a type ii transmembrane glycoprotein belonging to the m28 peptidase family. the protein acts as a glutamate carboxypeptidase on various substrates, including the nutrient folate and the neuropeptide n-acetyl-l-aspartyl-l-glutamate. psma is considered to be the best-established target antigen in prostate cancer as it is highly and specifically expressed on the surface of prostate tumor cells at all tumor, making psma an excellent target for both imaging and therapy. previous studies have shown that [68ga]-psma pet t imaging can detect lesions that were not previously recognized in mri images and at lower median psa levels(1,6).various therapeutic trials using beta emitters bound to psma have also confirmed that treatmentslike -177lu-psma are safe and effective options for patients with metastatic or local recurrence of prostate cancer and has a low toxicity profile as positive response to therapy in terms of decline in psa occurs in about 70% of patients(7-10). spect imaging after injection of 177lu-psma for therapeutic purposes clearly shows sites of local recurrences or distant metastases(11). this opportunity, while lack of pet scanners in some centers has made the diagnostic use of [68ga]-psma pet impossible, brings to mind that low doses of 177lu-psma may also help physicians to find unidentified locations of disease re1nuclear medicine department, shohadaye tajrish hospital, school of medicine, shahid beheshti university of medical sciences. 2urology department, shohadaye tajrish hospital, school of medicine, shahid beheshti university of medical sciences. *correspondence: nuclear medicine department, shohadaye tajrish hospital, school of medicine, shahid beheshti university of medical sciences. tel: +98 2122723263, fax: +2122723263, e-mail: ghodsiradma@sbmu.ac.ir, gho.rad@gmail.com. received july 2019 & accepted march 2020 urology journal/vol 17 no. 4/ july-august 2020/ pp. 374-378. [doi: 10.22037/uj.v0i0.5451 ] currence or metastases which were not shown in traditional imaging (mri, bone scintigraphy, etc..). in this study we investigated the benefit of using low doses of 177lu-psma in prostate cancer patients with biochemical recurrence (psa rise), whom all other imaging was negative, to find places of recurrence or distant metastases. materials and methods we studied 26 prostate cancer patients between august 2015 and september 2016 with biochemical recurrence (psa rise). all patients had undetectable psa level after initial curative therapy (surgery and/or radiotherapy) and later in different intervals during the follow up showed psa elevation. initial assessments including pelvic mri and mrs as well as bone scan, were all negative. after injection of 5-mci (185mbq)177lu-psma-617 diagnostic planar whole-body scan (with bed speed of 10 mm/min) and spect(64 30 second views over 360 degree( ( siemens symbia evo excel dual head variable angle gamma camera, lehr collimator) study was obtained after 3 hours, 24 hours and 72 hours. the images were inspected visually by an expert nuclear medicine physician for the presence of active regional or distant lesions and abnormal findings were confirmed by ct scan. then the results were gathered and analyzed using spss software versions 23. the study was approved by ethics committee of shahid beheshti university of medical sciences. the procedure was fully discussed with patients and a written consent was obtained. in addition, results a total of 26 patients, with a mean age of 70 years table1. characteristics of patients investigated in the study. patient no age gleason score psa level(ng/dl) positive finding location of metastasis 1 63 8 15 no 2 78 7 4.34 yes mediastinum 3 61 6 2.50 no _ 4 62 9 1.53 no 5 59 7 2.38 no 6 78 8 2.17 no 7 72 9 1.53 no 8 78 8 1.27 no 9 78 7 12.60 yes abdominal lymph nodes 10 82 8 9 yes lung 11 71 7 4.02 yes lung 12 61 9 3.03 yes abdominal lymph node 13 59 8 2.72 yes lung 14 62 9 5.33 no 15 73 7 1.54 no 16 89 7 2.12 no 17 46 8 2.60 no 18 82 7 2.67 no 19 86 7 200 yes mediastinum 20 77 8 3.7 yes lung 21 68 7 2.04 no 22 72 8 2.34 no 23 66 6 3.24 no 24 73 8 1.70 no 25 57 8 2.35 no lung 26 61 9 3.2 yes lung figure 1. a anterior planar, b posterior planar, c transaxial spect, d coronal spect and e computed tomography images of the patient no 8. images a-d are obtained 24 hours after iv injection lu177-psma. the abnormal focus is shown with red arrow in each image. abnormal activity in the base of the left lung indicates lung metastasis which was confirmed in ct scan images. diagnostic lu 177 psma prostate cancer – ghodsirad et al. vol 17 no 04 july-august 2020 375 ma pet/ct with high sensitivity can show places of local recurrence or distant metastases which were not unidentified in previous imaging(15). it is clear that pet imaging is superior to spect in resolution and may delineate more lesions than that of spect, however pet is more expensive and is less in hand than spect. to our knowledge this is the first study to evaluate low doses of lu-psma spect in detecting recurrence in prostate cancer patients and was performed in the time that 68ga-psma or 99mtc-psma were not available for imaging. our study showed that more than one third of patients with biochemical evidence of disease recurrence and negative initial imaging may benefit from spect imaging using 177-lu psma. it is very important to note that this technique can find lesion in less expected regions like lung and mediastinum which are not routinely checked by mri or bone scintigraphy. one may claim that using 177-lu psma harbors risk of beta radiation; but with low dose administration, this risk is ignorable(16). among 19,316 routine autopsies performed from 1967 to 1995 on men older than 40 years of age, the reports from those 1,589 (8.2%) with prostate cancer were analyzed. hematogenous metastases were present in 35% of 1,589 patients with prostate cancer, with most frequent involvement being bone (90%), lung (46%), liver (25%), pleura (21%), and adrenals (13%) among 26 patients we studied, 10 patients were diagnosed with distant metastasis and lung was the most common site. although lung is not generally supposed to be involved in the process of prostate cancer but our study and other studies as well contradict the belief , for example in a recent study, lung metastases was proved pathologically in a patient with prostate cancer(17). therefore, using psma ligand imaging may increase the frequency of detection of unusual metastatic sites. the main disadvantage of 177lu-psma imaging is low spacial resolution of this imaging technique, however it can be used in patients who cannot afford 68ga-pet/ ct, and sometimes in pre-radioligand therapy to assess psma avidity of metastatic lesions. our study gives an estimation of sensitivity of 177lu-psma spect, in these patients. limitations: it was optimal to prove positive findings of the imaging with biopsy, however obtaining biopsy in most cases was very difficult and in some cases was impossible, so regarding few false positive reports, we employed ct scan to confirm positive findings which is however to some degrees suboptimal. conclusions although pet imaging using ga68-psma with its high sensitivity and positive predictive value is the most promising imaging method in patients with prostate cancer recurrence(18-21) when is not available can be replaced with spect imaging using 177-lu psma as a great asset in cases of biochemical recurrence and negative traditional imaging (mri, ct, bone scintigraphy) which is able to demonstrate sites of malignant involvement in more than one third of patients. conflict on interest no conflict of interest was declared by the authors. references 1. afshar-oromieh a, babich jw, kratochwil c, et al. the rise of psma ligands for diagnosis and therapy of prostate cancer. j nucl med. 2016;57:79s-89s. 2. kurreck a, vandergrift la, fuss tl, habbel p, agar nyr, cheng ll. prostate cancer diagnosis and characterization with mass spectrometry imaging. prostate cancer prostatic dis. 2018;21:297-305. 3. yajun c, yuan t, zhong w, bin x. investigation of the molecular mechanisms underlying postoperative recurrence in prostate cancer by gene expression profiling. exp ther med. 2018;15:761-8. 4. artibani w, porcaro ab, de marco v, cerruto ma, siracusano s. management of biochemical recurrence after primary curative treatment for prostate cancer: a review. urol int. 2018;100:251-62. 5. sarkar s, das sjbe, biology c. a review of imaging methods for prostate cancer detection: supplementary issue: image and video acquisition and processing for clinical applications. 2016;7:becb. s34255. 6. grubmuller b, baltzer p, d'andrea d, et al. (68)ga-psma 11 ligand pet imaging in patients with biochemical recurrence after radical prostatectomy diagnostic performance and impact on therapeutic decision-making. eur j nucl med mol imaging. 2018;45:23542. 7. ahmadzadehfar h, eppard e, kurpig s, et al. therapeutic response and side effects of repeated radioligand therapy with 177lupsma-dkfz-617 of castrate-resistant metastatic prostate cancer. oncotarget. 2016;7:12477-88. 8. ahmadzadehfar h, essler m. predictive factors of response and overall survival in patients with castration-resistant metastatic prostate cancer undergoing (177)lu-psma therapy. j nucl med. 2018. 9. ahmadzadehfar h, rahbar k, kurpig s, et al. early side effects and first results of radioligand therapy with (177)lu-dkfz-617 psma of castrate-resistant metastatic prostate cancer: a two-centre study. ejnmmi res. 2015;5:114. 10. baum rp, kulkarni hr, schuchardt c, et al. 177lu-labeled prostate-specific membrane antigen radioligand therapy of metastatic castration-resistant prostate cancer: safety and efficacy. j nucl med. 2016;57:1006-13. 11. emmett l, willowson k, violet j, shin j, blanksby a, lee j. lutetium (177) psma radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. journal of medical radiation sciences. 2017;64:52-60. diagnostic lu 177 psma prostate cancer – ghodsirad et al. vol 17 no 04 july-august 2020 377 12. miller et, salmasi a, reiter re. anatomic and molecular imaging in prostate cancer. cold spring harb perspect med. 2018;8. 13. scattoni v, montorsi f, picchio m, et al. diagnosis of local recurrence after radical prostatectomy. 2004;93:680-8. 14. lenzo np, meyrick d, turner jh. review of gallium-68 psma pet/ct imaging in the management of prostate cancer. diagnostics (basel). 2018;8. 15. evangelista l, sepulcri m, maruzzo m. prostate cancer imaging: when the game gets tough, the hard one gets done! eur j nucl med mol imaging. 2018. 16. kabasakal l, toklu t, yeyin n, et al. lu177-psma-617 prostate-specific membrane antigen inhibitor therapy in patients with castration-resistant prostate cancer: stability, bio-distribution and dosimetry. mol imaging radionucl ther. 2017;26:62-8. 17. reinstatler l, dupuis j, dillon jl, black cc, phillips jd, hyams esjucr. lung malignancy in prostate cancer: a report of both metastatic and primary lung lesions. 2018;16:119. 18. dundee p, gross t, moran d, et al. gapsma pet: still just the tip of the iceberg. 2018;120:187-91. 19. de visschere pj, standaert c, fütterer jj, et al. a systematic review on the role of imaging in early recurrent prostate cancer. 2018. 20. heath cl, tao d, greene k, et al. single center prospective evaluation of ga-68psma-11 in the us with one-year follow-up correlation. 2018;59:1505-. 21. kang f, zhang j, wang s, et al. performance of 68ga-psma pet/ct in the guidance of initial prostate cancer biopsy: comparison with two predicting nomograms. 2019;60:292-. urological oncology 378 spop, daxx, rarres1, and lamp2 genes in prostate cancer-jamali et al. urol_v03_no3_001_editorial.indd reconstructive surgery 160 urology journal vol 3 no 3 summer 2006 urethroplasty for long anterior urethral strictures report of long-term results mahmoudreza moradi, as’ad moradi introduction: we reviewed the long-term outcome of substitution urethroplasty with skin flaps for anterior urethral strictures, comparing 1-stage with 2-stage repairs. materials and methods: a total of 45 patients with urethral strictures, 2.5 cm or longer, had undergone skin flap urethroplasty. a 1-stage surgical operation had been done in 10 patients (orandi and bilateral pedicle island of penile skin) and a 2-stage surgical repair had been performed in 35 using the johanson technique. they were followed up by retrograde urethrography for 1 to 10 years. results: the mean age of the patients was 46.3 ± 17.1 years. etiology of the stricture was instrumentation in 33.3% of the patients, urethritis in 28.9%, trauma in 13.3%, and unknown in 24.5%. at the first postoperative year, the success rate was 75.6%. this rate was 71.4% and 90% for the 1-stage and 2-stage operations, respectively (p = .23). there were 1 (10%) and 10 (28.6%) cases of recurrent structure and 1 (10%) and 3 (8.6%) cases of fistula in the patients with the 1-stage and 2-stage operations within the first year, respectively. during the 5 postoperative years, 70% of the patients with the 1-stage repair, 57.1% with the 2-stage repair, and 60% in total had no complications. conclusion: based on the previous studies and our experience, we recommend skin flap urethroplasty. however, some measures such as proper tailoring of the flap and the extension of the incision onto the intact segments should be considered for achieving a better outcome. urol j (tehran). 2006;3:160-4. www.uj.unrc.ir keywords: urethra, stricture, urethroplasty, skin flap urology-nephrology research center, kermanshah university of medical sciences, kermanshah, iran corresponding author: mahmoudreza moradi, md department of urology, 4th shaheed-e-mehrab hospital, doalatabad blvd. kermanshah, iran e-mail: drmrmoradi@yahoo.com received june 2005 accepted may 2006 introduction urethral stricture is a disturbing urologic disease with scar formation in the urethra and corpus spongiosum (spongiofibrosis) and subsequent urinary symptoms or urinary tract infections (prostatitis or epididymitis). making an appropriate therapeutic decision is influenced by the location, length, depth, and severity of the stricture. of the treatment options are urinary diversion, dilation of the urethra, endoscopic urethrotomy, and open surgical repair.(1) open surgical techniques include 2 main approaches: resection of the stricture with endto-end anastomosis and substitution techniques by grafts or flaps, namely substitution urethroplasty. the latter technique is often used for long strictures in which resection and anastomosis are not possible.(1,2) penile skin flaps enjoy ample vascular supply and are applicable for the repair of the long anterior urethral strictures. moreover, urologists usually have greater experience in harvesting skin flaps compared to grafts. these factors make the use of penile skin graft reasonable and, subsequently, emerges a better understanding of their outcome and complications. the urethroplasty for long urethral strictures—moradi and moradi urology journal vol 3 no 3 summer 2006 161 reported results of the anterior urethroplasty, either 1-stage or 2-stage procedures, with skin flaps from the external genitalia have been contradictory.(3-6) this warrants measures to evaluate and identify the outcome of these surgeries and to find out the key points for the betterment of the surgical techniques used in every urological center. accordingly, we reviewed the long-term outcome of the substitution urethroplasty with skin flaps for anterior urethral strictures. materials and methods we reviewed the records of all patients with surgical repair of long anterior urethral strictures (2.5 cm or longer) preformed from 1993 to 2001 at our surgical center. a total of 45 patients with available surgical and follow-up records were selected in this study. the collected data were the demographic and surgical information including the etiology, length, and location of the urethral stricture, surgical technique, and urinary diversion approach. the follow-up records were also reviewed for recurrent stricture, fistula, urethral diverticulum, hair growth, chordee, meatal stenosis, skin graft necrosis, and ejaculatory dysfunction. surgical technique thirty-five patients had undergone a 2-stage surgical repair using the johanson technique. at the first stage, the urethra and the corpus spongiosum at the stricture site were opened following the skin incision. the exposure was extended to the intact urethral segments at the proximal and distal ends of the stricture. complete hemostasis was done and then the urethra and the corpus spongiosum were sutured to the skin with a 4-0 chromic suture material. the patient was discharged and the second surgical stage was performed at least 3 months later; 2 parallel asymmetric incisions were made on the skin at each side of the urethra and the harvested skin flap was tubed on an 18-f nelaton catheter by 4-0 vicryl sutures. afterwards, a covering layer made of the surrounding dartos tissue, the scrotum, or the tunica vaginalis was drawn onto the suture and fixed. in case of glanular stricture, glanoplasty would be performed and then the skin would be repaired. a urethral catheter was fixed for all and a percutaneous cystostomy was placed for 13 patients. a 1-stage surgical operation had been done on 10 patients, 5 with the orandi method and 5 with bilateral pedicle island of penile skin (bipips). the orandi method was used for the strictures of the penile urethra and the bipips for those of the bulbar urethra. in both techniques, the hair-free skin of the ventral penis was harvested as a flap. first, an incision along the stricture was made and the skin flap, tailored to the stricture length, was harvested. the defect was covered by the penile skin flap. the anastomosis was made by a 4-0 or 5-0 suture. in bipips technique, the flap was transformed on the stricucure segment through a tunnel under the scrotum. a protecting layer was drawn onto the suture line and the skin was repaired. the urethral catheter and cystostomy were placed for all of the patients. intravenous antibiotic prophylaxis by cephalothin and gentamicin was administered for 48 to 72 hours postoperatively and oral antibiotics were started on thereafter. the patients were discharged on the 5th postoperative day, on average. their catheters were removed 2 weeks later and antegrade voiding cystourethrography (vcug) or retrograde urethrography was carried out. follow-up on the 6th month follow-up, physical examination and history with a special attention to voiding pattern were done. at the first postoperative year, retrograde urethrography was performed, as well. the next follow-up visits would be based on physical examination and history if the retrograde urethrography was unremarkable. appropriate diagnostic measures would be done in case of any obstructive or irritative symptoms, ejaculatory dysfunction, or recurrent urinary tract infections (uti). the patients were followed up for an average of 5 years (range, 1 to 10 years). a successful surgical outcome was considered when a proper voiding achieved, no fistula developed, and retrograde urethrography results were uneventful during the first postoperative year. the 1-year outcomes of the 1-stage and 2-stage repairs were compared using the chi-square test and the fisher exact test. urethroplasty for long urethral strictures—moradi and moradi 162 urology journal vol 3 no 3 summer 2006 results forty-five patients with the mean age of 46.3 ± 17.1 years and the mean urethral stricture of 7.16 ± 3.65 cm (range, 2.5 cm to 15 cm) had undergone urethroplasty. the etiology of the stricture was instrumentation in 15 patients (33.3%), urethritis in 13 (28.9%), trauma in 6 (13.3%), and unknown in 11 (24.5%). the location of the urethral stricture was penile in 24 patients (53.3%), bulbar in 7(15.6%), and bulbopenile in 14 (31.1%). overall, 11 cases of recurrent stricture (24.5%) and 4 cases of fistula (8.9%) were seen in 11 patients within the first year. thus, the overall success rate was 75.6% (figures 1 and 2). this rate was 71.4% and 90% for the 1-stage and 2-stage operations, respectively (p = .23). there were 1 (10%) and 10 (28.6%) cases of restructure and 1 (10%) and 3 (8.6%) cases of fistula in the patients with the 1-stage and 2-stage operations, respectively. the complications occurred during the 5 years’ follow-up are summarized in table. chordee was not detected in any patients. regarding the limited follow-up duration in a large proportion of the patients, the 5-year comparison of the complications between the 2 groups was not performed. during the 5 postoperative years, 70% of the patients with the 1-stage repair, 57.1% with the 2-stage repair, and 60% in total had no complications (table). all recurrent strictures were mild and proximal to the anastomosis, which were treated by internal urethrotomy and dilation. meatal strictures were relieved by meatotomy. one out of 3 cases of urethral diverticulum was accompanied by calculus formation and led to open surgical repair and calculus removal. the other 2 cases were asymptomatic, thus, were observed. the only case of hair growth was seen during cystoscopic evaluation of a patient with recurrent uti. discussion for choosing a well tailored substitution urethroplasty technique, 3 decisive factors must be considered: type of the flap, vascular supply of the flap, and the transfer mechanism of the flap.(1) complications of the substitution urethroplasty increase in the long run and anastomotic repair is preferred if viable.(7) however, some authors have complications and success rate of urethroplasty* *values in parentheses are percents unless otherwise indicated. one-stage repair two-stage repair complications recurrent stricture 2 (20) 14 (40) fistula 1 (10) 3 (8.6) diverticulum 1 (10) 2 (5.7) meatal stricture 0 1 (2.9) ejaculatory dysfunction 0 1 (2.9) hair growth 1 (10) 0 chordee 0 0 necrosis of flap 0 0 success rate 1-year, % 90 71.4 5-year, % 70 57.1 figure 1. preoperative retrograde uerthrography in a patient with complicated stricture of the bulbar urethra following drainage of a perianal abscess. figure 2. retrograde urethrography after repair of the bulbar urethral stricture using bilateral pedicle island of penile skin. urethroplasty for long urethral strictures—moradi and moradi urology journal vol 3 no 3 summer 2006 163 demonstrated acceptable results with urethroplasty. for a 1-stage repair, quartey used a transverse flap from the prepuce and the penis based on the superficial external pudendal vessels. the prepuce is hair free and its pedicle allows it to be used as a tube or a patch in any part of the meatus to the prostatic urethra. quartey followed the patients by urethroscopy up to 6 months and observed no stricture of the anastomosis site or permanent fistula. but, 1 case of stricture due to incomplete excision of the primary stricture and 3 cases of hair growth in the new urethra were seen.(2) we found a significant number of recurrent strictures in our patients, most of which were proximal to the anastomosis site. it seems that such strictures result from an incomplete opening of the lumen and the fibrotic tissue. hence, it is recommended that the incision made in surgical repair be continued on the adjacent intact area distal and proximal to the stricture site. most recurrent strictures in our patients were relatively short and were relieved by internal urethrotomy and dilation. in 1 patient with recurrent uti, we found hair growth on cystoscopy although retrograde urethrography was uneventful. de la rosette and colleagues performed 1-stage repair in 50 patients using skin flap. recurrence was mostly reported in cases with a history of 3 or more urethrotomies within a short period. they found recurrent strictures in 32% and fistula in 20% of the patients. they recommended open surgical repair when 1 or 2 internal urethrotomies fail.(3) moreover, joseph and colleagues reported the results of managing anterior urethral strictures previously treated with urethroplasty and/or urethrotomy. they found that the increased rate of revision in the staged procedures compared with the excellent outcome of 1-stage procedures appeared to be mostly in patients with multiple previous procedures.(8) motiwala and colleagues reported the outcome of 1-stage repair in 16 patients and 2-stage repair (johanson) in 12 with long urethral strictures. etiologies of the strictures in their patients varied and fistula and diverticulum were present in most of the cases. they used vascularized flap of the longitudinal ventral penile skin in most 1-stage cases and transverse scrotal flap and duckket transverse preputial flap in 2. the success rate of the treatment was 100% and 75% in the 1-stage and 2-stage operations; hence, they recommended 1-stage repairs regardless of the length of the stricture.(9) overall, the published studies to date are indicative of the superiority of the 1-stage urethroplasty over the 2-stage repairs. this approach is also cost-effective and the patients are more satisfied. however, the success rate of these surgeries is dependent on the length and severity of the urethral stricture, the availability of an appropriate skin flap, and the past surgical history of the patient. our study failed to show a better outcome for either of the techniques. but, the number of our patients with 1-stage repair was too small. on the other hand, in long strictures, especially in patients who are circumcised, a 2-stage repair is still of help. nonetheless, we prefer a 1-stage repair when an enough long flap with ample vascular supply can be easily harvested. in a study by provet and coworkers, island scrotal flap was used in the 1-stage repair of severe strictures of the bulbomembranous urethra. twenty percent of the patients required revision due to recurrent stricture, fistula, and pseudodiverticulum. they believed that an aggressive tailoring of a hair-free flap can prevent from diverticulum, hair growth, and calculus formation. they concluded that if there is a severe scar tissue and viability of a full-thickness free graft is questionable, their method is an appropriate alternative to the staged surgical approaches.(4) we used supporting layers on the suture line and made sure the flap enjoyed a good vascular supply. thus, fistula was not seen frequently. the diverticula formed in our patients were all in the proximal part of the urethra. a proper tailoring of the flap especially proximal to the stricture may help in such cases, as well as making sure of the opening of the distal urethra and substitution with the flap in the dorsal segment of the defect. it has been reported that onlay island flap urethroplasty can be performed in 1 stage for the treatment of long multiple strictures, and it results in acceptable outcomes and low complication rate.(5) osegbe and associates performed 1-stage repair by penile transverse flaps in patients with severe stricture and multiple urethrocutaneous fistula in the scrotum and perineum. they reported a 100% success rate, although active infection was present at operation. they suggested these flaps when infection and fibrosis preclude the use of grafts.(6) furthermore, it has been shown that placing the flap on the dorsal segment of the defect can result in a better urethroplasty for long urethral strictures—moradi and moradi 164 urology journal vol 3 no 3 summer 2006 anatomical and functional outcome compared to ventral type.(10,11) skin flaps are useful in the treatment of urethral strictures when the length of the defect and scarring tissue make anastomotic repair impossible. these flaps usually enjoy a good vascular support. urologists are usually experienced in the harvesting of the flaps. however, complications, mostly recurrent stricture and fistula, make substitution urethroplasty a suboptimal alternative. such complications were relatively frequent in our patients. also, we found 1 case of hair growth accidentally during cystoscopy in a patient with recurrent uti. we could not perform cystoscopy in all patients as a routine study. thus, we might have more cases of hair growth. conclusion various surgical repair methods are applicable for the treatment of anterior urethral strictures, but the choices for long lesions are limited. based on the previous studies and our experience, we recommend skin flap urethroplasty. however, choosing an appropriate technique, a good vascular supply for the flap, the use of a protective layer, proper tailoring of the flap, proper diversion, and the extension of the incision onto the intact segments should be considered to achieve a better outcome. conflict of interest none declared. references 1. walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. 2. quartey jk. one-stage penile/preputial cutaneous island flap urethroplasty for urethral stricture: a preliminary report. j urol. 1983;129:284-7. 3. de la rosette jj, de vries jd, lock mt, debruyne fm. urethroplasty using the pedicled island flap technique in complicated urethral strictures. j urol. 1991; 146:40-2. 4. provet ja, surya bv, grunberger i, johanson ke, brown j. scrotal island flap urethroplasty in the management of bulbar urethral strictures. j urol. 1989;142:1455-7; discussion 1457-8. 5. kocvara r, dvoracek j, kriz j. [onlay island flap urethroplasty in the treatment of urethral strictures]. rozhl chir. 1998;77:493-6. czech. 6. osegbe dn, ntia i. one-stage urethroplasty for complicated urethral strictures using axial penile skin island flap. eur urol. 1990;17:79-84. 7. andrich de, dunglison n, greenwell tj, mundy ar. the long-term results of urethroplasty. j urol. 2003;170:90-2. 8. joseph jv, andrich de, leach cj, mundy ar. urethroplasty for refractory anterior urethral stricture. j urol. 2002;167:127-9. 9. motiwala hg, visana kn, joshi sp, patel pc. anterior urethroplasty--changing concepts. urol int. 1992; 48:313-9. 10. bhandari m, dubey d, verma bs. dorsal or ventral placement of the preputial/penile skin onlay flap for anterior urethral strictures: does it make a difference? bju int. 2001;88:39-43. 11. dubey d, kumar a, bansal p, et al. substitution urethroplasty for anterior urethral strictures: a critical appraisal of various techniques. bju int. 2003;91:215-8. 1411vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l 1 department of pediatric surgery, faculty of medicine, izmir university, izmir, turkey. 2 denizli state hospital, clinics of pediatric surgery, 20.100, denizli, turkey. erdal turk,1 fahri karaca,2 yesim edirne2 determining external genital abnormalities with a pre-circumcision examination in previously undiagnosed male school children corresponding author: erdal turk, md yeni girne bulvarı 1825 sok., no:12 karsiyaka , izmir, turkey. tel: +90 232 399 5050 fax: +90 232 367 0559 e-mail: eturk19@yahoo.de received march 2013 accepted january 2014 purpose:weinvestigatedwhetherchildrengettingreadyforcircumcisionunderlocalanesthesiahadanyadditionalgenitalregionabnormalitiesnotdetectedbeforethecircumcision. materials and methods:weperformedcircumcisionunderlocalanesthesiaforchildrenwith normalphysicalexaminationfindings,andtogetherwithcorrectivesurgeryforthosewithother genitalanomaliesamongthechildrenaged6yearsoldandoverpresentingatthepediatricsurgerydepartmentofourhospitalduringtheschoolbreak. results:circumcisionwasplannedunderlocalanesthesiainatotalof1,695casesagedbetween6and17yearsduringthejunetoseptember2010and2011periods.wefoundanexternalgenitalanomalyinthepre-circumcisionphysicalexaminationin58patients(3.4%),witha meanageof7.87±1.49years.thesepatientswereoperatedonwithcorrectivesurgerywhile 1,637childrenunderwentcircumcisionunderlocalanesthesia.themostcommonanomaly wasinguinalherniaseenin14(24.1%),followedbyhypospadiasin11(18.9%),hydrocelein9 (15.9%)andundescendedtestisin8(13.8%). conclusion:incountrieswherecircumcisionistraditional,aninterventionroomwithinthe hospitaltoperformcircumcisionunderlocalanesthesiacanenablemanychildrentobecircumcisedunderhospitalconditionsandpreviouslyundetectedgenitalabnormalitiestobefound withapre-circumcisiongenitalregionexamination. keywords:circumcision;disordersofsexdevelopment;male;genitaldiseasesgenitalia;child, preschool. pediatric urology 1412 | pediatric urology introduction inturkey,asinothermuslimcountries,circumcisionisaroutinesurgicalproceduremainlyperformedforreli-giousreasons.so,mostturkishboysarecircumcised atsometimefromtheeighthdayafterbirthtotheageof puberty.circumcisionshouldbeconsideredasasurgical operationwhichrequiresmaximumcareandshouldbeperformedbylicensedsurgeonsinsterilehospitalconditions. unfortunately,of100circumcisioncasesperformedinour country,approximately85%areperformedbytraditional circumcisers,10%byhealthtechniciansandonly5%by licensed surgeons.(1,2)theratioofcircumcisionsperformed bysurgeonsis5-10%inpakistan56.5%iniran,and85%in theunitedarabicemiratesandsaudiarabia.(3,4) mostparentsarenotawareofthenormalanatomyofthe genitalregion,leadingtodelaysinthediagnosisofgenital abnormalities.familiescanfeelashamedofthecondition and delay going to a physician. inguinal and scrotal hernias andhydrocelesarecommonpediatriccongenitaldisorders. (5,6) avoidingsuchproblemsrequiresearlydiagnosisand treatment.unfortunately,regularscreeningfortheseprogramsinbabiesandchildrenisnotavailableinturkey. theaimofthisstudyistoemphasizehowimportantitis tohaveaninterventionroomwithinthehospitaltoperformcircumcisionunderlocalanesthesiathatcanenable manychildrentobecircumcisedunderhospitalconditions andanypreviouslyundetectedgenitalabnormalitiescanbe foundwithapre-circumcisiongenitalregionexamination by specialists. materials and methods thisstudywasconductedonatotalof1,695childrenwho werescheduledtoundergocircumcisionduringthebreakin theschoolyearintheyears2010-2011atthedenizlistate hospital,pediatricsurgeryoutpatientdepartment.childrenaged6yearsandoverwhopresentedatthehospitalto undergocircumcisionwerescheduledatarateof5-15circumcisionsaday.thecasesthatcamefortheappointments underwentadetailedphysicalexaminationby3separate pediatricsurgeryspecialists.patientswhohadhypospadias, inguinal hernia, hydrocele, undescended testis or other genitalregionpathologiesduringthephysicalexamination underwent thecircumcision togetherwithcorrectivesurgeryaftertheirfamilıeswereinformed. results a total of 2,489 cases aged 0-17 years presented at the pediatricsurgeryoutpatientdepartmentofourhospitalfor circumcisionbetweenjune1standseptember30th20102011.the 326 cases (13%) that did not attend their appointmentwerenotincludedinthestudy.amongthe2,163 remainingcasesweplannedtooperateonthe1,695cases aged6-17years(78.3%)underlocalanesthesiaandthe468 casesaged0-6years(21.6%)undergeneralanesthesia. further58childrenwhowereolderthan6yearsbutwere found to have additional abnormalities during the precircumcisionroutinephysicalexaminationunderwentcircumcisiontogetherwithcorrectivesurgeryundergeneral anesthesia after the family was informed, although local anesthesiawasplannedatfirst. wefoundagenitalregionabnormalityduringthepre-circumcisionphysicalexaminationin58patientsaged6-13 yearswithameanageof7.87±1.49years.table1presents themeanageinwhichtheseabnormalitiesweredetected andthecorrectivesurgeryperformed.themostcommon abnormality was inguinal hernia at 24.1%, followed by hypospadiasat18.9%(11patients). minorcomplicationsdevelopedin11(0.6%)ofthechildrenundergoingcircumcision.theseconsistedofbleeding in6patientsandthiswasstoppedbylocalcompressin4 patientsandsuturingattheoperatingroomin2patients. thehematomadevelopedin3patientsandinfectiondevelopedin2patientsafterthecircumcisionwhichrecovered withconservativetreatment.onepatientwasoperatedon undergeneralanesthesiaforpenilechordeeandpresented3 dayslaterwithmarkedbruisingandswellingofthepenis. thepreoperativetestswerenormalbutthecompleteblood countcheckrevealedathrombocytecountof6,000/mm3. thechildwasthereforeevaluatedbythepediatrichematologyspecialistandtreatmentwasstartedwithadiagnosisof acuteidiopathicthrombocytopenicpurpura. discussion circumcisionisunavoidableduetomanyreligiousandsocialreasonsinturkeyandtheincidencereaches99%inthe malepopulation.(1,7)theidealtimeandanesthesiaarethe 0-2 years age group and general anesthesia, but the rituals 1413vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l male external genital abnormalities | turk et al ofmuslimcountriesintheruralareasusuallymeanthat itisperformedaftertheageof5years.(3,4,8)approximately600,000malechildrenarecircumcisedinourcountry everyyearandapproximately85%oftheseareperformed bytraditionalcircumcisers.(1,2,8)thesefiguresaresimilar inothermuslimcountries.(3,4)itseemsunlikelythatsuch ahighdemandforcircumcisioncanbemetwithgeneral anesthesia.wethereforecircumcisechildrenwhopresent duringschoolbreakwhenthedemandincreasesunderlocalanesthesiaasmostofthesechildrenareolderthan6 years.ourhospitalprovidessecondaryhealthcareservices andtheestablishmentofunitswherecircumcisioncanbe performedunderhealthyconditionswithlocalanesthesia andalsoextendingthistotertiaryhealthcarefacilitiesmay enablemanypatientstobecircumcisedunderhospitalconditions in countries where the procedure is traditionally performedatolderages. children need to be observed carefully in the newborn, preschoolandschoolagestopreventthedevelopmentof latecomplications.(9,10)screeningteststodeterminegenital regionabnormalitiesinchildrenarethereforeperformedat the school age in such countries.(6,10-13)wehave1200-1500 childrenayearwhopresentatthehospitalthemselveswithoutanysymptomsandweselectthosewithanabnormality throughaphysicalexamination.our3.4%(n=58patients) rateinthisstudymayseemtobelowcomparedtotherates of6.18-18.31%foundinepidemiologicalstudiesofschool agechildrenpreviously.(6,10,11,13)however,thereasonsare thatourgrouphadalimitedagerangeof6-13years,female children were not included in the study and our study was limitedtotheexternalgenitalregion. thecomplicationratesare1-5%inchildrencircumcisedby physicians,10%inthosecircumcisedbyhealthcaretechniciansandupto85%inchildrencircumcisedbytraditional circumcisers.(1,2,14)mostofthesecomplicationsarebleeding andhematomathatcanbestoppedbyasimpleintervention butseriouscomplicationssuchasamputationordeathcan also be encountered.(1,4,15-17)circumcisingmanychildrenat thesametimemeansthatchildrenarecircumcisedrapidly, usuallyunderconditionsthatarenotveryhealthyandusuallybytraditionalcircumcisersorhealthcaretechnicians. (1,2,7,8)suchproceduresarelegalintheenglandaslongas table . the general characteristics and operations of anomalous cases. genital anomaly no. % age, year (range) operation inguinal hernia 14 7.85 ± 1.40 (6-10) high ligation right 9 left 5 24.1 hypospadias 11 8.54 ± 2.01(6-13) glanular 7 meatoplasty megameatus 4 18.9 tubularized incised plate urethroplasty hydrocele 9 8.11 ± 1.16 (6-10) high ligation + fenestration right 6 left 3 15.6 undescended testis 8 7.62 ± 1.40 (6-10) orchiopexy right 4 left 4 13.8 buried penis 5 8.6 7.4 ± 1.34 (6-9) degloving and circumcision penile chordee 5 8.6 8 ± 1.58 (6-10) chordee release and circumcision penile torsion 4 6.9 6.75 ± 0.95 (6-8) detorsion and circumcision cord cyst 2 3.4 7.5 ± 0.70 (7-8) high ligation right 2 100.0 left ----total 58 7.87 ± 1.49 (6-13) ----1414 | they are carried out by a physician.(18)itisknownthatthe circumcisionofmanychildrentogetherbytraditionalcircumcisersinourcountryandothercountrieswherecircumcisionistraditionalincreasescircumcisioncomplications. themostimportantreasonfortheverylowpercentageof 0.6%andonlyminorcomplicationsbeingobservedinthe 1,637patientswecircumcisedinourstudyisthattheyunderwenttheprocedureinaperiodofthreemonthsandby aspecialistwhooperatedonalimitednumberofpatients daily.increasingsuchapplicationswilldecreasecircumcisioncomplicationsandwillalsodecreasetheinterestofthe publicintraditionalcircumcisersandmasscircumcisions. theincidencesofindirectinguinalherniasisapproximately1-5%,hypospadiasbetween0.8and8.2per1000live malebirths,hydroceleinchildrenolderthan1yearofage probablylessthan1%andundescendedtestisinfull-term boys1-2%inthegeneralpopulation.(6,11)ourrateswere 0.82%foringuinalhernia,0.65%forhypospadias,0.53% forhydroceleand0.47%forundescendedtestes.thereasonforourlowerprevalencethanthegeneralpediatricpopulation could be that our patient group was generally aged 6-13yearsandmostly6-8years.itisimportanttodetect andtreatgenitalsystemabnormalitiestopreventtheseriouscomplicationsthatcanarise.alltheproblemswefound shouldhavebeenoperatedonattheageof0-2yearsbut themeanageinourstudywas7.87±1.49years.however, thisdoesnotdecreasethevalueofourstudyandwecould sayweweresuccessfulaswepreventedthedevelopment ofcomplicationsinthesechildrenwhohadnotyetexperiencedacomplicationuntilschoolage. conclusion unitssuchascircumcisionoutpatientssothatalargenumberofchildrencanbecircumcisedunderhospitalconditions in communities where children are traditionally circumcisedatschoolagewilldecreasecomplicationsbyensuringcircumcisionisperformedunderhealthyconditionsand alsoenablethedetectionofexternalgenitalabnormalities withapre-circumcisionphysicalexaminationofthepotential patient population. conflict of interest none declared. pediatric urology references 1. atikeler mk, gecit i, yuzgec v, yalcin o. complications of circumcision performed within and outside the hospital. int urol nephrol. 2005;37:97-9. 2. ozdemir e. significantly increased complication risks with mass circumcisions. br jurol. 1997;80:136-9 3. rizvi sa, naqvi sa, hussain m, hasan as. religious circumcision: a muslim view. bju int. 1999;83 suppl 1:13-6. 4. yegane ra, kheirollahi ar, salehi na, bashashati m, khoshdel ja, ahmadi m. late complications of circumcision in iran. pediatr surg int. 2006;22:442-5. 5. ashcraft kw, murphy jp, sharp rj, sigalet dl, snyder cl: pediatric surgery. philadelphia, wb saunders company; 2000. p. 114-138. 6. yegane ra, kheirollahi ar, bashashati m, rezaei n, tarrahi mj, khoshdel ja. the prevalence of penoscrotal abnormalities and inguinal hernia in elementary-school boys in the west of iran. int j urol. 2005;12:479-83. 7. senel fm, demirelli m, oztek s. minimally invasive circumcision with a novel plastic clamp technique: a review of 7,500 cases. pediatr surg int. 2010;26:739-45. 8. senel fm, demirelli m, pekcan h. mass circumcision with a novel plastic clamp technique. urology. 2011;78:174-9. 9. tabel y, haskologlu zs, karakas hm, yakinci c. ultrasonographic screening of newborns for congenital anomalies of the kidney and the urinary tracts. urol j. 2010;7:161-7. 10. yucesan s, dindar h, olcay i, et al. prevalence of congenital abnormalities in turkish school children. eur j epidemiol. 1993;9:373-80. 11. al-abbadi k, smadi sa. genital abnormalities and groin hernias in elementary-school children in aqaba: an epidemiological study. east mediterr health j. 2000;6:293-8. 12. ghazzal am. inguinal hernias and genital abnormalities in young jordanian males. east mediterr health j. 2006;12:483-8. 13. zivkovic d, varga j, grebeldinger s, dobanovacki d, borisev v. [external genital abnormalities in male schoolchildren: an epidemiological study]. med pregl. 2004;57:275-8. 14. mahmoudi h. evaluation of meatal stenosis following neonatal circumcision. urol j. 2005;2:86-8. 15. gluckman gr, stoller ml, jacobs mm, kogan ba. newborn penile glans amputation during circumcision and successful reattachment. j urol. 1995;153:778-9. 16. neulander e, walfisch s, kaneti j. amputation of distal penile glans during neonatal ritual circumcision--a rare complication. br j urol. 1996;77:924-5. 17. ozkan s, gurpinar t. a serious circumcision complication: penile shaft amputation and a new reattachment technique with a successful outcome. j urol. 1997;158:1946-7. 18. beecham l. gmc issues guidelines on circumcision. bmj. 1997;314:1573. 1079vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l this article is pretty interesting, but i would like to point out some matters, since i have been interested in this subject for many years. of 1500 patients in the study 94.6% had had successful intercourse using vacuum constriction device (vcd). this rate of positive response to vcd is amazing. the initial overall response rate is approximately 80% to 90%. however, satisfaction with vcd treatment typically fades with time, as patients report dissatisfaction with how awkward or unnatural the devices are to use, hinging or buckling of the erection with thrusting, and dissatisfaction with the fact that the erection is false one (and therefore cold) which can be off-putting to the partner. patients who have diminished sensation in their penis, especially men with spinal cord injury, are at higher risk for trauma with repeated use of the constriction ring. it should be used with extreme caution in this group of patients and the band should be applied for only short periods of time. unlike the manufacturer (hamrah co.) which advertise the use of vcd for correction of penile curvature too, men with peyronie’s disease (pd) (acquired penile curvature) or congenital penile curvature, with significant degrees of curvature should be discouraged from using a vcd, as the even curved cylinder may exert significant stress on the bent penis resulting in trauma to the already curved shaft of the penis. i have visited many men with congenital penile curvature who developed sever and progressive pd, after using vcd with curved cylinder for treatment of ed. other authors also reported development of pd with long term vcd use.(1) i strongly disagree with recommendation of vcd in patients with ed and curvature correction. also patients with hematologic types of veno-occlusive priapism (sickle cell disease, thalassemia, or leukemia) should not use a vcd at all. moreover, for considerable number of patients the vcd is unacceptable. they believe this way due to two important factors, namely cosmetics and difficulty integrating intercourse with vcd into love-making. in the white men the entry of blood alongside with the application of a constriction ring renders the penis cool and results in a large amount of superficial vein swelling. these factors make the vcd induced erection a non-cosmetic one and the younger men and the impotent patient who is currently not in a stable long-term relationship often find this undesirable and unacceptable. in an average man using vcd will typically take 10-20 minutes to result in a significant penile rigidity sufficient for penetration. this time frame plus the unnatural erection, makes this treatment option cumbersome for most men and they may have great difficulty integrating it into sexual life. in additions, the vcd has own complications. bruising, skin breakdown, and penile pain associated with the application of the constructive ring have already been known. the tightness of the band, most of the time result in failure to achieve an antegrade ejaculation and sexual satisfaction. one of the important drawback with the erection obtained with the vcd is that it may cause penile hinge at the point of ring application. as a result, the penis behind the constrictive band is soft and only that portion of the penile shaft that is past the ring has any degree of unnatural rigidity. hence, the constrictive ring must be applied as far towards the base of the penis as possible. drop-out rates of up to 65% have been reported(2) and the most common reasons for drop-out include, penile pain, poor rigidity, failure to ejaculate, dissatisfaction with penile appearance mohammad reza safarinejad m.d clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran e-mail: info@safarinejad.com editorial 1080 | sexual disfunction and infertility and temperature, bothersome, and embarrassment. embarrassment is an important factor and affected mostly with cultural issue. as a result the rate of embarrassment varies in different community. in my opinion, the most important factor in our community for the reluctance to use the vcd is embarrassment. on the contrary with the results of present study, of patients who address themselves to me for treatment of impotence and are good candidate for using the vcd, less that 10% accept even to try the vcd. the severity of erectile dysfunction (ed) is a significant factor in drop-out rates. unfortunately, despite a large study sample size (n=1500), study subjects have not been categorized by severity of ed. the participants can be categorized into three subgroup according to iief erectile function domain score, namely patients with mild, moderate, and sever ed. in a study by dutta and francois’s 129 patients with organic ed who were interested in the vcd received the device after thorough training.(2) their attrition rate was 65% overall and was lowest among patients with moderate ed (55%). all patients with mild ed discontinued use, and 70% of patients with complete ed also discontinued use. of the patients who discontinued, most stopped vcd use early (median 1 month, mean 4 months). the overall failure rate was 65%. the authors of present study claim that success rates are highly influenced by the degree of training. in dutta and colleagues’ study the participants were highly motivated and best trained cohort of patients clinically possible. before drawing final conclusion we should wait for further studies from the same region. with respect, i would like to inform you that all patients participated in this study were either refused or had failure to respond to intracavernosal injection of vasodilator drugs. meanwhile the patients and their spouses where explained about advantages and disadvantage of vacuum constrictive device (vcd) and penile prosthesis (e.g. cost, probability of infection and malfunction, smaller penis and invasiveness). the success rate of 94.4% is regarding ability to perform vaginal penetration and issues regarding success rate have been discussed in detail at the discussion of the article. patient and their spouses where free to choose any treatment modality. despite the disadvantages’ of vcd most of them were happy using vcd for treatment of erectile dysfunction (ed) than going for prosthesis surgery or doing nothing. we did not ordinarily include patients with peyronie’s disease (pd), congenital penile curvature, and hematologic types of veno-occlusive priapism in the study. kim’s finding on development of pd with long term use of vcd is just a case report and no other such report or study exists in the literature. also we have a group of patients with spinal cord injury and ed under observation and the paper of the study will be released in near future. i admire editor’s opinion regarding reluctantly of using vcd in our community and his points of views but we know that personal points of view have its own level of value. amongst our patients only less than 2% discontinued and excluded from the study. this is very different from the duttas’s study, which possibly may be due to easily available other effective modalities (penile prosthesis) in those countries. the aim of our study was to evaluate the effect of vcd on erection and the cause of losing it during intercourse, and we have evaluated the issue in detail for the first time and no other study have mentioned importance of patients’ spouses in men using vcd for treatment of their ed. with respect to the editorial comments, that repeatedly has emphasized over the disadvantages of vcd, i would like to mention a point that considering all side effect and disadvantages, vcd is considered as the first line of therapy after phosphodiesterase type 5 inhibitors in guidelines published by eau 2013. at the end i believe it is better to be fair regarding various treatment modalities rather than writing only and only about vcd drawbacks. references 1. kim jh, carson cc 3rd. development of peyronie's disease with the use of a vacuum constriction device. j urol. 1993;149:1314-5. 2. dutta tc, eid jf. vacuum constriction devices for erectile dysfunction: a long-term, prospective study of patients with mild, moderate, and severe dysfunction. urology. 1999;54:891-3. reply by authors urology journal unrc/iua vol. 2, no. 4, 224-226 autumn 2005 printed in iran 224 introduction epidermoid cysts of the testis are benign tumor-like intratesticular masses. they are rare, representing less than 1% of all testicular tumors, and approximately 300 cases have been reported in the literature. treatment of epidermoid cysts is controversial with the traditional treatment being radical orchidectomy. awareness of this entity and the criteria for differential diagnosis will enhance the possibility of testicular preservation, averting unnecessary orchidectomy, especially for bilateral lesions. we report a case of bilateral epidermoid cysts in a 19-year-old man in whom the testes were preserved with conservative surgical management. case report a 19-year-old bahraini man presented with bilateral testicular pain of 5 months' duration. three years earlier, he had undergone right scrotal exploration and evacuation of a hematocele following blunt trauma to the scrotum. physical examination revealed 2 nontender masses (2 × 2 cm) in the midportion of both testes bilaterally. they were separate from the scrotal wall and epididymides. there was no clinically detectable hydrocele, gynecomastia, or palpable abdominal or inguinal mass. high-resolution testicular ultrasonography showed a 1.6 × 1.5 cm well-defined, spherical hypoechoic bilateral lesions with peripheral hyperechogenicity and normal surrounding parenchyma. serum levels of tumor marker (β-human chorionic gonadotropin and α-fetoprotein) were in the reference ranges. the patient underwent bilateral inguinal exploration. a soft clamp was placed on the spermatic cord, prior to delivery of the testis from the scrotum. the testes were bisected, and well-circumscribed cysts were identified. the lesions were completely enucleated. on incision of the cysts, yellow-white, putty-like material was extruded, revealing smooth cystic lesions (figure 1). the testes were replaced in the scrotum after tunical closure. frozen section histopathologic examination of both lesions confirmed the diagnosis of an epidermoid cyst. histologic examination of paraffin sections validated this (figure 2). the patient's postoperative course was uneventful, and he was well on follow-ups at 3, 6, and 12 months. results of analysis of his semen are normal 1 year after the surgery, and no recurrence has been detected clinically or by ultrasonography. conservative surgical management of bilateral epidermoid cysts of the testis: a case report and review of literature mohammed h al-durazi,* hamad a al-helo, ashok k malik, abdulameer e kadhim urology unit, surgical department and pathology department, salmaniya medical complex, kingdom of bahrain key words: epidermoid cyst, testes, conservative surgical management received october 2005 accepted november 2005 *corresponding author: po box 12, kingdom of bahrain. tel: ++973 3965 5977 e-mail: mddurazi@hotmail.com fig. 1. macroscopic appearance of the epidermoid cyst filled with pale pasty material al-durazi et al 225 discussion epidermoid cysts of the testis are uncommon, accounting for 1.5% to 2% of testicular tumors.(2,3) since their first report in 1942 by dockerty and priestly, more that 300 cases have been reported in the literature.(1) to our knowledge, this case represents the fourth reported case of bilateral epidermoid cyst in an adult patient and the third reported case with bilateral conservative management.(4,5) the histogenesis of epidermoid cysts has not been completely elucidated; however, the prevailing hypothesis is that of germ-cell origin, developing along the line of epidermoid differentiation as a monodermal expression of a teratoma.(2,6) other theories have been postulated, such as squamous metaplasia of the seminiferous epithelium, metaplasia of the rete testis, and inclusion of epidermoid cysts.(2,6) its relationship with other germ cell tumors is supported by the age and racial distribution of patients affected, and by its reported occurrence in the ovary and cryptorchid testes.(2) diagnosis of a lesion as a simple benign epidermoid cyst of the testis is confirmed pathologically when the following 5 criteria, set by prince in 1969, are met: the lesion is a cyst located within the parenchyma of the testis; the lumen is filled by keratinized debris; the wall of the cyst is composed of fibrous tissue with complete or incomplete lining of squamous epithelium; no teratomatous elements or dermal adnexal elements are present either within the cyst wall or elsewhere within the parenchyma of the testis; and no scar is present in the remaining testicular parenchyma.(2) strict adherence to these criteria clearly separates this benign entity from the more complex bidermal and tridermal testicular teratomas, all of which have malignant potential.(2) pathologically, an epidermoid cyst is typically a round or oval encapsulated lesion. the lumen contains squamous epithelium and keratin debris that may vary from complex fluid to a thick, pasty consistency.(6) the wall is composed of fibrous tissue that may be calcified.(6) epidermoid cysts of the testis usually present as incidental findings of a painless nodule during self-examination or routine physical examination.(1) most epidermoid cysts of the testis (86%) occur in young men in the second to fourth decades of life, but neither the young nor the aged are spared.(2) clinically, epidermoid cyst cannot be differentiated from other testicular tumors. they usually measure 2 to 3 cm on average, with a slight predominance to the right testis, similar to germ cell tumor.(1) bilateral occurrence is rare. clinically, an epidermoid cyst appears as a circumscribed, firm, smooth, and nontender intratesticular mass.(1) they apparently have no predilection for central-hilar parts rather than polar regions of the testis.(2) tumor markers, such as serum β-human chorionic gonadotropin and α-fetoprotein, are negative.(6) scrotal ultrasonography is a common diagnostic procedure for evaluating palpable scrotal masses to distinguish intratesticular from extratesticular lesions, and to exclude contralateral lesions. the ultrasonographic characteristics of epidermoid cysts include a wellcircumscribed hypoechoic mass with a hyperechogenic rim.(7) the ongoing deposition of keratinized material inside the cyst creates an echogenic whorl forming an onion-skin typical appearance.(1,7) the wall may calcify, and it may even develop a bony shell.(6) absence of flow on color doppler ultrasonography is consistent with the avascular nature of these lesions. several authors have found typical patterns that are highly suggestive of malignancy rather than benign conditions. the presence of a hypoechoic mass and bright echoic foci, as well as heterogeneous parenchymal echo patterns, all have been found to be suspicious for tumors.(8) on magnetic resonance imaging, epidermoid cysts show concentric rings of alternating highsignal and low-signal intensity corresponding to fig. 2. pathologic examination shows epidermoid lining with distinct granular layers and keratin flakes filling the lumen of the cyst (hematoxylin-eosin, × 100). management of bilateral epidermoid cyst of the testis226 the pathologic finding of multiple layers of keratin.(1,6) there is no contrast enhancement.(6) testicular lesions have traditionally been treated by radical orchidectomy when any mass was detected, but up to a third of these operations may be unnecessary.(8) treatment of epidermoid cysts remains controversial. it may be that the controversy regarding the histogenesis of epidermoid cysts has had a direct effect on the surgical approaches. nevertheless, radical orchidectomy has been the gold standard, although is now less frequently used.(1,3-6,9,10) indeed, more conservative approaches based on testis-sparing surgery are gaining more acceptance. a most recent literature review shows that almost all of reports published in the last decade on this subject invariably emphasize the safety and importance of conservative treatment of epidermoid cysts in all age groups.(1) the rationale of a less aggressive approach is that no local recurrence, distant metastases, or deaths have been reported in patients treated conservatively, from follow-up information available for up to 37 years.(2,3) many factors have led to this shift in the surgical approach. the typical ultrasonographic features of epidermoid cyst have facilitated a more accurate preoperative diagnosis allowing preoperative planning of testicular preservation.(7) the high accuracy of intraoperative frozen section is another factor that has promoted safe testicular preservation.(1) moreover, the macroscopic appearance of an epidermoid cyst at the time of testicular exploration is typical, with a light yellowish-tan well-encapsulated tumor that contains keratin plug and shells out easily from the testis.(9,10) if the ultrasonographic characteristics before surgery, age, physical examination, and tumor markers are in concordance with a strong possibility that a given mass is benign, a limited inguinal exploration and subsequent frozensection analysis can be used to reduce the number of unnecessary orchidectomies.(8) considering the psychological implications, preservation of a testicle in a young man is crucial. furthermore, most patients are of reproductive age, and preservation of fertility is a major issue in testicular surgery. however, it should be emphasized that all solid intratesticular lesions must be presumed as being malignant. the principles of cancer surgery must be followed, the testis should be isolated with nontraumatic clump, and the wound protected from potential spillage of tumor cells. the tunica albuginea should be opened over the mass, and the tumor must be excised in-toto and submitted for frozen section examination. references 1. malek rs, rosen js, farrow gm. epidermoid cyst of the testis: a critical analysis. br j urol. 1986;58:55-9. 2. chitale s, morrow dr, jena r, ball ry, webb rj. conservative surgery for epidermoid cyst of the testis. br j urol. 1997;80:506-7. 3. lev r, mor y, leibovitch i, et al. epidermoid cyst of the testis in an adolescent: case report and review of the evolution of the surgical management. j pediatr surg. 2002;37:121-3. 4. shenoy v, triest we, el-bash o. bilateral epidermoid cysts of the testis: report of a case with preservation of 1 testis. j urol. 1995;153:1933-4. 5. davi rc, braslis kg, perez jl, soloway ms. bilateral epidermoid cysts of the testis. eur urol. 1996;29:122-4. 6. docal i, crespo c, pardo a, prieto a, alonso p, calzada j. epidermoid cyst of the testis: a case report. pediatr radiol. 2001;31:365-7. 7. moghe pk, brady ap. ultrasound of testicular epidermoid cysts. br j radiol. 1999;72:942-5. 8. passarella m, usta mf, bivalacqua tj, hellstrom wj, davis r. testicular-sparing surgery: a reasonable option in selected patients with testicular lesions. bju int. 2003;91:337-40. 9. gupta sk, golash a, thomas ja, cochlin d, griffiths d, jenkins bj. epidermoid cysts of the testis: the case for conservative surgery. ann r coll surg engl. 2000;82:411-3. 10. ross jh, kay r, elder j. testis sparing surgery for pediatric epidermoid cysts of the testis. j urol. 1993;149:353-6. urology journal vol. 11 no. 04 july august 2014 1806 diagnosis and treatment of ureteral endometriosis: study of 23 cases dawei mu,1 xuesong li,2 gaobiao zhou,1 heqing guo1 1department of urology, air force general hospital, beijing, 100142, china. 2department of urology, pe king university first hospital, institute of urology, peking university, beijing, 100034, china. corresponding author: heqing guo, md department of urology, air force general hospital, bei jing, 100142, china. tel: +86 029 84777443 fax: +86 029 84777443 e-mail: heqingguo010@163. com received august 2013 accepted may 2014 purpose: to describe our experience in the diagnosis and treatment of 23 patients with ureteral endometriosis. materials and methods: we performed a retrospective analysis of 23 cases of ureteral endometriosis with histopathological results from 2002 to 2011. results: in patients with ureteral endometriosis, 23 cases were diagnosed by ultrasound, 21 by intravenous urography, 11 by retrograde urography, 16 by computed tomography, and 8 with magnetic resonance imaging. all cases were treated by operative treatment. the treatments included ureterolysis in 3 cases, partial ureteral resection and ureteroneocystostomy in 6 cases, partial ureteral resection and end-to-end ureteral anastomosis in 12 cases, and endoscopic resection of ureteral endometriosis lesion in 2 cases. all of the pathologic examination results were endometriosis. conclusion: our findings suggest that surgery is an effective treatment option in most patients with ureteral endometriosis exhibiting mild or moderate to severe hydronephrosis. the type of technique depends on the location and depth of the lesion. keywords: endometriosis; surgery; diagnosis; complications; treatment outcome; abnormalities; ureteral diseases. female urology preoperative evaluation included, assessment with the evaluation of ureteral endometriosis related pain using a visual analogue scale (vas) (10 point rating scale: 0 = absent, 10 = unbearable)11 for six components of disease related pain: dyspareunia, low back pain, menoxenia, hypogastralgia, hematuria and dysmenorrhea. surgical and clinical data of all cases were collected and recorded in a computerized database. some patients had previous medical and surgical treatment six months before surgery, whereas none were given hormonal treatment in this period. all patients were preoperatively examined by ultrasonography, and some patients also underwent intravenous urography (21 cases), retrograde urography (11 cases), computed tomography (ct) (16 cases) or magnetic resonance imaging (mri) (8 cases) examinations to assist in confirming the disease. the results revealed that all cases had hydronephrosis. all cases were treated by surgical therapy, including open surgery and laparoscopic surgery. the treatments included ureterolysis in 3 cases, segmental ureterectomy and ureteroneocystostomy in 6 cases, segmental ureterectomy and ureteroureterostomy in 12 cases, unilateral ovarian cyst excision in 9 cases and laparoscopy fulguration in 2 cases. the cases with negligible adherent involvement that required no specific procedures were excluded. follow-up included clinical evaluation and radiologic assessments (urography or ultrasonography examination) every 3 months for 2 years and then every year. main outcome measures were preoperative findings, operative details (type and site of ureteral endometriosis, type of intervention), postoperative urinary function, pain relief, hydronephrosis relief and complications. results of 1135 patients with endometriosis in the study period from 2002 to 2011, twenty-three cases of ureteral endometriosis were observed, a prevalence of 2.03%. table 1 shows the preoperative characteristics and findings of the 23 patients in the study. in most patients, the main symptoms were low back pain (17 cases, 73.9%) and hypogastralgia (15 cases, 65.2%). of the 23 patients, 9 patients (39.13%) had previous medical treatments, such as danazol (3 cases), progesterone (1 case) and gonadotropin-releasing hormone analogue (gnrh)-α (5 cases); 10 patients (43.48%) had previous surgical treatment, which consisted of ipsilateral ureterolysis (3 cases), nephrostomy for ureteral obstruction (4 cases), open ureteroneocystostomy (1 case) and ipsilateral dilatation of ureteral stenosis (2 cases). however, no patients had received hormonal therapy six months before surgical treatment. the 23 patients all were examined by ultrasonography before surgery; the results showed that all patients had hydronephrosis to a certain extent and ureterectasia. moreover, the ultrasonography examination also showed an ovarian cyst in 9 of the 23 patients and uterine myoma in 7 of the 23 patients. twenty-one patients underwent preoperative intravenous urography, which revealed a stricture of the lowest portion of the ureter that was 1.5 to 4.3 cm long. thirteen patients had mild (5 cases) or moderate to severe (8 cases) hydronephrosis. the results introduction ureteral endometriosis is a rare yet important condition and it is estimated that less than 1% of women with endometriosis also have ureteral endometriosis.(1) there is some evidence that the incidence of ureteral endometriosis is about 1%,(2) whereas other studies reported an incidence of only 0.1%.(3) although ureteral endometriosis is relatively uncommon and accounts for a small minority of cases, it can lead to renal failure because of the silent obstruction of the ureter. ureteral endometriosis can be subcategorized into two types: intrinsic or extrinsic.(4) intrinsic ureteral endometriosis is rare and characterized by the presence of endometriotic tissue in the ureteral wall. however, extrinsic ureteral endometriosis is more frequent and represented by the presence of endometrial stromal and glandular in the ureteral submucosa and adventitia.(5) ureteral endometriosis presents a clinical challenge both in diagnosis and treatment. the frequency of ureteral endometriosis is sometimes negligible and missed because patients do not display typical symptoms. frequently, nonspecific symptoms are those typically connected with endometriosis, including dyspareunia, dysmenorrhea and pelvic pain.(6,7) however, the indicative symptoms such as cyclic colicky flank pain and renal colic is relatively rare and about 50% of patients are asymptomatic.(8) therefore, it is very difficult to diagnose ureteral endometriosis before surgical procedures. the surgical treatment of ureteral endometriosis remains the gold standard which should relieve ureteral obstruction and avoid the recurrence.(9) different conservative surgeries have been proposed according to the pathological conditions of ureteral endometriosis, including laparoscopic management,(10) which could remove the pathologic tissue. the preoperative diagnosis and choice of an appropriate surgical approach are both essential for the treatment of patients with ureteral endometriosis. therefore, the aim of this study was to report the clinical, pathologic, diagnostic and management findings in a retrospective cohort of 23 cases undergoing various types of surgery for ureteral endometriosis. materials and methods twenty-three cases of ureteral endometriosis were gathered from the urinary surgery department in the air force general hospital and peking university first hospital between january 2002 and october 2011. all of the women who underwent surgery with pathological examination confirmation of ureteral endometriosis were included in this study. patients who had medication treatment for ureteral endometriosis or undergone surgery for other types of endometriosis were excluded. patient’s age, body mass index (bmi, kg/m2), history of previous medical treatment and surgical treatment, presenting symptoms and site of involvement were obtained by review of the medical records and pathology reports wherever available. slides from all cases were summarized for pattern of ureteral involvement (intrinsic or extrinsic) and for any additional related pathologic findings. the affected side was the right and left in 9 and 14 cases, respectively. there was no bilateral case. 1807 female urology urology journal vol. 11 no. 04 july august 2014 1808 ureteral endometriosis-mu et al of the 23 patients, follow-up data were obtained for 20 patients, while 3 cases were lost to follow-up (table 2). the 20 patients were submitted to clinical and radiological follow-up (ultrasonography and intravenous urography) every 6 months for the first 2 postoperative years and then every year thereafter. relief from pain was noted in 18 patients (90%). only 1 of the 20 patients (case no. 18) underwent repeated laparoscopy after 7 months because of the recurrence of pelvic pain. however, preoperative intravenous urography and ultrasonography in this woman; did not show ureteral dilatation. in the 20 patients, no relapses of ureteral endometriosis were found within the follow-up period of 41 months (range 7-98 months). relief from hydronephrosis was observed in all patients and the symptoms of ureteral disease disappeared in 12 patients. additional hormonal medications were given to 8 patients who had severe ureteral endometriosis. according to the follow-up data of all cases, we found that surgery is an effective treatment option in patients with ureteral endometriosis exhibiting mild or moderate-to-severe hydronephrosis. after ureterolysis and segmental ureterectomy, there were no relapses of disease during the follow-up period. our study increased the degree of awareness in clinicians and providing evidence in choosing a more adequate clinical management method for the lesser understood aspects of the disease. discussion endometriosis is one of the most common gynecologic disease in women, it usually occurs between menarche and menopause as a result of the fluctuating levels of progesterone and estrogen required for the propagation and stimulation of endometrial proliferation.(12) the insidious onset of endometriosis portends considerable morbidity, and thus, the disease need a high index of suspicion for both urologists and gynecologists.(13) about 10% of women in the reproductive age have involvement of the genitourinary tract by endometriosis, whereas disease affecting the ureter is infrequent, accounting for less than 0.3% of all types of endometriosis. although the morbidity of ureteral lesions is relatively low, the disease can cause severe silent loss of renal function.(14) in contrast to the literature, in our study, the ureter was involved in 23/1135 (2.03%) cases. the peak incidence of ureteral endometriosis is around 30-45 years, and the patients were either nulliparous (9 cases, 39.1%) or had one (8 cases, 34.8%) or two children (6 cases, 26.1%), born several years ago. also indicated normal kidney function in 13 patients, which was accompanied with a filling defect of the lower ureter in 2 of the 13 patients. moreover, 11 of the 13 patients had a stricture of the lower ureter. eight patients who had absent or extremely faint kidney images were further examined by retrograde pyelography. the results indicated that 5 patients had hydronephrosis, dilation of upper ureteral and stricture of the lower ureter. three patients who failed to be examined by retrograde pyelography were assessed using mri. sixteen of the 23 patients underwent preoperative ct scan, which revealed that 14 of the patients had strictures of the lower ureter and a soft-tissue mass around the tube wall, and 2 patients had a mass in the lumen of the ureter. as shown in figure, enhanced ct scan imaging shows the space occupying lesion in lower part of left ureter. retrograde pyelography of patients shows hydronephrosis in left kidney, dilatation in upper part of ureter, and filling defect in lower part of left ureter. ureteroscopy shows the papillary neoplasm in lower part of left ureter. eight patients underwent preoperative mri; the results showed that all patients had dilatation of the upper ureter and hydronephrosis. the results of clinical evaluation support the notion that all patients may suffer from ureteral endometriosis. in 15 cases, endometriosis involved the left ureter, whereas the right ureter was involved in 9 cases. no patient had bilateral involvement. all patients were affected in the distal third of the ureter. moreover, ureteral involvement by endometriosis was extrinsic in 18 cases, but intrinsic in 5 cases. all cases were treated by surgical therapy, including open surgery and laparoscopic surgery; the surgical methods are summarized in table 2. intraand post-operative complications are reported in table 3. there were no cases of complications requiring re-intervention. intraoperative complications include bladder injury in 1 case (4.3%), ureteral injury in 3 cases (13.0%), hemorrhage in one case (4.3%) and large vessel injury in one patient (4.3%). after surgery, 2 patients displayed dysuria, blood loss causing anemia occurred in 3 cases, hematuria occurred in one patient, 4 patients developed fever, and vaginal infection and urinary infection occurred in 1 and 2 cases, respectively. follow-up ranged from 7 to 98 months. the median follow-up was 3.42 years (3 years, 5 months). the maximum follow-up was 8.17 years (8 years, 2 months) and the minimum follow-up was 7 months. figure. (a) enhanced computed tomography scan of patients. white arrow shows the space occupying lesion in lower part of left ureter. (b) retrograde pyelography of patients. white arrow shows hydronephrosis in left kidney and dilatation in upper part of ureter. black arrow shows the filling defect in lower part of left ureter. (c) ureteroscopy shows the papillary neoplasm in lower part of left ureter. types.(15,16) the extrinsic form (70%-80% of cases) is characterized by ureteral endometriosis can be divided into extrinsic and intrinsic case no. age bmi previous medical treatment previous surgical treatment presenting symptoms (years) (kg/m2) 1 42 21.3 + dyspareunia, menoxenia, low back pain 2 34 22.6 + low back pain, hypogas tralgia 3 45 23.1 + dysmenorrhea, menoxenia, low back pain, hypogastralgia 4 42 22.6 + dyspareunia, menoxenia 5 23 18.6 + hematuria, hypogastralgia 6 50 22.4 + low back pain, hypogastralgia 7 45 23.5 + dyspareunia, low back pain 8 37 23.3 + dysmenorrhea, menoxenia, hypogastralgia 9 43 22.2 low back pain, hypogastralgia 10 44 24.0 + hematuria, low back pain hypogastralgia 11 41 21.9 + + dyspareunia,low back pain 12 26 18.8 menoxenia, hypogastralgia 13 33 23.7 menoxenia, low back pain 14 29 21.5 + dysmenorrhea, low back pain, hypogastralgia 15 27 20.9 + + dysmenorrhea, menoxenia low back pain, hypogastralgia 16 47 22.4 dyspareunia,low back pain 17 39 21.7 hypogastralgia 18 33 19.9 + low back pain, hypogastralgia 19 35 23.6 + hematuria, low back pain, hypogastralgia 20 22 18.9 + dysmenorrhea, menoxenia, low back pain 21 34 20.5 dyspareunia,low back pain hypogastralgia 22 21 20.7 + hypogastralgia hematuria 23 40 22.5 + dysmenorrhea,low back pain, hypogastralgia mean 36.2(sd = 4.5) 36.2 (sd = 2.6) ----table 1. characteristics of cases in the study. abbreviation: bmi, body mass index. 1809 female urology urology journal vol. 11 no. 04 july august 2014 1810 the surrounding organs or structures. the intrinsic form (20%-30% of cases) is less common than the extrinsic form. the intrinsic ureteral endometriosis always occurred in the ureteral mucosa or the muscular layer, because of hematogenous metastasis or lymphatic metastasis. ureteral obstruction caused by external compression by surrounding endometriosis. in the extrinsic form, patients were found to have ureter strictures, ureteral obstruction and hydronephrosis, because endometriosis lesions affect the external ureteral tunics through adherence to case no. surgical therapy duration of surgery follow-up intraoperative complication post operative (min) (month) complication 1 left ureteroureterostomy and 150 33 ureter injury, hemorrhage anemia left ovarian cyst resection 2 right ureteroureterostomy 195 lost to follow-up none none 3 right ureteroureterostomy and 237 31 bladder injury hematuria right ovarian cyst resection 4 left ureteroneocystostomy and 359 56 none dysuria, fever left ovarian cyst resection 5 right ureterolysis 187 48 none none 6 right ureteroureterostomy 285 51 none none 7 left ureteroureterostomy 169 98 ureter injury uti, vaginal infection, fever 8 right ureteroneocystostomy and 415 45 large vessel injury anemia right ovarian cyst resection 9 left ureteroureterostomy 177 68 none none 10 left ureteroneocystostomy and 430 40 ureter injury none left ovarian cyst resection 11 right ureteroureterostomy 265 54 none anemia 12 left ureteroureterostomy and 345 35 none uti, fever left ovarian cyst resection 13 left ureterolysis 280 42 none none 14 right ureteroureterostomy 330 65 none ` none 15 left ureteroneocystostomy 385 49 none dysuria, fever 16 left ureteroureterostomy and 430 37 none none left ovarian cyst resection 17 right ureteroneocystostomy 210 40 none none 18 left laparoscopy fulguration 240 12 none none 19 left ureterolysis 335 9 none none 20 left ureteroneocystostomy and 395 lost to follow-up none none left ovarian cyst resection 21 left ureteroureterostomy 248 11 none none 22 right laparoscopy fulguration 155 7 none none 23 left ureteroureterostomy and 310 lost to follow-up none none left ovarian cyst resection mean/median ---- 284 (mean) 41 (median) ---- (sd = 3.69) (7 ~ 98 months) table 2. surgical and follow-up data of study subjects. abbreviation: uti, urinary tract infection. ureteral endometriosis-mu et al quires demonstration of endometrial tissue on a pathology specimen. the general principles of treatment for ureteral endometriosis should be considered to relieve the ureteral obstruction and symptoms, and to protect renal function. the therapeutic methods for endometriosis include medical and surgical therapy.(17) surgical therapy is the paramount consideration for the patients with hydronephrosis; most scholars argue that ureterolysis is the first choice for treating patients with hydronephrosis.(18) bosev and colleagues believe that ureterolysis is an effective treatment option in vast majority of cases that can be safely accomplished, even in patients with moderate to severe hydronephrosis.(10,19) however, the management of ureteral endometriosis in cases of moderate to severe hydronephrosis is still contentious; some researchers believe that ureterolysis is more suited to cases with mild hydronephrosis, whereas patients with moderate to severe hydronephrosis should be treated by resection of the diseased ureter and subsequent ureteroneocystostomy or ureteroureterostomy, which can prevent further renal damage.(20,21) pelvic endometriosis should be treated if the patients have ureteral endometriosis accompanied with pelvic endometriosis. in cases with severe local lesions, perioperative auxiliary treatment with hormones (such as progestone, nemestran or danazol) can reduce tissue edema, narrow lesions and reduce the recurrence rate. in the current study, preoperative assessment by ct scan and mri examination and intraoperative ascertainment of 23 patients revealed that 5 patients had lesser degrees of obstruction and mild hydronephrosis. these patients were treated by relatively conservative ureterolysis and laparoscopy fulguration. the other patients (18 cases) suffered from high degrees of obstruction and moderate to severe hydronephrosis. of the 18 patients, segmental ureteral resection and ureteroneocystostomy were performed in 6 cases, segmental ureteral resection and ureteroureterostomy were carried out in 12 patients and ovarian cyst resection was performed in 9 cases in the corresponding period. of the 23 patients, follow-up data were obtained for 20 patients, ultrasonography and intravenous urography were performed to recheck for symptoms, and the results showed that the hydronephrosis has been alleviated in all patients. the symptoms of 12 cases disappeared after surgery; 8 cases were observed to have serious lesions intraoperatively, auxiliary treatment with hormones was given after surgery, but there was no recurrence during the follow-up period. overall, these results revealed that the surgical management is a better choice for patients with hydronephrosis. the effects of surgical management is associated with a number of factors, such as patient’s age, symptoms, degree of obstruction, the surgery thoroughness, adjuvant therapy and the desire to preserve reproductive function. conclusion we concluded that ureterolysis is an effective treatment option for patients with lesser degrees of obstruction and mild hydronephrosis, whereas resection of the diseased ureter and subsequent ureteroneocystostomy or ureteroureterostomy were more suitable for patients ureteral endometriosis is often asymmetrical, more commonly involving the distal segment of the left ureter.(5) in the current study, in all cases of ureteral endometriosis involving the distal segment of the ureter and occurring on a single side, the affected side was the left in fourteen and the right in nine of the twenty-three cases, whereas, bilateral involvement was not found in the twenty-three patients. of the 23 patients, 18 cases (78.3%) presented with extrinsic ureteral endometriosis, whereas 5 of the 23 patients presented with intrinsic form. the ratio of extrinsic and intrinsic forms was consistent with the literature reports.(16) the onset of ureteral endometriosis is latent. indeed, clinical symptoms and signs are often silent (52.2% of our cases), owing to the non-specific symptoms; the disease always progressed to silent obstruction and the loss of renal function. therefore, the diagnosis of ureteral endometriosis is very difficult. along with extensive pelvic endometriosis, some patients presented the clinical symptoms of dysmenorrhea, dyspareunia, pelvic pain, infertility and repeated urinary tract infections. also, symptoms of chronic pelvic inflammation, interstitial cystitis, irritable bowel syndrome and other diseases often co-occurred. thus, the surgeon should distinguish ureteral endometriosis from other diseases. the preoperative diagnosis is very difficult when specific symptoms of ureteral endometriosis are lacking. ureteral endometriosis is increasingly recognized with the greater the awareness of it. on clinical examination, ureteral endometriosis can be easily missed. a delay in diagnosis can lead to significant morbidity,(17) such as a consequent worsening of hydronephrosis and silent renal function loss. therefore, early diagnosis is very important for this disease. multiple diagnostic tests can be used to confirm the existence of ureteral endometriosis. ultrasonography, laparoscopy, intravenous urography, ureteroscopy with endoluminal ultrasound, ct scan and mri are common diagnostic tools.(14) in the current study, the 23 cases were examined by ultrasonography, laparoscopy, intravenous urography, ct scan and mri. based on the medical history, signs, results of imaging modalities and ureteroscopy of the patients, we suspected that all cases suffered from ureteral endometriosis. however, the final diagnosis of the disease reintraoperative postoperative complication number (%) complication number (%) bladder injury 1 4.3 dysuria 2 8.7 ureter injury 3 13.0 anemia 3 13.0 hemorrhage 1 4.3 hematuria 1 4.3 large vessel injury 1 4.3 vaginal infection 4.3 uti 2 8.7 fever 4 17.4 table 3. intraoperative and postoperative complications. abbreviation: uti, urinary tract infection. 1811 female urology urology journal vol. 11 no. 04 july august 2014 1812 the same pathogenesis. obstet gynecol surv. 2009;64:830-42. 18. camanni m, delpiano em, bonino l, deltetto f. laparoscopic conser vative management of ureteral endometriosis. curr opin obstet gynecol. 2010;22:309-14. 19. bosev d, nicoll lm, bhagan l, et al: laparoscopic management of ure teral endometriosis: the stanford university hospital experience with 96 consecutive cases. j urol. 2009;182:2748-2752. 20. marco c, luca b, elena d, et al. laparoscopic conservative management of ureteral endometriosis: a survey of eighty patients submitted to urete rolysis. reprod biol endocrinol. 200912;7:109. 21. chapron c, chiodo i, leconte m, et al. severe ureteral endometriosis: the intrinsic type is not so rare after complete surgical exeresis of deep endometriotic lesions. fertil steril. 2010;93:2115-120. with moderate to severe hydronephrosis. conflict of interest none declared. references 1. gabriel b, nassif j, trompoukis p, barata s, wattiez a. prevalence and management of urinary tract endometriosis:a clinical case series. uro logy. 2011;78:1269-74. 2. nezhat c, nezhat f, nezhat ch, nasserbakht f, rosati m, seidman ds. urinary tract endometriosis treated by laparoscopy. fertil steril. 1996;66:920-4. 3. donnez j, brosens i. definition of ureteral endometriosis? fertil steril. 1997;68:178-80. 4. blaustein’s pathology of the female genital tract. 5th ed., springer verlag, new york, 2002. p 1193-1247. 5. yohannes p. ureteral endometriosis. j urol. 2003;170:20-5. 6. frenna v, santos l, ohana e, bailey c, wattiez a. laparoscopic mana gement of ureteral endometriosis: our experience. j minim invasive gy necol. 2007;14:169-71. 7. gustilo-ashby am, paraiso mfr. treatment of urinary tract endometri osis. j minim invasive gynecol. 2006;13:559-65. 8. seracchioli r, mabrouk m, montanari g, manuzzi l, concetti s, venturoli s. conservative laparoscopic management of urinary tract endometriosis (ute): surgical outcome and long-term follow-up. fertil steril. 2010;94:856-61. 9. ghezzi f, cromi a, bergamini v, serati m, sacco a, mueller md. out come of laparoscopic ureterolysis for ureteral endometriosis. fertil steril. 2006;86:418-22. 10. mereu l, gagliardi ml, clarizia r, mainardi p, landi s, minelli l. la paroscopic management of ureteral endometriosis in case of modera te-severe hydroureteronephrosis. fertil steril. 2010;93:46-51. 11. stepniewska a, grosso g, molon a, et al. ureteral endometriosis: clini cal and radiological follow-up after laparoscopic ureterocystoneostomy. hum reprod. 2011;26:112-6. 12. kumar s, tiwari p, sharma p, et al. urinary tract endometriosis: review of 19 cases. urol ann. 2012;4:6-12. 13. hosseini sy, safarinejad m. endometriosis of the urinary tract: a report of 3 cases. urol j. 2005;2:45-8. 14. donnez j, nisolle m, squifflet j. ureteral endometriosis: a complica tion of rectovaginal endometriotic (adenomyotic) nodules. fertil steril. 2002;77:32-7. 15. hsieh mf, wu iw, tsai cj, huang ss, chang lc, wu ms. ureteral endometriosis with obstructive uropathy. intern med. 2010;49:573-6. 16. antonelli a, simeone c, frego e, minini g, bianchi u, cunico sc. sur gical treatment of ureteral obstruction from endometriosis: our experien ce with thirteen cases. int urogynecol j pelvic floor dysfunct. 2004;15:407-12. 17. berlanda n, vercellini p, carmignani l, aimi g, amicarelli f, fedele l. ureteral and vesical endometriosis: two different clinical entities sharing ureteral endometriosis-mu et al u j all final for web.pdf 807vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l a novel technique for treatment of distal ureteral calculi early results bayram guner,1 cenk gurbuz,2 turhan caskurlu2 keywords: ureter, calculi, ureteral calculi, ureteroscopy introduction m(swl) and ureteroscopy are commonly used treatment modalities for removal of distal ureteral stones. analysis of the literature for the past 3 years indicates especially, improvements in the design and accessories of ureteroscopes have led to increase in success rates. teral stones. corresponding author: bayram guner, md department of urology, state hospital, mus, turkey tel: +90 532 582 9016 fax: +90 216 570 9165 e-mail: gunerbayram@yahoo.com received november 2011 accepted october 2012 1 department of urology, mus state hospital, mus, turkey 2 department of urology, istanbul goztepe research and training hospital, istanbul, turkey point of technique 808 | point of technique case report orenoscopy to treat ureteral stones at the department of urology of clinical hospital center of goztepe and mus lithoclast, electro medical systems). informed consent pre-operatively. thereafter, all of them period. voiding cystourethrography (vcug) or cystoscopy (a) showing intramural ureteral calculi; (b & c) radiofrequency incision of superior wall of the intramural ureter; (d) extraction of calculi with endoscopic grasper. 809vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l radiofrequency energy in intramural ureteral stones | guner et al technique only for impacted ureteral calculi localized intramurally in ergy. after the stone had been reproduced into the bladder, st the patients had urinary tract infection and hydronephrosis peri-operatively. rd postopdiscussion ser, and basket catheter. stone size, composition, and localization, hydronephrosis, symptoms, anatomic variation, infection, duration of the ment, and swl are contributory factors for selection of ureteral calculi treatment. the stone-free rate of semi-rigureteral calculi can have impairment of the kidney function at presentation. in our study, all of the patients had hydronephrosis, and the average time of diagnosis to treatst postplication. patients characteristic. variables median (range) age, y 52.1 (31 to 80) stone size, mm 12.4 (10 to 16) hydronephrosis, grade 2 (1 to 3) operation time, min 18 (12 to 24) hospitalization, day 1.1 (1 to 3) follow-up, month 16.7 (11 to 21) 810 | conflict of interest none declared. references 1. knispel hh, klan r, heicappell r, miller k. pneumatic lithotripsy applied through deflected working channel of miniureteroscope: results in 143 patients. j endourol. 1998;12:513-5. 2. osti ah, hofmockel g, frohmuller h. ureteroscopic treatment of ureteral stones: only an auxiliary measure of extracorporeal shockwave lithotripsy or a primary therapeutic option? urol int. 1997;59:177-81. 3. du fosse w, billiet i, mattelaer j. ureteroscopic treatment of ureteric lithiasis. analysis of 354 urs procedures in a community hospital. acta urol belg. 1998;66:33-40. 4. harmon wj, sershon pd, blute ml, patterson de, segura jw. ureteroscopy: current practice and long-term complications. j urol. 1997;157:28-32. 5. tiselius hg, ackermann d, alken p, buck c, conort p, gallucci m. guidelines on urolithiasis. eur urol. 2001;40:362-71. 6. erhard m, salwen j, bagley dh. ureteroscopic removal of mid and proximal ureteral calculi. j urol. 1996;155:38-42. 7. wu cf, shee jj, lin wy, lin cl, chen cs. comparison between extracorporeal shock wave lithotripsy and semirigid ureterorenoscope with holmium:yag laser lithotripsy for treating large proximal ureteral stones. j urol. 2004;172:1899-902. 8. hendrikx aj, strijbos we, de knijff dw, kums jj, doesburg wh, lemmens wa. treatment for extended-mid and distal ureteral stones: swl or ureteroscopy? results of a multicenter study. j endourol. 1999;13:727-33. 9. vaughan ed, jr., gillenwater jy. recovery following complete chronic unilateral ureteral occlusion: functional, radiographic and pathologic alterations. j urol. 1971;106:27-35. 10. irving so, calleja r, lee f, bullock kn, wraight p, doble a. is the conservative management of ureteric calculi of > 4 mm safe? bju int. 2000;85:637-40. point of technique vol 12. no 02 march-april 2015 2096 miscellaneous penile mondor’s disease: primum non nocere!* purpose: penile mondor’s disease (superficial thrombophlebitis of the dorsal vein of the penis) is a rare clinical diagnosis. it is an easily diagnosed and treated disease. nevertheless, when reviewing the literature, we considered that unnecessary tests are carried out for diagnosis. in this study, we aimed to indicate the redundancy of doppler ultrasonography for diagnosis of penile mondor’s disease. materials and methods: seven patients with the clinical presentation of penile mondor’s disease were included in the study. in the first two patients, penile doppler ultrasonography was performed for diagnostic purposes by applying a vasoactive intracavernosal agent. this diagnostic procedure was not implemented in the next five patients. results: physical examinations revealed cord-like thickening lesions on dorsal and dorsolateral penis. in the first two patients, who penile doppler ultrasonography with an intracavernosal vasoactive agent was used for diagnostic purposes, was developed priapism. we did not use penile doppler for more patients as this would be unethical according to us. conclusion: recovery from penile mondor’s disease is usually spontaneous and smooth. a simple physical examination is sufficient for diagnosis, and palliative treatment is effective. for the diagnosis of this disease, unnecessary tests should be avoided so that patients are not harmed. keywords: penis; blood supply; thrombophlebitis; physiopathology; thrombosis; diagnosis, differential; penile diseases; ultrasonography. introduction superficial vein thrombosis was initially described by mondor in 1939 in the subcutaneous veins of the anterolateral thoracoabdominal wall.(1) penile mondor’s disease was first described by braun-falco in the 1950s. the incidence of this disease has recently been estimated to be 1.39%.(2) penile mondor’s disease is characterized by thrombosis in the superficial dorsal penile vein. patients complain of a generally painful or painless cordlike induration on the dorsal and dorsolateral aspect of the penis. the etiology of penile mondor’s disease is not completely understood, but various causes have been reported, including penile trauma, prolonged sexual abstinence, vigorous and prolonged sexual intercourse, infection, constrictive elements used during certain sexual practices, pelvic tumors and pelvic surgery.(35) in the literature the most common cause is stated as prolonged sexual intercourse.(3,4) on physical examination of the dorsum and dorsolateral surface of the penis, a hard, spermatic cord-like structure is palpated. from the literature, it is clear that doppler ultrasonography is often carried out for diagnostic purposes as a further investigation (with or without an intracavernosal vasoactive agent).(6-13) materials and methods after study was approved by the local institutional review board seven patients with the clinical presentation of penile mondor's disease were included in this study. between june 2012 and april 2014, seven patients with preliminary diagnoses of penile mondor’s disease were prospectively evaluated, treated and followed up. detailed history was taken from all patients. all patients had complained of swelling on the dorsum of the penis. there were also three patients who complained of pain. a patient without having pain in the dorsal aspect of the penis had mild dysuria complaint. on physical examination, all patients presented subcutaneous cord-like indurations on the penis’ dorsal/dorsolateral surface. a mean of 3.6 days (2-10 days) elapsed between the onset of symptoms and seeking medical attention at the outpatient clinic. in the first two patients, advanced examination was performed using diagnostic color doppler ultrasonography with an intracavernosal vasoactive agent (60 mg papaverine hydrochloride) injection after obtaining their informed consent. further investigation was not carried out in the next five patients. for the three patients who had pain, dexketoprofen trometamol (25 mg) pills were administered twice daily. clinical improvement was judged by improvement in the induration and pain. to resolve their anxiety, the patients were informed about the benign nature of the disease. it was recommended that they refrain from sexual activity during treatment. results the mean age of patients was 34.2 years (range, 22-45). none of the patients had specific anamnesis before the development of painful or painless superficial thrombosis 1 department of urology, faculty of medicine, adiyaman university, adiyaman, turkey. 2 department of radiology, faculty of medicine, adiyaman university, adiyaman, turkey. * primum non nocere is a latin phrase that means "first, do no harm." **correspondence: department of urology, faculty of medicine, adiyaman university, adiyaman, turkey. tel: +90 416 216 1015-3317. e-mail: mozyucel@yahoo.com. received september 2014 & accepted february 2015 haci polat,1 mehmet ozgur yucel,1** alper gok,1 can benlioglu,1 ali cift,1 mehmet akif sarica2 miscellaneous 2096 of the penis. physical examination in four patients showed cord-like indurations parallel to the coronal sulcus. three patients had cord-like induration in the dorsal aspect of the proximal penis. color doppler ultrasonography was carried out on the first two patients. the ultrasonography findings were similar for these patients, including an increase in the diameter of superficial dorsal vein, non-compressibility and intraluminal thrombus in the superficial dorsal vein (figure). the venous current spectrum in this vein was not observed via color doppler examination. after intracavernosal vasoactive agent injection (60 mg papaverine hydrochloride), doppler ultrasonography did not show any disorder in the cavernosal arteries. following intracavernosal vasoactive agent administration, the first patient’s average cavernosal artery diameter was 0.7 mm, peak systolic velocity was 47 cm/sec on the right and 49 cm/sec on the left; moreover, end diastolic velocity was -3 cm/sec on the right and -2 cm/sec on the left. in the second patient, the mean artery diameter was 0.6 mm; peak systolic velocity was 34 cm/sec on the right and 32 cm/sec on the left; and end diastolic velocity was -5 cm/sec on the right and -2 cm/sec on the left (table). both of these patients developed priapism after doppler ultrasonography. fortunately, the patients, taking our suggestions into consideration pre-procedure, applied to the hospital when an erection maintained six hours after the procedure. patients were treated without any problems by applying corpus cavernosum drainage with a 21 gauge butterfly needle. the next five patients did not undergo diagnostic examination except for the patient history and physical examination. all patients who were invited to the weekly follow-up, improved completely within 3–5 weeks of the onset of symptoms, as indicated in the literature. discussion penile mondor’s disease is a benign condition that is spontaneously resolved. however, it can sometimes create anxiety in patients. patients almost always complain of cord-like induration on the penis; this can sometimes be painful. in terms of etiology, various reasons for this condition are given, particularly prolonged sexual activity, but the exact cause is not known. our patients had no specific medical history. in our region, patients with a conservative sociocultural background may be reluctant to provide accurate medical history regarding sexual activity. on physical examination of patients with penile mondor’s disease, the subcutaneous cord-like mobile induration is easily palpable. in the literature, diagnostic penile doppler ultrasonography with an intracavernosal vasoactive agent injection has been reported.(11-13) such examination was carried out in our first two patients; these patients developed priapism. we decided that although the priapism was corrected with proper treatment, ultrasonography was an unnecessary examination. thus, we concluded that this type of imaging for diagnosis to be harmful because penile mondor’s disease is considered to have a benign course. as a result, we decided that doppler examination was unethical and we did not want to use it for our next patients, and it was penile mondor’s disease-yucel et al. figure. ultrasound showing thrombosis of the superficial dorsal vein of the penis (arrows). when there was current flow in the other veins of the penis, this was not monitored in the superficial dorsal vein. patients mean cavernosal peak systolic peak systolic velocity end diastolic velocity end diastolic velocity artery diameters (mm) velocity on the right (cm/sec) on the left (cm/sec) on the right (cm/sec) on the left (cm/sec) 1 0.7 47 49 -3 -2 2 0.6 34 32 -5 -2 table. the first two patients’ doppler ultrasonography results with application of an intracavernosal agent. vol 12. no 02 march-april 2015 2097 not employed for the next five patients. all of the patients were improved within 3–5 weeks, as expected. dexketoprofen trometamol (25 mg) pills were given twice daily to patients experiencing pain. penile mondor’s disease patients are usually young and sexually active. in these patients, erectile function is generally normal and the risk of developing priapism is higher than in patients with erectile dysfunction after penile doppler ultrasonography with intracavernosal vasoactive agent injection. we think that priapism is a much more serious condition than penile mondor’s disease when considering the possible consequences. penile mondor’s disease is easily recognizable with medical history taking and physical examination. the patient consistently presents with a mobile, cord-like induration on the dorsum and dorsolateral aspects of the penis which has become thickened and adherent to the overlying skin. we do not consider that additional scrutiny is required. to arrive at these results, we do not consider that more patients need to be examined. sclerosing lymphangitis and peyronie’s disease have been emphasized in differential diagnosis of penile mondor’s disease.(10) the morphology of sclerosing lymphangitis is serpiginous and it is characterized by thickened and dilated lymphatic vessels. peyronie’s disease results from a thickening of the tunica albuginea and presents as a well-defined immobile fibrotic plaque on the penis. conclusion although penile mondor’s disease is fairly uncommon, it is easily diagnosed. it improves with conservative treatment or spontaneously, but the diagnosis is important because the condition may create fear in patients. in our view, patients should not be exposed to diagnostic penile doppler ultrasonography with an intracavernosal vasoactive agent injection, as this is unnecessary and has the potential to cause serious harm. as noted in the literature, if the greatest cause of this disease is prolonged sexual intercourse, these investigations should be contraindicated. primum non nocere! conflict of interest. none declared. references 1. nachmann mm, jaffe js, ginsberg pc, horrow mm, harkaway rc. sickle cell episode manifesting as superficial thrombophlebitis of the penis. j am osteopath assoc. 2003;103:1024. 2. kumar b, narang t, radotra bd, gupta s. mondor’s disease of penis: a forgotten disease. sex transm infect. 2005;81:480-2. 3. rodríguez faba o, parra muntaner l, gómez cisneros sc, martín benito jl, escaf barmadah s. thrombosis of the dorsal penis vein (of mondor’s phlebitis). presentation of a new case. actas urol esp. 2006;30:80-2. 4. koh js, suh hj, choe hs, et al. superficial thrombophlebitis of the dorsal vein of the penis (penile mondor’s disease). korean j urol. 2004;45:399-401. 5. boscolo-berto r, raduazzo di. penile mondor’s disease: long term functional follow-up. urol j. 2012;9:525-6. 6. kraus s, ludecke g, weidner w. mondor’s disease of the penis. urol int. 2000;64:99-100. 7. lilas la, mumtaz fh, madders dj, et al. phimosis after penile mondor’s phlebitis. bju int. 1999;83:520-1. 8. sasso f, gulino g, basar m, carbone a, torricelli p, alcini e. penile mondor’s disease: an underestimated pathology. br j urol. 1996;77:729-32. 9. ozkara h, akkuş e, akpınar h, alıcı b, hattat h. superficial dorsal penile vein thrombosis (penile mondor’s disease). int urol nephrol. 1996;28:387-91. 10. swierzewski sj 3rd, denil j, ohl da. the management of penile mondor’s phlebitissuperficial dorsal penile vein-thrombosis. j urol. 1993;150:77-8. 11. han hy, chung dj, kim kw, hwang cm. pulsed and color doppler sonographic findings of penile mondor’s disease. korean j radiol. 2008;9:179-81. 12. ozel a, issayev f, erturk sm, halefoglu am, karpat z. sonographic diagnosis of penile mondor’s disease associated with absence of a dorsal penile artery. j clin ultrasound. 2010;38:263-6. 13. benson cb, doubilet pm. ultrasound and doppler evaluation of the penis. in: introduction to vascular ultrasonography. 4th ed. ed. zwiebel wj. philadelphia, pa: wb saunders co. 2000. p. 481–8. penile mondor’s disease-yucel et al. miscellaneous 2098 urol_v03_no3_001_editorial.indd endourology and stone disease 134 urology journal vol 3 no 3 summer 2006 pediatric cystine calculi in west of iran a study of 22 cases abolhassan seyedzadeh, hossein e momtaz, mahmoud reza moradi, asaad moradi introduction: cystinuria is an autosomal recessive disorder which clinically presents as cystine calculi. in this study, we reviewed cystine calculi cases in the west of iran to determine their common presentations and response to different therapeutic modalities. materials and methods: between 1999 and 2005, we had 22 pediatric patients (11 boys and 11 girls) with cystine calculi. the demographic characteristics and clinical data of the patients as well as the treatment results were reviewed. results: the mean age of the patients was 34.20 ± 42.99 months (range, 4 to 156 months). they were followed for a mean duration of 23 months (range, 3 to 70 months). thirteen patients (59.1%) had bilateral and 9 (41%) had unilateral kidney calculi. the sizes of the calculi were between 2 mm and 20 mm. nine patients (41%) had renal atrophic changes and 1 (4.5%) had obstructive acute renal failure. hydration and urinary alkalinization were administrated to all of the patients which yielded an excellent result in 54.5% and a poor response in 27.2%. captopril started for 5 patients was effective only in 1. d-penicillamine had no favorable response. extracorporeal shockwave lithotripsy was successful in 5 attempts and failed in 4. surgical interventions were performed for 13 patients (59.1%) and 6 (27.2%) required more than 1 surgical operation. conclusion: we recommend metabolic workup of childhood urolithiasis and appropriate medical management of its underlying disease. we also recommend minimally invasive urologic techniques including shockwave lithotripsy only when there are clear indications for nonmedical procedures. urol j (tehran). 2006;3:134-8. www.uj.unrc.ir keywords: cystine, child, urinary calculi, treatment urology-nephrology research center, kermanshah university of medical sciences, kermanshah, iran corresponding author: abolhassan seyedzadeh, md razi children hospital, shaheed beheshti blvd, kremanshah, iran email: aseyedzadeh2001@yahoo.com received march 2006 accepted june 2006 introduction cystinuria is an autosomal recessive disorder in reabsorptive transport of cystine and other dibasic amino acids (lysine, ornithine, and arginine) in the kidney and the small intestine.(1,2) thus, there is execessive urinary excretion of dibasic amino acids. but, only cystinuria is of clinical significance due to its insolubility in the normal urinary ph. it has also the highest tendency to be crystallized and cause recurrent urolithiasis.(3) cystinuria may be particularly more important in children, firstly because it accounts for 6% to 8% (in some reports up to 10%) of pediatric urinary calculi compared with 1% to 2% in adults(2); secondly, if the underlying problem is not properly diagnosed and treated, there is a high risk of damage to the kidney due to its recurring nature.(4-6) in this study, we describe 22 cases of cystine calculi in pediatric patients and evaluate their common presentations and response to different therapeutic modalities. materials and methods between 1999 and 2005, 22 pediatric pediatric cystine calculi—seyedzadeh et al urology journal vol 3 no 3 summer 2006 135 patients with cystine calculi had presented to pediatric nephrology clinic of razi hospital in kermanshah. we retrospectively reviewed their medical records. the demographic characteristics and clinical data of the patients were studied focusing on the initial presentations, number of the calculi, bilateral or unilateral involvement of the kidney, complications of the calculi, the treatment, and the outcome. cystinuria was confirmed in the patients by one or a combination of the following criteria: detection of cystine crystals in the first morning urine sample, positive cyanide nitroprusside test, and analysis of the calculi. all of the patients were managed by our conservative treatment protocol including hydration (2 l/m2/d of oral water intake), urine alkalinization (potassium citrate oral solution, 2 meq/kg/d in 3 divided doses), and dietary sodium restriction. adequacy of the alkali therapy was evaluated according to the urine ph measured by urine ph meter and proper hydration was monitored by maintaining urine specific gravity around 1.010. physical examination and laboratory evaluations including ultrasonography, urine ph, and urine specific gravity were performed monthly for followup. an excellent response to treatment was defined as no calculus formation after the treatment regarding ultrasonographic results; a partial response was defined as less than 3 calculi per year; and a poor response was defined as 3 or more calculi per year. for the patients with a poor response to this initial protocol, captopril (0.5 mg/kg/d to 1 mg/kg/d) was added and their response to the treatment was reevaluated. d-penicillamine (20 mg/kg to 40 mg/kg) was started for the patients with a poor response to captopril and the efficacy of this drug was also evaluated regarding the promotion of further calculus formation. in special cases, such as large symptomatic calculi or obstruction, we referred the patients to a pediatric urologist for performing extracorporeal shockwave lithotripsy (swl) or surgical intervention. results of 22 patients, 11 (50%) were boys and 11 (50%) were girls. thirteen patients (59.1%) were younger than 2 years of age at presentation. the mean age of the patients at presentation was 34.20 ± 42.99 months (range, 4 to 156 months). they were followed for a mean duration of 23 months (range, 3 to 70 months). the initial presentations of the patients and number of their calculi are summerized in table 1. thirteen patients (59.1%) had bilateral and 9 (41%) had unilateral kidney calculi. the calculi were detected in the kidneys, the kidneys and the ureters, and the bladder and the kidneys in 17 (77.3%), 3 (13.6%), and 2 (9.1%) patients, respectively. the sizes of the calculi were between 2 mm and 20 mm. complications occurred in 10 patients (45.5%), mostly before the initiation of the treatment. nine patients (41%) had renal atrophic changes and 1 (4.5%) had obstructive acute renal failure. all of the patients were first treated cnservatively and excellent response was achieved in 12 (54.5%). their response to the treatments and the next measures are shown in table 2. shockwave lithotripsy was performed for 8 patients (36.4%). two did not return for the follow-up and the 6 remaining underwent an overall of 9 sessions of swl which was successful in 5 cases (55.6%). surgical interventions were performed for 13 patients (59.1%) and 6 (27.2%) required more than 1 surgical operation. for 12 (54.5%), 4 (18.1%), and 1 (4.5%) patients, open lithotomy (18 times), percutaneous nephrolithotomy, and transureteral lithotomy were performed, respectively. three patients (13.6%) required a combination of these surgical methods. discussion the incidence of cystinuria and cystine calculi varies table 1. number of calculi and clinical presentations in patients with cystine calculi* *values in parentheses are in percents. †because of rounding, percentages may not all total 100. characteristics number of patients † initial clinical presentation nonspecific 13 (59.1) urinary tract infection 7 (31.8) hematuria 1 (4.5) failure to thrive 1 (4.5) number of calculi ≥ 4 14 (63.6) 2 or 3 4 (18.2) 1 4 (18.2) pediatric cystine calculi—seyedzadeh et al 136 urology journal vol 3 no 3 summer 2006 according to geographic areas. newborn screening programs have estimated a prevalence of 1:2000 in the united kingdom, 1:4000 in australia, 1:15 000 in the united states, and 1:2500 in libyan jews.(2) more than 50% of cystinuric patients develop cystine calculi during their lifetime.(4) in children, review of the literature on the composition of urinary calculi yields different contributions of cystine calculi in various populations. for example, in croatia, up to 10% of the pediatric urolithiasis cases are cystine calculi,(7) while this rate is 2%, 2%, 2.4%, and 2% in armenia,(8) turkey,(9) kuwait,(10) and the united states,(11) respectively. only 1 published study of childhood urolithiasis has been performed in iran in which cystinuria has been detected in 6 of 125 patients (4%).(12) in the present study, we described 22 cases of cystine calculi in children in the west of iran during a 6-year period (1999 to 2005). in our case series, the numbers of boys and girls were equal. in a study of urolithiasis in tunisian children, there were 4 cases of cystine calculi, 3 of whom were boys and only 1 was girl.(13) in another study in jordan on 20 patients with cystine calculi, 16 were male and 4 were female, but only 4 patients were younger than 14 years.(14) in another study in italy, the female-male ratio (especially in adults) was 0.64:1.(15) the early presentation of the cystine calculi was one of the most interesting findings in our patients. the peak age of onset of urolithiasis is the third decade of life;(2) however, in our patients, mean age of the disease onset was 34 months and we had even a 4-month-old patient with cystine calculus. this implies that cystinuria should be considered as a likely etiology of urolithiasis even in very young patients. therefore, metabolic workup of cystinuria is mandatory in young children presenting with urinary calculi. in addition, significant differences in the age of presentation of cystine calculi in various reports could be due to the genetic factors in the cystinuric patients who had been studied.(1) thirteen out of 22 cases in our series were detected during the evaluation of nonspecific symptoms by ultrasonography. this allows us to speculate that some cases of cystine calculi in adulthood are the undiagnosed cases since infancy and childhood. urinary tract infection was present in 32% of our patients. this finding emphisizes the consideration for the underlying metabolic disorders in such conditions. bilateral nephrolithiasis was detected in 59% of our patients, and 14 patients (63.6%) had more than 4 calculi. the presence of multiple calculi together with the recurring nature of the cystine calculi predispose the patients to renal parenchymal damage. on the other hand, in 9 (41%) patients, only 1 kidney was involved. some other reports of cystine calculi have also mentioned this laterality of the cystine calculi in adults.(16) we have no clear explanation for this laterality, but it could be due to minor anatomical differences between the 2 kidneys or some undetermined factors. our patients had a rather high rate of complications (45.4%). nine (41%) of them had atrophic changes in the kidneys mostly at presentation and before any therapeutic intervention. this finding indicates the importance of the early diagnosis and treatment of cystine calculi before any irriversible kidney damage. all of our patients were initially treated by hydration, dietary sodium restriction, and alkali therapy. of the patients, 12 (54.5%) showed excellent response to this method of treatment, which is indicative of the efficacy of conservative treatment. interesingly, in spite of undesirable taste of the alkali solution, we had a low rate of noncompliance even in young infants. this is in contrast to some reports of adult patients with high rates of noncompliance to the conservative treatment.(17) captopril was started on for 5 patients; 1 had excellent response, 2 had partial table 2. patients’ response to medical treatments* *values in parentheses are in percents. outcome treatment modality excellent response partial response poor response lost to follow-up discontinuation of treatment conservative 12 (54.5) 0 6 (27.3) 2 (9.1) 2 (9.1) captopril 1 (4.5) 2 (9.1) 2 (9.1) 0 0 d-penicillamine 0 0 2 (9.1) 0 0 pediatric cystine calculi—seyedzadeh et al urology journal vol 3 no 3 summer 2006 137 response, and 2 had poor response to captopril. there are conflicting reports of captopril efficacy in cystinuria. some researchers have found it to significantly decrease urinary cystine excretion and calculus formation, especially in adults. in contrast, several reports have failed to show a significant effect of this drug, mostly in children.(18) our results indicate that, at least in children, captopril cannot be assumed as a very effective treatment of cystine calculi and should be tried in case of noncompliance and poor response to conservative treatments. we started d-penicillamine for 2 patients, but no decrease was seen in the calculus formation; however, we did not find any significant side effect either. for editorial comment see p 138 finally, swl was successful in 5 attempts and failed in 4. this is in agreement with other reports indicating that the stone-free rates after swl are significantly higher in children comparing to adults;(4) nonetheless, it may depend on the localization of the calculi.(19) surgical interventions were required in the majority of our patients (59%). about 27% of them underwent more than one operation and many of these operations were performed before starting the medical management. this trend can impose a significant financial burden on the patient’s family and the medical system and also a higher risk of renal parenchymal damage. conservative and pharmacologic treatment may decrease the need of surgical intervention significantly and should be tried initially. conclusion in pediatric urolithiasis, we recommend metabolic workup, appropriate medical management of the underlying cause, and using minimally invasive urologic techniques including swl when there are clear indications of nonmedical procedures. conflict of interest none declared. references 1. goodyer p, saadi i, ong p, elkas g, rozen r. cystinuria subtype and the risk of nephrolithiasis. kidney int. 1998;54:56-61. 2. shekarriz b, stoller ml. cystinuria and other noncalcareous calculi. endocrinol metab clin north am. 2002;31:951-77. 3. rutchik sd, resnick mi. cystine calculi. diagnosis and management. urol clin north am. 1997;24:16371. 4. knoll t, zollner a, wendt-nordahl g, michel ms, alken p. cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and followup. pediatr nephrol. 2005;20:19-24. 5. kirsch-noir f, thomas j, fompeydie d, debre b, zerbib m, arvis g. cystine lithiasis: study of a series of 116 cases. prog urol. 2000;10:1135-44. 6. tekin a, tekgul s, atsu n, sahin a, bakkaloglu m. cystine calculi in children: the results of a metabolic evaluation and response to medical therapy. j urol. 2001;165:2328-30. 7. biocic m, saraga m, kuzmic ac, et al. pediatric urolithiasis in croatia. coll antropol. 2003;27:745-52. 8. sarkissian a, babloyan a, arikyants n, hesse a, blau n, leumann e. pediatric urolithiasis in armenia: a study of 198 patients observed from 1991 to 1999. pediatr nephrol. 2001;16:728-32. 9. ozokutan bh, kucukaydin m, gunduz z, kabaklioglu m, okur h, turan c. urolithiasis in childhood. pediatr surg int. 2000;16:60-3. 10. el-reshaid k, mughal h, kapoor m. epidemiological profile, mineral metabolic pattern and crystallographic analysis of urolithiasis in kuwait. eur j epidemiol. 1997;13:229-34. 11. sternberg k, greenfield sp, williot p, wan j. pediatric stone disease: an evolving experience. j urol. 2005;174:1711-4. 12. kheradpir mh, bodaghi e. childhood urolithiasis in iran with special reference to staghorn calculi. urol int. 1990;45:99-103. 13. kamoun a, daudon m, abdelmoula j, et al. urolithiasis in tunisian children: a study of 120 cases based on stone composition. pediatr nephrol. 1999;13:920-5. 14. bani hani i, matani y, smadi i. the value of family screening for patients with cystine stone disease in northern jordan. br j urol. 1998;81:663-5. 15. trinchieri a, dormia g, montanari e, zanetti g. cystinuria: definition, epidemiology and clinical aspects. arch ital urol androl. 2004;76:129-34. 16. purohit rs, stoller ml. laterality of symptomatic cystine calculi. urology. 2003;62:421-4. 17. pietrow pk, auge bk, weizer az, et al. durability of the medical management of cystinuria. j urol. 2003;169:68-70. 18. joly d, rieu p, mejean a, gagnadoux mf, daudon m, jungers p. treatment of cystinuria. pediatr nephrol. 1999;13:945-50. 19. slavkovic a, radovanovic m, siric z, vlajkovic m, stefanovic v. extracorporeal shock wave lithotripsy for cystine urolithiasis in children: outcome and complications. int urol nephrol. 2002-2003;34:457-61. pediatric cystine calculi—seyedzadeh et al 138 urology journal vol 3 no 3 summer 2006 editorial comment i read, with great interest, the article by dr seyedzadeh and his colleagues. the authors described the medical management and prevention of the cystine calculi. previous studies from our country have suggested that captopril regimen and strict urinary alkalinization could prevent the recurrence of the cystine calculus in 34 children.(1) furthermore, based on our experience, we propose a therapeutic algorithm for patients with cystine nephrolithiasis. hyperdiuresis, alkalization (optimally by potassium citrate and simple urinary ph measurement every 6 hours for citrate dosage adjustment), and diet precautions (moderate animal protein and salt intake) should be initially presented to all patients as the basic therapeutic regimen. thiol derivatives should be considered early perioperatively or to dissolve preexisting stones in patients with a heavy cystinuria of 800 mg or greater daily, or high metabolic calculus activity of more than 1 calculus yearly. thiols should also be administered when basic measures fail to inhibit calculus recurrence or the significant growth of preexisting calculi. in any case, hyperdiuresis and alkalization should not be neglected. to our knowledge, our report represents the largest single-center study (516 patient-year) of the long-term results of medical therapy for cystine urolithiasis to date, and the 17 years’ follow-up will be published soon for clarifying the long-term durability, effectiveness, feasibility, and cost-effectiveness of these strict massures. certain comparable singlecenter studies using a similar therapeutic schedule have been reported.(2) the study of chow and streem included 16 adults followed for 104 patient-year with a minimum follow-up of 6 months (average, 6.5 years). results in our patients generally confirm those of chow and streem and highlight the difficulty of arresting calculus formation in patients with homozygous cystinuria even when treated by a homogeneous dedicated team that performs frequent clinical, radiological, and laboratory followup studies. we observed that the overall compliance and longevity of the treatment success in our patient population are optimal. interestingly patient perception of the degree of compliance corresponded poorly to the physician perception, educational status, as well as to the results of 24-hour urine samples. while patients who achieved therapeutic success considered themselves compliant, similar self-perceptions were noted in noncompliant patients. this lack of insight portends obvious difficulties in those with uncontrolled cystinuria. these difficulties noticed by our patients clearly suggest avenues for improving future medications and dose regimens. abolmohammad kajbafzadeh children’s hospital medical center, tehran university of medical sciences, tehran, iran references 1. kajbafzadeh am, vejdani k. captopril and strict urinary alkalinization for the prevention of cystine stone recurrence in children. j endourol. 2002: 16;a108. 2. chow gk, streem sb. medical treatment of cystinuria: results of contemporary clinical practice. j urol. 1996;156:1576-8. the association between serum follicle-stimulating hormone levels and the success of microdissection testicular sperm extraction in patients with azoospermia mehmet erol yildirim,1 akif koc,2 ikbal cekmen kaygusuz,3 hüseyin badem,4 omer faruk karatas,1 ersin cimentepe,1 dogan unal5 1department of urology, turgut ozal university, faculty of medicine, ankara 06510, tur key. 2department of urology, balı kesir university, faculty of me dicine, balikesir 10310, turkey. 3department of gynecology and obstetrics, turgut ozal univer sity faculty of mediine, ankara 06510, turkey. 4department of urology, yüksek i̇htisas training and research hospital, ankara 06520, tur key. 5department of urology, hacet tepe university faculty of me dicine, ankara 06520, turkey. corresponding author: mehmet erol yildirim, md department of urology, tur gut ozal university school of medicine, 06510, yenimahalle, ankara, turkey. tel: +90 312 2035221 fax: +90 312 2213670 e-mail:doctorerol@yahoo.com received april 2014 accepted june 2014 purpose: to evaluate the predictive power of luteinizing hormone (lh), follicle-stimulating hormone (fsh), testosterone, testicular biopsy histology and male age were evaluated with respect to the success of sperm retrieval in a microdissection testicular sperm extraction (microtese) procedure, pregnancy and live birth rates. materials and methods: we examined the data of 131 infertile men with non-obstructive azoospermia, who have undergone microtese operation. the men were classified into two groups based on serum follicle-stimulating hormone (fsh) levels ≤ 15 miu/ml (group 1) and > 15 miu/ml (group 2). results: group 1 consisted of 59 patients (mean age 36.2 ± 6.2 years) and group 2 consisted of 72 (mean age 38.8 ± 7.4 years) patients. sperm retrieval and pregnancy rates were 66.1% and 16.9% in normal fsh group, respectively. these parameters were higher than those of men with fsh > 15 (43% and 8.3%, respectively). only 128 patients had histopathological diagnosis. sperm was retrieved from 12/30 (40%) patients with maturation arrest, 9/29 (31.03%) patients with seminiferous tubules atrophy, 14/40 (35%) patients with sertoli cell only syndrome and 13/13 (100%) of patients with hypospermatogenesis. there was no statistically significant difference in pathological diagnosis between pregnancy and live birth rates. conclusion: these results demonstrate that there is a significant difference with sperm retrieval, pregnancy rates and live birth rates comparing the fsh levels. histopathological findings did not associate with successful microtese, pregnancy rates and live birth rates. keywords: infertility, male; microdissection; sperm retrieval; testicular diseases; azoospermia; spermatogenesis. 1825 sexual dysfunction and fertility sexual dysfunction and fertility urology journal vol. 11 no. 04 july august 2014 1826 association of fsh on microtese success-yildirim et al when further dissection would jeopardize the testicular blood supply. a sample was taken for histopathological investigation from each procedure. the patients were divided into two groups based on their serum fsh levels; ≤ 15 miu/ml (group 1) and > 15 miu/ml (group 2). the patients were also classified according to their testicular pathology, such as maturation arrest, testicular atrophy, sertoli cell only syndrome or hypospermatogenesis. the groups were compared with regards to sperm retrieval, pregnancy and live birth rates. informed consent was taken from all patients in order to use their data. also, ethics approval was obtained from our institutional ethics committee. statistical analysis data were analyzed using statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. independent groups were compared using the mann whitney u test and group rates were compared by the student’s t-test. p values of < .05 were considered as statistically significant. results the average age of patients undergoing microtese was 37.72 ± 5.8 (range, 26-57) years. there were 59 patients in group 1 and 72 patients in group 2. the mean age of group 1 and 2 were 36.2 ± 6.2 and 38.8 ± 7.4, respectively. there were statistically significant differences between both groups with regards to sperm retrieval (p = .008), but not to pregnancy rates (p = .136) nor live child delivery rates (p = .136) (table 1). the mean serum fsh levels were 17.4 ± 16 (95% confidence interval [ci]: 13.6-21.3) m i u / m l and 24.1 ± 15.8 (95% ci: 20.1-28.2) miu/ml in the sperm retrieved and non-sperm retrieved groups. there was a statistically significant difference in serum fsh levels (p = .03) between sperm retrieved and non-sperm retrieved groups. however, there were neither statistically significant differences in serum fsh levels between pregnancy and non-pregnancy groups (p = .655) nor between child delivered and non-child delivered groups (p = .655) (table 2). with regards to the patient’s ages, there were no statistically significant differences between sperm retrieved and non-retrieved groups (p = .66), child delivered and non-child delivered groups (p = .457) and pregnancy and non-pregnancy groups (p = .457) (table 2). there is a negative correlation between sperm retrieval and both serum fsh levels and patient ages (r = -0.207, p = .018 and r = -0.159 p = .07, respectively). we could collect only 128/131 patients’ data regarding their testicular histology. according to these data, there were no statistically significant difference between histological findings and sperm retrieval (p = .178), pregnancy rate (p = .198), or child delivered groups (p = .063) (table 3). also there was only a positive correlation between hypospermatogenesis and sperm retrieval (r = .281, p = .001). discussion introduction infertility is defined as the inability to conceive a child after one year of regular unprotected intercourse. (1) infertility is a major health problem that effects approximately 15% of couples, and nearly 50% of this is because of male infertility. (2) there are many reasons for male infertility, but testicular factors play the leading role. assisted reproductive techniques, such as in vitro fertilization (ivf) and intracytoplasmic sperm injection (icsi), offer the possibility of fertilizing oocytes even if only a small number of spermatozoa are found in the ejaculate. in cases of azoospermia, sperm is obtained from the epididymis and testes by surgical procedures. microdissection testicular sperm extraction (microtese) is performed to recover sperm from azoospermic patients and was shown to be successful even in testes with only small islets of spermatogenesis.(3) however, every failed microtese-icsi procedure exposes the couple to an emotional and financial burden. it becomes increasingly important to predict the success of sperm retrieval using non-invasive parameters before the attempted treatment. there are many studies about using a patient’s hormonal status and previous testicular biopsy histology to predict the success of microtese in recent years. (4) in our study, the predictive power of luteinizing hormone (lh), follicle-stimulating hormone (fsh), testosterone, testicular biopsy histology and male age were evaluated with respect to the success of sperm retrieval in a microtese procedure, pregnancy and live birth rates. materials and methods study subjects the data of 131 patients with non-obstructive azoospermia who have undergone microtese between january 2006 and november 2012 were examined. inclusion criteria were, no sperm found in the ejaculate, existence of bilateral vas deferens and no history of genital infection, surgery or vasectomy. azoospermia was confirmed via analysis of two different semen analyses according to world health organization (who) criteria.(5) a semen sample was also collected on the day of microtese. all hormonal levels were determined by the chemiluminescent immunoassay (immulite 2000, siemens diagnostics, los angeles, c a , usa) method. the reference range of fsh was 1.5-15 miu/ml, lh was 4-8.6 miu/ ml and testosterone was 245-1600 ng/dl. all patients underwent microtese with local anesthesia. after a midline scrotal incision, we pushed out the biggest testis and opened the tunica vaginalis. after the visualization of the tunica albuginea, the remainder of the procedure was performed under × 20 magnification with an operative microscope. small samples were excised from the testis. each sample was examined immediately by the embryologist under × 200 magnification. if no spermatozoa were identified in the initial sample, the incision of the tunica albuginea was expanded and subsequent samples were taken from the larger and more opaque tubules, if needed, from the contralateral testis. the procedure stopped when enough spermatozoa were retrieved or therefore, according to ramasamy and colleagues, we can retrieve sperm by microtese even despite fsh values o f 2-3 times higher than normal. otherwise, pregnancy (46%, 50%, 52% and 46%, respectively) and live birth rates (38%, 45%, 44% and 36%, respectively) were similar in both serum fsh normal and higher groups.(4) bohring and colleagues showed that both serum fsh and inhibin b are relevant with spermatogenesis. but they had not concluded these hormones to be definite predictive factors because despite the abnormal levels of these hormones, successful microtese were performed. many studies have shown that the histopathology of testes to be the best predictor concerning the retrieval of sperms in microtese. (13) but, there is some controversy as to whether a random sampling may not represent the inherent heterogeneity, because augmentation of the sampling may cause inflammatory changes, hematoma, parenchymal fibrosis or permanent devascularization of the testis. (14) tunç and colleagues reported a 42.1% sperm retrieval rate at germinal aplasia, and the best (83.3%) at hypospermatogenesis.(15) su and colleagues reported 24% sperm retrieval rates at sertoli cell only syndrome (scos) and higher rates were 79% at hypospermatogenesis.(16) tournaye and colleagues reported 67% sperm retrieval rates at scos, 82% at maturation arrest and 100% at hypospermatogenesis. (17) our sperm retrieval rates were 35% at scos, 40% at maturation arrest, 31.03% at seminiferous tubules atrophy and 100% at hypospermatogenesis, which are consistent with current literature. as we grouped patients according to the histopathologic diagnoses, there was no correlation with sperm retrieval rates, pregnancy rates and live birth rates except in patients with hypospermatogenesis. the main paradox of the testis biopsy is the doubt about the histology of the rest of the testis. evaluation of serum fsh levels with testis histology can be a predictor for sperm retrieval in microtese. there was a correlation between low serum fsh and hypospermatogenesis at sperm retrieval; on the other hand, there was not any correlation between maturation arrest and scos. (3) in another study, a group of 17 men with hypospermatogenesis, 22 men with obstructive azoospermia and 29 men with normal spermatogenesis in whom sperm was retrieved successfully with microtese, there was no difference in serum fsh levels. (18) maturation arrest (50%) was the common pattern in the serum fsh normal group, and otherwise scos (51.1%) was the main group in the higher serum fsh group in our study. about 15% of couples have infertility problems.(2) the chances of having a pregnancy increases from the first month (25%) to a year (90%).(6) male factors play an important role in 50% of infertile couples.(7) today, microtese plus icsi gives the chance to have a baby to infertile couples.(8) many infertile couples who were considered desperate cases in past years may now have children with the rise of microtese and icsi techniques in clinical practice. while there are significant contributions of microtese procedures to infertility, it has a particular organic and psychological morbidity due to its invasiveness. for this reason, predictive markers are needed for the clinician to make decisions about the first or repetitive microtese. most of the past studies have focused specifically on testicular histology and serum fsh levels to make the decision about microtese. the present study focuses on whether any association between serum fsh, lh and testosterone levels, testicular histology and sperm retrieval, pregnancy and live birth rates. our threshold level for fsh was 15 miu/ml. some reports mentioned that we can’t retrieve sperm by microtese with higher serum fsh levels because of existing testicular atrophy. (9) ezeh and colleagues showed a weak correlation between serum fsh level and successful microtese. (10) no matter how high the serum fsh level that, there is always a chance to retrieve sperm.(11) in our study, the sperm retrieval rates at serum fsh normal group and serum fsh > 15 miu/ml group were 64.4% and 43%, respectively, and pregnancy and live birth rates were 16.9% and 8.33%, respectively. even if there was a statistically significant difference between sperm retrieval rates and serum fsh levels (p = .008), there was not such a correlation between serum fsh levels and pregnancy and live birth rates. ramasamy and colleagues reported that sperm retrieval rates in the groups with serum fsh values of 15-30 miu/ml, 31-45 miu/ml and > 45 miu/ml were 60%, 67% and 60%, respectively, and this was, surprisingly, higher than the normal serum fsh (51%) group.(4) variables serum fsh levels (miu/ml) p value ≤ 15 > 15 sperm retrieved 38/59 (66.1) 31/72 (43) .008 pregnancy rate 10/59 (16.9) 6/72 (8.33) .136 live birth rate 10/59 (16.9) 6/72 (8.33) .136 table 1. sperm retrieval, pregnancy and live birth rates compared between two groups.* variables sperm retrieval pregnancy occurrence child delivery yes (n = 69) no (n = 62) p value yes (n = 69) no (n = 62) p value yes (n = 69) no (n = 62) p value serum fsh (miu/ml) 17.48 ± 6.02 24.1 ± 15.8 .03 15.9 ± 14.3 21.2 ± 16.4 .655 15.9 ± 14.0 21.2 ± 16.4 .652 age (years) 37.5 ± 5.5 38.5 ± 7.8 .66 37.2 ± 5.9 38.1 ± 6.7 .457 37.4 ± 6.2 38.2 ± 6.6 .457 table 2. comparison of fsh levels and age according to the sperm retrieval, pregnancy and live birth rates. * data are presented as no. (%). 1827 sexual dysfunction and fertility urology journal vol. 11 no. 04 july august 2014 1828 10. ezeh ui, moore hd, cooke id. correlation of testicular sperm extra ction with morphological, biophysical and endocrine profiles in men with azoospermia due to primary gonadal failure. hum reprod. 1998;13:3066-74. 11. kim ed, gilbaugh jh 3rd, patel vr, turek pj, lipshultz li. testis biop sies frequently demonstrate sperm in men with azoospermia and signifi cantly elevated follicle-stimulating hormone levels. j urol. 1997; 157:144-6. 12. bohring c, schroeder-printzen i, weidner w, krause w. serum levels of inhibin b and follicle-stimulating hormone may predict successful sperm retrieval in men with azoospermia who are undergoing testicular sperm extraction. fertil steril. 2002;78:1195-8. 13. seo jt, ko wj. predictive factors of successful testicular sperm recovery in non-obstructive azoospermia patients. int j androl. 2001;24:306-10. 14. schlegel pn, su lm. physiological consequences of testicular sperm extraction. hum reprod. 1997;12:1688-92. 15. tunc l, kirac m, gurocak s, et al. can serum inhibin b and fsh levels, testicular histology and volume predict the outcome of testicular sperm extraction in patients with non-obstructive azoospermia? int urol neph rol. 2006;38:629-35. 16. su lm, palermo gd, goldstein m, veeck ll, rosenwaks z, schlegel pn. testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia: testicular histology can predict success of sperm retrieval. j urol. 1999;161:112-6. 17. tournaye h, liu j, nagy pz, et al. correlation between testicular histol ogy and outcome after intracytoplasmic sperm injection using testicular spermatozoa. hum reprod. 1996;11:127-32. 18. ballescá jl, balasch j, calafell jm, et al. serum inhibin b determination is predictive of successful testicular sperm extraction in men with non-obstructive azoospermia. hum reprod. 2000;15:1734-8. conclusion sperm retrieval, pregnancy and live child birth chances are better in serum fsh normal patients when compared to the serum fsh higher groups; however, statistical analyses showed no significant difference between both fsh groups concerning these three parameters. even though there is a relationship between sperm retrieval, pregnancy and live birth rates, and hypospermatogenesis, there are not statistically significant differences from the other histopathological diagnoses. conflict of interest none declared. references 1. griffin dk, finch ka. the genetic and cytogenetic basis of male inferti lity. hum fertil. 2005;8:19-26. 2. bhasin s, de kretser dm, baker hw. clinical review 64: pathophy siology and natural history of male infertility. j clin endocrinol metab. 1994;79:1525-9. 3. tournaye h, verheyen g, nagy p, et al. are there any predictive fac tors for successful testicular sperm recovery in azoospermic patients? hum reprod. 1997;12:80-6. 4. ramasamy r, lin k, gosden lv, rosenwaks z, palermo gd, schlegel pn. high serum fsh levels in men with nonobstructive azoospermia does not affect success of microdissection testicular sperm extraction. fertil steril. 2009;92:590-3. 5. world health organisation. who laboratory manual for the examinati on of human semen and sperm-cervical mucus interaction. 3rd ed. camb ridge, uk: cambridge university press; 1992. 6. jarow jp, sharlip id, belker am, et al. male infertility best practice policy committee of the american urological association inc. best pra ctice policies for male infertility. j urol. 2002;167:2138-44. 7. ceylan gg, ceylan c, elyas h. genetic anomalies in patients with seve re oligozoospermia and azoospermia in eastern turkey: a prospective study. genet mol res. 2009;8:915-22. 8. devroey p, liu j, nagy z, et al. pregnancies after testicular sperm ext raction and intracytoplasmic sperm injection in non-obstructive azoos permia. hum reprod. 1995;10:1457-60. 9. van steirteghem av, nagy p, joris h, et al. results of intracytoplasmic sperm injection with ejaculated, fresh and frozen thawed epididymal and testicular spermatozoa. hum reprod. 1998;13 suppl 1:134-42. histopathology number sperm retrieved pregnancy rate live birth maturation arrest 30 12 1 1 seminiferous tubules atrophy 29 9 2 2 sertoli cell only syndrome 40 14 3 3 normal histology 16 14 5 3 p values ---- .178 .198 .063 table 3. classification of sperm retrieval, pregnancy and live birth rates according to the histopathological findings. association of fsh on microtese success-yildirim et al urological oncology role of chronic inflammation as a predictor of upstaging/upgrading in prostate cancer: finding a new group eligible for active surveillance mohammad reza nowroozi, mohsen ayati, erfan amini, seyed majid aghamiri, seyed ali momeni, solmaz ohadian moghadam, farzin valizadeh* purpose: we aimed to investigate the correlation between presence of inflammation and pathology upgrading/ upstaging in patients with prostate cancer. materials and methods: a retrospective study was accomplished on 315 patients with prostate cancer, eligible for active surveillance except prostate-specific antigen (psa) level (psa<30ng/dl), who underwent radical prostatectomy between 2005 and 2015. patients were divided into two groups based on needle biopsy: a; with evidence of inflammation (chronic prostatitis) and b; without inflammation. the frequency of upstaging and upgrading in both groups was compared in different ranges of psa level (<10, 10-20 and 20-30ng/dl). upgrading/upstaging was defined as increase from one prognostic grade group to another. statistical analyses were performed to investigate the relation between inflammation and upgrading/upstaging. results: the mean age of the patients was 68.2 years and the mean psa level was 10.2 ng/ml. chronic prostatitis was identified in 82 of 315 cases therefore upgrading/upstaging were seen in only three patients (3.7%) while 39 of 233 (16.7%) patients without inflammation had upgrading/upstaging in final pathology (p = 0.003). other variables including the patient's psa before surgery, psa density, and the presence of hypoechoic areas in ultrasound had a significant relationship with the incidence of postoperative upgrading/upstaging. among studied variables, presence of inflammation in biopsies was found to be the most important predictor of upstaging/upgrading (or: 0.205). conclusion: our data demonstrated that patients with concurrent prostatitis and pca may have a better prognosis even if the psa level is higher than 10ng/ml. keywords: prostate cancer; chronic prostatitis; serum psa; active surveillance introduction prostate cancer is considered as the most common cancer and the second most common cause of cancer-related mortality in adult men and the incidence of disease is increasing globally(1, 2). due to widespread use of psa screening, the number of diagnosed prostate cancer patients has increased in recent years. however, many patients may receive unnecessary treatments for clinically localized and insignificant cancer(3, 4). active surveillance is considered as a management method for low-risk prostate cancer but the main challenge is to determine low risk prostate cancer patients. therefore, in order to achieve an accurate prediction of pathologic stage, it is necessary to have more sensitive markers and more accurate criteria. we conducted this study to evaluate baseline factors that might predict upstaging/upgrading in those who are candidates for active surveillance. one of the baseline characteristics that has the potential to predict upstaging/upgrading is the presence of chronic prostatitis in biopsy specimens. prostate specific antigen (psa) is elevated in patients with chronic prostatitis and this elevation though related to inflammation may erroneously exclude patients uro-oncology research center, tehran university of medical sciences, tehran, iran. *correspondence: uro-oncology research center, tehran university of medical sciences, tehran, iran. email: farzin259@gmail.com tel/fax: +98 21 66 43 79 69 received june 2019 & accepted december 2019 from active surveillance program(5-7). we hypothesized that presence of chronic prostatitis may overestimate the risk of disease and therefore patients with chronic prostatitis and higher serum psa levels who are otherwise appropriate for active surveillance may benefit from surveillance. patients and methods our institution prospectively records demographic, clinical, and pathological data for patients who undergo radical prostatectomy for prostate cancer. among all men who underwent radical prostatectomy between 2005 and 2015, 213 patients had psa ≤ 10 ng/ml, clinically localized prostate cancer (ct1), biopsy gleason score ≤ 6 and involvement of 2 cores or less and met inclusion criteria for active surveillance. patients with total biopsy cores less than 12 were excluded from analysis. in addition, 84 patients with psa level between 10 and 30 ng/ml who met the remaining criteria for active surveillance were also included in the analysis to assess the possibility of expanding criteria for active surveillance. upstaging and upgrading were defined as urology journal/vol 17 no. 4/ july-august 2020/ pp. 370-373. [doi: 10.22037/uj.v0i0.5375 ] pathologic stage ≥ t3 and presence of gleason pattern 4 in radical prostatectomy specimens. incidence of upstaging/upgrading was determined in both groups and the impact of baseline characteristics in predicting upstaging/upgrading was evaluated. all baseline characteristics including age, body mass index (bmi), pre-operative psa, prostate volume, psa density, transition zone volume, psa transition zone density, gleason score, presence of hypoechoic lesions in ultrasound and chronic inflammation in biopsy specimens were compared between patients with and without upstaging/upgrading. clinical staging was determined based on digital rectal exam findings, whole body bone scan and cross sectional imaging (mri or ct). in our institution, patients with low risk prostate cancer also routinely undergo bone scan and cross sectional imaging prior to surgery. chronic prostatitis was defined according to the consensus classification system proposed by nickel et al. and was defined as presence of multifocal stromal, glandular or periglandular infiltration with inflammatory cells, including lymphocytes, plasma cells and macrophages. multivariable analysis was also performed to assess which factors can independently predict upstaging/upgrading in each psa category. statistical analysis the results for quantitative variables were expressed as the mean and standard deviation (mean ± sd) and for qualitative variables as percentages. kolmogorov-smirnov (k-s) test was used to evaluate the normal distribution of quantitative variables. in the case of normal distribution, the comparison of the mean quantitative variables in two qualitative groups was done by independent t-test. the comparison between qualitative variables was done using chi-square test or fisher's exact test. furthermore, for examining the predictive power of variables, binary logistic regression analysis was done. data analyses were performed using package for social sciences (spss) version 16. the p values of < 0.05 were considered significant. results in this study, 273(87%) patients had no upstaging/upgrading postoperatively, and only 42 (13%) patients showed upstaging/upgrading. table 1 compares baseline characteristics between the study groups. as shown in the table, psa, psa density, presence of hypoechoic lesion and chronic prostatitis has the potential to predict upstaging/upgrading. upstaging/upgrading was more frequent among patients with hypoechoic lesion in ultrasound compared to those who did not show hypoechoic lesion (20.4% vs. 9.9% respectively; p = 0.010), whereas it was less frequent in patients with chronic prostatitis (3.7% upstaging/upgrading in patients with chronic prostatitis vs. 16.7% in patients without prostatitis, p = 0.003). in a second analysis, we assessed the impact of chronic prostatitis and hypoechoic lesions on predicting upstaging/upgrading in patients with psa>10 ng/ml. in patients with psa between 10 and 30 ng/ml, chronic prostatitis was significantly associated with upstaging/ upgrading. among 24 patients with chronic prostatitis and psa>10, only 2(8.3%) showed upstaging/upgrading whereas reclassification happened in 19 (31.7%) patients without prostatitis (p = 0.026). we found no statistically significant association between hypoechoic lesions and upstaging/upgrading in patients with serum psa>10. multivariable logistic regression analysis also showed that serum psa level, presence of hypoechoic lesions and chronic prostatitis can independently predict upstaging/upgrading in potential candidates for prostate cancer active surveillance. table 1. comparing baseline characteristics between study groups. upstaging/upgrading p-value present absent age mean(sd) 69.5(9.0) 68.0(8.2) 0.29* bmi mean(sd) 25.23(4.02) 25.58(3.39) 0.37* prostate volume mean(sd) 38.60(17.77) 35.52(17.87 0.21* psa mean(sd) 15.33(8.32) 9.46(4.84) < 0.001* psa density mean(sd) 0.47(0.36) 0.33(0.21) 0.039* psa transition zone density mean(sd) 0.99(1.71) 0.72(2.51) 0.238* hypoechoic lesion in transrectal ultrasound number (%) present 21(20.4) 82(79.6) 0.010† absent 21(9.9) 191(90.1) chronic prostatitis in biopsy specimen number (%) present 3(3.7%) 79(96.3%) 0.003† absent 39(16.7%) 194(83.3%) * independent t-test † chi-square test hazard ratio (95% ci) p-value psa ≤10 ng/ml (referent) 3.517 (1.757-7.039) < 0.001 10-30 hypoechoic lesion absent (referent) 2.231(1.120-4.443) 0.022 present inflammation absent (referent) 0.171(0.050-0.580) 0.005 present table 2. binary logistic regression analysis to determine independent predicting factors of upgrading/upstaging. prostatitis in prostate cancer surveillance-nowroozi et al. vol 17 no 04 july-august 2020 371 discussion in the present study we showed that presence of chronic inflammation in association with prostate cancer in biopsy specimens may be a predictor of low risk disease and many of these patients can be a suitable candidate for as regardless of serum psa level. it also should be considered that there is no consensus on the role of psa level in predicting outcomes and gs is considered as the most important factor for treatment decision making(11). therefore, in contrast to epstein’s criteria for as, some patients with elevated serum psa level, even those with psa between 20 and 30, may be suitable candidate for as. in the current study, the upgrading/upstaging rate between patients with preoperative psa level less than 10 ng/ml and patients with psa level between 10 and 20 ng/ml had a significant difference. however, those with chronic inflammation had a significantly lower risk of upstaging/upgrading. the previous study by faisal et al., showed that patients with psa between 10 and 20 ng/ml could not be considered as suitable candidates for the active surveillance management strategy. moreover, they suggested that concurrent existence of prostate cancer and prostatitis may make these patients candidates for as(12). moreover, those with psa density < 0.15 ng/ml/gr are appropriate cases for as. this simply means patients with more prostate volume will be less likely to be at risk(12). besides, kwak et al. have shown that increased prostate volume was associated with the severity of inflammation(13). on the other hand, jiwoon yu et al., concluded that upstaging/upgrading in patients with psa level >20 ng/ml was significantly higher than patients with a psa level <20 ng/ml(14). however, spahn m et al., suggested that 10 year mortality rate for prostate cancer with psa >20 ng/ml and gleason score ≤7 or gs>7 is 5% and 35% respectively(15). considering histological inflammation in needle biopsy sample and serum psa level of non-prostate cancer men, okada k et al. proposed that aging, prostate volume and histological evidence of inflammation were significantly associated with increased levels of psa, especially in those with a larger prostate(15). this was in contrary to the study of chang sg et al., in which they found that the chronic inflammation of prostate is not associated with increased psa level and prostate volume mentioned as the most important cause of increased serum psa levels in patients with negative prostate biopsy for cancer(17). our results revealed that among studied factors, presence of inflammation as well as hypoechoic areas in ultrasound, and psa are the parameters that are significantly associated with upstaging/upgrading. additionally, binary logistic regression showed that the presence of inflammation and hypoechoic lesions are independent factors that have the potential for predicting upgrading/upstaging. the retrospective nature was one of the limitations of the current study. conclusions our study showed that the presence of inflammation in biopsies as well as presence of hypoechoic areas in ultrasound are independent predictors of upstaging/upgrading. the presence of inflammation in the prostate tissue is associated with a reduced risk of prostate cancer. therefore, concurrent prostatitis and an elevated psa level (>10 ng/ml) can lead to an error in selection of patients for the as strategy. acknowledgements we give special thanks to all members of uro-oncology research center for helpful discussions and friendly support. this research has been supported by tehran university of medical sciences, tehran, iran. conflict of interest the authors report no conflict of interest. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2018. ca: ca cancer j clin. 2018;68(1):7-30. 2. pishgar f, haj-mirzaian a, ebrahimi h, saeedi moghaddam s, mohajer b, nowroozi mr, et al. global, regional and national burden of testicular cancer, 1990-2016: results from the global burden of disease study 2016. bju international. 2019;124(3):386-94. 3. carroll pr. early stage prostate cancer—do we have a problem with over-detection, overtreatment or both? the j urol. 2005;173(4):1061-2. 4. cooperberg mr, broering jm, kantoff pw, carroll pr. contemporary trends in low risk prostate cancer: risk assessment and treatment. j urol. 2007;178(3 pt 2):s14-9. 5. hoekx l, jeuris w, van marck e, wyndaele jj. elevated serum prostate specific antigen (psa) related to asymptomatic prostatic inflammation. acta urol belg. 1998;66(3):12. 6. nickel jc. clinical evaluation of the man with chronic prostatitis/chronic pelvic pain syndrome. urology. 2002;60(6 suppl):20-2; discussion 2-3. 7. nadler rb, humphrey pa, smith ds, catalona wj, ratliff tl. effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels. j urol. 1995;154(2 pt 1):407-13. 8. krieger jn, riley de, cheah py, liong ml, yuen kh. epidemiology of prostatitis: new evidence for a world-wide problem. world j urol. 2003;21(2):70-4. 9. klotz l. active surveillance for prostate cancer: for whom? j clin oncol : official journal of the american society of clinical oncology. 2005;23(32):8165-9. 10. klotz l, zhang l, lam a, nam r, mamedov a, loblaw a. clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. j clin oncol : official journal of the american society of clinical oncology. 2010;28(1):126-31. 11. reese ac, pierorazio pm, han m, partin aw. contemporary evaluation of the national urological oncology 372 prostatitis in prostate cancer surveillance-nowroozi et al. comprehensive cancer network prostate cancer risk classification system. urology. 2012;80(5):1075-9. 12. faisal fa, sundi d, pierorazio pm, ball mw, humphreys eb, han m, et al. outcomes of men with an elevated prostate-specific antigen (psa) level as their sole preoperative intermediateor high-risk feature. bju international. 2014;114(6b):e120-e9. 13. kwak c, ku jh, kim t, park dw, choi ky, lee e, et al. effect of subclinical prostatic inflammation on serum psa levels in men with clinically undetectable prostate cancer. urology. 2003;62(5):854-9. 14. yu j, kwon ys, kim s, han cs, farber n, kim j, et al. pathological outcome following radical prostatectomy in men with prostate specific antigen greater than 10 ng/ml and histologically favorable risk prostate cancer. j urol. 2016;195(5):1464-70. 15. okada k, kojima m, naya y, kamoi k, yokoyama k, takamatsu t, et al. correlation of histological inflammation in needle biopsy specimens with serum prostatespecific antigen levels in men with negative biopsy for prostate cancer. urology. 2000;55(6):892-8. prostatitis in prostate cancer surveillance-nowroozi et al. vol 17 no 04 july-august 2020 373 sexual dysfunction and infertility 106 urology journal vol 5 no 2 spring 2008 intracytoplasmic sperm injection outcome using ejaculated sperm and retrieved sperm in azoospermic men tahira naru,1 m nasir sulaiman,2 atiya kidwai,3 m hammad ather,2 sana waqar,4 saadia virk,1 javed h rizvi1 introduction: we aimed to determine pregnancy and miscarriage rates following intracytoplasmic sperm injection (icsi) cycles using retrieved epididymal and testicular sperm in azoospermic men and ejaculated sperm in oligospermic and normospermic men. materials and methods: this retrospective study was carried out on 517 couples who underwent icsi. they included 96 couples with azoospermia and 421 with oligospermia or normal sperm count in the male partner. of the men with azoospermia, 69 underwent percutaneous epididymal aspiration (pesa) and 47 underwent testicular sperm extraction (tese). in the 421 men with oligospermia or normal sperm count, ejaculated sperm was used for icsi. the differences in the outcomes of icsi using pesa or tese and ejaculated sperm were evaluated. the main outcome measures were pregnancy and miscarriage rates. results: no significant differences were seen in pregnancy and miscarriage rates with surgically retrieved and ejaculated sperm. the pregnancy rates (including frozen embryo transfer) were 43.5%, 36.2%, and 41.4% in couples with pesa, tese, and ejaculated sperm, respectively (p = .93). the miscarriage rates were 16.7%, 23.5%, and 12.1%, respectively (p = .37). conclusion: intracytoplasmic sperm injection in combination with pesa and tese is an effective method and can successfully be performed to treat men with azoospermia. the outcomes with these procedures are comparable to icsi using ejaculated sperm. urol j. 2008;5:106-10. www.uj.unrc.ir keywords: azoospermia, sperm retrieval, intracytoplasmic sperm injection, fertilization 1department of obstetrics and gynecology, aga khan university, karachi, pakistan 2department of urology, aga khan university, karachi, pakistan 3unit of embryology in concept fertility centre, clifton, karachi, pakistan 4aga khan university, karachi, pakistan corresponding author: tahira naru, md department of obstetrics and gynecology aga khan university hospital stadium road, karachi po box 3500 karachi-74800, pakistan tel: +92 21 486 4647 fax: +92 21 493 4294 email: tahira.naru@aku.edu received march 2008 accepted may 2008 introduction azoospermia, the absence of sperm in ejaculated semen, is the most severe form of male-factor infertility. it affects approximately 5% of all men and accounts for onethird of all male-factor infertility cases.(1) prior to the availability of assisted reproductive techniques, the use of donor sperm was the only option offering the realistic chance of conception for couples affected by azoospermia or severe oligospermia. over the past 2 decades, the availability of surgical sperm retrieval methods and introduction of intracytoplasmic injection (icsi) in assisted reproduction have been landmark achievements in the treatment of severe male-factor infertility.(2,3) several surgical techniques have been used to retrieve sperm for assisted reproduction, including microsurgical epididymal sperm retrieval in azoospermic men—naru et al urology journal vol 5 no 2 spring 2008 107 aspiration, percutaneous epididymal aspiration (pesa), testicular sperm extraction (tese), and testicular sperm aspiration.(4) percutaneous epididymal sperm aspiration, a less invasive procedure for retrieval of epididymal spermatozoa, can be performed under local anesthesia.(5) if pesa fails, then tese can also be attempted, as it has been shown to be an efficient minimally invasive method.(6) it has been shown that hormone level and testicular histology are unable to predict which men with azoospermia will have sperm retrieved by pesa or tese.(7) there are few published studies comparing the results of icsi between epididymal or testicular retrieved sperm and ejaculated sperm.(8,9) the aim of this study was to compare the outcomes of icsi cycles using pesa or tese in azoospermic men with those using ejaculated sperm in oligospermic and normospermic men. materials and methods patients this retrospective study was carried out in a private center for assisted reproduction from january 2004 to december 2006. the cohort included 517 infertile couples treated by icsi. these included 96 couples with azoospermia and 421 with oligospermia or normal sperm count in the male partner, according to the world health organization criteria.(10) a total of 116 successful retrieval procedures were performed in the 96 azoospermic men, 69 of which were pesa and 47 were tese procedures. in the 421 men with oligospermia or normal sperm count, 437 icsi cycles were performed using ejaculated sperm. procedures all men presenting with infertility who had azoospermia on at least 2 semen analyses were further evaluated. the patients had a comprehensive history taken followed by physical examination including inguinoscrotal examination. testicular volume was determined by a prader orchidometer and the status of the epididymis and the presence or absence of vas deferens was noted. hormone levels including follicle-stimulating hormone were evaluated in all azoospermic men. other tests for hormones such as serum levels of testosterone, luteinizing hormone, and prolactin were done more selectively as dictated clinically. if there was suspicion of obstructive azoospermia, further evaluation, including transrectal ultrasonography, was performed to rule out ejaculatory duct obstruction. all men with azoospermia were counseled for need of further workup including genetic testing. data, however, is not included in the present analysis due to its lack of direct bearing on the objectives of the study. patients with a testicular volume of 15 ml or greater underwent a diagnostic pesa. if no spermatozoon was found, tese under the same local or general anesthesia was performed. on confirmation of the spermatozoa on pesa or tese, the couple was counseled to undergo therapeutic pesa or tese on the day of ovum pickup. cycle treatment with controlled ovarian hyperstimulation was started 6 to 8 weeks after the diagnostic procedure. percutaneous epididymal aspiration was performed on an outpatient basis under local or general anesthesia. negative pressure was utilized with a 27.5-gauge insulin syringe prefilled with 0.1 ml of 4-(2-hydroxyethyl)-1piperazineethanesulfonic acid-buffer human tubal fluid. in order to aspirate the maximum quantity of material possible, the needle was directed into the most prominent part of the epididymal head. the sample was further divided using 2 needles of 1 ml (29 gauge) and examined under a magnification of × 400 in the microscope for the presence of sperm cells. discontinuous density gradients (isolation) were used in all cases to separate spermatozoa and spermatids. the gradient scales and compositions applied were 3 minidensity gradients containing volumes of only 0.3 ml to 0.5 ml of different density gradient materials (50%, 70%, and 85% isotonic solutions). after centrifugation (300 rpm), another medium bath was made up (0.3 ml) into a pelletcontaining spermatozoa. all metaphase ii oocytes were injected for icsi according to the standard protocols. ovarian stimulation was performed using long protocol of standard technique of gonadotropinreleasing hormone agonist downregulation and sperm retrieval in azoospermic men—naru et al 108 urology journal vol 5 no 2 spring 2008 controlled stimulation with recombinant folliclestimulating hormone. cycle was monitored by ultrasonography and estradiol levels from the 7th day of stimulation. once the follicular sizes exceeded 1.7 × 1.7 cm, ovum pickup under general anesthesia and ultrasonographic control was conducted 36 hours after injection of human chorionic gonadotropin. the total number of oocytes retrieved in a cycle was 10 or more. on the same day, sperm retrieval was performed by pesa or tese. after retrieval and preparation of an adequate number of sperm, icsi was performed on mature eggs. fertilization was confirmed 24 hours later and embryo transfer was performed on day 3 of ovum pickup. the number of embryos transferred was 2 to 3 per cycle. only high-quality embryos (grades 1 and 2) were transferred. if more than 3 good embryos were left after embryo transfer, they were cryopreserved, thawed, and transferred in frozen embryo transfer cycle. statistical analyses data were analyzed using the spss software (statistical package for the social sciences, version 14.0, spss inc, chicago, ill, usa). results were expressed as mean ± standard deviation for continuous variables. the independent sample t test was used to compare the mean differences in testicular volume and ages of each partner between pesa and tese groups. the chi-square test was used to compare presence of vas deferens, pregnancy rate, and miscarriage rate between the groups of couples. a p value less than .05 was considered significant. results the mean ages of men in the pesa and tese groups were 36 ± 8 years and 37 ± 7 years, respectively. while the mean ages of the male and female partners in the pesa and tese groups were not significantly different (table 1), those of the couples with normal sperm count or oligospermia in the male partner were slightly higher (31 ± 5 years and 41 ± 6 years, respectively). the mean testicular volume was not significantly different between the two groups of pesa and tese as shown in table 1. the average fertilization rate in our private center is 80% and the average implantation rates for icsis with pesa, tese, and ejaculated sperm are 20%, 18.8%, and 18.2%, respectively. the pregnancy rates after pesa-icsi and tese-icsi were 43.5% and 36.2%, respectively. these were comparable with the pregnancy rate achieved with ejaculated sperm (41.4%; p = .93). there was no significant difference in miscarriage rates between the three groups of couples (table 2). overall, 38 normal deliveries yielded birth of 54 babies in the pesa/tese group and 159 normal deliveries led to birth of 226 babies in the ejaculated sperm group. the rates of multiple pregnancies were not significantly different between the two groups with pesa/tese and parameters pesa tese ejaculated sperm p treatment cycles† 69 47 437 … number of couples 53 43 421 … frozen embryo transfer cycles 18 3 65 … pregnancy 30 (43.5) 17 (36.2) 181 (41.4) 0.93 miscarriage‡ 5 (16.7) 4 (23.5) 22 (12.1) 0.37 table 2. pregnancy and miscarriage rates after intracytoplasmic sperm injection using sperm supplied by percutaneous epididymal aspiration (pesa), testicular sperm extraction (tese), and ejacutaion* *ellipses indicate not applicable. values in parentheses are percents. †treatment cycles included transvaginal ovum pickup plus embryo transfer. ‡percentages are calculated with the number of pregnancies as denominator. characteristics pesa tese p number of couples 53 43 … mean age, y male partner 36 ± 8 37 ± 7 .52 female partner 29 ± 6 29 ± 6 .99 testicular volume, ml 15.07 ± .71 15.02 ± .77 .74 presence of vas deferens 34 (64.1) 27 (62.8) .89 number of cycles treated 69 47 … table 1. characteristics in couples with azoospermic malefactor infectility who underwent percutaneous epididymal aspiration (pesa) and testicular sperm extraction (tese)* *ellipses indicate not applicable. values in parentheses are percents. sperm retrieval in azoospermic men—naru et al urology journal vol 5 no 2 spring 2008 109 ejaculated sperm (table 3). the total number of women who got pregnant after pesa/tese cycles in all age groups was 47/116 (40.5%). a higher pregnancy rate was achieved among female partners with an age between 20 and 29 years, and those older than 35 years had a significantly lower conception rate. the same results were found in the group of the couples with ejaculated sperm (table 4). discussion the approach to azoospermic patients has changed significantly with the introduction of sperm retrieval techniques and assisted reproduction, especially the icsi. in addition to improving pregnancy rates using sperm from ejaculated semen, icsi has opened new possibilities for achieving pregnancy with sperm retrieved from the epididymes or testes which have been performed for more than 10 years. satisfactory results have been achieved in various studies using these techniques.(2,3,11) the results of this study showed that there was no significant difference in the treatment outcome following icsi using surgically retrieved sperm (pesa/tese) and ejaculated sperm. pregnancy rates of 43.5% and 36.2% from pesa-icsi and tese-icsi were similar to that of 41.4% found in the cases of icsi with ejaculated sperm. the miscarriage rate was 16.7% and 23.5% in pesa and tese, whereas in icsi cycles with ejaculated sperm the miscarriage rate was 12.0% (p = .37). there was also no significant difference in miscarriage rates between pesa and tese groups (p = .85). other researchers have reported that the use of testicular sperm leads to a higher spontaneous miscarriage rate.(12,13) on the other hand, aboulghar and colleagues and other authors did not find any significant difference between the treatment results following icsi with ejaculated sperm and with epididymal sperm.(8,9) a recent meta-analysis of surgical sperm retrieved in azoospermic patients, however, concluded that sperm origin does not affect cycle outcome.(14) age of the female partner, however, has been shown to exert substantial influence on the success of icsi treatment. in line with our findings, devroey and associates found that the delivery rate in women younger than 40 years was 25.4%, while in those older than 40 years, it was 8.5%.(15) silber and colleagues also reported low delivery rate in women aged more than 37 years. (16) of the other factors considered for prediction of successful icsi are hormone profile, testicular volume, and histopathology findings; few studies have reported that these parameters are unable to predict which procedure would be successful in azoospermic men.(7,17) in our study, the main emphasis was on genital examination to measure the testicular volume with orchidometer, the status of epididymis, and presence or absence of the vas deferens. we used pesa procedure as a diagnostic technique in all azoospermic men. it is parameters pesa tese ejaculated sperm p successful delivery 25 13 159 … twins 7 (28.0) 5 (38.5) 43 (27.0) 0.68 triplets 1 (4.0) 1 (7.7) 12 (7.5) 0.81 multiple pregnancy rate, % 32.0 46.2 34.6 0.66 table 3. multiple pregnancies following intracytoplasmic sperm injection using sperm supplied by percutaneous epididymal aspiration (pesa), testicular sperm extraction (tese), and ejaculation* *ellipses indicate not applicable. values in parentheses are percents. pesa/tese ejaculated sperm age, y patients pregnancy (%) patients pregnancy (%) 20 to 29 52 29 (55.8) 161 81 (50.3) 30 to 35 28 15 (53.6) 127 63 (49.6) > 35 16 3 (18.7) 133 37 (27.8) table 4. pregnancy rates according to age groups of female partners* *frozen embryo transfer cycles are included in the rates. pesa indicates percutaneous epididymal aspiration and tese, testicular sperm extraction. sperm retrieval in azoospermic men—naru et al 110 urology journal vol 5 no 2 spring 2008 desirable to perform a diagnostic pesa procedure before planning an icsi and committing resources to ovulation induction treatment and to select the patients with greater chance of successful retrieval. this facilitates counseling of couples and has financial and medicolegal benefits, as well. as pregnancy rates are acceptable in men with azoospermia, icsi associated with sperm retrieval techniques should be employed in assisted reproduction centers. it allows good pregnancy rates in relation to patients with azoospermia. on the basis of our results, pesa should be the first option offered to patients. if spermatozoa cannot be recovered, tese can be offered. conclusion in conclusion, our study confirms that minimally invasive techniques of pesa and tese can be successfully performed to retrieve sperm for icsi in the treatment of azoospermic men. it should be emphasized that icsi for the treatment of severe male-factor infertility is especially important in our culture, because the use of donor spermatozoa is forbidden. the result of this study indicates that treatment outcomes of pesa/tese-icsi including frozen embryo transfer cycles compare favorably with that of icsi using ejaculated sperm. conflict of interest none declared. references 1. irvine ds. epidemiology and aetiology of male infertility. hum reprod. 1998;13 suppl 1:33-44. 2. palermo g, joris h, devroey p, van steirteghem ac. pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. lancet. 1992;340:17-8. 3. palermo gd, schlegel pn, hariprashad jj, et al. fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. hum reprod. 1999;14:741-8. 4. khorram o, patrizio p, wang c, swerdloff r. reproductive technologies for male infertility. j clin endocrinol metab. 2001;86:2373-9. 5. craft i, tsirigotis m, bennett v, et al. percutaneous epididymal sperm aspiration and intracytoplasmic sperm injection in the management of infertility due to obstructive azoospermia. fertil steril. 1995;63:103842. 6. silber sj, van steirteghem ac, liu j, nagy z, tournaye h, devroey p. high fertilization and pregnancy rate after intracytoplasmic sperm injection with spermatozoa obtained from testicle biopsy. hum reprod. 1995;10:148-52. 7. ou jp, zhuang gl, zhou cq, et al. [sperm retrieval methods and pregnancy outcome of 100 azoospermia patients]. zhonghua nan ke xue. 2002;8:258-60. chinese 8. meniru gi, gorgy a, batha s, clarke rj, podsiadly bt, craft il. studies of percutaneous epididymal sperm aspiration (pesa) and intracytoplasmic sperm injection. hum reprod update. 1998;4:57-71. 9. aboulghar ma, mansour rt, serour gi, et al. fertilization and pregnancy rates after intracytoplasmic sperm injection using ejaculate semen and surgically retrieved sperm. fertil steril. 1997;68:108-11. 10. world health organization. who laboratory manual for the examination of human semen and semencervical mucus interaction. 3rd ed. cambridge: cambridge university press; 1992. 11. palermo gd, cohen j, alikani m, adler a, rosenwaks z. intracytoplasmic sperm injection: a novel treatment for all forms of male factor infertility. fertil steril. 1995;63:1231-40. 12. ghazzawi im, sarraf mg, taher mr, khalifa fa. comparison of the fertilizing capability of spermatozoa from ejaculates, epididymal aspirates and testicular biopsies using intracytoplasmic sperm injection. hum reprod. 1998;13:348-52. 13. pasqualotto ff, rossi-ferragut lm, rocha cc, iaconelli a, jr., borges e, jr. outcome of in vitro fertilization and intracytoplasmic injection of epididymal and testicular sperm obtained from patients with obstructive and nonobstructive azoospermia. j urol. 2002;167:1753-6. 14. nicopoullos jd, gilling-smith c, almeida pa, normantaylor j, grace i, ramsay jw. use of surgical sperm retrieval in azoospermic men: a meta-analysis. fertil steril. 2004;82:691-701. 15. devroey p, godoy h, smitz j, et al. female age predicts embryonic implantation after icsi: a casecontrolled study. hum reprod. 1996;11:1324-7. 16. silber sj, nagy z, devroey p, camus m, van steirteghem ac. the effect of female age and ovarian reserve on pregnancy rate in male infertility: treatment of azoospermia with sperm retrieval and intracytoplasmic sperm injection. hum reprod. 1997;12:2693-700. 17. su lm, palermo gd, goldstein m, veeck ll, rosenwaks z, schlegel pn. testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia: testicular histology can predict success of sperm retrieval. j urol. 1999;161:112-6. 1232 | department of uro-oncology, imam khomeini hospital, tehran university of medical sciences, tehran, iran. hassan jamshidian, mohsen hashemi, mohammad reza nowroozi, mohsen ayati, mahdieh bonyadi, vahid najjaran tousi sensitivity and specificity of urinary hyaluronic acid and hyaluronidase in detection of bladder transitional cell carcinoma corresponding author: vahid najjaran tousi, md department of uro-oncology, imam khomeini hospital, tehran university of medical sciences, tehran, iran. tel: +98 912 380 1237 fax: +98 21 6658 1627 e-mail: najjaran_vahid@yahoo.com received january 2011 accepted june 2011 purpose: to the assess sensitivity and specificity of urinary levels of hyaluronic acid (ha) and hyaluronidase (haase) as an individual or a combined test to diagnose bladder transitional cell carcinoma (tcc). materials and methods: one hundred and ninety-four urine specimens were collected from individuals between july 2007 and march 2008. the urinary level of hyaluronic acid (ha) was measured by enzyme-linked immunosorbent assay. thereafter, the urinary levels of ha and haase were normalized to urinary creatinine level and expressed as ng/mg and µ/mg. results: eighty percent of patients with bladder cancer had urinary ha level < 500 ng/mg, and 90% of controls showed ha level < 500 ng/mg (p < .001). the mean urinary levels of ha in controls did not vary significantly (p < .05), whereas they significantly increased (2.5 to 6.5 folds) in all grades of tcc. more than 80% of patients with grades 2 and 3 tcc had urinary haase level < 10 µ/mg and over 80% of controls showed haase level < 10 µ/mg (p < .05). hyaluronidase levels increased in patients with grades 2 and 3 bladder tcc. conclusion: measurement of urinary levels of ha and haase (with 89% sensitivity and 83% specificity) appears to be a highly accurate and non-invasive method for detecting bladder tcc and evaluating its grade. keywords: hyaluronic acid; diagnostic errors; urinary bladder neoplasms; transitional cell; neoplasm grading. urological oncology urological oncology 1233vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l introduction genitourinary cancers are among the most common cancers in men and the fifth most common one in women.(1) transitional cell carcinoma of the bladder (tcc) is the second most common malignancy of the urinary tract.(2) approximately, 54 000 new cases of bladder cancer are diagnosed annually in the united states.(3) despite successful treatment of the initial tumor, bladder tumors frequently recur; hence, close follow-up of patients is mandatory.(4) therefore, early detection of bladder cancer affects prognosis of patients with bladder cancer. current standard methods for detection and follow-up of the bladder cancer consist of cystoscopy, urine cytology, and biopsy from the suspicious area.(5) the gold standard method is the combination of cystoscopy and biopsy, but it is invasive and expensive.(6) urine cytology is easy to perform, but is particularly insensitive in detection of grade 1 (g1) and grade 2 (g2) tumors.(7) biochemical measurement of soluble markers in urine, such as nuclear matrix protein 22 (nmp22), bladder tumor antigen (bta), urinary bladder cancer (ubc), and fibrinogen degradation product (fdp) were also investigated, but they cannot replace cystoscopy. such measurements are non-invasive and can be performed frequently, but could not be useful except in combination with cystoscopy.(8-10) hyaluronic acid (ha) is an unsulfated anionic linear glycosaminoglycan polymer composed of a repeating glucuronic acid and n-acetylglucosamine disaccharide motif.(11) it is a substrate of cell adhesion and originally stimulates angiogenesis. as a result, ha plays a key role in promoting of tumor invasion.(12) some prostatic histopathologies indicated that ha content of the stroma increased in benign prostatic hyperplasia.(13) hyaluronidase (haase) is an endoglycosidase enzyme that predominantly degrades ha.(14) some studies show that haase is involved in tumor growth, muscle infiltration by tumor, and tumor angiogenesis.(15,16) in this study, we simultaneously measured urinary levels of ha and haase to examine the sensitivity and specificity of these markers as an individual or combined test to detect bladder cancer (tcc) and evaluate its grade. materials and methods urine specimens in this cross-sectional study, 194 voided urine specimens were collected from individuals between july 2007 and march 2008. the study was approved by the medical ethics committee of tehran university of medical sciences, and a written informed consent was obtained from each participant. samples were obtained using clean-catch method and stored at 20ºc. the samples were divided into two groups as follows: group 1 (cases, n = 97), which included patients with bladder cancer; group 2 (controls, n = 97), which was subdivided into three groups, normal individuals (n = 19), those with other genitourinary diseases (n = 51), and patients with a history of tcc, but without active tumor (n = 27). characteristics of patients and controls are demonstrated in table 1. table 2 shows clinicopathological characteristics of patients with tcc. tissue extraction fresh tissue specimens were obtained from individuals undergoing cystoscopy. transurethral resection-biopsy was performed on patients with bladder tumor. enzyme-linked immunosorbent assay the urinary level of ha was measured by enzyme-linked immunosorbent assay. with this method, plates coated with 200 µg/ml ha were incubated with using serial dilutions of urine specimens in hyaluronidase assay buffer at 37°c for 16 to 18 hours. following incubation, the degraded ha was washed off and ha remaining in the wells was quantitated using a biotinylated ha-binding protein. thereafter, the urinary levels of ha and haase were normalized to urinary level of creatinine and were expressed as ng/mg and µ/mg. statistical analyses data are presented as mean ± sd. data were analyzed with spss software (the statistical package for the social sciences, version 10.0, spss inc., chicago, illinois, usa). sensitivity, specificity, and accuracy were calculated as follows: sensitivity: test positive/total number of patients with tcc specificity: test negative/total number of individuals without bladder cancer accuracy: number of true positive + number of true negative/ total number of studied individuals results urinary levels of ha were very similar in normal individuals (206 ± 28 ng/mg), patients with genitourinary diseases (317 ± 87 ng/mg), and those with history of bladder cancer (377 ± urinary hyaluronic acid and bladder tcc | jamshidian et al 1234 | 37 ng/mg) (p < .05). cut-off limit was set at 500 ng/mg for the ha test for detection of bladder cancer. in the majority of individuals in these three groups, the urinary level of ha was less than 500 ng/mg. however, it increased in patients with the bladder cancer (1119 ± 127 ng/mg), regardless of the tumor grade (i.e., g1, g2, and g3) (p < .05). the mean urinary levels of ha in control group do not vary significantly (p < .05), whereas they significantly increased (2.5 to 6.5 folds) in patients with all grades of tcc (table 3). eighty percent of patients with the bladder cancer had urinary ha level < 500 ng/mg, and 90% of controls showed ha level < 500 ng/ mg (tables 4 and 5). the differences in the mean ha levels in patients with tcc (g1 to g3) (1119 ± 127 ng/mg) and in controls were statically significant (p < .001). ten µ/mg was set as cut-off point for the haase test for detecting tcc g2 and g3. distribution of urinary levels of haase among normal subjects (3.4 ± 1.8 μ/mg), patients with genitourinary diseases (20.3 ± 2.1 μ/mg), patients with history of bladder cancer (6.7 ± 2.1 μ/mg), and patients who had tcc g1 at the time of recruitment (7.3 ± 1.4 μ/mg) was very similar. furthermore, haase levels in majority of individuals in this category were less than 10 µ/mg. however, they increased (3 to 7 folds) in patients with tcc g2 (22.1 ± 5.3 μ/mg) and g3 (28.1 ± 4.3 μ/mg). more than 80% of patients with tcc g2 and g3 had urinary haase level < 10 µ/mg and more than 80% of controls showed haase level < 10 µ/mg (p < .05). the data obtained by ha and haase tests for each study specimen were combined and analyzed as a “combined ha-haase test” for detecting tcc. the cut-off points for the combined ha-haase test were the same as an individual one. any individual with urinary level above the mentioned cut-off point (separately or in combination) was considered positive on the combined ha-haase test. the data showed that more patients with tcc had positive hatable 1. characteristics of study subjects. group male, no. (%) female, no. (%) total, no. (%) average ,age years cases 68 (70) 29 (30) 97 (100) 63 (34-91) controls normal 13 (13.4) 6 (6.2) 19 (19.6) 59.7 (51-69) history of tcc 19 (19.6) 8 (8.2) 27 (27.8) 63 (50-76) other gu disease 60 (35-85) bph 12 (12.3) 12 (12.3) renal stone 5 (5.2) 8 (8.2) 13 (13.4) interstitial cystitis 1 (1) 1 (1) ureterocele 1 (1) 1 (1) urethral stricture 3 (3.1) 3 (3.1) renal cell carcinoma 5 (5.2) 2 (2.1) 7 (7.3) prostate cancer 3 (3.1) 3 (3.1) bladder diverticulum 2 (2.1) 2 (2.1) tuberculosis 1 (1) 1 (1) bladder stone 4 (4.1) 1 (1) 5 (5.1) upjo 1 (1) 2 (2.1) 3 (3.1) key: tcc, transitional cell carcinoma; bph, benign prostate hyperplasia; upjo, ureteropelvic junction obstruction. table 2. distribution of tcc with respect to tumor grade and stage (%). grade ta cis t1 t2 t3 g1 24.8 0 1 4.1 0 g2 9.3 7 (21.2) 0 0 0 g3 5.2 5.2 6.2 11.3 16.5 key: tcc, transitional cell carcinoma. urological oncology 1235vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l haase test than on individual ha and haase tests. these results indicated that ha-haase test was more sensitive and less specific than individual tests alone (table 6). discussion measurement of urinary levels of ha and haase (ha-haase test) appears to be a highly accurate and non-invasive method for detecting bladder tcc and evaluating its grade. furthermore, none of them require complex technical skills or equipments and small quantity of urine specimen (50 ml urine) is adequate for both ha and haase tests. an interesting finding was that 3 patients with g1 showed positive haase test, but a negative ha test. although these were considered as “falsepositive” on haase test, 2 of them developed g2 tumor 3 to 6 months later. tumor volume also can affect the results. for example, a large-volume tumor would ensure to secrete much amount of any marker in urine, but this investigation suggests that outcome of ha-haase test is not influenced by the tumor volume. for instance, sensitivity of ha-haase test to detect carcinoma in situ (cis) is 80%, but carcinoma in situ seldom presents with high volume tumor. our finding that haase test preferentially detect g2 and g3 tumors is consistent with previous studies demonstrating that haase secretion is associated with invasive/metastatic potential of tumor cells.(14) combined test can detect both tcc g1-ta and cis with high sensitivity.(7) in a study, the urinary levels of ha and haase were measured in 513 urine specimens. the ha test showed 83.1% sensitivity, 90.1% specificity, and 86.5% accuracy to detect bladder cancer, regardless of the tumor grade and the haase test demonstrated 81.5% sensitivity, 83.8% specificity, and 82.9% accuracy in detecting g2 and g3,(17) which urinary hyaluronic acid and bladder tcc | jamshidian et al table 3. mean concentrations of ha and haase in each group category ha (ng/mg) haase (µ/mg) tcc 1119 ± 127 20.3 ± 2.1 g1 893 ± 105 7.3 ± 1.4 g2 1177 ± 95 22.1± 5.3 g3 1238 ± 115 28.1± 4.3 tcc history 377 ± 37 6.7 ± 2.1 normal 206 ± 28 3.4 ± 1.8 other gu disease 317 ± 87 6.1± 2.9 key: tcc, transitional cell carcinoma; ha, hyaluronic acid; hasae, hyaluronidase; gu, genitourinary. table 4. sensitivity of ha and haase regard to grade and stage of tcc grade and stage, no. (%) ha test , no. (%) haase test , no. (%) ha-haase test , g1 (23/29) 79.3 (7/29) 24.1 (24/29) 82.7 g2 (23/25) 92 (22/25) 88 (23/25) 92 g3 (34/43) 79.1 (38/43) 88.4 (40/43) 93 cis (4/5) 80 (4/5) 80 (4/5) 80 ta (30/38) 78.9 (14/38) 36.8 (32/38) 84.2 t1 (8/11) 72.8 (9/11) 81.8 (10/11) 90.9 t2 (19/21) 90.5 (20/21) 95.2 (20/21)95.2 t3 (19/22) 86.4 (20/22) 90.9 (21/22) 95.4 tcc * (80/97) 82.5 (60/68) 88.2** (87/97) 89.7 key: tcc, transitional cell carcinoma; ha, hyaluronic acid; hasae, hyaluronidase. *sensitivity in all grades and stages of tcc. ** denominator of fraction is the sum of g2 + g3 1236 | urological oncology is consistent with our study. lokeshwar and colleagues reported that urinary ha measurement has a sensitivity and specificity of 91.9% and 92.8% to detect bladder cancer, respectively.(18) therefore, urinary ha measurement is a simple, non-invasive, yet a highly sensitive and specific method for detecting the bladder cancer. conclusion results of this study suggest that urinary levels of ha and haase are very sensitive and specific as tcc markers. with over 89% sensitivity and 83% specificity, ha-haase test would have a practical application for post-treatment surveillance prior to clinical diagnosis (ie, cystoscopy) and a “falsenegative” result may signal a future recurrence. however, further studies are needed to replicate our results. conflict of interest none declared. table 5. specificity of ha and haase in case and control groups. ha test , no (%) haase test , no (%) ha-haase test , no (%) tcc (87/97) 89.7 (103/126)* 81.7 (81/97) 83.5 normal (18/19) 94.7 (18/19) 94.7 (18/19)94.7 history of tcc (23/27) 85.2 (21/27) 77.8 (21/27) 77.8 bph (11/12) 91.7 (10/12) 83.3 (10/12) 83.3 renal stone (12/13) 92.3 (11/13) 84.6 (11/13)84.6 other gu disease (23/26) 88.5 (21/26) 80.8 (21/26) 80.8 key: tcc, transitional cell carcinoma; ha, hyaluronic acid; hasae, hyaluronidase; gu, genitourinary. *denominator of fraction is number of g1 control group. references 1. simpson ma, lokeshwar vb. hyaluronan and hyaluronidase in genitourinary tumors. front biosci. 2008;13:5664-80. table 6. sensitivity, specificity and accuracy of ha, haase, ha-haase tests on detecting tcc. category ha test , no. (%) haase test , no. (%) ha-haase test , no. (%) sensitivity 82.5 88.2 89.7 specificity 89.7 81.7 83.5 accuracy 86.1 84 86.6 key: tcc, transitional cell carcinoma; ha, hyaluronic acid; hasae, hyaluronidase. 2. johansson sl, cohen sm. epidemiology and etiology of bladder cancer. semin surg oncol. 1997;13:291-8. 3. jemal a, siegel r, ward e, hao y, xu j, thun mj. cancer statistics.ca cancer j clin. 2009;59:225-49. 4. herr hw. natural history of superficial bladder tumors: 10to 20year follow-up of treated patients. world j urol. 1997;15:84-8. 5. kriegmair m, baumgartner r, knuchel r, stepp h, hofstadter f, hofstetter a. detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. j urol. 1996;155:105-9. 6. mufti gr, singh m. value of random mucosal biopsies in the management of superficial bladder cancer. eur urol. 1992;22:288-93. 7. meredith f. campbell pcw, alan b. retik, e. darracott vaughan. campbell's urology. 9th edition ed 2007. volume 3, page 2465. 8. halling kc, king w, sokolova ia et al. a comparison of bta stat, hemoglobin dipstick, telomerase and vysis urovysion assays for the detection of urothelial carcinoma in urine. j urol. 2002;167:2001-6. 9. nussbaum rl, mcinnes rr, willard hf, thompson mw. thompson & thompson genetics in medicine. 6th ed philadelphia: saunders; 2001. p. 234. 10. burchardt m, burchardt t, shabsigh a, de la taille a, benson mc, sawczuk i. current concepts in biomarker technology for bladder cancers. clin chem. 2000;46:595-605. 11. fraser jr, laurent tc, laurent ub-hyaluronan: its nature, distribution, functions and turnover. j intern med. 1997;242:27-33. 12. west dc, hampson in, arnold f, kumar s-angiogenesis induced by degradation products of hyaluronic acid. science. 1985;228:1324-6. 13. de klerk dp, lee dv, human hj.glycosaminoglycans of human prostatic cancer. j urol. 1984;131:1008-12. 1237vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l references 1. simpson ma, lokeshwar vb. hyaluronan and hyaluronidase in genitourinary tumors. front biosci. 2008;13:5664-80. 2. johansson sl, cohen sm. epidemiology and etiology of bladder cancer. semin surg oncol. 1997;13:291-8. 3. jemal a, siegel r, ward e, hao y, xu j, thun mj. cancer statistics.ca cancer j clin. 2009;59:225-49. 4. herr hw. natural history of superficial bladder tumors: 10to 20year follow-up of treated patients. world j urol. 1997;15:84-8. 5. kriegmair m, baumgartner r, knuchel r, stepp h, hofstadter f, hofstetter a. detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. j urol. 1996;155:105-9. 6. mufti gr, singh m. value of random mucosal biopsies in the management of superficial bladder cancer. eur urol. 1992;22:288-93. 7. meredith f. campbell pcw, alan b. retik, e. darracott vaughan. campbell's urology. 9th edition ed 2007. volume 3, page 2465. 8. halling kc, king w, sokolova ia et al. a comparison of bta stat, hemoglobin dipstick, telomerase and vysis urovysion assays for the detection of urothelial carcinoma in urine. j urol. 2002;167:2001-6. 9. nussbaum rl, mcinnes rr, willard hf, thompson mw. thompson & thompson genetics in medicine. 6th ed philadelphia: saunders; 2001. p. 234. 10. burchardt m, burchardt t, shabsigh a, de la taille a, benson mc, sawczuk i. current concepts in biomarker technology for bladder cancers. clin chem. 2000;46:595-605. 11. fraser jr, laurent tc, laurent ub-hyaluronan: its nature, distribution, functions and turnover. j intern med. 1997;242:27-33. 12. west dc, hampson in, arnold f, kumar s-angiogenesis induced by degradation products of hyaluronic acid. science. 1985;228:1324-6. 13. de klerk dp, lee dv, human hj.glycosaminoglycans of human prostatic cancer. j urol. 1984;131:1008-12. urinary hyaluronic acid and bladder tcc | jamshidian et al 14. stern r, jedrzejas mj-hyaluronidases: their genomics, structures, and mechanisms of action. chem rev. 2006;106:818-39. 15. lokeshwar vb, cerwinka wh, isoyama t, lokeshwar bl. hyal1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. cancer res.2005;65:7782-9. 16. lokeshwar vb, cerwinka wh, lokeshwar bl. hyal1 hyaluronidase: a molecular determinant of bladder tumor growth and invasion. cancer res.2005;65:2243-50. 17. lokeshwar vb, obek c, pham ht, et al. urinary hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade. j urol. 2000;163:348-56. 18. lokeshwar vb, obek c, soloway ms, block nl. tumor-associated hyaluronic acid: a new sensitive and specific urine marker for bladder cancer. cancer res. 1997;57:773-7. urology journal unrc/iua vol. 1, no. 4, 278-279 autumn 2004 printed in iran 278 primary tuberculosis of glans penis: a case report amir-zargar ma*1, yavangi m2, ja'fari m3, mohseni mj 1department of urology, ekbatan hospital, hamedan university of medical sciences, hamedan, iran 2department of obstetrics, ekbatan hospital, hamedan university of medical sciences, hamedan, iran 3department of pathology, ekbatan hospital, hamedan university of medical sciences, hamedan, iran key words: primary tuberculosis, tuberculosis of glans, diagnosis introduction an extremely rare form of genitourinary tract tuberculosis (tb) is tb of glans, being reported in 139 cases up to 1971.(1-4) penile glans may be affected through different mechanisms(1,2,4,5): primary, as an ulcerative lesion of glans; secondary, which is due to tb of other parts in urinary tract system--usually extended through urethra; and finally, hematogenous. long ago, circumcision was a risk factor when mycobacterium could enter the wounded glans from affected circumcision operators.(3,6) at present, tb of glans in adults is usually a primary or secondary form. primary glans tb can be acquired by either intercourse with a patient suffering from genital tb, or contact with contaminated fabric. the secondary form is the subsequent complication of lung tuberculosis or other organs involvement.(3) we report a case of primary glans tb, which is, to our best knowledge, the first report in iran. case report a 48-year-old blind man was referred with an ulcerative burgeon (granulated) lesion on his glans. physical examination revealed the involvement of the entire glans tissue (fig. 1), but no other sign or symptom in the genitourinary system. the patient had received different antibiotic therapies in the last two years, without a desirable response. according to a positive culture for staphylococcus aureus, the patient was started on gentamicin and cephalexin, but no improvement yielded. direct examination of the lesion discharge was negative for mycobacterium tuberculosis. also, vdrl test was negative, but a positive tuberculin test was reported. eventually, since the lesion had a tumor mimicking feature, frozen section biopsy was performed and the primary report showed tuberculosis, confirmed by repeated biopsies (fig. 2). further assessments for tb with intravenous pyelography and chest xray were normal. subsequently, anti-tb treatment was initiated, using pyrazinamide, 2mg/kg/day, isoniazid, 300 mg/day, refampin, 450 mg/day, for two months, and isoniazid, 500 mg, 3 times per week, rifampin, 900 mg, 3 times per week, for another additional two months. complete improvement was achieved following the treatment and reconstructive surgery was done on the glans. also, the spouse of the patient was evaluated and genital tuberculosis was detected by physical examination and paraclinical received january 2001 accepted april 2001 *corresponding author: tel: +98 918 111 7950, e-mail: dr_amirzargar@yahoo.com fig. 1. involvement of the entire glans by an ulcerative lesion amir-zargar et al 279 and imaging assessments. she was referred to a gynecologist and treated successfully. discussion recently, the prevalence of tb in developing countries has had a declining trend(7) and multiple-organ involvement with tb is hardly seen.(4,8) however, afghanistan wars in the last decade has led to immigration of the afghans to iran, resulted in re-development of tb in the country and subsequently various forms of tb were found again. involvement of glans of penis was first described by hellerstrom and later by bafverstedt and hagemen.(9) the prevalence is higher in japan and has been termed as penile tuberculosis.(10) tb of glans presents as a superficial lesion,(6,10) which is difficult to differentiate from malignant tumors.(3,7,10) the lesion can be extensive, with the involvement of urethra and corpus cavernosum.(3) rarely it may present as a hardened nodule or even cavernositis accompanied with ulcer.(3) biopsy must be done to confirm diagnosis, in which tuberculide granuloma with giant cells and caseous foci can be seen.(3,7,11) to determine whether a tb of glans is a primary or a secondary disease, intravenous pyelography and chest x-ray must be taken.(3,8,12,13) tb of glans usually responds to short-term anti-tubeculosis triple-drug chemotherapy.(4,11,14,15) references 1. sekhon gs, lal mm, dhall jc. tuberculosis of the penis. j indian med assoc. 1971;56:316-8. 2. lewis el. tuberculosis of the penis. a report of 5 new cases and complete review of literature. j urol. 1946;56:737. 3. johnson wd jr, johnson cw, lowe fc. tuberculosis and parasitic diseases of the genitourinary system. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.750-1. 4. guy m, eisenkraft s, eliraz a. primary tuberculosis of the glans penis. harefuah. 1993;125:260-1, 328. 5. narayana as, kelly dg, duff fa. tuberculosis of the penis. br j urol. 1976;48:274. 6. venkataramaiah nr, van raalte ja, dutta sn. tuberculous ulcer of the penis. postgrad med j. 1982;58:59-60. 7. ueda h, ohara h, sakakibara t, et al. tuberculosis of the contralateral adrenal gland: a case report. hinyokika kiyo. 1985;31:449-56. 8. sah sp, ashokraj g, joshi a. primary tuberculosis of the glans penis. australas j dermatol. 1999;40:106-7. 9. jeyakumar w, ganesh r, mohanram ms, shanmugasundararaj a. papulonecrotic tuberculids of the glans penis: case report. genitourin med. 1988;64:130-2. 10. nishigori c, taniguchi s, hayakawa m, imamura s. penis tuberculides: papulonecrotic tuberculides on the glans penis. dermatologica. 1986;172:93-7. 11. tanikawa k, matsushita k, ohkoshi m. tuberculosis of the penis: report of a case and review of the literature. hinyokika kiyo. 1985;31:1065-70. 12. agarwalla b, mohanty gp, sahu lk, rath rc. tuberculosis of the penis: report of 2 cases. j urol. 1980;124:927. 13. antonio d, gow jg. renal calcification in genito-urinary tuberculosis a clinical study. int urol nephrol. 1975;7:289-95. 14. fox w. short course chemotherapy for tuberculosis. in: fleneley dc, editor. recent advances in respiratory medicine. 2nd ed. edinburgh: churchill livingstone; 1980. p.83. 15. nakamura s, aoki m, nakayama k, kanamori s, onda s. penis tuberculid (papulonecrotic tuberculid of the glans penis): treatment with a combination of rifampicin and an extract from tubercle bacilli (t.b. vaccine). j dermatol. 1989;16:150-3. fig. 2. multiple granulomas in the epithelium of glans mucosa, containing epithelioid and giant granulomatous cells. caseous necrosis is seen in the center of one of the granulomas. hyperplasia of superficial epithelium has occurred. no malignancy was detected. miscellaneous treatment of recurrent bacterial cystitis by intravesical instillations of hyaluronic acid tomasz ząbkowski,1* beata jurkiewicz2, marek saracyn3 purpose: to evaluate the results of intravesical instillations of hyaluronic acid (ha) in the treatment of recurrent bacterial cystitis (rbc), and to assess the rate of tolerability, the rate of recurrence of rbc and side effects of treatment. materials and methods: the study included 23 female patients from september 2012 to may 2013, aged 28-42 years. twenty three women with a history of rbc, received intravesical instillations of ha once weekly for 6 weeks then once monthly for 8 months. results: in 16 (69.6%) of patients, symptoms of rbc resolved after 8 months. in 5 (21.7%) patients after 8 months of ha treatment, urgency was reduced only by 30%. therefore, it was decided to use combined therapy of ha and alpha blockers in this cohort group. there was a specific reduction (75%) in frequent urination at day and at night without urgency. despite the use of above mentioned treatment, in 2 (8.7%) patients, rbc was still present and therefore the treatment was discontinued. conclusion: the use of ha protects mucosa of urinary bladder and alleviates symptoms of infection. the intravesical instillations of ha and combination of ha + alpha blockers seems to be an effective therapeutic alternative in patients with rbc. keywords: anti-bacterial agents; administration; therapeutic use; drug therapy; female; recurrence; urinary tract infections. introduction the recurrent bacterial cystitis (rbc) is character-ized by persistent symptoms like pain, urgency, and frequency. it is still a challenge to find an effective, suitable therapy in clinical practice. hyaluronic acid (ha) has a long-term positive effects on treatment of symptoms of rbc. the glycosaminoglycan (gag) layer on inside surface of urinary bladder is thought to be protective against microorganisms, carcinogenic substances, microcrystals and other agents in urine. it is also claimed that it is a natural defense mechanism, protecting epithelium of urinary bladder against irritating agents in urine. the cavities in protecting layer gag, covering the epithelium of urinary bladder may disturb its protecting functions and they may cause adherence of bacteria, microcrystals, molecules of proteins and iron to epithelium of urinary bladder wall. ha temporarily replaces the deficient gag layer of the bladder wall which helps to relieve the symptoms of pain, frequency and urgency. urinary tract infections (utis) are among the most common bacterial infections, affecting women at a much higher frequency than men.(1,2) estimates suggest that about a third of women will have at least one episode of uti requiring antibiotic therapy by the time they are 24 years old, and over a lifetime a half of them will have at least one uti.(1,3) there is also a high level of recurrence of uti and 25-35% of initial uti episodes will be followed by a recurrent infection within 3-6 months.(2,4) although utis have traditionally been managed by intermittent or prolonged antibiotic therapy,(2,6) increasingly there is a renewed interest in the mechanisms of uti and the development into recurrent infections. materials and methods study population in a preliminary study, 56 women suffering from cystitis were subjected to antibiotic therapy. in 23 patients, the antibiotic therapy was not efficient and there were recurrences. these patients were qualified to the treatment by intravesical instillations of ha. the study included 23 female patients from september 2012 to may 2013, aged 28-42 years. twenty three women with a history of rbc, received intravesical instillations of ha once weekly for 6 weeks then once monthly for 8 months. inclusion and exclusion criteria the inclusion criteria were: age between 20-50 years, routine negative urine examination and urine culture, normal blood chemistry tests and cystitis symptoms last over 1 month. the exclusion criteria were: pregnancy, cystitis symptoms caused by known reasons such as bladder tumor, previous operation, acute cystitis, urethral stenosis, incapable to provide informed consent due to neurological or psychological disor1 urological outpatient clinic, warsaw, poland. 2 children's hospital in dziekanow lesny, warsaw, poland. 3 military institute of medicine, warsaw, poland. *correspondence: szaserów 128, 00-909 warsaw, poland. tel: +48 791 533555. e-mail: urodent@wp.pl. received november 2014 & accepted april 2015 miscellaneous 2192 ders, poor compliance and severe alcoholism or drug addiction, a known sensitivity to any component of the ha preparation used for bladder instillation. woman (28 > years old) recruited for the study were referred to the outpatient clinic of the author’s institution specifically for the treatment of rbc, and had been followed in the department for this problem for at least a year. all patients had a thorough clinical and radiological evaluation. the former was designed to exclude patients with urethral stenosis or external genitourinary abnormalities. the radiological examination included ultrasonography, and flexible cystoscopy. treatment twenty three women (mean age 35 years, range 28-42, sd 4.16) with a history of rbc, received intravesical instillations of ha (40 mg in 50 ml nacl solution) once weekly for 6 weeks then once monthly for 8 months. in 5 (21.7%) patients after 8 months of ha treatment, urgency was reduced only by 30%. therefore, it was decided to use combined therapy of ha and alpha blockers (tamsulosin 0.4 mg once daily) in this cohort group (figure 1). the ha instillations were administrated using a sterile single-use catheter and a sterile instillation gel. the patients were recommended not urinating for at least 1 to 2 hours. no prophylactic antibiotic was given before, during, or after bladder instillations. outcome measures there were 3 follow-up times from starting ha instillations. after 6 weeks, 3 months and 8 months of treatment, presence of uti was checked by urine culture taken before catheterization and instillation. in addition, patients rates their preand posttreatment as well as their present symptoms, and the level of pain was determined on a 100 mm visual analog scale (vas, 0-10). all of the patients were asked to comment on their personal benefit on quality of life. response to therapy was assessed using a questionnaire administrated to all patients at baseline and at each hospital visit. the questionnaire assessed dayand night-time urinary frequency. all patients were given a diary and asked to record relevant symptoms between visits. the primary outcome measures were the number of utis per patient per year and the mean time to uti recurrence at the reported longest follow-up. the secondary outcome measures were 24h urinary frequency (number of voids in one day) and the pelvic pain and urgency/frequency (puf) symptoms assessed using the puf symptom scale. statistical analysis for the statistical analysis, the number of utis was calculated for the retrospective (before ha) and prospective (after ha treatment) phases of the study. continuous variables were compared using the wilcoxon rank-sum test. the time to recurrence of infection before and after ha therapy was analyzed using a kaplan-meier survival function; in the retrospective assessment (before ha) this was defined as the mean time elapsed between each infection, and in the prospective assessment (after ha) as the time elapsed between the first ha instillation and the first recurrent infection. differences in continuous variables were expressed as mean difference (md) with 95% confidence intervals (ci). results twenty-three patients were included (mean age 35 years old) who had been attending the outpatient clinic for about one year. the patients had a long history of recurrent utis. the most common pathogens identified during infections were: escherichia coli, enterobacter species, enterococcus species, klebsiella species, and proteus mirabilis. all patients received antibiotic treatment, the most common antibiotics used were: amoxicillin/clavulanic acid (40%), ciprofloxacin (30%), and cotrimoxazole (20%) (figure 2). in 16 (69.6%) patients, symptoms of rbc resolved after 8 months. in 5 (21.7%) patients after 8 months of ha treatment, urgency was reduced only by 30%. therefore, it was decided to use combined therapy of ha and alpha blockers in this cohort group. there was 75% reduction in frequent urination at day and at night without urgency. despite the use of above mentioned treatment, in 2 (8.7%) patients, rbc was still present and therefore the treatment was interrupted (figures 3 and 4). the remaining cohort group of twenty one (91.3%) patients decided to continue the treatment and there are no side effects. the tolerability of ha and ha + alpha blockers treatment was good. figure 1. overview of the study and results. figure 2. the type of pathogens identified during infections. treatment of bacterial cystitis by intravesical hyaluronic acid-ząbkowski et al. vol 12 no 03 may-june 2015 2193 the meta-analysis showed a significant difference between the two group within the results on uti rates per patient per year (a group treated by ha and a group treated by combined therapy) (md = 3.41, 95% ci: 4.33-2.49, p < .00001). it was reported outcomes on 24-h urinary frequency measured as 3-day voids (number of voids in 3 days), which were not significantly improved after therapy (md = 2.53, 95% ci: 8.43-1.25, p = .15), but a significantly better puf total score (md = 7.17, 95% ci: 9.86-4.48, p < .00001) was detected in a group treated only by ha. over the course of 9.5-month intravesical instillation with ha, 2 patients had a recurrence. in the extended follow-up (mean 12.5 months) none of the patients had a recurrence. of patients, 21 (91.3%) were recurrence free after 9.5-month treatment. it was reported 95% decrease in the number of recurrences per year (rate of uti: pre-treatment 4.1 ± 1.51 per patient/year vs. 0.2 ± 0.4 post-treatment, p < .001). frequency score decreased from 7.56 ± 1.57 to 3.12 ± 2.11 (p < .001). urgency score decreased from 7.21 ± 3.02 to 3.21 ± 2.23 (p < .001). patient outcomes, expressed in terms of mean dayand night-time voids and mean pain scores showed no change in the average level of daytime voids, but did indicate an improvement in the average number of night-time voids. the percentage of patients improved, the magnitude and the duration of response were all measured by vas, based on symptom response. of patients, 91.3% reported an improvement ≥ 2 on the vas score at the end of follow-up; 5% of patients experienced no change in symptoms. the absence of recurrent uti was compared before and after ha instillations by plotting kaplan-meier curves for each period. based on the follow-up for patients with or with no recurrence the median time to recurrence after the first instillation of ha predicted by the model was 478 days; the median time to recurrence before ha was 83 days, which shows a significant difference (p < .0001). discussion this study demonstrates clear evidence that instilling ha into the bladder of woman with a history of recurrent utis is feasible and well accepted by patients, and significantly reduces the incidence of recurrent lower utis. in 13 of 17 patients, symptoms of rbc resolved. the phase of ha treatment lasted about 10 months, with weekly administrations for the first month followed by monthly treatments for 8 months. this regimen was based on pragmatic experience with ha therapy in patients with uti at the authors’ hospital, during which one patient had a recurrence uti. however, the protective effect of ha was maintained even after direct treatment had stopped. contemporary treatment options for women with a history of recurrent uti usually include intermittent or prolonged antibiotic therapy, with variations in specific antibiotics, their dose, and duration of therapy.(1,5) alternatively, estrogen replacement therapy has been suggested as a strategy to decrease the incidence of recurrent utis in postmenopausal women, by reversing the changes in vaginal ph, and this is an example of an intervention not based on antibiotics.(6,7) raz and stamm(7) found that in women treated with intravaginal estriol cream there was a reduction in uti recurrence and at 6 months ≈80% of the treated patients remained infection-free. however no menopausal women were included in the present study and hence these patients would be ineligible for this antibiotic-free treatment. the third therapeutic approach targets bacterial adherence to bladder mucosa. the most successful have used cranberry juice, effective through its phenolic components.(8) the principle of gag substitution for preventing utis was shown experimentally in animals for heparin,(9) and for sodium pentosan polysulphate.(10) in the study of sinanoglu and colleagues on comparison of intravesical administration of chondroitin sulfate and colchicine in rat protamine/lipopolysaccharide induced cystitis model, it was reported that colchicine may be an alternative to other treatment modalities for painful bladder conditions such as interstitial cystitis. intravesical administration of colchicine decreased leucocyte and mast cell infiltration to the same extent of chondroitin sulfate in protamine sulfate and lipopolysaccharide induced bladder inflammation in rat.(11) we demonstrated that, bladder instillations of ha reduce figure 3. number of patients continuing the treatment. figure 4. results of recurrent bladder cystitis treatment by hyaluronic instillations. treatment of bacterial cystitis by intravesical hyaluronic acid-ząbkowski et al. miscellaneous 2194 the incidence of recurrent uti, possibly through a protective effect on the gag layer, and may offer an alternative to the widespread use of antibiotics, which are not always successful or well accepted by patients. conclusion the use of ha protects mucosa of urinary bladder and alleviates symptoms of infection. the intravesical instillations of ha seems to be an effective therapeutic alternative in patients with recurrent bacterial cystitis. however, it is a very expensive method of treatment. conflict of interest none declared. references 1. foxman b. epidemiology of urinary tract infections: incidence, morbidity and economic costs. am j med. 2002;113(supl. 1a):5s-13s. 2. ronald a. the etiology of urinary tract infection: traditional and emerging pathogens. am j med. 2002;113:14s-9s. 3. foxman b, barlow r, d’arcy h, gillespie b, sobel jd. urinary tract infection. selfreported incidence and associated costs. ann epidemiol. 2000;10: 509-15. 4. foxman b, gillespie b, koopman j, et al. risk factors for second urinary tract infection among college women. am j epidemiol. 2000;151:1194-205. 5. hooton tm. recurrent urinary tract infection in women. int j antimicrob agents. 2001;17:259-68. 6. eriksen b. a randomized, open, parallel-group study on the preventive effect of an estradiolreleasing vaginal ring (estring) on recurrent urinary tract infections in postmenopausal women. am j obstet gynecol. 1999;180:10729. 7. raz r, stamm we. a controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. n engl j med. 1993;329:753-6. 8. sobota ae. inhibition of bacterial adherence by cranberry juice; potential use for the treatment of urinary tract infections. j urol. 1984;131:1013-6. 9. ruggieri mr, chelsky mj, rosen si, shickley tj, hanno pm. current findings and future research avenues in the study of interstitial cystitis. urol clin north am. 1994;21:163-76. 10. ruggieri mr, hanno pm, samadzadeh s, johnson ew, levin rm. heparin inhibition of increased bacterial adherence following overdistension, ischemia and partial outlet obstruction of the rabbit urinary bladder. j urol. 1986;136:132-5. 11. sinanoglu o, dogan ekici i, ekici s. comparison of intravesical application of chondroitin sulphate and colchicine in rat protamine/lipopolysaccharide induced cystitis model. urol j. 2014;11:1296-300. treatment of bacterial cystitis by intravesical hyaluronic acid-ząbkowski et al. vol 12 no 03 may-june 2015 2195 urology journal vol. 11 no. 04 july august 2014 1788 urological oncology diode laser ablation of prostate and channel transurethral resection of prostate in patients with prostate cancer and bladder outlet obstruction symptoms department of laser application in medical sciences research center, shohadae tajrish hospital, shahid beheshti university of medical sciences.tehran, iran. corresponding author: babak javanmard, md department of laser application in medical sciences, shohadae tajrish hospital, shahid behesh ti university of medical sciences, tehran, iran. tel: +98 21 22718006 e-mail: drbabakjavanmard@gmail. com received june 2013 accepted june 2014 babak javanmard, amin hasanzadeh hadad, mohammad yaghoobi, behzad lotfi purpose: to evaluate the efficacy of diode laser ablation of prostate for treating lower urinary tract symptoms (luts) in patients with locally advanced prostate cancer and comparing results with palliative transurethral resection of prostate (pturp). materials and methods: thirty-six known cases of locally advanced prostate cancer with a maximum urinary flow rate (qmax) of 12 ml per second or less and an international prostate symptom score (ipss) of 20 or more were included in this study. patients were randomized into two groups. the first group underwent pturp and for the second group diode laser ablation of prostate was done. in 6 months post-operative follow up, patients were evaluated for ipss, post void residual (pvr) urine volume, qmax and possible complications such as urethral stricture or urinary incontinence. results: postoperatively, mean ipss was 11.1 ± 4.1 in turp group and 11.7 ± 3.6 in laser group (p = .64). mean pvr was 18.4 ± 3.5 ml in turp group and 17.7 ± 6.3 ml in laser group (p = .68). mean qmax in turp and laser groups were measured 20.1 ± 4.5 ml/s and 19.4 ± 2.6 ml/s, respectively (p = .57). while there was a significant improvement in ipss and qmax and pvr in both groups, statistical analysis did not show any significant difference postoperatively between pturp and laser groups. conclusion: diode laser ablation of prostate and pturp, both improved significantly ipss, pvr and qmax. but hospital stay and post-operative catheterization time was less in laser group. keywords:: laser therapy; prostatectomy; methods; prostatic neoplasms; complications; transurethral resection of prostate; treatment outcome; urinary bladder neck obstruction. standard cardiac monitoring. pturp was performed using a continuous flow 26 french (f) resectoscope. it was not attempted to remove maximum amount of prostate tissue, but to produce a channel, which would improve urinary flow. therefore procedure was stopped when it was visually estimated that prostatic fossa was wide enough. laser therapy was conducted in a side firing technique. a 600 nm, side firing laser fiber was introduced through a 24f continuous flow laser cystoscope. sterile isotonic saline was used as an irrigant solution. the 980-1470 nm diode laser generator could deliver 50w to 150w energy in continuous mode. we began vaporizing tissue from surface of the median lobe, sweeping the fiber slowly and continuously in a gentle rotation movement in a 5 o’clock to 7 o’clock direction, keeping the fiber in direct contact to the prostatic tissue. when the median lobe was reduced we proceeded to the right lateral lobe, using the same technique and then to the left lateral lobe. the slow continuous motion assured hemostasis and constant reassessing of position. postoperatively a 20f two-way foley catheter was placed and no irrigation was needed. the catheter was removed the next day and patients were discharged. in 6-month post-operative follow-up, patients were evaluated for ipss, pvr, serum creatinine, qmax and possible complications such as urethral stricture or urinary incontinence. statistical analysis continuous data was reported as mean ± sd and dichotomous variables were reported as frequency and percent. chi-square test was used for statistical analysis of nominal variables and paired t-test and independent t-test were used for continuous variables. all statistical analysis was done by statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. p value less than .05 was considered statistically significant. results the mean age of patients was 70.8 ± 8.7 years in turp group and 69.1 ± 6.6 years in laser group (p = .51). the mean prostate volume was 45.8 ± 7.2 ml and 43.4 ± 5.5 ml in turp and laser groups, respectively. the mean psa before surgery was 27.2 ± 5.5 ng/ml in turp group and 31.4 ± 7.3 ng/ml in laser group (p = .59). three patients (16.6%) in laser group and 5 (27.7%) in turp group had mild to moderate hydronephrosis. mean serum creatinine level for turp and laser group were 1.81 ± 0.9 mg/dl and 1.65 ± 0.7 mg/dl, respectively. the average time from external beam radiotherapy to pturp was 31.2 ± 5 months in laser group and 35.5 ± 7.7 months in turp group (p = .56). preoperative data are shown in table. the mean operation time was 36.8 ± 5.2 minutes and 28.1 ± 4.8 minutes for turp and laser groups, respectively. time of surgery was measured from the beginning of laser firing or first bite of turp to the insertion of foley catheter. in the turp group, there was one case of turp syndrome (5.5%) and one patient needed blood transfusion after the procedure. neither turp syndrome nor any need for blood transfusion was observed in laser group. during the first week after the procedure 3 patients (16.6%) needed re-catheterization and a short and mild irrigation because of introduction complications of locally advanced prostate cancer are often overlooked in the treatment of prostate cancer, which can have significant morbidity. despite advances in early detection and treatment of prostate cancer, as many as 10% of patients present with or develop symptomatic locally advanced prostate cancer.(1) acute urinary retention is a common complication of a neoplastic prostate. transurethral resection of prostate (turp) can offer immediate relief of the obstruction in patients with benign prostatic hyperplasia (bph).(2) in contrast, palliative turp (pturp) (the socalled “channel” turp), is transurethral resection of prostate tissue in a patient with metastatic or locally advanced and/or previously treated prostate cancer to alleviate obstructive voiding symptoms. therefore, resection to the depth of the prostatic capsule is not attempted.(3) although turp is commonly performed to relieve bladder outlet obstruction (boo) symptoms in patients with bph,(4) little known about the outcome of laser ablation of prostate in patients with locally advanced prostate cancer. in this study, diode laser ablation of prostate and pturp were performed for 36 consecutive patients with locally advanced prostate cancer and refractory urinary retention and preoperative and postoperative results of both procedures were compared. materials and methods in a period of two years, from february 2011 to january 2013, thirty-six patients were included in this study. inclusion criteria were maximum urinary flow rate (qmax) of 12 ml per second or less with voided volume of 150 ml or greater and international prostate symptom score (ipss) of 20 or more, in a patient with locally advanced (stage t3 or t4) prostate carcinoma. external beam radiotherapy with or without adjuvant hormone therapy was the initial treatment for their cancer. ethical approval for the study was obtained from medical ethics committee of shahid beheshti university of medical sciences. using simple randomization method, patients were divided into two groups. the first group underwent palliative pturp and for the second group diode laser ablation of prostate was done. patients had no specific management for lower urinary tract symptoms (luts) before the procedure except for α1blockers administration. preoperatively ipss was determined in all of the patients and cystoscopy was performed to roll out possible urethral stricture. uroflowmetry was also done. all patients underwent ultrasound study to evaluate kidneys and prostate volume and pvr. blood tests comprised complete blood count (cbc), serum chemistry, serum prostate specific antigen (psa) and coagulation tests. patients with abnormal coagulation tests or those who were using anticoagulant agents and could not stop taking their drugs for a while before surgery were excluded from the study. urine analysis and urine culture were also attained and appropriate antimicrobial therapy was initiated in patients with a positive urine culture, before the surgery. in all cases prophylactic antibiotics were administered. a single urologist performed both pturp and diode laser ablation of prostate. all procedures were performed using spinal anesthesia with 1789 urological oncology urology journal vol. 11 no. 04 july august 2014 1790 catheter or suprapubic tube. thomas and colleagues(11) randomized 22 patients presenting with acute urinary retention secondary to locally advanced prostate cancer into two groups. ten patients underwent pturp and bilateral orchiectomy and 12 patients underwent bilateral orchiectomy alone. four patients treated by pturp had difficulties in voiding and one of them underwent further turp. while only 2 patients in orchiectomy group needed turp and symptoms subsided in the rest. they recommended that initial pturp should not be carried out and this procedure should be reserved for patients who cannot void two months after initiation of hormone therapy. there has been many documentation of the absorption of irrigating solutions into the circulatory system after turp.(12,13) therefore, at the time of a prostate resection, cancer cells may be free to infuse under pressure into open lymphatic and venous channels, thereby enhancing the dissemination of tumor cells potentially capable of metastasizing. several studies since then have raised the possibility that palliative turp contributes to metastatic spread of disease via tumor spillage and hematologic dissemination.(14,15) however, babaian and archer(16) retrospectively reviewed data of 285 patients with clinical stage c adenocarcinoma of prostate and studied the impact of turp on dissemination of cancer and found no association between turp and progression of cancer. our experience with diode laser for treating bph, has demonstrated successful results. therefore we decided to study its efficacy for treating obstructive symptoms in patients with locally advanced prostate cancer and comparing the results with pturp. any innovative laser therapy of prostate must stand up to comparison with 80w potassium titanyl phosphate (ktp) laser.(1) an advantage of diode laser compared to ktp laser is its less dependency to good blood perfusion. strong absorption of the wavelength in diode laser by hemoglobin and water allows a tissue penetration of 2-3 mm so that heat is concentrated in a small volume of tissue and cells are lysed by rapid vaporization of their cellular water. due to probable prior radiotherapy or administrated finasteride in patients with prostate cancer and urinary obstruction, a reduced perfusion in prostate tissue is expected in such patients compared to bph. because the procedure is performed with isotonic solution, laser vaporization of the prostate is an attractive option when compared with standard turp because of the lack of absorption of hypotonic fluid and the potential cardiac and pulmonary complications.(1) the coagulation effect of diode laser leads to a minimum hemorrhage and theoretically, prevents possible dissemination of the cancer cells. hajdinjak(17) used diode laser to treat patients with luts. four patients in the study were known cases of prostate cancer. after one month of follow up, all patients could urinate freely without difficulty. kumar(18) described the use of ktp laser to vaporize urethral obstructive prostate cancer. eight patients with locally advanced prostate cancer with a mean psa of 10 ng/ml, underwent potassium titanyl phosphate laser vaporization of the prostate. catheter drainage was discontinued 24 hours after the procedure. no patients required continuous bladder irrigation and none required replacement of the obstruction, cause by residual necrotic tissue of prostate in laser group. at 6 months visit after the procedure, one patient from the turp group and two patients from laser group were lost. urge incontinence was developed in three patients (17.6%) in turp group and none was noticed in patients who underwent laser ablation. postoperatively, mean ipss was 11.1 ± 4.1 in turp group and 11.7 ± 3.6 in laser group (p = .64) (table). mean pvr was 18.4 ± 3.5 ml in turp group and 17.7 ± 6.3 ml in laser group (p = .68). mean qmax in turp and laser groups were measured 20.1 ± 4.5 ml/s and 19.4 ± 2.6 ml/s, respectively (p = .57). mean serum creatinine was 1.53 ± 0.5 mg/dl in turp group and 1.49 ± .06 mg/dl in laser group (p = .73). discussion luts are not uncommon in men with prostate cancer. besides hematuria, boo with its complications such as urinary retention, a high pvr, bladder stones or hydronephrosis, is the most frequent complication of locally advanced prostate cancer.(5) today such complications of locally advanced disease are overlooked in the management of prostate cancer. in a series of 478 men with newly diagnosed prostate cancer in pre psa era, up to 82% presented with obstructive symptoms.(6) a few studies have focused on clinical findings in prostate cancer patients, receiving pturp for urinary retention and obstructive symptoms. but the role of laser ablation of prostate in such patients as a palliative therapy is not well defined in the literature. turp has been the gold standard therapy for the relief of boo for more than 70 years. turp for boo due to prostate cancer has been used in clinical practice throughout this time and has been a viable option for prostate cancer obstructing the urethra for several decades.(3) it has been estimated that approximately 25% to 35% of patients on watchful waiting may ultimately require pturp.(7) in a series of 209 patients who underwent radiotherapy for stage c prostate cancer, 17 patients required subsequent pturp for local progression of the disease.(8) marszalek and colleagues(9) reviewed the outcome of pturp, performed for 89 patients with locally advanced prostate cancer. the mean interval between the diagnosis and pturp was 1.5 years. indications for surgery in their study included: refractory urinary retention (30%), severe boo with pvr of > 100 ml (43%) and bladder stones, hematuria and hydronephrosis in 9% of patients. eighth patients (9%) needed blood transfusion after the procedure and in follow up, after 11 months, a repeat turp was necessary in 22 patients (25%). they concluded that pturp is a fairly safe procedure, although the pre and post-operative mortality was significantly higher (2%) than for contemporary series of bph (< 0.25%). crain and colleagues(10) performed 24 pturp in 19 patients with locally advanced prostate cancer. the initial therapy for all of them was radiotherapy or hormone therapy. the average time from prostate cancer diagnosis to pturp was 44.7 months. after the procedure ipss was significantly reduced but no significant improvement in qmax was observed. of patients in this study 24% required repeat procedures for bleeding or obstruction and 21% ultimately required long term bladder drainage via a foley diode laser ablation of prostate and turp in patients with prostate cancer-javanmard et al case report 1471 7. whitmore wf, warner ja, thompson im. expectant management of localized prostatic cancer. cancer. 1991;67:1091-1096. 8. gibbons rp, mason jt, correa rj, jr., et al. carcinoma of the prostate: local control with external beam radiation therapy. j urol. 1979;121:310 2. 9. marszalek m, ponholzer a, rauchenwald m, madersbacher s. palliative transurethral resection of the prostate: functional outcome and impact on survival. bju int. 2007;99:56-9. 10. crain ds, amling cl, kane cj. palliative transurethral prostate resec tion for bladder outlet obstruction in patients with locally advanced pros tate cancer. j urol. 2004;171:668-71. 11. thomas dj, balaji vj, coptcoat mj, abercrombie gf. acute urinary retention secondary to carcinoma of the prostate. is initial channel turp beneficial? j r soc med. 1992;85:318-9. 12. harrison rh, 3rd, boren js, robison jr. dilutional hyponatremic shock: another concept of the transurethral prostatic resection reaction. j urol. 1956;75:95-110. 13. oester a, madsen po. determination of absorption of irrigating fluid during transurethral resection of the prostate by means of radioisotopes. j urol. 1969;102:714-9. 14. engelhardt pf, riedl cr. re: palliative transurethral prostate resection for bladder outlet obstruction in patients with locally advanced prostate cancer. j urol. 2005;173:324-5. 15. forman jd, order se, zinreich es, lee dj, wharam md, mellits ed. the correlation of pretreatment transurethral resection of prostatic cancer with tumor dissemination and disease-free survival. a univariate and multivariate analysis. cancer. 1986;58:1770-8. 16. babaian rj, archer js. dissemination of disease following transurethral resection for locally advanced prostate cancer. urology. 1988;31:30-3. 17. hajdinjak t. initial experience with vaporization of benign or cancerous prostate using 980-nm diode laser. webmedcentral urology 2011;2:wmc002526. 18. kumar sm. photoselective vaporization of the prostate: a volume reducti on analysis in patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia and carcinoma of the prostate. j urol. 2005;173:511-3. catheter. transrectal ultrasound was performed before and after the procedure, revealing a 51% average reduction in prostate volume. no patients required transfusion, needed to be readmitted, or developed incontinence. conclusion treatment of patients with locally advanced prostate cancer and refractory urinary retention by pturp and diode laser ablation of prostate shows successful results. diode laser seems to be a promising option for patients with significant urethral obstruction secondary to locally advanced prostate cancer. conflict of interest none declared. references 1. anast jw, andriole gl, grubb rl 2nd. managing the local complicati ons of locally advanced prostate cancer. curr urol rep. 2007;8:211-6. 2. montorsi f, naspro r, salonia a, et al. holmium laser enucleation ver sus transurethral resection of the prostate: results from a 2-center, prospe ctive, randomized trial in patients with obstructive benign prostatic hy perplasia. j urol. 2004;172:1926-9. 3. mazur aw, thompson im. efficacy and morbidity of “channel” turp. urology. 1991;38:526-8. 4. mebust wk, holtgrewe hl, cockett at, peters pc. transurethral prostatectomy: immediate and postoperative complications. a coopera tive study of 13 participating institutions evaluating 3,885 patients. j urol. 1989;141:243-7. 5. scherr d, swindle pw, scardino pt. national comprehensive can cer network guidelines for the management of prostate cancer. urology. 2003;61:14-24. 6. brawn pn, johnson eh, speights vo, et al. incidence, racial differences, and prognostic significance of prostate carcinomas diagnosed with obst ructive symptoms. cancer. 1994;74:1607-11. variables pturp diode laser preoperative postoperative p value preoperative postoperative p value ipss 28.3 ± 5.6 11.1 ± 4.1 .001 29.5 ± 4.1 11.7 ± 3.6 .001 pvr, ml 68.1 ± 23.9 18.4 ± 3.5 .001 60.1 ± 18.9 17.7 ± 6.3 .001 qmax, ml/s 8.8 ± 1.8 20.1 ± 4.5 .001 9.5 ± 0.9 19.4 ± 2.6 .001 serum creatinine, 1.81 ± 0.9 1.53 ± 0.5 .2 1.65 ± 0.7 1.49 ± 0.06 .4 mg/dl table. preoperative and post-operative data of study subjects.* abbreviations: ipss, international prostate symptom score; sd, 2 standard deviation; pvr, post void residual urine volume; pturp, palliative transurethral resection of prostate; qmax, maximum urinary flow rate. * data are presented as mean ± sd. 1791 urological oncology urology journal unrc/iua 102 sexual dysfunction and infertility seminal plasma magnesium and premature ejaculation: a case-control study mohammadreza nikoobakht,* mehdi aloosh, mohammad hasani urology research center, sina hospital, tehran university of medical sciences and health services, tehran, iran abstract introduction: our aim was to determine the relationship between genuine premature ejaculation and serum and seminal plasma magnesium. materials and methods: in a case-control study carried out between january 2002 and december 2003, 19 patients with premature ejaculation were evaluated and compared with 19 patients without premature ejaculation. patients with organic and psychogenic causes were excluded. seminal plasma and serum magnesium levels were measured using atomic absorption spectrophotometery. results: seminal plasma magnesium levels in study patients (94.73 ± 10.87 mg/l) were significantly lower than they were in controls (116.68 ± 11.63 mg/l, p < 0.001), but there were no such differences regarding serum magnesium levels (study patients, 20.26 ± 2.66 mg/l; controls, 20.73 ± 2.80 mg/l). semen-to-serum-magnesium ratio was significantly lower in patients with premature ejaculation (p < 0.001). also, a reverse relationship between body mass index and genuine premature ejaculation was found (p = 0.027). conclusion: genuine premature ejaculation has a significant relationship with decreased levels of seminal plasma magnesium. further studies are needed to clarify the actual role of magnesium in the physiology of the male reproductive tract, especially its association with premature ejaculation. key words: genuine premature ejaculation, seminal plasma magnesium, plasma magnesium vol. 2, no. 2, 102-105 spring 2005 printed in iran introduction premature ejaculation is the most common sexual dysfunction in men.(1) magnesium is one of the elements present in human semen, and it is required for enzymes that act on phosphatecontaining substrates. a decrease in magnesium level will result in an increase of thromboxane a2 (txa2), and this will lead to a rise in endothelial intracellular calcium, and subsequently, a decline in nitric oxide (no).(2,3) since no is a vascular smooth-muscle-relaxing factor,(4) cavernosal smooth muscle contraction, resulting from decreased no, may be a contributing factor to premature ejaculation.(5) few studies have been performed that assess the possible relationship between semen magnesium levels and genuine premature ejaculation. our objective was to evaluate factors that may contribute to premature ejaculation, with special consideration given to the role of magnesium.received august 2004 accepted february 2005 *corresponding authoer: urology research center, sina hospital, hassanabad sq., tehran 19953-45432. tel: ++98 21 66701041-9, fax: ++98 21 66717447 e-mail: nikoobakht_m@hotmail.com nikoobakht et al 103 materials and methods in a case-control study carried out between january 2002 and december 2003, 19 patients with premature ejaculation were evaluated and compared with 19 patients without premature ejaculation. the patients were randomly selected from among the patients referred to our clinic at sina hospital, in tehran, iran. premature ejaculation was defined based on criteria of the diagnostic and statistical manual of mental disorders, fourth edition (dsm-iv).(6) each patient's history was taken, and a systemic physical examination was performed. duration of being sexually active, smoking (pack-years), coital habits, level of education, and the history of psychiatric problems were also assessed. the patient's weight and height were recorded. special attention was paid to the presence of gynecomastia, genital abnormalities, and secondary sexual characteristics. laboratory studies included complete blood count, fasting blood sugar, blood urea nitrogen, serum creatinine, cholesterol, thyroid function tests, liver function tests, testosterone, prolactin, lh, and fsh. inclusion criteria were duration of marriage longer than 6 months, history of premature ejaculation for more than 6 months, and the lack of response to sex therapy. patients were excluded if they had organic disorders such as diabetes mellitus, hypertension, vascular disorders, endocrine disorders, renal failure, previous genitourinary surgery, premature ejaculation for less than 6 months, intermittent premature ejaculation, abnormal mental status, or history of psychiatric disorder. nineteen patients complaining of premature ejaculation and fulfilling the inclusion criteria were selected as study patients, and 19 persons with nephrolithiasis and other normal parameters were chosen as control patients. duration of marriage, smoking habits, level of education, history of drug abuse, and body mass index (bmi) were compared between the two groups. the demographic characteristics of all patients are shown in table 1. semen analyses were performed according to who guidelines.(7) after 3 to 5 days of abstinence, semen was collected by masturbation (without using any lubricant gel) into a sterile acid-wash container. specimens were centrifuged within 30 minutes of collection at 100 rpm for 10 minutes at 4°c. aliquoted samples were stored at -80°c until they were assayed. blood samples were taken at the same time. serum magnesium levels were measured using atomic absorption spectrophotometry (aa670, shimadzu, japan). the supernatant samples were liquefied at room temperature and diluted 1:10 in deionized water. phosphate ions were eliminated by lanthanum chloride. the magnesium stock standard was obtained from tetrazol (sigma, st louis, mo). semen samples contaminated with blood or pus, in addition to those with ph < 7 or ph > 8, were excluded. statistical analyses data are expressed as means ± standard deviation. spss software (statistical package for the social sciences, version 9.05, ssps inc, chicago, ill, usa) was used for data analyses. the kolmogorov-smirnov test was used to determine that magnesium levels had normal distribution. the relationships between parameters were analyzed using student t and chi-square tests. a value for p less than 0.05 was considered significant. results analyses of the clinical variables are presented in table 1. a statistically significant relationship was found only between bmi and genuine table 1. demographic characteristics of the pateints case control p value number 19 19 age (year) 31.37 ± 3.84 34.1 ± 8.81 0.22 duration of marriage (year) 3.13 ± 3.53 7.10 ± 9.39 0.93 smokers (number) 8 7 0.74 smoking (pack-year) 13.89 ± 26.59 14.78 ± 28.83 0.92 bmi (kg/m2) 23.12 ± 210 24.73 ± 2.22 0.027 history of drug abuse 3 1 0.29 seminal plasma magnesium and premature ejaculation104 premature ejaculation (p = 0.027), corresponding to a slightly lower bmi in patients with premature ejaculation. a similar relationship was found between seminal plasma magnesium levels (table 2) and premature ejaculation; magnesium levels were higher in the seminal fluid of the study patients (p < 0.001). it was also found that seminal-plasma-magnesium-to-serum-magnesium ratio was significantly higher in study patients (p < 0.001). there was no significant correlation between serum magnesium levels and genuine premature ejaculation (p = 0.597). discussion the magnesium ion has an essential role in enzyme activation in the body. it is known that seminal plasma magnesium in each person (> 70 mg/l) is much higher than its serum levels (17 mg/l to 24 mg/l).(8) there is tremendous evidence that a long duration of physical effort in men leads to a decrease in extracellular magnesium due to a transient shift between extracellular and intracellular magnesium components and a simultaneous increase in urinary excretion.(9,10) this transient hypomagnesaemia may be manifested by uncontrolled contractility of the male genital tract, causing emission and ejaculation. hypomagnesaemia stimulates angiotensininduced aldosterone synthesis and txa2 overproduction by phospholipase a2. engagement of txa2 results in ca++ influx.(2,11) elevated cytosolic ca++ in endothelial cells promotes phosphodiesterases and decreases g-cyclase activity,(3,4) resulting in decreased no production and its release from the endothelium.(2) this causes decreased cgmp, which in turn results in decreased no production. since no is a vascular smooth muscle relaxing factor,(4) decreased levels of no consequently lead to vasoconstriction. this could be responsible for the lack of tumescence associated with premature ejaculation. decreased prostaglandin i2 (pgi2) production associated with magnesium decline is another mechanism (figure 1).(3) in a study by omu and coworkers, levels of magnesium, zinc, copper, and selenium were evaluated in serum and seminal plasma of 3 groups, consisting of 15 men with normal sperm parameters, 15 with oligoasthenospermia, and 9 with genuine premature ejaculation. serum and semen levels of all elements in the 3 groups were normal, except for seminal plasma magnesium levels, which were lower in men with premature ejaculation.(5) the association between low seminal table 2. semenal plasma and serum magnesium case control p value serum magnesium (mg/l) 20.26 ± 2.66 20.73 ± 2.80 0.597 semenal plasma magnesium (mg/l) 94.73 ± 10.87 116.68 ± 11.63 < 0.001 semenal magnesium / serum magnesium 4.71 ± 0.58 5.68 ± 0.66 < 0.001 fig. 1. the suggested machanism of hypomagnesemia effect on premature ejaculation hypomagnesemia ↓ pgi2 lack of tumescence ↓ txa2 ↑ ca ++ influx vasoconstriction ↑ phosphodiesteras ↓gcyclase ↓ no covernosal smooth muscle contraction premature ejaculation ↓ cgmp nikoobakht et al 105 magnesium levels and genuine premature ejaculation found in our study is of clinical significance and accordingly, 3 hypotheses can be suggested: 1, seminal magnesium decline could be a consequence of a defect in the active transport system that transports magnesium from blood to semen; 2, there may be a magnesium-diminishing factor like chelating factors in the semen of persons with premature ejaculation; and 3, hypomagnesaemia in the past, caused by low consumption of magnesium, may contribute to seminal plasma magnesium decline. epidemiologic studies have reported that the amount of magnesium consumption in most individuals is 20% to 30% less than the recommended dietary allowance during prolonged periods.(12) thus, it is probable that the consumption of higher amounts of magnesium leads to an increase in seminal levels of magnesium. bmi in our study patients may have been a confounding factor. we found that a sedentary lifestyle and higher bmi may decrease the incidence of premature ejaculation. more studies are required to elucidate this. conclusion genuine premature ejaculation has a significant relationship with decreased levels of seminal plasma magnesium and semen—to—serummagnesium ratio. also, there is a relationship between the bmi and genuine premature ejaculation. however, more studies are warranted to determine the role of magnesium in the physiology of the male reproductive tract and especially its association with premature ejaculation. interventional studies with magnesium supplements seem to be useful as well. references 1. rosen rc. prevalence and risk factors of sexual dysfunction in men and women. curr psychiatry rep. 2000;2:189-95. 2. ryzen e, rude rk. low intracellular magnesium in patients with acute pancreatitis and hypocalcemia. west j med. 1990;152:145-8. 3. kanmura y, itoh t, kuriyama h. mechanisms of vasoconstriction induced by 9,11-epithio-11,12-methanothromboxane a2 in the rabbit coronary artery. circ res. 1987;60:402-9. 4. baltrons ma, saadoun s, agullo l, garcia a. regulation by calcium of the nitric oxide/cyclic gmp system in cerebellar granule cells and astroglia in culture. j neurosci res. 1997;49:333-41. 5. omu ae, al-bader aa, dashti h, oriowo ma. magnesium in human semen: possible role in premature ejaculation. arch androl. 2001;46:59-66. 6. sadock va. normal human sexuality and sexual and gender identity disorders. in: sadock va, sadock bj, editors. kaplan and sadock's comprehensive textbook of psychiatry. 7th ed. philadelphia: lippincott williams and wilkins; 2000. p. 1592-93. 7. world health organization. who laboratory manual for the examination of human semen and semencervical mucus interaction. 3rd ed. new york: cambridge university press; 1993. p. 5-23. 8. enders db, rude rk. mineral and bone metabolism. in: bartis ca, ashwood er, editors. tietz fundamentals of clinical chemistry. 5th ed. philadelphia: wb saunders; 2001. p. 805. 9. haralambie g. electrolytes, trace-elements and vitamins in exercise. med sport. 1981:13:134-52. 10. rayssiguier y, guezennec cy, durlach j. new experimental and clinical data on the relationship between magnesium and sport. magnes res. 1990;3:93102. 11. whang r, ryder kw. frequency of hypomagnesemia and hypermagnesemia. requested vs routine. jama. 1990 jun 13;263(22):3063-4. 12. papadakis ma. fluid and electrolyte disorders. in: tierney lm, mcphee sj, papadakis ma, editors.current medical diagnosis and treatment. 3rd ed. new york: mcgraw-hill; 2001. p. 742-67. urological oncology needle tip culture after prostate biopsy: a tool for early detection for antibiotics selection in cases of post-biopsy infection ian-seng cheong1, yuh-shyan tsai2, chun-hsiung kang1, yeong-chin jou1,3, pi-che chen1, chang-te lin1* purpose: to investigate biopsy needle tip culture after prostate biopsies for bacteria prediction and antibiotics selection. materials and methods: from may 2017 to april 2019, 121 patients who underwent a prostate biopsy were enrolled. all biopsy needle tips were sent for aerobic and anaerobic culture. patients were divided into positive and negative culture groups. perioperative data were recorded and compared between the two groups. the culture time and susceptibility of febrile patients were analyzed. blood cultures were conducted for all patients who experienced fever after biopsy. the time and results of the needle and blood cultures were recoded for descriptive analysis. results: there were 59 (48.8%) positive needle cultures. other than fever (p = 0.023), there were no statistical significances in clinical data between the two groups. fever occurred in eight patients, and seven febrile patients had positive needle cultures, six of whom had positive blood cultures. these six needle and blood cultures were consistent with the susceptibility test results. as compared to the waiting time for blood cultures, target antibiotics were administered at an average of 48.0 h earlier based on needle cultures. none of the patients with positive anaerobic cultures developed a fever, while all eight febrile patients had negative anaerobic cultures. conclusion: fevers developed at statistically significant higher rate among those who had positive needle cultures. needle and blood cultures were consistent with the susceptibility test results. needle cultures can help us administer target antibiotics earlier to febrile patients without the need to wait for blood cultures. keywords: biopsy; needle; culture; anti-bacterial agents; prostatic neoplasms introduction prostate cancer was the second most common cause of cancer-related death among men in the united states in 2018.(1) transrectal ultrasound-guided prostate biopsy (truspb) is the gold standard for the diagnosis of prostate cancer.(2) regardless of whether the objective is diagnosis or active surveillance of prostate cancer, or whether the method involves systematic sextant biopsy or a combined method of magnetic resonance imaging with ultrasound fusion-guided targeted biopsy, with any transrectal procedure, infection remains a common complication. despite the prescription of antibiotic prophylaxis, the infection rate after truspb is reportedly 0%–6.3% and can potentially progress to sepsis.(2,3) although sepsis-related mortality is relatively rare, with an incidence of 0.095%–0.24%,(4, 5) mortality and the development of sepsis after truspb are disastrous. according to the surveillance of multicenter antimicrobial resistance in taiwan in 2018, the ciprofloxacin resistance rate of e.coli was about 31.2%, and this associated with risk of infection.(6) as for high risk patients, such as those with diabetes mellitus and geriatric patients,(7-9) physicians 1department of urology, ditmanson medical foundation chia-yi christian hospital, 539 chung-hsiao road, chiayi city, taiwan. 2department of urology, national cheng kung university hospital, college of medicine, national cheng kung university, 138 shengli road, tainan city, taiwan. 3department of food nutrition and health biotechnology, asia university, taichung city, taiwan. correspondence: department of urology, ditmanson medical foundation chia-yi christian hospital, 539 chunghsiao road, chiayi city, taiwan. tel: 886-5-2332-3456. e mail: 01160@cych.org.tw received january 2020 & accepted july 2020 concerned with severe complications may delay prostate biopsy procedures. hence, it is important to find an antibiotics selection detection tool. because infection may lead to sepsis or even mortality, post truspb infection-related issues are concerning; thus, management is needed to prevent such complications both before and after a biopsy.(10-12) more specifically, the prediction of pathogenic bacteria and the choice of an appropriate antimicrobial agent are the most important considerations. although blood culture (b/c) and rectal swab cultures are advocated, the former is time-consuming and the latter is used for prevention, not post-biopsy infection management, as it is focused on prophylaxis and the prediction of antimicrobial resistance preoperatively, rather than the management of post truspb infection of febrile patients. pathogens in the rectal mucosa can be inoculated in the prostate and blood stream by the biopsy needle, thereby inducing infection.(13) typically discarded as medical waste, the biopsy needle is the first instrument to come in contact with pathogens, thus it is relatively simple to culture pathogens attached to the needle that induce fever after truspb in real-time. tip cultures of intravenous lines, suction tubes, and urology journal/vol 18 no. 3/ may-june 2021/ pp. 307-313. [doi: 10.22037/uj.v16i7.5912] chest tubes have been investigated as predictors of infection and even bacteremia in previous studies.(1416) furthermore, peacock et al. reported that 23.5% of positive intravenous line tip cultures were associated with b/c positivity for the same microbial species with matching susceptibility test results.(14) unlike investigations of other tip cultures, the use of a biopsy needle tip culture (n/c) after truspb has not been reported, which peaked our interest in n/c studies of febrile patients after truspb. in order to investigate whether n/c can predict pathogens and help to choose an appropriate antimicrobial agent, we evaluated the clinical data on truspb cases over a 2 year period at our hospital. materials and methods the institutional review board of chiayi christian hospital approved the study protocol (chiayi, taiwan; approval no. 2018079). the study cohort was limited to patients who underwent truspb at chiayi christian hospital from may 2017 to april 2019 and men with either an increased concentration of prostate-specific antigen (psa) (ng/ml) and/or suspicious digital rectal examination results. patient histories of perineal pain, chronic pelvic pain syndrome, previous truspb, rectal-related disease, prostate volumes, and abnormal prostate findings by transrectal ultrasound were recorded. routine blood analysis as well as urinalysis and urine culture (u/c) were checked preoperatively. antibiotic prophylaxis with fluoroquinolone was administered for a total of three days (preoperative day 1, the day of surgery, and postoperative day 1). bard® max-core® disposable core biopsy instruments (c.r. bard, murray hill, nj, usa) were used for all biopsies. the biopsy needle tips were cut off with sterile wire cutters, 4–5 cm in length, for aerobic and anaerobic cultures. b/cs of febrile patients were conducted upon return to our hospital. patient characteristics, blood/urine analysis, number of biopsy cores, postoperative complications, b/c, and n/c results were recorded for analysis. the saving time was also recorded by calculating from the time of prescribing target antibiotics based on n/c results to the time of obtaining the b/c results of febrile patients. table 1. stratification of variable of interest for patients with positive (n = 59) and negative (n = 62) biopsy needle culture results positive negative p value demographic variables patients, n 59 62 age, years mean ± sd 66.55 ± 8.60 66.92 ± 8.64 0.813 prostate volume (ml) mean ± sd 55.91 ± 28.59 54.37 ± 21.97 0.767 psa (ng/ml) median (25th–75th percentile) 14.1 (7.12–35.96) 12.85 (7.89–49.88) 0.620 pre-op wbc (×103/ul) mean ± sd 7.51 ± 2.18 6.77 ± 2.32 0.129 pre-op cr (mg/dl) mean ± sd 0.97 ± 0.30 0.94 ± 0.35 0.652 pre-op sugar (g/dl) mean ± sd 123.67 ± 43.89 118.51 ± 40.83 0.576 pre-op got (u/l) mean ± sd 23.40 ± 7.47 28.59 ± 13.78 0.057 pre-op gpt (u/l) mean ± sd 20.82 ± 7.77 27.59 ± 22.25 0.057 pre-op pt (s) mean ± sd 11.04 ± 0.80 11.10 ± 0.95 0.759 pre-op aptt (s) mean ± sd 33.51 ± 4.06 34.05 ± 3.68 0.528 pre-op urine culture (n) 0.485 positive 7 5 negative 52 57 pathology (n) benign 34 28 0.170 malignant 25 34 fever (n) 0.023a fever 7 1 no fever 52 61 cpps (n) 0.588 yes 1 2 no 58 60 diabetes mellitus (n) 0.138 yes 10 5 no 49 57 hypertension (n) 0.716 yes 12 11 no 47 51 rectal disease (n) 0.818 yes 5 6 no 54 56 ap < 0.05. pre-op = preoperative; wbc = white blood cell; cr = creatinine; got = glutamic oxaloacetic transaminase; gpt = glutamic pyruvic transaminase; pt = prothrombin time; aptt = activated partial thromboplastin time; cpps = chronic pelvic pain syndrome. needle tip culture for biopsy infection-cheong et al. urological oncology 308 vol 18 no 3 may-june 2021 309 descriptive and comparative analyzes were performed using ibm spss statistics software, version 21.0 (ibm corp., armonk, ny, usa). three types of statistical analyzes were used (i.e., an independent-sample t-test, mann–whitney u test, and chi-squared test) to identify differences in variables between patient groups with positive vs. negative n/c results. a probability (p) value of < 0.05 was considered statistically significant. results in total, 121 consecutive patients (mean age, 66.7 ± 8.62 years) underwent truspb in our hospital during the study period. the mean prostate volume was 55.1 ± 25.46 ml and the median prostate-specific antigen (psa) was 13.5 (25th–75th percentile, 7.54–42.92) ng/ ml. preoperative u/c results were positive in twelve patients. eight patients (6.6%) developed fever after truspb and the mean time to fever onset after the biopsy in the study period was 51.57 ± 36.05 hours. biopsy needle cultures were positive in 59 (48.8%) of 121 patients. the patients were assigned to the n/c-positive or -negative group. as shown in table 1, there were no significant differences between two groups in age, prostate volume, psa level, preoperative laboratory tests, and u/c results. there was also no significant difference in the pathology results and underline diseases. the postoperative fever was the only variable with a significant difference (p = 0.023) between the two groups. furthermore, we recorded the b/c and n/c results of the febrile patients; seven of eight febrile patients with n/c results were positive for escherichia coli (e. coli). as shown in table 2, the b/c results of six patients were also positive for e. coli. all of the pathogens detected by n/c and b/c were resistant to fluoroquinolone and notably, they were susceptible to piperacillin/tazobactam, amikacin, and carbapenem. furthermore, the n/c and b/c results were consistent with the findings of the susceptibility tests. the culture times of all positive n/cs are shown in figure 1a and the times to obtain the n/c and b/c results of febrile patients are shown in figure 1b. of the 121 patients, the n/c results were positive in 59 (48.8%), which included 54 positive aerobic cultures and nine positive anaerobic cultures. among the 59 positive n/ cs, only four cases had positive results for both aerobic and anaerobic bacteria. seven of eight febrile patients had positive n/c results, including six positive and two were negative for b/c (figure 1b). the saving times were 25, 73, 43, 26, 62, and 59 h in cases 8, 15, 49, 93, 118, and 120, respectively. the mean saving time was 48.0 h. in case 49 of figure 1b, the n/c results were obtained before the onset of fever and returning to the hospital; the mean time to receiving the b/c results was 43.0 h. upon receiving a positive n/c result, the patient was administered the target therapeutic antimicrobial agent based on n/c in the emergency room. the saving time was 43.0 h. of the positive n/c samples (n = 59), the most common bacterium was e. coli (n = 34, 57.6%), which was identified in seven of eight febrile patients and 27 of 62 afebrile patients. nine patients had positive anaerobic n/c results, but none developed a fever. details of the detected bacteria are listed in table 3. discussion in the present study, the n/c results were positive for 59 (48.8%) patients. the most common bacterium was e. coli (57.6%). fever developed in eight patients. seven of them had positive n/c and all the results were e. coli and six of the seven n/c results were consistent with the b/c findings. the average saving time was 48.0 h (figure 1b). of the nine patients with positive anaerobic cultures, none developed a fever and none of the four febrile patients had positive anaerobic cultures. in general, the prediction of pathogenic bacteria and the early administration of target antibiotics were based on the b/c and u/c results. b/c is the gold standard and first-line test for blood stream infections,(17) but it is time-consuming and does not always yield positive results for febrile patients. although many new methods and automated b/c systems for the diagnosis of positive b/cs with reduction of culture time are available,(18) the indication for b/c was that bacteremia was suspected, such as fever or leukocytosis;(19) therefore, the timing of collecting b/cs was later than that of n/cs; thus, b/c results might be obtained later. because the biopsy needle is the first real time object to come into contact with potential pathogens, n/c was performed needle tip culture for biopsy infection-cheong et al. table 2. description of biopsy needle tip cultures and blood cultures of febrile patients case 8 case 15 case 18 case 49 case 93 case 118 case 120 case 121 n/ca b/cb n/c b/c n/c b/c n/c b/c n/c b/c n/c b/c n/c b/c n/c b/c bacteria e.coli e.coli e.coli e.coli e.coli e.coli e.coli e.coli e.coli e.coli e.coli e.coli e.coli susceptibility test ampicillin/sulbactam rd r s s s s s s s s s r r piperacillin/tazobactam se s s s s s s s s s s s s gentamicin s s s s s r r s s r r r r amikacin s s s s s s s s s s s s s levofloxacin r r r r r r r r r r r r r ertapenem s s s s s s s s s s s s s meropenem s s s s s s s s s s s s s trimethoprim/sulfamethoxazole r r r r r r r r r r r r r cefazolin r r r r r s s r r i i r r cefuroxime if r r r r s s r r s s r r cefotaxime r r r r r s s r s i i r r cefepime s s dg d d s s d s s s r r saving timec (h) mean 48.0 h 25 73 43 26 62 59 abiopsy needle tip culture. bblood culture. csaving time: saving the waiting time for blood culture the time from prescribing antibiotics based on susceptibility tests of t/c to getting results of b/c. dresistant. esusceptible. fintermediate. gsusceptible-dose dependent. immediately after the biopsy. therefore, the n/c results were obtained earlier than those of b/c for the timely diagnosis of fever when patients presented to the hospital. in the cohort of the present study, there were six febrile patients with positive results for both b/c and n/c. notably, the b/c and n/c results of each patient were consistent with the findings of the susceptibility tests. in the previous use of target antibiotics, we often waited for the susceptibility test results of b/c.(12) if the n/c and b/c results are in agreement with those of the susceptibility tests, time can be saved waiting for b/c results, as it is possible to prescribe target antibiotics for pathogens based on the n/c results alone. in this study, we did not have to wait for b/c, and we were able to save an average time period of 48.0 h to identify a target antimicrobial agent based on n/c results, which was truly clinically beneficial (figure 1b, table 2). in regard to pathogen prediction, the b/c results are not always positive in febrile patients. the reported b/c positivity rate of febrile patients after truspb ranges widely from 16% to 78%.(20-22) in this study, six of eight febrile patients (75%) had positive b/c results, which is consistent with previous reports. two febrile patients (case 18 and 121, 25%) had negative b/c results; thus, the susceptibility test of n/c was useful for selection of an appropriate antimicrobial agent. because the n/c and b/c results were mostly consistent, if the b/c result was negative, n/c becomes the most important reference to select target antibiotics (table 2). u/c was also considered for the prediction of potential pathogens. however, as noted in previous studies, pathogens pre-existed in the rectum rather than the urinary tract, thus dysuria or a history of urinary tract infection was not predictive of a truspb-related infection.(20) therefore, preoperative u/c is less useful for the identification of pathogens after truspb. this was revealed in the present study showing that only seven patients had positive preoperative u/c results, demonstrating no significance with the onset of fever. other than b/c and u/c, cultures of rectal swabs was recommended for the prediction of pathogens.(23) because prophylaxis with fluoroquinolone is recommended by the guidelines of the american urological association and european urological association, rectal swabs were used to identify fluoroquinolone-resistant bacteria to facilitate target antibiotic prophylaxis in previous studies.(24) however, other investigations have revealed that this strategy does not reduce post truspb-related infectious complications or hospitalization. (25,26) therefore, using rectal swab cultures to prevent infection after truspb remains controversial. furthermore, rectal swab cultures focus on the prediction of antimicrobial resistance to direct appropriate administration of prophylactic antimicrobial agents. in addition, rectal swab cultures are usually conducted several days before a scheduled biopsy and, therefore, represent bacteria existing in the rectum several days beforehand, rather than real-time detection of pathogens that could induce fever after truspb. moreover, antimicrobial prophylaxis does not always prevent sepsis after transrectal prostate biopsy.(27,28) at present, rectal swab cultures are not widely applied, as mentioned at the 2019 american society of clinical oncology meeting in a report by jonathan shoag of the surveillance, epidemiology and end results data.(29) in this study, of 246,299 males who underwent prostate biopsies, only 0.5% utilized pre-biopsy rectal swab procedures. another interesting point of discussion is the role of anaerobic bacteria in post truspb infections. however, limited studies have mentioned anaerobic bacteria as potential pathogens of post truspb infections.(30) in our study, prophylactic anti-anaerobic antimicrobial agents were not prescribed even though nine patients had positive n/c results for anaerobic bacteria (table 3). nonetheless, none of these nine patients developed table 3. aerobic and anaerobic bacteria of febrile and afebrile patients non-fever fever aerobic (patient number,%) 47(38.8%) 7(5.8%) escherichia coli 27 7 enterococcus faecalis 7 streptococcus mitis/oralis (viridans group) 5 klebsiella pneumoniae 5 streptococcus group b 4 streptococcus anginosus (viridans group) 3 bacillus spp. 2 acinetobacter baumannii 2 enterococcus hirae 1 enterococcus raffinosus 1 enterococcus faecium 1 enterobacter agglomerans 1 streptococcus pasteurianus (s. bovis biotype ii.2) 1 streptococcus alactolyticus (viridans group) 1 brevundimonas diminuta/vesicularis 1 streptococcus anginosus (viridans group) 1 streptococcus salivarius 1 sphingomonas paucimobilis 1 granulicatella adiacens 1 anaerobic (patient number,%) 9(7.4%) 0(0%) bacteroides fragilis 3 clostridium perfringens 1 bacteroides thetaiotaomicron 1 bifidobacterium spp 1 fusobacterium nucleatum 1 parabacteroides distasonis 1 peptostreptococcus anaerobius 1 needle tip culture for biopsy infection-cheong et al. urological oncology 310 vol 18 no 3 may-june 2021 311 a fever and all febrile patients had negative n/c results for anaerobic bacteria. therefore, we suppose that anaerobic bacteria are not regularly pathogens that induce fever after truspb. n/c is not expensive according to taiwan national health insurance as each n/c costs about 6.3 us dollars. if considering cost effectiveness, we suggested that n/c can be applied in high risk geriatric, diabetes mellitus and immunosuppressed patients. in addition to a reduction in hospital stay, the advantages of n/c are as follows: (1) allows for early use of target antimicrobial agents to prevent the clinical course progression to a more severe or irreversible condition; (2) b/c may be substituted by n/c when b/c is negative; (3) n/c can shorten the broad-spectrum antibiotic course to decrease the production of antimicrobial agents resistance; (4) early use of target antimicrobial agents can decrease the adverse effects of broad-spectrum antibiotics. limitations of the present study included the following: (1) the relatively low number of cases, which should be increased in future studies to increase the strength of evidence; (2) the rate of e. coli detection by n/c and b/c in febrile patients was consistent with that of the susceptibility test, although we did not identify the strains of these e. coli isolates. thus sequencing of 16s rdna is needed to arrive at a definitive confirmation; (3) we only calculated the saving time with the same culture procedure in our hospital, thus future studies of different cultural procedures are needed; and (4) postoperative u/c of febrile patients was not a focus of this study because of the delay in obtaining results; thus, further analyses are needed to determine if the collection of urine immediately after truspb might have different results. conclusions fever was statistically significant in the n/c positive group. the n/c and b/c results were consistent with those of susceptibility testing. n/c can help to administer earlier targeted antibiotics to febrile patients, thus eliminating the need to wait for b/c results. figure 1. time-consuming after procedure. each number along the y-axis represents a patient with a positive needle tip culture. blue bars represent positive aerobic needle tip cultures, yellow bars represent positive anaerobic needle tip cultures, pure red bars represent positive blood cultures, and red-black bar represents negative blood cultures. a. calculation of the saving time in four febrile patients after biopsy. each number along the y-axis represents each febrile patient after biopsy. blue bars represent positive aerobic needle tip cultures, pure red bars represent positive blood cultures, red-black bar represents negative blood cultures, and blue-black bar represents negative aerobic needle tip cultures. a: the days the needle tip cultures were performed. b: the times of obtaining results of needle tip cultures. c: the times the blood cultures of febrile patients were performed. d: the times the blood culture results were obtained. e: the times that antimicrobial agents were prescribed based on needle tip cultures. x: no growth in blood culture or needle tip culture. e to d: the saving time (48.0 h in average). needle tip culture for biopsy infection-cheong et al. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2018. ca cancer j clin. 2018;68:730. 2. loeb s, vellekoop a, ahmed hu, et al. systematic review of complications of prostate biopsy. eur urol. 2013;64:876-892. 3. bennett hy, roberts mj, doi sa, gardiner ra. the global burden of major infectious complications following prostate biopsy. epidemiol infect. 2016;144:1784-1791. 4. pinsky pf, parnes hl, andriole g. mortality and complications after prostate biopsy in the prostate, lung, colorectal and ovarian cancer screening (plco) trial. bju int. 2014;113:254-259. 5. loeb s, carter hb, berndt si, ricker w, schaeffer em. complications after prostate biopsy: data from seer-medicare. j urol. 2011;186:1830-1834. 6. lee yl, lu mc, shao pl, et al. nationwide surveillance of antimicrobial resistance among clinically important gram-negative bacteria, with an emphasis on carbapenems and colistin: results from the surveillance of multicenter antimicrobial resistance in taiwan (smart) in 2018. int j antimicrob agents. 2019;54:318-328. 7. loeb s, van den heuvel s, zhu x, bangma ch, schroder fh, roobol mj. infectious complications and hospital admissions after prostate biopsy in a european randomized trial. eur urol. 2012;61:1110-1114. 8. carignan a, roussy jf, lapointe v, valiquette l, sabbagh r, pepin j. increasing risk of infectious complications after transrectal ultrasound-guided prostate biopsies: time to reassess antimicrobial prophylaxis? eur urol. 2012;62:453-459. 9. cheong i-s, lin c-t, jou y-c, cheng m-c, shen c-h, chen p-c. one day hospitalization for trans-rectal ultrasound guided prostate biopsy: experiences of a single institution. urol science. 2017;28:235-239. 10. derin o, fonseca l, sanchez-salas r, roberts mj. infectious complications of prostate biopsy: winning battles but not war. world j urol. 2020. 11. roberts mj, bennett hy, harris pn, et al. prostate biopsy-related infection: a systematic review of risk factors, prevention strategies, and management approaches. urology. 2017;104:11-21. 12. liss ma, ehdaie b, loeb s, et al. an update of the american urological association white paper on the prevention and treatment of the more common complications related to prostate biopsy. j urol. 2017;198:329-334. 13. batura d, rao gg, nielsen pb. prevalence of antimicrobial resistance in intestinal flora of patients undergoing prostatic biopsy: implications for prophylaxis and treatment of infections after biopsy. bju int. 2010;106:1017-1020. 14. peacock sj, eddleston m, emptage a, king a, crook dw. positive intravenous line tip cultures as predictors of bacteraemia. j hosp infect. 1998;40:35-38. 15. sankar b, ray p, rai j. suction drain tip culture in orthopaedic surgery: a prospective study of 214 clean operations. int orthop. 2004;28:311-314. 16. yamauchi y, isaka m, maniwa t, takahashi s, kurai h, ohde y. chest tube tip culture as a predictor of postoperative infection in lung cancer operations. ann thorac surg. 2013;96:1796-1802. 17. chandrasekar ph, brown wj. clinical issues of blood cultures. arch of int med. 1994;154:841-849. 18. opota o, croxatto a, prod'hom g, greub g. blood culture-based diagnosis of bacteraemia: state of the art. clin microbiol and infect. 2015;21:313-322. 19. coburn b, morris am, tomlinson g, detsky as. does this adult patient with suspected bacteremia require blood cultures? jama. 2012;308:502-511. 20. lindert ka, kabalin jn, terris mk. bacteremia and bacteriuria after transrectal ultrasound guided prostate biopsy. j urol. 2000;164:76-80. 21. anderson e, leahy o, cheng ac, grummet j. risk factors for infection following prostate biopsy a case control study. bmc infect dis. 2015;15:580. 22. raaijmakers r, kirkels wj, roobol mj, wildhagen mf, schrder fh. complication rates and risk factors of 5802 transrectal ultrasound-guided sextant biopsies of the prostate within a population-based screening program. urology. 2002;60:826-830. 23. gottesman t, yossepowich o, hararischwartz o, tsivian a, idler j, dan m. the value of rectal cultures in treatment of sepsis following post-transrectal ultrasound-guided prostate biopsy. urol int. 2015;95:177-182. 24. hasanzadeh a, black p, pourmand mr, pourmand g. clinical and bacterial risk factors for development of post-prostate biopsy infections. urol j. 2019;16:603-608. 25. summers sj, patel dp, hamilton bd, et al. an antimicrobial prophylaxis protocol using rectal swab cultures for transrectal prostate biopsy. world j urol. 2015;33:2001-2007. 26. cheung c, patel hd, landis p, carter hb, han m. targeted antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy during active surveillance: effect on hospitalization. urol oncol. 2018;36:158 e157-158 e112. 27. korkmaz n, gurbuz y, sandikci f, kul g, tutuncu ee, sencan i. the role of ciprofloxacin resistance and extendedspectrum beta-lactamase (esbl) positivity in infective complications following prostate biopsy. urol j. 2020;17:192-197. 28. jiang p, liss ma, szabo rj. targeted antimicrobial prophylaxis does not always prevent sepsis after transrectal prostate biopsy. j urol. 2018;200:361-368. needle tip culture for biopsy infection-cheong et al. urological oncology 312 vol 18 no 3 may-june 2021 313 29. jonathan shoag, tianyi sun, morgan pantuck. risk factors for post prostate biopsy infection. j clin oncol, 37: 2019 (suppl 7s; abstr 103) https://meetinglibrary.asco.org/ record/170060/abstract. 30. harris lf, jackson rt, breslin ja, alford rh. anaerobic septicemia after transrectal prostatic biopsy. arch int med. 1978;138:393395. needle tip culture for biopsy infection-cheong et al. incisional hernia after renal transplantation and its repair with propylene mesh mahdavi r*, mehrabi m department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran abstract purpose: kidney recipients are susceptible to incisional hernia. we studied predisposing factors for incisional hernia in our patients and the results of its repair with propylene mesh. materials and methods: from 1989 to 2002, 589 patients had undergone kidney transplantation in our hospital. of these, patients who developed incisional hernia were evaluated in this study. the following data were collected from their records: age, gender, weight, age at graft rejection, surgical complications, treatment method, and the treatment results with propylene mesh. results: of 589 recipients, 16 (3%) developed incisional hernia in surgical site. the median interval between kidney transplantation and developing of incisional hernia was 48 (range 12 to 425) days. predisposing factors were overweight, age over fifty years, and female gender (p <0.005). in four patients, hernia was small, and the repair was performed without using mesh. three patients were reluctant to hernia repair, and in 9, due to the large size of hernia, repair was done using propylene mesh. having these 9 patients treated with propylene mesh, 2 developed serous collection in surgical site, which were managed successfully with multiple punctures. hernia recurrence or infection was not noted in these patients during 3 to 36 months follow-up periods. conclusion: incisional hernia is not a rare entity after kidney transplantation. predisposing factors, such as overweight, age over 50 years, and female gender have a role in its development. also, repeated surgeries in kidney recipients can increase the risk of incisional hernia. managing this complication with propylene mesh is a safe and effective method. key words: incisional hernia, kidney transplantation, propylene mesh 259 urology journal unrc/iua vol. 1, no. 4, 259-262 autumn 2004 printed in iran introduction incisional hernia is a prevalent complication in kidney allograft recipients, due to prolonged dialysis, immunosuppressive drugs, especially, corticosteroids, and high prevalence of diabetes. overall incidence rate of incisional hernia after abdominal surgery in normal population is 2% to 13%.(1-3) but, its incidence after kidney transplantation is unclear. incisional hernia repair following an abdominal surgery without using mesh, leads to a higher recurrence rate (30 % to 50%). since the introduction of propylene mesh for repair of incisional hernia by usher in 1958, the recurrence rate has reduced to 10%.(4,5) the use of immunosuppressive drugs increases the chance of infection with synthetic materials such as propylene mesh. on the other hand, using mesh in order to prevent hernia recurrence in patients with multiple predisposing factors is necessary. unfortunately, there is little information received may 2003 accepted november 2004 *correspondng author: department of urology and kidney transplant, imam reza hospital, mashhad, iran. fax: +98 511 859 8946, email: drmahdavireza@yahoo.com. incisional hernia after renal transplantation regarding the use of propylene mesh in incisional hernia after kidney transplantation. in this study, we report our experience in incisional hernia repair after kidney transplantation, using propylene mesh. materials and methods in a 12-year period, from1989 to 2002, 630 kidney transplantations had been done in our hospital. of these, 41 cases were in the patients who had received a second kidney allograft in this center. we retrospectively studied all cases of incisional hernia. median age of the recipients was 31 (range 6 to 68) years. of recipients, 384 were male and 195 were female. kidney allografts were from living donors in 620 cases and cadaver in 10 cases. in kidney transplantation, paramedian incision was used, so that muscle splitting would not be required i.e. access to pelvic space would be provided by incising the fascia of internal or external oblique muscles or transverse muscle. arterial anastomosis of kidney allograft to internal or external iliac artery and end to end venous anastomosis were performed in pelvis. in all the patients, two hemovac drains were inserted into surgical sites, one in the upper portion of incision in retroperitoneum and the other, adjacent to the ureterovesical anastomosis. fascia was repaired in two layers with nylon-0 using continuous suture in adults and interrupted sutures in children. in patients who had copious subcutaneous fat, a third subcutaneous drain was placed for 2 to3 days. sutures were removed 14 days after transplantation. our immunosuppression protocol was 3-drug regimen with cyclosporine, azathioprine, and prednisolone. recently, in some patients, azathioprine was replaced with mycophenolate mofetil, due to its lower complication rates. in case of acute rejection, methylprednisolone 1 gr per day would be administered for three days and in the refractory cases, anti-lymphocyte globulin would be used. after discharge, all of the patients were followed periodically. in cases with incisional hernia, patients were referred to the surgeon and evaluated regarding weight, presence of diabetes mellitus, age, gender, previous history of acute rejection, surgical complications such as hematoma, lymphocele, infection, and the size of hernia and its impact on patient. patients with relatively large incisional hernia in transplantation site underwent hernia repair with the assistance of a general surgeon, using propylene mesh, preceded by informing them of the possible complications. propylene mesh was used with two methods; if approximation of fascial edges was possible mesh would be placed on the fascia--this method was applicable only in 2 cases. when hernia was extensive (in 7 cases), the edges of fascia were identified, peritoneum was repaired, and while mesh was placed on peritoneum, it was sutured to the edges of fascia with nylon-0 sutures. before closure of the wound, a hemovac drain was inserted over the mesh, remaining for 2 to 3 days. all patients received broad-spectrum antibiotics perioperatively and were followed in the first, third, and sixth postoperative mouths and some were followed up to 6 years. statistical analysis was done with student t test and chi-square test. a p value less than 0.05 was regarded significant. results of 589 recipients, 16 developed incisional hernia. of these, 4 had small size incisional hernia, which was repaired without using mesh. three were reluctant to hernia repair, and the nine remainders underwent hernia repair with the use of propylene mesh, due to the large size of hernia. developing time of incisional hernia in a 52-year-old obese woman, wound dehiscence and evisceration of bowels occurred in the first post-transplantation week. although primary repair was performed, incisional hernia developed four weeks later. due to the large size of hernia and the thinned skin overlying the hernial sac, extensive hernia repair was done 4.5 months after transplantation. in this patient, nearly the entire abdominal wall was covered with propylene mesh. figures 1 and 2 demonstrate the incisional hernia before and after repair. in 5 patients hernia was diagnosed in the first few weeks postoperatively and in 10 patients, it was detected 3 weeks to 6 months later. finally, incisional hernia developed in the second post-transplant year in 1 case. predisposing factors gender: of 16 patients, 11 (70%) were male and 5 (30%) were female (p = 0.02). age: twelve patients were above 50 years old, and 4 were 50 or less (p = 0.05). obesity: eight patients were over 75 kg, and 8 were less than 75 kg. body mass index was not measured in this study. however, 75% of women 260 mahdavi and mehrabi with incisional hernia were apparently overweight. diabetes mellitus: of 16 patients with incisional hernia, 5 were diabetic (p = 0.2). post-transplantation surgical complications: in 2 patients, urinary fistula developed and after surgical repair of fistula, incisional hernia occurred. in one kidney recipient, after the repair of lymphocele, an incisional hernia was formed. daily corticosteroid doses during incisional hernia were 10 to 60 mg. three patients received short-term high dose methylprednisolone, due to acute rejection. complications after incisional hernia repair with mesh after hernia repair with propylene mesh, serous fluid collection was formed in two cases, which were treated successfully with multiple punctures. infection or recurrence was not observed postoperatively. discussion the general prevalence of incisional hernia is 2% to 13%.(1,3) its predisposing factors are age, obesity, alcoholism, smoking, emergency surgeries, foreign body implantation, wound infection, hematoma, technical error, and unsuitable suture material. in addition, medical illnesses such as chronic renal failure, liver insufficiency, and pulmonary diseases are among predisposing factors.(6-8) in patients with chronic renal failure, who have undergone kidney transplantation, multiple factors interfere with wound healing, such as long-term uremia, malnutrition before kidney transplantation, and administration of corticosteroids and azathioprine, postoperatively. the prevalence of incisional hernia in our patients was 3%. in other studies, the reported prevalence of incisional hernia after kidney transplantation is between 2% and 3.8%.(4,7) incisional hernia is not a rare entity after kidney transplantation. detecting predisposing factors and subsequently, meticulous surgical operation can reduce its prevalence. it can occur immediately or some years postoperatively, but in more than half of the cases, it develops in the first postoperative three months, and in up to 70% it occurs in the first postoperative year. only in 10% it develops between one to five years after transplantation.(4,5,9) in our patients, 95% (16) of cases were seen within 6 months after kidney transplantation and only one patient developed incisional hernia one year post-operatively. in a 52-year-old woman wound dehiscence occurred in the first post-transplantation week that was accompanied by evisceration. urgent surgical repair was done, but after 3 weeks, when she was discharging, an extensive incisional hernia had occurred (fig. 1). hernia gradually increased within 3 months causing problems with walking, and the majority of bowels were in hernial sac. four months after kidney transplantation, her incisional hernia was repaired successfully with propylene mesh. in a 35-year-old male, surgery was complicated by lymphocele. his large lymphocele was marsupialized into peritoneum 4 weeks after kidney transplantation, but in the second month of follow-up, an incisional hernia was detected. of 16 patients with incisional hernia, 11 (70%) were female and most of them were over 50 years old and weighed over 75 kg. it seems that, gender, age, and weight are among important predisposing factors for incisional hernia. doubtlessly, corticosteroids play an important role in developing incisional hernia, because they can interfere with wound healing. long-term use 261 fig. 1. a 52-year-old woman with incisional hernia, 1 month after kidney transplantation fig. 2. incisional hernia repair. nearly the entire abdominal wall is covered with propylene mesh. incisional hernia after renal transplantation of corticosteroids, especially during acute rejection, in which higher doses of methylprednisolone (1gr/ daily) are administered, has a considerable impact on developing incisional hernia.(6,10) of 16 patients in our study, four suffered from acute rejection and received high dose methylprednisone. other assumed predisposing factors in our patients were: hematoma in surgical site in 3 (19%), lymphocele in 1 (6%), and urinary fistula in 2 (12%). repeated surgeries in the last two items predispose the patient to incisional hernia. the risk of recurrence after repair of incisional hernia without using mesh is more than 50%,(11) but after introduction of mesh usage in hernia repair by usher and colleagues in l958, the rate of recurrence reduced to 10%.(5) the resultant inflammatory response and connective tissue proliferation conduce to fibrosis formation and a thick scar plate. this can prevent recurrence of hernia.(2,4,11,12) despite valuable results with propylene mesh, synthetic material can cause infection, migration into bladder or intestine, and damage to the adjacent tissues such as spermatic cord.(11,13,14) these complications increase in immunosuppressed patients. one of the important complications in our patients was the serous collection in the site of surgery that subsided after multiple punctures. hernia recurrence and infection in surgical site were not seen in our series. however, the sample size was small in our study and further studies in large scales are needed. conclusion one of the surgical complications after kidney transplantation is incisional hernia. it often develops in the first year, especially the first few months after transplantation. this complication is more prevalent in females, patients over 50 years, and overweight ones. patients with surgical complications such as hematoma, lymphocele, or urinary fistula are also predisposed to incisional hernia. determining the predisposing factors and considering strict surgical principles, are of great essence. surgical treatment of incisional hernia with propylene mesh is a safe and effective treatment method. references 1. eubanks ws. hernias. in: townsend cm, mattox kl, evers bm, editors. sabiston text book of surgery. 16th ed. philadelphia: wb saunders; 2001. p.783-801. 2. houck jp, rypins eb, sarfeh ij, juler gl, shimoda kj. repair of incisional hernia. surg gynecol obstet. 1989;169:397-9. 3. wants ge. abdominal wall hernias. in: shwartz si, shires gt, spencer fc, daly jm, fischer je, galloway ac, editors. principles of surgery. 7th ed. mcgraw hill; 1999. p.1585-611. 4. clemente ramos lm, burgos revilla fj, et al. reconstructive surgery with polypropylene mesh associated with kidney transplant. actas urol esp. 1998;22:320-5. 5. usher fc, ochsner j, tuttle ll jr. use of marlex mesh in the repair of incisional hernias. am surg. 1958;24:969-74. 6. morris pj. azathioprine and steroids. in: morris pj, editor. kidney transplantation principles and practice. 5th ed. wb saunders; 2001. p. 217-26. . 7. pirsch jd, armbrust mj, knechtle sj, et al. obesity as a risk factor following renal transplantation. transplantation. 1995; 59:631-3. 8. sugerman hj, kellum jm jr, reines hd, demaria ej, newsome hh, lowry jw. greater risk of incisional hernia with morbidly obese than steroid-dependent patients and low recurrence with prefascial polypropylene mesh. am j surg. 1996;171:80-4. 9. ellis h, gajraj h, george cd. incisional hernias: when do they occur? br j surg. 1983;70:290-1. 10. barry jm. renal transplantation. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.345-73. 11. klinge u, klosterhalfen b, muller m, schumpelick v. foreign body reaction to meshes used for the repair of abdominal wall hernias. eur j surg. 1999;165:665-73. 12. liakakos t, karanikas i, panagiotidis h, dendrinos s. use of marlex mesh in the repair of recurrent incisional hernia. br j surg. 1994;81:248-9. 13. deveney ke. hernia and other lesions of the abdominal wall. in: way lw, doherty gm, editors. current surgical diagnosis and treatment. 11th ed. lange medical book/mcgraw hill; 2003. p.783-96. 14. leber ge, garb jl, alexander ai, reed wp. long-term complications associated with prosthetic repair of incisional hernias. arch surg. 1998;133:378-82. 262 letter 145urology journal vol 6 no 2 spring 2009 re: conservative management of early bladder rupture after postoperative radiotherapy for prostate cancer urol j. 2009;6:145. www.uj.unrc.ir sir, in urology journal 2008;5:269-71, basiri and radfar reported on the serious but rare complication of spontaneous intraperitoneal bladder rupture following salvage radiotherapy for biochemically recurrent prostate cancer.(1) this was successfully managed by conservative methods. bladder rupture has been described as a complication of both pelvic external beam radiation therapy and brachytherapy in patients with cervical, prostate, and sarcomatous soft tissue malignances, but with a much longer latent period of 7 to 15 years. unusually, this case occurred following salvage external beam radiation therapy for prostate cancer completed just 8 months previously and following an alternative hyperfractionated schedule of 72 gy at 1.2 gy per day as stated. while there are hyperfractionated (< 2 gy per day) regimens employed in the management of men undergoing definitive treatment of prostate cancer,(2) these have used as twice-daily treatment and have not been associated with increased acute or late toxicity. to my knowledge, there are no hyperfractionated salvage radiotherapy protocols for prostate carcinoma in current clinical use. while there are no details regarding bladder dose volume constraints, nor regarding on treatment urogenital toxicity, i am concerned that this unusual toxicity may have been related to the use of a nonstandard fractionation schedule in a patient who appeared to have an enhanced normal tissue reaction as evidenced by the soft tissue fibrosis they developed while on treatment. this case serves to reinforce the need for standardization of fractionation schedules in the multidisciplinary management of prostate cancer. this will be especially important as more patients with biochemical failure, margin positivity, or pt3 disease are referred for salvage or adjuvant radiation, based on recent demonstration of a survival advantage for these patients. noel john aherne north coast cancer institute, rcs faculty of medicine, university of new south wales, sydney, australia e-mail: noel.aherne@ncahs.health.nsw.gov.au references 1. basiri a, radfar mh. conservative management of early bladder rupture after postoperative radiotherapy for prostate cancer. urol j. 2008;5:269-71. 2. forman jd, duclos m, shamsa f, porter at, orton c. hyperfractionated conformal radiotherapy in locally advanced prostate cancer: results of a dose escalation study. int j radiat oncol biol phys. 1996;34:655-62. 3. swanson, gp, thompson im, tangen c, et al. update of swog 8794: adjuvant radiotherapy for pt3 prostate cancer improves metastasis free survival. int j radiat oncol biol phys. 2008;72:s31. 1216 | department of urology, first hospital of jilin university, changchun, china. qinglong chi, yan wang, ji lu, xiaoqing wang, yuanyuan hao, zhihua lu, jinghai hu, fengming jiang, qihui chen, haifeng zhang, ning xu, yuchuan hou, chunxi wang, yanbo wang ultrasonography combined with fluoroscopy for percutaneous nephrolithotomy: an analysis based on seven years single center experiences corresponding author: yanbo wang, phd department of urology, first hospital of jilin university, 71 xinmin st, 130021, changchun, jilin province, china. tel: +86 0431 8878 2321 e-mail: doctorwyb@126. com received march 2013 accepted july 2013 purpose: to assess the efficacy and safety of percutaneous nephrolithotomy (pcnl) under the guidance of ultrasonography and fluoroscopy. materials and methods: we retrospectively analyzed 562 renal calculi patients (313 men and 249 women; mean age 46 years, ranged from 13 to 70 years) who underwent 582 pcnl from march 2004 to october 2011 in our department. results: of participants, 89.6% experienced less than 3 puncture times; 2 patients (0.4%) experienced puncture failures; percentage of single or multiple tracts was 89.7% and 10.3%, respectively, 55 patients (9.5%) needed auxiliary measures after one pcnl (24 second pcnl and 31 extracorporeal shock wave lithotripsy). the mean operative time was 82.3 min (range, 45-190 min). the stone free rate was 90.5%. thirty five patients (6.0%) had postoperative fever and responded to antibiotics. three patients (0.5%) developed pleural effusion and recovered after closed drainage of thoracic cavity. thirteen patients (2.2%) needed blood transfusion. twelve patients (2.1%) developed septic shock and were given anti-shock therapy. two patients (0.3%) needed angiographic renal embolization or nephrectomy. conclusion: with its high success rate for achieving access to the targeted calyx and high stone clearance rate, the guidance of ultrasonography and fluoroscopy should be the first option in pcnl. keywords: nephrostomy; percutaneous; methods; retrospective studies; humans; fluoroscopy. endourology and stone disease endourology and stone disease 1217vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l introduction percutaneous nephrolithotomy (pcnl) has become the preferred method of treating patients with large or complex stone burdens since the first successful removal of a renal calculus via a nephrostomy tract in 1976. (1) pcnl is usually performed in the prone position with fluoroscopy guidance.(2) however, long-term x-ray exposure may cause deleterious effects for both patient and physician. ultrasonography (us) guided pcnl has become more and more popular recently.(3) us-guided access does well to avoiding adjacent and visceral injury. but the learning curve of us is longer than that of x-ray. with the growing of the number of these papers,(4-6) a debate has ensued in the urological literature regarding the optimal guiding approach. in our center, we adopted the method that combines us with fluoroscopy for pcnl in the prone position. the aim of our study was to evaluate the efficacy and safety of pcnl under the guidance of combined us and fluoroscopy. materials and methods study participants a total of 562 renal calculi patients (313 men and 249 women, mean age 46 years, ranged from 13 to 70 years) who underwent 582 pcnl from march 2004 to october 2011 were retrospectively reviewed. all the patients were diagnosed definitely before operations with a plain film x-rays, intravenous pyelography, or computed tomography (ct) scan. the inclusion criteria were patients who had kidney stones of diameter > 2.0 cm. patients were excluded from the study if they had serious cardiovascular and cerebrovascular diseases. all surgeries were performed by the same doctor. informed consent was obtained from patients before operation. the study protocol was approved by institutional review board of the first hospital of jilin university. equipment and instruments a 18-gauge coaxial needle (cook medical inc., bloomington, in, usa), fascial dilators (cook medical inc., bloomington, in, usa), zebra guide wire ((zebra® wire, boston scientific, natick, ma, usa), x-force n30 nephrostomy balloon dilation catheter (bcr inc. ny, usa), f9 olympus ureteroscope (kuehnstmsse st. 22045 hamburg, germany), f20 storz nephroscope (karl storz, tuttlingen, germany), lumenis 60w holmium lithotripter (santa clara, ca 95051, usa), cybersonics double-catheter system (cybersonics, erie, pa, usa), and aloka 5 multicolor ultrasound instrument with transducer frequency 3.5 mhz fluoroscopic table (siemens, erlangen, germany). technique of pcnl the entire procedure was performed in the urology department with the patient under general anesthesia. after the patient was placed in lithotomy position, retrograde ureter catheterization with a 5-french (f) open-ended ureteral catheter was performed. all the other procedures were completed in the prone position. under the guidance of ultrasound and x-ray, the coaxial needle was placed in the desired calyx. in the meantime, an assistant injected 0.9% sodium chloride into the ureter catheter. successful placement was confirmed if water flowed from the needle sheath. a 0.032-inch floppy-tipped guide wire was then passed through the needle into the collecting system. the working channel was then dilated by using the plastic dilator system under x-ray control to either 18f or 26f. and then, the 9f ureteroscope or the 20f nephroscope was placed directly into the kidney through the established tract. the lumenis 60w lithotripter or cybersonics double-catheter system was used to fragment the renal stone. an x-ray check for residual stone fragments was performed at the end of the procedure and the condition of residual fragments was assessed. we routinely antegradely put a double j ureteral catheter into the ureter in prone position which is to be removed about 1 month later after the operation in the out-patient clinic. a clamped 14f or 20f foley catheter was placed as a nephrostomy tube which was opened within 24 hours. the tube was removed if there was no extravasation within approximately 4 days after the operation. patients were considered stone-free when no stone > 4 mm was visualized. residual fragments > 5 mm in diameter were treated with extracorporeal shock wave lithotripsy (swl) or the second phase pcnl. hospitalization time referred to the time from admission to discharge. however, because of the reason of health insurance, almost all preoperative examination of patients was performed after patients admitted to hospital. it took 2-3 days to arrange the operation after the relevant lab results came out. meanwhile, some patients ultrasonography combined with fluoroscopy in pcnl | chi et al 1218 | needed antibiotics before operation since they often merged with infection, which further makes the average hospitalization time increase in all patients. stone diameter referred to the longest diameter of stones. results the average stone diameter was 3.2 cm (range, 2.1-7.6 cm). of study subjects 101 patients (18.0%) had positive preoperative urine culture, and 15 patients (2.7%) had a stone intervention in the same kidney (previous pcnl, 6 patients; previous pyelolithotomy or nephrolithotomy, 9 patients). the number of solitary kidney and horseshoe kidney patients was 18 (3.2%) and 8 (1.5%), respectively (table 1). the total access success rate was 99.5%. access to calices through a subcostal route was established in 503 renal units (89.9%) and the other was supracostal 12th rib approach. the lower posterior calices were the most common sites of entry (72.5%). of these, 501 (89.6%) got less than 3 punctures, while 58 (10.4%) got more than 3 punctures. the success rate in achieving access to the targeted calyx was 99.6%. there were 2 (0.4%) puncture failures. of patients 522 (89.7%) needed a single tract, while 60 (10.3%) needed multiple tracts. of study subjects 495 (89.7%) were treated by lumenis 60w lithotripter and the remainders (10.3%) were treated by cybersonics double-catheter system. fifty five patients (9.5%) needed auxiliary measures after one pcnl (24 second pcnl and 31 swl). the mean operative time was 82.3 min (range, 45-190 min). the stone free rate was 90.5%. mean (±sd) hemoglobin before pcnl was 14.2±2.3 and after procedure it was 12.2 ±1.5 (p < .05). mean hospital stay was 10.2 days (range, 6-16 days) (table 2). thirty five patients (6.0%) had postoperative fever and responded to antibiotics. three patients (0.5%) had pleural effusion and recovered after drainage of thoracic cavity was closed. thirteen patients (2.2%) needed blood transfusion, 12 patients (2.1%) developed septic shock and were given antishock therapy and 2 patients (0.3%) needed angiographic renal embolization or nephrectomy. discussion access to the collecting system is the first and most important step in pcnl. access is usually achieved by using fluoroscopy, ultrasonography, or ct guidance. some scholars found that the puncture success rate of pcnl under us and fluoroscopy was 98%.(4,7) in our study, the success rate in achieving access to the targeted calyx was 99.6%. many centers perform pcnl under fluoroscopy only,(8,9) which results in patients’ longer radiation exposure during operation. bush and colleagues(10) reported that mean fluoroscopy time were 8 min under the exclusive use of fluorosendourology and stone disease table 1. demographic and clinical characteristics of study patients. no. % mean range age (year) ------46.2 13-70 male/female 313/249 ---------stone side (left/right) 272/310 ---------average stone diameter (cm) ------3.2 2.1-7.6 bmi (kg/m2) ------23.9 20-28 hydronephrosis 515 91.6 ------positive preoperative urine culture 101 18.0 ------renal intervention history 15 2.7 ------one phase nephrostomy 23 4.1 ------solitary kidney 18 3.2 ------horseshoe kidney 8 1.5 ------1219vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l ultrasonography combined with fluoroscopy in pcnl | chi et al table 2. intraoperative and postoperative data. puncture position no % subcostal 503 89.9 intercostal 56 10.1 calyx puncture lower 405 72.5 middle 142 25.4 upper 12 2.1 puncture times > 3 501 89.6 > 3 58 10.4 puncture failure 2 0.4 no. of tracts single 522 89.7 multiple 60 10.3 fragment instrument lumenis 60w lithotripter 495 85.1 cybersonics double-catheter system 87 14.9 seconder procedure requirement 55 9.5 duration of radiation exposure, sec (range) 18.3 (5-42) mean blood loss(δhb), g/dl 1.8 ± 1.2 mean hospital stay, day (range) 10.2 (6-16) complications postoperative fever 35 6.0 pleural effusion 3 0.5 required blood transfusion 13 2.2 septic shock 12 2.1 requiring angiographic renal embolization or nephrectomy 2 0.3 copy in pcnl. longer radiation exposure could cause skin changes such as erythema, ulcers, telangiectasia, and dermal atrophy are deterministic side effects and radiation-induced cancers. wahib and colleagues(11) evaluate the intraoperative outcomes of pcnl using fluoroscopic-guided access (fga) or endoscopic-guided access (ega). they found that patients undergoing ega had shorter fluoroscopy time (3.2 vs. 16.8 minutes, p < .001). agarwal and colleagues(12) recently compared the safety and efficacy of us or fluoroscopy in pcnl. they described that the duration of radiation exposure in the group of fluoroscopy was 28.6 sec and in the group of us was 14.4 sec. in this study, mean fluoroscopy time was only 18.3 sec. ultrasonography guidance was a burgeoning method in pcnl.(3) the us approach allowed imaging of intervening structures between the skin and kidney. the ideal puncture tract should lead straight from the papilla of target calyx into the renal pelvis, which could minimize the likelihood of bleeding. the us approach could evaluate the pelvicalyceal system of kidney in three dimensional (3d) orientation and help to distinguish between anterior and posterior calyces with great accuracy. it also showed the exact relationship 1220 | endourology and stone disease between stone and pelvicalyceal system. us-guided access do well to avoiding adjacent and visceral injury. in our study, none of the patients experienced injuries to the adjacent organs. a few published studies have discussed us-guide puncture in pcnl. karami and colleagues(4) compared ultrasonography-guided access for pcnl with the patient in the flank position with conventional fluoroscopy-guided access. they concluded that us has a high ability to access calculi more easily through the pelvicalyceal system with the patient in the flank position. falahatkar and colleagues(5) compared totally ultrasound versus fluoroscopically guided complete supine pcnl. they showed that totally ultrasound-guided complete supine pcnl was safe and feasible even in reoperative patients. given the electronic dotted line helped in assessing the depth and plane of the puncture needle, desai and colleagues(13) believed that us-guided access was optimal. the high stone clearance rate of pcnl was an important successful landmark.(14) in our study, the stone free rate was 90.5%. the use of us at the end of the pcnl helps the urologist to look for residual stones. this advantage was more obvious when there were nonopaque and semiopaque stones that were not visualized by radiography. still, the effect of x-ray was also very important when fluid leaked around the kidney resulting in that ultrasound could not accurately determine the residual stones during a longer operative time. karami and colleagues(15) compared pcnl safety and efficacy in prone, supine and flank positions. the success rates were comparable among them. our result was a little lower than them in prone position. the reason may be that the stone burden of them was small in their literature. the overall complication rate during or after pcnl may up to 83%,(16,17) including transfusion (11.2%-17.5%) and fever (21.0%-32.1%); whereas major complications, such as septicemia (0.3%-4.7%) and colonic perforation (0.2%-0.8%), were rare. in our study, only 2.2% of patients needed blood transfusion and 6.0% had postoperative fever. the incidence of septic shock and severe renal bleeding that needed angiographic renal embolization or nephrectomy was 2.1% and 0.3%, respectively. compared with them, the complications in our study were relatively fewer. this study had some limitations. for example, it was not a randomized and prospective study; the number of patients was not enough for full assessment. conclusion with its high success rate for achieving access to the targeted calyx and high stone clearance rate, the combined guidance of us and fluoroscopy was an efficient and safe method in pcnl and it should be the first option in pcnl. acknowledgment qinglong chi and yan wang contributed equally to this work. conflict of interest none declared. references 1. fernstroem i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. duty b, okhunov z, smith a, okeke z. the debate over percutaneous nephrolithotomy positioning: a comprehensive review. j urol. 2011:186:20-5. 3. kalogeropoulou c, kallidonis p, liatsikos en. imaging in percutaneous nephrolithotomy. j endourol. 2009;23:1571-7. 4. basiri a, ziaee am, kianian hr, mehrabi s, karami h, moghaddam sm. ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2008;22:281-4. 5. karami h, rezaei a, mohammadhosseini m, javanmard b, mazloomfard m, lotfi b. ultrasonography-guided percutaneous nephrolithotomy in the flank position versus fluoroscopy-guided percutaneous nephrolithotomy in the prone position: a comparative study. j endourol. 2010;24:1357-61. 6. falahatkar s, neiroomand h, enshaei a, kazemzadeh m, allahkhah a, jalili mf. totally ultrasound versus fluoroscopically guided complete supine percutaneous nephrolithotripsy: a first report. j endourol. 2010;24:1421-6. 7. montanari e, serrago m, esposito n, et al. ultrasound-fluoroscopy guided access to the intrarenal excretory system. ann urol (paris). 1999;33:168-81. 8. majidpour hs. risk of radiation exposure during pcnl. urol j. 2010;7:87-9. 9. kumar p. radiation safety issues in fluoroscopy during percutaneous nephrolithotomy. urol j. 2008;5:15-23. 10. bush wh, brannen ge, gibbons rp, correa rj jr, elder js. radiation exposure to patient and urologist during percutaneous nephrostolithotomy. j urol. 1984;132:1148-52. 1221vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l 11. isac w, rizkala e, liu x, noble m, monga m. endoscopic-guided versus fluoroscopic-guided renal access for percutaneous nephrolithotomy: a comparative analysis. urology. 2013;81:251-6. 12. agarwal m, agrawal ms, jaiswal a, kumar d, yadav h, lavania p. safety and efficacy of ultrasonography as an adjunct to fluoroscopy for renal access in percutaneous nephrolithotomy (pcnl). bju int. 2011;108:1346-9. 13. desai m. ultrasonography-guided punctures-with and without puncture guide. j endourol. 2009;23:1641-3. 14. skolarikos a, papatsoris ag. diagnosis and management of post percutaneous nephrolithotomy residual stone fragments. j endourol. 2009;23:1751-5. 15. karami h, mohammadi r, lotfi b. a study on comparative outcomes of percutaneous nephrolithotomy in prone, supine, and flank positions. world j urol. 2013;31:1225-30. 16. maurice stephan michel, lutz trojan, jens jochen rassweiler. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899906. 17. wang y, jiang f, wang y, et al. post-percutaneous nephrolithotomy septic shock and severe hemorrhage: a study of risk factors. urol int. 2012;88:307-10. ultrasonography combined with fluoroscopy in pcnl | chi et al vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2044 case report renal artery thrombosis secondary to blunt abdominal trauma with accessory renal artery supplying the kidney segment: a rare case report guang-yong li,* yu gao, pei-jun li , meng li keywords: wounds, nonpenetrating; renal artery; thrombosis; etiology. introduction traumatic renal artery thrombosis (rat) is an uncommon disease especially secondary to blunt trauma. there are some reports about rat but reports of rat involving accessory renal arteries are rare. therapy of rat is often surgical management such as nephrectomy, arterial revascularization or conservative management.(1,2) we report a 15-year-old girl with rat and accessory renal artery supplying the kidney segment. case report a 15-year-old female who was struck by a motor vehicle had been admitted to our hospital 5 hours after the injury. on physical examination the patient had no remarkable wounds and her blood pressure was stable (110/70 mmhg). her laboratory data revealed; hematocrit 33.80%, serum creatinine 4.10 mmol/l, urea 4.10 mmol/l, aspartate aminotransferase 50.2 u/l, alanine transaminase 67.0 u/l, creatine kinase 548.9 u/l, lactate dehydrogenase 3253 u/l and amylase 158.7 u/l. emergency management included intravenous administration of blood and crystalloids. a contrast-enhanced computer tomography (ce-ct) scan revealed very faint perfusion of the right kidney and an enhancement in a small portion of the upper pole of the right kidney (figure 1). we performed ct angiography (cta) in which there was no dye excretion in the right kidney and an accessory renal artery supplied segmental kidney was seen（figure 2a). another cta (figure 2b) showed normal left kidney. as the diagnosis of rat was made, the patient underwent close conservative therapy to preserve her right renal function, considering her age and accessory renal artery blood supply. at post treatment month-1, -2 and -5 her blood pressure was 120/85 mmhg, 110/75 mmhg and 118/78 mmhg, respectively. discussion renal vascular injury following blunt abdominal trauma is rare. in a review of 945,326 patients from the american national trauma data bank with blunt trauma, only 517 patients (0.05%) had injuries to the renal artery.(1) the rat case with accessory renal artery blood supply is much more infrequent. because of the symptom of rat are difficult to elicit, most of urologic surgeons in our country often ignored the entity and couldn’t make early department of urology, general hospital of ningxia medical university, yinchuan, 750004, china. *correspondence: department of urology, general hospital of ningxia medical university, no. 804, shengli south street, xingqing district, yinchuan, china. tel: +86 095 16743248. fax: +86 095 14082981. e-mail: guangyongli2018@126.com. received september 2014 & accepted december 2014 figure 1. contrast-enhanced computed tomography demonstrated remarkably reduced perfusion in right kidney and the enhancement of a little portion in the upper pole of the right kidney. figure 2. (a) computed tomography angiography showed right main renal artery occlusion and accessory renal artery supplying a small portion of the upper pole of the right kidney; (b) computed tomography angiography showed proximal end of right main renal artery and normal left kidney. diagnosis. the syndrome and laboratory data of rat are not specific.(2) the diagnosis mainly depend on changes on ct, angiography, dimercaptosuccinic acid scan and intravenous urography, however, which is more efficient for stablishing rat diagnosis are not know and have not been compared so far.(2) the proposed mechanisms of rat are: 1) sudden deceleration or crash injury results in vascular subintimal tears and then thrombosis and 2) renal artery is compressed by the power between the anterior abdominal wall and the vertebral bodies. (2-4) it is usually unilateral and left side is involved more frequently, possibly because of its shorter length. maximum angulation and traction occur within 1 to 2 cm of the point where the renal artery is fixed to the aorta.(5) another mechanism which may cause this type of injury is that the left kidney is more mobile than the right.(4,6) our patient’s injuries were caused by means of compression and sudden deceleration. in case of rat, the treatment for this disease are revascularization and conservative observation.(2,7) however open surgical operation for treatment of rat is seldom performed, because its lower success rate.(1,2) more and more trauma surgeons prefer to use minimally invasive surgical revascularization whenever possible for prompt revascularization in order to preserve renal function.(2-4) for the patients who encountered uncontrolled renovascular hypertension, nephrectomy should be considered.(1,2,8) rat involving accessory renal arteries is rare condition, and we don’t know the most appropriate treatment because of its rarity. however, like as this case report, close conservative therapy seems an advisable choice. conflicts of interest none declare. references 1. sangthong b, demetriades d, martin m, et al. management and hospital outcomes of blunt renal artery injuries: analysis of 517 patients from the national trauma data bank. j am coll surg. 2006;203:612-7. 2. singh o, gupta ss, sharma d, lahoti bk, mathur rk. isolated renal artery thrombosis because of blunt trauma abdomen: report of a case with review of the literature. urol int. 2011;86:233-8. 3. rha sw, wani sp, suh sy, et al. successful percutaneous renal intervention in a patient with acute traumatic renal artery thrombosis. circulation. 2006;114:e583-5. 4. nakayama t1, okaneya t, kinebuchi y, murata y, iizuka k. thrombolytic therapy for traumatic unilateral renal artery thrombosis. int j urol. 2006;13:168-70. 5. letsou gv, gusberg r. isolated bilateral renal artery thrombosis: an unusual consequence of blunt abdominal trauma--case report. j trauma. 1990;30:509-11. 6. evans a, mogg ra. renal artery thrombosis due to closed trauma. trans am assoc genitourin surg. 1970;62:40-6. 7. haas ca, dinchman kh, nasrallah pf, spirnak jp. traumatic renal artery occlusion: a 15-year review. j trauma. 1998;45:557-61. 8. sullivan mj, smalley r, banowsky lh. renal artery occlusion secondary to blunt abdominal trauma. j trauma. 1972;12:509-15. renal artery thrombosis secondary to blunt abdominal trauma-li el al case report 2045 141 urology journal unrc/iua vol. 2, no. 3, 141-147 summer 2005 printed in iran evaluating expression and potential diagnostic and prognostic values of survivin in bladder tumors: a preliminary report seyed javad mowla,1* mojtaba emadi bayegi,1 seyed amirmohsen ziaee,2 parvaneh nikpoor1 1department of genetics, faculty of basic sciences, tarbiat modarres university, tehran, iran 2urology and nephrology research center, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: survivin, an inhibitor of apoptosis (iap), has been reported to be capable of regulating both cellular proliferation and apoptotic cell death. survivin expression has been described during embryonic development and in adult cancerous tissues, with greatly reduced expression in adult normal differentiated tissues, particularly if their proliferation index is low. in the present study, the expression and potential diagnostic and prognostic value of survivin in bladder tumors was evaluated. materials and methods: primary and recurrent bladder tumor specimens were obtained from patients referred to the shaheed labbafinejad medical center in tehran, iran. total rna was isolated from frozen tissues, reverse transcribed and amplified by means of a nested polymerase chain reaction technique. results: survivin was detected in 3 cases of primary tumors (42.8%) and 6 cases of recurrent tumors of bladder (60%). survivin-∆ex3 expression was seen in 41.2% of the 17 cases with bladder cancer. conclusion: our findings suggest that the expression of survivin and survivin-∆ex3 is well associated with invasive and more-aggressive forms of bladder cancer. our data also indicate that the presence of survivin-∆ex3 is better correlated with tumorigenesis of bladder cancer compared with survivin expression. key words: survivin, apoptosis, bladder cancer, polymerase chain reaction introduction bladder cancer is one of the most common malignant tumors worldwide. it is the fourth most-common type of cancer in men and the eighth most-common type in women. the incidence of bladder cancer increases with age, where people older than 70 years develop the disease 2 to 3 times more often than do those aged 55 to 69 years, and 15 to 20 times more often than those aged 30 to 54 years.(1) despite the fact that there is no comprehensive statistical report on the incidence rate of bladder cancer in iran, according to clinical reports it has a very high incidence rate, and most cases are transitional cell carcinoma (tcc), similar to that in europe and north america. tumor growth depends on 2 main factors: cell proliferation and cell death by apoptosis.(2) apoptosis is a form of programmed cell death characterized by morphologic, biologic, and genetic features. abnormalities of apoptosis may lead to uncontrolled cellular proliferation and ultimately carcinogenesis. several studies have received april 2004 accepted april 2005 *corresponding author: department of genetics, faculty of basic sciences, tarbiat modarres university, al-e-ahmad hwy, tehran, iran. po box: 14115-175, tel: ++98 21 8801 1001-3464 e-mail: sjmowla@modares.ac.ir expression of survivin in bladder tumors142 reported significant correlations between apoptosis and prognosis in malignant tumors such as lung, breast, and esophageal cancer. two protein families are responsible for controlling apoptosis: bcl-2 and the inhibitors of apoptosis proteins (iap). inhibitors of apoptosis proteins are a group of evolutionary conserved proteins characterized by the presence of 1 to 3 domains known as baculoviral iap repeat (bir) domains, which is necessary for the antiapoptotic property of iaps.(3,4) survivin, a new member of iaps, is structurally unique, because it has only a single bir domain and lacks the cooh-terminal ring finger domain.(5) survivin also plays critical roles in regulating the cell cycle and mitosis. its primary expression in most human malignancies and its low or absence of expression in normal tissues suggest that it would be a good diagnostic and prognostic marker as well as an ideal target for cancer-directed therapy.(5,6) extensive studies have been carried out to elucidate the mechanism of its function; however, its role in regulating cell survival and cell cycle is poorly understood.(7) mahotka and colleagues(8) have cloned and characterized 2 novel splice variants of survivin, lacking exon 3 (survivin-∆ex3) or retaining a part of intron 2, as a cryptic exon (survivin-2b). both sequence alterations cause marked changes in the structure of the corresponding proteins, including structural modifications of the bir domain. they also have reported a conservation of antiapoptotic properties for survivin-∆ex3 and a markedly reduced antiapoptotic potential for survivin-2b. the reduced antiapoptotic activity of survivin-2b is possibly due to a dominantnegative mechanism of competitive binding to the interactive partners of surviving.(9) using molecular markers for diagnosing and determining the prognosis of bladder tumors can be of great value. considering the potential application of survivin as a specific tumor marker for cancers, we decided to evaluate the expression of survivin in bladder tumors using reverse transcription-polymerase chain reaction (rt-pcr) to determine the potential association of its variants with the malignant behavior of the tumor. materials and methods specimen preparation tissue specimens were obtained from patients with bladder cancer who had been referred to the shaheed labbafinejad medical center in tehran, iran, from december 2002 to july 2003. the specimens were obtained under the supervision of a urologist and categorized into 2 groups according to their clinical criteria: group 1 consisted of the specimens from patients with newly diagnosed bladder cancer via conventional diagnostic methods such as cystoscopy and urine cytology. group 2 was composed of known bladder cancer cases that were on follow-up (table 1). tumoral specimens were collected in 2 ways; if the tumor was in stage ta or t1, low-grade, and noninvasive, the tissue was removed from the suspected area by cystoscopic biopsy. a piece of unused tissue was then put into an rnase-free, 1.5-ml tube, immediately snap frozen in nitrogen vapor, and kept at -80°c until rna extraction. for the tumors in stages t2-t4, that is, those invading the muscular layer, the whole bladder was removed by radical cystoscopy. a piece of tumoral specimen was then removed and put in an rnase-free tube, snap frozen, and kept at 80°c for later use. rna extraction total rna was isolated from frozen tissues using the rnx-plus solution (cinnagen, tehran, iran) according to the manufacturer's instructions and as previously described.(10) the purity and integrity of the extracted rna were evaluated by optical density measurements (260:280 nm ratios) and by visual observation of specimens electrophoresed on agarose gels. both methods confirmed the integrity of the extracted rna with little or no protein contamination. after extraction, the isolated rna was treated with dnase to eliminate a probable genomic dna contamination. rt-pcr reaction specific primers of human b2m (β2-microglobulin as an internal control; accession number: nm-004048) and human survivin (accession number: u75285) were designed by using generunner software (hastings software, inc, hastings, ny, usa). the sequences of the designed primers are as follow: external, forward primer: 5'tggcagccctttctcaag -3' external, reverse primer: 5'-gagagagagaagcagccac 3' these primers amplified a 632 bp segment of mowla et al 143 human survivin cdna located between nucleotides 77 and 708. internal, forward primer: 5'accaccgcatctctacattc -3' internal, reverse primer: 5'ctggtgccactttcaagac -3' these primers amplified a 556 bp segment from human survivin cdna located between nucleotides 96 and 651. b2m forward primer: 5' tcg cgc tac tct ctc ttt ctg 3' b2m reverse primers: 5' gct tac atg tct cga tcc cac 3' these primers amplified a 334 bp segment from human b2m cdna located between nucleotides 41 and 374. complementary dna (cdna) synthesis reactions were performed using 5 µg rna and mmlv reverse transcriptase (gibco brl, germany) with oligo (dt)18 priming in a 20 µl reaction as described elsewhere.(11) the designed primers as well as the oligo (dt)18 primer were synthesized by mwg biotech company (ebersberg, germany) as highly purified salt-free grade. all designed primers were blast(12) compared against the human table 1. patients' characteristics and their clinicopathological conditions m: male, f: female, na: not available, tcc: transitional cell carcinoma, scc: squamous cell carcinoma, n/c ratio: nucleuscytoplasm ratio groups specimens age (year) sex stage grade pathological diagnosis description 1 47 m a/pt1 2 papillary tcc high mitotic activity, high n/c ratio 2 68 m na na papillary tcc multiple nodular mass in bladder 3 67 f a/pt1 low/ small foci of high grade carcinoma in situ high mitotic activity, high n/c ratio 4 72 m a/pt1 2 papillary tcc primary biopsy diagnosis as carcinoma in situ 5 59 m na na papillary tcc 5 67 f a na papillary tcc rapid recurrent after 4 months of primary diagnosis group 1 7 60 m a 2 papillary tcc rapid recurrent after 3 months of primary diagnosis 1 76 m na na papillary tcc under follow-up for a long period of time, small tumor 2 56 m b2/pt3a high/3 papillary tcc high mitotic activity 3 62 m na poorly differentiated undifferentiated carcinoma high level of necrosis 4 46 m a low/2 papillary tcc radical cystectomy 5 67 m b2/pt3a poorly differentiated scc invading carcinoma with extensive necrosis 6 67 m pt2 nx mx/b1 high high-grade invasive urothelial carcinoma transition from tcc to scc 7 81 m na na tcc 8 83 m pt3b low /2 papillary tcc invasion to surrounding soft tissues 9 71 m pt3b nx mx high /3 tcc necrotic tumoral tissue invading lamina propria group 2 10 81 f na poorly differentiated undifferentiated carcinoma presence of diffuse necrosis expression of survivin in bladder tumors144 genome to make sure they are not complementary with other regions of genome. pcr was performed using 5 µl of synthesized cdna with 1.25 u of taq polymerase (roche, germany), as described elsewhere.(10,11) the pcr amplification was performed for 25 to 35 cycles. the cycling conditions were as follows: 94°c for 30 seconds, 55°c for 30 seconds, 72°c for 1 minutes, and a final extension at 72°c for 10 minutes. pcr products were then separated on a 1.5% agarose gel and visualized by ethidium bromide staining. restriction enzyme digestion to confirm the identity of pcr products of survivin variants, we determined the restriction size pattern of all amplified products digested with mboi restriction enzyme (mbi fermentas, hanover, germany). the enzyme cuts survivin cdna at nucleotide 588 generating 2 shorter bands that are detected on 8% polyacrylamide gel electrophoresis. results rt-pcr optimization to find the optimal number of amplification cycles, external primers were first used to amplify a piece of survivin, which generates a 632-bp segment. a band corresponding to the expected size appeared in the first round of pcr at cycles 35 and 40 (data not shown). owing to the weak intensity of the signal, nested pcr was performed on the product during the first round of pcr, using internal primers for 25 to 35 cycles. the results showed 2 bands with sizes of 556 and 438 bp, as expected from the sizes previously reported for different variants of the gene (data not shown). for the rest of the experiments, all pcr reactions were performed at 30 cycles for b2m and 35 cycles, first round, and 30 cycles, second round, for survivin. evaluating the expression of survivin and its splice variants overall, 17 tumoral specimens were studied. the ages of the patients were between 46 and 83 years. demographic and clinicopathological characteristics of all patients are listed in table 1. to be sure equal amounts of rna were used in all reactions, we used b2m as an internal control. for each specimen, the rt-pcr was performed under similar conditions (except for the number of cycles) in 2 separate tubes, 1 for b2m and 1 for survivin. b2m was expressed in all tumoral specimens (figure 1). nested rt-pcr results on the same specimens revealed an expected band for survivin with a size of 556 bp, as well as another band with the approximate size of 438 bp (figure 1). the experiment was repeated at least twice for all specimens. the reappearance of the smaller band in the same specimens points to the potential detection of a survivin splice variant. changing the pcr conditions (ie, increasing the fig. 1. rt-pcr analysis of the expression of b2m and survivin in tumoral specimens, a. patients with no previous incidence of bladder cancer, b. patients with recurrence of bladder cancer. mowla et al 145 annealing temperature and/or decreasing the concentrations of the primers) did not affect the intensity of the bands. in group 1 (specimens from patients with no previous history of bladder cancer), 4 out of 7 cases (specimens 3, 4 , 6, and 7) showed no detectable signal for survivin, while 2 cases (specimens 1 and 2) showed 2 bands with the sizes of 438 and 556 bp, and 1 (specimen 5) had a single 556 bp band (figure 1a). in group 2 (specimens from patients with previous diagnoses of bladder tumors, currently under follow-up surveillance), 4 out of 10 cases (specimens 3, 6, 9, and 10) showed no signal for survivin. five cases (specimens 2, 4, 5, 7, and 8) showed 2 bands of 438 and 556 bp, and 1 (specimen 1) had a single 556-bp band (figure 1b). overall, survivin was detected in 3 cases of primary tumors (42.8%) and 6 cases of recurrent bladder tumors (60%). survivin-∆ex3 expression was seen in 41.2% of the 17 cases with bladder cancer. survivin-2b was not detected in any of our cases. confirming the identity of survivin variants the identity of the amplified bands in pcr, which are the bands corresponding to the survivin splice variants, was confirmed by means of restriction enzyme digestion. for this purpose, mboi enzyme was applied, which cuts survivin cdna at nucleotide 588 to generate 2 shorter segments (64 and 492 bp for surviving, and 64 and 374 bp for survivin-∆ex3; figure 2). discussion in the present study, we determined the expression pattern of survivin splice variants in patients diagnosed with bladder cancer. the main aim of the study was then to examine any potential correlation of gene expression with degree of malignancy, pathological behavior, and the recurrence of bladder cancer. our results revealed that survivin and/or survivin-∆ex3 were expressed in 42.8% of cases in group 1 (primarily detected tumors) and 60% of cases in group 2 (recurrent tumors). in the original report by swana and coworkers,(13) where expression of survivin was determined by immunohistochemistry, no detectable survivin was reported in normal transitional cells, but it was present in 78% of tumoral specimens. in contrast, lehner and colleagues have reported that survivin is not only detectable in tumoral specimens, but also is present in some nontumoral specimens of the bladder.(14) also recently, gazzaniga and colleagues have reported that they were able to detect survivin expression by rt-pcr technique only in 9 out of 30 specimens (< 30%) of superficial bladder cancer.(15) accordingly, in another report by nakanishi and colleagues, survivin protein was detected by immunohistochemistry in only 12.7% of tcc specimens.(16) the high expression of survivin in specimens 1 and 2 in group 1 as well as a moderate expression of the gene in specimen 2 of group 2 (which had a high mitotic activity and nucleusplasma ratio) is in complete agreement with the role of survivin in regulating cell proliferation and its upregulation in the g2/m phase.(17) in other words, because of the increased rate of cell division in these specimens, the expression of survivin is high. what differentiates specimen 3 in group 1 from other cases, despite having high mitotic activity and high nucleus-plasma ratio, was the presence of the cells with a big granulated nucleus, a characteristic of necrotic cells. there was also a significant amount of necrosis in specimens 3, 9, and 10 in group 2. since there is a continuous spectrum of cell death by necrosis or apoptosis,(18) the lack of survivin gene expression in these cases is predictable. specimen 5 in group 2, which was survivin positive, had some degree of necrosis, and it was expected to be survivin negative. from a closer look at the pathological and microscopic report fig. 2. electrophoresis of digested products of amplified survivin segments by mboi on 8% polyacrylamide gel. the enzyme cleaves the pcr products at nucleotides 588 of survivin cdna and generated 2 smaller pieces (64 and 492 bp for survivin and 64 and 374 bp for survivin-∆ex3). expression of survivin in bladder tumors146 and from the fact that the tumor was heterogeneous in nature, we speculated that the sampling might have been taken from parts of the tumor lacking obvious necrosis. what makes this case more complicated is a transformation of the tumor from tcc to scc (which is more aggressive); since there is little information about the nature of this transformation, a reliable interpretation of the case is difficult. specimen 1 in group 2 was from a 76-year-old man being followed up for bladder cancer, and after a long period from primary tumor diagnosis, a small tumor of low stage with a negative urine cytology result had been found. all of these data suggest an appropriate biological behavior of the tumor, and the sole expression of survivin (but not survivin-∆ex3-which has poorer prognosis) could have been anticipated. the absence of survivin-∆ex3 variant in this case and in specimen 5 in group 1 makes them different from other survivin-positive cases. despite previous reports on the presence of survivin-∆ex3 and survivin-2b in a variety of tumoral tissues and cell lines, there are no reports on the involvement of the same variants in bladder tumors. mohatka and colleagues detected these alternatively spliced variants for the first time in renal cell carcinoma cell lines.(8) the variants differ from each other, not only because of having different sizes, but also because of their different antiapoptotic activities.(19) primers were blast compared against the human genome to make sure they do not have nonspecific complementary sequences on the genome. also, we used nested rt-pcr to increase the specificity and sensitivity of the reaction. thus, we can conclude that the 2 amplified bands are indeed different variants of survivin. however, we failed to detect one of the previously reported variants of survivin, survivin-2b, in the examined specimens. this might be due to the low number of tumors with low stages in the current study. a reduced expression of survivin2b variant has been shown to be correlated with a poor prognosis of gastric carcinoma.(20) also, it is claimed that expression of these variants might have a role in tumor progression and clinical behavior of soft tissue sarcomas,(21) colorectal carcinomas,(22) medulloblastoma,(23) breast cancer,(24) and other cancers. to examine this hypothesis, we reviewed the patients' archival records and found that patients who were positive for survivin-∆ex3 had either been operated on by cystectomy or had recently been a candidate for cystectomy. in other words, the presence of the variant is correlated with a poor diagnosis and a more rapid disease recurrence. conclusion in conclusion, it seems that under various physiological and pathological conditions, apoptosis regulation depends not only on the extent of survivin gene expression, but also on how its primary transcript is processed to produce different splice variants. therefore, determining the generation of different variants of the gene in different tumors and normal tissues would provide valuable diagnostic and prognostic information. acknowledgement we are grateful to dr daryoush eskandari and mahmoud faraz for their excellent technical assistance. this research was supported, in part, by a grant from the urology and nephrology research center, shaheed beheshti university of medical sciences and health services. references 1. landis sh, murray t, bolden s, wingo pa. cancer statistics, 1998.ca cancer j clin. 1998;48:6-29. 2. guo m, hay ba. cell proliferation and apoptosis. curr opin cell biol. 1999;11:745-52. 3. lacasse ec, baird s, korneluk rg, mackenzie ae. the inhibitors of apoptosis (iaps) and their emerging role in cancer. oncogene. 1998;17:3247-59. 4. adams jm, cory s. the bcl-2 protein family: arbiters of cell survival. science. 1998;281:1322-6. review. 5. o'driscoll l, linehan r, clynes m. survivin: role in normal cells and in pathological conditions. curr cancer drug targets. 2003;3:131-52. 6. velculescu ve, madden sl, zhang l, et al. analysis of human transcriptomes. nat genet. 1999;23:387-8. 7. altieri dc, marchisio pc. survivin apoptosis: an interloper between cell death and cell proliferation in cancer. lab invest. 1999;79:1327-33. 8. mahotka c, wenzel m, springer e, gabbert he, gerharz cd. survivin-deltaex3 and survivin-2b: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. cancer res. 1999;59:6097-102. 9. islam a, kageyama h, hashizume k, kaneko y, nakagawara a. role of survivin, whose gene is mapped to 17q25, in human neuroblastoma and identification of a novel dominant-negative isoform, survivin-beta/2b. med pediatr oncol. 2000;35:550-3. 10. nikpoor p, mowla sj, movahedin m, ziaee sa, tiraihi t. mowla et al 147 catsper gene expression in postnatal development of mouse testis and in subfertile men with deficient sperm motility. hum reprod. 2004;19:124-8. 11. sambrook j, russel dw. molecular cloning: a laboratory manual. 3rd ed. new york: cold spring harbor laboratory press; 2001. 12. blast genome [database on the internet]. bethesda (md): national library of medicine (us). available from: http://www.ncbi.nlm.nih.gov/genome/seq/hsblast.html 13. swana hs, grossman d, anthony jn, weiss rm, altieri dc. tumor content of the antiapoptosis molecule survivin and recurrence of bladder cancer. n engl j med. 1999;341:452-3. 14. lehner r, lucia ms, jarboe ea, et al. immunohistochemical localization of the iap protein survivin in bladder mucosa and transitional cell carcinoma. appl immunohistochem mol morphol. 2002;10:134-8. 15. gazzaniga p, gradilone a, giuliani l, et al. expression and prognostic significance of livin, survivin and other apoptosis-related genes in the progression of superficial bladder cancer. ann oncol. 2003;14:85-90. 16. nakanishi k, tominaga s, hiroi s, et al. expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract. virchows arch. 2002;441:559-63. 17. altieri dc. survivin, versatile modulation of cell division and apoptosis in cancer. oncogene. 2003;22:8581-9. 18. jaattela m. escaping cell death: survival proteins in cancer. exp cell res. 1999;248:30-43. 19. li f. role of survivin and its splice variants in tumorigenesis. br j cancer. 2005;92:212-6. 20. krieg a, mahotka c, krieg t, et al. expression of different survivin variants in gastric carcinomas: first clues to a role of survivin-2b in tumour progression. br j cancer. 2002;86:737-43. 21. taubert h, kappler m, bache m, et al. elevated expression of survivin-splice variants predicts a poor outcome for soft-tissue sarcomas patients. oncogene. 2005;24:5258-61. 22. suga k, yamamoto t, yamada y, miyatake s, nakagawa t, tanigawa n. correlation between transcriptional expression of survivin isoforms and clinicopathological findings in human colorectal carcinomas. oncol rep. 2005;13:891-7. 23. fangusaro jr, jiang y, holloway mp, et al. survivin, survivin-2b, and survivin-deitaex3 expression in medulloblastoma: biologic markers of tumour morphology and clinical outcome. br j cancer. 2005 ;92:359-65. 24. ryan b, o'donovan n, browne b, et al. expression of survivin and its splice variants survivin-2b and survivindeltaex3 in breast cancer. br j cancer. 2005;92:120-4. introduction posterior urethral stricture or pelvic fracture urethral distraction defect (pfudd) is relatively uncommon in children. trauma and iatrogenic injury are the most common causes of stricture occurrence.(1) given the specificity of children’s urethra, treating their posterior urethral stricture is difficult, specifically for the children with long segment urethral stricture. we report a successful perineal urethroplasty for 6 cm long pfudd in a 9 year-old boy. case report a 9 year-old boy with a long pfudd was admitted to our hospital in april 2013. five months before the admission, the boy suffered pelvic fracture and posterior urethral disruption caused by a traffic accident. given the severity of the combined injuries, he underwent suprapubic cystostomy for acute phase management. five months later, we performed urethrogram and cystoscopy and found that the urethral distraction defect was 6 cm in length (figure 1). perineal urethroplasty was thereby performed. in the operation, the boy was placed in the lithotomy position. the bulbospongiosus muscle was dissected through an inverted y-shaped incision. afterwards, the bulbar urethra was circumferentially dissected down to its proximal end and sharply divided at the strictured segment. to increase the perineal space, the midline intercrural incision was made and the lower part of pubic symphysis was removed with a power drill. the scar tissue involving the membranoprostatic region was excised using retrograde piecemeal method until healthy, soft and pliable mucosa of proximal urethra was identified. this step was assisted by antegrade passage of a bougie through the suprapubic tract. in the last procedure, we placed a 10 french foley catheter through the urethra into the bladder and performed the end-to-end anastomosis. the operation lasted for five case report 2576 case report successful perineal urethroplasty for long pelvic fracture urethral distraction defect (pfudd) in a 9 year-old boy zhai jianpo,* wang jianwei, li guizhong, wang hai, he feng, huang guanglin, man libo keywords: fractures; bone; complications; pelvic bones; urethra; injuries; surgery; treatment outcome. department of urology, beijing jishuitan hospital, beijing 100035, china. *correspondence: department of urology, beijing jishuitan hospital, beijing 100035, china. tel: +86 010 58398241. e-mail: dczhaijp@126.com. received may 2015 & accepted november 2015 figure 1. preoperative combined cystography and retrograde urethrography. figure 2. postoperative cystourethrography. vol 13 no 01 january-february 2016 2577 hours, and the blood loss was less than 200 ml. one month after the operation, the foley catheter was removed, wherein no post-operative complications were found. the boy recovered well without penile curvature or penile shortening. urinary incontinence and urethral diverticula were not observed. currently, the boy has normal urination functions and does not need urethral dilatation (figure 2). discussion posterior urethral stricture in children is common and the causes include pelvic fracture, straddle injuries, or crush injuries. sunay and colleagues(2) reported that the most frequent cause of urethral stricture is urethral injury (78.6%), which results from pelvic fracture caused by a traffic accident. in the study by pfalzgraf and colleagues,(3) 47.1% of the children have post-traumatic strictures. the urethral distraction defect in the present case report was also caused by pelvic fracture. urethral strictures in children, whether caused by trauma or surgery, are difficult to treat due to smaller pelvic confines, decreased caliber urethra, and increased tissue fragility. posterior urethral trauma imposes severe impairment on the quality of life and is considered one of the most debilitating injuries if not managed properly. it can cause urinary incontinence and impotence, as well as urethral stricture which may require repeated interventions.(4) several treatments options, including urethral dilatation, endoscopic visual internal urethrotomy, and open urethral reconstruction, are available for the management of urethral strictures in children. urethral dilatation is one of the commonly applied procedures in the initial management of urethral strictures. however, the long-term outcome of this procedure is unsatisfactory. anastomotic urethroplasty is another option for the treatment of urethral strictures. podesta and podesta(5) reviewed records of 49 male children with pfudds who underwent anastomotic urethroplasties from 1980 to 2006. the median follow-up time was 6.5 years and they found that the primary success rate was 89.7%. similarly, shenfeld and colleagues(6) evaluated the safety and efficacy of urethroplasty, which applies the perineal approach for bulbar and membranous urethral strictures in children and adolescents. the study showed that the primary success rate of the surgery was 93%. the mean maximal urinary flow rate increased from 2.65 ml/s preoperatively to 27.65 ml/s postoperatively, and no significant complications occurred. the researchers suggested that in pediatric patients, bulbar and membranous strictures can be treated successfully with urethroplasty using the perineal approach. these patients probably shouldn’t be treated “conservatively” with urethral dilatation or endoscopic incision. in addition, the long-term treatment effect of perineal urethroplasty was also confirmed by orabi and colleagues.(7) therefore, perineal urethroplasty is a safe and effective treatment for urethral strictures in children. the maximum length of stricture that can be treated by end-to-end anastomosis is inconclusive. koraitim(8) found that a satisfactory perineal anastomosis could be achieved if the stricture segment was up to 3 cm in length. moreover, morey and colleagues demonstrated that they could successfully bridge a urethral gap of up to 5 cm in length after fully mobilizing the urethra.(9) regardless of the length of stricture segment, the key to a high success rate in urethral stricture repair is the excision of all of the fibrous tissues along with the complete mobilization of the proximal and distal urethra so as to achieve a tension-free anastomosis. partial symphysiectomy is sometimes needed to achieve this goal. (10) given that the length of urethral stricture is 6 cm in this case report, partial symphysiectomy (the lower part ) was performed to insure tension-free anastomosis. conclusions in conclusion, perineal urethroplasty is an excellent surgical procedure for treating children with long segment pfudd. partial symphysiectomy is sometimes needed to achieve the tension-free anastomosis. conflict of interest none declared. references 1. lumen n, hoebeke p, willemsen p, de troyer b, pieters r, oosterlinck w. etiology of urethral stricture disease in the 21st century. j urol. 2009;182:983-7. 2. sunay m, karabulut a, dadalı m, bağbancı s, emir l, erol d. single-institution outcomes of open reconstruction techniques for management of pediatric and adolescent post-traumatic urethral strictures. urology. 2011;77:706-10. 3. pfalzgraf d, isbarn h, meyer-moldenhauer wh, fisch m, riechardt s. etiology and outcome of the perineal repair of posterior and bulbar urethral strictures in children: a single surgeon experience. j pediatr urol. 2013;9:769-4. 4. singh a, panda ss, bajpai m, jana m, baidya dk. our experience, technique and long-term outcomes in the management of posterior urethral strictures. j pediatr urol. 2014;10:404. urethroplasty for pfudd in boy-zhai jianpo et al. urethroplasty for pfudd in boy-zhai jianpo et al. 5. podesta m, podesta m jr. delayed surgical repair of posttraumatic posterior urethral distraction defects in children and adolescents: long-term results. j pediatr urol. 2015;11:67. e1-6. 6. shenfeld oz, gdor j, katz r, gofrit on, pode d, landau eh. urethroplasty, by perineal approach, for bulbar and membranous urethral strictures in children and adolescents. urology. 2008;71:430-3. 7. orabi s, badawy h, saad a, youssef m, hanno a. post-traumatic posterior urethral stricture in children: how to achieve a successful repair. j pediatr urol. 2008;4:2904. 8. koraitim mm. gapometry and anterior urethrometry in the repair of posterior urethral defects. j urol. 2008;179:1879-81. 9. morey af, kizer ws. proximal bulbar urethroplasty via extended anastomotic approach. what are the limits? j urol. 2006; 175:2145-9. 10. ranjan p, ansari ms, singh m, chipde ss, singh r, kapoor r. post-traumatic urethral strictures in children: what have we learned over the years? j pediatr urol. 2012;8:234-9. case report 2578 introduction the prostate cancer (pca) is the most frequent cancer in men as well in europe and usa.(1) the pca counts for 11% of all men cancers and it’s responsible for 9% of the mortality by cancer in men in europe. in france in 2010, the incidence of pca was 71577 cases and the related mortality of pca at the same year was 8791 deaths which represent a 2.5% less mortality per year during last years.(2) the multidisciplinary team management becomes an obligation for all oncologic fields as mentioned by the french government law: cancer program 2003-2007, this program stipulate that each new patient should benefit from multidisciplinary team management (mdtm) decision-making process, organize the setting of mdtm and also gives tools to develop trials of research for a new diagnosis and therapeutic arsenal.(3) some urologists express some doubt about the interest of mdtm because of it’s a new burden without assigned budget while others see in the mdtm an equality of chance of patients, and possibility to include patients in trials and protocols. number of european study showed the interest of mdtm and its beneficial impact on survival.(4,5) the efficiency of decisions made at mdtm is obvious but the evidence about their reproducibility remains doubtful. through patients underwent a radical prostatectomy (rp) for localized pca and represented identically, we evaluated a reproducibility of decision made at mdtm. materials and methods from january 2011 to march 2012, 183 patients underwent radical prostatectomy for localized pca, all of them were presented at mdtm and decision of diagnosis and treatment validated. within those patients some files were selected prospectively for a second presentation. all of the patients were presented identically under a fake identity 6 to 12 months later. each file contained a full filled form including all decision-making parameters concerning patient (appendix). patients were selected after agreement of their urologist who didn’t participate at decision making process at a second presentation. we also presented a case of patient urological oncology prostate cancer: what about reproducibility of decision made at multidisciplinary team management? younes bayoud,* pierre yves loock, rabah messaoudi, thomas ripert, jean pierrevelcin, sebastien kozal, priscilla leon, majorlaine kamdoum, cholley irène, johann menard. purpose: the prostate cancer (pca) treatment is multimodal. thus multidisciplinary team management (mdtm) decision-making process appears as a tool to answer all aspects of pca treatment. our aim was to evaluate the reproducibility of therapeutic decisions made at mdtm. materials and methods: we compared therapeutic decisions of pca by presenting the same file of patient under a fake identity after 6 to 12 months from the first presentation. forty-nine files of radical prostatectomy (rp) (28 pt2, 21 pt3) performed for clinical localized pca were represented at mdtm which included urologist, oncologist, pathologist and radiologist. analysis of therapeutic decisions comprised criteria such as: tnm stage, gleason score, margin status and comorbidities. the reproducibility was assessed statistically by kappa coefficient. results: study subjects included 49 patients who underwent radical prostatectomy (rp). the mean age was similar in pt2 and pt3 groups (p = .09). the mean serum psa value was 8.32 ng/ml (range, 3.56-19.5) in pt2 group and 9.4 ng/ml (range, 3.8-22) in pt3 group. the margin status in pt2 and pt3 groups was positive in 25.0% and 47.6%, respectively. the decisions made at first and second mdtm for pt2 group were the same in 100% of cases with a perfect kappa coefficient (k = 1). in the group of pt3 (n = 21), the decisions were different in 33% at the second mdtm in comparison to the first mdtm. especially for pt3b only 29% were reproducible decision with a slight agreement (k = 0.1). concerning pt3a, 86% of the decisions were reproducible with a substantial agreement (k = 0.74). conclusion: we showed a reliability and reproducibility of decision made at mdtm when guidelines are well defined. the therapeutic attitudes were less reproducible in locally advanced pca but decision concerning those cases should be made in the setting of guidelines. keywords: decision making; prostatic neoplasms; therapy; decision support systems; clinical; individualized medicine; methods. department of urology and andrology, robert debré academic hospital, avenue du general koenig, reims 51092, france. *correspondence: department of urology and andrology, robert debré academic hospital, avenue du general koenig, reims 51092, france. tel: +33 624 540234. fax: +33 140 514154. e-mail: younes.bayoud@wanadoo.fr. received july 2014 & accepted january 2015 urological oncology 2079urological oncology 2078 vol 12. no 02 march-april 2015 1995 which can be susceptible for debate and distinguished two groups. first one with localized pca with or without positive margins (pt2 r0 or r1) and second one with advanced pca (pt3a or b, r0 or r1) according to 2002 ptnm classification. criteria of selection was to select patients with localized and advanced pca, we also selected those at low and high risk of local and systemic relapse based on ptnm and gleason score, two only important parameters «predicting local and systemic relapse after rp» we had at this moment of decision making process. (1) thus we tried to have each half of group with gleason score at low and high risk of relapse. the group of pt2 comprised approximately 50% of patient with gleason score > 6 and the group of pt3 comprised approximately 50% of patient with gleason score ≤ 3+4 (table). we compared a decision made for each patient in both mdtm. all decisions were made accordingly to usual criteria such as ptnm stage, gleason score, margin status, comorbidities and choice of patients. mdtm comprised 5 urologists’ seniors and 2 juniors, 1 pathologist, 1 medical oncologist, 1 radiotherapist and 1 radiologist which get organized weekly. statistical analysis the statistical analysis chosen for comparison between first and second decision made at mdtm was kappa coefficient (k) which scale vary from non-agreement to perfect. the coefficient kappa is a statistical tool to assess reproducibility. it also allows an estimate of concordance of qualitative judgments for the same situations by two different observers.(6) we compared all criteria of study with student’s t-test for independent samples using means ± standard deviation (sd). results from january 2011 to march 2012, 183 patients underwent rp for localized pca. from this population 49 patients were selected prospectively and distribution of cancer and reproducibility of decisions-bayoud et al. figure 1. therapeutic decisions made for pt3an0m0 group at mdtm 1 and 2. abbreviations: mdtm; multidisciplinary team management; ebrt, extra beam radiation therapy; adt, androgen deprivation therapy. figure 2. therapeutic decisions made for pt3bn0m0 group at mdtm 1 and 2 abbreviations: mdtm; multidisciplinary team management; ebrt, extra beam radiation therapy; adt, androgen deprivation therapy. variables pt2n0m0 pt3an0m0 pt3bn0m0 p value (pt2 vs. pt3) number of patients 28 14 7 na mean age, years (range) 64 (53-75) 64.7 (53-75) 69.3 (66-74) .09 mean psa, ng/ml (range) 8.32 (3.56-19.5) 10.98 (3.8-22) 19.99 (2.9-85) .06 gleason grade, n (%) ≤ 6 13 (47) 10 (48) na 3+4 na 4+3 15 (53) 11 (52) na > 7 na positive surgical margin (%) 18 47.6 .01 comorbidities and previous surgery n (%) 4 (14.2) 7 (33.4) .06 surgical approach n (%) laparoscopic 19 (67.9) 13 (61.9) na retropubic 4 (14.3) 3 (14.3) na perineal 5 (17.8) 5 (23.8) na abbreviation: na, not applicable. table. baseline characteristics of patients group and t-test of independent sample. vol 12. no 02 march-april 2015 2079 patients was as follows: 28 pt2c and 21 pt3 (14 pt3a and 7 pt3b). baseline characteristics of patient group and t-test are shown in table. we observed a reproducibility of 100% of the group of pt2c independently of the margin status and gleason score. kappa coefficient was perfect (k = 1). in the group of pt3a, decisions were reproducible in 86% of cases, with therapeutic attitude putting in balance surveillance or extra beam radiation therapy (ebrt) (figure 1). the distribution of decisions was as follows: 28% for ebrt, 72% for surveillance at mdtm 1 and 14% for ebrt and 86% for surveillance at mdtm 2. the coefficient kappa was substantial with a value of 0.74. in the group of pt3b, decisions were reproducible in only 29% of cases. therapeutic decisions were ebrt plus androgen deprivation therapy (adt) in 71% of patients and surveillance in 29% of patients at mdtm 1, while therapeutic decisions at mdtm 2 were 14.5% for ebrt, 14.5% for ebrt plus adt and 71% for surveillance (figure 2). the kappa coefficient was slight with a value of 0.1. discussion our study showed the pertinence of mdtm recommended by law of cancer program 2003-2007.(3) many european studies showed the interest for mdtm,(4,5) but number of urologists expresses some doubts about benefits, exposing as argument a new burden without assigned budget. this position is partly supported by asher and colleagues, they reported in 124 cases of urological cancer, mdtm changed therapeutic attitude in only 2% of cases, thus authors suggested that urologist could presented only few patients to mdtm which reduced significantly a working cost without compromising therapeutic patient’s chance. (7) van belle(8) showed that mdtm established by the belgian governmental program was a success thanks to specifically assigned budget. authors reported also indirect evidence between mdtm and survival rate of cancer in belgium, because it’s within the five best european rates.(2,3,8) this hypothesis was sustained by results of sternberg and colleagues’ study, they concluded of beneficial effect of mdtm on free recurrence survival of pca in patients at high risk of recurrence, in particular phase iii of tax 3501 where was compared treatment with immediate or differed adt with or without docetaxel after rp.(9) our study showed reliability and reproducibility of decisions made at mdtm. this is valid in pt2 patients group in whom 100% of reproducibility was observed, while pt3a patients group showed 86% reproducibility (k= 0.74). however pt3b patients group showed worse rate of reproducibility with 29% (k = 0.1). these results should be interpreted with caution considering the smallness of sample (n = 7). further studies with larger sample sizes are mandatory to make final conclusion. those cases are still complex situations demanding mdtm decision-making process. the lack of well-defined recommendations certainly contributes to the weak rate of reproducibility of decision made at mdtm for locally advanced pca. groupe d'etude des tumeurs uro-génitales (getug) 17 trial which compares immediate ebrt associated to adt versus deferred ebrt at biochemical recurrence with adt for patients underwent rp in whom definitive pathology result is pt3 r1 ( r1: positive surgical margins) will contribute to clarify recommendations. the interest of mdtm is to include patients in the same trial. to support this idea, nguyen and colleagues showed in their study for breast cancer which recommendations are well designed that 92% of mdtm decisions were in accordance to recommendations and 96% of these decisions were followed by patient’s responsible doctor. they conclude also of the interest of including patients in trial.(10) the same conclusions were reported by carducci and colleagues, they surveyed prospectively 8 cancers in 6 hospitals, and they showed that 128 patients of 153 (84%) benefited from specific therapeutic decisions thanks to mdtm. authors insisted on the interest of mdtm in advanced pca and inclusion of patients in trial.(11) several studies seem to end on the interest of a tool to standardize and optimize the therapeutic decisions. thus, benjamin and colleagues reported significant differences in care of localized pca in the united states of america. between 2000 and 2001, 2775 cases of localized pca were collected from 55160 patients. they considered many criteria such as geographic location, type of institution (academic hospital or community hospital), pathology analysis and follow-up after treatment. significant differences were observed regarding geographic origin and type of institution where treatment was provided. besides, criteria such as tumor volume, extra capsular extension and ptnm stage were considered for making decision process respectively only in 37.1%, 68.6% and 48.2%.(11) hardly 55% of patients benefited from a follow-up.(12) clarke and colleagues showed in cohort of 30 urologists for whom were subjected questionnaires representing patients’ scenarios with pca, a mean of 3 cues from 9 were used to make therapeutic decision. criteria such as life expectancy, digital rectal examination, age of patient and patient’s choice were rarely used. the authors also reported that urologists made a different therapeutic decision in 31.4% of cases when they answered a same questionnaire at different time. they conclude that well defined recommendations and mdtm will standardize process of making decision and enhance reproducibility of decisions.(13) these observations were also demonstrated by wilson and colleagues in their study concerning 32 urologists from great britain, for whom 70 questionnaires representing medical history of pca were subjected. thirteen questionnaires among 70 were repeated to evaluate intra-observer reproducibility. they reported that intra-observer reproducibility varied from 56% to 79%, while inter-observer reproducibility varied from 24% to 57%. authors conclude on interest of standardizing therapeutic scheme and working in mdtm process for better decision reproducibility.(14) the mdtm appears as an answer to this need of optimizing the care process. conclusion in our study we showed a reliability and reproducibility of decision made at mdtm. reproducibility is acquired when recommendations are well defined. this is proved for localized pca. on the other hand decisions for advanced pca were less reproducible even if decisions were made in the setting of recommendations of french urologist association. these last cases justify more submission in the mdtm in the purpose to standardize the care process, facilitate inclusion in trial. this will allow having well-defined recommendations for complex cancer and reproducibility of decisions-bayoud et al. urological oncology 2080 cases of pca, and leading to best reproducibility of decision made at mdtm. conflict of interest none declared. references 1. heidenreich a, aus g, bolla m, et al. eau guidelines on prostate cancer. european association of urology. eur urol. 2008;53:6880. 2. salomon l, azria d, bastide c, et al. oncology committee of the french association of urology (ccafu). [recommendations onco-urology 2010: prostate cancer]. prog urol. 2010;20 suppl 4:s217-51. 3. plan cancer 2003-2007 (french government law): http://www.afssa.fr/et/documentset/ plan cancer.pdf 4. verdecchia a, francisci s, brenner h, et al. recent cancer survival in europe: a 2000-02 period analysis of eurocare-4 data. lancet oncol. 2007;8:784-96. 5. berrino f, de angelis r, sant m, et al. survival for eight major cancers and all cancers combined for european adults diagnosed in 1995-99: results of the eurocare-4 study. lancet oncol. 2007;8:773-83. 6. bergeri i, michel r, boutin jp. [everything (or almost everything) about the kappa coefficient]. med trop (mars). 2002;62:634-6. 7. acher pl, young aj, etherington-foy r, mccahy pj, deane am. improving outcomes in urological cancers: the impact of "multidisciplinary team meetings". int j surg. 2005;3:121-3. 8. van belle s. how to implement the multidisciplinary approach in prostate cancer management: the belgian model. bju int. 2008;101 suppl 2:2-4. 9. sternberg cn, krainer m, oh wk, et al. the medical management of prostate cancer: a multidisciplinary team approach. bju int. 2007;99:22-7. 10. nguyen td, legrand p, devie i, cauchois a, eymard jc. [qualitative assessment of the multidisciplinary tumor board in breast cancer]. bull cancer. 2008;95:247-51. 11. carducci ma, carroll pr. multidisciplinary management of advanced prostate cancer: changing perspectives on referring patients and enhancing collaboration between oncologists and urologists in clinical trials. urology. 2005;65(5 suppl):18-22. 12. spencer ba, miller dc, litwin ms, et al. variations in quality of care for men with early-stage prostate cancer. j clin oncol. 2008;26:3735-42. 13. clarke mg, wilson jr, kennedy kp, macdonagh rp. clinical judgment analysis of the parameters used by consultant urologists in the management of prostate cancer. j urol. 2007;178:98-102. 14. wilson j, kennedy k, ewings p, macdonagh r. analysis of consultant decision-making in the management of prostate cancer. prostate cancer prostatic dis. 2008;11:288-93. cancer and reproducibility of decisions-bayoud et al. vol 12. no 02 march-april 2015 2081 cancer and reproducibility of decisions-bayoud et al. appendix first name: family name: gender: date of birth: patient’s id: new patient urologist responsible: family doctor: date of mdtm: file of patient presented by: for: discussion patient consent for mdtm: yes oral written initial location: date of diagnosis: dd/mm/yyyy clinical tnm stage: pathology result (specimen): pt: xx pn: xx -m: xx status of margin (r): rx motive: diagnosis therapeutic decision therapeutic adjustment surveillance after treatment another motive medical history: results of examinations: (e.g. ct scan, mri, bone scan, medical notice of colleague ……). patient’s choice: who general health status: 0 1 2 3 4 comorbidities: therapeutic suggestion: final therapeutic decision: application of reference table (recording) discussion in the setting of reference table discussion out of reference table therapeutic trial urological oncology 2082 1569vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l department of urology, ulm university medical center, prittwitzstrasse 43, d-89075 ulm, germany. andreas al ghazal, thomas j. schnoeller, christian baechle, julie steinestel, florian jentzmik, sandra steffens, christian hirning, mark schrader, andres j. schrader capsulotomy for treatment of compartment syndrome in patients with post extracorporeal shock wave lithotripsy renal hematomas: safe and effective, but also advisable? corresponding author: andres jan schrader, md department of urology, ulm university medical center, prittwitzstrasse 43, d-89075 ulm, germany. tel: +49 731 500 58013 fax: +49 321 211 59100 e-mail: ajschrader@gmx.de. received may 2013 accepted december 2013 purpose: to examine whether surgical decompression of hematomas by capsulotomy can help to improve long-term renal function following extracorporeal shock wave lithotripsy (swl). materials and methods: this study retrospectively identified 7 patients who underwent capsulotomy for post swl renal hematomas between 2008 and 2012. the control group comprised 8 conservatively treated patients. the median follow-up time was 22 months. results: the two groups were comparable in age, gender, body mass index, risk factors for developing hematomas (renal failure, urinary flow impairment, indwelling ureteral stent and diabetes mellitus) and the selected swl modalities. hematoma size was also similar. however, significantly more patients in the surgical group had purely intracapsular hematomas (85.7% vs. 37.5%) without a potentially pressure-relieving capsular rupture. there were no significant differences in the post-interventional drop in hemoglobin, rise in retention parameters or drop in glomerular filtration rate (gfr). no capsulotomy-related complications were observed, but surgery required a significantly longer hospital stay than conservative management (median, 9 days vs. 5 days). the two groups also showed comparable recovery of renal function at long-term follow-up (median change in gfr from baseline, 97.1% and 97.8%, respectively). conclusion: since renal function did not differ between the two treatment groups, the conservative management remains the standard treatment for post-swl renal hematoma. keywords: hematoma; etiology; therapy; lithotripsy; adverse effects; urolithiasis; decompression; surgical. endourology and stone disease 1570 | introduction extracorporeal shock wave lithotripsy (swl) is an effective noninvasive method for treating urolithi-asis, particularly in the pelvicalyceal system and upper third of the ureter.(1,2) generation of focused acoustic shock waves (electromechanical, electrohydraulic or piezoelectric) achieves stone fragmentation by the resulting tear and shear forces and cavitation.(3,4) this noninvasive technique has limited side effects. the intended stone disintegration and subsequent passage of stone fragments cause most of the complications (renal colic and ureteral obstruction). in rare cases, however, post-swl renal and/or perirenal hematomas can also occur as more serious complications. the reported incidence of clinically significant post-swl renal hematomas varies between 0.28 and 4.1%, depending on the publication.(5-8) bleeding is thought to occur because the tear and shear forces and cavitation induced for stone disintegration not only impact the target concrement but also act on and arise from surrounding soft tissues and organs. this can already lead to damage at the cellular level with subsequent bleeding and hematomas. morphological analyses of porcine kidneys after swl therapy have shown that the applied energy causes damage particularly to the renal vessels from the cortical capillaries to the interlobular vessels or the arcuate arteries and veins.(8,9) the following have been identified as risk factors for postswl hematomas: advanced age (≥ 70 years), arterial hypertension, clotting disorders, oral anticoagulant therapy [particularly with acetylsalicylic acid (aspirin)], diabetes mellitus, overweight [body mass index (bmi) ≥ 30 kg/m2], oral corticosteroid therapy, arteriosclerosis, impaired renal function and urinary obstruction at the time of intervention. (5,8,10) bleeding usually manifests clinically as flank pain and orthostatic symptoms. ultrasonography (us) and computed tomography (ct) scan are now most commonly used to identify and evaluate post-swl renal hematomas.(6) the literature primarily favors conservative treatment of post-swl renal hematomas, particularly in hemodynamically stable patients and recommends surgery only in cases of uncontrollable bleeding with unstable hemodynamics.(6,8) capsulotomy is an alternative treatment approach for large hematomas that impair renal tissue perfusion. it involves incising gerota’s fascia, decompressing the hematoma, and inserting a drain.(11) in recent years, this surgical procedure has been performed in individual cases of subcapsular renal hematoma with compression of the renal parenchyma and relevant impairment of renal perfusion and function demonstrated in some cases with tc99m-mag3 (mercaptoacetyltriglycine) scan. the idea behind this surgical intervention was to achieve early kidney decompression in cases of compression-induced functional impairment comparable to lower extremity compartment syndrome. this case-control study evaluates the safety, effectiveness and potential benefit of capsulotomy in a defined number of patients. the intervention was performed in patients with significant hematoma-related impairment of renal perfusion and/or function on contrast-enhanced ct scan or mag3 scans in the acute phase after swl. materials and methods swl was performed to treat urolithiasis in 1,344 patients at the department of urology, ulm university medical center, between 2008 and 2012. the siemens lithoskop lithotripter (siemens ag healthcare, erlangen, germany) from 2007 was used in all cases. retrospective analysis of all treatment cases identified seven patients who developed a significant hematoma and were treated by capsulotomy during this period. the reference group comprised eight patients with post-swl hematomas that were treated conservatively during the same period. to enable a comparison of the two groups (with and without capsulotomy), the following data were collected in patients with post-swl hematomas: gender, age, bmi, comorbidities such as arterial hypertension, diabetes mellitus and urine transport disorders, preand post-swl renal function, the number and strength of shock waves applied, the hematoma size and the hemoglobin drop recorded in the laboratory as well as the hospital stay after swl treatment. in addition, patients were monitored by us for residual post-swl renal hematomas at follow-up. the two groups were compared. statistical analysis data presentation and analysis were done using the statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. data not normally distributed were given as median values; their distribution was deendourology and stone disease 1571vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l capsulotomy for treatment of compartment syndrome after swl | ghazal et al scribed using “interquartile ranges” (iqr). results the median as well as the mean follow-up of the total patient population (n = 15) was 22 (iqr, 10-37) months and did not differ significantly between the patients who underwent capsulotomy and those who received conservative treatment (see table). patient population the two groups (with and without capsulotomy) did not differ significantly in their risk of developing a hematoma: 71.4 and 75.0% were men; 14.3 and 12.5% had urinary obstruction at the time of swl treatment; 28.6 and 25.0% showed renal failure prior to therapy (table). their median bmi was also comparable (28.1 and 28.2 kg/m2). patients submitted to capsulotomy had a somewhat higher median age (63 versus 52 years; p = .27, mann-whitney u test), already had an indwelling ureteral splint more often at the time of shock wave therapy (71.4 vs. 25.0%, p = .13, fisher’s exact test) and suffered significantly more often from arterial hypertension (57.1 vs. 0.0%; p = .03, fisher’s exact test) (table). swl treatment patients were treated with a median total dose of 3,000 shock waves; a total energy of 50 joules was applied and a maximum energy level of 3.0 was reached. here too, no significant differences were found between the two treatment groups (also see table). treatment results and long-term complications the median size of renal hematomas did not differ (71 and 68 mm; table). similarly, both groups had a comparable drop in the hemoglobin level. the median level of hemoglobin at diagnosis of the hematoma was 86.9 and 87.1% of the baseline level. however, far more patients in the surgical group had purely intracapsular hematomas without evidence of capsular rupture (85.7 vs. 37.5%; figure 1). renal function before swl treatment did not differ between the two groups. the median serum creatinine level was initially 89 µmol/l (iqr, 78-101 µmol/l) in the patients who later underwent capsulotomy and also 89 μmol/l (iqr, 83-95 µmol/l) in those who received conservative treatment. accordingly, baseline glomerular filtration rate (gfr) values were similar. after developing the post-swl renal hematoma, the gfr showed a similar median decrease in both groups, dropping to 69.5% of baseline (iqr 59.5-83.7%) in the capsulotomized group and to 80.6% of baseline (iqr 62.3-93.6%) in the conservatively treated group (p = .49, mann-whitney u test). no difference in renal function was found between the two groups after a median follow-up of 22 months; the gfr was 97.1% (iqr 94.8-136.8%) and 97.8% (iqr 92.0106.8%) of the baseline value (p = 1.00, mann-whitney u figure 1. examples of a purely intracapsular postextracorporeal shock wave lithotripsy renal hematoma (a) with increased intrarenal pressure and reduced renal perfusion as well as a hematoma with partial capsular rupture (b). 1572 | test; figure 2). the median hospital stay after swl differed significantly between the two groups; 9 (6-14) days for the surgically and 5 (2-7) days for the conservatively treated group (p = .003; fisher’s exact test). discussion the current literature favors conservative management for post-swl renal bleeding in hemodynamically stable patients. an active approach in terms of a surgical intervention is only recommended in cases of uncontrollable bleeding and unstable hemodynamics.(6,8,9) various studies have shown that conservative treatment of renal hematomas is usually not associated with any marked long-term defects like impaired renal function.(9,12) it has also been reported that most renal hematomas dissolve over a period of two years with no long-term functional or morphological sequelae.(8,9,12) on the other hand, reductions in renal function have also been described during the long-term follow-up after (repeated) swl therapy.(13-16) surgical decompression by capsulotomy is an invasive experimental treatment option for post-swl renal subcapsular hematomas. the idea behind this approach is early kidney decompression as a strategy for managing compartment syndrome, which is associated with shortand possibly long-term parenchymal damage (page kidney).(11) the aim was to avoid acute but particularly also persistent impairment of renal function and sequelae such as arterial hypertension, renal failure and shortened life expectancy. the indication for capsulotomy in the retrospectively investigated patient population was based on the following: the patient’s symptoms, the ct scan morphology of hematoma extension (including compression of the renal parenchyma), significant reduction of renal perfusion and, if available, the detection of impaired renal function on mag3 scans in the acute phase. the primary aim was ideally to achieve fast and complete recovery of renal function by early surgical decompression of the kidney. this retrospective analysis was performed to determine the long-term benefit or harm of capsulotomy, since it is still considered an experimental treatment. seven patients identified as having undergone capsulotomy between 2008 and 2012 were compared with a control group who received conservative treatment. all patients included in the study still exhibited residual swl-induced defects and/or hematomas on follow-up us scans (after a median of 22 months). this finding contradicts reports in the literature describing complete “resolution” of hematomas within several months, two years at most.(12,17) our case-control study with a limited number of patients revealed no difference between the two treatment groups with regard to long-term impairment of renal function. both surgically and conservatively treated patients regained median values of renal function nearly identical to the pre-swl baseline values. the two groups only differed significantly in the length of hospital stay with a median of 9 days in the surgical and 5 days in the conservative group. the results presented here do not support capsulotomy as a routine procedure for treating significant renal hematomas. long-term results were similar after surgical and conservative treatment. thus the invasive intervention cannot be recommended without a verifiable long-term benefit. however, this is a purely retrospective analysis involving very limited number of patients, and not all of them had preoperative or follow-up renal scans to assess split renal function. the specific symptoms of hematoma experienced by each individual (which may have influenced the decision to perform surgery) could no longer be clearly established retrospectively and endourology and stone disease figure 2. overall kidney function (glomerular filtration rate, gfr) relative to preextracorporeal shock wave lithotripsy renal function in the acute phase of the hematoma and in the interval after a median follow-up of 22 months. 1573vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l thus could not be compared between the two groups. the localization of hematomas also differed between the groups. six (85.7%) of the seven hematomas in the surgical group but only 3 (37.5%) of the eight in the conservative group had a purely intracapsular localization .hematomas also showed extracapsular and retroperitoneal extension through capsular rupture in 1 (14.3%) and 5 (62.5%) patients. the latter cases could thus have been associated with lower intracapsular and intrarenal pressure and thus with potentially less long-term renal parenchymal damage. complications due to postoperative bleeding, infections or renal failure did not occur in either group. conclusion in conclusion, capsulotomy appears to be safe and effective, already achieving short-term results in cases of significant post-swl renal hematomas compressing the parenchyma. since long-term renal function did not differ from that in the conservatively treated reference group, however, a conservative approach remains the standard of care. capsulotomy might only be considered in individual cases of purely intracapsular hematomas and significantly impaired renal perfusion and function. acknowledgment andreas al ghazal and thomas j. schnoeller both contributed equally in this work. conflict of interest none declared. capsulotomy for treatment of compartment syndrome after swl | ghazal et al table . patient-specific characteristics, treatment and results. parameters all patients (n = 15) capsulotomy (n = 7) medical management (n = 8) p follow-up, median (days) 680 (30-1443) 680 (30-1443) 685 (141-1205) .82* age1, median (years) 54 (40-85) 63 (43-85) 52 (40-81) .27* bmi1, median (kg/m2) 28.2 (24.6-38.5) 28.1 (24.6-38.5) 28.2 (25.2-31.2) .91* male gender1 11 (73.3%) 5 (71.4%) 6 (75.0%) 1.00** urinary obstruction1 2 (13.3%) 1 (14.3%) 1 (12.5%) 1.00** ureteral stent1 7 (46.7%) 5 (71.4%) 2 (25.0%) .13** arterial hypertension1 4 (26.7%) 4 (57.1%) 0 .03** diabetes mellitus1 2 (13.3%) 2 (28.6%) 0 .20** preexisting renal failure1 4 (26.7%) 2 (28.6%) 2 (25.0%) 1.00** anticoagulants1 0.0 0.0 0.0 na total energy applied, median (joules) 50 (14.4-81.1) 56.6 (27.9-78.3) 47.4 (14.4-81.1) .20* number of shock waves, median 3000 (1500-3500) 3500 (2500-3500) 3000 (1500-3500) .28* maximum energy level, median 3.0 (1.7-4.0) 3.5 (2.2-4.0) 2.9 (1.7-4.0) .22* hematoma size, median (mm) 70 (30-100) 71 (47-100) 68 (30-99) .36* purely intracapsular hematoma, no. (%) 9 (60.0) 6 (85.7) 3 (37.5) .12** hb acute2 (% of baseline value) 87.0 (62.0-100) 86.9 (62.0-100) 87.1 (70.3-97.5) .95* gfr acute2 (% of baseline value) 70.7 (56.8-100) 69.5 (56.8-100) 80.6 (60.7-94.9) .49* gfr in the interval3 (% of baseline value) 97.4 (76.1-150.7) 97.1 (76.1-138.1) 97.8 (80.0-150.7) 1.00* hospital stay (days) 6 (2-14) 9 (6-14) 5 (2-7) .003* keys: hb, hemoglobin; gfr, glomerular filtration rate; na, not applicable; bmi, body mass index. 1= pre-swl; 2 = at diagnosis of hematoma; 3 = in the interval relative to the individual lengths of follow-up prior to analysis. * mann-whitney u test. ** fisher’s exact test. references 1. rassweiler jj, knoll t, kohrmann ku, et al. shock wave technology and application: an update. eur urol. 2011;59:784-96. 2. pearle ms. shock-wave lithotripsy for renal calculi. n engl j med. 2012;367:50-7. 3. chaussy c, bergsdorf t, thuroff s. extracorporeal shockwave lithotripsy. past, present and future. urologe a. 2006;45 suppl 4:189-94. 4. kostakopoulos a, stavropoulos nj, macrychoritis c, deliveliotis c, antonopoulos kp, picramenos d. subcapsular hematoma due to swl: risk factors. a study of 4,247 patients. urol int. 1995;55:21-4. 1574 | endourology and stone disease 5. kim tb, park hk, lee ky, kim kh, jung h, yoon sj. life-threatening complication after extracorporeal shock wave lithotripsy for a renal stone: a hepatic subcapsular hematoma. korean j urol. 2010;51:212-5. 6. labanaris ap, kuhn r, schott ge, zugor v. perirenal hematomas induced by extracorporeal shock wave lithotripsy (swl). therapeutic management. scientificworldjournal. 2007;7:1563-6. 7. sugihara t, yasunaga h, horiguchi h, et al. renal haemorrhage risk after extracorporeal shockwave lithotripsy: results from the japanese diagnosis procedure combination database. bju int. 2012;110:e332-8. 8. silberstein j, lakin cm, kellogg parsons j. shock wave lithotripsy and renal hemorrhage. rev urol. 2008;10:236-41. 9. mcateer ja, evan ap. the acute and long-term adverse effects of shock wave lithotripsy. semin nephrol. 2008;28:200-13. 10. collado serra a, huguet perez j, monreal garcia de vicuna f, rousaud baron a, izquierdo de la torre f, vicente rodriguez j. renal hematoma as a complication of extracorporeal shock wave lithotripsy. scand j urol nephrol. 1999;33:171-5. 11. duchene da, williams rd, winfield hn. laparoscopic management of bilateral page kidneys. urology. 2007;69:1208 e1-3. 12. krishnamurthi v, streem sb. long-term radiographic and functional outcome of extracorporeal shock wave lithotripsy induced perirenal hematomas. j urol. 1995;154:1673-5. 13. treglia a, moscoloni m. irreversible acute renal failure after bilateral extracorporeal shock wave lithotripsy. j nephrol. 1999;12:190-2. 14. sheng b, he d, zhao j, chen x, nan x. the protective effects of the traditional chinese herbs against renal damage induced by extracorporeal shock wave lithotripsy: a clinical study. urol res. 2011;39:89-97. 15. koga h, matsuoka k, noda s, yamashita t. cumulative renal damage in dogs by repeated treatment with extracorporeal shock waves. int j urol. 1996;3:134-40. 16. fischer c, wohrle j, pastor j, morgenroth k, senge t. extracorporeal shock-wave lithotripsy induced ultrastructural changes to the renal parenchyma under aspirin use. electron microscopic findings in the rat kidney. urologe a. 2007;46:150-5. 17. miernik a, wilhelm k, ardelt p, bulla s, schoenthaler m. modern urinary stone therapy: is the era of extracorporeal shock wave lithotripsy at an end? urologe a. 2012;51:372-8. u j all final for web.pdf 811vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l multicystic renal cell carcinoma a rare kidney tumor in children dogan atilgan,1 nihat uluocak,1 fikret erdemir,1 bekir suha parlaktas,1 resit dogan koseoglu,2 ozgur boztepe1 keywords: kidney, neoplasms, cysts, child, nephrectomy introduction r it is (2) ond reported case of mcrcc in a child in english literature. case report lindau disease. corresponding author: dogan atilgan, md gaziosmanpasa üniversitesi tıp fakültesi, üroloji ad 60100 tokat, turkey tel: +90 533 312 9667 fax: +90 356 212 9417 e-mail: datilgan@msn.com received november 2009 accepted january 2010 1 department of urology, faculty of medicine, gaziosmanpasa university, tokat, turkey 2 department of pathology, faculty of medicine, gaziosmanpasa university, tokat, turkey case report 812 | case report nous pyelography revealed a right hydronephrotic kidney with the pre-operative diagnosis of hydronephrosis and a the specimen consisted of one kidney and attached perirenal tortions in renal contours. sectioning revealed multilocular necrotic, granular material. the uninvolved normal renal locular cystic lesion (figure 2). according to fuhrman nuclear grading scheme, the nuclear discussion childhood cancers are much less common than adult cancers. leukemia and brain and spinal cord tumors are the most common type of cancers found in children. other intumor, muscle or bone cancers, lymphoma, and rcc. in (3) although rccs may include cystic or solid structures, cystic the avabdominal pain, hematuria, and fever are the most common symptoms of crcc. even if palpable mass occurs (6) multilocufigure 1. computed tomography showing a heterogeneous cystic lesion in the lower pole of the right kidney. figure 2. the cystic tumoral formation with multilocular appearance is seen in macroscopic section. the normal kidney tissue is seen in a small area in the upper part. 813vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l multicystic renal cell carcinoma | atilgan et al multicystic rcc is also an unusual entity in children and reported previously in the literature.(7) because of the raring pathologic features, natural history, clinical behavior, and prognosis remain uncertain. there are no treatment protocols agreed upon for pediatric mcrcc due to limlescent or adult patients in the literature. these tumors are not radiosensitive, and chemotherapy results have been phrectomy. it seems that mcrcc has better prognosis than non cystic rcc. should be performed, especially in younger patients and in feasible intra-operatively. literature that mcrcc has better prognosis, malignant potential of this disease should be considered and management should be handled according to this point. taken into account in the differential diagnosis of the kidney conflict of interest none declared. figure 3. histolological sections revealed multiple cysts seperated by fibrous hypocellular septa. small papillary structures are seen among cystic areas. the cysts are filled with necrotic material (hematoxylin and eosin stain, ×10). figure 4. papillary structures included true fibrovascular cores, and lining cells had mild nuclear pleomorphism and hyperchromasia. some of the atypical cells showed eosinophilic cytoplasm. psammomatous calcification and the appearence of atypical cells in high magnification (hematoxylin and eosin stain, ×30). references 1. bassil b, dosoretz de, prout gr, jr. validation of the tumor, nodes and metastasis classification of renal cell carcinoma. j urol. 1985;134:450-4. 2. selle b, furtwangler r, graf n, kaatsch p, bruder e, leuschner i. population-based study of renal cell carcinoma in children in germany, 1980-2005: more frequently localized tumors and underlying disorders compared with adult counterparts. cancer. 2006;107:2906-14. 3. uchiyama m, iwafuchi m, yagi m, et al. treatment of childhood renal cell carcinoma with lymph node metastasis: two cases and a review of literature. j surg oncol. 2000;75:266-9. 4. bielsa o, lloreta j, gelabert-mas a. cystic renal cell carcinoma: pathological features, survival and implications for treatment. br j urol. 1998;82:16-20. 814 | 5. carcao md, taylor gp, greenberg ml, et al. renal-cell carcinoma in children: a different disorder from its adult counterpart? med pediatr oncol. 1998;31:153-8. 6. halat sk, maclennan gt. multilocular cystic renal cell carcinoma. j urol. 2007;177:343. 7. menon p, rao kl, kakkar n, saxena ak, singh m. multilocular cystic renal cell carcinoma in a child. j pediatr surg. 2004;39:e14-6. 8. androulakakis pa, polychronopoulou-androulakaki s, michael v, stephanidis a, yannakis c. renal cell carcinoma in children under 14 years old: long-term survival. bju int. 1999;83:654-7. 9. nassir a, jollimore j, gupta r, bell d, norman r. multilocular cystic renal cell carcinoma: a series of 12 cases and review of the literature. urology. 2002;60:421-7. 10. corica fa, iczkowski ka, cheng l, et al. cystic renal cell carcinoma is cured by resection: a study of 24 cases with long-term followup. j urol. 1999;161:408-11. case report erratums erratum: flexible ureterorenoscopy versus semirigid ureteroscopy for the treatment of proximal ureteral stones: a retrospective comparative analysis of 124 patients mert ali karadag,1 aslan demir,1 kursat cecen,1 ramazan kocaaslan,1 mustafa sofikerim,2 fatih altunrende3 1 department of urology, kafkas university, faculty of medicine, kars, turkey. 2 department of urology, acibadem university, faculty of medicine, kayseri, turkey. 3 department of urology, bilim university, faculty of medicine, istanbul, turkey. this corrects the article on pages 1867-72, volume 11 number 5, pmid: 25361706. the fifth author (mustafa sofikerim) has requested to delete his name from the authors list. the corresponding author “mert ali karadag” accepted the author's request. the corresponding author apologize for this and its repercussions. the corrected author list is as follows. mert ali karadag,1 aslan demir,1 kursat cecen,1 ramazan kocaaslan,1 fatih altunrende2 1 department of urology, kafkas university, faculty of medicine, kars, turkey. 2 department of urology, bilim university, faculty of medicine, istanbul, turkey. the authors list was corrected online. vol 12 no 04 july-august 2015 2294 news the second urology and nephrology research festival (avicenna) 227 urology journal unrc/iua vol. 2, no. 4, 227-229 autumn 2005 printed in iran the urology and nephrology research center (unrc) began its activity in 1999. the unrc works toward its mission by conducting studies at national level and by supporting and coordinating with researchers, research institutions, universities and academic centers, and other related settings. in accordance with the responsibilities of this center, a research festival is designated to be held yearly, and the first urology and nephrology research festival was held in 2004 by the unrc. the second urology and nephrology research festival was held in december 9, 2005 and the best research projects in the field of urology and nephrology were selected and appraised. the underlying objectives of this festival are firstly to encourage the research in urology and nephrology fields; secondly to appreciate the researchers' efforts, and thirdly, to introduce the them and their findings to the scientific societies. juries evaluating in methodology, subject, creativity and problem solving first carefully assessed the research projects. scores were gathered and after standardization and sorting the projects, the final decision was made. the winners were invited to take part in the award ceremony at imam ali conference hall in shaheed beheshti university, tehran. this year, dr seyed hossein riazimand from heidelberg university, was the first prize winner of this festival for his work "a rat model for studying the effects of sacral neuromodulation and interaction between neurotransmitter antagonists and sacral neuromodulation in rats with chronic hyperactive bladder." more details of this study are described later on in this report. the second winner was dr mousarreza hadjzadeh. he is associate professor of physiology in mashhad university of medical sciences. the ethanolic extract of nigella sativa was the subject of his research. concerning its anti-analgesic and anti-inflammatory effects, and the increasing effect on glutathione in kidney, he studied a rat model to investigate the effect of nigella sativa on kidney stones in rats. he has found that the number of calcium oxalate deposits in the kidneys are reduced when nigella sativa is added to the drinking water of rats. also, the best dissertation in the field of urology was selected by the jury and dr amir haji mohammad mehdi arbab, resident of urology in shohada-e-tajrish hospital, won the prize. he investigated the presence of human papillomavirus infection in patients with bladder tumor of different local stages and grades and in a control group. he has conducted this study under the supervision of dr mohammadreza barghi, assistant professor of urology in shohadae-tajrish hospital. the first prize winner seyed hossein riazimand was born in 1963 in zunuz, iran. he graduated from the university of mainz in germany in 2001, with a phd degree in natural sciences. now he continues his scientific activity in the institut für anatomie und zellbiologie iii at the university of heidelberg. it is indeed a great honor to recognize dr riazimand for all his great effort as an iranian scientist and to bestow upon him the 2005 first rank urology and nephrology research award. dr riazimand and his colleague, dr siegfried mense, have carried out an animal study to evaluate the electrical stimulation of the sacral nerves with electrodes in the sacral foramina, namely sacral neuromodulation. they developed an animal model in which the effect of sacral neuromodulation on a chronic hyperactive urinary bladder can be studied. their results were published in 2004 in bju international.(1) in the next step, they introduced a modified rat model to investigate the interactions between antagonists of spinal neurotransmitters and the effect of sacral neuromodulation (figure 1). the second urology and nephrology research festival (avicenna) riazimand and mense's experiments were based on the hypothesis that sacral neuromodulation releases neurotransmitters in the spinal neurons, and consequently reduce the bladder contractions. if one of these neurotransmitters is involved in the neuromodulatory effects, intrathecal administration of an antagonist should reduce the effects of neuromodulation. they used 39 female rats and induced cystitis in 24 by instillation of turpentine oil into the bladder (figure 2). the other 15 rats served as controls. all rats survived for 10 days and thereafter, the induced cystitis was considered chronic. then, they anesthetized the rats and introduced a catheter into their bladders. to record bladder contractions, they connected a pressure transducer to the catheter. the rats were mounted in a spinal frame and the sacral foramina from s1 to s3 were surgically exposed. two stimulating cathodes were placed in the foramina of s1 bilaterally (figure 3). for topical spinal (intrathecal) administration of the antagonist or blocker, respectively, a laminectomy from vertebrae l6 to t12 was performed with a plastic ring. they termed this technique of intrathecal administration spinal superfusion. in rats with both inflamed and intact bladder, they first filled the pool with cerebrospinal fluid and applied sacral neuromodulation. then, they exchanged the pool contents with memantine, an antagonist of n-methyl-d-aspartate (nmda) receptors; 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (cnqx), an antagonist of α-amino3 hy d r ox y 5 m e t hy l 4 i s ox a z o l e p r o p a n o i c acid/kainite receptors; and l-n-nitroarginine p-nitroanilide (l-napna), a blocker of neuronal no syntase. they tested only one antagonist in each rat and sacral neuromodulation was repeated for 2 minutes. the results of this study were as follows: memantine and l-napna paused the cystitis228 fig. 1. the modified model: the right side shows the pool for spinal superfusion of the test substances on the dorsal surface of the spinal segment s1; on the left side the arrangement of the electrodes for sacral neuromodulation is depicted. fig. 2. cystitis induced by instillation of bladder with 2.5% turpentine oil: calcitonin gene-related peptide-ir nerve endings exhibited an inflammation-induced increase in innervation density (immunofluorescence). fig. 3. two cuff electrodes are attached to s1 sacral spinal nerves, intraoperatively. fig. 4. effect of memantine superfusion on cystitisinduced contractions the second urology and nephrology research festival (avicenna) induced bladder contractions for 4 minutes and 37 minutes, respectively (figure 4). the cerebrospinal fluid and cnqx caused a insignificant pause in contractions. electrical sacral modulation with no antagonists also transiently abolished the bladder contractions; at the highest intensity used, the pause was 2 to 3 minutes. superfusion of the spinal cord with cnqx reduced this effect of neuromodulation significantly, whereas memantine had no influence, and l-napna increased the neuromodulation-induced pause. dr riazimand and his colleague have suggested that non-nmda receptors are involved in the effects of sacral neuromodulation, whereas nmda receptors appear to have no role. nitric oxide is essential for maintaining the chronic hyperactive state of the urinary bladder. the report of this study is published in bju international.(2) references 1. riazimand sh, mense s. a rat model for studying effects of sacral neuromodulation on the contractile activity of a chronically inflamed bladder. bju int. 2004;94:158-63. 2. riazimand sh, mense s. interaction between neurotransmitter antagonists and effects of sacral neuromodulation in rats with chronically hyperactive bladder. bju int. 2005;96:900-8. 229 case report 203urology journal vol 5 no 3 summer 2008 radical retropubic prostatectomy as a solo therapy for treatment of adult rhabdomyosarcoma cuneyd sevinc,1 haluk akpinar,1 ilter tufek,1 can obek,2 ali riza kural3 urol j. 2008;5:203-5. www.uj.unrc.ir keywords: prostate neoplasms, rhabdomyosarcoma, prostatectomy, treatment protocol 1department of urology, istanbul bilim university, istanbul, turkey 2department of urology, yeditepe university, istanbul, turkey 3department of urology, medical school of cerrahpasa, university of istanbul, istanbul, turkey corresponding author: cuneyd sevinc, md hakki yeten st, no 8/5 fulya besiktas, istanbul, turkey tel: +90 533 557 5696 fax: +90 212 219 0987 e-mail: cuneydsevinc@gmail.com received september 2007 accepted march 2008 introduction incidence of prostate rhabdomyosarcoma in adults is not yet known. together with other sarcoma subtypes they cover less than 0.1% of the primary prostate malignancies.(1) we report an adult patient diagnosed with localized rhabdomyosarcoma treated with radical prostatectomy alone. case report a 57-year-old man presented with obstructive urinary symptoms for 6 months. physical examination did not reveal any abnormality except for the slightly enlarged prostate. prostate volume was estimated to be 55 ml, and serum level of prostate-specific antigen (psa) was 5.4 ng/ml. eight-quadrant transrectal biopsy revealed no malignancy. transurethral prostate resection was done and pathologic examination revealed benign prostatic hyperplasia. postoperative period was uneventful. seven months thereafter, he was admitted with urinary retention. on urethrocystoscopy, proliferative tissue obstructing the prostatic urethra was seen and resected. histopathological evaluation of the 6-ml resected material revealed mesenchymal malignant cells including rhabdomyoblasts in the subepithelial region of all resected specimens. these mesenchymal cells showed positive staining for desmin and myoglobin. there was no evidence of local or distant invasion of the tumor on thoracic and abdominal computed tomography. bilateral pelvic lymph node dissection and radical prostatectomy were performed. the tumor was measured 2.8 × 2.2 × 1.5 cm and was located between the right peripheric and transitional zones (figure 1). surgical margins figure 1. macroscopic view of prostate rhabdomyosarcoma (arrow). the tumor is extended through the prostatic urethra. the capsule is intact and the surgical margin is negative for tumoral tissue. treatment of adult rhabdomyosarcoma—sevinc et al 204 urology journal vol 5 no 3 summer 2008 were negative. histopathological evaluation of the radical prostatectomy specimen confirmed the diagnosis of embryonal rhabdomyosarcoma (figures 2 and 3). in addition to the sarcomatous tissue, a 3-mm tumor was detected which was prostate adenocarcinoma with a gleason score of 6 (3 + 3). the recovery was uneventful and no adjuvant therapy was instituted. under the surveillance with magnetic resonance imaging and regular measurement of serum psa, no evidence of recurrence has been found during the 54-month follow-up period. discussion there are limited reports of adult prostate rhabdomyosarcoma in the literature. rapidly progressing obstructive lower urinary tract symptoms are the major complaint as in our patient.(2) the age of onset may be less than what is expected for benign prostatic hyperplasia or prostate carcinoma. diagnosis of prostate rhabdomyosarcoma is challenging and is usually made by transrectal ultrasonography-guided biopsy or transurethral resection of the prostate.(1) digital rectal examination suggests no specific finding. serum psa may be within normal limits because of the nonepithelial origin of the disease. however, due to concomitant adenocarcinoma, psa may be elevated, too, as in the present case. at the initial presentation, digital rectal examination and transrectal ultrasonographyguided biopsy revealed no evidence of malignancy in our patient. definite diagnosis was made only after the second resection of the prostate performed because of the urinary retention. there is no pathognomonic radiological finding for prostate rhabdomyosarcoma. extensive local invasion of the bladder neck and the trigone may be accompanied by some changes related to ureteral obstruction.(3) ultrasonography and computed tomography are not valuable for early detection of the disease. magnetic resonance imaging has been the study of choice for most sarcomas, but may not be helpful for prostatic lesions.(4) histopathological evaluation of rhabdomyosarcoma usually reveals variable differentiation along the myogenesis pathway and may appear as strap cells or myotubes that sometimes contain muscle crossstriations. as what we observed in our case, rhabdomyosarcoma cells may demonstrate positive immunohistochemical results for musclespecific markers such as myoglobin, actin, and desmin.(5) embryonal rhabdomyosarcoma, mainly its botryoides subtype, is the usual presentation of urogenital rhabdomyosarcoma in infants and toddlers. they respond well to radiation and chemotherapy.(6) in contrast, adults usually present with nonembryonal subtypes which tend to be widely disseminated. the results are poor and despite good initial responses to figure 2. microscopic evaluation of prostate rhabdomyosarcoma. tumoral tissue is seen on the right side, while normal prostatic ducts are on the left (hematoxylin-eosin, × 40). figure 3. cytoplasmic staining with desmin antibody in tumoral cells, counterstained with hematoxylin (× 400). treatment of adult rhabdomyosarcoma—sevinc et al urology journal vol 5 no 3 summer 2008 205 chemotherapy, they eventually die of their disease.(7) localized presentation and favorable prognosis of our case may be due to his histological subtype. although it is difficult to compare data from different series because of varying documentation and very small number of patients with prostate rhabdomyosarcoma, the overall survival for adults is discouraging. the largest group of patients reported recently by dotan and colleagues included 131 patients with urogenital sarcoma. within this group, 21 of the tumors were originated from prostate and only 9 (6.8%) were rhabdomyosarcomas. this small subgroup of patients had the worst survival rates. at initial presentation, 9% of the prostate sarcomas were smaller than 5 cm, 10% were low grade, and 38% were free of metastasis. however, only 24% of them were free of disease at long-term follow-up.(8) treatment of prostatic rhabdomyosarcoma is multidisciplinary. the main aim of surgery for rhabdomyosarcoma is to completely remove the tumor with negative surgical margins while preserving all functional tissue. if feasible, it should be performed even in case of documented metastasis. however, definitive surgery is usually delayed until chemotherapy and/or radiotherapy has caused the shrinkage of large tumors that are not initially resectable.(9) radical prostatectomy alone may be an alternative only when the sarcoma is small and confined to the prostate. quinlan and colleagues reported a prostate sarcoma treated with radical prostatectomy, hemicystectomy, and ureteroureterostomy.(10) they instituted no adjuvant treatment and their patient was healthy on the 6th year of followup. in another study, sakura and coworkers reported a 19-year-old man treated with radical prostatectomy without any additional therapy. on follow-up, he developed bilateral metastases to the obturator lymph nodes that led to chemotherapy and pelvic radiation.(11) to our knowledge, our patient is the only one so far treated alone with radical prostatectomy with an uneventful long-term follow-up. conflict of interest none declared. references 1. sexton wj, lance re, reyes ao, pisters pw, tu sm, pisters ll. adult prostate sarcoma: the m. d. anderson cancer center experience. j urol. 2001;166:521-5. 2. cheville jc, dundore pa, nascimento ag, et al. leiomyosarcoma of the prostate. report of 23 cases. cancer. 1995;76:1422-7. 3. king dg, finney rp. embryonal rhabdomyosarcoma of the prostate. j urol. 1977;117:88-90. 4. nabi g, dinda ak, dogra pn. primary embryonal rhabdomyosarcoma of prostate in adults: diagnosis and management. int urol nephrol. 2002;34:531-4. 5. pappo as, shapiro dn, crist wm. rhabdomyosarcoma. biology and treatment. pediatr clin north am. 1997;44:953-72. 6. crist wm, garnsey l, beltangady ms, et al. prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies i and ii. intergroup rhabdomyosarcoma committee. j clin oncol. 1990;8:443-52. 7. russo p. urologic sarcoma in adults. memorial sloan-kettering cancer center experience based on a prospective database between 1982 and 1989. urol clin north am. 1991;18:581-8. 8. dotan za, tal r, golijanin d, et al. adult genitourinary sarcoma: the 25-year memorial sloan-kettering experience. j urol. 2006;176:2033-8. 9. ferrer fa, isakoff m, koyle ma. bladder/prostate rhabdomyosarcoma: past, present and future. j urol. 2006;176:1283-91. 10. quinlan dm, stutzman re, peters ca, walsh pc. unilateral nerve-sparing radical prostatectomy and hemicystectomy in management of prostate sarcoma. urology. 1993;41:308-10. 11. sakura m, tsukamoto t, yonese j, ishikawa y, aoki n, fukui i. successful therapy of a malignant phyllodes tumor of the prostate after postoperative local failure. urology. 2006;67:845.e11-3. case report 206 urology journal vol 5 no 3 summer 2008 spermatocele presenting as acute scrotum atsuya hikosaka, yutaka iwase urol j. 2008;5:206-8. www.uj.unrc.ir keywords: spermatocele, epididymis, acute scrotum, torsion abnormality department of urology, toyota kosei hospital, toyota, japan corresponding author: atsuya hikosaka, md department of urology, toyota kosei hospital, 500-1, ibobara, josui-cho, toyota, aichi 470-0396, japan tel: +81 565 43 5000 fax: +81 565 43 5100 e-mail: uropatho@ybb.ne.jp introduction spermatocele, a retention cyst of the scrotum which is or has been in communication with the semen-carrying system,(1) is a relatively common clinical entity. it presents typically as an intrascrotal paratesticular mass, but it usually has few subjective symptoms. here, we report a case of spermatocele manifested with acute scrotum due to its unique feature. case report a 25-year-old man presented to our hospital complaining of persistent left scrotal pain with a sudden onset 12 hours earlier. he had no history of scrotal injury or vasectomy. physical examination noticed a thumb-head-sized soft subcutaneous ovoid mass with severe tenderness above the left testicle, but bilateral testes were normally palpable. laboratory findings were unremarkable. doppler ultrasonography showed a simple cystic mass adjacent to the upper pole of the left testis and normal appearance of the both testes. however, slight decrease of blood flow in the left testis was suggested (figure 1). due to these confusing findings and perpetual pain, immediate surgical exploration was performed, which revealed a cystic lesion with a short stalk arising from the head of the left epididymis (figure 2). the cyst was filled with yellowish turbid fluid and was twisted about 180 degrees. histologically, the inner surface of the cyst wall was lined with columnar epithelial cells with cilia (figure 3, left). on cytological examination, the fluid in the cyst included spermatozoa (figure 3, figure 1. left, scrotal ultrasonography demonstrates a cystic lesion adjacent to the left testicle. right, doppler ultrasonography suggests slight decrease in the blood flow of the left testis compared with the right one. miscellaneous impact of voiding and incontinence symptoms on health-related quality of life in serbian male population uros babic,1* milena santric-milicevic,2,3 zorica terzic,2,3 aleksandar argirovic,5 dejan kojic,4 mihailo stjepanovic,1 dejan lazovic,1 vesna bjegovic-mikanovic,2,3 vinka vukotic,3,4 purpose: to investigate the impact of lower urinary tract symptoms on health-related quality of life (qol) in serbian population considering socio-demographic characteristics, habits, and health status. materials and methods: the study was conducted in the primary healthcare center «novi beograd», serbia. the study included 1424 male participants, aged 40 years and above. qol was assessed by using the -36item short form health survey (sf36-) questionnaire, while voiding and incontinence symptoms were measured using the international continence society male short form (ics male sf) questionnaire. results: voiding and incontinence symptoms significantly correlate with all domains of qol. voiding and incontinence symptoms have a high influence on general health, social functioning, physical functioning and body pain. after adjusting for age and education, voiding and incontinence symptoms had a similar influence on qol. in the multivariate model the influence of cardiovascular diseases and income on qol was lower than voiding and incontinence symptoms.. conclusion: voiding and incontinence symptoms affect qol domains differently. incontinence symptoms have a greater impact on qol than voiding symptoms. keywords: urinary incontinence; quality of life; cultural characteristics; psychology; male. introduction the world statistics is showing the high prevalence of lower urinary tract symptoms (luts) such as urine storage, voiding and post-micturition(1) among older population.(2) a prediction is that even a greater portion of persons will be affected with luts due to population aging. only storage symptoms are estimated to affect 1.6 billion, while overactive bladder will affect additional 546 million individuals by 2018 due to population growth and the overall ageing of the worldwide population.(3) luts influence normal daily activities and all domains of health related quality of life (hrqol).(4) therefore, luts is related to significant healthcare costs, absenteeism, low work productivity and sexuality dissatisfaction, leading to sleep disorders, limited mobility, loneliness, anxiety and depression.(5,6) all that makes luts a significant clinical and public health management issue.(2,7) the incidence of having ‘at least one’ storage luts is high, ranging from 43% in canadian men, and 45% of korean men to 48% of men in the european prospective investigation into cancer and nutrition (epic) study and 69.4% of men in the epidemiology of lower urinary tract symptoms (epiluts) study.(8-11) luts can be divided into three categories: storage, voiding and post-micturition.(7) storage symptoms are nocturia, urgency, increased micturition frequency and urinary in1 clinical center of serbia, belgrade, serbia. 2 institute of social medicine, belgrade, serbia. 3 faculty of medicine, university of belgrade, belgrade, serbia. 4 clinical center “dr dragisa misovic-dedinje”, belgrade, serbia. 5 clinical center “zemun”, belgrade, serbia. *correspondence: clinic of urology, clinical center of serbia, pasterova 2, 11000 belgrade, serbia. tel: +38 163 63305600. e-mail: urosb2001@yahoo.com. received: december 2014 & accepted: march 2015 continence. voiding symptoms are weak stream, intermittent flow, hesitancy and straining. post-micturition symptoms are a sensation of incomplete emptying and a post-micturition dribble. voiding and post-micturition symptoms are not as prevalent as storage symptoms, as epidemiology studies report that storage and voiding symptoms occur most often together in 18-21% men.(8,9) many people are not aware of the significance of those symptoms and tolerate and neglect luts considering this condition as a result of ageing.(5) benign prostatic hyperplasia (bph), urethral stenosis and hypermobility and detrusor overactivity, bladder stones or bladder tumors usually cause luts in men. in addition, various system conditions like hypertension, diabetes mellitus, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, hyperinsulinemia are known to influence luts occurrence.(12) serbia is one of the oldest populations in europe region, with standardized death rate per 100,000 population due to diseases of genitourinary system that vary from 14 in 2001 to 19 in 2011.(13) in 2013, the specific mortality rate for males only was 32 per 100,000 population due to diseases of genitourinary system. (14) the same year, general practice services have registered over 86000 cases with prostate hyperplasia or 15 per 1000 population(14) which is considerably higher than 12.5 per 1000 or over 71000 cases registered in miscellaneous 2196 2012.(15) to our knowledge, there were no published hrqol studies on persons with luts in serbia. the aim of this study was to estimate the impact of voiding and incontinence symptoms on quality of life (qol) in urban male population considering socio-demographic characteristics, habits, and health status. materials and methods study design and population this is a descriptive study of hrqol of series of male patients that have visited general practitioners at the primary healthcare center “novi beograd” (phc) of belgrade (capital of serbia) from december 2011 until may 2012 (six-month period). the study was carried out in the largest municipality of belgrade (novi beograd) which accounts for 214,000 residents (2011 census).(16) the underlying reason for community based phc approach is because persons with luts do not perceive luts as a health problem for a long time, but when they decide to seek help, they have to visit their general practitioner first (gate keeper).(17,18) according to official statistics,(16) the study participants represent 2.8% of the total male population of 40 years or older residing at novi belgrade. respondents’ age structure, marriage and education status, number of household members and weight profile appropriately represent the population of the municipality.(14,15) however, risk behavior such as smoking and alcohol consumption was less frequent than reported by other authors,(14,15) very likely because study respondents were those who visited general practitioners for a therapy or advice and being aware of their health status most of them have abandoned unhealthy life style habits. diabetes mellitus in serbia affects 8.6% of population(14) while in our study 5.3% of respondents had diabetes mellitus. in addition, most of our respondents had cardiovascular diseases that are the most frequent non-communicable disease in serbia.(14,15) regarding all the above-mentioned points, our study population reasonably represents the population of serbia as well. the study had two inclusion criteria, being male and aged 40 years or older. patients with diagnosed cancer of any organ at any stage and diagnosed depression, or anxiety were excluded from the study. participants who did not complete the questionnaires were also excluded. all eligible patients were informed orally and in written form about the purpose and ethical standards of the study and were kindly asked to voluntary participate in the study. all persons gave their informed consent prior their inclusion to study. this study has been approved by ethics committee of phc novi beograd. a total of 1424 patients fulfilling criteria were included in the study and anonymously and properly completed three types of questionnaires. the response rate was 95% (1424/1500). study instruments the first questionnaire was about general socio-economic status (age, education, profession, employment, marital status, having children, apartment/house ownership, salary level), and general health data (body weight and height, daily smoking of 20 cigarettes and more, alcohol consumption, being diagnosed with angina pectoris, myocardial infarction, stroke and diabetes). the second questionnaire was the international continence society male short form (ics male sf), intended for evaluating the occurrence of luts.(19) the questionnaire has been translated and culturally adapted. translation was done by two professional english translators. firstly, the questionnaire was translated to serbian language and then secondly, professional english translator undertook a back translation to english language. the back translated questionnaire was compared to the original questionnaire and no significant differences were observed. a pilot study with five patients was performed, and these patients evaluated the serbian version of questionnaire. minor changes were undertaking with by their suggestions. the questionnaire contained voiding symptoms (5 questions) and incontinence symptoms (6 questions) domains. this questionnaire also had three additional questions, urination frequency during day and night, and overall impact of urinary problems on life. responses were designed by five-point likert scale type, where a lower grade represented better condition. two extracted components of total eleven questions explained 69.9% of variance. high reliability was observed in five items of voiding symptoms, cronbach›s α = 0.893 (α if item deleted 0.860-0.886) and six items of incontinence symptoms, cronbach's α = 0.894 (α if item deleted 0.862-0.894). the third questionnaire was the 36-item short form health survey (sf-36) generic assessment domain for hrqol, previously translated and adapted for serbian population.(20) this questionnaire contains eight domains intended for evaluating physical health and mental functioning. the first four domains (physical functioning, role-physical, bodily pain and general health) were used to assess physical health from the patient›s point of view whilst others deal with vitality, social functioning, role-emotional and mental health issues. patients gave answers on numerical scale. answers were coded, and scores for the eight domains were calculated on a 0-100 scale. higher scores represented better results from patient›s point of view.(20) statistical analyses the results were presented as frequency with percent and mean ± sd. principal components analysis with varimax rotation and reliability analysis were used for validation of ics male sf questionnaire. spearman correlation, pearson correlation, point bi-serial correlation were determined to assess relationship between patients characteristics (socio-demographic, health status, luts) and qol. linear regression modeling was applied to assess correlation of voiding and urinary symptoms with qol. modeling was done in several steps to avoid the influence of confounding factors. in the first step, only voiding and incontinence scores were entered as independent variables and the eight domains of the sf-36 as dependent variables. in the second step, voiding and incontinence symptoms were adjusted for age. then, in the next step, urinary symptoms were adjusted for age and education. in the fourth model, adjustment was made for age and education and one of the following: morbidity, income, number of household members and apartment/house ownership. in the final step, all predictors were entered into the model. in order to shorten the results, only standardized beta and p values of voiding and incontinence symptoms were presented, as well as r square. all data were analyzed using statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. all p values less than .05 were considered significant. results luts and quality of life-babic et al. vol 12 no 03 may-june 2015 2197 participants were mostly males in their sixties and with secondary school or higher education. two thirds had own apartments but one eight lived alone. more than 51% had 200€ net monthly incomes which is the minimal income in 2012 in serbia according to the statistical office of the republic of serbia. half respondents were either overweight or obese (according to body mass index for adults). a quarter of them were smokers and alcohol consumers. one fifth of them had cardiovascular diseases, in most cases angina pectoris (table 1). our study population had characteristics similar to the other those studies conducted in serbia . most participants (61.1%) claimed that voiding has no effect on their qol (table 2). average voiding (vs) and incontinence symptoms (is) were low. physical functioning and social functioning had the highest score, and general and mental health had the lowest average values (table 2). vs and is have a statistically significant relationship with sf-36 domains. correlation coefficients are lower in some domains such as mental health, emotional health, and role physical. but, correlation coefficients of these variables are higher than others in number of qol domains (table 3). all five steps of regression modeling are presented in table 4, thus the first model is non-adjusted, the second is age, and education adjusted, third is age, education and morbidity adjusted. the fourth model is age, education and income adjusted model. the final model is age, education, morbidity, income, household member number and apartment ownership adjusted (table 4). voiding and incontinence symptoms correlate significantly with all domains of qol, measured through the sf-36 questionnaire. in the non-adjusted model voiding symptoms highly correlated with physical functioning and general health, while incontinence symptoms are correlated with physical functioning, body pain, general health and social functioning. after adjusting for age and education, standardized beta were lower in all domains, mostly in physical functioning. after adjusting for age, education and morbidity or income, coefficients were very similar as well after adjusting for all predictors (the previous including household members and apartment/house ownership) (table 4). discussion this study is the first conducted in serbia assessing the impact of voiding and incontinence symptoms on life quality in urban males of belgrade. it is to emphasize that countries with limited health care resources, like serbia, should take an advantage of qol assessments in order to involve patients with certain health disorders in better understanding of their health problems and in decision making about potential treatments. based on the results of our study, almost two-thirds of participants claimed that voiding has no effects to hrqol. for the other third, we found a highly significant statistical relationship between voiding and incontinence symptoms with all sf-36 hrqol domains except mental health (perhaps because of exclusion of patients with mental illness from the study). according to serbian national health survey, 3.9% of males of 15 years and older had urinary incontinence.(21) our study highlighted that voiding and incontinence symptoms have higher influence on some domains like general health, social functioning, physical functioning and body pain than on role physical, vitality and role emotional, although effects were statistically significant. it is important to emphasize that incontinency had a higher impact on role physical and social functioning than voiding symptoms. same domains of hrqol are associated with luts severity (social functioning, vitality and role physical).(6) also, revealed a high correlation between luts intensity and hrqol, especially on role physical, social functioning, vitality, mental health and general health domains.(22) in our study, explained variability was low as in other studies.(23,24) similar to findings of other researchers(23,24) the intensity of voiding or storage bother, had a significant correlation with hrqol. due to chronic character of these problems, our patients could have adapted to their difficulties, thus mental health was not as poor as was emotional role. one half of our study participants’ had salaries below minimum, which suggested difficult living conditions. therefore reduced social functioning was expected. experts agreed that it is difficult to determine normal voiding frequency. a majority of males without lower urinary tract symptoms in the usa, had a frequency of 7 voiding per day.(25) on the contrary, the incontinence society of singapore claimed that normal 24-hour voiding frequency was of 4 to 5 voiding.(26) voiding frequency is in direct correlation with ageing and it is expected to increase during life.(22,27) in our study almost half table 1. demographic and clinical characteristics of the study participants. variables n (%) age, mean ± sd (min-max) 55.5 ± 10.1 (40-80) married (or union) 982 (69.0) number of household members 1 182 (12.8) 2-4 1116 (78.4) ≥ 5 126 (8.8) education basic 130 (9.1) high school 775 (54.4) college/faculty 519 (36.9) own apartment/house 968 (68.0) income higher than 200 euros 690 (48.5) body mass index < 25 664 (46.6) 25-29.9 588 (41.3) ≥ 30 172 (12.1) smoking 347 (24.4) alcohol consumption 378 (26.5) co-morbidity (all) 288 (20.2) angina pectoris 211 (14.8) myocardial infarction 19 (1.3) stroke 13 (0.9) diabetes mellitus 75 (5.3) abbreviation: sd, standard deviation. luts and quality of life-babic et al. miscellaneous 2198 table 2. urinary status (ics male sf) and quality of life (sf-36). questionnaire variables no. % ics male sf voiding frequency during day 4 hours or more 658 46.2 3 hours 392 27.5 2 hours 245 17.2 every hour 129 9.1 voiding frequency during night (time) none 587 41.2 once 436 30.6 2 241 16.9 3 117 8.2 ≥ 4 43 3.0 impact of voiding on life not at all 870 61.1 some 395 27.7 quite 127 8.9 much 32 2.2 mean ± sd median (min-max) voiding symptoms 3.8±4.5 2 (0-20) incontinence symptoms 3.2±4.4 1 (0-24) sf-36 physical functioning 69.5 ± 27.9 75 (0-100) role-physical 56.7 ± 43.4 75 (0-100) bodily pain 59.9 ± 27.4 52 (0-100) general health 53.8 ± 15.4 52 (0-100) vitality 56.1±10.8 55 (20-100) social functioning 62.2±22.6 62.5 (0-100) role-emotional 58.3±43.7 66.6 (0-100) mental health 50.4±6.8 52.0 (16-80) abbreviations: sf-36, 36-item short form health survey; ics male sf, international continence society male short form. sf-36 domains voiding score incontinence score ≤ 1 2-5 ≥ 6 0 1-4 ≥ 5 physical functioning 81.5 ± 23.7 65.5 ± 26.8 56.0 ± 27.3 81.9 ± 23.1 69.5 ± 25.6 50.2 ± 26.1 role-physical 62.0 ± 44.7 57.8 ± 42.1 48.3 ± 41.5 64.5 ± 44.0 58.4 ± 42.4 42.8 ± 40.1 bodily pain 68.0 ± 26.8 59.9 ± 27.8 48.5 ± 23.5 69.1 ± 26.8 61.9 ± 25.9 43.7 ± 21.8 general health 57.8 ± 14.3 55.2 ± 14.3 47.1 ± 15.5 57.8 ± 14.6 56.5 ± 14.0 44.8 ± 14.0 vitality 58.3 ± 10.4 55.5 ± 11.1 53.4 ± 10.7 58.2 ± 10.2 57.0 ± 10.8 51.6 ± 10.5 social functioning 68.8 ± 22.3 61.0 ± 22.4 53.9 ± 20.3 69.4 ± 22.2 64.3 ± 21.4 48.9 ± 18.3 role-emotional 63.9 ± 44.0 59.6 ± 42.1 49.2 ± 43.2 65.7 ± 43.9 62.8 ± 41.3 58.3 ± 43.6 mental health 50.0 ± 6.5 49.6 ± 7.1 51.6 ± 6.7 50.3 ± 6.3 49.7 ± 6.8 51.1 ± 7.3 abbreviation: sf-36, 36-item short form health survey. table 3. voiding score and incontinence score tertiles and quality of life measured by sf-36. luts and quality of life-babic et al. vol 12 no 03 may-june 2015 2199 table 4. multivariate regression analyses with sf-36 domains as dependents and voiding and incontinence symptoms as independents variables.* regression models voiding symptoms incontinence symptoms r2 standardized β r2 standardized β model 1 no adjustment physical functioning 0.188 -0.433 0.224 -0.473 role-physical 0.024 -0.155 0.042 -0.206 bodily pain 0.115 -0.339 0.137 -0.371 general health 0.148 -0.385 0.148 -0.385 vitality 0.055 -0.235 0.065 -0.255 social functioning 0.104 -0.322 0.139 -0.372 role-emotional 0.028 -0.169 0.060 -0.244 mental health 0.020 0.141 0.006 0.080 model 2 adjusted for age and education physical functioning 0.239 -0.345 0.264 -0.388 role-physical 0.040 -0.111 0.053 -0.167 bodily pain 0.153 -0.295 0.167 -0.325 general health 0.191 -0.327 0.185 -0.320 vitality 0.098 -0.183 0.103 -0.197 social functioning 0.142 -0.289 0.169 -0.340 role-emotional 0.037 -0.145 0.064 -0.230 mental health 0.044 0.110 0.035 0.031 ns model 3 adjusted for age, education and morbidity physical functioning 0.239 -0.348 0.264 -0.388 role-physical 0.041 -0.104 0.054 -0.165 bodily pain 0.153 -0.292 0.168 -0.322 general health 0.206 -0.309 0.205 -0.308 vitality 0.100 -0.175 0.105 -0.194 social functioning 0.145 -0.280 0.173 -0.335 role-emotional 0.037 -0.143 0.064 -0.230 mental health 0.055 0.095 0.048 0.022 ns model 4 adjusted for age, education and income physical functioning 0.239 -0.345 0.264 -0.388 role-physical 0.040 -0.111 0.053 -0.168 bodily pain 0.156 -0.295 0.169 -0.323 general health 0.207 -0.327 0.198 -0.315 vitality 0.115 -0.182 0.118 -0.192 social functioning 0.151 -0.289 0.175 -0.337 role-emotional 0.040 -0.145 0.066 -0.228 mental health 0.049 0.110 0.040 0.028 ns model 5 adjusted for age, education, income, number of household members and own apartment physical functioning 0.279 -0.341 0.271 -0.380 role-physical 0.044 -0.101 0.057 -0.161 bodily pain 0.163 -0.286 0.175 -0.312 general health 0.224 -0.307 0.220 -0.300 vitality 0.130 -0.170 0.132 -0.180 social functioning 0.165 -0.273 0.188 -0.322 role-emotional 0.042 -0.137 0.068 -0.224 mental health 0.062 0.096 0.055 0.021 ns abbreviation: ns, not significant. *all p values for all models are less than .001. luts and quality of life-babic et al. miscellaneous 2200 of participants had normal voiding frequency (every 4 hours or more), while less than 30% had frequent urination (every two hours or less). these results should be to considered with regard to the fact that voiding frequency during the day depends on liquid intake. the studies that explored correlation of lifestyle and luts, found that alcohol consumption correlated with urgency and voiding and incontinence symptoms.(12) nocturia represents one or more than one voiding during night, interrupting sleep. however, some researches claim that nocturia is more than one voiding during the night.(28) epic study revealed that nocturia is the most frequent luts. also according to results of the boston area community health (bach) cohort study, more than 25% of males suffer from nocturia, where diabetes mellitus, cardiovascular disease, cerebrovascular disease, obesity and diuretics are predisposing factors.(1) but, if we applied a stricter criterion (two or more voidings during night), 30% of our participants had nocturia. similar results were obtained in cross-sectional study among elderly men in 21 general practices.(29) in epiluts study, a majority of participants (92.8%) did not show any kind of bother. (3) in our study most of participants claimed no bother or some bother (89%), which demonstrates a similar percentage of urinary bother in both populations. aging and education are in positive correlation with luts intensity.(2,30-32) our study population’s age and education level varied and it was necessary to adjust the relation of voiding and incontinence symptoms with them. the impact of voiding and incontinence symptoms on qol domains was still significant after adjustment for age and education and that was found in other studies as well.(31,32) morbidity and luts are correlated, especially in some chronic diseases such as diabetes mellitus, coronary artery disease and stroke. these morbidities have a negative impact on luts intensity because of vascular and neurological pathogenesis.(33) after adjustment for age, education and morbidity (diabetes mellitus, cardiovascular and cerebrovascular diseases and asthma), no significant changes in regression coefficients were obtained in any specific qol domains. it indicates that influence of urinary bother on qol is higher than observed diseases. other studies have similar results as our study, which confirms a high impact of luts on qol, higher than many other conditions. (30,31) the bach and urepic studies (the urepik survey collected information on this relationship in the netherlands, korea, france and the uk) showed that luts had a similar or higher effect on qol as stroke, myocardial infarction and other life threatening disease.(32) the same studies revealed that morbidity, excepting myocardial infarction, had no influence on the mental component as qol domain. a higher impact of luts on qol than of diabetes mellitus, gout and hypertension was also confirmed by other researchers.(24) age, education and income adjusted model, revealed that voiding and incontinence symptoms had a higher impact than income. the final model with additional adjustment for, household members, and apartment ownership did not change coefficients significantly. study limitations the findings of this study are limited to the one male community in belgrade. for better generalization, further studies should be conducted on a larger scale and should include possibility of comparing the qol data between the patients with luts and patients with no symptoms. the questionnaires were self-administered by participants and data affected participant’s memory and perception to some extent, thus findings might be under or overestimated. this study, nonetheless, is an original attempt to assess the hrqol of male adults with luts in serbia. in line with that, in this study the ics male sf questionnaire has been translated and culturally adapted for serbian population, therefore it provides a foundation for further research. the inclusion of general practitioners in the collection of data has raised their awareness about the relationship between the quality of lofe and luts and might have enhanced their approach to clinical management of luts for the better hrqol of patients. conclusion luts have a high impact on qol. incontinence symptoms have higher impact on qol than voiding symptoms. voiding and incontinence symptoms significantly affect different domains of qol after adjustment for comorbidities, income and household characteristics. conflict of interest none declared. acknowledgements authors were supported from the ministry of education, science, and technological development of the republic of serbia (grant no. 175087 and contract no. 175042). we would also like to thank the management and general practitioners of the primary healthcare center “novi beograd” in belgrade for their help. special thanks to participants for their valuable input. references 1. irwin de, milsom i, kopp z, abrams p, artibani w, herschorn s. prevalence, severity, and symptom bother of lower urinary tract symptoms among men in the epic study: impact of overactive bladder. eur urol. 2009;56:14-20. 2. irwin de, kopp zs, agatep b, milsom i, abrams p. worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. bju int. 2011;108:1132-8. 3. abrams p, manson j, kirby mg. incidence and epidemiology of storage lower urinary tract symptoms. eur urol rev. 2012;7:50-4. 4. coyne ks, wein aj, tubaro a, et al. the burden of lower urinary tract symptoms: evaluating the effect of luts on healthrelated quality of life, anxiety and depression: epiluts. bju int. 2009;103 suppl 3:4-11. 5. coyne ks, sexton cc, irwin de, kopp zs, kelleher cj, milsom i. the impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional well-being in men and women: results from the epic study. bju int. 2008;101:1388-95. 6. coyne ks, kvasz m, ireland am, milsom i, luts and quality of life-babic et al. vol 12 no 03 may-june 2015 2201 kopp zs, chapple cr. urinary incontinence and its relationship to mental health and healthrelated quality of life in men and women in sweden, the united kingdom, and the united states. eur urol. 2012;61:88-95. 7. irwin de, mungapen l, milsom i, kopp z, reeves p, kelleher c. the economic impact of overactive bladder syndrome in six western countries. bju int. 2009;103:202-9. 8. coyne ks, kaplan sa, chapple cr, et al. epiluts team. risk factors and comorbid conditions associated with lower urinary tract symptoms: epiluts. bju int. 2009; 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[http://www.euro.who.int/en/data-andevidence/databases/european-health-for-alldatabase-hfa-db] 14. the institute of public health of serbia “dr milan jovanovic batut”, health statistical yearbook 2013. p. 123. 15. the institute of public health of serbia “dr milan jovanovic batut”, health statistical yearbook 2012; 2013. p. 123. 16. statistical office of the republic of serbia. population by age and sex, by settlements. [http://popis2011.stat.rs/?page_ id=2162&lang=en\] 17. teunissen d, van weel c, lagro-janssen t. urinary incontinence in older people living in the community: examining help-seeking behavior. br j gen pract, 2005;55:776-82. 18. buckley bs, lapitan mc. prevalence of urinary and faecal incontinence and nocturnal enuresis and attitudes to treatment and help-seeking amongst a community-based representative sample of adults in the united kingdom. int j clin pract. 2009;63:568-73. 19. donovan jl, peters tj, abrams p, brookes st, de aa rosette jj, schäfer w. scoring the short form ics male sf questionnaire. international continence society. j urol. 2000;164:194855. 20. ware je, sherbourne cd. the mos 36item short-form health survey (sf-36), i: conceptual framework and item selection. med care. 1992;30:473-83. 21. boricic k, vasic m, grozdanov j, et al. results of the 2013 health survey of the population of serbia. belgrade: the institute of public health of serbia “dr milan jovanovic batut”. 2014. p. 34 22. hunter dj, mckee m, black na, sanderson cf. health status and quality of life of british men with lower urinary tract symptoms: results from the sf-36. urology. 1995;45:96271. 23. engström g, henningsohn l, walkerengström ml, leppert j. impact on quality of life of different lower urinary tract symptoms in men measured by means of the sf36 questionnaire. scand j urol nephrol. 2006;40:485-94. 24. welch g, weinger k, barry mj. quality-oflife impact of lower urinary tract symptoms: results from the health professionals follow-up study. urology. 2002;59:245-50. 25. latini jm, mueller e, lux mm, fitzgerald mp, kreder kj. voiding frequency in a sample of asymptomatic american men. j urol. 2004;172:980-4. 26. tatt fk: society for continence, singapore; 2001. 27. kay l, stigsby b, brasso k, mortensen so, munkgaard s. lower urinary tract symptoms-a population survey using the danish prostatic symptom score (dan-pss) questionnaire. scand j urol nephrol. 1999;33:94-9. 28. tikkinen ka, johnson tm 2nd, tammela tl, et al. nocturia frequency, bother, and quality of life: how often is too often? a populationbased study in finland. eur urol. 2010;57:48896. 29. gourova lw, van de beek c, spigt mg, nieman fh, van kerrebroeck pe. predictive factors for nocturia in elderly men: a crosssectional study in 21 general practices. bju int. 2006; 97:528-32. 30. hawkins k, pernarelli j, ozminkowski rj, et al. the prevalence of urinary incontinence and its burden on the quality of life among older adults with medicare supplement insurance. qual life res. 2011;20:723-32. 31. malmsten ug, milsom i, molander u, norlen lj. urinary incontinence and lower urinary tract symptoms: an epi-demiological study of men aged 45 to 99 years. j urol. 1997;158:1733-7. 32. engstrom g, walker-engstrom ml, loof l, leppert j. prevalence of three lower urinary tract symptoms in men a population-based study. fam pract. 2003;20:7-10. 33. martin s, lange k, haren mt, taylor aw, luts and quality of life-babic et al. miscellaneous 2202 wittert g. members of the florey adelaide male ageing study. risk factors for progression or improvement of lower urinary tract symptoms in a prospective cohort of men. j urol. 2014;191:130-7. luts and quality of life-babic et al. vol 12 no 03 may-june 2015 2203 1175ff.pdf 886 | 1department of urology, haydarpasa numune training and research hospital, istanbul, turkey 2 department of histology and embryology, marmara university school of medicine, istanbul, turkey orhan koca,1 ali murat gökçe,1 metin i̇shak öztürk,1 feriha ercan,2 necati yurdakul,2 muhammet i̇hsan karaman1 effects of intensive cell phone (philips genic 900) use on the rat kidney tissue corresponding author: orhan koca, md departman of urology, haydarpaşa numune training and research hospital, üsküdar, istanbul, turkey tel: +90 216 414 4502 fax: +90 216 345 5982 e-mail: drorhankoca@ hotmail.com received october 2011 accepted january 2013 purpose: to investigate effects of electromagnetic radiation (emr) emitted by cell phones on the rat kidney tissue. materials and methods: twenty-one male albino rats were divided into 3 groups, each comprising 7 rats. group 1 was exposed to a cell phone in speech mode for 8 hours/day for 20 days and their kidneys were removed. group 2 was exposed to emr for 20 days and then their kidneys were removed after an interval of 20 days. cell phone used in the present study was philips genie 900, results: revealed glomerular damage, dilatation of bowman’s capsule, formation of large spaces between verity score was 4.64 ± 1.7 in group 1, 4.50 ± 0.8 in group 2, and 0 in group 3. while there was no p > .05), the mean severity scores of groups 1 p = .001 for each). conclusion: considering the damage in rat kidney tissue caused by emr-emitting cell phones, high-risk individuals should take protective measures. keywords: kidney, cellular phone, electromagnetic radiation cellular and molecular urology cellular and molecular urology 887vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l introduction advances in technology have introduced many new devices emit electromagnetic radiation (emr). these devices include radars, cell phones, radio and television transmitters, certain devices used in medical and industrial practice, high-voltage transmission lines, microwave ovens, and household electrical appliances. cell phones that have an increasing use in our daily life also emit varying degrees of emr. various studies have shown that radiation emitted by cell phones or base stations have a negative impact on human health.(1) there are publications in which cancer development, negative effects on reproduction, and development of neurological disorders associated with cell phone use have been reported.(2,3) furthermore, there are studies suggesting elevated tissue levels of free radicals associated with the cell phone use.(4) ute and are thereby at high risk of being affected by harmful substances.(5) generally, radiation emitted by the cell phones operating at 900 mhz that are mostly carried on the belts is mostly absorbed by the kidneys as compared to other organs. in the present study, we aimed to investigate the effects of emr emitted by the cell phones, which are intensively used in all countries, on the rat kidney tissue in order to predict their possible effects on human kidneys. materials and methods twenty-one adult male wistar albino rats were allocated into 3 groups, each comprising 7 rats, and housed in standard cages measuring 40 × 60 cm. group 1 was exposed to cell phone for 8 hours/day in speech mode and for 16 hours/ day in standby mode for 20 days; their kidneys were then removed. group 2 was exposed to emr for 20 days, and their kidneys were removed after an interval of 20 days. group 3 was the control group and the rats were monitored in a standard laboratory environment without any exposure to emr. the rats were maintained on a 12 hour/12 hour light/dark cycle at 21 °c and 40% to 60% relative humidity, and they were provided food (mbd experimental animal food, gebze, kocaeli, turkey) and water ad libitum. in the present study, philips genie 900® (singapore) cell phone was used as a 1800-mhz continuous wave electroabsorption rate (sar, 1.52 w/kg) on the market. cell phones phones were left on charge for 24 hours, and 8 hours/day in speech mode and 16 hours/day in standby mode. one of the removed kidneys was prepared for light microscopic examination and the other was prepared for electron microscopic examination. specimen preparation for light microscopy for light microscopic examination, the kidneys were reserial alcohol solutions of increasing concentrations, and then cleared with toluene. for general morphological assessment, sections approximately 5 m in thickness were stained with hematoxylin and eosin and examined using an olympus bx51 photomicroscope. during microscopic examination, tissue sections were examined for the presence of damage of bowman’s capsule, glomeruli, and the proximal and distal tion. of these three criteria, each was scored as absent (0), minimal (1), moderate (2), and severe (3). at least 5 microsessed by two separate investigators (n.y. and f.e.) and the two investigators. the total score ranged from 0 to 9. both of two investigators (n.y. and f.e.) were blinded to each of three groups. specimen preparation for transmission electron microscopy for transmission electron microscopic examination, the kidated in a 1% phosphate-buffered osmium tetroxide solution. after dehydration in serial alcohol solutions of increasing concentrations, the samples were embedded in epon 812 and polymerized at 60 °c in an oven. using a jeol 1200 tem (tokyo, japan) scanning electron microscope, tests were performed on thin sections nearly 60 nm in thickness, which were obtained and stained with uranyl acetate and lead citeffects of cell phone on kidney | koca et al 888 | rate. the present study was approved by the ethics committee of marmara university faculty of medicine. mann-whitney u test was used for statistical analysis. a p value of less than .05 results light microscopic examination of the kidney tissues obtained from group 1 revealed glomerular damage, dilatation of bowman’s capsule, formation of large spaces between the age, dilatation of bowman’s capsule, formation of large spaces between the tubules, and tubular damage were observed in group 2 (figure 2a). control group was observed to have a regular morphology of renal parenchyma (figure 3a). the mean severity score was 4.64 ± 1.7 in group 1, 4.50 ± 0.8 difference between group 1 and group 2 (p = .86), the mean than that of the control group (p = .001 for each). electron microscopic examination of the kidney tissues in group 1 revealed that podocytes had a regular appearance, whereas irregular thickening of the basement membrane, irregularity of the capillary endothelium (figure 1b), and large dissociation of the junctions between the tubule cells (figure 1c) were observed. while podocytes and pedicels had relatively regular morphological appearance in group 2, local irregularities of the capillary endothelium, thickening of the basement membrane (figure 2b), and large dissociation of the junctions between the tubules were observed (figure 2c). in the control group, podocytes, pedicels, basement membrane (figure 3b), and tubules (figure 3c) were observed to have a regular morphology. discussion advances in science and technology have introduced many newly developed devices. such technological developthey have certain disadvantages that threaten human health. electromagnetic radiation emitted by many devices that are used in everyday life affects many living kinds. cell phones figure 1. group 1. dilatation of bowman’s capsule and glomerular damage (*), formation of large spaces between the tubules (arrow), tubular damage (arrow head), perivascular edema and inflammatory cell infiltration (>) (a) irregular thickening of the basement membrane (*), local irregularities of pedicels; (b) dissociation of the junctions between the tubular cells (*); and (c) a: hematoxylin and eosin staining, original magnification: ×100, small picture: ×200; b & c: electron micrograph. cellular and molecular urology c 889vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l are the leading devices that emit emr and have an increasing use worldwide.(6) the effects of emr emitted by these devices and base stations on human body have still not been radiofrequency waves emitted by cell phones are thought to cause detrimental effects at cellular and molecular level. (7) previous studies have reported that radiofrequency waves emitted particularly by the third generation cell phones might have an effect on the immunological status, nervous system, hematological status, cardiac functions, urinary system, normal growth and development, and genetic.(6,8,9) electromagnetic radiation emitting from base station and cell phones have destructive effects on tissues in two ways. first, thermal effects occur via increase in corporeal heat by electromagnetic energy, which is absorbed by body. second, non-thermal effects appear as change in brain functions and sleep, atten(10) along with this, emr may also lead to dna damage.(11) this information suggests the need for further research on the effects of cell phones and base stations on human health. studies on the effects of emr emitted by cell phones have yielded controversial results. there are studies in the literature reporting that cell phones do not have an effect on blood-brain barrier, testes, sperm morphology, seminiferous tubules of the rats, and leydig cells and do not cause a sig(12-15) similarly, in comprehensive studies conducted in the usa and denmark, it was reported that cell phone use was not associated with increased risk of brain tumor.(16,17) there are also studies suggesting that emr emitted by and colleagues observed that emr led to histopathological changes in mouse testes and reported that chronic long-term exposure to emr might affect amount of epididymal sperm, sperm morphology, and weight and morphology of the testes and epididymis.(18) there are also studies reporting that emr emitted by cell phones leads to a change in the diameter of seminiferous tubules and rectal temperature.(13) it should be kept in mind that high levels of emr used in the studies may lead to testicular heating; thus, unfavorable effects observed in the studies may result from increased temperature. close proximity of cell phones to the kidneys as well as figure 2. group 2. dilatation of bowman’s capsule and glomerular damage (*), formation of large spaces between the tubules (arrow), and tubular damage (arrow head) (a) local thickening of the basement membrane and mild irregularity of the capillary wall (arrow); (b) dissociation of the junctions between the tubular cells (*); and (c) a: hematoxylin and eosin staining, original magnification: ×100, small picture: ×200; b & c: electron micrograph. effects of cell phone on kidney | koca et al c b 890 | higher risk of the kidneys to be affected by external factors indicates the need for research on the effects of cell phones on the kidney health. in their study, özgüner and associates showed the formation of free radicals associated with cell phone use and the negative effects of these free radicals on the rat kidney tissue.(1) devrim and coworkers reported that emr led to an increase in the levels of oxygen radicals in the kidney tissue.(19) in our study, negative effects of emr on the kidney tissue were shown by light and electron microscopic examination. this tissue damage was thought to be associated with oxygen radicals. studies have indicated that the kidneys are radiation-sensitive organs.(20) we showed tubular damage in our study. furthermore, on electron microscopic examination, we observed dissociation of the junctions between the tubules. tubular damage plays an important role in all causes of acute renal failure. in addition, observation of glomerular damage indicates the severity of this damage. irregularity of the capillary endothelium observed on electron microscopic examination indicates the severity of glomerular damage. necessitate large-scale measures to be taken for cell phone use. reducing cell phone usage intervals, using protective clothes, and keeping cell phone devices away from body as far as possible may be the protective measures. the limitations of the present study include the inability to higher exposures of rats to emr compared with emr dosages produced by usual daily cell phone usage, and the lack of molecular research accompanying histological changes. conclusion in our study, we showed negative effects of emr on the rat kidney tissue. considering these detrimental effects, individuals at high risk should take preventive measures. if these to individual measures, legal regulations should be enacted in order to minimize the risk. conflict of interest none declared. figure 3. control group. glomerular and tubular structure of regular morphology (a) podocytes, pedicels, and basement membrane; (b) and tubular structure; and (c) that have a regular morphology. a: hematoxylin-eosin staining, original magnification: ×100; b & c: electron micrograph. cellular and molecular urology 891vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l 13. dasdag s, ketani ma, akdag z, et al. whole-body microwave exposure emitted by cellular phones and testicular function of rats. urol res. 1999;27:219-23. 14. forgacs z, somosy z, kubinyi g, et al. effect of whole-body 1800mhz gsm-like microwave exposure on testicular steroidogenesis and histology in mice. reprod toxicol. 2006;22:111-7. 15. celik o, hascalik s. effect of electromagnetic field emitted by cellular phones on fetal heart rate patterns. eur j obstet gynecol reprod biol. 2004;112:55-6. 16. johansen c, boice j, jr., mclaughlin j, olsen j. cellular telephones and cancer--a nationwide cohort study in denmark. j natl cancer inst. 2001;93:203-7. 17. muscat je, malkin mg, thompson s, et al. handheld cellular telephone use and risk of brain cancer. jama. 2000;284:3001-7. 18. akdag mz, celik ms, ketani a, nergiz y, deniz m, dasdag s. effect of chronic low-intensity microwave radiation on sperm count, sperm morphology, and testicular and epididymal tissues of rats. electro-and magnetobiology. 1999;18:133-45. 19. devrim e, erguder ib, kilicoglu b, yaykasli e, cetin r, durak i. effects of electromagnetic radiation use on oxidant/ antioxidant status and dna turn-over enzyme activities in erythrocytes and heart, kidney, liver, and ovary tissues from rats: possible protective role of vitamin c. toxicol mech methods. 2008;18:679-83. 20. cassady jr. clinical radiation nephropathy. int j radiat oncol biol phys. 1995;31:1249-56. references 1. ozguner f, oktem f, ayata a, koyu a, yilmaz hr. a novel antioxidant agent caffeic acid phenethyl ester prevents longterm mobile phone exposure-induced renal impairment in rat. prognostic value of malondialdehyde, n-acetyl-beta-dglucosaminidase and nitric oxide determination. mol cell biochem. 2005;277:73-80. 2. bartsch h, bartsch c, seebald e, et al. chronic exposure to a gsm-like signal (mobile phone) does not stimulate the development of dmba-induced mammary tumors in rats: results of three consecutive studies. radiat res. 2002;157:183-90. 3. leszczynski d, joenvaara s, reivinen j, kuokka r. nonthermal activation of the hsp27/p38mapk stress pathway by mobile phone radiation in human endothelial cells: molecular mechanism for cancerand blood-brain barrierrelated effects. differentiation. 2002;70:120-9. 4. ozguner f, oktem f, armagan a, et al. comparative analysis of the protective effects of melatonin and caffeic acid phenethyl ester (cape) on mobile phone-induced renal impairment in rat. mol cell biochem. 2005;276:31-7. 5. irmak mk, fadillioglu e, gulec m, erdogan h, yagmurca m, akyol o. effects of electromagnetic radiation from a cellular telephone on the oxidant and antioxidant levels in rabbits. cell biochem funct. 2002;20:279-83. 6. meral i, mert h, mert n, et al. effects of 900-mhz electromagnetic field emitted from cellular phone on brain oxidative stress and some vitamin levels of guinea pigs. brain res. 2007;1169:120-4. 7. ono t, saito y, komura j, et al. absence of mutagenic effects of 2.45 ghz radiofrequency exposure in spleen, liver, brain, and testis of lacz-transgenic mouse exposed in utero. tohoku j exp med. 2004;202:93-103. 8. oktem f, ozguner f, mollaoglu h, koyu a, uz e. oxidative damage in the kidney induced by 900-mhz-emitted mobile phone: protection by melatonin. arch med res. 2005;36:350-5. 9. oral b, guney m, ozguner f, et al. endometrial apoptosis induced by a 900-mhz mobile phone: preventive effects of vitamins e and c. adv ther. 2006;23:957-73. 10. nakamura h, matsuzaki i, hatta k, nobukuni y, kambayashi y, ogino k. nonthermal effects of mobile-phone frequency microwaves on uteroplacental functions in pregnant rats. reprod toxicol. 2003;17:321-6. 11. yakymenko i, sidorik e. risks of carcinogenesis from electromagnetic radiation of mobile telephony devices. exp oncol. 2010;32:54-60. 12. finnie jw, blumbergs pc, cai z, manavis j, kuchel tr. effect of mobile telephony on blood-brain barrier permeability in the fetal mouse brain. pathology. 2006;38:63-5. effects of cell phone on kidney | koca et al 1731vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l a circumcision method in an old surgical textbook (cerrahiyyetul haniyye): reminding of a forgotten procedure atilla senayli,1 murat aksu,2 munir atalar3 corresponding author: atilla senayli, md department of pediatric surgery, children’s health and disease hematology-oncology education and research hospital, ankara, turkey. tel: +90 506 6917990 fax: +90 312 347 1330 e-mail: atillasenayli@gmail.com received february 2014 accepted april 2014 1 department of pediatric surgery, children’s health and disease hematology-oncology education and research hospital, ankara, turkey. 2 department of the history of medicine and ethics, school of medicine, izmir university, izmir, turkey. 3 department of history, faculty of science and fine arts, gaziosmanpasa university, tokat, turkey urology in history purpose: circumcision is one of the historical surgical procedures. some sources throughout the history contain various definitions about different circumcision methods. we described the details of the method, and aimed to remind the possibility of contemporary usage. materials and methods: we compared circumcision chapters of sabuncuoglu and zahrawi to explain the historical origin of sabuncuoglu’s favorite circumcision method. results: we found a method which might be summarized as “knotting with rope technique” in one of historical textbooks named as cerrahiyyetul haniyye (imperial surgery) written by serefeddin sabuncuoğlu (1385-1468?) in 1465. conclusion: this circumcision method is not used currently. in addition this method has not been defined in the history of medical literature yet. keywords: circumcision; humans; history, 18th century; serefeddin sabuncuoglu. 1732 | urology in history introduction circumcision is one of the ancient surgical procedures performed in all over the world.(1) there are old sources to obtain information about the history of circumcision and different ancient circumcision methods. one of the sources is a book written by serefeddin sabuncuoğlu (1385-1468?) in 1465. he wrote cerrahiyyetul haniyye (imperial surgery) referring to ebu kasim-ul zahravi’s (albucasis) textbook of surgery.(2) we read a special chapter of cerrahiyyetul haniyye while evaluating the historical information for circumcision. meanwhile, we found out that sabuncuoğlu’s favorite circumcision type was not in contemporary use. in this study, we aimed to put forward this forgotten circumcision method by comparing with some contemporary methods. we suppose that reminding the procedure may be clinically useful. materials and methods we compared circumcision chapters of sabuncuoglu and zahrawi to demonstrate the historical origin of sabuncuoglu’s favorite circumcision method before the study. bayat’s dissertation has turkish translation of zahrawi’s circumcision chapter, and we evaluated the related section.(3) we found that the chapters were totally same. the method was originated from zahrawi’s textbook. to perform a methodological evaluation for the circumcision method, we used sabuncuoglu’s textbook. for this purpose, 57th chapter of cerrahiyyetul haniyye (imperial surgery) that was prepared by uzel in latin alphabet was evaluated.(4) original chapter in uzel’s book was revealed in figure 1. the chapter was translated in english during the study. we draw the pictures of aforementioned surgery to clarify the translated chapter. after the translation and illustrations, we discussed the explanations in the light of the literature, and evaluated some controversies. results the translation chapter 57 this is a chapter about the circumcision of the children and informs for the mistakes on this subject. investigator don’t consider the circumcision as tearing the adhesion or wound after injury. the book of the nations before islam did not deal with this subject because it was not written in their religious believes. the fact, circumcision, is only in question of islam. i felt responsible that i had to put forward a circumcision method which was performed easily, successfully and healthy. we had seen persons circumcised with razor, scissor or bastinado, some persons cut after knotting with rope or cut with nails. in fact, we experienced; the best and easiest was the knotting with a rope and cut with scissor. because, if you use razor, the prepuce would be two layers and only upper layer would be cut and lower layer would left. therefore, you have to cut prepuce again as a second stage. if bastinado was used without attention, glans penis would pass through the bastinado and cut by mistake. there was a danger with nail circumcision because if the mould turned away by mistake, operation would be wrong or penile skin would be shortened after the operation. in our experience we determined that some children born without a need of circumcision. we experienced advantages about circumcision with scissor. however, scissor has to be functional and adequate in this procedure for cutting and the switch lever of the scissor must be in the middle of the scissor. scissor has to be curved and both side must be just enough and must cut at first attempt. binding the skin to get both layers together makes the work correct. at first, you will not scare the boy you will circumcised. you will say something that makes child happy. by hiding the cutting instrument in your clothes or under your foot, you should protect the child from the fear caused by the instrument. then let the child stand up, release child’s prepuce from glans and urethra totally. you have to clean the smegma under the prepuce. you have to tear the prepuce, mark the cutting line with silk rope and fasten (figures 2 and 3). tie another silk rope below the first silk rope, then hold the prepuce with your two fingers and pull down (figure 4), cut among these two silk ropes (figure 5). then, immediately raise the penile skin, you have to take urethra out, and then let an amount of bleeding for preventing swelling and for aeration. you have to clean the blood with a wet cloth and have to spread dried pumpkin cinders. i experienced dried pumpkin cinders and this is the best or you have to spread mill dust, which is good, too. you have to apply yolk mixed with rose oil, which is cooked in rose water with eye brass. it has to be on the wound for a day. then, you have to manage with other drugs to heal. you can see the scissors shapes aforementioned and you 1733vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l a circumcision method in an old surgical textbook | senayli et al can understand what do they like (figure 1). states for circumcision errors if part of the inner layer of the prepuce escaped from the mould during circumcision, cut immediately either with a nail or a scissor or you have to tear with your nail to left it above and if you are unsuccessful, you have to leave it till the end of swelling. after the swelling was absorbed, peel the remaining prepuce posterior. after this, cut with any method you want. you have to protect urethral mea. if it is not cut with these, you have to medicate with healing drugs like eye brass. if prepuce is cut too much and skin is not hold above, that is not important and you have to heal, god willing. discussion surgical excision of the foreskin on the glans is simply named as circumcision.(5) it is one of the oldest procedures.(6) investigations on egyptian mummies revealed circumcision evidences.(6) pre-islamic and early islamic documentations also demonstrated complications related to circumcisions.(7) nevertheless, circumcision is a safe surgical procedure in experienced hands.(5) all over the world, the estimated frequency circumcision is 1 in 25 min.(5) in usa, 1.2 million newborn are circumcised each year.(8) as it is mentioned before, the aim of circumcision is prepuce excision.(6) different methods and equipment may be used for this purpose.(7) wood cutter, razor, various clamps or surgical techniques were used.(5-7,9) there are different clamps called plastibell, gomco, shang ring and mogen.(5,810) the effectiveness of this clamp is controversial.(5) for example, in plastibell procedures need 2-3 days to complete the circumcision, and sometimes, suture must be placed around the foreskin to finalize the circumcision.(8) also preputial plasty is suggested as an alternative surgery for circumcision.(6) also, there are many surgical methods. sleeve resection is the most similar method with sabuncuoglu’s circumcision. in sleeve resection, prepuce is not squeezed as in figure 1. original circumcision chapter in uzel’s book. figure 3. “… mark the cutting line with silk rope and fasten.” figure 4. “tie another silk rope below the first silk rope, then hold the prepuce with your two finger and pull down.” figure 2. “you have to tear the prepuce…” 1734 | urology in history sabuncuoglu's method, and prepuce is excised as a free flap.(11) the main difference between sleeve resection and the historical technique is; tightening the prepuce within two silk ropes. we realize that sabuncuoglu’s favorite circumcision method is not present in english and turkish literature as a contemporary surgical method. sabuncuoglu’s described different methods for circumcision in the textbook. he stated different types of devices for these circumcision methods like bastinado, razor, scissor, and he also described equipment for nail circumcision in the first section of the circumcision chapter. for practitioners, he emphasized in the second part of the circumcision chapter that cutting with scissor after the knitting with rope technique will be better. in this technique, the penile shaft was bonded with a silk rope. then the prepuce was torn on this silk rope. after this, another silk rope was bonded distally. as a result the prepuce squeezed between these ropes and he performed the circumcision adequately. the main purpose for circumcision is best cosmesis, lower morbidity, optimum attention to sepsis and hemostasis.(6) postoperative treatments for circumcision were not defined in details in cerrahiyyetul haniyye. for ancient books, anesthesia of circumcision was not reported, and ashes were used to stop hemorrhage.(7) incomplete excision is the most seen complication.(7) phimosis and concealed penis can be seen subsequently.(7) different techniques are developed to minimize these complications, and to simplify the procedure.(10) the main purpose of sabuncuoglu was performing an easy and cosmetic procedure. our study tried to remind this historical circumcision method. however, we did not aim to evaluate the availability of the method for contemporary clinical usage. nevertheless, incisional complications like urethra trauma or minimal bleeding with inadequately fixed ropes may be seen. surgical comfort and suturing may be better. conclusion there are many methods for circumcision. however, the circumcision technique emphasized in sabuncuoglu’s textbook hasn’t been in use currently. we are pleased to reveal this old and forgotten technique. it may be modified for contemporary usage. this experience shows us that history will always enlighten the future. same circumstances may be possible for other surgical methodological trials. devices, suture techniques or methods may be used to brighten the contemporary surgical procedures. conflict of interest none declared. figure 5. “…cut among these two silk ropes.” references 1. basar h, yılmaz e, başar mm, batislam e, tuglu d. window technique on circumcision. int urol nephrol. 2006;38:599-601. 2. keskil s and sabuncuoglu h. endoscopy in the 15th century. minim invas neurosurg. 2002;45:45-6. 3. bayat ah. tarihte sünnet ve tarihimizde sünnet şenlikleri (dissertation). i̇zmir, ege üniversitesi tıp tarihi ve deontoloji kürsüsü, 1979. 4. uzel i serefeddin sabucuoglu cerrahiyyetul haniyye. ankara: türk tarih kurumu yayınları iii. dizi-1992; sa. 15a 5. morris bj. why circumcision is a biomedical imperative for the 21st century. bio essays. 2007;29:1147-58. 6. williams n, kapila l. complications of circumcision. br j surg. 1993;80:1231-6. 7. rizvi sah, naqvi saa, hussain m. hasan as. religious circumcision: a muslim view. bju int. 1999;83:13-6. 8. kurtis ps, desilva hm, bernstein ba, malakh l, schechter nl. a comparison of the mogen and gomco clamps in combination with dorsal penile nerve block in minimizing the pain of neonatal circumcision. pediatrics. 1999;103:e23. 9. task force on circumcision. male circumcision. pediatrics. 2012;130:e756. 10. barone ma, ndede f, li ps, et al. the shang ring device for adult male circumcision: a proof of concept study in kenya. j acquir immune defic syndr. 2011;57:e7-e12. 11. o’sullıvan dc and heal mr. powell circumcision: how do urologists do it? br j urol. 1996;78:265-70. urol_v03_no3_001_editorial.indd 188 urology journal vol 3 no 3 summer 2006 obituary professor parviz jabalameli it is with great sadness that urology journal announces professor jabalalemi’s passing after years of struggle with cancer, in july 2006, at the age of 62 years. he will be forever remembered by his colleagues not only as a great physician, but also as a brilliant teacher in clinic, university, and life. he was born in 1944, in the town of shahroud, iran. in 1973, he graduated from tehran university of medical sciences and decided to specialize in dermatology, but after six months of studying that, he shifted to urology and turned out to be one of professor alaedin manouchehri’s best residents. then, he could join the department of urology in sina hospital and soon thereafter was appointed to the chair in urology in 1980. the iran-iraq war began in 1980 and he went to the war-torn cities and spent about 2 years treating the wounded. after returning to tehran, he was elected as the president of sina hospital in 1983. dr jabalameli was entitled the associate professor of urology in 1987 and 1 year later, he was appointed as the dean of the medical faculty of tehran university of medical sciences. he never stopped learning; he attended advanced courses on urological oncology, kidney transplantation, and endourology at the cleveland clinic, pittsburgh medical faculty of pennsylvania university, and claude bernard university. thanks to his efforts, the kidney transplantation department of imam khomeini was established in 1988 and the first fellowship program of urological oncology was started in 1996. also, publishing several books and papers and training many current famous urologists in iran were the outcomes of his fruitful scientific activities. professor jabalameli was considered one of the most eminent surgeons to whom urology, young a specialty as it is in iran, is greatly indebted. he was the section editor of urological oncology in the urology journal. we, in the editorial team are greatly sorry to lose him. we extend our deepest condolences to his bereaved family and the urologists’ society. urol_v3_no2_001_editorial.qxd urology journal unrc/iua vol. 3, no. 2, 82-86 spring 2006 printed in iran 82 received october 2005 accepted february 2006 *corresponding author: department of kidney transplantation, chamran hospital, nobonyad sq, pasdaran st, tehran, iran. tel: +98 912 304 6074, e-mail: hgholamrezaie@unrc.ir kidney transplantation en bloc kidney transplantation from pediatric cadaveric donors to adult recipients reza mahdavi,1 davood arab,1 rahim taghavi,1 hamid reza gholamrezaie,2* mohammad yazdani,3 nasser simforoosh,4 ali tabibi4 1department of kidney transplantation, imam reza hospital, mashhad university of medical sciences, mashhad, iran 2department of kidney transplantation, chamran hospital, tehran medical branch, islamic azad university, tehran, iran 3department of kidney transplantation, khorshid hospital, esfahan university of medical sciences, isfahan, iran 4department of kidney transplantation, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: the shortage of cadaveric donors for kidney transplantation has led to the expansion of the criteria used for donor selection, such as the use of pediatric cadaveric donors. in this study we reviewed our results of en bloc kidney transplantation of pediatric cadaveric donors to adults. materials and methods: from may 2001 to may 2005, 245 cadaveric kidney transplants have been performed in our hospitals. seven of these were en bloc kidney transplantations in adult recipients from marginal pediatric donors (age < 5 years, donor weight < 15 kg, high creatinine clearance, or kidney length < 8 cm). we reviewed their records. follow-up (range, 3 to 24 months) included ultrasonography, dimercaptosuccinic acid renal scintigraphy, and magnetic resonance imaging. results: serum levels of creatinine ranged between 0.8 m/dl to 1.9 mg/dl during the follow-up period. one patient died of myocardial infarction 3 months postoperatively. one-year graft and patient survivals were both 85.7%. complications included acute tubular necrosis in 1 patient (managed by conservative therapy and dialysis for 2 weeks), renal vein thrombosis in 1 (treated by anticoagulation), and subcutaneous hematoma in 1. there were no urologic complications. median size of the grafts was 7.2 cm preoperatively that reached 9.6 cm, 3 months postoperatively (p = .018). twelve months following operation, the median size of the grafts reached 11 cm (p = .045). conclusion: en bloc pediatric kidney transplantation is a safe and suitable alternative for adult recipients. one-year graft and patient survivals are acceptable and complication rate is low. key words: kidney transplantation, pediatric donor, cadaveric donor mahdavi et al 83 introduction the shortage of cadaveric donors for kidney transplantation has prompted physicians to expand the criteria used for donor selection. the use of pediatric cadaveric en bloc kidneys is one of those expanded criteria.(1-3) the lower graft survival of pediatric kidney allografts due to the technical complications and hyperfiltration injury is challenging.(4,5) several studies have shown that the outcomes of transplantation using pediatric donors are not favorable when compared with transplantation using adult donors.(6-8) however, some reports have recently revealed that survival of kidney allografts from pediatric cadaveric donors younger than 5 years is the same as those from adult donors.(8-10) in this study, we depicted our experience in transplantation of pediatric cadaveric en bloc kidney allografts to adult recipients. materials and methods from may 2001 to may 2005, a total of 245 cadaveric kidney transplants have been performed in our hospitals (imam reza hospital in mashhad, shaheed labbafinejad medical center and chamran hospital in tehran, and khorshid hospital in isfahan, iran). of those, 7 were en bloc kidney transplantations from marginal pediatric cadaveric donors (ie, donors with at least one of these criteria: age < 5 years, weight < 15 kg, a high creatinine clearance, and kidney length < 8 cm) which were transplanted to adult recipients. immunosuppressive protocol was a triple therapy by prednisolone, cyclosporine, and mycophenolate mofetil. acute rejection episodes were treated by pulse steroid and antilymphocyte globulin. the patients were followed up for 3 to 24 months. dimercaptosuccinic acid renal scintigraphy was performed during 24 months' follow-up periodically (figure 1) and the sizes of the kidneys were evaluated by magnetic resonance imaging (mri) and/or ultrasonography, 3 and 12 months postoperatively (figure 2). we reviewed the hospital records of our patients retrospectively, and collected data including demographic characteristics of the kidney recipients and donors; size and weight of the kidney allografts before and after transplantation; serum creatinine levels at postoperative months 3, 6, 12, 18, and 24; complications; and the overall outcome of patient and graft. technique. both kidneys of pediatric cadaveric donors were harvested and irrigated with wisconsin solution and heparinized ringer lactate in 3 and 4 cases, respectively. the kidneys were placed extraperitoneally in the iliac fossa of the recipients via a gibson incision. in 6 patients, the fig. 1. dimercaptosuccinic acid renal scintigraphy in a 34year-old woman 3 months postoperatively fig. 2. magnetic resonance imaging in a 43-year-old woman 3 months postoperatively en bloc kidney transplantation84 aorta and the inferior vena cava (ivc) of donor were anastomosed end to side to the external iliac artery and vein with 5-0 or 6-0 prolene sutures (figure 3), but in 1 patient, the end-toside anastomosis was made to the recipient's aorta and ivc. to prevent kinking of renal vessels, the upper pole of the grafts was fixed to the iliopsoas muscle. the ends of the two ureters were anastomosed medially together and then ureteroneocystostomy was performed using lich gregoir extravesical technique, but in 1 patient, ureteroureterostomy was carried out. in all patients, ureteral stents were placed for 4 to 6 weeks. the ureteral catheter was removed 5 days postoperatively. statistical analyses. the collected data were analyzed by spss software (statistical package for the social sciences, version 13, spss inc, chicago, ill, usa). the spearman rank correlation was used to determine the correlation between variables and wilcoxon signed rank test to analyze the difference between size of the kidneys before and after transplantation. kaplanmeier method was used to determine non-deathcensored graft survival and patient survival. continuous variables were shown as medians and p values less than .05 were considered significant. results median age of the donors was 4.2 years (range, 2 to 8 years) and their median weight was 12 kg (range, 8 to 20 kg). four of them were boys and 3 were girls. median age of the recipients was 34 years (range, 13 to 42 years) and their median weight was 58 kg (range, 37 to 70 kg). three patients received their second kidney allografts. one-year graft and patient survivals were both 85.7%. one patient died of myocardial infarction 100 days postoperatively while he had a functioning graft. the median follow-up was 12 months (range, 3 to 24 months). delayed graft function occurred in 1 patient due to acute tubular necrosis, which was managed by medical therapy and dialysis for 2 weeks. the remaining 6 patients had a reasonable urine output early after transplantation. complications included renal vein thrombosis in 1 patient, which was treated by anticoagulation, and subcutaneous hematoma in 1, which was drained completely. there were no reports of ureteral stenosis, ureteral leakage, or lymphocele during the followup period (table 1). serum creatinine levels ranged between 0.8 mg/dl and 1.9 mg/dl from 3 to 24 months postoperatively (table 2). there was not any correlation between the last serum creatinine levels and the recipients' weights and ages (p = .70; p = .39). fig. 3. end-to-side anastomosis of the aorta and the inferior vena cava (ivc) of donor to the external iliac artery and vein table 1. demographic and clinical features of the patients with en bloc kidney transplantation *the patient died of myocardial infarction 100 days postoperatively. patients’ number sex age (year) follow-up (month) last creatinine (mg/dl) complications 1 female 42 24 1 subcutaneous hematoma 2 male 35 12 1.3 acute tubular necrosis 3 female 13 18 1.2 4 male 25 24 1.1 renal vein thrombosis 5 female 15 12 1.9 6 male 38 3 * 1 7 female 34 12 .8 mahdavi et al 85 table 3 demonstrates the sizes of grafts measured during the follow-up. ultrasonography and mri revealed a significant increase in sizes of grafts during 3 to 12 month postoperatively. median size of the grafts was 7.2 cm preoperatively and reached 9.6 cm, 3 months postoperatively (p = .018). twelve months following operation, the median size of the grafts reached 11 cm (p = .045). discussion mortality of patients who are on the waiting list of kidney transplantation is about 6.3% per year in the united states, but it reaches 10% in diabetics and/or old patients.(10) therefore, in 5 years, mortality rate exceeds 30% in nondiabetic patients who are on a waiting list.(10) a limited graft procurement cannot supply the high demand, prompting the extension of the criteria used for donor selection. using marginal donors including nonheart-beating donors,(11) older donors,(12) hepatitis c positive donors for recipients with hepatitis c,(13) and pediatric donors(14-16) is now considered, especially in countries whose donor source is mainly cadaveric. the use of pediatric cadaveric donors younger than 5 years old can result in a high rate of technical complications; the main challenges are a high risk of graft thrombosis, suboptimal nephron mass, frequent rejection episodes, a low graft survival, an increased rate of hyperfiltration injury, and difficulties in adjustment of immunosuppressive drugs.(17-21) thus, pediatric donors are marginal especially when a single pediatric kidney is transplanted to an adult. pediatric grafts can be transplanted to pediatric patients; however, there is not always a pediatric recipient available for transplantation. we encountered this problem in our centers and adult recipients were allocated for pediatric donors. to reduce the risks, we preferred en bloc kidney transplantation. today, en bloc kidney transplantation is recommended for pediatric donors younger than 3 years, with a body weight less than 15 kg, and with a kidney length less than 8 cm.(22) beasley and colleagues reviewed 16 en bloc pediatric kidney transplants performed in 2 centers and reported a 3-year graft survival of 94%. two deaths with functioning grafts occurred secondary to cardiac and infectious etiologies. graft thrombosis was not seen in any patients. acute rejection developed in 7 patients who were treated with steroid and antilymphocyte antibody and the kidneys returned to the normal function. other complications included 1 lymphocele and 4 ureteral complications (managed by ureteral reimplantation).(23) between 1996 and 2002, elsheikh and colleagues performed 15 en bloc pediatric kidney transplants. one-year graft and patient survivals were 92.8% and 100%, respectively. there were no ureteral complications, but 1 lymphocele developed.(24) we had 1 death in our patients due to cardiac disorder. the resultant graft survival at 1 and 2 years was comparable to the survival of other cadaveric transplantations in our institutions. however, a more precise comparison is warranted with larger series. we showed that the pediatric kidney allografts had a significant increase in size following en bloc transplantation, confirmed by mri. it can be speculated that the kidneys grow rapidly in recipient's body to support the blood volume needed to be filtrated in an adult. in accordance with our findings, merkel has demonstrated that the size of pediatric kidneys will be doubled within 2 to 3 posttransplant weeks and it reaches the adults' size 18 months after operation.(25) in our series, 1 patient developed renal vein thrombosis 10 days postoperatively, which was treated by anticoagulation therapy. hence, it table 2. postoperative serum creatinine levels in recipients of en bloc kidney allografts from pediatric cadaveric donors table 3. kidney allograft sizes before and after transplantation postoperative months serum creatinine levels (mg/ dl) 3 6 12 18 24 median 1.2 1.05 1 1.7 1.45 minimum .8 .8 .8 1.2 1.1 maximum 1.9 1.9 1.9 1.7 1.8 number of patients 7 6 6 3 2 kidney size (cm) before operation three months after operation twelve months after operation median 7.2 9.6 11 minimum 5.5 6.25 10 maximum 8.5 10.5 13 number of patients 7 7 6 en bloc kidney transplantation86 seems that technical problem was not the main cause of thrombosis. there were no urologic complications such as ureteral stenosis and ureteral leakage in our study, but drakopoulos and coworkers reported ureteral complications in 28% of en bloc transplantations in 13 patients.(6) however, the reported complications did not affect graft function in long term. in our preliminary report, 1 graft developed acute tubular necrosis. warm and cold ischemia may play a role in this complication. conclusion pediatric en bloc kidney transplantation is a safe and suitable alternative for adult recipients. one-year graft and patient survivals are acceptable and complication rate is low. to confirm these findings, a long-term follow-up of larger series and prospective studies comparing the outcome with other donor sources are required. references 1. ishikawa n, tanabe k, tokumoto t, et al. transplantation of pediatric cadaveric kidneys into adult or pediatric recipients. transplant proc. 2004;36:2018-9. 2. borboroglu pg, foster ce 3rd, et al. solitary renal allografts from pediatric cadaver donors less than 2 years of age transplanted into adult recipients. transplantation. 2004;77:698-702. 3. dharnidharka vr, stevens g, howard rj. en-bloc kidney transplantation in the united states: an analysis of united network of organ sharing (unos) data from 1987 to 2003. am j transplant. 2005;5:1513-7. 4. abouna gm, kumar ms, chvala r, mcsorley m, samhan m. transplantation of single pediatric kidneys into adult recipients--a 12-year experience. transplant proc. 1995;27:2564-6. 5. modlin c, novick ac, goormastic m, hodge e, mastrioanni b, myles j. long-term results with single pediatric donor kidney transplants in adult recipients. j urol. 1996;156:890-5. 6. drakopoulos s, koukoulaki m, vougas v, apostolou t, hadjiyannakis ei, hadjiconstantinou v. transplantation of pediatric kidneys to adult recipients: an analysis of 13 cases. transplant proc. 2004;36:3161-3. 7. bresnahan ba, mcbride ma, cherikh ws, hariharan s. risk factors for renal allograft survival from pediatric cadaver donors: an analysis of united network for organ sharing data. transplantation. 2001;72:256-61. 8. neumayer hh, huls s, schreiber m, riess r, luft fc. kidneys from pediatric donors: risk versus benefit. clin nephrol. 1994;41:94-100. 9. kamel mh, rampersad a, mohan p, hickey dp, little dm. cadaveric kidney transplantation in children < or =20 kg in weight: long-term single-center experience. transplant proc. 2005;37:685-6. 10. meier-kriesche h, port fk, ojo ao, et al. deleterious effect of waiting time on renal transplant outcome. transplant proc. 2001;33:1204-6. 11. sanchez-fructuoso ai, prats d, torrente j, et al. renal transplantation from non-heart beating donors: a promising alternative to enlarge the donor pool. j am soc nephrol. 2000;11:350-8. 12. andres a, herrero jc, praga m, et al. double kidney transplant (dual) with kidneys from older donors and suboptimal nephronal mass. transplant proc. 2001;33:1166-7. 13. morales jm, campistol jm, andres a, et al. use of kidneys from anti-hcv positive donors. transplant proc. 2001;33:1776-7. 14. hiramoto js, freise ce, randall hr, et al. successful long-term outcomes using pediatric en bloc kidneys for transplantation. am j transplant. 2002;2:337-42. 15. gourlay w, stothers l, mcloughlin mg, manson ad, keown p. transplantation of pediatric cadaver kidneys into adult recipients. j urol. 1995;153:322-5 6. 16. strey c, grotz w, mutz c, et al. graft survival and graft function of pediatric en bloc kidneys in paraaortal position. transplantation. 2002;73:1095-9. 17. hayes jm, novick ac, streem sb, et al. the use of single pediatric cadaver kidneys for transplantation. transplantation. 1988;45:106-10. 18. satterthwaite r, aswad s, sunga v, et al. outcome of en bloc and single kidney transplantation from very young cadaveric donors. transplantation. 1997;63:1405-10. 19. terasaki pi, gjertson dw, cecka jm, takemoto s, cho yw. significance of the donor age effect on kidney transplants. clin transplant. 1997;11:366-72. 20. smith ay, van buren ct, lewis rm, et al. the outcome of repeat cadaveric kidney transplants in recipients managed with cyclosporine. transplant proc. 1988;20:180-93. 21. hayes jm, steinmuller dr, streem sb, novick ac. the development of proteinuria and focal-segmental glomerulosclerosis in recipients of pediatric donor kidneys. transplantation. 1991;52:813-7. 22. ko dsc, delmonico fl. surgical aspect of renal transplantation. in: owen wf, pereira bjg, sayegh mh, editors. dialysis and transplantation: a companion to brenner & rector's the kidney. philadelphia: wb saunders; 2000. p. 542-3. 23. beasley ka, balbontin f, cook a, et al. long-term followup of pediatric en bloc renal transplantation. transplant proc. 2003;35:2398-9. 24. el-sheikh mf, gok ma, buckley pe, et al. en bloc pediatric into adult recipients: the newcastle experience. transplant proc. 2003;35:786-8. 25. merkel fk. five and 10 year follow-up of en bloc small pediatric kidneys in adult recipients. transplant proc. 2001;33:1168-9. 1695vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l donor specific antibodies median fluorescence intensity levels are the best indicator for monitoring desensitization treatment in kidney transplant francisco boix,1 santiago llorente,2 anna mrowiec,1 jorge eguia,1 ruth lópez-hernández,1 maria victoria bernardo,1 maría rosa moya-quiles,1,3 josé a. campillo,1,3 alfredo minguela,1,3 luisa jimeno,2 maría r. álvarezlópez,1,3 manuel muro1,3 corresponding author: manuel muro, phd immunology service, university hospital “virgen arrixaca”, murcia 30120, spain. tel: +34 968 369599 fax: +34 968 349678 e-mail: manuel.muro@carm.es received december 2012 accepted december 2013 1 department of immunology, university hospital virgen arrixaca, 30120. murcia, spain. 2 department of nephrology and urology, university hospital virgen arrixaca, 30120. murcia, spain. 3 centro de investigación biomédica en red de enfermedades hepáticas y digestivas (ciberehd), spain. case report keywords: kidney transplantation; predictive value of tests; hla antigens; histocompatibility testing; isoantibodies; fluorescence. introduction donor-specific human leukocyte antigen (hla) antibodies (dsa) are increasingly recognized as a risk factor for kidney transplant graft failure. nowadays, new se-rum screening methods have greatly enhanced the detection and specificity analysis of anti-hla class ii antibodies in sensitized patients.(1,2) panel-reactive antibodies (pra) rate has historically been performed by complement-dependent cytotoxicity (cdc) method. (3) in this respect, many histocompatibility laboratories have changed pra for calculated reaction frequency (crf) and implemented single antigens beads (sab) analysis.(3) additionally, different protocols that use b lymphocyte-depleting molecules (anti-cd20), intravenous immunoglobulin (ivig) and plasmapheresis (pp) have also been developed.(4) this work reports a kidney transplant case of an antibody-mediated rejection (amr) that has been treated with a desensitization protocol (plasmapheresis/ivig) and anti-cd20. luminex-based antibody detection results (mean fluorescence intensity; mfi) were consistent with therapy effectiveness, whereas luminex pra/crf outcomes were not informative. case report a 69-year-old caucasian woman was transplanted in our hospital with a kidney from an agematched deceased donor (71 years old). the transplant was performed with total hla-a, -b 1696 | and -dr incompatibility. the donor-recipient hla typings were: a*01, *02; b*07, *18; drb1*01, *04 for the donor, and a*11, *26; b*38, *44; drb1*13, -, for the recipient. microbeads array-luminex (one lambda hd kits, canoga park, ca, usa) and cdc techniques showed a pra level of 0%, which confirmed that the patient, who did not have any previous transplant or pregnancy history, was not sensitized to hla antigens (figure, a). before the transplantation, cdc cross-matching (cm) was negative. the maintenance immunosuppressive regimen consisted of prednisone (dacortin; merck farma y química, barcelona, spain), mycophenolate mofetil (cellcept, f. hoffman-la roche, basel, switzerland) and tacrolimus (prograf; astellas, killorglin co., kerry, ireland), as previously published.(5) on the 15th day of the post-transplantation monitoring period (15th day ptp), we detected de novo anti-hla class ii antibodies (igg) with luminex (one lambda, canoga park, ca, usa) (figure, b). anti-hla class i and anti-mica antibodies screening by luminex was negative. a goat anti-human igg coupled with phycoerythrin was used for antibody detection. with the luminex analyzer (labscan), reporter fluorescence intensity of each bead was determined and expressed as mean fluorescence intensity (mfi) which is directly proportional to the amount of antibody bound to the microspheres. mfimax is defined as the highest mfi level. the cut off value was calculated using negative sera (blood group ab sera from 35 non-transfused healthy males). a mean value and 3 standard deviations were calculated with a cut-off value of 3.0 and allowing an ambiguous area from 2.5 to 3.0, as previously reported.(5) additionally, we detected anti-dqb1*03:02 (donor had this allele) antibodies with mfimax 5673 and pra/crf = 3% (ls2pra, labscreenpra, ol, ca, usa) (figure, c), and with an apparently normal level of creatinine (cr = 1.0 mg/ dl) and proteinuria (pr = 1.2 g/24hr). one week later (22th day ptp), the patient had developed significant instability in renal function [(cr = 2.1 mg/dl) and proteinuria (pr = 6.5 g/24hr)], and was highly positive (mfimax 7986 and pra/crf = 37% [single antigen (sa) = 10%]) for antidrb1*04 and -dqb1*03:02 (donor typing) (ls2a01, ol, ca, usa) (figure, d). moreover, we performed cm of post-transplantation b-cells and preor post-transplant sera, by cdc assay. the results showed that cm was negative for pre-transplant serum, and positive for post-transplant. the cm test was performed as previously published.(3,5) in addition, the sera sample were tested against a panel of b cells from frozen donor spleens (23 donors) by cdc screening, showing negative (pra = 0%) and positive (pra = 8.6%-17.4%) results for pre-transplant and post-transplant serum, respectively. based on these facts, nephrologists from our hospital indicated a renal biopsy which was positive for c4d deposition (diffuse staining), compatible with humoral allograft rejection. the patient was pulsed with methylprednisolone (three 500 mg boluses), multiple plasmapheresis (three sessions a day, every 5 days) and ivig post-session (0.25 g/kg; 1 gr/kg in the last session), from the 22nd day ptp on, without functional improvement. one week later, the mfimax data was not different to those obtained before the treatment. thus, we administered 500 mg anti-cd20 (rituximab, roche pharmaceuticals, basel, switzerland) intravenously case report figure . (a) luminex pre-transplant data showing a pra (panelreactive antibodies)/crf (calculated reaction frequency) = 0% for hla class ii screening. the patient did not present antibodies; (b) luminex mix post-transplant data [15th day ptp (posttransplantation period)] positive for hla class ii. anti-hla class ii antibodies did appear in this second screening; (c) luminex pra post-transplant data (15th day ptp) showing a pra/crf = 3% in specificities analysis; (d) luminex pra post-transplant data (22nd day ptp) showing a pra/crf = 37%; (e) luminex pra/crf posttransplant with rituximab treatment data (45th day ptp) showing a pra/crf = 34%, without appreciable variation compared with the previous determination; (f) luminex pra/crf post-transplant with rituximab treatment data (52th days ptp) showing a similar pra/ crf = 34%, indicating reversion of humoral rejection. 1697vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l amr treatment, pra/crf/sa and mfi levels | boix et al (two doses on the 36th and 43rd days ptp) and the initial clinical response was highly favorable. biopsies performed on the 45th day ptp (post-anti-cd20 administration) appeared to show reversion of the humoral rejection [(cr = 1.4 mg/dl) and proteinuria (pr = 3.2 g/24hr)]. analysis of the serum on the 45th day ptp revealed that the mfimax of the anti-donor dr4 had fallen to 2021 (pra/crf = 34%, sa = 10%) (figure, e) and seven days later to mfimax 1176 (pra/crf = 34%, sa = 10%) (figure, f). despite the outcome of the treatment, all samples in this study showed similar pra/crf and sa levels (34-37% and 10%, respectively). thus, the results suggest that the recognized antigens are always the same, regardless of the antibody concentration in serum. to date, there has been an improvement in the patient's condition (an increased diuresis), although the renal function improves very slowly [(cr = 1.4 mg/dl) and proteinuria (pr = 2.7 g/24hr)]. the renal ultrasound scan shows a normal renal graft and the renal gammagraphy shows a good perfusion. discussion few articles compare the different methods of hla antibodies screening(1,2) for the detection of hla antibodies. indeed, current hla class ii matching strategies in kidney transplantation consider only the serologically defined hla-dr antigens controlled by the drb1 locus, although mismatching for hla-dq and hla-dp appears associated with lower graft survivals and the development of clinically relevant alloantibodies in transplant recipients.(2,5.6) consequently, hla-specific antibodies found in post-transplantation patients have been shown to be strongly associated with allograft failure.(6) thus, de novo dsa in serum present at the time of a biopsy increases the probability of microcirculation inflammation and damage lesions, and a subsequent graft loss. consistent with recent publications,(4,7) our data shows that the majority of de novo dsa are usually dsa ii. de novo dsa is associated with microcirculation changes typical of microcirculation inflammation (glomerulitis, peritubular capillaritis) and deterioration (transplant glomerulopathy, mesangial matrix increase, peritubular capillary basement membrane multilayering) and with diffuse c4d staining.(7) accordingly, our patient presented c4d diffuse staining. in heart transplant patients, a similar predominance of dsa ii and an association with cardiac allograft vasculopathy and decreased graft survival can be observed,(8) as well as an increased risk of rejection and coronary artery disease.(9) similarly, anti-class ii dsa are associated with bronchiolitis obliterans syndrome in lung transplantation.(10) with respect to our case, all samples showed a very similar luminex pra/crf level (34-37%), regardless of the treatment outcome. only mfi levels showed a correlation with the treatment evolution and were predictive of the clinical outcome of the patient. thus, this case underlines the importance of identifying patients who develop de novo post-transplant antibodies by using very sensitive screening methods, and emphasizes the importance of mfi quantification over of pra/crf (still demanded by some clinicians) and sa percentages. in fact, luminex technology is regarded as the most sensitive and safest method for antibody detection and is preferred over other antibody-detection techniques.(3,7) conclusion mfi levels, quantified by luminex method, are a better indicator for monitoring the development of humoral rejection than pra/crf/sa percentages. acknowledgements this work was has been supported in part by fondo de investigación sanitaria (fis) grants pi11/02686 and pi080446; ciberehd, funded by the instituto de salud carlos iii, spain; seneca foundation grant nº04487/germ/o6, and cajamurcia. conflict of interest none declared. references 1. muro m, llorente s, marín l, et al. acute vascular rejection mediated by hla antibodies in a cadaveric kidney recipient: discrepancies between flowpratm, elisa and cdc vs luminex screening. nephr dyal transplant. 2005;20:223-6. 1698 | 2. mizutani k, terasaki pi, hamdani e, et al. the importance of antihla-specific antibody strength in monitoring kidney transplant patients. am j transplant. 2007;7:1027-31. 3. bosch a, llorente s, diaz ja, et al. low median fluorescence intensity could be a nonsafety concept of immunologic risk evaluation in patients with shared molecular eplets in kidney transplantation. hum immunol. 2012;73:522-5. 4. gloor jm, sethi s, stegall md, et al. transplant glomerulopathy: subclinical incidence and association with alloantibody. am j transplant. 2007;7:2124-32. 5. muro m, gonzález-soriano mj, salgado g, et al. specific “intra-allele” (ia) and “intra-broad antigen” (iba) hla alloantibodies in kidney graft transplantation. hum immunol. 2010;71:857-60. 6. mao q, terasaki pi, cai j, et al. extremely high association between appearance of hla antibodies and failure of kidney grafts in a five year longitudinal study. am j transplant. 2007;7:864-71. 7. hidalgo lg, campbell m, sis b, et al. de novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure. am j transplant. 2009;9:2532-41. 8. kaczmarek i, deutsch ma, kauke t, et al. donor-specific hla alloantibodies: long-term impact on cardiac allograft vasculopathy and mortality after heart transplant. exp clin transplant. 2008;6:229-35. 9. lietz k, john r, burke e, et al. immunoglobulin mto immunoglobulin g anti-human leukocyte antigen class ii antibody switching in cardiac transplant recipients is associated with an increased risk of cellular rejection and coronary artery disease. circulation. 2005;112:2468-76. 10. palmer sm, davis rd, hadjiliadis d, et al. development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome. transplant. 2002;74:799-804. case report urol_v3_no1_001_editorial.qxd urology journal unrc/iua 38 introduction infertility occurs in approximately 14% of couples, and abnormalities in the male partner are estimated to be present in up to 50% of cases.(1,2) efforts to evaluate the causes of azoospermia have shown that regardless of traditionally recognizable causes (abnormal karyotype, obstruction, varicocele, hormonal defect, etc), most cases (50% to 75%) are unexplained and are considered idiopathic.(3) the existence of an essential spermatogenesis factor called azoospermia factor (azf) was suspected as early as 1976, from de novo yq deletions in azoospermic patients.(4) polymerase chain reaction (pcr) studies of sequence-tagged sites (stss) distributed every 30 kb enabled detection of small deletions in the azf region that had been undetectable with classical cytogenetic techniques.(5,6) this led to the identification of 3 loci in yq11 carrying genes involved in the control of spermatogenesis, corresponding to 3 deleted regions: azfa, azfb, and azfc.(7,8) y y chromosome microdeletions in idiopathic infertile men from west azarbaijan mir davood omrani,1* saied samadzadae,2 mortaza bagheri,1 kiarash attar2 1department of genetics, urmia university of medical sciences, urmia, iran 2department of urology, imam khomeini hospital, urmia university of medical sciences, urmia, iran abstract introduction: although assisted reproduction techniques are used extensively in iran, screening for y chromosome microdeletions before intracytoplasmic sperm injection is often undervalued. our aim was to investigate y chromosome microdeletions in men with idiopathic azoospermia or severe oligospermia. materials and methods: in 99 selected patients with azoospermia or severe oligospermia and elevated levels of follicle-stimulating hormone and luteinizing hormone in combination with low serum testosterone levels, 20 pairs of sequencetagged site-based primer sets specific for the y microdeletion loci were analyzed. primers were chosen to cover azoospermia factor (azf) regions as well as deleted in azoospermia (daz) and the sex-determining region on y chromosome (sry) genes. also, 100 healthy men served as a control group. results: twenty-four patients (24.2%) had microdeletions in azf genes, but no microdeletions were found in men in the control group. in 15 patients (62.5%), 1 deletion was found. six patients (25%) had 2, and 3 (12.5%) had 3 deletions. the deletions mainly comprised the azfc region (in 21 of 24 patients; 87.5%), which corresponds to the daz gene. deletions in azfb were found in 7 patients (29.2%), and 4 (16.7%) had deletions in the proximal part of azf regions near sry gene. no microdeletions were seen in the azfa or sry gene. conclusion: our results emphasize that y chromosome microdeletion analysis should be carried out in all patients with idiopathic azoospermia or severe oligospermia who are candidates for intracytoplasmic sperm injection. keywords: oligospermia, microdeletion, infertility, y chromosome vol. 3, no. 1, 38-43 winter 2006 printed in iran received december 2004 accepted december 2005 *corresponding author: department of genetics, mottahary hospital, kashani st, urmia, iran. tel: +98 441 224 0166, fax: +98 441 223 4125 e-mail: davood_omrani@umsu.ac.ir omrani et al 39 chromosome microdeletions are the most frequently encountered genetic abnormality in male infertility. up to 30% of men with idiopathic azoospermia have microdeletions of the y chromosome,(3,9-13) and the incidence of y chromosome microdeletions in infertile men varies between studies, from 1% to 55%.(14) the molecular diagnostics of the y chromosome have been restricted mostly to selected patients presenting with either azoospermia or severe oligospermia (sperm concentration of less than 5 × 106/ml), so that the majority of y chromosome microdeletions have appeared in this group of infertile men. screening for y chromosome microdeletions is recommended in patients with severely impaired spermatogenesis, in particular, before intracytoplasmic sperm injection (icsi).(15) in the west azarbaijan province of iran, at least 5 infertility centers are involved in treating infertile couples, but none of them checks their male candidates for y chromosome microdeletions. our study aimed to determine the incidence of y chromosome microdeletions in our patients in urmia, the center of west azarbaijan. the findings of this study may provide enough evidence for clinicians to decide whether or not to screen all idiopathic infertile men for y chromosome microdeletions before attempting icsi procedures. materials and methods in a case-control study, 99 consecutive men examined in our infertility clinics from november 2001 to december 2003 were screened for y chromosome microdeletions. the inclusion criteria were azoospermia or severe oligospermia (sperm concentration of less than 5 × 106/ml), small testis volume, elevated serum levels of follicle-stimulating hormone (fsh) and luteinizing hormone (lh), low serum testosterone level, and the 46,xy karyotype. informed consent was obtained from each patient, according to protocols approved by the ethics review board of urmia university of medical sciences. semen analysis was carried out using who criteria(16) with a nikon phase contrast microscope (nippon kogaku, tokyo, japan). serum hormone levels of fsh, lh, and testosterone were measured by solid-phase, twosite chemiluminescent enzyme immunometric assay (immulite, diagnostic products corporation, los angeles, calif, usa). normal reference ranges for men were fsh, less than 10 miu/ml; lh, less than 10 miu/ml, and testosterone, 270 ng/dl to 1070 ng/dl. cytogenetic analysis was carried out on peripheral lymphocytes to rule out cases of abnormal karyotypes. gtg-banding was performed according to standard procedures. one hundred age-matched fertile men with a normal semen analysis without genital abnormalities, selected from couples who had been referred for tubectomy or vasectomy, served as controls. the pcr and cytogenetic analyses were carried out in controls, too. polymerase chain reaction amplification of the three azf loci. genomic dna was obtained from peripheral leukocytes using the nucleon kit ii (scotlab, wiesloch, germany). a set of 20 y-specific stss spanning the euchromatic region of yq from centromere to interval 7, with particular interest in interval 6 (the azf region), was tested in each patient. to check the azfa region, pcr amplifications were carried out to evaluate the sy81, sy83, and sy121 sites. using the sy128, sy130, sy133, and sy143 sites, the azfb region was checked. the azfc region was screened using the sy147, sy149, sy242, sy231, sy254, sy255, sy182, and sy238 sites. in addition, sy202, sy158, and sy157 were included, corresponding to the downstream area of the daz (deleted in azoospermia) gene, as well as sy14 for the sex-determining region on the y chromosome (sry) gene and sy274 as the site next to the sry region. as a negative control, every pcr reaction included 1 sample of female genomic dna. a sample was considered negative if a product of the expected size was not obtained after 3 pcr attempts. the pcr program was as follows: amplification of dna by 35 cycles with 94°c for 50 seconds, 57°c for 30 seconds, and 72°c for 90 seconds; including an initial denaturation step at 94°c for 2 minutes, and a final extension step at 72°c for 10 minutes. the pcr products were separated on 1.5% agarose gels. statistical analyses. frequencies of the y chromosome microdeletions were compared between the patients with infertility and controls using the chi-square test. values for p less than .05 were considered statistically significant. results overall, of 99 infertile men, 39 (39.4%) had y chromosome deletions in idiopathic infertile men40 oligospermia and 60 (60.6%) had azoospermia. the paraclinical data of infertile patients are summarized in table 1. of 39 patients with oligospermia, 6 (15.4%) had deletions, and of 60 patients presenting with azoospermia, 18 (30%) had deletions in the azf region of the y chromosome. five of the 6 patients with oligospermia and y chromosome microdeletions had a sperm concentration of less than 0.1 × 106/ml with only a few immotile spermatozoa observed after centrifugation of the specimen. the sperm concentration of the sixth patient in this group was 2.4 × 106/ml. in general, 24 infertile men (24.2%) showed microdeletions of the y chromosome, while no microdeletions were detected in controls (p < .001). some of the patients' pcr products that were run on a 1.5% agarose gel are shown in figure 1. in 15 patients (62.5%), 1 deletion was found. six patients (25%) had 2, and 3 (12.5%) had 3 deletions. the deletions mainly comprised the azfc region (in 20 out of 24 patients; 83.4%), which corresponds to the daz gene. deletions in azfb were found in 7 patients (29.2%), and 4 (16.7%) had deletions proximal to the azf regions near the sry gene. no microdeletions in the azfa or sry genes were identified. a schematic diagram of the sts markers used in this study and the deleted markers are summarized in figure 2. chromosome analyses of peripheral lymphocytes of all selected patients and controls were normal male karyotype (46,xy). discussion interest in y chromosomal deletion analysis in infertile men arises largely from the likelihood that yq microdeletions will be transmitted by icsi and cause the same infertility problem in male offspring. this transmission of microdeletions has been described previously,(17) an observation that underlines the necessity of proper genetic counseling in infertile men. some authors have emphasized the importance of genetic counseling and testing for y chromosome microdeletions in all icsi candidates, irrespective of their sperm concentration. of 99 patients examined in our study, 24 had microdeletions in the azf regions on the y chromosome (24.2%), which is in agreement with previous studies. the kurd and azari ethnic groups are the majority in our region; thus, it can be inferred that y chromosome microdeletion fig. 1. an example of deletions of the y chromosome in the azf region in men with oligospermia: pcr products of the azf region from 19 tested patients, which were run on 1.5% agarose gel identified a deleted region in 6 patients. table 1. mean serum concentrations of fsh, lh, and testosterone in men with severe oligospermia and azoospermia mean (range) men with oligospermia men with azoospermia infertile men fsh (miu/ml) 9.9 (2 to 28) 14.9 (6 to 28) 14.1 (2 to 44) lh (miu/ml) 5.2 (1 to 18) 7.6 (2 to 11) 6.3 (1 to 18) testosterone (ng/dl) 366 (135 to 565) 344 (223 to 482) 355 (135 to 565) omrani et al 41 may be relatively prevalent in west azarbaijan. the deletions mainly involved the azfc region (in 87.5% of the patients), which corresponds with the daz gene, as well as deletion in the azfb (in 29.2% of the patients). no microdeletions in the azfa or the sry gene have been identified. we found deletions in the proximal part of the azf region near the sry gene in 16.7% of the patients. the deletion of this region may affect sry gene function, but to check this hypothesis, we must perform more experiments including functional studies. despite of the report of pryor and associates,(3) no microdeletions were found in healthy men of our control group. this variability in the detection of microdeletions between studies is probably explained by the different clinical selection criteria used by different research groups. stringent selection of patients according to histologic, endocrinologic, and clinical criteria have been found to be associated with high deletion frequencies.(7,14,18) for instance, foresta and colleagues have studied patients with idiopathic azoospermia and bilateral sertoli-cell-only syndrome and found a very high number of yq11 microdeletions.(14) by contrast, less stringent criteria for selection has been associated with low deletion frequencies in studies on a large number of men with oligospermia.(19,20) our study shows the influence of the selection criteria on the reported incidence of microdeletions; we had a high rate of y chromosome deletion in our patients since we used strict patient selection criteria. microdeletion frequency in a sample of infertile men is not significantly related to the number of sts loci analyzed.(21) kent-first and colleagues have analyzed a large number of stss in different y chromosome regions.(22) they have shown that each sts is statistically correlated with male infertility. it seems that patients' selection criteria have a much more profound effect on the rate of detection of microdeletions than do the numbers of stss analyzed. of the 24 infertile men with microdeletions of the y chromosome, 18 had azoospermia and 6 had severe oligospermia. in fact, most microdeletions have been found in men with azoospermia and severe oligospermia, because in fig. 2. schematic diagram of a y chromosome illustrating sequence-tagged sites, azf regions, and the different deletion patterns of the patients in this study. a "-" denotes deletion of a specific sequence-tagged site. y chromosome deletions in idiopathic infertile men42 the majority of the studies published so far, the analyses were limited to patients with severe defects of spermatogenesis. pryor and colleagues were the first to examine 200 consecutive patients who included 102 men with a normal sperm count. they found deletion frequencies of 23.1%, 9.7%, and 1% in infertile men with azoospermia, oligospermia, and normal sperm count, respectively. they concluded that the microdeletion in men with a normal sperm count probably indicated a polymorphism, because it comprised only one sts, which was also found in fertile men.(3) finally, all of the men with y chromosome microdeletions in our study were cytogenetically normal, showing that pcr-based assay is needed to detect microdeletions in the y chromosome. conclusion the correlation between y chromosome microdeletions and infertility, and the relative absence of such deletions in fertile men, suggests a cause-and-effect relationship between the deletions and infertility. as compared with other known causes of infertility, y chromosome microdeletions are relatively frequent, and their frequency increases with the severity of the spermatogenic defect. however, y chromosome microdeletions cannot be predicted on the basis of clinical findings or even the results of semen analyses. the role of analyses of y chromosome microdeletions in evaluating men with infertility remains to be determined. with the advent of icsi, the potential for passing on these defects to offspring is serious and should be considered when infertile couples are counseled about this procedure. acknowledgments we wish to thank the enrolled families for their cooperation in the study and also, we gratefully thank dr. agenta nordenskjold from the department of molecular medicine and genetics of karolinska university hospital in solna, sweden for kindly providing us some of the material in this project. this study was funded in part by the research deputy of urmia's university of medical sciences. references 1. swerdloff rs, overstreet jw, sokol rz, rajfer j. ucla conference. infertility in the male. ann intern med. 1985;103:906-19. 2. mosher wd. reproductive impairments in the united states, 1965-1982. demography. 1985;22:415-30. 3. pryor jl, kent-first m, muallem a, et al. microdeletions in the y chromosome of infertile men. n engl j med. 1997;336:534-9. 4. tiepolo l, zuffardi o. localization of factors controlling spermatogenesis in the nonfluorescent portion of the human y chromosome long arm. hum genet. 1976;34:119-24. 5. foote s, vollrath d, hilton a, page dc. the human y chromosome: overlapping dna clones spanning the euchromatic region. science. 1992;258:60-6. 6. vollrath d, foote s, hilton a, et al. the human y chromosome: a 43-interval map based on naturally occurring deletions. science. 1992;258:52-9. 7. reijo r, lee ty, salo p, et al. diverse spermatogenic defects in humans caused by y chromosome deletions encompassing a novel rna-binding protein gene. nat genet. 1995;10:383-93. 8. vogt ph, edelmann a, kirsch s, et al. human y chromosome azoospermia factors (azf) mapped to different subregions in yq11. hum mol genet. 1996;5:933-43. 9. nagafuchi s, namiki m, nakahori y, kondoh n, okuyama a, nakagome y. a minute deletion of the y chromosome in men with azoospermia. j urol. 1993;150:1155-7. 10. kobayashi k, mizuno k, hida a, et al. pcr analysis of the y chromosome long arm in azoospermic patients: evidence for a second locus required for spermatogenesis. hum mol genet. 1994;3:1965-7. 11. najmabadi h, huang v, yen p, et al. substantial prevalence of microdeletions of the y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged sitebased mapping strategy. j clin endocrinol metab. 1996;81:1347-52. 12. reijo r, alagappan rk, patrizio p, page dc. severe oligozoospermia resulting from deletions of azoospermia factor gene on y chromosome. lancet. 1996;347:1290-3. 13. vogt ph, edelmann a, kirsch s, et al. human y chromosome azoospermia factors (azf) mapped to different subregions in yq11. hum mol genet. 1996;5:933-43. 14. foresta c, ferlin a, garolla a, et al. high frequency of well-defined y-chromosome deletions in idiopathic sertoli cell-only syndrome. hum reprod. 1998;13:302-7. 15. krausz c, forti g, mcelreavey k. the y chromosome and male fertility and infertility. int j androl. 2003;26:70-5. 16. world health organization. who laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. cambridge (uk): cambridge university press; 1999. 17. silber sj, alagappan r, brown lg, page dc. y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm omrani et al 43 injection after testicular sperm extraction. hum reprod. 1998;13:3332-7. 18. stuppia l, calabrese g, franchi pg, et al. widening of a y-chromosome interval-6 deletion transmitted from a father to his infertile son accounts for an oligozoospermia critical region distal to the rbm1 and daz genes. am j hum genet. 1996;59:1393-5. 19. kent-first mg, kol s, muallem a, et al. the incidence and possible relevance of y-linked microdeletions in babies born after intracytoplasmic sperm injection and their infertile fathers. mol hum reprod. 1996;2:943-50. 20. kremer ja, tuerlings jh, meuleman ej, et al. microdeletions of the y chromosome and intracytoplasmic sperm injection: from gene to clinic. hum reprod. 1997;12:687-91. 21. simoni m, kamischke a, nieschlag e. current status of the molecular diagnosis of y-chromosomal microdeletions in the work-up of male infertility. initiative for international quality control. hum reprod. 1998;13:1764-8. 22. kent-first m, muallem a, shultz j, et al. defining regions of the y-chromosome responsible for male infertility and identification of a fourth azf region (azfd) by y-chromosome microdeletion detection. mol reprod dev. 1999;53:27-41. case report behçet's disease detecting by attacks of recurrent epididymo-orchitis: case reports emre ulukaradag*, omur memik, bekir voyvoda, levent ozcan keywords: behcet syndrome; comorbidity; male; epididymitis; orchitis; etiology. introduction behçet's disease (bd) is a systemic vasculitis characterized by the involvement of joints, gastrointestinal sys-tem, central nervous system, as well as recurrent genital and oral ulcerations, and ocular involvement. bd also may affect any sizes of arteries and veins. central nervous system and major vessel involvement account for most of the deaths from this disease.(1) epididymitis, occasionally recurrent, occur in 4% to 11% of patients. we report two bd patients presenting with attacks of recurrent epididymo-orchitis. case report thirty two and twenty seven years old two male patients were admitted to our clinic with sensitivity in left testis in both. in their medical history, recurrent attacks of epididymo-orchitis have occurred since 2-3 weeks ago, but never treated with different types of antibiotic and anti-inflammatory therapies. they also had genital ulcers and recurrent aphthous stomatitis history occurred 5-6 times per year. but they never admitted to any dermatology clinic with these complaints. when they came to our clinic with those symptoms, we made a physical examination and performed blood tests. they had genital ulcers and aphthous stomatitis. because of epididymo-orchitis is a rare symptom of bd, we performed a pathergy test and dermatology consultation. the pathergy tests were positive in both. then we diagnosed bd and began colchicine and prednisone (1 mg/kg/day). after the initiation of the therapy epididymo-orchitis resolved spontaneously. discussion acute epididymo-orchitis is an inflammatory disease of testis and epididymis. it generally presents unilaterally and occurs because of a specific or nonspecific urinary tract infection like cystitis, prostatitis or urethritis that seeds to the epididymis and testis through the lymphatic vessels or ductus deferens.(2) it can also occur as a result of viral infections, trauma, autoimmune disorders, or amiodarone use. surgeries on the lower urinary tract, different urogenital malformations, bladder outlet obstruction may also play a role in the etiology of acute epididymo-orchitis. our patients have no history like amiodarone use, trauma, urogenital malformation, or surgery. bd was first described by dr. hulusi behçet in 1937 which is characterized by the triad of recurrent aphthous stomatitis, genital ulcerations, and recurrent uveitis.(3) the disease may start with one or more symptoms but others symptoms may gradually appear over the years.(1) epididymo-orchitis is not the first symptom of bd but appears during follow up. the etiology of bd is unknown, but presumed to be multifactorial, including genetic predisposition, infectious triggers, and dysregulation of the immune system. its prevalence is the highest in middle east, asia and mediterranean region. the prevalence is 80 to 370 cases per 100,000 population in turkey.(4) the usual age of onset is around 30 years, and male to female ratio shows variation as 1:1 to 1:3.(1) generally its main clinical manifestation is oral ulcers, and disease occurs mainly between 18 to 40 years.(4) there is no specific test for the definite diagnosis of bd, it depends on the clinical criteria. the criteria of the international study group have been widely accepted since 1990.(3) according to them, the presence of oral ulcerations in addition to the presence of two criteria from among recurrent genital ulcerations, skin lesions, ocular lesions or positive pathergy test is sufficient for diagnosis of bd.(3) in our cases, the presence of oral ulcers, positive pathergy test, and genital ulcer confirmed the diagnosis of bd. these two patients also had epididymo-orchitis as a rare symptom of bd. the interesting part of our cases is that, untreated epididymo-orchitis with antibiotic therapy might be a symptom of bd, and in our cases the way to determine this disease was began from this point. conclusions in any patient with epididymo-orchitis, bd should be remembered and investigations for other symptoms of the disease especially in regions with a high prevalence of it should be made. department of urology, derince training and research hospital, kocaeli, turkey. *correspondence: department of urology, 41900 derince training and research hospital, kocaeli, turkey. tel: +90 262 3178000. fax: +90 262 2334641. email: eulukaradag@gmail.com. received april 2015 & accepted july 2015 vol 12 no 05 september-october 2015 2379 conflict of interest none declared. references 1. saleh z, arayssi t. update on the therapy of behçet disease. ther adv chronic dis. 2014;5:112-34. 2. banyra o, shulyak a. acute epididymoorchitis: staging and treatment. cent european j urol. 2012;65:139-43. 3. pektaş a, devrim i, beşbaş n, bilginer y, cengiz ab, ozen s. a child with behçet's disease presenting with a spectrum of inflammatory manifestations including epididymoorchitis. turk j pediatr. 2008;50:7880. 4. saadoun d, wechsler b. behçet's disease. orphanet j rare dis. 2012;7:20. behçet's disease epididymo-orchitis-ulukaradag et al. case report 2380 urol_v3_no1_001_editorial.qxd urology journal unrc/iua 20 introduction although, urinary calculi, especially bladder calculi, are a rare entity in children in developed countries, it are a common disease among children in developing countries.(1,2) during the past decade, transurethral lithotripsy has become an alternative to open cystolithotomy; however, the method is hampered in children with narrow caliber urethra.(1,3) we present our results of percutaneous cystolithotripsy (pccl) without the use of fluoroscopy in children with bladder calculi. materials and methods between april 2001 and february 2005, we performed 30 percutaneous stone removal procedures from the bladders of 27 boys and 3 girls (mean age, 6.06 ± 2.64 years; range, 1.5 to 12 years). the diagnosis was based on plain abdominal radiography and ultrasonography (figure 1). the mean size of the largest diameters of the calculi was 24.8 ± 8.47 mm (range, 13 to 50 mm). the mostcommon presenting complaints were urinary retention, dysuria and/or frequency, and hematuria. urine culture was performed in all patients preoperatively, and if needed, antibiotic therapy was carried out. the surgical operations were performed under general anesthesia, following prior informed parental consent and if possible, assent from the children. all patients underwent an initial cystourethroscopy to exclude any subvesical obstruction. then, an 8-f or a 10-f foley catheter was inserted into the bladder. the bladder was filled with saline to its maximum capacity. a 1-cm transverse incision was made 1 percutaneous treatment of bladder calculi in children: 5 years experience hassan ahmadnia,1* mehdi younesi rostami,1 ali asghar yarmohammadi,1 seyed mohammad javad parizadeh,2 mohammad esmaeili,2 mohammad movarekh1 1department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran 1department of pediatrics, ghaem hospital, mashhad university of medical sciences, mashhad, iran abstract introduction: we sought to evaluate the safety and efficacy of percutaneous cystolithotripsy in children. materials and methods: thirty children (27 boys and 3 girls; mean age, 6.06 ± 2.64 years; range, 1.5 to 12 years) with bladder calculi underwent percutaneous stone removal. the mean size of the largest diameters of the calculi was 24.8 ± 8.47 mm (range, 13 mm to 50 mm). under general anesthesia, a 1-cm incision was made 1 to 2 cm above the pubic symphysis. a 26-f nephroscope was introduced into the bladder following tract dilation, and the calculi were removed. if the calculi were larger than 1 cm, fragmentation was performed. the procedure was done without fluoroscopy. finally, a urethral catheter was placed for 48 hours. results: all patients became stone free. the mean operative time was 23.13 ± 8.38 minutes (range, 12 to 40 minutes). all patients were discharged 24 hours after operation, except 1, who was hospitalized 2 more days for suprapubic pain and severe irritating symptoms. no significant intraoperative or postoperative complications were seen. conclusion: percutaneous suprapubic cystolithotripsy is an efficient and safe technique for treating bladder calculi in children. we recommend this technique for treating large bladder calculi (larger than 1 cm) in children. key words: bladder calculi, percutaneous cystolithotripsy, children vol. 3, no. 1, 20-22 winter 2006 printed in iran received june 2005 accepted december 2005 *corresponding author: 136 farhang ln, tehran st, mashhad 91366, iran. tel: +98 511 859 5880, fax: +98 511 841 7404 e-mail: ahmadnia2001@yahoo.com ahmadnia et al 21 to 2 cm above the pubic symphysis. the bladder was punctured with an 18-gauge needle, and a 0.035-inch j-type guide wire was placed into the bladder. subsequently, using telescoping metal dilators, the tract was dilated up to 30 f over the guide wire. an amplatz sheath with an inner diameter of 30 f was introduced into the bladder (figure 2). a 26-f nephroscope was introduced after tract dilation, and the calculus was removed if it was small, or fragmented with a swiss lithoclast (ems, lausanne, switzerland) if it was larger than 1 cm (figure 3). the fragments were removed with a grasping forceps. the procedure was done without fluoroscopy. at the end of the procedure, an 8-f or a 10-f urethral catheter was introduced into the bladder for 48 hours. no suprapubic catheter was needed. antibiotic prophylaxis continued for 5 days after the operation. in cases without complications, patients were discharged from the hospital 24 hours after the surgery. in all patients, ultrasonography was performed after the 5th postoperative day. results two patients with positive preoperative urine cultures were treated with appropriate antibiotics. the mean operative time was 23.13 ± 8.38 minutes (range, 12 to 40 minutes). no significant intraoperative or postoperative complications were seen. all of the patients were discharged 24 hours after the operation, with the exception of a 5-year-old child who complained of suprapubic pain and severe, irritating symptoms. he was discharged 48 hours after catheter removal. in all of the patients, the urethral catheter was removed 48 hours after the operation. seven patients complained of increased urinary frequency and dysuria after catheter removal, which improved by anticholinergic agents. ultrasonography on the fifth postoperative day showed no collection, and the bladder was free of stones in all patients. no pain or irritation at the site of operation was reported 5 days postoperatively. calculi were composed of ammonium acid urate in 11 (36.7%), ammonium acid urate and calcium oxalate in 16 (53.3%), and cystine in 3 patients (10%). discussion urinary calculi are relatively uncommon in children compared with adults and are formed in association with a variety of factors, including identifiable metabolic and genetic disorders, geographic and socioeconomic boundaries, and exposure to medication and other environmental influences.(4) urinary calculi in children are categorized into 3 broad epidemiologic patterns: calculi seen in premature infants of very low birth weight, upper urinary tract calculi seen in children and adolescents, and endemic bladder calculi.(1,4) in developed countries, occurrence of fig. 1. plain abdominal radiography in a 3-year-old girl with a large bladder calculus fig. 2. a 30-f amplatz which is inserted into the bladder following dilation in a 3-year-old girl fig. 3. endoscopic feature of the bladder calculus in a 3year-old girl treatment of bladder calculi in children22 urinary calculi in children represents 1% to 5% of all urinary calculi, and moreover, urinary bladder calculi are very rare.(1) at the same time, in developing countries (such as those in the middle east, thailand, and indonesia), occurrence of urinary calculi in children represents 30% of all urinary calculi. the endemic bladder calculus is still a common disease in childhood.(1,2,4) most pediatric bladder calculi in endemic areas are composed of ammonium acid urate, calcium oxalate, or mixtures thereof.(5) the occurrence of such calculi may be traced to the common practice in endemic areas of feeding infants human breast milk and cereal foods, such as polished rice or millet. human breast milk, in contrast with cow's milk, is low in phosphorus, as is polished rice. such low-phosphate diets result in high peaks of urinary ammonia excretion.(1,4) various techniques have been used to remove calculi from the bladder including open cystolithotomy, transurethral lithotripsy, and percutaneous cystolithotripsy (pccl).(6-9) open surgery has the inherent problems of a long scar, prolonged catheterization, extended hospitalization, and risk of infection.(10) in children, especially in boys, because of the size limitations secondary to the small urethra and concerns about iatrogenic urethral stricture, transurethral endoscopic removal may be more difficult and fraught with danger. gopalakrishnan and colleagues were the first to report use of a percutaneous suprapubic approach in managing bladder calculi.(8) the morbidity of pccl is significantly less than that of open cystolithotomy.(1,3) using the percutaneous suprapubic approach, a 26-f nephroscope can be introduced into the bladder without urethral injury. in this manner, the large and hard stones can be disintegrated and removed in large fragments, so that the intervention can be performed quickly. in our study, the largest calculus was 5 cm in diameter. in this study, we used a single percutaneous puncture. the access site was positioned 1 cm to 2 cm above the pubic symphysis, and the puncture was performed with a distended bladder to avoid inadvertent bowel injury. the 30-f amplatz sheath allowed for passage of a standard nephroscope, and the calculi were removed using fragmentation, if necessary. the procedure was done without fluoroscopy, and no significant complications were seen. salah and coworkers have reported successful pccl in 117 children, 77% of whom were younger than 5 years. in their study, dilation of the tract was made under fluoroscopy, and this could be associated with complications.(1) we preferred blind dilation to prevent any complication. also, salah and colleagues used ultrasonic lithotripsy, while we used pneumatic lithotripsy. agrawal and colleagues have performed this procedure on 38 children without fluoroscopy.(3) the largest calculus diameter in their study was 2.8 cm. no eventful complications were reported in these studies. postoperatively, the authors performed a cystostomy in all patients. in comparison, we inserted a foley catheter, and the largest diameter in our patients was 5 cm. it seems that all these approaches in percutaneous stone removal in children are successful. conclusion percutaneous suprapubic cystolithotripsy is an efficient and safe technique for treating bladder calculi in children. we recommend this technique for treating large bladder calculi (greater than 1 cm) in children. references 1. salah ma, holman e, toth c. percutaneous suprapubic cystolithotripsy for pediatric bladder stones in a developing country. eur urol. 2001;39:466-70. 2. johnson o. vesical calculus in ethiopian children. ethiop med j. 1995;33:31-5. 3. agrawal ms, aron m, goyal j, elhence ip, asopa hs. percutaneous suprapubic cystolithotripsy for vesical calculi in children. j endourol. 1999;13:173-5. 4. menon m, resnick mi. urinary lithiasis: etiology, diagnosis, and medical management. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 3289-92. 5. vanwaeyenbergh j, vergauwe d, verbeeck rm. infrared spectrometric analysis of endemic bladder stones in niger. eur urol. 1995;27:154-9. 6. cain mp, casale aj, kaefer m, yerkes e, rink rc. percutaneous cystolithotomy in the pediatric augmented bladder. j urol. 2002;168:1881-2. 7. van savage jg, khoury ae, mclorie ga, churchill bm. percutaneous vacuum vesicolithotomy under direct vision: a new technique. j urol. 1996;156:706-8. 8. gopalakrishnan g, bhaskar p, jehangir e. suprapubic lithotripsy. br j urol. 1988;62:389. 9. mahran mr, dawaba ms. cystolitholapaxy versus cystolithotomy in children. j endourol. 2000;14:423-5; discussion 426. 10. maheshwari pn, oswal at, bansal m. percutaneous cystolithotomy for vesical calculi: a better approach. tech urol. 1999;5:40-2. endourology and stone diseases factors influencing complications of percutaneous nephrolithotomy: a single-center study sedat oner, muhammed masuk okumus, murat demirbas,* efe onen, mustafa murat aydos, mehmet hakan ustun, metin kilic, sinan avci purpose: percutaneous nephrolithotomy (pnl) is a minimally invasive procedure used for successful treatment of renal calculi. however, it is associated with various complications. we assessed the complications and their potential influencing factors in patients who had undergone pnl. materials and methods: in total, 1750 patients who had undergone pnl from november 2003 to june 2011 were evaluated retrospectively. pnl complications and possible contributing risk factors (age, sex, serum creatinine level, previous operations, hydronephrosis, calculi size, localization, opacity, surgeon’s experience, accessed calyxes, number of accesses, and costal entries) were determined. receiver operating characteristic (roc) analysis was used to investigate the cutoff values of the data. ideal cutoff value was determined by youden's j statistic. all the demographic and clinical variables were examined using backward stepwise logistical regression analysis. continuous variables were categorized with logistic regression analysis according to the cutoff values. results: complications occurred in 396 (24.4%) patients who had undergone pnl. hemorrhage requiring blood transfusion occurred in 221 (12.6%) patients, hemorrhage requiring arterial embolization occurred in 7 (0.4%) patients, perirenal hematoma occurred in 17 (0.97%) patients, hemo-pneumothorax occurred in 32 (1.8%) patients, and colon perforation occurred in 4 (0.22%) patients. three patients (0.06%) died of severe urosepsis, and one patient (0.02%) died of severe bleeding. the calculus size, localization, access site, number of accesses, presence of staghorn stones, surgeon’s experience, and duration of the operation significantly affected the complication risk. conclusion: our retrospective evaluation of this large patient series reveals that, pnl is a very effective treatment modality for kidney stones. however, although rare, serious complications including death can occur. keywords: nephrostomy; percutaneous; multivariate analysis; postoperative complications; etiology; retrospective studies; treatment outcome. introduction access to the collecting system of the kidneys was first reported in the 1950s, whereas access to the collecting system for the purpose of kidney stone treatment was first performed in the 1970s and 1980s. (1-3) nowadays percutaneous nephrolithotomy (pnl) is gold standard treatment modality for upper urinary tract stones.(4) pnl has a success rate of over 95% depending on the kidney anatomy, stone size, stone localization, patient-specific anatomical factors, and surgeon’s experience; however, it is associated with some complications; including death.(5) in this study, we retrospectively analyzed the complication rates and the factors that might affect these complications in a large number of patients treated by pnl. materials and methods study population the data of patients who underwent pnl by a single surgeon were examined retrospectively. detailed physical examinations, blood biochemistry assays, urinalysis, and urine culture were performed preoperatively in all the patients. they also underwent preoperative direct urinary tract radiography, urinary ultrasonography, and intravenous urography, and unenhanced spiral computed tomography, if necessary. calculated stone surface area (csa) was evaluated by multiplying the maximum diameter, width, ¼ π of the stone seen on the plain radiography. appropriate antibiotic therapy was administered to those patients with growth on their preoperative urine cultures. patients without sterile urinary cultures despite appropriate antibiotic therapy, underwent pnl under antibiotic administration. surgical procedure a 6 to 7 french (f) ureteral catheter was inserted under c-arm fluoroscopy. the patients were placed in the prone position, and the collecting system of the kidney was accessed with needle puncture under fluoroscopy guidance. after amplatz dilation, 30 f sheath was positioned and only in a small number of children 20 f sheath was used. stone fragmentation was then performed with pneumatic lithotripter. clearance of the stone fragments was assessed with fluoroscopy. at the end of the procedures, a re-entry nephrostomy catheter department of urology, sevket yilmaz training and research hospital, bursa, turkey. *correspondence: department of urology, sevket yilmaz training and research hospital, mimar sinan mh. emniyet cd. yildirim, bursa 16310, turkey. tel: +90 532 2364838. fax: +90 224 3660416. e-mail: muratdemirbas@doctor.com received february 2015 & accepted september 2015 vol 12 no 05 september-october 2015 2317 was placed, and antegrade pyelography was performed to check for extravasation and colonic injury. stone clearance was assessed on a direct urinary tract x-ray. post-operative evaluations patients with no opacities on the x-ray were considered stone free, those with opacities of under 4 mm were considered to have clinically insignificant residual fragments (cirf) and those with opacities of over 4 mm was defined as failure. nephrostomies were withdrawn after recovery of hematuria. fever was considered to be present in patients with a body temperature over 38°c during the postoperative period. cold compression, antipyretics, and antibiotic treatment were administered as necessary. a ureteral double j stent was placed if urine leakage from the nephrostomy tract continued for 72 to 96 hours. anteroposterior chest radiography was performed to evaluate possible pleural injury in patients in whom supracostal and upper pole access was performed. patients with mild effusion on chest radiographs were followed up, and those with severe effusion were treated by insertion of a chest tube. pnl-associated complications such as hemorrhage requiring transfusion, fever, prolonged urinary drainage, severe urosepsis, pleural injury, colon injury, and hemorrhage requiring arterial embolization, perirenal hematoma, and death were classified according to modified clavien classification. the patient-related factors including age, sex, serum creatinine level, previous operations, presence of hydronephrosis, kidney stone size and opacity, presence of a solitary kidney, horseshoe kidney, staghorn stones and urinary tract infection and the procedure-related factors including the surgeon’s experience, caliceal accesses, number of accesses, duration of the operation, and supracostal punctures that might influence the development of pnl associated complications were analyzed. patients were classified according to the presence of hydronephrosis on radiologic assessment. the degree of hydronephrosis was not evaluated as a separate factor. the stones were divided according to location as simple (pelvis, isolated calyx) or complex (multiple calices, staghorn). the presence of a staghorn stone was re-evaluated as a separate factor apart from the stone size. the accessed calyx was evaluated as either isolated or multiple, and the number of accesses were evaluated as either single or multiple. the cutoff values of the stone size, the surgeon’s experience (assessed according to the number of patients surgically treated) and the duration of the operation (the time from initial calyx access to the placement of the nephrostomy catheter) for the development of complications was evaluated. statistical analysis receiver operating characteristic (roc) analysis was used to investigate the cutoff values of the data. ideal cutoff value was determined by youden's j statistic. all the demographic and clinical variables were examined using backward stepwise logistical regression analysis as to be a risk factor or not. continuous variables which had significant cutoff values, was categorized with logistic regression analysis according to the cutoff values. values of p < .05 were considered to be statistically significant. the data were entered into an exceltm (microsoft, redmond, wa, usa) database and analyzed with statistical package for the social science (spss inc, chicago, illinois, usa) version 20.0. results a total of 1750 patients underwent pnl from november 2003 to june 2011. the patient and operation data are shown in table 1. stone free status was obtained in 1485 (84.8%) of the 1750 patients, cirf were evident in 217 (12.4%), and failure occurred in 48 (2.7%). complications occurred in 396 (24.4%) patients and related data are summarized according to the modified clavien classification in table 2. the complications were compared with those reported in the literature (table 3). urosepsis developed in three (0.17%) patients during the postoperative period, and one patient (0.05%) developed severe bleeding; all four of these patients died. the factors that might affect the complication rates are shown in tables 4 and 5 according to categorized and continuous variables, respectively. the cutoff value of stone size for the development of complications was 710 mm2 (sensitivity 41.7%; specificity 69.4%), the variables values mean age, years (range) 45.82 (3-81) gender, no (%) male 1055 (60.3) female 695 (39.7) stone site, no (%) left 857 (51) right 893 (49) solitary, no (%) 36 (2.05) previous operation, no (%) yes 329 (18.8) no 1421 (81.8) mean serum creatinine (mg/dl) 1.03 mean stone size, cm2 (range) 7.5 (0.25-95) presence of hydronephrosis, no (%) yes 1220 (69.7) no 530 (30.3) stone opacity, no (%) semi/non opaque 35 (2) radiopaque 1715 (98) mean operation time, min (range) 56.79 (15-330) access number, mean (range) 1.40 (1-7) single 1298 (74.2) multiple 452 (25.8) calyx entry, no (%) supracostal 93 (5.3) subcostal 1657 (94.7) mean duration with nephrostomy, days (range) 2.49 (1-12) mean hospitalization, days (range) 3.08 (1-25 ) table 1. clinical characteristics of the study patients and features of operations. factors influencing complications of pnl-oner et al. endourology and stone diseases 2318 cutoff value of operation time was 67 minutes (sensitivity 41.4%; specificity 79.2%) and the cutoff value of the cases for convenient skills to decrease complication rates was 565 (sensitivity 72.3%; specificity 48%). although supracostal access did not increase the risk for general complications, it was a risk factor for pleural injury. pleural injury was observed in 15 of 95 patients who underwent supracostal access (16.1%), whereas it occurred in 17 of 1657 patients (1.1%) who underwent subcostal access (p < .001). while the presence of staghorn stone, multiple-caliceal accesses, large stone size and the longer duration of operation significantly increased the risk of the most common complication (blood transfusion), the presence of a horseshoe kidney and greater surgical experience were associated with a significantly decreased rate of blood transfusion (tables 6 and 7). discussion pnl is considered to be the standard treatment for staghorn renal calculi, large volume renal calculi, upper tract calculi refractory to other treatment modalities, difficult lower pole stones, cysteine nephrolithiasis, and calculi in anatomically abnormal kidneys.(6) pnl is typically a very safe and well-tolerated procedure, but it is associated with a specific set of complications.(7,8) michel and colleagues evaluated more than 100 patients and found that the most common complications of pnl were extravasation (7.2%) (grade 3a), blood transfusion (11.2%-17.5%) (grade 2), and fever (21.0%-32.1%) (grade 1).(5) the rarer complications in their study were septicemia (0.3%-4.7%) (grade 4b), colon injury (0.2%-4.8%) (grade 4a), and pleural injury (0.3%1.0%) (grade 4a). the complications seen in our study are summarized in table 2 according to the modified clavien system. fever was the most common grade 1 complication which was treated with cold compression and antipyretics. the most common grade 3a complication was urinary leakage that exceeded 72 hours in 28 (1.6%) patients. a double j ureteral catheter was placed in these patients. the grade 3b complications included perirenal hematoma and arteriovenous fistula. arterial embolization was performed in the patients with arteriovenous fistulas, and conservative treatment or placement of a double j ureteral catheter was performed in the patients with perirenal hematomas. the most common grade 4a complications were pleural injury and colon injury. a chest tube was placed in 18 of the patients with pleural injury; the remaining 14 were treated with conservative management. one of the patients with colon injury underwent an operation by a general surgeon perioperatively, and three underwent repair procedures postoperatively. sepsis developed in three patients (grade 4b), and these patients died despite intense antibiotic and supportive treatment. these findings are consistent with those in the literature.(6,8-10) hemorrhage is an important morbidity associated with pnl. kessaris and colleagues reported a 0.8% rate of hemorrhage requiring embolization following pnl.(10) in another large series, the incidence of serious arterial bleeding after pnl was reportedly 0.5% to 1.0%. (11) additionally, mousavi-bahar and colleagues reported a 0.6% transfusion rate among 671 patients, while el-nahas and colleagues reported a 16.0% transfusion rate among 241 patients.(12,13) in our study, hemorrhage requiring transfusion occurred in 221 (12.6%) patients, while hemorrhage requiring arterial embolization occurred in 7 (0.4%). sampaio reported a 67% vessel injury rate and a 17% arterial (interlobar) injury rate in percutaneous intertable 2. complication rates according to modified clavien classification. modified clavien classification values grade 1 (fever) 80 (4.5) grade 2 (blood transfusion) 221 (12.6) grade 3a (extravasation) 28 (1.6) grade 3b perirenal hematoma 7 (0.4) arteriovenous fistula 17 (0.97) grade 4a colon injury 4 (0.22) pleural injury 32 (1.82) grade 4b (sepsis) 3 (0.17) grade 5 (death) 4 (0.22) data are presented as no. (%). complications mousavi-bahar(12) (n = 671) rosetta(6) (n = 5803) lee(9) (n = 582) our experience (n = 1750) transfusion 0.6 5.7 11.2 12.6 hemorrhage requiring intervention 0.15 na 1.2 0.4 fever na 10.5 22.4 4.5 sepsis 0 na 0.8 0.17 colon injury na na 0.2 0.22 pleural injury 0.7 1.8 3.1 1.82 extravasation/urine leakage 5.2 3.4 7.2 1.6 death 0.3 0.3 0.3 0.22 abbreviation: na, not available. data are presented as %. table 3. comparison of our complications in percutaneous nephrolithotomy with the literature. factors influencing complications of pnl-oner et al. vol 12 no 05 september-october 2015 2319 ventions performed on upper calices.(14) considering this anatomic feature of the kidney, lower-calyx access is considered to be safest with respect to complications. however, kukreja and colleagues showed that the location of the calyx did not affect the development of complications.(15) although this is a controversial finding, the complication rates associated with upper calyx access in our study were lower than those associated with lower calyx access, although not statistically significant (19.2% vs. 21.5%, respectively) (table 4). upper calyx table 4. the factors that might affect the complication rates (categorized variables). factors patients, no complications, no (%) p value gender male 1055 198 (18.8) _____ female 695 198 (28.5) localization simple 772 149 (19.3) _____ complex 978 247 (25.3) access site lower calyx 619 133 (21.5) < .001 middle calyx 592 113 (19.1) upper calyx 172 33 (19.2) multiple calices 367 117 (31.9) number of accesses single access 1298 251 (19.3) < .001 multiple accesses 452 145 (32.1) costal entry subcostal 1657 374 (22.6) _____ supracostal 93 22 (23.7) staghorn stone yes 164 59 (36) < .001 no 1586 337 (21.2) solitary kidney yes 36 12 (33.3) _____ no 1714 384 (22.4) horseshoe kidney yes 39 5 (12.8) _____ no 1711 391 (22.8) opacity semi/non opaque 35 6 (17.1) _____ radiopaque 1715 390 (22.7) previous operation yes 329 72 (21.9) _____ no 1421 324 (22.8) hydronephrosis yes 1220 262 (21.5) _____ no 530 134 (25.3) preoperative infection yes 165 45 (27.3) _____ no 1585 351 (22.1) factors influencing complications of pnl-oner et al. endourology and stone diseases 2320 access increases the risk of pleural injury; however, establishing access from this site may be easier than lower and middle calyx access, because the guide can be more easily placed in the ureter when it is inserted from the upper calyx. amplatz dilatation performed through a guide in the ureter can be more easily and rapidly accomplished. moreover, manipulations related the renal pelvis and other calices can be performed more comfortably with upper-pole than with lower-pole access. placement of a guide in the renal pelvis and ureter is sometimes difficult with lower calyx access; this can result in problems, particularly bleeding during dilatation. in the present series, most blood transfusions occurred in association with access of multiple calyxes, followed by lower calyx access (22.1% and 12.6%, respectively) (table 5). this rate was 8.3% in the middle-calyx group, and lowest requirement for blood transfusion occurred in association with isolated upper calyx access. the blood transfusion rates in patients with isolated lower calyx access were significantly higher than those in patients with isolated middle and isolated upper calyx access (p = .014 and p = .009, respectively). no significant difference in the rate of blood transfusion was found between middle and upper calyx access (p = .884). lower calyx access is generally recommended in the literature. according to our own experience, however, upper calyx access seems to be more convenient and is associated with lower hemorrhage rates. therefore, we do not believe that the surgeon should be insisted on lower calyx access; if the middle and upper calyxes seem to facilitate stone removal, it would be wise to utilize access through these calyxes. table 5. the factors that might affect the complication rates (continuous variables). variables values age cutoff value _____ auc (se) 0.478 (0.017) p value .188 duration of operation (min) cutoff value 67 auc (se) 0.637 (0.016) p value < .001 surgeon’s experience (no.) cutoff value 565 auc (se) 0.383 (0.017) p value < .001 stone size (cm2) cutoff value 7.10 auc (se) 0.560 (0.016) p value < .001 abbreviations: auc, area under the curve; se, standard error. factors patients (no.) blood transfusion no. (%) p value access site lower calyx 619 78 (12.6) < .001 middle calyx 592 49 (8.3) upper calyx 172 13 (7.6) multiple calices 367 81 (22.1) number of access single 1298 127 (9.8) < .001 multiple 452 94 (20.8) staghorn stone yes 164 41 (25.0) < .001 no 1586 180 (11.3) horseshoe kidney yes 39 0 (0) no 1711 221 (12.9) table 6: factors affecting blood transfusion (categorized variables). factors influencing complications of pnl-oner et al. vol 12 no 05 september-october 2015 2321 pnl is associated with lower success rates and higher risks of complications in the treatment of staghorn and complex stones than in the treatment of simple stones. generally, more than one working channel is needed to clear these stones. stoller and colleagues found that the formation of multiple working channels increased the hemorrhage rate.(16) according to the kidney stone guidelines of the american urological association (aua), the complication rate associated with staghorn stones is 7% to 27%, and the transfusion rate is about 18%.(7) the presence of staghorn kidney stones and the formation of multiple working channels are independent factors associated with the development of hemorrhage.(16,17) in a retrospective study of factors affecting hemorrhage in 193 patients who underwent pnl, multiple accesses increased bleeding.(18) additionally, akman and colleagues reported that the bleeding rates were higher in association with multiple calyx than isolated calyx access.(19) in a study of 619 individuals, akman and colleagues found that stone size was an enhancing factor for transfusion rates.(19) in the present study, we found that a larger stone was an enhancing factor for both complications and blood transfusions (p = < .001 and p = .001, respectively; cutoff value, 593 mm2). in a study of the vascular structure of horseshoe kidneys, jenetschek and kunzel reported that a significant portion of the blood flow in the kidneys occurs on the medial surface; therefore, posterior access would cause fewer vascular injuries in horseshoe kidneys.(20) the present study supports this finding. the transfusion rate in our series was 12.6% in general, and no blood transfusion was needed following pnl in 39 patients with horseshoe kidneys. similarly darabi and colleagues and ghoneimy and colleagues reported no blood transfusion in their series of pnl in horseshoe kidney.(21,22) a prolonged operation time is another factor that enhances the rates of complications and blood transfusions according to the general literature. akman and colleagues reported that the cutoff operation time for blood transfusion was 58 minutes; operation times exceeding this value increased the need for blood transfusions 2.82-fold.(19) in the present study, the cutoff time was found to be 67 minutes, and the complication frequency increased in patients who underwent operations exceeding this duration. the surgeon’s experience is also a potential factor influencing the complications and the hemorrhage risk. previous studies have shown that there is a negative correlation between surgical experience and bleeding risk.(17) allen and colleagues suggested that 60 pnl cases are needed for surgical adequacy, while 115 are needed for surgical excellence. (23) in the present study, the blood transfusion rate was 31.0% for the first 100 cases and 9.2% for the 500th to 1750th case. the cutoff surgeon experience was found to be 565 cases for decreasing complications and 647 cases for decreasing blood transfusion rates. the possible explanation for the high cutoff values of surgical experience in our study was considered to be the effect of increasing the number of difficult and complex cases as surgeon experience increases. conclusions although pnl is generally a safe treatment modality for kidney stones, the surgeon must remember that serious complications such as death may occur. the complication rates in the present study were consistent with those in the general literature. larger stones, complex stone, multiple-calyx access, an increased number of accesses, presence of staghorn stones, lower surgical experience, and prolonged operation times increased the complication rates. conflict of interest none declared. references 1. ogg cs, saxton hm, cameron js. percutaneous needle nephrostomy. br med j. 1969;4:657-60. 2. fernström i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 3. badlani g, eshghi m, smith ad. percutaneous surgery for ureteropelvic junction obstruction table 7. factors affecting blood transfusion (continuous variables). age cutoff value values auc (se) 0.496 (0.021) p value .858 duration of operation (min) cutoff value 67 auc (se) 0.679 (0.020) p value < .001 surgeons experience (no.) cutoff value 647 auc (se) 0.361 (0.021) p value < .001 stone size (cm2) cutoff value 5.93 auc (se) 0.588 (0.022) p value < .001 abbreviations: auc, area under the curve; se, standard error. factors influencing complications of pnl-oner et al. endourology and stone diseases 2322 (endopyelotomy): technique and early results. j urol. 1986;135:26-8. 4. basiri a, tabibi a, nouralizadeh a, et al. comparison of safety and efficacy of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in patients with renal pelvic stones: a randomized clinical trial. urol j. 2014;11:1932-7. 5. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899-906. 6. de la rosette j, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol. 2011;25:11-7. 7. preminger gm, assimos dg, lingeman je, nakada sy, pearle ms, wolf js jr; aua nephrolithiasis guideline panel). chapter 1: aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005;173:19912000. 8. rudnick dm, stoller ml. complications of percutaneous nephrostolithotomy. can j urol. 1999;6:872-5. 9. lee wj, smith ad, cubelli v, et al. complications of percutaneous nephrolithotomy. ajr am j roentgeno. 1987;148:177-80. 10. kessaris dn, bellman gc, pardalidis np, smith ag. management of hemorrhage after percutaneous renal surgery. j urol. 1995;153:604-8. 11. patterson de, segura jw, leroy aj, benson rc jr, may g. the etiology and treatment of delayed bleeding following percutaneous lithotripsy. j urol. 1985;133:447-51. 12. mousavi-bahar sh, mehrabi s, moslemi mk. percutaneous nephrolithotomy complications in 671 consecutive patients: a single-center experience. urol j. 2011;8:271-6. 13. el-nahas ar, eraky i, shokeir aa, et al. factors affecting stone-free rate and complications of percutaneous nephrolithotomy for treatment of staghorn stone. urology. 2012;79:1236-41. 14. sampaio fjr. how to place a nephrostomy safely. contemp urol. 1994;6:41-6. 15. kukreja r, desai m, patel s, bapat s, desai m. factors affecting blood loss during percutaneous nephrolithotomy: prospective study. j endourol. 2004;18:715-22. 16. stoller ml, wolf js jr., st lezin ma. estimated blood loss and transfusion rates associated with percutaneous nephrolithotomy. j urol. 1994;152:1977-81. 17. el-nahas ar, shokeir aa, el-assmy am, et al. post-percutaneous nephrolithotomy extensive hemorrhage: a study of risk factors. j urol. 2007;177:576-9. 18. turna b, nazli o, demiryoguran s, mamadov r, cal c. percutaneous nephrolithotomy: variables that influence hemorrhage. urology. 2007;69:603-7. 19. akman t, binbay m, sari e, et al. factors affecting bleeding during percutaneous nephrolithotomy: single surgeon experience. j endourol. 2011;25:327-33. 20. janetschek g and kunzel kh. percutaneous nephrolithotomy in horseshoe kidneys. br j urol. 1988;62:117-22. 21. darabi mahboub mr, zolfaghari m, ahanian a. percutaneous nephrolithotomy of kidney calculi in horseshoe kidney. urol j. 2007;4:147-50. 22. el ghoneimy mn, kodera as, emran am, orban tz, shaban am, el gammal mm. percutaneous nephrolithotomy in horseshoe kidneys: is rigid nephroscopy sufficient tool for complete clearance? a case series study. bmc urol. 2009;16;9:17. 23. allen d, o’brien t, tiptaft r, glass j. defining the learning curve for percutaneous nephrolithotomy. j endourol. 2005;19:27982. factors influencing complications of pnl-oner et al. vol 12 no 05 september-october 2015 2323 sexual dysfunction and infertility comparison between microsurgical subinguinal varicocelectomy with and without testicular delivery for infertile men: is testicular delivery an unnecessary procedure? yi hou, ying zhang, yun zhang, wei huo, hai li* purpose: controversy still exists as to whether testicular delivery during microsurgical subinguinal varicocelectomy (msv) provides benefit to the patient or not. this study specifically compared the therapeutic effect of msv with and without testicular delivery for the treatment of varicocele in a cohort of infertile men. materials and methods: we conducted a prospective, randomized, controlled study to evaluate the therapeutic efficacy of msv with and without testicular delivery for the treatment of varicocele in infertile men. a total of 100 patients were specifically recruited using strict inclusion criteria to undergo msv with testicular delivery (group1, n = 50) or msv without testicular delivery (group 2, n = 50). all patients were followed-up at 3, 6 and 12 months following surgery. semen parameters, pregnancy and recurrence rates, and complications were monitored. results: mean surgical time for group 1 was significantly longer than group 2 (90.50 ± 15.60 min vs. 84.30 ± 15.58 min; p = .001). sperm count and motility were significantly improved at the 12-month follow-up appointment in both groups compared with pre-operative values, but were not significantly different at 3, 6, and 12 months when compared between the two treatment groups. the incidence of scrotal edema, and spermatic/testicular engorgement were higher in group 1 (both p = .001), although natural pregnancy rate was not significantly different between the two groups at the 12 month follow-up appointment (46% vs. 42%) (p = .817). conclusion: msv with testicular delivery did not reduce the risk of recurrence and led to improved semen quality compared with msv without testicular delivery. however, there was a higher risk of complication with this technique, which must be borne in mind when considering the clinical implications of our dataset. keywords: microsurgery; recurrence; treatment failure; varicocele; surgery; young adult; semen analysis; treatment outcome. introduction the negative impact of varicocele upon spermato-genesis has been recognized for some time and manifests in 21%-41% of men presenting with primary infertility, and 75%-81% of men diagnosed with secondary infertility.(1,2) when untreated, this condition can lead to impaired spermatogenesis, poor leydig cell function, and lead to reductions in testicular volume. (3) compared to non-microscopic surgery, msv permits clinicians to specifically identify the testicular artery and associated lymphatic system, thus minimizing the potential risk of arterial injury while also reducing the chances of complication and post-operative recurrence. (4) the recurrence of varicocele is a major concern for urologists, and some studies report that the predominant factor underlying this problem are the gubernacular veins.(5,6) testicular delivery during surgery allows the gubernacular veins to be ligated, which is likely to reduce the incidence of varicocele recurrence. however, this practice remains a controversial issue. whether msv with testicular delivery is a superior technique to that without testicular delivery is still unclear. to our best knowledge, only one study has directly compared these two methods in the published literature, and concluded that testicular delivery does not offer any beneficial effect.(7) however, this earlier study is s retrospective analysis without a randomized controlled study (rct) design, and is therefore very limited in terms of evidence-based medical science. up until now, there has been no rct carried out in order to specifically compare the therapeutic outcome of the two types of microscopic varicocelectomy. in the present study, we prospectively evaluated and compared sperm count, motility, pregnancy and recurrence rates, and complication rates of msv with and without testicular delivery in a cohort of infertile men using an rct design. materials and methods study participants this prospective rct was carried out in the china and japan union hospital (changchun, china), with appropriate institutional ethical approval. we enrolled a total of 100 infertile male patients diagnosed with varicocele who sought treatment in our center from april 2011 to august 2012. according to the date of hospital admission, patients were randomly divided into two groups: group 1 (msv with testicular delivery, n = 50) department of urology, china and japan union hospital of jilin university, 126 xiantai street, changchun city, jilin province, china. *correspondence: department of urology, china and japan union hospital of jilin university, 126 xiantai street, changchun city, jilin province, china. tel: +88 604 3189876981. fax: +88 604 3189876971. e-mail: muandkamu_2012@ aliyun.com. received july 2015 & accepted august 2015 sexual dysfunction and infertility 2261 and group 2 (msv without testicular delivery, n = 50). allocation of patients into the two treatment groups was carried out according to the date of admission; if the date was an odd number, then the patients were allocated to group 1, otherwise patients were allocated to group 2. evaluations patient age and history of infertility was recorded, and semen was analyzed twice after 3-5 days of abstinence, at a minimum of 15-day intervals, in accordance with the latest world health organization (who) guidelines for human semen analysis. the mean value of these 2 tests showed at least 1 abnormal parameter and serum follicle stimulating hormone (fsh), testosterone (t), and prolactin (prl) were also measured prior to operation. physical examination and color doppler ultrasound were used to diagnose varicocele. the degree of varicocele was defined according to the established dubine and amelar’s classification.(8) testicular volume was also measured ultrasonographically using the formula: 0.71 × length × width × height. patients were selected for the rct according to the following criteria: 1) if the diameter of the internal spermatic vein was greater than 3mm and/or presence of venous reflux without valsalva maneuver; 2) if there was no history of urogenital abnormality or infection, trauma or surgery; 3) if sperm count was abnormal (< 20 × 106/ml) and/or motility was poor (< 50%); 4) if there was a negative mixed agglutination reaction for immunoglobulin (ig) g and iga; 5) if fsh level was normal; or 6) if gynecological assessment of the spouse was normal. any patients who did not complete the follow-up period were excluded from the study. the study protocol, and the potential table 1. demographic and clinical characteristics of patients in each treatment group. variables group 1 (n = 50) group 2 (n = 50) p value age, years 27.94 ± 3.46 28.32 ± 3.89 .59 age of spouse, years 26.12 ± 3.14 25.82 ± 2.27 .57 grade of varicocele, no. i 6 7 .77 ii 13 10 .48 iii 31 33 .68 serum hormone levels t (ng/ml) 6.24 ± 2.25 6.74 ± 2.17 .23 fsh (iu/l) 5.25 ± 0.94 5.08 ± 0.86 .39 prl (miu/l) 197.80 ± 65.93 202.43 ± 56.612 .67 laterality, no. (%) left 36/50 (72) 35/50 (70) .83 bilateral 14/50 (28) 15/50 (30) .83 abbreviations: t, testosterone; fsh, follicle stimulating hormone, prl, prolactin. group 1 = microsurgical subinguinal varicocelectomy with testicular delivery; group 2 = microsurgical subinguinal varicocelectomy without testicular delivery. group 1 = microsurgical subinguinal varicocelectomy with testicular delivery; group 2 = microsurgical subinguinal varicocelectomy without testicular delivery. variables group 1 (n = 50) group 2 (n = 50) p value operation time (min) 90.50 ± 15.60 84.30 ± 15.58 .001 postoperative hospital stay (day) 2.04 ± 0.49 2.01 ± 0.14 .77 complications, no. (%) hydrocele 0 0 ---- recurrence 0 0 ---- scrotal edema 24/50 (48.0) 7/50 (14.0) .001 wound infection 1/50 (0.2) 3/50 (0.6) .31 spermatic engorgement 22/50 (44.0) 6/50 (12.0) .001 testicular engorgement 14/50 (28.0) 4/50 (8.0) .001 orchitis and epididymitis 1/50 (2.0) 0 ---- testicular hardness 1/50 (2.0) 0 ----table 2. operative data and post-operative complications in the two treatment groups. vol 12 no 04 july-august 2015 2262 microsurgical subinguinal varicocelectomy with and without testicular delivery-hou et al. complications were explained to each patient in detail and all patients provided written informed consent prior to surgery. to ensure that the study was robust and consistent, all surgical procedures were performed by the same surgeon and all ultrasound tests were performed by the same sonographer using the same instrument. this ensured consistency and therefore added rigor to the experimental design and analysis. a flow chart depicting this process is given in figure 1. given that this was a single-blinded rct, only the patient group needed to be blinded. operative technique msv with testicular delivery surgery was conducted under spinal or general anesthesia and began with a 2 cm traverse incision being made in the skin over the external inguinal ring in order to approach the spermatic cord. following deepening of the incision, a babcock clamp was used to grasp and deliver the spermatic cord, along with the testis, directly onto a rubber tissue. surgical steps were carried out using a surgical microscope at 8×-15× magnification, focused upon the field of operation. external spermatic veins, and the gubernacular, trans-scrotal and collateral veins were ligated and divided following exposure. once the spermatic fascia had been opened, we separated, ligated and divided the internal spermatic veins either with or without the assistance of color doppler ultrasound. the isolated artery (or arteries) and associated lymphatic system were preserved. msv without testicular delivery this procedure was similar to the one described above (msv with testicular delivery), with the exception that, here, the testis was not delivered, and the gubernacular, trans-scrotal, and collateral veins, were not ligated. the lengths of time taken for surgery, and the length of hospital stay following the operation, were recorded, as was the incidence of complications. given that all of our patients received either spinal or general anesthesia, there was an absolute requirement for a 1-2 day post-operative stay in hospital. operative times were determined for unilateral varicocele. if patients exhibited bilateral varicocele, then operative time was designated as one and half times that allocated for unilateral surgery. patients were followed up, and examined physically and with ultrasound, at 3, 6 and 12 months postoperative periods. semen parameters were evaluated by semen analysis, and pregnancy rate was determined following the 12 months follow-up appointment. persistence or recurrence of varicocele was determined by the valsalva maneuver. testicular atrophy is defined as when there is a 20%, or greater, differential in volume between the two testicles.(9) statistical analysis statistical analysis was performed on the basis of ‘intention to treat’. all data are described herein as mean ± standard deviation (sd), and were analyzed using statable 3. comparison of sperm count and motility between preoperative and one year follow-up in study groups. variables preoperative one year follow-up p value group 1 (n = 50) motility 25.14 ± 10.38 39.34 ± 14.23 .001 count 20.46 ± 5.79 27.99 ± 8.90 .001 group 2 (n = 50) motility 24.20 ± 9.91 40.59 ± 13.05 .001 count 21.36 ± 6.48 29.54 ± 10.99 .001 group 1 = microsurgical subinguinal varicocelectomy with testicular delivery; group 2 = microsurgical subinguinal varicocelectomy without testicular delivery. group 1 = microsurgical subinguinal varicocelectomy with testicular delivery; group 2 = microsurgical subinguinal varicocelectomy without testicular delivery. variables group 1 (n = 50) group 2 (n = 50) p value sperm count (×106/ml) preoperative 20.46 ± 5.79 21.36 ± 6.48 .39 3 months 23.5 ± 4.49 24.8 ± 5.88 .18 6 months 28.34 ± 9.48 26.91 ± 8.79 .27 12 months 27.99 ± 8.90 29.54 ± 10.99 .14 sperm motility (%) preoperative 25.14 ± 10.39 24. 20 ± 9.91 .58 3 months 31.99 ± 12.62 30.86 ± 11.85 .64 6 months 38.172 ± 13.55 37.21 ± 12.44 .69 12 months 39.34 ± 14.23 40.59 ± 13.05 .63 spontaneous pregnancy, no. (%) 21/50 (42.1) 24/50 (44.7) .817 table 4. postoperative semen quality and pregnancy outcome in the two study groups. sexual dysfunction and infertility 2263 microsurgical subinguinal varicocelectomy with and without testicular delivery-hou et al. tistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. raw data was tested for normality prior to analysis. given that our data were normally distributed, they were subsequently compared using the unpaired student’s t-test or χ2 test as appropriate. differences in which p < .05 were considered statistically significant. results all 100 of our recruited patients completed the trial to the 12 months follow up, and therefore none were excluded. no significant differences were detected between the two treatment groups in terms of mean patient’s age, age of spouse, laterality, grade of varicocele, or pre-operative hormonal levels (fsh, t and prl) (table 1). mean operation time for group1 (with testicular delivery) was significantly longer than that of group 2 (90.50 ± 15.60 min vs. 84.30 ± 15.58 min, p < .001; table 2). no significant differences were detected between the two groups in terms of post-operative hospital stay (2.04 ± 0.49 days vs. 2.01 ± 0.14 days) (p > .05; table 2). compared to pre-operative values, sperm count and motility were significantly increased in both groups when measured at the 12 months follow-up appointment (p < .001; table 3). interestingly, sperm count and sperm motility were not significantly different between the two groups when measured at the 3, 6, and 12 months follow-up appointments (p > .05; table 4). natural pregnancy rate was not significantly different between the two groups when calculated at the 12 months follow-up appointment: 21/50 (42%) in group1 and 23/50 (46%) in group 2 (p > .05). compared with group 1, a higher complication rate was observed in group 2 (table 2), including the incidence of scrotal edema (24/50 vs. 7/50), spermatic cord edema (22/50 vs. 6/50), and testicular engorgement (14/50 vs. 4/50). one case of epididymitis, and one case of testicular hardness, were observed in group 1. there was no recorded recurrence of varicocele, or hydrocele, in either of the two groups. discussion over recent years, several studies have recommended msv as the standard method for treating varicocele in infertile men.(10,11) evidence for the use of msv in such patients includes lower recurrence and hydrocele rates, better improvement of spermatogenesis and higher spontaneous pregnancy rates.(11,12) using this technique, it is possible to additionally ligate the gubernacular, trans-scrotal, and collateral veins, a practice believed to reduce the incidence of varicocele recurrence.(5,6) however, there appears to be confusion over whether msv should involve testicular delivery or not, and this, therefore, remains a controversial issue. it is not yet clear whether msv with testicular delivery is a superior technique to that without testicular delivery. thus far, only one study has directly compared these two methods, and concluded that testicular delivery does not appear to offer any beneficial effect.(7) however, this earlier study is a retrospective study without a rct design, and is therefore limited in terms of evidence-based fact. the present study was carried out to represent the first rct, to specifically compare therapeutic outcome of the two different types of microscopic varicocelectomy. in the present study, we found no statistically significant difference in terms of varicocele reoccurrence when compared between patients receiving msv with or without testicular delivery. this was in line with the data reported earlier by ramasamy and schlegel, who also observed equivalent post-operative outcomes with and without testicular delivery.(7) interestingly, an earlier study, involving venography, reported that recurrence can be caused by the parallel, gubernacular, and trans-scrotal veins.(13) however, several studies involving msv have reported a very low recurrence rate (0-2%) in patients where the veins thought to underlie recurrence were not ligated.(14,15) indirectly, such studies demonstrated that testicular delivery might not be of use in helping to reduce the recurrence rate of varicocele following microsurgical varicocelectomy. although there was no difference in the recurrence rate of varicocele between the treatment groups in the present study, the complication rate in group 1 (with testicular delivery) was significantly higher than that for group 2 (without testicular delivery). scrotal edema and testicular engorgement were observed in two patients from group 1. while these complications are highly likely to disappear gradually over a 2 months period following the operation, these complications would worry the patients and cause discomfort. ramasamy and schlegel(7) have previously stated that inflammatory changes in the scrotum are associated with the increased trauma and surgical time involved with testicular delivery. the precise mechanism(s) underlying the testicular engorgement observed in the present study remain unknown at this time. however, since the main difference between the two techniques used in the present study was that the gubernacular, trans-scrotal, and collateral veins were ligated during msv with testicular delivery in one group, but not in the other group, strongly suggests that obstruction of blood drainage contributed to profuse small vein ligation, and thus represent the main pathological reason for testicular engorgement. one of our cases was particularly interesting; testicular hardness was found by palpation following engorgement but had disappeared by the time of the first follow up. subsequent color doppler ultrasound revealed normal blood flow in the testis but no improvement in sperm paramevol 12 no 04 july-august 2015 2264 microsurgical subinguinal varicocelectomy with and without testicular delivery-hou et al. ters by the end of the follow up period. the underlying cause for this observation could not be determined as the patient refused to undergo testicular biopsy. fibrosis of the testicular tissues secondary to engorgement is therefore our best assumption at this time. our study, therefore indicates that excessive ligation of veins is not necessary, and supports the earlier observations of will and colleagues(16) who claimed that some veins must be preserved so as to allow drainage of blood from the testis and thus prevent vascular engorgement. preservation of the testicular artery and associated lymphatic system is another vital advantage of microscopic varicocelectomy, although some urologists believe that it is impossible to ligate the internal spermatic artery without inducing testicular atrophy.(17) however, abul-fotouh and colleagues(12) reported a 2.5% incidence rate of atrophy using non-microsurgical methods. penn and colleagues(17) further reported an incidence of 14% when the testicular artery was purposefully ligated during renal transplantation. animal studies have also reported detrimental effects upon ipsilateral testicular blood flow and morphology following ligation of the spermatic artery.(18,19) collectively, these results indicate that preservation of the testicular arteries plays an important role in preventing irreversible morbidity and improving spermatogenesis. hydrocele formation, however, is caused by ligation of the lymphatic system, a hypothesis that was proven by the fact that protein concentration of the hydrocele fluid was consistent with that of the lymphatic fluid.(20) in the present study, we successfully preserved the lymphatic system, and at least one testicular artery, in all of our patients irrespective of treatment grouping, and did not observe testicular atrophy or post-operative hydrocele. in summary, varicocelectomy leads to an improvement in key sperm parameters (sperm count, total and progressive motility), and reduces sperm dna damage and seminal oxidative stress, while improving leydig cell function and serum t levels.(21-23) while the msv technique is advocated as the most effective treatment for varicocele in infertile men,(6,24) there has been some confusion over whether msv should be carried out with or without testicular delivery. the present study represented the first rct to address this controversial issue and concluded that msv with testicular delivery confers no additional benefit to the patient than if the procedure was carried out without testicular delivery. we further found that sperm count and motility were significantly increased at post-operative follow up in both treatment groups compared to pre-operative values, although there was no significant difference between the two groups. there was no difference between the two groups in terms of spontaneous pregnancy rate, but complications were more likely in the group undergoing testicular delivery. future research should expand these initial data by examining a larger cohort of patients over a longer follow-up period. in our current rct all operations were performed by the same surgeon and all ultrasound tests were performed by the same sonographer using the same instrument. the purpose behind this strategy was to enhance consistency and increase the rigor of our experimental design and thus, analysis. however, it is conceivable that there may have been some potential bias, especially given our small sample size and short follow-up period. together, these factors represent the main limitations of our study, and should be considered when interpreting the clinical implications of our data. conclusions in conclusion, msv with testicular delivery did not provide additional benefit to reducing the risk of reoccurrence, or to the improvement of semen quality, compared with msv without testicular delivery. indeed, msv carried out with testicular delivery was appears to carry greater risk of complication. conflict of interest none declared. references 1. saypol dc. varicocele. j androl. 1981;2:6171. 2 . g o r e l i c k j i , g o l d s t e i n m . l o s s o f fertility in men with varicocele. fertil steril.1993;59:613-6. 3. kaneko t, sasaki s, yanai y, umemoto y, kohri k. effect of microsurgical repair of the varicocele on testicular function in adolescence and adulthood. int j urol. 2007;14:1080-3. 4. ding h, tian j, du w, zhang l, wang h, wang z. open non-microsurgical, laparoscopic or open microsurgical varicocelectomy for male infertility: a meta-analysis of randomized controlled trials. bju int. 2012;110:1536-42. 5. nourparvar p, herrel l, hsiao w. microsurgical subinguinal varicocelectomy with testicular delivery. fertil steril. 2013;100:e42. 6. chalouhy e, kassardjian z, merhej s, et al. microsurgical high inguinal varicocelectomy with delivery of the testis. j med liban. 1994;42:105-8. 7. ramasamy r, schlegel pn. microsurgical inguinal varicocelectomy with and without testicular delivery. urology. 2006;68:1323-6. 8. dubin l, amelar rd. varicocelectomy as therapy in male infertility. a study of 504 cases. j urol. 1975;113:640-1. 9. vanderbrink ba, palmer ls, gitlin j, levitt sb, franco i. lymphatic-sparing laparoscopic varicocelectomy versus microscopic varicocelectomy: is there a difference? urology. 2007;70:1207-10. 10. al-kandari am, shabaan h, ibrahim hm,elshebiny yh, shokeir aa. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology. 2007;69:417-20. 11. watanabe m, nagai a, kusumi n, tsuboi h, nasu y, kumon h. minimal invasiveness and effectivity of subinguinal microscopic varicocelectomy: a comparative study with retroperitoneal high and laparoscopic sexual dysfunction and infertility 2265 microsurgical subinguinal varicocelectomy with and without testicular delivery-hou et al. approaches. int j urol. 2005;12:892-8. 12. abul-fotouh, abdel-maguid, ibrahim othman. microsurgical and nonmagnified subinguinal varicocelectomy for infertile men: a comparative study. fertil steril. 2010;94:2600-3. 13. murray rr jr, mitchell se, kadir s, et al. comparison of recurrent varicocele anatomy following surgery and percutaneous balloon occlusion. j urol. 1986;135:286-9. 14. orhan i, onur r, semerciöz a, et al. comparison of two different microsurgical methods in the treatment of varicocele. arch androl. 2005;51:213-20. 15. cayan s, kadioglu tc, tefekli a, kadioglu a, tellaloglu s. comparison of results and complications of high ligation surgery and microsurgical high inguinal varicocelectomy in the treatment of varicocele. urology. 2000;55:750-4. 16. will ma, swain j, fode m, sonksen j, christman gm, ohl d. the great debate: varicocele treatment and impact on fertility. fertil steril. 2011;95:841-52. 17. penn i, mackie g, halgrimson cg, starzl te. testicular complications following renal transplantation. ann surg. 1972;176:697-9. 18. yilmaz, omer, genc, et al. long-term effect of pentoxifylline and ng-nitro-l-arginine methyl ester on testicular function in spermatic artery ligation. scand j urol nephrol. 2006;40:12-6. 19. guler f, bingol-kologlu m, yagmurlu a, et al. the effects of local and sustained release of fibroblast growth factor on testicular blood flow and morphology in spermatic artery--and vein-ligated rats. j pediatr surg. 2004;39:70916. 20. szabo r, kessler r. hydrocele following internal spermatic vein ligation: a retrospective study and review of the literature. j urol. 1984;132:924-5. 21. agarwal a, deepinder f, cocuzza m, et al. efficacy of varicocelectomy in improving semen parameters: new meta-analytic approach. urology. 2007;70:532-8. 22. baazeem a, belzile e, ciampi a, et al. varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. eur urol. 2011;796-808. 23. zhang m, du l, liu z, qi h, chu q. the effects of varicocelectomy on testicular arterial blood flow: laparoscopic surgery versus microsurgery. urol j. 2014;11:1900-6. 24. ghanem h1, anis t, el-nashar a, shamloul r. subinguinal microvaricocelectomy versus retroperitoneal varicocelectomy: comparative study of complications and surgical outcome. urology. 2004;64:1005-9. vol 12 no 04 july-august 2015 2266 microsurgical subinguinal varicocelectomy with and without testicular delivery-hou et al. urology journal unrc/iua vol. 1, no. 4, 286-287 autumn 2004 printed in iran 286 news iranian award winner for the best laparoscopic paper at the world congress on endourology 2004 "the effect of warm ischemia duration on graft outcome in laparoscopic and open donor nephrectomy" was the title of a paper rewarded with the olympus prize for the best laparoscopic paper at the occasion of the wce 2004 in mumbai, india. the twenty-second world congress on endourology was held in november 2004 and 70 researchers from iran had papers or videos to present in the meeting. twelve papers were from urology/nephrology research center and among which, there was a randomized clinical trial by drs. nasser simforoosh, abbas basiri, amir mohsen ziaee, ali tabibi, and nasser shakhssalim that won the first prize of the congress. professor nasser simforoosh, a distinguished urologist renowned for introducing laparoscopic donor nephrectomy in the region, specialized in urology at mt. sinai medical center, chicago, usa in 1981. immediately after finishing his studies in the us, he came back to iran and found the urology department (1981) and then kidney transplant department (1982) at shaheed labbafinejad medical center, tehran. he and his colleagues started the first planned living-unrelated donor transplantation in 1984 and subsequently now, iran has the largest experience of livingunrelated donor kidney transplantation, with superior results to cadaveric transplantation and comparable survival rates with living-related transplantation. thanks to their pioneering attempts in 2000, shaheed labbafinejad center came first in performing laparoscopic donor nephrectomy in the middle east, now enjoying the record of 2300 transplantations and over 400 laparoscopic donor nephrectomies. one of the interesting points in their exclusive modified technique is the highly cost-effectiveness of the procedure that can be advocated in developing countries; they could save $600 in each nephrectomy by the use of medium-large clips instead of endo gia and extracting the kidney via a suprapubic approach using hand instead of endo-catch bag. as one of the most active transplant centers in the country, their department has conducted a vast educational program of kidney transplant and laparoscopic donor nephrectomy, through which the transplant team has expanded its experience all over iran. this has led to over 17000 kidney transplantations being performed in 25 centers in iran, at least 5 of those using laparoscopic approach. professor simforoosh has presented more than 80 papers at international meetings, 20 of which published in reputable journals worldwide. he was also elected as iran's professor of the year in 1998. this “gentleman with a gentle manner” (as described in the wce daily newsletter) who is stepping into the 7th decade of his life, is at the moment the active leader of an outstanding kidney transplant team “heading a very busy urology department at shaheed beheshti university in iran”. iranian award winner at wce 2004 287 a unique study comparison of the outcomes of kidney allografts from laparoscopic donor nephrectomy with those from open donor nephrectomy has been reported in many studies, but a unique one has been carried out by professor simforoosh and coworkers; a randomized clinical trial was set up after gaining experience from 90 cases of laparoscopic donor nephrectomies, and included 100 cases of laparoscopic donor nephrectomies and 100 of open donor nephrectomies performed between july 2001 and september 2003. they showed that serum creatinine levels and graft survival rate in the two groups were not different (comparison of laparoscopic and open donor nephrectomy: a randomized controlled trial, simforoosh n, et al. bju int. in press). warm ischemic time is longer in laparoscopic donor nephrectomy, but they believe that it does not impact the outcome. accordingly, a part of the randomized clinical trial was to focus on warm ischemic time. the results were discussed in a paper presented in wce 2004, which won the award of best presentation. the abstract of this paper is as follows: the effect of warm ischemia duration on graft outcome in laparoscopic and open donor nephrectomy simforoosh n, basiri a, ziaee sam, tabibi a, shakhssalim n urology/nephrology research center, iran introduction: to assess the impact of warm ischemia duration on graft outcome (delayed graft function [dgf], graft loss, and graft function) in laparoscopic and open donor nephrectomy (odn). method: a hundred kidney donors undergoing laparoscopic donor nephrectomy (ldn) were compared with an equal number of open donor nephrectomy cases, in the first reported randomized controlled trial. graft outcome was compared between the 2 groups. also, we divided the laparoscopically harvested kidneys into 3 groups according to their warm ischemia times (group a: 4-6 minutes, group b: 6.1-10 minutes and group c:>10 minutes) to compare graft outcome between these three groups. result: mean follow-up in ldn and odn groups was similar (406.1 versus 403.8 days, p = 0.9). although mean kidney warm ischemia time in ldn was significantly longer than in odn (8.7 versus 1.87 minutes, p = 0.00), the graft outcome was similar in the two groups. long-term graft survival in the laparoscopic and open groups was 93.8% and 92.7%, respectively (p = 0.7). also, graft outcome (dgf, graft loss and mean serum creatinine) was not significantly different between the 3 groups in the ldn cases. conclusion: different levels of warm ischemia time in ldn were not associated with an adverse outcome in kidney transplantation. consequently, it is not reasonable to rush to decrease warm ischemia time at the expense of jeopardizing kidney donors during ldn. urol_v3_no2_001_editorial.qxd case report intravesical explosion during endoscopic transurethral resection of prostate mohammadali mohammadzadeh rezaee* department of urology, ghaem hospital, mashhad, iran key words: benign prostatic hyperplasia, bladder explosion, intra-operative complications 109 urology journal unrc/iua vol. 3, no. 2, 109-110 spring 2006 printed in iran introduction transurethral resection of prostate (turp) and bladder tumors is one of the most common surgeries in urology.(1) this approach is frequently being performed in most medical centers in iran. several intra-operative and postoperative complications of these surgeries have been reported in literature; but, one of the most uncommon complications of this technique is intravesical explosion during the surgery. few cases of this complication have been reported.(1-3) we report 3 cases of intravesical explosion during turp in patients with benign prostatic hyperplasia (bph) and discuss its mechanism and the possible preventive measures. case report during our 15-year surgery experience, we had 3 cases of intravesical explosion in 3 patients with bph who underwent tur. the type of anesthesia was spinal and the bladder washing liquid was sterile distilled water. the cautery device used for these operations was a martin me 400 surgical unit (gebruder martin, tuttlingen, germany) and the coagulation and cutting powers were 60 w and 70 w, respectively. the resectoscope sheet used was 24 f with intermittent irrigation. in all cases, the explosion occurred at the end of the operation while anterior lobe resection was being performed at 12 o'clock position. the noise of the explosion was heard and its vibration was sensed in the suprapubic area. in 2 patients, the explosion was not accompanied by any significant complications, but in 1, the bladder was ruptured in the dome region. after the explosion, the returned amount of washing liquid decreased. on cystoscopy, a rupture was noted in the bladder dome, from which the intestinal loops were seen. the patient was secured in a position suitable for achieving a median suprapubic incision. on laparotomy, we noticed a 3to 4-cm rupture in the bladder dome. the remained liquid was immediately evacuated and the rupture was repaired in 2 layers. a urethral catheter was inserted, and after 1 week, the patient was discharged without any complications. discussion intravesical explosion is an extremely rare complication during endoscopic prostate and bladder surgeries. a case of pelvic explosion during endoscopic pelvic tumor resection has been reported in 1991.(4) explosion is more prevalent during turp than transurethral resection of pelvic and bladder tumors, because turp is being preformed more frequently.(3) a mild explosion in the bladder generally does not cause complications; but, if it is severe, bladder rupture may occur, leading to severe complications especially when the surgeon does not notice the rupture and the treatment is delayed. the explosion is caused by the explosive gases, mainly oxygen and hydrogen, which are formed during the procedure. about 30% and 3% of the released gases in bladder are h2 and o2, respectively.(5) a flammable mixture of these received september 2005 accepted february 2006 *corresponding author: department of urology, ghaem hospital, mashhad, iran. tel: +98 915 111 6023, e-mail: m-rezaee@mums.ac.ir intra-operative intravesical explosion gases and the air introduced into the bladder during turp explode when resectoscope loop contacts the gases.(5) the accumulated hydrogen, itself, does not cause explosion, but when mixed with oxygen, becomes flammable.(4) these mechanisms have been demonstrated through in vitro studies.(2) intracellular fluid electrolysis results in the release of the explosive gases during cutting and resection of the organs due to the high temperature of resectoscope. the more is the temperature of the resectoscope, the more is the gas accumulation.(5,6) all the 3 cases of intravesical explosion occurred during the first 4 years of our experience. thereafter, we considered some technical points which were anticipated to reduce the risk of explosion and subsequently, did not encounter this complication. thus, to prevent intravesical explosion, we recommend the following measures: avoiding a high-temperature cautery during turp; decreasing the mean time of tissue resection; using continuous irrigation sheets (because with intermittent sheet, some air enters the bladder during its evacuation that causes explosion); and evacuating the air in the bladder using suprapubic catheter or suprapubic pressure during bladder dome tumor fulguration or during prostate anterior lobe resection (at 12 o'clock position). gas enters the bladder, especially after tissue resection using an ellik evacuator. references 1. ning tc jr, atkins dm, murphy rc. bladder explosions during transurethral surgery. j urol. 1975;114:536-9. 2. hansen ri, iversen p. bladder explosion during uninterrupted transurethral resection of the prostate. a case report and an experimental model. scand j urol nephrol. 1979;13:211-2. 3. horger dc, babanoury a. intravesical explosion during transurethral resection of bladder tumors. j urol. 2004;172:1813. 4. andrews pe, segura jw. renal pelvic explosion during conservative management of upper tract urothelial cancer. j urol. 1991;146:407-8. 5. davis tr. the composition and origin of the gas produced during urological endoscopic resections. br j urol. 1983;55:294-7. 6. blandy jp, notley rj. transurethral resection. 4th ed. oxford: isis medical media; 1998. p. 148. 110 urology journal unrc/iua vol. 2, no. 1, 20-22 winter 2005 printed in iran 20 pediatric urology gil-vernet antireflux surgery in treatment of lower pole reflux fahimeh kazemi-rashed*, nasser simforoosh urology-nephrology research center, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: prevalence of ureter and kidney duplication is roughly 1 per 125 people, and is associated with vesicoureteral reflux to lower pole in about 45% of cases. from antireflux surgical principles viewpoint, standard antireflux surgeries can be performed in these kidneys without releasing ureters from each other. we studied the results of gil-vernet antireflux surgery in 12 patients with duplicated collecting system and lower pole reflux. materials and methods: between 1996 and 2000, 12 patients with unilateral duplicated system underwent gil-vernet antireflux surgery. there were 8 (67%) females and 4 (33%) males with a median age of 5.6 years. of the patients, 50% had unilateral lower pole reflux in duplex system and 50% had bilateral reflux. results: twelve patients with lower pole reflux in duplicated system, and overall, 18 refluxing renal units were treated, using gil-vernet antireflux surgery. in 11 (92%) patients, upper pole orifices were non-refluxing and without ureterocele. one (8%) patient had upper pole ureterocele that was treated by a small medial incision in the same session. median hospital stay was 4 days, and median follow-up was 10 months, in 10 patients who were followed. of patients, 80% and of refluxing units, 94% improved. overall, success rate was 88%. conclusion: gil-vernet antireflux surgery is a simple technique, associating with minimum ureteral manipulation for releasing them. accordingly, we recommend gilvernet antireflux surgery as the first line surgical modality for duplicated ureters with lower pole reflux, without upper pole ureterocele. key words: duplicated ureter, vesicoureteral reflux, antireflux surgery introduction duplication anomalies are seen in 1 per 125 people. the prevalence is twice as high in female gender. unilateral duplication is six times as prevalent as bilateral duplication, and right and left side involvement are nearly equal.(1) genetically, it is transmitted as an autosomal dominant disorder with incomplete penetrance. according to few reports, environmental factors are considered to be implicated in its development. the position of ureteral orifices in duplicated ureters is usually inverse, in proportion to collecting system; the orifice of lower pole has a cranial and lateral position, and the orifice of upper pole is located in a caudal and medial position. this is nominated as weigert-mayer rule and applicable for nearly all cases of duplicated ureter.(2) due to cranial and lateral position of lower pole ureteral orifice, lower pole reflux is a common finding in duplicated systems and is seen in 45% of cases. on the other hand, about 10% of antireflux received september 2003 accepted january 2005 *corresponding author: urology department, imam khomeini hospital, tabriz, iran. tel: ++98 411 335 7328, e-mail: fah_kaz@yahoo.com kazemi-rashed and simforoosh 21 surgeries are performed in duplicated systems. duplicated ureters have common blood supply. in consequence, avoiding extensive separation of ureters from each other, all antireflux surgical methods can be used in these patients. as less manipulation of ureters and minimizing tissue ischemia increase surgical success rate, it seems that gil-vernet is an appropriate antireflux technique in this type of reflux. we report the results of gil-vernet antireflux surgery in 12 cases of duplicated collecting system with lower pole reflux. materials and methods between 1996 and 2000, 12 patients with unilateral duplicated system and lower pole reflux, underwent gil-vernet antireflux surgery. median patient age at time of surgery in 11 patients was 5.6 years (range 1 to 12). one patient was 26 years old. of patients,8 (7%) were female and 4 (33%) were male. nine (75%) patients presented with urinary tract infection (uti), fever and chills; one had uti without fever; and in the two remainders, uti was proved in screening tests. four (33%) patients complained of bladder dysfunction symptoms in the form of frequency and enuresis. all of the patients had unilateral duplicated systems and all had lower pole reflux. six (50%) patients had only reflux into lower pole ureter, but the other 6 (50%) patients had bilateral reflux (lower pole reflux with reflux in the normal contra-lateral ureter). one patient had upper pole ureterocele that was detected during surgery. gil-vernet antireflux surgery was performed in all the patients and data of postoperative outcomes, including primary improvement, hospital stay, complications, and follow-up records, were collected and assessed. minimum grade of reflux was ii, though it was associated with a contra-lateral grade iii or iv reflux. of 18 refluxing units, 15 (83%) had grade iii to grade iv reflux and three had grade ii reflux. surgical method a transverse incision was made between lower pole and contralateral ureteral orifices, and ureteral sheaths were released. ureteral sheaths were approximated with 4.0 or 5.0 vicryl suture materials and mucosa was repaired with 4.0 chromic catgut. bladder and abdominal wall were repaired with the conventional method. results all of the patients had complete unilateral ureteral and renal duplication. six (50%) patients had simultaneously contralateral reflux. eleven patients (92%) had non-refluxing upper pole orifice without ureterocele. one (8%) patient had upper pole reflux and ureterocele, which was treated concurrently with a small incision in medial and distal portions of the ureterocele. one of the four patients with frequency and fever had moderate bladder trabeculation. interureteral sutures were made with 4.0 or 5.0 vicryl. median operative time was 64 (range 45 to 90) minutes. five patients underwent surgery without using ureteral stent, urethral catheter, and drain. in six patients, surgery was done without ureteral stent, but with urethral catheter and drain. one patient had cystostomy and drain. median hospital stay was 5 (range 2 to14) days. only one patient was hospitalized for 14 days. ten patients were followed up, 4 with voiding cystourethrography (vcug) and six with radionuclide cystography. they were followed for 4 to 16 months. reflux was improved completely in 8 (80%) patients and 94% of refluxing units. recurrence of reflux was seen in two patients. in one who had undergone ureterocele incision, grade ii upper pole reflux developed. in one patient suspected to have neurogenic bladder, grade iii reflux had been reduced to grade i to ii, which was treated medically. discussion gil-vernet antireflux is a simple and effective surgical technique. primary reflux improvement in non-duplicated kidneys is over 95% in various grades. we have previously reported the results of gil-vernet antireflux surgery in 60 and 100 refluxing units, and also without using ureteral stent, urethral catheter, and drain.(3) in this study, we reported the results of gilvernet antireflux surgery in 12 patients with duplicated ureters within 4 years. of the patients, 10 were followed up, and the improvement rate was over 90%. reflux improved in all of the normal ureters. recurrence or development of reflux was seen only in patients with suspected neurogenic bladder or those with ureterocele incision and gil-vernet antireflux surgery in the same session. generally, patients with lower pole reflux without upper pole ureterocele or neurogenic bladder had the highest rates of gil-vernet antireflux surgery in treatment of lower pole reflux22 improvement. indications for surgery in these patients are similar to those in other patients with reflux, and surgical methods with minimum ureteral manipulation are recommended in these patients. today, even teflon and polydimethylsiloxane injections are also reported for the treatment of lower pole reflux with 80% success rate.(4,5) also, double-ureter reimplantation has been used in these patients with success rates of 94% and 96%.(6,7) in one report of ureteroceles detected intraoperatively, reimplantation of both ureters was successful.(8) in one case, we encountered an unexpected ureterocele, which was treated with incision and gil-vernet antireflux surgery in the same session, but it was complicated with upper pole reflux developement. therefore, gil-vernet antireflux surgery is recommended only in duplicated systems with lower pole reflux and not with upper pole orifice ureterocele. cases of developing bladder stone following gil-vernet antireflux surgery using nylon suture have been reported.(9) we used vicryl suture material, so that we did not encounter bladder stone during the follow-up period. overall, success rate in our study was 94% and taking the one postoperatively developed reflux into account, it was 88%. conclusion for ureteral reimplantation in duplicated ureters, surgical methods with minimum manipulation are recommended. gil-vernet antireflux surgery is a simple technique with minimum ureteral manipulation. we recommend this method as the first choice of surgical intervention for lower pole reflux without upper pole ureterocele in duplicated systems. however, in cases that reflux is associated with neurogenic bladder, the most suitable surgical intervention is a matter of controversy. references 1. schlussel rn, retik ab. ectopic ureter, ureterocele, and other anomalies of the ureter. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.2038. 2. park jm. normal and anomalous development of the urogenital system. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.1749-1750. 3. simforoosh n, karami h. results of 100 cases of gilvernet with absorbable sutures in children. iranian j urology. 2000;25:27-29. 4. viville c. endoscopic treatment of ureterocele and antireflux injection with teflon paste. eur urol. 1990;17:321-4. 5. aboutaleb h, bolduc s, khoury ae, et al. polydimethylsiloxane injection versus open surgery for the treatment of vesicoureteral reflux in complete duplex systems. j urol. 2003;170:1563-5. 6. ellsworth pi, lim dj, walker rd, stevens ps, barraza ma, mesrobian hg. common sheath reimplantation yields excellent results in the treatment of vesicoureteral reflux in duplicated collecting systems. j urol. 1996;155:1407-9. 7. barrieras d, lapointe s, houle h. is common sheath extravesical reimplantation an effective technique to correct reflux in duplicated collecting systems? j urol. 2003;170:1545-7. 8. share jc, lebowitz rl. the unsuspected double collecting system on imaging studies and at cystoscopy. ajr am j roentgenol. 1990;155:561-4. 9. ballesteros jj, guzman a, cortadellas r. urinary infection and stone formation as complications of gilvernet's antireflux procedure. int urol nephrol. 1992;24:613-6. urology journal unrc/iua vol. 2, no. 1, 54-56 winter 2005 printed in iran 54 renal allograft mucormycosis: report of two cases nasser tayyebi meybodi, sakineh amouian*, na'ma mohammadian-roashan department of pathology, emam reza hospital, mashhad university of medical sciences, mashhad, iran key words: mucormycosis, kidney transplant, graft rejection, fungal infection, immunosuppression introduction mucormycosis infection, as a sporadic worldwide infection, is often seen in immunosuppressed patients and those with hematologic malignancies and diabetes mellitus. this opportunistic pathogen, which widely exists in our environment, enters the body via respiratory system, gastrointestinal tract and skin wounds.(2) mucormycosis infection can be isolated or disseminated and may rarely involve kidney alone.(3) rhinocerebral mucomycosis is the most common form and its isolated form rarely involves organs such as lung, gastrointestinal tract, and brain. also disseminated form has been reported in these patients.(1) with respect to the potential role of mucormycosis infection in allograft rejection, it is crucial to consider it as a differential diagnosis in cases with graft rejection, so that prompt treatment can rescue the patient and the kidney allograft. we report two cases of renal mucormycosis infection in kidney recipients, which were both diagnosed by histopathological examinations, following nephrectomy due to rejection. case reports case 1 the patient was a 31-year-old man from mashhad, who was a known case of end-stage renal disease, resulted from bilateral hydronephrosis due to ureteropelvic junction obstruction, and had received cadaveric kidney transplantation in july 2003. two months later, he was admitted with nausea, vomiting, flank pain, dysuria, and terminal hematuria. on physical examination, he had pain in allograft site and tenderness on the incisional line. laboratory tests results were as follows: negative blood culture, hb: 9 mg/dl, white blood cell count: 12 000/µl, neutrophils: 68%, blood urea nitrogen: 25 mg/dl, and plasma creatinine: 5 mg/dl. urinalysis revealed wbc 20 to 25 wbc/hpf and 12 to 20 rbc/hpf. urine culture was negative. further evaluations with ultrasonography and renal scan were indicative of acute rejection. in september 2003, the patient underwent operation. the graft was swollen and had color changes in the lower pole; subsequently, nephrectomy was done. in macroscopic examination, the outer layer of the kidney was congestive and multifocal bleeding was seen on the necrotized incisional surface. in microscopic view, extensive necrosis of kidney with disseminated mucormycosis invasion and obstructive infectious thrombosis, accompanying a large amount of fungal elements in renal artery wall, other small arteries, and the adjacent tissues were seen (fig. 1). the patient was discharged with good general condition. received november 2003 accepted july 2004 *corresponding author: department of pathology, emam reza hospital, mashhad, iran. tel: ++98 511 854 3031, fax: ++98 511 859 3038, e-mail: s_amouian@mums.ac.ir fig. 1. extensive mucormycosis hyphae, without transverse septum, having lateral right angle branch (×100) tayyebi meybodi et al 55 case 2 a 58-year-old woman from sabzevar (current citizen of mashhad), was referred with fever and chills, oliguria, and incisional inflammation, 9 months after kidney transplantation. she had been a known case of polycystic kidney disease and undergone living-unrelated kidney transplantation in october 2002. also, she had been treated for hyperacute rejection in the first post-transplant hours and also for urinary tract infection and acute rejection one month later. laboratory tests results were as follows: negative blood culture, white blood cell count: 13000/µl, neutrophils: 68%, blood urea nitrogen: 28 mg/dl, and plasma creatinine: 5.5 mg/dl. urinalysis showed 20 wbc/hpf and 15 rbc/hpf. urine culture was negative. diagnostic workup for acute rejection was done and the patient underwent operation with acute rejection diagnosis. thick purulent secretions were evacuated and nephrectomy was done. in macroscopic examination, the kidney had irregular external surface, creamy color, covered by fibrin, with necrotized surface of the incision. amorphic necrotic elements were seen in calyces sections (fig. 2). in microscopic examination, fungal elements invasion with broad hyphae, without transverse septum, and with right angled branches were seen in small and major kidney arteries (fig. 3), accompanying with intensive coagulative necrosis in parenchyma (fig. 4). obstructive infectious thrombosis, accompanying by a large amount of fungal hyphae, invading the artery and adjacent tissue were seen in renal artery wall (both samples were sent to laboratory fixed in formalin, so that it was impossible to culture the fungi). the patient was discharged with good general condition. discussion mucormycosis (zygomycosis) is an opportunistic upper respiratory tract and lung infection caused by mucorales fungi, and its most common pathogen species is rhizopus oryzae. the infection is transmitted by spores in the air.(3) it can enter the body through gastrointestinal tract and wounded skin.(2) different clinical forms of mucormycosis infection have been described, among which rhinocerebral mucormycosis is the most common form. mucormycosis may rarely involve the kidney alone. rhiozopus oryzae often invades blood vessels and disseminates through the hematogenous route. urinary system involvement can be asymptomatic or can manifest as signs and symptoms of kidney infection, such as pain, dysuria, gross hematuria, or acute renal failure. kidney involvement has been seen in 50% of the patients who have died of disseminated mucormycosis. several vessel thromboses may lead to segmental or subtotal kidney infarction. involvement can be unilateral or bilateral. microscopically, necrotizing purulent inflammation is seen accompanying by fig. 2. multifocal necrosis in external and internal kidney views fig. 3. fungal elements invasion in transplanted kidney artery walls (× 40) fig. 4. fungal elements and coagulative necrosis of kidney parenchyma (×40) renal allograft mucormycosis56 thrombosis of arcuate and interlobar arteries. fungal hyphae are usually wide (20 to 50 µm or more) with irregular margins and different shapes. although most of them seem to be without transverse septum, they are, in fact, pauciseptate with few transverse septa. of course, transverse septa can be hardly seen in the tissue samples. peripheral branches have a lateral right angle branching shape. hyphae septum in hematoxylin-eosin staining is basophyl or amphophil. we can detect the organisms using grocott methenamine-silver staining or using antibody attached to fluorescent elements.(3) mucormycosis can be seen in three different forms in a patient with kidney disease. the first form is primary isolated infection of kidney. primary mucormycosis of kidney is rare and can result in disseminated infection. the most common predisposing factors are aids, drug addiction, and diabetes mellitus, which must be considered in every single patient with flank pain, fever, and sterile urine without clinical response to antibiotic therapy.(3-5) the second type of mucormycosis infection in patients with kidney disease is the involvement of other organs of kidney recipients. mucormycosis infection in lung, gastrointestinal system,(6) nose, sinuses, and brain(7) has been reported in immunocompromised patients with renal transplantation. the third form, to which our reported cases belong, is mucormycosis infection in transplanted kidney, which is very rare and, to our best knowledge, has been reported in 5 cases, so far.(8) in these cases, patients have normal diuresis after transplantation and level of serum creatinine is also normal. however, from the third postoperative day to the second month they are affected with decreased urinary flow, increased creatinine, and flank pain, with no significant microscopic finding in urine, urine culture, and blood culture.(8) afterwards, severe pain, decreased blood pressure, and hematogenic shock will occur. in one case, isolated mucormycosis of renal artery is reported to lead to renal artery rupture, hematoma formation around transplanted kidney and posterior peritoneum, and immediate death.(9) in another patient, biopsy of transplanted kidney had been done before surgical operation showing necrotic tissue of kidney and intensive fungal infiltration, which was confirmed in culture.(9) our patients had been referred with rejection signs, flank pain, and hematuria two to nine months after transplantation and nephrectomy was performed for both of them. mucormycosis in transplanted kidney is a very rare and fatal infection. it seems that livingunrelated kidney transplantation is a probable risk factor in developing countries. fungal colonization can take place during transplantation.(9) mucormycosis infection diagnosis in transplanted kidney usually takes time, because culture of the organism is difficult to perform, and there is no available diagnostic serological test for its diagnosis.(8) thus, in every single patient with rejection signs, flank pain, and without any specific changes in microscopic urine exam, urine culture, or blood culture, mucormycosis must be considered even if no specific changes in microscopic urine exam, urine culture and blood culture is seen. early treatment with anti fungal agents can result in a better prognosis for the patient. references 1. armaly z, khankin e, ramadan r, et al. two cases of renal mucormycosis in renal transplanted patients. clin nephrol. 2002;58:247-9. 2. cavallo t. tubulointerstitial nephritis. in: jennette jc, olson jl, schwartz mm, silva fg, editors. heptinstall's pathology of the kidney. 5th ed. lippincott-raven; 1998. p.688. 3. carbone km, pennington lr, gimenez lf, burrow cr, watson aj. mucormycosis in renal transplant patients--a report of two cases and review of the literature. q j med. 1985;57:825-31. 4. chkhotua a, yussim a, tovar a, et al. mucormycosis of the renal allograft: case report and review of the literature. transpl int. 2001;14:438-41. 5. fisher j, tuazon cu, geelhoed gw. mucormycosis in transplant patients. am surg. 1980;46:315-22. 6. flood hd, o'brien am, kelly dg. isolated renal mucormycosis. postgrad med j. 1985;61:175-6. 7. chandler fw, watts jc. zygomycosis. in: conner dh, chandler fw, schwartz da, manz hj, lack ee, editors. pathology of infectious diseases. stamford, ct: appleton & lange; 1997. p.1113-8. 8. lussier n, laverdiere m, weiss k, poirier l, schick e. primary renal mucormycosis. urology. 1998 nov;52(5):900-3. 9. minz m, sharma a, kashyap r, et al. isolated renal allograft arterial mucormycosis: an extremely rare complication. nephrol dial transplant. 2003;18:1034-5. u j all final for web.pdf 815vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l a rare paraneoplastic dermatomyositis in bladder cancer with fatal outcome ran xu, zhaohui zhong, hongyi jiang, lei zhang, xiaokun zhao keywords: paraneoplastic syndromes, dermatomyositis, urinary bladder neoplasms introduction pared to the general population. only a small number of cases of dermatomyositis associated case report 2 solid tumor on the corresponding author: hongyi jiang, md department of urology, the second xiangya hospital, central south university, changsha, hunan, china tel: +86 138 7480 3788 fax: +86 073 185 294 082 e-mail: ddf20@sina.com received january 2011 accepted april 2011 the second xiangya hospital, central south university, changsha, hunan, china case report 816 | munological tests, including anti-double-stranded dna antient metastatic disease. rectum or pelvic lymphatics. because of concern for healing impairment due to long-term corticosteroid administration, forming an intestinal neobladder. discussion case report association between dermatomyositis and bladder cancer in the english literature.£ reference age, y gender initial diagnosis time interval treatment pathology prognosis 1* 79 male bc 24 m turbt + intravesical immunotherapy g1 btcc death 2 60 male bc 2 w chemotherapy g3t3n2 btcc metastasis death 3 61 male bc 2 w surgery + radiotherapy t2 btcc metastasis death 4 68 male bc 13 m surgery + radiotherapy g4 btcc metastasis death 5* 62 male concurrent radical cystectomy + ileal conduit + radiotherapy t3 btcc metastasis death 6 64 male dm 12 m surgery + chemotherapy g3t2n2 btcc metastasis death 7* 75 male concurrent surgery + radiotherapy g3t1b btcc 8 63 male dm 2 m surgery btcc £bc indicates bladder cancer; dm, dermatomyositis; turbt, transurethral resection of bladder tumor; btcc, bladder transitional cell carcinoma; m, months; and w, weeks. *symptoms of dm improved after treatment of bladder cancer. 817vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l fatal paraneoplastic dermatomyositis in bladder cancer | xu et al transitional cell carcinoma in all the subjects. improvement of clinical symptoms of dermatomyositis after treatment of these observations suggest dermatomyositis as a paraneoplastic syndrome. malignancies may occur before, concurdermatomyositis, symptoms of bladder cancer are relatively latent. a thorough urologic evaluation should be undertakported, and all of them had high-risk bladder cancer. this is that too much attention is paid to the dermatomyositis, dermatomyositis itself may be a marker of poor prognosis in malignancy. carcinoma, and indicates a poor prognosis. third, a thorough urologic evaluation should be undertaken for dermatomyfor bladder cancer recurrence. conflict of interest none declared. references 1. sabio jm, vargas-hitos ja, jimenez-alonso j. paraneoplastic dermatomyositis associated with bladder cancer. lupus. 2006;15:619-20. 2. garcia-donoso c, sanchez-munoz a, lopez-medrano f. dermatomyositis and transitional cell carcinoma of the bladder: a rare paraneoplastic syndrome associated with tumor recurrence. eur j intern med. 2003;14:397-8. 3. robinson aj, alcock cj. dermatomyositis in association with transitional cell carcinoma of the bladder. clin oncol (r coll radiol). 2001;13:50-1. 4. federman dg, radonich m, kirsner rs. fatal bladder cancer and dermatomyositis. south med j. 2000;93:492-3. 5. talanin ny, bushore d, rasberry r, rudolph t, tuli m, friedman-musicante r. dermatomyositis with the features of inclusion body myositis associated with carcinoma of the bladder. br j dermatol. 1999;141:926-30. 6. rankin wr, herman jr. rapidly progressive transitional cell carcinoma associated with dermatomyositis. j urol. 2002;167:639-40. 7. mallon e, osborne g, dinneen m, lane rj, glaser m, bunker cb. dermatomyositis in association with transitional cell carcinoma of the bladder. clin exp dermatol. 1999;24:94-6. 8. apaydin r, gul u, bahadir s, siviloglu c, ofluoglu i. dermatomyositis without muscle weakness associated with transitional cell carcinoma of the bladder. j eur acad dermatol venereol. 2002;16:172-4. kidney transplantation expression levels of lncrnas in the patients with the renal transplant rejection mohsen nafar1, shiva kalantari1, sayyed mohammad hossein ghaderian2, mir davood omrani3, hamid fallah4, shahram arsang-jang5, tahereh abbasi1, shiva samavat1, nooshin dalili1, mohammad taheri6*, soudeh ghafouri-fard4** purpose: long non-coding rnas (lncrnas) include a vast portion of human transcripts. they exert regulatory roles in immune responses and participate in diverse biological functions. recent studies indicated dysregulation of lncrnas in the process of transplant rejection. in the current study, we aimed at identification of the expression of five lncrnas (oip5-as1, fas-as1, tug1, neat1 and pandar) in association with the process of transplant rejection. material and methods: we assessed expression of these lncrnas in the peripheral blood of 61 kidney transplant receivers including 29 transplant rejected patients and 32 transplant non-rejected patients using real time pcr technique. results: expression of fas-as1 was significantly higher in rejected group compared to non-rejected group in males, however, differences between case and control groups were insignificant among females. for other lncrnas no significant differences were detected between two study groups. quantile regression model showed that patients’ gender was an important parameter in determination of fas-as1 expression (beta = 9.46, t =2.82, p = 0.007) but not for other lncrnas expressions. significant pairwise correlations were detected between expression levels of lncrnas in a disease related manner. conclusion: based on the higher expression of fas-as1 in patients with transplant rejection, this lncrna might be associated with the pathogenesis of renal transplant rejection. keywords: kidney transplant; rejection; lncrna; oip5-as1; fas-as1; tug1; neat1; pandar introduction end stage renal disease (esrd) is a catastrophic con-dition which has limited therapeutic options including renal transplantation(1). the fate of renal transplants is endangered by acute rejection which might happen in spite of application of immunosuppressive treatment and sophisticated surgical techniques(2). the dependence of diagnosis of acute rejection on the invasive method of renal biopsy has encouraged researchers to find suitable non-invasive methods for this purpose(3). long non-coding rnas (lncrnas) as main regulators of immune response have been suggested to exert functional roles in the process of immune-mediated tissue rejection(3). these transcripts regulate expression of target genes through different mechanisms and at different genomic, transcriptomic and post-transcriptomic levels. they have interaction domains for almost all fundamental biological molecules including dna, mrnas, mirnas, and proteins(4). consequently, they participate 1chronic kidney disease research center, shahid beheshti university of medical sciences, tehran, iran. 2cellular and molecular biology research center, shahid beheshti university of medical sciences, tehran, iran. 3urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 4department of medical genetics, shahid beheshti university of medical sciences, tehran, iran. 5clinical research development center (crdu), qom university of medical sciences, qom, iran. 6urogenital stem cell research center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urogenital stem cell research center, shahid beheshti university of medical sciences, tehran, iran. tel & fax: 00982123872572. e mail: mohammad_823@yahoo.com. **correspondence: department of medical genetics, shahid beheshti university of medical sciences, tehran, iran. e mail: s.ghafourifard@sbmu.ac.ir. received july 2019 & accepted november 2019 in regulation of nearly all aspects of life. their interactions with toll-like receptors result in modulation of expression of immune response genes(5). a previous study in patients with acute rejection and control subjects revealed that tens of lncrnas are differentially expressed between groups(6). besides, lncrna microarrays have shown distinctive expression profiles of acute rejection in renal transplant biopsies(7). another study in animal models has shown the role of prins lncrna in allograft rejection linking between persistent ischemia and transplant rejection(8). in the present study, we selected five lncrnas to assess their expression profile in the peripheral blood of renal transplant receivers including patients with acute rejection and those with normal glomerular filtration rate (gfr) and no sign of rejection. lncrnas were selected based on their involvement in regulation of immune response or cell apoptosis. the lncrna opa-interacting protein 5 antisense transcript 1 (oip5-as1) participates in reguurology journal/vol 16 no. 6/ november-december2019/ pp. 572-577. [doi: 10.22037/uj.v0i0.5456] vol 16 no 06 november-december2019 573 lation of cell proliferation and apoptosis through interaction with pten/pi3k/akt pathway(9). this pathway has crucial roles in regulation of chemokine-induced recruitment of immune cells and their function. moreover, a certain isoform of pi3k controls development and activity of b and t cells. notably, suppression of this pathway has decreased the strength of inflammatory responses in animal models(10). fas –antisense 1 (fas-as1) is transcribed from antisense stand of fas. defects in fas or fas ligand (fasl) leads to systemic autoimmune responses in both human subjects and animals(11). moreover, excessive release of autoantibodies have been reported following fas defects in t and b lymphocytes or dendritic cells(12). taurine up-regulated gene 1 (tug1) participates in regulation of cell apoptosis and inflammatory responses in diverse pathological conditions. such functions are possibly exerted through modulation of activation of immune-related signaling pathways namely nf-κb and jak/stat (13). nuclear paraspeckle assembly transcript 1 (neat1) binds to splicing factor proline and glutamine rich and participates in modulation of the innate immune system and production of il-8(14). the lncrna promoter of cdkn1a antisense dna damage activated rna (pandar) recruits polycomb repressive complexes and inhibits expression of senescence-enhancing genes (15). a recent study has reported up-regulation of this lncrna in peripheral blood of multiple sclerosis (ms) patients(16). consequently, the selected lncrnas in the current project are possibly associated with immune response regulation and are hypothesized to participate in acute transplant rejection. patients and methods patients the current retrospective study was conducted on 29 transplant rejected patients (18 males and 11 females) and 32 transplant non-rejected patients (24 males and 8 females). patients were admitted to labbafi-nejad hospital, tehran, iran during 2016-2018. patients who received renal transplant during the mentioned period entered the study. exclusion criteria were delayed graft function, urinary obstruction and urinary tract infection. protocol biopsies of the renal allografts were performed based on the guidelines of the transplant center. renal function was evaluated by creatinine clearance, protein excretion and renal ultrasound and angiography. biopsy was performed in cases with at least 25% creatinine rise during two consecutive measurements after rule out of drug toxicity and obstructions. acute rejection was scored based on banff criteria(17). control subjects (non-rejected group) were matched to rejected group regarding sex and age parameters. these individuals either had no creatinine rise in the prior 3 months or protocol biopsy ruled out the transplant rejection. patients were under treatment with tacrolimus, cellcept and prednisolone with no significant inter/intra-group differences in treatment regimens. in antibody-mediated rejection, t cell-mediated rejection and non-rejected groups, 10%, 28% and 50% of patients received transplants from live donors, respectively. the study protocol was approved by ethical committee of shahid beheshti university of medical sciences (ir.sbmu.retech.rec.1398.193). written consent forms were obtained from all study participants. expression analysis peripheral blood was obtained from the enrolled patients at the day of biopsy in the same time and stored at -80 °c until additional investigations. total rna was isolated from all specimens using hybrid-r blood rna (geneall biotech, korea). all steps were performed based on the protocol provided by the company. subsequently, cdna was produced from all samples using primescript 1st strand cdna synthesis kit (clontech, japan). expressions of five lncrnas were measured in real-time pcr system (rotor gene 6000, corbett, australia) using the hprt1 gene as the reference gene. the realq plus master mix (ampliqon, denmark) was used for amplification of lncrnas. primers and pcr conditions were the same as our recently published study(18). statistical methods mean values (± standard error of mean) of lncrnas extable 1. demographic and clinical data of study participants. groups parameters antibody-mediated rejected t cell-mediated rejected non-rejected age (mean ± standard error of mean) 40.7 (±15.2) 39.33 (±15.1) 35.6 (±16.1) sex ratio (female/ male) 9/ 13 1/ 6 8/ 24 estimated gfr (egfr) before transplantation 8.76 ± 1.4 8.98 ± 1.32 7.96 ± 1.24 1 month after transplantation 41.9 ± 3.2 43.7 ± 3.4 55.39 ± 3.8 2 months after transplantation 47.195 ± 2.9 57.064 ± 3.9 64.119 ± 4.32 3 months after transplantation 40.97 ± 1.95 60.29 ± 4.2 60.935 ± 4.2 figure 1. relative expression of lncrnas in study groups based on the gender of subjects (black dots show the expression level in each patient, red crosses show outlier values). lncrnas and renal transplant rejection-nafar et al. pressions were compared between study groups using bayesian regression model. the observation effects were regarded as random in the analysis model. the t student/gaussian prior distribution was assumed for parameters with 8000 iteration and 1000 warm-up. the effects of possible confounding parameters were judged by quantile regression model. the box-cox transformation was used for normalization of the data. p-values were estimated from frequentist method. stan package in r 3.5.1 environment was used for statistical analysis. p < 0.05 was regarded as significant. results general data of patients table 1 shows demographic and clinical data of patients. in transplant rejected patients, graft biopsy revealed t cell mediated rejection and antibody-mediated rejection in 22 and 7 patients respectively. in non-rejected patients, 12 patients had no creatinine rise whereas others had creatinine rise. in rejected group, mean (± standard error of mean) values of serum levels of creatinine were 3.14 ± 1.8 mg/dl and 2.04 ±1.74 mg/ dl prior and post-transplantation, respectively. in this group, one patient died and nephrectomy was done for one patient(19). expression assays the results of expression analysis of lncrnas in rejected and non-rejected groups are shown in figure 1. expression of fas-as1 was significantly higher in rejected group compared to non-rejected group in males, however, differences between case and control groups were insignificant among females. for other lncrnas no significant differences were detected between two study groups. as shown in table 2, expression of fasas1 was different between rejected and non-rejected groups (relative expression difference = 4.0647, p value = 0.005). however, gender-based analysis showed that the difference was due to the dissimilar expression levels in males, as females did not show any significant difference in this regard. quantile regression model showed that patients’ gender was an important parameter in determination of fasas1 expression (beta = -9.46, t = -2.82, p = 0.007) but not for other lncrnas expressions. table 3 shows the results of quantile regression for assessment of association between expression ratio and independent variables. subsequently, we assessed expression of lncrnas between four subgroups (t cell mediated rejection, antibody-mediated rejection, stable gfr, non-rejected with creatinine rise). the results of bayesian regression model after adjustment of the effects of gender showed no significant difference in lncrna expressions between four study subgroups (table 4). correlations between expression levels of lncrnas finally, we assessed correlations between expression lncrnas groups rejected non-rejected relative expression difference a se p-value b 95% cri oip5-as1 total 29 32 -0.0936 0.07 0.623 [-0.22, 0.04] male 25 19 -0.1268 0.07 0.581 [-0.27, 0.02] female 7 10 -0.0102 0.17 0.765 [-0.35, 0.33] fas-as1 total 29 32 4.0647 2.07 0.005 [0.01, 8.18] male 25 19 4.0609 2 0.005 [0.19, 8] female 7 10 -1.822 3.88 0.347 [-9.42, 5.95] tug1 total 29 32 -0.0964 0.08 0.310 [-0.24, 0.05] male 25 19 -0.0664 0.08 0.282 [-0.22, 0.1] female 7 10 -0.1718 0.19 0.744 [-0.55, 0.21] neat1 total 29 32 -0.057 0.06 0.210 [-0.18, 0.07] male 25 19 -0.0647 0.07 0.194 [-0.2, 0.07] female 7 10 -0.0406 0.15 0.949 [-0.33, 0.26] pandar total 29 32 -0.0462 0.06 0.527 [-0.17, 0.07] male 25 19 -0.0496 0.08 0.572 [-0.2, 0.1] female 7 10 -0.0344 0.11 0.917 [-0.26, 0.19] table 2. the results of bayesian regression model to compare gene expression ratios between study groups with adjusting the effects of gender (a expression difference: rejected non-rejected, b p-value estimated from frequentist method). lncrna variable beta se t p-value 95 % ci for beta oip5-as1 group -0.05 0.10 -0.49 0.623 [-0.26, 0.16] gender -0.09 0.15 -0.61 0.542 [-0.38, 0.2] group*gender -0.03 0.20 -0.15 0.884 [-0.42, 0.37] fas-as1 group 5.14 1.76 2.91 0.005 [1.61, 8.68] gender 3.36 2.48 1.35 0.181 [-1.61, 8.32] group*gender -9.46 3.36 -2.82 0.007 [-16.19, -2.74] tug1 group -0.13 0.13 -1.03 0.310 [-0.38, 0.12] gender 0.02 0.18 0.11 0.909 [-0.33, 0.37] group*gender 0.04 0.24 0.18 0.859 [-0.44, 0.52] neat1 group -0.11 0.09 -1.27 0.210 [-0.3, 0.07] gender -0.09 0.13 -0.74 0.460 [-0.35, 0.16] group*gender 0.13 0.17 0.74 0.460 [-0.22, 0.47] pandar group -0.05 0.07 -0.64 0.527 [-0.19, 0.1] gender -0.12 0.10 -1.15 0.257 [-0.32, 0.09] group*gender 0.03 0.14 0.23 0.818 [-0.25, 0.31] table 3. the results of quantile regression for assessment of association between expression ratio and independent variables (group: rejected/ non-rejected; gender: male/female). lncrnas and renal transplant rejection-nafar et al. kidney transplantation 574 vol 16 no 06 november-december2019 575 levels of lncrnas in rejected and non-rejected groups (figures 2 and 3). significant inverse correlations were found between expression levels of oip5-as1 and fas-as1 as well as fas-as1 and neat1 in both study groups. expression levels of fas-as1 and tug1 were inversely correlated in transplant-rejected group. however, no significant correlation was found between expressions of them in the other group. expression levels of fas-as1 and pandar were inversely correlated in non-rejected group but not the other group. expression levels of oip5-as1 and pandar were positively correlated in transplant-rejected patients but not the other group. expressions of other pairs of lncrnas were correlated in both groups. discussion in the current study, we assessed expression of five lncrnas in the peripheral blood of transplant receivers with and without transplant rejection. the role of lncrnas in the process of transplant rejection has been assessed previously though high throughput or single gene expression analysis in biopsied samples(7,20). moreover, genome-wide assessment of lncrna signatures in peripheral blood samples has shown that expression profile of two lncrnas can be used as non-invasive diagnostic biomarker for transplant rejection(3). although the selected lncrnas in the current study were previously shown to be associated with regulation of immune response, our expression analysis showed dysregulation of only one of them in patients with transplant rejection. expression of fas-as1 was significantly higher in rejected group compared to non-rejected group in males, however, differences between case and control groups were insignificant among females. fas-as1 is transcribed from the antisense direction of intron 1 table 4. the results of bayesian regression model for comparison of gene expression ratios between subgroups with adjusting the effects of gender (reference category: antibody-mediated rejection). lncrna group relative expression difference se p-value 95% cri oip5-as1 t-cell mediated rejection -0.15 0.11 0.259 [-0.37, 0.07] stable gfr 0.02 0.1 0.836 [-0.17, 0.21] non-rejected with creatinine rise 0.08 0.08 0.750 [-0.08, 0.23] fas-as1 t-cell mediated rejection -0.09 0.12 0.220 [-0.33, 0.16] stable gfr 0.07 0.1 0.327 [-0.13, 0.28] non-rejected with creatinine rise 0.08 0.09 0.283 [-0.11, 0.25] tug1 t-cell mediated rejection 5 2.94 0.540 [-0.83, 10.88] stable gfr 0.34 2.53 0.602 [-4.56, 5.24] non-rejected with creatinine rise -1.99 2.11 0.430 [-6.05, 2.17] neat1 t-cell mediated rejection -0.14 0.1 0.159 [-0.33, 0.06] stable gfr -0.03 0.08 0.989 [-0.19, 0.14] non-rejected with creatinine rise 0.05 0.07 0.537 [-0.09, 0.18] pandar t-cell mediated rejection -0.17 0.1 0.835 [-0.36, 0.03] stable gfr 0.02 0.08 0.557 [-0.15, 0.19] non-rejected with creatinine rise 0 0.07 0.760 [-0.14, 0.14] figure 2. correlation between expression levels of lncrnas in transplant rejected individuals (bivariate scatter plots with confidence ellipses below the diagonal, histograms on the diagonal, and pearson correlations above the diagonal; expression levels of lncrnas are shown in xand yaxes; the expression value of an lncrna (designated by points) determines the relative position of the symbol along the x-axis and the expression value of a second lncrna determines the relative position of the symbol along the y-axis.). figure 3. correlation between expression levels of lncrnas in transplant non-rejected individuals (bivariate scatter plots with confidence ellipses below the diagonal, histograms on the diagonal, and pearson correlations above the diagonal; expression levels of lncrnas are shown in xand yaxes; the expression value of an lncrna (designated by points) determines the relative position of the symbol along the x-axis and the expression value of a second lncrna determines the relative position of the symbol along the y-axis.). lncrnas and renal transplant rejection-nafar et al. of the fas gene(21). this lncrna has a putative role in preservation of t lymphocytes from fas-induced apoptosis(21). consequently, higher expression of this lncrna in peripheral blood of transplant-rejected patients reflects higher activity of lymphocytes in these patients and is in accordance with pathogenic process of graft rejection. previous studies have shown inverse correlation between levels of fas-as1 and soluble fas (sfas)(22). sfas is regarded as an endogenous apoptosis suppressor that hinders the binding of fas to fas-l, precludes monocyte-induced and t cell–induced endothelial cell apoptosis which participate in the process of rejection(23). the observed effect of gender on expression of fas-as1 has also been reported previously. for instance, fas-as1 expression has been associated with schizophrenia in a subgroup of male subjects but not in female subjects(24). moreover, a previous study has demonstrated an association between female sex hormones and the fas/fasl system in reproductive tissues (25). when dividing patients into four subgroups, we could not detect any significant difference between expressions of mentioned lncrnas between them. such lack of difference might be due to the small sample size in each subgroup. so we recommend design of similar studies with larger sample sizes to appraise whether expressions of these lncrnas are involved in the pathogenesis of t cell mediated or antibody mediated transplant rejection. finally, we appraised correlations between expression levels of lncrnas in the study groups and found distinct patterns of correlation in each group. from this data, it is possible to speculate that immune-related mechanisms during allograft rejection influence/ are influenced by the interactive network between lncrnas. future studies are required to unravel the underlying mechanisms and clarify the cause-effect relationship. in brief, in the current study we have shown dysregulation of fas-as1 in male transplant receivers who experienced acute rejection. future studies in larger sample sizes are needed to evaluate the potential of this lncrna as peripheral biomarker for allograft rejection. the difference in expression level of this lncrna between rejected and non-rejected groups might be applied as biomarker for stratifying patients if future studies in larger sample sizes verify the results of the current study. our study has limitations regarding sample size and lack of functional assessment of underlying molecular mechanisms for participation of fas-as1 in transplant rejection. when dividing patients into subgroups, the size of sample in each subgroup was small, so the relation between fas-as1 expression and rejection should be interpreted with caution. another limitation of our study was lack of assessment of other lncrnas with putative function in transplant rejection. moreover, the retrospective nature of the study limits its potential to be translated into clinical application. conclusions based on the higher expression of fas-as1 in patients with transplant rejection, this lncrna might be associated with the pathogenesis of renal transplant rejection. acknowledgement this study was financially supported by urology and nephrology research center. conflict of intereset the authors declare they have no conflict of interest. references 1. saidi rf, broumand b. current challenges of kidney transplantation in iran: moving beyond the "iranian model". transplantation. 2018;102:1195-7. 2. jalalzadeh m, mousavinasab n, peyrovi s, ghadiani mh. the impact of acute rejection in kidney transplantation on long-term allograft and patient outcome. nephrourol mon. 2015;7:e24439. 3. ge yz, xu t, cao wj, et al. a molecular signature of two long non-coding rnas in peripheral blood predicts acute renal allograft rejection. cell physiol biochem. 2017;44:1213-23. 4. fernandes jcr, acuna sm, aoki ji, floeterwinter lm, muxel sm. long non-coding rnas in the regulation of gene expression: physiology and disease. noncoding rna. 2019;5. 5. carpenter s, aiello d, atianand mk, et al. a long noncoding rna mediates both activation and repression of immune response genes. science. 2013;341:789-92. 6. sui w, lin h, peng w, et al. molecular dysfunctions in acute rejection after renal transplantation revealed by integrated analysis of transcription factor, microrna and long noncoding rna. genomics. 2013;102:31022. 7. chen w, peng w, huang j, et al. microarray analysis of long non-coding rna expression in human acute rejection biopsy samples following renal transplantation. mol med rep. 2014;10:2210-6. 8. zou xf, song b, duan jh, hu zd, cui zl, yang t. prins long noncoding rna involved in ip-10-mediated allograft rejection in rat kidney transplant. transplant proc. 2018;50:1558-65. 9. yang n, chen jq, zhang h, et al. lncrna oip5-as1 loss-induced microrna-410 accumulation regulates cell proliferation and apoptosis by targeting klf10 via activating pten/pi3k/akt pathway in multiple myeloma. cell death & disease. 2017;8. 10. hawkins pt, stephens lr. pi3k signalling in inflammation. biochimica et biophysica acta-molecular and cell biology of lipids. 2015;1851:882-97. 11. nikolov np, shimizu m, cleland s, et al. systemic autoimmunity and defective fas ligand secretion in the absence of the wiskott-aldrich syndrome protein. blood. 2010;116:740-7. 12. ramaswamy m, siegel rm. a fascinating receptor in self-tolerance. immunity. lncrnas and renal transplant rejection-nafar et al. kidney transplantation 576 vol 16 no 06 november-december2019 577 2007;26:545-7. 13. zhang hf, li h, ge a, guo ey, liu sx, zhang lj. long non-coding rna tug1 inhibits apoptosis and inflammatory response in lps-treated h9c2 cells by down-regulation of mir-29b. biomedicine & pharmacotherapy. 2018;101:663-9. 14. imamura k, imamachi n, akizuki g, et al. long noncoding rna neat1-dependent sfpq relocation from promoter region to paraspeckle mediates il8 expression upon immune stimuli. mol cell. 2014;53:393-406. 15. puvvula pk, desetty rd, pineau p, et al. long noncoding rna panda and scaffoldattachment-factor safa control senescence entry and exit. nat commun. 2014;5:5323. 16. dastmalchi r, ghafouri-fard s, omrani md, mazdeh m, sayad a, taheri m. dysregulation of long non-coding rna profile in peripheral blood of multiple sclerosis patients. mult scler relat disord. 2018;25:219-26. 17. racusen l, rayner d, trpkov k, olsen s, solez k. the banff classification of renal allograft pathology: where do we go from here? transplant proc. 1996;28:486-8. 18. sayad a, taheri m, omrani md, fallah h, kholghi oskooei v, ghafouri-fard s. peripheral expression of long non-coding rnas in bipolar patients. j affect disord. 2019;249:169-74. 19. nafar m, kalantari s, omrani md, et al. suppressor of cytokine signaling genes in renal transplant receivers: association with transplant fate. transpl immunol. 2019;56:101228. 20. qiu j, chen y, huang g, zhang z, chen l, na n. transforming growth factor-beta activated long non-coding rna atb plays an important role in acute rejection of renal allografts and may impacts the postoperative pharmaceutical immunosuppression therapy. nephrology (carlton). 2017;22:796-803. 21. yan md, hong cc, lai gm, cheng al, lin yw, chuang se. identification and characterization of a novel gene saf transcribed from the opposite strand of fas. hum mol genet. 2005;14:1465-74. 22. sehgal l, mathur r, braun fk, et al. fasantisense 1 lncrna and production of soluble versus membrane fas in b-cell lymphoma. leukemia. 2014;28:2376-87. 23. wang t, dong cm, stevenson sc, et al. overexpression of soluble fas attenuates transplant arteriosclerosis in rat aortic allografts. circulation. 2002;106:1536-42. 24. safari mr, komaki a, arsang-jang s, taheri m, ghafouri-fard s. expression pattern of long non-coding rnas in schizophrenic patients. cell mol neurobiol. 2019;39:21121. 25. song j, rutherford t, naftolin f, brown s, mori g. hormonal regulation of apoptosis and the fas and fas ligand system in human endometrial cells. molecular human reproduction. 2002;8:447-55. lncrnas and renal transplant rejection-nafar et al. 1666 | miscellaneous the value of neutrophil elastase in diagnosis of type iii prostatitis jun zhu, changhai yang, zhichun dong, liming li corresponding author: changhai yang, md department of urology, tianjin medical university general hospital, 154 anshan road, heping district, tianjin 300052, china. tel: +86 22 6553 9807 fax: +86 22 6553 9807 e-mail: ychanghai@yahoo.com received august 2013 accepted april 2014 department of urology, tianjin medical university general hospital, 154 anshan road, heping district, tianjin 300052, china. miscellaneous purpose: to explore the value and significance of neutrophil elastase (ne) in diagnosis of type iii prostatitis. materials and methods: the prospective study recruited 123 patients diagnosed with type iii prostatitis (iiia, 36 cases; iiib, 87 cases) and 84 healthy controls, between april 2008 and july 2012. ne concentrations in expressed prostatic secretions (eps), eps routine examination, bacterial culture and the national institute of health chronic prostatitis symptom index (nihcpsi) score were detected in all the subjects. difference of ne, cpsi score, and withe blood cell (wbc) count between 2 or more than 2 groups and relationships between ne concentrations and wbc count were all analyzed. results: there was significant difference in levels of ne (p < .05) between iiia and iiib groups, and obviously positive correlation between the level of ne and number of leukocyte in type iiia prostatitis group was observed (p < .05). the values of cpsi score between iiia and iiib groups was statistically significant (p = .037). the levels of leukocyte mount, ne and cpsi were statistically significant between iiia and the control group (p < .05). ne concentration and cpsi score were statistically significant between iiib and control group (p < .05), while the numbers of leukocyte was not statistically significant (p = .360). conclusion: the level of ne in eps is a significant indicator in diagnosis of type iiia and iiib prostatitis. keywords: prostatitis; classification; diagnosis chronic disease; leukocyte elastase; chemistry. 1667vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l the value of ne in diagnosis of type iii prostatitis | zhu et al introduction prostatitis is an inflammation of the prostate and chronic prostatitis is the most common urologic disease in men less than 50 years old, accounting for approximately 8-25% of the urology outpatients.(1,2) in the us, over 2 million patient-visits per year are a result of prostatitis.(3) data has shown that about 50% of men suffer from prostatitis in a period of their lifetime.(4) it is not only brought kinds of discomfort to the patients, but also took significant harm to their mental health(5-8) and caused huge economic burden on public health.(9-12) due to the complexity of its etiology and various symptoms, clinical diagnosis of the cause and therapy has been lack of effective programs and methods and the therapy effect is usually unsatisfactory. according to the national institute of health (nih) classification method in 1995, type iii prostatitis (chronic nonbacterial prostatitis) is the most common disease, accounting for approximately 95% of the urology outpatients.(13) it is also divided into two subtypes iiia and iiib according to whether there are white blood cells (wbcs) in expressed prostatic secretions (eps). more evidences revealed that the therapy and treatment were significantly different between two subtypes of type iii prostatitis.(14,15) however, in clinical treatment, iiia and iiib of chronic prostatitis has similar clinical symptoms and it is difficult and not effective to distinguish them by wbc count only.(16,17) researchers tried to find other factors, in addition to leukocytes, which could effectively differentiate iiia and iiib prostatitis, for chronic prostatitis caused the prostate secretory abnormality on prostate secretory functions.(18-21) in this study, we detected concentrations of the neutrophil elastase (ne) in eps among iiia, iiib prostatitis patients and normal control group and compared the difference of ne concentrations in eps among type iiia, iiib chronic prostatitis patients and normal control group to attempt to provide a reliable measure for distinguishing and diagnosing the type iii chronic prostatitis. materials and methods an observational prospective design was applied in this study. a total of 123 patients diagnosed with type iii prostatitis were recruited to participate in the study between april 2008 and july 2012. the exclusion criteria were the presence of cancer of the genitourinary tract; active urinary stone disease or herpes of the genitourinary system; perirectal inflammatory disorders; inflammatory bowel disease; a history of pelvic radiation or systemic chemotherapy; a history of intravesical chemotherapy; urethral stricture 12 french (f) or smaller; neurologic disease or disorder affecting the bladder; and prostate surgery within the past 3 months. the inclusion criteria were, patients between 18 to 50 years old to reduce the effect of age factor, the course of the disease lasted for a period of at least three months, patients receiving no antibiotic treatment for any reason for the last 4 weeks, patients whose prostatic fluid having no bacterial growth and patients having symptoms of discomfort or pain in the pelvic region. the diagnosis of patients was consistent with the nih definition of the chronic prostatitis/pelvic pain syndrome.(22) patients with type iii prostatitis were classified as having subtype iiia (36 cases) or iiib (87 cases). ejaculated samples from healthy men showed a good sperm density and progressive motility and morphology (≥ 20%) and were considered normal ejaculates according to world health organization criteria.(23) eighty-four normal volunteers who didn’t show any signs of prostatic diseases were used as controls. they were recruited from the subjects undergoing complete history and physical examination. informed consent was obtained from their parents. study protocols were approved by figure . correlation analysis of ne and wbc count between iiia and b groups. ne concentrations was positively correlated with wbc count (spearman's rank correlation coefficient, r = 0.596, p < .05). keys: wbc, white blood cell; ne, neutrophil elastase. 1668 | the institutional research ethics committee of the general hospital of tianjin medical university. a complete history and physical examination were performed, including laboratory analysis, which was microscopy and culture of the urine specimen before massage, and eps and/or urine specimen after prostatic massage. for category iiia the eps and/or urine specimen after prostatic massage had to be sterile with no uropathogenic growth, and there had to be a documented inflammatory pattern on microscopy of eps that was greater than 10 wbcs per high power field (hpf), and/or urine sediment after prostatic massage that was greater than 5 wbcs per hpf. to be classified as iiib, the eps and/or urine specimen after prostatic massage had to be sterile with no uropathogen growth, and there had to be no documented inflammatory pattern on microscopy of eps that was less than 10 wbcs per hpf, and/or urine sediment after prostatic massage that was less than 5 wbcs per hpf. all patients had a complete medical history, a physical examination, and a 4-glass urinalysis, wbc counts in eps, serum prostate specific antigen (psa), nih-cpsi score, and transrectal ultrasonography, according to hochreiter and colleagues.(24) prostatic fluid samples were obtained at the hospital by prostatic massage, after a period of sexual abstinence of 3-5 days. the samples were collected in a sterile container and transferred to a cryovial, stored at –20°c. standard microbial investigations (e.g., for aerobic and anaerobic bacterial infections, ureaplasma urealyticum and mycoplasma infections, chlamydia trachomatis, trichomonas vaginalis and candida infections) were performed for all prostatic fluid samples. some of the fluid was transferred for storage at –80°c until it was used for the analysis of ne. the remaining fluid on the glass slide was placed under a coverslip and examined for wbc count in 5 fields at high power (400 ×). the average number of wbcs per hpf was recorded. ne was determined by quantitative sandwich enzyme immunoassay [human pmn elastase elisa (enzyme-linked immunosorbent assay), ray biotech., inc., minneapolis, mn, usa] according to the manufacturer’s instructions. the intensity of the color was measured at 450 nm. statistical analysis data were analyzed by using the statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. normally distributed continuous data are presented as means ± standard deviation (sd) and were compared using t tests. non-normally distributed continuous data are presented as the median and range, and were compared using the rank test. difference among 2 or more than 2 groups were miscellaneous table 1. changes in ipss and uroflowmetry parameters after treatment with tamsulosin. characteristics patients controls iiia iiib --number of subjects 36 87 84 mean age, years 32 30 28.88 course (months) 3-6 22 52 -----> 6 14 35 bacterial infection positive 0 0 0 negative 36 87 84 cpps symptom 36 87 ----associated symptom luts 28 48 non-luts 8 39 cpps treatment α-blockers 28 65 nsaid 25 48 keys: cpps, chronic pelvic pain syndrome; nsaid, nonsteroidal anti-inflammatory drug; luts, lower urinary tract symptoms. 1669vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l assessed by using t tests, anova or post hoc dunnett's t3 tests, as required. correlations of ne, nih-cpsi score and wbc count were analyzed by spearman's rank correlation coefficient. the p value < .05 was considered statistically significant. results patients' characteristics a total of 207 participants in tianjin medical university general hospital were studied. there were 36 cases of type iiia prostatitis, 87 cases of type iiib prostatitis and 84 cases of normal controls. the general characteristics of the recruited patients are shown in table 1. ne concentrations were elevated in prostatitis patients as compared with controls we summarized the wbc count, nih-cpsi score and ne concentrations in prostatitis iiia, iiib and control groups, respectively (table 2). ne concentration in patients with prostatitis iiia displayed significantly higher as compared with that of prostatitis iiib group (median 907.33 ng/ml, in controls vs. 94.92 ng/ml, respectively, p < .05; table 3). association analysis of ne levels cpsi score and wbc count as shown in table 3 and figure, the level of ne was positively correlated with wbc count (spearman's rank correlation coefficient, r = 0.596, p < .05). data revealed that there was significant differences on the values of cpsi between prostatitis iiia and prostatitis iiib (p = .037). test data of the experimental and control groups were also compared by spss 19.0. the ne in eps of patients with prostatitis iiia and iiib was statistically different from that of control group (all p < .05). the cpsi score of patients with prostatitis iiia and iiib was also statistically different from that of control group (all p < .05). wbc count in patients with prostatitis iiia displayed statistically significant difference as compared with that of control group (p < .05), but there was no statistical difference on wbc count between prostatitis iiib group and control group (p = .360). disccussion it has been diagnosed as type iii prostatitis that patients showing obvious symptoms of chronic bacterial prostatitis but microbiological culture results were negative.(25) however, with the improvement and optimization of culture methods, we observed the microbial growth in the eps from patients that were traditionally diagnosed for type iii prostatitis. for example, coagulase-negative cocci was difficult to grow in general medium, however, after obligate culture, it was demonstrated that coagulase negative cocci existed in the eps of about 68% of patients with type iii prostatitis, which was further to be confirmed by microscopic examination.(26) the traditional culture method had played an important role in the diagnosis and treatment of prostatitis, but it was a time-consuming and laborious process and susceptible to contaminate, especially, only a small number of microbial species were able to cultivate.(27,28) thus, the traditional culture method played a limited role in the course of recognition about type iii prostatitis related microorganisms. elastase is a kind of enzyme that can hydrolyze elastin in the body and named by the generated sites, such as neutrophils elastase (ne), which was present in neutrophils. under physiological conditions, ne played an effective protection in host defense system, and its activity was strictly regulated by the inhibitors of endogenous protease. in early stage of inflammation, wbcs were the first line of defense when pathogen invaded into the body. the gathered at the site of inflammation by chemotaxis of kinds of chemokines and ne were released by neutrophils. ne can escape from the regulation the value of ne in diagnosis of type iii prostatitis | zhu et al table 2. related data in the test groups and the control group.* groups no. wbc count nih-cpsi score ne iiia 36 17.89 ± 6.18 24.50 ± 5.41 907.33 ± 769.70 iiib 87 4.01 ± 2.21 21.80 ± 5.01 0.119 ± 0.009 control 84 3.60 ± 2.21 1.72 ± 0.74 0.068 ± 0.015a keys: wbc, white blood cells; nih-cpsi, national institutes of health-chronic prostatitis symptom index; ne, neutrophil elastase (ng/ml). * data are expressed as means ± sd. 1670 | of multiple protease inhibitors at the inflammation site. the balance was broke out between ne and its endogenous protease inhibitors and ne maintained the activated state, resulting in the damage and dysfunction of the tissues and organs. recent studies have found that infectious ne levels in eps of prostatitis patients were significantly higher than that in patients with non-infectious prostatitis, which demonstrated that ne could distinguish infectious and non-infectious prostatitis to a certain extent.(29) some researchers reported that compared with c3, the terminal complement complex and plasma ceruloplasmin, ne was the best indicator to diagnose of the acute and chronic urethritis/prostatitis.(30,31) simultaneously, ne also can be used as a detected indicator of clinical efficacy. ne concentration rapidly increased to more than 290 ng/ml from the normal level at the stage of acute inflammation until the inflammation was cured. otherwise, the concentration of ne would maintain a high level.(32) decreased ne levels showed that anti-inflammatory treatments were effective. if ne levels had not declined, the treatment plan should be redesigned, prompting doctors to find out the other chronic inflammatory lesions.(11) in the study, we identified a ne cutoffs (246.4 ng/ml) for diagnosing type prostatitis patients, which is slightly lower than the revised cutoff of 280 ng/ml for diagnosing inflammatory disease as depicted in the literature. (30) this findings may be the results that ne secretion is different in various tissues and organs or affected by different individuals or populations. besides, we measured the ne concentration in eps of patients with type iiia and iiib prostatitis. we found that ne concentrations in eps of prostatitis iiia was significantly higher than that of prostatitis iiib. ne concentrations in eps of patients with type iiia and iiib prostatitis were both significantly higher than that in the normal control group. these results indicated that patients with type iiia and type iiib prostatitis were both infected with microorganisms. the infection in patients with type iiia prostatitis was more serious than that with type iiib prostatitis. when tissues were infectious, ne was released by neutrophils. thus, we can make a conclusion that antibiotic treatment may be a possible method for the type iii prostatitis, especially type iiia chronic prostatitis. in addition, we compared the correlation between ne concentration and leukocytes in eps of patients and found that ne concentration positively correlated with leucocyte amount, which indicated that ne can be used as a meaningful indicator in the diagnosis of type iii prostatitis, and also demonstrated that the levels of ne concentration were able to reflect the severity of chronic prostatitis. however, we also observed that higher ne concentration accompanied with few leucocyte amount or low cpsi score which was uncommon, but with some meaning. for example, the results that high ne concentration accompanied with few wbcs were observed and it was largely because prostate duct was blocked that the wbcs at inflammatory sites could not spread into eps and were not calculated, but ne could spread miscellaneous table 3. difference of related indicators among 2 or more than 2 groups. groups iiia/iiib iiia/control iiib/control iii (a+b)/control md (i-j) p md (i-j) p md (i-j) p t p wbc count 14.061 < .05 14.591 < .05 0.530 .360 6.438937 < .05 nih-cpsi score 2.695 .037 23.762 < .05 21.067 < .05 44.99526 < .05 ne 812.4092 < .05 834.7583 < .05 22.34914 .097 5.125425 < .05 keys: wbc, white blood cells; nih-cpsi, national institutes of healthchronic prostatitis symptom index; ne, neutrophil elastase; md, mean difference. table 4. correlation analysis of wbc count, nih-cpsi score and ne between iiia and iiib groups. parameters wbc/nih-cpsi score wbc/ne nih-cpsi score/ne r 0.402 0.596 0.382 p < .05 < .05 < .05 keys: wbc, white blood cells; nih-cpsi, national institutes of healthchronic prostatitis symptom index; ne, neutrophil elastase; r, pearson correlation coefficient. 1671vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l the value of ne in diagnosis of type iii prostatitis | zhu et al into eps. currently, the main criteria of prostatitis in clinical diagnosis were that wbc count was more than 10 in eps, but it was not accurate only relying on one diagnostic indicator. diagnosis of prostatitis should be a systematic work and all of the treatment should be checked including the symptoms, pathological examination (eps microscopy), physiological and biochemical test, bacteriological examination, ultrasound examination and urodynamic examination and etc. all of the diagnostic treatments should be a comprehensive, objective and scientific on prostatitis. in conclusion, ne concentration in eps of patients can be used as a reference for diagnosis of type iii a and b prostatitis. with the promotion of inspection techniques, such as protein chip, the detection of ne concentration would be more convenient and may become one of the diagnostic indicators of type iii prostatitis. conclusion the limitation of our study is the lack of a large group of patients which may create the risk of a type ii statistical error, but despite that, the study has shown that the level of ne in eps is a significant indicator in diagnosis of type iiia and iiib prostatitis. there was a positive correlation between ne concentration and the leukocyte mount, which demonstrated the levels of ne in eps could reflect the severity of type iii chronic prostatitis. conflict of interest none declared. references 1. krieger jn, riley de, cheah py, liong ml, yuen kh. epidemiology of prostatitis. new evidence for a world-wide problem. world j urol. 2003;21:70-4. 2. rizzo m, marchetti f, travaglini f, trinchieri a, nickel jc. prevalence, diagnosis and treatment of prostatitis in italy: a prospective urology outpatient practice study. bju int. 2003;92:955-9. 3. izadyar f, den ouden k, stout ta, et al. autologous and homologous transplantation of bovine spermatogonial stem cells. reproduction. 2003;126:765-74. 4. kulchavenya e, azizoff a, brizhatyuk e, et al. improved diagnostics of chronic inflammatory prostatitis. minerva urol nefrol. 2012;64:273-8. 5. nickel jc, tripp da, chuai s, et al. nih-cpcrn study group. psychosocial variables affect the quality of life of men diagnosed with chronic prostatitis/chronic pelvic pain syndrome. bju int. 2008;101:59-64. 6. tripp da, nickel jc, wang y, et al. national institutes of healthchronic prostatitis collaborative research network (nih-cpcrn) study group. catastrophizing and pain-contingent rest predict patient adjustment in men with chronic prostatitis/chronic pelvic pain syndrome. j pain. 2006;7:697-708. 7. clemens jq, brown so, calhoun ea. mental health diagnoses in patients with interstitial cystitis/painful bladder syndrome and chronic prostatitis/chronic pelvic pain syndrome: a case/control study. j urol. 2008;180:1378-82. 8. lee ks, choi jd. chronic prostatitis: approaches for best management. korean j urol. 2012;53:69-77. 9. calhoun ea, mcnaughton collins m, pontari ma, et al. chronic prostatitis collaborative research network. the economic impact of chronic prostatitis. arch intern med. 2004;164:1231-6. 10. clemens jq, markossian t, calhoun ea. comparison of economic impact of chronic prostatitis/chronic pelvic pain syndrome and interstitial 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secretions. urology. 2000;56:1025-9. 25. magri v, wagenlehner fm, montanari e, et al. semen analysis in chronic bacterial prostatitis: diagnostic and therapeutic implications. asian j androl. 2009;11:461-77. 26. amann ri, ludwig w, schleifer kh. phylogenetic identification and in situ detection of individual microbial cells without cultivation. microbiol rev. 1995;59:143-69. 27. bjerklund johansen te, gruneberg rn, guibert j, et al. the role of antibiotics in the treatment of chronic prostatitis: a consensus statement. eur urol. 1998;34:457-66. 28. delavierre d, rigaud j, sibert l, labat jj. symptomatic approach to chronic prostatitis/chronic pelvic pain syndrome. prog urol. 2010;20:940-53. 29. zorn b, virant-klun i, meden-vrtovec h. semen granulocyte elastase: its relevance for the diagnosis and prognosis of silent genital tract inflammation. hum reprod. 2000;15:1978-84. 30. ludwig m, kummel c, schroeder-printzen i, ringert rh, weidner w. evaluation of seminal plasma parameters in patients with chronic prostatitis or leukocytospermia. andrologia. 1998;30(suppl 1):41-7. 31. zopfgen a, priem f, sudhoff f, et al. relationship between semen quality and the seminal plasma components carnitine, alpha-glucosidase, fructose, citrate and granulocyte elastase in infertile men compared with a normal population. hum reprod. 2000;15:840-5. 32. cumming ja, dawes j, hargreave tb. granulocyte elastase levels do not correlate with anaerobic and aerobic bacterial growth in seminal plasma from infertile men. int j androl. 1990;13:273-7. 1493vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l figure 1. kidney-ureter-bladder x-ray demonstrates multiple radio-opaque shadows in left renal area. figure 2. extracted 323 renal stones measuring from 5 mm to 2 cm. figure 3. postoperative kidney-ureter-bladder x-ray shows no residual calculus. 323 renal stones in a functional kidney bhavesh devkaran, navneet sharma, alok pandey, arun kumar gupta corresponding author: bhavesh devkaran, md department of surgery, indira gandhi medical college, shimla himachal pradesh, india. tel: +91 177 2628919 fax: +91 177 2883401 e-mail: devkaranbhavesh@gmail. com received march 2013 accepted april 2013 department of surgery, indira gandhi medical college, shimla himachal pradesh, india. a 50yearsoldmalepatientpresentedwithoccasionalleftflankpainandirritativelowerurinarytractsymptomswith1to2episodesofhematuriasince1to2yearsago.nohistoryofothermedicalorsurgicaldiseaseswasnoted.hisgeneralphysicalexaminationandroutineinvestigationswerenormal.kidney-ureter-bladder(kub) x-rayrevealedmultipleradio-opaqueshadowsinleftrenalarea(figure1).onultrasonography,multiplecalculiinleftkidneywithprominentpelvicalycealsystemcausingureteropelvicjunction(upj)narrowingwasseen.intravenousurography (ivu)demonstratedbilateralfunctioningkidneys,multiplecalculiwithprominentpelvisandgradeivhydronephrosisin leftside,andupjnarrowing.renalscintigraphyrevealedrelativefunctionof40%.diagnosisofleftrenalcalculiwithupj narrowingwasmade.patientwasplannedforsurgeryandleftpyelonephrolithotomywithanderson-hynespyeloplastywere done.intraoperatively,lefthydronehprotickidneywithimpactedmultiplestoneswereseen.renalparenchymawasthinned outatplaces.upjnarrowingwasalsopresent.maximumstoneswereextractedthroughpyelolithotomyandrestthrough nephrolithotomywhichwere323innumber,measuringfrom5mmto2cm(figure2).intraoperativelystonefreestatuswas confirmedwithc-arm.postoperativelyhiskubx-rayshowsnoresidualcalculus(figure3). pictorial female urology risk factors for women to have urodynamic stress urinary incontinence at a turkish tertiary referral center: a multivariate analysis study sinharib citgez,1* bulent onal,1 sarper erdogan,2 cetin demirdag,1 merve korkmaz,3 oktay demirkesen,1 zubeyr talat,1 ahmet erozenci,1 bulent cetinel1 purpose: to investigate the risk factors in women with urodynamic stress urinary incontinence (ustic) at a turkish tertiary referral center. materials and methods: the urodynamic records of 3038 consecutive women were analyzed between 1990 and 2011. the patients who had etiological factor of neurologic disease were excluded. there were 1187 women who had ustic after urodynamic investigation and 274 women who had no incontinence symptoms were included in the study. multivariate analyses were done using logistic regression test to determine the risk factors for ustic. results: the mean age was 50.1 years (range, 86-18). increased age, vaginal delivery, cesarean section, anterior prolapse existence in physical examination, previous anti-incontinence surgery, and previous pelvic organ prolapse surgery was found to be significant risk factors for ustic at multivariate analyses. conclusion: there are risk factors for women to have ustic. increased age, having vaginal delivery, having cesarean section, anterior prolapse, previous anti-incontinence surgery and previous prolapse surgery were found to be risk factors for women to have ustic at this study. keywords: turkey; epidemiology; health behavior; pelvic floor; physiopathology; prevalence; prospective studies; urinary ıncontinence; stress. introduction stress urinary incontinence (sui) is urinary incon-tinence (ui) during exertion, straining, exercise, coughing or sneezing.(1) sui is a non-life threatening condition, but can have negative impacts on social and psychological status. ui will occur without detrusor contraction, if there is an inability of urethral closure mechanism (sphincter insufficiency) when abdominal pressure increases due to exertion, straining, exercise, coughing or sneezing under urodynamic observation. this type of incontinence is defined as urodynamic stress urinary incontinence (ustic) in terminology of international continence society (ics).(2) ustic is an objective and valuable data for physicians to start treating sui in patients. many epidemiological studies have investigated potential risk factors for ui.(3-6) increased age, gynecological surgery, menopausal status, multiparity and etc. have been proposed as risk factors. we aimed to select frequently seen variables. we investigated the age, diabetes mellitus and pelvic organ prolapse (pop) as non-modifiable variables; and vaginal delivery, cesarean section, previous anti-incontinence or pop surgery, previous pelvic surgery and hysterectomy as modifiable variables to be a risk factor for ustic in this study. we aimed to investigate the risk factors in women with ustic and help the other physicians use our findings at their daily examinations. materials and methods study population a total of 3038 women who had urodynamic tests in our clinic between 1990 and 2011 were retrospectively reviewed. our urodynamic unit is a specialized clinic at our department. the archives of the patients are collected by a specialized nurse at our urodynamic unit. the cases were selected depending on our present multivariate analyses study. women who had neurological diseases were excluded. there were 1187 women who were diagnosed as ustic after urodynamic examination, and 274 women without urinary incontinence complaint were included in the study out of 1461 women. vaginal examination with cough stress test, measurement of urine volume, urinary flow study and measurement of post voiding residual urine (pvr) were performed prior to multi-channel urodynamic study in our urodynamic unit. a multichannel urodynamic study, including the pressure-flow study, was also performed, if it is required. all urodynamic studies were performed according to the guidelines of the ics.(7) three physicians (bc, od, bo) who were experienced and well trained in urodynamic study, analyzed patient’ medical records including questionnaires and the urodynamic studies of the patients retrospectively. all terms and definitions are in accordance with the ics terminology. (2) the term ustic, which was used in this study, was defined by ics as the involuntary leakage of the urine 1 department of urology, cerrahpasa school of medicine, university of istanbul, istanbul, turkey. 2 department of public health, cerrahpasa school of medicine, university of istanbul, istanbul, turkey. 3 cerrahpasa school of medicine, university of istanbul, istanbul, turkey. *correspondence: kocamustafapasa cd. no:53 34098 fatih, istanbul, turkey. tel: + 90 212 571 3570 . e-mail: drsinharib@yahoo.com. rceived october 2014 & accepted march 2015 vol 12 no 03 may-june 2015 2187 during increased abdominal pressure in the absence of a detrusor contraction.(2) approval for this study was given by ethical committee of cerrahpasa school of medicine, istanbul university (irb number: 32821). statistical analysis the dependent variable of the study was having ustic. the independent variables of this study were age, vaginal delivery, cesarean section, diabetes mellitus, pop, previous anti-incontinence surgery, previous pop surgery, previous pelvic surgery (colorectal operations and other gynecological operations such as oophorectomy), and hysterectomy. numerical variables were expressed with mean and standard deviation (sd), while categorical variables were expressed with frequency and percentage (%) values in this study. all independent variables were included in the logistic regression test. menopausal status which can be independent variable of the study, was not included in multivariate analysis because of its correlation with age. risk analysis was done separately for vaginal delivery and cesarean section. odds ratio (or) and 95% confidence interval (ci) were calculated. risk factors for ustic were examined by using backward logistic regression in multivariate analysis. the entry and removal threshold p values were .05 and .10 for this study. statistical analyzes were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. the p value < .05 was accepted as statistically significant. results the mean age was calculated as 50.1 years (range, 18-86). in multivariate analysis; age, vaginal delivery, cesarean section, anterior prolapse finding in physical examination, previous anti-incontinence surgery and previous pop surgery were the significant risk factors for ustic (table 1). increasing age was associated with increased detection of ustic (or = 1.03, 95% ci: 1.02-1.04; p < .001). vaginal delivery and cesarean section were found to be independent risk factors for ustic (or = 2.81, 95% ci: 2.08-3.78; p < .001 and or = 2.51, 95% ci: 1.47-4.30; p < .001, respectively). anterior prolapse was found to be an independent risk factor for ustic (or = 2.56, 95% ci: 1.783.76; p < .001), however posterior or apical prolapse were not. previous anti-incontinence surgery and previous pop surgery were as independent risk factors for ustic (or = 2.69, 95% ci: 1.18-6.15; p < .019 and or = 2.30, 95% ci: 1.08-4.92, respectively), however hysterectomy or previous pelvic surgery were not. in addition, diabetes mellitus did not reach statistical significance as a risk factor for sui. the risk analysis for vaginal delivery and cesarean section was assessed separately with univariate analysis. calculated or value was 3.66 (95% ci: 2.75-4.87) for having birth (table 2). in addition, while or for vaginal delivery was 3.09 (95% ci: 2.35-4.07), the value for cesarean delivery was not statistically significant (table 3). discussion sui is a common condition in women with a prevalence of 35.5% in urology and obstetrics and gynecology outpatient clinics in our country.(8) it is similar in the other european countries with a prevalence of 35%.(9) the potential risk factors for sui have been investigated in some epidemiological studies.(3-6) age, diabetes mellitus, menopause, genetic factors, ischemic heart disease and lung disease have been considered as non-modifiable variables and pregnancy/childbirth, obesity/body mass index, hormone replacement therapy, hysterectomy, smoking, diet and many other variables have been considered as modifiable variables risk factors for ui in existing literature,.(10-16) in this multivariate analysis study that we investigated the risk factors for ustic in women, age was as a non-modifiable variable and vaginal delivery, cesarean section, variables number adjusted odds p value ratio (95% ci) age 1461 1.03 (1.02-1.04) < .001 vaginal delivery no 386 reference < .001 yes 1075 2.81 (2.08-3.78) cesarean section no 1328 reference < .001 yes 133 2.51 (1.47-4.30) anterior prolapse no 446 reference < .001 yes 1015 2.56 (1.78-3.76) previous anti-incontinence surgery no 1364 reference .019 yes 97 2.69 (1.18-6.15) previous pelvic organ prolapse surgery no 1336 reference .032 yes 125 2.30 (1.08-4.92) previous pelvic surgery no 1093 reference .067 yes 368 0.54 (0.28-1.05) previous hysterectomy no 1280 reference .064 yes 181 1.94 (0.96-3.94) table 1. the multivariate predictors of urodynamic stress urinary incontinence (ustic). abbreviation: ci, confidence interval. variables ustic total no yes number to have a birth no 113 (37.2) 191 (62.8) 304 (100.0) yes 161 (13.9) 996 (86.1) 1157 (100.0) total 274 (18.8) 1187 (81.2) 1461 (100.0) abbreviations: ustic, urodynamic stress urinary incontinence; or, odds ratio; ci, confidence interval. * data are presented as no (%). or was 3.66 (95% ci: 2.75-4.87) for having a history of birth.* table 2. the risk analysis for birth and ustic. risk factors for sui in turkish women-citgez at al. female urology 2188 anterior prolapse, previous anti-incontinence surgery and previous pop surgery were modifiable variables. recent many studies have found increased prevalence of ui with increasing age.(3-5) notwithstanding, ui is not inevitable with increasing age. however the bladder and the pelvic structures change with age, and these changes contribute to ui.(10) while stress type ui is common in young and middle-aged women, urge type and mixed type ui is common in middle-aged and older age.(5) increasing age was found as a significant risk factor for ustic in women in our study (or = 1.03, 95% ci: 1.02-1.04; p < .001). sui can be seen throughout pregnancy, especially in third trimester and generally improves after delivery. however, they may occur after delivery again and continue.(11,12) in addition, women who have sui in pregnancy have higher risk for sui throughout life, even if they recover after delivery.(13) the reason for this is unclear. physiological changes during pregnancy may be the cause of sui. the patients who have chance to get sui, might result in having the sui because of the physiological changes regardless the pregnancy, or pregnancy might trigger the existing problem. there are many studies about ui at delivery and after delivery in existing literature.(14,15) or was 2.81 (95% ci: 2.08-3.78; p < .001) for vaginal delivery in our study. some studies emphasized that the increased risk of ui by one labor, has not more increased even if the number of parity increase.(15) however, some contrary studies have demonstrated the increased risk of ui with increasing parity.(17) it is difficult to differentiate the risk at pregnancy and vaginal delivery. the risk at vaginal delivery may be explained by the injury caused by stretching of pudendal and other nerves or tissue damage that support pelvic floor.(18) the women who had vaginal delivery are compared to those who have cesarean section by the authors to reveal the differentiation between the impact of vaginal delivery separately from the impact of pregnancy itself for the risk of ui. vaginal delivery compared with cesarean section was found to be a risk factor for incontinence in postpartum period, later in life and particularly for sui in most of these studies.(19) rortveit and colleagues, in their comprehensive studies that involved more than 15,000 women, have demonstrated increased risk for sui and mixed ui (or = 1.5) in women who had only cesarean section compared with nulliparous.(19) furthermore, they demonstrated that those women who had only vaginal delivery have higher risk for sui than women who had only cesarean section (or = 2.4). the effects of different types of delivery on ui have been addressed in some studies. the women, with vaginal delivery have greater risk (1.7 to 2.8 folds) for developing sui compared with the women who had cesarean section.(5,19) in the present study or for vaginal birth was 2.81 (95% ci: 2.08-3.78; p < .001) and or for cesarean section was 2.51 (95% ci: 1.47-4.30; p < .001) which demonstrates statistically significant difference. in addition, we performed univariate analysis to assess the risk analysis separately for vaginal and cesarean birth. as a result, calculated or value was 3.66 (95% ci: 2.75-4.87) for having birth (table 2). the estimated relative risk for vaginal birth was 3.09 (95% ci: 2.35-4.07), while the risk for cesarean section was not statistically significant (table 3). pop and ui are common conditions in women and mostly seen together. pelvic floor with fascia and muscles is important in maintaining continence and pelvic support. due to factors such as changing of pelvic floor muscles and collagen structure, deterioration of continence and pelvic support may be possible with aging and delivery. support for the bladder neck is important, especially for sui. the signs of pelvic denervation have been shown with increasing age and after birth,(20,21) and these changes are more common in women with pop or sui.(22) in addition, authors against denervation hypothesis couldn’t find signs of denervation in pelvic floor at biopsies of women with pop and ui.(23) in samuelsson and colleagues’ studies that involves 641 young and middle-age women, demonstrated that women with anterior prolapse had higher risk for sui and estimated relative risk was 2.5-fold (95% ci: 1.5-4.2).(17) anterior prolapse was as a significant risk factor with an or of 2.56 (95% ci: 1.78-3.76; p < .001) at our present study. prior incontinence surgery was also found as a risk factor in the present study (or = 2.69, 95% ci: 1.18 6.15; p < .019). in fact, treatment failure and relapses are not unexpected situations. in these patients, the reasons for incontinence are still discussed that if it’s due to treatment failure, relapse or damage in pelvic nerves and pelvic support due to operation. since we think that all of these factors may play a role, previous incontinence surgery was added to the statistical analysis and found to be an independent risk factor for ustic. effects of pelvic surgery and especially hysterectomy on ui in women are situations that were investigated and are still being researched.(24,25) as an example, the effect of pop surgery in sui is complex. sometimes after pop surgery, ustic will improve and sometimes due to pop, sui that was hidden will occur.(26) the pop surgery’s approach, injury to pelvic nerves and supporting structures may affect this result. as a result, pop surgery may be a risk factor for sui. previous pop surgery was found to be a risk factor for ustic in the present study, (or = 2.30, 95% ci: 1.08-4.92; p < .032). however in multivariate analysis, previous other pelvic surgeries (e.g., other gynecological operations) were not found to be a risk factor (p = .067). hysterectomy is thought that may cause to ui because of the damage to pelvic nerves and pelvic support structable 3. the correlation between type of delivery and ustic. variables ustic* total no yes number cesarean section no 255 (19.2) 1073 (80.8) 1328 (100.0) yes 19 (14.3) 114 (85.7) 133 (100.0) total 274 (18.8) 1187 (81.2) 1461 (100.0) vaginal delivery ustic* total no yes number no 127 (32.9) 259 (76.1) 386 (100.0) yes 147 (13.7) 928 (86.3) 1075 (100.0) total 274 (18.8) 1187 (81.2) 1461 (100.0) abbreviations: ustic, urodynamic stress urinary incontinence; or, odds ratio; ci, confidence interval. * data are presented as no (%). or was 3.09 (95% ci: 2.35-4.07) for vaginal delivery. risk factors for sui in turkish women-citgez at al. vol 12 no 03 may-june 2015 2189 tures.(24,25) however, in a large proportion of the studies, significant increase in ui after hysterectomy has not demonstrated.(27) in addition, some studies have shown statistically significant decrease of ui after hysterectomy.(28) although content of these studies is not high quality; the more comprehensive and prospective studies also have not found any increase in rate of ui in follow-up of patients with a history of hysterectomy.(29) while the relationship between hysterectomy and ui was not shown in these prospective studies, ui was related to women with previous hysterectomy and estimated relative risk was ranged from 1.2 to 2.1 in some studies.(30) in a prospective study, urge incontinence was found to be related with hysterectomy but not stress incontinence.(31) as a result, relationship between hysterectomy and ui is not clear. in our study the multivariate analysis showed that hysterectomy does not increase the risk of ustic (p = .064). there are several limitations in our study. one weakness of our study is that our data were collected retrospectively. the data were verified retrospectively while they were collected longitudinally and that might cause error. our center is one of the major hospitals in our region. a total of 1461 consecutive women were included in this study. however, the majority of our patients were referred from other hospitals; this may create an extensive patient selection bias and may influence our results. our results suggest that; age, vaginal delivery, cesarean section, anterior prolapse finding in physical examination, previous anti-incontinence surgery and previous pop surgery were statistically significant risk factor for ustic in women. however, future studies should be prospectively designed to overcome existing limitations. conclusion in summary, there are risk factors for ustic in women. in this multivariate study, age, vaginal delivery, cesarean section, anterior prolapse finding in vaginal examination, previous anti-incontinence surgery and previous pop surgery have found to be statistically significant risk factors for ustic. physicians should remember these modifiable variables and share with patients who will have vaginal delivery, cesarean section or other surgeries, mentioned above. however, there is no consensus to prevent sui or ustic in this patient group. in addition, age is a non-modifiable variable risk factor for ustic in women during their life. conflict of interest none declared. references 1. haylen bt, de ridder d, freeman rm, et al. an international urogynecological association (iuga)/international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. int urogynecol j. 2010;21:5-26. 2. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002;21:167-78. 3. hannestad ys, rortveit, g, sandvik h, hunskaar s. a community based epidemiological survey of female urinary incontinence: the norwegian epincont study. epidemiology of incontinence in the county of nord-trondelag. j clin epidemiol. 2000;53:1150-7. 4. aggazzotti g, pesce f, grassi d, et al. prevalence of urinary incontinence among institutionalized patients: a cross-sectional epidemiologic study in a midsized city in northern italy. urology. 2000;56:245-9. 5. peyrat l, haillot o, bruyere f, boutin jm, bertrand p, lanson y. prevalence and risk factors of urinary incontinence in young and middle-aged women. bju int. 2002;89:61-6. 6. guzelsoy m, demirci h, coban s, belkiz güngör b, ustunyurt e, isildak s. impact of urinary incontinence on the quality of life among residents living in turkey. urol j. 2014;11:1447-51. 7. schafer w, abrams p, liao l, et al. international continence society. good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies. neurourol urodyn. 2002;21:261-74. 8. cetinel b, demirkesen o, tarcan t, et al. hidden female urinary incontinence in urology and obstetrics and gynecology outpatient clinics in turkey: what are the determinants of bothersome urinary incontinence and helpseeking behavior? int urogynecol j pelvic floor dysfunct. 2007;18:659-64. 9. hunskaar s, lose g, sykes d, voss s. the prevalence of urinary incontinence in women in four european countries. bju int. 2004;93:324-30. 10. diokno ac, brown mb, brock bm, herzog ar, norolle dp. clinical and cystometric characteristics of continent and incontinent noninstitutionalized elderly. j urol. 1988;140:565-71. 11. burgio kl, zyczynski h, locher jl, richter he, redden dt, wright kc. urinary incontinence in the 12-month postpartum period. obstet gynecol. 2003;102:1291-8. 12. viktrup l, lose g. the risk of stress incontinence 5 years after first delivery. am j obstet gynecol. 2001;185:82-7. 13. altman, d, ekstrom a, gustafsson c, lopez a, falconer c, zetterström j. risk of urinary incontinence after childbirth: a 10-year prospective cohort study. obstet gynecol. 2006;108:873-8. 14. persson j, wolner-hanssen p, rydhstroem h. obstetric risk factors for stress urinary incontinence: a population based study. obstet gynecol. 2000;96:440-5. 15. rortveit g, hannestad ys, daltveit ak, hunskaar s. ageand type-dependent effects of parity on urinary incontinence: the norwegian epincont study. obstet gynecol. 2001;98:1004-10. 16. reena c, kekre an, kekre n. occult stress risk factors for sui in turkish women-citgez at al. female urology 2190 incontinence in women with pelvic organ prolapse. int j gynaecol obstet. 2007;97:31-4. 17. samuelsson e, victor a, svardsudd k. determinants of urinary incontinence in a population of young and middle aged women. acta obstet gynecol scand. 2000;79:208-15. 18. handa vl, harris ta, ostergard dr. protecting the pelvic floor: obstetric management to prevent incontinence and pelvic organ prolapse. obstet gynecol. 1996;88:470-8. 19. rortveit g, daltveit ak, hannestad ys, hunskaar s. urinary incontinence after vaginal delivery or cesarean section. n engl j med. 2003;348:900-7. 20. smith arb, hosker gl, warrell dw. the role of partial denervation of the pelvic floor in the aethiology of genitourinary prolapse and stress incontinence of urine. a neurophysiological study. br j obstet gynaecol. 1989;96:24-8. 21. snook sj, swash m, mathers se, henry mm. effect of vaginal delivery on the pelvic floor: a 5-year follow-up. br j surg. 1990;77:1358-60. 22. gilpin sa, gosling ja, smith ar, warrell dw. the pathogenesis of genitourinary prolapse and stress incontinence of urine. a histological and histochemical study. br j obstet gynaecol. 1989;96:15-23. 23. heit m, benson t, russell b, brubaker l. levator ani muscle in women with genitourinary prolapse: indirect assessment by muscle histopathology. neurourol urodyn. 1996;15:17-29. 24. parys bt, haylen bt, hutton jl, parsons kf. the effects of simple hysterectomy on vesicourethral function. br j urol. 1989;64:594-9. 25. parys, bt, woolfenden ka, parsons kf. bladder dysfunction after simple hysterectomy: urodynamic and neurological evaluation. eur urol. 1990;17:129-33. 26. borstad e, abdelnoor m, staff ac, kulsenghanssen s. surgical strategies for women with pelvic organ prolapse and urinary stress incontinence. int urogynecol j. 2010;21:17986. 27. farquharson di, shingleton hm, orr jw jr, hatch kd, hester s, soong sj. the shortterm effect of radical hysterectomy on urethral and bladder function. br j obstet gynaecol. 1987;94.351-357. 28. virtanen h, makinen j, tenho t, kiilholma p, pitkanen y, hirvonen t. effects of abdominal hysterectomy on urinary and sexual symptoms. br j urol. 1993;72:868-72. 29. bhattacharya s, mollison j, pinion s, et al. a comparison of bladder and ovarian function two years following hysterectomy or endometrial ablation. br j obstet gynaecol. 1996;103:898-903. 30. fenner de, trowbridge er, patel dl, et al. establishing the prevalence of incontinence study: racial differences in women›s patterns of urinary incontinence. j urol. 2008;179:145560. 31. jackson sl, scholes d, boyko ej, abraham l, fihn sd. predictors of urinary incontinence in a prospective cohort of postmenopausal women. obstet gynecol. 2006;108:855-62. risk factors for sui in turkish women-citgez at al. vol 12 no 03 may-june 2015 2191 miscellaneous evaluation of urinary calculi by infrared spectroscopy mehrsai a1, taghizadeh afshar a2, zohrevand r1, djaladat h1 steffes hj3, hesse a3, pourmand gh1 1urology department, tehran university of medical sciences, tehran, iran 2urology department, oroomieh university of medical sciences, oroomieh, iran 3urology department, bonn university, bonn abstract purpose: to analyze urinary calculi composition and its relationship with gender, age, calculus weight, color, and location. materials and methods: two hundred and forty one patients with urinary calculus, who had undergone open lithotomy from june 1999 to april 2001, were enrolled in this prospective study which was performed by tehran and oroomieh medical sciences universities. the calculi compositions were analyzed by infrared spectroscopy in bonn university. statistical analyses were made by paired t test results: one hundred and forty five males with a mean age of 40.4 years and 96 females with a mean age of 42.5 years were enrolled in this study. mean calculus weight was 4.28 gr. mean calculus number was 4.33. thirty four (14.1%) calculi were pure (carbonate apatite: 2, brushite: 1, uric acid: 19, cystine: 3, weddellite: 6, mononh4-urate: 2, struvite: 1), 207(85.6%) were mixed and none of them contained octa-caphosphate, apatite, newberyte, 2,8-dihydroxyadenine, mono-na-urate, or xanthine. weddellite was found in 77% of calculi. it comprised more than 50% of them in 26% of cases. whewellite crystals were found in 78% of calculi. it comprised more than 50% of them in 46% of cases. the most common pure calculus was uric acid and the most common component of calculi was whewellite followed by weddellite. conclusion: although there is no comprehensive study on urolithiasis incidence and prevalence in iran, it can be concluded that whewellite and weddellite may be the most common components of urolithiasis in iran and uric acid calculi are the most common pure calculi. there was no significant difference in calculi composition in our study. key words: urinary stone, infrared spectroscopy, whewellite, weddellite 191 urology journal unrc/iua vol. 1, no. 3, 191-194 summer 2004 printed in iran introduction urinary calculi have a long history returning to 7000 years age. renal and bladder calculi were the first to be discovered in egypt about 4800 bc.(1) despite long history, no accurate method has been detected so far to control and prevent the formation of these calculi. the exact prevalence and incidence rates of urinary calculi in iran are not clear. in this survey 241 iranian patients with urinary calculi underwent open surgery and their calculi composition was analysed by infrared spectroscopy in bonn university. obviously, obtaining information about calculi composition could lead to find out their metabolic bases, effective factors in their formation and the way to prevent them. the relationship between calculi composition and gender, age, calculus weight, location, and color were also studied in this survey. the results were accepted for publication in april 2004 evaluation of urinary calculi by infrared spectroscopy compared to the results of similar studies conducted in iran and other countries. materials and methods one hundred and forty five males and 96 females with mean ages of 40.4 and 42.5 years, respectively, were enrolled in this study, whose urinary calculi were removed through open surgery from june 1999 to april 2001. one hundred and sixty seven of these patients were referred to tehran university of medical sciences (sina hospital) and 74 were referred to oroomieh university of medical sciences. the calculi were analyzed by infrared spectroscopy in bonn university (med einrichtungen der universitat bonn). number of calculi, their color, weight, surface, components, as well as patients' gender and age were studied. the results were analyzed by paired t test. results one hundred and forty five males and 96 females with a mean age of 42.15 (range 3 to 85) years, whose urinary calculi were removed by an open surgery, were studied. seventy five females and 92 males were referred to tehran university of medical sciences (sina hospital), while, 23 females and 51 males were referred to oroomieh university of medical sciences. the results of calculi analysis were as follows: six children under 12 years were among the patients. their calculi composition consisted of whewellite (mostly), weddellite, struvite, carbonate apatite, mono-nh4-urate, and cystine. the mean calculus weight was about 4.28 gr (3.95 gr in females and 4.53 gr in males). the mean number of calculi was about 4.33 (range 1 to 20). the location of calculi was right kidney in 65(26.9%), left kidney in 73(30.2%), right ureter in 46(19%), left ureter in 47(20%), and bladder or urethra in 10(4%). according to calculus analysis, 34 calculi (14.1%) were pure (table 1). uric acid calculi were the most common pure calculi. the other 207(85.9%) calculi were mixed calculi, which were composed of different components. none of them contained octa-ca-phosphate, newberyte, apatite, 2,8-dihydroxyadenine, mono-na-urate, and xanthine. weddellite was seen in 77% of them. it contained more than 50% of the calculus in about 26% of patients. moreover, whewellite was found in 78% of them and it contained more than 50% of the calculus in 46% of patients. the incidence of other crystals is indicated in table 2. brown was the most common color of urinary calculi (more than 90% of calculi with whewellite or weddellite components). there was no significant difference between the results of calculus analysis and components in the patients who were referred to tehran university of medical sciences (167 patients) and oroomieh university of medical sciences (74 patients). the distribution of calculi location according to gender is indicated in table 3. discussion generally, the possibility of calculus formation differs in various parts of the world: 1% to 5% in asia, 5% to 9% in europe, 13% in north america, and 20% in saudi arabia.(2) the accurate incidence rate of urinary calculi in iran is not clear; however, regarding this study, mixed calculi (85.9%) were the most common ones and whewellite crystals were the most common component of urinary calculi. these results are consonant with previous studies, which indi192 the material of pure calculus number uric acid 19 oxalate-ca-dihydrate 6 cystine 3 carbonate apatite 2 mono-nh4-urate 2 brushite 1 struvite 1 table 1. frequency of pure calculi according to calculus material number minimum (%) maximum (%) mean (%) standard deviation whewellite 191 5 95 51.43 23.11 weddellite 190 5 100 43.71 24.35 struvite 7 5 100 50 38.62 carbonate apatite 94 5 100 18.01 22.26 whitlockite 1 20 20 20 0 brushite 2 10 100 55 63.64 uric acid 39 5 100 71.06 34.45 hs-dihydrate 6 10 20 18.33 4.08 mono-nh4urate 12 10 100 42.50 29.28 cystine 3 100 100 100 0 table 2. distribution of calculus components in 241 patients right kidney left kidney right ureter left ureter bladder urethra male 32 42 28 31 10 gender female 33 31 18 16 0 table 3. distribution of the place of calculus according to gender evaluation of urinary calculi by infrared spectroscopy cate the frequency of upper urinary system calculi in patients from industrial countries (such as the united states and germany) and developing countries (such as sudan and thailand).(3,4) no particular relationship was seen between the location of calculus or its weight and the components. considering previous studies, primary bladder calculi are relatively common in asia and mostly formed from nh4-urate and ca-oxalate crystals;(5) while, in this study weddelitte crystals were the most common components of bladder and urethral calculi. the incidence rate of cystine calculi is nearly 1% to 3%.(6) about 1% of calculi were cystine in this study. different results of calculi analysis by infrared have been obtained from similar studies, conducted in various parts of the world. as in a study performed on 80 urinary calculi in morocco in 2000, it was found that calcium monohydrate was the most common component of oxalate calculi. the calculi were mixed in 91.25% of cases.(7) although mixed calculi were the most common in this study (85.9%), whewellite and weddellite were the most common components of them in all ages. calcium oxalate is the most common calculus component in sudanese children and this result is the same in germany, but with a lower prevalence.(8) furthermore, the analysis of children urinary calculi in morocco by infrared spectroscopy indicated that whewellite was found in 84.4% of cases and weddellite in 26.7%.(9) these results agree with our findings. obviously, for more accurate determination of the prevalence of calculi components in iranian children, further studies are needed. the prevalence of uric acid calculi in our patients was 16%, which was a little more than that in sudan and germany (12%).(8) the distribution of uric acid calculi in german males was more than that in females (10 to 1); while, this ratio was equal in sudan and 1.5 to 1 in our patients. other studies indicate that struvite calculi are more common in females; while, a female to male ratio of 2/5 was obtained in this study. the prevalence of other calculi components was approximately similar in both genders. regarding previous studies, the prevalence of mono-nh4-urate calculi is very low in germany; however, these calculi were seen in 5% of the cases in this study and in more than 30% of calculi of sudanese children, which was due to their malnutrition. a high prevalence of mono-nh4urate calculi was seen in thai patients.(8) it seems that genetic or nutritional factors (high consumption of protein in industrial countries and high consumption of carbohydrates in developing countries) accounts for the difference of calculi components in various countries. conclusion there is no comprehensive study on the prevalence and incidence rates of urinary calculi in iran. however, considering the findings of this study and similar previous studies,(10) weddellite and whewellite were the most common calculi components in our patients. urinary calculi components in iran may be approximately similar to those of sudan, taiwan,(11) and germany. however, components such as weddellite and carbonate apatite are more common in sudanese patients. moreover, mono-nh4-urate calculi were less common in the studied iranian children as well as german children in comparison to sudanese children.(8) there was no significant difference in the results of urinary calculi analysis of patients who were referred to tehran university of medical sciences and oroomieh university of medical sciences. references 1. menon m, parulkar bp, drach gw. urinary lithiaisis: etiology, diagnosis and medical management. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell's urology. 7th ed. philadelphia: wb saunders; 1998. p. 2661-2734. 2. ramello a, vitale c, maangella m. epidemiology of nephrolithasis. j nephrol 2000 nov-dec; 13 (suppl 3): s45-50. 3. sutor dj. ammonium acid urate and its role in the pattern of stone composition. in: van reen r, editor. proceeding who regional symposium on vesical calculus disease. dhew publication no. (nih) 77-1191; 1972. p. 206-213. 4. sutor dj, woley se, illing worth jj. a geographical and historical survey of the composition of urinary stones. j urol 1974; 43: 393-407. 5. trinchieri a. epidemiology of urolithiasis; arch ital urol androl 1996 sep; 68(4): 203-49. 6. menon m, resnick mi. urinary lithiaisis: etiology, diagnosis and medical management. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 3264-3265. 7. bennani s, debbagh a, oussama a, el mrini m, benjelloun s. infrared spectrometry and urolithiasis: report of 80 cases. ann urol 2000 dec; 34(6): 376-83. 193 evaluation of urinary calculi by infrared spectroscopy 8. balla aa, salah am, khattab ah, et al. mineral composition of renal stones from the sudan. urol int 1998; 61: 154-156. 9. oussama a, kzaiber f, mernari b, semmoud a, daudon m. analysis of calculi by infrared spectroscopy in children from the moroccan mid-atlas region. ann urol 2000 dec; 34(6): 384-90. 10. minon cifuentes j, pourmand g. mineral composition of 103 stones from iran. brit j urol 1983; 55(5): 465-8. 11. lee yh, chen mt, huang jk, chang ls. analysis of urinary calculi by infrared spectroscopy. zhonghua yi xue za zhi (taipei). 1990; 45(3): 157-65. 194 review recombinant human erythropoietin for kidney transplantation: a systematic review and meta-analysis jiaojiao zhou1, jing lu2, diming cai1*. purpose: the protective effect of recombinant human erythropoietin (rhuepo) on kidney transplantation has not been established. therefore, we conducted a systematic review and meta-analysis to evaluate the potential influence of rhuepo on transplanted kidneys. materials and methods: to identify relevant studies, we searched electronic databases (pubmed, medline, embase, ovid, the cochrane library, and major nephrology journals) from inception until june 15, 2018. two independent reviewers assessed study quality. the systematic review and meta-analysis were performed with fixedor random-effects models according to heterogeneity, and results are expressed as risk ratios (rr) or weighted mean differences. results: six randomized controlled trials with a total of 435 patients met the inclusion criteria. rhuepo, compared with placebo, had no statistically significant effect on delayed graft function (rr = 0.89, 95% confidence interval [ci] , 0.73 to 1.07; p = 0.22) and slow graft function (rr = 0.93, 95% ci, 0.60 to 1.43; p = 0.73). the rhuepo and control groups did not differ in thromboembolic events, mortality, acute rejection, and blood transfusion. a significant difference was found in long-term estimated glomerular filtration rate (rr = 3.65, 95% ci, -4.45 to 11.75; p = 0.003). conclusion: our findings suggests that rhuepo has a limited nephroprotective effect in patients undergoing kidney transplantation and does not increase the susceptibility to adverse events. keywords: recombinant human erythropoietin; kidney transplantation; allograft function; delayed graft function; systematic review and meta-analysis introduction erythropoietin (epo) is a hematopoietic growth fac-tor synthesized in response to hypoxemia by fibroblast-like cells in the kidney cortex. it is widely used to treat renal and non-renal anemia, especially in chronic kidney disease and hematopoietic diseases.(1) however, it has pleiotropic effects beyond the maintenance of red blood cell mass,(2,3) playing a role in the protection from inflammation and apoptosis due to of hypoxia, toxicity, or injury.(4) previous studies suggested recombinant human epo (rhuepo) has important cytoprotective effects on various cells and organs, as well as providing protection from ischemia-reperfusion injury (iri).(5-7) kidney transplantation is the treatment of choice for patients with end-stage renal disease to optimize survival, with more favorable lifestyle results and a reduction in mortality rate.(8,9) delayed graft function (dgf), leading to major comorbidities including iri, plays a crucial role in long-term graft function after transplantation.(10,11) a previous report estimated an average annual dgf rate of 21.9% for deceased-donor kidney transplants and 3.5% for living-donor kidney transplants in the united states.(12) improving renal allograft function and survival is a significant challenge in kidney transplantation. therefore, rhuepo is also included in the post-kidney transplantation management, which is a classical model of acute kidney injury (aki) due to iri. to verify this finding, several randomized controlled trials (rcts) have been performed in adult patients undergoing kidney transplantation; nevertheless, the results have been controversial. in this study, we performed a comprehensive systematic review and meta-analysis of rcts to examine the efficacy and safety of rhuepo on allograft function in patients receiving kidney transplantation. materials and methods this study was conducted in accordance with the preferred reporting items for systematic reviews and meta-analysis (prisma) statement.(13) literature search and selection criteria two reviewers (jiaojiao zhou and jing lu) independently searched pubmed, medline, embase, ovid, the cochrane library, and major nephrology journals from inception to january 28, 2015 without any limitation. to identify eligible rcts comparing the effect of rhuepo versus placebo on the prevention of dgf and 1division of ultrasound, west china hospital of sichuan university, chengdu, sichuan, china. 2division of nephrology, the seventh people's hospital of chengdu, the oncology hospital of chengdu, chengdu, sichuan, china. *correspondence:address: department of ultrasound, west china hospital of sichuan university, chengdu, 610041, p.r.china telephone and fax: 86 28 85423193. e-mail: doccai@163.com. received june 2019 & accepted december 2019 urology journal/vol 17 no. 3/ may-june 2020/ pp. 217-223. [doi: 10.22037/uj.v0i0.5399] slow graft function (sgf) after transplantation, we used the search terms “epo” or “epoetin” or “erythropoietin” or “rhuepo” and “renal transplantation” or “kidney transplantation.” reference lists of identified articles were searched for relevant studies and manually scanned to include additional eligible studies. we included studies that met the following criteria: (1) study population composed of adult patients (≥18 years of age) undergoing kidney transplantation; (2) rhuepo was compared with placebo; (3) the primary outcomes were the incidence of dgf and sgf; (4) rct study design. only articles that met all inclusion criteria were included in this study. definitions the classical definition of dgf as the need for dialysis within the first week after kidney transplantation was generally used, either totally unaltered or with minor additions. sgf was defined as a ≤40% decrease in serum creatinine at postoperative day 3. shortand longterm estimated glomerular filtration rates (egfrs) were considered as the values obtained 4 to 6 weeks and 6 months postoperatively, respectively. short-term blood pressure was defined as the value obtained 4 to 6 weeks postoperatively. data extraction and outcomes data extraction was performed by two reviewers (jiaojiao zhou and jing lu); the following items of were extracted: first author, publication year, baseline characteristics of patients, sample size, study design, intervention in the rhuepo group, intervention in the control group, the incidence of dgf and sgf, and adverse events related to rhuepo. additionally, extracted data were reexamined by a third reviewer (diming cai), and any disagreements were resolved by discussion. the primary outcomes were the incidence of dgf and sgf. secondary outcomes were allograft function, adverse events related to rhuepo, and mortality. statistical analysis outcome data were analyzed quantitatively using revman software version 5.3 (cochrane collaboration, 2014, london, uk). study quality was independently evaluated by two reviewers (jiaojiao zhou and jing lu) using a risk of bias summary graph. for categorical outcomes, risk ratios (rr) with 95% confidence intervals (ci) were estimated. for continuous outcomes, weighted mean differences (wmd) with 95% ci were calculated. cochran’s q-test and ι2 index were used to assess statistical heterogeneity. fixed-effects analysis (i2 < 50%) and random-effects analysis (i2 > 50%) were used in the systematic review and meta-analysis according to standard protocol. for sensitivity analyses, we removed each study separately, calculating rr or wmd after each removal for related outcomes and examined whether any significant changes occurred. results study characteristics of the 427 records identified, 404 were excluded after initial screening: 43 were duplicate records and 361 studies were rejected based on the title and abstract. of the remaining 23 full texts, 15 were excluded and 8 studies were retrieved for detailed evaluation. finally, six rcts fulfilled the inclusion criteria and were included in our study.(14-19) a flow diagram of the systematic literature search is presented in figure 1, and the basic characteristics of the included rcts are summarized in table 1. in total, 435 patients were included; of these, 212 patients (48.7%) were treated with rhuepo and 223 (51.3%) served as controls. most included studies showed a low to moderate risk of bias; detailed findings are displayed in table 2. remarkably, the rct of martinez et al.(17) had a high risk of bias because it was an open-label study in which the control group did not receive epo. moreover, the method of allocation rhuepo in kidney transplantation-zhou et al. table 1. the basic characteristics of studies included in the meta-analysis. author and year country study design rhuepo group control group patients (epo/con) follow-up time martine,2010 france open-label rct epo-β na 51/53 3 months aydin, 2012 netherlands double-blind rct epo-β saline 45/47 12 months hafer, 2012 germany double-blind rct epo-α saline 44/44 12 months sureshkumar, 2012 usa double-blind rct epo-α saline 36/36 1 month nafar, 2012 iran double-blind rct epo-α na 17/23 6 months coupes, 2015 uk double-blind rct epo-β saline 19/20 3 months rhuepo: recombinant human erythropoietin; epo: erythropoietin; na: not available; rct: randomized controlled trial; con:control. references random allocation blinding of blinding of outcome selective incomplete other sequence generation concealment participans and assessment reporting outcome data personnel martine, ? ? _ + + ? + 2010 aydin, + ? + + + + ? 2012 hafer, ? ? + ? + + + 2012 sureshkumar， + ? + ? + ? ? 2012 nafar, + ? + ? + + ? 2012 coupes, + ? + ? + + + 2015 table 2. the risk of bias summary graph. symbol explanation: (+): low risk of bias, (?): unclear risk of bias, (_): high risk of bias. review 218 vol 17 no 03 may-june 2020 219 concealment was unclear in all studies.(14-19) details of rhuepo treatment, as well as demographic and clinical characteristics of recipients and donors, are shown in tables 3 and 4, respectively. allograft function the incidence of dgf and sgf, primary non-function (pnf), and egfr values were recorded as the common parameters of allograft function endpoints. as described in figure 2a, a trend of reduced incidence of dgf was found in the rhuepo group (rhuepo vs. control groups: rr=0.89). however, this decrease did not reach statistical significance (five rcts, 95% ci, 0.73 to 1.07; p = 0.22). there was also no statistically significant difference in the occurrence of sgf between the two groups (three rcts, rr = 0.93, 95% ci, 0.60 to 1.43; p = 0.73). statistical heterogeneity across studies was not significant (p = 0.57, i2 = 0%, figure 2b). pnf rates were documented in three studies, and no significant difference was detected between patients treated with rhuepo and the control groups (figure 2c). no significant difference was detected in the occurrence of graft loss between the two groups (figure 2d). shortterm egfr data are shown in figure 3a; no significant difference was found between groups. on the contrary, a significant difference was seen in long-term egfr between the rhuepo and control groups (figure 3b). adverse events based on 435 patients in 6 trials, thromboembolic events were observed in 21 (10%) of 212 patients in the rhuepo groups and in 13 (5.8%) of 223 patients in the control groups. an efficacy meta-analysis indicated that, compared with control groups, rhuepo groups did not show a significant increase in the risk of thromboembolic events (five rcts, rr =1.64, 95% ci, 0.86 to table 3. the detail and method of rhuepo. author type single rhuepo dose total rhuepo dose no. of doses method of rhuepo martine, 2010 epo-β 30 000 iu 120 000 iu 4 0.5–3 h before kt 12–24 h after kt 7 days after kt 14 days after kt aydin, 2012 epo-β 33 000 iu 99 000 iu 3 3 h before kt 24 h after kt 48 h after kt hafer, 2012 epo-α 40 000 iu 120 000 iu 3 at intraoperation 3 days after kt 7 days after kt sureshkumar,2012 epo-α 40 000 iu 40 000 iu 1 at intraoperation nafar, 2012 epo-α 2000 u 6000 u 3 thrice per week, 1 day after kt for one week coupes, 2015 epo-β 33 000 iu 99 000 iu 3 at intraoperation 24 h after kt 48 h after kt rhuepo: recombinant human erythropoietin; epo: erythropoietin; kt: kidney transplantation study martine aydin hafer sureshkumar nafar coupes epo/con epo/con epo/con epo/con epo/con epo/con age(years) 60.0 ± 7.7/58.9±9.5 51.0 ± 14.0 53.6 ± 1.8/49.8±1.6 58.0 ± 11.0/56.0 ± 13.0 45.4 ± 12.2/48.3 ± 15.5 51(43-63)/53(46-66) gender(males %) 66.7%/56.6% 71.0%/70.0% 56.8%/59.1% 56.0%/53.0% 59.0%/52.0% 53.0%/65.0% bmi(kg/m2) 25.1 ± 4.6/23.8 ± 4.1 na 25.3 ± 0.6/25.9 ± 0.6 27.8 ± 5.4/28.3 ± 6.4 na 25(23-27)/ 25(23-29) cold ischemia 18.8 ± 4.9/19.9 ± 6.9 17.0 ± 4.0/17.0 ± 4.0 12.5 ± 0.6/13.4 ± 0.8 24.1 ± 6.1/26.3 ± 8.0 na 16.9/16.8 time (hours) donor age (years) 65.3 ± 9.4/65.1 ± 8.4 45.0 ± 13.0/49.0±17.0 na 39.0 ± 17.0/41.0 ± 17.0 na 52(45-58)/ 53(46-66) donor death 64.7%/73.6% 44%/40% na 19%/39% na 74%/70% from cva(%) donor renal function 91.6 ± 39.5/92.3 ± 36.0 0.86 ± 0.58/0.93 ± 0.57 na 1.14 ± 0.85/1.18 ± 0.90 na 61(51-87)/ 77(66-96) (egfr,ml/min) (scr, mg/dl) (scr, mg/dl) (μmol/l) induction basiliximab daclizumab basiliximab basiliximab or na basiliximab immunosuppr-ession alemtuzumab or atg maintenance immunosuppr-ession tacrolimus, cyclosporine, tacrolimus or tacrolimus or cyclosporine tacrolimus, mmf, prednisone mmf, steroids cyclosporine, cyclosporine, mmf, prednisone mmf, mmf, prednisone mmf, steroids prednisolone recipient previous 48%/50% 4.3 ± 1.7 /4.0 ± 1.9 88.4 ± 5.1/67.6 ± 4.9 na na 30(6-51)/42(22-52) dialysis (%) (years) (month) (month) epo: erythropoietin; con:control; bmi: body mass index; na: not available; cva: cerebral vascular accident; mmf: mycophenolate mofetil; egfr: estimated glomerular filtration rate; scr: serum creatinine ; atg: antithymocyte globulin. data are presented as percentages or mean±standard deviation or median (iqr). table 4. the demographic and clinical characteristics of recipients and donors. rhuepo in kidney transplantation-zhou et al. 3.13; p = 0.13) with negligible statistical heterogeneity (i2 = 41%, figure 4a). four studies showed no statistically significant difference in the occurrence of acute rejection between the two groups (figure 4b). furthermore, the incidence of blood transfusion was similar in the two groups (figure 4c). mortality was documented in all studies; sureshkumar et al.(14) and nafar et al.(18) reported no deaths in their studies (figure 4d). blood pressure was assessed at different timepoints in each study. in the studies by sureshkumar et al. 14) and martinez et al.(17) blood pressure was reported at 4 weeks after transplantation, while aydin et al. recorded blood pressure 6 weeks postoperatively.(15) we defined blood pressure recorded 4 to 6 weeks postoperatively as short-term blood pressure. no significant difference was found in short-term systolic blood pressure (sbp) and diastolic blood pressure (dbp, p > 0.05, figure 3c, 3d). discussion our findings of this individual patient data systematic review and meta-analysis show that rhuepo has a certain nephroprotective effect in patients with kidney transplantation without increasing the susceptibility figure 1. flow diagram of systematic literature search figure 3. forest plot of the effects of rhuepo on short-time egfr (a), long-time egfr (b), short-time sbp (c), and short-time dbp (d) in patients treated with rhuepo compared with controls. figure 2. forest plot with 95% confidence interval in dgf (a), sgf (b), pnf (c), and graft loss (d) in patients treated with rhuepo compared with controls. figure 4. forest plot with 95% confidence interval in thromboembolic events (a), acute rejection (b), blood transfusion (c), and mortality (d) in patients treated with rhuepo compared with controls. a b c d a d c b rhuepo in kidney transplantation-zhou et al. review 220 vol 17 no 03 may-june 2020 221 to adverse events. a recent large clinical study with a total of 3716 kidney transplantations with a long-term follow-up of 25-30 years showed that the outcomes of living unrelated and related donors were comparable in terms of patient and graft survival.(20) therefore, transplants from living unrelated donors might be an acceptable management alternative for patients with end-stage renal disease. recent trials and meta-analyses have raised concerns about the safety of rhuepo use in patients with renal failure, malignancies, chronic heart failure, and acute st-segment elevation myocardial infarction, but also in kidney transplantation.(21-23) although vlachopanos et al.(24) and xin et al.(25) have conducted meta-analyses examining the clinical efficacy and safety of high-dose rhuepo in kidney transplant recipients including four rcts, we included additional studies, one of which was recently published.(18,19) the six rcts were of relatively high quality and included samples from europe, america, oceania, and asia. except for the study by martinez et al., which was an open-label study, there was a low risk of bias since the other studies were double-blind rcts.(17) although nafar et al.(18) used lower rhuepo doses than other studies, the impact of rhuepo administration on dgf was not examined. the use of low-dose rhuepo was also evaluated as part of the endpoints. since their results may be different or explained from a new perspective, their study was also included. there were various differences in dosage and timing administration between the studies, which warrant caution when interpreting the results. the doses of rhuepo used in the included studies ranged from 2000 to 40,000 iu of singe doses and 6000 to 120,000 iu of total dosage. single doses of 30,000 to 40,000 iu were used in most rcts, which was considered enough to confer a routine nephroprotective effect and to increase hypertension and thromboembolic events. we considered that this rhuepo dosage was the smallest dose administered in experimental studies for safety reasons. (18) the timing of rhuepo dosing also varied considerably among the included studies. some patients received the first dose of rhuepo every 3 h or thrice per week, while others received the first dose during surgery. after successful transplantation, the timing of administration ranged from 12 h to 14 days. previous data have suggested that nephroprotective drugs should be administered from at least 30 min before ischemia until 6 h after ischemia. however, the included rcts continued rhuepo administration until postoperative day 14.(17) we conducted a systematic review and meta-analysis of rcts evaluating early and rhuepo administration for dgf as the primary endpoint. this review (figure 2a) including data from five trials yielded an overall estimate of the rr for dgf of 0.89, a modest effect in favor of rhuepo, but not demonstrating a significant difference between rhuepo and control groups. the result was very close to previous studies including four rcts.(24, 25) in the latest rct by coupes et al.(19) dgf was higher than that reported in three previous studies (10/19 = 52.6% and 11/20 = 55.0% in rhuepo and control groups, respectively), but lower than that reported in the study by aydin et al.(15) we also found that the occurrence of sgf was not significantly different between the two groups. including two more rcts and performing a meta-analysis did not did not lead to different results regarding dgf, pnf, and graft loss compared to previous reviews.(24,25) however, it was encouraging that long-term egfr, which was not included in previous meta-analyses, was improved in the rhuepo group compared with the control group.(24,25) this finding indicates that high-dose rhuepo could improve egfr 6 months after transplantation. sureshkumar et al.(14) and coupes et al.(19) measured two novel biomarkers, neutrophil gelatinase-associated lipocalin and il-6, which have been demonstrated to identify patients at risk of developing iri-aki earlier. however, they found similar levels between rhuepo-treated patients and controls. three of the studies(14,15,19) showed no significant differences between groups, while two(16,17) found higher hemoglobin levels in rhuepo-treated patients. as for adverse events, we mainly included thromboembolic events, which are common in patients receiving rhuepo. after pooling data from six rcts, we demonstrated that high-dose rhuepo could increase the incidence of thromboembolic events. seizures were only noted in one patient treated with rhuepo in coupes et al.(19) in the meta-analysis by vlachopanos et al., sbp was significantly higher in rhuepo-treated patients at 4 weeks after kidney transplantation.(24) nevertheless, short-term sbp and dbp were significantly different in rhuepo-treated patients in our analysis. on the contrary, rhuepo did not affect mortality, acute rejection, and the incidence of blood transfusion. some potential limitations should be considered. first, only six rcts with a total of 435 patients were included. an incorrect estimation of the effect of rhuepo is more likely to occur in smaller trials. second, the timing of administration and type of rhuepo varied across the six rcts. based on the existing literature, selection models centered on heterogeneity testing have some limitations. however, the analysis of binary data using fixed-effect models uses large sample asymptotic variances, so it may perform poorly for studies with very low or very high event rates or small sample sizes. on the other hand, in random-effect models, the weight distribution mainly depends on its accuracy. the weight of each study is equal to the reciprocal of variance (w=1/v). therefore, the contribution of studies with large samples to the total merged effect is larger than that of studies with small samples, which makes the findings from small sample studies easier to overlook, resulting in them having less weight allocated to them. conclusions in summary, although there was a trend in favor of rhuepo in all studies, it failed to reach statistical significance regarding allograft function; however, longterm egfr was improved. the clinical safety of highdose rhuepo was explored in patients with kidney transplantation. primary adverse events occurring during the transplantation procedure and follow-up period, including thromboembolic events, acute rejection, seizures, and mortality, were distributed equally between the rhuepo and control groups. to verify the clinical relevance of rhuepo administration, additional larger, prospective studies of patients undergoing kidney transplantation with uniform rhuepo administration methods and long follow-up periods are needed. rhuepo in kidney transplantation-zhou et al. acknowledgments this study was supported by grants from the sichuan provincial science and technology key r & d projects [no.2019yfs0282 and 2017sz0113]. references 1. brines m, cerami a. discovering erythropoietin’s extrahematopoietic functions: biology and clinical promise. kidney int. 2006; 70: 246-50. 2. lappin tr, maxwell ap, johnston pg. epo’s alter ego: erythropoietin has multiple actions. stem cells. 2002; 20: 485-92. 3. goldman sa, nedergaard m. erythropoietin strikes a new cord. nat med. 2002; 8:785-87. 4. chateauvieux s, grigorakaki c, morceau f, dicato m, diederich m. erythropoietin, erythropoiesis and beyond. biochem pharmacol. 2011;10: 1291-303. 5. celik m, gokmen n, erbayraktar s, akhisaroglu m, konakc s, ulukus c, et al. erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. proc natl acad sci usa. 2002; 99: 2258-63. 6. toro l, barrientos v, león p, rojas m, gonzalez m, gonzález-ibáñez a, et al. erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury. kidney int. 2018;93:1131-41. 7. parsa cj, matsumoto a, kim j, riel ru, pascal ls, walton gb, et al. a novel protective effect of erythropoietin in the infarcted heart. j clin invest. 2003; 112: 999-1007. 8. reynolds bc, tinckam kj. sensitization assessment before kidney transplantation. transplant rev (orlando). 2017; 31:18-28. 9. zomorrodi a, mohammadipoor anvari h, kakaei f, solymanzadeh f, khanlari e, bagheri a. bolus injection versus infusion of furosemide in kidney transplantation: a randomized clinical trial. urol j. 2017; 4:3013-7. 10. gill js, tonelli m, mix ch, pereira bj. the change in allograft function among longterm kidney transplant recipients. j am soc nephrol. 2003; 14:1636-42. 11. yarlagadda sg, coca sg, formica rj, poggio ed, parikh cr. association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. nephrol dial transplant. 2009; 24:1039-47. 12. matas aj, smith jm, skeans ma, thompson b, gustafson sk, schnitzler ma, et al. optn/ srtr 2012 annual data report: kidney. am j transplant. 2014; 14 1:11-44. 13. panic n, leoncini e, de belvis g, ricciardi w, boccia s. evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analysis (prisma) statement on the quality of published systematic review and meta-analyses. plos one. 2013; 26: e83138. 14. sureshkumar kk, hussain sm,tina y, thai nl, marcus rj. effect of high-dose erythropoietin on graft function after kidney transplantation: a randomized, doubleblind clinical trial. clin j am soc nephrol. 2012; 7: 1498-506. 15. aydin z, mallat m, schaapherder a, van zonneveld aj, van kooten c, rabelink tj, et al. randomized trial of short-course high-dose erythropoietin in donation after cardiac death kidney transplant recipients. am j transplant. 2012; 12: 1793-800. 16. hafer c, becker t, kielstein jt, bahlmann e, schwarz a, grinzoff n, et al. high-dose erythropoietin has no effect on shortor longterm graft function following deceased donor kidney transplantation. kidney int. 2012; 81:314-20. 17. martinez f, kamar n, pallet n, lang p, durrbach a, lebranchu y, et al. high dose epoetin beta in the first weeks following renal transplantation and delayed graft function: results of the neo-pdgf study. am j transplant. 2010; 10: 1695-700. 18. nafar m, abdei ba, ahmadpoor p, ahmadpoor p, pour-reza-gholi f, samadian f, et al. effect of erythropoietin on kidney allograft survival: early use after transplantation. iran j kidney dis. 2012; 6: 44-8. 19. coupes b, de freitas dg, roberts sa, read i, riad h, brenchley pe, et al. rherythropoietin-β as a tissue protective agent in kidney transplantation: a pilot randomized controlled trial. bmc res notes. 2015; 3:21. 20. simforoosh n, basiri a, tabibi a, javanmard b, kashi ah, soltani mh, et al. living unrelated versus related kidney transplantation: a 25-year experience with 3716 case. urol j. 2016; 13:2546-51. 21. bohlius j, schmidlin k, brillant c, schwarzer g, trelle s, seidenfeld j, et al. recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a metaanalysis of randomised trials. lancet. 2009; 373:1532-42. 22. van der meer p, groenveld hf, januzzi jl jr, van veldhuisen dj. erythropoietin treatment in patients with chronic heart failure: a metaanalysis. heart. 2009; 95:1309-14. 23. wen y, xu j, ma x, gao q. high-dose erythropoietin in acute st-segment elevation myocardial infarction: a metaanalysis of randomized controlled trials. am j cardiovasc drugs. 2013; 13:435-42. 24. vlachopanos g, kassimatis t, agrafiotis a. perioperative administration of highdose recombinanthuman erythropoietin for delayed graft function prevention in kidney transplantation: a meta-analysis. transpl int. rhuepo in kidney transplantation-zhou et al. review 222 vol 17 no 03 may-june 2020 223 2015; 28:330-40. 25. xin h, ge yz, wu r, yin q, zhou lh, shen jw, et al. effect of high-dose erythropoietin on graft function after kidney transplantation: a meta-analysis of randomized controlled trials. biomed pharmacother. 2015; 69: 29-33. rhuepo in kidney transplantation-zhou et al. review articles surgical management of stress urinary incontinence farzaneh sharifi-aghdas* department of urology, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: this review evaluates the most recent knowledge regarding surgical management of stress urinary incontinence. materials and methods: a comprehensive medline search was performed, limited to those articles published from 1995 to 2005. in total, 470 articles were reviewed—the most relevant of which were considered, and additional ones were selected by reviewing these studies' bibliographies. overall, 53 articles were selected and used in this study. results: few randomized controlled trials have been performed. the best results of retropubic procedures are seen when the intrinsic urethral sphincter is competent and its effectiveness is sustained in the long term. a laparoscopic approach, although less popular and with a lower short-term cure rate, is an alternative. sling surgeries can be the first-line treatment for all types of stress urinary incontinence. autologous grafts are still considered the gold standard, but synthetic materials such as tensionfree tape have comparable results with standard open retropubic procedures. still, long-term cure and complication rates have not yet been elucidated. using urethral bulking agents is the least invasive approach, applicable in both intrinsic sphincter deficiency and urethral hypermobility. however, it has a poor long-term outcome and necessitates repeat injections. conclusion: long-term data suggest that burch colposuspension and sling procedures produce similar objective cure rates. new synthetic suburethral slings such as tension-free vaginal tape have gained popularity in recent years. complications of traditional and newer suburethral slings are declining but still occur and often are associated with serious morbidity. new therapies must be studied in randomized clinical trials. key words: stress urinary incontinence, pubovaginal sling, retropubic procedure, tensionfree vaginal tape 175 urology journal unrc/iua vol. 2, no. 4, 175-182 autumn 2005 printed in iran introduction stress urinary incontinence (sui) is the most common type of incontinence in women, with 86% of incontinent women presenting with symptoms of sui in either pure (50%) or mixed (36%) forms.(1) stress urinary incontinence, the complaint of involuntary leakage during exertion, occurs at least weekly in one third of adult women. although sui is not life-threatening, it may have considerable impact on a woman's quality of life. however, no considerable research on the prevention of urinary incontinence has been done. initial treatment includes nonsurgical *corresponding author: department of urology, shaheed labbafinejad medical center, 9th boustan, pasdaran, tehran 1666679951, iran. tel: ++98 912 175 8340 e-mail: fsharifiaghdas@yahoo.com surgical management of stress urinary incontinence management,(2) and although surgical procedures are more likely to cure sui, they are associated with more adverse events. nearly, 300 procedures have been proposed for sui, but only a few have survived with enough supportive evidence to be recommended. currently, less-invasive modifications of these procedures are being done, and studies on their efficacy are ongoing. pathophysiological concepts and theories on the clinical staging of sui have changed in recent years. for decades, the physiological concepts of urinary incontinence were a summation of factors and forces. the urethral closure mechanism is composed of the urethral mucosal seal, the submucosal vascular plexus, and competence of the bladder neck, as well as intrinsic and extrinsic sphincters. this closure mechanism is supported by the pelvic floor muscles and their fascial coverings, which function as a hammock.(3) the normal position of the bladder base and urethra provides pressure transmission, so that pressure from the intraabdominal cavity is exerted equally on the bladder dome and the proximal urethra.(4) the logical extension of these ideas is that sui is caused by a loss of pressure transmission and hammock-like support due to urethral hypermobility and prolapse and impaired intrinsic sphincter function.(3,5) the foregoing is known as integral theory. first introduced by petros and ulmsten,(6,7) this theory initiated crucial changes in the way clinicians view the management of sui. integral theory emphasizes the importance of fixation of the midurethra to the pubic bone by pubourethral ligaments and suggests that opening and closing of the urethra and bladder neck are regulated by a "battery of surrounding structures."(7) this theory has led to a novel anti-incontinence support therapy known as tension-free vaginal tape (tvt).(8) tension-free vaginal tape is placed in the midportion of the urethra instead of at the level of the bladder neck, and it should be loose enough to ensure that the urethra is compressed as little as possible at rest. surgical treatment of sui can be divided into 3 basic types: colposuspension, suburethral sling procedures, and injection of urethral bulking agents. it is recommended that women who plan for future pregnancies postpone colposuspension and sling procedures until they have completed their family. although not documented, it has been suggested that postmenopausal women with urogenital atrophy receive vaginal estrogen prior to surgery.(9) the question that confronts the clinician is which procedure to use for which patient—tvt, or one of its modifications, colposuspension, or conventional slings. few studies compare these procedures. and unfortunately, many postoperative patients experience continued incontinence, despite improvement of sui. although surgical procedures have been adopted based on "expert" opinion, the fact remains that untested techniques and materials frequently have been introduced without careful human subject testing. when choosing surgical management then, the surgeon must weigh the chance of cure against the chance of severe complications. less common, but still serious complications, such as vascular and bowel injuries, require further studies with large samples of patients that compare the different surgical approaches. diagnostic and treatment managements to diagnose sui, clinical and urodynamic (simple or complex) examinations must be performed to evaluate the bladder filling and emptying phases. loss of urine through the urethra with a simultaneous increase in intraabdominal pressure can be seen visually. the role of radiology such as cystography, sonography, and magnetic resonance imaging is controversial. thirty percent of stress incontinent patients may show some forms of detrusor overactivity during urodynamic study, which may be associated with a decrease in the cure rate after surgery. nonetheless, there have been no randomized trials on the influence of a comprehensive preoperative evaluation (including urodynamic study) compared with a basic preoperative clinical evaluation on the treatment outcome in women with sui symptoms. in a cohort study of 442 women, black and coworkers(10) reported improvement of the severity of sui in 87% of patients and cure (continence) in only 28% after surgical operation. these improvements persisted for at least 12 months. the likelihood ratio of improvement was similar regardless of whether urodynamic studies had been conducted before operation or not. generally, conservative therapy should be attempted initially in women with sui. conservative treatments include pelvic muscle exercises, bladder retraining, pharmacologic 176 sharifi-aghdas therapy, functional electrical or magnetic stimulation, and the use of mechanical devices such as pessaries. although not documented, it is suggested that postmenopausal women with urogenital atrophy receive topical estrogen. in the past decade, surgeons have put their efforts into differentiating intrinsic sphincter deficiency from hypermobility, choosing a pubovaginal sling or bulking agents for the former and colposuspension for the latter. this was based initially on a preliminary report in which women younger than 50 years with urethral closure pressure less than 20 cm h2o had a higher failure rate after a burch colposuspension than did women with a closure pressure greater than 20 cm h2o.(11) recently, however, this dichotomy has been called into question, substituted by the idea that all women with sui have some degree of sphincter weakness. to date, it is not clear from which surgeries women with hypermobility and degrees of sphincter weakness benefit. as sui is considered a degenerative tissue disorder, the outcomes of different surgical procedures are relatively similar at short-term follow-up; however, the cure rate dramatically declines at long-term follow-up for the majority of procedures. retropubic procedures these procedures are indicated for women with the diagnosis of urodynamic sui and hypermobility of the proximal urethra and bladder neck. the best results are seen when the urethral sphincter (intrinsic sphincter or bladder neck) is competent. marshall and colleagues,(12) in 1949, first described retropubic urethrovesical suspension for the treatment of sui. in 1961, burch introduced his technique.(13) although numerous terms and variations of retropubic repair have been described, the goal is the same: to stabilize the urethra by lifting tissues near the bladder neck and proximal urethra in the area of the pelvis behind the pubic symphysis to prevent their descent, and to allow urethral compression against a stable suburethral layer. the approach may be either abdominal (open or laparoscopic) or vaginal. the 3 most popular retropubic procedures are the burch colposuspension, the marshall-marchetti-krantz vesicourethropexy, and the paravaginal defect repair. of these 3, the burch colposuspension has been studied most extensively. the surgical technique in most studies on the burch colposuspension is a modification described by tanagho in 1976.(14) two to 3 permanent or delayed absorbable sutures are passed through the endopelvic fascia lateral to the midurethra and bladder neck and then through the ipsilateral cooper's ligament and tied with gentle tension. many studies have reported their results with the burch technique, mostly with methodologic limitations. a few randomized trials have been or are being conducted. a short-term cure rate (defined as the percentage with complete continence) of 73% to 92%, and a success rate (defined as the percentage with cure or improvement) of 81% to 96% have been reported.(15) this technique's effectiveness continues for the long term; after 5 to 10 years, approximately 70% of patients are still continent.(15,16) several studies have assessed the long-term outcome of the burch procedure. alcaly and coworkers have studied 109 women with the burch colposuspension for a mean follow-up of 13.8 years.(17) the cure rate in this population is 69%. this rate has been significantly lower in women who had had pervious bladder neck surgery. results from a cochrane review indicate that open colposuspension is the most effective treatment for sui, especially for long-term outcomes. patient satisfaction has been reported high (82% in 146 patients with colposuspension).(18) voiding dysfunction (in 2% to 27% of patients) and de novo detrusor overactivity (in 8% to 27% of patients) are the most frequently reported complications of the burch method.(18-20) it has been reported that 5% to 13.6% of women with a history of burch colposuspension may develop an enterocele,(13,17,21) although all do not require surgical correction. in an evaluation of pelvic organ prolapse following isolated burch colposuspension, kwon and colleagues(22) concluded that the majority of patients undergoing an isolated tanagho modification of the burch procedure without preoperative prolapse did not appear to be at increased risk for subsequent operative intervention. a recent systematic review(23) evaluating the effectiveness of laparoscopic colposuspension compared 5 trials of laparoscopic with open colposuspension. the objective cure rate (assessed as leakage on clinical stress and urodynamically) was lower for laparoscopic than 177 surgical management of stress urinary incontinence for open colposuspension. however, the subjective cure rate was comparable between the 2 groups at 6-month to 18-month follow-up. trends were shown toward higher complication rates, less postoperative pain, shorter hospital stays, and less time to return to normal function for laparoscopic compared with open colposuspension. ankardal and colleagues have reported a higher cure rate (subjective and objective) at 1-year follow-up for open colposuspension (120 patients) compared with the laparoscopic (120 patients) approach.(24) further well-designed and adequately powered randomized trials are required to definitively compare these 2 approaches. suburethral slings aldridge(25) introduced the fascial suburethral sling in 1942. a suburethral sling procedure is used mainly as a treatment of intrinsic sphincter deficiency (isd) or failed previous sui surgery. however, few studies have been performed that evaluate the suburethral sling as a first-line procedure.(26) the materials used as a sling can be categorized as autologous, cadaveric, xenograft, and synthetic. these categories can be further subdivided into rectus fascia, fascia lata, and vaginal wall for autologous materials; freezedried irradiated cadaveric fascia lata, solventdehydrated cadaveric fascia lata, fresh-frozen cadaveric fascia lata, and cadaveric dermis for cadaveric materials; and porcine dermis, porcine subintestinal mucosa, and porcine pericardium for xenograft; and polypropylene, polyester, silastic, and expanded polytetrafluoroethylene for synthetic materials. the advantages of using allografts or synthetic slings include a reduction in the morbidity of harvesting from a second surgical site, decreased operative time, early postoperative recovery, and an unlimited supply of artificial material. nonetheless, autologous rectus fascia and fascia lata are the most common materials used. additionally, they are considered the gold standard for slings to which the outcomes of all other materials are compared.(27) it has been said that failure of sling procedures—especially those of autografts and allografts—become apparent in the first 6 months after surgery. this is related to degeneration of the fascia or breakdown of anchoring sutures; however, after this phase, surgical results remain stable. allografts carry a theoretical risk of unwanted transmission of infections. experimental studies have shown no difference in mechanical strength between autografts and cadaveric allografts.(28,29) however, the long-term durability of allograft fascia continues to be studied. morgan and associates,(30) in 247 women, reported an 88% overall cure rate (91% for type-2 and 84% for type-3 sui) using autologous rectus fascia at a mean follow-up of 51 months. chaikin(31) has reported a 92% objective cure rate in 25 patients followed for an average of more than 1 year. the overall reported cure rates (defined as the percentage with complete continence) vary between 73% and 95%, and success rates (defined as the percentage with cure or improvement) vary between 64% and 100%.(19,32) outcomes might be better in primary as opposed to repeat surgery. synthetic materials have the disadvantage of potentially generating an inflammatory reaction to a foreign body. this may result in a higher risk of erosion and fistula formation compared with autologous materials, although this has not been proved in a comparative trial. in the short term, objective cure rates using polyester and polypropylene mesh are reported as being 73% to 93%.(27) many conventional synthetic materials— including polytetrafluoroethylene or teflon,(33-37) expanded polytetrafluoroethylene (gore-tex; wl gore & associates, inc, newark, del, usa), silicone, and polyester (protegen; boston scientific, natick, mass, usa)—have been withdrawn owing to erosion and infection. the most frequently reported complications of sling procedures are postoperative voiding dysfunction in an average of 12.8% of patients (range, 2% to 37%),(26) urinary retention and selfcatheterization in 2% to 7.8%,(26,27,31) de novo urge incontinence in 6% to 14% of patients,(19,38,39) and erosion of the sling in the bladder, urethra, and vagina, mostly after synthetic slings, in up to 5% of patients.(19,38,39) misplacement of the suburethral sling to the distal urethra or proximal to the bladder neck also can be a problem. in general, synthetic materials seem to be associated with lower cure rates and higher complication rates than autologous materials.(27) tension-free vaginal tape tension-free vaginal tape procedure is based on a theory of sui pathophysiology by petros and ulmsten.(6) the concept behind the tvt is that sui is the result of inadequate urethral support 178 sharifi-aghdas due to weak pubourethral ligaments in the midurethra. tension-free vaginal tape aims at reinforcing the functional pubourethral ligaments and secure proper fixation of the midurethra to the pubic bone to maintain continence. under local or regional anesthesia, a strip of polypropylene tape is inserted via a small incision. the patient is asked to cough frequently to adjust the position of the tape and to lie in a resting position to exert sufficient pressure on the urethra only during stress, not at rest.(6,7,39) cure rates (complete dryness) of 66% to 91% have been reported.(18,40,41,42) the long-term objective results of the tvt procedure have been demonstrated by nilsson and colleagues,(43) who found an 85% cure, 10.6% improvement, and a 4.7% failure rate at a median follow-up of 56 months. the operative time of tvt is relatively short and is performed mainly under local or regional anesthesia, with a short hospitalization (ie, outpatient or overnight). the success of tvt has encouraged the introduction of similar products with modified methods of midurethral sling placement (ie, retropublic top-down, prepubic, and transobturator approaches). ward and colleagues have reported the 2-year follow-up of 344 women with sui in a multicenter, randomized, controlled trial comparing tvt and open burch colposuspension. the objective cure rate (defined as the percentage of patients with a negative 1-hour pad test) ranged from 63% to 85% for the tvt procedure and 51% to 87% for open colposuspension.(18) however, with regard to subjective assessment, only 43% of the women in the tvt group and 37% in the open colposuspension group reported having a cure. women undergoing tvt are more likely to have a cystocele after surgery; whereas, those undergoing burch colposuspension are more likely to have apical prolapse. since its description, it is estimated that more than 800 000 tvt procedures have been performed worldwide, and there has been increasing interest in the transobturator tape (tot) approach. tension-free vaginal tape mainly suits patients with urethral hypermobility and mild degrees of intrinsic sphincter deficiency (known as "good urethra"), and we should rely on the old concepts of urethral compression to treat sui with a "bad (scarred, open) urethra."(10) complications. adverse events are related to entry into the retropubic space and include bleeding, retropubic hematoma, and injury to adjacent structures such as the bladder, urethra, and vagina. bladder perforation is the most frequent intraoperative complication, occurring in between 0% to 25% of patients.(44-46) there is a higher risk in patients who have previously undergone surgery for incontinence. voiding difficulties occur in 3% to 5%,(17,47) and de novo urgency is reported in 6% to 15% of patients.(44,48,49) urinary tract infection occurs in 6% to 22% of patients, and retropubic hematoma in 0% to 5%.(50) other complications such as bowel injury, erosion to the vagina or urethra, and injury to the greater and lesser vessels (epigastric arteries) and obturator nerve are rare, but may occur.(50) for the first time, johnson and associates have reported necroticizing fascitis as a very rare complication after tvt, resulting in exploration and wide debridement of the anterior rectus fascia.(51) according to the unpublished data, there have been 7 deaths reported after tvt, 6 associated with bowel perforation, and 1 of vascular injury.(52) no such data are available for other techniques. within the last 2 years, numerous other surgical devices for stress incontinence have been introduced worldwide. one example is tot, which was designed in 1998. theoretically, this procedure avoids the risk of bladder, bowel, or vascular injury, because the procedure passes the polypropylene midurethral sling through the obturator membrane along its ischiorectal fossa path, bypassing the pelvic cavity altogether. however, the surgical effectiveness and complication rates of this procedure remain to be established. urethral bulking agents several bulking agents have been used to treat sui in women. the rationale for their use arises from the need for a washer effect on the tissues at the proximal urethra and the bladder neck.(53,54) this approach is the least invasive surgical procedure, originally described for patients with sui caused by intrinsic sphincter deficiency, although it might be effective in patients with urethral hypermobility. it can be done under local anesthesia on an outpatient basis. various bulking agents are available including autologous fat, glutaraldehyde cross-linked bovine dermal (gax) collagen, silicone microparticles, carboncoated zirconium beads, and dextranomer/ 179 surgical management of stress urinary incontinence hyaluronic acid copolymer.(53,54) the challenges of these bulking agents (eg, carbon-coated zirconium beads, calcium hydroxylapatite and dextranomer/ hyaluronic acid [dx/ha] copolymer, silicone, polytetrafluoroethylene and bovine collagenase) are their durability, cost-effectiveness, safety (concerns regarding migration, foreign-body reaction, and immunologic reaction), and longterm results. organic substances may be reabsorbed, while synthetic and biocompatible products seem to have a better stability.(54) the agent is injected transurethrally or transvaginally into the periurethral tissue around the bladder neck, proximal to midurethra, to increase outlet resistance. many reports have studied gax collagen as a bulking agent. dmochowski and colleagues(55) have summarized the literature on gax collagen for suis caused by intrinsic sphincter deficiency. they also found that most patients had a history of failed antiincontinence surgeries with a fixed bladder neck or "bad urethra." the cure rate was 7% to 83% in 17 studies. only 8 studies had defined intrinsic sphincter deficiency (either as valsalva leak point pressure lower than 60 cm h2o or stress videourodynamic to assess bladder neck opening). in general, short-term cure rates of gax collagen (defined as complete dryness) are 30% to 78%. success rates (defined as leakage of less than 1 pad per day) are 40% to 86%.(53,54) long-term results (up to 2 years) suggest a continuous decline in cure and success rates.(19) in a randomized controlled trial, gax collagen and durasphere (advanced uroscience, st paul, minn, usa) have had similar results for suis due to intrinsic sphincter deficiency.(56) the disadvantages of bulking agents include the need for repeat injections, their costs, and the occurrence of adverse effects (eg, migration, introduction of a foreign body, and generalized immunologic reaction) of using nonautologous materials. in addition, the surgeon is unable to precisely determine the quantity of materials needed for an individual patient.(57) complications such as urgency, urinary retention, and urinary tract infections are rare; thus, this therapy might be more suitable for women who wish to avoid complications associated with more invasive surgery.(58) several new bulking agents and techniques are in various stages of development, including microballoons, human collagen, autologous cartilage, bioglass, cross-linked hyaluronic acid, calcium hydroxylapatite, hyaluronic acid, dextranomer microspheres, silicone, and ethylene vinyl alcohol polymers.(55) at present, use of bulking agents is not widely accepted, since data are limited.(58) the recommended indications for injection are previous surgical failure, high risk of surgical operation, and patient preference. conclusion stress urinary incontinence is common in women and may impact their activity and quality of life. after a basic evaluation, most women can receive treatment. conservative management should precede surgery. however, surgical management is the most effective treatment, albeit it has more adverse events. long-term data suggest that burch colposuspension and sling procedures produce similar objective cure rates. these results are supported by several randomized trials as well as a large number of case series. it has been shown that laparoscopic burch technique has a lower cure rate; however, better-designed studies are ongoing. new synthetic suburethral slings such as tvt have gained popularity in recent years. short-term results of tvt demonstrate success rates similar to those of burch colposuspension. long-term complications after burch colposuspension, pubovaginal slings, and tvt are mostly related to voiding dysfunction and urgency. the complications of traditional and newer suburethral slings are declining but still occur and often are associated with serious morbidities. despite the advantages of synthetic materials, the lack of an ideal material and treatment for incontinence persists. bulking agents have poor long-term results, necessitating repeat injections. further research is needed to study the factors that impact treatment success and durability of various techniques. new therapies must be studied in randomized clinical trials preceding general clinical use, determining the efficacy as well as the safety of new surgical techniques. references 1. hannestad ys, rortveit g, sandvik h, hunskaar s; norwegian epincont study. epidemiology of incontinence in the county of nord-trondelag. a community-based epidemiological survey of female urinary incontinence: the norwegian epincont study. epidemiology of incontinence in the county of nordtrondelag. j clin epidemiol. 2000 ;53:1150-7. 2. wilson pd, bo k, hay-smith j, et al. conservative treatment in women. in: abrams p, cardozo l, khoury 180 sharifi-aghdas 181 s, wein a, editors. incontinence. 2nd ed. plymouth (uk): plymbridge distributors; 2002. p. 571-624. 3. delancey jo. structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. am j obstet gynecol. 1994;170:1713-20; discussion 1720-3. 4. enhorning ge. a concept of urinary continence. urol int. 1976;31:3-5. 5. haab f, zimmern pe, leach ge. female stress urinary incontinence due to intrinsic sphincteric deficiency: recognition and management. j urol. 1996;156:3-17. 6. petros pe, ulmsten ui. an integral theory of female urinary incontinence. experimental and clinical considerations. acta obstet gynecol scand suppl. 1990;153:7-31. 7. ulmsten u. some reflections and hypotheses on the pathophysiology of female urinary incontinence. acta obstet gynecol scand suppl. 1997;166:3-8. 8. ulmsten u, henriksson l, johnson p, varhos g. an ambulatory surgical procedure under local anesthesia for treatment of female urinary incontinence. int urogynecol j pelvic floor dysfunct. 1996;7:81-5; discussion 85-6. 9. fantl ja, cardozo l, mcclish dk. estrogen therapy in the management of urinary incontinence in postmenopausal women: a meta-analysis. first report of the hormones and urogenital therapy committee. obstet gynecol. 1994 ;83:12-8. 10. black n, griffiths j, pope c, bowling a, abel p. impact of surgery for stress incontinence on morbidity: cohort study. bmj. 1997;315:1493-8. 11. sand pk, bowen lw, panganiban r, ostergard dr. the low pressure urethra as a factor in failed retropubic urethropexy. obstet gynecol. 1987;69:399-402. 12. marshall vf, marchetti aa, krantz ke. the correction of stress incontinence by simple vesicourethral suspension. 1949. j urol. 2002 oct;168(4 pt 1):1326-31. 13. burch jc. urethrovaginal fixation to cooper's ligament for correction of stress incontinence, cystocele, and prolapse. am j obstet gynecol. 1961;81:281-90. 14. tanagho ea. colpocystourethropexy: the way we do it. j urol. 1976 ;116:751-3. 15. petri e. retropubic cystourethropexies. in: cardozo l, staskin d, editors, textbook of female urology and urogynaecology. 1st ed. london: martin dunitz; 2001. p. 513-24. 16. eriksen bc, hagen b, eik-nes sh, molne k, mjolnerod ok, romslo i. long-term effectiveness of the burch colposuspension in female urinary stress incontinence. acta obstet gynecol scand. 1990;69:45-50. 17. alcalay m, monga a, stanton sl. burch colposuspension: a 10-20 year follow up. br j obstet gynaecol. 1995 sep;102(9):740-5. 18. ward k, hilton p; united kingdom and ireland tensionfree vaginal tape trial group. prospective multicentre randomised trial of tension-free vaginal tape and colposuspension as primary treatment for stress incontinence. bmj. 2002 ;325:67. 19. smith t, daneshgari f, dmochowski rr, et al. surgical treatment of incontinence in women. in: abrams p, cardozo l, khoury s, wein a, editors. incontinence. 2nd ed. plymouth (uk): plymbridge distributors; 2002. p. 823-63. 20. bidmead j, cardozo l, mclellan a, khullar v, kelleher c. a comparison of the objective and subjective outcomes of colposuspension for stress incontinence in women. bjog. 2001;108:408-13. 21. langer r, ron-el r, neuman m, herman a, bukovsky i, caspi e. the value of simultaneous hysterectomy during burch colposuspension for urinary stress incontinence. obstet gynecol. 1988 ;72:866-9. 22. kwon ch, culligan pj, koduri s, goldberg rp, sand pk. the development of pelvic organ prolapse following isolated burch retropubic urethropexy. int urogynecol j pelvic floor dysfunct. 2003;14:321-5; discussion 325. 23. moehrer b, carey m, wilson d. laparoscopic colposuspension: a systematic review. bjog. 2003;110:230-5. 24. ankardal m, ekerydh a, crafoord k, milsom i, stjerndahl jh, engh me. a randomised trial comparing open burch colposuspension using sutures with laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. bjog. 2004;111:974-81. 25. aldridge ah. transplantation of fascia for the relief of urinary incontinence. am j obstet gynecol. 1942;44: 398-411. 26. jarvis gj. surgery for genuine stress incontinence. br j obstet gynaecol. 1994;101:371-4. 27. bidmead j, cardozo l. sling techniques in the treatment of genuine stress incontinence. bjog. 2000 ;107:147-56. 28. flynn bj, yap wt. pubovaginal sling using allograft fascia lata versus autograft fascia for all types of stress urinary incontinence: 2-year minimum followup. j urol. 2002 ;167:608-12. 29. lemer ml, chaikin dc, blaivas jg. tissue strength analysis of autologous and cadaveric allografts for the pubovaginal sling. neurourol urodyn. 1999;18:497-503. 30. morgan to jr, westney ol, mcguire ej. pubovaginal sling: 4-year outcome analysis and quality of life assessment. j urol. 2000;163:1845-8. 31. chaikin dc, rosenthal j, blaivas jg. pubovaginal fascial sling for all types of stress urinary incontinence: longterm analysis. j urol. 1998;160:1312-6. 32. weber am, walters md. burch procedure compared with sling for stress urinary incontinence: a decision analysis. obstet gynecol. 2000;96:867-73. 33. weinberger mw, ostergard dr. long-term clinical and urodynamic evaluation of the polytetrafluoroethylene suburethral sling for treatment of genuine stress incontinence. obstet gynecol. 1995;86:92-6. 34. errando c, batista je, arano p. polytetrafluoroethylene sling for failure in female stress incontinence surgery. world j urol. 1996;14 suppl 1:s48-50. 35. debodinance p, de bievre p, parmentier d, dubrulle r, querleu d, crepin g. the "hazards" of using a gore-tex sling in the treatment of stress urinary incontinence. j gynecol obstet biol reprod (paris). 1994;23:665-70. 36. duckett jr, constantine g. complications of silicone sling insertion for stress urinary incontinence. j urol. 2000;163:1835-7. 37. kobashi kc, dmochowski r, mee sl, et al. erosion of woven polyester pubovaginal sling. j urol. 1999;162:2070-2. 38. young sb, howard ae, baker sp. mersilene mesh sling: shortand long-term clinical and urodynamic outcomes. am j obstet gynecol. 2001;185:32-40. 39. jensen jk, rufford hj. sling procedures-artificial. in: cardozo l, staskin d, editors, textbook of female urology and urogynaecology. 1st ed. london: martin dunitz; 2001. p. 544-61. 40. ulmsten u, falconer c, johnson p, et al. a multicenter study of tension-free vaginal tape (tvt) for surgical treatment of stress urinary incontinence. int urogynecol j pelvic floor dysfunct. 1998;9:210-3. 41. nilsson cg, kuuva n. the tension-free vaginal tape procedure is successful in the majority of women with indications for surgical treatment of urinary stress incontinence. bjog. 2001;108:414-9. 42. moran pa, ward kl, johnson d, smirni we, hilton p, bibby j. tension-free vaginal tape for primary genuine stress incontinence: a two-centre follow-up study. bju int. 2000;86:39-42. 43. nilsson cg, kuuva n, falconer c, rezapour m, ulmsten u. long-term results of the tension-free vaginal tape (tvt) procedure for surgical treatment of female stress urinary incontinence. int urogynecol j pelvic floor dysfunct. 2001;12 suppl 2:s5-8. 44. abouassaly r, steinberg jr, lemieux m, et al. complications of tension-free vaginal tape surgery: a multi-institutional review. bju int. 2004;94:110-3. 45. tamussino k, hanzal e, kolle d, ralph g, riss p; austrian urogynecology working group. the austrian tension-free vaginal tape registry. int urogynecol j pelvic floor dysfunct. 2001;12 suppl 2:s28-9. 46. kuuva n, nilsson cg. a nationwide analysis of complications associated with the tension-free vaginal tape (tvt) procedure. acta obstet gynecol scand. 2002;81:72-7. 47. ward kl, hilton p; uk and ireland tvt trial group. a prospective multicenter randomized trial of tension-free vaginal tape and colposuspension for primary urodynamic stress incontinence: two-year follow-up. am j obstet gynecol. 2004;190:324-31. 48. levin i, groutz a, gold r, pauzner d, lessing jb, gordon d. surgical complications and medium-term outcome results of tension-free vaginal tape: a prospective study of 313 consecutive patients. neurourol urodyn. 2004;23:7-9. 49. rodriguez lv, raz s. prospective analysis of patients treated with a distal urethral polypropylene sling for symptoms of stress urinary incontinence: surgical outcome and satisfaction determined by patient driven questionnaires. j urol. 2003;170:857-63. 50. karram mm, segal jl, vassallo bj, kleeman sd. complications and untoward effects of the tension-free vaginal tape procedure. obstet gynecol. 2003 ;101:929-32. 51. johnson dw, elhajj m, obrien-best el, miller hj, fine pm. necrotizing fasciitis after tension-free vaginal tape (tvt) placement. int urogynecol j pelvic floor dysfunct. 2003;14:291-3. 52. nygaard ie, heit m. stress urinary incontinence. obstet gynecol. 2004;104:607-20. 53. van kerrebroeck p, ter meulen f, farrelly e, larsson g, edwall l, fianu-jonasson a. treatment of stress urinary incontinence: recent developments in the role of urethral injection. urol res. 2003;30:356-62. 54. meschia m, pifarotti p, gattei u, crosignani pg. injection therapy for the treatment of stress urinary incontinence in women. gynecol obstet invest. 2002;54:67-72. 55. dmochowski rr, appell ra. injectable agents in the treatment of stress urinary incontinence in women: where are we now? urology. 2000;56 (6 suppl 1):32-40. 56. lightner d, calvosa c, andersen r, et al. a new injectable bulking agent for treatment of stress urinary incontinence: results of a multicenter, randomized, controlled, double-blind study of durasphere. urology. 2001;58:12-5. 57. appell ra. intra-urethral injection therapy. in: cardozo l, staskin d, editors, textbook of female urology and urogynaecology. 1st ed. london: martin dunitz; 2001. p. 479-91. 58. pickard r, reaper j, wyness l, cody dj, mcclinton s, n'dow j. periurethral injection therapy for urinary incontinence in women [cochrane review]. in: cochrane library, issue 1. chichester (uk): john wiley & sons; 2003. surgical management of stress urinary incontinence182 1589vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l reduced radiation fluoroscopy protocol during retrograde intrarenal surgery for the treatment of kidney stones mustafa kirac,1 abdulkadir tepeler,2 cagri guneri,1 senad kalkan,2 sina kardas,2 abdullah armagan,2 hasan biri3 corresponding author: mustafa kirac, md department of urology, koru hospital, ankara, turkey. tel: +90 533 357 2617 fax: +90 312 287 9898 e-mail: mkirac@gmail.com received march 2014 accepted may 2014 1 department of urology, koru hospital, ankara, turkey. 2 department of urology, bezmialem vakif university, istanbul, turkey. 3 department of urology, gazi university, ankara, turkey. purpose: to discuss whether fluoroscopic imaging is essential during the ureteroscopic treatment of kidney stones in an effort to diminish radiation exposure. materials and methods: seventy-six patients with kidney stones were treated with retrograde intrarenal surgery (rirs). in the operation room, a mobile c-arm fluoroscopy system was ready to use in case fluoroscopic imaging was needed. the manipulations were performed with tactile and visual cues. the perioperative and postoperative parameters were retrospectively evaluated. results: the mean age of the patients was 39.9 ± 13.8 years. the mean stone size was 14.1 ± 4.1 mm. the insertion of the access sheath was performed over the guidewire under single shoot fluoroscopic imaging in all patients. additional fluoroscopic imaging was required to localize the stone (n = 2) and to determine the collecting system anatomy (n = 2) for 4 (5.2%) patients with previous renal surgery and severe hydronephrosis. stone-free status was accomplished in 63 (82.9%) patients. conclusion: the rirs with low-dose fluoroscopy protocol for kidney stones can be safely and effectively performed in patients with no special circumstances such as anatomical abnormalities or calyceal diverticular stones. keywords: fluoroscopy; kidney calculi; surgery; lithotripsy; adverse effects; treatment outcome; ureteroscopy. endourology and stone disease 1590 | introduction retrograde intrarenal surgery (rirs) is an alterna-tive method for the treatment of kidney stones. rirs has become a safe and optimal treatment modality for renal stones of different sizes.(1) indications for this technique have recently increased, and many authors have reported increases in the success of this technique, which has a non-invasive method compared to other surgical treatments (percutaneous nephrolithotomy or open surgery) of kidney stones.(2-5) imaging methods contribute to the diagnosis and treatment of urolithiasis. fluoroscopy is used in many urologic procedures, including ureteroscopy (rigid or flexible) and percutaneous nephrolithotomy (pnl).(6) conventionally, fluoroscopy is used in almost every stage of ureteroscopic procedures and facilitates all stages of the operation. it is well known that radiation exposure by fluoroscopy has potential risks such as genetic mutations and cancers.(7) in recent years, there have been several studies investigating methods to minimize the duration of fluoroscopic imaging during ureteroscopy (flexible or rigid) and presenting fluoro-less ureteroscopy procedures in patients with kidney and ureter stones.(2-4,7) in this study, we investigated the necessity of fluoroscopy in the rirs technique and aimed to present the outcomes of rirs technique including fluoroscopy reduced radiation. materials and methods patients between september 2010 and may 2013, 76 patients with kidney stones who underwent rirs (including reduced radiation fluoroscopy) procedure by two experienced endourologists (mk and at) in two centers were retrospectively evaluated. patients with stones in anatomically abnormal kidneys (horseshoe, pelvic, and mal-rotated kidneys, bifid pelvis, ectopic pelvic fusion anomaly, calyceal diverticulum stones) and patients with non-opaque stones that might require additional and detailed fluoroscopic scans during ureteroscopy were excluded from the study. an informed consent form was completed by all patients before the procedure. the patients had a failure of prior procedures as shock wave lithotripsy (swl) selected for rirs. all patients were evaluated by urinalysis, urine culture, complete blood cell count, serum biochemistry, coagulation tests and imaging methods [plain radiography, ultrasonography, computed tomography (ct), and/or intravenous urography] before the procedure. the stone size was determined by the longest axis of the stone. rirs technique all procedures were performed with the patient under general or spinal anesthesia by two experienced senior endourologists (mk and at) using 7.5 french (f) flexible ureteroscopes (karl storz endoscopy, tuttlingen, germany). the patients were placed in the lithotomy position. the surgical team was protected with lead aprons and thyroid shields. in the operation room, a mobile c-arm fluoroscopy system (ziehm solo, ziehm imaging, nürnberg, germany; siemens muenchen, germany) was ready to use in case fluoroscopic imaging was necessary. a cysto-urethroscopic examination was performed in all patients for any urethral or bladder pathologies. a rigid ureteroscope (8 or 9.5f) was routinely used before flexible ureteroscopy in all patients to detect ureteral stones or dilation of the ureter and to place a hydrophilic guide-wire into the renal pelvis. a 0.035/0.038inch safety guide-wire (boston scientific, natick, ma, usa) was gently inserted into the renal pelvis with the endoscopic visualization. a ureteral access sheath (12/14f, 35 or 45 cm length, for females or males, respectively; cook medical, bloomington, indiana, usa) was placed over the guidewire. during the procedure, all manipulations (guidewire, balloon dilatation, etc.) were performed with visual and tactile cues, as previously described in the literature. (2) the ureteral access sheath insertion was terminated if any difficulty arose. single-shot fluoroscopic images were taken to verify the place of the access sheath. for patients in whom a ureteral access sheath could not be placed, the flexible ureteroscope was pushed forward to the renal pelvis over the guide wire with direct vision. the pelvicalyceal collecting system was displayed and the stone was found using endoscopic vision. the stones were fragmented with a holmium laser (dornier medtech gmbh. argelsrieder feld 7, d-82234 wessling, germany; quanta system srl, milano, italy) until they were deemed small enough to pass spontaneously. basket extraction of the residual fragments endourology and stone disease 1591vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l low dose radiaton ureteroscopy | kirac et al was not routinely performed, but some residual fragments were removed by nitinol baskets for stone analysis. the decision to place a ureteral stent was made by the surgeon intraoperatively. stent placement was performed with endoscopic visualization over a guide-wire. if a ureteral stent was placed at the end of the procedure, it was removed approximately 14 to 21 days postoperatively. follow-up for all cases, the patient demographics, fluoroscopic imaging and fluoroscopy time (ft) operative and postoperative parameters were evaluated. the results were classified as stone-free, clinically insignificant residual fragments (cirfs) and unsuccessful. cirfs were defined as ≤ 4 mm, non-obstructing, non-infectious and asymptomatic residual fragments.(6) the patients with a complete absence of residual fragments were accepted as stone-free. the first follow-up evaluation was performed on the first day following the operation. second evaluation was performed postoperatively first month, after which patients were seen every 3 months during the first year. in postoperative first day, plain radiography, and abdominal ultrasonography were performed to all patients. in postoperative firs mount, ct scan was performed to all patient. results the mean age of the patients was 39.9 ± 13.8 years (range 19 to 75 years). the mean stone size was 14.1 ± 4.1 mm (range 7 to 26 mm). the stone localization was in the upper, middle, pelvic or lower poles or in multiple calices in 12, 15, 24, 17 and 8 patients, respectively. multiple stones were present in 15 (19.7%) patients. preoperative stents were present in 17 (22.3%) patients. of the patients, 43 (56.5%) were previously treated by swl, but the results were unsuccessful by means of stone clearance. the demographic data of the patients are summarized in table 1. the mean operation time was 58.5 ± 16.1 minutes (range 35 to 120 min.), and the mean hospitalization time was 28.1 ± 10.2 hours (range 16 to 48 hours). in the first postoperative month, stone-free status was accomplished in 63 (82.9%) patients. a ureteral access sheath was placed in 65 (85.5%) patients. a double j stent was inserted using endoscopic vision in 65 (88.2%) patients. additional procedures including swl, pnl and ureterorenoscopy (urs) were performed in 3 (3.9%) patients (one patient swl, one patient pnl and one patient urs). a re-treatment was needed for 2 (2.6%) patients. the operative and postoperative outcomes are given in table 2. there were 5 (6.5%) non-severe complications in the patable 1. characteristics of study participants. characteristics n = 76 mean age (years) 39.9 ± 13.8 gender, no. (%) male 50 (65.8) female 26 (34.2) mean stone size (mm) 14.1 ± 4.1 stone location, no. (%) upper pole 12 (15.8) middle pole 15 (19.7) pelvis 24 (31.6) lover pole 17 (22.4) multi calix 8 (10.5) multiple stones, no. (%) 15 (19.7) presence of preoperative stent, no. (%) 17 (22.3) hydronephrosis, no. (%) none 64 (84.3) grade 1 7 (9.2) grade 2 4 (5.2) grade 3 1(1.3) table 2. perioperative outcomes and postoperative complications. outcomes n = 76 mean operation time (min) 58.5 ± 16.1 mean hospitalization stay (hour) 28.1 ± 10.2 mean fluoroscopy time (sec) 5.27 ± 1.8 stone-free rate, no. (%) 63 (82.9) clinically insignificant residual fragments, no. (%) 7 (9.2) rest (unsuccessful), no. (%) 6 (7.9) double j stent insertion, no. (%) 67 (88.2) ureteral access sheath insertion, no. (%) 65 (85.5) complications, no. (%) 5 (6.5) urinary tract infection 2 (2.6) fever 1 (1.3) hematuria 1 (2.6) ureteral mucosal injury 1 (1.3) 1592 | tients. two patients (2.6%) had urinary tract infections detected by urine cultures in the postoperative period. these patients were treated properly with antibiotics. one (1.3%) patient had a fever postoperatively, which resolved spontaneously. persistent hematuria (which did not decrease the hemoglobin level) occurred in one patient. in this patient, the hematuria spontaneously improved postoperatively. a ureteral mucosal injury, which was observed under the ureteroscope, occurred in one patient. the double j stent was inserted in this patient. there were no major intraoperative complications during the operations. fluoroscopic imaging (additional singe-shots) was required for only 4 (5.2%) patients. the mean fluoroscopy time was 5.27 ± 1.8 seconds in 2 patients, c-arm fluoroscopic screening was used to find and confirm the stone location in a dilated collecting system. in 2 patients, fluoroscopic screening was needed to assess the anatomy of the collecting system, in which the calyceal stones underwent renal surgery (for mapping of the collecting system with severe dilation). discussion over the years, fluoroscopic imaging during ureteroscopy has become a necessary tool in urologic practices. recently, fluoroscopy has been standardly used in swl, pnl and rirs and provides a significant contribution to these surgical methods. rirs or flexible ureterorenoscopy (furs) are used for the treatment of kidney stones with a small or medium diameter. traditionally, fluoroscopic imaging in rirs was necessary and increased safety and the success rate of the procedure. in this study, we performed a reduced radiation fluoroscopy protocol of rirs and discussed the necessity of fluoroscopy during the rirs procedure. recent studies have emphasized the risk of secondary malignancies associated with ionizing radiation from diagnostic imaging.(9,10) the cumulative cancer risk of the radiation exposure from diagnostic methods is estimated at 0.4-0.9% in united states.(10,11) fluoroscopic imaging plays a major role in endourology. fluoroscopy is commonly used during ureteroscopy (flexible or rigid) to place the guide-wires, to detect the stone location and renal anatomy, for ureteral balloon dilatation and for placement of the ureteral stents. little long term data exist that describe the incidence of secondary malignancies in urologists. the development of ureteroscopic and endoscopic techniques and the common use of fluoroscopic imaging with these techniques will increase the radiation exposure to the patient, surgeon and operating room staff during the procedure. the effect of ionizing radiation may be dangerous for urologists in the long-term. in this study, we performed a rirs technique including reduced radiation fluoroscopy protocol for kidney stones to decrease the effects of fluoroscopy induced ionizing radiation. krupp and colleagues(10) concluded that the radiation emitted from fluoroscopy devices during urs should not be disregarded. in this study, organ-tissue-specific radiation doses were measured during the simulation of ureteroscopy on cadavers. on the one hand, fluoroscopy for ureterorenoscopy (urs) uses a relatively low dose of radiation,(4,12) but on the other hand, the cumulative effects of fluoroscopy can theoretically cause an increased risk of cancers. hellawell and colleagues detected that surgeons received a mean of 11.6 µgy per urologic case.(12) although this radiation dose is low, a high-volume surgeon, who may perform up to 500 cases per year, would receive 5.8 mgy per year. this dose is more than half of the effective dose of a non-contrast ct scan of the abdomen. the effect of fluoroscopy during ureteroscopic procedures should be seriously considered. in the literature, there are several limited studies investigating the effect of fluoro-less or low dose fluoroscopy techniques during ureteroscopic procedures. mandhani and colleagues(13) reported the results of distal ureteric stones treated with a fluoro-less urs technique. in their series, fluoroscopic imaging was needed for only 6 patients (4.0%). ureteric balloon dilatation and placement of the double j stent were performed under endoscopic vision. the authors reported that there were no severe complications during the fluoroless urs. tepeler and colleagues reported the outcomes of 93 patients with distal or proximal ureteral stones treated with urs without fluoroscopic imaging.(2) they reported that fluoroscopic imaging was required for 7 patients, with a mean fluoroscopy time of 9 ± 4.72 seconds, and the urs was successfully performed in 86 patients (92.4%) without the need for fluoroscopic imaging. there were no major complications in this series. the authors also emphasized endourology and stone disease 1593vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l surgical experience in their study and concluded that the treatment of ureteral stones can be safely and effectively performed in experienced hands with limited or no usage of fluoroscopy. however, this study did not include patients with kidney stones, whereas our study did include patients with kidney stones treated by rirs. greene and colleagues(4) published a series of uncomplicated ureteroscopies in which the fluoroscopy protocol reduced the radiation. in this series, the operation time and stone-free rate were similar in the patients with the lower fluoroscopy dose protocol and the conventional fluoroscopy protocol. in their single-center, retrospective study, the authors concluded that the reduced fluoroscopy protocol resulted in an 82% reduction in fluoroscopy time without altering patient outcomes, and these simple radiation-reducing techniques are safe and improve the safety of the patient, surgeon and operating room staff by reducing radiation exposure. in another study, hsi and colleagues(3) presented 162 patients (94 renal stones, 26 proximal/mid ureteral stones and 49 distal ureter stones) who underwent retrograde intrarenal surgery. in their study, the authors described fluoro-less ureterorenoscopy that used no fluoroscopy during the entire ureteroscopic proportion of the procedure. in their study, ureteral access, placement of wire, placement of the doublej stent and other ureteroscopic parts of the procedure were performed utilizing tactile and endoscopic guidance. they found that, excluding fluoroscopy usage to confirm ureteral stent placement, 75% of the patients did not require any fluoroscopy time (fluoro-less) and 85% required 2 seconds or less of fluoroscopy. in their study, the authors concluded that the reduced fluoroscopy protocol resulted in minimal fluoroscopy time and radiation exposure, which was significantly lower than reported in the literature, and that fluoro-less ureteroscopy is safe and feasible. in our study, we defined fluoro-less rirs as a procedure with only single-shot screening by fluoroscopy during the operation. we performed the procedure in all patients without fluoroscopic imaging. only 4 patients needed fluoroscopy (additional single-shot screening) during the procedure. according to our outcomes, this rirs technique (reduced fluoroscopy protocol), in which there is a reduced fluoroscopy time and radiation exposure, is a safe and feasible technique for patients with kidney stones. studies have demonstrated that radiation-reducing and fluoro-less ureteroscopy protocols have no impact on an operation’s success, time or complication rates and do not increase the technical difficulty.(2-4,8,13) in our study, the urs procedure was successfully performed without the need for fluoroscopy in all patients. we successfully performed the low-dose radiation ureteroscopy technique in kidney stone patients. reducing the fluoroscopy time is a necessity for the endoscopic interventions. avoiding from irradiation is very important for both patient and health workers. during the endoscopic procedures some techniques such as tactile clues, insertion of guides by direct vision through the cystoscope, experienced surgery staffs, preferring advanced fluoroscopic devices (laser guided etc.), covering the extraurinary areas of the body with lead aprons may reduce the fluoroscopy time.(4) on the other hand, awareness of the surgeons own fluoroscopy time and have opportunity for comparison with other surgeons may reduce the fluoroscopy time.(14) many authors reported that rirs is a safe and effective method for the treatment of renal stones. in the literature, the success rate of this method has been reported to range from 65-92%.(16-20) in our study, we detected similar results in the stone-free and success rates. in this study, the stonefree rate was 82.9%, and the complication rate was 6.5%. there were no major complications in our series. our study has some limitations and shortcomings. the major limitations of the present study are its retrospective, multi-centered and non-randomized nature. fluoroscopy was used for single-shot imaging during the procedures, and the duration of the fluoroscopic screening was not measured. the lack of information regarding the amount of radiation exposure is another limiting factor of this study. conclusion as a conclusion, fluoroscopic imaging has an essential role during rirs procedures. it is important to consider the amount of radiation patients, surgeons and operating room staffs are exposed to from fluoroscopy during rirs for kidney stones. the reduced radiation fluoroscopy protocol low dose radiaton ureteroscopy | kirac et al 1594 | references 1. c, knoll t, petrik a, sarica k, seitz c, straub m. guidelines on urolithiasis 2012 http://www.uroweb.org/gls/pdf/20_urolithiasis_lr%20 march%2013%202012.pdf 2 tepeler a, armagan a, akman t, et al. is fluoroscopic imaging mandatory for endoscopic treatment of ureteral stones? urology. 2012;80:1002-6. 3. hsi rs, harper jd. fluoroless ureteroscopy: zero-dose fluoroscopy during ureteroscopic treatment of urinary-tract calculi. j endourol. 2013;27:432-7. 4. greene dj, tenggadjaja cf, bowman rj, agarwal g, ebrahimi ky, baldwin dd. comparison of a reduced radiation fluoroscopy protocol to conventional fluoroscopy during uncomplicated ureteroscopy. urology. 2011;78:286-90. 5. brisbane w, smith d, schlaifer a, anderson k, baldwin dd. fluoroless ureteral stent placement following uncomplicated ureteroscopic stone removal: a feasibility study. urology. 2012;80:766-70. 6. rassweiler jj, renner c, eisenberger f. the management of complex stones. bju int. 2000;86:919-28. 7. shah dj, sachs rk, wilson dj: radiation-induced cancer: a modern view. br j radiol. 2012;85:1166-73. 8. ngo tc, macleod lc, rosenstein di, reese jh, shinghal r. tracking intraoperative fluoroscopy utilization reduces radiation exposure during ureteroscopy. j endourol. 2011;25:763-7. 9. berrington de gonzález a, sweetland s, green j. comparison of risk factors for squamous cell and adenocarcinomas of the cervix: a meta-analysis. br j cancer. 2004;90:1787-91. 10. krupp n, bowman r, tenggardjaja c, et al. fluoroscopic organ and tissue-specific radiation exposure by sex and body mass index during ureteroscopy. j endourol. 2010;24:1067-72. 11. perisinakis k, damilakis j, anezinis p, et al. assessment of patient effective radiation dose and associated radiogenic risk from extracorporeal shock-wave lithotripsy. health phys. 2002;83:847-53. 12. hellawell go, mutch sj, thevendran g, wells e, morgan rj. radiation exposure and the urologist: what are the risks? j urol. 2005;174:948-52. 13. mandhani a, chaudhury h, gupta n, singh h.k, kapoor r, kumar. is fluoroscopy essential for retrieval of lower ureteric stones? urol int. 2007;78:70-2. 14. lipkin me, mancini jg, zilberman de, et al. reduced radiation exposure with the use of an air retrograde pyelogram during fluoroscopic access for percutaneous nephrolithotomy. j endourol. 2011;25:563-7 15. semins mj, trock bj, matlaga br. the safety of ureteroscopy during pregnancy: a systematic review and meta-analysis. j urol. 2009;181:139-43. 16. resorlu b, unsal a, ziypak t, et al. comparison of retrograde intrarenal surgery, shockwave lithotripsy, and percutaneous nephrolithotomy for treatment of medium-sized radiolucent renal stones. world j urol. 2013;31:1581-6. 17. takazawa r, kitayama s, tsujii t. successful outcome of flexible ureteroscopy with holmium laser lithotripsy for renal stones 2 cm or greater. int j urol. 2012;19:264-7. 18. grasso m, ficazzola. retrograde ureteropyeloscopy for lower pole caliceal calculi. j urol. 1999;162:1904-8. 19. bozkurt of, resorlu b, yildiz y, can ce, unsal a. retrograde intrarenal surgery versus percutaneous nephrolithotomy in the management of lower-pole renal stones with a diameter of 15 to 20 mm. j endourol. 2011;25:1131-5. 20. mariani aj. combined electrohydraulic and holmium:yag laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. j urol. 2007;177:168-73. of rirs for kidney stones can be performed in the majority of cases. in this study, we demonstrated that rirs with low-dose radiation (or the reduced fluoroscopy protocol) for kidney stones can be safely and effectively performed. this technique adds no difficulty and may improve the procedure’s safety in terms of radiation exposure to the patient, surgeon and operating room staff. conflict of interest none declared. endourology and stone disease sexual dysfunction and infertility erectile dysfunction is positively correlated with mean platelet volume and platelet count, but not with eosinophil count in peripheral blood alper otunctemur,1 muammer bozkurt,1 hüseyin beşiroğlu,1 emre can polat,2* levent ozcan,3 emin ozbek1 purpose: increased eosinophil count (ec), mean platelet volume (mpv), and platelet count (pc) are important in vascular disorders which are main factors resulting in endothelial dysfunction. we aimed to investigate the association between mpv, and ec, with erectile dysfunction (ed). materials and methods: two hundred thirty participants (130 patients with ed, and 100 healthy controls) were enrolled in this study. a detailed psychosexual history obtained, and physical, and laboratory examination were performed. international index of erectile function (iief)-5 questionnaire was used to evaluate the erectile status objectively. iief-5 score was applied to all patients, and iief-5 score under 22 was considered as ed. the mpv, pc, and ec were compared between the two groups. results: the mean age of the patients with ed and control group was 55.62 ± 8.90 years and 54.19 ± 4.10 years, respectively. mpv and pc levels were significantly higher in ed group (8.51 ± 1.00 fl and 8.16 ± 0.94 fl; 244.59 ± 57.3 cells/μl and 230.17 ± 48.44 cells/μl, respectively (p < .05). ec and white blood cell count were not significantly different between study and control groups. conclusions: in our study a relationship was found between elevated mpv, and pc with ed. mpv and pc may be used as a biomarker in patients with ed. keywords: erectile dysfunction; etiology; risk factors; blood platelets; platelet count; eosinophils; leukocyte count. introduction erectile dysfunction (ed) is defined as a difficulty in initiating or maintaining penile erection adequate for sexual inter course. penile erection is the result of a complex interaction between psychological, neural, vascular, and endocrine factors. one of the largest current studies of ed, the massachusetts male aging study, found that ed may be present in up to half of the male population between 40 and 70 years old.(1) this condition has been estimated to affect 150 million individuals worldwide,(2) and data from the enhancing neuro imaging genetics through meta-analysis (enigma) consortium study in 2004 suggested that the condition is prevalent in approximately 17% of all european men are affected.(3) several epidemiological studies have reported that ed is a marker of cardiovascular disease (cvd).(4-6) a 2011 meta-analysis of 12 prospective cohort studies provided strong evidence that ed is indeed significantly and independently associated with an increased risk of not only cvd but also coronary heart disease, stroke, and all-cause mortality.(7) clearly, ed is now regarded as a major health problem for the increasingly healthy aging population. in the etiology of ed, generally, organic and psychogenic factors come together. however, if the penis is considered as a specialized vascular bed, it is wellknown that vascular reasons dominate in the etiology of ed.(8) during the last 20 years, many new facts about the basic physiology and pathology of ed have been determined, especially at the molecular level. diabetes mellitus, atherosclerosis, coronary disease, and hypertension contribute to the development of ed via endothelial dysfunction and peripheral artery disease.(9) it has also been hypothesized that ed is an early messenger of cvd.(10) the mean platelet volume (mpv) (expressed as fem to litre, fl) is one of the leading indicator in platelet function reflecting the platelet production rate and platelet stimulation. elevated mpvs are reported in cvds.(11) the mpv, the most commonly used measure of platelet size, is a potential marker of platelet reactivity. larger platelets are metabolically and enzymatically more active and have greater prothrombotic potential. elevated mpv is associated with other markers of platelet activity, including increased platelet aggregation, thromboxane synthesis, and increased expression of adhesion molecules.(12) furthermore, a higher mpv may take place in vascular pathologies and increase the risk of cvd, suggesting a common mechanism by which these factors may increase the risk of cvd and ed. an as1 department of urology, okmeydani training and research hospital, istanbul, turkey. 2 department of urology, istanbul medipol university, istanbul, turkey. 3 department of urology, derince training and research hospital, kocaeli, turkey. *correspondence: department of urology, istanbul medipol university, istanbul, turkey. tel: +90 532 71496 04. e-mail: ecpolat@medipol.edu.tr. received march 2015 & accepted september 2015 vol 12 no 05 september-october 2015 2347 sociation between ed and ischemic heart disease has been suggested as a consequence of vascular lesions of the penile arteries.(13) there is a relationship between vascular dysfunction with eosinophilia. it is known that eosinophils play an important role inendothelial dysfunction, vasoconstriction, inflammation, and thrombosis.(14) eosinophils stimulate the activation and aggregation of platelets. moreover, they ease the formation of thrombosis via inhibition of thrombomodulin.(15,16) perhaps, increased eosinophil count (ec, expressed as cells/μl) could lead to ed through endothelial dysfunction. these pathophysiological approach to the issue let us consider that ed might be associated with increased platelet count (pc, expressed as cells/μl) and volume as well as ec. in this study, we aimed to investigate the association between the mpv, pc, and ec with ed, in comparison with a control group. materials and methods we have conducted a prospective study in participants who visited okmeydani training and research hospital. a total of 230 patients were evaluated for ed and they were divided into two groups: 130 patients suffering from ed for > 1 year were classified as a study group and 100 patients without ed who were sexually active and married were classified as a control group. local ethics committee approval had been obtained before the beginning of the study. all patients had a complete detailed and careful history taken, with special attention to the sexual history, including details to differentiate between psychogenic and organic ed; a complete physical examination, including genital and neurological examination; blood glucose assay, urine analysis, complete blood count (cbc), and kidney and liver function. erectile function was assessed using the five-item version of the international index of erectile function questionnaire (iief-5), a validated, self-administered questionnaire. the score of 22–25 indicate normal erectile function, while scores < 22 indicate ed. according to the iief-5 score, ed was classified as severe (5–7), moderate (8–11), mild-to-moderate (12–16), or mild (17–21). exclusion criteria included the followings: the patients using anti-platelet or anticoagulant drugs, patients with congestive heart failure (ejection fraction < 50%), pulmonary hypertension, coroner artery disease, stroke, known peripheral atherosclerotic disease, surgical coronary intervention, percutaneous coronary angioplasty and/or stenting, stable and unstable angina pectoris, impaired renal function (creatinine > 1.4 mg/ dl), unstable endocrine or metabolic diseases, patients with peyronie’s disease, acute/chronic hepatic or hepatobiliary disease, and malignancy. patients who have undergone radical prostatectomy and/or pelvic surgery, history of pelvic trauma and taking beta-blocker, spironolactone, corticosteroids, antioxidant vitamins, and alcohol were also excluded from the study. furthermore patients who had a recent history of an acute infection and/or high body temperature (> 38°c), an inflammatory, or an allergic disease were excluded from the study. blood samples of all patients were taken from an antecubital vein following an overnight fasting state. fasting blood glucose, mpv, pc, ec, white blood cell (wbc) total cholesterol, high-density lipoprotein cholesterol (hdl-c), low-density lipoprotein cholesterol (ldl-c), and triglyceride (tg) levels were measured in the hospital’s chemistry laboratory. statistical analysis statistical analyses were performed by the statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. the quantitative demographic values were evaluated by student’s t-test or mann whitney u test whether the parameters were suitable for normal distribution or not. if the parameters are qualitative, chi-square test was used. kruskal-wallis test was conducted to evaluate the difference between subgroups of the patients stratified for age. logistic regression analyses were conducted to estimate the risk ratios. pearson correlation test was performed to determine possible correlation between mpv, and pc with iief-5 score. all tests were performed using a 2-tailed analysis, and a p value of < .05 was considered statistically significant. results table 1. clinical characteristic of study patients. variables ed group (n=180) control group (n=120) p value age (year) 55.62 ± 8.90 54.19 ± 4.10 .120 diabetes mellitus, no. 41 24 .619 hypertension, no. 50 31 .743 triglyceride (mg/dl) 143.20 ± 68.22 146.08 ± 57.24 .243 hdl-c (mg/dl) 42.43 ± 13.19 41.24 ± 11.87 .435 bmi (kg/m2) 26.9 ± 6.5 25.2 ± 5.3 .504 mpv (fl) 8.51 ± 1.00 8.16 ± 0.94 .015 pc (cells/μl) 244.59 ± 57.3 230.17 ± 48.44 .034 ec (cells/μl) 0.24 ± 0.18 0.21 ± 0.14 .314 wbc (103/mm3) 7.47-1.33 7.23-1.56 .154 abbreviations: ed, erectile dysfunction; hdl, high-density lipoprotein; bmi, body mass index; mpv, mean platelet volume; pc, platelet count; ec, eosinophil count; wbc, white blood cells. data are presented as mean ± sd. erectile dysfunction is positively correlated with mean platelet volume and count-otunctemur et al. sexual dysfunction and infertility 2348 a total of 230 patients between the ages of 40 and 65 years were analyzed and divided into two groups: 130 patients with ed and 100 patients without ed (control group). the baseline characteristics of the patients are demonstrated in table 1. the mean age was 55.62 ± 8.90 years in patients with ed and 54.19 ± 4. 10 years in control group. there was no significant differences between two groups with respect to age, body mass index (bmi), frequencies of diabetes mellitus, hypertension, smoking and levels of fasting blood glucose, total-c, ldl-c, hdl-c, tg, and wbc (p > .05 for all). we compared the mpv, pc, ec values between groups. it seems that the patients with ed have higher mpv and pc levels than control group. mpv level was 8.51 ± 1.00 fl in patients with ed and 8.16 ± 0.94 fl in control group. pc level was 244.59 ± 57.3 μl in patients with ed and 230.17 ± 48.44 μlin control group. there was statistically significant difference for mpv and pc levels between the patients with ed and control group (p < .05) (table 1). in logistic regression analyses the parameters assumed to be related to ed were examined. the patients were stratified into three groups as 40-50 years, 50-60 years, and 60-70 years. patients with > 70 years old and < 40 years old were not evaluated as separate group, since the frequencies of them were not suitable for a robust statistical analysis. although mpv and pc were not statistically different between each group, iief-5 score was statistically different. the details are demonstrated in table 2. we also evaluated the groups in terms of ed severity which was classified as mild, mild to moderate, moderate and severe. when examining the distribution of the patient frequencies into the subgroups stratified by ed severity, there was statistically significant difference between three groups (p = .02). the details are shown in table 3. in logistic regression analyses the parameters assumed to be related to ed were evaluated. the parameters were adjusted for age, diabetes mellitus, hypertension, dyslipidemia, and alcohol consumption. table 4 represents the 95% confidence interval (ci) and adjusted odds ratios (ors) for the associations between certain relevant associated risk factors and ed. patients with higher pc (or = 1.005; 95% ci: 1.003-1.010) and mpv (or = 1.256; 95% ci: 1.088-1.4) had increased risk for development of ed. the ec was not correlatedwith ed in logistic regression model. discussion ed is one of the most prevalent urological disorders resulting from variable organic and psychologic derangements. vascular pathologies take great part in organic causes via the impairment of endothelial function which is crucial in erection physiology. the presence of a number of common risk factors, the presence of several known pathophysiologic links, and a number of retrospective association studies have reinforced the idea that the link between ed and cad is important and real. this idea is defined that ed and coronary artery disease (cad) are different manifestations of a common underlying vascular pathology. ed may be the early clinical manifestation of a generalized vascular disease and carries an independent risk for cardiovascular events.(17,18) many patients present with underlying systemic cvd and their first symptom can be ed.(19) one study of 132 men correlated angiographic results with ed symptoms and scores on the iief-5; 58% reported experiencing ed before the diagnosis of cvd.(20) prospective angiographic study showed that almost one in five men presented with erectile function abnormalities of vascular origin had angiographically documented silent cad.(21) in the light of this information, young men with ed may be ideal candidates for cardiovascular risk factor screening and medical intervention. ed precedes other manifestations of systemic atherosclerosis, such as cad and cerebrovascular disease, may be partially explained by blood vessel size.(22) the penile arteries are typically 1 to 2 mm in diameter, whereas the coronary arteries are 3 to 4 mm in diameter and the carotid arteries, 5 to 7 mm in diameter. therefore, an atherosclerotic plaque of a given size should occlude and hemodynamically affect a penile artery earlier than a coronary or carotid artery. ultimately, small arteries such as the pudendal and penile arteries begin to degenerate, and end-organ ischemia results. table 2. the study parameters stratified by age (years). variables 40-50 (n = 31) 50-60 (n = 66) 60-70 (n = 75) p value platelet count (cells/μl) 237.99 ± 37.5 240.05 ± 61.04 247.82 ± 56.32 .530 mean platelet volume (fl) 8.24 ± 0.68 8.54 ± 1.08 8.60 ± 1.09 .553 iief-5 score 15.12 (7-22) 16.19 (7-22) 13.16(6-21) .001 abbreviation: iief, international index of erectile function. data are presented as mean ± sd. abbreviation: ed, erectile dysfunction. ed severity, no. 40-50 (n = 31) 50-60 (n = 66) 60-70 (n = 75) p value mild 6 35 17 mild to moderate 16 15 33 .02 moderate 7 10 14 severe 2 6 11 table 3. erectile dysfunction severity stratified by age (years). erectile dysfunction is positively correlated with mean platelet volume and count-otunctemur et al. vol 12 no 05 september-october 2015 2349 (23) pathophysiologic link between ed and cad is endothelial dysfunction. many patients with ed exhibit evidence of inflammation and endothelial dysfunction independent of their cad status.(24,25) endothelial dysfunction is the key event in the pathophysiology of ed and, importantly, men with penile vascular.(24) endothelial dysfunction can carry a heightened risk of future cad events because it results in dysregulated intimal proliferation, inappropriate vasoconstriction, and a pro-inflammatory environment that causes plaque destabilization.(26) the fact that ed and atherosclerotic vascular diseases share such a large number of common risk factors has led to the clinical consensus that most cases of organic ed are probably part of the spectrum of atherosclerotic vascular disease. (10) there are many studies about the relationship between mpv and some thrombotic and cardiac disorders.(27,28) it has been demonstrated that mpv is correlated with platelet function and activation.(29,30) small platelets have lower functional capabilities than larger ones.(30) there are many evidences suggesting the important role of mpv as a marker of inflammation, disease activity and efficacy of antiinflammatory treatment in several chronic inflammatory disorders. therefore, mpv has been used as an indicator of platelet function for inflammatory diseases.(29-31) due to vascular causes, we investigated the relationship between ed and mpv, and pc. in a study by ciftci and colleagues(32) on 90 cases, pc and mpv values were increased in patients with vasculogenic ed. in our study, we found that the mpv and pc values were significantly higher in patients with ed than in the controls. eosinophils activate coagulation system and platelets, and they also cause vasospasm such as coronary artery spasm. also eosinophil granule proteins are involved in vascular injury, and eosinophils may also affect cardiovascular system through inflammatory cell infiltration. (33) recent studies showed that eosinophils were associated with stent thrombosis, stent restenosis, and acute coronary syndromes. umemoto and colleagues reported that peripheral ecs were significantly higher in patients with severe coronary spasm than that in patients with no spasm. they also speculated that ec could predict vasospastic angina pectoris.(33) eosinophils are equipped with several granule-associated molecules that play a role in the occurrence of thrombosis and vascular injury. eosinophils generate an increased tendency to thrombosis through leukocyte, platelet stimulation, and release of tissue factor.(34-36) all these effects contribute to procoagulation through preventing the activation of thrombin and formation of endorsing fibrin. sakai and colleagues demonstrated that large thrombus has greater ec both in thrombi and in peripheral blood.(37) they also speculated that thrombus growth might be facilitated in patients with higher ec in the peripheral blood.(37) the powerful vasoconstrictor and procoagulant effects of eosinophils, made us hypothesize that there might be a correlation between ec and ed. increased ec in patients with ed might be due to vasoconstriction and thrombosis. study addressing the relationship between ec and ed has not been conducted yet. thrombotic and vascular effects of ec and cad with common etiology of ed are known. in light of this, we might hypothesize that ed could be associated with higher mpv and pc. however, there was no significant relationship between ed and ec in our study. further studies with larger population are needed to yield more reliable results in this issue. conclusions there is a relationship between elevated mpv, and pc with ed, through endothelial dysfunction. whereas there is no statistically significant relationship between ed and ec. in the light of this data, mpv and pc values may be used as a biomarker in patients with ed. conflict of interest none declared. references 1. feldman ha, goldstein i, hatzichristou dg, krane rj, mckinlay jb. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994;151:54–61. 2. aytaç ia, mckinlay jb, krane rj. the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999;84:50–6. 3. de boer bj, bots ml, lycklama a nijeholt aa, et al. erectile dysfunction in primary care: prevalence and patient characteristics. the enigma study. int j impot res. 2004;16:358–64. 4. inman ba, sauver jl, jacobson dj, et al. a population-based, longitudinal study of erectile dysfunction and future coronary artery disease. mayo clin proc. 2009;84:108–13. 5. clark ng, fox km, grandy s. shield study group. symptoms of diabetes and their association with the risk and presence of diabetes: findings from the study to help improve early evaluation and management of risk factors leading to diabetes (shield). diabetes care. 2007;30:2868–73. table 4. multivariate logistic regression analysis for the risk factors for erectile dysfunction adjusted for age, diabetes mellitus, hypertension, alcohol consumption, and dyslipidemia. variables or ci (95%) p value wald mean platelet volume 1.256 1.088-1.484 .014 7.083 platelet count 1.005 1.003-1.010 .026 4.236 eosinophil count 0.937 0.821-0.993 .165 0.031 abbreviations: or, odds ratio; ci, confidence interval. erectile dysfunction is positively correlated with mean platelet volume and count-otunctemur et al. sexual dysfunction and infertility 2350 6. chung sd, chen yk, lin hc, lin hc. increased risk of stroke among men with erectile dysfunction: a nationwide populationbased study. j sex med. 2011;8:240–6. 7. dong jy, zhang yh, qin lq. erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. j am coll cardiol. 2011;58:1378–85. 8. simonsen u, garcía-sacristán a, prieto d. penile arteries and erection. j vasc res. 2002;39:283–303. 9. gratzke c, 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2006;107:558-65. 15. rohrbach ms, wheatley cl, slifman nr, gleich gj. activation of platelets by eosinophil granule proteins. j exp med. 1990;172:12714. 16. olsen eg, spry cj. relation between eosinophils and endomyocardial disease. prog cardiovasc dis. 1985;27:241-54. 17. thompson im, tangen cm, goodman pj, probstfield jl, moinpour cm, coltman ca. erectile dysfunction and subsequent cardiovascular disease. jama 2005;294:2996–3002. 18. ponholzer a, temml c, obermayr r, wehrberger c, madersbacher s. is erectile dysfunction an indicator for increased risk of coronary heart disease and stroke? eur urol. 2005;48:512–8. 19. roumeguère t, wespes e, carpentier y, hoffmann p, schulman cc. erectile dysfunction is associated with a high prevalence of hyperlipidemia and coronary heart disease risk. eur urol. 2003;44:355-9. 20. solomon h, man jw, jackson g. erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. heart. 2003;89:251-3. 21. vlachopoulos c, rokkas k, ioakeimidis n, et al. prevalence of asymptomatic coronary artery disease in men with vasculogenic erectile dysfunction: a prospective angiographic study. eur urol. 2005;48:996-1002. 22. montorsi p, ravagnani pm, galli s, et al. the artery size hypothesis: a macrovascular link between erectile dysfunction and coronary artery disease. am j cardiol. 2005;96:19m-23m. 23. o’rourke mf, hashimoto j. mechanical factors in arterial aging: a clinical perspective. j am coll cardiol. 2007;50:1-13. 24. elesber aa, solomon h, lennon rj, et al. coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. eur heart j. 2006;27:824-31. 25. vlachopoulos c, aznaouridis k, ioakeimidis n, et al. unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease. eur heart j. 2006;27:2640-8. 26. rodriguez jj, al dashti r, schwarz er. linking erectile dysfunction and coronary artery disease. int j impot res. 2005;17(suppl 1):s12-s8. 27. gasparyan ay, ayvazyan l, mikhailidis dp, kitas gd. mean platelet volume: a link between thrombosis and inflammation? curr pharm des. 2011;17:47-58. 28. yazici s, yazici m, erer b, et al. the platelet indices in patients with rheumatoid arthritis: mean platelet volume reflects disease activity. platelets. 2010;21:122-5. 29. martin jf, trowbridge ea, salmon g, plumb j. the biological significance of platelet volume: its relationship to bleeding time, thromboxane b2 production and megakaryocyte nuclear dna concentration. thromb res. 1983;32:443-60. 30. thompson cb, eaton ka, princiotta sm, rushin ca, valeri cr. size dependent platelet subpopulations: relationship of platelet volume to ultrastructure, enzymatic activity, and function. br j haematol. 1982;50:509-19. 31. gasparyan ay, sandoo a, stavropouloskalinoglou a, kitas gd. mean platelet volume in patients with rheumatoid arthritis: the effect of antitnf-α therapy. rheumatol int. 2010;30:1125-9. 32. ciftci h,yeni e, demir m, yagmur i,et al. can the mean platelet volume be a risk factor for vasculogenic erectile dysfunction? world j mens health. 2013;31:215-9. 33. umemoto s, suzuki n, fujii k, et al. eosinophil counts and plasma fibrinogen in patients with vasospastic angina pectoris. am j cardiol. 2000;85:715-9. erectile dysfunction is positively correlated with mean platelet volume and count-otunctemur et al. vol 12 no 05 september-october 2015 2351 34. moosbauer c, morgenstern e, cuvelier sl, et al. eosinophils area major intravascular location for tissue factor storage and exposure. blood. 2007;109:995-1002. 35. levi m, hack ce, de boer jp, brandjes dp, buller hr, ten cate jw. reduction of contact activation related fibrinolytic activity in factor xii deficient patients. further evidence for the role of the contact system on fibrinolysis in vivo. j clin invest. 1991;88:1155-60. 36. rodeghiero f, castaman g, ruggeri m, cazzavillan m, ferracin g, dini e. fibrinolytic studies in 13 unrelated families with factor xii deficiency. haematologica. 1991;76:28-32. 37. sakai t, inoue s, matsuyama ta, et al. eosinophils may be involved in thrombus growth in acute coronary syndrome. int heart j. 2009;50:267-77. erectile dysfunction is positively correlated with mean platelet volume and count-otunctemur et al. sexual dysfunction and infertility 2352 case report 130 urology journal vol 6 no 2 spring 2009 splenogonadal fusion presented with cryptorchidism mansour molaeian, hadi shojaei urol j. 2009;6:130-1. www.uj.unrc.ir keywords: congenital abnormalities, spleen, testicular diseases, cryptorchidism department of pediatric surgery, bahrami children’s hospital, tehran university of medical sciences, tehran, iran corresponding author: hadi shojaei, md the bahrami children’s hospital, damavand st., tehran, iran tel: +98 912 317 3314 e-mail: hadi.shojaee@gmail.com received october 2007 accepted june 2008 introduction splenogonadal fusion is a rare congenital condition which was first reported in 1883 by boestrom.(1) then in 1956, putschar and manion published a review of 30 cases and classified the condition into 2 types of continuous and discontinuous fusions.(2) we report a case of splenogonadal fusion presented with undescended left testis. case report a 2-week-old boy was referred to our hospital for evaluation of left cryptorchidism. he was a result of a full-term normal pregnancy. the infant was well developed proportional to his age. on genital examination, the right testis was in normal size and located in the scrotum, but the left testis was not palpable in the scrotum. no other physical abnormalities were detected. outpatient follow-up till the age of 1 year revealed no change in his clinical picture. thus, left orchiopexy was planned. the operation was performed through a left lower-quadrant incision. after exploration, the left testis was found in the abdominal cavity adjacent to the lower pole of the left kidney. a reddish-brown structure appeared posteriorly. the incision was laterally extended and a cord of dark-red structure was found, which was in close relation to the spermatic cord and the vessels. the structure was traced to the lower pole of the spleen and excised completely (figure). then, the spermatic cord vessels were ligated, and finally after 3 months, a left orchiopexy-on-vas was performed. histopathological examination of the structure revealed normal splenic tissue. discussion splenogonadal fusion is most commonly an incidental finding during groin exploration for an undescended testis or hernia. the diagnosis is rarely suspected preoperatively.(3) it is usually present on the left side (98%) and in males (95%) with a male-female ratio of about 16:1. however, the reported incidence may not reflect its true incidence in females because of the inaccessibility of the ovary for examination.(3,4) in a previous study, 37% of the patients with intra-operative gross photograph of the spleen attached to the left testis in a 1-year old boy with splenogonadal fusion. splenogonadal fusion—molaeian and shojaei urology journal vol 6 no 2 spring 2009 131 splenogonadal fusion underwent an unnecessary orchiectomy for suspicion of a primary testicular neoplasm. another presentation is acute painful scrotal swelling secondary to affection of the ectopic splenic tissue by various processes.(5) falmann and settle reported cases of splenogonadal fusion presenting with painful scrotal swelling secondary to malaria.(6,7) three cases were preoperatively diagnosed by 99mtcsulphur colloid liver-spleen scintigraphy.(8) many congenital abnormalities have been described to be accompanied by splenogonadal fusion, especially the continuous type, including limb defects and micrognathia.(3,9-11) continuous and unconscious types of splenogonadal fusion occur in equal frequencies.(2,3) in the continuous type, there is a direct anatomical connection between the main spleen and the gonad by a cord which is totally splenic or is composed of fibrous tissue. there is no anatomic connection between the ectopic and main spleens in the discontinuous type. discontinuous splenogonadal fusion may be very rarely associated with the same congenital abnormalities as the continuous type is.(3) the etiology of malformation is not determined yet. most probably, it arises during the 5th through 8th week of the embryonic life when the developing spleen is close to the mesonephricgonadal anlage.(9,12) however, there is no evidence suggesting that discontinuous splenogonadal fusion has a similar etiology.(10) additionally, right splenogonadal fusions cannot be explained with the above theory. it is therefore proposed that the discontinuous type may present a rare variant of an accessory spleen.(2,9) in summary, splenogonadal fusion is a rare congenital abnormality that is rarely suspected preoperatively. careful medical history recording and high suspicion for the condition may prevent the patient from unnecessary orchiectomy. conflict of interest none declared. references 1. boestrom e. demonstration eines praparates von verwachsung der milz mit dem linken hoden. gellschaft deutscher naturforscher und artze verhandlungen der 56 versammlung. freiburg.1883;149. 2. putschar wg, manion wc. splenicgonadal fusion. am j pathol. 1956;32:15-33. 3. carragher am. one hundred years of splenogonadal fusion. urology. 1990;35:471-5. 4. watson rj. splenogonadal fusion. surgery. 1968;63:853-8. 5. karaman mi, gonzales et jr. splenogonadal fusion: report of 2 cases and review of the literature. j urol. 1996;155:309-11. 6. falmann im. nebenmilzen in nebenhoden und samenstrang. virchows arch. 1926;259:237-43. 7. settle ev. the surgical importance of accessory spleens with a report of two cases. am j surg. 1940;50:22-6. 8. guarin u, dimitrieva z, ashley sj. splenogonadal fusion-a rare congenital anomaly demonstrated by 99tc-sulfur colloid imaging: case report. j nucl med. 1975;16:922-4. 9. le roux pj, heddle rm. splenogonadal fusion: is the accepted classification system accurate? bju int. 2000;85:114-5. 10. bonneau d, roume j, gonzalez m, et al. splenogonadal fusion limb defect syndrome: report of five new cases and review. am j med genet. 1999;86:347-58. 11. aslan p, burn j, farrell c. spleno-gonadal fusion of the testis. aust n z j surg. 1997;67:899-900. 12. pauli rm, greenlaw a. limb deficiency and splenogonadal fusion. am j med genet. 1982;13:8190. urology journal unrc/iua vol. 2, no. 4, autumn 2005 printed in iran 230 subject index to volume 2 benign prostatic hyperplasia aghamir smk, mohseni mg, arasteh s. the effect of voiding position on uroflowmetry findings of healthy men and patients with benign prostatic hyperplasia, 216-221 endourology darabi mr, keshvari m. bilateral same-session ureteroscopy: its efficacy and safety for diagnosis and treatment, 8-12 irani d, eshratkhah r, amin-sharifi ar. efficacy of extracorporeal shock wave lithotripsy monotherapy in complex urolithiasis in the era of advanced endourologic procedures, 13-19 tabibi a, akhavizadegan h, noori mahdavi k, najafi semnani m, karbakhsh davari m, niroomand ar. percutaneous nephrolithotomy with and without retrograde pyelography: preliminary results of a randomized controlled trial, 132-136 female urology hosseini sy, safarinejad mr. endometriosis of the urinary tract: a report of 3 cases, 45-48 rajaei isfahani m, haghighat m. measurable changes in hydronephrosis during pregnancy induced by positional changes: ultrasonic assessment and its diagnostic implication, 97-101 fallahian m, mashhady e, amiri z. asymptomatic bacteriuria in users of intrauterine devices, 157-159 sharifi-aghdas f. surgical management of stress urinary incontinence, 175-182 infectious diseases moradi mr, abbasi mr, moradi a, boskabadi a, jalali a. effect of antibiotic therapy on asymptomatic bacteriuria in kidney transplant recipients, 32-35 tayyebi meybodi n, amouian s, mohammadianroashan n. renal allograft mucormycosis: report of two cases, 54-56 darabi mr, keshvari m. bilateral emphysematous pyelonephritis: a case report, 118-119 alimagham m, amini-afshar s, farahmand s, pourkazemi a, pour-reza-gholi f, masood s. frequency of infectious skin lesions in kidney transplant recipients, 193-196 kidney transplantation moradi mr, abbasi mr, moradi a, boskabadi a, jalali a. effect of antibiotic therapy on asymptomatic bacteriuria in kidney transplant recipients, 32-35 kheradmand ar, shahbazian h. the role of pretransplant smoking on allograft survival in kidney recipient, 36-39 tayyebi meybodi n, amouian s, mohammadianroashan n. renal allograft mucormycosis: report of two cases, 54-56 ahmadnia h, shamsa a, yarmohammadi aa, darabi mr, asl zare m. kidney transplantation in older adults: does age affect graft survival?, 93-96 ameli j, ghoddusi k, kachuee h, poorfarziani v, einollahi b. subacute polyneuropathy after initiation of peritoneal dialysis, improved following kidney transplantation, 122-124 shakeri s, aminsharifi ar, khezri aa, monabbati a, tanideh n. can thymic tissue induce tolerance to kidney allografts?, 148-152 taghizadeh afshari a, shirpoor ar, dodangeh balakhani e. the effect of garlic on cyclosporine-ainduced hyperlipidemia in male rats, 153-156 aliasgari m, dadkhah f, tara a, noshad h, akhavizadegan h, birashk g. improvement of severe heart failure with multivalvular dysfunction after kidney transplantation, 171-173 alimagham m, amini-afshar s, farahmand s, pourkazemi a, pour-reza-gholi f, masood s. frequency of infectious skin lesions in kidney transplant recipients, 193-196 shahbazian h, shahbazian h. short-term and longterm outcomes of kidney transplantation in diabetic and nondiabetic patients, 197-200 pediatric urology kazemi-rashed f, simforoosh n. gil-vernet antireflux surgery in treatment of lower pole reflux, 20-22 asgari sa, ghanaie m, simforoosh n, kajbafzadeh am, zare' a. acute urinary retention in children, 23-27 moradi mr, moradi a, ghaderpanah f. comparison of snodgrass and mathieu surgical techniques in anterior distal shaft hypospadias repair, 28-31 kajbafzadeh am. congenital urethral anomalies in boys. part i: posterior urethral valves, 59-78 mahmoudi h. evaluation of meatal stenosis following neonatal circumcision, 86-88 yarmohammad aa, ahmadnia h, asl zare m. transitional cell carcinoma in children: report of a case and review of the literature, 120-121 kajbafzadeh am. congenital urethral anomalies in boys. part ii, 125-131 feizzadeh kerigh b, mohamadzadeh rezaei ma. subject index to volume 2 231 crossed testicular ectopia: a case report, 222-223 reconstructive surgery irani d, hekmati p, amin-sharifi ar. results of buccal mucosal graft urethroplasty in complex hypospadias, 111-114 hosseini sy, safarinejad mr. early versus delayed internal urethrotomy for recurrent urethral stricture after urethroplasty in children, 165-168 mehrsai ar, djaladat h, sina ar, salem s, pourmand g. buccal mucosal graft in repeat urethroplasty, 206-210 salehipour m, khezri aa, askari r, masoudi p. primary realignment of posterior urethral rupture, 211-215 sexual dysfunction and infertility nikoobakht mr, pourkasmaee m, nasseh hr. the relationship between lipid profile and erectile dysfunction, 40-44 nikoobakht mr, aloosh m, hasani m. seminal plasma magnesium and premature ejaculation: a case-control study, 102-105 mehraban d, ansari m, keyhan h, sedighi gilani ma, naderi gh, esfehani f. comparison of nitric oxide concentration in seminal fluid between infertile patients with and without varicocele and normal fertile men, 106-110 nikoobakht mr, saraji a, meysamie am. preoperative corporal biopsy as a predictor of postoperative results in venoocclusive erectile dysfunction, 160-164 barghi mr. the relation of enuresis and irritable bowel syndrome with premature ejaculation: a preliminary report, 201-205 feizzadeh kerigh b, mohamadzadeh rezaei ma. crossed testicular ectopia: a case report, 222-223 al-durazi mh, al-helo ha, malik ak, kadhim ae. conservative surgical management of bilateral epidermoid cysts of the testis: a case report and review of literature, 224-226 stone disease irani d, eshratkhah r, amin-sharifi ar. efficacy of extracorporeal shock wave lithotripsy monotherapy in complex urolithiasis in the era of advanced endourologic procedures, 13-19 pourmand g, nasseh hr, sarrafnejad af, mehrsai ar, hamidi alamdari d, nourijelyani k, shekarpour l. urinary tamm-horsfall protein and citrate: a case-control study of inhibitors and promoters of calcium stone formation, 79-85 tabibi a, akhavizadegan h, noori mahdavi k, najafi semnani m, karbakhsh davari m, niroomand ar. percutaneous nephrolithotomy with and without retrograde pyelography: preliminary results of a randomized controlled trial, 132-136 urological oncology hosseini sy. invasive bladder cancer: the role of bladder preserving therapy, 1-7 dadkhah f, salimi mr, kaviani a. benign retroperitoneal schwannoma mimicking adrenal mass, 49-51 kheradmand ar. choriocarcinoma presenting as bilateral renal tumor: a case report, 52-53 aliasgari m, soleimani m, hosseini moghaddam smm. the effect of acute urinary retention on serum prostate-specific antigen level, 89-92 mohammadi torbati p, parvin m, ziaee sam. malignant mesothelioma of the spermatic cord: case report and review of the literature, 115-117 yarmohammad aa, ahmadnia h, asl zare m. transitional cell carcinoma in children: report of a case and review of the literature, 120-121 zargar ma, soleimani mj, moslemi mk. comparative evaluation of urinary bladder cancer antigen and urine cytology in the diagnosis of bladder cancer, 137-140 mowla sd, emadi baygi m, ziaee sam, nikpoor p. evaluating expression and potential diagnostic and prognostic values of survivin in bladder tumors: a preliminary report, 141-147 djaladat h, mehrsai ar, nasseh h, pourmand g. synchronous renal fossa recurrence with bladder metastases due to renal cell carcinoma, 169-170 hosseini sy, salimi mr, hosseini moghaddam smm. changes in serum prostate-specific antigen level after prostatectomy in patients with benign prostatic hyperplasia, 183-188 mehrabi s, ghafarian shirazi hr, rasti m, bayat b. analysis of serum prostate-specific antigen levels in men aged 40 years and older in yasuj, iran, 189-192 urology journal unrc/iua 148 introduction the thymus plays an important role in developing tolerance to alloantigens and is critical for tolerance to self-antigens,(1-5) in which potentially autoreactive t cells are deleted or anergized by exposure to the appropriate selfantigens, presented by either bone marrow derived cells or thymic stromal cells.(1) the definition of tolerance in the context of transplantation is challenging. in simple terms, transplantation tolerance is the survival and vol. 2, no. 3, 148-152 summer 2005 printed in iran received april 2004 accepted september 2005 *corresponding author: department of surgery, faghihi hospital, shiraz, iran. tel: ++98 711 233 6669, fax: ++98 711 233 1006 e-mail: amin_sharifi@hotmail.com kidney transplantation can thymic tissue induce tolerance to kidney allografts? saeed shakeri,1 alireza aminsharifi,1* abdolaziz khezri,1 ahmad monabbati,2 nader tanideh2 1department of urology, shiraz university of medical sciences, shiraz, iran 2department of pathology, shiraz university of medical sciences, shiraz, iran abstract introduction: the aim of this study was to investigate the beneficial effect of donor thymic tissue to induce tolerance in thymokidney allografts, transplanted to thymectomized cross-bred canines. materials and methods: seven pairs of transplant donors and recipients were selected from 3to 4-month-old cross-bred canines with major histocompatibility complex (mhc) mismatches. recipients underwent partial thymectomy 4 weeks before transplantation and received an autologous thymic graft under the renal capsule, which had been engrafted in the donors 3 months before transplantation (thymokidney). successful engraftment with evidence of thymocyte development in the donors was determined by gross and histologic examination at the time of transplantation. biopsy specimens were obtained at the transplant day and 3 months after transplantation and were studied histologically for evidence of hyperacute or acute rejection. results: at 90 days after the operation, all 7 juvenile thymic grafts had developed with normal thymic structure under the renal capsule. hyperacute rejection was not observed in allografts, and all of them were functioning until the end of follow-up; however, all of the allografts showed acute cell-mediated rejection 3 months after transplantation. conclusion: no tolerance was induced by vascularized donor thymokidneys in mhcmismatched canines. the advantages of tolerance over chronic immunosuppression are so great that a potentially tolerogenic approach such as thymic transplantation would seem worthy of further investigations on large animal models. to evaluate the beneficial effects of thymic tissue in tolerance induction, utilizing a short course, lowdose adjuvant immunosuppressant to this regimen and/or application of in-bred mhcmatched canines is suggested. key words: kidney transplantation, thymus, thymokidney, allograft rejection, canine shakeri et al 149 function of a graft in the absence of continuing immunosuppression. although this is only a functional definition that defines any particular mechanism as being responsible for the tolerant state, it may not be appropriate as multiple mechanisms are being increasingly found that can be used to promote the development and maintenance of tolerance to a defined set of antigens in vivo.(10) what is most important, is that the tolerant state be effective in practice, and that it allows the survival and function of a graft in the absence of a destructive immune response against the transplanted tissue.(10) to transplant a donor's thymus as a composite, the thymokidney graft is a recently described method that creates a vascularized thymic graft by implanting autologous thymic tissue under the renal capsule.(11) such thymokidneys have been able to reconstitute t cells and restore immunocompetency in pigs and mice.(9) previous tolerance-induced regimens to kidney allografts by thymic tissue have been found to be effective in rodents and miniature swine.(6-8) transplanting a donor's thymus as a part of the vascularized organ graft in previously thymectomized major histocompatibility complex (mhc)-matched mice and miniature swine has allowed the thymus to function immediately after transplantation and to induce durable tolerance to the allograft.(6-8) meanwhile, many of the methods used to induce tolerance in rodents have failed in large animals or human studies.(9) thus, before testing new approaches clinically, it is necessary to examine these methods in large animal models. in the present study, we investigate the effectiveness of thymic tissue for inducing tolerance to kidney allografts in fully mhcmismatched canines. materials and methods animals seven pairs of transplant donors and recipients were selected from 3to 4-month-old cross-bred canines. the mismatched status of the pairs was confirmed by positive wbc cross-match test. therefore, fully mhc-mismatched juvenile animals were used. the experimental protocols used in this study were approved by the committee on animal research at our institution. surgical procedure all of the recipients underwent total thymectomy through cervical incision 4 weeks prior to the transplantation. creation of the thymokidney in the donors was done 3 months before transplantation. through a cervical longitudinal incision in the donors, approximately three fourths of the thymus was removed to provide autologous thymic tissue. it was minced into 2-mm3 to 3-mm3 pieces and put under the renal capsule of the left kidney, which was exposed through a flank approach. thymic tissue was vascularized under the renal capsule for 3 months to create the thymokidney. to confirm successful engraftment, vascularization, and evidence of thymocyte development in the autologous thymic graft, biopsies of the thymokidney were performed before transplantation. thereafter, 7 thymokidneys were transplanted into the thymectomized juvenile full mhcmismatched canines. the renal artery and vein of the donor were harvested with aortic and inferior vena cava patches, respectively; transferred to the recipient; and anastomosed end-to-side to the abdominal aorta and inferior vena cava of the recipient, respectively. urinary drainage was accomplished via a ureterovesical anastomosis. at the first postoperative day, a biopsy of the allograft was obtained for any evidence of hyperacute rejection. all of the animals were fed appropriately and stored in a well-equipped animal house in a 12-hour light/dark stable with a well-controlled environment. three months after the transplantation, recipients were killed, and the thymokidney allograft was removed, fixed in formalin, and studied histopathologically for evidence of acute rejection. before killing, multiple biopsies were taken from the cervical area and anterior mediastinum for any residual thymic tissue. no immunosuppression was administered to the recipients. results gross and histologic examinations of the thymokidneys showed that the thymic grafts were well vascularized by vessels from both the renal capsule and the renal parenchyma in all canines. they had normal thymic structures and thymocytes, 90 days postoperatively (figure 1). hyperacute rejection was not detected in any of the allografts after transplantation, and gross and histologic examinations of the transplanted thymokidneys a few hours after transplantation thymic tissue for tolerance to kidney allografts150 showed normal kidney tissue. single native kidney was preserved in all recipients, and overall kidney function was normal at 3 months' follow-up, with acceptable plasma creatinine levels and urine output. however, all 7 allografts demonstrated evidence of acute cell-mediated rejection, including tubulitis, microvascular thrombosis, and vasculitis with destruction of glomerulus on histopathologic examination of the allograft (figure 2). necropsy of the recipients and multiple biopsies from the cervical area and anterior mediastinum showed no residual thymic tissue. discussion the phenomena of rejection and transplantation tolerance are related to each other, although they follow different immunologic mechanisms. one of the most important organs for inducing tolerance to allografts is the thymus. the most essential mechanism for inducing tolerance is clonal t-cell deletion, through which compatible t cells are developed by the thymus during the embryonic and infancy periods. after production of different t cells in the bone marrow, t cells are transferred to the thymus, where incompatible ones are removed by apoptosis. therefore, thymic tissue seems to be the main physiologic organ for tolerance induction. lee and coworkers have used thymic tissue in thymectomized cell-depleted mice to induce tolerance to renal allografts. the same strategy has been applied for tolerance to skin grafts.(12,13) placing the thymic tissue under the renal capsule and transferring the resultant composite organ are not only technically simpler than transferring the thymus and kidney as separate organs, but they also are effective in inducing tolerance to renal allografts.(6) the following potential mechanisms have been suggested as inducing tolerance in swine: 1. t-cell progenitors may be positively or negatively selected by donor thymic stroma and/or dendritic cells by a mechanism similar to that of self tolerance.(2) immunohistochemistry studies have demonstrated that donor-type dendritic cells remain for more that 3 months after transplant. negative selection of potentially autoreactive thymocytes occurs mainly in the thymus and is thought to be induced primarily by interaction with bone-marrow-derived cells.(2) other reports have shown that thymic epithelial cells are capable of participating in both positive and negative selection of thymocytes(14,15) and of inducing anergy.(16) thus, the long-term presence of donor stromal cells (donor epithelial cells and dendriticlike vascular endothelial cells) in the donor thymic graft may play an important role in the induction of tolerance by deletion, anergy, or a combination of the two. consistent with this hypothesis, it has been shown that new t cells, generated in thymectomized recipients receiving thymokidneys, are taught by both host and donor elements in the thymic graft.(6) 2. after thymectomy, recipients were not t-cell depleted, and mature t cells were present in the recipients of composite thymokidneys. however, mature peripheral t cells also have fig. 1. histopathology of the thymokidney. note the normal thymic tissue (arrows) adjacent to the normal kidney tissue (hematoxylin-eosin × 40). fig. 2. acute cell-mediated rejection in the thymokidney allograft. leukocyte infiltration with evidence of tubular and glomerular destruction is noted (hematoxylineosin × 40). shakeri et al 151 been shown to become unresponsive to donor antigens by recirculation to the thymus.(17) alloreactive t cells could enter the donor thymic graft and could be taught. 3. another possibility is that thymic emigrants from the thymic graft (which may include regulatory cells) facilitate tolerance induction peripherally. such peripheral tolerance could be mediated by a changed cytokine status or suppressive mechanisms.(18,19) however, thymic tissue transplants did not facilitate the induction of tolerance in canines. there are several ways to look at these observations. one of the most important factors in graft rejection is the existence or lack of compatibility between the mhc antigens of donors and those of recipients. whenever the donor and recipient are matched in class i mhc and class ii mhc, or at least in class ii mhc, tolerance will be induced spontaneously at the level of cd4+ helper t cells. therefore, the main cells involved in rejection will be suppressed. since cd4+ cells control the activity of cd8+ cytotoxic t cells through cytokines, tolerance at the level of cd4+ cells will suppress the function of cd8+ cells. in nearly all previous reports indicating the beneficial effect of thymic tissue in tolerance induction, the donor-recipient pairs were mhc-matched or at least matched in class ii mhc antigens.(6-8) however, the most recent studies on tolerance have revealed that this phenomenon can be effective in mhc-mismatched pairs. yamada and colleagues have shown that tolerance can be induced in miniature swine using composite thymokidney across fully mhcmismatched barriers.(20) also, li and colleagues have indicated that donor bone marrow can induce tolerance to lung allografts in mhcmismatched rats.(21) it seems that although tolerance-inducing protocols work better in mhcmatched pairs, they also can be effective in mhcmismatched ones. we used a canine model to evaluate the beneficial effect of thymic tissue in this species. the rejection phenomenon and recognition of selffrom nonself-antigens varies among different species. a review of veterinary literature revealed that the rejection phenomenon is very severe in canines, since it is reported that despite applying matched donor-recipients and administering immunosuppressive therapy after transplantation, up to 60% of allografts will be lost owing to acute rejection. given the different tolerance-inducing protocols in different animal models, we can conclude that to induce tolerance to a specific allograft, that these methods are more effective if the animal models are smaller (eg, rat, mice, and miniature swine), since tolerance has been achieved using more-simple protocols. nevertheless, when we use large animal models with more complex immunological systems (as in the present study), adjuvant modalities (eg, use of biologic agents or immunosuppressive drugs) will be beneficial. despite the difficulty in inducing tolerance to allografts in larger animal models, it seems likely that investigations using these protocols in humans will be appropriate for humans in the future. the interaction of immunosuppressive drugs on tolerance induction is one of the main challenges to allograft tolerance. in many of the previous studies in which thymic tissues have caused the induction of tolerance, immunosuppressive drugs had been used.(5-8) cyclosporin a can effectively inhibit both the cd4 helper pathway and the direct cd8 helper pathway.(22) immunosuppressives, even in low doses and/or for a short course, might block or inhibit development of rejection in the presence of thymic tolerance. on the other hand, contrary to the above-mentioned findings, recent studies have shown that calcineurin inhibitors (such as cyclosporin a), administered along with tolerance-inducing regimens, might block or inhibit the induction of tolerance. experiments have revealed that tolerance to the alloantigens could not be induced in interleukin-2 knockout mice. with the administration of calcineurin inhibitors, interleukin-2 gene transcription would be inhibited. therefore, tolerance might not be induced.(23) it also has been established that in the presence of calcineurin inhibitors, apoptosis and, in turn, clonal t-cell deletion (which is the major mechanism for tolerance induction) will be blocked.(24) something else must be taken into consideration: as discussed before, different immunosuppressive drugs in various animal models may have different effects on tolerance induction, considering the complexity of the immunologic system in these animals. at present, the advantages or disadvantages of immunosuppressive drugs on tolerance remain to be proved. thymic tissue for tolerance to kidney allografts152 conclusion although the capability of thymic tissue to induce tolerance, with and without immunosuppression, is acceptable in small animal models such as mice, the thymus could not induce tolerance to kidney allografts in fully mhc-mismatched canines. this may be related to parameters such as which animal model is used, the mhc-mismatched status of donor and recipients, and the abandonment of immunosuppressive drugs. owing to the strength of the immune system in large animal models and the difficulty in suppressing it, introduction of any novel strategy for tolerance induction into clinical practice will necessitate more investigations. to prove the potential effects of thymic tissue for tolerance induction, combining this approach with one or more immunosuppressive drugs at the time of transplantation and/or applying mhc-matched pairs is suggested. how clinically successful this approach would be remains unclear. references 1. kappler jw, roehm n, marrack p. t cell tolerance by clonal elimination in the thymus. cell. 1987;49:273-80. 2. sprent j, lo d, gao ek, ron y. t cell selection in the thymus. immunol rev. 1988;101:173-90. review. 3. kappler jw, staerz u, white j, marrack pc. selftolerance eliminates t cells specific for mls-modified products of the major histocompatibility complex. nature. 1988;332:35-40. review. 4. ramsdell f, fowlkes bj. clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. science. 1990;248:1342-8. 5. coutinho a, salaun j, corbel c, bandeira a, le douarin n. the role of thymic epithelium in the establishment of transplantation tolerance. immunol rev. 1993;133:22540. review. 6. yamada k, shimizu a, utsugi r, et al. thymic transplantation in miniature swine. ii. induction of tolerance by transplantation of composite thymokidneys to thymectomized recipients. j immunol. 2000;164:307986. 7. yamada k, gianello pr, ierino fl, et al. role of the thymus in transplantation tolerance in miniature swine. i. requirement of the thymus for rapid and stable induction of tolerance to class i-mismatched renal allografts. j exp med. 1997;186:497-506. 8. yamada k, shimizu a, ierino fl, et al. thymic transplantation in miniature swine. i. development and function of the "thymokidney". transplantation. 1999;68:1684-92. 9. french me, batchelor jr. enhancement of renal allografts in rats and man. transplant rev. 1972;13:115-41. 10. wad kj. approaches to induction of tolerance. in: morris pj, editor. kidney transplantation, principles and practice 5th ed. philadelphia: wb saunders; 2001. p.326-37. 11. lambrigts d, fransse c, martens h, et al. development of thymus allografts under the kidney capsule in pig: a new organ for xenotransplantation. xeno transplantation. 1996;3:296. 12. lee la, gritsch ha, sergio jj, et al. specific tolerance across a discordant xenogeneic transplantation barrier. proc natl acad sci u s a. 1994;91:10864-7. 13. zhao y, swenson k, sergio jj, arn js, sachs dh, sykes m. skin graft tolerance across a discordant xenogeneic barrier. nat med. 1996;2:1211-6. 14. hugo p, kappler jw, godfrey di, marrack pc. thymic epithelial cell lines that mediate positive selection can also induce thymocyte clonal deletion. j immunol. 1994;152:1022-31. 15. lo d, reilly cr, burkly lc, dekoning j, laufer tm, glimcher lh. thymic stromal cell specialization and the t-cell receptor repertoire. immunol res. 1997;16:3-14. review. 16. schonrich g, momburg f, hammerling gj, arnold b. anergy induced by thymic medullary epithelium. eur j immunol. 1992;22:1687-91. 17. agus db, surh cd, sprent j. reentry of t cells to the adult thymus is restricted to activated t cells. j exp med. 1991;173:1039-46. 18. hall bm, gurley ke, pearce nw, dorsch se. specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. ii. sequential changes in alloreactivity of t cell subsets. transplantation. 1989;47:1030-3. 19. pearce nw, spinelli a, gurley ke, dorsch se, hall bm. mechanisms maintaining antibody-induced enhancement of allografts. ii. mediation of specific suppression by short lived cd4+ t cells. j immunol. 1989;143:499-506. 20. yamada k, vagefi pa, utsugi r, et al. thymic transplantation in miniature swine: iii. induction of tolerance by transplantation of composite thymokidneys across fully major histocompatibility complexmismatched barriers. transplantation. 2003;76:530-6. 21. li s, louis lb 4th, kawaharada n, yousem sa, pham sm. intrathymic inoculation of donor bone marrow induces long-term acceptance of lung allografts. ann thorac surg. 2003;75:257-63; discussion 263. 22. auchincloss h jr, winn hj. murine cd8+ t cell helper function is particularly sensitive to cyclosporine suppression in vivo. j immunol. 1989;143:3940-3. 23. dai z, konieczny bt, baddoura fk, lakkis fg. impaired alloantigen-mediated t cell apoptosis and failure to induce long-term allograft survival in il-2-deficient mice. j immunol. 1998;161:1659-63. 24. wells ad, li xc, li y, et al. requirement for t-cell apoptosis in the induction of peripheral transplantation tolerance. nat med. 1999;5:1303-7. 403 forbidden
vol 12. no 01 jan-feb 2015 1995 pediatric urology does the histopathologic pattern of the ureteropelvic junction affect the outcome of pyeloplasty? oktay issi,1 hasan deliktas,2 abdullah gedik,3* selver ozekinci,4 mehmet kamuran bircan,5 hayrettin şahin2 purpose: to investigate the effects of the histopathologic pattern of obstructed ureteropelvic junction (upj) specimens, including collagen type 3, elastin, fibrosis and cajal cells, on the outcome of pyeloplasty. materials and methods: histopathological specimens obtained following anderson-hynes pyeloplasty from 52 patients with intrinsic ureteropelvic junction obstruction (upjo) between january 2005 and january 2008 were evaluated histopathologically. patients with extrinsic or secondary upjo were excluded. preoperative and postoperative radiographic evaluations were performed either via diuretic renography or intravenous pyelography, or both. six months post-surgery the patients were divided into 2 groups, as successful surgery (group 1) and unsuccessful surgery (group 2). histopathological findings (collagen type 3, elastin, fibrosis and cajal cells) in each group were statistically compared. results: the study included 52 patients (21 female and 31 male). mean age of the entire study population was 39.42 ± 14.5 years, versus 39.63 ± 14.9 years in group 1 (n = 47) and 37.4 ± 10.0 years in group 2 (n = 5). median follow-up was 18 months. there weren’t any significant differences in collagen type 3, elastin, fibrosis, or cajal cells between the 2 groups (p > .05). conclusion: the histopathologic pattern of upj was not a factor associated with the success of pyeloplasty. based on the present findings, we conclude that surgical technique is more important than the histopathologic pattern of upj for the successful treatment of upjo. keywords: kidney pelvis; surgery; treatment outcome; ureteral obstruction; follow-up studies; physiopathology. introduction ureteropelvic junction obstruction (upjo) is the most common congenital urinary tract obstruction, which occurs in 1 per 1000 newborns.(1) the underlying mechanism of upjo remains unclear. a decrease in smooth muscle cells at the ureteropelvic junction (upj), abnormal muscle orientation, and collagen deposition, as well as a reduction in cajal cells(2) and neural elements(3) have been suggested to play a role in the pathogenesis of congenital upjo. open pyeloplasty remains a viable treatment option for primary repair of primary upjo, along with long-term follow-up.(4,5) despite the efficacy of open pyeloplasty, in some patients the procedure is unsuccessful and additional intervention is required to treat persistent obstruction. the cause of pyeloplasty failure is not clear and the role of the histopathological pattern of the upj in this failure is contentious. the present study aimed to investigate the effect of the histopathological pattern of the upj on the outcome of pyeloplasty in patients with upjo. materials and methods histopathological specimens obtained following andersonhynes pyeloplasty in 52 patients with intrinsic upjo between january 2005 and january 2008 were evaluated histopathologically. patients with extrinsic upjo and those with a history of surgical treatment were excluded. in preoperative evaluation, the patients whose ureters were visualized in intravenous urography (ivu) were excluded from the study. patients whose ureters were not visualized in ivu were investigated via diuretic renogram. during diuretic renogram, intravenous furosemide was injected to the patients 20 minutes after radiotracer injection. clearance half-time of the tracer (t1/2) from the collecting system was then measured. patients who had t1/2 ≥ 20 min were accepted as having obstruction and then had pyeloplasty operation. in postoperative 3rd month evaluation while patients whose ureters were visualized in ivu were evaluated as successful surgery, patients whose ureters were not visualized in ivu were investigated via diuretic renogram. also patients whose ureters were visualized in ivu and who had t1/2 < 20 min in diuretic renogram were evaluated as successful surgery (group 1, n = 47). the patients who had obstruction in post-operative 3th month were investigated via diuretic renogram again post-operative 6th month and patients who had t1/2 ≥ 20 min were accepted as having obstruction and evaluated as unsuccessful surgery (group 2, n = 5). all surgeries were performed by the same surgeon. all patients had an indwelling double pigtail stent placed intraoperatively, which was removed 4-6 weeks post-surgery. the upj segments excised in each group (successful surgery [group 1] and unsuccessful 1 department of urology, bingol state hospital, bingol, turkey. 2 department of urology, school of medicine, mugla sitki kocman university, mugla, turkey. 3 department of urology, school of medicine, dicle university, diyarbakir, turkey. 4 department of pathology, school of medicine, dicle university, diyarbakir, turkey. 5 department of urology, memorial hospital, diyarbakir, turkey. *correspondence: department of urology, school of medicine, dicle university, diyarbakir, turkey. tel: +90 412 2488001. fax: +90 412 2488440. e-mail: gedikabd@gmail.com. received july 2014 & accepted december 2014. vol 12. no 01 jan-feb 2015 2028 surgery [group 2]) were compared histopathologically (collagen type 3, elastin, fibrosis, and cajal cells). pathological evaluation all excised upj segments were examined at dicle university, school of medicine, pathology lab. sections 4 µm thick were obtained from formalin-fixed paraffin blocks, stained with hematoxylin & eosin, and examined under a light microscope. reticulin and masson’s trichrome staining was performed to determine collagen type 3 status in the submucosa and the presence of fibrosis. immunohistochemical method cross sections 4 µm thick obtained from the paraffin blocks of selected patients were transferred to positively charged slides for immunohistochemical examination using a cd117/c-kit (catalogue no. cme 296 ak, biocare medical, concord, ca, usa) and elastin (catalog no. gtx29519 genetex, inc. tx, usa antibodies). sections were deparaffinized. dehydration was performed in 96-degree ethyl alcohol and antigen recovery was carried out in a microwave oven in ph 6.0 citrate buffer solution. the sections were cooled for 20 min at room temperature and kept in phosphate buffered saline (pbs) solution for 10 min. the tissues were circled using a hydrophobic pen, and then maintained in protein block solution (ultra v block) for 5 min. the sections were then washed with pbs and incubated for 40 min using a cd117/c-kit and elastin. next, they were washed with pbs, maintained at room temperature for 20 min with coenzyme value primer antibody enhancer, and then washed with pbs solution. afterwards, they were treated with value horseradish peroxidase (hrp) polymer for 30 min in a dark environment. they were then washed with pbs, maintained in 3-amino-9ethylcarbazol (aec) single solution, and then washed with distilled water. contrast staining was performed for 2 min using mayer’s hematoxylin. after drying at room temperature they were covered with aqueous mounting material (ultramount, labvision, fremont, ca, usa), and then evaluated under a light microscope. evaluation of cd117, elastin, masson’s trichrome, and reticulin staining cajal cells between the muscle layers stained with cd117 were enumerated in the 10 times enlarging area (tea) and evaluated as follows: n = 0-1 (–); n = 2-5 (+); n = 6-10 (++); n = ≥ 11 (+++). macrophages in the mucosa and submucosa were evaluated as positive controls. evaluation of elastin staining was positive (+) or negative (–). the blood vessel wall was evaluated as a positive control. masson’s trichrome staining evaluation was performed according to fibrosis in the submucosa. variables surgically successful group (n = 47) surgically unsuccessful group (n = 5) age, years (mean ± sd) 39.63 ± 14.9 37.4 ± 10.0 male, no 28 3 female, no 19 2 right side, no 26 3 left side, no 21 2 table 1. demographic characteristics of study patients. the parameters evaluated surgically successful group surgically unsuccessful group p value histopathologically (group 1, n = 47) (group 2, n = 5) cajal cells −* 6 (12.8) 0 (0) .910 +** 24 (51.1) 4 (80) .446 ++*** 11 (23.4) 0 (0) .521 +++**** 6 (12.8) 1 (20.0) 1.000 elastin (+) 8 (17.0) 0 (0) .726 elastin (-) 39 (83.0) 5 (100) fibrosis (+) 13 (27.7) 2 (40.0) .952 fibrosis (-) 34 (72.3) 3 (60.0) collagen type 3 (+) 6 (12.8) 2 (40.0) .341 collagen type 3 (-) 41(87.2) 3 (60.0) p = chi-square test. data are presented as no (%). * = 0-1 cajal cell ** = 2-5 cajal cells *** = 6-10 cajal cells **** = ≥ 11 cajal cells table 2. the results of statistical analysis. upj histopathology and outcome of pyeloplasty-issi et al pediatric urology 2029 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2030 elastin couldn’t be separated, as the collagen, elastin, and other connective tissues were stained blue; staining was considered positive (+) if there was blue coloring under the epithelium and negative (–) if there wasn’t. reticulin was evaluated according to the thickness of the fibers in the submucosa, as positive (+) or negative (–); reticulin fibers observed via low magnification were considered positive (+) and those that were not were considered negative (–). statistical analysis statistical analysis of the data was performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. frequencies and means for all data in both groups were calculated. between-group comparisons were made using the chisquare test with yates correction. the level of statistical significance was set at p < .05. results the study included 52 patients (21 female and 31 male). mean age of the entire study population was 39.42 ± 14.5 years, versus 39.63 ± 14.9 years in group 1 (n = 47) and 37.4 ± 10.0 years in group 2 (n = 5). median follow-up time was 18 months. mean duration of surgery was 65 min and mean duration of hospitalization was 5 days. intraoperative and early postoperative complications were not observed. in all, at 3 months post-surgery 47 patients were free of obstruction, whereas 5 had persistent obstruction, which persisted in all 5 at the 6-month post-surgery follow-up; these 5 patients with persistent obstruction constituted the group 2 (unsuccessful surgery group). among the 5 patients in group 2, 1 underwent a second open pyeloplasty, 3 underwent antegrade endopyelotomy and 1 underwent nephrectomy. the case who underwent nephrectomy was determined as having decreased renal function (17%) in scintigraphy via techenetium-99m-labeled diethylenetriaminepentaacetic acid (99mtc-dmsa) in preoperative. the case underwent nephrectomy due to determining significantly decreased renal function (6%) in scintigraphy (via 99mtc-dmsa) in postoperative 6th month. patient characteristics are given in table 1. the upj segments in the 2 groups were examined histopathologically. there weren’t any differences in the quantity of collagen type 3, elastin, fibrosis, or cajal cells in the examined upj segments between the 2 groups (p > .05) (table 2, and figure, a and b). discussion several open and minimally invasive surgical techniques are used for the treatment of upjo. although open surgery remains the gold standard, with a success rate as high as 97%,(6,7) alternative techniques have been developed in order to reduce the occurrence of morbidity associated open pyeloplasty while maintaining a high success rate. the overall success rate in the present study was 90.4%. the role of surgical technique and histopathological pattern of the upj in surgical success remains unclear. many studies have compared the histopathological pattern of normal and obstructed upj segments, but none have examined the role of the histopathological pattern of upjo segments in surgical success. to the best of our knowledge the present study is the first to investigate the role of the histopathological pattern of upjo segments in surgical success. it is well known that cajal cells are required to generate smooth muscle electrical slow waves.(8,9) solari and colleagues(2) were the first to observe c-kit-positive cajal cells in the normal human upj. as in gastrointestinal motility, cajal cells may play an important role in the propagation, coordination and modulation of ureteropelvic peristalsis. many studies have examined cajal cells in the histopathologic examination of upj segments. cajal cells were determined via cd117 tyrosine kinase receptor. this method is inadequate to determine all the cajal cells and able to determine only functional active cajal cells. koleda and colleagues(10) reported that the number of cajal cells in obstructed upj segments was higher than in normal upj segments, concluding that the observed increase in cajal cells compensates for the effects of obstruction. kuzgunbay and colleagues(11) reported that the number of cajal cells increases during the early period of obstruction, as peristaltic activity increases, but that during the late period of obstruction as peristaltic activity decreases the number cajal cells also decreases. in the same study, the number of cajal cells were seen to decrease with increasing age in a pediatric group. (10) in our study, there were few cases in unsuccessful surgery group thus we thought that it was not essential to re-group the patients in unsuccessful surgery group figure. immunoperoxidase × 400 cd117 positive cajal cells. (a) a 32 years old male patient with successful surgery; (b) a 38 years old male patient with unsuccessful surgery upj histopathology and outcome of pyeloplasty-issi et al depending age range. in the present study there wasn’t a significant difference in cajal cells between the 2 groups. as all of the present study’s specimens were obtained in the late period of obstruction when cajal cells were decreased, we don’t think that the number of cajal cells will change and affect the surgical success. kim and colleagues(12) reported that an increase in the collagen-smooth muscle ratio and an increase in elastin content in the obstructed upj contribute to inelasticity and low compliance, resulting in slower recovery of hydronephrosis following pyeloplasty. kaselas and colleagues(14) studied the role of renal pelvis collagen, elastin and smooth muscle thickness in postoperative radiologic recovery, and reported that collagen and elastin did not play a role, whereas as an increase in smooth muscle thickness prolonged radiologic recovery. similarly as kaselas and colleagues,(14) in the present study there weren’t any significant differences in collagen or elastin between the 2 groups. in an animal model of pyeloplasty passerotti and colleagues(15) studied the histopathologic pattern of the upj 15 days post-surgery, and reported that fibrosis and accumulation of collagen type 3 were lower in the roboticassisted laparoscopy group than in the open pyeloplasty and hand-assisted laparoscopy group. they concluded that the superior visual capability of robotic-assisted laparoscopy facilitates less traumatic surgery. in the present study there weren’t any significant differences in collagen accumulation or fibrosis between the 2 groups, clearly indicating that they did not play a role in surgical success. as passerotti and colleagues(15) reported, we also think that excessive dissection during pyeloplasty causes tissue hypoxia, resulting in fibrosis and accumulation of collagen. we think that the amount of fibrosis in the resected upj region does not have an effect on surgical success, but that fibrosis due to hypoxia and accumulation of collagen might negatively affect surgical success. kim and colleagues(13) separated excised upjs into 3 segments, as renal pelvis, upj and ureter, and examined elastin in each segment separately. they concluded that the amount of elastin in the remaining ureter and renal pelvis following excision of the upj could be an important factor affecting surgical success. in the present study the specimens were examined without separation. the effect of histopathology on surgical success would be better comprehended when histopathologic structure of remaining segments of ureter and pelvis that end to end anastomosis is done, is evaluated instead of histopathologic structure of excised segment. conclusion the success of the surgical treatment of upjo primarily depends on surgical technique and less so on the histopathological pattern of the upj. during surgery excessive dissection should be avoided and vascularization should be preserved: the resected amount should be in proper amount and the anastomosis should be tension free. conflict of interest none declared. references 1. wang y, puri p, hassan j, miyakita h, reen dj. abnormal innervation and altered nerve growth factor messenger ribonucleic acid expression in ureteropelvic junction obstruction. j urol. 1995;154:679-83. 2. solari v, piotrowska ap, puri p. altered expression of interstitial cells of cajal in congenital ureteropelvic junction obstruction. j urol. 2003;170:2420-2. 3. murakumo m, nonomura k, yamashita t, ushiki t, abe k, koyanagi t. structural changes of collagen components and diminution of nerves in congenital ureteropelvic junction obstruction. j urol. 1997;157:1963-8. 4. o’reilly ph, brooman pj, mak s, et al. the long-term results of anderson-hynes pyeloplasty. bju int. 2001;87:287-9. 5. inagaki t, rha kh, ong am, kavoussi lr, jarrett tw. laparoscopic pyeloplasty: current status. bju int. 2005;95 suppl 2:102-5. 6. bonnard a, fouquet v, carricaburu e, aigrain y, el-ghoneimi a. retroperitoneal laparoscopic versus open pyeloplasty in children. j urol. 2005;173:1710-3. 7. reed mj, williams mp. open pyeloplasty in children: experience with an improved stenting technique. urol int. 2003;71:201-3. 8. huizinga jd, thuneberg l, kluppel m, malysz j, mikkelsen hb, bernstein a. w/ kit gene required for interstitial cells of cajal and for intestinal pacemaker activity. nature. 1995;373:347-9. 9. thomsen l, robinson tl, lee jc, et al. interstitial cells of cajal generate a rhythmic pacemaker current. nat med. 1998;4:848-51. 10. koleda p, apoznanski w, wozniak z, et al. changes in interstitial cell of cajal-like cells density in congenital ureteropelvic junction obstruction. int urol nephrol. 2012;44:7-12. 11. kuzgunbay b, doran f, bayazit y, turunc t, satar n, kayis aa. the effects of ureteral obstruction on cajal-like cells in rats. j pediatr urol. 2009;5:269-73. 12. kim wj, yun sj, lee ts, kim cw, lee hm, choi h. collagen-to-smooth muscle ratio helps prediction of prognosis after pyeloplasty. j urol. 2000;163:1271-5. 13. kim ds, noh jy, jeong hj, kim mj, jeon hj, han sw. elastin content of the renal pelvis and ureter determines post-pyeloplasty recovery. j urol. 2005;173:962-6. 14. kaselas c, aggelidou s, papouis g, kazakis c, philippopoulos a. [thickness of the renal pelvis smooth muscle indicates the postoperative course of ureteropelvic junction obstruction treatment]. actas urol esp. 2011;35:605-9. 15. passerotti cc, passerotti am, dall’oglio mf, et al. comparing the quality of the suture anastomosis and the learning curves associated with performing open, freehand, and roboticassisted laparoscopic pyeloplasty in a swine animal model. j am coll surg. 2009;208:57686. upj histopathology and outcome of pyeloplasty-issi et al pediatric urology 2031 urology journal vol. 11 no. 04 july august 2014 1852 pictorial urinary bladder herniation into pubic ramus fracture mandeep singh ghuman,1 shabdeep kaur,2 kavita saggar1 a young adult male was admitted after suffering polytrauma due to road traffic accident. emergency radiography showed pelvic fracture. computed tomography (ct) scan was performed which revealed presence of comminuted displaced fracture of left superior pubic ramus. fracture line was extending till pubic symphysis but no symphyseal diastasis was noted. in addition, a part of urinary bladder was seen herniating in between the gaping bony margins of the fractured superior pubic ramus (figures 1 and 2, arrows). in view of this unexpected ct scan finding, it was decided not to do external fixation and the patient was taken up for open reduction and internal fixation. although urological injuries are common in pelvic fractures, herniation or interposition of bladder into pelvic fractures is very rare phenomenon with available case reports mentioning herniation and subsequent entrapment into pubic symphyseal diastasis.(1-3) interposition of the bladder into pubic rami fracture has not been reported before in the literature. operative management is recommended in pelvic fractures with incorporated bladder.(1) high index of suspicion is required to detect any herniation of bladder, not only in cases of pubic diastasis but also in the presence of rami fractures as overlooking this significant finding will lead to subsequent incarceration of urinary bladder following external fixation.(2,3) 1department of radiodiagnosis, dayanand medical college and hospital, ludhiana-141001, india. 2department of radiodiagnosis, indira gandhi medical college, shimla-171001, india. corresponding author: mandeep singh ghuman, md department of radiodiagnosis, dayanand medical college and hospital, ludhiana-141001, india. e-mail: dr.msghuman@gmailcom received october 2013 accepted february 2014 references 1. finnan rp, herbenick ma, prayson mj, mccarthy mc. bladder incarceration following anterior external fixation of a traumatic pubic symphysis diastasis treated with immediate open reduction and internal fixation. patient saf surg. 2008;2:26. 2. bartlett cs, ali a, helfet dl. bladder incarceration in a traumatic symphysis diastasis treated with external fixation: a case report and review of the literature. j orthop trauma. 1998;12:64-7. 3. min w, gaines rj, sagi hc. delayed presentation of bladder entrapment secondary to nonoperative treatment of a lateral compression pelvic fracture. j orthop trauma. 2010;24:e44-8. figure 1. pelvic computed tomography scan, coronal sections, demonstrates herniation of urinary bladder (arrows) into the left superior pubic ramus fracture. figure 2. pelvic computed tomography scan, axial and sagittal sections, shows herniation of urinary bladder (arrows) into the left superior pubic ramus fracture. vol 12. no 02 march-april 2015 2105 minimally invasive therapy using intralesional onabotulinumtoxina in peyronie’s disease sexual dysfunction and infertility carlos arturo muñoz-rangel,1 elieser fernandez-vivar,1 ruben alejandro bañuelos-gallo,2 alejandro gonzalez-ojeda,3 michel dassaejv macias-amezcua,3 mariana chavez-tostado,3 kenia militzi ramirez-campos,3 anais del rocio ramirez-arce,3 jose antonio cortes-lares,3 clotilde fuentes-orozco3* purpose: to determine the effectiveness of intralesional administration of onabotulinumtoxina in patients with peyronie’s disease (pd). materials and methods: a prospective therapeutic cohort study was undertaken in patients aged ≥ 18 years with stable pd. intervention included one-time intralesional application of 100 u of onabotulinumtoxina. we included 22 patients who attended the urology clinic from october 1, 2011 to june 30, 2012. primary outcome measure was degree of curvature. secondary outcome measures were thickness of the fibrous plaque, improvement in erectile function and pain. erectile function was evaluated using the international index of erectile function (iief-5) questionnaire. the visual analog scale (vas) was used to measure pain during an erection. statistical analyses were performed by pearson’s chi-squared test for categorical variables and student’s t-test for quantitative variables. any p value < .05 was considered statistically significant. results: the size of the fibrous plaque was reduced from 0.34 ± 0.20 to 0.27 ± 0.13 cm after treatment (p = .014). the curvature initially averaged 32.95 ± 9.21°, and improved to 25 ± 9.38° (p = .025). according to the kelami classification, the curvature was < 30° in 14 cases (63.6%) and was 30°-60° in eight cases (36.4%). at 16 weeks, the curvature was < 30° in 19 cases (86.4%) and 30°-60° in three cases (13.6%). the iief-5 score was 16.18 ± 4.46 before treatment and 18.22 ± 4.55 after treatment (p = .002). pain was reduced from 3.36 ± 3.48 before treatment to 1.14 ± 1.58 after treatment (p = .001). conclusion: the administration of onabotulinumtoxina may improve the clinical manifestations of pd resulting from fibrosis, thus improving sexual function in patients. keywords: penile induration; therapy; treatment outcome; drug therapy; botulinum toxins; type a acetylcholine release inhibitors. introduction peyronie’s disease (pd) involves scarring and fibrosis of connective tissue of the tunica albuginea via chemical tactile mediators. peyronie’s fibrous plaque causes pain during erection and, therefore, sexual dysfunction. the disease may also include penile deformity, sometimes > 45°, causing distal flaccidity and rendering coitus impossible.(1,2) the management of this disease is controversial and there is no gold standard treatment. onabotulinumtoxina has been shown to reduce fibrosis in hypertrophic scars and keloids,(3-6) thus offering new avenues for the study and treatment of illnesses such as pd. however, recent evidence does not support a beneficial effect of botulinum toxin in the treatment of keloid scars.(7,8) yet, the toxin is used widely in the treatment of various urological diseases. we decided to investigate any beneficial effect of one intralesional administration of the onabotulinumtoxina to evaluate the clinical effectiveness in patients with pd. materials and methods study population a prospective cohort for therapeutic intervention was designed using 22 patients seeking consultation for sexual intercourse problems related to pd at the department of urology of the high specialty medical unit, specialties hospital of the western medical center, mexican institute of social security in guadalajara, mexico from october 1, 2011 to june 30, 2012. the inclusion criteria were patients aged ≥ 18 years with pd confirmed by the presence of stable plaque (at least 12 months from the onset of illness) as detected using ultrasonography; no medical or surgical treatment for the previous 6 months; and authorization obtained through signed informed consent. patients were excluded if they were in an active stage, had calcified plaques, or had a history of allergy or sensitivity to any of the components of the medication (onabotulinumtoxina). the study variables were clinical history, degree of curvature, pain, erectile dysfunction department of urology,1 bañuelos radiologos,2 research unit in clinical epidemiology,3 medical unit of high specialty, specialties hospital of the western medical center, mexican institute of social security, guadalajara 44349, jalisco, mexico. *correspondence: research unit in clinical epidemiology, western medical center, avenida belisario dominguez #1000, colonia independencia, cp 44340, guadalajara, jalisco, méxico. tel: +52 33 31230241. e-mail: clotilde.fuentes@gmail.com. received october 2014 & accepted february 2015 (ed) and thickness of the fibrous plaque. the follow-up was for 16 weeks, with visits performed at 2, 4, 8, and 16 weeks. measurements were taken at the beginning and at 16 weeks after treatment. the primary outcome measure was the degree of curvature. the secondary outcome measures were the thickness of the fibrous plaque and improvement in ed and pain during erection. the penis was assessed on its ventral surface via high-frequency lineal tests, together with longitudinal and cross-sectional views. the penile curvature was measured (at the baseline and at the followup) during penile erection after the administration of intracavernosal onabotulinumtoxina, and measurements were recorded by a single person using a goniometer at the point of maximum angulation during maximum penile rigidity. the severity of deformity, which was assessed using the kelami modified classification, was divided into three types: mild penile deformity (≤ 30°), moderate penile deformity (31°-60°), and severe penile deformity (> 60°).(8) the visual analog scale (vas) was used to measure pain during an erection; the pain was graded on a 0–10 scale represented on a 10 cm line, with 0 as no pain and 10 as maximum pain. doppler ultrasonography, with a 7.5 to 12 mhz linear transducer for small organs and superficial lesions, was used to determine the thickness of the plaque, as well as its size, depth, and localization (dorsal, left lateral, right lateral, ventral, dorsoventral, or ventrolateral) and the presence of hyperechogenicity suggestive of calcification. erectile function was evaluated using the international index of erectile function (iief) questionnaire, with normal erectile function as 22-25 points, mild dysfunction 17-21, mild-to-moderate ed 12-16, moderate ed 8-11, and severe ed 5-7 points. onabotulinumtoxina administration technique to prepare the vials, dilution was performed using a sterile technique by introducing 4 ml of solution slowly into 100 u of onabotulinumtoxina without forming bubbles. after the penile asepsis, the solution was injected into the fibrous plaque in quadrants, using a 20-gauge needle. statistical analysis a descriptive analysis was performed using raw numbers, percentages, and measures of central tendency and spread. the analytic phase was carried out using pearson’s chisquared test for categorical variables and student’s t-test for quantitative variables. statistical significance was set at p < .05, and all tests were two-sided. statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0 was used for statistical analyses. ethical considerations the study was conducted according to the principles of the 1989 declaration of helsinki and the mexican health guidelines. the ethics and research committees of the specialties hospital approved all protocols (code 2012/1301/78). full written informed consent was obtained from all patients before their inclusion in the study. results the average age was 56.6 ± 10.1 years (range, 35-68 years). the associated morbid conditions are described in table 1. the history of genital trauma was present in eight cases. at the onset of the disease, during the active phase, the first symptom was pain in 10 (45.5%) patients, palpable fibrous plaque in 5 (22.7%) and penile deformity in 7 (31.8%) patients (table 2). three (13.64%) patients mentioned a sudden onset of the disease; in 19 (86.36%) patients the progression was gradual and then stable. the plaque fibrosis was progressive in 17 (77.27%) patients, table 1. demographic and clinical characteristics of study subjects. variables no. % comorbidity diabetes mellitus 7 31.8 hypertension 13 59.1 cardiac disease 3 13.6 spinal surgery 3 13.6 hypercholesterolemia 4 18.2 hypertriglyceridemia 5 22.7 genital trauma 8 36.3 previous oral treatments colchicine 9 40.9 vitamin e 7 31.8 nonsteroidal anti-inflammatory drugs 3 13.6 pentoxifylline 1 4.5 previous intralesional treatments verapamil 2 9 interferon 1 4.5 table 2. clinical characteristics of patients with peyronie’s disease before treatment with onabotulinumtoxina. first sign or symptom n % pain during erection 10 45.5 plaque 5 22.7 penile curvature 7 31.8 pain during intercourse 12 54.5 penile deformity sudden 3 13.6 gradual 19 86.4 sexual trauma 6 27.3 other 2 9.1 pain initial 5 22.7 always 12 54.5 absent 5 22.7 penile curvature direction dorsal 8 36.4 ventral 5 22.7 left lateral 3 13.6 right lateral 6 27.3 intralesional onabotulinumtoxina in peyronie’s disease-muñoz-rangel et al. sexual dysfunction and fertility 2106 vol 12. no 02 march-april 2015 2107 whereas 5 (22.73%) patients always had the same characteristics. the penile curvature had a dorsal direction in 8 (36.4%) patients, ventral direction in 5 (22.7%) patients, left lateral direction in 3 (13.6%) patients, and right lateral direction in 6 (27.3%) patients. the penile deformities caused by the peyronie’s fibrous plaque included 4 (18.2%) cases of hinge or notch on the glans, 1 (4.5%) case of a hinge or notch at the base of the glans, 7 (31.8%) cases of curves of the erection to the right, 3 (13.6%) cases of curves of the erection to the left, 1 (4.5%) case of hourglass-shaped plaque in the base, 1 (4.5%) case of hourglass-shaped plaque in the middle of the penis and 1 (4.5%) case of hourglass-shaped plaque close to the glans. the penile curvature was evident in 4 (18.2%) patients in flaccid state. pain during sexual intercourse was reported by 5 (22.7%) patients at the beginning of the illness, 12 (54.5%) had pain throughout the duration of the illness, and 5 (22.7%) patients never had pain. thirteen (59.1%) patients reported dyspareunia in their partners, 20 (90.9%) reported difficulty in penetration due to the curvature, 4 (18.2%) patients had a “hinge” effect and 11 (50%) patients reported loss of firmness. during the progression of the disease, all patients reported shortening of the penis, by an average of 2.6 ± 1.54 cm. the relationships of the couples were affected in 13 (59.1%) patients, and emotional state was affected in 16 (72.7%) patients. libido was normal in 13 (59.1%), reduced in 6 (27.3%) and increased in 3 (13.6%) patients. the ability to ejaculate was preserved in 21 (95.5%) patients; coitus was done by 20 (90.9%), masturbation was performed by 8 (36.4%) and oral sex was used by 2 (9.1%) patients. the localization of the fibrous plaque, as assessed by ultrasonography, had the following distribution: dorsal in 7 (31.8%), ventral in 1 (4.5%), dorsolateral in 13 (59.1%) and ventrolateral in 1 (4.5%) patients. no complications were observed after intralesional application of onabotulinumtoxina. the dimensions of the penis were similar before and after the administration of the drug, with an average of 10.34 ± 0.96 cm. the penile curvature (according to the kelami classification) was 32.95° ± 9.21° before treatment and 25° ± 9.38° after treatment (p = .025). nineteen (86.4%) patients had mild-to-moderate ed, and 1 (4.5%) patient had severe ed. after the treatment, 7 (30.8%) patients had normal sexual function, 14 (63.6%) patients still had mild-to-moderate ed and only 1 (4.5%) patient had severe ed. table 3 lists these characteristics with statistical differences after the intralesional application of the toxin (p = .002). the average thickness of the initial fibrous plaque was 0.34 ± 0.20 cm; this was reduced to 0.27 ± 0.13 cm after the treatment (p = .014). the penile angle before treatment was 32.95° ± 9.21°; after treatment, it was reduced to 25° ± 9.38° (p = .025). the total iief-5 score was 16.18 ± 4.46 initially and 18.22 ± 4.55 after treatment (p = .002). there was also a significant reduction in pain, from 3.36 ± 3.48 to 1.14 ± 1.58 (p = .001) on the vas, as shown in table 4. discussion the pharmacological and surgical treatments that have been used for decades to manage pd include oral, topical and local therapies, as well as extracorporeal shock wave lithotripsy and intralesional treatments. the results vary, as the illness has a chronic progression. patients’ quality of life decreases in relation to their own and their partners’ sexual activity.(9) social taboos and the desire to maintain a masculine façade hinder the seeking of treatment in the early stages of the disease. primary care providers often have little knowledge of the illness, and patients lack interest in follow-up because of the low efficacy of the treatment. thus, this disease is chronic, progressive and without a definite treatment.(10-12) trost and colleagues published the results of a retrospective series of 127 patients who received intralesional interferon-α2b. they reported improvement in 54% of the patients, and a reduction of 9° in the curvature, but no effect on the iief score.(13) intralesional and topical steroids have also been used to treat individuals under 50 years of age.(14) hellstrom and colleagues showed that, in 31 of 50 patients treated with intralesional interferon α-2b (5 × 106 u in 10 ml of saline solution administered twice weekly for 12 weeks), the initial average curvature of 49.9° ± 2.4° was reduced to 36.4° ± 2.1° (p = .001) at the end of treatment period.(15) in 1980, williams and green reported the results of a consecutive series of patients who were treated with 25 mg of triamcinolone.(16) they observed a marked improvement in symptoms in patients with small and distal plaques. more recently, dickstein and colleagues reported a small series of patients who received 50 mg of subcutaneous triamcinolone in the plaque area.(17) they observed a complete reduction in pain in the 16 cases, but no change in the curvature or the size of the plaque. collagenase from clostridium species was used by jordan. (18) in 25 patients with repeated low-dose administrations, a 25% improvement in penile curvature was achieved in 57% of the patients; however, the majority of them had adverse effects such as pain, edema and ecchymosis. orgotein, an anti-inflammatory drug with pronounced activity on superoxide dismutase, has been used in small groups of patients with pd and led to a reduction in plaque size and penile curvature.(19) however, patients experienced significant adverse events such as pain, table 3. international index of erectile function (iief-5) score before and after the administration of onabotulinumtoxina. initial no. % final no. % 22–25 2 9.1 22–25 7 31.8 17–21 9 40.9 17–21 9 40.9 12–16 8 36.4 12–16 4 18.2 8–11 2 9.1 8–11 1 4.5 5–7 1 4.5 5–7 1 4.5 variables initial final p value penile curvature 32.95 ± 9.21 25 ± 9.38 .025 plaque thickness 0.34 ± 0.20 0.27 ± 0.13 .014 iief-5 score 16.18 ± 4.46 18.22 ± 4.55 .002 vas score 3.36 ± 3.48 1.14 ± 1.58 .001 abbreviations: iife, international index of erectile function; vas, visual analog scale. table 4. response to the intralesional administration of onabotulinumtoxina. intralesional onabotulinumtoxina in peyronie’s disease-muñoz-rangel et al. edema, paresthesia, dysesthesias and cutaneous rash. calcium channel blockers (principally verapamil and nicardipine) have also been used for the treatment of pd. these drugs inhibit the formation of the extracellular matrix by reducing the proliferation of fibroblasts and increasing the amount of local collagenase.(20) in 1994, levine and colleagues published the first series of 16 patients treated with multiple intralesional injections of verapamil.(21) a publication that followed included a larger number of patients (140 patients).(22) levine and colleagues observed a significant reduction in plaque consistency and in penile curvature. in the first clinical trial with verapamil administered by the intralesional application of saline solution, rehman and colleagues demonstrated a 57% reduction in plaque size, with an initial average curvature of 37.7° ± 9.3° and a final result of 29.57° ± 7.3°.(23) however, the difference was not statistically significant. the plaque was softer in all patients, with a 42.8% erectile function improvement in the verapamil group. no systemic or local toxicity was reported. bennett and colleagues reported the prevention of the progression of pd using 6 intralesional injections of verapamil every 2 weeks (10 mg in 5 ml of saline solution), with a follow-up at 3 months after the last administration.(24) the study included 94 patients with an average age of 44 ± 18 years. before the administration of the drug, 86% of the patients had dorsal penile curvature and 14% had lateral curvature, with an average penile curvature of 50° ± 28°. the average follow-up was 5.2 ± 1.8 months after the last administration of the drug. ten percent of the patients exhibited improvement in the curvature, 60% had no change and 22% worsened; however, pain improved in 100% of the patients. the total average curvature was reduced to 47° ± 35°, with no statistical significance. shirazi and colleagues reported the results of a controlled clinical trial, in which they could not demonstrate any improvement in penile curvature, pain intensity, consistency of the fibrous plaque, or sexual function in the verapamil study group patients compared with the control group.(25) chung and colleagues induced peyronie’s plaque in 12 adult male rats using an established pd animal model. (26) at 4 weeks, the rats were divided into group 1 with 0.1 mg/0.1 ml intralesional verapamil injected every second day for 2 weeks, group 2 with 0.1 ml intralesional normal saline injection, and group 3, which served as a control. at weeks 6 and 8, penile pressure was measured and serial immunohistochemical staining of penile tissue sections was performed. intralesional injection of verapamil and normal saline resulted in macroscopic and microscopic changes in penile curvature and peyronie’s plaque size. decreased collagen and elastin fibers were observed, together with a significant reduction in smooth muscle α-actin (p < .05). changes were greater in group 1 than they were in group 2 (p < .05). intralesional verapamil injection was associated with greater recovery of electrostimulated penile pressure, which is a surrogate of erectile function, compared with the saline and control groups. this research paradigm provides the opportunity to examine whether saline hydrodistention alone plays a significant role in inducing tissue remodeling. soh and colleagues compared the application of nicardipine with that of placebo.(27) they reported a significant reduction in the score of the sexual function index, the size of the plaque, and penile curvature, without a numerically significant reduction in curvature. over more than 5 decades, intralesional treatments have shown little promise for the treatment of pd, and there is no gold standard local treatment for this disease.(28) according to the treatment guidelines for pd published in 2010 and 2012, the intralesional treatment of the illness receives a grade b recommendation for interferon and grade c and d recommendations for calcium channel blockers, intralesional steroids, collagenase and orgotein. (6) a one-time application of onabotulinumtoxina, which is indicated in other fibrotic pathologies, has been shown to cause an improvement in the signs and symptoms of patients with exaggerated scarring processes, without changing the tissue from a histological point of view. the average effective time is ≤ 6 months.(29) pd shows great similarities regarding genetic expression with other processes in which fibrosis reduces the function of the affected organ. dupuytren’s disease shares a genetic overexpression of the transforming growth factor (tgf) β, which stimulates two types of receptors (1 and 2), and, with the contribution of the connective tissue and platelet-derived growth factors, favors the deposition of extracellular matrix and collagen while inhibiting the metalloproteinases that are in charge of breaking down collagen, to avoid excess scarring. this process allows the persistence of a dynamic form of over scarring and fibrosis in the palmar fascia and tunica albuginea.(30) similar to pd and dupuytren’s disease, hypertrophic and keloid scars also involve the overexpression of tgf-β. the exposure of fibroblast cultures of these scars from animal and human models to the botulinum toxin reduces the expression of this facilitating fibrosis factor.(30) onabotulinumtoxina derived from a gram-positive bacteria, clostridium botulinum with variety of usages in medicine for more than 20 years, demonstrating good efficacy and safety in various disorders. many studies demonstrated that onabotulinumtoxina can inhibit the growth of hypertrophic scars, but the molecular mechanism for this action is unclear at all. growing evidence suggests that onabotulinumtoxina, influences cell apoptosis and proliferation and therefore may play a role in the expression of genes relevant to abnormal fibroblast proliferation.(29) tgf-β1 is known to be the most potent growth factor involved in wound healing and is believed to be the key regulator in the pathogenesis of hypertrophic scars . it is associated with an excessive deposition of scar tissue and fibrosis and modulates the expression of matrix metalloproteinases. xiao and colleagues demonstrated that blocking tgf-β1 may attenuate the fibroproliferative response of hypertrophic scars and make its manipulation an attractive therapeutic strategy.(5) connective transforming growth factor (ctgf) works as an independent mediator in fibrosis and collagen deposition in scars. onabotulinumtoxina may inhibit the growth of fibroblasts, which in turn may lead to a decrease expression of tgf-β1 protein and ctgf protein expression, therefore getting improvement of wound healing process. these results could partly explain the molecular mechanism for onabotulinumtoxina based therapies for hypertrophic scar. this findings led the hypothesis that onabotulinumtoxina reduces the expression of ctgf protein in fibroblast derived from hypertrophic scars. this have a relationship with tgf-β1 that decreased its expression too in fibroblast proliferation, also they saw tension diminishing around lesions by denervation stimulation due to onabotulinumtoxina, not affecting novo fibrosis, no histologic changes around lesions. therefore getting improvement of wound healing intralesional onabotulinumtoxina in peyronie’s disease-muñoz-rangel et al. sexual dysfunction and fertility 2108 vol 12. no 02 march-april 2015 2109 process.(3-6) sahinkanat and colleagues use onabotulinumtoxina in urethral strictures in rats compared with control group, finding less inflammation and fibrosis associated with less fibroblasts and collagen in tissues where have been applied botulinum toxin a.(31) however, two recent publications do not support any beneficial effect in the treatment of human keloids. gauglitz and colleagues administered onabotulinumtoxina in 4 patients (doses varying from 70 to 140 speywood units per session) injected directly into their keloids every 2 months for up to 6 months. differences in height and volume were evaluated clinically and measured with a 3-d optical profiling system. keloid-derived fibroblasts were treated with different concentrations of onabotulinumtoxina, and expression of collagen as col1a1, col1a2, col3a1, tgf-β1, tgf-β2, tgfβ3, fibronectin-1, laminin β2, and a-sma was determined by real-time quantitative polymerase chain reaction (qrt-pcr) method. intralesional administration of onabotulinumtoxina did not result in regression of keloid tissue. they found no differences in expression of endothelial cell markers (ecm) markers, collagen synthesis, or tgfβ could be observed after onabotulinumtoxina treatment of keloid fibroblasts. in addition, cell proliferation and metabolism of keloid fibroblasts was not affected by onabotulinumtoxina treatment.(7) haubner and colleagues(8) tested patient-specific keloid tissue in a cell culture model to assess the effects of onabotulinumtoxina incubation on cell proliferation and expression of the following cytokines and growth factors: interleukin-6, vascular endothelial growth factor and tgfβ. they found no evidence that these parameters of human keloid tissue were affected by onabotulinumtoxina incubation. in contrast, wang and colleagues(6) found that, the s100a4 gene was highly expressed in keloid fibroblasts. s100 proteins belong to the superfamily of ef-hand calcium-binding proteins and have multifunctional roles in various cellular processes, including cell growth and differentiation, cell cycle regulation, apoptosis, transcription, and cell surface receptor activities. onabotulinumtoxina treatment can significantly affect the pathogenesis of keloids, particularly the invasive growth of keloid fibroblast cells, by influencing the regulation of some genes involved in cell invasion. through gene microarray and qrt-pcr, they confirmed modulation of expression in 5 genes (s100a4, tgf-β1, vegf, mmp1, and pdgfa) in keloid-causing fibroblast cells treated with onabotulinumtoxina. we designed this protocol taking into account these precedents, together with extensive experience in the use of onabotulinumtoxina in the treatment of multiple urological problems and hypertrophic and keloid scars. (3-6,29) conclusion we considered the fact that intralesional treatments should require several administrations. our results are promising with only one administration of the toxin. our results suggest that onabotulinumtoxina may be a new intralesional alternative therapy for pd. however, these findings should be evaluated with further randomized clinical trials including an adequate number of patients with multiple intralesional administrations with longer follow-up period, to confirm the potential therapeutic efficacy of this neurotoxin. acknowledgments the authors thank hector solano moreno and ismael arana limon for their assistance in collecting clinical and follow-up data for this study. conflict of interest none declared. references 1. mulhall jp, schiff j, guhring p. an analysis of the natural history of peyronie’s disease. j urol. 2006;175:2115-8. 2. sommer f, schwarzer u, wassmer g, et al. epidemiology of peyronie’s disease. int j impot res. 2002;14:379-83. 3. lee bj, jeong jh, wang sg, lee jc, goh ek, kim hw. effect of botulinum toxin type a on a rat surgical wound model. clin exp otorhinolaryngol. 2009;2:20-7. 4. wang l, tai nz, fan zh. effect of botulinum toxin type a injection on hypertrophic scar in rabbit ear model. zhonghua zheng xing wai ke za zhi. 2009;25:284-7. 5. xiao z, zhang m, liu y, ren l. botulinum toxin type a inhibits connective tissue growth factor expression in fibroblasts derived from hypertrophic scar. aesthetic plast surg. 2011;35:802-27. 6. wang x, chen x, xiao z. effects of botulinum toxin type a on expression of genes in keloid fibroblasts. aesthet surg j. 2014;34:154-9. 7. gauglitz g, bureik d, dombrowski y, pavicic t, ruzicka t, schauber j. botulinum toxin a for the treatment of keloids. skin pharmacol physiol. 2012;25:313-8. 8. haubner f, leyh m, ohmann e, sadick h, gassner hg. effects of botulinum toxin a on patient-specific keloid fibroblasts in vitro. laryngoscope. 2014;124:1344-51. 9. kadioglu a, tefekli a, erol b, oktar t, tunc m, tellaloglu s. a retrospective review of 307 men with peyronie’s disease. j urol. 2002;168:10759. 10. ralph d, gonzalez-cadavid n, mirone v, et al. the management of peyronie’s disease: evidence-based 2010 guidelines. j sex med. 2010;7:2359-74. 11. hatzimouratidis k, eardley i, giuliano f, et al. european association of urology. eau guidelines on penile curvature. eur urol. 2012;62:543-52. 12. levine la. the clinical and psychological impact of peyronie’s disease. am j manag care. 2013;19(4 suppl):s55-s61. 13. trost lw, ates e, powers m, sikka s, hellstrom wj. outcomes of intralesional interferon α2b for the treatment of peyronie’s disease. j urol. 2013;190:2194-9. intralesional onabotulinumtoxina in peyronie’s disease-muñoz-rangel et al. 14. furey ca jr. peyronie’s disease: treatment by the local injection of meticortelone and hydrocortisone. j urol. 1957;77:251-66. 15. hellstrom wj, kendirci m, matern r, et al. single-blind, multicenter, placebo controlled, parallel study to assess the safety and efficacy of intralesional interferon alpha-2b for minimally invasive treatment for peyronie’s disease. j urol. 2006;176:394-8. 16. williams g, green na. the nonsurgical treatment of peyronie’s disease. br j urol. 1980;52:392-5. 17. dickstein r, uberoi j, munarriz r. severe, disabling, and/or chronic penile pain associated with peyronie’s disease: management with subcutaneous steroid injection. j androl. 2010;31:445-9. 18. jordan gh. the use of intralesional clostridial collagenase injection therapy for peyronie’s disease: a prospective, single-center, nonplacebo-controlled study. j sex med. 2008;5:180-7. 19. hellstrom wj. medical management of peyronie’s disease. j androl. 2009;30:397-405. 20. roth m, eickelberg o, kohler e, erne p, block lh. ca2+ channel blockers modulate metabolism of collagens within the extra-cellular matrix. proc natl acad sci usa. 1996;93:547882. 21. levine la, merrick pf, lee rc. intralesional verapamil injection for the treatment of peyronie’s disease. j urol. 1994;151:1522-4. 22. levine la, goldman ke, greenfield jm. experience with intraplaque injection of verapamil for peyronie’s disease. j urol. 2002;168:621-5. 23. rehman j, benet a, melman a. use of intralesional verapamil to dissolve peyronie’s disease plaque: a long-term single-blind study. urology. 1998;51:620-6. 24. bennett ne, guhring p, mulhall jp. intralesional verapamil prevents the progression of peyronie’s disease. urology. 2007;69:1181-4. 25. shirazi m, haghpanah ar, badiee m, afrasiabi ma, haghpanah s. effect of intralesional verapamil for treatment of peyronie’s disease: a randomized single-blind, placebo-controlled study. int urol nephrol. 2009;41:467-71. 26. chung e, garcia f, de young l, solomon m, brock g. a comparative study of the efficacy of intralesional verapamil versus normal saline injection in a novel peyronie disease animal model: assessment of immunohistopathological changes and erectile function outcome. j urol. 2013;189:380-4. 27. soh j, kawauchi a, kanemitsu n, et al. nicardipine vs. saline injection as treatment for peyronie’s disease: a prospective, randomized, single-blind trial. j sex med. 2010;7:3743-9. 28. larsen sm, levine la. review of non-surgical treatment options for peyronie’s disease. int j impot res. 2012;24:1-10. 29. chancellor mb, elovic e, esquenazi a, et al. evidence-based review and assessment of botulinum neurotoxin for the treatment of urologic conditions. toxicon. 2013;67:129-40. 30. qian a, meals ra, rajfer j, gonzalez-cadavid nf. comparison of gene expression profiles between peyronie’s disease and dupuytren’s contracture. urology. 2004;64:399-404. 31. sahinkanat t, ozkan ku, ciralik h, ozturk s, resim s. botulinum toxin-a to improve urethral wound healing: an experimental study in a rat model. urology. 2009;73:405-9. intralesional onabotulinumtoxina in peyronie’s disease-muñoz-rangel et al. sexual dysfunction and fertility 2110 urological oncology detrusorrhaphy and intrafascial nerve-sparing during robot-assisted radical prostatectomy on recovery of continence and potency: surgical feasibility, one-year functional and oncologic outcomes tae young shin, yong seong lee* purpose: to report the 1-year functional outcomes, oncologic outcomes, and postoperative complications in patients who underwent modified robot-assisted radical prostatectomy (rarp) procedures for achieving early recovery of continence and potency postoperatively. materials and methods: this study included 165 patients who underwent rarp. overall, 98 patients underwent rarp using our modified detrusorrhaphy and intrafascial nerve-sparing techniques (group 1) and 67 underwent standard rarp (group 2). continence and potency rates were assessed at 1 week, 1, 3, 6, and 12 months after rarp. oncologic outcomes comprised positive surgical margins (psms) and biochemical recurrence (bcr) rate. results: the continence rates were 61.2% and 6.0%, 72.5% and 11.9%, 79.6% and 20.9%, 91.8% and 58.2%, and 97.9% and 74.6% at 1 week, 1, 3, 6, and 12 months in group 1 and 2, respectively. the potency rates were 66.3% and 11.9%, 78.6% and 38.8%, 85.7% and 50.8%, 92.9% and 70.2%, and 95.9% and 79.1% at 1 week, 1, 3, 6, and 12 months in group 1 and 2, respectively. overall postoperative complication rates (< 10%) were similar between the groups. the psms rate was 17.4% and 16.4% in the two groups. the rate of psms in the cohort of patients with stage pt2 disease decreased to 13.6% and 12.5% in groups 1 and 2, respectively. bcr rate was 5.1% and 6.0% in groups 1 and 2, respectively. conclusion: the use of detrusorrhaphy and intrafascial nerve-sparing techniques is safe and feasible, with our results demonstrating early return to continence and potency. further studies should be conducted. keywords: prostate cancer; robot-assisted radical prostatectomy; continence; nerve-sparing; erectile function introduction over the past decades, impaired urinary and sexual function has restricted the quality of life (qol) of patients after radical prostatectomy.(1) studies have described numerous surgical adaptations to improve the functional outcomes of radical prostatectomy and the use of advantageous robotic ergonomics and tools during robot-assisted radical prostatectomy (rarp) has allowed the introduction of various surgical techniques. (2–7) still, the complications are unresolved after rarp, with incidences ranging from 10% to 69% at 1-year follow-up.(8,9) particularly in increasing number of patients who are younger, postoperative urinary incontinence and erectile dysfunction considerably influence patients’ qol.(10) in our institution, we have implemented several surgical techniques during rarp in an attempt to achieve early potency and continence. first, to preserve the entire neurovascular bundle (nvb), we focused on the modified clipless intrafascial nerve-sparing approach. second, we performed a modified detrusorrhaphy technique, which involves reinforcing the posterior detrusor muscles using a zigzag flap during bladder neck reconstruction. the objective of the present study is to describe the detrusorrhaphy and clipless intrafascial urology department, hallym university sacred heart hospital, hallym university college of medicine, anyang, korea. *correspondence: urology department, hallym university sacred heart hospital, hallym university college of medicine, anyang, korea. tel: +82 31 380 3850. fax: +82 31 380 3852. e-mail: novavia@hallym.or.kr. received january 2020 & accepted may 2020 nerve-sparing approaches and to evaluate the postoperative 1-year functional and oncologic outcomes after rarp. materials and methods study population and design between march 2015 and august 2018, 280 patients underwent rarp in our institution. all procedures were performed by one surgeon who had experience performing > 800 rarps. each patient preoperatively underwent multiparametric magnetic resonance imaging (mpmri). this was a retrospective, non-randomized study. medical records of 280 patients who underwent rarp were retrospectively reviewed. inclusion and exclusion criteria were: 1) we included 208 patients with 1-year of follow-up and those who had preoperative continence and potency, defined as a sexual health inventory for men (shim) questionnaire score of ≥ 17, 2) patients with localized low-risk prostate cancer and gleason score ≤ 7 (ct1–2n0m0) were evaluated, 3) exclusion criteria were any neoadjuvant hormonal treatment, prior radiation therapy, and previous history of urethral stricture and urinary incontinence, 4) we excluded nine patients who presented insufficient data and six patients who urology journal/vol 18 no. 3/ may-june 2021/ pp. 314-321. [doi: 10.22037/uj.v16i7.5915] vol 18 no 3 may-june 2021 315 were transferred to our institution after being diagnosed with prostate cancer in other hospitals. finally, 165 of the 208 patients were included in the study (figure 1): those who underwent the detrusorrhaphy and intrafascial nvb sparing techniques (group 1, 98 patients) between october 2016 and august 2018 and those who underwent standard rarp approach (group 2, 67 patients) between march 2015 and september 2016. the enrolled patients were divided into two subgroups according to a time criterion to compare the learning detrusorrhaphy and nerve-sparing techniques-shin et al. figure 1. study flow diagram. figure 2. operative steps. (a) exposure of the prostate capsule by detaching the overlying periprostatic fascia and prostatic pedicles. (b) further mobilization of the prostatic pedicles, including the neurovascular bundles, by using antegrade dissection (distal end of the prostatic pedicles, white arrow). (c) combined blunt and sharp dissection of the neurovascular bundles as far distally to the apex as possible until reaching the urethra (prostate capsule, white star; urethra, white arrow). (d) after complete prostate dissection, the preserved neurovascular bundles and prostatic pedicles are clearly visible and become thick. curve. the study protocol was approved by the university hospital ethics committee (no. 2018-05-012). surgical techniques all patients underwent transperitoneal rarp. patient positioning and port placement were those as described previously.(11) the da vinci xi surgical system was used in all cases. intrafascial nerve-sparing technique the endopelvic fascia was preserved in those with clinical stage ≤ t2c disease. our intrafascial nerve-sparing technique essentially aims to preserve the surrounding periprostatic structures to the fullest extent. the prostate capsule is carefully exposed after detaching the overlying fat and periprostatic fascia (figure 2a). arterial pulsations from the cavernous vessels within the nvb are easily recorded with further lateral dissection. these vessels are preserved by gently pushing them posterolaterally toward the rectum. the prostatic pedicles are further mobilized off the prostate capsule in an anterior direction until the most distal ends of the vascular pedicle (figure 2b). the identified vascular pedicles are swept off the prostate, further mobilizing the nvbs, which are then gently eased out of the posterolateral surface of the prostate capsule with a combination of blunt and sharp dissection. we continued antegrade dissection by peeling off the periprostatic fascia, nvbs, and the prostatic pedicle en bloc until reaching the urethra (figure 2c). the use of monopolar electrocautery and clips is vigorously avoided during this dissection. if bleeding occurs from the periprostatic vessels, a brief increase in insufflation pressure can be applied to the bleeding source using hemostatic gauze, while slight venous bleeding is left uncontrolled. in cases of pulsatile arterial bleeding, ligation is performed with 4-0 v-loc suture. the preserved nvbs are clearly visible after prostate dissection (figure 2d). bladder reconstruction and detrusorrhaphy technique we designed the detrusorrhaphy technique which is designed for thickening and strengthening the detrusor muscles from the posterior bladder neck to the bilateral dissected pedicles area. it was based on the theory that anatomically correct reconstructions would provide functional reinforcement of the detrusor muscles. our simple modification is different from conventional detrusorrhaphy.(12,13) the difference of the our detrusorrhaphy technique is the use of zigzag suturing, which thickens and strengthens the deteriorated detrusor muscles during posterior dissection of the bladder (figure 3). the conventional reconstruction method focuses on narrowing the bladder neck and suturing both wings of the dissected bladder. the aim of the detrusorrhaphy technique is to reconstruct the detrusor muscles while maintaining a physiologically and anatomically ideal shape. this posterior reinforcement is based on the principles of parsons and colleagues.(14) pelvic lymph node dissection (plnd) plnd was performed in 88 patients (89.8%) and 61 patients (91.0%) in group 1 and 2, respectively. extended plnd until common iliac artery area was performed in patients with a risk of lymph node involvement of >5% in the briganti nomogram.(15) a limited plnd until obturator fossa was performed in patients with an estimated risk of <5%. hem-o-lok clips are used instead of cauterization to prevent lymphocele formation. data collection and statistical analysis we assessed following demographic data: age, body mass index (bmi), american society of anesthesiologist (asa) score, prostate volume, psa level, biopsy gleason score, and d'amico risk classification. baseline sexual function before rarp was assessed with shim questionnaire and preoperative continence was evaluated using the international prostate symptom score (ipss) score. postoperative complications were recorded and evaluated using the clavien–dindo classification.(16) the primary end point was the postoperative functional and oncologic outcomes. postoperative functional figure 3. operative and schematic view of the detrusorrhaphy technique using a flap of dynamic detrusor cuff muscles (detrusor muscles, white arrow; bladder neck opening, white star). detrusorrhaphy and nerve-sparing techniques-shin et al. urological oncology 316 vol 18 no 3 may-june 2021 317 and oncologic results were analyzed between the two groups. the catheter was removed at 1 week postoperatively. we evaluated the potency rate using a shim questionnaire and continence rate using a pad test per day at 1 week and 1, 3, 6, and 12 months after rarp. we considered return to erectile function postoperatively as score of ≥ 4 on question 2 of the shim or the ability to have successful sexual intercourse. a patient was considered as continent if he applied “0 pad–” per day. pathologic variables including pathologic stage, gleason score, and positive surgical margins (psms) were evaluated. according to american urological association guidelines, biochemical recurrence (bcr) was defined as two consecutive psa values of ≥ 0.2 ng/ml.(17) continuous variables were reported as median values and interquartile ranges (iqrs), and categorical variables of frequencies and proportions were reported as percentages. patient characteristics with continuous variables were analyzed using student’s t-test and nonparametric mann–whitney test. independent factors with categorical variables were analyzed using the chi-square test. chi-square test was used to compare the rate of continence and potency between the groups. we evaluated the rates of psms in the two groups. the same analyses were performed in a subgroup of patients with a suspicion of posterolateral tumor at preoperative mpmri. a p value of < .05 was considered to indicate a statistically significant difference. all statistical analyses were conducted using ibm® spss® statistics table 1. demographic, preoperative, perioperative, and histopathologic data for groups 1 and 2 demographic and preoperative group 1 group 2 p-value patients, number 98 67 age, median (iqr), year 60.5 (52.0–69.0) 61.5 (53–70.0) .685 bmi, median (iqr), kg/m2 25.4 (23.8–28.0) 25.8 (24.4–29.5) .927 asa score, median (iqr) 2.0 (1.0–2.0) 2.0 (1.0–2.0) .875 prostate volume, median (iqr), cc 39.6 (22.5–70.5) 38.5 (21.0–105) .435 psa, median (iqr), ng/ml 6.9 (3.2–11.5) 7.5 (3.5–19.8) .075 biopsy gleason score, median (iqr) 6 21 (21.4%) 16 (23.9%) .565 7 77 (78.6%) 51 (76.1%) .492 mpmri site of tumor (%) negative 14 (14.3%) 11 (16.4%) .459 apical 21 (21.4%) 14 (20.9%) .667 basal 10 (10.2%) 7 (10.4%) .728 posterolateral 26 (26.5%) 18 (26.9%) .814 anterior 8 (8.2%) 5 (7.5%) .452 multiple 19 (19.4%) 12 (17.9%) .756 ipss score, median (iqr) 12 (2.0–21.0) 13.5 (3.0–23.0) .475 shim score, median (iqr) 20.0 (17–25) 20.5 (17-25) .798 d’amico risk group (%) low risk 77 (78.6%) 47 (70.2%) .645 intermediate risk 15 (15.3%) 13 (19.4%) .422 high risk 7 (7.1%) 7 (10.4%) .785 perioperative and histopathologic operative time, median (iqr), min 230 (140–250) 210 (130–300) .522 blood loss, median (iqr), ml 200 (80–600) 200 (100–600) .892 blood transfusion rate (%) 1 (1.0%) 2 (2.9%) .535 nerve sparing (%) bilateral 90 (91.8%) 59 (88.1%) .673 unilateral 5 (5.1%) 5 (7.5%) .495 none 3 (3.1%) 3 (4.5%) .521 plnd (%) 88 (89.8%) 61 (91.0%) .348 extended plnd 8 (9.1%) 7 (11.5%) .255 limited plnd 80 (91.9%) 54 (88.5%) .282 complications (%) clavien grade 1 clavien grade 2 8 (8.2%) 6 (9.0%) .592 clavien grade 3 0 0 pathologic stage (%) pt2 88 (89.8%) 56 (83.6%) .228 pt3a 7 (7.1%) 7 (10.4%) .136 pt3b 3 (3.1%) 4 (6.0%) .318 pathologic gleason score (%) <6 20 (20.4%) 13 (19.4%) .785 7 73 (74.5%) 47 (70.2%) .682 >8 5 (5.1%) 7 (10.4%) .115 psms rate (%) overall 17 (17.4%) 11 (16.4%) .485 among pt2 patients 12 (13.6%) 7 (12.5%) .755 among pt3 patients 5 (50.0%) 4 (36.4%) .361 psms site (%) apical 9 (52.9%) 5 (45.5%) .125 posterolateral 5 (29.4%) 4 (36.3%) .355 multifocal 3 (17.7%) 2(18.2%) .223 positive plnd (%) 0 0 iqr, interquartile range; bmi, body mass index; asa, american society of anesthesiologist; psa, prostate–specific antigen; ipss, international prostate symptoms score; shim, sexual health inventory for men; plnd, pelvic lymph node dissection. detrusorrhaphy and nerve-sparing techniques-shin et al. for windows, version 22.0 (ibm corp., armonk, ny, usa). results demographics table 1 summarizes the baseline demographic, clinical, and pathological data for the 165 participants. no significant differences were observed between group 1 and 2 with respect to preoperative demographic and clinical data. operative outcomes and complications median operative time in groups 1 and 2 was 230 (iqr: 140–250) and 210 (iqr: 130–300) min, respectively. total operating and console time were comparable between the two groups. the estimated blood loss and overall complication rates (< 10%) were similar between the groups (table 1). no patient experienced any intraoperative complications. up to 1 year postoperatively, none of the patients had urinary retention, and there were no complications, such as lymphocele, that required further procedures. none of the patients showed the positive pelvic lymphadenopathy findings. continence outcomes continence rates in groups 1 and 2 were 61.2% and 6.0%, 72.5% and 11.9%, 79.6% and 20.9%, 91.8% and 58.2%, and 97.9% and 74.6% at 1 week, 1, 3, 6, and 12 months of follow-up after rarp, respectively (table 2). up to 3 months, the continence recovery rate in group 1 was significantly higher than that in group 2 (p < .001). on learning curve analysis, a progressive change in the number of continent patients and the difference in operative time between groups at each time point was not recorded. continence was also assessed using the ipss score, which revealed no significant between group differences in preoperative ipss scores (12 and 13.5, respectively). the ipss scores were comparable between groups at 1, 3, 6, and 12 months of follow-up postoperatively (11.5 and 12.5, 10.5 and 12.5, 6.5 and 8.5, and 6.5 and 8.0, respectively; p > .05). potency outcomes potency rates in groups 1 and 2 were 66.3% and 11.9%, 78.6% and 38.8%, 85.7% and 50.8%, 92.9% and 70.2%, and 95.9% and 79.1% at 1 week, 1, 3, 6, and 12 months of follow-up after rarp, respectively (table 2). up to 3 months, the potency recovery rate in group 1 was significantly higher than that in group 2 (p < .05). of the 98 patients, 84 were potent at 3 months. the remaining fourteen patients could achieve partial erections, but not sufficient for penetration, with or without the use of oral phosphodiesterase type 5 inhibitors agents. in these patients, in the case of suspected seminal vesicle invasion or encountered adhesion between the nvb and prostate, a slightly wider dissection or unilateral extrafascial nerve-sparing approach was performed to avoid an iatrogenic positive surgical margin. pathologic findings and oncologic results table 1 shows histopathologic data. the two groups had no differences in their pathologic stage (p > .05). the majority of patients (88 patients; 89.8%) in group 1 presented organ-confined disease; seminal vesicle invasion (pt3b) was identified in 3 of the patients (3.1%) and extraprostatic extension (pt3a) was found in 7 patients (7.1%). the postoperative gleason score 7 corresponded to 73 patients (74.5%) in group 1 (29 gleason 3 + 4, 39.7%; 44 gleason 4 + 3, 60.3%). overall, 28 of 165 (16.9%) patients in the two groups revealed psms at postoperative pathology, without a significant difference between the two groups (groups 1 and 2: 17.4% and 16.4%, respectively; p > .05). the rate of psms in the cohort of patients with stage pt2 disease decreased to 13.6% (12 of 88 patients with pt2 stage) in group 1and 12.5% (7 of 56 patients with pt2 stage) in group 2, respectively (p > .05). the vast majority of psms was found to be apical margin 52.9% (9 patients) and 45.5% (5 patients) and posterolateral margin 29.4% (5 patients) and 36.3% (4 patients) in group 1 and 2, respectively. the psms in the posterolateral margin were seen in 9 patients in two groups. a subanalysis of patients with a suspicion of posterolateral tumor in preoperative mpmri (26 and 18 patients in group 1 and 2) was performed. the posterolateral psms were found in 5 (19.2%) of 26 patients in group 1 and 4 (22.2%) of 18 patients in group 2. it shows that there was no significant difference in posterolateral psms rate between the two groups. the patients had a median follow-up period of 27 months (iqr: 17–36). bcr was seen in 5 cases (5.1%) and four cases (6.0%) in group 1 and 2, respectively. median psa level at the time of bcr was 0.3 (iqr: 0.2–0.95) ng/ml. patients with bcr were analyzed with pelvic mri, bone scintigraphy, and chest and abdominal computed tomography. no metastasis was observed in any case, and patients received adjuvant radiotherapy and/or androgen deprivation therapy. discussion the last decade has seen increased acceptance of rarp as s surgical treatment option for younger and sexually healthier patients with localized prostate cancer.(10) although rarp is prioritized with consistent oncological outcomes and a lower risk of complications,(18) postrarp urinary incontinence and erectile dysfunction still have remained the major complications and not shown a satisfactory reduction as expected. the physiological mechanisms related to post-prostatectomy urinary incontinence have not been fully elucidated. potential causes of incontinence after rarp are table 2. continence and potency data at various follow-up points after catheter removal in groups 1 and 2 time patients achieving continence, n (%) p-value patients achieving potency, n (%) p-value group 1 (n=98) group 2 (n=67) group 1 group 2 1 week 60 (61.2%) 4 (6.0%) < .001* 65 (66.3%) 8 (11.9%) < .001* 1 month 71 (72.5%) 8 (11.9%) < .001* 77 (78.6%) 26 (38.8%) < .001* 3 months 78 (79.6%) 14 (20.9%) < .001* 84 (85.7%) 34 (50.8%) .036* 6 months 90 (91.8%) 39 (58.2%) .026* 91 (92.9%) 47 (70.2%) .208 12 months 96 (97.9%) 50 (74.6%) .138 94 (95.9%) 53 (79.1%) .165 * significant at p < .05. detrusorrhaphy and nerve-sparing techniques-shin et al. urological oncology 318 vol 18 no 3 may-june 2021 319 known to be due to the disruption of normal anatomic contributors to continence.(19) studies have described numerous surgical adaptations to improve the continence rate of patients.(5–7) we developed the zigzag detrusorrhaphy technique, which is specially designed for thickening and strengthening the detrusor muscles from the posterior bladder neck to the bilateral dissected pedicles area. performing bladder neck narrowing using zigzag suturing with the detrusorrhaphy technique achieves morphologically and fundamentally different results when compared to using the classic tennis racquet procedure, which simply uses a side by side stitch to narrow the wide-opened bladder neck. when dissecting the base of the prostate, the tissue around the prostate and bladder neck is very tight and the boundaries are unclear. we inevitably deteriorate a large amount of detrusor muscle. our modified procedure aims to reconstruct the detrusor muscles to maintain a physiologically and anatomically ideal form. the aspect of the detrusorrhaphy technique involves dynamic detrusor cuff detrusorrhaphy, which supports the proximal urethra and bladder neck with contractile detrusor tissue and constricts this outlet.(20) reconstruction of our detrusorrhaphy technique is thought to prevent hypermobilization of the bladder neck area, thereby reducing stress urinary incontinence, and is considered important for the recovery of continence. our results revealed early continence rates of 61.2%, 72.5%, 79.6%, 91.8%, and 97.9% at 1 week, 1, 3, 6, and 12 months of follow-up after rarp, respectively. these results are consistent with those of other studies demonstrating the benefits of early recovery of urinary continence, although discrepancies exist in surgical techniques and continence definitions vary. a nonrandomized single-arm study by porpiglia et al. achieved similar continence rates (71.8%, 77.8%, 89.3%, 94.4%, and 98.0%) at 1 day, 1, 4, 12, and 24 weeks, respectively, after catheter removal.(11) recent studies have suggested that the course of nvbs is more involved than that previously described by walsh.(21) tewari et al. described a hammock-like nerve distribution on which the prostate rests, revealing that nvb is more a network of multiple finely dispersed nerves than a distinct structure.(22,23) furthermore, eichelberg et al. showed that only 46%–66% of all nerves were found in the classical posterolateral location relative to the prostate, while 21%–29% were identified on the anterolateral surface.(24) nerve-sparing is an important step in radical prostatectomy that determines the functional outcomes of the procedure. we have performed antegrade nerve-sparing, which was similar to the method initially reported by kursh et al.(25) in developing our athermal clipless intrafascial nvb sparing technique, we focused on two technical principles to spare the nvbs. our antegrade intrafascial approach included completely eliminating the use of monopolar electrocautery (athermal). additionally, we dissected the nvbs off the prostate in a medial to lateral direction without ligating the vascular pedicles by hem-o-lok clips (clipless). it is possible to eliminate bulk clipping of the pedicles by dividing the pedicle vessels as they enter the prostate. we believe that these factors may result in more viable tissue preservation within the nvbs. our clipless technique is similar to that described by chien et al.(26) the risk of psms is highly possible when using the method of following the posterior plane laterally and anteriorly. however, our technique did not seem to affect the oncologic results. the overall psms rate (group 1 and 2: 17.4% and 16.4%, respectively) was higher than that noted in a previously reported study.(27) however, the psms rate in the cohort of patients with pt2 stage (group 1 and 2: 13.6% and 12.5%, respectively) was similar or lower than that noted in another study. (28) in the subanalysis of posterolateral psms, the posterolateral psms were found in 5 (19.2%) of 26 patients in group 1 and 4 (22.2%) of 18 patients in group 2. it shows that there was no significant difference in posterolateral psms rate between the two groups. using a validated sexual function questionnaire at 1 week after rarp, we found that the patients returned to 66.3% of their baseline preoperative sexual function scores, which then increased to 78.6%, 85.7%, 92.9%, and 95.9% at 1, 3, 6, and 12 months, respectively. this is a favorable outcome compared with other series of rarp using the same validated questionnaire, in which the percentage of patients reporting a return to baseline sexual function was 53.1%, 69.9%, 82.3%, and 86.7% at 1, 3, 6, and 12 months, respectively.(29) the limitations of this study are the retrospective nature, the small sample size, and only one surgeon performing the surgeries at a single institution. the design of this study is not a randomized study. basically, the two groups could not be extracted at the same time, which could result in potential selection bias and running curve bias in patients using the modified surgical methods. however, we believe that these biases can be minimized because the operator has already performed more than 800 rarps from 2007 to the present and the modified surgical methods are not challenging techniques. although our data are still maturing, our initial results have shown early recovery of urinary continence and potency. longer follow-ups on a larger number of patients comparing two concomitant cohorts of patients undergoing our techniques is necessary to evaluate postoperative recovery of urinary continence and potency in a standardized fashion. furthermore, preexisting comorbidities such as diabetes mellitus and smoking history, prostate weight, bmi, d'amico risk classification, and nerve-sparing bilaterality, which could potentially affect the continence and potency status,(30) were not recorded. therefore, we should perform multivariate analysis using various other factors in future studies. conclusions the use of the detrusorrhaphy and intrafascial nerve-sparing approach during rarp helped to achieve early recovery of continence and potency without compromising oncologic outcomes. the detrusorrhaphy and intrafascial nerve-sparing techniques are safe and feasible. our findings should be validated to assure reproducibility of the measurement in a prospective comparative study. acknowledgement no competing financial interests exist. conflict of interest the authors report no conflict of interest. references 1. willis dl, gonzalgo ml, brotzman m, feng z, trock b, su lm. comparison of outcomes detrusorrhaphy and nerve-sparing techniques-shin et al. between pure laparoscopic vs robot-assisted laparoscopic radical prostatectomy: a study of comparative effectiveness based upon validated quality of life outcomes. bju int. 2012;109:898–905. 2. menon m, shrivastava a, bhandari m, satyanarayana r, siva s, agarwal pk. vattikuti institute prostatectomy: technical modifications in 2009. eur urol. 2009;56:89– 96. 3. patel vr, schatloff o, chauhan s, et al. the role of the prostatic vasculature as a landmark for nerve sparing during robot-assisted radical prostatectomy. eur urol. 2012;61:571–6. 4. basiri a, de la rosette jj, tabatabaei s, woo hh, laguna mp, shemshaki h. comparison of retropubic, laparoscopic and robotic radical prostatectomy: who is the winner? world j urol. 2018;36:609–21. 5. vora aa, dajani d, lynch jh, kowalczyk kj. anatomic and technical considerations for optimizing recovery of urinary function during robotic-assisted radical prostatectomy. curr opin urol. 2013;23:78–87. 6. basiri a, hosseini sharifi sh. revisiting vesicourethral anastomosis during open radical retropubic prostatectomy; a simple and reproducible technique: a single center experience with 200 cases. urol j. 2019;16:475–7. 7. kohjimoto y, yamashita s, kikkawa k, et al. the 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17. cookson ms, aus g, burnett al, et al. variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the american urological association prostate guidelines for localized prostate cancer update panel report and recommendations for a standard in the reporting of surgical outcomes. j urol. 2007;177:540–5. 18. froehner m, novotny v, koch r, leike s, twelker l, wirth mp. perioperative complications after radical prostatectomy: open versus robot-assisted laparoscopic approach. urol int. 2013;90:312–5. 19. tewari ak, ali a, ghareeb g, et al. improving time to continence after robot-assisted laparoscopic prostatectomy: augmentation of the total anatomic reconstruction technique by adding dynamic detrusor cuff trigonoplasty and suprapubic tube placement. j endourol. 2012;26:1546–52. 20. moinzadeh a, shunaigat an, libertino ja. urinary incontinence after radical retropubic prostatectomy: the outcome of a surgical technique. bju int. 2003;92:355–9. 21. walsh pc, donker pj. impotence following radical prostatectomy: insight into etiology and prevention. j urol. 1982;128:492–7. 2 2. tewari ak, ali a, metgud s, et al. functional outcomes following robotic prostatectomy using athermal, traction free risk-stratified grades of nerve sparing. world j urol. 2013;31:471–80. 23. tewari ak, srivastava a, huang mw, et al. anatomical grades of nerve sparing: a riskstratified approach to neural-hammock sparing during robot-assisted radical prostatectomy (rarp). bju int. 2011;108:984–92. 24. eichelberg c, erbersdobler a, michl u, et al. nerve distribution along the prostatic capsule. eur urol. 2007;51:105–10. 25. kursh ed, bodner dr. alternative method of nerve-sparing when performing radical retropubic prostatectomy. urology. 1988;32:205–9. 26. chien gw, mikhail aa, orvieto ma, et al. modified clipless antegrade nerve preservation in robotic-assisted laparoscopic radical prostatectomy with validated sexual function evaluation. urology. 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detrusorrhaphy and nerve-sparing techniques-shin et al. vol 18 no 3 may-june 2021 321 pictorial obstructive azoospermia secondary to obstructed ejaculatory ducts treated with resection of the verumontanum michael s floyd (jr),1* sylvia connolly,2 hosea baba yisa gana1 a 25-year old male presented with primary infertility. he and his partner had been trying to conceive for over 12 months despite normal gynecological investigations. there was no history of chronic respiratory disease, infections, sexual dysfunction, genetic abnormalities, trauma or illicit substance use. secondary sexual characteristics were normal. physical examination including digital rectal examination was unremarkable. scrotal ultrasound demonstrated a grade 0 varicocele. karyotype and hormonal profile were normal. semen analysis was consistent with obstructive azoospermia, with absent sperm, low ph and reduced volume. magnetic resonance imaging of his pelvis revealed an 8 mm midline cyst and dilated seminal vesicles (figures 1a and 1b). subsequent cystoscopy demonstrated an edematous verumontanum which, when resected, immediately released retained semen (figures 2a and 2b). a clinical diagnosis of obstructed ejaculatory ducts was suspected. ejaculatory duct obstruction causes disruption of spermatozoa transport from the vas deferens to the prostatic urethra via the ejaculatory ducts. clinical findings such as azoospermia, low volume acidic ejaculate with normal sexual development and dilated seminal vesicles with a midline cyst are highly suggestive.(1) transurethral resection of the ejaculatory ducts (tured) and verumontanum has been shown to increase semen volume in patients and successful pregnancies have been reported.(2,3) references 1. paick js. transurethral resection of the ejaculatory duct. int j urol. 2000;7 suppl:s42-7. 2. fisch h, lambert sm, goluboff et. management of ejaculatory duct obstruction: etiology, diagnosis, and treatment. world j urol. 2006;24:604-10. 3. fuse h, mizuno i, iwasaki m, akashi t. transurethral treatment of ejaculatory duct obstruction in infertile men. arch androl. 2003;49:429-31. figure 1. magnetic resonance imaging of pelvis demonstrates an 8 mm midline cyst (a) and dilated seminal vesicles (b). figure 2. cystoscopy demonstrates an edematous verumontanum (a) which, when resected, immediately released retained semen (b). departments of urology1 and radiology,2 whiston hospital, st helen's and knowsley hospital nhs trust, merseyside l35 5dr, uk. *correspondence: department of urology, whiston hospital, st helen's and knowsley hospital nhs trust, merseyside, l35 5dr, uk. tel: 00 44 1514261600. fax: 00 44 151 4301405. e-mail: nilbury@gmail.com. received december 2014 & accepted march 2015 poctorial 2204 urological oncology the utility of fluorescence in situ hybridization for diagnosis and surveillance of bladder urothelial carcinoma jian-wen huang,1,2 jia-gui mu,2 yun-wei li,2 xiu-guo gan,2 lu-jie song,1 bao-jun gu,1 qiang fu,1 yue-min xu,1* rui-hua an2 purpose: to evaluate the clinical value of fluorescence in situ hybridization (fish) for diagnosis and surveillance of bladder urothelial carcinoma (buc). materials and methods: between november 2010 and december 2013, patients suspected of having buc were examined using urine cytology and fish assay. based on histopathological examination results, fish results were compared with urine cytology. in addition, patients with a history of non-muscle invasive buc were also examined using urine cytology and fish assay at the first time of visit and then monitored with cystoscopy during follow-up period. results: a total of 162 patients included in this study and 12 patients were excluded due to uninformative fish assays. the remaining 150 patients consisted of 108 patients suspected for buc and 42 patients with a history of non-muscle invasive buc. the sensitivities of fish analysis and urine cytology were 72.8% and 27.2%, respectively, and the difference was statistically significant (p <.05). difference between specificity of urine cytology (100%) and fish assay (85%) was not statistically significant (p >.05). at the first visit, of 42 patients, one patient had positive cystoscopy, and fish assay was positive in 26 of 41 patients with negative cystoscopy. during the follow-up period (mean, 29.5 months), 18 of 26 patients developed recurrence, and recurrence occurred in only one of 15 patients with negative fish analysis. conclusion: our results suggest that fish analysis can be used as a non-invasive diagnostic tool for patients suspected of having new buc. in addition, fish analysis may provide important prognostic information to better define the individual risk for buc recurrence. keywords: in situ hybridization; fluorescence; neoplasm recurrence; tumor markers; urinary bladder neoplasms; predictive value of tests; urine; cytology. introduction bladder urothelial carcinoma (buc) is the fifth most common cancer in the world.(1) approxi-mately 80% of buc is non-muscle invasive and 20% is muscle invasive. most buc tumors can be treated with transurethral resection of bladder tumor (turbt) and additional intravesical chemoor immunotherapy. however, patients with non-muscle invasive buc have a significant risk of recurrence and progression to muscle invasive one.(2) therefore, it is necessary to monitor recurrence and progression in patients with buc using some modalities. cystoscopy and urine cytology have been the standard diagnostic and surveillance tools for buc. however, cystoscopy is invasive and generally cannot be accepted by every patient. meanwhile, some flat or very small lesions, such as carcinoma in situ, cannot be detected by cystoscopy.(3) although urine cytology has high specificity and is a noninvasive method for detecting carcinoma cells, the procedure has poor sensitivity to tumor cells, particularly in low grade tumors.(4) therefore, researchers have been looking for a noninvasive method with both good sensitivity and high specificity for detection and monitoring of buc. previous studies have found a number of frequent genetic aberrations, such as aneuploidy of chromosomes 1, 3, 7, 9, 11 and 17 and deletions or the total loss of chromosome 9 in urothelial carcinoma (uc).(5,6) in addition, some studies have reported that some genetic mutations are usually associated with occurrence and development of buc, such as ki-67, bcl-2 and ca199.(7,8) fish technology is one of the standard methods for detecting these genetic mutations which uses fluorescently labeled dna probes to detect numerical or structural abnormalities of the chromosomes in tumor cell. it has been demonstrated that multicolor fish assay consisted of 4 probes for chromosomes 3, 7, 17 and p16 locus of chromosome 9 has 1department of urology, shanghai jiao tong university, affiliated sixth people’s hospital, shanghai, china. 2department of urology, harbin medical university, affiliated first hospital, harbin, china. *correspondence: department of urology, shanghai jiao tong university, affiliated sixth people’s hospital, shanghai, china. tel: +86 21 64369181 . fax: +86 21 6764 7129. e-mail: xuyuemin2006@aliyun.com. received may 2014 & accepted october 2014 urological oncology 1974 highest sensitivity for diagnosis of buc from a series of 10 different probes.(9) previous studies have reported that multicolor fish assay as an ancillary tool could be used for diagnosis and surveillance of buc.(10-14) however, some studies have reported that the sensitivity and specificity of fish analysis to detect carcinoma were low,(15,16) and the value of fish assay as a diagnostic tool and prognostic marker for buc remains a controversial topic. in the present study, we aimed to compare the accuracy of fish assay with urine cytology for diagnosing buc and to determine the clinical implication of this assay for predicting the risk of buc recurrence. materials and methods study subjects between november 2010 and december 2013, patients suspected of having buc, who presented with gross hematuria and an ultrasound diagnosis of suspicious bladder lesion before participating in the study were examined using both urine cytology and fish analysis before doing cystoscopy. patients with negative cystoscopy and positive urine cytology or positive fish analysis underwent follow-up cystoscopy every 6 months (figure 1a). likewise, patients with a history of non-muscle invasive buc were examined by urine cytology and fish assay before cystoscopy at time of their first visits and then monitored with cystoscopy approximately every 3 months for 2 years with decreasing frequency thereafter to detect signs of recurrence of buc (figure 1b). the study was approved by our institutional review board and all patients provided written informed consent. cytology analysis and pathological examination urine cytology analysis was conducted by centrifuging a part of urine samples from whole volume of voided urine, and then using the papanicolaou staining method. the used cytologic criteria were according to modern cytopathology.(17) cytology results were interpreted by a trained cytopathologist who was blinded to the patients’ clinical records and fish results. cytology results were considered positive only in cases where carcinoma cells or suspicious carcinoma cells were detected, while results were considered negative showing atypical or negative cells in three consecutive voided urines. histopathological examination was performed in patients with buc who underwent turbt or biopsy. tumor stage and grade were determined according to the international union against cancer tnm classification and the world health organization (who) 2004 classification method. fish analysis fish assay was conducted using bladder cancer kits (gp medical technologies, ltd, beijing, china) in accordance with the manufacturer’s instructions as described elsewhere.(18) briefly, the remaining urine specimen after cytological processing was collected from each patient and then centrifuged. cells were mixed using fresh carnoy fixative protocol, and the cell suspension was placed onto two slides and air dried. the slides were then washed in the 2 × standard saline citrate (ssc) and incubated in pepsin solution. they were then washed, fixed in methanol and dehydrated in 70%, 80% and 100% figure 1. study flow chart. figure 2. fluorescence in situ hybridization; (a and b) normal cell showing two chromosomes 3 (green), two chromosomes 7 (red), two chromosomes 17 (green) and two 9p21 locus (red); (c and d) two examples ofabnormal cells showing aneuploidy of chromosome 3, 7 and 17; (e and f) two examples of abnormal cells showing heterozygous and homozygous deletions of the 9p21 locus. fish in diagnosis and surveillance of bladder urothelial carcinoma-huang et al vol 11. no 06 nov-dec 2014 1975 ethanol, and then air dried. after dna denaturation, two probe sets (csp 3/csp 7 and glp p16/csp 17) comprising chromosome 3 (spectrum green)/7 (spectrum red) and chromosome 17 (spectrum green)/specific locus p16 of chromosome 9 (spectrum red) were incubated with the specimens on the two slides and the cells were counterstained with dapi (4, 6-diamidine, 2-phenylindole). finally, specimens were analyzed using a fluorescence microscope equipped with the appropriate excitation and emission filters. we have evaluated fish results based on the criteria supplied by the bladder cancer kit, using the following protocol. at least 100 consecutive cells were scored. an indicator was considered positive if the ratio of cells showing deletion of the p16 locus was ≧ 15% or the multiplication of cep 3, cep 7 or cep 17 was ≧ 10%. a sample was considered fish-positive if at least one of the following criteria was met: 1) at least 2 indicators were positive; 2) more than 15% of cells showed complete deletion of the p16 locus. we have determined fish results according to scanning method if the indicator fell below the percentages (10% or 15%) required to be considered indicator-positive, but was above certain thresholds (the mean percentage + 3 standard error [sd] of cells with polysomy or deletion observed in specimens from 20 normal donors). the thresholds for incomplete and complete loss of the p16 locus were 2.5% and 4.4%, respectively; for cep 3, cep 7 and cep 17 the thresholds were 6.5%, 3.8% and 3.0%, respectively. based on the scanning method, 25 morphologically abnormal cells with unclear enlargement, irregular nuclear borders and patchy dapi staining were scored from each sample. sample was considered fish-positive if there were ≧ 4 cells with polysomy on at least 2 chromosomes (cep 3, 7 or 17) or 12 cells showing homozygous loss of the p16 locus. statistical analysis the sensitivities of fish assay and urine cytology were determined for patients with biopsy-proven buc, and the specificities were calculated for patients diagnosed with benign disease. the significant differences between fish assay and assay urine cytology results were determined using the mcnemar test. differences were considered statistically significant at p values < .05. the statistical package for the social science (spss inc, chicago, illinois, usa) version 13.0 was used for statistical analysis. results a total of 162 patients were recruited in this study and 12 patients were excluded due to uninformative fish assays. the remaining 150 patients consisted of 108 patients suspected of having buc and 42 patients with a history of non-muscle invasive buc. of 108 patients suspected of having buc, 81 had pathology confirmed buc, 4 had ureter uc (located at the lower ureter, close to ureteral orifice) without bladder tumors and 3 had bladder adenocarcinoma. the remaining 20 patients were diagnosed with benign bladder disease, and served as the control group. among the 81 patients, 59 cases were fish-positive (72.8%) (figure 2), while only 22 cases had positive urine cytology (27.2%). the sensitivity of fish assay was superior to that of urine cytology (p < .05). of 20 control cases, fish testing was negative in 17 and positive in 3 (2 glandular cystitis and 1 granulomatous cystitis), while all 20 cases had negative urine cytology, resulting in specificities of 85% and 100%, respectively. although the specificity of urine cytology was higher than that of fish assay, the difference was not statistically significant (p > .05). in addition, the positive predictive values (ppv) of fish assay and urine cytology were 95.2% and 100%, respectively, while the negative predictive values (npv) were 43.6% and 25.3%, respectively (table). the sensitivities of fish assay and urine cytology, broken down according to buc stage and grade (table). among four patients with pathtologically confirmed ureter uc, three patients were fish-positive, while only one had positive urine cytology result. all three patients with bladder adenocarcinoma were fish-positive. seventy-nine (97.5%) of the buc cases were detected by cystoscopy and two cases were not detected, thereby to the sensitivity of cystoscopy was superior than that of fish assay (72.8%) (p < .05). among 42 patients with a history of buc, follow-up cystoscopy detected a recurrent tumor in one patient; the tumor was pathologically confirmed as recurrent lowgrade and non-muscle invasive buc. of 41 patients with variables patients no. fish assay* urine cytology* p value sensitivity stage non-muscle invasive 53 35 (66.0) 6 (11.3) .000 muscle invasive 28 24 (85.7) 10 (57.1) .018 grade low 48 33 (68.8) 4 (8.3) .000 high 33 26 (78.8) 18 (54.5) .037 total 81 59 (72.8) 22 (27.2) .000 specificity controls 20 17 (85.0) 20 (100) .72 ppv ....... 59/62 (95.2) 22/22 .29 npv28 ....... 17/39 (43.6) 20/79 (25.3) .44 abbreviations: fish, fluorescence in situ hybridization; ppv, positive predictive value; npv, negative predictive value. * data are presented as no. (%). table. sensitivities, specificities and the predictive values of fish assay and urine cytology for diagnosis of bladder carcinoma. fish in diagnosis and surveillance of bladder urothelial carcinoma-huang et al urological oncology 1976 negative cystoscopy and negative urine cytology results at the time of the first visit, 26 patients were fish-positive, and 18 of 26 patients developed recurrence during the follow-up period (mean, 29.5 months). there was recurrence in only one of 15 patients who was fish-negative. among the three patients with negative urine cytology and positive fish assay in the control group, none of them was diagnosed with buc or upper tract uc during follow-up period (mean, 28.2 months). discussion in the current study, we compared the accuracy of fish assay with that of urine cytology to determine the clinical utility of this assay for detecting buc. our results indicated that the sensitivity value of fish assay was significantly higher than that of urine cytology, regardless of the grade and stage of the disease, particularly in cases of low grade and non-muscle invasive tumors and there was no significant difference between the specificity of fish assay and urine cytology, which are consistent with previous reports.(10,11,13,14) among the 59 patients who had negative cytology, 39 (66.1%) were fish-positive. the fish-positive result seems to provide a significant additional and complementary clue for detecting buc when urine cytology results are negative or equivocal.(14) in 59 patients with negative urine cytology, 37 of 57 patients who had positive cystoscopy were also positive for fish analysis, and the remaining 2 cases with negative cystoscopy had positive fish assays. the study results demonstrate that in patients with negative urine cytology results, although the cases with positive cystoscopy could be detected by fish assay, fish analysis was unnecessary to detect obvious tumors, because the tumors was easy to be revealed by cystoscopy and subsequent biopsies, but it was beneficial in those patients with negative cystoscopy findings. previous study reported that if considering the low incidence of cancer (1.1%) in the patients with negative urine cytology and normal cystoscopy and the high cost (up to $800/fish assay) of fish assay, fish analysis might not be cost effective assay.(15) likewise, the fish probes (gp medical technologies, ltd, beijing, china) in the current study are expensive and the patient needs to spend about $400 for fish assay. hence, the current high cost for fish assay seems to hinder its clinical application for diagnosis and surveillance of buc. in addition, in another study it has been reported that fish assay is beneficial in patients with atypical urine cytology and negative cystoscopy,(19) and fish assay is more helpful in patients with atypical urine cytology than negative urine cytology. the possible explanation was that, patients with atypical urine cytology might be more susceptible to have abnormal chromosomes than negative cytology.(15) in the present study, fish assays missed 22 patients with confirmed buc; 16 (72.7%) of those patients had low grade tumors and 20 (90.9%) had non-muscle invasive tumors, which is consistent with previous report.(11) one explanation is that, low grade lesions do not actively shed carcinoma cells into the bladder lumen or, alternatively, such lesions do not exhibit the chromosomal changes that are detected by fish assay.(20) furthermore, the majority of the 22 patients with fish-negative results also had negative urine cytology test results, and surprisingly, two cases who had negative fish analysis were identified using urine cytology. one another possible explanation is that there were sufficient malignant cells in the specimen for urine cytology and insufficient malignant cells in the residual specimen for fish assays after cytology processing; the other explanation is that malignant cells with morphologically abnormal unclear for urine cytology, did not have the most frequently altered chromosomes (3, 7, 9, and 17) for fish analysis, but had another altered chromosomes.(21) fish assay as an independent prognostic factor on a chromosomal basis in non-muscle invasive buc can predict recurrence or progression of tumor.(22) in our study, 69.2% of patients with positive fish assay developed recurrent buc during follow-up period, while only 6.7% of fish-negative patients had recurrence. this finding agrees with previous reports.(20,23) it seems that the false-positive fish results actually have not been false, but have preceded a tumor that could be detected by cystoscopy. our results suggest that fish assay may be useful as an early predictor of tumor recurrence. fish-positive result may signal a high risk, while fish-negative result signal a low risk for early recurrence and this finding may reduce frequency of follow-up cystoscopy. however, some studies reported that fish assay did not provide any additional information and there was no evidence that positive fish assay provided any “expectation” of future recurrence.(24,25) so far, a more aggressive workup of patients with positive fish assay and negative cystoscopy is not currently justified.(26) as such, further studies are necessary to determine whether the fish assay can provide additional information for evaluating the risk for recurrence or not. in the control group, among the three patients with positive fish assay, no one was diagnosed with buc or upper tract uc during follow-up period. this might suggest that chromosomal instability is not absolutely specific for bladder carcinoma,(27) and these could also be observed with reactive states, especially in the area of superficial urothelial cells.(28) the false-positive fish results reduce the specificity of this assay. according to one prior study, the karyotypic profile of the upper urinary tract uc is similar to that of the buc. (29) some researchers used fish assay as an adjunct tool in managing upper urinary tract uc and reported that the cases could be diagnosed with a high specificity, using fish assay.(18) in addition, it has been reported that fish analysis is significantly better than urine cytology for diagnosing upper urinary tract uc.(30) in present study, among four patients with pathologically confirmed ureter uc, three patients were fish-positive, while only one had positive urine cytology results. furthermore, our study also included three patients who had bladder adenocarcinoma. as reported previously,(20) obvious amplifications of cep 3, 7 and 17 have been found in all patients’ urine shedding cells and the patients were fish-positive. it is difficult to assess the clinical implications of fish assays in cases of upper urinary tract uc and bladder non-urothelial carcinoma, because the sample size of this study is low. in our study, 12 patients were excluded due to uninformative fish assays. the uninformative result occurs when there are insufficient shedding cells and presence fish in diagnosis and surveillance of bladder urothelial carcinoma-huang et al vol 11. no 06 nov-dec 2014 1977 of massive granulocytes and bacteria in the voided urine. it was extremely difficult for the examiner to distinguish granulocytes from shedding cells during interpretation. in addition, bacterial signals that adhered to the shedding cells made accurate signal detection impossible. this is a limitation of the assay itself. our study has several limitations. firstly, we did not evaluate the utility of fish assay for detection of buc in the patients with atypical urine cytology and negative or equivocal cystoscopy. generally, fish assay should not be used in patients with positive urine cytology or cystoscopy; fish results are crucial for the clinician to detect new or recurrent bladder carcinoma in patients with atypical urine cytology and negative or equivocal cystoscopy results. secondly, small sample size precluded evaluating the specificity of fish and urine cytology. finally, in addition to relatively small sample size the follow-up period for surveillance of buc was also short. conclusion our results suggest that fish assay can be used as a non-invasive diagnostic tool for patients suspected of having new buc. in addition, fish analysis may provide important prognostic information to better define the individual risk for buc recurrence. however, large scale prospective studies are needed to better determine if negative fish results can reduce the frequency of cystoscopy during follow-up period as well as to evaluate the prognostic role of fish assay. acknowledgements this work was supported by the clinical application fund for molecular biology of the chinese medical association (camb032010). yue-min xu and rui-hua an contributed equally. conflict of interest none declared. references 1. parkin dm, bray f, ferlay j, pisani p. global cancer statistics, 2002. ca cancer j clin. 2005;55:74-108. 2. placer j, espinet b, salido m, solé f, ge labert-mas a. clinical utility of a multiprobe fish assay invoided urine specimens for the detection of bladder cancer and its recurrenc es, compared with urine cytology. eur urol. 2002;42:547-52. 3. wiener hg, mian c, haitel a, pycha a, schatzl g, marberger m. can urine bound diagnostic tests replace cystoscopy in the management of bladder cancer? j urol. 1998;159:1876-80. 4. konety br, getzenberg rh. urine based markers of urological malignancy. j urol. 2001;165:600-11. 5. bala´zs m, carroll p, kerschmann r, sauter g, waldman fm. frequent homozygous de letion of cyclin-dependent kinase inhibitor 2 (mts1, p-16) in superficial bladder cancer detected by fluorescence in situ hybridiza tion. genes chromosomes cancer. 1997;19:84-9. 6. zhao j, richter j, wagner u, et al. chromo somal imbalances in noninvasive papillary bladder neoplasms (pta). cancer res. 1999;59:4658-61. 7. pal k, roy s, mondal sa, chatterjee u, ti wari p, bera m. urinary level of ca19-9 as a tumor marker in urothelial carcinoma of the bladder. urol j. 2011;8:203-8. 8. goyal s, singh ur, sharma s, kaur n. cor relation of mitotic indices, agnor count, ki-67 and bcl-2 with grade and stage in pap illary urothelial bladder cancer. urol j. 2014;11:1238-47. 9. sokolova i, halling kc, jenkins rb, et al. the development of a multitarget, multicolor fluorescence in situ hybridization assay for the detection of urothelial carcinoma in urine. j mol diagn. 2000;2:116-123. 10. song mj, lee hm, kim sh. clinical useful ness of fluorescence in situ hybridization for diagnosis and surveillance of bladder cancer. cancer genet cytogenet 2010; 198:144-50. 11. kwakkw, kimsh, leehm. the utility of fluorescence in situ hybridization for detec tion of bladder urothelial carcinoma in rou tine clinical practice. j korean med sci. 2009;24:1139-44. 12. galván ab, salido m, espinet b, et al. a multicolor fluorescence in situ hybridization assay: a monitoring tool in the surveillance of patients with a history of non-muscle inva sive urothelial cell carcinoma: a prospective study. cancer cytopathol. 2011;119:395 403. 13. li hx, wang mr, zhao h, cao j, li cl, pan qj. comparison of fluorescence in situhybri dization, nmp22 bladderchek, and urinar y liquid-based cytology in the detection of bladder urothelial carcinoma. diagn cyto pathol. 2013;41:852-7. 14. dimashkieh h, wolff dj, smith tm, houser pm, nietert pj, yang j. evaluation of urovy sion and cytology for bladder cancer detec tion: a study of 1835 paired urine samples with clinical and histologic correlation. can cer cytopathol. 2013;121:591-7. 15. youssef rf, schlomer bj, ho r, sagalowsky ai, ashfaq r, lotan y. role of fluorescence in situ hybridization in bladder cancer survei llance of patients with negative cytology. urol oncol. 2012;30:273-7. 16. kehinde eo, al-mulla f, kapila k, anim jt. comparison of the sensitivity and speci ficity of urine cytology, urinary nuclear ma trix protein-22 and multi target fluorescence in situ hybridization assay inthe detection of bladder cancer. scand j urol nephrol 2011; fish in diagnosis and surveillance of bladder urothelial carcinoma-huang et al urological oncology 1978 45:113-21. 17. geisinger kr, stanley mw, raabstephen s. modern cytopathology. philadelphia: churchill living-stone; 2003. p. 235-42. 18. huang wt, li ly, pang j, et al. fluoresce nce in situ hybridization assay detects upper urinary tract transitional cell carcinoma in patients with asymptomatic hematuria and negative urine cytology. neoplasma. 2012; 59:355-60. 19. schlomer bj, ho r, sagalowsky a, ashfaq r, lotan y. prospective validation of the clin ical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carci noma of the bladder. j urol. 2010;183:62-7. 20. yoder bj, skacel m, hedgepeth r, et al. re flex urovysion testing of bladder cancer sur veillance patients with equivocal or negative urine cytology: a prospective study with fo cus on the natural history of anticipatory pos itive findings. am j clin pathol.2007; 127: 295-301. 21. steidl c, simon r, bu¨rger h, et al. patterns of chromosomal aberrations in urinary blad der tumours and adjacent urothelium. j path ol. 2002;198:115-20. 22. mian c, lodde m, comploj e, et al. multi probe fluorescence in situ hybridisation: prognostic perspectives in superficial bladder cancer. j clin pathol. 2006;59:984-7. 23. zellweger t, benz g, cathomas g, et al. multitarget fluorescence in situ hybridiza tion in bladder washings for prediction of recurrent bladder cancer. int j cancer. 2006; 119:1660-5 24. daniely m, rona r, kaplan t, et al. com bined analysis of morphology and fluoresce nce in situ hybridization significantly increa ses accuracy of bladder cancer detection in voided urine samples. urology. 2005; 66: 2005;66:1354-9. 25. nguyen ct, litt db, dolar se, ulchaker jc, jones js, brainard ja. prognostic signif icance of nondiagnostic molecular changes in urine detected by urovysion fluorescence in situ hybridization during surveillance for bladder cancer. urology. 2009;73:347-50. 26. ferra s, denley r, herr h, dalbagni g, jhan war s, lin o. reflex urovysion testing in suspicious urine cytology cases. cancer cy topathol. 2009;117:7-14. 27. banek s, schwentner c, täger d, et al. pro spective evaluation of fluorescence-in situ hybridization todetect bladder cancer: res ults from the uro-screen-study. urol oncol. 2013;31:1656-62. 28. wojcik em, brownlie rj, bassler tj, mill er mc. superficial urothelial (umbrella) cells. a potential cause of abnormal dna ploidy results in urine specimens. anal quant fish in diagnosis and surveillance of bladder urothelial carcinoma-huang et al vol 11. no 06 nov-dec 2014 1979 cytol histol. 2000;22:411-5. 29. fadl-elmula i, gorunova l, mandahl n, et al. cytogenetic analysis of upper urinary tract transitional cell carcinomas. cancer genet cytogenet. 1999;115:123-7. 30. mian c，mazzoleni g，vikoler s，et al. fiuorescence in situ hybridization in the diagnosis of upper urinary tract tumors. eur urol. 2010;58:28892. female urology paraurethral cyst in adult women: experience with 85 cases farzaneh sharifiaghdas, azar daneshpajooh,* mahboubeh mirzaei purpose: to present the clinical experience in the management of skene’s duct cysts (paraurethral cysts) in women. materials and methods: a retrospective chart review of patients who have been undergone surgical treatment for paraurethral cyst between 2002 and 2012 was performed. a total of 85 women were diagnosed with paraurethral cyst over a 10-year period. the paraurethral cysts were detected at vaginal examination. evaluations consisted of urine analysis and culture and urinary tract ultrasound. the first 20 cases underwent cystourethroscopy as well. all patients underwent surgical incision, drainage and marsupialization of the cyst. they were followed up for evidence of any complications and recurrence. results: the mean follow up time was 5.5 years. totally, 83 patients (97.6%) were cured. there were two cases of recurrence which were treated with second surgical attempt. conclusion: most paraurethral cysts in women may be diagnosed by history and physical examination alone. simple incision and marsupialization of the female paraurethral cyst was effective in more than 97% of our patients, without recurrence. keywords: genital diseases; female; cysts; diagnosis; surgery; treatment outcome; urethral diseases. introduction skene’s glands, or paraurethral glands, are bilateral, prostate homologues which are, located at the bot-tom of the distal urethra.(1,2) their role is to secrete a mucoid material, which helps to lubricate the urethral meatus.(3) obstruction of the ducts leads to the formation of cyst.(1) a paraurethral cyst presents as a small, cystic mass, just lateral or inferolateral to the urethral meatus. although the etiology of ductal obstruction is unknown in neonates in adults, paraurethral cysts may be caused by infection and inflammation.(1,4) disorders of the skene’s glands are rare during the prepubertal period. when a cyst or abscess occurs, women in the third or fourth decade of their life are most affected.(5) as skene’s ducts are embryologically derived from the urogenital sinus, these cysts are lined by stratified squamous epithelium.(1) presenting symptoms include a palpable or visible mass, pain, dyspareunia, a distorted voiding stream and vaginal discharge. paraurethral cysts may be totally asymptomatic and are usually discovered during routine pelvic examination.(6) the management of paraurethral cysts is controversial.(7-9) in this article, we report our clinical experience with the diagnosis and management of paraurethral cysts. materials and methods a retrospective chart review of patients who have been undergone surgical treatment of paraurethral cyst in between 2002 and 2012 was performed. during a 10-year period, more than 100 cases of paraurethral cysts have been presented to our clinic, some of which were referred by gynecologists or other urologists. the medical records of all patients were reviewed. in most cases, diagnosis was based on the patient’s history and physical examination. the lesions were assessed for location, mobility, tenderness and consistency. urine analysis, urine culture and urinary tract ultrasound were also done in all patients. conservative treatments were unsuccessful in all patients. according to the medical records, cystourethroscopy has been performed in the first 20 cases to rule out urethral diverticulum before surgery. the cysts were inferolateral to the urethral meatus, displacing it to the other side (figure 1). the patients were operated as outpatient, under intravenous sedation or local anesthesia. at the start of the procedure, a urethral foley catheter was inserted. paraurethral cysts were incised, drained (figure 2) and marsupialized by four separated 4-0 chromic sutures (figure 3). the anterior cyst wall was sent for pathological examination and the posterior cyst wall remained in situ (figure 4). the foley catheter was removed at the end of the procedure. patients were examined postoperatively and then followed up annually for evidence of any recurrence. at each clinical visit, they were asked questions regarding any symptoms related to the cyst, voiding abnormality and sexual function. urology and nephrology research center, labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. * correspomdence: urology and nephrology research center, labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. tell: +98 21 22567222; fax: +98 21 22567282. e-mail: azdaneshpajooh@yahoo.com. received april 2013 & accepted july 2014 female urology 1896 results only 85 out of 100 patients, who had marsupialization of paraurethral cyst, were eligible to enroll in this study. mean age was 33.2 years (20-77 years). of study subjects 76 were multiparous and nine were nulliparous. the size of paraurethral cysts ranged from 0.5 to 4.5 cm. the most common symptom was the sensation of a mass [63 (74%)]. other symptoms were irritative urinary symptoms in 42 (49%), dyspareunia in 24 (28%) and obstructive voiding symptoms in 11 patients (13%). the mean operation time was 10 min (range, 6-15 min). the operation was uneventful, with no postoperative complications. the patients were followed up for an average of 5.5 years (6 months to 9 years). a total of 83 patients (97.6%) were cured, while remaining two developed recurrence of cysts after 2 and 4 years. the second attempt of surgical marsupialization was successful and uneventful as well. in all the specimens pathological examination revealed benign cyst walls, lined with transitional or stratified squamous epithelium (figure 5). all cultures of the drained mucous secretions were sterile. discussion benign cystic lesions of the vagina are frequently encountered in gynecological and urological practice. true cystic lesions of the vagina originate from vaginal tissues, but lesions arising from the urethra and surrounding tissues may present as cystic lesions in the vagina as well.(1) the differential diagnosis of vaginal wall masses are; cysts with embryonic origin (mullerian cysts, gartner’s duct cysts, skene’s duct cysts, bartholin’s duct cysts, vaginal adenosis, cysts of canal of nuck), cysts with urethral origin (urethral caruncle, urethral diverticulum), epidermal inclusion cysts, endometriosis, ectopic ureterocele and pelvic organ prolapse. skene’s gland cysts are very rare, the lesion typically arising secondary to the obstruction of the duct. the cysts usually present as mass lesions with associated pain, dyspareunia, dysuria and distorted voiding stream.(3) blaivas and colleagues reported a diagnosis of paraurethral masses in 4% of their patient sample population, and most masses were urethral diverticula (84%). paraurethral cysts were less commonly diagnosed, in 7% of patients.(10) cross and colleagues examined 140 asymptomatic womfigure 2. incision and drainage of paraurethral cyst. figure 3. marsupialization of cyst. figure 4. anterior cyst wall. figure 1. the cyst has displaced urethral meatus to the other site. paraurethral cyst in women-sharifiaghdas et al vol 11. no 05 sept-oct 2014 1897 en (mean age 41 years) by using endovaginal and perineal sonography. a proportion of 2.9% of cases revealed asymptomatic paraurethral cystic structures lying lateral to the urethra, while the communication with the urethra was not convincingly demonstrated in any of the cases. (11) there are very few studies in the literature describing the evaluation and management of paraurethral cysts in adult women.(7) we reported our first experience with 25 cases of paraurethral cysts during a 7 years interval, between 1995 and 2001.(6) therefore, this is the second report from the same center with more patients and longer follow-up period. in our study, most of the patients were multiparous (76 vs. 9), which indicates multiparity as a risk factor for paraurethral cyst. most of the cases were in the fourth and fifth decades of life. however, a few were in the post-menopausal period (4 patients, 4.7%). the position of the cyst is very important in physical examination. the most common location of the mullerian cyst is along the anterolateral aspect of the vagina. gartner’s duct cysts are almost always located along the lateral wall of vagina. bartholin’s duct cysts are in the lateral introitus, medial to the labia minora. cysts of the canal of nuck are generally found in the upper edge of the labia majora or inguinal canal. the preferred region occurrence vaginal adenosis is in the upper third of the vagina, primarily along the anterior wall. epidermal inclusion cysts are found at previous sites of trauma. the most important differential diagnosis of paraurethral cyst is the urethral diverticulum (ud). most urethral diverticula are located ventrally over the middle and proximal portions of the urethra, corresponding to the area of the anterior vaginal wall 1 to 3 cm inside the introitus.(12) patients with ud most commonly have anterior vaginal wall tenderness, with or without a concomitant palpable suburethral mass. pressure on the mass may demonstrate expressible purulent or bloody discharge from the ud or meatus, and firmness of the area may indicate a diverticular stone or neoplasm.(13) skene’s duct cysts are adjacent to the urethra and inferior or lateral to the urethral meatus. differentiation from ud can often be made during physical examination, because these lesions are located relatively distally on the urethra, often distorting the urethral meatus as compared with ud, which most commonly occur over the mid and proximal urethra. after such large number of cases reported in our center, we now believe that the preliminary diagnosis of paraurethral cysts can be easily made by physical examination in most cases. nevertheless, cystourethroscopy still remains necessary to diagnosis. also, our findings have no impact on the treatment planning. there was no need to perform a complete urological imaging palette (intravenous urography, voiding cystourethrogram, and magnetic resonance imaging), and perhaps these evaluations should be reserved for more complicated cysts, or cysts located at the proximal or mid part of the urethra. according to the literature, there is no consensus on the treatment of paraurethral cysts. conservative treatment or needle aspiration is an appropriate option in the neonates,(4,14) while surgical excision is an option if the cyst recurs or fails to resolve within a few months.(15) in adults, several methods of management have been recommended, including waiting for spontaneous rupture, needle aspiration, marsupialization and complete excision of the cyst.(7-9,16) complete excision of the paraurethral cyst holds the risk of urethral injury or weakening the tiny muscle fibers around the urethra. martin and colleagues reported the complete excision of the paraurethral cyst in four patients. two out of the four cases had urethral injury, which was surgically repaired and the foley catheter remained in place for 1 week to preserve the urethra.(10) lucioni and colleagues reported complete periurethral cyst excision in six patients, yielding an average recurrence free outcome with follow-up duration of 29 months. they also left in place the foley catheter for 24-48 hours due to close dissection around the urethra.(17) urinary incontinence, urethro-vaginal fistula and urethral stricture represent the other complications associated with the complete excision of paraurethral cysts. we treated all the patients by simple marsupialization of the cysts. all symptoms were completely resolved after surgery and there was no complication such as hematoma, pain, infection, scar formation and dyspareunia. in our first study, we reported simple marsupialization of paraurethral cysts as a safe and effective procedure. in the present study, we confirm the effectiveness of this procedure on a larger population and with longer follow-up. conclusion according to our knowledge, this is the largest case series with the largest follow-up ever published concerning female paraurethral cysts. we demonstrated that paraurethral cysts are benign lesions with excellent response to simple marsupialization procedure. conflict of interest none declared. references 1. eilber ks, raz s. benign cystic lesions of the vagina: a literature review. j urol. 2003;170:717 22. 2. flamini ma, barbeito cg, gimeno ej, portian sky el. morphological characterization of figure 5. pathological characteristics of benign paraurethral cyst. paraurethral cyst in women-sharifiaghdas et al female urology 1898 the female prostate (skene’s gland or paraure thral gland) of lagostomus maximus maximus. ann anat. 2002;184:341-5. 3. anderson sr. benign vulvovaginal cysts. diag histop. 2010;16:495-9. 4. soyer t, aydemir e, atmaca e. paraurethral cysts in female newborns: role of maternal es trogens. j ped adol gynecol. 2007;20:249-51. 5. nickles sw, burgis jt, menon s, bacon jl. prepubertal skene’s abscess. j ped adol gyne col. 2009;22:e21-2. 6. sharifi‐aghdas f, ghaderian n. female paraurethral cysts: experience of 25 cases. bju int. 2004;93:353-6. 7. isen k, utku v, atilgan i, kutun y. experience with the diagnosis and management of paraure thral cysts in adult women. can j urol. 2008;15:4169-73. 8. imamverdiev sb, bakhyshov aa. surgical treatment of paraurethral cysts in women. urol (moscow). 2009;2:39-41. 9. yilmaz y, celik ih, dizdar ea, et al. paraure thral cyst in two female newborns: which ther apy option?. scand j urol nephrol. 2012;46:78 80. 10. blaivas jg, flisser aj, bleustein cb, panagop oulos g. periurethral masses: etiology and diag nosis in a large series of women. obst gyne col. 2004;103:842-7. 11. cross jj, fynes m, berman l, perera d. prev alence of cystic paraurethral structures in as ymptomatic women at endovaginal and perineal sonography. clin radiol. 2001;56:575-8. 12. eric s, rovner md. bladder and female urethral diverticula. in: wein aj, editor. campbell’s urology.10th ed. philadelphia: saunders; 2012. p. 2262-89. 13. hsiao kc, kobashi kc. urethral diverticulum and fistula. in: cardoz l, staskin dr, editors. text fem urol urogynecol. 3th ed. lon don: informa healthcare; 2010. p. 971-90. 14. fujimoto t, suwa t, ishii n, kabe k. paraure thral cyst in female newborn: is surgery always advocated? j ped surg. 2007;42:400-3. 15. badalyan v, burgula s, schwartz rh. congeni tal paraurethral cysts in two newborn girls: dif ferential diagnosis, management strategies, and spontaneous resolution. j ped adol gyne col. 2012;25:e1-4. 16. busto ml, barguti i, andraca az, gómez ir, castañón lb. cyst of the skene’s gland: report of four cases and bibliographic review. arch urol. 2010;63:238-42. 17. lucioni a, rapp de, gong em, fedunok p, bales gt. diagnosis and management of peri urethral cysts. urol int. 2007;78:121-5. paraurethral cyst in women-sharifiaghdas et al vol 11. no 05 sept-oct 2014 1899 foreign body in the penile prosthesis reservoir a 55-year-old male patient reported a mechanical failure 4 months after inflatable ams® 700 cx penile prosthe-sis (ipp) implantation. patient underwent surgical exploration and the cylinders and pump were removed and replaced with a new ipp but the reservoir was left in situ. one month later he complained a second time for mechanical failure again, and a 3-4 cm foreign body was observed inside the reservoir during abdominal ultrasound (figure 1) and was confirmed after a scond surgical procedure (figures 2 and 3). urology department. hospital del henares. avda. marie curie s/n. 28822. coslada. madrid. spain. *correspondence: urology department. hospital del henares. avda. marie curie s/n. 28822. coslada. madrid. spain. phone number: + 34 911912000. fax number + 34 911912284. e-mail: pgabad@hotmail.com. received november 2015 & accepted february 2016 pictorial pablo garrido-abad*, bryan sinués-ojas, laura martínez-blázquez, pablo conde-caturla, delfina estévezsánchez, manuel fernández-arjona keywords: foreign body; penile prosthesis pictorial 2930 figure 1. ultrasound revealing an echogenic density inside the reservoir figure 2. extracting reservoir from the patient figure 3. foreign body inside the reservoir the reservoir was retrieved and a new reservoir was placed. the microbiology analysis did not identiy pus cells, no organism was visualized on gram stain and no growth was identified on culture. in our opinion, this foreign body could correspond to a detachment of the parylene® coating of the internal reservoir surface. complications of retained reservoirs include: migration, infection, erosion into the bladder, sigmoid colon, neobladders, seminal vesicles and ureters(1). to the best of our knowledge, we herein report the first case of a foreign body into an ipp reservoir. the patient remained well at follow-up visits both 1 month and 6 months after the procedure, with no mechanical failure reported. references 1. cui t, terlecki r, mirzazadeh m. infrequent reservoir‐related complications of urologic prosthetics: a case series and literature review. sexual medicine. 2015; 3: 334-338. foreign body in penile prosthesis-garrido-abad et al. vol 13 no 06 november-december 2016 2931 urol_v3_no1_001_editorial.qxd 49 urology journal unrc/iua vol. 3, no. 1, 49-53 winter 2006 printed in iran introduction micturition is dependent on a synchronized interaction of the bladder and the urethra under control of the central nervous system.(1) there are many mechanical factors affecting micturition in different situations that may affect diagnosis and treatment of voiding dysfunctions. these factors include: pressure of abdominal muscles and viscera(2) and transmission of this pressure to the bladder and the urethra,(3) relaxation degree of pelvic floor muscles in different positions of micturition,(4) and relaxation degree of adductor and anterior muscles of the thigh which directly affects the relaxation of pelvic floor muscles.(5) also, there are other factors which are expected to impact voiding such as the bladder position in the pelvis, the angle between the bladder neck and the urethra, patient's comfort in each voiding position, and anal sphincter tone during micturition.(4) changes in voiding position may have a significant impact on the abovementioned factors and subsequently on micturition function. for instance, in crouching position, increased intra-abdominal pressure, its transmission to the bladder, and complete relaxation of anterior and adductor thigh muscles uroflowmetry findings in patients with bladder outlet obstruction symptoms in standing and crouching positions mohsen amjadi,* seyed kazem madaen, hamid pour-moazen department of urology, imam khomeini medical center, tabriz university of medical sciences, tabriz, iran abstract introduction: bladder emptying in crouching position is a conventional way in many eastern countries. our aim was to evaluate uroflowmetry parameters as an index of obstruction severity in standing and crouching positions and comparison of them in patients with bladder outlet obstruction symptoms. materials and methods: uroflowmetry in standing and crouching positions was done in 83 patients with bladder outlet obstruction symptoms due to benign prostatic hyperplasia (bph). the patients were 50 years old or older and their maximum flow rate in standing position was less than 15 ml/s. the maximum flow rate, average flow rate, maximum flow time, and postvoid residual urine volume were measured and recorded. the results in standing and crouching positions were compared. results: the mean maximum flow rate and mean average flow rate in crouching position increased 86% and 51%, respectively (p < .001; p = .012), while mean maximum flow time and postvoid residual volume decreased 40% and 46%, respectively (p < .001; p < .001). these changes were also significant in patients with maximum flow rates of less than 10 ml/s and 10 ml/s to 15 ml/s in standing position, except for the maximum flow time in the latter group. conclusion: a more complete emptying of bladder in crouching position in patients with bph can be attributed to the increased bladder pressure due to a good transmission of intra-abdominal pressure and a complete and coordinated relaxation of pelvic floor muscles. this position can help improve patients' symptoms. key words: voiding position, uroflowmetry, lower urinary tract symptoms received august 2004 accepted july 2005 *corresponding author: department of urology, imam khomeini hospital, tabriz, iran. tel: +98 914 313 9452, fax: +98 411 335 7328 e-mail: amjadizm@yahoo.com uroflowmetry in standing and crouching positions50 and the pelvic floor can affect urinary flow. on the other hand, nowadays, there is a growing trend towards conservative treatment of benign prostatic hyperplasia (bph),(6) and taking a proper voiding position is regarded as a helpful recommendation in patients. moreover, increased severity of symptoms in patients with bph makes them urinate in sitting or crouching positions, because these positions contribute a full relaxation of pelvic floor muscles and let the patients with hesitancy wait enough without exhaustion.(7) generally, among many people in eastern countries (especially among muslims), bladder emptying is done in crouching position and according to religious recommendations, voiding in sitting or crouching position is preferred compared to standing position. but, the routine way of bladder emptying in western countries is standing position. in addition to the fact that presenting corroborative evidence for a religious suggestion is fascinating, achieving useful results from a simple recommendation for voiding position can help improve symptoms in patients with bladder outlet obstruction. thus, we decided to evaluate uroflowmetry findings in patients with bladder outlet obstruction in standing and crouching positions. materials and methods in a cross-sectional study, 105 men, 50 years old or older, with lower urinary tract symptoms were selected from among those presented in urology clinics of imam khomeini and sina hospitals in tabriz, iran, using a simple sequential sampling. all of the patients underwent complete history taking, and physical and rectal examination. the routine blood chemistry tests, urinalysis, urine culture, and measurement of prostate-specific antigen (psa) serum level were performed. then, upper and lower urinary tract system ultrasonography was carried out and the patients were examined with a 14-f catheter to rule out urethral obstruction. patients with lesions other than bph, such as prostate cancer, bladder stone, neurological dysfunction of the bladder, diabetes mellitus, meatal stenosis, and urinary tract infections were excluded from the study. patients with a diagnosis of bph were instructed to the study and informed consent was obtained. they underwent uroflowmetry for 2 times with pufs 2000 ambulatory urodynamic device (mms, enshede, the netherlands). the first uroflowmetry was performed in standing position and the results were recorded. immediately after the test, postvoid residual urine volume was measured with an 8-f nelaton catheter and gentamycin, 80 mg, was injected intramuscularly as prophylaxis. if the maximum flow rate in the first uroflowmetry was more than 15 ml/s, the patient was considered nonobstructive and excluded from the study. then, the second uroflowmetry was carried out the next day in crouching position. the second uroflowmetry was performed on a special chair which was designed and made for this purpose. this chair provided a completely similar situation to traditional iranian toilets for crouching. there were two bars in front and lateral sides of the chair for balance maintenance. postvoid residual urine volume was measured at the end of uroflowmetry. we made effort to keep the sum of voided urinary volume and postvoid residual volume between 150 ml/s and 300 ml/s in both uroflowmetries to prevent a significant impact on uroflowmetry results. in all patients, maximum flow rate, average flow rate, maximum flow time, and postvoid residual urine volume were recorded in standing and crouching position and the results were compared. the results in standing and crouching positions were analyzed in all of the patients and separately in those with maximum flow rates of less than 10 ml/s and 10 ml/s to 15 ml/s in standing position. for statistical analyses, paired t test and wilcoxon signed rank test were used and a p value less than .05 was considered significant. results of 105 patients, 83 were eligible and completed the study. the mean age of the patients was 61.2 ± 8.4 years. the details of the results in all patients are shown in table 1. changing the position from standing to crouching increased the mean maximum and mean average flow rates (p < .001; p = .012) and decreased the mean maximum flow time and mean postvoid residual urine volume (p < .001; p < .001). the results were analyzed in 2 groups; patients with a maximum flow rate less than 10 ml/s in standing position (n = 66) and those with a maximum flow rate between 10 ml/s and 15 ml/s (n = 17). the same changes were seen in the uroflowmetry results and postvoid residual amjadi et al 51 volume of the patients of the first group, all of which were significant (paired t test). in the patients of the second group, the increase in maximum and average flow rates and decrease in postvoid residual volume were significant, but the mean maximum flow time had an insignificant decrease (wilcoxon signed rank test). the details of the results are presented in tables 2 and 3. discussion the present study showed that micturition in crouching position improved uroflowmetry findings in patients with severe bladder outlet obstruction (maximum flow rate of less than 10 ml/s) and in those with moderate obstruction (maximum flow rate of 10 to 15 ml/s). in crouching position, patients with severe obstruction (defined by maximum flow rate) moved into the group with moderate obstruction. in other words, maximum flow rate increased form less than 10 ml/s in standing position to more than 10 ml/s in crouching position. furthermore, the mean average flow rate, maximum flow time, and postvoid residual volume changed significantly in favor of decrease in obstruction severity. patients with a moderate obstruction (10 ml/s to 15 ml/s) based on the maximum flow rate in standing position were no longer classified in obstructive group while crouching; ie, maximum flow rate increased reaching a level higher than 15 ml/s. other parameters in our investigation changed considerably in favor of decreased obstruction, too. the results showed that the more severe is the obstruction, the more significant is the improvement by position change. for example, in severe obstruction, increase in maximum flow rate in crouching position was 116%, while in moderate obstruction, this value was 41%. unsal and cimentepe have studied the urodynamic parameters of 44 men with symptomatic bph in sitting and standing positions. they have found no significant differences in the maximum flow rate, average table 1. uroflowmetry findings in standing and crouching positions for all patients table 2. uroflowmetry findings in standing and crouching positions for patients with a maximum flow rate of 10 ml/s or less in standing position table 3. uroflowmetry findings in standing and crouching positions for patients with a maximum flow rate of 10.1 ml/s to 15 ml/s in standing position parameter standing crouching percentage of difference p value maximum flow rate (ml/s) 6.6 12.3 86% < .001 average flow rate (ml/s) 4.1 6.2 51% .012 maximum flow time (s) 22.4 13.4 40% < .001 postvoid residual urine volume (ml) 144.7 76.8 46% < .001 parameter standing crouching percentage of difference p value maximum flow rate (ml/s) 5 10.8 116% < .001 average flow rate (ml/s) 2.5 5.6 104% < .001 maximum flow time (s) 26.1 15.2 41% < .001 postvoid residual urine volume (ml) 160 86.8 45% < .001 parameter standing crouching percentage of difference p value maximum flow rate (ml/s) 12.6 17.8 41% .019 average flow rate (ml/s) 5.7 8.5 49% .008 maximum flow time (s) 7.9 6.5 17% .091 postvoid residual urine volume (ml) 85.3 37.9 55% < .001 uroflowmetry in standing and crouching positions52 flow rate, and postvoid residual urine volume values.(8) however, in this study, increase in average flow rate and decrease in postvoid residual volume were 51% and 46%, respectively, from standing to crouching position. on the other hand, a study on 80 women performed by moore and colleagues has shown that patients who micturate in crouching position have a 21% decrease in the average flow rate and a 149% increase in postvoid residual urine volume compared with complete sitting position.(9) the results reported by moore and colleagues are related to the posture that women take over public toilet seats; thus, they have concluded that patients may benefit from a comfortable position while undergoing uroflowmetry. we provided a special chair for our patients and found that their uroflowmetry parameters improved significantly. controversial results urge more studies on all voiding positions, with special attention to the subject's health status, sex, habits, and convenience at voiding. to our knowledge, our study is the first comparison of crouching position with standing position in bph patients. increased severity of bph makes patients micturate in sitting position. because of hesitancy in patients, sitting position enables them to stay longer in toilet without exhaustion, which means a more complete micturition. in addition, more relaxation of the pelvic floor muscles leads to decreased resistance of the bladder outlet and better micturition.(7,9) below are some possible mechanisms which result in increased flow rate and decreased residue in crouching and sitting positions: the first mechanism is that in crouching, abdominal muscles act appropriately, completely and symmetrically to help micturition. moreover, pressure from abdominal contents and their interposition, and transmission of pressure to the lower part of abdomen and the bladder is an important factor in micturition that increases the flow rate. measuring the pressures at the mea and detrusor muscles simultaneously, sorensen has shown that postural changes from supine to sitting position changess in increased pressure of bladder and mea, but the bladder pressure increase is more than that of meatal pressure, due to the increased passive pressure of abdominal contents and activity of pelvic floor muscles.(3) natural micturition entails a raise in forward-moving forces to the urine and a reduction in forces causing bladder outlet obstruction. intravesical pressure is the sum of detrusor pressure and intra-abdominal pressure. in a normal state, micturition is met by detrusor contraction without any increase in intraabdominal pressure. but if detrusor contractility is not sufficient for emptying, or high pressure is required (in men with bph), an increase in intraabdominal pressure can be helpful.(2) hence, crouching increases vesical pressure by increasing intra-abdominal pressure for a more complete emptying. a second mechanism could be explained; the urine flow rate correlates directly with detrusor pressure and inversely with outlet resistance. thus, when outlet resistance decreases, flow rate increases.(2) there are 2 reasons for relaxation of pelvic floor musculature and eventual decrease in bladder outlet resistance in crouching positing. first, muscles of the medial and anterior part of the thigh are relaxed in this position. it has been shown that contraction of these muscles inhibits the bladder contraction and leads to insufficient relaxation of pelvic floor muscles. the relaxation of the previously mentioned muscles has opposite effect.(10) second, while crouching, the knees and the head of femur are in complete flexion which causes symmetry and a good fixation of pelvis to facilitate relaxation and finally the relaxation of pelvic floor muscles.(4) wennergren and colleagues have shown that supporting legs during micturition (by putting a pillow under the feet) in various situations leads to a better relaxation of pelvic floor musculature. they studied 20 healthy girls in 3 positions: supine, sitting, and crouching. they found that supporting legs in supine and sitting positions, improves pelvic floor relaxation, but in crouching position it has no effect on relaxation degree. they demonstrated that the most relaxation of pelvic floor is achieved by crouching per se.(4) we can speculate a third mechanism; innervations of anal sphincter and urethra have the same origin (s2 to s4) and these two sphincters act coordinately and simultaneously. therefore, synchronously relaxing one and contracting another is a partially difficult task. in standing position and especially in public conveniences, in order to prevent intestinal gas passing and maybe stool, one should contract anal sphincter and relax urethral sphincter for voiding. this causes incoordination in pelvic floor muscles, and then complete relaxation of pelvis and the resultant bladder emptying does not amjadi et al 53 happen; subsequently, urinary flow rate is decreased. in crouching, the patient uses an isolated toilet and is not obligated to keep anal sphincter tone, there is no incoordination in musculature, and complete relaxation is met. this per se makes a decrease in bladder outlet obstruction and a better emptying. apart from cases of bph, patients with low functional capacity of the bladder (eg, urgency, detrusor instability) benefit from relaxation of pelvic floor musculature and complete bladder emptying. an increase in postvoid residual urine volume equals increased susceptibility to infection, especially in women. thus, crouching seems to be the recommended voiding position in those at the risk of cystitis. the position of bladder in pelvic floor and the change in the angle between the bladder neck and the urethra may have a role in emptying improvement in crouching position. these concerns should be more investigated by videourodynamics, pressure flow study, and simultaneous recording of electromyography from pelvic floor and adjacent muscles. conclusion bladder emptying in crouching position is a simple solution for cases with bladder outlet obstruction symptoms and dysfunctional voiding, without any complication. the effects appear immediately and may last for a long time. obstruction improvement following increased intravesical pressure originates from a good transmission of abdominal pressure to the bladder and coordinated complete relaxation of the pelvic floor in crouching. other factors contributing to decrease in bladder outlet resistance such as bladder position in pelvic floor and change of the angle between the bladder and the urethra in crouching should be studied with more complete and precise methods such as videourodynamics and pressure flow study. however, there is fair evidence that makes this voiding position recommendable to patients with bph and dysfunctional voiding to increase flow rate and decrease residue. references 1. abrams p. urodynamics. 2nd ed. london: springerverlag; 1997. p. 8-16. 2. steers wd. physiology and pharmacology of the bladder and urethra. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell's urology. 7th ed. philadelphia: wb saunders; 1998. p. 870-906. 3. sorensen s. urethral pressures during bladder filling. scand j urol nephrol suppl. 1989;125:45-51. 4. wennergren hm, oberg be, sandstedt p. the importance of leg support for relaxation of the pelvic floor muscles. a surface electromyograph study in healthy girls. scand j urol nephrol. 1991;25:205-13. 5. mandal ac. the seated man (homo sedens) the seated work position. theory and practice. appl ergon. 1981;12:19-26. 6. lepor h. natural histoty, evaluation, and nonsurgical management of benign prostatic hyperplasia. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell's urology. 7th ed. philadelphia: wb saunders; 1998. p. 1453-78. 7. presti jc jr. neoplasms of the prostate gland. in: tanagho ea, mcaninch jw, editors. smith's general urology. 15th ed. new york (usa): lange medical books/mcgraw-hill; 2000. p. 399-403. 8. unsal a, cimentepe e. effect of voiding position on uroflowmetric parameters and postvoid residual urine volume in patients with benign prostatic hyperplasia. scand j urol nephrol. 2004;38:240-2. 9. moore kh, richmond dh, sutherst jr, imrie ah, hutton jl. crouching over the toilet seat: prevalence among british gynaecological outpatients and its effect upon micturition. br j obstet gynaecol. 1991;98:569-72. 10. christopher rc, scott am, editors. urodynamics made easy. 2nd ed. philadelphia: wb saunders; 2000, p. 75-95. urol_v03_no3_001_editorial.indd endourology and stone disease 130 urology journal vol 3 no 3 summer 2006 extracorporeal shock wave lithotripsy in prone and supine positions for patients with upper ureteral calculi ali afshar zomorrodi, amirreza elahian, nematollah ghorbani, anahita tavoosi introduction: the aim of this study was to evaluate the treatment of upper ureteral calculi with extracorporeal shock wave lithotripsy (swl) in the supine and prone positions. materials and methods: a total of 68 patients with upper ureteral calculi underwent swl. in 35 patients, the procedure was performed in the supine position (group 1), while in the 33 remainders, it was performed in the prone position (group 2). the stone-free rate, the number of swl sessions required, and the number of shocks per treatment session were compared between the 2 groups. results: the mean calculus size was 12.4 ± 3.1 mm and 12.2 ± 2.9 mm in groups 1 and 2, respectively. the stone-free rate was 81.8% in group 1 and 82.9% in group 2 (p = .91). the number of sessions for achieving the stone-free status was similar in the patients of the 2 groups (1.9 ± 0.8 in group 1 versus 1.9 ± 0.8 in group 2; p = .79). the mean number of shock waves per treatment session was not significantly different between the 2 groups. no major complications were seen and none of the patients required hospitalization, placement of a ureteral catheter, or a double-j stent. conclusion: our study showed that in the prone position, treatment of the upper ureteral calculi by swl is as safe and effective as the supine position. urol j (tehran). 2006;3:130-3. www.uj.unrc.ir keywords: extracorporeal shock wave lithotripsy, upper ureter, urinary calculi, therapy department of urology, imam komeini hospital, tabriz university of medical sciences, tabriz, iran corresponding author: ali afshar zomorrodi, md imam khomeini hospital, tabriz, iran tel: +98 914 114 7229 e-mail: dr_afshar@hotmail.com received march 2006 accepted july 2006 introduction since its initial application in 1980,(1) the indications for extracorporeal shock wave lithotripsy (swl) have rapidly expanded from the kidney calculi to almost all urinary calculi. however, the overall stone-free rates after swl vary from 50% to 87% depending on many factors.(2,3) stone clearance rate after swl is influenced by the size, location, and chemical composition of the calculus as well as the type of the lithotripter. coz and coworkers(3) analyzed the outcome of swl in 2016 urinary tract calculi regarding the site of the calculus. stone-free rates of the lower caliceal calculi and the middle or upper ureteral calculi are less than the overall stone-free rate. limitations in each part of the ureter have urged investigation of the best patient position during swl. some modifications in patient positioning, such as placement in the prone position proposed by jenkins and gillenwater, allow a safe and effective fragmentation of the lower ureteral calculi.(4,5) this approach reduces the negative effect of the pelvic bones on the power transduction of the shock waves to the target.(6) shock wave lithotripsy in prone and supine—afshar zomorrodi et al urology journal vol 3 no 3 summer 2006 131 concerning the calculi of the upper ureter, guidelines of the american urological association (aua) state that swl, percutaneous nephrolithotomy, and ureteroscopic lithotripsy are all acceptable choices for the calculi of 1 cm and larger in adults.(7) however, the best position for an optimal swl is still a controversy. some authors believe that the supine position, the current preferred approach, is cost-effective and has a low morbidity rate,(8,9) but the transverse processes of the vertebrae adjacent to the upper ureter intervene with transmission of the shock wave.(6) few studies have been carried out to compare different positions for swl of the upper ureteral calculi.(10,11) while the prone position may bring about a superior outcome, its potential complications such as perforation of the small intestine must be regarded.(9,12,13) we evaluated the outcome of swl in the patients with upper ureteral calculi sized 1 cm to 2 cm in the supine and prone positions. materials and methods between november 2003 and july 2004, a total of 68 patients with solitary upper ureteral calculus were treated by swl in the supine or prone positions. the location of the calculus was confirmed by intravenous urography or plain abdominal radiography. upper ureteral calculi were defined as those located between the ureteropelvic junction and the upper border of the sacrum. patients with calculi in other parts of the urinary tract and the ones with calculi smaller than 10 mm or larger than 20 mm were excluded from the study. assignment of the patients in either of the groups was done according to the surgeon’s decision; if the stone targeting was possible in the supine position, the patient was treated in this position (group 1), and if it was not possible in the supine position, the patient was treated in the prone position (group 2). the patients provided informed consent before the procedure. lithotripsy was performed by lithostar (siemens, erlangen, germany) under fluoroscopic targeting. two weeks later, a plain abdominal x-ray was taken to assess the fragmentation of the calculus. if no calculus was detected or the residual fragments were 5 mm in diameter or smaller at this stage, the patient would be considered stone free and was asked to return 3 months later for control radiography. if any calculus material larger than 5 mm was revealed, swl was repeated. this procedure would be performed up to 3 times, if needed. the calculus size, number of shock waves per treatment sessions, and number of sessions required for achieving the stone-free status were recorded. calculus size was registered as the maximum diameter measured on plain abdominal radiography. the patients were followed up for at least 3 months and complications were evaluated. the results were analyzed using the student t test, mann-whitney test, and chi-square test, and a p value of less than .05 was considered statistically significant. results of 68 patients who were studied, 47 (69.1%) were men with an age range of 18 to 81 years, and 21 (30.9%) were women aged 24 to 78 years. size of the calculus was 10 to 15 mm in 55 patients (80.8%) and larger than 15 mm in 12 (19.2%). there were 33 patients in group 1 and 35 in group 2. the mean calculus size was 12.4 ± 3.1 mm and 12.2 ± 2.9 mm in groups 1 and 2, respectively. there were no differences in the age, sex, and calculus size between the 2 groups (table). overall, 56 patients (82.4%) became stone free. the stone-free rate was 81.8% in group 1 and 82.9% in group 2 (p = .91). the number of sessions for achieving the stone-free status was similar in the patients of the 2 groups (1.9 ± 0.8 in group 1 versus 1.9 ± 0.8 in group 2; p = .79, mann-whitney test). the mean number of shock waves applied per treatment session was not significantly different between the 2 groups. the clinical characteristics of the patients are demonstrated in table. the patients in both groups had minor complications such as self-limiting hematuria, dysuria, and pain (responding to oral analgesics). none of the patients required hospitalization, placement of a ureteral catheter, or a double-j stent. discussion treatment of the urinary tract calculi has been changed by swl during the recent 15 years.(10,14) today, swl is widely accepted; while, many urologists criticized it when this innovative technique for extracorporeal fragmentation of the kidney calculi shock wave lithotripsy in prone and supine—afshar zomorrodi et al 132 urology journal vol 3 no 3 summer 2006 was presented in 1983 by chaussy.(10) nowadays, there are almost 5500 lithotripters throughout the world.(5) shock wave lithotripsy is reportedly effective and safe in 98% of patients.(11,15) nevertheless, long-term complications and its effect on the reduction of the relapses are still a matter of debate.(16,17) ureteral calculi located above the iliac crest can primarily be candidates for treatment with swl. according to the guidelines of the american urological association, swl, percutaneous nephrolithotripsy, and ureteroscopic lithotripsy are all effective for treating adults with upper ureteral calculi larger than 1 cm.(7) among these techniques, swl is the leastinvasive and most popular one. however, the optimal position for swl of upper ureteral calculi is still a controversy. the supine position is cost-effective and has a low morbidity rate, while the prone position is accompanied by an increased risk of complications and radiation exposure.(8,9,12,13) bowel perforation during swl in the prone position has been reported in a few cases of swl for calculi in different parts of the urinary tract.(9,12,13) furthermore, it has been shown that the number of treatment sessions per patient, number of shock waves per treatment sessions, shock voltage per session, and fluoroscopy time per session are significantly lower in the supine position than in the prone.(8,18,19) in a study on 96 patients with upper urinary tract calculi, goktas and colleagues observed that the patients generally tolerated the supine position better. discomfort on inspiration and expiration and pain localized to the lumbar vertebrae were seen among patients in the prone position. the mean session number per patients was 1.64 ± 0.75 in the supine group and 1. 33 ± 0.59 in the prone group (p = .22).(8) our study failed to show any differences in the numbers of the shock waves and sessions between the supine and prone positions while swl. in addition, we found no remarkable complication during or after the procedure. it is speculated that the transverse processes of the vertebrae adjacent to the upper ureter intervene with shock wave transmission when swl is performed in the conventional supine position.(6) some authors believe in the effectiveness of the prone position, but they have mostly evaluated calculi of the other parts of the ureter.(4,19-21) ahlawat and colleagues evaluated ureteral calculi in 107 renal units treated by lithostar lithotripter. the overall satisfactory clearance was unaffected by the position of the patient during treatment.(19) also, a prone position has been suggested mostly for the distal ureteral and presacral calculi.(20,21) we found that the stone-free rate is acceptable in the patients of group 2, and there was no difference between the 2 groups in this regard. goktas and colleagues showed that the stone-free rates 3 months after swl were 88.3% and 90.6% in the supine and prone groups, respectively (p > .05).(8) thus, it seems that swl in the prone position is as effective as that in the supine position, but the complications require to be investigated more. we could not provide a randomized study and the number of patients participated was limited. however, our findings are indicative of that the prone position can be a good alternative. other positions such as semilateral prone and supine have also been studied.(6) a comprehensive large study is suggested to compare characteristics group 1 (supine) group 2 (prone) p age, y 46.1 ± 16.3 43.6 ± 16.8 .54 sex .49 male 22 (66.7) 26 (74.3) female 11 (33.3) 9 (25.7) calculus size, mm 12.4 ± 3.1 12.2 ± 2.9 .71 in stone-free cases 12.0 ± 3.2 11.4 ± 2.4 .46 in failed cases 14.3 ± 2.3 15.8 ± 2.3 .31 stone-free patients 27 (81.3) 29 (82.4) .91 no of swl sessions 1 12 (36.3) 13 (37.2) 2 11 (33.4) 13 (37.2) 3 10 (30.3) 9 (25.6) .90 shocks per treatment session 6018.2 ± 2857.4 5768.6 ± 3104.2 .73 *values are shown as means ± standard deviations unless otherwise numbers (percents). swl indicates shock wave lithotripsy. clinical and demographic characteristics of the patients who underwent swl in supine and prone positions* shock wave lithotripsy in prone and supine—afshar zomorrodi et al urology journal vol 3 no 3 summer 2006 133 all the possible positions and draw a definite conclusion regarding the efficacy and safety of swl. conclusion our findings showed that the treatment of upper ureteral calculi by swl in the prone position is as safe and effective as the supine position. however, concerns about the complications and costs warrant further studies. moreover, the patient’s preference can influence the decision made by the surgeon. overall, where required, we can attempt the prone position in the swl of the upper ureteral calculi. conflict of interest none declared. references 1. chaussy c, brendel w, schmiedt e. extracorporeally induced destruction of kidney stones by shock waves. lancet. 1980;2:1265-8. 2. rüffer jh, prikler l, ackermann dk. factors of fragment retention after extracorporeal shockwave lithotripsy (eswl). braz j urol. 2002;28: 3-9. 3. coz f, orvieto m, bustos m, et al. extracorporeal shockwave lithotripsy of 2000 urinary calculi with the modulith sl-20: success and failure according to size and location of stones. j endourol. 2000;14:239-46. 4. jenkins ad, gillenwater jy. extracorporeal shock wave lithotripsy in the prone position: treatment of stones in the distal ureter or anomalous kidney. j urol. 1988;139:911-5. 5. tombolini p, ruoppolo m, bellorofonte c, zaatar c, follini m. lithotripsy in the treatment of urinary lithiasis. j nephrol. 2000;13:71-82. 6. hara n, koike h, bilim v, takahashi k, nishiyama t. efficacy of extracorporeal shockwave lithotripsy with patients rotated supine or rotated prone for treating ureteral stones: a case-control study. j endourol. 2006;20:170-4. 7. segura jw, preminger gm, assimos dg, et al. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. the american urological association. j urol. 1997;158: 1915-21. 8. goktas s, peskircioglu l, tahmaz l, kibar y, erduran d, harmankaya c. is there significance of the choice of prone versus supine position in the treatment of proximal ureter stones with extracorporeal shock wave lithotripsy? eur urol. 2000;38:618-20. 9. kurtz v, muller-sorg m, federmann g. perforation of the small intestine after nephro-uretero-lithotripsy by eswl—a rare complication. chirurg. 1999;70:306-7. 10. chaussy c, schmiedt e, jocham d, brendel w, forssmann b, walther v. first clinical experience with extracorporeally induced destruction of kidney stones by shock waves. j urol. 1982;127:417-20. 11. lingeman je, woods j, toth pd, evan ap, mcateer ja. the role of lithotripsy and its side effects. j urol. 1989;141:793-7. 12. kajikawa t, nozawa t, owari y, et al. [bowel perforation after extracorporeal shock wave lithotripsy: a case report]. nippon hinyokika gakkai zasshi. 2001;92:586-8. japanese. 13. rodrigues netto n jr, ikonomidis ja, longo ja, rodrigues netto m. small-bowel perforation after shockwave lithotripsy. j endourol. 2003;17:719-20. 14. drach gw, dretler s, fair w, et al. report of the united states cooperative study of extracorporeal shock wave lithotripsy. j urol. 1986;135:1127-33. 15. wilson wt, preminger gm. extracorporeal shock wave lithotripsy. an update. urol clin north am. 1990;17:231-42. 16. chaussy cg, fuchs gj. side effects and complications of extracorporeal shock-wave lithotripsy. curr opin urol. 1993;3:323. 17. tolley da, downey p. current advances in shock wave lithotripsy. curr opin urol. 1999;9:319-23. 18. guntekin e, kukul e, kayacan z, baykara m, sevuk m. morbidity associated with patient positioning in extracorporeal shock wave lithotripsy of distal ureteral calculi. int urol nephrol. 1994;26:13-6. 19. ahlawat rk, bhandari m, kumar a, kapoor r. treatment of ureteral calculi with extracorporeal shock wave lithotripsy using the lithostar device. j urol. 1991;146:737-41. 20. amiel j, touabi k, peyrottes a, toubol j. [extracorporeal piezoelectric lithotripsy in the treatment of calculi of the ureter. apropos of a series of 143 cases]. ann urol. 1990;24:135-9. french. 21. jenkins ad. dornier extracorporeal shock-wave lithotripsy for ureteral stones. urol clin north am. 1988;15:377-84. endourology and stone diseases arterial injury during percutaneous nephrostomy: angiography findings from an isolated porcine kidney model houmeng yang,1,2 guobin weng,2 xuping yao,2 chunbo tang,2 yuxi shan1* purpose: to investigate the extent of renal arterial injury incurred by different size of nephrostomy tracts from 10 french (f) to 32f in vitro porcine kidney. materials and methods: to simulate the technique of percutaneous nephrostomy we set up 12 groups of different size nephrostomy tracts from 10f to 32f, including 40 nephrostomy tracts in each group. digital subtraction angiography (dsa) was used to inspect and analysis of arterial injury. results: when the size of nephrostomy tracts is increased from 10f to 32f, the degree of arterial injury is also aggravated. with 14f compared to 24f, the number of nephrostomy tracts with serious arterial injury was 12 (12/40) and 23 (23/40), respectively (p < .05). with 18f compared to 30f, the number of nephrostomy tracts with serious arterial injury was 16 (16/40) and 30 (28/40), respectively (p < .01). conclusion: when the size of nephrostomy tract is increased, the degree of renal arterial injury is also heightened. when 18f tracts was compared to 30f tracts and 14f tracts compared to 24f tracts, obvious reduction of arterial injury is observed. keywords: nephrostomy, percutaneous; kidney; angiography, digital subtraction; hemorrhage; animal. introduction percutaneous nephrolithotomy (pcnl) is a well-es-tablished treatment option for managing upper urinary tract stones.(1,2) despite advances in equipment and increased experience with this treatment, renal hemorrhage remains the most concerning complication of pcnl. the reported transfusion rate following pcnl in the literature ranges from 8-37%.(3-5) although most patients with bleeding can be managed conservatively, severe hemorrhage is occasionally life-threatening, and nephrectomy is occasionally required in cases of failed angiography and embolization.(6) massive hemorrhage is a severe complication following pcnl and is one of the classical indication of selective artery embolization (sae), which has a high success rate, and the reported frequency of severe hemorrhage requiring sae after pcnl is 0.3-1.5%.(6-10) over the past decades, modifications to the conventional pcnl technique have been made to decrease morbidity. in 1997, jackman and colleagues(11) initially described the “mini-pcnl” technique in children using an 11f peel-away vascular access sheath. lahme and colleagues(12) also reported their experience with mini-pcnl in 2001. small pncl tracts are believed to cause less trauma to kidney than standard pcnl tracts, but rare studies have confirmed this hypothesis. angiography is a good method to evaluate vascular injury following percutaneous nephrostomy and for demonstrating the tracts associated with trauma. routine angiography following pcnl is unrealistic and inhumane; therefore, isolated porcine kidneys from sacrificed miniature pigs were used as a model for evaluating with angiography. to our best knowledge, this is the first report to investigate arterial injury following percutaneous nephrostomy based on angiography findings in an isolated porcine kidney model. this study evaluated the trauma from differently sized percutaneous nephrostomy tracts. materials and methods study subjects this study was performed in strict accordance with the recommendations in the guide for the care and use of laboratory animals of the national institutes of health. the protocol was approved by the committee on the ethics of animal experiments of the university of ningbo. the materials were fresh in vitro kidneys taken from mixed breed adult farm pigs slaughtered at 4 to 5 1 department of urology, the second affiliated hospital of soochow university, sanxiang road 1055, suzhou, 215004, china. 2 department of urology, ningbo urologic and nephrotic hospital, qianhe road 1, ningbo 315000, china. *correspondence: department of urology, the second affiliated hospital of soochow university, sanxiang road 1055, suzhou 215004, china. tel: +86 137 32112880. fax: +86 0574 83038510. e-mail: yhm0130@sohu.com. received february 2015 & accepted november 2015 vol 12 no 06 november-december 2015 2396 months of age and 60 to 90 kg of weight. the kidneys were 160 ± 10 g, whose length, width, and thickness were 14.0 ± 1.0 cm, 6.5 ± 0.5 cm and 3.2 ± 0.2 cm, respectively. percutaneous nephrostomy was performed in the upper, middle, and lower part in each kidney. the vascular system was completely perfused with heparin and physiological saline and then fixed on the bench. percutaneous nephrostomy was performed in a manner similar to pcnl in human patients. an 18 gauge needle was punctured into the targeted calyx, and then, a 0.038 inch guide wire was inserted through the needle into the renal pelvis. the nephrostomy tract was dilated with fascial dilators (cook urological, spencer, in, usa) from the cortex to the pelvis along the guide wire. then, from 10f to 32f, 12 groups with nephrostomy tracts were established, with each group including of 40 nephrostomy tracts. the kidney artery was then connected to the angiography system, and digital subtraction angiography (dsa) was performed to identify arterial injuries. evaluation and statistical analysis during angiography, the nephrostomy tracts with obvious contrast agent are considered as renal arterial injury (figure 1). the incidences of arterial injury were recorded and compared between the groups. statistical analyses were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. categorical variables between the two groups were compared with a chi-squared test. a p value less than .05 was considered statistically significant. results a total of 480 tracts were established in 12 groups, with 40 tracts in each group. when from 10f to 32f were compared, arterial injury is increased with increasing tract diameter (figure 2). when we compared 14f to 24f, the number of nephrostomy tracts with serious arterial injury was 12 (12/40) and 23 (23/40), respectively (χ2 = 6.15, p < .05). when 18f compared with 30f, the number of nephrostomy tracts with serious arterial injury was 16 (16/40) and 30 (28/40), respectively (χ2 = 7.27, p < .01). discussion trauma from percutaneous tracts to the kidney is one of the most frequently concerning issues in pcnl due to the potential risk of post-pcnl severe hemorrhage and related renal function damage. the risk of blood loss in pcnl depends on a variety of factors, including general patient condition, stone burden, operative technique, and experience. kukreja and colleagues prospective evaluated factors affecting blood loss during pcnl.(4) they reported that, diabetes, multiple tract procedures, prolonged operation time and intraoperative complications were associated with significantly greater blood loss. turna and colleagues(2) performed a prospective study with multivariate regression analysis; they identified five significant factors that figure 1. the upper nephrostomy tract with obvious contrast agent is considered as renal arterial injury. figure 2. the relationship between the size of nephrostomy tract and renal arterial injury. arterial injury during percutaneous nephrostomy-yang et al. endourology and stone diseases 2397 influenced pcnl related hemorrhage: stone type, tract number, dilation method, diabetes and stone surface area. upper calyceal puncture, solitary kidney, staghorn stone, multiple punctures and an inexperienced surgeon were also significant risk factors for severe bleeding. (3) an increased percutaneous tract size potentially induced lacerations to vessels during dilation during the pcnl procedures. the elastic reaction of the vessels affect blood loss during percutaneous nephrostomy. clayman and colleagues(13) and traxer and colleagues(14) examined the extent of renal damage caused by different nephrostomy tract dilatation sizes in pigs and found that the mean scar volume was 0.294-0.43 mm3 and that the ratio to total kidney volume was 0.13-0.16%. no significant differences were noted. in a clinical study, li and colleagues did not observe significant advantages of mini-pcnl in terms of reduced surgical trauma and associated invasiveness compared with standard pcnl based on determination of acute-phase markers, namely tumor necrosis factor-alpha (tnf-alpha), interleukin-6 (il-6), il-10, c-reactive protein (crp), and serum amyloid a (saa).(15) unfortunately, the immediate effects of percutaneous nephrostomy tracts on kidney vessels have not yet been determined. but, in the recent literature, miniperc and ultraminiperc (ump) are associated with similar clearance rate as the standard pcnl but they are associated with decreased hemoglobin drop, hospital stay, analgesic requirement, and complication rates.(16-18) in this study, we investigated the extent of renal arterial injury incurred by different size of nephrostomy tracts in vitro porcine kidney. we found that the fascial dilators gradually pushed the renal artery and parenchymal away during the dilation procedures. in the range of 10f to 32f, the number of nephrostomy tracts with evident arterial injury increased as the tract diameter enlarged. it is notable that the number of tracts with evident arterial injury was half the total in the group of 22f tracts. decreasing the tract size will further decrease the complications while maintaining similar stone-free rate. this is the basis to further narrow the tract size. the ump technique is normally always use tract small than 14f, but the 24f tract is normally used in standard pcnl. in this study, we found that the number of tracts with arterial injury in 14f and 24f groups was 12 (12/40) and 23 (23/40), respectively, and the incidence of arterial injury was significantly different between two groups (p < .05). the 18f percutaneous tract is universally used in china as a chinese mini-pcnl. the 30f tract is the commonly used big tract in worldwide practices. in this study, we found that 18f tracts induced fewer renal arterial injury than 30f tracts. the limitation of this study is that the vessels of isolated porcine kidneys lack of plasma thromboplastin component and complete elasticity compared with kidneys in vivo. to confirm our present findings, a study based on porcine kidneys in vivo is required. conclusions our findings indicate that the renal arterial injury is aggravated when the nephrostomy tract grows bigger, and it is of proven advantage to use smaller nephrostomy tracts to prevent renal arterial injury. conflict of interest none declared. references 1. antonelli ja, pearle ms. advances in percutaneous nephrolithotomy. urol clin north am. 2013;40:99-113. 2. tefekli a, cordeiro e, de la rosette jj. an update on percutaneous nephrolithotomy: lessons learned from the croes pcnl global study. minerva med. 2013;104:1-21. 3. srivastava a, singh kj, suri a, et al. vascular complications after percutaneous nephrolithotomy: are there any predictive factors? urology. 2005,66:38-40. 4. kukreja r, desai m, patel s, bapat s, desai m. factors affecting blood loss during percutaneous nephrolithotomy: prospective study. j endourol. 2004;18:715-22. 5. silverstein ad, terranova sa, auge bk, et al. bilateral renal calculi: assessment of staged v synchronous percutaneous nephrolithotomy. j endourol . 2004;18:145-51. 6. pappas p, leonardou p, papadoukakis s, et al. urgent superselective segmental renal artery embolization in the treatment of lifethreatening renal hemorrhage. urol int. 2006;77:34-41. 7. richstone l, reggio e, ost mc, et al. first prize (tie): hemorrhage following percutaneous renal surgery: characterization of angiographic findings. j endourol. 2008;22:29-1135. 8. martin x, murat fj, feitosa lc, et al. severe bleeding after nephrolithotomy: results of hyperselective embolization. eur urol. 2000,37:136-9. 9. kessaris dnn, bellman gc, pardalidis np, smith ag. management of hemorrhage after percutaneous renal surgery. j urol. 1995;153:604-8. 10. gupta m, bellman gc, smith ad. massive hemorrhage from renal vein injury during percutaneous renal surgery: endourological management. j urol. 1997;157:795-7. arterial injury during percutaneous nephrostomy-yang et al. vol 12 no 06 november-december 2015 2398 11. jackman sv, docimo sg, cadeddu ja, bishoff jt, kavoussi lr, jarrett tw. the “mini-perc” technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol. 1998;16:371-4. 12. lahme s, bichler kh, strohmaier wl, götz t. minimally invasive pcnl in patients with pelvic and calyceal stones. eur urol. 2001;40:619-24. 13. clayman rv, elbers j, miller rp, williamson j, mckeel d, wassynger w. percutaneous nephrostomy: assessment of renal damage associated with semi-rigid (24f) and balloons (36f) dilation. j urol. 1987;138:203-6. 14. traxer o, smith tg 3rd, pearle ms, corwin ts, saboorian h, cadeddu ja. renal parenchymal injury after standard and mini percutaneous nephrostolithotomy. j urol. 2001;165:1693-5. 15. li ly, gao x, yang m, et al. does a smaller tract in percutaneous nephrolithotomy contribute to less invasiveness? a prospective comparative study. urology. 2010;75:56-61. 16. yamaguchi a, skolarikos a, buchholz np, et al. clinical research office of the endourological society percutaneous nephrolithotomy study group. operating times and bleeding complications in percutaneous nephrolithotomy: a comparison of tract dilation methods in 5537 patients in the clinical research office of the endourological society percutaneous nephrolithotomy global study. j endourol. 2011;25:933-9. 17. knoll t, wezel f, michel ms, honeck p, wendt-nordahl g. do patients benefit from miniaturized tubeless percutaneous nephrolithotomy? a comparative prospective study. j endourol. 2010;24:1075-9. 18. mishra s, sharma r, garg c, kurien a, sabnis r, desai m. prospective comparative study of miniperc and standard pnl for treatment of 1 to 2 cm size renal stone. bju int. 2011;108:896-9. arterial injury during percutaneous nephrostomy-yang et al. endourology and stone diseases 2399 1203vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l 1 department of radiology, necmettin erbakan university, meram faculty of medicine, konya, turkey. 2 department of urology, necmettin erbakan university, meram faculty of medicine, konya, turkey. corresponding author: abdussamet batur, md department of radiology, necmettin erbakan university, meram faculty of medicine, konya, 42080, turkey. tel: +90 332 2236337 fax: +90 332 2236181 e-mail: drsamet56@yahoo.com a 22-year-old male patient had admitted with pelvic pain and he-matospermia. there was no pathology on physical examination and blood tests. deformation ratio of sperms was 86% and motility disorder ratio was 72% on semen analysis. computed tomography (ct) scan revealed the lesion as a mass with 26 hounsfield unit (hu) density. separation of solid-cystic initially failed,where upon magnetic resonance imaging (mri) was performed. ct and mr pyelography showed an absent left kidney (figure 1) accompanying cystic lesion in the high internal density located to the left posterio-lateral of the bladder (figure 2). mri examination of the lesion revealed cystic dilatation of left seminal vesicle with hyperintense signal changes on both t1 and t2 weighted images indicating a high content of protein (figure 3). right seminal vesicle was normal. the patient underwent diagnostic cystoscopy and there was no left ureteral orifice. seminal vesicle cyst was surgically removed. seminal vesicle cysts (svc) are seen with a prevalence of less than 0.005%. (1) patients usually present with irritative or obstructive voiding symptoms. (2) they are usually detected in patients between 18 and 41 years of age, the period of maximal sexual and reproductive activity.(3) in about two-thirds of the patients with svc, ipsilateral renal agenesis was also found.(1) congenital seminal vesicle cyst accompanying ipsilateral renal and ureteral agenesis pictorial urology figure 1. left renal agenesis (blue arrow) and compensatory hypertrophy of right kidney (red arrow) on contrast-enhanced computed tomography (a) and magnetic resonance pyelography (b). figure 2. contrast-enhanced tomography: seminal vesicle cyst (arrows) in the high internal density (26 hu). figure 3. a) coronal t2 weighted image demonstrates dilated ejaculatory duct (blue arrow), and b) axial t1 weighted image demonstrates cystic dilatation of left seminal vesicle (red arrows) with hyperintense signal change. abdussamet batur,1 serdar karakose,1 giray karalezli2 references 1. kosan m, tul m, inal g, ugurlu o, adsan o. a large seminal vesicle cyst with contralateral renal agenesis. int urol nephrol. 2006;38:591-2. 2. cihan a, cimen s, secil m, kefi a, aslan g. congenital seminal vesicle cyst accompanying ipsilateral renal agenesis and rudimentary ureter. int urol nephrol. 2006;38:133-5. 3. tadeu f, rocha a. semen analysis in an infertile man with seminal vesicles cysts associated with ipsilateral renal agenesis. int urol nephrol. 2006;38:101-3. 1362 | renal autotransplantation in postchemotherapy retroperitoneal lymph node dissection: a case report abbas basiri, nasser shakhsesalim, mahmood reza nasiri, mohammad hadi radfar keywords: kidney transplantation; humans; case reports; lymph node excision; testicular neoplasms; retroperitoneal space. introduction retroperitoneal lymph node dissection (rplnd) is a critical modality in the manage-ment of testicular cancer performed in two main settings; primary and postchemother-apy.(1) postchemotherapy rplnd is generally associated with an increased incidence of major complications compared to primary one.(2) renal vessels and ureter injuries during rplnd could lead to nephrectomy in some patients. renal autotransplantation is a kidney saving procedure enabling the surgeon to avoid imperative nephrectomy or high diversion of urinary system in complicated cases.(3) to our knowledge, there is only one case report describing renal autotransplantation as an adjunctive surgery in a patient who underwent rplnd.(4) case report a 38-year-old man with a history of mixed germ cell tumor in his left undescended testis was referred to our institute. he had undergone left radical orchiectomy two years previously. the tumor pathology was mixed germ cell tumor containing embryonal carcinoma and immature corresponding author: mohammad hadi radfar, md department of urology, urology and nephrology research center, shahid labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. tel: +98 21 2254 1185 e-mail: mhadirad@yahoo.com received august 2012 accepted march 2013 urology and nephrology research center, department of urology, shahid labbafinejad hospital, shahid beheshti university, tehran, iran. case report case report 1363vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l renal autotransplantation in postchemotherapy rplnd | basiri et al teratoma. postoperatively, tumor markers remained elevated, and computed tomography (ct) scan revealed a retroperitoneal mass measured 70 × 85 mm. after receiving four courses of chemotherapy, tumor markers normalized but retroperitoneal mass did not change. the mass was located in the left paraaortic area, adjacent to the left renal hilum (figure 1). the patient was scheduled for rplnd. after a thoracoabdominal incision, it was revealed that the tumor was severely adhesive to the psoas muscle. furthermore, left renal artery, vein, and ureter were encroached by the tumor. after very difficult dissection of the tumor from psoas muscle and aorta, it was impossible to separate the mass from renal vessels and ureter (figure 2). since the kidney itself was not involved by the tumor, we decided to perform renal autotransplantation. after clamping renal vessels and cutting the ureter in an uninvolved portion, en bloc removal of the kidney, ureter, and the mass was performed. the removed specimen was totally placed in cold normal saline, and intravascular washing of the kidney with cold kidney-preserving solution (ringer lactate serum, heparin, sodium bicarbonate, and lidocaine) was started. tumor was separated from the kidney and uninvolved proximal portions of the renal vessels and ureter (figure 3). the kidney was placed in the contralateral iliac fossa because of tissue adhesion and extensive dissection of ipsilateral pelvic cavity. due to shortness of the renal vein, the kidney was rotated upside-down. renal artery and vein were anastomosed to right common iliac artery and vein, respectively. cold ischemic time was 20 minutes. since we had to remove a significant length of the middle ureter, ureter was shortened and its direction was upward. we decided to anatomize distal part of the left ureter to the proximal right ureter. frozen section and permanent pathology of the margins were negative. complete bilateral rplnd was carried out. pathology report revealed embryonal carcinoma and immature teratoma. the patient was followed three months postoperatively with ct scan, laboratory tests including serum tumor markers and creatinine, intravenous urography (ivu), and diethylene triamine pentaacetic acid (dtpa) scan. serum tumor markers and creatinine were normal. ivu and dtpa illustrated normal functioning transplanted kidney (figure 4). discussion rplnd, as a crucial step in the testicular cancer management, and is associated with some complications. baniel and colleagues reported complication rate of 10.6% for primary rplnd, and 20.7% in postchemotherapy rplnd.(5) intraoperative complications and need for additional procedures have been reported to occur in 11%-51.9% of postchemotherapy rplnd (pc-rplnd) patients in different studies. (2,6) intraoperative complications/additional procedures in pc-rplnd include nephrectomy, vascular injury, inferior vena cava (ivc) resection, ivc prosthesis, aortic replacement, arterial graft, orchiectomy, bowel resection, hepatic resection/biopsy, caval thrombectomy, adrenalectomy, cholecystectomy, ureteral resection with end-to-end anastomosis, figure 1. preoperative computed tomography scan showed the tumor adjacent to the renal pedicle. 1364 | case report and ureteral reimplantation.(2,6) the most common additional procedure in pc-rplnd is en bloc nephrectomy followed by vascular procedures.(6) in a report on en bloc nephrectomy in pc-rplnd patients published by nash and colleagues, indications of nephrectomy included contiguous involvement of perirenal structures in 73%, renal vein thrombosis in 6%, and a combination of these conditions in 16% of patients.(7) kapoor and colleagues described a case of renal arterial injury to a solitary kidney during pc-rplnd. they performed aortorenal revascularization and saved the patient’s kidney. (8) renal autotransplantation is applied in complex urological reconstructions to avoid nephrectomy, but is reported in only one rplnd patient. outcomes of renal autotransplantation have showed that it is an effective treatment to save the kidney when in situ techniques are not feasible.(9) in urological oncology, renal autotransplantation has been applied mainly in renal cell carcinoma or urothelial tumors of the upper tract being present bilaterally or in a solitary kidney. there is only one report of performing renal autotransplantation in a rplnd patient. kobayashi and colleagues reported a pc-rplnd patient in whom left renal artery was involved by a lymph node; renal function was impaired postoperatively but returned to normal in a short time.(4) we presented our experience in a pcfigure 2. intraoperative view shows the mass adhered to renal hilum and ureter. figure 4. postoperative intravenous urography showed functional transplanted kidney. figure 3. in-vitro dissection of the renal hilum and separating it from the mass. 1365vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l rplnd patient with involvement of renal vessels and ureter that made in situ vascular surgery impossible. preserving the kidney was very important here due to the probable need for future nephrotoxic chemotherapy. conclusion regarding the incidence of need for nephrectomy in pcrplnd, considering renal autotransplantation might be a solution to avoid ablative surgery in some instances. conflict of interest none declared. references 1. subramanian vs, nguyen ct, stephenson aj, klein ea. complications of open primary and post-chemotherapy retroperitoneal lymph node dissection for testicular cancer. urol oncol. 2010;28:504-9. 2. mosharafa aa, foster rs, koch mo, bihrle r, donohue jp. complications of post-chemotherapy retroperitoneal lymph node dissection for testis cancer. j urol. 2004;171:1839-41. 3. wotkowicz c, libertino ja. renal autotransplantation. bju int. 2004;93:253-7. 4. kobayashi y, sekihara t, nakamura m, et al. retroperitoneal lymph node dissection for testicular tumor with renal autotransplantation: a case report. hinyokika kiyo. 1990;36:359-62. 5. baniel j, sella a. complications of retroperitoneal lymph node dissection in testicular cancer: primary and post-chemotherapy. semin surg oncol. 1999;17:263-7. 6. heidenreich a, thuer d, polyakov s. postchemotherapy retroperitoneal lymph node dissection in advanced germ cell tumours of the testis. eur urol. 2008;53:260-72. 7. nash pa, leibovitch i, foster rs, bihrle r, rowland rg, donohue jp. en bloc nephrectomy in patients undergoing post-chemotherapy retroperitoneal lymph node dissection for non-seminomatous testis cancer: indications, implications and outcomes. j urol. 1998;159:707-10. 8. kapoor a, zippe c, gill is. emergency aortorenal revascularization during salvage retroperitoneal lymph node dissection. j urol. 1999:162:1377-8. 9. novick ac, jackson cl, straffon ra. the role of renal autotransplantation in complex urological reconstruction. j urol. 1990;143:452-7. renal autotransplantation in postchemotherapy rplnd | basiri et al review 73urology journal vol 6 no 2 spring 2009 supine percutaneous nephrolithotomy, is it really effective? a systematic review of literature abbas basiri, mehrdad mohammadi sichani introduction: this systematic review was performed to determine the clinical value of percutaneous nephrolithotomy in the supine position in comparison with the convention of performing the procedure in the prone position. materials and methods: a systematic review of the medical literature was conducted searching for studies on percutaneous nephrolithotomy in the supine position, limited to publications appeared in the pubmed between 1980 and july 2008. non-english articles were considered if deemed relevant by providing additional data. in the retrieved articles, reference lists were hand-searched to identify additional relevant articles. results: there were 9 original articles on percutaneous nephrolithotomy in the supine position. five studies were retrospective and 4 were prospective, of which only 1 was a well-designed randomized controlled trial published in 2008. the success rate of the procedure was reported between 69.6% and 95%. the risk of requiring blood transfusion was between zero and 8%. duration of hospital stay was variable, but generally less than that in the prone position. no colon perforation was reported. conclusion: in carefully selected patients with uncomplicated urinary calculi, percutaneous calculus removal in the supine position can yield similar outcomes to that in the prone position. urol j. 2009;6:73-7. www.uj.unrc.ir keywords: kidney calculi, surgical procedures, percutaneous nephrostomy, methods, supine position, prone position department of urology, shahid labbafinejad medical center and urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: mehrdad mohammadi sichani, md urology and nephrology research center, no 44, 9th boustan, pasdaran, tehran 1666668111, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: m_mohammadi@med.mui.ac.ir introduction percutaneous nephrolithotomy (pcnl) is usually performed in the prone position. this approach, however, has some disadvantages; first, it compromises blood circulation and ventilation, especially in obese patients (limitation in respiratory movement).(1,2) second, position changes during the procedure is inevitable, because preplacement of a ureteral catheter is commonly required in the dorsal lithotomy position before turning the patient to the prone position. these prolong duration of the procedure.(3) third, if the procedure is carried out under spinal or epidural anesthesia, conversion to general anesthesia with endotracheal intubation will represent a great challenge to the anesthetist.(1,4) fourth, sometimes it is impossible for the patient to lie prone because of body habitus such as ankylosing spondylitis, severe lordosis or kyphosis, or hip or lower limb contractures.(5) fifth, operating on a patient in the prone position, the surgical team stands in close proximity to the patient, making them relatively more vulnerable to radiation exposure. whereas supine percutaneous nephrolithotomy—basiri and mohammadi sichani 74 urology journal vol 6 no 2 spring 2009 in the supine position, the bodies and limbs of the surgical team remain outside the field of the fluoroscope.(4) finally, the prone position is especially dangerous in patients with severe cervical spondylosis, and care of the pressure area is problematic. to overcome these drawbacks and simplify the procedure, pcnl in the supine position has also been described.(1) this approach has also certain disadvantages that make it a disputable alternative. the first problem with the supine position is that there is not enough space for a third tract if needed.(6) also, access to the anterior and upper calyxes is more difficult; as the angle between the plane of the operation table and the anterior calyxes is smaller than that in other positions, it is difficult to access the calculi in the anterior calyxes.(1,5,6) approaching the upper calyx, especially if placed excessively medially is more difficult in supine position, as well.(4,7) this problems is more pronounced on the left side. of other drawbacks of pcnl in the supine position is the mobility of kidneys which is more than that in the prone position. therefore, the kidneys are easy to move anteromedially during tract dilation in the supine position.(1,4,6) finally, the pyelocaliceal system is constantly collapsed in this position, and consequently, nephroscopy is more difficult.(7) some limited studies have tries to clarify the safety and efficacy of pcnl in the supine position; however, there is not consensus on its outcome, yet. the aim of this study was to review the published original articles on pcnl in the supine position, and to systematically analyze their reported results. materials and methods we searched the pubmed for articles published between 1980 and july 2008 using the mesh terms percutaneous, nephrolithotomy, nephrolithotripsy, and supine. the reference list of the retrieved articles was additionally studied to identify any relevant articles. letters to editors or congress abstracts were excluded, and non-english articles were considered if deemed relevant by providing additional data. thereafter, we read all of the retrieved articles and designed a table to determine the study sample, study design, success rate, hospital stay, and reported complications of the studies. the results were compared, summed up, and discussed. results we found 9 published original articles on pcnl in the supine position,(1,4-10) the data of which are summarized in tables 1 to 3. the overall number sample size study publication year supine prone study design inclusion/exclusion criteria success rate, % anesthesia valdivia uria et al(10) 1998 557 … retrospective calculi, tumors, upjos 93 is shoma et al(1) 2002 53 77 clinical trial all sizes of calculi 89 sa║ ng et al(7) 2004 62 … retrospective all sizes of calculi 76 ga or high sa steele and marshall(11) 2007 322 … clinical trial all sizes of calculi 91 ga or high sa manohar et al(9) 2007 62 … retrospective all sizes of calculi, high-risk patients† 95 ga and ea neto et al(8) 2007 88 … clinical trial all sizes of calculi 70.5 not mentioned zhou et al(6) 2008 92 … retrospective all sizes of calculi 69.6‡ sa and ea rana et al(4) 2008 184 … retrospective all sizes of calculi 84 § ga de sio et al(5) 2008 39 36 rct multiple and staghorn calculi excluded 88.7 ga table 1. studies on supine position in percutaneous nephrolithotomy* *rct indicates randomized controlled trial; upjo, ureteropelvic junction obstruction; is, intravenous sedation; sa, spinal anesthesia; ga, general anesthesia; and ea, epidural anesthesia. ellipses indicate not applicable. †only patients with american society of anesthesiologists grades 3 and 4 were included. ‡primary calculus clearance rate. §total calculus clearance rate. ║two cases were converted to general anesthesia. supine percutaneous nephrolithotomy—basiri and mohammadi sichani urology journal vol 6 no 2 spring 2009 75 of patients with pcnl in the supine position was 1459 in these studies. the technique of procedure was nearly similar; they put the patient in the supine position with a water bag below the ipsilateral flank. thus, the flank was elevated up to 20 degrees, causing the posterior calyx to project more laterally, often becoming parallel (30 degrees) to the fluoroscopy table. a retrograde ureteral catheter was fixed through the ipsilateral ureteral orifice. the skin was punctured in the posterior axillary line, 1 cm below the last rib, for a lower caliceal puncture, and above the last rib, for an upper caliceal one. they used either c-arm fluoroscopy or ultrasonography for the first access and tract dilation.(3-11) the tract was dilated using balloon, plastic, or metal telescopic dilators (table 2). the calculi were then fragmented and extracted. a 22-f nephrostomy tube was fixed at the end of the procedure in most studies. the first report in this field belongs to valdivia uria and colleagues who performed more than 500 nephroscopies in the supine position. they included not only urinary calculi, but also ureteropelvic junction obstruction and ureteral tumors in their study. the aim of the study was to show possibility and safety of pcnl and the other procedures in the supine technique. significant blood loss that required transfusion was reported only in 8 cases. the colon and the pleura were not damaged in any of the patients. they used intravenous sedation with diazepam, buprenorphine, atropine, and occasionally, ethinamate. the patients were conscious during the procedure.(10) shoma and coworkers compared the results of pcnl in the supine and prone positions. their study was not randomized. however, the preoperative parameters of the two groups were comparable. the mean hospital stay, retreatment rate, success rate, and complications study mean hospital stay, d operative time, min double-j catheter insertion intraoperative imaging lithotripter dilator valdivia uria et al(10) … 15 to 240 … fluoroscopy … alken shoma et al(1) 2.5 … 2 cases with leak fluoroscopy pneumatic ultrasound plastic telescopic ng et al(7) 8.7 … … us and fluoroscopy pneumatic metal telescopic steele and marshall(11) 6 † 15 to 300 usually fluoroscopy pneumatic holmium balloon manohar et al(9) … 20 to 250 all patients us and fluoroscopy … alken neto et al(8) 5.4 60 to 300 if residual is significant fluoroscopy pneumatic ultrasound metal zhou et al(6) … 45 to 350 all patients us pneumatic holmium telescopic (up to 16 f) rana et al(4) 2 45 to 110 10% of patients fluoroscopy pneumatic alken de sio et al(5) 4.3 25 to 120 … fluoroscopy ultrasound alken table 2. operative data of studies on supine position in percutaneous nephrolithotomy* *ellipses indicate not available. us indicates ultrasonography. †six days with double-j catheter and 3 days without double-j catheter. study transfusion rate, % embolization, % pleural injury, % valdivia uria et al(10) 1.4 0.5† 0 shoma et al(1) 9.4 … 0 ng et al(7) 3.2 0 0 steele and marshall(11) 3.7 0.3 0 manohar et al(9) 3.2 0 0 neto et al(8) 7.9 2.3 0 zhou et al(6) 1.0 … 0 rana et al(4) 3.8 … 0.5 de sio et al(5) 0 0 0 table 3. complications of supine position in percutaneous nephrolithotomy* *ellipses indicate not available. †one patient underwent open hemostasis; 1, nephrectomy; and 1, embolization. supine percutaneous nephrolithotomy—basiri and mohammadi sichani 76 urology journal vol 6 no 2 spring 2009 were not significantly different between the two groups. it is important to note that they had only 3 staghorn calculi in each group.(1) zhou and colleagues evaluated the clinical value of the realtime ultrasonography-guided minimally invasive pcnl technique in the supine position. it is one of the studies that used ultrasonography to access the system.(6) de sio and associates published a well-designed, randomized controlled trial that compared the supine and prone positions. transfusion rate and other complications were similar, but the operative time was significantly shorter in the supine position.(5) colon injury was not reported in any of the reviewed studies. discussion percutaneous nephrolithotomy is traditionally performed in the prone position for a safe approach to the kidney. nevertheless, acute bleeding requiring blood transfusion in 3% to 12%, delayed hemorrhage in less than 1%, and bowel perforation in 0.2% to 0.5% of the patients are the major concerns in this approach.(12-14) moreover, the prone position has some inherent drawbacks which were discussed here earlier. as a consequence, modified supine pcnl positions were suggested to overcome such problems.(10) some aspects and concerns about the supine position are discussed below based on the reviewed articles: colonic injuries there had been concerns that the supine approach may have put the colon at a higher risk of injury than the prone position. in all the published studies on 1459 cases, there was no colonic injury in patients treated in the supine position. the contemporary data regarding pcnl with the patient in the supine position has not yet reported a single incidence of injury to the colon. transfusion rate valdivia uria and coworkers(10) reported the rate of serious bleeding requiring transfusion to be about 1.5%. ng and colleagues(7) reported a rate of 3%, and shoma and colleagues(1) reported a rate of 9%, but attributed it to their learning curve. rana and colleagues reported a rate of 3.8% for bleedings that required transfusion,(4) which was directly related to the calculus size, procedure duration, and creation of multiple tracts. in contrast to all assumptions, the risk of bleeding with the supine position must be less. obstruction of the inferior vena cava during pcnl in the prone position and backflow of blood to the renal vein may explain why bleeding in the prone position is more likely than in the supine position. success rate methods for assessment of stone-free rate varied between the reviewed studies. nephroscopy, noncontrast computed tomography, plain radiography, and ultrasonography are all mentioned. it is clear that in this condition, it is impossible to compare the data. on the other hand, the size of calculi was variable, although the authors mentioned that they included calculi with all sizes, staghorn calculi were constituted a small percentage of the cases in most studies. success rate is dependent on many factors; hence, only in prospective randomized studies, we can determine the efficacy of supine pcnl unquestionably. in their randomized controlled study, de sio and colleagues reported that the stone-free rate was good in both groups of pcnl in the spine and prone positions (88.7% versus 91.6%, respectively; p = .12).(5) shoma and coworkers,(1) in the only prospective nonrandomized study published so far, reported similar results for the supine and prone positions (89% versus 84%, respectively). however, we should consider some limitations in the supine position as well; it is obvious that lateral deflection of the rigid nephroscope into an anterior calyx is difficult because of the side of the bed. then, it is predictable to use flexible nephroscope for this position more often than that for the prone position, and therefore, more limited vision and less success rate is anticipated. it means that the supine position should be used for highly selected patients. operative time the definition of operating time was different among the reviewed studies. de sio and colleagues(5) defined it as the time from supine percutaneous nephrolithotomy—basiri and mohammadi sichani urology journal vol 6 no 2 spring 2009 77 ureteral catheterization to the placement of the nephrostomy tube; however, rana and associates(4) calculated it from the anesthesia charts. in most of the studies, the operative time was not clearly defined, but it is obvious that the time of pcnl is dramatically lower in the supine position compared to that in the prone position. the only parameter that reached a statistical difference in de sio and colleagues’ randomized controlled trial was the operative time (43 minutes versus 68 minutes; p < .001).(5) the authors stated that this difference was attributed to turning the patient at the beginning and the end of pcnl in the prone position. conclusion we conclude that supine pcnl is safe, and because of its advantages in high-risk patients, it is necessary that every endourologist increases his/her skills in this technique. however, the supine position is not a substitute for the prone position for pcnl. we need more prospective randomized studies in this field to draw an affirmative conclusion. conflict of interest none declared. references 1. shoma am, eraky i, el-kenawy mr, el-kappany ha. percutaneous nephrolithotomy in the supine position: technical aspects and functional outcome compared with the prone technique. urology. 2002;60:388-92. 2. kerbl k, clayman rv, chandhoke ps, urban da, de leo bc, carbone jm. percutaneous stone removal with the patient in a flank position. j urol. 1994;151:686-8. 3. clayman rv, bub p, haaff e, dresner s. prone flexible cystoscopy: an adjunct to percutaneous stone removal. j urol. 1987;137:65-7. 4. rana am, bhojwani jp, junejo nn, das bhagia s. tubeless pcnl with patient in supine position: procedure for all seasons?--with comprehensive technique. urology. 2008;71:581-5. 5. de sio m, autorino r, quarto g, et al. modified supine versus prone position in percutaneous nephrolithotomy for renal stones treatable with a single percutaneous access: a prospective randomized trial. eur urol. 2008;54:196-202. 6. zhou x, gao x, wen j, xiao c. clinical value of minimally invasive percutaneous nephrolithotomy in the supine position under the guidance of realtime ultrasound: report of 92 cases. urol res. 2008;36:111-4. 7. ng mt, sun wh, cheng cw, chan es. supine position is safe and effective for percutaneous nephrolithotomy. j endourol. 2004;18:469-74. 8. neto ea, mitre ai, gomes cm, arap ma, srougi m. percutaneous nephrolithotripsy with the patient in a modified supine position. j urol. 2007;178:165-8; discussion 8. 9. manohar t, jain p, desai m. supine percutaneous nephrolithotomy: effective approach to high-risk and morbidly obese patients. j endourol. 2007;21:44-9. 10. valdivia uria jg, valle gerhold j, lopez lopez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol. 1998;160:1975-8. 11. steele d, marshall v. percutaneous nephrolithotomy in the supine position: a neglected approach? j endourol. 2007;21:1433-7. 12. el-kenawy mr, el-kappany ha, el-diasty ta, ghoneim ma. percutaneous nephrolithotripsy for renal stones in over 1000 patients. br j urol. 1992;69:470-5. 13. jones dj, russell gl, kellett mj, wickham je. the changing practice of percutaneous stone surgery. review of 1000 cases 1981-1988. br j urol. 1990;66:1-5. 14. segura jw, patterson de, leroy aj, et al. percutaneous removal of kidney stones: review of 1,000 cases. j urol. 1985;134:1077-81. 1413.pdf 866 | urological oncology 1department of radiology, hazrat rasoul akram university hospital; school of medicine, tehran university of medical sciences, tehran, iran 2research unit, medical imaging center, tehran university of medical sciences, tehran, iran 3school of medicine, tehran university of medical sciences, tehran, iran 4department of urology, hazrat rasoul akram university hospital, school of medicine, tehran university of medical sciences, tehran, iran 5deputy of research and technology, ministry of health and medical education, tehran, iran mahyar ghafoori,1 madjid shakiba,2 atefeh ghiasi,3 nazanin asvadi,3 kamal hosseini,5 manijeh alavi6 value of mri in local staging of bladder cancer corresponding author: mahyar ghafoori, md department of radiology, hazrat rasoul akram university hospital, niyayesh st., shahrara, tehran, 1445613131, iran tel: +98 21 6650 9057 fax: +98 21 6651 7118 e-mail: mahyarghafoori@gmail. com received march 2012 accepted august 2012 purpose: to evaluate the accuracy of magnetic resonance imaging (mri) in bladder cancer materials and methods: a total number of 108 bladder tumors in 86 patients (86% men and 14% women) were evaluated by 1.5 tesla mri machine. the tumor stages that were determined by mri study were compared with pathology results after resection of the tumor. results: the most common stage determined by both mri and pathology was t2a. considerp mri and pathology was 0.87 (p < .0001). considering stages in details, we had 22 (20.3%) mismatches in staging between mri and pathology; 10 (45.5%) were underestimation and 12 (54.5%) were overestimation. combining groups a and b in each stage, we had 14 (13%) mismatch cases; 6 (46.2%) were underestimation and 8 (53.8%) were overestimation. the detection rate of mri was 0% in stage ta, 80% in stage t1, 88.1% in stage t2, 81.2% in stage t3, conclusion: magnetic resonance imaging is a reliable modality for determining the stage of bladder tumors with high accuracy, and could show the depth of invasion and extension of tumor that is useful for treatment planning. keywords: urinary bladder neoplasms, magnetic resonance imaging, neoplasm staging urological oncology 867vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l mri in local staging of bladder cancer | ghafoori et al introduction bladder cancer is one of the most common malignan-cies of the urinary tract that accounts for almost 4% of all malignancies.(1) bladder tumors considering the depth of invasion are categorized into different stages. tnm staging system is the accepted method for worldwide staging of bladder cancer.(2) histopathologic evaluation of the tumor after surgical resection or transurethral resection nent of tumor stage. since tumor staging is crucial for choosing the treatment method, a reliable modality for pretreatment staging is necessary. magnetic resonance imaging (mri) has been recognized as the best imaging modality for bladder cancer staging.(3,4) since there has been no published study about the accuracy of mri in bladder cancer staging in iran, we conducted this study to evaluate the accuracy of mri in detertumors from invasive one. materials and methods magnetic resonance imaging of the bladder was performed for all the patients who were diagnosed as having bladder masses by means of ultrasonography, computed tomography scan, or mri, and were referred to the department of radiology in hazrat rasoul akram university hospital from december 2009 to april 2011. have bladder cancer by histopathologic study were enrolled in this study. patients without documented bladder cancer, those who could not perform mri study because of cardiac pacemakers or metallic objects in their bodies, and patients that refused to undergo mri because of claustrophobia or any other reasons were excluded from the study. magnetic resonance imaging of the bladder was performed in all the patients by a 1.5 tesla mri machine (avento; siemens, erlangen, germany) using pelvic-phased array coil. our mri protocol was as follows: axial, coronal, and sagittal t2-weighted fast spin-echo, axial t1-weighted fast spinecho, axial fat suppressed t1-weighted fast spin-echo, and axial and coronal 3d volumetric interpolated breath-hold sequence (vibe) before and after administration of intravenous contrast medium. all the images were reviewed by an expert uroradiologist in the workstation. staging of bladder tumors was performed stages that were determined by mri were compared with pathologic staging after resection of tumors. in 10 patients with 11 tumors, tur of the tumor and in 76 patients with 97 tumors, radical cystectomy was performed. in six patients, the procedure was repeated between 3 to 5 weeks after the the following guidelines were used for staging by mri: an intact hyposignal line (muscle layer) at the base of the ner margin of the hyposignal line, stage t2a; a disrupted hylesion with an irregular, shaggy outer border and streaky areas of the same signal intensity of the tumor in perivesical fat, stage t3b (figure 2); and a lesion extending into an adjacent organ or abdominal and pelvic side walls with the same signal intensity of the primary tumor, stage t4a or t4b.(3) since the most important factor in the selection of the curative modality is the depth of tumor invasion, we only considered the t stage of the tumor from the tnm system. than evaluation of mri accuracy in each stage, we evalutwo groups:(4) to t1 invasive tumors: if the tumor stage was more than or equal to t2a extension of the tumor beyond the bladder and involvement mor recurrence and patients’ survival. the accuracy of mri tumors into two groups:(4) to t2b equal to t3b the ethics committee of tehran university of medical sciences approved the protocol for the research project. this study conforms to the provisions of the declaration of helsinki (as revised in edinburgh 2000). the objectives and methods of the study were explained to all the subjects and a written informed consent was obtained. statistical analysis 868 | and pathology. furthermore, we assessed the diagnostic invalue, negative predictive value, positive likelihood ratio, and negative likelihood ratio of the mri versus pathology as gold standard results. data were analyzed by spss software (the statistical package for the social sciences, version 16.0, spss inc, chicago, illinois, usa) and p < .05 was assumed results overall 108 tumoral lesions were diagnosed histopathologically as transitional cell carcinoma. seventy-four of the patients were men (86%) and 12 were women (14%). the mean ± standard deviation age of the patients was 59.7 ± 12 years (range, 32 to 86 years). the mean age of the men and women was 61.9 ± 15.6 years and 59.4 ± 12.7 years, respectively (p = .53). based on mri, the most common stage was t2 [43 (39.8%) garding histopathology results, again stage t2 was the most common stage that was diagnosed in the patients (42 tumors; 25 in the t2a and 17 in the t2b stage; table 1). regarding tumor location, the most common tumor site was the posterior between mri and histopathology was 0.8 (p < .0001; table 2). combining groups a and b in each stage for mri and urological oncology table 1. details of tumor stages based on mri and histopathology. ta t1 t2 t3 t4 mri, n (%) 0 11 (10.2) 43 (39.8) 28 (25.9) 26 (24.1) a b a b a b 0 11 (10.2) 30 (27.8) 13 (12) ----28 (25.9) 18 (16.7) 8 (7.4) histopathology, n (%) 1 (0.9) 10 (9.3) 42 (38.9) 32 (29.6) 23 (21.3) a b a b a b 1 (0.9) 10 (10.2) 25 (23.1) 17 (15.7) 7 (6.5) 25 (23.1) 15 (13.9) 8 (7.4) mri indicates magnetic resonance imaging. figure 1b. coronal t2-weighted image.figure 1a. axial t2-weighted image. 869vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l between mri and pathology (p < .0001; table 3). considering detailed stages, we had totally 22 mismatch cases. as it is shown in table 2, 10 (45.5%) of these mismatches were underestimation and 12 (54.5%) were overestimation. eight cases happened in the same stage, but different subdivisions (eg, stage t2a was reported as t2b). therefore, we had totally 14 (13%) mismatch cases in staging between mri and pathology. as table 3 shows, there were totally 8 (53.8%) cases of stage overestimation and 6 (46.2%) cases of stage underestimation. the detection rates of mri in each stage were as follows: stage ta, 0%; stage t1, 80%; stage t2, 88.1%; stage t3, 81.2%; and stage t4, 100%. considering stages ta and t1 as culated the kappa agreement and diagnostic indices of mri versus pathology as the gold standard. the sensitivity and the kappa agreement and diagnostic indices of mri versus ity of mri were 0.93 and 0.94, respectively (table 5). discussion t2a was the most common stage that was diagnosed by both mri and histopathology in our study that is in contrast with western countries, in which t1 is the most common diagnosed bladder cancer.(5-7) this could be due to later admission of patients to physicians in iran. if we consider all stages in details, including a and b subgroups in each of the t stages, and compare it with pathology results, we had totally 22 (12.2%) cases of mismatch between mri staging and pathology reports. of those, 10 (45.5%) were underestimation and 12 (54.5%) were overestimation. since 8 mismatch cases were seen in the same t stages, then considering the t component of staging alone, regardless of a or b subgroup, the number of overor under-staging decreases to totally 14 (13%) mismatch cases; of which 6 (46.2%) were underestimation and 8 (53.8%) were overestimation resulting in more accuracy of mri in staging. in a study by tekes and colleagues, most patients (32%) were over-staged (p < .0001),(4) which is similar to our study. buy table 2. agreement of mri and histopathology considering staging. mri staging total ta t1 t2 t3 t4 a b a b a b pathology staging ta ta 0 1 0 0 0 0 0 0 1 t1 t1 0 8 2 0 0 0 0 0 10 t2 a 0 2 22 1 0 0 0 0 25 b 0 0 4 10 0 2 1 0 17 t3 a 0 0 2 2 0 3 0 0 7 b 0 0 0 0 0 23 2 0 25 t4 a 0 0 0 0 0 0 15 0 15 b 0 0 0 0 0 0 0 8 8 total 0 11 30 13 0 28 18 8 108 mri indicates magnetic resonance imaging. mri in local staging of bladder cancer | ghafoori et al figure 1c. axial fat-suppressed t1-weighted image with contrast. a tumoral mass is evident in the right lateral wall of the bladder that shows enhancement after contrast medium injection. the hyposignal muscular layer under the tumor is intact with no evidence of tumor invasion, a finding that is consistent with stage t1 tumor. 870 | and associates reported 33% underestimation in their study (p < .0001). they assessed their patients with a 0.5t mri scanner without contrast agent injection. furthermore, their study had a much smaller sample size compared to ours.(8) considering all stages in details, including a and b subdivisions, the detection rate of mri was equal to 80% that points to a good correlation between mri and pathology (table 2). if we consider t stages alone, regardless of a and b subdivisions, the detection rate of mri becomes even much better and equal to 87% because many overor under-stagings happened in the same t stage (stage a was diagnosed as stage b or vice versa) (table 3). over-staging was more common than under-staging in our study. abnormal signals that are detected in perivesical fat at the site of the tumor and are misdiagnosed as tumor invasion are one of the reasons for over-staging of bladder cancer. the source of these abnormal signals could be hyperemia and engorged vessels in the vicinity of the tumors due to their high process that happens in perivesical tissues following tur or biopsy of bladder tumors,(1) especially in t2-weighted and gadolinium-enhanced images.(3,9-11) the most common under-staging happened between stages t2a and t2b and was due to underestimation of the depth of tumor invasion into the hyposignal muscular layer of the bladder. among all mismatch cases between mri and pathology, in more than 90% of misstaged tumors, the over-or under-stagings were diagnosed by mri only as one stage higher or lower than the histopathology diagnosis. only in one case, a t2b stage tumor was diagnosed in mri as t4a tumor, which was a posteriorly located tumor with obliterated fat plan between the tumor and the adjacent seminal vesicle presumably due to vesicle involvement. the overall reported accuracy of mri in local staging of bladder cancer is between 52% and 93%. (3,4,12,13) the use of gadolinium can increase this accuracy to 73% to 100%.(4) to determine the treatment plan and the patient’s prognosis, cer is very important. the treatment is dramatically changed urological oncology table 3. crosstabulation of mri and pathology results in terms of staging. pathology total ta t1 t2 t3 t4 mri ta 0 0 0 0 0 0 t1 1 8 2 0 0 11 t2 0 2 37 4 0 43 t3 0 0 2 26 0 28 t4 0 0 1 2 23 26 total 1 10 42 32 23 108 mri indicates magnetic resonance imaging. figure 2b. coronal t2-weighted image.figure 2a. axial t2-weighted image. 871vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l are treated with tur with or without adjuvant intravesical chemotherapeutic agents while deep tumors are treated by more aggressive approaches, including cystectomy and palliative chemotherapy, radiotherapy, or both.(14) mors, the reported accuracy is 75% to 92%.(4,15,16) according to our study, the kappa agreement between mri and hisand 0.82, respectively. using 1.5 tesla mri machine with t1-weighted and t2-weighted images, tekes and colleagues by reviewer 2.(4) takeuchi and coworkers used t2-weighted images alone, t2-weighted with diffusion weighted (dw) images, t2-weighted plus contrast agent images, and all three together with a 1.5 tesla mri machine. they reported enhanced images were 94% and 86%, respectively, and of t2-weighted plus dw images were 88% and 100%, respectively.(7) magnetic resonance imaging has been shown highly accurate in diagnosing perivesical fat involvement considering previous studies.(17) our study showed that the sensitivity which is a satisfying result. abou-el-ghar and colleagues evaluated the accuracy of mri in staging of bladder carcinomas and compared two mri techniques with a 1.5 tesla mri in dw images and 75.7% in t2-weighted images. the accu(69.7% versus 15.1%; p < .001).(18) takeuchi and associates found that in t2-weighted contrast enhanced images, mri table 4. diagnostic indices of mri versus pathology in differentiation of superficial and deep tumors. diagnostic index sensitivity (95% ci) 0.98 (0.93 to 0.99) specificity (95% ci) 0.82 (0.48 to 0.98) positive predictive value (95% ci) 0.98 (0.93 to 0.99) negative predictive value (95% ci) 0.82 (0.48 to 0.98) positive likelihood ratio (95% ci) 5.4 (1.5 to 18.9) negative likelihood ratio (95% ci) 39.7 (99.8 to 160.8) kappa agreement (95% ci) 0.8 (0.61 to 0.99) mri indicates magnetic resonance imaging; and ci, confidence interval. table 5. diagnostic indices of mri versus pathology in differentiation of organ-confined and non-organ-confined tumors. diagnostic index sensitivity (95% ci) 0.93 (0.82 to 0.98) specificity (95% ci) 0.94 (0.84 to 0.99) positive predictive value (95% ci) 0.94 (0.85 to 0.99) negative predictive value (95% ci) 0.93 (0.82 to 0.98) positive likelihood ratio (95% ci) 16.4 (5.4 to 49.3) negative likelihood ratio (95% ci) 12.9 (5 to 33.4) kappa agreement (95% ci) 0.87 (0.78 to 0.96) mri indicates magnetic resonance imaging; and ci, confidence interval. mri in local staging of bladder cancer | ghafoori et al figure 2d. coronal fat-suppressed t1-weighted image with contrast. a tumoral mass is evident in the left lateral wall of the bladder that shows enhancement after contrast medium injection. the full thickness of the bladder wall is involved by the tumor and invasion of the tumor to perivesical fat is noted, a finding that is consistent with stage t3b tumor.figure 2c. axial fat-suppressed t1-weighted image with contrast. 872 | urological oncology 8. buy jn, moss aa, guinet c, et al. mr staging of bladder carcinoma: correlation with pathologic findings. radiology. 1988;169:695-700. 9. neuerburg jm, bohndorf k, sohn m, teufl f, guenther rw, daus hj. urinary bladder neoplasms: evaluation with contrast-enhanced mr imaging. radiology. 1989;172:739-43. 10. sparenberg a, hamm b, hammerer p, samberger v, wolf kj. [the diagnosis of bladder carcinomas by nmr tomography: an improvement with gd-dtpa?]. rofo. 1991;155:117-22. 11. sohn m, neuerburg j, teufl f, bohndorf k. gadoliniumenhanced magnetic resonance imaging in the staging of urinary bladder neoplasms. urol int. 1990;45:142-7. 12. scattoni v, da pozzo lf, colombo r, et al. dynamic gadolinium-enhanced magnetic resonance imaging in staging of superficial bladder cancer. j urol. 1996;155:1594-9. 13. tanimoto a, yuasa y, imai y, et al. bladder tumor staging: comparison of conventional and gadolinium-enhanced dynamic mr imaging and ct. radiology. 1992;185:741-7. 14. sutton d. textbook of radiology and imaging. 7 ed: churchill livingstone; 2003;31:1008-10. 15. narumi y, kadota t, inoue e, et al. bladder tumors: staging with gadolinium-enhanced oblique mr imaging. radiology. 1993;187:145-50. 16. hayashi n, tochigi h, shiraishi t, takeda k, kawamura j. a new staging criterion for bladder carcinoma using gadolinium-enhanced magnetic resonance imaging with an endorectal surface coil: a comparison with ultrasonography. bju int. 2000;85:32-6. 17. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001;19:666-75. 18. abou-el-ghar me, el-assmy a, refaie hf, el-diasty t. bladder cancer: diagnosis with diffusion-weighted mr imaging in patients with gross hematuria. radiology. 2009;251:415-21. references 1. barentsz jo, jager gj, van vierzen pb, et al. staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced mr imaging. radiology. 1996;201:185-93. 2. greene fl, compton cc, fritz ag, shah jp, winchester dp. ajcc cancer staging atlas. berlin, germany: springer; 2006. 3. kim b, semelka rc, ascher sm, chalpin db, carroll pr, hricak h. bladder tumor staging: comparison of contrastenhanced ct, t1and t2-weighted mr imaging, dynamic gadolinium-enhanced imaging, and late gadoliniumenhanced imaging. radiology. 1994;193:239-45. 4. tekes a, kamel i, imam k, et al. dynamic mri of bladder cancer: evaluation of staging accuracy. ajr am j roentgenol. 2005;184:121-7. 5. sharma s, ksheersagar p, sharma p. diagnosis and treatment of bladder cancer. am fam physician. 2009;80:717-23. 6. kaufman ds, shipley wu, feldman as. bladder cancer. lancet. 2009;374:239-49. 7. takeuchi m, sasaki s, ito m, et al. urinary bladder cancer: diffusion-weighted mr imaging--accuracy for diagnosing t stage and estimating histologic grade. radiology. 2009;251:112-21. t2 and lower tumors with stage t3 and higher tumors. they also concluded that despite the belief that tumor contours could be evaluated more accurately by dw images, this technique did not improve mri accuracy in detecting extravesical involvement in their study.(7) tekes and coworkers report(4) conclusion despite some differences between mri and histopathology results, mri could be an acceptable modality for bladder cancer staging. improvement of mri techniques and utilizaaccuracy.(4) acknowledgements this study was founded by a medical research grant from the research deputy of tehran university of medical sciences. conflict of interest none declared. vol 12. no 02 march-april 2015 1995vol 12. no 02 march-april 2015 2119 case report idiopathic spontaneous bladder perforation: a rare case erdal uysal,1* mehmet dokur,2 mehmet ali ikidag,3 turkay kirdak4 keywords: rupture; spontaneous; radiography; female; urinary bladder diseases; surgery. introduction idiopathic, spontaneous bladder perforation is a very rare and life threatening clinical condition. it is not always possible to diagnose by radiological imaging.(1) on the other hand, cystography is more proper diagnostic choice for the patients who may have the possibility of urinary bladder perforation.(2) however, idiopathic, spontaneous bladder perforation is not primarily considered for the patients because of its rareness. bladder perforations are usually iatrogenic or encountered secondary to trauma, malignancies or radiation exposure.(3) patients usually admit with lower abdominal pain, dysuria or anuria. there are findings compatible with acute abdomen in physical examination. white blood cell count, urea, creatinine and c-reactive protein (crp) levels may be elevated.(4) blood is usually observed in urine test. despite these radiological evaluations and findings in laboratory and physical examinations, correct diagnosis is usually made by laparoscopy. urgent surgery, repairing and drainage are the first choice of therapy. delay in diagnosis and treatment increase mortality and morbidity.(3) in this case report, we present a case of idiopathic spontaneous bladder perforation. case report a 78 years old female was admitted to our hospital with complaints of nausea, vomiting and severe abdominal pain, starting 4 days ago and gradually increasing. in our case, bladder perforation was not associated with cancer, ureterolithiasis, surgery, urinary retention and radiotherapy. her prior medical history was insignificant, except for hypertension. there is also no voiding problem in her medical history. on physical examination, there were abdominal tenderness, defense and rebound in all quadrants, consistent with acute abdomen. white blood cell was 5300/mm3 (normal range, 4.8 -10.8 103/mm3). blood chemistry tests revealed blood urine nitrogen 9 mg/dl (normal range, 6-20 mg/dl), serum creatinine level of 3 mg/dl (normal range, 0.6-1.3 mg/dl), potassium 6.2 mmol/l (normal range, 3.5-5.1 mmol/l) and crp 372 mg/l (normal range, 0-5 mg/l). a urinary catheter was placed as a first step, and approximately 80 ml cloudy and dark urine was observed. however, we did not observe any increased amount of urine even after intravenous liquid replacement. hematuria was observed in the urine test. abdominal computed tomography (ct) scan revealed free fluid in perihepatic, perisplenic and both paracolic spaces, prominent in pelvic region and right subdiaphragmatic space. due to the increased preoperative creatinine value, renal or urological pathologies could be also considered. since there were the symptoms of acute abdomen, and existence of free abdominal liquid, gastrointestinal perforation was primarily considered and because of the possibility of idiopathic, spontaneous bladder perforation the patient underwent urgent laparotomy with midline incision. there were widespread free abdominal purulent fluid and peritonitis. whole gastrointestinal tract was examined, but perforation was not found. a perforation in the dome of the bladder, which was 1 cm in size, was found eventually (figure). contours of the perforation were debrided, and inside of the bladder was explored, but no underlying condition was found. multiple biopsies were taken from the bladder and perforation side. samples from free fluid were taken for cytological and microbiological analyses and culture, but no bacterial growth was observed. bladder was sutured primarily. the patient was followed up in intensive care unit. she was intubated, and supportive positive inotropes were delivered. wide spectrum antibacterial therapy was administered. ventilator related pneumonia developed in 7th day of operation. gram negative (pseudomonas species) and positive bacteria (staphylococcus) were found in broncho alveolar culture. despite intensive therapy, sepsis and related multiple organ failures developed, and finally cardiac arrest occurred. the patient did not respond to resuscitation and she died on the fifteenth day after the surgery. biopsy samples from bladder were reported as inflammation and necrosis. no atypical cells were found in the abdominal fluid sample. discussion spontaneous bladder perforation is usually not considered in the differential diagnosis of acute abdomen because of its departments of general surgery,1 emergency2 and radiology3, faculty of medicine, sanko university, 27090 gaziantep, turkey. 4 department of general surgery, faculty of medicine, uludag university, 16059 bursa, turkey. *correspondence: department of general surgery, faculty of medicine, sanko university, 27090 gaziantep, turkey. tel: +90 506 4845803. fax: +90 342 2115010. e-mail: drerdaluysal@hotmail.com. received october 2014 & accepted january 2015 spontaneous bladder perforation-uysal et al. case report 2120 rarity. there is no specific diagnostic tool for it, and the diagnosis is usually made during operation.(4) the most prominent symptom is sudden onset of lower abdominal pain. mortality and morbidity increase significantly in lack of prompt diagnosis and early treatment.(5) the most challenging factor that influences management and therapy, seems to be the difficulty in preoperative diagnosis. also, in our case, diagnosis of preoperative bladder perforation was possible after the surgery. laparoscopy is an effective procedure for diagnosis and treatment which allows examining wide range of the area by a small incision. also, in our case, this procedure might be used for diagnosis and treatment. however, we preferred direct laparotomy approach because the patient was in hypovolemia, and partial carbon dioxide level increased in the blood with low saturation. another reason to choose direct laparotomy approach was also that the surgeon has less experience in this kind of urgent case. cystography is very helpful tool to diagnose bladder perforation. especially, in the case of suspicion of bladder perforation, it provides accurate diagnosis as well as helps in planning medical treatment. moreover, cystography is pretty successful tool to diagnose bladder perforation for the patients who experience penetrating or blunt abdominal trauma. nowadays, computed cystotomography is an alternative of conventional cystography to diagnose bladder perforation, and has several advantages including quickly and easily use, and allowing to investigate surrounding tissues in depth. on the other hand, cystography could be also considered to support the diagnosis of preoperative urinary bladder perforation, or, for small perforation, conservative treatment approach with urinary catheter might be also considered. however, we planned laparotomy for our patient due to the presence of the symptoms of acute abdomen. sampling of abdominal free fluid by ultrasound guidance and measuring the levels of urea and creatinine may be helpful in the diagnosis, but diagnosis of bladder perforation must be remembered before for this. biopsy samples from bladder wall revealed inflammation and necrosis. but there were no clusters of bacteria. the reason of necrosis and inflammation could not be explained. the changes in bladder wall capillary microcirculation may lead to ischemia and necrosis.(6) late admission of the patient leaded to generalized peritonitis and adverse influence in healing process. though intense care and broad spectrum antibacterial therapy, sepsis and multiple organ failures could not be prevented. the lack of early diagnosis and therapy onset may be the main reason of mortality in this patient. bladder perforations are usually iatrogenic or encountered secondary to trauma, malignancies, or radiation exposure. only a few cases of idiopathic spontaneous perforation of bladder are reported until today (table).(1,3-7) moreover, spontaneous perforation of bladder for puerperal patients due to the extreme bladder distension was also reported.(8) conclusion in conclusion, idiopathic, spontaneous bladder perforation is a very rare and life threatening clinical condition that is difficult to recognize preoperatively. the possibility of it should be kept in mind among other acute abdomen reasons. conflict of interest none declared. references 1. wieloch m, bazylińska k, ziemniak p. spontaneous, idiopathic urinary bladder perforation--case report. pol przegl chir. 2013;85:727-9. study age/sex comorbidity preoperative time time of diagnosis type of surgery type of operation mortality morbidity wieloch et al.1 84/f ht+af several day preoperatively open primary suture yes no ahmed et al.5 47/f no unknown preoperatively open primary suture no no al-qassim et al.7 33/f no 5 days preoperatively laparoscopy primary suture no no limon et al.6 52/f diabetes mellitus unknown preoperatively open primary suture yes no cusano et al.4 60/f no unknown preoperatively open primary suture no no albino g et al.3 73/m no unknown preoperatively open primary suture yes no current case 78/f ht 4 days preoperatively open primary suture yes no table. demographic and clinical characteristics of patients in different studies. abbreviations: ht, hypertension; af, atrial fibrillation; f, female; m, male. figure. a perforated about 1 cm was discovered at the dome of the urinary bladder vol 12. no 02 march-april 2015 2121 2. iverson aj, morey af. radiographic evaluation of suspected bladder rupture following blunt trauma: critical review. world j surg. 2001;25:1588-91. 3. albino g, bilardi f, gattulli d, maggi p, corvasce a, marucco ec. spontaneous rupture of urinary bladder: a case report and review. arch ital urol androl. 2012;84:224-6. 4. cusano a, abarzua-cabezas f, meraney a. spontaneous bladder perforation unrelated to trauma or surgery. bmj case rep. 2014;12:2014. 5. ahmed j, mallick ih, ahmad sm. rupture of urinary bladder: a case report and review of literature. cases j. 2009;2:7004. 6. limon o, unluer ee, unay fc, oyar o, sener a. an unusual cause of death: spontaneous urinary bladder perforation. am j emerg med. 2012;30:2081.e3-5. 7. al-qassim z, mohammed a, england r, khan z. idiopathic spontaneous rupture of the urinary bladder (srub). a case report and review of literature. cent european j urol. 2012;65:235-7. 8. sailo sl, sailo l. spontaneous puerperal bladder perforation presenting with urinary retention. urol j. 2014 6;11:1854. spontaneous bladder perforation-uysal et al. study subjects the mean age of the 21 patients (19 women and 2 men) was 50 years (range 18 to 74 years). the mean duration of symptoms was 32 months (12 to 72 months). the typical symptom was pain or discomfort of the perineum and pelvic cavity related to bladder filling. in addition, this symptom was usually accompanied by urgency, frequency and intermittent gross hematuria of different degrees. the quality of sleep and life of these patients was obviously decreased. all 21 patients had a history of multiple courses of antibiotic therapy and symptomatic analgesia. after admission, urinalysis, urine culture, urine cytology and urinary acid-fast bacilli, color doppler ultrasound examination and determination of residual urine female urology 2417 female urology role of bladder hydrodistention and intravesical sodium hyaluronate in the treatment of interstitial cystitis jin-yi yang,1* wei wei,1 yu-long lan,2 jun-qiang liu,2 hai-bo wang,1 shao li2** purpose: to evaluate the clinical efficacy of bladder hydrodistention and intravesical sodium hyaluronate in the treatment of interstitial cystitis (ic). materials and methods: twenty-one patients with ic received intravesical sodium hyaluronate therapy under nerve block or intravenous anesthesia. bladders were perfused with 100 cmh 2 o perfusion pressure and expanded for 10 min and were later injected with 40 mg/50 ml sodium hyaluronate through the catheter. after 1 h, the perfusion fluid was released. perfusion was applied once per week, 4 to 6 times as a course of treatment. results: under anesthesia, the average bladder capacity was 191.62 ± 88.67 ml, and after bladder expansion, the bladder capacity reached 425.33 ± 79.83 ml (p = .000). there were 2 suspected bladder ruptures after bladder expansion at 6.5 min and 7.2 min. after 10 min of bladder expansion, there were 19 cases of significantly gross hematuria. after treatment, the catheters of 17 patients were removed at 24 h; for the 2 cases of hematuria, catheters were removed at 72 h and for the 2 cases of suspected bladder rupture, catheters were removed after 4 days. after catheter removal, the pain threshold significantly decreased, and the maximum urinary output increased slightly. compared with values before treatment, the day before the second injection of sodium hyaluronate, the frequency of urination decreased significantly (32.8 vs. 18.5 times/24 h), the maximum urinary output increased significantly (86.7 vs. 151.9 ml), the pain decreased significantly (8.7 vs. 3.0), and the o'leary-sant ic score and quality of life score were significantly decreased (30.0 vs. 17.0 and 5.9 vs. 2.4, respectively) (p = .000). conclusion: bladder hydrodistention under anesthesia for patients with severe intractable ic produces immediate effectiveness; sodium hyaluronic infusion can alleviate frequent urination and pain, and the efficacy was positively correlated with the duration of treatment. keywords: anesthesia; cystitis, interstitial; therapy; female; prospective studies; urinary bladder; dilatation; methods; treatment outcome; lower urinary tract symptoms; etiology. introduction the etiology of interstitial cystitis (ic) is highly complex, and at present, no treatment has shown good efficacy. different from cardiovascular disease or cancer, ic will not directly lead to death. however, the suffering resulting from the poor quality of life (qol) can make patients end their life decisively.(1) it is notably difficult to cure ic, and the current purpose of treatment is to alleviate its symptoms and improve the qol. using bladder hydrodistention and intravesical sodium hyaluronate under anesthesia to treat 21 cases with severe stubborn ic, we achieved good clinical efficacy, as reported below. materials and methods 1 department of urology, dalian friendship hospital, liaoning 116001, china. 2 department of physiology, dalian medical university, dalian, 116044, china. *correspondence: department of urology, dalian friendship hospital, sanba square, dalian city, china 116001. tel: +86 411 88223408. e-mail: yangjinyi90@hotmail.com. **correspondence: department of physiology, dalian medical university, 9 western district, lvshun south road, dalian city, china. tel: +86 411 86110352. e-mail: lishao89@hotmail.com. received april 2015 & accepted november 2015 bladder hydrodistention and intravesical sodium hyaluronate for interstitial cystitis-yang et al. volume were performed to eliminate the diagnosis of urinary tract infection, tuberculosis, urinary calculi, cancer and other diseases. examination by computed tomography (ct), intravenous urography (ivu) or magnetic resonance hydrography was performed if necessary, and cystoscopy and bladder biopsy under anesthesia were also available. the protocol of the study was approved by the ethics committees of our hospital and was fully explained to the patients before informed consent was obtained. treatment methods 1. therapeutic method: nerve blocking or intravenous anesthesia was performed. the residual urine volume was again determined by cystoscopy, and a conventional cystoscopy check was performed. if findings were suspicious, multiple bladder biopsies were taken. the bladder capacity was measured. under normal pressure (usually 60 cmh 2 o pressure), the bladder was continuously expanded for 2 min, the bleeding point of the bladder mucosa was observed, the cystoscope was removed, and three-way urethral foley catheters were inserted. for patients without biopsies, the perfusion fluid was allowed to flow by gravity (100 cmh 2 o pressure) until it slowed down, and hydrodistention was maintained for 10 min. the perfusion fluid could be observed going into the bladder, and pressure was assessed by a water column, connected to the catheter, that moved up and down with the fluctuation in respiration. after 10 min, the perfusion was stopped, the perfusion fluid was released, and bladder capacity was measured after expansion. the bladder was rinsed through the threeway urethral foley catheter until there was no active bleeding. sodium hyaluronate (xi shitai, bioniche life sciences inc. ontario, canada) 40 mg/50 ml was infused, and after 1 h, the perfusion fluid was released. the urinary canal was retained for 24 h then removed. perfusion was applied once a week for 4 to 6 weeks as a course of treatment. for patients with biopsies, the above process was performed one week after excluding the possibility of other diseases. 2. monitoring indicators: clinical symptom scores were evaluated with a voiding diary before and after treatments during the 1st week, 2nd week, 5th week, 3rd month, and 6th month. the voiding diary registered consecutive records for 3 days, and the pain was evaluated by the visual analogue scale (vas); the o'leary-sant ic questionnaire score was applied;(2) qol was evaluated using a benign prostatic hyperplasia (bph)-specific, symptoms-based qol questionnaire. statistical analysis statistical package for the social science (spss inc, chicago, illinois, usa) version 13.0 was used for the statistical analysis. data are expressed as means ± sd. the paired t-test was used to compare continuous variables. the kolmogorov-smirnov test was used to address continuous variables. the wilcoxon signed-rank test and pearson chi-square test were used for the preoperative and postoperative comparison. the mann-whitney u test was used to assess the degree of pain. p < .05 was considered significant. results cystoscopy and the results of the water expansion by cystoscopic examination, we found that 15 cases had typically congestive erythema and small globular bleeding. of these cases, 8 also had findings of small fountain-like active bleeding at scattered in the bladder mucosa, and 4 cases had typical hunner’s ulcers. diagnostic expand the 19 cases bladder under 80 cmh 2 o pressure for 2 min. all 19 cases with gross hematuria were found to have typical congestive erythema and small globular bleeding, and 12 of these cases were severe. pathological reports of 5 cases with biopsies of the muscular layer and mucosa showed that there was inflammatory cell infiltration in the muscular layer and mucous, and the bladders displayed a chronic inflammatory response state. only one case had a typical mast cell infiltration. under anesthesia, the average bladder capacity was 98~382 (191.62 ± 88.67) ml, and after 10 min of bladder expansion under 100 cmh 2 o, bladder capacity reached 320~575 (425.33 ± 79.83) ml (p = .000). there were 2 suspected bladder ruptures after bladder expansion at 6.5 min and 7.2 min resulting from the sudden increase in perfusion speed. the urinary canal was opened, and the perfusion fluid was released, and after three days, sodium hyaluronate was perfused. the catheter was retained for 1 day and then removed. there was 1 case of significantly gross hematuria after 10 min of bladder expansion. changes in symptoms in patients before and after treatment after treatment, the catheters of 17 patients were removed at 24 h; the catheters in 2 cases of hematuria were removed at 72 h; the catheters in 2 cases of suspected bladder rupture were removed after 4 days. after removal of the catheter, the pain threshold was significantly reduced and the maximum urinary output increased slightly. compared to values before treatment, the day before the second injection of sodium hyaluronate, the frequency of urination decreased significantly (32.8 vs. 18.5 time/24 h), the maximum urinary output vol 12 no 06 november-december 2015 2418 increased significantly (86.7 vs. 151.9 ml), and the pain reduced significantly (8.7 vs. 3.0). after the third treatment, the symptoms continued to improve; in the fifth week, during which the sixth injection of sodium hyaluronate was performed, the treatment effects were optimal. although the time of follow-up was limited to 6 months, at the time of the sixth month, symptom rebounded, but the changes from baseline to the end of study had great significance (p < .0001) (table). the changes in questionnaire scores of patients before and after treatment the o'leary-sant ic questionnaire score of the patients and was calculated, and qol was evaluated in a short time after treatment. similar to the improved clinical symptoms, after removal of the urinary canal, both declined obviously (p = .000) compared with before treatment. the score was lowest during the fifth week, after the sixth perfusion. at the sixth month, both the o’leary-sant score and qol rebounded slightly; however, compared with the value before treatment, the difference remained statistically significant (p = .000) (table). the treatment efficacy over time is shown in figure using a kaplan-meyer curve. comparing the first week and the second week, no parameter was significantly different except the vas score (p = .008). comparing the fifth week and the third month, no parameter was significantly different, except 24 h frequency (p = .002) and the o’leary-sant score (p = .04). comparing the 3rd month and the 6th month, no parameter was significantly different except the vas score (p = .01). compared with assessments before treatment, odynuria, frequency of urination, maximal urine volume, o'leary-sant ic score and qol showed a tendency to decline over time. discussion about the definition of ic ic is a clinical diagnosis based on symptoms of urinary urgency, urinary frequency and suprapubic pain related to bladder filling. to relieve these symptoms, the efforts of many doctors have been directed toward determining its pathophysiology and treatment.(3) currently, however, the great controversy concerning ic is its definition. (4,5) the american urological association (aua) guidelines recommend that a diagnosis be made according to the bladder pain syndrome based on urinary tract symptoms including urgency, odynuria and frequent pelvic pain together with the finding of typical bleeding and/or ulceration of the bladder mucous membrane observed by bladder endoscopy. at present, china does not have published ic diagnosis and treatment guidelines, and in recent literature, ic has been generally regarded as an interchangeable concept.(5-9) of the 21 patients in the table. the comparison of clinical symptoms and scores between the before and after bladder hydrodistention and intravesical sodium hyaluronate of 21 cases with interstitial cystitis.* time 24 h urinary frequency maximum voided volume (ml) vas scores d’leary-sant scores qol scores p value before treatment 32.8 ± 10.4 86.7 ± 37.9 8.7 ± 1.1 30.0 ± 4.2 5.9 ± 0.3 .000 after treatment 1st week 18.5 ± 8.0 151.9 ± 72.2 3.0 ± 0.8 17.0 ± 4.4 2.4 ± 0.9 .000 2nd week 13.6 ± 7.3 190.5 ± 84.2 2.2 ± 1.0 13.8 ± 3.9 1.6 ± 1.0 .000 5th week 10.2 ± 4.0 209.5 ± 98.2 2.8 ± 1.1 12.1 ± 4.2 1.9 ± 1.0 .000 3rd month 15.1 ± 5.4 203.8 ± 94.6 3.3 ± 1.0 15.8 ± 3.5 2.1 ± 1.0 .000 6th month 17.8 ± 6.9 165.7 ± 79.2 4.5 ± 1.2 19.0 ± 6.5 2.8 ± 1.1 .000 abbreviations: vas, visual analog scale; qol, quality of life. * data are presented as mean ± sd. figure. kaplan-meyer curve of treatment efficacy. abbreviations: ic, interstitial cystitis; qol, quality of life. bladder hydrodistention and intravesical sodium hyaluronate for interstitial cystitis-yang et al. female urology 2419 group, pain was the main complaint and was also the main cause of repeated visits to a doctor . the timing of cystoscopy and pathologic findings for patients with ic, cystoscopy is necessary. it is better when performed under general anesthesia because local anesthesia can aggravate patients’ pain and fear, making patients uncooperative with the inspection and causing suspicious inspection results. after anesthesia, the bladder mucosa is inspected first. if this reveals an abnormal finding, especially a highly suspected bladder tumor, multiple biopsies for pathological examination should be taken. one week after the diagnosis of ic is confirmed, bladder expansion therapy is conducted. before this study, 3 patients with symptoms of ic were ultimately diagnosed with bladder cancer. two of them had bladder cancer in situ and were treated for a bladder tumor. however, these cases were not included in this study. if a bladder tumor is not detected, cystoscopy can also result in satisfactory analgesic effects, and most patients do not require painkillers in the week before bladder expansion therapy. although cystoscopy can eliminate the possibility of bladder cancer, it is necessary to obtain biopsies of suspicious areas.(10) of the 8 cases with biopsies, only one was found to have a typical mast cell infiltration. the remaining biopsy results were nonspecific except for inflammatory cell infiltration in the mucosa and muscularis mucosa, and only two of 21 cases had typical hunner’s ulcers. we believe that punctate hemorrhage has important diagnostic significance for ic. if a patient with symptoms of ic has punctate hemorrhage, the diagnosis of ic can be confirmed. injection of tiny bleeding usually appeared in typical cases by cystoscopy inspection. however, spot bleeding is more common 2 min after expansion of the bladder. also, 2 min after expansion, 16 cases (76.2%) were found to have obvious gross hematuria, which might be related to the fact that all cases of this group were refractory. measure of bladder capacity cystoscopy should be carried out before 2 minutes of diagnostic bladder expansion because there is a high rate of punctate hemorrhage during diagnostic bladder expansion, and hemorrhage will affect the results of cystoscopic examination. the determination of bladder capacity should be carried out after the biopsy under general anesthesia. although the measure of bladder capacity during anesthesia cannot represent the bladder capacity during physiological conditions, the bladder capacity of patients with ic was obviously decreased. among 21 patients, only 4 had a bladder capacity > 300 ml, 10 had a capacity < 100 ml, and the average capacity was 191.6 ± 88.7 ml; 10 min after the expansion, 5 cases had a capacity > 500 ml, only 1 case had a capacity < 350 ml, and the average capacity increased to 425.3 ± 79.8 ml, which is close to the average capacity of a normal bladder. after expansion, bladder capacity increased significantly compared with before treatment. height and time of the bladder hydrodistention the pressure of bladder hydrodistention generally settled at below 80 cmh 2 o. diagnostic expansion requires 2~3 min.(11) therapeutic expansion requires 8 min. according to this method, we expanded the bladders of 3 cases, but the effect was not satisfactory. therefore, we increased the pressure to 100 cmh 2 o for 10 min, and the effect appeared better. when the flow slowed down, we began the perfusion. after beginning the perfusion, the perfusion continued into the bladder, and its effect was evaluated by a water column, which moved up and down with fluctuating respiratory frequency in order to receive a maximum capacity of expansion and monitor for rupture of the bladder. there were 2 suspected bladder ruptures after expansion at 6.5 min and 7.2 min. however, these 2 cases achieved a cure that lasted until six months without using any painkillers and without further complications. this might be related to the expansion to maximum volume. bladder expansion alone can immediately relieve the pain, but the long-term effect is not satisfactory and also cannot significantly alleviate the frequency of urination. bladder endoscopy and bladder hydrodistention are the gold standard of diagnosis and treatment. the treatment method is simple and effective. the volume of bladder hydrodistention should be increased to a maximum in order to achieve the best treatment efficacy; next, we increased the distension height to 100 cm and increased the time to 10 min from the basic level (distension height 80 cm and distension time 8 min). although we achieved a satisfactory efficacy, the potential risk of bladder rupture should not be ignored. intravesical sodium hyaluronate the etiology of ic is complex and can lead to typical comprehensive symptoms through various ways.(12) parsons found that the bladder epithelial glycosaminoglycan (gags) layer of patients with ic was decreased significantly.(13) the gags can adjust the permeability of the bladder mucosa and have an anti-adhesion function that can prevent bacteria from contacting the urinary tract epithelium. any cause of damage to the gag layer of the urinary tract epithelium will result in an increased permeability of the bladder mucosa and the penetration of chemical substances into the submubladder hydrodistention and intravesical sodium hyaluronate for interstitial cystitis-yang et al. vol 12 no 06 november-december 2015 2420 cosa. this can lead to injury and inflammation of the bladder, which can make the body produce pain through stimulating the sensory nerves. hyaluronic acid (a type of gag) has the possible ability to cover and repair the bladder mucosa to relieve and even cure the symptoms of ic. foreign researchers believe that intravesical sodium hyaluronate might be a useful therapeutic option for patients with ic, whereas a domestic report indicated that it could be used in conjunction with the therapeutic effect of bladder hydrodistention.(14,15) other authors suggest that the dosage is not a critical factor for the effectiveness of hyaluronic acid. the dose of sodium hyaluronate did not have an apparent effect on efficacy because the package model is consolidated to 50 ml/40 mg, and we used one at a time. the o'leary-sant ic questionnaire and a bph qol questionnaire were used to evaluate the patients’ urination over the past month. however, during the weeks after treatment, asking patients to evaluate urination of the days before investigation can also be an objective index, especially when the patients are in the hospital or have just been discharged. patients can carefully respond to the questionnaires, and the results are also statistically valuable. our results show that bladder hydrodistention under anesthesia for patients with severe intractable ic is rapidly effective; intravesical sodium hyaluronate can alleviate frequent urination and pain, and the efficacy was positively correlated with the duration of treatment. the combination of the two treatments has a better shortterm effect and is worthy of clinical promotion. acknowledgments the work was supported by the national natural science foundation of china (81571061, 81371223 and 81371437), the research fund for the doctoral program of higher education of china (20122105110010). conflict of interest none declared. references 1. hanno p, nordling j, van ophoven a. hat is new in bladder pain syndrome/interstitial cystitis? curr opin urol. 2008;18:353-8. 2. irani d, heidari m, khezri aa. the efficacy and safety of intravesical bacillus-calmetteguerin in the treatment of female patients with interstitial cystitis: a double-blinded prospective placebo controlled study. urol j. 2004;1:90-3. 3. aghamir sm, mohseni mg, arasteh s. intravesical bacillus calmette-guerin for treatment of refractory interstitial cystitis. urol j. 2007;4:18-23. 4. victal ml, lopes mhbm, d’ancona cal. adaptation of the o’leary-scant and the puf for the diagnosis of interstitial cystitis for the brazilian culture. revista da escola de enfermagem de usp. 2013;47:312-9. 5. erickson dr, kunselman ar, bentley cm, et al. changes in urine markers and symptoms after bladder distention for interstitial cystitis. j urol. 2007;177:556-60. 6. namazi h. intravesical botulinum toxin a injections plus hydrodistension can reduce nerve growth factor production and control bladder pain in interstitial cystitis: a molecular mechanism. urology. 2008;72:463-4. 7. seth a, teichman jm. what's new in the diagnosis and management of painful bladder syndrome/interstitial cystitis? curr urol rep. 2008;9:349-57. 8. davis nf, brady cm, creagh t. interstitial cystitis/painful bladder syndrome: epidemi ology, pathophysiology and evidence-based treatment options. eur j obstet gyn r b. 2014;175:30-7. 9. berry sh, bogart lm, pham c, et al. development, validation and testing of an epidemiological case definition of interstitial cystitis/painful bladder syndrome. j urol. 2010;183:1848-52. 10. aihara k, hirayama a, tanaka n, fujimoto k, yoshida k, hirao y. hydrodistension under local anesthesia for patients with suspected painful bladder syndrome/interstitial cystitis: safety, diagnostic potential and therapeutic efficacy. int j urol. 2009;16:947-52. 11. fall m, peeker r. methods and incentives for the early diagnosis of bladder pain syndrome/ interstitial cystitis. expert opin med diagn. 2013;7:17-24. 12. wu y, shi c, deng j, zhang x, song b, li l. expression and function of muscarinic subtype receptors in bladder interstitial cells of cajal in rats. urol j. 2014;11:1642-7. 13. parsons cl. the potassium sensitivity test: a new gold standard for diagnosing and understanding the pathophysiology of interstitial cystitis. j urol. 2009;182:432-4. 14. neuhaus j, schwalenberg t. intravesical treatments of bladder pain syndrome/ interstitial cystitis. nat rev urol. 2012;9:70720. 15. fiander n. painful bladder syndrome and interstitial cystitis: treatment options. br j nurs. 2013;22:s26, s28-33. bladder hydrodistention and intravesical sodium hyaluronate for interstitial cystitis-yang et al. female urology 2421 1615vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l pre-operative tumor localization and evaluation of extra-capsular extension of prostate cancer: how misleading can it be? raymond wai-man kan, chi-fai kan, lap-yin ho, steve wai-hee chan corresponding author: raymond wai-man kan , department of surgery, queen elizabeth hospital, kowloon, hong kong. tel: +852 9814 9642 e-mail: kwm.raymond@yahoo.com received june 2013 accepted march 2014 department of surgery, queen elizabeth hospital, kowloon, hong kong. urological oncology purpose: to verify the accuracy of transrectal ultrasound-guided prostatic biopsy (trus bx), magnetic resonance imaging (mri) and their combination in evaluating the laterality of prostate cancer and to determine the accuracy of mri in assessing extra-capsular extension of prostate cancer. materials and methods: we retrospectively reviewed our past 100 consecutive series of radical prostatectomy performed between february 2010 and april 2012 at our institution. their trus bx and mri results were compared with the pathology of the radical prostatectomy specimens. for tumor localization, we calculated the accuracies in unilateral diseases, bilateral diseases, overall accuracies and cohen kappa concordance coefficient of trus bx, mri and their combination. for the assessment of extra-capsular extension, we calculated the sensitivity, specificity, positive predictive value, negative predictive value, overall accuracy, likelihood ratio positive and likelihood ratio negative of mri. results: eighty-two percent of our radical prostatectomy specimens had bilateral tumor involvement and 32% had extra-capsular extension. the accuracies of trus bx in unilateral disease, bilateral disease and overall accuracy were 15.2%, 91.4% and 43.6%, respectively. the accuracies of mri in unilateral disease, bilateral disease and overall accuracy were 11.1%, 66.7% and 38.9%, respectively. when combining the assessment of trus bx and mri, the accuracies in unilateral disease, bilateral disease and overall accuracy were 16.7%, 75% and 55.6%, respectively. the cohen kappa concordance co-efficient of trus bx, mri, and combination of them were 0.1165, -0.2047 and -0.1084, respectively. the positive predictive value, negative predictive value, sensitivity, specificity, overall accuracy, likelihood ratio positive and likelihood ratio negative of mri in assessing extra-capsular extension were 33.3%, 69.8%, 5.9%, 94.9%, 67.9%, 1.16 and 0.99, respectively. conclusion: trus bx, mri, and their combination had poor concordance and limited accuracies in assessment of the laterality of tumor involvement. the combination of trus bx and mri offered a better of accuracy when compared to either modality alone. mri was a specific, but not sensitive tool in assessing the presence of extra-capsular extension. keywords: neoplasm invasiveness; prostatic neoplasms; image interpretation; neoplasm staging; predictive value of tests; sensitivity and specificity; magnetic resonance imaging. 1616 | introduction since the adoption of prostate-specific antigen (psa) testing, the incidence of prostate cancer had been gradually climbing up in the ranking of most prevalent cancers. in the united states, prostate cancer had become the most common solid-organ cancer diagnosed in 2012.(1) in hong kong, prostate cancer ranked fifth with 1,492 new cases registered in 2010.(2) in addition, a larger proportion of prostate cancer was diagnosed in their early and low-risk stage.(3) thus, the demand for definitive treatment, such as radical prostatectomy, was unprecedented. continence and erectile function are two major concerns affecting the post-operative quality of life. nerve-sparing technique was shown to offer early return of continence(4) and preservation of erectile function,(5) hence nerve-sparing prostatectomy had become the standard of care for organconfined prostate cancer.(6) pre-operative risk assessment and tumor localization are important for operative decisions. tools for pre-operative tumor localization, however, had arguable accuracy despite technological advancement. transrectal ultrasound-guided 12-core prostatic biopsy (trus bx) was used to diagnose and to determine the laterality of prostate cancer. magnetic resonance imaging (mri) of the prostate, besides the laterality of tumor, also provides information regarding extra-capsular extension of the tumor.(7) based on our experience, we conducted this review with the primary objective to determine the accuracy of trus bx, mri and their combination in evaluating the laterality of prostate cancer. our second objective was to determine the reliability of mri in assessing extra-capsular extension of prostate cancer. materials and methods we retrospectively reviewed our past 100 consecutive series of radical prostatectomy performed between february 2010 and april 2012 at our institution. their trus bx and mri results were compared with the final pathology of the radical prostatectomy specimens. all radical prostatectomy specimens were submitted for standardized slicing and processing,(8) and were reported by experienced pathologists. trus bx with at least 12 cores, performed at our institution and elsewhere with retrievable pathology reports were included for analysis. our institution adopted the use of aloka prosound 6 ultrasound machine (prosound alpha 7, aloka, tokyo, japan) and pajunk delta cut biopsy system. in order to minimize the confounding factor of using different mri scanners and sequences, only those scans performed at our institution were included. we used the siemens magnetom avanto 1.5-tesla mri system (siemens magnetom avanto, erlangen, germany). with a pelvisphased body array coil system, our scanner produced t1 and t2 images with contrast phase, as well as diffusion weight images. our mri scans were reported by at least one experienced radiologist. the above specifications were in accordance with the minimal requirement established by the european consensus meeting in 2009.(7) the key information we retrieved from the mri reports were laterality of the tumor, and whether there was extra-capsular extension. regarding the evaluation of tumor laterality, we calculated the accuracy in unilateral disease, accuracy in bilateral disease, and overall accuracy for trus bx, mri and their combination. bilateral disease in combination was defined as bilateral disease in either trus bx or mri, or when trus bx and mri indicated unilateral disease of opposite sides. we calculated the cohen kappa to indicate the concordance of trus bx, mri and their combination with the final pathology. statistical analysis statistical analysis was performed using the statistical packurological oncology table 1. tumor characteristics (n = 100). variables % psa level ng/ml < 10 64 10-20 29 > 20 7 gleason score 3 + 3 79 3 + 4 / 4 + 3 19 4 + 4 or above 2 laterality on final pathology bilateral 82 left only 11 right only 7 extra-capsular extension absent 68 present 32 key: psa, prostate-specific antigen. 1617vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l evaluation of extra-capsular extension of prostate cancer | kan et al age for the social science (spss inc, chicago, illinois, usa) version 10.0. regarding extra-capsular extension, we computed the sensitivity, specificity, positive predicted value, negative predictive value, overall accuracy, likelihood ratio positive and likelihood ratio negative of mri in assessing the presence of extra-capsular extension in the final pathology. results table 1 showed the tumor characteristics of our cohort of 100 patients who underwent radical prostatectomy. sixtyfour patients had a pre-operative psa level of less than 10 ng/ml, 29 patients had a level between 10 and 20 ng/ml, while 7 patients had a level greater than 20 ng/ml. regarding gleason score, 79 patients had a score of 3 + 3 in the final pathology, 19 patients had a score of 7, while 2 patients had a score of 8 or above. regarding laterality of tumor in the prostatectomy specimen, 82 patients had bilateral tumor involvement, while 18 had unilateral disease. among these 100 radical prostatectomy specimens, 32 had extra-capsular extension. table 2 showed our results in pre-operative evaluation of tumor laterality. there were 94 patients whose trus bx reports were available for analysis. fifty six patients had their mri scans performed at our institution, among which 20 scans did not visualize the biopsy-proven prostate cancer. therefore we performed our analysis based on the remaining 36 mri scans. the accuracies of trus bx in unilateral disease, bilateral disease and overall accuracy were 15.2%, 91.4% and 43.6%, respectively. the accuracies of mri in unilateral disease, bilateral disease and overall accuracy were 11.1%, 66.7% and 38.9% respectively. when combining the assessment of trus bx and mri, the accuracies in unilateral disease, bilateral disease and overall accuracy were 16.7%, 75% and 55.6%, respectively. the concordance of trus bx, mri and their combination, as indicated by their cohen kappa co-efficient, were 0.1165, -0.2047 and -0.1084, respectively. table 3 demonstrated our analysis regarding the assessment of extra-capsular extension. among these 56 patients, 17 (30.4%) had extra-capsular extension on the prostatectomy specimens. the positive predictive value, negative predictive value, sensitivity, specificity, overall accuracy, likelihood ratio positive and likelihood ratio negative of mri in assessing extra-capsular extension were 33.3%, 69.8%, 5.9%, 94.9%, 67.9%, 1.16 and 0.99, respectively. discussion trus bx is one of the most important pre-operative investigations to determine the tumor laterality, however, our results fell short of satisfying. due to the multifocal nature of prostate cancer, 82% of all radical prostatectomy specimens in our series were bilaterally involved. as these foci were microscopically present, they easily succumbed to sampling table 2. accuracy in prediction of tumor laterality. variables final pathology cohen kappa (к) data analysis (%) right only left only bilateral total accuracy of unilateral disease = 15.2 accuracy of bilateral disease = 91.4 overall accuracy = 43.6trus bx (n = 94) right only 4 4 19 27 0.1165 95% ci = 0.0066 – 0.2265 left only 1 5 26 32 bilateral 2 1 32 35 total 7 10 77 94 mri (n = 56) visible (n = 36) not seen (n = 20) right only 0 0 8 8 -0.2047 95% ci = -0.4397 – 0.0302 accuracy of unilateral disease = 11.1 accuracy of bilateral disease = 66.7 overall accuracy = 38.9 left only 0 2 8 10 bilateral 4 2 12 18 total 4 4 28 36 combination (n = 36) right only 0 0 5 5 -0.1084 95% ci = -0.3767 – 0.1600 accuracy of unilateral disease = 16.7 accuracy of bilateral disease = 75 overall accuracy = 55.6 left only 0 2 5 7 bilateral 4 2 18 24 total 4 4 28 36 keys: ci, confidence interval; trus bx, transrectal ultrasound-guided prostatic biopsy; mri, magnetic resonance imaging. 1618 | urological oncology error in trus bx. as a result, most of the apparently unilateral disease in trus bx turned out to be bilaterally involved in the prostatectomy specimens. this resulted in a very disappointing accuracy in unilateral disease of 15.2%. notwithstanding, the accuracy in bilateral disease was a reassuring 91.4%. the cohen kappa coefficient of trus bx was 0.1165, indicating only slight agreement between trus bx and final pathology. it was evident that trus bx had limited reliability in evaluating unilateral disease. a handful of cases where trus bx indicated unilateral disease turned out to be unilaterally involved on the opposite side in the prostatectomy specimens. this situation was also present in other similar studies.(9,10) this “unilateral vanishing cancer syndrome” was another proof of the multifocal nature of prostate cancer. advances in mri had allowed a combination of modern mri sequences into a more informative multi-parametric mri scanning. to address the diversity in techniques and image interpretation, the european consensus meeting had established a set of guidelines regarding the multi-parametric mri scanning.(7) the evidence regarding multi-parametric mri scanning was conflicting. although in general the performance of multi-parametric mri was reckoned promising,(11,12) there existed conflicting opinion regarding its accuracy and usefulness.(13) we routinely recommended mri scanning for all patients diagnosed with prostate cancer who opted to undergo radical prostatectomy. the scan was scheduled 8-12 weeks after trus bx. among the 56 mri scans performed at our institution, 20 scans could not visualize a biopsy-proven prostate cancer. for the remaining 36 scans, the accuracy in unilateral disease was 11.1% and the accuracy in bilateral disease was 66.7%, both of which were worse than those of trus bx. this resulted in an overall accuracy of 38.9%. the cohen kappa coefficient of mri was negative, which indicated no agreement between mri evaluation and final pathology. our results clearly showed that the use of our mri scanning sequences, which met the minimal requirement as suggested by the european consensus meeting(7) was suboptimal. the adoption of higher magnetic field power and endorectal coil, as well as the addition of dynamic contrast enhancement and spectroscopy could arguably increase the sensitivity and accuracy in tumor localization.(11) the complementary combination of trus bx and mri was able to improve the accuracy in evaluating unilateral disease, as well as the overall accuracy, when compared to either modality alone. the overall accuracy of their combination reached 55.6%. regarding the assessment of extra-capsular extension, our results showed that mri was a highly specific, but not sensitive tool. the specificity was as high as 94.9%, but the sensitivity was unacceptably low at 5.9%. this might be partly explained by the difference between macroscopic and microscopic extra-capsular extension. the other explanation might be the inter-observer variability in deciphering the mri images. the inter-observer variability, and the differences in imaging criteria used for a positive mri finding contributed to the wide range of accuracy in mri performance.(11) in an attempt to standardize the interpretation and reporting of mri scanning, the european society of urogenital radiology had proposed the prostate imaging reporting and data system (pi-rads) scoring system.(14) the adoption of this objective and structured reporting system, together with designating an experienced group of urogenital radiologists for the interpretation, might aid to reduce the inter-observer variability and to enable comparison among different patients. as new technologies regarding mri scanning was develtable 3. accuracy in prediction of extra-capsular extension. variables pathology ppv = 1/3 (33.3%) npv = 37/53 (69.8%) sensitivity = 1/17 (5.9%) specificity = 37/39 (94.9%) overall accuracy = 38/56 (67.9%) lr (+) = 1.16 lr (-) = 0.99 ece no ece total mri (n = 56) ece 1 2 3 no ece 16 37 53 total 17 39 56 keys: ppv, positive predictive value; npv, negative predictive value; lr (+), likelihood ratio positive; lr (-), likelihood ratio negative; mri, magnetic resonance imaging; ece, extra-capsular extension. 1619vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l evaluation of extra-capsular extension of prostate cancer | kan et al references 1. siegel r, naishadham d, jemal a. cancer statistics, 2012. ca cancer j clin. 2012;62:10-29. 2. hong kong cancer registry, hospital authority, hong kong. accessed on: www.ha.org.hk/cancereg. 3. cooperberg mr, broering jm, kantoff pw, carroll pr. contemporary trends in low risk prostate cancer: risk assessment and treatment. j urol. 2007;178:s14-9. 4. srivastava a, chopra s, pham a, et al. effect of a risk-stratified grade of nerve-sparing technique on early return of continence after robot-assisted laparoscopic radical prostatectomy. eur urol. 2013;63:438-44. 5. meuleman ej, mulders pf. erectile function after radical prostatectomy: a review. eur urol. 2003;43:95-101. 6. montorsi f, wilson tg, rosen rc, et al. best practice in robot-assisted radical prostatectomy: recommendations of the pasadena consensus panel. eur urol. 2012;62:368-381. 7. dickinson l, ahmed hu, allen c, et al. magnetic resonance imaging for the detection, localisation, and characterisation of prostate cancer: recommendations from a european consensus meeting. eur urol. 2011;59:477-94. 8. samaratunga h, montironi r, true l, et al. international society of urological pathology (isup) consensus conference on handling and staging of radical prostatectomy specimens. working group 1: specimen handling. mod pathol. 2011;24:6-15. 9. frota r, stein rj, turna b, et al. are prostate needle biopsies predictive of the laterality of significant cancer and positive surgical margins? bju int. 2009;104:1599-603. oping inexorably, we believed the role of mri in prostate cancer could be potentially pivotal when making important clinical decisions in the future. conclusion trus bx, mri and their combination had poor concordance and limited accuracies in evaluating the laterality of tumor involvement. the combination of trus bx and mri offered a better overall accuracy when compared to either modality alone. mri was a specific, but not sensitive tool in assessing the presence of extra-capsular extension. when planning for nerve-sparing radical prostatectomy, urologists should recognize the limitations of each pre-operative investigation in terms of tumor localization and assessment of extra-capsular extension. conflict of interest none declared. 10. jeong cw, ku jh, moon kc, et al. can conventional magnetic resonance imaging, prostate needle biopsy, or their combination predict the laterality of clinically localized prostate cancer? urology. 2012;79:1322-7. 11. kirkham ap, emberton m, allen c. how good is mri at detecting and characterizing cancer within the prostate? eur urol. 2006;50:1163-74. 12. puech p, huglo d, petyt g, lemaitre l, villers a. imaging of organconfirmed prostate cancer: functional ultrasound, mri and pet/ computed tomography. curr opin urol. 2009;19:168-76. 13. kelloff gj, choyke p, coffey ds, prostate cancer imaging working group. challenges in clinical prostate cancer: role of imaging. am j roentgenol. 2009;192:1455-70. 14. barentsz jo, richenberg j, clements r, et al. esur prostate mr guidelines 2012. eur radiol. 2012;22:746-57. vol 13 no 02 march-april 2016 2590vol 13 no 02 march-april 2016 2612 purpose: the purpose of this study was to assess the impact of music on anxiety and perceived pain during transrectal ultrasound-guided prostate biopsy. materials and methods: forty consecutive men with an elevated serum prostate specific antigen (psa) level and/ or an abnormal digital rectal examination referred for transrectal ultrasound-guided prostate biopsy were recruited and allocated to a music (n = 20) or a non-music (n = 20) group. anxiety was assessed prior to and after biopsy and pain was assessed after biopsy in each patient using visual analog scales (vas) in the same setting, and group anxiety scores were compared. results: patients in the music group experienced less anxiety (p = .046) during the procedure, but group pain scores were not significantly different. conclusion: music was found to decrease anxiety effectively during transrectal ultrasound-guided prostate biopsy. keywords: prostatic neoplasms; diagnosis; ultrasonography; interventional/methods; biopsy; pain management; analgesia; anxiety; prevention & control; music therapy; instrumentation. introduction the prostate is the most common site of cancer in older males in the us, and transrectal ultrasound-guided prostate biopsy is the standard procedure used to determine the presence of prostate cancer.(1,2) local anesthesia is usually adopted to reduce anxiety and pain during prostate biopsy, but some studies have reported that a considerable proportion of patients experience significant anxiety and pain.(3,4) furthermore, it has been suggested that anxiety and pain related to prostate biopsy are influenced not only by physical aspects of the procedure but also by psychological factors. (5) however, no study has previously investigated the use of music to reduce anxiety and pain during prostate biopsy. accordingly, the aim of the present study was to investigate the impact of music on anxiety and pain during transrectal ultrasound-guided prostate biopsy. materials and methods institutional review board approval was not required for this study and written informed consent was obtained from all patients prior to study commencement. the study was performed using a prospective, randomized design on 40 consecutive men suspected of having prostate cancer and scheduled for transrectal ultrasound-guided biopsy from june 2004 to december 2004. the inclusion criteria for the study were an elevated serum prostate specific antigen (psa) level (≥ 4.0 ng/ml) and/or abnormal digital rectal examination findings. no patient had a history of previous prostate biopsy. patients with a painful condition of the rectum and/or anus (e.g., hemorrhoids, anal fissure, or clinically evident prostatitis) or a known allergy to prilocaine were excluded from the study; 10 patients were excluded for these reasons. patients allocated to the music and non-music groups randomly using a computer generated randomization list. group designations were placed in sealed envelope and allocated consecutively. all study participants and those that assessed outcomes were unaware of group assignments. patients in the experimental group chose music before the procedure from a compilation of ballads. volume and pitch were controlled at a comfortable level. music was played continuously from before patient arrival until after patient departure. a controlled environment was created to minimize the effects of additional variables. the office door was closed, a “research in progress-do not disturb” sign was posted and lights were turned on. before biopsy, anxiety was assessed in each subject using a visual analog scale (vas). bilateral urological oncology effect of music on reducing anxiety for patients undergoing transrectal ultrasound-guided prostate biopsies: randomized prospective trial seong whi cho, hyuck jae choi* department of radiology, kangwon national university hospital, chuncheon, korea. *correspondence: department of radiology, kangwon national university hospital, 156 baengnyeong-ro, chuncheon 200722, korea. tel: +82 33 2582479. fax: +82 33 2582120. e-mail: choihjmd@gmail.com. received september 2015 & accepted february 2016 periprostatic nerve blockages (pnb) were performed bilaterally using 5 mg of 1% prilocaine into the prostatic vascular pedicle region. each subject also assessed for pain during anesthesia, biopsy, and immediate after biopsy using a 10 point vas scale, were 0 indicated “no pain” and 10 indicated “worst pain imaginable”. fluoroquinolone was administered 30-60 min before biopsy and continued for 2-3 days after biopsy. the primary outcome measures were vas anxiety and pain scores during prostate biopsy. there was no secondary outcome measure because music therapy has no side effects is easily performed. the mann-whiney u test was used to compare group scores. p values of < .05 were considered statistically significant, and post-hoc powers were calculated. results of 50 men that underwent biopsy at our institute during a 7-month period, 40 were randomized equally to the music (n = 20) or non-music (n = 20) groups. the two groups were well-matched, and no significant intergroup differences were found for patient characteristics, which included prostate volume, psa level, and age (table). a statistical difference was found between vas anxiety scores before prostate biopsy (p = .046) but no significant difference was found between pain scores during anesthesia, during biopsy, or immediately after biopsy (table). post-hoc power analysis showed statistical power was greatest for pre-biopsy anxiety. discussion transrectal ultrasound-guided prostate biopsy is an important component of the urologic armamentarium and is frequently performed in offices and outpatient urology centers worldwide.(1,2) men undergoing transrectal ultrasound-guided prostate biopsy experience considerable stress, due to fear of a diagnosis of cancer, anal penetration, anticipated pain, and fear associated with the fact that the subject organ is part of the sexual system.(2,6) music therapy has been demonstrated to be effective in patients before surgery and in medically ill patients(8-13) and to reduce sympathetic nervous system activity, to induce a relaxation response, and to produce a sense of well-being.(11,12) recently the effectiveness of music therapy has been evaluated for biopsies and other painful procedures and shown to usefully reduce anxiety and pain.(14-17) furthermore, it has been reported music may increase pain thresholds by promoting relaxation and reducing anxiety(18,19) and to distract patients from worries and anxieties, and thus, reduce pain and distress.(20,21) in the present study, a significant reduction in anxiety was found pre-biopsy step with a statistical power of 72.5%. on the other hand, pain scores were not significantly different in the two study groups, no significant pain reduction was observed in the music group during or immediately after biopsy. some limitations of this study warrant consideration. first, the number of patients enrolled was small, which we suspect was responsible for the lack of significant differences between pain scores. second, pain associated with ultrasound probe manipulation and anxiety on arrival at the office were not assessed. third, we used a vas scale to evaluate anxiety rather than the hamilton anxiety scale or the beck anxiety inventory, and thus, we suggest that these tools be utilized any future study. conclusions in conclusion, this preliminary study suggests music can reduce anxiety before transrectal ultrasound-guided prostate biopsy, and that, although not found to be statistically significant, music has the potential to reduce pain during and after the procedure. acknowledgments this research was supported by grants from national research foundation of korea grant funded by the korean government (no. 220090083512). conflict of interest none declared. table. patient characteristics and visual analog scale scores for music and non-music groups. groups prostate serum psa age (year) visual analog scale score volume (cm3) (ng/ml) anxiety* anesthesia biopsy anxiety** music (n = 20) 65.4 ± 49.4 16.3 ± 12.2 63.4 ± 7.2 5.6 ± 1.8 5.0 ± 2.2 5.6 ± 2.5 4.1 ± 2.1 non-music (n = 20) 68.1 ± 37.1 13.41 ± 11.8 59.8 ± 10.9 4.2 ± 1.7 4.8 ± 2.3 5.6 ± 2.4 5.0 ± 2.6 p value .246 .766 .502 .046 .663 .865 .303 abbreviations: psa, prostate specific antigen. * anxiety before biopsy. ** anxiety after biopsy. values are presented as mean ± standard deviation effect of music on transrectal ultrasound guided prostate biopsy-cho et al. urological oncology 2613 vol 13 no 02 march-april 2016 2614 references 1. cooner wh, mosley br, rutherford cl, et al. prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. j urol. 1990;143:1146-54. 2. collins gn, lloyd sn, hehir m, mckelvie gb. multiple transrectal ultrasound guided prostatic biopsies: true morbidity and patient acceptance. br j urol. 1993;71:460-3. 3. nash pa, bruce je, indudhara r, shinohara k. transrectal ultrasound guided prostatic nerve blockage ease systematic needle biopsy of the prostate. j urol. 1996;155:607-9. 4. soloway ms, obek c. periprostatic local anesthesia before ultrasound guided prostate biopsy. j urol. 2000;163:172-3. 5. oliffe j. transrectal ultrasound prostate biopsy (trus-bx): patient perspectives. surgeon 2004;2:221-4. 6. rodrigez lv, terris mk. risks and complications of transrectal ultrasound guided prostate needle biopsy: a prospective study and review of the literature. j urol. 1998;160:2115-20. 7. zemann dh, ishigooka m, doggweiler r, schimidt ra. neurological insights into the etiology of genitourinary pain in men. j urol. 1999;161:903-8. 8. buers jf, smyth ka. effect of a music intervention on noise annoyance, heart rate, and blood pressure in cardiac surgery patients. am j crit care. 1997;6:183-91. 9. miluk kb, matejek m, stupnicki r. the effects of music listening on changes in selected physiological parameters in adult presurgical patients. j music ther. 1996;33:20818. 10. johnston k, davis rj. an introduction to music therapy: helping the oncology patient in the icu. crit care nurs. 1996;18:54-60. 11. weber s. the effects of relaxation exercises on anxiety levels in psychiatric patients. j holistic nurs. 1996;14:196-205. 12. yung pmb, szeto ck, french p, chan tmf. a controlled trial of music and preoperative anxiety in chinese men undergoing transurethral resection of the prostate. j adv nurs. 2002;39:352-9. 13. chan ym, lee pw, ng ty, wong lc. the use of music to reduce anxiety for patients undergoing colposcopy: a randomized trial. gynecol oncol. 2003;91:213-7. 14. zahid mf. methods of reducing pain during bone marrow biopsy: a narrative review. ann palliat med. 2015;4:184-93. 15. shabanloei r, golchin m, esfahani a, dolatkhah r, rasoulian m. effects of music therapy on pain and anxiety in patients undergoing bone marrow biopsy and aspiration. aorn j. 2010;91:746-51. 16. nguyen tn, nilsson s, hellström al, bengtson a. music therapy to reduce pain and anxiety in children with cancer undergoing lumber puncture: a randomized clinical trial. j pediatr oncol nurs. 2010;27:146-55. 17. bufalini a. role of interactive music in oncological pediatric patients undergoing painful procedures. minerva pediatr. 2009;61:379-89. 18. amir d. musical and verbal intervention in music therapy: a qualitative study. j music ther. 1999;36:144-75. 19. almerud s, petersson k. music therapy: a complementary treatment for mechanically ventilated intensive care patients. intensive crit care nurs. 2003;19:21-30. 20. burns jl, labbe e, arke b, capeless k, cooksey b, steadman a, gonzales c. the effects of different types of music on perceived and physiological measures of stress. j music ther. 2002;39:101-16. 21. magil levreault l. music therapy in pain and symptom management. j palliat care. 1993;9:42-8. effect of music on transrectal ultrasound guided prostate biopsy-cho et al. pictorial management of migrated intravesical staples post laparoscopic colposuspension michael st john floyd (jr),1 david hughes,2 paul witold kutarski1 a 43 years old female presented with recurrent urinary tract infections. her past history included a laparoscopic colposuspension aged 33 years in which mesh was stapled to the ileopectineal ligament. she developed recurrent incontinence 12 years later and underwent trans-vaginal tape insertion. cystoscopy revealed two encrusted staples in her bladder which had migrated following her colposuspension. they were located adjacent to the left ureteric orifice and on the right had side of the bladder wall (figures 1 and 2). plain x-ray revealed tacks along the pelvic brim (figure 3). she was initially managed conservatively with antimicrobial prophylaxis but continued to complain of left sided pelvic pain and infections. using a suprapubic approach a laparoscopic port was inserted into the bladder and the encrusted staples were grasped with rigid forceps via the port. the adjacent urothelium was incised cystoscopically using a holmium laser, the staples removed and a catheter placed for seven days. at 6 months postoperatively the patient was infection free. management of iatrogenic foreign bodies following incontinence procedures has been documented with pain and infections being frequent presenting symptoms.(1) transurethral endoscopic excision is used to treat mesh erosions, but a modified technique can remove bladder staples effectively.(2,3) departments of urology1 and radiology 2,wirral universi ty hospital trust, arrowe park, upton, merseyside, ch49 5pe, united kingdom. corresponding author: department of urology, wirral university hospital trust, arrowe park, upton, merseyside, ch49 5pe, united kingdom. e-mail: nilbury@gmail.com received february 2014 accepted june 2014 figure 1. staples are located adjacent to the left ureteric orifice. figure 2. on the right staples had side of the bladder wall. figure 3. plain x-ray demonstrates tacks along the pelvic brim. references 1. frenkl tl, rackley rr, vasavada sp, goldman hb. management of iatrogenic foreign bodies of the bladder and urethra following pelvic floor surgery. neurourol urodyn. 2008;27:491-5 2. doumouchtsis sk, lee fy, bramwell d, fynes mm. evaluation of holmium laser for managing mesh/suture com plications of continence surgery. bju int. 2011;108:1472-8. 3. davis nf, smyth lg, giri sk, flood hd. evaluation of endoscopic laser excision of polypropylene mesh/sutures following anti-incontinence procedure. j urol. 2012;188:1828-32. 1853 pictorial vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2527 urological oncology evaluation of vitronectin expression in prostate cancer and the clinical significance of the association of vitronectin expression with prostate specific antigen in detecting prostate cancer yue niu,1 ling zhang,2 xing bi,1 shuai yuan,1 peng chen1* purpose: to detect the expression of vitronectin (vtn) in the tissues and blood serum of prostate cancer (pca) patients, and evaluate its clinical significance and to evaluate the significance of the combined assay of vtn and prostate specific antigens (psa) in pca diagnosis. materials and methods: to detect the expression of vtn as a potential marker for pca diagnosis and prognosis, immunohistochemistry was performed on the tissues of 32 patients with metastatic pca (pcam), 34 patients with pca without metastasis (pca), and 41 patients with benign prostatic hyperplasia (bph). the sera were then subjected to western blot analysis. all cases were subsequently examined to determine the concentrations of psa and vtn in the sera. the collected data were collated and analyzed. results: the positive expression rates of vtn in the tissues of the bph and pca groups (including pca and pcam groups) were 75.61% and 45.45%, respectively (p = .005). vtn was more highly expressed in the sera of the bph patients (0.83 ± 0.07) than in the sera of the pca patients (0.65 ± 0.06) (p < .05). it was also more highly expressed in the sera of the pca patients than in the sera of the pcam patients (0.35 ± 0.08) (p < .05). in the diagnosis of bph and pca, the youden indexes of psa detection, vtn detection, and combined detection were 0.2620, 0.3468, and 0.5635; the kappa values were 0.338, 0.304, and 0.448, respectively, and the areas under the receiver operating characteristic curve were 0.625, 0.673, and 0.703 (p < .05), respectively. conclusion: vtn levels in sera may be used as a potential marker of pca for the diagnosis and assessment of disease progression and metastasis. the combined detection of vtn and psa in sera can be clinically applied in pca diagnosis. keywords: cell line; tumor; prostatic neoplasms; vitronectin; metabolism; humans; biomarkers; early detection of cancer; prostate-specific antigen. introduction prostate cancer (pca) is a malignant tumor common among male europeans and americans. the incidence of this disease in china has gradually increased in recent years.(1) prostate specific antigen (psa) is the most widely used prostate tumor markers. serum psa concentrations significantly affect treatment modalities in males with pca. however, psa tend to increase during benign prostate hyperplasia (bph), prostatitis, urethral catheter, and digital rectal exams.(2) over-diagnosis and the resulting over-treatment of occult cancer are thus common. psa detection suffers from limited sensitivity and specificity. furthermore, the significance of psa declines in the later stages of the disease.(3,4) the search for effective serum tumor markers for pca is significant in improving the level of the diagnosis of pca and determining treatment prognosis. vitronectin (vtn) is a glycoprotein, which is a member of the integrin family. it changes in the sera and tissues of people, and is associated with the occurrence and metastasis of tumor.(5) however, the studies on vtn and pca are relatively rare. hence, the present study aimed to explore the expression of vtn in the tissues and sera of pca patients and the significance of the combined detection of vtn and psa in the diagnosis and treatment of pca. materials and methods study patients patient data, blood samples, and prostate tissue samples were collected from the prostate disease patients of the urology department of the xinjiang medical university affiliated tumor hospital between december 2010 and february 2015. all cases were examined for psa. 1 affiliated tumor hospital of xinjiang medical university, xinjiang, china. 2 center for disease control and prevention of xinjiang uygur autonomous region, xinjiang, china. *correspondence: affiliated tumor hospital of xinjiang medical university, xinjiang, china. tel: +88 991 7819152. fax: +88 991 7968111. e-mail: alex-new@163.com. received june 2015 & accepted november 2015 10% ≤ color area < 50%, 2 points; 50% ≤ color area < 75%, 3 points; color area ≥ 75%. color intensity was multiplied with color area; a score of 3 or more was considered as positive, whereas a score of less than 3 was considered as negative. western blot analysis of vtn in sera western blot analysis was carried out according to the instruction manual, which provided guidelines regarding the preparation of sodium dodecyl sulfate (sds)-polyacrylamide gel electrophoresis (page), addition of samples, electrophoresis, transfer, sealing, addition of the first antibody (mouse anti-human, r&d co., 614 mckinley place ne minneapolis, mn 55413, usa), cleaning, addition of the second antibody (rabbit anti-mouse, sigma co., st. louis, mo, usa), cleaning, chemiluminescence, exposure, development, and so on. pictures of the chromogenic results were taken with an image analysis system, which was used to record the optical density and intensity values of the electrophoretic bands. the calculation formula for the optical density ratios was (intensity value of vtn band × optical density value of vtn band) / (intensity value of β-actin band × optical density value of β-actin band). the analysis was semi-quantitative. expression of vitronectin in patients with pca-niu et al. urological oncology 2528 pathological types were determined via biopsy or operation, whereas metastasis was determined via computed tomography (ct) scan, magnetic resonance imaging (mri) and bone scan. finally, 34 patients with prostate cancer without metastasis (pca), 32 patients with prostate cancer with metastasis (pcam), and 41 patients with bph were included. the mean ages of the patients with pca, pcam, and bph were 65.27 ± 9.07, 67.02 ± 10.02, and 64.12 ± 7.33 years, respectively. immunohistochemistry for vtn in tissues all tissue samples were collected via surgery or biopsy. multiple 4-µm-thick sections of representative formalin-fixed, paraffin-embedded tissues were cut for immunohistochemical studies. a polymer-based immunohistochemical was used to detect vtn (mouse anti-human, r&d co, 614 mckinley place ne minneapolis, mn 55413, usa). all immunostained sections were examined under a light microscope (olympus ckx41, olympus optical co., ltd., tokyo, japan) to evaluate vtn. vtn staining was cytoplasmic. the standards for determining immunohistochemistry were as follows. color intensity: 0 point; no stain, 1 point; faint cytoplasmic stain, 2 points; diffuse cytoplasmic stain, 3 points; diffuse intense cytoplasmic stain. color area: 0 point; color area < 10%, 1 point; table 1. vitronectin expression in prostate cancer tissues and its relationship with clinicopathological factors. factor positive, no. negative, no. expression rate, % χ2 p value age, years < 70 16 19 45.16 0.002 .964 ≥ 70 14 17 45.71 psa, ng/ml < 4 2 0 100.00 11.24 .004 4-10 11 3 78.57 > 10 17 33 34.00 clinical stage t2 7 5 58.33 7.41 .025 t3 13 7 65.00 t4 10 24 29.41 gleason score ≤ 6 8 2 80.00 11.06 .004 7 12 8 60.00 ≥ 8 10 26 27.78 tumor metastasis yes 9 23 28.12 7.52 .006 no 21 13 61.76 abbreviation: psa, prostate specific antigen. vol 13 no 01 january-february 2016 2529 determination of the concentrations of vtn and psa in sera the vtn concentrations in the sera of all the patients were detected via an enzyme-linked immunoassay (synergy 2 multimode microplate reader, biotek co., usa; enzyme-linked immunoassay kit, r&d co., 614 mckinley place ne minneapolis, mn 55413, usa), whereas the psa concentrations were detected via an electrochemiluminescence immunoassay (cobas 6000 fully automatic electrochemistry luminescence instrument and corresponding kit, roche co., grenzach, germany). the positive results of the combined parallel detection indicated that psa or vtn was positive in the pca patients. statistical analysis data analysis and processing were performed with the statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. the immunohistochemistry results, the vtn expression in pca tissue, and the relationship of such expression with clinicopathological factors were analyzed with the chi-square test. the western blot results were obtained via variance analysis and the student-newman-keuls (snk) method, α = 0.05. the evaluation indexes of vtn detection, psa detection, and combined parallel detection in the sera from the pca and bph groups included kappa values, sensitivity, specificity, youden indexes, and total coincidence rates. a receiver operating characteristic (roc) curve was drawn using the sensitivity and specificity indexes to compare vtn detection, psa detection, and their combined parallel detection in sera for pca diagnosis. results immunohistochemistry of vtn in tissue samples and its relationship with clinicopathological factors vtn protein was expressed in pca tissues (including pca and pcam tissues) and bph tissues, as shown in figures 1 and 2, respectively. the cytoplasm was stained brown, as shown in both figures. according to the immunohistochemical results, the positive expression rates of vtn in the bph and pca groups (including the pca and pcam groups) were 75.61% and table 2. comparison of experimental diagnosis indexes of sera with and without metastatic prostate cancer. test index sensitivity % specificity % total coincidence rate, % youden index vtn detection 56.90 77.78 64.89 0.3468 psa detection 76.75 49.45 59.57 0.2620 combined parallel detection 80.23 76.12 67.12 0.5635 abbreviations: vtn, vitronectin; psa, prostate specific antigen. figure 1. vitronectin expression in tissue samples of patients with benign prostatic hyperplasia. a) no stain (0 point); b) faint cytoplasmic stain (1 point); c) diffuse cytoplasmic stain (2 points); d) diffuse intense cytoplasmic stain (3 points). figure 2. vitronectin expression in tissue samples of patients with and without metastatic prostate cancer. a) no stain (0 point); b) faint cytoplasmic stain (1 point); c) diffuse cytoplasmic stain (2 points); d) diffuse intense cytoplasmic stain (3 points). expression of vitronectin in patients with pca-niu et al. 45.45%, respectively. the vtn protein expression in the bph group was higher than that in the pca group (including pca and pcam; p = .005). the vtn expression in the pca tissues (including pca and pcam tissues) was related to the psa of newly diagnosed patients, clinical stage, gleason score, and tumor metastasis; however, it was not associated with patient age (table 1). western blot analysis of vtn in serum samples figure 3 shows that vtn could be detected in the serum samples from the pcam, pca, and bph groups. specific bands appeared with a relative molecular mass of 72 kda. the optical density ratios of vtn in the serum samples from the bph, pca, and pcam groups were 0.83 ± 0.07, 0.65 ± 0.06, and 0.35 ± 0.08, respectively. the results of the variance analysis showed that the optical density ratios of vtn in the serum samples from the bph, pca, and pcam groups were not totally equal (f = 396.72, p = .000). the results of the snk method showed that vtn expressions in the three groups differed. the optical density ratios of vtn in the serum samples from the bph group were higher than those from the pca group. in addition, vtn expression in the pca group was higher than that in the pcam group (figure 4). combined parallel detection of vtn and psa for pca and bph diagnosis the vtn concentrations in the bph, pca, and pcam groups were 219.63 ± 25.30, 201.72 ± 19.37, and 170.05 ± 23.80 ng/ml, respectively, with statistically significant differences (p < .05). the psa concentrations in the bph, pca, and pcam groups were 5.45 ± 3.48, 15.45 ± 9.66, and 65.29 ± 31.50 ng/ml, respectively, with statistically significant differences (p < .05). kappa values were used to evaluate the reliability of the diagnostic tests. the kappa values of vtn detection, psa detection, and combined parallel detection in the pca and pcam groups were 0.338, 0.304, and 0.408, respectively. according to kanidis and koch’s standards, combined parallel detection was found to be more consistent than single detection in the pca and pcam groups, with such consistency being moderate. it yielded a certain value for pca diagnosis. sensitivity, specificity, the youden index, and the total coincidence rate were analyzed. the calculated results showed that the single detection of psa in pca exhibited high sensitivity but low specificity and total coincidence rate. by contrast, the single detection of vtn yielded opposite results. in addition, the specificity of the combined parallel detection of psa and vtn was figure 3. vitronectin expression detected by western blot analysis. figure 3 shows that vitronectin could be detected in the serum samples from the pcam, pca, and bph groups. specific bands of vitronectin appeared with a relative molecular mass of 72 kda, and β-actin appeared with 42 kda. abbreviations: bph, benign prostatic hyperplasia; pca, prostate cancer; m, metastasis. 1: bph; 2: pca; 3: pcam. figure 4. optical density ratios of vitronectin for serum samples from each group. figure 4 shows that the optical density ratios of vitronectin in the serum samples from the bph, pca, and pcam groups were 0.83 ± 0.07, 0.65 ± 0.06, and 0.35 ± 0.08, respectively. the results were statistically significant. abbreviations: bph, benign prostatic hyperplasia; pca, prostate cancer; m, metastasis. expression of vitronectin in patients with pca-niu et al. urological oncology 2530 vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2531 slightly lower than that of single psa detection. however, the sensitivity, total coincidence rate, and youden index were better in the combined approach (table 2). the values of psa and vtn detection for pca diagnosis were evaluated with the roc curve. the areas under the curves (aucs) of psa and vtn were 0.625 and 0.673 in the pca and pcam groups (figure 5), respectively; the difference was statistically significant (p < .05). the auc of the combined parallel detection of vtn and psa was 0.703 in both the pca and pcam groups (figure 5); thus, the accuracy of this combined detection method is better than that of single detection (p < .05). discussion the vtn protein is a specific ligand of the αvβ3 integrin family that is present on the surface of vascular endothelial cells.(6) because it contains the rgd peptide sequence (arg-gly-asp). the interaction of vtn and αvβ3 promotes the adhesion of monocytes and endothelial cells in blood circulation. αvβ3 is widely expressed on the surface of malignant tumor cells and vascular endothelial cells in different tissues; this marker promotes malignant biological behavior, such as the occurrence, development, angiogenesis, invasion, and metastasis of malignant tumors.(7–9) the high expression of matrix metalloproteinases (mmps) is closely related to the invasion and metastasis of malignant tumors. (10) αvβ3 can interact with mmps and decompose fibronectin, as well as promote the invasion and metastasis of various malignant tumor cells.(11) in serum protein chips of hepatocellular carcinoma patients, vtn was degraded into small peptides with mmp-2; the outcome confirmed that small peptides of vtn could be used for the serological diagnosis of liver cancer.(12) in addition, vtn interacts with urokinase receptors (upars), which control cell adhesion and migration.(13) to date, studies on the relationship between vtn and pca are relatively rare. the present study is the first to detect vtn protein expression in pca and bph tissues via immunohistochemistry. according to the immunohistochemical results, the positive expression rates of vtn in the bph and pca groups (including pca and pcam groups) were 75.61% and 45.45%, respectively. the expression of vtn protein was the highest in the bph group, followed by the pca group. simultaneously, the expression of vtn in patient sera was detected via western blot analysis, the results of which are consistent with the immunohistochemistry results. this outcome showed that vtn in the serum samples from the bph group was higher than that in the serum samples from the pca group. moreover, the vtn expression in the pca group was higher than that in the pcam group. in addition, the vtn expression in the pca tissues (including pca and pcam tissues) was related to the psa of newly diagnosed patients, clinical stage, gleason score, and tumor metastasis. therefore, vtn may participate in the occurrence and development of pca via cell adhesion and migration. as a member of the integrin family, vtn promotes the adhesion of monocytes and endothelial cells in blood circulation. vtn also interacts with upar to adjust cell adhesion and migration, which are directly involved in pca metastasis. vtn can interact with mmps to promote the invasion and metastasis of pca. with an increased expression of αvβ3, upar, and mmps during the occurrence and mineralization process of pca, vtn combines with αvβ3, interacts with upar, and is degraded by mmps, thereby gradually reducing the vtn content in serum. therefore, vtn levels in sera may be used as a potential marker of pca for the diagnosis and assessment of disease progression and metastasis. in addition, the analysis of psa and vtn concentrations in sera and their roc curves for the pcam and pca patients showed that the combined parallel detection of vtn and psa achieved better diagnostic accuracy than the pca detection method based on a single index. therefore, combined parallel detection can be figure 5. receiver operating characteristic curves of prostate specific antigen detection, vitronectin detection, and combined parallel detection of vitronectin and prostate specific antigen. figure 5 shows that the areas under the receiver operating characteristic curves of prostate specific antigen detection, vitronectin detection, and combined parallel detection of vitronectin and prostate specific antigen were 0.625, 0.673 and 0.703 for the prostate cancer and metastatic prostate cancer groups; the difference was statistically significant (p < .05). hence, the accuracy of combined parallel detection is better than that of single detection. expression of vitronectin in patients with pca-niu et al. clinically applied in pca diagnosis. the results of this study provide only preliminary clues. the number of samples was limited, and no follow-up was conducted after radical operation of pca. therefore, larger samples and long-term follow-up are needed to confirm the role of vtn detection in serum to diagnose and judge the prognosis of pca. conclusions the vtn expression in the sera and prostate tissues of the bph patients was higher than that in the sera and prostate tissues of the pca patients. vtn levels in sera may be used as a potential marker of pca for the diagnosis and assessment of disease progression and metastasis. the combined parallel detection of vtn and psa in sera can be clinically applied in pca diagnosis. conflict of interest none declared. references 1. na yq, ye zq, sun g. chinese urology disease diagnosis and treatment guidelines. beijing: people's medical publishing house; 2011. p. 49. 2. xu y, zhang zh. prostate cancer. beijing: science and technology literature press; 2009. p. 115. 3. partin aw, carter hb, chan dw, et al. prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. j urol. 1990;143:747-52. 4. özdemir e, çiçek t, kaya mo. association of serum ykl-40 level with tumor burden and metastatic stage of prostate cancer. urol j. 2012;9:568-73. 5. paradis v, degos f, dargère d, et al. identification of a new marker of hepatocellular carcinoma by serum protein profiling of patients with chronic liver diseases. hepatology. 2005;41:40-7. 6. zhang cl, wang rf, zhang l, et al. (131)i labeling and bioactivity evaluation of a novel rgd diner targeted to integrin αvβ3 receptor. beijing da xue xue bao. 2011;43:295-300. 7. ai wb, liu xy, xiong zy, et al. effect of integrin αvβ3 on cell proliferation and invasive ability of c6 glioma in vitro. chin j cancer prev treat. 2007;14:1450-3. 8. reuning u. integrin αvβ3 promotes vitronectin gene expression in human ovarian cancer cells by implicating rel transcription factors. j cell biochem. 2011;112:1909-19. 9. pola c, formenti sc, schneider rj. vitronectin-αvβ3 integrin engagement directs hypoxia-resistant mtor activity and sustained protein synthesis linked to invasion by breast cancer cells. cancer res. 2013;73:4571-8. 10. ni xg, bai xf, wang gq, et al. clinical significance of expressions of mmp-2 and pcna in pancreatic cancer tissues. chin j cancer prev treat. 2011;18:108-11. 11. jiao y, feng x, zhan y, et al. matrix metalloproteinase-2 promotes αvβ3 integrinmediated adhesion and migration of human melanoma cells by cleaving fibronectin. plos one. 2012;7:e41591. 12. paradis v, degos f, dargère d, et al. identification of a new marker of hepatocellular carcinoma by serum protein profiling of patients with chronic liver diseases. hepatology. 2005;41:40-7. 13. rea ve, lavecchia a, di giovanni c, et al. discovery of new small molecules targeting the vitronectin-binding site of the urokinase receptor that block cancer cell invasion. mol cancer ther. 2013;12:1402-16. expression of vitronectin in patients with pca-niu et al. urological oncology 2532 urol_v3_no2_001_editorial.qxd review articles adrenal myelolipoma: diagnosis and management siamak daneshmand,1* marcus l quek2 1section of urologic oncology, division of urology and renal transplantation, oregon health and science university, portland, usa 2department of urology, loyola university stritch school of medicine, maywood, illinois, usa abstract introduction: adrenal myelolipomas are benign lesions that contain hematopoietic and fatty elements. they are usually hormonally inactive and asymptomatic until they reach large sizes. with the routine use of cross-sectional imaging, these lesions are now being discovered with increasing frequency. materials and methods: we performed a comprehensive review of the literature using the pubmed database containing the key word adrenal myelolipoma. results: we identified 492 articles written from 1956 to 2006 and reviewed 93 in detail including the authors' own experience. in this review, we highlighted the salient diagnostic features of adrenal myelolipomas and offered a guide for management of these benign lesions. conclusion: adrenal myelolipomas may grow over time, but they can usually be followed without surgical excision. in some cases, very large myelolipomas can present with pain and can be confused with necrotic adrenal carcinomas, thus necessitating their surgical removal. key words: adrenal gland neoplasm, myelolipoma, diagnosis, adrenal imaging 71 urology journal unrc/iua vol. 3, no. 2, 71-74 spring 2006 printed in iran introduction adrenal myelolipomas are rare benign tumors composed of mature adipose and hematopoietic tissue. in 1905, gierke first described the occurrence of a mass lesion in the adrenal glands composed of mature fat and mixed myeloid and erythroid cells.(1) they were subsequently termed formations myelolipomatoses by oberling in 1929.(2) thought to arise from metaplasia of undifferentiated stromal cells, these tumors used to be discovered primarily at autopsy; however, today they are typically incidental findings due to the widespread use of ultrasonography, computerized tomography (ct), and magnetic resonance imaging (mri). although the true incidence of these tumors is unknown, less than 100 cases have been described in the literature and the incidence is estimated at 0.08% to 0.25%.(3,4) myelolipomas account for approximately 3 to 5% of all primary adrenal tumors. they are usually noted in late adult life with a mean age at presentation of 62 years in one of the larger series.(5) men and women appear to be equally affected. these lesions are usually unilateral and asymptomatic, although a number of bilateral tumors have been described in the literature.(6) myelolipomas are often less than 4 cm in diameter when discovered; however, they can attain very large sizes.(7) the largest adrenal myelolipoma reported in the literature weighed 5900 g.(8) after excision, they generally do not recur, with recurrence-free survival rates of up to *corresponding author: section of urologic oncology, division of urology & renal transplantation, oregon health & science university, 3181 sw sam jackson park rd, l588, portland, or 97229, usa. tel: +1 503 494 1342, fax: +1 503 494 8671 e-mail: siadaneshmand@yahoo.com adrenal myelolipoma 12 years being reported.(5) these tumors are generally hormonally-inactive, although there are case reports of their association with overproduction of adrenal hormones. myelolipomas have been associated with overproduction of dehydroepiandrosteronesulphate (dheas), congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, congenital adrenal 17 α-hydroxylase deficiency, cushing disease, conn syndrome, adrenal insufficiency, and pheochromocytoma.(9,10) some of these tumors coexist with adrenal adenomas which may in part account for the hormonal activity. among them, congenital adrenal hyperplasia and cushing syndrome appear to be the two most common endocrine disorders described. overall, more than 25 cases of endocrine dysfunction associated with myelolipoma have been reported in the english and japanese literature.(11) diagnosis imaging. most adrenal myelolipomas are asymptomatic. symptoms associated with large myelolipomas are typically vague and include back or abdominal pain. ultrasonography, ct, and mri are effective in diagnosing adrenal myelolipomas in more than 90% of cases, with ct being the most sensitive diagnostic imaging modality.(12,13) myelolipomas appear as welldelineated heterogeneous masses with low-density mature fat (less than -30 hounsfield units [hu]) interspersed with more dense myeloid tissue (figure 1).(14) a fatty adrenal mass is virtually diagnostic of myelolipoma, although other less common adrenal tumors containing fat such as teratoma, lipoma, and liposarcoma should be considered. the differential diagnosis should also include angiomyolipoma, although it is much more common in the kidneys. although adrenal adenomas may appear as low-density lesions (with attenuation values less than 18 hu), they are more dense and homogeneous than myelolipomas. myelolipomas often have a discrete capsule, and the soft tissue component is enhanced after the administration of intravenous contrast, whereas liposarcomas generally exhibit an infiltrative pattern with attenuation coefficients up to +30 hu.(15) on ultrasonography, myelolipomas appear as a well-defined tumor with varying degrees of hyperechoic areas (fatty tissue) and hypoechoic areas (myeloid tissue).(12) magnetic resonance imaging does not add significantly to the tissue characterization of these tumors; however, it can help in distinguishing the origin of the tumor and assessing tissues planes for surgical planning. magnetic resonance imaging shows that this tumor has a signal intensity equal to subcutaneous and retroperitoneal fat on all spin echo pulse sequences.(16) the tumors are generally large when they are discovered in part due to the fact that they are asymptomatic until they begin to cause compression of adjacent structures. calcification can be seen in up to 27% of adrenal myelolipomas and is also a feature of other benign lipomatous tumors of the adrenal glands on imaging.(5) fine-needle aspiration. if the diagnosis of adrenal myelolipoma cannot be made with confidence using noninvasive imaging, fine-needle aspiration (fna) biopsy should be considered.(17-19) also in cases where expectant management is being considered, fna can definitively rule out malignancy. the presence of mature adipocytes and hematopoietic elements is diagnostic of myelolipoma.(18,20) approximately 15 case reports have described cytological findings of this tumor obtained by fna.(21) management the increasing number of incidentally discovered adrenal myelolipomas raises the question of appropriate treatment modalities which include watchful waiting and surgical removal. small asymptomatic tumors less than 4 cm can be monitored expectantly since they pose little risk of spontaneous rupture or bleeding. we 72 fig. 1. abdominal ct scan in a 37-year-old woman who presented to our department with vague right abdominal discomfort of 4 weeks' duration. the large adrenal mass is composed mostly of fat with well-defined borders. daneshmand and quek suggest that symptomatic tumors or myelolipomas larger than 7 cm should be removed since the risk of spontaneous rupture with retroperitoneal hemorrhage is increased. in addition, we believe bilateral myelolipomas should be treated similarly to bilateral angiomyolipomas of the kidney with removal of the larger, more symptomatic mass and expectant management of the smaller mass in order to avoid lifelong steroid substitution. observation. most lesions found incidentally that are homogenous on imaging and do not have any malignant characteristics can be safely followed with annual imaging. han and colleagues reported on 16 adrenal myelolipomas followed without surgical intervention for an average of 3.2 years (range 0.3 to 10.8 years). thirteen patients remained asymptomatic and 2 experienced persistent vague abdominal discomfort. a total of 13 tumors from 12 patients were serially imaged, with tumor size increasing in 6, decreasing in 2, and remaining unchanged in 5.(22) these data suggest that at least half of adrenal myelolipomas can be treated conservatively. however, there are several situations in which surgical removal of the tumor may be warranted. symptomatic masses should be removed since observation is doubtful to relieve pain or discomfort associated with the mass. additionally, myelolipomas have been reported to grow significantly during observation and there are a number of case reports of spontaneous hemorrhage or bleeding with minor trauma.(23-28) surgical treatment. although myelolipomas are benign, their size and propensity to grow often warrant surgical removal. rare hormonallyactive tumors should also be excised. smaller tumors are amenable to laparoscopic resection; however, large symptomatic tumors often warrant wide operative exposure via a chevron or thoracoabdominal incision. in some experienced centers, even large tumors have been successfully removed laparoscopically.(29) gaining adequate exposure is crucial in avoiding injury to the vena cava on the right or the aorta on the left. myelolipomas are generally encapsulated and peel off of surrounding structures. gross anatomical section typically shows sharply defined yellow adipose tissue with varying amounts of red-brown hematopoietic elements (figure 2).(14) microscopic examination reveals scattered islands of fat cells intermixed with hematopoietic stem cells (figure 3).(14) although rare, areas of hemorrhage and necrosis may be observed. a difficult dissection should warn the surgeon of the possibility of a malignancy such as a liposarcoma, and frozen sections should be 73 fig. 3. histological examination showed a typical myelolipoma composed of a mixture of mature adipocytes and hematopoietic elements (hematoxylin-eosin, × 200). fig. 2. the patient subsequently underwent a right thoracoabdominal adrenalectomy. gross anatomical section showed an encapsulated tumor with sharply defined yellow adipose tissue with varying amounts of red-brown hematopoietic elements. adrenal myelolipoma obtained in order to ascertain whether adequate margins are obtained. conclusion most myelolipomas are benign and clinically silent tumors which can be definitively diagnosed with cross-sectional imaging. there is an increasing number of cases reporting the association of myelolipoma with various endocrine disorders which emphasizes the importance of a thorough pre-operative workup. smaller, asymptomatic myelolipomas can be observed expectantly with surgical resection reserved for large or symptomatic tumors. references 1. gierke e. uber knochenmarksgwebe in der nebenniere. zeiglers beitr path anat. 1905;suppl 7:311-24. 2. oberling c. les formations myelolipomateuses. bull ass fr etude cancer. 1929;18:234-46. 3. olsson ca, krane rj, klugo rc, selikowitz sm. adrenal myelolipoma. surgery. 1973;73:665-70. 4. mcdonnell wv. myelolipoma of adrenal. ama arch pathol. 1956;61:416-9. 5. lam ky, lo cy. adrenal lipomatous tumours: a 30 year clinicopathological experience at a single institution. j clin pathol. 2001;54:707-12. 6. bishoff jt, waguespack rl, lynch sc, may da, poremba ja, hall cr. bilateral symptomatic adrenal myelolipoma. j urol. 1997;158:1517-8. 7. vierna j, laforga jb. giant adrenal myelolipoma. report of a case and review of the literature. scand j urol nephrol. 1994;28:301-4. 8. boudreaux d, waisman j, skinner dg, low r. giant adrenal myelolipoma and testicular interstitial cell tumor in a man with congenital 21-hydroxylase deficiency. am j surg pathol. 1979;3:109-23. 9. wagnerova h, lazurova i, bober j, sokol l, zachar m. adrenal myelolipoma. 6 cases and a review of the literature. neoplasma. 2004;51:300-5. 10. umpierrez mb, fackler s, umpierrez ge, rubin j. adrenal myelolipoma associated with endocrine dysfunction: review of the literature. am j med sci. 1997;314:338-41. 11. hisamatsu h, sakai h, tsuda s, shigematsu k, kanetake h. combined adrenal adenoma and myelolipoma in a patient with cushing's syndrome: case report and review of the literature. int j urol. 2004;11:416-8. 12. vick cw, zeman rk, mannes e, cronan jj, walsh jw. adrenal myelolipoma: ct and ultrasound findings. urol radiol. 1984;6:7-13. 13. musante f, derchi le, zappasodi f, et al. myelolipoma of the adrenal gland: sonographic and ct features. ajr am j roentgenol. 1988;151:961-4. 14. quek ml, daneshmand s. urology photo quiz: adrenal myelolipoma. resid staff physician. 2003;50:19. 15. szolar dh, schmidt-kloiber c, preidler kw. computed tomography evaluation of adrenal masses. curr opin urol. 1999;9:143-51. 16. musante f, derchi le, bazzocchi m, avataneo t, gandini g, pozzi-mucelli rs. mr imaging of adrenal myelolipomas. j comput assist tomogr. 1991;15:111-4. 17. deblois gg, demay rm. adrenal myelolipoma diagnosis by computed-tomography-guided fine-needle aspiration. a case report. cancer. 1985;55:848-50. 18. gaboardi f, carbone m, bozzola a, galli l. adrenal incidentalomas: what is the role of fine needle biopsy? int urol nephrol. 1991;23:197-207. 19. galli l, gaboardi f. adrenal myelolipoma: report of diagnosis by fine needle aspiration. j urol. 1986;136:6557. 20. wadih ge, nance kv, silverman jf. fine-needle aspiration cytology of the adrenal gland. fifty biopsies in 48 patients. arch pathol lab med. 1992;116:841-6. 21. settakorn j, sirivanichai c, rangdaeng s, chaiwun b. fine-needle aspiration cytology of adrenal myelolipoma: case report and review of the literature. diagn cytopathol. 1999;21:409-12. 22. han m, burnett al, fishman ek, marshall ff. the natural history and treatment of adrenal myelolipoma. j urol. 1997;157:1213-6. 23. albala dm, chung cj, sueoka bl, memoli va, heaney ja. hemorrhagic myelolipoma of adrenal gland after blunt trauma. urology. 1991;38:559-62. 24. hoeffel c. rupture and growth of adrenal myelolipoma in two patients. br j radiol. 1998;71:693. 25. wong kw, lee ip, sun wh. case report: rupture and growth of adrenal myelolipoma in two patients. br j radiol. 1996;69:873-5. 26. goldman hb, howard rc, patterson al. spontaneous retroperitoneal hemorrhage from a giant adrenal myelolipoma. j urol. 1996;155:639. 27. catalano o. retroperitoneal hemorrhage due to a ruptured adrenal myelolipoma. a case report. acta radiol. 1996;37:688-90. 28. russell c, goodacre bw, vansonnenberg e, orihuela e. spontaneous rupture of adrenal myelolipoma: spiral ct appearance. abdom imaging. 2000;25:431-4. 29. schaeffer em, kavoussi lr. adrenal myelolipoma. j urol. 2005;173:1760. 74 the effect of garlic powder on human urinary cytokine excretion ergun alma,1 alper eken,3 hakan ercil,4 kazım yelsel,2 nebile daglioglu5 corresponding author: ergun alma, md department of urology, ceyhan state hospital, ceyhan, adana, turkey. tel: +90 505 7596371 e-mail: almaerim@yahoo.com received january 2013 accepted june 2013 1 department of urology, ceyhan state hospital, ceyhan, adana, turkey. 2 department of urology, viransehir state hospital, viransehir, urfa, turkey. 3 department of urology, acibadem adana hospital, adana, turkey. 4 department of urology, adana numune education and research hospital, adana, turkey. 5 department of forensic medicine, cukurova university, adana, turkey. purpose: to evaluate the effects of orally administered dehydrated garlic powder on cytokine excretion in the urinary tract. materials and methods: a total of 60 healthy volunteers, randomized into 3 groups, were given a single oral dose of 1 g or 3 g of dehydrated garlic powder or placebo. urine samples were obtained 6.0 and 24.0 h after garlic intake and assayed for interleukin-8 (il-8), interleukin-12 (il-12), tumor necrosis factor-alpha (tnf-α), diallyl disulfide (dads) and diallyl sulfide (das). results: significant increases in il-12 levels over baseline were noted in urine samples obtained after oral intake of 1 g and 3 g of garlic powder (p < .001). in the 1 g and 3 g garlic powder treatment groups, time-dependent variations in il-12 levels over the study period were significantly different from the placebo group (p < .001). in both garlic treatment groups, urinary levels of il-8 and tnf-α were not significantly different from baseline and placebo levels (p > .017). dads and das were not detected in the urine samples at any time after garlic powder intake. conclusion: oral intake of doses of garlic traditionally used for daily supplementation increases urinary levels of il-12, which is a potent stimulator of t helper cell 1 (th-1) immune responses. this observation encourages further studies investigating the immunostimulatory role of garlic in the urinary tract. keywords: cytokines; secretion; garlic; humans; administration; oral; interleukin. 1308 | miscellaneous miscellaneous 1309vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l garlic powder and urinary cytokine excretion | alma et al introduction since ancient times, garlic has been used as a phytop-harmaceutical agent and a dietary supplement. an-cient egyptian documents dating to 1550 after death (ad) describe oral and topical use of garlic as a remedy for tumors.(1) since the 1950s, the scientific basis of garlic’s medicinal effects has been partially elucidated by studies demonstrating that thiosulfate extracts from garlic inhibited tumor growth in sarcomas.(2) in a rat model of intravesical transitional cell carcinoma, intravesical aqueous garlic extract instillation enhanced local lymphocyte and macrophage responses and inhibited macroscopic tumor growth.(3) in addition, a reduction of tumor volume was reported in a rat model when garlic extract was administered orally.(4) attempts to elucidate the mechanisms responsible for the antitumor effects of garlic revealed that the component diallyl disulfide (dads) induces apoptosis through caspase-3 activity. dads and diallyl sulfide (das) also inhibited nacetyl-transferase activity in the t-24 human bladder cancer cell line.(5,6) to our knowledge, the cytokine response in the human urinary tract after oral intake of garlic has not been documented. we assessed garlic’s immune potency by monitoring urinary cytokine excretion following administration of oral garlic supplements to healthy subjects. materials and methods after receiving approval from the institutional ethics committee, a total of 60 healthy volunteers, comprised of 34 male participants and 26 female participants between 20 and 40 years of age were enrolled in this study (table 1). study participants all volunteers included in this study were determined to be healthy by a physician, who performed the following laboratory tests: complete blood count, c reactive protein, erythrocyte sedimentation rate, urine analysis, fasting blood glucose and plasma cholesterol levels, kidney function tests (creatinine, blood urea nitrogen) and liver function tests. participants were also required to have a normal body mass index. all participants underwent abdominal and pelvic ultrasonographic evaluation and electrocardiographic examination before the study. because inflammatory cytokine levels can be affected by a variety of factors, the following list of exclusion criteria was used: the existence of urinary, respiratory, cardiovascular, gastrointestinal and hepatic disorders, the use of medications, including antimicrobial, antiviral and antiinflammatory medications, in the 2 weeks prior to the study, and pregnancy or menstruation at the time of the study. written informed consent was obtained from eligible participants. participants were asked to avoid ingestion of vegetables in the allium family and processed derivatives of these vegetables for 15 days prior to the study. the participants were randomized into 3 groups: one group received placebo, and two groups received dried garlic powder in a dose of either 1 g or 3 g. investigators and outcome assessors were blinded to treatment group assignments. preparation of garlic powder denuded fresh garlic was frozen at -70°c in a lyophilizer and dried under a vacuum. the resulting dried garlic was blended in a blender until it was ground into a fine powder. from approximately 8.75 g of denuded raw garlic, 1 g of dried powder was obtained. on a precise scale, powder aliquots weighing 1 g and 3 g were allocated to individual packets. on the study day, the content of each packet was thawed and placed in caches, which were similar to those of the placebo (flour). sampling and laboratory analysis placebo, 1 g and 3 g of garlic powder were administered orally to participants in the appropriate treatment group after 12 h of overnight fasting. urine samples were obtained from each participant before and 6 h and 24 h after powder administration. the collected urine was immediately centrifuged at 3000 rpm for 5 minutes, and the supernatant was divided into 3 tubes and stored at 80°c until further analysis. urine cytokine assays were performed in duplicate by enzyme linked immunosorbent assay (elisa) using commercially available kits for il-8, il-12 and tnf-α (quantikine, r&d systems europe, ltd. abingdon ox14 3nb, uk) according to manufacturer instructions. detection of dads and das in the collected urine samples was performed using a gas chromatograph (6890n, agilent technologies, massy, france) coupled to a mass selective detector (5973, agilent technologies, massy, france). manual sampling was performed by a fiber column (supelco solid phase microextraction, supelco park, bellefonte, pa, 1310 | 16823 usa) mounted to the analyzer. the following conditions were used for gas chromatography and mass spectrometry: column, hp-5 ms 0.25 mm × 30 m × 0.25 qm; carrier gas, helium (2 ml/min); temperature of the injection port, 280°c; mode, scan; applied method, pulsed splitless solvent; and delay, 1 min. the heating program was as follows: initial temperature, 40°c; increase rate, 10°c/min, target temperature, 150°c; and duration, 3 min. samples were thawed at room temperature before analysis. extraction was performed by the solid phase micro extraction (spme) method using 85 µm film thickness polyacrylate fiber. the inlet temperature was adjusted to 280°c, and the fiber was conditioned for one hour. two ml aliquots were removed from each urine sample tube, transferred to vials and mixed with 1 g of nacl. the vials were stoppered and stirred in a stirrer for 20 min at room temperature. during mixing, fiber was placed into the vial without contacting the urine. garlic metabolites absorbed into the fiber were manually injected onto the gas chromatography/mass spectrometry apparatus. calibration curves were drawn for das and dads standards for concentrations ranging from 1.2520 parts-per billion (ppb). the retention times for das and dads were 4.84 min (correlation coefficient, r2 = 1.0) and 9.62 min (correlation coefficient r2 = 0.99), respectively. the detection limit was 0.5 ppb. the values were expressed as a function of urine creatinine concentration (pg/mg creatinine). statistical analysis deviations from the normal distribution were evaluated for il-8, il-12 and tnf-α concentrations using the shapirowilk w test for normality. descriptive statistics were expressed as the median and percentiles (25th 75th). significant time-dependent variations in il-8, il-12 and tnf-α levels within groups were assessed using the bonferronicorrected wilcoxon signed–rank test. a p value < .0056 was considered significant for comparisons within groups. variations in the urinary levels of il-8, il-12 and tnf-α between the baseline and 6 h samples, between the baseline and 24 h samples and between the 6 h and 24 h samples were calculated. the significance of time-dependent variations in levels of il-8, il-12 and tnf-α between groups was evaluated using the bonferroni-corrected kruskal-wallis test, with p values < .017 considered statistically significant. for variations that were determined to be significant using the kruskal-wallis test, the groups with significant variation were identified using the nonparametric multiple comparison test. all statistical analyses were conducted using the statistical package for the social science (spss inc, chicago, illinois, usa) for windows version 11.5. results il-8 assays the median baseline urinary il-8 level for the healthy participants was 31.88 pg/mg creatinine, ranging from 11.52 pg/ mg creatinine (25th percentile) to 62.72 pg/mg creatinine (75th percentile). the median baseline il-8 levels of the placebo, 1 g and 3 g garlic powder groups were not significantly different (p > .017). compared to baseline levels, median il-8 levels were not significantly different 6 h or 24 h after administration of placebo, 1 g or 3 g of garlic powder (each p > .0056). il-8 levels after 24 h were not significantly different from il-8 levels after 6 h (p > .0056). when the groups were compared sequentially, significant time-dependent median il-8 variations were not observed between the placebo and 3 g garlic powder treatment groups or between the 1g and 3g garlic powder treatment groups (p > .017) (table 2). il-12 assays table 1. characteristic data of study groups. variables placebo 1 g garlic 3 g garlic total 20 20 20 male 10 13 12 female 10 7 8 mean age, years (range) 30.2 (20-38) 31.7 (23-40) 32.3 (26-39) miscellaneous 1311vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l the median baseline urinary il-12 level for all participants was 0.00 pg/mg creatinine (0.00 1.42 pg/mg creatinine). there were no significant differences in the median baseline levels of the three groups (p > .017). in the placebo group, the median il-12 levels after 6 h and 24 h were not different from baseline levels (p > .0056 for each) (table 3). in the group that was given 1 g garlic powder, the median il-12 levels after 6 h and 24 h were significantly higher than the baseline level (p < .001). the observed increase after 24 h was significantly higher than the placebo group (p < .001) (table 4, figure). however, after 6 h, the observed increase was not significantly different from the placebo (p = .094). in the group that was administered 3 g of garlic powder, il12 levels after 6 h were significantly higher than the baseline level (p < .001). after 24 h, il-12 levels were not significantly different from the baseline or 6 h levels (p > .0056) (table 3). in the 3 g garlic treatment group, when time-dependent variations in il-12 levels were compared with those of the placebo group, significant differences were observed after 6 and 24 h (p < .009 and p = .0054, respectively) (table 4). when time-dependent variations in il-12 levels for the 1 g treatment group were compared with those of the 3 g treatment group, the observed differences were significant after 24 h, but not after 6 h (p < .001 and p > .32, respectively). tnf-α assay the median baseline urinary tnf-α level in the healthy participants was 13.94 pg/mg creatinine (9.31-22.82 pg/mg creatinine). compared with baseline levels, tnf-α levels were not significantly different in the placebo and garlic treatment groups after 6 h and 24 h (p > .0056 for each). likewise, time-dependent variations in tnf-α levels between the 1 and 3 g garlic treatments groups throughout the study period were not significantly different from the placebo group (p > .017 for each) (table 5). dads and das assays neither dads nor das was detected in any urine samples tested using the described gas chromatography and mass spectrometry assays. adverse effects the participants tolerated both doses of dried garlic powder well. only one participant, who was administered 1 g of garlic powder, reported mild gastrointestinal discomfort, which manifested as distension and nausea that subsided within two hours of onset. no adverse reactions were reported. discussion changes in urinary cytokine levels have been observed in patients with urinary tract infection(7), urinary calculi,(8) genitourinary infections or pregnancy,(9) tubular damage caused by diabetes mellitus or obesity-related nephropathy,(10) dietary fat-induced hepatic inflammation (steatohepatitis) or inflammatory bowel disease,(11) hypertension and cardiovascular disease,(12) or drug use (e.g., anti-inflammatory drugs or cyclophosphamide).(13) these factors were assessed when screening participants, and sixty healthy volunteers were included in this study. because the body mass index of the participants was normal and ultrasonographic evaluation did not reveal hepatosteatosis, dietary changes (particularly a low-fat diet) were not suggested. the prophylactic and therapeutic benefits of garlic against cancer have been known since ancient times. efforts to discover the antitumor mechanism of garlic in the modern era began with the study of weinsberger and persky, who demonstrated that in vitro and in vivo administration of thiosulfinate extracts from garlic inhibited the growth of malignant cells. (2) in addition, study by marsh and colleagues demonstrated table 2. comparison of time dependent variation of urinary interleukin-8 levels among the study groups. variables placebo 1 g powder 3 g powder p * p ** p *** baseline, 6th h 7.77 (-49.68-27.65) -12.01 (-39.73-19.23) -13.22 (-32.74-8.33) .320 .445 .816 baseline, 24th h 1.74 (-11.49-34.68) -31.38 (-46.68-10.55) -3.50 (23.82-20.78) .002 .365 .019 6-24th h 7.61 (-14.00-48.08) -10.52 (-54.57-0) 2.58 (-11.25-27.86) .013 .921 .017 values are as median (25th-75th percentile), (pg/mg urinary creatinine), n = 20. * 1 g powder vs. placebo, where p < .01 is considered as significant due to bonferroni correction. ** 3 g powder vs. placebo. *** 1 g vs. 3 g powder. garlic powder and urinary cytokine excretion | alma et al 1312 | in a rat transitional cell carcinoma model that intravesical administration of garlic extracts caused tumor volume regression comparable to bcg (bacillus calmette-guerin) instillation, tumor necrosis and lymphocyte and macrophage infiltration.(3) the accumulated data suggesting that the antitumor effect of garlic may be related to immune stimulation prompted us to evaluate the activation of immune responses within the urothelium of healthy humans after oral intake of garlic. urinary cytokine levels were chosen as the main outcome of the study because of the well-described increases in urinary cytokine levels following oral administration of the immunostimulatory agents bropirimine, bcg, keyhole limpet hemocyanin and corynebacterium parvum. we studied the kinetics of urinary il-8, il-12 and tnf-α after oral administration of dehydrated garlic powder. we chose these cytokines because tumor recurrence is associated with tnf-α and il-8 levels, and il-12 has antitumor activity in in vivo models of bladder cancer.(14-17) the sources of il-8 in the bladder are the transitional epithelium, endothelial cells, mast cells, neutrophils, t-lymphocytes and macrophages.(18) previous studies assessing urinary levels of il-8 in bcg-instilled human bladder transitional cell carcinoma reported contradicting results. rabinowits and colleagues demonstrated no variation in il-8 levels between patients with tumor recurrence and remission after 6 cycles of bcg instillation.(19) in contrast, sheryka and colleagues demonstrated reduced il-8 levels during remission.(20) in our study, the 1 g and 3 g dried garlic powder treatment groups demonstrated no differences in urinary il-8 levels when compared to baseline levels or placebo levels (table 2). il-12, a bioactive cytokine produced by macrophages, dendritic cells, t-cells and natural killer (nk) cells, plays a key role in the differentiation of naïve t cells into th-1 cells. il12 is a potent stimulator of interferon gamma (inf-γ) production in t-helper and nk cells. urinary il-12 levels have been reported to increase after intravesical bcg instillation. (21) in our study, 6 h and 24 h after oral intake of a single dose of 1 g of garlic powder, we observed significant increases in urinary il-12 levels compared to baseline levels. in the 3 g treatment group, significant increases were observed 6 h after administration of garlic powder. a decrease in median il-12 levels 24 h after intake of 3 g of garlic and an increase table 3. urinary interleukin-12 levels in the study groups. variables placebo 1 g garlic 3 g garlic baseline 0 (0-4.96) 0 (0-0) 0 (0-2.90) 6th hour 3.44 (0-11.83) 4.77 (2.32-11.24) 9.87 (6.66-13.63) 24th hour 0 (0-1.43) 7.85 (5.93-14.63) 3.764 (1.36-7.42) baseline vs. 6th h p = .881 p < .001 p < .001 baseline vs. 24th h p = .101 p < .001 p = .086 6th vs. 24th h p = .012 p = .370 p = .009 values are median (25th-75th percentile), (pg/mg urinary creatinine), n = 20. p < .01 is considered significant due to bonferroni correction. table 4. comparison of time dependent variation of urinary interleukin-12 levels among the study groups. variables placebo 1 g powder 3 g powder p * p ** p *** baseline, 6th h 2.23 (0-9.58) 4.44 (2.32-11.24) 8.04 (4.32-11.05) .094 .009 .320 baseline, 24th h 0 (-4.11-0.27) 7.82 (5.92-14.63) 3.33 ( -0.74-7.31) .001 .005 .001 6-24th h -2.59 (-9.04-0) 2.39 (-2.92-7.01) -5.48 (-10.73-0.40) .006 .799 .003 values are as median (25th-75th percentile), (pg/mg urinary creatinine), n = 20. * 1 g powder vs. placebo, where p < .01 is considered as significant due to bonferroni correction. ** 3 g powder vs. placebo. *** 1 g vs. 3 g powder. miscellaneous 1313vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l in median il-12 levels 6 h after intake of the placebo may have adversely affected our analysis of significance (tables 3 and 4) (figure). we believe these effects were due to extreme values that altered the normal distribution because of our relatively small sample size. nevertheless, our results strongly encourage further studies assessing the importance of urinary il-12 levels, particularly studies that have a larger number of participants and studies that administer garlic for a longer period of time. intravesically instilled bcg and garlic extract are known to induce tnf-α production by macrophages and nk cells. maki and colleagues and shintani and colleagues measured urinary levels of tnf-α after bcg instillation in bladder tumor patients and reported increased levels in responders. (22,23) in contrast to these studies, we chose to administer garlic orally to determine the importance of garlic in a normal diet and to investigate the possible protective effect of garlic in the urinary system. we demonstrated that a single oral dose of garlic powder has no effect on urinary tnf-α levels (table 5). however, because the study period was restricted to 24 h, late responses to oral garlic intake may have been missed. fresh raw garlic consists of 85% water. during the dehydration process, only water is removed from the garlic. to date, the recommended doses of fresh and processed garlic have not been standardized for clinical studies. in 1988, the german commission e monograph advised 4 g of fresh garlic for maximum daily oral intake without evidence-based referral.(24) in their study assessing the immunostimulatory effects of garlic in humans, abdullah and colleagues and kandil and colleagues used orally administered aged garlic extract in amounts ranging from 1.8 g to 10 g, within safety limits. (25,26) in our study we empirically chose a single dose of 1 g or 3 g of garlic powder, which corresponds to approximately 8.75 g (2 cloves) and 26.25 g (7 cloves) of fresh garlic, respectively, based on traditional doses for daily supplementation. depending on the amount and duration of consumption, various adverse effects of garlic have been described, including as diarrhea, bronchial asthma, contact dermatitis and hepatotoxicity.(27-30) organosulfur constituents of garlic inhibit lipooxygenase and cyclooxygenase enzyme activities in the gastric mucosal membrane. prostanoid compounds in garlic are reported to cause reflux and esophagitis through esophageal sphincter relaxation.(31) our participants tolerated a single dose of 3 g of garlic powder quite well. only one participant in the 1 g garlic powder treatment group suffered from dyspepsia, which subsided within two hours. dads and das, the oil-soluble organic sulfur constituents of garlic to which some of the biological effects of garlic have been attributed, were not detected in the urine of any of our participants. this outcome is inconsistent with the findings of amagase and colleagues and germain and colleagues, who demonstrated that the absence of urinary das and dads activity was due to rapid and extensive hepatic metabolism by the enzyme alliinase, which converts alliin to allicin, and with findings of lawson and colleagues, who reported that more than half of the alliin precursor for dads and das was lost during the dehydration of fresh garlic.(32-34) conclusion we observed a significant increase in il-12, a potent stimulator of th-1 immune responses, following oral intake of garlic table 5. comparison of time dependent variation of urinary tumor necrosis factor-α levels among the study groups. variables placebo 1 g powder 3 g powder p * p ** p *** baseline, 6th h 2.10 (-3.25-7.33) 2.73 (-2.11-7.43) 4.08 (-1.38-14.42) .694 .287 .500 baseline, 24th h -0.11 (-3.13-7.35) 0.73 (-8.61-7.73) -1.57 (-6.57-7.17) .912 .603 .682 6-24th h -3.25 (-15.33-5.19) -1.49 (-17.03-3.90) -5.77 (-19.93-7.52) .723 .782 .938 values are as median (25th-75th percentile), (pg/mg urinary creatinine), n = 20. * 1 g powder vs. placebo, where p < .01 is considered as significant due to bonferroni correction. ** 3 g powder vs. placebo. *** 1 g vs. 3 g powder. garlic powder and urinary cytokine excretion | alma et al 1314 | in doses representative of traditional daily supplementation doses. these results encourage further studies investigating the immunostimulatory effects of garlic in the urinary system. in addition, other forms of garlic supplementation, such as essential oil, oil macerate, and aged extract should be included in future studies assessing the efficacy of long-term garlic consumption on a wide spectrum of parameters. conflict of interest none declared. figure. urinary interleukin-12 levels in the study groups. references 1. block e. chemistry of garlic and onion. sci am. 1985;252:114-9. 2. weinsberger as, pensky j. tumor inhibition by a sulfhydryl-blocking agent related to an active principle of garlic (allium sativum). cancer. 1958:18:1301-8. 3. marsh cl, torrey rr, woolley jl, barker gr, lau bh. superiority of intravesical immunotherapy with corynebacterium parvum and allium sativum in control of murine bladder cancer. j urol. 1987:137:359-62. 4. riggs dr, dehaven ji, lamm dl. allium sativum (garlic) treatment for murine transitional cell carcinoma. cancer. 1997;79:1987-94. 5. lu hf, sue cc, yu cs, chen sc, chen gw, chung jg. diallyldisulfide (dads) induced apoptosis undergo caspase-3 activity in human bladder cancer t24 cells. food chem toxicol. 2004;42:1543-52. 6. chung jg, lu hf, yeh cc, cheng kc, lin ss, lee jh. inhibition of nacetyltransferase activity and gene expression in human colon cancer cell lines by diallyl sulfide. food chem toxicol. 2004;42:195-202. 7. rodhe n, löfgren s, strindhall j, matussek a, mölstad s. cytokines in urine in elderly subjects with acute cystitis and asymptomatic bacteriuria. scand j prim health care. 2009;27:74-9. 8. carrasco-valiente j, anglada-curado fj, aguilar-melero p, et al. state of acute phase markers and oxidative stress in patients with kidney stones in the urinary tract. actas urol esp. 2012;36:296-301. 9. basso b, gimenez f, lopez c. il-1beta, il-6 and il-8 levels in gynecoobstetric infections. infect dis obstet gynecol. 2005;13:207-11. 10. navarro jf, mora c, gómez m, muros m, lópez-aguilar c, garcía j. influence of renal involvement on peripheral blood mononuclear cell expression behaviour of tumour necrosis factor-alpha and interleukin-6 in type 2 diabetic patiens. nephrol dial transplant. 2008;23:919-26. 11. taha as, grant v, kelly rw. urinalysis for interleukin-8 in the noninvasive diagnosis of acute and chronic inflammatory diseases. postgrad med j. 2003;79:159-63. 12. zhang w, wang w, yu h, et al. interleukin 6 underlies angiotensin ii-induced hypertension and chronic renal damage. hypertension. 2012;59:136-44. 13. mcbride wt, allen s, gormley sm, et al. methylprednisolone favourably alters plasma and urinary cytokine homeostasis and subclinical renal injury at cardiac surgery. cytokine. 2004;7;27:81-9. 14. scheringa m, ijzermans jn, jeekel j, marquet rl. the anti tumour activity of the interferon inducer bropirimine is partially mediated by endogenous tumour necrosis factor alpha. cancer immunol immunother. 1990;32:251-5. 15. luo y, chen x, o’donnel ma. role of th1 and th2 cytokines in bcginduced ifn-gamma production:cytokine promotion and stimulation of bcg effect. cytokine. 2003;21:17-26. 16. spazierer d, skvaro h, dawid m, et al. t helper 2 biased de novo immune response to keyhole limpet hemocyanin in humans. clin exp allergy. 2009;39:999-1008. 17. satoh m, inagawa h, shimada y, soma g, oshima h, mizuno d. endogenous production of tumor necrosis factor in normal mice and human cancer patients by interferon and other cytokines combined with biological response modifiers of bacterial origin. j biol response mod. 1987;6:512-24. 18. krishnaswamy g, kelley j, yerra l, smith jk, chi ds. human endothelium as a source of multifunctional cytokines; molecular regulation and possible role in human disease. j interferon cytokine res. 1999;19:91-104. 19. rabinowitz r, smith ds, tiemann dd, hudson ma. urinary interleukin 8/creatinine level as a predictor of response to intravesical bacilluscalmette-guerin therapy in bladder tumor patients. j urol. 1997;138:1728-31. miscellaneous 1315vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l 20. sheryka e, wheeler ma, hausladen da, weiss rm. urinary interleukin-8 levels are elevated in subjects with transitional cell carcinoma. urology. 2003;62:162-6. 21. fleischmann jd, toossi z, ellner jj, wentworth db, ratliff tl, imbembo al. urinary interleukins in patients receiving intravesical bacillus-calmette-guerin therapy for superficial bladder cancer. cancer. 1989;64:1447-54. 22. maki y, nasu y, tsusima t, et al. intravesical bacillus-calmette-guerin therapy for carcinoma in situ of the bladder and urinary cytokines. nishinikan j urol. 1998;60:698-702. 23. shintani y, sawada y, inagaki t, kohjimoto y, uekado y, shinka t. intravesical instillation therapy with bacillus-calmette-guerin for superficial bladder cancer: study of the mechanism of bacillus-calmette-guerin immunotherapy. int j urol. 2007;14:140-6. 24. german komission e monograph. bundesanzeiger nr.122 vom 06.07.1988, monographie: allii sativi bulbus,1988 (knoblauchwiebel). 25. abdullah th, kirkpatrick dv, carter j. enhancement of natural killer activity in aids with garlic. j oncol. 1989;21:52-53. 26. kandil om, abdullah th, taburi am, et al. potential role of allium sativum in natural cytotoxicity. arch aids res. 1988;1:230-231 27. caporaso n, smith sm, eny rhk. antifungal activity in human urine and serum after ingestion of garlic (allium sativum). antimicrob agents chemoter. 1983;23:700-2. 28. lybarger ja, gallagher js, pulver dw, litwin a, brooks s, bernstein il. occupational asthma induced by inhalation and ingestion of garlic. j allergy clin immunol. 1982;69:448-54. 29. burden ad, wilkinson sm, beck mh, chalmers rj. garlic induced systemic contact dermatitis. contact dermatitis. 1994;30:299-300. 30. ciplea ag, richter kd. the protective effect of allium sativum and crataegas on isoprenaline-induced tissue necrosis in rats. arzneimittelforschung. 1988;38:1583-92. 31. block g, purcell pf, yolen sr. onions and heartburn. am j gastroenterol. 1992;87:679-80. 32. amagase h, petesch bl, matsuura h, kasuga s, itakura y. intake of garlic and its bioactive components. j nutr. 2001;131:955-62. 33. germain e, auger j, ginies c, siess mh, teyssier c. in vivo metabolism of diallyl disulfide in the rat: identification of two new metabolites. xenobiotica. 2002;32:1127-38. 34. lawson ld, wang zj. pre-hepatic fate of the organosulfur compounds derived from garlic (allium sativum). planta medica. 1993;59:688-689. garlic powder and urinary cytokine excretion | alma et al laparoscopic removal of an intrauterine contraceptive device migrated into the bladder: a case report davide campobasso,1 matteo ciuffreda,1 umberto maestroni,1 francesco dinale,1 antonio frattini,2 stefania ferretti1 1department of surgery, univer sity hospital of parma, parma, it aly. 2hospital of guastalla, guastalla, italy. corresponding author: davide campobasso, md urology o. u. (chief: pietro cortellini), surgical department, hospital and university of parma, via gramsci, 14; 43126 parma, italy. tel: +39 338 8220525 fax: +39 0521 704782 e-mail: d.campobasso@virgilio. it received november 2013 accepted may 2014 keywords: laparoscopy; devicer emoval; methods;f oreign-bodymigration; intrauterine devices; urinarybladder. introduction intrauterine device (iud) is a worldwide commonly used contraceptive method. with an incidence of 0.003%-0.87%, migration into the abdomen after uterus or cervix perforation, usually occurring during insertion, is a major though infrequent complication. diagnosis is frequently made within one year after insertion.(1,2) surgical removal is usually difficult due to adhesions or lesions made to the surrounding organs. here we report a case of a 39 years old lady who underwent laparoscopic removal of an iud perforating the bladder. case report the patient came to our attention for dysuria and recurrent urinary tract infections caused by escherichia coli. her past medical history included 2 pregnancies, a medical abortion in 2008 and an iud insertion in 2009. pelvic examination, urine culture and routine blood tests were normal, whereas ultrasound scans reported a suspicious bladder lesion, revealed as a granulomatous area in the dome of the bladder, without productive lesions, on cystoscopic evaluation. computed tomography (ct) urography demonstrated a dislocated iud outside the uterus, perforating the dome of the bladder with one of its arms, without any stranding of contrast outside the urinary tract (figure). a transperitoneal laparoscopic exploration was carried out in the standard supine position. in addition to the perforation, fibrosis and extensive adhesions between the iud and a small bowel loop were also noted. the retrieval of the iud was carried out with blunt dissection (figure), avoiding diathermy because of the presence of copper in the device. bowel resection was not required. bladder defect was sutured with interrupted stitches. the patient was discharged on the fourth postoperative day and the urethral catheter was removed on the thirteenth postoperative day upon obtaining negative cystography. 1847 case report case report urology journal vol. 11 no. 04 july august 2014 1848 laparoscopic removal of an iud migrated into the bladder-campobasso et al combined laparosco-endoscopic procedure can sometimes be carried out, when part of the device is in the lumen within a hollow organ (i.e. bowel or bladder).(2,3,6-8) during the operation, special care should be paid when using monopolar diathermy, for the risk of indirect thermal injury in case the active electrode comes in direct contact with the metallic part of the device. moreover, strong traction should be avoided to prevent damage to adhering organs. iud removal should therefore be carried out under direct vision of the entire device. conclusion we think that the all migrated iud should be removed laparoscopically. a contrast enhanced ct scan could clarify its exact location and its relation with the surrounding organs, thus helping in the treatment plan. conflict of interest none declared. references 1. markovitch o, klein z, gidoni y, holzinger m, beyth y. extrauterine mislocated iud: is surgical removal mandatory? contraception. 2002;66:105-8. 2. ozgun mt, batukan c, serin is ozcelik b, basbug m, dolanbay m. surgical management of intra-abdominal mislocated intrauterine devic es. contraception. 2007;75:96-100. 3. gill rs, mok d, hudson m, shi x, birch dw, karmali s. laparoscopic removal of an intra-abdominal intrauterine device: case and systematic review. contraception. 2012;85:15-8. 4. world health organization. sexual and reproductive health. available at: http://www.who.int/reproductivehealth/publications/maternal peri natal_health/en/index.html. 5. rajaie esfahani m, abdar a. unusual migration of intrauterine device into bladder and calculus formation. urol j. 2007;4:49-51. 6. nouira y, rakrouki s, gargouri m, fitouri z, horchani a. intravesi cal migration of an intrauterine contraceptive device complicated by bladder stone: a report of six cases. int urogynecol j. 2007;18:575-8. 7. shin d, kim t, lee w. intrauterine device embedded into the bladder wall with stone formation: laparoscopic removal is a minimally invasive alternative to open surgery. int urogynecol j. 2012;23:1129-31. 8. taras a, kaufman j. laparoscopic retrieval of intrauterine device perfo rating the sigmoid colon. jsls. 2010;14:453-5. discussion although rare, given the potential risk of relevant complications, a high index of suspicion is mandatory towards iud migration, and its occurrence should be suggested by painful or difficult insertion. afterwards a gynecological examination ought to be performed after 6 weeks. the most frequent sites of migration are, omentum (26.7%), douglas pouch (21.5%), large bowel (10.4%), myometrium (7.4%), broad ligament (6.7%), free within in the abdomen (5.2%), adhesion to ileal loop serosa (4.4%) or to large bowel serosa (3.7%) and mesentery (3%).(3) rare sites are represented by appendix, abdominal wall, ovary and bladder.(3) symptoms are not specific, depending on the organs involved; patients usually complain of dysuria, suprapubic pain or metrorrhagia. diagnosis is often made during investigations for a pregnancy (30%) or in asymptomatic patients undergoing scans for other reasons.(3) the world health organization (who) advices removal of all migrated devices, even in asymptomatic patients, because of medicolegal implications.(4) moreover, patients may feel anxious about the poor predictability of the outcome of such complications, as the device could migrate and injury surrounding organs, create adhesions with possible bowel obstruction or infertility, get infected or form an abscess. however, management is still debated. some authors suggest that surgical removal is not necessary in asymptomatic patients.(1) in fact, adhesions occurring at the time of uterine perforation could fasten iud, thus preventing secondary migration or infection, especially with third generation iuds. there is no clear evidence supporting either theory. an adhesion between iud, the small bowel and the symptomatic bladder perforation was found in this patient. the operation should be carried out laparoscopically, as the minimally invasive technique offers clear advantages over open surgery with regards to postoperative morbidity. the success rate in the literature is over 60%.(3) laparotomy approach is also described,(5) but in our opinion is strictly indicated in case of sepsis, and is an option in case of bowel perforation. a figure. a and b: intraoperative images showing the adhesion between the intrauterine device (iud), the bladder wall and the ileum; c: preoperative computed tomography scan with the partial migration of the iud into the bladder. urology journal unrc/iua vol. 2, no. 4, autumn 2005 printed in iran 232 author index to volume 2 abbasi mr, see moradi mr, 32 aghamir smk, mohseni mg, arasteh s. the effect of voiding position on uroflowmetry findings of healthy men and patients with benign prostatic hyperplasia, 216 ahmadnia h, shamsa a, yarmohammadi aa, darabi mr, asl zare m. kidney transplantation in older adults: does age affect graft survival?, 93-96 ahmadnia h, see yarmohammad aa, 120 akhavizadegan h, see aliasgari m, 171 akhavizadegan h, see tabibi a, 132 al-durazi mh, al-helo ha, malik ak, kadhim ae. conservative surgical management of bilateral epidermoid cysts of the testis: a case report and review of literature, 224 al-helo ha, see al-durazi mh, 224 aliasgari m, soleimani m, hosseini moghaddam smm. the effect of acute urinary retention on serum prostate-specific antigen level, 89-92 aliasgari m, dadkhah f, tara a, noshad h, akhavizadegan h, birashk g. improvement of severe heart failure with multivalvular dysfunction after kidney transplantation, 171-173 alimagham m, amini-afshar s, farahmand s, pourkazemi a, pour-reza-gholi f, masood s. frequency of infectious skin lesions in kidney transplant recipients, 193 aloosh m, see nikoobakht mr, 102 ameli j, ghoddusi k, kachuee h, poorfarziani v, einollahi b. subacute polyneuropathy after initiation of peritoneal dialysis, improved following kidney transplantation, 122-124 amini-afshar s, see alimagham m, 193 amin-sharifi ar, see irani d, 111 amin-sharifi ar, see irani d, 13 aminsharifi ar, see shakeri s, 148 amiri z, see fallahian m, 157 amouian s, see tayyebi meybodi n, 54 ansari m, see mehraban d, 106 arasteh s, see aghamir smk, 216 asgari sa, ghanaie m, simforoosh n, kajbafzadeh am, zare' a. acute urinary retention in children, 23-27 askari r, see salehipour m, 211 asl zare m, see ahmadnia h, 93 asl zare m, see yarmohammad aa, 120 barghi mr. the relation of enuresis and irritable bowel syndrome with premature ejaculation: a preliminary report, 201 bayat b, see mehrabi s, 189 birashk g, see aliasgari m, 171 boskabadi a, see moradi mr, 32 dadkhah f, salimi mr, kaviani a. benign retroperitoneal schwannoma mimicking adrenal mass, 49-51 dadkhah f, see aliasgari m, 171 darabi mr, keshvari m. bilateral emphysematous pyelonephritis: a case report, 118-119 darabi mr, keshvari m. bilateral same-session ureteroscopy: its efficacy and safety for diagnosis and treatment, 8-12 darabi mr, see ahmadnia h, 93 djaladat h, mehrsai ar, nasseh h, pourmand g. synchronous renal fossa recurrence with bladder metastases due to renal cell carcinoma, 169-170 djaladat h, see mehrsai ar, 206 dodangeh balakhani e, see taghizadeh afshari a, 153 einollahi b, see ameli j, 122 emadi baygi m, see mowla sd, 141 esfehani f, see mehraban d, 106 eshratkhah r, see irani d, 13 fallahian m, mashhady e, amiri z. asymptomatic bacteriuria in users of intrauterine devices, 157-159 farahmand s, see alimagham m, 193 feizzadeh kerigh b, mohamadzadeh rezaei ma. crossed testicular ectopia: a case report, 222 ghaderpanah f, see moradi mr, 28 ghafarian shirazi hr, see mehrabi s, 189 ghanaie m, see asgari sa, 23 ghoddusi k, see ameli j, 122 haghighat m, see rajaei isfahani m, 97 hamidi alamdari d, see pourmand g, 79 hasani m, see nikoobakht mr, 102 hekmati p, see irani d, 111 hosseini moghaddam smm, see aliasgari m, 89 hosseini moghaddam smm, see hosseini sy, 183 hosseini sy, safarinejad mr. early versus delayed internal urethrotomy for recurrent urethral stricture after urethroplasty in children, 165-168 hosseini sy, safarinejad mr. endometriosis of the urinary tract: a report of 3 cases, 45-48 hosseini sy, salimi mr, hosseini moghaddam smm. changes in serum prostate-specific antigen level after prostatectomy in patients with benign prostatic hyperplasia, 183 hosseini sy. invasive bladder cancer: the role of bladder preserving therapy, 1-7 irani d, eshratkhah r, amin-sharifi ar. efficacy of extracorporeal shock wave lithotripsy monotherapy in complex urolithiasis in the era of advanced endourologic procedures, 13-19 irani d, hekmati p, amin-sharifi ar. results of buccal author index to volume 2 233 mucosal graft urethroplasty in complex hypospadias, 111-114 jalali a, see moradi mr, 32 kachuee h, see ameli j, 122 kadhim ae, see al-durazi mh, 224 kajbafzadeh am. congenital urethral anomalies in boys. part i: posterior urethral valves, 59-78 kajbafzadeh am. congenital urethral anomalies in boys. part ii, 125-131 kajbafzadeh am, see asgari sa, 23 karbakhsh davari m, see tabibi a, 132 kaviani a, see dadkhah f, 49 kazemi-rashed f, simforoosh n. gil-vernet antireflux surgery in treatment of lower pole reflux, 20-22 keshvari m, see darabi mr, 118 keshvari m, see darabi mr, 8 keyhan h, see mehraban d, 106 kheradmand ar, shahbazian h. the role of pretransplant smoking on allograft survival in kidney recipient, 36-39 kheradmand ar. choriocarcinoma presenting as bilateral renal tumor: a case report, 52-53 khezri aa, see salehipour m, 211 khezri aa, see shakeri s, 148 mahmoudi h. evaluation of meatal stenosis following neonatal circumcision, 86-88 malik ak, see al-durazi mh, 224 mashhady e, see fallahian m, 157 masood s, see alimagham m, 193 masoudi p, see salehipour m, 211 mehraban d, ansari m, keyhan h, sedighi gilani ma, naderi gh, esfehani f. comparison of nitric oxide concentration in seminal fluid between infertile patients with and without varicocele and normal fertile men, 106-110 mehrabi s, ghafarian shirazi hr, rasti m, bayat b. analysis of serum prostate-specific antigen levels in men aged 40 years and older in yasuj, iran, 189 mehrsai ar, djaladat h, sina ar, salem s, pourmand g. buccal mucosal graft in repeat urethroplasty, 206 mehrsai ar, see djaladat h, 169 mehrsai ar, see pourmand g, 79 meysamie am, see nikoobakht mr, 160 mohamadzadeh rezaei ma, see feizzadeh kerigh b, 222 mohammadi torbati p, parvin m, ziaee sam. malignant mesothelioma of the spermatic cord: case report and review of the literature, 115-117 mohammadian-roashan n, see tayyebi meybodi n, 54 mohseni mg, see aghamir smk, 216 monabbati a, see shakeri s, 148 moradi a, see moradi mr, 28 moradi a, see moradi mr, 32 moradi mr, abbasi mr, moradi a, boskabadi a, jalali a. effect of antibiotic therapy on asymptomatic bacteriuria in kidney transplant recipients, 32-35 moradi mr, moradi a, ghaderpanah f. comparison of snodgrass and mathieu surgical techniques in anterior distal shaft hypospadias repair, 28-31 moslemi mk, see zargar ma, 137 mowla sd, emadi baygi m, ziaee sam, nikpoor p. evaluating expression and potential diagnostic and prognostic values of survivin in bladder tumors: a preliminary report, 141-147 naderi gh, see mehraban d, 106 najafi semnani m, see tabibi a, 132 nasseh h, see djaladat h, 169 nasseh hr, see nikoobakht mr, 40 nasseh hr, see pourmand g, 79 nikoobakht mr, aloosh m, hasani m. seminal plasma magnesium and premature ejaculation: a case-control study, 102-105 nikoobakht mr, pourkasmaee m, nasseh hr. the relationship between lipid profile and erectile dysfunction, 40-44 nikoobakht mr, saraji a, meysamie am. preoperative corporal biopsy as a predictor of postoperative results in venoocclusive erectile dysfunction, 160-164 nikpoor p, see mowla sd, 141 niroomand ar, see tabibi a, 132 noori mahdavi k, see tabibi a, 132 noshad h, see aliasgari m, 171 nourijelyani k, see pourmand g, 79 parvin m, see mohammadi torbati p, 115 poorfarziani v, see ameli j, 122 pourkasmaee m, see nikoobakht mr, 40 pour-kazemi a, see alimagham m, 193 pourmand g, nasseh hr, sarrafnejad af, mehrsai ar, hamidi alamdari d, nourijelyani k, shekarpour l. urinary tamm-horsfall protein and citrate: a case-control study of inhibitors and promoters of calcium stone formation, 79-85 pourmand g, see mehrsai ar, 206 pourmand g, see djaladat h, 169 pour-reza-gholi f, see alimagham m, 193 rajaei isfahani m, haghighat m. measurable changes in hydronephrosis during pregnancy induced by positional changes: ultrasonic assessment and its diagnostic implication, 97-101 rasti m, see mehrabi s, 189 safarinejad mr, see hosseini sy, 165 safarinejad mr, see hosseini sy, 45 salehipour m, khezri aa, askari r, masoudi p. primary realignment of posterior urethral rupture, 211 salem s, see mehrsai ar, 206 salimi mr, see dadkhah f, 49 salimi mr, see hosseini sy, 183 saraji a, see nikoobakht mr, 160 sarrafnejad af, see pourmand g, 79 sedighi gilani ma, see mehraban d, 106 shahbazian h, shahbazian h. short-term and longterm outcomes of kidney transplantation in diabetic and nondiabetic patients, 197 shahbazian h, see kheradmand ar, 36 shahbazian h, see shahbazian h, 197 shakeri s, aminsharifi ar, khezri aa, monabbati a, author index to volume 2234 tanideh n. can thymic tissue induce tolerance to kidney allografts?, 148-152 shamsa a, see ahmadnia h, 93 sharifi-aghdas f. surgical management of stress urinary incontinence, 175 shekarpour l, see pourmand g, 79 shirpoor ar, see taghizadeh afshari a, 153 simforoosh n, see kazemi-rashed f, 20 simforoosh n, see asgari sa, 23 sina ar, see mehrsai ar, 206 soleimani m, see aliasgari m, 89 soleimani mj, see zargar ma, 137 tabibi a, akhavizadegan h, noori mahdavi k, najafi semnani m, karbakhsh davari m, niroomand ar. percutaneous nephrolithotomy with and without retrograde pyelography: preliminary results of a randomized controlled trial, 132-136 taghizadeh afshari a, shirpoor ar, dodangeh balakhani e. the effect of garlic on cyclosporine-ainduced hyperlipidemia in male rats, 153-156 tanideh n, see shakeri s, 148 tara a, see aliasgari m, 171 tayyebi meybodi n, amouian s, mohammadianroashan n. renal allograft mucormycosis: report of two cases, 54-56 yarmohammad aa, ahmadnia h, asl zare m. transitional cell carcinoma in children: report of a case and review of the literature, 120-121 yarmohammadi aa, see ahmadnia h, 93 zare' a, see asgari sa, 23 zargar ma, soleimani mj, moslemi mk. comparative evaluation of urinary bladder cancer antigen and urine cytology in the diagnosis of bladder cancer, 137-140 ziaee sam, see mohammadi torbati p, 115 ziaee sam, see mowla sd, 141 urology for people 146 urology journal vol 6 no 2 spring 2009 what’s up in urology journal, spring 2009? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. the persian translation of this article is available from www.uj.unrc.ir. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2009;6:146-7. www.uj.unrc.ir your surgeon predicts whether you will get rid of stones shock wave lithotripsy is a method of treatment of kidney stones by the breaking power of sound waves. so, if you have stones, your surgeon may choose this way to remove it. however, it is not always successful and you may need several sessions of treatment and even switching to another treatment. this depends on the nature of the stone, its size, and its location in your urinary system. dr arshadi and his colleagues in children’s medical center of tehran tried to find an easy way to predict the results of shock wave lithotripsy. in their research project, they categorized the patients into 2 groups with more than 75% chance of fragmentation and with 50% to 75% estimated chance of fragmentation. their categorizing was based on the shape, location, and density of the stone as seen in radiography films. they found that 92.4% with the predicted higher chance had successful treatment, while 64.4% of those with lower chance had their stones removed. such an easy prediction can help surgeons to choose the best treatment for the patients with kidney stone. but still only god knows if your treatment will be 100% successful or not! see page 88 for full-text article vesicostomy care in children: a challenge for the parents? newborns and children with congenital bladder diseases have problems in emptying the bladder and it may lead to irreversible damage to the kidneys. to prevent this, physicians may decide to divert the pathway of urine and make an opening form the bladder out through the abdomen. they put a tube that opens on the skin of the lower abdomen. the child may have to live with the tube for a long time and the parents or caregivers will have a demanding job to take care of the tube and to keep the child dry. special diapers should be used during the day and the caregiver should be trained for this. dr prudente and his colleagues in sao paolo, brazil, decided to re-evaluate the status of their patients with vesicostomy. they reported that the treatment outcome was favorable, but they also tried to see if the parents and caregivers were used to the job. subjective evaluation of 20 cases showed that 18 children remained dry during the day and 14 caregivers/ parents felt they had acquired the skills necessary to handle a patient with vesicostomy. they gave an average satisfaction score of 8.7 to vesicostomy. dr prudente and his colleagues concluded that vesicostomy is a simple surgery that protects the urinary tract system of the child, and that there was adequate adjustment to vesicostomy and a positive overall evaluation as reported by the parents and caregivers. see page 96 for full-text article urinary consequences of mustard gas in veterans mustard gas is a fatal weapon that has been rarely used in wars. however, the iranian experienced urology for people urology journal vol 6 no 2 spring 2009 147 exposing to this brutal weapon several times during their war against iraq in 1980s. now, the physicians in iran have a huge population of patients with long-term effects of mustard gas. the most affected organs by mustard are the lungs, the skin, and blood. however, not all the destructive effects of this weapon are known. studies on animals have shown that immediately after exposure, the gas is diffused rapidly throughout the body, especially the kidneys. based on this knowledge, dr soroush and his colleagues at janbazan medical and engineering research center did a survey on 289 iranian male veterans to see if they have had any kidney and urinary disorders during the past 20 years of living with the mustard-induced diseases. fifty veterans (17.3%) had experienced urinary stones, 25 (8.7%) had recurrent urinary tract infections, and 2 (0.7%) had kidney failure. none of them had experienced cancer of the urinary tract. therefore, they concluded that fortunately, mustard gas seems to not have any major effect on the kidneys and the urinary tract. however, they cannot say this strongly, because they relied only on what the veterans reported. the next step is to do clinical and laboratory examinations to confirm this finding. see page 114 for full-text article avicenna’s and bladder diseases the canon of medicine of avicenna, the iranian scientist, has a great amount of interesting information on every organ of the body. that is why dr madineh has continued his job of reviewing avicenna’s notes on bladder disease in the third part of his article series on history of medicine. avicenna had explained bladder infection, pelvic abscess, urethritis, cystitis, prostatitis, bladder tumors, bladder dysfunction, urinary retention, and neurogenic bladder. the interesting point is that although the causes of diseases like cancer was not known 10 centuries ago, avicenna had described almost all diseases of the blabber. his approach to diagnosis complies with the modern methodology, and even in some interventions such as routes of drug administration and catheterization, his points are astonishing. see page 138 for full-text article urology journal unrc/iua 122 subacute polyneuropathy after initiation of peritoneal dialysis, improved following kidney transplantation javad ameli,* kazem ghoddusi, hossein kachuee, vahid poorfarziani, behzad einollahi department of internal medicine, bagiatallah medical university, tehran, iran key words: polyneuropathy, peritoneal dialysis, kidney transplantation, immunomodulatory therapy, inflammatory demyelinating neuropathy vol. 2, no. 2, 122-124 spring 2005 printed in iran introduction uremic neuropathy is the most common neurologic complication of uremia, and it affects more than 60% of patients with end-stage renal disease (esrd) who undergo dialysis.(1) this type of neuropathy symmetrically involves the distal extremities, especially the lower limbs. on electrophysiological assessment, an axonal pattern is dominant. the clinical course and the intensity of uremic neuropathy vary from one individual to another. coexisting chronic conditions such as diabetes mellitus can aggravate the symptoms,(2) while dialysis can stop or delay progression of chronic uremic neuropathy.(3) complete improvement occurs after kidney transplantation.(4) recently, acute and subacute neuropathies in esrd patients have also been reported.(5-8) these conditions have a demyelinating feature and develop after the initiation of continuous ambulatory peritoneal dialysis (capd). the pathogenesis of these nonchronic forms of neuropathy remains unclear. we report 2 cases of subacute uremic polyneuropathy that improved following kidney transplantation. case report case 1. a 54-year-old man presented with progressive weakness of the extremities of 5 months' duration. he had been diagnosed with esrd for 13 years and with diabetes mellitus for 25 years. he had been receiving peritoneal dialysis for 6 months, and his current symptoms had appeared after 3 to 4 weeks. within 2 months, he had lost the ability to walk. results of a neurologic examination of the cranial nerves were normal. atrophy of the calf and thigh muscles, loss of hair in legs, and pseudomotor changes in the skin of the calf were apparent. muscle strength of the wrist extensors and flexors, the elbow extensors, and shoulder abductors was 4/5. muscle strength of the hip extensors and flexors, knee flexors, and knee and ankle extensors was 3/5, 2/5, and 1/5, respectively. tendon reflexes were diminished. pain and heat senses in the distal lower extremities were disrupted up to the knees, and the proprioceptive sense in the feet was disturbed. electrophysiological assessment showed demyelinating peripheral neuropathy. capd was continued, and 2 courses of intravenous immunoglobulin therapy (20 mg daily) were initiated but had no positive effect. subsequently, plasma exchange was attempted at 2 liters daily for 5 consecutive days and then weekly for 2 months. considerable improvement was achieved, and the patient was able to do fine handwork and walk with the help of a cane. the patient underwent kidney transplantation, and immunomodulatory treatment was discontinued. neurologic symptoms and signs persisted but began to improve gradually after 4 months. by the first posttransplant year, the patient was able to do fine movements with his hands and walk on his own. however, diminished reflexes and mild muscular atrophy of the lower extremities persisted. case 2. a 55-year-old man presented in whom esrd had been diagnosed following admission for acute pulmonary edema 6 months earlier. he had a 5-year history of diabetes mellitus and a 2-year history of uncontrolled hypertension. received july 2004 accepted november 2004 *corresponding author: department of internal medicine, baqiatallah hospital, mollasadra st, vanak sq, tehran, iran. tel: ++98 912 154 2560 e-mail: j.ameli@bmsu.ac.ir ameli et al 123 following a few hemodialysis sessions, peritoneal dialysis was begun. within 2 months, weakness of the extremities developed and previous tingling and numbness in the distal extremities became aggravated. he was not able to walk on his own after 1 month. results of a physical examination of the 12 cranial nerves were normal. atrophy was present in the interosseous muscles of the fingers and the muscles of forearms, thighs, calves, and feet. muscle strength was about 4/5 in the upper and 3/5 in the low extremities. tendon reflexes were completely diminished. pain, heat, and positional senses in the lower extremities were abnormal. without further treatment, the patient underwent kidney transplantation. on electrophysiological assessment, peripheral neuropathy with a predominant demyelination pattern was detected. on follow-up, movement power in the extremities returned, and sensory disorders were alleviated. he was able to walk on his own after 6 months. the ability to do fine movements, however, remained mildly impaired. atrophy of the calf and interosseous muscles of the hand persisted. on 1-year follow-up, no recurrence or aggravation of symptoms was seen. discussion acute and subacute forms of uremic neuropathy in esrd patients have been reported in few studies. these forms, which are demyelinating peripheral neuropathies, become symptomatic within a few weeks after the start of capd and cause severe disability in the patients within 1 to 3 months.(5-8) ropper, in 1994, described 4 cases of subacute and acute neuropathy following capd. the patients developed generalized limb weakness over days or weeks, severe imbalance, diminished reflexes, and numbness within a few weeks after the initiation of capd. spinal fluid protein levels were elevated, and some demyelinating features were noted on electrophysiological testing. in 1 patient, neuropathy was alleviated by more frequent peritoneal dialysis and improved after kidney transplantation. but in 2 patients with diabetes mellitus, the neuropathy progressed.(5) toepfer and colleagues reported 3 patients with acute inflammatory demyelinating neuropathy, which developed 4 to 10 weeks following the initiation of capd. they also detected elevated spinal fluid protein and signs of demyelinating neuropathy. none of the patients improvement with intensified peritoneal dialysis, but immunomodulatory treatments were effective. one patient responded to hemodialysis and improved completely after receiving a kidney allograft.(6) lui and coworkers have described 2 cases of acute neuropathy, occurring 6 to 10 weeks after peritoneal dialysis. the disease resolved after kidney transplantation in 1 and with immunomodulatory therapies in another.(8) in all reported acute and subacute uremic neuropathy cases, the patients have had esrd and a history of prolonged diabetes mellitus. it seems that the combination of esrd and diabetes predisposes patients to this type of neuropathy. acute and subacute forms of nerve involvement (eg, plexopathy and radiculopathy) are common,(9,10) but they affect the extremities asymmetrically, while uremic neuropathy has a symmetric pattern and affects both upper and lower limbs at the same time. another pathologic cause of neuropathy in these patients can be acute inflammatory polyneuropathy. this condition, namely guillainbarre syndrome, develops over a period of less than 1 month and results in severe disability. high-dose intravenous immunoglobulin therapy and plasma exchange can aid a more rapid remission of patients.(11,12) a relative improvement with immunomodulatory treatments in some patients, as was true in our second patient, suggests a role for an inflammatory process and the coincidental occurrence of subacute inflammatory neuropathy in esrd patients. nonetheless, evidence exists against this explanation for subacute neuropathy in esrd patients. first, immunomodulatory treatments are not always effective in these cases, and second, resolution of disease after kidney transplantation can provide reason to reject this hypothesis. in agreement with other studies,(5-8) our patients were involved with polyneuropathy when they received peritoneal dialysis. this indicates a causal relationship, probably due to a metabolic disturbance, between acute and subacute polyneuropathy and capd. however, further studies are warranted to ellucidate the pathogenesis of this disease. subacute polyneuropathy, improved following kidney transplantation124 references 1. asbury ak. uremic neuropathy. in: dyck pj, thomas pk, lambert eh, bunge r, editors. peripheral neuropathy. 2nd ed. philadelphia: wb saunders; 1984. p. 1811. 2. tyler hr. neurologic disorders in renal failure. am j med. 1968;44:734-48. 3. nielsen vk. the peripheral nerve function in chronic renal failure. vii. longitudinal course during terminal renal failure and regular hemodialysis. acta med scand. 1974;195:155-62. 4. bolton cf, baltzan ma, baltzan rb. effects of renal transplantation on uremic neuropathy. a clinical and electrophysiologic study. n engl j med. 1971;284:1170-5. 5. ropper ah. accelerated neuropathy of renal failure. arch neurol. 1993;50:536-9. 6. toepfer m, schiffl h, fricke h, et al. inflammatory demyelinating neuropathy in patients with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (capd). perit dial int. 1998;18:172-6. 7. chen j, guest s. inflammatory demyelinating neuropathy presenting in a temporal relationship with the initiation of peritoneal dialysis. perit dial int. 1998;18:542-3. 8. lui sl, hui ck, chan tm, lo wk, lai kn. progressive demyelinating neuropathy after initiation of continuous ambulatory peritoneal dialysis--report of two cases. clin nephrol. 2001;56:407-10. 9. bastron ja, thomas je. diabetic polyradiculopathy: clinical and electromyographic findings in 105 patients. mayo clin proc. 1981;56:725-32. 10. garland h. diabetic amyotrophy. br med j. 1955;(4951):1287-90. 11. hughes ra, rees jh. clinical and epidemiologic features of guillain-barre syndrome. j infect dis. 1997;176 suppl 2:s92-8. 12. kuwabara s. guillain-barre syndrome: epidemiology, pathophysiology and management. drugs. 2004;64:597610. kidney transplantation determinants of willingness to become organ donors among dialysis patients’ family members makmor tumin,1 nurul huda mohd satar,2 roza hazli zakaria,2 raja noriza raja ariffin,1 lim soo-kun,3 ng kok-peng,3 khaled tafran4 purpose: this study explores the factors affecting the willingness of dialysis patients’ family members to become involved in living and deceased organ donation. materials and methods: we utilize cross sectional data on 350 family members of dialysis patients collected through self-administered survey from june to october 2013. the factors affecting willingness to become deceased and living organ donors among respondents were identified by running logistic regressions. results: the findings reveal that ethnicity, education and role in family are significant factors explaining willingness for living donation, while ethnicity, knowledge of organ donation and donor age drive willingness for deceased donation. we also find that the reasons of respondents being unwilling to donate center on the lack of information and family objections for deceased donation, while being medically unfit, scared of surgery and family objections are the reasons for unwillingness to donate living organs. conclusion: in light of our findings, educational efforts are suggested to decrease the reluctance to become involved in living and deceased donation. keywords: health knowledge; attitudes; practice; decision making; motivation; tissue donors; psychology; tissue and organ procurement; kidney transplantation; living donors. introduction many countries including malaysia are facing se-vere shortages of donated organs. indeed, malaysia has one of the lowest donation rates in the world. in 2008, the deceased donation rate only stood at 0.48 per million population (pmp) which is much lower than the donation rates in other countries, such as spain, (34.13 pmp) the united states (26.27 pmp), and singapore (6 pmp).(1) although modern medical technologies allow transferring organs from living bodies, this process does not help increase supply. further, while in some countries including malaysia, incentives have been used to increase living and deceased, the outcomes remain minimal. this finding suggests that a deeper understanding of the factors affecting potential donors’ willingness to become involved in living and deceased organ donation is vital. previous studies indicate that many factors explain people’s willingness to donate organs, such as relational ties for living donations,(1,2) gender, income,(1,3) cultural and religious beliefs,(4-6) and educational level.(1) however, knowledge of organ donation and transplantation and family influence on organ donation decisions have been found to be the most important factors influencing living and deceased organ donation.(2,3,6-9) previous studies of the factors influencing decisions to become an organ donor have also highlighted the importance of knowledge, values, attitudes and social norms towards donation, as found by ghorbani and colleagues,(10) trompeta and colleagues(11) and morgan and miller.(12,13) rodrigue and colleagues(14) compare the characteristics of donor and non-donor families, finding that in addition to race, marital status and employment status, attitudes towards organ donation play a significant role in explaining the probability of consenting to donation. they also find that family members with more favorable attitudes towards organ donation are more likely to give their consent. morgan(15) and trompeta and colleagues(11) studied the importance of communication about organ donation in the family to increase the likelihood of them giving their consent and thus influence the rate of organ donation. in parallel, for the malaysian case, earlier studies have shown that a lack of knowledge of the medical issues related to organ donation is the primary reason behind malaysians’ reluctance to donate their organs after death.(16) on the other hand, some studies have found that in multiethnic communities, ethnicity could be a significant factor in determining willingness to donate, for both living and deceased donations.(1,3,17) 1 department of administrative studies and politics, faculty of economics and administration, university of malaya, 50603 kuala lumpur, malaysia. 2 department of economics, faculty of economics and administration, university of malaya, 50603 kuala lumpur, malaysia. 3 department of medicine, faculty of medicine, university of malaya, 50603 kuala lumpur, malaysia. 4 institute of research management and monitoring, university of malaya, 50603 kuala lumpur, malaysia. *correspondence: department of administrative studies and politics, faculty of economics and administration, university of malaya, 50603 kuala lumpur, malaysia. tel: +60 3 79673690 . fax: +60 3 79673719. e-mail: makmor@um.edu.my. received: november 2014 & accepted: june 2015 kidney transplantation 2245 the present paper examines the factors affecting the decision to donate living and deceased organs among dialysis patients’ family members. specifically, it explores the determining factors affecting organ donation willingness by using logistic regressions and analyzes the reasons behind unwillingness to become a donor in malaysia. this study examines willingness to donate among those who have personal experience of kidney failure patients, specifically whether such personal contact leads to altruistic behavior. materials and methods sampling and data collection a survey of the views of family members of dialysis patients regarding their willingness to donate living and deceased organs was carried out, involving 350 individuals. three nurses informed 175 dialysis patients that two of their family members (one man, one woman) would be asked to participate in the survey. the questionnaire was prepared in three languages (malay, english, and mandarin). patients that had no family members present were excluded from the survey. we started the survey in june 2013 and had collected 350 responses by october 2013. first, we asked respondents about their willingness to donate living and deceased organs, finding that 51.7% (181) are willing to be deceased organ donors (p = .521), while a significantly higher number are willing to become living donors 60.9% (213) (p = .00). unwilling donors were asked to indicate the reasons behind their refusal. six reasons were given for refusing to donate living organs (medically unfit, against religion, do not trust hospital procedures, believe humans cannot live with one kidney, scared of surgery, objection by family) and five reasons were stated for refusing to donate deceased organs (do not trust hospital procedures, against religion, inadequate information, objection by family, do not want to donate). estimation approach to understand the factors influencing respondents’ willingness to become organ donors, we estimated two logistic regression. we estimated their willingness to become organ donor (1 = agree, 0 = disagree) against their demographic backgrounds, patients’ characteristics and knowledge of organ donation. the first estimation concerns living donation and the second estimation is for deceased donation. the logistic regressions were carried out by using the statistical package for the social science (spss inc, chicago, illinois, usa) version 21.0. the estimated model is presented as follows: willingness = f (age of respondent, education, gender, ethnicity, role in the family, marital status, knowledge about organ donation, age of patient, relationship with patient, importance of patient’s income). to gauge the level of knowledge of organ donation among the family members of dialysis patients, we constructed a seven-item knowledge statement, as shown in table 1. for every correct statement, a point was given and the total score was computed to ascertain the knowledge scores. the remaining variables of the models are described in table 2. results before illustrating the results, it is worthy describing respondents’ socioeconomic and sociodemographic backgrounds. of the 350 respondents, 58.9% are women. the ethnic composition resembles that of malaysia’s population, where malays comprise the largest proportion (54.7%), followed by chinese (32.0%) and table 1. elements of the ‘knowledge of organ donation’ variables. no statement correct answer 1 healthy individuals can lead a normal life with one kidney. true 2 organs from a deceased donor could be harvested even without consent of the donor’s family. false 3 a person is actually dead if his/her brain stopped functioning, even though his/her heart is still beating with the help of a machine. true 4 an organ donated by a malay, chinese, indian, or other ethnicity would only be transplanted to a patient of the same ethnicity. false 5 if we do not complete a form declaring that we do not want our organs to be transplanted to others upon death, false the government can procure our organs for the purpose of transplantation without our consent. 6 the deceased body of a donor will not remain intact (with some mutilation or disfigurement) after their organs have been harvested. false 7 completing a form from certified medical officers is the only method for a person to become a deceased donor. false variables description willingness 1 – willing, 0 – unwilling education secondary and lower, tertiary, other (tertiary as base) gender male – 1, female – 0 role in the family spouse / parents, children, others (spouse / parents as base) marital status single, married, other (married as base) relationship with patient close – 1, not close – 0 importance of patient’s income very important, important, not important (not important as base) table 2. description of the model variables. vol 12 no 04 july-august 2015 2246 willingness to become organ donors-tumin et al. indians (10.8%), with the remaining 2.5% from other ethnic groups. the majority of respondents have secondary and primary education. respondents’ are typically low-income earners, while the reported household income shows that many of them earn more than malaysian ringgit (myr) 4000 per month (1000 myr = 265 usd). married respondents are predominantly represented in the sample. the age of respondents ranges between 17 and 76 years old, the average age is 41 years old and 54.6% of respondents are aged below 40 years. just over half (54.6%) of respondents stated that they are either a parent or a spouse (i.e. the main decision makers of the household), with 40.6% of respondents declaring they are children in the family (the majority aged between 21 and 30 years old), which means most of the children are already financially independent. factors affecting the probability of being an organ donor we estimated the model to understand the determinants of willingness to donate, using binary logistic regressionsunder the stepwise method to examine the most influential factors. the results of the regressions for living and deceased donation (tables 3 and 4) revealed that none of the patient’s characteristics influenced the probability of their family members becoming an organ donor. the estimation found that the decision to become a living organ donor is influenced by education level, ethnicity and role in the family. based on the regression results, the signs of the estimated coefficient suggested that chinese are more likely to become organ donors compared with malays (p =.01), while there is no significant difference between malays and indians (p =.528) and other races (p =.207). in terms of education, those with lower education are less likely to be organ donors compared with respondents with higher education (p =.020). the findings also showed that if the respondent is a child in the family, she/he is more likely to be an organ donor compared with being a spouse or table 3. willingness to become living donor. variables b standard error wald test** significance exp(b) role in the family child .748 .325 5.287 .021* 2.113 other .814 .723 1.266 .260 2.257 education primary -.815 .349 5.452 .020* .443 other .530 .713 .552 .457 1.698 ethnicity chinese 1.119 .339 10.892 .001* 3.063 indian .293 .464 .398 .528 1.340 other 1.105 .875 1.593 .207 3.019 constant .292 .338 .747 .388 1.339 the relationship between the odds ratio and the coefficient (given in the column labeled "b"). exp(b) this is the exponentiation of the b coefficient, which is an odds ratio. * significant at the 5% significance level. ** the wald test in the context of logistic regression is used to determine whether a certain predictor variable is significant or not. it rejects the null hypothesis of the corresponding coefficient being zero. the relationship between the odds ratio and the coefficient (given in the column labeled "b"). exp(b) this is the exponentiation of the b coefficient, which is an odds ratio. * significant at the 5% significance level. ** the wald test in the context of logistic regression is used to determine whether a certain predictor variable is significant or not. it rejects the null hypothesis of the corresponding coefficient being zero. variables b standard error wald test** significance exp(b) knowledge .229 .104 4.825 .028* 1.258 age .051 .011 20.990 .000* .950 ethnicity chinese 1.466 .342 18.401 .000* 4.334 indian 1.256 .481 6.815 .009* 3.512 other 1.891 .915 4.272 .039* 6.629 constant .246 .725 .115 .735 1.278 table 4. willingness to become a deceased donor. kidney transplantation 2247 willingness to become organ donors-tumin et al. a parent (p = .021). by running the same regression for deceased donation, we found that knowledge, age and ethnicity explain the probability of becoming a deceased donor. as for ethnicity, similar to living donation, chinese are more likely to become organ donors compared with malays (p = .000). we also found that the probability of becoming a deceased donor is higher for indians (p = .010) and other ethnic groups (p = .039) compared with malays. in the decision to become a deceased donor, we found that knowledge plays a role. as expected, the higher the knowledge, the more likely the individual is to be an organ donor (p = .028). the coefficient estimate for age indicates that the older the age of the respondent, the less likely he will be a deceased organ donor. further examination of the age factor revealed that respondents aged below 30 years (p = .002) and between 31 and 40 years (p = .084) have a greater tendency to agree to deceased donation, while there is no significant difference on the choice of becoming a deceased donor for respondents aged between 41 and 50 years. on the contrary, the oldest age group (above 50 years) recorded a significantly higher number of respondents being unwilling to become involved in organ donation (p = .005). reluctance to become a donor altogether, 39.4% of reluctant respondents indicated that they are ‘medically unfit’ to be organ donors. other reasons behind their unwillingness to be living donors included being ‘scared of surgery’ (27.1%) and ‘objection by family’ (24.9%). as for deceased donation, the most cited reason among respondents was ‘inadequate information’ (42.0%), followed by ‘objection by family’ (33.4%). since the logistic regression results suggest that the likelihood of being a living or deceased organ donor differs by ethnicity, it is worth analyzing ethnic differences. the results shown in table 5 and figure 1 report that malays and chinese cited ‘medically unfit’ as the main reason for being unwilling to donate. indians cited ‘objection by family’ the most, although this reason was less influential for malays (26.3%) and chinese (19%). on the contrary, chinese (21.6%) appeared to be less ‘scared of surgery’ than malays (30.1%) and indians (30.8%). finally, over half (53.4%) of chinesebelieve they are ‘medically unfit’ compared with malays (32.3%) and indians (30.8%). for deceased donation, all ethnicities cited ‘inadequate table 5. reasons behind being unwilling to be a living donor, by ethnic group.* reasons ethnicity total malay chinese indian other medically unfit 60 (32.3) 62 (53.4) 12 (30.8) 4 (44.4) 138 (39.4) against religion 8 (4.3) 4 (3.4) 0 (0.0) 0 (0.0) 12 (3.4) do not trust hospital procedures 7 (3.8) 2 (1.7) 1 (2.6) 0 (0.0) 10 (2.9) believe that humans cannot live with one kidney 6 (3.2) 1 (9.0) 1 (2.6) 0 (0.0) 8 (0.0) scared of surgery 56 (30.1) 25 (21.6) 12 (30.8) 2 (22.2) 95 (27.1) objection from family 49 (26.3) 22 (19.0) 13 (33.3) 3 (33.3) 87 (24.9) total 186 (100.0) 116 (100.0) 39 (100.0) 9 (100.0) 350 (100.0) * data are presented as no (%). figure 1. reasons behind being unwilling to be a living donor, by ethnic group; percentages. all numbers are within-group percentages. shaded rectangles represent the within-group most cited statement. figure 2. reasons behind being unwilling to be a deceased donor, by ethnic group; percentages. all numbers are within-group percentages. shaded rectangles represent the within-group most cited statement. vol 12 no 04 july-august 2015 2248 willingness to become organ donors-tumin et al. table 6. reasons behind being unwilling to be a deceased donor, by ethnic group. reasons ethnicity total malay chinese indian other do not trust hospital procedures 11 (5.9) 7 (6.0) 1 (2.6) 1 (11.1) 20 (5.7) against religion 14 (7.5) 13 (11.2) 0 (0.0) 0 (0.0) 27 (7.7) inadequate information 91 (48.9) 36 (31.0) 16 (41.0) 4 (44.4) 147 (42.0) objection by family 52 (28.0) 42 (36.2) 19 (48.7) 4 (44.4) 117 (33.4) just don't want to donate 16 (8.6) 14 (12.1) 2 (5.1) 0 (0.0) 32 (9.1) other 2 (1.1) 4 (3.4) 1 (2.6) 0 (0.0) 7 (2.0) total 186 (100.0) 116 (100.0) 39 (100.0) 9 (100.0) 350 (100.0) information’ and ‘objection by family objection’ as their main obstacles to becoming a deceased donor. however, chinese (36.2%), indians (48%), and other ethnicities stressed ‘objection by family’ more than malays (28%) and the other minor ethnic groups. the reason ‘inadequate information’ comprised about half of malays’ reluctance to be deceased organ donors. however, in a general sense, the variations among ethnicities were not as significantly high as expected see table 6 and figure 2. discussion the literature on the determinants of organ donation has found that many socioeconomic and sociodemographic factors affect willingness to donate organs. however, influencing factors seem to be country-specific rather than globally standardized. in this sense, our results accord with one part of the literature and refute another. the logistic regressions proved the significance of ethnicity in explaining willingness to be involved in living and deceased donations, which concurs with the research findings.(1,3,16) similarly, educational level and role in the family were found to affect living organ donation, as stated in previous works such as boulware and colleagues,(2) irving and colleagues,(2) mossialos and colleagues(18) and trompeta and colleagues. (11) these results suggest that knowledge of organ donation and age of donors are also contributing factors in explaining willingness to be involved in deceased donation, which match the findings of irving and colleagues,(2) simpkin and colleagues(9) and ghorbani and colleagues.(10) by contrast, the findings of our logistic regression refute that gender, marital status, income or relationship with the patient explain the willingness of family members to donate their organs, ether in living or in deceased donation. respondents’ stated reasons for being unwilling donors strengthened the notion that a lack of information is a vital factor causing the low donation rates in malaysia. this finding accords with our logistic analysis on deceased donation. additionally, matching a large part of the literature, objection by family appeared to be another vital factor influencing the deceased donation decision. in this context, we suggest that family rejection is a part of the lack of information problem. in other words, when family members are not well informed about organ donation, they will refuse it, not only for themselves but also for their relatives. some studies go further on this point, stating that peoples’ willingness to donate their organs is higher than their willingness to donate those of their relative.(18,19) family objections to deceased donation may apply to living donation as well. this factor was cited by about 24% of respondents and ranked as the third most important driving force of rejecting living donation. however, the lack of information on living donation seems to be less influential than that on deceased donation, since our living logistic analysis didnot list this factor among the significant variables. furthermore, other factors were cited as more influential than knowledge for the living donation case, namely ‘medically unfit’ and ‘scared of surgery.’ the results of both estimations and elaboration of respondent’s reasoning suggests that ethnicity should be taken into consideration in any effort to increase the rate of organ donation. the majority of malays seem to be in need of information on organ donation, while the objection by family issue seems to influence chinese and indians on deceased donations to a greater extent. for living donations, assuming that being medically unfit is based on the opinion of health professionals, solving the family objection issue seems to be more influential for encouraging donations from indians than from malays and chinese, conquering being ‘scared of surgery’ for the latter two ethnicities may result in decreasing refusal rates for living donation. in sum, our regression analysis of the responses of 350 family members of dialysis patients showed that willingness for deceased donation is driven by ethnicity, knowledge of donation and age of donor, while for living donation willingness is affected by ethnicity, role in the family and level of education. in parallel, the elaboration of unwilling respondents’ reasoning revealed that being ‘medically unfit’ and ‘scared of surgery’ are the most cited reasons for being unwilling to donate living organs. a lack of information was the most cited reason for deceased donations. objection by family is a commonly cited reason for both living and deceased donations. further, ethnicity-specific variations hold, too. nonetheless, we admit that our findings have some limitations. it would have been more comprehensive to collect data on level of altruism as well as on the values and attitudes of respondents towards organ donation. since many recent studies have discussed the role of communicating organ donation in the family, we aimed to extend these findings by including the elements of communication in our survey. conclusions the outcomes of this study suggest that providing peokidney transplantation 2249 willingness to become organ donors-tumin et al. ple with suitable information on organ donation could be a channel to overcome the low deceased organ donation rates in malaysia. an educational effort is also suggested for living donation to relax the negative attitudes towards living donation surgery of about 27% of potential donors. moreover, we suggest that providing potential donors with adequate medical education on living and deceased organ donation may increase donation rates indirectly by reducing the huge influence of family objection to donations. acknowledgments the authors wish to thank the ministry of higher education malaysia and the university of malaya for funding this research under the exploratory research grant scheme (project number: er019-2012a). conflict of interest none declared. references 1. global observatory on donation and transplantation. final report on organ donation and transplantation: activities, laws and organization in 2010. available at http://www.transplantobservatory.org/pages/ datareports.aspx 2. boulware le, ratner le, sosa ja, cooper la, laveist ta, powenr. determinants of willingness to donate living related and cadaveric organs: identifying opportunities for intervention. transplantation. 2002;73:168391. 3. irving m, tong a, jan s, et al. factors that influence the decision to be an organ donor: a systematic review of the qualitative literature. nephrol dial transpl. 2011;27:2526-33. 4. stothers l, gourlay wa, liu l. attitudes and predictive factors for live kidney donation: a comparison of live kidney donors versus nondonors. kidney int. 2005;67:1105-11. 5. bilgin n. the dilemma of cadaver organ donation. transplant proc. 1999;31:3265-8. 6. yong bh, cheng b, ho s. refusal of consent for organ donation: from survey to bedside. transplant proc. 2000;32:1563. 7. frutos ma, blanca mj, mansilla jj, et al. organ donation: a comparison of donating and nondonating families. transplant proc. 2005;37:1557-9. 8. siminoff, la, gordon, n, hewlett, j, arnold, rm. factors influencing families’ consent for donation of solid organs for transplantation. jama. 2001;286:71-7. 9. simpkin al, robertson lc, barber vs, young jd. modifiable factors influencing relatives' decision to offer organ donation: systematic review. bmj. 2009;339:b991. 10. ghorbani hr, khoddami-vishteh o, ghobadi s, shafaghi a, rostamilouyeh k, najafizadeh. causes of family refusal for organ donation. transplant proc. 2011;43:405-6. 11. trompeta ja, cooper, ba, ascher nl, kools, sm, kennedy cm, chen, jl. asian american adolescents’ willingness to donate organs and engage in family discussion about organ donation and transplantation. prog transplant. 2012; 22:33-40. 12. morgan se, miller jk. beyond the organ donor card: the effect of knowledge, attitudes, and values on willingness to communicate about organ donation to family members. health commun. 2002;14:121-34. 13. morgan, se, miller, jk. communicating about gifts of life: the effect of knowledge, attitudes and altruism on behavior and behavioral intentions regarding organ donation. j appl commun res. 2002;30:163-78. 14. rodrigue jr, cornell dl, howard rj. organ donation decision: comparison of donor and nondonor families. am j transplant. 2006;6:190-8. 15. morgan se. the power of talk: african americans’ communication with family members about organ donation and its impact on the willingness to donate organs. j soc pers relat. 2004;21:112-24. 16. tumin m, noh a, jajri i, chong cs, manikam r, abdullah n. factors that hinder organ donation: religio-cultural or lack of information and trust. exp clin transplant. 2013;11;207-10. 17. morgan m, kenten c, deedat s, donate programme team. attitudes to deceased organ donation and registration as a donor among minority ethnic groups in north america and the uk: a synthesis of quantitative and qualitative research. ethnic and health. 2013;18:367-90. 18. mossialos e, costa-font j, rudisill c. does organ donation legislation affect individuals' willingness to donate their own or their relative's organs? evidence from european union survey data. bmc health serv res. 2008;8:48. 19. roels l, roelants m, timmermans t, hoppenbrouwers k, pillen e, bande-knops j. a survey on attitudes to organ donation among three generations in a country with 10 years of presumed consent legislation. transplant proc. 1997;29:3224-5. vol 12 no 04 july-august 2015 2250 willingness to become organ donors-tumin et al. narrowing of the dorsal vein complex technique during laparoscopic radical prostatectomy: a simple trick to simplify the control of venous plexus alejandro garcía-segui,* manuel sánchez, aleixandre verges, juan p. caballero, juan a. galán laparoscopic urology purpose: the control of the dorsal venous complex (dvc) is crucial to the recovery of urinary continence during laparoscopic radical prostatectomy (lrp). the size of dvc may affect the venous control. we developed a trick to simplify the suturing of the dvc. materials and methods: forty-seven patients with localized prostate cancer were divided into two groups: group 1 (n = 24) underwent lrp with a conventional ligature of dvc, and in group 2 (n = 23) the venous control was done with “narrowing” of dvc technique (n-dvc). our technique involves maintaining pressure on a metallic urethral sound inserted into the urethra, just at the time of ligature. the width of dvc in group 2 was measured before and after applying the technique. the numbers of attempts to place the stitch adequately were recorded and compared in both groups. the demographic and perioperative data, perioperative data and results were compared retrospectively. results: operation time, estimated blood loss, prostate weight, positive surgical margins rates and potency results showed no significant differences between the groups. the immediate 1-month, and 3-month continence rates were significantly greater in group 2 (30.4% vs. 12.5%, p = .048; 73.9% vs. 50%, p = .037, respectively). for all patients in group 2, width of dvc decreased and the ligation stitch was effective at the first attempt. in 37.5% of patients in group 1, the controlling of the dvc was obtained in more than one attempt. conclusion: the n-dvc simplifies the control of dvc during lrp and may contribute to the early recovery of continence. keywords: prostatic neoplasms; surgery; laparoscopy; ligation; methods; prostatectomy; adverse effects; sutures. introduction robot assisted-radical prostatectomy (rarp) and laparoscopic radical prostatectomy (lrp) are usually applied in the treatment of organ confined prostate cancer. during these surgeries, an anatomical approach for management of the dorsal venous complex (dvc) is crucial to recover urinary continence, control bleeding and ensure precise apical dissection.(1,2) the urethral sphincter is covered by the central portion of dvc, and its veins run in parallel. sutures are employed usually to control the venous plexus, but the depth of the stitch for ligation cannot be clearly visualized. thus, suturing may lead to injury of the muscle fibers of the rhabdosphincter, which could affect the functional outcome of continence. (3-6) the critical points in the control of the dvc include the proper identification of the plane between the venous plexus, urethra and sphincter and the full incorporation of the veins without injury to the sphincter muscle.(7) however, several factors increase the difficulty of controlling the dvc, including the following: variability of the pelvic space, the anatomy of the pubic bone, the different morphologies of the prostatic apex, the presence of large prostate, and plentiful amount of fatty tissue in retzius space in obese patients.(8-10) in these cases, the ligature of the venous plexus may be more difficult because the anatomical space between the prostatic apex and pubic bone may be short and it is uncomfortable to place stitches. several efforts to optimize the control of the dvc have been made by applying various techniques and devices. (3-5,9,11-15) extremely large venous plexus can make the surgical procedure more difficult by demanding vascular control.(16) we developed a simple maneuver named “narrowing” of dorsal vein complex technique (n-dvc) in order to get better exposure and optimal vision with the aim to simplify the suturing of venous plexus, mobilizing the urethra by a metallic urethral sound. we observed that pushing down urethra with a metal sound deforms apical tissues and produces anatomical changes that can improve vision. employing the view of the 30° scope, these small changes may optimize the vision to simplify dvc ligation. the perioperative parameters and functional outcomes were compared with those of conventional suture in a non-randomized retrospective study. our main objective was to present our technique and evaluate its potential benefits in the ligation of dvc. materials and methods forty-seven consecutive patients who had clinically localized prostate cancer with indication for lrp were included in the study. the patients were divided into two groups: group 1 (n = 24) underwent lrp with conventional ligature, and group 2 (n = 23) underwent ligature with n-dvc. all patients were enrolled consecutively without eligibility criteria and they were analyzed in a retrospective, non-randomized and descriptive study. the department of urology, hospital del vinalopó, alicante, spain. * correspondence: c/tónico sansano mora, 14, elche-alicante, 03293-spain. tel: +34 966 67 9800. e-mail: agarciasegui@gmail.com. received july 2013 & accepted february 2014 vol 11. no 05 sept-oct 2014 1873 demographic and perioperative variables were recorded: age, serum prostate specific antigen (psa), gleason score, stage, body mass index (bmi), operation time, estimated blood loss, specimen prostate weight and surgical margin. included patients were followed up for 12 months. the surgical videos of all patients were recorded and reviewed with emphasis on the step of dvc ligation. two items were recorded to evaluate the impact on the simplification of the ligature: 1. the width of dvc: the decrease in the width of the dvc produced by urethral sound wasconsidered as criteria of simplification. screen shots were taken before and after applying the maneuver, and the venous plexus was measured in each situation. the pictures stored in compressed jpg (joint photographic experts group) and the adobe photoshop® program was used to measure the width of dvc mark was placed. in order to take photos at the same distance, a mark on the outside of the endoscope, which provide guidance for the assistant to hold the instrument immobile during capture. dvc measurements were standardized as a percentage of decrease of the width. although measurement provides some imprecision, the decrease of the width of dvc is obvious and unquestionable to the eye, and was used in an effort to standardize and to quantify the impact of the technique. 2. the attempts to place the stitch: the numbers of attempts to place the stitch in both groups were recorded. continence and potency were evaluated during follow up at 1, 3, 6, 9 and 12 months after surgery. the continence was defined as the absence of the requirement of wearing figure 1. a metallic urethral sound is inserted into the urethra, and the assistant’s hand maintains pressure on the distal tip of this device in a posterior direction, just at the time of passing of the ligature stitch of venous plexus, displacing the urethra posteriorly and causing stretching of dorsal venous complex. figure 2. pushing down the urethra with a metallic urethral sound results in the narrowing of the dorsal venous complex. (a) intraoperative, schematic and sagittal views of the dorsal venous complex in a conventional position; (b) intraoperative, schematic and sagittal views of the dorsal venous complex narrowed while the urethra was pushed down. variables group 1 (n = 24) group 2 (n = 23) p value age (years) 64.04 ± 6.10 62.05 ± 6.96 ns psa (ng/ml) 7.32 ± 3.24 9.72 ± 4.31 ns gleason score 5.95 ± 0.97 6.2 ± 0.89 ns stage, no (%) t1 15 (62.5) 17 (73.9) ns t2 9 (37.5) 6 (26.0) ns bmi (kg/m2) 26.02 ± 3.87 26.96 ± 2.92 ns operation time (min) 201 ± 33.20 196.75 ± 32.69 ns blood loss (ml) 553 ± 338 580 ± 295 ns prostate weight (g) 45.59 ± 13.53 49.16 ± 19.11 ns positive surgical margins (%) 20.83 21.73 ns potency (%) 66.6 61.53 ns table 1. demographic and perioperative characteristics of study subjects.* abbreviations: ns, not significant; psa, prostate specific antigen; bmi, body mass index. * data are presented as mean ± standard deviation. narrowing of dorsal vein complex technique during laparoscopic radical prostatectomy-garcía-segui et al laparoscopic urology 1874 pads. the groups were retrospectively compared. statistical analysis the statistical tests used were student’s t-test for continuous variables and chi-squared analysis for categorical variables (stata corp, stata statistical software, version 10.1, stata corporation, college station, texas, usa). a p value of < .05 was considered to be statistically significant. technique the 4-trocar lrp transperitoneal technique was applied in all patients. a 30° scope was employed in both groups. dissection of the retzius space was performed to expose the puboprostatic ligaments; and the endopelvic fascia was bilaterally incised. a blunt dissection of the periapical tissues of the gland was performed to expose the dvc. a midprostatic suture was placed to prevent venous back-bleeding. the puboprostatic ligaments were preserved in all patients. in group 1 (conventional ligature), the control of dvc was done with a figure-of eight suture employing a polyglactin suture on a ct-1 needle. in group 2, the n-dvc technique was applied. our technique involves a metallic urethral sound that is inserted into the urethra, and the assistant’s hand maintains pressure on the distal tip of this device in a posterior direction, just at the time of passing the ligature stitch of venous plexus (figure 1). it produces cephalic displacement of the prostate, and simultaneously the urethra is pushed down and the dvc is stretched (figures 2a and 2b). a 30° scope was placed in the lateral view to enhance the visualization of the anatomical structures and guide needle insertion during suturing(10,14) (figures 3a and 3b). after the suture passed, the scope was switched to the contralateral position to visually control the exit of the needle tip in the correct anatomical location (figures 3c and 3d), and finally the threads are knotted like a figure-of-eight suture over the venous plexus. once again, during the athermal transection of the dvc, the assistant repeated the maneuver to avoid injury to the sphincter during cutting. at the end of the cut, the anterior aspect of the urethra was immediately exposed by the presence of the urethral device, which expanded its lumen (figures 4a and 4b). the urethra was incised at the prostatic apex to expose the metallic urethral sound. the prostate was dissected with a nerve-sparing technique without using thermal energy in a retrograde approach. the vesico-urethral anastomosis was performed in a running fashion using absorbable polyglyconate self-retained barbed suture. results the two groups were comparable in terms of age, serum psa levels, gleason score, stage and bmi. the perioperative parameters (operation times, estimated blood loss, specimen prostate weight and positive surgical margins rates) and functional potency results showed no significant differences between the groups (table 1). in group 1, 29.16% of the patients were transfused, which was 26.085% in group 2. the immediate continence included cases that were continent after catheter removal 1 month after surgery. the continence results are shown in table 2. the early continence rates (immedate and 3 months) were significantly greater in group 2 than in group 1. at 6 and 12 months, the continence rates were similar in both figure 3. (a and b) a 30° scope was placed in the lateral view to enhance the visualization of the anatomical structures and guide needle insertion during suturing; (c and d) the scope was switched to the contra-lateral position to visually control the exit of the needle tip in the correct anatomical location. figure 4. at the end of the cut of the dorsal venous complex, the anterior aspect of urethra was immediately exposed by the presence of the urethral device, which expanded its lumen.(a) schematic view; (b) intraoperative view. continence group 1(n = 24) group 2 (n = 23) p value immediate 3 (12.5) 7 (30.4) .048 (1 month) three months 12 (50) 17 (73.9) .037 six months 18 (75) 20 (86.9) ns nine months 20 (83.3) 21 (91.3) ns twelve months 22 (91.6) 22 ( 95.6) ns table 2. continence results in study groups. abbreviation: ns, not significant. * data are presented as no (%). narrowing of dorsal vein complex technique during laparoscopic radical prostatectomy-garcía-segui et al vol 11. no 05 sept-oct 2014 1875 groups. there were no conversions or complications attributable to the use of the urethral sound. positive surgical margin rates (group 1, 20.83% and group 2, 21.73%) and potency functional results at 12 months (group 1, 66.6% and group 2, 61.53%) showed no significant differences between groups. our study did not evaluate the oncological results of the n-dvc technique, whereby location of the surgical margins were not analyzed. in all patients of group 2, the n-dvc technique causes modifications in the shape of venous plexus and decreases its size by up to 20% of original size. the ligation stitch was positioned properly at the first attempt in group 2, and 9 patients (37.5%) in group 1 required more than one attempt. the n-dvc technique was successful in all patients of group 2, and we did not need conversion to “conventional” ligature. discussion the adequate control of the dvc ensures bloodless surgery and optimizes the conditions for an accurate apical dissection.(15) the dvc is commonly controlled by a single suture prior to the apical dissection; however, to avoid bleeding, the suture may be placed deep, which could damage the rhabdosphincter and affect the recovery of urinary continence.(3,4) occasionally, the suture ligation of the dvc may be a challenge, especially for a novice laparoscopist,(13) in obese patients(8) or those with adverse anatomical characteristics, such as a deep and narrow pelvis, a bulky prostate, a prominent apex, or exostosis of the symphysis pubis. jeong and colleagues(16) showed that dvc varies in sizes among individuals, and they found it is a significant predictor for recovery of the continence and the incidence of transfusions. these authors explain that a large dvc can make the surgical procedure more difficult by demanding vascular control. we developed a simple surgical trick to get better exposure and optimal vision to simplify the control of the dvc. in our technique the prostatic apex moves away from the pubic bone, which slightly increases the workspace while the dvc elongates, narrows and its anatomical boundaries are defined more clearly. furthermore, employing the view of the 30° scope, these small changes optimize the vision below the pubic bone and may simplify dvc ligation. in our opinion, it is obvious that the control of a narrow venous plexus is easier and the passage of the needle is faster than a larger size dvc. subjectively, we observe that our technique makes a more comfortable control of the dvc. additionally, the n-dvc technique keeps away the urethra of the passage of the needle, which may reduce the risk of injuring the sphincter and favorably affect early continence recovery. during the transition of the dvc, the maneuver is repeated, avoiding injury to the sphincter. previously, several authors have reported using a metallic urethral sound to displace the urethra to avoid the inadvertent transgression of the urethra by devices used for ligation,(9,13) and many authors routinely use a urethral sound during lrp. our trick not only involves the insertion of a urethral sound, but also includes maintaining pressure on it to push down the urethra and modify the shape of the dvc to better recovery of continence. several alternatives have been proposed to control the dvc. lei and colleagues,(3) porpiglia and colleagues,(4) guru and colleagues(5) and sasaki and colleagues(12) reported using athermal dvc control prior to apical dissection followed by a subsequent or selective ligation during lrp or rarp. they reported shorter operation times, reduced apical positive surgical margins and faster recovery of continence. moreover, some automated devices have been used to effectively control the dvc, as reported by nguyen and colleagues(9) and wu and colleagues,(11) who used the endovascular stapler. abreu and colleagues (13) employed an automated system with a titanium knot during ligation of the venous plexus. recently, tüfek and colleagues(15) described a novel technique to control the dvc during rarp and demonstrated a shorter operation time and quicker recovery of continence using a bulldog clamp. the critical point in control of dvc is the proper identification of the plane between the venous plexus, urethra and sphincter through accurate visualization of the anatomical structures; this identification is crucial to prevent bleeding or injury to the sphincter.(7,10) the n-dvc technique modifies the shape of the venous plexus and exposes the edges more clearly, simplifying the identification of anatomical structures. sasaki and colleagues(14) demonstrated the impact of a lateral view apical dissection in lrp on the reduction of surgical margins and the recovery of postoperative continence. for procedures with restricted views using a rigid scope, they significantly improved the view of the apical structures by inserting the scope at mcburney’s point. tewari and colleagues(10) reported the advantages of circumferential visualization of the prostatic apex and membranous urethra for precise dissection by employing a 30° scope during rarp. in our study, we obtained similar perception because the lateroapical view of the 30° scope improved the visualization of the anatomical aspects of the prostatic apex and apical tissues that were not observed with the rigid 0-degree scope. furthermore, the n-dvc technique in combination with the use of the 30° scope optimized the identification of anatomical structures allowing placement of the stitch under excellent visual control. our manuscript has several limitations. it is a retrospective, descriptive and non-randomized study. the number of patients is very small and the groups were not matched. furthermore, there may be many sources of potential bias or imprecision, and more studies involving larger numbers of patients, with statistical analysis are needed to establish solid conclusions. the n-dvc technique did not report better results with respect to rates of bleeding or transfusion, nor was it effective to shorten the operation time or improve the status of surgical margins, however, it is an effective and very simple trick which may improve the exposure and simplify the ligature of dvc, that is inexpensive, safe, without risks, not time consuming, may be applicable in all scenarios and may contribute to the recovery of continence. conclusion the n-dvc technique simplifies the control of the dvc during lrp and may contribute to the early recovery of continence because it may reduce the risk of injuring the sphincter. conflict of interest narrowing of dorsal vein complex technique during laparoscopic radical prostatectomy-garcía-segui et al laparoscopic urology 1876 none declared. references 1. reiner wg, walsh pc. an anatomical approach to the surgical management of the dorsal vein and santorini’s plexus during radical retropubic surgery. j urol. 1979;21:198-200. 2. hrebinko rl, o’donnell wf. control of the deep dorsal venous complex in radical retropubic prostatectomy. j urol. 1993;149:799-800. 3. lei y, alemozaffar m, williams sb, et al. athermal division and selective suture ligation of the dorsal vein complex during robot-assisted laparoscopic radical prostatectomy: description of technique and outcomes. eur urol. 2011;59:235-43. 4. porpiglia f, fiori c, grande s, morra i, scarpa rm. selective versus standard ligature of the deep venous complex during laparoscopic radical prostatectomy: effects on continence, blood loss, and margin status. eur urol. 2009;55:1377-83. 5. guru ka, perimutter ae, sheldon mj, et al. apical margins after robot-assisted radical prostatectomy: does technique matter? j endourol. 2009;23:123-7. 6. cathelineau x, sanchez-salas r, barret e, et al. radical prostatectomy: evolution of surgical technique from the laparoscopic point of view. int braz j urol. 2010;36:129-39. 7. koch mo. management of the dorsal vein complex during radical retropubic prostatectomy. semin urol oncol. 2000;18:33-7. 8. zilberman de, tsivian m, yong d, albala dm. surgical steps that elongate operative time in robot-assisted radical prostatectomy among the obese population. j endourol. 2011;25:793-6. 9. nguyen mm, turna b, santos br, et al. the use of an endoscopic stapler vs suture ligature for dorsal vein control in laparoscopic prostatectomy: operative outcomes. bju int. 2007;101:463-6. 10. tewari ak, srivastava a, mudaliar k, et al. anatomical retro-apical technique of synchronous (posterior and anterior) urethral transection: a novel approach for ameliorating apical margin positivity during robotic radical prostatectomy. bju int. 2010;106:1364-73. 11. wu sd, meeks jj, cashy j, perry kt, nadler rb. suture versus staple ligation of the dorsal venous complex during robot-assisted laparoscopic radical prostatectomy. bju int. 2010;106:385-90. 12. sasaki h, miki j, kimura t, et al. upfront transection and subsequent ligation of the dorsal vein complex during laparoscopic radical prostatectomy. int j urol. 2010;17:960-1. 13. abreu sc, rubinstein m, messias fi, et al. use of titanium knot placement device (tk-5) to secure dorsal vein complex during laparoscopic radical prostatectomy and cystoprostatectomy. urology. 2006;67:190-4. 14. sasaki h, miki j, kimura t, et al. lateral view dissection of the prostato-urethral junction to reduce positive apical margin in laparoscopic radical prostatectomy. int j urol. 2009;16:664-9. 15. tufek i, atug f, argun b, et al. the use of bulldog clamp to control the dorsal vein complex during narrowing of dorsal vein complex technique during laparoscopic radical prostatectomy-garcía-segui et al robot-assisted radical prostatectomy. j endourol. 2012;26:1605-8. 16. jeong cw, oh jj, jeong sj, et al. effect of dorsal vascular complex size on the recovery of continence after radical prostatectomy. world j urol. 2013;31:383-8. vol 11. no 05 sept-oct 2014 1877 1287vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l the authors have addressed an important issue in an appropriate manner. the psa test has been widely used to screen men for prostate cancer (pca). it is important to mention that the psa test is not panacea. most men with increased serum psa levels have benign prostatic hyperplasia, which is a normal part of aging. conversely, low serum concentrations of psa do not rule out the presence of pca. in addition nowadays it has been demonstrated that serum psa levels can be influenced by several medical conditions such as type 2 diabetes mellitus,(1) dietary factors,(2) certain clinical cardiovascular disorders(3) and obesity.(4) even some supplemental materials such as γ linolenic acid and coenzyme q10(5) and opium consumption (a worldwide growing problem) can alter significantly serum psa levels. (6,7) some scientific associations and health care providers now recommend against the use of the psa test to screen for pca because the benefits, if any, are small and the tribulations can be considerable. for example the u.s. preventive services task force, doesn't recommend routine psa screening for men in the general population, regardless of age. the american cancer society, the american college of preventive medicine, the american urological association, and the centers for disease control and prevention, all recognize the controversy surrounding screening with the psa test and the lack of firm evidence that screening can prevent deaths from pca. on may 21, 2012, the u.s. preventive services task force (uspstf) released final recommendations against psa-based screening for pca, asserting that there is "moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits," and discouraged the use of the test by issuing it a grade d rating. the american urological association (aua) is outraged and believes that the task force is doing men a great disservice by disapproving what is now the only widely available test for pca, a potentially fatal disease. screening for pca needs to be an individualized decision. physicians should discuss the benefits and risks of pca screening by psa testing with men especially in high-risk men. physicians must help men make their own decisions about pca screening, based on age, family history, life expectancy, personal preferences, and other risk factors. the american urological association (aua) recommends that men talk to their doctors about getting a baseline psa test at age 40. this could help them settle on when to screen in the future and to determine possible future risk and test results. the impacts of cardiovascular disease on serum psa levels have been well documented,(3) such as present study. although the work is considered to be interesting, several substantive points need to be clarified. in present study actual values for psa have been reported, while geometric means is a more accepted statistically method. as prostate volume has not been calculated, therefore psa density could not be assessed and presented to see if it follows a similar or different pattern as the total psa. although statistically psa was altered, longer studies are necessary to reach an appropriate conclusion. also, studies need to be done to determine whether treatment of the coronary artery syndrome allows the psa values to return back to pretreatment levels in long term period. psa velocity may be an important tool for assessment; which also has not been reported. mohammad reza safarinejad md clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com editorial comment 1288 | references 1. wallner lp, morgenstern h, mcgree me, et al. the effects of type 2 diabetes and hypertension on changes in serum prostate specific antigen levels: results from the olmsted county study. urology. 2011;77:137-41. 2. sonn ga, aronson w, litwin ms. impact of diet on prostate cancer: a review. prostate cancer prostatic dis. 2005;8:304-10. 3. açıkgöz ş, can m, doğan sm, et al. prostate specific antigen levels after acute myocardial infarction. acta biochim pol. 2011:58:541-5. 4. grubb rl 3rd, black a, izmirlian g, et al. plco project team. serum prostate-specific antigen hemodilution among obese men undergoing screening in the prostate, lung, colorectal, and ovarian cancer screening trial. cancer epidemiol biomarkers prev. 2009;18:74851. 5. safarinejad mr, shafiei n, safarinejad s. effects of epa, γ-linolenic acid or coenzyme q10 on serum prostate-specific antigen levels: a randomised, double-blind trial. br j nutr. 2013;110:164-71. 6. safarinejad mr, asgari sa, farshi a, et al. the effects of opiate consumption on serum reproductive hormone levels, sperm parameters, seminal plasma antioxidant capacity and sperm dna integrity. reprod toxicol. 2013;36:18-23. 7. hosseini sy, amini e, safarinejad mr, soleimani m, lashay a, farokhpey ah. influence of opioid consumption on serum prostate-specific antigen levels in men without clinical evidence of prostate cancer. urology. 2012;80:169-73. miscellaneous u j all final for web.pdf 747vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l purpose: to discuss the role of membrane androgen receptors and to investigate the potential role of testosterone-albumin conjugate in the prostate cancer (pca) treatment. materials and methods: results: the androgen receptor plays a critical role in both development and progression of vival of prostatic cells to an independent autocrine process. this malignant conversion is due lial cells. thus, treatments for neoadjuvant, adjuvant, and recurrent disease, all center on the evidence of a direct apoptotic action induced by activation of the membrane androgen receptor by testosterone-albumin conjugates. conclusion: membrane androgen receptors in the androgen-independent pca cell is important on the one lishment of activators of membrane androgen receptors. in addition, study of the testosteronekeywords: androgen receptors, testosterone, prostatic neoplasms, therapeutics department of urology, “tzaneio” general hospital of piraeus, piraeus, greece konstantinos stamatiou, nikolaos pierris review could testosterone have a therapeutic role in prostate cancer? corresponding author: konstantinos stamatiou, md 2 salepoula st., 18536 piraeus, greece tel: +30 210 459 2387 e-mail: stamatiouk@gmail.com received april 2012 accepted september 2012 748 | review introduction steroid hormone receptors t -cer (pca) development, and its progression is conduration of adt, adt formulation, or disease status. furthermore, there is evidence that even hormone-refractory pca cells continue to be affected by androgen signaling despite adt. this fact indicates that androgen receptors are the key element in pca development rather than androgens themselves. according to current literature, steroid molecules, such as testosterone, enter the target cell, eg, of the prostate gland, by passive transport through the cell membrane by diffusion. sulting in the formation of a dna binding area. this phenomenon results from the conversion of testosterone into its hydrotestosterone and receptor) migrates to the nucleus and triggers off the transcription of genes into mrna to produce functions.(2) the time from initiation until the completion of transporting proteins, it acts on local cytoplasmic channels leading to the activation of cyclic amp. this activity takes it represents an additional function of the classic cytoplasmic receptors. indeed, the manifestation of rapid non-genomic phenomena resulting from steroid hormone signaling may be for steroid hormones possibly located in the cell membrane, (6) such steroid hormone rerapid non-genomic phenomena, have already been described sic receptors (monocytes, t-lymphocytes). merely as of a the cell membrane of cells carrying classic androgen receptors, such as osteoblasts and cells of the prostatic glandular epithelium. have through these receptors has not been fully elucidated. the established mechanisms up to date are kinase regulation, cyclic nucleotide modulation, and intracellular calcium changes. the aforementioned activities are very rapid: progesterone minute. testosterone increases intracellular calcium in and leads to the synthesis of the molecular messengers, such as 749vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l in only ten seconds.(22) this activity is dose-related, it is not span of time. terone on muscle cells of male rats and of androstenedione on human porcine ovarian cells resulted in a similar rise in intracellular calcium and trebling of the levels of ip3. the rise in intracellular calcium seen in the above-mentioned man cells. rapid androgen action has also been described in (26,27) as in the neuronal cells(7) and hepatocytes. the fact that the above-mentioned functions have been demonstrated in cells lacking a functional nucleus, such as erythare not inhibited by nuclear androgen receptor inhibitors (hyfunctions are affected by non-classic steroid receptors. androgen stimulation despite their lack of classic androgen materials and methods searching the medline database of the national library cytoplasmic androgen receptor, and membrane androgen reconjugate, and prostate cancer treatment”. references in the not included in the medline or pubmed search. results androgen receptors and prostate cancer portant factor affecting the proliferation and function of the normal prostate gland. prostatic glandules and prostatic pores cells do not carry classic androgen receptors, but are differenclassic androgen receptors, into secreting and neuroendocrine androgens play an important role in the development and maintenance of both normal and neoplastic prostate tissue. dle of the previous century since the discovery of androgen deprivation therapy for pca by huggins and hodges. androgen blockade in its complete form (elimination of testicular testosterone and inhibition of the classic androgen receptor) remains the golden standard management of metastatic pca and is also used as adjuvant and neo-adjuvant therapy in advanced cancer. unfortunately, despite an initial positive response to androgen deprivation therapy, many cancers progress to androgen-independent or androgen-resistant forms and relapse ultimately. because of this, androgen deprivation the androgen receptors themselves are responsible for the androgens, it is today believed that androgen receptors unandrogen-resistant state the levels of detectable prostate androgen receptors are reduced, there are strong evidences for the presence of androgen receptors in androgen-independent cancers, those under androgen deprivation, and cancers relapsing during androgen deprivation therapy. tion or re-emergence of the androgen receptor. furthermore, the observation of an intermediate state of hormone sistance (androgen deprivation syndrome) lends merit to the festation of a mutation phase of the androgen receptor. testosterone and prostate cancer | stamatiou and pierris 750 | review (36) although, as already mentioned, in the hormone-resistant state the levels of detectable prostate androgen receptors are reduced and the androgen-resistant cells multiply irrespecgen receptors for their survival.(37) indeed, if by intracellular duced beyond a certain point, these cells stop multiplying and die. this property characterizes the non-classical cells. the role of androgens and non-classic androgen receptors as opposed to the classic cytoplasmic androgen receptor, membrane androgen receptors have not been studied non-genomic functions, including kinase regulation, cyclic nucleotide modulation, and intracellular calcium changes. the latter seems to be related to the apoptotic process and programmed cell death. studies on both cultured human pca human pca provided strong evidence of an immediate antineoplasmic activity after the activation of membrane androof lncap cancer cells, induction of apoptosis, release of the reduction in migration, adhesion, and development of the the fact that the above-mentioned antineoplastic functions administration both in iar-negative human cancer cells nucleotide) positive for cytoplasmic androgen receptors cultors possibly at the level of membrane androgen receptors. ready mentioned. anticancer activity. in fact, albumin inhibits the production of actin and therefore affects the formation of the cytoskeleton contributing thus to the apoptotic remission of human pca cells. on the other hand, testosterone and other the migration of pca cells by activation of estrogen receptor b (erb) and the resultant signaling. another biochemitivation of the receptor of tumor necrosis factor (tnf) rsf6 and produce its end product. ert anticancer properties in organs other than the prostate. activation of membrane androgen receptors by the testosterof cancer cells. apoptotic regression of prostate cancer through activation of membrane androgen receptors of membrane androgen receptors by the testosterone-albuthrough mobilization of intracellular calcium, on cytoskeletal actin. the latter is of vital importance for cell survival as it is a structural element of the cellular substrate and thus cytoskeleton through membrane androgen receptors has not 751vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l been fully elucidated. ing pca cells (lncap) to the testosterone-bovine albumin changes in its assembly. oid hormones, such as the androgens, modify the action of cytoskeletal reassembly. control of cellular development, cell survival, malignant transformation, and invasiveness appears to be pi-3 kinase, outcomes depending on the direction. activation of pi-3 membrane androgen receptors of human cancer lncap cells cytoskeletal actin and the formation of cell membrane evagi such cytoskeletal reassembly has been linked to malignant transformation, cellular migration, and cancer invasiveness. pca. pi-3 kinase. cantly affect the invasive potential of cancer cells (on the one lipodia), in fact their role in cellular response differs depending on cell type. in epithelial cells, such as in the prostate, cells and inhibits migration and invasion. it is therefore possible that the development or inhibition of development of the cancer cell depends on the direction of activation of piman cancer lncap cells) and the different outcome depending on the case seem to support the above hypothesis. the phenomenon is dose-dependent and time-dependent. culture medium. according to recent observations, chronic stimulation of membrane androgen receptors indeed leads to inhibition of cell development and to apoptosis through chronic androgen deprivation seems to increase the resistance of cancer cells to the induction of apoptosis through the same mechanism. despite the undoubtable observation that membrane receptors are the mediators of the above acmembrane androgen receptors remain unclear. conclusion optosis through activation of the membrane androgen receptors in the androgen-independent pca cell is important on the one hand because future manipulation of this mechanism can characteristics of pca, and on the other hand, can contribute to the establishment of activators of membrane androgen receptors. the latter could constitute a novel aspect in the sideration that testosterone binding areas of the membrane constitute a constant feature of both positive for androgen testosterone and prostate cancer | stamatiou and pierris 752 | future treatments for pca. in such a case, the testosteronetiandrogens already in use. conflict of interest none declared. review 11. chambliss kl, shaul pw. estrogen modulation of endothelial nitric oxide synthase. endocr rev. 2002;23:665-86. 12. chambliss kl, 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lc, collard jg. inhibition of invasion of epithelial cells by tiam1-rac signaling. science. 1997;278:1464-6. 52. burridge k, chrzanowska-wodnicka m. focal adhesions, contractility, and signaling. annu rev cell dev biol. 1996;12:463-518. 53. rodriguez-fernandez jl. why do so many stimuli induce tyrosine phosphorylation of fak? bioessays. 1999;21:106975. 54. hall a. rho gtpases and the actin cytoskeleton. science. 1998;279:509-14. 55. krasilnikov ma. phosphatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. biochemistry (mosc). 2000;65:59-67. 56. jimenez c, portela ra, mellado m, et al. role of the pi3k regulatory subunit in the control of actin organization and cell migration. j cell biol. 2000;151:249-62. 57. adam l, vadlamudi r, kondapaka sb, chernoff j, mendelsohn j, kumar r. heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase. j biol chem. 1998;273:28238-46. 58. tremblay l, hauck w, aprikian ag, begin lr, chapdelaine a, chevalier s. focal adhesion kinase (pp125fak) expression, activation and association with paxillin and p50csk in human metastatic prostate carcinoma. int j cancer. 1996;68:164-71. review vol 13 no 02 march-april 2016 2590vol 13 no 02 march-april 2016 2622 pro and cons of transurethral self-catheterization in boys: a long-term teaching experience in a pediatric rehabilitation centre purpose: to describe the acceptance and efficacy of clean intermittent catheterization (cic) in the management of lower urinary tract (lut) dysfunction regardless of the age of the children and their degree of urethral sensation. materials and methods: we retrospectively evaluated boys managed with cic at a pediatric teaching hospital between 1992 and 2014. age, urethral sensation, acceptance, efficacy in terms of continence and preserving upper urinary tract and genitourinary complications were reviewed in the medical records. results: sixty boys managed with cic for lut dysfunction due to neurological or urological disorders were identified. the median age at cic initiation was 8.2 years (range, 1.4-18). with regard to age, cic was well tolerated in younger boys and without genital sensation. failure in the cic protocol occurred within the first six months (n = 9). more boys with genital sensation were socially continent with cic (91% versus 83%, p = .05). vesicoureteral reflux was resolved in 69% of boys (p = .03), and hydronephrosis in 54% (p = .07). conclusion: cic was effective in terms of continence and renal protection. the procedure was feasible even in boys with preserved urethral sensation. therapeutic education by a dedicated urotherapy nurse is the key factor in ensuring long-term cic compliance and acceptability. keywords: patient education as topic; self-care; urinary catheterization; nursing; community health nursing; male; child; urinary tract infection. 1 department of pediatric physical therapy and rehabilitation, trousseau hospital, 75012 paris, france. 2 department of pediatric surgery, trousseau hospital, 75012 paris, france. 3 sorbonnes universités, upmc university, paris 06, france. *correspondence: department of pediatric physical therapy and rehabilitation, trousseau hospital, 26 avenue du docteur arnold netter, 75012 paris, france. tel: +33 144 736226. fax: +33 144 735309. e-mail: alice.faure@ap-hm.fr. received october 2015 & accepted february 2016 pediatric urology alice faure,1* matthieu peycelon,2,3 pauline lallemant,1 georges audry,2,3 veronique forin1 introduction the introduction of clean intermittent transurethral catheterization (cic) by lapides and colleagues in 1972 radically changed the management of lower urinary tract (lut) dysfunction in patients with congenital or acquired neurogenic bladder.(1) other methods to manage lut dysfunction include anticholinergic agents, chronic indwelling suprapubic or urethral catheters, continent catheterizable channels (ccc) or incontinent reservoirs. the therapeutic objective is to increase complete bladder emptying at regular intervals, thus maintaining a low level of intravesical pressure, which prevents vesicoureteral reflux (vur) and decreases the risk of urinary tract infection (uti).(2) cic is commonly used in the management of neurogenic lut dysfunction. long-term follow-up studies in the adult population reported that the technique is effective, well tolerated and associated with minimal complications. the indications for cic have been extended to boys with neurogenic lut dysfunction and normal urethral sensation. cic has a reputation for causing discomfort, and consequently catheterization may not be as easily tolerated by individuals with preserved urethral sensation as those without sensation.(3) the purpose of this study was to evaluate the acceptance and efficacy of cic for lut dysfunction in boys as a function of their age and degree of urethral sensation. materials and methods study population medical charts of all boys with lut dysfunction managed with cic between october 1992 and may 2014 were retrospectively reviewed, following approval by our institutional research ethics board. the main evaluation criteria were acceptance and long-term effectiveness in terms of urinary continence and prevention of upper urinary tract dilation. procedures all of the boys underwent the following investigations before cic initiation: plasma creatinine assay, voiding cystourethrography (vcug), and urinary tract ultrasonography (us) to look for upper urinary tract dilation. the decision to offer cic to the patients and families was based on the bladder diary findings interpreted in accordance with the recommendations of the international children’s continence society (iccs).(4) initiating cic was considered for boys who had lut voiding dysfunction with or without hydronephrosis, impaired renal function and recurrent utis. the indications and modalities of cic were explained to the patients and their parents during a physician visit. an urotherapy nurse provided therapeutic education and practical hands-on instructions in cic. the educational materials used included anatomical drawings, information booklets, and dolls. the nurse provided practical tips aimed at facilitating the procedure as much as possible. the first catheterizations were performed at the outpatient clinic. the nurse listened carefully to the concerns voiced by the boys and parents to minimize the level of anxiety. the family’s lifestyle was evaluated to determine the optimal times for cic. finally, the cooperation of the school physician was enlisted. the technique was demonstrated to the parents, who then performed cic on their child under the supervision of the urotherapy nurse. during the learning phase, the parents could contact the nurse by telephone in the event of problems or questions. when the acceptance of the procedure by the child was in doubt, the educational sessions were postponed. no child was forced to accept cic. the same cic technique with a regular coated (pre-lubricated) catheter was used in all age groups since 1992. in patients with urodynamic evidence of detrusor overactivity, oral anticholinergic drug therapy (oxybutynin) was started as soon as regular cic was achieved. in boys with detrusor overactivity that was inadequately controlled by anticholinergic therapy, a second-line therapy with a detrusor injection of botulinum-a toxin was proposed.(5) evaluations the study data were abstracted from the medical charts. the following data were recorded for each patient: age, cause of the lut dysfunction, prior neurosurgical procedures for spinal cord decompression or release, prior urological surgical procedures, history of utis (with or without fever), and whether the patient had anal incontinence. boys and families who had been lost to follow-up were contacted by telephone and were asked to return for a new in-person clinic visit. if there was no answer to the telephone call, they were excluded from the study. long-term acceptance, defined as agreeing to perform cic routinely, and efficacy of cic defined as achieving continence and protecting the urinary tract, were assessed. the following data were collected routinely in a standardized manner at 6-month intervals: difficulties or complications such as pain, discomfort, gross hematuria, febrile or afebrile utis, epididymitis, urinary incontinence assessed using the schulte-baukloh score. (6) plasma creatinine level, urinary tract us (appearance of the upper urinary tract, bladder wall thickness, and post-voiding residual urine) and vucg was performed only in boys with vur and/or febrile utis. inclusion and exclusion criteria all boys with lut dysfunction managed by cic per urethra were included. the urethral sensation in children with neurogenic bladder was defined by the feeling of burning or tingling when performing cic. the exclusion criteria were incomplete medical files or boys using a catheterizable channel such as a mitrofanoff continent urinary diversion. statistical analysis the data are presented as the number and percentage or as the means ± standard deviation (sd) or median and range, as appropriate. nonparametric tests were used. stochastic variables were compared using nonparametric chi-square, pearson, and fisher tests and continuous variables using the mann-whitney u test. a cox regression model was built for the univariate analysis. p values ≤ .05 were considered significant. characteristics number total number of boys 60 median serum creatinine level, µmol/l (range) 32.1 (23-62) vur at baseline, no (%) 13 (22) unilateral 9 bilateral 4 upper urinary tract dilation at baseline, no (%) 13 (22) unilateral 1 bilateral 12 history of febrile uti, no (%) 12 (20) urinary incontinence, no (%) 57 (95) fecal incontinence, no (%) 18 (30) prior neurosurgery for spinal cord decompression, no (%) 28 (46.7) prior urological surgery, no (%) 23 (38) table 1. patient characteristics before clean intermittent catheterization initiation. abbreviations: vur, vesicoureteral reflux; uti, urinary tract infection. a long-term teaching experience of self-catheterization in boys-faure et al. pediatric urology 2623 vol 13 no 02 march-april 2016 2624 results patient population between 1992 and 2014, 73 boys who met the criteria for cic were identified. sixty boys agreed to start cic for lut dysfunction during the study period. the median age at cic initiation was 8.2 years (range from 1.2 to 18 years). the other 13 boys did not start catheterizing because parents refused cic (n = 11), and two patients had urethral strictures after valve ablation. before cic initiation, 57 (95%) of the 60 boys who agreed to start cic had socially unacceptable incontinence according to iccs and schulte baukloh scale. the remaining three boys (5%) were continent, but were at risk for upper urinary tract dilation. underlying diagnoses included congenital neurogenic lut dysfunction (78.4%, n = 47), bladder exstrophy (8.3%, n = 5), underactive bladder (3.3%, n = 2), bladder tumor resection (3.3%, n = 2) and epispadias (1.6%, n = 1). table 1 demonstrates the main patient characteristics. of the 60 boys, 30 (50%) had the catheterizations initially performed by another person (at a median age of 5.6 years (range from 1 to 15.3 years). twelve of these thirty boys subsequently performed self-catheterization. thus, 42 boys were self-catheterizing at a median age of 10.8 years (range from 5.9 to 18.4 years). the switch from heteroto self-catheterization occurred after a median of 2.1 years (range from 2 months to 7.8 years). mean follow-up time was 9.9 years (± 4.3). at the end of the study, 11 of the 60 boys (18%) failed to remain on cic. acceptance with regard to age, cic was well accepted in younger boys (table 2). boys older than 13 years reported more difficulties during the learning period than the younger boys (33% in the 13-18 years group versus 21% in the group 1-8 years, p = .06). the usual cause was the child’s fear of potential pain and harm to bodily parts. however, more young boys stopped cic (n = 5/9, 17.8%). most parents (n = 4) reported too much anxiety in performing hetero-catheterization and the absence of immediate benefits. discontinuation of cic occurred within the first 6 months. in one case of a 7-year-old boy, the protocol failed after 8 months because he could not tolerate cic after a urethral false passage. two boys who were completely incontinent were lost to follow-up after stopping cic because of family difficulties. during subsequent follow-ups, fewer boys reported difficulties performing cic in each age group. one of them had fibrous phimosis hindering foreskin retraction, three had genitourinary complications, two experitable 2. acceptance and effectiveness of cic in terms of urinary continence for boys as a function of their age at cic initiation. variables group 1, 1-8 years (n = 28) group 2, 9-13 years (n = 14) group 3, 14-18 years (n = 18) p value median age at cic initiation, years (range) 5.6 (1-7.8) 9.2 (8-11.3) 15.7 (13.5-18.3) ns mean age, years ± sd at cic initiation 4.9 ± 2.05 9.4 ± 1.23 15.7 ± 1.33 ns percentage of patients doing hetero/self cic 92 / 8 21 / 79 6 / 94 ns patients with failure in the cic protocol, % (no) 17.8 (5) 14 (2) 11 (2) ns patients with initial difficulties, % (no) 21 (6) 28.5 (4) 33 (6) ns patients with persistent difficulties, % (no) 14 (4) 14 (2) 11 (2) ns patients socially continent with cic* 71 (20) 92 (13) 88 (16) ns abbreviations: cic, clean intermittent transurethral catheterization; sd, standard deviation; ns, not significant. *refers to the schulte-baukloh incontinence scale score. variables normal urethral sensation (n = 24) no genital sensation (n = 36) p value median age at cic initiation, years (range) 12.5 (7.4-18.2) 5.9 (1-18.4) ns mean age (years) ± sd at cic initiation 12.2 ± 0.4 7.2 ± 0.79 ns percentage of patients doing hetero/self cic 65 / 35 40 / 60 ns patients with failure in the cic protocol, % (no) 16.7 (4) 13.8 (5) ns patients with initial difficulties, % (no) 29 (7) 25 (9) ns patients with persistent difficulties, % (no) 12.5 (3) 13.8 (5) ns patients socially continent with cic* 91 (22) 83 (30) .05 abbreviations: cic, clean intermittent transurethral catheterization; sd, standard deviation; ns, not significant. *refers to the schulte-baukloh incontinence scale score. table 3. acceptance and effectiveness of cic in terms of urinary continence for boys as a function of their urethral sensation. a long-term teaching experience of self-catheterization in boys-faure et al. enced difficulties switching from heteroto self-catheterization, and two had poor compliance due to a limited understanding of the risks and benefits. with regard to urethral sensation, cic was well accepted in boys without genital sensation (n = 25, table 3). boys with normal urethral sensation reported more difficulties during the learning period (29% versus 25% for boys without sensation, p = .06). they reported urethral pain (n = 2) or anxiety (n = 5) during the introduction of cic. more boys with normal genital sensation stopped cic (16.7%, n = 4) at the median time of five months after starting cic (range from 1 to 8 months). the protocol failed in three boys because they had anatomical difficulties due to bladder exstrophy and were not able to succeed in cic. the other boy did not experience benefits from cic. during the follow-up, an equivalently low number of boys (n = 6) had persistent difficulties performing cic. continence of the 57 boys who started cic for unacceptable incontinence, 53 (93%) became socially continent (totally dry or wet only once a day, usually at night) according to the schulte-baukloh score, with no statistically significant difference between the heteroand self-catheterization groups. among them, 21 boys (36.8%) required anticholinergic therapy. the three remaining boys who started cic because they were at risk for upper urinary tract dilation remained continent with cic. fifteen boys (26.3%) required bladder augmentation in addition to cic to achieve continence. furthermore, young-dees-leadbetter and pippi-salle bladder neck reconstruction were performed in nine and six cases, respectively. one patient underwent bladder augmentation, bladder neck reconstruction and a mitrofanoff procedure. of these 15 patients, 13 (86.7%) were continent after surgery and cic. the two remaining patients with persistent unacceptable incontinence complied poorly with treatment recommendations (discontinuation of cic and refusal of additional bladder neck reconstruction) and were lost to follow-up. in five boys with cic who were taking anticholinergic therapy, social continence was achieved with a botulinum-a toxin detrusor injection for detrusor overactivity as examined by urodynamic studies. an endoscopic periurethral bulking agent injection was performed in three patients. the goal of the bulking agent injection was to increase the urethral closing pressure after increasing bladder capacity by injecting botulinum-a toxin. two boys with considerable sphincter deficiency, despite dextranomer treatment, are currently waiting for a second surgery. with regard to age, 92% of teenagers were socially continent with cic. the five boys with persistent incontinence were younger than eight years old. among them, three had insufficient urethral closing pressure, and two complied poorly with the cic protocol. three boys (5%) had a malignant tumor in regression after irradiation. they stopped cic because of the disappearance of voiding problems and spontaneous complete micturition. with regard to urethral sensation, more boys with normal urethral sensation were socially continent with cic (91% versus 83% with neurogenic bladder, p = .05). protection of the upper urinary tract before cic initiation, 13 (21.7%) boys had vur including four with bilateral vur. early in the study period, ureteral re-implantation, in addition to cic, was performed in three boys with high grade vur. at last follow-up, the reflux had disappeared in 69% (n = 9) of cases. before cic initiation, 13 boys (21.7%) had upper urinary tract dilation on us including 12 with bilateral dilation. hydronephrosis without vur was observed in 4 boys. at last follow-up, dilation had resolved in 54% of cases (n = 7). no patient experienced worsening of pre-existing dilation or de novo development of dilation. the two boys with persistent bilateral ureteral hydronephrosis had caudal regression syndrome with obstructive megaureters. in two boys (3.3%) in whom cic provided insufficient protection of the upper urinary tract, urinary diversion was required (one case each of incontinent cystostomy and ureterostomy). the three boys (5%) with baseline renal failure experienced improvements in kidney function with cic. plasma creatinine levels (mean, 30.8 µmol/l ± 1.7) remained normal for their age throughout the follow-up in the remaining 57 boys (95%). no patient experienced a decline in renal function during follow-up. no kidney transplantation was required. no differences were observed in protecting the upper urinary tract as a function of age or urethral sensation. genitourinary complications a single episode of gross hematuria occurred in three boys during the learning phase. in four boys, catheterization became impossible at some point, and cystoscopy showed urethral false passage in two boys, urethral stricture in one patient, and bladder neck hypertrophy in one patient. those complications occurred after the learning period at the median time of ten months (range from 1 to 14 months). the two boys (3.3%) with false passages were 6.2 and 8.3 years without genital sensation. they were managed for a few days with ina long-term teaching experience of self-catheterization in boys-faure et al. pediatric urology 2625 vol 13 no 02 march-april 2016 2626 dwelling catheterization. once their symptoms abated, cic was resumed with no further difficulties for one boy. the family of the other boy stopped cic because of anxiety. one patient (1.6%) who was 9.3 years old with urethral strictures required multiple dilatations. finally, the patient who had difficulty with abutment of the catheter against a bladder neck hypertrophy was managed with continent cystostomy. the incidence of urethral lesions did not increase at puberty and showed a non-significant decrease in the group performing self-catheterization. epididymitis occurred in four boys (6.7%) including three with bladder exstrophy requiring bladder neck reconstruction, and one with immunosuppression due to chemotherapy for an iliac ewing sarcoma. this complication did not lead to further non-acceptance in the cic protocol. before cic initiation 12 (20%) boys had a history of febrile utis. the number of patients with febrile utis decreased to four with cic (p = .05). factors significantly associated with febrile utis during cic were hydronephrosis, vur, and prior febrile uti (p = .05). neither the continence status (p = .33) nor the catheterization method (p = .25) influenced the risk of febrile utis. discussion we present a large series of cic procedures with a mean follow-up of 10 years, and an examination of the procedure’s acceptance and efficacy. cic used to treat lut dysfunction in boys was well accepted regardless of age and of the degree of urethral sensation.(7) our study showed that cic could be successfully started and continued in older children even if they expressed more difficulties during the first six months than the younger boys. nevertheless after the learning period, a small proportion of patients reported persistent difficulties in every age group. special attention was required for adolescents when changes occurred in their life habits, which may play a role the decreasing motivation to continue performing cic. young adults needed specialized care, especially when they were transferred from pediatric to adult practices. our findings provide a reassuring long-term outcome of well-accepted cic in the neonatal period or in infancy despite the need for a learning period. with regard to the degree of urethral sensation, boys with normal sensation expressed more difficulties starting cic, but after a learning period, the rate of persistent difficulties was equivalent in all groups. our study showed that cic could be successfully started in children with genital sensation, regardless of their age in the beginning. the oldest boys started cic at 17 years old. the success rate for cic in those patients was 83.3%. in limited series, the success rates for children genitally sensate who performed cic have been reported to be between 65% and 70%.(8) we believe that our high success rate was due to the heavy involvement of an experienced nurse who was directly available to assist in the teaching and maintenance of the cic technique. compliance with the cic program correlated significantly (p < .05) with urinary continence outcomes. this study showed that cic is effective in achieving urinary continence in boys with sufficient bladder capacity (92% of patients were socially continent with cic). of the 24 boys with normal urethral sensation, 91% were continent with cic. only 8% (n = 2) were incontinent at the last follow-up. concurrent procedures, such as ccc (mitrofanoff or monti channels), that provide an alternative drainage access to the bladder are often debated in children with difficult access through the native urethra. focusing on long-term outcomes (greater than five years), incontinence was one of the most frequent complications with ccc.(9) in a large series of 189 patients, leslie et al. reported a 65% rate of incontinence in the first three years after the initial operation (p = .7). surgical revision was performed in 10% of patients for incontinence. in that study, they concluded that incontinence arose during the long-term evaluation. as many interventions are carried out in children with bladder voiding dysfunction, it is important to evaluate patients for issues that may arise over a long period of time. in our experience, despite an initial trial period, cic provide a reassuring long-term outcome, regardless of the age of initiation and the degree of urethral sensation. because of the development of late problems with ccc upon long-term evaluation, we promote the use of non-invasive procedures as long as possible. in our center, we have established an effective infrastructure to support education and training in cic, as well as satisfactory social support. in a real world experience, however, long-term compliance with cic is a main concern. to re-engage children and parents who were initially successful but subsequently became non-compliant, we introduced an individualized educational care plan involving the boy and the urotherapist. we offered the child the opportunity to speak face-toface with the dedicated nurse to review anatomy, evaluate appropriate catheter material and catheterization technique, and also to discuss any concerns that they encountered in daily life and with the family. in addition, each patient was systematically asked to attend a long-term teaching experience of self-catheterization in boys-faure et al. clinic every 6 months. thus, any obvious recurrent episodes of incontinence episode or urinary tract infections could be detected. there was an important finding regarding urethral safety during cic. during the learning phase, 16 boys reported difficulties with catheter insertion, especially in the non-neurogenic population and in boys with hetero-catheterization. most complications occurred within the first two years and were followed by a relatively complication-free period. our results are in line with the previous literature,(10) although we observed that complications did not lead to non-compliance. we also compared our data to those of other studies of boys using mitrofanoff or monti channels for cic.(9-11) as depicted, an initial peak in the number of events (including surgical revision, redo operation, bulking agent injection and prolapse correction) was followed by a relatively stable complication-free period. nevertheless, long-term follow up problems were detected that were related to wear and tear of the conduits. even with a learning period, the healing process of cic by the native urethra was well performed by boys or their family members with a low rate of complications. in boys with normal urethral sensation, ccc and cic are both associated with a high morbidity rate. we also focused on the rates of stenosis. in our study, urethral stenosis developed in a single patient (1.7%), as a probable result of an inflammatory response to repeated catheter-induced trauma. recently, administration of triamcinolone ointment for lubrication of the catheter following internal urethrotomy has been shown to decrease the stricture recurrence rate.(12) in pediatric studies, the urethral stenosis rate has ranged from 0%(13) to 25%.(14) our incidence of epididymitis was commensurate with those found in the literature, which ranged from 3.6%(14) to 19%(13) and was not correlated with the number of years of cic (p = .05). cic may constitute the most effective means of preventing febrile utis by achieving sufficient bladder capacity with low intravesical pressures and regular voiding. utis appear to be the main cause of morbidity and upper urinary tract alterations in pediatric patients with bladder dysfunction. in our study, regular cic was associated with a low incidence of febrile utis (p = .05). vur that was present at baseline resolved in 69% of patients, and upper urinary tract dilation improved in 54%. thus, cic is very effective in protecting the upper urinary tract. our study has several limitations that warrant mention aside from its retrospective design. in the absence of validated anxiety assessment tool, the evaluation of tolerance was difficult. patients did report fear of pain and injury to the body as well as general anxiety. furthermore in many cases, a variety of additional procedures, such as urethral bulking agent injections, bladder augmentation, mitrofanoff channel creation, bladder neck surgery or intradetrusor botulinum toxin injections, were required to achieve continence, thus challenging the assessment of cic efficacy. despite the relative small number of children and these limitations, our study highlights a high rate of long-term acceptance of cic, although promoting non-invasive procedures as long as possible is still advisable. conclusions cic used to treat lut dysfunction in boys is well accepted and effective in ensuring urinary continence and protecting the upper urinary tract for most children with or without genital sensation. despite initial difficulties performing cic during the learning period, high longterm success and compliant rates were observed. cic exhibited low rates of genitourinary complications regardless of the presence of urethral sensation. particular attention is needed for the initiation of cic in young children and boys with non-neurogenic bladder to optimize acceptance. an individually tailored education program delivered by an urotherapy nurse is crucial. acknowledgments we thank blandine beauvois, daniel sikavi and anna ionson for help in writing the manuscript. conflict of interest none declared. references 1. lapides j, diokno ac, silber sj, lowe bs. clean intermittent self-catheterization in the treatment of urinary tract disease. j urol. 1972;107:458-61. 2. edelstein ra, bauer sb, kelly md, et al. the long-term urological response of neonates with myelodysplasia treated proactively with intermittent catheterization and anticholinergic therapy. j urol. 1995;154:1500-4. 3. neel kf. feasibility and outcome of clean intermittent catheterization for children with sensate urethra. can urol assoc j. 2010;4:4035. 4. austin pf, bauer sb, bower w, et al. the standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the international children's continence society. neurourol urodyn. 2015 mar 14. doi: 10.1002/nau.22751. [epub ahead a long-term teaching experience of self-catheterization in boys-faure et al. pediatric urology 2627 vol 13 no 02 march-april 2016 2628 of print] 5. gamé x, mouracade p, chartier-kastler e, et al. botulinum toxin-a (botox) intradetrusor injections in children with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic literature review. j pediatr urol. 2009;5:156-64. 6. schulte-baukloh h, michael th, stürzebecher b, knispel hh. botulinum-a toxin detrusor injection as a novel approach in the treatment of bladder spasticity in children with neurogenic bladder. eur urol. 2003;44:139-43. 7. van savage jg, sackett ck, wilhelm cl, sessions rp, mesrobian hg. indications for and outcomes of clean intermittent catheterization in children with normal genital sensation. j urol. 1997;157:1866-8. 8. pohl hg, bauer sb, borer jg, et al. the outcome of voiding dysfunction managed with clean intermittent catheterization in neurologically and anatomically normal children. bju int. 2002;89:923-7. 9. leslie b, lorenzo aj, moore k, farhat wa, bägli dj, pippi salle jl. long-term followup and time to event outcome analysis of continent catheterizable channels. j urol. 2011;185:2298-302. 10. campbell jb, moore kn, voaklander dc, mix lw. complications associated with clean intermittent catheterization in children with spina bifida. j urol. 2004;171:2420-2. 11. welk bk, afshar k, rapoport, macneily ae. complications of the catheterizable channel following continent urinary diversion: their nature and timing. j urol. 2008;180:1856-60. 12. hosseini j, kaviani a, golshan ar. clean intermittent catheterization with triamcinolone ointment following internal urethrotomy. urol j. 2008;5:265-8. 13. perez-marrero r, dimmock w, churchill bm, hardy be. clean intermittent catheterization in myelomeningocele children less than 3 years old. j urol. 1982;128:779-81. 14. lindehall b, abrahamsson k, hjälmås k, jodal u, olsson i, sillén u. complications of clean intermittent catheterization in boys and young males with neurogenic bladder dysfunction. j urol. 2004;172:1686-8. a long-term teaching experience of self-catheterization in boys-faure et al. 1517vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l laparoscopic management of symptomatic giant adrenal pseudocyst: a case report mohammad asalzare,1 behnam shakiba,2 amir abbas asadpour,1 alireza ghoreifi2 corresponding author: behnam shakiba, md department of urology, imam reza hospital, razi st., mashhad, iran. tel: +98 511 8022553 e-mail: b_shakiba@razi.tums.ac.ir received january 2013 accepted july 2013 1 department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran. 2 department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran. case report keywords:adrenalglanddiseases;cysts;laparoscopy;treatmentoutcome. introduction cysticlesionsoftheadrenalglandarerareentitieswithanestimatedincidenceof0.064-0.18%inautopsyseries.(1)therearefourcategoriesofadrenalglandcyst:epithelial, endothelial, parasitic and pseudocyst.(2)adrenalpseudocystsarefibrous surroundedcystswithoutanyendothelialorepitheliallining,andaregenerallyfilledwith freshbloodorclotsduetohemorrhageintothecysts.(3)themajorityofadrenalpseudocysts areasymptomaticandoflimitedclinicalsignificance.theseasymptomaticsimplepseudocystsrequirenofurtherevaluation.treatmentofadrenalpseudocystsusuallyindicatedin largeandcomplicatedcysts.(4)wereportasymptomatichugeadrenalpseudocystmeasuring about19cminlargestdiameter,whichmanagedwithlaparoscopicexcision. case report a35year-oldwomanwasreferredtoourhospitalwiththechiefcomplaintofpainandfeeling ofpressureintheleftupperquadrantsincesixmonthsearlier.personalandfamilyhistoryhad notrelevantinformation.onphysicalexamination,thepatienthadnormalbloodpressureand 1518 | intheabdominalexaminationtherewasapalpablemassin theleftflankandleftupperquadrantwithouttenderness.the patientwasadmittedforfurtherinvestigation.theresultsof laboratorystudiesincludingbloodcounts,bloodchemistry andelectrolyteswerewithinnormallimits.abdominalultrasonographydemonstrateda17cmunilocularcysticmass occupyingtheleftabdomen.abdominalcomputedtomography(ct)scanshoweda19×17×13cmsuprarenalwelldefinedcysticmass(figure1).thiscystlocatedbetweenthe spleen,leftkidney,andpancreasandarisingfromtheleft adrenalgland.theleftkidneywasdisplaceddownwardto theleftlowerquadrantoftheabdomenbythemass.there wasnoseptation,calcificationandcontrastenhancementin themass.hormonalexamination,including24hoursurine catecholamines,17-hydroxycorticosteroids,17-ketosteroids, adrenocorticotropichormone,serumcatecholamines,cortisol,aldosterone,24-hoururinaryexcretionofmetanephrines andvanillylmandelicacidandplasmareninactivitieswere allwithinnormallimits. theclinicaldiagnosisofadrenalcystwasmadebasedon symptoms,radiographicfindingsandnon-functionalstatus of the mass.a laparoscopic transperitoneal cyst excision withpreservationoftheremainingpartoftheglandwasperformed(figure2).thecystwasadherenttotheunderlying kidneyandleftadrenalgland.therewerenoadhesionsbetween the cyst and the pancreatic tail and spleen. it was separatedfromtheadjacentorgansbymonopolarelectrocautery scissorwithoutanydifficulties.occasionally,fordissection weusedbipolarelectrocauteryscissor.intraoperatively,after separationofcystfromkidneyandspleen,weperformedpercutaneousaspiration.afteraspiration,thecystwasnotcollapsed;becauseitcontaineddegeneratedoldclots.afterseparationthecystfromadjacentorgans,itwasremovedwith anopenincision.theoperativetimewasabouttwohours. thebloodlosswasminimalandtherewasnointraoperative complication. grossappearanceshowedathin-walled,yellowishunilocularadrenalmasscontainedhemorrhagicfluidanddegeneratedoldclots.pathologicalexaminationrevealedan“adrenalpseudocyst”withoutanepithelialorendotheliallining (figure3).therewasnoevidenceofmalignancy.postoperatively,sherecovereduneventfullyandwasdischargedon thesecondpostoperativeday.theleftabdominalpainand discomfortresolvedafterremovalofthepseudocyst.atfollow-up28monthslater,thepatientwasasymptomaticand withoutpathologicalfindings. discussion adrenalcystsoriginatingwithintheadrenalcortexormedulla,wasdescribedfirstbythevienneseanatomistgreiselius in 1670.(5)therearefourtypesofadrenalcysts:endothelial cysts, pseudocysts, epithelial cysts and parasitic cysts. adrenalpseudocystsrepresentabout32-80%ofadrenalcysts. thecauseandmechanismofadrenalpseudocystsremains unknown. possible etiologies include: degeneration of a primaryadrenalneoplasm,degenerationofavascularneoplasm,andhemorrhagewithinnormaladrenaltissueorinto anadrenaltumor.(4) although adrenal pseudocysts can occur at any age, studies haveshowedthattheyaremostcommonlydiagnosedinthe fourthandfifthdecadesoflife.pseudocystismorecommon case report figure 1. abdominal computed tomography showed a 19 × 17 × 13 cm suprarenal well-defined cystic mass. 1519vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l laparoscopic management of adrenal pseudocyst | asalzare et al inwomenthanmen,witharatioofapproximately2-3:1.(6) mostcasesareasymptomatic;however,abdominalorflank pain,afullnessormassinabdomenorflankarethemost commonpresentingfeaturesofpersonswithsymptomatic adrenal pseudocysts.(7,8) the differential diagnosis varies basedonlocation,butcommonlyincludesspleniccysts,hepaticcysts,renalcysts,mesentericorretroperitonealcysts, urachalcystsandsolidadrenaltumors.(9) avarietyofradiologicmodalitieslikeultrasonography(us), ctscanandmagneticresonanceimaging(mri)areusedfor diagnoseofadrenalcysts.theusappearancesofadrenal cystsareunilocularormultilocularcysticlesionssimilarto those seen elsewhere in the body. ctscanistheimagingmodalityofchoicefordiagnosisof adrenal cysts. the sensitivity and diagnostic accuracy of preoperativectforadrenalcystare96%and62.5-96%,respectively.(6,10)usuallyctscanofpseudocystsdemonstrates well-demarcatedroundorovalmasseswithlowdensity.internalhemorrhagemayduetosomeatypicalfeaturesinct scanincluding,thickwalls,internalseptationsandcalcifications.calcificationmaybepresent inthewallorseptum. (2,9,11) histopathologicalexaminationofthespecimenconfirmsthe diagnosisofadrenalcysts.trueadrenalcystsarelinedwith endothelial or epithelial cells, but adrenal pseudocysts are devoidofarecognizablelayerofliningcellsandenclosedbya fibroustissuewall.(7) themanagementofadrenalpseudocystsdependsonsome factorssuchassize,presenceofsymptoms,functionalstatus andprobabilityofmalignancy.ifthecystsaresmall(<5-6 cm)withnear-waterdensityandhaveathin(<3mm)wall, andarenotcausingsymptoms,carefulobservationwithperiodicctscansisoftendone.surgicalexcisionisindicated in the presence of symptoms, suspicious for malignancy, increaseinsizeanddetectionofafunctioningadrenalcyst. surgicaltreatmentincludesopenorlaparoscopicapproach. somestudiesrecommendedthatopenresectionispreferred techniqueinpatientswithlargesizedcysts(>6cm)andthe laparoscopicapproachmaybeavaluabletreatmentforcysts smallerthan6cm.(4,11,12)basedonourknowledge,thereare a few reports, that showed the feasibility of laparoscopic techniqueforlarge(>6cm)adrenalcystsandmasses.(13-15) conclusion inpresentreport,weusedlaparoscopicresectionasaneffectiveminimallyinvasiveapproachforahugesymptomaticadrenalpseudocystmeasuringabout19cminlargestdiameter. conflict of interest none declared. figure 2. laparoscopic transperitoneal cyst excision is shown. the cyst was adherent to the underlying kidney. figure 3. pathological examination of surgical specimen revealed an “adrenal pseudocyst” without an epithelial or endothelial lining. references 1. rozenblit a, morehouse ht, amis es jr. cystic adrenal lesions: ct features. radiology. 1996;201(suppl 2):541-8. 1520 | 2. ujam ab, peters cj, tadrous pj, webster jj, steer k, martinez-isla a. adrenal pseudocyst: diagnosis and laparoscopic management a case report. int j surg case rep. 2011;2:306-8. 3. demir a, tanidir y, kaya h, turkeri ln. a giant adrenal pseudocyst: case report and review of the literature. int urol nephrol. 2006;38:167-9. 4. kim bs, joo sh, choi si, song jy. laparoscopic resection of an adrenal pseudocyst mimicking a retroperitoneal mucinous cystic neoplasm. world j gastroenterol. 2009;15:2923-6. 5. doran ah. cystic tumour of the suprarenal body successfully removed by operation, with notes on cases previously published. br med j. 1908;1:1558-63. 6. salemis ns, nisotakis k. giant adrenal pseudocyst: laparoscopic management. anz j surg. 2011;81:185-6. 7. medeiros lj, lewandrowski kb, vickery al jr. adrenal pseudocyst: a clinical and pathologic study of eight cases. hum pathol. 1989;20:660-5. 8. fan f, pietrow p, wilson la, romanas m, tawfik ow. adrenal pseudocyst: a unique case with adrenal renal fusion, mimicking a cystic renal mass. ann diagn pathol. 2004;8:87-90. 9. momiyama m, matsuo k, yoshida k, et al. a giant adrenal pseudocyst presenting with right hypochondralgia and fever: a case report. j med case rep. 2011;5:135. 10. el-hefnawy as, el garba m, osman y, eraky i, el mekresh m, ibrahim el-h. surgical management of adrenal cysts: single-institution experience. bju int. 2009;104:847-50. 11. erbil y, salmaslioğlu a, barbaros u, et al. clinical and radiological features of adrenal cysts. urol int. 2008;80:31-6. 12. stimac g, katusic j, sucic m, ledinsky m, kruslin b, trnski d. a giant hemorrhagic adrenal pseudocyst: case report. med princ pract. 2008;17:419-21. 13. ramacciato g, mercantini p, la torre m, et al. is laparoscopic adrenalectomy safe and effective for adrenal masses larger than 7 cm? surg endosc. 2008;22:516-21. 14. novitsky yw, czerniach dr, kercher kw, perugini ra, kelly jj, litwin de. feasibility of laparoscopic adrenalectomy for large adrenal masses. surg laparosc endosc percutan tech. 2003;13:106-10. 15. kar m, pucci e, brody f. laparoscopic resection of an adrenal pseudocyst. j laparoendosc adv surg tech a. 2006;16:478-81. case report sexual dysfunction and infertility surgical treatment of erectile dysfunction and peyronie’s disease using malleable prosthesis ufuk yavuz,* seyfettin ciftci, murat ustuner, hasan yilmaz, melih culha purpose: peyronie’s disease (pd) is a condition of middle aged men and frequently accompanied by erectile dysfunction (ed) which was attributed to penile deformity, vascular pathology and psychological components. the implantation of semi-rigid penile prosthesis allows for these patients to undergo a simple procedure aimed at correction both penile deformity and ed. the aim of this study was to investigate surgical and clinical outcomes and patient satisfaction rate at long term follow-up after semi-rigid penile prosthesis implantation (ppi) in men with pd and ed. materials and methods: a total of 66 patients with mean age of 49.2 (range, 30-76) years old underwent semi-rigid ppi between 1995 and 2006. genesis (coloplast®) was used for implantation in a standard manner by penoscrotal approach without using any graft and remodeling technique. in all patients, dilatation of corpora was performed without any difficulty and straightening of the penis was achieved. a retrospective review of clinical database and prospective telephone survey were conducted in all patients. results: the mean follow-up time was 9.7 years (range, 6 to 17). there wasn’t any clinical infection and complication during follow-up period. fifty-nine patients were sexually active at the time of the interview. none of the patients reported residual curvature. the overall patient satisfaction was 91.5% (54 patients). primary reasons for dissatisfaction were decreased penile length and prosthesis problems. conclusion: based on our results semi-rigid ppi is effective and easy procedure for treatment of men with pd and ed without any complication and with high patient satisfaction rate in long-term follow up period. keywords: penile induration; surgery; penile prosthesis; erectile dysfunction; patient satisfaction; questionnaires; penis. introduction peyronie’s disease (pd) which was first described by a french physician de la peyronie in 1743, is an acquired local connective tissue disorder including changes in the collagen composition and characterized by development of a fibrotic plaque over the tunica albuginea on the corporal bodies of penis.(1) this fibrous plaque occasionally calcifies and leads to painful penile erection, penile deformities and associated sexual dysfunction.(2) pd appears to be a sexual medicine condition of middle aged men and frequently accompanied by erectile dysfunction (ed) which is attributed to penile deformity, vascular pathology and psychological problems. the typical presentations of the disease are pain during erection, ed and penile deformities.(3,4) pd is accompanied by ed which was attributed to penile deformity, vascular pathology and psychological components. ed has been reported in a range of 20%-54% of men with pd;(5) however ed-pd concomitance may increase up to 83%.(6) several procedures have been described to manage penile curvature and ed. chung et al reported patients who had severe penile curvature ( greater than 60 ) undewent graft surgery and about 65% of them dissatisfied with the treatment outcomes such as ed development in their study.(7) penile prosthesis surgery with or without corrective surgery for curvature is one of the valuable choice in the literature.(8-10) implantation of semi-rigid penile prosthesis allows for these patients to undergo a simple procedure aimed at correction both penile deformity and ed. in this study, we evaluated our experience in 66 patients with pd and ed in whom a semi-rigid penile prosthesis was implanted and deformities were corrected with a simple procedure and at long-term follow-up. surgical and clinical outcomes and patient's satisfaction rate were assessed. materials and methods department of urology, school of medicine, university of kocaeli, kocaeli, turkey. *correspondence: department of urology, university of kocaeli, campus of umuttepe, 41380, kocaeli, turkey. tel: +90 262 3038708. fax: +90 262 3038001. e-mail: drufukyavuz@gmail.com. received march 2015 & accepted september 2015 vol 12 no 06 november-december 2015 2428 penile prosthesis in peyronie’s disease-yavuz et al. sexual dysfunction and infertility 2429 study population between 1995 and 2006, a total of 66 patients aged from 30 to 76 years old (mean 49.2) with pd and ed were underwent malleable penile prosthesis implantation (ppi) without additional plaque surgery including graft and remodeling technique. most of the patients were evaluated in our andrology department, also some of them were referred to our clinic. evaluations initially, a detailed history and physical examination were performed and patients completed international index of erectile function (iief) questionnaire. all patients had various severity of difficulty to have sexual intercourse which was refractory to the conservative treatment such as phosphodiesterase type 5 (pde5) inhibitors. in this study one stage procedure was planned for both ed and pd treatment. degree of the penile curvature was less than 30° in 28 patients (42.4%), between 30°-60° in 29 patients (43.9%) and more than 60° in 9 patients (13.7%). direction of the curvature was dorsal in 32 (48.5%), lateral in 15 (22.7%), ventral in 10 (15.2%) and dorsolateral in 9 patients (13.6%) (table1). the median preoperative duration of pd was 27 months (range, 13-66). none of the patients in our series had undergone previous penile surgery. patients with stable disease, defined as at least one year from onset and at least six months of stable deformity were admitted to the surgery. patients with very hard and calcified plaques were excluded and treated mostly with grafting procedure. penile vascular conditions were assessed with doppler ultrasonography and vascular pathologies such as arterial insufficiency and/or veno-occlusive dysfunction were determined. all patients were informed about the procedure and we obtained a written consent for ppi. a retrospective review of clinical database and prospective telephone survey were conducted in all patients. at the time of review, all patients were specifically asked about of satisfactory sexual intercourse and recurrent curvature for which they underwent surgery. patient satisfaction was defined as successful and satisfactory sexual intercourse at each attempt. surgery procedure perioperative antibiotic prophylaxis included intravenous injection of 200 mg teicoplanin and 80 mg gentamycin 1 h preoperatively to be repeated before discharge and followed by an oral quinolone every 12 h for 5 days. semi-rigid malleable genesis (coloplast®) penile prostheses were implanted by a standard manner by a single surgeon (mc) using penoscrotal approach without using any additional surgery. tunica albuginea was incised vertically approximately 3-4 cm and the corporal bodies were dilated with hegar dilators of 7-13 french before the insertion of the malleable prosthesis. in patients who had less than 60° of curvature, we achieved penile straightening and adequate dilatation without additional procedure. we measured the corporal body length at the maximal stretch position with furlow inserter, and the appropriate size of malleable penile prosthesis was implanted. particularly, in 3 patients who had more than 60° of curvature, penis is not adequately straightened as a result of cylinder implantation. the cylinders are then forcibly counter-flexed in the direction opposite that of the curvature and relaxing incisions were made using scissors to the most fibrotic part of the tunica, not so deeply, avoiding any tunical rupture. in one patient the plaque was incorporated into the neurovascular bundle, the latter was dissected through the plaque. after straightening of the penis in all patients, the closure of the tunica albuginea was performed with interrupted 2-0 polyglactin absorbable sutures. the subcutaneous tissue and skin were closed with continues 3-0 polyglactin absorbable sutures. the penis was dressed with an elastic bandage and a foley catheter was inserted for one day. prophylactic antibiotics were used in all patients for seven days. a retrospective review of clinical database and prospective telephone survey were conducted in all patients. patients questioned about the sexual activity, prosthesis problems, satisfactory sexual intercourse and residual curvature. the iief-5 questionnaire was used to obtain sexual function and satisfaction data (table 2). standard t-test was used to compare various means and proportions and p value less than .05 accepted as statistable 1. characteristics of study subjects. variables values age, years (iqr mean) 49.2 (30 76) degree of curvature, no. (%) < 30° 28 (42.4) 30°60° 29 (43.9) 61°90° 9 (13.7) direction of curvature, no. (%) dorsal 32 (48.5) lateral 15 (22.7) ventral 10 (15.2) dorsolateral 9 (13.6) abbreviation: iqr, inter quartile range. age is presented as median (range, minimum-maximum). tically significant. results mean age of patients, degree and direction of curvatures were summarized in table 1. median iief scores were significantly high in postoperative period than in preoperative (table 2, p < .001). the mean degree of the penile curvatures was 39.77° (range, 20°-90°). in 9 patients the degrees of curvature were ≥ 60°. corporal perforation and/or urethral injury during the procedures were not seen. as far as postoperative early complications were concerned, we determined hematoma and edema in few patients that resolved spontaneously without any morbidity. mean follow-up period was 9.6 years (range, 6 to17). during the follow–up period, no implant infection and any other complications were observed. overall, 59 patients were sexually active at the time of review. five patients were lost in the follow-up period. the median iief-5 domain score for erectile function of the sexually active men was 28 (27 to 29). three patients (4.5%) were very depressed about the decreased penile length. two of the 59 men (3.3%) complained with prosthesis problems inhibiting them for sexual intercourse due to inadequate girth of the penis. none of the patients reported residual curvature, glans hypermobility and penile sensitivity impairment. the overall patient satisfaction was 91.5% (54 patients). primary reason for dissatisfaction was decreased penile length. the other reason was prosthesis problems which lead to unsatisfactory sexual intercourse owing to inadequate girth. discussion ed has been reported in a wide range of 20%-83% in patients with pd.(5,6) recently penile vascular abnormalities are found preoperatively in more than 50% of the patients who had pd.(11) although corporal veno-occlusive dysfunction is the most frequent pathological finding, cavernous artery inflow can also be affected. (6) pd causes an increased incidence of veno occlusive abnormalities and ed caused by venous leak. therefore straightening procedures are not always successful in restoring erectile function in patients with pd.(12,13) many surgical procedures used to correct penile deformities and type of procedure is dependent on the type of deformity, erectile function, penile length, hourglass deformity, patient expectations, and surgeon’s preference.(14) ppi is the standard of care for patients with pd and concomitant ed nonresponsive to medical treatment to achieve curvature straightening and for definitive mechanical erection. incision of the fibrotic plaque followed by implantation the small-carrion penile prosthesis was first described by raz and colleagues.(15) the authors reported successful treatment in 11 of 12 patients with the follow-up of 6 months to 2 years. a single prosthesis removal owing to prosthesis infection was reported. kelami and colleagues(16) treated 15 of 22 patients with pd and ed with implantation of small-carrion semi-rigid penile prosthesis using infrapubic approach without excision and/ or incision of the fibrous plaque. no complication was noted with the follow-up period of 2-12 months except penile edema which was seen in the first weeks of the operation. ghanem and colleagues(17) reported an 80% success rate using semi-rigid penile prosthesis in patients with pd and ed without any plaque surgery. no operative complication was encountered in their study. the procedure was performed in 20 patients using subcoronal incision and had satisfactory straightness and table 2. comparison of preoperative and postoperative iief scores. ieff domains preoperative postoperative p value* erectile function 8 28 .01 (q 1. 2. 3. 4. 15) orgasmic function 5.3 8.8 .01 (q 9. 10) 5.3 sexual desire 6.1 9 .01 (q 11. 12) intercourse satisfaction 4.1 11.1 .01 (q 6. 7. 8) overall satisfaction 3.1 8.8 .01 abbreviations: iief, international index of erectile function; q, question. * the p values obtained in the t-test results. penile prosthesis in peyronie’s disease-yavuz et al. vol 12 no 06 november-december 2015 2430 rigidity of the penis. a total of 16 patients achieving minimum 12 months follow-up were identified in the study. all of them were engaged in sexual intercourse successfully. among them, only 2 patients were dissatisfied with glans hypermobility leading to deviation of urine stream and cosmetic appearance. cohen and colleagues(18) presented a proximal approach while performing semi-rigid ppi in 22 patients with pd and ed. overall, 94% of patients were able to resume the sexual intercourse at the time of review. vascular compromise and/or skin slough were noted in 3 patients at the follow up period. all these studies reported the short term follow-up results of their surgical outcomes after ppi in patients with pd and ed. furthermore, similar to our study, they did not perform any additional surgery regarding to penile plaque. although our follow-up period was higher than those of above stated studies, we concluded similar satisfaction rate. similar study was carried out by montorsi and colleagues.(9) they treated a total of 50 patients with pd using semi-rigid penile prosthesis without any additional surgical procedures and maneuvers. the authors re-evaluated 48 patients 60 months after the surgery and did not encounter any major periand post-operative complications. overall, 44 (92%) patients were sexually active at the time of review. in their opinion the actual rate of satisfied patients should be assess at long term follow up. twenty three of 48 patients were totally satisfied with the sexual activity after the surgery. the most common reason for dissatisfaction was loss of the penile girth. avoiding additional plaque surgery, using semi-rigid penile prosthesis and long-term follow-up period are similar to our study. however, our study group was larger than montorsi and colleagues' study. we performed relaxing incisions in three patients. considering the dissatisfaction rates of both studies, patient expectations may be different between these two different study groups. in the literature, there are some studies in which the outcomes of semi-rigid and inflatable ppi procedures have been reported. ganabathi and colleagues(19) used ppi in the treatment of the pd in 8 patients with a mean follow-up period of 49 months. penoscrotal approach was used for implanting semi-rigid penile prosthesis in 6 and inflatable penile prosthesis in 2 patients. they reported penile prosthesis infection in one man in semi-rigid group 3 months after the surgery and removed the prosthesis. in inflatable group, one patient has died at the time of review. remaining 6 patients were evaluated and all of them had satisfactory sexual intercourse. there was no patient with recurrent penile curvature. they did not compare these 2 groups because of low number of patients. eigner and colleagues(8) also reported 35 men who had undergone ppi for the treatment of pd with ed. of the 26 patients who underwent semi-rigid ppi with infrapubic approach, only 5 required further surgical intervention for peyronie’s plaque to achieve an adequate cosmetic result. in inflatable penile prosthesis group, additional plaque surgery was performed in 6 of 9 patients to achieve adequate straightness. two complications were encountered in their study; moderate hematoma required no specific therapy and urethral perforation during corporal dilation in semi-rigid group. their overall satisfaction rate was 88% with a mean follow-up of 6.9 years. the difference of this study from the current one is additional plaque surgery in both groups. comparing semi-rigid and inflatable penile prosthesis for pd was the advantage of this study. ppi without any additional procedure and manual modeling correct the majority of the curvatures during prosthetic surgery. eigner and colleagues(8) considered the infrapubic approach allowing access to peyronie’s plaque without degloving the penile shaft. the other study that reported the results of semi-rigid and inflatable prosthesis in pd was carried out by djordjevic and colleagues.(14) the authors used malleable semi-rigid and inflatable penile prosthesis in 49 and 13 patients with pd, respectively. in patients whose curvatures degree ranged from 45° to 85°, additional relaxing tunical incisions were performed. overall, 95% of the patients had complete penile straightness with a median follow-up of 35 months. in semi-rigid group, there was decrease of penile girth in 7 of 49 patients, 3 of which were treated with replacement of inflatable penile prosthesis. no device infection or mechanical failure was reported. in semi-rigid group, 23 men had glans numbness which spontaneously decreased and disappeared in 6 months after the surgery. in patients with mild degrees of curvature, straightening can be achieved with only ppi without any plaque surgery. the satisfaction rate and absence of recurrent curvature were similar to our study. some authors used only inflatable ppi in the treatment of pd and ed. malloy and colleagues reported use of inflatable ppi in 19 patients, 18 of them were treated successfully using inflatable penile prosthesis.(20) the authors achieved adequate straightness and rigidity in 10 patients with performing only placement of the prosthesis. additional surgery as incision of the plaque was necessary for obtaining satisfactory results in 8 patients. (20) levine and colleagues used inflatable penile prossexual dysfunction and infertility 2431 penile prosthesis in peyronie’s disease-yavuz et al. thesis in 90 men for the treatment of pd and ed refractory to medical treatment.(21) a complete penile straightness was achieved in 4% of patients with ppi alone. to accomplish complete straightness manual modeling, plaque incision and graft requirement were needed in 71%, 4%, and 13% of patients, respectively. only one patient had prosthesis infection and 7% of patients reported mechanical failure of the prosthesis. the overall satisfaction rate of curvature correction was 84% with mean follow up of 49 months. inflatable penile prostheses may have an advantage for the correction of minimal or mild residual curvatures (less than 30°). it acts as a tissue expander at each inflation during attempts at sexual intercourse.(2) both inflatable and malleable implants can be used for the treatment of both procedure, but inflatable prostheses are associated with higher functional satisfaction and lower persistent curvature rates.(14) in our series we also did not observe any residual curvature, additional relaxing incisions were made in three patients and 5 patients were dissatisfied with the prosthesis. advantage of our study was higher follow-up period and large study sample size. this study is not without limitations. first we did not address the partner satisfaction. second there was no an inflatable penile prosthesis group to make an appropriate comparison. further prospective studies with semi-rigid and inflatable ppi are needed to draw final conclusion. conclusions our experience suggests that implantation of a semi-rigid prosthesis in patients with pd and ed, leads to the satisfactory straightening of the penis without curvature recurrence, and provides high patient satisfaction rate in long-term follow-up, despite inadequate penile girth. conflict of interest none declared. references 1. de la peyronie f. sur quelque obstacles puis’opposental’ejaculationnaturelle de la semence. mem acad r chir. 1743;1:425. 2. ralph d, gonzalez-cadavid n, mirone v, et al. the management of peyronie's disease: evidence-based 2010 guidelines. j sex med. 2010;7:2359-74. 3. smith jf, walsh tj, lue tf. peyronie's disease: a critical appraisal of current diagnosis and treatment. int j impot res. 2008;20:44559. 4. briganti a, salonia a, deho f, et al. peyronie's disease: a review. curr opin urol. 2003;13:417-22. 5. usta mf, bivalacqua tj, tokatli z, et al. stratification of penile vascular pathologies in patients with peyronie's disease and in men with erectile dysfunction according to age: a comparative study. j urol. 2004;172:259-62. 6. lopez ja, jarow jp. penile vascular evaluation of men with peyronie's disease. j urol. 1993;149:53-5. 7. chung e, clendinning e, lessard l, brock g. five-year follow-up of peyronie's graft surgery: outcomes and patient satisfaction. j sex med. 2011;8:594-600. 8. eigner eb, kabalin jn, kessler r. penile implants in the treatment of peyronie's disease. j urol. 1991;145:69-71. 9. montorsi f, guazzoni g, bergamaschi f, rigatti p. patient-partner satisfaction with semirigid penile prostheses for peyronie's disease: a 5-year followup study. j urol. 1993;150:1819-21. 10. wilson sk, delk jr, 2nd. a new treatment for peyronie's disease: modeling the penis over an inflatable penile prosthesis. j urol. 1994;152:1121-3. 11. gasior bl, levine fj, howannesian a, krane rj, goldstein i. plaque-associated corporal veno-occlusive dysfunction in idiopathic peyronie's disease: a pharmacocavernosometric and pharmacocavernosographic study. world j urol.1990;8:90-6. 12. chiang ph, chiang cp, shen mr, huang ch, wang cj, huang iy, shieh ty. study of the changes in collagen of the tunica albuginea in venogenic impotence and peyronie's disease. eur urol. 1992;21:48-51. 13. gentile v, modesti a, la pera g, et al. ultrastructural and immunohistochemical characterization of the tunica albuginea in peyronie's disease and veno-occlusive dysfunction. j androl. 1996;17:96-103. 14. djordjevic ml, kojovic v. penile prosthesis implantation and tunica albuginea incision without grafting in the treatment of peyronie's disease with erectile dysfunction. asian j androl. 2013;15:391-4. 15. raz s, dekernion jb, kaufman jj. surgical treatment of peyronie's disease: a new approach. j urol. 1977;117:598-601. 16. kelami a. peyronie disease and surgical treatment: a new concept. urology 1980;15:559-61. 17. ghanem hm, fahmy i, el-meliegy a. malleable penile implants without plaque surgery in the treatment of peyronie's disease. int j impot res. 1998;10:171-3. 18. cohen es, schmidt jd, parsons cl. peyronie's disease: surgical experience and presentation of a proximal approach. j urol. 1989;142:7402. 19. ganabathi k, dmochowski r, zimmern penile prosthesis in peyronie’s disease-yavuz et al. vol 12 no 06 november-december 2015 2432 pe, leach ge. peyronie's disease: surgical treatment based on penile rigidity. j urol. 1995;153:662-6. 20. malloy tr, wein aj, carpiniello vl. advanced peyronie's disease treated with the inflatable penile prosthesis. j urol. 1981;125:327-8. 21. levine la, benson j, hoover c. inflatable penile prosthesis placement in men with peyronie's disease and drug-resistant erectile dysfunction: a single-center study. j sex med. 2010;7:3775-83. penile prosthesis in peyronie’s disease-yavuz et al. sexual dysfunction and infertility 2433 1447vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l impact of urinary incontinence on quality of life among residents living in turkey muhammet guzelsoy, hakan demirci, soner coban, buket belkiz güngör, emin ustunyurt, serhat isildak corresponding author: hakan demirci, md department of family medicine, sevket yilmaz research hospital, yildirim, bursa, 16310, turkey. tel: +90 536 896 3330 e-mail: drhakandemirci@hotmail. com received june 2013 accepted february 2014 department of family medicine, sevket yilmaz research hospital, yildirim, bursa, 16310, turkey. female urology purpose:toassesstheimpactofurinaryincontinenceonthequalityoflifeinturkishpopulation. materials and methods:thiswasacross-sectionalstudyperformedon530participants admittedtosevketyilmazresearchhospitalinturkey.qualityoflife(qol)wasassessed usingincontinenceimpactquestionnaire(iiq-7).frequencyandseverityofurinaryincontinence(ui)werediagnosedbyanswerstotheinternationalconsultationonincontinence questionnaireshortform(iciq-sf)instrument.therelationshipbetweenseveraldemographicdataandqolwasexamined. results:themeanageoftheattendeeswas55.36±10.62years(range40-91).atotalof 109(44%)womenand46(16%)mensufferedinvoluntaryurineleakage.qolchangesfor alldomainsshowedsignificantdeteriorations.frequencyandseverityofuiwerenegatively associatedwiththeqolscores. conclusion:ourresultshaveshownthat,uiconsiderablyworsensqol.challengewithui shouldbepriorityofanyprojectaimingtopromotethequalityoflife. keywords:urinaryincontinence;qualityoflife;female;male;cross-sectionalstudies;turkey. 1448 | introduction theinternationalcontinencesocietydefinesurinaryincontinence(ui)as‘involuntarylossofurinethatisasocialorhygienicproblem’.(1)thesesocialand hygienicproblemsimpairthequalityoflife(qol)inpatientswithui.assessmentofqolcanbeachievedbyvariousquestionnairesinpatientswithuiamongthemincontinenceimpactquestionnaire(iiq-7)isawell-knownand easilyapplicableinstrumenttodetermineimpactofuion qol.(2)itisaself-reportedquestionnairefilledinbypersons andconsistsofsevenitemsaddressingfourmaindomainsof life:physicalactivity,socialrelations,travelandemotional status.thisinstrumentwasvalidatedtoturkishbycamand colleagues.(3)ontheotherhand,generalcharacteristicsof uicanbeevaluatedbytheinternationalconsultationon incontinencequestionnaireshortforminstrument(iciqsf).(4)althoughurodynamictestsareknowntobeagold standard for classification of ui, history taking has been shownbeanalternativetoit.(5-8) urinaryincontinenceiscommonespeciallyamongelderly butitcanbeexperiencedatanyage.althoughitisaquite bothersomesituationtothepatientssomepatientssuffering fromuidonotgotoahealthcareproviderbecausetheyfeel theproblemasanormalphysiologicsituationandsomehide thesituationastheyareashamed.(9-11)admissiontoahospitalwiththecomplaintofuiisshowntobelowespecially infemalegenderandtheymayusuallyprefertosolvethe problembythemselvesusingsomeadsorbentpads.severity ofui,typeofthediseaseandimpairmentinqolhasbeen showntoaffecthelpseekingbehavior.(12-14) theaimofthepresentstudywastoexaminetheimpactof uionqolamongturkishresidentsandfindoutananswer tothequestion“whydotheygotoaphysicianinrelationto qol”? material and methods study population a cross sectional study was conducted in 168 participants withuiwhowerereferredtotheoutpatientclinicsofurologyandgynecology&obstetricsdepartments insevket yilmaztrainingandresearchhospitalbetween1january 2013and31may2013.patientswerequestionediftheyhad uiandthefirstpatientofthedayduringthestudyperiod whohadthecomplaintofuiwasaskedtoparticipateinthe study. demographic data including age distribution, sex, education,occupationandmaritalstatuswerenoted.help seekingattemptsofthepatientswasrecorded. participantswereasked tofill iiq-7andiciq-sfforms. qualityoflifewasevaluatedbyusingiiq-7.scoresobtained fromparticipantsweremultipliedby33toestimatetheseverityof thechanges inqol.thegeneralcharacteristics ofurinaryincontinencewereassessedbythedataprovided fromtheanswerstotheiciq-sf.itenabledustodetermine frequency,quantityandclassificationofui.frequencyof uiwascategorizedin6groupsrangingfromnonetoalways andquantityofuiwasexaminedin4groupsasnone,alittle,moderateandalot.maneuversthatuiprovokedwas askedinthequestionnaire,andsourge,stress,mix,overactiveandtotalincontinencewasdifferentiated. exclusioncriteriawerepatientswithahistoryofaneurologicorpsychiatricdisease,patientswhohadbeenoperatedfor prostaticdisease,andpatientswhowereunabletocomplete thequestionnaires. ethicalapprovalforthisstudywasobtainedfromtheethical committee of sevket yilmaz training and research hospital.participantswereinformedaboutthestudyobjectivesandawritteninformedconsentwasobtainedfromeach ofthem. statistical analysis allstatisticalanalyseswereperformedwiththestatistical female urology table 1. sociodemographic characteristics of study participants. variables number marital status single 2 married 166 education literate 31 primary 91 secondary 37 high 9 occupation housewife 85 retired 55 working 27 unemployed 1 self-reported economic status low 21 moderate 133 high 12 1449vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l urinary incontinence on quality of life | guzelsoy et al package for the social science (spss inc, chicago, illinois,usa)version20.0.fordescriptivestatistics,means, standarddeviations(sd)andfrequencieswerecalculated. weusedthestudent’sttestforthecomparisonofmeanage between groups. mann whitney utestwasusedtocompare twogroups,kruskal-wallistestwasusedtocomparethree ormoregroupsfornominalvalues(i.e.;scoresofiiq-7).p valueslessthan.05wereconsideredasstatisticallysignificant. results atotalof168participants(107womenand61men)sufferedinvoluntaryurineleakage.therewere10patientsexcludedwhocouldn’tabletofillthequestionnaires.noneof thepatientsrefusedtoparticipateinthestudy.themeanage oftheattendeeswas59.8±11.2years(range40-91).sociodemographiccharacteristicsofthestudygroupareshown intable1. theimpactofuionqolwasmildtomoderateinthestudy group.qolscoresforeachitemweresimilarinbothgenders(table2).agingwasstatisticallysignificantlyassociatedwithqolinwomen(figure1). totallytherewere55patientswithurgeincontinence,41 patientswithstressincontinence,51patientswithmixedincontinence,12patientswithoveractiveincontinenceand9 patientswithtotalincontinence.themostcommontypeof uiwasurgeincontinence(48.3%)inmenandstressincontinence(35.5%)inwomen. relationshipsbetweengeneralcharacteristicsofuisuchas thefrequency,severityandtypeandqolscoreswereshown intable3andfigures2-4.physicalactivitiesandemotional healthwereimpairedinpatientswhohadadmittedtoaphysicianwiththecomplaintofui.socialrelationshipsdidnot showasignificantdifferencebetweenhelpseekersandthe restofthestudygroup(table4).duration,frequencyand quantityofuiaffectedthedecisiontogotoaphysician.patientswithuiwhoseekformedicalhelpwereolderthanwho do not, [t=3.090,degreesoffreedom(df)=156,p =.002]. table 2. impact of urinary incontinence on each life activity.* gender household physical entertainment travel social emotional feeling female 31.4 ± 3.5 35.8 ± 3.5 31.3 ± 3.6 35.8 ± 3.6 39.2 ± 3.7 45.8 ± 3.2 48.0 ± 3.2 male 28.2 ± 5.2 32.7 ± 4.5 27.6 ± 4.5 31.6 ± 4.9 38.9 ± 5.0 47.6 ± 4.4 44.7 ± 4.8 total 30.2 ± 2.9 34.7 ± 2.7 30.0 ± 2.8 34.3 ± 2.9 39.1 ± 2.9 46.4 ± 2.6 46.9 ± 2.7 * iiq-7 scores (mean ±se) were multiplied by 33 to put scores on a scale of 0 to 100. figure 1. relationship between quality of life and age of the participant. figure 2. type of the urinary incontinence and average quality of life scores. 1450 | discussion patientswithself-reporteduireportedamildtomoderate impairmentofqol,similartoreportsfrompreviousstudiesinturkey.(15,16)themostaffecteddomainofqolwas emotionalhealth. frequencyandquantityofuiaffectedqol.barentsenand colleaguesreportedthatseverityratherthantypeofuiwas associated with qol.(12) however, some authors claimed thattypeofincontinenceaffectsqol.(13,14) in the present studyweonlyfoundthatqolwasnotstatisticallydifferent betweenurge,stressormixedincontinencepatients. thedecisionofhelpseekingbehavioramongturkishresidentswasdeterminedbyimpairmentinalldomainsofqol otherthan‘participationinsocialactivities’.physicaldisabilityandimpairmentinemotionalhealthdirectthesepatients foramedicalhelpinthestudygroup. limitationsofthisstudyincludethefactthatitwasnotpopulation-based,soresultsmaynotreflectthewholeturkish population.and,typesofuiwerediagnosedbyself-reported history;animprovedapproachwouldmeasureuibyurodynamictests. table 3. relationships between characteristics of urinary incontinence and quality of life scores for each domain. characteristics physical activity travel social relationships emotional health frequency of ui χ2 = 40.088 χ2 = 39.232 χ2 = 39.115 χ2 = 37.312 df = 5 df = 5 df = 5 df = 5 p = .000 p = .000 p = .000 p = .000 quantity of ui χ2 = 40.203 χ2 = 41.999 χ2 = 41.643 χ2 = 33.348 df = 3 df = 3 df = 3 df = 3 p = .000 p = .000 p = .000 p = .000 type of ui χ2 = 18.631 χ2 = 14.888 χ2 = 14.836 χ2 = 21.081 df = 4 df = 4 df = 4 df = 4 p = .001 p = .005 p = .005 p = .000 keys: ui, urinary incontinence; df, degrees of freedom. figure 3. frequency of the urinary incontinence and average quality of life scores. figure 4. quantity of the urinary incontinence and average quality of life scores. female urology 1451vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l table 4. help seeking behavior and incontinence impact questionnaire quality of life scores* variables household physical entertainment travel social emotional feeling help-seeker 41.9 ± 5.1 44.1 ± 4.5 39.8 ± 4.8 41.4 ± 4.6 44.6 ± 4.8 55.2 ± 3.7 54.3 ± 4.1 none help-seeker 19.3 ± 3.2 26.7 ± 3.5 21.0 ± 3.3 27.5 ± 3.8 34.1 ± 3.9 39.1 ± 3.7 40.3 ± 3.8 statisticalanalysis** z = -3.304 z = -2.813 z = -2.867 z = -2.167 z = -1.520 z = -3.043 z = -2.505 p = .001 p = .005 p = .004 p = .030 p = .129 p = .002 p = .012 * average scores (mean ± se) were multiplied by 33 to put scores on a scale of 0 to 100. ** mann whitney u test. the z score is a test of statistical significance that helps you decide whether or not to reject the null hypothesis. conclusion ourresultsdemonstratedthattheimpactofuionqolwas mildtomoderateamongturkishresidents.emotionalhealth waspredominantlyimpairedinpatientswhoseekforhelp. attemptstoovercomeuimaypromotepatients’well-being. conflict of interest none declared. references 1. abrams p, andersson ke, birder l, et al. fourth international consultation on incontinence recommendations of the international scientific committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. neurourol urodyn. 2010;29:213-40. 2. uebersax js, wyman jf, shumaker sa, mcclish dk, fantl ja. short forms to assess life quality and symptom distress for urinary incontinence in women: the incontinence impact questionnaire and the urogenital distress inventory. continence program for women research group. neurourol urodyn. 1995;14:131-9. 3. cam c, sakallı m, ay p, cam m, karateke a. validation of the short form of the incontinence impact questionnaire (iiq-7) and the urogenital distress inventory (udi-6) in a turkish population. neurourol urodyn. 2007;26:129-33. 4. cetinel b, demirkesen o, tarcan t, et al. hidden female urinary incontinence in urology and obstetrics and gynecology outpatient clinics in turkey: what are the determinants of bothersome urinary incontinence and help-seeking behavior? int urogynecol j. 2007;18:659-64. 5. mckertich k. urinary incontinence-assessment in women: stress, urge or both? aust fam physician. 2008;37:112-7. 6. van leijsen sa, hoogstad-van evert js, mol bw, et al. the correlation between clinical and urodynamic diagnosis in classifying the type of urinary incontinence in women. a systematic review of the literature. neurourol urodyn. 2011;30:495-502. 7. hajebrahimi s, nourizadeh d, hamedani r, pezeshki mz. validity and reliability of the international consultation on incontinence questionnaire-urinary incontinence short form and its correlation with urodynamic findings. urol j. 2012;9:685-90. 8. seckiner i, yesilli c, mungan na, aykanat a, akduman b. correlations between the iciq-sf score and urodynamic findings. neurourol urodyn. 2007;26:492-4. 9. jaunin-stalder n, lagro-janssen al. urinary incontinence: neither men nor women should be forgotten. rev med suisse. 2013;9:15357. 10. saleh n, bener a, khenyab n, al-mansori z, al muraikhi a. prevalence, awareness and determinants of health care-seeking behaviour for urinary incontinence in qatari women: a neglected problem? maturitas. 2005;50:58-65. 11. el-azab as, shaaban om. measuring the barriers against seeking consultation for urinary incontinence among middle eastern women. bmc womens health. 2010;10:3. 12. barentsen ja1, visser e, hofstetter h, maris am, dekker jh, de bock gh. severity, not type, is the main predictor of decreased quality of life in elderly women with urinary incontinence: a populationbased study as part of a randomized controlled trial in primary care. health qual life outcomes. 2012;10:153. 13. minassian va, devore e, hagan k, grodstein f. severity of incontinence and effect on quality of life in women by incontinence type. obstet gynecol. 2013;121:1083-90. 14. howard f, steggall m. urinary incontinence in women: quality of life and help-seeking. br j nurs. 2010;19:742, 744, 746, 748-9. 15. basak t, uzun s, arslan f. incontinence features, risk factors, and quality of life in turkish women presenting at the hospital for urinary incontinence. j wound ostomy continence nurs. 2012;39 84-9. 16. kocak i, okyay p, dundar m, erol h, beser e. female urinary incontinence in the west of turkey: prevalence, risk factors and impact on quality of life. eur urol. 2005;48:63441. urinary incontinence on quality of life | guzelsoy et al review articles congenital urethral anomalies in boys. part i: posterior urethral valves abdolmohammad kajbafzadeh* department of pediatric urology, children's hospital medical center, tehran university of medical sciences, tehran, iran abstract introduction: the aims of this review are one, to consider that congenital urethral anomalies are not a simple disease entity in all patients. this is accomplished by reviewing the evidence for presence of posterior urethral valve subtypes and comorbidity of various unexplained clinical conditions in some children leading to chronic renal failure. the review's second aim is to describe the effects of fetal lower urinary tract obstruction on postnatal bladder function and the consequence of bladder dysfunction on the remaining postnatal renal function. materials and methods: the literature was extensively reviewed concerning the different types of congenital urethral outlet obstruction presentations, diagnosis, different types of treatment modalities, morbidity, mortality, and new concepts for this old problem. these findings were compared with conventional approaches to these anomalies. the 739 published papers on posterior urethral valves were evaluated, and a quarter of those are addressed. all radiologic presentations and figures in this review were selected from among the records of iranian patients treated by the author during the last 25 years. results: a significant overlap of presentation before antenatally diagnosed era was observed. the natural history of these anomalies is becoming clear and the hypothesis of posterior urethral diaphragm is popular among several investigators in comparison to the original valves classification by young in 1903. conclusions: further molecular investigation of the urinary tract is needed to better understand the pathophysiology of renal and bladder function in children who are born with antenatally diagnosed congenital urethral obstruction. these anomalies must be treated by urologists with a vast experience with valves and other rare congenital urethral anomalies. key words: urethral abnormalities, anterior urethra, posterior urethra, valves this article is part of a review on the anomalies of the male urethra with unknown etiology or those believed to result from a androgen deficiency. it includes part i: 1. posterior urethral valves and part ii: 2. anterior urethral valves, 3. lacuna magna (sinus of guérin), 4. syringocele, 5. megalourethra, 6. urethral duplications, and 7. prostatic urethral polyps. 59 urology journal unrc/iua vol. 2, no. 2, 59-78 spring 2005 printed in iran *corresponding author: no. 36, 2nd floor, 7th st., aaadat-abad ave., tehran 19987, iran. tel: ++98 21 2208 9946, fax: ++98 21 2206 9451, e-mail: kajbafzd@sina.tums.ac.ir posterior urethral valves introduction posterior urethral valve (puv) is one of the most common causes of lower urinary tract obstruction in male neonates. although not precisely known, its prevalence is reportedly 1/8000 to 1/25000 live births.(1,2) puv has been observed exclusively in boys,(3) but several reports in adults have been published.(4-7) the definitions of many of the disease manifestations have changed in recent years. advances in the prenatal diagnosis of this disease and subsequent surgical treatment, either intrauterine or immediately after birth, have contributed to a better understanding of the pathophysiology and nature of this disease, as well as considerable improvement in the longevity of affected children. the primary pathology is a mucosal membrane in the prostatic urethra, although secondary complications of this membrane result in injuries in the kidneys and the urinary bladder, which determine the fate of the children with this primary urethral membrane.(8-11) background puv was first described in 1515 and subsequently observed at autopsies. in 1802, the first definition for puv was written and presented in an article on lithotomy.(12) the first report in british journals is found in the lancet, in which dr budd reported a puv in a 16-yearold boy who had died of renal failure.(13) he stated that severe dilation of the kidneys and the urinary tract, as well as renal failure, had all been due to the obstruction caused by the puv. in 1913, young reported the first clinical case of puv, before which all the cases had been diagnosed postmortem.(14) in 1919, he published a report of 36 cases from the papers of that time, 12 being his own patients and the other 24 from various other papers.(15) it was in this paper in which he presented a classification for the puv. the numbers of case reports or case series of the patients continued to grow from the early 20th century, so that by 1949, there were 207 published cases of puv worldwide.(16-18) in the last 10 years, several hypotheses have been proposed regarding bladder function and its relationship with renal function following correction of the primary obstruction, as well as several urodynamic studies and their relation with renal function and treatment options, all of which has led to major progress in the field. still, after 300 years since the initial diagnosis of this disease, more than one third of the affected children develop renal failure. in some cases, cystoplasty is needed to decrease the intravesical pressure.(19) anatomy and embryology of the posterior urethral valve the normal male urethra extends from the bladder neck to the external urethral meatus and is anatomically divided into 2 or 3 portions: the prostatic and membranous portions or the posterior urethra, and the spongy portion or the anterior urethra. the prostatic urethra, from the base to the tip of the prostate, is the widest and the most distensible part. the urethral crest is a mucosal ridge that gives a specific form to the posterior urethra and is fully apparent in the urethral section. on each side of this crest there is a dip, known as the prostatic sinus. in almost half as long as the urethral crest, and there is the verumontanum (colliculus seminalis), a bulge on the posterior urethral floor on which there the foramen of the prostatic utricle lies. the urethral crest continues naturally below the verumontanum and binds from both sides as a small midline bridge. this membrane, extending laterally and downward, eventually vanishes.(3) the shortest, narrowest, and least distensible part of the urethra is the membranous part, surrounded by the urinary sphincter. embryologically, the prostatic urethra, up to the prostatic utricle, originates from the vesicoureteral cloaca and adjoins into the terminal mesonephric duct. the rest of the prostatic urethra includes the urogenital sinus, which is the anterior cloacal portion and is divided by the urogenital septum. the anterior urethra, up to the glans, forms from urogenital fusion or the urethral fold. the classic form of puv is in the prostatic urethra, below or after the verumontanum (figures 1a and 1b). pathogenetically, puv is a congenital phenomenon occurring sporadically, although familial forms also have been rarely reported.(20-22) this congenital anomaly is believed to occur due to a mixed effect of a few minor genes and cannot be ascribed to a single gene mutation. therefore, it is recommended that 60 posterior urethral valves kajbafzadeh all the brothers of the affected child (especially twins) be evaluated, even when asymptomatic, to prevent undiscovered renal damage.(22) the precise embryologic mechanism of this disease process is not yet known.(23) in 1932, 4 theories were described by campbell, which remained unchanged until today: 1. hypertrophy of the urethral mucosal folds, proposed by tolmatschew(24) in 1870 2. bazy's theory,(25) the persistence and continuation of the urogenital membrane, proposed in 1903 3. abnormal development of the wolffian or mullerian duct, proposed by lowsley(26) in 1914 4. fusion of the colliculus seminalis or the posterior urethral roof epithelium, proposed by watson(27) in 1922. none of these theories has been, however, complete and descriptive of the entire pathology of the urethral valve. classification of posterior urethral valves young described 3 types of puv.(14) types 1 and 2 are presented as a bicuspid valve of mucosal folds that attach to the verumontanum in 2 different ways. in the first type, the valve extends from the verumontanum distally, while in the second type, it extends from the verumontanum toward the bladder neck. the third type is in the form of a mucosal web. this third type was the first definition of puv described in 1856 by the french physician, jarjavay. the common belief in the current century for the posterior valve is also consistent with the membrane, or the third type definition. in a study reported in 1995 by kajbafzadeh and colleagues(28) from the united kingdom, 80% of these valves were of the membranous type, and the other 20% also were initially membranous but ruptured during catheterization for cystography or in the fetal period due to high bladder pressure, which led to its final presentation in the type 1 form, the bicuspid valve. the issue proposed here is that in some children, although catheterized, one may still observe an unruptured membranous valve. the theory suggested states that the foramen of the membranous valve is not always located peripherally; sometimes it is located centrally, with the catheter passing occasionally through the central foramen without being able to rupture it. a virgin urethra phenomenon has been proposed in this case, stating that if the urethral valve is diagnosed in the fetal period and before birth, and a suprapubic 6-f catheter for cystography is placed immediately after birth without manipulation of the urethra, 80% of the valves appear to be of the virgin type, with a totally different pathophysiology from type 1, which probably ruptured in the fetal period into a bicuspid form.(29) the above phenomenon was tested in 1969 by robertson during autopsies of children who had died of this anomaly. at first, he isolated the entire urinary tract including the kidneys, ureters, urinary bladder, prostate, and the entire urethra, and noted that the nature of the puv was membranous or the third type. he stated that the bicuspid valves were not anatomically correct.(30) the same results were obtained 5 years later in a similar report.(31) in another study based on the theory of a virgin urethra (urethra not manipulated by a catheter or other device) performed by the author 61 fig. 1. a. type i valves. oblique view shows degrees of obstruction and dilatation of posterior urethra, b. voiding cystourethrogram shows filling defect of obstruction by type iii valves. posterior urethral valves at a children's medical center on over 30 patients with puv before birth, the same theory was established—that the puvs exist in the form of a complete membrane with a small peripheral foramen. at the time, the valve is confirmed by antegrade cystography, and urethroscopy is performed by direct videoscopic view; the posterior valve is seen as a complete diaphragm. it is interesting that a 1-time passage of a urethral catheter causes a rupture of the valve into the triangular bicuspid form or the type 1 in young classification. therefore, it seems that all posterior valves are initially of the diaphragmatic type (type 3), which convert into type 1 after the passage of a fine catheter. the type 2 valve does not exist, and it seems that mucosal folds are seen in children with sphincteric dyssynergia due to neurologic or nonneurologic injuries. the distended posterior valve and the folded membranes of the urethral floor that extend from the bladder neck toward the verumontanum have no anatomic relation with the puv and seem to be a mere clinical flaw (figure 2a). type 4 valves are not true valves but typically presented with a prune-belly syndrome (figure 2b). more than 12 radiologic patterns of puv are shown in figure 3. it is worth noting that classification of the puv has no clinical value with regard to treatment and prognosis, and the clinical symptoms are not related to the valve type.(32) pathophysiology of the posterior urethral valve the importance of the posterior valve is based on 2 things: first, the secondary effects of urinary outflow obstruction of the fetal bladder, and second, the secondary effects of bladder function on the fetal kidney, as well as its effects after birth or even after elimination of the urethral valve. disorders of renal function in the posterior urethral valve there are multiple mechanisms for renal dysfunction and valve effects on the kidneys. these include the following: 1. primary renal dysplasia 2. dysplasia due to urinary outflow obstruction in the fetus and its detrimental effects on nephrogenesis 3. intrauterine hydronephrosis and secondary destructive effects of obstruction on nephron production in the fetal period, probably due to backward pressure to the fetal kidneys 4. postnatal urinary tract infections with or without reflux 5. persistent bladder dysfunction after valve elimination renal dysplasia the simultaneous occurrence of renal dysplasia and puv is a known fact, although their cause and effect relation is not yet known.(33) renal dysplasia can be due to either obstruction or teratogenic effects of the valve. renal dysplasia with urinary reflux is a known phenomenon. in the first evaluation of the children with puv, 62 fig. 2. a. type ii valve prostatic urethral dilatation and mucosal folds are seen in children with sphincteric dyssynergia due to myelomeningocele neuropathic bladder. b. type iv valve in prune-belly syndrome. kajbafzadeh 63 fig. 3. tracing of filling defects caused by urethral valves in 12 different urethrograms showing variations in radiograph pattern. 1 3 5 7 9 11 2 4 6 8 12 10 posterior urethral valves reflux was seen in 30% to 70% of cases.(34) it seems that the presence of reflux at the time of nephrogenesis might cause dysplastic changes in the kidneys. on the other hand, a cystic dysplastic change in a kidney affected by reflux has been reported.(35) according to some researchers, renal dysplasia is an accompanying feature with puv and not a secondary cause.(33) in another report on puv and reflux, histologic findings of 32 kidneys were studied (14 kidneys from autopsies and 18 from nephrectomies of nonfunctioning kidneys of patients with puv). this study showed that 24 of the kidneys had been dysplastic.(36) another study confirmed dysplasia, histologically, in 22 nephrectomized renal units.(37) the very important point in this study was that there is a direct relation between the location of the ureteral opening in the bladder and the degree of dysplasia; that is, the higher the grade of dysplasia, the more lateral was the ectopy of the ureteral opening. this study confirms that the cause of dysplasia is a developmental phenomenon rather than a direct effect of reflux or urinary outflow tract obstruction. urinary concentration disorder in posterior urethral valves loss of urinary concentrating power leads to production of a large volume of dilute urine, as observed in children with urinary valves.(38) the prevalence and severity of antidiuretic hormoneresistant nephrogenic diabetes insipidus is not known. in an assessment of 28 patients in 1970, waldbaum and marshall observed 2 patients with polydipsia and polyuria, suggestive of nephrogenic diabetes insipidus.(39) there are various other records of the urethral valve and nephrogenic diabetes insipidus in the literature.(40,41) some researchers have noted that in most children developing renal failure because of puv, hemodialysis is needed much later, if this failure is accompanied with polyuria.(42) on the other hand, most children with puv develop ureteral dilatation following valve resection, due to a 2to 4-fold increase in urine volume.(43) this group of patients doesn't respond to a 14-hour water restriction. treatment of these children is very difficult, and they quickly present symptoms of dehydration and acidosis with a minor stress or a gastroenteritislike disease.(44) classification of the upper urinary tract anatomy in urethral valve hendren classifies the pathology of kidneys and ureters in patients with puv into 4 groups as follows: group 1: no secondary changes are seen in patients with urethral valves in the ureters and kidneys, including paraurethral diverticula, reflux, or upper urinary tract dilatation group 2: mild dilatation of the upper urinary tract group 3: severe reflux and renal destruction is seen group 4; severe destruction of the kidneys, together with hydroureteronephrosis, megaureter, and often azotemia(45) this classification was used in a group of children with urethral valves (124 cases), with 43% going into group 1, 34% into group 2, 14.5% into group 3, and 8.5% into group 4.(46) initial diagnosis and clinical manifestations two types of symptomatic presentation and clinical manifestations are seen in these children. the first group shows obstructive symptoms including straining during urination, intermittent voiding with reduced urinary flow rate, and a palpable midline bladder. the second group presents with infectious signs including septicemia, failure to thrive, and urinary tract infections, which are the most prominent features of this disease. in the neonatal and infantile periods, the primary obstructive symptoms are more prevalent, while at older ages, the infectious signs are dominant.(47) in a study of valve diagnosis, 26% appeared in the first month of life, 23% in the first year, and 51% between the ages of 1 and 15 years.(48) in another report, one third occurred in the first month, one third in the first year, and the rest after 1 year of age. two decades ago, when diagnostic and treatment advances were performed on fetuses, fetal uropathies were diagnosed and patients affected by puv could be diagnosed (figures 4a, 4b, 4c, and 4c).(49) initial reports on fetal-stage diagnosis of puv show a better prognosis for those patients diagnosed prenatally as compared with those occurring after birth.(50) diagnostic evidence of the urethral valve appears in children presenting with severe bilateral hydronephrosis and 64 kajbafzadeh increased serum creatinine, with or without respiratory problems. respiratory symptoms in a newborn with puv might be related to oligohydramnios, which is accompanied by severe pulmonary hypoplasia.(51) these respiratory disorders are more prevalent in children with urine ascites due to spontaneous renal rupture in the fetal period. diagnosis at older ages seems to come with a better prognosis, as those with renal failure present their symptoms quite early. differential diagnosis of the posterior urethral valve the differential diagnoses of the posterior urethral valve include the following: 1. perirenal urinary extravasation(52) 2. presacrococcygeal teratoma(53) 3. urethral duplication(54) 4. megalourethra(55) 5. anterior urethral valve or diverticulum(56) 6. syringocele and mormon's ring(57) 7. prune belly syndrome(58) 8. urethral hypoplasia 9. urinary retention 10. ectopic ureterocele 11. urethral strictures 12. anterior or posterior myelomeningocele whenever bilateral hydronephrosis with a thickwalled, persistently full bladder is observed in the fetal period, urethral valve should be the first diagnosis. however, the prune-belly syndrome and neuropathic bladder should also be considered.(58) treatment it is best to drain bladder urine immediately after diagnosis. placement of a suprapubic 6-f urinary catheter is feasible in most centers after local anesthesia with topical anesthetic creams, and without general anesthesia. when the bladder is empty, normal saline can be infused 65 fig. 4. a. fetal hydroureteronephrosis and distended bladder, b. typical keyhole sign (distended bladder and posterior urethra), c. spontaneous ruptures of kidney in a fetus with puv and urinoma around the fetal kidney with severe renal parenchyma echogenicity, d. postnatal voiding cystourethrogram confirmed the puv. posterior urethral valves into the bladder through the meatus, without urinary catheterization. the advantages of suprapubic catheter placement are that first, it does not lead to urethral infection with its consequent strictures and complications, second, the urethra remains virgin, third, cystography can be performed suprapubically as the catheter can be fixed with a suture, with little chance of its spontaneous displacement, and fourth, a suprapubic catheter can be maintained for a longer period of time. an important advantage of using a suprapubic catheter is during physiologic urodynamic studies before and after valve destruction, in which vesical pressure measurements can be made in various positions without the use of a urethral catheter. a novel option is fetal surgical intervention for posterior valve and placement of a shunt in the fetal bladder and the amniotic fluid, which can be performed in specific cases by a special team in fetal surgery. immediately after placement of the suprapubic catheter after birth, a urine sample can be taken for urinalysis, urine culture, and other parameters. an appropriate antibiotic should be administered thereafter, and in case of the absence of infection, prophylactic antibiotics should be given, especially if a urinary reflux is also present. hypercalcemia and acidosis are severe and prevalent problems in children with puv. before the invention of fine endoscopic instruments for neonates, various options were suggested for urethral valve removal including perineal urethrotomy,(59) suprapubic cystostomy,(60) and valve destruction using fogarty balloon,(61) all of which were accompanied by severe complications including urethral rupture, urinary incontinence, and urethral strictures.(9) a major revolution occurred with the production of neonatal cystoscopes, numbered 7.5 to 8, in which the valve can be operated primarily at every age and at any weight. a hook was made by whitaker, which could be connected directly to an electrocautery device, that could approach and reach the valve directly and destroy it.(62) cystography must be performed after valve destruction to ensure complete valve removal. in some children, the creatinine level does not change much even after 2 weeks of bladder drainage.(63) if there is no change in renal and ureteral dilation by precise sonographic measurement of the diameters, supravesical urinary diversion must be considered. if the pelvic and ureteral diameters are reduced, a vesicostomy may be performed after 2 weeks. if valve destruction is not feasible, as in cases of urethral hypoplasia, where a cystoscope cannot be passed, a vesicostomy may be performed. however, if severe pelvic and ureteral dilation still persists, ureterostomy or pyelostomy should be considered.(63) vesicostomy can be closed 1 or 2 years later, and a suprapubic vesical catheter can be fixed. with this, bladder drainage and the status of the urethra may be assessed. if the urethra is back to its normal state and bladder drainage is complete, the catheter may be removed. in a comparison between vesicostomy and primary urinary diversion in the treatment of puv in neonates and in children who have been initially operated on for valve resection, it has been shown that bladder dysfunction is greater in the first group than those whose valves had been initially operated on. the status of the urethra can be described as either favorable or unfavorable.(34) the urethra is said to be in a favorable state when the creatinine level decreases quickly, and renal function is good on isotope scan. the presence of a pop-off mechanism reflects a positive prognosis. conversely, in case of azotemia and renal malfunction on sonography, the child's prognosis must be viewed unfavorably.(53) in all, if the renal failure continues despite all the measures, renal transplantation should be considered, although initially, chances of success in these patients was believed to be less.(64,65) however, if the bladder function and urodynamic and other parameters are fully assessed and the bladder problems treated, there is no difference in transplant outcome in these patients. late complications of the urethral valve every child with a resected puv must undergo long-term surveillance and follow-up until puberty and afterward. parameters like urethral patency, renal function, bladder function, reflux, and urinary tract infections must be considered. one month after valve destruction surgery, serum creatinine level measurement together with cystography and renal ultrasonography and isotope (dmsa) scan must be repeated. if there 66 kajbafzadeh is still an obstruction in the urinary outflow tract, a proper decision must be made and a repeat evaluation be done after 3 months. if the obstruction persists, cystoscopy should be performed. measurement of the glomerular filtration rate (gfr) with the isotope method (edta chromium) gives an accurate portrayal of renal function.(66) table 1 gives the means of long-term follow-up for children with puv. the correct treatment for severe cases of valve, reflux and urinary tract dilation is still debatable. the time for ureteral reimplantation in cases of severe reflux or megaureter is not known. some believe that the reflux and dilation of the ureter and kidney will resolve spontaneously if the valve is completely removed and if bladder function is normal according to urodynamic studies.(36) approach to reflux in children with posterior urethral valves it is not yet certain whether reflux is an anatomically accompanying feature of the urethral valve or is secondary to it. the prevalence of urinary reflux from the bladder to the kidneys is reportedly to be 26% up to 72%. in some initial reports, reflux prevalence was reported as 44%, with 16% being bilateral and 28% being unilateral.(67,68) there is a direct relation between the reflux and the age of disease incidence. the key question is why is the presence of reflux such a determining factor in children with urethral valves. in answer to this, the following are suggested(34): first, the presence of infection and reflux could lead to scarring and a greater decrease in renal function; second, reflux might have unfavorable effects on bladder function; and third, during voiding, most of the urine enters the kidneys, and the child is said to void in his place and into his kidneys. the dilatation of the posterior urethra in children with puv and severe reflux is much more evident than it is in a child without reflux (figures 5a and 5b). after voiding, a high volume of urine flows from the kidneys into the bladder, refilling it immediately. fourth, it aggravates the function of a dilated ureter; and fifth, if the voiding pressure is high, renal destruction might also be greater. reflux is spontaneously resolved in 35% to 50% of cases.(66,68) some believe that patients with reflux need not to be operated on, as it will automatically resolve as soon as the bladder function returns to normal.(36) others believe that the bladder needs to be operated on if the reflux is accompanied by recurrent urinary tract infections.(45) this can occur when the urodynamic performance of the bladder is normal.(1) it must be noted, however, that ureteral reimplantation in a thick bladder is very difficult, several complications are possible, and the chance of failure is very high.(69) in another study on 82 boys with urethral valves who had long-term follow-up, unilateral reflux by ipsilateral dysplasia continued in 21%, after successful valve surgery. ten of the cases had a dysplastic kidney upon nephrectomy.(70) it must be noted here that a dysplastic kidney with severe reflux on the same side is a safety valve mechanism for the bladder, so that sometimes, after nephroureterectomy of the dysplastic kidney, bladder pressure increases and the contralateral kidney develops new reflux, a phenomenon referred to as the valve's ureteric reflux and dysplasia (vurd) syndrome. prognosis is excellent in children with this syndrome. on the other hand, one must know that if the child is in need of a cystoplasty in the future, the method of choice would be ureterocystoplasty with the use of the dilated 67 table 1. long-term follow-up for children with posterior valves types of evaluation intervals blood pressure measurement routinely in every visit growth and weight routinely in every visit creatinine and electrolyte measurements initially every 3 months then yearly urinary tracts ultrasonography one month, 3 months, 1 year postoperatively, and then yearly dtpa isotope scan at the ages of 3 months and 1 year then yearly urodynamics-uroflowmetry yearly, since urinary continence indirect cystography at the time of dtpa isotope scan dmsa isotope scan yearly, if uti and reflux are present voiding cystourethrography 1 month after valve resection and yearly for 3 to 4 years posterior urethral valves ureter. in another report of 6 cases of nephroureterectomy, it was observed that a dysplastic kidney can sometimes lead to renal failure.(71) another long-term study has shown that the presence of reflux in the dysplastic kidney has protective effects on the other kidney, and it is generally advised that nephroureterectomy of the dysplastic kidney be carried out with caution.(72) urethral stricture following urethral valves resection all methods of valve surgery carry the risk of a urethral stricture, with a reported prevalence of 8% to 28%.(73,74) the use of a large, unsuitable cystoscope, inappropriate urinary catheter, and especially valve resection in a dry urethra (when there is a vesicostomy) all increase the chance of a stricture.(73) the prevalence of urethral stricture is currently very low. undescended testis and sexual function in boys with urethral valves the prevalence of undescended testis is 12% in these patients. boys with a puv might have retrograde ejaculation after puberty, due either to the anatomy of the urethra and the bladder neck, or to valve surgery complications.(48) fertility is possible for children with a history of valve surgery. however, slow ejaculation is seen in 38% of these children.(10) at times an absence of ejaculation due to an obstruction of the ejaculative tracts has been reported. paramo has also reported a case of sterility due to retained ejaculation in the posterior urethra.(75) prognosis of children with posterior urethral valves the prognosis of these children is quite poor. in long-term follow-up, at least one third of such children have a poor outcome with respect to renal function.(76) in one study, 26% of patients older than 18 years with a history of urethral valve had a renal failure.(8) in another study, 50% of children whose valve had been diagnosed before the age of 1 year showed some degree of renal failure.(77) if the patient has a protecting mechanism at birth, the prevalence of renal failure reaches 5%. these factors are valve bladder syndrome, large bladder diverticulum, and fetal urine ascites due to bladder or kidney rupture. mortality of the patients affected by posterior urethral valve mortality of these children was reported to be 40% to 50% in the previous two or three decades,(57,78) having reduced to zero in the previous decade.(53) this improvement is mainly due to a higher awareness of this disease among the physicians, prompt treatment of the urinary tract infections, improvement in surgical instruments and medical treatments, and dialysis and renal transplantation in small children. 68 fig. 5. a. severe posterior urethral dilatation in a child with puv and no vur, b. high-grade vur and less dilatation of posterior urethra in spite of typical puv. kajbafzadeh bladder function in children with posterior valves the lower urinary tract consists of the bladder and urethra, which compose a single unit. each part has two functions, reserving urine, and disposing thereof,(79) which is under neural tract support, as well as smooth and striated muscle. the nerves effective in voiding include somatic and autonomic (sympathetic and parasympathetic) nerves. there is no evidence of disordered innervation in urethral valve cases. in these children, the determining point in bladder function is the amount of collagen types i, iii, and iv, whose ratio significantly changes because of an outflow tract obstruction of the compliant fetal bladder. this plays a major role in bladder function even after valve removal. normally, the bladder fills without any increase in its internal pressure. this occurs because of the bladder's relaxing ability, under the effect of central and local nerves. paucid vesicoelastic structures, also, enable it to be filled at low pressures. this relation between the change of intravesical pressure (dp) and the change of volume (dv) is referred to as the compliance (c = dp/dv). a change of bladder morphology due to collagen ratio or muscular hypertrophy leads to a reduced compliance. during natural bladder filling, the pressure increases very slightly or does not increase at all, and this is known as normal compliance.(79) in adults, the raise in bladder pressure after filling with 300 ml of water must be less than 10 cm h2o and at final volume less than 15 cm h2o.(80) the high compliance of the bladder allows it to receive a large volume of urine at a low pressure. low compliance, on the contrary, means that the bladder receives a low volume of urine at a very high pressure, which predisposes the urinary tract to infections, renal dilation and dysfunction, and renal failure in due course.(38) these definitions are given according to the international association for disease control. for example, the term "unstable bladder" is used when the bladder contracts automatically during filling and the patient tries to avoid urination.(79) the stimulating factors for this state could be rapid filling, change of position, and coughing. such contractions are considered involuntary when detrusor contraction pressures exceed 15 cm h2o.(81) in one study, the results of which were published recently, it was shown that bladder dysfunction in children with puv is a determining prognostic factor in the probability of developing renal failure in this group of patients. a bladder with poor compliance and myogenic failure has a poorer prognosis, while children with bladder instability will have the lowest prevalence of renal failure following valve removal (figures 6a and 6b). some investigators agree that long-term bladder free drainage (vesicostomy) could cause long-term bladder dysfunction.(79) bladder capacity in children normal bladder capacity in children has been calculated by many, eventually giving the following formula for the calculation of bladder capacity with age(82-84): bladder capacity (ml) = (age in years + 2) × 30 normal bladder capacity of the neonate is given by the following formula: newborn's bladder capacity (ml) = weight in kilograms × 7 natural history voiding in children the voiding phenomenon is a response to increased urine volume in the bladder, in which urethral relaxation and detrusor contraction 69 fig. 6. a. initial uroflowmetry shows obstructive pattern in a 6-year-old boy with type iii valves. b. uroflowmetry following valves ablation in the same child with a type iii puv. posterior urethral valves occur simultaneously with pelvic floor muscle relaxation and funneling of the bladder neck. this neuromuscular phenomenon is very complex. the relation between bladder pressure and urine flow rate has been studied extensively. one researcher, in 1970, calculated the maximal voiding pressure of the bladder in children as equal to 73.6 cm h2o.(85) others, however, have calculated this pressure in the adult population as 40 cm h2o to 60 cm h2o.(86) urodynamics in children affected by urethral valves urodynamics, one of the most important tests, is the study of lower urinary tract function. urodynamic studies include the following assessments(87-92): 1. urinary history 2. frequency volume chart 3. uroflowmetry 4. urodynamics in the forms of: videourodynamics physiologic urodynamics isotope urodynamics 5. uroflowmetry and pelvic floor emg history is the most important part of the urodynamic assessment. during history taking, one must consider intermittent voiding, narrowstream voiding with high or low pressure, such that the patient urinates on the scrotum. moreover, urination with force, severe crying, and squatting during voiding are among the most important issues and initial points in urodynamic studies. to make a frequency volume chart, the child's parents are asked to calculate the volume of voided urine in every session and record the time and volume in a table. if the child is using diapers, estimated urine volume can be obtained by weighing the diaper before and after each episode of urination. using this method, the number of voids in 24 hours, average volume of urination, and total daily urine volume are obtained. physical examination only rarely is an abnormal point found in the physical examination of children with urethral valves. however, the observation of abnormal hair growth on the skin over the sacral bone, perineal sensory disorders, or abnormal tendon reflexes can all be signs of a neurogenic lesion of the bladder rather than the urethral valve. urinary flowmetry in children who have reached the age of urinary continence is a very simple and noninvasive test, in which the volume, urine curve form, and maximal voiding in one second must be noted (figures 7a and 7b). (93) ultrasonography of the urinary tract ultrasonography of the upper and lower urinary tracts, before and after voiding, is of paramount importance in the evaluation of these children. calculation of residual urine volume, 70 fig. 7. a. urodynamic study before valve ablation (maximum voiding pressure = 320 cm h2o) and b. after valve ablation in the same child with type iii valves (maximum voiding pressure = 112 cm h2o). kajbafzadeh assessment of renal pelvic and ureteral diameters before and after bladder drainage with a thick bladder wall, voiding time, and posterior urethral diameter are among the most important points to be considered in ultrasonography. ultrasonography of the urinary tract is the first assessment in the newborn with a history of bilateral hydronephrosis and a distended bladder during the fetal period. isotope study of the urinary tract is a further specific study in patients with urethral strictures. intravenous urography has no role in the evaluation of puv.(94) cystometry determining the relation between the bladder volume and pressure is a valuable test essential in every child affected by a valve. some young physicians think that cystometry is the same as urodynamics, being the first step in the study of the urinary tract. however, with respect to all initial issues, cystometry is the last part of the urodynamic studies. for cystometry, a catheter must be placed in the bladder to measure its pressure, another catheter must be placed in the rectum to measure the perivesical pressure, which is transferred from the abdomen to the bladder muscles. the device obtains the detrusor pressure by a simple subtraction of these two pressures.(88) it must be kept in mind that some of the urodynamic findings change with the amount and rate of bladder filling and the temperature of the fluid entering the bladder.(89,90) video-urodynamics was first suggested by bates in 1970, giving more information including visualization of the bladder's function at the same time as the pressure measurements.(91,92) in this method, the status of the diverticulum, bladder neck, urethra, reflux, and involuntary contractions during bladder filling can be compared by measuring intravesicular pressure changes. obstructive bladder changes due to urethral valve the bladder muscles show a wide range of different responses to degrees of outflow obstruction. these changes are important, not only morphologically, but also with respect to bladder function.(95) these responses have been observed in experimental studies on the rabbit bladder, too, and the above changes studied both for the period of obstruction and the period after its relief.(96) the first response to obstruction is bladder distension, followed by a thickening in the bladder wall. this thickening is at first due to a submucosal swelling, later replaced by an increase in collagen and the muscular mass eventually substituted by connective collagen tissue. this point is more prominent in the fetal bladder. the degree of hypertrophy depends on the severity of obstruction. in other words, muscular hypertrophy leads to a moderate obstruction, and hyperplasia is seen when the obstruction is severe. in the bladder of the growing rabbit, if an outflow tract obstruction is made, at first the bladder smooth muscles are doubled, enlarging to as much as 6 times their normal size within 8 weeks. a 10-time hypertrophic muscular increase is seen in the obstruction of the mature rat. these lesions show that the amount of bladder collagen increases to 4 times its initial amount.(97, 98) apparently, the bladder's elasticity increases with increasing collagen.(99) these morphologic changes lead to a hardening of the bladder wall.(38) morphologic studies in the bladders of the patients with outflow tract obstruction confirm similar changes.(100) in cases in whom an obstruction in the urethra occurs, the force of voiding increases and the urine flow rate decreases at the same time. the signs of instability are observed in 64% of cases and the bladder end-filling pressure reaches 55 cm h2o.(101) studies of the bladder nerves show that in obstruction the amount of autonomic nerves in the detrusor muscle is reduced.(102) in another study, the same changes are described in the bladder facing an outflow tract obstruction.(103) such changes are also seen in men affected by prostate enlargement, in 45% of whom involuntary contractions are seen. after obstruction relief, these involuntary contractions are relieved in 62% of the patients only.(104) in urinary postprostatectomy urinary incontinence, involuntary contractions (instability) are seen in 66% of the patients.(105) in a similar study, such disorders are reported in 60% after prostatectomy.(106) the more severe the obstruction, the prevalent are the involuntary bladder contractions.(107) unfortunately, studies in animal models of fetuses are very difficult because severe 71 posterior urethral valves obstruction of the fetal urethra is accompanied by oligohydramnios, which leads to fetal pulmonary hypoplasia and death, making the postnatal study impossible.(108) another problem in animal models is fetal bladder decompression due to urethral obstruction because of automatic opening of the urachus.(51) until now, most of the studies centered on the assessment of effects of urethral obstruction on the kidneys (108,109), but recently the researcher's attention has moved toward the effects of urethral obstruction on the bladder, in experimental animal fetuses. in one study, urethral obstruction in the sheep fetus at mid-pregnancy led to a 4-fold increase in bladder weight, together with hypertrophy and hyperplasia of the bladder muscles, with a reduced compliance in cystometric evaluations.(110) in these animal models, the maximum vesical pressure, as well as the amount of residual urine, increases.(111) these changes are due to increased gestational proteins of the cellular matrix and collagen production in response to obstruction.(112) the vurd syndrome urethral valve in children causes evidences of urethral outflow tract obstruction, similar to the urinary tract obstruction in benign prostatic hyperplasia in adults.(113) however, there are considerable differences between these two age groups (children and adults) with respect to the effects of obstruction on the developing kidney and the forming bladder in the fetus and the newborn.(114) it was reported about 70 years ago that 70% of children with a urethral valve have urinary incontinence, which was thought to be caused by bladder overflow of urine. forty years later, williams reported that two thirds of these patients have some degree of urinary incontinence.(68) at the same time, another theory was proposed for these children's wetting, suggesting bladder dysfunction as being responsible for the urinary incontinence in children with a urethral valve.(115) in 1977, the first urodynamic studies showed that the external sphincter is normal, rejecting the theory that urinary incontinence after valve surgery is due to traumatizing of the external sphincter.(116) at the beginning of this study, 5 types of bladder function in children affected by a valve were introduced(116-119): normal bladder, myogenic failure, increased voiding pressure, uninhibited contraction, and low-volume highpressure bladder. an interesting study was done on persistence of ureteral dilation after valve resection.(117) in this study, upper tract urodynamics were performed and 3 urodynamic classes were found for the renal pelvis and the dilated ureters. for this, a fine catheter was introduced percutaneously into the renal pelvis and the pelvic and ureteral pressures were studied in 3 positions with an empty and a full bladder. this study was performed in children whose ureteral dilation had not been relieved after relief of the urethral obstruction. these dilated ureters are classified, urodynamically, into 3 obstructive types: type 1, obstructive; type 2, nonobstructive with a full bladder; and type 3, nonobstructive with an empty bladder. the study showed that most nonobstructive dilated ureters exist at the time of bladder emptying and become obstructed upon bladder filling. this phenomenon, in which and increased bladder wall resistance and pressure leads to a resistance to urine flow from the ureter to the bladder was introduced as the valve bladder.(118) the important point is that placement of a foley catheter can itself be considered as a foreign body and a means of pressure on the trigon, so that the ureteral distension might not be relieved after drainage through a foley catheter. now, if a nelaton catheter replaces this catheter, the effect on ureteral drainage will improve.(119) in general, the high intravesical resting pressure is one of the important reasons for persistence of ureteral and pelvic dilation following valve surgery.(120) on the other hand, if the urinary incontinence persists after the age of 5 years, this is considered a poor prognosis for renal function. the urodynamic evaluation of children affected by urethral valve shows 3 types of urinary disorders after valve surgery(120): myogenic failure, bladder hyperreflexia, and hypertonic bladder. these findings prove that sphincter disorders are rare, and that the children with urinary incontinence face severe renal and ureteral disorders.(9) there is a direct relation between disordered voiding, reduced compliance, and the risk of renal failure.(122) increased voided urine volume and the loss of renal urine concentrating capacity aggravate signs of lower urinary tract disorders.(81) 72 kajbafzadeh renal dysfunction in the long run is well known in myelomeningocele patients,(123,124) which is due to a low-volume high-pressure bladder that causes a disordered urine emptying from the ureter into the bladder, especially if this is concomitant with detrusor-sphincter dyssynergia. also in urethral valve, it seems that the higher the bladder pressure, the lower the gfr.(125) this critical pressure is, by definition, 40 cm h2o, which can eventually destroy the kidneys.(126) in subsequent studies, the bladder's resting pressure (20 cm h2o to 25 cm h2o) is also claimed to be hazardous for the kidneys.(113,127,128) almost 4% to 5% of children with a urethral valve have persistent bladder dysfunction resistant to therapy, requiring augmentation cystoplasty. it is interesting that in 1 of our studies 40% to 50% of these patients have normal voiding after cystoplasty, without a need for urinary catheterization.(129) in the urodynamic assessment of neonates who are diagnosed prenatally, a fine, 2-mm, suprapubic catheter is introduced into the bladder immediately after birth, connected to the urodynamics device, and the bladder function monitored for 12 hours. in this study, the voiding pressure had risen to up to 350 cm h2o in some children. interestingly, this pressure did not changed much after valve resection, although radiologically and clinically, the urine flow had been normal and the urethra had no obstruction. still more interesting is that if the urethra is not catheterized at birth, cystography can be performed through a suprapubic catheter leaving the urethra intact. almost 80% of the urethral valves in this group appear to be of the third type, which is in contrast with existing reports. there is as yet no report of urethroscopy without catheterization. it has been shown in these patients that if the bladder is catheterized with a 6-f catheter, the valve changes from type 3 into type 1, explaining the higher prevalence of the type 1 valve.(128) in the urodynamic study before and after valve resection at birth, the intravesical voiding pressure does not change, whereas the residual urine disappears. all these patients have hypocompliant bladders, with a formed entity after the age of 1 year, which is classified as described earlier.(129,130) 73 fig. 8. diagnosis and treatment protocol of posterior urethral valve. antenatally diagnosed puv immediate postpartum ultrasound normal abnormal prophylactics for 4 weeks vcug normal vur stop follow-up treat as vur protocol insert cystofix + antegrade vcug puv biochemistry & baseline gfr physiologic fill urodynamic unstable child bladder free drainage stable child puv resection posterior urethral valves there are several reports regarding prenatal diagnosis of puv in the previous 2 decades. whenever bilateral hydroureteronephrosis with a large, full bladder is shown on the renal ultrasonography of a fetus, a puv must be considered. if the diagnosis is made before 24 weeks of gestation, the prognosis is poor, and if oligohydramnios is also present, the status of the fetus is even worse and needs to receive a treatment from an expert team. the basic point, anyway, is that there is no need to terminate pregnancy or have a premature delivery as the neonate may actually die at birth of lung underdevelopment at any gestational age. bilateral pneumothorax might occur in these children upon the first inspiration after birth, which requires specific treatments, proper action, and care if the child's life is to be saved.(28,93,94,128133) the protocol presented in figures 8 and 9 is used in the division of pediatric urology children's medical center, tehran, iran.(131) references 1. casale aj. early ureteral surgery for posterior urethral valves. urol clin north am. 1990;17:361-72. review. 2. atwell jd. posterior urethral valves in the british isles: a multicenter b.a.p.s. review. j pediatr surg. 1983;18:70-4. 3. williams di, eckstein hb. obstructive valves in the 74 fig. 9. treatment protocol in cases in which resection is not possible. puv resection technically possible impossible continue px. & follow –up u/s in 3 months vesicostomy delayed puv resection & vesicostomy closure follow-up ultrasound abnormal normal vcug vur no vur follow-up u/s every 6 m continue px. & urodynamic follow-up till puberty abnormal normal stop px. re-evaluation re-scope & medical therapy kajbafzadeh posterior urethra. j urol. 1965;93:236-46. 4. saraf pg, cockett at. marcello mapighi--a tribute. urology. 1984;23:619-23. 5. mueller sc, marshall ff. spectrum of unrecognized posterior urethral valves in the adult. urology. 1983;22:139-42. 6. mahony dt, laferte ro. congenital posterior urethral valves in adult males. urology. 1974;3:724-34. 7. nieh pt, hendren wh. obstructing posterior urethral valves in octogenarian. urology. 1979;13:412-3. 8. parkhouse hf, woodhouse cr. long-term status of patients with posterior urethral valves. urol clin north am. 1990;17:373-8. 9. connor jp, burbige ka. long-term urinary continence and renal function in neonates with posterior urethral valves. j urol. 1990;144:1209-11. 10. woodhouse cr, reilly jm, bahadur g. sexual function and fertility in patients treated for posterior urethral valves. j urol. 1989;142(2 pt 2):586-8; discussion 603-5. 11. drozdz d, drozdz m, 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1988;62:59-62. 77. warshaw bl, hymes lc, trulock ts, woodard jr. prognostic features in infants with obstructive uropathy due to posterior urethral valves. j urol. 1985;133:240-3. 78. johnston jh, kulatilake ae. the sequelae of posterior urethral valves. br j urol. 1971;43:743-8. 79. bates p, bradley we, glen e, et al. the standardization 76 kajbafzadeh of terminology of lower urinary tract function. j urol. 1979;121:551-4. 80. torrens m. urodynamics in the physiology of the lower urinary tract. in: torrens m, morrison jfb, editors. the physiology of the lower urinary tract. berlin: springer verlag; 1987. p. 277-307. 81. styles ra, neal de, griffiths cj, ramsden pd. longterm monitoring of bladder pressure in chronic retention of urine: the relationship between detrusor activity and upper tract dilatation. j urol. 1988;140:330-4. 82. starfield b. functional bladder capacity in enuretic and nonenuretic children. j pediatr. 1967;70:777-81. 83. koff sa. estimating bladder capacity in children.urology. 1983;21:248. 84. berger rm, maizels m, moran gc, conway jj, firlit cf. bladder capacity (ounces) equals age (years) plus 2 predicts normal bladder capacity and aids in diagnosis of abnormal voiding patterns. j urol. 1983;129:347-9. 85. gierup j. micturition studies in infants and children. intravesical pressure, urinary flow and urethral resistance in boys without infravesical obstruction. scand j urol nephrol. 1970;4:217-30. 86. saxton hm. urodynamics: the appropriate modality for the investigation of frequency, urgency, incontinence, and voiding difficulties. radiology. 1990;175:307-16. review. 87. podesta m, ruarte ac, gargiulo c, et al. bladder function associated with posterior urethral valves after primary valve ablation or proximal urinary diversion in children and adolescents. j urol. 2002;168(4 pt 2):18305; discussion 1835. 88. o'donnell pd. pitfalls of urodynamic testing. urol clin north am. 1991;18:257-68. review. 89. myers da, walker rd 3rd. prevention of 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groenewegen aam. urodynamic studies in boys with posterior urethral valves. proceedings of the american academy of pediatrics, annual meeting. 1991. 123.mcguire ej, woodside jr, borden ta, weiss rm. prognostic value of urodynamic testing in myelodysplastic patients. j urol. 1981;126:205-9. 124.bauer sb, hallett m, khoshbin s, lebowitz rl, winston kr, gibson s, colodny ah, retik ab. predictive value of urodynamic evaluation in newborns with myelodysplasia. jama. 1984;252:650-2. 125.steinhardt gf, goodgold hm, samuels ld. the effect of intravesical pressure on glomerular filtration rate in patients with myelomeningocele. j urol. 1988;140(5 pt 2):1293-5. 126.wang sc, mcguire ej, bloom da. a bladder pressure management system for myelodysplasia--clinical outcome. j urol. 1988;140:1499-502. 127.bauer sb. the thick walled neurogenic bladder. dial pediatr urol. 1990;13:3-5. 128.weston pm, robinson lq, williams s, thomas m, stephenson tp. poor compliance early in filling in the neuropathic bladder. br j urol. 1989;63:28-31. 129.kajbafzadeh am, quinn fm, duffy pg, ransley pg. augmentation cystoplasty in boys with posterior urethral valves. j urol. 1995;154(2 pt 2):874-7. 130.lopez pereira p, martinez urrutia mj, espinosa l, lobato r, navarro m, jaureguizar e. bladder dysfunction as a prognostic factor in patients with posterior urethral valves. bju int. 2002;90:308-11. 131.kajbafzadeh am. posterior urethral valves, urodynamics study: why and when? proceedings of the puv seminar; 1994 dec 9; the hospital for sick children, and the institute of child health, london. 132.kajbafzadeh am, quinn fmj, duff pg, ransley pg. posterior urethral valve and urethral duplication. a report of 7 cases. proceedings of the european society of paediatric urology [espu]; 1996; london. 133.kajbafzadeh am, urodynamics studies in boys with posterior urethral valves. proceedings of the 7th international pediatric congress; 1995 oct 14-19; tehran university of medical sciences, tehran. 78 urology journal unrc/iua 106 comparison of nitric oxide concentration in seminal fluid between infertile patients with and without varicocele and normal fertile men darab mehraban, mohammad ansari, hossein keyhan,* mohammadali sedighi gilani,† gholamhossein naderi, fateme esfehani department of urology, shariati hospital, tehran university of medical sciences, tehran, iran abstract introduction: elevated nitric oxide (no) levels have been shown to have toxic effects on sperm function and motility. this study was conducted to compare no levels in the seminal fluid of infertile men with varicocele with those of infertile and fertile men without varicocele. materials and methods: semen samples were obtained from 40 infertile men with varicocele (group 1), 40 infertile men without varicocele (group 2), and 40 fertile volunteers without varicocele (group 3). no levels in the seminal plasma of patients in each group were measured and compared. in infertile men with varicocele, semen parameters, including sperm count and motility, and grade of varicocele were also determined. results: mean no concentrations were 52.34 ± 26.62 µmol/l, 37.06 ± 20.39 µmol/l, and 33.7 ± 18.99 µmol/l in groups 1, 2, 3, respectively. concentrations in group 1 were significantly higher than those in groups 2 and 3 (p = 0.001). in group 1, no significant correlations were seen between no concentrations and grades of varicocele, sperm count, sperm motility, or ages of the patients. conclusion: data from the current study suggest a possible role of no in damaging the sperm function in varicocele as demonstrated by an increased concentration of no in the seminal fluid of infertile men with varicocele compared with the seminal fluid of fertile and infertile men without varicocele. key words: varicocele, male infertility, nitric oxide, seminal fluid vol. 2, no. 2, 106-110 spring 2005 printed in iran introduction nitric oxide (no) was first described in 1979 as a potent relaxant of peripheral vascular smooth muscles, with an action mediated by cyclic guanosine phosphate (cgmp).(1) subsequently, endothelium-derived relaxing factor was identified as no or a chemically unstable nitrous precursor.(2) no is synthesized from endogenous l-arginine by nitric oxide synthase (nos). it has several roles in biological processes, such as neurotransmission (in nonadrenergic, noncholinergic pathways), tumor cell killing, and inflammatory and immune responses.(3) recent studies have shown that no levels increase in the spermatic veins and seminal plasma of patients with varicocele.(4,5) some observations have indicated that no could modulate sperm functions. low concentrations of exogenous no donors have been shown to enhance human sperm motility, viability, capacitation, and binding to the zona pellucida.(6-8) conversely, at higher concentrations, they decrease human sperm motility and induce sperm toxicity.(9,10) received april 2005 accepted june 2005 *corresponding author: tel: ++98 912 311 0306, fax: ++98 21 2295 1133 e-mail: hosseinkeyhan@yahoo.com †financial interest and/or other relationships with royan institute mehraban et al 107 varicocele is the most common correctable cause of male infertility; however, the mechanism by which varicocele affects testicular function remains unclear.(11) in the present study, we compared no levels in the seminal fluid of infertile men with varicocele with those of infertile and fertile men without varicocele. we also evaluated the relationship between no concentration and total sperm count, sperm motility, and grade of varicocele in infertile men with varicocele. materials and methods from october 2003 to november 2004, semen samples were obtained from 40 infertile men with varicocele (group 1), 40 infertile men without varicocele (group 2), and 40 fertile men without varicocele (group 3). the patients in groups 1 and 2 were recruited from outpatient infertility clinics of the dr. shariati hospital and royan infertility institute, tehran, iran, on a nonrandomized basis. healthy age-matched volunteers with proven fertility were selected from among male employees of the dr. shariati hospital. this casecontrol study was approved by ethical committee of tehran university of medical sciences. informed consent was obtained from all subjects, before entering the study. infertility was considered when no pregnancy had occurred despite couples having regular intercourse without contraception for at least 1 year. inclusion criteria were clinically diagnosed varicocele, being the only risk factor of infertility in the couples of group 1; and proven infertility in men without clinical varicocele for group 2. in groups 1 and 2, the mean duration of infertility was 3.1 years (range, 1 to 8 years); partners had a mean age of 24.2 ± 4.36 years; and there was no female factor contributing to a couple's infertility, as reported by the consulting gynecologist. the third group consisted of men without clinical varicocele, proven recent fatherhood (less than 2 years), and normal results on genital examination. exclusion criteria were the presence of active genitourinary infection, leukocytospermia (> 1 million wbc/ml), and treatment with nitrate derivatives. varicocele was classified in 3 grades; grade 1, a pulse that can be palpated in the scrotum during a valsalva maneuver; grade 2, a varicocele that is large enough for tortuous and dilated veins to be palpable without a valsalva maneuver; and grade 3, a varicocele is visible through the scrotal skin.(12) a sample size of 40 men in each group would be sufficient to detect a difference of 7 µmol/l in the mean of no concentration in the seminal fluid, assuming a standard deviation of 9 µmol/l,(6) a power of 90%, and significance level of 5%. semen specimens were collected into sterile containers after 72 hours of abstinence in all participants. specimens were allowed to liquefy for 30 minutes at room temperature, and a conventional semen analysis was performed under sterile conditions within 1 hour after collection. a fraction of semen was stored at -80°c for no assay. no analysis total nitrite and nitrate levels of seminal plasma were determined as a measure of no radical production, using a griess reagent. the griess reagent consists of sulfanilamide and n-1naphtyl ethylenediamine.(6,13) the frozen semen was allowed to thaw and reach a temperature of 25°c. the liquefied semen was then centrifuged. one hundred microliters of supernatant was mixed with 100 µl of griess reagent. enzyme linked immunosorbent assay (elisa) was used to measure the photometric absorbance of the mixed solution at 540 nm. this would indirectly determine no concentration in seminal plasma. statistical analysis normality of distribution was checked as needed. the results of continuous variables were expressed as median (range) and mean (± sd). owing to the abnormal distribution of some data, the nonparametric mann-whitney u and kruskalwallis tests were used to compare the no levels between groups. the relationship between no levels in seminal plasma and semen parameters and grade of varicocele were investigated by correlation analysis. a level for p less than 0.05 was regarded as statistically significant. results mean ages of the patients in groups 1, 2, and 3 were 29.8 ± 5.36 years, 30.4 ± 5.17 years, and 27.9 ± 4.44 years, respectively (anova, p = 0.685). the distribution of varicocele grades in group 1 was grade 1 in 11 patients (27.5%), grade 2 in 14 (35%), and grade 3 in 15 (37.5%). the median no concentrations in the seminal nitric oxide in seminal fluid of infertile patients with and without varicocele108 plasma of patients in group 1 (infertile men with varicocele) were significantly higher than those of patients in group 2 (p = 0.006) and group 3 (p = 0.001); however, there was no significant difference between patients in groups 2 and 3 (p = 0.525). no concentration and distribution in seminal fluids of the 3 groups are shown in table 1 and figure 1. there was no significant linear relationship between the mean no concentration in the seminal plasma of patients in group 1 and total sperm count (r = 0.035, p = 0.831), sperm motility (r = 0.06, p = 0.713), and grade of varicocele (r = 0.06, p = 0.674). also, there was no significant linear relationship between mean no concentration in seminal plasma of patients in group 1 and age (r = 0.126, p = 0.44). discussion in humans, no is an important biologic substance and is found in a variety of tissues including those of the reproductive system. no has been implicated as protecting against reactive oxygen species (ros)-mediated damage; however, in situations of inappropriate nos regulation, no may exacerbate ros-mediated pathology.(14) the relationship between ros and varicocele has been the subject of several studies. it has been reported that varicocele is associated with elevated sperm ros production and diminished seminal plasma antioxidant capacity.(15, 16) some studies show that no may modulate sperm functions. low levels of no, generated under physiological conditions, might be beneficial for sperm functions, but excessive levels of no under pathological situations (eg, infections or endometriosis) might be toxic for sperm. infertile patients, especially those with pyospermia, have higher no levels in the seminal plasma than do fertile controls, and a positive correlation has been found between the level of no and number of immotile sperm.(17) nos is selectively inhibited by ng-nitro-larginine-methyl ester (l-name). one study has indicated that endothelial nos (enos) plays a role in human sperm's capacity to fuse with an oocyte but not in zona pellucida binding.(18) this study showed that l-name, added from the onset of capacitation, strongly inhibits spermoocyte fusion. the relationship between infertility, varicocele, and no concentration has not been clearly identified. some animal and human investigations have shown that no concentration increases in seminal plasma, spermatic veins, and leydig cells of patients with varicocele.(4,5,19) in a study by romeo and coworkers, it was found that elevation of no in adolescents with varicocele creates an oxidative stress status and as such, should be an indication for varicocele treatment.(15) aksoy and colleagues compared semen samples from 55 infertile patients with varicocele and 48 normal controls. the median no concentration in the seminal plasma of patients with varicocele was significantly higher than it was in controls (p < 0.001). a significant negative correlation was noted between no and sperm motility (r = -0.29, p = 0.003) and also sperm count (r = -0.26, p = 0.008).(5) in another study, the same authors showed increased levels of no in the seminal plasma of patients with varicocele and oligotable 1. no levels (µmol/l) in the 3 groups of infertile men with varicocele (group 1), infertile men without varicocele (group 2), and fertile men without varicocele (group3) kruskal-wallis, p = 0.001 group mean ± sd median (range) 1 52.34 ± 26.62 46.80 (17.23 to 100) 2 37.06 ± 20.39 30.91 (7.40 to 93.75) 3 33.70 ± 18.99 28.90 (2.90 to 100) fig. 1. no distribution (µmol/l) in the 3 groups of infertile men with varicocele (group 1), infertile men without varicocele (group 2), and fertile men without varicocele (group 3) groups 32 1 70 60 50 40 30 20 34 37 52 m e a n n o ( µ m o l/ l ) mehraban et al 109 and/or asthenozoospermia, compared with oligoand/or asthenozoospermia in subjects without varicocele and a control group. in that study, 19 men with varicocele and oligoand/or asthenozoospermia (group 1), 30 patients without varicocele and oligoand/or asthenozoospermic (group 2), and 20 healthy subjects (control group) were recruited. the authors also showed an inverse correlation between no concentration in the seminal plasma and sperm motility and concentration.(20) in the present study, regardless of semen analyses, we found that no concentrations in the seminal plasma of infertile men with varicocele were significantly higher than those in both infertile and fertile men without varicocele. however, we could not show any correlation between seminal plasma no levels and sperm count, sperm motility, grade of varicocele, and age of infertile men with varicocele. in view of some supportive studies,(5,20) our negative result needs further consideration. one possible explanation could be the effect of the laboratory technician's performance. whether or not the increased seminal plasma no in varicocele translates into a detrimental effect on spermatogenesis and fertility should be clarified by further studies with larger sample sizes. in addition, there remain other unanswered questions that should be considered by further research: could the increased seminal plasma no levels be used to decide which adolescent with varicocele should be followed and which should undergo varicocelectomy? could this and other similar studies contribute to the introduction of new medical therapies for varicocele using nos inhibitors such as l-name? conclusion this study demonstrates a statistically significant increase in no concentration in the seminal fluid of infertile men with varicocele as compared with that in fertile and infertile men without varicocele. however, age, semen parameters, and grades of varicocele did not show a significant correlation with no concentration. this study provides an opportunity for further studies to examine no as a possible factor that is detrimental to sperm function in varicocele. references 1. gruetter ca, barry bk, mcnamara db, gruetter dy, kadowitz pj, ignarro l. relaxation of bovine coronary artery and activation of coronary arterial guanylate cyclase by nitric oxide, nitroprusside and a carcinogenic nitrosamine. j cyclic nucleotide res. 1979;5:211-24. 2. ignarro lj, buga gm, wood ks, byrns re, chaudhuri g. endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. proc natl acad sci usa. 1987 dec;84:9265-9. 3. griffith ow, stuehr dj. nitric oxide synthases: properties and catalytic mechanism. annu rev physiol. 1995;57:707-36. 4. romeo c, ientile r, santoro g, et al. nitric oxide production is increased in the spermatic veins of adolescents with left idiopathic varicocele. j pediatr surg. 2001 feb;36:389-93. 5. aksoy h, aksoy y, ozbey i, altuntas i, akcay f. the relationship between varicocele and semen nitric oxide concentrations. urol res. 2000;28:357-9. 6. hellstrom wj, bell m, wang r, sikka sc. effect of sodium nitroprusside on sperm motility, viability, and lipid peroxidation. fertil steril. 1994;61:1117-22. 7. zini a, de lamirande e, gagnon c. low levels of nitric oxide promote human sperm capacitation in vitro. j androl. 1995;16:424-31. 8. sengoku k, tamate k, yoshida t, takaoka y, miyamoto t, ishikawa m. effects of low concentrations of nitric oxide on the zona pellucida binding ability of human spermatozoa. fertil steril. 1998;69:522-7. 9. rosselli m, dubey rk, imthurn b, macas e, keller pj. effects of nitric oxide on human spermatozoa: evidence that nitric oxide decreases sperm motility and induces sperm toxicity. hum reprod. 1995;10:1786-90. 10. weinberg jb, doty e, bonaventura j, haney af. nitric oxide inhibition of human sperm motility. fertil steril. 1995;64:408-13. 11. howards ss. treatment of male infertility. n engl j med. 1995;332:312-7. 12. goldstein m. surgical management of male infertility and other scrotal disorders. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 1571-5. 13. moshage h, kok b, huizenga jr, jansen pl. nitrite and nitrate determinations in plasma: a critical evaluation. clin chem. 1995;41:892-6. 14. kanner j, harel s, granit r. nitric oxide as an antioxidant. arch biochem biophys. 1991;289:130-6. 15. romeo c, ientile r, impellizzeri p, et al. preliminary report on nitric oxide-mediated oxidative damage in adolescent varicocele. hum reprod. 2003;18:26-9. 16. kisa u, basar mm, ferhat m, et al. testicular tissue nitric oxide and thiobarbituric acid reactive substance levels: evaluation with respect to the pathogenesis of varicocele. urol res. 2004;32:196-9. nitric oxide in seminal fluid of infertile patients with and without varicocele110 17. nobunaga t, tokugawa y, hashimoto k, et al. elevated nitric oxide concentration in the seminal plasma of infertile males: nitric oxide inhibits sperm motility. am j reprod immunol. 1996;36:193-7. 18. francavilla f, santucci r, macerola b, ruvolo g, romano r. nitric oxide synthase inhibition in human sperm affects sperm-oocyte fusion but not zona pellucida binding. biol reprod. 2000;63:425-9. 19. santoro g, romeo c, impellizzeri p, et al. nitric oxide synthase patterns in normal and varicocele testis in adolescents. bju int. 2001;88:967-73. 20. aksoy y, ozbey i, aksoy h, polat o, akcay f. seminal plasma nitric oxide concentration in oligoand/or asthenozoospermic subjects with/without varicocele. arch androl. 2002;48:181-5. o r i g i n a l a r t i c l e s endourology a comparison between laparoscopic and open pyeloplasty in patients with ureteropelvic junction obstruction simforoosh n*, basiri a, tabibi a, danesh ak, sharifi-aghdas f, ziaee sam, nooralizadeh a, hosseini-moghaddam smm urology/nephrology research center, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: to compare clinical and radiological outcomes, complications, and hospital stay in laparoscopic and open pyeloplasty. materials and methods: from february 2002 to february 2003, 69 patients with ureteropelvic junction obstruction (upjo) were assigned into two groups. thirty-seven patients underwent transperitoneal laparoscopic pyeloplasty and 32 underwent open surgical pyeloplasty. clinical symptoms were assessed before and after surgery, subjectively. radiological assessment was also done three months postoperatively. results: mean operative time was 3.2 hours and 2.2 hours in laparoscopic and open pyeloplasty groups, respectively. intraoperative bleeding was trivial in both groups and no complication or conversion to open surgery occurred. postoperative complication rates were 24% and 6% in laparoscopic and open pyeloplasty groups, respectively. mean hospital stay was similar (6.2 days) in the two groups. mean follow-up was 16.5 months versus 11.4 months. clinical and radiological success rates were 89% and 83.8% for laparoscopy group versus 96.5% and 87% for open pyeloplasty group. due to recurrence of stricture, repeated surgery was performed in 4 patients of laparoscopy and 1 of open pyeloplasty groups. conclusion: laparoscopic pyeloplasty is a less invasive method with less pain, cosmetic advantages, no long incision, and outcome comparable with open surgery. hospital stay is also not longer than that in open surgeries. hence, laparoscopic pyeloplasty can be a substitute for skilled surgeons. key words: ureteropelvic junction, pyeloplasty, laparoscopy 165 urology journal unrc/iua vol. 1, no. 3, 165-169 summer 2004 printed in iran introduction common treatments of ureteropelvic junction obstruction (upjo) consist of open surgical pyeloplasty, laparoscopic approaches, and endourologic methods.(1) open surgery is the standard treatment with more than 90% success rate.(2,3) different methods are advocated, of whom dismembered pyeloplasty is the most accepted one. nowadays, open pyeloplasty is still a popular approach, particularly in patients with long strictures, in cases accompanied with renal stone, and in those less invasive surgeries have failed. nonetheless, this method is an invasive one with undesirable cosmetic outcome. accepted for publication in august 2003 *corresponding author: department of kidney transplantation, shaheed labbafinejad medical center, boustan 9, pasdaran, tehran, iran. email: simforoosh@iurtc.org.ir a comparison between laparoscopic and open pyeloplasty in patients with ureteropelvic junction obstruction endopyelotomy is a substitute method, but it is not popular among urologists due to a 10% to 30% lower success rate, comparing to open surgery and complications such as bleeding. it is usually performed using either antegrade or retrograde approach. this method is not recommended in cases with long stricture, aberrant vessel, or hydronephrosis.(4) trends toward less invasive surgeries have been increasingly considered. since 1993, when the first laparoscopic pyeloplasty was performed, published reports have shown comparable results, complication rates, and recovery time with open pyeloplasty. eventually, laparoscopic pyeloplasty is less invasive and more successful rate than endoscopic approach, mostly performed using dismembered or y.v.plasty methods.(5,6) also, another method is fengerplasty.(7) this study's aim was to compare the success rates of open pyeloplasty with laparoscopic one, in a prospective fashion. materials and methods in a clinical trial from february 2001 to february 2003, 69 patients with upjo were assigned into two groups. thirty-seven patients underwent transperitoneal laparoscopic pyeloplasty and 32 underwent open surgery. the first group included 23 males and 14 females and the latter included 20 males and 12 females. mean age was 18.2 (range 5 to 38) and 23.1 (range 5 to 67) years, respectively. none of the patients had a previous surgical intervention for his or her current complaint. mean weight was 48.7 kg and 47.3 kg, respectively. the patients who were visited at the clinics of the study researchers were assigned in the first (laparoscopy) group and the ones who were visited at the clinics of the study cooperators were assigned in the second (open) group. the type of operation was selected according to surgeon's preference. preoperative evaluations were done using ivp and diuretic renogram. moreover, laboratory tests including urinalysis, urine culture, bun, and creatinine were also done. patients with a kidney function of 10% or less were excluded form the study. the assessment for any probable aberrant vessel was not done before the operation. all the cases were symptomatic prior to surgery, of whom 29 were right sided and 40 were left sided. transperitoneal operation was done in laparoscopy group using three trocars, placed in 10 cm from umbilicus, 5 cm superior to umbilicus, and 10 cm on midaxillary line in the opposite of umbilicus. in open group, dismembered pyeloplasty was done with subcostal incision. stent was placed by cystoscopy in open group and intraoperatively in laparoscopy group. anastomosis was made with polyglycolic 4.0 suture. foley catheter and drain were inserted and removed after 48 hours. regular diet was initiated at the first postoperative day. stent was removed after four weeks and ivp was done three months after the operation. physical examination was made postoperatively and compared with that before the procedure considering pain and clinical signs. improvement was defined as patent ureteropelvic junction or decrease in severity of hydronephrosis in ivp. it would be considered as failure in treatment if symptoms and signs were subsided but the degree of hydronephrosis did not decrease. fenger or close dismembered methods were used in laparoscopy group depending on the surgeon's decision. in cases with aberrant vessels, vein was freed and clamped and artery was freed, transported, and fixed to perirenal fat or renal pelvis, if any. chi-square and fisher's exact tests were used for statistical analysis of data and a p value of lower than 0.05 was considered as significant. results surgical operation was done successfully in all patients with no intraoperative complication or necessity of blood transfusion, intra-or post-operatively. mean follow-up was 16.5 months in laparoscopy group and 11.4 months in open group, which were significantly different (p=0.006). symptoms before the treatment were pain (86.8%), urinary tract infection (25%), nausea and vomiting (12%), and hematuria (4.2%) (table 1). of the patients, 18 (47%) and 7 (21.7%) had aberrant vessels in laparoscopy and open groups respectively (p<0.05). of the patients in laparoscopy group, 18 and 19 166 table 1. symptoms before and after the operation in laparoscopy and open groups ��������� � �������� ���� ��� �� ����� ���� ��� ��� ���� ���� �� ��� ������������������������ ���� ��� ��� ��� � �� ���� ������������� ����!� ��� ������ ��� ��� ��� ��� "� ������� �������� ��������� ����� ��� a comparison between laparoscopic and open pyeloplasty in patients with ureteropelvic junction obstruction underwent fenger and dismembered pyeloplasty, respectively. dismembered pyeloplasty was done in all of the patients in open group. mean operation time (consisting of cystoscopy, dj stent placing, and surgical repair) was 3.2 hours in laparoscopy group and 2.2 hours in open group (p=0.00) (table 2). hospital stay was 6.2 days for both groups. surgical complications occurred in 9(24%) and 2(6.2%) of the patients in laparoscopy and open groups, respectively (p<0.05). postoperative complications during the followup period in laparoscopy group consisted of urinary tract infection in 5, urine leakage in 3, and collection in one, all treated with non-surgical measures. in open group, two patients developed febrile urinary infection, which were hospitalized and treated medically (table 3). clinical success rate was 89% in laparoscopy and 96.5% in open groups and radiological improvement was 83.8% and 87.5% respectively, whit no significant statistical difference (p=0.46) (fig 1,2). it should be noted that clinical improvement was assessed based on the patient's opinion, pain or other symptoms, urinalysis considering hematuria, and urine culture. radiological assessment was done using the latest ivp or renal scan, and postoperative ultrasonography in comparison with that before the operation. four out of 37 patients underwent reoperation in laparoscopy group, one due to collection in operation site, not responded to conservative treatments, and three due to symptomatic recurrence of stricture. two patients were asympto167 �������� � �� �� ��������������� �� �� ����� � ����� ��������� ��� � ��� ���� ���� �������������� ��� � ��� ���� ���� � ����������� ���� ����� ������� ������ � �������� ���� ��� �� ������������������������ ���������� ���� ��� ���#����� ��������$��%�!�� ����#����� &� ����� ��� '�$$������� ����� ��� &� ��������� table 2. mean and standard deviation of operative time table 3. postoperative complication rates in laparoscopy and open groups fig.1. a 35-year-old male with upjo, a: before laparoscopic pyeloplasty, b: after the operation fig.2. a 25-year-old female with upjo, a: before laparoscopic pyeloplasty, b: after the operation a b a b a comparison between laparoscopic and open pyeloplasty in patients with ureteropelvic junction obstruction matic, but without improvement in radiology and renal scan, who were followed. in open group, one patient experienced pain, in which investigations showed recurrence and reoperation was considered. in open group, 2 asymptomatic patients had still obstruction in imaging modalities with increased hydronephrosis. they were followed conservatively. discussion open surgery has been known as the gold standard treatment for upjo with more than 90% success rate.(2,3) due to postoperative pain, longterm recovery, and long incision in open pyeloplasty, several less invasive methods have been proposed, including antegrade and retrograde endopyelotomy; nevertheless, their success rates are 10% to 30% lower comparing to open pyeloplasty, particularly when aberrant vessels, kidney function impairment, or severe hydronephrosis are present.(4,8) on the other hand, bleeding occurs in 3% to 11%, requiring blood transfusion.(9,10) laparoscopic pyeloplasty has been recently advocated as an alternative in the treatment of upjo. we decided to compare laparoscopy and open pyeloplasty through this study. most previous reports have not considered such a comparison and few studies have compared these two approaches retrospectively. bauer and coworkers compared laparoscopic and open pyeloplasty in 70 cases, retrospectively.(11) in 2001, soulie performed a study to compare laparoscopic retroperitoneal pyeloplasty with open surgery.(12) however, to our best knowledge, our study is the first prospective clinical trial in the respective issue. at present, two techniques, namely, dismembered and fenger (heinke mikulicz) are the most common ones used in laparoscopic pyeloplasty that we applied both in our patients. there was no definite criterion to select the technique in our study and it depended on the surgeon's decision intraoperatively. clinical and radiological success rate was similar, with no statistically significant difference between the two groups (90% clinically improvement and 85% radiologically improvement). eden reported 50 cases of laparoscopic pyeloplasty of which two led to open conversion and one developed late recurrence.(13) a study by jarrett and colleagues showed decreased the degree of hydronephrosis in 96% of 100 patients undergone laparoscopic pyeloplasty,(14) and soulie reported 88.5% and 89.3% success rate in laparoscopy and open pyeloplasty groups, respectively.(12) hospital stay was the same for both groups, but operation time was longer for laparoscopy, which may be probably due to the cystoscopy and ureteral stent insertion. however, operation time did not differ significantly from the group with fenger technique to the one with dismembered techniques. our results were acceptable when compared to other studies; jarrett reported an average operation time of 4.2 hours in 100 patients(14) and this it was 2.45 hours in eden's study.(15) the results of fenger and dismembered pyeloplasty were similar. the surprising point was the higher rate of aberrant vessels in laparoscopy group (47% versus 21.7% in open group). consonant with our study, jarrett detected aberrant vessels in 57% of the patients(14) and bauer reported a rate of 80% in laparoscopy group and 38% in open group.(11) postoperative complications were significantly more in laparoscopy group (24% versus 6.2%), which may be due to difficult intracorporeal suture technique and promoting skills may improve it. complication rate has been around 12% in different studies.(14,16) conversion to open surgery did not occur in our cases and no intraoperative complication or need to transfusion was observed. in soulie's study, 5.4% of cases required conversion to open surgery. inclusion and exclusion criteria were similar for all the patients. most background variables such as weight, degree of hydronephrosis, aberrant vessels, or the involved renal unit did not impact on patient selection and the outcome. the results of fenger and dismembered pyeloplasty were similar. however, fenger method requires lower level of skill. twelve out of 18 patients with fengeroplasty had abberant vessels which were freed, transferred upwards, and fixed intraoperatively. on the other hand, the advantages of laparoscopy such as cosmetic results, less pain, and earlier resumption of normal daily activities are indispensable. but, laparoscopic pyeloplasty is totally dependent on a great talent in suturing. conclusion laparoscopic pyeloplasty is a less invasive method with less pain, cosmetic advantages, no long incision, and outcome comparable with open surgery. the operation time was acceptable in our study when compared with other reports and it 168 a comparison between laparoscopic and open pyeloplasty in patients with ureteropelvic junction obstruction can be similar with open pyeloplasty if cystoscopy and stent placing are eliminated. hospital stay is also not more than in open surgeries. hence, laparoscopic pyeloplasty can be a substitute for skilled surgeons. editorial comment regarding the desirable results of laparoscopic pyeloplasty reported in this study, it seems that more experience can also decrease reoperation to a comparable rate to that in open pyeloplasty. references 1. carr mc. anomalies and surgery of the ureteropelvic junction in children. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 1995-2004. 2. o'reilly ph, brooman pj, mak s, et al. the long term results of anderson hynes pyeloplasty. bju int 2001 mar; 57(4): 287-9. 3. lowe fc, marshall ff. ureteropelvic junction obstruction in adults. urology 1984; 23: 33. 4. chen rn, moore rg, kavoussi lr. laparoscopic pyeloplasty. indications, technique, and long-term outcome. urol clin of north am 1998 may; 25(2): 323-30. 5. kavossi lr, peters ca. laparoscopic pyeloplasty. j urol 1993; 150: 1891-4. 6. schuessler ww, grune mt, tecuanhuey lv, preminger gm. laparoscopic dismembered pyeloplasty. j urol 1993; 150: 1795-9. 7. janetschek g, peschel r, bartsch g. laparoscopic fengerplasty. j endourol 2000 dec; 14(10): 889-93. 8. van cangh pj, wilmart jf, opsomer rj, et al. long term results and late recurrence after endoureteropyelotomy: a critical analysis of prognostic factors. j urol 1994; 151: 934-7. 9. kletscher ba, segura jw, leroy aj, et al. percutaneous antegrade endoscopic pyelotomy: review of 60 cases. j urol 1995; 153: 701-3. 10. brooks jd, kavoussi lr, preminger gm, et al. comparison of open and endourological approaches to the obstructed ureteropelvic junction. urology 1995 dec; 46(6):791-5. 11. bauer jj, bishoff jt, moore rg, et al. laparoscopic versus open pyeloplasty assessment of objective and subjective out come. j urol 1999 sep; 162(3 pt1): 692-5. 12. soulie m, thoulouzan m, seguin p, et al. retroperitoneal laparoscopic versus open pyeloplasty with a minimal incision: comparison of two surgical approaches. urology 2001 mar; 57(3): 443-7. 13. eden cg, sultana sr, murray kh, et al. extraperitoneal laparoscopic dismembered fibrin-glued pyeloplasty medium term results. br j urol 1997 sep; 80(3): 382-9. 14. jarrett tw, chan dy, charambura tc, et al. laparoscopic pyeloplasty: the first 100 cases. j urol 2002 mar; 167(3): 1253-6. 15. eden cg, cahill d, allen jd. laparoscopic dismembered pyeloplasty: 50 consecutive cases. bju int 2002 oct; 88(6): 526-31. 16. soulie m, salomon l, patard jj, et al. extraperitoneal laparoscopic pyeloplasty: a multi centric study of 55 procedures. j urol 2002 jul; 166(1): 48-50. 169 urol_v3_no2_001_editorial.qxd sexual dysfunction and infertility prevalence of infertility in tabriz in 2004 yadollah ahmadi asr badr,* kazem madaen, sakineh haj ebrahimi, amir hassan ehsan nejad, hossein koushavar department of urology, sina hospital, tabriz university of medical sciences, tabriz, iran abstract introduction: our aim was to determine the prevalence of primary and secondary infertility in tabriz population and to compare the marriage age between infertile and fertile groups. we also evaluated the rate of seeking help for treatment of infertility among the patients. materials and methods: in a survey, we evaluated the prevalence of infertility in tabriz in 2004 using cluster random sampling. tabriz was divided into 360 zones and from each zone, 10 couples were selected. six interviewers filled out the questionnaires by direct reference to interviewees' homes. overall, 3600 couples were evaluated for infertility. results: of 3600 couples, 3183 were married for more than a year and answered the questions appropriately. prevalence of infertility was 3.27% (2.04% as primary and 1.23% as secondary infertility). among couples whose wives were in their reproductive age (15 to 49 years), the overall prevalence of infertility was 3.35% (2.05% as primary and 1.30% as secondary). mean age of women at marriage was significantly higher in couples with primary infertility (20.87 ± 5.4 versus 18.75 ± 4.04; p < .001). treatment seeking was 79.6% and 67.6% among patients with primary and secondary infertility, respectively. in general, 75% of the patients had referred to medical centers. conclusion: the prevalence of primary infertility was almost the same as other asian countries, but the prevalence of secondary infertility was lower than other countries. a higher marriage age was accompanied with a significant decrease in fertility of the couple. primary infertile patients had referred to medical center slightly more often than secondary infertile patients. key words: primary infertility, secondary infertility, population, prevalence 87 urology journal unrc/iua vol. 3, no. 2, 87-91 spring 2006 printed in iran introduction studies on infertility prevalence are rare in iran, and to our knowledge, there has been one study in this area in which the infertility prevalence is reported among couples referring to medical centers of the west part of tehran.(1) however, this study is not a representative sample of the society. the aim of this study was to determine the prevalence of primary and secondary infertility in tabriz population (one of the major cities of iran, in the northwest) and to compare the marriage age between fertile and infertile couples. we also evaluated the rate of seeking medical help among infertile couples. materials and methods in a survey, we selected 3600 couples using a cluster random sampling in 2004 to determine infertility rate among couples in tabriz, iran. the received june 2005 accepted december 2005 *corresponding author: department of urology, sina hospital, tabriz, iran. tel: +98 914 311 3167, fax: +98 411 541 2151 e-mail: ahmadiy@tbzmed.ac.ir infertility in tabriz study was approved by the institutional review board of tabriz university of medical sciences. the city was divided into 360 areas (according to the geographic map), and 10 couples were randomly selected from each area. six interviewers were trained to refer to the couples' homes and fill out the questionnaires. considering cultural issues, the interviewers were chosen from among women to achieve the best outcomes. the questions included the couples' ages, marriage duration, willing to have a child, pregnancy history, and history of seeking for medical help to evaluate infertility (appendix). the questionnaire and the interviewers were evaluated by the psychology and research divisions of our university. in some areas, the data were controlled by the researchers to confirm their accuracy. since most of previous studies had evaluated 15to 49-year-old women,(2) we evaluated the infertility in couples whose wives were in this age range. primary infertility was defined as no conception during marriage after at least 12 months' period of intercourse without using contraception. secondary infertility was defined as no conception after at least 12 months' period of intercourse without using contraception in a couple who had at least 1 conception before. the data were analyzed using spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa). student t test was used to compare continuous variables and chi-square test was used to determine the relationship between age groups and infertility. a p value less than .05 was considered significant. results of studied couples, 417 were excluded from analyses; 41 were married for less than one year and 376 couples had not answered the questions appropriately. of 3183 couples, 104 (3.27%) were infertile, of whom 65 (2.04%) had primary and 39 (1.23%) had secondary infertility. eighty percent of the couples had desired to have a child. there were 2623 couples whose wives were at their reproductive age (15 to 49 years old); 88 couples (3.35%) were infertile, of whom 54 couples (2.05%) had primary and 34 (1.30%) had secondary infertility. women of the infertile couples had a higher mean age at marriage compared to those of fertile couples (p < .001). tables 1 and 2 show the mean ages of the patients in fertile, primary infertile, and secondary infertile groups. to evaluate the age at marriage and its relation to infertility, the couples were divided into two groups of younger than 35 years and 35 years or older according to the ages of men and women. eighty-five out of 2528 couples with wives younger than 35 at marriage were infertile, while infertility was present in 3 out of 7 with wives aged 35 years or older at marriage (3.4% versus 42.9%; p = .004). these rates were 82 out of 2431 for men younger than 35 years and 6 out of 104 for men aged 35 years or older (3.4% versus 5.8%; p = .161). the results for primary and secondary infertility are shown in tables 3 and 4, respectively. among the 88 infertile couples, 66 (75%) had referred to medical consultation centers for treatment of infertility; 43 couples (79.6%) from primary and 23 (67.6%) from secondary infertility groups had sought medical help. 88 table 1. age at marriage in fertile and primary infertile couples with wives in their reproductive ages (15 to 49 years) table 2. age at marriage in fertile and secondary infertile couples with wives in their reproductive ages (15 to 49 years) fertile couples primary infertile couples p value number of couples 2535 54 women’s mean age at marriage (year) 18.75 ± 4.04 20.87 ± 5.44 < .001 men’s mean age at marriage (year) 24.99 ± 5.33 27.04 ± 8.04 .008 fertile couples secondary infertile couples p value number of couples 2535 34 women’s mean age at marriage (year) 18.75 ± 4.04 20.03 ± 4.78 .08 men’s mean age at marriage (year) 24.99 ± 5.33 27.74 ± 4.25 .488 ahmadi asr badr et al discussion world health organization (who) has estimated that there are 50 million to 80 million infertile couples worldwide.(3) few studies have been performed to determine the prevalence and causes of infertility in many populations. infertility may have different prevalence rates in different populations.(4) among published reports, only one study has been performed in iran; in 2000, marzieh estimated the infertility rate to be 12% in the west part of tehran.(1) however, since our study was a population-based study, the lower result is reasonable. there is no official statistics from neighboring countries, but according to the published data by who, the prevalence of primary infertility has been reported to be 1.8%, 2%, 2.8%, and 2.6% in bangladesh, india, sri lanka, and thailand, respectively; these rates are similar to our findings.(5) however, infertility prevalence is higher in some asian and african countries such as indonesia, nepal, and central african republic (4.2%, 9.1%, and 6.9%, respectively).(6) in nigeria, the prevalence of infertility (including primary and secondary), and primary infertility are reported to be 30.3% and 9.2% due to the high prevalence of genital infections.(7) it seems that in some of these countries, socioeconomic and regional factors play a role in addition to genital infections. in industrial countries, the prevalence of primary infertility is a bit more than that in our study. in a recent study performed in united states, the prevalence of infertility reaches 8.5% among 15to 44-year-old women.(8) in a study performed in sweden, the influence of copper melting factories were evaluated, but no relation was found. in this study, primary and secondary infertility had a prevalence of 6% and 3 %, respectively.(9) in industrial counties, contact with chemical materials, air pollution, marriage at older ages, and high-risk sexual behavior may have an impact on the prevalence of infertility. the prevalence of secondary infertility is less in our study comparing with other asian countries. secondary infertility prevalence in women is reported to be 26.5% to 18.9% and 12.9% in central africa and west siberia.(2,6) the cause of this difference is probably related to socioeconomic factors and a lower prevalence of venereal diseases in our country. one of the belgian universities has performed a study in gabon in which the prevalence of primary infertility in semirural and rural areas has been 3% and 5.7%, and the prevalence of secondary infertility has been 22.4% and 20%, respectively. the probable causes are delivery of the first child at home and a positive history of abortion.(10) this can also be attributable to the rural areas of our country, but there is no information available in this regard. of 88 patients in our study, 79.6% with primary 89 table 3. comparison of primary infertility rates in men and women regarding their ages table 4. comparison of secondary infertility rates in men and women regarding their ages fertility status of couple younger than 35 years thirty-five years or older p value women fertile 2528 (98%) 7 (78%) primary infertile 52 (2%) 2 (22%) .014 men fertile 2431 (98%) 104 (95.4%) primary infertile 49 (2%) 5 (4.6%) .074 fertility status of couple younger than 35 years thirty-five years or older p value women fertile 2528(98.7%) 7(87.5%) secondary infertile 33(1.3%) 1(12.5%) .101 men fertile 2431(98.7%) 104(99.05%) secondary infertile 33(1.3%) 1(0.95%) .592 infertility in tabriz and 67.6% with secondary infertility had referred to medical centers for treatment. in another study performed in scotland, this rate was 62%.(11) in havana, cuba, this rate reaches 85.7% because of good nursing coverage and increased knowledge of the couples.(12) this shows the value of nursing training services in the treatment of infertility. also, it depends on the desire of the couples to have a child. in some countries such as denmark, this rate is 47.4%,(13) which shows their less desire for having a child. this factor may not have an essential role in our country because of a more desire of the couples to have a child. conducting of this study encountered some limitations; a face to face interview was required and we used women to perform the interview to reduce the difficulties of obtaining data. however, incorrect information was given by some interviewees especially about their ages. repeated evaluations were required to decrease the rate of unreliable data, but finally about 10% of the couples were excluded. we evaluated men's and women's ages at marriage which are, however, dependent variables to each other. as the female factor and male factor infertilities could not be determined by interview only, a precise assessment of each partner's age effects on infertility was not possible. conclusion according to our study, the prevalence of primary infertility in tabriz is the same as other countries in the region, while the prevalence of secondary infertility is less, and so is the overall rate of infertility. in tabriz, most couples wish to have children. this factor may have an impact on the rates of infertility. thus, a comparison between the findings in different areas and countries must be done considering the desire of the couples to conceive. further studies in other cities are recommended to estimate the prevalence of infertility in iran. acknowledgment the authors wish to thank mrs a zakeri for her cooperation in performing this research. appendix the questionnaire of the study on the prevalence of infertility in tabriz-2004: cluster no:……… family no:……… address:………… tel:……………… 1) husband's age:…… wife's age:…… duration of marriage:….. 2) have you and your spouse ever decided to have a baby? yes � for the first child � second child � no � we have enough children � 3) did you/your wife conceive when you wished for it? no � yes � the outcome of pregnancy: abortion � still birth � live birth � death after birth � how long after the marriage, pregnancy occurred without contraception? ……......month(s) do you use contraceptive methods? yes � no � 4) have you ever referred to a medical center or a doctor's office for treatment of infertility? yes � no � references 1. marzieh n. epidemiology of infertility in the west of tehran in 2000. j am med womens assoc. 2002;57:219. 2. philippov os, radionchenko aa, bolotova vp, voronovskaya ni, potemkina tv. estimation of the prevalence and causes of infertility in western siberia. bull world health organ. 1998;76:183-7. 3. montoya jm, bernal a, borrero c. diagnostics in assisted human reproduction. reprod biomed online. 2002;5:198-210. 4. wood c, dawson k. assisted fertilization. in: sachs b, beard r, papiernik e, russell c, editors. reproductive health care for women and babies. 1st ed. oxford: oxford university press; 1995. p. 322-45. 5. who regional office for south-east asia. women's health status: reproductive health in south-east asia. available from: http://www.whosea.org/women/ tablelistf.htm. 6. larsen u. infertility in central africa. trop med int health. 2003;8:354-67. 7. adetoro oo, ebomoyi ew. the prevalence of infertility 90 ahmadi asr badr et al in a rural nigerian community. afr j med med sci. 1991;20:23-7. 8. wagner mg, stephenson pa. infertility in industrialized countries: prevalence and prevention. soz praventivmed. 1992;37:213-7. 9. wulff m, hogberg u, stenlund h. infertility in an industrial setting--a population-based study from northern sweden. acta obstet gynecol scand. 1997;76:673-9. 10. schrijvers d, dupont a, meheus a. prevalence and type of infertility in gabon. ann soc belg med trop. 1991;71:317-23. 11. templeton a, fraser c, thompson b. the epidemiology of infertility in aberdeen. bmj. 1990;301:148-52. 12. guillen perez m, candelario madariaga m, cruz roja z, leonard castillo a, padron duran rs. the prevalence of infertility and the importance of nursing work in this field. rev cubana enferm. 1992;8:92-101. 13. schmidt l, munster kr, helm p. infertility and treatment in a representative population. ugeskr laeger. 1997;159:1602-6. 91 re: the effect of fasting on erectile function and sexual desire on men in the of month ramadan editorial comment i read with great interest the present article by talib et al. such analyses are invaluable to the study the effects of long term fasting on sexual function outcomes in muslim countries. however, 45 subjects may be inadequate to provide conclusive answers to questions raised by the authors. the authors have addressed an important issue. to date, no randomized prospective clinical trials (rct) have been carried out comparing the two groups (fasted versus non-fasted) and so to draw final conclusion, we should wait for rcts in this regard. as there is no long-term data comparing functional outcomes after fasting in the month of ramadan, present study has attempted to provide some data about this topic in terms of ef, sexual desire, and sex hormones. although the primary feasibility endpoint of this study was set as iief-5/iief-ef domain, the presentation of the results performed less clear. in the results section, only total iief-5 score has been mentioned. moreover, only the changes in total iief-5 score were shown (before vs. after), but not for each iief-5 studied questions. the usual practice of presenting the results of ef is to provide the percentage changes in preand post-fasting iief-ef domain scores.(1-4) unfortunately, this essential information was not reported in the article. the only information that we could obtain was the preand post-fasting total iief-5 score. therefore, we would greatly appreciate if the authors could provide further clarification of the results (preand post-fasting score for each iief-5 questions). this would help readers to better assess the potential role of fasting on ef. of most importance is the follow-up period. the end of study is the end of the month of ramadan (end of fasting), whereas the effects of fasting may appear or continue in the following next weeks after long term fasting. an evaluation of the subjects in iief-5 ef domain at 3-month post ramadan would be valuable for readers, but these were not provided by the authors. there are several important limitations of this study. the main limitation of this study is the lack of a control arm. in addition, the penile hemodynamics have not been assessed. the study sample size and as a result the study power is low. in addition, there are many confounding factors which can affect ef of a man, the most important are, age, comorbidities such as renal, hepatic and cardiac diseases, serum lipid profile, the quality of relationship with partner, monthly income, daily exercise, medication used, occupational status and etc. all of the confounding factors should put in multivariate analysis, and then the results should be reported after adjustments for these confounding factors. another important limitation is lack of partner satisfaction evaluation. the clinical global impression scale adapted for sexual function (cgi-sf),(5) is a useful tool for measuring preand postintervention sexual function in women. (6) the finding of decreased serum follicle stimulating hormone (fsh) is important. serum fsh level has negative feedback with spermatogenesis. whether this decreased serum fsh level is due to alteration in spermatogenesis or is due to impairment in section by hypophysis gland, is not clear. a paragraph explaining this issue in discussion section would be very informative. i think the importance of this finding is more than deteriorated ef. moreover, we don’t know periods of impaired ef and decreased serum fsh time lasted for how many time (days, weeks, months). this finding highlights the importance of including a control group. collectively, these limitations and findings raise concern about the bias in study findings. despite the limitations mentioned above, the current study sets the stage for further exploring of this important issue. this study provides important insight into the long-term results in ef, spermatogenesis and serum sex hormones after long term fasting for the month of ramadan. finally, ef of a man or woman has important correlation with his/her quality of life. most of men or women have no problem with their sexual dysfunction. it was better to assess the impact of decreased ef on study subjects’ quality of life. quality of life can be assessed by short form-36 health survey (sf36). sf-36 is a standard diagnostic tool evaluating different aspects of the qol related with health over the previous 4 weeks.(7) changes in sf-36 may be more generalizable than the absolute reported changes of iief-5 total score. as the sole study in the literature to date, this report open new era for further studies addressing the long term effects of long term fasting on ef, sex hormone and spermatogenesis. this purpose mandates rcts, or at least large scale studies with control group and long term follow up periods. in addition we need to know the underlying pathophysiology which has resulted in altered ef and sex hormone. conditions in which there is endothelial dysfunction, imply that decreased production of nitric oxide (no) by endothelial cells could be a common denominator. no, produced by endothelial cells, is responsible for penile erection. increase in the concentrations of inflammatory markers such as, interleukin-6 (il-6), il-1β, high-sensitive c-reactive protein (hscrp), endothelial-prothrombotic markers/mediators, tumor necrosis factor-α (tnf-α), von-willebrand factor (vwf), plasminogen activator inhibitor-1 (pai-1), tissue plasminogen factor (tpa), and fibrinogen have been reported in patients with erectile dysfunction.(8) further studies are needed to elucidate the potential role of long term fasting on ef, sex hormones and spermatogenesis. mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specializing in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com vol 12. no 02 march-april 2015 2103 references 1. safarinejad mr, hosseini sy. salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study. j urol. 2008;179:1066-71. 2. safarinejad mr. evaluation of the safety and efficacy of sildenafil citrate for erectile dysfunction in men with multiple sclerosis: a double-blind, placebo controlled, randomized study. j urol. 2009;181:252-8. 3. montorsi f, brock g, stolzenburg ju, et al. effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: a randomised placebocontrolled study (reactt). eur urol. 2014 mar;65(3):587-96. 4. safarinejad mr1, shafiei n, safarinejad s. an open label, randomized, fixed-dose, crossover study comparing efficacy and safety of sildenafil citrate and saffron (crocus sativus linn.) for treating erectile dysfunction in men naïve to treatment. int j impot res. 2010;22:240-50. 5. guy w. the clinical global impression severity and improvement scales. ecdeu assessment manual for psychopharmacology. us department of health, education and welfare publication (adm). 76-338. rockville, md: national institute of mental health; 1976. p. 218–22. 6. safarinejad mr. reversal of ssri-induced female sexual dysfunction by adjunctive bupropion in menstruating women: a doubleblind, placebo-controlled and randomized study. j psychopharmacol. 2011;25:370-8. 7. ware je, kosinski m. sf-36 physical and mental health summary scales: a manual for users of version 1, 2nd edn. quality metric incorporated: lincoln, ne, 2001. 8. vlachopoulos c, aznaouridis k, ioakeimidis n, et al. unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease. eur heart j. 2006;27:2640-8. impact of the month of ramadan on sexual function-talib et al. sexual dysfunction and fertility 2104 urology journal unrc/iua 250 effect of smoking on prognostic factors of transitional cell carcinoma of the bladder mohseni mg*, zand s, aghamir smk department of urology, sina hospital, tehran university of medical sciences, tehran, iran abstract purpose: this study was conducted to evaluate the effects of smoking on the clinical characteristics and growth trend of transitional cell carcinoma (tcc) of the bladder. material and method: in a retrospective case-control study from february 2000 to march 2003, patients with tcc of bladder, referred to our clinic, were selected and divided into high-grade and low-grade groups. groups were matched for other known risk factors and the effect of smoking on size, number, and presenting grade of tcc in each group was evaluated. results: a total of 185 patients, with a mean age of 65.1 ± 14.0 year, were included in this study, of whom 36 were females and 149 were males (male to female ratio of 4.1 to 1). eighty-three patients were smokers (44.9%) with a mean 20.01 ± 11.09 packyear (range 0.75 to 60) smoking history. history of smoking was positive in 36.1% of the patients with low-grade tumors; whereas, 90% of the patients with high-grade tumors were smokers (p = 0.000, or = 15.9, 95% ci: 6.7-36.9). there was a statistically significant correlation between the history of smoking and size and number of tumoral lesions (p = 0.000, p = 0.000, respectively). positive history of smoking was also associated with higher grades of tumor in both men and women (or = 12.8 and 8.8, respectively). conclusion: this study showed that smoking not only induces bladder cancer, but also, once it develops, it can increase the grade of tumor, resulting in worse prognosis. thus, smoking cessation might favorably alter the course of bladder cancer. key words: transitional cell carcinoma, smoking, tumor grade vol. 1, no. 4, 250-252 autumn 2004 printed in iran introduction bladder is the most common site of involvement with cancer in the urinary tract system. more than 53200 new cases of bladder cancer were diagnosed in 2000 in the united states,(1) which makes the bladder tumor as the fourth common tumor in men and the eighth one in women.(1) among middle aged men, bladder cancer is the second common malignancy.(2) over 12200 cases of death have been reported during 2000 in united states.(1) it means that bladder cancer is the seventh common cause of death due to cancer.(1) several risk factors have been proposed for bladder cancer development, such as industrial chemicals,3 chemical materials,4 genetic disorders (p53 gene mutation,(5,6) retinoblastoma gene(7)), cyclophosphamide,(8) chronic urinary tract infection,(9) and cigarette smoking.(10) parameters such as pathological grade and stage of the tumor can alter the natural history, prognosis, and survival rate of patients.(11,12) hence, describing factors, which may impact the grade or other prognostic factors in bladder cancer can help us improving the survival rate of patients. this study was designed to evaluate the role of smoking in prognostic characteristics of bladder transitional cell carcinoma (tcc). received july 2003 accepted may 2004 *corresponding author: department of urology, sina hospital, hassan-abad sq., tehran, iran. e-mail: mgmohseni@sina.tums.ac.ir mohseni et al 251 materials and methods in a retrospective case-control study from february 2000 to march 2003, the referred patients to our clinic, suspected of bladder cancer, had undergone cystoscopic examination, if necessary. those with documented tcc of bladder based on biopsy, were included in this study and divided into high-grade group (tumor grade iii) and low-grade group (pathologic grade less than iii), according to who grading system for tcc.(13) patients' age, sex, smoking status, history of other known risk factors of bladder cancer, and cystoscopic report of tumor characteristics such as size and number of lesions were recorded for each group. tumors smaller than 2 cm were considered as small, 2 to 5 cm as moderate, and larger than 5 cm, as large. statistical analysis was done using chi-square test, independent t test, and analysis of variance to compare variables in low-grade and high-grade groups. a p value less than 0.05 was considered significant. results a total of 185 patients with tcc of the bladder were included in this study. mean age of the patients was 65.1 ± 14.1 years, and of whom, 149 (80.5%) were men and 36 (19.5%) were women. male to female ratio was 4.1 to 1. there were 83 (44.9%) patients with a positive history of smoking, who had a mean of 20.01 ± 11.09 (range 0.75 to 60) pack-year history. thirty patients were assigned in high-grade group (16.3%) and 155 (83.7%) in low-grade group (table 1). when gender and age of the patients were considered, there was no statistically significant difference between smokers and non-smokers. also, age and gender distribution differences were not statistically significant in highand lowgrade groups either. overall, 36.1% of the patients with low-grade tumors had a positive history of smoking; whereas, 90% of the patients in high-grade group were smokers (p = 0.000, or = 15.9, 95% ci: 6.7-36.9). among non-smokers, 75.5% of the tumors were small in size, but 75.9% were moderate or large in smokers (p = 0.000). of 102 non-smokers 93.1% had a single tumor lesion, but in smokers, 63.1% had multiple lesions (p = 0.000). there was a significant difference in smoking rate between low-grade and high-grade groups, using analysis of variance test (p = 0.000)(table 1). mean smoking was 21.54 ± 11.8 pack-years in grade iii and zero in grade 0. bonferoni post hoc test demonstrated that that the difference mostly existed between grade iii and ii rather than the other grades (p = 0.000 vs. p = 0.002). on the other hand, cigarette smoking rate was statistically higher in patients with high-grade tumors. this difference could be seen in both men and women (p = 0.000 and p = 0.001, respectively) (table 2). discussion smoking is a well known risk factor of bladder cancer and smokers have up to a 2-fold higher incidence rate of bladder cancer than the people who have never smoked.(10) however, there are few studies on evaluating the effect of smoking on the tumor growth pattern, pathological grade, and other prognostic characteristics. the main purpose of this study was to evaluate this potential association. mean age of the patients in our study was similar to that in the previous studies.(14) male to female ratio was 2.5 to 1 and 3 to 1 in other studies,(1,15) which were slightly different from our findings (4.1 to 1). the presence of larger tumoral lesions in smokers has also been demonstrated previously. busto catanon et al have shown that tumor lesions larger than 3 cm have higher grades.(16) raitanen et table 1. patients and tumors' characteristics in low-grade and high-grade groups table 2. odds ratios for smoking in different groups �������� � �� ����� �� ���� �� ���� �� ������ �� ������ � � �� �� ���� �� ����� ��� ���� ���������������� ������������ ��� ���� ��� � �� ����� �� � ������ ��� �� ������ � � ����� � ���� ��� ���� ����� ��� �� � ��� ����� �� �������������! � ���� � � ��� � � � �� ��� ��� ������ ����� � ���� ��� � ��� ����� ���� ���� ���" ������ ����� ������ � �� ��� � ��� ���� ��� ��� ������ �� � � �� ����� �� ����� ���� ��� �� � �� �� # ��� � � � ���� �� ����� ��� ��� �� ��� �� � �� �� ����� �� ��� ��� ������ �������������$���� ��� ��� ����� �� ��� �� � � �� ������ ���$%� ��� �������������$����� �� ���� � �� ������� � ������ ������ � � � ����� ��� ����� �� � ����� � � ��������� � ��� �� �� ������������� ����� ���� ���� �� �������������������� � ��� ���� ���� �� ���������������������� � ��� ���� ���� smoking and transitional cell carcinoma252 al(17) reported that recurrence rate is higher among patients with more than 3 tumoral foci. our study not only showed that larger lesions had higher grade, but also demonstrated that smokers had larger and more lesions. patients with multiple lesions had higher mean smoking rate than those with a single tumor (20.89 vs. 6.01 pack-years). this finding suggests the probable smoking effect on tumor characteristics. the main finding of our study was the relation between tumor grade and history of smoking. as we indicated, smokers had a higher chance of having high-grade tumors (or=15.9). thompson(18) also suggested that there is a significant association between smoking history and stage, grade, and rate of recurrences; however, fleshner et al(19) did not find such a significant relation and reported that the frequency of each grade was not different between smokers and non-smokers. our study showed that the history of smoking was associated with up to 15.9 (95% ci: 6.7-36.9) fold higher chance of having high-grade tumors. this association also existed in both men and women. a greater impact of smoking on women has also been reported in another study.(20) hence, it seems that smoking not only increases the risk of bladder cancer, but also it is associated with higher tumor grades. conclusion while cigarette smoking is the most potent risk factor for bladder cancer, its effect on the natural history of the disease is also considerable. consequently, we should bear in mind that patients with tcc of bladder who have a positive history of smoking may have high-grade tumors and a more rigorous follow-up program is necessary. references 1greenlee rt, murray t, bolden s, wingo pa. cancer statistics, 2000. ca cancer j clin. 2000;50:7-33. 2feldman ar, kessler l, myers mh, naughton md. the prevalence of cancer. estimates based on the connecticut tumor registry. n engl j med. 1986;315:1394-7. 3morrison as, cole p. epidemiology of bladder cancer. urol clin north am. 1976;3:13-29. 4stadler wm. molecular events in the initiation and progression of bladder cancer. int j oncol. 1993;3:549. 5esrig d, elmajian d, groshen s, et al. accumulation of nuclear p53 and tumor progression in bladder cancer. n engl j med. 1994;331:1259-64. 6cordon-cardo c. mutations of cell cycle regulators. biological and clinical implications for human neoplasia. am j pathol. 1995;147:545-60. 7cote rj, dunn md, chatterjee sj, et al. elevated and absent prb expression is associated with bladder cancer progression and has cooperative effects with p53. cancer res. 1998;58:1090-4. 8morrison as. advances in the etiology of urothelial cancer. urol clin north am. 1984;11:557-66. 9kantor af, hartge p, hoover rn, narayana as, sullivan jw, fraumeni jf jr. urinary tract infection and risk of bladder cancer. am j epidemiol. 1984;119:510-5. 10burch jd, rohan te, howe gr, et al. risk of bladder cancer by source and type of tobacco exposure: a casecontrol study. int j cancer. 1989;44:622-8. 11holmang s, hedelin h, anderstrom c, holmberg e, johansson sl. the importance of the depth of invasion in stage t1 bladder carcinoma: a prospective cohort study. j urol. 1997;157:800-3. 12millan-rodriguez f, chechile-toniolo g, salvador-bayarri j, palou j, vicente-rodriguez j. multivariate analysis of the prognostic factors of primary superficial bladder cancer. j urol. 2000;163:73-8. 13epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j srug pathol. 1998; 22:1435-48. 14lynch cf, cohon mb. urinary system. cancer. 1995; 75(1 suppl):316-29. 15wingo pa, tong t, bolden s. cancer statistics, 1995. ca cancer j clin. 1995;45:8-30. erratum in: ca cancer j clin. 1995;45:127-8. 16busto catanon l, sanchez merino jm, picallo sanchez ja, gelabert mas a. clinical prognostic factors in superficial cancer of the urinary bladder. arch esp urol. 2001 mar;54:131-8. 17raitanen mp, tammela tl. impact of tumour grade, stage, number and size, smoking habits and sex on the recurrence rate and disease-free interval in patients with transitional cell carcinoma of the bladder. ann chir gynaecol. 1995;84:37-41. 18thompson im, peek m, rodriguez fr. the impact of cigarette smoking on stage, grade and number of recurrences of transitional cell carcinoma of the bladder. j urol. 1987; 137:401-3. 19fleshner n, garland j, moadel a, et al. influence of smoking status on the disease-related outcomes of patients with tobacco-associated superficial transitional cell carcinoma of the bladder. cancer. 1999;86:2337-45. 20xavier b. bladder cancer risk higher for women smokers [news]. br m j 2001; 322:948. u j all final for web.pdf 818 | intravesical migration of an intrauterine device bayram guner, ozgur arikan, gokhan atis, lutfi canat, turhan çaskurlu keywords: urinary bladder, intrauterine devices, intrauterine device migration, uterine perforation introduction intrauterine device (iud) is the most commonly used, safe, and reversible method of contra-ception. uterine perforation is a rare complication of iud. migration could occur to the case report bladder on computed tomography (ct). corresponding author: bayram guner, md department of 2nd urology, goztepe research and training hospital, 34730, istanbul, turkey tel: +90 352 216 570 9162 e-mail: gunerbayram@ yahoo.com received february 2011 accepted june 2011 department of 2nd urology, goztepe research and training hospital, istanbul, turkey case report case report 819vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l intravesical migration of intrauterine device | guner et al traction (figures 2 and 3). bladder perforation that occurred st postoperative tend annually for outpatient visits and to seek medical help if discussion intrauterine device is one of the most effective and reversible complications, such as uterine perforation, undesired preg uterine perfoliterature.(6,7) it becomes more susceptible due to reduction in genemia in the lactation and postpartum periods. generfigure 1. intrauterine device had been partially penetrated to the bladder wall. figure 2. gentle traction with grasper for intrauterine device in the bladder lumen. figure 3. intrauterine device is taken with grasper. figure 4. post-removed image of the intrauterine device. 820 | ever, most authors believe that iud placement by specialists is very important in preventing perforation primarily. through the bladder due to infection, adhesion, and tissue damage caused by the vaginal speculum during iud insertion. cal situation. related symptoms, such as chronic pelvic pain, dysuria, pollacuria, microscopic hematuria, pyuria, dyspareunia, recurrent and persistent urinary tract infection, vaginal infections, can occur before the diagnosis ranging from 3 these patients may have multiple antibiotic therapies if they are not evaluated appropriately. been reported in the literature. the most accurate methods for diagnosis of lost iud are radiography, ultrasonography, intravenous urography, ct, and cystoscopy. partial perforaimaging studies. although ct is the most effective imaging method for diagnosis, but cystoscopy is the optimal therapeutic approach to manage iud migration to the bladder. minimally-invasive methods, such as laparoscopy or endoscopy, are standard approach for removal of migrated iud. scopic surgery. conflict of interest none declared. references 1. ozcelik b, serin is, basbug m, aygen e, ekmekcioglu o. differential diagnosis of intra-uterine device migrating to bladder using radiographic image of calculus formation and review of literature. eur j obstet gynecol reprod biol. 2003;108:94-6. 2. hoscan mb, kosar a, gumustas u, guney m. intravesical migration of intrauterine device resulting in pregnancy. int j urol. 2006;13:301-2. 3. guvel s, tekin mi, kilinc f, peskircioglu l, ozkardes h. bladder stones around a migrated and missed intrauterine contraceptive device. int j urol. 2001;8:78-9. 4. markovitch o, klein z, gidoni y, holzinger m, beyth y. extrauterine mislocated iud: is surgical removal mandatory? contraception. 2002;66:105-8. 5. harrison-woolrych m, ashton j, coulter d. uterine perforation on intrauterine device insertion: is the incidence higher than previously reported? contraception. 2003;67:53-6. 6. sepulveda wh, ciuffardi i, olivari a, gallegos o. sonographic diagnosis of bladder perforation by an intrauterine device. a case report. j reprod med. 1993;38:911-3. 7. zakin d, stern wz, rosenblatt r. complete and partial uterine perforation and embedding following insertion of intrauterine devices. i. classification, complications, mechanism, incidence, and missing string. obstet gynecol surv. 1981;36:335-53. 8. atakan r h, kaplan m, ertrk e. intravesical migration of intrauterine device resulting in stone formation. urology. 2002;60:911. 9. nceboz us, ozcakir ht, uyar y, caglar h. migration of an intrauterine contraceptive device to the sigmoid colon: a case report. eur j contracept reprod health care. 2003;8:229-32. 10. disu s, boret a. asymptomatic ileal perforation of an intrauterine device. arch gynecol obstet. 2004;269:230-1. 11. dietrick dd, issa mm, kabalin jn, bassett jb. intravesical migration of intrauterine device. j urol. 1992;147:132-4. 12. neutz e, silber a, merendino vj. dalkon shield perforation of the uterus and urinary bladder with calculus formation: case report. am j obstet gynecol. 1978;130:848-9. 13. grimaldi l, de giorgio f, andreotta p, d'alessio mc, piscicelli c, pascali vl. medicolegal aspects of an unusual uterine perforation with multiload-cu 375r. am j forensic med pathol. 2005;26:365-6. 14. ozgur a, sismanoglu a, yazici c, cosar e, tezen d, ilker y. intravesical stone formation on intrauterine contraceptive device. int urol nephrol. 2004;36:345-8. 15. phupong v, sueblinvong t, pruksananonda k, taneepanichskul s, triratanachat s. uterine perforation with lippes loop intrauterine device-associated actinomycosis: a case report and review of the literature. contraception. 2000;61:347-50. case report vol 13 no 02 march-april 2016 2590vol 13 no 02 march-april 2016 2650 case report giant vesicoprostatic calculus combined with vesico-cutaneous fistula georgios goumas, konstantinos stasinopoulos, charalampos fragkoulis, georgios papadopoulos,* georgios stathouros, konstantinos ntoumas keywords: urinary bladder; calculi; etiology; prostatic diseases; prostate; pathology; male. department of urology, athens general hospital ‘‘g. gennimatas’’, athens, greece. *correspondence: 1b, kefallinias st., maroussi, athens, pc: 15126, greece. tel: +30 694 5540032. fax: +30 210 6106258. e-mail: gipapadopoulos@yahoo.gr. received june 2015 & accepted february 2016 introduction bladder lithiasis is a common condition that accounts for 5% of all urinary calculi.(1) predisposing factors in-clude bladder outlet obstruction, neurogenic bladder abnormalities, as well as foreign bodies.(2) the size of the stones is rarely large and some sporadic case reports of calculi with giant dimensions have been published. in our reference we report a case of an extremely sizable calculus covering the whole vesicoprostatic lumen, from bladder dome to verumontanum accompanied by vesicocutaneous fistula. figure 1. kidney-ureter-bladder x-ray shows sizable vesicoprostatic stone. figure 2. suprapubic protrusion produced by bladder stone. figure 3. stone burden after removal. case report a 56-year-old man was referred to our urological clinic complaining of lower urinary tract symptoms (luts) and vesicocutaneous fistula (in the mid of the distance between umbilicus and pubic symphysis) which he had first detected a few days before. his personal history comprised an abdominal operation because of a severe car accident 3 decades ago. the exact abnormality and operation of that accident was not clear (records were not available) but might have played a role in bladder innervations and emptying, especially if pelvic area had been involved. his medications included amlodipine due to arterial hypertension and tamsulosin for the aforementioned luts. however, patient was not on proper follow-up due to a particular mentality and temperament. clinical examination revealed the above fistula as well as a characteristic suprapubic protrusion which was quite clear due to patient’s low body mass index (figure 1). the area was firm and produced a blunt sound on percussion. biochemical assays revealed a slightly impaired renal function [serum urea and creatinine were 58 mg/dl (normal values: 20-50 mg/dl) and 1.8 mg/dl (normal values: 0.8-1.4 mg/dl), respectively]. his hematocrit was 32.8% and white blood cells count were marginally elevated (11.800/mm3). urinalysis showed pyuria and microscopic hematuria. urine culture confirmed escherichia coli colonization. subsequent imaging with plain x-ray and computerized tomography (ct) scan displayed a large calculus occupying the whole bladder and prostatic area (figure 2). moreover, mild bilateral pelvicalyceal dilatations were observed. the patient was subsequently admitted to our department. two days later he underwent an open cysto-prostato-lithotomy and fistula repair (endoscopic cystoscopy was initially performed, to assess urethra’s patency, but the scope could not be negotiated further than verumontanum). bladder wall was very thin and a large diverticulum on left lateral wall was also fully occupied by stones. fortunately, the diverticular ‘‘neck’’ was wide, so the stones in it could be removed. surprisingly, the whole prostatic urethra and prostatic adenoma area were also occupied by calculi that were removed with the usage of index finger, like the technique applied in transvesical prostatectomy. the vesico-cutaneous fistula was easily removed (in fact, this was too short, due to the small distance between bladder wall and skin). the whole stone burden removed weighed 2.4 kg with a maximum diameter of 12 cm (figures 3). bladder was sutured in two layers and a 3-way urethral catheter was placed. this was removed on the 8th postoperative day and the patient started restoring his voiding. however, due to the long presence of the above described condition, the patient could not empty his bladder and retained a postvoid residual urine volume of constantly over 300 ml. therefore, he is now (1 year later), on clean intermittent catheterizations. stone analysis showed magnesium ammonium phosphate. discussion vesical calculi, though commonly diagnosed, are rarely over 100 gr in weight. in our paper we present one of the heaviest (possibly the heaviest) vesical stones (2.4 kg). moreover, the stone occupied the whole prostatic urethra, being imaged as having replaced prostatic adenoma completely (figure 2). in literature there have been published a number of sizable vesical calculi and a smaller one regarding prostatic stones.(3,4) our case, not only describes the biggest stone but combines vesical and prostatic anatomical areas, both in the same patient. most of such stones are of mixed composition. if infection is present, struvite is the major constituent.(5) regarding symptoms, there is a variety of manifestations of the problem, namely luts, hematuria, obstruction, infection, renal failure and bladder rupture.(6-8) in the patient we present, the main sign was vesicocutaneous fistula. this has also been reported.(9,10) moreover, it has been claimed that weakening of the anterior abdominal wall and bladder due to previous operations might be a predisposing factor to that, since the strength of the rectus abdominis muscle between the bladder and skin, functions protectively regarding fistula formation in that region. conflict of interest none declared. references 1. schwartz bf, stoller mf. the vesical calculus. urol clin north am. 2000;27:333-46. 2. hammad ft, kaya m, kazim e. bladder calculi: did the clinical picture change? urology. 2006;67:1154-8. 3. farshi a, sari motlagh r, jafari arismani r. delivery of huge bladder stone in a thirty-five-year-old man. nephrourol mon. 2014;6:e20574. 4. bello a, maitama hy, mbibu nh, kalayi gd, ahmed a. unusual giant prostatic urethral calculus. j surg tech case rep. 2010;2:30-2. 5. hizli f, yilmaz e. a giant bladder struvite stone in an adolescent boy. urol res. 2012;40:273-4. giant vesicoprostatic calculi-goumas et al. case report 2651 vol 13 no 02 march-april 2016 2652 6. komeya m, sahoda t, sugiura s, sawada t, kitami k. a huge bladder calculus causing acute renal failure. urolithiasis. 2013;41:85-7. 7. thakur rs, minhas ss, jhobta r, sharma d. giant vesical calculus presenting with azotaemia and anuria. indian j surg. 2007;69:147-9. 8. kaur n, attam a, gupta a, amratash. spontaneous bladder rupture caused by a giant vesical calculus. int urol nephrol. 2006;38:487-9. 9. kobori y, shigehara k, amano t, takemae k. vesicocutaneous fistula caused by giant bladder calculus. urol res. 2007;35:161-3. 10. motiwala hg, joshi sp, visana kn, baxi h. giant vesical calculus presenting as vesicocutaneous fistula. urol int. 1992;48:1156. giant vesicoprostatic calculi-goumas et al. urology journal unrc/iua vol. 2, no. 1, 36-39 winter 2005 printed in iran 36 the role of pretransplant smoking on allograft survival in kidney recipients alireza kheradmand*, heshmatollah shahbazian department of urology, golestan hospital, ahwaz university of medical sciences, ahwaz, iran abstract purpose: cigarette smoking contributes to a number of health-related problems, but its impact on allograft survival in kidney recipients is not clear. this study was performed to evaluate the relationship between smoking and graft survival. materials and methods: a total of 199 adult kidney recipients were enrolled in this study. all transplantations had been done in our center and all grafts had been taken from living donors. the patients were asked about their cigarette smoking behavior before transplantation and assessed for diabetes mellitus, hypertension, and hyperlipidemia, preand post-operatively. results: of 199 recipients, 142 (71.4%) were male and 57 (28.6%) were female. they were 40.45 (range 18 to 65) years old. forty-one recipients (20.6%) were smokers before kidney transplantation that 87.7% of them continued smoking after transplantation. mean pack-year smoking was 13.2. of the patients, 32.7% and 33.7% had hypertension, 19.3% and 23.1% had diabetes mellitus, and 46.2% and 42.2% had hyperlipidemia, before and after transplantation, respectively, showing no significant difference. pretransplant smoking was significantly associated with reduced overall graft survival (p = 0.01), but no correlation between smoking cessation after transplantation with survival graft was found. conclusion: cigarette smoking before kidney transplantation contributes significantly to allograft loss. however, smoking is not associated with increase in rejection episodes. although we could not prove it, smoking cessation after renal transplantation may have beneficial effects on graft survival. these effects should be emphasized for patients with end-stage renal disease who are candidates for kidney transplantation. key words: smoking, kidney transplantation, graft survival introduction kidney transplantation is one of the recommended treatment modalities for young patients with chronic renal failure.(1) however, kidney transplant patients have an increased risk of atherosclerosis and neoplasm due to their chronic immunosuppressed state.(2,3) on the other hand, cigarette consumption is one of the well known causes of many systemic diseases and factors increasing mortality,(4) and considering the above-mentioned factors, renal transplant patients who smoke increase the risk of cardiac and pulmonary diseases, in comparison with those who do not smoke. however, does cigarette smoking affect the survival rate of kidney allograft? there are few studies pertaining to this topic(5,6,7); some point to the positive outcome in those patients who quit smoking. based on our review of the literature, there have not been such studies in our country. in this study, we reviewed the effect of pretransplant cigarette smoking on the survival of the received december 2002 accepted june 2004 *corresponding author: urology department, golestan hospital, jundishpur (ahwaz) medical university, ahwaz, iran. tel & fax: ++98 611 334 9293 e-mail: kheradmand_a@yahoo.com kheradmand and shahbazian 37 transplant kidney in our center. materials and methods from 1989 to 2002, 360 patients underwent renal transplant from live donors at golestan hospital of ahwaz (affiliated with ahwaz medical school). all of the above-mentioned cases had complete records from the onset of their evaluation. these records had been updated upon each readmission. in addition, all of the patients had been under the care of the nephrologists in the area. the inclusion criteria were age greater than 18, transplant at the above-mentioned center, receiving a first transplant, having at least one year post-transplant follow-up, being alive at the time of the study, and having the last evaluation record within the 6 months before the study. given the above considerations, 199 patients were eligible for this study. reviewing the hospital records, the following data were collected: age, sex, age at time of transplant, history of diabetes, hypertension, and hyperlipidemia prior to transplant, rejection history, and history of smoking. the completed forms were reviewed by the authors and the most recent status of the patient (with regard to condition of the transplanted kidney, smoking status, diabetes, hypertension, and hyperlipidemia) were recorded. after transplantation, all patients had been started on immunosuppressive agents including cyclosporine, azathioprine, and corticosteroids. in cases of rejection, patients had been treated with pulse steroid therapy or anti-thymus antibodies or anti-lymphocyte antibodies. all collected data were analysed with spss 9.0 software package. the survival of the transplanted kidney was cumulatively calculated using kaplan-meier method. the subjects were divided into two groups of smokers and nonsmokers prior to transplantation. differences between groups were examined, using t test for continuous variables and chi-square test for differences for categorical data. the cumulative survival of graft in the two groups were calculated and compared with kaplan-meier method and log-rank test. p value less than 0.05 was considered statistically significant. results one hundred and forty-two (71.4%) of 199 recipients were male and 57(28%) were female. female to male ratio was 2 to 5. mean age was 40.45 (range 19 to 65) years. characteristics of smokers prior to transplantation are shown in table 1. forty-one recipients were smokers prior to transplantation (20.6%). the smokers had a mean 13.2 pack-year smoking history. of this group, 87.7% continued to smoke after transplant and only 5 patients stopped smoking after receiving a renal transplant (12.2%), and 4 cases started smoking after transplant (all of them smoked less than half a pack per day. there was not any significant age difference between smokers and non-smokers (47.9 ± 12.5 years vs. 42.6 ± 14.5 years) at transplantation time. however, smoking was more prevalent among males: 36 of 142 male recipients (25.4%) versus 5 of 57 female recipients (8.8%). mean 1and 5-year cumulative graft survival were 78% and 67% in smokers and 84% and 73% in non-smokers (p = 0.01). yet, this reduction of graft survival was not associated with acute rejection. in addition, gender had no major role in the effect of smoking on survival of transplanted kidney. thirty-eight recipients (19.9%) had suffered from diabetes before transplant and after transplant this number increased to 46 cases (21.61%). hypertension increased from 32.7% to 33.7% after transplant and hyperlipidemia increased from 42.2% to 46.2% (table 2). table 1. smoking behaviors in kidney recipients table 2. diabetes, hypertension, and hyperlipidemia in smokers and non-smokers number of patients (%) smoking history 41 (20.6) <5 pack-year 5-10 pack-year 11-15 pack-year 16-20 pack-year >20 pack-year 8 (19.5) 8 (19.5) 5 (12.2) 11 (26.8) 9 (22) smoking after transplant (continued) 36 (87.7) smoking after transplant (start) 4 (2) smokers non-smokers pretransplant posttransplant pretransplant posttransplant diabetes mellitus 8 10 30 36 hypertension 14 14 51 54 hyperlipidemia 20 20 72 67 pretransplantation smoking and kidney allograft survival38 five recipients quit smoking after transplant, yet in comparison to those who continued to smoke, there was no increase in survival of the allograft (p = 0.3) discussion kidney transplant recipients are susceptible to many illnesses, some of which are due to immunosuppressants.(7) cigarette smoking increases risk of many diseases such as cancer and cardiac or pulmonary disorders. combination of smoking and renal transplant may increase the risk of complications, resulted from either of these factors.(2,8) renal transplant patients are at increased risk for atherosclerosis after transplant which may be the result of hypertension, hyperlipidemia, and hyperglycemia, all of which may be exacerbated with smoking.(9,10) smoking alone increases the risk of coronary disease and vascular disorders.(5,11) in addition, smoking accelerates atherosclerosis in transplant recipients, which can lead to decreased survival of the allograft. this may be due to microvascular changes in the allograft, decreased plasma flow, elevation of endothelin-1, increased platelet aggregation, and increased thickness of renal artery.(12-14) in our review, we have shown that smoking leads to a decrease in allograft survival. however, acute rejection rate in smokers was the same as that in non-smokers; therefore, smoking may not decrease survival via rejection. but, smoking can lead to microvascular injury, subacute rejection, and other unknown disorders relating to allograft rejection.(7) although the amount of smoking (pack-year) did not correlate significantly with the allograft survival rate, there has been a relative correlation with allograft survival in other studies.(6,7,15) in addition, it has been shown in some studies that cessation of smoking increases graft survival. thus, it is not possible to know whether the decrease in graft survival is a result of smoking before transplantation or keeping on smoking after the transplantation.(7,15,16) in our study, we could not show a clear association of improvement in allograft survival with smoking cessation. however, this may be due to the small number of cases who quit smoking in our series. in this study, there was not a significant difference in the rate of hypertension, hyperlipidemia, and diabetes between smokers and non-smokers before and after transplantation. therefore, it does not appear that smoking decreases allograft survival via the above-mentioned disorders. another point mentioned in the literature is the social, economic, and educational differences between smokers and non-smokers, which makes them different in their cooperation and compliance.(17,18) for example, the majority of our smoker patients failed to follow the recommendation of their physicians to quit smoking. this may be a representation of noncompliance which can be seen in other areas of their health care. in our study, the number of recipients who started smoking after transplant surgery was very small and the quantity of smoking in this group was also very low. yet, the effect of smoking after transplantation was not studied. conclusion cigarette smoking prior to receiving a renal transplant is associated with a decrease in graft survival, which seems not to be due to acute rejection. cessation of smoking after receiving a transplant appears to have positive impact. however, this conclusion should be considered more in renal transplant candidates. references 1. barry jm. renal transplantation. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.345-76. 2. duvoux c, delacroix i, richardet jp, et al. increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis. transplantation. 1999;67:418-21. 3. kasiske bl. risk factors for accelerated atherosclerosis in renal transplant recipients. am j med. 1988;84:98592. 4. national center for health statistics. births and deaths: preliminary data for 1997. in: national vital statistics report 1998. vol 47(4). p.5-7. available from: http://www.cdc.gov/nchs/products/pubs/pubd/nvsr/nvs r.htm. 5. cosio fg, falkenhain me, pesavento te, et al. patient survival after renal transplantation: ii. the impact of smoking. clin transplant. 1999;13:336-41. 6. kasiske bl, klinger d. cigarette smoking in renal transplant recipients. j am soc nephrol. 2000;11:753-9. 7. sung rs, althoen m, howell ta, ojo ao, merion rm. excess risk of renal allograft loss associated with cigarette smoking. transplantation. 2001;71:1752-7. 8. king gn, healy cm, glover mt, et al. increased prevalence of dysplastic and malignant lip lesions in kheradmand and shahbazian 39 renal-transplant recipients. n engl j med. 1995;332:1052-7. 9. kasiske bl, tortorice kl, heim-duthoy kl, awni wm, rao kv. the adverse impact of cyclosporine on serum lipids in renal transplant recipients. am j kidney dis. 1991;17:700-7. 10. curtis jj. hypertension following kidney transplantation. am j kidney dis. 1994;23:471-5. 11. radovancevic b, poindexter s, birovljev s, et al. risk factors for development of accelerated coronary artery disease in cardiac transplant recipients. eur j cardiothorac surg. 1990;4:309-12; discussion 313. 12. vollmer e, bosse a, bogeholz j, et al. apolipoproteins and immunohistological differentiation of cells in the arterial wall of kidneys in transplant arteriopathy. morphological parallels with atherosclerosis. pathol res pract. 1991;187:957-62. 13. remuzzi g. cigarette smoking and renal function impairment. am j kidney dis. 1999;33:807-13. 14. oberai b, adams cw, high ob. myocardial and renal arteriolar thickening in cigarette smokers. atherosclerosis. 1984;52:185-90. 15. kaplan el, meier p. nonparametric estimation from incomplete observations. j am stat assoc 1958; 53: 45781. 16. gambaro g, verlato f, budakovic a, et al. renal impairment in chronic cigarette smokers. j am soc nephrol. 1998;9:562-7. 17. butkus de, meydrech ef, raju ss. racial differences in the survival of cadaveric renal allografts. overriding effects of hla matching and socioeconomic factors. n engl j med. 1992;327:840-5. 18. choiniere r, lafontaine p, edwards ac. distribution of cardiovascular disease risk factors by socioeconomic status among canadian adults. cmaj. 2000;162(9 suppl):s13-24. editorial comment to: impact of sexual activity on glycated hemoglo bin levels in patients with type 2 diabetes mellitus after penile prosthesis implantation mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specialized in urologi cal and andrological genetics,tehran, iran. e-mail: info@safarinejad.com the authors have addressed an important issue. congratulation! type 2 diabetes mellitus (dm) is a complex and multifactor metabolic disorder. one of the complications of type 2 dm is the sexual dysfunction, mainly in the form of erectile dysfunction in men. hemoglobin a 1c (hba 1c ) is an invaluable tool for watching long-term glycemic control in patients with dm. in present retrospective study the authors aimed to determine the relationship between sexual activity and serum levels of hba 1c with an inappropriate manner. as a result, the manuscript suffers from some important drawbacks. there are many confounding factors which can interfere with serum hba 1c concentration measurements. also, there are several situations in which the level of hba 1c may not loyally reflect the actual values. without adjusting for these confounding factors, the results might not be reliable. genetic variants (e.g. hbs trait, hbc trait), elevated fetal hemoglobin (hbf) and chemically altered derivatives of hemoglobin (e.g. carbamylated hb) all can affect the accuracy of serum hba 1c measurements. the impacts differ depending on the specific hb variant or derivative and the method used for serum hba 1c measurement. any disorder or illness that reduces erythrocyte survival or shortens mean erythrocyte age will falsely lower serum hba 1c test results irrespective of the laboratory method used.(1) hba 1c results from patients with hbss, hbcc, and hbsc must be interpreted with cautiousness given the pathological processes, including anemia, increased red blood cell turnover, and transfusion, that adversely affect serum hba 1c levels. other methods of measurement such as glycated serum protein or glycated albumin would be considered for these cases. there are some systemic disorders such as certain forms of dyslipidemia, malignancies, and cirrhosis which can affect the serum hba 1c concentrations. the iron deficiency anemia is a common condition which can lead to an increase in serum hba 1c level by 1% to 1.5%.(2) in agreement with that observation, iron replacement therapy decreases both serum hba 1c and fructosamine levels in individuals with or without dm.(3) also, any medical disorders or illnesses which are associated with changes in the relationship between mean glycemia and serum hba 1c concentration, can alter serum hba 1c levels too. the main disorders are those affecting red blood cells, comprising persistent fetal hemoglobin, hemoglobin s, c, or d, end stage renal disease, or diseases characterized by hemolysis or other conditions with decreased life span of red blood cells.(4) 1817 sexual dysfunction and fertility urology journal vol. 11 no. 04 july august 2014 1818 abetes registry. diabetes care. 2013;36:611-7. 6. pani ln, korenda l, meigs jb, et al. effect of aging on a1c levels in individuals without diabetes: evidence from the framingham offspring study and the national health and nutrition examination survey 2001 2004. diabetes care. 2008;31:1991-6. 7. harding ah, sargeant la, welch a, oakes s, et al. fat consumption and hba(1c) levels: the epic-norfolk study. diabetes care. 2001;24:1911 6. the hba 1c concentrations also have a quadratic association with sleep duration; namely, a shorter or longer sleep duration is associated with a higher level compared with a sleep duration of 6.5-7.4 h.(5) some of the factors that influence hba1c and its measurement are as below:(1-4) increased hba 1c : iron deficiency, vitamin b12 deficiency, decreased erythropoiesis, alcoholism, chronic renal failure, splenectomy, hyperbilirubinemia, carbamylated hemoglobin, large doses of aspirin, chronic opiate use, genetic heterozygous variants of hemoglobins s, c and e, medications, such as corticosteroids and antipsychotic agents, malaria, rheumatoid arthritis and increased serum triglyceride. decreased hba 1c : administration of erythropoietin, iron and vitamin b12, reticulocytosis, chronic liver disease, small doses of aspirin, vitamin c and e, certain hemoglobinopathies, splenomegaly, medications such as antiretrovirals, ribavirin and dapsone, acute and chronic blood loss, hemolytic anemia, hereditary persistence of hemoglobin f, genetic heterozygous variants of hemoglobins s, c and e and malnutrition. it has been demonstrated that older non-diabetic individuals have higher hba 1c values than younger subjects, being approximately 0.4% higher at 70 years than at 40 years,(6) even after adjusting for confounding factors. lower total fat intake is associated with lower hba 1c . saturated fat intake is positively associated with hba 1c .(7) finally, measurement method of hba 1c is fundamental. accurate and reliable methods to measure hba 1c are necessary for optimal use. the most widely adopted system is that of the national glycohemoglobin standardization program (ngsp). none of the above mentioned confounding factors have been addressed in this study. accounting for all of them is nearly impossible. but, it was very worthwhile if the study results have been put in multivariate regression analysis and adjusted for total energy intake, protein, alcohol use, age, family history of diabetes and physical activity. therefore, i believe that the results of the present study should be interpreted with caution. references 1. goldstein de, little rr, lorenz ra, malone ji, nathan d, peterson cm. american diabetes association technical review on tests of gly cemia. diabetes care. 1995;18:896-909. 2. sundaram rc, selvaraj n, vijayan g, bobby z, hamide a, rattina das se n. increased plasma malondialdehyde and fructosamine in iron defi ciency anemia: effect of treatment. biomed pharmacother. 2007;61:682 5. 3. coban e, ozdogan m, timuragaoglu a. effect of iron deficiency ane mia on the levels of hemoglobin a1c in nondiabetic patients. acta hae matol. 2004;112:126-8. 4. peacock tp, shihabi zk, bleyer aj et al. comparison of glycated albu min and hemoglobin a(1c) levels in diabetic subjects on hemodialysis. kidney int. 2008;73:1062-8. 5. ohkuma t, fujii h, iwase m, et al. impact of sleep duration on obesity and the glycemic level in patients with type 2 diabetes: the fukuoka di impact of sexual activity on hba 1c levels-talib et al reply by author as principal co-authors of this paper, we welcome the opportunity to respond to the editorial comments on our article. in editorial comment, it was mentioned that there are some genetic variants, systemic illnesses and disorders, which can affect the serum hemoglobin a 1c (hba 1c ) concentrations. our study was performed retrospectively and analyzed medical records from computer files of patients that underwent penile prosthesis implantation. we strongly agree with the comment and accept that serum hba 1c concentrations could be effected by some situations. however, hba 1c is the most commonly used test to examine long-term glycemic control in patients with diabetes mellitus. we also agree that adjusted results after getting information on diet and physical activity would make our study more powerful. as we pointed out in discussion section of our study, observational nature of our cohort, our findings must be interpreted within the context of the limitations applicable to observational, retrospective data. as mentioned in the editorial comment, it has been demonstrated that older non-diabetic individuals have higher hba 1c values than younger subjects. in our study, we compared the hba 1c results nearly 2 years (the mean time was 22.6 months) after the surgery of the same patients. we believe that this time period is insignificant and valid for every patients included in this study. 1819 sexual dysfunction and fertility sexual dysfunction and infertility the relation of enuresis and irritable bowel syndrome with premature ejaculation: a preliminary report mohammadreza barghi* department of urology, shohada-e-tajrish hospital, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: in this retrospective study, we reviewed the outpatient data of patients with premature ejaculation to investigate the association of that disorder with irritable bowel syndrome and a positive history of enuresis. materials and methods: all patients with premature ejaculation who had presented to the author's office from march 2002 to june 2003 were selected. their medical records were reviewed, and data including symptoms of irritable bowel syndrome, history of enuresis, and psychologic disorders were collected. the results of our analysis were compared with the worldwide reported prevalence of enuresis and irritable bowel syndrome in the male general population. results: forty-one consecutive patients were asked whether they had ever experienced irritable bowel syndrome, enuresis, psychologic problems, and/or the feeling of tickling or sexual pleasure at ejaculation. of those 41 patients, 18 reported the symptoms of irritable bowel syndrome (43.9% versus 10% in the general population; p < .001). a reliable answer about the history of enuresis was obtained from 35 patients, 14 of which had experienced that disorder (40% versus 10% in the general population; p < .001). of those 35 patients, 6 (17.4%) had experienced both irritable bowel syndrome and enuresis. twenty-two of 37 patients (59.5%) reported psychologic problems including stress, agitation, and obsession-compulsive disorder. conclusion: the results of this study suggest the association of premature ejaculation with irritable bowel syndrome and enuresis, which in turn may indicate that those disorders share a common neurologic pathophysiology. a special attention of the physicians to the symptoms of these diseases together may be of great help for the patients. key words: premature ejaculation, irritable bowel syndrome, enuresis 201 urology journal unrc/iua vol. 2, no. 4, 175-6 autumn 2005 printed in iran introduction premature ejaculation (pe) is a common problem with a prevalence reported to be as high as 35% in men.(1-3) although pe has in the past been attributed only to psychologic problems, the complete pathophysiologic mechanism of that disorder remains undefined.(1,4) however, the oversensitivity of the penis to stimulation (the effect of which can be controlled by using local anesthetic sprays or a condom) or the effectiveness of antidepressants in the treatment of pe suggests a central disorder as the cause.(1,4-8) received october 2004 accepted june 2005 *corresponding author: shohada-e-tajrish hospital, tajrish sq, tehran, iran. tel: ++98 21 2718001 e-mail: mbarghi@yahoo.com premature ejaculation, irritable bowel syndrome, and enuresis patients with irritable bowel syndrome (ibs) and enuresis also benefit from treatment with antidepressants,(9) and the oversensitivity of the organs targeted in those disorders suggests the pathophysiologic mechanism of the disease.(8) electrophysiologic studies have shown that an abnormal reaction of the penile skin to sensory stimulation and the resultant response of the central nervous system are characteristic of patients with pe.(4,8) the association of ibs with urinary disorders and pe, if based on a common mechanism for all 3 disorders, is reasonable,(8,10) although further research to confirm that theory is required. this review of outpatient data was performed to investigate the frequency of ibs and a positive history of enuresis in patients with pe. materials and methods in this retrospective study, all patients with pe who had presented to the author's office in tehran, from march 2002 to june 2003, were selected. their records were reviewed, and the following data were collected: symptoms of ibs, history of enuresis, mood and other psychologic disorders, a feeling of tickling or sexual pleasure in the frenulum at ejaculation, and the results of sensory examination of genitalia in which very gentle touches of the examiner's finger and a wisp of cotton were used to assess the patient's subjective perception of the sensitivity of the frenulum and glans as opposed to the abdominal skin. in this study, ibs was defined according to rome ii criteria,(11) which specifies that the patient must have experienced at least 3 months of continuous or recurrent abdominal pain or discomfort that is relieved by defecation and/or is associated with a change in the frequency or consistency of stool, plus 2 or more of the following symptoms that occur at least one-fourth of the time: altered stool frequency, form, or passage; the passage of mucus; and bloating or abdominal distention. enuresis was defined as bedwetting after the age of 3 years.(12) patients in whom a history of enuresis and ibs were not confirmed because of vague or unreliable answers were excluded from the data analysis. the prevalence of enuresis and ibs in general population are 10% and 10%, respectively.(8,13) the results of this study were compared with those statistics by means of z approximation. data analyses were performed with spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa). a p value of less than 0.05 was considered significant. results from among 1150 patients who presented for the treatment of urologic problems, 72 (6%) had experienced pe. the last 41 consecutive patients had been asked whether they had experienced symptoms of ibs, enuresis, a psychologic disorder, and/or the feeling of tickling or sexual pleasure at ejaculation. of those 41, 18 reported ibs (43.9% versus 10% in general population; p < .001). a reliable answer about the history of enuresis was obtained in 35 patients, and 14 of those responses were positive for the disorder (40% versus 10% in general population; p < .001). of the 35 patients who reported enuresis, 6 (17.4%) also reported ibs. twenty-two (59.5%) of 37 patients reported psychologic problems including stress, agitation, and/or obsessioncompulsion. thirty-three patients had properly answered the question about experiencing a state of sexual pleasure or a tickling sensation in the frenulum at ejaculation, and 17 (51.5%) of those responses were "yes." the response to touching the frenulum was stronger than that to touching the glans, penile shaft, or abdomen in 20 (54.1%) of 37 subjects, and 9 (24.3%) subjects reported that their response to touching the glans was stronger. discussion premature ejaculation is a prevalent problem(1,2) that elicits concern about impotence in men and can cause dissatisfaction in their sexual partner and conflict in that relationship.(1,3) the prevalence of pe is reported to be as high as 35% in some studies.(1,3,4) men without pe can usually voluntarily postpone ejaculation after penetration for a time sufficient to enable the orgasm of the sexual partner, but that control is absent or too weak in men with pe.(1,4) some individuals with pe ejaculate before sexual contact occurs, and as a result, an erection firm enough to enable intercourse cannot be sustained. achieving pregnancy may be difficult for some couples as a result.(1-3) various authors have defined pe as the inability to postpone ejaculation until the sexual partner's orgasm has occurred in at least 50% of 202 barghi sexual contacts involving penetration.(1,3) premature ejaculation is considered a primary disease if the patient has experienced episodes of the disorder during his first sexual encounters. premature ejaculation that begins after years of sexual activity may be caused by a urinary tract infection, conflict between partners, or neurologic disorders.(1,14) the presenting complaint of some patients with pe may be irrelevant; instead of addressing their sexual dysfunction, they may refer to the small size of their penis or a concern about prostate disease, infertility, or low-back problems.(1,14) the cause of pe was thought in the past to be psychologic in origin, and treatment protocols usually consisted of psychotherapy and antidepressant drugs.(1,4) the effectiveness of such therapy and the correlation of pe with psychologic stress have supported that approach.(1,5-7,9) however, recent studies and neurophysiologic investigations suggest that this disorder may have an organic cause. (4,9) the oversensitivity of the penis to touch and vibrating stimulation or the overactivity of ejaculation center in the brain as a result of stimulation of the patient's genitalia may contribute to pe. investigations with positron emission tomography have shown that the right prefrontal cortex (in contrast to other cortical areas) exhibits increased activity during orgasm. that phenomenon can be the cause of the activation of subcortical portions of the brain that potentiate ejaculation. thus dysfunction in the right prefrontal cortex and its impact on the subcortical area may be a cause of pe.(4,9,15) surprisingly, positron emission tomography has revealed that in patients with ibs, blood circulation increases in the prefrontal cortex in association with rectal distention, but in healthy individuals, blood circulation increases in the anterior cingulate gyrus when the rectum is distended. such hyperemia in the frontal lobe can cause increased alertness as a result of the activation of a vigilance network. it seems that the anterior cingulate gyrus and frontal lobe are mutually inhibitory, and the dysfunction of this system may cause increased afferent sense input from autonomic nervous system.(8,10) ibs, however, seems to be associated with sexual dysfunction caused by disease-related stress and depression, which in turn can potentiate erectile dysfunction and pe.(10) however, the association of ibs with sexual dysfunction remains unsupported by sufficient evidence, although mood disorders have been reported in about 80% of patients with ibs.(8) it has been also demonstrated that a low threshold of sensory neurons correlates with increased motility of the intestine and colon in patients with ibs.(8) there are also clues about the pathophysiology of enuresis and its association with pe. disorders in central nervous system, particularly that of pontine reticular formation, may cause a lack of awareness of bladder distention and may contribute to the dysfunction of pelvic floor sphincters,(6,16-19) which may cause, for example, the relaxation of bladder sphincters during sleep. furthermore, a delay in the maturation of sensory-motor neurons as well as cognitive dysfunction are prevalent in children with enuresis.(18,20,21) attention deficit and hyperactivity disorder and encopresis (10% to 25%) are also not uncommon in that pediatric population.(22) treatments of pe, ibs, and enuresis have similar features that address the common pathophysiologic characteristics of those disorders. opioids are effective in the treatment of pe as well as ibs and enuresis.(23,24) the effectiveness of using local anesthetics and condoms to suppress the sensory impulses from the penis to the central nervous system indicates an oversensitivity of the penile skin, a mechanism characteristic of enuresis and ibs.(1,25) drugs such as antidepressants(5-7) or behavioral conditioning methods such as frequent intercourse, step-by-step sexual contact, and/or compression of the penis(1,26) may be successful in treating pe. the methods described above affect the central nervous system. antidepressants and conditional methods are also useful in the treatment of enuresis,(9,10,27) and antidepressants may help to control ibs by suppressing neural waves from the intestine to the brain.(7-10) the elimination of some special foods from the daily diet of patients with ibs(28) and considering allergens and hypercalciuria as potential causes of enuresis(20,29,30) indicate that local sensory stimulation can influence ibs and enuresis. the results of this study are limited by a lack of retrospective design; the small, nonrandomized sample size; and the lack of confirmed diagnoses (especially in patients with concomitant psychologic problems), and as a result, the 203 premature ejaculation, irritable bowel syndrome, and enuresis association of ibs and/or enuresis with pe cannot be definitively established. nevertheless, the frequency of ibs, enuresis, and psychologic problems in subjects with pe was significant in our study, which suggests that those disorders share common pathophysiologic features. conclusion weak control of target organs by the cerebral cortex and the abnormally low threshold of sensory neurons in the intestine and genitalia may be responsible for the severe reaction of the central nervous system in patients with pe, ibs, or enuresis. it thus seems reasonable that patients with those characteristics would be susceptible to all 3 disorders. however, the association of pe with ibs and enuresis suggested in this study requires additional research. physicians who remain alert for the symptoms of those disorders and consider the possibility of a common pathophysiologic mechanism of action will provide great help for their patients so afflicted. references 1. wiese ac, mcgoal s. abakong for premature ejaculation. abakong institute for men's health. available from: http://www.abakong-for-prematureejaculation.com/ 2. laumann eo, gagnon jh, michael rt, michaels s. the social organization of sexuality: sexual practices in the united states. chicago: university of chicago press; 1994. p. 351-76. 3. masters wh, johnson ve. human sexual inadequacy. boston: little, brown; 1970. p. 16-9. 4. ozcan c, ozbek e, soylu a, yilmaz u, guzelipek m, balbay md. auditory event-related potentials in patients with premature ejaculation. urology. 2001;58:1025-9. 5. chia s. management of premature ejaculation -a comparison of treatment outcome in patients with and without erectile dysfunction. int j androl. 2002;25:301-5. 6. yilmaz u, tatlisen a, turan h, arman f, ekmekcioglu o. the effects of fluoxetine on several neurophysiological variables in patients with premature ejaculation. j urol. 1999;161:107-11. 7. kim sc, seo kk. efficacy and safety of fluoxetine, sertraline and clomipramine in patients with premature ejaculation: a double-blind, placebo controlled study. j urol. 1998;159:425-7. 8. oivyang c. irritable bowel syndrome. in: kasper dl, braunwald e, fauci as, hauser sl, longo dl, jameson al, editors. harrison's principles of internal medicine. 16th ed. new york: mcgrow-hill; 2005. p. 1789-93. 9. siomopoulos v, seneczko lo. heterocyclic antidepressants in nonpsychiatric disorders. am fam physician. 1984;29:203-8. 10. read n. more on proctalgia fugax. prof n archive. gr 36, january 2000. gut reaction. the ibs network. available from: http://www.ibsnetwork.org.uk/ gutreaction/gutreactionarcrea00.htm 11. hasler wl, owyang c. irritable bowel syndrome. in: yamada t, alpers dh, laine l, owyang c, powell dw, editors. textbook of gastroenterology. 3rd ed. philadelphia: lippincott williams and wilkins; 1999. p. 1884. 12. tanagho ea. disorders of the bladder, prostate, and seminal vesicles. in: tanagho ea, mcaninch jw, editors. smith's general urology. 15th ed. new york: lange medical books/mcgraw-hill; 2000. p. 648. 13. wille s. primary nocturnal enuresis in children. background and treatment. scand j urol nephrol suppl. 1994;156:1-48. 14. screponi e, carosa e, di stasi sm, pepe m, carruba g, jannini ea. prevalence of chronic prostatitis in men with premature ejaculation. urology. 2001;58:198-202. 15. tiihonen j, kuikka j, kupila j, et al. increase in cerebral blood flow of right prefrontal cortex in man during orgasm. neurosci lett. 1994;170:241-3. 16. tomasi pa, siracusano s, monni am, mela g, delitala g. decreased nocturnal urinary antidiuretic hormone excretion in enuresis is increased by imipramine. bju int. 2001;88:932-7. 17. norgaard jp, hansen jh, wildschiotz g, sorensen s, rittig s, djurhuus jc. sleep cystometries in children with nocturnal enuresis. j urol. 1989;141:1156-9. 18. hallioglu o, ozge a, comelekoglu u, et al. evaluation of cerebral maturation by visual and quantitative analysis of resting electroencephalography in children with primary nocturnal enuresis. j child neurol. 2001;16:714-8. 19. kohyama j, kumada s, shimohira m, araki s, itoh m, iwakawa y. nocturnal enuresis and the pontine reticular formation. eur urol. 2000;38:631-4. 20. husmann da. enuresis. urology. 1996;48:184-93. 21. mimouni m, shuper a, mimouni f, grunebaum m, varsano i. retarded skeletal maturation in children with primary enuresis. eur j pediatr. 1985;144:234-5. 22. hublin c, kaprio j, partinen m, koskenvuo m. nocturnal enuresis in a nationwide twin cohort. sleep. 1998;21:579-85. 23. eledjam jj, viel e, bassoul b, bruelle p. non-analgesic effects of opioids. cah anesthesiol. 1991;39:111-4. 24. corazziari e. role of opioid ligands in the ibs. can j gastroenterol. 1999;13:71-5. 25. berkovitch m, keresteci ag, koren g. efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation. j urol. 1995;154:1360-1. 26. master wh, johnson ve. principles of the new sex therapy. am j psychiatry. 1976;133:548-54. 204 barghi 27. steers wd, lee ks. depression and incontinence. world j urol. 2001;19:351-7. 28. zar s, kumar d, kumar d. role of food hypersensitivity in ibs. minerva med. 2002;93:403-12. 29. valenti g, laera a, gouraud s, et al. low-calcium diet in hypercalciuric enuretic children restores aqp2 excretion and improves clinical symptoms. am j physiol renal physiol. 2002 ;283:f895-903. 30. neveus t, hansell p, stenberg a. vasopressin and hypercalciuria in enuresis: a reappraisal. bju int. 2002;90:725-9. 205 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2042 case report a childhood case of solitary intrascrotal and extratesticular neurofibroma asaad moradi, babak kazemzadehazad* keywords: testicular neoplasms; diagnosis; neurofibroma; scrotum. introduction neurofibroma is a common benign tumor composed of neuromesenchymal tissue with residual nerve axons, which results from an abnormal overgrowth of schwann cells .they can be present anywhere on the body but it is rarely localized in scrotum.(1) they are usually skin-colored, soft or rubbery, nodular lesions, which may be pedunculated. it can be solitary lesions or multiple, and the multiple neurofibromas are usually classified as neurofibromatosis.(2) the diagnosis is usually confirm with histological examination.(3) this case is a 2 year-old patient who is the youngest case of the solitary intrascrotal and extratesticular neurofibroma has been reported in the english literatures, so far. case report a 2 year-old boy with a history of gradually enlarging painless mass in his left hemiscrotum since last year, referred to our hospital. there was no history of trauma and no familial history of von recklinghausen neurofibromatosis (figure 1). in physical examination the mass was soft, non-tender without transillumination. both testes were in the scrotum and normal in size. there wasn’t any evidence of inguinal lymphadenopathy. patient’s skin was normal and there was not any sign of classic neurofibromatosis in physical examination. serum alpha fetoprotein, beta human chorionic gonadotropin and lactic dehydrogenase were in normal range. ultrasonography demonstrated a soft tissue, measuring 4 cm × 6 cm located in the left hemiscrotum. it was solid, hypoecho with fatty pattern. left testis was in normal size. since there was not any evidence of intratesticular malignancy in physical examination and diagnostic tests including sonography and laboratory tests the patient was operated under general anesthesia through a scrotal incision (figure 2). the mass was completely excisable without any capsule and the tissue had low vascularity; left testis was normal and tunica albuginea was intact. the pathology was neurofibroma and fragments of fibro-fatty tissue with no tumoral involvement; no evidence of atypia or mitosis was present and composed of uniformly distributed spindle cells with wavy nuclei. the postoperative period was uneventful with no recurrence after 6 months of follow up (figure 3). discussion only 10 cases of solitary neurofibroma of scrotum (not in the neurofibromatosis 1 complex) have been reported so far;(4,5) which just 2 of them were in childhood and our case was the youngest of them. all of the reported cases in this area were extratesticular. as a rule, these tumors are not encapsulated and have soft consistency. microscopically, neurofibromas are formed by mixed proliferation of schwann’s cells (usually are department of urology, kermanshah university of medical sciences; imam reza hospital, kermanshah, iran. *correspondence: department of urology, kermanshah university of medical sciences; imam reza hospital, kermanshah, iran. tel: +98 083 34276301. fax: +98 21 22009941. e-mail: bab1412000@yahoo.com. received august 2014 & accepted january 2015. figure 1. the appearance of the tumor before surgery. figure 2. intraoperative appearance. the most cellular elements in the tumor), fibroblasts and perineural cells.(1) the reported cases are in wide range of age (8-77 years) and size.(5) most of the cases were a painless swelling mass in left hemiscrotum. in all of the reported cases, the tumor had good prognosis, and its complete excision has yielded good results with no recurrence. (3) in most of the reported cases, like ours, the exact origin of the tumor was unknown.(6) although, we know that the testis, vas-deferens and epididymis were intact. references 1. fikret erdemir, bekir süha parlaktas, nihat uluocak, et al. intrascrotal extratesticular neurofibroma: a case report. marmara med j. 2008;21:064-7. 2. shibano, shintaro, taro iguchi, tatsuya nakatani. a case of scrotal neurofibroma originating from subcutaneous neural tissue. int j urol. 2010:17:387-8. 3. issa mm, yagol r, tsang d. intrascrotal neurofibromas. urology. 1993;41:350-2. 4. hosseini mm, geramizadeh b, shakeri s, karimi mh. intrascrotal solitary neurofibroma: a case report and review of the literature. urol ann. 2012;4:119-21. 5. gupta s, gupta r, singh s, pant l. solitary intrascrotal neurofibroma: a case diagnosed on aspiration cytology. diagn cytopathol. 2011;39:843-6. 6. türkyilmaz z, sönmez k, karabulut r, et al. a childhood case of intrascrotal neurofibroma with a brief review of the literature. j pediatr surg. 2004;39:1261-3. figure 3. appearance of scrotum 6 months postoperatively. childhood solitary scrotal neurofibroma-kazemzadehazad et al case report 2043 1818.pdf 873vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l urology and nephrology research center; department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran abbas basiri, mohammad ali ghaed, nasser simforoosh, ali tabibi, abdolkarim danesh, akbar nouralizadeh, mehdi kardoust parizi is modified retroperitoneal lymph node dissection alive for clinical stage i non-seminomatous germ cell testicular tumor? corresponding author: mohammad ali ghaed, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir received december 2012 accepted may 2013 purpose: management of patients with pathological stage (ps) i non-seminomatous germ cell testicular tumor (nsgct) in a retrospective study. materials and methods: between april 2002 and april 2012, 55 patients with clinical stage (cs) plate. clinicopathological parameters, retroperitoneal relapse, and antegrade ejaculation rate were evaluated in patients with ps i. results: of 55 patients, 41 (74.5%) and 14 (25.5%) subjects were in ps i and ii, respectively. in ps i group, the mean patients’ age was 32.8 years (range, 19 to 51 years) at the end of the follow-up period. three patients missed the follow-up; hence, were excluded from the study. mean follow-up at the end of the follow-up period. overall peri and postoperative complication rate was 18% (7 patients). out of 38 patients, 23 (61%) had post rplnd antegrade ejaculation at the end of the study. conclusion: with no retroperitoneal micrometastasis after the procedure. furthermore, this strategy may obviate the need for close, expensive, and potentially harmful follow-up protocol in patients with ps i nsgct. keywords: lymph node excision, testicular neoplasms, neoplasm metastasis urological oncology 874 | introduction retroperitoneal lymph node dissection (rplnd) has been accepted as a diagnostic and therapeutic management for patients with non-seminomatous germ cell testicular tumor (nsgct).(1,2) conventional bilatboth the kidneys and the ureters down to the bifurcation of the common iliac arteries. this radical surgery may result in delayed restoration of the bowel function, prolonged hospital stay, and loss of antegrade ejaculation.(3) however, very low recurrence rate (less than 2%) after this bilateral procedure (4) nerve-sparing rplnd involves preservation of sympathetic latory morbidity is achieved and more than 95% of patients may have antegrade ejaculation. however, dissection along the aorta and inferior vena cava may result in vessel disruption.(3,5) to limit contralateral dissection and accompany with faster patients’ recovery and preservation of antegrade ejaculation. (5) the potential risk of recurrence, due to unresected retroperitoneal lymph nodes, is the major oncological concern (4) ported as an unacceptable procedure for clinical stage (cs) i nsgct.(4,6) agement of cs i nsgct. materials and methods from april 2002 to april 2012, a total of 55 patients with and no evidence of malignancy in the abdominopelvic computed tomography (ct) scan and chest x-ray (cxr) after initial orchiectomy. peutic purpose. all the lymph nodes above the contralateral inferior mesenteric artery as well as ipsilateral lymph nodes between the kidneys, ureters, and common iliac bifurcation were resected. post rplnd evaluation in patients with pathological stage (ps) i included blood tests (liver function test and serum levels of calcium, phosphorus, and alkaline phosphatase) and 4 to 6 months after rplnd and at the end of the follow-up period. patients with ps ii underwent post rplnd chemotherapy. (4,5) rplnd was assessed. descriptive statistics for clinical and demographic characteristics of the patients are mentioned in other articles. surgical technique all of the 55 patients were operated on according to the nodes between the kidneys, ureters, and common iliac bifurcations were resected except the contralateral lymph nodes below the inferior mesenteric artery. therefore, in patients with right-sided tumor, pre-aortic, para-aortic, paracaval, precaval, interaortocaval, and right common iliac lymph nodes were resected. in patients with left-sided tumor, pre-aortic, para-aortic, precaval, interaortocaval, and left common iliac lymph nodes were resected (figure). results of 55 patients, 41 (74.5%) and 14 (25.5%) subjects were categorized in ps i and ii, respectively. pathological stage neal lymph nodes after rplnd. the clinico-oncological outcomes were reviewed in patients with ps i. three patients urological oncology left and right modified retroperitoneal lymph node dissection template. 875vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l missed the follow-up, and were excluded from the study. the mean age of the patients was 32.8 years (range, 19 to 51 years) at the end of the follow-up period. only one patient had a known risk factor for testicular tumor (undescending testis in the same side of the tumor). table demonstrates clinicopathological characteristics of 38 patients with ps i. two laparoscopic surgeries needed conversion to open approach due to great vessels injury in one subject and severe peri-operative bleeding in another. overall peri and postoperative complication rate was 18% (7 patients). complications included great vessels injury, peri-operative bleeding, incision site infection, and retroperitoneal hematoma that all were managed conservatively. blood transfusion was needed in 3 patients due to postoperative hemoglobin drop. mean follow-up duration was 56 months (range, 6 to 120 the end of the follow-up period. all the patients had norrplnd abdominal ct and cxr at the end of the follow-up period. out of 38 patients, 23 (61%) had post rplnd antegrade ejaculation at the end of the study. discussion approximately, one-third of patients with nsgct present with cs i, and optimal treatment for these patients is controversial. various treatment modalities have been described, including surveillance, chemotherapy, and rplnd,(7-10) with (11) retroperitoneal lymph node dissection results in excellent oncological outcomes in cs i; however, patients may suffer from surgical complications and loss of antegrade ejaculation.(12) rplnd and surveillance, it seems that surveillance should be performed in low-risk patients. long-term follow-up in patients who undergo surveillance strategy requires more patients’ compliance, greater expenses, and more x-ray exposure.(6) surgical management of retroperitoneal lymph nodes information and also therapeutic advantages.(5) in the present study, incidence of retroperitoneal micrometastasis in patients with cs i nsgct was 25.5% (14 patients) that was consistent with other studies.(13) this relatively high clinicopathological characteristics of 38 patients with stage i non-seminomatous germ cell testicular tumor at orchiectomy and modified rplnd. variables increased serum tumor marker before orchiectomy, n (%) alpha fetoprotein beta-human chorionic gonadotropin lactate dehydrogenase primary testicular tumor side, n (%) right left maximum testicular tumor size (range), mm orchiectomy pathology, n (%) pure teratoma pure yolk sac pure choriocarcinoma pure embryonalcarcinoma mixed germ cell (containing embryonalcarcinoma) mixed germ cell (without embryonalcarcinoma) rplnd type, n (%) open laparoscopy laparoscopy converted to open mean operative time (range), min peri and postoperative complications, n (%) great vessel injury visceral injury peri-operative bleeding myocardial infarction cerebrovascular accident deep venous thrombosis incision site infection retroperitoneal hematoma cheiloascitis acute renal failure pulmonary thromboemboli total mean serum hemoglobin before rplnd (range), mg/ dl mean serum hemoglobin one day after rplnd (range), mg/dl blood transfusion, n (%) mean hospitalization (range), day mean total number of dissected lymph nodes (range) mean follow-up duration (range), month postoperative antegrade ejaculation, n (%) 28 (73) 21 (55) 9 (23) 18 (47) 20 (53) 44 (15 to 98) 2 (5) 2 (5) 0 (0) 5 (13) 25 (66) 4 (11) 3 (8) 33 (87) 2 (5) 237 (80 to 470) 2 (5) 0 (0) 1 (3) 0 (0) 0 (0) 0 (0) 2 (5) 2 (5) 0 (0) 0 (0) 0 (0) 7 (18) 14.9 (9.5 to 7.5) 13.4 (10 to 16) 3 (8) 3.6 (2 to 7) 15.2 (1 to 38) 56 (6 to 120) 23 (61) rplnd indicates retroperitoneal lymph node dissection; and ps, pathological stage. modified rplnd in stage i nsgct | basiri et al 876 | ment of cs i nsgct. in order to reduce potential complicomparable oncological outcomes and acceptable complicaresecting all retroperitoneal lymph nodes noted in bilateral infrahilar regions except below the inferior mesenteric artery of contralateral side. urologists face with two questions. one, does this technique sible surgical complications and improve antegrade ejaculation? several investigators have reported various recurrence rates with cs i nsgct.(7,14) katz and eggener believe that higher cancer recurrence rate and more additional therapy are poten(2) were evaluated in 500 patients with cs i and ii nsgct (364 and 136 patients, respectively), including testicular tumor study group template (ttsg), indiana template, memorial sloan-kettering cancer center template (mskcc), innsbruck template, and johns hopkins university template (jhu).(5) 0% (mskcc and indiana) to 5% (jhu and innsbruck) extra template relapse rates were reported in cs i. post rplnd lymph node positive rates of 58% and 42% were reported in cs i and ii, respectively. it was concluded that retroperitotemplate, and this metastasis may contain chemoresistant teratoma. this study reported different extra template retrorplnd techniques (3% versus 23%, respectively). furthermore, extra template retroperitoneal relapse was nearly for such patients (mean of 54 months). this study demonstrated that absence of positive lymph nodes in mskcc roperitoneal relapse rates of 0% and 5%, respectively. the authors concluded that maximum oncological outcomes (less regional lymph node dissection. despite no extra template recurrence in patients with negative malignant intra template lymph nodes in eggener and associates’ study,(5) it seems that rplnd in such cases. management of 85 patients with cs i nsgct. according to his study, no intra template recurrence was noted and only one extra template retroperitoneal recurrence was detected. (14) for cs i nsgct. however, mean follow-up of 3 years does not seen enough for cancer control. patients with cs i nsgct and noted relapse rate of 15% and post rplnd antegrade ejaculation rate of 85% at the end of the 5-year follow-up period. although disease recurred in 14.5% of patients with ps i, no patient had intra or extra template retroperitoneal recurrence (all recurrences occurred in the liver or lung).(15) the unilateral retroperitoneal template in this study was limited and smaller than our sloan-kettering template. in our study, no subjects needed re-operation due to severe complications, and no mortality occurred as a result of operaa favorable factor that may prevent expensive and long-term possible harmful follow-up. one of the limitations of this study is the small sample size (41 patients), which decreases the power of study. therefore, further studies with greater sample size are recommended. conclusion the management of cs i nsgct, and may be considered as this strategy may obviate the need for close, expensive, and potentially harmful follow-up protocol in patients with ps i nsgct. conflict of interest none declared. urological oncology 877vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l modified rplnd in stage i nsgct | basiri et al references 1. tarin t, carver b, sheinfeld j. the role of lymphadenectomy for testicular cancer: indications, controversies, and complications. urol clin north am. 2011;38:439-49, vi. 2. katz mh, eggener se. the evolution, controversies, and potential pitfalls of modified retroperitoneal lymph node dissection templates. world j urol. 2009;27:477-83. 3. liu zw, zhou fj, han h, et al. [efficacy of modified retroperitoneal lymph node dissection for testicular nonseminomatous germ cell tumors]. ai zheng. 2008;27:1302-6. 4. stephenson aj, aprikian ag, gilligan td, et al. management of low-stage nonseminomatous germ cell tumors of testis: siu/icud consensus meeting on germ cell tumors (gct), shanghai 2009. urology. 2011;78:s444-55. 5. eggener se, carver bs, sharp ds, motzer rj, bosl gj, sheinfeld j. incidence of disease outside modified retroperitoneal lymph node dissection templates in clinical stage i or iia nonseminomatous germ cell testicular cancer. j urol. 2007;177:937-42; discussion 42-3. 6. stephenson aj, sheinfeld j. management of patients with low-stage nonseminomatous germ cell testicular cancer. curr treat options oncol. 2005;6:367-77. 7. stephenson aj, bosl gj, motzer rj, et al. retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. j clin oncol. 2005;23:2781-8. 8. nicolai n, miceli r, artusi r, piva l, pizzocaro g, salvioni r. a simple model for predicting nodal metastasis in patients with clinical stage i nonseminomatous germ cell testicular tumors undergoing retroperitoneal lymph node dissection only. j urol. 2004;171:172-6. 9. pizzocaro g, zanoni f, salvioni r, milani a, piva l, pilotti s. difficulties of a surveillance study omitting retroperitoneal lymphadenectomy in clinical stage i nonseminomatous germ cell tumors of the testis. j urol. 1987;138:1393-6? 10. cullen mh, stenning sp, parkinson mc, et al. short-course adjuvant chemotherapy in high-risk stage i nonseminomatous germ cell tumors of the testis: a medical research council report. j clin oncol. 1996;14:1106-13. 11. schmoll hj, souchon r, krege s, et al. european consensus on diagnosis and treatment of germ cell cancer: a report of the european germ cell cancer consensus group (egcccg). ann oncol. 2004;15:1377-99. 12. baniel j, foster rs, rowland rg, bihrle r, donohue jp. complications of primary retroperitoneal lymph node dissection. j urol. 1994;152:424-7. 13. huddart ra, birtle aj. recent advances in the treatment of testicular cancer. expert rev anticancer ther. 2005;5:12338. 14. richie jp. clinical stage 1 testicular cancer: the role of modified retroperitoneal lymphadenectomy. j urol. 1990;144:1160-3. 15. pizzocaro g, salvioni r, zanoni f. unilateral lymphadenectomy in intraoperative stage i nonseminomatous germinal testis cancer. j urol. 1985;134:485-9. 1673vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l is the double dose alpha-blocker treatment superior than the single dose in the management of patients suffering from acute urinary retention caused by benign prostatic hyperplasia? önder kara,1 merve yazici2 corresponding author: önder kara, md department of urology, hacettepe university school of medicine, 06100 ankara, turkey. tel: +90 533 237 4067 e-mail: onerkara@yahoo.com received february 2014 accepted april 2014 1 department of urology, hacettepe university school of medicine, 06100, ankara, turkey. 2 department of anesthesiology and reanimation, ankara university school of medicine, 06100, ankara, turkey. purpose: to compare the efficacy and safety of single (tamsulosin) and double dose (tamsulosin + alfuzosin) alpha-blocker therapy for treating catheterized patients with acute urinary retention (aur) due to benign prostatic hyperplasia (bph). materials and methods: seventy patients with aur due to bph were catheterized and randomized into two groups: the single dose group (0.4 mg tamsulosin, 35 patients) and the double dose group (0.4 mg tamsulosin + 10 mg alfuzosin, 35 patients). the catheter was removed after 3 days, and the patients were put on trial without catheter (twoc). results: seventy males (mean age, 71.2 years) were randomly assigned to receive double or single dose alpha-blocker (35 patients per group). the intent-to-treat population consisted of 70 males. twenty-seven individuals in the double dose group and 19 in the single dose group did not require re-catheterization on the day of the twoc (77% and 54%, respectively; p = .003). success using free-flow variables was also higher in the males who received double dose alpha-blocker compared with single dose therapy (48% vs. 40%; p = .017). conclusion: twoc was more successful in males treated with double dose alpha-blockers, and the subsequent need for re-catheterization was also reduced. the side-effect profiles were similar in the single and double dose alpha-blocker groups and were consistent with the known pharmacology. these results state that double dose alpha-blocker treatment can be recommended for treating males after catheterization for aur, which may reduce the need for re-catheterization. keywords: acute disease; administration; oral; prostatic hyperplasia; drug therapy; treatment outcome; urinary retention; adrenergic alpha-1 receptor antagonists. miscellaneous 1674 | miscellaneous introduction benign prostatic hyperplasia (bph) is one of the most common urinary disorders in elderly males.(1) the symptoms of bph include impaired physiological and functional well-being, which interferes with daily living.(2) although bph is rarely life-threatening, acute urological complications such as acute urinary retention (aur) can occur, which is considered to be the most serious complication with the progression of bph.(3) aur is particularly painful and distressing for the patient and has considerable economic costs.(4) early estimates of the incidence of aur varied widely, but recent population-based studies suggested an incidence of 5-25 per 1000 personyears or 0.5-2.5% per year.(5) however, the risk of aur is cumulative and increases with age. aur is one of the primary indications for transurethral resection of prostate (turp). a large study mentions that the risk of an aur at 23% for a 60 years old man if he lived for another 20 years.(6) after spontaneous aur, 15% patients in a long-term study experienced an additional episode of aur, and 75% underwent subsequent surgery.(7) the initial intervention for aur is the insertion of a urinary catheter to relieve the symptoms.(8) in addition to being uncomfortable for the patient, this is an avoidable risk factor for blood loss after turp if surgical intervention is necessary.(9) therefore, a trial without catheter (twoc) is preferable compared with leaving the catheter in place, and a 23-28% success rate has been reported. (10,11) nevertheless, most patients still require turp, either as an emergency or elective surgery. alpha-1 (α1)-blockers decrease smooth muscle tone in the prostate, thereby rapidly improving urinary symptoms and flow. currently available α1-blockers include the selective α1-blockers terazosin, doxazosin and alfuzosin and the highly selective α1a-blocker tamsulosin. these agents have comparable efficacy, and the major differences between these agents are their tolerability profiles.(12) by decreasing the resistance, α1-blockers can help relieve aur and improve the chances of successful twoc.(13) however, the optimum duration of therapy has not been fully assessed, and there is controversy regarding the length of time a catheter should remain in situ during the initial therapeutic phase. this study aimed to compare the efficacy of modified release single (0.4 mg daily tamsulosin hydrochloride) and double dose (tamsulosin + alfuzosin) combination therapy for the management of patients with aur who were suitable for twoc. materials and methods between 2008 and 2013, 70 males aged 48-85 years (mean, 71.2 years) were enrolled in the study. thirty-five patients received single dose α-blocker therapy with a modifiedrelease tamsulosin hydrochloride capsule (0.4 mg), and the remaining 35 received double dose combination therapy comprising modified-release tamsulosin hydrochloride (0.4 mg) and alfuzosin hydrochloride (10 mg), consumed daily in the tablet form. all patients were admitted to the urology and emergency department of the hospital for aur and had been catheterized in the previous 72 h. before catheterization and therapy, informed consent was received from all patients. males with initial catheterization volumes off > 1500 or < 500 ml were excluded from the study. other exclusion criteria included, evidence of renal or hepatic dysfunction, previous urinary tract surgery, neurogenic or other diseases of the bladder, upper urinary tract diseases such as uremia, any malignancy or the use of retention-enhancing medications. the study received ethics committee approval and conformed to the international guidelines for clinical trials. it was performed according to the declaration of helsinki, and all patients provided written informed consent. the duration between catheterization and the initial dose of medication was 72 h. in the single-dose group, a 0.4-mg figure . successful trial without catheter in each study group. 1675vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l double dose alpha-blocker treatment in bph | kara et al tamsulosin hydrochloride tablet was administered once daily before bed. in contrast, in the double-dose group, a 10-mg alfuzosin hydrochloride tablet was administered daily after breakfast, and 0.4-mg tamsulosin hydrochloride tablet once daily before bed. the duration of therapy was determined at the physician’s discretion (three or eight doses) according to their normal practice. patients were allowed to return home after a successful catheter-free void (flow rate of > 5 ml/s, a voided volume of > 100 ml and residual volume of 200 ml). in the absence of any internationally agreed outcome measures, investigators regarded a successful twoc as effective bladder emptying. patients were observed weekly (flow rate, ultrasound) and they could continue to consume medications for up to 36 weeks, but if re-catheterization was required (residual volume of > 200 ml) they were withdrawn from the study. results the mean age of patients in the singleand double-dose groups was 69.4 ± 8.8 and 72.2 ± 8.5 years, respectively, and the initial catheterization volumes recorded were 673.2 ± 80.3 and 723.7 ± 90.7 ml. therefore, these parameters were comparable between groups. single (tamsulosin) and double dose (tamsulosin + alfuzosin) therapies resulted in successful twoc in 54% (19/35) and 77% of (27/35) patients, respectively. twenty-seven individuals in the double dose group and 19 in the single dose group did not require re-catheterization on the day of the twoc (77% and 54%, respectively; p = .003) (figure). pre-determined criteria for defining a successful twoc revealed no significant benefits of double-dose therapy compared with single-dose therapy (42% vs. 31%, respectively, p = .175; table). however, secondary analysis of study data using two free-flow criteria revealed that double-dose α-blocker therapy resulted in a significantly better outcome compared with single-dose therapy (table). both single and double dose α-blockers were well tolerated. a common adverse effect reported in the double-dose group was dizziness (8.7% vs. 6.5% in the single-dose group). headache was the most common adverse effect in the double-dose group (11.4% vs. 9.3% in the single-dose group). moreover, retrograde ejaculation was reported in 13.4% and 11.7% of patients receiving double and single doses, respectively. none of the differences in adverse events between the single and double dose groups were statistically significant, and no severe hypotension event is recorded in each group that requires the discontinuation of therapy. discussion bph is a progressive disease that is primarily characterized by the deterioration of symptoms over time, the incidence of serious complications such as aur and the need for bph-related surgery in some patients.(14) aur is a common urological emergency that is characterized by the sudden and painful inability to pass urine. the incidence of aur in patients with bph varies widely from 0.4% to 25%.(15) the management of aur requires bladder decompression, usually through a urethral catheter. until recently, subsequent management almost exclusively comprised prostatic surgery within a few days (emergency surgery) or a few weeks (elective surgery) after the first aur episode. however, increased morbidity and mortality associated with emergency surgery and the potential morbidity associated with prolonged catheterization have led to an increased use of twoc. this involves catheter removal after 1-3 days, which allows the patient to void in 23-40% cases. surgery, if table 3. difference of related indicators among 2 or more than 2 groups. criteria double dose alpha-blocker group single dose alpha-blocker group total p number of patients 35 35 70 primary analysis* 14 (42) 11 (31) 25 (35) .175 any two free-flow criteria 17 (48) 14 (40) 31 (44) .017 two specified criteria** 22 (62) 18 (51) 40 (57) .035 any two criteria† 24 (68) 20 (57) 44 (62) .028 * primary analysis included three criteria: flow rate > 5 ml/s, voided volume > 100 ml and residual urine volume 200 ml. **flow rate > 5 ml/s and voided volume > 100 ml. †flow rate > 5 ml/s, voided volume > 100 ml and residual urine volume 250 ml. 1676 | miscellaneous required, can then be planned at a later stage in patients with unsuccessful twoc.(7) the primary objective of the present study was to evaluate the efficacy of tamsulosin compared with tamsulosin + alfuzosin for the management of catheterized patients with aur caused by bph by comparing the number of patients voiding successfully after catheter removal. the pre-determined primary criteria for defining a successful twoc revealed significant beneficial effects of double-dose α-blocker therapy. furthermore, the success rate of twoc with tamsulosin (54%) was comparable to previous observations by lucas and colleagues(16) and hua and colleagues,(17) who reported success rates of 48% and 61%, respectively. double dose α-blocker therapy resulted in a 77% success rate of twoc in our study. in addition, it was well tolerated and resulted in outcomes that were superior to those previously reported: 55% by mcneill and colleagues(18) 61.3% by gopi and colleagues(19) and 61.9% by mcneill and colleagues.(20) however, these outcomes were obtained using single-dose alfuzosin therapy. moreover, in a systematic review of metaanalysis group assessing the role of alfuzosin, tamsulosin, silodosin, doxazosin compared with placebo for twoc in patients with aur due to bph have been reported. compared to 38.9% (161/414) in control groups 56.8% (362/637) of patients receiving a1-blockers had a successful twoc.(21) the success rates were similar with our single dose tamsulosin group (56.8-54%). to the best of our knowledge, the present study is one of only a small number of prospective randomized trials performing a head-to-head comparison between singleand double-dose α-blocker therapies for twoc in aur. the common adverse events included hypotension, dizziness, and retrograde ejaculation. for drug related adverse events the results were statistically insignificant between two groups. in our study adverse events were low and comparable across studies which are made with selective α1blockers.(16-18,20,22-26) conclusion in males catheterized for aur, previous studies revealed that twoc was more successful when treated with alfuzosin or tamsulosin compared with placebo. in addition, our study suggests that, compared with single-dose therapy, double dose α-blocker therapy with alfuzosin and tamsulosin was well tolerated and improved the twoc success rates in patients with aur. conflict of interest none declared. references 1. kumar vl, dewan s. alpha adrenergic blockers in the treatment of benign hyperplasia of the prostate. int urol nephrol. 2000;32:67-71. 2. girman cj, epstein rs, jacobsen sj, et al. natural history of prostatism: impact of urinary symptoms on quality of life in 2115 randomly selected community men. urology. 1994;44:825-31. 3. hartung r. do alpha-blockers prevent the occurrence of acute urinary retention? eur urol. 2001;39(suppl. 6):13-8. 4. puppo p. long-term effects on bph of medical and instrumental therapies. eur urol. 2001;39(suppl 6):2-6. 5. roehrborn cg. the epidemiology of acute urinary retention in benign prostatic hyperplasia. rev urol. 2001;3:187-92. 6. jacobsen sj, jacobson dj, girman cj, et al. natural history of prostatism: risk factors for acute urinary retention. j urol. 1997;158:4817. 7. roehrborn cg, bruskewitz r, nickel gc. urinary retention in patients with bph treated with finasteride or placebo over 4 years. characterization of patients and ultimate outcomes. the pless study group. eur urol. 2000;37:528-36. 8. stamatiou k. management of benign prostatic hypertrophyrelated urinary retention: current trends and perspectives. urol j. 2009;6:237-44. 9. eimalik em, ibrahim ai, gahli am, saad ms, bahar ym. risk factors in prostatectomy bleeding: preoperative urinary infection is the only reversible factor. eur urol. 2000;37:199-204. 10. taube m, gajraj h. trial without catheter following acute retention of urine. br j urol. 1989;63:180-2. 11. murray k, massey a, feneley rc. acute urinary retention-a urodynamic assessment. br j urol. 1984;56:468-73. 12. montorsi f, moncada i. safety and tolerability of treatment for bph. eur urol suppl. 2006;5:1004-12. 13. mcneill sa. does acute urinary retention respond to alpha-blockers alone? eur urol. 2001;39(suppl 6):7-12. 14. emberton m. definition of at-risk patients: dynamic variables. bju int. 2006;97:12-5. 15. fitzpatrick jm, kirby rs. management of acute urinary retention. bju int. 2006;97:16-20. 16. lucas mg, stephenson tp, nargund v. tamsulosin in the management of patients in acute urinary retention from benign prostatic hyperplasia. bju int. 2005;95:354-7. 1677vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l 17. hua lx, wu hf, sui yg, chen sg, xu zq, zhang w. tamsulosin in the treatment of benign prostatic hyperplasia patients with acute urinary retention. zhonghua nan ke xue. 2003;9:510-1. 18. mcneill sa, daruwala pd, mitchell id, shearer mg, hargreave tb. sustained-release alfuzosin and trial without catheter after acute urinary retention: a prospective, placebo-controlled. bju int. 1999;84:622-7. 19. gopi ss, goodman cm, robertson a, byrne dj. a prospective pilot study to validate the management protocol for patients presenting with acute urinary retention: a community-based, nonhospitalised protocol. scientificworldjournal 2006;6:2436-41. 20. mcneill sa, hargreave tb, roehrborn cg. alfuzosin 10 mg once daily in the management of acute urinary retention: results of a double-blind placebo-controlled study. urology. 2005;65:83-9. 21. jun dg, bin gf, bo jx. a1-blockers in the management of acute urinary retention secondary to benign prostatic hyperplasia: a systematic review and meta-analysis. ir j med sci. 2014 mar 6. [epub ahead of print] 22. agrawal ms, yadav a, yadav h, singh ak, lavania p, jaiman r. a prospective randomised study comparing alfuzosin and tamsulosin in the management of the patients suffering from acute urinary retention caused by benign prostatic hyperplasia. indian j urol. 2009;25:474-8. 23. kumar s, tiwari dp, ganesamoni r, et al. prospective randomised placebo controlled study to assess the safety and efficacy of silodosin in the management of acute urinary retention. urology. 2013;82:171-5. 24. maldonado-avila m, manzanilla-garcia ha, siearra-ramirez ja, et al. a comparative study on the use of tamsulosin versus alfuzosin in spontaneous micturition recovery after transurethral catheter removal in patients with benign prostatic growth. int urol nephrol. 2014;46:687-90. 25. prieto l, romero j, lópez c, ortiz m, pacheco jj. efficacy of doxazosin in the treatment of urinary retention due to benign prostate hyperplasia. urol int. 2008;81:66-71. 26. tiong hy, tibung mj, macalalag m, li mk, consigliere d. alfuzosin 10 mg once daily increases the chances of successful trial without catheter after acute urinary retention secondary to benign prostate hyperplasia. urol int. 2009;83:44-8. double dose alpha-blocker treatment in bph | kara et al case report rapidly progressing malignant epithelioid renal angiomyolipoma: a case report seong whi cho,1 hyuck jae choi,1* seunkoo lee1 keywords: angiomyolipoma; diagnosis; differential; complications; kidney neoplasms. introduction typical angiomyolipoma (aml) is a benign neoplasm, which consists of a mixture of smooth muscle, fat, ab-normal blood vessels, and perivascular epithelioid cells, the latter of which have been described to be present in varying proportions.(1) recent reports have described renal masses comprised almost entirely of perivascular epithelioid cells and have designated them as “monotypic epithelioid angiomyolipomas (eamls)” or “renal epithelioid oxyphilic neoplasms”,(2,3) which are potentially malignant.(4) it has also been reported eaml sometimes exhibits aggressive growth, rupture, metastasis, or local recurrence.(5-7) here, we report a case of rapidly progressing eaml. 1 department of radiology, kangwon national university hospital, chuncheon, korea. 2 department of anatomic pathology, kangwon national university hospital, chuncheon, korea. *correspondence: department of radiology, kangwon national university hospital, 156 baengnyeong-ro, chuncheon 200722, korea. tel: +82 33 2582479. fax: +82 33 2582120. e-mail: choihjmd@gmail.com. received september 2015 & accepted february 2016 figure 1. a 47-year-old woman with malignant epithelioid angiomyolipoma. a) precontrast-axial computed tomography image showing an 11 cm sized isoattenuating solid mass in the left kidney interpolar area. note the subtle low-attenuated lesion (asterisk) in the central portion of the mass suggesting hemorrhage or necrosis; b) contrast-enhanced axial computed tomography image showing a moderately enhancing solid mass in the left kidney interpolar area. the mass involved renal pelvis (arrowheads) and contained a hypoattenuating area suggesting hemorrhage or necrosis (asterisk). the image also depicted a hypoattenuated lesion in the left renal vein suggestive of renal vein thrombosis; c) unenhanced axial t2-weighted (4000/110) image shows an isointense mass (relative to liver) in the interpolar area of the left kidney. foci of hyperintensity (arrowheads) were also observed in the central portion on t2-weighted images possibly representing necrosis or hemorrhage; d) out of phase coronal t1-weighted (450/10) precontrast image showing an isointense solid mass (relative to liver) in the left kidney. focal hyperintense lesions without signal drop (arrowheads), possibly due to hemorrhage, were also noted. figure 2. t1-weighted (450/10) postcontrast image showing a moderately enhancing solid mass in the left kidney interpolar area. the mass contained a non-enhancing hypointense area in its central portion suggestive of hemorrhage or necrosis (asterisk), and a non-enhancing filling defect was observed in the left renal vein suggestive of renal vein thrombosis (arrowheads). case report 2653 vol 13 no 02 march-april 2016 2654 case report a 47-year-old woman was referred for the evaluation of acute left abdominal pain. the patient had no history of tuberous sclerosis, and had no abnormal findings during a routine hematological workup or by urine analysis. a more thorough physical examination revealed a large palpable mass in the left abdomen. precontrast computed tomography (ct) scan showed an isoattenuated mass (versus the liver) with a hypoattenuated portion in the interpolar area of the right kidney (figure 1a). postcontrast ct depicted a well demarcated, heterogeneously enhancing, necrotic mass with renal vein thrombosis (figure 1b). the mass was of isosignal intensity versus the liver on t2-weighted images (figure 1c), and no detectable signal drop was observed on out-of phase chemical shift magnetic resonance (mr) images (figure 1d). dynamic enhanced mr images with fat suppression revealed heterogeneous enhancement and a necrotic portion (figure 2). based on these findings, renal cell carcinoma with renal vein thrombosis was diagnosed preoperatively. resultantly, left nephrectomy and retroperitoneal lymph node dissection were performed. on gross examination, the tumor was a gray, solid, expansible, 10.7 × 10 × 7.5 cm sized mass (figure 3) with necrosis and hemorrhage. in addition, adhesion between the tumor and perirenal fat and renal vein thrombosis were observed. permanent pathologic evaluation determined the left renal tumor to be eaml comprised mainly of epithelioid cells. tumor cells were cytologically malignant and exhibited marked pleomorphism and atypical mitotic figures. typical aml was observed in less than 5% of the mass. no fat component was seen in the typical aml portion, and more than 80% of the mass was necrotic. immunohistochemical findings were positive for anti-gp100 (hmb)-45, vimentin, α-smooth muscle actin, and cd-10, and negative for cytokeratin. one month after surgery, the patient presented with an abnormal liver function test (increased alkaline phosphatase, aspartate aminotransferase, and alanine transaminase), and a postcontrast ct scan and ultrasonography guided biopsies demonstrated the presence of multiple liver metastases, which were histopathologically confirmed as eaml. discussion aml arises mainly in the kidney and usually follows a benign course. aml can usually be diagnosed based on the radiologic detection of fat in the mass. however, it can sometimes be difficult to detect fat in a renal mass radiologically,(8) because intratumoral hemorrhage obscures fat, little fat is present(9) or because the mass represents renal cell carcinoma or potentially malignant eaml.(10) these latter possibilities are of clinical importance because they have substantially more severe clinical courses. eaml is a recently recognized variant of aml characterized by the presence of epithelioid cells(2,3) and its diagnosis is difficult as mature adipose tissue is not evident in this tumor. in fact, some cases of eaml have been misdiagnosed as renal cell carcinoma.(11) however, hmb45 is positive in sarcomatoid renal cell carcinoma, renal sarcoma, and in eaml.(12) in our case, hmb45 was positive which is a specific indicator of renal eaml. although several authors have discussed the appearance of eaml on ct scans, a correct preoperative diagnosis can only be achieved by pathologic examination. on ct scans these tumors appear as solid renal masses with or without a necrotic center and with accompanying metastases to a lymph node or another abdominal organ.(10,13) vanderbrink and colleagues reported a case of eaml with an enhancing element,(14) but to the best of our knowledge no report has been issued on the mri findings or out-of-phase chemical shift mri characteristics of eaml. in a previous study, eaml demonstrated invasion, recurrence, and metastasis, but poor prognoses were rare. (5-7,14) the renal mass in our patient showed peripheral enhancement with central low attenuation, suggesting necrosis, and there was no evidence of fat. these findfigure 3. photograph shows the solid renal mass with yellowish necrosis and reddish hemorrhage. note the mass invaded the renal sinus (arrow). giant vesicoprostatic calculi-goumas et al. ings are not consistent with the typical imaging findings of aml or aml with minimal fat and suggest the possibility of malignancy. in addition, our patient showed renal vein thrombosis on ct and mr images, which raised level of suspicion for renal cell carcinoma. conclusions the radiologic differentiation of eaml and renal cell carcinoma appears difficult, but whenever a solid renal mass with a necrotic portion and no fat component is encountered, even if accompanied by renal vein thrombosis, the possibility of malignancy should be considered and eaml included in the differential diagnosis. acknowledgments this study was supported by the national research foundation of korea funded by the korean government (grant no. 220090083512). conflict of interest none declared. references 1. fetsch pa, fetsch jf, marincola am, travis w, batts kp, abati a. comparison of melanoma antigen recognized by tcells (mart-1) to hmb-45: additional evidence to support a common lineage for angiomyolipoma, lymphangiomyomatosis, and clear cell sugar tumor. mod pathol. 1998;11:699-703. 2. pea m, bonettie f, martignonig, henske ep, manfrin e, colato c, bernstein j. apparent renal cell carcinomas in tuberous sclerosis are heterogeneous. am j surg path. 1998;22:1807. 3. eble jn, amin mb, young rh. epithelioid angiomyolipoma of the kidney: a report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component. am j surg pathol. 1997;21:112330. 4. cibas es, goss ga, kulke mh, demetri gd, fletcher cd. malignant epithelioid angiomyolipoma of the kidney: a case report and review of the literature. am j surg pathol. 2001;25:121-6. 5. pea m, bonetti f, martignoni g. apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. am j surg pathol. 1998;22:180-7. 6. varma s, gupta s, talwar j. renal epithelioid angiomyolipoma: a malignant disease. j nephrol. 2010;24:18-22. 7. tan g, liu l, qiu m, chen l, cao j, liu j. clinicopathologic features of renal epithelioid angiomyolipoma: report of one case and review of literatures. int j clin exp pathol. 2015;8:1077-80. 8. hélénon o, merran s, paraf f, et al. unusual fatcontaining tumors of the kidney. a diagnostic dilemma. radiographics. 1997;17:129-44. 9. jinzaki m, tanimoto a, narimatsu y, et al. angiomyolipoma: imaging findings in lesions with minimal fat. radiology 1997;205:497502. 10. radin r, ma y. malignant epithelioid renal angiomyolipoma in a patient with tuberous sclerosis. j comput assist tomogr. 2001;25:873-5. 11. pea m, bonetti f, martignoni g, et al. apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. am j surg pathol. 1998;22:180-7. 12. belanger e, dhamanaskar p, mai k. epithelioid angiomyolipoma of the kidney mimicking renal sarcoma. histopathology. 2005;47:433-35. 13. yamamoto t, ito k, suzuki k, et al. rapidly progressive malignant epithelioid angiomyolipoma of the kidney. j urol. 2002;168:190-1. 14. vanderbrink ba, munver r, tash ja, sosa re. renal angiomyolipoma with contrastenhancing elements mimicking renal malignancy: radiographic and pathologic evaluation. urology. 2004;63:584-6. giant vesicoprostatic calculi-goumas et al. case report 2655 1737vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l pictorial megalourethra: a rare clinical entity pawan vasudeva, niraj kumar, sanjeev kumar jha corresponding author: pawan vasudeva, md department of urology, vardhman mahavir medical college and safdarjang hospital, new delhi 110029, india. tel: 011 2670 7426 fax: 011 2619 0954 e-mail: drpawanvasudeva@gmail. com received august 2013 accepted december 2013 department of urology, vardhman mahavir medical college and safdarjang hospital, new delhi 110029, india.a a 7 years old boy presented with history of poor urinary stream, ballooning of penis during micturition and post void dribbling since birth. physical examination revealed an enlarged penis with redundant skin on the ventral surface (figure 1). both corpora cavernosa were normal. ultrasound of kidney, ureter and bladder demonstrated bilateral normal kidneys with negligible post void residual urine. computerized tomographic (ct) voiding cystourethrogram demonstrated marked dilatation of penile urethra along with left side grade i vesicoureteral reflux (vur) (figure 2). a diagnosis of scaphoid megalourethra was made and the patient underwent reduction urethroplasty (figure 3). at one year follow up, the patient is asymptomatic and the left vur has resolved. megalourethra, a rare congenital anomaly of the urethra, is characterized by a deficient corpus spongiosum with and without a deficient corpora cavernosum, leading to anterior urethral dilatation. two varieties are recognized: scaphoid, in which corpus spongiosum alone is deficient and fusiform, in which both corpus spongiosum and corpus cavernosum are deficient.(1,2) though the scaphoid variety is more commonly seen, it is the fusiform variety which is commonly associated with other congenital anomalies and hence carries a poorer prognosis.(2,3) references 1. kajbafzadeh a. congenital urethral anomalies in boys. part ii. urol j. 2005;2:125-31. 2. khan ra, wahab s, ullah e. clinics in diagnostic imaging (130). congenital megalourethra. singapore med j. 2010;51:352-5. 3. sharma ak, shekhawat ns, agarwal r, upadhyay a, mendoza wx, harjai mm. megalourethra: a report of four cases and review of the literature. pediatr surg int. 1997;12:458-60. figure 1. penile appearance at presentation. figure 3. reduction urethroplasty: a, degloved penis showing megalourethra; b, urethra opened ventrally; c, urethra tapered; d, urethral repair over catheter. figure 2. computed tomography voiding cystourethrogram: left, two dimensional reformatted image demonstrating megalourethra; right, three dimensional reformatted image demonstrating megalourethra and left vesicoureteral reflux. u j all final for web.pdf 755vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l department of urology, christian medical college, vellore, tamil nadu, india *e-mail: thatsagar@gmail.com grene of the penis secondary to a rubber-band constriction. he started using a rubber-band for marcation line at the penoscrotal junction (figcolor doppler ultrasonography revealed no underneath a necrosed skin, and only a debrideness skin grafting harvested from anterolateral priapism, venous thrombosis, and anticoaguend-stage renal disease. strangulation caused by hair, nuts, rings, threads, bands, and bottle necks has been reported mainly for autoerotism or in the mentally challenged.(2) color doppler ultrasonography can provide invaluable information regarding thrombosis or rupture of cavernosal and dorsal penile vessels.(3) of non-viability. sagar sabharwal, * john samuel banerji, nitin sudhakar kekre penile skin necrosis mimicking penile gangrene an unusual case references 1. singh v, sinha rj, sankhwar sn. penile gangrene: a devastating and lethal entity. saudi j kidney dis transpl. 2011;22:359-61. 2. malik mh, el amir z, ali m, ahmed a, farooqi ma. penile strangulation: a study of fifteen cases. rmj. 2012;37:30-3. 3. bargallo x, bunesch l, de juan c, vilana r, bru c. constrictive penile band injury: color doppler sonographic assessment. j ultrasound med. 2002;21:215-7. pictorial urology figure 1 figure 2 figure 4figure 3 153 urology journal unrc/iua vol. 2, no. 3, 153-156 summer 2005 printed in iran introduction cyclosporin a (csa) is a fungous peptid that has strong suppressive effects on the human immune system. the drug preferably affects activation of helper t lymphocytes, which can weaken the immune system. cyclosporin a is the most effective drug for preventing liver, heart, and kidney allograft rejection. consequently, it has widespread application in controlling rejection in all types of organ transplantations, especially kidney allografts.(1) however, it has severe adverse effects including nephrotoxicity, hypertension, electrolyte imbalance, genitourinary tract upsets, neurotoxicity, hepatotoxicity, and hyperlipidemia, which results in atherosclerosis.(1) currently, postoperative atherosclerosis is the main cause of mortality following transplantation. obviously, preventing csa-induced hyperlipidemia would mitigate the the effect of garlic on cyclosporine-a-induced hyperlipidemia in male rats ali taghizadeh afshari,1 alireza shirpoor,2 ehsan dodangeh balakhani2 1department of nephrology and kidney transplantation, imam khomeini hospital, urmia, iran 2department of physiology, faculty of medicine, urmia university of medical sciences, urmia, iran abstract introduction: cyclosporin a (csa) is a potent immunosuppressive drug. however, it has adverse effects that include elevation of plasma low-density lipoprotein (ldl). this study was designed to determine the effect of garlic on csa-induced hyperlipidemia in male rats. materials and methods: baseline serum blood samples from forty 10-month-old, male wistar rats were obtained. they received intraperitoneal (ip) injection of csa (25 mg/kg) for 28 days. blood samples were again obtained after the 28-day treatment. sixteen of 40 rats showed increased serum ldl levels. these 16 were divided into 2 groups of 8 rats each. in the first (experimental) group, 8 rats received garlic (tablets, 400 mg/d), csa (25 mg/kg ip), and regular diet for 28 days. in the second (control) group, 8 rats received the same regimen without the garlic tablets. at the end of the experiment, blood samples were taken from animals in both groups, and ldl levels were assessed. results: the mean baseline ldl level in animals in the control group was 17.75 ± 4.1 mg/dl. this increased to 21.5 ± 1.6 mg/dl after 28 days of csa administration. after 28 more days, the mean ldl level increased to 25.4 ± 4.9 mg/dl (p = .004). in animals in the experimental group, the baseline ldl level was 23.8 ± 3.7 mg/dl, which increased to 31.3 ± 1.6 mg/dl after the first 28 days (p < .001). after the second 28 days, it decreased to 26.0 ± 4.8 mg/dl (p = .06), and among 4 animals, the ldl level decreased more than 49%. conclusion: in a wistar rat model, animals given cyclosporin a subsequently treated with garlic demonstrated reduced ldl levels compared with controls. this treatment may be useful in patients receiving organ transplantations. key words: cyclosporine, low-density lipoprotein, rat, garlic received may 2004 accepted june 2005 *corresponding author: department of physiology, faculty of medicine, jaddeh nazloo, urmia, iran. tel: ++98 441 277 0698, fax: ++98 441 278 0801 e-mail: shirpoor@hotmail.com garlic and cyclosporine-a-induced hyperlipidemia154 adverse effects of csa in kidney transplant recipients. among herbal drugs used for medicine, garlic is particularly important for controlling hyperlipidemia and hyperglycemia. garlic contains an alkaloid, allicin, as well as antioxidants (ie, vitamin c, germanium, and sulphuric materials).(2,3) several studies of allicin have demonstrated its beneficial effects.(2-4) this study was designed to investigate the effectiveness of garlic on csa-induced hyperlipidemia in male wistar rats. materials and methods forty 10-month-old male wistar rats (250 ± 20 g) were obtained from the animal center of urmia university of medical sciences. all experimental protocols were approved by our institution's animal research committee. they were kept under normal light and temperature conditions (ie, 25 ± 5°c; 12-hour light/dark cycle). blood samples were obtained from the tails of all rats. following centrifugation, samples were analyzed for serum ldl levels. rats then received intraperitoneal (ip) injection of csa (25 mg/kg, sandoz, basel, switzerland) for 28 days. subsequent blood samples were drawn, and serum ldl levels were measured. rats with higher ldl levels in the second blood sampling were divided into 2 groups. animals in the first (experimental) group were given garlic tablets (400 mg/d), food (regular diet), 12.5 g, and csa (25 mg/kg ip). rats in the second (control) group were treated as were the animals in the experimental group, except that animals in the control group did not receive garlic tablets. animals in both groups were treated for a second period of 28 days. blood sampling was done again after 28 more days. serum and blood cells were separated by centrifuge (10 000 rpm) and analyzed for ldl levels. data were compared using the paired t test. the results are presented as means ± sem, and the differences between the 2 groups were considered significant if the value for p was less than .05. results of 40 rats, 16 had elevated ldl levels after the second blood sampling, and these animals were randomly divided into 2 groups-experimental and control-of 8 rats each. the mean baseline ldl level in animals in the control group was 17.75 ± 4.1 mg/dl. this increased to 21.5 ± 1.6 mg/dl after 28 days of csa administration, which was not statistically significant (p = .30). but, when 2 rats with minimal increases in their ldl levels were excluded from the analysis, the increase was significant (p = .015). after the second 28 days, mean ldl levels reached 25.4 ± 4.9 mg/dl, which was significantly higher compared with their baseline ldl levels (p = .004). in 50% of the animals in this group, ldl levels increased markedly, reaching more than 50% of their baseline levels. figure 1 shows the ldl changes in animals in the control and experimental groups. in animals in the experimental group, the mean baseline ldl level was 23.8 ± 3.7 mg/dl, increasing to 31.3 ± 1.6 mg/dl after the first 28 days (p < .001). after the second 28 days (csa and garlic administration), the mean ldl level decreased to 26.0 ± 4.8 mg/dl (p = .06). however, in more than 50% of these rats, the mean ldl level decreased by more than 49% (p = .023). discussion this study demonstrates the beneficial effects of garlic in reducing the csa-induced elevation in plasma ldl levels. ldl levels in rats in the control group increased during the second 28 days of this study and decreased in at least half of the rats in the experimental group. according to many investigations, hyperlipidemia is a severe csa-induced adverse effect following transplantation.(5) medical treatment is required to decrease or attenuate this phenomenon. lipidlowering drugs, used widely in human and animal models, have been shown to have adverse effects fig. 1. changes of serum ldl levels in garlic and control groups, before the exeperiment, after 28 days of cyclosporin administration, and after 28 days of cyclosporin and garlic administration in the experimantal group versus cyclosporin administration in controls 0 5 10 15 20 25 30 35 before the experiment after the first 28 days after the second 28 days l d l ( m g /d l ) control experimental taghizadeh afshari et al 155 including cancer.(6) consequently, herbal drugs are strongly advocated.(7) garlic is one of these drugs.(8) garlic-containing drugs have been used to treat hypercholesterolemia, even though their efficacy has not been generally documented. little is known about the mechanisms of action of the possible effects on cholesterol in humans.(9) studies in experimental animal models, however, have shown that dietary garlic supplementation may suppress the hepatic lipogenic activities and attenuate the activities of enzymes such as malic (which synthesizes fatty acids) and enzymes like glucose-6 phosphate dehydrogenase and 3hydroxy-3-methylglutaryl co-enzyme a (hmgcoa) reductase (which contribute to lipogenesis).(10) it is likely that garlic-derived substances (which have sulphur-containing compounds) may effectively decrease cholesterol levels. this is probably the result of inhibition of hepatic cholesterol synthesis.(10) meanwhile, garlic has some sulphur-containing materials such as sallylcysteine, vitamin c, and selenium which are strong antioxidants.(11) several studies have indicated that the ldl decreasing effect of garlic results from its antioxidant compounds including vitamin c and germanium.(12-14) garlic can play its role by scavenging free radicals, inhibition of the hmgcoa and biosynthesis of cholesterol.(15,16) another study by qureshi and coworkers has shown that garlic extract can decrease the blood lipid level by suppressing lipogenic and cholesterogenic enzyme activities.(17) wei and lau have reported that the sallylcysteine of garlic can control reactive oxygen species and prevent lipid peroxidation and ldl oxidation adverse effects in endothelial cells.(18) on the other hand, despite the numerous advantages of garlic, some studies have indicated that it does not produce any significant effect on decreasing blood lipid level. berthold and colleagues(19) and issacsohn and colleagues(20) have demonstrated that garlic has no significant effect on lipid profiles. however, our results are suggestive of an inhibitory effect on csa-induced hypercholesterolemia, which could be the basis of establishing a new treatment in organ transplant patients who receive csa. conclusion different effects of garlic on blood lipid levels have been reported. the exact mechanism of action of garlic in lowering blood lipid levels has not yet been established. as stated earlier, results from the present study indicate garlic's usefulness in decreasing blood ldl levels. this study differs somewhat from other studies in that we investigated the lipid-lowering effect of garlic in the presence of csa (which increases lipid levels). it seems that to better elucidate garlic's effect on ldl levels, further studies on cellular and molecular levels are needed. references 1. parfitt k, sweetman sc, blake ps, et al, editors. the complete drug reference. 32nd ed. taunton: pharmaceutical press; 1999. cyclosporin; p.519-25. 2. chi ms, koh et, stewart tj. effects of garlic on lipid metabolism in rats fed cholesterol or lard. j nutr. 1982;112:241-8. 3. greenwood tw. garlic therapy. br j clin pract. 1999;44:1-2. 4. agarwal kc. therapeutic actions of garlic constituents. med res rev. 1996;16:111-24. review. 5. andrade rj, lucena mi, gonzalez-correa ja, garciaarias c, gonzalez-santos p. short-term effect of various doses of cyclosporin a on plasma lipoproteins and its distribution in blood: an experimental study. hum exp toxicol. 1993;12:141-6. 6. newman tb, hulley sb. carcinogenicity of lipid-lowering drugs. jama. 1996;275:55-60. review 7. schulz v, hansel r, tyler ve, telger tc. rational phytotherapy: a physicians' guide to herbal medicine. berlin (germany): spring-verlag; 1998. p.133-5. 8. warshafsky s, kamer rs, sivak sl. effect of garlic on total serum cholesterol. a meta-analysis. ann intern med. 1993;119(7 pt 1):599-605. 9. chi ms, koh et, stewart tj. effects of garlic on lipid metabolism in rats fed cholesterol or lard. j nutr. 1982;112:241-8 10. yeh yy, yeh sm. garlic reduces plasma lipids by inhibiting hepatic cholesterol and triacylglycerol synthesis. lipids. 1994;29:189-93. 11. borek c. antioxidant health effects of aged garlic extract. j nutr. 2001;131(3s):1010s-5s. review. 12. abdullah th, kandil o, elkadi a, carter j. garlic revisited: therapeutic for the major diseases of our times? j natl med assoc. 1988;80:439-45. 13. jacques pf, sulsky si, perrone ga, schaefer ej. ascorbic acid and plasma lipids. epidemiology. 1994;5:19-26 14. bendich a, langseth l. the health effects of vitamin c supplementation: a review. j am coll nutr. 1995;14:12436. review. 15. broshe t, siegers cp, platt o. the effect of garlic therapy on cholesterol biosynthesis and on plasma and membrane lipids. med welt. 1991;42:10-1. garlic and cyclosporine-a-induced hyperlipidemia156 16. gebhardt r. inhibition of cholesterol biosynthesis by a water-soluble garlic extract in primary cultures of rat hepatocytes. arzneimittelforschung. 1991;41:800-4. 17. qureshi aa, abuirmeileh n, din zz, elson ce, burger wc. inhibition of cholesterol and fatty acid biosynthesis in liver enzymes and chicken hepatocytes by polar fractions of garlic. lipids. 1983;18:343-8. 18. wei zh, lau bhs. garlic inhibits free radical generation and augments antioxidant enzyme activity in vascular endothelial cells. nutr res.1998;18:61-70. 19. berthold hk, sudhop t, von bergmann k. effect of a garlic oil preparation on serum lipoproteins and cholesterol metabolism: a randomized controlled trial. jama. 1998;279:1900-2. 20. isaacsohn jl, moser m, stein ea, et al. garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial. arch intern med. 1998;158:1189-94. sexual dysfunction and infertility comparing the effectiveness of dietary vitamin c and exercise interventions on fertility parameters in normal obese men bahare rafiee,1,2 mohammad hossein morowvat,1* nasrin rahimi-ghalati3 purpose: comparing the effectiveness of dietary vitamin c and weight loss exercises interventions for weight loss on semen characteristics in normal obese man. materials and methods: a total number of 200 men were randomly allocated into two groups based on body mass index, exercise and vitamin c groups. also, 50 men with normal spermogram were placed in a control group. in exercise group, a 6 months intensive exercise program was designed under a coach’s supervision to reduce the body weight. in vitamin c group, 1,000 mg of vitamin c were given every other day as supplement. results: weight loss increased the volume of semen in participants with 25-30 (p = .02) and more than 30 body mass index (p = .001). the increased concentration of sperm per ml of semen in body mass index (bmi) 25-30 group (p = .01) and more than 30 (p = .003) bmi was significant. improving sperm motility after two hours in participants with more than 30 (p = .01) bmi was significant. in vitamin c group, the improvement of sperm concentration in participants who had less than 25 (p = .01), between 25 and 30 (p = .01), more than 30 (p = .02) bmi was significant. sperm motility improved in all three groups (p = .001, p = .02 and p = .003, respectively). conclusion: weight loss can significantly increase semen volume, its concentration, its mobility and percentage of normal morphology. consuming vitamin c significantly improves sperm concentration and mobility, but the semen volume and the percentage of normal morphology will not change significantly. keywords: ascorbic acid; administration; fertility; physiology; humans; nutritional requirements; population control; fertility; drug effects; infertility; male. introduction international committee for monitoring assisted re-productive technology (icmart) and the world health organization (who) guidelines, have defined the infertility as not becoming pregnant after one year sexual intercourse without protection due to the reproductive systems disease.(1) the regular rate of fecundity is 85-80% after 12 months.(2) about 15% of couples suffer infertility of which 25-50% is contributed to male factor.(3) pathology of male factors can be categorized into three groups. first are the pre-testicular factors. they include hypogonadism; hypothyroidism; follicle-stimulating hormone reducing drugs including spironolactone and cimetidine, and nitrofurantoin that decreases sperm motility; aberrant life style (cigarette smoking, chronic alcoholism, marijuana); and vigorous activities like energetic bicycle riding.(4,5) second are testicular factors. they include age, neoplasm e.g. seminoma, cryptorchidism, varicocele which account for 14%, mumps viral infection, klinefelter syndrome and idiopathic factors which account for 30 % of male infertility.(6,7) third are the post-testicular factors, including: impotence, vas deferens obstruction, lack of vas deferens, infection such as prostatitis, ejaculatory duct obstruction and hypospadias.(8) who has depicted the normal semen analysis chart, according to which the semen volume is the total amount of fluid ejaculated that should be ≥1.5 ml. sperm concentration (commonly known as ‘sperm count’) is regarded as the total number of sperm in a measured volume of an ejaculation. the sperm concentration is reported as the number of sperm per ml of semen that should be ≥15 million per ml. total sperm number (also known as ‘total sperm count’) is described as the total number of sperm in the ejaculate, calculated by multiplying the semen volume by the sperm that should be ≥ 39 million. sperm motility (i.e. swimming 1 pharmaceutical sciences research center, school of pharmacy, shiraz university of medical sciences, shiraz, iran. 2 midwifery school, shiraz university of medical sciences, shiraz, iran. 3 bagherian industrial school, ministry of education and training, shiraz, iran. correspondence: pharmaceutical sciences research center, school of pharmacy, shiraz university of medical sciences, shiraz, iran. tel: +98 71 32426729. e-mail: mhmorowvat@sums.ac.ir. received november 2015 & accepted february 2016 sexual dysfunction and infertility 2635 vol 13 no 02 march-april 2016 2636 or movability of sperm) or the number of motile (moving) sperm is compared with the number of non-motile sperm and is expressed as the percentage of the total number of sperm that should be ≥ 40% motile within 60 minutes of ejaculation. sperm vitality (‘live’ sperm) that is the number of sperms in the sample which are ‘alive’ is a percentage of the total number of sperms that should be ≥ 58%. sperm morphology (the shape of the sperm) that is defined as the number of ideally formed sperms (defined as ‘normal’) is compared to the number of incorrectly shaped sperms (normally defined as ‘abnormal’). it is described as the percentage of the total number of sperms that should be ≥ 4%. white blood cell count routinely occurs in semen. huge amounts of white blood cells in the ejaculate can be defined as an infection of the reproductive tract. however, in some men it happens for no known reason. this factor should be < 1 million per ml. semen ph is measured to test if the ejaculate is alkaline or acidic. semen should be slightly alkaline. more acidic semen, along with a low amount of semen, can be a sign of possible blockage in the flow of semen. its ph should be ≥ 7.2.(2) male germ cells are prone to produce ros (reactive oxygen species) in different levels of development such as the acrosomal reaction and fusion of sperm and oocyte. reactive oxygen species will be deactivated by existing antioxidants (vitamins c and e) in semen.(9) oxidative stress happens when either the level of reactive oxygen species is high or antioxidants defects occur.(10) increased levels of ros will reduce the sperm motility.(11,12) nowadays different techniques are designed to determine the level of spermatozoal dna destruction caused by oxidative stress. a reliable one is measuring of 8-hydroxy-dioxy guanosine biomarker.(13) obesity could intensify the risk of infertility in men. elevated body mass index (bmi) reduces the total amount of sperm and increases the dna damage in sperms.(14) calorie limiting diet would improve testicular gene expression in immature rhesus.(15) the reduction of body fat mass causes hypothalamic-pituitary-testicular fitness and increases in the production of testosterone in infertile men.(16) in humans, reducing calorie intake improves gene expression in epididymis (post testicular) and sperm maturation instead.(17) this study compared the effectiveness of exercise interventions for reducing bmi and vitamin c on male fertility parameters (semen volume, sperm concentration, motility and normal morphology). materials and methods this interventional study was conducted on 200 men who were referred to private clinics. they were 20 to 60 years old, did not have varicocele and chronic diseases history and used certain medications prescribed by the private clinics. their medical history including age, blood group, familial, medical, and sexual history, lifestyle, personal consent, intercourse frequency per month, drinking alcohol, using certain medications, smoking habits, chronic diseases and personal sexual satisfaction was documented. men with diabetes, hypertension, mumps history, sexually transmitted diseases and varicoceles were excluded from the study. the participants were randomly allocated into two groups based on bmi and also, 50 men of both groups with normal spermogram were placed in the control group. in both groups, men with a bmi of 30 to 35 were placed in group 1st group, those with a bmi of 25 to 30 in the 2nd group and those with a bmi less than 25 in 3rd group. in the exercise group, a six-month daily intensive exercise program was designed under a couch’s supervision to reduce weight. in the vitamin c group, 1,000 mg of vitamin c were given every other day as supplement. semen sampling method semen samples were collected once, at the beginning of study and at the end of the intervention. sperm samples were taken by masturbation after 3-5 days of sexual abstinence and kept in a plastic container. then it was incubated at 37°c for 30 minutes and was analyzed after one hour. the sperms were counted by light microscope with a magnification of 400. different characteristics of semen including the appearance, size; ph, color, viscosity, liquefaction time, concentration and sperm motility were table 1. semen parameters based on the body mass index before the 6-month exercise intervention. bmi, kg/m2 volume, ml concentration (million/ml) motility, % morphology, % control 3.54 ± 3.45 63.2 ± 1.24 67 55 < 25 3.12 ± 2.21 62.5 ± 2.2 62.2 51.2 25-30 2.64 ± 3.15 48.5 ± 1.95 51 40.2 31-35 1.8 ± 2.95 35.3 ± 2.11 45 28.2 abbreviation: bmi, body mass index. dietary vitamin c and exercise on fertility parameters-rafiee et al. investigated. statistical analysis was done by statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. p value significance was less than .05 and confidence interval was at 95%. paired t-test was used to compare the results before and after interventions. results the participants’ mean age was 35.2 years old. in exercise intervention group, the average of weight loss was 3.2 kg in the control group, 4 kg in men with a bmi less than 25, 6.1 kg in people with a bmi of 25 to 30 and 8.5 kg in those with bmi more than 30. the increase in semen volume of those with 25-30 (p = .02) and more than 30 bmi (p = .001) was significant (table 1). the increased concentration of sperm per ml of semen in those with 25-30 (p = .01) and more than 30 (p = .003) bmi was also significant. improving sperm motility after two hours in men with more than 30 bmi (p = .01) was significant. the increase in normal sperm morphologies in men with less than 25 (p = .02), 25 to 30 (p = .001) and more than 30 (p = .01) bmi were significant (table 2). in vitamin c group, the average semen volume did not change significantly (table 3). however, the improvement of sperm concentration in men less than 25 (p = .01), 25 to 30 (p = .01), more than 30 (p = .02) bmi was were significant. sperm motility increased in all three groups (p = .001), (p = .02) and (p = .003). the percentage of sperm with normal morphology was not significant (table 4). discussion according to the results of this study, decreasing the body mass index can improve volume, concentration, motility and normal morphology of the sperm. consumption of vitamin c can also improve of sperm concentration and motility. these findings are similar to findings of dawson and colleagues which was done on infertile smokers. their patients were given 1 gram per day of vitamin c and a high dosage regimen. they showed that diet improves fertility parameters.(18) in another study on 97 fertile men, eskenazi and colleagues found out that consuming vitamin c can increase sperm concentration and motility.(19) however, a study that was done by kessopoulou and colleagues showed that antioxidants, particularly vitamin e cannot affect sperm quality for eight weeks.(20) they stated that in this study the time for improvement of fertility parameters was too short in their study. regarding physiological aspect, antioxidants may protect germ cells from oxidative damage.(21) oxidative damage is associated with reduction of sperm mobility and capacity of oocytes-sperms fusion.(22) after facing with reactive oxygen species, sperm membrane will be rigid and cause fracture and damage in cell membrane. treatment with antioxidants can prevent the sperm membrane from lipoproxidation damages.(23) treatment with antioxidants also prevents the sperm dna damage and mutation.(24) obesity is a health problem that is related to male infertility and abnormal fertility parameters.(25) jensen and colleagues reported the semen analysis is abnormal in obese men and, the prevalence of oligospermia table 2. semen parameters in men according to body mass index after six months of exercise interventions. bmi, kg/m2 volume concentration (million/ml) motility, % morphology, % p valuea p valueb p valuec p valued control 3.6 ± 3.11 65.5 ± 2.21 65 65 .1 .2 ns ns < 25 3.10 ± 2.25 63.3 ± 3.11 63.1 61 .5 .3 ns .02 25-30 3.52 ± 3.51 55.8 ± 2.13 55.8 58.1 .02 .01 ns .001 31-35 2.85 ± 3.1 48.9 ± 3.11 54.1 35 .001 .003 .01 .01 abbreviations: bmi, body mass index; ns, not significant. a p value for semen volume, b p value for sperm concentration, c p value for sperm motility, d p value for sperm morphology. bmi, kg/m2 volume concentration (million/ml) motility, % morphology, % control 3.82 ± 3.26 64.5 ± 1.75 61.1 58 < 25 3.51 ± 4.12 61 ± 2.32 65.12 52.8 25-30 2.15 ± 3.62 45.2 ± 1.3 48.32 40.5 31-35 2.5 ± 3.16 40.1 ± 2.12 38.3 35.1 abbreviation: bmi, body mass index. table 3. semen parameters in men according to body mass index before taking vitamin c. dietary vitamin c and exercise on fertility parameters-rafiee et al. sexual dysfunction and infertility 2637 vol 13 no 02 march-april 2016 2638 is more, compared to men with normal bmi.(16) kort and colleagues noted that increase in bmi is negatively linked with number of normal sperm, sperm concentration, motility and serum testosterone levels. this is consistent with the results of our study.(14) studies show that weight loss can improve the quality of semen parameters leading to more fertility.(26) although obesity is associated with a reduced number of intercourse as well as erection dysfunction(27) it seems that a hormone deficiency is at the beginning of this vicious cycle that causes the disorder in semen parameters.(28) this would be interesting topic to evaluate the pathologic effects of obesity on sexual desire and erection dysfunction. moreover, other food regimen or supplements as major nutritional factor, could be examined for enhancing the sperm motility. conclusions the study was designed to assess of the relationship between weight loss interventions and semen parameters. it also investigated the influence of oral vitamin c, as an antioxidant on semen quality. weight loss can cause a significant increase in semen volume, sperm concentration, mobility and percentage of normal morphology. consumption of vitamin c can significantly improve sperm concentration and mobility. but the volume of semen and the percentage of normal morphology does not change significantly. acknowledgements this work was supported by research deputy of shiraz university of medical sciences, shiraz, iran (grant no. 94-01-36-10593). the authors would like to thank seyed muhammad hussein mousavinasab for his sincere cooperation in editing this manuscript. conflict of interest none declared referenes 1. zegers-hochschild f, adamson gd, de mouzon j, et al. international committee for monitoring assisted reproductive technology (icmart) and the world health organization (who) revised glossary of art terminology, 2009. fertil steril. 2009;92:15204. 2. world health organization (who). who laboratory manual for the examination and processing of human semen. 5 ed; 2010. 3. world health organization (who). who laboratory manual for the examination and processing of human semen. 4 ed; 1999. 4. leibovitch i, mor y. the vicious cycling: bicycling related urogenital disorders. eur urol. 2005;47:277-86. 5. nikoobakht mr, aloosh m, nikoobakht n, mehrsay ar, biniaz f, karjalian ma. the role of hypothyroidism in male infertility and erectile dysfunction. urol j. 2012;9:405-9. 6. dubin l, amelar r. etiologic factors in 1294 consecutive cases of male infertility. fertil steril. 1971;22:469-74. 7. huleihel m, lunenfeld e. regulation of spermatogenesis by paracrine/autocrine testicular factors. asian j androl. 2004;6:25968. 8. costabile ra, spevak m. characterization of patients presenting with male factor infertility in an equal access, no cost medical system. urology. 2001;58:1021-4. 9. agarwal a, sekhon lh. the role of antioxidant therapy in the treatment of male infertility. hum fertil. 2010;13:217-25. 10. venkatesh s, deecaraman m, kumar r, shamsi mb, dada r. role of reactive oxygen species in the pathogenesis of mitochondrial dna (mtdna) mutations in male infertility. indian j med res. 2009;129:127-37. 11. agarwal a, ikemoto i, loughlin kr. relationship of sperm parameters with levels of reactive oxygen species in semen specimens. j urol. 1994;152:107-10. 12. heidary m, vahhabi s, reza nejadi j, et al. effect of saffron on semen parameters of infertile men. urol j. 2008;5:255-9. 13. shen h-m, ong c-n. detection of oxidative dna damage in human sperm and its association with sperm function and male infertility. free radic biol med. 2000;28:52936. table 4. semen parameters in men according to body mass index after taking vitamin c. bmi, kg/m2 volume concentration (million/ml) motility, % morphology, % p valuea p valueb p valuec p valued control 3.75 ± 4.11 65.2 ± 2.11 60.5 58.2 ns .01 ns ns. < 25 3.42 ± 3.52 68 ± 2.14 68.7 55.8 ns .01 .001 ns 25-30 2.11 ± 2.13 55.8 ± 3.4 58.4 41.1 ns .02 .02 ns 31-35 2.10 ± 3.34 51.4 ± 2.11 45.5 39.2 ns .01 .003 ns abbreviations: bmi, body mass index; ns, not significant. a p value for semen volume, b p value for sperm concentration, c p value for sperm motility, d p value for sperm morphology. dietary vitamin c and exercise on fertility parameters-rafiee et al. 14. kort hi, massey jb, elsner cw, et al. impact of body mass index values on sperm quantity and quality. j androl. 2006;27:450-2. 15. sitzmann bd, mattison ja, ingram dk, roth gs, ottinger ma, urbanski hf. impact of moderate calorie restriction on the reproductive neuroendocrine axis of male rhesus macaques. open longev sci. 2010;3:38. 16. jensen tk, andersson a-m, jørgensen n, andersen a-g, carlsen e, skakkebæ k ne. body mass index in relation to semen quality and reproductive hormones among 1,558 danish men. fertil steril. 2004;82:863-70. 17. harrison rm, lewis rw. the male reproductive tract and its fluids. in: dukelow wr, erwin j, editors. comparative primate biology: reproduction and development. vol. 3. new york: alan r. liss, inc.; 1986. p. 101– 48. 18. dawson e, harris w, teter m, powell l. effect of ascorbic acid supplementation on the sperm quality of smokers. fertil steril. 1992;58:1034-9. 19. eskenazi b, kidd s, marks a, sloter e, block g, wyrobek a. antioxidant intake is associated with semen quality in healthy men. hum reprod. 2005;20:1006-12. 20. kessopoulou e, powers h, sharma k, et al. a double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin e to treat reactive oxygen species associated male infertility. fertil steril. 1995;64:825-31. 21. fraga cg, motchnik pa, shigenaga mk, helbock hj, jacob ra, ames bn. ascorbic acid protects against endogenous oxidative dna damage in human sperm. pnas. 1991;88:11003-6. 22. agarwal a, saleh ra, bedaiwy ma. role of reactive oxygen species in the pathophysiology of human reproduction. fertil steril. 2003;79:829-43. 23. lenzi a, gandini l, picardo m. a rationale for glutathione therapy. gamete res. 1998;24:127-34. 24. geva e, lessing j, lerner-geva l, amit a. free radicals, antioxidants and human spermatozoa: clinical implications. hum reprod. 1998;13:1422-4. 25. roth my, amory jk, page st. treatment of male infertility secondary to morbid obesity. nat clin pract endocrinol metab. 2008;4:4159. 26. norman rj, noakes m, wu r, davies mj, moran l, wang jx. improving reproductive performance in overweight/obese women with effective weight management. hum reprod update. 2004;10:267-80. 27. bacon cg, mittleman ma, kawachi i, giovannucci e, glasser db, rimm eb. a prospective study of risk factors for erectile dysfunction. j urol. 2006;176:217-21. 28. mauras n, bell j, snow bg, winslow kl. sperm analysis in growth hormone-deficient adolescents previously treated with an aromatase inhibitor: comparison with normal controls. fertil steril. 2005;84:239-42. dietary vitamin c and exercise on fertility parameters-rafiee et al. sexual dysfunction and infertility 2639 1595vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l 14. lipkin me, mancini jg, zilberman de, et al. reduced radiation exposure with the use of an air retrograde pyelogram during fluoroscopic access for percutaneous nephrolithotomy. j endourol. 2011;25:563-7 15. semins mj, trock bj, matlaga br. the safety of ureteroscopy during pregnancy: a systematic review and meta-analysis. j urol. 2009;181:139-43. 16. resorlu b, unsal a, ziypak t, et al. comparison of retrograde intrarenal surgery, shockwave lithotripsy, and percutaneous nephrolithotomy for treatment of medium-sized radiolucent renal stones. world j urol. 2013;31:1581-6. 17. takazawa r, kitayama s, tsujii t. successful outcome of flexible ureteroscopy with holmium laser lithotripsy for renal stones 2 cm or greater. int j urol. 2012;19:264-7. 18. grasso m, ficazzola. retrograde ureteropyeloscopy for lower pole caliceal calculi. j urol. 1999;162:1904-8. 19. bozkurt of, resorlu b, yildiz y, can ce, unsal a. retrograde intrarenal surgery versus percutaneous nephrolithotomy in the management of lower-pole renal stones with a diameter of 15 to 20 mm. j endourol. 2011;25:1131-5. 20. mariani aj. combined electrohydraulic and holmium:yag laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. j urol. 2007;177:168-73. hand-assisted, conventional and laparoendoscopic single-site surgery for partial nephrectomy without ischemia using a microwave tissue coagulator tetsuo nozaki, yoshihiro asao, tomonori katoh, kenji yasuda, hideki fuse correspondence author: tetsuo nozaki, md department of urology, graduate school of medicine and pharmaceutical sciences for research, university of toyama, 2630 sugitani, toyama 930-0194, japan. tel: +81 76434 2281 fax: +81 76434 5039 e-mail: nozaki0921@yahoo.co.jp received may 2013 accepted january 2014 department of urology, graduate school of medicine and pharmaceutical sciences for research, university of toyama, 2630 sugitani, toyama 9300194, japan. purpose: we report our experience of minimally invasive partial nephrectomy without ischemia using a microwave tissue coagulator (mtc) for hand-assisted laparoscopic partial nephrectomy (halpn), conventional laparoscopic partial nephrectomy (clpn), and laparoendoscopic single-site surgery for partial nephrectomy (lesspn). we retrospectively compared the results of these techniques to better define the individual role and the benefits. materials and methods: from july 2005 to september 2012, 28 patients with small and exophytic renal tumors underwent halpn (n = 12), clpn (n = 10) and lesspn (n = 6). in these procedures, the surgeon used an mtc for circumferential coagulation around the tumor. after coagulation, the tumor was resected without renal pedicle clamping. results: the mean operative time was 259, 194 and 174 min for the halpn, clpn and lesspn groups respectively. two patients (one in halpn group and one in lesspn group) converted to laparotomy due to an inability to maintain hemostasis; however, there were no conversions to ischemic partial nephrectomy or radical nephrectomy. no differences between halpn, clpn and lesspn were noted in terms of estimated blood loss, measured analgesic requirements, outcomes, or complications. conclusion: we believe that these techniques are feasible and that they minimize the risk of unexpected collateral thermal damage by appropriate mtc needle puncture. when deciding to use halpn, clpn or lesspn, our findings suggest that the choice of surgical approach should depend on the patient’s individual circumstance. keywords: carcinoma, renal cell; surgery; laparoscopy; microwaves; nephrectomy; organ sparing treatments; surgical procedures; minimally invasive; methods. laparoscopic urology 1596 | laparoscopic urology introduction laparoscopic partial nephrectomy (lpn) is becom-ing a popular treatment option for small renal tu-mors because it offers better cosmesis and reduces postoperative pain.(1,2) as lpn gains widespread acceptance, there is a great need for a novel surgical technique to be reliable and provides bloodless resection of the renal parenchyma without damaging the residual renal tissue.(3) in japan, microwave tissue coagulators (mtcs) are widely used for lpn.(4,5) in lpn, the mtc is applied peripherally in the healthy parenchyma surrounding the tumor, with circumferential punctures that produce coagulation of a conical-shaped portion of tissue. subsequently, a wedge resection can be achieved in the bloodless field without renal pedicle clamping. the aim of this study was to compare the various techniques of lpn such as hand-assisted laparoscopic surgery for pn (halpn), conventional lpn (clpn) and laparoendoscopic single-site surgery (less) for pn (lesspn) as well as their outcome in terms of operative time, postoperative pain and surgical site infection. materials and methods a retrospective study was carried out including patients operated on at toyama university hospital from july 2005 to september 2012. of the 28 patients included in the study, 12 were in the halpn group, 10 were in the clpn group and 6 were in the lesspn group. we began our study using halpn and then we gradually shifted to clpn and lesspn; indeed, from 2005-2008, 2007–2012 and 2011– 2012, we performed halpn, clpn and lesspn, in that order. choice of a particular surgical approach was based on the surgeon’s clinical judgment, taking into consideration patient and clinical factors. during this study, a single surgeon performed all preoperative counseling and surgery. the demographic characteristics are summarized in table 1. all renal tumors were categorized according to the nephrometry score determined from preoperative imaging as low, moderate and high complexity.(6) each group was comparable with regard to age, body mass index, and nephrometry scoring. in the less group, all patients underwent surgery after obtaining institutional review board approval from the ethical committee and informed patient consent. both transperitoneal and retroperitoneal approaches were taken at the surgeon’s discretion. all lesions were suspected of renal cell carcinoma (rcc), as were peripherally located and exophytic renal tumors with at least 5 mm of normal renal tissue between the tumor margin and the collecting system. outcome was assessed in the form of operative time, blood loss, in-hospital frequency of analgesia administration and overall complication rates. all complications were carefully graded using the modified clavien system.(7) renal function was determined by serum creatinine (mg/dl) measurement and postoperative serum creatinine was measured at 7 postoperative days. statistical analysis non-parametric statistical analyses (mann-whitney u test for two-way, and kruskal-wallis test for three-way analyses) were used for statistical analyses. halpn surgical technique the halpn technique used has been described in detail elsewhere.(8) briefly, halpn was carried out as follows. under general anesthesia, each patient was placed in a 70-degree lateral decubitus position. after an approximately 7 cm skin incision was made around the umbilicus, a handassisted device, gelport (applied medical, rancho santa margarita, ca) and two or three additional ports are placed. the kidney was mobilized within gerota’s fascia with the aid of the surgeon’s hand. the gerota’s fascia was incised to expose the tumor and surrounding normal renal capsule. the renal pedicle was not dissected. intra-abdominal ultrasound scanning was used to confirm the tumor shape, size and the depth of the tumor base. the incision line, which was 1 cm from the tumor margin, was marked circumferentially on the renal capsule using electrocautery scissors. next, the surgeon grasped the surgical handpiece of the mtc (microtaze ot-110m, aswell co., osaka, japan), which was originally designed for open surgical procedure, and introduced it through the gelport with the coaxial flexible cable. the mtc causes the thermal coagulation of tissues using microwave energy (2,459 mhz). this energy is transmitted from a generator through a coaxial cable to a probe, which consists of a handpiece and a needle-like electrode. the rapid oscillation of water particles caused by microwaves results in a high temperature and induces coneshaped tissue coagulation around the needle that is 7 to 10 1597vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l less for partial nephrectomy | nozaki et al mm in width without carbonization. the needle applicator consists of a 10-, 15-, or 20 mm long electrode. the length of antenna needle inserted changes depending on the depth of coagulation. the surgical handpiece of mtc could easily be inserted through the gelport, but attention was needed to avoid injuring other organs. needle puncture was performed every 7 to 10 mm along the demarcation line. the direction and angle of the needle puncture could be easily and precisely changed in a timely manner depending on the site of coagulation. microwave coagulation was carried out at 75 w for 45 sec, followed by 15 sec of dissociation. after coagulation, the tumor rose from the kidney and the base of the tumor was resected using a combination of laparoscopic scissors and blunt finger dissection. the excised tumor was removed through the gelport, and biopsies from the tumor bed were sent for frozen-section study to confirm complete tumor removal. indigo carmine (indigotindisulfonate sodium) was intravenously injected to investigate the presence of urine leakage. after ensuring that there was no further bleeding from the tumor bed, a drainage tube was placed around the tumor bed. clpn surgical technique at the beginning of the operation, four to five trocars were inserted transperitoneally or retroperitoneally. after tumor exposure and intra-abdominal ultrasound examination, a laparoscopic mtc probe (microtaze ot-110m, aswell co., osaka, japan) that bends at its distal near-object end was introduced through the 5 mm port. using the bendable laparoscopic mtc probe, microwave coagulation was applied peripherally to the healthy parenchyma surrounding the tumor, with circumferential punctures producing coagulation of a conical-shaped portion of tissue (figure). subsequently, the base of the tumor was resected using a combination of conventional 5 mm laparoscopic scissors and blunt dissection with a laparoscopic aspirator without renal pedicle clamping. the specimen was placed in the laparoscopic bag and retrieved through the abdominal incision. subsequently, the procedure was performed the same as in halpn. lesspn surgical technique the lesspn technique used has been described in detail elsewhere.(9) briefly, lesspn was carried out as follows. through the retroperitoneal approach, a 3 cm transverse skin incision was made just below the tip of the 12th rib, and the extraperitoneal space was carefully dissected with the index finger. the retroperitoneoscopic working space was dilated using a preperitoneal dissector balloon (pdb1000; covidien, mansfield, ma, usa) under the direct vision of a laparoscope. through the transperitoneal lesspn approach, to enhance the cosmetic result, we developed a unique intraumbilical technique whereby the umbilicus was completely extroflexed and a skin incision of approximately 3 cm in length was made longitudinally. after subcutaneous tissue dissection and fascial incision, the peritoneum was incised. next, a lapprotectortm (hakko medical industry, tokyo, japan) was set up through the small incision. the lapprotectortm offers wound protection and 360° of atraumatic wound retraction, which was maximized in order to pass surgical instruments into the abdominal cavity. then, an ez accesstm (hakko medical industry, tokyo, table 1. demographic characteristics of study group. variables halpn clpn lesspn p age (years) 67.2 ± 10.2 53.3 ± 15.2 56.3 ± 18.3 .121 bmi (kg/m2) 23.9 ± 3.1 25.5 ± 3.5 23.1 ± 0.6 .581 tumor size (cm) 1.9 ± 0.42 2.8 ± 1.5 1.8 ± 0.8 .097 imperative case (no.) 2.0 0.0 1.0 .484 nephrometry sum 5.08 ± 1.31 5.00 ± 1.09 5.16 ± 0.98 .584 low, 4-6 score (%) 10 (83.3) 9 (90) 6 (100) -- medium, 7-9 score (%) 2 (17.7) 1 (10) 0 (0.0) -- high, 10-12 score (%) 0 (0.0) 9 (0.0) 0 (0.0) --keys: bmi, body mass index; halpn, hand-assisted laparoscopic partial nephrectomy; clpn, conventional laparoscopic partial nephrectomy; lesspn, laparoendoscopic single-site surgery for partial nephrectomy. 1598 | japan), a silicone cap designed to cover the outer ring of the lapprotectortm, was set up in order to maintain the pneumoperitoneum. the ez accesstm allows the insertion of multiple trocars (three to four) freely into the abdominal cavity through its large surface area (5 cm diameter). the trocars could be positioned anywhere within the silicone cap; they were separated as far as possible from each other on the silicone cap, which more readily facilitated the spacing of instruments. the silicone cap is flexible and self-sealing; it acts as a pseudoabdominal platform for the trocars. if the surgeon wanted to change the trocar position and/or trocar size, the pore on the silicone cap was resealed afterwards. at the beginning of the operation, three 5 mm trocars were inserted into the silicone cap before it was mounted onto the lapprotectortm. the abdominal cavity was explored using a flexible 5 mm 0° olympus high-definition laparoscope (tokyo, japan). except for a reusable bendable laparoscopic mtc probe, all other instruments were conventional straight laparoscopic instruments, including a bipolar grasper, laparoscopic scissors, and a suction device. after exposure of the tumor, the 5 mm trocar was replaced with a 12 mm trocar to enable intra-abdominal laparoscopic ultrasound scanning. after ultrasound examination, the 12 mm trocar was replaced with the 5 mm trocar. there was no leakage of the pneumoperitoneum during multiple trocar exchanges using the ez accesstm. using the bendable laparoscopic mtc probe, the direction and angle of needle puncture could be easily and precisely changed in a timely manner depending on the site of coagulation, even with the less procedure. after coagulation, the base of the tumor was resected using a combination of conventional 5 mm laparoscopic scissors and blunt dissection using a laparoscopic aspirator under normal renal perfusion. the excised specimen can be removed by simply removing the silicone cap from the proximal ring. results the perioperative and postoperative variables are detailed in table 2. no significant differences were noted in the operative time, estimated blood loss and complication rates. there were two conversions to laparotomy (one in the halpn group and one in the lesspn group) as a result of an inability to maintain hemostasis; however, there were no conversions to ischemic partial nephrectomy or radical nephrectomy. with the exception of these two patients, complete hemostasis was achieved; therefore, the application of bolster, sealant or parenchymal stitches/collecting system closure was not necessary. the in-hospital frequency of analgesia administration was comparable between groups. all patients resumed oral intake and were ambulatory within 2 days. no postoperative complications such as delayed hemorrhage were observed in follow-up computed tomography (ct) imaging. however, one patient (16.7%) in the lesspn group developed urinoma formation, which was resolved with percutaneous drainage and ureteral stent placement. wound infection and dehiscence table 2. perioperative parameters, outcomes and complications. variables halpn clpn lesspn p (n = 12) (n = 10) (n = 6) mean operative time (min) 259 ± 75.2 194 ± 53.5 174 ± 13.8 .064 mean blood loss (ml) 298 ± 69 48 ± 6 892 ± 40.0 .128 complications* (no.) wound dehiscence 1.0 0.0 0.0 urine leakage** 0.0 0.0 1.0 frequency of analgesic use (no.) 1.16 ± 1.06 1.5 ± 1.37 1.16 ± 0.57 .831 delay in resuming normal activity (days) 1.3 ± 0.4 1.1 ± 0.4 1.0 .264 delay in resuming normal diet (days) 2.1 ± 0.5 2.3 ± 0.8 1.5 ± 0.6 .055 postoperative/preoperative serum creatinine (%) 106.0 ± 10.5 114.3 ± 13.8 112.4 ± 19.2 .451 keys: halpn, hand-assisted laparoscopic partial nephrectomy; clpn, conventional laparoscopic partial nephrectomy; lesspn, laparoendoscopic single-site surgery for partial nephrectomy. * complications classified using the modified clavien system. ** urine leakage requiring ureteral stent. laparoscopic urology 1599vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l occurred in one patient (8.3%) in the halpn group in the perioperative period, which was resolved with conservative treatment. the mean postoperative/preoperative creatinine (mg/dl) was 1.06, 1.14, and 1.12 for the halpn, clpn and lesspn groups (p = .451), respectively. in lesspn, the ez access, with its relatively large diameter (5 cm), facilitated the triangulation and spacing of instruments, despite actually operating through a smaller 3 cm skin incision. even in less surgery, internal and external instrument collision did not prevent the completion of the procedures. the abdominal view after the unique intraumbilical technique revealed an invisible umbilical scar. during the follow-up period, we observed one recurrence in the halpn group despite a 100% negative margin rate. this patient had previously undergone contralateral nephrectomy for rcc. two suspicious renal tumors were discovered in the remaining lower and middle pole kidney in follow-up imaging studies. both tumors were resected simultaneously, and intraoperative frozen section analysis and final pathologic examination revealed negative margins. however, local recurrence and pulmonary metastases developed 8 months after halpn. with the exception of this case, no local recurrence or distant metastases occurred during our midterm follow-up periods (mean 42.6 months post procedure). discussion although the mtc is a useful instrument that enables surgeons to perform lpn without renal pedicle clamping, one possible drawback of the mtc may be collateral thermal damage to surrounding structures, such as arteries, veins and the collecting system as a result of inadequate coagulation. this technique is better suited for polar tumors or small exophytic tumors located on the lateral convexity of the kidney. the indication for this procedure must be limited to small (< 4 cm) exophytic renal tumors with adequate intervening renal parenchyma as far as the renal collecting system (< 5 mm). therefore, this technique cannot be applied to central or hilar tumors. while limiting the indication, as a result of inappropriate needle puncture, unexpected postoperative complications, such as postoperative urinoma formation, pelvicaliceal stenosis, renal infarction or renal arteriovenous fistula, were reported.(5,10) considering that these complications have rarely been documented in open partial nephrectomy (opn) using the mtc, this should be recognized as a potential risk associated with the laparoscopic approach. the mtc probe, which was designed for purely laparoscopic surgery, is rigid and its movement is restricted by the fixed port site.(11) to insert the needle in the appropriate direction, it is mandatory to fully mobilize the antenna needle in the intraperitoneal space as in standard open surgery without stress. to allow the safe and widespread use of this apparatus in lpn, further innovative methods for precise needle puncture are needed. in an attempt to provide more precise and accurate coagulation, we propose the application of an “open” mtc for halpn.(8) hand-assisted laparoscopic surgery (hals) is a unique surgical approach that has several unique advantages (e.g., surgeons can insert a hand into the abdomen to achieve tactile sensation, three-dimensional orientation, hemorrhage control and improved organ retraction and removal, analogous to laparotomy.(12,13) in halpn using the mtc, needle puncture in the appropriate direction was quite easy and could be precisely changed in a timely manner. moreover, digital dissection allows better access and quick isolation of the tumor. as such, this technique does not require advanced laparoscopic skill. in our series, halpn was an effective procedure, and all measurable perioperative outcomes are equivalent, with no obvious disadvantage for halpn. although not significant, the longer operative time observed for halpn group potentially reflects underfigure. the microwave tissue coagulator is applied peripherally in the healthy parenchyma surrounding the tumor. less for partial nephrectomy | nozaki et al 1600 | lying bias due to the fact that halpn patients were more likely to be undergoing surgery during the early experience of using the mtc. however, in one patient, wound infection and dehiscence occurred. the primary disadvantage of halpn compared to clpn and lesspn is the larger incision. a large series summarizing the specific complications of hals has been reported.(14-16) these reports suggested that postoperative hals incision site complications, including wound infections and hernias, occur more often than with standard laparoscopy. an incisional hernia is often associated with significant morbidity and usually requires an additional procedure for its repair, which is associated with recurrence. various risk factors for the development of postoperative complications at the hals incision site have been proposed, including patient factors (smoking, diabetes, renal failure and obesity), wound factors (re-incision, midline incisions and wound infection), external factors (radiation and chemotherapy) and operative variables (prolonged operative time and lack of antibiotics). the surgeon should take these into account when considering halpn, and should bear these postoperative complications in mind during the surgery. to increase the cosmetic result of the surgery and to minimize patient discomfort, several authors successfully utilized lesspn.(17-19) in this study, we attempted lesspn without ischemia using the mtc. it is of note that the incidence of benign disease is high (approximately 30%) in small asymptomatic renal tumors.(20,21) the cosmetic outcome is a significant issue and a lower morbidity approach should be strongly recommended. clpn is routinely performed using more than four ports of entry into the abdomen. the use of multiple puncture sites, however, may decrease patient cosmetic satisfaction and could increase trocar-associated complications, such as trocar-site bleeding, herniation of viscera and wound infection. in this setting, lesspn could play a principal role in increasing patient satisfaction because less avoids the psychological trauma associated with multiple scars. despite recent technologic advances in less instrumentation and optics, there are concerns associated with technical difficulties, including internal or external instrument collisions or difficulties in driving the instruments. in order to allow the safe use of this apparatus in lesspn, further innovative methods for precise needle puncture are needed. in our lesspn group, we used the ez access port and bendable mtc probe for pn without ischemia. using these new types of devices for lesspn, the surgeon did not encounter internal or external instrument collisions or difficulties in driving the instruments, problems that were typical of less procedures. the analysis of our first six lesspns is encouraging and compares favorably with other lesspn without ischemia series. kaouk and colleagues published their experience with five cases of lesspn without ischemia using a harmonic scalpel.(17) the mean operating time was 160 min, with a mean estimated blood loss of 420 ml. they converted to standard laparoscopy in one patient to control parenchymal bleeding. cindolo and colleagues published their experience with six cases of lesspn without ischemia using a laparoscopic vessel sealing instrument (ligasure advance, covidien, mansfield, ma).(18) the average tumor size was 2.1 cm (range 1.0-3.5 cm) and mean operating time was 148 min (range 115-180 min), with a mean estimated blood loss of 201 ml. they added one additional 5 mm port in two cases to suture the renal parenchyma and for liver or tissue retraction. they converted to standard laparoscopy (adding two 5 mm ports) in one case to control parenchymal bleeding. our procedure provides optimal hemostasis, making lesspn easier and possible without renal pedicle clamping or hemostatic sutures. this technique should only be attempted in select patients who have favorable tumor anatomic features and should be performed by an experienced laparoscopic team. the only recognized benefit of less compared with conventional laparoscopy is improved cosmesis. the other potential patient benefits such as a decrease in postoperative pain and recovery time are equivalent, with no obvious advantage for lesspn. however, in our lesspn group, one patient (a 22-year old female) with von hippel-lindau disease was included. the retroperitoneal less approach was chosen to minimize the intra-abdominal adhesion and limit abdominal wall trauma. we postulate that the younger patient subset, which was more likely to undergo surgery for benign indications and more likely to undergo repeat surgery for recurrence disease, received the greatest benefit from less surgery. this study has several limitations. first, the study is retrospective and is susceptible to all limitations and biases laparoscopic urology 1601vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l references 1. campbell sc, novick ac, belldegrun a, et al. guideline for management of the clinical t1 renal mass. j urol. 2009;182:1271-9. 2. breau rh, crispen pl, jenkins sm, blute ml, leibovich bc. treatment of patients with small renal masses:a survey of the american urological association. j urol. 2011;185:407-13. 3. breda a, finelli a, janetschek g, porpiglia f, montorsi f. complications of laparoscopic surgery for renal masses: prevention, management, and comparison with the open experience. eur urol. 2009;55:836-50. 4. furuya y, tsuchida t, takihana y, araki i, tanabe n, takeda m. retroperitoneoscopic nephron-sparing surgery of renal tumor using a microwave tissue coagulator without renal ischemia: comparison with open procedure. j endourol. 2003;17:53-8. 5. terai a, ito n, yoshimura k, et al. laparoscopic partial nephrectomy using microwave tissue coagulator for small renal tumors: usefulness and complications. eur urol. 2004;45:744-8. 6. kutikov a, uzzo rg. the r.e.n.a.l. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. j urol. 2009;182:844-53. 7. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 8. nozaki t, morii a, yasuda k, watanabe a, komiya a, fuse h. handassisted laparoscopic partial nephrectomy by using an "open" device of microwave tissue coagulator. j laparoendosc adv surg tech a. 2010;20:461-4. 9. nozaki t, watanabe a, fuse h. laparoendoscopic single-site surgery for partial nephrectomy without ischemia using a microwave tissue coagulator. surg innov. 2013;20:439-43. 10. harabayashi t, shinohara n, kakizaki h, ameda k, nonomura k, koyanagi t. ureteral stricture developing after partial nephrectomy with a microwave tissue coagulator: case report. j endourol. 2003;17:919-21. 11. tanaka m, kai n, naito s. retroperitoneal laparoscopic wedge resection for small renal tumor using microwave tissue coagulator. j endourol. 2002;14:569-72. 12. devoe wb, kercher kw, hope ww, lincourt ae, norton hj, teigland cm. hand-assisted laparoscopic partial nephrectomy after 60 cases: comparison with open partial nephrectomy. surg endosc 2009;23:1075-80. 13. bylund jr, clark cj, crispen pl, lagrange ca, strup se. hand-assisted laparoscopic partial nephrectomy without formal collecting system closure: perioperative outcomes in 104 consecutive patients. j endourol. 2011;25:1853-7. 14. pareek g, hedican sp, gee jr, bruskewitz rc, nakada sy. meta-analysis of the complications of laparoscopic renal surgery: comparison of procedures and techniques. j urol. 2006;175:1208-13. 15. matin sf, abreu s, ramani a, et al. evaluation of age and comorbidity as risk factors after laparoscopic urological surgery. j urol. 2003;170:1115-20. 16. montgomery js, johnston wk 3rd, wolf js jr. wound complications after hand assisted laparoscopic surgery. j urol. 2005;174:2226-30. 17. kaouk jh, goel rk. single-port laparoscopic and robotic partial nephrectomy. eur urol. 2009;55:1163-9. 18. cindolo l, berardinelli f, gidaro s, schips l. laparoendoscopic single-site partial nephrectomy without ischemia. j endourol. 2010;24:1997-2002. 19. han wk, kim ds, jeon hg, et al. robot-assisted laparoendoscopic single-site surgery: partial nephrectomy for renal malignancy. urology. 2011;77:612-6. 20. nguyen mm, gill is, ellison lm. the evolving presentation of renal carcinoma in the united states: trends from the surveillance, epidemiology, and end results program. j urol. 2006;176:2397-400. 21. russo p. should elective partial nephrectomy be performed for renal cell carcinoma >4 cm in size? nat clin pract urol. 2008;5:482-3. inherent in a retrospective design. second, we used the frequency of analgesia administration as a surrogate for measuring postoperative pain. the optimal means of assessing postoperative pain would involve using a visual analog scale as well as measuring analgesic requirements. third, the study includes a relatively small number of patients and a relatively short follow-up period. further studies are necessary to investigate the actual benefits of these procedures in performing minimally invasive nephron sparing surgery. conclusion in conclusion, halpn, clpn and lesspn without ischemia by using mtc were feasible and safe. our preliminary findings can be used to better counsel patients when deciding between a halpn versus clpn or lesspn approach. the surgical outcomes were not significantly different and the choice of surgical approach therefore depends on the patient’s individual circumstance. conflict of interest none declared. less for partial nephrectomy | nozaki et al 1521vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l cavernous hemangıoma of the female urethra: a rare case report sakir ongun,1 serdar çelik,1 güven aslan,1 kutsal yörükoğlu,2 adil esen1 corresponding author: sakir ongun, md department of urology, dokuz eylul university school of medicine, izmir, turkey. tel: + 90 232 412 3451 e-mail: sakirongun@hotmail.com received january 2013 accepted june 2013 1 department of urology, dokuz eylul university school of medicine, izmir, turkey. 2 department of pathology, dokuz eylul university school of medicine, izmir, turkey. case report keywords:hemangioma;cavernous;female;urethra;treatmentoutcome. introducti̇on genitourinaryhemangiomasarerareentitiesthatcanaffectanyportionoftheuri-narysystem.theurethraisrarelyinvolved,andmostreportedcaseshaveoccurredinthemaleurethra.(1)toourknowledgefewcasesofhemangiomaoccurringinthe femaleurethrahavebeenreported.(2,3)wereportacavernoushemangiomaoftheurethrain afemalepatient. case report a68yearsoldwomanpresentedwithurethralmassanddifficultyinvoiding.thepatienthad nohematuriaepisodesandnootherrelatedurologicalormedicalhistory.onexaminationa 2cmerythematous,polypoidmasswasarisingfromtheurethra(figure1).itdidnotappear tobeanurethralcaruncle.laboratoryvalueswerenormal.therewasaclinicalsuspicionfor malignanttumor.computedtomography(ct)scanofabdomenandpelvicfloorwasnormal. excisionoftheurethralmasswasplanned.beforetheexcisioncystoscopywasperformed, showingnormalbladderneckandbladdermucosa.afoleycatheterwasplacedwithout 1522 | difficulty.thenmassexcisedcompletely.theurethralmucosawasevertedwithinterrupted3-0syntheticabsorbable sutures.inpathologicalexamination,anencapsulatedmass was composed of large, cavernous vascular spaces filled withbloodandseparatedbyconnectivetissuestroma(figures2and3)whichdiagnosedascavernoushemangiomaof theurethra.thefoleycatheterwasremovedattheseventh postoperativedayandthepatientwascontinentafterwards. thepatienthadnosymptomsat3-monthfollow-upwithno evidenceoftumorrecurrence. discussion hemangiomasoftheurinarytractareveryrareandhave beendescribedinthekidney,ureter,bladder,prostateand urethra.(1) involvement of urethra is extremely rare, and therehavebeenonlyafewreportedcasesinwomen.(2,3) themostcommonsymptomishematuriabutpatientscan alsopresentwithurethralmass. for a female urethral mass, urethral caruncle, polyps, prolapseandperiurethralabscessshouldbetakeninconsideration for benign entities. squamous cell carcinoma, transitionalcellcarcinoma,adenocarcinoma,sarcomaand melanomaareresponsibleofmalignentities indescendingsequence.thesemassesusuallyrelapseinspiteoftheir benignnature.treatmentofurethralhemangiomascanincludeobservation,oralsteroidsandvariousmodalitiesof endoscopictreatmentsuchaselectrocauteryorlaserablation.(4) single, localized lesions should be removed with wideexcisionasthesetumorshavetendencytorecurunless completelyexcised. conflict of interest none declared. figure 1. mass protruding from the urethra. figure 2. cavernous vascular spaces filled with blood, and some thrombosis. there is squamous metaplasia at the surface epithelium (×10). figure 3. urothelium at the surface and vascular structures with connective tissue stroma and inflammatory cells (×10). case report 1523vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l cavernous hemangıoma of the female urethra | ongun et al references 1. jahn h, nissen hm. haemangioma of the urinary tract: review of the literature. br j urol. 1991;68:113-7. 2. uchida k, fukuta f, ando m, miyake m. female urethral hemangioma. j urol. 2001;166:1008. 3. tabibian l, ginsberg da. thrombosed urethral hemangioma. j urol. 2003;170:1942. 4. hayashi t, igarashi k, sekine h. urethral hemangioma: case report. j urol. 1997;158:539-40. 5. parshad s, yadav sp, arora b. urethral hemangioma. an unusual cause of hematuria. urol int. 2001;66:43-5. urological oncology investigation of renal cell carcinoma by contrast-enhanced ultrasoundpredictive value of time intensity curve analysis in establishing local tumor invasion and stage: a pilot study attila tamas-szora,1 mihai socaciu,1 nicolae crișan,2 florentin dobrotă,2 paul prunduș,2 cătălina bungărdean,3 mircea buruian,4 ioan coman,2 iulian opincariu,5 radu badea1* purpose: contrast-enhanced ultrasound (ceus) allows for real-time examination of signal intensity changes in a region of interest (roi) and quantification of contrast agent kinetics. this study assessed the predictive ability of time-intensity curve (tic) parameters for local tumor invasion and t stage of renal cell carcinoma (rcc). materials and methods: renal tumors in 41 patients were examined by ceus. thirty-two met the inclusion criteria, with a total of 33 tumors (27 clear cell, 4 chromophobe, and 2 papillary type i). nineteen (57.6%) tumors were included in group a (stages pt1 and pt2) and 14 (42.4%) in group b (stage pt3). rois were established as: whole tumor (tuw); tumor area with the highest signal intensity (tumax) and renal cortex (ref). the tic parameters for each roi were calculated as below: peak signal intensity, time to peak (ttp), rise time (rt), and mean transit time (mtt). they were analyzed as a whole value for each roi and as a ratio between the different rois. results: there were significant differences between the tumors invading and not invading the renal sinus fat for ttp (tuw/ref) [0.98 (0.67–1.25) vs. 1.18 (1.08–1.3), p < .05]. for differentiation between groups a and b, the following ratios were proven as predictors by univariate regression analysis: ttp (tumax/tuw); mtt (tumax/tuw); rt (tumax/tuw) (p = .03, p = .01 and p = .02, respectively). the value derived from the receiver operating characteristic (roc) curve for rt (tumax/tuw) was 0.8 with sensitivity = 78.6%, specificity = 89.5%, and cutoff value of > 0.91. conclusion: tic parameters were predictors of locally noninvasive and invasive rcc. keywords: carcinoma; renal cell; radiography; kidney neoplasms; sensitivity and specificity; image interpretation, ultrasonography; contrast media; methods. introduction renal cell carcinoma (rcc) accounts for about 2% of malignant tumors in adults, with the clear cell form representing 60–70%.(1) mortality is directly dependent on the tumor stage and varies between 1.2 and 2.5 per 100,000.(2-4) staging is based on the tnm classification and can be assessed preoperatively using computed tomography (ct) scan or magnetic resonance imaging (mri), and after tumor resection by anatomopathological examination (the gold standard). stages t1 and t2 include tumors limited to the kidney, the key difference between the two being given by the cutoff maximal diameter of 7 cm.(5) stage t3 comprises tumors infiltrating the perirenal fat, sinus fat and the venous system (in stages t3b and t3c, the vena cava is invaded below and above the diaphragm, respectively). stage t4 includes exten1 department of ultrasonography, octavian fodor regional institute of gastroenterology and hepatology, iuliu hațieganu university of medicine and pharmacy, cluj-napoca, romania. 2 department of urology, cluj-napoca municipal hospital, iuliu hațieganu university of medicine and pharmacy, cluj-napoca, romania. 3 department of pathology, cluj-napoca municipal hospital, iuliu hațieganu university of medicine and pharmacy, cluj-napoca, romania. 4 department of radiology and imaging, târgu mureș county emergency hospital, university of medicine and pharmacy, târgu mureș, romania. 5 department of anatomy, iuliu hațieganu university of medicine and pharmacy, cluj-napoca, romania. *correspondence: no.19-21 croitorilor st., 400162 cluj napoca, romania. tel: +40 745 512680. fax: +40 264 534241. e-mail: rbadea@umfcluj.ro. received december 2014 & accepted april 2015 sion beyond gerota’s fascia or to the adrenal gland. accurate differentiation between stages t1/t2 and stage t3 (mainly t3a) aids in the selection of patients in whom nephron-sparing techniques may be performed.(6-11) staging sensitivity of ct scan and mri vary between 80–83% and 78–87%,(12) which indicates the disadvantages of ionizing radiation and contraindications of specific contrast agent (ca).(13) ultrasound (us) is frequently the initial method for detecting renal tumors, providing staging accuracy of 77–85%,(14-16) and 89–100% for venous invasion alone. (17) gas superpositions and the patient’s constitution hamper the grayscale scan, and the angle of the fascicle with the vessel axis, together with blood flow velocity, alters the doppler results. in consequence, poor staging performance is encountered in some cases. contrast-enhanced us (ceus) consists of intravenous administration of second-generation cas(18-20) vol 12 no 03 may-june 2015 2173 and allows for continuous, real-time visualization of the signal intensity changes in the blood column passing through a region of interest (roi). ca kinetics can be quantified and displayed as time–intensity curves (tics), from which, quantitative parameters are obtained associated with the roi hemodynamics. the method can be applied in patients in whom iodineand gadolinium-based cas are contraindicated, and provide perfusion estimation from small vessels for which doppler measurements are unavailable. several studies have been published on the value of ceus in assessing rcc,(21-24) and with respect to tumor staging, most have been focused on qualitative data evaluation for identifying venous invasion, rather than predicting the final t stage. although it provides insight into tumor vascularization (which correlates with proliferation, invasiveness and dissemination), tic has not been analyzed as a possible predictor of invasion and stage.(25) the present pilot study aimed to: 1) obtain quantitative parameters reflecting the perfusion kinetics of rcc using ceus and tic; 2) identify the parameters that can act as predictors of specific local invasion (of the sinus fat, intrarenal collecting system, and perirenal fat and venous system); 3) establish the parameters that can act as predictors of t stage, and 4) evaluate the diagnostic performance of the established predictors. materials and methods study patients approval from the “iuliu hatieganu’’ university of medicina and pharmacy ethics committee was obtained and all the patients gave their written informed consent before enrollment. the study was performed in a single center, between 1 january 2012 and 1 may 2014, and prospectively enrolled 41 consecutive patients (27 men, 14 women, aged 30–84 years old). the inclusion criteria were: age > 18 years, no previous history of rcc, diagnosis of solid renal tumor, and being a candidate for tumor resection. the participants were included without any restriction related to the stage of the disease. exclusion criteria were: advanced cardiopulmonary disease, pregnancy, breast feeding, and rcc not confirmed in the resected specimens by the pathological examination report.(26) we further excluded cases in which tic curve fitting was < 60% and in which unusable frames were obtained during motion compensation. a priori sample size estimation was not achievable; therefore, the study protocol managed to maximize the sample size given the research budget available, in an effort to overpower the study as much as possible. ultrasound examination investigations were performed by two examiners (r.b. and a.t.) using a general electric logiq 7 system (new york, usa) equipped with a convex wide-band transducer (2–5.5 mhz), with the patients in the dorsal or lateral decubitus position. the initial examination of the kidney and tumor consisted of b-mode, color and power doppler us with settings such as gain, depth and focus adapted to each case. consequently, the scanning window for ceus was determined and consisted of a coronal or sagittal plane that encompassed a section of the entire tumor and adjacent cortex. the two planes were chosen based on the ability to maintain the same section of the above-mentioned structures in the us window, even if there were small excursions of the structures (due to breathing). during the examination, the patients were asked to breathe shallowly and not move. as recommended by the european federation of societies for ultrasound in medicine and biology (efsumb) guidelines for ceus, the focus was positioned under the roi, the mechanical index was set at a low value (0.09–0.11) and the time gain compensation keys were centered.(27,28) after ca injection, dynamic data were captured continuously on movie sequences of 30 seconds over a time span of 90 seconds and stored as raw data in the device storage unit. the ca used was sonovue (bracco, milan, italy), which consists of sulfur–hexafluoride microbubbles encased in a phospholipid shell.(29,30) it was prepared on the spot and a dose of 1.6 ml was administered into the cubital vein figure 1. clear cell renal cell carcinoma of the left kidney, stage pt1b, in a -63year-old woman. b-mode sagittal sonogram (a) identifying the tumor between the calipers. selection of regions of interest (b) using the signal intensity map provided by the software (c). signal intensity and time intensity curve graphs (d), normal renal cortex (ref, yellow), whole tumor parenchyma (tuw, green) and tumor parenchyma with highest signal intensity (tumax, purple). contrast enhanced ultrasound of renal cell carcinomas-tamas-szora et al. urological oncology 2174 (using a 20 gauge catheter), followed by a 10-ml saline (0.9%) bolus. for each tumor, a single contrast study was performed and considered adequate if the following quality criteria were met: visualization of the entire tumor and adjacent renal cortex; and the same section of the tumor and adjacent cortex were permanently kept in the scanning window throughout the examination. ceus data analysis for tic computations, the data were exported from the device (in dicom format) on a workstation provided with the image arena and sonoliver software (tomtec, unterschleissheim, germany). before the perfusion analysis, the clips were concatenated into a single 90-second sequence. first, two rois were manually traced in consensus by the examiners, as follows: whole tumor (tuw), and renal cortex (ref). the automatic compensation of motion was applied in order to maintain the correspondence between the traced rois and the encompassed structures. cases in which movement compensation resulted in unusable frames were excluded. afterwards, using the intensity color map displayed by the software, the tumor area with the highest signal intensity (tumax) was also traced with the above method, and the software automatically integrated the new roi into the motion compensated clip. the depth of the ref, tuw and tumax in relation to the transducer was kept as much as possible at similar values. the roi area for tumax was set between 0.5 and 1 cm2, and for ref, it was ≥ 1 cm2. for each roi, the software automatically generated a tic (in direct proportion with ca concentration), with the point of origin corresponding to the moment of contrast injection (the zero second) and calculated the following parameters: (a) peak signal intensity (imax) (quantified as %; related to ref for which the value was always considered 100%); (b) rise time (rt) (the ascending slope of the curve, measured in seconds, independent of the time of origin); (c) time to peak (ttp) (measured in seconds, representing the time necessary for the signal to reach its peak intensity in the region of interest), and (d) mean transit time (mtt) (measured in seconds, corresponding to the gravity center of the perfusion model) (figure 1). the cases in which the tics had a poor quality of fit < 60% (as indicated automatically by the software) were excluded. histopathological examination all the surgical resection specimens were sent to the anatomopathology department, sectioned, and analyzed by the same specialist (c.b.). macroscopic and microscopic examination was performed for each specimen. the longest diameter of the tumor was assessed, together with the tumor cell type and fuhrman grade (for clear cell carcinoma). tumor invasion of the following anatomical structures was recorded: sinus fat, collecting system, perirenal fat, pararenal fat, renal and caval venous systems, and ipsilateral adrenal gland. the revised version of the tnm staging as proposed by the american joint committee on cancer in 2010(5) was used. statistical analysis the tumors were grouped according to the histopathological examination of invasion into the sinus fat, perirenal fat, collecting system and venous system (any of the following: renal vein, inferior vena cava below the diaphragm or above). also, the tumors were distributed into group a, which included stages t1 and t2, and group b, which included stage t3. the d’agostino and pearson omnibus normality test was first applied and the mann–whitney test u was used for comparison of medians (p < .05). the analysis was done with the help of graphpad prism (la jolla, ca, usa), medcalc (ostend, belgium) and microsoft excel 2010 (redmond, wa, usa). the parameters obtained following tic generation (imax, ttp, table 1. anatomopathological characteristics of the study population. tumor type no. (%) presence of (no.): sinus fat invasion collecting system invasion venous system invasion perirenal fat invasion clear cell 27 (75.8) 5 4 7 4 chromophobe 4 (9.1) 2 2 1 1 papillary type 1 2 (6.1) 0 0 0 0 roi imax (%) ttp (s) mtt (s) rt (s) ref 100*** 20.49 (18.97-23.48) 36.8 (30.9-43.04) 15.23 (12.27-17.18) tuw 71.95 (36.75-91.98) 24.45 (21.31-28.14) 52.4 (37.14-66.18) 20.44 (13.98-23.52) tumax 128.23 (92.96-196.35) 22.52 (18.41-25.14) 38.67 (27.46-47.74) 14.5 (11.21-17.88) tuw/ref** 0.72 (0.36-0.91) 1.08 (1.02-1.21) 1.26 (1.06-1.55) 1.16 (1.03-1.32) tumax/ref** 1.28 (0.92-1.96) 1.04 (0.94-1.14) 1 (0.83-1.23) 0.96 (0.83-1.13) tumax/tuw** 1.98 (1.66-2.45) 0.98 (0.9-0.99) 0.81 (0.7-0.96) 0.84 (0.69-0.98) abbreviations: roi, region of interest; ref, region of reference; tuw, whole tumor; tumax, area in the tumor with the highest signal intensity; imax, peak signal intensity; ttp, time to peak (of signal intensity); rt, rise time; mtt, mean transit time. * data are presented as medians (95% confidence intervals). ** without units of measurement, being ratios. *** for ref the imax value was always considered 100%. table 2. time-intensity curve parameters for the 33 tumors, non-discriminant for invasion and groups.* contrast enhanced ultrasound of renal cell carcinomas-tamas-szora et al. vol 12 no 03 may-june 2015 2175 rt and mtt) were included in the statistical analysis either as primary values or as ratios. primary values: for each roi (tuw, tumax and ref) of all the above groups were calculated and the medians of the parameters were compared according to the model: imax (tuw) of group a versus imax (tuw) of group b. ratios: the medians were calculated from the ratios obtained by dividing the parameters of tuw to ref, tumax to ref and tumax to tuw, according to the model: imax (tuw/ref) = imax (tuw) / imax(ref) and ttp (tuw/ref) = ttp (tuw) / ttp (ref). the resultant medians were compared between the groups, as follows (e.g.): imax (tuw/ref) of group a versus imax (tuw/ref) of group b. the statistically significant parameters were included in the univariate logistic regression analysis for establishing the predictive value. the predictors of invasion and group were included in the multivariate logistic regression analysis in order to identify the combined predictive value. for the identified predictors the receiver operating characteristic (roc) curve analysis was used and sensitivity (se), specificity (sp), area under the curve (auroc) and cutoff values were calculated. post-hoc power analysis was performed with the help of gpower software (universitat kiel, kiel, germany) by applying the post hoc analysis module to calculate the achieved power of the mann–whitney u test (two-tailed, α error probability set at 0.05). results of the 41 patients initially examined by ceus, nine were excluded. three had benign tumors (2 angiomyolipomas and 1 oncocytoma); two did not undergo surgery; two had tic fitting quality < 60%, and in two cases the whole tumor and adjacent renal cortex could not be maintained in the same scanning plane during ceus and thus resulted in unusable frames after motion compensation. in the remaining 32 patients (20 male and 12 female; age ± standard deviation [sd] 60.9 ± 10.43 years), 33 solid tumors were analyzed (1 case with bilateral rcc). partial nephrectomy was performed in five (15.15%) cases and 28 (84.84%) underwent radical surgery. the average time between ceus examination and surgery was 20.67 days (range 7–29 days). the median and 95% confidence interval (ci) for the maximal diameter (as measured by the pathologist) was 56 mm (32–76 mm). the histopathological features are presented in table 1. table 3. statistical analysis of medians for the invasion of sinus fat and for group.* parameters values mann-whitney u test univariate regression multivariate regression p value p value p value invasion of sinus fat versus no invasion ttp (tuw/ref) 0.98 (0.67-1.25) vs. 1.18 (1.08-1.3) .020 .067 ----mtt (tumax/tuw) 1.02 (0.7-1.68) vs. 0.76 (0.59-0.88) .045 .136 ----group a versus group b mtt (tumax/ref) 0.84 (0.65-1.05) vs. 1.29 (0.82-2.29) .034 .068 ----ttp (tumax/tuw) 0.91 (0.81-0.98) vs. 0.99 (0.91-1.06) .025 .036 .963 mtt (tumax/tuw) 0.67 (0.53-0.77) vs. 1(0.86-1.1) .001 .017 .157 rt (tumax/tuw) 0.76 (0.6-0.83) vs. 1 (0.89-1.05) .003 .021 .637 abbreviations: ttp, time to peak (of signal intensity); tuw, whole tumor; ref, region of reference; mtt, mean transit time; tumax, area in the tumor with the highest signal intensity; imax, peak signal intensity; rt, rise time. * the univariate and multivariate analyses for the determining of single and combined predictors for: invasion of sinus fat, localized, and locally invasive tumors. values are presented as medians (95% confidence intervals). group a, t1 and t2 anatomopathological stages; group b, t3 anatomopathological stage. parameters sample size of each group effect size resultant power (1-β) invasion of sinus fat versus no invasion ttp (tuw/ref) 7 and 26 0.76 0.39 mtt (tumax/tuw) 7 and 26 0.68 0.32 group a versus group b* mtt (tumax/ref) 19 and 14 0.79 0.56 ttp (tumax/tuw) 19 and 14 0.94 0.71 mtt (tumax/tuw) 19 and 14 1.05 0.80 rt (tumax/tuw) 19 and 14 1.01 0.77 abbreviations: ttp, time to peak (of signal intensity); tuw, whole tumor; ref, region of reference; mtt, mean transit time; tumax, area in the tumor with the highest signal intensity; imax, peak signal intensity; rt, rise time. * group a, t1 and t2 anatomopathological stages; group b, t3 anatomopathological stage. table 4. achieved power of the mann–whitney u test as obtained by post-hoc power analysis (two-tailed, α error probability set at 0.05). contrast enhanced ultrasound of renal cell carcinomas-tamas-szora et al. urological oncology 2176 nineteen (57.6%) tumors were included in group a (stages t1and t2) and 14 (42.4%) in group b (stage t3). the tic parameters for all 33 rccs are presented in table 2. there were significant differences for imax (ref) versus imax (tuw) (p = .001), imax (ref) versus imax (tumax) (p = .04) and imax (tuw) versus imax (tumax) (p = .003). no significant differences were found between ttp, mtt and rt of ref versus tuw, ref versus tumax, an dtuw versus tumax. analysis of the cases with invasion of the adjacent structures and the non-invading ones and the comparative analysis of groups a and b are presented in table 3 (for cases with p < .05). the table also contains the results of the univariate logistic regression analysis that identified the predictive factors of the sinus fat invasion and of the group (between groups a and b). the parameters that preserved their predictive value in the univariate regression were included in the multivariate logistic regression. for the parameters presented in table 3 that were significant as predictors of the groups (a and b), the roc curves were plotted (figure 2). the roc curve characteristics were: ttp (tumax/tuw): auroc = 0.73, se = 71.4%, sp = 63.2%, and cutoff value > 0.94; mtt (tumax/tuw): auroc = 0.82, se = 78.6%, sp = 84.2%, and cutoff value > 0.87; rt (tumax/tuw): auroc = 0.8, se = 78.6%, sp = 89.5%, and cutoff value ≥ 0.91. the post hoc power analysis is presented in table 4. discussion grayscale and doppler us represent useful techniques for the detection and characterization of rcc.(31) the accuracy in staging varies among studies, from 20%(32) to 77–85%.(14-16) the sensitivity for visualizing renal vein invasion is 100% and 89–100% for the inferior vena cava.(15,17,33,34) however, the method remains operator-dependent and may be ineffective in excessively obese patients. the current guidelines recommend the routine use of ct/mri, for which overall rcc staging accuracy is 80–83% (ct) and 78–87% ( mri).(12) with the advent of new-generation us equipment, ceus has repositioned us imaging in renal oncology, and thus a re-evaluation of its role in rcc staging is needed. the advantages of ceus are represented by the good temporal resolution, which is superior to contrast-enhanced ct (cect)/mri and the angiospecific character (ca remains strictly intravascular). the capacity of ceus to detect vascularization, even with low velocity is higher than that of cect.(35) also, there are general studies confirming that, when it comes to tumoral perfusion quantification, the findings of ceus are consistent with those obtained by dynamic contrast-enhanced mri, cect and fluorodeoxyglucose positron emission tomography.(36,37) it has been shown that the late-phase washout is suggestive for rcc (se = 77% and sp = 96%).(38) the performance of ceus in diagnosing rcc is still debated. zhou and colleagues mentioned se = 86% and sp = 93%, while ignee and colleagues in a study of 137 renal tumors concluded that the differentiation between rcc and benign tumors is difficult.(22,39) the efsumb guidelines currently recommend the use of ceus in kidney neoplasms for differentiation between solid and cystic tumors; between pseudotumors and tumors; for follow-up of tumors during/after us-guided ablations, and for differentiation of complex cystic masses into benign/undetermined/malignant.(27) recent studies, however, refer to the value of ceus in the staging of renal cancer.(28) the majority of the above-mentioned articles have focused on the qualitative assessment of the kinetics of cas. tic studies regarding renal malignancies are scarce. one of them mentions that a lower signal intensity is associated with a good response in the case of advanced/metastatic rcc treated by kinase inhibitors.(40,41) we could find only one study that described the usage of tic parameters for the diagnosis of rcc.(42) the authors investigated the most vascularized area of the tumor and assessed the differences between ttp and signal intensity in the rcc and ref. although the tic has the advantages of objecfigure 2. comparison of receiver operating characteristic (roc) curves. roc curves plotted for each of the group (a and b) predictors, ttp (tumax/tuw) in blue, mtt (tumax/tuw) in red, and rt (tumax/tuw) in yellow. abbreviations: roc, receiver operating characteristic; ttp, time to peak; tumax, tumor area with the highest signal intensity; tuw, whole tumor; mtt, mean transit time; rt, rise time. contrast enhanced ultrasound of renal cell carcinomas-tamas-szora et al. vol 12 no 03 may-june 2015 2177 tive, reproducible measurements of the contrast kinetics,(42-44) no studies have investigated their possible value as a predictor of tumor invasion and stage. we studied extensively the parameters obtained from the tic and identified predictive factors for the low or high t stages (groups a and b) in relation to the gold standard of histopathological analysis. the assessment was performed for three different rois (ref, tuw and tumax). we considered it necessary to explore tumax because most rccs in our group presented with non-enhancing areas or inhomogeneous enhancement. thus, we attempted to limit the influence on the results of those regions with reduced or absent perfusion (indicative for necrosis, hemorrhage, or fibrosis). evaluation of the imax was significant for all the rois; the scale of the imax being tumax > ref > tuw, without being associated with a certain type of invasion or a specific group. the assessment was quantitative and included the signal intensity data over an interval of 90 seconds. the imax is considered to correspond to the circulating blood volume in the tumor.(45) there is no unanimous acceptance regarding the signal intensity characteristics of rcc. jianga and colleagues have demonstrated a marked enhancement in over 80% of the renal cancers investigated.(46) xu and colleagues have found that most renal cancers are hyperor iso-enhancing in the cortical phase (93%), becoming hypo-enhanced in the late phase (82%).(47) these variations and the differences we found between the most enhancing tumoral area and the entire tumor were the reasons why we also used the ratios between the tic parameters of the different rois. another factor was the attempt to minimize the variability among patients, caused by the examination environment, the device settings, post-processing and individual hemodynamic status.(48) we consider that the ratios between tumax and tuw could also prove beneficial in the case of large tumors in which concomitant viewing of the entire tumor and adjacent parenchyma during ceus may be difficult. this was the case in two of our patients initially examined and afterwards excluded from the study. assessment of the other parameters (ttp, mtt and rt) between the tuw and tumax of all 33 tumors and the ref did not show significant differences. when looking at tumors that presented with pathologically proven invasion of the venous system in comparison with the non-invading ones, we found no consistent difference among the tic parameters (neither as absolute values nor as ratios). from this point of view, it has been described by others that qualitative interpretation of ceus data has a similar accuracy as cect for showing renal vein invasion.(27) regarding the targeted assessment of invasion into the collecting system, sinus and perirenal fat, the studies using ceus were limited and need completion. cokkinos and colleagues concluded that the presence of an enhancing structure in the caliceal system is a good criterion for differentiation between neoplastic tissue and debris/pus.(23) ignee and colleagues found that accurate ceus staging of rcc was obtained in 88% of cases (91% with cect).(22) in our study, the median values of ttp (tuw/ref) and mtt (tumax/tuw) were significantly different between the tumors invading and not invading the sinus fat, but none were significant as predictors. these results may be due to the small number of patients and tumors that invaded the sinus fat (7 cases). none of the parameters presented a statistically significant value in relation to invasion of the collecting system or perirenal fat. although these results were negative, this is believed to be the first time that tic parameters have been used for predicting local invasion of rcc. the comparative analysis of groups a and b demonstrated that several parameters differed significantly: mtt (tumax/ref), ttp (tumax/tuw), mtt (tumax/tuw) and rt (tumax/tuw). the highest power was demonstrated for mtt (tumax/tuw) and rt (tumax/tuw) (0.8 and 0.77, respectively). according to the univariate logistic regression analysis, only ttp (tumax/tuw), mtt (tumax/tuw) and rt (tumax/tuw) were predictors of the group. it is important to emphasize that all these parameters included tumax in the ratio. this suggests that inclusion in the analysis of the highest signal intensity area leads to consistent results (in the context of the analysis related to tuw). in contrast, multivariate logistic regression analysis did not validate any of the three predictors. this does not necessarily nullify the predictors, because it could be explained by the correlations among these parameters; all are related to the same perfusion model equation.(49) when we introduced the predictors of groups a and b (achieved by univariate analysis) into the analysis of the roc curves, the best diagnostic performances were obtained for mtt (tumax/tuw) (se = 78.6%, sp = 84.2%, auroc = 0.82, and cut-off value > 0.87) and rt (tumax/tuw) (se = 78.6%, sp = 89.5%, auroc = 0.8, and cutoff value > 0.91). these two parameters are of interest also because there were no super-positions between the median values of the two groups and this contributed to the predictive capacity. given these, the two seem to constitute as factors that are worthwhile investigating in future research. furthermore, owing to the fact that the abovementioned parameters did not use the adjacent renal cortex as a factor in the ratio, exclusion of patients related to the inability to maintain the ref in the scanning plane could be limited in forthcoming studies. our study did not assess the variations of the tic parameters owing to the settings of the equipment. regarding this, gauthier and colleagues proved that the rt is more constant compared with the mtt (variation coefficient 0.7–6.9% vs. 0.8–19%).(48) also, ignee and colleagues stated that rt and ttp do not vary significantly in relation to the depth and lateral shift.(50) to validate the diagnostic value of the parameters used in the prediction of localized and advanced rcc, it would have been ideal to compare larger patients groups and a control group. it was one of the limitations of the present study. other limitations were as follows. we did not quantify the inter-observer agreement for establishment of the rois; they were selected in consensus. no cases presented with invasion of the pararenal fat or adrenal gland, and a limited number presented with invasion of the venous system. some patients were excluded owing to benign pathology, tic poor fitting and inability to maintain both the ref and tumax in the scanning plane. in future studies, investigation of the following tic parameters might also prove useful: area under the entire curve, and area under the washin and wash-out curves (could not be calculated with the provided sonoliver software version).(45) despite its limitations, we believe that our study creates strong prerequisites for further research regarding the tic parameters and their potential role in rcc staging. using tic in predicting tumor stage could prove especially beneficial for those patients with contraindicacontrast enhanced ultrasound of renal cell carcinomas-tamas-szora et al. urological oncology 2178 tions for cect or mri (due to renal insufficiency, allergic reactions, or risk of nephrogenic systemic fibrosis). to date, we have not yet seen a one-stop imaging tool capable of overcoming all the challenges posed by rcc diagnosis and staging, but rather a combination of us, ceus, ct, mri and nuclear imaging. all these methods provide complementary data. ceus with its analysis of perfusion is an interesting and rapidly evolving technique. it provides an exciting new spectrum of information in addition to that of the above-mentioned techniques. in order to fulfill its potential considerable efforts are still needed.(51) conclusion the signal intensity differed significantly among the areas investigated; the scale being tumax > ref > tuw. quantitative assessment of the ca kinetic parameters extracted from the automatic analysis of the tic identified ttp (tumax/tuw), mtt (tumax/ tuw), and rt (tumax/tuw) as predictors of locally advanced tumors. among them, mtt and rt had the highest predictive performance. ceus is a non-invasive method, with minimal limitations, that may be valuable in the preoperative protocol of rcc staging. acknowledgments this paper was published under the frame of european social found, human resources development operational programme 2007-2013, project no. posdru/159/1.5/s/138776. the authors thank szasz maria for her 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jalil hosseini,1 mohammadreza rahmani,1 mohammadreza razzaghi,1 mohammadreza barghi,1 hossein karami,1 seyed mohammad mehdi hosseini moghaddam2 introduction: fournier gangrene is a rare, rapidly progressive, necrotizing fasciitis of the external genitalia, the perineum, or the abdominal wall that is associated with high morbidity and mortality. in this series, we describe 12 patients with fournier gangrene who had presented to our medical center. materials and methods: twelve men had been diagnosed with fournier gangrene in shohada-etajrish hospital between march 2002 and september 2005. their medical records were reviewed and the fournier gangrene severity index scores before and after the treatment were determined. results: fifty percent of the patients were diabetic and their mean age was 58.2 ± 17.8 years. the mean delay between the onset of the disease and the admission was 4.9 days and the mortality rate was 16.6%. the median fournier gangrene severity index scores before the admission and at the time of discharge were 4.5 (range, 0 to 11) and 0 (range, 0 to 9), respectively (p = .005). one of the patients who died had the scores of 11 and 9, respectively. split-thickness skin graft was performed for 5 patients (41.7%). conclusion: in fournier gangrene, a rapid diagnosis and emergent surgical intervention is crucial. the fournier gangrene severity index seems to be an excellent tool for outcome prediction. urol j (tehran). 2006;3:165-70. www.uj.unrc.ir keywords: fournier gangrene, scrotum, split-thickness skin graft 1shohada-e-tajrish hospital, shaheed beheshti university of medical sciences, tehran, iran 2urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: smm hosseini moghaddam, md urology and nephrology research center, no 44, 9th boustan, pasdaran, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: h_sasan@hotmail.com received april 2006 accepted july 2006 introduction fournier gangrene, a disease that almost exclusively affects men, is a necrotizing fasciitis of the external genitalia and the perineal region. the cause is a polymicrobial infection in association with superficial traumas, urologic diseases, and surgical operations, as well as colorectal diseases. diabetes mellitus, immunosuppression, alcoholism, and other severe illnesses are also frequent cofactors.(1) due to potential severe complications, it is important to diagnose the disease as early as possible. mortality rate of fournier gangrene can be reduced by intensive care and appropriate antibiotic therapy with the coverage of aerobic grampositive and gram-negative bacteria as well as anaerobic microorganisms combined with surgical treatment.(2) we conducted this study to analyze the outcome and identify the associated risk factors and prognostic indicators of fournier gangrene. to our knowledge, this is the first report from iran and advocates the use of fournier gangrene severity index (fgsi). materials and methods between march 2002 and september fournier gangrene—hosseini et al 166 urology journal vol 3 no 3 summer 2006 2005, this study was carried out in shohada-e-tajrish hospital, a tertiary referral medical center. a total of 12 patients with fournier gangrene were diagnosed, treated, and followed up in a multidisciplinary fashion. following admission, correction of the fluid and electrolyte imbalance, and estimation of the extension and depth of the gangrenous area, we determined the fgsi scores using 9 parameters including the body temperature, heart rate, respiratory rate, hematocrit, white blood count, and serum levels of sodium, potassium, creatinine (× 2 for acute renal failure), and bicarbonate.(3) these parameters were measured and the degree of deviation (either positive or negative) from the normal values was graded from 0 to 4. the total value was considered as the fgsi.(3) in addition, serum levels of calcium, and albumin, as well as fasting blood glucose and blood urea nitrogen (bun) were measured. an interview was conducted with the patients and their relatives to evaluate their past medical and surgical history including diabetes mellitus, alcoholism, and previous trauma or surgery. presence of concurrent illnesses including hypertension, urethral stricture or manipulation, malignancy, cerebrovascular accident, spinal cord injury, renal insufficiency, pneumonia, and other infections like perianal abscess were reviewed. the time between the onset of the disease and reference to the medical center and existence of the signs such as edema, erythema, necrosis, malodorous discharge, crepitation, and fluctuance were assessed. plain radiography and ultrasonography were requested for all patients. urine, blood, and tissue samples were taken for culture and antibiogram; however, a wide-spectrum antibiotic therapy had been initiated empirically before the results were obtained. this empiric therapy included the combination of a 3rd generation cephalosporin, an aminoglycoside, and metronidazole or clindamycin. then, antibiotic therapy was changed according to the results of tissue culture and continued until the active infection was controlled. we assessed the portal of entry for causative microorganisms and categorized them as colorectal, urologic, cutaneous, and unknown. following extensive debridement, urinary diversion with suprapubic cystostomy was performed in patients with urethral trauma or extravasation. colostomy was performed in cases with colonic or rectal perforation. orchiectomy or penectomy was performed in patients with involvement of the tunica albuginea. one or two days after the initial operation, surgical exploration was performed in order to exclude further extension of the necrosis. multiple reexplorations were continued until the infection was well controlled and the patients were prepared for grafting with at least a 2to 3-week interval (figure 1). the body surface area (bsa) involved by the infection was assessed using the burn index.(4) after multiple episodes of debridement (if needed) and development of the granulation tissue, we evaluated the protection of the testis in figure 1. the wound 4 weeks after debridement in a 64-year-old patient (patient number 12 in the tables) figure 2. patient number 12. the testes were placed in the superficial thigh pouch and the suprapubic and penile areas were repaired with a meshed graft and a nonmeshed splitthickness skin graft, respectively. fournier gangrene—hosseini et al urology journal vol 3 no 3 summer 2006 167 a subcutaneous thigh pouch or making a skin graft. our preferred integument for covering the penis was a thick, nonmeshed, split-thickness skin graft (stsg). in patients with skin loss in other sites, simple suture of wound or stsg was performed (figure 2). when stsg were used, 0.010to 0.015-inch grafts were harvested from the anterior thigh with a dermatome. in patients with scrotal skin loss involving less than 50% of the skin, we could close the wound successfully. split-thickness skin graft meshed 2:1 was used for patients with total scrotal skin loss. achieving satisfactory cosmetic results, normal voiding, and established sexual function were our goals in follow-up. three patients lost follow-up and 2 died. seven patients were followed routinely for 3 to 30 months. the comparison of the fgsi scores before and after the treatment was performed using wilcoxon signed rank test. results all of the patients were men. the mean age of the patients was 58.2 ± 17.8 years (range, 18 to 85 years). the mean delay between the onset of the symptoms and hospital admission was 4.9 days (range, 1 to 10 days). five (41.7%), 6 (50%), and 5 (41.7 %) patients had colorectal, urologic, and cutaneous lesions, and 4 (33.3%) patients had 2 underlying causes. table 1 shows the patients’ demographic and clinical table 1. demographic and clinical characteristics of 12 patients with fournier gangrene *bsa indicates body surface area. patients 1 2 3 4 5 6 7 8 9 10 11 12 age, y 82 63 57 68 47 64 57 34 74 70 18 64 etiology colorectal + + + + + urologic + + + + + + cutaneous + + + + + predisposing conditions diabetes mellitus + + + + + + alcoholism + trauma + + previous surgery + + + clinical signs edema + + + + + + + + + + + erythema + + + + + + + + + necrosis + + + + + + + + discharge + + + + + + + + crepitance + + + + + + + fluctuance + + + + blood urea nitrogen, mg/dl 45 108 36 61 18 20 25 11 22 29 11 18 location of lesions penile shaft + + + + + + + scrotum + + + + + + + + + + + perineum + + + + + + suprapubic + + + + inguinal + + + + + thigh + + + urethra + bsa involved with infection, %* 2.5 3 1 2 4.5 5 1.5 4.5 6 4.5 6.5 3 concurrent illnesses hypertension + + + + + urethral stricture/manipulation + + malignancy + cerebrovascular accident + septicemia + pneumonia + + perianal abscess + + + + + fournier gangrene—hosseini et al 168 urology journal vol 3 no 3 summer 2006 characteristics. six patients (50%) had type 2 diabetes mellitus for a mean period of 4.7 years (range, 1 to 8 years), one of whom had concurrent metastatic transitional cell carcinoma of the bladder. one patient (8.3%) was alcoholic. none of the patients immunocompromised. one patient (8.3%) had a history of the local trauma to perineum because of electric perineal massage. hypocalcaemia was diagnosed in all cases (100%). involvement of the corpus cavernosum, episodes of vomiting, dysuria, pain, and fever were detected in 1 (8.3%), 1 (8.3%), 6 (50%), 9 (75%), and 8 (66.7%) patients, respectively. no patient complained of diarrhea. urine culture was positive for bacteria in 5 (41.7%) patients demonstrating infections with escherichia coli and enterococcus faecalis. bacteremia with staphylococcus aureus was detected in 1 patient. tissue culture was positive in all patients demonstrating mixed gramnegative enteric, gram-positive cocci, and anaerobic microorganisms. we carried out total penectomy, partial orchiectomy, and total orchiectomy for 3 patients (25%). colostomy, suprapubic diversion, and a mixture of both techniques were performed in 1 (8.3%), 4 (33.3%), and 3 (25%) patients. no diversion was done for the remaining 4 patients (33.3%). for repairing the scrotum, we created a thigh pouch for 5 (41.7%) and used skin grafts for 2 (16.7%) patients. a simple closure of the scrotal skin was done in 1 patient. no surgical reconstruction was performed for the 3 patients with scrotal lesion. for repairing the lesions in the groin, perineum, penis and suprapubic area, we used skin grafts for 5 patients and simple closure for 3 patients (table 2). we had no cases of postoperative surgical complications. however, gastrointestinal bleeding, deep vein thrombosis, and pulmonary emboli occurred in 1 patient who died. additionally, renal dysfunction secondary to sepsis and pneumonia developed in another patient that was treated successfully. one patient (8.3%) experienced postoperative necrotizing pneumonia and died. the mortality rate in this series was 16.7% (2 out of 12). both patients who died had bun levels over 50 mg/dl at presentation. table 2 shows the fgsi scores in detail before and after the admission. the median fgsi scores before the admission and at discharge were 4.5 (range, 0 to 11) and 0 (range, 0 to 9), respectively (p = .005). discussion the clinical signs and symptoms of fournier gangrene in our patients were similar to that explained in the literature.(2,5) after a nondistinctive prodromal period consisting of local discomfort and fever, typical presentations including crepitus, swelling, and erythema developed. in patients with severe clinical presentations, progression of the gangrenous process leading to malodorous drainage and sloughing in affected sites were present and resulted in the deterioration of the patients’ conditions. considering rapidity of the spread of the gangrenous area that is reported to be up to 2 cm/h to 3 cm/h, prompt diagnosis and appropriate emergent management seems to be vital.(2) although laor and colleagues claimed that the interval between the onset of the disease and the hospital admission does not play an important role table 2. clinical course and outcome in 12 patients with fournier gangrene* *pp indicates partial penectomy; po, partial orchiectomy; to, total orchiectomy; stsg, split-thickness skin graft; and fgsi, fournier gangrene severity index. patients 1 2 3 4 5 6 7 8 9 10 11 12 diversion + + + + + + + + surgical procedures pp po to surgical debridement 2 2 3 1 2 3 4 1 3 2 3 4 reconstructive surgery meshedstsg meshedstsg stsg stsg stsg primary closure + + + + superficial thigh pouch + + + + + hospital stay, d 19 14 40 11 24 17 29 36 30 11 38 30 fgsi at admission 5 11 2 4 1 5 7 0 5 2 2 6 fgsi at discharge 0 9 0 0 0 5 0 0 2 0 2 2 mortality + + fournier gangrene—hosseini et al urology journal vol 3 no 3 summer 2006 169 in the prognosis and clinical outcomes, the mortality rate may increase in patients with a significant delay before the reference to the medical center.(3,6) anemia due to the lack of the functioning erythrocyte mass secondary to thrombosis and sepsis, elevated serum creatinine level, and hyponatremia were common in our patients. hypocalcaemia, diagnosed in all cases of our study, seems to be secondary to the destruction of triglycerides by bacterial lipases and release of the free fatty acids that are chelators of the ionized form of the calcium.(7) both patients who died in our series had a serum bun level higher than 50 mg/dl at presentation. these patients had also a significant hypoalbuminemia in their first laboratory studies. clayton and coworkers found that survival of patients with necrotizing fasciitis was associated significantly with a bun level of less than 50 mg/dl at presentation.(8) it is also suggested that hypoalbuminemia might be a noticeable factor for the prediction of the mortality rate.(6,9) the bsa of involvement and number of the episodes of the debridement were not important factors for predicting the outcome in this series. in addition, because of the limited number of the cases studied in this series, the comparison of fgsi score between the survivors and died patients was impossible. however, this index seems to be an outstanding prognostic factor for the assessment of the outcome.(3) lin and colleagues and also yeniyol and colleagues demonstrated that a cutoff point of 9 for fgsi is appropriate for the evaluation of the therapeutic options and prediction of the mortality rate.(10,11) multiple predisposing factors leading to fournier gangrene have been described in the literature including diabetes mellitus, local trauma, paraphimosis, periurethral extravasation of the urine, perirectal or anal infections, and surgeries such as circumcision or herniorrhaphy.(12) although the majority of the patients presented in this series had diabetes mellitus (50%), other predisposing factors including previous surgeries (25%), trauma (16.6%), and alcoholism (8.3%) were also present. since 50% of the patients in this series were nondiabetic, diabetes mellitus seems not to be a necessary underlying disease for fournier gangrene. there is still controversy as to whether the coexistence of diabetes mellitus influences prognosis.(13) some published series have emphasized that hyperbaric oxygen therapy can be helpful for the management of fournier gangrene. limitations in the availability and transfer of the patients to units offering this service restrict its application for the patients with fournier gangrene.(14,15) consequently, we did not utilize hyperbaric oxygen therapy for our patients. while traditional teaching holds that the testes are rarely affected in fournier gangrene because of their independent blood supply, testicular involvement is a recognized complication. the rate of patients requiring orchiectomy for nonviable testes is up to 21% in some series.(15,16) conclusion fournier gangrene is a life-threatening fasciitis of the external genitalia, the perineum, or the abdominal wall with noticeable morbidity and mortality rates. based on our finding, we can conclude that fgsi score as well as serum levels of calcium, albumin and bun might be good predictors of the outcome. conflict of interest none declared. references 1. ayan f, sunamak o, paksoy sm, et al. fournier’s gangrene: a retrospective clinical study on forty-one patients. anz j surg. 2005;75:1055-8. 2. paty r, smith ad. gangrene and fournier’s gangrene. urol clin north am. 1992;19:149-62. 3. laor e, palmer ls, tolia bm, reid re, winter hi. outcome prediction in patients with fournierfournier’s gangrene. j urol. 1995;154:89-92. 4. dahm p, roland fh, vaslef sn, et al. outcome analysis in patients with primary necrotizing fasciitis of the male genitalia. urology. 2000;56:31-5. 5. pizzorno r, bonini f, donelli a, stubinski r, medica m, carmignani g. hyperbaric oxygen therapy in the treatment of fournierfournier’s disease in 11 male patients. j urol. 1997;158:837-40. 6. jeong hj, park sc, seo iy, rim js. prognostic factors in fournier gangrene. int j urol. 2005;12:1041-4. 7. schaeffer aj. infections of the urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 590-1. fournier gangrene—hosseini et al 170 urology journal vol 3 no 3 summer 2006 8. clayton md, fowler je jr, sharifi r, pearl rk. causes, presentation and survival of fifty-seven patients with necrotizing fasciitis of the male genitalia. surg gynecol obstet. 1990;170:49-55. 9. chawla sn, gallop c, mydlo jh. fournier’s gangrene: an analysis of repeated surgical debridement. eur urol. 2003;43:572-5. 10. lin e, yang s, chiu aw, et al. is fournierfournier’s gangrene severity index useful for predicting outcome of fournierfournier’s gangrene? urol int. 2005; 75:119-22. 11. yeniyol co, suelozgen t, arslan m, ayder ar. fournierfournier’s gangrene: experience with 25 patients and use of fournierfournier’s gangrene severity index score. urology. 2004;64:218-22. 12. miller jd. the importance of early diagnosis and surgical treatment of necrotizing fasciitis. surg gynecol obstet. 1983;157:197-200. 13. morpurgo e, galandiuk s. fournier’s gangrene. surg clin north am. 2002;82:1213-24. 14. quatan n, kirby rs. improving outcomes in fournierfournier’s gangrene. bju int. 2004;93:691-2. 15. hejase mj, simonin je, bihrle r, coogan cl. genital fournier’s gangrene: experience with 38 patients. urology. 1996;47:734-9. 16. mindrup sr, kealey gp, fallon b. hyperbaric oxygen for the treatment of fournier‘s gangrene. j urol. 2005;173:1975-7. unclassified comparison of the efficacy of oxybutynin, phenazopyridine, celecoxib, and placebo in the treatment of urinary tract symptoms after bcg therapy in patients with bladder tumors koosha kamali1 , javad nikbakht1, erfan ayubi3, mostafa nabizadeh1, saeedeh sarhadi2* purpose: intravesical bcg (bacillus calmette–guérin) therapy is indicated as an effective treatment for patients with non-muscle-invasive bladder cancer, despite associate with the side effects. in this study, the incidence of bcg therapy adverse effects was compared among three groups of patients who received celecoxib, phenazopyridine, and oxybutynin with placebo. materials and methods: the randomized controlled clinical trial was conducted on four groups using the parallel group method. a checklist is used for weekly assessment of urinary symptoms, systemic symptoms of bcg therapy, and adverse drug reactions. results: the study included 120 patients, 10 female and 110 male. the mean age 59.65 ± 6.2 years. the results of multivariate analysis show that there is a significant decrease in urinary frequency for patients who received phenazopyridine (95% ci: 0.09, 0.31, or = 0.17, p <.001) and also celecoxib group (95% ci: 0.10, 0.43, or = 0.21, p <.001) compared to those in placebo group. patients in celecoxib group (95% ci: 0.02, 0.07 ,or = 0.04, p <.001), phenazopyridine (95% ci : 0.07, 0.37,or=0.16, p <.001) and oxybutynin (95% ci: 0.02, 0.12,or = 0.05, p <.001) were less likely to have urgency than those in placebo. moreover, significant decrease was found for dysuria in the three treatment groups in comparison with placebo group. conclusion: according to the results, celecoxib, phenazopyridine and oxybutynin can effectively decrease the side effects of bcg immunotherapy compared to placebo. among these three treatments, the most effective and safest treatment option is celecoxib. keywords: vaccine; complications; intravesical therapy; non-muscle invasive bladder cancer; urinary neoplasms introduction the treatment of high grade non-muscle-invasive bladder cancer (nmibc) is a combination of tur (transurethral resection), adjuvant intravesical chemotherapy, or bcg (bacillus calmette–guérin) immunotherapy.(1) the european organization for research and treatment of cancer (eortc) provides a scoring system for recurrence and progression risk in nmibcs that includes factors such as age, gender, recurrent tumor, number of tumors, t stage, cis, and grade.(2) however intravesical bcg therapy is effective treatment to prevent relapse or delay in progress in nmibc.(1,3) despite the recommendations by different guidelines in using bcg therapy as an effective treatment in non-invasive bladder cancers, is associated with adverse effects in the 6-week induction course. bcg therapy adverse effects are reported in 30-80% of cases in different studies.(4) irritative voiding symptoms and fever are the most common adverse effects of bcg immunotherapy(5,6) while other severe adverse effects like bladder contracture and sepsis are infrequent.(7) if adverse reactions persist over time or become intolerable, symptomatic treatment with spasmolytics, anticholinergics, analgesics, or antiphlogistics are indicated. administration of 1department of urology, iran university of medical sciences, hasheminejad kidney center hospital, tehran. 2department of community medicine, school of medicine, zahedan university of medical sciences, zahedan, iran. 3health promotion research center, zahedan university of medical sciences, zahedan, iran. *correspondence: department of community medicine, school of medicine, zahedan university of medical sciences, zahedan, iran. tel: +985433295720, fax: +98 5433295720, e-mail: dr.sarhadi93@gmail.com. received january 2020 & accepted september 2020 nsaids (non-steroidal anti-inflammatory drugs) and corticosteroids is effective for treatment of immunologic reactions like arthralgia.(6) because the completion of the induction course requires management of bcg adverse effects,(8) several studies have proposed different strategies to prevent control the adverse effects including decreasing the therapeutic dose of bcg, increasing the interval of injections, and administering anti tb drugs, ofloxacin, or antimuscarinic drugs such as tolterodine or oxybutynin. however, according to the latest results, none of these methods is useful in prevention of bcg adverse effects.(4,6,9,10) among the above drugs, oxybutynin has no positive effect according to a trial(11) and many complications treatment options are not evaluated during placebo-controlled studies.(6) although measures like decreasing the bcg dosage are effective, they cannot adequately control the risk of treatment complications. (12) irritative urinary symptoms are a common side effect of treatment of bcg and that often restrict treatment tolerance. while anticholinergic medications، antispasmodic agent and nsaid may be used for symptom prophylaxis, they have not been compared with placebo for efficacy in a randomized controlled trial. in this urology journal/vol 18 no. 4/ july-august 2021/ pp. 439-444. [doi: 10.22037/uj.v16i7.5947] vol 18 no 4 july-august 2021 440 prospective, randomized, double-blind, placebo-controlled trial, we compared the incidence of side effects of bcg therapy (dysuria, urinary frequency, urgency, fever, influenza-like symptoms, arthralgia) and adverse reactions (dry mouth, constipation, and dyspepsia) in three groups of patients receiving celecoxib, phenazopyridine, and oxybutynin versus placebo during six weeks. materials and methods this prospective, randomized, triple-blind, placebo-controlled trial was performed after acquisition of the approval of the iranian registry of clinical trials (irct20171225038070n1). ethical principles of this study was approved by the ethics committee of the university of medical sciences of iran and are in line with the 1964 helsinki declaration. study population the study population consists of 120 adult patients suffering from non-muscle-invasive bladder cancer attending hasheminejad hospital, tehran, iran in the semiannual of 2017. in this study all tumors were completely resected with any size and location and all patient became tumor-free. in addition, the tumors pathologically were limited to the mucosa without muscle involvement. the patients were candidates of bcg therapy as a 6-week induction protocol. inclusion and exclusion criteria the inclusion criteria include patients older than age 18 years, a pathology report confirming nmibc (cis, ta, or t1), and being a candidate for intravesical bcg immunotherapy. patients were excluded from study for an aua(american urological association) symptom score greater than 20, history of peptic ulcer disease, the use of medications for overactive bladder, pelvic surgery within the previous 6 months, a pvr (post-void residual)greater than 50 ml or other medical conditions that would be adversely affected by anticholinergics such as history of urinary retention due to bph(benign prostatic hyperplasia), constipation and history of narrow angle glaucoma. after obtaining informed consent, the patients were enrolled. procedures 120 eligible patients who met the inclusion and exclusion criteria were randomly assigned to one of the four treatment groups, celecoxib (n = 30), phenazopyridine (n = 30), oxybutynin (n = 30) and placebo (n = 30), using the blocked randomization method with equal block sizes. the object of this study was explained to the participants and their informed consents were obtained. assignments to treatment groups a to d was done by one of the researchers who was involved in including, excluding, and selecting the patients and opening the envelopes. thirty patients received celecoxib 100 mg every 12 hours, 30 patients received oxybutynin 5 mg every 12 hours, 30 patients received phenazopyridine 100 mg every 8 hours, and 30 patients received placebo (multivitamin pills) every 12 hours. all drugs were identical in shape and offered in similar capsules. the patients and the physicians were blinded to treatment assignment. also, the person who was involved in randomization had no role in the data analysis. evaluations the researcher used a checklist for each participant at the beginning (baseline symptoms) and during the study for weekly assessment of urinary symptoms, systemic symptoms of bcg therapy, and possible adverse drug reactions. this checklist included three voiding symptoms as primary outcomes (urinary urgency, urinary frequency, and dysuria), two non-urinary systemic figure 1. patients’ enrolment diagram. complications of bcg therapykamali et al. unclassified 441 symptoms of bcg therapy (fever and influenza-like symptoms, arthralgia), and adverse drug reactions, including dry mouth, constipation, and dyspepsia as secondary outcomes. systemic symptoms of bcg and adverse drug reactions were recorded as none (no symptoms), moderate (self-limited, no need for treatment), and severe (treatment required). urinary frequency was defined as the need to pass urine within 2 hours of the last micturition. urinary urgency was defined as a recurrent strong desire to void which was difficult to defer due to a fear of leakage or pain, and dysuria was defined as any burning, pain, or discomfort when urination. the urinary symptoms were recorded in an ordinal manner (1= never, 2= less than once in 5 times, 3= less than half of the time, 4= more than half of the time, 5= always). fever was defined as an oral body temperature above 38˚c, dry mouth(dryness or a feeling of stickiness in mouth), and other symptoms were defined as constipation( difficulty passing stool and abdominal fullness) , arthralgia( pain in one or more of joints ,that complications of bcg therapykamali et al. table 1. number (%) of urinary symptoms, systemic symptoms, adverse reactions in each treatment group in 6 weeks follow up urinary frequency week1 week2 week 3 week 4 week 5 week 6 no yes no yes no yes no yes no yes no yes treatment groups placebo 0 30 (100) 0 30 (100) 10 (33.3) 20 (66.7) 10 (33.3) 20 (66.7) 18 (60) 12 (40) 22 (73.3) 8 (26.7) celecoxib 26 (86.7) 4 (13.3) 8 (26.7) 22 (73.3) 14 (46.7) 16 (53.3) 14 (46.7) 16 (53.3) 18 (60) 12 (40) 18 (60) 12 (40) phenazopyridine 18 (60) 12 (40) 8 (26.7) 22 (73.3) 9 (30) 21 (70) 9 (30) 21 (70) 5 (16.7) 25 (83.3) 10 (33.3) 20 (66.7) oxybutynin 10 (33.3) 20 (66.7) 5 (16.7) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 25 (83.3) 20 (66.7) 10 (33.3) urgent urination week1 week 2 week 3 week 4 week 5 week 6 treatment groups no yes no yes no yes no yes no yes no yes placebo 5 (16.7) 25 (83.3) 0 30 (100) 5 (16.7) 25 (83.3) 10 (33.3) 20 (66.7) 10 (33.3) 20 (66.7) 20 (66.7) 10 (33.3) celecoxib 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) 22 (73.3) 8 (26.7) 26 (86.7) 4 (13.3) phenazopyridine 26 (86.7) 4 (13.3) 8 (26.7) 22 (73.3) 22 (73.3) 8 (26.7) 13 (43.3) 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) 17 (56.7) oxybutynin 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 20 (66.7) 10 (33.3) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) dysuria week1 week 2 week 3 week 4 week 5 week 6 treatment groups no yes no yes no yes no yes no yes no yes placebo 0 30 (100) 5 (16.7) 25 (83.3) 15 (50) 15 (50) 10 (33.3) 20 (66.7) 25 (83.3) 10 (33.3) 25 (83.3) 5 (16.7) celecoxib 26 (86.7) 4 (13.3) 13 (43.3) 17 (56.7) 17 (56.7) 13 (43.3) 18 (60) 12 (40) 18 (60) 12 (40) 18 (60) 12 (40) phenazopyridine 25 (83.3) 5 (16.7) 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) 22 (73.3) 8 (26.7) oxybutynin 20 (66.7) 10 (33.3) 5 (16.7) 25 (83.3) 15 (50) 15 (50) 15 (50) 15 (50) 15 (50) 15 (50) 20 (66.7) 10 (33.3) fever week1 week 2 week 3 week 4 week 5 week6 treatment groups no yes no yes no yes no yes no yes no yes placebo 20 (66.7) 10 (33.3) 15 (50) 15 (50) 10 (33.3) 20 (66.7) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 30 (100) 0 celecoxib 30 (100) 0 30 (100) 0 26 (86.7) 4 (13.3) 30 (100) 0 26 (86.7) 4 (13.3) 30 (100) 0 phenazopyridine 26 (86.7) 4 (13.3) 17 (56.7) 13 (43.3) 26 (86.7) 4 (13.3) 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) oxybutynin 30 (100) 0 15 (50) 15 (50) 20 (66.7) 10 (33.3) 15 (50) 15 (50) 15 (50) 15 (50) 20 (66.7) 10 (33.3) arthralgia week1 week2 week 3 week 4 week 5 week 6 treatment groups no yes no yes no yes no yes no yes no yes placebo 25 (83.3) 5 (16.7) 15 (50) 15 (50) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 30 (100) 0 30 (100) 0 celecoxib 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) phenazopyridine 22 (73.3) 8 (26.7) 22 (73.3) 8 (26.7) 18 (60) 12 (40) 18 (60) 12 (40) 14 (46.7) 16 (53.3) 18 (60) 12 (40) oxybutynin 30 (100) 0 20 (66.7) 10 (33.3) 15 (50) 15 (50) 15 (50) 15 (50) 15 (50) 15 (50) 10 (33.3) 20 (66.7) heartburn week1 week2 week3 week 4 week 5 week 6 treatment groups no yes no yes no yes no yes no yes no placebo 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 celecoxib 30 (100) 0 30 (100) 0 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) 22 (73.8) 8 (26.7) 26 (86.7) 4 (13.3) phenazopyridine 26 (86.7) 4 (13.3) 22 (73.8) 8 (26.7) 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) 22 (73.8) 8 (26.7) 22 (73.8) 8 (26.7) oxybutynin 30 (100) 0 20 (66.7) 10 (33.3) 20 (66.7) 10 (33.3) 20 (66.7) 10 (33.3) 15 (50) 15 (50) 20 (66.7) 10 (33.3) constipation week2 week 2 week3 week 4 week 5 week 6 treatment groups no yes no yes no yes no yes no yes no placebo 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 celecoxib 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) 17 (56.7) 13 (43.3) 22 (73.8) 8 (26.7) 22 (73.8) 8 (26.7) phenazopyridine 21 (70) 9 (30) 21 (70) 9 (30) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) 25 (83.3) 5 (16.7) oxybutynin 10 (33.3) 20 (66.7) 10 (33.3) 20 (66.7) 15 (50) 15 (50) 25 (83.3) 5 (16.7) 15 (50) 15 (50) 15 (50) 15 (50) dry mouth week3 week2 week 3 week4 week 5 week6 treatment groups no yes no yes no yes no yes no yes no placebo 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 30 (100) 0 celecoxib 26 (86.7) 4 (13.3) 26 (86.7) 4 (13.3) 22 (73.8) 8 (26.7) 22 (73.8) 8 (26.7) 22 (73.8) 8 (26.7) 22 (73.8) 8 (26.7) phenazopyridine 8 (26.7) 22 (73.3) 12 (40) 18 (60) 8 (26.7) 22 (73.3) 8 (26.7) 22 (73.3) 8 (26.7) 22 (73.3) 12 (40) 18 (60) oxybutynin 25 (83.3) 5 (16.7) 5 (16.7) 25 (83.3) 10 (33.3) 20 (66.7) 30 (100) 0 10 (33.3) 20 (66.7) 10 (33.3) 20 (66.7) abbreviations: or; odds ratio, ci; confidence interval vol 18 no 4 july-august 2021 442 may be described as sharp ,dull ,stabbing ,burning or throbbing), and dyspepsia( an epigastric burning sensation).the study outcomes categorized into dichotomous variables (with or without symptom). statistical analysis to describe the studied outcomes according to the treatment groups, the number (percent) was used. the patients were followed for 6 weeks and it is expected that the observations to be correlated over time. since our data was longitudinal with repeated measures, generalized estimating equation (gee) regression model was used for the data analysis. gee models were used to estimate the effect of three treatments including celecoxib, phenazopyridine and oxybutynin versus placebo on the urinary symptoms, systemic symptoms and adverse reactions. the studied outcomes were binary data, e.g. with and without urinary symptoms so, the link function in gee models was logit link. correlations between the outcomes measures over time was accounted with an unstructured working correlation matrix. the statistical analysis was conducted in two scenarios of univariate and multivariable after adjustment for age and gender. the estimated effects were presented using odds ratio (or) and 95% confidence interval (ci). p-values less than 0.05 were considered significant. the analysis was conducted using stata version 14. results 131 patients were evaluated for eligibility, 11 of these patients were excluded due to exclusion criteria. one patient was excluded for aua symptom score greater than 20, three patients for history of peptic ulcer disease, two patients for pvr (post-void residual) greater than 50 ml, three patients for history of urinary retention due to bph (benign prostatic hyperplasia), and two patients for history of constipation. the treatment continued for a 6-week period in all groups during which adverse effects of bcg were assessed and recorded. all of the patients completed treatment. details of patients’ enrollment flow diagram are outlined in figure 1. the study included 120 patients, 10 female and 110 male. the mean age of the participants was 59.65 ± 6.2 years. descriptive analysis number (%) of patients with and without the urinary symptoms, systemic symptoms, adverse reactions in the treatment groups during follow up are presented in table 1. at first week, the percent of urinary frequency among patient randomized to celecoxib, phenazopyridine, oxybutynin and placebo groups were 13.3%, 40%, 66.7% and 100%, respectively. however, corresponding figures at the end of follow up were 40%, 66.7%, 33.3% and 26.7%, respectively. there was relatively stable trend in percent of urinary urgency among patients in two of celecoxib and oxybutynin groups however there was an increase and decrease trend during follow up for those in phenazopyridine and in placebo group, respectively. there was a sensible fluctuation in the frequency of dysuria during time among those in placebo, celecoxib and phenazopyridine' however; there was no change in oxybutynin group. in two phenazopyridine and oxybutynin groups, the percent of fever symptom at end of follow up were 43.3% and 33.3%, respectively, while at 1st week corresponding figures were 13.3% and 0%, respectively. in other hands, the celecoxib group had no change in symptom of fever at 1st week compared to the end of the follow up. the observed trend for fever was also found for the symptom of arthralgia in the three treatment groups. although no changes occurred in the heartburn symptom in the placebo group, however; the symptom had an increasing trend in other three groups during follow up. a relatively constant trend for constipation was observed in the all 4 treatment groups during time. there was an increasing trend for dry mouth in patients in two groups of celecoxib and oxybutynin; however; the placebo group did not experience dry mouth during follow-up. the percent of dry mouth in the patients who received phenazopyridine decreased from 73.3% at 1st table2. univariate analysis for effect of treatment groups on urinary symptoms. urinary frequency urgent urination dysuria fever arthralgia treatment group or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value placebo reference reference reference reference reference celecoxib 0.23 (0.10, 0.51) < 0.001 0.06 (0.2, 0.13) < 0.001 0.32 (0.15, 0.70) 0.004 0.05 (0.02, 0.12) < 0.001 1.79 (0.47, 6.83) 0.39 phenazopyridine 0.30 (0.14, 0.67) 0.003 0.30 (0.15, 0.60) 0.001 0.24 (0.11, 0.51) < 0.001 1.11 (0.61, 2.00) 0.73 4.10 (1.37, 12.29) 0.01 oxybutynin 0.99 (0.46, 2.12) 0.98 0.06 (0.02, 0.18) < 0.001 0.53 (0.26, 1.06) 0.07 1.03 (0.57, 1.87) 0.91 4.23 (1.63, 10.95) 0.003 abbreviations: or; odds ratio, ci; confidence interval urinary frequency urgent urination dysuria fever treatment group or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value placebo reference reference reference celecoxib 0.17 (0.09, 0.31) < 0.001 0.04 (0.02, 0.07) < 0.001 0.25 (0.14, 0.46) < 0.001 0.02 (0.006, 0.10) < 0.001 phenazopyridine 0.21 (0.10, 0.43) < 0.001 0.16 (0.07, 0.37) < 0.001 0.18 (0.09, 0.36) < 0.001 0.64 (0.36, 1.14) 0.13 oxybutynin 0.61 (0.28, 1.32) 0.21 0.05 (0.02, 0.12) < 0.001 0.33 (0.17, 0.63) 0.001 0.48 (0.27, 0.88) 0.02 age 0.97 (0.94, 1.01 0.20 1.10 (1.05, 1.15) < 0.001 0.97 (0.93, 1.008) 0.13 0.94 (0.91, 0.98) 0.005 gender male reference reference reference female 0.17 (0.09, 0.33) < 0.001 0.12 (0.05, 0.25) < 0.001 0.15 (0.07, 0.32) < 0.001 not estimated table 3. multivariable analysis for effect of treatment groups on urinary symptoms. abbreviations: or; odds ratio, ci; confidence interval complications of bcg therapykamali et al. unclassified 443 week to 60% at end of follow up. association analysis the results of univariate analysis are presented in table 2. there was inadequate data in combination of treatment groups and some outcomes including heartburn, constipation and dry mouth, so the or (95% ci) did not be estimate. the results showed that the odds of urinary frequency decreased among patients in celecoxib and phenazopyridine compared to those in placebo group by 0.70 and 0.77, respectively. the results showed that the patients in the three treatment groups in comparison with to those in placebo tend, have lower level of the urinary urgency and dysuria e.g. the odds of urgent urination and dysuria in celecoxib were 0.94 and 0.68 lower than in placebo, respectively. in comparison with placebo, for a patient who received phenazopyridine, her/his odds of having arthralgia is multiplied by 4.10 at the end of follow up (95% ci: 1.37-12.29, or = 4.10, p = .01).moreover, (95% ci: 1.63-10.95, or = 4.23, p = .003) for arthralgia in oxybutynin compared to placebo. the results of multivariable analysis are shown in table 3. due to sparse data, or (95% ci) could not estimate for association between treatment groups and arthralgia. the odds of urinary frequency were lower among patients who received celecoxib compared to those who did receive placebo (95% ci: 0.090.31, or = 0.17, p = .001), after adjusting for age and gender. additionally, a significant decrease was observed in urinary frequency of patients who received phenazopyridine compared to those in placebo group. according to reciprocal entity of or, the or for having urinary frequency for phenazopyridine and oxybutynin in comparison with celecoxib approximately were 1.23 and 3.59, respectively. patients in celecoxib group (95% ci: 0.02 0.07, or = 0.04), phenazopyridine (95% ci: 0.070.37, or = 0.16) and oxybutynin (95% ci: 0.020.12, or = 0.05) were less likely to have urinary urgency than patients in placebo. moreover, significance decrease was found for dysuria in the three treatment groups in comparison of placebo group. the detail about or (95% ci) are presented in the table 3. discussion this study evaluated the effect of treatment with celecoxib, phenazopyridine, and oxybutynin on irritative voiding symptoms (urinary urgency, frequency, and dysuria) and systemic symptoms (fever, arthralgia) associated with bcg immunotherapy compared to placebo. the major adverse reactions of these drugs, including dry mouth, constipation, and dyspepsia were also recorded. the results showed that urinary frequency was the most common adverse effect of bcg therapy (64%) and fever was the second most common side effect. most symptoms associated with bcg immunotherapy are related to the immune stimulation that is necessary for effective removal of cancer cells. the symptoms contain urinary frequency and burning, mild malaise and low-grade fever.(8) a meta-analysis that performed by ari astram et al.(8) for effective dosage and side effects of bcg treatment shows that the most local complication is drug induced cystitis. this complication is manifested by urinary irritation with negative urine culture and hematuria that stops within 48 hours without suspension of bcg therapy. therefore, irritative symptoms in bcg therapy is a predictable occurrence, and there is no reason for the interruption of treatment.(8) in the study of xiaoming jian,(13) that compared intravesical bcg immunotherapy with radical cystectomy in intermediate or high risk non muscle invasive bladder cancer shows cystitis was the most common complication in the bcg group and rifampin and isoniazid prescribed to complete the course of treatment. however, in the eortc study, isoniazid administration with the bcg has not been effective in reducing side effects. in our study, celecoxib was more effective than placebo in reducing frequency, dysuria and urgency. also, in multivariate analysis, celecoxib is more effective in reducing frequency than phenazopyridine and oxybutynin. in this study, the second major complication of bcg therapy was fever (60%). while high fever in only one patient in the phenazopyridine group led to a oneweek cessation of treatment, in other patients, fever was controlled by acetaminophen prescribing. xioming et al.(8) reported 19% prevalence of fever in bcg treatment. they used oral acetaminophen to control the fever. they also found that fever was associated with decreased recurrence and increased toxicity in bcg immunotherapy. however, it is important to check for concurrent infection during experience of the fever. concomitant infection occurs locally or systemically in rare cases, and eruption of bcg therapy or antituberculosis drugs is used for treatment. in this paper, celecoxib was more effective in reducing fever.(14) micheeh and colleagues(11) in randomized control trial evaluated oxybutynin extended release versus placebo for urinary symptoms during intravesical bcg treatment. they reported increases in urinary frequency and burning on urination, fever, flu-like symptoms, dry mouth and constipation versus placebo. the prevalence of urinary frequency varied from 33.3% to 83.3% in oxybutynin group. in this research, multivariate analysis show that oxybutynin does not significantly reduce the odds of urinary frequency compared to placebo. additionally, significance decrease was observed in urgency, dysuria and fever in patients who received oxybutynin compared with placebo group. anticholinergic side effects from the use of oxybutynin is commonly observed, however, the severity of them did not lead to stoppage of treatment. numerous studies have been performed to achieve the greatest effectiveness of bcg therapy in the treatment of bladder tumors. however, the optimal treatment plan has not been clarified.(14) in our study, despite the limitations of the number of participants and inclusion of only age and sex as covariates, it was tried to compare the proposed treatments for better controlling of the side effects of bcg treatment. conclusions according to the results of the 6-week follow-up, urinary frequency and fever were common side effects of bcg induction therapy. celecoxib caused a significant reduction in the odds of irritative urinary symptoms (urinary urgency, urinary frequency, and dysuria) and fever compared to placebo group. phenazopyridine also decreased the odds of fever and irritative urinary symptoms, among which the decrease in fever was not significant compared to placebo group. moreover, complications of bcg therapykamali et al. vol 18 no 4 july-august 2021 444 significance decrease was found for irritative urinary symptoms and fever in the oxybutynin treatment group in comparison of placebo group. however, anticholinergic side effects were commonly observed during treatment. references 1. garcia c, jina h, bergersen p, chalasani v. bladder contracture a rare and serious side effect of intravesical bacillus calmetteguérin therapy. urol case rep. 2015; 4:2224. 2. dalkilic a, bayar g, kilinc mf. a comparison of eortc and cueto risk tables in terms of the prediction of recurrence and progression in all non-muscle-invasive bladder cancer patients. urol j. 2019;16(1):37-43. published 2019 feb 21. 3. krajewski w, zdrojowy r, grzególka j, et al. does mantoux test result predicts bcg immunotherapy efficiency and severe toxicity in non-muscle invasive bladder cancer. urol j. 2019;16(5):458-462. published 2019 oct 21. 4. brausi m, oddens j, sylvester r, et al. side effects of bacillus calmette-guérin (bcg) in the treatment of intermediateand high-risk ta, t1 papillary carcinoma of the bladder: results of the eortc genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance bcg. eur urol. 2014;65(1):69-76. 3. 5. saint f, irani j, patard jj, et al. 5. tolerability of bacilli calmette-guérin maintenance therapy for superficial bladder cancer. urology. 2001;57(5):883-888. 6. decaestecker k, oosterlinck w. managing the adverse events of intravesical bacillus calmette–guérin therapy. res rep urol. 2015; 7:163-57. 7. p m, koya ma, simon, soloway ms. complications of intravesical therapy for urothelial cancer of the bladder. j urol. june 2006; 175:2004-10. 8. astram a, khadijah a, yuri p, et al. effective dose and adverse effects of maintenance bacillus calmette-gue'rin in intermediate and high-risk non-muscle invasive bladder cancer: a meta-analysis of randomized clinical trial. acta med indones. 2014;46(4):298-307. 9. gandhi nm, morales a, lamm dl. bacillus calmette-guérin immunotherapy for genitourinary cancer. bju int. 2013;112(3):288-297. 10. maghsoudi r, farhadi-niaki s, etemadian m, et al. comparing the efficacy of tolterodine and gabapentin versus placebo in catheter related bladder discomfort after percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2018;32(2):168-174. 11. johnson mh, nepple kg, peck v, et al. randomized controlled trial of oxybutynin extended release versus placebo for urinary symptoms during intravesical bacillus complications of bcg therapykamali et al. calmette-guérin treatment. j urol. 2013;189(4):1268-1274. 12. damiano r, de sio m, quarto g, et al. shortterm administration of prulifloxacin in patients with nonmuscle-invasive bladder cancer: an effective option for the prevention of bacillus calmette-guérin-induced toxicity?. bju int. 2009;104(5):633‐639. 13. jian x, shen m, liao g. definitive bcg immunotherapy versus radical cystectomy in intermediate or high-risk nonmuscle invasive bladder cancer patients: a retrospective study. medicine (baltimore). 2019;98(36): e16873. 14 .guallar-garrido s, julián e. bacillus calmette-guérin (bcg) therapy for bladder cancer: an update. immunotargets ther. 2020; 9:1-11. urology journal unrc/iua vol. 1, no. 4, 280-281 autumn 2004 printed in iran 280 pseudoaneurysm following percutaneous nephrolithotomy karami h*, heidari f department of urology, shohada-e-tajrish hospital, shaheed beheshti university of medical sciencse, tehran, iran key words: pseudoaneurysm, percutaneous nephrolithotomy, embolization introduction delayed hemorrhage following percutaneous nephrolithotomy (pcnl) is secondary to pseudoaneurysm or arteriovenous fistula, which happens in less than 1% of pcnls. predisposing factors are: medial puncture instead of posterolateral puncture, arteriosclerosis, and hypertension. definite diagnosis is made by angiography and embolization, as a definite treatment, can be done through the same angiography session. open exploration and partial or total nephrectomy is rarely required. we report a case of pseudoaneurysm after pcnl, which was treated successfully using embolization. case report a 54-year-old man was referred to our center with a right kidney (middle calyx) stone. the stone was completely extracted with pcnl and owing to minor manipulation of collecting system, nephrostomy tube was not placed. only an external ureteral stent was inserted and removed 24 hours later. on the second postoperative day he was discharged, while he had no gross hematuria and had a good general condition. hemoglobin (hb) was 14 mg/dl. nonetheless, three weeks postoperatively, he was back with gross hematuria, hypotension and hb = 7 mg/dl. he received 4 units of whole blood and complete bed rest was ordered. after stabilization of vital signs, angiography was done. a pseudoaneurysm was seen in angiography (fig. 1) and embolization was done promptly (fig. 2). hematuria was completely ceased and the patient was discharged two days later with hb = 11 mg/dl. discussion gustore simon hidelberg performed the first percutaneous surgery of the kidney in 1871, applied for to sclerose renal cysts and drainage of hydronephrosis. he also proposed percutaneous extraction of renal stone.(1) since then, great advancements have been made in endourologic surgeries, so that its comreceived march 2003 accepted july 2004 *corresponding author: department of urology, shohada-e-tajrish hospital, tajrish sq., tehran, iran. tel: +98 912 114 2080, e-mail: karami_hosein@yahoo.com fig. 1. angiography was indicative of pseudoaneurysm. fig. 2. angiography after embolization karami and heidari 281 plication rate has reduced to less than 1%.(2) of more than 150 cases of pcnl performed in our center, only one was complicated with pseudoaneurysm. martin and colleagues reported eight cases with severe bleeding following percutaneous nephrolithotomy out of 808 pcnls. of these, 7 were treated by hyperselective embolization.(3) in another study, the reported rate of vascular complications after renal biopsy and percutaneous procedures were 7% to 17% and 1% to 3%, respectively.(4) their common symptom was hematuria, mostly gross than microscopic. in rare cases, pseudoaneurysm is asymptomatic(5) or leads to late cardiac failure.(6) there is consensus that, the definitive treatment for pseudoaneurysm is embolization.(2,3,5) references 1. zingg ej, futterlieb a. nephroscopy in stone surgery. br j urol. 1980;52:333-7. 2. patterson de, segura jw, leroy aj, benson rc jr, may g. the etiology and treatment of delayed bleeding following percutaneous lithotripsy. j urol. 1985;133:447-51. 3. martin x, murat fj, feitosa lc, et al. severe bleeding after nephrolithotomy: results of hyperselective embolization. eur urol. 2000;37:136-9. 4. lovaria a, nicolini a, meregaglia d, et al. interventional radiology in the treatment of urological vascular complications. ann urol (paris). 1999;33:156-67. 5. okamura t, tatsura h, kohri k. asymptomatic intrarenal arteriovenous fistula accompanying severe renal vein dilatation detected 30 years after percutaneous renal biopsy. urol int. 1998;61:261-2. 6. el-rassi i, jebara i, khoury a, kassab r, tabet g. cardiac failure caused by renal arteriovenous fistula fifty years after nephrectomy. a new case and review of the literature. arch mal coeur vaiss. 1997;90:1427-30. endourology and stone disease 92 urology journal vol 6 no 2 spring 2009 prevention of bradycardia by atropine sulfate during urological laparoscopic surgery a randomized controlled trial homayun aghamohammadi,1 sadrollah mehrabi,2 faramarz mohammad ali beigi3 introduction: cardiac arrhythmias are a well-recognized complication of anesthesia for laparoscopy. the aim of this study was to evaluate the efficacy of atropine sulfate for prevention of bradyarrhythmia during laparoscopic surgery. materials and methods: sixty-four candidates for urological laparoscopic surgery were randomly assigned into 2 groups to receive either atropine sulfate or hypertonic saline solution (as placebo), intravenously 3 minutes before induction of anesthesia for the laparoscopic procedure. then, all of the patients underwent anesthesia intravenous sodium thiopental and atracurium, followed by isoflurane or halothane inhalation. heart rate and blood pressure were recorded preoperatively in the recovery room, preoperatively in the operation room, after induction of anesthesia, after induction of pneumoperitoneum, and postoperatively. results: a significant decreasing trend was seen in the heart rates during the operation in patients without atropine sulfate. nine of 32 patients (28.1%) in this group developed bradycardia, while none of the patients with atropine sulfate prophylaxis had bradycardia perioperatively (p < .001). the mean decreases in systolic blood pressure between induction of anesthesia and pneumoperitoneum were 15.7 ± 10.2 mm hg in group 1 and 23.5 ± 9.8 mm hg in group 2 (p < .001). the mean decreases in diastolic blood pressure between these two measurements were 8.7 ± 5.2 mm hg in group 1 compared to 12.1 ± 6.2 mm hg in group 2 (p = .001). conclusion: this study suggests that routine prophylaxis with an anticholinergic agent might be helpful in prevention of sinus bradycardia during urological laparoscopic surgery. urol j. 2009;6:92-5. www.uj.unrc.ir keywords: urologic diseases, laparoscopy, bradycardia, atropine, cholinergic antagonists 1department of anesthesiology, shahid labbafinejad medical center, shahid beheshti university (mc), tehran, iran 2department of urology, yasuj university of medical sciences, yasuj, iran 3department of urology, shahrekord university of medical sciences, shahrekord, iran corresponding author: sadrollah mehrabi, md department of urology, shahid beheshti hospital, yasuj, iran tel: +98 741 333 7250 fax: +98 741 333 7250 e-mail: mehrabi390@yahoo.com received september 2008 accepted december 2008 introduction laparoscopic surgery is growing in popularity, and laparoscopic procedures are being done in a broad population of patients. as a result, we can anticipate more cases of cardiac arrhythmias, which are a well-recognized complication of anesthesia for laparoscopy.(1) conditions leading to development of arrhythmias are co2 insufflations, hypercapnea, increased vagal tone owing to traction on the pelvic or peritoneal structures, trendelenburg position, anesthetic drugs (especially, halothane in combination with spontaneous ventilation), preoperative patient’s anxiety, endobronchial intubation, and gas embolism.(1,2) bradycardia during laparoscopic surgery—aghamohammadi et al urology journal vol 6 no 2 spring 2009 93 anesthesiologist should be aware of the risk of cardiac arrhythmias and of the problems inherent to the pneumoperitoneum during laparoscopy. excessive vagal activity which causes severe bradycardia and hypotension can be life threatening.(2) prompt treatment is needed with the use of anticholinergic and sympathomimetic drugs.(3,4) there are studies addressing administration of anticholinergic agents, especially glycopyrrolate and atropine, for prevention of bradycardia during open surgeries in children and adults.(3-6) such studies have also been done for gynecologic laparoscopic surgeries(7); however, there are limited data on the efficacy of these drugs during urological laparoscopic surgeries. the aim of this study is to evaluate the efficacy of atropine sulfate for prevention of bradyarrhythmia during urological laparoscopic operations. materials and methods in a randomized double-blinded placebocontrolled trial, we enrolled patients who were candidates for elective urological laparoscopic surgical operation. after obtaining informed consent and approval of the study by ethics committee of our university, we selected patients aged between 15 and 50 years old who were candidates for elective urological laparoscopic surgery. all of the patients were in the american society of anesthesiologists’ categories i and ii and did not have any history of cardiac disease. the exclusion criteria were history of cardiac arrhythmias (such as sick sinus syndrome), drug-induced bradycardia, and cardiac disease, as well as contraindication of general anesthesia or laparoscopic surgery. a total of 64 eligible patients were selected and were randomly assigned into 2 groups by simple randomization method. in group 1, atropine sulfate, 0.6 mg, and fentanyl, 100 μg, were administered intravenously immediately before induction of anesthesia for the laparoscopic procedure. in group 2 (control), hypertonic saline solution, dispensed in similar bottles to atropine sulfate bottles, was administered intravenously along with fentanyl, before induction of anesthesia. then, all of the patients underwent a balanced anesthesia, including induction of anesthesia with intravenous sodium thiopental, 5 mg/kg to 6 mg/kg, followed by atracurium, 0.5 mg/ kg. after endotracheal intubation, maintenance of anesthesia was continued by inhalational anesthetic drugs (isoflurane or halothane) and positive pressure ventilation. the patients were secured slightly head down in the supine or semilateral position, and their intraabdominal pressure was maintained below 15 mm hg during the operation. they were monitored with a noninvasive arterial pressure measurement device, electrocardiography, pulse oximetry, and capnography. controlled ventilation was used throughout to maintain eucapnia. heart rate and blood pressure were recorded as following in all of the patients: (1) preoperatively in the recovery room, (2) preoperatively in the operation room, (3) after induction of anesthesia, (4) after induction of pneumoperitoneum, and (5) postoperatively. if arrhythmia or bradycardia developed, it would be controlled by atropine sulfate or other anti-arrhythmic drugs. the collected data were analyzed using the spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, illinois, usa). the t test was used to compare the age, heart rate, and blood pressure variables, and the chi-square test, to compare the frequency of bradycardia between the two groups. results all of the patients completed the study. the mean age of them were 24.4 ± 7.8 years and 20.8 ± 8.5 years in groups 1 and 2, respectively (p = .06). there were no significant differences in sex distribution between the participants in groups 1 and 2 (p = .27). the mean heart rates were not significantly different between the two groups preoperatively; however, a significant decreasing trend was seen in the heart rates during the operation in group 2, but not in group 1 with atropine sulfate (table). nine of 32 patients (28.1%) in group 2 developed bradycardia (heart rate < 60/min), while none of the patients in group 1 had bradycardia perioperatively (p < .001). bradycardia during laparoscopic surgery—aghamohammadi et al 94 urology journal vol 6 no 2 spring 2009 there were significant differences in the mean systolic and diastolic blood pressures after induction of pneumoperitoneum between groups 1 and 2 (p = .01 and p < .001, respectively). the mean decreases in systolic blood pressure between induction of anesthesia and pneumoperitoneum were 15.7 ± 10.2 mm hg in group 1 and 23.5 ± 9.8 mm hg in group 2 (p < .001). the mean decreases in diastolic blood pressure between these two measurements were 8.7 ± 5.2 mm hg in group 1 compared to 12.1 ± 6.2 mm hg in group 2 (p = .001). discussion during anesthesia, changes in heart rate may suggest alterations in the depth of anesthesia, vagal activity, co2 pressure, and the effects of drugs. simple vagal reactions, for instance, are usually improved when the stimulus is stopped.(2,3) cardiac arrhythmias are frequently seen during anesthesia in laparoscopic procedures, the most common of which is sinus tachycardia.(3) bradyarrhythmias (eg, atroventricular dissociation, nodal rhythm, sinus bradycardia) may develop independently or in combination with tachycardia during the same procedure.(1,3) in rare cases, asystolic cardiac arrest and cardiovascular collapse may develop.(5) the present study revealed prophylactic effect of intravenous atropine sulfate on cardiac arrhythmias (sinus bradycardia) during anesthesia with halothane for laparoscopic urological surgeries in adults. anticholinergic agents alter the balance between sympathetic and parasympathetic activity in the autonomic nervous system by blocking the parasympathetic muscarinic receptors.(6,7) in a study by annila and colleagues that evaluated intravenous atropine sulfate and glycopyrrolate on cardiac arrhythmias for adenoidectomy in children, the use of anticholinergics did not influence the incidence of ventricular arrhythmias during anesthesia with halothane in children. bradycardia was more common in the placebo group than in the atropine group.(3) although patients were young and the procedure was not laparoscopic, bradycardia was more common in the placebo group, which is similar to our results. adult sympathetic predominance may cause arrhythmias.(5,7) furthermore, suppressing vagal activity is an important protector against sudden cardiac death.(5) our results does not support the suggestion that anticholinergics are arrhytmogenic. bradycardia was more common in adults receiving no medication before the procedure than in those who received atropine sulfate. however, even in those with no atropine, the events were short and resolved after treatment with atropine or spontaneously after desufflation or cessation of painful stimulants. during laparoscopic surgery, the head-up position and high insufflator pressure reduce venous return and cardiac output with a decrease in the mean arterial pressure and cardiac index. conversely, the head-down position increases venous return and normalizes blood pressure.(8) in our study, the patient’s position was head-down and co2 pressure was below 15 mm hg. therefore, only during the postinduction period, there was a significant decrease in blood pressure between the two groups that could be due to the protecting effect of atropine againts bradycardia. sinus tachycardia occurred in none of our patients. heart rate tended to be higher during the operation, especially pneumoperitoneum induction; however, there was no significant difference in heart rate between the two mean heart rate, /min time group 1 group 2 p in recovery 88.4 ± 10.6 90.7 ± 13.7 .45 preoperation 94.1 ± 9.4 98.1 ± 12.9 .05 induction of anesthesia 101.6 ± 12.2 89.1 ± 6.4 .001 induction of pneumoperitoneum 107.6 ± 6.1 69.4 ± 15.7 < .001 postoperation 104.6 ± 10.8 105.8 ± 5.8 .56 heart rate at different times in relation to laparoscopic surgical operation in patients with atropine sulfate (group 1) and without it (group 2) bradycardia during laparoscopic surgery—aghamohammadi et al urology journal vol 6 no 2 spring 2009 95 groups postoperatively and in recovery room. hypercarbia, hypoxia, and type of the surgical operation affect the incidence of cardiac arrhythmias. these parameters were similar in our groups of patients, and there were no case of hypoxia or hypercarbia. bradycardia events were short and resolved spontaneously in atropine group or were treated with atropine sulfate. in conclusion although the use of new drugs such as propofol and isoflurane decreases the rate of cardiac complications, continuous monitoring of cardiovascular and pulmonary parameters is essential. conclusion this study suggests that prophylactic treatment with cholinergic antagonists such as atropine sulfate can be helpful in prevention of sinus bradycardia during laparoscopic surgeries. conflict of interest none declared. references 1. myles ps. bradyarrhythmias and laparoscopy: a prospective study of heart rate changes with laparoscopy. aust n z j obstet gynaecol. 1991;31:171-3. 2. hirvonen ea, poikolainen eo, paakkonen me, nuutinen ls. the adverse hemodynamic effects of anesthesia, head-up tilt, and carbon dioxide pneumoperitoneum during laparoscopic cholecystectomy. surg endosc. 2000;14:272-7. 3. annila p, rorarius m, reinikainen p, oikkonen m, baer g. effect of pre-treatment with intravenous atropine or glycopyrrolate on cardiac arrhythmias during halothane anaesthesia for adenoidectomy in children. br j anaesth. 1998;80:756-60. 4. burns jm, hart dm, hughes rl, kelman aw, hillis ws. effects of nadolol on arrhythmias during laparoscopy performed under general anaesthesia. br j anaesth. 1988;61:345-6. 5. shifren jl, adlestein l, finkler nj. asystolic cardiac arrest: a rare complication of laparoscopy. obstet gynecol. 1992;79:840-1. 6. desalu i, kushimo ot, bode co. a comparative study of the haemodynamic effects of atropine and glycopyrrolate at induction of anaesthesia in children. west afr j med. 2005;24:115-9. 7. ambrose c, buggy d, farragher r, troy a, mcnulty c, carey m. pre-emptive glycopyrrolate 0.2 mg and bradycardia during gynaecological laparoscopy with mivacurium. eur j anaesthesiol. 1998;15:710-3. 8. gerges fj, kanazi ge, jabbour-khoury si. anesthesia for laparoscopy: a review. j clin anesth. 2006;18:67-78. u j all final for web.pdf 821vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l recurrent painless hematuria secondary to malacoplakia of the urinary bladder a case report and review of literature rahul gupta, arti mahajan, surender atri, chaman lal gupta keywords: hematuria, urinary bladder, malacoplakia, granuloma introduction mass.(2) clinically, the presentations may vary from a solitary lesion to more often multiple bladder (3) we report a case of recurrent painless case report corresponding author: rahul gupta, md; ms; dnb (urology) post graduate department of surgery, govt. medical college jammu, jammu and kashmir, india tel: +91 979 622 1166 e-mail: rajaguptadr@ rediffmail.com received february 2011 accepted may 2011 postgraduate department of surgery, govt. medical college jammu, jammu and kashmir, india case report 822 | cystoscopy revealed multiple bladder lesions in the form cal michaelis-gutmann bodies (m-g bodies) on histologidiscussion munosuppressive treatments. (7) pathogonomic for malacoplakia. these m-g bodies (inclusion bodies) are clusters of phagolysosomes enclosing partially digested bacteria, such as lipid a, bacterial capsule salts and calcium phosphatase salts. this is the result of the malacoplakia can affect any organ, but involves the genitou clinically, urinary bladder malabiopsy of these lesions mandatory. agents (bethanechol) and ascorbic acid (the former increases ing intracellular bacterial digestion by macrophages) is often successful. if the medical treatment fails, then the patient antibiotic therapy to keep the urine abacteriuric.(7) to conclude, malacoplakia is a rare, but treatable cause of figure 1. tan-yellow nodules on cystoscopy. figure 2. classical michaelis-gutmann bodies on histological evaluation. case report 823vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l malacoplakia of the bladder | gupta et al references 1. michaelis l, gutmann c, 1902. einschlusse in blastentumoren. z klin med. 1902;47:208-15. 2. sulman a, goldman h. malacoplakia presenting as a large bladder mass. urology. 2002;60:163. 3. mukha rp, kumar s, ramani mk, kekre ns. isolated malacoplakia of the bladder: a rare case report and review of literature. int urol nephrol. 2010;42:349-50. 4. abdou ni, napombejara c, sagawa a, et al. malakoplakia: evidence for monocyte lysosomal abnormality correctable by cholinergic agonist in vitro and in vivo. n engl j med. 1977;297:1413-9. 5. witherington r, branan wj, jr., wray bb, best gk. malacoplakia associated with vesicoureteral reflux and selective immunoglobulin a deficiency. j urol. 1984;132:975-7. 6. streem sb. genitourinary malacoplakia in renal transplant recipients: pathogenic, prognostic and therapeutic considerations. j urol. 1984;132:10-2. 7. stanton mj, maxted w. malacoplakia: a study of the literature and current concepts of pathogenesis, diagnosis and treatment. j urol. 1981;125:139-46. 8. smith bh. malacoplakia of the urinary tract: a study of twenty-four cases. am j clin pathol. 1965;43:409-17. 9. long jp, jr., althausen af. malacoplakia: a 25-year experience with a review of the literature. j urol. 1989;141:132831. 10. krauel l, garcia-aparicio l, perez n, et al. urinary and gastrointestinal malakoplakia in a 12-year-old girl. urology. 2009;73:87-9. 11. cozar olmo jm, carcamo p, gaston de iriarte e, jimenez f, martinez-pineiro l, martinez-pineiro ja. genitourinary malakoplakia. br j urol. 1993;72:6-12. 12. darvishian f, teichberg s, meyersfield s, urmacher cd. concurrent malakoplakia and papillary urothelial carcinoma of the urinary bladder. ann clin lab sci. 2001;31:147-50. dency to persist or recur. conflict of interest none declared. case report adult ureterocele presenting with ureteral obstruction and urosepsis during pregnancy catherine r harris,1 amjad alwaal,1,2* glen yang,1 michael l eisenberg,1 benjamin n breyer1 keywords: pregnancy; ureterocele; adult; female; hydronephrosis; pathology. introduction ureteroceles are cystic dilatations of the distal ureter that occur due to congenital ureteric wall weakness.(1) they can be orthotopic, occurring in normal ureteric locations and most commonly seen in adults. on the other hand, heterotopic ureteroceles are located in ectopic ureters or in ectopic duplex renal systems, and are more common in children.(2) ureterocele causing obstruction in adults is less commonly reported. there are few case reports and small case series in the adult population that describe ureteral obstruction from ureteroceles,(3-5) and only one published report of a ureterocele presenting as prolapsed mass containing stones during pregnancy.(6) we describe a report of an adult presenting with an obstructing ureterocele and urosepsis during pregnancy. the ureterocele was successfully extirpated cystoscopically without radiation exposure to mother or fetus. we also review the varied presentations and management of obstructing ureteroceles in adults who have presented at our institution. case report a 35 year-old woman gravida 5 para 2 at 22 weeks gestation presented to the emergency room with fevers and right flank pain. she was febrile to 39.0oc, tachycardic at 120/min, with stable blood pressure. on physical examination she had right costovertebral angle tenderness. laboratory results revealed a leukocytosis of 19 × 109/l and creatinine of 0.5 mg/dl. her urinalysis with microscopy was positive for pyuria and bacteriuria. renal-bladder ultrasound showed moderate right hydroureter (grade 3) proximal and distal to the gravid uterus as well as a ureterocele at the ureterovesical junction (figure 1). the patient was otherwise healthy, with a history of a single urinary tract infection 2 years ago while not pregnant. surgical technique the patient was taken emergently to the operating room for endoscopic ureteral decompression. cystoscopy was performed which showed a 3 cm right ureterocele. a ureteral orifice was not apparent, and a guidewire was unable to be passed into the ureter. urine efflux was not visualized. an attempt to puncture the thick walled ureterocele with the bugbee electrode (medline industries, mundelein, il, usa) was unsuccessful. a collins knife (storz, tuttlingen, germany) was then used to incise the ureterocele. after extirpation with the collins knife, we were able to visualize what appeared to be a ureteral orifice at the lateral extend of the ureterocele (figure 2). a guidewire and 5-french ureteral exchange catheter passed through the ureteral orifice easily. we placed then a temporary 1 department of urology, university of california, san francisco, usa. 2 department of urology, king abdul aziz university, jeddah, saudi arabia. *correspondence: 400 parnassus avenue a633, san francisco, ca 94143-0738, usa. tel: +1 415 206 8805. fax: +1 415 206 5153. e-mail: amjadwal@yahoo.com. received february 2015 & accepted june 2015 abbreviations: m, male; f, female; ct, computed tomography; ivp, intravenous pyelography; dmsa, dimercaptosuccinic acid; uti, urinary tract infection. age (years) sex presenting diagnostic laterality type of associated surgical symptom imaging system stone technique 35 f pyelonephritis ultrasound right single, orthotopic no incision 61 m pyelonephritis ct, ivp bilateral single, orthotopic yes excision, laser lithotripsy, stent 27 f flank pain ct, dmsa left duplicated, ectopic no heminephrectomy 26 f recurrent uti ultrasound left single, orthotopic no incision 68 f recurrent uti ct left single, orthotopic no incision 22 m recurrent uti ct left single, orthotopic no open excision, ureteral reim plantation table. san francisco general hospital experience with adult ureteroceles 1996-2015. case report 2285 ureteral stent that was removed 4 weeks later. postoperative course the patient defervesced and her pain resolved after the procedure. her urine culture grew pansensitive escherichia coli. she was discharged on post-operative day two with a two-week course of amoxicillin. one month after her procedure she had complete resolution of her symptoms and was afebrile with a white blood cell count of 8 × 109/l. repeat ultrasound showed stable hydronephrosis and hydroureter bilaterally consistent with a 7-month pregnancy. her creatinine was 0.4 mg/dl at baseline. discussion our experience with adult ureteroceles is extremely varied, as shown in table. in the pediatric population, symptomatic ureterocele is related to a variety of complex congenital anomalies, such as duplex kidney, ectopic ureter and bladder outlet obstruction.(7) in contrast, adult ureteroceles are usually intravesical, small, and single system. another difference between ureterocele according to age is the presence of calculi within the ureterocele. calculi are commonly reported in adults, but are rare in children. it is likely that the formation of calculi over time from urinary stasis in an otherwise small asymptomatic ureterocele is the cause of delayed presentation of ureteroceles into adulthood. increased estimated glomerular filtration rate and hydronephrosis from ureteral compression by the gravis uterus are well known physiologic and anatomic manifestations of pregnancy.(8) physicians must therefore rely on clinical judgment to differentiate between physiologic and pathologic obstruction of the urinary system. the concern for fetal radiation also limits the use of more sensitive diagnostic imaging techniques such as computed tomography scan in determining the cause of obstruction. as this report demonstrates, it is important to carefully consider non-pregnancy related causes of obstruction in the pregnant population, such as ureterocele. conclusions in conclusion, this is the first report of an obstructing ureterocele in a pregnant woman. therefore, ureterocele should be considered as a potential cause for obstruction in pregnant women. conflict of interest none declared. references 1. neufang kf mu, beyer d. the roentgen diagnosis of ureterocele-with special reference to the simple orthotopic ureterocele in adults. rontgenblatter. 1981;34:9-14. 2. diard f cl, bondonny jm, elie g. simple orthotopic ureteroceles in children. j radiol. 1980;61:387-95. 3. sinha rk, singh s, kumar p. prolapsed ureterocele, with calculi within, causing urinary retention in adult female. bmj case reports. 2014;2014. 4. prakash j, goel a, kumar m, sankhwar s. stone in ureterocele peeping through ureteric orifice. bmj case reports. 2013;2013. 5. westesson k, goldman h. prolapse of a single-system ureterocele causing urinary retention in an adult woman. int urogynecol j. 2013;24:1761-3. 6. scovell jm, chan rc, khavari r. prolapse of a single system large ureterocele containing multiple stones in a pregnant woman. urology. 2014;83:e3-e4. 7. landi l ea, adorisio o. prolapsed vaginal ureterocele as a cause of urinary incontinence in a child. urol j. 2015;12:1999-2000. 8. hill cc, pickinpaugh j. physiologic changes in pregnancy. surgical clinics of north america. 2008;88:391-401. figure 1. bladder ultrasound showing right ureterocele. figure 2. cystoscopy showing the ureterocele preand post-extirpation. vol 12 no 04 july-august 2015 2286 adult ureterocele in pregnancy-harris et al. review articles congenital urethral anomalies in boys. part ii abdolmohammad kajbafzadeh* department of pediatric urology, children's hospital medical center, tehran university of medical sciences, tehran, iran abstract introduction: in the second part of this article, congenital urethral anomalies other than posterior urethral valve were reviewed. materials and methods: the anomalies considered in the current review were anterior urethral valve, lacuna magna, syringocele, cobb's collar, duplication of urethra, megalourethra, and prostatic urethral polyps. the literature was extensively reviewed concerning the presentations, diagnosis, different types of treatment modalities, morbidity, mortality, and new concepts for the above disorders. result: anterior urethral valves or diverticula are the most prevalent congenital anomalies of anterior urethra. the lacuna magna is the largest depression in the dorsal aspect of the fossa navicularis. it is demonstrable on a well-performed voiding cystourethrography of the distal urethra. the dilated cowper's gland duct is the other missed diagnosed anomaly of the urethra in boys. the congenital narrowing of the bulbar urethra with a variable clinical presentation and obstruction grade and different types of anterior urethral obstruction are the most common presentation of these anomalies. however, other symptoms or signs including, hematuria, bloody spotting on underwear, discomfort or sever pain in the vicinity of the glance, interrupted voiding, infection, bulging of anterior urethra, enuresis, and postvoiding dribbling are the only nonspecific manifestations of these disorders. conclusion: all of these disorders are demonstrable on a well-performed voiding cystourethrography of the distal urethra. the urologist must be aware about these uncommon congenital anomalies and the anterior urethra should be carefully evaluated for such anomalies. diagnosis of these entities is elusive unless the physician is looking for them. nonspecific symptoms mentioned here besides radiographic findings can be a valuable clue for diagnosis. key words: urethral anomalies, valves, obstruction, duplication, syringocele, megalourethra, polyp, lacuna magna, diverticula, boy 125 urology journal unrc/iua vol. 2, no. 3, 125-131 summer 2005 printed in iran anterior urethral obstruction anterior urethral valve (auv) is a rare cause of congenital urethral obstruction in boys. auv is associated mainly with a proximal diverticulum (figure 1).(1) it may be found anywhere distal to the membranous urethra, usually proximal to the penoscrotal junction.(2) depending on the age of the patient and the severity of obstruction, clinical presentation highly varies from a stream that dribbles and voids poorly to hydroureteronephrosis and end-stage renal disease. the most common cause of congenital urethral *corresponding author: no 36, 2nd floor, 7th st, aaadat-abad ave, tehran 19987, iran. tel: ++98 21 2208 9946, fax: ++98 21 2206 9451 e-mail: kajbafzd@sina.tums.ac.ir congenital urethral anomalies in boys obstruction is posterior urethral valve (puv), and auv is reported to be 7 times less common; however, it can be equally as devastating.(1) the embryological pathophysiology of auv remains uncertain. various proposed etiologies exist, including an abortive attempt at urethral duplication, failure of alignment between the proximal and distal urethra, incomplete formation of the ventral corpus spongiosum, congenital cystic dilation of the periurethral gland, and a ruptured cowper's duct cyst.(3) auv may locate in every portion of the anterior urethra with almost equal incidence.(4) it may even be found in fossa navicularis.(5) it is likely that a pathophysiologic spectrum exists from valve to diverticulum formation associated with the degree of urethral dilation.(1) intrauterine urethral obstruction can result in severe bladder dysfunction after birth, which does not necessarily resolve after valve resection. if severe neonatal obstruction exists, urinary diversion by vesicostomy, and antibiotics, electrolyte management, and assessment of renal function improvement are recommended.(6,7) the abnormal bladder function can occasionally be so severe as to end with augmentation cystoplasty. an anterior urethral diverticulum should be considered in every case of anterior urethral obstruction. urethral obstruction usually can be detected by antenatal scanning. when anterior urethral obstruction is suspected, an antegrade cystourethrogram is the investigation method of choice as any attempt at urethral catheterization may disrupt the pathology, and the exact diagnosis can be missed. urodynamic studies through a suprapubic catheter before and after valve ablation can be a helpful baseline investigation.(8) if secondary pathological changes such as bladder dysfunction and upper tract dilation do not improve after valve resection, other treatment options should be considered. the rapid improvement in bladder function and upper tract dilatation in these cases must be good prognostic factors. we recommend that urodynamic studies be performed in all patients with urethral obstruction before and after treatment to help predict the future prognosis. the association of auv with puv is extremely rare in the literature. in 1982, graham and colleagues(2) have reported an association of an anterior urethral diverticulum with puv in a newborn. patients may present with poor urinary stream, recurrent urinary tract infections, or kidney failure. depending on the severity of anatomic obstruction, patients may present early at birth or later in childhood if obstruction is minimal.(1) an auv in almost all cases is actually a congenital urethral diverticulum.(9) during voiding, the diverticulum expands, ballooning ventrally and distally beneath the thinned corpus spongiosum. the flaplike dorsal margin of the diverticulum then extends into the urethral lumen, occluding urinary flow (an obstructing valve). anterior urethral valves have been described in every portion of the anterior urethra with almost equal incidence. they may be small, minimally obstructive, and of limited clinical concern. often, though, they are severely obstructing and result in all the findings seen with puvs. diagnosis of auvs is confirmed on voiding cystourethrography. at times, difficulty with catheterization may be encountered because the catheter preferentially slips into the diverticulum. 126 fig. 1. typical radiologic appearance of anterior urethral valves kajbafzadeh however, this occurs less often than one might expect, because the proximal wall of the diverticulum is often not hollowed out nearly as extensively as the distal wall. because the diverticula almost always are placed ventrally in the midline, a dorsally oriented coudé-tipped catheter usually can be negotiated with less difficulty into the more proximal urethra. to establish the diagnosis, the entire penile urethra must be included in the voiding phase of the cystourethrography, or more distally located lesions will be missed. the etiology of these anomalies is not entirely clear, but they seem to represent incomplete fusion of a segment of the urethral plate. another possible cause might be a focally incomplete development of the corpus spongiosum with ballooning of the urethral mucosa due to inadequate support. small, nonobstructing diverticula often appear stable for many years and do not show continuous enlargement and progressively worsening obstruction. initial management of a congenital auv is the same as that for the more commonly seen puv. initial imaging studies assess the extent of hydronephrosis, the thickness and quality of the renal parenchyma (echogenicity on renal ultrasonography and uptake on renal scan), and the presence or absence of vesicoureteral reflux. infants presenting with urosepsis and/or severe renal insufficiency require a period of transurethral or suprapubic (by percutaneous route) catheter drainage for stabilization, antibiotics, electrolyte management, and assessment of renal functional improvement. as with infants with puvs, a temporizing tubeless diversion (vesicostomy, loop ureterostomy) may be chosen on an individual basis.(6) management of the urethral anomaly may be endoscopic or open. a hooked, single-wire, electrocautery knife can be used to engage the distal margin of the diverticulum and incise it in the midline. when performing this procedure, the surgeon must be very careful not to place the tip of the wire too close to the floor of the diverticulum. at this location, the wall of the urethra can be very thin, and thermal injury may result in development of a urethrocutaneous fistula. even after satisfactory destruction of the leaflet, postoperative urethrography is often disappointing, because the appearance of the diverticulum may be unchanged. one must carefully assess the quality of flow (flow rate if the child is old enough) and the extent of filling of the urethra distal to the anomaly, to evaluate the results of the procedure. some surgeons have advocated open resection and reconstruction of the diverticulum.(9) this technique allows one to completely excise the distal lip and provide a more homogeneous caliber to the urethra. in most cases, a patch graft urethroplasty is the preferred procedure. if the diverticulum is on the penile shaft, a sleeve dissection of the penile shaft skin from the corona to the penoscrotal angle allows the urethroplasty to be completed without overlapping suture lines. some auvs may not be associated with a urethral diverticulum. de castro and colleagues(10) have described 3 children with anterior urethral membranes without the associated diverticulum. lacuna magna or sinus of guerin formation of the distal glanular urethra may occur by a combination of 2 separate processes: proximal fusion of the urethral folds and distal ingrowth of ectodermal cells. it is generally thought that the stratified squamous lining of the fossa navicularis results from an ingrowth of surface ectoderm as far proximally as the valve of guerin. the lacuna magna (also known as the sinus of guerin), which can produce symptoms of hematuria and dysuria in some boys, may form as a result of dorsal extension of this ectodermal ingrowth. it has been suggested that the entire penile urethra might differentiate from fusion of the urethral plate via the mechanism of epithelialmesenchymal interactions.(11,12) the lacuna magna is the largest depression in the fossa navicularis. guerin(13) has described the valve of guerin as a septum between the lacuna magna and the urethral lumen, which may act as a valve (figure 2). the anomaly has been described in the urologic literature since 1980, at which time somner and stephens(14) first drew attention to the fact that it may present with specific symptoms and/or dysuria, hematuria, blood in urethra, and spotting of underclothes.(14-18) although it may be present in 30% of boys as a small pit or sinus,(17) only a few become symptomatic owing to the valvelike effect of the septum. if the inferior wall of the sinus balloons during micturition, it may elongate and trap urine in the lacuna magna. chronic distension and irritation of the diverticulum probably are 127 congenital urethral anomalies in boys responsible for the dysuria and hematuria.(14-16) micturating cystourethrography must be performed meticulously if this lesion is not to be missed, and the entire distal urethra must be included on the radiographic films (figure 2). contrast medium on towels or clothing may obscure or simulate the valve of guerin. similarly, retrograde studies, particularly those that employ the zipser clamp, may be less accurate, because the lacuna is compressed or a catheter may be placed beyond its orifice.(19) another fallacy is to misinterpret the diverticulum as contrast medium within the prepuce or on the skin. one must remember to keep the end of the urethra always in sight. syringocele the dilated cowper's gland duct is referred to as a syringocele (in greek, syringe means "tube" and cele means "swelling"). these anomalies seem to be more common than previously reported. syringoceles are cystic dilations of cowper's gland duct within the bulbous urethra.(20) they are usually small, inconsequential lesions. but rarely, they can be of sufficient size to cause varying degrees of outlet obstruction. lesions of cowper's gland duct have various appearances. a system to classify each of these appearances is offered to diagnose these lesions more precisely. the urethrographic and endoscopic characteristics of dilated cowper's gland ducts are classified in 4 groups: 1. simple syringocele, a minimally dilated duct 2. perforate syringocele, a bulbous duct that drains into the urethra via a patulous ostium and appears as a diverticulum 3. imperforate syringocele, a bulbous duct that resembles a submucosal cyst and appears as a radiolucent mass 4. ruptured syringocele, the fragile membrane that remains in the urethra after a dilated duct rupture(20) cystic dilatation of cowper's gland ducts (cowper's syringocele) is uncommon in children and is frequently asymptomatic; however, it may cause urinary infection, hematuria, dysuria, and obstructive voiding symptoms. only a quarter of children with obstructive syringocele need surgical intervention. the true clinical significance of cowper's syringocele lies in its potential to cause urethral obstruction. careful clinical, radiologic, endoscopic, and urodynamic evaluation is necessary to avoid unnecessary surgery.(21) management, where necessary, is usually by endoscopic unroofing. after unroofing, a diverticulumlike defect may result on the posterolateral wall of the bulbous urethra. however, these defects are rarely obstructing and do not need further management. marsupialization of the syringoceles can cure urinary infection and hematuria, but voiding symptoms may persist. cobb's collar the cobb's collar or moormann's ring is a congenital narrowing of the bulbar urethra with variable clinical presentation and obstruction grade. tubular or cystic dilatation of cowper's gland duct has been called a syringocele, while congenital urethral narrowing is known as cobb's collar. it is important to distinguish congenital urethral obstruction, cobb's collar, from type-iii puv as described by young.(22) congenital urethral obstruction, cobb's collar, should be differentiated from a congenital obstructive posterior urethral membrane. congenital obstructive posterior urethral membrane may be a variation of a type-i urethral valve, supporting the theory of unified morphology in boys with congenital obstruction of the posterior urethra. in some congenital obstructive posterior urethral membrane cases, the membrane may prolapse as far as the bulbar urethra. however, the leaflet is supported by attachments to the verumontanum in congenital obstructive posterior urethral membrane, but not in cobb's collar. meticulous cystourethroscopy is indispensable for detecting a clinically significant bulbar narrowing. transurethral incision of the lesion is useful as a primary treatment in the majority of 128 fig. 2. the lacuna magna (sinus of guerin) kajbafzadeh cases, even with concurrent vesicoureteral reflux and unstable bladder. a cold knife is preferable to electrocautery for incising this fine anterior urethral lesion.(23) it appears that syringoceles are often associated with a cobb's collar, in keeping with the possible origin of both structures from the region of the urogenital membrane. narrowing in the bulbar urethra may, however, be an incidental finding in many of the cases.(24) the more proximal lesion is a membranous obstruction that is able to prolapse as far as the bulbar urethra, but has paramedian folds that attach along the posterior wall of the urethra to the verumontanum and is due to persistence of an embryologic attachment between the distal verumontanum and the anterior wall of the posterior urethra. the more-distal narrowing is not always obstructive and is primarily a bulbar urethral membrane; it is independent of the verumontanum and external sphincter and may represent a persistence of part of the urogenital membrane. there are 2 distinct types of congenital obstruction of the proximal urethra, with an association to the verumontanum being the distinguishing feature.(25) cobb's collar or moormann's ring is a stricture of the bulbar urethra that is largely unrecognized but has considerable relevance urologically as the site of congenital or postinstrumental strictures.(26) duplication of urethra accessory urethra or duplication of the urethra is a rare anomaly. the vast majority occurs in the sagittal plane; however, collateral or side-by-side duplications in the absence of bladder duplication also exist. urethral duplications are divided into sagittal and collateral types.(27,28) those not associated with bladder duplications occur almost exclusively in males. they are often accompanied by other anomalies such as anorectal anomalies or duplication of the penis.(28,29) urethral duplication in females is almost always associated with bladder duplication (figure 3). the etiology of urethral duplication is not clear.(27) it is probably due to misalignment of some sort between the termination of the cloacal membrane and its relationship with the formation of the genital tubercle and urogenital sinus.(28) the following classification has been accepted in the literature: type i, incomplete duplication; type ii, complete duplication, iia. two meatuses, noncommunicating urethras arising independently from the bladder; iib, a second channel arising from the first and exiting independently, complete duplication joining at one meatus; type iii, duplication as a component of caudal duplication. this classification may apply to either dorsal or ventral duplications. the perineal or rectal type associated with a stenotic, normally located penile urethra, is placed in the iia category. the y-type fistula usually takes its origin from the prostatic urethra and is commonly associated with stenosis of the anterior portion of the normally situated urethra.(28) children with complete and incomplete forms of accessory urethras usually present with 2 urinary streams. infection in the partially stenotic orifice is sometimes the presenting symptom.(28) a proper clinical examination (under anesthesia, if needed), a micturating cystourethrography, an ascending urethrography, and a urethrocystoscopy will give a complete picture of the altered anatomy. based on the findings with reference to adequacy of channels, abnormality of location, and symptoms, individually tailored treatment is advised. most often, the ventral urethra is functionally better and can be utilized by plastic procedures, as necessary. the dorsal urethra becomes obliterated either spontaneously or by ablative intervention. 129 fig. 3. a typical urethral duplication with a hypospadias type congenital urethral anomalies in boys many asymptomatic children can be left untreated. cosmetic correction of the division of the septum and creating an apparently single terminal orifice may be necessary when the orifices are close to each other at the tip of the glans. in some cases an end-to-side urethrourethrostomy may be done.(30) megalourethra congenital megalourethra is a rare disorder characterized by the congenital absence of the corpus spongiosum and/or corpus cavernosum, leading to dilatation of the urethra. megalourethra was described originally by nesbitt(31) as a rare congenital abnormality characterized by dilation of the penile urethra. this defect has been classified as a scaphoid or fusiform deformity. in the scaphoid variety, the corpus spongiosum is thought to be the only abnormal segment, whereas the fusiform variety is also associated with defects of the corpora cavernosa. however, this distinction is arbitrary and is not based on any recognized embryologic difference between the two varieties.(29) megalourethra is especially common in association with the prune-belly syndrome and may represent a defect in development of the mesoderm, one of the proposed causes for the prune-belly anomaly.(32) prostatic urethral polyps congenital posterior urethral polyps are rare, benign lesions that can cause a variety of symptoms in young boys; the diagnosis is usually made by cystourethrography and ultrasonography where the polyp appears as a soft tissue mass arising at the base of the urinary bladder. hunter is credited with the first documented case of urethral polyp, and thompson reported the first case in a human.(33) urethral polyps are rare and anterior urethral polyps are even rarer. they are usually of congenital origin. urethral polyps in children occur exclusively in boys; the average age is 5.2 years. mostly, they arise in the posterior urethra, usually proximal to the membranous urethra. but, anterior urethral polyps are still very rare.(34) they are usually single and rarely multiple. urethral polyps have been speculated to represent a developmental error in the invagination process of the submucous glandular material of the inner zone of the prostate.(35) they are benign lesions (not to be confused with the polypoid masses of a sarcoma botryoides), and transurethral excision of the polyps is curative.(36) presentation of urethral polyps is varied consisting of dysuria,(37,38) retention,(37) secondary enuresis,(39) and hematuria.(33) they may present with obstructive symptoms.(40) occasionally, they present in adults with hematuria.(33) williams(41) has reported associated vesicoureteral reflux. diagnosis of anterior urethral polyps is by voiding cystourethrography and cystourethroscopy.(41) however, the penile and bulbar urethra should be palpated in patients presenting with retention or dysuria. indurated area or lump in the absence of radio-opaque stone on radiography is suggestive of stricture or rarely a polyp. the main symptom is bladder outlet obstruction, either intermittent or acute. color doppler ultrasonography may be diagnostic by revealing the polyp's vascular stalk arising from the posterior urethra.(42) transurethral resection of the polyp is the treatment of choice.(36) however, when this is complicated by the displacement of the polyp into the bladder, transvesical removal could be an acceptable alternative.(36-43) histologically, these lesions are benign and there have been no reported recurrences when they have been removed completely. the histologic examination reveals a fibroepithelial core with transitional epithelium with squamous metaplasia at times. references 1. firlit rs, firlit cf, king lr. obstructing anterior urethral valves in children. j urol. 1978;119:819-21. 2. graham sd jr, krueger rp, glenn jf. anterior urethral diverticulum associated with posterior urethral valves. j urol. 1982;128:376-8. 3. mclellan dl, gaston mv, diamond da, et al. anterior urethral valves and diverticula in children: a result of ruptured cowper's duct cyst? bju int. 2004;94:375-8. 4. karnak i, senocak me, gogus s, buyukpamukcu n, hicsonmez a. testicular enlargement in patients with 11hydroxylase deficiency. j pediatr surg. 1997;32:756-8. 5. scherz hc, kaplan gw, packer mg. anterior urethral valves in the fossa navicularis in children. j urol. 1987;138:1211-3. 6. rushton hg, parrott ts, woodard jr, walther m. the role of vesicostomy in the management of anterior urethral valves in neonates and infants. j urol. 130 kajbafzadeh 1987;138:107-9. 7. van savage jg, khoury ae, mclorie ga, bagli dj. an algorithm for the management of anterior urethral valves. j urol. 1997;158(3 pt 2):1030-2. 8. kajbafzadeh am, janguk p, ahmady yazdi c. anterior urethral valve associated with posterior urethral valves. j pediatr urol. 2005; 1:433-5. 9. tank es. anterior urethral valves resulting from congenital urethral diverticula. urology. 1987;30:467-9. 10. de castro r, battaglino f, casolari e, di lorenzo fp, messina p, pavanello p. [valves of the anterior urethra without diverticulum. description of 3 cases]. pediatr med chir. 1987;9:211-5. 11. kurzrock ea, baskin ls, cunha gr. ontogeny of the male urethra: theory of endodermal differentiation. differentiation. 1999;64:115-22. 12. kurzrock ea, baskin ls, li y, cunha gr. epithelialmesenchymal interactions in development of the mouse fetal genital tubercle. cells tissues organs. 1999;164:125-30. 13. guerin a. elements de chirurgie operatoire. 3rd ed. paris: chamerot ; 1864. p.587. 14. sommer jt, stephens fd. dorsal urethral diverticulum of the fossa navicularis: symptoms, diagnosis and treatment. j urol. 1980;124:94-7. 15. seskin fe, glassberg ki. lacuna magna in 6 boys with post-void bleeding and dysuria: alternative approach to treatment. j urol. 1994;152:980-2. 16. bellinger mf, purohit gs, duckett jw, cromie wj. lacuna magna: a hidden cause of dysuria and bloody spotting in boys. j pediatr surg. 1983;18:163-6. 17. friedman rm, king lr. valve of guerin as a cause of dysuria and hematuria in young boys: presentation and difficulties in diagnosis. j urol. 1993;150:159-61. 18. glenister tw. the origin and fate of the urethral plate in man. j anat. 1954;88:413-25. 19. duszlak ej jr, bellinger mf, boal dk, stanford a. dorsal diverticulum of the distal male urethra. ajr am j roentgenol. 1982;138:931-3. 20. maizels m, stephens fd, king lr, firlit cf. cowper's syringocele: a classification of dilatations of cowper's gland duct based upon clinical characteristics of 8 boys. j urol. 1983;129:111-4. 21. campobasso p, schieven e, fernandes ec. cowper's syringocele: an analysis of 15 consecutive cases. arch dis child. 1996;75:71-3. 22. young hh, frontz wa, baldwin jc. congenital obstruction of the posterior urethra. j urol. 1919;3:289-365. 23. nonomura k, kanno t, kakizaki h, koyama t, yamashita t, koyanagi t. impact of congenital narrowing of the bulbar urethra (cobb's collar) and its transurethral incision in children. eur urol. 1999;36:1448; discussion 149. 24. dewan pa. a study of the relationship between syringoceles and cobb's collar. eur urol. 1996;30:119-24. 25. dewan pa, keenan rj, morris ll, le quesne gw. congenital urethral obstruction: cobb's collar or prolapsed congenital obstructive posterior urethral membrane (copum). br j urol. 1994;73:91-5. 26. cranston d, davies ah, smith jc. cobb's collar--a forgotten entity. br j urol. 1990;66:294-6. 27. ciftci ao, senocak me, buyukpamukcu n, hicsonmez a. complete duplication of the bladder and urethra: a case report and review of the literature. j pediatr surg. 1995;30:1605-6. 28. dajani am, el-muhtasseb h, kamal mf. complete duplication of the bladder and urethra. j urol. 1992;147:1079-80. 29. appel ra, kaplan gw, brock wa, streit d. megalourethra. j urol. 1986;135:747-51. 30. middleton aw jr, melzer rb. duplicated urethra: an anomaly best repaired. urology. 1992;39:538-42. 31. nesbitt te. congenital megalourethra. j urol. 1955;73:839-42. 32. mortensen ph, johnson hw, coleman gu, lirenman ds, taylor g, mcloughlin mg. megalourethra. j urol. 1985;134:358-61. 33. downs ra. congenital polyps of the prostatic urethra. a review of the literature and report of two cases. br j urol. 1970;42:76-85. 34. coleburn nh, hensle tw. anterior urethral polyp associated with hematuria in six-year-old child. urology. 1991;38:143-4. 35. walsh ik, keane pf, herron b. benign urethral polyps. br j urol. 1993;72:937-8. 36. gleason pe, kramer sa. genitourinary polyps in children. urology. 1994;44:106-9. 37. anandan n, shetty sd, patil kp, ibrahim ai. acute urinary retention caused by anterior urethral polyp. br j urol. 1992;69:321-2. 38. azmy af. anterior urethral polyp in a child. br j urol. 1990;66:323. 39. redman jf. anterior urethral polyp in a boy. j urol. 1982;128:1316. 40. miroglu c, ilhan a, ozdiler e. congenital urethral polyp in an adult. br j urol. 1988;61:531-2. 41. bagley fh, davidson ai. congenital urethral polyp in a child. br j urol. 1976;48:278. 42. spyropoulos c, konidaris d, papanicolaou a, stephanidis a, michael v, androulakakis pa. posterior urethral polyp in a boy, diagnosed by colour doppler ultrasonography. bju int. 1999;84:881-2. 43. foster rs, garrett ra. congenital posterior urethral polyps. j urol. 1986;136:670-2. 131 urol_v3_no1_001_editorial.qxd 23 urology journal unrc/iua kidney transplantation posttransplant infectious complications: a prospective study on 142 kidney allograft recipients gholamreza pourmand,* mohammadreza pourmand, sepehr salem, abdorasoul mehrsai, mohsen taheri mahmoudi, mohammadreza nikoobakht, reza ebrahimi, ali saraji, shahram moosavi, babak saboury urology research center, division of transplantation, tehran university of medical sciences, iran abstract introduction: we evaluated the posttransplant complications resulting from infections and their association with graft function, immunosuppressive drugs, and mortality. materials and methods: a total of 142 kidney allograft recipients were followed for 1 year after transplantation. the patients' status was assessed during regular visits, and data including clinical characteristics, infections, serum creatinine level, acute rejection episodes, immunosuppressive regimen, graft function, and mortality were recorded and analyzed. results: infections occurred in 77 patients (54%). the lower urinary (42%) and respiratory (6.3%) tracts were the most common sites of infection. the most frequent causative organisms were klebsiella in 34 (24%) and cytomegalovirus in 25 patients (18%). wound infection occurred in 7 patients (5%). the mortality rate was 7.7% and infection-related death was seen in 5 patients (3.5%) who developed sepsis. graft loss was seen in 16 patients (11%), of whom 2 developed cytomegalovirus infection, 2 experienced urinary tract infection, and 5 developed sepsis and died. mycobacterial and hepatitis c infections were noticeably rare (0.7% and 2.8%, respectively). conclusion: this study showed that infections are important causes of morbidity and mortality during the posttransplant period. we recommend that serologic tests be performed before and after transplantation to recognize and meticulously follow those who are at risk. in our study, high-risk patients were those with elevated serum creatinine levels who received high doses of immunosuppressive drugs. as the urinary tract is the most common site of infection, early removal of urethral catheter is recommended to reduce the risk of infection. key words: kidney transplantation, infections, complications, mortality, cytomegalovirus, urinary tract infection vol. 3, no. 1, 23-31 winter 2006 printed in iran introduction kidney transplantation is an established, definitive, highly successful therapy for end-stage renal disease (esrd) and is more widely accessible now than in previous decades.(1,2) however, infectious complications after kidney transplantation are still associated with a significant morbidity and continue to be the most frequent cause of death during the early posttransplant period.(3,4) under standard immunosuppression, about 50% (6% to 86%) of all received may 2005 accepted september 2006 *corresponding author: urology research center, sina hospital, hassanabad sq, tehran 1995345432, iran. e-mail: gh_pourmand@hotmail.com posttransplant infectious complications24 kidney allograft recipients develop an infection within the first 6 months after engraftment.(2,5) in developing countries (with rates of 15% for tuberculosis, 30% for cytomegalovirus, and nearly 50% for bacterial infections), the spectrum of infections, their chronological occurrence, and their risk factors in kidney recipients seem to be different from those in developed regions.(6,7) owing to the progress made in the treatment of infections and the increasing expertise of the transplant team, deaths resulting from infections have decreased from 73% before 1976 to 20% between 1994 and 1996.(1,2,7) in the united states (1998), mortality due to infections was close to 0.3 deaths per 100 patient-years in 1998, corresponding to 20% of deaths in all transplant patients, and the medicare spending during the first year after transplantation was about us $88 000 for each patient, approximately, 20% of which was used for the diagnosis and treatment of infection.(2,7) due to environmental, social, and financial differences between countries, we assume that posttransplant infectious patterns may be different too; therefore, we planned this research to investigate posttransplant infectious complications and their association with patients' characteristics and transplantation outcomes. materials and methods from february 2002 to february 2004, 179 patients with esrd underwent kidney transplantation at sina hospital in tehran, iran. they were followed for 1 year for infectious complications and the outcomes of the kidney allograft. all donors and recipients received a single dose of intravenous prophylactic antibiotic 1 hour preoperatively (ceftriaxone 1 g). all kidney recipients received cephalothin for 4 days during the hospital stay and trimethoprimsulphamethoxazole for 6 months postoperatively as prophylaxis. the kidney allograft was placed retroperitoneally in the right or left iliac fossa. the ureter was anastomosed to the recipient's bladder. the native kidneys of the recipients were not removed. the foley catheter and ureteral double j stent were removed after 7 and 40 days of transplantation, respectively. all patients received prednisolone (1 mg/kg/d, tapered by 5 mg weekly), cyclosporine a (5 mg/kg/d), and mycophenolate mofetil (2 g/d). acute rejection was managed with antithymocyte globulin (atg) or pulse methylprednisolone. furthermore, atg was administered as prophylaxis in high-risk patients who had their second or third transplantation or had positive panel reactive antibodies and in recipients of cadaveric kidney allograft. blood cyclosporine levels were checked on the seventh postoperative day and monthly thereafter. during the hospital stay, clinical examinations and laboratory investigations including complete blood cell count with differential and serum urea, creatinine, and electrolytes were performed daily. urinalysis and urine culture were done twice per week. when indicated (presence of fever, leukocytosis, urinary symptoms, respiratory symptoms, diarrhea, abdominal pain, tenderness of the graft, discharge from the wound or catheter site, elevation of creatinine level, and decrease in the level of consciousness), one or more of the following investigations were performed according to the clinical status: smear and cultures of blood, urine, throat, sputum, synovial fluid, cerebrospinal fluid, and bronchoalveolar lavage fluid. moreover, serologic tests were carried out including: anticytomegaloviruc antibody (enzyme-linked immunosorbent assay), cytomegaloviruc (cmv) antigen (pp65), cmv dna (polymerase chain reaction), hepatitis b surface (hbs) antigen, antihbc antibody, hbv dna (polymerase chain reaction), antihepatitis c virus (anti-hcv) antibody (polymerase chain reaction), herpes simplex virus (hsv), and varicella-zoster virus (vzv). during follow-up, the patients were visited weekly for the first month, every 2 weeks in the second month, monthly up to the sixth month, and every 3 months thereafter. laboratory investigations, including complete blood cell count with differential, serum urea, creatinine, and electrolytes, urinalysis, and if necessary, imaging tests such as ultrasonography of the graft and renal radioisotope scan were carried out. although the presence of bacteriuria would fulfill the criteria for urinary tract infection (uti) in kidney transplant recipients,(8) other criteria, such as pyuria (more than 10 leukocytes/ml) and fever, are frequently used for diagnosing uti. for diagnosing uti and respiratory tract infections (rtis), we used the centers for disease control and prevention (cdc) definition.(9) wound pourmand et al 25 infection was defined as the presence of purulent discharge from a surgical wound (confirmed by culture). cytomegalovirus infection was defined as cmv antigen detection in the recipient's serum. the diagnosis of cmv disease was based on the presence of clinical symptoms (fever, malaise, arthralgia, myalgia, and organ involvement) and detection of cmv in clinical samples (such as blood and bronchoalveolar lavage fluid). we collected postoperative data regarding graft function (creatinine level), infectious episodes (types and time), episodes of acute rejection, dosage of immunosuppressive drugs, and rates of mortality. the study was performed in accordance with the international standards of good clinical practice and the world medical association declaration of helsinki and subsequent amendments,(10) and approved by the ethics committee at tehran university of medical sciences. meanwhile, written informed consent was obtained from all patients. the collected data were analyzed using the chisquare or fisher exact test for dichotomous variables and the student t test for continuous variables. analyses were carried out with spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa) and a p value less than .05 was considered significant. results of 179 kidney recipients, 142 were followed for 1 year posttransplant (table 1). the most frequent underlying causes of renal failure were hypertension in 51 (36%) and diabetic nephropathy in 17 patients (12%) (figure 1). overall, infections occurred in 77 (54%) patients. the most frequent causative organisms were klebsiella in 34 (24%) and cmv in 25 patients (18%) (table 2). lower urinary tracts (42%) and respiratory tracts (6.3%) were the most common sites of infections (figure 2). the following is the description of all infectious fig. 1. major causes of end-stage renal disease in kidney transplant patients table 1. characteristics of 142 kidney allograft recipients characteristics value (%) female sex 50 (35) age (years) mean ± standard deviation 41 ± 14.47 range 8 to 73 posttransplant hospitalization (days) mean ± standard deviation range 24 ± 13.12 9 to 113 donor-recipient relation living-unrelated 120 (85) living-related 12 (8) cadaveric 10 (7) retransplantation 3 (2) positive panel reactive antibodies 1 (0.7) posttransplant infectious complications26 complications evaluated in this study. donor type (living-related, living-unrelated, or cadaveric) was not associated with uti, cmv, and wound infection, but rtis were less common in kidney recipients from living-unrelated donors (table 3). age distribution of the patients with infectious diseases is shown in table 4. fig. 2. posttransplant infectious complications, acute rejection, and mortality during 1-year follow-up 0 5 10 15 20 25 30 35 1 2 3 4 5 6 7 8 9 10 11 12 posttransplant months n u m b e r o f p a ti e n ts cytomegalovirus disease urinary tract infections respiratory tract infections wound infections acute rejection death table 2. pathogens detected in infectious cases microorganisms urinary tract infections respiratory tract infections wound infections other infections total (%) bacterial klebsiella 31 1 2 34 (24) escherichia coli 10 1 2 1 14 (10) enterococci 10 2 1 13 (9) pseudomonas aeruginosa 6 1 7 (5) staphylococcus aureus 1 2 1 4 (3) staphylococcus coagulase-negative 1 1 1 1 4 (3) streptococci 1 2 3 (2) citrobacter 1 1 2 (1) mycoplasma 1 1 2 (1) mycobacterium tuberculosis 1 1 (0.7) viral cytomegalovirus 25 25 (18) hepatitis c virus 4 4 (3) hepatitis b virus 3 3 (2) varicella-zoster virus 2 2 (1) herpes simplex virus 1 1 (0.7) fungal yeast 3 3 (2) aspergillus 1 1 (0.7) candida 1 1 (0.7) protozoal entameba histolytica 2 2 (1) pourmand et al 27 bacterial urinary tract infections. fifty-nine patients(42%; 33 men, 26 women) developed uti (figure 2), of whom 37% and 10% were hypertensive and diabetic, respectively (table 5). sex distribution among patients with uti was not different from the entire group of kidney recipients (p = .062). thirty-eight percent of utis occurred during the hospital stay. the mean time between transplantation and the first episode of uti was 58.0 ± 114.5 days. the mean serum level of creatinine at the time of uti was 2.56 ± 2.07 mg/dl. urinary tract infection occurred in 4 of 10 cadaveric kidney recipients. the mean serum level of creatinine at the time of uti in cadaveric and living donor kidney recipients was 5.3 ± 1.65 mg/dl and 2.36 ± 1.95 mg/dl, respectively (p = .022). the mean dose of mycophenolate mofetil, prednisolone, and cyclosporine a at that time were 1516.9 ± 340.4 mg/d, 43.58 ± 12.6 mg/d, and 354.2 ± 109.8 mg/d, respectively. five of 10 patients who developed enterococcal uti had received atg previously, which table 3. donor type of recipients with posttransplant infectious complications donor type living-unrelated (%) living-related (%) cadaveric (%) p value urinary tract infections 51 (49.9) 4 (33.3) 4 (40) .82 respiratory tract infections 5 (4.2) 2 (16.7) 2 (20) .044 cytomegalovirus disease 22 (18.3) 1 (8.3) 2 (20) .67 wound infections 6 (5) 1 (10) .096 acute rejection 29 (24.2) 2 (16.7) 4 (40) .22 death 7 (5.8) 1 (8.3) 3 (30) .023 table 4. age distribution of posttransplant infectious complications age group (years) number of kidney recipients (%) urinary tract infections (%) cytomegalovirus disease (%) acute rejection (%) death (%) ≤ 14 6 (4) 4 (66.7) 1 (16.7) 2 (33.3) 15 to 29 33 (23) 12 (36.4) 4 (12.1) 5 (15.2) 3 (9.1) 30 to 44 45 (32) 14 (31.1) 10 (22.2) 14 (31.1) 3 (6.7) 45 to 59 45 (32) 20 (44.4) 9 (20.0) 11 (24.4) 3 (6.7) 59 < 13 (9) 9 (69.2) 1 (7.7) 3 (23.1) 2 (15.4) total 142 (100) 59 25 35 11 p value .085 .66 .57 .77 table 5. major causes of end-stage renal disease in kidney recipients with posttransplant complications and in dead patients hypertension diabetes mellitus glomerulonephritis polycystic kidney disease kidney calculi reflux nephropathy pyelonephritis urinary tract infections 22 6 4 4 5 2 1 respiratory tract infections 3 2 1 1 cytomegalovirus disease 7 4 3 2 2 1 wound infections 4 4 acute rejection 14 4 3 2 4 2 death 5 2 1 2 posttransplant infectious complications28 indicates a significant association between atg administration and enterococcal uti (p = .04). of all patients with uti, 13 developed acute rejection, and graft loss was seen in 2. five patients with the episodes of uti died within 1 year. the mean serum level of creatinine at the time of acute rejection in patients with and without a previous urinary infection was 6.73 ± 0.91 mg/dl and 3.98 ± 0.47 mg/dl, respectively (p = .032). pyelonephritis, caused by klebsiella and escherichia coli, occurred in 2 patients, the latter of which was in a diabetic patient. viral infections. cytomegalovirus disease occurred in 25 patients (18%; 17 men, 8 women), 28% and 16% of whom were hypertensive and diabetic, respectively. the mean time interval between transplantation and diagnosis of cmv disease was 136 ± 116.05 days (range, 14 to 331 days). nineteen percent of cmv disease cases were diagnosed during hospitalization. the mean serum level of creatinine at the time of positive cmv antigen detection was 2.18 ± 0.95 mg/dl. the mean dosages of mycophenolate mofetil, prednisolone, and cyclosporine a at that time were 1700 ± 240.5 mg/d, 18.9 ± 10.1 mg/d, and 285.4 ± 67.8 mg/d, respectively. three patients (12%) had received atg before infection. of patients with cmv disease, 15 had experienced uti before (klebsiella in 9 and escherichia coli in 3 were the most frequent causative organisms). acute rejection with a mean serum creatinine level of 4.26 ± 2.46 mg/dl was seen later in 8 patients (32%) who had cmv disease. two of them (8%) were cadaveric kidney recipients, and there were 2 kidney recipients from living donors who both died. hepatitis c serologic tests, at the time of transplantation, revealed the positive hcv antibody in 3 patients (hcv rna was negative). acute rejection occurred in 2 of them with serum creatinine levels of 2.6 mg/dl and 6.7 mg/dl at the time of diagnosis (170 days and 147 days postoperatively). one patient developed hcv infection (positive enzyme-linked immunosorbent assay and polymerase chain reaction results) 534 days after transplantation, in whom pretransplant serologic tests were negative. there was a significant association between positive hcv serologic tests and atg administration (p = .049). at the time of transplantation, 2 patients had a positive hbs antigen on serologic testing. urinary tract infection occurred in both. one patient with negative hbv tests at transplantation developed hbv infection 205 days after transplantation. two patients developed herpes zoster infection. the first patient was a 10-year-old boy with a serum creatinine level of 2 mg/dl, diagnosed 104 days postoperatively. the second was a 29-yearold man in whom herpes zoster infection was detected 144 days postoperatively and his serum creatinine level was 3.2 mg/dl at diagnosis. one patient developed herpes simplex infection 27 days after transplantation. this patient had a positive cmv antigen at the same time. wound infection. wound infection developed in 7 patients (5%), 4 of whom were diabetic. the mean time between transplantation and infection diagnosis was 147 ± 126.08 days (range, 10 to 355 days), and the mean age of the patients was 44 ± 8.33 years. the most common causative organisms were escherichia coli (2 cases), enterococci (2 cases), and staphylococcus aureus (2 cases). there was a significant correlation between cmv infection and staphylococcal (aureus and coagulase-negative) wound infection (p = .041). other infections. respiratory tract infections were seen in 9 patients (6.3%), of whom 5 developed pneumonia. the causative pathogens are demonstrated in table 2. tuberculosis was found in 1 patient. other infections and their characteristics are shown in table 6. acute rejection. there were 35 patients (25%) who experienced acute rejection. the mean time of the rejection was 85.32 ± 116.97 days after transplantation. the mean age of the patients was 45 ± 14.5 years, and the mean serum creatinine level was 4.87 ± 2.87 mg/dl. of patients with acute rejection episodes, 40% and 11% were hypertensive and diabetic, respectively. moreover, 14 had received atg before rejection, 4 had received cadaveric kidney allograft, and 3 died. simultaneous rejection and infection occurred in 10 patients (7%), and the concurrent infections were uti in 5, cmv disease in 2, sepsis in 2, and hcv infection in 1. at the time of acute rejection, the mean dosages of immunosuppressive drugs were as follows: mycophenolate mofetil, 1647.05 mg/d; pourmand et al 29 prednisolone, 28.6 mg/d; and cyclosporine a, 279.4 mg/d. graft loss there were 16 patients (11%) with graft loss within 1 year (5 due to rejection and 11 due to death). the mean age and mean time of graft loss were 43.4 ± 13.45 years and 151.8 ± 194.25 days after transplantation, respectively. of these patients, 2 had developed cmv infection, 2 had experienced uti, and 5 had developed sepsis before graft loss. mortality. overall mortality rate was 7.7% (11 patients; 7 men and 4 women). of the patients who died within the first posttransplant year, 45% and 18% were hypertensive and diabetic, respectively. infection-related mortality was 3.5% (5 patients), all due to sepsis. mortality was associated with gram-negative enterobacteriaceae (2 patients), staphylococcus aureus (1 patients), staphylococcus coagulase-negative (1 patient), and aspergillus (1 patient). discussion there are some studies with different results on the overall incidence of the posttransplant infections and most commonly involved sites.(11-16) maraha and colleagues(17) studied 192 patients between 1992 and 1997. they reported that 71% of patients developed an infection during the first year of transplantation, the most frequent of which were uti (61%), rti (8%) and intraabdominal infections (7%). the immunosuppressive regimen and donor type play important roles in developing infections.(16,18-20) fishman and rubin have reported that the net state of immunosuppression is a risk factor for infections.(5) bacterial infections often occur in the first month following transplantation, and technical factors may play an important etiologic role.(2,4,5,7,21,22) from the second to the sixth posttransplant month, two thirds of the febrile illnesses are caused by cmv disease.(2,5,7,23-25) cytomegalovirus is generally the most frequent single cause of infectious complications after kidney transplantation, but fewer than 20% of patients actually develop the typical symptoms of this infection.(4,7,11,25) enterobacteriaceae, especially escherichia coli and klebsiella are the table 6. fungal, protozoal, and other bacterial infections found in the patients of this study uc: urinary calculi, htn: hypertension, gn: glomerulonephritis, dm: diabetes mellitus, pckd: polycystic kidney disease, cmv: cytomegalovirus, rn: reflux nephropathy, u: living-unrelated, c: cadaveric infection number of patients (%) posttransplant day at diagnosis pathogen underlying disease donor type remarks 96 pckd c expired 134 dm u yeast 3 (2) 214 yeast gn u amebic dysentery 2 (1) 46 128 entameba histolytica pckd rn u u otitis media 2 (1) 59 83 mycoplasma staphylococcus (coagulase-negative) htn pckd u u cmv ag+ & acute rejection aspergillosis 1 (0.7) 125 aspergillus fumigatus uc u expired candidiasis 1 (0.7) 172 candida albicans htn u cmv ag+ osteomyelitis 1 (0.7) 120 staphylococcus aureus dm & htn u cmv ag+ & expired endocarditis 1 (0.7) 282 enterococci htn u cmv ag+ perirenal abscess 1 (0.7) 45 klebsiella gn u mycobacteria 1 (0.7) 355 mycobacterium tuberculosis htn u epididymioorchitis 1 (0.7) 190 escherichia coli dm u posttransplant infectious complications30 major pathogens among bacterial infections in kidney transplant patients.(1,11,17) mucocutaneous infections with herpes simplex virus and varicella-zoster virus occur more often in kidney transplant patients than they do in the normal population, most often in the first 6 months after transplantation.(7,21,26) hepatitis b infection occurs only in fewer than 5% of kidney allograft recipients, while the prevalence of positive hcv antibody in kidney transplant candidates is about 50% in some studies.(22,27) the overall rate of hcv positive patients in our study was 3%. the most common fungal infection after transplantation is candidiasis, which usually colonizes in mucosa and may cause superficial mucositis, such as esophagitis or cystitis. the second common fungal infection is aspergillosis, especially with aspergillus fumigatus and aspergillus flavus species.(2,7,11) mycobacterial infection is an important problem after kidney transplantation in developing countries and is more prevalent in transplanted patients than it is in a normal population. in one series reported from india, the incidence of mycobacterial infection in kidney allograft recipients during a median 3 years' follow-up was 13.3%.(28) also, a study in china revealed an incidence rate of 5% over a 2-year period.(29) mycobacterial infection is relatively less prevalent in the kidney recipients in western countries.(30) we had only 1 patient with mycobacterium tuberculosis. it has been shown that kidney allograft recipients who develop opportunistic infections during the first year after transplantation, usually have higher serum creatinine levels, receive higher doses of immunosuppressive drugs, and have more recurrent rejection episodes.(2,7) overall incidence of mortality in the first year after transplantation is 5% to 10%, half of which is caused by infectious complications.(4,12,20,31-33) in our study, the most common causative agents were klebsiella (34 cases) and cmv (25 cases). similar to other studies, the most frequent site of infection was the lower urinary tract (42%). the average time of detection of bacterial infections (58 days) and the average time of cmv development (136 days) were in agreement with other studies. our findings indicated that uti and cmv had no significant association with acute rejection. patients' sex had no impact on uti incidence. in contrast with hbv infection, incidence of hcv and mycobacterial infections were less frequent than those in other studies.(22,27-30) eleven patients died during the first year of transplantation, 5 of whom (45%) had developed an episode of infection before death, and the mean dosage of immunosuppressive drugs at the discharge time was significantly higher for these patients compared with others. justification of these results needs further well-designed studies. conclusion this study identifies infections as the important cause of morbidity and mortality during the posttransplant period. therefore, we recommend performing serologic tests before and after transplantation to recognize and meticulously follow those who are at risk. furthermore, kidney recipients who have a higher serum creatinine level and receive high doses of immunosuppressive drugs at the time of discharge will be considered as high-risk patients (regarding posttransplant infectious complications and death). these patients must be evaluated and followed more carefully. also, treatment of all infections in recipients before transplantation is recommended. in case of a symptomatic infection, empirical treatment should be initiated before the test results of collected tissue and body fluid specimens are known. as the urinary tract is the most common site of infection, attention should be paid to the urinary symptoms of high-risk patients (eg, diabetics). also, early removal of urethral catheter is recommended to reduce the risk of infection. references 1. ghasemian sm, guleria as, khawand ny, light ja. diagnosis and management of the urologic complications of renal transplantation. clin transplant. 1996;10:21823. 2. schmidt a, oberbauer r. bacterial and fungal infections after kidney transplantation. curr opin urol. 1999;9:459. 3. khalil ullah, iftikhar r, moin s, badsha s. post transplant complications. pak j med res. 2003;42:174-8. 4. hibberd pl, rubin rh. renal transplantation and related infections. semin respir infect. 1993 ;8:216-24. 5. fishman ja, rubin rh. infection in organ-transplant recipients. n engl j med. 1998;338:1741-51. pourmand et al 31 6. rizvi sa, naqvi sa, hussain z, et al. renal transplantation in developing countries. kidney int suppl. 2003;(83):s96-100. 7. snydman dr. infection in solid organ transplantation. transpl infect dis. 1999;1:21-8. 8. rubin rh, shapiro ed, andriole vt, davis rj, stamm we. evaluation of new anti-infective drugs for the treatment of urinary tract infection. infectious diseases society of america and the food and drug administration. clin infect dis. 1992;15 suppl 1:s216-27. 9. garner js, jarvis wr, emori tg, horan tc, hughes jm. cdc definitions for nosocomial infections, 1988. am j infect control. 1988 jun;16(3):128-40. 10. world medical association 2000 declaration of helsinki: ethical principles for medical research involving human subjects. 52nd world medical association general assembly, october 3-7, 2000; edinburgh, scotland, october, 2000. 11. viale p, scudeller l. infectious complications after renal transplantation]. g ital nefrol. 2004;21 suppl 26:s48-52. 12. morduchowicz g, pitlik sd, shapira z, et al. infections in renal transplant recipients in israel. isr j med sci. 1985;21:791-7. 13. conrad s, schneider aw, gonnermann d, ganama a, tenschert w, huland h. urologic complications after kidney transplantation. experiences in a center with 539 recipients]. urologe a. 1994;33:392-400. 14. goya n, tanabe k, iguchi y, et al. prevalence of urinary tract infection during outpatient follow-up after renal transplantation. infection. 1997;25:101-5. 15. schmaldienst s, dittrich e, horl wh. urinary tract infections after renal transplantation. curr opin urol. 2002;12:125-30. 16. ramos e, karmi s, alongi sv, dagher fj. infectious complications in renal transplant recipients. south med j. 1980;73:751-4. 17. maraha b, bonten h, van hooff h, fiolet h, buiting ag, stobberingh ee. infectious complications and antibiotic use in renal transplant recipients during a 1-year followup. clin microbiol infect. 2001;7:619-25. 18. bernabeu-wittel m, naranjo m, cisneros jm, et al. infections in renal transplant recipients receiving mycophenolate versus azathioprine-based immunosuppression. eur j clin microbiol infect dis. 2002;21:173-80. 19. ahern mj, comite h, andriole vt. infectious complications associated with renal transplantation: an analysis of risk factors. yale j biol med. 1978;51:513-25. 20. el-agroudy ae, bakr ma, shehab el-dein ab, ghoneim ma. death with functioning graft in living donor kidney transplantation: analysis of risk factors. am j nephrol. 2003;23:186-93. 21. john gt, date a, mathew cm, jeyaseelan l, jacob ck, shastry jc. a time table for infections after renal transplantation in the tropics. transplantation. 1996;6:970-2. 22. oguz y, bulucu f, oktenli c, doganci l, vural a. infectious complications in 135 turkish renal transplant patients. cent eur j public health. 2002;10:153-6. 23. sim sk, yap hk, murugasu b, prabhakaran k, ho cl. infections in paediatric renal transplant recipients. ann acad med singapore. 1997;26:290-3. 24. pascual j, alarcon mc, marcen r, et al. cytomegalovirus infection after renal transplantation: selective prophylaxis and treatment. transplant proc. 2003;35:1756-7. 25. dickenmann mj, cathomas g, steiger j, mihatsch mj, thiel g, tamm m. cytomegalovirus infection and graft rejection in renal transplantation. transplantation. 2001;71:764-7. 26. takahashi k, yagisawa t, hiroshi t, et al. infectious diseases in kidney transplant recipients treated with cyclosporin]. nippon hinyokika gakkai zasshi. 1989;80:175-84. 27. morales jm, dominguez-gil b, sanz-guajardo d, fernandez j, escuin f. the influence of hepatitis b and hepatitis c virus infection in the recipient on late renal allograft failure. nephrol dial transplant. 2004;19 suppl 3:iii72-6. 28. john gt, shankar v, abraham am, mukundan u, thomas pp, jacob ck. risk factors for post-transplant tuberculosis. kidney int. 2001;60:1148-53. 29. lui sl, tang s, li fk, et al. tuberculous infection in southern chinese renal transplant recipients. clin transplant. 2004;18:666-71. 30. queipo ja, broseta e, santos m, sanchez-plumed j, budia a, jimenez-cruz f. mycobacterial infection in a series of 1261 renal transplant recipients. clin microbiol infect. 2003;9:518-25. 31. nikonenko as, zavgorodnii sn, nikonenko tn. causes of renal allotransplant loss during first year after renal transplantation]. klin khir. 2002;(3):48-50. 32. tanphaichitr nt, brennan dc. infectious complications in renal transplant recipients. adv ren replace ther. 2000;7:131-46. 33. rashed a, aboud o. renal transplantation: seventeen years of follow-up in qatar. transplant proc. 2004;36:1835-8. urology journal unrc/iua vol. 1, no. 3, 170-173 summer 2004 printed in iran 170 endoscopic renal cyst ablation tadayon a*, a'yanifard m, mansoori d department of urology, shiraz university of medical sciences, shiraz, iran abstract purpose: to evaluate the result of simple renal cyst ablation by endoscope and compare the results with other techniques of renal cyst treatment. materials and methods: a prospective study was performed at shaheed faghihi hospital from january 2001 to january 2003. ten patients with symptomatic simple renal cyst were selected for this study. the exclusion criteria were history of previous renal surgery, parapelvic cyst, and cyst size less than 50 mm. urinalysis, urine culture, serum electrolytes, ultrasonography, and ct scan were done before operation. the patients underwent endoscopic renal cyst ablation and cytology of cyst fluid and histopathological examination of cysts' walls were done in all patients. the patients were followed with ultrasonography after two weeks and 2, 6, and 12 months postoperatively. disappearance of the cyst or decreasing its size to less than 50% of its primary size was considered as improvement. results: all the patients were female with a mean age of 55 (range 22 to 75) years. the operation was successful in 9 patients with no major complications. perinephric hematoma and excessive leakage were seen in two patients. the operative time was 38±10.8 minutes and hospital stay was 3±1.3 days. mean size of cyst before operation was 75±19.7 mm and changed to 12.7±15.3 mm after operation (p<0.001). flank pain subsided in 88.8% (p<0.008). conclusions: cyst ablation can be used for the treatment of simple renal cysts not responding to aspiration and sclerosing therapy, and if there is no laparoscopic facility. more studies are needed to confirm these results. key words: simple renal cyst, ablation, endoscope, treatment introduction simple renal cyst is a common finding and its incidence increases with age, corresponding to a rate of 33% in population over 60. there is no gender predilection and no genetic association. the etiology is unknown, but tubular obstruction and ischemia due to obstruction may have an etiologic role. fortunately, most patients have no symptoms. the presenting symptoms are flank pain, hypertension, hematuria, and caliceal obstruction.(1-6) the first line treatment of symptomatic simple renal cyst is ultrasound guided aspiration of the cyst and application of sclerosing agents (ethanol 95%).(7) recurrence rate depends on the technique of procedure. in recurrent cases laparoscopic cystectomy is recommended.(8) open surgical cystectomy is rarely needed. salas sironvalle et al(9) have reported endoscopic cyst ablation. in the present study, we evaluated endoscopic ablation in 10 symptomatic patients with simple renal cyst. materials and methods a prospective study was performed at shaheed faghihi hospital from january 2001 to january 2003. ten patients with symptomatic simple renal cyst, referred to urology clinic, were selected for this study. the exclusion criteria were history of previous renal surgery, parapelvic cyst, and cyst size less than 50 mm. detailed information about endoscopic surgery accepted for publication in april 2003 *corresponding author: department of urology, shiraz university of medical sciences, shiraz, iran. email: amin_sharifi@hotmail.com endoscopic renal cyst ablation 171 and risk of recurrence were described for all patients. the consent was taken from each patient. urinalysis, urine culture, serum electrolytes, ultrasonography, and ct scan were done before operation. the patients underwent endoscopic renal cyst ablation, cytology of cyst fluid, and histopathological examination of cysts wall. the procedure was done under general anesthesia in flank position. the entrance site to the cyst was determined by means of ultrasonography in operating room. a 19 gauge nephrostomy needle was advanced into cyst cavity and cyst puncture for cytology was done. a 0.038 inch guide wire was advanced through the needle into cyst cavity and the tract was dilated up to 26 f. a 30 f amplatz sheath was placed in cavity and resection and fulguration of the cyst wall and its bed was done with a 24 f resectoscope under direct vision. the cyst bed was irrigated with distilled water and a 16 f indwelling catheter was placed in cavity. drain was removed after one to three days. the patients were followed with ultrasonography two weeks and 2, 6, and 12 months postoperatively. disappearance of the cyst or decreasing its size to less than 50% of its primary size were defined as improvement.(1) paired t test and fisher's exact test were used for statistical analysis. results from january 2001 to january 2003, 10 patients underwent renal cyst ablation. one operation failed due to the small size of the cyst (34 mm) and changed to open renal cystectomy. all of the patients were female with a mean age of 55 (range 22 to 75) years. the operation was successful in 9 patients with no major complications (table 1). perinephric hematoma with no hemoglobin drop occurred in one patient. hematoma was drained under ultrasonography guidance after two weeks. excessive urine leakage was seen in one patient for 6 days. she had no perinephric collection after removing the drain. there were no trauma to major intraabdominal organs or great vessels. no pneumothorax or hemothorax were detected. the operative time was 38±10.8 minutes and hospital stay was 3±1.3 days. the patients were followed for 11.4±4.8 months. cytology was normal in all patients. pathologic reports of all cyst walls were in favor of benign renal cyst. the mean size of the cyst before operation was 75±19.7 mm and changed to 12.7±15.3 mm after operation (p<0.001) (fig. 1). the cyst was no longer seen in 5 (55.5%) cases and the size of cyst decreased to less than 50% in the remaining; therefore, the operation was successful in all patients. flank pain subsided in 8 (88.8%) patients (p< 0.008). pain remained in one patient as the same intensity as before operation, in spite of subsiding of the cyst in ultrasonography. thus, the pain was thought to have non-renal origin. there was no relationship between the result of operation and surgeon experience or the size of the cyst (less or more than 70 mm) (table 2). discussion most simple renal cysts are treated with aspiration and/or injection of sclerosing agents.(7) aspiration alone has 30% to 78% recurrence rate.(10) using sclerosing agents decrease recurrence rate dramatically. different types of sclerosing agents have been used. all had good results fig. 1. renal cyst size before and after operation 75.44 22.88 15.77 12.77 0 10 20 30 40 50 60 70 80 a v e ra g e ( m m ) before operation 2 weeks after operation 2 months after operation 6 months after operation table 1. cyst size before and after endoscopic ablation �������������������������������� � � ����� � �� �� �� �� �� �� �� � � �� �� � ������������������� ��� ��� ��� ��� ��� ��� ��� ���� ��� ������ ����������������� ��� �� �� �� �� �� ��� �� �� ������! ����������������� �� �� �� ��� ��� �� ��� �� �� ������! ����������������� �� �� �� �� ��� �� ��� �� �� �������! ����������������� �� �� �� �� ��� "� "� �� �� table 2. comparison of the results of therapy according to the primary cyst size ���������� ��� � ����������������������� ��� ������������������ �� ������������� �� �� �� ����������������� �� �� �� endoscopic renal cyst ablation172 with no priority to each other.(11) techniques and number of injections of sclerosing agents had different results. hanna and dahniya (1996) reported 32% recurrence rate after one injection of 95% ethanol and no recurrence within two years, after two injections with 48 hours interval in their patients.(12) when conservative therapy is not successful, aspiration, laparoscopic excision,(8) endoscopic ablation,(9) and open surgery is recommended. the technique used in this study is a novel one and has similarity to the technique used by salas sironvalle in 1993(9) and our results agree with these studies and are comparable with aspiration and with laparoscopic techniques (table 3). it is recommended to use this technique in the treatment of cysts larger than 50 mm. in our study, the operation was successful in all patients except one and the pain relieved in 88% of the patients. it is important to know that renal cyst aspiration is a simple procedure and has low morbidity with high recurrence rate.(13) using sclerosing agents significantly decrease recurrence rate. sclerosing agents injection rarely has sever complications such as ureteropelvic junction obstruction(14) or diffuse renal paranchymal inflammation, which may needs nephrectomy.(15) the advantages of endoscopic cyst ablation are as follows: 1it is safe and has comparable results with open and laparoscopic operation; 2it has better results than simple aspiration with or without using sclerosing agents; 3it is less expensive and simpler than laparoscopic procedure; 4urologists are more familiar with this technique; 5histopathologic evaluation of cyst wall can be done. the disadvantages of endoscopic cyst ablation are: 1need for general anesthesia, 2need for hospital admission (this procedure can be done as opd procedure), 3dependency on radiologist help in operating room (there was no radiologist help in this study), 4risk of tumor seeding, if the cyst is malignant. conclusion this technique can be used for the treatment of simple renal cysts not responded to aspiration and sclerosing therapy, and if there is no laparoscopic facility. more studies are needed to confirm these results. references 1. glassberg ki. renal dysgenesis and cystic disease of the kidney. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 1937-1974. 2. zegel hg, sherwin nm, pollack hm. renal masses. in: grainger rg, allison dg, editorss. diagnostic radiology: an anglo-american test book of imaging. edinburgh: churchill livingstone; 1992. p.1235. 3. rockson sg, stone ra, gunnells jc jr. solitary renal cyst with segmental ischemia and hypertension. j urol 1974 nov; 112(5): 550-2. 4. luscher tf, wanner c, siegenthaler w, vetter w. simple renal cyst and hypertension: cause or coincidence? clin nephrol 1986 aug; 26(2): 91-5. 5. rosenbaum rc, johnston gs. posttraumatic cardiac dysfunction: assessment with radionuclide ventriculography. radiology 1986 jul; 160(1): 91-4. 6. hinman f jr. obstructive renal cysts. j urol 1978 may; 119(5): 681-3. 7. bean wj. renal cyst: treatment with alcohol. radiology 1981; 138: 329-331. 8. stoller ml, irby pb 3rd, osman m, carroll pr. laparoscopic marsupialization of a simple renal cyst. j urol 1993 nov; 150(5 pt 1): 1486-8. 9. salas sironvalle m, vallancien g, brisset jm. endourological management of benign renal cyst: a simplified procedure. arch esp urol 1993; 46(10): 935-8. table 3. comparison of the results of different studies with shaheed fagihi hospital's cyst ablation results ���������� ��� � ���� ���������������� �������������� ��� ��� ���������� ������������ ������ ��� ��������� � ����� ���� ������ ��� �� ����� ������������������ ������������������� ���� � ���� ���� �� ��!������ �� ��!������ "� ##����� ��� ������ $ � ��������� ����� % ����� ��� ���� ����� &�!������ ' ��'����( ����� ������ ��)�������� �� ����� *��� � '��� #��������'��)�� ��)�������� �� ����� ���� �� ��!������ endoscopic renal cyst ablation 173 10. stevenson jj, sherwood t. conservative management of renal masses. br j urol. 1971 dec; 43(6): 646-7. 11. holmberg g, hietala so. treatment of simple renal cysts by percutaneous puncture and instillation of bismuthphosphate. scand j urol nephrol 1989; 23(3): 207-12. 12. paananen i., hellstron r., et al. treatment of renal cysts with single-session percutaneous drainage and ethanol sclerotherapy: long-term outcome. adult urology 2000; 30-33. 13. lang ek. renal cyst puncture studies. urol clin north am 1987; 14: 91-102. 14. camacho mf, bondhus mj, carrion hm, lockart jl, politano va. ureteropelvic junction obstruction resulting from percutaneous cyst puncture and intracystic isophendylate injection: an unusual complication. j urol 1979; 124: 713-714. 15. beyer d, fiedler v. is renal cyst puncture an available diagnostic procedure for differentiation of avascular, space-occupying renal lesions? urologe a 1977 nov; 16(6): 339-45. urology journal vol. 11 no. 04 july august 2014 1844 abdominal endometriosis arising in an exstrophy patient michael s floyd (jr),1 rahul mistry,2 charles t burrows,2 andrew david baird1 departments of urology 1 and pathology 2, aintree university hospital, lower lane, liverpool, l9 7al, united kingdom. corresponding author: michael s floyd (jr), specialist registrar, department of urology, aintree university hospital, lower lane, liverpool l9 7al, united king-dom. tel: +44 151 5293775 e-mail: nilbury@gmail.com received august 2013 accepted february 2014 keywords: abdomen; surgery; endometriosis; etiology; complications; bladder exstrophy. introduction bladder exstrophy is a rare congenital anomaly. associations with complete duplication of the genitourinary and gynecological systems have been reported. we describe a case of an abdominal swelling in an exstrophy patient which revealed endometriosis. case report a 29 years old nulliparous female presented to the urology outpatients with a four months history of an intermittently enlarging abdominal swelling located over a scar. her past history was remarkable for bladder exstrophy for which she underwent primary bladder closure on the third day of life. this had been followed by a succession of urological procedures over seven years. she had initiated self-intermittent catheterization following this. her menarche had been at the age of thirteen. on presentation she described episodic swelling over her inferior abdominal wall beneath her laparotomy scar. it was unrelated to her menses and no systemic upset occurred. on examination a firm indurated area was noted beneath the skin within the rectus sheath. subsequent magnetic resonance imaging (mri) confirmed the presence of a 3.5 cm × 2.7 cm × 3.9 cm enhancing mass within her abdominal wall which was separate from the peritoneum (figure 1). under general anesthesia an excisional biopsy was performed. intraoperatively a mass was found within the reconstructed rectus sheath. the peritoneum was opened and a segment from the dome of the bladder was removed as the mass was attached to it inferiorly. the remainder of the bladder was unremarkable. case report skin covered double bladder exstrophy has been reported along with complete duplication of the mullerian structures(4) and also separately with colonic sequestration with a normal hindgut.(5) following progression into adulthood the reconstructed female exstrophy patient may face problems with parturition, sexual health and gynecological concerns. krisoloff and colleagues have found that multiple surgical procedures with scarring in the abdominopelvic area may have a detrimental effect on body image and sexual function.(6) successful pregnancies have been reported in patients who have undergone exstrophy repair(7) but caesarean delivery is recommended(8) gynecological complications of exstrophy repair include mucocolpos and vaginal stone formation.(9,10) burbige and colleagues studied female exstrophy patients and found that none had endometriosis.(11) our patient was nulliparous and denied dyspareunia or endometriosis. we describe an abdominal mass in a corrected female exstrophy patient, which when excised, revealed endometriosis. reports exist of dual pathologies in exstrophy patients who underwent reconstruction in adulthood.(12) kitajima and colleagues reported a case of scar endometriosis is a 26 years old exstrophy patient who underwent repair as an infant.(13) our case differs, however, as the ectopic deposit was painless and unrelated to her menstrual cycle. conclusion we believe this to be the second reported case of scar related abdominal endometriosis in an exstrophy patient. as the long term follow up of this population is predominantly urological, female exstrophy patients with gynecological problems may present to the urologist. therefore, the differential diagnosis of an abdominal mass in a female exstrophy patient should include gynecological pathologies such as ectopic endometrial tissue. conflict of interest none declared. references 1. marshall vf, meucke ec. variations in exstrophy of the bladder. j urol. 1962:88;776-84. 2. sheldon ga, mclorie ga, khoury a, churchill bm duplicate bladder exstrophy: a new variant of clinical and embryological significance. j urol. 1990;144;334-6. 3. ahmed s, abu daia j. exstrophic abdominal wall defect without bladder exstrophy (pseudoexstrophy). br j urol. 1998;81:762-3. 4. berkowitz j, warlcik c, north a, gearhart jp. duplicate bladder exstro phy with complete duplication of mullerian structures. urology. 2007;70:811.e15-7. 5. kajbafzadeh am, aghdas fs, tajik p. complete covered duplication of the bladder, urethra, vagina, uterus and visceral sequestration. int j urol. 2006;13:1129-31. 6. krisiloff m, puchner pj, tretter w, macfarlane mt, lattimer jk. pregshe was discharged after 48 hours following removal of a suprapubic catheter. outpatient review at 2 months revealed no recurrence and she remained asymptomatic. final histopathological examination confirmed a 40 g specimen consisting of fibrous tissue containing glands typical of endometriosis (figure 2). discussion variants of classical bladder exstrophy have been described by marshall and colleagues(1) and include male and female epispadias with or without incontinence, superior vesical fissures, duplicated exstrophy and cloacal exstrophy. duplicate bladder exstrophy consists of either an anterior-posterior or side by side alignment.(2) pseudoexstrophy patients have normal functioning bladders and external genitalia but have the skeletal and abdominal findings of exstrophy.(3) in adults, figure 1. abdominal magnetic resonance image showing a mass located on the inferior abdominal wall which enhanced following the administration of contrast. figure 2. photomicrographs of a section from the excised mass demonstrating endometrial glands and stroma in fibrous tissue (hematoxylin and eosin; left × 40, right × 80. 1845 case report urology journal vol. 11 no. 04 july august 2014 1846 abdominal endometriosis-floyd et al nancy in women with bladder exstrophy. j urol. 1978:119;478-9. 7. sharma d, singhal sr, singhal sk. successful pregnancy in a patient with previous bladder exstrophy. aust n z j obstet gynaecol. 1998;38:227-8. 8. mathews ri, gan m, gearhart jp. urogynaecological and obstetric issues in women with the exstrophy-epispadias complex. bju int. 2003;91:845-9. 9. zorn kc, spiess pe, salle jl, jednak r. mucocolpos associated with bladder exstrophy; a case report. can j urol. 2005;12:2614-5. 10. eyk na, grover s, fink am. vaginal calculus as a late complication of bladder exstrophy. j pediatr adolesc gynecol. 2003;16:285-7. 11. burbige ka, hensle tw, chambers wj, leb r, jeter kf. pregnancy and sexual function in women with bladder exstrophy. urology. 1986;28:12 4. 12. quiroz-guerrero j, badillo m, munoz n, anaya j, rico g, maldona do-valadez r. bladder augmentation in a young adult female exstrophy patient with associated omphalocele; an extremely unusual case. j pedi atr urol. 2009;5:330-2. 13. kitajima t, inoue m, uchida k, otake k, kusunoki m. scar endometri osis in a patient with bladder exstrophy. int surg. 2013;98:145-8. female urology the results of grade iv cystocele repair using mesh zargar ma, emami m*, zargar k, jamshidi m department of urology, shaheed hasheminejad hospital, iran university of medical sciences, tehran, iran abstract purpose: to evaluate the results of grade iv cystocele repair by 4-corner bladder and bladder neck suspension technique, using prolene mesh. material and methods: thirty-one women with a median age of 61 years and severe anterior vaginal wall prolapse (grade iv cystocele) were treated by 4-corner bladder and bladder neck suspension technique, using prolene mesh. of these, 3 had associated uterine prolapse, rectocele, and enterocele, one had rectocele and enterocele, and 18 had rectocele only. in these cases, pelvic floor defects were also repaired simultaneously and in 3, vaginal hysterectomy was done. twelve patients had a previous failed cystocele repair. in a 32-month follow-up, the patients were evaluated with vaginal examination and upright cystography. urinary continence during increased intraabdominal pressure was also assessed, based on subjective symptoms. results: none of the patients had cystocele recurrence. urinary continence during increased intra-abdominal pressure was seen in all of the patients. intraoperative rectal or bladder injury did not occur. transfusion was not required in any of the cases. early complications (6 to 8 weeks postoperatively) included irritative urinary symptom in 17 patients, of whom, 8 had documented urinary tract infection that were treated successfully. late complications were spotting in 3 cases (two were treated with topical estrogen and vaginal mucosal repair was done in one), dyspareunia in 4 sexually active patients, changes in urination pattern in 28 (improved significantly with behavioral therapy), long-term urge incontinence (>8 weeks) in 5 (medical treatment was successful in these patients), and prolonged intermittent catheterization in 1. pelvic abscess and migration of mesh were not observed. conclusion: according to our findings, using mesh in patients with grade iv cystocele, who had a previous failed surgery or weakness in supportive pelvic tissue, is an appropriate treatment modality. key words: cystocele, surgical repair, mesh 263 urology journal unrc/iua vol. 1, no. 4, 263-267 autumn 2004 printed in iran introduction grade iv cystocele is defined as the protrusion of bladder floor into the vaginal introits and indicates severe anterior vaginal wall prolapse. this grade of cystocele is usually associated with four anatomic defects in pelvic floor: urethral hypermobility due to the anterior weakness of urethropelvic ligament; vesicopelvic fascia defect in the site of its attachment to the lateral pelvic walls (lateral defect); dissociation of fibers of vesicopelvic fascia in the central portion (central defect); and cardinal and sacrouterine ligaments weakness in the posterior part.(1,2) in 80% of cases, grade iv cystocele is associatreceived december 2002 accepted july 2004 *corresponding author: hasheminejad hospital, vanak sq., tehran, iran. e-mail: emami59658@yahoo.com. cystocele repair using mesh ed with other types of prolapse such as enterocele, rectocele, uterine prolapse, and vaginal vault prolapse. clinical manifestations are feeling a vaginal mass and urinary symptoms such as problem with bladder emptying, irritative urinary symptoms, and occasionally urinary incontinence.(3) repair of pelvic floor in one stage in this grade of cystocele necessitates thorough preoperative evaluation and the familiarity of surgeon with pelvic floor anatomy and different techniques. abdominal approaches such as marshall marchetti krants, burch, and paravaginal repair, are reserved for urethral hypermobility and mild cystocele.(4) vaginal approaches such as anterior colporrhaphy with kelly type plication, which is the most common method of cystocele repair, can correct vesicopelvic fascia defect in the central portion, but the defect in bladders lateral walls, urethral hypermobility, and dissociated cardinal ligaments cannot be repaired.(5,6) in this study, we evaluated the 4-corner bladder and bladder neck suspension technique for the repair of pelvic floor, using mesh. materials and methods from 1999 to september 2004, 31 patients with grade iv cystocele had undergone cystocele repair and in a retrospective study, hospital records of them were reviewed. preoperative evaluations were history taking, physical examination, urine analysis and urine culture, lateral and upright cystography, urinary tract ultrasonography, cystoscopy, and marshall test. surgical operation was performed under general or spinal anesthesia while patient was secured in lithotomy position and a 16 f indwelling urethral catheter was inserted and fixed. due to severe uterine prolapse, vaginal hysterectomy was done in two cases before attempting to repair cystocele. the stages of repair were as follows: stage 1: normal saline was injected into the submucosa of the anterior vaginal wall and vaginal mucosa was separated from submucosal layer through a standard goal post incision (fig. 1). urethropelvic ligaments in bladder neck region, vesicopelvic fascia in central region and cardinal ligament in the posterior portion were exposed (fig. 2). at the end of this stage, peritoneal hernia into pelvic floor (enterocele) was seen in the hindmost portion of separated vaginal mucosa in 4 patients that was repaired with modified mccul suture. stage 2: endopelvic fascia in either side of bladder neck was perforated and separated from retropubic space with finger. a 3-cm skin incision was made above the symphysis pubis on abdominal wall and a specialized needle after piercing the rectus fascia was directed through retropubic space into vagina. with a 1.0 prolene suture material, urethropelvic ligaments in either side of urethra, vesicopelvic fascia in the lateral sides of the bladder, and cardinal ligaments that were 264 fig. 2. a schematic view of the anterior wall of vagina after removing mucosa. the markers are recognizable: a. urethropelvic ligament, b. vesicopelvic ligament, c. cardinal ligament. fig. 1. goal post incision. a. urethra, b. incision, c. cystocele zargar et al grasped helically and separately using raz method,(5) all were brought out onto abdominal wall over the rectus fascia (suspension) (fig. 3). stage 3: vesicopelvic fascia re-approximated with mattress suture in the midline (fig. 4) and a prolene mesh was designed and mounted as a supportive tissue on the repaired site, before tying the suture and inducing tension on prolene sutures (the second stage of suspension, fig. 5). for prevention from the movement of mesh, its edges were sutured to adjacent tissue. figure 6 shows the designed mesh, composed of two main parts. stage 4: cystoscopy for detection of any bladder injury was done. stage 5: vaginal mucosa was repaired with 2.0 vicryl suture material. stage 6: the tension on the second stage sutures was adjusted, so that the urethra and bladder floor settled in the horizontal level and then they were tied over rectus fascia. finally, abdominal skin was repaired. after repairing the anterior vaginal wall, rectocele was also corrected in 22 cases. at the end of surgery, povidione iodine-saturated gauze was inserted into vagina and removed 24 hours later. 265 fig. 6. a sample of apron shape designed mesh. a. prolene suture, b. the first part of mesh, rolling as a sling (2 × 9 cm), c. the second part of mesh that supports cystocele repair. the size of this part was adjusted for each patient perioperatively. fig. 5. location of mesh in relation to urethra, urethropelvic ligament, and vesicopelvic fascia. a. prolene suture, b. strip shaped part of mesh that goes through retropubic line, c. second part of mesh, d. urethral catheter fig. 4. anterior wall of vagina after vesicopelvic fascia repair in order to correct central cystocele. a. vesicopelvic fascia fig. 3. a schematic view of the anterior wall of vagina after removing mucosa and appearance of ligaments: a. periureteral fascia, b. vesicopelvic ligament, c. cardinal ligament, d. prolene suture. cystocele repair using mesh hospital stay was between 5 and 7 days. operative complications, such as rectal, bladder, or ureteral injuries were not seen. antibiotic coverage with ampicillin and gentamicin was started 12 hours preoperatively and continued for 48 hours, postoperatively. oral antibiotic (ciprofloxacin) was administered for one week after urethral catheter removal. all of the patients were discharged with urethral catheter and followed for 32 months. first visit was done at the tenth postoperative day and urethral catheter was removed. the patients were followed in the 4th and 6th postoperative week and then every three months, assessing urinalysis and urine culture, physical examination of vagina, and post voiding residual urine. results median age of the patients was 61 (range 65 to 75) years and median weight was 72 (range 60 to 78) kg. parity had a range of 5 to 8 among the patients. twelve patients had a previous failed cystocele repair with kelly plication and 3 had previous hysterectomy. associated pelvic floor disorders were as follows: 3 (9.7%) patients had simultaneous grade iii uterine prolapse, rectocele, enterocele, and cystocele, 1 (3.2%) had enterocele, rectocele, and cystocele, 18 (58.1%) had associated rectocele, and 9 (29%) suffered from cystocele only. the chief complaints of the patients were feeling of vaginal mass in 12, stress urinary incontinence in 15, and urge incontinence in 18. marshall test was positive in 15 and 12 patients had a residual urine greater than 50 ml. thirty-one patients underwent repair of cystocele and associated pelvic defects. hospitalization time was between 5 and 7 days. eighteen had urinary retention, of which 17 improved after 3 weeks intermittent catheterization and post voiding residual urine declined to less than 50 ml. one patient was using intermittent catheterization during follow-up period. early complications (6 to 8 weeks postoperatively) included irritative urinary symptom in 17 patients, of whom, 8 had documented urinary tract infection that were treated successfully. spotting was one of the late complications (32 months follow-up) observed in 3 cases. two were treated with topical estrogen and in the other one, erosion of the vaginal mucosa was seen in the bends of mesh leading to vaginal mucosal repair and cutting the exposed bends of mesh. dyspareunia in 4 out of 32 sexually active patients was another late complication. in addition, changes in urination pattern in 28 (improved significantly with behavioral therapy), long-term urge incontinence (>8 weeks) in 5 (medical treatment was successful in these patients), and prolonged intermittent catheterization in 1 were observed. no serious complication such as pelvic abscess or migration of mesh was seen. in long-term, vaginal examination and cough test did not demonstrated any case of recurrence or urinary incontinence. up-right cystogram demonstrated that bladder was adjacent to symphysis pubis in all the patients, indicating a favorable anatomic correction. discussion multiple causes have proposed for severe anterior vaginal wall prolapse, consisting of multiparity, qualitative and quantitative collagen tissue change in menopause, neural injuries following difficult vaginal delivery, and direct damage to pelvic floor musculature.(3,7-9) furthermore, another iatrogenic cause is hysterectomy. if sacrouterine and cardinal ligaments re-approximation and colpoplasy during hysterectomy are not done, severe vaginal vault prolapse and cystocele develops.(1,7,10) abdominal approaches, such as paravaginal repair, burch, and marshall marketti kranz, are suitable for correction of urethral hypermobility and mild cystocele. these procedures will correct lateral defects, but correction of central defects is not possible; therefore, they are not amenable for grade iv cystocele.(4,9,11) vaginal surgeries, including anterior colporrhaphy with kelly plication can correct central defects, but they do not pertain to the correction of urethral hypermobility and bladder lateral defects.(1,2,9) the standard technique used in this study can rectify all these four defects in grade iv cystocele and also other associated pelvic floor defects can be repaired simultaneously with this technique.(9) however, it has come into question that whether using only suspension technique can bring about ideal results in longterm, when pelvic floor hernia is present and the tissue (fascia and levator ani muscles) is dissociated and not strong enough? it seems that using synthetic tissues in these procedures are an appropriate choice, as successful results have been reported. 266 zargar et al conclusion in grade iv cystocele, damages to ligaments and pelvic floor fascia are severe. supportive tissues are dissociated and are not capable of suspending lateral walls and pelvic floor. since using mesh in 4-corner bladder and bladder neck suspension technique does not prolong the operation and complications such as pelvic abscess, wound infection, or mesh migration, it can be an ideal treatment for grade iv cystocele and may have favorable long-term results. references 1. raz s, stothers l, chopra a. vaginal reconstructive surgery for incontinence and prolapse. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 7th ed. philadelphia, pa: wb saunders; 1998 p.1059-79. 2. stothers l, chopra a, raz s. vaginal reconstructive surgery for female incontinence and anterior vaginal-wall prolapse. urol clin north am. 1995;22:641-55. 3. migliari r, usai e. treatment results using a mixed fiber mesh in patient with grade iv cystocele. j urol. 1999;161:1255-8. 4. hurt wg. urogynecologic surgery. 2nd ed. lippincott williams & wilkins; 2000. p. 80-90. 5. raz s, stothers l, chopra a. raz techniques for anterior vaginal wall repair. in: raz s, ediror. female urology. 2nd ed. philadelphia, pa: wb saunders; 1996. p.34466. 6. raz s, little na, juma s, sussman em. repair of sever anterior vaginal wall prolapse (grade iv cystourethrocele). j urol. 1991;146:988-92. 7. nguyen a, mahoney s, minor l, ghoniem g. a simple objective method of adjusting sling tension. j urol. 1999;162:1674-6. 8. hsu th, rackley rr, appell ra. the supine stress test: a simple method to detect intrinsic urethral sphincter dysfunction. j urol. 1999;162:460-3. 9. nitahara ks, aboseif s, tanagho ea. long-term results of colpocystourethropexy for persistent or recurrent stress urinary incontinence. j urol. 1999;162:138-41. 10. safir mh, gousse ae, rovner es, ginsberg da, raz s. 4-defect repair of grade 4 cystocele. j urol. 1999;161:58794. 11. wahle gr, young gph, raz s. enterocele and vault prolapse. in: raz s, editor. female urology. 2nd ed. philadelphia, pa: wb saunders; 1996. p.465-8. 267 urol_v3_no2_001_editorial.qxd urology journal unrc/iua vol. 3, no. 2, 92-96 spring 2006 printed in iran 92 prediction of successful sperm retrieval in patients with nonobstructive azoospermia seyed amirmohsen ziaee,1* mohammadreza ezzatnegad,1 mohammadreza nowroozi,2 mohammadreza jamshidian,2 hamidreza abdi,1 seyed mohammad mehdi hosseini moghaddam1 1urology and nephrology research center and shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran 2imam khomaini hospital, tehran university of medical sciences, tehran, iran abstract introduction: our aim was to evaluate the predictive values of factors that indicate successful sperm retrieval in men with nonobstructive azoospermia. materials and methods: we evaluated 85 infertile men with nonobstructive azoospermia who underwent multiple bilateral testicular biopsies. factors including age, infertility period, surgical history, testicular volume, testicular consistency, serum follicle-stimulating hormone (fsh), serum inhibin b, serum luteinizing hormone, and serum total testosterone were assessed in relation to sperm retrieval results. results: spermatozoa were retrieved in 18 biopsies (21.2%). follicle-stimulating hormone, serum inhibin b, and testicular volume were associated with the results of sperm retrieval. men with a higher testicular volume, a higher serum inhibin b, and a lower fsh had successful sperm retrieval. the cutoff points were determined as 9.5 ml for testicular volume, 9.9 iu/l for serum fsh, and 39.8 pg/ml for serum inhibin b. these 3 factors had strong correlations with each other. the sensitivities and specificities were 88.9% and 94% for testicular volume, 97% and 83.3% for fsh, and 72.2% and 95.5% for serum inhibin b, respectively. the positive predictive value for a combination of serum fsh and inhibin b was 100%. conclusion: serum fsh and serum inhibin b are useful markers for evaluation of the presence of sperm in patients with nonobstructive azoospermia. inhibin b has a high specificity when combined with serum fsh and their measurements can be helpful in all patients with nonobstructive azoospermia before decision making for sperm retrieval. key words: azoospermia, testicular biopsy, follicle-stimulating hormone, inhibin b introduction men with nonobstructive azoospermia (noa) may be able to fertilize by intracytoplasmic sperm injection (icsi) if sperm can be retrieved by testicular sperm extraction (tese).(1,2) however, it has been reported that about half of the patients with noa undergo unnecessary surgeries.(2) each procedure in these patients must be accompanied by the partner preparation for oocyte retrieval, and on the other hand, the resultant irreversible traumatic injury and adhesion in testes arrest spermatogenesis for 6 to 8 weeks and brings about emotional and financial implications for the couple.(3) for reducing complications of tese, many researchers have tried to predict the success rate of sperm retrieval using hormonal or other received april 2005 accepted february 2006 *corresponding author: department of urology, shaheed labbafinejad medical center, 9th boustan st, pasdaran, tehran 1666679951, iran. tel: +98 21 2256 7222, fax: +98 21 2256 7282 e-mail: ziaee@hotmail.com ziaee et al 93 markers.(4-12) however, previous studies for introducing certain predictor factors have been failed. to overcome this problem, we launched a study on 85 men with noa and analyzed 9 preoperative factors to find a method to predict the success of tese. materials and methods between october 2002 and september 2004, infertile men with azoospermia in at least 2 semen analyses were studied. patients with klinefelter syndrome were excluded and 85 men who provided informed consent were selected. the patients underwent a full clinical evaluation; history, physical examination, and measurement of serum levels of folliclestimulating hormone (fsh; reference range, 1 iu/l to 10 iu/l), luteinizing hormone (lh; reference range, 1 iu/l to 9.5 iu/l), total testosterone (reference range, 2.4 ng/dl to 12 ng/dl), and inhibin b (enzyme-linked immunosorbent assay kits, serotec, oxford, uk). testicular volume was measured by orchidometer, and in some cases, by ultrasonography (a 7.5-mhz ultrasonic probe). results of testis consistency assessment were scored as 1, very soft; 2, soft; 3, normal; 4, firm; and 5, very firm. multiple tese was performed under local anesthesia. through a small vertical incision in the median scrotal raphe, the skin, dartos muscle, and tunica vaginalis were opened to expose the tunica albuginea. the tunica albuginea was incised at the upper pole near the head of the epididymis. a sufficient volume of testis was excised and examined. if no sperm were seen in the specimen, subsequent samples were taken from other locations, in the midline of the testis and at the lower pole opposite the rete testis, and subsequently from the contralateral testis. the procedure was terminated when sperm were retrieved or all three samples from upper, middle, and lower sites per testis had been examined for the presence of testicular sperm. statistical analyses were performed by student t test and chi-square test. in addition, the correlation between continuous variables was assessed by pearson correlation test and the best cutoffs of factors that influence sperm retrieval were determined based on receiver operating characteristic (roc) curves. all statistical analyses were performed with spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). continuous variables were shown as mean ± standard deviation. a p value of < .05 was considered significant. results sperm was found in 18 out of 85 (21.2%) patients with noa, and tese failed in 67 (77.8%). pathologic findings are summarized in table 1. the mean age of patients with and without retrieved sperm were not statistically different (p = .745). furthermore, infertility period and past surgical history did not show any significant difference between the two groups of patients (table 2). forty-seven patients underwent ultrasonography to determine testicular volume; the mean volume was 8.72 ± 5.92 ml in clinical measurement (by orchidometer) and 8.17 ± 5.40 ml on ultrasonography (p = .019). the mean testicular volume measured by orchidometer and ultrasonography was greater in the patients with retrieved sperm (p < .001), but testicular consistency score was not significantly different between the two groups of patients (table 2). table 1. pathologic reports of specimens from tese in patients with nonobstructive azoospermia tese: testicular sperm extraction, sco: sertoli-cell-only syndrome patients without retrieved sperm histologic finding number percent maturation arrest 32 47.8 sco 17 25.4 mixed germ cell aplasia 8 11.9 mixed germ cell aplasia with sco 3 4.4 maturation arrest with sco 3 4.4 atrophic testis 3 4.4 end stage testis 1 1.5 total 67 100 patients with retrieved sperm histologic finding number percent severe hypospermatogenesis 14 77.8 germ cell hyperplasia 3 16.7 maturation arrest 1 5.5 total 18 100 prediction of successful sperm retrieval94 serum levels of lh and testosterone were not significantly different, but the mean serum level of fsh was lower in the patients with retrieved sperm (5.83 ± 3.51 iu/l versus 20.82 ± 5.85 iu/l; p < .001) and the mean serum level of inhibin b was higher in this group of patients (48.77 ± 15.24 pg/ml versus 31.4 ± 5.91 pg/ml; p < .001) (table 2). the cutoff points were determined using roc curves (figures 1 and 2) that were 9.5 ml for testicular volume, 9.9 iu/l for serum fsh, and 39.8 pg/ml for serum inhibin b (areas under the curve 0.95, 0.96, and 0.84, respectively). these 3 variables had strong correlations with each other (fsh and inhibin b, r = -0.47, p < .001; fsh and testicular volume, r = -0.64, p < .001; inhibin b and testicular volume, r = 0.59, p < .001). the sensitivities and specificities were 88.9% and 94% for testicular volume, 97% and 83.3% for fsh, and 72.2% and 95.5% for serum inhibin b, respectively (table 3). discussion retrieval of testicular sperm for icsi is considered as a useful approach in patients with noa.(13,14) however, depending on the techniques, sperm retrieval chance for each biopsy is 20% to 50% in these patients.(15) partner preparation problems, emotional stress, high costs, drug reactions, damage to the testes due to each additional unnecessary biopsy, and the likelihood of negative findings in tese have motivated many researchers to find noninvasive techniques to predict sperm retrieval chance. in our study, the chance of sperm retrieval was 21.2% that was lower than the findings of other table 2. clinical and paraclinical values in the patients with and without retrieved sperm table 3. predictive values of tests for successful sperm retrieval in men with nonobstructive azoospermia* *values are percents. patients with sperm patients without sperm confidence interval p value age (year) 33.2 ± 6.1 34.5 ± 5.8 -4.43 to 1.79 .745 infertility period (year) 7.6 ± 5.7 8.4 ± 6.2 -4.02 to 2.44 .629 past surgical history no surgical history 13 (72.2%) 52 (77.6%) .892 scrotal or inguinal surgery 4 (22.2%) 12 (17.9%) orchidectomy 1 (5.6%) 3 (4.5%) testicular volume (ml) right testis 17.56 ± 3.5 5.71 ± 2.4 10.37 to 13.32 < .001 left testis 17.05 ± 4 5.65 ± 2.6 9.30 to 13.49 < .001 mean of both testes 17.5 ± 3.52 5.68 ± 2.44 10.32 to 13.30 < .001 testicular consistency scores right testis 3.18 ± 0.54 3.05 ± 0.63 0.28 to .54 .524 left testis 3.11 ± 0.58 2.87 ± 0.73 0.14 to 0.60 .219 serum lh (iu/l) 8.04 ± 6.31 9.06 ± 53 -4.59 to 2.54 .563 serum total testosterone (ng/dl) 5.81 ± 1.24 6.103 ± 3.91 -2.09 to 1.64 .810 serum fsh (iu/l) 5.83 ± 3.51 20.82 ± 5.85 -12.10 to -17.87 < .001 serum inhibin b (pg/ml) 48.77 ± 15.64 31.4 ± 5.91 -12.70 to -22.03 < .001 test sensitivity specificity positive predictive value negative predictive value fsh 97 83.3 88.2 95.5 inhibin b 72.2 95.5 81.3 92.8 testicular volume 88.9 94 80 96.9 fsh + inhibin b 55.6 100 100 89.3 fsh + inhibin b + testicular volume 50 100 100 88.2 ziaee et al 95 studies.(15-16) this is proportionally due to the more effective techniques used in these studies such as microdissection tese and testicular fineneedle aspiration. tsujimura and colleagues(2) have compared multiple tese and microdissection tese in 37 and 56 patients and found sperm retrieval rates of 35.1% and 42.9%, respectively. we demonstrated that testis volume measured either by ultrasonography or by orchidometry was greater in patients with successful sperm retrieval. in addition, a higher serum level of inhibin b and a lower serum level of fsh were found in these patients. the relationship between testicular consistency and sperm retrieval was not significant in our study. to our knowledge, this parameter has not been examined in any studies. in the study by tsujimura and colleagues,(2) serum levels of fsh, total testosterone, and inhibin b were the most influential preoperative factors. we found no association between total serum testosterone and sperm retrieval success. this is probably because in our study, the most common pathologic finding in patients without retrieved sperm was maturation arrest or sertolicell-only syndrome, while interstitial and leydig cells were not affected. our findings reiterate those of foresta and coworkers'.(9) in agreement with the results of other studies,(2,4,5) the difference of fsh level between the patients with or without successful sperm retrieval was significant in our study. however, serum level of fsh is correlated with the presence of germ cells and not with spermatogenesis. we expect normal serum fsh levels in maturation arrest or sertoli-cell-only syndrome. thus, serum fsh is dependent to the pathologic etiology of azoospermia and cannot be a good predictive factor. inhibin b is a heterodimeric glycoprotein secreted from the testis as a product of sertoli cells. a strong inverse correlation exists between inhibin b and fsh levels in men with normal and disturbed spermatogenesis.(8) measurement of inhibin b has raised many challenges between authors; vernaeve and colleagues(4) have not found any significant predictive value for inhibin b, while many other authors have emphasized that inhibin b can predict sperm retrieval.(2,5,7,9,11,12) we found a significant difference in serum inhibin b between the two groups. testicular volume was another influential factor on successful sperm retrieval. clinically, it is correlated with spermatogenesis, but topographical variations in testicular pathology independent of testicular volume can occur.(2) thus, testicular volume may not be a good predictive factor of successful sperm retrieval for icsi. serum fsh in combination with inhibin b has been reported to have a marked sensitivity and specificity in the retrospective studies by bohring and coworkers(6) and von eckardstein and colleagues.(15) based on our findings, a serum fsh ≤ 9.9 iu/l and a serum level of inhibin b ≥ 39.8 pg/ml can predict the possibility of successful sperm retrieval with 100% specificity and positive predictive value that is enough for a clinical decision making and avoids unnecessary biopsy. however, in other individuals with a testicular volume < 9.5 ml, a serum level of fsh > 9.9 iu/l, and a serum level of inhibin b ≤ 39.8 pg/ml, testis biopsy is indicated and these factors are not able to predict absence of sperm due to multifocal spermatogenesis in testes. thus, we have found a simple way for this prediction without including many factors. however, the limitation of our relatively small sample warrants further investigation of these findings. conclusion serum levels of fsh and inhibin b are useful markers for evaluation of sperm detection in patients with nonobstructive azoospermia. inhibin b has a high specificity when combined with serum fsh and we recommend these measurements in all patients with nonobstructive azoospermia who are candidates for icsi. further study to find more sensitive markers is warranted. references 1. plas e, riedl cr, engelhardt pf, muhlbauer h, pfluger h. unilateral or bilateral testicular biopsy in the era of intracytoplasmic sperm injection. j urol. 1999;162:2010-3. 2. tsujimura a, matsumiya k, miyagawa y, et al. prediction of successful outcome of microdissection testicular sperm extraction in men with idiopathic nonobstructive azoospermia. j urol. 2004;172:1944-7. 3. schoor ra, elhanbly s, niederberger cs, ross ls. the role of testicular biopsy in the modern management of male infertility. j urol. 2002;167:197-200. 4. vernaeve v, tournaye h, schiettecatte j, verheyen g, van steirteghem a, devroey p. serum inhibin b cannot prediction of successful sperm retrieval96 predict testicular sperm retrieval in patients with nonobstructive azoospermia. hum reprod. 2002;17:971-6. 5. ballesca jl, balasch j, calafell jm, et al. serum inhibin b determination is predictive of successful testicular sperm extraction in men with non-obstructive azoospermia. hum reprod. 2000;15:1734-8. 6. bohring c, schroeder-printzen i, weidner w, krause w. serum levels of inhibin b and follicle-stimulating hormone may predict successful sperm retrieval in men with azoospermia who are undergoing testicular sperm extraction. fertil steril. 2002;78:1195-8. 7. klingmuller d, haidl g. inhibin b in men with normal and disturbed spermatogenesis. hum reprod. 1997;12:2376-8. 8. von eckardstein s, simoni m, bergmann m, et al. serum inhibin b in combination with serum follicle-stimulating hormone (fsh) is a more sensitive marker than serum fsh alone for impaired spermatogenesis in men, but cannot predict the presence of sperm in testicular tissue samples. j clin endocrinol metab. 1999;84:2496-501. 9. foresta c, bettella a, petraglia f, pistorello m, luisi s, rossato m. inhibin b levels in azoospermic subjects with cytologically characterized testicular pathology. clin endocrinol (oxf). 1999;50:695-701. 10. samli mm, dogan i. an artificial neural network for predicting the presence of spermatozoa in the testes of men with nonobstructive azoospermia. j urol. 2004;171:2354-7. 11. brugo-olmedo s, de vincentiis s, calamera jc, urrutia f, nodar f, acosta aa. serum inhibin b may be a reliable marker of the presence of testicular spermatozoa in patients with nonobstructive azoospermia. fertil steril. 2001;76:1124-9. 12. pierik fh, vreeburg jt, stijnen t, de jong fh, weber rf. serum inhibin b as a marker of spermatogenesis. j clin endocrinol metab. 1998;83:3110-4. 13. devroey p, liu j, nagy z, et al. pregnancies after testicular sperm extraction and intracytoplasmic sperm injection in non-obstructive azoospermia. hum reprod. 1995;10:1457-60. 14. tournaye h, camus m, goossens a, et al. recent concepts in the management of infertility because of non-obstructive azoospermia. hum reprod. 1995;10 suppl 1:115-9. 15. von eckardstein s, simoni m, bergmann m, et al. serum inhibin b in combination with serum follicle-stimulating hormone (fsh) is a more sensitive marker than serum fsh alone for impaired spermatogenesis in men, but cannot predict the presence of sperm in testicular tissue samples. j clin endocrinol metab. 1999;84:2496-501. 16. friedler s, raziel a, strassburger d, soffer y, komarovsky d, ron-el r. testicular sperm retrieval by percutaneous fine needle sperm aspiration compared with testicular sperm extraction by open biopsy in men with non-obstructive azoospermia. hum reprod. 1997;12:1488-93. benign prostatic hyperplasia treatment with new physiotherapeutic device simon allen,1* ivan gerasimovich aghajanyan2 purpose: thermobalancing therapy, provided by therapeutic device, which contains a natural thermoelement, and is applied topically in the projection ofthe prostate,was aimed to improve blood circulation in the affected organ. we evaluated the effectiveness of new therapeutic device for the treatment of patients with benign prostatic hyperplasia (bph). materials and methods: we performed a clinical non-randomized controlled trial before and after 6-month treatment. therapeutic device was administered to 124 patients with bph as mono-therapy. the dynamic of the patients’ condition was assessed by the international prostate symptom score (ipss), ultrasound measurement of prostate volume (pv) and uroflowmetry. the control-group comprised 124 men who did not receive any treatment. the ipss score, maximum flow rate (qmax), and pv were compared between the groups. results: baseline evaluation (pre-treatment) for both groups were comparable to each other with no clinically significant difference regarding age, ipss score, qmax and pv volume. overall, thermobalancing therapy resulted in significant improvements from baseline to endpoint in ipss (p = .001), ipss storage and voiding subscores (both p = .001), and ipss quality of life index (qol) (p = .001) compared with control group. moreover, comparison of parameters after 6 months treatment showed that thermobalancing therapy also improved the qmax (p = .001), and pv (p = .001). conclusion: two years clinical trial demonstrated that thermobalancing therapy administered for 6 months provides a marked improvement in patients presenting with symptomatic bph not only on lower urinary tract symptoms (luts) but also in qol and qmax. thus urologists should be aware about thermobalancing therapy as a non-invasive physiotherapeutic treatment option for treatment of bph. keywords: case-control studies; humans; lower urinary tract symptoms; etiology; male; prostatic hyperplasia; treatment outcome; prospective studies; equipment design; quality of life. introduction benign prostatic hyperplasia (bph) is a disease in which the prostate gland enlarges beyond the normal volume of 20-30 ml as part of the aging process, thus it is common among older men,(1,2) bph causes bladder outlet obstruction (boo) among affected men and the several symptoms of bph, which include lower urinary tract symptoms (luts), can adversely affect quality of life (qol). bph symptoms are classified as storage or voiding. storage symptoms include urinary frequency, urgency, urgency incontinence, and voiding at night, named nocturia, which can lead to erectile dysfunction (ed).(3) bph is historically supposed to be a consequence of the ageing process and the abolition of the negative impact of an enlarged prostate in males should be done with the help of medical or surgical treatment. in the last decade, this view has been challenged. bph-lower urinary tract symptoms (luts) should not be considered as an inevitable disease of older men but part of the ageing process which can be treated.(4) in the last decade, the pathogenesis of bph began to consider from the perspective of vascular dysfunction,(3) chronic ischemic tissue,(5) and increased pressure in the prostate.(6) today, it is important to take into account the significant changes in the understanding of the etiology and pathogenesis of bph. recent developments suggest that bph is of vascular origin. it has been shown that chronic ischemia results in thickening and fibrosis of the prostatic stroma, and impairs neurogenic relaxation in the prostate.(7) recent results demonstrate that ischemic prostate tissue in rats produces increased contractile response to electrical and pharmacological stimulation, increased smooth muscle α-actin (α-sma), and increased collagen deposition.(8) this view on the pathogenesis of bph supports the hypothesis suggesting that the vascular system may play a role in the development of bph.(9) measurements of resistive index (ri) and blood flow velocity using color doppler ultrasound (cdus) in control and bhp patients support the hypothesis that age-related deterioration of the blood supply to the urinary pathways has a 1 fine treatment, 29 rewley road, oxford, ox1 2ra, united kingdom. 2 department of urology, yerevan state medical university, institute of surgery mikaelyan, republic of armenia. *correspondence: fine treatment, 29 rewley road, oxford, ox1 2ra, united kingdom. tel: +44 795 8878300. fax: +44 186 5728255 . e-mail: info@finetreatment.com. received: october 2015 & accepted: october 2015 vol 12 no 05 september-october 2015 2371 miscellaneous miscellaneous 2372 role in the development of bph, as arterial cdus flow velocity was increased in the transition zone of patients with bph.(10) in a study by zelli and colleagues, doppler ultrasound was used to check the differences in the hemodynamic characteristics of prostatic artery in dogs in normal and bph tissue and statistically significant differences were found in the study of the blood flow velocity in the arteries of the prostate gland in dogs in normal and bph.(11) a literature review of preclinical and clinical studies in the etiology and pathogenesis of bph show that, the vascular factor plays a decisive role, confirming that problems in the penis and the lower urinary tract accompanied by endothelial and neurological dysfunction that leads to hypoxia, vasoconstriction, contractility changes of smooth muscles, and damage to autonomic neurons and ganglia.(12) in an experimental study that used a model of spontaneously hypertensive rats (shr) was aimed to find out whether or not the unexpressed hypoxia in prostate is a possible mechanism that contributes to the development of bph. shr rats showed a significant increase in blood pressure and a significant decrease in blood flow in the prostate gland.(13) thus, development of prostatic hyperplasia may be associated with hypoxia in the prostate.(13) according to the minutes of the european association of urology for the treatment of symptoms of lutss, many bph patients do not express complaints about their conditions and therefore they are suitable for non-medication and non-surgical management, known as watchful waiting.(14) drug treatment or surgical procedures should be then offered only to men with severe lutss when conservative management options have been unsuccessful or are not appropriate. transurethral resection of the prostate (turp) and open prostatectomy are usually considered gold standard treatment options in these patients. the remarkable risk of mortality and morbidity of both procedures, especially turp syndrome and bleeding, has prompted the search for minimally invasive techniques. dr. allen hypothesized that the cause of chronic diseases of internal organs, including bph, is a violation of the microcirculation with the emergence of the focus of hypothermia, which is caused by increased pressure in the affected organ and the abnormal tissue growth. this theory is based on experimental studies that have shown that capillaries themselves are directly involved in the regulation of capillary recruitment and capillary blood flow distribution. the following possible hypothetical patterning rules are seen in all tissues of the body; “capillary network patterns in all tissues are determined by the same mechanisms”,(15) indicating that the growth of the tissue occurs at the micro-level when the tiniest blood vessels begin to spread. it has been found that changes in the tissues under the influence of prolonged stress are characterized as hypoxia, ischemia, and micro-hypothermia, which under the electron microscope look like a lack of blood in a large area of tissue.(16) it becomes a trigger for further growth of capillaries. the pressure in the tissue increases, which leads to new focuses of hypothermia, thus a vicious cycle is created. this factor dr. allen identified as pathological activity of capillaries leads to a problem in the prostate gland, its progressive growth, and chronic inflammation.(17) in this study, we investigated the effect of thermobalancing therapy on bph patients. thermobalancing therapy via therapeutic device is directed to improve blood circulation in the prostate gland. the device keeps the thermoelement in the projection of the prostate, providing relief from the symptoms of enlarged prostate. materials and methods study design we used a clinical controlled trial before and after 6-month treatment. enrolment began in april 2013. the ethics committee of the yerevan state medical university has approved the clinical study of therapeutic device. the effectiveness of thermobalancing therapy was studied by comparing men with bph who received treatment with therapeutic device for 6-month with the control group. participants and interventions from april 2013 to april 2015, a total of 124 patients (age > 55 years) diagnosed with severe luts due to bph (< 60 ml ) who were naive for treatment recruited into this study. initially a total of 226 men were examined and 124 patients selected for this clinical trial. eighty men were excluded, as their prostate volume (pv) was over 60 ml or they had severe co-morbidities; 10 preferred operation; 4 were suspected prostate cancer; 8 did not attend to the following examinations. the patient selection was achieved in a multidisciplinary manner in conjunction with urologist. inclusion criteria were symptomatic luts due to bph, international prostate symptom score (ipss) ≥ 12, serum prostatic specific antigen (psa) < 4 ng/ml, pv < 60 ml, and urinary peak flow rate (qmax) < 15 ml/s. exclusion criteria were history of any urogenital disease, malignancy or surgery, abnormal digital rectal examination (dre), and co-morbidities, such as impaired renal function (serum creatinine > 2 mg/dl and diabetes mellitus. we included patients on anticoagulant medication or any coagulopathy. evaluations the baseline evaluations included complete physical examination, medical history, dre, serum biochemistry, and psa measurements, electrolytes, urine and renal function tests. evaluations were made at baseline and 6 months after the treatment. at the baseline assessment, patients were evaluated for pv (ml), ipss, ipss quality of life score (ipss-qol), and uroflowmetry (maximum urinary flow rate (qmax, ml/s). ipss-qol scored as follow: delighted = 0, pleased = 1, mostly satisfied = 2, about equally satisfied and dissatisfied = 3, mostly dissatisfied = 4, hopeless = 5, and poor = 6. pv were measured at baseline and at 6 months after the treatment by ultrasonography (us-9000e2 ultrasound scanner, rising medical equipment co. ltd, beijing, china) and uroflowmetry was used for the measurement of the rate of urine flow parameters (sanuro2ul, santron meditronic, maharashtra, india). the standard ellipsoid formula length × width × height × 0.52 was used to determine prostate volume. outcome measures primary end points were the reduction of the ipss and the increase of qmax at 6-month after treatment. secondary end points were the reduction of pv, pvr, and changes in qol at 6 months after treatment. men in treatment group after the screening were given bph treatment with new physiotherapeutic device-allen et al. vol 12 no 05 september-october 2015 2373 therapeutic device. dr allen’s therapeutic device the therapeutic device is an elastic belt keepings a wax-based thermoelement mixture of waxes in the projection of the prostate (figures 1, a and b). the thermoelement allows the body heat accumulation and acts as the heat source for the prostate. the neoprene belt keeps the thermoelement to the skin and avoids not allow heat dissipation (figure 2). the commercial production of therapeutic device started in 2010 in england. in april 2010 the device was registered at the medicines and healthcare products regulatory agency (mhra) as class 1 medical device. according to independent authorized ce marking representative in uk or eu, class i medical device without a measuring function and supplied in non-sterile condition does not require the involvement of a notified body. in accordance with the ‘regulation of medical devices outside the european union’, low-risk products may only require a supplier’s declaration of conformity (sdoc), where the manufacturer is responsible for ensuring that the product complies with the relevant requirement and then produces a written self-declaration statement.(18) qmax is a key indicator of impaired urination and was measured as previously described.(19) statistical analysis the study’s quantitative variables are expressed as mean values, standard error, and minimum and maximum values, whereas the qualitative variables are expressed as numbers and percentages. for numerical data, independent sample t-tests were performed; for comparisons of before and after treatment, the non-parametric statistical hypothesis test by wilcoxon was used. statistical analysis was done by statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0. results prostate volume figure 3 shows the changes in pv (ml) in bph patients at the beginning and at the end of the study. in the control group, the mean pv increased from 45.54 ± 5.569 to 50.85 ± 6.696 ml at the end of the study period, whereas in the treatment group the mean pv decreased from 45.19 ± 3.995 to 31.86 ± 4.158 ml (p = .001). for the control group, the z value was 8.727 with p value of .001. for the treatment group, the z value was 9.669 with a p value of .001. these data suggested that the therapeutic device reduced the pv significantly, whereas in control group the pv would increase. uroflowmetry qmax figure 4 shows the results of the uroflowmetry qmax (ml/s) in bph patients. in the control group, the mean qmax decreased from 7.95 ± 2.871 to 7.7 ± 2.695 ml/s, where as in the treatment group the mean qmax increased from 8.10 ± 3.041 to 17.73 ± 4.392 ml/s. for the control group, the z value was 1.929 and the p value .054 (> .05), indicating no statistically significant difference. for the treatment group, the z value is 9.621 at the significance level of .001, indicating a significant increase in the qmax. therefore, our results demonstrate that the therapeutic device increased the uroflowmetry qmax significantly in bhp patients, whereas control group had no significant difference in the uroflowmetry qmax. figure 1. the thermo element therapeutic device alone. figure 2.the thermo element therapeutic device on patient. bph treatment with new physiotherapeutic device-allen et al. urinary symptoms we investigated the effect of the therapeutic device on alleviating urinary symptoms, as assessed using the ipss (figure 5). in the control group, the mean ipss increased from 13.45 ± 3.254 to 14.35 ± 3.396, whereas in the treatment group the mean ipss decreased from 14.33 ± 3.399 to 4.73 ± 2.754 at the end of the observation period. for the control group, the z value was 6.018 with a p value of .001. for the treatment group, the z value was 9.674 with a significance level .001. this indicates that the treatment with therapeutic device decreases the ipss significantly, while in absence of treatment these would increase significantly. quality of life we assessed the qol according to ipss (figure 6). in the control group, the mean qol increases from 3.43 ± 0.956 to 3.76 ± 0.983, whereas in the treatment group the mean qol decreases from 3.91 ± 0.755 to 1.39 ± 1.110. for the control group, the z value was 5.286 with a p value of .001. for the treatment group, the z value was 9.672 with a p value of .001. these results indicated that the treatment with therapeutic device decreased the qol while this increased in the control group. safety none of the patients who received thermobalancing therapy had side effects. discussion in this study we investigated whether long-term use of thermobalancing therapy with therapeutic device could reduce bph symptoms. our result allows us to concluded that the treatment reduces the pv significantly, increases the uroflowmetry qmax significantly, decreases ipss and that improves the qol significantly. these indicate that the thermobalancing is effective in the treatment of bph. clinical improvement and positive changes in the ultrasound and uroflowmetry parameters in men with bph who used therapeutic device could be explained by positive changes in the prostate. this is due to the natural thermoelement, which was tightly attached to the body in the projection of the prostate gland, and maintaining the accumulated temperature for a long period. we believe that the use of therapeutic device by keeping the temperature in the projection of the prostate gland acts on micro-focus of hypothermia and ischemia in it, removing the vicious cycle of spontaneous growth of capillaries in response to a trigger, micro-hypothermia, thereby relieving the bph symptoms. thermobalancing therapy provides an alternative to classical bph surgical treatments. studies show that figure 3. prostate volumes (ml) in patients with benign prostate hyperplasia and control group at the beginning and at the end of the study. figure 4. maximum urinary flow rate (qmax) (ml/s) in patients with benign prostate hyperplasia and control group at the beginning and at the end of the study. figure 5. international prostate symptom score (ipss) in patients with benign prostate hyperplasia and control group at the beginning and at the end of the study. figure 6. international prostate symptom score quality of life (ipss-qol) domain in patients with benign prostate hyperplasia and control group at the beginning and at the end of the study. bph treatment with new physiotherapeutic device-allen et al. miscellaneous 2374 vol 12 no 05 september-october 2015 2375 moderate to severe symptoms of luts significantly affects the qol of patients and that half (52.8%) of men with bph are dissatisfied with the results of medical treatment administered, according to current international guidelines for bph.(20) in addition, most commonly used bph medications have side effects, especially in the long-term use.(21) surgical treatment of prostate may also be accompanied by new challenges. thus, the results of a survey of sexually active men after three different laser surgeries from 2005 to 2010 concluded that these surgical techniques can have a negative impact on sexual function, and patients with normal preoperative sexuality are more at risk.(22) therefore, thermobalancing therapy could be an apt solution for bph treatment in these cases. conclusions the results of this study demonstrate improvement in men with bph after treatment with therapeutic device. we observed positive effects in the ipss symptom score, pv, and uroflowmetry parameters. more studies with thermobalancing therapy for bph are needed to draw final conclusion. conflict of interest the first author of this manuscript is the manufacturer of the device. this study was funded by fine treatment, united kingdom and institute of surgery mikaelyan, republic of armenia. references 1. lowe fc. treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: sexual function. bju int. 2005;95 suppl 4:12-8. 2. oelke m, bachmann a, descazeaud a, et al. european association of urology: eau guidelines on the treatment and followup of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2013;64:118–40. 3. shimizu s, tsounapi p, shimizu t, et al. lower urinary tract symptoms, benign prostatic hyperplasia/benign prostatic enlargement and erectile dysfunction: are these conditions related to vascular dysfunction? int j urol. 2014;21:856-64. 4. corona g, vignozzi l, rastrelli g, lotti f, cipriani s, maggi m. benign prostatic hyperplasia: a new metabolic disease of the aging male and its correlation with sexual dysfunctions. int j endocrinol. 2014;2014:329456. 5. andersson ke, nomiya m, yamaguchi o. chronic pelvic ischemia: contribution to the pathogenesis of lower urinary tract symptoms (luts): a new target for pharmacological treatment? luts. 2015:7;18. 6. cohen pg. abdominal obesity and intraabdominal pressure: a new paradigm for the pathogenesis of the hypogonadal-obesitybph-luts connection. horm mol biol clin investig. 2012;11:317-20. 7. kozlowski r, kershen rt, siroky mb, krane rj, azadzoi km. chronic ischemia alters prostate structure and reactivity in rabbits. j urol. 2001;165:1019-26. 8. zarifpour м, nomiya m, sawada n, andersson ke. protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia. prostate. 2015;75:233-41. 9. ghafar ma, puchner pj, anastasiadis ag, cabelin ma, buttyan r. does the prostatic vascular system contribute to the development of benign prostatic hyperplasia? curr urol rep. 2002;3:292-6. 10. berger ap, horninger w, bektic j, et al vascular resistance in the prostate evaluated by colour doppler ultrasonography: is benign prostatic hyperplasia a vascular disease? bju int. 2006;98:587-90. 11. zelli r, orlandi r, troisi a, cardinali l, polisca a. power and pulsed doppler evaluation of prostatic artery blood flow in normal and benign prostatic hyperplasiaaffected dogs. reprod domest anim. 2013;48:768-73. 12. cellek s, cameron ne, cotter ma, fry ch, ilo d. microvascular dysfunction and efficacy of pde5 inhibitors in bph–luts. nat rev urol. 2014;11:231-41. 13. saito m, tsounapi p, oikawa r, et al. prostatic ischemia induces ventral prostatic hyperplasia in the shr; possible mechanism of development of bph. sci rep. 2014;4:3822. 14. guidelines on the management of male lower urinary tract symptoms luts, european association of urology, eur urol. 2013;64:118-40. 15. hansen-smith fm. capillary network patterning during angiogenesis. clin exp pharmacol physiol. 2000;27:830-5. 16. baldwin al. a brief history of capillaries and some examples of their apparently strange behavior. clin exp pharmacol physiol. 2000;27:821-5. 17. allen s, adjani a. us 20110152986 a1, 2009, june 23. http://www.google.com/ patents/us20110152986 18. class i medical devices http://www.cemarking.com/medical-devices-class-i.html 19. mcvary kt. clinical evaluation of benign prostatic hyperplasia. rev urol. 2003;5 suppl 4:s3-s11. 20. fourcade ro, lacoin f, rouprêt м, et al. outcomes and general health-related quality of life among patients medically treated in general daily practice for lower urinary tract symptoms due to benign prostatic hyperplasia. world j urol. 2012;30:419-26. 21. gacci m, ficarra v, sebastianelli a, et al. impact of medical treatments for male lower urinary tract symptoms due to bph treatment with new physiotherapeutic device-allen et al. benign prostatic hyperplasia on ejaculatory function: a systematic review and metaanalysis. j sex med. 2014;11:1554-66. 22. elshal am, elmansy hm, elkoushy ma, elhilali mm. male sexual function outcome after three laser prostate surgical techniques: a single center perspective. urology. 2012;80:1098-104. bph treatment with new physiotherapeutic device-allen et al. miscellaneous 2376 urology for people 211urology journal vol 5 no 3 summer 2008 what’s up in urology journal, summer 2008? urol j. 2008;5:211-2. www.uj.unrc.ir bacteria and urological diseases dr al-marhoon from egypt has reviewed recent research on a bacterium that causes peptic ulcer. some researchers believe that this bacterium, namely helicobacter pylori, may cause other diseases, too. some bacteria can cause inflammation of the prostate gland. also, the body may react to the infections in other areas of the body that causes the release of agents in blood that can develop inflammation of the prostate. helicobacter pylori are present in the stomach of many people. so, it might cause response of the body and indirect involvement of the prostate. however, this is only a hypothesis and it should be tested in the future. also, some cancers are connected with infection, one of them being prostate cancer. however any relation of helicobacter pylori and prostate cancer has not been shown yet. helicobacter pylori can cause a specific kind of bladder cancer. researchers have shown that treatment of infection with these bacteria has a positive effect on the treatment of bladder lymphoma. a kidney tumor has been reported only in 1 patient with helicobacter pylori infection. so, we have to wait until further evidence. finally, physicians recommend treatment of helicobacter pylori infection in kidney transplant patients and those with kidney failure. to put it in a nutshell, we had better take helicobacter pylori seriously and try to get rid of it before any consequences is documented by researchers! black seeds in medicine black seeds are the seeds of an annual-flowering plant, native to southwest asia. they are used as a spice. dr hadjzadeh and his research group in mashhad have focused on black seeds. they have hypothesized that black seeds may treat kidney stones and even prevent it. they tried it in rats and found interesting results; they induced kidney stone formation in the rats and injected an extract of black seeds into the body of some of those. a month later, they observed that black seeds reduced the number and size of the stony deposits in the kidneys and the concentration of stone forming ingredients in urine. although this study recommends black seeds as a beneficial herb, it is still a long way to use it as a drug for kidney stones. urology for people is a new section in the urology journal for providing people a summary of what is published in this journal and describing urological entities in a simple language. the editors of the urology journal believe that the ultimate goal of scientific research is to improve the quality of life and prevent diseases. this point of view makes it an essence to inform the people of what is going on in medical research. herein, we describe some of the studies presented in this issue of the journal in order to promote knowledge of people on the current advances in urology. the persian translation of this article is available, too, from www.uj.unrc.ir. it is noteworthy that the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urology for people 212 urology journal vol 5 no 3 summer 2008 saffron and cancers saffron is another herb that has appealed researchers. many therapeutic effects have been suggested for saffron and dr feizzadeh and his colleagues have tested it on bladder tumors. they showed that the extract of saffron slowed down the growth of tumoral cells. this was achieved in laboratory and they hope that one day saffron can be beneficial for patients with bladder cancer. patient with hepatitis can enjoy kidney transplant patients with kidney failure may suffer from hepatitis c or hepatitis b infections. physicians’ concern is that these infections may impact their transplant kidneys if they undergo transplantation. they usually monitor patients with hepatitis after transplantation and report the results. dr shahbazian did the same in ahwaz. his team found that kidney transplant patients, with hepatitis c infection had slightly poorer but comparable results with other transplant recipients. so, these patients can be reassured about the favorable chance of living with a transplant kidney. however, they are at risk of the consequences of their infection and should be under vigilance care. stones in a horseshoe kidney horseshoe kidneys are a rare inborn abnormality. the kidneys of people with this abnormality are fused together and make a horseshoe shape. with a horseshoe kidney, one can live long without knowing even that, but they are at a higher risk of some diseases such as kidney stone. treatment of stones is somewhat more difficult in horseshoe kidneys. shock wave lithotripsy is an option, but some researchers offer extraction of the kidney stone through a small incision of the flank. dr soufi majidpour has done this procedure in 9 patients with horseshoe kidney in sanandaj, iran. he could treat 7 of them successfully. this experience was reported by dr darabi in mashhad, too (published in a previous issue of urology journal). patients with a horseshoe kidney can be reassured of many treatment options for their problems with these kidneys in many cities of iran. sophisticated laparoscopic surgeries by urologists laparoscopy is an advance surgical technique by which many sophisticated operations are done these days with only a few small incisions on the body. in fact, instruments go inside the body instead of the surgeon’s hands. dr sadeghinejad, an iranian urologist in the united states could remove both of the kidneys of a patient by a combination of 2 laparoscopic surgeries. usually, removal of both kidneys needs 2 separate surgeries, but dr sadeghi-nejad and his surgical team did it in 1 session with a few small incisions. these days experienced surgeons around the world report their achievements in using laparoscopy in various surgical operations. laparoscopy has also a special place in urological surgeries and in iran it has gained popularity among urologists. avicenna and his modern scientific viewpoint avicenna, a great iranian scientist has written the most famous medical book in the history. a thousand years ago, he donated a treasure to the world named canon of medicine. dr madinehie, a urologist interested in this book, has selected some chapters of the canon that are about bladder and its diseases. in his article, he shows the similarities of avicenna’s theories with modern theories. readers may find it interesting that 10 centuries ago, avicenna could through away the superstitious beliefs in medicine and substitute them with experimental methodology we believe in now. u j all final for web.pdf 756 | 1social determinants of health research center, yasuj university of medical sciences, yasuj, iran 2student research committee, shiraz university of medical sciences, shiraz, iran sadrollah mehrabi,1 ali mousavi zadeh,1mehdi akbartabar toori,1 farhad mehrabi2 general versus spinal anesthesia in percutaneous nephrolithotomy corresponding author: sadrollah mehrabi, md department of urology, faculty of medicine, yasuj university of medical sciences, yasuj, iran tel/fax: +98 741 222 6517 e-mail: sadrollahm@yahoo. com received december 2011 accepted august 2012 purpose: percutaneous nephrolithotomy (pcnl). materials and methods: t tests. results: p p p conclusion: cost-effective method for performing pcnl in adult patients. keywords: percutaneous nephrolithotomy, anesthesia, complications endourology and stone disease endourology and stone disease 757vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l introduction urinary tract stone disease is a major health-care problem, and after urinary tract infections and prostate pathology, is the third in rank among the diseases of the urinary system. although there are (eswl), transurethral lithotripsy (tul), and percutaneous nephrolithotomy (pcnl) during the last three decades, diagnostic and treatment methods for this kind of disease have been changed remarkably.(2) percutaneous nephrolithotomy is a minimally-invasive therapy for treatment of upper ureteral and renal stones. it is the treatment of choice for kidney stones larger than multiple or resistant to eswl. in most cases, pcnl is and the costs of general anesthesia are higher than spinal anesthesia.(6) changed from supine to prone. the most common complifects related to displacement of tracheal tube. ther spinal, epidural, or intrapleural anesthesia. due to high rate of complications and cost in general anesthesia materials and methods mm, staghorn stones, multiple renal stones, and stones resistant to eswl. they have been referred to our urology department for performing pcnl. ing to zelen randomization method. history and physical pre-operative laboratory tests, such as sodium, potassium, complete blood count (cbc), coagulation tests, renal function tests (urea and creatinine), urinalysis, and urine culture, done for better decision. traindication for spinal anesthesia, such as skin infection over lumbar spine, elevated intracranial pressure, or severe kyphoscoliosis, and failure of spinal anesthesia (inability to dazolam, thiopental, and atracorium, and inhalation of isopulmonary, visceral, and vascular complications, a nephrosposition and the bed changed to trendelenburg position general versus spinal anesthesia in pcnl | mehrabi et al 758 | gently and by assistance of anesthesiologists in the operatobtained using hypnotic and narcoleptic drugs, such as ketrecorded from the beginning of the anesthesia procedure checked by 7-point verbal test and visual analogue scale (vas), respectively. on the 2nd ity to remove kidney stones completely or residuals stone (2,3) and t test. results time (p controlled by ephedrine and metoclopramide. the compliplications related to anesthesia, such as hypotension (2 patachycardia (2 patients). the complication not related to anendourology and stone disease table 1. comparison of demographics and stone characteristics in two groups before operation.* variable general anesthesia spinal anesthesia p gender male, n (%) female, n (%) 35 (67.3) 17 (32.7) 31 (53.4) 27 (46.6) .07 stone location pelvic + staghorn, n (%) others, n (%) 29 (55.8) 23 (44.2) 37 (64.9) 20 (35.1) .11 mean age ± sd, y 43.7 ± 8.2 47.4 ± 7.6 .17 mean stone size ± sd, mm 30.9 ± 10.6 32.8 ± 9.6 .06 mean body mass index ± sd, kg/m2 24.1 ± 5.6 24.1 ± 7.2 .07 *sd indicates standard deviation. 759vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l type of anesthesia and intra-operative complications (p groups regarding intra-operative hypotension (p postoperative complications in spinal anesthesia group sion, and postoperative fever due to atelectasia occurred in and postoperative minor complications (p successfulness of operation in general and spinal groups according to radiography and ultrasonography results after surgery (complete clearance of system from stone or residthesia and result of radiography and renal ultrasonography after surgery (p p erage cost of drugs and materials used in spinal and general p discussion although general anesthesia is preferred in many centers for performing pcnl, but it can be a challenge in some situations, such as pcnl for staghorn calculi or patients cular disorders. sorption and electrolyte imbalance, especially in staghorn stones and also in morbid obese patients, regional or local anesthesia may be a good alternative for general anesthesia in these patients. has been addressed. in a study by kuzgunbay and colleagues, general versus combined spinal-epidural anestheregarding pre and postoperative variables, such as operastay.(7) studies. general versus spinal anesthesia in pcnl | mehrabi et al table 2. comparison of two groups based on intra-operative and postoperative variables. pspinal anesthesiageneral anesthesiavariable .0982.2 ± 9.892.3 ± 10.1mean operation time ± sd, min .238 (77.2)40 (80)patient satisfaction, n (%) .0230postoperative headache, n .0220low back pain, n .01112hypotension, n .6611.5212.35mean postoperative hb, g/dl *sd indicates standard deviation. 760 | esthesia, but if suitable anesthetic level can not be achieved and success decrease. regarding postoperative hemoglobin cacy and complications of spinal anesthesia in pcnl. the ing operation and postoperative rest and analgesics.(2) the tients had mild hemodynamic instability and hypotension, during the operation and improved spontaneously or by injection of ephedrine and metoclopramide. in our study, the combination of bupivacaine and fentanyl nd regarding dose of narcotic drugs after surgery and postoperative complications, this study is similar to andreoni candidate for pcnl. in the present study, need for opioid st used in spinal anesthesia. fentanyl and bupivacaine could be a good alternative for general anesthesia in pcnl. gonano and assoless than general anesthesia in orthopedic surgeries. aldespite general opinion that spinal anesthesia is not suitable for pcnl procedure of staghorn stones and stones in the upper pole of the kidney, our study results denote that also provides a good operation scope for access to all parts complications, such as pulmonary, neurologic, and vascular conclusion remove the kidney stones in both spinal and general anesendourology and stone disease table 3. need to opioid drugs (mg per day) after percutaneous nephrolithotomy in two groups. pt test spinal anesthesia general anesthesia time .032.23 7.8 ± 2.3 12.4 ± 3.11st postoperative day .061.8711.1 ± 2.1 13.2 ± 2.12nd postoperative day 761vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l general versus spinal anesthesia in pcnl | mehrabi et al 9. saied mm, sonbul zm, el-kenawy m, atallah mm. spinal and interpleural bupivacaine for percutaneous nephrolithotomy. middle east j anesthesiol. 1991;11:259-64. 10. andreoni c, olweny eo, portis aj, sundaram cp, monk t, clayman rv. effect of single-dose subarachnoid spinal anesthesia on pain and recovery after unilateral percutaneous nephrolithotomy. j endourol. 2002;16:721-5. 11. singh i, kumar a, kumar p. "ambulatory pcnl" (tubeless pcnl under regional anesthesia) -a preliminary report of 10 cases. int urol nephrol. 2005;37:35-7. 12. schuster m, gottschalk a, berger j, standl t. a retrospective comparison of costs for regional and general anesthesia techniques. anesth analg. 2005;100:786-94, table of contents. 13. gonano c, leitgeb u, sitzwohl c, ihra g, weinstabl c, kettner sc. spinal versus general anesthesia for orthopedic surgery: anesthesia drug and supply costs. anesth analg. 2006;102:524-9. references 1. rozentsveig v, neulander ez, roussabrov e, et al. anesthetic considerations during percutaneous nephrolithotomy. j clin anesth. 2007;19:351-5. 2. mehrabi s, karimzadeh shirazi k. results and complications of spinal anesthesia in percutaneous nephrolithotomy. urol j. 2010;7:22-5. 3. stoller ml, wolf js, jr., st lezin ma. estimated blood loss and transfusion rates associated with percutaneous nephrolithotomy. j urol. 1994;152:1977-81. 4. trivedi ns, robalino j, shevde k. interpleural block: a new technique for regional anaesthesia during percutaneous nephrostomy and nephrolithotomy. can j anaesth. 1990;37:479-81. 5. aravantinos e, karatzas a, gravas s, tzortzis v, melekos m. feasibility of percutaneous nephrolithotomy under assisted local anaesthesia: a prospective study on selected patients with upper urinary tract obstruction. eur urol. 2007;51:224-7; discussion 8. 6. el-husseiny t, moraitis k, maan z, et al. percutaneous endourologic procedures in high-risk patients in the lateral decubitus position under regional anesthesia. j endourol. 2009;23:1603-6. 7. kuzgunbay b, turunc t, akin s, ergenoglu p, aribogan a, ozkardes h. percutaneous nephrolithotomy under general versus combined spinal-epidural anesthesia. j endourol. 2009;23:1835-8. 8. kanaroglou a, razvi h. percutaneous nephrolithotomy under conscious sedation in morbidly obese patients. can j urol. 2006;13:3153-5. ureteral stones. acknowledgements nology department of yasuj university of medical scibeheshti hospital of yasuj for their cooperation. conflict of interest none declared. 1359vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l iatrogenic calyceal rupture in patient with unrecognized vesicoureteral reflux woong jin bae, seol kim, yong sun choi, su jin kim, hyuk jin cho, sung hoo hong, ji youl lee, tae-kon hwang, sae woong kim keywords: vesico-ureteral reflux; pathology; postoperative complications; kidney calices; rupture. introduction renal calyceal rupture, which is a radiographical finding indicating perirenal urinary extravasation associated with ureteric obstruction, is a rarely encountered clinical situation in urology. there are few cases reported in the literature. moreover, the majority of reported cases are associated with ureteric calculi.(1) we present a male patient, who developed an unusual complication when performing a suprapubic cystostomy. case report a 60-year-old man in vegetative state due to diffuse anoxic brain injury came to our hospital for 1 week fever and hematuria. he had kept urethral catheter for 5 years and experienced similar manifestations 3 months ago. his vital signs were as follows: blood pressure, 130/75 mmhg; pulse, 84 beats per minute and regular; respirations, 20 per minute; and body temperature, 38.0°c. blood tests showed a leukocyte count of 13.2 × 109/l with predominant neutrophils, c-reactive protein 7.1 mg/dl, blood urea nitrogen 15 mg/dl, and serum creatinine 1.2 mg/ dl. urinalysis showed 20 to 29 red cells and 30 to 49 white cells per field under high-power magnification. antibiotic therapy was started, and acute pyelonephritis which caused the fever was resolved. corresponding author: sae woong kim, md, phd department of urology, seoul st. mary’s hospital, the catholic university of korea 505 banpodong, seocho-gu, 137-040, seoul, korea. tel: +82 2 2258 6226 fax: +82 2 599 7839 e-mail: ksw1227@catholic.ac.kr received january 2013 accepted april 2013 department of urology, seoul st. mary’s hospital, the catholic university of korea, seoul, korea. case report 1360 | case report suprapubic cystostomy was planned in order to reduce recurrent nosocomial infection. even after filling 200 ml of normal saline into the bladder via indwelled urethral catheter, suprapubic distention was not seen. to determine the presence of bladder injury, cystography was then immediately performed. during the cystography, no perivesical leakage was identified on full bladder films, however right sided vesicoureteral reflux (vur) and a typical fluid collection around the right kidney was recognized (figure 1). an abdominal computed tomographic (ct) scan was performed, which showed right hydronephroureterosis, focal rupture of the right mid-renal calyceal system, hematoma formation and leakage to the retroperitoneal space (figure 2). indwelling urethral catheter was kept for 2 weeks and ct scan was performed again, which showed disappeared hydronephrosis but still remained perirenal hematoma (figure 3). discussion although published literature contains several small case reports, gershman and colleagues.(2) reported a retrospective review of 108 patients with renal forniceal or calyceal rupture. forniceal rupture was most commonly associated with ureteric obstruction caused by stones. the iatrogenic causes included ureteric injury after vaginal hysterectomy, occlusion of ureteric orifice by urethral catheter balloon, and prostatic occlusion by urethral catheter balloon. there was one case of calyceal rupture during instillation into the bladder, but that was because an unexpected small capacity of the bladder led the catheter to enter into the ureteral orifice in a child.(3) calyceal rupture leads to backflow of urine into the renal sinus, and the extravasated urine causes inflammatory reaction followed by an avascular deposition of collagen and fibrous tissue accounting for the urinoma formation.(4) the treatment depends upon the condition of the patient and the residual function of the affected kidney. placement of an indwelling ureteral stent or percutaneous catheter can relieve obstruction.(5) in our case, vur, which was the cause of calyceal rupture, was subsided after keeping a urethral catheter, and therefore we did not perform any procedures. suprapubic cystostomy is recommended to patients with figure 1. cystography demonstrating reflux into the ureter and perirenal fluid collection due to calyceal rupture. figure 2. noncontrast computed tomography axial section showing hydronephroureterosis, focal rupture of the right mid-renal calyceal system (a) and leakage to the retroperitoneal space (b). figure 3. contrast computed tomography axial section showing decreased perirenal hematoma and disappeared hydronephrosis. 1361vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l calyceal rupture in vesicoureteral reflux | bae et al references 1. koktener a, unal d, dilmen g, koc a. spontaneous rupture of the renal pelvis caused by calculus: a case report. j emerg med. 2007;33:127-9. 2. gershman b, kulkarni n, sahani dv, eisner bh. causes of renal forniceal rupture. bju int. 2011;108:1909-11. 3. emir l, karabulut a, germiyanoglu c, erol d. calyceal fornix rupture during cystography. int urol nephrol. 2001;32:335-6. 4. twersky j, twersky n, phillips g, coppersmith h. peripelvic extravasation, urinoma formation and tumor obstruction of the ureter. j urol. 1976;116:305-7. 5. koga s, arakaki y, matsuoka m, ohyama c. spontaneous peripelvic extravasation of urine. int urol nephrol. 1992;24:465-9. 6. dogra pn, goel r. complication of percutaneous suprapubic cystostomy. int urol nephrol. 2004;36:343-4. neurogenic bladder to prevent complications of long-term urethral catheter drainage. complications associated with the insertion of suprapubic catheters using a punch trocar technique include perforation of the ileum as well as serious retropubic hemorrhage.(6) it is well known that filling the bladder with normal saline before the procedure is an indispensable in order to avoid injury to bowel or blood vessel. however, there is no reported complication that we could encounter during the bladder filling. care should be taken during bladder filling for patients in vegetative state and paraplegic state. conflicts of interest none declared 1710 | case report aggressive vaginal angiomyxoma mimicking a bladder mass bulent erol,1 eyyup sabri pelit,1 sibel bektaş,2 aliriza şimşek3 corresponding author: eyyup sabri pelit, md dr. erkin cad. i̇stanbul medeniyet üniversitesi, göztepe eğitim ve araştırma hastanesi, kadıköy, i̇stanbul, turkey. tel: +90 506 388 3186 e-mail: dreyyupsabri@hotmail.com received may 2013 accepted january 2014 1 department of urology, istanbul medeniyet university, faculty of medicine, istanbul, turkey. 2 department of pathology, bulent ecevit university, faculty of medicine, kozlu, zonguldak, turkey. 3 department of urology, bulent ecevit university, faculty of medicine, kozlu, zonguldak, turkey. case report keywords: myxoma; vaginal neoplasms; diseases; diagnosis; diagnostic error; urinary bladder neoplasms; differential. introduction aggressive angiomyxoma is a rare, slow-growing myxoid neoplasm that occurs al-most exclusively in the genital, perineal and pelvic regions of adult women. be-cause of its rarity and pelvic occurrence, it is often initially misdiagnosed as a gynecological malignancy or mixed with other malignancies. case report a 48-year-old female patient presented with a history of abdominal swelling and hypertension. she had also difficulty in urination and defecation. on examination, a palpable large abdominal mass extending to the umbilicus was observed. ultrasonography revealed intravesical mass and right grade iv and left grade ii hydronephrosis. the computed tomography (ct) scan showed a large pelvic mass and bilateral hydronephrosis. (figure 1). the proximal vaginal wall involvement could not be ruled out on ct scan. in ct scan images, a huge intravesical mass was seen but it did not have the classical appearance of bladder tumor. under general anesthesia, a cystoscopy was performed initially to confirm intravesical mass. cystoscopic examination was very difficult due to the huge size of the mass elevating the base of 1711vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l vaginal angiomyxoma | erol et al the bladder and there was no papillary bladder tumor. double j ureteral stent was inserted to the left side. right ureteral orifice was not seen due to compression of huge mass. subsequently open exploration was planned. during the exploration, mass was thought to stem from posterior wall of bladder. the anterior bladder wall was incised, transversely. the mass was located between the posterior wall of the vagina and base of the bladder and originated from the posterior vaginal wall. transvesical enucleation of mass was made and complete extirpation could be performed after incision of posterior wall of the bladder. right ureteral orifice was excised simultaneously due to invasion of the orifice. right ureteroneocystostomy was performed using the paquin technique (figure 2). the postoperative period was uneventful. bilateral hydronephrosis was resolved and according to control ct scan no mass has been recurred on 6-month and 2-year postoperatively (figure 3). discussion aggressive angiomyxoma, synonymously referred to as deep angiomyxoma by the world health organization (who), was first described in 1983 as “aggressive angiomyxoma of the female pelvis and perineum”.(1) this neoplasm usually involves the deep soft tissues of the vulvovaginal region, pelvis and perineum of women in the reproductive age.(2,3) the reason of high prevalence in reproductive age group is thought to be estrogen-dependent nature of the tumor and estrogen and progesterone receptor positivity.(4,5) our patient is not in reproductive age group. aggressive angiomyxoma is often a large lesion that fills much of the pelvis, displacing rather than directly invading the pelvic structures.(6) it is a locally invasive neoplasm figure 1. large pelvic mass and bilateral hydronephrosis. figure 2. mass elevating the base of bladder and intact mucosa (a) with right ureteroneocystostomy (b). 1712 | with a distinct risk of local recurrence, especially in lesions that extend to the other pelvic organs.(7) in this case, pelvic mass was invade to bladder and ureteral orifice. thus our patient was presented with a difficulty in urination and defecation and bilateral hydronephrosis. local excision with tumor free margin is the standard treatment of the angiomyxoma. the excision of these tumors is difficult as they have the same consistency as that of normal connective tissue and therefore have a propensity for local recurrence (36-72%).(8) hormonal treatment with gonadotropin releasing hormone (lhrh) agonists, such as goserelin acetate, might be of value in the management of aggressive angiomyxoma, especially in recurrent or residual cases that are not amenable to surgical resection.(9) in this case, excision of pedunculated lesion was complete and the postoperative period was uneventful. thus there is no need for further treatment with lhrh agonist. for this lesion long-term follow-up is required due to high risk recurrence and minimal risk of metastasis.(10) in 1996, fetsch and colleagues reported a series of 29 women with pelvic angiomyxoma. in their series, there was no metastasis but recurrence has been frequently observed. eight patients developed recurrent tumor, from 10 months to 7 years after the initial resection and there were no tumor related deaths.(3) in the literature 71% of recurrences have occurred within the first 3 years. there was no correlation between the size of the tumors and the chance of recurrence.(8) in our case, ct imaging is the preferred method for detecting recurrences. the first follow-up imaging was performed via ultrasonography 3 months after the operation and thereafter follow-up ct scan was performed on first and second year postoperative period. there was no recurrence and metastasis during the 2-year follow-up. conclusion in conclusion, angiomyxoma is rare, benign and locally aggressive tumor which compresses the adjacent structure with mass affect. with the preoperative imaging methods, it is difficult to predict whether it is a bladder tumor or not. it can mimic a bladder mass in imaging modalities. thus, it should be noted that this type of pelvic masses may be gynecological origin other than urological origin. figure 3. postoperative computed tomography scan showing no mass and hydronephrosis. case report references 1. steeper ta, rosai j. aggressive angiomyxoma of the female pelvis and perineum. report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. am j surg pathol. 1983;7:463-75. 2. bégin lr, clement pb, kirk me, jothy s, mccaughey wt, ferenczy a. aggressive angiomyxoma of pelvic soft parts: a clinicopathologic study of nine cases. hum pathol. 1985;16:621-8. 3. fetsch jf, laskin wb, lefkowitz m, kindblom lg, meis-kindblom jm. aggressive angiomyxoma: a clinicopathologic study of 29 female patients. cancer. 1996;78:79-90. 4. ribaldone r, piantanida p, surico d, boldorini r, colombo n, surico n. aggressive angiomyxoma of the vulva. gynecol oncol. 2004;95:724-8. 1713vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l 5. mccluggage wg, patterson a, maxwell p. aggressive angiomyxoma of pelvic parts exhibits oestrogen and progesterone receptor positivity. j clin pathol. 2000;53:603-5. 6. mccluggage wg. recent developments in vulvovaginal pathology. histopathology. 2009;54:156-73. 7. magtibay pm, salmon z, keeney gl, podratz kc. aggressive angiomyxoma of the female pelvis and perineum: a case series. int j gynecol cancer. 2006;16:396-401. 8. chan ym, hon e, ngai sw, ng ty, wong lc. aggressive angiomyxoma in females: is radical resection the only option? acta obstet gynecol scand. 2000;79:216-20. 9. mccluggage wg, jamieson t, dobbs sp, grey a. aggressive angiomyxoma of the vulva: dramatic response to gonadotropin-releasing hormone agonist therapy. gynecol oncol. 2006;100:623-5. 10. mathieson a, chandrakanth s, yousef g, wadden p. aggressive angiomyxoma of the pelvis: a case report. can j surg. 2007;50:228-9. vaginal angiomyxoma | erol et al errata 213urology journal vol 5 no 3 summer 2008 errata in volume 5, number 2 of the urology journal (spring 2008), the following errors occurred: on page 108, in the title of table 2, ejacutaion should have read ejaculation. on page 123, the name of the last author, dr reza kaffash nayyeri, was missed. the article entitled “retroperitoneal ureterocyctoplasty in bilaterally functioning kidneys” should have had 4 authors as follows: mohammad ali zargar-shoshtari, kaveh mehravaran, hormoz salimi, and reza kaffash nayyeri. on page 129, the name of the second author should have read yashar moharamzad. on page 136, the first keyword of the article should have read congenital instead of congential. we regret the above errors in the past issue. urol j. 2008;5:213. www.uj.unrc.ir urology journal unrc/iua vol. 2, no. 1, 40-44 winter 2005 printed in iran 40 miscellaneous the relationship between lipid profile and erectile dysfunction mohammadreza nikoobakht*, maziar pourkasmaee, hamidreza nasseh urology research center, tehran university of medical sciences, tehran, iran abstract purpose: to evaluate the relationship between serum lipids including cholesterol, low-density lipoprotein (ldl), high-density lipoprotein (hdl), and triglyceride and erectile dysfunction (ed). materials and methods: from january 2000 to june 2003, 100 patients with organic ed, who were referred to our center, were selected and their lipid profile (cholesterol, triglyceride, hdl, ldl) were assessed. the results were compared with those in 100 healthy individuals. results: mean age of men in the study and control groups were 43.72 ± 9.76 and 43.59 ± 10.51 years, respectively. mean plasma cholesterol and ldl levels in individuals suffering from erectile dysfunction were significantly higher than controls (p = 0.04 and p = 0.02, respectively). however, no difference in the mean plasma triglyceride and hdl levels was seen. odds ratios for high plasma cholesterol level (>240 mg/dl) and high plasma ldl level (>160 mg/dl) were 1.74 and 1.97, respectively (r2 = 0.04 and r2 = 0.04). using linear regression analysis, the regression coefficient for cholesterol and ldl versus the international index of erectile dysfunction questionnaire (iief) score were -0.036 and -0.035, respectively (95% confidence interval: 0.98 2.5 for cholesterol and 1.13 2.81 for ldl). conclusion: the impact of total cholesterol and particularly ldl on men's erectile function underlines the role of hyperlipidemia treatment in prevention of ed and emerges a holistic management in ed patients. key words: erectile dysfunction, serum lipids, cholesterol, ldl introduction in the first international consultation on erectile dysfunction, which was held in paris in july 1999, they defined ed as a consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual performance, for at least a 3-month period.(1) the prevalence of complete ed in healthy men has tripled from 5% in 1940s to 15% in 1970s.(2) the incidence rate of erectile dysfunction is about 26 cases per 1,000 men annually, increasing with higher age, lower education, diabetes mellitus, heart diseases, and hypertension.(3) commonly, patients are divided into two groups: psychogenic and organic. the ratio of organic to psychogenic male sexual dysfunction has been reported to be directly associated with age; 70 % of patients under 35 years of age have psychogenic ed and 85 % of patients over 50 years of age have organic ed.(4) it is well known that ed is frequently seen in patients with manifestations of atherosclerotic diseases and this may be a symptom of a received november 2004 accepted february 2005 *corresponding author: urology research center, sina hospital, hassan abad sq., tehran 19953-45432. e-mail: nikoobakht_m@hotmail.com nikoobakht et al 41 systemic vascular problem related to risk factors such as smoking, hypertension, hyperlipidemia, and diabetes mellitus.(5) a marked increase in serum ldl and a decrease in serum hdl have been reported in patients with vasculogenic impotence, in comparison with those with nonvasculogenic erectile dysfunction.(6) blood cholesterol can also affect the sex hormones, especially in older men.(7) however, no comprehensive published study has been done on the prevalence and characteristics of ed and its relationship with hyperlipidemia in iran. in the present study we have compared the plasma lipid profile of patients suffering from organic ed with that in a healthy control group. materials and methods from january 2000 to june 2003, a total of 100 patients with organic erectile dysfunction, based on the international index of erectile dysfunction questionnaire (iief-5), were selected at sina hospital, to be enrolled in a case-control study. intracavernous injection (ici) and nocturnal penile tumescence monitoring by a rigi-scan (optional) was used to exclude patients with psychogenic (non-organic) ed. exclusion criteria were diabetes mellitus, hypertension (blood pressure >140/90), renal failure, hypogonadism, peyronie's disease, obesity (bmi >28 kg/m2), pelvic or spinal cord injury, history of vascular surgery, multiple sclerosis, thyroid dysfunction, cardiac diseases, drugs/narcotics administration, and smoking. for comparison, 100 healthy individuals, with no evidence of erectile dysfunction were selected. they were matched with the study group for age and the exclusion criteria. all the patients and controls were examined and assessed using the international index of erectile dysfunction questionnaire (iief-5). mild, moderate, and severe ed were defined corresponding to the scores of 18 to 24, 11 to 17, and 10 or less. scores between 25 and 30 were considered as potent (control group). physical examination consisted of penile palpation for peyronie's disease, assessment of penile and perianal sensation, anal sphincter tone, and response of the bulbocavernous reflex. plasma lipid profile including cholesterol, triglyceride, hdl, and ldl were measured in study and control groups with the same laboratory kits and technique (enzymatic spectrophotometery). optimum and normal upper limit levels were considered 180 and 240 mg/dl for cholesterol, and 130 and 160 mg/dl for ldl. the spss software package, version 9.00, was used for statistical analysis, and t test was used for groups comparison and p value less than 0.05 was considered statistically significant. results mean ages of the patients and controls were 43.59 ± 10.51 (range 20 to 60) years and 43.72 ± 9.76 (range 20 to 60) years, respectively. among 100 patients in the study group, 2 had mild, 41 had moderate, and 57 had severe ed. delay in seeking treatment was less than 1 year in 48 patients, 1 to 2 years in 27, and more than 3 years in 35. sleep disorder was found in 38 patients. in order to find out the influence of age, we divided the patients into two groups of <40 and ≥40 years old. mean plasma cholesterol level in study and control groups were 235.58 ± 76.56 mg/dl and 209.15 ± 47.63 mg/dl, respectively (p = 0.004). among the patients 40 years of age or older, the difference between the two groups in cholesterol and ldl was also significant (p = 0.02 and p = 0.004, respectively), but not in patients younger than 40 years (table 1). fortyeight per cent of patients (study group) and 17% of the controls had a plasma cholesterol level of 240 mg/dl or higher (p = 0.02). such significant difference was also found in individuals over 40 years old (38% vs. 15%, respectively, p = 0.03), but table 1. number and percent of individuals in subgroups according to total plasma cholesterol level and age age <40 ≥40 total controls (%) cases (%) controls (%) cases (%) controls cases ≤200 18 (47.3) 10 (31.2) 14 (22.5) 13 (19.1) 32 23 201-240 18 (47.3) 12 (37.5) 33 (53.2) 17 (25.0) 51 29 cholesterol (mg/dl) >240 2 (5.3) 10 (31.2) 15 (24.2) 38 (55.8) 17 48 total 38 32 62 68 100 100 lipid profile and erectile dysfunction42 not in those under 40. mean plasma ldl level in study and control groups were 163.68 ± 75 mg/dl and 136.79 ± 42.16 mg/dl, respectively (p = 0.002). in the patients younger than 40 years old, such a significant difference was not found. however, in those with an age of 40 or more, the difference was significant (p = 0.004). the results in subgroups according to serum ldl level and age is shown in table 2. overall, 53% of patients in the study group and 17% of the controls had high plasma ldl (≥160 mg/dl, p = 0.02). this difference was also seen in individuals over 40 years old (42% vs.13%, p = 0.04). nevertheless, it was not significant in individuals under 40. mean plasma triglyceride observed in the study and control groups were 257.53 ± 53.80 mg/dl and 251.28 ± 100.00 mg/dl, respectively (p = 0.58), the result of which was not significantly affected by age. mean plasma hdl level in the study and control groups were 39.82 ± 22.01 mg/dl and 42.42 ± 11.62 mg/dl, respectively (p = 0.29), and it was not affected by age. using the linear regression test, the regression coefficient for cholesterol versus the patients' score, obtained by iief-5, was -0.036, i.e. regardless of changes in other parameters, by each 1 mg/dl increase in cholesterol level we will note 0.036 decrease in the patient's score. the coefficient for ldl was -0.035. r square for ldl and cholesterol was calculated separately (0.04 for both of them), which means that 4 percent of ed is accounted for by cholesterol or ldl levels. odds ratios for high plasma cholesterol level (>240 mg/dl) and high plasma ldl level (>160 mg/dl) were 1.74 and 1.97, respectively (r2 = 0.04 and r2 = 0.04). discussion the association between hyperlipidemia and ed is originally attributed to atherosclerosis in the hypogastric-cavernosal arterial bed, with a subsequent insufficiency in penile arterial inflow.(8) more recently, the importance of cavernosal relaxation in the erectile process has been shown. impairment of endotheliumdependent relaxation in numerous vascular beds in men with hypercholesterolemia has been firmly established.(9,10,11) these impairments have also been shown to be reversible, using lipidlowering therapies.(12) in animal models of hypercholesterolemia, studies show both deficient endotheliumand neurogenic-dependent cavernosal relaxations.(13,14) these changes are also reversible by normalizing total plasma cholesterol levels through dietary changes. ultrastructural assessments in these studies have shown atherosclerotic-like processes in focal areas of the cavernosal sinusoids.(14) these changes are not thought to be the primary cause of ed, but more likely, precursors to later, more complex atherosclerotic lesions. although erectile dysfunction is frequently seen in patients with manifestations of arteriosclerotic diseases, the independent contribution of total plasma cholesterol in predicting erectile dysfunction is unclear. in the study done by wei et al,(15) every mmol/l increase in total cholesterol was associated with a 1.32-fold increase in the risk of erectile dysfunction (95% confidence interval: 1.04 1.68), while every mmol/l increase in high density lipoprotein cholesterol was associated with a 0.38-fold increase in the risk (95% confidence interval: 0.18 0.80). men with a hdl cholesterol measurement over 1.55 mmol/l (60 mg/dl) had 0.30 times the risk (95% confidence interval: 0.09 1.03) as did men with less than 0.78 mmol/l (30 mg/dl). men with total cholesterol over 6.21 mmol/l (240 mg/dl) had 1.83 times the risk (95% confidence interval: 1.00 3.37) as did men with less than 4.65 mmol/l (180 mg/dl). those differences remained essentially unchanged after adjustment for other potential confounders. the authors concluded that a high level of total cholesterol table 2. number and percent of individuals in subgroups according to serum ldl level and age age <40 ≥40 total controls (%) cases (%) controls (%) cases (%) controls cases ≤130 19 (50.0) 15 (46.9) 29 (46.8) 16 (23.5) 48 31 131-159 15 (39.5) 6 (18.7) 20 (32.2) 10 (14.7) 35 16 ldl (mg/dl) >160 4 (10.5) 11 (34.4) 13 (21.0) 42 (61.8) 17 53 total 38 32 62 68 100 100 nikoobakht et al 43 and a low level of high density lipoprotein cholesterol are important risk factors for erectile dysfunction. sanchez-cruz and colleagues(16) assessed the health-related quality of life factors associated with ed. the prevalence of ed based on iief was 18.9%. odds ratio was calculated for diabetes (4), hypertension (1.58), high cholesterol (1.63), peripheral vascular disease (2.37) and allergy (3.08). in the study done by pinnock et al,(17) high cholesterol level was an independent predictor of impotence. ed was strongly correlated with age in all seven domains of sexual function. high triglyceride levels, blood pressure medication, and non-cancer surgery for prostate disease were independent predictors of poor sexual function at older ages. high cholesterol level was an independent predictor of impotence. they concluded that cardiovascular risk factors were predictors of ed in these older men, suggesting that prevention may benefit sexual function. in a study by feldman et al,(18) after adjustment for age, a higher probability of impotence was directly correlated with heart disease, hypertension, diabetes, associated medications, and indices of anger and depression, and it was inversely correlated with serum dehydroepiandrosterone, high density lipoprotein cholesterol, and an index of dominant personality. manning et al(19) found a correlation between high ldl and organic erectile dysfunction (68.6% vs. 32.4% in the psychogenic impotence group) and a clear positive correlation between high ldl and caverno-venous insufficiency was determined. in the study conducted by kim,(20) the incidence of abnormally high level of ldl was significantly higher in the patients than in the control men, but there was no significant difference in the incidence of abnormally high blood level of total cholesterol or triglyceride and abnormally low blood level of hdl between the two groups. in a study by atahan et al,(21) lipoprotein a and triglyceride levels were higher in both peripheral and cavernosal samples of vasculogenic ed group than in non-vasculogenic ed group, with no differences between peripheral and cavernosal blood levels within the same groups. there was no significant change in tg and hdl levels in neither of the groups. our finding suggest that there is a significant correlation between total cholesterol and ldl with ed, probably indicating the etiologic role of these lipids in organic ed. according to our findings, every mg/dl increase in plasma cholesterol and ldl levels decreases iief-5 scores by 0.036 and 0.035, respectively. we have shown that this correlation was not significant in men aged under 40 years; thus, it can confirm the theory that organic factors play a role, especially in the elderly. conclusion we recommend that men's lipid profile be tested regularly, especially in aged individuals. the individuals at risk for hyperlipidemia are also at increased risk for ed, but they can prevent ed and other associated complications by modifying their lifestyle, more physical activity, and changing diet. ed is a symptom rather than a disease and we can almost always find a factor that causes ed. however, while visiting a patient, holistic management should not be neglected since several etiologic factors, including hyperlipidemia, can affect the whole body of patients. references 1. jardin a, wagner g, khoury s, giuliano f, padmanathan h, rosen r, editors. erectile dysfunction. proceedings of the 1st international consultation on erectile dysfunction; 1999 july 1-3; paris, france. plymouth: plymbridge distributors ltd; 2000. 2. broderick ga. intracavernous pharmacotherapy: treatment for the aging erectile response. urol clin north am. 1996;23:111-26. 3. johannes cb, araujo ab, feldman ha, derby ca, kleinman kp, mckinlay jb. incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the massachusetts male aging study. j urol. 2000;163:460-3. 4. mellinger bc, weiss j. sexual dysfunction in the elderly male. am urol assoc update series 1992: 11: 146-152. 5. virag r, bouilly p, frydman d. a study of arterial risk factors in 440 impotent men. lancet. 1985;1:181-4. 6. juenemann kp, muth s, rohr g, et al. does lipid metabolism influence the pathogenesis of vascular impotence? int j impot res. 1990;2 (suppl 2):33. 7. haffner sm, newcomb pa, marcus pm, klein be, klein r. relation of sex hormones and dehydroepiandrosterone sulfate (dhea-so4) to cardiovascular risk factors in postmenopausal women. am j epidemiol. 1995;142:925-34. 8. sullivan me, keoghane sr, miller ma. vascular risk lipid profile and erectile dysfunction44 factors and erectile dysfunction. bju int. 2001;87:838-45. 9. tanner fc, noll g, boulanger cm, luscher tf. oxidized low density lipoproteins inhibit relaxations of porcine coronary arteries. role of scavenger receptor and endothelium-derived nitric oxide. circulation. 1991;83:2012-20. 10. rosenfeld me. oxidized ldl affects multiple atherogenic cellular responses. circulation. 1991; 83:2137-40. 11. kugiyama k, kerns sa, morrisett jd, roberts r, henry pd. impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. nature. 1990;344:160-2. 12. leung wh, lau cp, wong ck. beneficial effect of cholesterol-lowering therapy on coronary endotheliumdependent relaxation in hypercholesterolaemic patients. lancet. 1993;341:1496-500. 13. azadzoi km, saenz de tejada i. hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. j urol. 1991; 146:238-40. 14. kim jh, klyachkin ml, svendsen e, davies mg, hagen po, carson cc 3rd. experimental hypercholesterolemia in rabbits induces cavernosal atherosclerosis with endothelial and smooth muscle cell dysfunction. j urol. 1994;151:198-205. 15. wei m, macera ca, davis dr, hornung ca, nankin hr, blair sn. total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. am j epidemiol. 1994;140:930-7. 16. sanchez-cruz jj, cabrera-leon a, martin-morales a, fernandez a, burgos r, rejas j. male erectile dysfunction and health-related quality of life. eur urol. 2003;44:245-53. 17. pinnock cb, stapleton am, marshall vr. erectile dysfunction in the community: a prevalence study. med j aust. 1999;171:353-7. 18. feldman ha, goldstein i, hatzichristou dg, krane rj, mckinlay jb. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994;151:54-61. 19. manning m, schmidt p, juenemann kp, et al. the role of blood lipids in erectile failure. int j impot res. 1996;8:167. 20. kim sc. hyperlipidemia and erectile dysfunction. asian j androl. 2000; 2:161-6. 21. atahan o, kayigil o, hizel n, metin a. is apolipoprotein(a) an important indicator of vasculogenic erectile dysfunction? int urol nephrol. 1998;30:185-91. urol_v3_no1_001_editorial.qxd urology journal unrc/iua 54 introduction hematuria is a common complaint among people who refer to urology clinics. in addition, defined as more than 3 red blood cells per highpower microscopic field (hpf), it is generally the most common finding in urinalysis.(1) it has been shown that 2.5% of men aging 28 to 57 years may have an occult hematuria.(2) blood in urine can be originated from any part of the urinary tract system, attributed to either glomerular or nonglomerular origins. glomerular hematuria almost always arises from a medical cause and diagnosis is made by histologic or serologic examinations. thus, imaging modalities are of no diagnostic value.(1,3) nonglomerular hematuria is mainly the sign of renal and bladder tumors, urinary tract infections, tuberculosis, trauma, urinary tract calculi, arteriovenous fistula, and renal vessels comparison of ultrasonography and intravenous urography in the screening and diagnosis of hematuria causes mohammad rajaie esfahani,1* ali momeni2 1department of urology, kashani hospital, shahr-e-kord university of medical sciences, shahr-e-kord, iran 2department of nephrology, kashani hospital, shahr-e-kord university of medical sciences, shahr-e-kord, iran abstract introduction: our aim was to compare transabdominal ultrasonography (us) and intravenous urography (ivu) in the evaluation of patients with hematuria. materials and methods: two hundred patients with hematuria were assessed by us and ivu, and if needed, by cystoscopy, ureteroscopy, and ct scan, to determine the definite cause of hematuria. the results of us and ivu were compared according to the definite diagnoses. results: of 97 patients with microscopic hematuria, 44 (45%) had a documented cause for hematuria, and of 103 patients with gross hematuria, 76 (74%) had a definite disorder (p < .001). urinary calculi were found in 105 patients, 93 (88.5%) and 73 (69.5%) of which were detected by us and ivu, respectively (p < .001). there were 3 and 6 cases of kidney and bladder neoplasms, respectively, all of which were revealed by us, but only 2 renal tumors were detectable on ivu. ultrasonography had a higher sensitivity than ivu for diagnoses of kidney calculi, lower ureteral calculi, and urologic neoplasms (95.3% versus 65.1% for kidney calculi, p = .039; 89.7% versus 69.2% for lower ureteral calculi, p < .001; and 100% versus 22.3% for urologic neoplasms, p < .001), but in calculi of the middle and upper ureter and of the whole ureter, there were no differences between us and ivu. conclusion: our results are in favor of using us in the initial evaluation of hematuria. however, we must choose our diagnostic tool according to the patient's condition and suspected disorders causing hematuria. key words: hematuria, ultrasonography, intravenous urography, urologic neoplasms, urinary calculi vol. 3, no. 1, 54-60 winter 2006 printed in iran received may 2005 accepted october 2005 *corresponding author: department of urology, kashani hospital, shahr-e-kord, iran. tel: +98 913 382 0669 e-mail: dr_mrajaei@yahoo.com rajaei esfahani and momeni 55 thrombosis. intravenous urography (ivu) is the first diagnostic step and, in a sense, the standard method for the evaluation of patients with hematuria.(1,4) its low cost and objective results, when compared with ct scan, has made ivu the popular method used in most studies.(4) however, some conditions, such as hypersensitivity to contrast media, moderate or severe kidney dysfunction, diabetes mellitus, multiple myeloma, congestive heart failure, and pregnancy limit the use of ivu or are accompanied by a high risk.(3,5,6) furthermore, this test has a low sensitivity in the diagnosis of small kidney and bladder neoplasms and is not able to differentiate cystic from solid masses.(4) transabdominal ultrasonography (us) is a noninvasive tool with an acceptable accuracy in evaluation of the kidney, vessels, prostate, and bladder anatomy.(7) since it is not dependent on contrast media excretion, us can be used regardless of the kidney function.(5) ultrasonography is currently the method of choice for the evaluation of children with congenital anomalies of the urinary tract system. it can be used to differentiate solid and cystic masses.(3,8) notwithstanding its many advantages, us is not recommended in the assessment of the urothelium and diagnosis of transitional cell carcinoma of the renal pelvis or the ureters.(4) although ivu is still the classic choice in the diagnosis of nonglomerular hematuria,(1) some clinicians use us in practice. we performed this study to compare the diagnostic value of us and ivu as the initial evaluation method in patients with hematuria. materials and methods from winter 2002 to autumn 2003, we performed a screening study on patients with hematuria at our urology clinic in shahr-e-kord, iran. a total of 200 consecutive eligible patients were enrolled. the exclusion criteria were fever, viral infections, heavy exercise within the past 48 hours, vaccination within the past week, menstruation period in women, genitourinary trauma, recent sexual activity, and urinary tract infection documented by laboratory assessments. patients with any condition that contraindicates ivu were excluded, as well. the patients underwent urinalysis and urine culture. the presence of dysmorphic erythrocytes was determined. if hematuria was documented in urinalysis (more than 3 red blood cells per hpf), ivu, consisting of a plain abdominal radiography and subsequent radiographies after contrast medium injection, was performed under the supervision of a single radiologist. also, transabdominal us of the urinary tract system with a 3.5-mhz probe was done by another radiologist who was blinded to ivu results. cystoscopy was performed in the following conditions: if ivu and us failed to demonstrate the cause, hematuria was reported to be at the beginning or the end of stream, or a pathology was found in the bladder. rigid ureteroscopy was performed in the following conditions: if ivu and us failed to diagnose hematuria cause despite the presence of unilateral or bilateral pain and other symptoms, if cystoscopy showed a unilateral hematuria from one ureter, or if hydronephrosis without reflux and a definite diagnosis was detected. in case of the detection of a renal tumor in ivu or us, ct scan was carried out. to reduce the potential bias, cystoscopies and ureteroscopies were carried out by a single urologist. data including patients' characteristics, physical examination, and diagnostic measures were collected and analyzed. the chi-square, mcnemar, and binomial tests were used and confidence intervals were calculated where appropriate. a p value less than .05 was considered significant. results two hundred patients with hematuria completed the study, of whom, 124 (62%) were male; thus, men were more likely to present with a chief complaint of hematuria. of 200 patients, 132 (66%) were 40 years old or younger and 68 (34%) were older than 40. the appearance of the urine specimen was colorless or pale yellow in 97 (48.5%) patients (microscopic hematuria), in 44 (45%) of whom an abnormal finding was detected in further investigation for hematuria causes, but the results were normal in the remaining 53 (55%). forty-two patients with microscopic hematuria had urinary tract calculi, 1 had a urethral stricture, and 1 had a urethral diverticulum. a red urine was reported in macroscopic examination of 103 patients' specimens (gross hematuria) which was at the beginning of stream, at the end, and during the entire stream in 3 (2.9%), 9 (8.7%), and 91 (88.3%) patients, respectively. no abnormal findings were found in ultrasonography in the diagnosis of hematuria causes56 27 (26%) of the patients with gross hematuria, while a cause for hematuria was confirmed in 76 (74%), including urinary calculi in 63 (61%), renal tumor in 3 (2.9%), bladder tumor in 6 (15.8%), and bleeding from vessels or mucosa of the bladder in 4 (3.8%). overall, a leading cause for hematuria was found in 120 patients (60%) and no abnormal results were detected in 80 (40%). identifying an etiology for hematuria was more likely if hematuria was gross (risk ratio = 1.63; confidence interval = 1.96 to 4.36; p < .001). table 1 demonstrates the causes found for hematuria and the results and sensitivities of ivu and us. urinary calculi were the definite diagnosis in 105 patients. ultrasonography revealed the calculi or evidence showing the existence of calculi (such as pathologic hydronephrosis) in 93 patients (46.5%) (58 men and 35 women; 64 in their first 4 decades and 29 older than 40 years). in comparison, ivu detected the calculi in 73 (36.5%) patients (43 men and 30 women; 41 in their first 4 decades and 32 older than 40 years). no significant differences in sex and age category were found between the patients with and those without urinary tract calculi. the results of ivu were normal in 21 of 93 patients (22.5%) with calculi or pathologic hydronephrosis detected by us; while, 3 of 73 patients (4%) with a diagnosis of calculi on ivu had a normal us result. a bladder calculus was found in 1 patient on us and confirmed by cystoscopy, but ivu could not detect it. there were 3 cases of kidney neoplasm and 6 cases of bladder neoplasm, diagnosed by ct scan and cystoscopy, respectively. all bladder tumors were smaller than 1.5 cm. ultrasonography was able to find all 9 urologic neoplasms, but only 2 renal tumors were detectable on ivu. overall, cystoscopy was carried out in 125 table 1. results of ultrasonography (us) and intravenous urography (ivu) in patients with urinary tract calculi, tumors, and other disorders found in the workup for hematuria *values in parentheses are the sensitivity rates (%) of the respective diagnostic tool †mcnemar test ‡binomial test disease definite diagnosis ivu us p value calculus kidney 43 28 (65.1) * 41 (95.3) < .001 † upper ureter 8 7 (87.5) 7 (87.5) .98 † middle ureter 14 11 (78.5) 9 (64.3) .5 † lower ureter 39 27 (69.2) 35 (89.7) .039 † ureter 61 45 (73.8) 51 (83.6) .21 † bladder 1 0 1 total 105 73 (69.5%) 93 (88.6%) < .001 tumor kidney 3 2 (66.7) 3 (100) bladder 6 0 (0) 6 (100) total 9 2 (22.3) 9 (100) < .001 ‡ other urethral stricture 1 urethral diverticulum 1 bleeding from vessels or mucosa 4 total 120 75 (62.5) 102 (85) < .001 † rajaei esfahani and momeni 57 patients and demonstrated 6 and 1 cases of bladder tumors and calculus, respectively. in addition, there were 1 patient with urethral stricture, 1 with urethral diverticulum, and 4 with bleeding from vessels or mucosa, all revealed by cystoscopy only. overall, ultrasonography was more sensitive than ivu in cases of kidney or lower ureteral calculi and those of urinary tract tumors (table 1), but in calculi of the middle and upper ureter and of the ureter as a whole, there were no differences in the sensitivity of us and ivu. ultrasonography falsely demonstrated hydronephrosis in 6 patients in whom no pathologic finding was revealed by ivu. also, us was unable to demonstrate hydronephrosis in 7 patients with a positive ivu result. taking ivu as the gold standard for diagnosis of hydronephrosis, us had an 89.1% sensitivity and a 95.6% specificity (table 2). moreover, us and ivu could detect the cause of hematuria in 102 and 75 patients, respectively (85% versus 62.5%; p < .001). discussion hematuria, either gross or microscopic, may be indicative of a serious disease of the genitourinary tract. our study showed that hematuria is more frequent in men than in women. we found no explanation for this sign in 40% of the patients. kidney and ureteral calculi were the most common causes of hematuria, followed by bladder and kidney neoplasms with a much lower frequency. in agreement with the literature,(1) a definite disorder could be found more frequently in patients with gross hematuria than in those with microscopic hematuria. intravenous urography is preferred for diagnosis of urologic causes of hematuria, because of its objective results and standard process.(1,4) it has been especially proved to be helpful for investigation of epithelial tumors of the kidney and the ureters.(4) however, in a study on 16 patients with ureteral tumor, it was shown that transabdominal us could detect all tumors. ten of 16 patients had an ivu, in 4 of which, a nonfunctional kidney, in 3, an unexplained hydroureteronephrosis, and in 3, a filling defect were detected. there were only 2 cases of filling defects with irregular margins. the authors concluded that us is a good diagnostic tool in ureteral tumors.(9) we had no cases of malignancy in the epithelium of the urinary tract system. there are different imaging methods that can be used for patients with hematuria, each with its own capabilities and disadvantages. a systematic approach is required to choose diagnostic tools in hematuria cases. a comparison of us and ivu in our series was in favor of us for both urinary tract calculi and tumors, raising a doubt in the use of ivu as the first choice (table 1). intravenous urography lacks a high sensitivity in the diagnosis of renal tumors, particularly the small ones in the anterior or posterior lobe that have not impacted the anatomy of the collecting system. also, if the patient is sensitive to contrast media or has a poor kidney function, ivu is contraindicated. on the other hand, given its low cost and noninvasive nature, us can be suggested as an alternative, regarding its accuracy in differentiating solid from cystic masses and to detect angiomyolipomas. although controversy still exists, some physicians prefer us and dipstick for hematuria to diagnose kidney neoplasms in their early stages, so that surgical treatment can be effective.(10) rafique and javed studied the diagnostic accuracy of ivu and transabdominal us in 100 patients with bladder carcinoma. they demonstrated that us is significantly more sensitive than ivu (96% versus 87%; p < .01). in addition, us could determine the pathology of the upper urinary tract such as ureteral obstruction secondary to bladder cancer when ivu failed due to a poor kidney function. they suggested that us be used as a cost-effective method in cases of suspected bladder tumor.(11) moreover, hoenig and coworkers have shown the value of us in 5 boys aged 11 to 18 years with transitional cell carcinoma.(12) although transrectal and transabdominal us cannot be used in the staging of tumors and determining their invasion to the bladder wall,(13) table 2. ultrasonography and intravenous urography results in the evaluation of hydronephrosis in patients with hematuria* *the sensitivity and specificity were 89.1% and 95.6% for ultrasonography. intravenous urography total + + 57 6 63 ultrasonography 7 130 137 total 64 136 200 ultrasonography in the diagnosis of hematuria causes58 they are able to show mucosal lesions greater than 4 mm to 5 mm when the bladder is full. in our series, 6 tumors of the bladder mucosa were detected by us and confirmed by cystoscopy, while ivu could not show tumors smaller than 1.5 cm. we speculate that since most bladder tumors are superficial and low grade, when detected by us, a bimanual physical examination of the pelvis and cystoscopy and resection are enough to assess the grade and invasion. consequently, ct scan is not necessary and transurethral resection of bladder tumors can be performed before pathologic examination. in a retrospective study by eshed and witzling, it was shown that ct scan, when carried out after us, could not provide additional information in children with kidney calculi aged 1 to 15 years. they suggested that us be used as the first step and ct scan be used only when us results are not normal or not definite.(14) in 2005, palmer and colleagues performed a study to determine the accuracy of us and ct scan without contrast in the diagnosis of urinary tract calculi in 75 children. symptoms including flank pain and/or hematuria were present in 72% of the patients. they found that us could not detect the calculus in 41% of symptomatic patients, while ct scan was unable to show the calculus in 5%. the sensitivity of ct scan was high regardless of the calculi location; whereas, us had a sensitivity of 90%, 38%, and 75% for calculi of the kidneys, the ureters, and both kidneys and ureters, respectively.(15) in contrast to eshed and witzling's conclusions, they suggested that ct scan be performed if us is negative for urinary tract calculi. the sensitivity of us and ivu were 95% and 65% in our patients. middleton and colleagues have shown a 91% sensitivity for us in the assessment of calculi remnants after percutaneous nephrolithotomy or shock wave lithotripsy.(16) on the contrary, a comparison between us, ct scan, plain radiography, and conventional linear tomography has shown that us has the lowest sensitivity for detecting calculi remnants.(17) marumo and coworkers have studied the hyperechoic spots accidentally found in the kidneys on us. they followed up 195 patients for 1 to 161 months and performed us on a yearly basis. thirty-nine patients had hyperechoic spots while no calculi were detected on radiography. they underwent spiral ct scan with 3-mm cuts and calculi were seen in 31 (79.5%). the authors reported that us is an effective diagnostic tool in finding calculi of patients with asymptomatic hematuria.(18) although most calculi that are seen only as hyperechoic spots have no clinical value, the cause of hematuria can be explained by us. yilmaz and colleagues have studied 112 adult patients with renal colic and a diagnosis of ureteral calculus was made by us, ivu, and ct scan. the sensitivity and specificity were 19% and 97% for us, 52% and 94% for ivu, and 94% and 97% for ct scan, respectively.(19) the sensitivity of us in our series was 87% for upper, 64% for middle, 89% for lower, and 83% for the entire ureteral calculi. these rates were 87%, 78%, 69%, and 73% for ivu, respectively. although doppler us with the measurement of resistive index and ureteral jet can increase the diagnostic value of us, ureteral calculi may not be detected when hydroureteronephrosis and ureteral dilatation is not present or when the patient is obese or has abdominal distention. we considered cases of pathologic hydronephrosis on us, when definite diagnose was also calculi, as positive for ureteral calculi and also there were many cases of calculi proximate to the bladder. this can explain the high accuracy of us that we have found. it is noteworthy that we had 6 patients with extrarenal pelvis which were falsely diagnosed as hydronephrosis on us. intravenous urography results were normal for hydronephrosis in these patients. such cases warrant supplemental diagnostic measures. intravenous urography is the gold standard with 100% sensitivity and specificity if excretion of contrast medium occurs. the results of us for lower ureteral calculi were superior to ivu; however, it is not a good diagnostic tool if hydronephrosis is absent and the calculus is not near to the ureterovesical junction. consequently, further studies are needed to confirm this finding. in addition, us did not have the same accuracy in different parts of the ureter for diagnosis of calculi and the overall comparison of us and ivu for urinary calculi showed no meaningful difference. a complementary imaging may help us achieve a better result with us. for instance, using us and plain abdominal radiography as the first step, henderson and colleagues reported a 97.1% sensitivity, higher than that of ivu, for urinary calculi in patients with hematuria and flank pain.(20) we found that the likelihood of detecting a rajaei esfahani and momeni 59 disease responsible for hematuria is higher when investigated by us compared with ivu (sensitivities, 85% versus 62.5%). mokulis and coworkers performed a study to assess patients with microscopic hematuria by us when the ivu results are normal. they found that 20% of 101 patients with a normal ivu result had abnormal findings on us. however, none of the findings were clinically important; ct scan and renal angiography revealed no findings in 6 of them. the authors concluded that us in not necessary in patients with microscopic hematuria and a normal ivp result.(21) a case-control study was done in italy to compare the results of us in 516 patients with hematuria and with those in 1788 controls. they reported a sensitivity of 93% and a specificity of 100% for diagnosis of hematuria causes.(22) it seems that the evaluation of us and ivp regarding all diseases of the urinary tract system may not achieve a consensus; however, we suggest us when the diagnostic choice cannot be identified by the history, physical examination, and laboratory test results in patients with hematuria. we had a limitation of few cases with bladder calculi and urethral lesions. measures such as vcug and cystoscopy can be helpful when initial hematuria and a suspected urethral pathology are present, while ivu and us results are normal. conclusion ultrasonography is operator dependent, compared to ivu. however, many clinicians rely on the us for the evaluation of patients with hematuria, especially when uremia, pregnancy, and other such conditions make ivu contraindicated. in the presence of less-invasive techniques such as shock wave lithotrpsy, transurethral resection, transureteral lithotripsy, ureteroscopy, and cystoscopy, us findings may sometimes be stuffiest to make therapeutic decisions. however, we must decide to choose our diagnostic tool according to the patient's condition and the most suspected disorders causing hematuria. references 1. gerber gs, brendler cb. evaluation of the urologic patient: history, physical examination, and urinalysis. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 83-110. 2. ritchie cd, bevan ea, collier sj. importance of occult haematuria found at screening. br med j (clin res ed). 1986;292:681-3. 3. schulam pg, kawashima a, sandler c, barron bj, lamki lm, goldman sm. urinary tract imaging--basic principles. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 122-67. 4. grossfeld gd, wolf js jr, litwan ms, et al. asymptomatic microscopic hematuria in adults: summary of the aua best practice policy recommendations. am fam physician. 2001;63:1145-54. 5. fleischer ac. renal and urological sonography. in: fleischer ac, james ae jr, editors. diagnostic sonography: principles and clinical applications. philadelphia: wb saunders; 1989. p. 433-517. 6. eberhardt sc, hricak h. radiology of the urinary tract. in: tanagho ea, mcaninch jw, editors. smith's general urology. 16th ed. new york (usa): lange medical books/mcgraw-hill; 2004. p. 62-111. 7. jones s, richards d. imaging investigation of the urogenital tract. in: sutton d, editor. textbook of radiology and imaging. 6th ed. new york: churchill livingstone; 1998. p. 1113-29. 8. yip sk, peh wc, tam pc, li jh, lam ch. role of ultrasonography in screening for urological malignancies in patients presenting with painless haematuria. ann acad med singapore. 1999;28:174-7. 9. hadas-halpern i, farkas a, patlas m, zaghal i, sabaggottschalk s, fisher d. sonographic diagnosis of ureteral tumors. j ultrasound med. 1999;18:639-45. 10. novick ac, campbell sc. renal tumors. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 2672-731. 11. rafique m, javed aa. role of intravenous urography and transabdominal ultrasonography in the diagnosis of bladder carcinoma. int braz j urol. 2004;30:185-90; discussion 191. 12. hoenig dm, mcrae s, chen sc, diamond da, rabinowitz r, caldamone aa. transitional cell carcinoma of the bladder in the pediatric patient. j urol. 1996;156:203-5. 13. yaman o, baltaci s, arikan n, yilmaz e, gogus o. staging with computed tomography, transrectal ultrasonography and transurethral resection of bladder tumour: comparison with final pathological stage in invasive bladder carcinoma. br j urol. 1996;78:197-200. 14. eshed i, witzling m. the role of unenhanced helical ct in the evaluation of suspected renal colic and atypical abdominal pain in children. pediatr radiol. 2002;32:205-8. 15. palmer js, donaher er, o'riordan ma, dell km. diagnosis of pediatric urolithiasis: role of ultrasound and computerized tomography. j urol. 2005;174:1413-6. 16. middleton wd, dodds wj, lawson tl, foley wd. renal calculi: sensitivity for detection with us. radiology. 1988;167:239-44. 17. lehtoranta k, mankinen p, taari k, rannikko s, ultrasonography in the diagnosis of hematuria causes60 lehtonen t, salo j. residual stones after percutaneous nephrolithotomy; sensitivities of different imaging methods in renal stone detection. ann chir gynaecol. 1995;84:43-9. 18. marumo k, horiguchi y, nakagawa k, et al. significance and diagnostic accuracy of renal calculi found by ultrasonography in patients with asymptomatic microscopic hematuria. int j urol. 2002;9:363-7; discussion 367. 19. yilmaz s, sindel t, arslan g, et al. renal colic: comparison of spiral ct, us and ivu in the detection of ureteral calculi. eur radiol. 1998;8:212-7. 20. henderson so, hoffner rj, aragona jl, groth de, esekogwu vi, chan d. bedside emergency department ultrasonography plus radiography of the kidneys, ureters, and bladder vs intravenous pyelography in the evaluation of suspected ureteral colic. acad emerg med. 1998;5:666-71. 21. mokulis ja, arndt wf, downey jr, caballero rl, thompson im. should renal ultrasound be performed in the patient with microscopic hematuria and a normal excretory urogram? j urol. 1995;154:1300-1. 22. scialabba a, li vecchi m, vigneri s, et al. [the ultrasonographic examination in hematuria. evaluation of its diagnostic possibilities]. minerva urol nefrol. 1992;44:185-90. italian. editorial comment the authors have mentioned that "evidence showing the existence of calculi" has been also considered as a diagnosis of urinary tract calculus on us. to elucidate, the authors have made an example, hydronephrosis which is only suggestive of calculi. however, the cause of hematuria cannot be determined by only the presence of hydronephrosis. one-third of the patients had hydronephrosis in their series, and if all of them are considered as patients with urinary tract calculi, a relatively large proportion of diagnoses by us are not definite. thus, the superiority of us may be questioned if only definite diagnoses of urinary tract calculi are taken into account. abbas basiri editor-in-chief reply by author we evaluated all patients with hematuria by complementary measures other than us and ivu, such as ureteroscopy, cystoscopy, and ct scan, to achieve a definite diagnosis. our aim was indeed to assess the potential of us for case finding in patients with hematuria, thus, considered cases of hydronephrosis and confirmed diagnosis of calculus (by later passage of calculus or diagnostic modalities) as pathologic hydronephrosis and positive for calculi. other cases of hydronephrosis were not included in this analysis. mohammad rajaie esfahani department of urology, shahr-e-kord university of medical sciences, shahr-e-kord, iran laparoscopic urology comparison of standard absorbable sutures with self-retaining sutures in retroperitoneoscopic partial nephrectomy: a retrospective study of 68 patients weifeng xu, hanzhong li,* yushi zhang, xuebin zhang, zhigang ji purpose: although laparoscopic partial nephrectomy (lpn) has been increasingly adopted in the treatment of small localized renal tumor, technical changes remain nowadays. the current study aimed to evaluate the safety and efficacy of the novel quilltm self-retaining system (srs) for renorrhaphy during lpn. materials and methods: sixty-eight patients with kidney neoplasm that accepted lpn at the peking union medical college hospital from july 2010 to march 2013 were retrospectively analyzed. thirty-five patients who received renal sutures with quilltm srs constituted group 1. the control group (group 2) composed of 33 patients who received standard absorbable vicryl sutures by the same surgeon. renorrhaphy was performed in both groups using two layers, with a closure of the deep vessels and collecting system, followed by a running closure of the renal capsule. the demographic and perioperative parameters [gender, laterality of the tumor, body mass index (bmi), tumor size, standardized nephrometry scoring system (r.e.n.a.l. nephrometry score)], estimated blood loss and warm ischemic time (wit)) were compared between the groups. risk factors of wit and blood loss were analyzed using logistic regression analysis. results: renorrhaphy was successfully completed in both groups. the baseline data of two groups did not differ significantly. logistic regression analysis showed wit decreased when the quilltm srs was used (21.8 ± 3.5 min vs. 25.6 ± 4.0 min; β = -4.109, p < .001). suture methods were an independent predictor of wit rather than blood loss (115.7 ± 57.9 ml vs. 137.9 ± 68.5 ml; p = .329). conclusion: quilltm srs can be effectively and safely used for renorrhaphy during lpn with the potential advantage of shortening wit. keywords: suture techniques; laparoscopy; kidney neoplasms; nephrectomy; methods; feasibility studies; sutures; treatment outcome. introduction laparoscopic partial nephrectomy (lpn) is effective in tumor control and renal function preservation.(1-3) lpn achieves comparable effects on t1a-stage kidney neoplasms to open partial nephrectomy.(4,5) lpn results in satisfactory effects on t1b-stage kidney neoplasms.(2) laparoscopic surgery has been adopted by an increasing number of urologists over traditional open surgery due to the following advantages: minimal invasiveness, more aesthetic wounds, less severe postoperative pain and faster recovery.(6) however, lpn remains technically challenging. during lpn, intraoperative warm ischemia of the affected kidney is often necessary. this treatment benefits the visualization of the tumor extent as well as complete tumor resection. in addition, it facilitates the closure of the parenchyma. however, ischemia reperfusion can lead to damage to renal function, and the severity of the damage is positively associated with warm ischemia time (wit); to better preserve renal function, wit should be shortened as much as possible.(7,8) renal suturing and knotting are the most time-consuming and challenging steps during lpn. simplifying these complex procedures can reduce wit and better preserve renal function. continuing innovation has led to the reduction of the wit through various technical modifications, such as sliding clip renorrhaphy, early hilar unclamping and unclamped partial nephrectomy.(9-11) the quilltm self-retaining suture (quilltm srs) (angiotech, vancouver, canada) is a barbed suture material (figure 1). the barbs change direction mid-suture, prevent slippage through tissue, and eliminate the need to maintain continuous tension while suturing and tying knots. quilltm srs is used primarily for wound closure during plastic surgery procedures. its potential application in urological surgery was assessed in an animal model of vesicourethral and ureteropelvic anastomoses and found to be a reliable knotless method of performing watertight anastomoses.(12,13) although the applicability of the self-retaining barbed suture v-loc™ 180 for the renal collecting system and parenchyma sutures in lpn has been reported,(14,15) to the best of our knowledge studdepartment of urology, peking union medical college hospital, chinese academy of medical sciences, beijing 100730, china. * correspondence: department of urology, peking union medical college hospital, chinese academy of medical sciences, beijing 100730, china. tel: +86 139 11095525; fax: +86 010 69156035. e-mail: lihanzhongcn@163.com. laparoscopic urology 1878 ies on the safety and efficacy of quilltm srs have not been found in literature. here, we evaluated the safety of quilltm srs for use in renal suturing in lpn. furthermore, we compared it with a standard suture for effectiveness on renal wit. materials and methods study subjects from july 2010 to march 2013, sixty-eight patients with kidney neoplasm who received lpn at the peking union medical college hospital were retrospectively analyzed. thirty-five of them subjected to renal sutures with quilltm srs between february 2012 and march 2013 constituted group 1. the remaining 33 of them subjected to standard absorbable vicryl (vicryl™, ethicon, johnson & johnson, somerville, nj, usa) sutures by the same surgeon between july 2010 and december 2011 comprised group 2. group 1 included 22 males and 13 females. the patients’ ages ranged from 42 to 75 years with a median age of 58.1 ± 8.1 years. group 2 included 21 males and 12 females. the patients’ ages ranged from 38 to 72 years (median, 57.4 ± 8.7 years). the inclusion criteria included single tumor with a clinical stage between ct1a and ct1b. the exclusion criteria included abnormalities in platelet or clotting time before operation, recurrent renal tumor, other simultaneous surgery and a history of surgery in the same operative region. for each patient, body mass index (bmi), tumor size, laterality, wit, estimated blood loss during surgery, and postoperative complications were recorded. the standardized nephrometry scoring system (r.e.n.a.l. nephrometry score) was used to evaluate the complexity of the surgery.(16) the r.e.n.a.l. nephrometry score consists of (r)adius (tumor size as maximal diameter), (e)xophytic/endophytic properties of the tumor, (n)earness of tumor deepest portion to the collecting system or sinus, (a)nterior (a)/ posterior (p) descriptor and the (l)ocation relative to the polar line. wit was calculated from the obstruction of the renal artery with the bulldog clip to the loosening of the clip. the final data were then compared between the groups. all the operations were performed by the same surgeon. the surgeon was experienced in retroperitoneoscopic surgery, who had performed lpn for hundreds of patients before this study. this study was conducted in accordance with the declaration of helsinki and with the approval of the institutional ethics committee of peking union medical college hospital. informed consent was obtained from all participants. surgical techniques the subjects in both groups underwent operations through patient characteristics quilltm srs absorbable suture p value group (n = 35) group (n = 33) age (years)a 58.1 ± 8.1 57.4 ± 8.7 .713 sex (male/female) 22/13 21/12 .947 bmi (kg/m2) 25.1 ± 1.6 24.7 ± 1.9 .337 side, left/right 18/17 19/14 .611 maximum tumour size (cm) 2.8 ± 0.6 2.9 ± 0.5 .513 r.e.n.a.l. score 6.3 ± 1.2 6.2 ± 1.0 .625 blood loss (ml) 115.7 ± 57.9 137.9 ± 68.5 .153 wit (min) 21.8 ± 3.5 25.6 ± 4.0 < .001 postoperative complications,b 1/35 1/33 1.0 pulmonary infection (i) 1 0 bleeding (iii) 0 1 postoperative pathology clear cell carcinoma 33 32 papillary cell carcinoma 2 1 abbreviation: quilltm srs, quilltm self-retaining system. * data are presented as means ± standard error of the means ( sx ± ). a the mean ± standard deviation of the mean. b clavien-dindo grade. table 1. baseline data and perioperative outcomes of patients in the study groups. figure 1. quilltm self-retaining system. figure 2. photograph of a quilltm self-retaining system used during an operation. self-retaining sutures in laparoscopic partial nephrectomy-xu et al vol 11. no 05 sept-oct 2014 1879 a retroperitoneal approach. a 10 mm trocar was placed 2 cm above the iliac crest at the middle axillary line into a 30° inspection glass; another 10 mm trocar was placed under the costal margin along the posterior axillary line as the major operating channel. a 5 mm trocar was placed under the costal margin along the anterior axillary line as the accessory channel. the renal pedicle was blocked by blocking the renal artery alone with a bulldog clip after isolation. in cases where an accessory renal artery was present on preoperative computed tomographic angiography, the artery was also blocked using a bulldog clip after being set free. the renal parenchyma was cut 0.5 cm away from the tumor margin by opening the renal capsule using an electric hook and then cutting off the entire tumor and a portion of the renal tissue using sharp scissors. electrical coagulation was used to stanch the bleeding if the blood vessels were clearly observed. methods for renal suture and renorrhaphy in group 1. group 1 received a quilltm srs. the suture was tightened unidirectionally and did not backslide because of the immobilization of the multiple barbs within the tissue. a series of 3-0 quilltm srs were used to repair the impaired collecting system. a hem-o-lok clip was placed at the end of a 15 cm long suture inserted from outside the kidney, and the inner layer was sutured and closed the collecting system. the needle was withdrawn from outside the renal capsule, and knotting was unnecessary because of fixation of the suture to the barbs. additional 0 size quilltm srs sutures were used to suture the second layer of the renal parenchyma. a hem-o-lok clip was also placed at the end of the sutures, and each suture was pulled tightly after the stitching. the sutures did not backslide due to the anchoring of the unidirectional barbs on the suture. renorrhaphy was completed using the same approach (figure 2). methods for renal suture and renorrhaphy in group 2. group 2 received standard absorbable sutures. the suturing and knotting involved in the repair of the open collecting system were performed using 1 or more 15 cm long 4-0 absorbable sutures. the suturing and ligation to the broken ends and bleeding points on the wound surface were completed. all of the knots were placed within the wound surface. the renal parenchyma was sutured continuously using 25 cm long 0 size absorbable sutures (the actual length used in lpn can be 15-25 cm long, which varies according to the tumor size and wound area, based on our experience), and a hem-o-lok clip was placed at the end of the sutures. the needle was inserted from outside the renal capsule and then withdrawn through the opposite capsule. after each stitch, the suture was pulled tightly, and a hem-o-lok clip was placed on the side on which the needle was withdrawn to avoid backsliding of the suture (figure 3). after completing the renorrhaphy, the suture was cut, the bulldog clip was loosened to restore the renal blood flow, and the restoration of normal renal blood supply was confirmed. statistical analysis statistical analyses were performed with the statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. measures of central tendency in continuous data were presented as means ± standard error of the means ( sx ± ).the differences in continuous variables between two groups were compared using independent t-tests and the associations of categorical variables were analyzed using chi-square tests. multivariate linear regression analysis was performed to determine the independent predictors of wit and blood loss. all statistics were tested using the two-tailed method. p < .05 was considered statistically significant. results baseline and perioperative data the baseline and perioperative data of the two groups are summarized in table 1. no significant differences in the baseline data were observed between the groups. renorrhaphy was successfully completed without any conversions to an open procedure or nephrectomy in both groups. the two groups did not show significant differences in the perioperative outcomes except for the wit dependent variable: wit dependent variable: blood loss parameters β p value β p value maximum tumour size -1.152 .501 96.238 .000 r.e.n.a.l. score 1.506 .085 -8.756 .421 suture method -4.109 .000 -11.395 .329 bmi 0.151 .552 -2.620 .412 table 2. multiple linear regression analysis: predictors of warm ischemia time and blood loss. abbreviations: wit, warm ischemia time; bmi, body mass index. figure 3. photograph of an absorbable suture in a patient in group 2. self-retaining sutures in laparoscopic partial nephrectomy-xu et al laparoscopic urology 1880 (21.8 ± 3.5 min vs. 25.6 ± 4.0 min, p < .001). for postoperative complications, one patient suffered pulmonary infection in group 1. after antibacterial treatment, the patient recovered. in group 2, there was 1 case of postoperative bleeding, which was cured by performing interventional angiography of the renal artery and super-selective embolization. multiple linear regression analysis the associations between possible risk factors and wit/ blood loss in patients subjected to lpn were analyzed using logistic regression analysis, which included maximum tumor size, r.e.n.a.l. score, suture method and bmi. the results are summarized in table 2. as shown in table 2, the wit decreased when the quilltm srs was performed (β = -4.109, p < .05) and suture methods were an independent predictor of wit. however, they were not predictive for blood loss (p = .329). discussion there have only been a few reports on the use of quilltm sutures in urological surgery, laparoscopic pyeloureteral anastomosis, and vesicourethral anastomosis.(12) no study has been conducted to evaluate the use of these sutures in partial nephrectomy until now; this is the first report on the use of quilltm sutures in renal tissue suturing and repair during lpn. this study evaluated the safety and efficacy of quilltm srs for renorrhaphy during lpn. in group 1, one patient presented with pulmonary infection after operation, which was proved unrelated to the new suture method. this finding indicates that quilltm srs sutures are safe for use as renal sutures. furthermore, logistic regression analysis showed that suture methods, rather than other factors, were an independent predictor of wit. this finding suggests that quilltm srs may benefit renal function protection by reducing the renal wit during lpn. moreover, patients with abnormalities in platelets or clotting time before operation were excluded from this study, which successfully avoided the possibility of bleeding caused by the hematological system. in addition, all the operations in this study were performed by the same surgeon, which greatly reduced the risk of bleeding caused by human factors. the regression analysis evidenced that suture methods were not associated with blood loss. therefore, quilltm srs is safe for renorrhaphy during lpn. partial nephrectomy is the standard treatment for localized renal tumors, achieving the same outcome as radical nephrectomy with respect to the tumor control rate;(17) this approach benefits the patients by preserving the function of the affected kidney.(17-20) laparoscopic partial nephrectomy has achieved the same efficacy as open surgery in terms of tumor treatment and renal function preservation, while offering the following advantages: less invasiveness, more aesthetic wounds, less severe postoperative pain, and faster recovery.(21) however, because this approach is technically difficult and risk its widespread use is limited because it requires performing renal tumor resection and renal suture, repair and knotting within a short period of time to reduce the renal wit and preserve the residual renal function. this procedure presents a significant challenge for beginners and even experienced laparoscopic surgeons, as the process of suturing and knotting under laparoscopic guidance is difficult and time-consuming. gill and colleagues reported that in 1800 cases of open and laparoscopic partial nephrectomy performed over the same period, despite the more complex conditions in the open surgery cases, the wit in the patients who underwent laparoscopy was 10 min longer than that of patients who underwent open surgery. (21) the renal wit can be reduced by simplifying the renal suturing and knotting process, thereby improving the surgical safety. although hemostatic colloids are applicable for capillary hemorrhage from the wound surface after partial nephrectomy, suturing hemostasis is a better choice for noticeable hemorrhage or hemorrhage from the broken ends of small arteries. furthermore, suturing can directly close the collective system, thereby reducing the incidence of postoperative urine leakage. during traditional laparoscopy, absorbable sutures are used to suture and close the renal collecting system and repair the renal parenchyma, either intermittently or continually. because it is easy for the sutures to backslide, it is usually necessary for the surgeon to pull the sutures tightly with one hand, leaving the other hand to stitch. this strategy leads to inapposite sutures and an increased risk of postoperative bleeding and urinary fistula. most surgeons adopt a modified suture method to reduce the technical difficulty and increase safety. suture retraction was avoided by applying a hem-o-lok clip to fix the suture after each stitch; the number of knots was also reduced. although this approach effectively simplifies the operation and improves the safety, repeatedly changing the needle carriers and hem-o-lok pliers increases the wit. moreover, the cost of surgery is increased due to the need for additional hem-o-lok clips. quilltm is a knotless, self-retaining barbed suture (srbs). there is one needle at each end of the suture, and a group of barbs is placed every 1 cm on the suture; these barbs change direction at the midpoint of the sutures. quilltm was first used for wound closure in plastic surgery and gynecology and obstetrics.(22,23) the initial application of srbs in urological surgery was in pyeloureteroplasty and vesicourethral anastomosis, achieving good results in both in vitro and animal experiments.(12,13) sergey shikanov and colleagues reported that in pigs, the same effect was achieved during partial nephrectomy to close the collecting system and repair the renal parenchyma, indicating that this novel suture is safe and reliable in renorrhaphy.(24) olweny and colleagues reported the use of another barbed suture, the v-loc suture, during laparoscopic renorrhaphy and collecting system closure and compared it with traditional absorbable sutures; the former approach significantly reduced the intraoperative renal wit. they also believed that barbed sutures would likely reduce the incidence of serious intraoperative bleeding.(25) sammon and colleagues reported that during robot-assisted laparoscopic partial nephrectomy, the use of v-loc sutures to suture and repair the kidneys and collecting systems improved the efficiency of the sutures, shortened the renal wit, and was safe and reliable. (26) jeon and colleagues reported that the use of v-loc for kidney suturing in transperitoneal lpn noticeably shortens the wit of the kidneys.(14) the same result was also self-retaining sutures in laparoscopic partial nephrectomy-xu et al vol 11. no 05 sept-oct 2014 1881 reported by selcuk and colleagues.(15) our results were consistent with those in literatures. however, none of the released studies focused on retroperitoneal partial nephrectomy. quilltm sutures solve the problem of knotting under laparoscopic guidance, thereby improving the efficiency of suturing. because its own barbs can exert a unidirectional anchoring effect within the renal tissue, there is no backsliding after pulling the suture tightly, which facilitates two-handed suturing by the operator. the strain is evenly distributed to multiple barbs along the length of the suture, which allows the suture to exert a greater stretching force at the wound margin and satisfies the wound margin apposition. no complications were observed regarding the suture material being incompatible with the renal tissue, suggesting good histocompatibility. additionally, there was no secondary bleeding or urinary fistula in group 1, indicating the safety of this approach. because there was no need to produce knots under laparoscopic guidance or to change the hem-o-lok clips, the renorrhaphy time and wit were significantly reduced, and improved renal function preservation was achieved. this study had limitations. first, the results of this study were based on only one surgeon’s experience. therefore, the wit and intraoperative hemorrhage volume values have limited generalizability. second, because this study was retrospective in nature, the two groups were not selected through match-pair. third, the sample size was small, and more cases remain to be analyzed in the future. conclusion the novel quilltm srs is as effective, efficient, and safe as a conventional technique in laparoscopic partial nephrectomy. compared with the standard absorbable suture, quilltm srs greatly shortened the renal wit. further studies are needed to corroborate these findings, but the present results indicate a promising development in reducing wit during minimally invasive partial nephrectomy. conflict of interest none declared. references 1. marszalek m, meixl h, polajnar m, rauchen wald m, jeschke k, madersbacher s. laparo scopic and open partial nephrectomy: a matched pair comparison of 200 patients. eur urol. 2009;55:1171-8. 2. simmons mn, weight cj, gill is. laparoscop ic radical versus partial nephrectomy for tumors > 4 cm: intermediate-term oncologic and func tional outcomes. urology. 2009;73:1077-82. 3. porpiglia f, volpe a, billia m, scarpa rm. laparoscopic versus open partial nephrectomy: analysis of the current literature. eur urol. 2008;53:732-42. 4. schiff jd, palese m, vaughan ed jr, sosa re, coll d, del pj. laparoscopic vs open partial ne phrectomy in consecutive patients: the cornell experience. bju int. 2005;96:811-4. 5. permpongkosol s, bagga hs, romero fr, sroka m, jarrett tw, kavoussi lr. laparoscop ic versus open partial nephrectomy for the treat ment of pathological t1n0m0 renal cell carci noma: a 5-year survival rate. j urol. 2006;176:1984-8. 6. gill is, matin sf, desai mm, et al. comparativ e analysis of laparoscopic versus open partial nephrectomy for renal tumors in 200 patients. j urol. 2003;170:64-8. 7. becker f, van poppel h, hakenberg ow, et al. assessing the impact of ischaemia time during partial nephrectomy. eur urol. 2009;56:625-34. 8. thompson rh, lane br, lohse cm, et al. ev ery minute counts when the renal hilum is clamped during partial nephrectomy. eur urol. 2010;58:340-5. 9. benway bm, wang aj, cabello jm, bhayani sb. robotic partial nephrectomy with sliding clip renorrhaphy: technique and outcomes. eur urol. 2009;55:592-9. 10. san fif, sweeney mc, wagner aa. robot-as sisted partial nephrectomy: early unclamping technique. j endourol. 2011;25:305-8. 11. nguyen mm, gill is. halving ischemia time during laparoscopic partial nephrectomy. j urol. 2008;179:627-32. 12. weld kj, ames cd, hruby g, humphrey pa, landman j. evaluation of a novel knotless self-anchoring suture material for urinary tract reconstruction. urology. 2006;67:1133-7. 13. moran me, marsh c, perrotti m. bidirection al-barbed sutured knotless running anastomosis v classic van velthoven suturing in a model system. j endourol. 2007;21:1175-8. 14. jeon sh, jung s, son hs, kimm sy, chung bi. the unidirectional barbed suture for ren orrhaphy during laparoscopic partial nephrec tomy: stanford experience. j laparoendosc adv surg tech a. 2013;23:521-5. 15. erdem s, tefik t, mammadov a, et al. the use of self-retaining barbed suture for inner layer renorrhaphy significantly reduces warm ischemia time in laparoscopic partial nephre ctomy: outcomes of a matched pair analysis. j endourol. 2013;27:452-8. 16. kutikov a, uzzo rg. the r.e.n.a.l. nephrom etry score: a comprehensive standardized sys tem for quantitating renal tumor size, location and depth. j urol. 2009;182:844-53. 17. lau wk, blute ml, weaver al, torres ve, zincke h. matched comparison of radical neph rectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a nor mal contralateral kidney. mayo clin proc. 2000;75:1236-42. 18. uzzo rg, novick ac. nephron sparing surgery for renal tumors: indications, techniques and outcomes. j urol. 2001;166:6-18. 19. campbell sc, novick ac, belldegrun a, et al. guideline for management of the clinical t1 renal mass. j urol. 2009;182:1271-9. 20. ljungberg b, cowan nc, hanbury dc, et al. self-retaining sutures in laparoscopic partial nephrectomy-xu et al laparoscopic urology 1882 eau guidelines on renal cell carcinoma: the 2010 update. eur urol. 2010;58:398-406. 21. gill is, kavoussi lr, lane br, et al. compari son of 1,800 laparoscopic and open partial neph rectomies for single renal tumors. j urol. 2007;178:41-6. 22. murtha ap, kaplan al, paglia mj, mills bb, feldstein ml, ruff gl. evaluation of a novel technique for wound closure using a barbed su ture. plast reconstr surg. 2006;117:1769-80. 23. greenberg ja, einarsson ji. the use of bidirec tional barbed suture in laparoscopic myomecto my and total laparoscopic hysterectomy. j min im invasive gynecol. 2008;15:621-3. 24. shikanov s, wille m, large m, et al. knotless closure of the collecting system and renal pa renchyma with a novel barbed suture during laparoscopic porcine partial nephrectomy. j en dourol. 2009;23:1157-60. 25. olweny eo, park sk, seideman ca, best sl, cadeddu ja. self-retaining barbed suture for parenchymal repair during laparoscopic par tial nephrectomy; initial clinical experience. bju int. 2012;109:906-9. 26. sammon j, petros f, sukumar s, et al. barbed suture for renorrhaphy during robot-assisted partial nephrectomy. j endourol. 2011;25:529 33. self-retaining sutures in laparoscopic partial nephrectomy-xu et al vol 11. no 05 sept-oct 2014 1883 case report 132 urology journal vol 6 no 2 spring 2009 endometriosis with pure urinary symptoms mohammad reza razzaghi, taban rahjoo, alireza golshan urol j. 2009;6:132-4. www.uj.unrc.ir keywords: endometriosis, urological manifestations, urinary bladder diseases laser in medical science research center, shohada-e-tajrish hospital, shahid beheshti university (mc), tehran, iran corresponding author: mohammad reza razzaghi, md shohada-e-tajrish medical center, tajrish sq, tehran, iran tel: +98 21 2271 8001 fax: +98 21 2271 9017 e-mail: rezarazaghi@yahoo.com received january 2008 accepted july 2008 introduction endometriosis is defined as abnormal growth of the endometrial glands and stroma beyond the normal confines of the uterus. although the condition is usually limited to the ovaries, uterosacral ligaments, and douglas’ pouch, it has been reported in almost every organ of the body. a total of 10% to 20% of women in reproductive ages may be affected. endometriosis may involve the urinary tract, and the most common site of involvement in this system is the bladder.(1) urinary presentation of pelvic endometriosis without previous genital symptoms is very rare.(1,2) in this report, a case of initial urinary presentation of pelvic endometriosis is described. case report a 38-year-old woman with 2 children (the 1st child born via normal vaginal delivery, and the 2nd, by cesarean) presented with abdominal pain, urgency, and frequency during the period of menstruation since her second delivery. she had no hematuria, flank pain, or history of urinary calculi. pelvic examination revealed no abnormal finding, and no palpable mass was detected. however, abdominal ultrasonography revealed a 31 × 14 × 11-mm mass in the posterior bladder wall (figure 1). transvaginal ultrasonography demonstrated a hypoechoic 29×13-mm node in the posterior bladder wall on the site of cesarean section incision, suggesting endometrioma (figure 2). on figure 1. preoperative abdominal ultrasonography showed a focus of soft tissue with the size of 31 × 14 × 11 mm in the posterior bladder wall. figure 2. preoperative transvaginal ultrasonography revealed a 29 × 13-mm hypoechoic node in the posterior bladder wall. endometriosis with urinary symptoms—razzaghi et al urology journal vol 6 no 2 spring 2009 133 abdominal diagnostic laparoscopy, the uterus, tubes, and ovaries were normal without any adherence and with normal motion. the douglas’ pouch was normal, too. cystoscopic examination identified a sessile irregular bluish lesion with a nodular surface on the posterior wall of the bladder inferior to the ureteral orifice (figure 3). the patient received gonadotropin-releasing hormone analogue for 6 months; however, there was no change in the size of the mass on the second cystoscopic examination. therefore, the patient underwent transurethral resection of the bladder mass with loop coagulation of the hemorrhagic vessels in the bladder. a urethral catheter was fixed and continuous bladder irrigation was initiated. postoperatively, the patient had no hemorrhage and no complaints. on the next morning, the urethral catheter was removed and the patient was discharged. hormone therapy was not administered. the pathologic findings revealed endometriosis in the bladder with chronic bullous cystitis. the macroscopic size of the mass was about 2 × 2 × 0.5 cm. microscopic features demonstrated urinary bladder mucosa with stromal edema, hyperemia, mild chronic inflammatory cell infiltration, and foci of endometrial glands and stroma (figure 4). discussion urinary tract endometriosis is detected in about 1% to 4% of the patients with pelvic endometriosis, and 70% to 80% of which involve the bladder.(2,3) the most common presenting symptoms are suprapubic pain along with cyclic irritative voiding symptoms that are aggravated during menstruation. cyclic hematuria was reported in less than 30% of the patients.(4) transabdominal ultrasonography is very helpful in evaluating the bladder wall.(5) for full-thickness lesions suspected of intravesical protrusion, cystoscopy and biopsy during the menstruation period is probably helpful in establishing the diagnosis.(6) agents including diethylstilbestrol, androgens, oral contraceptives, danazol, and gonadotropinreleasing hormone analogues have been proposed for the treatment of the condition with short-term improvement.(7) surgical therapy, generally used for the individual lesions, includes fulguration with cautery or laser, resection, and sometimes, oophorectomy and hysterectomy. the most effective option is surgical extirpation of the lesions with hysterectomy and bilateral oophorectomy. enucleation of the individual endometrial lesion is another procedure with a high success rate.(1,7) pure urinary symptoms as the initial and solitary presentation of endometriosis are absolutely rare in such patients. even after complete excision of figure 3. the patient’s cystoscopic feature of the disease: a sessile irregular bluish lesion with a nodular surface on the posterior wall of the bladder. figure 4. urinary bladder mucosa and foci of endometrial glands. mild chronic inflammatory cell infiltrate and foci of endometrial glands and stroma are seen (hematoxylin-eosin, × 10). endometriosis with urinary symptoms—razzaghi et al 134 urology journal vol 6 no 2 spring 2009 the abnormal tissue, new extra-urinary symptoms may develop. total abdominal hysterectomy and bilateral salpingo-oopherectomy may or may not eradicate the disease; more studies are indicated to elucidate it.(7) conflict of interest none declared. references 1. pais jr vr, strandhoy jw, assimos dg. pathophysiology of urinary tract obstruction. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p.1220-1. 2. moore jg, hibbard lt, growdon wa, schifrin bs. urinary tract endometriosis: enigmas in diagnosis and management. am j obstet gynecol. 1979;134:162-72. 3. bergqvist a. extragenital endometriosis. a review. eur j surg. 1992;158:7-12. 4. shook te, nyberg lm. endometriosis of the urinary tract. urology. 1988;31:1-6. 5. aldridge kw, burns jr, singh b. vesical endometriosis: a review and 2 case reports. j urol. 1985;134:539-41. 6. whitman gj, mcgovern fj. endometriosis of the bladder detected by pelvic ultrasonography. j ultrasound med. 1994;13:155-7. 7. abeshouse bs, abeshouse g. endometriosis of the urinary tract: a review of the literature and a report of four cases of vesical endometriosis. j int coll surg. 1960;34:43-63. u j all final for web.pdf 824 | testosterone replacement therapy in men testosterone is produced by the testicles and causes testosterone is necessary for maintaining body muscle mass, production of red blood cells, bone health, sense of crease in muscle bulk, increase in body fat (central obesity), possibly mild anemia, osteoporosis, decreased libido, impotence, and decrease in body hair. testosterone peaks during adolescence and early adulthood. as men get older, their blood testosterone level gradually some medical conditions can also result in testosterone deradiation, lung disease, metabolic syndrome (insulin resistcirrhosis, alcoholism, and some medications. administration of testosterone may have serious side effects. creased serum testosterone concentration by itself does not should consider testosterone replacement treatment. talking therapy is right for you. men should not consider testosterone therapy to help them feel younger and more vigorous. testosterone supplements have various forms: skin patch, gels, injections, and implants. oral testosterone is also available. can have adverse effects on the liver. the most appropriate form of testosterone supplements is skin patch. the most important testosterone replacement therapy side sleep apnea, and decreased testicular size. decreased testicubolic drugs, such as testosterone. see page 747 for full-text article. what’s up in urology journal, winter 2013? urology for people urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urology for people vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2541 fear of circumcision in boys considerably vanishes within ten days of procedure purpose: to compare fear of circumcision, before, immediately after, and ten days after the operation. materials and methods: this was a case-control study in which participants in the operation group consisted of children admitted for circumcision at the outpatient clinics of a hospital. the children’s fear scale and the venham picture test were administered by face-to-face interviews. results: the sample consisted of 100 boys who were circumcised and 99 who have not been circumcised yet. children’s fear scale scores measured before (p = .000) and immediately after the operation (p = .000) were significantly different from scores obtained on the 10th day after the operation. total fear scores of the venham picture test of boys whose families were in the higher economic level were higher than those of boys from low-income families (p < .05). the primary reason for admission for circumcision was religious, and the reason for the remaining boys was a combination of religious and hygienic factors. the boys who came to have circumcision solely because of religious reasons were found to be less fearful compared with the boys who were brought to surgery for both religious and medical reasons (p < .05). the lowest fear scores were obtained for boys who were six years of age or older. boys who knew what the circumcision meant were less afraid of circumcision compared with those who were unaware of the procedure. conclusion: fear from circumcision does not persist; it considerably vanishes within ten days. it seems reasonable to recommend circumcision for boys six years of age or older. pre-operative education may help boys to overcome fear originated from circumcision. keywords: circumcision; male; psychology; health education; health knowledge; attitudes; practice; case-control studies; socioeconomic factors; child behavior. 1 department of pediatric surgery, bursa yuksek ihtisas training and research hospital, bursa 16310, turkey. 2 department of family medicine, bursa yuksek ihtisas training and research hospital, bursa 16310, turkey. 3 department of urology, bursa yuksek ihtisas training and research hospital, bursa 16310, turkey. 4 department of psychiatry, bursa yuksek ihtisas training and research hospital, bursa 16310, turkey. 5 department of child and adolescent psychiatry, bursa yuksek ihtisas training and research hospital, bursa 16310, turkey. *correspondence: department of family medicine, bursa yuksek ihtisas training and research hospital, yildirim, bursa 16310, turkey. tel: +90 536 8963330. fax: +90 224 3660416. e-mail: drhakandemirci@hotmail.com. received june 2015 & accepted november 2015 pediatric urology serpil sancar,1 hakan demirci,2* muhammet guzelsoy,3 soner coban,3 rustem askin,4 mehmet erdem uzun,5 ali riza turkoglu3 introduction circumcision in boys is most common in muslim countries and israel. however, it has been also widely performed in predominantly non-muslim populations such as the united states and the united kingdom. the estimated rate of circumcision in the united states was 80.5%.(1) in recent years, however, there has been a worldwide decline in the rate of circumcision.(2,3) the decision regarding circumcision has been discussed for a long time. some authors have insisted that circumcision is beneficial, but some have opposed this idea.(4-8) the former group stressed that circumcision is protective against sexually transmitted diseases and, thus, some kinds of cancer (e.g., penile and cervical malignancies) can also be prevented because their causative etiologies have been shown to be associated with these infections.(9-12) there is substantial uncertainty about the psychological effects of circumcision on boys. the procedure has been blamed for causing psychological trauma that persists for a long time.(8,13,14) research evaluating fear of circumcision has not been tested yet. fear is a negative emotion. since it is a subjective complaint, it is hard to document the degree of fear accurately. however, there are two instruments validated to assess the degree of fear in children; these are the children's fear scale (cfs) and the venham picture test (vpt).(15,16) in this study our aim was to measure fear of circumcipediatric urology 2542 fear of circumcision-sancar et al. sion in boys aged 3–11 years just before, immediately after, and the 10th day after the operation. we studied to find out if the fear disappeared within ten days. materials and methods study population the study was designed as a case-control study. study participants in the operation group consisted of children who were admitted for circumcision at outpatient clinics of a hospital between june 2013 and september 2013. the control group was composed of children who were interviewed in places other than a hospital. none of the control patients has been circumcised. the cfs and the vpt were administered by face-to-face interviews. the cfs is a modified version of a test used in adults.(15) the test consists of 5 images of faces. the first image is normal, followed by images of fearful faces of increasing intensity. the children were asked to choose the face that show how scared they were. children pointing to the first image were given 0 points, and the other images were scored in order as 1, 2, 3 and 4 points. the vpt is another instrument developed to assess anxiety in children.(16) the test consists of eight pairs of pictures, in which one child is afraid, and one child is not afraid. children choosing the fearful image were given 1 point. otherwise, no point was given. all eight pictures were shown to each child. the total scores obtained for the eight pictured were used in the analysis. the boys’ height and weight were measured when they were wearing light clothes. body mass index (bmi) values were calculated using these data (bmi = weight/ height2). data on parental education and self-reported economic status were obtained. any plan of celebration related to circumcision is noted. the main reason ‘why the child was admitted for circumcision’ was classified as religious, hygienic or both. at the end of the interviews, the boys were asked (a) if they had been told why they had been taken to hospital, and (b) ‘what circumcision meant?’ statistical analysis statistical analysis of the data was performed by the statistical package for the social science (spss inc, chicago, illinois, usa) version 20. statistical significance was defined as results with p < .05. the distribution of age, height and weight was similar to the normal distribution. the means and standard deviation were calculated, and analyzes of these measures were made by parametric tests: student’s t-test and pearson correlation coefficient. since the results of the cfs and the vpt were not normally distributed, analyzes of these scales were conducted by nonparametric tests: the mann-whitney u test for independent samples; and the wilcoxon sign test for dependent variables. pearson’s correlation was used to examine a relationship between the variables. the χ² test was used to analyze categorical variables. linear regression analysis was performed to determine the extent to which there is a linear relationship between variables. ethics ethical approval for the study was obtained from sevket yilmaz education and research hospital. all the participants were informed about the study, and written permission was obtained from parents. exclusion criteria the exclusion criteria excluded boys who underwent another operation at the same time as circumcision. boys who were not 3–11 years of age, and participants who did not come for the second visit (10th day) were also excluded from the study. results there were 100 boys in the circumcised group and 99 boys in the control group. age (z = 1.229, p = .098), table 1. age distribution of participants. age (years) boys circumcised controls no. % no. % 3 3 3.0 3 3.0 4 5 5.0 5 5.1 5 6 6.0 6 6.1 6 19 19.0 19 19.2 7 24 24.0 24 24.2 8 19 19.0 19 19.2 9 13 13.0 13 13.1 10 8 8.0 8 8.1 11 3 3.0 2 2.0 total 100 100.0 99 100.0 variables religious religious and statistical reasons medical reasons analysis children’s fear 1.08 ± 1.35 1.82 ± 1.57 χ2 = 4.71 p = .030 scale scores* venham picture 2.02 ± 2.43 2.19 ± 2.34 χ2 = .26 p = .612 test scores* *arithmetic mean ± sd. table 2. relationship between reasons for circumcision and pre-op children’s fear scale scores. vol 13 no 01 january-february 2016 2543 height (z = .986, p = .285) and weight (z = .787, p = .566) values of two groups have normal distribution. mean differences in the ages, heights, and weights were not statistically significant (student’s t-test, p > .05). age distribution of the boys was shown in table 1. the educational levels of parents were similar between boys in the operation and control groups (χ² = 2.110, sd = 4, p = .716). self-reported economic status was also similar in both groups. (χ² = 3.844, sd = 2, p = .146). the difference between pre-operation and control group scores on the cfs was statistically significant (p < .001), according to the mann-whitney u test, with the boys in the operation group exhibiting more fear than the controls. however, pre-operation scores were not significantly different from scores obtained immediately after the operation (wilcoxon, z = -1.34, p = .181). children’s fear scale scores measured before (wilcoxon sign test, z = -5.59, p = .000) and immediately after the operation (wilcoxon sign test, z = -5.31, p = .000) were significantly different from scores obtained on the 10th day after the operation. the relationship between the cfs scores and the boys’ ages were examined using the pearson correlation. age was not correlated with the pre-operation scores of the operation group or the control group’s scores (p > .05). cfs scores right after the operation were negatively correlated with age (rs = -.241, p = .018), with older boys being was less afraid. a similar correlation, which is shown in figure, was also found between age and fear when the boys were tested on the 10th day (rs = -.249, p = .016), children’s fear scale scores and bmi were positively correlated (rs = .638, p = .000). this association was analyzed by regression analysis and the effect of bmi on fear scores was found to be dependent on age. the bmi alone was not significantly related to the fear scores (r2 = .107, t = 1.785, p = .080). when the answers about the reasons for circumcision were analyzed, the boys who came to have circumcision solely because of religious reasons were found to be less fearful compared with the boys who were brought to surgery for both religious and medical reasons (p < .05) (table 2). the celebration program for circumcision was not associated with fear of the child (p > .05). paternal education also was not associated with the boys’ fear (p > .05). total fear scores of the vpt of boys whose families were in the higher economic level were higher than those of boys from low-income families (p < .05) (table 3). there was no significant difference between the operated group and the control group on the vpt (p > .05). a comparison of fear before the operation and right after the operation revealed a statistical significance difference, as measured by the vpt (wilcoxon sign test, z = -2.35, p = .019). fear on the 10th day after circumcision was significantly lower than it was before the operation (wilcoxon sign test, z = -5.76, p = .000) or immediately after the operation (wilcoxon sign test, z = -5.30, p = .000), as measured by the vpt. the vpt scores were not associated with the bmi values of the boys (rs = -.044, p = .735). the fear scores of boys who knew the reason were not different from the scores of boys who did not know the reason (p > .05). boys who knew what circumcision were less afraid of the operation compared with those variables self-reported income (low) self-reported income (moderate to high) statistical analysis children’s fear scale scores* 0.77 ± 1.16 .93 ± 1.33 χ2 = 3.04 p = .081 venham picture test scores* 1.24 ± 1.63 1.92 ± 2.19 χ2 = 4.80 p = .028 *arithmetic mean ± sd. table3. effect of economic status on pre-op children’s fear scale scores. variables aware unaware statistical analysis children’s fear scale 0.96 ± 1.34 1.83 ± 1.53 u = 717.0 p = .003 venham picture test 1.47 ± 2.19 2.90 ± 2.42 u = 709.5 p = .002 table 4. relationship between pre-op fear scores and awareness about circumcision. figure. the relationship of 10th day fear scores and age of boys. fear of circumcision-sancar et al. who did not know anything about the procedure (table 4). discussion we have found that fear of circumcision vanished in ten days. boys who were circumcised had similar fear scores on the 10th day as the controls, who were interviewed outside of hospital settings and were not circumcised. these results indicate that circumcision does not cause a long-lasting fear for the children. children who knew ‘what the circumcision meant’ were less fearful compared with the rest of the study group. this result supports the idea that pre-operative educational information helps to overcome patients’ anxiety.(17-19) the information on circumcision can be provided by families, doctors or other educated healthcare stuff. obesity has been shown to be related to psychological problems such as anxiety and depression.(20-22) in the present study, we have shown that there was a link between fear and bmi. but, this relation was found to be age dependent. further investigations are needed to evaluate if there were a relationship between obesity and frightfulness in children. in western countries, circumcision is performed mainly for hygienic reasons. sahin and colleagues have shown that circumcision in turkey was mainly preferred because of religious and traditional beliefs.(23) in our study, the primary reason for admission for circumcision was also religious, and the reason for the remaining boys was a combination of religious and hygienic factors; no admissions were made solely for medical reasons among the participants. boys admitted for circumcision partially for medical reasons had higher fear scores, which could be associated with previous medical treatments. for example, boys suffering from phimosis might have experienced painful treatments such as forcing the foreskin to retract. the fear scores of boys ≥ 6 years of age were the lowest compared with other age groups. thus, a recommendation to perform circumcision at ages six years of age or older seems more reasonable. circumcision at earlier ages is preferred in most of the countries like the united states, but boys may be more fearful if the procedure is performed at these earlier ages. even in the absence of crying, body signals show that neonates experience pain during circumcision.(24) hence, it may be better to delay circumcision until the school-age years. conclusions in conclusion, fear of circumcision is not a persistent problem, and it decreases significantly within ten days. pre-operative educational information about the procedure may help children to be less afraid of circumcision. conflict of interest none declared. references 1. introcaso ce, xu f, kilmarx ph, zaidi a, markowitz le. prevalence of circumcision among men and boys aged 14 to 59 years in the united states, national health and nutrition examination surveys 2005-2010. sex transm dis. 2013;40:521-5. 2. owings m, uddin s, williams s. trends in circumcision for male newborns in us hospitals. 1979-2010. available at: http://www.cdc.gov/nchs/data/hestat/ circumcision_2013/circumcision_2013.pdf. accessed january 29, 2015. 3. yavuz m, demir t, dogangün b. [the effect of circumcision on the mental health of children: a review]. turk psikiyatri derg. 2012;23:63-70. 4. lawler fh, bisonni rs, holtgrave dr. circumcision: a decision analysis of its medical value. fam med. 1991;23:587-93. 5. american academy of pediatrics task force on circumcision. male circumcision. pediatrics. 2012;130:756-85. 6. american academy of pediatrics task force on circumcision. circumcision policy statement. pediatrics. 2012;130:585-6. 7. svoboda js, van howe rs. out of step: fatal flaws in the latest aap policy report on neonatal circumcision. j med ethics. 2013;39:434-41. 8. morris bj, wodak ad, mindel a, et al. the 2010 royal australasian college of physicians’ policy statement ‘circumcision of infant males’ is not evidence based. intern med j. 2012;42:822-8. 9. morris bj. why circumcision is a biomedical imperative for the 21(st) century. bioessays.2007;29:1147-58. 10. bleeker mc, heideman da, snijders pj, horenblas s, dillner j, meijer cj. penile cancer: epidemiology, pathogenesis and prevention. world j urol. 2009;27:141-50. 11. morris bj, gray rh, castellsague x, et al. the strong protective effect of circumcision against cancer of penis. adv urol. 2011;2011:812368. 12. albero g, castellsague x, giuliano ar, bosch fx. male circumcision and genital human papillomavirus: a systematic review and metaanalysis. sex transm dis. 2012;39:104-13. 13. boyle gj, goldman r, svoboda js, fernandez e. male circumcision: pain, trauma and psychosexual sequelae. j health psychol. 2002;7:329-43. 14. cansever g. psychological effects of fear of circumcision-sancar et al. pediatric urology 2544 vol 13 no 01 january-february 2016 2545 circumcision. br j med psychol. 1965;38:32131. 15. mcmurtry cm, noel m, chambers ct, mcgrath pj. children’s fear during procedural pain: preliminary investigation of the children’s fear scale. health psychol. 2011;30:780-8. 16. venham ll, gaulin-kremer. a self-report measure of situational anxiety for young children. pediatr dent. 1979;1:91-6. 17. milenin vv, tolasov kr, ostreikov if. efficiency assessment of preoperative preparatory programs in pediatric patients in dentistry. anesteziol reanimatol. 2013;1:4-7. 18. murphy-taylor c. the benefits of preparing children and parents for day surgery. br j nurs.1999;8:801-4. 19. frisch am, johnson a, timmons s, weatherford c. nurse practitioner role in preparing families for pediatric outpatient surgery. pediatr nurs. 2010;36:41-7. 20. esposito m, gallai b, roccella m, et al. anxiety and depression levels in prepubertal obese children: a case-control study. neuropsychiatr dis treat. 2014;10:1897-902. 21. de wit l, luppino f, van straten a, penninx b, zitman f, cuijpers p. depression and obesity: a meta-analysis of community-based studies. psychiatry res. 2010;178:230-5. 22. luppino fs, de wit lm, bouvy pf,et al.overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. arch gen psychiatry. 2010;67:220-9. 23. sahin f, beyazova u, aktürk a. attitudes and practices regarding circumcision in turkey. child care health dev. 2003;29:275-80. 24. goldman r. the psychological impact of circumcision. bju int. 1999;83:93-102. fear of circumcision-sancar et al. impact of sexual activity on glycated hemoglobin levels in patients with type 2 diabetes mellitus after penile prosthesis implantation department of urology, hamad general hospital, doha, qatar. corresponding author: onder canguven, md department of urology, hamad general hospital, andrology clinic, 3050, doha, qatar. tel: +974 44391864 fax: +974 44391842 cell phone: +974 77154697 e-mail: ocanguven@yahoo. com received august 2013 accepted april 2014 purpose: to examine the benefits of sexual activity on glycated hemoglobin (hba 1c )in penile prosthesis implanted patients with type 2 diabetes mellitus (dm). materials and methods: sixty-seven male subjects who had hba 1c levels of ≥ 6.5% before and could perform regular sexual activity after the implantations were enrolled. the contribution of sexual activity on glycemic control assessed by hba1clevel as well as age, duration of dm and frequency of sexual activity were evaluated. results: mean age and mean time from the surgery of the study patients was 59.9 years (range,30-82) and 22.6 months (range, 10-63), respectively. the average of penile prosthesis usage for sexual activity was 9.9 times per month (range, 2-28). compared with the preimplantation, the absolute mean change in hba 1c after penile prosthesis implantation was found as 0.2% (p > .05). this study also revealed that more sexual activity was associated with more reduction in hba 1c . conclusion: the present study demonstrated that sexual activity is associated with hba 1c reduction, which is clinically important in patients with type 2 dm after penile prosthesis implantation. keywords: erectile dysfunction; surgery; penile implantation; diabetes complications; hemoglobin a, glycosylated; metabolism. 1813 sexual dysfunction and fertility raidh a. talib, onder canguven, abdulla al ansari sexual dysfunction and fertility urology journal vol. 11 no. 04 july august 2014 1814 impact of sexual activity on hba 1c levels-talib et al 8-12 weeks. we asked global satisfaction question (gsq) “did the implant permit you to experience satisfactory sexual relations?” and a frequency question “how many times do you use your pp for sexual activity each month?” to all participants at the time of their participations. institutional review board approved this study and all the participants provided written informed consent before participation. statistical analysis qualitative and quantitative data values were expressed as frequency (percentage) and mean ± sd. quantitative variables means between preand post-surgery groups were compared using paired t-test. pearson correlation coefficient was used to examine and assess the linear relationship between the two quantitative variables. a two-sided p value < .05 was considered to be statistically significant. all statistical analyses were done using statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. results mean age of study patients was 59.9 ± 10.9 years (range, 30-82) (table). mean duration of dm and ed problem was 11.7 ± 3.4 years and 2.7 ± 1.9 years, respectively. the mean time from surgery was 22.6 months (range, 7-36). for gsq, all 67 patients responded as ‘yes’. for frequency question, 64 patients (95.5%) responded to use it frequently, while three (4.5%) declared they use it rarely because of partner related problems. the average of pp usage for sexual activity was 9.9 ± 5.7 times per month (range, 2-28). the average of sexual activity time was 22.5 ± 7.5 minutes (range, 10-40). paired t-test revealed that mean hba 1c at post-surgery was found to lowering of 2.5% (i.e. -0.2% in hba 1c ) compared to pre-surgery (8.3 ± 1.7% vs. 8.5 ± 1.9%). however, this difference was not statistically significant (p = .479). on the other hand, higher baseline levels of hba 1c were associated with greater hba 1c reductions after sexual activity (r = −0.52, p < .05). further, pearson’s correlation analysis revealed that variable monthly intercourse were inversely or negatively related to hba 1c and age (correlation coefficient r = -0.08; r = -0.185, respectively), again this correlation coefficient values were not statistically significant (p = .626; p = .260). there were also no significant changes in patients’ medications for dm (insulin or other oral medications) in the last two years. discussion in this study, we found that sexual activity produced a reduction of 2.5% in hba 1c level after pp usage in patients with type 2 dm. although the decrease in hba 1c was low compared to different exercise types that were analyzed in previous meta-analysis studies,(7,12,13) the clinical implications might be actually more than that according to studies investigating natural history of dm after exercise.(14,15) according to the united kingdom prospective diabetes study,(14) exercise therapy can cause a hba 1c lowering of -0.9% and may reduce retinopathy, nephropathy, and neuropathy in type 2 dm patients. moreover, the overall microvascular complication rate was decreased by 25%, and there was a 25% reduction in dm related deaths, a 7% reduction introduction diabetes mellitus (dm) is one of and may be the most im-portant risk factor for erectile dysfunction (ed). the cur-rent estimates suggest that as many as 85% of men with dm will develop some degree of ed at an earlier age.(1) many of patients with ed have not had a normal erection in many months or years. penile prosthesis (pp) implantation is the final and satisfying treatment option for patients who have ed and failed in the first and second line treatments. in different patient satisfaction studies it was shown that, of the pp implanted men more than 90% stated they were still using the pp for sexual intercourse with an average frequency of coitus of 5 times monthly.(2-4) nearly thirty years ago, it was shown that the metabolic expenditures during stimulation and orgasm were about 3.3 mets (mets are a measurement of the body’s capacity to utilize oxygen for a given workload, 3.5 ml/kg/min = 1 met).(5) another study also demonstrated that the heart rate and blood pressure responses to both sexual activity and stair climbing were similar.(6) in general, glycated hemoglobin (hba 1c ) is used to monitor blood glucose levels for the last 3 months’ average. recent studies provided convincing evidence that structured exercise training that consists of aerobic exercise, resistance training, or both combined is associated with hba 1c reduction in diabetic patients.(7,8) in agreement with the findings of single controlled studies, meta-analyses also confirmed that regular exercise improves glucose control and reduction in hba 1c obviously seen in dm.(9,10) although evidence supports the concept that average sexual activity ranks as mild to moderate in terms of exercise intensity,(11) the association of sexual activity on serum hba 1c levels after pp implantation is unclear. the aim of this study was to examine the influence of sexual activity on hba 1c levels after pp implantation in type 2 dm patients. materials and methods we retrospectively analyzed medical records from computer files of patients that underwent pp implantation surgery from january 2010 through january 2013. enrollment and data collection were conducted at follow-up visits at least 6 months and up to 3 years after implantation. sixty-seven male subjects who had hba 1c levels of ≥ 6.5% and active sexual life with aid of pp were enrolled in the study. given the long duration of the sexual activity period in present study, changes in hba 1c would be representative and were therefore chosen as an outcome measure. the principal eligibility criteria included patients who had a regular sexual intercourse with his wife after pp implantation surgery. any kind of cancer disease, myocardial infarction or stroke within 6 months, or congestive heart failure and severe renal or hepatic diseases comprised major exclusion criteria. fasting blood samples were obtained between 7-9 am in the morning. serum hba 1c levels were measured by standard radioimmunoassay kits. we limited the usage of pp for intercourse at least 6 months, since our main outcome of interest, hba 1c , reflects average blood glucose concentration from the previous durations of ≤ 150 minutes per week were associated with less hba 1c reductions (-0.36%).(10) more recently, umpierre and colleagues found that each aerobic exercise session added within a week might produce an additional reduction (-0.39%) in hba 1c level.(9) moreover, it has been suggested that aerobic training at a higher intensity results in a larger improvement in endothelial function.(8) in 2001, boule and colleagues published a meta-analysis showing beneficial effects of exercise training on one aspect of glucose control in diabetic patients, the percent of hba 1c in blood.(13) in that meta-analysis, investigators demonstrated that post-intervention hba 1c values were significantly reduced in the exercise groups compared with control groups while body mass was not.(13) we reported here for the first time the clinical correlates of hba 1c level after pp usage in type 2 dm. despite its practical value, our study has limitations. first, because of the observational nature of our cohort, our findings must be interpreted within the context of the limitations applicable to observational, retrospective data. a further limitation is the lack of objective data on daily physical activity and diet of patients. it should be pointed out that information on general daily activity and diet was subjective. although the study patients mentioned that their lifestyle did not change, they did not have any diary for activities and diet. it is obvious that sexual activity requires mild to moderate effort compared with daily activities. in this study, we demonstrated that sexual activity and intercourse by the aid of pp is associated with improved glycemic control in type 2 dm patients in this study. from a useful standpoint, our findings also implied that more sexual activity was associated with more reduction in hba 1c . the results of previous literature findings suggested that even small decrease in hba 1c could make invaluable decrease in microvascular complication rates, retinopathy, nephropathy, and neuropathy in type 2 dm patients in long term. conclusion we believe that our study using hba 1c added support to the hypothesis that sexual activity helps to decrease hba 1c in type 2 dm patients with pp. however, future researches are warranted with larger prospective design on different parameters of body composition changes. in all-cause mortality, and an 18% reduction in combined fatal and non-fatal myocardial infarction.(14) in a meta-analysis study, investigators confirmed that exercise training reduces hba 1c (-0.66%), an amount that would be expected to reduce the risk of diabetic complications significantly.(13) a previous study reported that long term aerobic exercise training can modify the natural history of peripheral diabetic neuropathy or even prevent its onset.(15) it is noteworthy that in the latter study by balducci and colleagues the difference in hba 1c values between two groups through the 4 years of the study was only -0.4%.(15) earlier studies provide convincing evidence that all forms of exercise training produce less or more benefits in the main measure of glucose control.(12) although it is well known that exercise is good for type 2 dm patients, which type exercise, aerobic or resistance, is better not known exactly. in a 2006 meta-analysis in which 27 controlled trials were evaluated, snowling and hopkins found that there were clear reductions (overall -0.8%; range, -0.1%-3.1%) in hba 1c with different (aerobic, resistance and combined training) exercise models. (12) the decrease in hba 1c levels is sometimes much more than the average calculated in meta-analysis studies. for example, in a single randomized controlled study with a younger age group, it was shown that there could be up to 29% decrease (-3.1 ± 1.0%) in hba 1c levels after aerobic exercise in dm patients.(16) although boudou and colleagues showed highest decrease in hba 1c in literature, limitation of their study was small population in that they had just ten patients in each arm of study and control groups.(16) although sexual activity might not be as intense as other exercises, it can be accepted as a kind of aerobic activity. fascinatingly, it was shown that peak heart rate could increase nearly to 140 per minute during sexual activity in healthy adults.(11) recently, a review of 26 randomized clinical trials confirmed that aerobic training and exercise volume (represented by frequency of sessions) was associated with changes in hba 1c , while no variables were correlated with glycemic control induced by resistance training.(9) reduction in hba 1c is associated with exercise frequency in supervised aerobic training, and with weekly volume of resistance exercise in supervised combined training. (9) it was confirmed that reduction in hba 1c is associated with exercise frequency in supervised aerobic training, and with weekly volume of resistance exercise in supervised combined training.(9) in agreement with the findings of other studies sought for change in hba 1c with exercise training, our findings showed that there was a reduction in hba 1c level after sexual activity with pp usage in patients with type 2 dm. an important observation of our study was that monthly intercourse frequency was inversely related to hba 1c reduction. although the correlation was statistically insignificant, the clinical relevance of this correlation should not be underestimated. pioneer studies on effects of exercise frequency on glucose control and related physiological parameters have been extensively studied in patients with type 2 dm.(9,14) in a systematic review article, it was shown that structured exercise durations of > 150 min per week were associated with hba 1c reductions (-0.89%), while structured exercise variables mean ± sd age (years) 59.9 ± 10.9 history of dm (years) 11.7 ± 3.4 history of ed (years) 2.7 ± 1.9 mean time from surgery (months) 22.6 ± 6.8 pp usage for sexual activity (months) 9.9 ± 5.7 average of sexual activity time (min) 22.5 ± 7.5 hba 1c ; before pp usage (%) 8.5 ± 1.9 hba 1c ; after pp usage (%) 8.3 ± 1.7 table. baseline demographics and clinical characteristics of study subjects. abbreviations: sd, standard deviation; dm, diabetes mellitus; ed, erectile dysfunction; pp; penile prosthesis implantation; hba 1c ; glycated hemoglobin. 1815 sexual dysfunction and fertility urology journal vol. 11 no. 04 july august 2014 1816 n engl j med. 1993;329:977-86. 15. balducci s, iacobellis g, parisi l, et al. exercise training can modify the natural history of diabetic peripheral neuropathy. j diabetes complicati ons. 2006;20:216-23. 16. boudou p, de kerviler e, vexiau p, fiet j, cathelineau g, gautier j. effects of a single bout of exercise and exercise training on steroid levels in middle-aged type 2 diabetic men: relationship to abdominal adipose tissue distribution and metabolic status. diabetes metab. 2000;26:450-7. acknowledgement a grant from the hamad medical corporation primarily supported this research. we would also like to acknowledge the careful work of dr. prem chandra for his assistance with the statistics used in this study. conflict of interest none declared. references 1. de berardis g, franciosi m, belfiglio m, et al. erectile dysfunction and quality of life in type 2 diabetic patients: a serious problem too often overlooked. diabetes care. 2002;25:284-91. 2. lux m, reyes-vallejo l, morgentaler a, levine la. outcomes and satisfaction rates for the redesigned 2-piece penile prosthesis. j urol. 2007;177:262-6. 3. carson cc, mulcahy jj, govier fe. efficacy, safety and patient satisfac tion outcomes of the ams 700cx inflatable penile prosthesis: results of a long-term multicenter study. ams 700cx study group. j urol. 2000; 164:376-80. 4. bettocchi c, palumbo f, spilotros m, et al. patient and partner satisfacti on after ams inflatable penile prosthesis implant. j sex med. 2010;7:304 9. 5. bohlen jg, held jp, sanderson mo, patterson rp. heart rate, rate-pres sure product, and oxygen uptake during four sexual activities. arch in tern med. 1984;144:1745-8. 6. larson jl, mcnaughton mw, kennedy jw, mansfield lw. heart rate and blood pressure responses to sexual activity and a stair-climbing test. heart lung. 1980;9:1025-30. 7. church ts, blair sn, cocreham s, et al. effects of aerobic and resistance training on hemoglobin a1c levels in patients with type 2 diabetes: a randomized controlled trial. jama. 2010;304:2253-62. 8. da silva ca, ribeiro jp, canto jc, et al. high-intensity aerobic training improves endothelium-dependent vasodilation in patients with metabolic syndrome and type 2 diabetes mellitus. diabetes res clin pract. 2012;95:237-45. 9. umpierre d, ribeiro pa, schaan bd, ribeiro jp. volume of supervised exercise training impacts glycaemic control in patients with type 2 diabe tes: a systematic review with meta-regression analysis. diabetologia. 2013;56:242-51. 10. umpierre d, ribeiro pa, kramer ck, et al. physical activity advice only or structured exercise training and association with hba1c levels in type 2 diabetes: a systematic review and meta-analysis. jama. 2011;305:1790-9. 11. rerkpattanapipat p, stanek ms, kotler mn. sex and the heart: what is the role of the cardiologist? eur heart j. . 2001;22:201-8. 12. snowling nj, hopkins wg. effects of different modes of exercise trai ning on glucose control and risk factors for complications in type 2 dia betic patients: a meta-analysis. diabetes care. 2006;29:2518-27. 13. boule ng, haddad e, kenny gp, wells ga, sigal rj. effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-a nalysis of controlled clinical trials. jama. 2001;286:1218-27. 14. the diabetes control and complications trial research group. the ef fect of intensive treatment of diabetes on the development and progres sion of long-term complications in insulin-dependent diabetes mellitus. impact of sexual activity on hba 1c levels-talib et al urological oncology tissue chromogranin a expression during prostate cancer progression: prediction of chemosensitivity yozo mitsui,1* naoko arichi,1 miho hiraki,1 yuji harada,2 hiroaki yasumoto,1 hiroaki shiina1 purpose: we investigated the clinical significance of chromogranin a (cga) expression as a neuroendocrine (ne) marker during prostate cancer (pca) progression, especially as a potential predictor of chemotherapeutic response in castration-resistant pca (crpc) patients based on immunohistochemical findings. materials and methods: sixteen crpc patients who underwent combination (docetaxel/estramustine/ carboplatin; dec) chemotherapy were retrospectively studied. immunostaining of cga was performed using prostate biopsy samples obtained at the initial pca diagnosis, during androgen deprivation therapy, at the time of crpc diagnosis, and after 2 cycles of dec therapy. the positive rate was expressed as the mean percentage of positively stained tumor cells against the total number of tumor cells. differences in positive rates among the treatment courses were compared using a mann-whitney test. results: the mean percentage of cga-positive pca cells increased in a stepwise manner until crpc development and then significantly decreased after dec therapy. subanalysis of cga at crpc diagnosis showed a more evident reduction of cga expression after dec therapy in patients who also had a high level of cga as compared to those with a low cga level (p = .003). likewise, longer prostate-specific antigen progression-free survival was related to crpc and high cga (p = .028). conclusion: ne differentiation of pca cells is accelerated despite androgen deprivation and reaches a peak at the time of crpc diagnosis. although further studies using larger samples are needed, cga expression in crpc may be a candidate tissue biomarker to reflect the chemotherapy sensitivity of individual pca cells. keywords: prostatic neoplasms; castration-resistant; neuroendocrine cells; chromogranin a; blood. introduction the normal human prostate is histologically com-posed of tubular and/or alveolar glands, with luminal basal and secretory cells and stromal components. neuroendocrine (ne) cells are dendritic intraepithelial cells known to regulate both prostatic growth and differentiation,(1) thus it is not surprising that they are actively involved in the process of prostate disease. (2) indeed, focal ne differentiation represents a common feature of prostate cancer (pca) and occurs in 30-100% of reported cases. a synergistic functional network between epithelial prostate-specific antigen (psa) secretory cells and the ne intra-prostatic system is the main trigger for induction and sustenance of ne differentiation.(3-5) chromogranin a (cga), ne-derived peptide, and levels in both serum and tissue are considered to be an excellent ne marker.(6) ne cells are thought to be resistant to androgen deprivation due to lack of an androgen receptor. previous studies have indicated that ne-positive cells in the prostate can survive and are likely to be activated in response to androgen deprivation.(4,7,8) thus, ne differentiation is believed to contribute to development of castration-resistant prostate cancer (crpc).(9,10) in addition, previous studies have shown that prostatic ne differentiation is closely associated with tumor progression and poor clinical outcome.(11-13) however, few reports have addressed the issue of active changes of ne differentiation in pca tissues obtained from the same individual. taxane-based chemotherapy has become a standard first-line therapy for crpc,(14,15) while platinum-based chemotherapy has a cytotoxic effect on ne cells.(16,17) therefore, combination chemotherapy with taxane and a platinum derivative is considered to be an attractive approach for treating patients with crpc, in whom ne-positive pca cells are likely to be activated. indeed, we previously reported excellent clinical outcomes with such a chemotherapy combination (docetaxel /estramustine /carboplatin; dec therapy) in patients with crpc.(18) based on the hypothesis that cancer cells with ne differentiation are actively involved in the process of castration resistance in pca and sensitive to platinum-based chemotherapy, we considered that analysis of ne differentiation of pca cells would contribute to prediction of therapeutic response and survival benefit in crpc patients treated with dec therapy. the purpose of this study was to evaluate tissue alterations of cga in the same individuals during their treatment course; namely at initial diagnosis, during androgen deprivation therapy (adt), at the time of diagnosis of crpc, and after 2 cycles of dec 1 department of urology, shimane university school of medicine, 89-1 enya-cho, 693-8501 izumo, japan. 2 department of surgical pathology, shimane university school of medicine, 89-1 enya-cho, 693-8501 izumo, japan. *correspondence: department of urology, shimane university school of medicine, 89-1 enya-cho, 693-8501 izumo, japan. tel: +81 853 202256. fax: +81 853 202250. e-mail: mitsui@med.shimane-u.ac.jp. received november 2014 & accepted april 2015 vol 12 no 03 may-june 2015 2165 chemotherapy. in addition, we assessed whether the expression of cga in affected tissues is a potential predictor of chemotherapeutic response in crpc patients. materials and methods patient selection for this retrospective analysis, we examined data obtained from 53 crpc patients who underwent dec therapy between october 1999 and april 2005 at our institution. patients were evaluated for response using samples from systematic sextant biopsies of the prostate at the time of crpc diagnosis and after 2 cycles of dec therapy. access for the biopsy was transrectal and the bioptic scheme included a minimum of 8 peripheral cores. we excluded 35 patients who did not undergo a prostatic biopsy at the initial pca diagnosis performed at our institution and 2 who did not undergo that after 2 cycles of dec therapy, yielding a 16-patient cohort. figure 1 diagrams the times of biopsy, the number of patients in this cohort for analysis and the number of ineligible patients. among these 16 patients, 7 underwent several prostate biopsies at the initial pca diagnosis, during adt, at crpc diagnosis, and after 2 cycles of dec chemotherapy, while the remaining 9 underwent prostate biopsies at the same time points, except for during adt. informed written consent was obtained from all patients after receiving institutional review board approval. all study protocols were approved by the ethics committee of shimane university faculty of medicine in accordance with the 1975 declaration of helsinki (20140919-2). treatment regimen of dec therapy eligibility criteria for dec chemotherapy were as follows: 1) eastern cooperative oncology group performance status (ps) score of 0-3; 2) baseline leukocyte count greater than 3000/μl; 3) hemoglobin 8.0 g/dl or greater; 4) platelet count exceeding 100,000/ μl; 5) adequate renal function defined as serum creatinine 1.5 times or less than the upper limit of normal (uln); 6) adequate liver function defined as bilirubin less than uln and aspartate transaminase less than 1.5 times uln, 7) adequate cardiac function; 8) life expectancy of more than 3 months; and 9) more than 8 weeks elapsed since any major surgery, radiotherapy, or prior chemotherapy. the dec therapy was comprised of weekly intravenous administrations of docetaxel at 30 mg/m2, daily oral estramustine at 10 mg/m2, and intravenous carboplatin every 28 days to reach an area under the curve value of 6 on day 1 of every 4-week cycle.(18) crpc was defined as three increases in the psa level at least 1 month apart, or evidence of a new clinical disease despite discontinuation of antiandrogen (androgen withdrawal) medication.(19) during dec therapy, ongoing adt was also applied. pretreatment evaluation procedures included medical history, physical examination, complete blood count, and chemistry profile, serum psa, alkaline phosphatase, and lactate dehydrogenase levels, 24-hour creatinine clearance, and 12-lead electrocardiogram, chest x-ray, bone scintigraphy, computerized tomography (ct) scan, and magnetic resonance imaging findings. treatment was continued until disease progression, an unacceptable adverse event, or patient refusal occurred. clinical evaluation of dec therapy response rate was determined according to standard phase ii response criteria(19) on the basis of imaging findings, including chest x-ray, ct scan, and bone scintigraphy, at least every 8 weeks for 4 cycles. complete response (cr) was defined as complete disappearance of all disease and partial response (pr) as ≥ 50% reduction in the sum of the values for the perpendicular diameters of all lesions. stable disease (sd) was defined as < 50% reduction or ≤ 25% increase in the sum of the values for the perpendicular diameters of all lesions. since changes in intensity or sizes of osseous lesions using bone scanning are difficult to interpret, the appearance of 1 or more new osseous lesions was required on bone scans to identify progressive disease. psa levels were measured every 4 weeks. psa progression was defined as 3 consecutive increases in that level of at least 50% over the nadir value at a minimum of 4 ng/ ml. time to psa progression was calculated from the first day of crpc treatment to the final day of the study or evidence of progressive disease. cause-specific survival was determined from the initiation of dec therapy to the day of death or last follow-up examination. immunohistochemistry biopsy samples were fixed in 10% buffered formalin (ph 7.0) for 12 hours and embedded in paraffin wax, then 5 consecutive 5 μm sections were cut from each block and used for hematoxylin and eosin staining for variables n = 16 age (years), median (range) 72 (52-86) performance statues, no (%) 0-1 12 (75.0) 2-3 4 (25.0) psa value at initial pca diagnosis, ng/ml median (range) 142.4 (0.8-6113.9) gleason score, no (%) 7 3 (18.7) 8 2 (12.5) 9 11 (68.8) duration of initial hormone therapy, months median (range) 18.6 (4.1-50.7) measurable extraosseous disease, no (%) negative 7 (43.8) positive 9 (56.2) lymph nodes 7 liver 3 lung 2 osseous disease, no (%) negative 2 (12.5) positive 14 (87.5) hormone therapy, no (%) maximum androgen blockade 16 (100) lh-rh analogue 11 (68.8) surgical castration 5 (31.2) table 1. demographic and clinical characteristics of 16 patients. abbreviations: psa, prostate specific antigen; pca, prostate cancer; lhrh, luteinizing-hormone releasing hormone. cga expression as predictive marker for pca-mitsui et al. urological oncology 2166 table 2. correlation of neuroendocrine differentiation with gleason score and serum psa value. variables mean cga expression ± sd (range) p value initial pca diagnosis gleason score ≦ 8 (n = 5) 8.24 ± 6.97 (0-17.05) .610 ＞ 8 (n = 11) 6.73 ± 5.22 (1.55-17.65) psa value, ng/ml ≦ 142.4 (n = 8) 8.26 ± 5.74 (0-17.65) .345 ＞ 142.4 (n = 8) 6.14 ± 5.05 (1.55-17.05) crpc diagnosis gleason score ≦ 8 (n = 5) 15.17 ± 5.88 (10.50-25.05) .428 ＞ 8 (n = 11) 19.69 ± 10.20 (10.10-41.45) psa value, ng/ml ≦ 91.7 (n = 8) 20.54 ± 11.52 (10.50-41.45) .462 ＞ 91.7 (n = 8) 16.02 ± 5.85 (10.10-25.05) abbreviations: pca, prostate cancer; psa, prostate specific antigen; crpc, castration resistant pca; cga, chromogranin a. variables high cga group (n = 8) low cga g roup (n = 8) p value age (years), median 72.0 72.5 .495 ps, median (range) 0.5 (0-3) 1 (0-3) .350 gleason sum, median 9 9 .590 duration until crpc (days), median 545 557 .833 laboratory data, median (range) hemoglobin (g/dl) 12.9 (10.5-14.8) 11.1 (9.1-14.3) .120 alp (iu/l) 312.5 (180-466) 350.5 (286-536) .216 ldh (iu/l) 203.5 (132-447) 222.5 (161-732) .418 ca++ (mg/dl) 9.3 (8.9-9.7) 9.3 (8.2-9.6) .512 psa value (ng/ml), median initial pca diagnosis 358.7 142.4 .833 crpc diagnosis 35.9 129.6 .074 after 2 cycles of chemotherapy 1.7 7.7 .156 psa decrease after 2 cycles of chemotherapy no (%) 90 or greater 50.0 (4/8) 50.0 (4/8) ----clinical outcome of measurable disease pr + cr no (%) lymph nodes 80.0 (4/5) 100 (2/2) .495 liver 100 (1/1) 100 (2/2) ---- lung 100 (2/2) ---- ---- bone 14.3 (1/7) 12.5 (1/8) .919 chemotherapy (more than 10 cycles) no (%) 62.5 (5/8) 37.5 (3/8) .317 cga expression at initial pc diagnosis (%) 8.7 3.3 .027 abbreviations: ps, performance status; crpc, castration resistant prostate cancer; alp, alkaline phosphatase; ldh, lactate dehydrogenase, ca++, calcium; psa, prostate specific antigen; pr, partial response; cr, complete response; cga, chromogranin a. table 3. clinical characteristics of high and low cga groups at time of crpc diagnosis. cga expression as predictive marker for pca-mitsui et al. vol 12 no 03 may-june 2015 2167 histological evaluation or immunostaining. cga immunohistochemistry was performed using a rabbit polyclonal antibody raised against cga (dako, kyoto, japan). each slide was de-paraffinized in xylene and rehydrated through graded concentrations of ethanol in water. endogenous peroxidase activity was blocked by incubation for 10 minutes with 3% hydrogen peroxide. sections were counterstained with hematoxylin, dehydrated with ethanol, and permanently coverslipped. evaluation of immunostaining all slides were independently reviewed by an experienced pathologist (y.h), who was blind to all clinical data. at least 200 tumor cells found in 10 randomly selected high-power fields of each slide were examined. the positive rate was expressed as the mean percentage of positively stained tumor cells against the total number of tumor cells, as noted in our previous study.(20) statistical analysis statistical analysis was performed using a mann-whitney u test, a χ2 test, or log-rank test. correlation analysis was performed using pearson’s coefficient correlation. survival curves were conducted using the kaplan-meier method, with the differences between curves analyzed using a log rank test. a two-tailed p value of less than .05 was considered to be statistically significant. figure 1. flow chart detailing the times of biopsy and the available patient cohort in this study. figure 2. cg a expression in pca cells at the time of initial pca diagnosis, during adt, at the time of crpc diagnosis, and after 2 cycles of dec therapy. (a) cga expression increased in a stepwise manner until crpc diagnosis, then significantly decreased after 2 cycles of dec chemotherapy. representative immunostaining for cga from the same patient (b) at the time of initial pca diagnosis, (c) during adt, (d) at the time of crpc diagnosis, and (e) after 2 cycles of dec chemotherapy. magnification, × 200. abbreviations: cga, chromogranin a; pca, prostate cancer; crpc, in castration-resistant prostate cancer; dec, docetaxel/estramustine/ carboplatin; adt, androgen deprivation therapy. cga expression as predictive marker for pca-mitsui et al. urological oncology 2168 results patients’ profiles clinical characteristics of the 16 patients are shown in table 1. their ages ranged from 52 to 86 years old, with a median of 72 years. twelve patients had a ps score of 0 or 1 and the remaining 4 had a score of 2 or 3. psa level at the time of initial diagnosis ranged from 0.8 to 6113.9 ng/ml, with a median of 142.4 ng/ml. of the 16 cases, 3 (18.7%) were gleason score 7, 2 (12.5%) were gleason score 8, and 11 (68.8%) were gleason score 9 at the initial pca diagnosis. during treatment, one case showed gleason score upgrade from 7 to 8. bidimensionally measurable extraosseous disease was preset in 9 (56.2%) patients (7 had lymph nodes, 3 had multiple liver metastases, and 2 had multiple lung metastases) and 14 (87.5%) demonstrated bone metastasis at the time of crpc diagnosis. for the initial treatment, all patients underwent adt by medical or surgical castration with anti-androgen. following the diagnosis of crpc, they were treated with dec therapy, ranging from 3 to 35 cycles, with a median of 10 cycles. cga expression and clinicopathological findings of the 16 patients, 1 (6.3%) had cga negative tumor cells and 12 (75%) immunoreactive neoplastic cells under 10% at the initial pca diagnosis. there were no pure ne carcinomas of the prostate such as small cell carcinoma or carcinoid. the mean percentage of pca cells with positive cga expression at the initial pca diagnosis, during adt, at crpc diagnosis, and after 2 cycles of dec chemotherapy were 7.2%, 11.0%, 18.3% and 11.1%, respectively. thus, cga expression increased in a stepwise manner until diagnosis of crpc, while it was significantly decreased after 2 cycles of dec chemotherapy (figure 2a). representative alterations of cga immunostaining in the same patient are shown in figures 2b-e. table 2 shows the correlation of ne differentiation with gleason score and serum psa value. cga expression at the initial pca diagnosis or crpc diagnosis was not associated with gleason score in each stage. in addition, after dividing the 16 cases into 2 groups according to median serum psa value at the initial pca (142.4 ng/ml) or crpc diagnosis (91.7 ng/ml), there was no significant correlation between serum psa level and cga expression in each stage. prognostic relevance of cga expression for development of crpc in 16 cases treated with dec therapy next, we classified the 16 patients who underwent dec therapy into 2 groups according to the median percentage of cga positive pca cells at crpc; namely the high and low cga groups. the clinical characteristics of both groups are summarized in table 3. there were no significant differences for age, ps score, gleason score, duration until crpc, hemoglobin, alkaline phosphatase, lactate dehydrogenase, or serum calcium between the groups. although there was a trend that psa value at the time of crpc diagnosis in the low cga group was higher than that of high group, the number of cases with a psa reduction rate of more than 90% was the same in 2 groups. of 5 assessable patients with lymphadenopathy, 4 (80%) attained pr or cr, and of 3 patients with measureable liver or lung metastasis, 3 attained pr or cr in the high cga group. the patients having lymphadenopathy or liver metastasis in the low cga group could also attain pr or cr. of 7 patients with positive bone metastasis in the high cga group, bone scan revealed improvement in only 1 (14.3%). similarly, the bone response rate in the low cga was only 12.5%. thus, the response rate for measurable lesions in each group was approximately equivalent. dec therapy of more than 10 cycles was figure 3. subanalysis of cga expression at time of crpc diagnosis. (a) a significant reduction in cga expression after 2 cycles of dec chemotherapy was seen in the high cga expression group, while that was not evident in the low cga expression group. (b) patients in the high cga group at the time of diagnosis of crpc showed a significant longer psa progression-free survival period as compared with those in the low cga group at the time of diagnosis of crpc. (c) patients with high cga at crpc diagnosis showed a longer cause-specific survival period than the low cga group, though the difference did not reach statistical significance. abbreviations: cga, chromogranin a; pca, prostate cancer; crpc, in castration-resistant prostate cancer; dec, docetaxel/estramustine/ carboplatin. cga expression as predictive marker for pca-mitsui et al. vol 12 no 03 may-june 2015 2169 more prevalent in the high than the low cga group (62.5% vs. 37.5%), though the difference was not statistically significant. interestingly, cga expression at the initial pca diagnosis was significantly higher in the high cga group than in the low cga group (p = .027). as shown in figure 3a, a significant reduction in cga-positive pca cells was found after 2 cycles of dec chemotherapy in the high cga group (p = .003), whereas no such reduction was found in the low cga group. there was no significant correlation between the change of psa value and change of cga expression score (data not shown). the median periods of psa progression-free and cause-specific survival were 378 and 1885 days, respectively. pca patients in the high cga group at the time of crpc diagnosis showed a significantly longer psa progression-free survival period as compared with those in the low cga group at crpc diagnosis (p = .028; figure 3b). likewise, the high cga group at diagnosis showed a longer cause-specific survival period than the low cga group, though the difference did not reach statistical significance (p = .063; figure 3c). discussion previous studies found that pca cells with ne differentiation are likely to be increased and functionally accelerated after acquiring castration resistance.(4,7,8) however, few reports have addressed the issue of active changes of ne markers in pca tissue obtained from the same individuals. in the current study, we focused on tissue alterations of cga during the course of treatment and report the clinical potential of ne differentiation in pca. as shown in figure 2a, pca cells with ne differentiation were activated despite androgen deprivation in a stepwise manner until acquisition of castration resistance. in addition, we found that ne differentiation of pca cells is not correlated with psa value, as previously reported in the literature.(8,12) in parallel with the acquisition of castration resistance, pca cells with ne differentiation are increased due to their survival capability despite androgen deprivation. thus, it is possible that pca cells with ne differentiation have an association with acquisition of castration resistance. although taxane-based chemotherapy is now considered to be a standard first-line chemotherapy for crpc, the median progression-free survival period appears to be less than 7 months.(21) since combination chemotherapeutic strategies such as dec therapy have been shown to have more prognostic relevance than conventional taxane-based chemotherapy, an ne-targeted chemotherapeutic strategy may be an attractive alternative to taxane-based chemotherapy for crpc patients. on the basis of findings that active involvement of ne differentiation is related to the process of castration resistance in pca, ne cells are considered to be chemosensitive to carboplatin, as shown in studies of small cell lung cancer.(22) also, the combination of taxane-based chemotherapy and carboplatin confers an excellent prognostic relevance for patients with crpc. (18,23) thus, we propose that therapeutic response to dec therapy as well as survival benefit in crpc patients may be predictable by determining pca cells with ne differentiation just prior to dec therapy. the present results showed that the reduction in ne-positive pca cells after 2 cycles of dec therapy was more significant in the high cga expression group than the low cga expression group. likewise, better psa progression-free probability was noted in crpc patients with a high level of cga expression. together, these findings suggest that cga expression in tissue at the time of crpc diagnosis may be useful as a biomarker for prediction of chemosensitivity. although no significant survival benefit was demonstrated in our study, cause-specific survival was longer in the high cga group at crpc diagnosis. as shown in table 3, 62.5% of the cases in the high cga group underwent dec therapy for more than 10 cycles, as compared to only 37.5% in the low cga group. therefore, we believe that crpc patients with a high level of cga expression can have dec therapy for a longer period because of delayed disease progression. pca is now the second leading cause of death in the united states of america,(24) and this notorious propensity is applicable to japan. in general, pca shares the characteristics of slow growth with a longer lifespan as compared to other types of cancer. however, despite radical treatment, pca patients harboring a biologically aggressive phenotype, such as those with positive ne differentiation, may unfortunately progress into early disease recurrence and ultimately death. in the present study, we found that pca cells with a higher level of cga expression at the time of crpc diagnosis also had higher cga expression at the initial pca diagnosis (table 3). a finding of persistently elevated cga expression despite adt in pca tissue might provide rationale for the neoadjuvant modality of platinum-based chemotherapy prior to radical treatment for pca patients, especially those with higher cga expression at the initial diagnosis, in order to prevent an unfavorable clinical outcome. there are several limitations in this study. first, the small number of cases analyzed retrospectively. our results demonstrated that the duration of adt is not associated with cga expression at crpc diagnosis. in contrast, abrahamsson and colleagues(25) reported that induction of ne differentiation was strongly related to the duration of adt. previous studies have reported an association of ne differentiation and a high gleason score(11,12,26) although we and other investigators failed to detect this relationship.(13,27,28) in addition, the prognostic significance of ne differentiation in pca is not well elucidated and controversial because most articles on the issue include relatively small number size. second, cga expression was performed by immunohistochemical staining using prostate biopsy samples. transrectal ultrasound guided prostate biopsy is associated with a certain degree of underand overstaging of pca, and it may fail to assess the definite tumor burden in the patients with metastasis. the measurement of serum cga may avoid tumor heterogeneity and tissue sample biases because it corresponds to the entire primary tumor cell population and its associated metastases.(27) furthermore, in addition to ne differentiation, there are other mechanisms contributing to development of crpc and prognosis such as multiple pathways related to androgen receptor or apoptosis related to the bcl-2 family(20,29,30) which were not evaluated in this study. taking into consideration these limitations, the validity of our results should be cautiously considered. thus, further research using a larger number of cases is required to verify our findings. conclusion ne differentiation of pca cells is accelerated despite androgen deprivation and reaches a peak at the time of urological oncology 2170 cga expression as predictive marker for pca-mitsui et al. crpc diagnosis, suggesting active involvement of ne differentiation in acquisition of castration resistance in affected patients. early prediction of chemosensitivity using tissue cga expression may provide a beneficial effect for crpc patients undergoing combination taxane chemotherapy with a platinum derivative, such as dec therapy. however, further research using a larger number of cases is needed to clarify our findings. conflicts of interest none declared. references 1. grube d. the endocrine cells of the digestive system: amines, peptides, and modes of action. anat embryol. 1986;175:151-62. 2. santamaria l, martin r, martin jj, alonson l. stereologic estimation of the number of neuroendocrine cells in normal human prostate detected by immunohisotochemistry. appl immunohistochem mol morphol. 2002;10:275-81. 3. nelson ec, cambio aj, yang jc, ok j-h, lara pn jr, evans cp. clinical implications of neuroendocrine differentiation in prostate cancer. prostate cancer prostatic dis. 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shiina h, urakami s, et al. bcl-2 expression as a predictive marker of hormonerefractory prostate cancer treated with taxanebased chemotherapy. clin cancer res. 2006;12:6116-24. 21. loriot y, massard c, gross-goupil m, et al. combining carboplatin and etoposide in docetaxel pretreated patients with castrationresistant prostate cancer: a prospective study evaluating also neuroendocrine features. ann oncol. 2009;20:703-8. 22. skarlos dv, samantas e, kosmidis p, et al. randomized comparison of etoposidecisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. a hellenic co-operative oncology group study. ann oncol. 1994;7:601-7. 23. kelly wk, curley t, slovin s, et al. paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer. j clin oncol. 2001;19:44-53. cga expression as predictive marker for pca-mitsui et al. vol 12 no 03 may-june 2015 2171 24. siegel r, ma j, zou z, jemal a. cancer statistics, 2014. ca: cancer j clin. 2014;64:929. 25. abrahamsson p-a, falkmer s, falt k, grimelius l. the course of neuroendocrine differentiation in prostatic carcinomas. pathol res pract. 1989;185:373-80. 26. speights vo, cohen mk, riggs mw, coffield ks, keegan g, arber da. neuroendocrine stains and proliferative indices of prostatic adenocarcinomas in transurethral resection samples. br j urol. 1997;80:281-6. 27. reis lo, vieira lf, zani el, denardi f, de oliveira lc, ferreira u. assessment of serum chromogranin-a as prognostic factor in high-risk prostate cancer. j investing med. 2010;58:957-60. 28. de nunzio c, albisinni s, presicce f, lombardo r, cancrini f, tubaro a. serum level of chromogranin a are not predictive of high-grade, poorly differentiated prostate cancer: results from italian biopsy cohort. urol onccol. 2014;32:80-4. 29. anvari k, seilanian toussi m, kalantari m, et al. expression of bcl-2 and bax in advanced or metastatic prostate carcinoma. urol j. 2012;9:381-8. 30. komiya a, yasuda k, watanabe a, fujiuchi y, tsuzuki t, fuse h. the prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients. mol clin oncol. 2013;1:257-62. cga expression as predictive marker for pca-mitsui et al. urological oncology 2172 urological oncology role of steroid hormone receptors in formation and progression of bladder carcinoma: a case-control study rahil mashhadi,1 gholamreza pourmand,1* farid kosari,2 abdolrasoul mehrsai,1 sepehr salem,1 mohammad reza pourmand,3 sudabeh alatab,1 mehdi khonsari,1 fariba heydari,1 laleh beladi,1 farimah alizadeh1 purpose: to compare the expression rate of sex steroid hormone receptors of estrogen (er), progesterone (pr) and androgen (ar) in normal urothelium and urothelial bladder cancer (ubc) and to evaluate the possible associations of these receptors expression with cancer progression and patient’s survival. materials and methods: we evaluated the clinical data and tumor specimens of 120 patients with pathologically confirmed primary ubc with 132 normal healthy controls. both patients and controls selected from list of subjects who have been referred to sina urology clinic, and had a minimum of one year follow-up duration. data collected from medical cords. for evaluation of expression, immunohistochemistry was performed on paraffin-embedded tissue sections using a monoclonal antibody for androgen, estrogen and progesterone receptors. presence of at least 10% positive cells defined as positive expression. results: none of the control subjects showed ar expression, while 22% of the patients were ar-positive. er/pr expressions were observed in 4.2%/ and 2.5% of the cases and in 2.3% and 1.5% of the controls, respectively. a statistically significant correlation was found between ar expression and tumor stage and grade (p < .001). ar-positive patients showed a significantly poorer prognosis than ar-negative cases (log-rank test, p = .02, hazard ratio = 2.12; 95% confidence interval: 1.36-4.65). conclusion: ar expression was significantly associated with higher grade and poorly differentiated tumors with unfavorable outcome. ar expression test might be useful as a diagnostic tool for determining the malignancy and outcome of ubc patients. keywords: receptors; androgen; estrogen; progesterone; tumor markers; biological; urinary bladder neoplasms; mortality; neoplasm recurrence; gene expression regulation; survival rate. introduction urothelial bladder cancer (ubc) is one of the most common cancers, as it is ranked the 9th most common cancer worldwide.(1) ubc is responsible for the death of 130,000 people annually worldwide(2) and its incidence is 3 times higher in men than women.(1) this cancer ranked the 7th most common cancer in men and the 17th most common in women.(1,3) ubc is the fourth most incident cancer in the usa and it is the 5th most common cancer in iran.(1,3,4) according to the 2008 report of iran’s national cancer registry, the incidence of bladder cancer was 13.03 in males and 3.32 in females per 100,000 population.(5) interestingly, in addition to dissimilarity in incidence, the tumor behavior is also different between two sexes. the female subjects tend to have more aggressive tumors with less favorable prognosis than male subjects(6-8) although the exact origin of this difference between the genders is unknown, it is assumed that part of this variation comes from higher exposure of male subjects to industrial, environmental and occupational chemicals and also tobacco use.(9,10) however higher incidence in males cannot be fully explained solely by above mentioned factors.(9) a study by mir and colleagues showed that, even after adjustment for carcinogenic factors, sex-associated differences in ubc risk was still exist.(10) some studies suggested the hormonal factors as a potential explanation for the gender disparity in the incidence and behavior of bladder cancer.(9) to support this hypothesis, some experimental animal studies showed that development of chemically induced ubc was less in female than in male animals.(10) moreover, these an1 urology research center, tehran university of medical sciences, tehran, iran. 2 department of pathology, sina hospital, tehran university of medical science, tehran, iran. 3 department of pathobiology, school of public health, tehran university of medical sciences, tehran, iran. *correspondence: hassan-abad square, sina hospital, urology research center, tehran, iran. tel: +98 21 6634 8560. fax: +98 21 6634 8560. e-mail: gh_pourmand@yahoo.com. received june 2014 & accepted november 2014 urological oncology 1968 imal studies generally demonstrate that hormonal manipulation changes the natural course of the tumors and that animals who have been treated with androgen inhibitors had better survival and more benign courses.(11,12) in agreement with these observations, some epidemiologic studies demonstrated that postmenopausal women have a greater risk for development of ubc as well as breast cancer than premenopausal women.(13,14) on the basis of these findings, sex steroid hormones and subsequently their receptors have been considered as a potential explanation for the different biologic behavior of ubc between men and women.(10) sex steroid hormones act by binding to their receptors including androgen receptors (ars), estrogen receptors (ers) and progesterone receptors (prs) in target cells. (7) it is well known that steroid hormone receptors are expressed in normal bladder urothelium,(15,16) although physiological functions of these receptors in the bladder are not completely understood.(17,18) on the other hand, it has been reported that the expression of ars, ers and prs play an essential role during development, growth and progression of several malignancies.(9,19-22) shen and colleagues showed that ers are expressed in human bladder cancers and their expressions augment with increase of the stage and grade of cancer. their results also demonstrated a strong inhibitory effect of antiestrogen treatment on ubc growth in vitro.(23) miyamoto and colleagues used n-butyl-n-(4-hydroxybutyl) nitrosamine to induce bladder cancer in both wild-type and ars knockout male and female mice, and showed that 92% of the wild-type male, 42% of the wild-type female mice and none of the ars knockout male and female mice developed tumors.(12) despite the importance of steroid hormone receptors in the initiation, progression and outcome of bladder cancer in experimental animal studies, its role in human ubc is still controversial.(24) in this regard, in present research we aimed to further clarify the role of sex steroid receptors (ar, pr and er) expression in development and progression of ubc in human subjects and to investigate whether or not there is an association between grade of the cancer and sex steroid receptor expression. to our knowledge this is the first study from our region in which the role of these receptors in outcome and prognosis of patients with ubc has been addressed. materials and methods study subjects and tissue specimens this is a retrospective case-control study, in which 252 subjects including 120 pathologically confirmed ubc patients and 132 non-ubc individuals were recruited. the study protocol was approved by medical ethics committee of tehran university of medical sciences. participants were drawn from the list of patients who attended the urology clinic at sina hospital, and had a bladder specimen through either transurethral resection of bladder tumor (turbt), cystectomy or cystoscopy. according to the sample size calculation and the literature review, there should be 133 subjects in each group, however due to nature of retrospective studies, we only could recruit 120 subjects in case group and 132 subjects in control group which provides a ratio of control/ case of 1.1/1. all of the subjects were between 18-85 years old. individuals who had pathologically confirmed ubc were placed in patient group. controls were subjects who did not have pathologically confirmed ubc and have been referred to urology clinic because of other causes such as hematuria, benign prostatic hyperplasia (bph), urethral stricture, bladder stones, pelvic trauma or chronic cystitis. patients who had concomitant or previous malignancies, or a history of hormonal therapy, chemotherapy and/or radiotherapy were excluded from the study. two groups were sex matched. the anthropometric characteristics of patients and medical history were obtained from medical records. definition for diabetes mellitus was use of anti-diabetic medication or at last two fast blood sugar levels of higher than 120 mg/dl. definition for hypertension was use of anti-hypertensive medication or the average blood pressure in two readings before admission was > 140/90 mmhg. patients were considered to have dyslipidemia when the serum total cholesterol level was ≥ 200 mg/dl, high density lipoprotein cholestrol was < 40 mg/dl, or triglyceride was ≥ 150 mg/dl. patients who were taking lipid lowering medications were also categorized in this group. smokers were those who had smoked at least 100 cigarettes in their lifetime, while those who consumed less than 100 cigarettes were defined as non-smokers. tissue specimens were examined by blinded pathologists to determine the grade, stage and other histopathological characteristics. grading of samples was performed according to the world health organization/ international society of urologic pathology classification of urothelial neoplasia.(25) pathological t stage (depth of invasion) was assessed according to american joint committee on cancer classification.(26) immunohistochemistry immunohistochemical (ihc) staining was performed on fixed paraffin embedded (3 µm) sections. briefly, after deparaffinization in xylene and rehydration by graded concentrations of alcohol to distilled water, the specimens were washed with phosphate buffered saline (pbs). endogenous peroxidase was blocked by 10-15 min incubation of specimens in 5% h 2 o 2 . the specimens were washed again with pbs and then antigen retrieval was performed in citrate buffer under 126°c and 2 atmosphere for 30 min. after washing with pbs, in order to decrease nonspecific antibody binding, protein blocking was carried out by incubation in protein block serum-free (code x0909, dako, glostrup, denmark) for 10 min at room temperature. the sections were then incubated with the following primary antibodies: anti-estrogen receptor (clone 1d5, 1/50 dilution, dako, glostrup, denmark), anti-androgen receptor (clone ar441, 1/50 dilution, dako, glostrup, denmark) and anti-progesterone receptor (clone pgr 636, 1/50 dilution, dako, glostrup, denmark). after washing with pbs, the slides were incubated with a dextran polymer reagent conjugated with peroxidase and secondary antibody (envision+, dako, glostrup, denmark) for staining detection for 1 h. we also used 3,3’-diaminobenzidine as a chromogen for color development and subsequently counterstained them with carazzi’s hematoxylin. role of steroid hormone receptors in bladder carcinoma-mashhadi et al vol 11. no 06 nov-dec 2014 1969 immunostained sections were evaluated under a light microscope by two experienced pathologists in blinded fashion. the immunoreactivity was scored on a fourpoint scale as follows: negative ( <10% of cells with nuclear staining), weak (10-50% of cells with nuclear staining), moderate (51-80% of cells with nuclear staining) and strong (> 80% of cells with nuclear staining). statistical analysis for statistical analyses, we used statistical package for the social science (spss inc, chicago, illinois, usa) version 21. data were presented as mean ± sd. fisher’s exact test, chi-square test and the independent sample t-test were used to investigate the association between steroid hormone receptors expression with pathological and clinical factors. in all statistical analyzes, p values less than .05 was considered as statistically significant. results the mean age of the patients was 66.2 ± 12.10 years in case group and 60.4 ± 15.54 years in control group (p = .001). over all the majority of subjects (85.7%, n = 216) were male. this rate in case and control groups was 87.5% (n = 105) and 84% (n = 111), respectively, however the ratio of male to female in case and control groups was not significantly different (p = .47). the mean follow-up period was 24.5 months (range, 12-60 months). figure 1 shows examples of ar/pr/er positive cases and four-point scale of staining score is shown in figure 2. evaluation of steroid hormone receptor expression revealed that only ar expression is significantly different between case and control groups (p = .0001). moreover, we could not find any significant difference between ar, pr and er expression in two genders in both case and control groups. the anthropometric and clinical characteristics of patients as well as steroid hormone receptor expression are presented in table 1. clinical and demographic characteristics of patients with ubc are summarized in table 2. we also assessed the possible associations between steroid hormone receptors expression and tumor recurrence, tumor progression, tumor metastasis, tumor grades and stages, death because of ubc and family history of ubc. we found that only ar expression had a significant association with tumor stage (p < .001) and variables control (n = 132) case (n= 120) p value age (year), mean ± sd 60.4 ± 15.54 66.2 ± 12.10 .001 male/female 111/21 (84/16) 105/15 (87.5/12.5) .47 smokers 67 (50.8) 73 (60.8) .12 hypertension 43 (32.6) 52 (43.3) .09 hyperlipidemia 7 (5.3) 15 (12.5) .04 diabetes mellitus 35 (26.5) 42 (35) .17 family history of cancer 1 (0.8) 5 (4.2) .10 ar expression 0 26 (21.7) <.0001 pr expression 3 (2.3) 5 (4.2) .48 er expression 2 (1.5) 3 (2.5) .67 table 1. anthropometric characteristics and steroid hormone expression in study groups.* abbreviations: ar, androgen receptor; pr, progesterone receptor; er, estrogen receptor. * data are presented as no (%). variables values stage t1 61 (50.8) t2 21 (17.5) t3 18 (15) t4 20 (16.7) grade low 20 (16.7) high 100 (83.3) recurrence yes 57 (47.5) no 63 (52.5) metastasis yes 14 (11.7) no 106 (88.3) mortality yes 10 (8.3) no 110 (91.7) chemotherapy yes 44 (36.7) no 76 (63.3) radiotherapy yes 11 (9.2) no 109 (90.8) table 2. tumor characteristics (n = 120).* * data are presented as no (%). figure 1. immunohistochemical staining of steroid hormone receptors in primary bladder cancer. (a) estrogen receptor, (b) progesterone receptor, (c) androgen receptor. role of steroid hormone receptors in bladder carcinoma-mashhadi et al urological oncology 1970 tumor grade (p < .0001). moreover, the rate of ar expression was higher in patients with family history of ubc (p = .04). interestingly, ar/pr-positive patients had a higher rate of metastasis in comparison to ar/ pr-negative patients (p < .05). also, ar-positive patients showed a poorer prognosis than ar-negative cases (log rank test, p = .08), while survival was not affected by pr/er expression. discussion the incidence of bladder cancer is higher in men (about three times) than women.(1) it seems that this difference is primarily due to a difference in chemical exposure and smoking.(1,9) however, animal studies have shown that chemically and spontaneous bladder cancer development is significantly higher in male rats than females.(12) epidemiological studies have also shown that the development of bladder cancer in postmenopausal women is more common than women who are premenopausal.(13) it has been shown that in bladder cancer cells with ar-positive, cell growth is promoted by androgens,(12,16,18) or in another study, it has been found that antiestrogens can inhibit urothelial carcinoma of the bladder in er-positive bladder cancer cell lines.(23) in another study on breast cancer, pr and er were considered as prognostic factors which play a role in the identification of patients who may benefit from hormonal therapy.(14) it should be noted that previous studies that assess the relationship between ar/pr/er expression and histopathological characteristics of the tumors have led to conflicting results.(7) so, the results of such studies cannot be clearly identified prognostic significance of ar/pr/er expression in patients with bladder cancer. variability seen in results of such studies could be due to differences in sample size, study methods or interpretation of the results.(7) moreover, there is no sufficient or strong evidence to establish epidemiological links between steroid hormone receptors and observed gender differences in development of cancer.(24) in the present study, we found that ar/pr/er expressions were similar in both sexes with ubc. similar results have also been reported in other studies.(24,27-29) in this study there is no correlation between ar/pr/er expression and gender differences in subjects with ubc. in a study by kirkali and colleagues loss of ar expression in malignant bladder urothelium is reported. they concluded that ar did not have a direct role in malignant transformation.(30) boorjian and colleagues reported that loss of ar expression might lead to invasive bladder cancer as they found a decreased ar expression in high stage tumors; also they observed ar expression in 53% of urothelial carcinoma and in 86% of normal urothelium cases.(27) another study showed a significant decrease in the expression of ar in bladder cancer compared to nonneoplastic bladder specimens.(7) in present study ar was positive in 22% of the 120 patients with bc, but none of the 132 normal urotheliums showed ar-positivity as observed in the studies by tuygun and colleagues,(24) and ruizeveld de winter and colleagues. (31) birtle and colleagues studied ar expression in 17 cases of high grade transitional cell carcinoma (tcc) of the bladder. they showed that ar staining was negative in all areas of normal urothelium, although ar was positive in 9/17 (52%) cases.(32) although, zhuang and colleagues reported nuclear immunoreactivity of ar in 7/9 (77%) urinary bladder cancers, they failed to detect positive immunohistochemical staining in normal urinary bladder. they mentioned that ar expression can be used as a diagnostic marker.(17) according to the available data, the prognostic role of the ar expression in bladder cancer is controversial. tuygun and colleagues reported a significant decrease in ar expression in higher grades and invasive tumors, which is consistent with the findings of boorjian and colleagues and miyamoto and colleagues.(17,24,27) in contrast, mir and colleagues in a study involving 472 patients, showed that ar-positivity was higher in muscle–invasive tumors (15%) compared to non-muscle invasive one (9%).(10) in another study with 33 superficial bladder cancers, authors reported that patients with high ar expression tended to have a higher recurrence rate, compared to patients with low ar expression.(12) in present study, we found a significant correlation between ar expression and high grade and high stage tumors (p < .0001 and p < .001, respectively). also, the present study demonstrated a significantly higher rate of metastasis in ar-positive patients compared to ar-negative patients (p = .009). moreover, relapse-free survival in ar-positive patients was lower than ar-negative patients (log-rank test, p = .08). therefore ar could be used as a prognostic factor (hazard ratio: 2.12; 95% confidence interval: 1.36-4.65). in this study, pr and er were positive in 2.5% and 4.2% of the ubc specimens, respectively. our results confirmed that pr/er expression is not associated with aggressiveness of ubc. similar to our findings, bolenz and colleagues reported that pr expression cannot be a prognostic factor in patients with ubc. in their study pr was not expressed in any of the ubc specimens.(9) in a study by basakci and colleagues er was positive in 12.4% of the superficial tcc specimens. they concluded that er does not play any direct role on the prognosis of superficial bladder tcc.(33) also in our study, er and pr expression do not have any direct roles in formation and progression of ubcs. this study has some limitations. first, since this study was a retrospective one, some of the data were not availfigure 2. staining score of androgen receptor in primary bladder cancer. (a) < 10% positive tumor cells, (b) 10-50% positive tumor cells, (c) 51-80% positive tumor cells, (d) > 80% positive tumor cells. role of steroid hormone receptors in bladder carcinoma-mashhadi et al vol 11. no 06 nov-dec 2014 1971 able. also, due to complex nature of the malignancies, there might be some confounders and effect modifiers that might interfere with the obtained results. we tried to control and limit the bias by using the blinded pathologist and including the control subjects from same population cohort. finally two groups were not age matched. conclusion we concluded that there was no significant difference in steroid hormone receptors expression between two sexes. of studied steroid hormone receptors, only ar expression had significant association with stage and grade of bladder cancer. based on study results, ar could be used as a prognostic factor in ubc. acknowledgements this research has been sponsored by tehran university of medical sciences, tehran, iran. the authors wish to thank mrs. b. pourmand for valuable helps in this study. conflict of interest none declared. references 1. yavari p, sadrolhefazi b, mohagheghi ma, mehrazin r. a descriptive retrospective stu dy of bladder cancer at a hospital in iran (1973-2003). asian-pac j cancer prev. 2009;10:681-4. 2. karimianpour n, mousavi-shafaei p, ziaee aa, et al. mutations of ras gene family in specimens of bladder cancer. urol j. 2008;5:237-42. 3. ploeg m, aben kk, kiemeney la. the pres ent and future burden of urinary bladder can cer in the world. world j urol. 2009;27:289 93. 4. nanda ms, sameer as, syeed n, et al. gen etic aberrations of the k-ras proto-oncoge ne in bladder cancer in kashmiri population. urol j. 2010;7:168-173. 5. report of national cancer registration iran. is lamic republic of iran. ministry of health and medical education, office health depu ty, center for disease control and preven tion. 2007-2008. 6. scosyrev e, noyes k, feng c, messing e. sex and racial differences in bladder cancer presentation and mortality in the us. cancer. 2009;115:68-74. 7. miyamoto h, yao j.l, chaux a, et al. expr ession of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. bju int. 2012;109:1716-26. 8. jemal a, siegel r, xu j, ward e. cancer sta tistics,2010. ca cancer j clin. 2010;60:277 300. 9. bolenz c, lotan y, ashfaq r, shariat sf. es trogen and progesterone hormonal receptor expression in urothelial carcinoma of the bladder. eur urol. 2009;56:1093-5. 10. mir c, shariat sf, van der kwast th, et al. loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi-institutional study. bju int. 2011;108:24-30. 11. nam jk, park sw, lee sd, chung mk. prognostic value of sex-hormone receptor expression in non-muscle-invasive bladder cancer. yonsei med j. 2014;55:1214-21. 12. miyamoto h, yang z, chen yt, et al. pro motion of bladder cancer development and progression by androgen receptor signals. j natl cancer inst. 2007;99:558-68. 13. mcgrath m, michaud ds, de vivo i. hor monal and reproductive factors and the risk of bladder cancer in women. am j epi demiol. 2006;163:236. 14. fortner rt, eliassen ah, spiegelman d, willett wc, barbieri rl, hankinson se. premenopausal endogenous steroid hor mones and breast cancer risk: results from the nurses’health study ii. breast cancer research. 2013;15:r19. 15. chavalmane ak, comeglio p, morelli a, et al. sex steroid receptors in male human blad der: expression and biological function. j sex med. 2010;7:2698-713. 16. liu z, li x, liu s, et al. flavokawain a inhib its urinary bladder carcinogenesis in the up ii-sv40t transgenic mouse bladder cancer model. proceedings of the 103rd annual me eting of the american association for cancer research. abstract. 2012;619. 17. zhuang y-h, blauer m, tammela t, tuohimaa p. immunodetection of androgen receptor in human urinary bladder cancer. histopathology. histopathology. 1997;30: 556-62. 18. johnson am, o’connell mj, miyamoto h, et al. androgenic dependence of exophytic tu mor growth in a transgenic mouse model of bladder cancer: a role for thrombospodin-1. b mc. urol. 2008;8:7. 19. lamb ca, helguero la, giulianelli s, et al. antisense oligonucleotides targeting the pro gesterone receptor inhibit hormone-indepen dent breast cancer growth in mice. breast cancer res. 2005;7:r1111-21. 20. rahmani ah, alzohairy m, babiker ay, khan aa, aly sm, rizvi ma. implication of androgen receptor in urinary bladder cancer: a critical mini-review. int j mol epidemiol genet. 2013;4:150-5. 21. chang c, lee so, yeh s, chang tm. andro gen receptor (ar) differential roles in hor mone-related tumors including prostate, role of steroid hormone receptors in bladder carcinoma-mashhadi et al urological oncology 1972 bladder, kidney, lung, breast and liver. onco gene. 2014;33:3225-34. 22. li y, izumi k, miyamoto h. the role of the androgen receptor in the development and progression of bladder cancer. jpn j clin on col. 2012;42:569-77. 23. shen ss, smith cl, hsieh jt, et al. expression of estrogen receptors-alpha and -beta in bladder cancer cell lines and human bladder tumor tissue. cancer.2006;106:2610-6. 24. tuygun c, kankaya d, imamoglu a, et al. sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: a comparative analysis of clinicopathological features and survival outcomes according to receptor expression. urol oncol. 2011;29: 43–51. 25. epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/inter national society of urological pathology consensus classification of urothelial (transi tional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998;22:1435-48. 26. greene fl, page dl, fleming id, et al. ajcc cancer staging manual, 6th ed. new york (ny): springer-verlag, 2002. 27. boorjian s, ugras s, mongan np, et al. an drogen receptor expression is inversely cor related with pathologic tumor stage in blad der cancer. urology. 2004;64:383-8. 28. boorjian sa, heemers hv, frank i, et al. ex pression and significance of androgen recep tor coactivators in urothelial carcinoma of the bladder. endocr relat cancer. 2009;16:123 37. 29. kauffman ec, robinson bd, downes mj, et al. role of androgen receptor and associated lysine-demethylase coregulators, lsd1 and jmjd2a, in localized and advanced human bladder cancer. mol carcinog. 2011;50:931 44. 30. kirkali z, cowan s, leake re. androgen receptors in transitional cell carcinoma. int urol nephrol. 1990;22:231-4. 31. ruizeveld de winter ja, trapman j, vermey m, mulder e, zegers nd, van der kwast th. androgen receptor expression in human tis sues: an immunohistochemical study. j his tochem cytochem. 1991;39:927-36. 32. birtle aj ,freeman a, munson p. the andro gen receptor revisited in urothelial carcino ma. histopathology. 2004;45:p98-9. 33. basakci a , kirkali z , tuzel e , yorukoglu k , mungan mu , sade m. prognostic signif icance of estrogen receptor expression in superficial transitional cell carcinoma of the urinary bladder. eur urol. 2002;41:342-5. role of steroid hormone receptors in bladder carcinoma-mashhadi et al vol 11. no 06 nov-dec 2014 1973 special feature 223urology journal vol 5 no 4 autumn 2008 intravesical foreign bodies review and current management strategies muhammad rafique introduction: the aim of this study was to evaluate the cause, diagnosis, and management of intravesical foreign bodies in patients treated at our hospital and to review and update management of intravesical foreign bodies reported in the current literature. materials and methods: sixteen patients had been treated for intravesical foreign bodies at nishtar medical college hospital, multan, pakistan during a 5-year period. records of these patients were analyzed retrospectively for etiology, presentation, diagnosis, and management. results: the age of the patients ranged from 14 to 70 years and 10 of them were men. seven patients (43.8%) had iatrogenic intravesical foreign bodies, 5 (31.3%) had migrated foreign bodies from the adjacent organs, and 4 (25.0%) had self-introduced foreign bodies into the bladder. the objects included copper wire, carrot, lead pencil, intrauterine device, surgical gauze, pieces of foley catheter, and teflon beak of resectoscope sheath. the most common presenting symptoms were urinary frequency and dysuria. endoscopic retrieval was possible in 8 (50.0%) patients, and the remaining underwent open cystostomy. conclusion: intravesical foreign bodies should be included in the differential diagnosis of patients with chronic lower urinary tract problems. radiological evaluation is necessary to determine the exact size, number, and nature of them. the most suitable method for removal of intravesical foreign bodies depends on the nature of the foreign body, age of the patient, and available expertise and equipment. most intravesical foreign bodies can be retrieved with minimally invasive techniques. urol j. 2008;5:223-31. www.uj.unrc.ir keywords: foreign bodies, bladder, foreign-body migration, urinary tract infections, hematuria, intrauterine devices, cystoscopy department of urology, nishtar medical college, multan, pakistan corresponding author: muhammad rafique, frcs, frcs, dip urol, febu no 5, altaf town, tariq rd, multan, pakistan tel: +92 61 457 1544 e-mail: rafiqanju@hotmail.com received october 2007 accepted july 2008 introduction during the past few decades, reports of intravesical foreign bodies have increased in the literature. a review of the literature on this subject reveals that almost any conceivable object has been introduced in to the urinary bladder. introduction into the bladder may be self-insertion (through the urethra), iatrogenic, migration from adjacent organs, or a results of penetrating trauma.(1-4) patients present with either acute or chronic symptoms due to complications. each foreign body poses a challenge to the urologist and treatment has to be individualized according to the size and nature of the foreign body and age of the patient.(5) previously, endoscopic extraction with or without perineal urethrotomy or open cystotomy were the only treatment options, but with the advent of newer minimally invasive intravesical foreign bodies—rafique 224 urology journal vol 5 no 4 autumn 2008 techniques, most intravesical foreign bodies can be removed endoscopically without resorting to open surgery.(6-9) this paper presents our experience of diagnosis and management of various intravesical foreign bodies at our hospital. in addition, the discussion focuses on reviewing and updating the knowledge on management of intravesical foreign bodies reported in the current literature. materials and methods hospital records of patients who had received treatment for intravesical foreign bodies during a period from january 2001 to december 2005 at the department of urology, nishtar medical college hospital, multan, pakistan, were retrospectively analyzed. the patients’ age and sex, clinical presentation, diagnosis, and offered treatment were reviewed. the study was approved by the hospital’s ethics committee. results there were 16 patients who had received treatment of intravesical foreign bodies at our hospital during the studied period. their age ranged from 14 to 70 years (median age, 33 years). ten patients were men and 6 were women (malefemale ratio, 1.7:1). they had presented with variable urinary symptoms (table 1). the most common symptoms were urinary frequency and dysuria. hematuria, difficulty with micturition, and urinary retention were the other complaints at presentation. seven patients (43.8%) had iatrogenic foreign bodies including retained surgical gauze (namely gossypiboma) in 5, a piece of a foley balloon catheter in 1, and teflon beak of a resectoscope sheath in 1 patient. all of the patients with surgical gauze had undergone open transvesical prostatectomy at peripheral hospitals and presented at variable intervals after the primary surgical operation. a piece of the foley catheter in 1 patient had probably been left in the bladder when the balloon of his “stuck” catheter was suprapubically punctured. one patient had transurethral resection of the prostate carried out 6 weeks before presentation, when the teflon beak of the resectoscope sheath became detached and was incidentally left in the bladder. he presented with hematuria. in 5 patients (31.3%), the foreign bodies had migrated into the urinary bladder from the patient age sex foreign body cause presentation time to presentation treatment 1 60 m surgical gauze iatrogenic acute urinary retention 3 months cystoscopy 2 70 m surgical gauze iatrogenic frequency, dysuria, difficulty with micturition 6 years open cystotomy 3 70 m surgical gauze iatrogenic difficulty with micturition, recurrent uti 3 years open cystotomy 4 67 m surgical gauze iatrogenic difficulty with micturition 3 weeks cystoscopy 5 65 m surgical gauze iatrogenic urinary retention 4 months open cystotomy 6 30 m piece of foley balloon catheter iatrogenic recurrent uti 6 months cystoscopy 7 60 m teflon beak of tur sheath iatrogenic hematuria, difficulty with micturition 6 weeks cystoscopy 8 28 f calculus on iud migration recurrent uti 5 years cystoscopy and litholopaxy 9 32 f calculus on iud migration hematuria 5 years open cystotomy 10 35 f calculus on iud migration frequency, dysuria 3 years open cystotomy 11 40 f calculus on iud migration hematuria, dysuria 2 years cystoscopy and litholopaxy 12 14 f metal wire migration hematuria, dysuria 3 weeks open cystotomy 13 25 m copper wire self-insertion hematuria 3 weeks open cystotomy 14 28 f carrot self-insertion hematuria 2 weeks cystoscopy and tur resection 15 18 f lead pencil self-insertion hematuria, dysuria 4 weeks cystoscopy 16 16 f ball pen self-insertion recurrent uti 6 months open cystotomy table 1. patients presented with intravesical foreign bodies* *m indicates male; f, female; uti, urinary tract infection; tur, transurethral resection; and iud, intrauterine device. intravesical foreign bodies—rafique urology journal vol 5 no 4 autumn 2008 225 surrounding structures. in 4 of them, intrauterine device (iud) had migrated into the bladder, and these patients presented between 2 and 5 years after insertion of the device when calculi had been formed over the iuds (figure 1). a mentally disabled boy who had swallowed a 3-in long metal wire 6 weeks earlier presented with hematuria and dysuria, and the metal wire was found to be lying in the bladder. in 4 patients (25.0%), the foreign bodies had been self-introduced into the bladder for sexual pleasure. these included a copper wire (figure 2), a carrot, a lead pencil (figure 3), and a ball pen. these patients were rather young with the ages ranged between 14 and 28 years. all of the patients had undergone ultrasonography of the urinary tract and plain abdominal radiography of the kidney, ureters, and bladder (kub) at the time of admission to our hospital. in 15 patients (93.8%), ultrasonography had detected the presence of an echogenic object in the bladder; however, only in 6 (37.5%), the presence of vesical foreign bodies had been correctly reported by the radiologist. nine of the cases (52.3%) had been erroneously reported to be bladder calculi. in 1 patient ultrasonography had failed to diagnose the presence of a piece of foley balloon catheter. plain kub had revealed the presence of a foreign body in 7 patients (43.8%), while in 2 patients (12.5%), who had a surgical gauze in the bladder, a faint radio-opaque shadow in the bladder area had been reported. in 2 patients who had transvesical prostatectomy, cystography had been performed that had strongly suggested the presence of a foreign body in the bladder by showing contrast material in some areas of filling defect. eight intravesical foreign bodies (50.0%) had been removed endoscopically, and the remaining, by open surgery. the operation had been carried out by different surgeons and surgeons in training. the number of the foreign bodies removed endoscopically could have been higher had the required endoscopic equipment and figure 1. pelvis radiography shows calculus formation on an intra-uterine device. figure 2. pelvis radiography shows a coiled-up metal wire in the bladder area. figure 3. ultrasonography shows a straight echogenic foreign body (lead pencil; arrow) and balloon of a foley catheter in the bladder. intravesical foreign bodies—rafique 226 urology journal vol 5 no 4 autumn 2008 expertise be available at the time of treatment of all cases. postoperatively, 2 patients had fever with rigors that settled with appropriate intravenous antibiotic therapy. one patient who had open surgical removal of a surgical gauze developed superficial wound infection. no other complications were recorded. discussion intravesical foreign bodies are an important consideration in the differential diagnosis of lower urinary tract problems. usually, foreign bodies are self-introduced, result of medical errors, migrated from the surrounding organs, or result of a penetrating injury. the variety of foreign bodies inserted in to bladder defies imagination and includes any types of objects. the most common motive associated with intravesical insertion of foreign bodies is sexual gratification. in some cases, it may be a consequence of a psychiatric illness. it is therefore surprising that objects as diverse as light bulbs, electric wire, glass rod, thermometer, battery, and blue tack have been self-introduced by patients.(2,9-12) occasionally, a foreign body is inadvertently inserted into the female urethra in an attempt to procure abortion or prevent conception. (13) furthermore, thermometers are frequently reported to slip into the female bladder during the patient’s attempts to determine the temperature in the vulva or urethra.(14,15) rarely, living objects, leech for instance, may enter the urinary bladder through the urethra.(16) a variety of objects have been reported to migrate into the urinary bladder from the surrounding pelvic organs, including iud, vaginal pessary, artificial urinary sphincter, prosthetic slings, nonabsorbable sutures used in stamey procedures, surgical gauze, etc.(17-22) almost any foreign body placed in the vicinity of the bladder has a potential of migration into the urinary bladder. calculus formation may develop on such foreign bodies. catheters and endoscopic instruments are the most common objects introduced into the bladder by urologists. thus, fragments of these instruments are the most common iatrogenic foreign bodies remaining in the bladder. catheter tips, parts of catheter balloon, bougies, and beak of resectoscope sheath are some of the reported iatrogenic foreign bodies recovered from bladder.(7,23-26) in addition, urethral stents used in reconstructive urological procedures such as hypospadias repair may migrate into the bladder. (27) retained suture material or staples used in bladder surgeries are of other iatrogenic objects, which may subsequently present as bladder calculi.(28) occasionally, surgical gauze or sponge (gossypiboma) may be left in the bladder.(29,30) recently, transvaginal tape has become one of the common procedures performed for the treatment of female stress incontinence. perforations of the bladder during the placement of transvaginal tape are relatively common, but are usually noted on cystoscopy and corrected intraoperatively. undetected bladder perforation may result in several complications including recurrent urinary tract infections, bladder calculus formation, and pelvic pain.(31,32) symptoms of intravesical foreign bodies are usually those of acute cystitis including urinary frequency, dysuria, hematuria, and strangury. some patients may present with swelling of the external genitalia, poor urinary stream, and urinary retention. more importantly, patients occasionally present with no symptoms or complaint of minimal discomfort.(23) however, signs that should raise the physician’s suspicion include undue anxiety during sexual history taking or attempts to avoid genital or rectal examination. previous bladder surgery or surgery on the adjacent organs may well be relevant.(1) radio-opaque intravesical foreign bodies can usually be detected on kub radiography. intravenous urography or retrograde urethrography may provide additional information and occasionally reveal surprising findings and unexpected radiolucent objects.(1) the use of abdominal and transvesical ultrasonography has been reported for the detection of non-radio-opaque intravesical foreign bodies.(33-35) the degree of the echogenicity of a foreign body is dependent on the difference in acoustic impedance between the foreign body and surrounding tissues. hence, the ultrasonographic appearance of intravesical foreign bodies will vary intravesical foreign bodies—rafique urology journal vol 5 no 4 autumn 2008 227 depending on their nature.(36) to confirm the presence of intravesical foreign body cystoscopy is utilized. in addition, cystoscopy will identify the type and location of the foreign body, as well as being the most adequate method for treatment.(2) complications of intravesical foreign bodies consist of chronic and recurrent urinary tract infections, acute urinary retention, calcification, obstructive uropathy, scrotal gangrene, vesicovaginal fistula, squamous cell carcinoma, and even death of sepsis.(37-44) initial management of patients with intravesical foreign bodies should consists of providing pain relief and control of irritative voiding symptoms by prescribing analgesics and anticholinergic drugs, respectively. antibiotics will be required for the control of urinary tract infection and prevention of sepsis in infected patients. definitive management of intravesical foreign bodies is aimed at providing complete removal of the foreign body with minimal complications such as trauma to the bladder and urethra, peritonitis, urinary tract infection, hematuria, etc. on rare occasions, foreign bodies may be spontaneously expelled from the bladder during urination.(45) most foreign bodies in the bladder may be removed either complete or after fragmentation via the endoscopic approach. however, the optimal technique is dictated by the patient’s condition, associated urinary tract injuries and size, and shape and nature of the foreign body. table 2 gives a brief summary of various authors’ experiences of management of intravesical foreign bodies recorded in the current literature.(1,3,7-11,13,16-18,24,45-80) conventionally, grasping forceps and retrieval baskets are used for removal of a foreign body. in some cases, grasping an object with an alligator or calculus forceps increases the effective diameter of that object and may make removal difficult and hazardous. in the past few decades, several modifications of endoscopic instruments and devices have been developed, especially for removing foreign bodies. reportedly, cylindrical foreign bodies and thermometers have been removed via transurethral route using rigid and flexible cystoscopy, respectively.(46,47) wise and king(48) reported magnetic extraction of a metallic foreign body (hair pin) from the bladder by specially designed magnetic retriever. in recent years, because of their larger diameter and straight and strong design, the use of percutaneous instruments has been suggested for removing longer and stiff intravesical foreign bodies.(49) younesi and colleagues(6) reported a similar technique for removal of a fragile glass foreign body (a lidocaine carpule) from the bladder. while marshall and associates(50) reported the use of a specially constructed prolene snare intra-operatively to facilitate safe and rapid extraction of an intravesical metallic pipe by cystoscopy. metal wires introduced into the bladder usually get curled up due to bladder contractions. in some cases, a wire can be removed endoscopically(12); however, in most cases, open surgery is required to minimize urethral trauma during perurethral extraction. ejstrud and poulsen(51) reported the use of intravesical laparoscopy to untie a complete knot of an electric wire. the bladder was distended with 100 ml of saline during the procedure. paraffin objects such as candles and crayons are frequently introduced into the bladder. in the past, various solvents like xylol, benzene, and kerosene had been used for minimally invasive treatment of such objects. since these solvents are known to be carcinogenic, their use is no longer suitable. endoscopic removal of wax and paraffin objects is often complicated by their characteristic of floating on water. this problem may be solved by infusing gases such as carbon dioxide for cystoscopic examination and removal.(1) wyatt and hammontree(8) reported the use of holmium:yttrium-aluminum-garnet laser to cut a foreign body, ie, a weed trimmer line, to facilitate its perurethral removal. they also tested many reported intravesical foreign bodies ex vivo and reported that most foreign bodies except glass appeared to be cut by the laser. as the glass object would not absorb laser energy, it was not fragmented. during the procedure, potential safety concerns about burns and exposure to byproducts of combustion appear to be mitigated by irrigation fluid. the authors suggest that many commonly reported intravesical foreign bodies are amenable to intravesical foreign bodies—rafique 228 urology journal vol 5 no 4 autumn 2008 treatment with laser. habermacher and nadler(7) reported the use of holmium laser to fragment a detached 26-f resectoscope sheath tip before its transurethral removal without any complications. hong and colleagues(32) used holmium laser to remove bladder-penetrating polyester suture in an earlier sling surgery that could not be removed completely by conventional cystoscopic equipment. the use of laser for intravesical fragmentation and subsequent removal of large intravesical foreign bodies is a promising new technique for urological surgeons. szlyk and jarrett(52) described the use of 20-f rigid hysteroscope in urological practice to remove deeply embedded foreign bodies from the lower reference foreign body technique for removal 55 iud cystoscopy 56,57 iud cystoscopy and suprapubic cystotomy 58 iud cystoscopy and transcervical removal 59 calculus on iud cystoscopy/cystolithotripsy 16,60,61 calculus on iud suprapubic cystostomy 62 calculus on iud cystoscopy/electrohydraulic lithotripsy 63 calculus on iud laparotomy 49 pencil percutaneous nephrolithotomy sheath and forceps 13 calculus on pencil cover cystoscopy 1 wax candle cystoscopy, air insufflation, and endoscopic removal 22,64 surgical gauze cystoscopy and removal with forceps 65 polypropylene mesh after laparoscopic hernioplasty suprapubic cystostomy 66 demobilization chain suprapubic cystostomy 13 bamboo stick cystoscopy 67 long plastic tube cystoscopy 3,68 electric wire cystoscopy 51 electric wire intravesical laparoscopic undoing of knots & removal 69 calculus on copper wire suprapubic cystostomy 70 calculus on metal wire open cystostomy 8 weed trimmer line holmium:yag laser 71 stamey sutures cystoscopy 72 suture and pledget of bladder neck suspension cystoscopy 31 tension-free vaginal tape suprapubically assisted operative cystoscopy for removal of mesh 32 bladder penetrating polyester suture of sling operation cystoscopy and holmium laser removal 73,74 polypropylene suture after anti-incontinence surgery cystoscopy/holmium laser excision 75 tampon cystoscopy 76 urethral incontinence plug cystoscopy 47 thermometer flexible cystoscopy 77 thermometer percutaneous removal with rigid nephroscope and forceps 78 aluminum rod open cystostomy 48 metallic hair pin magnetic extraction with magnetriever 17 migrated ams 800 urinary sphincter transvesical removal 11 battery suprapubic cystostomy 7 detached tip of resectoscope sheath holmium laser fragmentation and cystoscopic removal 24 calculus on a piece of foley balloon catheter tranurethral cystolitholapaxy cystoscopy 54 retained catheter tip with inflated foley balloon cystoscopy, puncture of balloon with sachse’s urethrotome knife, and endoscopic removal 79 calculus on ruptured foley balloon fragment cystoscopy 9 blue tack carbon dioxide insufflation cytoscopy for visualization and laparoscopic removal 80 retained silastic catheter cystoscopy for optical visualization and percutaneous removal with laparoscopic equipment 53 toy frog cystoscopic visualization and small open cystostomy table 2. reported intravesical foreign bodies in the literature and techniques used for their removal* *iud indicates intrauterine device; yag, yttrium-aluminum-garnet; and ams, american medical systems. intravesical foreign bodies—rafique urology journal vol 5 no 4 autumn 2008 229 urinary tract of 3 patients in whom previous attempts with standard cystoscopic equipment had been unsuccessful. delair and coworkers(53) reported a technique for rapid extraction of a large foreign body from the bladder. in this technique, the intravesical foreign body was visualized by cystoscopy. urinary bladder was entered through a small cystotomy using a cutto-the-light approach, and the foreign body (a toy frog) was rapidly extracted under cystoscopic guidance. the authors claimed that combination of endoscopy and cystotomy is rapid, safe, and potentially applicable for the removal of large vesical calculi. removal of the retained catheter tip of an inflated foley catheter’s balloon is difficult and sometimes frustrating. the spherical latex rubber balloon with little amount of air makes it of lighter density than water. therefore, it has tendency to float in the urinary bladder and rest near the dome, almost hiding itself. hemal and colleagues(54) reported 2 techniques to tackle such a situation. in the first technique, the bladder was evacuated of excess water and the balloon was trapped in the small space to be punctured with sachse’s urethrotome knife before its removal. in the second technique, a fine hypodermic needle without its hub was mounted on the biopsy forceps to puncture the balloon. the removal of intravesical foreign bodies in children poses a great therapeutic challenge. in contrast to intravesical foreign bodies in adults, the size of the pediatric urethra may preclude safe transurethral removal. reddy and daniel(9) reported a novel method for tackling such a situation. using cystoscopy as the optical device through the urethra, a 10-mm laparoscopic port was introduced suprapubically under the vision for extraction of the complex foreign body (ie, blue tack while the bladder remained insufflated with carbon dioxide at a pressure of 12 mm hg. by avoiding the use of irrigating fluid, they claimed that irrigating fluid-induced hypothermia can be avoided. percutaneous retrieval of intravesical foreign body in a 4-month-old infant using direct transurethral visualization has been reported by hutton and huddart.(80) conclusion intravesical foreign bodies are not uncommon and their presence should be included in the differential diagnosis of patients presenting with chronic lower urinary tract problems. radiological evaluation is necessary to determine the exact size, number, and nature of foreign bodies. the most suitable method for removal of intravesical foreign bodies will depend on the nature of the foreign body, age of the patient, and the available expertise and equipment. most intravesical foreign bodies can be retrieved with endoscopic and minimally invasive techniques without resorting to open surgery. conflict of interest none declared. references 1. eckford sd, persad ra, brewster sf, gingell jc. intravesical foreign bodies: five-year review. br j urol. 1992;69:41-5. 2. granados ea, riley g, rios gj, salvador j, vicente j. self introduction of urethrovesical foreign bodies. eur urol. 1991;19:259-61. 3. pal 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2005;10:72-3. 76. modrau is, poulsen eu. intravesical displacement and encrustation of urinary incontinence plugs. bju int. 2002;89:324. 77. nishiyama k, shimada t, yagi s, kawahara m, nakagawa m. endoscopic removal of intravesical thermometer using a rigid nephroscope and forceps. int j urol. 2002;9:717-8. 78. bakshi gk, agarwal s, shetty sv. an unusual foreign body in the bladder. j postgrad med. 2000;46:41-2. 79. juan ys, chen ck, jang my, et al. foreign body stone in the urinary bladder: a case report. kaohsiung j med sci. 2004;20:90-2. 80. hutton ka, huddart sn. percutaneous retrieval of an intravesical foreign body using direct transurethral visualization: a technique applicable to small children. bju int. 1999;83:337-8. erratum laparoscopic adrenalectomy: a report of the first experience in iran simforoosh n*, ahmadnia h, ziaee am, moradi m urology/nephrology research center, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran volume1, number 2, pages 77-81: some technical errors mainly due to persian to english translation were unnoticed and the published version was not the edited one. the correct version of the article follows. the publisher regrets this error. abstract purpose: to report the first experience in laparoscopic adrenalectomy and to study its efficacy and safety in the treatment of different adrenal diseases. materials and methods: from march 1997 to july 2001, 11 patients underwent laparoscopic adrenalectomy through transperitoneal approach, five of whom were males and 6 were females. their mean age was 35.5 (range 28 to52) years. lesion was located on the left side in 6 patients and on the right side in 5. all necessary evaluations were done preoperatively including ct scan, mri, mibg scan, and endocrine tests such as acth, cortisol, mineralocorticoid, 17-hydroxyprogesterone, and urinary vma. three (5, 10, and 12 mm) trocars were used in left laparoscopic adrenalectomy and three or four (12, 10, 5, and 5 mm) trocars were applied in right laparoscopic adrenalectomy. all the patients were followed up for three months with physical examination and paraclinical tests. results: mean operative time (including anesthesia and surgery) was 205±65.95 (range 130 to 310) minutes. no significant difference was seen between the operative time in the left side and the right side adrenalectomy (p=0.5). mean hospitalization was 5.54±3.4 (range 3 to15) days. mean size of mass was 5.45±1.7 (range 2 to 8) cm. blood transfusion was performed in 2 patients and open surgery was conducted for one because of extensive adhesions. no mortality was reported. during a 3-month follow-up, hormonal tests and blood pressure were normal for all the patients, with no medical treatment being required. conclusion: our study demonstrated that transperitoneal laparoscopic adrenalectomy is an effective and safe approach in the treatment of adrenal masses with the least morbidity. key words: adrenal neoplasm, laparoscopy, adrenalectomy 221 urology journal unrc/iua vol. 1, no. 3, 221-225 summer 2004 printed in iran introduction the first laparoscopic adrenalectomy was performed in 1992 by ganger.(1-3) this approach was quickly developed because of less hemorrhage during operation, shorter hospitalization, and faster postoperative improvement.(4-6) laparoscopic adrenalectomy may be conducted either transperitoneally or retroperitoneally.(4, 5, 7, 8) in this study, transperitoneal approach was the preferable method, which is the first report of laparoscopic adrenalectomy in iran and to our accepted for publication in august 2003 *corresponding author: department of kidney transplantation, shaheed labbafinejad medical center, boustan 9, pasdaran, tehran, iran. email: simforoosh@iurtc.org.ir laparoscopic adrenalectomy: a report of the first experience in iran knowledge the first one in a renal transplanted patient worldwide. materials and methods from march 1997 to july 2001, 11 patients underwent laparoscopic adrenalectomy through transperitoneal method, five of whom were males and 6 were females. their mean age was 35.5 (range 28 to 52) years. table 1 indicates clinical and pathological details. ultrasonography and abdominal ct scan was preoperatively performed for all patients (fig. 1). mri was conducted if ct scan was unclear. mibg scan would be performed if pheochromocytoma was suspected and if mri or ct scan were not helpful. routine biochemical tests such as serum potassium and sodium levels, fasting blood sugar, and endocrine analyses such as serum acth, cortisol, minralocorticoids, and 17-hydroxyprogesterone, and 24-hour urinary vma were conducted too. details of the procedure, its complications, and the probability of conversion to open surgery were explained for all of the patients. bowel preparation was performed 24 hours before the procedure. ng tube and urethral catheter were inserted under general anesthesia. then patients were secured in flank position with an angle of approximately 60 degrees. the bed was flexed 30 degrees and was reversed to trendelenburg 10 degrees to retract intestine from the field of surgery. after the preparation of patient veress needle was used through an umbilical incision and pneumoperitoneum was induced using co2. trocars were placed when the pressure reached 19 to 20 mmhg and then it was reduced to 14 to 15 mmhg. three 12, 10, and 5 mm trocars were applied in left adrenalectomy (for 6 patients). a 12 mm trocar was applied through umbilical incision and used for telescope. a 10 mm trocar was applied on breast line parallel to umbilicus and a 5 mm trocar was applied on midline between xiphoid and umbilicus. then peritoneum was opened from the colonic spleen curve to sigmoid on toldt line and colon was pushed inside. then gerota fascia was opened on renal vein, so that adrenal gland and vein were seen. adrenal vein was cut after clipping bilaterally. then fat tissue and the rest of the vessels were cut by mets or electrocautery after clipping bilaterally, so that adrenal gland was totally freed. three to four (12, 10, 5, and 5 mm) trocars were used in right adrenalectomy (for 5 patients). similar trocars were applied in left. the second 5 mm trocar was inserted on the breast line at the rib margin to retract the liver if needed. adrenal gland was seen at the right side behind peritoneum after retracting the liver upward. hepatocolic and peritoneal ligaments were cut; thus, anterior surface of adrenal gland was revealed. after freeing the gland at inferior, lateral, posterior, and finally medial surfaces and cutting adrenal vein, following bilateral clipping, adrenal gland was removed through an umbilical incision made for 12 mm trocar, after enlarging it (depending on the size of gland) (fig. 2). as a drain, an 18 f nelaton 222 no. age gender adrenal pathology side of operation 1 43 male conn’s syndrome right 2 40 female conn’s syndrome left 3 52 male pheocromocytoma right 4 32 male pheocromocytoma right 5 35 male pheocromocytoma left 6 34 female pheocromocytoma left 7 39 female adrenal medolary hyperplasia left 8 28 male pheocromocytoma left 9 29 female pheocromocytoma left 10 31 female conn’s syndrome right 11 28 female myelolipoma right table 1. patients' clinical and pathological characteristics fig. 2. laparoscopic surgical operation and the tumor fig. 1. a 35-year-old woman with dysuria. a 7 cm tumor in left adrenal gland was revealed. laparoscopic adrenalectomy: a report of the first experience in iran catheter was applied through 10 mm trocar for two or three days for all the patients. they were followed up with paraclinical tests and physical examination for three months (fig. 3,4). student's t test was used for comparison of the size of mass and time of the procedure. results the mean time of the procedure (including anesthesia and surgery) was 205±64.95 (range 130 to 310) minutes. mean time for left side was 227.5±53.1 (range 145 to 305) minutes. there was no significant difference in the time of procedure between left and right sides (p=0.5). mean hospitalization was 5.54±3.4 (range 3 to 15) days. the mean size of mass was 5.45±1.7 (range 2 to 8) cm. no significant difference was seen between the size of left sided masses and right sided ones (p=0.6). a 28-year female with a history of a 15-year renal transplantation was among the patients. she underwent laparoscopic adrenalectomy because of an adrenal mass, pathologic report of which was myelolipoma. blood transfusion was performed in 2 cases. normal diet was started for 9 patients at the first postoperative day. open surgery due to severe adhesion was conducted for one patient (9%), who underwent laparoscopic adrenalectomy because of pheochromocytoma. hypertensive crisis occurred during the procedure in one pheochromocytoma case, which was properly managed without any problem by the anesthesiologist. postoperative complications were reported in only one patient with left adrenalectomy. this patient underwent open surgery due to postoperative hemorrhage. no hernia or infection was seen at the site of trocars and no mortality was reported. blood pressure and hormonal tests were normal with no medical treatment during eight-month follow-up period. discussion surgical intervention is regarded as the main approach in several adrenal disorders. familiarity with adrenal gland anatomy and its pathophysiology is important for a successful procedure. open surgical incisions for adrenal mass removal consist of thoracoabdominal, flank, anterior, and posterior (lumbar). selecting the appropriate method depends on adrenal pathology, patient's physical structure, history of surgical operation, and surgeon's experience.(9) laparoscopic adrenalectomy is an effective and safe method to treat various endocrine and neoplasic adrenal diseases,(4,6,10,12) as it was shown in this study. several studies reported that the morbidity rate in laparoscopic adrenalectomy is less than that in open surgery.(4,5,7,13-15) previously, laparoscopic surgery needed a longer time than open surgery; however, the progress of technology and more laparoscopic experience have led to similar operative times.(14) patients in laparoscopic surgeries would be hospitalized shorter and would return to their normal activities sooner. younger patients could return to their sport activities sooner with no limitation. regarding cosmetic point of view, short incisions at trocar sites instead of long incisions would be more considerable particularly for females.(14) magnification by laparoscope would lead to easier detection of small vessels around adrenal mass which causes a distinguishable decrease of hemorrhage comparing to open adrenalectomy.(16) it also brings about a more accurate view of surgical anatomy of adrenal gland and helps differential diagnosis between adenoma and normal tissue of gland. elective 223 fig. 4. unrecognizable port site scars fig. 3. pathology: adrenaladenoma laparoscopic adrenalectomy: a report of the first experience in iran removal of adrenal lesion without total removal of the gland, which is problematic in open surgery, is more practical in laparoscopic surgery. guazzoin et al reported successful removal of 2 adrenal cysts without adrenal removal after which adrenal function was normal.(14) most authors agree on the effectiveness of laparoscopic therapy for conn's and cushing's syndromes.(4) because of hypertensive crisis during surgery, pheochromocytoma surgery differs form other adrenal tumoral surgeries.(4,5,17) it was believed that laparoscopic methods are contraindicated in pheochromocytoma, for the produced ponomoperitoneum with co2 and the increase of abdominal pressure would lead to hemodynamic changes and the release of catecholamines as well.(18) furthermore, co2 could cause hypercapnia and respiratory acidosis that would lead to hypertension during laparoscopy.(17,19) sprung et al have recently shown that laparoscopic hemodynamic changes are comparable with those of open surgery methods. the number of hypertension episodes and the highest level of hypertension during surgery were equal in both methods, while hypotension severity was lower in laparoscopic methods than open surgery.(20) consequently, pheochromocytoma could be treated by laparoscopic surgery, although large lesions could increase the chance of hemorrhage, hypertension and postoperative complications due to increased number of vessels.(21) in this study hypertension occurred only in one patient (out of 6) with pheochromocytoma, which was controlled with no complication. since ganger has indicated that lesions larger than 13 cm could be treated by laparoscopic adrenalectomy, the size of adrenal mass was no more considered as a limiting factor in laparoscopic surgery.(4,12) thus, larger masses which could mostly be malignant, would be removed by laparoscopic surgery, though, enlarging the incision of umbilicus would be essential.(14) dissection would be more difficult and the surgery would last in a way that could be beyond patient's tolerance.(21) moreover, large masses have many abnormal vessels which could increase hemorrhage.(22) bilateral adrenalectomy for cushing's syndrome after unsuccessful treatment of hypophysis adenoma (surgery or radiotherapy) or for secondary cushing's syndrome could lead to improper discharge of acth.(23,24) in our study, the decrease of wound infection risk, better postoperative respiratory capacity and shorter hospitalization would be main advantages of laparoscopy.(21) laparoscopy is used in the treatment of nonfunctional adrenal masses too, especially when their malignant nature is proved.(25) this is a common case as 20-22% of laparoscopic adrenalectomies are because of incidentaloma removal.(4,6) porpiglia et al reported that the incidence of incidentaloma was 30% of the whole laparoscopic adernalectomies.(21) several factors such as a mass larger than 6 cm (in ct scan or sonography), non-homogenized mass in ct scan and an increase of dhea or estradiol are used to distinguish malignant adrenal masses from benign.(26) in spite of these factors, adrenalectomy may be performed for an incidentaloma where cortical carcinoma may be detected by the analysis of pathologic sample. porpiglia et al reported such a carcinoma after laparoscopic removal of the mass. no sign of recurrence was reported after 40 months follow-up.(21) it is commonly believed that this treatment would be sufficient for proved malignant adrenal masses provided that the neoplasm is limited to the gland and a perfect and accurate laparoscopy is performed.(4,5) laparoscopic transperitoneal removal of adrenal glands includes anterior and lateral transperitoneal methods. in anterior transperitoneal method, adrenal anterior margin is usually freed at the end that occasionally leads to upward movement of adrenal, which makes it difficult to pull downward.(16) however, in this study anterior margin of adrenal gland was easily freed at the beginning after the retraction of the liver or spleen toward midline through lateral transperitoneal approach. thus, it seems that lateral transperitoneal approach would be better than anterior transperitoneal, particularly for large tumors. conclusion this study indicated that transperitoneal laparoscopic adrenalectomy is an effective and safe approach, which should be performed by a skilled laparoscopic surgeon to minimize potential intraoperative and postoperative complications such as infection and to avoid open incision. clinical outcomes of laparoscopic surgery in such circumstances would be much better than open surgery and its morbidity would be much lesser. 224 laparoscopic adrenalectomy: a report of the first experience in iran references 1. ganger m, lacroix a, bolte e. laparoscopic adrenalectomy in cushing's syndrome and pheochromocytoma. n engl j med 1992; 327: 1003. 2. ganger m, lacroix a, printz ra, et al. early experience with laparoscopic approach for adrenalectomy. surgery 1993; 114: 1120. 3. ganger m. lacroix a, bolte e. laparoscopic adrenalectomy. surg endosc 1993; 7: 122. 4. ganger m, pomp a, heniford bt, et al. laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. ann surg 1997; 226: 238. 5. janetschek g, altarac s, finkenstedt g, et al. technique and results of laparoscopic adrenalectomy. eur urol 1996; 30: 475. 6. terachi t, matsuda t, terai a, et al. transperitoneal laparoscopic adrenalectomy: experience in 100 patients. j endourol 1997; 11: 361. 7. gasman d, droupy s, koutani a, et al. laparoscopic adrenalectomy: the retroperitoneal approach. j urol 1998; 159: 1816. 8. walz mk, peitgen k, hoermann r, et al. posterior retro peritoneoscopy as a new minimally invasive approach for adrenalectomy: results of 30 adrenalectomies in 27 patients. world j surg 1996; 20: 769. 9. guz bv, straffon ra, novick ac. operative approaches to the adrenal gland. urol clin n amer 1989; 16: 527. 10. guazzoni g, montorsi f, bergamaschi f, et al. effectiveness and safety of laparoscopic adrenalectomy. j urol 1994; 152: 1375. 11. thompson gb, grant cs, van heerden ja, et al. laparoscopic versus open posterior adrenalectomy: a case control study of 100 patients. surgery 1997; 122: 1132. 12. vargas hi, kavoussi lr, bartlett dl, et al. laparoscopic adrenalectomy: a new standard of care. urology 1997; 49: 673. 13. bonjer hj, van der harst e, steyerberg ew, et al. retroperitoneal adrenalectomy: open or endoscopic? would j surg 1998; 22: 1246. 14. guazzoin g, montorsi f, bocciardi a, et al. transperitoneal laparoscopic versus open adrenalectomy for benign hyperfunctioning adrenal tumors: a comparative study. j urol 1995; 153: 1597. 15. winfield hn, hamilton bd, bravo el, et al. laparoscopic adrenalectomy: the preferred choice? a comparison to open adrenalectomy. j urol 1998; 160: 325. 16. terachi t, matsuda t, terai a, et al. transperitoneal laparoscopic adrenalectomy: experience in 100 patients. j endourol 1997; 11: 361. 17. mobius e, nies c, rothmund m. surgical treatment of pheochromocytomas: laparoscopic or conventional? surg endosc 1999; 13: 35. 18. joris j, hamoir e, hartstein gm, et al. hemodynamic changes and catecholamine release during laparoscopic adrenalectomy for pheochromocytoma. anesth analg 1999; 88: 16. 19. fernandez-cruz l, taura p., saenz a, et al. laparoscopic approach to pheochromocytoma: hemodynamic changes and catecholamine secretion would j surg 1996; 20: 762. 20. sprung j, o hara jf jr, gill is, et al. anesthetic aspects of laparoscopic and open adrenalectomy for pheochromocytoma. urology 2000; 55: 339. 21. porpiglia f, garrone c, giraudo g, et al. transperitoneal laparoscopic adrenalectomy: experience in 72 procedures. j endourol 2001; 15: 275. 22. ganger m. laparoscopic adrenalectomy. surg clin north am 1996; 76: 523. 23. ferrer fa, macgillivray dc, malchoff cd, et al. bilateral laparoscopic adrenalectomy for adrenocorticotropic dependent cushing's syndrome. j urol 1997; 157: 16. 24. lanzi r, montorsi f, losa m, et al. laparoscopic bilateral adrenalectomy for persistent cushing's disease after transsphenoidal surgery. surgery 1998; 123: 144. 25. mugiya s, suzuki k, masada h, et al. laparoscopic adrenalectomy for nonfunctioning adrenal tumor. j endourol 1996; 10: 539. 26. wells sa, merke dp, cutler gb, et al. therapeutic controversy: the role of laparoscopic surgery in adrenal disease. j clin endocrinol metab 1998; 83: 3041. 225 vol 12. no 02 march-april 2015 2111 editorial comment re: minimally invasive therapy using intralesional onabotulinumtoxina in peyronie’s disease peyronie's disease (pd) is a benign condition of unclear etiology. it results in penile deformities such as penile curvature, dimple, and shortening. the incidence of this disease has increased dramatically during the last decade, especially in younger men. more and more young people are affected by pd. in our community most of the affected men are in their 30s and 40s, and unlike pd in older men, the prognosis in these younger men is very poor, and the natural history of pd in these young patients mostly is rapid progression with resultant sever erectile dysfunction. younger patients are predominantly vulnerable to emotional, psychosexual, and relationship problems. most of my patients are men under 40. the onset of pd in men under 40 is often much more acute.(1) i believe that, this disease will become a health problem in most communities in the next decade, and a public health action plan is needed to determine the prevalence and causes for this disease. the reported prevalence of pd in some studies is up to 7%.(2-4) yet in my opinion, these reported prevalence are under estimated. researches are needed to better understand many known and potential causes of pd. medical and surgical treatment options are limited in number and efficacy for pd.(5-13) therefore addressing new treatment modalities (oral medication, intralesional injection, and surgery) is of utmost importance. development of novel therapeutic modalities is hampered by lack of standardized definition for pd and its complications. in addition the exact cause of pd is unknown and usually treatment focuses on the causative disorder. though two questionnaires, namely peyronie’s disease symptom bother domain (pdsbd) and the peyronie’s disease questionnaire (pdq), have been developed, but they are not sufficient. usually the results of different treatment approaches in different studies are not reproducible. because, pd has a wide range of presentation and different disease stages. the methods for plaque and penile curvature measurements have not been yet standardized. assigning patients into different stage of disease is mostly by physician desertion. as i mentioned above, pd is somewhat prevalent in our community. i have not seen any benefits from intralesional therapy (verapamil, interferon, collagenase and etc.). indeed in some cases intralesional therapy have resulted in catastrophe. multiple injections into multiple plaques are very traumatizing. i saw many patients who developed a short bony penis without any erection due to multiple injections. in these patients penile ultrasonography revealed a calcified plaque that involved the entire tunica albuginea of both corpora cavernosal. most of the existing pharmacological and other treatment regimens have not demonstrated consistent results in clinical trial.(14-16) the principal problem in pd is the plaque formation in the tunica albuginea of the penis. the plaque(s) prevent normal expansion of the penile tunica albuginea, resulting in penile curvature, deformity, and narrowing with a hinge effect. therefore every effective treatment modality should result in plaque disappearance or at least significant reduction in plaque(s) volume. the aim of intralesional pharmacotherapy in the treatment of pd is to direct delivery of large doses of pharmacologic agents into the plaque. multiple agents have been used, including corticosteroids, verapamil, collagenase, and interferon, among others.(5,7) in present study, the authors aimed to address this issue with new intralesional therapeutic agent. in present study the authors reported significant improvement with a single dose intralesional onabotulinumtoxina administration. onabotulinumtoxina (botox®, allergan, inc., irvine, ca) is a potent neurotoxin derived from the anaerobic bacteria clostridium botulinum. of the seven known toxin serotypes (a-g), only serotypes a and b are used in medicine. onabotulinumtoxina was first approved by the u.s. food and drug administration (fda) in 1989 for two therapeutic indications: blepharospasm and strabismus. (17) haubner and colleagues examined patient-specific keloid tissue in a cell culture model to clarify the effects of onabotulinumtoxina incubation on cell proliferation and the expression of cytokines and growth factors such as tgf-β, vascular endothelial growth factor (vegf), and il-6.(18) they demonstrated that none of the examined variables were affected by onabotulinumtoxina incubation and concluded that there was no enough evidence to suggest a significant therapeutic effect for intralesional onabotulinumtoxina injections in the treatment of keloids.(18) studies addressing the safety and efficacy of onabotulinumtoxina for treatment of wound scar, fibrotic tissue and keloid are very scarce and inconclusive. in present study, the authors reported beneficial effects from single dose intralesional injection of onabotulinumtoxina. but the reported results might be hampered due to following reasons. the study has no control group, the sample size and as a result the study power is low, the stage of disease in which the recruited patients were, is not clear, the followup period is short and standard questionnaires for pd such as pdsbd and pdq), have not been used. it is important to monitor both the subjective and objective response to any pd treatment. although there is no standard subjective questionnaire, some tasks should be employed to evaluate the patient’s perception of changes resulted from treatment. with the fact that erectile function may worsen over time and the penile plaque and curvature may relapse, the results at long-term follow-up should be considered. given the potential complications and possible recurrence of disease following intralesional therapy, the assessment of patient expectations and beliefs about the proposed treatment option and the determining and correction of mistaken beliefs are essential components prior to intralesional therapy. intralesional therapy is an invasive treatment with questionable benefits and potential complications. the european association of urology (eau) guidelines provided recommendations for the diagnosis and treatment of pd penile curvature.(19) but, this will be beneficial on patients in the early stage of the disease. in addition, the eau recommends intralesional clostridial collagenase use with a level of evidence 2b and recommendation grade c, based on two small studies, with poor samples of patients and insufficient follow-up periods.(20,21) many of the studies have had design flaws, which means more researches are required to confirm or disprove the results. yet, there is no effective treatment for pd when the plaque is densely fibrotic or calcified. despite a vague therapeutic benefit, off-label intralesional injection therapy has become the principal treatment for pd in different stages. when evaluating efficacy and safety, considering specific endpoints, which are, penile curvature, plaque volume, erectile function, and relationship with partner, need to be analyzed in a critical, evidence-based fashion. the sentence “surgical correction is ultimately successful in the majority of patients with pd”,(22) is not true. the majority of patients with advanced pd, have extensive “t” shape plaque formation. the plaque involved the entire tunica albuginea of both corpora cavernosum extending into raphe. this extensive involvement of tunica albuginea, severely deteriorate penile hemodynamics. the ultimate goal of every surgical procedure for pd, should be removing and restoring normal penile hemodynamics. correction of only penile curvature, will not treat pd and will not result in improved penile hemodynamics. it is important to monitor both the subjective and objective response to any pd treatment. the take home message is that treatment modalities for pd have a low success rate in advanced stage, usually are not reproducible, and that standardization for patient selection is crucial. pd is yet debilitating condition with increasing prevalence and morbidity. for introducing effective treatment option we need to completely understand the etiology and underlying pathophysiology of pd. if further studies are needed to determine the role of intralesional onabotulinumtoxina in the treatment of pd, i can’t recommend it. but additional basic science studies are needed to devise more effective treatments for this difficult condition. mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specializing in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com references 1. tefekli a, kandirali e, erol h, alp t, köksal t, kadioğlu a. peyronie's disease in men under age 40: characteristics and outcome. int j impot res. 2001;13:18-23. 2. dibenedetti db, nguyen d, zografos l, ziemiecki r, zhou x. a population-based study on peyronie's disease: prevalence and treatment patterns in the united states. adv urol. 2011;2011:282503. 3. mulhall jp, creech sd, boorjian sa, et al. subjective and objective analysis of the prevalence of peyronie's disease in a population of men presenting for prostate cancer screening. j urol. 2004;171:2350-3. 4. el-sakka ai, tayeb ka. peyronie's disease in diabetic patients being screened for erectile dysfunction. j urol. 2005;174:1026-30. 5. shaw ej, mitchell gc, tan rb, sangkum p, hellstrom wj. the non-surgical treatment of peyronie disease: 2013 update. world j mens health. 2013;31:183-92. 6. safarinejad mr. safety and efficacy of coenzyme q10 supplementation in early chronic peyronie's disease: a double-blind, placebocontrolled randomized study. int j impot res. 2010;22:298-309. 7. jordan gh, carson cc, lipshultz li. minimally invasive treatment of peyronie's disease: evidence-based progress. bju int. 2014;114:1624. 8. safarinejad mr, asgari ma, hosseini sy, dadkhah f. a double-blind placebo-controlled study of the efficacy and safety of pentoxifylline in early chronic peyronie's disease. bju int. 2010;106:240-8. 9. safarinejad mr. efficacy and safety of omega-3 for treatment of early-stage peyronie's disease: a prospective, randomized, double-blind placebocontrolled study. j sex med. 2009;6:1743-54. 10. tan rb, sangkum p, mitchell gc, hellstrom wj. update on medical management of p eyronie's disease. curr urol rep. 2014;15:415. 11. safarinejad mr. efficacy and safety of omega-3 for treatment of early-stage peyronie's disease: a prospective, randomized, double-blind placebocontrolled study. j sex med. 2009;6:1743-54. 12. safarinejad mr, hosseini sy, kolahi aa. comparison of vitamin e and propionyl-lcarnitine, separately or in combination, in patients with early chronic peyronie's disease: a double-blind, placebo controlled, randomized study. j urol. 2007;178:1398-403. 13. safarinejad mr. therapeutic effects of colchicine in the management of peyronie's disease: a randomized double-blind, placebocontrolled study. int j impot res. 2004;16:23843. 14. serefoglu ec, hellstrom wj. treatment of peyronie's disease: 2012 update. curr urol rep. 2011;12:444-52. 15. gur s, limin m, hellstrom wj. current status and new developments in peyronie's disease: medical, minimally invasive and surgical treatment options. expert opin pharmacother. 2011;12:931-44. 16. ralph d, gonzalez-cadavid n, mirone v, et al. the management of peyronie's disease: evidence-based 2010 guidelines. j sex med. 2010;7:2359-74. intralesional onabotulinumtoxina in peyronie’s disease-muñoz-rangel et al. sexual dysfunction and fertility 2112 vol 12. no 02 march-april 2015 2113 17. botox® (onabotulinumtoxina) for injection, for intra-muscular, intradetrusor, or intradermal use. 2013. full pre-scribing information. irvine, ca: allergan, inc. 18. haubner f, leyh m, ohmann e, sadick h, gassner hg. effects of botulinum toxin a on patient-specific keloid fibroblasts in vitro. laryngoscope. 2014;124:1344-51. 19. hatzimouratidis k1, eardley i, giuliano f, et al. eau guidelines on penile curvature. eur urol. 2012;62:543-52. 20. rybak j, hehemann m, cordero c, levine l. does calcification of peyronie’s disease plaque predict progression to surgical intervention? j urol 2012;187(suppl): e684. 21. gelbard mk, james k, riach p, dorey f. collagenase versus placebo in the treatment of peyronie’s disease: a double-blind study. j urol. 1993;149:56-8. 22. lacy gl 2nd, adams dm, hellstrom wj. intralesional interferon-alpha-2b for the treatment of peyronie's disease. int j impot res. 2002;14:336-9. intralesional onabotulinumtoxina in peyronie’s disease-muñoz-rangel et al. vol 12. no 02 march-april 2015 2113 reply by author we appreciate the pertinent editorial comments to our manuscript. certainly, the incidence of peyronie’s disease (pd) is increasing in male population, and the illness’ prognosis is unfavorable in many patients, particularly in sexual function. since the early description of the disease by peyronie, many treatments have been tested, achieving disconcerting results, as established in the different treatment guidelines recently published. the pathophysiology of the disease still remains unknown, so the gold standard treatment has not been described yet. according with the observations of common molecular and biological pathways of pd with hypertrophic scars, keloid scars and dupuytren’s contracture, some reports using botulinum toxin have demonstrated to have a slight-to-mild beneficial therapeutic effect. we designed this prospective cohort study with favorable results, but we clarified in our manuscript that the design of a prospective clinical trial is encouraged to demonstrate any therapeutic benefit. currently, a protocol is running at baylor college of medicine, entitled “h-22411: botox® for peyronie's disease”, with the identifying no. nct00812838 by mohit khera and colleagues, waiting for final results in january 2016. the authors would appreciate our article to be referred in the editorial comment as an accepted manuscript, since our results constitute the first literature report of treatment of pd with onabotulinumtoxina. clotilde fuentes-orozco, md, ph.d. corresponding author sexual dysfunction and fertility 2114 miscellaneous 114 urology journal vol 6 no 2 spring 2009 urogenital history in veterans exposed to high-dose sulfur mustard a preliminary study of self-reported data mohammad reza soroush,1 mostafa ghanei,1 shervin assari,1 hamid reza khoddami vishteh2,3 introduction: to date, little information exists regarding urogenital diseases in those who have been exposed to sulfur mustard (sm). we report the selfreported history of urologic conditions and findings on physical examination in a group of male veterans 19 to 26 years after exposed to high-dose sulfur mustard. materials and methods: data on urologic health conditions of a nationwide health survey were used in this study. this survey included all 289 iranian male veterans who had been exposed to high doses of sm between 1983 and 1989. demographic data, exposure-related data, health status, and also self-reported lifetime history of urologic conditions were analyzed. history of benign prostatic hyperplasia, recurrent urinary tract infections, pyelonephritis, urinary calculi, kidney failure, and urogenital neoplasms were specifically concerned. results: the mean age of the veterans was 45.0 ± 7.5 years (range, 30 to 75 years). an interval of 19 to 26 years had passed from exposure to sm. fifty veterans (17.3%) had a positive history of urinary calculi, 25 (8.7%) had recurrent urinary tract infections, 5 (1.7%) had bph, and 2 (0.7%) had kidney failure. none of them had experienced urogenital malignancies. neither recurrent urinary tract infections nor urinary calculi were significantly associated with age, medications and their doses, or sm-induced late complications in other organs. conclusion: this study adds the prevalence of self-reported urologic conditions to our limited knowledge on sm-exposed veterans’ health condition, without finding any link neither to demographic, nor to the severity of health complications related to the sm exposure. urol j. 2009;6:114-9. www.uj.unrc.ir keywords: chemical warfare, mustard gas, veterans, urologic diseases, health care surveys 1janbazan medical and engineering research center, tehran, iran 2department of psychiatry, medicine and health promotion institute, tehran, iran 3scientific writing network, tehran, iran corresponding author: shervin assari, md psychiatry department, medicine and health promotion institute, tehran, iran tel: +98 21 8126 4150 fax: +98 21 8803 7561 e-mail: cru_common@yahoo.com received november 2009 accepted march 2009 introduction although sulfur mustard (sm) enters all organs through systemic distribution when used as warfare, until now, the only systems which have been proven to be affected are the lung, skin, and blood.(1-4) it has not been wellinvestigated whether sm affects other body organs such as the urinary tract or neurological and gastrointestinal systems in the long run. the lack of knowledge has precluded ruling out any impairment of these organs by sm to date.(5) in particular, most previous studies assessing late complications of sm-exposed veterans have neglected the urogenital system.(6,7) urogenital history in veterans exposed to sulfur mustard—soroush et al urology journal vol 6 no 2 spring 2009 115 there is a great body of evidence regarding acute effects of sm on the urogenital system in animal model. boursnell and colleagues(8) showed that radioactive sm diffused rapidly throughout the body after intravenous injection in experiments on rabbits. activity was retained chiefly in the kidneys, and with approximately 20% of the sm activity being excreted in 12 hours. in rodents, the majority of the injected sm was excreted in the urine within 72 hours.(9,10) also, it was shown that several metabolites of sm which may theoretically affect the urogenital system were found in urine.(11) nearly, all we know about the effect of sm on the urogenital system has been derived from studies of acute phase of exposure in animal models,(12-14) while information on human data, especially on the late phase after exposure, is limited.(15) given the chemical attacks by iraq in 1980s, today in iran, a large population of sm-exposed veterans live with long-term complications. herein, we report the findings of a survey focusing on the history of urogenital conditions in male veterans exposed to sm, 19 to 26 years earlier. materials and methods setting data presented here is a part of the veterans health survey done by the janbazan medical and engineering research center, in isfahan, iran, in 2007. in this survey, all veterans exposed to high doses of sm between 1983 and 1989 were selected from all provinces of iran by census sampling. a total of 345 affected veterans were approached, of whom 289 agreed to participate in the health survey. high-dose exposure was defined as an exposure that has caused acute life-threatening effects which needed aggressive inpatient care during the early stages, accompanied by different chronic complications during the late phase.(7) veterans health survey for the veterans health survey, all veterans were invited to a health symposium of veterans held in isfahan, in 2007. in the first step, baseline information including age, sex, living place (urban/rural), and exposure-related data were registered. in the second step, the veterans underwent health survey which included a comprehensive review of systems done by 3 internists. in the third step, a through investigation by means of history taking, collection of laboratory data, and physical examination of the organs which have been proved to be affected by sm was done. chronic sm-induced complications in the skin, lung, and eye; decompensation rate; and medications and their dosages were recorded. decompensation rate was defined as the percentage of disability which is determined by a specialized commission in veteran’s affair in iran. the higher the decompensation rate, the poorer the health status of the veterans. this rate determines life time free healthcare and other facilities for the veteran. extracted data we considered the second part of the veterans health survey, namely comprehensive review of systems which were done by 3 internists who were blinded to data of other parts. we also analyzed the self-reported urogenital conditions including benign prostatic hyperplasia (bph), recurrent urinary tract infections (utis), urinary calculi, and kidney failure. recurrent uti was defined as 2 or more infections within 1 year, separated by a negative urine culture, or urosepsis.(16) statistical analyses data were analyzed with the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa). we reported the frequency of each diagnosed urologic condition and applied the chi-square test and independent sample t test or mann-whitney test to compare participants with and without recurrent utis and urinary calculi. p values less than .05 were considered significant. results all of the participants were men. their mean age was 45.0 ± 7.5 years (range, 30 to 75 years). an interval of 19 to 26 years had passed from exposure to sm to the time of survey (median, 21 years; interquartile range, 2 years). the mean urogenital history in veterans exposed to sulfur mustard—soroush et al 116 urology journal vol 6 no 2 spring 2009 decompensation rate was 49.0 ± 15.0% (range, 30% to 70%). most participants were living in urban areas and were diagnosed with bronchiolitis obliterans. baseline data are presented in the table. of a total of 289 sm-exposed veterans, 50 (17.3%) had a positive history of urinary calculi. recurrent utis and pyelonephritis were reported by 25 (8.7%) and 2 (0.7%) veterans, respectively. of the participants, 5 (1.7%) had bph and 2 (0.7%) suffered from kidney failure. none of the veterans had experienced urogenital malignancies, and no other urogenital diseases were mentioned. neither recurrent utis nor urinary calculi were not significantly associated with age, decompensation rate, interval from exposure to the study time, number of exposures, using preventive equipment at the time of exposure, type of lung disease due to exposure, severity of late respiratory effects due to chemical injury (symptoms severity and spirometry findings), and type or dose of medications. discussion according to our findings, 19 to 26 years after exposure to high-dose sm, 17.3%, 8.7%, 1.7%, 0.7%, and 0.7% of the veterans reported a history of urinary calculi, recurrent utis, bph, pyelonephritis, kidney failure, respectively. of interest, there were no reports of urogenital malignancies in this cohort of veterans. in addition, the history of these urologic conditions had no association with age, medications, and late complications in other organs due to sm exposure. self-reported data collected in surveys, although lack strong evidence, provide the primary information for a field, when we have less knowledge in a field. in the case of sm-related health problems, documented evidence on urological diseases is limited. in the united states, veterans exposed to sm reported a frequency of 3% for bladder diseases, 4% for chronic kidney disease, 4% for prostate disease, and 0.5% for kidney neoplasms.(17-19) in these reports, all exposed veterans had participated in chamber tests, with full equipment, which means all had been exposed to low-dose sm. information on the long-term effects of high doses of sm is lacking, and we have to rely on self-reported information. in our study, all of the participants had been exposed to high levels of the toxic gas, several of them without any preventive equipment. they were not only symptomatic, but also admitted to a hospital in the early phase.(17) in the acute phase of exposure to sm, early extraction of the toxin from urine has been reported.(19,20) also, the extraction of high levels parameter value (%) number of patients 289 (100) citizens of rural areas 30 (10.4) exposure-related data exposed in civil area 22 (7.6) exposure times 1 time 201 (69.6) > 1 time 88 (30.4) using protective equipments 130 (44.9) exposure-induced health status dyspnea all days 221 (76.5) most days 52 (18.0) some days 10 (3.4) rare 6 (2.1) no 0 sputum all days 205 (70.9) most days 53 (18.3) some days 21 (7.2) rare 7 (2.4) no 3 (1.0) dyspnea all days 250 (86.0) most days 32 (11.1) some days 6 (2.0) rare 0 no 1 (0.3) wheeze all days 244 (84.4) most days 29 (10.0) some days 14 (4.8) rare 2 (0.7) no 0 medications oral corticostroids 132 (45.7) inhaled corticostroids 210 (72.2) diagnosis of lung disease bronchiolitis obliterans 101 (34.9) chronic bronchitis 91 (31.5) bronchectasis 28 (9.7) asthma 37 (12.8) baseline data of veterans exposed to sulfur mustard urogenital history in veterans exposed to sulfur mustard—soroush et al urology journal vol 6 no 2 spring 2009 117 of sm from the kidney was documented 7 days after death of an iranian soldier due to high-dose exposure.(21) animal models have shown that following a single exposure to sm, the level of gas is highest in the kidneys, even higher than that in the lungs and other organs; therefore, this can be hypothesized that sm exposure may have some subsequent biological effects on the urogenital system.(8) however, the most prevalent late complication after exposure is seen in the respiratory system. in order to investigate the possible link between the reported urologic conditions and severity of exposure, we assessed their possible link with severity of respiratory complications measured by severity of symptoms and also spirometry indexes. such measures have been used previously as an indicator for severity of exposure.(22) we did not find any association of urologic conditions with this index of severity of sm exposure. we did not have a control group from among the general population, and thus, we cannot draw a definite conclusion whether the frequency of the assessed urological conditions were higher than those of the general population in iran or not. in addition, different definitions for the urologic outcomes make it difficult to compare our self-reported information with the published literature. concerning recurrent utis, we assume that sm-exposed patients in our study had a relatively high rate of the disease. we do not have distinctive nation-based information on the prevalence of uti in men, but it is speculated that uti prevalence in male population is low. on the other hand, the incidence of uti rises dramatically after the age of 50 years.(23-25) therefore, age-dependent nature of the disease precludes conclusion. in the united states, bacteriuria is seen in 0.1% of young men, and this rate reaches 10% in men older than 65 years old.(24) whereas, symptomatic recurrent utis was reported in 8.7% of our patients whose age ranged between 30 and 75 years. most of these patients had been receiving medications for several years, such as systemic corticosteroids, and they had experienced several hospitalizations and interventions. thus, regardless of the effect of sm, suffering from recurrent utis is anticipated in such patients. a positive history of urinary calculi was reported by 17.3% of the patients in our study, which seems to be high. it has been shown that the lifetime prevalence of urinary calculi is 10% in the united states, and 1 of 8 men experience it before the age of 70 years.(26) the frequency of bph, however, seems to be in line with our national data; in iran, bph was reported in 1.2% of men aged between 40 and 49 years and in 36% of those older than 70 years.(27) furthermore, kidney failure was seen in only 2 of 289 patients who participated in our study. nafar and colleagues(28) showed that in 2007, the prevalence of end-stage renal disease was estimated to be 0.04%. this cross sectional study describes the frequency of diagnosed urologic conditions in the smexposed population of iranian former veterans. as a result, we cannot rule out or confirm the possible links between sm exposure and urogenital health. further research is needed using control groups of nonexposed iranian men. we recommend series of research projects to be conducted by nephrologists, urologists, and toxicologists in these populations to assess any possible link between chronic urologic conditions and high-dose sm exposure. in such studies, the other risk factors of urologic conditions should be assessed, as well,(29) such as vesicoureteral reflux and bladder disorders. lack of data on the patients’ condition before the exposure was a limitation of our study. collecting such data is difficult in these veterans who were involved with chemical attacks more than 15 years age. overall, the frequencies of utis and urinary calculi in their self-reported history seem to be higher than their prevalence in the general population; however, we cannot make a definite conclusion about the effect of sm on these conditions. also we should mention that as we did not use any malignancy screening, we cannot be sure about the absence of urogenital neoplasms in the studied sample. this is still a controversy if sm is carcinogen or not(30); however, there are reports of such effects, most of which are extracted from animal data, and human data is sparse.(2,30) conclusion to all we now about chronic urogenital effects of urogenital history in veterans exposed to sulfur mustard—soroush et al 118 urology journal vol 6 no 2 spring 2009 sm exposure in human—which is very few—this study adds the prevalence of self-reported urologic conditions, without finding any link neither to demographic, nor to the severity of health complications related to the sm exposure. financial support this study was fully supported and funded by the janbazan medical and engineering research center, tehran, iran. conflict of interest none declared. references 1. ghanei m, fathi h, mohammad mm, aslani j, nematizadeh f. long-term respiratory disorders of claimers with subclinical exposure to chemical warfare agents. inhal toxicol. 2004;16:491-5. 2. ghanei m, vosoghi aa. an epidemiologic study to screen for chronic myelocytic leukemia in war victims exposed to mustard gas. environ health perspect. 2002;110:519-21. 3. ghanei m. delayed haematological complications of mustard gas. j appl toxicol. 2004;24:493-5. 4. dacre jc, goldman m. toxicology and pharmacology of the chemical warfare agent sulfur mustard. pharmacol rev. 1996;48:289-326. 5. pechura cm, rall dp. veterans at risk: the health effects of mustard gas and lewisite. washington dc: national academy press; 1993. p. 117-8. 6. balali-mood m, hefazi m. comparison of early and late toxic effects of sulfur mustard in iranian veterans. basic clin pharmacol toxicol. 2006;99:273-82. 7. balali-mood m, hefazi m, mahmoudi m, et al. longterm complications of sulphur mustard poisoning in severely intoxicated iranian veterans. fundam clin pharmacol. 2005;19:713-21. 8. boursnell jc, cohen ja, dixon m, et al. studies on mustard gas (betabeta’-dichlorodiethyl sulphide) and some related compounds: 5. the fate of injected mustard gas (containing radioactive sulphur) in the animal body. biochem j. 1946;40:756-64. 9. davison c, rozman rs, smith pk. metabolism of bisbeta-chloroethyl sulfide (sulfur mustard gas). biochem pharmacol. 1961;7:65-74. 10. davison c, rozman rs, bliss l, smith pk. studies on the metabolic fate of bis(2-chloroethyl) sulfide (mustard gas) in the mouse and human. proc am assoc cancer res. 1957;2:195. 11. roberts jj, warwick gp. studies of the mode of action of alkylating agents. vi. the metabolism of bis-2-chloroethylsulphide (mustard gas) and related compounds. biochem pharmacol. 1963;12:1329-34. 12. omaye st, elsayed nm, klain gj, korte dw, jr. metabolic changes in the mouse kidney after subcutaneous injection of butyl 2-chloroethyl sulfide. j toxicol environ health. 1991;33:19-27. 13. czerny k, ciszewska-popiolek b, mitura k. [histochemical studies of the kidney of white rats after experimental external application of sulfur mustard gas]. gegenbaurs morphol jahrb. 1990;136:89-94. german. 14. ghanei m, harandi aa. long term consequences from exposure to sulfur mustard: a review. inhal toxicol. 2007;19:451-6. 15. warren jw, brown v, jacobs s, horne l, langenberg p, greenberg p. urinary tract infection and inflammation at onset of interstitial cystitis/painful bladder syndrome. urology. 2008;71:1085-90. 16. memikoglu ko, keven k, sengul s, soypacaci z, erturk s, erbay b. urinary tract infections following renal transplantation: a single-center experience. transplant proc. 2007;39:3131-4. 17. pechura cm, rall dp. veterans at risk: the health effects of mustard gas and lewisite. washington dc: national academy press; 1993. p. 382-5. 18. vycudilik w. detection of mustard gas bis(2chloroethyl)-sulfide in urine. forensic sci int. 1985;28:131-6. 19. wils er, hulst ag, de jong al, verweij a, boter hl. analysis of thiodiglycol in urine of victims of an alleged attack with mustard gas. j anal toxicol. 1985;9:254-7. 20. drasch g, kretschmer e, kauert g, von meyer l. concentrations of mustard gas [bis(2-chloroethyl) sulfide] in the tissues of a victim of a vesicant exposure. j forensic sci. 1987;32:1788-93. 21. ghanei m, alavian sm, nassiri m, assari sh. alanin aminotransferase activity in veterans exposed to sulfur mustard. iran j metab endocrinol. 2007;9:29-35. 22. foxman b. epidemiology of urinary tract infections: incidence, morbidity, and economic costs. am j med. 2002;113 suppl 1a:5s-13s. 23. hummers-pradier e, ohse am, koch m, heizmann wr, kochen mm. urinary tract infection in men. int j clin pharmacol ther. 2004;42:360-6. 24. lipsky ba. urinary tract infections in men. epidemiology, pathophysiology, diagnosis, and treatment. ann intern med. 1989;110:138-50. 25. johnson jr. laboratory diagnosis of urinary tract infections in adult patients. clin infect dis. 2004;39:873. 26. pearle ms, calhoun ea, curhan gc. urologic diseases in america project: urolithiasis. j urol. mar 2005;173:848-57. 27. safarinejad mr. prevalence of benign prostatic hyperplasia in a population-based study in iranian men 40 years old or older. int urol nephrol. 2008;40:92131. 28. nafar m, mousavi sm, mahdavi m, et al. burden of chronic kidney disease in iran: a acreening program is of essential need. iran j kidney dis. 2008;2:183-92. 29. watson ap, jones td, griffin gd. sulfur mustard as a carcinogen: application of relative potency analysis urogenital history in veterans exposed to sulfur mustard—soroush et al urology journal vol 6 no 2 spring 2009 119 to the chemical warfare agents h, hd, and ht. regul toxicol pharmacol. 1989;10:1-25. 30. alpert lk. preliminary studies with sulfur mustard in human neoplastic diseases. ann n y acad sci. 1958;68:1223-4. editorial comment in 1985, the autopsy of body tissue and fluids of an iranian man who had died 7 days after exposure to sulfur mustard (sm) showed that concentration of sm in the kidney is several times higher than that in the liver, spleen, lung, muscle, and blood.(1) it is interesting for me as a pharmacologist that late effects of sm after a high-dose single exposure to sm is possible. by other means, sm may affect most of the organs, because it enters most systemic distribution when used as warfare. the urogenital system is not an exception. unfortunately, most of the research on late effects of sm have focused on negative impact of this toxic gas on the lung, skin, eyes, and blood.(2-7) do urologists and nephrologists know how they should approach to the late health effects of sm-exposed veterans? unfortunately, iran is within the few countries with massive single high-dose exposures, and clinicians cannot easily search the literature for such information. the literature should be made in iran, and it seems a must for iranian scientists to investigate all other possible effects of sm. as the literature shows, very few information exist regarding the urogenital system in those who have been exposed to sm, and in this regard, the current study by soroush and colleagues has provided us the information on medical history of urological conditions. self-reported data of medical history is considered as a step forward,(8) but much is remained in this regard. further studies may need control groups and comprehensive urological evaluations such as imaging and more specific investigations. in this secondary analysis of a health survey conducted by the janbazan medical and engineering research center, beside sociodemographic and exposure-related data, history of urologic conditions, namely benign prostatic hyperplasia, recurrent urinary tract infections, pyelonephritis, urinary calculi, kidney failure, and urogenital neoplasms have been reported. the most reported conditions included urinary calculi (17.3%) and recurrent utis (8.7%). the interesting point for me is the no report of urogenital neoplasms. sulfur mustard is considered as a “suspected carcinogen,(9)” and carcinogenicity of a single high-dose exposure has not been supported by the available scientific evidence. it is the long-term occupational exposures which have named sm as a carcinogen,(10) and this is not related to what we face in our veterans in iran. yunes panahi research center of chemical injuries and nephrology urology research center, baqiyatallah medical sciences university, tehran, iran e-mail: yunespanahi@yahoo.com references 1. drasch g, kretschmer e, kauert g, von meyer l. concentrations of mustard gas [bis(2-chloroethyl) sulfide] in the tissues of a victim of a vesicant exposure. j forensic sci. 1987;32:1788-93. 2. shohrati m, ghanei m, shamspour n, jafari m. activity and function in lung injuries due to sulphur mustard. biomarkers. 2008;13:728-33. 3. ghanei m, harandi aa. long term consequences from exposure to sulfur mustard: a review. inhal toxicol. 2007;19:451-6. 4. ghasemi h, ghazanfari t, babaei m, et al. longterm ocular complications of sulfur mustard in the civilian victims of sardasht, iran. cutan ocul toxicol. 2008;27:317-26. 5. emadi sn, moeineddin f, sorush mr. urinary and cutaneous complications of sulphur mustard poisoning preceding pulmonary and ocular involvement: an unusual sequence of symptoms. clin exp dermatol. 2008 nov 26. [epub ahead of print]. 6. balali-mood m, hefazi m, mahmoudi m, et al. longterm complications of sulphur mustard poisoning in severely intoxicated iranian veterans. fundam clin pharmacol. 2005;19:713-21. 7. shohrati m, peyman m, peyman a, davoudi m, ghanei m. cutaneous and ocular late complications of sulfur mustard in iranian veterans. cutan ocul toxicol. 2007;26:73-81. 8. parker as, cerhan jr, lynch cf, leibovich bc, cantor kp. history of urinary tract infection and risk of renal cell carcinoma. am j epidemiol. 2004;159:42-8. 9. goldman m, dacre jc. lewisite: its chemistry, toxicology, and biological effects. rev environ contam toxicol. 1989;110:75-115. 10. gottschall eb. occupational and environmental thoracic malignancies. j thorac imaging. 2002;17:189-97. miscellaneus are helicobacter pylori and benign prostatic hyperplasia related, and if so, how? ayhan verit,1* özgür haki yüksel,1 mithat kivrak,1 hanife aydin yazicilar,2 nurver özbay,3 fatih uruç1 purpose: although many virulence factors have been defined for helicobacter pylori (hp), vacuolating cytotoxin a (vaca) is known to be associated with apoptosis, the cag pathogenicity island protein (cag-pai), and growth factors. both apoptosis and growth factors are thought to be related to the etiology of benign prostatic hyperplasia (bph). additionally, the relation between atherosclerosis-bph and atherosclerosis-hp has also been reported in a limited number of studies. the aim of this pioneering study was to investigate the presence of hp in bph patients who had undergone transurethral resection of prostate (turp) and to discuss the potential pathophysiologic effects of hp on bph. materials and methods: a total of 113 cases who underwent turp due to infravesical obstruction due to bph were included in the study. preoperatively, parameters including, age, height, body weight, body mass index (bmi), prostate specific antigen (psa), prostate volume (pvo), maximum urinary flow rate (qmax), fasting plasma insulin, and international prostate symptom score (ipss) values were evaluated. the presence of hp was investigated in the prostate specimens with real-time polymerase chain reaction (rt-pcr) method. postoperatively, histopathological evidence of chronic prostatitis (hcp) was also analyzed. results: hp was detected in 1.8% (n = 2) of the participants. additionally, hcp was observed in 58.4% (n = 66) of the 113 patients. the demographic and clinical parameters confirmed the presence of bph disease. conclusion: although bph is a common disease, its physiologic etiology mechanisms are not clear. based on our pilot study, despite its gastric location, we believe that hp should be considered in cases with clinical bph because hp induces apoptosis and alterations in the equilibrium between apoptosis and local growth factors in addition to its recently demonstrated extragastric effects mediated via the atherosclerotic pathway. although our uncontrolled pioneer study was not designed to investigate the pathophysiologic mechanism, the isolation of hp from prostatic adenoma suggests the need for further well-designed studies on this topic. keywords: helicobacter infections; complications; epidemiology; humans; male; prostatic hyperplasia; etiology; physiopathology; risk factors. introduction benign prostatic hyperplasia (bph) is the most common benign adenoma in men. bph obstructs the bladder outflow, which leads to significant clinical symptoms, and nearly 40% of men are at risk of suffering from bph during their lifetimes.(1) although alterations in the levels of estrogens and androgens have been demonstrated to be etiologic factors that result in increases in prostatic stromal and epithelial cells, fibromuscular growth in bph is thought to be multifactorial and include the involvement of stromal growth factors induced by hypoxia secondary to abnormal blood flow. (2) the incidence and lifelong prevalence of helicobacter pylori (hp) infection are similar to those of bph (> 80%) and also increase similarly with age.(3) hp is a relatively recently discovered microorganism. in 1997, tomb and colleagues decoded and described complete genomic structure of hp.(4) analyses performed with the recently developed repetitive sequence-based polymerase chain reaction (rep-pcr) method have identified two main groups of hp. researchers have observed that the first group predominantly causes simple gastritis, while the second group primarily induces duodenal ulcers. thus, the idea of the presence of various disease-specific hp strains has been proposed. strains carrying the hp jhp947 gene have primarily been detected in association with duodenal ulcers and gastric carcinomas, which suggests that this gene is an important marker of pathogenicity.(5) hp has recently been considered in terms of its extragastric effects. indeed, potential associations have been proposed between some malignant neoplasms, atherosclerosis, and even alzheimer’s disease.(6-10) among the many hp-related virulence factors, vacuolating cytotoxin a (vaca) and cag pathogenicity island (cagpai) are known to be associated with apoptosis and growth factors, respectively.(11) based on a hypothesis similar pathophysiologies and considering the concomitancy of atherosclerosis with both bph and hp in addition to the potential influence of hp on apoptosis, we 1 department of urology, fatih sultan mehmet research and training hospital, istanbul, turkey. 2 department of clinical microbiology, fatih sultan mehmet research and training hospital, istanbul, turkey. 3 department of pathology, fatih sultan mehmet research and training hospital, istanbul, turkey. *department of urology, fatih sultan mehmet research and training hospital, içerenköy/ataşehir tr34752, istanbul, turkey. tel: +90 216 5783000 . fax: +90 21 6575 0406 . e-mail: veritayhan@yahoo.com. received september 2014 accepted june 2015 miscellaneous 2271 decided to investigate the possible association between bph and hp in this pilot study. materials and methods data from a total of 113 cases who underwent transurethral resection of the prostate (turp) in the urology department of fatih sultan mehmet research and training hospital due to infravesical obstructions resulting from bph between june 2012 and june 2013 were included in our study. the approval of this study was obtained from the ethics committee, and the study was conducted in compliance with the principles of the declaration of helsinki ethical principles for medical research involving human subjects. informed consent forms stating that participation in the study was voluntary were retrieved from all patients. patients with preoperative clinical and postoperative histopathological evidence of prostate carcinoma (pca) were excluded from the study. the medical histories of the patients were obtained. the preoperative parameters that included age, height, body weight, body mass index (bmi), prostate specific antigen (psa), prostate volume (pvo), maximum urinary flow rate (qmax), fasting plasma insulin, and the international prostate symptom score (ipss) were evaluated. additionally, the medical histories of acute urinary retention and systemic diseases were also obtained. evidence of histopathologically confirmed chronic prostatitis (cp) from the turp materials was analyzed. samples of approximately 1 cc were obtained from the prostate specimens of the patients and maintained in snap-cap eppendorf® tubes at -20˚c. amplification of the hp urec gen region to search for hp dna in the extracted samples, hp qls 1.0 hp dna fixation kits (fluorion®, lontek, turkey) and real-time pcr methods were used. using a real-time pcr device (fds, fluorion®, lontek,turkey), 156 base pairs (bp) of the urec gene of the hp genome were amplified. the pcr products were displayed using a fluorescent dye (sybr-green) during the reactions. the amplified dna was determined to be specific to the target region via melt curve analyses. results after the exclusions, 113 cases who underwent turp operations in our department were included in the study. the mean age of the group was 65.95 ± 7.67 years (range 50-83). demographic pre-and postoperative data and the comorbidities of the patients are given in tables 1 and 2. hp positivity was detected in the specimens from 2 (1.8%) patients. discussion bph is a chronic condition and generally exhibits a progressive course. lower urinary tract symptoms (luts) have been thought to be associated with both prostatic apoptosis and prostatic hyperplasia. in contrast, hp exerts long-term unexpected effects on human beings. the prevalence of hp infection is similar to that of bph, and both increase with age. in our study, we used a real-time pcr method to perform hp screening tests on the prostatic specimens of 113 patients with clinical bph that was refractory to medical treatment and thus necessitated turp operations. hp was detected in 1.8% (n = 2) of the cases who participated in the study. no significant differences were observed between the patients with and without hp in the preor postoperative data. associations of luts with prostatic apoptosis and hyperplasia have been recognized. it is well known thatluts can be very severe in cases with normal or small prostate volumes. literature reviews have demonstrated that this phenomenon can be explained by prostatic elastosis (i.e., elastic tissue loss). in a study (n = 65) of prostatic elastosis, associations of elastosis with increased age, prostatic atrophy, and local atherosclerosiswere observed, but no significant associations were detected with histologically confirmed cancer, higher grades of prostatic intraepithelial neoplasia, systemic atherosclerosis, nodular prostatic neoplasia, or acute inflammation.(12) however, the association with local atherosclerosis indicates that ischemia has a possible role in the etiopathogenesis.(12) in our study, prostatic elastosis was not separately evaluated. the prostate volumes of the cases with hp were not different from the mean prostate volume (60 ml) of the study group. additionally, local atherosclerotic foci have been observed in histopathological samples in which hp has been detected. atherosclerosis decreases blood flow through tissues, which leads to atrophy. additionally, table 1. demographic and clinical characteristics of patients who underwent transurethral resection of prostate. variables min-max mean ± sd age, (year) 50-83 65.95 ± 7.67 height, (m) 1.50-1.86 1.71 ± 0.07 body weight, (kg) 55-106 78.65 ± 11.26 bmi (kg/m2) 18.94-36.68 27.04 ± 3.62 insulin, (n = 46) 1.20-25.00 6.04 ± 4.25 pvo, (ml) 15-140 60.63 ± 21.22 qmax, (ml/s) 0-19 7.22 ± 3.53 ipss 12-25 21.29 ± 2.21 psa, (ng/ml) 0.2-22.0 3.88 ± 3.43 duration of medical treatment, 1-15 4.33 ± 3.03 (year) abbreviations: sd, standard deviation; bmi, body mass index; pvo, prostate volume; ipss, international prostate symptom score; psa, prostate specific antigen. table 2. frequencies of comorbidities and prostatitis in study patients. variables no. % hypertension 42 37.2 cad 23 20.4 copd 3 2.7 diabetes mellitus 22 19.5 other comorbidities 58 51.3 aur 25 22.1 chronic prostatitis 66 58.4 abbreviations: cad, coronary artery disease; copd, chronic obstructive pulmonary disease; aur, acute urinary retention. vol 12 no 04 july-august 2015 2272 helicobacter pylori and bph-verit et al. atherosclerosis increases the release of hypoxia-inducible factor and secondary growth factors, which results in potential stromal hyperplasia. impairment of the prostatic stromal cells has been demonstrated to be an important factor in the pathogenesis of bph and is the most prevalent etiological factor of bph in older men.(13) although estrogens and androgens have been confirmed as causes of increased numbers of prostatic stromal and epithelial cells, fibromuscular growth in bph is thought to be multifactorial.(14) however, some of these factors have been suggested to be stromal growth factors that are induced by hypoxia secondary to abnormal blood flow. interactions between growth factors and steroid hormones might tilt the balance to stimulate cellular proliferation in bph, which also corresponds to programmed cell death. some of the growth factors have been characterized in normal, hyperplastic, and neoplastic prostatic tissues. these factors include basic fibroblast growth factor (fgf-β), transforming growth factor β (tgf-β), epidermal growth factor (egf), and heparin-binding growth factor-alpha (α-fgf and others). tgf-β is potentially an inhibitor of normal epithelial cell proliferation in many tissues. in recent in vitro studies that utilized human prostatic stromal cell culture models, increases in growth factor secretions secondary to hypoxia have been detected. this phenomenon might indicate that hypoxia triggers prostatic enlargement.(15) hypoxia of the prostatic tissue might occur due to generalized or localized vascular damage. various studies have disclosed an association between diabetes mellitus (dm) and coronary artery disease (cad) that causes vascular damage and bph.(16) in our study, 51.3% (n = 58) of the cases also had comorbid diseases, such as hypertension (ht) (37.2%; n = 42), cad (20.4%; n = 23), and dm (19.5%; n = 22). luts might be induced by various conditions that affect the nervous system. nearly half of diabetes somatic neuropathy patients develop luts, and many symptoms resembling luts can be observed in this population. the impairment of the perfusion of the prostatic transitional zone (tz) has also been demonstrated.(17) if vascular damage is important in the pathogenesis of bph, then patients with peripheral arterial occlusive diseases and severe atherosclerotic entities, such as cad, who lack any dm-related neuropathic component should exhibit worse prostatic symptom scores and prostatic perfusion compared with controls. resistive index is the most reliable criterion for demonstrating blood flow in small prostatic vessels. in the necropsy specimens of 100 patients, atherosclerotic processes were evaluated based on decreases in the intima/media thickness. a total of 119 arterial specimens of 20 patients with diagnoses of bph were examined histopathologically, and atherosclerosis was detected in nearly 20% of these arteries.(18) in the same study, an association between pca, and atherosclerosis was also observed. overall, it seems reasonable to suggest that atherosclerosis might bea factor that affects the progression of bph but probably not its onset. as mentioned previously, the incidences and prevalence of hp infection and bph are similar and exhibit similar increases with age. although hp infection is a globally prevalent disease, its incidence differs between regionsand between different groups residing in the same region. the incidence of hp is strongly linked to socioeconomic status. in developing countries, the incidence of hp in middle-aged individuals is over 80%; however, its incidence in the same age group in developed countries varies between 20% and 50%.(3) when hp-positive and -negative patients have been compared, increases in carotid artery intima-media thickness, total oxidative status, total antioxidant capacity, oxidative stress index, and triglyceride values have been observed in the hp-positive patients. in contrast, associations of carotid atherosclerosis with severe clinical symptoms and caga-positive hp infection have been observed. (19) thus, a role of hp infection in atherosclerosis has been suggested. among the many virulence factors related to hp, vacaand cag-pai have been reported to be associated with apoptosis and growth factors, respectively.(20) as indicated above, associations of luts with both prostatic apoptosis and hyperplasia have previously been defined. one of the most important virulence factors related to hp is vaca. vaca also effects mitochondrial membranes and leads to the secretion of cytochrome c and the consequent formation of acidic vacuoles and cellular apoptosis. many strains of hp (60-80% in western and > 90% in asian countries) contain a 37kb genomic fragment termed cag-pai that contains 29 different virulence genes. caga is the one of the most important virulence factors and is synthesized by the cag gene, which is located in this gene island. caga has a molecular weight of 120 kd and is translocated into a host cell after its synthesis. this protein molecule is phosphorylated after its intracellular inclusion and bound to shp-2 tyrosine phosphatase, which results in the production of cytokinesin reaction to a cellular response that resembles that elicited by intracellular growth factors.(21) there is no doubt that hp has important roles in the pathogeneses of gastric cancerand lymphoma. in pilot studies, possible associations between hp and other gastrointestinal system neoplasms [i.e., liver, pancreas, oropharyngeal cancers (in the tonsillar and adenoid tissue), etc.] have been suggested.(7) interestingly, an association between hp and extragastrointestinal neoplasms (i.e., pulmonary and ocular adnexal lymphomas) has been reported.(8,9) the mechanism of the carcinogenic effect of hp has not yet been defined. however, hp might induce cellular transformations directly via its mutagenic and/or immunosuppressor affects or via increments in the productions of cytokines and regulatory molecules. although bph does not possess the trait of malignancy, fromthe pathophysiologic perspective, it nearly defines a group of neoplasms. actually, chronic inflammatory effects of hp on the gastric and duodenal mucosa have previously been recognized. additionally, many studies have provided evidence supporting the apoptotic and growth factor-stimulating effects of hp and its association with atherosclerosis. these conditions can induce the development of neoplasias or hyperplasias. several investigations have indicated that prostatic hyperplasia and/ or chronic infection can result in luts.(22) the associations between hp and chronic urologic pathologies, such as interstitial cystitis (ic) and chronic prostatitis have rarely been investigated, and a direct link between hp and urologic infections has not been demonstrated. (23) hp has been suggested to be a possible unidentified etiological factorin the development of hcp and ic via miscellaneous 2273 helicobacter pylori and bph-verit et al. its triggering of the release of interleukin 1β (il-1β), il-6, il-8, il-10, ifn-γ, and tnf-α.(24) we believe that an investigation of the potential association between hp and cp in a well-designed, large-scale series might aid in the discovery of more effective diagnostic and therapeutic methods for the management of cp. it is well known that the presence of clinical cp necessitates the rapid management of bph due to its disturbing symptoms; however, in an autopsy series, a significant correlation between bph and cp was not detected.(25) indeed, in our study, the percentage (58%) of specimens in which cp was detected during the histopathological examinations resembled that of a previous autopsy series in a patient population without bph. it is known that all microorganisms exert deleterious effects on tissues via bacterial or autoimmune pathways.(26) the effects of the substantially greater incidence of hpbph concomitancy on the etiology of the apparently multifactorial bph should be investigated. direct or indirect interactions between bph and many microorganisms have been investigated; however, these authors failed to detect any significant correlations between these factors.(27) nevertheless, the direct and indirect correlations between bph and hp have not yet been analyzed. the main limitation of our study was that it was an uncontrolled study that did not allow for satisfactory statistical analyses to achieve a high scientific value. however, the inclusion of a control group was nearly impossible for ethical reasons because there is no indication to extract normal prostate specimens. furthermore, it is well known that the majority of men in this age group exhibit histological bph, prostatitis and/or prostate cancer in postmortem studies; thus, it would have been nearly impossible to include males with “normal” prostates. our pioneering study is an indirect cause-effect study that did not investigate the underlying pathophysiologic mechanisms. the limited numbers of study patients and specimens that were sent to the histopathology laboratory, the inability to perform serologic tests, and the evaluations related to prostatic perfusion constitute limitations of our study. however, we revealed that hp can be detected in prostatic tissue specimens. in 2% of our cases (best referred to as random specimens), hp dna was detected. however, it must not to be forgotten that this small percentage was based on a limited number of specimens. notably, if all of the tur materials and whole prostate volumeswere considered, this percentage might have been much higher. additionally, previous pcr studies have revealed that the prostate rarely harbors a normal bacterial flora and thus contamination was a likely possibility.(28) although hp was detected in a limited number of cases and at a low percentage, we believe that hp localized inside the prostate does not play a role in the clinical manifestations or hcp but might be involved in the etiopathology of bph mediated by atherosclerosis, apoptosis and/or growth factors. to confirm the results of our pioneering study, multidisciplinary studies analyzing a large number of parameters with the possible support of gastroduodenoscopic and necropsy examinations of the prostate are needed. although the scientific value of the present study is not satisfactory, this pioneering manuscript may elicit future well-designed studies with multiple groups that potentially include cadaveric samples or animal models that evaluate the relationships of hp with prostatic diseases, such as bph, prostate cancer and prostatitis. conclusions although bph is a very frequently encountered disease, its etiophysiologic mechanisms are not clear. based on our pilot study, despite its use of gastric samples, we believe that hp should not be overlooked in cases of clinical bph based on the fact that hp induces apoptosis and alterations in the equilibrium between apoptosis and local growth factorsin addition to its recently discerned extragastric effects viathe atherosclerotic pathway. although our pioneering study was not designed with the intention of elucidating the relevant pathophysiologic mechanism, the isolation of hp from prostatic adenomas indicates the necessity of further investigations in this field. acknowledgements this study was been financially supported by the administration of the istanbul fatih sultan mehmet research and training hospital. conflict of interest none declared. references 1. fong yk, milani s, djavan b. natural history and clinical predictors of clinical progression in benign prostatic hyperplasia. curr opin urol. 2005;15:35-8. 2. ghafar ma, puchner pj, anastasiadis ag, cabelin ma, buttyan r. does the prostatic vascular system contribute to the development of benign prostatic hyperplasia? curr urol rep.2002;3:292-6. 3. no author listed. epidemiology of, and risk factors for, helicobacter pylori infection among 3194 asymptomatic subjects in 17 populations. the eurogast study group. gut. 1993;34:1672-6. 4. tomb jf, white o, kerlavage ar, et al. the complete genome sequence of the gastric pathogen helicobacter pylori. nature. 1997;388:539-47. 5. go mf, chan ky, versalovic j,koeuth t, graham dy, lupski jr. cluster analysis of helicobacter pylori genomic dna fingerprints suggests gastroduodenal diseasespecific associations. scand j gastroenterol. 1995;30:640-6. 6. stolzenberg-solomon rz, blaser mj, limburg pj, et al. helicobacter pylori seropositivity as a risk factor for pancreatic cancer. j natl cancer inst. 2001;93:937-41. 7. lukes p, astl j, pavlík e, potuzníková b, sterzl i, betka j. helicobacter pylori in tonsillar and adenoid tissue and its possible role in oropharyngeal carcinogenesis. folia biol (praha). 2008;54:33-9. 8. decaudin d, ferroni a, vincent-salomon vol 12 no 04 july-august 2015 2274 helicobacter pylori and bph-verit et al. a, et al. ocular adnexal lymphoma and helicobacter pylori gastric infection. am j hematol. 2010;85:645-9. 9. deng b, li y, zhang y, bai l, yang p. helicobacter pylori infection and lung cancer: a review of an emerging hypothesis. carcinogenesis. 2013;34:1189-95. 10. kountouras j, boziki m, zavos c, et al. a potential impact of chronic helicobacter pylori infection on alzheimer’s disease pathobiology and course. neurobiol aging. 2012;33:e3-4. 11. basyigit s, akbas h, suleymanlar i, kemaloglu d, koc s, suleymanlar g. the assessment of carotid intima-media thickness, lipid profiles and oxidative stress markers in helicobacter pylori-positive subjects. turk j gastroenterol. 2012;23:646-51. 12. billis a, magna la. prostate elastosis: a microscopic feature useful for the diagnosis of prostatrophic hyperplasia. arch pathol lab med. 2000;124:1306-9. 13. ricke wa, macoska ja, cunha gr. developmental, cellular and molecular biology of benign prostatic hyperplasia. differentiation. 2011;82:165-7. 14. elkahwaji je. the role of inflammatory mediators in the development of prostatic hyperplasia and prostate cancer. res rep urol. 2012;5:1-10. 15. berger ap, kofler k, bektic j, et al. increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia. prostate. 2003;57:57-65. 16. michel mc, mehlburger l. effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. j urol. 2000;163:1725–9. 17. berger ap, deibl m, leonhartsberger n, et al.vascular damage as a risk factor for benign prostatic hyperplasia and erectile dysfunction. bju int. 2005;96:1073-8. 18. hager m, mikuz g, bartsch g, kolbitsch c, moser pl.the association between local atherosclerosis and prostate cancer. bju int. 2007;99:46-8. 19. wu y, tao z, song c, et al. overexpression of ykl-40 predicts plaque instability in carotid atherosclerosis with caga-positive helicobacter pylori infection. plos one. 2013;8:e59996. 20. suerbaum s, michetti. helicobacter pylori infection. n engl j med. 2002;347:1175-86. 21. peek rm jr. orchestration of aberrant epithelial signaling by helicobacter pylori caga. sci stke. 2005:pe14. 22. lepor h. evaluating men with benign prostatic hyperplasia. rev urol.20046(suppl 1):s8-s15. 23. al-marhoon ms. is there a role for helicobacter pylori infection in urological diseases? urol j. 2008;5:139-43. 24. chen bf, xu x, deng y, et al. relationship between helicobacter pylori infection and serum interleukin 18 in patients with carotid atherosclerosis. helicobacter. 2013;18:124-8. 25. delongchamps nb, de la roza g, chandan v, et al. evaluation of prostatitis in autopsied prostates is chronic inflammation more associated with benign prostatic hyperplasia or cancer? j urol. 2008;179:1736-40. 26. mogensen th. pathogen recognition and inflammatory signaling in innate immune defenses. clin microbiol rev. 2009;22:24073. 27. st sauver jl, jacobson dj, mcgree me, girman cj, lieber mm, jacobsen sj. longitudinal association between prostatitis and development of benign prostatic hyperplasia. urology. 2008;71:475-9. 28. hochreiter ww, duncan jl, schaeffer aj. evaluation of the bacterial flora of the prostate using a 16s rrna gene based polymerase chain reaction. j urol. 2000;163:127-30. miscellaneous 2275 helicobacter pylori and bph-verit et al. 1687vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l role of frozen section examination in the management of testicular nodules: a useful procedure to identify benign lesions giorgio bozzini,1 barbara rubino,2 serena maruccia,1 carlo marenghi,1 stefano casellato,1 stefano picozzi,1 luca carmignani1 corresponding author: giorgio bozzini, md academic department of urology, istituto di ricovero e cura a carattere scientifico, policlinico san donato, university of milan, milan, italy. tel: +39 34 7794 5956 fax: +39 02 5277 4329 e-mail: gioboz@yahoo.it received february 2013 accepted december 2013 1 academic department of urology, istituto di ricovero e cura a carattere scientifico, policlinico san donato, university of milan, milan, italy. 2 pathology unit, istituto di ricovero e cura a carattere scientifico, policlinico san donato, university of milan, milan, italy. purpose: to assess the validity of frozen section examination (fse) on testis nodules. materials and methods: a series of 86 preselected patients with testicular nodules were recruited in this study. nodules smaller than 2 cm had been surgically removed and biopsies of the margins performed. larger nodules were just biopsied. orchiectomy was the treatment of choice for malignant lesions and stromal tumors. conservative surgery was performed on 2 previously monorchid patients with leydig cell tumor because of the presence of just one testis. conservative surgery was the treatment of choice for benign lesions in 32 cases. results: at fse we observed that nodules were malignant germinal tumors in 47% of the cases, stromal tumors in 7% of the cases, benign lesions in 45% of the cases and doubtful for lymphoproliferative lesion in 1 case. the diagnosis made by fse were confirmed in the definitive ones in all of them, we reported just 2 cases of leydig cell tumor and benign fibrosis lesion. in these 2 cases, definitive histology of the collected specimens revealed areas of leydig cell hyperplasia and seminomatous foci, respectively. conclusion: our data suggest that fse is a valid tool to discriminate between benign and malignant neoplastic lesions, particularly when an adequate sample is available. keywords: testicular nodules; testis; pathology; testicular neoplasms; diagnosis; abnormalities; frozen sections; biopsy. special feature 1688 | special feature introduction orchiectomy has represented for a long time the only surgical treatment approved for testicular tu-mors. this practice was justified by the high proportion of malignant testicular tumors reported in literature (80-90%) among all nodules. however, more recent data indicate that the prevalence of benign lesions (mainly about non palpable incidental lesions) ranges between 8% and 80% in different series.(1-8) similarly, the feasibility of organ-sparing surgery on malignant(9) and stromal testicular tumors(10) warrants a more careful evaluation of a radical approach. in particular, we note that, in 1986, haas and colleagues(6) reviewed their series of over 2800 patients undergoing orchiectomy and reported a 31% prevalence of benign testicular lesions. these results have prompted many investigator to reconsider the opportunity of radical surgery and to search for novel sensitive tools to discriminate between benign and malignant nodules. advances in ultrasonographic techniques allow a sensitivity exceeding 90% in the detection of non-palpable testicular lesions; however, the specificity of the test towards benign conditions (i.e. infarction, inflammation, atrophy, hematoma, and benign tumors) remains low.(2) about 70% of these benign lesions are smaller than 2 cm.(2,10) while the use of intraoperative histological frozen section examination (fse) has been widely investigated and this procedure is common in several human malignancies, its role in testis tumors is still debated. in fact, some reports encourage fse use indicating its validity to discriminate between adult(3-5,8,11) and children(12) benign and malignant lesions. the aim of our study was to assess fse validity in the diagnosis and management of different sized testis nodules. materials and methods between october 2007 and february 2012, 86 preselected patients (mean age 38 years, range 5-76) were referred to our academic division of urology in milan for palpable testicular lesions and/or ultrasonography (us) examination (83.72% us evidence, clinically negative). for this reason, after tumor markers evaluation and signed the consent form, they underwent inguinal explorative surgery. patients with multifocal lesions or lesions involving the whole testis were excluded from this study. the technique used included inguinal clamping of the spermatic cord and incision of the tunica albuginea in the corresponding area identified by intraoperative us and/or palpation. nodules less than 2 cm in diameter were surgically removed and biopsies of the margins of resection were performed. on larger nodules an incisional biopsy was performed. obtained specimens were evaluated using fse. briefly, samples were frozen using the leica cm 3000 cryostat (jung cm 3000; leica microsystems gmbh, wetzlas, germany); three 4 µm thick sections were then obtained and stained with hematoxylin and eosin. the time necessary for the histological diagnosis ranged between 10 and 15 minutes. two different genitor-urinary pathologists examined the specimens. lesions were then divided into germinal, stromal, benign, and doubtful. all samples were then routinely formalin fixed, paraffin embedded and comparatively reviewed. results patient’s age ranged from 5 to 76 years (average 37.7 years). the nodule size of all nodules included in the present study ranged between 0.44 cm and 10 cm (mean 2.4 cm), with a mean value of 3.7 cm for malignant tumors, 1.12 cm for benign lesions and 0.99 cm for stromal tumors. at fse we diagnosed 40/86 (47%) malignant germinal tumors, 1/86 (1%) case doubtful for lymphoproliferative lesion, 6/86 (7%) stromal tumors, and 39/86 (45%) benign lesions. malignant germinal tumors were represented from further defined as seminomas in 32 cases (80%), embryonal carcinomas in 7 (17%) cases, and choriocarcinoma in 1 (3%) case. mean diameters of specific lesions were 3.7 cm for malignant tumors, 1.12 cm for benign lesions and 0.99 cm for stromal tumors. the histological examination on paraffin-embedded sections confirmed the diagnosis of malignant germinal tumors made by fse in all cases, revealing a mixed nature in 5 seminomas (with teratomatous, embryonal, and yolk sack tumors components), in 2 embryonal carcinomas (with teratomatous and choriocarcinomatous components) and in the only case of choriocarcinoma (with teratomatous component). the one case that was judged doubtful for lymphoprolifera1689vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l frozen section in testicular nodules | bozzini et al tive lesion was confirmed to be the intratesticular localization of a non-hodgkin lymphoma. in all the patients with a diagnosis of malignant germinal tumor an orchiectomy was performed. the patient with a testicular localization of a non-hodgkin lymphoma was treated with conservative surgery. the diagnosis of stromal tumor was made at fse in 6 cases; 5 (83%) were leydig cell tumors and one of them (17%) was a large cell calcifying sertoli cell tumor. the diagnosis of stromal tumors made by fse was confirmed in the case of large cell calcifying sertoli cell tumor and in 4 of leydig cell tumors. only in one case a more extensive examination of the paraffin-embedded samples was needed and revealed a more diffuse leydig cell proliferation with intermixed atrophic tubules, allowing the diagnosis to be changed into a leydig cell hyperplasia. the mitotic rate observed for large cell calcifying sertoli tumor was of 3 × 10 high power field (hpf), for leydig cell tumors varied between 1 to and 2 × 10 hpf. the mitotic count was in the whole study confirmed by definitive histological examination. orchiectomy was the treatment performed for these kind of lesions, although in two patients with leydig cell tumors the urologist decided to spare the remaining testicular parenchyma because they were monorchids. the benign lesions diagnosed on fse were, fibrosis in 12 cases (32%), leydig cell hyperplasia in 5 (13%), adenomatoid tumors in 4 (10%), infarction in 5 cases (12%), granulomatous inflammation in 4 (10%), nodular periorchititis in 1 case (3%), epidermoid cyst in 1 case (3%), mesothelial hyperplasia in 1 case (3%), cystic benign mesothelioma in 1 case (3%), edema in 3 cases (8%) and epididymal appendix in 1 (3%) case. all the diagnosis were confirmed by definitive non-fse histological examination. for benign lesions, an organ sparing surgery was performed in all the cases except in one patient with leydig cell hyperplasia, 2 patients with adenomatoid tumor, and in 1 patable . pathological characteristics of studied testicular nodules. pathological characteristics no. % malignant tumors seminoma* 32 80 embryonal cell carcinoma 7 17.5 mixed (immature teratoma, choriocarcinoma) 1 2.5 doubtful non-hodgkin lymphoma 1 100 stromal tumors leydig cell tumor 5 83 calcifying large sertoli cell tumor 1 17 benign lesions adenomatoid tumor 4 10 nodular periorchitis 1 3 epidermoid cyst 1 3 leydig cell hyperplasia* 6 15 mesothelial hyperplasia 1 3 mesothelioma cystic benign 1 3 infarction 5 12 fibrosis 12 30.5 granulomatous inflammation 4 10 edema 3 7.5 epididymal appendix 1 3 * these values include cases with changed diagnosis. 1690 | tient with fibrosis. this decision was made in these 4 cases because of their past history of cryptorchidism (see table). in the last case a more extensive analysis of the testicular parenchyma revealed a seminomatous areas besides the known fibrosis. orchiectomy was also performed in 2 patients with parenchymal infarction and in one patient with a granulomatous inflammation for its widespread extension. during the follow-up period (1 to 36 months) no relapses were noted in patients with malignant germinal tumors and leydig cell tumors who underwent organ sparing surgery. discussion the increased incidence of benign testicular tumors determines a review of the radical surgical approach and led to consider the organ-sparing surgery as a valid option(8,9) for selected patients. however, the conservative management of testis requires to ensure the surgeon about the benign nature of the lesion. although us has a very high sensitivity, its low specificity represents a limit to select eligible patients for organ-sparing surgery. the fse could offer a valid support to discriminate between benign and malignant lesions. in the literature the fse specificity is reported to be ranging from 81% to 100%. in our study, using the fse procedure, we identified 40 on 40 malignant lesions (100%), 44 on 45 (98%) benign lesions and 5 on 6 (98%) stromal tumors. our results are similar to the ones reported in literature. tokuc and colleagues(11) showed a specificity of 100% to properly identify 24 malignant lesions by fse; leroy and colleagues(4), evaluating 15 patients, reported a specificity of 81% for benign lesions and 100% for malignant lesions. similar results were reported by elert and colleagues(5) on 354 patients, in which malignant and benign lesions were correctly identified on fse with a specificity of 100%. an aspect to take into account in performing fse is the adequacy of the biopsy submitted for fse. apparently in our study we had two discording diagnosis: one leydig cell tumor and one fibrosis. in both cases the urologist decided to perform the orchiectomy because the patients had a retained testis presenting with non-homogeneous us pattern. in the first case the histological examination revealed a more diffuse leydig cell proliferation with intermixed atrophic tubules and in the second case diffusely atrophic seminomatous foci were detected into the analyzed testicular parenchyma. these results, in our opinion, underline the importance to obtain an adequate sample and point out how submitting multiple samples of testicular parenchyma, in case of cryptorchidism, could help in having a proper pathological report. in our study the most of benign lesions had diameters under cm 2 (mean 1.12 cm), only the epidermoid cyst had the dimension of 10 cm. these results confirmed what postulated by other authors,(2,10) given the high percentage of benign lesions the fse is strongly recommended. another point of discussion is represented by spermatic cord stromal tumors, because actually we still do not really know what is their biological and pathological potential. in fact they represent the hardest histological lesion to be correctly diagnosed by fse. very few are the malignant cases reported in literature; 6 cases of malignant leydig cell tumor were described, one of them was in association with the adrenogenital syndrome.(13-15) sertoli cell tumors with malignant pattern have also been described.(16) in all these cases the features(17) described to confirm the malignant nature of the lesions were, dimension more than 5 cm, mitosis rate greater than 3 × 10 hpf, presence of angio/lymphatic invasion and necrosis. on fse we evaluated these parameters and no one of them was present. during the follow-up period no relapse of metastasis were observed in any case. these last data allowed us to hypothesize, as was done by other authors,(9) that a conservative surgery for stromal tumors, in absence of aspects of malignancy and clinical syndromes correlated, is feasible and risk-free. conclusions our results confirm that benign testicular lesions are becoming even more frequent. we found benign lesions in 45% of the cases analyzed. more frequently the benign nodules have dimension under 2 cm. in these cases fse is strongly recommended because it represents a valid tool to select the patients for organ sparing surgery. it is important to point out that the sample sent to pathologist must be adequate. moreover this technique may also be used to identify stromal tumors without malignant features. conflict of interest none declared. special feature 1691vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l frozen section in testicular nodules | bozzini et al references 1. chang sy, ma cp, tzeng cc. benign testicular tumours. eur urol. 1987;13:242-5. 2. passarella m, usta mf, bivalacqua tj, hellstrom wjg, davis r. testicular sparing surgery: a reasonable option in selected patients with testicular lesions. bju int. 2003;91:337-40. 3. carmignani l, gadda f, gazzano g, et al. high incidence of benign testicular neoplasms diagnosed by ultrasound. j urol. 2003;170:1783-6. 4. leroy xl, rigot jm, aubert s, ballereau c, gosselin b. value of frozen section examination for the management of nonpalpable incidental testicular tumors. eur urol. 2003;44:458-60. 5. elert a, olbert p, hegele a, barth p, hofmann r, heidenreich a. accuracy of frozen section examination of testicular tumors of uncertain origin. eur urol. 2002;41:290-3. 6. haas gp, shumaker bp, cerny jc. the high incidence of benign testicular tumours. j urol. 1986;136:1219-20. 7. sheynkin yr, sukkarieh t, lipke m, cohen hl, schulsinger da. management of nonpalpable testicular tumors. urology. 2004;63:11637. 8. horstman wg, haluszka mm, burkhard tk. management of testicular masses incidentally discovered by ultrasound. j urol. 1994;151:1263-5. 9. steiner h, holtl l, maneschg c, et al. frozen section analysis-guided organ-sparing approach in testicular tumours: technique, feasibility, and long-term results. urology. 2003;62:508-13. 10. masoudi jf, van arsdalen k, rovner es. organ-sparing surgery for bilateral leydig cell tumor of the testis. urology. 1999;54:744. 11. tokuc r, sakr w, pontes je, haas gp. accuracy of frozen section examination of testicular tumors. urology. 1992;40:512-6. 12. valla js for the group d'etude en urologie pédiatrique. testissparing surgery for benign testicular tumors in children. j urol. 2001;165:2280-3. 13. comiter cv, benson cj, capelouto cc, et al. nonpalpable intratesticular masses detected sonographically. j urol. 1995;154:1367-9. 14. kratzer ss, ulbright tm, talerman a, et al. large cell calcifying sertoli cell tumor of the testis: contrasting features of six malignant and six benign tumors and a review of the literature. am j surg pathol. 1997;21:1271-80. 15. cheville jc, sebo tj, lager dj, bostwick dg, farrow gm. leydig cell tumor of the testis: a clinicopathologic, dna content, and mib1 comparison of non-metastasizing tumours. am j surg pathol. 1998;22:1361-7. 16. hopps cv, goldstein m. ultrasound guided needle localization and microsurgical exploration for incidental nonpalpable testicular tumors. j urol. 2002;168:1084-7. 17. coret a, leibovitch i, heyman z, goldwasser b, itzchak y. ultrasonographic and clinical correlation of intratesticular lesions: a series of 39 cases. br j urol. 1995;76:216-9. urological oncology korean version of the functional assessment of cancer therapy (fact)-vanderbilt cystectomy index (vci): translation and linguistic validation myong kim,1 hahn-ey lee,1 sung-han kim,1 sung yong cho,2 seong jin jeong,3 seung-june oh,1 michael s. cookson,4 ja hyeon ku1* purpose: to develop a korean version of the functional assessment of cancer therapy (fact)-vanderbilt cystectomy index (vci) from the original english version, with subsequent linguistic validationin korean patients who underwent radical cystectomy with urinary diversion. materials and methods: translation and linguistic validation were carriedout between january and may of 2013, which consisted of the following stages:(1) permission for translation;(2) forward translation;(3) reconciliation;(4) backward translation;(5) cognitived ebriefing and(6) final proof-reading. results: during the forward translation phases,word ssuch as “bother”,“spend time”, “support”, “coping” and “concern” were adjusted to be more comprehensible to the target population. there conciled korean version was accepted without certain objections because the original version and the backward translation were almost congruent exceptfor minor differences in a subset of questions. the translation was tested using 5 korean-speaking subjects. the subjects took an average of 8.2 minutes to complete the questionnaire, without difficulty and found thequestionnaire clear andeasyto understand. the panel discussed each of the issues raised by subjects and most terms were judged by the panel as to not require further changes because the overall comprehension levels were relatively high and because the translated terms were accurately rendered in the target languages. conclusion: this report has demonstrated that despite translation difficulties, the linguistic validation of the fact-vciin the korean language was successful. the next step is to assess the psychometric properties of the korean version of fact-vci. keywords: cystectomy; psychometrics; quality of life; questionnaires; reproducibility of results; urinary bladder neoplasms; linguistics. introduction current awareness of the psychological and social sequelae of cancer is evident from the intensified clinical research on these problems. because of its impact on sexual function and body image, radical cystectomy for bladder cancer is probably more traumatic than many other cancer operations.(1) bladder cancer is the ninth most common malignancy in south korea, and annual incidence rate is reaching 6.8 cases per 100,000 people. the 5-year relative survival of bladder cancer was 78.3% in south korea, however about one thirds of whole patients eventually receive radical cystectomy.(2) however, the true impact of radical cystectomy with urinary diversion on distressing symptoms, quality of life and general well-being in survivors of bladder cancer remains controversial and requires further clinical investigation. quality of life instruments assess general health perceptions, sense of overall wellbeing, and physical, emotional and social functions. tools used to assess the quality of life in patients with bladder cancer include general instruments, cancer-specific instruments and instruments specific to bladder cancer. although modules specific to bladder cancer have recently become available, they have not been tested as extensively as other general cancer instruments that are more applicable to a variety of cancer types. in addition, almost all clinical studies of the quality of life in patients with bladder cancer have used ad hoc questionnaires of untested validity and reliability.(3-7) in 2003, cookson and colleagues(8) developed a new 1 department of urology, seoul national university hospital, seoul,korea. 2 department of urology, smg-snu boramae medical center, seoul, korea. 3 department of urology, seoul national university bundang hospital, seongnam, korea. 4 department of urology, university of oklahoma, oklahoma city, oklahoma. *correspondence: department of urology, seoul national university hospital, 101 daehak-ro, jongno-gu, seoul 110-744, korea. tel: +82 2 2072 0361. fax: +82 2 742 4665. e-mail: kuuro70@snu.ac.kr. received february 2014 & accepted july 2014 vol 11. no 06 nov-dec 2014 1961 questionnaire for patients treated with radical cystectomy and urinary diversion, the functional assessment of cancer therapy (fact)-vanderbilt cystectomy index (vci), on the basis of their clinical experiences. the questionnaire is a disease specific questionnaire that can objectively assess quality of life following radical cystectomy and urinary diversion, and has been shown to be clinically useful in validation studies. (9,10) a recent study has demonstrated that a simple 15-item summary score of fact-vci (vci-15) is a gender-neutral, reliable and valid measure of condition-specific quality of life in patients who undergo radical cystectomy and urinary diversion.(11) however, it is not simple to translate a questionnaire written in one language into a version in another language; translated versions must reflect differences in the culture and custom of subjects who use a given language. the linguistic validation is the first step of the cultural adaptation of a questionnaire.(12) the objective of the present study was to develop a korean version of the fact-vci from the original version, with subsequent linguistic validation among korean patients who underwent radical cystectomy with urinary diversion. to our best knowledge, the current study is the first translation and linguistic validation of the fact-vci. materials and methods original fact-vci questionnaire the questionnaire developed by cookson and colleagues(8) was selected for this study. the original english version of the fact-vci consists of the 27-items fact-g, divided into 4 subscales for physical, social/ family, emotional and functional well-being in addition to 17 radical cystectomy specific questions, which specifically relates to urinary, bowel and sexual function. ( 8) each item is scored in a 5point likert scale (from 0 for ‘not at all’ to 4 for ‘very much’), with higher scores indicating better quality of life. methodology this study was approved by the institutional review board at seoul national university hospital (seoul, korea; irb no. h-1305-033-487). the purpose of translating this instrument was to obtain a translated version in the korean language that is conceptually equivalent to the original, consistent across either of the two languages, and is easily understood by the subjects responding to the translated version, according to the standardized cultural adaptation process.(13) the previous korean validation studies in urologic filed were also consulted.( 14,15) the linguistic validation process took place under the guidance of a project leader of the panel. the following individuals were involved at various steps of this process: •a panel of six korean experts •two forward translators •one backward translator •one interviewer translation and linguistic validation were carried out between january and may of 2013 and consisted of us / english items first forward korean translation second forward korean translation reconciled korean version i have nausea 나는메스꺼움을느낀다 나는구역질이나어지럼증이있다 나는메스꺼움을느낀다 because of my physical condition, i have trouble meeting the needs 내신체적상태때문에내가족의필 나의육체적상태때문에가정의필 내신체상태때문에내가족이필요로 of my family 요를채우는데어려움이있다 요에충족하지못하고있다 하는것들을충족시키는데어려움이 있다 i am bothered by side effects 나는이치료의부작용때문에괴로움을느낀다 나는치료의부작용이신경쓰인다 나는치료부작용때문에불편하다 of treatment i am forced to spend time in bed 나는어쩔수없이침대에서시간을보내야만한다 나는침대에누워있는상태로시 나는어쩔수없이침대에서지내야만 간을보낼수밖에없다 한다 i get support from my friends 나는내친구들로부터지지를받는다 친구들이나를지지해준다 나는친구들로부터지지를받는 다 i am satisfied with family 나는내가족과내병에대해서이야 나의병에대하여가족들과의사소 나는가족과내병에대해서이야기하 communication about my illness 기하는것에만족한다 통하는것에만족한다 는것에만족한다 i feel close to my partner 나는내배우자 (또는나에게가장많은 나는내동반자가 (혹은주로부양 나는내동반자가 (혹은주로지지하 (or the person who is my main support) 지지가되는사람) 에게가깝게느낀다 하는사람) 가깝게느껴진다 는사람) 가깝게느낀다 regardless of your current level of 귀하의현재성생활과무관하게다 현재성활동의정도에무관하여 귀하의현재성활동정도와무관하게 sexual activity, please answer the 음의질문에답해주세요 다음질문에답변해주십시오 다음의질문에답해주세요 following question. i am satisfied with how i am coping 나는내가내병을견디고있는것에만족한다 나의투병방식에대해서만족감 나는내병에대처하고있는방식에만 with my illness 을느낀다 족한다 i am able to work (include work at home) 나는일을할수있다. (집에서하는일포함) 나는일할수있다 (재택근무포함) 나는일(집에서하는일포함)을할수 있다. i am able to enjoy life 나는내인생을즐길줄안다 나는인생을즐길수있다 나는삶을즐길수있다 additional concern 추가적인문제들 추가적인영향요소 추가적인문제들 i have to limit my sexual activity 나는내건강상태때문에내성생활을제한해야만한다 나의성생활을건강상태에따 나는내건강상태때문에성생활을제 because of my condition 라제한할수밖에없다 한해야만한다 table 1. reconciliation after two forward translations. korean version of the fact-vci-kim et al urological oncology 1962 seven stages. a schematic overview of a typical linguistic validation process is illustrated in figure. in brief, one corresponding author (jhk) contacted the author of the original version (msc) to obtain permission for the translation of the english version of the fact-vci by e-mail. all there translators (two forward and one backward) were bilingual but did not own the medical license of the korean medical association. two translations of the original version into the korean language were performed independently by two different translators according to the instructions for forward translation supplied by the corresponding author (korean versions 1.0a and 1.0b, respectively). the two translations were compared and reconciled into the korean language version after two meetings of a panel consisting of the aforementioned translators and the authors (korean version 1.1). to ensure that the korean language version is faithful to the original version, particularly at the conceptual level, the version 1.1 was given to a third translator who was versed in the two languages (english and korean) to formulate the questionnaire back into english. this backward-translated english version was subsequently compared to the original questionnaire by the panel. the discrepancies between the original english questionnaire and back-translated version led to subsequent changes to the reconciled translated version in the korean language. this resulted in the production of a second korean version and a report explaining the translation decisions (korean version 1.2). standardized interviews were conducted by a trained interviewer and completion of patient-reported outcome. the korean version 1.2 questionnaire was presented to five korean-speaking subjects who hand been treated with radical cystectomy and urinary diversion, to test the clarity, cultural adequacy, and the linguistic understanding of each item and the appropriateness of the translated questions. the debriefing interviews consisted of subjects paraphrasing each item and indicating any difficult or confusing terms to the interviewer. this feedback from the five subjects was analyzed, and the panel agreed on resolutions for each issue raised (korean version 1.3). the third version was proofread to check for spelling, grammar, and formatting, which corresponds with changes made for the final version (korean version 1.4) (appendix). results some of the terms in the original english version were replaced with korean expressions, which include ‘bother’, ‘spend time’, ‘support’, ‘coping’ and ‘concern’. during the forward translation phases, some of the words and phrases were adjusted to be more comprehensible to the target population (table 1). the problems that arose during the translation of questionnaire can be divided into the three categories: •sematic equivalence: there were multiple meanings to a given word or a phrase. this included changing the term ‘my condition’ as this expression connote broader interpretations in the korean language. thus, ‘my condition’ was replaced with ‘my health condition’. similarly, the word, ‘partner’ has many meanings in korean, in which the word can refer to ‘party’, ‘couple’, ‘friend’, ‘member’, and ‘spouse’. therefore, the word ‘partner’ was replaced by ‘spouse’ in order to convey the original meaning in the english version. •idiomatic equivalence: often the english word did original items forward translation (reconciled) backward translation i have nausea 나는메스꺼움을느낀다 i feel nauseous i feel close to my partner 나는내동반자가 (혹은주로지지하는사람) 가깝게느껴진다 i feel close to my companion (or the person who is my main support) (or my primary supporter) i am forced to spend time in bed 나는어쩔수없이침대에서지내야만한다 i cannot help but stay in bed i feel nervous 나는불안감을느낀다 i feel a sense of uneasiness table 2. backward translation. original items translation (reconciled) comprehension issue of subjects resolution i have a lack of energy. 나는에너지가부족하다 energy (1) translated term is identical to original english term. no change necessary. i have nausea. 나는메스꺼움을느낀다 nausea (1) translated term is conceptually equivalent to original english term. no change necessary. because of my physical condition, 내신체상태때문에내가족이필요로하 trouble meeting the needs translated terms are conceptually equivalent to i have trouble meeting the needs 는것들을충족시키는데어려움이있다 of my family (1) original english terms. no change necessary. of my family. i am forced to spend time in bed. 나는어쩔수없이침대에서지내야만한다 in bed (2) change made from ‘침대에서’ to ‘누워서’. i have control of my bowels. 나는배변활동을조절할수있다 bowels (1) conceptual issue in original english. no change necessary. i have trouble controlling my urine. 나는소변을조절하는데문제가있다 controlling my urine (1) translated term is identical to original english term. no change necessary. table 3. resolution of subject comprehension problems during cognitive debriefing interviews. korean version of the fact-vci-kim et al vol 11. no 06 nov-dec 2014 1963 신체적건강 전혀아님 아님 어느정도 꽤많이 아주많이 gp1 나는에너지가부족하다. 0 1 2 3 4 gp2 나는메스꺼움을느낀다. 0 1 2 3 4 gp3 내신체상태때문에내가족이필요로하는 0 1 2 3 4 것들을충족시키는데어려움이있다 gp4 나는통증이있다. 0 1 2 3 4 gp5 나는치료부작용때문에불편하다. 0 1 2 3 4 gp6 나는아프다고느낀다. 0 1 2 3 4 gp7 나는어쩔수없이누워서지내야만한다. 0 1 2 3 4 사회적/가족적건강 전혀아님 약간 어느정도 꽤많이 아주많이 gs1 나는친구들과가깝게느낀다. 0 1 2 3 4 gs1 나는가족으로부터정서적인지 0 1 2 3 4 지를받는다. gs3 나는친구들로부터지지를받는다. 0 1 2 3 4 gs4 가족은나의병을받아들였다. 0 1 2 3 4 gs5 나는가족과내병에대해서이야기 0 1 2 3 4 하는것에만족한다. gs6 나는내동반자가 (혹은주로지지 0 1 2 3 4 하는사람) 가깝게느껴진다. q1 귀하의현재성활동정도와무관하게다음 의질문에답해주세요. 만약답하고싶지 않다면, 이네모(□)에표시해주시고다음 부분으로넘어가주세요. gs7 나는나의성생활에만족한다. 0 1 2 3 4 지난 7일동안각각의내용들이귀하에게얼마나적합하였는지를각문항마다동그라미를한개만쳐주세요. 정서적건강 전혀아님 약간 어느정도 꽤많이 아주많이 ge1 나는슬픔을느낀다. 0 1 2 3 4 ge2 나는내병에대처하고있는방식에만 0 1 2 3 4 족한다. ge3 나는내병과싸우면서희망을 0 1 2 3 4 잃어가고있다. ge4 나는불안감을느낀다. 0 1 2 3 4 ge5 나는죽는것이걱정된다. 0 1 2 3 4 ge6 나의상태가악화될까걱정된다. 0 1 2 3 4 기능적건강 전혀아님 약간 어느정도 꽤많이 아주많이 gf1 나는일(집에서하는일포함) 0 1 2 3 4 을할수있다. gf2 내일(집에서하는일포함)에성취감을 0 1 2 3 4 느낀다. gf3 나는삶을즐길수있다. 0 1 2 3 4 gf4 나는내병을받아들였다. 0 1 2 3 4 gf5 나는잘잔다. 0 1 2 3 4 gf6 나는즐거움을위해주로하는활동들을 즐기고있다. 0 1 2 3 4 gf7 나는현재내삶의질에만족한다. 0 1 2 3 4 지난 7일동안각각의내용들이귀하에게얼마나적합하였는지를각문항마다동그라미를한개만쳐주세요. 추가적인문제들 전혀아님 약간 어느정도 꽤많이 아주많이 c2 나의체중이줄고있다. 0 1 2 3 4 c3 나는배변활동을조절할수있다. 0 1 2 3 4 c3 나는설사를한다. 0 1 2 3 4 c6 나는식욕이좋다. 0 1 2 3 4 c7 나는내외모에만족한다. 0 1 2 3 4 bl1 나는소변을조절하는데문제가있다. 0 1 2 3 4 itu7 내건강상태때문에밤에잠을깬다. 0 1 2 3 4 itu6 나는내건강상태때문에당혹스럽다. 0 1 2 3 4 c9 내소변상태를관리하는것이어렵다. 0 1 2 3 4 itu3 나는내건강상태때문에사회적활동을 0 1 2 3 4 제한해야만한다. itu4 나는내건강상태때문에신체적활동을 제한해야만한다. 0 1 2 3 4 itu5 나는내건강상태때문에성생활을 제한해야만한다. 0 1 2 3 4 itu1 나는친구들과나의건강상태에대해 의논하는것이편하다. 0 1 2 3 4 vc1 나는나의소변상태에만족한다. 0 1 2 3 4 itu2 나는화장실과멀리떨어져있는것이두렵다. 0 1 2 3 4 bl4 나는섹스에관심이있다. 0 1 2 3 4 bl3 (남성만해당) 나는발기가되고그상태를 0 1 2 3 4 유지할수있다. appendix. korean version of the functional assessment of cancer therapy-vanderbilt cystectomy index. 아래내용은귀하와같은병을앓았던다른환자들이중요하다고이야기한목록입니다.지난 7일동안각각의내용들이귀하에게얼마나적합하였는지를각문 항마다동그라미를한개만쳐주세요. korean version of the fact-vci-kim et al urological oncology 1964 not have quite the same conceptual meaning in the korean language. for example, the question, ‘i have control of my bowels’ was translated into ‘i have control of my defecation’. the question, ‘i have to limit my sexual activity because of my condition’ was translated to ‘i have to limit my sex life because of my health condition’ for a more natural expression. the item, ‘caring for my urinary condition is difficult’, was translated into ‘managing my urinary condition is difficult’, because of the possibility of difficulty in understanding of the expression ‘caring for’ in the korean language. •conceptual equivalence: some words hold different conceptual meaning between cultures. for instance, the meaning of ‘because of my physical condition, i have trouble meeting the needs of my family’ would differ between cultures because the word ‘family’ could potentially mean ‘immediate family’ or ‘family including extended relatives’. the reconciled korean version (version 1.1) was accepted without strong objections because the original version and the backward translation were almost congruent except for the questions listed in table 2. despite these differences, the meanings of respective items between both versions were judged to be almost identical. the translation was tested using 5 subjects. the mean age was 67 years (range 55 to 73), and all subjects were male. the length of education ranged from 6 to 14 years, with a mean of 9.2 years. four subjects had fewer than 12 years of education. the respondents completed the questionnaire within the average of 8.2 minutes, without difficulty, and reported the questionnaire to be clear and easy to understand. the panel discussed each of the issues raised by subjects to decide whether changes to the translation were needed. items that were subsequently changes by the panel were considered resolved issues (table 3). however, most terms were judged by the panel as not requiring changes because overall comprehension levels were relatively high and because the translated terms were accurately rendered in the target language. discussion the concept of quality of life can be defined as the extent to which the usual or expected physical, emotional, and social wellbeing is affected by a medical condition or its treatment. ( 16) having accurate baseline and post-treatment data is essential in evaluating the quality of life of patients and subsequently determining the effectiveness of management.( 17) measuring quality of life might be challenging for physicians as it may take a long time during the overall assessment of their patients. validated quality of life questionnaires are important tools to assess outcomes after surgery and help overcome this obstacle. in addition, the use of validated and standardized tools will allow comparison of outcomes across different studies and in meta-analyses.(18) radical cystectomy with urinary diversion is considered to be the most effective local treatment for invasive bladder cancer. quality of life after radical cystectomy may be affected by diversion type, body image, urinary function, and sexual function. although generic quality of life measures provide valuable information, they may not be sufficiently sensitive to detect cystectomyor diversion-specific changes. the development of bladder cancer-specific instruments has been essential in detecting differences in urinary, bowel, sexual, and body image outcomes in bladder cancer survivors. some condition-specific measures have been used to measure health-related quality of life in bladder cancer patients.( 19-21) however, only fact-vci and the bladder cancer index (bci) are reliable and validated disease-specific measures with known psychometric properties.( 8,22) between the two, the fact-vci has been found to have adequate internal consistency (cronbach’s α > 0.7).(8) interclass correlation for the first and second administration of the fact-vci was 0.79, which verifies the stability of the score derived from serial administrations of this questionnaire by the same respondent.( 8) convergent validity was investigated by correlating the factvci with the generic rand 36item health survey (sf-36) (r = 0.81).(8) differences in quality of life cannot simply be attributed to the disease process, when comparing culturally diverse populations.(23) cultural adaptation is the first step when validating instrument in new language. in general, translation of a questionnaire into a version in another language is not straightf orward, and differences in cultures and customs associated with each language have to be considered during the translation process. therefore, the availability of highquality translation is of vital importance to guarantee a successful implementation in the target language and to assure the international comparability of the data. (24) consequently, detailed guidelines and appropriate documentation of each step of translation processes have been proposed.(25,26) in this study, we have presented the korean version of the fact-vci by gaining permission of use from the original authors and verifying the appropriateness and reliability of the questionnaire in order for it to be officially used for patients in south korea. we found that korean subjects understood the translated questionnaire, figure. the standard linguistic validation algorithm. korean version of the fact-vci-kim et al vol 11. no 06 nov-dec 2014 1965 although a number of minor changes were made in an effort to improve the clarity and cultural appropriateness. this overall high comprehension rate and lack of significant unresolved comprehension issues demonstrated a high level of linguistic validity. potential limitations of the study included the small sample size and an imperfectly stratified subject pool in terms of level of education. psychometric validation of the translation produced may be a useful next step for verifying the cross-cultural validity of the translated questionnaire.(27,28) conclusion this report has demonstrated that despite the translation difficulties, the linguistic validation of the fact-vci in korean language was successful. we found that the translation was understood well by korean-speaking subjects. the korean version of the fact-vci questionnaire can be used as a tool for evaluating quality of life in patients who underwent radical cystectomy with urinary diversion and is expected to be useful in clinical research. the next step is to assess the psychometric properties of the korean version of fact-vci. acknowledgements this study was supported by grant no 05-2013-0010 from snuh research fund. yu kyoung lee, ha young kim, yu jin lee, and se ra park assisted with the development of the korean version of fact-vci. conflict of interest none declared. references 1. månsson a, månsson w. when the bladder is gone: quality of life following different types of urinary diversion. world j urol. 1999;17:211-8. 2. the korea central cancer registry. annual report of cancer statistics in korea in 2010. gyeonggi-do, republic of korea: national cancer center; 2012. p. 23-8 3. gotoh m, mizutani k, furukawa t, kinuka wa t, ono y, ohshima s. quality of mictu rition in male patients with orthotopic neo bladder replacement. world j urol. 2000;18:411-6. 4. fujisawa m, isotani s, gotoh a, okada h, araka wa s, kamidono s. healthrelated quality of life with orthotopic neobladder versus ileal conduit according to the sf-36 survey. urology. 2000;55:862-5. 5. miyake h, nakamura i, eto h, et al. an eval uation of quality of life in patients who unde rwent orthotopic bladder replacement after cystectomy: comparison of ileal neobladder versus colon neobladder. urol int. 2002;69:195-9. 6. yoneda t, igawa m, shiina h, shigeno k, urakami s. postoperative morbidity, functi onal results and quality of life of patients fol lowing orthotopic neobladder reconstruction. int j urol. 2003;10:119-25. 7. henningsohn l, wijkström h, steven k, et al. relative importance of sources of symp tom-induced distress in urinary bladder can cer survivors. eur urol. 2003;43:651-62. 8. cookson ms, dutta sc, chang ss, clark t, smith ja jr, wells n. health related quality of life in patients treated with radical cystec tomy and urinary diversion for urothelial car cinoma of the bladder: development and val idation of a new disease specific questionna ire. j urol. 2003;170:1926-30. 9. large mc, katz mh, shikanov s, eggener se, steinberg gd. orthotopic neobladder versus indiana pouch in women: a compari son of health related quality of life outcomes. j urol. 2010;183:201-6. 10. vakalopoulos i, dimitriadis g, anastasiadis a, gkotsos g, radopoulos d. does intubated uretero-ureterocutaneostomy provide better health-related quality of life than orthotopic neobladder in patients after radical cystecto my for invasive bladder cancer? int urol nephrol. 2011;43:743-8. 11. morgan tm, barocas da, penson df, et al. lymph node yield at radical cystectomy pre dicts mortality in node-negative and not nod e-positive patients. urology. 2012;80:632 40. 12. acquadro c, kopp z, coyne ks, et al. translat ing overactive bladder questionnaires in 14 languages. urology. 2006;67:536-40. 13. acquadro c, conway k, hareendran a, aar onson n; european regulatory issues and quality of life assessment (eriqa) group. literature review of methods to translate health-related quality of life questionnaires for use in multinational clinical trials. value health. 2008;11:509-21. 14. chung kj, kim jj, lim sh, kim th, han dh, lee sw. development and validation of the korean version of expanded prostate cancer index composite: questionnaire as sessing health-related quality of life after prostate cancer treatment. korean j urol. 2010;51:601-12. 15. min ks, kim yh, kim jm, shin kl, hong jy, kim me. development of a korean ver sion of the urinary tract infection sympto ms assessment questionnaire. korean j urol. 2009;50:361-8. 16. cella df. quality of life: concepts and defi nition. j pain symptom manage. 1994;9:186 92. 17. ikeda y, saku m, kawanaka h, nonaka m, yoshida k. features of second primary can cer in patients with gastric cancer. oncology. korean version of the fact-vci-kim et al urological oncology 1966 2003;65:113-7. 18. boers-doets cb, gelderblom h, lacouture me, et al. translation and linguistic valida tion of the fact-egfri-18 quality of life instrument from english into dutch. eur j oncol nurs. 2013;17:802-7. 19. cella d. facit manual: manual of the function al assessment of chronic illness therapy (facit) measurement system, 4th ed. evanston, il: center on outcomes rese arch and education; 1997. 20. gilbert sm, wood dp, dunn rl, et al. measuring health-related quality of life out comes in bladder cancer patients using the bladder cancer index (bci). cancer. 2007;109:1756-62. 21. eortc b. cancer qol questionnaires. avail able at: http://groups.eortc.be/qol. accessed may 2013. 22. gilbert sm, dunn rl, hollenbeck bk, et al. development and validation of the bladder cancer index: a comprehensive, disease spe cific measure of health related quality of life in patients with localized bladder cancer. j urol. 2010;183:1764-9. 23. månsson a, al amin m, malmström pu, wijk ström h, abol enein h, månsson w. patient-assessed outcomes in swedish and egyptian men undergoing radical cystec tomy and orthotopic bladder substitution--a prospective comparative study. urology. 2007;70:1086-90. 24. hertrampf k, wenz hj, koller m, springer i, jargot a, wiltfang j. assessing dentists’ knowledge about oral cancer: translation and linguistic validation of a standardized ques tionnaire from american english into ger man. oral oncol. 2009;45:877-82. 25. koller m, aaronson nk, blazeby j, et al. eortc quality of life group. translation procedures for standardised quality of life questionnaires: the european organisa tion for research and treatment of cancer (eortc) approach. eur j cancer. 2007;43:1810-20. 26. acquadro c, conway k, hareendran a, aar onson n. european regulatory issues and quality of life assessment (eriqa) group. literature review of methods to translate health-related quality of life questionnaires for use in multinational clinical trials. value health. 2008;11:509-21. 27. guillemin f, bombardier c, beaton d. cross-cultural adaptation of healthrelated quality of life measures: literature review and proposed guide-lines. j clin epidemiol. 1993;46:1417-32. 28. beaton de, bombardier c, guillemin f, fer raz mb. guidelines for the process of cross cultural adaptation of self-report measures. spine. 2000;25:3186-91. korean version of the fact-vci-kim et al vol 11. no 06 nov-dec 2014 1967 reconstructive surgery dorsal island penile fasciocutaneous flap for fossa navicularis and meatal strictures: short and intermediate term outcome in west african men kehinde habeeb tijani,1* rufus wale ojewola,2 benjamin odusanya,3 ganiyu lanre yahya4 purpose: the aim of this study was to evaluate the use of a dorsal island penile fasciocutaneous flap in the management of resistant fossa navicularis strictures in circumcised west african men. materials and methods: from january 2004 to december 2013 there were twenty-one patients with fossa navicularis strictures (fns) with or without meatal stenosis who underwent urethroplasty using a previously described technique and a dorsal island penile fasciocutaneous flap. the average patient follow-up was 25.9 months. results: urethral catheterization was the most common cause of fns. all of the patients had successful urethral function and acceptable cosmetic results. one patient had partial dorsolateral skin necrosis that healed with conservative measures. all patients, including the five patients with meatal stenosis, retained the natural shape of the external meatus and hada natural urine stream. conclusion: the penile cap technique uses a dorsal island fasciocutaneous flap and provides satisfactory functional and cosmetic outcomes in the management of fossa navicularis and meatal strictures. keywords: treatment outcome; urethra; surgery; urethral stricture; surgery; etiology; patient satisfaction; methods; nigeria. introduction fossa navicularis structures (fns) are common in adult men. however, the management constitutes a special challenge because success is not determined by the re-establishment of function alone but rather also requires acceptable cosmetic appearance of the glans.(1) the treatment options for fns include dilatation, urethrotomy, and urethroplasty. urethrotomy for fns is technically cumbersome and is palliative, similarly to dilatation.(2,3) thus, surgical reconstruction has the highest probability of cure.(4) the choice of reconstruction depends on the etiology, the state of the urethral plate, and the surgical preference. there are several surgical techniques for reconstructing the fossa navicularis (fn) and each method has advantages and disadvantages. there is currently no universal consensus on the preferred reconstructive technique for fns. in the presence of normal penile skin the techniques using local tissue transfer lead to a satisfactory functional outcome. however, the v-y plasty techniques popularized by blandy and colleagues. (5) have been criticized for their poor cosmetic results. additionally, splitting the glans and using a ventral island flap yields better cosmetic outcomes.(6) however, a ventrally raised flap compromises the vascularity of the skin covering the neo-urethra and may increase the risk of fistula formation. the use of a ventral flap in the penile cap approach is called penile cap urethroplasty (pcu) and was popularized by armenakas and colleagues.(7) this surgical technique has gained popularity because it avoids an incision of the glans and is associated with the best cosmetic outcome. in this study, we report the results of using a dorsal island penile fasciocutaneous flap (dipff) and the pcu approach to repair fns. materials and methods study population the patients in this study were treated with penile cap urethroplasty using a dipff for strictures involving the fossa navicularis and meatus. the surgeries were performed between january 2004 and december 2013. the preoperative diagnosis was based on patient history, physical examination, and the results of antegrade and/ or retrograde urethrogram studies in all cases. additional investigations were performed as necessary. the diagnosis was confirmed intraoperatively in all cases. this study included only intraoperatively confirmed cases of fns (with or without meatal stenosis) with less than 0.5 cm of extension into the proximal urethra. surgical technique the urethral reconstruction was performed using a combination of the pcu and a modified form of the ventral transverse island penile fasciocutaneous flap (vtipf) as described by jordan.(8) this modification involved degloving the penis, and a flap was then raised from the dorsum as a dipff. 1 department of surgery, section of urology, college of medicine, university of lagos, lagos state, nigeria. 2 department of surgery, section of urology, lagos university teaching hospital, lagos state, nigeria. 3 department of surgery, section of urology, lagos general hospital, lagos state, nigeria. 4 lagos continental hospital, lagos state, nigeria. *correspondence: department of surgery, section of urology, college of medicine, university of lagos, lagos state, nigeria. tel: +234 8023049739. e-mail: khtijani@cmul.edu.ng. received february 2015 & accepted june 2015 reconstructive surgery 2267 the penis was degloved to the base after making a subcoronal incision through the dartos and bucks fascia and exposing the urethra. the glans was then dissected from the ventral surface of the urethra to expose the strictured segment using blunt and sharp dissection. a ventral incision was then created in the urethra and extended 0.5 cm proximally into the normal urethra. in patients with meatal stenosis a mosquito artery forceps was used to invert the tip of the meatus into the wound to assist visualization of the external meatus (figure 1). the urethral incision was extended into the inverted external meatus using counter (distal) traction on the corona of the glans. in patients with meatal stenosis it was easier to start the incision at the inverted external meatus because it could be incised generously and then be extended to the proximal urethra (figure 2). an appropriately sized fasciocutaneous flap was then raised from the dorsum or dorsolateral surface of the penis. the pedicle was dissected close to the base of the penis. the flap was then brought to the ventral surface and sutured as a ventral urethral onlay using synthetic absorbable 4-0 vicryl sutures. the flap suturing was extended to the ventral margin of the inverted (and incised) meatus in patients with meatal stenosis. the second layer coverage was achieved using a dartos flap harvested dorsolaterally.the retracted glans was then replaced into its normal position and the penile skin was closed with absorbable synthetic 4-0 vicryl sutures. all patients received urethral stenting and had suprapubic drains placed. the urethral stent was removed after 3 weeks, and the suprapubic drainage was removed 1 week later if no problems occurred. outcome measures the postoperative follow-up included observations of the following parameters: urinary pattern, calibration with a size 16 french (f) foley catheter, uroflowmetry, post-void residual volume measurements using pelvic ultrasound, and evaluation of lower urinary tract symptoms. a successful outcome included the maintenance of normal glans shape, subjective and objective improvements in urinary flow, and aurethral lumen ≥16f, requiring no further urethral instrumentation during follow-up. the first author was involved in the management of all cases under review. results there were 21 cases of strictures involving the fossa navicularis repaired during the study period and these cases accounted for 7.8% of all urethroplasties performed. urethral catheterization was caused in 13 cases, and endoscopy was caused in 3 cases. there were 2 cases of purulent urethritis and one case each of external trauma, previous hypospadias repair, and idiopathic cause. the duration of symptoms ranged from 8 months to 11 years (mean 25.3 ± 4 months). the stricture lengths ranged from 1.2 cm to 3.1 cm (mean 2.0 cm).the stricture was limited to the glandular urethra (with or without meatal involvement) in 15 cases but extended proximally (by 0.5 cm or less) in 6 cases. the external meatus was involved in 5 cases, and all were associated with urethral catheterization. all patients were fully circumcised adults. there were16 (76.1%) patients previouslytreated with dilatation. there were 11 (52.4%) cases with a suprapubic cystostomy (either inserted at our center or by the referring hospital) to manage complications of acute urinary retention (4 cases), renal failure (3 cases), urethrocutaneous fistula (3 cases) and severe lower urinary symptoms (1 case) prior to surgery. the surgery achieved functional and cosmetic successes in all patients. one patient (4.8%) had partial dorsolateral skin necrosis that healed with conservative measures. there was mild splaying of the urinary stream in all patients after removal of the catheter. there were no patients that described as the condition as worrisome. the duration of follow-up ranged from 11 -92 months (mean 25.9 ± 4.1). figure1. incision about to be made on stenotic meatus (identified with the tip of artery forceps) in patient with fossa navicularis stricture and meatal stenosis. figure 2. wide incision into the meatus and part of fossa navicularis to be extended proximally in to normal urethra in same patient above. dorsally harvested skin flap will then be placed as a ventral onlay. vol 12 no 04 july-august 2015 2268 fossa navicularis stricture-tijani et al. discussion strictures of the fn and meatus are relatively uncommon in our region. there is no universally accepted surgical management for fns. however, factors including etiology, stricture length, and state of the glans are important considerations when choosing a surgical technique. although the one-stage flap techniques have consistently given excellent results, there are reports suggesting these techniques should be avoided in strictures caused by balanitis xerotica obliterans (bxo).(6,9) in this study, iatrogenic causes such as urethral catheterization accounted for most cases. while some studies(6,7) have reported bxo as the major cause of fn strictures, there were no cases in this study. bxo as a cause of urethral stricture is extremely rare in our environment and analysis of hospital records of over 2000 cases with urethral stricture disease in our facilities over the last 2 decades did not reveal a single bxo case. the routine infant (neonatal) circumcision practiced in our hospital may be the main factor responsible for this finding. there are only a few cases reporting external trauma as the cause of fn strictures. in this study, external trauma was uncommon and accounted for one case. the use of local skin flaps has become the mainstay of treatment of fn strictures not caused by bxo.(4-7) jordan(8) revolutionized the management of fn using a ventral fasciocutaneous onlay flap with glans splitting. armenakas and colleagues(7) used the same flap with a glans cap technique and achieved better cosmetic results. in both procedures the dissection was limited to the ventral surface of the penis. in our technique, the penis is degloved (not necessarily to the base) and the flap is raised from the dorsal or dorsolateral aspect of the distal penile skin. the flap harvest technique has been described in greater detail elsewhere.(9) in this study, the penis was degloved in a manner similar to the transverse preputial island flap popularized by duckets(10) for hypospadias repair. a greater retraction of the glans can be achieved using a circumferential incision because it allows direct visualization of the tip of the external meatus and extension of the ventral urethral incision to the external meatus. although there were a limited number of meatal stenosis cases in this study, this step was possible in all patients. in patients with meatal stenosis both excisinga generous core of the perimeatal glandular tissue and suturing the flap around the whole circumference of the meatus were important steps described by armenakas and colleagues(7) and others.(12) however, this may not apply to all patients with associated meatal stenosis. a simple generous incision and a ventral onlay extending to the ventral margin of the meatus were satisfactory in all patients. the use of these steps may help preserve the natural shape of the external meatus (figures 3 and 4) and prevent complications such as prolapse and retraction of the neo-urethra. these types of complications were absent in this series. significant urinary splaying after 3 months has been reported in most patients after pcu.(7,12) we have not noticed this issue in our patients. compared with pictures in other studies (7), there appears to be better preservation of the natural urine stream in our patients (figure 5). we believe preserving the natural shape of the meatus in our patients may be responsible for this result. raising a flap from the side or the dorsum after degloving the penis may also offer some technical advantages over the vitpff presently described in the literature. using a dartos flap to cover the neo-urethra is possible and the risk of devascularization of the ventral penile skin and the risk of fistula formation are negligible. this approach was particularly useful for the post-hypospadias repair patients. there was no fistula formation observed in this series. armenakas and colleagues(7) also reported there was no fistula formation in his series. however, other studies have reported fistula asa complication of ventral flaps.(13) a previously unreported problem noted in this study was the presence of several seconds of temporary arrest of micturition occurring only when urinating during early morning full erections. this symptom was confined to 2 patients in their 20’s and they typically felt the arrest at the distal end of the penile urethra. all of the postoperative parameters including imaging and urethroscopy were normal in these patients. in both patients the symptoms disappeared after 12 months. we wait 3 weeks before removing the urethral catheter because we do not routinely perform a pericatheter urethrogram because the patients could not afford this procedure. there have not been consequences as a result of this practice. figure 3. pre-operative picture of same patient in figure 1. figure 4. post operative picture of same patient in figure 1 at 3 months. reconstructive surgery 2269 fossa navicularis stricture-tijani et al. the dipff has some disadvantages. the dissection is more extensive and has anincreased surgical time. the procedure is completed in an average of 80 minutes, which is approximately twice the time reported by onol and colleagues for vipff.(12) however, all the strictures reported by onol and colleagues were less than 1.5 cm. there is also an associated circumferential sub-coronal scar, but this scar is not a problem for an average west african man because men are normally circumcised in infancy. in theory raising the flap from the dorsal rather than the ventral surface should increase the risk of penile torsion or chordee. however, while this problem is common after vipff techniques described in the literature there were no patients in the present study with these problems. the dissection of the flap pedicle close to the base of the penis in the dipf may be responsible for this result. this study had several limitations. first, the sample size of 21 cases is limited. compared with other strictures, isolated fns is uncommon in our region, and this is also the only study in sub-saharan africa examining the management of fns. the virtual absence of bxo in our country may be the major reason for this result. the data collection was another study limitation because the data from several patients were collected retrospectively. additionally, the average postoperative follow-up was approximately 2 years. the decision to commence the study was made in 2009, and data from 2004 2008 were collected retrospectively. the short average follow-up was paradoxically caused by the early cases in the series. at the beginning of the study, the local infrastructure for follow-up services in our region was limited. conclusion our results suggest that ditpff with a penile cap technique is associated with acceptable functional and cosmetic outcomes in patients with fn strictures. conflict of interest none declared. figure 5. same patient performing uroflowmetry at 3 months. splaying is minimal. references 1. tonkin jb, jordan gh. management of distal anterior urethral strictures. nat rev urol. 2009;6:533-8. 2. peterson ac, webster gd. management of urethral stricture disease: developing options for surgical intervention. bju int. 2004;94:971-6. 3. greenwell tj, castle c, andrich de, macdonald jt, nicol dl, mundy ar. repeat urethrotomy and dilation for the treatment of urethral stricture are neither clinically effective nor cost-effective. j urol. 2004;172:275-7. 4. singh sk, agrawal sk, mavuduru rs. management of the stricture of fossa navicularis and pendulous urethral strictures. indian j urol. 2011;27:371-7. 5. tonkin jb, jordan gh. management of distal anterior urethral strictures. nat rev urol. 2009;6:533-8. 6. virasoro r, eltahawy ea, jordan gh. longterm follow-up for reconstruction of strictures of the fossa navicularis with a single technique. bju int. 2007;100:1143-5. 7. armenakas na, morey af, mcaninch jw. reconstruction of resistant strictures of the fossa navicularis and meatus. j urol. 1998;160:359-63. 8. jordan gh. reconstruction of the fossa navicularis. j urol. 1987;138:102-4. 9. tijani kh, adesanya aa, ogo cn, osegbe dn. penile fasciocutaneous flap urethroplasty. recent experience and challenges in a sub-saharan african teaching hospital. urology. 2009;74:920-3. 10. duckett jw. transverse preputial island flap technique for repair of severe hypospadias. urol clin north am. 1980;7:423-30. 11. meeks jj, barbagli g, mehdiratta n, granieri ma, gonzalez cm. distal urethroplasty for isolated fossa navicular isand meatal strictures. bju int. 2012;109:616-9. 12. onol sy, onol ff, onur s, inal h, akbaş a, köse o. reconstruction of strictures of the fossa navicularis and meatus with transverse island fasciocutaneous penile flap. j urol. 2008;179:1437-40. vol 12 no 04 july-august 2015 2270 fossa navicularis stricture-tijani et al. 1550.pdf 878 | female urology maryam ghassamia,1 ali asghari,1 mohammad reza shaeiri,1 mohammad reza safarinejad2 validation of psychometric properties of the persian version of the female sexual function index corresponding author: nicholas g. cost, md division of pediatric urology, cincinnati children’s hospital medical center, 3333 burnet avenue, mlc 5037, cincinnati, ohio 45229, usa tel: +513 363 0773 fax: +513 636 6753 e-mail: nicholas.cost@sbcglobal.net received january 2012 accepted october 2012 female urology corresponding author: nicholas g. cost, md division of pediatric urology, cinci nati children’s hospital medical center, 3333 burnet avenue, mlc 5037, cincinnati, ohio 45229, usa tel: +513 363 0773 fax: +513 636 6753 e-mail: nicholas.cost@sbcglobal.n received january 2012 accepted october 2012 1department of psychology, shahed university, tehran, iran 2clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran corresponding author: mohammad reza safarinejad, md p.o. box 19395-1849, tehran, iran tel: +98 21 2245 4499 fax: +98 21 2245 6845 e-mail: info@safarinejad. com received july 2012 accepted april 2013 purpose: to examine the psychometric properties of a persian language version of the female sexual function index (p-fsfi) amongst a sample of healthy iranian women. materials and methods: all participants (562) completed a battery of questionnaires, including the p-fsfi, depression anxiety stress scales (dass), positive and negative affect scales (panas) and locke-wallace marital adjustment test (lwmat). the dimensions of the p-fsfi and its convergent and divergent validity were examined, using principal component analysis and pearson correlations, respectively. to examine the predictive validity of the p-fsfi, data collected from 562 healthy participants were compared with 108 women with sexual problems who completed the p-fsfi measure. the p-fsfi reliability was determined in two ways: calculating cronbach alpha results: the results indicated that the p-fsfi is conceptualized within a-four factor model. these factors were named as: sexual response, sexual desire, sexual-related pain, and sexual satisfaction. results also indicated that the p-fsfi and its 4 subscales had good internal consistency and p-fsfi and its 4 subscales with the scores of dass, panas and lwmat supported both the convergent and divergent validity for the p-fsfi. the results also indicated that the scores of the conclusion: iranian healthy females. keywords: psychometrics, sexual dysfunctions, stress, psychology 879vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l introduction female sexual dysfunction (fsd) is an important pri-mary care issue and associates with biological, psy-chological, interpersonal, social, and cultural factors. (1,2) sexual desire, genital arousal, orgasm, and genital pain associated with sexual intercourse.(1-3) epidemiological surveys report a variable prevalence of fsd ranging from 19% to 45%.(4-7) in spite of high prevalence of fsd, women’s sexual-related dysfunction had been neglected for many years. as a result, compared to male sexual dysfunction (msd), the fsd has been underestimated.(1,8) however, in recent years, the fsd has received more research interest.(9,10) having access to valid and reliable assessments tools for fsd is important from both research and treatment perspectives. (8,9,11) over the past decade, a number of psychometrically sound measures have been developed to assess the fsd.(11,12) of these, female sexual function index (fsfi) has received much research and clinical attention. the fsfi is a 19-item multidimensional self-report instrument for assessing six key domains of sexual function in women, including sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. the fsfi has two response formats; while items 1, 2, 15, and 16 are answered on a 1 to 5 likert scale, the rest of the items are answered using a 0 to 5 likert scale. the fsfi provides six separate scores for sexual desire, arousal, lubrication, orgasm, satisfaction, and pain as well as an overall score for sexual functioning (total fsfi). higher scores (on the total fsfi or on the six individual subscales), compared to lower scores, indicate a better sexual functioning.(8) the psychometric properties of the fsfi have been supported by several studies.(9,10,13,14) the fsfi has been used extensively in epidemiological studies(15-18) as well as in the treatment studies.(19-22) in sum, growing body of literature supports the practicability of the fsfi(9,10,13) and until now, it has been translated into more than 20 languages.(10,13,23) the aim of the present study was to examine the psychometric properties of a persian language version of the female sexual function index (p-fsfi) amongst sample of iranian females without sexual problems. materials and methods study subjects the sample size on which factor structure, divergent and convergent validity, and internal consistency of the p-fsfi were tested consisted of 650 healthy participants who were living in tehran, iran. these participants were selected using a convenience sampling method. the sample size calculation was based on tabachnick and fidell recommendations that sample size.(24) the participants had to meet the following inclusion criteria: (i) willing to participate in the study; (ii) being married and having a stable sexual relationship with their spouse for at least the past 6 months, and (iii) having at least 12 years of formal education. the exclusion criteria in this study were: (i) suffering from chronic and severe medical illnesses; (ii) seeing a psychiatrist, a psychologist, or a gynecologist due to sexual-related problems over the past 6 months, and (iii) unwilling to participate in the study. after consenting to the study protocol, a battery of questionnaires was given to each pose of the study and how to complete the measures. of the 650 collected questionnaires, 88 were excluded from the analysis due to incomplete data. the remaining 562 subjects were included in this study. the test-retest reliability of the p-fsfi was tested, using data collected from a sub sample of these healthy participants (n = 40). the participants completed the p-fsfi in a 4-week interval. measures several measures were used in this study: p-fsfi current guidelines for cross-cultural adaptation of measures generally recommend a multi-step process to certify the equivalence of the original and the back translated versions. in our translation of the fsfi, we incorporated some of these recommendations as follows:(1) two bilingual mental health practitioners independently translated the original version of the fsfi(8) from english into persian; differences were solved by agreement;(2) other two mental health practitionhad no knowledge regarding the questionnaire carried out persian version of the fsfi | ghassamia et al 880 | back translations; and (3) pilot testing was performed on a sample of 50 participants. these participants were asked to report any problems that they had in understanding the p-fsfi items. on the basis of the results of this pilot study, some additional changes were made to the p-fsfi. furthermore, as persian (farsi) language is a right-to-left language (while english is a left-to-right language), in the p-fsfi, each statement is written from right to left. apart from the above, the p-fsfi was very similar to the original version without compromising its comprehension and being adequate in persian (farsi) language (a copy of the p-fsfi, and its scoring syssion of the fsfi, the p-fsfi consists of 19 items. items refer to the past 4 weeks. the short form of depression anxiety stress scales (dass21) the dass-21 is a short form of the dass-42 that was originally developed by lovibond and lovibond to assess depression, anxiety, and stress.(25) seven items are allocated to each measure of depression, anxiety, and stress. all the items are rated on a 0 to 3 scale; higher scores are associated with more severe levels. positive and negative affect scales (panas) the panas is a 20-item self-report measure that measures two mood dimensions, including positive affect (pa; 10 items) and negative affect (na; 10 items). all items are rated on a 5 likert scale, while 1 equals very slightly or not at all and 5 equals extremely. it has been demonstrated that the panas has excellent validity and reliability.(26) locke-wallace marital adjustment test (lwmat) the mat is one of the measures widely used to assess marital quality. this 15-item test can be answered in 5 to 10 minutes. the mat yields a score ranging from 2 to 158, with higher scores indicating better marital functioning.(27) in addition to the above measures, the following characteristics were also recorded: age, education, occupation, duration of marriage, number of children, and menopausal status. data analysis all the data were collected, scored, and entered into a sedata were checked through the spss program for precision of data entry, missing values, normal distributions, and possible outliers.(24) in this study, data were analyzed in a number of ways: a principal component analysis (pca) was used to identify dimensions of the p-fsfi.(28) eigenvalues and scree plot were used to determine the number of components underlying the p-fsfi. reliability of the p-fsfi and its subscales was determined by examining both the internal consistency and test–retest stability of the p-fsfi and its subscales.(29) the convergent and the divergent validity of the p-fsfi were tested using pearson product-moment correlations between the p-fsfi scores and a series of interested variables. the predictive validity of the p-fsfi and its subscales was established by having compared two groups of healthy participants (n = 562) and a sample (n = 108) of females referred to sexual clinics due to fsd. before conducting statistical analyses, the data were screened for normality of distribution. no outliers were detected. all statistical analyses were performed with the use of spss software (the statistical package for the social sciences, version 17.0, spss inc, chicago, illinois, usa). results sample characteristics the mean ± standard deviation age of the participants was 31.9 ± 8.16 years (range, 19 to 57 years). all the participants years of formal education and 65% had at least 16 years of formal education), and 61% were working in public section. they were married on average for 100 ± 85 months (range, 6 to 372 months). principal component analysis principal component analysis (pca) was used to identify dimensions of the p-fsfi. the original pool of 19 items was submitted for initial analysis. a matrix that is factorable should consist of several considerable correlations. tabachnick and fidell believe that if none of the correlation surpasses 0.30, the use of factor analysis is debatable.(24) in this female urology 881vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l study, there were several correlations greater than 0.30. bar171, p = .0001) and kaiser–meyer–olkin measure of sample adequacy was 0.95. values of 0.60 and above are required for a good factor analysis.(24) the decision between orthogonal and oblique rotation was made by examining the correlations among factors.(24) since one of the correlations was greater than 0.32 (the correlation between factor 1 and factor 4 was equal to 0.57), the resulting factors were subjected to oblique (oblimin) rotation.(24) using pca with oblique rotation, 4 components were extracted. the eigenvalue of these components was greater than 1.0. the examination of the scree plot suggested that four for 78.28% of the variance in p-fsfi item scores. table 1 shows the factor loadings, communalities (h2), eigenvalues, and percentage of variance for the four-dimension solution. as has been recommended by meir and gati,(28) for each item, the difference between the two highest factor loadings must be greater than 0.10, otherwise, that item should be reported as a cross-loaded item. as can be seen in table 1, problematic cross loading across components were observed for two items: item 13 from the sexual response component (with factor loading = 0.78) cross-loaded on sexual satisfaction factor (with factor loading = 0.70). considering the content of this item, it was decided to accept it as one of the items table 1. principal component analysis of the persian language version of the female sexual function index factor loading and communalities (h2) for the four-component solution. item number and description c1 c2 c3 c4 h2 sexual response (arousal, lubrication, and orgasm) 7. how often did you become lubricated during sexual activity? 0.86 0.46 0.43 0.45 0.75 9. how often did you maintain your lubrication until completion of sexual activity? 0.85 0.52 0.37 0.41 0.74 10. how difficult was it to maintain your lubrication until completion of sexual activity? 0.84 0.59 0.25 0.46 0.75 6. how often have you been satisfied with your arousal during sexual activity? 0.83 0.45 0.45 0.66 0.76 8. how difficult was it to become lubricated during sexual activity? 0.82 0.56 0.26 0.44 0.71 12. when you had sexual stimuli or intercourse, how difficult was it for you to reach orgasm? 0.82 0.52 0.23 0.56 0.71 5. how confident were you about becoming sexually aroused during sexual activity? 0.82 0.41 0.57 0.58 .076 11. when you had sexual stimuli or sexual intercourse, how often did you reach orgasm? 0.81 0.36 0.37 0.60 0.70 4. how would you rate your level of sexual arousal during sexual activity? 0.79 0.41 0.62 0.54 0.74 3. how often did you feel sexually aroused during sexual activity? 0.78 0.33 0.57 0.54 0.71 13. how satisfied have you been with your ability to reach orgasm during sexual activity? 0.78 0.52 0.29 0.70 0.71 sexual-related pain 17. how often did you experience discomfort or pain during vaginal penetration? 0.53 0.94 0.21 0.36 0.89 18. how often did you experience discomfort or pain following vaginal penetration? 0.51 0.93 0.27 0.39 0.87 19. how would you rate the level of discomfort or pain during or following vaginal penetration? 0.58 0.91 0.25 0.43 0.84 sexual desire 2. how would you rate your level of sexual desire or interest? 0.47 0.32 0.88 0.39 0.81 1. how often did you feel sexual interest or desire? 0.41 0.24 0.88 0.26 0.78 sexual satisfaction 16. how satisfied have you been with your overall sex life? 0.55 0.40 0.31 0.93 0.87 15. how satisfied have you been with your sexual relationship with your partner? 0.58 0.40 0.34 0.93 0.87 14. how satisfied have you been with the amount of emotional closeness during sexual activity? 0.72 0.49 0.26 0.78 0.73 eigenvalue 10.8 1.57 1.22 1.1 percentage variance 56.90 8.27 6.42 5.6 primary loadings are indicated in bold. items with cross-loadings are indicated in italic. persian version of the fsfi | ghassamia et al 882 | for sexual response component. similarly, item 14 from the sexual satisfaction component (with factor loading = 0.78) cross-loaded on sexual response component (with factor loading = 0.72). consistent with rosen and colleagues study in which item 14 was loaded on satisfaction component,(8) in the present study, this item was accepted as one of the items of sexual satisfaction component. dressed problems related to arousal, lubrication, and orgasm; we called this component as sexual response. the second component had 3 items and assessed pain experience during or following vaginal penetration; we called this component as sexual-related pain. the third component with 2 items addressed desire and was called sexual desire. the fourth component with 3 items addressed problems related to sexual satisfaction; we called this component as sexual satisfaction. reliability reliability was determined by examining both the internal consistency (cronbach’s alpha) and test–retest stability of the full scale of the p-fsfi and its four above-mentioned subscales. internal consistency the internal consistency of the total scale of the p-fsfi and its 4 subscales were examined, using cronbach’s alpha. the cronbach’s alphas for the full scale and its four subscales of sexual response, pain, sexual desire, and satisfaction were indicate that the p-fsfi and its 4 subscales have satisfactory internal consistency (>0.70).(29) test–retest reliability forty participants from the original sample (562) were randomly selected to complete the p-fsfi again 4 weeks after the initial assessment. pearson correlations were calculated between the time 1 and time 2 assessments for the full scale of the p-fsfi and its 4 subscales. pearson correlation for the time 1 and the time 2 of assessment for the total fsfi was 0.82 (p < .001) and for subscales 1, 2, 3, and 4 was 0.81, 0.78, 0.66, and 0.72, respectively. all correlations were stap the p-fsfi and its 4 subscales are reliable over time. predictive validity as has been mentioned, in order to establish the predictive validity of the fsfi, the healthy participants (n = 562) were compared to the sample of 108 people with fsd on the total scale of the p-fsfi and its 4 subscales, using a series of independent sample t tests. the assumption of equal variance between these two groups was examined by levene’s test for equality of variance. in order to prevent type i errors, a bonferroni correction was used (0.05/5 = 0.01). therefore, only t values at or below the 0.01 alpha level were considered over a period of 5 months (march to july 2010), 108 females were referred to the family and sexual health clinic at the university of shahed and a private urology clinic in tehran, iran. these patients were interviewed by a clinical psychologist or a urologist, using diagnostic and statistical manual of mental disorders (4th edition) (dsm-iv)(3) criteria for sexual dysfunctions. the mean age of these 108 clinical samples was 32.37 ± 4.25 years (range, 23 to 42 years). all partici12 years of formal education and 63% had at least 16 years of formal education), and 60% were homemakers. they got married on average for 94.52 ± 52 months (range, 6 to 370 months). table 2 summarizes the results of t tests comparing the healthy participants and clinic samples. before conducting t test, the pre-assumptions of t tests (ie, normality of distribution and equality of variance) were examined. as expected, the healthy participants reported better sexual functioning than the clinic (patients) sample. these results support the predictive validity of the fsfi and its subscale. convergent and divergent validity of the p-fsfi scale and its four subscales in order to examine the convergent validity of the p-fsfi, correlations between the p-fsfi and its 4 subscales scores and scores on measures of depression, anxiety, stress, and negative affect. in order to establish the divergent validity female urology 883vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l cant and positive correlations between the p-fsfi and its 4 subscales scores and scores on measures of positive affect and marital adjustment. the results of these analyses are pre4 subscales have convergent and the divergent validity. discussion in the present study, the psychometric properties of the p-fsfi amongst a sample of healthy iranian females were tested. the results of this study demonstrate that in a healthy sample, the p-fsfi is best conceptualized as a multidimensional measure tapping 4 dimensions: sexual response, sexual desire, pain, and satisfaction. furthermore, the reliability indexes (internal consistency and test-retest stability) of the p-fsfi have been shown in this study. finally, the predictive validity as well as the divergent and the convergent validity in the original fsfi validation study,(8) one factor. however, the mixed factor of desire/arousal was separated into two measurable dimensions based on a clinical decision. the results of the present study do not agree with as 6 dimensions. as has been mentioned, while three of the rosen and associates’ original subscales (ie, sexual desire, pain, and satisfaction) remained intact when their items were subjected to pca, the items of the three subscales of arousal, lubrication, and orgasm items collapsed into a single factor, which was called sexual response. this study is not without limitations. first, the participants in the present study were not selected randomly from the population. thus, the sample may not be representative of iranian females, and the generalizability of the results to all iranian based on a healthy sample; therefore, they cannot be applied to patients. examining the factorial structure of the p-fsfi with a clinical sample is clearly warranted. third, participants in this study included only married women with sexually functioning partners. those who were not married (single, divorced, or widowed) were excluded from this study. therefore, we should be cautious about applying the p-fsfi to unmarried women or those without a partner. despite the above-mentioned limitations, the present study’s to those interested in using the p-fsfi in clinical and research settings in iran. these strengths include the use of widely recognized methods for translating the measure from english into farsi, the adequate size of the sample studied for the analyses conducted, as well as the employment of other well-validated and established scales for comparison. our table 3. correlation between dimensions of p-fsfi with mat and subscales of dass and panas (n = 562). marital adjustmentpositive affectnegative affectstressanxietydepressiondimensions 0.48*0.36*0.23*0.37*0.29*0.44*sexual response 0.35*0.28*0.23*0.29*0.25*0.31*pain 0.37*0.29*0.13*0.21*0.12*0.27*desire 0.60*0.37*0.24*0.47*0.30*0.52*satisfaction 0.53*0.39*0.26*0.41*0.31*0.48*full scale p-fsfi indicates persian version of female sexual function index; mat, marital adjustment test; dass, depression anxiety stress scales; and panas, positive and negative affect scales. *p < .001 persian version of the fsfi | ghassamia et al table 2. comparison between patients and healthy participants. variable healthy participants (n = 562), mean ± sd clinic sample (n = 108), mean ± sd t p sexual response 13.1 ± 3.90 10 ± 1.76 12.82 .0001 pain 4.20 ± 1.61 3.53 ± 1.31 4.66 .0001 sexual desire 3.30 ± 0.93 2.97 ± 0.76 3.57 .001 satisfaction 4.81 ± 1.23 3.41 ± 0.69 16.45 .0001 total fsfi scale 25.41 ± 6.58 19.96 ± 2.65 14.42 .0001 sd indicates standard deviation; and fsfi, female sexual function index. 884 | of arousal, orgasm, and lubrication were not clearly distinguishable. this may be due to different culture and medical conditions between the two populations. conclusion the p-fsfi is a valid and reliable instrument to measure multidimensional aspects of sexual function in healthy iranian women. this measure can be used both in clinical and research settings to measure sexual function in iranian women. conflict of interest none declared. references 1. basson r, berman j, burnett a, et al. report of the international consensus development conference on female sexual dysfunction: definitions and classifications. j urol. 2000;163:888-93. 2. basson r. women’s sexual dysfunction: revised and expanded definitions. cmaj. 2005;172:1327-33. 3. american psychiatric association. diagnostic and statistical manual of mental disorders. 4th ed. washington, dc: american psychiatric association; 1994. 4. laumann eo, paik a, rosen rc. sexual dysfunction in the united states: prevalence and predictors. jama. 1999;281:537-44. 5. lindau st, schumm lp, laumann eo, levinson w, o'muircheartaigh ca, waite lj. a study of sexuality and health among older adults in the united states. n engl j med. 2007;357:762-74. 6. palacios s, castano r, grazziotin a. epidemiology of female sexual dysfunction. maturitas. 2009;63:119-23. 7. safarinejad mr. female sexual dysfunction in a populationbased study in iran: prevalence and associated risk factors. int j impot res. 2006;18:382-95. 8. rosen r, brown c, heiman j, et al. the female sexual function index (fsfi): a multidimensional self-report instrument for the assessment of female sexual function. j sex marital ther. 2000;26:191-208. 9. meston cm. validation of the female sexual function index (fsfi) in women with female orgasmic disorder and in women with hypoactive sexual desire disorder. j sex marital ther. 2003;29:39-46. 10. sun x, li ch, jin l, fan y, wang d. development and validation of chinese version of female sexual function index in a chinese population-a pilot study. j sex med. 2011;8:110111. 11. rosen rc. assessment of female sexual dysfunction: review of validated methods. fertil steril. 2002;77 suppl 4:s89-93. 12. daker-white g. reliable and valid self-report outcome measures in sexual (dys)function: a systematic review. arch sex behav. 2002;31:197-209. 13. takahashi m, inokuchi t, watanabe ch, saito t, kai i. the female sexual function index (fsfi): development of a japanese version. j sex med. 2011;8:2246-54. 14. sidi h, abdullah n, puteh se, midin m. the female sexual function index (fsfi): validation of the malay version. j sex med. 2007;4:1642-54. 15. sidi h, puteh se, abdullah n, midin m. the prevalence of sexual dysfunction and potential risk factors that may impair sexual function in malaysian women. j sex med. 2007;4:311-21. 16. safarinejad mr, shafiei n, safarinejad s. quality of life and sexual functioning in young women with early-stage breast cancer 1 year after lumpectomy. psychooncology. 2012 jul 9. doi: 10.1002/pon.3130. [epub ahead of print]. 17. song sh, jeon h, kim sw, paick js, son h. the prevalence and risk factors of female sexual dysfunction in young korean women: an internet-based survey. j sex med. 2008;5:1694-701. 18. aslan e, beji nk, gungor i, kadioglu a, dikencik bk. prevalence and risk factors for low sexual function in women: a study of 1,009 women in an outpatient clinic of a university hospital in istanbul. j sex med. 2008;5:2044-52. 19. safarinejad mr. reversal of ssri-induced female sexual dysfunction by adjunctive bupropion in menstruating women: a double-blind, placebo-controlled and randomized study. j psychopharmacol. 2011;25:370-8. 20. brotto la, heiman jr, goff b, et al. a psychoeducational intervention for sexual dysfunction in women with gynecologic cancer. arch sex behav. 2008;37:317-29. 21. smith wj, beadle k, shuster ej. the impact of a group psychoeducational appointment on women with sexual dysfunction. am j obstet gynecol. 2008;198:697 e1-6; discussion e6-7. 22. safarinejad mr. evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: a double-blind placebocontrolled, fixed dose, randomized study. j sex med. 2008;5:887-97. female urology 885vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l persian version of the fsfi | ghassamia et al 23. proqolid. female sexual function index (fsfi). available at: http://www.proqolid.org/instruments/female_sexual_ function_index_fsfi. 24. tabachnick bg, fidell ls. using multivariate statistics. 3rd ed. new york: harper collins; 1996. 25. lovibond sh, lovibond pf. manual for the depression anxiety stress scales. 2nd ed. sydney, australia: psychology foundation of australia; 1995. 26. watson d, clark la, tellegen a. development and validation of brief measures of positive and negative affect: the panas scales. j pers soc psychol. 1988;54:1063-70. 27. locke hj, wallace km. short marital-adjustment and prediction tests: their reliability and validity. marriage fam living. 1959;21:251-5. 28. meir ei, gati i. guidelines for item selection in inventories yielding score profiles. educ psychol meas. 1981;41:1011-6. 29. nunnally jc, bernstein ih. psychometric theory. 1994. 3rd ed. new york: mcgraw-hill; 1994. u j all final for web.pdf 762 | 1laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran 2iranian national center for laser science and technology mohammad reza razzaghi,1 abdollah razi, mohammad mohsen mazloomfard,1 amin golmohammadi taklimi,2 reza valipour,1 zahra razzaghi1 safety and efficacy of pneumatic lithotripters versus holmium laser in management of ureteral calculi a randomized clinical trial corresponding author: mohammad mohsen mazloomfard, md laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran tel: +98 212 274 9221 fax: +98 218 852 6901 e-mail: mazloomfard@ yahoo.com received april 2012 accepted january 2013 purpose: management of ureteral stones. materials and methods: to delineate the ureteral anatomy. results: the laser and pneumatic groups, respectively (p conclusion: laser lithotripsy is a superior approach for the management of upper ureteral stones keywords: ureteral calculi, lasers, lithotripsy endourology and stone disease endourology and stone disease 763vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l introduction uuropathy can deteriorate renal function. the predictors for renal function loss. furthermore, there is no clear time threshold for irreversible damage. therefore, inureteral obstruction unless close monitoring of renal function is available.(2) several reports have suggested that ureteroscopy should be ible ureteroscopic lithotripsy using a variety of lithotripters, including ultrasonic, electrohydraulic, pneumatic, and laser. stone migration. recently, there has been an increase in the use of the hol(6) the mation of plasma bubble at the tip of the holmium:yag laser (7) holmium:yag laser and pneumatic lithotripter in transurecm ureteral calculi. materials and methods using pneumatic or holmium:yag laser, respectively. one gical procedures in both groups. the ethics committee of the laser application in medical sciences research center aptained from all the subjects. pregnancy, severe musculoskeletal deformity, and history of cluded from the study. before the procedure, urine cultures all of the subjects should have negative urine cultures preureteroscope in both holmium:yag laser and pneumatic lithpumped manually and intermittently during the procedure. ing in pneumatic lithoclast group. under direct vision to detect any residual stone or injury to st postoperative the ureteral anatomy and renal function status at 3 months postoperatively. cations, such as hematuria, mucosal damage (evidenced by edema or hemorrhage), ureteral perforation, and postoperamonths after the treatment routinely. t test and spectively. a p pneumatic lithotripters versus holmium laser for ureteral calculi | razzaghi et al 764 | results pneumatic group (p groups, respectively (p p p table 2 summarizes the intra-operative and postoperative such as perforation, mucosal injury, and bleeding, there group (p intravenous pyelography. discussion include eswl, ureteroscopy, percutaneous nephrolithotomy, laparoscopy, and rarely open surgery.(2) park and colleagues compared the results of eswl and ureteroscopy for ureteral ureteroscopic manipulation did not change by the stone size in fact, endourologic procedures source affects the ureteroscopic method and the type of used instruments, varying results have been reported. lithoclast lithotripsy fragments calculi in a mechanism similar to that of a pneumatic jackhammer. compressed ond. breakup occurs as the probe tip repetitively impacts holmium:yag lithotripsy mainly uses photothermal mechanism to fragment stones. holmium:yag laser makes stone crater and small fragments by its thermal effect on the stone endourology and stone disease table 1. demographic and clinical characteristics of patients.* variable laser (n = 56) pneumatic (n = 56) p mean age ± sd, y 35.9 ± 13.4 36.4 ± 12.5 .90 male, n (%) 44 (78.5) 40 (71.5) .383 previous history of tul, n (%) 4 (7.1) 8 (14.3) .222 stone laterality right side, n (%) left side, n (%) 35 (62.5) 21 (37.5) 30 (53.6) 26 (46.4) .338 stone location proximal, n (%) middle, n (%) distal, n (%) 12 (21.4) 12 (21.4) 32 (57.1) 14 (25) 12 (21.4) 30 (53.6) .897 stone diameter, mm 11.7 ± 4.5 10.0 ± 5.6 .434 *sd indicates standard deviation; and tul, transurethral ureterolithotripsy. 765vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l pneumatic lithotripters versus holmium laser for ureteral calculi | razzaghi et al during the pneumatic procedure, there is no electricity, and mild and transitory. holmium:yag laser energy is delivered in a pulsatile manas the lithotripsy is performed under direct vision. for holmium laser lithotripsy for the management of the for this purpose, a better outmany centers, the use of holmium laser is appropriate and matic procedure. in this study, the operation time considered for stone fraghas to change position of the ureteroscope to seek out the mobile stones. furthermore, lithoclast lithotripsy fragments the calculi into multiple chunks that need to be basketed and removed. holmium:yag laser can be used for a variety of urological procedures, such as prostate resection and ablation, strictures incision, and urothelial tumors ablation. the small methods. conclusion holmium:yag laser is a more safe and effective lithotripter large scale studies are needed. conflict of interest none declared. table 2. patients intra-operative and postoperative data. group laser (n = 56) pneumatic (n = 56) p complications hematuria, n (%) mucosal damage, n (%) ureteral perforation, n (%) postoperative fever, n (%) 0 (0) 2 (3.6) 0 (0) 1 (1.8) 0 (0) 1 (1.8) 0 (0) 2 (3.6) 1 1 mean operation time ± sd, min 13.7 ± 12.6 7.9 ± 4.2 .029 mean hospital stay ± sd, hr 24.4 ± 3.2 25.3 ± 0.3 .89 immediate stone-free status, n (%) 56 (100) 46 (82.1) .001 3-month stone-free status, n (%) 56 (100) 49 (87.5) .013 stone location stone-free status proximal, n (%) middle, n (%) distal, n (%) 12/12 (100) 12/12 (100) 32/32 (100) 6/14 (42.9) 10/12 (83.3) 30/30 (100) .002 .478 sd indicates standard deviation. 766 | endourology and stone disease 15. sun y, wang l, liao g, et al. pneumatic lithotripsy versus laser lithotripsy in the endoscopic treatment of ureteral calculi. j endourol. 2001;15:587-90. 16. karami h, arbab ah, hosseini sj, razzaghi mr, simaei nr. impacted upper-ureteral calculi >1 cm: blind access and totally tubeless percutaneous antegrade removal or retrograde approach? j endourol. 2006;20:616-9. 17. jeon ss, hyun jh, lee ks. a comparison of holmium:yag laser with lithoclast lithotripsy in ureteral calculi fragmentation. int j urol. 2005;12:544-7. 18. zarrabi a, gross aj. the evolution of lasers in urology. ther adv urol. 2011;3:81-9. references 1. lam js, greene td, gupta m. treatment of proximal ureteral calculi: holmium:yag laser ureterolithotripsy versus extracorporeal shock wave lithotripsy. j urol. 2002;167:1972-6. 2. hemal ak, goel a, goel r. minimally invasive retroperitoneoscopic ureterolithotomy. j urol. 2003;169:480-2. 3. erhard m, salwen j, bagley dh. ureteroscopic removal of mid and proximal ureteral calculi. j urol. 1996;155:38-42. 4. mugiya s, nagata m, un-no t, takayama t, suzuki k, fujita k. endoscopic management of impacted ureteral stones using a small caliber ureteroscope and a laser lithotriptor. j urol. 2000;164:329-31. 5. harmon wj, sershon pd, blute ml, patterson de, segura jw. ureteroscopy: current practice and long-term complications. j urol. 1997;157:28-32. 6. yin x, tang z, yu b, et al. holmium: yag laser lithotripsy versus pneumatic lithotripsy for treatment of distal ureteral calculi: a meta-analysis. j endourol. 2012. 7. razaghi m, razi a, mazloomfard mm, mokhtarpour h, javanmard b, mohammadi r. trans-ureteral ureterolithotripsy of ureteral calculi: which is the best; pneumatic or holmium laser technique? j lasers med sci. 2011;2:59-62. 8. park h, park m, park t. two-year experience with ureteral stones: extracorporeal shockwave lithotripsy v ureteroscopic manipulation. j endourol. 1998;12:501-4. 9. sozen s, kupeli b, tunc l, et al. management of ureteral stones with pneumatic lithotripsy: report of 500 patients. j endourol. 2003;17:721-4. 10. denstedt jd, eberwein pm, singh rr. the swiss lithoclast: a new device for intracorporeal lithotripsy. j urol. 1992;148:1088-90. 11. robert m, bennani a, guiter j, averous m, grasset d. treatment of 150 ureteric calculi with the lithoclast. eur urol. 1994;26:212-5. 12. vorreuther r, klotz t, heidenreich a, nayal w, engelmann u. pneumatic v electrokinetic lithotripsy in treatment of ureteral stones. j endourol. 1998;12:233-6. 13. vassar gj, chan kf, teichman jm, et al. holmium: yag lithotripsy: photothermal mechanism. j endourol. 1999;13:18190. 14. teichman jm, vassar gj, bishoff jt, bellman gc. holmium:yag lithotripsy yields smaller fragments than lithoclast, pulsed dye laser or electrohydraulic lithotripsy. j urol. 1998;159:17-23. 157 urology journal unrc/iua vol. 2, no. 3, 157-159 summer 2005 printed in iran female urology asymptomatic bacteriuria in users of intrauterine devices masoumeh fallahian,1* esmat mashhady,2 zohreh amiri3 1infertility and reproductive research center, shaheed beheshti university of medical sciences, tehran, iran 2department of obstetrics and gynecology, arak university of medical sciences, arak, iran 3faculty of biostatistics, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: the aim of this study was to compare the frequency of asymptomatic bacteriuria in women who use intrauterine devices (iuds) as a contraceptive method with subjects who use tubal ligation (tl). materials and methods: a cohort study was conducted on women who were candidates for iud insertion or tl (control). the patients were followed for 3 months, and urine cultures were assessed for bacteriuria at the end of the study. results: overall, 131 women (mean age, 31.9 ± 4.25 years) in the iud group and 78 (mean age, 32.1 ± 4.0 years) in the control group were studied. the parity score was 2 or more in 72% of the women in the iud group and in 74% of the controls. the average intercourse frequency was twice per week in 82% of iud users and 80% of controls. fifty-seven percent of the women in the iud group and 55% of the women in the control group had graduated secondary school (high school). asymptomatic bacteriuria was detected in 13 iud users (9.9%) and in 1 woman (1.3%) in the control group (risk ratio = 7.74, confidence interval: 1.03 to 58.03; p = .019). the detected microorganism in the urine culture was escherichia coli in 12 iud users and in 1 patient in control group. klebsiella was found in 1 iud user. conclusion: use of an iud is a risk factor for urinary tract infection and should be considered, especially in women with recurrent urinary tract infections. key words: intrauterine device, urinary tract infection, contraception introduction one fifth of women will have a urinary tract infection (uti) at some time.(1) it has been suggested that early infection or colonization of the upper urinary tract occurs in a proportion of women with lower genitourinary tract infection.(1) it is unclear how many of these women subsequently develop acute pyelonephritis if left untreated.(1) urinary tract infection is a result of an interaction between a uropathogen and the host, and increased bacterial virulence appears to be necessary to overcome host resistance. contraceptive methods are among the independent risk factors for uti. using a diaphragm or cervical cap appears to increase the risk of bladder infection.(2,3) women who use spermicides regularly have increased vaginal colonization with the bacterium escherichia coli after intercourse.(4) also, in british prospective studies on high-dose oral contraceptives, it has been shown that utis increase by 20%.(5) received january 2005 accepted september 2005 *corresponding author: no 20, second park st, aghdassieh, pasdaran ave, tehran 1957719495, iran. fax: ++ 98 21 8884 4304 e-mail: m_ fallahian@yahoo.com bacteriuria in users of intrauterine devices158 there is a paucity of research, however, regarding the prevalence of utis in users of intrauterine devices (iuds). pelvic inflammation and probably congestion of bladder trigone in iud users may affect the bladder and facilitate utis. some physicians have already suggested this, but there is not enough evidence yet. this study was designed to investigate the risk of asymptomatic bacteriuria among iud users. materials and methods a cohort study was conducted at the imam hossein hospital from november 1999 to february 2001. women who were candidates for iud insertion or tubal ligation (tl) were selected through a nonrandom convenience sampling to enroll in the study. inclusion criteria were being of childbearing age (25 to 44 years) and choosing an iud or tl for contraception. those with a history of recurrent uti (2 or more episodes per year), urinary tract stone, or gynecologic problems such as vaginitis or cervicitis were excluded. patients were assigned into 2 groups: iud users (iud group) and tl (control group), according to their preferences. informed consent was obtained from all participants, and the respective procedures were performed. the type of iud used was a cu-t 380a (paragard, fei women's health, us), and the technique used for tl was the parkland method. all women were followed and visited 3 months later, since pelvic inflammatory disease is more prevalent during the first 20 days after insertion of an iud.(6) patients provided a fresh, single, midstream urine specimen, at the same laboratory, for urinalysis and urine culture. a urine specimen with a colony count of more than 100000/ml (based on the standard definition of a positive culture) in the absence of urinary symptoms was defined as asymptomatic bacteriuria. other pelvic infections that usually are manifested with urethral symptoms but with a colony count less than 100000/ml were not considered as bacteriuria. data were collected and matched for age (with 5-year intervals), parity scores, level of education (primary, secondary, or academic), and sexual activities (frequency of coitus, approximately 2 times a week, more, or less); unmatched records were excluded. data were analyzed with a t test for quantitative variables, and chi-square and relative risk tests for qualitative variables, using spss software (statistical package for the social sciences, version 9.0, ssps inc, chicago, ill, usa). a p value less than .05 was considered statistically significant. results a total of 228 patients participated in this study. records of 19 iud users were excluded to match the groups for age. overall, 131 women in the iud group and 78 in the control group were studied. the mean age of patients in the iud group was 31.9 ± 4.25 years, and it was 32.1 ± 4.0 years in controls. the parity score was 2 or more in 72% of the women in the iud group and in 74% of controls. the average intercourse frequency was twice per week in 82% of iud users and 80% of controls. fifty-seven percent of women in the iud group and 55% in the control group had graduated secondary school (high school). asymptomatic bacteriuria were detected in 13 iud users (9.9%) and in 1 woman (1.3%) in the control group (risk ratio = 7.74, confidence interval: 1.03 to 58.03; p = .019). the detected microorganism in urine culture was escherichia coli in 12 iud users and in 1 patient in control group. klebsiella was found in 1 iud user. discussion urinary tract infection is one of the most common infections in all age groups of women. contraceptive devices are indirect risk factors for uti predisposition. some contraceptive methods such as the diaphragm, oral contraceptive pills, and cervical cap are contributing factors for uti. using a diaphragm or cervical cap appears to increase the risk of bladder infection. the problem may relate not only to mechanical obstruction, but also to alterations in vaginal flora produced by the spermicides accompanying a diaphragm or cap.(2,3) women who use spermicides alone, regularly, have increased vaginal colonization with escherichia coli and may be predisposed to bacteriuria after intercourse.(4) chlamydial colonization of the cervix appears to be more likely in contraceptive pill users than in nonusers.(7) in addition, some mucopurulent cervicitis and vulvovaginal infections caused by chlamydia trachomatis and neisseria gonorrhoeae have symptoms of uti.(7) in the present study, iud was associated with fallahian et al 159 an increased risk of developing uti. although some physicians already have considered this, not enough evidence exists regarding the urinary infectious complications of iud use. pelvic and vaginal inflammation and congestion of bladder trigone in iud users may affect the bladder and facilitate uti. bacterial vaginosis, which is one of the most common forms of vaginitis, has previously been referred to as nonspecific or gardnerella vaginitis.(7) in an epidemiologic survey of 2228 women by moi, from sweden,(8) those using barrier contraceptives had a significantly lower prevalences of bacterial vaginosis than did those using an intrauterine device or no contraceptive. these findings may have implications regarding complications associated with lower genital tract infections and may strengthen the hypothesis that bacterial vaginosis is a risk factor for pelvic inflammatory disease. cervicovaginitis seems not to be the main cause of uti in iud users, as other studies have revealed that inflammation of bladder trigone secondary to pelvic inflammation disease is a causal factor. in 1976, zahran and colleagues(9) compared the incidence of bacteriuria and cystoscopic changes in 200 women who had used oral contraceptives between 1 month and 2 years and 150 iud users with 50 women who had used neither method. bacteriuria was present in 40.5% of pill users, 20% of women fitted with iud, and 16% of women in control group. bladder trigone congestion was observed in 24.6% of iud users: 56% of whom had used an iud between 1 and 3 months, 35% of whom had used it for more than 2 years, and no users between these time parameters. they concluded that to avoid urinary bladder effects and inflammatory pelvic disease, iuds should not be used more than 2 to 3 years continuously. our results emphasize that these changes in the genitourinary tract system can lead to bacteriuria and uti. therefore, any symptom of uti warrants iud users to detect and treat the infection. conclusion the iud is an appropriate choice for women in long-term monogamous sexual relationships who are not at high risk for infection. it is a reversible contraception, especially for older and parous women. long-term use of the iud is associated with impressive safety, but the increasing risk of uti should always be considered. in patients with a history of recurrent utis, iud may not be a method of choice, and other contraceptives are preferred. references 1. tuomala r. gynecologi infections. in: ryan kj, berkowitz rs, barbieri rl. kistner's gynecology: principles and practice. 6th ed. st louis: mosby-year book; 1995. p.518-9. 2. ceruti m, canestrelli m, condemi v, piantelli g, de paolis p, amone f, tovagliari d. methods of contraception and rates of genital infections. clin exp obstet gynecol. 1994;21:119-23. 3. roy s. nonbarrier contraceptives and vaginitis and vaginosis. am j obstet gynecol. 1991;165(4 pt 2):12404. review. 4. hooton tm, hillier s, johnson c, roberts pl, stamm we. escherichia coli bacteriuria and contraceptive method. jama. 1991;265:64-9. 5. speroff l, glass rh , kase ng. oral contraception. in: speroff l, kase ng, glass rh, editors. clinical gynecologic endocrinology and infertility. 6th ed. philadelphia: lippincott williams & wilkins; 1999. p.911. 6. speroff l. intrauterine contraception: the iud. in: speroff l, kase ng, glass rh, editors. clinical gynecologic endocrinology and infertility. 6th ed. philadelphia: lippincott williams & wilkins; 1999. p.984. 7. soper de. genitourinary infection and sexually transmitted diseases. in: berek js, editor. novak's gynecology. 13th ed. philadelphia: lippincott williams& willkins; 2002: p.467. 8. moi h. prevalence of bacterial vaginosis and its association with genital infections, inflammation, and contraceptive methods in women attending sexually transmitted disease and primary health clinics. int j std aids. 1990;1:86-94. 9. zahran mm, osman mi, kamel m, fayad m, mooro h, youssef af. effects of contraceptive pills and intrauterine devices on urinary bladder. urology. 1976;8:567-74. case reports endometriosis of the urinary tract: a report of 3 cases seyyed yousef hosseini, mohammadreza safarinejad* department of urology, shaheed modarress hospital, shaheed beheshti and military universities of medical sciences, tehran, iran key words: endometriosis, bladder, ureter, urinary tract, diagnosis 45 urology journal unrc/iua vol. 2, no. 1, 45-48 winter 2005 printed in iran introduction approximately 10% to 15% of premenopausal women are affected by endometriosis.(1) about 1% of women with endometriosis have urinary tract lesions, of which 84% involve the bladder.(2) because of insidious onset of endometriosis, this condition portends considerable morbidity, necessitating a high index of suspicion for both urologists and gynecologists. we report 3 cases of endometriosis of the urinary tract with striking radiographic findings, and briefly review the literature on urinary tract endometriosis. case report case 1 a 42-year-old woman presented with a 4-year history of dysuria, frequency, and urgency. she experienced exacerbation of dysuria and urinary frequency during her menses. her past history was significant for 4 cesarean sections, latest of them was done 13 years ago. several physicians had treated her for urinary tract infection, pelvic inflammatory disease, and cystitis. serum and urine investigations were unremarkable. excretory urogram (ivp) showed normal upper and lower urinary tracts. ultrasonography was normal in non-menstruation days (fig. 1), but it revealed a 31 × 66 × 23 mm mass on the posterior bladder wall during menstruation (fig. 2). on cystoscopy in premenstrual days, a small nodule was seen. punch biopsy from this lesion showed normal transitional cell epithelium with underlying vascular congestion of the submucosa. cystoscopy during menstruation revealed a 3.0-cm pale pink nodular mass. on received december 2003 accepted may 2004 *corresponding author: p.o. box: 19395-1849, tel: +98 912 109 5200, e-mail: safarinejad@unrc.ir fig. 1. premenstrual transabdominal median longitudinal ultrasound scan of pelvis. the bladder has normal appearance. fig. 2. transabdominal median longitudinal ultrasound scan of pelvis during menstruation shows conical vegetation in posterior wall of the bladder (arrow). endometriosis of the urinary tract transurethral resection of this lesion, a chocolatecolored material was seen. the final pathologic report was bladder wall endometriosis. case 2 a 40-year-old woman presented with primary infertility. she complained of painful urination and suprapubic pressure. prior urological evaluation at other centers included urine culture, pelvic and urinary tract ultrasound, and an office cystoscopic procedure. on cystoscopic inspection, a small submucosal bluish nodule had been reported. punch biopsy from this nodule had showed severe nonspecific inflammation of bladder wall. the patient underwent cystoscopy at our institute during her menses. a 0.5 × 0.7 × 1 cm edematous, bluish, submucosal nodule covered with normal bladder mucosa was seen. transurethral resection of the lesion revealed focal glandular formation within the muscular wall of the bladder. the glands were lined by flattened columnar epithelium and the pathologic diagnosis of that was bladder wall endometriosis. case 3 a 45-year-old lady presented with a history of left loin pain. the patient had a history of one cesarean section and one dilatation and curettage. urine culture and cytology were negative. intravenous urography demonstrated severe left hydroureteronephrosis, but no evidence of urolithiasis (fig. 3). retrograde ureterography confirmed the level and degree of obstruction (4 cm), but was not diagnostic. on cystoscopy in second day of her menses, a red polypoid mass protruding from the left ureteral orifice was seen. one year before, in an attempt for ureteral dilatation, this lesion had not been seen. the mass was resected. histologic examination revealed ureteric endometriosis. hysterectomy, bilateral oophorectomy, and left ureteroneocystostomy were performed. at 2 months, the patient was asymptomatic and both intravenous urography (fig. 4) and isotope renography confirmed complete resolution of the obstruction. discussion endometriosis of the urinary tract is rare, and the bladder is the most common site of involvement. endometriosis usually occurs between menarch and menopause, because of the fluctuating levels of estrogen and progesterone 46 fig 3. intravenous urogram demonstrating left sever hydroureteronephrosis with normal drainage of right system fig. 4. follow-up intravenous urogram showing resolution of left upper tract dilatation after excision of the stricture and ureteroneocystostomy hosseini and safarinejad required for stimulation and propagation of endometrial proliferation. several theories have been proposed to explain the appearance of ectopic endometrium. generally, these proposals regarding the origin of endometriosis are grouped as metaplastic, embryologic, and migratory. most cases of endometriosis can be explained by the migratory theory developed by sampson.(3) retrograde menstruation of viable endometrial tissue through the fallopian tubes during menstruation can allow endometrial glands to reach an ectopic position, e.g. bladder and ureter. recently jaques donnez et al(4) reported that primary bladder endometriosis must be considered as a retroperitoneal adenomyotic nodule, which is the consequence of metaplasia of müllerian rests. patients most commonly complain of suprapubic pressure and lower tract irritability with frequency and dysuria related to urination or bladder distention. although cyclical gross hematuria is pathognomonic for vesical endometriosis, it is only present in 20% of patients.(5) patients with ureteric endometriosis can present with loin pain, symptoms of "cystitis", and pelvic discomfort.(6) early diagnosis and treatment of urinary tract endometriosis are necessary to avoid loss of kidney function.(7) the incidence of silent loss of renal function resulting from ureteral endometriosis is reported to be as high as 25% to 43%.(8) urinalysis with cytologic examination, ivp, and computerized tomography are all non-specific for diagnosis of urinary tract endometriosis.(9) cystoscopy is the most valuable diagnostic procedure with vesical endometriosis.(10) bladder endometriosis varies both cystoscopically and histologically during the menstrual cycle and diagnosis can therefore be difficult.(10) in our patients, cystoscopy was fortuitously performed during their menses. this made lesions more evident endoscopically. premenstrually, there may be an increased elevation over the area of tumor surrounded by a congested, edematous mucosal membrane. as the endometrial tumor increases in size, during menstruation, the cystic areas develop an intensified bluish hue. the size of the mass or cysts and the color of the lesions increase prior to and during menstruation only to regress in mid-cycle. the final diagnosis is made by the pathologist, who can confirm endometrial glands and stroma in the specimen. a positive punch biopsy definitively documents the presence of endometriosis, but a negative biopsy does not exclude it. transurethral resection is usually diagnostic, but it is not recommended as a definite treatment, because any attempt at complete resection of the transmural involvement may result in bladder perforation.(10,11) due to small and intramural nature of bladder endometriosis, it is better that imaging procedures such as ultrasound be performed during menstruation. in an attempting to determine the appropriate therapy for vesical endometriosis, patient age, desire for reproduction, severity of symptoms, overall distribution of endometriosis, and size of the vesical lesion must be considered. therapy for endometriosis includes bilateral oophorectomy, castration by radiation and drugs such as danazol or gonadotropin-releasing hormone agonists, as well as surgical resection of the lesion.(12) for endometriosis of the urinary tract, treatment should be aimed primarily at elimination of the obstructive uropathy. cases of diffuse endometriosis or large vesical lesions are more likely to require surgery for effective and definitive management. when the bladder lesion is small and the symptoms are not debilitating, it is appropriate to use hormone manipulation as a first time approach, especially in patients who have previously had children and desire some relief from symptoms before another pregnancy. however, such hormonal therapies do no recommend for obstructive uropathy because of the lack of response of fibrotic tissue to hormone suppression.(13) given the frequently prolonged diagnostic delay with related morbidity and erroneous treatments, we suggest a high index of suspicion of vesical endometriosis in all premenopausal women complaining of irritative urinary symptoms with negative urine cultures. imaging and cystoscopy should be scheduled during or near a menstrual period to allow for the best chance of diagnosis. punch biopsy usually does not provide appropriate tissue for definite diagnosis. transurethral resection is usually diagnostic. references 1hasson hm. incidence of endometriosis in diagnostic laparoscopy. j reprod med. 1976;16:135-8. 2shook te, nyberg l m. endometriosis of the urinary tract. urology. 1988;31:1-6. 3ridley jh. the validity of sampson's theory of 47 endometriosis of the urinary tract endometriosis. am j obstet gynecol. 1961;82: 777-82. 4donnez j, spada f, squifflet j, nisolle m. bladder endometriosis must be considered as bladder adenomyosis. fertil steril. 2000;74:1175-81. 5batler ra, kim sc, nadler rb. bladder endometriosis: pertinent clinical images. urology. 2001;57:798-9. 6patel a, thorpe p, ramsay jw, shepherd jh, kirby rs, hendry wf. endometriosis of the ureter. brit j urol. 1992;69:495-8. 7nezhat c, nezhat f, nezhat ch, nasserbakht f, rosati m, seidman ds. urinary tract endometriosis treated by laparoscopy. fertil steril. 1996;66: 920-4. 8stillwell tj, kramer sa, lee ra. endometriosis of the ureter. urology. 1986;28:81-5. 9schneider v, smith mj, frable wj. urinary cytology in endometriosis of the bladder. acta cytol. 1980;24:30-3. 10aldridge kw, burns jr, singh b. vesical endometriosis: a review and two case reports. j urol. 1985;134:539-41. 12nezhat cr, nezhat fr. laparoscopic segmental bladder resection for endometriosis. obstet gynecol. 1993;81:882-4. 13sampson ja. peritoneal endometriosis due to the menstrual dissemination of the endometrial tissue into the peritoneal cavity. am j obstet gynecol. 1927; 14:422-69. 48 letter to editor re: clinical application of computed tomography on prostate volume estimation in patients with lower urinary tract symptoms sir, we have read this article with interest due to a sparse literature data regarding a comparison of prostatic volume (pv) measurement by computed tomography (ct) scan and transrectal ultrasonography (trus).(1) the authors have to be congratulated for implementation of bonaventura cavalieri’s principle for measurement of irregular bodies volume using the 3d reconstruction of ct scan images. however, several concerns regarding this study should be raised. prostatic glands don't have unique shape. therefore, there is no a single formula for accurate volume calculation for different prostates. an ellipsoid formula, which has been used in this paper, is associated with overestimation of volumes in larger glands as well as underestimation of volume in smaller glands.(2) rodriguez and colleagues have shown that ellipsoid formula consistently underestimates the actual gland size in radical prostatectomy specimen. (3) previously, mcmahon and colleagues have found that a formula for bullet shape (v = height (h) × length (l) × width (w) × 5π/24) is more convenient for prostates with volume < 55 cm3.(4) therefore, the authors have not used more accurate formula for prostate volume calculation in more than 75% of samples in the study. usage of ct scan for prostate volume measurement can’t be justified in clinical settings due to significant dose of irradiation (approximately 20-30 msv). however, ct scan performed for unrelated reasons could serve for measurement of prostatic volume. as the authors rightfully stated, this technique also has some drawbacks due to difficulties in determinations of appropriate borders, particularly at the base and the apex of prostate. 3d ct scan prostate volume measurement using cavalieri’s principle is time consuming procedure, and surprisingly is more inaccurate than measurement using ellipsoid formula. probably, small movements of prostate during data acquisition could be one of reasons for overestimation of prostatic volume by ct scan. on the other side, further refinements of computer program enabling tracing of borders in two planes might be required for more accurate tracing in the apical and basal area of the gland. unfortunately, this study has not been designed to enable judgement of intrapersonal nor interpersonal variation of measurement. various authors have shown significant intrapersonal and interpersonal variability of prostate contour tracing on ct scan as well as measurement of dimensions and volume of prostate.(5,6) certainly, accurate measurement of prostatic volume will remain significant challenge waiting for definite solution. jovo bogdanović, vuk sekulić, senjin djozić clinical center of vojvodina, clinic of urology and faculty of medicine, university of novi sad, novi sad, serbia. references 1. kang tw, song jm, kim kj, et al. clinical application of computed tomography on prostate volume estimation in patients with lower urinary tract symptoms. urol j. 2014;11:1980-3. 2. bienz, m, hueber pa, al-hathal n, et al. accuracy of transrectal ultrasonography to evaluate pathologic overestimation of volume in larger prostates and underestimation of prostate weight: correlation with various prostate size groups. urology. 2014;84:169-74. 3. rodriguez e jr, skarecky d, narula n, ahlering te. prostate volume estimation using the ellipsoid formula consistently underestimates actual gland size. j urol. 2008;179:501-3. 4. macmahon pj, kennedy am, murphy dt, maher m, mcnicholas mm. modified prostate volume algorithm improves transrectal us volume estimation in men presenting for prostate brachytherapy. radiology. 2009;250:273-80. 5. fiorino c, reni m, bolognesi a, cattaneo gm, calandrino r. intraand inter-observer variability in contouring prostate and seminal vesicles: implications for conformal treatment planning. radiother oncol. 1998;47:285-92. 6. berthelet e, liu mc, agranovich a, patterson k, currie t. computed tomography determination of prostate volume and maximum dimensions: a study of interobserver variability. radiother oncol. 2002;63:37-40. letter to editor 2124 vol 12. no 02 march-april 2015 1995vol 12. no 02 march-april 2015 2125 reply by author dr. bogdanovic and colleagues raised two issues for our article entitled “clinical application of computed tomography on prostate volume estimation in patients with lower urinary tract symptoms”. first of all, they mentioned that there is no a single formula for accurate volume calculation for different prostates. furthermore, they recommended that modified prostate volume (pv) algorithm developed by mcmahon and colleagues is more convenient for prostates with volume < 55 cm3.(1) i agree with their opinion. in 2010, yang and colleagues reported modified ellipsoid formula at different stage of benign prostatic hyperplasia.(2) they also pointed out inaccuracy of volume estimation by ultrasound like dr. bogdanovic and colleagues. however, the authors desinged eccentricity parameter to improve accuracy of pv measurement by ultrasoud. interestingly, bullet formular was also as inaccutate as ellipsoid formular in smaller gland. furthermore, we suggested pv determination by ct scan using formula as preferable alternative in the clinics for quick volume measurement. actually, we think that many physicians and urologists are familiar with ellipsoid formula. secondly, we could not show intrapersonal and interpersonal variation of measurement because of retrospective study design. in addition, we just focused on the reliability and possibility of clinical use of pv measured by ct scan using the ellipsoid formula. therefore, further studies are needed to validate intrapersonal and interpersonal variation of measurement. thanks for all the suggestions and tips. jae hung jung, md department of urology and radiology, yonsei university, wonju college of medicine, wonju, republic of korea. references 1. macmahon pj, kennedy am, murphy dt, maher m, mcnicholas mm. modified prostate volume algorithm improves transrectal us volume estimation in men presenting for prostate brachytherapy. radiology. 2009;250:273-80. 2. yang ch, wang sj, lin at, jen ym, lin ca. evaluation of prostate volume by transabdominal ultrasonography with modified ellipsoid formula at different stages of benign prostatic hyperplasia. ultrasound med biol. 2011;37:331-7. vol 13 no 04 july-august 2016 2744 review evaluation of dialysis adequacy in hemodialysis patients: a systematic review hengameh barzegar1, mahmood moosazadeh2, hedayat jafari3, ravanbakhsh esmaeili4* purpose: hemodialysis is the common kidney replacement therapy in iran. doing an adequate and effective dialysis can improve patients’ quality of life and reduce kidney failure complications. additionally, dialysis quality is an important factor in reducing mortality in patients with chronic kidney failure. this systematic review has investigated the adequacy of dialysis in studies done on hemodialysis patients of iran. materials and methods: all articles related to the dialysis adequacy in hemodialysis patients in english and farsi (contemporary persian) were identified by searching the related keywords in various electronic databases. according to the inclusion criteria, 21 studies were identified. the results were analyzed using stata software version 11. results: a number of 6677 patients had been enrolled in 21 studies that were chosen for this systematic review. based on the random effects model, the overall dialysis adequacy (kt/v) (k: clearance of urea, t: duration of dialysis, v: distribution of urea) more than 1.2 and its confidence interval were 36.3% and 26.4-46.2, respectively. also, based on random effects model more than 65% urea reduction ratio in all studies was 28.8% and the confidence interval was 14.4-43.3. conclusion: kt/v and urea reduction ratio were much less desirable in hemodialysis patients and the dialysis quality was also undesirable. it seems that inadequate dialysis prescription, use of inappropriate filters, low pump speed (blood flow speed), and the short duration and few times of dialysis are the major causes of this inadequacy. keywords: dialysis adequacy; hemodialysis; systematic review; kidney failure introduction increased burden of chronic diseases is an existing challenge in the health systems worldwide.(1) chronic kidney failure is a progressive and irreversible disorder in the kidney function in which the body's ability to maintain fluid and electrolyte balance and metabolic waste excretion is lost, ultimately leading to uremia.(2) the advanced stage of the disease is known as end stage kidney disease.(3) until the middle of twentieth century, people who suffered from the kidney failure were helpless people who were waiting for their fate, but not death.(4) today, in iran and many countries, the most common treatment method is hemodialysis. the purpose of dialysis is to remove the excess material and stabilize body’s internal environment as well as removing the toxins that cause permanent injury.(5) by the end of 2014, 70% of patients with chronic kidney failure were on hemodialysis. also by that time the number of dialysis patients in iran was around 27,457 people, of which about 25,934 patients (94%) were treated by hemodialysis.(6) several factors affect the survival in end-stage kidney disease patients including the cause of disease, alternative medicine, synchronism of other diseases such as cardiovascular disease and dialysis adequacy.(7) dialysis quality is a predictor of mortality in dialysis patients. evidences suggest that when there is enough 1 school of nursing and midwifery, student research committee, mazandaran university of medical sciences, sari, iran. 2 health sciences research center, mazandaran university of medical sciences, sari, iran. 3 department of medical-surgical nursing, mazandaran university of medical sciences, sari, iran. 4 department of medical-surgical nursing, orthopedic research center, mazandaran university of medical sciences, sari, iran. *correspondence: department of medical-surgical nursing, orthopedic research center, mazandaran university of medical sciences, farahabad road, sari, iran. tel: +98 113 336 7341. fax: +98 113 336 7341. e-mail: r.esmaeili90@gmail.com. received december 2015 & accepted february 2016 effective hemodialysis treatment, there is less mortality in patients with kidney disease.(8) by improving the dialysis adequacy, uremic complications and their effects on different organs will be reduced. therefore, increasing dialysis quality is effective on various aspects of life in patients with chronic kidney failure. if it is improved, a lot of physical health problems and subsequent psychosocial problems will be solved.(9) the most accepted methods for determining dialysis adequacy are the kt/v standard (k: clearance of urea, t: duration of dialysis, v: distribution of urea) and urea reduction ratio (urr).(10) according to renal physicians association and the national kidney foundation’s disease outcomes quality initiative, the dialysis quality results using kt/v and urr are preferred because they reflect urea removal more accurately. several studies have shown that if the rate of kt/v reaches 1.2 or urr is more than 65%, this is effective in improving dialysis patients’ prognosis.(11) today, doing a correct and reasonable dialysis can prevent many complications and also by preventing repeated hospital stays and applying the savings on healthcare costs, it can provide better quality of life for dialysis patients.(12) there are different statistics about dialysis adequacy in iran and there is still no general estimation. according to electronic searches, several studies with different vol 13 no 04 july-august 2016 2744 number of patients have investigated dialysis adequacy in different dialysis centers of iran. the rising trend of chronic kidney disease and absence of adequate dialysis are the main causes of death in kidney patients. thus, determining dialysis adequacy in hemodialysis patients can help to develop better healthcare. this study has systematically reviewed the studies which had been conducted on dialysis adequacy in iran. materials and methods the dialysis adequacy (kt/v and urr) in hemodialysis patients of iran was estimated by a systematic literature review. the indexed articles in the available databases, including magiran, scientific information database of iran (sid), google scholar, iranmedex, and pubmed central, were used to find published studies on the subject. all studies were published in english and farsi (contemporary persian) between october 2000 and october 2014. the search was undertaken mainly using keywords of dialysis adequacy in these two languages including hemodialysis adequacy, hemodialysis efficiency, and iran with all possible combinations. the search with essential keywords was done using ‘and’ and ‘or’. the search was carried out from 24 to 28 october 2014 by two researchers independently. search evaluation was done by a member of the research team. the reference list of published studies was also studied to increase sensitivity and find the more articles. inclusion and exclusion criteria the full text or abstracts of all papers and documents from the search were extracted. first the articles were evaluated based on title, author name, year and publication place and duplicates were removed. then, the articles were carefully studied by researchers and the related articles were selected. then irrelevant cases were removed. all studies were evaluated by the checklist. the list was designed using the contents of strengthening the reporting of observational studies in epidemiolodialysis adequacy in hemodialysis patientsbarzegar et al. table 1. characteristics of studies included in this systematic review first author year journal title language number of patients kt/v > 1.2 urr > 65% percentage percentage 1 lesanpezeshki m 2001 ce(1380 h) feyz persian 37 18.9 2 delavari a.r 2001 ce (1380 h) sci j kurdistan persian 62 21.1 univ med sci 3 shahbazian h 2002 ce (1381 h) sci med j persian 74 4 taziki o 2003 ce (1382 h) j mazandaran persian 50 univ med sci 5 mozafari n 2005 ce(1383 h) res sci j ardabil persian 70 10 univ med sci 6 afshar r 2006 ce(1385 h) iran j pathol english 54 33.3 11.1 7 mousavi movahed t 2007 ce(1386 h) qom univ med sci j persian 238 44.5 21 8 monfared a 2008 ce(1387 h) j guilan univ med sci persian 139 76.3 72.7 9 pourfarziani v 2008 ce (1387 h) saudi j kidney english 338 dis transpl 10 hojat m 2009 ce(1388 h) j crit care nurs persian 68 11 raiesifar a 2009 ce(1388 h) j crit care nurs persian 45 2.3 6.6 12 malekmakan l 2010 ce(1388 h) iran j kidney dis english 632 32.1 13 shariati a.r 2010 ce (1389 h) j gorgan univ med sci persian 113 77.9 14 moghareb m 2010 ce(1389 h) j birjand univ med sci persian 50 5 6 15 amini m 2011 ce(1389 h) iran j kidney dis english 4004 43.3 16 mohseni r 2011 ce(1390 h) hayat persian 50 14 10 17 shasti s 2011 ce (1390 h) ebnesina persian 100 50.5 46 18 hashemi m 2012 ce(1391 h) j north khorasan persian 63 47.5 36.1 univ med sci 19 shariati a.r 2012 ce(1391 h) jhpm persian 389 57.9 56.3 20 abedi samakoosh m 2013 ce(1392 h) j mazand med sci persian 60 41.7 20 21 roozitalab m 2013 ce(1392 h) life sci j english 41 41.5 31.7 abbreviation: urr, urea reduction ratio. review 2745 vol 13 no 04 july-august 2016 2746 gy (strobe) list. the checklist included 12 questions that covered aspects of study design, sample size, age groups, sampling, objectives, study population, inclusion and exclusion criteria, matching samples method, analysis method, and presenting findings appropriately. each questions had one point and any study that had at least eight points entered our systematic review. all farsi and english articles that determined dialysis adequacy in hemodialysis patients with kt/v standard > 1.2 and urr > 65% between 2000 and 2014 in iran were selected. studies which access to their full text was not possible, had insufficient data, were publish before 2000, and were related to dialysis adequacy with variables such as quality of life and quality of sleep were excluded. data extraction data were obtained for each of the original studies by researchers based on the title, name of the first author, publication year, place of study, study design, sample size, average age of the population, kt/v > 1.2, and urr > 65%. statistical analysis data were transferred to the stata software version 11 for analysis. the standard error for dialysis adequacy of patients in each study was calculated on the basis of a binomial distribution. the index of dissimilarity or heterogeneity between the studies was determined using cochran (q). according to the heterogeneity using the meta command (meta) in the meta-analysis the random effects model was used to assess dialysis adequacy. additionally, to minimize the random distribution of studies’ point estimates, all studies’ findings were adjusted using the bayesian analysis. the point estimate of the dialysis adequacy with 95% confidence interval was calculated in the accumulation graph (forest plots) that was the square size in this chart and it represented the weight of each study and for both sides with 95% confidence interval. results by searching in the databases including sid (68 cases), magiran (55 cases), pubmed (74 cases), iranmedex (55 cases), scopus (40 cases), science direct (45 cases) and google scholar (347 cases), a total number of 684 studies were found. by limiting the search with ‘and’ and ‘or’ operators, the number of articles was decreased to 342. in the initial review of the studies, 134 articles were excluded because they were duplicates, 145 studies were also excluded due to being non-relevant to the topic. in the second review after reading the abstracts and texts of 63 articles, 41 studies were again excluded. two articles with a review of relevant articles were included in the study. three researches were excluded after evaluating their full texts and lack of sufficient data. finally, 21 articles that had the required criteria for a systematic review were included (figure 1). among the 21 articles in our systematic review, 20 studies were analytical and descriptive and only one study was a comparative study. 16 articles were in farsi and five were in english. the details of the included studies are illustrated in table 1.thus, in this systematic review the dialysis adequacy was studied in 6677 hemodialysis patients. optimal dialysis adequacy (kt/v more than 1.2) was from 2.3% in raisifar et al. study with 45 patients to 77.9% in shariati et al. study with 113 patients. the overall dialysis adequacy was also estimated using a random effects model (i-squared = 98.1%, q = 822.6, p < 0.001), (26.4-46.2, 36.3%) (figure 2). urr was between 5% in moghareb’s study and 72.7% in monfared’s study. additionally, the urr of all studies was estimated using random effects model (i-squared = 97.5%, q = 396.5, p < 0.001), (14.4-43.3, 28.8%) (figure 3). the secondary objectives were also evaluated in the studies including: sex, age, dialysis times per week and its duration. the relationship between gender and dialysis adequacy was assessed in the reviewed studies. nine studies showed significant differences.(8, 11-18) dialysis adequacy was higher in women than men and also no significant difference was observed in seven researches.(9, 19-24) the average ages of the studied populations in all studies were from 47.07 years in the ruzitalab’s study in yasouj to 62.27 years in shasti’s study in tehran. a significant difference was observed in two studies which had investigated the relationship between age and dialysis adequacy. thus dialfigure 2. frequency of kt/v > 1.2 in hemodialysis patients in each study and the overall estimate. abbreviations: ci, confidence interval; es, effect size. figure 1. flow chart of selecting studies for review. dialysis adequacy in hemodialysis patientsbarzegar et al. ysis adequacy had reduced with increase of age.(11,25) the relationship between dialysis times per week and dialysis adequacy was significant in three studies.(11,12,23) the studies showed that patients who were on dialysis three times a week had a higher dialysis adequacy. also, there was no significant relationship between dialysis adequacy and dialysis history in any of the reviewed studies. discussion in this systematic review 6677 hemodialysis patients were studied from 21 studies. about ⅓ of population had kt/v and urr more than 1.2 and 65%, respectively. their dialysis adequacy was optimal. survey results have shown that being women, having an older age and dialysis times per week can affect dialysis adequacy. in malekmakan and colleagues’ study in shiraz, 32.1% had kt/v at the optimal level.(18) in egypt, a study showed that 45% of patients had optimal level of dialysis adequacy on the basis of kt/v and urr criteria, while 44% of people had dialysis adequacy at an optimal level.(26) but the results in great britain and other european countries have been much better. the percentage of patients in britain who had good urr has increased from 56% in 1998 to 86% in 2010.(27) although national standards, internal investigations, and disease specific guidelines of the ministry of health of iran have determined kt/v > 1.2 as the minimum acceptable quality of dialysis, the international standards are higher. for example, the association of american nephrologists has announced the kt/v level of 1.4 to 1.7.(28, 29) therefore, obtaining the minimum acceptable quality in iran is difficult. in studies in various countries including egypt, spain, poland, thailand, and sweden, the acceptable kt/v level have been 1.5, 1.9, 1.4, 1.8, and 1.3, respectively,(3034) all of which are higher than standards in iran. therefore the results of iranian studies on dialysis quality of hemodialysis patients are weaker compared to foreign studies. it seems that inadequate dialysis prescription, inappropriate use of filters, pumps with low speed (blood flow speed) and lack of time for dialysis are major causes of this inadequacy. there were significant differences in dialysis adequacy between developed countries and iran, to some extent that may result in repeated use of highflux filter. blood flow rate is higher in these countries compared to iran. rapid reduction of blood urea in the dialysis process with high blood flow may show the extracted urea level higher than the real rate because cells’ urea does not have the adequate time to exit the cell and adjust with the extracellular fluids.(18) in a review article in london, the average age of patients who did hemodialysis was from 45 to 64 years. this was 60.7 years in a study in spain, 57.5 years in abbas and colleagues’ study in egypt, and 61.7 years in tyne and colleagues’ study in china. (30,35-37) these are consistent with our results. since the patients’ mean age in these studies was close, it is a guideline which shows the population at risk. patients’ age is an issue which should be considered in particular. because chronic kidney failure patients are elderly with special conditions and needs of living, they need emotional and educational support. the results showed that as age increases, kt/v reduces. therefore some decisions should be made to improve the quality of older patients’ dialysis such as increasing hours of dialysis according to patient's tolerance, filter type, number of dialysis times per week, nutrition and physical activity. the results of our study showed that in some studies the dialysis adequacy in women was higher than men. this may be because of the using similar dialysis filters in both genders. therefore it is better for women due to the smaller size, less weight and urea distribution. in this research the dialysis quality in patients who underwent dialysis, three times a week was more than those who did it twice a week. it seems that with changing treatment plans intended for dialysis patients from two to three times a week, the dialysis quality can be increased. conclusions most iranian patients have kt/v and urr much lower than the desirable level. they also have undesirable dialysis qualities. the prevalence of this condition increases mortality in these patients. due to the increase of chronic diseases such as diabetes and high blood pressure as a result of an increase in hemodialysis patients, it is necessary to increase dialysis adequacy. this can be done with a review of confounding factors such as nutrition diet, filter type, dialysis device, dialysis duration, patient education, and underlying disease. thus, the medical costs can be reduced further and eventually the quality of life in hemodialysis patients can increase. acknowledgments the authors thank deputy of research of mazandaran university of medical sciences who funded this study (grant no: 1327). the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. conflict of interest none declared. references 1. karimi s, javadi m, jafarzadeh f. economic burden and costs of chronic diseases in iran and the world. director general. 2012;8(7):996. figure 3. the frequency of hemodialysis patients in each study and the estimated urr. abbreviations: ci, confidence interval; es, effect size. note: weights are from random effects analysis overall (i-squared = 97.5%, p = 0.000) id shariati mousavi mohseni roozitalab abedi samakoosh moghareb afshar monfared shasti raiesifar hashemi study 28.85 (14.42, 43.28) es (95% ci) 56.30 (51.37, 61.23) 21.00 (15.83, 26.17) 10.00 (1.68, 18.32) 31.70 (17.46, 45.94) 20.00 (9.88, 30.12) 6.00 (-0.58, 12.58) 11.10 (2.72, 19.48) 72.70 (65.29, 80.11) 46.00 (36.23, 55.77) 6.60 (-0.65, 13.85) 36.10 (24.24, 47.96) 100.00 weight 9.31 9.30 9.13 8.63 9.00 9.24 9.13 9.19 9.03 9.20 8.85 % 28.85 (14.42, 43.28) es (95% ci) 56.30 (51.37, 61.23) 21.00 (15.83, 26.17) 10.00 (1.68, 18.32) 31.70 (17.46, 45.94) 20.00 (9.88, 30.12) 6.00 (-0.58, 12.58) 11.10 (2.72, 19.48) 72.70 (65.29, 80.11) 46.00 (36.23, 55.77) 6.60 (-0.65, 13.85) 36.10 (24.24, 47.96) 100.00 weight 9.31 9.30 9.13 8.63 9.00 9.24 9.13 9.19 9.03 9.20 8.85 % 0 -80.1 0 80.1 dialysis adequacy in hemodialysis patientsbarzegar et al. review 2747 vol 13 no 04 july-august 2016 2748 [in persian] 2. javanbakhtian ghahfarokhi r, abbaszadeh a. the relationship between quality of life and demographic variables in hemodialysis patients. j jahrom univ med sci. 2012; 10:16. 3. dos reis santos i, danaga ar, de carvalho aguiar i, et al. cardiovascular risk and mortality in end-stage renal disease patients undergoing dialysis: sleep study, pulmonary function, respiratory mechanics, upper airway collapsibility, autonomic nervous activity, depression, anxiety, stress and quality of life: a prospective, double blind, randomized controlled clinical trial. bmc nephrol. 2013; 14:215. 4. mottahedian-tabrizi e, najafi mehri s, samiey s, einollahi b, babaei gh. r, mohammadi e. effect of programmed nursing care in prevention of hemodialysis complications. iran j crit care nurs. 2009;2:55-9. 5. tayyebi a, shasti s, ebadi a, eynollahi b, tadrisi sd. the relationship between blood pressure and dialysis adequacy in dialysis patients. j crit care nurs. 2012;5:49-54. 6. islamic republic news agency. number of advanced kidney failure patients is increasing 6% annually in iran. 20/07/2015. available from: www.irna.ir/fa/news/81687836/. retrived on 05/08/2015 [in persian] 7. beladi mss, hosaini nk, zeraati aa. the evaluation of dialysis adequacy by kt/v in hemodialysis patients. jundishapur sci med j. 2012;11:43-48. 8. abedi samakoosh m, aghaie n, gholami f, shirzad m, yosefi e, teymoorzadeh baboli m. assesment dialysis adequacy in hemodialysis patients of qaemshar razi hospital in 2012. j mazand med sci. 2013;23:20-7. [in persian] 9. shariati a, asayesh h, nasiri h, et al. comparison of dialysis adequacy in patient's that referred to golestan province hemodialysis centers. jhpm. 2012;1:55-63.[in persian] 10. eshghizadeh m, basirmoghadam k, baloochi beydokhti t, safarpoor gharib z, mokhtari s. dialysis adequacy in diabetic and non-diabetic patients admitted to hospital in gonabad, iran in 2012. med surg nurs j. 2014;3:77-83. [in persian] 11. mohseni r, ilali es. assessment of adequacy of dialysis in patients undergoing dialysis with bicarbonate solution. hayat. 2011;17:6372. [in persian] 12. mogharab m, madarshahian f, rezai n, mohammadi a. dialysis adequacy in chronic hemodialysis patients in educational center vali-asr in birjand. j birjand univ med sci. 2010;17:206-14. [in persian] 13. afshar r, jalali nadoushan m, sanavi s, komeili a. assessment of hemodialysis adequacy in patients undergoing maintenance maneuver by laboratory tests. iran j pathol. 2006;1:55-60. [in persian] 14. amini m, aghighi m, masoudkabir f, et al. hemodialysis adequacy and treatment in iranian patients. iran j .kidney dis. 2011;5:103-9. 15. hashemi m, garshad a. assissing the adequacy of dialysis and some biochemical factors related to it in patient under heamodialysis in dialysis ward of emam ali hospital of bojnourd. j north khorasan univ med sci. 2014;4:665-70. [in persian] 16. hojjat m. hemodialysis adequacy in patients with chronic renal failure. j crit care nurs. 2009;2:61-6. [in persian] 17. lesanpezeshki m, matini s, taghadosi m, mousavi s. dialysis adequacy in hemodialysis patients in kashan. feyz. 2001;5:82-7. [in persian] 18. malekmakan l, haghpanah s, pakfetrat m, et al. dialysis adequacy and kidney disease outcomes quality initiative goals achievement in an iranian hemodialysis population. iran j kidney dis. 2010;4:39-43. 19. delavari ar, sharifian a, rahimi ea. dialysis efficacy in three dialysis centers in kurdistan province. sci j kurdistan univ med sci . 2001;5:18-22. [in persian] 20. monfared a, orang pour r, kohani m. evalution of hemodialysis adequency on patient undergoing hemodialysis in razi hospital in rasht. j guilan univ med sci. 2007;17:44-9. [in persian] 21. raiesifar a, torabpour m, mohsenizad p, shabani h, tayebi a, masoumi m. dialysis adequacy in patients of abadan hemodialysis center. j crit care nurs. 2009;2:87-90. [in persian] 22. roozitalab m, mohammadi b, najafi s, mehrabi s, fararouei m. kt/v and urr and the adequacy of hemodialysis in iranian provincial hospitals: an evaluation study. life sci j. 2013;10:13-16. 23. shariati ar , mojerloo m , hesam m, et al. hemodialysis efficacy in patients with end stage renal disease in gorgan, northern iran 2008. j gorgan univ med sci. 2010;12:80-4. [in persian] 24. shasti s, baba haji m. the assesment of dialysis adequacy among hemodialysis patients in tehran city. ebnesina. 2011;14:237. [in persian] 25. mousavi movahed s, m, komeili movahed t, komeili movahed a, dolati m. assessment of adequacy of dialysis in patients under continuous hemodialysis in kamkar and hazrat vali asr hospitals, state of qom, 2006. qom univ med sci j. 2007;1:45-52. [in persian] 26. azar a. the influence of maintenance quality of hemodialysis machines on hemodialysis dialysis adequacy in hemodialysis patientsbarzegar et al. efficiency. saudi j kidney dis transpl. 2009;20:49-56. 27. adas h, al-ramahi r, jaradat n, badran r. assessment of adequacy of hemodialysis dose at a palestinian hospital. saudi j kidney dis transpl. 2014;25:438-42. 28. fried l, hebah n, finkelstein f, piraino b. association of kt/v and creatinine clearance with outcomes in anuric peritoneal dialysis patients. am j kidney dis. 2008;52:1122-30. 29. gotch f. the basic, quantifiable parameter of dialysis prescription is kt/v urea; treatment time is determined by the ultrafiltration requirement; all three parameters are of equal importance. blood purif. 2007;25:18-26. 30. abbas tm, sheashaa ha, saad ma, sobh ma. does provision of a higher kt/v urea make a difference? a hemodialysis controversial issue. hemodial int. 2005;9:153-8. 31. chirananthavat t, tungsanga k, eiam-ong s. accuracy of using 30-minute post-dialysis bun to determine equilibrated kt/v. j med assoc thai. 2006;89:54-64. 32. del pozo c, lópez-menchero r, sánchez l, álvarez l, albero md. accumulated experience in the analysis of quality indicators in a haemodialysis unit. nefrología. 2009;29:42-52. 33. grzegorzewska ae, banachowicz w. comparisons of kt/v evaluated using an online method and calculated from urea measurements in patients on intermittent hemodialysis. hemodial int. 2006;10:5-9. 34. uhlin f, fridolin i, magnusson m, lindberg lg. dialysis dose (kt/v) and clearance variation sensitivity using measurement of ultraviolet-absorbance (on-line), blood urea, dialysate urea and ionic dialysance. nephrol dial transplant. 2006;21:2225-31. 35. maduell f, vera m, serra n, et al. kt as control and follow-up of the dose at a hemodialysis unit. nefrologia. 2008;28:43-47. 36. tian xk, wang t. dissociation between the correlation of peritoneal and urine kt/v with sodium and fluid removal: a possible explanation of their difference on patient survival. int urol nephrol. 2005;37:611-4. 37. suri rs, nesrallah ge, mainra r, et al. daily hemodialysis: a systematic review. clin j soc nephrol. 2006;1:33-42. dialysis adequacy in hemodialysis patientsbarzegar et al. review 2749 urology journal vol. 11 no. 04 july august 2014 1820 does metabolic syndrome increase erectile dysfunction and lower urinary tract symptoms? 1department of urology, şevket yilmaz training and research hospital, bursa, turkey. 2department of endocrinol ogy and metablism, şevket yilmaz training and research hospital, bursa, turkey. 3department of urology, school of medicine, afyon kocatepe university, afyon karahisar, turkey. corresponding author: ibrahim keleş, md adnan kahveci bulvari, no:67/1, selçuklu mah., selçuklu konaklari, a blok kat 3 daire: 7 uydukent, afyon karahisar, turkey. tel: +90 505 2166143 fax: +90 272 2463322 e-mail: drkeles@hotmail. com received october 2013 accepted june 2014 purpose: to evaluate the impact of metabolic syndrome (ms) on erectile dysfunction (ed) and lower urinary tract symptoms (luts). materials and methods: we included patients who had presented at the urology outpatients with luts or ed complaints and at the endocrinology outpatients for diabetes between may 2012 and april 2013. ms was present in 50 of the 107 patients (42.7%). the blood pressure, fasting blood sugar, serum lipid profile, triglyceride, total cholesterol, body mass index (bmi) and total prostate specific antigen (psa) values were recorded. the international prostate symptom score (ipss), quality of life score and international erectile function index (iief-5) values were determined for the patients. all patients also underwent uroflowmetry together with prostate volume and residual urine volume measurement. results: there was a significant negative correlation between the ipss and iief scores of the patients (p < .001, r = -0.42). there was no significant difference regarding ipss scores between patients with and without ms (p = .6), while the iief-5 scores were significantly lower in the ms group (p = .03). conclusion: we found that metabolic syndrome did not significantly affect luts but could significantly contribute to ed. we therefore feel patients presenting with ed complaints should also be carefully evaluated for ms. keywords: erectile dysfunction; physiopathology; metabolic syndrome; risk factors; urination disorders; lower urinary tract symptoms. soner coban,1 soner cander,2 mehmet sakir altuner,2 ibrahim keles,3 ozen oz gul2 sexual dysfunction and fertility tive immunoassay using direct chemiluminescent technology and the age-related reference intervals are 241-827 ng/dl for males aged 2039 years and 141-703 ng/dl for males aged 40-89 years. the advia centaur psa assay is a sandwich immunoassay utilizing two antibodies that bind to different sites on the psa molecule and the suggested cut off level is 4 ng/ml. all patients underwent uroflowmetry (maximum urinary flow rate [qmax], mean urinary flow rate [qmean], voiding volume and residual urine volume), prostate volume and residual urine volume measurement by the suprapubic method and determination of international prostate symptom score (ipss), quality of life score, and international erectile function index (iief-5) values. patients were grouped by ipss scores as 0-7 mild, 8-19 moderate, 20-35 severe symptomatic and by iief5 scores as 5-7 severe, 8-11 moderate, 12-16 mild to moderate and, 17-21 mild ed and 22-25 no ed. the ms diagnosis of the patients was made using the international diabetes federation (idf) 2005 criteria as validated for the turkish population (table 1).(8) statistical analysis the statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0 was used for statistical analyses. visual (histogram and probability graphs) and analytical (the kolmogorov-smirnov test) were used to determine conformance of the variables to normal distribution. descriptive analysis results for normally distributed variables were presented as mean ± standard deviations. the relatiship between ipss and iief-5 and various parameters was determined by the spearman/pearson correlation tests, pearson chi-square test, student tt est and the mann-whitney u test as necessary. the independent effects of various parameters on the ipss and iief-5 were evaluated using a multivariate linear regression model. statistical significance was set at p < .05. results the mean age of the study patients was 57.11 ± 6.16 (range, 44-73) years. ms was present in 46.7% of the patients. there was a nonsignificant difference for age between patients with and without ms and the mean age was 57.94 ± 6.23 and 56.39 ± 6.05 years, respectively (p = .19). taking all patients into account, 36 patients ( 3 3 . 6 % ) had hypertension, 59 (55.1%) had dm or disturbed fasting glucose, 46 (43%) had dyslipidemia and 37 (34.5%) had central obesity. these figures were 27 (54%) for hypertension, 37 (74%) for dm or disturbed fasting glucose, 28 (56%) for dyslipidemia and 23 ( 4 6 % ) for central obesity 23 in the ms group. the ipss scores of the 107 patients (mean 7.33 ± 6.19) were distributed as 67 mild (62.6%), 36 (33.6%) moderate and 4 (3.8%) severe luts cases. as regards iief5 scores (mean 16.9 ± 7.05) there were 21 severe (19.6%), 13 moderate (12.1%), 13 mild to moderate (12.1%) 26 mild (24.4%) ed patients and 34 (31.8%) patients without ed (table 2). there was a significant negative correlation between the ipss scores and iief-5 scores of the patients when the total patient group was introduction the lower urinary tract symptoms (luts) and erectile dys-function (ed) rates increase with advancing age and they are important health problems decreasing the quality of life. bladder outflow obstruction due to benign prostate hyperplasia (bph) is thought to be one of the major causes of luts.(1,2) it is postulated that vascular problems such as pelvic atherosclerosis and endothelial dysfunction in the elderly male can cause bladder dysfunction and play a role in luts pathogenesis.(3) ed is another pathology that increases with advancing age. ed etiology is multifactorial and has been shown to be associated with many risk factors such as hypertension, cardiac disease, aging, obesity, dyslipidemia, diabetes mellitus, smoking and vascular pathologies.(4) studies have shown a bph prevalence of 56% and ed prevalence of 40% in males over the age of 40 years.(5) the metabolic syndrome (ms) is an endocrinopathy that starts with insulin resistance and continues with the addition of abdominal obesity, glucose intolerance or diabetes mellitus (dm), dyslipidemia, hypertension and coronary artery disease. it has been shown to be associated with many disorders including cardiovascular disease.(6) a study by the metabolic syndrome association in turkey in 2010 revealed an ms rate of 41.4% in males, increasing to 57% with age. (7) the aim of our study was to evaluate impact of ms on ed and luts. materials and methods study subjects we included a total of 107 patients who had presented at the urology outpatients with luts or ed complaints and at the endocrinology outpatients for dm between may 2012 and april 2013. the consent of the uludag university school of medicine ethics committee was obtained for the study. study inclusion criteria were defined as sexually active patients aged 44 years and over who were mentally able to provide consent for the study. we excluded patients using α-blockers or 5 α-reductase inhibitors or medical treatment for ed, and those with a history of chronic obstructive pulmonary disease, urogenital system tumor, urogenital system surgery, neurogenic bladder, hypogonadism, liver or kidney failure, urethral stenosis, bladder stone, hyperactive bladder or chronic pancreatitis. depressed patients and those using medication that affected libido and erection negatively were also excluded from the study. the blood pressure, fasting blood sugar, serum lipid profile, triglyceride, total cholesterol, body mass index (bmi) and total prostate specific antigen (psa) values were recorded. measurements fasting blood glucose, total cholesterol, triglycerides and hdl were studied by standard biochemical methods. serum total testosterone and total psa levels were measured by radioimmunoassay methods on the advia centaur® (siemens diagnostics, nj, usa) auto analyzer. the advia centaur testosterone assay is a competi1821 sexual dysfunction and fertility urology journal vol. 11 no. 04 july august 2014 1822 erectile dysfunction in metabolic syndrome-coban et al lee and colleagues found a positive correlation between waist circumference and the prostate volume, psa and ipss values and reported that increased waist circumference made urination more difficult. (12) however, there was no difference regarding ipss and quality of life scores between our groups with and without ms. aktaş and colleagues also found no effect on luts in the presence of ms while ed increases significantly.(13) there was a significant correlation between ipss and iief-5 scores as well in our study when the total patient group was taken into account. demir and colleagues studied 190 patients with a mean age of 59.7 years and found that obesity, increased fasting blood sugar and hypertension had an effect on the development of severe (ipss 20-35) luts and that all these factors could play a role in ed pathogenesis.(14) another study found a relationship between ms and prostate enlargement rate but no significant difference regarding ipss scores between patients with and without ms.(10) it is still debated whether obesity is a risk factor for luts by itself. some studies have shown increased luts rates due to bph in obese males.(15,16) however, another study reported no relationship between anthropometric values and bph.(17) taken into account (p < .001, r = -0.42). there was no significant difference between the ipss score of bph patients with and without ms (p > .05) while the iief-5 scores were significantly lower in the ms group (p = .03). the iief-5 scores were also significantly lower in the dm group when compared with the non-diabetic group (p = .005). there was also no significant difference between the prostate volume, qmax, voiding volume, quality of life score and serum testosterone levels (p > .05) (table 3). we also found no correlation between the waist circumference measurements of the patients and the prostate volume, total psa, ipss, qmax and iief5 scores (p > .05). the mean age was significantly higher in the 21 patients in the severe ed group compared to those in the other 4 ed groups (p < .001). multiple linear regression analysis revealed that only age and iief5 scores had an effect on ipss among factors such as age, ms, prostate volume, total testosterone, bmi and waist circumference. the ipss increased 0.25 for each 1-year increase in age and the ipss decreased 0.38 for each 1 unit increase of iief-5 (p < .001). discussion the ms is an endocrinopathy that starts with insulin resistance and continues with the addition of abdominal obesity, glucose intolerance or dm, dyslipidemia, hypertension and coronary artery disease. (6) several studies have demonstrated a relationship between ms and voiding symptoms.(9,10) ozden and colleagues have demon strated higher prostate growth rates in bph patients with ms.(10) there are 4 serious hypotheses indicating a common pathogenesis for luts and ed. the decreased nitric oxide synthesis with aging, the increased sympathetic activity following hypertension, obesity and hyperinsulinemia in ms, the decreased smooth muscle relaxation following the activation of the alpha adrenergic mediator rho-kinase and the decreased blood flow to the bladder, prostate and penis following pelvic atherosclerosis indicate that the same pathophysiological mechanisms are active in the emergence of luts and ed.(11) this is the reason phosphodiesterase type-5 enzyme inhibitors are added to α-blockers in the current treatment of luts due to bph. at least one of the following: diabetes mellitus or impaired glucose tolerance or insulin resistance and at least two of the following: hypertension (systolic blood pressure > 130 mmhg, diastolic blood pressure > 85 mmhg or use of antihypertensive drugs) dyslipidemia (triglyceride levels > 150 mg/dl or high density lipoprotein level male < 40 mg/dl, female < 50 mg/dl) abdominal obesity (body mass index > 30 kg/m2 or waist circumference: male > 94 cm, female 80 cm)* table 1. the metabolic syndrome diagnostic criteria 2005 as suggested by the society of endocrinology and metabolism of turkey, metabolic syndrome workgroup (adapted from the international diabetes federation 2005 guide). * there is no local data on international diabetes federation 2005 guidelines which are based on the recommended values for europeans. figure 1. the mean international prostate symptom score (ipss) of the patients in both groups. figure 2. the mean international index of erectile function-5 (iief) of the patients in both groups. study with the endocrine department, and the resultant slightly high rate of ms patients. however, we did not find a significant difference between the ipss scores of the diabetic and nondiabetic groups and the groups with and without ms despite these limitations. christian and colleagues failed to find any correlation between luts and ms in a wide-ranging study on 2371 males and 731 females.(19) as regards ed, jun ho and colleagues found ipss and iief-5 scores to be 9 and 19 respectively with a significant correlation between the two values in their study on 2564 patients with a mean age of 49 years.(20) we found the ipss and iief5 scores of our patients to be 7.33 and 16.9, respectively, with a significant correlation between them. there was also a significant decrease in iief-5 scores in the ms group. weinberg and colleagues have shown that poor glycemic control, disturbed insulin sensitivity and ms are found together with ed.(21) it is widely accepted that dm causes bladder dysfunction through the functional parasympathetic route due to autonomic neuropathy. decreased detrusor function leads to a further decrease in qmax and the bladder outflow obstruction causes increased post voiding residual urine volume.(18) we also found significantly higher voiding volume and residual urine values with uroflowmetry in our diabetic patients. abnormal fasting blood sugar is one of the diagnostic criteria of ms. however, it was not correlated with the presence of luts in our study. the reason may be that the actual fasting blood sugar does not enable making a diagnosis for diabetes mellitus and it would be low in patients receiving diabetes mellitus treatment. this study was a joint study between the urology and endocrinology clinics. patients who were on medical treatment or had undergone surgery for lower urinary system symptoms or a diagnosis of ed were excluded from the study, decreasing the mean age of bph patients. some limitations of our study were the relatively low number of patients, the large number of diabetics (55.1%) as this was a joint variables groups ipss severity with ms (n =50) without ms (n=57) total p value mild 30 (44.8) 37 (55.2) 67 (100) .87 moderate 18 (50) 18 (50) 36 (100) severe 2 (50) 2 (50) 4 (100) total 50 57 107 ed severity no ed 10 (29.4) 24 (70.6) 34 (100) .08 mild 14 (53.8) 12 (46.2) 26 (100) mild to moderate 5 (38.5) 8 (61.5) 13 (100) moderate 8 (61.5) 5 (38.5) 13 (100) severe 13 (61.9) 8 (38.1) 21 (100) total 50 57 107 table 2. the distribution of ipss and iief-5 scores in both study groups.* abbreviations: ms, metabolic syndrome, ipss: international prostate symptom score; iief, international index of erectile function; ed, erectile dysfunction. * data are presented as no. (%). variables with ms (n = 50) without ms (n = 57) p value age (years) 57.94 ± 6.23 56.39 ± 6.05 .19 ipss 8.10 ± 6.64 6.65 ± 5.74 .37 iief 14.52 ± 7.14 17.42 ± 6.75 .03 fasting blood glucose (mg/dl) 166.90 ± 86.36 132.61 ± 86.79 < .001 total cholesterol (mg/dl) 201.50 ± 39.89 188.37 ± 51.14 .26 triglycerides (mg/dl) 179.94 ± 80.88 128.80 ± 71.83 < .001 hdl (mg/dl) 43.88 ± 8.61 44.11 ± 13.59 .70 total testosterone (ng/ml) 337.22 ± 108.96 346.52 ± 151.08 .49 total psa (ng/ml) 1.71 ± 1.08 1.09 ± 0.97 .25 prostate volume (ml) 41.78 ± 51.35 39.33 ± 23.46 .81 qmax (ml/s) 14.96 ± 9.38 13.70 ± 10.07 .54 bmi (kg/m2) 29.98 ± 3.54 27.62 ± 3.44 .001 waist circumference (cm) 104.76 ± 8.80 96.83 ± 9.45 < .001 quality of life 2.26 ± 1.72 2.04 ± 1.69 .52 table 3. demographic and clinical characteristics of study patients. abbreviations: ms, metabolic syndrome; ipss, international prostate symptom score; iief, international index of erectile function; psa, prostate specific antigen; qmax, maximum urinary flow rate; bmi, body mass index; hdl, high density lipoprotein. 1823 sexual dysfunction and fertility urology journal vol. 11 no. 04 july august 2014 1824 15. rohrmann s, smit e, giovannucci e, platz ea. for the third national health and nutrition examination survey. association between serum concentrations of micronutrients and lower urinary tract symptoms in older men in the third national health and nutrition examination sur vey. urology. 2004;64:504-9. 16. seim a, hoyo c, ostbye t, vatten l. the prevalence and correlates of urinary tract symptoms in norwegian men: the hunt study. bju int. 2005;96:88-92. 17. burke jp, rhodes t, jacobsen dj, et al. association of anthropometric measures with the presence and progression of benign prostatic hyperp lasia. am j epidemiol. 2006;164:41-6. 18. michel mc, mehlburger l, schumacher h, bressel hu, goepel m. effe ct of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. j urol. 2000;163:1725-9. 19. temml c, obermayr r, marszalek m, et al. are lower urinary tract sy mptoms influenced by metabolic syndrome? urology. 2009;73:544-8. 20. lee jh, kwon h, park yw. association of lower urinary tract sy mptom/benign prostatic hyperplasia measures with international in dex of erectile function 5 in middle-aged policemen of korea and the role of metabolic syndrome and testosterone in their relationship. urology. 2013;82:1008-12. 21. weinberg ae, eisenberg m, patel cj, chertow gm, leppert jt. diabet es severity, metabolic syndrome, and the risk of erectile dysfunction. j sex med. 2013;10:3102-9. conclusion in conclusion, we found a significant correlation between increasing age and luts and ed. however, we found that ms did not significantly affect luts due to bph while contributing significantly to ed. we believe that patients who present with ed complaints should be evaluated for ms. conflict of interest none declared. references 1. jacobsen sj, girman cj, lieber mm. natural history of benign prostatic hyperplasia. urology. 2001;58:5-16. 2. barry mj, cockett at, holtgrewe hl, mcconnell jd, sihelnik sa, winfield hn. relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. j urol. 1993;150:351-8. 3. tarcan t, azadzoi km, siroky mb, goldstein i, krane rj. age-related erectile and voiding dysfunction: the role of arterial insufficiency. br j urol. 1998;82:26-33. 4. erdemir f, kilciler m, atılgan d. evaluation of the effect of lower uri nary tract symptoms/benign prostatic hyperplasia on erectile dysfuncti on. turk urol sem. 2010;1:99-105. 5. porst h, mcvary kt, montorsi f, et al. effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symp toms of benign prostatic hyperplasia. eur urol. 2009;56:727-35. 6. balkan f. metabolic syndrome, ankara med j. 2013;13:85-90. 7. oğuz a, altuntaş y, karsidag k, et al. the prevalence of metabolic sy ndrome in turkey. obesity reviews. 2010;11:486. 8. international diabetes federation. the idf consensus worldwide defi nition of the metabolic syndrome. available from: info@idf.org. acces sed october 20, 2007. 9. rohrmann s, smit e, giovannucci e, platz ea. association between markers of the metabolic syndrome and lower urinary tract symptoms in the third national health and nutrition examination survey (nhanes iii). int j obes. 2005;29:310-6. 10. ozden c, ozdal ol, urgancioglu g, et al. the correlation between meta bolic syndrome and prostatic growth in patients with benign prostatic hyperplasia. eur urol. 2007;51:199-203. 11. chun-hou liao, han-sun chiang, po-jen hsiao. lower urinary tract sy mptoms and erectile dysfunction. urol sci. 2011;22:135-40. 12. lee rk, chung d, chughtai b, te ae, kaplan sa. central obesity as measured by waist circumference is predictive of severity of lower uri nary tract symptoms. bju int. 2012;110:540-5. 13. aktas bk, gokkaya cs, bulut s, dinek m, ozden c, memis a. impact of metabolic syndrome on erectile dysfunction and lower urinary tract symptoms in benign prostatic hyperplasia patients. aging male. 2011;14:48-52. 14. demir o, akgul k, akar z, et al. association between severity of lower urinary tract symptoms, erectile dysfunction and metabolic syndrome. aging male. 2009;12:29-34. erectile dysfunction in metabolic syndrome-coban et al o r i g i n a l a r t i c l e s urological oncology changes in serum prostate-specific antigen level after prostatectomy in patients with benign prostatic hyperplasia seyyed yousef hosseini, mohammadreza salimi, seyyed mohammad mehdi hosseini moghaddam* urology and nephrology research center and shaheed modarres hospital, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: the goal of this study was to investigate the effect of transurethral resection of the prostate and open prostatectomy on the serum prostate-specific antigen (psa) level in men with benign prostatic hyperplasia. materials and methods: serum prostate-specific antigen levels were determined before and 6 months after operation in 86 patients with benign prostatic hyperplasia who had undergone transurethral resection of the prostate or open prostatectomy. we measured the prostate volume by means of transrectal ultrasonography and weighed the surgical specimen. changes in serum psa levels and their correlation with prostate volume and the resected prostate weight were evaluated. results: of 86 patients, 45 underwent transurethral resection of the prostate and 41 underwent open prostatectomy. mean psa levels were reduced by 67.4 % (range, 0.40 ng/ml to 7.60 ng/ml) in the patients who had undergone transurethral resection of the prostate and 80.7% (range, 1.00 ng/ml to 14.50 ng/ml) in the patients with open prostatectomy. removal of 1g of prostate tissue reduced serum psa levels by an average of 0.15 ng/ml in those who underwent transurethral resection of the prostate and 0.10 ng/ml in those treated with open prostatectomy (p = .018). forty patients (88.9%) in the group who underwent transurethral resection of the prostate and 39 (95.1%) in the open prostatectomy group exhibited a postoperative psa level of less than 2.00 ng/ml (p = .20). conclusion: a modified reference range seems necessary for the screening of prostate cancer via psa level in men who have undergone prostatectomy for benign prostatic hyperplasia. key words: prostate-specific antigen, benign prostatic hyperplasia, prostatectomy 183 urology journal unrc/iua vol. 2, no. 4, 183-188 autumn 2005 printed in iran introduction prostate-specific antigen (psa), a useful marker for malignant prostate disease, is produced by prostate epithelial cells. the increased psa level in patients with benign prostatic hyperplasia (bph) is caused by the enlargement of the transitional zone.(1) after the resection of an received september 2004 accepted april 2005 *corresponding author: urology and nephrology research center, no 44, 9th boustan, pasdaran, tehran 1666679951, iran. tel: ++98 21 2256 7222, fax: ++98 21 22567 7282 e-mail: h_moghaddam@unrc.ir serum prostate-specific antigen after prostatectomy in benign prostatic hyperplasia adenoma of the prostate, psa levels are expected to decrease to the reference range.(2) stamey and colleagues(3) have demonstrated that after adenectomy for bph, serum psa levels are reduced drastically in direct proportion to the volume of tissue removed. a modified reference range of psa levels after bph adenectomy has been suggested.(4) in this study, we investigated the effect of transurethral resection of the prostate (turp) and open prostatectomy (op) on serum psa level in men with bph. materials and methods between march 2001 and february 2003, 104 patients with bph were referred to our medical center for surgical treatment. the inclusion criteria for this clinical trial were as follows: age older than 50 years, the existence of urinary retention and persistent gross hematuria, and failure of prior medical therapy. patients with a malignancy, liver disease, or a history of prostate surgery or treatment with either antiandrogenic drugs or finasteride were excluded from this study. eighty-six patients were enrolled, and 18 were excluded (5 because of postoperative death, 5 because of adenocarcinoma, and 8 who refused to participate). all patients were evaluated by digital rectal examination (dre), determination of the serum psa level, and transrectal ultrasonography (trus) before surgical operation. long (l) and short (s) diameters and depth (d) were measured, and prostate volume was obtained by means of a prostate ellipse volume calculation (l × s × d × 0.5236), as described previously.(5) the serum psa level was measured with the microwell elisa kit (diagnostic systems laboratories inc, calabasas, california, usa) with a normal cutoff point of 4 ng/ml. in subjects with a psa level greater than 4 ng/ml or a suspicious result from dre, trus-guided biopsy was performed, and 3 tissue specimens were obtained from each lobe. the psa density was calculated by dividing the serum psa level by the prostatic volume. based on the results of dre, trus, and cystoscopy, we decided to perform turp in 45 patients and op in 41 (the turp and op groups, respectively). two weeks after operation, patients were examined, and their urine culture results and the report of pathologic examination were recorded. the serum psa level was measured 6 months after surgery. statistical analyses were performed with spss software (statistical package for the social sciences, version 9.0, ssps inc, chicago, ill, usa), and the student t test, the paired t test, the chi-square test, the mann-whitney test, and the pearson correlation were used as appropriate (significance, p < .05). results forty-five (52.3%) and 41 (47.7%) patients underwent turp and op, respectively. the mean serum psa level before surgery was 5.35 ± 3.68 ng/ml (range, 0.80 ng/ml to 17.50 ng/ml). of 86 patients, 43 (50%) had a preoperative serum psa value below the normal reference range (< 4 ng/ml). the mean preoperative prostate volume was 57.96 ± 33.82 ml (range, 15.00 ml to 190.00 ml). the preoperative psa level correlated with the prostate volume determined by trus (figure 1; r = 0.699, p < .001). this correlation was also seen in the op and turp groups (r = 0.606, p < .001 and r = 0.595, p < .001). overall, the preoperative psa density was 0.09 ± 0.05 (range, 0.03 to 0.33). the mean serum psa level after the surgery was 1.08 ± 0.68 ng/ml (range, 0.20 ng/ml to 3.10 ng/ml). none of the patients in our study had a postoperative serum psa level greater than 4 ng/ml (table 1). forty patients (88.9%) in the turp group and 39 (95.1%) in the op group had a postoperative psa less than 2 ng/ml (p = .20). serum psa levels decreased postoperatively in all patients, and the mean psa levels were reduced by 67.4 % (range, 0.40 ng/ml to 7.60 ng/ml) and 80.7% (range, 1.00 ng/ml to 14.50 ng/ml) in the patients in the turp and op groups, respectively. the mean decrease in serum psa level was 4.28 ± 3.5 ng/ml (p < .001; confidence interval: 3.51 to 5.04). this variable 184 table 1. distribution of serum psa levels before and after the procedures psa: prostate serum-specific antigen psa (ng/ml) preoperative number of patients (%) postoperative number of patients (%) ≤ 2 11 (12.8) 81 (91.9) ≤ 4 44 (51.2) 86 (100) ≤ 10 76 (88.4) > 10 10 (11.6) hosseini et al was 2.63 ± 1.97 ng/ml (p < .001; confidence interval: 2.03 to 3.22) in the patients in the turp group and 6.08 ± 4.02 ng/ml (p < .001; confidence interval: 4.81 to 7.35) in those in the op group (figure 2; p < .001; confidence interval, 4.79 to 2.11). the preoperative serum psa level correlated with the mean decrease in the serum psa level (figure 3; r = 0.95, p < .001; op group: r = 0.97, p < .001; turp group: r = 0.88, p < .001). the mean weights of the resected adenomas in the turp and op groups were 18.67 ± 10.33 g (range, 6.00 g to 50.00 g) and 65.00 ± 38.32 g (range, 13.00 g to 200.00 g, p < .001; confidence interval, 58.13 to 34.53). there was a significant correlation between the preoperative prostatic volume determined by trus and the weight of the resected adenomas (figure 4; r = 0.87, p < .001). this correlation in the turp and op 185 fig. 1. estimated ultrasonographic correlation of the preoperative serum psa level with prostate volume. prostate volume (ml) 2001000 s e ru m p s a l e v e l b e fo re s u rg e ry ( n g /m l ) 20 10 0 open pros tatectomy turp 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1 2 s e ru m p s a l e v e l c h a n g e s (n g /m l ) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1 2 s e ru m p s a c h a n g e s (n g /m l ) (n g /m l ) (n g /m l ) fig. 2. changes in the postoperative serum psa level in patients who underwent turp or op. s e ru m p s a l e v e l b e fo re s u rg e ry ( n g /m l ) prostate volume (ml) open prostatectomy turp serum prostate-specific antigen after prostatectomy in benign prostatic hyperplasia groups was also significant (turp group: r = 0.53, p < .001; op group: r = 0.85, p < .001). the correlation coefficient between the mean postoperative decrease in the serum psa level and the weight of the adenoma in the turp and op groups was 0.475 (p = .001) and 0.58.7 (p < .001), respectively (figure 5). the mean ratio of the postoperative decrease in the serum psa level to the adenoma weight in 86 patients was 0.13 ± 0.09 ng/ml/g (range, 0.03 ng/ml/g to 0.51 ng/ml/g). this ratio in the patients in the turp and op groups was 0.15 ± 0.12 ng/ml/g and 0.10 ± 0.06 ng/ml/g, respectively (p = .018). 186 fig. 3. the correlation between the preoperative serum psa level and the postoperative decrease in the psa level in all patients. serum psa level before surgery (ng/ml) 20100 s e ru m p s a l e v e l d e c re a se ( n g /m l ) 16 14 12 10 8 6 4 2 0 open prostate ctomy turp fig. 4. the relationship between prostate volume estimated ultrasonographically and the resected adenoma weight. prostate volume (ml) 2001000 r se c te d a d e n o m a w e ig h t (g ) 300 200 100 0 open pros tatectomy turp s e ru m p s a l e v e l d e c re a se ( n g /m l ) serum psa level before surgery (ng/ml) open prostatectomy turp r e se c te d a d e n o m a w e ig h t (g ) prostate volume (ml) open prostatectomy turp hosseini et al discussion in this study, half of the patients with bph exhibited a preoperative serum psa value above the normal reference range (> 4 ng/ml). in addition, the mean preoperative prostate volume was approximately 58 ml. furuya and colleagues(2) have reported a smaller mean prostate volume (38.8 ± 23.9 ml), and 48.7% of their patients had exhibited preoperative psa levels above 4 ng/ml. aus and colleagues(6) have demonstrated a preoperative serum psa value above normal reference range in 50% of their patients and a mean prostate volume of 47.9 ml. considering prostate volume, our patients had relatively lower serum psa levels. using a transrectal biopsy specimen from the prostate in patients with a moderately elevated level of serum psa, catalona and colleagues(7) identified cancer in only one-third of the patients studied. kehinde and colleagues(8) have demonstrated that bph and bph with prostatitis appear to be more frequent causes of serum psa levels greater than 10 ng/ml in arab men than in male caucasians in the united states and europe. this suggests that in our geographic region (the middle east), bph may be a more common cause of elevated serum psa (> 4 ng/ml) than is cancer. moreover, the calculated psa density revealed in our study is similar to that demonstrated by lloyd and colleagues (0.068),(1) but it is much lower than that in the study by furuya and colleagues (0.17).(2) aus and colleagues(6) have reported a decrease in serum psa levels by 70% (range, 6 ng/ml to 1.9 ng/ml) after turp. they have also noted that prostate volume was reduced by 58% (range, 63.3 ml to 26.5 ml). in our study, the patients who underwent op or turp had a reduction in the mean serum psa level by 80.7% and 67.4%, respectively. in addition, we noted a reduction in prostate volume by 84% in the op group and 54.2% in the turp group. our findings show that in patients who underwent op, the greater the volume of transitional zone removed, the greater the reduction in the mean serum psa level. the psa reduction per gram of resected adenoma weight was 0.10 in patients who underwent op, 0.15 in those treated with turp, and 0.12 overall. in 2 studies, similar results were found in patients who underwent turp,(1,4) but furuya and colleagues(2) reported a higher ratio (0.18 ng/ml/g) in japanese patients. because large prostate glands contain more epithelial tissue than do smaller prostates, the incomplete maturation of epithelial cells and their secretory dysfunction may be a reason for which the psa level decreases less after op than after turp. the main reason for that difference is not clear, 187 fig. 5. the correlation between the decrease in psa levels and the resected adenoma weight. serum p sa level decrease (ng/ml) 1614121086420 r e se c te d a e n o m a w e ig h t (g ) 300 200 100 0 open pros tatectomy turp r e se c te d a d e n o m a w e ig h t (g ) serum psa level decrease (ng/ml) open prostatectomy turp serum prostate-specific antigen after prostatectomy in benign prostatic hyperplasia and additional research is necessary to clarify that issue. in this study, postoperative serum psa levels were less than 2 ng/ml in 91.9% of patients and between 2 and 4 ng/ml in 8.13%, regardless of operative technique. no patients exhibited a postoperative serum psa level greater than 4 ng/ml. there was no significant difference between the results of the 2 techniques in achieving postoperative serum psa levels of less than 2 ng/ml. aus and coworkers(6) have reported a postoperative psa value of less than 4 ng/ml after turp in 90% of patients. our patients exhibited much greater reductions in postoperative serum psa levels, which might have been resulted from the use of op in our study. long-term follow-up for patients who underwent turp in a study by marks and colleagues(4) showed that the subjects with prostatic cancer had a mean psa level of 1.4 ng/ml. considering the low accuracy of rectal examination after prostatectomy, a modified reference range of psa seems necessary for the screening of prostate cancer in men who undergo prostatectomy for bph. conclusion after either turp or op for bph, the serum psa level decreases significantly. because rectal examination is not accurate in the early detection of prostate cancer and because the likelihood of this malignancy remains even after turp or op, the serum psa level cannot be determined accurately when bph is treated by these operations. thus, further studies to find a modified cutoff point for the serum psa level in such patients are warranted. references 1. lloyd sn, collins gn, mckelvie gb, hehir m, rogers ac. predicted and actual change in serum psa following prostatectomy for bph. urology. 1994;43:472-9. 2. furuya y, akakura k, tobe t, ichikawa t, igarashi t, ito h. changes in serum prostate-specific antigen following prostatectomy in patients with benign prostate hyperplasia. int j urol. 2000;7:447-51. 3. stamey ta, yang n, hay ar, mcneal je, freiha fs, redwine e. prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. n engl j med. 1987;317:909-16. 4. marks ls, dorey fj, rhodes t, et al. serum prostate specific antigen levels after transurethral resection of prostate: a longitudinal characterization in men with benign prostatic hyperplasia. j urol. 1996;156:1035-9. 5. terris mk, stamey ta. determination of prostate volume by transrectal ultrasound. j urol. 1991;145:984-7. 6. aus g, bergdahl s, frosing r, lodding p, pileblad e, hugosson j. reference range of prostate-specific antigen after transurethral resection of the prostate. urology. 1996;47:529-31. 7. catalona wj, hudson ma, scardino pt, et al. selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves. j urol. 1994;152(6 pt 1):2037-42. 8. kehinde eo, sheikh m, mojimoniyi oa, et al. high serum prostate-specific antigen levels in the absence of prostate cancer in middle-eastern men: the clinician's dilemma. bju int. 2003;91:618-22. 188 news first urology and nephrology research festival (avicenna) 57 urology journal unrc/iua vol. 2, no. 1, 57-58 winter 2005 printed in iran in 1999, the urology and nephrology research center (unrc) began its activation. since then, it has operated as the focal point for urology and nephrology research in iran. the goals of the unrc, in general, are to take all the necessary measures within the domains of its responsibilities to advance existing health and medical knowledge in preventing, diagnosing, and treating diseases and disabilities in urology and nephrology field. the unrc works toward its mission by conducting studies at national level and by supporting and coordinating with researchers, research institutions, universities and academic centers, and other related settings. in order to promote research in areas of common interest the unrc has collaborated with governmental, and non-governmental organizations, which operate domestically and internationally. some of the unrc's most important objectives are: � to conduct need-assessment, set priorities, and call for proposals for high-quality research with the aim of maintaining and improving health � to assess appropriate as well as affordable health technology and healthcare services that meet national needs in terms of health, quality of life and economic competitiveness; � to disseminate and promote the resulting new knowledge among physicians, healthcare professionals, scientific centers as well as managers. � to improve infrastructure for urology nephrology research in several ways by: � providing facilities to research � providing the necessary financial resources for research � establishing national registers and databases for all activation in urologynephrology field � collaboration with different research institutions which operate inside and outside the country � participation in international congresses for obtaining more experience and knowledge the first urology and nephrology research festival was held in december 16, 2004 and the best research projects in the field of renal and urinary tract diseases were selected and acclaimed. the underlying objective of this festival is first to support the researchers financially and scientifically; secondly to appreciate their efforts, and third, to introduce the researchers and their findings to the scientific societies. juries evaluating in methodology, subject, creativity and problem solving first carefully assessed the research projects. scores were gathered and after standardization and sorting the projects, the final judgment was made. the winners were invited to take part in the award ceremony. this year, dr. mohammad reza safarinejad, was the first prize winner of this festival. "prevalence and risk factors for erectile dysfunction in a population-based study in iran" and "urinary mineral excretion in healthy iranian children" were the names of his studies. m. r. safarinejad was born on february 17, 1959 in tabriz, iran. he began his professional life with a m.d. degree from the university of medical sciences of tabriz. he decided that urology was a more interesting and challenging dr. m.r. safarinejad, first prize winner of festival first urology and nephrology research festival field, and he completed his urology residency at shaheed beheshti university of medical sciences in 1997. from 1998 he was an assistant professor in the department of urology. he became vice councilor for education and research of university of medical sciences in 2002. through hard work, vision and creativity he built an excellent urology department at the university. doctor safarinejad is an excellent role model who has had a hand in training as well as academic researches. he is a member of american urological association (aua) and european association of urology (eau). he is associate editor of the urology journal. it is indeed a great honor to recognize doctor safarinejad for all that he has done to help establish, protect and serve the field of urology and to bestow upon him the 2004 first rank urology nephrology research award. 58 1142 | brief communication antenatal diagnosis of renal duplication by ultrasonography: report on four cases at a referral center edward enéas d. queiroga júnior,1 marília g. martins,1 lívia t. rios,1 edward araujo júnior,2 ricardo v. oliveira,1 luciano m. nardozza,2 antonio f. moron,2 abstract duplication of the renal collecting system is the commonest major congenital mal-formation of the urinary tract, with an incidence of 1% among live births. antena-tal diagnosing of renal duplication and an associated ureterocele is infrequent. we report four cases of prenatally diagnosed unilateral duplication of the renal collecting system. in two of them, the renal duplication was associated with an ectopic ureterocele. keywords: fetal diseases; hydronephrosis; ultrasonography; ureteral obstruction; kidney; abnormalities. introduction the urinary tract is the system that is third most commonly affected by congenital malformations, preceded by the central nervous system and the cardiovascular system. congenital abnormalities of the urinary tract are found relatively frequently, in around 0.5% of all pregnancies.(1) the detection rate for urinary tract abnormalities in routine prenatal ultrasonography examinations is around 20 to 30% of the total number of malformations.(2) duplication of the upper urinary tract is the most common congenital malformation of the urinary tract.(3) it is one of the commonest congenital obstructive urological diseases, occurring in around 1% of live births.(4) females are more affected than males, and this condition occurs unilaterally in 83% to 90% of the cases.(5) the upper renal segment is involved in 85% of the cases and ureteroceles occur between 24 and 47% of the cases.(5) ureteroceles have been reported in up to 50% of renal duplications, with hydronephrosis of the upper pole.(6) the diagnosis of pyeloureteral duplication can be made prenatally by means of ultrasonog corresponding author: edward araujo júnior, phd department of obstetrics, federal university of são paulo (unifesp), rua carlos weber, 956 apto. 113 visage, alto da lapa, são paulo-sp, cep 05303-000, brazil. telephone / fax: +55 11 3796 5944 e-mail: araujojred@terra.com.br received january 2013 accepted june 2013 1 gynecology and obstetrics service, federal university of maranhão (ufma), são luiz, ma, brazil. 2 department of obstetrics, federal university of são paulo (unifesp), são paulo, sp, brazil. brief communication 1143vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l antenatal diagnosis of renal duplication | queiroga júnior, et al raphy. the findings that lead to suspicion of pyeloureteral duplication are identification of two separate renal poles, dilatation or cystic areas in an upper or lower pole, a dilated ureter and an anechoic cystic structure projecting into the bladder that is suggestive of ureteroceles.(7) because renal duplication occurs relatively frequently, is the largest malformation of the urinary tract identified prenatally and requires surgical treatment, the present case reports had the aim of describing the antenatal ultrasonographic findings that may lead to suspicion and early diagnosing of this condition, thereby easing the possible postnatal complications. materials and methods this was a descriptive analysis on cases of fetal renal duplication diagnosed and followed up at the obstetrics and gynecology service of the university hospital, federal university of maranhão (ufma) between january 2007 and may 2012. the cases were described and analyzed based on data gathered from the patients’ medical files and ultrasonography reports and on evaluations on images stored in the database. this study only included fetuses with an antenatal diagnosis of renal duplication that was confirmed postnatally. this study was approved by the research ethics committee of ufma. the identities of and data on all the patients involved in this study were kept confidential, thus ensuring these individuals’ privacy. all the patients gave their signed consent for their cases to be published. results after surveying the data from obstetric examinations carried out over a six-year period (january 2007 to may 2012), our sample consisted of five cases with diagnostic suspicion of renal duplication, with antenatal and postnatal ultrasonographic examinations. one of the cases was excluded because there was no postnatal confirmation. all of the pregnant women were young, with ages ranging from 22 to 37 years, of whom four were primigravidae. all the pregnancies went to full term, with vaginal delivery, and all the newborns were female with good vitality: apgar indexes of 8 or 9 at the first and fifth minutes (table 1). in all of the cases with postnatal confirmation (table 2), ultrasonography identified two separate renal poles with dilatation or cystic areas in an upper or lower pole and a dilated ureter. in only two cases was an anechoic cystic structure observed projecting into the bladder, and these were suggestive of an ureterocele. in only one patient (case 4) were other associated malformations encountered: type 1 pulmonary cystic adenomatoid malformation in the left hemithorax, a single umbilical artery and absence of the right kidney. case 1 the patient was a 27-year-old primigravida with a gestational age of 38 weeks and 4 days, who was referred to our service for ultrasonography to be performed because of unilateral hydronephrosis shown in a previous ultrasonographic examination. she did not have any relevant family history or personal antecedents. a new ultrasonographic examination was requested: in longitudinal renal slices, this showed a homogenous cystic structure at the upper pole that simulated a renal cyst. in additional coronal and transverse slices, this revealed that the kidney had a duplicated collecting system, with hydronephrosis of the upper unit associated with ureteral dilatation. a ureterocele was observed in the bladder, which suggested a diagnosis of complete renal duplication (figure 1). the kidney affected was the right kidney and the fetus was female. no malformation was found in any other system. the diagnosis of duplication of the collecting system was confirmed after birth, by means of ultrasonography on the newborn’s urinary tract. case 2 the patient was a 28-year-old primigravida, with a gestational age of 37 weeks and 1 day, who was referred to our service for ultrasonography to be performed in the third trimester because of unilateral hydronephrosis that had been shown in previous ultrasonography. she did not have any relevant family history or personal antecedents. a new ul1144 | trasonographic examination was requested: in the region of the right kidney, this showed two collecting systems and two ureters, with dilatation of the upper unit and an ureterocele compatible with complete renal duplication. no malformation was found in any other system. the diagnosis of duplication of the collecting system was confirmed after birth, by means of ultrasonography on the newborn’s urinary tract. case 3 the patient was a 25-year-old primigravida, with a gestational age of 31 weeks and 3 days, who was referred to our service for ultrasonography because of unilateral hydronephrosis that had been shown in previous ultrasonography. she did not have any relevant family history or personal antecedents. she did not have any relevant family history or personal antecedents. a new ultrasonographic examination was requested: this showed that the fetal right kidney presented signs of duplication of the collecting system, with moderate pyeloureteral dilatation of the upper unit, but without signs of ectasia or dilatation of the lower unit. there were no images suggestive of an ureterocele in the fetal bladder (figure 2). no malformation was found in any other system. the diagnosis of duplication of the collecting system was confirmed after birth, by means of ultrasonography on the newborn’s urinary tract. case 4 the patient was a 37-year-old woman in her second pregnancy, with a gestational age of 28 weeks, who was referred to our service for ultrasonography because of abnormalities that had been shown in previous ultrasonography. she did not have any relevant family history or personal antecedents. a new ultrasonographic examination was requested, which showed a normal (non-ectopic) pregnancy of 28 weeks, with the following: amniotic fluid volume slightly above normal; type 1 pulmonary cystic adenomatoid malformation occupying the middle and lower thirds of the left lung; left renal duplication, with pyelectasis of the upper and lower units; renal pelvis measuring 0.6 cm in the upper unit and 0.7 cm in the lower unit; absence of image of the right kidney; displacement of the cervical spine (hemivertebra); and a single umbilical artery. an additional ultrasonography examination was performed in the 33rd week, which confirmed the findings described previously. the diagnosis of duplication of the collecting system was confirmed after birth, by means of ultrasonography on the newborn’s urinary tract. table 1. distribution of maternal age, parity, fetal sex, gestational age at delivery and apgar indices (1 st and 5 th minutes) of the cases with an antenatal diagnosis of renal duplication and postnatal confirmation. patient maternal age parity fetal sex gestational age at delivery apgar 1 st / 5 th 1 27 g1p0 female 38w1d 9/9 2 28 g1p0 female 39w4d 9/9 3 25 g1p0 female 37w5d 8/9 4 37 g2p1 female 37w3d 8/9 keys: w, week; d, day. table 2. ultrasonographic findings identified among the cases of antenatal diagnosis of renal duplication with postnatal confirmation. case gestational age at diagnosis fetal sex kidney with duplication two separate renal poles dilatation or cystic areas at upper or lower pole dilated ureter on the affected side ureterocele 1 38w4d female right yes yes yes yes 2 37w1d female right yes yes yes yes 3 31w3d female right yes yes yes no 4 28w0d female left yes yes yes no keys: w, week; d, day. brief communication 1145vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l discussion duplication of the renal collecting system is the commonest major congenital malformation of the urinary tract, and females are affected more than males.(4,6,8) this was also observed in the present series, in which all the cases were in females. this condition has been found to be unilateral in 83 to 90% of the cases,(4,6,8) and this was seen in 100% of the cases in the present series. in the present series, an ureterocele was present in half of the cases. this narrowing gave rise to significant dilatation of the upper renal unit and the ureter that drained it, in 85% of the cases.(9) in the cases reported here, there was dilatation of the upper unit and dilatation of the corresponding ureter. the ureter that drains the upper unit commonly presents relative obstruction, thus leading to dysplasia of the upper renal pole. on the other hand, the ureter that drains the lower unit is inserted topically in the vesical trigone, and may present ureteral-vesical reflux.(8) dilatation of the upper unit of the collecting system may simulate a large renal cyst at the upper pole.(4) in the cases reported here, there was moderate hydronephrosis of the upper units and these was no report of cysts at the upper renal pole. to increase the renal duplication detection rate on antenatal ultrasonography, a systematized search for the following ultrasonographic findings is recommended: 1) length of the kidney in the sagittal plane (including the upper pole); 2) figure 1. (a) hydronephrosis in the upper unit of the right kidney, with dilated and tortuous ureter. (b) fetal bladder showing ureterocele. figure 2. (a) moderate pyeloureteral dilatation of the upper unit of the right kidney, without signs of ectasia or dilatation of the lower unit. (b) bladder not showing ureterocele. antenatal diagnosis of renal duplication | queiroga júnior, et al 1146 | cysts imaged at the upper pole surrounded by renal parenchyma; 3) kidney with two renal pelvises that are not in communication; 4) dilated ureter, which usually drains the upper pole; and 5) cysts imaged in the bladder (ureterocele). (6) in all four cases described here, the findings comprised cysts imaged at the upper pole, two renal pelvises that were not in communication and a dilated ureter. an ureterocele was present in two cases. the case numbers of fetal renal duplication was small. despite our service to be a public referral hospital in the maranhão state in the northeast of brazil, the prenatal care is deficient and several pregnant women are referenced in advanced gestational age, damaging the prenatal diagnosis. due of low quality of prenatal care in the public services in brazil, our service has a protocol of investigation of several congenital infections in all pregnant women, mainly toxoplasmosis and syphilis. these infections have high incidence in the northeast of brazil. in summary, based on our series of four cases of fetal renal duplication, the condition was correctly identified in all cases, by using the ultrasonographic descriptions of whitten and colleagues.(4) with regard to antenatal classification of the likelihood that cases would really present renal duplication, the cases of the present study fitted into the category of high probability. lastly, the importance of making an accurate antenatal diagnosis that allowed early introduction of prophylactic measures in order to diminish the potential risks of complications like infection, or of evolution to renal dysplasia with loss of renal function during the postnatal period, was highlighted. conclusion the prenatal diagnosis of renal duplication is very important to counseling of parent and follow of these cases in reference services with multidisciplinary team. these actions can contribute to reduce the risk of complications in the postnatal period. conflict of interest none declared. references 1. elder js. antenatal hydronephrosis. fetal and neonatal management. pediatr clin north am. 1997;44:1299-321. 2. pope jc 4th, brock jw 3rd, adams mc, stephens fd, ichikawa i. how they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, cakut. j am soc nephrol. 1999;10:2018-28. 3. smith p, dunn m. duplication of the upper urinary tract. ann r coll surg engl. 1979;61:281-86. 4. whitten sm, mchoney m, wilcox dt, new s, chitty ls. accuracy of antenatal fetal ultrasound in the diagnosis of duplex kidneys. ultrasound obstet gynecol. 2003;21:342-46. 5. vergani p, ceruti p, locatelli a, et al. accuracy of prenatal ultrasonographic diagnosis of duplex renal system. j ultrasound med. 1999;18:463-7. 6. abuhamad az, horton ce jr, horton sh, evans at. renal duplication anomalies in the etus: clues for prenatal diagnosis. ultrasound obstet gynecol. 1996;7:174-7. 7. adiego mb, martinez p, perez j, illescas t, barron e. prenatal diagnosis of renal duplex systems. ultrasonographic features and postnatal outcomes. ultrasound obstet gynecol. 2010;36(suppl 1):149. 8. mackie gg, stephens fd. duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. j urol. 1975;114:274-80. 9. mascatello vj, smith eh, carrera gf, berger m, teele rl. ultrasonic evaluation of the obstructed duplex kidney. ajr am j roentgenol. 1977;129:113-20. brief communication 1492 | pictorial spinning top urethra on voiding cystourethrogram pankaj gupta, akshay kumar saxena, kushaljit singh sodhi corresponding author: akshay kumar saxena, md department of radiodiagnosis and imaging, post graduate institute of medical education and research, chandigarh 160012, india. tel: +91 172 2756381 e-mail: fatakshay@yahoo.com received march 2013 accepted june 2013 department of radiodiagnosis and imaging, post graduate institute of medical education and research, chandigarh 160012, india. a 10-year-oldgirlwasreferredforavoidingcystourethrogram(vcug)withahistoryofrecurrenturinarytractinfections.examinationincludingneurologicalevaluationwasunremarkable.ultrasonographyofthekidneysandbladderwasnormal.voidingphaseofvcugwassubsequentlyperformed.bladder capacityandoutlinewerenormal(figure1).therewasmarkeddilatationofposteriorurethra(figure2)withsmoothtaperingtowards distalendresemblinga“spinningtop”.novesicoureteralrefluxorpost-voidresidualurinewasnoted.spinningtopurethra(stu) representsawidenedposteriorurethraseenmainlyingirls.foralongtime,itwasconsideredanormalvariation,duetocontraction oftransversefibersofurethralsphincterlocatedinthedistalurethra.(1)proponentsofstuasapathologicalentityhaveattributedit variablytomeatalstenosis,urethralring,distalsphincterdyssynergia,bladderinstabilityandcongenitalwidebladderneckanomaly (cwbna).(2)formerthreemechanismswererefutedbystudiesshowinghighurineflowratesinsubjectswithstu.forthelattertwo mechanisms,controversyexistsbecausemajorityofcaseswithinstabilityandcwbnadonotshowstu.thus,oneshouldconsider stuanormalvariant,sometimesoccurringinchildrenwithinstabilityorcwbna.differentialdiagnosisincludeslyon¹s(fibrous) ringingirlsandurethralvalvesinmales.(3) pictorial references 1. shopfner ce, hutch ja. the normal urethrogram. radiol clin north am. 1968;6:165-89. 2. saxton hm, borzyskowski m, mundy ar, vivian gc. spinning top urethra: not a normal variant. radiology. 1988;168:147-50. 3. lyon rp, tanagho ea. distal urethral stenosis in little girls. j urol. 1965;93:379-88. figure 1. voiding phase of voiding cystourethrogram demonstrates normal ladder capacity and outline. figure 2. marked dilatation of posterior urethra with smooth tapering towards distal end resembling a “spinning top”. miscellaneous smoking and lower urinary tract symptoms mustafa suat bolat,1* ekrem akdeniz,1 sevket ozkaya,2 ali furkan batur,3 kerem gencer kutman,3 resit goren,4 fikret erdemir,5 ferah ece2 purpose: pharmacologic effects of nicotine are multifaceted and complicated. despite numerous studies, the effect of smoking on lower urinary tract functions, have not been yet studied in detail. in this study, we aimed to investigate the effects of smoking addiction on lower urinary tract and sexual functions on the basis of respiratory functions. materials and methods: a total of 186 male patients who have been evaluated between may 2014 and january 2015 were recruited in this study. smoking history, respiratory symptoms, respiratory function tests, uroflowmetry parameters relating to lower urinary tract symptoms (luts), prostate volume, post-voiding residual urine volume and sexual functions of patients have been retrospectively investigated. results: we determined that as the mean number of cigarettes smoked daily increases, post-void residual urine volume and international prostate symptom score (ipss) also increase. moreover in accordance with this finding, mean urinary flow rates and quality of life scores were statistically significantly decreased. in smoking addicts who have high mean package/year, post-void residual urine volume and ipss levels were increased but proportionately maximum urinary flow rate and average urinary flow rate plus quality of life scores were found to be statistically significantly decreased. in patients with forced expiratory volume in first second:forced vital capacity (fev1/ fvc) ratio less than 80%, mean urinary flow rates were found to be statistically significantly low. also, we determined that in smoking addicts who have high mean package/year, erectile functions were statistically significantly impaired. conclusion: we showed negative impacts of smoking addiction on luts, patient’s quality of life, and sexual functions. keywords: risk factors; smoking; adverse effects; lower urinary tract symptoms; etiology; urinary bladder. introduction world health organization (who) defines the smoking addiction as ‘world’s fastest growing and longest epidemic.(1) cigarette smoking is associated with increased peripheral vascular disease and erectile dysfunction (ed). smokers have increased risk for both pulmonary and cardiac complications.(2) pharmacologic effects of nicotine are multifactorial and complicated. nicotine might induce a contraction through an interaction with nicotinic receptors located on the terminal nerves of, possibly, (i) parasympathetic cholinergic, (ii) sympathetic non-adrenergic and (iii) non-sympathetic purinergic nerves in guinea-pig detrusor preparations. in addition a portion of the contraction is due to the purine nucleotide released which may be potentiated by 1 department of urology, samsun training and research hospital, samsun, turkey. 2 department of pulmonology, faculty of medicine, bahcesehir university, istanbul, turkey. 3 department of urology, nafiz körez state hospital, sincan, ankara, turkey. 4 department of urology, faculty of medicine, baskent university, adana, turkey. 5 department of urology, gazi osman pasa university, tokat, turkey. *correspondence: department of urology, samsun training and research hospital, samsun, turkey. tel: +90 362 3111500. e-mail: msbolat@gmail.com. received march 2015 & accepted october 2015 intramural prostaglandin(s). parasympathetic cholinergic output might be modulated by an unknown excitatory substance released by nicotine from sympathetic nerve.(3) despite numerous studies, those investigate effects of smoking on different organs and systems, the effect of smoking on lower urinary tract functions, have not been yet studied in detail. some researchers suggested that the current cigarette smoking was not consistently associated with the lower urinary tract symptoms (luts) and the possible association in former smokers warrants further investigation.(4-6) in this study, we aimed to investigate the effects of smoking addiction on lower urinary tract and sexual functions on the basis of spirometry parameters. miscellaneous 2447 smoking and luts-bolat et al. materials and methods study population a total of 186 male patients who have been admitted to samsun training and research hospital and samsun gazi state hospital between may 2014 and january 2015 were recruited in this study. data regarding smoking history, respiratory symptoms, respiratory function tests, and uroflowmetry parameters relating to luts, prostate volume, post-void residual urine volume and sexual function of patients were gathered from the medical records. urine analysis has also been performed for excluding bladder cancer. smoking history of patients were evaluated as pack/year and stick per day. in pack / year group, patients were categorized into 2 subgroups as low smoking group (smoked less than 28.6 pack / year) and high smoking group (smoked more than 28.6 pack / year). patients were also classified as light smoker (< 20.9 daily cigarettes) and heavy smoker (> 20.9 daily cigarettes). the study was performed in accordance with the ethical principles in the good clinical practice guidelines, in addition to applicable local regulatory requirements and the study protocol was approved by local ethics review boards. all the patients read the patient information form about the study procedure and written informed consents were obtained. evaluations spirometry was performed for evaluation of respiratory functions. international prostate symptom score (ipss) and international index of erectile functions (iief) questionnaires were used for evaluation of luts and erectile function, respectively. average urinary flow rate (qave), maximum urinary flow rate (qmax) and urination time were measured using uroflowmetry. prostate volume and post-voiding residual urine voltable 1. characteristics of study patients. characteristics values* age (years) 61.1 ± 8.9 (30-82) smoking, no. daily 20.9 ± 9.6 (1-60) pack/year 28.6 ± 20.4 (1-120) pulmonary function test results, (%) fev1 (ml) 2809 ± 870 (96.9 ± 30.9) fvc (ml) 3421 ± 986 (95.4 ± 30.5) fev1/fvc 86.4 ± 47.3 uroflowmetry results qmax (ml/s) 20.5 ± 7.8 (7-54) qave (ml/s) 10.4 ± 4.5 (3.3-32) qol 2.2 ± 1.3 (0-6) ipss 15.1 ± 4.9 (1-29) serum psa levels (ng/ml) 1.6 ± 1.4 (0.1-10.3) pvr, ml 30.2 ± 36.6 (0-212) prostate volume (ml) 44.6 ± 19.2 (12-139) erectile dysfunction, no. (%) severe 44 (24.2) moderate 48 (26.4) mild to moderate 29 (15.9) mild 23 (12.6) none 38 (20.9) abbreviations: ed, erectile dysfunction; fev1, forced expiratory volume in 1 second; fvc, forced vital capacity; iief, international index of erectile function; ipss, international prostate symptom score; psa: prostate specific antigen; pvr, post voiding residual urine volume; qol, quality of life. * data are presented as mean ± sd (min-max). characteristics low group (daily cigarette) high group (daily cigarette) p value* qol 2.7 ± 1.6 2.1 ± 1.2 .01 ipss 12.8 ± 4.8 15.7 ± 47 .00 urine volume (ml) 294 ± 184 303 ± 178 .849 qmax (ml/s) 19.6 ± 7.9 20.7 ± 7.8 .49 qave (ml/s) 10.7 ± 5.9 10.4 ± 5.2 .04 voiding time (s) 59.9 ± 12.2 37.3 ± 16 .03 serum psa level (ng/ml) 1.57 ± .9 1.7 ± 1.5 .59 pvr (ml) 14.4 ± 27.1 34.4 ± 27.7 .00 prostate volume (ml) 41.1 ± 22.2 45.5 ± 22.3 .21 abbreviations: ipss, international prostate symptom score; psa, prostate specific antigen; pvr, post voiding residual urine volume; qave, average urine flow per second; qmax, maximum urine flow per second; qol, quality of life. * data are presented as mean ± sd. table 2. the relationship between daily cigarette consumption with qol, uroflowmetry and urological parameters. vol 12 no 06 november-december 2015 2448 ume (pvr) were calculated tridimentionally by using suprapubic ultrasound. statistical analysis results were analyzed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0. results are presented as mean ± standard deviation and p < .05 was considered as statistically significant. descriptive data were compared using the unpaired student t-test and pearson chi-square test. results one hundred and eighty-six male patients were enrolledin to the study. the characteristics of patients are presented in table 1. mean age of patients was 61.1 ± 8.9 years. mean duration of smoking addiction was 28.6 ± 20.4 years; mean number of cigarettes smoked were 20.9 ± 9.6 daily. results of respiratory test functions for forced expiratory volume in first second (fev1)/forced vital capacity (fvc) (fev1/fvc) ratio were 2809 ± 870 ml (96.9% ± 30.9%), 3421 ± 986 ml (95.4% ± 30.5%), and 86.4% ± 47.3%, respectively. mean ipss was 15.1 ± 4.9; quality of life (qol) score was 2.28 ± 1.3. number of patients according to their iief score for severe, moderate, mild to moderate, and mild ed and without ed were 44 (24.2%), 48 (26.4%), 29 (15.9%) and 38 (20.9%), respectively. mean pvr was 30.2 ± 36.6 ml, and mean serum prostate specific antigen (psa) level was 1.6 ± 1.4 ng/ml. regarding to uroflowmetry parameters, mean qmax was 20.5 ± 7.8 ml/s and mean qave was 10.4 ± 4.5 ml/s. evaluation of relationship between smoking addiction level with qol and uroflowmetry parameters demonstrated that pvr and ipss were statistically significantly high (p = .00) but qave (p = .04) and qol (p = .01) were statistable 3. the relationship between pack/year smoking status with qol, uroflowmetry and urological parameters. characteristics low group (pack/year) high group (pack/year) p value* qol 1.9 ± 1.2 2.6 ± 1.3 .00 ipss 13.9 ± 4.9 16.7 ± 4.5 .00 flowvolume (ml) 329 ± 206 274 ± 149 .24 qmax (ml/s) 22.3 ± 8.1 18.2 ± 6.7 .00 qave (ml/s) 11.3 ± 4.7 9.3 ± 4 .00 voiding time (s) 44.5 ± 71.4 37.6 ± 16.8 .42 serum psa level (ng/ml) 1.4 ± 1.2. 1.9 ± 1.6 .04 pvr (ml) 22.3 ± 29.5 40.7 ± 42.3 .00 prostate volume (ml) 42.6 ± 16.4 47.2 ± 22.3 .11 abbreviations: ipss, international prostate symptom score; psa, prostate specific antigen; pvr, post voiding residual urine volume; qave, average urine flow per second; qmax, maximum urine flow per second; qol, quality of life. * data are presented as mean ± sd. characteristics fev1/fvc < 80% fev1/fvc ≥ 80% p value* qol 2.3 ± 1.2 2 ± 1.2 .28 ipss 15.5 ± 4.4 15 ± 4.7 .49 flowvolume (ml) 277.9 ± 222.1 306.8 ± 175.3 .64 qmax (ml/s) 19.3 ± 7.7 21.8 ± 7.8 .08 qave (ml/s) 9.6 ± 4.3 11.3 ± 4.7 .03 voiding time (s) 39.5 ± 19.5 35.9 ± 15.2 .20 serum psa level (ng/ml) 1.9 ± 1.6 1.5 ± 1.4 .16 pvr (ml) 28.4 ± 34.4 31 ± 36.6 .69 prostate volume (ml) 48.9 ± 22.9 41.9 ± 16.1 .03 abbreviations: ipss, international prostate symptom score; psa, prostate specific antigen; pvr, post voiding residual urine volume; qave, average urine flow per second; qmax, maximum urine flow per second; qol, quality of life; fev1, forced expiratory volume in 1 second; fvc, forced vital capacity. * data are presented as mean ± sd. table 4. the relationship between pulmonary function test results with qol, uroflowmetry and urological parameters. smoking and luts-bolat et al. miscellaneous 2449 tically significantly low in heavy smoker group (table 2). when correlation between smoking addiction level (mean smoked package/year) and qol with uroflowmetry parameters were evaluated, qol and qmax values were found to be statistically significantly low (p = .00), in contrast pvr and ipss values were statistically significantly high (p = .00) in heavy smoker group (table 3). qave values of patients with fev1/fvc ratio less than 80%, were statistically significantly low (p = .04) (table 4). when correlation between erectile functions and mean number of cigarettes smoked daily were compared with those who have fev1/fvc ratio less than 80%, erectile function was statistically significantly lower (p = .001) in heavy smoker group (table 5). discussion because studies comparing the correlation between smoking addiction level, respiratory function test parameters and luts are lacking, the discussion part of this article is limited. when we investigated the correlations between smoking addiction levels and qol with uroflowmetry parameters, we determined that as the mean number of cigarettes smoked daily increases, pvr and ipss values increase. also in accordance with this finding, mean urinary flow rates and qol scores were statistically significantly decreased. in smoking addicts who have high mean package/year ratio, pvr and ipss levels and proportionately qmax and qave plus qol scores were found to be statistically significantly decreased. in a study with similar setting to ours, it has been reported that in 40-75 years age group, inpatients with ≥ 35 cigarettes smoked daily, development of benign prostate hyperplasia is statistically significantly higher.(7) the main reason attributed to this increase was elevated serum testosterone levels in heavy smokers. in patients with fev1/fvc ratio less than 80%, mean urinary flow rates were found to be statistically significantly low. we reported a parallel reduction in air flow rate and mean urinary flow rate. we hypothesize that stimulating and inhibitory effects of nicotine might be the cause of this reduction. in a study that analyzed the effects of nicotine on detrusor muscles in rats, the authors have shown stimulating effects of nicotine onmuscarinic (m 1 ) receptors and inhibitory effects on m 2 receptors at synaptic junctions.(7) in addition, we determined that in smoking addicts who have high mean package/year, erectile function was statistically significantly impaired. numerous studies have investigated the association between cigarette smoking and ed, and it has been reported that smoking nearly double the risk of moderate or severe ed at a ten years follow up.(8) at another study in men aged 30-79 years old, it has been shown that, risk of ed has increased 2.3-fold in men with history of 20 package/year of smoking.(9) in concordance with our study, it has been reported that there is a statistically significant correlation between cigarette smoking and ed development, and this correlation becomes stronger as the mean number of cigarettes smoked daily increases.(10) conclusions in conclusion, as with other studies in which the effects of cigarette smoking on luts have been investigated, we also showed negative impacts of smoking addiction on luts, patient’s qol and sexual functions. in this study, interestingly we would like to express that we determined a statistically significant relationship between spirometry and uroflowmetry parameters in smoking addicts. conflict of interest table 5. the relationship between erectile function with daily cigarette consumption, pack/year smoking status and pulmonary function test results. characteristics severe ed moderate ed mild to moderate ed mild ed no ed p value daily smoke, no. (%) low group 6 (15.8) 9 (23.7) 5 (13.1) 4 (10.5) 14 (36.8) .11 high group 37 (26.2) 38 (26.9) 23 (16.3) 19 (13.4) 248 (17.0) pack/year,no. (%) low group 15 (14.7) 29 (28.4) 16 (15.6) 17 (16.6) 25 (24.5) .01 high group 28 (36.3) 18 (23.3) 12 (15.5) 6 (7.7) 13 (16.8) fev1/fvc, no. (%) < 80% 15 (33.3) 11 (24.4) 7 (15.5) 7 (15.5) 5 (11.1) .38 ≥ 80% 21 (20.1) 26 (25) 19 (18.2) 16 (15.3) 22 (21.1) abbreviations: ed, erectile dysfunction; fev1, forced expiratory volume in 1 second; fvc, forced vital capacity. smoking and luts-bolat et al. vol 12 no 06 november-december 2015 2450 none declared. references 1. world health organization. a who / the union monograph on tb and tobacco control: joining forces to control two related global epidemics [who/htm/tb/2007.390] geneva: world health organization; 2007. 2. kendirci m, nowfar s, hellstrom wj. the impact of vascular risk factors on erectile function. drugs today. 2005;41:6574. 3. hisayama t, shinkai m, takayanagi i, toyoda t. mechanism of action of nicotine in isolated urinary bladder of guinea-pig. br j phar. 1988;95:465-72. 4. rohrmann s, crespo cj, weber jr, smit e, giovannucci e, platz ea. association of cigarette smoking, alcohol consumption and physical activity with lower urinary tract symptoms in older american men: findings from the third national health and nutrition examination survey. bju int. 2005;96:77-82. 5. mehraban d, naderi gh, yahyazadeh sr, amirchaghmaghi m. sexual dysfunction in aging men with lower urinary tract symptoms. urol j. 2008;5:260-4. 6. akil io, ozmen d, cetinkaya ac. prevalence of urinary incontinence and lower urinary tract symptoms in school-age children. urol j. 2014;11:1602-8. 7. onoue s, yamamoto n, seto y, yamada s. pharmacokinetic study of nicotine and its metabolite cotinine to clarify possible association between smoking and voiding dysfunction in rats using uplc/esi-ms. drug metab pharmacokinet. 2011;26:416-22. 8. somogyi gt, de groat wc. evidence for inhibitory nicotinic and facilitatory muscarinic receptors in cholinergic nerve terminals of the rat urinary bladder. j auton nerv syst. 1992;37:89-97. 9. feldman ha, goldstein i, hatzichristou dg, krane rj, mckinlay jb. impotence and its medical and physiological correlates: results of the massachusetts male ageing study. j urol. 1994; 151:54-61 10. kupelian v, link cl, mckinlay jb. association between smoking, passive smoking and erectile dysfunction: results from boston area community health (bach) survey. eur urol. 2007;52:416-22. smoking and luts-bolat et al. miscellaneous 2451 urol_v3_no2_001_editorial.qxd urology journal unrc/iua 110 urological survey african journal of urology the african journal of urology is the official journal of the pan african urological surgeons' association (pausa). this journal is a bilingual publication, accepting articles in english and french. the editor-in-chief of the african journal of urology is professor ismail m khalaf from egypt. you can find the website of this journal in the african journals online available from: http://www.ajol.info/index.php. here are the abstracts of the original articles in its current issue (2005, volume 11, number 4): results and predictors of success of vesico-vaginal fistula repair at a national reference level in rwanda hategekimana t, rwamasirabo e, banamwana r, van den ende j kigali hospital center, kigali, rwanda; national university of rwanda, butare and institute of tropical medicine, antwerp, belgium vol. 3, no. 2, 110-115 spring 2006 printed in iran objective: vesico-vaginal fistulas (vvf's) cause enormous harm to women in developing countries. this prospective study intends to highlight epidemiological, etiological and pathological data, and to define predictors of surgical results in a national referral hospital setting. material and methods: all consecutive patients with vvf presenting at the kigali hospital centre of rwanda between 1997 and 2001 were included. data on epidemiology, pathology, therapy and outcome were prospectively obtained. the risk factors for therapeutic failure were identified by multivariate analysis. results: ninety eight percent of all cases were of obstetrical origin. twenty five percent of vvf were categorized as simple, 64% as complex and 11% as complicated. complete closure and continence were obtained in 87 (77.7%) cases and closure with moderate incontinence in 7 cases (6.3%). in 18 cases (16%) closure failed even after 3 surgical attempts. the independent risk factors for therapeutic failure were vaginal fibrosis (p<0.001) and total destruction of the bladder neck (p=0.002). conclusion: we conclude that failure is basically linked to the level of destruction of the bladder neck as well as the magnitude of pelvic scarring. surgery of complex and complicated vvf remains a challenge and requires multiskilled surgeons. the lasting solution is the development of maternity services and the training of health personnel in reproductive health. african journal of urology 111 injuries encountered during rigid ureteroscopy in training centers mbibu nh, mourad m, khalaf i al-azhar university, cairo, egypt objective: to analyze the peroperative injuries encountered during ureterorenoscopy (urs) in two training centers in egypt over a four-month period. patients and methods: a prospective computerized database of 88 patients (38 males and 50 females) who underwent urs at two urologic university training centers (al-azhar university hospital, cairo and assiut university hospital, assiut, egypt) between july and october 2003 was analyzed. the procedures were elective in all cases. the indication for urs, the state of the ureter, associated pathologies, intraoperative injuries encountered and their management were recorded for analysis. results: all but seven patients were operated the effect of gum arabic oral treatment on the iron and protein status in chronic renal failure patients under regular hemodialysis in central sudan ali aa, khalid ke, ali ke university of gezira, wad medani, sudan objective: to assess the effect of gum arabic (acacia senegal) oral treatment on the iron and protein status in chronic renal failure patients. material and methods: thirty-six chronic renal failure (crf) patients (under regular hemodialysis), and 10 normal subjects participated in this study. the patients were randomly allocated into the following groups: group a (n=12): crf patients under low protein diet (lpd) (less than 40 gram/day), and gum arabic (50 g/day) treatment; group b (n=14): crf patients under lpd, gum arabic, iron (ferrous sulphate 200 mg/day) and folic acid (5 mg/day) treatment; group c (control group, n=10): crf patients under lpd, iron and folic acid treatment; group d (n=10): normal volunteers who were kept on normal diet beside a daily dose of 50 gm gum arabic. each of the above treatments was continued for three consecutive months. predialysis blood samples were collected from each subject before treatment, and twice per month for three months. hemoglobin (hb), hematocrit, total protein, albumin, globulin and 24-hour urine volume as well as serum iron, total iron-binding capacity (tibc),transferrin saturation, packed cell volume (pcv) and, mean corpuscular hemoglobin concentration (mchc) were determined. results: following administration of gum arabic oral treatment for three months, serum iron increased by 5.85% and 4.81% for groups a and b, respectively. these increases were significantly different from the baseline (p<0.05), and control group c (p<0.01). tibc was significantly decreased in group a (4.44%) and in group b (4.31%) as compared with the baseline and control group c (p<0.05). transferrin saturation was significantly increased by 7.77%, and 9.59% for groups a and b, respectively, compared with the baseline (p<0.05) and control group c (p<0.01). hb, pcv, mchc, serum total protein, albumin and globulin, and 24-hour urine volume showed no statistically significant differences from the baseline and control groups. conclusion: the improvement in iron status due to oral administration of gum arabic could reduce the need for oral iron prescription. urological survey112 scheduling tunneling turp in carcinoma of the prostate okeke li university college hospital, ibadan, nigeria objective: some patients with obstructing carcinoma of the prostate may fail to resume spontaneous voiding following bilateral orchidectomy. this group of patients would require an additional procedure in the form of limited transurethral resection of the prostate gland (tunneling turp) to be able to resume spontaneous voiding. the objective of this study was to compare performing simultaneous tunneling turp and bilateral orchidectomy on skin closure after groin hernia repair in children: a comparative study of three suture materials and two suture techniques osuigwe an, ekwunife cn, ihekwoba ch nnamdi azikiwe university teaching hospital, nnewi, nigeria objective: the surgical scar is of great importance both to the patient and surgeon. for the patient an ugly scar may not only present a cosmetic problem but in some cases it may also impair function, and the surgeon is always confronted with the problem of possible litigation. this study was undertaken to evaluate the effect of different suture materials and skin suture techniques on surgical scars. patients and methods: three suture materials (chromic catgut 3/0, silk 3/0 and nylon 3/0) and two skin closure techniques (transcutaneous interrupted mattress and subcuticular continuous running sutures) were compared in a randomized partially blinded fashion using a groin skin crease incision. the resulting scars were graded after two years using a conceived three-level scale. results: subcuticular nylon sutures gave the best cosmetic results followed by subcuticular chromic catgut. transcutaneous interrupted mattress silk sutures left the worst scars followed by subcuticular continuous running silk sutures. conclusion: the use of suture materials for skin closure is still the norm in developing countries. we therefore suggest that for any particular suture material, the subcuticular continuous running technique should be used and whenever possible the suture material of choice should be nylon. for therapeutic indications, mainly stone disease and ureteric strictures. peroperative injuries were encountered in 14 patients (15.9%) with the commonest type being mucosal laceration (57%) followed by minor ureteric perforations. major injuries in the form of ureteric avulsion, laceration and extravasation were noted in 2% of the cases. the procedure was associated with inadvertent bladder or urethral injury in three patients. in all cases the diagnosis of the ureteric injury was prompt and confirmed by intraoperative ureterography. treatment was started immediately. conclusion: urs, although an important tool in the management of upper tract pathology, is an invasive procedure, especially for therapeutic indications. it may result in significant complications that may jeopardize the integrity of the concerned renal unit. recent technology in the design of ureteroscopes and their accessories may minimize injuries, especially if applied in teaching hospitals where the learning curve of urs is a demanding task. african journal of urology 113 the artificial urinary sphincter in the male a study of 23 cases karra h, safai k, dargent f, colombeau p fleyriat hospital, paris, france objectives: to evaluate our experience with the placement of artificial urinary sphincters and to review the literature about the indications, additional measures required and prognosis of the device. patients and methods: this retrospective study was based on 23 male patients who received artificial urinary sphincters of the ams 800 type at the university hospital of dupuytren, limoges, between april 1996 and april 2005. the mean age of our patients was 70.3 years (range 47 to 77 years). eight patients had been treated previously by pelvic radiotherapy for prostate cancer. sphincter insufficiency occurred following radical prostatectomy in 10, endoscopic resection of a prostatic adenoma in 5, transvesical adenectomy in 4 and endoscopic sphincterotomy with bladder augmentation in 2 patients, as well as following external radiotherapy for the treatment of a localized prostatic adenocarcinoma stage t2a in one and a cystoprostatectomy with camey ii type bladder replacement in the remaining case. routine investigations included urine analysis, assessment of a possible concomitant inflammation or infection, urethroscopy and a urodynamic work-up. pelvic floor training was done in all cases, while macroplastique was administered in 15 cases only. finally, an artificial sphincter was placed in periurethral position in all cases. results: the functional results of the artificial sphincter were assessed 6 months after activation of the sphincter and were based on the clinical results as well as on the patient's satisfaction. eighteen out of our 23 patients are completely satisfied, while the 5 remaining patients report minimal urinary leakage. one of them reported a reduction of urinary flow. in 9 cases late complications were noted; three of them could be easily repaired (a technical problem caused by high pressure in the balloon, one minimal vesicoparietal fistula and migration of the pump needing reposition). the 6 remaining cases suffered from urethral erosion caused by the cuff of the device which incurred within a mean time of 5 years following the placement of the artificial sphincter. conclusion: the high rate of satisfaction reported by the patients has proved the efficacy of the ams 800 artificial sphincter in the treatment of urinary incontinence caused by sphincteric insufficiency. nevertheless, a number of failures is still reported. they may cause severe complications eventually leading to the removal of the device, especially in cases of erosion. for this reason, it is mandatory to respect the indications, to carefully select the patients and to ensure an adequate follow-up to avoid any late complications. one hand with deferring channel turp for at least one month after bilateral orchidectomy in cases where the patient has failed to resume spontaneous voiding on the other. patients and methods: forty-seven patients with obstructing carcinoma of the prostate were studied. group i consisted of 22 patients who had simultaneous bilateral orchidectomy and tunneling turp of the prostate, while group ii consisted of 25 patients who had tunneling turp at least one month after bilateral orchidectomy. the groups were compared with regard to the ease of operation and postoperative management. results: intra-operative bleeding, the need for repeated cleaning of the resection loop, the operating time and the hospital stay were significantly less in group-ii patients compared to group i. conclusion: the results suggest that tunneling turp when performed at least one month after bilateral orchidectomy allows enough time for a significant reduction of tissue friability, tissue adhesion to the resection loop, tumor circulation, intra-operative bleeding, operating time and postoperative hospital stay. urological survey114 abscess of the psoas: diagnostic and therapeutic aspects moudouni ms, dahami z, hocar o, gabsi m, boukhari m, barjani f, elhaous a, lakmichi ma, sarf i marrakech, maroc objective: abscess of the psoas which was first described by mynter in 1881 is a rare disease. herein, the authors report on their experience with the treatment of this pathology. patients and methods: between januar 1999 and december 2002, 15 patients with abscess of the psoas were seen at our department. they were 12 males (80%) and 3 females (20%) with a mean age of 53 years (range: 27 70 years). mean hospital stay was 6 weeks (range: 2 24 weeks). all patients were examined by abdominal ultrasonography, 9 by computed tomography. surgical drainage via a small incision of 5 cm was done in 12 patients, while three patients received medical treatment in combination with a percutaneous drainage. results: the clinical manifestation included fever in 9 (60%), psoitis in 6 (40%), a mass in the lumbar region in 5 (33%) and an inguinal mass in 3 (20%) patients. hyperleucocytosis varying between 13000 and 340000/mm3 was found in all patients. the main organisms isolated were staphylococcus aureus (54%), koch's bacillus (38.4%), escherichia coli (15%) and klebsiella (8%). de novo abscess of the psoas was found in 4 patients (26.6%), while it was secondary in 11 study of erectile dysfunction in a population of young and sexually active men in burkina faso kambou t, zango b, fongang c, sombie i, dao b objective: this study was carried out among a young population of working men to determine the prevalence of erectile dysfunction (ed) in our environment and to evaluate the patients' knowledge about and attitude towards this problem. patients and methods: this study was based on a survey carried out on male subjects aged 18 and above over a period of six months. the survey was done during an annual medical checkup of men working in local companies and some civil servants. those who agreed to participate in the investigation (855 men), had to complete two questionnaires: the 5-item questionnaire of the international index of erectile function (iief-5) evaluating the quality of erectile function and a questionnaire drawn up by our team with the aim of evaluating the participants' knowledge about and their attitude towards the problem of ed. the questionnaires were analyzed using the epi info program. results: the 855 subjects that took part in the investigation accounted for 80% of all men that had been asked to participate in the survey. the average age was 37.4 ± 9.1 years; more than two thirds of the participants (78%) were married and 69% were monogamous. the overall prevalence of ed was 47% and we noticed that it increased with age. three risk factors were identified: age, arterial hypertension and hemorrhoidal disease. age and arterial hypertension are classic risk factors for ed, while hemorrhoidal disease has so far not been considered as such. in our study, especially for the men interviewed, it has played an important role. 93.2% of the questioned subjects said that they would be ready to consult for ed, whereas in fact only 3.8% had taken medical advice. conclusion: ed appears to be a real problem, also for younger men, in our environment. however the results of this study cannot be generalised, and we are planning to undertake other studies based on the general population which will allow us to draw more valid conclusions and to better organize treatment of these patient. african journal of urology 115 patients (73.3%). surgical drainage of the pus was done via the anterolateral extraperitoneal lumbar approach in 8 patients and via the high inguinal approach in 4 patients. in three patients medical treatment combined with percutaneous drainage was sufficient. the immediate outcome was good in all patients. conclusion: the pathogenesis of de novo abscess of the psoas is unknown as yet, and its diagnosis remains a challenge for the physician. however, the precise clinical diagnosis and the choice of the therapeutic measures have been facilitated by the development of modern imaging facilities. surgical treatment should be reserved to those cases where percutaneous drainage has failed. editprial comments re: erectile dysfunction is positively correlated with mean platelet volume and platelet count, but not with eosinophil count in peripheral blood penile erection is a vascular phenomenon, and blood flow via the small vessels of the penis is very dependent to their structural and functional changes. instead of being thought of as a late result of a localized vascular disease, vasculogenic erectile dysfunction (ed) is nowbeginning to be considered an initial sign of generalized vascular disease. the diagnosis of ed and the succeeding assessment of underlying cardiovascular risk could improve general preventive procedures of vascular health in men. erectile dysfunction (ed) is now documented as a marker of greater cardiovascular risk both acutely and chronically and regarded as an early indicator of widespread vascular disease predicting all-cause mortality, cardiovascular mortality, coronary artery diseases (cad), stroke, and peripheral artery disease in men with and without known cad.(1) notably, ed shares with cad similar risk factors and is principally vasculogenic, demonstrating the common source of endothelial dysfunction.(2) vlachopoulos and colleagues(3) have over several years examined the independent link between ed and cardiovascular disease (cvd) using some biomarkers as a means of detecting the men most at risk of a cvd. they evaluated 92 757 subjects and found that ed was correlated with increased cvd and all-cause mortality. the most recent review by gandaglia and colleagues(4) who carried out a systematic review of the relationship between ed and cvd reported that ed and cvd should be considered as 2 different signs of the same systemic disease with ed usually foregoing cvd, and ed should, then, be regarded as an early marker for cvd of precise significance in the asymptomatic younger men and in those with diabetes mellitus. there is no uncertainty that the men with ed aged 30 to 60 years are at higher risk of having undiagnosed silent cad, and it might well be that a combination of biomarkers, vessels wall stiffness, and multidetector cardiac computed tomography is the best modality to evaluate these individuals. it remains vital because the risk is investigated to prompt the cardiologist in particular that it is within their responsibility, and the general physician who detects a patient with ed (asking routinely) should immediately order an assessment of cardiovascular risk system even once symptoms of a cvd are not existing. with the acknowledgement that endothelial dysfunction is the common contributing factor linking vascular disease to ed came the understanding that ed may not just be a result of vascular disease, particularly cad, but a harbinger of silent coronary disease-‘a sentinel’.(6) moderate-to-severe but not mild ed in a health screening research was considered to increase the 10 year relative risk of developing cad by 65% and stroke by 43%.(7) all men with ed and no cardiac symptoms require a detailed cardiac investigation. we should consider of ed as standing for erectile dysfunction, endothelial dysfunction, and early detection. the common denominator for these speciously different problems is endothelial dysfunction, a principal etiology of ed.(8) in this issue of the urology journal, otunctemur and colleagues have reported for the first time a study of 130 patients with ed. they matched these patients with a control group of normal subjects (n = 100) without clinical evidence of arterial disease and without ed and searched for mean platelet volume (mpv), and platelet count (pc). they found that mpv and pc levels were significantly higher in ed group. an interesting finding in this study is that patients with higher pc (or = 1.005; 95% ci: 1.003-1.010) and mpv (or = 1.256; 95% ci: 1.088-1.4) had increased risk for development of ed. mpv has developed in recent years asa potential independent risk factor for poor clinical outcomes in patients with cad.(9,10) because mpv is an indicator of platelet activation and associates with agreeability, larger and hyperactive platelets can speed up the development of intra coronary thrombus and thus play avital role in the pathophysiology of vascular artery disease. in recent years, the idea of mpv as a predictor of an hostile prognosis in acute coronary syndromes was extensively studied, with encouraging results.(11) if such an impressionis valid, then mpv might be a smart prognostic factor, as it is routinely measured as a part of the complete blood cell count (cbc).measurement of mpv is fast, cheap, and widely available for all physicians. despite the broad evidence mentioned above, mpv measurement in clinical practice is hampered by several pitfalls. first, it must be emphasized that of all blood cells, platelets are the most fragile components. it is known that platelet volume increases after blood drawing, particularly in ethylenediaminetetraacetic acid (edta)-coatedtubes.(12) previous investigations also have not yielded us with a consistent cut-off value. the threshold value in researches was usually derived ad hoc using receiver operating characteristic (roc) curves; less often, it was derived from values in healthy volunteers. according to my knowledge, it varies from 8.9 to 11.5 fl.(13,14) furthermore, there is a lack of data in specific populations, such as patients later after acute coronary syndrome, where the thrombotic risk is lesser than in the acute phase. only few researches have focused on such peoples and many of them initiated in the thrombolytic era.(15) the study of otunctemur and colleagues published in this issue of the urology journal provides us imperative data about the correlation of mpv to increased incidenceof ed. in logistic regression analysis, the mpv was mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specializing in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com. vol 12 no 05 september-october 2015 2353 confirmed to be the only independent predictor of ed incidence. i would like to highlight the amazing fact that traditional risk factors of ed, such as age, serum lipid profile, hypertension, body mass index (bmi) or diabetes mellitus, did not have any significant impact on ed incidence. unfortunately, these results were not completely analyzed or discussed by the authors; therefore, the implication of their findings in clinical practice is difficult. if these data will be confirmed in further studies, a rigorous study for underlying mechanisms is needed. thus, the key point is whether routine measurement of mpv on admission could alter our clinical management, as “statistically significant” does not necessarily imply “clinically significant.” hence, could the blood level of mpv guide our clinical practice? or, is it merely a "population" prognosis indicator lacking of "individual" clinical impact? unfortunately, there is no further study, and these questions cannot be responded to yet; therefore, further studies are required to find the importance of mpv measurement in the clinical evaluation of patients with ed. overall, the study of otunctemur and colleagues offersfurther evidence about the value of mpv measurement in risk stratification of patients with ed. regardless of all controversies, mpv measurement should not be ignored as a marker of impairedprognosis of patients with ed. congratulations to authors for their excellent work! reerences 1. nehra a, jackson g, miner m, et al. the princeton iii consensus recommendations for the management of erectile dysfunction and cardiovascular disease. mayo clin proc. 2012;87:766-78. 2. solomon h, man jw, jackson g. erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. heart. 2003;89:251-3. 3. vlachopoulos cv, terentes-printzios dg, ioakeimidis nk, aznaouridis ka, stefanadis ci. prediction of cardiovascular events and all-cause mortality with erectile dysfunction: a systematic review and meta-analysis of cohortstudies. circ cardiovasc qual outcomes. 2013;6:99-109. 4. gandaglia g, briganti a, jackson g, et al. a systematic review of the association between erectile dysfunction and cardiovascular disease. eur urol. 2014;65:968-78. 5. jackson g. erectile dysfunction: a marker of silent coronary artery disease. eur heart j. 2006;27:2613-4. 6. montorsi f1, briganti a, salonia a, et al. erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. eur urol. 2003;44:360-4. 7. ponholzer a, temml c, obermayr r, wehrberger c, madersbacher s. is erectile dysfunction a n i n d i c a t o r f o r i n c r e a s e d r i s k o f coronary heart disease and stroke? eur urol. 2005;48:512-8. 8. levine la, kloner ra. importance of asking questions about erectile dysfunction. am j cardiol. 2000;86:1210-3. 9. azab b, torbey e, singh j, et al. mean platelet volume/platelet count ratio as a predictor of long term mortality after non-st-elevation myocardial infarction. platelets 2011;22 :55766. 10. tekbaş e, kara af, ariturk z, et al. mean platelet volume in predicting short and longterm morbidity and mortality in patients with or without st-segment elevation myocardial infarction. scand j clin lab invest. 2011;71:613-9. 11. chu sg, becker rc, berger pb, et al. mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. j thromb haemost. 2010;8:148-56. 12. bath pm, butterworth rj. platelet size: measurement, physiology and vascular disease. blood coagul fibrinolysis. 1996;7:157-61. 13. jakl m, sevcik r, ceral j, fatorova i, horacek jm, vojacek j. mean platelet volume and platelet count: overlooked markers of high ontreatment platelet reactivity and worse outcome in patients with acute coronary syndrome. anadolu kardiyol derg. 2014;14:85-6. 14. taglieri n, saia f, rapezzi c, et al. prognostic significance of mean platelet volume on admission in an unselected cohort of patients with non st-segment elevation acute coronary syndrome. thromb haemost. 2011;106:13240. 15. burr ml, holliday rm, fehily am, whitehead pj. haematological prognostic indices after myocardial infarction: evidence from the diet and reinfarction trial (dart). eur heart j. 1992;13:166-70. editorial comment 2354 miscellaneous effect of different times of intraperitoneal injections of human bone marrow mesenchymal stem cell conditioned medium on gentamicin-induced acute kidney injury purpose: this study examined the effect of mesenchymal stem cells’ conditioned media on the severity of acute kidney injury. materials and methods: acute kidney injury was induced in male rats with 100 mg/kg of gentamicin for six consecutive days intraperitoneally. after inducing the standard model of acute kidney injury, the conditioned medium of 5 × 106 cells was calculated for each kilogram of body weight of the rats. then, it was injected in three different injection patterns other than the baseline injection of gentamicin. the rats were randomly divided into four groups: control group (n = 18) that did not receive any treatment, gentamicin group (n = 18) that received gentamicin at a dosage of 100 mg/kg for six consecutive days intraperitoneally, sham group (n = 54) that received gentamicin for six consecutive days, and an experimental group (n = 54) that received gentamicin for six consecutive days. serum biochemical analysis and histological changes were studied and analyzed in all groups. results: although human mesenchymal stem cells’ conditioned media did not improve serum and tissue markers in the treatment groups, a relative improvement was observed in some indicators of tissue damage. conclusion: secretory factors of human mesenchymal stem cells can be partly protective against gentamicin-induced nephrotoxicity. keywords: acute kidney injury; gentamicin; mesenchymal stem cells; conditioned culture media; secretory factors. introduction as a common and grave illness with a high mor-tality rate, acute kidney injury is caused by toxic or ischemic insult from chemotherapy, antibiotics, or shock occurring from infection or major surgery. acute kidney injury can lead to dysfunction and apoptosis/ necrosis of renal tubular epithelial cells, in addition to a loss of renal endothelial cells.(1) acute kidney injury occurs in 1% of hospital admissions. up to 7% of hospitalized patients develop acute kidney injury.(2) moreover, around 25% of patients in the intensive care unit develop acute kidney injury and 5% of them require kidney replacement therapy.(2,3) despite the use of modern dialysis techniques, such as intermittent or continuous kidney replacement therapy and kidney transplantation,(4,5) the syndrome still has a high mortality and morbidity rate.(4) however, kidney transplantation is hampered by shortage of donors. dialysis is lifesaving and the main treatment in these patients, but it has several limitations. it is not a complete kidney replacement therapy and is associated with several socio-economic problems for the patients. hence, it 1 kharazmi university, tehran, iran. 2 department of animal biology, kharazmi university, tehran, iran. 3 department of pathology, tehran university of medical sciences, tehran, iran. *correspondence: department of animal biology, kharazmi university, tehran, iran. tel:+98 21 77001185. fax:+98 21 77001185. e mail: abedi.masoomeh93@gmail.com. received september 2015 & accepted april 2016 is imperative to accelerate the understanding of underlying causes of acute kidney injury and to develop new interventional and therapeutic modalities.(6) in recent years, much attention has been focused on the plasticity of bone marrow-derived mesenchymal stem cells (mscs).(7-9) however, systemic administration of mscs has resulted in remarkable functional improvements in injured tissues without either long-term engraftment or differentiation in many clinical and experimental situations.(10) moreover, improvements of injured tissues take place too rapidly to be explained by differentiation of mscs. the emerging evidences suggest that most of the beneficial effects could be explained by secretion of therapeutic factors that have multiple effects, including modulation of inflammatory and immune reactions, protection from cell death, and stimulation of endogenous progenitor cells.(11) moreover, it has been shown that mscs secrete a large number of cytokines under normal culture conditions.(12) more importantly, they can be activated to express high levels of additional therapeutic factors by cross-talk with injured cells or microenvironments.(13) azam abedi 1*, mahnaz azarnia2 , mansor jamali zahvarehy3, tahereh foroutan2 , sara golestani1 miscellaneus 2707 based on these evidences, it has been hypothesized that for protection against kidney failure, direct transplantation of stem cells is not necessary and administration of the conditioned media of the cells may also be effective. (14) gentamicin as an aminoglycoside drug can induce renal tubular cell injury such as derangement of lysosomal, mitochondrial, and plasma membrane structure. it has been shown that gentamicin-induced nephrotoxicity is characterized by direct tubular necrosis, which is localized mainly in the proximal tubule. in this study we evaluated the therapeutic effects of conditioned media derived from human mscs (hmscs) in animal models of gentamicin-induced kidney failure. materials and methods a total number of 144 adult male wistar albino rats weighting 180-220 grams were housed under standard laboratory conditions (12 hours of light/dark cycles) in a room with controlled temperature (24 ± 3°c) during the experiment. they were provided from a local veterinary research institute. the rats were housed in plastic cages under standard conditions with free access to drinking water and basic diet. all experimental procedures were conducted in accordance to the guide of care and use of laboratory animals. human mscs were isolated from aspirate samples in the laboratory according to fiedler and fickert’s procedure using ficoll (sucrose concentration gradient). the isolated bone marrow mscs were transferred to dulbecco's modified eagle's medium (dmem) containing 10% fetal bovine serum and 1% penicillin-streptomycin. after the incubation time, the cell supernatant was used for the treatment of animals. each animal was injected per kilogram of body weight with conditioned medium derived from 5×106 cells intraperitoneally. these amounts were injected at three equal volumes for three consecutive days. design model of acute kidney injury firstly, an experiment was designed to achieve a standard animal model. a group of six rats received no injection as the control group. ten rats (with six times table 1. the study groups and their treatments. group name subgroups no. of animals procedure of injection control group ---- 18 no injection gentamicin group ---- 18 gentamicin was injected at a dosage of 100 mg/kg for six consecutive days non-conditioned media group a. sham 1 54 (gentamicin was injected at a dosage of 100 mg/kg for six consecutive days) + b. sham 2 (ncm injection for three consecutive days with three of d. sham 3 different injection patterns than the injection of gentamicin) experimental group a. experimental 54 (gentamicin was injected at a dosage of 100 mg/kg for six consecutive days) + b. experimental 2 (conditioned medium for three consecutive days with three of different d. experimental 3 injection patterns than the injection of gentamicin) abbreviation: ncm, non-conditioned medium. abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell parietal cells of tubules are normal and there is no injury. + there is acute kidney injury in less than one-third of the tubules. ++ there is acute kidney injury in one-third to two-thirds of tubules. +++ there is acute kidney injury in more than two-thirds of the tubules. groups acute cell swelling necrosis tubules aggregation inflammatory cells glomerular injury hyaline cast control genta (models group) +++ +++ + + ++ genta + medium (a) +++ +++ + + ++ genta+ cm (a) +++ +++ + genta+ medium (b) +++ +++ + + ++ genta+ cm (b) ++ ++ + genta+ medium (d) +++ +++ + + ++ genta+ cm (d) ++ +++ + + ++ table 2. the cm-hmsc impact on changes of renal tissue on the third day of review. intraperitoneal injections of hmscs in aki-abedi et al. vol 13 no 03 may-june 2016 2708 repetition) were in the second group. they received 100 mg/kg of gentamicin for six consecutive days intraperitoneally. every day one rat was anesthetized for blood collection from the heart. creatinine and blood urea nitrogen levels were studied for ten days by obtained peak day of the gentamicin effect in the period. the highest proportion of urea in respect to creatinine was on the 3rd and 5th days to determine the peak day of gentamicin effect. for further investigate, the 8th day was added to the study. experimental design the animals were randomly divided into four groups in order to study the effect of conditioned medium-derived mscs on the disease process. finally, on the 3rd, 5th and 8th days after gentamicin injection, kidney and blood samples of all rats were collected for histological and biochemical analysis. study groups the study groups were as follows (table 1): 1) control group (n = 18) that did not receive any treatment, 2) gentamicin group (n = 18) that received gentamicin at a dosage of 100 mg/kg for six consecutive days intraperitoneally, 3) sham group that received gentamicin for six consecutive days as well as non-conditioned medium in equal injection volume to the experimental group intraperitoneally for three consecutive days. this group was divided into three subgroups as follows (n = 18 for each sub-group): a. sham 1: non-conditioned medium injection began simultaneously with gentamicin injection. b. sham 2: non-conditioned medium injection began one day before gentamicin injection. d. sham 3: non-conditioned medium injection began one day after gentamicin injection. 4) experimental group that received gentamicin for six consecutive days as well as hmsc conditioned media intraperitoneally for three consecutive days. this group was also divided into three subgroups as follows (n = 18 for each sub-group): a. experimental 1: hmsc conditioned media injection began simultaneously with gentamicin injection. b. experimental 2: hmsc conditioned media injection began one day before gentamicin injection. intraperitoneal injections of hmscs in aki-abedi et al. figure 1. gentamicin significantly increased the concentration of serum cr (mg/dl) on the second, third, fourth, fifth, sixth, seventh and eighth days after injection compared with the control group. (a: p < .001) (b: p < .01) (c: p < .05) (n = 6). figure 2. verification induction of the animal model in acute renal disease through the analysis amount of changes in concentration bun (mg/dl) of blood serum ten days after gentamicin injection compared with the control group. (a: p < .001) (b: p < .01) (c: p < .05) (n = 6). figure 3. effect of cm-hmsc on the amount of serum concentrations bun (mg/dl) in the experimental group (a) compared with the model group. (***p < .001) (*p < .05) (n = 6). abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell. figure 4. effect of cm-hmsc on the amount of serum concentrations cr (mg/dl) in the experimental group (a) compared with the model group. cm-hmsc had no significant decrease is in the amount of serum concentrations cr (mg/dl) in animals treated on the third, fifth, and eighth days in the experimental group (a) compared with the model group. (***p < .001) (*p < .05) (n = 6). abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell. miscellaneus 2709 d. experimental 3: hmsc conditioned media injection began one day after gentamicin injection. measuring kidney’s functional indices on the 3rd, 5th and 8th days after gentamicin injection, all groups were anesthetized with a solution of ketamine-xylazine. blood samples were taken from the heart and kidneys after dissecting the body. they were washed with saline and placed in 10% formalin. the collected blood samples were centrifuged and the serum was separated and analyzed for serum creatinine and blood urea nitrogen. four-micron sections were prepared from kidney samples and stained with hematoxylin and eosin. in the prepared slides, acute cell swelling, necrosis tubules, aggregation inflammatory cells, glomerular injury, and hyaline cast were evaluated by light microscopy and all tissue injuries were scored from (-) to (+++) for each kidney.(14) briefly, random cortical and medulla fields were analyzed using a × 40 objective light microscopy. to evaluate the degree of acute cell swelling and necrosis tubules, 150 tubules were counted in the cortical of each kidney randomly: (-) = parietal cells of the tubules were normal and there were no acute cell swellings and necrosis tubules; (+) = there were acute cell swelling and necrosis tubules in less than one-third of the tubules; (++) = there were acute cell swelling and necrosis tubules in one-third to two-thirds of tubules; (+++) = there were acute cell swelling and necrosis tubules in more than two-thirds of the tubules. for scoring the degree of glomerular injury, 15 glomeruli were counted in the cortical of each kidney randomly: (-) = glomeruli were normal and there were no swelling, enlargement and lower urinary space; (+) = there were swelling, enlargement and lower urinary space in less than one-third of the glomeruli; (++) = there were swelling, enlargement and lower urinary space in onethird to two-thirds of the glomeruli. (+++) = there were swelling, enlargement, and lower urinary space in more than two-thirds of the glomeruli. to evaluate the aggregation of inflammatory cells, 10 microscopic fields were counted in the cortical of each kidney randomly: (-) = there were no aggregated inflammatory cells in the space of between the tubules; figure 5. effect of cm-hmsc on the amount of serum concentrations bun (mg/dl) in the experimental group (b) compared with the model group. (***p < .001) (**p < .01) (*p < .05) (n = 6). abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell. figure 6. effect of cm-hmsc on the amount of serum concentrations cr (mg/dl) in the experimental group (b) compared with the model group. cm-hmsc had no significant decrease in the amount of serum concentrations bun (mg/dl) on the third and fifth days in the experimental group (b) compared with the model group. (***p < .001) (*p < .05) (# # #p < .001) (n = 6). abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell. figure 7. effect of cm-hmsc on the amount of serum concentrations bun (mg/dl) in the experimental group (d) compared with the model group. cm-hmsc had no significant decrease is in the amount of serum concentrations bun (mg/dl) in animals treated on the third, fifth, and eighth days in the experimental group (d) compared with the model group (***p < .001) (n = 6). abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell. intraperitoneal injections of hmscs in aki-abedi et al. vol 13 no 03 may-june 2016 2710 (+) = there were aggregated inflammatory cells in less than one-third space between the tubules; (++) = there were aggregated inflammatory cells in one-third to twothirds space between the tubules; (+++) = there were aggregated inflammatory cells in more than two-thirds space between the tubules. finally, to evaluate hyaline casts, 10 microscopic fields were counted in the medulla of each kidney randomly: (-) = there was no casts in the tubules; (+) = there were casts in less than one-third of the tubules; (++) = there were casts in one-third to two-thirds of the tubules. (+++) = there were casts in more than two-thirds of the tubules. statistical analysis the statistical analysis was carried out using statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. the differences between groups were analyzed by one-way variance analysis (anova) and dunnett's test. p value less than .05 was considered as statistically significant. results creatinine and blood urea nitrogen were the most important serum markers in diagnosis of acute kidney injury. biochemical serum analysis of the studied animals showed that creatinine and blood urea nitrogen increased significantly in rats that were treated with 100 mg/kg dosage of gentamicin for six days. gentamicin significantly increased the concentration of serum creatinine and blood urea nitrogen in the 2nd to 8th days after injection. the most significant difference (p < .001) was on the 3rd and 5th days compared to the control group (figures 1 and 2). considering that the of table 3. the cm-hmsc impact on changes of renal tissue on the fifth day of review. groups acute cell swelling necrosis tubules aggregation inflammatory cells glomerular injury hyaline cast control genta (models group) ++ ++ + + + genta + medium (a) ++ ++ + + + genta+ cm (a) ++ ++ + + + genta+ medium (b) ++ ++ + + + genta+ cm (b) + ++ + genta+ medium (d) ++ ++ + + + genta+ cm (d) ++ ++ + + + abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell. parietal cells of tubules are normal and there is no injury. + there is acute kidney injury in less than one-third of the tubules. ++ there is acute kidney injury in one-third to two-thirds of tubules. +++ there is acute kidney injury in more than two-thirds of the tubules. groups acute cell swelling necrosis tubules aggregation inflammatory cells glomerular injury hyaline cast control genta (models group) ++ +++ + + ++ genta + medium (a) ++ +++ + + ++ genta+ cm (a) + ++ + + ++ genta+ medium (b) ++ ++ + + ++ genta+ cm (b) genta+ medium (d) ++ +++ + + ++ genta+ cm (d) ++ +++ + + ++ abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell. parietal cells of tubules are normal and there is no injury. + there is acute kidney injury in less than one-third of the tubules. ++ there is acute kidney injury in one-third to two-thirds of tubules. +++ there is acute kidney injury in more than two-thirds of the tubules. table 4. the cm-hmsc impact on changes of renal tissue on the eighth day. intraperitoneal injections of hmscs in aki-abedi et al. miscellaneus 2711 highest levels of blood urea nitrogen, creatinine and the ratio between the two were three days after injection of gentamicin during the ten-day period of study, this day was the acute phase of the disease. blood urea nitrogen and creatinine are the most important pathological indicators of acute kidney injury. measuring serum concentration of waste products is their most common detection method. hence, biochemical analysis of this material was done on collected serum of the studied animals. our results showed that after intraperitoneal injection of hmsc conditioned media for three consecutive days and simultaneous with the beginning of gentamicin injection, no significant decrease was seen in the 3rd, 5th and 8th days in blood urea nitrogen and creatinin(mg/ dl) levels of the rats in the sub-group a of the experimental group compared to the gentamicin group (figures 3 and 4). intraperitoneal injection of hmsc conditioned media for three consecutive days and 24 hours before injecting gentamicin had no significant effect in the 3rd, 5th and 8th days in the experimental group (sub-group b) compared to gentamicin (figure 5). no significant decrease was seen in the creatinine of blood serum in the 3rd and 5th days in blood urea nitrogen levels of the rats in the experimental group (sub-group b) compared to the gentamicin group. but on the 8th day the level of creatinine (0.68 mg/dl) decreased significantly (p < .001) in sub-group b of the experimental group compared to the gentamicin group (0.63 mg/dl) (figure 6). intraperitoneal injection of hmsc conditioned media for three consecutive days and 24 hours after injection of gentamicin had no significant effect on the amount of blood serum concentrations of blood urea nitrogen (mg/ dl) and creatinine (mg/dl) in the 3rd, 5th and 8th days in sub-group d of the experimental group compared to gentamicin group (figures 7 and 8). histological study of the kidney histological analysis is very efficient for evaluating kidney damage. damage induced by gentamicin occurs mainly in the proximal tubule(15) which is the golden key in the diagnosis of acute kidney injury. in this study, the accuracy of inducing acute kidney injury was examined with preparing sections from the tested kidneys of the figure 8. effect of cm-hmsc on the amount of serum concentrations cr (mg/dl) in the experimental group (d) compared with the model group. (***p < .001) (*p < .05) (n = 6). abbreviations: cm, conditioned medium; hmsc, human mesenchymal stem cell. figure 9. verify the induction of acute kidney injury by histological analysis of the kidney of tested animals: light microscopic image of kidney tissue of animals receiving gentamicin (model), renal tubular necrosis (yellow marker), acute cellular swelling (red marker), accumulation of inflammatory cells (orange marker) and glomerular injury (black marker) in the renal cortical (left figure), and also hyaline cysts (green marker) be clearly visible in the renal medulla (right figure). intraperitoneal injections of hmscs in aki-abedi et al. vol 13 no 03 may-june 2016 2712 animals. the results showed that a dosage of 100 mg/kg of gentamicin for six days causes renal tubular necrosis, acute cellular swelling, accumulation of inflammatory cells, hyaline cysts glomerular injury, all of which are symptoms of acute kidney injury (figure 9). in contrast, the kidney tissue of control animals was normal and free from damage. the impact of hmsc conditioned media on the changes of kidney tissue on the 3rd day to assess the protective effect of hmsc conditioned media on the 3rd day, the kidney tissues were examined in all groups three days after the gentamicin injection. microscopic analysis (with h & e staining) showed that the kidneys of animals in the control group were completely normal and there was no tissue damage. however, kidneys in the gentamicin group had acute cellular swelling, renal tubular necrosis, and accumulation of inflammatory cells in the space between the tubules, hyaline cysts, and glomerular injury. the subgroup a of the experimental group showed no change in the rate of renal tubular necrosis, acute cellular swelling, and accumulation of inflammatory cells. however, glomerular damage and hyaline cysts was reduced. the amount of acute cellular swelling, renal tubular necrosis, hyaline casts, and glomerular injury was reduced in sub-group b of the experimental group compared to the model group. but no change occurred in the rate of accumulation of inflammatory cells. evaluation of tissue damage in sub-group d of the experimental group only showed a slight reduction in the acute cellular swelling. no further reduction was visible in the amount of tissue damages in this group compared to the model group (table 2). the impact of hmsc conditioned media on the changes of kidney tissue on the 5th day to assess the protective effect of hmsc conditioned media on the 5th day, the kidney tissues were examined in all groups five days after gentamicin injection and staining with h & e. the kidneys of the control group were normal like the 3rd day and there was no tissue damage. however, kidneys in the gentamicin group had acute cellular swelling, renal tubular necrosis, and accumulation of inflammatory cells in the space between the tubules, hyaline cysts, and glomerular injury. the results of sub-groups a and d of the experimental group did not show any changes in the amount of tissue damage compared to the model group. in the sub-group b of the experimental group a significant reduction was seen in the amount of acute cellular swelling, glomerular damage and hyaline cysts in urine-collecting tube compared to the model group (table 3). the impact of hmsc conditioned media on the changes of kidney tissue on the 8th day to assess the protective effect of hmsc conditioned media on the 8th day, the kidney tissues were examined in all groups eight days after the gentamicin injection. microscopic analysis (with h & e staining) showed that the kidneys of animals in the control group were completely normal. however, kidneys in the gentamicin group had acute cellular swelling, renal tubular necrosis, accumulation of inflammatory cells in the space between the tubules, hyaline cysts, and glomerular injury. the sub-group a of the experimental group showed a slight reduction in the rate of acute cellular swelling and no improvement was observed in other cases of tissue damage. in sub-group d of the experimental group all signs of tissue injuries were observed without any improvement in the kidney tissue. this showed that hmsc conditioned media has no protective effect against acute kidney injury. the results of sub-group b of the experimental group showed a significant decrease in the extent of tissue injury criteria measured in this study, indicating hmsc conditioned media has protective effects against acute kidney injury (table 4). discussion according to some previous studies the culture of mscs have protective effects on animal models with acute kidney injury.(16) although the culture of mscs led to restoration of some tissue damage parameters in the days after the injection of gentamicin in the experimental group, almost no significant effect was observed in reducing serum chemical biomarkers on the studied days (except in sub-group b of the experiment group on the 8th day). aminoglycoside antibiotics are widely used in treating many infections produced by gram-negative bacteria and bacteria endocarditis.(17) a relatively large amount (about 10%) of the intravenously administered dosage is accumulated in the kidney, whereas little distribution of aminoglycosides into other tissues is observed. (18) the tubular toxicity of gentamicin has two aspects: (i) the death of tubular epithelial cells associated with a very important inflammatory component and (ii) the nonlethal, functional alteration of key cellular components involved in water and solute transport. indeed, the gentamicin-induced necrosis and apoptosis in the tubular epithelial cells, decreases tubular function, and dysfunctional reabsorption process of water and electrolytes. growth factors derived from msc contain high levels intraperitoneal injections of hmscs in aki-abedi et al. miscellaneus 2713 of vascular dilation. prostaglandins lead to vasodilatation and increased kidney blood and glomerular filtration rate. therefore, mscs can increase glomerular filtration rate, and consequently decrease the creatinine and urea levels.(19) in our study, no significant reduction was seen in serum biomarkers (except on the 8th day in sub-group b of the experimental group). in this study we could see some improvement in histological parameters. sub-group b of the experimental group showed the highest restoration rate compared to the other two groups. also, the simultaneous injection of hmsc conditioned media with gentamicin was more effective than the injection of hmsc conditioned media one day after starting gentamicin injection. parekkadan and colleagues showed the presence of vascular endothelial and hepatocyte growth factors and other anti-apoptotic molecules in msc conditioned medium.(20) they stated that bioactive molecules can lead to increased survival of the recipient animals.(20) gheisari and colleagues assessed the therapeutic effect of conditioned media of mouse bone marrow mscs and human umbilical cord blood somatic stem cells on acute kidney injury.(14) indeed they could not confirm the beneficial effects of msc conditioned medium in decreasing blood urea nitrogen and creatinine in acute kidney injury. some previous studies have identified that administration of growth factors before and after kidney damage in animal models improves the damage and its healing. this might be because of its anti-apoptotic effects.(21,22) human mscs conditioned media activate the pathway of phosphatidylinositol protein kinase b signaling that reduces apoptosis and increases the survival of proximal tubular epithelial cells.(19) protein kinase b provides survival signals by several independent mechanisms. protein kinase b directly phosphorylates and inhibits proapoptotic factors such as bcl-2-associated death and others.(23) in our study some improvements were seen in the histological parameters. sub-group b of the experimental group showed the highest restoration rate compared to the other two groups. hence, we assumed this was attributed to the protective effect of hmsc conditioned media injection one day before gentamicin injection. this is because if factors necessary for the repair at the time of injury should stay in place they can be more helpful. also, the simultaneous injection of hmsc conditioned media with gentamicin was more effective than the injection of hmsc conditioned media one day after the start of gentamicin injection. in most previous studies, administration of hmsc conditioned media had been done after the induction of acute kidney injury. in a study in which injections of stem cell and granulocyte-macrophage colony-stimulating factors was done simultaneously with the beginning of the induction of acute tubular necrosis, zhang and colleagues stated that stem cell and granulocyte-macrophage colony-stimulating factors effectively mobilized bone marrow cells. this partially led to creating the treatment effects in acute tubular necrosis induced by gentamicin.(18) also, in another example in which the injections of growth factors was done before the beginning of the induction of acute kidney injury, morin and colleagues showed that epidermal growth factor accelerates repair in a rat model of gentamicin nephrotoxicity.(24) there are some problems in using hmsc conditioned media for treating acute kidney failure. for examples, each bioactive molecule works in a defined concentration and in some cases they show different functions in different concentrations.(2) it is possible that the concentration of mediators secreted by stem cells in the culture is not in the appropriate range for a renoprotective effect. also, many researchers assume that stem cells secrete defined sets of mediators in a temporally and spatially regulated manner in response to injury.(25) in fact, when stem cells reach the location of injury, they secrete special factors based on the specific signals received from the injury microenvironment.(14) today, it is not clear that what other factors that are secreted by msc can offer kidney protection. identification and purification of these factors would provide new avenues for pharmacological therapy of acute kidney injury and avoid injection of a large volume of hmsc conditioned media.(26) despite all the information that is obtained in different studies there is no final conclusion that whether the effects of mscs are involved in kidney repair directly by cellular differentiation or are due to fusion between bone marrow cells and injured cells or indirectly by various paracrine-endocrine effects created by mscs on tubular cells.(27-29) if the protective effect is mediated in an endocrine manner, then injection of the cells themselves would not be required. rather the factors that those cells secrete could be provided immediately at the time of kidney injury.(9) the results of this study showed that the protective effect of mscs might be due to their endocrine function which is in agreement with a number of previous studies described above. conclusions although conditioned media derived from humans in an animal model of gentamicin-induced kidney failure did not improve all of serum and tissue markers in the treatintraperitoneal injections of hmscs in aki-abedi et al. vol 13 no 03 may-june 2016 2714 ment groups, relative improvement in some indicators of tissue damage was observed (especially in the hmsc conditioned media injection one day before gentamicin injection). it can be assumed that the injection time of hmsc conditioned media has a role in injury recovery. in addition to the injection time of hmsc conditioned media, other factors such as injections dosages, longevity factor, etc. can have a role in achieving positive and negative results. however, these findings suggest that secretory factors of hmscs can be partially protective against gentamicin-induced nephrotoxicity. acknowledgments this study was funded by the faculty of biological sciences of kharazmi university in tehran. the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. conflict of interest none declared. references 1. eliopoulos n, zhao j, bouchentouf m, et al. human marrow-derived mesenchymal stromal cells decrease cisplatin renotoxicity in vitro and in vivo and enhance survival of mice post-intraperitoneal injection. am j physiol renal physiol. 2010;299:1288-98. 2. lameire n, van biesen w, vanholder r. the changing epidemiology of acute renal failure. nat clin pract nephrol. 2006;2:364-77. 3. waikar ss, liu kd, chertow gm. the incidence and prognostic significance of acute kidney injury. curr opin nephrol hypertens. 2007;16:227-36. 4. xue jl, daniels f, star ra, et al. incidence and mortality of acute renal failure in medicare beneficiaries, 1992 to 2001. j am soc nephrol. 2006;17:1135-42. 5. hammerman mr. tissue engineering the kidney. kidney int. 2003;63:1195-204. 6. zarjou a, kim j, traylor am, et al. paracrine effects of mesenchymal stem cells in cisplatin-induced renal injury require heme oxygenase-1. am j physiol renal physiol. 2011;300:f254-62. 7. tsai ry, kittappa r, mckay rd. plasticity, niches, and the use of stem cells. dev cell. 2002;2:707-12. 8. anglani f, forino m, del prete d, tosetto e, torregrossa r, d'angelo a. in search of adult renal stem cells. j cell mol med. 2004;8:47487. 9. bi b, schmitt r, israilova m, nishio h, cantley lg. stromal cells protect against acute tubular injury via an endocrine effect. j am soc nephrol. 2007;18:2486-96. 10. lee rh, oh jy, choi h, bazhanov n. therapeutic factors secreted by mesenchymal stromal cells and tissue repair. j cell biochem. 2011;112:3073-8. 11. prockop dj, kota dj, bazhanov n, reger rl. evolving paradigms for repair of tissues by adult stem/progenitor cells (mscs). j cell mol med. 2010;14:2190-9. 12. caplan ai. why are mscs therapeutic? new data: new insight. j pathol. 2009;217:31824. 13. lee rh, oh jy, choi h, bazhanov n. therapeutic factors secreted by mesenchymal stromal cells and tissue repair. j cell biochem. 2011;112:3073-8. 14. gheisari y, ahmadbeigi n, naderi m, nassiri sm, nadri s, soleimani m. stem cellconditioned medium does not protect against kidney failure. cell biol int. 2011;35:209-13. 15. nagai j, takano m. molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity. drug metab pharmacokinet. 2004;19:159-70. 16. zhang h, bai h, yi z, he x, mo s. effect of stem cell factor and granulocyte-macrophage colony-stimulating factor-induced bone marrow stem cell mobilization on recovery from acute tubular necrosis in rats. ren fail. 2012;34:350-7. 17. lopez-novoa jm, quiros y, vicente l, morales ai, lopez-hernandez fj. new insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. kidney int. 2011;79:33-45. 18. masoud ms, anwar ss, afzal mz, mehmood a, khan sn, riazuddin s. pre-conditioned mesenchymal stem cells ameliorate renal ischemic injury in rats by augmented survival and engraftment. j transl med. 2012;10:243. 19. vukicevic s, simic p, borovecki f, et al. role of ep2 and ep4 receptor-selective agonists of prostaglandin e(2) in acute and chronic kidney failure. kidney int. 2006;70:1099-106. 20. parekkadan b, van poll d, suganuma k, et al. mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. plos one. 2007;2:e941. 21. hammerman mr. growth factors and apoptosis in acute renal injury. curr opin nephrol hypertens. 1998;7:419-24. 22. hammerman mr. new treatments for acute renal failure: growth factors and beyond. curr opin nephrol hypertens. 1997;6:7-9. 23. sanz ab, santamaría b, ruiz-ortega m, egido j, ortiz a. mechanisms of renal apoptosis in health and disease. j am soc nephrol. 2008;19:1634-42. 24. morin nj, laurent g, nonclercq d, et al. epidermal growth factor accelerates renal tissue repair in a model of gentamicin intraperitoneal injections of hmscs in aki-abedi et al. miscellaneus 2715 nephrotoxicity in rats. am j physiol. 1992; 263:806-11. 25. imai e, iwatani h. the continuing story of renal repair with stem cells. j am soc nephrol. 2007;18:2423-4. 26. lin f. renal repair: role of bone marrow stem cells. pediatr nephrol. 2008;23:851-61. 27. baer pc, geiger h. mesenchymal stem cell interactions with growth factors on kidney repair. curr opin nephrol hypertens. 2010;19:1-6. 28. camargo fd, finegold m, goodell ma. hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. j clin invest. 2004;113:1266-70. 29. willenbring h, bailey as, foster m, et al. myelomonocytic cells are sufficient for therapeutic cell fusion in liver. nat med. 2004;10:744-8. intraperitoneal injections of hmscs in aki-abedi et al. vol 13 no 03 may-june 2016 2716 case report 1471 laparoscopic urology department of urology, zhejiang provincial people’s hospital, zhejiang university, hangzhou 310014, zhejiang province, china. corresponding author: dahong zhang, md department of urology, zhejiang provincial people’s hospital, zhejiang university, hangzhou 310014, zhejiang province, china. tel: +8657185893312 fax:+8657185893587 e-mail: urology@zju. edu.cn received april 2013 accepted june 2014 laparoscopic plasty for reconstruction of symptomatic horseshoe kidney qi zhang, feng liu, xiaolong qi, yuelong zhang, xiang he, dahong zhang purpose: to report our experience of transperitoneal laparoscopic plasty for reconstruction in patients with horseshoe kidney. materials and methods: we retrospectively analyzed 12 patients with the symptomatic horseshoe kidney who presented to our institution from march 2005 to july 2008 and underwent laparoscopic reconstruction for horseshoe kidney. computed tomography angiography was performed prior to surgery for evaluation of the anatomic variations, since preoperative knowledge is necessary for achieving reliable vascular control. five patients had renal stones which were extracted during surgery. all laparoscopic operations were performed by the same urologist. results: all procedures were completed successfully and no one needed for conversion to open surgery. mean operative time was 150 min and no major complications were observed. the average follow-up time was 28.7 months. all patients had good renal function and improved drainage with successful reconstruction. conclusion: laparoscopic reconstruction has since been demonstrated to be an attractive alternative in the management of the horseshoe kidney. it provides a feasible and effective alternative to conventional management. keywords: horseshoe kidney; kidney; abnormalities; laparoscopy; urologic surgical procedures; kidney pelvis; surgery. vol. 11 no. 04 july august 2014 14721757 laparoscopic urology tion before surgery. preoperative computed tomography angiography (cta) (figure 1a and 1b) of the abdomen provides the surgeon with valuable anatomic information, including isthmus thickness, calyceal extension into the isthmus and ectopic location. magnetic resonance imaging (mri) with three-dimensional reconstruction was performed to delineate the renal anatomy optimally prior to surgery. all laparoscopic operations were performed by the same urologist. the laparoscopic transabdominal approach was used in all cases. the patients were put in the right lateral decubitus position under general anesthesia. prophylactic antibiotics were given. a 14 mmhg pneumoperitoneum was established first. positioning and trocar placement are shown in figure 2. the posterior peritoneal reflection was incised and the colon reflected medially. we exposed the lower pole of the left kidney, so the dilated renal pelvis and the isthmus with crossing vessels were visible. the isthmus was then exposed using blunt dissection and keeping a special watch on the aberrant blood supply. the isthmus was freed circumferentially, where many anterior and posterior vessels were selectively controlled using hemo-o-lock (figure 3). we observed the range of blood supply before we ligated these vessels. the blood supply consists of a single renal artery to each kidney in five cases. seven patients had atypical with duplicate or even triplicate renal arteries. the isthmus received a branch from main renal artery or from the aorta in three cases. four patients had accessory renal artery supply to the lower pole of the left kidney which was ligated for the purposes of nephropexy. the isthmus was divided using the endoscopic stapler (ref 6tb45, 45 mm staple line, 3.5 mm staple leg length, 6 rows, ethicon endo-surgery, llc, ethicon, inc. new jersey, usa) (figure 4). generally we chose two figure-of-eight suture instead of classic nephropexy (figure 5). no significant bleeding was noted from the divided isthmus. choice of laparoscopic pyeloplasty was based on the nature of the ureteropelvic junction obstruction and anatomical findings at surgery. dismembered pyeloplasty was the first choice for most patients. in all cases a 6 french (f) double j ureteral stent was inserted in an antegrade fashion through a 5 mm trocar with the assistance of a ureteral open-end catheter before completing the suture. if crossing vessels were present, the ureter and renal pelvis were transposed to the opposite side of the vessels before completion of the anastomosis. in 5 patients renal stones were removed using pyelolithotomy. no additional lithotripsy techniques were used. if the right kidney has hydronephrosis or stones, we may handle it later or simultaneously, depending on the patient’s situation. the operative duration was defined from the initial port incision to the closure of all laparoscopic ports. a procedure was defined as successful by the reduction in the hydronephrosis and absence of symptoms. results all procedures were completed successfully and no one needed for conversion to open surgery in our series. the main results are shown in table. the mean operative duration was 150 (125~170) min and introduction horseshoe kidney is the most common renal fusion abnor-mality occurring in approximately 1/400 births to 1/1000 births.(1-3) in the great majority of cases the kidneys are fused at the lower pole which can be a brand of fibrous or a thick functional renal parenchymal isthmus.(1,4) the normal ascent of the kidney is arrested by the inferior mesenteric artery and fails to normally rotate.(5-7) consequently, the renal pelvis is ventrally placed and the ureters often course over the isthmus. the vascular supply to the horseshoe kidney may be complex.(2) the blood supply consists of a single renal artery to each kidney in only 30% of the cases.(4) in most cases, it may be atypical with duplicate or even triplicate renal arteries and veins that supply each kidney. the isthmus usually has a separate blood supply which may arise from each main renal artery or from the aorta, inferior mesenteric or iliac arteries. although most patients with horseshoe kidney are asymptomatic, they may be associated with complications based on ureteropelvic junction obstruction, such as hydronephrosis, nephrolithiasis and recurrent urinary tract infections.(4,7-10) as the most common complication of the horseshoe kidney which necessitating surgical intervention, urolithiasis has an incidence of 20% to 60% and ureteropelvic junction (upj) obstruction occurs at an incidence of 15% to 33%.(5,11,12) the most common etiology is believed to be the abnormal course of the ureter as it passes over the anterior surface of the isthmus, high insertion of the ureter into the renal pelvis, and secondary to an anomalous blood supply to the isthmus crossing the upj.(9,13,14) in the long term, they may cause renal damage and results in nephrectomy. laparoscopy is becoming the standard surgical management for many renal diseases, and major advances in laparoscopic surgery have enabled less invasive surgery in urology with the benefits of decreased postoperative discomfort and improved convalescence. application of laparoscopic reconstruction in the horseshoe kidney has been limited. we report our experience of transperitoneal laparoscopic plasty for reconstruction in patients with horseshoe kidney. the details of the technique were provided in the report. materials and methods between march 2005 to july 2008, five men and seven women (aged 8 and 59 years) were referred to our institution for symptomatic ureteropelvic junction obstruction (upjo) associated with horseshoe kidney (table). in eleven patients only the left kidney was affected, and one patient had bilateral involvement of the kidney on preoperative evaluation. five patients had associated renal stones that were extracted during laparoscopic reconstruction. the major presenting symptoms were recurrent back pain in 7 patients (58%), intermittent lower abdominal pain in 2 (17%), recurrent urinary tract infection in 2 (17%) and hematuria in 1 (8%). none of the patients had previous abdominal surgery (table). all patients were evaluated with intravenous urography (ivu) and isotope renogram, and all had normal renal funclaparoscopic reconstruction in horseshoe kidney-zhang et al urology journal vol. 11 no. 04 july august 2014 1758 computed tomography angiography (cta), isotope renogram and ivu at 3-month postoperatively and annually thereafter. all had good renal function and improved drainage with successful isthmectomy confirmed by cta at 3-month after surgery (figure 6). postoperative ivu also showed improved drainage. one patient had mild residual hydronephrosis at 3 months, but this was resolved completely at 1 year. discussion the first description of horseshoe kidney was by berengario da carpi in 1522.(15) due to the rarity of this renal anomaly, few reports address the treatment of upjo in adults with horseshoe kidney. for several decades, open pyeloplasty was the main treatment for upjo. for open surgical repair, the need to divide the isthmus, nephropexy of the ipsilateral kidney and dismembered pyeloplasty have been described. (9,16,17) minimally invasive techniques were developed in the 1980s and applied in horseshoe kidney to decrease postoperative morbidity associated with open surgery.(11) retrograde endopyelotomy treatment was reported by jabbour and colleagues,(18) with a long-term success and no major bleeding complications. several groups have since reported their experience with different laparoscopic procedure in horseshoe kidneys in case reports and small series. laparoscopic pyeloplasty offers the advantages of a minimally invasive approach and the success rates comparable with an open procedure.(19) application of estimated blood loss was 100 ml. there were no intraoperative complications. in five patients with renal stones, these were removed laparoscopically. an x-ray after surgery showed good positioning of the double j ureteral stent in all cases. no additional lithotripsy was needed during surgery, but there was a residual calculus in one patient, who was successfully treated later with extracorporeal shockwave lithotripsy (swl). physical activity and oral intake were resumed on the day after surgery. the mean hospital stay was 7.6 days and the mean follow-up was 28.7 months (range 24 to 60). no long term complication was devel-oped. the patients were scheduled for follow up at 4~6 weeks post-operatively for stent removal. patients underwent patient no, concomitant disease main presenting symptoms procedure operation duration blood loss results* follow up, age (min) (ml) radiologic, clinical (months) 1, 15 none intermittent lower abdominal pain lt .laparoscopic reconstruction 135 50 improved drainage 15, 25 2, 15 none recurrent back pain lt. laparoscopic reconstruction 160 75 improved drainage 15, 26 3, 26 bilateral pelvis stones recurrent back pain lt. laparoscopic reconstruction 155 135 a residual stone 15, 24 and pyelolithotomy treated with swl 4, 15 none hematuria lt. laparoscopic reconstruction 170 105 improved drainage 15, 24 5, 5 left pelvis stones recurrent urinary tract infection lt. laparoscopic reconstruction 155 150 improved drainage 15, 24 and pyelolithotomy 6, 5 none recurrent back pain lt. laparoscopic reconstruction 125 70 mild residual 51, 60 hydronephrosis at 3 months 7, 51 left pelvis stones recurrent back pain lt. laparoscopic reconstruction 155 85 improved drainage 15, 24 and pyelolithotomy 8, 15 left pelvis stones recurrent urinary tract infection lt. laparoscopic reconstruction 160 120 improved drainage 15, 24 and pyelolithotomy 9, 15 none recurrent back pain lt. laparoscopic reconstruction 145 125 improved drainage 15, 25 10, 15 none recurrent back pain lt. laparoscopic reconstruction 160 95 improved drainage 15, 25 11, 15 none recurrent back pain lt. laparoscopic reconstruction 140 105 improved drainage 39 , 39 12, 39 left pelvis stones intermittent lower abdominal pain lt. laparoscopic reconstruction 145 90 improved drainage 13, 24 table. demographic and clinical characteristics of study subjects. abbreviations: lt, left; swl, extracorporeal shock wave lithotripsy. * confirmed by computed tomography angiography, isotope renogram and intravenous urography. figure 1. preoperative computed tomography angiography. 1759 laparoscopic urology urology journal vol. 11 no. 04 july august 2014 1760 and vein for preoperative knowledge that will be necessary for achieving reliable vascular control.(26) also cta could conduct isthmectomy and show the patency of the ureter during treatment. the isthmus usually consists of parenchymal tissue with its own blood supply.(4) occasionally it is a flimsy midline structure composed of fibrous tissue.(27) several techniques have been described for division of the isthmus and this procedure was achieved by use of microwave coagulator device,(28) argon beam, harmonic scalpel(13) or more commonly the endoscopic stapler.(26,29,30) the isthmus, with or without functional parenchyma, was divided using the endoscopic stapler for this purpose as it is safe and may aid in maintaining patency of the repair. identification of any vessel supplying the isthmus if present is essential.(25,27) in our experience, endoscopic stapler are always effective. depending on the thickness of the isthmus, the staplers can be used several times and should be consecutively placed in line and transected at the aortic impression where the thinnest part of the isthmus presents. during placement of the stapler, one must be aware that the isthmus is supplied by vessels entering dorsally, and intrusion into the collecting system or parenchyma during placement must be avoided. in our serial, the endoscopic stapler was employed well away from the remaining collecting system and with excellent hemostasis. the overall success rate in our series is higher than previous reports for either open surgery (55%-80%) and endoscopic management (78%), equivalent to laparoscopic surgery with horseshoe kidney (91%). (15,16,21) if repair is considered for these patients, thorough preoperative evaluation and counseling are recommended. the operative duration of 150 min, was no more than other laparoscopic treatments in patients with horseshoe kidney using standard laparoscopy, and in the present series this duration included the extraction of calculi in five casesthe mean hospital stay of 7.6 days was longer than other series. this is explained by that the health insurance covers hospitalization expenses regardless of duration, making the patient tend to a longer hospital stay. therefore, the mean hospital stay might be a poor measure of comparison.(3) some technical points should be emphasized. when performing laparoscopic surgery for the patients with horseshoe kidney, understanding laparoscopic pyeloplasty in the horseshoe kidney has been limited; the first laparoscopic pyeloplasty was reported in 1996(20) and the largest published series has only five patients.(21) the laparoscopic management of upjo in patients with horseshoe kidneys follows similar principles for treatment of patients with conventional open surgery. we report the technique of laparoscopic plasty for the reconstruction of horseshoe kidney. the laparoscopic approach provided excellent surgical exposure with a comparable operative time as open surgery. concomitant pyelolithotomy could also be performed using the laparoscopic approach, allowing for intact stone removal in a single operative session. although improvements in laparoscopic instruments have been introduced recently, the unique anatomic considerations and difficulty of this technique are still disadvantages. accordingly, the transabdominal approach was chosen because of a wide working space is needed for this kind of complicated procedure. (22) the unique features of horseshoe kidney, such as its low fixed position secondary to malrotation, the anterior renal pelvis, its variant and multiple vasculature, and presence of functional parenchyma in the isthmus, are technical challenges that contribute to making a laparoscopic approach for reconstruction in horseshoe kidney technically challenging.(10,23-26) cta is required prior to surgery for evaluation of the anatomic variations, including ectopic location, malrotation, the thickness of the isthmus, and extrarenal anatomy of the renal artery figure 2. port sites. figure 3. the isthmus was freed circumferentially and vessels were selectively controlled. figure 4. nephropexy is shown. laparoscopic reconstruction in horseshoe kidney-zhang et al conflict of interest none declared. references 1. tobias-machado m, massulo-aguiar mf, forseto ph jr, juliano rv, wroclawski er. laparoscopic left radical nephrectomy and hand assisted isthmectomy of a horseshoe kidney with renal cell carcinoma. urol int. 2006;77:94-6. 2. janetschek g, kunzel kh. percutaneous nephrolithotomy in horseshoe kidneys. applied anatomy and clinical experience. br j urol. 1988;62:117-22. 3. chammas m jr, feuillu b, coissard a, hubert j. laparoscopic robot ic-assisted management of pelvi-ureteric junction obstruction in pa tients with horseshoe kidneys: technique and 1-year follow-up. bju int. 2006;97:579-83. 4. stroosma ob, schurink gw, smits jm, kootstra g. transplanting horseshoe kidneys: a worldwide survey. j urol. 2001;166:2039-42. 5. viola d, anagnostou t, thompson tj, smith g, moussa sa, tolley da. sixteen years of experience with stone management in horseshoe kid neys. urol int. 2007;78:214-8. 6. etemadian m, maghsoudi r, abdollahpour v, amjadi m. percutane ous nephrolithotomy in horseshoe kidney: our 5-year experience. urol j. 2013;10:856-60. 7. symons sj, ramachandran a, kurien a, baiysha r, desai mr. uro lithiasis in the horseshoe kidney: a single-centre experience. bju int. 2008;102:1676-80. 8. lampel a, hohenfellner m, schultz-lampel d, lazica m, bohnen k, thürof jw. urolithiasis in horseshoe kidneys: therapeutic management. of the number,(13) location and extra-renal anatomy of the renal artery, vein and accessory vessels leads to the achievement of reliable vascular control and makes the operation successfully, otherwise particularly the direct branches from the aorta to the isthmus, or isthmectomy will result in severe hemorrhage.(31) from a technical perspective, isthmectomy allows the kidneys to lie in a more dependent position that maintains the patency of the repaired outflow tract, as the medial portions of the separated kidneys rotate to lessen the obstruction and get better urine drainage for the lower calyx.(13) another important point is careful isthmus dissection while it is important not to violate the collecting system of the contralateral kidney at the lower pole. we considered that the conventional notion that nephropexy should accompany division of the isthmus to protect the remaining kidney from developing upjo caused by renal vein. in some patients, pyeloplasty alone could not help because of the abnormal compression of the ureter passing between the left renal vein and isthmus, so we abducted the lower pole of the left kidney and fixed it to psoas muscle to release the ureter from outside compression. the pyeloplasty after isthmectomy may adjust high insertion of the ureter into the renal pelvis. long term follow up cta revealed improved drainage and satisfactory separation of the divided horseshoe kidney. minimally invasive surgery using laparoscopy is rapidly coming to the forefront as a reasonable option for horseshoe kidney. preoperative ct and mr angiography may be helpful in guiding surgical therapy. the improvement in laparoscopic instruments and techniques has since paved the way for the management of reconstruction of the horseshoe kidney. conclusion transperitoneal laparoscopic reconstruction has since been demonstrated to be a feasible and effective method in the management of the horseshoe kidney. it is a challenging approach and more experience is needed before it becomes the standard of care. the present series involved division of the isthmus, and had good clinical and radiological results. good laparoscopic skill and patience plays a definitive role in the management of complications associated with the horseshoe kiney. figure 5. the isthmus was divided using the endoscopic stapler. figure 6. computed tomography angiography at 3 months postoperatively showed improved drainage. 1761 laparoscopic urology aroscopic radical heminephrectomy for renal-cell carcinoma in a horse shoe kidney. j endourol. 2007;21:1485-7. 26. donovan jf1, cooper cs, lund go, winfield hn. laparoscopic ne phrectomy of a horseshoe kidney. j endourol. 1997;11:181-4. 27. saggar vr, singh k, sarangi r. retroperitoneoscopic heminephrectomy of a horseshoe kidney for calculus disease. surg laparosc endosc per cutan tech. 2004;14:172-4. 28. hayakawa k1, baba s, aoyagi t, ohashi m, ishikawa h, hata m. lapa roscopic heminephrectomy of a horseshoe kidney using microwave co agulator. j urol. 1999;161:1559. 29. dasgupta r, shrotri n, rane a. hand-assisted laparoscopic hemine phrectomy for horseshoe kidney. j endourol. 2005;19:484-5. 30. ao t, uchida t, egawa s, iwamura m, ohori m, koshiba k. laparo scopically assisted heminephrectomy of a horseshoe kidney: a case re port. j urol. 1996;155:1382-3. 31. bhayani sb, andriole gl. pure laparoscopic radical heminephrectomy and partial isthmusectomy for renal cell carcinoma in a horseshoe kid ney: case report and technical considerations. urology. 2005;66:880. urology. 1996;47:182-6. 9. nakamura k, baba s, tazaki h. endopyelotomy in horseshoe kidneys. j endourol. 1994;8:203-6. 10. nouri-mahdavi k, izadpanahi mh. laparoscopic heminephrectomy in horseshoe kidney using bipolar energy: report of three cases. j endourol. 2008;22:667-70. 11. yohannes p, smith ad. the endourological management of complica tions associated with horseshoe kidney. j urol. 2002;168:5-8. 12. hsu th, presti jc jr. anterior extraperitoneal approach to laparoscopic pyeloplasty in horseshoe kidney: a novel technique. urology. 2003;62:1114-6. 13. nadler rb, thaxton cs, kim sc. hand-assisted laparoscopic py eloplasty and isthmectomy in a patient with a horseshoe kidney. j endou rol. 2003;17:909-10. 14. darabi mahboub mr, zolfaghari m, ahanian a. percutaneous nephroli thotomy of kidney calculi in horseshoe kidney. urol j. 2007;4:147-50. 15. pitts wr jr, muecke ec. horseshoe kidneys: a 40-year experience. j urol. 1975;113:743-6. 16. das s, amar ad. ureteropelvic junction obstruction with associated re nal anomalies. j urol. 1984;131:872-4. 17. culp os, winterringer jr. surgical treatment of horseshoe kidney: com parison of results after various types of operations. j urol. 1955;73:747 56. 18. jabbour me, goldfischer er, stravodimos kg, klima wj, smith ad. endopyelotomy for horseshoe and ectopic kidneys. j urol. 1998;160:694-7. 19. siqueira tm jr, nadu a, kuo rl, paterson rf, lingeman je, shalhav al. laparoscopic treatment for ureteropelvic junction obstruction. urol ogy. 2002;60:973-8. 20. janetschek g, peschel r, altarac s, bartsch g. laparoscopic and ret roperitoneoscopic repair of ureteropelvic junction obstruction. urology. 1996;47:311-6. 21. bove p, ong am, rha kh, pinto p, jarrett tw, kavoussi lr. lapa roscopic management of ureteropelvic junction obstruction in patients with upper urinary tract anomalies. j urol. 2004;171:77-9. 22. kawauchi a, fujito a, yoneda k, et al. laparoscopic pyeloplasty and isthmectomy for hydronephrosis of horseshoe kidney: a pediatric case. j endourol. 2005;19:984-6. 23. patankar s, dobhada s, bhansali m. case report: laparoscopic hemi nephrectomy in a horseshoe kidney using bipolar energy. j endourol. 2006;20:639-41. 24. tsivian a, shtricker a, benjamin s, sidi aa. laparoscopic partial nephrectomy for tumour excision in a horseshoe kidney: part ii. eur urol. 2007;51:1433-4. 25. araki m1, link ba, galati v, wong c. case report: hand-assisted lap laparoscopic reconstruction in horseshoe kidney-zhang et al urology journal vol. 11 no. 04 july august 2014 1762 vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2533 a prospective randomized trial comparing a combined regimen of amikacin and levofloxacin to levofloxacin alone as prophylaxis in transrectal prostate needle biopsy. yu miyazaki,1,3 shusuke akamatsu,1,3* sojun kanamaru,2 yuki kamiyama,2 atsushi sengiku,1 ryo iguchi,2 takeshi sano,2 akira takahashi,1 masaaki ito,1 jun takenawa,2 noriyuki ito,2 keiji ogura1 purpose: we investigated whether addition of amikacin to levofloxacin-based antimicrobial prophylaxis reduces febrile urinary tract infections after transrectal ultrasound-guided prostate needle biopsy (trusb). materials and methods: a total of 447 patients undergoing trusb were prospectively randomized into two groups. the 230 patients in group a were given one oral dose of levofloxacin 400 mg prior to trusb; the 217 patients in group b each received the same dose of levofloxacin and one 200 mg intravenous dose of amikacin. patients’ characteristics were assessed prior to trusb and their symptoms were checked after the trusb. results: both regimens were well tolerated with no side effects. no statistically significant difference in patients’ characteristics, or in incidence of inflammationor infection-related symptoms was seen between the two groups; nor any significant difference among those who developed fever and those who did not. two group a patients and one group b patient developed febrile urinary tract infections. accountable pathogens determined by urine and blood cultures were fluoroquinolone-resistant e.coli and extended-spectrum β-lactamase-producing e.coli. all pathogens isolated were levofloxacin-resistant, amikacin-susceptible species. conclusion: although the present study was under-powered by unexpectedly low overall incidence of febrile urinary tract infections, addition of one intravenous administration of amikacin to one oral administration of levofloxacin showed no advantage compared with levofloxacin alone as antimicrobial prophylaxis in trusb. strikingly, all pathogens isolated from febrile patients were sensitive to amikacin in vitro. therefore, further understanding of amikacin’s drug kinetics in the prostate is necessary to develop a more efficient drug delivery system for amikacin. keywords: antibiotic prophylaxis; methods; bacterial infections; prevention & control; prostatic neoplasms; diagnosis; anti-bacterial agents; administration & dosage. introduction currently, transrectal ultrasound-guided prostate needle biopsy (trusb) is accepted as a standard procedure for pathologic diagnoses of prostate cancer. however, trusb is an invasive procedure with complications such as pain, dysuria, hematuria, hematospermia, rectal bleeding, urinary retention, non-febrile and febrile urinary tract infection (uti), and sepsis. infectious complications, especially acute prostatitis and sepsis may result in severe morbidity, and even death. (1) hence, antibiotic prophylaxis is routinely administered to lower incidence of infectious complications after trusb.(2-4) fluoroquinolone (fq) antimicrobial agents are widely used as prophylaxis due to their broad spectrum of activity against gram-positive and gram-negative bacteria. moreover, fqs are available orally, have a widely acceptable safety profile, and penetrate well into the prostatic cytosol.(5-7) until the early 2000s, multiple randomized studies have shown fqs to be effective in lowering the incidence of infectious complications after trusb.(2,8-10) however, wide use of fqs has led to development of fq-resistant bacteria, such as extended-spectrum β-lactamase (esbl)-producing coliforms.(11) a number of studies during the last decade have shown a trend of increasing fq resistance in cases of bacterial infections after trusb.(11-13) several studies have tested alternative antibiotic prophylaxis regimens, or combinations of other antibiotics with fqs to lower the incidence of these complications. the american urological association (aua) guideline for antimicrobial prophylaxis for trusb recommends 1 department of urology, japanese red cross otsu hospital, 1-35 nagara 1-chome otsu city, shiga, 520-8511, japan. 2 department of urology, nishi-kobe medical center, 7-1 kojidai 5-chome, nishi-ku, kobe city, hyogo, 651-2273, japan. 3 department of urology, kyoto university graduate school of medicine, 54 shougoin kawahara-cho, sakyo-ku, kyoto, 606-8507, japan. *correspondence: department of urology, kyoto university graduate school of medicine, 54 shougoin kawahara-cho, sakyo-ku, kyoto, 606-8507, japan. tel: +81 75 7513325 . fax: +81 75 7613441. e-mail: akamats@kuhp.kyoto-u.ac.jp. received: may 2015 & accepted: october 2015 urological oncology fqs or cephalosporins as the agents of first choice, and lists aminoglycosides, aztreonam, or trimethoprim-sulfamethoxazole (tmp-smx) as alternatives to fqs.(14) aminoglycosides have also been recommended as alternative antimicrobials for preoperative prophylaxis for a number of other surgical procedures in the guideline. amikacin (amk) is a low-cost aminoglycoside drug available in japan, and has a good sensitivity profile against esbl-producing coliforms.(12,15) however, there is no report of a prospective randomized study on the combined use of amk and fqs for trusb. the aim of this prospective study is to assess whether the addition of amk to levofloxacin (lvfx)-based antimicrobial prophylaxis reduces febrile uti after trusb. materials and methods study patients from november 2007 to december 2009, patients undergoing trusb at nishi-kobe medical center and japanese red cross otsu hospital, two tertiary referral hospitals 80 km apart, were recruited to the study. these patients had standard indications for trusb, such as abnormal findings on digital rectal examination and/or elevated serum prostate specific antigen (psa) levels. patients with indwelling urethral catheters, untreated uti, current use of antibiotics, severe heart disease, abnormal liver function (aspartate transaminase (ast) and alanine transaminase (alt) > × 2.5 upper limit of normal), abnormal renal function (serum creatinine > 1.2 mg/dl), immunosuppressive status, or histories of hypersensitivity to fqs or aminoglycosides were excluded. we calculated that with a two-sided alpha of 0.05, a power of 0.8, and expected reduction in incidence of febrile uti from 2% in the group a control arm to 0.5% in the group b, we needed 201 samples for each arm. all patients were sufficiently informed of the aims of this trial and all possible complications. the 447 patients who agreed to this trial gave written consent documents to be enrolled in this study, which was approved by institutional review boards at each hospital (irb approval number 200904 for nishi-kobe medical center, and 109-2009 for japanese red cross otsu hospital). methods patients were prospectively randomized into two groups using a computer-generated random number table. group a received a single oral administration of lvfx (400 mg), two hours before trusb. group b received the same dose of lvfx two hours before trusb and a single intravenous administration of amk (200 mg), 30 minutes before trusb. this trial was performed as a single blind trial: the patients were not informed of the group they were randomized to. patient characteristics, including age, serum psa, prostate volume, international prostate symptom score (ipss), quality of life (qol) score, presence of dysuria, comorbidities, history of previous trusb, use of anticoagulant agents, antimicrobials, or steroid drugs, were assessed prior to trusb. for analgesia, each patient had a diclofenac sodium suppository (50 mg) 30 minutes before the procedure. we established an intravenous line before each trusb to prepare for hypotensive side effects, and performed each trusb using a disposable automated biopsy gun with 18-gauge biopsy needles. all biopsies were carried out using a systematic approach in which 10 specimens were taken from each patient. of note, the method of bowel preparation was not predetermined in the current study. as a result, all the patients who underwent trusb at the nishi-kobe medical center took sennoside orally (24 mg, before sleep), and were administered an enema (glycerine enema 120 ml, under 70 years old/ glycerine enema 60 ml over 71 years old) on the day of trusb, whereas the patients at japanese red cross otsu hospital did not receive any bowel preparation. all the other procedures were identical between the two institutions. patients were instructed to record symptoms associated with their trusbs, including pain at trusb, gross hematuria, rectal bleeding, hematospermia, perineal discomfort, urination pain, difficulty voiding, urinary retention, fever, and symptomatic adverse drug events, using provided check sheets, which were collected at 2-4 weeks after each trusb. patients were instructed to contact the office immediately if any problems occur, especially febrile symptoms (body temperature higher than 38.0°c). urine and blood cultures were collected immediately from patients who developed febrile symptoms, and the patients were immediately treated with meropenem. antimicrobial susceptibility was evaluated by clinical and laboratory standards institute (clsi) broth microdilution method, and a bacterial isolate was considered non-susceptible to an antimicrobial agent when it tested resistant, intermediate, or non-susceptible. multiple drug resistance was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories. the primary endpoint of the present study was incidence of febrile uti in each group. secondary endpoints were incidence of non-febrile symptoms, tolerability, and safety of the combined regimen, and determination of variables associated with febrile uti. results were analyzed using jmp 9 software (sas institute inc, cary, north carolina, usa); p amikacin and levofloxacin for prophylaxis in prostate biopsy-miyazaki et al. urological oncology 2534 vol 13 no 01 january-february 2016 2535 values were calculated with student’s t-test, chi-square test and fisher’s exact test, and p < .05 was considered significant. results there was no significant difference in incidences of non-infectious complications after trusb, such as pain at trusb, gross hematuria, rectal bleeding, and hematospermia. moreover, we could not detect any significant difference in incidences of symptoms related to inflammation or infection including perineal discomfort, micturition pain, difficulty voiding, urinary retention, and fever (table 1). two patients from group a and one patient from group b developed febrile symptoms. urine and blood cultures were collected immediately from these patients, and the patients were promptly treated with intravenous administration of meropenem. table 2 shows details of the three patients and results of their urine and blood cultures. the history of previous trusb is reported as one of the significant risk factors of febrile uti. in the present study, 46/230 (20.0%) in group a, and 38/217 (17.5%) in group b had prior trusb, however, the three patients who developed febrile symptoms had not undertaken trusb previously. all three patients were diagnosed with acute prostatitis; none progressed to septic shock, and all were cured with intravenous meropenem. accountable pathogens, as determined by urine and blood cultures were fq-resistant e.coli in two cases and esbl-producing e.coli in another. all pathogens isolated were lvfx-resistant, amk-susceptible species (table 2). both regimens were well tolerated with no side effects. no patient had deterioration of renal function. no patient was lost to follow up. there was no statistically significant difference in patients’ characteristics between the two groups before trusbs (table 3). overall, prostate cancer was detected in 208 (46.5%) cases by trusb. prostate cancer detection rates were similar between the two groups (105 [45.6%] of 230 in group a, 103 [47.4%] of 217 in group b). the survey of urine culture results from all the symptomatic uti patients in the two hospitals between 2006 and 2009 showed that the detection rate of lvfx-resistamikacin and levofloxacin for prophylaxis in prostate biopsy-miyazaki et al. table 1. complications after transrectal ultrasound-guided prostate needle biopsy. variables group a group b p value single-dose lvfx single-dose lvfx + amk iv. (n = 230) (n = 217) pain at trusb, no. 40 28 .160 † hematuria, no. 77 72 .865 † (mean duration of symptoms, days) 3.64 3.32 rectal bleeding, no. 40 44 .464 † (mean duration of symptoms, days) 1.33 1.33 hematospermia, no. 13 11 .812 † perineal discomfort, no. 34 25 .265 † (mean duration of symptoms, days) 1.38 1.62 urination pain, no. 9 9 .933 †† (mean duration of symptoms, days) 4.33 2.89 feeling of residual urine, no. 19 17 .903 † (mean duration of symptoms, days) 4 3.35 difficulty voiding, no. 3 8 .179 †† (mean duration of symptoms, days) 1 1 urinary retention, no. 3 2 .935 †† (mean duration of symptoms, days) 4.33 3 fever > 38°c 2 1 .950 †† (mean duration of symptoms, days) 3.5 5 symptomatic adverse drug event, no. 0 0 ---- abbreviations: trusb, transrectal ultrasound-guided prostate needle biopsy; lvfx, levofloxacin; amk, amikacin; iv, intravenous. † chi-square test; †† fisher’s exact test. ant e.coli among all e.coli had increased from 17.2% in 2006 to 22.2% in 2009, and that of esbl-producing e. coli from 3.80% to around 10% (figure 1). amk showed a very high sensitivity rate (99.0%) to coliforms from urine cultures of all uti patients. furthermore, amk showed almost similar sensitivity rate (97.1%) to esbl producing e.coli (figure 2). discussion introduction of psa testing into clinical practice led table 2. characteristics of the patients who developed febrile urinary tract infection, and results of urine / blood cultures. variables patient 1 patient 2 patient 3 p value (vs. afebrile patients) group a a b –----age, years 78 68 75 .282 † psa, ng/ml 6.88 14.1 13.7 .00106 † prostate volume, cc 35 45.8 62.4 .636 † antimicrobial history –---- –---- –---- .850 †† comorbidities re-biopsy dysuria dysuria; use of anticoagulant agents; –---- diabetes mellitus; hypertension complications after trusb hematuria; feeling of urination pain urination pain; –---- residual urine urinary retention prostate cancer detection + + + 0.0625 †† interval from biopsy to febrile symptom, days 1 3 1 –----organism isolated e. coli (urine) e. coli esbl-producing e. coli –----(source) (urine and blood) (urine) antimicrobial sensitivity levofloxacin resistant resistant resistant –---- amikacin sensitive sensitive sensitive –----abbreviations: trusb, transrectal ultrasound-guided prostate needle biopsy; e. coli, escherichia coli. † chi-square test; †† fisher’s exact test. figure 1. ratios of lvfx-resistant e.coli and esbl-producing e.coli to all e.coli isolated from urine cultures of patients with uti at the two hospitals. abbreviations: lvfx, levofloxacin; e. coli, escherichia coli; esbl, extended-spectrum β-lactamase; uti, urinary tract infection. figure 2. drug susceptibility of extended-spectrum β-lactamase producing e.coli at the two hospitals. abbreviations: amk, amikacin; lvfx, levofloxacin; mino: minocycline; s/t, sulfamethazine /trimethoprim. amikacin and levofloxacin for prophylaxis in prostate biopsy-miyazaki et al. urological oncology 2536 vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2537 to a dramatic increase in trusbs. about 700,000 patients are diagnosed with prostate cancer worldwide annually.(16) e.coli is the major cause of symptomatic infection after trusb.(17) although prophylactic antimicrobial administrations lower the risk of infection after trusb,(18) no standard antimicrobial prophylaxis regimen has been established, and a variety of antimicrobial prophylaxis regimens are administered without clear evidence,(4,19) fqs are the most widely used antimicrobial in trusb, and is recommended as a firstline agent for prophylaxis in both aua and european association of urology (eau) guidelines.(14,20) in the united states and europe, ciprofloxacin (cpfx) is commonly used, whereas in japan lvfx is popular. increasing resistance to fqs and wide emergence of esbl-producing e.coli has been reported,(11-13) which would pose more patients receiving fqs alone as prophylaxis before trusb at risk of developing febrile utis. because of these increases in fq-resistant coliforms, the urgent need to develop new prophylactic strategies have been emphasized.(21-23) batura and colleagues examined resistance rates of organisms which were isolated from rectal swab during trusbs to cpfx, co-amoxiclav, and amk, and found amk to have the lowest resistance rate (0.22%) compared to cpfx (10.6%) and co-amoxiclav (13.3%).(15) furthermore, a recent survey of 3000 patients who underwent trusb in france showed that the resultant pathogen for acute bacterial prostatitis were 95% resistant to fqs, and only 5% resistant to amk.(24) the resistance rates of these pathogens to third-generation cephalosporin, gentamicin, and imipenem were 25%, 55%, and 0% respectively. these results suggest the possible advantage of adding amk to conventional fq-based regimen, although it has never been tested in a prospective randomized controlled trial. batura and colleagues have retrospectively reviewed the addition of amk to their conventional regimen (cpfx + co-amoxiclav + metronidazole) and reported decreased incidence of febrile infections, from 3.9% to 1.4%.(23) however, two patients in their study, who received amk as a part of combined regimen, also developed febrile infections from amk-sensitive coliforms. in the present study, although all organisms isolated from patients developing table 3. patient characteristics. variables group a group b p value single-dose lvfx single-dose lvfx + amk iv. (n = 230) (n = 217) age, years (mean ± sd) 69.4 ± 7.82 69.5 ± 7.38 .994 † psa, ng/ml (median) 7.90 (iqr 5.38-13.85) 7.51 (iqr 5.58-14.25) .771 † prostate volume, cc (mean ± sd) 41.3 ± 22.7 41.0 ± 24.2 .886 † ipss score (mean ± sd) 12.2 ± 7.60 11.5 ± 7.16 .543 † qol score (mean ± sd) 3.28 ± 1.54 3.17 ± 1.56 .916 † presence of previous trusb 46 38 .465 †† dysuria 73 69 .924 †† use of anticoagulant agents 30 24 .557 †† long term use of antimicrobials 1 4 .334 ††† use of steroid drugs 5 1 .0856 ††† diabetes mellitus 21 31 .106 †† hypertension 69 63 .807 †† cardiovascular disease 21 18 .656 †† respiratory disease 5 9 .486 ††† liver disease 2 3 .667 ††† renal disease 2 3 .667 ††† cerebrovascular disease 11 6 .363 ††† number of prostate cancers detected 105 103 .603 †† abbreviations: trusb, transrectal ultrasound-guided prostate needle biopsy; lvfx, levofloxacin; amk, amikacin; psa, prostate specific antigen; qol, quality of life; sd, standard deviation; ipss, international prostate symptom score; iqr, interquartile range; iv, intravenous. † student’s t-test; †† chi-square test; ††† fisher’s exact test. amikacin and levofloxacin for prophylaxis in prostate biopsy-miyazaki et al. acute prostatitis were resistant to lvfx and sensitive to amk, patients with combined regimen also developed acute prostatitis, and there was no overall benefit of the combined regimen. these results underscore the theoretical efficacy of amk to lvfx-resistant e.coli, however, the clinical ineffectiveness of combining amk to lvfx in prophylaxis of trusb associated febrile uti suggests suboptimal drug delivery or tissue penetrance of amk to prostate tissue. there is no report on the optimal dosage or administration method of amk as prophylaxis in trusb. goto and colleagues reported a high concentration of amk in the prostate tissue after a single dose (200 mg, intramuscularly).(25) however, özden and colleagues reported esbl-producing isolates had a significant reduction in activity for most antimicrobial agents, including fqs and amk.(11) further studies to elucidate the precise drug kinetics of amk in the prostate could lead to a more efficient drug delivery method for amk. the reported incidence of febrile infection is similar between cpfx and lvfx: 0.1–3% in cpfx,(2,3,26) and 0.6–5% in lvfx.(27-29) although we expected the incidence of febrile uti to be 2% in the lvfx group (group a) in power calculation, in the present study, only 3 (0.67%) of 447 cases developed febrile uti. this low incidence of overall febrile uti in the present study lowered the power of the study, and might partially explain the lack of significant difference between the two groups. increasing sample size may detect smaller difference due to addition of amk; however, at the cost of a larger number needed to treat (nnt), which would limit its clinical benefit. prostate volume, history of previous trusb, and use of antimicrobials have been reported to be associated with febrile utis after trusb;(12,13,30) however, we could not detect any clinical variables statistically associated with febrile utis except psa, which was higher in the febrile patients (table 2). although there was no difference in clinical variables between the two hospitals, all febrile utis occurred in patients at japanese red cross otsu hospital. to identify any possible cause, we reviewed all the maneuvers associated with trusb at the two hospitals, and found that the only difference was the way of bowel preparation prior to trusb. all the patients who developed acute prostatitis did not receive any bowel preparation. the combined antimicrobial prophylaxis protocol was adopted for one year following the end of patient recruitment for this study. during this one-year period, another four febrile uti cases occurred, exclusively in the patients not receiving any bowel preparation, suggesting a possible prophylactic role of bowel preparation in trusb. kim and colleagues reported that using enemas significantly decreased the incidence of acute prostatitis (15 [1.6%] of 913 in enema group, and 3 [30%] of 10 in no enema group).(31) on the contrary, carey and colleagues have retrospectively reviewed the usefulness of enemas in trusb, and found no significant difference in the incidence of acute prostatitis (10 [4.4%)] of 225 in enema group, 6 [3.2%] of 185 in no enema group).(32) therefore, a well-designed randomized study is necessary to confirm the role of bowel preparation in trusb. fq resistant e-coli continue to be a growing threat for patients undergoing trusb. the rate of lvfx resistant e-coli among all the e-coli isolated from urine samples has been increasing even after 2009 at japanese red cross otsu hospital, and is approaching 35% in 2015 (figure 3). considering the cost of treating trusb induced sepsis, newer prophylactic methods are certainly needed, and multiple studies to improve efficacy of prophylaxis including personalized approach based on pre-biopsy rectal swab are underway. conclusions there is a strong rationale to add amk to conventional fq-based regimens, since fq-resistant coliforms show strong sensitivity to amk in vitro. however, in the present randomized control study, addition of a single figure 3. ratios of lvfx-resistant e.coli and esbl-producing e.coli to all e.coli isolated from urine cultures of patients with uti between 2002 and 2015 at japanese red cross otsu hospital. abbreviations: lvfx, levofloxacin; e. coli, escherichia coli; esbl, extended-spectrum β-lactamase; uti, urinary tract infection. amikacin and levofloxacin for prophylaxis in prostate biopsy-miyazaki et al. urological oncology 2538 vol 13 no 01 january-february 2016 2539 intravenous administration of amk to single oral administration of lvfx did not show any advantage compared with lvfx alone as an antimicrobial prophylaxis in trusb. more strikingly, all the pathogens isolated from febrile patients were sensitive to amk. therefore, further understanding of drug kinetics of amk in the prostate is necessary to develop a more efficient drug delivery method for amk. factors other than antimicrobial prophylaxis, such as bowel preparation, should also be considered in the future studies. conflicts of interest none declared. references 1. tufan zk, bulut c, yazan c, et al. a lifethreatening escherichia coli meningitis after prostate biopsy. urol j. 2011;8:69-71. 2. sieber pr, rommel fm, agusta ve, breslin ja, huffnagle hw, harpster le. antibiotic prophylaxis in ultrasound guided prostate biopsy. j urol. 1997;157:2199-200. 3. kapoor da, klimberg iw, malek gh, et al. single-dose oral ciprofloxacin versus placebo for prophylaxis during transrectal prostate biopsy. urology. 1998;52:552-8. 4. shandera kc, thibault gp, deshon ge jr. variability in patient preparation for prostate biopsy among american urologists. urology. 1998;52:644-6. 5. schwartz bf, swanzy s, thrasher jb. a randomized prospective comparison of antibiotic tissue levels in the corpora cavernosa of patients undergoing penile prosthesis implantation using gentamicin plus cefazolin versus an oral fluoroquinolone for prophylaxis. j urol. 1996;156:991-4. 6. cambau e, gutmann l. mechanisms of resistance to quinolones. drugs. 1993;45 suppl 3:15-23. 7. carratala j, fernandez-sevilla a, tubau f, dominguez ma, gudiol f. emergence of fluoroquinolone-resistant escherichia coli in fecal flora of cancer patients receiving norfloxacin prophylaxis. antimicrob agents chemother. 1996;40:503-5. 8. isen k, kupeli b, sinik z, sozen s, bozkirli i. antibiotic prophylaxis for transrectal biopsy of the prostate: a prospective randomized study of the prophylactic use of single dose oral fluoroquinolone versus trimethoprimsulfamethoxazole. int urol nephrol. 1999;31:491-5. 9. aron m, rajeev tp, gupta np. antibiotic prophylaxis for transrectal needle biopsy of the prostate: a randomized controlled study. bju int. 2000;85:682-5. 10. griffith bc, morey af, ali-khan mm, canby-hagino e, foley jp, rozanski ta. single dose levofloxacin prophylaxis for prostate biopsy in patients at low risk. j urol. 2002;168:1021-3. 11. özden e, bostanci y, yakupoglu ky, et al. incidence of acute prostatitis caused by extended-spectrum beta-lactamase-producing escherichia coli after transrectal prostate biopsy. urology. 2009;74:119-23. 12. felicano j, teper e, ferrandino m, et al. the incidence of fluoroquinolone resistant infection after prostate biopsy – are fluoroquinolones still effective prophylaxis? j urol. 2008;179:952-5. 13. young jl, liss ma, szabo rj. sepsis due to fluoroquinolone-resistant escherichia coli after transrectal ultrasound-guided prostate needle biopsy. urology. 2009;74:332-8. 14. american urological association. best practice policy statement on urologic surgery antimicrobial prophylaxis. available at:http:// www.auanet.org/education/guidelines/ antimicrobial-prophylaxis.cfm 15. batura d, gopal rao g, nielsen p. prevalence of antimicrobial resistance in intestinal flora of patients undergoing prostatic biopsy: implications for prophylaxis and treatment of infections after biopsy. bju int. 2010;106:1017-20. 16. parkin dm, bray f, ferlay j, pisani p. global cancer statistics, 2002. ca cancer j clin. 2005;55:74-108. 17. bentley fd, kitchens dm, bell te. antimicrobial prophylaxis and patient preparation for transrectal prostate biopsy: review of the literature and analysis of costeffectiveness. infect urol. 2003;16:3-12. 18. bootsma am, laguna pes mp, geerlings se, goossens a. antibiotic prophylaxis in urologic procedure: a systematic review. eur urol. 2008;54:1270-86. 19. lee g, attar k, laniado m, karim o. transrectal ultrasound guided biopsy of the prostate: nationwide diversity in practice and training in the united kingdom. int urol nephrol. 2007;39:185-8. 20. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part 1:screening, diagnosis, and local treatment with curative intent-update 2013. eur urol. 2014;65:124-37. 21. shigemura k, yasufuku t, yamashita m, arakawa s, fujisawa m. prophylactic use of isepamicin and levofloxacin for transrectal prostate biopsy: a retrospective single center study. int j urol. 2009;16:723-5. 22. ho hs, ng lg, tan yh, yeo m, cheng cw. intramuscular gentamicin improves the efficacy of ciprofloxacin as an antibiotic prophylaxis for transrectal prostate biopsy. ann acad med singapore. 2009;38:212-6. 23. batura d, gopal rao g, nielsen p, charlett a. adding amikacin to fluoroquinolone-based amikacin and levofloxacin for prophylaxis in prostate biopsy-miyazaki et al. antimicrobial prophylaxis reduces prostate biopsy infection rates. bju int. 2011;107:7604. 24. campeggi a, ouzaid i, xylinas e, et al acute bacterial prostatitis after transrectal ultrasoundguided prostate biopsy: epidemiological, bacteria and treatment patterns from a 4-year prospective study. int j urol. 2014;21:152-5. 25. goto t, makinose s, ohi y, et al. diffusion of piperacillin, cefotiam, minocycline, amikacin, and ofloxacin into the prostate. int j urol. 1998;5:243-6. 26. cam k, kayikci a, akman y, erol a. prospective assessment of the efficacy of single dose versus traditional 3-day antimicrobial prophylaxis in 12-core transrectal prostate biopsy. int j urol. 2008;15:997-1001. 27. shigemura k, tanaka k, yasuda m, et al. efficacy of 1-day prophylaxis medication with fluoroquinolone for prostate biopsy. world j urol. 2005;23:356-60. 28. miura t, tanaka k, shigemura k, nakano y, takenaka a, fujisawa m. levofloxacin resistant escherichia coli sepsis following an ultrasound-guided transrectal prostate biopsy: report of four cases and review of the literature. int j urol. 2008;15:457-9. 29. yamamoto s, ishitoya s, segawa t, kamoto t, okumura k, ogawa o. antibiotic prophylaxis for transrectal prostate biopsy: a prospective randomized study of tosufloxacin versus levofloxacin. int j urol. 2008;15:6046. 30. chiang in, chang sj, pu ys, huang kh, yu hj, huang cy. major complications and associated risk factors of transrectal ultrasound guided prostate needle biopsy: a retrospective study of 1875 cases in taiwan. j formos med assoc. 2007;106:929-34. 31. kim sj, kim si, ahn hs, choi jb, kim ys, kim sj. risk factors for acute prostatitis after transrectal biopsy of the prostate. korean j urol. 2010;51:426-30. 32. carey jm, korman hj. transrectal ultrasound guided biopsy of the prostate. do enemas decrease clinically significant complications? j urol. 2001;166:82-5. amikacin and levofloxacin for prophylaxis in prostate biopsy-miyazaki et al. urological oncology 2540 miscellaneous use of lidocaine 2% gel does not reduce pain during flexible cystoscopy and is not cost-effective maría del carmen cano-garcía,1 rosario casares-perez,1 miguel arrabal-martin,2* sergio merino-salas,3 miguel angel arrabal-polo1 purpose: to compare the use of lubricant gel with lidocaine versus lubricant gel without anesthetic in flexible cystoscopy in terms of pain and tolerability. materials and methods: in this observational non-randomized study, 72 patients were divided into two groups. group 1 included 38 patients in whom lidocaine gel 2% was used and group 2 included 34 patients in whom lubricant gel without anesthetic was administered. the main variables analyzed were score in visual analogue scale (vas) and score in spanish pain questionnaire (spq). student's t-test and chi-square test were used to compare differences between 2 groups. the p values < .05% were considered statistically significant. results: mean age of patients in group 1 was 64.50 ± 12.39 years and 67.79 ± 10.87 years in group 2 (p = .23). the distribution according to sex was 29 men and 9 women in group 1 and 25 men and 9 women in group 2 (p = .78). the total vas score was 2.21 ± 2.05 in group 1 versus 1.59 ± 1.61 in group 2 (p = .16). in the spq, the current intensity value was 1.82 ± 0.86 in group 1 versus 1.53 ± 0.74 in group 2 (p = .14), and the total intensity value was 1.92 ± 1.86 in group 1 versus 1.03 ± 1.75 in group 2 (p = .04). the cost of gel with lidocaine is 1.25 euro and gel without anesthetic 0.22 euro. conclusion: the use of lidocaine gel does not produce benefit in terms of pain relief in flexible cystoscopy and also is costly. keywords: cystoscopy; methods; adverse effects; diagnosis; anesthetics; local; lidocaine; therapeutic use; treatment outcome; pain prevention & control; pain measurement. introduction flexible cystoscopy is a very useful outpatient tech-nique for studying the urethra and bladder, and especially for diagnosis and management of lower urinary tract diseases. in most cases cystoscopy is performed with local anesthesia. this technique revolutionized the diagnostic area in urology, resulting in the replacement of rigid cystoscopy with flexible cystoscopy in most hospitals.(1) although the diagnostic cystoscopy procedure can be performed using either rigid or flexible cystoscope, in men it is preferable to use flexible instruments because it is better tolerated, causing less pain and fewer complications.(2) in women, however, indiscriminate use of flexible or rigid cystoscopy is generally well tolerated.(3,4) overall, cystoscopy is not associated with a high perception of pain, although it is an uncomfortable procedure that usually produces more pain with the first procedure and less pain in subsequent procedures.(5) flexible cystoscopy can be performed with or without local anesthetic lubricant (mainly lidocaine). choosing each, depends primarily on the availability at the hospital and preference of the urologist performing the procedure, since there is no uniformity about whether the use of lubricant gel with or without anesthetic is better. some studies indicate that the gel with lidocaine reduces moderate to severe pain during the procedure,(5) while others concluded that there is no significant difference in visual analogue scale.(6) the aim of this study was to evaluate the differences in visual analogue scale (vas) and the spanish pain questionnaire (spq) score in patients undergoing flexible cystoscopy using lubricant gel with 2% lidocaine versus lubricant gel without anesthetic. materials and methods study design this is a non-randomized observational study comparing the use of lidocaine 2% gel versus lubricant gel without anesthetic in patients undergoing simple flexible cystoscopy. patients were recruited between september and december 2014. the indications for cystoscopy were hematuria, bladder cancer follow-up, lower urinary tract symptoms (luts), recurrent urinary tract infections, and others. the procedure was performed by two different urologists with the same level of experi1 department of urology, la inmaculada hospital, huercal overa (almeria), spain. 2 department of urology, granada universitary hospital, ibs granada, spain. 3 department of urology, poniente hospital, el ejido (almería), spain. *correspondence: department of urology, poniente hospital, el ejido (almería), spain. tel: +34 628 837188. fax: +34 958 023084. e-mail: arrabalp@ono.com. received january 2015 & accepted april 2015 miscellaneous 2362 ence in flexible cystoscopy. one urologist used lubricant gel with lidocaine and the other used lubricant gel without anesthetic, following their usual clinical practice. the nurse was blinded for the type of lubricant. consecutive patients attending the urology outpatient clinic in the urology department in la inmaculada hospital in huercal-overa (almería, spain) were selected for this study. inclusion criteria were men or women ≥ 18 years of age with hematuria, bladder cancer follow-up, luts, or recurrent urinary infections. exclusion criteria were patients younger than 18 years old with suspicion for urethral stricture, permanent bladder or suprapubic catheter, ureteral stent, active urinary tract infection, or sensibility problems. all patients were informed about the study and their informed consent was obtained. the ethics committee of our health area approved the study protocol. all procedures were performed in the same manner: supine (men) or lithotomy (women) position, skin and genital preparation with povidone iodine, and introducing an 18 french (f) flexible cystoscope using gel with lidocaine or gel without anesthetic. a total of 72 patients were recruited and divided into two groups: group 1 included 38 patients who underwent flexible cystoscopy with lubricant gel with lidocaine 2%. group 2 included 34 patients who underwent flexible cystoscopy with lubricant gel without anesthetic. main variables the main variables studied after the procedure were the pain score evaluated using visual analogue scale (vas) and spanish pain questionnaire (spq).(7) the spq is consisting of two parts: current intensity value (0-14 points) and total intensity value (0-5) and vas is measured as mild pain (0-3), moderate pain(4-7), or intense pain(8-10). others variables analyzed include sex, age, reason for cystoscopy, results of cystoscopy and cost. statistical analysis for a study population of 150,000 inhabitants, taking a precision of 5% and (1-α) of 95%, and 5% of dropout rate, at least 72 patients are needed. statistical analysis was performed using student's t-test for analysis of qualitative and quantitative variables and chi-squared test for analysis of dichotomous variables. a multivariate analysis was performed by binary logistic regression model. normality of variables was checked using kolmogorov-smirnov test and analysis of variance with levene's test was also performed. statistical significance was set as p < .05. analyses were performed with statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0 for windows. results seventy-two patients were included in the study with a mean age of 64.50 ± 12.39 years in group 1 and 67.79 ± 10.87 years in group 2 (p = .23). the sex ratio (men:women) was 29:9 in group 1 and 25:9 in group 2 (p = .78). the body mass index in group 1 was 28.7 ± 5.6 kg/m2 and in group 2 27.9 ± 4.9 kg/m2, with no statistically significant difference. about educational level, in group 1, 35% presented university studies, 40% medium studies and 25% basic studies and in group 2, 40% had university studies, 40% had medium studies and 20% had basic studies with no differences. in occupational status, in group 1, 25% were employed and 75% were retired, and in group 2, 20% were employed and 80% were retired, with no significant differences. the reason and results of cystoscopy are shown in table 1. the main pain score based on vas was 2.21 ± 2.05 in group 1 versus 1.59 ± 1.61 in group 2 (p = .16). in the spq, the current intensity value was 1.82 ± 0.86 in group 1 versus 1.53 ± 0.74 in group 2 (p = .14), and the total intensity value was 1.92 ± 1.86 in group 1 versus 1.03 ± 1.75 in group 2 (p = .04). these data are depicted in figure. in group 1, 24 patients presented a vas ≤ 2 (mild pain) versus 26 patients in group 2, which had no statistically significant difference (p = .221). in a multivariate analysis by binary logistic regression including age, sex, occupational status, body mass index and education level, no significant relation have been observed (table 2). discussion some studies have analyzed the role of anesthetic lubricant in rigid and flexible cystoscopy tolerability. the studies have shown no differences in pain and tolerability between immediate and delayed placement of flexible cystoscopy after intraurethral anesthetic installation.(8,9) in the study by herr and colleagues(8) with 288 patients undergoing flexible cystoscopy, they observed table 1. main reasons for and results of cystoscopy. no significant differences were observed in reasons for cystoscopy and results of cystoscopy analyzed with chi-square test. variables group 1 (n = 38) group 2 (n = 34) reasons for cystoscopy, no. bladder cancer follow up 19 20 hematuria 8 6 luts 8 1 others 3 7 results of cystoscopy normal 18 18 bladder cancer 10 6 edema / swelling 3 1 trabecular bladder 0 1 others 7 5 * punctuation is a result coefficient of multivariate analysis that appears with spss program. variables punctuation* gel p value sex .253 1 .615 age 1.812 1 .178 body mass index 2.620 1 .106 education level .013 1 .910 occupational status .194 1 .660 global statistics 4.967 5 .420 table 2. multivariate analysis by binary logistic regression using different independent variables related to use lubricant with or without local anesthesia. no significant differences were observed. lidocaine for pain reduction in flexible cystoscopy-cano-garcía et al. vol 12 no 05 september-october 2015 2363 that neither immediate nor delayed cystoscopy after the instillation of intraurethral lidocaine gel interfered with the results of the vas. losco and colleagues(9) agreed with herr and co-workers’ conclusion,(8) in that performing flexible cystoscopy immediately or delaying after the instillation of local anesthetic gel does not change the perception of pain by the patient. indeed, the controversy of whether or not intraurethral instillation with lidocaine improves tolerability and pain is ongoing. studies have shown some benefit of lidocaine gel versus plain lubricating gel,(5,10) while others have shown no benefit in using an anesthetic except adding to the cost of the procedure.(11-13) borch and colleagues(10) showed that intraurethral instillation of lidocaine 2% gel reduced pain compared to plain lubricating gel in patients undergoing cystoscopy. similarly, aaronson and colleagues(5) showed reduction in moderate to severe pain with the use of lidocaine gel compared to not using any local anesthetic. on the other hand, studies by kobayashi and colleagues(10,11) demonstrated no benefit from the use of an anesthetic gel; moreover, the anesthetic gel may produce a more painful sensation in the patient. the study of palit and colleagues(13) demonstrated that most patients undergoing flexible cystoscopy with lignocaine gel or lubricant gel without anesthetic, gave a score in vas of < 3, with no significant differences between them. in the study by chen and colleagues,(6) a score in vas of 2.8 versus 2.6 was observed among patients undergoing flexible cystoscopy using lubricant gel with lidocaine 2% versus lubricant gel without anesthetic, respectively, with no statistically significant difference. in our study, the results demonstrate that the use of lubricant gel with lidocaine 2% give no benefit during the procedure and actually produces more pain based on spq (total intensity value). in fact, most patients in our study commented that the lubricant anesthetic gel produced a stinging sensation in the urethra. also, the use of lubricant gel with lidocaine increased the cost of the procedure: the individual cost of lubricant gel with anesthetic is 1.25 euro and lubricant gel without anesthetic is 0.22 euro. as we know, there have been different studies assessing the tolerability of the procedure using intraurethral gel with local anesthetic versus no anesthetic. some of the studies show the benefit of using local anesthetic gel, while in others no significant differences are observed. in our study, lubricant with lidocaine did not produce any benefit and added to the cost of the procedure. therefore, we do not recommend its use. other techniques, drugs or maneuvers have been used to reduce pain and improve tolerability during the cystoscopy procedure such as increased hydrostatic pressure during cystoscopy,(14) inhaled nitrous oxide,(15) and self-viewing during cystoscopy.(16-18) they appear to be effective, but they have yet to become popular and are not routinely used. we know that our study have some limitations such as the number of patients and non-randomized manner, so it is necessary to design a randomized clinical trial with one surgeon and blinded to lubricant to avoid bias and to obtain a definitive conclusion. conclusions as a conclusion of this study, the use of lubricant gel without anesthetic is recommended when performing flexible cystoscopy, as it is not associated with more pain sensation in comparison with lidocaine, in addition it is more cost effective than lidocaine gel. acknowledgements this article is part of the doctoral thesis by maria del carmen cano-garcia whose thesis director is miguel angel arrabal-polo. conflict of interest none declared. references 1. pillai pl, sooriakumaran p. flexible cystoscopy: a revolution in urological practice. br j hosp med (london). 2009;70:583-5. 2. ciclone a, cantiello f, damiano r. cystoscopy in non-muscle-invasive bladder cancer: when and how (rigid or flexible). urologia. 2013;80:11-5. 3. gee jr, waterman bj, jarrard df, hedican sp, bruskewitz rc, nakada sy. flexible and rigid cystoscopy in women. jsls. 2009;13:135-8. 4. quiroz lh, shobeiri sa, nihira ma, brady j, wild ra. randomized trial comparing office flexible to rigid cystoscopy in women. int urogynecol j. 2012;23:1625-30. 5. aaronson ds, walsh tj, smith jf, davies bj, hsieh mh, konety br. meta-analysis: does lidocaine gel before flexible cystoscopy provide pain relief? bju int. 2009;104:506-9. 6. chen yt, hsiao pj, wong wy, wang cc, yang ss, hsieh ch. randomized doubleblind comparison of lidocaine gel and plain lubricating gel in relieving pain during flexible cystoscopy. j endourol. 2005;19:163-6. 7. ruiz lópez r, pagerols m, ferrer i. 1991b. el cuestionario del dolor en español. pain. 5: 110s. figure. comparison of visual analogue scale (vas) score and in spanish pain questionnaire (spq) scores between two groups show no benefit for lubricant gel with lidocaine 2% in the flexible cystoscopy procedure. lidocaine for pain reduction in flexible cystoscopy-cano-garcía et al. miscellaneous 2364 8. herr hw, schneider m. immediate versus delayed outpatient flexible cystoscopy: final report of a randomized study. can j urol. 2001;8:1406-8. 9. losco g, antoniou s, mark s. male flexible cystoscopy: does waiting after insertion of topical anaesthetic lubricant improve patient comfort? bju int. 2011;108 suppl 2:42-4. 10. borch m, scosyrev e, baron b, encarnacion j, smith em, messing e. a randomized trial of 2% lidocaine gel versus plain lubricating gel for minimizing pain in men undergoing flexible cystoscopy. urol nurs. 2013;33:18793. 11. kobayashi t, nishizawa k, ogura k. is instillation of anesthetic gel necessary in flexible cystoscopic examination? a prospective randomized study. urology. 2003;61:65-8. 12. kobayashi t, nishizawa k, mitsumori k, ogura k. instillation of anesthetic gel is no longer necessary in the era of flexible cystoscopy: a crossover study. j endourol. 2004;18:483-6. 13. palit v, ashurst hn, biyani cs, elmasray y, puri r, shah t. is using lignocaine gel prior to flexible cystoscopy justified? a randomized prospective study. urol int. 2003;71:389-92. 14. gunendran t, briggs rh, wemyss-holden gd, neilson d. does increasing hydrostatic pressure ("bag squeeze") during flexible cystoscopy improve patient comfort: a randomized controlled study. urology. 2008;72:255-9. 15. calleary jg, masood j, van-mallaerts r, barua jm. nitrous oxide inhalation to improve patient acceptance and reduce procedure related pain of flexible cystoscopy for men younger than 55 years. j urol. 2007;178:1848. 16. soomro kq, nasir ar, ather mh. impact of patient´s self-viewing of flexible cystoscopy on pain using a visual analog scale in a randomized controlled trial. urology. 2011;77:21-3. 17. patel ar, jones js, angie s, babineau d. office based flexible cystoscopy may be less painful for men allowed to view the procedure. j urol. 2007;177:1843-5. 18. cornel eb, oosterwijk e, kiemeney la. the effect on pain experienced by male patients of watching their office-based flexible cystoscopy. bju int. 2008;102:1445-6. lidocaine for pain reduction in flexible cystoscopy-cano-garcía et al. vol 12 no 05 september-october 2015 2365 111 urology journal unrc/iua vol. 2, no. 2, 111-114 spring 2005 printed in iran miscellaneous results of buccal mucosal graft urethroplasty in complex hypospadias darioush irani,* payman hekmati, alireza amin-sharifi department of surgery, shaheed faghihi hospital, shiraz university of medical sciences, shiraz, iran abstract introduction: urethral reconstruction in complex hypospadias poses a significant challenge. we report our experience using buccal mucosa to repair complex hypospadias. materials and methods: from february 2001 to september 2003, 16 urethral reconstructions were performed using buccal mucosal graft. twelve of the patients had previously failed urethroplasties, while the other 4 had perineal or scrotal hypospadias. grafts were harvested from the lower lip. onlay grafts were used in 8 cases, and tubularized grafts were used for the others. results: after 14 to 27 months' follow-up, 11 of 16 (69%) patients developed complications, including meatal stenosis in 2 (12.5%), urethral stricture in 5 (31%), and urethrocutaneous fistula in 4 (25%). no oral complications were seen, and all of the urethroplasty complications were managed successfully. conclusion: urethroplasty using a buccal mucosal graft may be accompanied by a relatively high complication rate, which is more common in patients with tubularized graft; however, all complications can be managed successfully. we believe that urethroplasty using buccal mucosal graft in complex hypospadias is an acceptable treatment modality. key words: hypospadias, urethra, buccal mucosa introduction patients requiring urethral reconstruction, who have a paucity of usable genital tissue, present a considerable technical challenge to reconstructive surgeons. most of these patients require a free tissue graft for neourethra construction. previously, extragenital skin from the groin, inner arm, posterior auricle, or bladder mucosa were used in urethral reconstruction; however, shortand long-term follow-up have indicated that they are far from ideal replacements.(1,2) another potential source for such grafts is the buccal mucosa. humby is credited as being the first person to use buccal free grafts for urethroplasty in 1941,(3) but it was burger and coworkers who popularized the use of buccal mucosal free grafts for hypospadias repair in recent decades.(4) in our center, buccal mucosal free graft was not used in hypospadias repair prior to this study. herein, we present our experience with the use of buccal mucosa for repairing complex hypospadias. received january 2004 accepted january 2005 *corresponding author: office of surgery, shaheed faghihi hospital, shiraz university of medical sciences, zand blvd, shiraz, iran. tel: ++98 917 112 3899, fax: ++98 711 233 1006 e-mail: iranid@sums.ac.ir buccal mucosal graft urethroplasty in complex hypospadias112 materials and methods from february 2001 to september 2003, 16 buccal mucosal grafts were used in 16 patients (mean age, 10.25 ± 3.42 years; range, 4 to 20 years) to repair complex hypospadias. twelve patients (75%) had a history of multiple previous failed hypospadias repairs (5 of them had undergone 3 previous urethroplasties, 4 had undergone 2 previous urethroplasties, and 3 had undergone 1 previous urethroplasty). the remaining 4 patients had perineal or penoscrotal hypospadias associated with a paucity of genital skin and no history of a previous operation (fresh cases). the procedure and probable complications were discussed with the patients, and the operation was performed after patients had given written, informed consent. the repair was started with conventional correction of the chordee. the actual urethral gap was measured after this correction. the chordee was corrected as much as possible before buccal mucosal was graft harvested to minimize the interval between removal and implantation of the graft. depending on the status of the urethra, the abnormal segment might be excised entirely, or the urethral plate could be saved for subsequent onlay of the graft. mucosa was harvested from the inner surface of the lower lip. free mucosal margins of the lip were not sutured together. excised mucosa was trimmed by sharp dissection to remove any excessive submucosal tissue or salivary glands to decrease the natural tendency toward elastic retraction. in 8 patients (50%) whose hypospadias was repaired with the urethral tube, the harvested graft was placed over an appropriately sized urethral catheter with the mucosa inward and tubularized with a running inverted 6-0 polyglactin suture. a wide spatulated anastomosis was performed with 6-0 polyglactin suture between the neourethra and the recipient urethra. in the remaining 8 patients (50%), the graft was used in onlay fashion, one side of it was sutured to the urethral strip using a running 6-0 polyglactin suture and trimmed in situ over an appropriately sized urethral catheter. the repair was completed by suturing the contralateral mucosal margin to the other edge of the plate. skin coverage was done after interposing a dartos flap and completing glenoplasty. in all patients, the urethral catheter served as a urinary drain and also as a stent within the graft, and it was removed on the seventh postoperative day. penile dressings were removed on the third postoperative day. all patients received 7 days of cephalosporin as a prophylactic antibiotic. to minimize postoperative gastrointestinal discomfort, a regular diet was instituted on the third postoperative day. patients were reexamined 1 day, 2 weeks, and 1 month after catheter removal, and then again in 6 months. during follow-ups, retrograde urethrogram or urethral calibration was done, if needed. results median follow-up was 23 months (range, 14 to 27 months). overall, complications occurred in 11 of 16 patients (69%), 2 occurred in the patients with a first repair and 9 were in redo cases. seven of the complications developed in tube grafts and 4 others occurred in onlay grafts. two patients (12.5%) developed meatal stenosis, necessitating meatoplasty, and 4 others (25%) developed a small urethrocutaneous fistula at the proximal part of neourethra (all in the onlay graft method). all fistulas were successfully repaired with delayed closure, 6 to 12 months later, on an outpatient basis. five patients (31%) developed full-thickness urethral strictures, lengthened 2-5 mm on follow-up. four of them developed midneourethral strictures, which were managed with external stricturotomy without applying any free graft, and were closed successfully 1 year later. of the 2 complicated cases among the first repairs, 1 was a stricture at the site of the anastomosis of the neourethra to the native urethra, and the other was a case of urethrocutaneous fistula; the former was managed successfully by excision of the stricture and reanastomosis. the sole complication among the onlay graft urethroplasties was urethrocutaneous fistula. no other complications were seen with this method. the overall complication rate in the patients with primary urethroplasty by buccal mucosa was 50% (2 of 4), whereas it was 75% (9 of 12) in those with "redo" hypospadias (p = 0.547, fisher exact test). no oral complications were seen, and all oral wounds healed completely in 8 weeks. irani et al 113 discussion several choices are available for urethral reconstruction with a concomitant lack of available genital tissue, which occurs most commonly in children or adults with multiple previous failed attempts at hypospadias repair. full-thickness skin from non-hair-bearing skin of the groin, buttocks, and upper arm has been used with early success, but significant complications, such as stricture formation, graft shrinkage, and scarification of the donor site, have been reported in studies with longer follow-ups.(1,5,6) the use of bladder mucosa may be difficult in children with a previous bladder operation, chronic cystitis, or even long-term suprapubic cystostomy. bladder mucosal grafting also may be a challenging procedure in patients with neurogenic dysfunction, whose bladder walls have become thickened and trabeculated. besides the complexity of harvesting, the major drawback with bladder mucosa is related to the neomeatus, which tends to prolapse in an exfoliative fashion.(2,7-9) humby was the first to report the use of buccal mucosa for repair of hypospadias, about 60 years ago.(3) subsequently, duckett(10) and burger(4) separately presented their series with relatively low complication rates in late 1980s, and since then this technique has been revived. these authors found that in comparison with penile skin, buccal mucosa has a thicker epithelium and a thinner lamina propria, so that inosculation and revascularization of the graft would be easier than that of other grafts. apart from these, abundant vascularity in the submucosal layer of the buccal mucosa graft also promotes its neovascularization. this is an accessible, nonhair-bearing material, and the intraoral donor site guarantees an excellent cosmetic result. in agreement with many other reports, our overall complications of urethral reconstructions with buccal mucosal graft were relatively high (69%). these are categorized in 3 major problems: 1urethral stricture: neourethra stricture, especially at the site of the anastomosis, is quite acceptable in virtually any procedure to repair hypospadias, including those using buccal mucosal grafts. in this study, we had a stricture rate of 31%, which is comparable with similar series: metro,(11) andrich,(12) and duckett(10) had 23%, 45%, and 17% stricture rates in their series (table 1). it should be mentioned that this study was the report of our first experience and logically, one would expect higher urethral stricture rates. 2meatal stenosis: we had a 12.5% (2 of 16 cases) incidence of meatal stenosis, which is most likely due to ischemia. frequent meatal dilation will avoid narrowing, but since most of our patients were adolescents, poor compliance with meatal dilation program may have contributed to this complication. in previous reports, the rate of meatal stenosis is different. burger and colleagues used buccal mucosa in 6 patients, of whom 1 developed meatal stenosis (17%).(4) meanwhile, duckett and coworkers,(10) metro and coworkers,(11) caldamone and coworkers,(9) burger and coworkers,(4) and ricabonra and coworkers(13) reported 28%, 17%, 9%, 17%, and 41% meatal stenosis in their series, respectively. 3urethrocutaneous fistula: as mentioned previously, most of our patients had multiple previous failed urethroplasties, and the graft bed had local scarring with poor vascularity. thus, urethrocutaneous fistula could be anticipated. in our series, we had 4 fistulas (25%) which is comparable with that in the studies of duckett,(10) buger,(4) and yerkes(14), who reported fistula rates of 6%, 50%, and 38%. the only complication following the onlay graft procedure was fistula formation. all fistulas were in the proximal part of the neourethra. therefore, it seems that our series is similar to others with regard to patients' population and the variety of complications. there was no case of meatal exuberance. our overall complication rate was relatively high (69%), and all of the cases needed reoperation. fifty-five percent of reoperations were simple closure of urethrocutaneous fistula or meatotomy, and the rest were more extensive. well-vascularized tissue for covering the neourethra is essential for taking a free graft. many of our patients had multiple previous attempts of reconstruction. subsequently, using buccal mucosa as a salvage technique in the most complicated cases may be associated with a higher complication rate, as a result of poor tissue quality and unavailable well-vascularized tissue for adequate coverage of neourethra after multiple repairs. although the rates of complications were relatively high, not only these were comparable with similar reports, but many of them also were managed by simple buccal mucosal graft urethroplasty in complex hypospadias114 interventions, such as internal urethrotomy for stricture, meatotomy for meatal stenosis, and simple closure of a fistula. therefore, the occurrence of such complications is not such a disappointment. no differences were apparent with regard to success and complication rates among patients with a positive history of previous hypospadias surgery and those without such a history. this may be due to the selection of patients with more proximal hypospadias, in whom there is inadequate prepuce for repair. this also shows the complex nature of these patients. finally, it is noteworthy that when the buccal mucosa is harvested from the cheek, potential injury to the stenson's duct would be expected, especially when the urologist is not so familiar with the anatomy of the oral cavity. herein, we harvested buccal mucosa from the lower lip. this simple modification not only maintains the efficacy of the original procedure, but it eliminates potential injury to the stenson's duct. thus, it is suitable for surgeons who are not familiar with oral cavity anatomy, especially in their first cases. conclusion for urethroplasty, our preference is always to use local tissue. on the other hand, recent popularization of tubularized incised plate (tip) urethroplasty has obviated the need for using free graft tissues in many cases. this procedure, however, is not suitable for complex cases such as multiple previous failed urethroplasties. in such cases, buccal mucosa tissue provides an alternative source for graft material. it can be used in carefully selected patients. careful and realistic counseling of patients is necessary. onlay grafts are preferable where the urethral plate may be preserved. however, in many complex cases, complete resection of previously constructed urethral segments is inevitable. due to the complex nature of patients treated with buccal mucosal graft urethroplasty, complications are not unexpected but each complication can be managed with somewhat simple intervention(s). acknowledgement the authors would like to thank the center for development of clinical research of nemazee hospital, shiraz university of medical sciences in shiraz, iran, and miss shayan for her help with the statistical analyses. references 1. webster gd, brown mw, koefoot rb jr, sihelnick s. suboptimal results in full thickness skin graft urethroplasty using an extrapenile skin donor site. j urol. 1984;131:1082-3. 2. kinkead tm, borzi pa, duffy pg, ransley pg. longterm followup of bladder mucosa graft for male urethral reconstruction. j urol. 1994;151:1056-8. 3. humby g. a one-stage operation for hypospadias. br j surg. 1941;29:84-6. 4. burger ra, muller sc, el-damanhoury h, tschakaloff a, riedmiller h, hohenfellner r. the buccal mucosal graft for urethral reconstruction: a preliminary report. j urol. 1992;147:662-4. 5. hendren wh, crooks kk. tubed free skin graft for construction of male urethra. j urol. 1980;123:858-61. 6. burbige ka, hensle tw, edgerton p. extragenital split thickness skin graft for urethral reconstruction. j urol. 1984;131:1137-9. 7. ehrlich rm, reda ef, koyle ma, kogan sj, levitt sb. complications of bladder mucosal graft. j urol. 1989;142:626-7; discussion 631. 8. memmelaar j. use of bladder mucosa in a one stage repair of hypospadias. j urol 1947;l58:68-70. 9. caldamone aa, edstrom le, koyle ma, rabinowitz r, hulbert wc. buccal mucosal grafts for urethral reconstruction. urology. 1998;51(5a suppl):15-9. 10. duckett jw, coplen d, ewalt d, baskin ls. buccal mucosal urethral replacement. j urol. 1995;153:1660-3. 11. metro mj, wu hy, snyder hm 3rd, zderic sa, canning da. buccal mucosal grafts: lessons learned from an 8year experience. j urol. 2001;166:1459-61. 12. andrich de, mundy ar. substitution urethroplasty with buccal mucosal-free grafts. j urol. 2001;165:1131-3; discussion 1133-4. 13. riccabona m. reconstruction or substitution of the pediatric urethra with buccal mucosa: indications, technical aspects, and results. tech urol. 1999;5:133-8. 14. yerkes eb, adams mc, miller da, brock jw 3rd. coronal cuff: a problem site for buccal mucosal grafts. j urol. 1999;162:1442-4. miscellaneous 120 urology journal vol 6 no 2 spring 2009 desmopressin as an alternative solution for urinary leakage after ureterocaliceal surgeries mohammad reza razzaghi,1,2 alireza rezaei,1 babak javanmard,1 behzad lotfi1 introduction: persistent urine leakage is common following iatrogenic urinary collecting system injuries. management of a urine leak usually includes manipulations such as catheter drainage, ureteral stenting, and percutaneous nephrostomy placement. the aim of this study was investigation the potential beneficial effect of desmopressin in reduction of urinary leakage duration. materials and methods: fifteen patients with incisional urinary leakage were enrolled in this study. they had undergone pyeloplasty (n = 9), pyelolithotomy (n = 4), and ureterocaliceal anastomosis (n = 1). all of them had ureteral stenting or nephrostomy catheters, and urinary leakage had lasted for at least 15 days. seven patients received desmopressin spray, 1 puff, twice a day, from the 16th days of urinary leakage, and 8 patients (control group) did not receive any medical treatment. the duration of urinary leakage was compared between the two groups. results: the patients were 5 women and 10 men with the median age of 37 years (range, 26 to 58 years). none of the patients had urinary obstruction. there were no significant differences in age and sex distribution between the two groups. the mean urinary leakage duration was 28.7 ± 7.2 days in the patients of desmopressin group and 47.7 ± 8.8 days in those of the control group (p = .04). conclusion: our study showed that desmopressin can reduce the duration of incisional urinary leakage. we conclude that patients with prolonged urinary leakage after pyelocaliceal surgery who does not respond to surgical urinary drainage may benefit from desmopressin. urol j. 2009;6:120-2. www.uj.unrc.ir keywords: postoperative complications, urinary leakage, desmopressin 1department of urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran 2laser research center, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran corresponding author: babak javanmard, md department of urology, shohada-etajrish hospotal, tajrish sq, tehran, iran tel: +98 21 2271 28001-9 fax: +98 21 2271 9017 e-mail: dr_javanmard@yahoo.com received december 2008 accepted april 2009 introduction urine leakage and urinoma result from disruption of the urinary collecting system at any level from the calyx to the urethra. persistent urine leakage is common following iatrogenic injuries.(1,2) management of urine leakage usually involves some manipulations such as catheter drainage, ureteral stenting, and percutaneous nephrostomy placement with open repair versus nephrectomy reserved for persistent leakage.(1) however, to our knowledge, the efficacy of medical therapy in urinary leakage have not been described before. we speculated that decrease in urinary output can help improvement of urinary leakage. in order to examine this hypothesis, we used desmopressin, which has antidiuretic effects and can reduce urinary output. herein, we report our preliminary experience of the effect of desmopressin in reduction of urinary leakage duration following urological surgeries. desmopressin for urinary leakage—razzaghi et al urology journal vol 6 no 2 spring 2009 121 materials and methods we prospectively studied on 16 patients with incisional urinary leakage documented by antegrade pyelography or follow-up nephrostography between 2000 and 2008. our inclusion criteria were ureteral stenting or nephrostomy catheters and the minimum urinary leakage duration of 15 days. the eligible participants provided written consent to be enrolled in the study after they were informed of the study protocol. creatinine levels of incisional excretions were more than 10 mg/dl in all patients. all stents and catheters were from a same company and all of the patients had received a first-generation cephalosporin as a prophylactic antibiotic. the patients were assigned into 2 groups alternatively, 15 days after the operation. we gave an opportunity of these 15 days for healing of sutures. eight patients received desmopressin acetate spray (minirin nasal spray, ferring pharmaceuticals, new south wales, australia), 1 puff, twice a day, starting from the 16th days of urinary leakage diagnosis. daily check of serum sodium and potassium levels were performed. patients in the control group underwent watchful waiting management after performing sufficient urinary drainage. the drains discontinued when their output was less than 30 ml/d. the urinary leakage duration was compared between the two groups. all continuous parameters are expressed as mean ± standard deviation. comparisons between groups were performed using the fisher exact test and the mcnemar test. significant p value was considered to be less than .05. results sixteen patients were included in the study, but 1 in the desmopressin group was excluded during our study, because of flushing and hyponatremia. the patients who were finally analyzed were 5 women and 10 men with the median age of 37 years (range, 26 to 58 years). all of them were shown to have urine leakage by creatinine level measurements. none of the patients had urinary obstruction. there were no significant differences in age and sex distribution between the two groups. the patients’ characteristics are shown in the table. the mean urinary leakage duration was 28.7 ± 7.2 days in the patients of desmopressin group and 47.7 ± 8.8 days in those of the control group (median, 26 days and 44 days, respectively; p = .04). all of the patients were discharged with good condition and re-operation was not performed for any of them. discussion vasopressin is a nonapeptide with a disulphide bridge between its two cysteine residues. the gene for vasopressin is situated on chromosome 20, not far from the gene for oxytocin. vasopressin is synthesized as a large prohormone, which is called preprovasopressin. this prohormone is synthesized principally by the magnocellular neurons of the paraventricular and supraoptic nuclei in the hypothalamus.(3) desmopressin is a synthetic analogue of arginine vasopressin, which is commercially available since 1974. this drug is proven effective for the treatment of nocturnal enuresis, central diabetes insipidus, and some coagulopathies.(4-12) a contra-indication for use of desmopressin is severe allergic reaction. the drug should discontinue if allergic reaction, anaphylaxis, and water toxicity are induced. one of our patients developed flushing and hyponatremia, which led to his withdrawal from the study group. the antidiuresis induced by desmopressin is more potent than that of arginine vasopressin, resulting in an increased urine osmolality and a characteristics desmopressin group control group number of patients 7 8 age, y 43.3 ± 7.5 40.0 ± 6.3 males 5 (71.4) 5 (62.5) operation type pyeloplasty 4 (57.1) 5 (62.5) pyelolithotomy 2 (28.6) 2 (25.0) ureterocaliceal anastomosis 1 (14.3) 0 duration of urinary leakage, d 28.7 ± 7.2 47.7 ± 8.8 demographic and surgical characteristics of patients treated with desmopressin and controls* *values in parentheses are percents. desmopressin for urinary leakage—razzaghi et al 122 urology journal vol 6 no 2 spring 2009 decreased urine output. cimentepe and colleagues reported a patient with prolonged urinary drainage after percutaneous nephrolithotomy who had not responded to insertion of a double pig-tail stent. they showed that treatment with oral desmopressin could reduce urinary leakage.(13) in the present study, we benefited from the antidiuretic effect of desmopressin in the management of urinary leakage after pyelocaliceal operations in a limited number of patients. we used desmopressin in patients who did not respond to surgical procedures of urinary drainage. our study showed desmopressin can reduce the duration of urinary leakage in these patients. although the number of patients in each arm of the study was not enough to make a definite conclusion, reducing the duration of urinary leakage (up to nearly 40%) was considerable. conclusion the use of desmopressin may improve the beneficial effect of other procedures such as catheter drainage, ureteral stenting, and percutaneous nephrostomy placement for incisional urinary leakage. thus, patients with prolonged urinary leakage after pyelocaliceal surgeries who do not respond to surgical urinary drainage can benefit from desmopressin. however, our study had limitations such as a small sample, and larger sample sizes can help to test more accurately the effect of diuretics on incisional urinary leakage. this study can be considered as a clue to the use of antidiuretic therapy in the management of postoperative urinary leakage. conflict of interest none declared. references 1. meeks jj, zhao lc, navai n, perry kt, jr., nadler rb, smith nd. risk factors and management of urine leaks after partial nephrectomy. j urol. 2008;180:2375-8. 2. simmons mn, gill is. decreased complications of contemporary laparoscopic partial nephrectomy: use of a standardized reporting system. j urol. 2007;177:2067-73. 3. vincent jl, su f. physiology and pathophysiology of the vasopressinergic system. best pract res clin anaesthesiol. 2008;22:243-52. 4. asplund r, sundberg b, bengtsson p. desmopressin for the treatment of nocturnal polyuria in the elderly: a dose titration study. br j urol. 1998;82:642-6. 5. asplund r, sundberg b, bengtsson p. oral desmopressin for nocturnal polyuria in elderly subjects: a double-blind, placebo-controlled randomized exploratory study. bju int. 1999;83:591-5. 6. mattiasson a, abrams p, van kerrebroeck p, walter s, weiss j. efficacy of desmopressin in the treatment of nocturia: a double-blind placebo-controlled study in men. bju int. 2002;89:855-62. 7. lose g, lalos o, freeman rm, van kerrebroeck p. efficacy of desmopressin (minirin) in the treatment of nocturia: a double-blind placebo-controlled study in women. am j obstet gynecol. 2003;189:1106-13. 8. kim rj, malattia c, allen m, moshang t, jr., maghnie m. vasopressin and desmopressin in central diabetes insipidus: adverse effects and clinical considerations. pediatr endocrinol rev. 2004;2 suppl 1:115-23. 9. fukuda i, hizuka n, takano k. oral ddavp is a good alternative therapy for patients with central diabetes insipidus: experience of five-year treatment. endocr j. 2003;50:437-43. 10. ziai f, walter r, rosenthal im. treatment of central diabetes insipidus in adults and children with desmopressin. arch intern med. 1978;138:1382-5. 11. hanebutt fl, rolf n, loesel a, kuhlisch e, siegert g, knoefler r. evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders. haemophilia. 2008;14:524-30. 12. coppola a, di minno g. desmopressin in inherited disorders of platelet function. haemophilia. 2008;14 suppl 1:31-9. 13. cimentepe e, unsal a, akbulut z, balbay md. prolonged urinary drainage from nephrostomy tract after percutaneous nephrolithotomy can be treated with oral desmopressin. scand j urol nephrol. 2004;38:266-7. urol_v03_no3_001_editorial.indd urology journal vol 3 no 3 summer 2006 189 erratum in volume 3, number 2 of the urology journal, 2 figures had been omitted in the final revision of the manuscript, prediction of successful sperm retrieval in patients with nonobstructive azoospermia. but in page 94, they are referred to following the first sentence of the second paragraph in the results. this article does not have any figures. we regret this error. erratum 1027vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l urology department, irccs policlinico san donato, university of milan, via morandi 30, 20097, san donato milanese, milan, italy. * e-mail: stepico@tin.it a 64-year old patient presented in hospital with abdominal discomfort. seven years before the patient had undergone radical cystectomy for invasive bladder cancer with orthotopic bladder reconstruction. a large medial hernia and two solid masses that rub together were palpated in the lower abdomen. a computed tomography (ct) scan of abdomen shows into the neo-bladder two big stone formations of 6 cm and 9 cm (figure 1). he underwent to a median suprapubic neo-cystolithotomy (figure 2). the most common long term complications in patients with ileal neobladder are metabolic acidosis, chronic urine retention, hernia and stone formation in the upper and lower urinary tract. in patients with adequate follow-up, stones can be identified and removed before they cause major symptoms. symptomatology is often very subtle and nonspecific but commonly presents with irritative lower urinary tract symptoms, pain and hematuria. for this reason, in some cases the stone can become quite large without the patient being aware. surgery is currently the gold standard of care and, depending on the size of the stone, we can use either trans-urethral lithotripsy or cystolithotomy. stefano picozzi, alberto macchi, luca carmignani giant bladder stones pictorial urology figure 1. a computed tomography (ct) scan of abdomen shows into the neo-bladder two big stone measuring 6 and 9 cm. figure 2. the removed neobladder stones during neocystolithotomy. 1465vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l vitrification of neat semen alters sperm parameters and dna integrity mohammad ali khalili, maryam adib, iman halvaei, ali nabi corresponding author: maryam adib, phd research and clinical center for infertility, shahid sadoughi university of medical sciences, yazd, iran. tell: +98 351 8247085 fax: +98 351 8247087 e-mail: hyperlink "mailto:blueocean10221@yahoo. com" blueocean10221@yahoo.com received march 2013 accepted july 2013 research and clinical center for infertility, shahid sadoughi university of medical sciences, yazd, iran. sexual dysfunction and infertility purpose:ouraimwastoevaluatetheeffectofneatsemenvitrificationonhumanspermvital parametersanddnaintegrityinmenwithnormalandabnormalspermparameters. materials and methods:semensampleswere17normozoospermicsamplesand17specimenswithabnormalspermparameters.semenanalysiswasperformedaccordingtoworld healthorganization(who)criteria.then,thesmearwasprovidedfromeachsampleandfixed forterminaldeoxynucleotidyltransferasedutpnickendlabeling(tunel)staining.vitrificationofneatsemenwasdonebyplungingcryoloopsdirectlyintoliquidnitrogenandpreserved for7days.thesampleswerewarmedandre-evaluatedforspermparametersaswellasdna integrity.besides,thecorrelationbetweenspermparametersanddnafragmentationwasassessedpre-andpostvitrification. results:cryopreservedspermatozoashowedsignificantdecreaseinspermmotility,viability andnormalmorphologyafterthawinginbothnormalandabnormalsemen.also,therateof spermdnafragmentationwassignificantlyhigheraftervitrificationcomparedtofreshsamplesinnormal(24.76±5.03and16.41±4.53,p=.002)andabnormal(34.29±10.02and 23.5±8.31, p<.0001),respectively.therewasnegativecorrelationbetweenspermmotility andspermdnaintegrityinbothgroupsaftervitrification. conclusion:vitrificationofneatejaculateshasnegativeimpactonspermparametersaswell asdnaintegrity,particularlyamongabnormalsemensubjects.itis,therefore,recommend toprocesssemensamplesandvitrifythespermpellets. keywords:vitrification;humans;dnadamage;cryopreservation;methods;infertility;spermatozoa;semenpreservation.. 1466 | sexual dysfunction and infertility introduction cryopreservation of human spermatozoa is per-formed routinely in assisted reproductive tech-nology (art) program. sperm bank is mainly developedformenthatareundergoingchemotherapy/radiotherapy,arttreatmentcycles,orhaveejaculationabnormalitiesandazoospermia.ithasbeenreportedthatsperm cryopreservationmighthaveseveralimpactsonspermcell, such as excessive dehydration, damage to plasma membrane and acrosome cap, mitochondria injury, apoptosis and sperm dna fragmentation.(1-3) there are currently threemethodsofcryopreservationnamely:slowfreezing, rapid freezing and vitrification. the first two techniques have been in practice for decades. however, they have somedrawbacks,suchasrequiringexpensiveequipment, aretimeandlaborconsumingandhavelimitedefficacy.(4) vitrificationisthefreezingmethodbasedonultra-rapidcoolingofwatertoglassystateatthehighviscositywithnointracellular ice formation.(5) vitrification of sperm freezing wasfirstintroducedbytheisachenko’sgroup,inwhichthe samplesweredirectlyandquicklyplungedintotheliquidnitrogen(ln).(6,7)spermvitrificationisfast,simpleandmore costeffectivecomparedtoslowfreezing.also,vitrification canpreventspermcryo-injuries.(6-9) while, it is shown that slowfreezingandthawingisassociatedwithspermdna damageandapoptosisinhumanejaculatedspermatozoa,littleisknownabouttheeffectofvitrificationoninductionof humanspermdnafragmentation.cryopreservationofraw orpreparedsemenhasremainedamatterofdebateintheliterature.(2)nawrothandcolleaguesreportedthatrecoveryrate ofmotilespermatozoaaswellasnormalmorphologyafter vitrificationwashigherinnativespermatozoaincomparison to cryoprotectant used ones.(6)theyalsofoundthatspermrecoveryrateandnormalmorphologywillbehigheraftervitrificationinpreparedspermatozoacomparedtonativegroup. (6)recently,satirapodandcolleaguesshowedthattherate ofdnafragmentationwillbereducedincryopreservedraw semenwithsolidsurfacevitrificationcomparedtostandard freezingmethod.(10) there are several techniques in order to determine sperm dnafragmentation.(11-13)terminaldeoxynucleotidyltransferasedutpnickendlabeling(tunel)assayisareliable techniquetoevaluatedoublestranddnafragmentation.(14) themaingoalofthisstudywastoevaluatetheeffectofvitrificationofneatsemensamplesinbothnormalandabnormal semengroupsonthespermparametersanddnastatususing tunelassay. materials and methods sampling and spermatozoa evaluation ejaculates were obtained from men aged between 30-50 yearsold(17normaland17abnormalsemensamples)by masturbationafter48-hourofsexualabstinence.innormal semengroup,theinclusioncriteriawasinfertilityduetofemalefactorandintheinfertilementhecoupleswereinfertile duetomalefactor.after liquefaction,semenanalysiswas performedaccordingtoworldhealthorganization(who) guidelines.(15)spermcountandmotilitywereassessedusingneubauerchamberunderthelightmicroscope(×400). motilitytypeswerecategorizedinto:progressive,non-progressive,andimmotile.thespermviabilitywasassessedusingeosin-nigrosinstainingprotocol.thedeadspermatozoa werestainedred,whiletheliveoneswereunstained(figure 1).also,spermmorphologywasevaluatedbypapanicolaou stainingprocedure.atleast,200spermatozoawerechecked underlightmicroscopeforhead,neckandtailabnormalities. vitrification and warming vitrificationmethodwasaccordingtopreviousreportswith somemodifications.(16)thesemenwasloadedoncoppercryoloopsof2.5mmdiameterbydippingtheloopsinsuspensiontoobtainathinfilmof8±2µlandtheloadedloops wereplungedintheln.afterstoragefor7days,thesamples werewarmedbyplungingtheloopsintoatubecontaining 2.5mlham'sf10at37ºc.afterwarmingof10loopsinone tube,thetubewasplacedinaco2incubatorfor5-10min. then,thespermatozoawerecentrifugedat300gfor10min andtheresultantpelletwasresuspendedin100µlofham's f10andprocessedforfurtherevaluation. tunel staining insitucelldeathdetectionkit(rochediagnosticsgmbh. rocheappliedscience.68298mannheim,germany)was applied for tunel assay.after providing the smear, the slideswerefixedin100%methanolsolutionfor4minat roomtemperature.blockingwasperformedbyputtingthe slidesin3%h2o2inmethanolfor10minindarkness.before andafterblocking,theslideswerewashedwithphosphate bufferedsaline(pbs).forspermpermeabilization0.1%tritonx-100in0.1%sodiumcitratebufferwasused(10min 1467vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l neat semen vitrification and sperm parameters | khalili et al on ice). the slides were incubated with tunel reaction mixture1-hourwithhighhumidityat37˚c.afterwashing with pbs, the slides were incubated with convertor-probe followedbyincubationwith3,3'-diaminobenzidine(dab) (dab,roche,mannheim,germany)solution.twohundred spermcellswereanalyzedunderthelightmicroscopeat× 1000.abnormalspermatozoahaddarkbrownnuclear(figure 2).forpositivecontrols0.1iudnase(hoffmann-laroche diagnostics,mannheim,germany)wasappliedfor15minat 37˚candthereactionmixturehadnoterminaldeoxynucleotidyltransferase(tdt)fornegativecontrols. statistical analysis thedataareshownasmean±sd.spermparametersbefore andaftervitrificationwasanalyzedusingpairedttest.linear pearsoncorrelationtestwasappliedtofindoutthecorrelationbetweentheapoptosisandspermparameters.thelevel ofstatisticalsignificancewassetatp<.05. results thespermcellcountwere120.70±68.14and15.15±2.58 (106/ml)innormalandabnormalsemengroups,respectively. regardingspermmotility,56.11±10.45and28.11±8.15 were progressive motility and 67.58 ± 10.01 and 35.58 ± 11.94weretotalmotility,respectively.spermviabilitywere 78.47±9.38and50.58±15.15andspermmorphologywere 46.05±10.46and12.52±13.87,respectively. thedatashowedthatspermvitrificationcausedsignificant decreaseinspermmotility,viabilityandmorphologyinnormozoospermicsamples(table1).also,vitrificationwasinvolvedwithsignificantincreaseinspermdnafragmentation whichwasabout8%inabnormalsemengroup.inaddition, therewassignificantreductionforallspermparametersafter table 1. sperm parameters before and after vitrification in normozoospermic samples.* sperm parameters before vitrification after vitrification p count (×106/ml) 120.70 ± 68.14 89.00 ± 9.30 .134 progressive motility (%) 56.11 ± 10.45 5.29 ± 5.05 .000 total motility (%) 67.58 ± 10.01 8.64 ± 6.81 .000 normal morphology (%) 46.05 ±10.46 37.00 ± 11.72 .024 viability (%) 78.47 ± 9.38 11.05 ± 7.30 .000 tunel positive cells 16.41 ± 4.53 24.76 ± 5.03 .002 key: tunel, terminal deoxynucleotidyl transferase dutp nick end labeling. *data are shown as mean ± sd. figure 1. evaluation of human sperm viability using eosinnigrosin staining; (a) unstained (white) alive spermatozoa, (b) stained (red) dead spermatozoa. figure 2. evaluating the sperm dna fragmentation using tunel test. dark brown cells are abnormal spermatozoa. key: tunel, terminal deoxynucleotidyl transferase dutp nick end labeling. 1468 | sexual dysfunction and infertility vitrificationinabnormalsemengroup(table2). dnafragmentationwas11%higherinsemenwithabnormal spermparameterscomparedtobaseline.therewasnegative correlationbetweenspermdnafragmentationandviability innormozoospermicsamplesaftervitrification(r = -0.6, p = .004).thenegativecorrelationwasonlyobservedbetween spermdnafragmentationandprogressivemotilityaftervitrificationinnormozoospermicmen(table3).nosignificant correlationwasfoundbetweenabnormalspermdna,viabilityandmorphologyaftervitrificationinsemenwithabnormal spermparameters(table4). discussion thedatashowedasignificantdecreaseinspermparameters aswellassignificantincreaseinspermdnafragmentation aftervitrificationinbothgroupsofnormalandabnormalsemensamples.commonly,cryopreservationhasnegativeimpactonspermmotilityandviability.ourdataweresimilarto othersthatcryopreservationcauseddecreaseinspermmotilityandviability.(8,10)satirapodandcolleaguesinvestigated theefficacyofnewvitrificationmethodonnormozoospermic samples.theyevaluatedtheroleofrawsemensolidsurface vitrificationincomparisontorapidfreezingmethodonsperm parameters.theirdatashowedthatspermmotility,viability, morphologyanddnaintegritywerenoticeablyreducedafter vitrification.(10)incomparisontoourstudy,theirspermrecoveryrateaswellasdnadamagewashigher.oneprobable causewouldbethemethodofspermvitrification.alsothey usedcommercialcryoprotectant,whileweusedcryoprotectantfreemethod.nawrothandcolleaguesalsoreportedreducedspermparametersafterneatsemenvitrificationofnormaldonors.thedatashowedthatspermrecoverywouldbe muchhigherafterswimupcomparedtonativespermatozoa. (6)formationoflethalintracellularicecrystalsandosmoticstressmaybethemaincauseforreductioninspermcell motilityandviabilityduringcryopreservation.(17)isachenko andcolleaguescomparedspermmotilityafterfourdifferent cryoprotectant-freevitrificationtechniquesandshowedthat cryoloopmethodresultedinalowerspermmotilitycompared to droplets, open pool straws and open straws.(18)ourdata alsoshowedthatvitrificationimpairsspermnormalmorphologyinnormalandabnormalsemengroups.thefindingswere similartootherreportsintermsofnegativeeffectsofcryopreservation on normal sperm morphology.(1,10) it appears thatthemostprobablereasonfortheeffectoffreezingon spermmorphologyistheformationoficecrystalsoutsidethe spermcellwhichcanalterspermarchitecture.(1) generally,itisbelievedthatnormozoospermicsemensamplesmaybemoreresistanttocryo-injurycomparedtoabnormal oligozoospermic or asthenozoospermic specimens. table 2. sperm parameters before and after vitrification in abnormal semen.* sperm parameters before vitrification after vitrification p count (×106/ml) 19.15 ± 2.58 17.82 ± 2.87 .806 progressive motility (%) 42.11 ± 16.15 3.70 ± 2.35 .000 total motility (%) 55.58 ± 18.94 7.88 ± 3.34 .000 normal morphology (%) 18.52 ± 13.87 11.52 ± 9.57 .018 viability (%) 60.58 ± 19.15 8.64 ± 3.66 .000 tunel positive cells 23.50 ± 8.31 34.29 ± 10.02 .000 key: tunel, terminal deoxynucleotidyl transferase dutp nick end labeling. *data are shown as mean ± sd. table 3. correlation between sperm dna integrity and sperm parameters in normal semen before and after vitrification. variables progressive motility morphology viability count tunel positive spermatozoa (%) before vitrification r = -0.23 r = -0.85 r = -0.03 r = 0.15 p = .35 p = .000 p = .89 p = .54 after vitrification r = -0.49 r = 0.45 r = -0.6 r = -0.53 p = .04 p = .06 p = .004 p = .02 key: tunel, terminal deoxynucleotidyl transferase dutp nick end labeling. 1469vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l neat semen vitrification and sperm parameters | khalili et al table 4. correlation between apoptosis and sperm parameters in abnormal semen. variables progressive motility morphology viability count tunel positive spermatozoa (%) before vitrification r = -0.73 r = 0.15 r = -0.67 r = 0.18 p = .001 p = .54 p = .003 p = .48 after vitrification r = -0.6 r = -0.37 r = -0.32 r = -0.12 p = .01 p = .13 p = .2 p = .62 key: tunel, terminal deoxynucleotidyl transferase dutp nick end labeling. ourresultsshowedthatspermparametersanddnafragmentationdecreasedatthesamemannerinbothgroupsof normal and abnormal semen groups, which is in conflict withsomereports.donnellyandcolleaguesfoundthatspermatozoafrominfertilemenwouldbelessresistanttocryoinjuriescomparedwithspermatozoaoffertilemen.(19)one probablecausesofthisdiscrepancymaybemethodofcryopreservation.theyusedrapidfreezingmethod(freezingin lnvapor),whileourcryopreservationmethodwastypical vitrification.also,weusednocryoprotectantinthefreezing method.permeablecryoprotectantisusedinslowfreezingin ordertoreducecellshrinkageduringcryopreservation.using permeableandnon-permeablecryoprotectantsinspermcryopreservationnotonlymayhavenobeneficialeffects,butalso caninducedamageevenatroomtemperature.(16) it has been reportedthatcryoprotectantshavesomecelltoxicitysuchas osmoticdamageandchemicaltoxicity.(20) regarding probableeffectofcryoprotectantsonspermdna,itisshownthat presenceofcryoprotectantshasnonegativeimpactonsperm dna integrity.(16)ourdatashowedthatvitrificationcansignificantlyincreasespermdnafragmentationinbothnormal andabnormalsemengroups.theresultsweresimilartothe braziliangroup.theyfoundcryopreservationinduceddna fragmentationinbotholigozoospermicandnormozoospermicsamples.(21)andcolleaguesalsoshowedthat84.66%of spermatozoashowundamageddnafollowingvitrification/ warminginswim-uppreparednormalspecimens.(22)theeffectofcryopreservationonspermdnastatushasremained controversial.someinvestigatorsbelievethatcryopreservationhasnonegativeeffectonspermdnastatus.(16,23) while, others have shown that the cryopreservation is associated withnegativeeffectonspermdnaintegrityandchromatin stability.(2,24)oxidativestressmaybeoneoftheimportant causes of increasing sperm dna fragmentation.(25) cryopreservationmaychangethefluidityofspermmitochondrial membraneandconsequentlyincreasethepotentialofmitochondrialmembrane,finallyreactiveoxygenspecies(ros) will be produced and released.(2)weverifiedthatsemensamplesandnon-spermcellsinseminalfluidarepotentialsources ofrosproduction.also,itisshownthatpresenceofseminal leukocytesisassociatedwithmorerosproductionduring coolingto4˚c.(26)thethawingseemstohavemoreimportantroleininductionofdnadamageinspermcells.itwas reportedthatthehighestdegreeofspermdnafragmentation willbeoccurredduringthefirst4-hourofincubationafter thawinginfertiledonors.(27) anotherfindingwasthenegativecorrelationbetweensperm progressivemotilityanddnafragmentationaftervitrificationinnormozoospermicmen.itwasshownthatthereisa negativerelationshipbetweenspermmotility,vitalityorconcentrationandspermdnadamage.(28,29)but,therewasno significantcorrelationbetweenspermmorphologyanddna integrity, which was similar to other findings.(19) it seems thatthespermmorphologicalfeatureisnotrepresentativeof spermdnaquality.cryopreservationofraworpreparedsemenhasremainedmatterofdebateintheliterature.(2) it is believed thatseminalplasmacontainsnaturalantioxidants which can protect spermatozoa from cyro-injuries during cryopreservationandtheseseminalplasmaantioxidantswill beeliminatedwithspermpreparationmethods.neatsemen cryopreservationwouldberapidandcost-effectiveaswell. inthisstudywecryopreservednormalandabnormalrawsemen.maybe,rosproductionbynon-spermcellsinseminal plasmaishigherthanseminalplasmaantioxidantscapacity, especiallyinsubnormalspecimens. conclusion vitrificationofhumanneatsemencanimpairvitalspermparametersofmotility,viability,morphologyaswellasdna integrity.itmightbebettertovitrifytheprocessedsemen, especiallyforcaseswithmalefactorinfertility. conflict of interest none declared. 1470 | sexual dysfunction and infertility references 1. ozkavukcu s, erdemli e, isik a, oztuna d, karahuseyinoglu s. effects of cryopreservation on sperm parameters and ultrastructural morphology of human spermatozoa. j assist reproduc genet. 2008;25:403-11. 2. said tm, gaglani a, agarwal a. implication of apoptosis in sperm cryoinjury. reprod biomed online. 2010;21:456-62. 3. di santo m, tarozzi n, nadalini m, borini a. human sperm cryopreservation: update on techniques, effect on dna integrity, and implications for art. adv urol. 2012;2012:3. 4. al-hasani s, ozmen b, koutlaki n, schoepper b, diedrich k, schultzemosgau a. three years of routine vitrification of human zygotes: is it still fair to advocate slow-rate freezing? reprod biomed online. 2007;14:288-93. 5. fahy gm. the relevance of cryoprotectant “toxicity” to cryobiology. cryobiology. 1986;23:1-13. 6. nawroth f, isachenko v, dessole s, et al. vitrification of human spermatozoa without cryoprotectants. cryo letters. 2002;23:93-102. 7. isachenko e, isachenko v, katkov ii, dessole s, nawroth f. vitrification of mammalian spermatozoa in the absence of cryoprotectants: from past practical difficulties to present success. reprod biomed online. 2003;6:191-200. 8. isachenko e, isachenko v, weiss j, et al. acrosomal status and mitochondrial activity of human spermatozoa vitrified with sucrose. reproduction. 2008;136:167-73. 9. isachenko v, maettner r, petrunkina a, et al. vitrification of human icsi/ivf spermatozoa without cryoprotectants: new capillary technology. j androl. 2012;33:462-8. 10. satirapod c, treetampinich c, weerakiet s, wongkularb a, rattanasiri s, choktanasiri w. comparison of cryopreserved human sperm from solid surface vitrification and standard vapor freezing method: on motility, morphology, vitality and dna integrity. andrologia. 2012;44 suppl 1:786-90. 11. khalili ma, aghaie-maybodi f, anvari m, talebi ar. sperm nuclear dna in ejaculates of fertile and infertile men: correlation with semen parameters. urol j. 2006;3:154-9. 12. nabi a, khalili ma, halvaei i, roodbari f. prolonged incubation of processed human spermatozoa will increase dna fragmentation. andrologia. (article first published online : 12 mar 2013, doi: 10.1111/and.12088. 13. halvaei i, sadeghipour roodsari hr, naghibi harat z. acute effects of ruta graveolens l. on sperm parameters and dna integrity in rats. j reprod infertil. 2012;13:33-8. 14. gavrieli y, sherman y, ben-sasson sa. identification of programmed cell death in situ via specific labeling of nuclear dna fragmentation. j cell biol. 1992;119:493-501. 15. who. who laboratory manual for the examination and processing of human semen. 5 ed: cambridge university press; 2010. 16. isachenko v, isachenko e, katkov ii, et al. cryoprotectant-free cryopreservation of human spermatozoa by vitrification and freezing in vapor: effect on motility, dna integrity, and fertilization ability. biol reprod. 2004;71:1167-73. 17. muldrew k, mcgann le. mechanisms of intracellular ice formation. biophys j. 1990;57:525-32. 18. isachenko v, isachenko e, montag m, et al. clean technique for cryoprotectant-free vitrification of human spermatozoa. reprod biomed online. 2005;10:350-4. 19. donnelly et, steele ek, mcclure n, lewis se. assessment of dna integrity and morphology of ejaculated spermatozoa from fertile and infertile men before and after cryopreservation. hum reprod. 2001;16:1191-9. 20. katkov ii, katkova n, critser jk, mazur p. mouse spermatozoa in high concentrations of glycerol: chemical toxicity vs osmotic shock at normal and reduced oxygen concentrations. cryobiology. 1998;37:325-38. 21. de paula ts, bertolla rp, spaine dm, cunha ma, schor n, cedenho ap. effect of cryopreservation on sperm apoptotic deoxyribonucleic acid fragmentation in patients with oligozoospermia. fertil steril. 2006;86:597-600. 22. isachenko e, isachenko v, katkov ii, et al. dna integrity and motility of human spermatozoa after standard slow freezing versus cryoprotectant‐free vitrification. hum reprod. 2004;19:932-9. 23. duty s, singh n, ryan l, et al. reliability of the comet assay in cryopreserved human sperm. hum reprod. 2002;17:1274-80. 24. hammadeh m, askari a, georg t, rosenbaum p, schmidt w. effect of freeze-thawing procedure on chromatin stability, morphological alteration and membrane integrity of human spermatozoa in fertile and subfertile men. int j androl. 1999;22:155-62. 25. thomson l, fleming s, aitken r, de iuliis g, zieschang j-a, clark a. cryopreservation-induced human sperm dna damage is predominantly mediated by oxidative stress rather than apoptosis. hum reprod. 2009;24:2061-70. 26. wang aw, zhang h, ikemoto i, anderson dj, loughlin kr. reactive oxygen species generation by seminal cells during cryopreservation. urology. 1997;49:921-5. 27. gosálvez j, cortés-gutierez e, lópez-fernández c, fernández jl, caballero p, nuñez r. sperm deoxyribonucleic acid fragmentation dynamics in fertile donors. fertil steril. 2009;92:170-3. 28. shen hm, dai j, chia se, lim a, ong cn. detection of apoptotic alterations in sperm in subfertile patients and their correlations with sperm quality. hum reprod. 2002;17:1266-73. 29. zhang hb, lu sm, ma cy, wang l, li x, chen zj. early apoptotic changes in human spermatozoa and their relationships with conventional semen parameters and sperm dna fragmentation. asian j androl. 2008;10:227-35. 1471vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l vitrificationhasbroughtaboutimportantchangesincryopreservationandhumanfer-tilitypreservation.easinessandspeedandnoneedforcostlyfreezingtechnologiesarereasonsforitsrapiddevelopment.vitrificationisthesolidificationofaliquid withoutcrystallization.ascoolingcontinues,however,themolecularwavesintheliquidpermeatingthetissuedecline.finally,an"arrestedliquid"stateknownasaglassisattained.vitrificationhasbeendemonstratedtoaffordhigherpreservationforanumberofcells,including monocytes,ovaandearlyembryosandpancreaticislets.(1) thereareanumberofmajorcontestsforperformingofvitrificationfortissueengineered medicalproducts.withoutadheringtothesestandards,certainlytheprocessofvitrification willfail.thefirstoneisvitreousstate.thereisnoexplanationaboutvitreousstateinthis study.stabilityofthevitreousstateiscriticalforthemaintenanceofvitrifiedtissueintegrity andviability.inpresentstudythemethodofvitrificationhasnotbeenexplainedindetailsand itseemsmostofstandardsforvitrificationhavenotbeenconsidered.vitrificationmethodsto preservationhavesomeofthelimitationsassociatedwithconventionalfreezingmethods.(2) first,bothmethodsentaillowtemperaturestorageandtransportationconditions.neithercan bestoredabovetheirglasstransitiontemperatureforlongwithoutsignificantriskofproduct damageduetoinherentinstabilitiesresultingtoiceformationandgrowth.bothmethodsuse cryoprotectantswiththeirassociatedproblemsandnecessitateexperiencedtechnicalsupport duringrewarmingandcryoprotectantelutionphases.theveryhighconcentrationsofcryoprotectantsneededtofacilitatevitrificationarepotentiallytoxicsincethecellsmaybeexposedto thesehighconcentrationsathighertemperaturesthaninfreezingmethodsofcryopreservation. cryoprotectantscankillcellsbydirectchemicaltoxicity,orindirectlybyosmotically-induced stressesduringsuboptimaladditionorremoval.(3)uponcompleteachievementofwarming, thecellsshouldnotbeexposedtotemperaturesabove0ocformorethanafewminutesbefore theglass-formingcryoprotectantsareremoved.itispossibletoemployvitrifiedproductsin highlycontrolledenvironments,suchasacommercialmanufacturingfacilityoranoperating theater,butnotinanoutpatientoffice.thereisn’tanydataaboutabovementionedpointsin this study.(4)anotherissueisheattransfer.heattransferissuesaretheprimaryproblemfor scalingupthesuccessesinsomewhatsmalltissuespecimenstolargertissuesandorgans.the limitsofheatandmasstransferinbulkysystemsresultinnon-uniformcoolingandleadsto stressesthatmightbegincracking.infact,thehighercoolingratesthatfacilitatevitrification willtypicallyleadtohighermechanicalstresses.(5)inpresentstudythereisnoinformationon theusedmaterialpropertiesofvitreousaqueoussolutions.materialpropertiessuchasthermal conductivityandfracturestrengthofvitreousaqueoussolutionshavemanyconnectionswith theirinorganicanaloguesthathappenatnormaltemperatures.anymaterialthatisunrestricted willundergoachangeinsize(thermalstrain)whensubjectedtoachangeintemperature. additionalimportantissuethathasnotbeenaddressed,isthestressesthatarisetobilletthe differentialshrinkage.thermalstresscandefinitelyreachtheproducedstrengthofthefrozen tissueresultinginplasticdeformationsorfractures.(6)onemoremajorobstacleforperforming editorial comment on: vitrification of neat semen alters sperm parameters and dna integrity mohammad reza safarinejad m.d clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com 1472 | ofvitrificationisthetechniqueusedforwarming.thisissuealsohasbeenignoredinpresent study.thewarmingtechniqueshouldbehighlyeffectivetopreventdevitrificationandice growth by recrystallization. therationalforvitrificationofneatsemenhasnotbeenmentioned.whataretheadvantages ofvitrificationofsemeninsteadofsperm?isthereanyscientificbackgroundforthisprocedure?forvitrification,itisrecommendedthat,eventheplasmaofspermshouldberemoved. forvitrificationthespermplasmaisremoved,itmeansthatbyusingthistechniquemany infectingagentssuchashiv,hepatitisandotherviruseswillberemovedfromthesperm,and thereforetheseinfectiousmicroorganismcannotbetransmittedviasperm.hencehiv+men willhavethechancetofatherchildrenwithouttheriskofpassinginfectiousorganismstobaby andmother.afterseparationofplasmafromthesperm,thevitrifiedspermshouldbestoredin anultra-colddeepfreezeat-86ºcenvironment.thismethodhasseveraladvantagescompared toothermethods,firstthemotilityofrethawedspermincreasessignificantly(75%usingthis methodvs.31%usingconventionalmethods)secondahighernumberofviablespermcanbe achievedandthiscanresultinhigherchanceoffertilizationinarts,suchasivfandicsi.(7) however,twodecadespastthefirstlive-birthfromvitrifiedembryos,therearestillsome uncertaintiesonthesafetyofthesetechniquesanditspossibletoxiceffectsonthehealthof childrenbornfromvitrifiedembryosoroocytes.thereisfearthatuseofhighconcentrations ofcryoprotectantsmayresultingeneticorepigeneticabnormalitieswithensuinginbornmalformations.therefore,thereisnoagreementorscientificrecommendationsforthereplacementofslowfreezingmethodwithvitrificationuniversally. thetechniquesforperformingvitrificationareevolving.recentlyvitrificationofmetaphase iioocyteshasbeendescribedtoholdabilityforoocytepreservation,whichcanbevitalin countrieswherealimitednumberofoocytescanbeinseminatedandembryocryopreservation isillegal,aswellasinoocytedonationandfertilitypreservationpriortocancertreatment.(8) thetwomostcommonlyusedteststodeterminespermdnadamagearethetunelassayandthespermchromatinstructureassay(scsa).(9)thetunelassayhasneverbeen adjustedforusewithhumanspermatozoaandlowernormalthresholdvalueshavenotbeen obviouslyrecognized.dnatestingbyscsahasbeenwidelystandardized.tuneltesthas notbeenstandardizedtothesamelevelasscsa.tunelassaycannotselectivelydifferentiateclinicallysignificantdnafragmentationfromclinicallyinsignificantfragmentation.the assayalsocannotdifferentiatenormaldnagroovesfrompathologicgrooves.moreover,the tuneltestdoesnotgiveanyinformationconcerningtheparticulargenesthatmaybeaffectedbydnafragmentation.thisassaycanonlydeterminetheamountofdnafragmentationthatensues,withthehypothesisthathigherlevelsofdnafragmentationarepathologic. (10)nowadays,theonlyreliabletesttodeterminespermdnafragmentationisscsa.this testhasvalidatedclinicalreferencerangeandcriteriatointerprettheyieldedresultsprecisely. usingthescsatestonecantest5,000individualspermwithahigh-precisionflowcytometer. tointerprettheresultsofscsatestdnafragmentationindex(dfi)isused,whichrepresents thepopulationofcellswithdnadamage.(11,12) finallyamajorlimitationofpresentstudyisabsenceofpicturesbothfromtunelresults andvitrifiedsperms. sexual dysfunction and infertility 1473vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l references 1. arav a, natan y. vitrification of oocytes: from basic science to clinical application. adv exp med biol. 2013;761:69-83. 2. aerts jm, de clercq jb, andries s, leroy jl, van aelst s, bols pe. follicle survival and growth to antral stages in short-term murine ovarian cortical transplants after cryologic solid surface vitrification or slow-rate freezing. cryobiology. 2008;57:163-9. 3. merino o, aguagüiña we, esponda p, et al. protective effect of butylated hydroxytoluene on sperm function in human spermatozoa cryopreserved by vitrification technique. andrologia. 2014 feb 24. doi: 10.1111/and.12246. [epub ahead of print] 4. imaizumi k, nishishita n, muramatsu m, et al. a simple and highly effective method for slow-freezing human pluripotent stem cells using dimethyl sulfoxide, hydroxyethyl starch and ethylene glycol. plos one. 2014;9:e88696. 5. steif ps, palastro m, wan cr, baicu s, taylor mj, rabin y. cryomacroscopy of vitrification, part ii: experimental observations and analysis of fracture formation in vitrified vs55 and dp6. cell preserv technol. 2005;3:184-200. 6. rabin y, podbilewicz b. temperature-controlled microscopy for imaging of living cells: apparatus, thermal analysis, and temperature dependency of embryonic elongation in caenorhabditis elegans. j microsc. 2000;199:214-23. 7. steif ps, palastro mc, rabin y. the effect of temperature gradients on stress development during cryopreservation via vitrification. cell preserv technol. 2007;5:104-15. 8. baicu s, taylor mj, chen z, rabin y. cryopreservation of carotid artery segments via vitrification subject to marginal thermal conditions: correlation of freezing visualization with functional recovery. cryobiology. 2008;57:1-8. 9. zini a, boman jm, belzile e, et al. sperm dna damage is associated with an increased risk of pregnancy loss after ivf and icsi: systematic review and meta-analysis. hum reprod. 2008;23:2663-8. 10. mitchell la, de iuliis gn, aitken rj. the tunel assay consistently underestimates dna damage in human spermatozoa and is influenced by dna compaction and cell vitality: development of an improved methodology. int j androl. 2011;34:2-13. 11. safarinejad mr. sperm dna damage and semen quality impairment after treatment with selective serotonin reuptake inhibitors detected using semen analysis and sperm chromatin structure assay. j urol. 2008;180:2124-8. 12. safarinejad mr. sperm chromatin structure assay analysis of iranian mustard gas casualties: a long-term outlook. curr urol. 2010;4:71-80. neat semen vitrification and sperm parameters | khalili et al 1119vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l achievements in postgraduate urologic education in iran: a quantitative study nasser simforoosh1, shima tabatabai 2, seyed amir mohsen ziaee1 corresponding author: shima tabatabai, phd school of medical education, shahid beheshti university of medical sciences, tehran, iran. tel: +98 21 2240 5611 fax: +98 21 2258 8016 e-mail: shtabatabai@yahoo.com received august 2013 accepted october 2013 1 urology and nephrology research center, department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2 school of medical education, shahid beheshti university of medical sciences, tehran, iran. miscellaneous purpose: the study focus is on the quantitative achievements in urology education and growth trends in urologic surgical workforce and fellowships by gender since 1979. materials and methods: this comprehensive national quantitative study was performed in iranian academy of medical science. the first hand data gathered from the iran specialty training council of and also from medical council of iran. results: over the period 1979 to 2012, the numbers of resident’s admission in urology/ fellowships have increased from 5 to 51 and from 0 to 24 respectively, and graduated urologists of national programs has grown from 5 (14%) in 1979 to 47 (100%) in 2012. iranian urologists workforce haves increased from 315 in 1979 to 1637 in 2012. in 1979, there was 1 urologist for every 117,460 population, while in 2012 there was 1 urologist for every 46120 population. iran urologists to population rate is 1:46120. these statistics represents significant improvement from 34 years ago. number of female urologists has progressively increased from 1 in 1979 (0%) to 110 (7%) in 2012. urology fellowships are offered in 6 fields since 1994 in iran. the number of trained fellowships grew sharply and reached to 221 in 2012. conclusion: the current urology training is successful to improve urology health care. along with expansion of urology and fellowship training, the number of iranian female urologists significantly increased. to our knowledge iran had the greatest growth rate of female urologist training in the middle east, and is comparable with those in the most progressed countries in the world. keywords: urology; education; iran; specialization; health planning; primary health care. 1120 | introduction there has been an increase in urologic surgical work-force in iran over the last 34 years. after establish-ment of ministry of health and medical education (mohme), based on health policies to improve health care, increasing the number of specialists and surgeons was a priority.(1) in 1970s, there were a few iranian urologists in main cities. health care centers in small towns and rural areas were run by many non-iranian urologist in part.(1) so, the shortage of physicians was a very serious issue, and that time only measure taken to solve this problem was hire foreign physicians,(2) (e.g. indian urologists). since 1979, great advances have been made in clinical postgraduate medical education.(3) training competent urologic surgical specialist and subspecialist based on community health needs is one the priorities in the strategic plan provided by urology curriculum committee of medical education and specialty council of mohme in 2007. fellowship training has officially been initiated from the year 1992 following the assembly of the “council on medical education.” at the present time, fellowships related to urology specialty are offered in 6 fields of study at more than 25 academic urology training program. monitoring the surgical health care workforce and analyzing the ratio of surgeon supply to population whether is growing and whether supply is adequate to meet future demand is important task of medical educators. analysis of urologic education and urologist workforce growth trends is important in a country like iran with diverse demographic characteristics and different health care needs. population aging increases the demand of specialties for elderly care such as urology, while younger population increase demand for subspecialty treatment that serve special group of patients (children). the aim of this study is to provide important information on quantitative achievements of urologic education and growth of urologic surgeons’ workforce since 1979, which can be used by health policy makers. materials and methods this comprehensive national quantitative study was performed in iranian academy of medical science. data about the overall urologists were obtained from the department of information and statistics of medical council of iran and data of admitted/graduated residents were obtained from the iranian council in specialty and subspecialty training and the department of exam evaluation of ministry of health and medical education (mohme). the data included information about number of registered residents and total urologists from (1978-1979) till (2011-201) by gender and trained fellowships in urologic subspecialty fields. first, the data were extracted from paper base records and entered into structured databases, and then data analyzed. results our results confirm that, urologic education has experienced a sharp quantitative growth in iran over the last 3 decades. there has been rise in the number of admitted residents in urology specialty from 5 in 1978-79 to 51 in 2011-12 (figure 1). during 2012, 97 percent of admitted residents in urology specialty in iran were men. one major expansion in urologic education in the last 3 decades has been spectacular increase in the number of residents. the number of female residents who participate in urologic surgery training programs is significantly improved over last years. today 10 percent of urologic residents are women the number of urologists who are graduates of iran’s medical schools has increased from 5 in 1979 to 47 residents in 2012 (figure 2). the proportion of urologic surgeons trained in iran has risen sharply. in 1980, 86% of urologists were graduated from foreign medical universities, while by 2012, 100% of graduated urologists, have been trained in national universities. at the end of training, graduated urologists attend in iranian board of medical specialties examination. after board certification specialists could enter to academic positions in universities. to this date 60 board examinations have been held. the number of urologists who were successfully certified nationally was 4 in 1979, which was increase to 47 in 2012. there has been a significant increase in the supply of urologist relative to population growth in iran. the number of urologists increased from 315 in 1979 to 350 in 1980 to 699 in 1990, to 1225 in 2000, and to 1637 in 2012 (figure 3). the number of male urologists increased from 315 in 1979 to 1527 in 2012. in 1979 there was only 1 female urologist in iran, while in 2012 there were 110 female urologists in iran miscellaneous 1121vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l postgraduate urologic education in iran | simforoosh et al (figure 3). in 2012, 93% of iranian urologists were men, while 7% of them are women. we can see the same male: female ratios in england. according to association of american medical colleges (aamc) 2012 data, 94.2% of urologists in usa were men (table 1). in 1979, there were only 315 urologists for 37 million of population in iran. most of the urologic surgeons in remote regions were not iranian specialists. shortage of urologists was a very serious issue in most of the iran’s provinces. at that time only solution was hiring foreign urologists from (india, bangladesh, etc.). since 1979, great advances have been made in clinical postgraduate medical education. the urologic training has experienced a steady quantitative growth. the number of residents entered to urology training increased in iran. urology continues to be attractive due to the serious need of the patients. in 2012, there were 1637 urologists for 75.5 million of population (table 1). in 1979, there was 1 urologist for every 117,460 people in iran and in 2012 there was 1 urologist for every 46,120 people in iran. this ratio represents significant improvement from 34 years ago. in 2012 the ratio of urologic surgeons per 100,000 was 2.17. during the period of 1979-2012, number of iranian urologic surgeons per 100,000 populations has 155.3% increases (table 2). during 1981-2010 in usa, number of urologic surgeons per 100,000 populations decreased by 1.3 % (table 2). the information presents in table 2 shows urologist supply increase in each decade in iran vs. usa. this ratio represents significant improvement in iran urology workforce supply over 3 decades. fellowships many urologists desire extra training in one particular aspect of the field. this means applying for post-residency fellowship training. most fellowships are 1-2 year programs integrating both clinical and research experiences.(4) fellowship training has officially been initiated from the year 1992. fellowships placed more of an emphasis on, research, and scholarly work.(4) at the present time, fellowships related to urology specialty are offered in 6 fields of urology, including; pediatric urology, kidney transplantation, uro-oncology, endourology, female urology and reconstructive urology. table 3 shows the year each fellowship program has approved, duration of each field. these fellowships programs are growing in quantity and quality very quickly as a result of the large number of patients being referred. two hundred eight urologists graduated from fellowship programs till 2012, and 94% of them are men. table 3 shows the total trained fellowships number and number of women urolotable 1. number and percentage of urologists by sex in iran versus usa and england. male female total urologists number percent number percent usa * 9,824 9,257 94.2 567 5.8 iran 2012 1,637 1,527 93 110 7 england 2012 ** 875 814 93 61 7 *source: association of american medical colleges (aamc) 2012 physician specialty data book.) **source: british association of urological surgeons ) http://www.baus.org. uk/aboutbaus/workforce. table 2. sources of growth in urologic surgeons supply: iran and usa 1979-2012. supply of urologic surgeons urologic surgeon per 100,000 population period country urologists period % change 1980-81 iran 350 iran 1979 2012 0.85 2.17 +155.3 usa 7423 1990-91 iran 759 usa 8825 2000-01 iran 1179 usa 9649 *usa 1980 2010 3.23 3.18 -1.3* 2010-11 iran 1592 2012 usa 9824 iran 1637 *urology workforce trends. bulletin of the american college of surgeons, 2012. 1122 | gists graduated from each subspecialty field. we can see significant quantitative growth and expansion of fellowship training in the various subspecialty areas since last decade (figure 4). endourology fellowships are currently very much in demand. two areas of urology that motivated the urologists are renal transplantation and pediatric urology (figure 4). discussion adequacy of the current urology workforce there are a number of indicators of the adequacy of a surgical workforce. no single measure can provide a definitive assessment for urologic surgical supply. however we can use the most recommended benchmark to study whether urology workforce is adequately meeting current demand of population or if there is a significant shortfall or oversupply. one of the indicators chosen is surgeon/population ratio (spr).(5) a usa submission to the 1988 doherty enquiry suggested that the spr for urology should be 1:65,000. this calculation was based on the british association of urological surgeons recommendation that the spr be 1:130,000 with two urologists per unit. at that time the spr for the usa was 1:40,000, for the england was 1:130,000 and for the ireland was 1:170,000. there was no firm basis for this original prediction. in 1992 a royal australasian college of surgeons (racs) manpower study subsequently adapted this figure of 1:60,000 despite strong opposition from the usa. the usa suggest that the spr for australia should be in the range of 1:80,000 to 1:85,000. the fact that the current specialist spr is slightly below this benchmark could be taken to indicate there is a shortage of urologists.(5) in 1994, there is a large range of urologist/popfigure 1. urology admission growth trend in iran since 1979. figure 3. urologists workforce growth trends in iran since 1979. figure 2. comparing graduation trends in urology specialty since 1979. figure 4. growth trends in urologic subspecialty fellowship disciplines. miscellaneous 1123vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l ulation ratios, ranging from 1:27,700 in usa to 1:214,300 in south africa. differences in health structures make international comparisons difficult, for example in the usa and germany (spr 1:30,800) urologists provide primary care that is as general practitioners in urology. this has resulted in reduced number of surgical operations per urologist.(5) in 2012, usa with a population of 313 million people, urology spr was 1:31000.(6) in 2012, england has 875 urologic surgeons, calculating for 63.7 million populations.(7) the england urology spr was 1:72800. europe is a large region and in 2012 has a population of approximately 730 million people, in these countries some 15,000 urologists have registered with national registration.(8) in 2012 europe urology spr was 1:49000. in 2012, iran has 1637 urologists for 75.5 million of population. iran urologic spr was 1:46120. to our knowledge iran had the greatest growth rate of urologic surgical workforce in the middle east. outstanding achievements of iranian urologic education and current urology workforce, is comparable with those in the most progressed countries in this field. iran has met the high standards for urologic surgeon per population in the world. urologic surgical supply and health outcome urologist can make a great impact on a patient’s quality of life.(4) research has shown an association between a higher density of urologists and lower mortality from prostate, bladder, and kidney cancer.(9) despite small number of urology-specific studies, consumers and payers are increasingly convinced that individual surgeon case volume is important. in addition to mortality, length of stay and complication, health service researchers are also exploring the relationship between volume and other outcomes. literature suggests that low volume surgeons may tend to offer restricted options to the patient, expend more resources per case or have higher recurrence rates in oncology cases.(10) fellowship training fellowship training is one of the most important contributors to progress in the field of urology. american board of urology supported the importance of fellowship training to the future of urology.(10) fellowships enhance the overall quality of a training program and aid in faculty recruitment and retention. an example in iran is the kidney transplantation. in 1979, there has been less than 100 kidney transplantation in iran, while according to report in middle east society of organ transplantation (mesot) congress 2011, the number of kidney transplantation was over 30,000 in iran in 2011, which is number one in middle eastern countries.(11) kidney transplantation department of shahid labbafinejad medical table 3. approval year and duration of each urologic fellowships and graduated numbers. fellowship discipline year program approved duration (months) total trained fellowships up to dec. 2012 female trained fellowships kidney transplantation 1987 to 92 and 1997 12 85 3 endourology * 1994 24 59 0 pediatric urology 1994 12 33 6 uro-oncology 1999 12 20 0 reconstructive surgery 2007 18 8 0 female -urology 2010 12 3 3 sum: 208 12 (6%) * the endourology-laparoscopy fellowship program at shahid labbafinejad medical center includes 15 months of clinical training in laparoscopy and 9 months in endourology. table 4. surgeon/population ratio for urology in 2012, ordered by surgeon/population ratio (spr). total urologists population urologic spr usa 10,090 * 313 million 1:31000 iran 1637 75.5 million 1:46120 european union 15,000 730 million 1:49000 england 875 63.7 million 1:72800 *source: american urological association. postgraduate urologic education in iran | simforoosh et al 1124 | center with more than 3,500 kidney transplantation was elected as one of the ten major kidney transplantation centers outside the us according to the statistics of clinical transplantation 2010 book.(12) fellows in the endourology-laparoscopy fellowship program at iranian urology and transplantation center (iurtc) are actively involved in laparoscopic urologic surgery. uro-laparoscopy is a minimally invasive option for urologic procedures and treatment of kidney disease. by the end of 2012, more than 5000 urologic laparoscopy procedures had been done in iran. female urologist practice and patient satisfaction urology is a surgical subspecialty focusing on the urinary tract of men and women, as well as the reproductive system of men.(4) women constitute a large portion of the patients seen by urologists and they have demand for same sex physician. historically the specialty like urologic surgery has been a male dominated field. most women interested in a surgical career may have some hesitation about selecting urology.(4) however, women entering urologic surgical specialty training have steadily increased in the last 3 decades. in usa since 1981, the number of female urologic surgeons has grown from 34 to 512.(13) in iran the number of female physicians rose steadily, from 2 in 1980 to 110 in 2012. in iran female physicians entering in urology have been increased since 1990 base in health policies that emphasize on integral role of female training in specialties to satisfy patients with accessing to same gender physician. during the period of 1992 to 2012 the supply of female urologists dramatically improved and grew by 10%. several studies have investigated patients' preference for the gender of their doctor. the england national health system (nhs) has designed studies to examine the patient preference with urologic problems for gender of urologists. however, within these studies, the patients have predominantly been females. women were more likely to prefer the same gender urologist than males.(14) the number of women in medicine continues to rise steadily. despite this increase until recently women remained a small minority in urology and other surgical fields.(15) more women are becoming urologists, which parallels trends in other surgical subspecialties.(16) american urologic residency strategic planning group committee expressed a strong desire to keep urology more attractive to women and intensify efforts to recruit a large number of women and minorities into the specialty.(10) conclusion based on the available information, it is fair to conclude that iran is one the most powerful countries in urologic surgical education and growth of urologic workforce. growth trends suggest that the overall number of urologists in iran is at the highest per capita since1979. obviously, urologic educational models of the last decade will not match for another decade. educational planners must consider urologic growth trends, evolution of urologic care, and population needs. acknowledgments this research work was supported by the academy of medical science of iran. the authors greatly appreciate the cooperation of council on medical education and specialty training and information and statistics department of medical council of iran to gather the first hand data. the authors wish to acknowledge dr. mohammad reza nowroozi for his kind help in medical council of iran. conflict of interest none declared. references 1. marandi a. integrating medical education and health services: the iranian experience. med educ. 1996;30:4-8. 2. marandi a. the integration of medical education and health care system in the islamic republic of iran. med educ. 2001;1:8-11. 3. azizi f. the reform of medical education. med educ. 1997;31:159-62. 4. freeman brian. the ultimate guide to choosing a medical specialty. in: the ultimate guide to choosing a medical specialty. new york: mcgraw-hill; 2004. p. 443-57. 5. australian medical workforce advisory committee -the urology workforce in australia-supply, requirements and projections. 1995-2006 –amwac report. 6. american medical colleges (aamc) 2012 physician specialty data book. miscellaneous 1125vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l 7. british association of urological surgeons. http://www. baus.org.uk/aboutbaus/workforce. 8. debruyne fm. future of european urology. world j surg. 2000;24:1215-9. 9. odisho ay, cooperberg mr, fradet v, ahmad ae, carroll pr. urologist density and countylevel urologic cancer mortality. j oncol prac. 2010;28:2499-504. 10. mcconnell john d, ralph v. clayman, robert c. flanigan, et al. the future of urology and urologic education in americafuture of urologic residency strategic planning committee, 2006 report. 11. simforoosh n. kidney donation and rewarded gifting: an iranian model. nature clin pract urol. 2007;4:292-3. 12. simforoosh n. shahid labbafinejad hospital center of excellence in urology and kidney transplantation. in: clinical transplantation 2010, los angeles: terasaki foundation laboratory; 2010. p. 462-463. 13. neuwahl s, thompson k, fraher e, ricketts t. hpri data tracks. urology workforce trends. bull am coll surg. 2012;97:46-9. 14. tempest hv, vowler s, simpson a. patient’s preference for gender of urology. int j clin pract. 2005; 59:526-8. 15. blanchet kd. a gender transformation in urology: women find the specialty family-friendly and full of opportunities. bju int. 2010;105:ii-v. 16. davis ec, risucci da, blair pg, sachdeva ak. women in surgery residency programs: evolving trends from a national perspective. j am coll surg. 2011;212:320-6. postgraduate urologic education in iran | simforoosh et al 1175ff.pdf 892 | mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran e-mail: info@safarinejad.com editorial comment the authors have addressed an important issue in timely manner. the effect of cell phone radiation on human health is the matter of recent awareness and debate, as a result of the enormous increase in cell phone usage worldwide. up to november 2011, there were about 6 billion subscriptions throughout the world.(1) cell phones use electromagnetic radiation (emr) in the microwave range. the who has classigroup 2b, may be carcinogenic. it means that there “could be some risk” of carcinogenicity; hence, further studies on the long-term, profound use of cell phones are warranted.(2) several national radiation advisory authorities have suggested measures to decrease exposure to their citizens as a precautionary measure.(3) many researchers have studied possible health effects of cell phone radiation. a recent evaluation (4) it denotes that the three lines of evidence, viz. animal, likely to result in an increase in cancer in humans". cell phones have also radiation absorption, thermal, non-thermal, cognitive, genotoxic, sleep and electroencephalography, behavioral, and blood–brain barrier effects, which have not been addressed in the present study. part of the radio waves emitted by a cell phone handset is absorbed by the human head. the radio waves emitted by a global system for mobile communications (gsm) handset preserve a peak power of 2 watts. one well-documented effect of microwave radiation is dielectric heating, in which any dielectric material, such as living tissue, is heated by rotations of the communications protocols used by cell phones often give rise to low-frequency pulsing of the (5,6) most studies have addressed the effects of cell phone usages on the head cancer. to my knowledge, there is no study addressing the effects of cellular telephone use on the kidney cancer. therefore, the present animal study is welcome as a pilot study. in 2007, hardell and colleagues, from örebro university in sweden, reviewed published epidemiological studies and concluded that:(7) a study entitled "public health implications of wireless technologies" cites that hardell and associbefore age 20 increased the risk of brain tumors by 5.2-fold, compared to 1.4-fold for all ages.(8) a review article by hardell and colleagues found that current cell phones are not safe for long-term exposure.(9) several national radiation advisory authorities, such as austria,(3) france,(10) germany,(11) and sweden,(12) have recommended measures to minimize exposure to their citizens, such as: cellular and molecular urology 893vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l effects of cell phone on kidney | koca et al the effects of the non-ionizing radiation emitted by cell phones depend on a number of factors besides the duration of transmission, eg, the type of cell phone and the distance from the cell phone tower. the authors examined only the controlled studies on human are needed to clarify whether the emr from cell phones affects the kidney, and to determine the mode of action of such a possible damaging effect. references 1. "market data summary (q2 2009)". gsm association. http:// www.gsmworld.com/newsroom/market-data/ market_ data_summary.htm. retrieved 2010-01-30. 2. "iarc classifies radiofrequency electromagnetic fields as possibly carcinogenic to humans". international agency for research on cancer. 2011-05-31. retrieved 2011-06-02. 3. "information: wie gefährlich sind handystrahlen wirklich?" marktgemeinde pressbaum. retrieved 2008-01-23. 4. "conclusions on mobile phones and radio frequency fields". european commission scientific committee on emerging and newly identified health risks (scenihr). retrieved 2008-12-08. 5. foster kr, repacholi mh. biological effects of radiofrequency fields: does modulation matter? radiat res. 2004;162:219-25. 6. glaser, roland (december 2005). "are thermoreceptors responsible for "non-thermal" effects of rf fields?" (pdf). edition wissenschaft (bonn, germany: forschungsgemeinschaft funk) (21). oclc 179908725. retrieved 2008-01-19. 7. hardell l, carlberg m, soderqvist f, mild kh, morgan ll. long-term use of cellular phones and brain tumours: increased risk associated with use for > or =10 years. occup environ med. 2007;64:626-32. 8. sage c, carpenter do. public health implications of wireless technologies. pathophysiology. 2009;16:233-46. 9. hardell l, carlberg m, hansson mild k. epidemiological evidence for an association between use of wireless phones and tumor diseases. pathophysiology. 2009;16:113-22. 10. "téléphones mobiles : santé et sécurité" (french). le ministère de la santé, de la jeunesse et des sports. 2008-0102. retrieved 2008-01-19. . 11. "precaution regarding electromagnetic fields". federal office for radiation protection. 2007-12-07. retrieved 2008-01-19. . 12. "exponering". swedish radiation protection authority. february 2006. retrieved 2008-01-19. reply by author there are many studies investigating the effect of emr on human body.(1,2) many of these studies research about cancer. however, long-term outcomes of these studies are unclear. in our study, we could not come up with any conclusion about cancer due to the lack of follow-up. however, there are a lot of non-cancer effects of emr,(3) which we aimed to investigate in this study. the use of the mobile phone puts the head area at greater risk.(2,4) this situation can also hide possible risks for other organs. in this study, we investigated the effects of references 1. leszczynski d, joenvaara s, reivinen j, kuokka r. nonthermal activation of the hsp27/p38mapk stress pathway by mobile phone radiation in human endothelial cells: molecular mechanism for cancerand blood-brain barrierrelated effects. differentiation. 2002;70:120-9. 2. ono t, saito y, komura j, et al. absence of mutagenic effects of 2.45 ghz radiofrequency exposure in spleen, liver, brain, and testis of lacz-transgenic mouse exposed in utero. tohoku j exp med. 2004;202:93-103. 3. nakamura h, matsuzaki i, hatta k, nobukuni y, kambayashi y, ogino k. nonthermal effects of mobile-phone frequency microwaves on uteroplacental functions in pregnant rats. reprod toxicol. 2003;17:321-6. 4. finnie jw, blumbergs pc, cai z, manavis j, kuchel tr. effect of mobile telephony on blood-brain barrier permeability in the fetal mouse brain. pathology. 2006;38:63-5. a prospective interventional study in chronic prostatitis with emphasis to clinical features konstantinos stamatiou, hipocrates moschouris department of urology, tza neio hospital, pireas, greece. corresponding author: stamatiou konstantinos, md 2 salepoula str., 18536 piraeus, greece. tel: +30 210 452 6651 fax: +30 210 429 6987 e-mail: stamatiouk@gmail.com received july 2013 accepted january 2014 purpose: chronic bacterial prostatitis displays a variety of symptoms (mainly local pain exhibiting variability in origin and intensity). these symptoms often persist despite bacterial eradication. the purpose of this article is to exam the role of phytotherapeutic agents as complementary treatment in patients with bacterial prostatitis. materials and methods: the material consisted of individuals with reported pelvic discomfort and genital pain with or without lower urinary tract symptoms (luts) and sexual dysfunction visiting our department from march 2009 to march 2011. patients underwent stamey-meares test (several cases underwent the two glass test). depending on history and specific symptoms urethral smear and semen cultures were additionally obtained from several patients. all patients were randomized into two groups. subjects in the first group (72 patients) received appropriate antibiotic (according to the sensitivity test) for 15 days, while subjects in the second group (72 patients) received phytotherapeutic agents for 30 days, additionally the conventional 15 days antibiotic treatment. the response was tested using laboratory and clinical criteria. results: we found no statistically significant differences between the two groups regarding bacterial and symptom persistence rate, however, symptoms burden was lower in patients receiving combinational treatment. conclusion: phytotherapeutic agents may improve pain and prostatitis related difficulty in urination. further randomized, placebo-controlled studies are needed to substantiate safer conclusions. keywords: administration; oral; phytotherapy; plant preparations; therapeutic use; prospective studies; prostate; pathology; prostatitis; drug therapy. 1829 miscellaneous miscellaneous urology journal vol. 11 no. 04 july august 2014 1830 phytotherapy in chronic bacterial prostatitis-stamatiou et al study. patients suffering from neurological disorders, those with anatomic abnormalities of the urinary tract and immunosuppressed patients were excluded from the study, as these are all conditions which can affect the clinical manifestation of the disease and could alter the outcome of the study. depending on history and specific symptoms urethral smear and semen cultures were additionally obtained from several patients. microbiological assessment the stamey-meares test was deemed positive if: 1) bacteria were cultured in the expressed prostatic secretion (eps) and the vb3 urine specimens (or post prostate massage) and were not cultured in the vb1 and vb2 (or prostate massage) specimens, 2) bacterial colony count in the vb3 specimen was 10 times that in the vb1 and vb2 specimens and 3) leukocyte numbers in the eps and vb3 were 10 times those in the vb1 and vb2. no lower cut-off value for the number of colonies was set. cultures for gonococcus, mycoplasma and ureaplasma and the semi-quantitative assessment were performed using biomerieux reagents (biomerieux, canada inc., 4535 rue dobrin, saint-laurent, québec h4r 2l8, canada). chlamydia trachomatis were detected using direct immunofluorescence (kallestad anti-membrane lipopolysaccharide monoclonalantibodies). urine specimens were centrifuged and cultured in blood and macconkey agar for aerobic and anaerobic gram-positive and negative bacteria (biomerieux culture media). all processing and final assessment of samples in this study were performed by the same specialist microbiologist to whom the medical history of the patients was not disclosed. questionnaire the chronic prostatitis nhi-cpsi questionnaire includes 9 questions in 3 sections [character-site of pain, urinary symptoms and effect on quality of life (qol)]. the resultant sum ranges from 0 to 43 (character-site of pain: 0-21, urinary symptoms: 0-10 and qol: 0-12). the greater the resulting sum the greater the disturbance. ultrasound evaluation prostatic volume and echo pattern (unequal echogenicity, hypo echogenicity, hyper echogenicity) as well as the presence and the pattern of calcifications (diffuse or periurethral) were assessed with a ge logiq 3 pro ultrasound machine (ultraschall deutschland gmbh & co. kg. beethovenstr. 239, 42655 solingen. germany) with convex array (2-5 mhz) and a 10 mhz frequency transrectal probe. statistical analysis statistical analyses were performed with the statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. descriptive statistics were used to estimate the frequencies, means and standard deviations of the study variables. differences between study groups in baseline characteristics and clinical outcomes were assessed with the use of chi-square test for categorical variables and student’s t tests for continuous variables. the accepted statistical significance cut-off value was p value < .05. introduction the incidence of chronic prostatitis is around 3/1000 and peaks between the ages of 20-49 years. moreover, chronic prostatitis constitutes a frequent diagnosis in men aged over 65 years primarily as a histological finding or in relation to benign prostatic hyperplasia (bph) symptoms.(1-3) between 1990 and 1994, there were more than 2 million outpatient visits in the usa related to chronic prostatitis cases, whereas currently 15% of men who visit a doctor due to lower urinary tract symptoms (luts) are diagnosed with prostatitis.(4) this particular disease has been characterized as a significant and developing clinical enigma given that its etiopathogenesis remains to a great extent unclear. its presentation is related to an infective focus in the distant -mainlyprostatic glandular element and ducts involving gram-negative uropathogens and less frequently gram-positive bacteria.(5) it exhibits an array of symptoms, most notably pelvic pain (at various sites and of varying intensity), urinary symptoms (obstructive and irritative) as well as erectile and sexual dysfunction. similar symptoms are also encountered in bph and are attributed to both obstruction and secondary inflammation. the effectiveness of phytotherapeutic agents used for symptoms related to bph justifies their use in the treatment of chronic prostatitis.(6) the aim of the study is to assess the effectiveness of phytotherapeutic agents in the management of these symptoms. materials and methods from a pool of 234 patients with reported pelvic discomfort and genital pain with or without luts and sexual dysfunction visiting our department from march 2009 to march 2011, those found with chronic bacterial prostatitis confirmed by the stamey-meares test (a few cases underwent the two glass test), consisted the subjects of this study. in this particular study the encountered situation was a two treatment comparison in an undetermined sample size of patients. given that the overall 2 numbers of patients was small, equal sample sizes had to be formed in order to obtain a precise comparison. for this reason, patients were randomized into two groups depending on the date of attendance (odd/even day of the month). subjects in the first group (72 patients) received the appropriate antibiotic treatment for 15 days, while subjects in the second group (72 patients) received phytotherapeutic agents for 30 days, additionally to the conventional 15 days antibiotic treatment. the choice of antibiotic for both groups was based on antibiotic sensitivity testing while the choice of phytotherapeutic for group 2 was based on the price of the least expensive product in the category at the time of enrolment. microbial response was assessed by the stamey-meares test and the response to symptoms by the patients report at 4 and 8 weeks from the beginning of the study (15 after the completion of antimicrobial therapy). the final clinical evaluation was assessed by national institutes of health chronic prostatitis symptom index (nih-cpsi) questionnaire, the ultrasonography (us) and digital rectal examination (dre) findings 8 weeks from the beginning of the visit (table 2). at the second follow-up visit, 47 patients of the group 1 were asymptomatic and bacterial free, 15 were found with symptom or bacterial persistence while 10 patients were lost to follow up. similarly, 54 patients of the group 2 were asymptomatic and bacterial free, 14 were found with symptom or bacterial persistence while 4 patients were lost to follow-up. there was no statistically significant difference in the overall outcome between the two groups at the second follow-up visit (table 2). of note, there was discordance between subjective self-reported symptoms relief and documentation of symptoms in the nih-cpsi report, since most patients who reported symptoms regression had nih-cpsi score between 2-12 (20 of the group 1 and 11 of the group 2). similarly, several patients who reported symptom persistence had lower nih-cpsi scores in the follow-up period than that at baseline. of note only 35 patients of both groups provided a completed nih-cpsi score at endpoint. similarly, data on variations in dre findings were available in 133 cases and data on variations in prostate us were available in 50 patients. difference in mean nih-cpsi score at the second follow-up between group 1 and group 2 was statistically significant (p < .05). no statistically significant differences in us and dre findings (p > .05) were found between the two groups. differences in the side effects rate between the two groups were not statistically significant (p > .05). discussion the herbs saw palmetto and pygeum africanum have been used to treat men with bph, to help relieve some of the bothersome symptoms of bph, including nocturia and difficulty urinating. lately they have been the object of focused research into the treatment of infections of the urinary tract, having been used as a sole agent, combined with antibiotics, with alpha-blockers, anti-inflammatory agents and 5-alpha reductase inhibitors. however, their precise mechanism(s) of action on prostatic inflammation remain partly explained.(7) in addition, it is unclear whether they potentiate the effect of antibiotics. actually, the active ingredient of both herbs is the beta-sitosterol complex. this includes beta-sitosterol, campesterol, stigmasterol and brassicasterol. all these phytosterols exhibits an anti-androgenic activity, related to the inhibition of conversion of testosterone to the more potent androgen dihydrotestosterone at the level of androgen receptors. this is particularly important given that androgen receptor enhance the migration of macrophages and macrophage-mediated stromal cell proliferation.(8) inhibition of conversion of testosterone results in a reduction of the hormonal response of macrophages and leukocytes and the inhibition of their migration to the site of inflammation. as a consequence there is a reduction in the release of myeloperoxidase which causes destruction of the inflamed tissue and of platelet-derived growth factor and growth factor-beta which induce inflammation.(9-11) recently it has been demonstrated that atraric acid isolated from bark material of pygeum africanum exhibits an indirect anti-androgenic anti-inflammatory activity by inhibiting the transac results the most prominent symptoms (as reported by the patients) were chronic suprapubic, scrotal, perineal and penile pain (and feeling of burning as well) alone or in combination with a variety of symptoms. in most of the cases, symptoms lasted more than three months; however many patients (especially those experiencing frequent recurrences) were able to recognize them earlier. interestingly, only 12 out of the 155 subjects had recurrent episodes of acute infection (epididymitis and prostatitis). sexual and erectile dysfunctions were reported by only 6 patients. more precisely, 46 patients of the group 1 and 54 of the group 2 had a history of prostatitis or associated conditions; the mean age was the 45.45 years for group 1 and 40.98 years for group 2, while the mean nih-cpsi score was 26.62 for group 1 and 25.78 for group 2. no statistically significant differences in history, age and nih-cpsi score at baseline were found between the two groups (table 1). on clinical examination, 76 prostates (39 of the group 1 and 37 of group 2) were abnormal in palpation-suggestive of prostatitis. forty one out of the 144 patients (22 of the group 1 and 19 of the group 2) had abnormal prostate us. no statistically significant differences in abnormal dre and us findings at baseline were found between the two groups. the most common microorganisms were escherichia coli (e. coli) and enterococcus faecalis. while most e. coli isolates (almost 79%) were sensitive to a wide range of antibiotics, enterococcus faecalis and proteus isolates were so in only half of the cases (55% and 50% respectively). almost 36% of the bacterial cultures revealed gram (+) bacteria other than enterococcus faecalis, with coagulase-negative staphylococcus being the most common. twenty seven out of the 72 patients of the group 1 received plurifloxacin, 33 ciprofloxacin, 6 levofloxacin, 2 trimethoprim/sulfamethoxazole (tmp-smx), 2 tetracycline and 2 azithromycin. a few patients additionally received aminoglycosides for up to 5 days. thirty two of the group 2 received combination of plurifloxacin and saw palmetto, 6 levofloxacin and saw palmetto, 11 ciprofloxacin and saw palmetto, 10 ciprofloxacin and pygeum africanum, 4 plurifloxacin and pygeum africanum, 4 roxithromycin and pygeum africanum, 2 tmp-smx and saw palmetto and 5 levofloxacin and pygeum africanum. the dosage for pygeum africanum was 200 mg daily while that for saw palmetto was 320 mg daily. at the first follow up visit, 44 patients of the group 1 who reported complete or near complete symptom relief were bacterial free. in contrast, 2 patients of the same group were found with bacterial persistence despite absence of symptoms. seventeen patients of the group 1 reported symptom persistence despite bacterial eradication and 9 patients of the same group had both symptom and bacterial persistence. similarly, 49 patients of the group 2 were asymptomatic and bacterial free, 16 reported symptom persistence despite bacterial eradication and 7 were found with bacterial persistence despite absence of symptoms. there was no statistically significant difference in the overall outcome between the two groups at the first follow-up 1831 miscellaneous urology journal vol. 11 no. 04 july august 2014 1832 reference to an improvement of pain, urgency, strangury and nocturia. data on variations in prostate volume, as measured by dre were available in 84 (26.5%) patients. no significant change was observed. maximum urinary flow rate (qmax) after treatment was measured in 83 (26%) patients. it did not show significant changes from the baseline. no untoward side effect was reported in any case.(17) aliev and colleagues examined retrospectively the efficacy of serenoa repens extract in the prevention of chronic prostatitis recurrences as an adjuvant to standard antibiotic therapy. according to their results serenoa repens extract improved both subjective [international prostate symptom score (ipss) and qol scale] and objective symptoms (absence of the disease progression and adverse effects and enhancement of the erectile function).(18) magri and colleagues found a 94% symptoms regression rate and improved qol in patients who underwent one or more cycles of combination therapy (ciprofloxacin/ azithromycin, alpha-blocker and serenoa repens extract) after an extended follow-up of 30 months.(19) the cumulative eradication rate of this study calculated on a total of 137 enrolled patients was 83.9%, however it is unknown to which extend this result is due to serenoa repens extract administration. of note, kulchavenia and colleagues found a 4-fold microbiological eradication rate for e. coli in the combination treatment group (sparfloxacin and serenoa repens extract) versus control (sparfloxacin only), and a 2-fold microbiological eradication rate for chlamydia and ureaplasma.(20) based on the above we expect the effectiveness of phytotherapeutics in an array of symptoms related to prostatitis to depend on the presence of prostatic hypertrophy, any preexisting obstruction, co-administered treatments and the duration of treatment. this hypothesis explains the differences between the present study and what has been discussed above. however, the small number of patients included in the above mentioned studies as well as differences in methodology tivation mediated by the ligand-activated human androgen receptor. (12) on the other hand, serenoa repens (isolated from saw palmetto extract) exhibits a direct androgen-independent anti-inflammatory activity by inhibiting epidermal growth factor-dependent growth and proinflammatory responses of the prostate epithelial cells.(13,14) only a few clinical trials examining the effect of complementary phytotherapeutic agents administration to the conventional antibiotic treatment of chronic bacterial prostatitis exists. most of them have shown impressive clinical effects, a finding which is not in accordance with our results. in a small study, pygeum africanum extract (200 mg/daily for 60 days) was used either alone or in combination with antibiotics to treat 18 patients suffering from sexual disturbances due to chronic prostatitis. pygeum improved all the urinary parameters investigated by medical history and prostatic transrectal us, and improved sexual function despite the fact that there were no significant differences between hormonal levels and nocturnal penile tumescence and rigidity monitoring before and after therapy.(15) cai and colleagues in a prospective randomized trial examined whether a combination of saw palmetto extract with other phytotherapeutics is able to improve the efficacy of prulifloxacin in bacterial prostatitis patients. one month after treatment, 89.6% of patients who had received prulifloxacin associated with phytotherapeutics were free of symptoms, whilst only 27% of patients who received antibiotic therapy alone were recurrence-free. significant differences were also found between groups in terms of symptoms and qol.(16) similarly, pavone and colleagues administered to 320 patients suffering from prostatitis related luts a combination of saw palmetto extract with other phytotherapeutics for a minimum duration of 30 days to a maximum of a year, either alone or in association with antibiotics or alpha-blockers. variations in symptom score could be fully evaluated only in 80 of 320 patients (25%), of whom 68 (85%) reported a significant benefit, with special variables number mean standard deviation p value group 2 group 1 group 2 group 1 group 2 group 1 age (years) 72 72 45.4583 40.9861 11.43375 12.46346 .176 history of prostatitis 72 72 0.56940 0.65280 0.498630 0.47943 .707 baseline nih-cpsi score 72 72 17.9306 20.5000 12.93573 2.15162 .659 table 1. difference between groups 1 and 2 with regard to age, prostatitis related history and nih-cpsi score upon introduction into the study. abbreviation: nih-cpsi, national institutes of health chronic prostatitis symptom index. follow-up visits number mean standard deviation p value group 2 group 1 group 2 group 1 group 2 group 1 first 72 72 0.5139 0.56940 0.919170 0.81925 .342 second 72 72 0.3056 0.3750 0.57259 0.63772 .375 table 2. differences in overall outcome between study groups in first and second follow-up visits. phytotherapy in chronic bacterial prostatitis-stamatiou et al 2002;41:447-51. 8. wang x, lin wj, izumi k, et al. increased infiltrated macrophages in benign prostatic hyperplasia (bph): role of stromal androgen receptor in macrophage-induced prostate stromal cell proliferation. j biol chem. 2012;287:18376-85. 9. hill b, kyprianou n. effect of permixon on human prostate cell growth: lack of apoptotic action. prostate. 2004;61:73-80. 10. marks ls, hess dl, dorey fj. et al. tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic and rogens. urology. 2001;57:999-1005. 11. latil a, libon c, templier m. et al. hexanic lipidosterolic extract of serenoa repens inhibits the expression of two key inflammatory media tors, mcp-1/ccl2 and vcam-1, in vitro. bju int. 2012;110:e301-7. 12. papaioannou m, schleich s, prade i, et al. the natural compound atraric acid is an antagonist of the human androgen receptor inhibiting cellular invasiveness and prostate cancer cell growth. j cell mol med. 2009;13:2210-23. 13. wadsworth τ, carroll j, mallinson r. et al. saw palmetto extract sup presses insulin-like growth factor-i signaling and induces stress-activa ted protein kinase/c-jun n-terminal kinase phosphorylation in human prostate epithelial cells. endocrinology. 2004;145:3205-14. 14. iglesias-gato d, carsten t, vesterlund m, pousette a, schoop r, nors tedt g. androgen-independent effects of serenoa repens extract (prosta san®) on prostatic epithelial cell proliferation and inflammation. phytot her res. 2012;26:259-64. 15. carani c, salvioli v, scuteri a, et al. urological and sexual evaluation of treatment of benign prostatic disease using pygeum africanum at high doses. arch ital urol nefrol androl. 1991;63:341-5. 16. cai t, mazzoli s, bechi a. et al. serenoa repens associated with urtica dioica (prostamev) and curcumin and quercitin (flogmev) extracts are able to improve the efficacy of prulifloxacin in bacterial prostatitis patients: results from a prospective randomised study. int j antimicrob agents. 2009;33:549-53. 17. pavone c, abbadessa d, tarantino ml, et al. associating serenoa re pens, urtica dioica and pinus pinaster. safety and efficacy in the treat ment of lower urinary tract symptoms. prospective study on 320 patients. urologia. 2010;77:43-51. 18. aliaev iug, vinarov az, demidko iul, spivak lg. treatment of chro nic prostatitis in prophylaxis of prostatic adenoma. urologiia. 2012;2:39 40. 19. magri v, trinchieri a, pozzi g. et al. efficacy of repeated cycles of combination therapy for the eradication of infecting organisms in chronic bacterial prostatitis. int j antimicrob agents. 2007;29:549-56. 20. kulchavenia ev, breusov aa, brizhatiuk ev, kholtobin dp. approac hes to raising efficacy of treatment of patients with chronic prostatitis associated with intracellular infections. urologiia. 2010;6:55-8. and outcomes render the drawing of conclusions problematic. this study has some limitations. the most prominent one is the relatively small sample size and this is probably the reason why we found no significant relationships from the data. in fact statistical tests normally require a larger sample size to ensure a representative distribution of the population and to be considered representative of groups of people to whom results will be generalized or transferred. another limitation of this study is the use of various antimicrobial agents and of two different phytotherapeutic agents. however; there is no evidence of synergistic antibacterial effect of phytotherapeutic agents while both saw palmetto and pygeum africanum have similar properties and comparable efficacy. therefore it is not expected that this limitation eventually matter and, if so, to a limited extent. in this study we haven’t associate the bacterial virulence with the outcome, however currently there is no evidence of an association between bacterial virulence and phytotherapeutic agents’ effect. in the light of lack of prior research studies on the topic, this limitation can serve as an important opportunity for further research. conclusion although, phytotherapy seems to be effective in the treatment of pain symptoms in chronic bacterial prostatitis, results from the existent studies are conflicting. on the other hand, conditions such as chronic bacterial and chronic non-bacterial prostatitis and prostatic hypertrophy overlap, many of the symptoms are common, while conditions and diseases of organs other than the prostate can contribute towards the presentation or deterioration of these symptoms. more randomized placebo-controlled studies are required to substantiate safer conclusions. conflict of interest none declared. references 1. cheah py, liong ml, yuen kh, et al. chronic prostatitis: symptom survey with follow-up clinical evaluation. urology. 2003;61:60-4. 2. nickel jc, elhilali m, vallancien g. alf-one study group. benign prostatic hyperplasia (bph) and prostatitis: prevalence of painful ejacu lation in men with clinical bph. bju int. 2005;95:571-4. 3. fall m, baranowski ap, elneil s, et al. eau guidelines on chronic pelvic pain. eur urol. 2010;57:35-48. 4. collins mm, stafford rs, o›leary mp, barry mj. how common is prostatitis? a national survey of physician visits. j urol. 1998;159:1224 8. 5. nickel jc, moon t. chronic bacterial prostatitis: an evolving clinical enigma. urology. 2005;66:2-8. 6. levin rm, das ak. a scientific basis for the therapeutic effects of py geum africanum and serenoa repens. urol res. 2000;28:201-9. 7. dreikorn k, berges r, pientka l, jonas u. phytotherapy of benign prostatic hyperplasia. current evidence-based evaluation urologe a. 1833 miscellaneous vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2569 miscellaneous simple renal cysts: prevalence, associated risk factors and follow-up in a health screening cohort bora özveren,1* efe onganer,2 levent n. türkeri1 purpose: to investigate the prevalence of simple renal cysts in an adult health-screening cohort, and to evaluate clinical characteristics, associated risk factors and the natural course. materials and methods: between april and november 2008, a thousand individuals diagnosed with simple renal cyst by ultrasonography in a check-up program were chart-reviewed for demographic-clinical characteristics and cyst features. follow-up was done via electronic patient records. univariate and multivariate analyses to evaluate the relationship of outcomes and correlation analysis were done to measure the degree of association between parameters. results: the prevalence was 7.7%. there were 123 cysts in 77 patients, followed for 3.5 years (mean). individuals with cysts were older (p < .01). prevalence rates were 2.7% in individuals younger than 40 years and 23.9% in older than 60. the cysts were predominantly (94.8%) detected in males and most (63.6%) were solitary. no relation with body mass index and total cholesterol levels was found but serum creatinine values were significantly increased in individuals with cysts (p < .01). there was no difference in the diagnosis of hypertension and microscopic hematuria in patients with renal cysts, however diabetes/hyperglycemia were more common and increasing age correlated with higher number of cysts (all p < .05). follow-up revealed that the number of cysts were increased and/or the same in 86.5%; the sizes of cysts were larger and/or the same in 78.4% of patients, while in 14% of patients the cyst disappeared. conclusion: in a cohort of adults undergoing a health-screening, the prevalence of simple renal cyst was found 7.7% by ultrasonography. renal cysts were more common in males and elders, and associated with increased levels of serum creatinine and diabetes. keywords: kidney diseases, cystic; complications; epidemiology; etiology; prevalence; turkey. 1 department of urology, acibadem university school of medicine, istanbul 34752, turkey. 2 department of family medicine, acibadem university school of medicine, istanbul 34752, turkey. *correspondence: department of urology, acibadem university school of medicine acibadem kadikoy hospital, istanbul 34718, turkey. tel: +90 216 5444276. fax: +90 216 4284444. e-mail: ozverenb@yahoo.com; bora.ozveren@acibadem.edu.tr. received: july 2015 &accepted: september 2015 introduction simple renal cysts are the most common types of acquired renal cysts. the majority are detected incidentally at the time of radiological imaging for non-renal conditions and do not have associated clinical symptoms. the prevalence of simple cysts differs according to sex and increases with age.(1-3) clinical observations have revealed that most are unilocular, and since they arise from the cortex, they may distort the renal contour. although most simple cysts probably remain stable in size and feature, some may enlarge with time and occasionally cause subtle flank discomfort and fullness on physical examination. intervention for simple renal cysts is seldom warranted. although renal cysts are generally regarded as of minor clinical significance, detection and awareness of these lesions may entail anxiety in patients. besides, recent studies have associated simple cyst incidence with hypertension, atherosclerotic vascular diseases and renal dysfunction.(4-9) usually, renal cysts are typical “incidental” findings in imaging studies for various medical purposes. likewise, “check-up” programs which aim for early detection of chronic conditions and malignant diseases represent a way of discovering this kidney pathology. patients may naturally be concerned about its relevance to general health, natural course and need recommendations on how to deal with this finding. in the present study we aimed to investigate the prevalence of simple renal cysts in a cohort of adults who went through a “health-screening”, and to evaluate their clinical characteristics, associated risk factors and the natural course in our population. materials and methods study population the study was performed retrospectively by reviewing the electronic charts of 1380 individuals (905 men, 475 women; mean age, 38.74 years; age range, 18–77 years) who presented for a health check-up program between april and november 2008. inclusion criteria: among them, 1000 patients who had an abdominal ultrasonographic evaluation as part of a routine screening were included in this study. this study focused on simple renal cysts (category i according to bosniak classification) diagnosed by ultrasonography (usg). procedures and evaluations: all cases underwent an abdominal usg by staff radiologists. the presence and characteristics of simple renal cysts were reported. the number, site (lower, middle or upper part of kidney), and maximum diameter of cysts were recorded. patient records were also reviewed for evaluation of potential risk factors. these parameters included age, sex, body mass index (bmi; kg/m2), history of diabetes and hypertension, blood pressure measurement. for the purposes of this study hypertension was defined as a systolic blood pressure of > 140 mmhg, a diastolic blood pressure of > 90 mmhg, or current use of antihypertensive medication. biochemical variables included in analysis were serum total cholesterol, fasting glucose and serum creatinine levels. results of urine analysis were recorded and microscopic hematuria was defined as > 3 red blood cells per high-powered field. patients with renal cysts were followed from electronic records for a mean of 3.5 (range: 1-6) years and sequential changes in number and size of the cysts were documented. statistical analysis analyses were performed by using ncss (number cruncher statistical system) 2007 & pass (power analysis and sample size) 2008 statistical software® program (utah, usa). means, medians, ranges, and frequencies were recorded as descriptive statistical parameters. univariate analyses were performed by fisher’s exact test, student’s t-test, and yates’ continuity correction test (yates’ chi-squared test). spearman’s correlation analysis was conducted to measure the degree of association between parameters. multivariate analysis of risk predictors for the presence of renal cysts was assessed by logistic regression. p values < .01 and < .05 were considered statistically significant. results the study group was comprised of 36% female (n = 363) and 64% male (n = 637) individuals with a mean age of 42.76 years. a total of 77 patients (7.7%) were diagnosed with simple renal cysts. table 1 compares the demographic and clinical features of individuals with and without simple cysts. of total, 5.5% had a history/diagnosis of hypertension and 9.6% had a history/diagnosis of diabetes. the mean total cholesterol level was 195.14 mg/dl (range: 80 to 475 mg/ dl). urine analyses showed microscopic hematuria in 5% of the cohort. the mean serum creatinine was 0.76 mg/dl (range: 0.34 to 1.5). the overall prevalence of simple cysts was 7.7% (77/1000). there were a total of 123 cysts in these 77 patients. the mean largest diameter of renal cysts was variables total cyst (-) cyst (+) univariate multivariate (n = 1000) (n = 923) (n = 77) p value or (95% ci), p value mean ± sd mean ± sd mean ± sd age, year 42.76 ± 10.89 41.97 ± 10.51 52.26 ± 10.91 a.001** 1.10 (1.07-1.14), p < .001** gender (male); n (%) 637 (63.7) 564 (61.1) 73 (94.8) b.001** 6.61 (2.08-20.99), p = .001** bmi, kg/m2 26.71 ± 4.41 26.65 ± 4.48 27.45 ± 3.28 a.078 0.98 (0.91-1.06), p = .673 creatinine, mg/dl 0.76 ± 0.17 0.75 ± 0.17 0.87 ± 0.16 a.001** 8.61 (1.08-68.34), p = .042* total cholesterol, mg/dl 95.14 ± 40.04 195.05 ± 39.95 196.23 ± 41.39 a.804 ----hypertension, n (%) 55 (5.5) 49 (5.3) 6 (7.8) c.306 ----diabetes mellitus n (%) 96 (9.6) 82 (8.9) 14 (18.2) b.014* 1.43 (0.68-3.01), p = .348 microhematuria, n (%) 50 (5.0) 49 (5.3) 1 (1.3) c.170 ----table 1. demographic and clinical characteristics of the cohort. abbreviations: bmi, body mass index; sd, standard deviation; or, odds ratio, ci, confidence interval. a, student t-test; b, yates’ continuity correction test; c, fisher’s exact test. *p < .05; **p < .01. simple renal cyst prevalence-ozveren et al. miscellaneous 2570 vol 13 no 01 january-february 2016 2571 27.86 mm with a range of 5 to 66 mm. the mean number of cysts per individual was 1.59 cysts (range 1-7). in majority of patients (63.6%) a solitary renal cyst was detected. of patients with multiple cysts, 3.9% had more than five cysts. table 2 summarizes the descriptive characteristics of all 123 simple cysts with respect to laterality, number and localization. individuals with simple renal cysts were significantly older than those without cysts (p < .01). when the cohort was sorted in age groups, the prevalence rates emerged as 2.7% in individuals younger than 40 years, 10% in ages between 40-60, and 23.9% in older than 60 (figure 1). the cysts were predominantly (94.8%) detected in male individuals. simple renal cysts were observed in 11.45% of the men and 1.10% of the women in our cohort. thus, the male-to-female ratio was 10.41. the higher prevalence of renal cysts in male gender was statistically significant (p < .01). analysis revealed a statistically significant increase in the mean serum creatinine values of patients with simple renal cysts (p < .01). multivariate logistic regression analysis showed that older age, male gender and a higher serum creatinine level were significant independent predictors for the presence of renal cysts (p < .001, p = .001, p = .042, respectively) (table 1). there were no statistically significant differences in bmi values and total cholesterol levels in individuals with or without renal cysts. no significant difference was found in the incidence of hypertension and microscopic hematuria in either group (p > .05). however, in patients with renal cysts, history/diagnosis of diabetes and presence of hyperglycemia were significantly more common (p < .05) (table 1). in patients with renal cysts, statistical analysis revealed a significant but weak positive correlation of increasing age with the number of cysts (p < .05) (figure 2). bmi and serum creatinine parameters did not correlate with the number of cysts (p > .05) (table 3). of the 77 patients who had simple renal cysts, only 43 were available for follow-up for a mean 3.5 years from electronic-chart review. in the following 1 to 6 years, four of these patients had abdominal magnetic resonance imaging (mri) and the rest had usg results that could be utilized for further evaluation of the previously diagnosed cysts. in six patients no renal cyst was found in further evaluations. overall, 7 cysts were previously documented in these patients with a mean age of 43.67 years (range: 34-61). the mean diameter of the “vanished” cysts was 10.79 mm (range: 9-13.5). in others, the number of cysts was found to be increased in 15, the same in 17, and decreased in 5 patients. during the follow-up of 37 patients, the diameters of cysts were increased in 14, decreased in 8, and the size remained simple renal cyst prevalence-ozveren et al. table 2. descriptive characteristics of all 123 cysts in a total of 77 individuals. cyst no. % right side 24 31.1 left side 38 49.4 bilateral 15 19.5 solitary 49 63.6 multiple 28 36.4 lower pole 31 25.2 mid 65 52.8 lower pole 26 21.1 parapelvic 1 0.8 variables cyst (+) (n = 77) d r (95% ci) p value age, year* number of cysts 0.290 (0.055-0.495) .010* bmi, kg/m2* number of cysts -0.061 (-0.302-0.203) .637 serum creatinine, mg/dl* 0.058 (-0.311-0.237) .614 number of cysts table 3. evaluation of clinical characteristics according to number of renal cysts. abbreviations: bmi, body mass index; ci, confidence interval. d, spearman’s correlation coefficient; *p < .05. figure 1: age-related prevalence of renal cysts the same in 15 patients. discussion in the current study, the prevalence of simple renal cysts was 7.7% in an adult health-screening cohort. simple cysts were found as more common in males and elderly individuals in our study. the results of several published series report the prevalence of simple renal cysts in a range from 5% to 40%.(2,10-16) incidence of simple renal cysts between birth and age 18 is only 0.2 percent. by contrast, autopsy series have revealed that 50% of patients older than 50 years have grossly recognizable renal parenchymal cysts.(3) studies which discovered higher prevalence rates (19.9 – 41%) have mostly assessed incidental computerized tomography (ct) findings.(1,10,11) superior imaging quality of ct or mri improves the detection of small cystic lesions and therefore may explain higher rates found in some studies. yet, most of the published prevalence studies have utilized usg in diagnosis due to its non-invasive characteristics and feasibility. aside from dependence on the technical qualities of the imaging modality used, the prevalence rates may also alter according to the screened population. there are several prevalence studies from different parts of the world where varied patient databases were used (table 4). these results suggest that there may be geographically determined variations in the prevalence rates.(4,1218) additionally, cysts are seen more frequently in “renal patients” as opposed to “non-renal” subjects. marumo and colleagues reported the incidence of renal cysts as 32.6% for ages 60 years or older in patients referred for asymptomatic microscopic hematuria.(19) a study from nigeria showed a 15.4% prevalence rate of cystic kidney disease in adult patients from a nephrology unit.(20) in a group of 684 outpatients from an internal medicine clinic who had usg for various reasons, 13.7% were diagnosed with simple renal cysts.(21) the prevalence of simple cysts is well known to correlate with demographic factors. renal cysts are more frequent in men and the incidence correlates with advancing age.(1,3) furthermore, cysts are observed more in number and larger in size in older individuals.(10,12,15) the prevalence rates should therefore be gaged by age groups, since any cohort comprising a greater proportion of older individuals would render higher average rates. statistical analysis of our results confirm these previously established characteristics concerning age and gender. although the overall prevalence was 7.7% in our cohort, the age-specific rate raised from 2.7% in younger than 40 year-olds to 23.9% in individuals older than 60 years (figure 1). our study group was composed of people who underwent routine health checkup; and 45% of them were younger than 40 years, and author (year) region prevalence (%) number age range cohort nko’o amvere et al. (1991)(17) cameroon 3.08 1527 0-82 in-patients pedersen et al. (1993)(18) denmark 5.2 686 30-70 volunteers yasuda (1993)(14) japan 14.0 30316 8-92 in-patients pal et al. (1997)(16) india 5.06 1500 8-86 in-patients terada et al. (2004)(13) japan 9.9 17914 18-92 check-up mosharafa et al. (2005)(12) middle-east 4.2 8551 20->80 check-up chin et al. (2006)(4) korea 7.8 6603 15-89 check-up chang et al. (2007)(15) taiwan 10.7 577 20-94 check-up present study (2008) turkey 7.7 1000 18-77 check-up table 4. simple renal cyst prevalence studies from various parts of the world. simple renal cyst prevalence-ozveren et al. figure 2: relation of age to the number of renal cysts (spearman’s correlation coefficient p < .05) miscellaneous 2572 vol 13 no 01 january-february 2016 2573 merely 7.1% were older than 60 years. while confirming the high prevalence of simple renal cysts in elderly individuals, the current results also reveal particular information on the prevalence of this pathology in younger people. we found a significant predominance of male sex in occurrence of simple renal cyst. though the published studies usually report high male to female ratios, we observed an even greater gender disparity in the renal cyst prevalence in our study group (male to female ratio of approximately 10:1 in the present study). this disproportion is uncommon and may be associated with the relatively younger median age of our cohort compared to previous epidemiological studies. the detection of a solitary lesion in two-thirds of all the individuals with cysts and the correlation of increasing number of cysts with older age in the present study population is in parallel with the descriptive findings in previous epidemiological studies.(12-15) the causal and temporal relationship of renal cysts with hypertension and renal dysfunction remain controversial. serum creatinine, hypertension and atherosclerotic diseases are among the main implicated risk factors in the occurrence of simple renal cysts.(4-9,12,13) chin and colleagues have concluded that presence and characteristics of cysts were not related to decreased glomerular filtration rates.(4) their results also suggested that number, size and locations of cysts were related to hypertension. in another study, hong and colleagues, analyzing the data of 29,666 patients, confirmed the association of presence and characteristics of simple renal cysts with a significantly increased incidence of hypertension.(5) lee and colleagues furthermore assessed the time-dependent relationship between cysts and incident hypertension, and came to a conclusion that after adjusting for confounding factors, renal cysts still significantly increased the risk of hypertension.(6) others have additionally observed an increased incidence of renal cysts in patients with abdominal aortic aneurysms and dissection, signifying a commonality of connective tissue degeneration.(7-9) however, pathogenesis of simple renal cysts still remains unsubstantiated. the connection of renovascular and arterial pathologies with simple renal cysts can merely be coincidental to age-related changes in renal tubules and ducts. while origins and evolution of renal simple cysts still need to be explored, the only established link is senility.(1) we observed a significant increase in the mean serum creatinine values of individuals with renal cysts. comparable outcomes have previously been reported in several investigations on non-renal screening cohorts. (4) the mechanism that links kidney cysts to age and renal function is unknown but it is likely that irregular tubular growth may lead to cystic changes. while renal cysts may be an early sign of renal impairment, older-age should be regarded as a confounding factor for the correlation of higher creatinine with renal cysts. (22) nevertheless, in the current study, it would be injudicious to derive any association of simple renal cysts with renal parenchymal dysfunction because there was no correlation of cyst number to higher creatinine levels. moreover, contrary to a common belief that simple cysts cause microscopic hematuria, we did not observe any increased incidence of microscopic hematuria in individuals with cysts. our results also showed a higher incidence of hypertension in the group with simple renal cysts, but statistical analysis failed to reveal a nonrandom association. there was also no difference in the bmi, and total cholesterol levels of individuals with and without renal cysts. however there was a significantly increased proportion of individuals with a history and/ or diagnosis of diabetes among individuals with simple renal cysts. evidently, our results do not allow us to simply deduce a correlation of simple renal cysts with a group of risk factors relating to metabolic syndrome. the natural history of simple renal cysts appears to be exceedingly benign. in addition to our prevalence study, we traced our patients with cysts. chart review allowed us to obtain information on 43 of 77 patients with cysts, for a mean period of 3.5 years. in 6 patients, subsequent usg examinations did not show any renal simple cysts. the patients whose cysts “disappeared” in follow-up did not have any distinguishing demographic feature but the average sizes of these cysts were remarkably smaller than the overall mean largest diameter. the reasons for the disappearance or shrinkage are unclear, but might include bleeding into the cyst or spontaneous rupture of the cyst into the perirenal space or the collecting system.(24) a study found that in children, diameter of renal cysts increased in 49%, decreased in 10%, unchanged in 31%, and disappeared in 10% when followed-up for a mean 2.9 years.(25) since the present study lacks any large numbered prospective data of follow-up, we did not attempt to analyze the changes in lesion diameter. when the data was assessed on patient-basis, we found that the number of cysts increased or stayed the same in 86.5%; the sizes of cysts were larger or the same in 78.4% of patients. in their study of 61 patients with a mean follow-up period of 9.9 years, terada and associates concluded that the majority of simple renal cysts continued to increase in size and number, but some may involute and disappear over time. the cysts they followed had an average increase simple renal cyst prevalence-ozveren et al. of 1.6 mm in size and 3.6% rate of enlargement, which appeared to decrease with age.(23) the main limitation of the current study lies in the retrospective chart-review format. we also acknowledge that the small number of our cohort makes it difficult to explain the lack of any significant change in cyst features in the follow-up data. measurement reliability of usg should also be taken into account. a prospective fashion of follow-up would give more insight on the natural course of cyst dimensions and spontaneous disappearance of these lesions. we also believe that lower median age of our check-up cohort might have influenced the striking gender difference in the prevalence rate. conclusions in a cohort of adults evaluated for a health-screening program, the prevalence of simple renal cyst was found to be 7.7% by ultrasonography. simple renal cysts were more common in males and elders, and associated with increased levels of serum creatinine and diabetes in our study. acknowledgement ms. emire bor, empiar statistics consulting, assisted with statistical analysis. conflict of interest none declared. references 1. laucks sp jr, mclachlan msf. aging and simple cysts of the kidney. br j radiol. 1981;54:12-4. 2. ravine d, gibson rn, donlan j, sheffield lj. an ultrasound renal cyst prevalence survey: specificity data for inherited renal cystic diseases. am j kidney dis. 1993;22:803-7. 3. kausik s, segura jw, king bf jr. classification and management of simple and complex renal cysts. aua update series 2002; lesson 11 vol xxi:81-7. 4. chin hj, ro h, lee hj, na ky, chae dw. the clinical significances of simple renal cyst: is it related to hypertension or renal dysfunction? kidney int. 2006;70:1468-73. 5. hong s, lim jh, jeong ig, choe j, kim cs, hong jh. what association exists between hypertension and simple renal cyst in a screened population? j hum hypertens. 2013;27:539-44. 6. lee yj, kim ms, cho s, kim sr. association between simple renal cysts and development of hypertension in healthy middle-aged men. j hypertens. 2012;30:700-4. 7. kim ek, choi er, song bg, et al. presence of simple renal cysts is associated with increased risk of aortic dissection: a common manifestation of connective tissue degeneration? heart. 2011;97:55-9. 8. song bg, park yh. presence of renal simple cysts is associated with increased risk of abdominal aortic aneurysms. angiology. 2014 aug 26.pii:0003319714548565. [epub ahead of print] 9. yaghoubian a, de vigilio c, white ra, sarkisyan g. increased incidence of renal cysts in patients with abdominal aortic aneurysms: a common pathogenesis? ann vasc surg. 2006;20:787-91. 10. tada s, yamagishi, j, kobayashi h, hata y, kobari t. the incidence of simple renal cyst by computed tomography. clin radiol. 1983;34:437-9. 11. carrim zi, murchison jt. the prevalence of simple renal and hepatic cysts detected by spiral computed tomography. clin radiol. 2003;58:629-9. 12. mosharafa aa. prevalence of renal cysts in a middle-eastern population: an evaluation of characteristics and risk factors. bju int. 2008;101:736-8. 13. terada n, arai y, kinukawa n, yoshimura k, terai a. risk factors for renal cysts. bju int. 2004;93:1300-2. 14. yasuda m, masai m, shimazaki j. a simple renal cyst. nippon hinyokika gakkai zasshi. 1993; 84:251-7 15. chang cc, kuo jy, chan wl, chen kk, chang ls. prevalence and characteristics of simple renal cyst. j chin med assoc. 2007;70:486-91. 16. pal dk, kundu ak, das s. simple renal cyst: an observation. j indian med assoc. 1997;95:555-8. 17. nko’o amyene s, biwola sida m, kayembe l, shu d, pisoh t, malonga e. renal cysts at younde (cameroon): prevalence and echographic profile. ann urol (paris). 1991;25:217-20. 18. pedersen jf, emamian sa, nielsen mb. significant association between simple renal cysts and arterial blood pressure. br j urol. 1997;79:688-91. 19. marumo k, horiguchi y, nakagawa k, et al. incidence and growth pattern of simple cysts of the kidney in patients with asymptomatic microscopic hematuria. int j urol. 2003;10:637. 20. chijioke a, aderibigbe a, olarenwaju to, makusidi am, oguntoyinbo ae. prevalence and pattern of cystic kidney diseases in iiorin, nigeria. saudi j kidney dis transpl. 2010;21:1172-8. 21. suher m, koc e, bayrak g. simple renal cyst prevalence in internal medicine department and concomitant diseases. ren fail. 2006;28:14952. simple renal cyst prevalence-ozveren et al. miscellaneous 2574 vol 13 no 01 january-february 2016 2575 22. al-said j, brumback ma, moghazi s, baumgarten da, o’neill wc. reduced renal function in patients with simple renal cysts. kidney int. 2004;65:2303-8. 23. terada n, arai y, kinukawa n, terai a. the 10-year natural history of simple renal cysts urology. 2008;71:7-11. 24. friedland gw. shrinking and disappearing renal cysts. urol radiol. 1987;9:21-5. 25. bayram mt, alaygut d, soylu a, serdaroğlu e, cakmakçi h, kavukçu s. clinical and radiological course of simple renal cysts in children. urology. 2014;83:433-7. simple renal cyst prevalence-ozveren et al. miscellaneus analysis of renal trauma in adult patients: a 6-year own experiences of trauma center tomasz ząbkowski,1* ryszard skiba,1 marek saracyn,2 henryk zieliński1 purpose: abdominal trauma itself accounts for approximately 3% of all trauma cases. among cases of multiple organ trauma, abdominal trauma accounts for 8-10% of cases. the frequency of genitourinary tract trauma is 10%. the renal trauma is 1-5% of all trauma cases. the aim of this study was to determine treatment's strategy according to analysis of renal trauma severity. materials and methods: since 2008, the military institute of medicine, followed by the trauma center, treated 1119 trauma patients, of which 52 were renal trauma cases. in most cases, renal trauma was concomitant with multiple organ trauma. results: of the 52 renal trauma cases, 35 (67%) were caused by transportation, 5 (10%) by falls, 8 (15%) by iatrogenic factors, 2 (4%) by batteries, and 2 by idiopathic factors. in our study cohort, 31 cases (60%) experienced renal trauma concomitant with multiple organ trauma. renal trauma involved injury to both kidneys in 9 (20%) patients, and to only 1 kidney in 34 (80%) patients. conclusion: the use of computed tomography scan in combination with strict observation of conservative treatment protocols and intravascular techniques results in effective treatment of renal trauma. keywords: kidney; injuries; tomography, x-ray computed; epidemiology; poland. introduction with the growing popularity of extreme sports, the prevalence of sport-related injuries, including renal trauma, is on the rise. abdominal trauma itself accounts for approximately 3% of all trauma cases. among cases of multi-organ trauma, abdominal trauma accounts for 8-10% of cases. the frequency of genitourinary tract trauma is 10%.(1) some studies have reported that 1-5% of all trauma cases are renal trauma.(2) in 2011, the trauma center was established at the military institute of medicine in poland. the trauma center is the only center for comprehensive trauma treatment for the population of over 5 million individuals. the groups which are particularly exposed to renal injuries are young men doing sports, the injured of road accidents, victims of accidents in the house or at work, victims of fights and assaults. the results of conducted studies indicate that hematuria, pain, and ecchymosis in the lumbar region, fractured ribs, as well as abdominal mass may be the symptoms of renal injury. there are blunt and penetrating renal injuries as well as a 5-level classification of kidney injuries according to a degree of injuries, american association for the surgery of trauma (aast). this classification enables a standardization of different patient groups and a choice of a proper therapy and a prediction of the treatment’s results.(3) the mechanism of injury, its placement and severity are the standard guidelines within a choice of diagnostic methods and indications for treatment’s strategy. the imaging examinations are necessary in diagnostics of abdomen injuries with a suspicion of renal injury. among the imaging examinations used in diagnostics of injuries of urogenital system and renal injuries, it is to enumerate: ultrasonography, computed tomography (ct) scan, intravenous urography (ivu), arteriography, and angiography. ct scan of abdomen with contrast injected into an intravenous line is a gold standard in diagnostics of renal injuries. if ct is not available, it is recommended to perform ultrasonography as an examination of first choice. the aim of the study was to determine treatment's strategy according to analysis of renal trauma severity. materials and methods this study was conducted from january 2008 to december 2013 at the trauma center, military institute of medicine in poland. since 2008, the military institute of medicine, followed by the trauma center, treated 1119 trauma patients, 43 of whom were cases of renal trauma. a total of 43 (3.84%) patients were enrolled into the study. our study cohort included 70% (n = 30) male and 30% (n = 13) female patients. the patient's mean age was 39.5 years. in a population of 43 patients there were 9 cases, in which both kidneys were affected. according to the fact that the grade of trauma in both kidneys results in completely different treatment method, we consider these cases separately. for example, one of these patients suffers from grade ii of right kidney trauma and grade v of left kidney trauma. right kidney was treated conservatively and in left kidney trauma nephrectomy was performed. as a result, we collected 52 renal trauma cases. in most cases, renal departments of urology,1 and nephrology2 military medical institute, szaserów street 128, 04-141 warsaw, poland. *correspondence: departments of urology, military medical institute, szaserów street 128, 04-141 warsaw, poland. tel: +48 791 533 555. fax: +48 791 533 555. e-mail: urodent@wp.pl. received september 2014 & accepted february 2015 vol 12 no 04 july-august 2015 2276 trauma was concomitant with multiple organ trauma. we conducted a retrospective study using computer databases. the database was searched using the icd-10 codes, and s37.0 and s35.4 for renal trauma and trauma of renal vessels. we included renal trauma cases from all departments of the military institute of medicine. we assessed the following features of the renal trauma cases: etiology of trauma, stage of trauma, treatment method, prevalence of hematuria, and need for blood transfusion. in addition, we analyzed the prevalence of coincidental trauma using the structure of the trauma center, military institute of medicine. the grade of renal trauma was assessed by performing imaging examinations using 64-slice computed tomography and operation protocols. the grade of renal trauma was defined using the kidney injury scale developed by the aast. (3) the data were collected in a designed data bank and were analyzed with aast scale. this strategy enables a further management based on european association of urology (eau) guidelines. results between 2008 and 2013, 52 cases of renal trauma were treated at the trauma center, military institute of medicine in poland. our study cohort included 70% (n = 30) male and 30% (n = 13) female patients. the mean patient age was 39.5 years. of the 52 renal trauma cases, 35 (67%) were caused by transportation, 5 (10%) by falls, 8 (15%) by iatrogenic factors, 2 (4%) by batteries, and 2 by idiopathic factors (figure 1). among the iatrogenic trauma cases, 3 (6%) resulted from extracorporeal shock wave lithotripsy (eswl), 3 (6%) from percutaneous nephrolithotomy (pcnl), and 2 (3%) from percutaneous renal biopsy (pcrb). in our study cohort, 31 cases (60%) experienced renal trauma concomitant with multiple organ trauma. renal trauma involved injury to both kidneys in 9 (20%) cases, and to only 1 kidney in 34 (80%) cases. trauma cases were classified into groups according to the aast trauma scale as follows: grade i, 25 patients (48%); grade ii, 10 patients (19%); grade iii, 10 patients (19%); grade iv, 4 patients (8%); and grade v, 3 patients (6%) (figure 2). hematuria occurred in 16 cases (30%), including 2 (3%) with grade i injury, 3 (6%) with grade ii injury, 7 (14%) with grade iii injury, 2 (3%) with grade iv injury, and 2 (3%) with grade v injury. among the 52 cases, 6 (11%) had penetrating injuries, and the remaining had blunt injuries. according to eau guidelines, 31 cases (60%) were treated conservatively, 7 cases (13%) were treated with organ-sparing therapy using surgical techniques (suturing of the kidney or hemostatic agents), and 6 cases (11%) were treated with transcatheter super-selective embolization (tse) of the renal arteries. two patients (4%) required pigtail catheter installation because of urine leakage caused by injury to the pyelocaliceal system. nephrectomy was performed in 6 cases (11%) (figure 3). laparotomy was performed in 16 cases because of coexisting injuries; however, after abdominal revision, only 4 patients required nephrectomy. during the laparotomy procedures, 13 splenectomies were performed, and 1 patient required surgical management of the liver. two patients needed persistent renal replacement therapy (rrt), because of vital injury to the kidney (figure 4). one patient, required temporary renal replacement therapy, including repeated hemodialysis every third day, because of acute tubular necrosis (atn) caused by rhabdomyolysis after trauma. five patients required neurosurgical intervention because of intracranial hemorrhage, and 7 patients required orthopedic management. among the 52 cases, there were 6 deaths associated with intracranial hemorrhage or large vessels injuries, all unrelated to renal or abdominal injury. twenty-one patients required blood transfusion. the minimum transfusion was 2 units of blood (600 ml), and the maximum transfusion was 21 units of blood (6300 ml). figure 1. mechanisms of injury in study subjects. figure 2. grade of injury according to american association for the surgery of trauma (aast). figure 3. treatment modalities in study subjects. abbreviations: tse, transcatheter super-selective embolization; dj, double j ureteral catheter. miscellaneous 2277 renal trauma in adult-ząbkowski et al. discussion renal trauma is one of the most frequent injuries observed in urological practice.(4) a basic diagnostic tool of renal trauma is ct scan. using contrast medium, it allows for precise assessment of the scope of renal injury and the functioning of the uninjured kidney, and furthermore, can determine injuries to other organs. the use of helical ct scan is recommended for rapid renal diagnosis.(5) short examination time requires a careful evaluation of pyelocaliceal system injury, because of the time required for the contrast medium to pass from the cardiovascular system to urine. the ct scan technique has an established position in the diagnosis of renal trauma, and its value has been well documented in the literature.(6) in case of hemodynamic instability forcing immediate surgical intervention, intraoperative ivu is recommended.(7) this allows the determination of the function of the second kidney, which can affect surgical decision-making. the rule of thumb for renal trauma treatment should be an organ-sparing treatment (figure 5). most cases in our cohort were treated conservatively with good results. treatment consisted of bed rest, monitoring of vital signs (blood pressure, heart rate) and laboratory parameters (complete blood count, creatinine), and repeated evaluation of trauma scale in imaging examinations.(8) this conservative treatment had good outcomes for the 27 cases of grade i and ii trauma in our cohort. the main issue is the treatment of grade iii and grade iv renal trauma cases. it is worth mentioning that in our study, 1 of 10 grade iii injuries and 1 of 4 grade iv injuries were successfully managed conservatively. the clinical state of the patient should be crucial in this case. surgical intervention should be performed in hemodynamically unstable patients (tachycardia, hypotension), with symptoms indicating hypovolemic neurogenic shock or with blood loss without shock symptoms, identified with repeated complete blood count examinations or observation of hematoma in imaging examinations. advancement of intravascular techniques (tse), has allowed for effective treatment of renal trauma associated with vessel trauma. in this study, embolization was successfully performed in 6 patients, achieving patient stabilization (figure 6). in the literature, the effectiveness of tse has been established, and it has been described as a good alternative to surgical treatment.(8) in case of pyelocaliceal system injury, the treatment must be adjusted to the scope of the injury. for minor injuries with involution, an expectant approach is recommended. urine leakage with a tendency of continuing or increasing, should be treated by temporary (4-6 weeks) urine drainage using a double j (dj) ureteral catheter.(9) severe injury of the renal pelvis requires surgical intervention. the treatment of grade v renal trauma is associated with a high rate of surgical intervention,(10) though selected cases may be treated conservatively. in our study, all grade v cases required surgical intervention. in all cases, urgent nephrectomy was performed in the hospital emergency department because of hypovolemic shock. among the iatrogenic causes of renal trauma in our cohort, some were associated with eswl, pcnl, and pcrb. the frequency of complications of the above-mentioned interventions in our center did not deviate from that reported in the literature. in pcrb, the rate of surgical intervention requiring an urological intervention is approximately figure 4. severe left kidney injury, which resulted in nephrectomy. figure 6. this patient underwent transcatheter super-selective embolization. figure 5. this patient underwent organ-sparing treatment. vol 12 no 04 july-august 2015 2278 renal trauma in adult-ząbkowski et al. 0.5–1%, and the rate of surgical intervention resulting in nephrectomy is only 0.1–0.2%.(11) one of the main limitations of this study was its retrospective design. conclusions in summary, we highlight the use of precise methods for the evaluation of trauma range. the use of ct scan in combination with strict observation of conservative treatment protocols and intravascular techniques results in effective treatment of renal trauma. surgical intervention is necessary in only 2% of cases, of which the frequency of nephrectomy is 11%.(12) the right renal trauma classification according to aast scale enables a further management based on eau guidelines. renal injuries are incidental to multiple organ trauma, therefore, it is necessary to be treated in specialized health center. in vast majority of patients, conservative treatment is preferred and efficient. conflict of interest none declared. references 1. salimi j, nikoobakht mr, zareei mr. epidemiologic study of 284 patients with urogenital trauma in three trauma center in tehran. urol j. 2004 spring;1:117-20. 2. aragona f, pepe p, patanè d, malfa p, d'arrigo l, pennisi m. management of severe blunt renal trauma in adult patients: a 10year retrospective review from an emergency hospital. bjui int. 2012;110:744-8. 3. buckley jc, mcaninch jw. revision of current american association for the surgery of trauma renal injury grading system. j trauma. 2011;70:35-7. 4. salimi j, nikoobakht mr, khaji a. epidemiology of urogenital trauma in iran: results of the iranian national trauma project. urol j. 2006 summer;3:171-4. 5. morey af, brandes s, david dugi iii d. urotrauma: aua guideline. j urol. 2014;192:1-9. 6. ortega sj, netto fs, hamilton p, chu p, tien hc. ct scanning for diagnosing blunt ureteral and ureteropelvic junction injuries. bmc urol. 2008;8:3. 7. morey af, mcaninch jw, tiller bk, duckett cp, carroll pr. single shot intraoperative excretory urography for the immediate evaluation of renal trauma. j urol. 1999;161:1088-92. 8. santucci ra, fisher mb. the literature increasingly supports expectant (conservative) management of renal trauma – a systematic review. j trauma. 2005;59:493-503. 9. alsikafi nf, mcaninch jw, elliott sp, garcia m. nonoperative management outcomes of isolated urinary extravasation following lacerations due to external trauma. j urol. 2006;176:2494-7. 10. davis ka , reed rl , santaniello j, et al. predictors of the need for nephrectomy after renal trauma. j trauma. 2006;60:164-9. 11. mohsen t, el-assmy a, el-diasty t. longterm functional and morphological effects of transcatheter arterial embolization of traumatic renal vascular injury. bju int. 2008;101:4737. 12. centers for disease control and prevention: injury prevention & control: data & statistics. 2010; http://www.cdc.gov/injury/wisqars/ leadingcauses.html. accessed september 8, 2013. miscellaneous 2279 renal trauma in adult-ząbkowski et al. 1620 | comparing supportive properties of poly lactic-co-glycolic acid (plga), plga/collagen and human amniotic membrane for human urothelial and smooth muscle cells engineering farzaneh sharifiaghdas,1 mohammad naji,2 reza sarhangnejad,1 sareh rajabi-zeleti,3 hamid mirzadeh,4 mojgan zandi,5 mahdi saeed5 corresponding author: mohammad naji, msc urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: naji_m_f@yahoo.com received june 2013 accepted february 2014 1 urology and nephrology research center, department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2 urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 3 department of stem cells and developmental biology at cell science research center, royan institute for stem cell biology and technology, academic center for education, culture and research, tehran, iran. 4 faculty of polymer and petrochemistry, iran polymer and petrochemical institute, tehran, iran. 5 biomaterials department, iran polymer and petrochemical institute, tehran, iran. urological oncology urological oncology purpose: to compare human urothelial and smooth muscle cells attachment and proliferation using three different matrices; poly lactic-co-glycolic acid (plga), plga/collagen and human amniotic membrane (ham). materials and methods: human urothelial and smooth muscle cells were cultured and examined for expression of urothelium (pancytokeratin and uroplakin iii) and smooth muscle cells [desmin and alpha smooth muscle actin (α-sma)] markers. cells were cultured on three scaffolds; plga, plga/collagen and ham. thereafter, they were analyzed for cell growth on days 1, 3, 7, 14 and 21 after seeding by 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide (mtt) assay. scaffolds were fixed and processed for hematoxylin and eosin (h&e) staining and immunohistochemistry against their cell specific markers after 7 and 14 days of culture. results: mtt assay results revealed that collagen has improved cell attachment features of plga and led to significant increase of mtt signal in plga/collagen compared to plga (p < .001) and ham (p < .001). ham was a weaker matrix for both cell types as demonstrated in mtt assay and scanning electron microscope (sem) images. sem micrographs showed normal phenotype and distribution on plga and plga/collagen. in the same line, cells formed a well-developed layer either on plga or plga/collagen, which maintained expression of their corresponding markers. conclusion: our findings demonstrated significant improvement of cell attachment and growth achieved by collagen coating (plga/collagen) compared to plga and ham. ham despite of its natural entity was a weaker matrix for bladder engineering purposes. keywords: biocompatible materials; cell proliferation; membranes; artificial; polyglycolic acid; urinary bladder; regeneration; tissue engineering; amnion; muscle; smooth; cell culture techniques. 1621vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l implication of plga/collagen and ham for bladder engineering | sharifiaghdas et al introduction various disorders, such as infection, trauma, can-cer and congenital abnormalities may affect func-tional and anatomical characteristics of the bladder and may result in organ damage and even organ loss.(1) consequently, reconstructive surgery may be needed to save the bladder normal functions. tissue engineering has been proposed as a novel potential curative approach substituting enterocystoplasty as the most frequent practice which is associated with several complications, including, infection, metabolic disorders, urolithiasis, increased mucus production and malignancies.(2,3) to address this challenge, various matrices have been used in vitro and in vivo for genitourinary tissues which could be categorized as naturally derived materials, acellular tissue matrices and synthetic materials. (4,5) concerning the scaffolds, biocompatibility, minimal immunogenicity and mechanical properties of matrices (permeability, stability, elasticity, flexibility, plasticity and resorbability at harmonious rate with original tissue) are key parameters for tissue substitutes.(6,7) in this regard, naturally derived materials are biocompatible, resorbable and contain cell recognition groups but possess poor mechanical features and modifications in their structural properties are not easily reachable during preparation processes. in contrast, synthetic scaffolds are versatile and various methods like co-polymering, hybrid scaffolding and addition of cell anchorage groups or bioactive molecules can be recruited to modify or improve their elements.(8) amniotic membrane (am) has been greatly considered in tissue engineering due to its natural essence and supportive features such as reduction of scarring and inflammation; improving wound healing and providing proper performance as a scaffold for cell proliferation and differentiation.(9) in addition, different components of extracellular matrix (ecm) such as, collagens, laminin, fibronectin, nidogen and proteoglycans, exist in the layers of am which all motivated its application in various disciplines of regenerative medicine. (10-12) poly lactic-co-glycolic acid (plga) is a copolymer of two linear aliphatic polyesters, polylactic acid (pla) and polyglycolic acid (pga) and is well-recognized for its superior biodegradability and biocompatibility which lead to its frequent use as polymer for scaffold fabrication.(13) in addition, plga has been widely studied and accepted as drugdelivery vehicle(14) and suture material.(15) a numerous array of studies have been focused on plga employment in different contexts of tissue engineering.(16-18) however, lack of cell recognition (binding) sites has limited and hindered many potential applications of plga and several other synthetic polymers, such as polycaprolactone (pcl), poly-dl-lactide) (pdlla) and pga.(19) a growing body of studies have been dedicated to improve different aspects of synthetic polymers such as addition of ecm molecules, to improve cell attachment and function, or various treatments and preparations for alternation in fibers alignment and diameter or exposing new chemical groups.(20,21) in the current work, we studied the capacity of plga, plga/collagen and ham as culture matrices for urothelial and bladder smooth muscle cells to compare a naturally derived material, ham, with a synthetic polymer (plga) at first and furthermore, to evaluate the effects of collagen addition on supportive features of plga. material and methods scaffold preparation frozen amniotic membranes in phosphate buffered saline (pbs) containing 10% dimethylsulfoxide (dmso) (royan institute, tehran, iran) were thawed and washed with pbs several times. to remove amniotic epithelial cells, 0.05% trypsin-ethylenediaminetetraacetic acid (edta) was added and membranes were incubated at 37°c with 5% co2 for 30 minutes, then scraped using a sterile cell scraper (spl life sciences, eumhyeon-ri, naechon-myeon, pocheon-si, gyeonggi-do, south korea) until full detachment. after being thoroughly washed with pbs, they were cut and loaded with cells. an electrospinning apparatus (co881007nyi series, asian nanostructure company, tehran, iran) was used for fabrication of nanofibrous mats. this device was equipped with drum collector with 70 mm diameter and 50 mm width. the electrospinning process, which was used in this study, was the conventional process. the proper plga solution (12.5%) (boehringer ingelheim, germany,) in 1, 1, 1, 3, 3, 3, hexafluoro-2-propanol (hfip) has electrospun under the conditions mentioned in table. then, nanofibrous mats were coated with collagen via dipping method in 0.1% collagen solution (sigma-aldrich corp., st. louis, mo, usa). thereafter, the coated collagen was crosslinked using adjacency to 1622 | urological oncology glutaraldehyde vapor (sigma-aldrich corp., st. louis, mo, usa) for 3 hours in order to reduce the collagen solubility in water. finally, the crosslinked scaffolds were washed by pbs three times to remove residual crosslinker. isolation of smooth muscle and urothelial cells all necessary cell culture materials were purchased from paa laboratories gmbh, paa strasse 1,a-4061 pasching, austria, except where mentioned otherwise. after obtaining written informed consents, normal human bladder tissues were obtained during open surgery for reasons other than cancer, including open prostatectomy or anti-reflux surgery (n = 11). tissue biopsies (approximately 0.3-0.5 cm2) were transferred to laboratory in dulbecco’s modified eagle’s medium (dmem) containing 2% penicillin/streptomycin and 2% fungizone (invitrogen, grand island, ny, usa) on ice. under sterile condition, each tissue was rinsed with hank’s balanced salt solution (hbss) and mucosal layer was dissected off the smooth muscle layer. mucosal and smooth muscle layers were incubated with 2 mg/ml collagenase type xi (sigma-aldrich corp., st. louis, mo, usa) and 1 mg/ ml dispase (invitrogen, grand island, ny, usa) for 1 hour at 37ºc in separate tubes. cold hbss was added to digestion solution to dilute out the enzymes followed by passing through 70 µm cell strainer. after 5 minutes centrifugation table. electrospinning conditions for poly lactic-co-glycolic acid scaffold preparation. drum linear speed drum rotational speed feeding rate electrode distance potential difference 5 mm/sec 2000 round per min 2 ml/h 150 mm 22 kv figure 1. sem analysis of plga and plga/collagen; (a and b) electrospun plga scaffolds and (c and d) plga/collagen. keys: plga, poly lactic-co-glycolic acid; sem, scanning electron microscope. figure 2. phenotypic characterization of urothelial and smooth muscle cells; (a) propagated colonies of human urothelial cells in different size 4 days after culture, (b) prominent expression of pancytokeratin in cultured urothelium, (c) strong expression of uroplakin iii in colonies, (d) isolated human smooth muscle cells in passage 4, (e) expression of α-sma and (f ) desmin were verified via immunocytochemical assay. brown color was developed by dab substrate. keys: dab, 3, 3 َ-diaminobenzidine; α-sma, alpha smooth muscle actin. 1623vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l implication of plga/collagen and ham for bladder engineering | sharifiaghdas et al at 1500 at 4ºc, pellets of urothelial and muscle cells were resuspended in keratinocyte serum-free medium supplemented with 50 µg/ml bovine pituitary extract, 5 ng/ml human epidermal growth factor (all from invitrogen, grand island, ny, usa), 30 ng/ml cholera toxin subunit b (sigma-aldrich corp., st. louis, mo, usa) and 2% and high glucose dmem supplemented with 10% fetal bovine serum (fbs), respectively. cell suspensions were plated in t-25 tissue culture flasks (spl life sciences, eumhyeon-ri, naechon-myeon, pocheon-si, gyeonggi-do, south korea) and incubated at 37°c with 5% co2. immunocytochemistry to characterize cultured cells, immunocytochemical expression of four markers was studied. cells were fixed in 4% paraformaldehyde, permeabilized with 0.2% triton x-100 (sigma-aldrich corp., st. louis, mo, usa) in pbs, and blocked with 1% bovine serum albumin (sigma-aldrich corp., st. louis, mo, usa) for 1 hour. rabbit polyclonal anti-uroplakin iii, anti-pancytokeratin, anti-desmin (santa cruz biotechnology, inc., santa cruz, ca, usa), and mouse monoclonal anti-human α-sma (abcam ltd. 31 cambridge science park, milton road. cambridge cb4 0fx, uk) antibodies were diluted 1:50 in blocking buffer and incubated overnight at 4°c. primary antibodies binding sites were probed with secondary antibody including in vectastain universal elite abc kit (vector laboratories, burlingame, ca, usa) or fluorescein isothiocyanate (fitc)-conjugated goat antimouse antibody (sigma-aldrich corp., st. louis, mo, usa) for 30 minutes at room temperature (rt). for chromogenic system (uroplakin iii, pancytokeratin and desmin), staining was followed by biotinylated horseradish peroxidase incubation at rt for 30 minutes. 3, 3′-diaminobenzidine (dab; vector laboratories, burlingame, ca, usa) substrate was used to reveal expression of markers and allowed to develop for 3 minutes. counterstaining was performed using hematoxylin or propidium iodide (sigma-aldrich corp., st. louis, mo, usa) for chromogenic and fluorescent systems, respectively. finally, cells were examined using an inverted microscope (ckx41, olympus, shinjuku, japan) and photographed by dp71 camera (olympus, shinjuku, japan) cell seeding on scaffolds scaffolds were sterilized in 70% ethanol for one hour followed by three washes of pbs to remove ethanol. scaffolds were incubated with culture medium for 30 minutes. after trypsinization and determination of cell concentration, 250 µl of cell suspension containing 100 000 viable cells was figure 3. histological analysis of scaffolds after cell seeding with h&e staining; (a and b) human urothelial cells on the surface of plga/collagen formed a continuous sheet after 7 days of culture containing 2 to 3 layer of cells and (c and d) human smooth muscle cells 7 days after loading on plga/collagen made multiple layers. keys: plga, poly lactic-co-glycolic acid; h&e, hematoxylin and eosin. figure 4. immunohistochemical expression of human urothelial and smooth cell markers after proliferation on scaffolds; (a) apparent expression of pancytokeratin and (b) uroplakin iii in urothelial cells after 7 days on plga/collagen, (c) expression of α-sma and (d) desmin were also continued after 7 days of culture. no distinctive difference in the expression level of markers was observed between plga/collagen and plga. keys: plga, poly lactic-co-glycolic acid; α-sma, alpha smooth muscle actin. 1624 | urological oncology transferred onto scaffolds or ham. cells were allowed to attach and propagate at 37°c and 5% co2. owing to high density of cells seeded on scaffolds, the medium was refreshed every other day. histological analysis of scaffolds to evaluate cell layering and expression of above-mentioned markers, hematoxylin and eosin staining and immunohistochemistry were performed on 5 µm sections of formalin-fixed paraffin-embedded scaffolds on days 7 and 14 after cell seeding. briefly, sections were dewaxed in xylene (merck kgaa, darmstadt, germany), rehydrated in descending grades of ethanol, and permeabilized with 0.2% triton x-100 (sigmaaldrich corp., st. louis, mo, usa). to block non-specific binding sites, 1% normal horse serum was added to sections for 30 minutes. primary antibodies against urothelial and muscular markers were diluted in blocking buffer (1:100) and incubated at 4°c for overnight. biotinylated universal secondary antibody (vectastain universal elite abc kits; vector laboratories, burlingame, ca, usa) was applied for 30 minutes. biotinylated horseradish peroxidase was added afterward and the expression sites were revealed by dab chromogene (vector laboratories, burlingame, ca, usa). finally, slides were counterstained in hematoxylin, mounted with entellan (merck kgaa, darmstadt, germany), and observed using a light microscope (bx41, olympus, shinjuku, japan). scanning electron microscopy (sem) of scaffolds scaffolds and ham were fixed in 2.5% glutaraldehyde (merck kgaa, darmstadt, germany) for 24 hours followed by two consecutive washes in pbs for 20 minutes. samples were dehydrated in ascending concentrations of ethanol, and then, air-dried for 24 hours. they were mounted on stubs, coated with gold-palladium, and examined by sem (tescan vega-ii, las vegas, nevada, 89118, usa). bare scaffolds were analyzed without any processing. mtt assay at each time point (1, 3, 7, 14 and 21 days after cell seeding), 1 ml of 0.5 mg/ml mtt solution (sigma-aldrich corp., st. louis, mo, usa) was added to each scaffold for 3 hours at 37°c and 5% co2 in the dark. after formation of formazan during reduction process, isopropanol containing 0.01 n hcl (merck kgaa, darmstadt, germany) was added for 30 minutes at 37°c in the dark with moderate agitation to disrupt the cells and solubilize formazan. absorbance at 560 nm (biophotometer, eppendorf ag, hamburg, germany) was measured as an indicator of live cells, which were contributed to the reduction of mtt. statistical analysis data were exhibited as the mean ± standard error. anovas statistical analysis was used to evaluate cell viability during 14 days of cultivation on matrices using spss software (the statistical package for the social sciences, version 18.0, spss inc, chicago, illinois, usa). p values less than .05 were considered statistically significant. results structure and chemical features of scaffolds figure 5. representative images of sem of plga, plga/collagen and ham after cell seeding; (a) human urothelial cells colonized normally on the plga/collagen after 5 days (3000 ×), (b) smooth muscle cells proliferated on plga after 5 days while scaffolds fibres could be observed between cells (1500 ×), (c) colonies of human urothelial cells on ham is loose and dispersing after 3 days (1500 ×) and (d) human smooth muscle cells could be seen infrequently on ham on day 3 post seeding (1500 ×). no difference in distribution and growth pattern of cells was detected between plga and plga/collagen. keys: plga, poly lactic-co-glycolic acid; am, amniotic membrane; ham, human amniotic membrane; sem, scanning electron microscopy. 1625vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l implication of plga/collagen and ham for bladder engineering | sharifiaghdas et al according to the sem micrographs, it was observed that the mats had a partial alignment, and no significant changes were detected in their structures after being coated with collagen. but fiber diameters showed a little enhancement (569.91 ± 228.78 nm vs. 484.85 ± 270.48 nm, p = .43), which may be as a result of fiber swelling or addition of collagen coating (figure 1). human bladder smooth and urothelial cells small colonies of urothelial cells appeared 24 hours after initial plating and proliferated to form large colonies, which contained cubical cells with epithelial features after 4 days of culture (figure 2a). immunocytochemical studies showed the expression of uroplakin iii and pancytokeratin in cultured urothelium (figures 2b and 2c). urothelial cells were passaged after 70% confluency. cultured smooth muscle cells were distinguished with their elongated morphology and strong expression of α-sma as well as moderate expression of desmin (figures 2d to 2f). cell layering and histological characterizations of scaffold cell-scaffold interaction is much looser than the native tissue; thus, the invasive process of sectioning and staining leads to cell shedding. despite cell detachment, a well-developed and continuous layer of cells was observed in most microscopic fields in plga and plga/collagen (figure 3), but no cell remained on ham surface (data not shown). no significant difference was observed between days 7 and 14. because of cell detachment, a meaningful comparison of plga and plga/ collagen regarding layering was not possible. we examined the cells after seeding on scaffolds for expression of markers. expression of pancytokeratin and uroplakin iii was continued in urothelial cells (figures 4a and 4b) while smooth muscle cells maintained the expression of desmin and α-sma on scaffolds surface (figures 4c and 4d). distribution and morphology of the cells on scaffolds scanning electron microscopy is a valuable method for monitoring cell morphology and distribution on electrospun scaffolds in comparison with light microscopy. five days after seeding, urothelial cells showed expansion on plga and plga/collagen beside regular appearance for colonies (figure 5a). smooth muscle cells also proliferated efficiently and spread all over the surface (figure 5b). no obvious difference was recognized between plga and plga/collagen in each cell type. on the other hand, cells on ham, as expected from immunohistochemistry results, showed very low density, and dispersing colonies of urothelial cells were noticed after 3 days of culture, confirming unfavorable attributes of ham for prolonged cell culture (figure 5c). smooth muscle cells were also rarely observed on ham (figure 5d). viability of cells on scaffolds figure 6. mtt assay for urothelial cell viability after culture on scaffolds and ham; (a) human urothelial cells showed more significant increase for mtt signal on plga/collagen opposed to plga and ham. asterisks represent comparisons between plga or plga/collagen with ham, while # stands for plga vs. plga/ collagen comparisons. keys: plga, poly lactic-co-glycolic acid; ham, human amniotic membrane; mtt, 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide. * p < .05, ** p < .01, *** p < .001. figure 7. mtt assay for bladder smooth muscle cell viability after culture on scaffolds and ham; (a) human bladder smooth muscle cells showed more significant increase for mtt signal on plga/collagen opposed to plga and ham. asterisks represent comparisons between plga or plga/collagen with ham, while # stands for plga vs. plga/collagen comparisons. keys: plga, poly lactic-co-glycolic acid; ham, human amniotic membrane; mtt, 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide. * p < .05, ** p < .01, *** p < .001. 1626 | mtt assay is a convincing way to compare the capabilities of scaffolds related to initial cell attachment and proliferation. mtt assay provides indirect information regarding cell proliferation. in supportive scaffolds, before contact inhibition due to limited surface of scaffolds, cells proliferate to a summit. in the present study, cells on supportive scaffolds (plga and plga/collagen) showed a similar pattern. collagen was used to include cell recognition site on plga and promote cell adhesion and proliferation. initial cell attachment (the first day post seeding), cell viability and proliferation increased significantly in plga/collagen scaffolds compared to plga for urothelial (p < .01 for day 1 and p < .001 for days 3, 7 and 14) and smooth muscle cells (p < .001 for days 1, 3 and 7) (figures 6 and 7). ham was not as supportive as plga and plga/collagen; hence, mtt absorbance of both cells significantly increased on synthetic scaffolds versus ham (figures 6 and 7). discussion tissue engineering has emerged due to incorporation of material science, engineering and cell biology and achieved increasing importance in regenerative strategies over the last decade. scaffolds and cell sources are two essential elements of tissue engineering. supporting matrices, scaffolds, in tissue engineering should simply incorporate with host tissue and provide favorable signals for cells to adhere, proliferate, differentiate and resume their normal function. fabrication of scaffolds by electrospinning method has recently received growing attention in tissue engineering. fibrous nature of electrospun scaffolds can imitate ecm ultra structure and their non-woven format in addition to high surface/volume ratio and porosity, play significant role in distribution of nutrients, cell migration, attachment and proliferation.(22,23) proper capacity of electrospun scaffolds has received support from the results of numerous tissue engineering studies of bone, cartilage, blood vessels.(24,25) our findings showed significant effect of collagen for improvement of cell attachment, followed by increased number of cells after cultivation. cultured urothelial cells revealed their typical appearance and were positive for expression of uroplakin iii and pancytokeratin and remained proliferative. similar to our results, some studies have revealed the expression of uroplakin iii in the primary culture of urothelium.(26,27) conversely, southgate and colleagues reported that uroplakin iii could not be detected in the primary culture of urothelial cells.(28) differences in culture conditions, species, method of detection and its sensitivity may lead to the conflicting results. preserving normal phenotype of cells is a key prerequisite of scaffolds in tissue engineering. in the current study, both cell types on plga and plga/collagen preserved the expression of their pertinent markers after 7 and 14 days of culture. consistent with the expression of markers, sem observations demonstrated normal appearance for colonies of urothelium and monolayer of smooth muscle cells on plga and plga/ collagen which could be continued up to confluency ending to a continuous layer (data not shown) which is critical for urothelium function.(29) mtt assay has been frequently used for assessment of cytotoxic effects of scaffolds.(30) herein, it was demonstrated that coating with collagen can enhance initial cell plating on plga which lead to significant increase in cell number during 14 days of culture as revealed by mtt assay. on the other hand, cell attachment on ham after 1 day was significantly lower than plga/collagen and plga. cells did not grow on ham over the time and mtt signal gradually declined. despite of formation of a continuous cell layer on plga and plga/collagen, invasive process of sectioning detached the superficial cells from scaffold surface and limited more detailed analysis of layering. plga with or without coating by collagen not only elicited any cytotoxic effect on cells but also supported their proliferation, layering and colonization. current knowledge of nanotechnology proposed new methods to fabricate scaffolds which imitate ecm structure with their nano-size dimensions. diameter of fibers in our work was about 500 nm which could be efficient for cell deposition and slow diffusion of nutrients, and growth factors.(31) nano-scaffolds could provide more suitable environment for cells owing to superior adsorption of ecm proteins, such as fibronectin.(32) additionally, it was reported that nanometer surface features could hamper calcium oxalate stone formation.(33) regarding bladder engineering technologies, nanoscale plga, pcl and polyether urethane (pu) were more supportive matrices compared to micron ones.(34,35) implantation of cell-seeded scaffolds is an important issue of tissue engineering which incorporate cell based therapy and scaffolding; so investigation to find appropriate scaffolds for urological oncology 1627vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l cell cultivation is an essential issue. in this regard, superior regenerative properties of scaffolds seeded with cells have been reported.(36) plga was selected owing to its previously reported exploit for reconstruction of different organs especially bladder;(37,38) nevertheless, preparation methods and properties were primarily different form current study. on the other hand, ham is intrinsically a collagenous membrane with promising reports for tissue engineering.(10-12) we previously showed that ham could be a superior supportive matrix compared to peritoneum and omentum membranes. (39) so, it was assumed that ham can be a proper matrix for cell adhesion and cultivation. moreover, it was showed that denuded ham was a better matrix than intact ham.(40) in our study, initial adherence of cells on ham was satisfactory but cells did not proliferate further and their morphology was quite different from plga and culture plates. this phenomenon could be addressed to low porosity of ham and its mechanical features. on the contrary, plga showed encouraging results for cells growth and collagen, ,as it was predicted, significantly improved cell adhesion. conclusion plga is a suitable scaffold for human bladder regeneration regarding cell attachment, growth and preserving normal phenotype of cells. in addition, collagen can improve supportive nature of plga. ham despite the natural origin and favorable composition may not be useful in this framework without more modification. acknowledgment this study is financially supported by a grant from urology and nephrology research center. conflict of interest none declared. implication of plga/collagen and ham for bladder engineering | sharifiaghdas et al references 1. falke g, caffaratti j, atala a. tissue engineering of the bladder. world j urol. 2000;18:36-43. 2. atala a, bauer sb, hendren wh, retik ab. the effect of gastric augmentation on bladder function. j urol. 1993;149:1099-102. 3. mcdougal ws. metabolic complications of urinary intestinal diversion. j urol. 1992;147:1199-208. 4. atala a. tissue engineering in urology. curr urol rep. 2001;2:83-92. 5. kim bs, baez ce, atala a. biomaterials for tissue engineering. world j urol. 2000;18:2-9. 6. baguneid ms, seifalian am, salacinski hj, murray d, hamilton g, walker mg. tissue engineering of blood vessels. br j surg. 2006;93: 282-90. 7. yang s, leong kf, du z, chua ck. the design of scaffolds for use in tissue engineering. part i. traditional factors. tissue eng. 2001;7:679-89. 8. dhandayuthapani b, yoshida y, maekawa t, kumar ds. polymeric scaffolds in tissue engineering application: a review. int j polym sci. 2011;2011:1-19. 9. niknejad h, peirovi h, jorjani m, ahmadiani a, ghanavi j, seifalian am. properties of the amniotic membrane for potential use in tissue engineering. eur cell mater. 2008;15:88-99. 10. azuara-blanco a, pillai ct, dua hs. amniotic membrane transplantation for ocular surface reconstruction. br j ophthalmol. 1999;83:399-402. 11. jin cz, park sr, choi bh, lee ky, kang ck, min bh. human amniotic membrane as a delivery matrix for articular cartilage repair. tissue eng. 2007;13:693-702. 12. mohammad j1, shenaq j, rabinovsky e, shenaq s. modulation of peripheral nerve regeneration: a tissue-engineering approach. the role of amnion tube nerve conduit across a 1-centimeter nerve gap. plast reconstr surg. 2000;105:660-6. 13. ma px. biomimetic materials for tissue engineering. adv drug deliv rev. 2008;60:184-98. 14. jain ra. the manufacturing techniques of various drug loaded biodegradable poly (lactide-co-glycolide) (plga) devices. biomaterials. 2000;21:2475-90. 15. benicewicz bc, hopper pk. polymers for absorbable surgical sutures. j bioact compat `polym. 1991;6:64-94. 16. zamani f, amani-tehran m, latifi m, shokrgozar ma. the influence of surface nanoroughness of electrospun plga nanofibrous scaffold on nerve cell adhesion and proliferation. j mater sci mater med. 2013;24:1551-60. 17. qi y, du y, li w, dai x, zhao t, yan w. cartilage repair using mesenchymal stem cell (msc) sheet and mscs-loaded bilayer plga scaffold in a rabbit model. knee surg sports traumatol arthrosc. 2012 oct 30. [epub ahead of print] 18. chen g, xia y, lu x, zhou x, zhang f, gu n. effects of surface functionalization of plga membranes for guided bone regeneration on proliferation and behavior of osteoblasts. j biomed mater res a. 2013;101:44-53. 19. kim bs, mooney dj. development of biocompatible synthetic extracellular matrices for tissue engineering. trends biotechnol.1998;16:224-30. 1628 | 20. vance rj, miller dc, thapa a, haberstroh km, webster tj. decreased fibroblast cell density on chemically degraded poly-lactic-coglycolic acid, polyurethane, and polycaprolactone. biomaterials. 2004;25:2095-103. 21. barrera d, zylstra e, lansbury p, langer r. synthesis and rgd peptide modification of a new biodegradable copolymer system: poly (lactic acid-co-lysine). j am chem soc. 1993;115:11010-1. 22. li wj, laurencin ct, caterson ej, tuan rs, ko fk. electrospunnanofibrous structure: a novel scaffold for tissue engineering. j biomed mater res. 2002;60:613-21. 23. min bm, lee g, kim sh, nam ys, lee ts, park wh. electrospinning of silk fibroin nanofibers and its effect on the adhesion and spreading of normal human keratinocytes and fibroblasts in vitro. biomaterials. 2004;25:1289-97. 24. yoshimoto h, shin ym, terai h, vacanti jp. a biodegradable nanofiber scaffold by electrospinning and its potential for bone tissue engineering. biomaterials. 2003;24:2077-82. 25. xu c1, inai r, kotaki m, ramakrishna s. electrospun nanofiber fabrication as synthetic extracellular matrix and its potential for vascular tissue engineering. tissue eng. 2004;10:1160-8. 26. thangappan r, kurzrocke a. three clonal types of urothelium with different capacities for replication. cell prolif. 2009;42:770-9. 27. oottamasathien s, williams k, franco oe, et al., bladder tissue formation from cultured bladder urothelium. dev dyn. 2006;235:2795801. 28. southgate j, masters jr w, trejdosiewicz lk. culture of human urothelium. in culture of epithelial cells (eds freshney r. i., freshney m. g.), j wiley and sons; inc. new york, 2002. p. 381-400. 29. bolland f, southgate j. bio-engineering urothelial cells for bladder tissue transplant. expert opin biol ther. 2008;8:1039-49. 30. pariente jl, kim bs, atala a. in vitro biocompatibility assessment of naturally derived and synthetic biomaterials using normal human urothelial cells. j biomed mater res. 2001;55:33-9. 31. tian f, hosseinkhani h, hosseinkhani m, et al. quantitative analysis of cell adhesion on aligned microand nanofibers. j biomed mater res a. 2008;84:291-9. 32. chun yw, lim h, webster tj, haberstroh km. nanostructured bladder tissue replacements. wiley interdiscip rev nanomed nanobiotechnol. 2010 aug 20. [epub ahead of print] 33. chun yw1, khang d, haberstroh km, webster tj. the role of polymer nanosurface roughness and submicron pores in improving bladder urothelial cell density and inhibiting calcium oxalate stone formation. nanotechnology. 2009;20:085104. 34. thapa a, miller dc, webster tj, haberstroh km. nano-structured polymers enhance bladder smooth muscle cell function. biomaterials. 2003;24:2915-26. 35. thapa a, webster tj, haberstroh km. polymers with nano-dimensional surface features enhance bladder smooth muscle cell adhesion. j biomed mater res a. 2003;67:1374-83. 36. drewa t, sir j, czajkowski r, wozniak a. scaffold seeded with cells is essential in urothelium regeneration and tissue remodeling in vivo after bladder augmentation using in vitro engineered graft. transplant proc. 2006;38:133-5. 37. salem sa, hwei nm, bin saim a, et al. polylactic-co-glycolic acid mesh coated with fibrin or collagen and biological adhesive substance as a prefabricated, degradable, biocompatible, and functional scaffold for regeneration of the urinary bladder wall. j biomed mater res a. 2013;101:2237-47. 38. nakanishi y, chen g, komuro h, et al. tissue-engineered urinary bladder wall using plga mesh-collagen hybrid scaffolds: a comparison study of collagen sponge and gel as a scaffold. j pediatr surg. 2003;38:1781-4. 39. sharifiaghdas f, hamzehiesfahani n, moghadasali r, ghaemimanesh f, baharvand h. human amniotic membrane as a suitable matrix for growth of mouse urothelial cells in comparison with human peritoneal and omentum membranes. urol j. 2007;4:71-8. 40. koizumi n, fullwood nj, bairaktaris g, inatomi t, kinoshita s, quantock aj. cultivation of corneal epithelial cells on intact and denuded human amniotic membrane. invest ophthalmol vis sci. 2000;41:2506-13. urological oncology is bladder cancer more common among opium addicts? asgari ma*, kaviani a, gachkar l, hosseini-nassab sr department of urology, shaheed modarress hospital, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: many environmental and occupational risk factors have been proposed for bladder cancer, among which opium consumption has been considered in few studies. we designed a study to determine the relationship between opium consumption and bladder cancer. materials and methods: in a retrospective, case-control study, male patients with bladder cancer, who had been referred to our hospital in a three-year period, were selected. data regarding age, gender, smoking, and opium consumption were collected from patients' records and compared with data of a control group, consisting of patients with benign prostatic hyperplasia (bph). results: fifty-two male patients with bladder tumor (group 1) were compared with 108 patients with bph (group 2). of the patients with bladder cancer, 36 (68%) were smokers, of whom 12 were also opium addicts. in general, 13 (25.5%) patients were opium consumers (one opium consumer was not smoker). from 108 patients with bph, 25 (23%) were smokers, of whom, 5 were also opium addicts. mean duration of cigarette smoking was 31 ± 13.6 and 20.2 ± 14.7 years in patients with bladder cancer and bph, respectively. the duration of opium consumption was 11.9 ± 1.4 and 6.2 ± 1.3 years in groups 1 and 2, respectively. the duration of cigarette smoking and opium consumption in group 1 was greater than that in group 2. in addition, smoking increases the risk of bladder cancer 3.8-fold (or = 8.3, 95% ci = 1.8-7.8). simultaneous cigarette smoking and opium consumption increases the risk of bladder cancer 6.2-fold (or = 6.2, 95% ci = 2.04-18.7). conclusion: there are few studies regarding the carcinogenic effect of opium on bladder. we demonstrated that, the incidence of bladder cancer in smokers, who are simultaneously opium consumers, was higher than in patients who were only smokers. simultaneous opium addiction and cigarette smoking may have some roles in the pathogenesis of bladder tumor. however, further studies with large sample sizes are warranted. key words: bladder cancer, risk factors, cigarette smoking, opium addiction 253 urology journal unrc/iua vol. 1, no. 4, 253-255 autumn 2004 printed in iran introduction bladder cancer is the fourth common cancer in men and the eighth in women.(1) the known risk factors are smoking, little water consumption, aristolochia (a chinese herb using to lose weight), exposure to aromatic amines, immunosuppressives, cyclophosphamide, radiotherapy, arsenic, chronic cystitis, and with in all probability, tea and coffee.(2) few researchers have also proposed opium as a risk factor for bladder cancer, but there is not enough evidence of carcinogenic effect of opium in bladder malignancies. we designed this study to determine the relationship between opium consumption and bladder cancer. materials and methods in a case-control study, all of the male patients with a pathological diagnosis of bladder cancer or received december 2003 accepted november 2004 *corresponding author: department of urology, shaheed modarress hospital, sa'adatabad ave., tehran, iran. tel: +98 912 118 6460 bladder cancer and opium addiction bph, who had undergone surgery in shaheed modarress medical center, between 1997 and 2000, were reviewed. data regarding age, gender, cigarette smoking, and opium consumption, and the duration of smoking or addiction were collected from patients' records. patients with bladder cancer and bph were considered as subjects (group 1, 52 cases) and controls (group 2, 108 cases), respectively. females were excluded from this study in order to achieve more matched groups. the age range was 48 to 75 years and mean age was 67.5 ± 7.4 and 65.3 ± 9.8 years in group 1 and 2, respectively. the statistical analysis was done using chi-square and odds ratio tests. the p value less than 0.05 was considered significant. results the mean age was 61.2 ± 16.6 (median 61.5) years in the patients with bladder cancer and 67.0 ± 7.4 (median 65.5) years in those with bph. without considering opium consumers, 36 patients (68%) with bladder cancer and 25 with bph (23%) were smokers (p <0.01). the probability of cigarette smoking in patients with bladder cancer (with and without opium consumption) was 7.5-fold greater than that in patients with bph (or = 7.5; 95% ci = 3.6-15.6). the rate of simultaneous cigarette smoking and opium consumption was 23.3% and 4.6% in groups 1 and 2, respectively (p <0.001, table 1). in comparison with control group, the probability of simultaneous cigarette smoking and opium consumption in patients with bladder tumor (group 1) was 6.2-fold greater (or = 6.2; 95% ci = 2.04-18.7). excluding opium consumers, the rate of cigarette smoking was 46.1% and 17.3% in groups 1 and 2, respectively (p <0.001) and the probability of cigarette smoking in patients with bladder tumor was 3.8-fold greater in comparison with control group (or = 8.3; 95% ci = 1.8-7.8). regular cigarette smoking duration was significantly longer in patients with bladder cancer than in control group (p <0.005, table 1). also, opium positives in group 1 had a longer history of opium consumption (p <0.0001, table 1). the likelihood of bladder cancer in association with simultaneous cigarette smoking and opium consumption is twice in comparison with only smoking. there was not any significant relationship between opium consumption and bladder tumor. discussion the prevalence of cigarette smoking and opium consumption is relatively high in iran.(2) although various studies have been done on the carcinogenic effect of opium in esophageal cancer in the northeast of iran, studies regarding its relationship with bladder cancer are scarce. investigations on the prevalence of esophageal cancer in the northeast of iran have shown its association with opium, especially the burned form, (opium pyrolysates).(3-7) cigarette and alcohol are the most important risk factors of esophageal cancer; ethanol increases dna alkalization in mucosal cells and it has been reported that high doses of morphine can have the same effect in rats.(8) accordingly, narcotic agents may have the same pathogenesis that can lead to malignancy. this study demonstrated that the number of smokers and opium addicts are higher in subject group. in addition, simultaneous cigarette smoking and opium consumption increases the likelihood of bladder tumor 2-fold in comparison with only smoking. however, due to the paucity of opium-only consumers (one patient), the correlation between opium and cancer could not be assessed in our study. sadeghi and co-workers in shiraz showed that of 3500 opium addicts, 15 had bladder cancer, while the prevalence of bladder cancer in the respective province was 6.6 in 100000. they concluded that, opium is a risk factor for bladder cancer.(2) nonetheless, 85% of patients had been smokers, and of 15 patients with bladder cancer, 14 were smokers, so that only simultaneous smoking and opium consumption could be considered as the risk factor for bladder caner. documentation of the carcinogenic effect of opium on bladder tumor requires further studies with purely opium addict subjects, but due to the paucity of such a population, it is not viable unless through a great scale study. also, animal experimental studies can shed light on this issue. 254 table 1. statistic data of the patients in groups 1 and 2 � ��������� �� ���� ���������� ���������� ��������� �� ������ ���������� ������� ��� ���� ���������������������������� ��� �� �� ��� �� �� ���������������� ��� ���� �� �� �� �� ����������� � � � ��� �� ��� ���� �� ������������������� � �� ���� �� �� � �� ������!��������������������� ��� ���� �� �� �� �� �������� �������� ������������ ������� ��� ���������������� �������� ��������� � ���������� � asgari et al conclusion it seems that simultaneous opium consumption and cigarette smoking plays a role in bladder tumor pathogenesis, but for clarifying the effect of opium, separately, further studies with greater subjects are needed. references 1. messing em. urothelial tumors of the renal pelvis and ureter. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.2737-41. 2. behmard s, sadeghi a, mohareri mr, kadivar r. positive association of opium addiction and cancer of the bladder. results of urine cytology in 3,500 opium addicts. acta cytol. 1981;25:142-6. 3. ribeiro pinto lf, swann pf. opium and oesophageal cancer: effect of morphine and opium on the metabolism of n-nitrosodimethylamine and n-nitrosodiethylamine in the rat. carcinogenesis. 1997;18:365-9. 4. friesen m, o'neill ik, malaveille c, garren l, hautefeuille a, bartsch h. substituted hydroxyphenanthrenes in opium pyrolysates implicated in oesophageal cancer in iran: structures and in vitro metabolic activation of a novel class of mutagens. carcinogenesis. 1987;8:1423-32. 5. ghadirian p, stein gf, gorodetzky c, et al. oesophageal cancer studies in the caspian littoral of iran: some residual results, including opium use as a risk factor. int j cancer. 1985;35:593-7. 6. friesen m, o'neill ik, malaveille c, et al. characterization and identification of 6 mutagens in opium pyrolysates implicated in oesophageal cancer in iran. mutat res. 1985;150:177-91. 7. malaveille c, friesen m, camus am, et al. mutagens produced by the pyrolysis of opium and its alkaloids as possible risk factors in cancer of the bladder and oesophagus. carcinogenesis. 1982;3:577-85. 8. hewer t, rose e, ghadirian p, et al. ingested mutagens from opium and tobacco pyrolysis products and cancer of the oesophagus. lancet. 1978;2 494-6. editorial comment as the authors acknowledged in this retrospective study, the data regarding opium consumption were from the patients' record. due to legal and social aspects of opium consumption, such retrospectively collected data could not be accurate. also due to the paucity of sample size, one cannot separate smokers from opium addicts. as a result, estimating the independent effect of opium on bladder cancer is not valuable. the results with wide confidence intervals are due to the little sample size. however, it should be noted that conducting a prospective and comprehensive research on the issue is not easily possible, and since there are few studies showing the association of simultaneous cigarette smoking and opium consumption with bladder cancer, the result achieved in this study are valuable. ziaee sam urology/nephrology research center 255 79 urology journal unrc/iua o r i g i n a l a r t i c l e s endourology and stone disease urinary tamm-horsfall protein and citrate: a case-control study of inhibitors and promoters of calcium stone formation gholamreza pourmand,1* hamidreza nasseh,1 abdolfattah sarrafnejad,2 abdolrasoul mehrsai,1 darioush hamidi alamdari,3 keramat nourijelyani,4 leila shekarpour1 1urology research center, department of urology, tehran university of medical sciences, tehran, iran 2department of immunology, school of public health, tehran university of medical sciences, tehran, iran 3nour pathobiology institute, tehran, iran 4department of biostatistics, tehran university of medical sciences, tehran, iran abstract introduction: this study aimed to compare urinary tamm-horsfall protein (thp), citrate, and other inhibitors and promoters of stone formation in calcium stone formers with those in healthy individuals. materials and methods: from january 2002 to june 2004, 100 calcium stone formers (mean age, 38.6 ± 10.3 years) who had at least 2 episodes of calcium stone formation were compared with 100 healthy individuals (mean age, 33.8 ± 9.7 years). their 24-hour urine thp (using the sodium dodecyl sulfate polyacrylamide gel electrophoresis method), citrate, calcium, uric acid, oxalate, and magnesium values were measured and compared. results: the mean 24-hour urine thp was 3.3 ± 8.1 mg in patients in the study group and 4.6 ± 19.2 mg in controls (p = 0.5). however, thp in individuals with and without bacteriuria was significantly different (15.8 ± 33.6 versus 2.6 ± 10.2, p < 0.001). mean 24-hour urinary calcium, citrate, and oxalate values were 232.6 ± 95.3 mg and 177.8 ± 82.7 mg (p < 0.001), 132 ± 103.2 mg and 395 ± 258.5 mg (p < 0.001), and 18.9 ± 22.5 mg and 10.4 ± 8.5 mg (p < 0.001) in patients in the study and control groups, respectively. there was a significant positive correlation between urinary citrate and promoters of stone formation, including urinary calcium, oxalate, and uric acid, in patients in the control group, but not in patients in the study group. conclusion: thp in the urine of stone formers is not quantitatively different from that of healthy individuals, but it is different in patients with bacteriuria. increased urinary excretion of calcium, oxalate, and uric acid in stone formers with no increase in urine citrate may play a role in the pathogenesis of recurrent stone formation. key words: calcium stone formation, tamm-horsfall protein, citrate, metabolic abnormalities vol. 2, no. 2, 79-85 spring 2005 printed in iran received january 2005 accepted march 2005 *corresponding author: urology research center, sina hospital, hassanabad sq, tehran 19953 45432, iran. e-mail: gh_pourmand@hotmail.com urinary tamm-horsfall protein and citrate effects on calcium stone formation80 introduction urinary stones have been recognized since ancient times. the prevalence of urinary stone disease is estimated to be between 4% and 9% in males and between 1.7% and 4.1% in females, and the likelihood of developing stone disease in a white man by age 70 is about 1 in 8.(1) the recurrence rate for patients with calcium oxalate renal stones—without treatment—is about 10% to15% at 1 year, 35% to 50% at 5 years, and 50% to 60% at 10 years.(2,3) unfortunately, laboratory evaluation cannot discern patients who will have stone recurrence from those who will not.(4) one study has shown that about 20% of patients with recurrent stone disease who underwent surgery for obstruction and infection, developed mild renal insufficiency.(5) the etiology of stone formation is one of the important issues in urologic research. measuring urinary inhibitors and promoters of stone formation can be helpful, not only in establishing medical treatment protocols, but also in predicting the probability of stone formation in individuals with a positive family history. the tamm-horsfall protein (thp), synthesized in the renal thick ascending limb of henle's loop and distal tubule, is the most potent aggregation inhibitor identified to date.(6) in addition, thp may incorporate into the stone matrix.(7) thus measurement of urinary thp levels and their correlation with metabolic abnormalities may help shed light on thp's role in stone formation. citrate is the most important ion that binds to calcium in urine and reduces ionic calcium concentration.(8) hypocitraturia is considered a major correctable cause of calcium oxalate nephrolithiasis and has been reported in 15% to 63% of patients with nephrolithiasis.(8) this study sought to determine the role of urinary proteins and other risk factors to better understand the pathogenesis of calcium stone formation. materials and methods from january 2002 to june 2004, 100 consecutive patients at sina hospital in tehran, iran, were enrolled in this cross-sectional casecontrol study. there were 70 men and 30 women, aged 38.6 ± 10.3 years (range, 20 to 50 years), who had at least 2 episodes of calcium (calcium oxalate and/or calcium phosphate) stone formation documented by imaging evaluations (intravenous urography, kub, ultrasonography) and stone analysis. patients with a history of endocrine diseases (hyper and hypoparathyroidism, hyper and hypothyroidism, and diabetes mellitus) were excluded. also, patients with a history of urologic intervention or renal colic over the 4 weeks prior to the evaluations, as well as those with test results showing impaired kidney function were excluded. medications known to interfere with metabolism of calcium, oxalate, citrate, uric acid, magnesium, or phosphate were discontinued at least 2 weeks prior to the evaluation. none of the female patients were menopausal or pregnant. for comparison, 100 sexand age-matched healthy individuals (67 men and 33 women, aged 33.9 ± 9.7 years) without renal stones (as confirmed by urinalysis and ultrasonography) volunteered to participate in our study. all the patients and controls underwent ambulatory metabolic evaluations, while adhering to their free-choice diet. serum sampling for creatinine and bun levels was performed, as was a random urine test for bacterial culture, and a 24-hour urine collection. the 24-hour urine collection was refrigerated. urine volume was measured and divided into samples for uric acid, ph, and urine protein electrophoresis. hcl was added as conservative. then urinary sodium, potassium, calcium, oxalate, citrate, phosphate, and magnesium values were measured. patients and controls who had collected 24-hour urine specimens in an incorrect manner (according to 24-hour creatinine) were excluded from the study. methods used for measuring each of the metabolites were as follows: methylthymol blue method for calcium, phenol-aminophenazone peroxidase method for uric acid, xylidyl blue for magnesium, uv method with molybdate for phosphorus, standard method for sodium and potassium, and enzymatic method for oxalate and citrate measurement. twenty-four-hour urinary levels of proteins were evaluated using sodium dodecyl sulfate polyacrylamide gel electrophoresis (sds-page method). concentration of urine protein was assessed measured by the bradford method.(9) sds-page of unconcentrated urine protein was performed on a vertical discontinuous gradient gel (stacking part 4%, resolving part 6%, 11%, and 15%).(10) polyacrylamide gels (0.6 mm thick) were cast between 12 × 12 cm glass plates. each urine sample (20 µl) was incubated at 100°c for 3 minutes with 20 µl of sample buffer (4% sds, pourmand et al 81 0.125 m tris hcl, ph 6.8, 20% glycerol, 0.01% bromophenol blue) before electrophoresis. then 40 µl of each sample was applied on the gel using a hamilton syringe. sds-page was run at 30 ma for 2.5 hours. silver staining was performed according to fast silver staining protocol.(11) all values are presented as means ± sd. the sas system version 8.00 was used for statistical analyses. pearson product moment correlation coefficient was used to test the relationship between the variables, and analysis of variance and friedman tests were used for group comparisons. a p value less than 0.05 was considsred statistically significant. results the concentrations of fractionated proteins in the urine samples of patients in the study and control groups are shown in table 1. of urinary proteins, only albumin and transferrin levels were statistically higher in patients in the study group; the differences of thp, alpha-1 microglobulin, and beta-2 microglobulin levels were not statistically significant. however, there was a significant difference between urinary excretion of thp among individuals with and without bacteriuria, both in patients in the study group and in controls (table 2). urinary parameters in the study and control groups are shown in table 3. in 24-hour urine, only calcium, oxalate, and citrate values were statistically different between the two groups. comparing the mean values of metabolites and urinary proteins, there were no significant differences between calcium oxalate and calcium phosphate stone formers; however, there was a significant difference between their 24-hour urine ph values (5.2 in calcium oxalate stone formers versus 7.3 in calcium phosphate cases, p < 0.001). the correlations between each urinary metabolite and other parameters in controls and study subjects are shown in tables 4 and 5; there were significant positive correlations between urine citrate, and urine calcium, uric acid, oxalate, and magnesium in our controls, but not in our study subjects. discussion to our knowledge, this is the largest casecontrol study of urinary protein excretion and urinary metabolites in iranian renal calcium stone formers. however, concerning calcium oxalate stone formation, there is no clear-cut factor to differentiate the population of stoneformers from healthy individuals. calcium stone all values are shown as mean ± sd table 1. main fractionated urinary proteins (mg/24 h) in controls and study patients as measured by urine protein electrophoresis (sds-page method), n = 100 in each group (rows in ascending order, according to molecular weight). parameters controls subjects p value 24-hour urine beta 2-microglobulin 0.0 ± 0.0 0.27 ± 2.67 0.31 24-hour urine hemoglobin 0.0 ± 0.0 0.29 ± 2.85 0.31 24-hour urine light chain 0.0 ± 0.0 0.18 ± 1.27 0.16 24-hour urine apoprotein a1 0.0 ± 0.0 0.55 ± 2.96 0.066 24-hour urine alpha 1-microglobulin 0.0 ± 0.0 0.75 ± 4.42 0.08 24-hour urine albumin 74.26 ± 46.05 163.31 ± 151.92 < 0.001 24-hour urine transferrin 0.40 ± 3.56 8.09 ± 27.59 0.006 24-hour urine thp 4.63 ± 19.24 3.35 ± 8.15 0.53 24-hour urine immunoglobulin g 0.0 ± 0.0 19.45 ± 110.97 0.08 24-hour urine immunoglobulin m 0.0 ± 0.0 1.16 ± 7.44 0.12 table 2. mean thp in individuals with and without bacteriuria (mg/24 h). all values are shown as mean ± sd. bacteriuria: more than 100,000 colony-forming units per milliliter group individuals without bacteriuria individuals with bacteriuria p value control group 3.00 ± 13.54 (n = 93) 26.22 ± 52.04 (n = 7) 0.002 study group 2.36 ± 4.74 (n = 87) 10.19 ± 18.13 (n = 13) 0.009 total 2.67 ± 10.25 (n = 180) 15.80 ± 33.53 (n = 20) 0.001 urinary tamm-horsfall protein and citrate effects on calcium stone formation82 formation is unlikely to have a single cause, and a combination of risk factors should be considered.(12) in the present study, mean thp levels in study patients and in controls were not statistically different. in general, available studies suggest no difference in urinary thp excretion between kidney stone formers and nonstone formers.(13-16) nevertheless, in some studies, urinary thp excretion was reduced in stone formers or their subgroups.(17-20) glauser and coworkers showed decreased excretion of thp in calcium stone formers and its correlation with stone forming ions, calcium and oxalate, in healthy individuals.(17) ganter and coworkers found reduced thp and citrate excretion in calcium oxalate stone-forming patients and indicated a tubular dysfunction of the distal section.(18) bichler and colleagues showed lower thp excretion in patients with uric acid urinary stones. nevertheless, they expressed that the role of thp is still unclear. it is unknown whether it acts as a protector, an inhibitor, a promoter, or even as a direct transporter.(19) it has been suggested that in highly concentrated urine, thp polymerizes readily to such an extent table 4. correlation between inhibitors and promoters of calcium stone formation in control group (in each cell, upper row shows pearson correlation coefficient and lower row shows p value). table 3. urinary metabolites (mg/24 h) in controls and study subjects, n = 100 in each group. all values are shown as mean ± sd. table 5. correlation between inhibitors and promoters of calcium stone formation in case group (in each cell, upper row shows pearson correlation coefficient and lower row shows p value). metabolic parameters controls subjects p value 24-hour urine sodium 190.3 ± 90.19 182.46 ± 74.7 0.05 24-hour urine potassium 47.56 ± 39.07 42.44 ± 32.98 0.31 24-hour urine calcium 177.80 ± 82.87 232.59 ± 95.3 < 0.001 24-hour urine phosphorus 572.19 ± 251.13 639.79 ± 234.30 0.05 24-hour urine uric acid 470.88 ± 178.78 490.95 ± 234.42 0.49 24-hour urine citrate 395.01 ± 258.47 131.95 ± 103.20 < 0.001 24-hour urine oxalate 10.41 ± 8.5 18.90 ± 22.48 < 0.001 24-hour urine magnesium 101.13 ± 46.19 100.25 ± 39.21 0.88 24-hour urine volume 1252.31 ± 559.41 1495.85 ± 671.93 < 0.001 24-hour urine ph 5.85 ± 0.82 5.31 ± 0.67 < 0.001 urine calcium urine oxalate urine uric acid urine magnesium urine citrate urine thf urine calcium 0.13 (0.19) 0.39 (< 0.001) 0.56 (< 0.001) 0.23 (0.02) -0.06 (0.545) urine oxalate 0.13 (0.19) 0.38 (< 0.001) 0.13 (0.20) 0.23 (0.02) 0.02 (0.86) urine uric acid 0.39 (< 0.001) 0.38 (< 0.001) 0.46 (< 0.001) 0.21 (0.04) 0.05 (0.65) urine magnesium 0.56 (< 0.001) 0.13 (0.20) 0.46 (< 0.001) 0.33 (< 0.001) 0.125 (0.21) urine citrate 0.23 (0.020) 0.23 (0.02) 0.21 (0.04) 0.33 (< 0.001) -0.09 (0.37) urine thp -0.06 (0.545) 0.02 (0.86) 0.05 (0.65) 0.125 (0.21) -0.09 (0.37) urine calcium urine oxalate urine uric acid urine magnesium urine citrate urine thf urine calcium 1.00 0.03 (0.790) 0.39 (< 0.001) 0.335 (< 0.001) 0.05 (0.63) 0.09 (0.37) urine oxalate 0.03 (0.79) 1.00 -0.03 (0.73) 0.20 (0.05) 0.04 (0.68) -0.02 (0.85) urine uric acid 0.39 (< 0.001) -0.03 (0.73) 1.00 0.39 (< 0.001) 0.08 (0.44) 0.22 (0.02) urine magnesium 0.335 (0.00) 0.20 (0.05) 0.39 (< 0.001) 1.00 -0.10 (0.31) 0.01 (0.93) urine citrate 0.04 (0.68) 0.04 (0.68) 0.08 (0.44) -0.10 (0.31) 1.00 0.4 (0.68) urine thp -0.02 (0.85) -0.02 (0.85) 0.22 (0.02) 0.01 (0.93) 0.4 (0.68) 1.00 pourmand et al 83 that it overwhelms the inhibitors in urine and strongly promotes agglomeration of calcium oxalate monohydrate crystals.(21) our study showed that thp level as an inhibitor of stone formation does not differ quantitatively. boeve and coworkers showed that thp particles are smaller and have different electrical potential in normal subjects compared with stone formers. they concluded that differences in molecular structures may cause functional differences in the ability of thp to inhibit aggregation. they emphasized that research on the role of thp in stone formation should not be restricted to the urinary environment only, and that understanding the role of thp at a cellular level in the early stage of stone formation could be very useful.(22) results of tardivel and colleagues' study showed that urinary alpha-1 microglobulin was significantly lower in calcium oxalate stone formers. they concluded that this protein could influence the risk of crystallization in vivo.(23) pupek-musialik found higher beta-2 microglobulin excretion in the urine of patients with metabolically active urolithiasisstone formers. they suggested a dysfunction of the proximal tubule in stone formers.(24) our study did not show a statistical difference between study subjects and controls with regard to urinary alpha-1 microglobulin and beta-2 microglobulin. there was a statistically significant difference in the albumin and transferrin means between study subjects and controls. of note, the higher level of albumin and transferrin found in the 24hour urine specimens of stone formers is a new finding. indeed, we do not expect glomerular impairment in stone formers, but we speculate that urinary albumin and transferrin may serve as a nidus for crystallization. using the sdspage method, siddiqui and colleagues isolated several proteins (thp, albumin, and transferrin) from urinary stones. because the same proteins are present in the urine of stone formers in high concentrations, but not or only to a very minor extent in the urine of nonstone formers, the authors concluded that they are selectively incorporated into renal stones, and that they most likely have a role in creating a nidus and therefore, in early stone formation.(25) similar results have been found by faraij.(26) however, chen and coworkers have shown the in vitro inhibitory effect of albumin on crystallization.(27) the exact roles of albumin and transferrin remain to be elucidated. significant differences between thp means in individuals with and without bacteriuria have been previously reported in the literature.(28,29) the normal physiologic function of thp remains elusive, however, despite extensive studies. the biochemical properties of thp make it possible that a host defense factor might be involved in clearing bacteria from the urinary tract. bates and colleagues have shown that thp serves as a soluble receptor for type 1 fimbriated e. coli and helps eliminate bacteria from the urinary tract .(29) mo and coworkers provided evidence clearly establishing thp on the first line of host defenses against both renal stone formation and bacterial infection.(30) how the renal epithelium responds to hyperoxaluria or calcium oxalate crystals might prove to be a contributing factor in the development of clinical urolithiasis.(31) the significant positive correlation between urine citrate and urinary promoters of stone formation (urinary uric acid, oxalate, and calcium) in controls but not in study patients suggests the probability that increased urinary excretion of citrate in response to elevated levels of stone formation promoters is a protective response. this might explain why the high frequency of metabolic abnormalities in patients in the control group did not lead to stone formation. we hypothesize that impairment of this response in stone formers might predispose them to stone formation. boruczkowska found this correlation in patients with urolithiasis.(32) in this study, in 24-hour urine specimens, only the mean levels of calcium, oxalate, and citrate were statistically different between the two groups. for the past 25 years, it has been recognized that other than a reduction in urine volume, increased urinary excretion of oxalate is a major risk factor for calcium oxalate stone formation.(12) hypercalciuria appears to play, at most, only a secondary role in the genesis of calcium stones compared with mild hyperoxaluria.(33) we can now hypothesize that decreased excretion of citrate and impairment of its increase in response to elevated levels of urinary promoters of stone formation might be another important risk factor. the higher 24-hour urine volume found in stone formers (which was statistically significant although not large enough to prevent stone urinary tamm-horsfall protein and citrate effects on calcium stone formation84 formation) might be due to greater liquid consumption by patients who considered the advice of health practitioners. conclusion thp in the urine of calcium stone formers is not quantitatively different from that of healthy individuals, but it increases in with the presence of bacteriuria. albumin and transferrin were significantly higher in the urine of calcium stone formers, suggesting their role in matrix and stone formation. increased urinary excretion of calcium, oxalate, and uric acid in stone formers with no increase in urinary citrate might play a role in the pathogenesis of recurrent stone formation. being able to control this predisposing factor would undoubtedly constitute a major breakthrough in preventing recurrence of calcium oxalate stones. references 1. soucie jm, thun mj, coates rj, mcclellan w, austin h. demographic and geographic variability of kidney stones in the united states. kidney int. 1994;46:893-9. 2. uribarri j, oh ms, carroll hj. the first kidney stone. ann intern med. 1989;111:1006-9. 3. sutherland jw, parks jh, coe fl. recurrence after a single renal stone in a community practice. miner electrolyte metab. 1985;11:267-9. 4. strauss al, coe fl, parks jh. formation of a single calcium stone of renal origin. clinical and laboratory characteristics of patients. arch intern med. 1982;142:504-7. 5. menon m, koul h. clinical review 32: calcium oxalate nephrolithiasis. j clin endocrinol metab. 1992;74:703-7. 6. grover pk, marshall vr, ryall rl. tamm-horsfall mucoprotein reduces promotion of calcium oxalate crystal aggregation induced by urate in human urine in vitro. clin sci (lond). 1994;87:137-42. 7. ryall rl, grover pk, stapleton am, et al. the urinary f1 activation peptide of human prothrombin is a potent inhibitor of calcium oxalate crystallization in undiluted human urine in vitro. clin sci (lond). 1995;89:533-41. 8. pak cy. medical management of nephrolithiasis. j urol. 1982;128:1157-64. 9. bradford mm. a rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. anal biochem. 1976;72:248-54. 10. laemmli uk. cleavage of structural proteins during the assembly of the head of bacteriophage t4. nature. 1970;227:680-5. 11. ausubel f, brent r, kingston re, et al. short protocols in molecular biology. 4th ed. new york: john wiley & sons inc; 1999. 12. robertson wg, peacock m, heyburn pj, marshall dh, clark pb. risk factors in calcium stone disease of the urinary tract. br j urol. 1978;50:449-54. 13. bichler kh, kirchner c, ideler v. uromucoid excretion of normal individuals and stone formers. br j urol. 1975;47:733-7. 14. samuell ct. uromucoid excretion in normal subjects, calcium stone formers and in patients with chronic renal failure. urol res. 1979;7:5-12. 15. thornley c, dawnay a, cattell wr. human tammhorsfall glycoprotein: urinary and plasma levels in normal subjects and patients with renal disease determined by a fully validated radioimmunoassay. clin sci (lond). 1985;68:529-35. 16. erwin dt, kok dj, alam j, et al. calcium oxalate stone agglomeration reflects stone-forming activity: citrate inhibition depends on macromolecules larger than 30 kilodalton. am j kidney dis. 1994;24:893-900. 17. glauser a, hochreiter w, jaeger p, hess b. determinants of urinary excretion of tamm-horsfall protein in non-selected kidney stone formers and healthy subjects. nephrol dial transplant. 2000;15:1580-7. 18. ganter k, bongartz d, hesse a. tamm-horsfall protein excretion and its relation to citrate in urine of stoneforming patients. urology. 1999;53:492-5. 19. bichler k, mittermuller b, strohmaier wl, feil g, eipper e. excretion of tamm-horsfall protein in patients with uric acid stones. urol int. 1999;62:87-92. 20. romero mc, nocera s, nesse ab. decreased tammhorsfall protein in lithiasic patients. clin biochem. 1997;30:63-7. 21. scurr ds, robertson wg. modifiers of calcium oxalate crystallization found in urine. iii. studies on the role of tamm-horsfall mucoprotein and of ionic strength. j urol. 1986;136:505-7. 22. boeve er, cao lc, de bruijn wc, robertson wg, romijn jc, schroder fh. zeta potential distribution on calcium oxalate crystal and tamm-horsfall protein surface analyzed with doppler electrophoretic light scattering. j urol. 1994;152:531-6. 23. tardivel s, medetognon j, randoux c, et al. alpha-1microglobulin: inhibitory effect on calcium oxalate crystallization in vitro and decreased urinary concentration in calcium oxalate stone formers. urol res. 1999;27:243-9. 24. pupek-musialik d. [usefulness of determining beta-2microglobulin in serum and urine in patients with metabolically active kidney calculi and healthy individuals]. pol tyg lek. 1993;48:464-6. polish. 25. siddiqui aa, sultana t, buchholz np, waqar ma, talati j. proteins in renal stones and urine of stone formers. urol res. 1998;26:383-8. 26. fraij bm. separation and identification of urinary proteins and stone-matrix proteins by mini-slab sodium dodecyl sulfate-polyacrylamide gel electrophoresis. clin chem. 1989;35:658-62. pourmand et al 85 27. chen wc, lin hs, chen hy, shih ch, li cw. effects of tamm-horsfall protein and albumin on calcium oxalate crystallization and importance of sialic acids. mol urol. 2001;5:1-5. 28. wolska-duda i, dulawa j, kokot f. [urinary excretion of tamm-horsfall protein, albumin and beta-2 microglobulin in children with recurrent urinary tract infection]. pol merkuriusz lek. 2001;11:36-9. polish. 29. bates jm, raffi hm, prasadan k, et al. tamm-horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. kidney int. 2004;65:7917. 30. mo l, huang hy, zhu xh, shapiro e, hasty dl, wu xr. tamm-horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. kidney int. 2004;66:1159-66. 31. marengo sr, chen dh, kaung hl, resnick mi, yang l. decreased renal expression of the putative calcium oxalate inhibitor tamm-horsfall protein in the ethylene glycol rat model of calcium oxalate urolithiasis. j urol. 2002;167:2192-7. 32. boruczkowska a. [estimation of 24-h excretion of some promotors and inhibitors of crystallization and degree of urine saturation with calcium oxalate in calcium urinary calculi]. pol arch med wewn. 1994;92:289-98. polish. 33. robertson wg, peacock m. the cause of idiopathic calcium stone disease: hypercalciuria or hyperoxaluria? nephron. 1980;26:105-10. editorial comment the authors have reapproached the longstanding debate on whether or not thp is implicated in calcium stone formation. over 130 peer-reviewed papers have been published so for on this subject with no unified consensus. part of this ambiguity is due to the fastidious nature of thp assays. we found, for example, that urine samples must be processed within 4 hours of collection or instantly frozen over liquid nitrogen, otherwise, any slower freeze-thaw cycle would lead to stubborn uromucoid aggregation and confound the results of future analyses.(1) despite these efforts to curb interfering factors, their samples were collected on an ambulatory basis from patients on an uncontrolled diet. dietary ca, p, and mg load each have been proven to grossly influence urinary thp excretion.(2) this may have played a significant role in the present results. even given a constant level of thp, sumitra and coworkers recently showed that antiaggregation and antinucleation effects of the uromucoid are radically influenced by the antioxidant content of the daily diet.(3) therefore, while commending the authors on such hard-won results, one must consider keeping such confounding elements in mind. pejman shadpour department of urology, shaheed hasheminejad hospital, iran university of medical sciences, tehran, iran references 1. shadpour p, zargar ma, soleimani mj, ghorbani gh. comparison of the urinary concentration of tammhorsfall protein between active stone formers and healthy controls. iranian journal of urology. 1995;2:259. 2. dulawa j, drab m, drobisz m, kokot f. urinary excretion of tamm-horsfall glycoprotein in healthy subjects and patients with renal diseases. nieren hochdruckkr 1993;22(suppl):110-3. 3. sumitra k, pragasam v, sakthivel r, kalaiselvi p, varalakshmi p. beneficial effect of vitamin e supplementation on the biochemical and kinetic properties of tamm-horsfall glycoprotein in hypertensive and hyperoxaluric patients. nephrol dial transplant. 2005;20:1407-15. reply by author ambulatory evaluation is routine in thp studies as mentioned in the literature (references 17-19, 25, and 26 of the article). besides, we should consider that effect of confounding factors can be overwhelmed by designing a case-control study, in which two groups are matched. gholamreza pourmand urology research center, tehran university of medical sciences, tehran, iran case report 135urology journal vol 6 no 2 spring 2009 a huge penile mass which turned out to be an epidermoid inclusion cyst ali kaviani, jalil hosseini, ali reza vazirnia urol j. 2009;6:135-7. www.uj.unrc.ir keywords: epidermal cyst, penis, male genital neoplasms department of urology, shohadae-tajrish hospital, shahid beheshti university (mc), tehran, iran corresponding author: ali kaviani, md department of urology, shohada-etajrish hospital, tajrish sq, tehran, iran tel: +98 912 148 1096 e-mail: akaviani@hotmail.com received february 2008 accepted july 2008 introduction congenital epidermoid cysts may form along the median raphe of the penis on the penile shaft or the glans.(1) epidermal inclusion cysts may develop after circumcision, repair of hypospadias, or other types of penile surgery when islands of epithelium are left behind in the subcutaneous tissue. these cystic lesions should be treated by simple excision.(1) in the present study, we report a huge, firm, disfiguring, distal penile mass in a 21-year-old man which turned out to be an epidermoid inclusion cyst. case report a 21-year-old man presented to our clinic with an asymptomatic slow-growing soft mass of the distal part of the penis (figure 1). the mass had been growing slowly within the past 8 years before diagnosis. the patient’s reason of presentation was correction of his significant penile deformity before his marriage. the patient did not have painful erections and denied any history of sexual intercourse, trauma, inflammation, urinary tract infection, hematuria, or dysuria. he had been circumcised during the first year of his life. on physical examination, a mass sized about 5 cm in diameter was palpable which was firm, nontender, and nonmobile with a smooth surface. the penile skin overlying the lesion was intact and mobile. there was no sign of inflammation including erythema, warmness, or urethral discharge. no inguinal lymphadenopathy was detected, either. ultrasonography revealed a 5 × 4 × 3-cm heterogeneous mass that appeared to be of extracorporeal figure 1. a huge firm disfiguring distal penile mass was noted on physical examination. epidermoid inclusion cyst of penis—kaviani et al 136 urology journal vol 6 no 2 spring 2009 origin. it had distorted both corpora without invasion. the patient underwent complete resection of the mass under spinal anesthesia. after incision of the skin, dissection was performed down to the buck’s fascia and meticulous dissection was done around the mass. after careful dissection, the smooth capsule of the tumor was incised and the tumor was enucleated from the surrounding tissues. there was no clear stalk. the mass essentially “popped” out of the bed of resection. after excision of the lesion, the dartos muscle and skin were closed by 4-0 and 3-0 vicryl sutures, respectively (figure 2). the diagnosis of epidermoid inclusion cyst of the penis was made by pathologic examination (figure 3). two months after the surgery, the patient had normal erectile function and was satisfied with the cosmetic results of the operation. he was followed up for 2 years, and no recurrence was noted. discussion epidermal cysts are benign tumors that may arise from the infundibular part of the hair follicles. they form spontaneously or subsequently to trauma. these cysts are not common in the penis and those found in this area are usually congenital with unknown etiology.(2,3) some authors believe that it may develop from abnormal closure of the median raphe during embriogensis.(4-6) penile epidermoid cysts are diagnosed by a careful examination accompanied by ultrasonography and/or computed tomography. some differential diagnoses include dermoid cyst, teratoma, and urethral diverticulum.(4) they often contain keratin, while a dermoid cyst contains skin and its appendages, and a teratoma contains derivatives of other germ cells.(4) neoplastic transformation of the epithelium of epidermoid cysts has been reported rarely but not in penile cases.(7) the best treatment of penile epidermoid cysts is total excision.(2,8) we excised the lesion and did not note local recurrence or any findings of malignancy in our patient after 2 years of follow-up. similar results have been reported by other surgeons.(2,4) however, although malignant transformation of epidermoid cysts is very rare, they should be followed up for a long time after complete removal. conflict of interest none declared. references 1. elder js. abnormalities of the genitalia in boys and their surgical management. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbellwalsh urology. 9th ed. philadelphia: saunders; 2007. p. 3745-60. 2. suwa m, takeda m, bilim v, takahashi k. epidermoid figure 3. pathologic examination of the dissected mass confirmed the epidermoid inclusion cyst of the penis (hematoxylin-eosin, × 10). figure 2. left, good plane of cleavage around the mass. right, reconstructed penis after removal of the mass. epidermoid inclusion cyst of penis—kaviani et al urology journal vol 6 no 2 spring 2009 137 cyst of the penis: a case report and review of the literature. int j urol. 2000;7:431-3. 3. dini m, innocenti a, romano gf. basal cell carcinoma arising from epidermoid cyst: a case report. dermatol surg. 2001;27:585-6. 4. lópez-ríos f, rodríguez-peralto jl, castaño e, benito a. squamous cell carcinoma arising in a cutaneous epidermal cyst: case report and literature review. am j dermatopathol. 1999;21:174-7. 5. khanna s. epidermoid cyst of the glans penis. eur urol. 1991;19:176-7. 6. little js jr, keating ma, rink rc. median raphe cysts of the genitalia. j urol. 1992;148:1872-3. 7. chiu my, ho st. squamous cell carcinoma arising from an epidermal cyst. hong kong med j. 2007;13:482-4. 8. rattan j, rattan s, gupta dk. epidermoid cyst of the penis with extension into the pelvis. j urol. 1997;158:593. 1721vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l tumor enucleation with zero ischemia for renal cell carcinoma by robotic retroperitoneal approach nicolae crisan,1,2 cristina ivan,1 vitalie gherman,1 calin neiculescu,1 ioan coman1,2 corresponding author: nicolae crisan, md 11 tabacarilor street, 400139, clujnapoca, romania. tel: +47 3540 6101 e-mail: drnicolaecrisan@gmail.com received october 2013 accepted april 2014 1 department of urology, clinical municipal hospital, cluj-napoca, romania. 2 iuliu hatieganu university of medicine and pharmacy, clujnapoca, romania. case report keywords: kidney neoplasms; surgery; laparoscopy; robotics; methods. introduction we present a surgical technique with zero ischemia enucleation of a right renal tumor using the robotic retroperitoneal approach (ra). case report a 67 year-old male, with a 14 mm right upper pole renal tumor, located on the posterior kidney surface, discovered accidentally after a computer tomography (figure 1). the preoperative aspects and dimensions used for an anatomical (padua) score was 7. after general endotracheal anesthesia was administered, the patient was placed in the full flank position. the body was flexed to expand the distance between iliac crest and the tip of the 12th rib. the retroperitoneum was entered through a 12 mm incision (for 12 mm trocar) in the angle between the 12th rib and paravertebral muscles in gaur manner.(1) at 9 cm of this trocar, above the iliac crest another 12 mm trocar was introduced under camera vision (optic trocar for robotic camera). at 9 cm distance from the second trocar, on the line obtained through extending the line from the 12th rib, an 8 mm robotic trocar was placed. this way a favorable triangular position for the robotic trocars resulted, avoiding the conflict between robotic arms and between robot and assistant surgeon. two 10 mm trocars were placed for the assistant surgeon, laterally and medially from the optic trocar (figure 2). finally, the first 12 mm trocar 1722 | was replaced with an 8 mm robotic trocar. the da vinci robot was then docked over the patient's head and shoulders. the ra allows us a direct access to the ureter and renal hilum. we found three distinct renal arteries that were skeletonized on the vessel loop, without using vascular clamps for the ischemia (figures 3 and 4). after localization and preparation of the posterior aspect of the kidney, we performed a zero-ischemia enucleation of the tumor (figure 5). renography was performed using 2.0 vicryl. the specimen was then bagged and recovered at the end of the case through the camera-port incision. the retroperitoneal space was prepared in 10 minutes and the insertion of the five trocars took 15 minutes, with 5 minutes docking. the operative time was 90 minutes, with 250 ml blood-loss. no postoperative complication was noted. surgical margins were negative, and a pt1a fuhrman 1 grade was found. he was discharged on the 6th day after the procedure. discussion there are two issues regarding the presented case that need figure 1. renal tumor on the posterior side of the right kidney (ct aspect). figure 3 . renal pedicle with two renal arteries. figure 4 . renal vein and the third renal artery. figure 2. trocar placement for robotic retroperitoneal approach. case report 1723vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l robotic retroperitoneal enucleation of a renal tumor | crisan et al further discussion. the first concerns the robotic partial nephrectomy with ra and the second concerns the zero ischemia time with robotic approach. the favorable perioperative results for ra (operative time, ischemia time) are explained through the rapid and direct access on the renal artery(2,3,4) and to the posterior side of the kidney, with a facile management of postoperative blood or urine loss.(5) the disadvantages for ra are related to the conflict among the robotic arms or between the robot and the assistant surgeon and the difficulty of the surgeon in recognizing the anatomy while using ra.(6,7) the enucleation consists of blunt dissection in the avascular cleavage between the tumor pseudocapsule and the renal parenchyma without clamping the renal artery (zero ischemia). this technique is considered to follow the oncological principles imposed by the eau guidelines.(8,9) in the literature there are few data about robotic renal enucleation with ra. recently, the results of a multicenter study were published, which included 886 cases of robotic partial nephrectomies, but none with zero ischemia time.(10) conclusion we concluded that this case is important by presenting two new aspects of surgical technique: robotic ra for performing a renal tumor enucleation without ischemia time. conflict of interest none declared. references 1. gaur dd. laparoscopic operative retroperitoneoscopy: use of a new device. j urol. 1992;148:1137-9. 2. rogers c, laungani r, krane ls, bhandari a, bhandari m, menon m. retroperitoneal robotic renal surgery: technique and early results. j robotic surg. 2009;3:1-5. 3. rogers c, laungani r, krane ls, bhandari a, bhandari m, menon m. robotic nephrectomy for the treatment of benign and malignant disease. bju int. 2008;102:1660-5. 4. hughes-hallett a, patki p, patel n, barber nj, sullivan m, thilagarajah r. robot-assisted partial nephrectomy: a comparison of the transperitoneal and retroperitoneal approaches. j endourol. 2013;27:869-74. 5. patel m, porter j. robotic retroperitoneal partial nephrectomy. world j urol. 2013;31:1377-82. 6. gettman mt, blute ml, chow gk, neururer r, bartsch g, peschel r. robotic-assisted laparoscopic partial nephrectomy: technique and initial clinical experience with da vinci robotic system. urology. 2004;64:914-8. 7. krambeck ae, gettman mt. robotic renal surgery: radical and partial nephrectomy. arch esp urol. 2007;60:462-70. 8. ficarra v, galfano a, cavalleri s. is simple enucleation a minimal partial nephrectomy responding to the eau guidelines' recommendations?. eur urol. 2009;55:1315-8. 9. minervini a, vittori g, lapini a, et al. morbidity of tumour enucleation for renal cell carcinoma (rcc): results of a single-centre prospective study. bju int. 2012;109:372-7. 10. tanagho ys, kaouk jh, allaf me, et al. perioperative complications of robot-assisted partial nephrectomy: analysis of 886 patients at 5 united states centers. urology. 2013;81:573-9. figure 5 . robotic enucleation of renal tumor. 1727vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l the whitaker test richard b. johnston, christopher porter corresponding author: richard johnston, md department of urology, virginia mason medical center, 1100 ninth ave c7-uro, seattle, washington 98101, usa. tel: +1 206 625 7459 fax: +1 206 223 7650 e-mail: richard.b.johnston@gmail. com received may 2013 accepted december 2013 virginia mason medical center, seattle, wa, usa. urology in history purpose: the whitaker test was conceived and developed by roger h. whitaker (may 25, 1939) while he was a resident at cambridge university in the late 1960s and early 1970s. the test combines a urodynamic study with antegrade pyelography to measure the pressure differential between the renal pelvis and the bladder. the test can differentiate between patients with residual or recurrent obstruction and those with dilatation secondary to permanent changes in the musculature. materials and methods: we present the history of the whitaker test and its place in modern practice. results: it is useful in evaluating patients with questionable ureteropelvic or ureterovesical junction obstruction and primary defects in the ureteral musculature. it can also be used to determine when percutaneous nephrostomy tubes can be safely discontinued in postoperative patients. conclusion: the merit of the whitaker test in comparison to other less invasive tests, specifically diuretic renography, is the subject of much debate. however, such debate erroneously presupposes that the tests are directly comparable, which they are not. the correct use for the whitaker test is to assesses potential upper tract obstruction in equivocal cases and should only be utilized when equivocal results are obtained by other less invasive tests, obstruction is suspected in a poorly functioning kidney, a negative renogram with colic, intermittent obstruction, and percutaneous access already exists and the cause of dilatation needs investigating. keywords: diagnostic techniques; urological; standards; dilatation; pathologic; diagnosis; pressure; ureteral obstruction; physiopathology. 1728 | urology in history introduction dilatation and obstruction of the urinary tract are not synonymous and it is not possible to estimate the pressure in the renal pelvis by cross-sectional imaging. even when an obstructing lesion, such as a ureteric calculus, is identified, the presence or absence of dilatation does not predict the extent to which ureter is obstructed. the correct diagnosis and treatment plan can often be determined by intravenous urography (ivu), ascending urogram, computed tomography (ct) scan with contrast and nuclear medicine isotope studies, such as diuretic renograms, when correlated with the symptom of pain as a surrogate for obstruction. however, important additional information is occasionally required in the event that these noninvasive tests yield equivocal results. for instance, dilatation may result in a poorly emptying but not actually obstructed system, leading to the stagnation of urine flow and an increased risk of developing a urinary infection. also, when dilatation is not resolved post-surgical repair, the question arises of whether the system is still obstructed. additionally, a subgroup of patients with normal renograms consistently present with intermittent loin pain. in these situations, a whitaker test can help differentiate cases of renal pathology from drug seeking or psychological pathology. the increased use of cross-sectional imaging and early ‘b’ mode ultrasound in the 1950s and 1960s resulted in considerable advances in the understanding of abnormal ureters, especially in the pediatric population.(1) however, the measurement of renal pelvis pressure received little attention and there was no well-described way to distinguish between congenital or postoperative causes of obstruction and unobstructed dilatation. this all changed in 1972 when roger h. whitaker (figure 1), a young resident from cambridge university who had spent a year in the research lab at johns hopkins (19689), published the results of his studies and described his now eponymous test – the whitaker test. while the concept of a dynamic perfusion-pressure flow (ppf) study was not new, with several animal model experiments and clinical trials already published,(1-3) all previous studies had used, at the least, a two cannula technique and did not describe an exact methodology based on sound physiologic principles. materials and methods the whitaker test sustained complete obstruction of the ureter leads to complete loss of function and, as such, is easily diagnosed and must be treated by relieving the obstruction. in contrast, transient or partial obstruction offers a far more difficult clinical situation. while nephron loss will eventually occur, it is obviously preferable to identify and treat the obstruction prior to this irreversible confirmation. however, differentiating between transient or partial obstruction and dilatation is not possible with only a single pressure measurement in the renal pelvis or without knowledge regarding flow. therefore, whitaker developed a test to measure the pressure differential between the renal pelvis and the bladder at a steady flow based on several physical principles. first, bernoulli's principle states that under conditions of steady flow, the sum of all forms of mechanical energy in a fluid along a streamline is the same at all points in that streamline. therefore, the velocity of a fluid is proportional to its dynamic pressure. p = pressure; v= velocity; = density of water however, application of this principle to the ureter is complicated as the diameter of the pipeline is not constant. due to the venturi effect, this causes differential speeds and pressures in the system (figure 2). moreover, the ureter is not a rigid tube and, as such, both intra-abdominal and intravesical pressure affect the upper tract. in fact, adjustment of the subject’s position can result in a variation of 10-38 mm hg in the renal pelvis.(4) finally, the kidney continues to produce urine, resulting in a contribution to the flow from the nephrons that cannot be calculated. whitaker overcame these issues by standardizing his methodology (figure 3). first, he pioneered the use of a single cannula, which he attached to a perfusion pump that maintained a fast flow rate of 10 ml per minute. the choice of 10 ml per minute was based in part on it being close to the physiologic maximum that a normal kidney can produce, meaning that the test is theoretically performed in a physiologic range. also, by standardizing the flow rate the results could be compared among patients. finally, the positioning of the patient was crucial for obtaining reproducible and interpretable results. early experiments were carried out on pigs at the brady 1729vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l the whitaker test | johnston et al urological institute at john hopkins. whitaker subsequently performed 170 studies on 112 patients with a history of equivocal obstruction based on previous conventional radiologic studies.(5) on the basis of these studies, he recognized five diagnostic patterns: 1. unobstructed system: at a flow rate of 10 ml/min, absolute pressure (pressure within the renal pelvis once the pressure produced by perfusion of the nephrostomy tube or needle is subtracted) of less than 25 cmh2o and relative pressure (pressure drop across the site of suspected obstruction obtained by subtracting bladder pressure from absolute pressure) of less than 15 cmh2o. 2. obstruction between the renal pelvis and bladder: relative pressure greater than 22 cmh2o and normal bladder pressure. 3. hypertonic bladder: absolute pressure greater than 25 cmh2o with a partially filled bladder and relative pressure less than 15 cmh2o. 4. hypertonic bladder and separate upper tract obstruction: both the absolute and relative pressures are elevated. 5. equivocal or partially obstructed: relative pressure between 15 and 22 cmh2o. using his test, whitaker was able to classify 96% of patients into groups 1-4. only 4% of the cases remained equivocal. results reception and usefulness of the test while whitaker’s initial report generated significant interest, the exact place in the urologic armory for the whitaker test has been widely debated over the last 40 years. without question, prior to its inception there was a considerable gap in our understanding of upper tract dilatation and its relationship to transient or partial obstruction. although it is not a physiological test, it is based on physiological principles. the standard infusion rate of 10 ml/min is an arbitrary number; however, the value was determined by whitaker after extensive experimental and clinical observations.(6) initially criticized as being too high, studies on healthy volunteers have shown that a kidney can produce 10 ml/min.(7) in fact, more recently the rate has been criticized as being too low, with rates of up to 20 ml/min being necessary to unmask transient, so-called high output, obstruction.(8) the clinical importance of these findings is limited, as these high rates, while possible, would seldom be seen. the exception would be in the case of dietl’s crisis, often seen in young men who drink large volumes of beer, when forced diuresis causes extreme pain due to an undiagnosed underlying ureteropelvic junction obstruction. the whitaker test is less accurate in massively dilated systems. once the capacity of the renal pelvis exceeds 70 ml, its concordance with diuretic renography drops from nearly 90% to less than 50%.(9) in addition, some studies have found an inconsistent relationship between obstrucfigure 1. roger h. whitaker, cambridge university staff photo. figure 2. the pressure at "1" is higher than at "2" and the fluid speed at "1" is lower than at "2" because the cross-sectional area at "1" is greater than at "2". 1730 | tion of the ureter and increased pressure in the renal pelvis. while the relationship should be consistent in an inelastic system, elastic recoil, which contributes to the pressure, can vary among patients with the same degree of obstruction. some kidneys with almost completely obstructed ureters can maintain normal pressures.(10) however, proponents of the test point out that low-pressure obstruction does not cause nephron damage. in fact, it is believed that a pressure above 22 cm h2o is required to cause damage,(11) and, as such, any clinically relevant obstruction, i.e. requiring treatment to prevent renal damage, can be identified by the whitaker test. the whitaker test is a dynamic test and interpretation of the numbers alone overlooks the purpose of the investigation in the first place, which is to make a diagnostic decision in the face of other equivocal tests. conclusion obstruction can only be defined in dynamic terms and the whitaker test gives the most dynamic results. therefore, it is not surprising that after 40 years it is still the go-to test in situations where other imaging and investigations have proved to be equivocal. the whitaker test should not be the first choice of test, nor was ever designed to be used as such. (9) to quote whitaker: this type of pressure flow perfusion study must be kept in perspective. it is not a panacea for all obstructions and should not be used as a short cut to a quick diagnosis. that we have done only 170 such studies in 8 years for the many thousands of patients who have passed through our unit suggests that we have been selective and, indeed, many of our cases have been referred from other hospitals just for the study. however, the individual patient with such a difficult diagnostic problem should not be denied the advantage of a study since it may well be the only present means of obtaining the correct decision in terms of management’ we are indebted to whitaker for his contribution to urology that has led to a greater understanding of dilated upper tract pathology. his test has helped many patients receive appropriate therapy that otherwise would have managed based on equivocal results. urology in history references 1. backlund l, reuterskiold ag. the abnormal ureter in children. scand j urol nephrol. 1969;3:219-28. 2. johnston jh. the pathogenesis of hydronephrosis in children. br j urol. 1969;41:724-34. 3. kill f. the function of the ureter and renal pelvis. oslo university press; 1957. p. 185. 4. ellis jh, campo rp, marx mv, et al. positional variation in the whitaker test. radiology. 1995;197:253-5. 5. whitaker rh. methods of assessing obstruction in dilated ureters. br j urol. 1973;45:15-22. 6. whitaker rh. the whitaker test. urol clin north am. 1979;6:529-39. 7. o’reilly ph. diuresis renography. recent advances and recommended protocols. br j urol. 1992;69:113-20. 8. lupton ew, holden d, george nj, barnard rj, rickards d. pressure changes in the dilated upper urinary tract on perfusion at varying flow rates. br j urol. 1985;57:622-4. 9. djurhuus jc, sørensen ss, jørgensen tm, taagehøj-jensen f. predictive value of pressure flow studies for the functional outcome of reconstructive surgery for hydronephrosis. br j urol. 1985;57:6-9. 10. koff sa. the diagnosis of obstruction in experimental hydroureteronephrosis. invest urol. 1981;19:85-8 11. george nr, o’reilly ph, barnard rj, blacklock nj. high pressure chronic retention. bmj 1983; 286:1780-3 figure 3. whitaker test setup. absolute pressure differences across the ureter are obtained by subtracting bladder pressure from renal pelvis pressure, which also cancels the effect of intra-abdominal pressure. editprial comments re: comparison of sexual functions in pregnant and non-pregnant women there are important physical and psychological changes during pregnancy, and in combination with cultural, social, religious, and emotional impacts, pregnancy might in fluences sexuality and sexual activity. physicians are often challenged with giving instruction to pregnant women and their husbands concerning these potential changes in pregnancy. sexual function and sexuality are imperative issues during pregnancy and postpartum period. although these issues have been addressed in some previously published papers, but we needs more data from different cultures and population. i congratulate the authors on a very nice paper, and am flattered by their interest in the sexual function during pregnancy. sexuality is a vital element of health and well-being in a woman's life. sexual behavior, which is affected by psychological, biological, cultural, and social factors, changes as pregnancy advances.(1) based on the literature review, the reasons for reducing and avoiding sexual activities during pregnancy are the fright of damaging the fetus(2,3) and the discomfort during intercourse.(4,5) the reported frequency of sexual dysfunction in this study is quite high, but the same results have also been reported by many other researchers. in a study of 141 pregnant women by bartellas and colleagues,(6) 71% of the participants who completed the questionnaires, reported a decline in intercourse in cidences during pregnancy compared to before pregnancy sexual activities. as mentioned above, fears of harming the fetus or inducing preterm labor are among other contributors to the decline in sexual activity. between 45% and 49% of women and 55% to 62% of their partners reported fear of producing some type of obstetric complication resulting from sexual intercourse during pregnancy.(7,8) nonetheless, the literature does not support a relationship between sexual activity and higher risk of preterm labor and delivery. in an otherwise normal pregnancy, there is no convincing data that demonstrate that sexual intercourse should be considered a risk to the fetus or a risk factor for inducing miscarriage or premature labor and delivery. in this study only sexual function has been studied, it was worthwhile that, the sexual health concern was also being addressed. the permission, limited information, specific suggestions, intensive therapy (plissit) model is one method that has been suggested for evaluation of sexual health concerns. this model was developed in 1976 by annon and has been used as a framework in many clinical settings.(9) alteneder and colleagues(10) proposed the use of the plissit method by nurses to address and plan interventions concerning sexual needs throughout the antepartum, intrapartum, and postpartum periods. in addition, this study has been done in married women. the amount of births to unmarried women has raised greatly in recent decades, rising from 5% in 1960 to 32% in 1995. after some steadiness in the mid-1990s, there was a steadyincrease from 1997 through 2008, from 32 to 41%. the rate seems to have stabilized again, and was at 41%. in 2013.(11) women who achieve pregnancy outside of marriage tend to be more deprived than their married counterparts, both before and after the pregnancy. unmarried mothers usually have lower salaries, lower education levels, and possibly are dependent on welfare support compared with married mothers.(12,13) therefore the context of sexual issue in these types of women should be studied in separate researches. in the national health and social life survey (nhsls) of 1749 women and 1410 men 18 to 59 years of age, only 10% to 20% of women reported seeking help for sexually related problems.(14) women are not talking about their fears to health care providers, and physicians are not routinely comprising sexual health issues or discussions in their office visits.(15) physicians often have a decreased sense of confidence to address sexual health problems, perceive an absence of treatment modalities, and underestimate how prevalent female sexual dysfunction might be. opening sexual health discussions and initiating a conversation can be exclusivelyvaluable during prenatal care visits. according to the world health organization (who), sexual health includes physical, mental, emotional, and social well-being in all sexual behaviors and beliefs.(16) many studies assessing sexual function during pregnancy were carried out more than two decades ago. changes in approaches concerning sexuality in pregnancy since that time may limit the significance of earlier studies. changing patterns of sexual behavior and sexuality in combination with changing advice from physicians and health care providers may make generalization from these early studies to the present day inappropriate. references 1. pauleta jr, pereire nm, graca lm. sexuality during pregnancy. j sex med. 2010;7:136–142. 2. serati m, salvatore s, siesto g, et al. female sexual function during pregnancy and after childbirth. j sex med. 2010;7:2782–90. 3. senkumwong n, chaovisitsaree s, rugpao s, chandrawongse w, yanunto s. the changes of sexuality in thai women during pregnancy. j med assoc thai. 2006;89(4 suppl):s124–9. 4. fok wy, chan ly, yuen pm. sexual behavior and activity in chinese pregnant women. acta obstet mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specializing in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com. vol 12 no 05 september-october 2015 2345 gynecol scand. 2005;84:934–8. 5. eryilmaz g, ege e, zincir h. factors affecting sexual life during pregnancy in eastern turkey. gynecol obstet invest. 2004;57:103–8. 6. bartellas e, crane jm, daley m, bennett ka, hutchens d. sexuality and sexual activity in pregnancy. bjog. 2000;107:964-8. 7. nakić radoš s, soljačić vraneš h, šunjić m. sexuality during pregnancy: what is important for sexual satisfaction in expectant fathers? j sex marital ther. 2015;41:282-93. 8. trutnovsky g, haas j, lang u, petru e. women's perception of sexuality during pregnancy and after birth. aust n z j obstetgynaecol. 2006;46:282–7. 9. annon js. the plissit model: a proposed conceptual scheme for the behavioral treatment of sexual problems. j sex educ ther. 1976;2:1–15. 10. alteneder rr, hartzell d. addressing couples' sexuality concerns during the childbearing period: use of the plissit model. j obstet gynecol neonatal nurs. 1997;26:651–8. 11. national center for health statistics, national vital statistics system: http://www.cdc.gov/ nchs/nvss.htm 12. lichter dt, graefe dr, brown jb. is marriage a panacea? union formation among economically disadvantaged unwed mothers. social problems. 2033;50:60-86. 13. terry-humen e, manlove j, moore ka. births outside of marriage: perceptions vs. reality. child trends research brief. washington, dc: child trends. 2001. available at: http://www. childtrends.org/wp-content/uploads/2013/03/ rb_032601.pdf 14. laumann eo, paik a, rosen rc. sexual dysfunction in the united states: prevalence and predictors. jama. 1999;281:537–44. 15. politi mc, clark ma, armstrong g, mcgarry ka, sciamanna cn. patient-provider communication about sexual health among unmarried middle-aged and older women. j gen intern med. 2009;24:511–6. 16. world health organization. defining sexual health: report of a technical consultation on sexual health, january 28–31, 2002. geneva, switzerland: world health organization; 2006;1–35. editorial comment 2346 sexual dysfunction and infertility the effects of varicocelectomy on testicular arterial blood flow: laparoscopic surgery versus microsurgery minghui zhang,1,2 lizhen du,2 zhijun liu,2 hengtao qi,3 qiang chu2* purpose: to investigate the long term effects of laparoscopic varicocelectomy (lv) and microsurgical subinguinal varicocelectomy (mv) on ipsilateral testicular microcirculation using color doppler flow imaging (cdfi). materials and methods: a total of 29 patients with left varicocele who underwent lv and 30 patients who underwent mv were examined with cdfi for intratesticular flow parameters before and at 3and 6-month after surgery. preoperative and postoperative semen parameters were also evaluated. results: the mean values of peak systolic velocity, pulsatility index (pi) and resistive index (ri) of capsular artery (ca) and intratesticular artery (ita) decreased significantly after lv and mv, whereas no significant change was observed in end-diastolic velocity. comparing between two groups, the pi and ri values of left ca and ita on 3rd month and of ita on 6th month postoperatively in mv group were significantly lower than those in lv group. lv and mv resulted in a statistically increase in the sperm density, morphology and total motile sperm count. moreover, the pi and ri values of ipsilateral ca and ita seemed negatively correlated with sperm quality. conclusion: a significant improvement occurs in testicular blood supply and sperm parameters after either lv or mv, among mv advances an early and a more obvious hemodynamics promotion than lv. the values of ri and pi of ipsilateral ca and ita are two important indexes for the prognosis after varicocelectomy. keywords: laparoscopy; microsurgery; postoperative complications; spermatic cord; varicocele; surgery; treatment outcome. introduction varicocele is defined as the hemodynamic impair-ment of testicular venous network with continu-ous blood reflux in pampiniform plexus and characterized by the abnormal dilation and retrograde flow in the affected veins.(1) the estimated incidence of varicocele is about 20% in the general population rising to almost 40% in subfertile men.(2) the effects of varicocele include reduced ipsilateral testicular volume, impaired sperm production ranging from oligozoospermia to complete azoospermia, and reduced fertility.(3) although proposed factors, as elevated testicular temperature caused by increased testicular blood flow, venous stasis secondary to increased venous pressure, reflux of adrenal/renal metabolites, hormonal imbalance and directly injuries due to the generation of excessive reactive oxygen species, may partly explain the impaired spermatogenesis, the exact mechanisms of the deleterious effects of varicocele on spermatogenesis are poorly understood.(3-6) the method for treatment of varicocele is mainly varicocelectomy, though various approaches exist, including traditional open inguinal (ivanissevich)/high retroperitoneal (palomo), laparoscopic, microscopic inguinal and microscopic subinguinal surgery. regardless of these different approaches, changes in semen parameters after varicocelectomy have been well demonstrated, with improved sperm concentration, motility and morphology and increased total motile sperm counts (tmsc) and pregnancy rates.(2,3,7) nevertheless, pathophysiology of this relationship between improved semen quality and varicocelectomy remains controversial.(8) it is hypothesized that impaired venous drainage causes increase in venous pressure of the spermatic veins. the condition of venous stasis may decrease the arterial blood supply and microperfusion of the testes by down-regulating arterial inflow to maintain the homeostasis of the intratesticular vascular pressure, thus inducing hypoxia and deficiency in testicular microcirculation.(2,9) besides, it is thought that, this hypoxia could be responsible for defective energy metabolism at mitochondrial levels causing dysfunction of both leydig and germinal cells.(4,5,10) the arterial supply to the testis has three major components: the testicular artery (ta), the cremasteric artery and the deferential artery, among which two thirds are supplied by ta. ta divides into two branches in testis, while the capsular artery (ca) continues in the surface of 1 department of ultrasound, cardiovascular institute and fuwai hospital, chinese academy of medical sciences and peking union medical college, beijing 100037, china. 2 department of ultrasound, qingdao municipal hospital, qingdao university, qingdao 266071, china. 3 department of ultrasound, shandong medical imaging research institute, shandong university, jinan 250021, china. * correspondence: department of ultrasound, qingdao municipal hospital, qingdao university, no. 5, donghaizhong rd., qingdao 266071, china. tel: +86 532 88905330; fax: +86 532 85968434. e-mail: qdultrasound@gmail.com. received march 2014 & accepted june 2014 sexual dysfunction and infertility 1900 the testis and the intratesticular artery (ita) in the parenchyma and deep.(11) previous studies indicate that color doppler flow imaging (cdfi) is well established to illustrate macro-microvascularity and therefore perfusion of the testis.(10-12) the arterial flow velocities (peak systolic velocity, psv, and end diastolic velocity, edv) and the resistance indices against this flow (resistive index, ri, and pulsatility index, pi) in the testis can be accurately measured with cdfi technique. in our hospital, microsurgical subinguinal varicocelectomy (mv) has been the principle method in the latest two years, however, laparoscopic varicocelectomy (lv) was the mainstream before. the aim of this study is to investigate the effects of varicocelectomy, both lv and mv, on testicular arterial blood flow using cdfi, and to clarify whether the present mv is superior to the previous lv. materials and methods study patients a total of 59 adults with clinical left varicocele and with various scrotal complaints were included (table 1). the varicocele had been detected on physical examination and scrotal ultrasonography. no comorbidities such as hypertension, diabetes, psoriasis, or other internal diseases existed, besides bilateral/subclinical/recurrent varicocele, history of varicocelectomy and azoospermia, any scrotal pathology other than varicocele were also excluded. lv was performed during may 2010 and november 2011, and mv was performed since january 2012. the same surgeon (zl) performed either of the two operations in all patients, and all patients were obligated to have follow-up visits including physical and sonographic examinations 3 and 6 months after surgery. informed consent was obtained from all patients, and the study protocol was approved by the ethics committee of our hospital (qmh20100046, qmh-20120013). color doppler ultrasonographic examination all patients were examined via ge logiq 9 ultrasound system using a 9.0~12.0 mhz linear-array transducer (ge medical systems, llc, milwaukee, wi, usa) in the supine position during normal respiration and during valsalva maneuver. the diagnostic criteria for varicocele were as the common view.(13) all patients were studied between 16:00 and 18:00 pm in a warm quiet room and they rested for at least 15 min before the ultrasonography. routine scrotal ultrasonography was analyzed for testicular size. the volume of the testis was calculated using the formula for a prolate ellipse (a × b × c × 0.52), where a, b and c are the 3 longest diameters of the testis.(14) the left intratesticular blood flow parameters were measured just prior to surgery and were repeated at 3rd and 6th months follow-up, moreover parameters of the right side were measured as control. built-in software was used for automatic calculation, on the frozen spectral display, of the psv, edv, ri and pi on spectral doppler waveforms. ri was calculated as [(psv-edv)/psv]. pi was calculated as [(psv-edv)/tamaxv], with tamaxv = time-averaged maximum flow velocity. the doppler sample window was set at 1 mm. on each doppler tracing, measurements were performed only when the waveform modulation and amplitude remained stable on at least three consecutive cardiac cycles. all the exams were done by the same researcher (mz) and reevaluated by another researcher (qc). we had calculated a κ between the researcher (p = .910). surgery laparoscopic varicocelectomy (lv) patients were placed in a right lateral low lithotomy position under general anesthesia. three ports (one 10and two 5-mm trocars) were placed in a triangle formation, with a camera port (10 mm) just below the umbilicus and the other two ports at the lateral border of each rectus abdominis muscle. after dissecting the adhesion between the intestine/mesentery and the varicoceles if exist, a retroperitoneal incision was made in the lateral aspect from the point 3 cm superior to the internal inguinal ring along variables lv group (n = 29) mv group (n = 30) total (n = 59) p value patients number 29 30 59 grade of varicocele grade ii 20 19 39 grade iii 9 11 20 .785 chief complaint pain 10 9 19 mass 13 9 22 infertility 6 12 18 .251 age (range, years) 18-35 18-35 ---- age (median, years) 23 24 ---- .484 table 1. demographic and clinical characteristics of patients in study groups. abbreviations: lv, laparoscopic varicocelectomy; mv, microsurgical subinguinal varicocelectomy. variables lv group mv group patients number 29 30 preoperative (left) 12.71 ± 2.16 12.63 ± 3.08 3 months 13.01 ± 2.96 12.87 ± 2.91 6 months 12.97 ± 2.67 12.83 ± 3.14 preoperative (right) 13.04 ± 3.02 12.76 ± 3.03 3 months 12.94 ± 3.40 12.73 ± 3.29 6 months 13.11 ± 3.12 12.89 ± 3.33 abbreviations: lv, laparoscopic varicocelectomy; mv, microsurgical subinguinal varicocelectomy. * all p values are statistically non-significant (p > .05). table 2. testicular volume (ml, mean ± sd) of patients in study groups.* varicocelectomy affects testicular supply-zhang et al vol 11. no 05 sept-oct 2014 1901 the testicular vessels. the lymphatic vessels and ta were identified and likewise preserved. the para-arterial veins that paralleled or sandwiched the ta were separated, ligated by hem-o-lok clips (weck closure systems, research triangle park, nc, 27709, usa) and cut.(1) patients were discharge on the second post-operative day (pod2). microsurgery subinguinal varicocelectomy (mv) patients were placed in the supine position after induction of adequate spinal anesthesia. a 2.5 cm subinguinal incision was made and the testicle was then delivered. through the operating microscope at 6-15 × magnification, the vas deferens, vasal vessels, ta (or tas) and as lymphatic channels as possible were preserved, all internal spermatic veins were identified and dissected and then ligated with 4-0 mersilk sutures (ethicon inc., shanghai, china). the spermatic cord was then repeatedly examined until no veins other than deferential veins remain. the gubernaculum was also thinned sufficiently so that veins on both sides can be identified and ligated.(10) the spermatic cord was last returned to its bed. incision was closed layers by layers, while skin closure was performed with sterile strip enforcement. patients were discharge on the next day (pod1). semen analysis semen specimens were collected on site after two-five days of sexual abstinence preoperatively and repeated at 6th month after surgery, and only from the subfertile and patients who were married and receptive to the test, as semen collection by masturbation was somehow ridiculous for the virgin boys. sperm concentration, motility and morphology were assessed using world health organization (who) 2010 manual for the examination and processing of human semen.(15) tmsc (i.e., ejaculate volume × concentration × motile fraction) was calculated. a 50% or more tmsc increase from baseline was accepted capsular artery intratesticular artery variables psv (cm/s) edv (cm/s) pi ri psv (cm/s) edv (cm/s) pi ri preoperative 10.71 ± 3.53 3.6 2 ± 1.67 1.07 ± 0.19 0.62 ± 0.09 7.23 ± 1.17 3.32 ± 0.77 0.91 ± 0.11 0.59 ± 0.06 (left) 3 months 9.17 ± 1.97** 3.51 ± 1.39 0.98 ± 0.11** 0.55 ± 0 .06‡ 6.77 ± 1.04 3.21 ± 0.69 0.82 ± 0.09† 0.55 ± 0.05† 6 months 9.18 ± 1.92** 3.52 ± 1.47 0.92 ± 0.09‡§ 0.53 ± 0.05‡ 6.47 ± 0.98† 3.19 ± 0.73 0.79 ± 0.07‡ 0.54 ± 0.04‡ preoperative 9.52 ± 3.96 3.59 ± 1.52 1.11 ± 0.34 0.60 ± 0.08 7.06 ± 0.97 3.26 ± 0.67 0.83 ± 0.11 0.54 ± 0.07 (right) 3 months 9.53 ± 3.66 3.64 ± 1.40 1.02 ± 0.28 0.59 ± 0.06 7.07 ± 1.01 3.21 ± 0.59 0.86 ± 0.10 0.56 ± 0.07 6 months 9.51 ± 3.38 3.55 ± 1.05 1.05 ± 0.27 0.61 ± 0.09 7.03 ± 1.09 3.11 ± 0.71 0.87 ± 0.13 0.57 ± 0.09 abbreviations: lv, laparoscopic varicocelectomy; psv, peak systolic velocity; edv, end diastolic velocity; pi, pulsatility index; ri, resistive index. * data are presented as mean ± sd. ** p < .05 compared with the preoperative data. † p < .01 compared with the preoperative data. ‡ p < .001 compared with the preoperative data. § p < .05 data of 6th month postoperatively compared to that of 3rd month, p = .0269 exactly. table 3. comparison of preoperative and postoperative blood flow parameters in both testes (lv group, n = 29).* capsular artery intratesticular artery variables psv (cm/s) edv (cm/s) pi ri psv (cm/s) edv (cm/s) pi ri preoperative 11.11 ± 4.04 3.79 ± 1.76 1.11 ± 0.20 0.60 ± 0.12 7.13 ± 1.50 3.30 ± 0.85 0.97 ± 0.17 0.58 ± 0.08 (left) 3 months 9.28 ± 2.54** 3.62 ± 1.67 0.91 ± 0.14‡# 0.52 ± 0.05†# 6.43 ± 0.99** 3.29 ± 0.73 0.69 ± 0.17‡& 0.49 ± 0.06‡& 6 months 9.17 ± 2.83** 3.65 ± 1.93 0.92 ± 0.15‡ 0.54 ± 0.06** 6.58 ± 1.16 3.31 ± 0.69 0.67 ± 0.15‡& 0.50 ± 0.07**$ preoperative 9.17 ± 3.34 3.44 ± 1.60 1.01 ± 0.44 0.59 ± 0.12 7.22 ± 0.87 3.27 ± 0.76 0.87 ± 0.12 0.55 ± 0.07 (right) 3 months 9.23 ± 3.82 3.61 ± 1.54 1.13 ± 0.39 0.62 ± 0.11 7.19 ± 0.91 3.20 ± 0.50 0.84 ± 0.17 0.53 ± 0.06 6 months 9.21 ± 3.11 3.57 ± 1.37 1.15 ± 0.31 0.61 ± 0.13 7.23 ± 1.00 3.21 ± 0.61 0.88 ± 0.13 0.54 ± 0.08 abbreviations: mv, microsurgical subinguinal varicocelectomy; psv, peak systolic velocity; edv, end diastolic velocity; pi, pulsatility index; ri, resistive index. * data are presented as mean ± sd. ** p < .05 compared with the preoperative data. † p < .01 comparing to the preoperative data ‡ p < .001 comparing to the preoperative data. data comparison of the same time point between the two groups, table 3 and table 4: # p < .05; $ p < .01; & p < .001. table 4. comparison of preoperative and postoperative blood flow parameters in both testes (mv group, n = 30).* varicocelectomy affects testicular supply-zhang et al sexual dysfunction and infertility 1902 as a significant improvement in the semen parameters.(12) statistical analysis pasw statistics version 18.0 software (ibm spss inc., chicago, il, usa) was used for statistical analysis. results were expressed as the mean ± standard deviation. the demographic data were compared using a chi-square or mann-whitney u test, and preand postoperative data were compared using a student’s t-test for paired samples. a p value of < .05 was considered statistically significant. results patients’ information is summarized in table 1. no operative or postoperative complication was observed within six months, and no post-operative varicocele recurrence was identified. no participants were lost to follow up, as they were all local citizens. in lv group, 50% (5/10) of patients with the chief complaint of pain and 84.6% (11/13) of patients with the complaint of mass were cured, and the rest were relieved; while in mv group, the cure rate was 88.9% (8/9) no matter complaining of pain or mass, and then the relieve rate was 11.1% (1/9). no couple achieved spontaneous pregnancy within the follow-up in either group. the mean testicular volumes for the lv and mv groups are presented in table 2. there was no statistically significant difference among the preand postoperative values within either lv or mv group (p > .05). there was also no statistically significant difference in those values for the testes between the two groups (p > .05). all the preoperative and postoperative blood flow parameters in both testes are listed in table 3 and table 4. within each (lv or mv) group, the values of ri, pi and psv in the left ita and ca decreased significantly after surgery (p < .05), among which the values of ri and pi seemed more sensitive than psv (with smaller p values), and those of 6th month were insignificantly lower (p > .05) than 3rd month postoperatively except pi of ca in lv group (p < .05). no significant change was observed in edv (p > .05). no differences were detected in the right ita and ca between the preoperative and postoperative blood flow parameters (p > .05). comparing between two groups, the initial (preoperative) parameters were statistically equal (p > .05), but the interim data (3rd month postoperative), the values of pi and ri of ca and ita, in mv group were significantly lower than those in lv group (p < .05), moreover in the ultimate (6th month postoperative) data, the values of pi and ri of ita were also lower in mv group (p < .01). of study participants 41.4% (12/29) and 46.7% (14/30) of patients underwent semen analyses in lv and mv groups, respectively (table 5). in both groups, sperm density, percent normal morphology, and tmsc were improved after surgery (p < .05), however, sperm motility remained unchanged (p > .05). tmsc was the most important indicator of sperm quality, and ≥ 50% tmsc increase postoperatively was considered as a meaningful improvement.(12) according to this criteria, tmsc improved (≥ 50%) in 66.7% (8/12) and 78.6% (11/14) of patients in lv and mv groups, respectively, the rest remained unchanged (< 50% increase). the preoperative and postoperative mean cdfi values were respectively listed in table 5 in the 19 patients with tmsc improvement versus in the remaining 7 patients with no semen improvement. in tmsc improved subgroup, the values of pi and ri of ipsilateral ca and ita were significantly decreased (p < .05), whereas in tmsc unchanged subgroup, the values of pi and ri of lv group (n = 12) mv group (n = 14) parameters preoperative postoperative p value preoperative postoperative p value total motile sperm counts (million) 63.69 ± 16.60 92.72 ± 17.73 .0004 60.11 ± 18.25 96.08 ± 20.44 < .0001 sperm count (million/ml) 34.23 ± 9.30 53.91 ± 12.06 .0002 32.74 ± 9.41 56.22 ± 13.00 < .0001 motility (%) 52.83 ± 12.96 56.44 ± 17.73 .5748 50.14 ± 10.99 57.35 ± 17.05 .1251 normal morphology (%) 29.52 ± 13.69 43.59 ± 15.24 .0265 27.06 ± 10.97 40.31 ± 13.67 .0072 table 5. preand postoperative semen parameters in study groups. abbreviations: lv, laparoscopic varicocelectomy; mv, microsurgical subinguinal varicocelectomy. tmsc improved subgroup (n = 19) tmsc unchanged subgroup (n = 7) parameters preoperative postoperative p value preoperative postoperative p value tmsc (million) 58.91 ± 14.47 96.27 ± 16.37 < .0001 69.50 ± 15.22 89.81 ± 18.03 .0419 ca-psv (cm/s) 11.21 ± 5.36 9.24 ± 2.74 .1623 10.36 ± 4.92 9.77 ± 2.81 .7876 ca-pi 1.11 ± 0.19 0.90 ± 0.15 .0006 1.01 ± 0.19 0.92 ± 0.13 .3214 ca-ri 0.60 ± 0.08 0.54 ± 0.07 .0188 0.60 ± 0.08 0.55 ± 0.07 .2371 ita-psv (cm/s) 7.17 ± 1.46 6.60 ± 1.09 .1811 7.09 ± 1.33 6.77 ± 1.23 .6486 ita-pi 0.96 ± 0.15 0.70 ± 0.16 < .0001 0.91 ± 0.15 0.76 ± 0.10 .0480 ita-ri 0.57 ± 0.09 0.51 ± 0.06 .0208 0.54 ± 0.09 0.51 ± 0.05 .4557 table 6. correlation between preand postoperative tmsc and ipsilateral cdfi parameters. abbreviations: tmsc, total motile sperm counts; cdfi, color doppler flow imaging; edv, end diastolic velocity; pi, pulsatility index; psv, peak systolic velocity; ri, resistive index; ca, capsular artery; ita, intratesticular artery. varicocelectomy affects testicular supply-zhang et al vol 11. no 05 sept-oct 2014 1903 ipsilateral ca and ita were accordingly unchanged (p > .05). in both subgroup, the values of psv of ca and ita were insignificantly decreased (p > .05). discussion varicocele is a commonly encountered disease in urology clinic. doppler is not only helpful for the diagnosis of varicocele, but also can monitor the changes of testicular blood flow parameters before and after varicocelectomy. (10-12,14,16,17) the arteriovenous system of the testis is highly complex and under a fine regulation to maintain a proper spermatogenesis environment. the testicular, deferential and cremasteric arteries all provide the blood supply to the testis, and they form numerous anastomoses at the upstream of testicular parenchyma. at this point, they can not directly reflect testicular microcirculation but ca and ita, which locate just in the capsule surface and deep parenchyma of the testis respectively, are more reliable. normally pampiniform plexus can not only take away testicular metabolic waste but also play a role in cooling the arterial blood before it reaches the testis, helping ensure the organ stays at the proper temperature, yet the drainage and cooling function are impaired when varicocele arises. varicocelectomy can partly restore the innate function of plexiform plexus in order to rectify the testicular microcirculation.(9,18) animal studies have shown indeterminate changes in testicular blood flow in association with varicocele. li and colleagues demonstrated a decrease in testicular blood flow in rats after experimentally induced varicocele;(19) ozturk and colleagues indicated that artificial varicocele induced by partial stenosis of the ipsilateral renal vein has no effect on testicular blood flow of both sides as determined by flow cytometry;(20) while others showed that testicular blood flow increased after the creation of experimental varicocele in dogs and rats and returned to baseline levels after varicocelectomy in rats.(21) this discrepancy may be partly explained by methodological differences in blood flow measurement and the durations of the created varicocele. furthermore, experimentally induced varicocele models in animals are not completely identical to human, especially regarding different effects of gravity between human bipedalism and animal quadrupedalism. several clinical studies have investigated the effects of varicocele on testicular blood flow. tarhan and colleagues reported that blood flow in varicocele bearing testicles is less abounded than normal control in men;(22) akcar and colleagues reported that subclinical varicocele does not affect the intratesticular arterial ri,(14) and ünsal and colleagues proved that increased ri and pi values of ca on spectral doppler examination are indicators of impaired testicular microcirculation in patients with clinical varicocele.(17) concerning varicocelectomy, sun and colleagues used doppler to investigate the changes in testicular perfusion following laparoscopic varicocele clipping in children and reported no significant change. however, they examined only the magnitude of arterial perfusion, and did not use any arterial flow parameters (psv, edv, ri, and pi) reflecting arterial flow hemodynamics.(23) tanriverdi and colleagues compared microsurgery and high ligation varicocelectomy by evaluating intratesticular arterial flow by cdfi seven days after surgery, and reported no statistically difference between the preoperative and postoperative ri values in both groups.(16) a similar study comparing two laparoscopic surgical methods at 3 months follow-up demonstrated that mean ri value in the group of patients with spermatic artery ligation was comparable to the group of spermatic artery preservation. (24) most importantly, balci and colleagues first evaluated the long term effects of varicocelectomy on testicular blood flow. in their research, 26 infertile patients with left varicocele were operated and monitored up to the sixth month after the operation, though only ita was evaluated and the microsurgical varicocelectomy technique was not applied. they found that the mean edv value was increased, the ri and pi values were decreased, and the psv value was unchanged after surgery.(12) three years after balci’s study, tarhan and colleagues observed the effects of microsurgical inguinal varicocelectomy (not mv) on testicular blood flow.(10) their results showed that within six months after surgery the mean psv and edv of left ta increased, and ri and pi values of left ca and ita decreased. no significant difference was detected between the preoperative and postoperative blood flow parameters in the right ta, ca and ita. they believed that psv and edv values showed flow velocity; ri and pi values showed resistance against blood flow, so they assumed that the blood flow into the ipsilateral testis increased and the resistance against blood flow in affected testis decreased after surgery. therefore they concluded that the psv and edv values increase in ta and the pi and ri values decrease in ca and ita, and they were the indicators of an increase in testicular arterial blood flow into the testicular tissue. our study is a prospective case-controlled cohort study, and initially intended to investigate the long term changes on the testicular microcirculation before and after laparoscopic varicocelectomy using cdfi in adults, however, surgical techniques evolve over time, subsequently an added purpose was to compare the two surgical techniques. for the first purpose, we found from the our results that the values of ri, pi and psv in the left ita and ca decreased within six months after surgery, which was similar to tarhan’s report.(10) smaller ri and pi values reflect that arterial resistance of ipsilateral testis decreases after surgery, and smaller psv values does not simply mean ipsilateral testicular blood supply decrease, but should be a self-regulation of preload due to the lighten afterload. as hemodynamic changes involving the capillary bed and/or venous drainage have direct effects on arterial impedance,(25) we infer that hydrostatic pressure (afterload) of affected testicular venous column decrease after pampiniform plexus is cleared.(10,12,17) the self-regulation must be gradually completed over pods, so we have reason to believe that psv and edv values of ca and ita would increase at the early postoperative period (within pod7 or pod30?) , then more such data are need in future. for the second purpose, our case-matched data demonstrate that mv is superior to lv based upon our limited cdfi data. the superiority is not caused by the learning curve though mv is performed posterior to lv as the surgeon (zl) has passed the learning curve (> 20 years experiences), but mainly due to the surgical techniques. we suppose that the application of magnification make the microanatomy of spermatic cord sharper, and varicocelectomy affects testicular supply-zhang et al sexual dysfunction and infertility 1904 the high-definition operative field is positive to a better postoperative outcome. the microsurgical technique (inguinal or subinguinal) is an innovative technique that allows the ligation of all of the veins except the vasal vein while sparing the local arteries and lymphatics, and is proved to reduce the recurrence rate and complications.(26) the subinguinal approach (mv) does not incise the external oblique aponeurosis, reducing pain for the patient, but at the expense of the increased number of veins that must be ligated.(7) as such, mv is considered the gold-standard technique for varicocelectomy in adults. semen evaluation is not a principle index in our study, and infertility is neither our target illness, because merely less than half participants accepted this test. in the present study, only semen samples on two time points were collected, so correlation analysis between semen and cdfi parameters can not be quantified. moreover, if we divide such handful of patients into four subgroups according to the surgical approaches multiply by semen improvement, the numbers of individual subgroups will be too small, thus meaningless for further statistical analyses. these are all limitations of our study. even though, we can develop the trend that semen parameters are improved after varicocelectomy (lv or mv), which is in agreement with the majority of previous reports.(2,3,10,12) besides, the values of pi and ri of ipsilateral ca or ita seem negative correlated with sperm quality, which is also in accord with others.(10-12) although the majority of patients achieved an improved tmsc, no couple achieved spontaneous pregnancy within the follow-up in either group, which is possibly because of the limited patient number and relatively short observation interval. additionally, the maximal improvements in the cdfi parameters appeared as early as the 3rd month in mv group, while on the 6th month in lv group. this finding can partly explain al bakri’s report that the sperm quality improves by 3 months after mv and then does not improve further.(27) as logically, if couples plan to receive intrauterine insemination or in vitro fertilization/intracytoplasmic sperm injection after correcting the male factor infertility associated with a varicocele, the efficient surgical approach for varicocele repair is mv rather than lv. conclusion in conclusion, varicocelectomy (either lv or mv) results in a significant decrease in the values of psv, pi, or ri of ipsilateral ita or ca, and an improvement in semen parameters in left clinical varicocele patients, which suggests an improvement of the testicular blood supply or sperm quality. the values of ri and pi of ita and ca will be two important indexes for the prognosis after varicocelectomy. mv has advantage to lv on postoperative cdfi parameters, and the former can advance an early and a more obvious promotion than the latter. because the present study covered only a 6-month follow-up period, further studies in larger series, longer periods and with more time points are needed to test the relationship between testicular perfusion and sperm parameters after different varicocelectomy approaches. acknowledgements this study is granted by the postgraduate research fund of qingdao university belonging to professor shibao fang, department of ultrasound, affiliated hospital of qingdao university and the author (mz). conflicts of interest none declared. references 1. cimador m, castagnetti m, gattuccio i, pens abene m, sergio m, de grazia e. the hemody namic approach to evaluating adolescent varico cele. nat rev urol. 2012;9:247-57. 2. pasqualotto f, borges e, roth f, lara l, pasqualotto e. varicocele: to fix or not to fix. in: sabanegh es, editor. male infertility: huma na press; 2011. p. 65-79. 3. schauer i, madersbacher s, jost r, hubner wa, imhof m. the impact of varicocelectomy on sp -erm parameters: a meta-analysis. j urol. 2012;187:1540-7. 4. agarwal a, hamada a, esteves sc. insight into oxidative stress in varicocele-associated male infertility: part 1. nat rev urol. 2012;9:678-90. 5. hamada a, esteves sc, agarwal a. insight into oxidative stress in varicocele-associated male infertility: part 2. nat rev urol. 2013;10:26-37. 6. smit m, romijn jc, wildhagen mf, veldhoven jl, weber rf, dohle gr. decreased sperm dna fragmentation after surgical varicocelec tomy is associated with increased pregnancy rate. j urol. 2013;189:s146-50. 7. choi ws, kim sw. current issues in varicocele management: a review. world j mens health. 2013;31:12-20. 8. hsiao w, rosoff js, pale jr, powell jl, gold stein m. varicocelectomy is associated with in creases in serum testosterone independent of clinical grade. urology. 2013;81:1213-7. 9. reyes jg, farias jg, henriquez-olavarrieta s, et al. the hypoxic testicle: physiology and path ophysiology. oxid med cell longev. 2012;2012:929285. 10. tarhan s, ucer o, sahin mo, gumus b. longterm effect of microsurgical inguinal vari cocelectomy on testicular blood flow. j androl. 2011;32:33-9. 11. pinggera gm, mitterberger m, bartsch g, et al. assessment of the intratesticular resistive index by colour doppler ultrasonography measure ments as a predictor of spermatogenesis. bju int. 2008;101:722-6. 12. balci a, karazincir s, gorur s, sumbas h, egil mez e, inandi t. long-term effect of varicocele repair on intratesticular arterial resistance index. j clin ultrasound. 2008;36:148-52. 13. chiou rk, anderson jc, wobig rk, et al. col or doppler ultrasound criteria to diagnose var icoceles: correlation of a new scoring system with physical examination. urology. 1997;50:953-6. 14. akcar n, turgut m, adapinar b, ozkan ir. in tratesticular arterial resistance and testicular varicocelectomy affects testicular supply-zhang et al vol 11. no 05 sept-oct 2014 1905 volume in infertile men with subclinical varico cele. j clin ultrasound. 2004;32:389-93. 15. lu wh, gu yq. insights into semen analysis: a chinese perspective on the fifth edition of the who laboratory manual for the examina tion and processing of human semen. asian j androl. 2010;12:605-6. 16. tanriverdi o, miroglu c, horasanli k, altay b, caliskan kc, gumus e. testicular blood flow measurements and mean resistive index values after microsurgical and high ligation varicoce lectomy. urology. 2006;67:1262-5. 17. unsal a, turgut at, taskin f, kosar u, kara man cz. resistance and pulsatility index in crease in capsular branches of testicular artery: indicator of impaired testicular microcirculation in varicocele? j clin ultrasound. 2007;35:191 5. 18. kroese ac, de lange nm, collins ja, evers jl. varicocele surgery, new evidence. hum re prod update. 2013;19:317. 19. li h, dubocq f, jiang y, tiguert r, gheiler el, dhabuwala cb. effect of surgically induced varicocele on testicular blood flow and sertoli cell function. urology. 1999;53:1258-62. 20. ozturk h, surer i, okur h, demirbag s, cet inkursun s. testicular blood flow alterations and flow cytometric analysis in prepubertal rats with experimentally induced unilateral varicoc -ele. eur surg res. 2003;35:98-102. 21. turner tt. the study of varicocele through the use of animal models. hum reprod update. 2001;7:78-84. 22. tarhan s, gumus b, gunduz i, ayyildiz v, goktan c. effect of varicocele on testicular ar tery blood flow in men--color doppler investi gation. scand j urol nephrol. 2003;37:38-42. 23. sun n, cheung tt, khong pl, chan kl, tam pk. varicocele: laparoscopic clipping and col or doppler follow-up. j pediatr surg. 2001;36:1704-7. 24. student v, zatura f, scheinar j, vrtal r, vra na j. testicle hemodynamics in patients after laparoscopic varicocelectomy evaluated using color doppler sonography. eur urol. 1998;33:91-3. 25. nelson tr, pretorius dh. the doppler signal: where does it come from and what does it mean? ajr am j roentgenol. 1988;151:439-47. 26. mehta a, goldstein m. microsurgical varicoce lectomy: a review. asian j androl. 2013;15:56 60. 27. al bakri a, lo k, grober e, cassidy d, cardoso jp, jarvi k. time for improvement in semen parameters after varicocelectomy. j urol. 2012;187:227-31. varicocelectomy affects testicular supply-zhang et al sexual dysfunction and infertility 1906 erratum laparoscopic adrenalectomy: a report of the first experience in iran simforoosh n*, ahmadnia h, ziaee am, moradi m urology/nephrology research center, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran volume1, number 2, pages 77-81: some technical errors mainly due to persian to english translation were unnoticed and the published version was not the edited one. the correct version of the article follows. the publisher regrets this error. abstract purpose: to report the first experience in laparoscopic adrenalectomy and to study its efficacy and safety in the treatment of different adrenal diseases. materials and methods: from march 1997 to july 2001, 11 patients underwent laparoscopic adrenalectomy through transperitoneal approach, five of whom were males and 6 were females. their mean age was 35.5 (range 28 to52) years. lesion was located on the left side in 6 patients and on the right side in 5. all necessary evaluations were done preoperatively including ct scan, mri, mibg scan, and endocrine tests such as acth, cortisol, mineralocorticoid, 17-hydroxyprogesterone, and urinary vma. three (5, 10, and 12 mm) trocars were used in left laparoscopic adrenalectomy and three or four (12, 10, 5, and 5 mm) trocars were applied in right laparoscopic adrenalectomy. all the patients were followed up for three months with physical examination and paraclinical tests. results: mean operative time (including anesthesia and surgery) was 205±65.95 (range 130 to 310) minutes. no significant difference was seen between the operative time in the left side and the right side adrenalectomy (p=0.5). mean hospitalization was 5.54±3.4 (range 3 to15) days. mean size of mass was 5.45±1.7 (range 2 to 8) cm. blood transfusion was performed in 2 patients and open surgery was conducted for one because of extensive adhesions. no mortality was reported. during a 3-month follow-up, hormonal tests and blood pressure were normal for all the patients, with no medical treatment being required. conclusion: our study demonstrated that transperitoneal laparoscopic adrenalectomy is an effective and safe approach in the treatment of adrenal masses with the least morbidity. key words: adrenal neoplasm, laparoscopy, adrenalectomy 221 urology journal unrc/iua vol. 1, no. 3, 221-225 summer 2004 printed in iran introduction the first laparoscopic adrenalectomy was performed in 1992 by ganger.(1-3) this approach was quickly developed because of less hemorrhage during operation, shorter hospitalization, and faster postoperative improvement.(4-6) laparoscopic adrenalectomy may be conducted either transperitoneally or retroperitoneally.(4, 5, 7, 8) in this study, transperitoneal approach was the preferable method, which is the first report of laparoscopic adrenalectomy in iran and to our accepted for publication in august 2003 *corresponding author: department of kidney transplantation, shaheed labbafinejad medical center, boustan 9, pasdaran, tehran, iran. email: simforoosh@iurtc.org.ir laparoscopic adrenalectomy: a report of the first experience in iran knowledge the first one in a renal transplanted patient worldwide. materials and methods from march 1997 to july 2001, 11 patients underwent laparoscopic adrenalectomy through transperitoneal method, five of whom were males and 6 were females. their mean age was 35.5 (range 28 to 52) years. table 1 indicates clinical and pathological details. ultrasonography and abdominal ct scan was preoperatively performed for all patients (fig. 1). mri was conducted if ct scan was unclear. mibg scan would be performed if pheochromocytoma was suspected and if mri or ct scan were not helpful. routine biochemical tests such as serum potassium and sodium levels, fasting blood sugar, and endocrine analyses such as serum acth, cortisol, minralocorticoids, and 17-hydroxyprogesterone, and 24-hour urinary vma were conducted too. details of the procedure, its complications, and the probability of conversion to open surgery were explained for all of the patients. bowel preparation was performed 24 hours before the procedure. ng tube and urethral catheter were inserted under general anesthesia. then patients were secured in flank position with an angle of approximately 60 degrees. the bed was flexed 30 degrees and was reversed to trendelenburg 10 degrees to retract intestine from the field of surgery. after the preparation of patient veress needle was used through an umbilical incision and pneumoperitoneum was induced using co2. trocars were placed when the pressure reached 19 to 20 mmhg and then it was reduced to 14 to 15 mmhg. three 12, 10, and 5 mm trocars were applied in left adrenalectomy (for 6 patients). a 12 mm trocar was applied through umbilical incision and used for telescope. a 10 mm trocar was applied on breast line parallel to umbilicus and a 5 mm trocar was applied on midline between xiphoid and umbilicus. then peritoneum was opened from the colonic spleen curve to sigmoid on toldt line and colon was pushed inside. then gerota fascia was opened on renal vein, so that adrenal gland and vein were seen. adrenal vein was cut after clipping bilaterally. then fat tissue and the rest of the vessels were cut by mets or electrocautery after clipping bilaterally, so that adrenal gland was totally freed. three to four (12, 10, 5, and 5 mm) trocars were used in right adrenalectomy (for 5 patients). similar trocars were applied in left. the second 5 mm trocar was inserted on the breast line at the rib margin to retract the liver if needed. adrenal gland was seen at the right side behind peritoneum after retracting the liver upward. hepatocolic and peritoneal ligaments were cut; thus, anterior surface of adrenal gland was revealed. after freeing the gland at inferior, lateral, posterior, and finally medial surfaces and cutting adrenal vein, following bilateral clipping, adrenal gland was removed through an umbilical incision made for 12 mm trocar, after enlarging it (depending on the size of gland) (fig. 2). as a drain, an 18 f nelaton 222 no. age gender adrenal pathology side of operation 1 43 male conn’s syndrome right 2 40 female conn’s syndrome left 3 52 male pheocromocytoma right 4 32 male pheocromocytoma right 5 35 male pheocromocytoma left 6 34 female pheocromocytoma left 7 39 female adrenal medolary hyperplasia left 8 28 male pheocromocytoma left 9 29 female pheocromocytoma left 10 31 female conn’s syndrome right 11 28 female myelolipoma right table 1. patients' clinical and pathological characteristics fig. 2. laparoscopic surgical operation and the tumor fig. 1. a 35-year-old woman with dysuria. a 7 cm tumor in left adrenal gland was revealed. laparoscopic adrenalectomy: a report of the first experience in iran catheter was applied through 10 mm trocar for two or three days for all the patients. they were followed up with paraclinical tests and physical examination for three months (fig. 3,4). student's t test was used for comparison of the size of mass and time of the procedure. results the mean time of the procedure (including anesthesia and surgery) was 205±64.95 (range 130 to 310) minutes. mean time for left side was 227.5±53.1 (range 145 to 305) minutes. there was no significant difference in the time of procedure between left and right sides (p=0.5). mean hospitalization was 5.54±3.4 (range 3 to 15) days. the mean size of mass was 5.45±1.7 (range 2 to 8) cm. no significant difference was seen between the size of left sided masses and right sided ones (p=0.6). a 28-year female with a history of a 15-year renal transplantation was among the patients. she underwent laparoscopic adrenalectomy because of an adrenal mass, pathologic report of which was myelolipoma. blood transfusion was performed in 2 cases. normal diet was started for 9 patients at the first postoperative day. open surgery due to severe adhesion was conducted for one patient (9%), who underwent laparoscopic adrenalectomy because of pheochromocytoma. hypertensive crisis occurred during the procedure in one pheochromocytoma case, which was properly managed without any problem by the anesthesiologist. postoperative complications were reported in only one patient with left adrenalectomy. this patient underwent open surgery due to postoperative hemorrhage. no hernia or infection was seen at the site of trocars and no mortality was reported. blood pressure and hormonal tests were normal with no medical treatment during eight-month follow-up period. discussion surgical intervention is regarded as the main approach in several adrenal disorders. familiarity with adrenal gland anatomy and its pathophysiology is important for a successful procedure. open surgical incisions for adrenal mass removal consist of thoracoabdominal, flank, anterior, and posterior (lumbar). selecting the appropriate method depends on adrenal pathology, patient's physical structure, history of surgical operation, and surgeon's experience.(9) laparoscopic adrenalectomy is an effective and safe method to treat various endocrine and neoplasic adrenal diseases,(4,6,10,12) as it was shown in this study. several studies reported that the morbidity rate in laparoscopic adrenalectomy is less than that in open surgery.(4,5,7,13-15) previously, laparoscopic surgery needed a longer time than open surgery; however, the progress of technology and more laparoscopic experience have led to similar operative times.(14) patients in laparoscopic surgeries would be hospitalized shorter and would return to their normal activities sooner. younger patients could return to their sport activities sooner with no limitation. regarding cosmetic point of view, short incisions at trocar sites instead of long incisions would be more considerable particularly for females.(14) magnification by laparoscope would lead to easier detection of small vessels around adrenal mass which causes a distinguishable decrease of hemorrhage comparing to open adrenalectomy.(16) it also brings about a more accurate view of surgical anatomy of adrenal gland and helps differential diagnosis between adenoma and normal tissue of gland. elective 223 fig. 4. unrecognizable port site scars fig. 3. pathology: adrenaladenoma laparoscopic adrenalectomy: a report of the first experience in iran removal of adrenal lesion without total removal of the gland, which is problematic in open surgery, is more practical in laparoscopic surgery. guazzoin et al reported successful removal of 2 adrenal cysts without adrenal removal after which adrenal function was normal.(14) most authors agree on the effectiveness of laparoscopic therapy for conn's and cushing's syndromes.(4) because of hypertensive crisis during surgery, pheochromocytoma surgery differs form other adrenal tumoral surgeries.(4,5,17) it was believed that laparoscopic methods are contraindicated in pheochromocytoma, for the produced ponomoperitoneum with co2 and the increase of abdominal pressure would lead to hemodynamic changes and the release of catecholamines as well.(18) furthermore, co2 could cause hypercapnia and respiratory acidosis that would lead to hypertension during laparoscopy.(17,19) sprung et al have recently shown that laparoscopic hemodynamic changes are comparable with those of open surgery methods. the number of hypertension episodes and the highest level of hypertension during surgery were equal in both methods, while hypotension severity was lower in laparoscopic methods than open surgery.(20) consequently, pheochromocytoma could be treated by laparoscopic surgery, although large lesions could increase the chance of hemorrhage, hypertension and postoperative complications due to increased number of vessels.(21) in this study hypertension occurred only in one patient (out of 6) with pheochromocytoma, which was controlled with no complication. since ganger has indicated that lesions larger than 13 cm could be treated by laparoscopic adrenalectomy, the size of adrenal mass was no more considered as a limiting factor in laparoscopic surgery.(4,12) thus, larger masses which could mostly be malignant, would be removed by laparoscopic surgery, though, enlarging the incision of umbilicus would be essential.(14) dissection would be more difficult and the surgery would last in a way that could be beyond patient's tolerance.(21) moreover, large masses have many abnormal vessels which could increase hemorrhage.(22) bilateral adrenalectomy for cushing's syndrome after unsuccessful treatment of hypophysis adenoma (surgery or radiotherapy) or for secondary cushing's syndrome could lead to improper discharge of acth.(23,24) in our study, the decrease of wound infection risk, better postoperative respiratory capacity and shorter hospitalization would be main advantages of laparoscopy.(21) laparoscopy is used in the treatment of nonfunctional adrenal masses too, especially when their malignant nature is proved.(25) this is a common case as 20-22% of laparoscopic adrenalectomies are because of incidentaloma removal.(4,6) porpiglia et al reported that the incidence of incidentaloma was 30% of the whole laparoscopic adernalectomies.(21) several factors such as a mass larger than 6 cm (in ct scan or sonography), non-homogenized mass in ct scan and an increase of dhea or estradiol are used to distinguish malignant adrenal masses from benign.(26) in spite of these factors, adrenalectomy may be performed for an incidentaloma where cortical carcinoma may be detected by the analysis of pathologic sample. porpiglia et al reported such a carcinoma after laparoscopic removal of the mass. no sign of recurrence was reported after 40 months follow-up.(21) it is commonly believed that this treatment would be sufficient for proved malignant adrenal masses provided that the neoplasm is limited to the gland and a perfect and accurate laparoscopy is performed.(4,5) laparoscopic transperitoneal removal of adrenal glands includes anterior and lateral transperitoneal methods. in anterior transperitoneal method, adrenal anterior margin is usually freed at the end that occasionally leads to upward movement of adrenal, which makes it difficult to pull downward.(16) however, in this study anterior margin of adrenal gland was easily freed at the beginning after the retraction of the liver or spleen toward midline through lateral transperitoneal approach. thus, it seems that lateral transperitoneal approach would be better than anterior transperitoneal, particularly for large tumors. conclusion this study indicated that transperitoneal laparoscopic adrenalectomy is an effective and safe approach, which should be performed by a skilled laparoscopic surgeon to minimize potential intraoperative and postoperative complications such as infection and to avoid open incision. clinical outcomes of laparoscopic surgery in such circumstances would be much better than open surgery and its morbidity would be much lesser. 224 laparoscopic adrenalectomy: a report of the first experience in iran references 1. ganger m, lacroix a, bolte e. laparoscopic adrenalectomy in cushing's syndrome and pheochromocytoma. n engl j med 1992; 327: 1003. 2. ganger m, lacroix a, printz ra, et al. early experience with laparoscopic approach for adrenalectomy. surgery 1993; 114: 1120. 3. ganger m. lacroix a, bolte e. laparoscopic adrenalectomy. surg endosc 1993; 7: 122. 4. ganger m, pomp a, heniford bt, et al. laparoscopic adrenalectomy: lessons learned from 100 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study of 100 patients. surgery 1997; 122: 1132. 12. vargas hi, kavoussi lr, bartlett dl, et al. laparoscopic adrenalectomy: a new standard of care. urology 1997; 49: 673. 13. bonjer hj, van der harst e, steyerberg ew, et al. retroperitoneal adrenalectomy: open or endoscopic? would j surg 1998; 22: 1246. 14. guazzoin g, montorsi f, bocciardi a, et al. transperitoneal laparoscopic versus open adrenalectomy for benign hyperfunctioning adrenal tumors: a comparative study. j urol 1995; 153: 1597. 15. winfield hn, hamilton bd, bravo el, et al. laparoscopic adrenalectomy: the preferred choice? a comparison to open adrenalectomy. j urol 1998; 160: 325. 16. terachi t, matsuda t, terai a, et al. transperitoneal laparoscopic adrenalectomy: experience in 100 patients. j endourol 1997; 11: 361. 17. mobius e, nies c, rothmund m. surgical treatment of pheochromocytomas: laparoscopic or conventional? surg endosc 1999; 13: 35. 18. joris j, hamoir e, hartstein gm, et al. hemodynamic changes and catecholamine release during laparoscopic adrenalectomy for pheochromocytoma. anesth analg 1999; 88: 16. 19. fernandez-cruz l, taura p., saenz a, et al. laparoscopic approach to pheochromocytoma: hemodynamic changes and catecholamine secretion would j surg 1996; 20: 762. 20. sprung j, o hara jf jr, gill is, et al. anesthetic aspects of laparoscopic and open adrenalectomy for pheochromocytoma. urology 2000; 55: 339. 21. porpiglia f, garrone c, giraudo g, et al. transperitoneal laparoscopic adrenalectomy: experience in 72 procedures. j endourol 2001; 15: 275. 22. ganger m. laparoscopic adrenalectomy. surg clin north am 1996; 76: 523. 23. ferrer fa, macgillivray dc, malchoff cd, et al. bilateral laparoscopic adrenalectomy for adrenocorticotropic dependent cushing's syndrome. j urol 1997; 157: 16. 24. lanzi r, montorsi f, losa m, et al. laparoscopic bilateral adrenalectomy for persistent cushing's disease after transsphenoidal surgery. surgery 1998; 123: 144. 25. mugiya s, suzuki k, masada h, et al. laparoscopic adrenalectomy for nonfunctioning adrenal tumor. j endourol 1996; 10: 539. 26. wells sa, merke dp, cutler gb, et al. therapeutic controversy: the role of laparoscopic surgery in adrenal disease. j clin endocrinol metab 1998; 83: 3041. 225 vol 12. no 02 march-april 2015 1995 sexual dysfunction and infertility the effect of fasting on erectile function and sexual desire on men in the month of ramadan raidh a. talib, onder canguven,* khalid al-rumaihi, abdulla al ansari, mohammed alani purpose: to determine the effect of ramadan intermittent fasting on erectile function (ef), sexual desire and serum hormone levels. materials and methods: eligible male participants completed the two domains of international index of erectile function (iief) questionnaire for ef and sexual desire. they also provided information on any known disease, treatment taking, smoking habits and frequency of sexual intercourse. frequency of sexual intercourse, two domains of iief questionnaire, serum hormone levels, body weight before and four-weeks after the end of month of ramadan were also recorded. results: overall, 45 men, with a mean age of 37 ± 7.2 years, participated in the study. frequency of sexual intercourse (p = .046), sexual desire (p = .002), body weight (p = .009) and serum follicle stimulating hormone (fsh) level (p = .016) decreased significantly at the end of month of ramadan compared to baseline. no statistically significant differences were found on ef (p = .714), serum testosterone (p = .847), luteinizing hormone (p = .876), estradiol (p = .098) and dehydroepiandrosterone sulfate levels (p = .290). conclusion: ramadan intermittent fasting might be associated with decrease in sexual desire, frequency of sexual intercourse and serum fsh level. keywords: fasting; metabolism; adverse effects; risk factors; sexual dysfunction. introduction fasting is a practice that is observed by many cultures and religions. in islam, during the month of ramadan, able-bodied muslims abstain from food, fluid, smoking and sexual relations for 12-14 hours daily at daytime. they eat before sunrise, retire later and consume large meals after sunset to replenish energy and fluid levels. well-documented effects of ramadan intermittent fasting (rif) include changes in circadian rhythms, metabolic and endocrine function, as well as reductions in daytime hydration, blood glucose and body temperature.(1) collectively these changes may cause physiological and psychological perturbations that could have detrimental effects on sexual function. to our knowledge, there is only single study on the effect of rif over intercourse frequency.(2) in that study, berrada and colleagues examined both sex and found that rif results in dramatic decrease in frequency of sexual intercourse.(2) one of their study limitations was that they included different marital statuses i.e. single and married which might have affected the result of their study on frequency of sexual intercourse.(2) in this study, we planned to include married men in order to overcome limitation of finding partner. materials and methods study participants this study was completed on 45 volunteer male participants in a tertiary teaching hospital. participants were selected from staff (doctors and nurses) working in different clinics of the hospital. participants completed a self-reported questionnaire on demographic, lifestyle characteristics and on erectile function (ef), using the international index of erectile function (iief). iief is the most reliable measure of ef and has been culturally, linguistically and psychometrically validated.(3) the index uses a 15-item self-administered questionnaire, which comprehensively assesses sexual function in five response domains. in this study, we evaluated two domains of iief questionnaire (i) ef (questions 1–5 and 15) and (ii) sexual desire (questions 11 and 12). information on any known disease and drug therapy, blood pressure, serum glucose and lipid levels were also obtained. criteria for inclusion were being married, male, in good health, non-smoker, not taking any medicines and not being on a diet. additional criteria were having normal ef and fasting during the month of ramadan. the participant should also have had regular sexual relationship with his wife. furthermore, wife of the participant should not have been away from the house they live together during the study period. patients who were under any kind of hormonal treatment and were diagnosed with any kind of cancer were excluded from the study. other exclusion criteria were using any kind of drugs related with erection e.g. phosphodiesterase type 5 inhibitor and herbal medications in the last 6 months from the study period. institutional review board approved and granted this study and all the participants provided written informed consent before participation. department of urology, hamad general hospital, doha, qatar. *correspondence: department of urology, hamad general hospital, doha, qatar. tel: +974 44391864. fax: +974 44391842. e-mail: ocanguven@yahoo.com. received october 2014 & accepted february 2015. vol 12. no 02 march-april 2015 2099 vol 12. no 02 march-april 2015 2100 evaluations hormonal evaluation tests and frequency questions were applied one week before the month of ramadan and at the end of ramadan (29th and 30th day of month of ramadan). blood samples were taken from each participant early in the morning (7:00-8:00 am) by a technician who was assigned by the research center for this study. therefore, the participants did not wait in the queue with other patients. weight and height were measured in duplicate using a digital scale and standard stadiometer. body mass index (bmi) was calculated as weight in kg/height in m2. serum levels of following sex hormones were measured: total testosterone, free testosterone, bioavailable testosterone, sex hormone binding globulin (shbg), dehydroepiandrosterone sulfate (dheas), luteinizing hormone (lh), follicle stimulating hormone (fsh) and estradiol. statistical analysis qualitative and quantitative data values were expressed as frequency (percentage) and mean ± sd. quantitative variables means between preand post-rif results were compared using paired t-test. a two-sided p value of < .05 was considered to be statistically significant. all statistical analyses were done using statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. main outcome measures the primary end points of the present study were to assess whether rif affect baseline ef, sexual desire and monthly frequency score of sexual intercourse four weeks later (at the end of the month of ramadan). the secondary end point was to compare baseline serum hormone levels with the study end results. results the final cohort included 45 male participants with a mean age ± sd of 37±7.2 years (range, 27-56), who fulfilled the inclusion criteria, were identified and included in this study. there were no dropouts during the study. at baseline, the mean iief-ef and sexual desire scores for the entire cohort were 28 ± 1 and 9 ± 1, respectively. at the end of rif, the mean iief-ef and sexual desire scores for the entire cohort were 27 ± 1 and 6 ± 2, respectively (p < .05 for sexual desire). mean serum hormone levels and characteristics of participants are shown in table. body weight, bmi, fsh and frequency of sexual intercourse also decreased significantly after rif (p < .05). no statistically significant differences were found in serum testosterone, lh, estradiol and dheas levels that were taken before and at the end of month of ramadan (table). discussion fasting during the month of ramadan leads to alterations in feeding habits, sleep duration, pattern and architecture. (4) several studies have demonstrated that psychomotor performance, subjective alertness and memory are adversely affected during the month of ramadan.(5,6) the present study examined the effects of rif on ef, sexual desire, frequency of sexual intercourse and serum hormone levels in men. the results indicated that rif caused significant decrease in sexual desire and frequency of sexual intercourse during the month of ramadan compared to previous month. we also demonstrated that serum fsh level and bmi significantly decreased at the end of the month of ramadan. although there were some changes in testosterone, estradiol, dheas and lh levels, the results were not statistically significant. previously, it has been demonstrated that rif has some effects on physical activity.(1,7) long-lasting modifications as in rif have been shown to result in a phase delay of many biological rhythms.(5,8) in our study, we found table. demographic and clinical characteristics of study subjects at baseline and at the end of study. variables before ramadan end of ramadan p value (mean ± sd) (mean ± sd) weight (kg) 94.67 ± 17.3 94.00 ± 17.2 .009* bmi (kg/m2) 30.15 ± 4.9 29.94 ± 4.9 .009* intercourse frequency (number/month) 7.96 ± 2.4 6.62 ± 1.8 .046* iief-erectile function domain score 28 ± 1 27 ± 1 .714 iief-sexual desire domain score 9 ± 1 6 ± 2 .002* serum hormone levels total testosterone (nm/l) 14.93 ± 4.5 15.03 ± 3.6 .847 free testosterone (nm/l) 0.3 ± 0.06 0.28 ± 0.1 .682 bioavailable testosterone (nm/l) 6.45 ± 1.36 6.67 ± 1.2 .512 shbg (nm/l) 29.11 ± 12.8 29.27 ± 12.9 .817 dheas (µm/l) 7.4 ± 3.2 7.2 ± 3.4 .290 lh (iu/l) 2.93 ± 1.7 2.98 ± 1.7 .876 fsh (iu/l) 2.97 ± 1.8 2.68 ± 1.7 .016* estradiol (pmol/l) 83.3 ± 21.5 78.23 ± 22.6 .098 abbreviations: bmi, body mass index; iief, international index of erectile function; shbg, sex hormone binding globulin; dheas, dehydroepiandrosterone sulfate; lh, luteinizing hormone; fsh, follicle stimulating hormone. *p < .05 and statistically significant. impact of the month of ramadan on sexual function-talib et al. sexual dysfunction and fertility 2100 vol 12. no 02 march-april 2015 1995 that the frequency of sexual intercourse in married men decreased nearly 20% at the end of month of ramadan after 4 weeks of intermittent fasting. earlier, frequency of sexual intercourse has been investigated in only one study by berrada and colleagues.(2) in the latter study, investigators found that the frequency of 2 to 3 times per week (for 56%) before ramadan, dropped to 29% of participants.(2) surprisingly, 16% of the study group did not have sexual intercourse during ramadan, although all the participants had sexual intercourse on at least one occasion the month before.(2) in the present study, all of participants had sexual intercourse at least two times per month even during ramadan. this controversy might be attributed to the differences in marital status of two studies. it is noteworthy that nearly one third (27.4%) of the participants in berrada and colleagues’ study were single.(2) since there was no information on their partners and relations, the single participants might not have had an opportunity for sexual intercourse. additionally, out of wedlock sexual relation is forbidden in islam as in other monotheistic religions. the latter might have also affected the study results of single participants of berrada and colleagues. the results of the present study also showed that there is a significant decrease in sexual desire, the drop was nearly 30%. from a practical standpoint, our findings imply that less desire might have led less frequent sexual intercourse. in literature, there are conflicting results on change of serum fsh levels during the month of ramadan.(9,10) bogdan and colleagues found statistically significant decrease in the 24-hour mean level of serum fsh during ramadan.(9) as has been found in the latter study, the current study showed that serum fsh level decreased significantly at the end of four-week rif. on the other hand, mesbahzadeh and colleagues showed significant increase in serum fsh levels in single male participants. (10) in interpreting the findings of the mesbahzadeh and colleagues’ study, it is important to note that there was no information on sexual activity of the participants which might have influenced hormone results.(10) in the current study, although it was statistically no significant, we demonstrated that participants had higher serum testosterone and lower estradiol levels at the end of rif. the results of the present study also showed that there was, albeit small, significant decrease of approximately 0.7 kg in body weight of our participants. the altered testosterone/estrogen ratio might be explained, in part, by weight loss. the study by fejes and colleagues is particularly informative in respect to the relation between testosterone/estradiol ratio and bmi.(11) in their study, they confirmed that testosterone/estradiol ratio was significantly reduced in the high bmi group as compared to the low bmi group.(11) another explanation for testosterone/estradiol ratio might be changing in sleeping pattern during the month of ramadan. it has been reported that the average sleep time was one-hour shorter during ramadan than it had been during the control period.(8) to our knowledge, this is the second study that investigated the effects of rif on the ef and sexual desire. the effects of fasting during ramadan month on ef and serum hormones in muslim men were not researched together. our results carry important clinical implications. in particular, they suggest that rif affect serum fsh levels and frequency of sexual intercourse. on the other hand, the present study might have some limitations. a limitation of this study is that we did not record participants’ diet and sleeping pattern details. since the main purpose of our study was to consider the modifications in serum hormone levels and sexual life in participating subjects observing the rule of ramadan, we did not attempt to change the subjects’ environmental conditions or behavioral customs, including their eating habits and sleeping times. additionally, the differences of parameters in this study are coming from smaller sample size. therefore further studies with larger sample sizes are needed for more confirmatory and to generalize the findings. conclusion in conclusion, our study demonstrated that, fasting during the month of ramadan has an impact on sexual life. the frequency of sexual intercourse and sexual desire of the subjects studied here were reduced significantly. on the other hand, rif restrictions do not seem to change the sexual hormone levels, except for fsh. acknowledgements a grant from the hamad medical corporation primarily supported this research. we would also like to acknowledge the careful work of mr. fadi qasem for their assistance during collection of blood samples for this study. conflict of interest none declared. references 1. chaouachi a, leiper jb, chtourou h, aziz ar, chamari k. the effects of ramadan intermittent fasting on athletic performance: recommendations for the maintenance of physical fitness. j sports sci. 2012;30 suppl 1:s53-73. 2. berrada s, dorhmi s, bouhaouli l, kadri n. sexualité durant le mois de ramadan. sexologies. 2008;17:83-9. 3. rosen rc, riley a, wagner g, osterloh ih, kirkpatrick j, mishra a. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997;49:822-30. 4. chaouachi a, coutts aj, chamari k, et al. effect of ramadan intermittent fasting on aerobic and anaerobic performance and perception of fatigue in male elite judo athletes. j strength cond res. 2009;23:2702-9. 5. roky r, houti i, moussamih s, qotbi s, aadil n. physiological and chronobiological changes during ramadan intermittent fasting. ann nutr metab. 2004;48:296-303. 6. degoutte f, jouanel p, begue rj, et al. food restriction, performance, biochemical, psychological, and endocrine changes in judo athletes. int j sports med. 2006;27:9-18. 7. zerguini y, dvorak j, maughan rj, et al. influence of ramadan fasting on physiological and performance variables in football players: summary of the f-marc 2006 ramadan fasting impact of the month of ramadan on sexual function-talib et al. vol 12. no 02 march-april 2015 2101 sexual dysfunction and fertility 2102 study. j sports sci. 2008;26 suppl 3:s3-6. 8. bogdan a, bouchareb b, touitou y. response of circulating leptin to ramadan daytime fasting: a circadian study. br j nutr. 2005;93:515-8. 9. bogdan a, bouchareb b, touitou y. ramadan fasting alters endocrine and neuroendocrine circadian patterns. meal-time as a synchronizer in humans? life sci. 2001;68:1607-15. 10. mesbahzadeh b, ghiravani z, mehrjoofard h. effect of ramadan fasting on secretion of sex hormones in healthy single males. east mediterr health j. 2005:1120-3. 11. fejes i, koloszar s, zavaczki z, daru j, szollosi j, pal a. effect of body weight on testosterone/ estradiol ratio in oligozoospermic patients. arch androl. 2006;52:97-102. impact of the month of ramadan on sexual function-talib et al. urology journal unrc/iua vol. 1, no. 4, 268-272 autumn 2004 printed in iran 268 miscellaneous the effect of camphor on the male mice reproductive system nikravesh mr*, jalali m department of anatomy, school of medicine, mashhahd university of medical sciences, mashhad, iran abstract purpose: in iranian traditional medicine there is a belief that camphor is a suppressor of sexual activity. based on this idea and since there are few studies on this issue, we evaluated the effect of camphor on histopathological changes of reproductive system in young male mice of balb/c racial type. materials and methods: thirty-six premature male balb/c mice, were divided into 3 paired groups of experimental, control, and sham (n = 6). experimental groups 1 and 2 received 30 mg/kg camphor dissolved in olive oil (orally) for 10 and 20 days, respectively. the control groups received the same volume of olive oil during the same periods of time, and no intervention was done in sham groups. all groups were kept in the same environmental condition. at the end of exposure time, each group was anesthetized and their testes were removed for obtaining serial sections, and histological staining. results: comparing to the control groups less vascularization in testis tissue of experimental groups was seen. furthermore, using stereological methods demonstrated that internal diameters of seminiferous tubules in experimental groups were significantly smaller than those in control groups (p <0.005). also, the number of released sexual cells was lower in experimental groups (p <0.005). no meaningful difference was seen between controls and sham groups. conclusion: administration of camphor and its effects on male mice reproductive system may result in significant structural changes, including vascularization and proliferation of sexual cells. this can affect maturation of seminiferous tubules and subsequently, reproductive function of testes in mice. key words: camphor, male reproductive system, balb/c mouse introduction although camphor, a natural substance, which was known by the asian nations since ancient times, is derived from cinnamomum camphora tree, its synthetic form is now available, being produced for medical, sanitary, and industrial usage.(1-3) as it is believed by the ancients, camphor is used not only as an aromatic material, but also for different purposes such as stimulation of circulatory and respiratory system, psychological stimulation, and cosmetics (as a reddener) for external use.(4-5) in addition, due to an olden belief, camphor can be used for modulating sexual activity, contraception, inducing abortion, and reducing milk production in lactating received october 2003 accepted may 2004 *corresponding author: anatomy department, school of medicine, daneshgah st., mashad, iran. cellphone: +98 915 311 4419, e-mail: nikravesh@hotmail.com nikravesh and jalali 269 women.(6-10) accordingly, camphor may affect sexual activity and although not documented, studies in different parts of the world are in agreement with this belief. administration of 100 mg/kg of camphor to mice, which have been under gamma rays, has modulated spermatogenesis in their testes.(10) camphor derived oxidant substances have been traced in umbilical cord, blood, and fetal tissues (including brain, liver, and kidneys) and it has been shown that camphor can easily pass placental barrier and affect fetal development.(11) in spite of the strong belief regarding the effect of this substance on male reproductive system, there is no documentation. thus, sketching this theory that camphor affects spermatogenesis in animals, it can be postulated that in human model it may have the same effect. we designed this study in order to evaluate the effect of this substance on the development of seminiferous tubules and differentiation of spermatocytes (sexual cells) in male mouse. materials and methods experimental animals and route of administration according to the fact that seminiferous tubules in mouse testis take 40 days to reach full differentiation after birth,(12) 36 twenty-day-old mice of balb/c racial type were selected and divided into 6 groups ( 2 experimental, 2 control, and 2 sham groups) and kept under standard condition of animals' hutch. then experimental groups 1 and 2 received camphor dissolved camphor in olive oil,(13) 30 mg/kg/day, orally as gavage for 10 and 20 days, respectively. the control groups received only the same volume of olive oil during the same periods of time. the sham groups were kept in animals' hutch under similar condition, with no intervention. sampling and tissue preparing at the end of each period, anesthesia was made for mice in each group, using chloroform and then their testes were removed for sampling and primary fixation with the use of ventricular perfusion and the exploit of formalin 10%. removed testes were transferred to codified glasses containing formalin 10%, as fixative, for the final fixation. in the next step, fixation and tissue preparation were performed with conventional histological methods and serial horizontal cuts of 7 micron thickness were obtained from tissue blocks. out of each 5 obtained sections related to each sample, one was selected randomly and stained with hematoxylin and eosin for further study. measurement of tissue elements in order to determine volume density of specified parts in the structure of testicular tissue in different groups it was attempted to measure internal and external diameters of seminiferous tubules based on morphometric studies,(14) and to count free and lining cells, using dissector technique.(15) for this purpose, the obtained serial sections from testes of each group were studied with light microscope. the method used was as follows: by putting a scaled square over the subjective lens of the microscope, a specific unit for measuring microscopic field was designed. afterwards, one field out of each four fields was studied by displacing the samples under microscope. as well as counting sexual cells, each two cells were counted as one for those cells which were situated on the edge of the fields. in addition, the internal and external diameters of one seminiferous tubule out of each four were measured and the results were recorded. results the results were obtained from more than 200 fields in the prepared sections of each case and along with determination of the mean of the measured parameters in each mouse, a total mean for each group (table 1) was calculated and compared with the other groups. comparisons of the groups' samples showed significant differences between the two experimental and control groups; the main proportion of seminiferous tubules in the experimental group 1 (fig. 1) was not canalized and only in a small proportion, canalization had been initiated. noncanalized tubules were solid with a high concentration of cells and microscopic assessment showed that the interstitial tissue of the tubules had developed less than that in the control group table 1. mean (± sd)* of changes in tubules’ characteristics and sexual cells in experimental and control groups *tubules diameters are reported in µm and cell and vascular cross-sectional count in mm3. †the results of sham group are not included because of their proximity to controls. ����������� ��� � � � ��������������� ���������� ��������������� ���������� ����� � � ���������������������� � �� � ������������� ������������� ������������ �� ����� �� ���� � ���������������������� � �� � ���������� �� ����������� � ����������� � ������������ ����� � ����������� � ���������� � �������� ���������� ���������� ����� � ����� ��� �� ������� � � ����� �� ������� �� ������� �� ���������� ����� � � � ������� ! ������ � ��������� ���������� ��������� �������� ���� � camphor and reproductive system270 1. also, the first signs of release of sexual cells were seen in few spaces developed in some tubules, while this process was seen more prominent in the control group one (fig. 2). there was no significant difference between the mean external diameters of seminiferous tubules, but the difference was meaningful between the internal diameters (p <0.005) (table 1). in the experimental group 2, as shown in figure 3, the internal space of seminiferous tubules was not fully developed, while complete development was seen extensively in the similar samples of the control group 2 (fig. 3). here, also mean external diameters were not significantly different in the two groups, but internal diameters were different (p <0.005). although tubular wall thickness and the number of cell layers were less in the control group as compared with the experimental group (fig. 3,4), the presence of cells derived from germinal layer, containing large round hyperchromatic nucleus indicated active mitosis in this area, but in the experimental samples, the concentration of cells in tubular wall was more and the nuclei were smaller. in this condition the amount of released sexual cells were different in the experimental group as compared with controls (p <0.005). it seems that spermatocytes' fig. 4. a cross-section of seminiferous tubules from a sample of experimental group 2, showing a single tubule. here, although central canal is formed and external diameter of the tubule is maximal, multiplicity and concentration of cell layers in tubular wall and considerable population of spermatocytes (arrows), which have remained in internal layers and have not been differentiated into spermatozoids, indicates delayed spermatogenesis (× 400). fig. 3. a cross-section of seminiferous tubules from a sample of control group 2, showing a single tubule. the central canal is fully formed. the cells derived from germinal layer are seen with large hyperchromatic nucleus, showing that cells contain a large amount of chromatin and have active mitosis. reduced cell wall layer as compared with experimental group's samples (fig. 4), indicates that differentiation and release of spermatocytes is taking place rapidly and a large amount of cells in the terminal stages of differentiation can be traced in the lumen (× 400). fig. 2. a cross-section of seminiferous tubules from a sample of control group 1, showing canalization in all tubules. but, small internal area of each tubule and condensed layers of cells in tubular wall indicates that tubular maturation is not complete (× 40). fig. 1. a cross-section of seminiferous tubules from a sample of experimental group 1, showing the initiation of canalization in some of the tubules (arrows). in this stage, some of the tubules (stars) are still non-canalized and cells are compressed to each other(× 40). nikravesh and jalali 271 maturity and release had been delayed and they were compressed to layers near the central canal of the tubule. finally, no meaningful difference was seen between control and sham groups. discussion the administered dosage of camphor in various experiments is different in published reports. intraperitoneal injection of 300 to 400 mg/kg; 1, 2 or 3 times, has not shown toxic effects in behavioral or autopsy studies;(16) whereas, it has been reported that administration of 400 to 550 mg/kg of camphor to rats has led to rigor and seizure.(17) on the other hand, administration of 1000 mg/kg of this substance to mouse causes toxicity along with reduced consumption of food and water and salivary secretion,(18) and 2200 mg/kg was the minimum lethal dose in mouse.(16) however, the non-toxic dose of 100 mg/kg has been identified as a dose that affects testicular tissue activity, which could alter the process of spermatogenesis.(10) in this study, we used 30 mg/kg of camphor in time periods of 10 and 20 days and evaluated the probable effects on testicular tissue. with this reduced dosage the probability of toxicity was further diminished. in this regard, in one of the few reports, it is shown that intraperitoneal injection of 100 mg/kg of camphor to 8week-old mice could reduce the number of primary spermatocytes temporarily, but the difference was not significant after one week.(18) on the other hand, it seems that if the experimental samples are treated for a long period of time, seminiferous tubular structure and probably supporting tissues may be affected as well as camphor's impact on proliferation and differentiation of spermatocytes.(10,18) this study showed that the differences between experimental and control groups were significant as the proliferation and differentiation activity are lower in experimental group. the reason is that the vascular expansion, pertinent to tissue expansion, which is necessary for activity and multiplication of cells, is lacking.(19) although in control group two less vascularization was observed than in control group one, it should be considered that the testicular tissue in control group one was an immature tissue and had more angiogenesis during its own development and after reaching full development and maturity, angiogenesis would become closer to that in control group two and vascular bed would have limited development.(19) this theory is supported by that, despite this decrease, the significant difference between experimental and control groups remained unchanged. on the other hand, comparing the figures obtained from different groups shows that the internal diameter of seminiferous tubules in experimental groups is less than that of control groups and this significant difference was also seen between experimental groups one and two. the cells in seminiferous tubules have not been differentiated adequately and therefore, they can not become mature and subsequently release into the lumen. in these circumstances two events happen; first, due to the paucity of the released cells and their immaturity, as shown in the figures, the thickness of seminiferous tubular wall increases and their internal diameter decreases. second, counting of free cells in tubular lumen showed that they were lesser in experimental groups than in control groups. conclusion it can be concluded that although the exact mechanism of camphor effect is not known to us, one point can not be ignored, and it is that continuous administration of low doses of camphor can affect the development and differentiation of testicular tissue and reduce its spermatogenesis activity. references 1. yu sc, bochot a, bas gl, et al. effect of camphor/cyclodextrin complexation on the stability of o/w/o multiple emulsions. int j pharm. 2003;261:1-8. 2. lattanzi a, iannece p vicinanza a, scettri a. renewable camphor-derived hydroperoxide: synthesis and use in the asymmetric epoxidation of allylic alcohols. chem commun (camb). 2003;(12):1440-1. 3. anczewski w, dodziuk h, ejchart a. manifestation of chiral recognition of camphor enantiomers by alphacyclodextrin in longitudinal and transverse relaxation rates of the corresponding 1:2 complexes and determination of the orientation of the guest inside the host capsule. chirality. 2003;15:654-9. 4. reynolds jef. martindale: the extra pharmacopeia. 31st ed. london: royal pharmaceutical society; 1996. p.1684-5. 5. gerald g b, rogher k f, sumner j y. drugs in pregnancy and lactation. sixth edition. lippincott williams and wilkins, philadelphia. u.s.a. 2002; pp: 172-3. 6. jacobziner h, raybin hw. camphor poisoning. arch pediatr. 1962;79:28-30. 7. liebelt el, shannon mw. small doses, big problems: a selected review of highly toxic common medications. pediatr emerg care. 1993; 9: 292-7. camphor and reproductive system272 8. gibson de, moore gp, pfaff ja. camphor injestion. am j emerg med. 1989;7:41-3. 9. blackmon wp, curry hb. camphor poisoning; report of case occurring during pregnancy. j fla med assoc. 1957;43: 999-1000. 10. goel hc, singh s, adhikari js, rao ar. radiomodifying effect of camphor on the spermatogonia of mice. jpn j exp med. 1985;55:219-23. 11. riggs j, hamilton r, homel s, mccabe j. camphorated oil intoxication in pregnancy; report of a case. obstet gynecol. 1965;25:255-8. 12. adler id. comparison of the duration of spermatogenesis between male rodents and humans. mutat res. 1996;352:169-72. 13. budavari s, o'neil mj, smith a, heckelman pe, kinneary jf. merck index, an encyclopedia of chemicals, drugs, and biologicals. 12th ed. new jersey (usa): merck & co; 1996. p.1779-80. 14. wing ty, christensen ak. morphometric studies on rat seminiferous tubules. am j anat. 1982;165:13-25. 15. behnam-rosouli m, nikravesh mr, mahdavi-shahri n, tehranipour m. postoperative time effects after sciatic nerve crush on the number of alpha motoneurons, using a stereological counting metod (disector). iran biomed j. 2000;4:41-9. 16. american conference of governmental industrial hygienists: camphor synthetic and occupational exposure. cirainnati o h (usa): 1999. 17. sampson wl, fernandez l. experimental convulsions in the rat. j pharmacol exp ther. 1939;65:275-80. 18. leuschner j. reproductive toxicity studies of d-camphor in rats and rabbits. arzneimittelforschung. 1997;47:124-8. 19. behnam-rasouli m, nikravesh mr. the application of stereological methods in a morphometric and morphologic study of vascularization in cortical region of brain. urmia med j. 1997;8:160-70. vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2519 however, extraperitoneal lrp has potential disadvantages, including a smaller working space, difficulty accessing the pelvis, and less luminosity, compared with the intraperitoneal approach.(10) due to the small laparoscopic working space, we have previously experienced technical difficulties in performing extraperitoneal lrp. such difficulties can result in increased operative time and/or the amount of bleeding. indeed, a longer operative time increases the risk of an elevated creatine phosphokinase.(11) additionally, increased bleeding may lead to conversion to open surgery and/or necessitate blood transfusion. due to the small working space in extraperitoneal lrp, the body habitus of the patient, which includes factors such as body fat and skeletal structure around the prostate, is likely to affect perioperative outcomes. however, few studies have specifically assessed the perioperative outcomes of extraperilaparoscopic urology impact of body habitus on operative difficulties during extraperitoneal laparoscopic radical prostatectomy yu weimin,1,2 nobuhiro haga,1* tomohiko yanagida,1 noriaki kurita,3 hidenori akihata,1 yoshiyuki kojima1 purpose: the aim of the present study was to investigate whether patients’ body habitus affects the operative difficulties associated with extraperitoneal laparoscopic radical prostatectomy (lrp). therefore, the associations between body habitus and perioperative outcomes of surgery, including bleeding, operative time, and resection margins, were evaluated. materials and methods: between august 2010 and july 2012, 40 consecutive patients with preoperative magnetic resonance imaging and abdominal x-ray examinations underwent extraperitoneal lrp for localized prostate cancer at our institution. the associations between anthropometric measurements and demographics of patients, operation duration, estimated blood loss (ebl), and resection margins were analyzed retrospectively. multivariate analyses were performed, and p < .05 was considered significant. results: on multiple regression analysis, the view of the prostatic apex (vpa) was significantly associated with ebl (p = .02), and body mass index (bmi) was significantly associated with operative time (p = .02). on multiple logistic regression analysis, protrusion of the prostate into the bladder was significantly associated with positive resection margins (p = .04). conclusion: the findings of the present study suggest that poor vpa, protrusion of the prostate into the bladder, and high bmi were related to operative difficulties in extraperitoneal lrp. if operative difficulty is predicted preoperatively, it would be better to prepare blood for transfusion and/or special instruments (e.g. flexible scope), or switch to other therapeutic procedures. keywords: blood loss; surgical; laparoscopy; methods; operative time; prostatectomy; prostatic neoplasms; surgery. introduction laparoscopic radical prostatectomy (lrp) for or-gan-confined prostate cancer (pca) is mainly carried out via two distinct approaches, transperitoneal and extraperitoneal. many papers have reported good outcomes and various technical modifications of lrp. (1-5) since raboy and colleagues first reported extraperitoneal lrp in 1997,(6) extraperitoneal lrp underwent further modifications and developments to become the first-line alternative for lrp.(7,8) extraperitoneal lrp allows direct access to retzius’ space, avoiding potential intraperitoneal complications, such as bowel injuries, peritonitis, postoperative ileus, intraoperative bleeding, or intraperitoneal urine leakage.(8,9) thus extraperitoneal lrp has the advantages of both open radical prostatectomy and minimally-invasive laparoscopic procedures. 1 department of urology, fukushima medical university school of medicine, fukushima, japan. 2 department of urology, renmin hospital, wuhan university, wuhan, china. 3 department of innovative research and education for clinicians and trainees (direct), fukushima medical university hospital, fukushima, japan. *correspondence: department of urology, fukushima medical university school of medicine, hikarigaoka, fukushima 960-1295, japan. tel: +81 24 5471316. fax: +81 24 5483393. e-mail: pessoco@fmu.ac.jp. received april 2015 & accepted december 2015 toneal lrp related to the body habitus of patients. the aim of the present study was to investigate whether patients’ body habitus affects the technical difficulties that are associated with extraperitoneal lrp. therefore, the associations between body habitus and technical difficulties were evaluated. materials and methods study population between august 2010 and july 2012, 40 consecutive patients with preoperative magnetic resonance imaging (mri) and abdominal x-ray examinations underwent extraperitoneal lrp for localized pca at our institution. forty patients were included as the maximum number because our institution introduced robot-assisted lrp after the end of the study. the transperitoneal approach was not used; only the extraperitoneal approach was used in the patients undergoing endoscopic surgery during the period of this study. two patients whose surgery was converted to open surgery because severe adhesions had occurred in retzius’ space owing to previous inguinal hernia repair and one patient whose pathology was not diagnosed due to neoadjuvant hormonal therapy were excluded from the analysis. the institutional review board for research involving human subjects approved this retrospective analysis. operative technique with minor modifications, extraperitoneal lrps were performed as previously described.(12-16) briefly, a hasson trocar (12 mm) was inserted through the paraumbilical incision for the rigid 30° endoscope that was held by the second assistant. the second trocar (12 mm) and third trocar (12 mm) were lateral to the rectus muscle, approximately 2 finger-breadths below the umbilicus on the right and left sides, respectively; the fourth trocar (5 mm) and fifth trocar (5 mm) were placed approximately 2 finger-breadths inside the right and left superior anterior iliac spines. in the present study, limited lymphadenectomy was performed in the external iliac vein and obturator area in all patients regardless of d’amico risk figure 1. body habitus assessed by magnetic resonance imaging and abdominal x-ray films. a) angle between the pubic bone and the prostate; b) view of the prostatic apex (good); c) view of the prostatic apex (poor). figure 2. body habitus assessed by magnetic resonance imaging and abdominal x-ray films. a) depth of the prostatic apex; b) protrusion of the prostate into the bladder. effect of body habitus on extraperitoneal lrp-yu et al. laparoscopic urology 2520 vol 13 no 01 january-february 2016 2521 classification. the endopelvic fascia was then exposed and incised. the puboprostatic ligament was sectioned, and the dorsal vein complex (dvc) was ligated with an x-stich using 2-0 polyglactin suture (vicryltm ct-1).(14) the bladder neck was then transected, and the prostate was pulled anteriorly to incise the retrotrigonal layer. the ampullae and seminal vesicles were identified and dissected free. upward traction of the ampullae and seminal vesicles exposed denonvilliers’ fascia, which could then be incised sharply, exposing the anterior surface of the rectum. the prostate pedicles were dissected with a harmonic or bipolar scalpel. the dvc was then incised. the prostate remained attached only to the urethra and its surrounding structures. high mobility of the prostate allowed the urethra to be transected without damaging the urethral sphincter. after the prostate and seminal vesicles were removed, reconstruction of the bladder neck and urethral anastomosis was performed using a running 2-0 poliglecaprone suture (monocryltm ur-6) around a 20-f foley catheter. the neurovascular bundle was not preserved in the present cohort in which the emphasis was on cancer control rather than erectile dysfunction, because no patients wanted neurovascular bundle preservation. the role of the rocco stitch(17) for posterior reconstruction of denonvilliers’ fascia in terms of earlier continence recovery is encouraging but still controversial.(18) therefore, in the present study, posterior reconstruction was not performed to simplify the operative procedures. additionally, intussusception of the bladder neck(19) was not performed due to the technical challenges of the laparoscopic approach. extraperitoneal lrp was performed by two surgeons (t.y. and n.h.). both surgeons had considerable experience performing laparoscopic surgeries, such as radical nephrectomy, nephroureterectomy, donor nephrectomy, pyeloplasty, and so on. t.y. had performed about 300 laparoscopic surgeries, and n.h. had performed about 250 cases. in addition, both surgeons were board-certified in urological laparoscopy by the japanese endoscopic surgical qualification system. this system checks the surgeons’ skills related to laparoscopic surgery through review of their own unedited video recordings of their operations. because the examination pass rate is only about 50%, certification by the japanese endoscopic surgical qualification system guarantees the skills of laparoscopic surgeons. however, with respect to extraperitoneal lrp, 58 cases had been performed by the end of the study, and the two surgeons shared the cases equally. there were no differences in terms of amount of bleeding, operative duration, and positive surgical margin rate between the two surgeons (data not shown). hence, they were equally skillful with regard to performing lrp. evaluation of operative difficulty operative time, estimated blood loss (ebl), and positive resection margins were recorded as surrogate markers of operative difficulty. effect of body habitus on extraperitoneal lrp-yu et al. female urology 2419 table 1. patients’ characteristics and perioperative outcomes.* variables values age, years 68 (55 75) psa, ng/ml 8.9 (4.1 35.8) prostate volume, cm3 45 (20 90) gleason score 7 (6 9) operative time, min 339 (191594) estimated blood loss, ml 895 (200 2300) pt2: ≥ pt3, no. 23:14 positive resection margin rate, no. (%) 35 (37) * data are presented as median (range). ebl operative duration mean ± sd c.c p value c.c p value ebl, ml 1059 ± 570 -------- .50 .001 operative time, min 365 ± 83 .50 .001 ---------bmi, kg/m2 23.6 ± 2.8 .16 .32 .52 .0007 prostate volume, cm3 29.6 ± 18.3 .24 .17 .02 .88 angle pubic bone and prostate, degree 38.1 ± 0.9 .27 .62 .42 .008 depth of prostatic apex, cm 3.7 ± 0.6 .27 .09 .11 .51 area of pelvic entrance, cm2 138 ± 15 -.11 .48 .05 .74 abbreviations: ebl, estimated blood loss; sd, standard deviation; bmi, body mass index: c.c.; correlation coefficient. table 2. associations among patients’ characteristics, imaging assessment of body habitus, and estimated blood loss or operative time. univariate analysis using simple regression analysis. mri technique mri was performed using a 1.5-t whole-body magnetic resonance scanner (signa; general electric medical systems, milwaukee, wisconsin, usa). at 1 h before mri, all patients were instructed to empty the bladder and drink 1-2 glasses of water, and they were then asked to try to empty their bowels.(20) when the patients felt accumulation of urine in the bladder, they were examined in the supine position, using the body coil for excitation and a pelvic phased array coil (signa). axial fast spinecho proton density-weighted imaging was performed using the following parameters: repetition time (tr), 1400 ms; echo time (te), 22.8 ms; echo train length (etl), 5; slice thickness (st), 4 mm; interslice gap, 0.4 mm; field of view (fov), 20 cm; matrix, 320 × 224; and three excitations. coronal and sagittal t2-weighted fast recovery fast spin echo imaging was performed with the following parameters: tr, 3500 ms; te, 102 ms; etl, 11; st, 4 mm; interslice gap, 0.4 mm; fov, 20 cm; matrix, 320 × 256; and two excitations. parameters assessed mri and abdominal x-ray films were reviewed by a blind reviewer (a.h.) to assess the image for anatomic parameters. to evaluate whether the viewing field of the prostatic apex was good or poor during surgery, the following three parameters were evaluated, as mentioned below. first, the angle between the prostate and pubic bone was defined by the angle between the prostatic urethra and the posterior side of the pubic bone in the mid-sagittal plane of the mri (figure 1a). second, the view of the prostatic apex (vpa) was defined as the intersection point between the tangent line passing though the prostatic apex and the posterior side of the pubic bone and the perpendicular line from the promontory of the pelvis in the mid-sagittal plane of mri.(21) good vpa was defined as a position with the intersection point outside the body (figure 1b). poor vpa was defined as a position with the intersection point inside the body (figure 1c). third, depth of the prostatic apex was defined as the craniocaudal distance from the most proximal margin of the symphysis pubis to the level of the distal margin of the prostatic apex as measured on the mid-sagittal plane of mri (figure 2a).(22,23) because a large median lobe in the prostate is one of the risk factors for poor perioperative outcomes during robot-assisted laparoscopic radical prostatectomy (rarp),(24) the presence or absence of protrusion of the prostate into the bladder was evaluated. if the tip of the prostate protruded to the base of the urinary bladder in the sagittal plane of mri, protrusion of the prostate into the bladder was considered present (figure 2b).(25) to evaluate the working space during surgery, the area of pelvic entrance was calculated using the following formula: area of pelvic entrance (cm2) = transverse diameter (cm) × true conjugate (cm) (figure 3), where transverse diameter was the longest distance of the iltable 3. associations among patients’ characteristics, imaging assessment of body habitus, and estimated blood loss or operative time. univariate analysis using simple regression analysis. univariate analysis using the mann-whitney u test. no. ebl (ml) p value operative time (min) p value view of the prostatic apex .002 .04 good 31 943 ± 523 353 ± 83 poor 6 1679 ± 398 429 ± 55 protrusion of the prostate .33 .09 yes 11 1200 ± 509 401 ± 94 no 26 1002 ± 592 351 ± 76 abbreviation: ebl, estimated blood loss. ebl operative time β p value β p value bmi -.19 .27 .35 .02 view of the prostatic apex -.35 .02 .03 .81 angle of the prostate and pubic bone -.05 .74 -.16 .31 protrusion of the prostate .002 .98 .16 .24 abbreviations: ebl, estimated blood loss; bmi, body mass index; β, standard partial regression coefficient. table 4. associations among patients’ characteristics, imaging assessment of body habitus, and estimated blood loss or operative duration. multivariate analysis using multiple linear regression analysis. effect of body habitus on extraperitoneal lrp-yu et al. laparoscopic urology 2522 vol 13 no 01 january-february 2016 2523 io-pectineal line (figure 3a), and the true conjugate was the distance from the promontory of the pelvis to the dorsal side of the pubic bone (figure 3b).(21) statistical analysis all values are presented as means ± standard deviation or medians. a two-sided mann-whitney u test or a chi-squared test was used to determine significant differences in binary variables. the correlations between continuous variables were investigated by simple regression analysis using spearman’s rank correlation coefficient. multivariate analyses were performed using multiple linear regression and multiple logistic regression to identify the risk factors associated with operative difficulties. p values < .05 were considered significant. analyses were performed with stat view version 5.0 software (abacus concepts, berkeley, ca, usa). results the baseline characteristics of the patients and their perioperative outcomes are shown in table 1. all mri examinations were performed successfully and resulted in high-quality images; thus, complete datasets were obtained for 37 patients. both univariate and multivariate analyses showed associations between body habitus and perioperative outcomes, as follows (tables 2-7). tables 2-4 presents the associations among patients’ characteristics, image assessment of body habitus, and estimated blood loss or operative time. tables 5-7 presents the associations among patients’ characteristics, imaging assessments of body habitus, and resection margin. the vpa was significantly associated with ebl on multiple regression analysis (p = .02) (table 4). bmi was significantly associated with operative duration on multiple regression analysis (p = .02) (table 4). protrusion of the prostate into the bladder was significantly associated with positive resection margins on multiple logistic regression analysis (p = .04) (table 7). discussion although the experience of the surgeon may be a more decisive factor affecting surgical outcome, one cannot completely exclude the impact of a patient’s physique on the technical difficulty of performing extraperitoneal lrp due to the small working space. whereas several reports have demonstrated an association between anthropometric measurements and perioperative outcomes in various modalities of radical prostatectomy,(21-23,26-28) there is only one report specifically on extraperitoneal lrp by nam and colleagues.(29) they evaluated two parameters assessed by mri, i.e. the amount of protrusion of the pubic symphysis in the pelvis and the depth of the prostatic apex, as anthropometric measurements, and they concluded that the depth of the prostatic apex is significantly associated with operative difficulties. in the present study, to acquire more information about the associations between patients’ body habitus and operative difficulties, several parameters from multiple viewtable 5. associations among patients’ characteristics, imaging assessment of body habitus, and resection margin. univariate analysis using the mann-whitney u test. rm (-) (n = 25) rm (+) (n = 12) p value ebl, ml 987 ± 635 1198 ± 404 .28 operative time, min 350 ± 80 396 ± 84 .10 bmi, kg/m2 23.5 ± 2.9 23.7 ± 2.6 .78 prostate volume, ml 32.5 ± 20.9 24.6 ± 11.6 .23 angle between the prostate and pubic bone, degree 37.4 ± 9.3 39.4 ± 9.9 .54 depth of the prostate apex, cm 3.7 ± .6 3.7 ± .6 .87 area of pelvic entrance, cm2 138 ± 14 138 ± 15 .97 abbreviations: rm, resection margin; ebl, estimated blood loss; bmi, body mass index. rm (-) rm (+) p value view of the prostatic apex .37 good 21 10 poor 3 3 protrusion of the prostate .01 yes 4 7 no 20 6 t classification .3 ≤ pt2 17 7 pt3 7 6 abbreviation: rm, resection margin. table 6. associations among patients’ characteristics, imaging assessment of body habitus, and resection margin. univariate analysis using the chisquare test. effect of body habitus on extraperitoneal lrp-yu et al. points, such as the positional relationship between the prostate and pelvic anatomical features and the working space during surgery, were evaluated. the vpa is a parameter that was developed to evaluate the physical relationship between the gradient or protrusion of the pubic bone and the prostatic apex in retropubic radical prostatectomy (rrp).(21) in their study, poor vpa was significantly associated with ebl, which was consistent with the present study. therefore, the vpa might be a valuable parameter in preoperatively estimating ebl not only in rrp, but also in extraperitoneal lrp. when we dissected the prostate apex during extraperitoneal lrp, we sometimes found that the rigid laparoscope was in contact with the forceps due to the smaller working space than with intraperitoneal lrp. this situation resulted in insufficient visualization of the prostate apex, leading to risks of increased bleeding and/or positive surgical margins of the prostatic apex. on the other hand, with the flexible laparoscope, it was easy to avoid contact with the forceps. as a result, use of a flexible scope was considered to achieve better visualization than with a rigid scope. although the association between the vpa and the working space was not evaluated in the present study, we consider that the flexible scope was useful for providing better visualization when the vpa was poor. in the present study, protrusion of the prostate into the bladder was significantly associated with positive surgical margins. in rarp, as well as in the present study, protrusion of the prostate into the bladder was significantly associated with positive surgical margins of the prostatic base.(30) it is thought to be related to the fact that protrusion of the median lobe is considered to add technical difficulty during division between the prostate and bladder in both rarp and lrp.(30) as a result, when we operated on patients with protrusion of the median lobe, we had a tendency to dissect incorrect planes between the prostate and its surrounding tissues. hence, the positive surgical margin rate was increased both in rarp and lrp. if protrusion of the median lobe is identified on preoperative mri, surgeons should pay more attention to dissecting between the prostate and its surrounding tissues, and, if possible, change to the transperitoneal approach, which might make it easier to dissect between the prostate and its surrounding tissue than with the extraperitoneal approach owing to the larger working space, or they may add novel surgical procedures, such as a “rescue stitch” retracting the large median lobe anteriorly out of the bladder lumen. (31) the present study demonstrated that bmi was independently associated with operative duration, which was in accordance with previous studies of lrp and rarp.(32,33) theoretically, obesity could further exacerbate the limited working space and obscure anatomic landmarks due to a large amount of fat. hence, careful surgical dissection may be needed to avoid injury to the pelvic viscera. in addition, it would take more time to remove fat debris in retzius’ space. as a result, the optable 7. associations among patients’ characteristics, imaging assessment of body habitus, and resection margin. multivariate analysis using multiple logistic regression analysis. or 95% ci p value ebl 1.0 .99 1.02 .43 operative duration 1.0 .99 1.00 .55 bmi 1.0 .7 1.4 .97 view of the .81 .07 8.98 .86 prostatic apex -good angle between the 1.05 .94 -1.29 .36 prostate and pubic bone protrusion of the .11 .01 -.96 .04 abbreviations: or, odds ratio; ci, confidence interval; ebl, estimated blood loss; bmi, body mass index. figure 3. area of pelvic entrance: a) transverse diameter; b) true conjugate. area of pelvic entrance (cm2) = transverse diameter (1) (cm) × true conjugate (2) (cm) effect of body habitus on extraperitoneal lrp-yu et al. laparoscopic urology 2524 vol 13 no 01 january-february 2016 2525 erative duration may increase due to a large amount of fat. several limitations of the present study must be considered. first, the current study was retrospective in nature and included a small sample size. it may have been underpowered to identify associations between patients’ characteristics and operative difficulties. second, the potential for intra-observer error during radiological measurement should not be overlooked. third, although they had performed many laparoscopic surgeries, the surgeons had less experience with extraperitoneal lrp. ahlering and colleagues reported that, based on the learning curve, achieving mastery of lrp is assumed to require 40 to 60 cases for a skilled laparoscopic surgeon.(34) judging from the paper by ahlering and colleagues, our experience might be insufficient for complete mastery of extraperitoneal lrp. yao and colleagues reported that a large prostate and a narrow and deep bony pelvis are associated with operative difficulties with robot-assisted lrp only for novice surgeons.(35) however, the association between operative outcomes and pelvic dimensions has disappeared for experienced surgeons. thus, insufficient experience may affect surgical outcomes. therefore, the present data might be especially helpful to institutions in the introduction period of lrp or to novice surgeons attempting lrp. however, the impact of body habitus on operative difficulties during extraperitoneal lrp might decrease with surgical experience, as in the report by yao and colleagues. in conclusion, the findings of the present study suggest that poor vpa, protrusion of the prostate into the bladder, and high bmi were related to operative difficulties 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[predicting blood loss during radical prostatectomy using internal pelvimetry]. hinyokika kiyo. 2007;53:19-23. 22. hong sk, chang ih, han bk, et al. impact of variations in bony pelvic dimensions on performing radical retropubic prostatectomy. urology. 2007;69:907-11. 23. matikainen mp, von bodman cj, secin fp, et al. the depth of the prostatic apex is an independent predictor of positive apical margins at radical prostatectomy. bju int. 2010;106:622-6. 24. huang ac, kowalczyk kj, hevelone nd, et al. the impact of prostate size, median lobe, and prior benign prostatic hyperplasia intervention on robot-assisted laparoscopic prostatectomy: technique and outcomes. eur urol. 2011;59:595-603. 25. lee jw, ryu jh, yoo tk, byun ss, jeong yj, jung ty. relationship between intravesical prostatic protrusion and postoperative outcomes in patients with benign prostatic hyperplasia. korean j urol. 2012;53:478-82. 26. neill mg, lockwood ga, mccluskey sa, fleshner ne. preoperative evaluation of the "hostile pelvis" in radical prostatectomy with computed tomographic pelvimetry. bju int. 2007;99:534-8. 27. ongun s, demir o, gezer ns, gurboga o, bozkurt o, secil m. impact of pelvic biometric measurements, visceral and subcutaneous adipose tissue areas on trifecta outcome and surgical margin status after open radical retropubic prostatectomy. scand j urol. 2015;49:108-14. 28. von bodman c, matikainen mp, yunis lh, et al. ethnic variation in pelvimetric measures and its impact on positive surgical margins at radical prostatectomy. urology. 2010;76:1092-6. 29. nam dh, hwang ec, im cm, et al. factors affecting the outcome of extraperitoneal laparoscopic radical prostatectomy: pelvic arch interference and depth of the pelvic cavity. korean j urol. 2011;52:39-43. 30. jeong cw, lee s, oh jj, et al. quantification of median lobe protrusion and its impact on the base surgical margin status during robotassisted laparoscopic prostatectomy. world j urol. 2014;32:419-23. 31. abreu al, chopra s, berger ak, et al. management of large median and lateral intravesical lobes during robot-assisted radical prostatectomy. j endourol. 2013;27:1389-92. 32. gu x, araki m, wong c. does elevated body mass index (bmi) affect the clinical outcomes of robot-assisted laparoscopic prostatectomy (ralp): a prospective cohort study. int j surg. 2014;12:1055-60. 33. sundi d, reese ac, mettee lz, trock bj, pavlovich cp. laparoscopic and robotic radical prostatectomy outcomes in obese and extremely obese men. urology. 2013;82:6005. 34. ahlering te, skarecky d, lee d, clayman rv. successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. j urol. 2003;170:173841. 35. yao a, iwamoto h, masago t, et al. anatomical dimensions using preoperative magnetic resonance imaging: impact on the learning curve of robot-assisted laparoscopic prostatectomy. int j urol. 2015;22:74-9. effect of body habitus on extraperitoneal lrp-yu et al. laparoscopic urology 2526 115 urology journal unrc/iua vol. 2, no. 2, 115-117 spring 2005 printed in iran case reports malignant mesothelioma of the spermatic cord: case report and review of the literature peyman mohammadi torbati,1* mahmoud parvin,1 seyyed amirmohsen ziaee2 1department of pathology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran 2department of urology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran key words: paratesticular tumors, malignant mesothelioma, spermatic cord introduction paratesticular malignant mesothelioma is a rare tumor, previously reported in only 76 cases. most of these lesions originate from the tunica vaginalis, and few cases arise from the epididymis or spermatic cord. middle-aged men are most often affected, although an age range of 7 of 84 years has been reported in patients with paratesticular malignant mesothelioma.(1) as in benign mesothelial lesions, malignant mesothelioma almost always manifests with hydrocele,(4,5) fluid collection of which occurs faster, leading to symptomatic disease in less than 1 year. in 41% of cases, a history of contact with asbestos has been documented.(2,3) we report a case of malignant mesothelioma of the spermatic cord in a 52-year-old man. case report a 52-year-old man presented at our institution in july 2002 with right scrotal enlargement. he had no history of granulomatous diseases such as tuberculosis or sarcoidosis. his symptoms were limited to enlargement of scrotum and a sensation of heaviness. changes in sexual function, hematuria, and hemospermia were not present. no unusual mass was detected on physical examination and ultrasonography. accordingly, he underwent right battle neck hydrocelectomy under spinal anesthesia. since there was no apparent macroscopic lesion, histopathological examination was not performed. one year later, the patient returned with recurrent hydrocele of the same side, and ultrasonography revealed 2 multicystic lesions in the right side of the scrotum (figure 1). hydrocelectomy was repeated, and 2 cysts with multiple cavities (1 that had adhered to the spermatic cord and another that had adhered to the epididymis) were excised. macroscopic features of the 2 cysts were similar. the external surface of the cysts' walls was cream-grey, and the internal surface of both had papulonodular vegetation. both cysts contained yellow, turbid, condensed discharge and had multiple cavities. the cyst that had adhered to the spermatic cord measured 73 × 63 mm, and the one that had adhered to the epididymis was 35 × 24 mm. microscopic evaluation of the cysts demonstrated neoplastic malignancies with a papulonodular growth pattern. there were foci of invasion to the underlying desmoplastic stroma. the tumoral cells were cube-shaped epithelioid, containing various amounts of eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli with a moderate mitotic activity of 3 mitoses per 10 hpf in atypical shapes (figure 2). based on the aforementioned, the differential diagnoses were primary papillary adenocarcinoma, epithelioid malignant mesothelioma, received february 2004 accepted june 2005 *corresponding author: department of pathology, shaheed labbafinejad hospital, 9th boustan, pasdaran st., tehran 1666679951, iran. tel: ++98 21 2254 9010, fax: ++98 21 2254 9039 e-mail: p2000torbati@yahoo.com malignant mesothelioma of the spermatic cord116 and metastatic papillary adenocarcinoma of unknown origin. to make a definite diagnosis, histochemical and immunohistochemical methods were used, and the following results were found: negative reaction for periodic acid-schiff and mucicarmine; strong positive reaction for calretinin, thrombomodulin, and cytokeratin 5/6 markers (figure 2); diffused positive immunostaining for epithelial membrane antigen and ca-125 makers; and negative for leu-m1, carcinoembryonic antigen, b72.3, plasma alkaline phosphatase, human chorionic gonadotrophin, and alpha-fetoprotein. considering the above, especially positive calretinin and thrombomodulin, malignant mesothelioma of the spermatic cord and epididymis was confirmed. abdominal and thoracic computed tomography (ct) scans and an isotope scan of the thyroid gland and bones were done to rule out any other neoplastic foci. distant metastases were not present. radical orchidectomy was done, and 9 months later, in april 2003, tumor resection was performed owing to local recurrence. in the summer of 2004, metastases to the inguinal lymph nodes were resected, and eventually, in january 2005, metastases to the ileac lymph nodes were diagnosed. the patient refused further treatment and has survived to date, without tumor resection, chemotherapy, or radiotherapy. discussion malignant mesothelioma is an uncommon neoplastic lesion, seen in middle-aged and elderly persons. paratesticular mesothelioma is believed to originate from a serosal cavity that covers the anterior and lateral sides of the testis and fig. 3. positive immunoreaction for calretinin (× 400) fig. 2. tubulopapillar feature in malignant mesothelioma (hematoxilin-eosin, × 400) fig. 1. two multicystic lesions in the right scrotum on sonography torbati et al 117 epididymis. it has been suggested that an oncogene may have a role in the pathogenesis of this tumor, and a history of contact with asbestos also has been implicated.(5) multiple fragile, cystic, or solid masses are the macroscopic feature of paratesticular mesothelioma, and light microscopy shows epithelioid cells, fusiform cells, or a mixture of these patterns. complementary techniques, including immunostaining, immunohistochemistry, and electron microscopy can help differentiate the lesion from adenocarcinoma. mesothelioma can produce large amounts of hyaluronic acid, which results in positive alcian blue and colloidal iron staining. however, a positive reaction to periodic acid-schiff staining and mucicarmine is highly suggestive for ruling out malignant mesothelioma.(6,7) on electron microscopy, microvilli are longer and thinner in malignant mesothelioma than in adenocarcinoma.(8) positive reactivity for cytokeratin cocktail, vimentin, epithelial membrane antigen, and s-100, and occasionally to desmin and bcl-2, is seen on immunohistochemistry, but reactions for carcinoembryonic antigen, leu-m1, and b72.3 markers are almost always negative.(9) plas and colleagues reviewed 73 cases of malignant mesothelioma of tunica vaginalis diagnosed during a 30-year period.(10) they concluded that the prognosis is poor, corresponding to a mean survival of 23 months. radical orchiectomy and extensive surgical resection of the suspicious sites is the definitive treatment. chemotherapy and radiotherapy do not increase survival rate significantly, unless distant metastases are present at diagnosis. a common clinical course of paratesticular mesotheliomas is the local recurring of the tumor and subsequently, metastases to inguinal and iliac lymph nodes.(11) it should be noted that macroscopic and histopathological examinations of scrotal lesions in patients with hydrocele are necessary to help determine the etiology of these lesions. references 1. reynard jm, hasan n, baithun si, newman l, lord mg. malignant mesothelioma of the tunica vaginalis testis. br j urol. 1994;74:389-90. 2. jones ma, young rh, scully re. malignant mesothelioma of the tunica vaginalis. a clinicopathologic analysis of 11 cases with review of the literature. am j surg pathol. 1995;19:815-25. 3. gupta np, agrawal ak, sood s, hemal ak, nair m. malignant mesothelioma of the tunica vaginalis testis: a report of two cases and review of literature. j surg oncol. 1999;70:251-4. 4. whitaker d, papadimitriou jm, walters mn. the mesothelium; techniques for investigating the origin, nature and behaviour of mesothelial cells. j pathol. 1980;132:263-71. 5. morikawa y, ishihara y, yanase y, et al. malignant mesothelioma of tunica vaginalis with squamous differentiation. j urol pathol. 1994;2:95-102. 6. kwee ws, veldhuizen rw, golding rp, et al. histologic distinction between malignant mesothelioma, benign pleural lesion and carcinoma metastasis. evaluation of the application of morphometry combined with histochemistry and immunostaining. virchows arch a pathol anat histol. 1982;397:287-99. 7. mccaughey wt, colby tv, battifora h, et al. diagnosis of diffuse malignant mesothelioma: experience of a us/canadian mesothelioma panel. mod pathol. 1991;4:342-53. 8. burns tr, greenberg sd, mace ml, johnson eh. ultrastructural diagnosis of epithelial malignant mesothelioma. cancer. 1985;56:2036-40. 9. holden j, churg a. immunohistochemical staining for keratin and carcinoembryonic antigen in the diagnosis of malignant mesothelioma. am j surg pathol. 1984;8:277-9. 10. plas e, riedl cr, pfluger h. malignant mesothelioma of the tunica vaginalis testis: review of the literature and assessment of prognostic parameters. cancer. 1998;83:2437-46. 11. butnor kj, sporn ta, hammar sp, roggli vl. welldifferentiated papillary mesothelioma. am j surg pathol. 2001;25:1304-9. comparison between retroperitoneal and transperitoneal approaches in the laparoscopic treatment of bosniaktype i renal cysts: a retrospective study laparoscopic urology levent ozcan,1* emre can polat,2 efe onen,1 oguz ozden cebeci,1 omur memik,1 bekir voyvoda,1 emre ulukaradag,1 burak yavuz kara3 purpose: we retrospectively compared laparoscopic transperitoneal and retroperitoneal approaches for the decortication of simple renal cysts with respect to safety, postoperative pain, and clinical results. materials and methods: the study included 40 patients (28 males and 12 females) with symptomatic simple renal cysts and who underwent laparoscopic cyst decortication, and they were evaluated retrospectively. patients’ age, gender, disease-specific history, comorbid disease and family history, in general and urological and physical examination findings were recorded. patients prior to surgery were evaluated by urinalysis, serum creatinine level, blood count, urinary tract ultrasonography, and unenhanced and contrast-enhanced abdominal computed tomography. patients were informed about laparoscopic surgery and their written informed consent was taken. for those who preferred the laparoscopic approach, the placement of the cyst, history of prior surgery and obesity were evaluated. all patients filled out the visual analog scale (vas) to evaluate postoperative pain. results: the mean age of the patients were 54.65 ± 5.26 years in the retroperitoneal group and 56.0 ± 4.66 years in the transperitoneal group. for all patients the indication for surgery included right or left flank pain. the mean operative time for the transperitoneal approach was 51.5 min, and that for the retroperitoneal approach was 44.75 min. this difference was statistically significant between the two groups (p < .05). according to vas scale, the retroperitoneal scoring method was found to be lower than the transperitoneal scoring method. all patients were discharged on the first postoperative day, and the drains were taken out. none of the patients had complications. at the end of six months, no clinical and radiological recurrence was detected in any patient. conclusion: we consider the retroperitoneal approach to be the first-choice because of its shorter operation time and particularly low level of postoperative pain. keywords: kidney diseases; cystic; laparoscopy; surgery; retrospective studies. introduction simple renal cyst is a relatively common disease of renal parenchyma, with a reported incidence of about 10% in the general population.(1,2) the incidence increases with age and between 40-60 years of age is up to 30%.(3,4) although its etiology is unknown, no genetic factor has been found to be associated with the condition (5) however, it is speculated that men tended to have a higher incidence than women.(1) in the majority of patients, simple renal cyst is asymptomatic and intervention is not necessary unless it develops symptoms or complications. the most common symptom requiring intervention is dull flank pain; other reported symptoms and complications are: hypertension, infection, upper urinary tract obstruction, hematuria, and even renal failure.(6) prior to the introduction of the laparoscopic approach, ultrasound-guided percutaneous aspiration and sclerosing agents injection were the first option for treatment. (7,8) laparoscopic renal cyst decortication was first described by hulbert and colleagues as a good alternative to open surgery.(9) laparoscopic surgery can be a transperitoneal or a retroperitoneal approach.(10) the transperitoneal approach is the most preferred one in the literature. it has advantages especially for anteriorly located exophytic and parapelvic cysts. conversely, the retroperitoneal approach is beneficial for posteriorly located cysts.(10) organ injury is less, unlike in the transperitoneal approach, and there is no risk of peritonitis, as the intracystic fluid does not interact with the peritoneum.(11) we retrospectively compared laparoscopic transperitoneal and retroperitoneal approaches for the decortication of simple renal cysts with respect to safety, postoperative pain, and clinical results. materials and methods study population the study included 40 patients (28 males and 12 females) with symptomatic simple renal cysts who underwent laparoscopic cyst decortication, and they were evaluated retrospectively. patients’ age, gender, disease-specific history, comorbid disease and family history, in general and urological and physical examination findings were recorded. patients prior to surgery were evaluated by urinalysis, creatinine level, blood count, 1 department of urology, derince training and research hospital, kocaeli, turkey. 2 department of urology, facultyy of medicine, istanbul medipol university, istanbul, turkey. 3 department of urology, medibafra hospital, samsun, turkey. *correspondence: department of urology, derince training and research hospital, 41900 derince, kocaeli, turkey. tel: +90 262 3178000. fax: +90 262 2334641. e-mail: drleventozcan@yahoo.com. received november 2014 & accepted june 2015 vol 12 no 04 july-august 2015 2218 urinary tract ultrasound (usg), and unenhanced and contrast-enhanced abdominal computed tomography (ct) scan. patients were informed about laparoscopic surgery and their written informed consent was taken. for those who preferred the laparoscopic approach, the placement of the cyst, history of prior surgery and obesity were evaluated. the transperitoneal approach using three ports was used for cyst decortication in all patients. surgical techniques the patients were initially positioned supine for intravenous access. after the induction of general anesthesia, endotracheal intubation, bladder catheterization, and nasogastric tube placement, the patients were positioned in a modified lateral decubitus position. approximately 45 degrees of rotation of the chest and abdomen was conducted. the table was flexed as needed, and padding was used to support the buttocks and flank. the patients were taped in position with multiple strips of wide cloth tape. as the surgical technique used, pneumoperitoneum of 15 mmhg was conducted used a veress needle (karl storz, tuttlingen, germany) introduced in the umbilical region. once the port was placed, the abdomen was then inspected for any injury from the veress needle placement. then, two more 5-mm trocars were inserted under direct vision in the flank lateral to the rectus. after the lateral peritoneal line of toldt was incised, the colon was reflected medially, and the overlying fat and tissue were cleared, the retroperitoneal space was exposed. after visual inspection, the dome of the cyst was opened using bipolar scissors, and the fluid was aspirated using the suction irrigation device. in the retroperitoneal approach, the retroperitoneal laparoscopic procedure was performed. in brief, a 1.0 cm transverse skin incision was made over the midaxillary line, 1.5 cm above the iliac crest. the underlying musculature was spared by hemostat, and the retroperitoneal cavity was blunt dilated. a hasson trocar was inserted, and another two 5 mm trocars were inserted in the anterior and posterior axillary lines below the costal under laparoscopic direction. the renal fascia was dissected until the cyst was recognized. after visual inspection, the dome of the cyst was opened using bipolar scissors, and the fluid was aspirated using the suction irrigation device. a drain tube was inserted through the trocar in the posterior axillary line incision. after the cyst wall was excised, it was sent for pathologic interpretation. a sample of the fluid obtained for cytological analysis. about 5 h postoperatively all patients were filled out the visual analog scale (vas) to evaluate postoperative pain. all patients underwent radiological follow-up with a repeated ct and/or usg immediately and six months after surgery. procedural success was defined as no recurrence of the cyst and pain relief declaration by the patients. statistical analysis the mann-whitney u test and chi-square test was used for comparing the groups of patients. p < 0.05 was considered statistically significant. the statistical package for the social science (spss inc, chicago, illinois, usa) version 12.0.1. results the mean age of the patients were 54.65 ± 5.26 years in the retroperitoneal group and 56.0 ± 4.66 years in the transperitoneal group. for all patients the indication for surgery included right or left flank pain. the transperitoneal approach was performed in 20 (20/40) patients and the retroperitoneal approach was performed in 20 (20/40) patients. according to localization, 16 cysts were located in the upper pole (16/40), 8 cysts in the medial pole (8/40) and 16 cysts in the lower pole (16/40). variables transperitoneal retroperitoneal p value number 20 20 ----age, (mean) y 56.0 ± 4.66 54.65 ± 5.26 .634 size of cyst, cm 5.55 ± 1.32 5.25 ± 0.85 .605 locatization of cysts upper pole 7 9 .747 middle pole 5 3 .692 lower pole 8 8 ----table 1. clinical and demographic characteristics of study patients. abbreviation: vas, visual analog scale. variables transperitoneal retroperitoneal p value time, min upper pole 55 ± 4.08 45 ± 3.54 .001 middle pole 52 ± 2.74 43.3 ± 2.88 .02 lower pole 48.13 ± 4.58 45 ± 3.78 .148 total 51.5 ± 4.89 44.75 ± 3.43 .001 vas score 6 ± 0.86 1.8 ± 0.52 .001 table 2. comparision of time of operations and visual analog scale score between study groups. laparoscopic treatment of bosniak type i renal cysts-ozcan et al. laparoscopic urology 2219 the mean cyst size was 5.4 cm. the mean cyst size was for the transperitoneal and retroperitoneal approaches, was 5.5 cm and 5.25 cm, respectively. among the cysts, 18 (18/40) were on the right side and 22 (22/40) were on the left side. the characteristics of the patients are summarized in table 1. the mean operative time from skin incision to the placement of last stitch for the transperitoneal approach was 51.5 min and that for the retroperitoneal approach was 44.75 min. this difference was statistically significant between the two groups (p < .05). when two methods were compared according to the location of the cysts that settled in the upper and middle poles, duration of operation is significantly shorter in the retroperitoneal approach than in the transperitoneal approach (p = .001 and p = .02, respectively), and it when it was determined in terms of time in the lower pole cysts, the difference between the two methods was not statistically significant (p = .148) (table 2) (figure 1). vas in the range of 0-10 was used in the scoring system of the patients (0 = absence of pain; 10 = worst possible pain). all patients filled out the vas to evaluate postoperative pain. according to this scale, the retroperitoneal scoring method was found to be lower than the transperitoneal scoring method. this result was statistically significant (p < .05) (table 2) (figure 2). none of our patients had the need for a fourth port during the operation. all patients were discharged on the first postoperative day, and the drains were taken out. none of the patients had complications. at the end of six months, no clinical and radiological recurrence was detected in any patient. all patients had negative cytological and pathological findings for malignancy or any other abnormalities. discussion benign cystic disease of the kidney is a common disease that is accidentally diagnosed by radiological examination. in recent years, with the increasing use of diagnostic tools such as us and ct scan, the number of renal cysts diagnosed has increased dramatically although most of them do not require treatment.(12) bosniak classification by ct scan is necessary after the diagnosis of cysts by ultrasonography.(13) simple cysts are type i and type ii cysts according to bosniak classification. in our study, bosniak classification was applied to all patients after the diagnosis by us and ct scan. only bosniak type 1 cysts were included in the study. the percutaneous cyst aspiration is non-invasive and does not require hospitalization; therefore, it is the first choice of treatment, but recurrence rates are reported to be up to 78%.(14) the first percutaneous intervention for the treatment of simple renal cysts was performed by dean in 1939.(4) many sclerosing agents such as ethanol, tetracycline, glucose phenol, povidone–iodine, bismuth-phosphate, cholohydrolactate, polidocanol, pantopaque and ethanolamine oleate have been used to prevent the re-growth of cysts and the return of symptoms.(15) the literature presents some successful reports about the usage of sclerosing agents, but the recurrence rates still range from 32% to 100%.(16,17) although rare, sclerosing agents have potential side effects such as migration to the collecting system, allergy, anaphylaxis, pneumothorax, hematoma and adjacent organ damage. moreover the entry of a sclerosing substance into the collecting system could cause ureteropelvic junction obstruction in long term follow-up.(16-18) a previous study by okeke and colleagues compared the percutaneous treatment with the laparoscopic excision and found that laparoscopic treatment was the better option. (19) in generally simple renal cyst is asymptomatic and intervention is not necessary unless it develops symptoms or complications. in our series, our indication was pain unresponsive to analgesics. today, laparoscopic cyst decortication has become the method of choice due to its lower rates of relapse, mortality, and morbidity compared with open surgery.(20) although the transperitoneal approach has been used in the laparoscopic treatment of renal cysts for years, the retroperitoneal approach has recently become an alternative method.(21-23) the most important advantages of the retroperitoneal approach are that the risk of intraperitoneal organ damage is low and that the retroperitoneum is limiting in conditions such as bleeding and urinoma. its most important disadvantage is its narrow operational area.(14) although many authors prefer the transperitoneal approach for renal cysts, the retroperitofigure 1. comparison of operating time according to the types of surgical procedure. figure 2. comparison of vas score according to the types of surgical procedure. abbreviation: vas, visual analog scale. laparoscopic treatment of bosniak type i renal cysts-ozcan et al. vol 12 no 04 july-august 2015 2220 neal approach is accepted as the simpler method particularly for cysts located in the dorsal part of the kidney. (15) the transperitoneal approach was demonstrated to be more effective and associated with minimal morbidity particularly for large renal and adrenal cysts, regardless of the location.(15,24) conversely, the retroperitoneal approach is more preferred to reduce the complications associated with the challenge in port entries caused by the adhesion in patients with previous abdominal surgery.(20) in their series, huri and colleagues showed that previous abdominal surgery was not important in preferring the transperitoneal or the retroperitoneal approach.(20) in our case, we used the retroperitoneal method in two patients with previous abdominal surgery. in the literature, the symptomatic success rate ranges between 78% and 100%, and the radiological success rate is between 80% and 100% in patients who underwent laparoscopic surgery. in a survey on 19 consecutive patients, tefekli and colleagues reported a radiological success rate of 88.2% and a symptomatic success rate of 89.5%, they used the retroperitoneal approach in all of their cases.(25) geçit and colleagues reported radiological and symptomatic success rates of 100%.(26) in our series, the symptomatic and radiological success rates were 100% in both methods. compared in terms of success, none of the methods was superior. when analyzed in terms of operation time, rassweiler and colleagues reported a mean operation time of 65 min in their series consisting of 50 cases of laparoscopic retroperitoneal cyst decortication.(27) in a similar study to ours, huri and colleagues reported that the mean operation time was 57.3 min for the transperitoneal approach and 47.2 min for the retroperitoneal approach in their series of 24 cases.(20) in recent years, surgeons have made some modifications, such as finger assisted laparoscopic cyst excision to decrease the operation time.(10) in our series, the mean operation time was 51.5 min for the transperitoneal approach and 44.75 min for the retroperitoneal approach. in our study, the patients completed a vas 5 h after the operation for postoperative pain assessment. according to this scale, the score of patients operated on using the retroperitoneal method was significantly lower than that of the patients who were operated using the transperitoneal method. we consider the low level of pain associated with the retroperitoneal method to be due to the absence of preperitoneal insufflation which may cause lower postoperative pain. conclusions in conclusion, based on the present experience, laparoscopic cyst excision is a good alternative to open surgery as a safe, effective, and minimally invasive method. although the transperitoneal and retroperitoneal approaches are not superior to each other, we consider the retroperitoneal approach to be the first-choice because of its shorter operation time and particularly low level of postoperative pain. conflict of interest none declared. references 1. terada n, ichioka k, matsuta y, okubo k, yoshimura k, arai y. the natural history of simple renal cysts. j urol. 2002;167:21-3. 2. tsugaya m, kajita a, hayashi y, okamura t, kohri k, kato y. detection and monitoring of simple renal cysts with computed tomography. urol int. 1995;54:128-31. 3. glassberg ki. renal dysplasia and cystic disease of the kidney. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell’s urology. vol. 2, 7th ed. philadelphia: w. b. saunders; 1998. p. 1757-813. 4. sandler cm, houston gk, hall jt, morettin lb. guided cyst puncture and aspiration. radiol clin north am. 1986;24:527-37. 5. tadayon a, ayanifard m, mansoori d. endoscopic renal cyst ablation. urol j. 2004;1:170-3. 6. dunn md, clayman rv. laparoscopic management of renal cystic disease. world j urol. 2000;18:272-7. 7. moufid k, joual a, debbagh a, el morini m. lumboscopic treatment of simple renal cysts: initial experience with 17 cases. prog urol. 2002;12:1204-8. 8. zulluaga gomez a, arrabal martin m, de la fuente serrano a, mijan ortiz yl, martinez torres jl, fernandez rodriguez a. laparoscopic treatment of the symptomatic renal cyst: the indications and bibliographic review. arch esp urol. 1995;48:282-90. 9. hulbert jc. laparoscopic management of renal cystic disease. semin urol. 1992;10:23941. 10. kilciler m, istanbulluoğlu mo, basal s, bedir s, avci a, ozgök y. finger assisted laparoscopic renal cyst excision: a simple technique. urol j. 2010;7:90-4. 11. su lm. laparoscopic renal cyst ablation: technique and results. in: gill is, ed. textbook of laparoscopic urology. new york: taylor and francis ltd; 2006:259-78. 12. laucks sp jr, mclachlan ms. aging and simple cysts of the kidney. br j radiol. 1981;54:12-4. 13. bosniak ma. the current radiological approach to renal cysts. radiology. 1986;158:1-10. 14. atug f, burgess sv, ruiz-deya g, mendestorres f, castle ep, thomas r. long-term durability of laparoscopic decortication of symptomatic renal cysts. urology. 2006;68:272-5. 15. abbaszadeh s, taheri s, nourbala mh. laparoscopic decortication of symptomatic renal cysts: experience from a referral center in iran. int j urol. 2008;15:48648-9. 16. gupta np, goel r, hemal ak, kumar r, ansari ms. retroperitoneoscopic decortication of symptomatic renal cysts. j endourol. 2005;19:831-3. 17. thwaini a, shergill is, arya m, budair z. laparoscopic treatment of bosniak type i renal cysts-ozcan et al. laparoscopic urology 2221 longterm follow-up after retroperitoneal laparoscopic decortication of symptomatic renal cysts. urol int. 2007;79:352-5. 18. camacho mf, bondhus mj, carrion hm, lockhart jl, politano va. ureteropelvic junction obstruction resulting from percutaneous cyst puncture and intracystic isophendylate injection: an unusual complication. j urol. 1980;124:713-4. 19. okke aa, mitchelmore ae, keeley fx, timoney ag. a comparison of aspiration and sclerotherapy with laparoscopic de-roofing in the management of symptomatic simple renal cysts. bju int. 2003;92:610-3. 20. huri e, akgül t, karakan t, yücel ö, germiyanoğlu c. comparison between retroperitoneal and transperitoneal approaches in laparoscopic treatment of bosniak type i renal cysts. (article in turkish) turkish j urol. 2009;35:7-10. 21. hemal ak, aron m, gupta np, seth a, wadhwa sn. the role of retroperitoneoscopy in the management of renal and adrenal pathology. bju int. 1999;83:929-6. 22. hoenig dm, mcdougall em, shalhav al, elbahnasy am, clayman rv. laparoscopic ablation of peripelvic renal cysts. j urol. 1997;158:1345-8. 23. munch lc, gill is, mcroberts jw. laparoscopic retroperitoneal renal cystectomy. j urol. 1994;151:135-8. 24. asalzare m, shakiba b, asadpour aa, ghoreifi a. laparoscopic management of symptomatic giant adrenal pseudocyst: a case report. urol j. 2014;11:1517-20. 25. tefekli a, altunrende f, baykal m, sarılar o, kabay s, müslümanoğlu ay. retroperitoneal laparoscopic decortication of simple renal cysts using the bipolar plasmakinetic scissors. int j urol. 2006;13:331-6. 26. geçit i̇, kaba m, pirinççi n, güneş m, canbey ö, ceylan k. treatment of the symptomatic simple renal cysts: our first short-term laparoscopic results. (article in turkish) turkish j urol. 2011;6:29-32. 27. rassweiler jj, seemann o, frede t, henkel to, alken p. retroperitoneoscopy: experience with 200 cases. j urol. 1998;160:1265-9. laparoscopic treatment of bosniak type i renal cysts-ozcan et al. vol 12 no 04 july-august 2015 2222 urol_v03_no3_001_editorial.indd miscellaneous urology journal vol 3 no 3 summer 2006 171 epidemiology of urogenital trauma in iran results of the iranian national trauma project javad salimi, mohammad reza nikoobakht, ali khaji introduction: we report the incidence, distribution, etiology, and outcome of the urogenital trauma in 8 major cities of iran according to the database of national trauma project. materials and methods: between 2000 and 2004, we prospectively collected the data of all the traumatic patients hospitalized for more than 24 hours in 8 cities (tehran, mashad, ahwaz, shiraz, tabriz, qom, kermanshah, and babol). we analysed the data taken from 17 753 trauma admissions. patients with sustained urogenital traumas were identified and studied. results: a total of 175 patients (0.98%) had injuries to the urogenital system. male to female ratio was 4. the patients’ mean age was 25 ± 16 years (range, 2 to 80 years). of 175 patients, 159 (90.9%) had blunt trauma and 16 (9.1%) had penetrating trauma. road traffic accident was the most common cause of trauma (65.1%). the most common injured organs were the kidney in 61.1% and the bladder in 13.7%. one hundred and forty-two patients (81.1%) had associated intra-abdominal injuries and 129 (73.7%) had other accompanying injuries. sixty (34.2%) patients required surgical intervention. nine patients (5.2%) died due to the severity of the injuries. all patients who died had severe injuries (injury severity score >12). conclusion: in iran, blunt traumas including road traffic accidents are the main cause of urogenital traumas. the majority of the patients with urogenital trauma have multiple injuries and require a multidisciplinary approach. urol j (tehran). 2006;3:171-4. www.uj.unrc.irkeywords: urogenital, trauma, iran trauma and surgery research center, sina hospital, tehran university of medical sciences, tehran, iran corresponding author: javad salimi, md sina trauma and surgery research center, sina hospital, hassan abad sq, tehran 11364, iran tel: +98 21 6673 5018 fax: +98 21 6673 5018 e-mail: mjsalimi@sina.tums.ac.ir received august 2005 accepted june 2006 introduction disabilities caused by trauma has become one of the most serious public health problems in developed countries as well as countries with low total annual income.(1) urogenital traumas are responsible for up to 10% of trauma admissions in the united states.(2) they are commonly seen in the emergency rooms, and the primary-care physician plays a pivotal role in the initial evaluation and treatment of them. although urogenital traumas are rarely life threatening, they can cause significant long-term morbidities such as sexual dysfunction or urinary tract disorders.(3) up to 10% of the patients with multiple trauma have involvement of the urogenital system; 10% to 15% of the traumatic patients with abdominal injuries have urogenital involvement.(4) during the evaluation of the patients with multiple trauma, the probability of urogenital traumas should be considered in order to detect them at early stages.(5) kidney injuries constitute 45% of all urogenital traumas and the most common cause is blunt trauma. bladder injuries are most commonly caused by the pelvic fractures. in 5% to 10% of the cases with pelvic fracture, urinary tract urogenital trauma in iran—salimi et al 172 urology journal vol 3 no 3 summer 2006 injuries are detected.(6,7) mortality from the upper urinary tract trauma is primarily attributable to other associated injuries and morbidity rate is reported to be 26%.(4) an ideal management of patients with urogenital trauma requires comprehensive epidemiological information which may be different in each region or time. updated data concerning these traumas in our country is a requisite. we decided to perform this study to determine the incidence, severity, and treatment outcome of urogenital trauma in iran. materials and methods during a 4-year period (2000 to 2004), a crosssectional study was performed as a part of the national trauma project in 8 major cities (tehran, for 13 months; mashad and ahwaz for 7 months; and shiraz, tabriz, qom, kermanshah, and babul for 4 months). the study was set up in accordance with the american college of surgeons national trauma registry system (tracs) and the national trauma data bank (ntdb) using a valid questionnaire.(8,9) a group of physicians were trained for the process of data collection during several sections. during the study period, the trained physicians visited traumatic patients at their first 24-hour admission to the emergency rooms and wards and completed the questionnaires. a total of 17 753 patients were referred to the trauma centers of those cities and hospitalized for more than 24 hours. data obtained included patients’ demographics, prehospital care, diagnosis, glasgow coma scale (gcs) and vital signs at the time of presentation to emergency departments, injury severity score (iss), therapeutic measures, duration of hospital stay and intensive care unit, the outcome, and the source of reimbursement. the type of the injury and mechanism of the accidents were coded according to the international classification of diseases, 10th revision (icd-10).(10) the iss was used to provide an overall score for patients with multiple injuries. each injury is assigned an abbreviated injury scale (ais) score and is allocated to one of the 6 body regions (head, face, chest, abdomen, and extremities [including pelvis], and external).(11) only the highest ais score is used in each body region. the first 3 most severely damaged body regions have their score squared and added together to produce the iss score. traumatic patients with confirmed injuries to the urogenital system were enrolled in the study. the collected data were analyzed using spss software (statistical package for the social sciences, version 10.0, spss inc, chicago, ill, usa). results of 17 753 traumatic patients, 175 (0.98%) had injuries to the urogenital system. one hundred and forty (80%) patients were men and 35 (20%) were women (male-female ratio, 4). the patients’ mean age was 25.0 ± 16.0 years (range, 2 to 80 years). the highest incidence (29.7%) was seen in the age group of 21 to 30 years followed by 26.9% and 18.3% in the groups of 11 to 20 years and 1 to 10 years, respectively. table 1. characteristics of trauma in patients with urogenital trauma trauma patients (%) mechanism accident 114 (65.1) pedestrian 47 (26.8) passenger or driver 33 (18.8) motorcycle rider 23 (13.1) bicycle rider 7 (4.0) others 4 (2.2) fall 31 (17.7) blunt object 12 (6.9) cutting 7 (4.0) gunshot 5 (2.9) shotgun 1 (0.6) others 5 (2.9) place home 23 (13.1) work place 23 (13.1) road 117 (66.9) recreation and sport centers 6 (3.4) others 6 (3.4) injured organs kidneys 107 (61.1) bladder 24 (13.7) urethra 15 (8.6) ovary 5 (2.8) external genitalia 4 (2.3) ureter 3 (1.7) uterus 1 (0.6) renal vessels and other pelvic organs 16 (9.2) associated injuries head and neck 64 (36.6) thorax 40 (22.9) abdomen and pelvis 142 (81.8) upper extremities 36 (20.6) lower extremities 56 (32.0) urogenital trauma in iran—salimi et al urology journal vol 3 no 3 summer 2006 173 of 175 patients, 159 (90.9%) had blunt trauma and 16 (9.1%) had penetrating trauma. trauma mechanisms are listed in table 1. road traffic accident was the most common type (114 patients, 65.1%). in addition, 117 patients (66.9%) and 23 patients (13.1%) were injured in street clashes and at work, respectively (table 1). the most common injured organ was the kidney in 61.1% of the patients, followed by the bladder in 13.7% (table 1). one hundred and forty-two patients (81.1%) had associated intra-abdominal injuries and 129 (73.7%) had other accompanying injuries (table 1). blunt multiple trauma was the most common type in the patients with accompanying injuries (95 patients; 73.6%). sixty (34.2%) patients required surgical management on the urogenital system (table 2). forty-five out of 46 patients (97.8%) with isolated urinary tract trauma survived. nine patients (5.2%) died due to the severity of the injuries, 8 of whom had accompanying injuries (7 patients with kidney injury and 1 with bladder injury). table 3 shows the scores according to the iss; 31% and 43% of the patients had mild (iss < 7) and severe (iss > 12) injuries, respectively. all died patients had severe injuries. discussion trauma registries have been extensively used for the evaluation of the management and outcome of trauma and are superior to administrative databases that may report misdiagnoses, therapeutic intervention, and survival.(12,13) the national trauma project was set up to study all aspects of trauma management including prehospital care, accident and emergency services, and inpatient management in iran. this study was performed at 8 cities in accordance with the american college of surgeons national trauma registry system (tracs) and the national trauma data bank (ntdb). a total of 17 753 patients had referred to trauma centers of these cities and had been hospitalized for more than 24 hours. there were 175 patients (about 1%) with urogenital trauma. injuries to the urogenital system developed in few traumatic patients in this study similar to the findings of other studies.(13) the characteristics of the injured patients were comparable with those in the literature and the number of the men admitted to the hospitals was nearly 4 times higher than that of women.(14,15) the age range of 20 to 30 years was the most common age group included in this study and other studies have also reported trauma to be mainly prevalent in men and in productive age groups.(14-16) blunt traumas were more frequent than the penetrating traumas. the most common mechanism of the trauma was road traffic accident and pedestrians were the major victims of these accidents (41%). in our study, firearm injury was less frequent than that in other countries. this may be due to the low rate of firearms being available in our country. compared with more than half of the patients who had associated injuries, few patients with isolated urogenital trauma were hemodynamically compromised at the time of presentation. hemodynamically unstable patients are more likely to have multiple injuries. injuries to the kidney and table 2. managements of urogenital trauma treatment patients (%) operative management 51 (29.1) nephrectomy 17 (9.7) bladder repair 16 (9.2) urethra repair 10 (5.7) kidney repair 7 (4) ureter repair 1 (0.5) conservative management 115 (65.7) mortality 9 (5.2) total 175 (100.0) table 3. outcome of patients according to iss* *values in parentheses are percents. iss indicates injury severity score. iss group survived patients dead patients total iss 1 (< 7) 55 (31.4) 0 (0) 55 (31.4) iss 2 (7 to 12) 43 (24.6) 0 (0) 43 (24.6) iss 3 (> 12) 68 (38.9) 9 (5.1) 77 (44.0) total 166 (94.9) 9 (5.1) 175 (100) urogenital trauma in iran—salimi et al 174 urology journal vol 3 no 3 summer 2006 the bladder, associated with other injuries (higher iss) result in a higher mortality rate. however, it seems that there is no relationship between the severity of the isolated urogenital trauma and the outcome in these patients, a finding that has been previously reported.(6,7) it means that the patient with multiple trauma requires a multidisciplinary approach, preferably by an experienced emergency surgeon.(6,17) although nearly all traumatic patients with isolated injuries to the urogenital system survived in this series, management should not be delayed.(17,18) these injuries may lead to urogenital dysfunction, and neglecting them can cause serious sequelae.(19) kidney was the most common injured organ and nephrectomy was the most common surgical management in this study which may be due to the high prevalence of blunt traumas as the most common mechanism of the injury. similar to other studies, ureteral injuries due to blunt trauma were the least common injuries.(5,6) conclusion analysis of the present study allows a greater understanding of the urogenital traumas in iran that are mostly resulted from blunt trauma due to the road traffic accidents. the high frequency of road traffic accidents suggests that planning is required in preventing these injuries. we suggest that an integrated trauma system be established in iran to improve the quality of trauma care. conflict of interest none declared. funding support the source of funding for this study was provided by the trauma and surgery research center of sina hospital, tehran university of medical sciences. references 1. smith gs, barss p. unintentional injuries in developing countries: the epidemiology of a neglected problem. epidemiol rev. 1991;13:228-66. 2. mcaninch jw, santucci ra. urogenital trauma. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3707. 3. rosenstein d, mcaninch jw. urologic emergencies. med clin north am. 2004;88:495-518. 4. dandan is, farhat w. trauma, upper urogenital. emedicine [updated 2005 december 7]. available from: http://www.emedicine.com/emerg/topic608.htm 5. palmer ls, rosenbaum rr, gershbaum md, kreutzer er. penetrating ureteral trauma at an urban trauma center: 10-year experience. urology. 1999;54: 34-6. 6. kuo rl, eachempati sr, makhuli mj, reed rl 2nd. factors affecting management and outcome in blunt renal injury. world j surg. 2002;26:416-9. 7. hsieh ch, chen rj, fang jf, et al. diagnosis and management of bladder injury by trauma surgeons. am j surg. 2002;184:143-7. 8. world health organization. international statistical classification of diseases and health related problems (the icd-10). 2nd ed. geneva: world health organization; 1994. 9. the american college of surgeons national trauma registry system. [updated 2005june 21]. available from: http://www.facs.org/trauma/national_tracs/ tracmenu.html 10. national trauma data bank (ntdb). available from: http://www.facs.org/trauma/ntdb.html 11. baker sp, o’neill b, haddon w jr, long wb. the injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. j trauma. 1974;14:187-96. 12. wynn a, wise m, wright mj, et al. accuracy of administrative and trauma registry databases. j trauma. 2001;51:464-8. 13. bariol sv, stewart gd, smith rd, mckeown dw, tolley da. an analysis of urinary tract trauma in scotland: imnpact on management and resource needs. surgeon. 2005;3:27-30. 14. salimi j, nikoobakht mr, zareei mr. epidemiologic study of 284 patients with urogeniyal trauma in three trauma centers in tehran. urol j (tehran). 2004;1:117120. 15. paparel p, n’diaye a, laumon b, caillot jl, perrin p, ruffion a. the epidemiology of trauma of the urogenital system after traffic accidents: analysis of a register of over 43,000 victims. bju int. 2006;97:33841. 16. roudsari bs, sharzei k, zargar m. sex and age distribution in transport-related injuries in tehran. accid anal prev. 2004;36:391-8. 17. dobrowolski zf, weglarz w, jakubik p, lipczynski w, dobrowolska b. treatment of posterior and anterior urethral trauma. bju int. 2002;89:752-4. 18. husmann da, gilling pj, perry mo, morris js, boone tb. major renal lacerations with a devitalized fragment following blunt abdominal trauma: a comparison between nonoperative (expectant) versus surgical management. j urol. 1993;150:1774-7. 19. peterson ne. current management of acute renal trauma. in: rous se, editor. urology annual. 5th ed. mcgraw-hill; 1991. p. 151-79. u j all final for web.pdf 767vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l 1department of urology, george washington university hospital, washington, d.c., usa 2associated urologists of orange county, the center for cancer prevention and treatment at st. joseph hospital, orange, ca, usa jason d. engel,1 stephen b. williams2 unclamped hand-assisted laparoscopic partial nephrectomy for predominantly endophytic renal tumors corresponding author: stephen b. williams, md 1801 n. broadway, santa ana, 92607, ca, usa tel: +1 714 6391915 fax: +1 714 6391127 e-mail: williams@ocurology.com received august 2011 accepted may 2012 purpose: nephrectomy for predominantly endophytic renal masses in the setting of relative contraindication materials and methods: results: conclusion: population. keywords: kidney neoplasms, hand-assisted laparoscopy, nephrectomy, ischemia laparoscopic urology 768 | introduction with the increased utilization of cross-sectional imaging, there has been an increased detection that partial nephrectomy results in improved long-term renal as compared to radical nephrectomy. the american uromasses recommend partial nephrectomy for the manageof preservation of renal function. it has been demonstrated (2) laparoscopic partial nephrectomy may offer sooner return to contion of laparoscopic partial nephrectomy, several groups have demonstrated the feasibility of robotic partial nephrectomy. the concept of zero ischemia to eliminate any damage to remaining nephrons during partial nephrectomy has been unclamped laparoscopic partial nephrectomy partial nephrectomy may lead to an increased utilization of laparoscopic partial nephrectomy. we describe unclamped laparoscopic hand-assisted partial nephrectomy for predominantly endophytic renal masses in the setting of relative evaluation of pathologic margins before renal reconstruction. materials and methods prior to initiation of the study, the surgeon had performed mies as an attending surgeon. system.(6) the chronic kidney disease epidemiology col(7) of the dressing. standard laparoscopic approach to small renal masses. patients are selected for unclamped hand-assisted laparoscopic rim around the tumor on computed tomography (ct) is an important indicator of the feasibility of this approach. a hand port is placed either via a muscle-splitting gibson inas for radical nephrectomy. a dissection identical to that of standard hand-assisted laparoscopic radical nephrectomy is performed. the tumor is localized, and the fat overlying the specimen. a laparoscopic renal ultrasonography is performed dicate encapsulation. the hilum is completely dissected, but clamps are not applied. mannitol or other diuretics are not given. the renal capsule around the tumor is then scored circumdle in open surgery (figure 2). the plane typically leaves a small amount of normal parenchyma on the tumor, and follaparoscopic urology 769vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l unclamped hand-assisted laparoscopic partial nephectomy | engel and williams of margins. as long as the plane has not been forced in any ily managed by manual compression of the defect. bleeding pathologic analysis of the specimen. in the setting of negative margins, no further resection is performed. if there is a positive margin, or if there is clinical blood loss to guide further resection. nephrectomy is perdeeper resection is not safe or feasible. bulldog clamps may be applied at this point if a more aggressive standard laparoscopy or open partial nephrectomy is deemed feasible. figure 1. computed tomography scan revealing a 2.2 cm enhancing lesion in the anterior mid-pole and a 1.6 cm enhancing lesion in the postero-medial lower pole. figure 2. the lesion before and after enucleation with use of the finger fracture technique. 770 | injection of methylene blue and spot suturing of defects or pinpoint bleeding, the renal defect is closed as for all laparoscopic partial nephrectomies at our institution. argon beam standard closure of the renal defect is performed utilizing collagen bolsters, pro-coagulants, and capsular sutures. results unclamped hand-assisted partial nephrectomy (ie, zero ishematocrit and egfr. agulation. operative decision to perform a radical nephrectomy. discussion partial nephrectomy is emerging as the standard of care for small renal masses. laparoscopic partial nephrectomy remains a technically challenging procedure and may not perience. robotic-assisted laparoscopic partial nephrectomy logic results and peri-operative outcomes. approach. furthermore, although the goal of zero ischemia is preferred in order to preserve renal function, laparoscopic partial nephrectomy in order to further bridge these areas of uncertainty. the mean operation time and blood loss tumor and time elapsed for intra-operative frozen section analysis, there appeared to be enough compression time to hancing rim around the tumor on pre-operative ct imaging in these sometimes challenging cases. it had been uniformly applied. although the safe duration of recent studies suggest superiority of no vascular clamping in preserving renal function. laparoscopic urology 771vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l unclamped hand-assisted laparoscopic partial nephectomy | engel and williams thus, it appears logical that minimizing or eliminating any tion during partial nephrectomy. recent studies have sug(2) feel the ability to perform unclamped partial nephrectomy in this patient population should be thought of as an imporpreservation of renal function is tantamount. of angles to be unparalleled in comparison. although no true that the ability to hold and maneuver the kidney during resecthe tumor. during standard laparoscopic or robotic partial nephrectomy a small biopsy performed at the tumor base, and the renal defect is immediately closed prior to clamp removal. recent studies have suggested the role of anatomical vascular mi(3) to fully inspect the tumor base, obtain a margin from the resected specimen, and re-biopsy the tumor bed several times demographic characteristics and peri-operative outcomes.£ characteristic hand-assisted laparoscopic partial nephrectomy (n = 8) gender male, n (%) female, n(%) 4 (50) 4 (50) age, mean (range), y 55.8 (38 to 68) body mass index, mean (range), kg/m2 30.5 (26.5 to 37.4) asa score, mean (range) 2.3 (2 to 3) side left, n (%) right, n (%) 4 (50) 4 (50) tumor size, mean (range), cm 3.7(1.7 to 8.5) anterior, n (%) 5 (62.5) posterior, n (%) 3 (37.5) pre-operative egfr, mean (range) 69.1 (46 to 94) operation time, mean (range), min 236.9 (175 to 272) estimated blood loss, mean (range), ml 368.8 (100 to 800) warm ischemia time, mean (range), min 0 length of stay, mean (range), day 3.3 (2 to 6) intra-operative complications, n 0 post-op complications, clavien grade* i ii iiia iiib iv v 0 1 0 0 1 0 post-op transfusion, n (%) 1 (12.5) post-op hematocrit change, n (%) -3.1 (-7.5) post-op egfr change, n (%) -1.6 (-2.4) pathology clear cell, n (%) 4 (50) papillary, n (%) 3 (37.5) chromophobe, n (%) 1 (12.5) positive surgical margin, n (%) 1 (12.5)** £asa indicates american society of anesthesiology; and egfr: estimated glomerular filtration rate. *based on modified clavien classification.7 **positive surgical margin was identified intra-operatively. 772 | proach. initial frozen section analysis of both tumor and residual tumor, and close inspection of the tumor bed intraa small nest of carcinoma visualized at the deepest site of resection. therefore, the inadvertent leaving of tumor behind to obtain margins from both the resected specimen and the tumor bed prior to renal reconstruction are perhaps the greatest advantages afforded to the patient by the hand-assisted approach. design. first, this is a small series of patients and further studeral applicability to all endophytic renal masses in all cases has not been demonstrated here. third, the larger incision remay lead to slightly higher morbidity and should be considperforming an unclamped hand-assisted laparoscopic partial conclusion tial nephrectomy for predominantly endophytic renal masses higher-risk patient population. conflict of interest none declared. references 1. campbell sc, novick ac, belldegrun a, et al. guideline for management of the clinical t1 renal mass. j urol. vol 182; 2009:1271-9. 2. gill is, kamoi k, aron m, desai mm. 800 laparoscopic partial nephrectomies: a single surgeon series. j urol. 2010;183:34-41. 3. gill is, eisenberg ms, aron m, et al. "zero ischemia" partial nephrectomy: novel laparoscopic and robotic technique. eur urol. 2011;59:128-34. 4. tan yh, young md, l'esperance jo, preminger gm, albala dm. hand-assisted laparoscopic partial nephrectomy without hilar vascular clamping using a saline-cooled, highdensity monopolar radiofrequency device. j endourol. 2004;18:883-7. 5. thompson rh, lane br, lohse cm, et al. comparison of warm ischemia versus no ischemia during partial nephrectomy on a solitary kidney. eur urol. 2010;58:331-6. 6. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 7. levey as, stevens la, schmid ch, et al. a new equation to estimate glomerular filtration rate. ann intern med. 2009;150:604-12. 8. winfield hn, donovan jf, lund go, et al. laparoscopic partial nephrectomy: initial experience and comparison to the open surgical approach. j urol. 1995;153:1409-14. 9. janetschek g, daffner p, peschel r, bartsch g. laparoscopic nephron sparing surgery for small renal cell carcinoma. j urol. 1998;159:1152-5. 10. rogers c, sukumar s, gill is. robotic partial nephrectomy: the real benefit. curr opin urol. 2011;21:60-4. 11. thompson rh, lane br, lohse cm, et al. every minute counts when the renal hilum is clamped during partial nephrectomy. eur urol. 2010;58:340-5. 12. thompson rh, leibovich bc, lohse cm, zincke h, blute ml. complications of contemporary open nephron sparing surgery: a single institution experience. j urol. 2005;174:855-8. laparoscopic urology 773vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l unclamped hand-assisted laparoscopic partial nephectomy | engel and williams 13. lane br, babineau dc, poggio ed, et al. factors predicting renal functional outcome after partial nephrectomy. j urol. 2008;180:2363-8; discussion 8-9. 14. gill is, patil mb, abreu al, et al. zero ischemia anatomical partial nephrectomy: a novel approach. j urol. 2012;187:807-14. 15. ng ck, gill is, patil mb, et al. anatomic renal artery branch microdissection to facilitate zero-ischemia partial nephrectomy. eur urol. 2012;61:67-74. the efficacy of acupuncture in extracorporeal shock wave lithotripsy agah m*, falihi a department of anesthesiology, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: to evaluate the safety and efficacy of acupuncture in comparison with intravenous (iv) sedation in extracorporeal shock wave lithotripsy (eswl). material and methods: one hundred patients, who were scheduled for eswl, were divided randomly into two groups of fifty patients (acupuncture and iv sedation). in the first group, acupuncture was carried out with special needles (0.30 × 18 mm), in two points 30 minutes before the procedure: point of 36 from the stomach meridian with an angle of 90 degrees and point of 60 from the urinary bladder meridian with an angle of 90 degrees. in the iv sedation group morphine 0.1 mg/kg was injected intramuscularly 30 minutes and intravenous diazepam 0.1 mg/kg for muscle relaxation and anti-anxiety, one minute before the procedure. the two groups were similar in terms of confounding factors. pain (scored in 4 levels), blood pressure, heart rate, respiratory rate, and arterial blood oxygen saturation were recorded prior to iv sedation or acupuncture, 30 minutes after each, at the beginning of eswl, 10 minutes after eswl, and at the end of the procedure (times 1 to 5). results: in acupuncture group the pain intensity was less than iv sedation group (for time 3, p=0.019, for time 4, p=0.002, for time 5, p=0.05). considering the pain incidence (each pain score except zero), there was a significant difference at time 4 (p=0.012). none of the procedures was stopped because of pain and none of the patients experienced complications during operation. arterial blood oxygen saturation was between 95% and 100% for all of the patients in acupuncture group and recovery time was shorter (p<0.0001). conclusion: acupuncture is a safe and effective method for analgesia. it has a faster recovery time and economical benefits. it also provides the ability to increase the shock wave voltage. we believe that it is a good alternative for iv sedation in eswl, particularly in patients with lung and heart disease. key words: acupuncture, eswl, pain, analgesia, lithotripsy 195 urology journal unrc/iua vol. 1, no. 3, 195-199 summer 2004 printed in iran introduction extracorporeal shock wave lithotripsy (eswl) is one of the newest methods in the treatment of urolithiasis, which was used in germany for the first time. today, eswl is known as the treatment of choice in selected urinary tract stones. at the initiation of its advent, it was tried to use it in outpatient services and proportionally to use a proper anesthesia method for outpatients.(1) the cause of pain during eswl is tissue damage as the result of shock wave direct pressure effect, cavitation, and the effect of sound waves with low frequency.(1,2) in the past times, general or epidural anesthesia was used for pain relief.(3) in many studies, it was tried to use various methods for analgesia in eswl. some of these methaccepted for publication in may 2004 *corresponding author: department of anesthesiology, shaheed labbafinejad medical center, boustan 9, pasdaran, tehran, iran. postal code: 16666. tel: +98 21 2549010-16, fax: +98 21 2549039. the efficacy of acupuncture in extracorporeal shock wave lithotripsy ods were high frequency jet ventilation,(4) paravertebral nerve block,(5) local anesthesia,(6) and different types of intravenous sedation,(1) but none of these anesthesia methods were accepted completely. on the other hand, with the advent of lithotripor (dornier mpl 9000), the need to general or local anesthesia has declined, because with the advent of new technology in eswl, the intensity of painful stimulus is reduced, but the need to analgesia is still remained.(7) acupuncture has a very old history in china and human civilization and it is one of the treatments of pain and anxiety.(8) in terms of using acupuncture in lithotripsy, there are not many published researches, but it is recommended to use the analgesic result of acupuncture when the painful stimulus is not so strong. grabow studied the analgesic effect of acupuncture in eswl and showed that its result was comparable to placebo.(9) some of the studies (although not case-control) confirmed the analgesic effect of acupuncture in many painful syndromes(10,11) and in some of the researches the effect of acupuncture was equal to analgesic effect of placebo.(12) furthermore, in acupuncture the sedative drugs or analgesic are not used, so there is lower complications. in order to compare the analgesic effect of acupuncture in eswl with iv sedation, this study was designed. materials and methods one hundred patients with ages from 18 to 70 years, who were candidates for elective eswl, with asa class i, ii, were scheduled for this prospective study. addiction and psychiatric illness were the exclusion criteria. patients were randomly divided into two groups of acupuncture (group one) and iv sedation (group two). in these two groups variables such as pain score, blood pressure, heart rate (hr), respiratory rate (rr), arterial blood oxygen saturation (spo2) and recovery time (defined as the time between the end of eswl procedure and the patient's discharge without vertigo, hemodynamic instability, dyspnea, nausea, and vomiting ) were recorded. these variables were recorded in both groups at the same times, which are mentioned below: 1. before starting sedation/acupuncture (time 1) 2. 30 minutes after sedation/acupuncture (time 2) 3. at the beginning of eswl (time 3) 4. 10 minutes after starting eswl (time 4) 5. at the end of eswl (time 5) in order to evaluate the analgesic effect in two acupuncture and sedation methods, pain intensity was evaluated by this scoring: score 0 as completely painless, score i as mild pain (tolerable by patients), score ii as moderate pain (with patient's complaint and tendency to ask a doctor for help), and score iii as severe and intolerable pain. each pain score except zero was considered as a case of pain incidence. in all the patients in group two, 0.1 mg/kg im morphine was administered 30 minutes before lithotripsy as premedication. in order to reduce anxiety and produce muscle relaxation 0.1 mg/kg diazepam iv was administered 1 minute before starting lithotripsy. acupuncture was performed in group one by electro-acupuncture method using defined points in traditional chinese medicine. in this group of patients, no analgesic and sedative drugs were administered for premedication. half an hour before starting the procedure, acupuncture started and continued during lithotripsy and at the end of the procedure, acupuncture stopped. acupuncture was done by short sterile special acupuncture needles (0.30 × 18 mm). for performing acupuncture, two points were used for punctures: point of st 36 from stomach meridian and point of 60 from urinary bladder meridian (ub 60). these points are on the known meridians in traditional chinese medicine and are used in musculoskeletal pains, skeletal muscle relaxation, and sedation. as the pain source in lithotripsy is mostly musculoskeletal (and not somatic), these spots were selected for patient's analgesia and sedation. point of st 36 is located four fingers below the lateral patellar notch and point of ub 60 is in the middle of the presumed line between lateral malleolus and calcaneus internal view. a pulse generator performed the stimulation. the low voltage-high frequency method, which is applied for acute pain was used for stimulating. frequency was set on 60 and voltage increased gradually from zero till the paresthesia was felt in the needle place. afterwards, in case of elimination of paresthesia feeling and patient tolerance, voltage was increased with 5 minute intervals until another episode of paresthesia occurred. this process was continued up to 30 minutes before the initiation of procedure. 196 the efficacy of acupuncture in extracorporeal shock wave lithotripsy at this time, voltage increased to a maximum of 2 volts and after 30 minutes lithotripsy started and electro-stimulation was continued during lithotripsy. at the end of lithotripsy, acupuncture was stopped. a single specialist performed the punctures in group one and the injections of group two and all the measurements were done by another single anesthesiologist and an anesthesiology resident, blinded to the analgesia method. a dornier mpl 9000 machine was used to perform lithotripsy. two percent of the shock waves were in the range of 10 to 16 kv and others were from 16 from 18 kv and produced local pressure intensity was around 700 bar. informed consents had been obtained from the patients before the procedures. data were analyzed by spss software using t, paired t, mannwhitney u, and chi-square tests for statistical significant difference. results one hundred patients, who were candidates for lithotripsy, were divided into two groups of 50 patients for acupuncture and iv sedation. in each group, there were 30 men and 20 women. the demographic data and stones' sizes are shown in table 1. regarding age, sex, weight, asa class, and stone size, there was no significant difference between the two groups. pain intensity in group one was significantly less than that in group two (p=0.5). considering pain incidence (each pain score except zero) in time 3 and 5, there wasn't any significant differences between the two groups (time 3, p=0.109 and time 5, p=0.086), but for time 4, the pain intensity was significantly less in group one (p=0.012) (fig. 1,2). none of the patients' treatment was stopped because of pain and none of the patients experienced complications during operation. spo2 was between 95 % and 100% for all of the patients. mean recovery time in group one was less than that in group two (p<0001) (fig. 3). discussion the present study showed that acupuncture with electro-acupuncture method is more effective than iv sedation in relieving pain in eswl with dornier mpl 9000 machine. in 1997, national institute of health (nih) recommended acupuncture for pain, nausea, and vomiting treatment and encouraged the scientists to perform more researches on the efficacy of acupuncture in different clinical problems.(13) mechanism of analgesia in acupuncture method is not still explained properly, but some of the proposed mechanism are as follows: some researches have shown that acupuncture 197 table 1. demographic and stone size in each group group mean stone diameter (mm) class asa (i/ii) weight (±sd) age (±sd) sex (f/m) acupuncture 16(7) 40/10 49(6) 52(7) 20/30 ivsedation 18(6) 38/12 51(6) 52(8) 20/30 table 2. recovery time in both groups group number recovery time (min) p value acupuncture 50 17 iv sedation 50 63 p<0.0001 fig. 1. pain score in time 4 �� �� � �� � � �� �� �� �� �� �� �� �� � ��� �� �������� �� ����������� �������� �� fig. 3. recovery time �� �� � �� �� �� �� �� �� �� ��� ���� ���������� fig.2. pain score in time 5 �� �� �� �� � �� �� �� �� ��������� ������ !��������� "�#$ ������ the efficacy of acupuncture in extracorporeal shock wave lithotripsy increases the secretion of different types of betaendorphin, serotonin and norepinephrine, which play a role in nociception.(14,15) in acupuncture, the needling regions have their own properties in a 1-millimeter diameter. the electrical resistance of the skin is low in these special regions. its connective tissue appearance is different from surrounding area.(16) in general, electrical stimulus causes releasing the neurohumoral chemical transmitters.(16) anyway the acupuncture analgesia is not associated with physiological disorders and doesn't cause the inhibition of central or peripheral nervous system and the patient is awake during the procedure. also, it has no complications such as drug overdosage or hypersensitivity and there has not been any report about mortality related to acupuncture, although the efficacy of acupuncture is limited,(10) and on the other hand, some people are more sensitive to its effects.(9) intravenous sedation has been used successfully history for pain relief in eswl, but it has its own complications.(1,2) in addition, sometimes it does not produce effective analgesia.(7) grabow reported that acupuncture and placebo have a same analgesic effect.(9) in this study, we compared acupuncture with iv sedation and there was not a placebo group. in grabow's study, eswl was performed with lithostar machine, but in this study we used dornier mpl9000. in this study, the acupuncture was started 30 minutes before the initiation of painful stimulus (eswl) and there was enough time for induction of the acupuncture. the needling regions in this study was different from that in grabow's study. also, the intravenous medications were different in the two studies. grawbow used visual analogue scale (vas) for determining the pain intensity, but we scored the pain intensity as it was mentioned above. therefore, it seems that the different results of the two studies are due to the considerable differences in their settings. peterson et al performed eswl without any anesthesia in some patients.(17) although many patients tolerated the procedure, some of them needed sedation and analgesia . in addition, these patients could not tolerate the energy more than 16 kv. of course all of the patients had received premedication, consisting of pethidine, diazepam, and topical lidocaine-prilocaine, which were applied for the area of eswl procedure. loening et al used local anesthesia infiltration and they had successful results.(6) short-term treatment results and long-term follow-up had no differences in comparison with general anesthesia group. finally, the results of the above studies show that the need to analgesia in eswl is reduced with the progress in its technology and nowadays we can provide enough analgesia by less non-invasive anesthesia methods. as the analgesia effect of the acupuncture is basically limited, these findings about the reduction of the need for analgesia in eswl have coordination with the results of this study about the efficacy of acupuncture in this regard. the limitation of our study was the absence of a control group. for moral consideration, we must have a medical intervention to relief the patient's pain. on the other hand, treatment by acupuncture needs adequate information and experience and the basis of diagnosis and treatment in traditional chinese medicine is different with the contemporary medicine.(12) in traditional chinese medicine, the treatment changes according to every person's conditions and also the details of treatment can be altered in each person during the treatment procedure.(12) hence, it is not matched completely with the research methods of scientific era (controlled, double-blind clinical trials), therefore, if the acupuncture is performed under these conditions, it may reduce or even eliminate the optimum effects of acupuncture. finally, although there are several documents denoting the efficacy of acupuncture, a doubleblinded study with placebo-control design should be performed in the future to evaluate the general efficacy of acupuncture and its specific role in eswl. conclusion acupuncture is a safe and effective method for analgesia. it has faster recovery time, and economical benefits, providing the ability to increase the shock wave voltage. thus, it can be an appropriate alternative. references 1. puppo p, bottino p, germinale f. painless extracorporeal shock wave lithotripsy for outpatients: a new option. eur urol 1989; 16: 12-14. 2. graff j, schmidt a, postor j, et al. new generator for low pressure lithotripsy with dornier hm3: preliminary experience of 2 centers. j urol 1988; 139: 904-907. 3. gaussy c, schmidt e, jocham d, et al. extracorporeal 198 the efficacy of acupuncture in extracorporeal shock wave lithotripsy shock wave lithotripsy (eswl) for treatment of urolithiasis . urology 1984; 23 (suppl 5): 59. 4. meyer wh, becker h, klosterhalfen h. higher efficiency of extracorporeal shock wave lithotripsy by the use of high frequency jet ventilation. j urol 1986; 135 (part 2): 150a. 5. fair wr, malhotra v. extracorporeal shock wave lithotripsy (eswl) using local infiltration anesthesia. j urol 1986; 135 (part 2): 181a. 6. loening s, kramolowsky ev, willoughby b; use of local anesthesia for extracorporeal shock wave lithotripsy. j urol 1987; 137: 626-628. 7. allman db, richlin dm, ruttenberg m. et al. analgesia in anesthesia-free extracorporeal shock wave lithotripsy: a standardized protocol. j urol, 1991; 146: 718-720. 8. wang sm, kain zn. auricular acupuncture: a potential treatment for anxiety. anesth analg. 2001; 92: 548-553. 9. grabow l, controlled study of the analgetic effectivity of acupuncture. arzneimittelforschung. 1994; 44: 554-8. 10. dias pl, subramanium s. minilaparatomy under acupuncture analgesia. j r soc med 1984; 77: 295-8. 11. hansen pe, hansen jh. acupuncture treatment of chronic facial pain-a controlled cross-over trial. headache 1983; 23: 66-69. 12. tavola t, gala c, conte g. et al. traditional chinese acupuncture in tention-type headache: a controlled study. pain 1992; 48: 325-9. 13. nih consensus development panel on acupuncture. acupuncture. jama 1998; 280: 1518-24. 14. clement-jones v, mcloughlin l, tomlin s, et al. increased beta-endorphin but not met-enkephalin levels in human cerebrospinal fluid after acupuncture for recurrent pain. lancet 1980; 2: 946-949. 15. hardebo je, ekman r, and eriksson m. low csf metenkephaline levels in cluster headache are elevated by acupuncture. headache 1989; 29: 494-497. 16. vallette c, niboyet jeh, imbert-martelet m. et al. acupuncture analgesia and cesarean section. the journal of reproductive medicine 1980; 25: 108-112. 17. pettersson b, tiselius h-g., andersson a and eriksson i: evaluation of extracorporeal shock wave lithotripsy without anesthesia using a dornier hm3 lithotriptor without technical modifications. j urol 1989; 142: 1189-1192. 199 1088 edited1.pdf 898 | miscellaneous tight swimming trunks to prevent post scrotal surgery hematoma an experimental justification yahya a al-abed, thomas w carr purpose: to conduct a study to measure the pressure effects of the different scrotal supports applied on a simulated expanding scrotal hematoma. materials and methods: we created a model of an expanding hematoma with simultaneous pressure tion of any support. then, three types of scrotal supports were tested, including euron net knickers, scrotal suspensory bandage, and tight swimming trunks brand speedo® brief and shorts. subsequent pressures were recorded using the model created, which was applied inside the supports worn by two male volunteers a and b. results: without any external compression, the pressure inside the simulated expanding hematoma “balloon” reached a maximum of 15 cmh2o. the pressures measured whilst wearing “netelast knickers” in both subjects a and b reached a maximum of 15 cmh2o suggesting that this garment exerted no measurable compression. the suspensory scrotal support was then tested in both subjects. resulting in falling of the balloon outside the scrotal support. subsequently, speedo® briefs and shorts 2 2o were reached in subjects a and b, respectively. when using speedo® shorts, however, maximum pressures of 55 cmh2 2 conclusion: the use of tight swimming trunks (speedo®) has led to satisfactory results in the prevention of hematoma post scrotal surgery. keywords: scrotum, hematoma, injuries, wounds, testis corresponding author: yahya a al-abed, md; mrcs (eng) southend university hospital, prittlewell chase, westcliff-on-sea ss0 0ry, united kingdom tel: +44 170 243 5555 fax: +44 170 238 5833 e-mail: yalabed@yahoo. co.uk received august 2011 accepted january 2012 department of urology, southend university hospital, prittlewell chase, westcliff-on-sea ss0 0ry, united kingdom miscellaneous 899vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l introduction hematoma following scrotal surgery is a well rec-ognized complication and can be associated with ity, and psychological distress. the reported incidence of scrotal hematoma following surgery varies in different stud(1) while others (2) several techniques have been described in the literature to minimize the risk of bleeding associated with scrotal surgery. a number of studies were performed using different methods of compression applied to the scrotum in an attempt to prevent hematoma formation. in practice, these methods of scrotal compression include “netelast knickers”, suspensory scrotal support, and scrotal bandaging. however, no study has attempted to measure the pressure exerted on the scrotum by these different techniques. we doubt that any of these scrotal supports exert enough pressure around the lax scrotum to prevent hematoma collection. in our clinical experience, the use of tight swimming trunks (speedo®) has led to satisfactory results in the prevention of hematoma post scrotal surgery. we set out to test the physiological basis of this method by conducting a study to measure the pressure effects of the different scrotal supports on a simulated expanding scrotal hematoma. materials and methods we created a model of an expanding hematoma with simultaneous pressure recording using urodynamic system duet 1). this catheter was attached to the urodynamic machine to ensure that the compliance of the balloon alone was low, this model was initially tested without applying any external pressure. the total pressure rise under these conditions was 15 cm h2 tal supports used in this study were: “netelast knickers” tight swimming trunks speedo® brief and shorts (warnaco the empty condom attached to the double lumen urethral the scrotum of two volunteers (a and b) while wearing the methods were recorded. results matoma “balloon” rose to a maximum of 15 cmh2 1a). the pressures measured whilst wearing “netelast knickers” in subjects a and b reached a maximum of 15 cmh2 measurable compression; this maximum was obtained in the suspensory scrotal support was then tested on both lated hematoma pushed the scrotal support forward resultfigure 1. the simulated expanding hematoma. post surgery scrotal hematoma | al-abed and carr 900 | ing in falling of the balloon outside the scrotal support. the 2o when the result was similar in both subjects. we infer that some compression was exerted, but as the hematoma expanded, the garment could not contain it and its usefulness was compromised. and shorts, were tested in subjects a and b. the result 2 cmh2o in subjects a and b, respectively, when the balloon quently, the speedo® shorts were tested in both subjects. as 2 pressure continued to raise steadily reaching maximum of 55 cmh2 2o in subject b at the discussion methods of scrotal support used after scrotal surgery. historically, post-surgery scrotal hematoma is the urologists’ ity. the lax nature of the scrotum makes it prone to hematoma formation. practice in scrotal surgery to ensure good hemostasis and to carefully suture the dartos muscle layer as it is a common source of bleeding. it seems likely that most scrotal hematomas occur as a refigure 2a. euron net knickers “netelast knickers”. figure 3. testing the simulated expanding hematoma while wearing a speedo® shorts in a male volunteer. figure 2b. suspensory scrotal support. figure 2c. tight swimming trunks speedo® brief and shorts. miscellaneous 901vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l post surgery scrotal hematoma | al-abed and carr sult of capillary or venous bleeding as arterial bleeding will be easily seen and dealt with at the time of operation. a relatively modest increase in scrotal pressure achieved with external compression should therefore be effective in the prevention of this debilitating complication. in our study design, we simulated an expanding hematoma using a novel model created by the authors. this study shows that the currently used methods of scrotal support in hospitals have limited value as the pressure exerted by these methods on the scrotum is not high enough to prevent hematoma formation. the results clearly show a lack of compression in respect to “netelast pants” and scrotal supports. however, the use of tight swimming trunks, speedo® briefs and shorts, showed promising results. the pressures exerted nal compression is exerted at an early stage of the hematoma formation, thereby hopefully preventing expansion. speedo® swimwear was 55 cmh2 thought to be high enough to prevent a hematoma formation yet unlikely to affect testicular perfusion and subsequent damage. other techniques to achieve the same end have been reported. possibly the most practical are the so-called “turban”(1) they require pendulous testicles and are not suitable to apply in men with smaller scrotums. although we did not include these techniques in the present study, for reasons of comfort, we anticipate that it would provide good compression. the neck of the scrotum can be constricted excessively if the bandage is too tight. it is impossible for the patients to redesign was created to simulate an expanding scrotal hematoma, we appreciate the scrotal wall structure and compliance is different. an animal model might be therefore more realistic. however, an ideal next step would be a clinical of hematoma post scrotal surgery. graph a graph d graph b graph e graph c graph f h 2 o h 2 o h 2 o h 2 o h 2 o h 2 o 902 | conclusion whilst we recognize this study’s limitations, we believe that of use and absence of discernible risk justify its routine use. conflict of interest none declared. acknowledgements collie for their assistance in the urodynamics laboratory during this study. references 1. manson al, macdonald g. "turban" scrotal dressing. j urol. 1987;137:238-9. 2. moloney ge. comparison of results of treatment of hydrocele and epididymal cysts by surgery and injection. br med j. 1975;3:478-9. 3. shah pa, dewoolkar vv, changlani tt. ambulatory hydrocele surgery: a review of 50 cases. j r coll surg edinb. 1992;37:385-6. 4. mandler ji. an improved scrotal pressure dressing. j urol. 1966;96:235. 5. griffin jh, canning jr. the scrotal hitch for hemostasis and edema prevention in scrotal surgery. urology. 1996;47:9189. 6. nieh pt, kerr ws, jr. simple scrotal compression dressing. urology. 1984;23:73. 7. haas gp, melser m, miles bj. method of circumferential pressure dressing of scrotum following bilateral orchiectomy. urology. 1989;33:429-30. 8. oesterling je. scrotal surgery: a reliable method for the prevention of postoperative hematoma and edema. j urol. 1990;143:1201-2. 9. shreedhar r, duncan t. a technique for preventing postoperative scrotal haematoma. br j clin pract. 1984;38:93-4. 10. henry gd. the henry mummy wrap and the henry finger sweep surgical techniques. j sex med. 2009;6:619-22. review 78 urology journal vol 6 no 2 spring 2009 cyp1a1 polymorphisms and risk of prostate cancer a meta-analysis abjal pasha shaik,1 kaiser jamil,2 prabhavathy das2 introduction: two common polymorphisms in cytochrome p450; family 1, subfamily a, polypeptide 1 (cyp1a1); have been implicated as a risk factor of prostate cancer, but individual studies have been inconclusive or controversial. we reviewed studies on cyp1a1 polymorphisms in patients with prostate cancer. materials and methods: the strategy searching in the pubmed was based on combinations of prostate cancer, cyp1a1, cyp1a1 gene polymorphism, and genetic susceptibility. the last search update was may 2008. the retrieved articles and their bibliographies of were evaluated and reviewed independently by 2 experts. we shortlisted 19 studies, of which 14 on sporadic prostate cancer were analyzed. overall, 2573 patients with prostate cancer and 2576 controls were analyzed. results: the random effects odds ratio was 1.350 (95% confidence interval, 1.110 to 1.641; p = .003) for t/c polymorphism and 1.085 (95% confidence interval, 0.863 to 1.364; p = .49) for a/g polymorphism. the a/g polymorphism was not associated with increased risk of prostate cancer. however, the t/c polymorphism showed conflicting results in different studies, while overall, this polymorphism showed significant effects on the susceptibility to prostate cancer. there was no significant betweenstudy heterogeneity for both polymorphisms with respect to distribution of alleles. conclusion: this meta-analysis suggests that while the cyp1a1 t/c polymorphism is likely to considerably increase the risk of sporadic prostate cancer on a wide population basis, the a/g polymorphism may not influence this risk. however, the association of polymorphisms may be significant with respect to smoking history, diet habits, ethnicity, and race. urol j. 2009;6:78-86. www.uj.unrc.ir keywords: prostatic neoplasms, meta-analysis, cyp1a1, genetic polymorphisms 1research wing, indo-american cancer hospital and research centre, hyderabad, india 2department of genetics, bhagwan mahavir medical research centre, masab tank, hyderabad, india corresponding author: kaiser jamil, md department of genetics, bhagwan mahavir medical research centre, masab tank, hyderabad-500 004, india phone: +91 40 6666 2032 e-mail: kaiser.jamil@gmail.com received july 2008 accepted november 2008 introduction prostate cancer is one of the most common malignancies in men, and the prostate is the leading site for cancer incidences, accounting for 31% of new cancer cases in men.(1) the incidence of prostate cancer varies greatly with race and geography. in india, the annual mortality in 2000 was 700 000, and the annual estimate of cancer for the year 2001 was 980 000. it is relatively rare for prostate cancer to be diagnosed in men younger than 50 years old, but above this age, the incidence and mortality rates increase exponentially.(1,2) genetic susceptibility to prostate cancer is an important research area, especially since the incidence of prostate cancer has been rapidly increasing. prostate cancer susceptibility loci have been reported to be hereditary prostate cancer 1 gene at 1q24, cyp1a1 and prostate cancer—shaik et al urology journal vol 6 no 2 spring 2009 79 predisposing for prostate cancer gene at 1q42, x-linked hereditary prostate cancer gene at xq27, capsule biosynthesis protein gene at 1p36, and hereditary prostate cancer 20 gene at 20q13.(2) the association of prostate cancer with polymorphisms of common variants in genes involved in steroid hormone metabolism including androgen receptor (ar), steroid-5alpha-reductase, alpha polypeptide 2, cytochrome p450 subfamily xvii, vitamin d receptor, etc, have been extensively examined.(3-7) cytochrome p450, family 1, subfamily a, polypeptide 1 (cyp1a1) is involved in xenobiotic metabolism and classified as a phase i enzyme. the expression of the cyp1a1 is induced in a ligand-dependent fashion by the aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator.(1,2,8) the cyp1a1 gene plays an important role in carcinogenesis of various cancers, and it might affect carcinogenesis of prostate cancer through alteration of genotoxicity and hormone imbalance. it is inhibited by fluoroquinolones and macrolides, induced by aromatic hydrocarbons. there are 3 main subtypes of cyp1a: m1, m2, and m3. cyp1a1 and cyp1b1 are regulated by the aryl hydrocarbon receptor, a ligand-activated transcription factor which is a part of the phase i reactions in drug metabolism.(8) current published evidence suggests that both environmental and genetic factors influence the pathogenesis of prostate cancer.(9,10) polymorphisms of the cyp1a1 may modify the risk for prostate cancer.(8,9) the cyp1a1 gene encodes a phase i cytochrome, p-450 enzyme, that converts environmental procarcinogens to reactive intermediates having carcinogenic effects.(11) in addition, cyp1a1 is involved in the oxidative metabolism of estrogens, which may play a critical role in the etiology of prostate cancer.(12) two common polymorphisms in cyp1a1 have been reported: one is a t/c substitution located 264 bp downstream from the 3’-flanking region, forming an msp1 restriction site (cyp1a1m1); the second is a g/a substitution at the 4889 bp position of exon 7, which leads to an amino acid substitution (ile to val) of its protein (cyp1a1m2).(1,13) the association of these cyp1a1 single nucleotide polymorphisms (snps) with cancer (eg, lung, oesophageal, breast, oral cavity cancers) has been well documented.(1,14) more recently, the association between cyp1a1 snps and prostate cancer has been reported in some groups.(13) molecular epidemiological studies have presented seemingly contradictory results concerning the potential role of the cyp1a1 polymorphisms in prostate cancer susceptibility. using relevant accumulated data, a quantitative methodology was used to estimate the strength of cyp1a1 genetic associations. materials and methods identification of relevant studies we considered all studies that examined the association of the cyp1a1 gene polymorphisms with prostate cancer. we shortlisted 19 studies, of which 14 were analyzed further. results of only sporadic prostate cancer were considered for meta-analyses. we excluded studies with familial linkage designs. all of the obtained studies (familial and sporadic) were tabulated to have an overview of the number of studies carried out in prostate cancer which used cyp1a1 gene for analyses. search sources included medline which was searched through pubmed. the last search update was may 2008. the search strategy was based on combinations of prostate cancer, cyp1a1, cyp1a1 gene polymorphism, and genetic susceptibility. the retrieved articles and their bibliographies of were evaluated and reviewed independently by 2 experts. case-control studies were eligible if they had determined the distribution of cyp1a1 genotypes in prostate cancer cases and in a concurrent control group of prostate cancer-free subjects using a molecular method for genotyping. we accepted disease-free controls regardless of whether they had benign prostatic hyperplasia or did not. cases with prostate cancer were eligible regardless of whether they had a first-degree relative with prostate cancer or not. however, we excluded hereditary prostate cancer results from 2 family-based studies.(15,16) data extraction the following information was sought from cyp1a1 and prostate cancer—shaik et al 80 urology journal vol 6 no 2 spring 2009 extracted data: authors, journal and year of publication, country of origin, selection and characteristics of prostate cancer cases and controls, demographics, racial descent of the study population, eligible and genotyped cases and controls, and number of cases and controls for each cyp1a1 genotype. meta-analysis the primary analysis for all cyp1a1 gene polymorphisms was based on distribution of genotypes among various populations, and then, evaluation of the overall differences within them. we also examined the contrast of the two groups of homozygotes (the dominant and recessive). the odds ratio (or) was used for analyses of results. for each genetic contrast, we estimated the between-study heterogeneity across all eligible comparisons, using the modified chi-square test. heterogeneity was considered significant is p value was less than .05. all analyses were conducted using the comprehensive meta-analysis software version 2 (biostat, englewood, new jersey, usa). results eligible studies fourteen studies probing the relationship between the cyp1a1 gene polymorphism and prostate cancer susceptibility were identified.(15-28) two studies by chang and colleagues and cunningham and coworkers(15,16) also included a family-based history; therefore, the data of only sporadic prostate cancer cases were collected (table 1). most of the studies had selected patients with prostate cancer based on a histological diagnosis from biopsy and/or prostatectomy. in 1 study by nock and coleagues,(17) controls were unaffected brothers of the patients with prostate cancer. controls did not have a clinical diagnosis of prostate cancer, confirmed using additional screening (with digital rectal examination, prostate specific antigen [psa < 4 ng/ml], and needle biopsy or prostate resection; table 1). a few investigators had also matched their groups for smoking status and alcoholism in relation to risk of prostate cancer. molecular methods for genotyping were checked. all studies had used polymerase chain reaction assay, and 3 studies had also used sequencing. meta-analysis the selected studies included a total of 5832 subjects (2766 patients and 3066 controls) while the eligible subjects were 2573 patients and 2576 controls. allele and genotype frequencies per samples age of studied population, y study population patients controls patients controls chang et al, 2003(15) caucasians and african-americans 159 familial and 245 sporadic 222* mean, 61.0 for familial and 58.7 for sporadic mean, 58 beer et al, 2002(18) caucasians 117 183 ≥ 18 ≥ 18 atkas et al, 2004(19) turkish 100 107† mean, 68.2 (49 to 86 ) mean, 67.8 (43 to 87) mittal and srivastava, 2007(20) indian 130 140 mean, 62.5 mean, 58.5 li, 2008(21) chinese 208 230 median, 72.0 (46 to 94) median, 67 (45 to 81) cunningham et al, 2007(16) hispanic, caucasian, and african-american 438 familial and 499 sporadic 493 45 to 89 45 to 89 yang et al, 2006(22) south chinese 225 250 mean, 71.6 mean, 71.0 nock et al, 2006(17) caucasians, african americans, and asians 439 479‡ mean, 61.5 mean, 62.8 silig et al, 2006(23) turkish 152 169 50 to 85 49 to 88 caceres et al, 2005(26) chilean 103 132 mean, 68.7 mean, 63.3 figer et al, 2003(27) israeli 224 250 mean, 64.6 (45 to 81) mean, 61.7 (35 to 83) murata et al, 2001(28) japanese 115 204 mean, 73.0 mean, 71.2 suzuki et al, 2003(24) japanese 81 105 mean, 70.6 (40 to 88) mean, 71.2 (51 to 88) acevedo et al, 2003(25) chilean 128 102† mean, 68.6 mean, 63.4 table 1. characteristics of the study population in selected studies included in meta-analyses *of the controls, 5.6% had brothers or a father affected with prostate cancer. †the controls were men with benign prostatic hyperplasia. ‡the controls were unaffected brothers of the patients with prostate cancer. cyp1a1 and prostate cancer—shaik et al urology journal vol 6 no 2 spring 2009 81 group are shown in tables 2 and 3. some other studies not included in the meta-analysis but found relevant are presented in table 4.(9,16,17,27-31) the t allele was the most highly represented among controls and cases of all studies irrespective of the descent. overall, the prevalence of tt, tc, and cc genotypes was 52.6%, 67.7%, and 20.6% in the control individuals and 48.0%, 61.2%, and 13.9% in the patients with prostate cancer. for the ile/val polymorphism, the prevalence of aa, ag, and gg genotypes was 66.6%, 26.8%, and 6.4% in the controls and 64.3%, 28.8%, and 6.7% in the patients. the distribution of genotypes in both of the groups was consistent with hardyweinberg equilibrium in all studies. overall effects for alleles the t/c polymorphism was associated with increased risk of prostate cancer (summary random effects or, 1.350; 95% confidence interval [ci], 1.110 to 1.641; p = .003; figure 1). no association was found between a/g polymorphism with prostate cancer .the summary random effects or for g/a polymorphism was 1.085 (95% ci, 0.863 to 1.364; p = .49; figure 2). however, there was no significant heterogeneity between the 14 study comparisons for both polymorphisms with respect to distribution of alleles. the q-value for t/c polymorphism was 9.799 (i2 = 28.561; p = .20; table 5), while for a/g polymorphism, it was 7.968 (i2 = 24.702; p = .24; table 6). to assess the publication bias among the selected patients genotype (mspi) in studies prostate cancer controls chang et al, 2003(15) tt 188 (83.9) 135 (75.0) tc 36 (16.1) 39 (21.7) cc 0 6 (3.3) mittal and srivastava, 2007(20) tt 55 (42.3) 75 (53.6) tc 69 (53.1) 58 (41.4) cc 6 (4.6) 7 (5.0) li, 2008(21) tt 78 (37.5) 102 (44.4) tc 100 (48.1) 84 (36.5) cc 30 (14.4) 44 (19.1) yang et al, 2006(22) tt 76 (33.8) 96 (38.4) tc 116 (51.6) 112 (44.8) cc 33 (14.7) 42 (16.8) silig et al, 2006(23) tt + tc 142 (94.0) 153 (90.0) cc 10 (6.0) 16 (10.0) caceres et al, 2005(26) tt 39 (38.2) 74 (56.2) tc 50 (48.0) 47 (35.4) cc 14 (13.8) 11 (8.4) murata et al, 2001(28) tt 60 (52.2) 118 (59.0) tc 49 (42.6) 74 (37.0) cc 6 (5.2) 8 (4.0) suzuki et al, 2003(24) tt 46 (35.8) 46 (43.8) tc 39 (48.1) 37 (35.2) cc 13 (16.0) 22 (21) acevedo et al, 2003(25) tt 39 (38.2) 72 (56.2) tc 49 (48.0) 45 (35.1) cc 14 (13.7) 11 (8.5) table 2. distribution of cyp1a1 mspi polymorphism in various populations patients genotype (ile/val) in studies prostate cancer controls chang et al, 2003(15) aa 210 (93.8) 162 (90.0) ag 14 (16.1) 18 (10.0) gg 0 0 beer et al, 2002(18) aa 101 (91.8) 129 (88.3) ag 7 (6.4) 17 (11.6) gg 2 (1.2) 0 atkas et al, 2004(19) aa 41 (41.0) 50 (46.7) ag 45 (45.0) 51 (47.7) gg 14 (14.0) 6 (5.6) li, 2008(21) aa 120 (57.7) 150 (65.2) ag 75 (36.1) 66 (28.7) gg 13 (6.2) 14 (6.1) yang et al, 2006(22) aa 113 (50.2) 151 (60.4) ag 90 (40.0) 86 (34.4) gg 22 (9.8) 13 (5.2) murata et al, 2001(28) aa 60 (52.2) 125 (62.5) ag 42 (36.5) 64 (32.0) gg 13 (11.3) 11 (5.5) suzuki et al, 2003(24) aa 39 (48.1) 65 (61.9) ag 34 (42.0) 33 (31.4) gg 8 (9.9) 7 (6.7) table 3. distribution of cyp1a1 ile/val polymorphism in various populations cyp1a1 and prostate cancer—shaik et al 82 urology journal vol 6 no 2 spring 2009 samples age, y study population patients controls studied genotype patients controls interpretation cunningham et al, 2007(16) hispanic, caucasian, and african-american 499 493 snp analysis 45 to 89 45 to 89 no significant association nock et al, 2006(17) asians, caucasian, and african-american 439 479 cyp1a1 (ile/val) mean, 61.5 mean, 62.8 no significant association nock et al, 2007(31) asians, caucasian, and african-american 637 244 cyp1a1 (ile/val) mean, 60.8 mean, 71.6 no significant association figer et al, 2003(27) 224 250 cyp1a1 (ile/val) mean, 64.6 mean, 61.7 no significant association gao et al, 2003(9) chinese 48 112 cyp1a1 (ile/val) … … a/g associated with pc risk murata et al, 1998(28) japanese 115 204 cyp1a1 (mspi) cyp1a1 (ile/val) mean, 73 mean, 71 ile/val and val/val associated with pc risk guan et al, 2005(30) chinese 83 115 gene chip technique … … no significant association vijayalakshmi et al, 2005(29) south indian 100 100 cyp1a1 (mspi) cyp1a1 (ile/val) … … t/c associated with increased risk, a/g associated with decreased risk of pc table 4. results of cyp1a1 polymorphisms in some additional studies* *snp indicates single nucleotide polymorphism; cyp1a1, cytochrome p450, family 1, subfamily a, polypeptide 1; and pc, prostate cancer. figure 1. odds ratio and 95% confidence interval of the distribution of cyp1a1 mspi polymorphism (tc genotype). figure 2. odds ratio and 95% confidence interval of the distribution of cyp1a1 ile/val polymorphism (ag genotype). cyp1a1 and prostate cancer—shaik et al urology journal vol 6 no 2 spring 2009 83 studies, funnel plots were constructed for both t/c and a/g polymorphisms (figures 3 and 4). discussion cyp1a1 is likely to play an important role in the etiology of prostate cancer through its function in activating environmental procarcinogens and catalyzing the oxidative metabolites of estrogens. to test the hypothesis that genetic polymorphisms in the cyp1a1 gene may be associated with the risk of prostate cancer, studies have been performed in various populations. in chinese men,(15) 3801t/c and 2455a/g were each individually associated with the risk of prostate cancer. beer and colleagues(18) performed genotyping of cyp1a1 (ile/val) gene in 117 patients with prostate cancer and 183 populationbased controls. their cohort failed to identify a relationship between the above polymorphisms and prostate cancer. atkas and coworkers(19) studied the association of cyp1a1 with prostate cancer in 100 patients and 107 controls of turkish origin. no statistical differences were observed in the distribution of the cyp1a1 ile/val genotype between the two groups (or, 1.076; 95% ci, 0.605 to 1.913). however, the patients with cyp1a1 val/val revealed a 2.8-fold higher risk of having prostate cancer than those with the wildtype ile/ile (or, 2.846; 95% ci, 1.004 to 8.064). vijayalakshmi and associates(29) investigated the effect size and 95% confidence interval test of null (2-tail) heterogeneity model number of studies point estimate lower limit upper limit z p q df(q) p i-squared fixed 8 1.354 1.150 1.594 3.645 < .001 9.799 7 .20 28.561 random 8 1.350 1.110 1.641 3.007 .003 … … … … table 5. heterogeneity between study populations assessed for cyp1a1 mspi polymorphism (tc genotype)* *ellipses indicate not applicable. effect size and 95% confidence interval test of null (2-tail) heterogeneity model number of studies point estimate lower limit upper limit z p q df(q) p i-squared fixed 7 1.117 0.922 1.354 1.130 .26 7.968 6 .24 24.702 random 7 1.085 0.863 1.364 0.696 .49 … … … … table 6. heterogeneity between study populations assessed for cyp1a1 ile/val polymorphism (ag genotype) figure 3. funnel plot to estimate the amount of publication bias in studies on cyp1a1 mspi polymorphism (tc genotype). figure 4. funnel plot to estimate the amount of publication bias in studies on cyp1a1 ile/val polymorphism (ag genotype). cyp1a1 and prostate cancer—shaik et al 84 urology journal vol 6 no 2 spring 2009 association between two snp’s in south indian population. individuals with w1/m1 genotype at 3’utr of cyp1a1 were at a higher risk of prostate cancer (or, 4.64; 95% ci, 1.51 to 14.86; p < .01), while the cyp1a1 ile/val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk of the cancer (or, 0.17; 95% ci, 0.02 to 0.89; p = .03). different grades of tumors did not have a significant association with the variant genotypes. the role of cyp1a1, cigarette smoking, and age was analyzed by mittal and srivastava(20) in 130 patients with prostate cancer and 140 controls using polymerase chain reaction assay and binary logistic regression model. the t/c polymorphism of cyp1a1 revealed a significant association with smoking for prostate cancer risk. li and colleagues(21) analyzed cyp1a1 with respect to genetic susceptibility to prostate cancer in chinese men. they genotyped 208 patients and 230 age-matched controls and analyzed the results according to age at diagnosis, prostate-specific antigen levels, and cancer stage and grade (gleason score). no significant differences in the frequency distributions of cyp1a1 polymorphisms were observed between the patients and the controls. in another study, cyp1a1 was analyzed in a case-control fashion, but the data was not statistically significant after appropriate corrections for multiple comparisons.(16) yang and colleagues(22) investigated the association of cytochrome p450 1a1, smoking, alcohol drinking, and the risk of prostate cancer in a han population in southern china (225 patients and 250 age-matched controls). the cyp1a1 val/ val genotype significantly increased the risk of prostate cancer (or, 2.26; 95% ci, 1.09 to 4.68). heavy smoking history (or, 1.61; 95% ci, 1.04 to 2.50) significantly increased the susceptibility of prostate cancer. nock and coworkers(17) investigated the relationship between cigarette smoking and cyp1a1 ile/val polymorphism using a familybased case-control design (439 patients with prostate cancer and 479 controls); however, the results were not statistically significant. in another study, 83 patients and 115 age-matched healthy controls were genotyped for genetic polymorphisms of cyp1a1 by the genechip technique. there were no significant differences in the frequency of cyp1a1 polymorphisms between the patients and the healthy controls.(30) silig and colleagues(23) studied on cyp1a1mspi in 321 turkish individuals (152 patients with prostate cancer and 169 age-matched controls). no association was observed between cyp1a1 polymorphism and prostate cancer or smoking history. associations between genetic polymorphisms of cyp1a1 and prostate cancer were analyzed by murata and associates(32) in a case-control study of 315 individuals. the frequency of val/val genotypes for cyp1a1 was 11.3% in patients with cander compared with 5.5% in controls. this polymorphism, thus, was associated with a significantly increased risk of prostate cancer (or, 2.4; 95% ci; 1.01 to 5.57). the study also confirmed that the cyp1a1 polymorphism in combination with glutathione s-transferase m1 (gstm1) gene polymorphism may be associated with prostate cancer susceptibility in the japanese population. gao and colleagues(9) studied the possible relationship between cyp1a1 genetic polymorphisms and the susceptibility of prostate cancer in 48 patients and 112 healthy individuals. among patients and their matched controls, the frequencies of alleles and genotypes were significantly different with ile/val gene polymorphisms (p < .05); the allele g and gg genotypes were significantly more frequent than those in the controls with an (or, 1.59 and or, 3.06; respectively). but, no significant differences of the frequencies of the mspi alleles and genotypes were found between the patients with prostate cancer and the controls. the association between genetic polymorphisms of cyp1a1 and familial prostate cancer risk was examined in a case-control study of 185 individuals by suzuki and associates.(24) the presence of any mutated alleles significantly increased cancer risk in comparison with wildtype genotypes by combination analysis (or, 2.38; 95% ci, 1.72 to 3.29; p = .007). acevedo and colleagues(25) studied on the associations between cyp1a1 msp1 and prostate cancer in a case-control study. their findings suggest that the cyp1a1 and prostate cancer—shaik et al urology journal vol 6 no 2 spring 2009 85 chilean carrying single or combined gstm1 and cyp1a1 polymorphisms were more susceptible to prostate cancer. caceres and colleagues(26) suggested that the interaction between genetic polymorphisms in gst (t1;m1) and cyp1a1 m1 would play a significant role as a modifying factor on prostate cancer risk in chilean people. figer and coworkers(27) showed in 224 patients that cyp1a1 gene polymorphisms did not show a significant association with prostate cancer. finally, murata and coworkers(28) analyzed genetic polymorphisms of the xenobiotic-metabolizing enzymes, cyp1a1, and gstm1 in 115 patients with cancer and 204 controls. the cyp1a1 val/ val genotype significantly increased the risk of prostate cancer (or, 2.6; 95% ci, 1.11 to 6.25) and the ile/val genotype showed a similar tendency (or, 1.4; 95% ci, 0.86 to 2.29). the combination of the cyp1a1 val allele and gstm1 (0/0) genotype was associated with a higher risk (or, 2.3; 95% ci, 1.18 to 4.48) than the cyp1a1 val allele alone. conclusion this meta-analysis included data from 14 casecontrol comparisons with approximately 6000 genotyped patients with prostate cancer and controls. the overall data demonstrated that the cyp1a1 g/a polymorphism is unlikely to be a major risk factor of prostate cancer on a wide population basis. however, although individual studies have shown conflicting results, the t/c polymorphism may considerably influence the risk of this cancer. the cyp1a1 polymorphism, therefore, may be an important population-wide risk factor of prostate cancer with respect to the t/c polymorphism. this meta-analysis could not address conclusively familial prostate cancer because hereditary forms of this cancer with many members affected in a family are not very common. future studies are being planned to explore whether the cyp1a1 polymorphism may have any effects on the risk of prostate cancer specifically in this setting. control groups of the different studies were not well characterized as to the extent of inclusion of subjects with benign prostatic hyperplasia, which may again affect the results. studies are also planned to determine the influence of t/c polymorphism with the risk of prostate cancer on a wider population basis. acknowledgment the authors would like to thank indo-american cancer hospital and research centre and bhagwan mahavir medical research centre for facilities provided. they would also like to acknowledge the colleagues for providing expert advice in shortlisting the studies and for evaluating the studies for meta-analyses. conflict of interest none declared. references 1. kawajiri k. cyp1a1. iarc sci publ. 1999;(148):15972. 2. haas gp, sakr wa. epidemiology of prostate cancer. ca cancer j clin. 1997;47:273-87. 3. masson lf, sharp 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[polymorphism of metabolic gene and genetic susceptibility to prostate cancer]. zhonghua wai ke za zhi. 2005;43:1467-70. chinese. 31. nock nl, tang d, rundle a, et al. associations between smoking, polymorphisms in polycyclic aromatic hydrocarbon (pah) metabolism and conjugation genes and pah-dna adducts in prostate tumors differ by race. cancer epidemiol biomarkers prev. 2007;16:1236-45. 32. murata m, watanabe m, yamanaka m, et al. genetic polymorphisms in cytochrome p450 (cyp) 1a1, cyp1a2, cyp2e1, glutathione s-transferase (gst) m1 and gstt1 and susceptibility to prostate cancer in the japanese population. cancer lett. 2001;165:171-7. pcnl in the management of lower pole caliceal calculi ziaee sam*, abdollah nasehi, basiri a, simforoosh n, danesh ak, sharifi aghdas f, tabibi a urology/nephrology research center, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: several therapeutic methods are used in the management of lower pole caliceal calculi. this survey has been conducted to evaluate the safety and efficacy of percutaneous nephrolithotomy in the management of lower pole calculi. materials and methods: fifty-five patients, 43 males and 12 females with a mean age of 41.5 (range 11 to 75) years, who had suffered from lower pole caliceal calculi and treated by standard percutaneous nephrolithotomy (pcnl) between 1997 and 2001, were enrolled in this study. the stones were classified as follows: small (less than 25 mm), intermediate (25 to 34 mm) and large (more than 35 mm). mean follow-up was 6.2 months (range 2 weeks to 34 months). results: the stones were completely extracted by one session pcnl in 43 patients (79%). repeat pcnl was needed in one patient and another method was used for stone extraction in another patient. regarding the size of stone, 88%, 79%, and 74% of small, intermediate, and large stones were completely extracted, respectively. no major complication was noted. conclusion: pcnl has high success rate in patients with stones larger than 2 cm and its morbidity would be low, provided that it is performed by skilled surgeons. key words: percutaneous nephrolithotomy, calculus, lower pole calyx, treatment urology journal unrc/iua vol. 1, no. 3, 174-176 summer 2004 printed in iran 174 introduction controversy still remains in the treatment of lower pole caliceal calculi. extracorporeal shock wave lithotripsy, percutaneous nephrolithotomy (pcnl), and flexible ureteroscopy are the currently used therapeutic methods. while swl has lower morbidity, its success is directly related to the size and composition of stone; moreover, stone clearance is dependent on anatomic features.(1-6) percutaneous therapeutic methods are effective, but they have a higher morbidity rate. pcnl is preferred to swl in the management of stones larger than 20 mm.(7-10) retrograde flexible ureteroscopy for lower pole caliceal calculi is a remarkable alternative for pcnl or swl in small stones. furthermore, it is potentially less invasive than pcnl. this study has been conducted to evaluate the efficacy and safety of only pcnl in the management of lower pole caliceal calculi. materials and methods one thousand patients with renal stone, who had been treated by pcnl at shaheed labbafinejad medical center from january 1998 through january 2002, were studied in a retrospective fashion. fifty patients (56 kidneys) had symptomatic renal stones, exclusively in lower pole. those who simultaneously had stones at other parts of kidney were excluded from the study. one session pcnl was performed for all the patients following general anesthesia and insertion of ureteral catheter. all phases were controlled via fluoroscopy with contrast media. nephrostomy tract was made toward the stone through lower pole and dilatation was made by dilatators. following the insertion of amplatz accepted for publication in august 2003 *corresponding author: department of urology, shaheed labbafinejad medical center, boustan 9, pasdaran, tehran, iran. postal code: 16666. tel: +98 21 2549010-16, fax: +98 21 2549039. pcnl in the management of lower pole caliceal calculi 175 sheet and nephroscopy, the stone was fragmented, if needed; otherwise, it was extracted by grasping forceps. to extract the residual fragments, revision of system was performed 48 hours after the procedure with an analgesic injection (with no anesthesia), and then nephrostomy tube was fixed. patients were followed up two weeks later by kub, urinary system ultrasonography, and chemical analysis of stone. mean follow-up was 6.2 months (2 weeks to 34 months). results fifty-five patients (56 kidneys) with renal stone, exclusively in lower pole, underwent pcnl. patients consisted of 43 males and 12 females with a mean age of 41.5 (range 11 to 75 years). the stones were located at left in 38 and bilaterally in one. size of the stones was classified into 3 groups: small (less than 25 mm), intermediate (25 to 35 mm) and large (more than 35 mm). the stones were single in 27 patients and multiple in 29; however, all stones were located at lower pole calices. a history of open renal surgery or pcnl was noted in 16 patients and 19 had failed swl (1 to 9 sessions). pcnl by itself led to complete extraction of stone in 43 patients (79%). revision was required in one patient and a new nephrostomy tract was needed in another one to extract the stone. lithotripsy with pneumatic probe was performed in 27 patients; while, the stone was extracted only by grasping forceps in 27. the remaining 12 patients were lost to follow up. considering the size of stones, 88%, 79%, and 74% of small, intermediate, and large stones were extracted, respectively. complications included hemorrhage (required transfusion) in 4 patients, delayed hemorrhage in 1, long-term urinary leakage from nephrostomy site in 2, urinary tract infection in 2, and mild increase of creatinine in 4, which were medically managed. mean hospitalization was 5.9 (range 3 to 19) days and mean time of procedure was 55 (range 40 to 80) minutes. according to the chemical analyses, the stones consisted of calcium oxalate in 22 patients, calcium oxalate and calcium phosphate in 17, calcium oxalate and uric acid in 7, calcium phosphate in 6, cystine in 2, and uric acid in one. discussion different management methods are used for lower pole caliceal calculi; however, the selection of proper therapeutic method has still been a matter of discussion. in this study the outcomes of pcnl in the management of lower pole calculi has been reported and compared to other reported studies and methods. this report is the first of its kind throughout the country. extracorporeal lithotripsy is an alternative therapeutic method for most patients with stone and without urinary system problem. lower pole caliceal calculi which are treated by swl have low stone-free rate due to anatomic position of lower pole.(11,12) the size of stone is the most important factor that has been considered in the outcome of swl in many studies;(1,11) furthermore, factors such as stone composition and anatomic position could potentially affect the outcome of swl.(2) infundibulopelvic angle as well as infundibular width and length are three anatomic factors which affect stone clearance. an open infundibulopelvic angle, and a short and wide infundibulum positively affect stone clearance.(12) however, some authors do not consider such factors.(13) when the stone is larger than 20 mm stone-free rate after swl decreases considerably; while, the rate of repeated therapies and complementary therapeutic methods increase.(1,11) although some authors suggest swl for stones smaller than 20 mm, this size has been recently lowered to smaller than 10 mm.(3,11) following swl, other measures should be taken for most of patients with unimportant small fragments.(14) some authors suggest that holding the patients upside-down and hitting his back could be useful in the expulsion of such fragments.(15) inserting ureteral catheter before swl and direct washing of lower pole calices during swl in order to increase stone-free rate have been reported.(16,17) probably, the chance for recurrent stone formation following swl is higher, which is due to the fragments and their migration to the respective calices.(2) prognostic factors cited for the failure of swl consist of hard stones which need high voltage and multiple sessions of swl, multiple stones in lower pole calyx, history of pcnl, and lower pole calculi, which are formed in other parts of the kidney following the swl.(18) ureteroscopy for lower pole caliceal calculi is an acceptable alternative therapeutic method. although it is more invasive than swl, it can be done outpatiently. it is slightly more successful than swl in the management of stones smaller than 1 cm and considerably more successful for pcnl in the management of lower pole caliceal calculi176 stones between 1 to 2 cm. applying zero-type basket increases the success rate of this method, by which the stones are led to pelvis and upper pole, where swl can be performed in a better situation.(6,9) moreover, it highly prevents any damage to ureteroscope which mostly occurs during bending and lithotripsy by laser. comparing to swl, anatomic situation is less important in ureteroscopy; however, when anatomic abnormalities are present it may have a negative effect.(12) furthermore; surgeon should be talented enough to insert the ureteroscope and grasp the stone. some authors believe that pcnl is the choice therapeutic method in the management of stones larger than 2cm, while others recommend pcnl for stones larger than 1 cm.(3,11) regarding stone clearance, pcnl is more effective than swl and ureteroscopy for large stones.(6) pcnl is also preferred to swl considering repeated treatment and other modalities.(1,11) economically, pcnl is more cost effective than swl for lower pole caliceal calculi larger than 2 cm.(8) although pcnl has a higher morbidity rate than swl or ureteroscopy, regarding the recent progresses in pcnl technique and high stone-free rate as well as earlier return to daily life, morbidity of pcnl is not so higher than swl; therefore, it should be considered for calculi between 1 to 2 cm.(3,11) this study indicates that outcome of pcnl is better than swl for small and intermediate calculi (88% and 79% comparing to 69% and 44%) and ureteroscopy is more appropriate for small, intermediate, and large calculi (88%, 79%, and 74% comparing to 82%, 71%, and 65%). moreover, the need for repeated treatments and other treatment modalities is lower in pcnl. findings of this study also show good outcome of pcnl in the treatment of lower pole caliceal calculi in comparison with ureteroscopy and swl outcome, reported in other articles. however, only the outcome of pcnl in our center was reported in this article and the comparison of findings should be performed in another study with proper circumstances. conclusion pdnl is a safe and effective method for lower pole caliceal calculi greater that 2 cm. this method in skilled hand surgeons is safe and has low morbidity rates. references 1. havel d, saussine c, et al. single stones of the lower pole of the kidney. eur urol 1998; 33: 396. 2. nouri m, tligui m, et al. predictive factors of successful treatment of lower caliceal calculi with edap lt02 extracorporeal lithotripsy. porg urol 2000; 10(4): 529-36. 3. lingeman je, siegel yi, et al. management of lower pole nephrolithasis: a critical analysis. j urol 1994; 151: 663667. 4. hollenbeck bk, schuster tg, et al. flexible ureteroscopy in conjunction with in situ lithotripsy for lower pole calculi. urology 2001; 58(6): 859-63. 5. tuckey j, devasia a, et al. is there a simpler method for predicting lower pole stone clearance after shock wave lithotripsy than measuring infundibulopelvic angle? j endourol 2000; 14(6): 475-8. 6. sampaio fj. renal collecting system anatomy cur opin urol 2001; 11(4): 359-66. 7. schuster ta, hollenbeck bx, et al. ureteroscopic treatment of lower pole calculi. j urol 2002; 168(1): 43-5. 8. may dj, chandhoke ps. efficacy and cost-effectiveness of extracorporeal shock wave lithotripsy lower pole renal calculi. j urol 1998; 159: 24-27. 9. auge bk, dahm p, et al. ureteroscopic management of lower-pole renal calculi. j endourol 2001; 15(8): 835-8. 10. netto nr jr, claro jf, lemos gc, cortado pl. renal calculi in lower pole calices: what is the best method of treatment? j urol 1991; 146(3): 721-3. 11. albala dm, assimos dg, et al. lower pole 1: a prospective randomized trial of exlracorporeal shock wave lithotripsy and percutaneous nephrolithotomy for lower pole nephrolithiasis initial results. j urol 2001; 166: 2072-2080. 12. elbahnasy am, shalhav al, et al. lower caliceal stone clearance after shock wave lithotripsy or ureteroscopy. j urol 1998; 159: 676-682. 13. madbouly k, sheir kz, et al. impact of lower pole renal anatomy on stone clearance after shock wave lithotripsy. j urol 2001; 165(5): 1415-8. 14. streem sb, agnes y, et al. clinical implication of clinically insignificant stone fragments after extracorporeal shock wave lithotripsy. j urol 1990; 155: 1186-1190. 15. pace xt, taria n, et al. mechanical percussion, inversion and diuresis for residual lower pole fragments after shock wave lithotripsy. j urol 2001; 166: 2065-201. 16. nicely er, maggio mi, et al. the use of a cystoscopically placed cobra catheter for directed irrigation of lower pole caliceal stones during extracorporeal shock wave lithotripsy. j urol 1999; 148: 1036-1039. 17. graham j b, nelson j b. percutaneous caliceal irrigation during extracorporeal shock wave lithotripsy for lower pole renal calculi. j urol 1994; 152: 2227. 18. talic rf, el faqih sr. extracorporeal shock wave lithotripsy for lower pole nephrolithasis. urology 1998; 51(4): 544-547. urological oncology a significant upregulation of mir-886-5p in high grade and invasive bladder tumors atefeh khoshnevisan,1 mahmoud parvin,2 nasim ghorbanmehr,3 nasim hatefi,2 hamid galehdari,1 seyed amir mohsen ziaee,4* seyed javad mowla5 purpose: to investigate the expression alteration of mir-886-5p in bladder tumors and evaluating its expression level as a potential biomarker in this type of cancer. materials and methods: formalin-fixed paraffin-embedded (ffpe) samples of bladder tumors belonging to 70 patients whom had been referred to the shahid labbafi-nejad medical center were obtained from the archival collection of pathology department. after rna extraction and cdna synthesis, expression levels of mir886-5p were quantified by a real-time reverse transcription polymerase chain reaction (rt-pcr) approach. results: our data revealed a significant upregulation (~3 times) of mir-886-5p in high grade bladder tumors, compared to the low grade ones (p < .05). moreover, its expression level could significantly discriminate noninvasive (ta, t1) from invasive (t2-t4) tumor stages. conclusion: our data suggests a potential role for mir-886-5p in progression of bladder cancer. keywords: carcinoma; transitional cell; gene expression regulation; micrornas; genetics; urinary bladder neoplasms. introduction bladder cancer is the most common form of malig-nancy in the urinary tract, however, its molecular pathogenesis is incompletely understood.(1) it develops in a multistep process with a variety of distinct biological and functional features.(2) conventional clinical and pathological parameters are widely used to classify bladder tumors with different grades and stages, and also to predict the clinical outcome of the disease. nevertheless, the predictive ability of these parameters is limited. (3) therefore, there has been a great effort in the field to discover novel molecular pathways involved in bladder cancer, to improve its diagnosis, prognosis and treatment. micrornas (mirna) are small (~19-25 nucleotides) single-stranded rna molecules, with an important role in post-transcriptional regulation of their targets via repressing gene translation or degrading target mrnas. mirnas are involved in development as well as in progression of a number of human cancers, including bladder cancer.(4-10) based on a vast number of profiling experiments, the mirna signatures are tumor typeand tissue-specific. moreover, the signature is often related to the grade and stage of the tumors. thus, mirna expression analysis could be used to classify tumors according to their grades of malignancies. it has been recently proposed that the combined expression of stem cell associated factors and specific oncogenes could induce a non-differentiated state in cancer cells which can then progress into high-grade ones.(11-13) strikingly, histologically poorly differentiated tumors display a preferentially elevated expression of genes normally enriched in embryonic stem (es) cells.(11) these molecular markers, alone or in combination with conventional approaches, have the capacity to improve diagnosis, identifying patients who will respond to chemotherapy, and finding molecular targets for novel therapeutic interventions.(14-19) regarding the potential role of mir-886-5p in stem cell self-renewal, pluripotency and differentiation, we encouraged to investigate its potential expression in bladder cancer tissues, and also its potential expression alteration in tumors with different grades of malignancies. materials and methods sample collection and preparation formalin-fixed paraffin-embedded (ffpe) specimens of bladder cancer and associated patients› data were collected from labbafi-nejad hospital (tehran, iran). a total of 70 specimens were obtained from patients who had been undergone operations between 1 department of genetics, shahid chamran university of ahvaz, ahvaz, iran. 2 department of pathology, labbafi-nejad medical centre, shahid beheshti university of medical sciences, tehran, iran. 3 department of anatomy, school of medical sciences, tarbiat modares university, tehran, iran. 4 urology and nephrology research center, labbafi-nejad medical center, shahid beheshti university of medical sciences, tehran, iran. 5 department of molecular genetics, faculty of biological sciences, tarbiat modares university, tehran, iran. *correspondence: urology and nephrology research center, labbafi-nejad medical center, shahid beheshti university of medical sciences, tehran, iran. tel: +98 21 2256 7222. fax: +98 21 2256 7282. e-mail: samziaee@gmail.com. received august 2013 & accepted june 2014 urological oncology 2160 2005 and 2011. the histopathological features of the samples were re-examined and confirmed by an expert pathologist (m.p.), according to the grading and tnm system for stage classification of the world health organization. written informed consent had been obtained from all subjects prior to sampling. the samples with inadequate tissue size, incomplete clinicopathological information, unclear tumor cells from pathological view and multiple samples from recurrent patients were excluded from the study. the medical ethics committee of tarbiat modares university approved the experiment design. ffpe blocks were cut into thin sections and prepared for rna extraction. rna extraction sections of 15 μm thickness were prepared from each ffpe specimen. paraffin was removed by xylene (merck kgaa, darmstadt, germany) treatment and tissues were washed out for three times with absolute ethanol (merck kgaa, darmstadt, germany) to remove xylene. after drying, tissues were treated with proteinase k (fermentas, vilnius, lithuania) at 56˚c for 3 hours. the homogenized tissues were then employed for total rna extraction, which was performed by acid guanidinium phenol chloroform procedure using trizol solution (invitrogen, carlsbad, ca, usa), according to the manufacturer’s instructions. rna purity and quantity were assessed by means of spectrophotometry (gene quest), where a260/a280 and 230/260 ratios were used to monitor any potential contamination with genomic dna and proteins. dnase treatment and cdna synthesis to remove any possible genomic dna contamination, total rnas were treated with dnase i (fermentas, london, uk) at 37ºc for 30 minutes. reverse transcription (rt) reaction was performed on 2 μg of purified total rna by reverse transcriptase enzyme (takara holdings, kyoto, japan), as described previously. (20) rt reactions also contained 0.15 μm stem-loop rt primer (table 1), 3 μm random hexamer (macrogen inc. seoul, south korea), and 1 × rt buffer (takara holdings, kyoto, japan). the 10 μl reactions were then incubated at 16ºc for 30 minutes, at 42ºc for 30 minutes, and at 85ºc for 5 minutes and then held at 4ºc till being used. all rt reactions, including no-template and no-rt controls, were run in duplicate. quantitative real-time reverse transcription polymerase chain reaction (rt-pcr) quantitative real-time rt-pcr was performed using the abi7500 system (applied biosystems, ca, usa). the relative expression of mir-886-5p was assessed in comparison to u6 snrna, as a reference internal control, using specific primers. all primers were designed as shown in table 1. real-time pcrs were performed in a final reaction volume of 20 μl including, 10 ng cdna, 10 μl of sybr green i master mix (takara holdings, kyoto, japan), and 200 nm of forward and reverse primers, according to the manufacturer’s instructions. the pcr reactions were carried out as follows: an initial denaturation at 95ºc for 5 minutes, followed by 40 cycles of denaturation at 95ºc for 10 seconds, annealing at 60ºc for 30 seconds and extension at 72ºc for 30 seconds. authenticity of the pcr products was examined by examining the sizes of the pcr products by polyacrylamide gel electrophoresis, as well as by inspecting the uniqueness of the products melt curves. to compensate for the inter-pcr variations, the expression of the target gene was normalized of that of endogenous control u6 snrna. for this analysis, the comparative ct (threshold cycle number) method (δct) was used. cloning and sequencing of the amplicons table 1. the sequence of primers used in this study. name primer primer sequence ( 5› to 3›) pcr product length (nucleotides) mir-886-5p stem-loop (for cdna synthesis) gtcgtatccagtgcagggtccgaggtattcg cactggatacgacccgctt forward cgggtcggagttagctca 58 reverse gtgcagggtccgaggt rnu6 forward gaacgatacagagaagattagc 54 reverse gaatttgcgtgtcatccttg abbreviation: pcr, polymerase chain reaction. variables score age (minimum-maximum), years 38-87 gender, no. male 65 female 5 stage, no. ta/t1 40 t2-t4 25 undetermined 5 grade, no. low grade 28 high grade 35 undetermined 7 surgical procedure, no. tur-bt 48 radical cystectomy 22 abbreviation: tur-bt, transurethral resection of bladder tumor. table 2. demographic and clinical characteristics of the patients with bladder cancer. upregulation of mir-886-5p in bladder tumors-khoshnevisan et al. vol 12 no 03 may-june 2015 2161 the amplified product of the real-time pcr with the expected size was cloned via the instaclonetm pcr cloning kit (thermo fisher scientific, waltham, ma, usa). the vector was then amplified through transformation into dh5α, and the isolated clones were then sent for direct sequencing (macrogen inc. seoul, south korea). statistical analysis the obtained data were statistically analyzed by graphpad software (la jolla, california, usa, www.graphpad.com). the data were presented as mean ± standard deviation (sd) and the student unpaired t-test was used to determine the significance of the observed differences between different groups. a p value less than .05 was considered statistically significant. in addition, (roc) receiving operating characteristic curve analysis, with calculation of both the area under the curve and the corresponding 95% confidence intervals (ci), was used to assess the specificity and sensitivity with which the expression level of mir-886-5p could discriminate between low and high grade/stage tumors. results mir-886-5p is upregulated in high grade bladder tumors to evaluate the expression alteration of mir-886-5p in different bladder tumors, we collected ffpe samples from 70 patients. the age of the patients was 38-87 years old (mean, 61 years), of whom there were 65 male and 5 female. all tumor types were transitional cell carcinoma, from which 35 were high grade, and 28 were low grade. total rna extraction and real-time pcr performed on all samples and the authenticity of the pcr products were confirmed by direct sequencing of the pcr products. all data were normalized to the expression of u6, as a house-keeping internal control. there were no non-specific products or primer-dimer peaks in melt-curve analysis by abi-7500 pcr instrument. analysis of gene expression among different grades of malignancies of bladder tumors revealed a significant upregulation (fold change: 2.84, p = .0187) of mir-886-5p in high grade tumors, compared to that of low-grade ones (figure 1). mir-886-5p expression in cancer tissues with different stages as shown in figure 2, there was a significant difference in the expression level of mir-886-5p in tumors with different stages. considering the invasiveness, bladder cancer can be categorized either as noninvasive (ta/t1) or invasive tumors (t2-t4). comparing the expression level in tumors with different stages revealed that mir-886-5p is significantly upregulated (with a fold change of 4.147, p = .036) in invasive tumors. analyzing the validity of mir-886-5p as a tumor marker for bladder cancer we used the roc curve analysis to estimate the sensitivity and specificity by which the mir-886-5p expression level could discriminate between bladder tumors with different grades and stages. as depicted in figure 3, roc curve analysis yielded an auc (the areas under the curve) of 0.742 (95% ci: 0.6198-0.8642) and 0.67 (95% ci: 0.535-0.799) for mir-886-5p to discriminate tumors with different stages and grades, respectively. an auc > 0.70 indicates a good ability of a marker to discriminate two groups of samples. discussion in recent years, tremendous advances have been made in the discovery of new markers associated with alterations at the molecular level of bladder cancer. the studies have shown considerable clinical relevance in different areas such as tumor classification and prognosis. there are some studies which have been focused on expression analysis of some micrornas involved in bladder cancer progression and tumor behavior. saito and colleagues reported that mir-127 is down regulated in bladder carcinoma.(17) furthermore, gottardo and colleagues(18) identified 10 up regulated mirnas in cancer samples such as mir-185, mir-203, mir-205, mir-221 and etc. in this study, we found a significant upregulation of mir-886-5p in high grade urinary bladder cancer tissues, compared to the low grade ones. in addition, the expression of mir-886-5p showed a significant elevation in invasive tumors, compared to the noninvasive samples. employing the roc curve analysis, we further discovered that this microrna could pofigure 1. comparing the expression level of mir-886-5p in bladder tumors with different grades of malignancies. figure 2. comparing the expression of mir-886-5p in bladder tumors with different stages. upregulation of mir-886-5p in bladder tumors-khoshnevisan et al. urological oncology 2162 tentially being used as a good tumor marker to discriminate between high and low grade bladder cancer, as well as for discriminating invasive bladder tumors from noninvasive ones. to the best of our knowledge, these findings are the first report on the expression of mir-886-5p in bladder cancer. therefore, we could not compare our results with previously reported data. as another limitation to our study, we failed to collect enough normal bladder tissue to compare mir886-5p expression between normal and tumor tissues. mir-886-5p is known as one of the mirnas associated with the pluripotency state of stem cells. wilson and colleagues reported the expression of mir-886-5p in human embryonic stem cells (hesc) and induced pluripotent stem (ips) cells, where it is down regulated upon the induction of differentiation in both types of pluripotent cells.(15) as indicated by ben-porath and colleagues a stem cell signature is present in poorly differentiated and high grade bladder tumors.(11) according to their findings, specific transcriptional regulators which are normally active in stem cells are overexpressed in poorly differentiated tumors arising in bladder. based on our obtained data, we hypothesized that mir-886-5p regulate some pathways involved in progression, invasion and metastasis of bladder tumors, probably by down regulating the expression of some mrnas functioning in preventing these pathways. an oncogenic role for mir-886-5p has already been provided by li and colleagues' work in which mir-886-5p inhibits apoptosis of cervical cancer cells by down-regulating the expression of bax.(16) there are controversies in literatures on the exact nature of mir-886-5p. in some reports it has been designated as a vault rna or a non-coding rna. stadler and colleagues claimed that the sequence of this microrna is a part of a longer rna named vtrna2.(19) later, lee and colleagues introduced the pre-mir-886 as a 102-nucleotide long rna which is abundantly presents in the cytoplasm of the cells with unique features which differs from those of a genuine pre-micrornas or vault rnas. (21) they found a much lower percentage of mature mir886-5p compared to its precursor form, pre-mir-886, in lung cancer cell lines. the later finding could be due to either a low rate of cleavage of pre-mir-886 into mature mir-886-5p, or that, mature mir-886-5p is only a degradation intermediate of pre-mir-886. they also found that pre-mir-886 is suppressed in some cancer cell lines and clinical specimens, where it functions through regulation of protein kinase rna-activate (pkr).(21) part of the aforementioned controversies arises from the innate differences in the strategies and methods used to amplify micrornas, and most importantly how to discriminate mature form the precursor from. in the current study, we designed a stem-loop rt primer to specifically amplify the mature form of mir-8865p. the stability of the stem-loop structure of the rt primer precludes its annealing to the prior pre-mirna, due to a steric hindrance.(22,23) despite the fact that stem-loop primers are more difficult to design,(23) they are highly specific for amplifying mature mirnas.(24,25) the later claim was further reinforced by our direct sequencing of the real-time pcr products which proved the specific amplification of mature mir-886-5p. regardless of the nature of amplified product in our study, as either a genuine mirna or a piece of a longer non-coding rna, its differential expression in tumors with different grades and stages is of great interest. regardless of our findings on the potential role of mir-886-5p in progression and invasion of bladder tumor, more studies in other cancer types (especially tumor vs. non-tumor states of samples) are necessary in order to determine whether this short non-coding rna is suitable as a molecular marker for diagnosis and prediction of prognosis of cancers. acknowledgments we would like to thank ms. mahshid malakootian for her technical helps and supports. this work is financially supported by a research grand from urology and nephrology research center (unrc), shahid labbafi-nejad medical center. conflict of interest none declared. references figure 3. receiver operating characteristic (roc) curve analysis to examine the suitability of mir-886-5p expression to discriminate bladder tumors with: a) different grades of malignancies with the areas under the roc curve of 0.67 (95% ci: 0.535-0.799) and a p value of .02, with sensitivity of 73% and specificity of 54%. b) different stages of progression with the areas under the roc curve of 0.742 (95% ci: 0.6198-0.8642) and a p value of .001, with sensitivity of 60% and specificity of 80%. upregulation of mir-886-5p in bladder tumors-khoshnevisan et al. vol 12 no 03 may-june 2015 2163 1. kirkali z, chan t, manoharan m, et al. bladder cancer: epidemiology, staging and grading, and diagnosis. urology. 2005;66:434. 2. shariat sf, ashfaq r, karakiewicz pi, saeedi o, sagalowsky ai, lotan y. survivin expression is associated with bladder cancer presence, stage, progression, and 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expression patterns in hepatocellular carcinoma and non-tumorous tissues. oncogene. 2006;25:2537-45. 10. yu sl, chen hy, chang gc, et al. microrna signature predicts survival and relapse in lung cancer. cancer cell. 2008;13:48-57. 11. ben-porath i, thomson mw, carey vj gr, bell gw, regev a, weinberg ra. an embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. nat genet. 2008;40:499-507. 12. hochedlinger k, yamada y, beard c, jaenisch r. ectopic expression of oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. cell. 2005;121:465-77. 13. valk-lingbeek me, bruggeman sw, van lohuizen m. stem cells and cancer; the polycomb connection. cell. 2004;118:409-18. 14. bartel dp. micrornas: genomics, biogenesis, mechanism, and function. cell. 2004;116:28197. 15. wilson kd, venkatasubrahmanyam s, jia f, sun n, butte aj, wu jc. microrna profiling of human-induced pluripotent stem cells. stem cells dev. 2009;18:749-58. 16. li jh, xiao x, zhang yn, et al. microrna mir-886-5p inhibits apoptosis by downregulating bax expression in human cervical carcinoma cells. gynecol oncol. 2011;120:145-51. 17. saito y, liang g, egger g, et al. specific activation of microrna-127 with down regulation of the proto-oncogene bcl6 by chromatin-modifying drugs in human cancer cells. cancer cell. 2006;9:435-43. 18. gottardo f, liu cg, ferracin m, et al. microrna profiling in kidney and bladder cancers. urol oncol. 2007;25:387-92. 19. stadler pf, chen jj, hackermüller j, et al. evolution of vault rnas. mol biol evol. 2009;26:1975-91. 20. monfared h, ziaee sa, hashemitabar m, khayatzadeh h, kheyrollahi v, tavallaei m, mowla sj. co-regulated expression of tgf-β variants and mir-21 in bladder cancer. urol j. 2013;10:981-7. 21. lee k, kunkeaw n, jeon sh, et al. precursor mir-886, a novel noncoding rna repressed in cancer, associates with pkr and modulates its activity. rna. 2011;17:1076-89. 22. kramer mf. stem-loop rt-qpcr for mirnas. curr protoc mol biol. 2011; chapter 15:unit 15.10. 23. benes v, castoldi m. expression profiling of microrna using real-time quantitative pcr, how to use it and what is available. methods. 2010;50:244-9. 24. varkonyi-gasic e, wu r wm, walton ef, hellens rp. protocol: a highly sensitive rtpcr method for detection and quantification of micrornas. plant methods. 2007;3:12. 25. chen c, ridzon da, broomer aj, et al. real-time quantification of micrornas by stem-loop rt-pcr. nucleic acids res. 2005;33:e179. upregulation of mir-886-5p in bladder tumors-khoshnevisan et al. urological oncology 2164 urology journal unrc/iua vol. 2, no. 4, 206-210 autumn 2005 printed in iran 206 reconstructive surgery buccal mucosal graft in repeat urethroplasty abdorasol mehrsai,1 hooman djaladat,2* alireza sina,1 sepehr salem,1 gholamreza pourmand1 1department of urology, sina hospital, tehran university of medical sciences, tehran, iran 2department of urology, mohammadi hospital, hormozgan university of medical sciences, bandarabbas, iran abstract introduction: our aim was to evaluate the efficacy of a tubed buccal mucosal graft in repeat urethroplasty for patients with urethral stricture and failed previous operations. materials and methods: ten patients (aged 12 to 47 years) with urethral stricture were entered into the study. all had a history of failed previous urethroplasties, and 5 had failed internal urethrotomies, too. repeat urethroplasties were performed by excising the fibrous tissue around the stricture; buccal mucosa was then harvested from the inner cheek, made into graft tubing, and interposed into the defect. the patients were followed at 1, 6, and 12 months. results: the procedure was technically successful in all the patients. the mean operative time was 150 minutes. the stricture sites were in the posterior urethra in 8 and the anterior urethra in 2 patients. the mean urethral defect length was 4.9 cm. the primary etiology was pelvic fracture in 7 patients. strictures recurred postoperatively in 3 patients, all of whom had a urethral defect longer than 5 cm, and 2 of whom had more than 1 previous failed urethroplasties (compared with 1 out of 7 in the successful cases). urinary flow rate increased significantly (from 0 to 10.4 ± 7.33 ml/s) postoperatively (p = .018). longer strictures produced signifcantly poorer graft urethroplasty outcomes (p = .001). conclusion: urethroplasty with buccal mucosal grafts is tough, resilient, easy to harvest, and leaves no scar. it appears to be an optimal substitute for anterior and posterior urethral strictures longer than 3 cm. key words: urethroplasty, graft, urethral stricture, buccal mucosa introduction reconstruction of long urethral strictures that cannot be excised and reanastomosed remains controversial.(1) augmenting or replacing the circumference of the urethra using a patch or a tube has been introduced as a means of substitution urethroplasty.(2) flaps are preferred for substitution urethroplasty because of the theoretical advantage that they carry their own blood supply, and therefore, their viability is more secure. recently, there has been a trend toward grafts, particularly buccal mucosal free grafts.(2) humby was the first surgeon to use a buccal mucosal graft for urethroplasty more than received october 2004 accepted september 2005 *corresponding author: urology and transplant research center, sina hospital, hassan-abad sq, tehran, iran. tel: ++98 21 6671 7447, fax: ++98 21 6671 7447 e-mail: hoomanj@hums.ac.ir mehrsai et al 207 60 years ago.(3) burger and colleagues are responsible for generating recent interest in the use of buccal mucosa initially for hypospadias repair and subsequently, for urethral strictures.(4) buccal mucosa has been used in both primary and salvage urethroplasties, as dorsal onlay, ventral onlay, and as tubed grafts in posterior and anterior urethral strictures. these grafts may be used in 1-stage or 2-stage operations with wide range of outcomes, most likely dependent on patient selection and expertise of the surgeons. there are several reports of substitution urethroplasty in the literature, the majority of which have short follow-ups. none of them are particular to repeat urethroplasty. we describe our experience using tubed buccal mucosal grafts in 10 patients with failed urethroplasties. materials and methods between september 2000 and october 2002, we performed a prospective study on 10 patients (mean age, 28.4 ± 10.4 years; range, 12 to 47 years) with urethral stricture who had a history of failed previous urethroplasty and were unable to void through the urethra. all of the patients had undergone an end-to-end anastomosis in their previous urethroplasties. five of them had a history of failed internal urethrotomy, as well. patients were selected for buccal mucosal graft urethroplasty. patients were informed of the study protocol, and informed consent was obtained. the institutional board review and the medical ethics committee of tehran university of medical sciences in tehran, iran, approved the study protocol. routine laboratory tests, retrograde urethrography, and antegrade cystourethrography via a cystostomy catheter were done, preoperatively. patients underwent a urethroplasty that utilized a tubed buccal mucosal graft. under general anesthesia, using a nasotracheal tube, the mucosa of the inner cheek was infiltrated with epinephrine (concentration 1:200 000), and a free graft of buccal mucosa was harvested, with care taken to avoid injury to stensen's duct. edges of the buccal mucosa at the harvest site were approximated with 4-0 suture in a simple running fashion. the graft was defatted and tubed around an 18-f nelaton catheter using a series of interrupted 4-0 polyglactin sutures. these sutures also were used to anastomose the graft to both ends of the urethra after resection of fibrotic tissue through a midline perineal incision. a penrose drain was left in place for 2 postoperative days. a 16-f silicone urethral catheter was left in place for 3 weeks postoperatively. suprapubic drainage continued until patency of the urethra could be ensured by postoperative antegrade cystourethrography. all patients were followed with urine culture, periodic urine flowmetry, and cystourethrography at 6 and 12 months. stricture recurrence was defined as developing symptoms that required urethrography or urethroscopy to confirm the diagnosis of stricture, or finding an abnormality on follow-up. data were analyzed using the wilcoxon rank sum test to compare the uroflowmetry results before and after intervention, and the mannwhitney u, kruskal-wallis, and spearman rank correlation tests to evaluate the effects of preoperative factors on the outcomes. all analyses were done using spss software (statistical package for the social sciences, version 9.0, spss inc, chicago, ill, usa). results the mean length of the urethral defect was 4.9 ± 0.99 cm (range, 3 to 6.2 cm). none of the patients were able to void; thus, uroflowmetry could not be performed preoperatively. the most common cause of urethral stricture was pelvic fracture (70%). the majority of the cases were posterior urethral strictures (80%). all patients completed the study, and buccal mucosal graft urethroplasty was technically successful in all of the patients. the mean operative time was 150 minutes (range, 120 to 210 minutes). none of the patients required a blood transfusion. mean follow-up was 22 months (range, 10 to 30 months). patient characteristics and procedural outcomes are listed in table 1. early complications consisted of cheek edema in 2 patients with spontaneous resolution, and perineal wound infection in 1 patient, which was treated using empiric antibiotic therapy. stricture recurred in 3 patients within 90 days (range, 10 to 90 days). all of these patients had a long urethral defect (≥ 5 cm), and 2 had 2 previous failed urethroplasties. urethrography results were satisfactory in the other 7 patients who showed no evidence of a reduced caliber or other abnormality (figure 1). none required intervention on follow-up. the average urinary flow rate increased significantly (from 0 to 10.4 ± 7.33 ml/s) postoperatively buccal mucosal graft in repeat urethroplasty208 (p = .018). the primary etiology and the stricture site did not affect the postoperative uroflowmetry results (p = .11 and p = .08). longer strictures were responsible for poorer graft urethroplasty outcomes (lower urinary flow rates) (p = .001). although 2 of the 3 patients with failed operations had more than 1 previous operation (compared with 1 of 7 patients with successful operations), no statistically significant difference was found (p = .52) discussion urethroplasty with genital skin flaps and buccal mucosal grafts is the most dependable singlestage procedure for urethral strictures longer than 3 cm.(5) fig. 1. a. preoperative cystourethrography of a 40-year-old man with ruptured posterior urethra due to blunt trauma, b. cystourethrography of the same patient, 6 months postoperatively table 1. demographic and clinical characteristics of 10 patients with failed previous urethroplasties who underwent buccal mucosal graft urethroplasty *failed buccal mucosal grafts age (year) etiology of urethral stricture site of lesion number of prior operations length of lesion (cm) preoperative average urinary flow rate (ml/s) postoperative average urinary flow rate at 12 months (ml/s) 12 prior surgery anterior 1 3 0 18 25 * pelvic fracture posterior 2 6 0 0 26 pelvic fracture posterior 2 4 0 16 29 * pelvic fracture posterior 2 5 0 0 35 straddle injury posterior 1 5 0 15 42 pelvic fracture posterior 1 5 0 14 47 * pelvic fracture posterior 1 6 0 0 19 straddle injury anterior 1 4 0 15 24 pelvic fracture posterior 1 6 0 12 patients 25 pelvic fracture posterior 1 5 0 14 a b mehrsai et al 209 buccal mucosa has a thick epithelium rich in elastin that makes it easy to handle and durable. the lamina propria is thin compared with the bladder mucosa and skin, which facilitate inoculation and neovascularization. it has a high capillary density and is easily harvested.(6) such grafts may offer no advantage in terms of graft survival and stricture cure, but they are easier and quicker to apply than a flap and leave no visible scar.(2) split skin grafts are not satisfactory for urethroplasty because they contract by as much as 50%.(2) it is believed that the buccal cheek mucosa and the mucosa of the inner aspect of the lip are preferred for urethral repair on the shaft of the penis and the glandular urethra, respectively.(2) we used the mucosa of the inner cheek for all of our patients. also, buccal mucosa has a slight tendency to contract by about 10%. thus, we harvest a slightly larger strip in all cases. venn and mundy have shown that the early results of buccal mucosal graft urethroplasty are encouraging (45% success rate).(7) in 1998, wessells and mcaninch reviewed the literature on free-graft and pedicled skin-flap urethroplasty. they have claimed that free grafts are successful in 84.3% of patients, and flaps are successful in 85.9% of patients. they also have shown that the buccal mucosal graft is the most successful method of reconstructing bulbar urethral strictures.(1) a literature review shows that the average success rate of grafts and flaps in urethroplasty is about 85%.(2) we had a 70% success rate, which could be related to the inherent nature of these lesions in which ischemia due to repeat surgeries was a problem. onlay grafts usually have better results than do tubed grafts.(8) wessells and mcaninch have attributed the superior results of onlay versus tubed grafts to the preservation of spongy tissue that serves as a graft bed.(9) we were obliged to use the tubed grafts because of extensive fibrosis and dissection. graft urethroplasty may be associated with meatal prolapse, stricture, and fistula formation.(5) we did not encounter any of these complications during follow-up. in 3 patients, stricture recurred within 3 months. age, urethral defect length, number of previous operations, extent of dissection, and the primary etiology of the urethral stricture may have some roles. in addition, recipient site vascularity is very important to neovascularization and graft take.(8) regarding our results, the primary etiology, stricture site, and multiple operations had no significant effect on postoperative uroflowmetry. we found an association only between urethral stricture length and outcome. a success rate of 55% has been reported for use of tubed grafts in anterior urethral strictures.(7) the 100% success rate in our patients with anterior urethral stricture may be due to the low number of patients examined and the etiologies of their diseases. also, releasing the anterior urethra is much easier than releasing the posterior part, and subsequently, anastomosis and outcome appear to be more promising. conclusion our results lend credence to the idea that use of buccal mucosal grafts is acceptable for patients with failed previous urethroplasties. the graft is an excellent source of material for urethral replacement in complex urethroplasties. as substitution urethroplasty has an annual attrition rate, the results of this study (70% success rate at an average of 22 months' follow-up) should be confirmed by long-term studies. acknowledgement we wish to thank drs rahimi and saraji for their help with this manuscript. references 1. wessells h, mcaninch jw. current controversies in anterior urethral stricture repair: free-graft versus pedicled skin-flap reconstruction. world j urol. 1998; 16:175-80. 2. andrich de, mundy ar. substitution urethroplasty with buccal mucosal-free grafts. j urol. 2001; 165:1131-3; discussion 1133-4. 3. humby g. a one stage operation for hypospadias. br j surg.1941; 29: 84-92. 4. burger ra, muller sc, el-damanhoury h, tschakaloff a, riedmiller h, hohenfellner r. the buccal mucosal graft for urethral reconstruction: a preliminary report. j urol. 1992;147:662-4. 5. zinman l. optimal management of the 3to 6-centimeter anterior urethral stricture. curr urol rep. 2000; 1:180-9. 6. duckett jw, coplen d, ewalt d, baskin ls. buccal mucosal urethral replacement. j urol. 1995; 153:1660-3. 7. venn sn, mundy ar. early experience with the use of buccal mucosa for substitution urethroplasty. br j urol. 1998; 81:738-40. 8. el-sherbiny mt, abol-enein h, dawaba ms, ghoneim buccal mucosal graft in repeat urethroplasty210 ma. treatment of urethral defects: skin, buccal or bladder mucosa, tube or patch? an experimental study in dogs. j urol. 2002; 167:2225-8. 9. wessells h, mcaninch jw. use of free grafts in urethral stricture reconstruction. j urol. 1996; 155:1912-5. 1253vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l department of urology, s.b. ankara dıskapı yıldırım beyazıt training and research hospital, ankara, turkey. can tuygun, ufuk ozturk, hasan nedim goksel goktug, kursad zengin, nevzat can sener, hasan bakirtas evaluation of frozen section results in patients who have suspected testicular masses: a preliminary report corresponding author: can tuygun, md s.b ankara dışkapı eğitim ve araştırma hastanesi, üroloji kliniği sekreterliği, altındağ, ankara, turkey. tel: +90 312 418 28 78 fax: +90 312 442 52 24 e-mail: drct36@hotmail.com received april 2013 accepted december 2013 purpose: to report our experience with patients who have suspected testicular masses (stm) managed by ex vivo technique of testicular sparing surgery (tss) after radical orchiectomy. materials and methods: between 2007-2011 years, 10 patients with stm were evaluated by history, physical examination, testicular ultrasound and serum tumor markers. stm were defined as; no paratesticular lesions, size of the lesion smaller than 20 mm, and no known presence of elevated tumor markers or metastatic disease. the principles of tss followed by radical orchiectomy were applied to the removed surgical specimen. excised mass, multiple biopsies of the adjacent parenchyma and the remaining testis were sent for frozen-section analysis (fsa). histopathologic sections were re-reviewed for definitive pathologic diagnosis. results: the mean patient age, mean size and mean length of history of stm were 37 years (25-64), 17.5 mm (10-20) and 6 months (2-12). all stm were palpable and painless. tumor markers were negative in all patients. six tumors were benign (2 adenomatoid tumor, 1 epididymitis nodosa, 1 leydig cell tumor, 1 sertoli cell tumor, 1 fibrous pseudotumor) and 4 tumors were malignant (3 seminoma, 1 embryonal carcinoma) on definitive pathologic diagnosis. excluding one benign lesion, fsa correctly determined 9 lesions and all malignant lesions. three patients had testicular intraepithelial neoplasia (ones seminoma, ones embryonal carcinoma, ones adenomatoid tumor). conclusion: our preliminary report reveals that stm tend to be benign rather than malignant in nature. also, a careful patient selection and an accurate fsa are crucial points for tss and it has the potential to become the primary option in selected patients who have testicular lesions instead of the traditional method. keywords: organ sparing treatments; prognosis; testicular neoplasms; testis; pathology; surgery; frozen sections; humans. urological oncology 1254 | introduction recently, the extensive use of scrotal ultrasound (us) for diagnosis of various disorders led to more frequently detection of suspected testicular masses (stm) due to the several reasons. first, it sometimes can be difficult to distinguish benign intratesticular lesions from malignant lesions because of the specificity of imaging findings of us may decrease.(1) second, some patient features such as no palpable lesions on examination of testicles, no elevated serum tumor markers, no testicular lesions with a large diameter, no testicular microlithiasis on us exam, no history of cryptorchidism and no past operation history for testicular cancer are also factors to contribute to inconclusive us results.(2,3,4) on the other hand, radical orchiectomy traditionally has been performed for definitive treatment in the presence of a normal contralateral testicle as 90%-95% of primer testicular masses are malignant germ cell tumors.(5,6) in recent clinical studies, it has been reported that the probability of malignancy of stm can be lower than expected, and unnecessary orchiectomies can be prevented by testis-sparing surgery (tss) using guided frozen-section analysis (fsa) in selected patients with testicular masses.(7,8,9) despite these exciting reports, clinical problems remain on whether to perform tss in patients with stm for following reasons. first, the safety of tss is completely based on the findings of fsa, if surgical principles are respected. therefore, misdiagnosis of a malignancy can result in serious problems on the oncologic outcomes. second, the data of patients with stm is relatively few in the literature as these cases are rarely encountered in urological practice. last, it has been stated by the management guidelines on testicular cancer that tss is not absolutely indicated in patients with stm.(10) for features mentioned above, initially, the surgeons should carefully determine stm cases, and also should be aware of their capability of internal pathological assessment before starting to perform tss. in this preliminary report, we aimed to present the first outcomes in our stm cases that were applied tss with ex vivo approach following radical orchiectomy. material and methods between 2007-2011 years, 10 patients with stm were evaluated by history, physical examination, testicular ultrasound and serum tumor markers, preoperatively. stm were confirmed by two radiologists. patients with stm were defined as; no paratesticular lesions, size of the lesion smaller than 20 mm, normal tumor markers and no presence of known metastatic disease. radical orchiectomy was performed and then, the principles of tss were applied to surgical specimen as in vitro. excised mass, multiple biopsies of the adjacent parenchyma and the remaining testis were sent for fsa like performing a routine tss. histopathologic sections were rereviewed to confirm the results of fsa. results the mean patient age was 37 years ,range (25-64), the mean mass size was 17.5 mm ,range (10-20) and the mean suspected history 6 months ,range (2-12). all of the testicular masses were palpable and painless. preoperatively, serum tumor markers were negative in all patients. all of the patients with stm were consulted by two radiologists. all patients were undergone radical orchiectomy and then, the principles of tss were applied to the removed testicle and obtained specimen was sent to fsa (figure). a benign testicular tumor was found in 6 (2 adenomatoid tumor, 1 epididymitis nodosa, urological oncology figure 1. the macroscopic appearance of excised masses. a) adenomatoid tumor, b) epididymitis nodosa, c) seminoma, d) embryonal carcinoma. 1255vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l 1 leydig cell tumor, 1 sertoli cell tumor, 1 fibrous pseudotumor) and a malignant tumor in 4 (3 seminoma, 1 embryonal carcinoma) of the 10 patients on definitive pathology. comparing the results of fsa and definitive pathology, excluding one benign lesion, fsa correctly determined 9 lesions and all of the malignant lesions. the results of ultrasound, fsa and definitive pathology of patients were shown in table. discussion the results of our study have shown that stm could be benign at a rate of 60% and radical orchiectomy could be avoided by the tss in these patients. we also noticed that our internal pathologic assessment has a high capability to predict pathological outcomes which fsa results are correlated with definitive pathologic outcomes in malignant lesions and nearly all benign lesions. the promising findings of our preliminary study have inspired us to take a step ahead to perform tss from radical orchiectomy. the long established knowledge states the radical orchiectomy as the definitive treatment for all patients with intratesticular masses.(5,6) but radical orchiectomy for any stm could be overtreatment as an unexpected ratio of benign tumors has been encountered.(2) recently, tss is gradually gaining popularity in preventing unnecessary orchiectomies suspected testicular masses and frozen section analysis | tuygun et al table . characteristics of study subjects. patients testicular ultrasonography excised mass multiple biopsies remaining testis definitive pathology no. 1 upper-pole, 15 × 10 mm hypoechoic solid adenomatoid tumor no tumor present no tumor present adenomatoid tumor no. 2 middle-pole, 18 × 11 mm hypoechoic solid embryonal carcinoma no tumor present no tumor present embryonal carcinoma no. 3 upper-pole, 16 × 16 mm hypoechoic solid sex cord stromal tumor no tumor present no tumor present adenomatoid tumor no. 4 upper-pole, 20 × 16 mm hyperechoic solid epididymitis nodosa no tumor present no tumor present epididymitis nodosa no. 5 lower-middle-pole, 20 × 20 mm hypoechoic solid seminoma no tumor present no tumor present seminoma no. 6 lower-middle-pole, 20 × 15 mm hypoechoic solid sex cord stromal tumor no tumor present no tumor present leydig cell tumor no. 7 middle-pole, 15 × 15 mm hyperechoic solid sex cord stromal tumor no tumor present no tumor present sertoli cell tumor no. 8 upper-pole, 16 × 16 mm hyperechoic solid fibrous pseudotumor no tumor present no tumor present fibrous pseudotumor no. 9 middle-pole, 17 × 10 mm hypoechoic solid seminoma no tumor present no tumor present seminoma no. 10 middle pole, 18 × 16 mm hypoechoic solid seminoma no tumor present no tumor present seminoma 1256 | references 1. coret a, leibovitch i, heyman z, goldwasser b, itzchak y. ultrasonographic evaluation and clinic correlation of intratesticular lesions: a series of 39 cases. br j urol. 1995;76:216-9. 2. haas gp, shumaker bp, cerny jc. the high incidence of benign testicular tumors, j urol. 1986;1219-20. 3. kressel k, schnell d, thon wf, heymer b, hartmann m, altwein je. benign testicular tumors: a case for testis preservation? eur urol. 1988;15:200-4. 4. carmignani l, gadda f, gazzano g, et al. high incidence of benign testicular neoplasm diagnosed by ultrasound. j urol. 2003;170:17-6. 5. ulbright tm, amin mb, young rh. tumors of the testis, adnexa, spermatic cord and scrotum. atlas of tumor pathology. third series. washington: american registry of pathology; 1997. 6. jerome pr, graeme ss. neoplasms of the testis. in campbell’s urology, 8th ed. edited by walsh pc, retik ab, vaughan ed, wein aj. philadelphia: w.b saunders co; 2002. vol 4, chapt.81, p. 2876-2919. 7. robertson gsm. radical orchiectomy and benign testicular conditions. br j urol. 1995;82:342-5. 8. connolly ss, d'arcy ft, bredin hc, callaghan j, corcoran mo. value of frozen section analysis with suspected testicular malignancy. urology. 2006;67:162-5. 9. passarella m, usta mf, bıvalacqua tj, hellstrom wj, davis r. testicular-sparing surgery: a reasonable option in selected patients with testicular lesions. bju int. 2003;91:337-40. 10. laguna mp, pizzacaro g, klepp o, algaba f, kisbenedek l, leiva o. eau guidelines on testicular cancer. eur urol. 2001;40:102-10. 11. weissbach l. organ preserving surgery of malignant germ cell tumors. j urol. 1995;153:90-93. urological oncology for patients with stm.(11-14) in these reports, it has been emphasized that stm can be of benign nature in a considerable number of patients and tss can be a better approach than radical orchiectomy. but, clinical trials have provided no strong evidence for the efficacy of tss in patients with stm as only very few clinical studies have been published. also, the validity of tss has still been obscured in the management guideline especially in patients with contralateral “normal” testicle.(10) in the presented report, benign natures of testicular lesions were established by definitive pathology in 6 of 10 patients with stm. because the limited number of patients included in the study and the surgical technique of tss has been carried out as ex vivo approach, it is difficult to suggest tss as the primary treatment choice for all patients with stm. but it has revealed that a curative treatment for 60% of our patients can be established. defining the enrollment criteria has been one of the cornerstones for tss candidates with stm. it has been reported that the probability of benign testicular lesions can be increased if the patients have negative tumor markers or/and have a small diameter of lesions especially.(7,8) in fact, passarella and colleagues reported that the incidence of benign nature of testicular lesions has increased up to 81% in selected cases.(9) the study consisted of patients who had small, palpable testicular lesions and negative serum tumor markers. moreover, non-palpable testicular masses -incidentally detected by ultrasoundin patients with negative tumor markers and small lesions can be reported as better candidates for tss.(15-17) in those studies, the rates of benign testicular lesions were about 60–100%. for our selection criteria, -all patients have had no paratesticular lesions, size of the lesion smaller than 20 mm, normal tumor markers and no presence of known metastatic diseasethe rates of benign testicular lesions were 60%. another critical point of tss is fsa and it has a crucial importance on decision during the operation whether to keep on with tss or not. therefore, an effective communication between surgeons and pathologists is essential to obtain more accurate results and to minimize the number of misdiagnosis. fortunately, both specificity and sensitivity of fsa on predicting the definitive diagnosis in stm patients is almost 100%, if the surgical principles were respected (4,18). our report revealed a relatively high concordance between the frozen-section findings and the definitive histologic results. conclusion our preliminary report reveals that stm tend to be benign rather than malignant in nature. the selection of patients with stm, the correct application of surgical principles of sparing surgery and the results of fsa are the important aspects for tss. also, the surgeons should be aware of the capability of own’s pathology unit before the beginning to perform tss. we think that tss may be a potential treatment option for patients with stm in our center instead of radical orchiectomy in the future. conflict of interest none declared. 1257vol. 11 | no. 01 | jan-feb 2014 |u r o lo g y j o u r n a l references 1. coret a, leibovitch i, heyman z, goldwasser b, itzchak y. ultrasonographic evaluation and clinic correlation of intratesticular lesions: a series of 39 cases. br j urol. 1995;76:216-9. 2. haas gp, shumaker bp, cerny jc. the high incidence of benign testicular tumors, j urol. 1986;1219-20. 3. kressel k, schnell d, thon wf, heymer b, hartmann m, altwein je. benign testicular tumors: a case for testis preservation? eur urol. 1988;15:200-4. 4. carmignani l, gadda f, gazzano g, et al. high incidence of benign testicular neoplasm diagnosed by ultrasound. j urol. 2003;170:17-6. 5. ulbright tm, amin mb, young rh. tumors of the testis, adnexa, spermatic cord and scrotum. atlas of tumor pathology. third series. washington: american registry of pathology; 1997. 6. jerome pr, graeme ss. neoplasms of the testis. in campbell’s urology, 8th ed. edited by walsh pc, retik ab, vaughan ed, wein aj. philadelphia: w.b saunders co; 2002. vol 4, chapt.81, p. 2876-2919. 7. robertson gsm. radical orchiectomy and benign testicular conditions. br j urol. 1995;82:342-5. 8. connolly ss, d'arcy ft, bredin hc, callaghan j, corcoran mo. value of frozen section analysis with suspected testicular malignancy. urology. 2006;67:162-5. 9. passarella m, usta mf, bıvalacqua tj, hellstrom wj, davis r. testicular-sparing surgery: a reasonable option in selected patients with testicular lesions. bju int. 2003;91:337-40. 10. laguna mp, pizzacaro g, klepp o, algaba f, kisbenedek l, leiva o. eau guidelines on testicular cancer. eur urol. 2001;40:102-10. 11. weissbach l. organ preserving surgery of malignant germ cell tumors. j urol. 1995;153:90-93. 12. kırkalı z, tuzel e, candan ae, mungan mu. testis sparing surgery for the treatment of a sequential bilateral testicular germ cell tumor. int j urol. 2001;8:710-2. 13. heidenreich a, holtl w, albrect w, pont j, engelmann uh. testis-preserving surgery in bilateral germ cell tumors. br j urol. 1997;79:2537. 14. elert a, olbert p, hegele a, barth p, hofmann r, heidenreich a. accuracy of frozen section examination of testicular tumors of uncertain origin. eur urol. 2002;41:290-3. 15. horstman wg, haluszka mm, burkhard tk. management of testicular masses incidentally discovered by ultrasound. j urol. 1994;151:1263-5. 16. sheynkin yr, sukkarieh t, lipke m, cohen hl, schulsinger da. management of nonpalpable testicular tumors. urology. 2004;63:11637. 17. comiter cv, benson cj, capelouto cc, et al. nonpalpable intratesticular masses detected sonographically. j urol. 1995;154:1367-9. 18. tokuç r, sakr w, pontes je, haas gp. accuracy of frozen section examination of testicular tumors. urology. 1992;40:512-6. suspected testicular masses and frozen section analysis | tuygun et al urol_v03_no3_001_editorial.indd pediatric urology urology journal vol 3 no 3 summer 2006 139 technetium tc 99m dimercaptosuccinic acid renal scintigraphy in diagnosis of urinary tract infections in children with negative culture ahmad ali nikibakhsh,1 zahra yekta,2 hashem mahmoodzadeh,1 mohammad karamiyar,1 mehdi fazel3 introduction: the aim of this study was to evaluate the accuracy of technetium tc 99m dimercaptosuccinic acid (99mtc-dmsa) renal scintigraphy in the diagnosis of urinary tract infection (uti) in children with suspected infection but with a negative urine culture. materials and methods: the records of all children with suspected or definite diagnosis of uti presented during a 2-year period were reviewed in this study. abnormal findings on renal scintigraphy, voiding cystourethrography (vcug), and ultrasonography were evaluated and compared between the patients with the definite diagnosis of uti and those with suspected uti and negative urine cultures. results: of 210 patients, 86 had a definite diagnosis of uti (group 1) and 124 had suspected uti without a positive culture (group 2). abnormal findings on dmsa scans were seen in 76 patients (88.4%) in group 1 and 84 (67.7%) in group 2. vesicoureteral reflux was detected by vcug in 50% and 32.3% of the patients in groups 1 and 2, respectively. in group 2, vesicoureteral reflux was seen in 40.5% of the patients with abnormal dmsa scan. ultrasonography findings were abnormal in 51.3% and 39.8% of the patients with abnormal dmsa scan findings in groups 1 and 2, respectively. conclusion: according to our findings, in children with a negative urine culture and abnormal urinalysis, 99mtc-dmsa renal scintigraphy is helpful in diagnosing uti and vesicoureteral reflux; we recommend vcug when dmsa scan supports uti despite a negative urine culture and a normal ultrasongraphy. urol j (tehran). 2006;3:139-44. www.uj.unrc.ir keywords: urinary tract infection, vesicoureteral reflux, dimercaptosuccinic acid scan 1department of nephrology, imam khomeini hospital, urmia university of medical sciences, urmia, iran 2department of social medicine, urmia university of medical sciences, urmia, iran 3department of nuclear medicine, imam khomeini, urmia university of medical sciences, urmia, iran corresponding author: ahmad ali nikibakhsh, md pediatric nephrology department, emam khomeini hospital, urmia, iran tel: +98 441 346 1524 e-mail: anikibakhsh@yahoo.com received october 2005 accepted may 2006 introduction urinary tract infection (uti) is considered as a complicated disease in childhood and its recurrence may result in damage to the kidneys, finally leading to chronic kidney disease at puberty.(1-5) the symptoms of uti are nonspecific in children (including malnutrition, diarrhea, vomiting, restlessness, and failure to thrive). on the other hand, urine sampling from most children is difficult in outpatient settings. therefore, the diagnosis of uti with the classic criteria used for adult patients is not always possible in children. this may lead to missed diagnosis of uti in this group of patients.(4,6-8) furthermore, in young ages, the probability of damage to the kidney parenchyma is high and it may result in irreversible complications. thus, early diagnosis of uti requires more sensitive techniques. renal scintigraphy using technetium tc renal scintigraphy and urinary tract infections—nikibakhsh et al 140 urology journal vol 3 no 3 summer 2006 99m dimercaptosuccinic acid (99mtc-dmsa) is one of the imaging methods with a significant role in the diagnosis of both acute pyelonephritis and its complications on the kidney parenchyma.(9-16) suprapubic sampling is not a routine technique for detection of uti in out-patient setting; therefore, 99mtc-dmsa renal scintigraphy may be helpful in children at the risk of kidney scarring.(17,18) the aim of this study was to evaluate the accuracy of this technique in the diagnosis of uti in children with suspected infection but a negative urine culture. materials and methods the records of all children with a suspected or definite diagnosis of uti presented to imam khomeini hospital of urmia between 2000 and 2002 were reviewed in this study. the children were divided into groups 1 and 2 based on the following characteristics: group 1 consisted of the children with the definite diagnosis of acute pyelonephritis according to the concurrent signs of an auxiliary temperature over 37.5˚c, a positive urine culture for a microorganism with a colony count of 105 or greater (using urinebag sampling), and pyuria (more than 8 white blood cells per high-power microscopic field [hpf]). group 2 consisted of the children with the diagnosis of uti but a negative urine culture. diagnosis had been made in the absence of the classic criteria in favor of uti, with (1) nonspecific symptoms, (2) abnormal urinalysis results including more than 8 white blood cells per hpf solely or accompanied by microscopic hematuria, or more than 5 red blood cells per hpf solely or with pyuria, and (3) a colony count of less than 102 for a microorganism cultured in a urine-bag sample or the mixed/negative urine culture of the microorganisms. for editorial comment see p 143 reports of renal scintigraphy with 99mtc-dmsa were reviewed and the results were considered abnormal if a significant decreased radioisotope uptake in the renal cortex (cortical inflammation) and obvious defects in the kidney contours (scar formation) were present.(9,10) voiding cystourethrography (vcug) and ultrasonography (us) had been performed in all children of both groups. voiding cystourethrography would be performed if dmsa scan and us revealed abnormal findings or if recurrent pyuria or microscopic hematuria (in more than 3 laboratory studies) were present. the results of dmsa scan, vcug, and us were compared between the 2 groups. the chi-square test was used for comparison of qualitative variables. results of 210 patients, 86 had a definite diagnosis of uti (group 1) and 124 had a suspected uti without a positive urine culture (group 2). in group 2, there were 35 boys (28.2%) and 89 girls (71.8%), with a mean age of 6.0 ± 1.7 years. thirtythree (26%) patients were younger than 1 year old, 45 (33%) were 1 to 5, 35 (28%) were 6 to 10, and 11 (13%) were older than 10 years old. in this group, 84 patients (67.7%) had abnormal findings on dmsa scans (table 1), of whom 22 (26.2%) were boys, 62 (73.8%) were girls, and 48 (57.1%) were 5 years old or younger. vesicoureteral reflux (vur) was detected by vcug in 50% and 32.3% of the patients in groups 1 and 2, respectively (table 1). detection of vur reached 40.5% in group 2 when dmsa scan was abnormal (table 2). in addition, there were 34 children in group 2 with normal dmsa scan and us that only 3 of them had vur. reflux grades in the patients of group 2 are demonstrated in table 3. ultrasonography findings were abnormal in 51.3% and 39.8% of the patients with abnormal dmsa scan in groups 1 and 2, respectively (table 4). the detected abnormalities on us of the patients in group 2 are shown in table 5. table 1. results of diagnostic tools in patients with definite diagnosis of uti (group 1) and those with a suspected uti (group 2)* *values in parentheses are percents. uti indicates urinary tract infection; dmsa, dimercaptosuccinic acid; vcug, voiding cystourethrography; and us, ultrasonography. group 1 group 2 diagnostic tool abnormal normal abnormal normal dmsa scan 84 (67.7) 40 (32.3) 76 (88.4) 10 (11.6) vcug 40 (32.3) 84 (67.7) 43 (50) 43 (50) us 40 (32.3) 84 (67.7) 43 (50) 43 (50) renal scintigraphy and urinary tract infections—nikibakhsh et al urology journal vol 3 no 3 summer 2006 141 table 3. grade of vur in patients with suspected uti (group 2)* *values in parentheses are percents. uti indicates urinary tract infection and vur, vesicoureteral reflux. unilateral involvement bilateral involvement vur grade right left right left mild (grades 1 and 2) 8 (53.3) 6 (50) 3 (23.1) 3 (23.1) moderate (grade 3) 6 (40) 6 (50) 9 (69.2) 8 (61.5) severe (grades 4 and 5) 1 (6.7) 0 (0) 1 (7.7) 2 (15.4) total 15 12 13 13 table 2. results of dmsa scan and vcug in patients with definite diagnosis of uti (group 1) and those with suspected uti (group 2)* *values in parentheses are percents. uti indicates urinary tract infection; dmsa, dimercaptosuccinic acid; and vcug, voiding cystourethrography. †p = .50. ‡p = .005. vcug groups abnormal normal total dmsa scan in group 1 † abnormal 39 (51.3) 37 (48.7) 76 normal 4 (40) 6 (60) 10 total 43 (50) 43 (50) 86 dmsa scan in group 2 ‡ abnormal 34 (40.5) 50 (59.5) 84 normal 6 (15) 34 (85) 40 total 40 (32.3) 84 (67.7) 124 table 4. results of dmsa scan and us in patients with definite diagnosis of uti (group 1) and those with suspected uti (group 2)* *values in parentheses are percents. uti indicates urinary tract infection; dmsa, dimercaptosuccinic acid; and us, ultrasonography. †p = .50. ‡p = .005. us groups abnormal normal total dmsa scan in group 1 † abnormal 39 (51.3) 37 (48.7) 76 normal 4 (40) 6 (60) 10 total 43 (50) 43 (50) 86 dmsa scan in group 2 ‡ abnormal 34 (40.5) 50 (59.5) 84 normal 6 (15) 34 (85) 40 total 40 (32.3) 84 (67.7) 124 the associations of the clinical and paraclinical findings with dmsa scan results are shown in table 6. there were no association of dmsa scan results with fever, pyuria, hematuria, leukocytosis, erythrocyte sedimentation rate, and c-reactive protein. discussion in our study, the frequency of abnormal dmsa scan in children with a definite diagnosis of uti was 88.4%, which agrees with most of the previous studies.(9-11,13,16,19,20) in the children with a probable diagnosis of uti (with abnormal findings on urinalysis and a negative culture), 67.7% had an table 5. abnormal findings on us in patients with suspected uti (group 2)* *values in parentheses are percents. uti indicates urinary tract infection and us, ultrasonography. †more than 2 mm with a full bladder and more than 5 mm with an empty bladder findings patients mild hydronephrosis 11 (27.5) calculi 3 (7.5) more than 2 cm difference in sizes of the kidneys 10 (25) increased echogeneity of the kidney parenchyma 8 (20) ectopic kidney 1 (2.5) doubled system 2 (5) increased thickness of the bladder † 5 (12.5) total 40 (100) renal scintigraphy and urinary tract infections—nikibakhsh et al 142 urology journal vol 3 no 3 summer 2006 abnormal dmsa scan. also, fever was not present in nearly half of the patients with an abnormal dmsa scan which shows that there is no specific hallmark such as fever in patients with uti. ultrasonography was not as accurate as 99mtcdmsa renal scintigraphy for showing the pathologic changes in the kidney due to uti; in our study, the us findings were abnormal in 40.5% and 51.3% of those with abnormal dmsa scan in groups 1 and 2, respectively. in other studies, the same results have been reported.(19,20) in a study on 89 children with uti, approximately 50% of normal kidneys on us showed either suspected or established scars on dmsa scan.(20) however, morin and colleagues have reported better results by high-resolution us.(12) in most studies,(15,20-22) detection rate of vur in uti has been reported to be 30% to 50%. in our study, abnormal dmsa scan was associated with vur. in group 2, vur was present in one-third of the patients, and we could find vur in 40.5% of the patients with an abnormal dmsa scan as a criterion of uti diagnosis when the urine culture was negative. when uti is accompanied by an abnormal finding on renal scintigraphy, it is a main risk factor of damaging the kidney parenchyma even without the existence of vur(13,15); therefore, using 99mtc-dmsa renal scintigraphy can be emphasized when the diagnosis of uti is uncertain.(3,13-15,18,20,22) we found that vur in the patients with abnormal dmsa scan was more frequent when the urine culture was positive for uti. we reviewed the records of the patients to find out the probable cause of such a difference. most of the patients in group 1 had recurrent pyelonephritis. this finding may be an explanation for the significant difference mentioned. such a difference has also been demonstrated in other studies.(10,18) nammalwar and colleagues studied 2 groups of children with pyelonephritis with positive and negative urine cultures. of children with a positive urine culture, 92.9% had features of pyelonephritis on dmsa scan, of whom 82.1% had vur, while in children with a negative urine culture and a positive dmsa scan, 65.4% had vur.(18) levtchenko and coworkers evaluated the diagnosis of acute pyelonephritis with negative urine culture. sixty percent of patients with clinical and scintigraphic evidence of pyelonephritis had vur. this emphasizes the helpful role of renal scintigraphy for diagnosing vur in the group of patients with pyelonephritis and negative urine culture.(10) the rate of vur is higher in the abovementioned study compared to our report which may be due to the selection of only febrile patients in these studies. there are also some limited studies on renal scintigraphy in febrile children with unknown etiology. it has been shown that renal scintigraphy can reveal uti in such cases.(10,17,18) conclusion urinary tract infection is a very common disease in children and may be easily neglected. renal scintigraphy using 99mtc-dmsa helps in the diagnosis of uti in pediatric cases with unknown etiology. our findings showed that an abnormal dmsa scan is a guidance to perform vcug for the detection of vur. according to our results, in children with a negative urine culture and abnormal urinalysis, us and dmsa scan help us decide whether to perform vcug or not; vcug is most probably negative for vur if the results of us and dmsa scan are normal and enough evidence in favor of uti lacks. in contrast, we recommend vcug when dmsa table 6. results of dmsa scan in association with clinical and paraclinical findings in patients with suspected uti (group 2)* *values in parentheses are percents. dmsa indicates dimercaptosuccinic acid; esr, erythrocyte sedimentation rate; and crp, c-reactive protein. dmsa scan findings abnormal normal total p fever 47 (56) 20 (50) 67 (54.0) .53 pyuria 70 (83.3) 35 (87.5) 105 (86.7) .54 hematuria 47 (56) 23 (57.5) 70 (56.5) .87 peripheral blood leukocytosis 42 (50) 23 (57.5) 65 (52.4) .43 esr (more than 20 mm/h) 40 (47.6) 16 (40) 56 (45.2) .42 crp 2+ 10 (11.9) 6 (15) 16 (12.9) .63 crp 3+ 10 (11.9) 7 (17.5) 17 (13.7) .39 renal scintigraphy and urinary tract infections—nikibakhsh et al urology journal vol 3 no 3 summer 2006 143 scan supports uti despite a negative urine culture and a normal us. conflict of interest none declared. references 1. rubenstein jn, schaeffer aj. managing complicated urinary tract infections: the urologic view. infect dis clin north am. 2003;17:333-51. 2. practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. american academy of pediatrics. committee on quality improvement. subcommittee on urinary tract infection. pediatrics. 1999;103:843-52. 3. panaretto k, craig j, knight j, howman-giles r, sureshkumar p, roy l. risk factors for recurrent urinary tract infection in preschool children. j paediatr child health. 1999;35:454-9. 4. pylkkanen j, vilska j, koskimies o. diagnostic value of symptoms and clean-voided urine specimen in childhood urinary tract infection. acta paediatr scand. 1979;68:341-4. 5. bagga a, babu k, kanitkar m, srivastava rn; indian pediatric nephrology group. indian academy of pediatrics. consensus statement on management of urinary tract infections. indian pediatr. 2001;38:1106-15. 6. hansson s, brandstrom p, jodal u, larsson p. low bacterial counts in infants with urinary tract infection. j pediatr. 1998;132:180-2. 7. pead l, maskell r. study of urinary tract infection in children in one health district. bmj. 1994;309:631-4. 8. ramage ij, chapman jp, hollman as, elabassi m, mccoll jh, beattie tj. accuracy of clean-catch urine collection in infancy. j pediatr. 1999;135:765-7. 9. biggi a, dardanelli l, pomero g, et al. acute renal cortical scintigraphy in children with a first urinary tract infection. pediatr nephrol. 2001;16:733-8. 10. levtchenko en, lahy c, levy j, ham hr, piepsz a. role of tc-99m dmsa scintigraphy in the diagnosis of culture negative pyelonephritis. pediatr nephrol. 2001;16:503-6. 11. biggi a, dardanelli l, cussino p, et al. prognostic value of the acute dmsa scan in children with first urinary tract infection. pediatr nephrol. 2001;16:800-4. 12. morin d, veyrac c, kotzki po, et al. comparison of ultrasound and dimercaptosuccinic acid scintigraphy changes in acute pyelonephritis. pediatr nephrol. 1999;13:219-22. 13. camacho v, estorch m, fraga g, et al. dmsa study performed during febrile urinary tract infection: a predictor of patient outcome? eur j nucl med mol imaging. 2004;31:862-6. 14. hansson s, dhamey m, sigstrom o, et al. dimercapto-succinic acid scintigraphy instead of voiding cystourethrography for infants with urinary tract infection. j urol. 2004;172:1071-3. 15. moorthy i, easty m, mchugh k, ridout d, biassoni l, gordon i. the presence of vesicoureteric reflux does not identify a population at risk for renal scarring following a first urinary tract infection. arch dis child. 2005;90:733-6. 16. lin ky, chiu nt, chen mj, et al. acute pyelonephritis and sequelae of renal scar in pediatric first febrile urinary tract infection. pediatr nephrol. 2003;18:362-5. 17. kao c, hsieh j, tsai s, et al. using technetium-99m dimercaptosuccinic acid renal cortex scintigraphy to differentiate acute pyelonephritis from other causes of fever in patients with spinal cord injury. urology. 2000;55:658-62. 18. nammalwar br, vijayakumar m, sankar j, ramnath b, prahlad n. evaluation of the use of dmsa in culture positive uti and culture negative acute pyelonephritis. indian pediatr. 2005;42:691-6. 19. moorthy i, wheat d, gordon i. ultrasonography in the evaluation of renal scarring using dmsa scan as the gold standard. pediatr nephrol. 2004;19:153-6. 20. bhatnagar v, mitra dk, agarwala s, et al. the role of dmsa scans in evaluation of the correlation between urinary tract infection, vesicoureteric reflux, and renal scarring. pediatr surg int. 2002;18:128-34. 21. gordon i, barkovics m, pindoria s, cole tj, woolf as. primary vesicoureteric reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and meta-analysis. j am soc nephrol. 2003;14:739-44. 22. mingin gc, nguyen ht, baskin ls, harlan s. abnormal dimercapto-succinic acid scans predict an increased risk of breakthrough infection in children with vesicoureteral reflux. j urol. 2004;172:1075-7. editorial comment the foremost merit of this paper is drawing attention toward an often neglected proportion of cases in which the indolent course of urinary tract infection, unaccompanied by constitutional symptoms, eludes aggressive treatment and follow-up. having conveyed this message, one must bear in mind that a number of ambiguities in their study design preclude any further extrapolation from its data unless they are corroborated by more refined research. sterile pyuria in children, for instance, usually denotes sampling error or partial treatment rather than atypical infection, and therefore cannot be taken as a distinct entity. this is especially true since the history of previous uti has not been recorded. this should have been formally assessed in the culture negative group. lack of a well defined group of normal controls can seriously flaw the significance of dmsa findings in group 2, particularly if the imaging was done in single-photon emission computed tomography renal scintigraphy and urinary tract infections—nikibakhsh et al 144 urology journal vol 3 no 3 summer 2006 format, as apposed to the older pinhole scanning. normal individuals, even without deceptive anatomical aberration of the kidney parenchyma, have been found to have abnormal dmsa scan in up to 35% of cases. an upper pole defect can even be expected to occur in 70% of the studied normal kidneys.(1) practical recommendations must therefore await further study comparing the present findings with a normal group. pejman shadpour hasheminejad kidney center, iran university of medical sciences, tehran, iran references 1. de sadeleer c, bossuyt a, goes e, piepsz a. renal technetium-99m-dmsa spect in normal volunteers. j nucl med. 1996;37:1346-9. reply by author the authors would like to thank dr shadpour and acknowledge his comment. the following explanation may more elucidate the points mentioned. it can be concluded from this study that in the children with the possibility of uti, if pyuria has been repeated for several times and has been accompanied by abnormalities in the dmsa scan, cystography should be performed for detection of the vur. although this finding is often observed in the children, it may be neglected because of the obscure clinical findings. therefore, the diagnosis of uti is delayed and the disease is detected after some irreversible damage to the kidneys. madani and colleagues reported that in iran, the most common cause of the chronic kidney disease in children is reflux nephropathy.(1) in this study, we tried to notify that recurrent pyuria can be a guide for the diagnosis of reflux due to the uti with incomplete criteria. more studies in this regard are warranted. also, the normal variations in dmsa scan, including uptake reduction in the upper pole of the right kidney due to the compressive effect of the liver, have been considered by the authors. overall, dmsa scan is a reliable diagnostic tool in the diagnosis of uti and its sensitivity and specificity have been reported to be high.(2-5) ahmad ali nikibakhsh department of nephrology, imam khomeini hospital, urmia university of medical sciences, urmia, iran references 1. madani k, otoukesh h, rastegar a, van why s. chronic renal failure in iranian children. pediatr nephrol. 2001 feb;16(2):140-4. 2. lee bf, chiou yy, chuang cm, wu ps, wu yc, chiu nt. evolution of differential renal function after acute pyelonephritis. nucl med commun. 2002 oct;23(10): 1005-8. 3. moorthy i, easty m, mchugh k, ridout d, biassoni l, gordon i. the presence of vesicoureteric reflux does not identify a population at risk for renal scarring following a first urinary tract infection. arch dis child. 2005;90:733-6. 4. kao c, hsieh j, tsai s, et al. using technetium-99m dimercaptosuccinic acid renal cortex scintigraphy to differentiate acute pyelonephritis from other causes of fever in patients with spinal cord injury. urology. 2000;55:658-62. 5. nammalwar br, vijayakumar m, sankar j, ramnath b, prahlad n. evaluation of the use of dmsa in culture positive uti and culture negative acute pyelonephritis. indian pediatr. 2005;42:691-6. pictorial prolapsed vaginal ureterocele as a cause of urinary incontinence in a child luca landi,1 antonio elia,1 ottavio adorisio2* a 5-year-old child was referred to our department with a clinical history of urinary incontinence, dysuria and urinary tract infections. physical examination (abdomen and genitalia) was unremarkable. abdominal ultrasonography revealed the presence of a left duplicated system (figure 1a) with normal bladder (figure 1b). antenatal history was unremarkable. magnetic resonance imaging of the abdomen and pelvis was performed in order to clarify the anatomy of the duplicated system (figure 2). voiding cystourethrography showed no vesicoureteral reflux (figure 3) while renal scan showed a poor function of the upper pole. as the patient was complaining of urinary leakage and dysuria, transvaginal voiding vaginoscopy/urethroscopy was performed. vaginoscopy demonstrated the presence of a cystic mass on the left-anterior vaginal wall (figure 4). a 3 french ureteral catheter was inserted and an un-roofing of the ureterocele was performed, followed by a left hemi-nephroureterectomy of the upper pole because of its poor function. in most of reported cases, an interlabial mass is usually evident,(1) conversely, in our case, physical examination was normal and a correct assessment of the anatomical defect was obtained only with endoscopic investigation. approximately 80% of ectopic ureteroceles are associated with the upper pole moiety of a duplex system leading often to urinary retention. conversely, in this case, urinary incontinence was present.(2,3) for this reason, a vaginal prolapsed ectopic ureterocele, despite its rarity, would be considered, as a cause of urinary leakage in a child, especially when radiological imaging is not confirmative. in this situation performing cystoscopy/vaginoscopy is essential in order to make accurate diagnosis. 1 department of pediatric surgery, pediatric urology unit, anna meyer children’s hospital, florence, italy 2 department of pediatric surgery, bambino gesù children’s hospital, rome, italy. *correspondence: department of pediatric surgery, bambino gesù children’s hospital, research institute, via della torre di palidoro, 00050, passoscuro rome, italy. tel: +39 06 68593373. e-mail: odomenico.adorisio@opbg.net. received june 2014 & accepted december 2014. figure 1. (a) ultrasound showing left kidney; (b) ultrasound picture of the bladder. figure 3. voiding cystourethrography. figure 4. vaginoscopy showing the ectopic prolapsed vaginal ureterocele. figure 2. magnetic resonance imaging demonstrates the presence of a left duplicated collecting system (upper pole, bold arrow; lower pole, narrowed arrow; white circle, presumptive insertion of the duplicated system into the bladder without evidence of the ectopic prolapsed ureterocele). pictorial 1999 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2000 references 1. abdelgadir i, mallya p, alam m. ureterocele presenting as a vulval mass in a newborn girl. bmj case rep. 2010;6;2010. 2. arrabal-polo ma, nogueras-ocaña m, tinautranera j, zuluaga-gomez a, arrabal-martin m. vulval tumor in an infant: prolapse of ureterocele. j pediatr. 2012;161:964. 3. minevich e, moayed a, wacksman j, lewis ag, sheldon ca. unusual anatomic presentation of ectopic ureteroceles. j pediatr surg. 1999;34:474-6. prolapsed vaginal ureterocele-adorisio et al vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2010 urological oncology association between tissue mir-141, mir-200c and mir-30b and bladder cancer: a matched case-control study ali mahdavinezhad,1 seyed habibollah mousavibahar,2 jalal poorolajal,3 reza yadegarazari,1 mohammad jafari,4 nooshin shabab,1 massoud saidijam1* purpose: to evaluate the expression of micrornas in tissue samples from patients with bladder cancer and to compare it with healthy adjacent tissue samples as controls. materials and methods: thirty five tissue samples from patients with newly diagnosed untreated bladder transitional cell carcinoma and 35 adjacent normal urothelium were collected during 2013 to 2014. trizol reagent was used to isolate total rna including micrornas. rna concentration and purity were determined using a nanodrop spectrophotometer. also 1% agarose gel electrophoresis was used to assess integrity of rna. real-time quantitative reverse transcription pcr (qrt-pcr) method was performed using the parsgenome microrna rt-pcr system. data was analyzed by stata 11. results: a couple of patients were female the remainder were male. mean age of patients were 71.06 ± 11.43 years. the expression level of mir-30b, mir-141 and mir-200c in case group were significantly higher than that of control normal tissue samples. mir-141 had higher expression rate in malignant tissue than two other mirnas (p < .001). conclusion: there was a more expression rate of mir-200c, mir-141 and mir-30b in bladder cancer tissues than healthy adjacent control tissues. further studies are needed to draw final conclusion. keywords: carcinoma, transitional cell; gene expression regulation; micrornas; genetics; urinary bladder neoplasms. introduction bladder cancer (bc) is the ninth prevalent and the second most common genitourinary tract malignant tumor with high mortality and 70% recurrence rate worldwide.(1,2) it is the fourth most common cancer in western industrialized countries(2,3) and is among the top ten leading causes of cancer death.(4) in 2008 and 2010, 386,300 and 70,530 new cases and 150,200 and 14,680 deaths from bc was estimated worldwide, respectively.(5-7) although the exact pathogenesis of bc is unknown, however, a range of irreversible genetic and reversible epigenetic changes, chromosomal anomalies and genetic polymorphisms involve in tumorigenesis and progression of bc. genetic alterations are important in bc prognosis and treatment.(8,9) micornas (mirnas) are a class of small non-coding rna molecules, almost 22 (18-25 nt) nucleotides, which bind to the 3′ untranslated region of target mrnas to control protein synthesis or degradation of the mrnas. more than 1000 human mirnas are known until now. mirnas regulate protein expression, negatively regulate gene expression and modulate biological processes such as cell differentiation, proliferation, death, apoptosis, metabolism, tumorigenesis, immune response and viral infection. mirnas and changes in their expression may play an important role in initiation, differentiation, suppression and development of various malignant tumors.(1,3,8,10,11) mirnas are obviously expressed in human cancers and affect carcinogenesis and cancer progression. mirnas may be tumor suppressors or oncogenes.(3) different mirnas expression between tumor and normal tissues can identify mirnas involved in carcinogenesis which can be used as novel therapeutic, diagnostic and prognostic markers.(11) altered mirnas expression and function have also been reported as an important modulators in most urologic cancers.(8) higher number of mirnas species have been detected in the samples from patients with urothelial cancers.(12) alteration in mirnas expression may occur early in bc and affect carcinogenesis and tumor behavior.(13) altered mirnas expression in bc first reported in 2007 by gottardo and colleagues.(14) they 1 department of genetics and molecular medicine, research center for molecular medicine, hamadan university of medical sciences, hamadan, iran. 2 urology and nephrology research center, hamadan university of medical sciences, hamadan, iran. 3 department of epidemiology and biostatistics, modeling of non communicable diseases research center, school of public health, hamadan university of medical sciences, hamadan, iran. 4 department of pathology, medical school, hamadan university of medical sciences, hamadan, iran. *correspondence: department of genetics and molecular medicine, research center for molecular medicine, hamadan university of medical sciences, hamadan, iran. tel: +98 912 1324616. fax: +98 81 38380208. e-mail: sjam110@yahoo.com. received august 2014 & accepted december 2014 reported upregulation of 10 mirnas. to date, several large-scale profiling experiments have been described about different mirnas expression in bc.(8,13) dyrskjot and colleagues analyzed 117 samples and found altered expression of many mirnas.(15) therefore changing in mirnas expression play an important role in bladder tumorigenesis. some researchers have reported up-regulation of mir200c, mir-141 cluster,(16) mir-141,(17) mir-200c,(18) mir 200c, hsa-mir-14(19) and mirna 141(20) in bc. other researchers have reported down regulation of mir200 family,(21) mir-141, mir-200c and mir-30b(22) in bc. among these mirnas, in a study, three mirnas panel including mir-200c, mir-141 and mir-30b had a sensitivity of 100% and a specificity of 96.2% to differentiate invasive bc from noninvasive bc.(22) according to sensitivity of mir-200c, mir-30b and mir-141 in tissue samples of patients with bc and controversy among different studies, we aimed to evaluate the level of these mirnas in tissue samples of patients with bc and healthy adjacent tissue samples. materials and methods demographic characteristics of participants in this study 2 females and 33 male were included. twentythree of them lived in urban and the other 12 were from rural areas. twenty-three patients were smoker and 12 were nonsmoker. thirty subjects had no history of carcinogen exposure and 5 had history of carcinogen exposure. the study protocol was approved by the medical ethics committee of the hamadan university of medical science (hamadan, iran) and written informed consent was obtained from all patients after explaining the purpose of the study. inclusion and exclusion criteria we included all eligible patients irrespective of sex and age. all patients had pathologically confirmed bladder transitional cell carcinoma (tcc). the exclusion criteria were patients with other organ cancers, genitourinary infection and history of radiotherapy and chemotherapy. data collection tools a predetermined questionnaire including two parts was used for data-gathering. the first part includes the demographic characteristics of the participants such as sex, age, smoking history, history of exposure to carcinogens and urban/rural residence. the second part of the questionnaire encompasses imaging and pathological findings such as tumor size, grade, muscle invasion and tumor type. tissue sample collection thirty five tissue samples were collected from newly diagnosed and untreated bc. control samples were matched adjacent normal urothelium resected about 10 cm far from the neoplastic lesions. both samples from each subject were washed with rnase-free cold saline solution, snap-frozen in liquid nitrogen and stored at -80ºc until pathologic examination and further analysis.(20) pathological examinations all samples were examined by two pathologists. tumor staging and histological grading were done according to the international union against cancer and world health organization/international society of urological pathology criteria of 2004, respectively. rna extraction trizol reagent (invitrogen corp., carlsbad, ca, usa) was used to isolate total rna including mirnas from about 50 mg tissue samples according to the manufacturer’s instructions. the isolated rna was dissolved in 20-50 µl rnase-free water depending on the amount of precipitation. rna concentration and purity were determined by optical density measurement using a nanodrop spectrophotometer (biotek, winooski, vermont, usa). one percent agarose gel electrophoresis was used to assess integrity of rna. reverse transcription and real-time polymerase chain reaction analysis reverse transcription and real-time polymerase chain reaction (qrt-pcr) steps were completed by the parsgenome microrna rt-pcr system (tehran, iran) according to the manufacturer’s instructions. briefly this system is a three-step protocol. first, poly a enzyme step added a polya tail to 3’ end of rna, second, firststrand cdna synthesis produced specific mir cdna product using specific primers and finally real-time qrt-pcr amplification with sybr green master mix and mir specific primers with thermal cycling was done as follows: polymerase activation/denaturation at 95º, 5 min, 35 amplification cycle including denaturation at 95º, 5 s, annealing at 62º, 20 s, extension at 72º, 30 s and melting curve analysis. to analyze microrna expression by qrt-pcr, 2 µg of rna was reversely transcribed and 50 ng of synthesized cdna used in the parsgenome microrna rt-pcr system in a cfx96 realtime pcr detection system (bio-rad, biosystems, foster city, california, usa). the ct values were normalized using 5s rrna as reference gene. all reactions were run in duplicate and to assess contamination, no template control (ntc) included in each pcr run. all ntc were negative. the 2(-∆∆ ct) method was used to calculate relative quantification of mirna expression. (23,24) mirna ∆∆ct formula is as follow: ∆∆ct = ∆ct1 – ∆ct2 , which ∆ct1 = ct of the mirna target ( tumor sample) – ct of the reference gene ( tumor sample) and ∆ct2 = ct of mirna target ( normal tissue sample) – ct of reference gene ( normal tissue sample). statistical analysis statistical analysis was performed using stata11 (statacorp, college station, tx, usa) software. all values were reported as mean ± sd. the differences in expression levels between case and control was estimated by paired t-test and p value less than .05 was considered as significant. results in this study 70 tissue samples from 35 patients with bc were studied (35 from malignant site and 35 from adjacent normal urothelium). in processing stage two rna samples from each group were damaged; therefore, 66 specimens were studied. all of the cancers were tcc. two (6%) of patients were female and 33 (94%) were male. mean age of the patients were 71.06 ± 11.43 (range, 44-91) years. there was no difference between mean ct values of 5s rrna in two groups (case 14.93 ± 2.05 and control 16.07 ± 3.19, p = .084). therefore, it was suitable as a reference gene to normalize gene expression between malignant and healthy tissues. a single peak was observed on melting curve analysis, confirmed specificity of primers. mir-141, mir-200c and mir-30b and bladder cancer-mahdavinezhad et al urological oncology 2011 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2012 the higher ∆ct means the lower expression; therefore the expression level of mir-30b, mir-141 and mir-200c in case group showed a statistically significant increase compared to control normal tissue samples. overall expression of these mirnas was noticeably upregulated in bc tissue samples than control tissues, but we observed individually that mir-141, mir-200-c and mir-30b were down regulated or unchanged in 3, 7 and 12 of malignant tissue samples, respectively. mean, standard deviation and p value of all mirna are shown in table. as shown in table, mir-141expression level had a closer relationship with malignancy than two other mirnas (p < .001 vs. p = .005). in case group the expression of mir-30b and mir200c was significantly higher than that of control group. mean ∆∆ct of mir-30b, mir-141 and mir-200c were -1.28,-4.30 and -1.60, respectively. average relative quantification of mirnas calculated by applying 2(∆∆ct). table demonstrates average fold change of mir-30b, mir-141 and mir-200c in cancer group compared to control group. mean relative expression of mir-141 was remarkable (mean fold change = 19.7). discussion mirnas play an important role in cancer initiation, progression and metastasis.(25) one systematic review study has concluded that the deregulated mirnas are common in bc.(26) limited studies have investigated the exact function of mirnas and their roles in bc. the results of this study were similar to han and colleagues, scheffer and colleagues, xie and colleagues and ratert and colleagues studies.(16,17,19,20) han and colleagues reported that mir200c and mir-141 are upregulated in bc compared to healthy control group.(16) in scheffer and colleagues’ research mir-141 level has increased in bc patients compared to control.(17) ratert and colleagues investigated mirna profile for bc diagnosis and clinical outcome. mir-141 was one of the seven upregulated mirnas.(20) hsa-mir -200c and mir-141 were also upregulated in infiltrating bc compared to non-infiltrating cancer.(19) the other research identified low expression of mir-30b, mir-31, mir-141, mir-200a, mir-200b and mir-200c in invasive bc cell lines as well as mir-21 and mir-99a, which showed high expression in the same cell lines.(22) in contrast to our study results, wszolek and colleagues demonstrated that expression of mir-30b, mir-141 and mir-200c was reduced in invasive bc.(22) this may be due to different study design which they investigated invasive and non-invasive bc but we compared bc tissue with normal tissue. mir-200 family in wang and colleagues’ study was down regulated in urine of bc patients.(21) in advanced cancer, mir-200 family (mir-200a,-200b, -200c, -141 and -429) are frequently silenced and play a role in epithelial to mesenchymal transition.(27) in a research, mirna expression was correlated with tumor grade, size and presence of carcinoma in situ for mir-222, recurrence (mir-222 and mir-143), progression (mir222 and mir-143), disease specific survival (mir-222), and overall survival rate (mir-222).(13) in this study we did not evaluate clinical and histological parameter of bc and mirna expression. further longitudinal studies are needed to determine the association between mirna expression with different stage, grade and other clinicopathologic features of bc. mir-200c, mir-141 and mir-30b are best classifier of invasive from noninvasive bc, and poor prognosis is linked to low levels of these three mirnas.(22) different results may be explained by different methods, regions, genetics and epigenetics alterations, lifestyles, study population, sample size, tumor grade and stage. follow up of bc patients demonstrated that down regulation of mir-200c expression is related to progression of cancer to muscle and is associated with poor prognosis. therefore mir-200c expression can be helpful in prediction of bc progression and treatment decisions.(27) song and colleagues demonstrated that, mir200c, mir-141 and mir-30b potentially can be used to diagnose invasive bladder tumors that were misdiagnosed in pathologic assessment of bladder biopsy specimens.(11) according to another study some of mirnas were down regulated in low grade and upregulated in high grade bc.(8) certain mirnas may have therapeutic effects on bc.(5) epithelial to mesenchymal transition is regulated by mir-200 expression in the bc cells and helps treatment with epidermal growth factor receptor.(28) conclusion we demonstrated a more expression of mir-200c, mir141 and mir-30b in bc tissues compared to normal healthy adjacent tissues. further studies should be performed about mirna alterations in bc to better understand the role of mirnas in tumor initiation, progression, metastasis and treatment response. acknowledgments this paper is a part of the a. mahdavinezhad phd thesis in molecular medicine. we would like to thank operating room personnel of shaheed beheshti and buali hospitals for their cooperation to prepare the tissue samples. this study was funded by the vice-chancellor of research and technology, hamadan university of medical sciences. conflict of interest variables cases controls difference paired t-test fold change in bc vs. normal number mean sd number mean sd mean p value mir-30b 33 5.16 1.87 33 6.44 1.67 1.28 .005 2.42 mir-141 33 1.44 2.56 33 5.74 2.64 4.30 < .001 19.7 mir-200c 33 -.44 2.46 33 1.16 2.73 1.60 .005 3.03 table. relative expression of the three mirnas in bladder cancer and control tissue. abbreviation: bc, bladder cancer. mir-141, mir-200c and mir-30b and bladder cancer-mahdavinezhad et al none declared. references 1. yoshino h, enokida h, chiyomaru t, et al. tumor suppressive microrna-1 mediated novel apoptosis pathways through direct inhibition of splicing factor serine/arginine-rich 9 (srsf9/ srp30c) in bladder cancer. biochem biophys res commun. 2012;417:588-93. 2. shirodkar sp, lokeshwar vb. potential new urinary markers in the early detection of bladder cancer. curr opin urol. 2009;19:488-93. 3. tatarano s, chiyomaru t, kawakami k, et al. mir-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer. int j oncol. 2011;39:13-21. 4. parker j, spiess pe. current and emerging bladder cancer urinary biomarkers. scientificworldjournal. 2011;11:1103-12. 5. chen h, lin y-w, mao y-q, et al. microrna449a acts as a tumor suppressor in human bladder cancer through the regulation of pocket proteins. cancer lett. 2012;320:40-7. 6. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin. 2011;61:69-90. 7. ploeg m, aben kk, kiemeney la. the present and future burden of urinary bladder cancer in the world. world j urol. 2009;27:289-93. 8. catto jwf, alcaraz a, bjartell as, et al. microrna in prostate, bladder, and kidney cancer: a systematic review. european urology. eur urol. 2011;59:671-81. 9. lin y, wu j, chen h, et al. cyclin-dependent kinase 4 is a novel target in micorna-195mediated cell cycle arrest in bladder cancer cells. febs lett. 2012;586:442-7. 10. bao b, azmi as, ali s, et al. the biological kinship of hypoxia with csc and emt and their relationship with deregulated expression of mirnas and tumor aggressiveness. biochim biophys acta. 2012;1826:272-96. 11. song t, xia w, shao n, et al. differential mirna expression profiles in bladder urothelial carcinomas. asian pac j cancer prev. 2010;11:905-11. 12. weber ja, baxter dh, zhang s, et al. the microrna spectrum in 12 body fluids. clin chem. 2010;56:1733-41. 13. puerta-gil p, garcia-baquero r, jia ay, et al. mir-143, mir-222, and mir-452 are useful as tumor stratification and noninvasive diagnostic biomarkers for bladder cancer. am j pathol. 2012;180:1808-15. 14. gottardo f, liu cg, ferracin m, et al. microrna profiling in kidney and bladder cancers. urol oncol. 2007;25:387-92. 15. dyrskjot l. classification of bladder cancer by microarray expression profiling: towards a general clinical use of microarrays in cancer diagnostics. expert rev mol diagn. 2003;3:63547. 16. han y, chen j, zhao x, et al. microrna expression signatures of bladder cancer revealed by deep sequencing. plos one. 20110;6:e18286. 17. scheffer ar, holdenrieder s, kristiansen g, von ruecker a, muller sc, ellinger j. circulating micrornas in serum: novel biomarkers for patients with bladder cancer? world j urol. 2014;32:353-8. 18. lee h, jun sy, lee ys, lee hj, lee ws, park cs. expression of mirnas and zeb1 and zeb2 correlates with histopathological grade in papillary urothelial tumors of the urinary bladder. virchows arch. 2014;464:213-20. 19. xie p, xu f, cheng w, et al. infiltration related mirnas in bladder urothelial carcinoma. j huazhong univ sci technolog med sci. 2012;32:576-80. 20. ratert n, meyer ha, jung m, et al. mirna profiling identifies candidate mirnas for bladder cancer diagnosis and clinical outcome. j mol diagn. 2013;15:695-705. 21. wang g, chan es, kwan bc, et al. expression of micrornas in the urine of patients with bladder cancer. clin genitourin cancer. 2012;10:106-13. 22. wszolek mf, rieger-christ km, kenney pa, et al. a microrna expression profile defining the invasive bladder tumor phenotype. urol oncol. 2011;29:794-801.e1. 23. schmittgen t, livak k. analyzing real-time pcr data by the comparative c(t) method. nat protoc. 2008;3:1101-8. 24. livak kj, schmittgen td. analysis of relative gene expression data using realtime quantitative pcr and the 2-∆∆ct method. methods. 2001;25:402-8. 25. martello g, rosato a, ferrari f, et al. a microrna targeting dicer for metastasis control. cell. 2010;141:1195-207. 26. hussain sa, ganesan r, reynolds g, et al. hypoxia-regulated carbonic anhydrase ix expression is associated with poor survival in patients with invasive breast cancer. br j cancer. 2007;96:104-9. 27. wiklund ed, bramsen jb, hulf t, et al. coordinated epigenetic repression of the mir200 family and mir-205 in invasive bladder cancer. int j cancer. 2011;128:1327-34. 28. adam l, zhong m, choi w, et al. mir-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. clin cancer res. 2009;15:5060-72. mir-141, mir-200c and mir-30b and bladder cancer-mahdavinezhad et al urological oncology 2013 1714 | misplaced nephrostomy catheter in left renal vein: a case report of an uncommon complication following percutaneous nephrolithotomy hüseyin tarhan, i̇lker akarken, ozgür cakmak, ertan can, yusuf ozlem ilbey, ferruh zorlu corresponding author; hüseyin tarhan, md 126/7 sok. no.5/3 evka-3 bornova, i̇zmir, turkey. tel: +90 23 2469 6969 fax: +90 23 2433 0756 e-mail: httarhan@yahoo.com received october 2013 accepted april 2014 department of urology, tepecik education and research hospital, i̇zmir, turkey. case report keywords: urologic surgical procedures; methods; nephrostomy; percutaneous; instrumentation; renal vein; injuries. introduction in 1941 rupel and brown used a rigid cystoscope to extract the residual stones through a drain tract following open surgery.(1) that was the beginning idea of endoscopic renal surgery. l shaped endoscopes were used for visualizing calyceal stones during open procedures. the percutaneous nephrostomy was described by goodwin in 1955 as a temporary solution for obstruction secondary hydronephrotic patients.(2) finally, fernstrom and johansson performed percutaneous nephrolithotomy (pcnl) successfully in three patients in 1976.(3) although pcnl is a safe and effective procedure which improves by experience and technology, complications may occur as the procedure in essence is controlled renal trauma. here, we report an uncommon pcnl complication and our management. case report a 48 years old male who had previously undergone a left open nephrolithotomy 5 years prior underwent a left pcnl. pre-operative hemoglobin level was 15.2 g/dl. the stones were in the renal pelvis and inferior pole of the kidney. an 18 gauge, 2 piece entry needle was advanced case report 1715vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l misplaced nephrostomy catheter in left renal vein | tarhan et al in a straight pathway into the mid pole calyx, another access to posterior inferior calyx was achieved and guidewires were placed. dilatation of the tract was achieved by using 8 french (f) co-axial and 30f amplatz dilator set over the guidewire. bleeding was moderate but renal pelvis was not accessible due to infundibular obstruction of the mid pole calyx, possibly because of the previous nephrolithotomy operation. during the procedure, stones were not visible and the bleeding became severe which led to interruption of the procedure, and a nephrostomy tube was inserted to control bleeding. in order to check intraoperatively if nephrostomy tube was in the right place or not, an antegrade nephrostography was performed and it showed the filling in both inferior calyx and renal pelvis with no contrast extravasation. in addition to that, any additional extravasation suggesting an additional venous or arterial injury was not detected (figure 1). as a routine application, the nephrostomy tube was opened three hours after the procedure and there was no bleeding and post-operative hemoglobin level was 12.8 g/dl. on the seventh hour postoperatively, severe bleeding from the nephrostomy tube was noted, the blood pressure was decreased to unmeasurable levels and hemoglobin level was 6.4 g/dl. after 3 units of blood transfusion and appropriate fluid replacement, vital signs of the patient were stabilized and hemoglobin level was increased to 9.1 gr/dl. first postoperative day a contrast enhanced computer tomography (ct) scan was performed and displayed that the nephrostomy catheter was inside the left renal vein (figure 2). after the patient became hemodynamically stable, the nephrostomy catheter was removed by open surgery under general anesthesia by the vascular surgeon in the operation team. no hemorrhage occurred after nephrostomy tube was removed, and hemodynamics was stable during the operation. eventually, a silicone drain was placed into the retroperitoneal space. the drain was removed two days after the operation and the patient was discharged four on the fourth day postoperatively, and neither hemodynamic instability nor hematocrit level decrease was observed. the stones that have remained in the patient were removed by the 2nd pcnl operation one month later without any complication observed, hence the patient became stone-free. discussion today, pcnl is the frequently preferred option for the treatment of inferior calyx stones and large multiple stones. (4) renal hemorrhage is the most common complication of percutaneous renal surgery but hemorrhage which needs intervention is a rare complication.(5) in the literature, various rates from 0.6% to 23.8% have been reported regarding transfusion rates.(6) sepsis, intestinal injury, pleural injury, adjacent organ injury and extravasation are other complications of percutaneous renal surgery.(7) nephrostomy tube placement is a routine procedure following percutaneous renal surgery. major renal vascular figure 1. antegrade nephrostography demonstrates the filling in both inferior calyx and renal pelvis with no contrast extravasation. figure 2. contrast enhanced computer tomography scan shows that the nephrostomy catheter is inside the left renal vein. 1716 | complications which are recognized during the operation can be resolved by the placement by placing a nephrostomy tube under the guidance of a fluoroscopy, without open surgery.(8) although tube placement is an effective method to control venous bleeding, smaller size nephrostomy tube placement or tubeless procedures are being used for better patient comfort.(9,10) our study is the third report in the literature regarding misplacement of nephrostomy tube into the vascular system and the second report of a complication following pcnl.(1-11) in our case, an antegrade nephrostography was performed after placement of the nephrostomy tube but showed no extravasation to renal vein. on the seventh hours postoperatively, severe bleeding through the nephrostomy tube has occurred following inappropriate mobilization of the patient, and the tube was re-clamped in order to control the bleeding and the patient was immobilized. a contrast enhanced computer tomography was performed on the first day postoperatively and the misplacement of the nephrostomy tube was detected, which should be the result of an unrecognized preoperative injury caused by an inadvertent amplatz dilatation or an inappropriate mobilization of the patient. we performed open surgery unlike other cases in the literature because of the patient’s choice and the legal restrictions about malpractice. the patient was discharged on the fourth day postoperatively without any complication. in our pcnl practices, we routinely verify the placement of the nephrostomy tube intraoperatively by antegrade nephrostography without fail after placing nephrostomy tube and check whether there is any extravasation or not. we think that this is a compulsory procedure. the migration of the nephrostomy tube should have occurred if severe bleeding is observed postoperatively, and an attentive control with computer tomography imaging following appropriate management of hemorrhage is essential. conclusion it is strongly recommended that in case of misplacement of the tube the manipulation of the nephrostomy catheter should be handled under fluoroscopy guidance while the surgical team is ready to intervene. conflict of interest none declared. case report references 1. mazzucchi e, mitre a, brito a, arap m, murta c, srougi m. intravenous misplacement of the nephrostomy catheter following percutaneous nephrostolithotomy: two case reports. clinics (sao paulo). 2009;64:69-70. 2. goodwin w, casey w, woolf w. percutaneous trocar (needle) nephrostomy in hydronephrosis. jama. 1955;157:891-4. 3. fernstrom i, johansson b. percutaneous pyelolithotomy: a new extraction technique. scand j urol nephrol. 1976;10:257-9. 4. etemadian m, shadpour p, haghighi r, mokhtari mr, maghsoudi r. a rare, but lifethreatening complication of percutaneous nephrolithotomy. massive ıntraabdominal extravasation of irrigation fluid. urol j. 2012;9:614-6. 5. srivastava a, singh kj, suri a, et al. vascular complications after percutaneous nephrolithotomy: are there any predictive factors? urology. 2005;66:38-40. 6. mousavi-bahar sh, mehrabi s, moslemi mk. percutaneous nephrolithotomy complications in 671 consecutive patients. a singlecenter experience. urol j. 2011;8:271-6. 7. maurice stephan michel, lutz trojan, jens jochen rassweiler. complications in percutaneous nephrolithotomy. euro urol. 2007;51:899-906. 8. mantu gupta, gary c, bellman and arthur d. smıth massıve hemorrhage from renal veın injury during percutaneous renal surgery: endourological management j urol. 1997;157:795-7. 9. maheshwari pn, andankar mg, bansal m. nephrostomy tube after percutaneous nephrolithotomy: large-bore or pigtail catheter? j endourol. 2000;14:735-7. 10. lojanapiwat b, soonthornphan s, wudhikarn s. tubeless percutaneous nephrolithotomy in selected patients. j endourol. 2001;15:711-3. 11. dias-filho ac, coaracy ga, borges w. right atrial migration of nephrostomy catheter. int braz j urol. 2005;31:470-1. urology journal unrc/iua 160 sexual dysfunction and infertility preoperative corporal biopsy as a predictor of postoperative results in venoocclusive erectile dysfunction mohammadreza nikoobakht,* ali saraji, alimohammad meysamie urology research center, tehran university of medical sciences, tehran, iran abstract introduction: our aim was to investigate the association of corporeal cavernosal pathology with venoocclusive erectile dysfunction (ed) and whether preoperative corporeal biopsy can help predict postoperative results. materials and methods: thirty-six patients with venoocclusive ed underwent corporeal cavernosal biopsy and venous ligation. preoperative assessment included complete physical examination, international index of erectile dysfunction (iief) scoring, nocturnal penile tumescence, penile doppler ultrasonography, cavernosography, and, if needed, cavernosometry. three months postoperatively, all patient parameters were reevaluated and compared with the preoperative results. biopsy results of 43 patients with penile fracture were used for controls. results: the mean age of the patients with ed was 32.1 ± 8.6 years. the iief score and peak systolic velocity of the cavernosal artery in the patients did not differ postoperatively. the mean end diastolic velocity, however, decreased from 11.0 cm/s to 5.1 cm/s (p = .023). only 2 patients had satisfactory penile rigidity after venous ligation. pathologically, 23 patients had a slight decrease of cavernosal smooth muscle cells, while in 9 patients, the cavernosal smooth muscles were markedly decreased and replaced by collagen fibers. four patients had normal histologies, and all responded either partially or completely to surgical therapy. in the control group, 41 of 43 patients had normal histologies, and 2 had a slight decrease of smooth muscle cell mass. conclusion: decreased cavernosal smooth muscle mass may impair erectile function. its association with venoocclusive ed may be a poor prognostic factor of the outcome of surgical therapy. for the preoperative evaluation of patients, we propose cavernosal biopsy. key words: erectile dysfunction, venous leakage, biopsy, smooth muscles vol. 2, no. 3, 160-164 summer 2005 printed in iran introduction erectile dysfunction (ed) is a common medical problem in men that can destroy the family bonds if neglected or improperly managed. by definition, ed is the inability to establish enough penile rigidity for acceptable intercourse, or an inability to maintain full penile rigidity enough for complete intercourse. generally, the etiology of ed can be either organic or psychogenic; most eds are organic, which is more common in older men. vasculogenic causes are the most common form of organic ed. venoocclusive dysfunction (venous leakage) is an important form of received december 2004 accepted may 2005 *corresponding author: urology research center, sina hospital, hassanabad sq, tehran 19953 45432 tel: ++98 21 66701041-9, fax: ++98 21 66717447 e-mail: nikoobakht_m@hotmail.com nikoobakht et al 161 vasculogenic ed. different surgical procedures are used to manage venoocclusive ed, including dorsal and circumflex penile vein ligation or rearterialization, unfortunately however, they have high postoperative failure rates. in the current study, we compared the preoperative corporeal pathology with the postoperative outcome in patients with venoocclusive ed after venous ligation and with patients without ed. materials and methods between 1996 and 2003, 36 patients presented with venoocclusive ed to our andrology clinic. none had comorbid diseases (hypertension, diabetes mellitus, or neurologic disorders). their histories were negative for previous urogenital trauma, urogenital surgery, and medical treatment. preoperative assessment included complete physical examination, international index of erectile dysfunction (iief) scoring, hormonal study (follicle-stimulating hormone, luteinizing hormone, prolactin, and testosterone), biochemical tests (fasting plasma glucose and serum urea, creatinine, triglyceride, and cholesterol), nocturnal penile tumescence, penile doppler ultrasonography, cavernosography, and, if needed, cavernosometry. informed consent was obtained from all patients. all patients underwent circumflex, superficial, and deep dorsal vein ligation. at the same time, intraoperative cavernosal wedge biopsies were taken for pathologic examination. at 3 and 12 months after surgery, all patients were reevaluated, and the clinical results were compared with the pathological findings. biopsy results from 43 patients with penile fracture were used as controls. histologic slides were prepared using hematoxylin-eosin and trichrome staining for each specimen. one pathologist, blinded to the study objectives, reviewed all slides in 3 sessions. the degree of smooth muscle reduction was graded as slight reduction or marked reduction; the latter was accompanied by replacement with collagen fibers. data analyses were performed using spss software (statistical package for the social sciences, version 11.5, ssps inc, chicago, ill, usa), with chi-square test, kolmogorov-smirnov test, paired t test, and wilcoxon signed rank test, as appropriate. values for p less than .05 were considered statistically significant. results the demographic and clinical characteristics of the patients with venoocclusive ed are shown in table 1. in all of the patients, venous leakage was clearly demonstrated by cavernosography, before ligation. postoperatively, the mean iief and peak systolic velocity (psv) of the cavernosal artery did not differ significantly (table 1). the mean end diastolic velocity (edv), however, decreased from 11.0 cm/s to 5.1 cm/s (p = .023). in 7 patients, the edv was more than 7 cm/s, and cavernosography demonstrated venous leakage. twelve months after surgery, no venous leakage was demonstrated by cavernosography. clinically, only 2 patients recovered full penile erection (at 3 months' follow-up), while 2 other patients required intracorporeal injection of prostaglandin e1, and 1 required sildenafil administration to recover penile rigidity. figures 1 through 4 show the changes in smooth muscle mass in a patient with ed and the normal pathologies in a patient in the control group. pathologically, 23 patients showed slight decreases in cavernosal smooth muscle mass, while in 9 patients, the cavernosal smooth muscles were completely replaced with collagen table 1. demographic characteristics and preand postoperative parameters in patients with venoocclusive ed iief: international index of erectile dysfunction, psv: peak systolic velocity of the cavernosal artery, edv: end diastolic velocity of the cavernosal artery number of patients 36 mean age (years) 32.1 ± 8.6 mean follow-up (months) 49.0 ± 24.1 preoperative assessments iief 11.0 ± 3.1 psv (cm/s) 38.0 ± 3.2 edv (cm/s) 11.0 ± 2.6 postoperative assessments (3 months) iief 10.9 ± 2.6 p = .31 psv (cm/s) 39.2 ± 3.8 p = .30 edv (cm/s) 5.1 ± 2.4 p = .023 outcome full erection 2 (3.4%) erection with intracorporeal injection. 2 (3.4%) erection with sildenafil 1 (2.7%) preoperative corporal biopsy in venoocclusive erectile dysfunction162 tissue (marked reduction). only 4 patients had normal cavernosal smooth muscle mass, all of whom were among the recovered patients (table 2). on the other hand, 41 of 43 patients in the control group had normal results on pathological study, and only 2 patients had a slight decrease in cavernosal smooth muscle mass (p < .001). three patients in the control group developed venoocclusive ed, postoperatively, documented with penile doppler study and cavernosography. the main postoperative complications in the patients with venoocclusive ed were numbness in 2 patients and penile edema in 4, which spontaneously resolved after 3 weeks. discussion vasculogenic impotence is the most common form of ed, and venoocclusive ed disease is a peculiar form of it, which imposes a major challenge for andrologists. unfortunately, no known medical therapy for this form of the disease currently exists, and surgical therapy (venous ligation) is associated with a high failure rate. during detumescence phase, sinusoidal smooth muscles contract to expel the table 2. histologic examination results in patients with venoocclusive ed and in controls pathology patients with venoocclusive ed (%) controls (%) normal 4 (11.2) 41 (95.3) slight reduction of smooth muscle mass 23 (63.9) 2 (4.7) marked reduction of smooth muscle mass 9 (25) 0 (0) p < .001 fig. 1. normal cavernosal histology of a young man with penile fracture (hematoxylin-eosin × 40) fig. 2. cavernosal pathology of an impotent man with venoocclusive ed showing a significant decrease of smooth muscle fibers (hematoxylin-eosin, × 40) fig. 3. trichrome staining of a normal cavernosal specimen of a patient with penile fracture (× 40) fig. 4. trichrome staining of cavernosal specimen of a patient with venoocclusive ed (× 40) nikoobakht et al 163 intracavernosal blood at low pressure through the emissary veins, while during tumescence phase, there is complete sinusoidal smooth muscle relaxation and cavernosal arterial dilation. to rapidly fill the corpora cavernosal spaces, the emissary veins compress between the internal and external layers of the tunica albuginea. this abolishes blood leakage from the corporal bodies and maintains full rigidity.(1,2) cavernosal smooth muscle damage precludes proper sinusoidal expansion, the albuginea layers do not tightly compress, the emissary veins improperly close, and venous leakage ensues. this leads to early detumescence and ed. jevtich and colleagues have compared cavernosal biopsy results of patients with ed and healthy individuals. they have shown that 42% of patients with ed had marked decreases of cavernosal smooth muscles and increases of collagen, while only 5% of controls had decreases of smooth muscles or collagen.(3) in a similar study, karadeniz and coworkers demonstrated that significant decreases in smooth muscles and increases of interstitial fibrous tissue occur in patients with venoocclusive ed.(4) although mesdorf and coworkers have not defined the specific pathological forms for every type of ed, they have reported a decrease of cavernosal smooth muscles and an increase of collagen tissue in patients with ed when compared with controls.(5) wespes and colleagues have demonstrated that when computerized morphometry was used in young patients with a curved penis but one that can maintain a hemodynamically adequate erection, that the corpora cavernosa was composed of 40% to 52% smooth muscle compared with 19% to 36% in elderly men with corporeal venoocclusive dysfunction and 10% to 25% in those with arterial impotence. in addition, collagen was correspondingly increased.(6) until now, there has been no accurate index to assess the normal values of cavernosal tissue components. however, several studies have demonstrated that there is an association between the percentage of cavernosal smooth muscle and venous leakage, which is considered a significant postoperative prognostic factor. sattar and coworkers have compared the biopsy results of 5 potent patients with 17 impotent ones. they showed that the average cavernosal elastic tissue in potent patients was 9%, while it was 5% and 4% in those with the venoocclusve and arterial insufficiency types of ed, respectively. no association between age and cavernosal elastin ratio was observed. they also showed that a 29% cavernosal smooth muscle is the cutoff for a good postoperative prognosis.(7) in the abovementioned studies, no association between cavernosal pathology and specific type of ed was found. in the present study, of 36 patients with venoocclusive ed, 23 had a slight decrease of cavernosal smooth muscles, and 9 had a marked decrease in smooth muscle and an increase collagen tissue. only 4 patients had normal histologies, all of whom had favorable postoperative responses (partial or complete). unfortunately, because of technical shortages and the unavailability of highly specialized pathological facilities, we were unable to assess the ultrastructural characteristics of the smooth muscles or the different types of collagens. further studies of the cavernosal smooth muscle and collagen ultrastuctures are needed. the current study demonstrates that venous leakage is secondary to primary cavernosal muscle pathology, and that penile doppler and cavernosography can be used to assess the final manifestations of this pathology. in a study of penile biopsies in 50 patients, malovrouvas and coworkers reported that biopsy gun specimens were as representative as were open biopsy specimens.(8) accordingly, in preoperative evaluation of patients with ed, needle biopsy may be useful in avoiding unsuccessful surgery. conclusion surgical intervention in venoocclusive ed is disappointing. however, preoperative cavernosal needle biopsy may be helpful in patient selection and surgical decision making. references 1. lue tf, tanagho ea. physiology of erection and pharmacological management of impotence. j urol. 1987;137:829-36. 2. krane rj, goldstein i, saenz de tejada i. impotence. n engl j med. 1989;321:1648-59. 3. jevtich mj, khawand ny, vidic b. clinical significance of ultrastructural findings in the corpora cavernosa of normal and impotent men. j urol. 1990;143:289-93. 4. karadeniz t, topsakal m, aydogmus a, gulgun c, aytekin y, basak d. correlation of ultrastructural alterations in cavernous tissue with the clinical diagnosis vasculogenic impotence. urol int. 1996;57:58-61. 5. mersdorf a, goldsmith pc, diederichs w, et al. preoperative corporal biopsy in venoocclusive erectile dysfunction164 ultrastructural changes in impotent penile tissue: a comparison of 65 patients. j urol. 1991;145:749-58. 6. wespes e, goes pm, schiffmann s, et al. computerized analysis of smooth muscle fibers in potent and impotent patients. j urol. 1991;146:1015-7. 7. sattar aa, wespes e, schulman cc. computerized measurement of penile elastic fibres in potent and impotent men. eur urol. 1994;25:142-4. 8. malovrouvas d, petraki c, constantinidis e, et al. the contribution of cavernous body biopsy in the diagnosis and treatment of male impotence. histol histopathol. 1994;9:427-31. urology journal unrc/iua 288 subject index to volume 1 vol. 1, no. 4, autumn 2004 printed in iran endourology simforoosh n, basiri a, maghsoodi r, shafi h. modern status of laparoscopic surgery in the urology of iran and world, 10-18 simforoosh n, tabibi a, nooralizadeh a, shayani nasab h. laparoscopic ureteropelvic junction decompression for the management of obstruction, 24-26 basiri a, simforoosh n, nikoobakht mr, hoseini moghaddam mm. the role of ureteroscopy in the treatment of renal transplantation complications, 27-31 simforoosh n, ahmadnia h. laparoscopic adrenalectomy : a report of the first experiment in iran, 77-81 etemadian n, amjadi m, simforoosh n. transcutaneous ultransound nephrolitho-tomy: the first report from iran , 82-84 basiri a, maghsoudi r, shadpur p. laparoscopicassisted ureterocystoplasty, 123-125 younesi m, ahmadnia h, asl zare m. an unusual foreign body in the bladder and percutaneous removal, 126-127 simforoosh n, basiri a, tabibi a, danesh ak, sharifiaghdas f, ziaee sam nooralizadeh a, hosseinimoghaddam smm. a comarison between laparoscopic and open pyeloplasty in patients with ureteropelvic junction obstruction, 165-169 tadayon a, a'yanifard m, mansoori d. endoscopic renal cyst ablation, 170-173 mohammadzadeh rezaee ma. endoscopic resection of lower ureter in upper urinary tract tumors, 208-210 karami h, heidari f. pseudoaneurysm following percutaneous nephrolithotomy, 280-281 female urology hajebrahimi s, madaen sk, sheikhzadeh p. effects of thyrotropin-releasing hormone on urethral closure pressure in females with voiding dysfunction, 35-39 irani d, heidari n, khezri aa. the efficacy and safety of intravesical bacillus-guerin in the treatment of female patients with interstitial cystitis: a doubleblinded prospective placebo conrtolled study, 90-93 zargar ma, emami m, zargar k, jamshidi m. the results of grade iv cystocele repair using mesh, 263-268 infectious diseases nasehi a, azadi sh. elephantiasis of penis and scrotum, 128-130 amir-zargar ma, yavangi m, ja'fari m, mohseni mj. primary tuberculosis of glans penis, 278-279 asgari sa. successful medical treatment of emphysematous pyelonephritis, 282-283 kidney transplantation lesan pezeshki m. the newest medications in kidney transplantation and their mechanisms of action, 19-23 basiri a, simforoosh n, nikoobakht mr, hoseini moghaddam mm. the role of ureteroscopy in the treatment of renal transplantation complications, 27-31 basiri a, simforoosh n, khoddam r, hoseini moghaddam mm, shayani nasab h. a comparison of augmentation cystoplasty before and after renal transplantation with the control group, 45-48 mahdavi r. preparing live donor for kidney donation, 71-76 shahbazian h. kaposi sarcoma in kidney transplanted patients, 111-114 haberal ma. living donor kidney transplantation: how far should we go?, 148-156 kazemeyni sm, bagheri chime ar, heidary ar. worldwide 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baharnoori m. renal malakoplakia simulating neoplasm in a child, 218-221 reconstructive surgery hosseini j, soltanzadeh k. a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran, 94-98 nikoobakht mr, mehrsai a, pourmand gh, djaladat h, nasseh hr. management of peyronie's disease by dermal grafting, 99-102 irani d, zeighami sh, khezri aa. results of dermal patch graft in the treatment of peyronie's disease, 103-106 tabibi a, nouralizadeh a. diverticulocystoplasty in a case with decreased bladder capacity, 121-122 sexual dysfunction dadkhah f, nahabidian a, ahmadi gh. the correlation between semen parameters in processed and unprocessed semen with pregnancy rate in intrauterine insemination in the treatment of male factor infertility, 273-245 nikoobakht mr, mehrsai a, pourmand gh, djaladat h, nasseh hr. management of peyronie's disease by dermal grafting, 99-102 irani d, zeighami sh, khezri aa. results of dermal patch graft in the treatment of peyronie's disease, 103-106 safarinejad mr, hosseini sy. erectile dysfunction: clinical guidelines (1), 133-147 safarinejad mr, hosseini sy. erectile dysfunction: clinical guidelines (2), 227-239 nikravesh mr, jalali m. the effect of camphor on the male mice reproductive system, 268-272 trauma salimi j, nikoobakht mr, zareei mr. epidemiologic study of 284 patients with urogenital trauma in three trauma centers in tehran, 117-120 urolithiasis aghamir smk, mohseni mg, ardastani a. the application of kub for detecting of submucosal ureteral stones, 32-34 etemadian n, amjadi m, simforoosh n. transcutaneous ultransound nephrolithotomy: the first report from iran , 82-84 ziaee sam, abdollah nasehi, basiri a, simforoosh n, danesh ak, sharifi-aghdas f, tabibi a. pcnl in the management of lower pole caliceal calculi, 174-176 mehrsai a, taghizadeh afshra a, zohrevand r, djaladat h, steffes hj, hesse a, pourmand gh. 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specific α-blocker, 115-116 darabi mr, barzegarnejad a. bilateral cryptorchid malignancy with persistent mullerian duct, 131-132 jalali nadoushan mr, peivareh h, azizzadeh delshad a. correlation between apoptosis and histological grade of transitional cell carcinoma of urinary bladder, 177-179 mohammadzadeh rezaee ma. endoscopic resection of lower ureter in upper urinary tract tumors, 208-210 dadfar mr, mostofi ne. adrenal myelolipoma, 211-212 khatami m, fanaie a, mehrvarz sh, kosari f. large adenocarcinoma of the right adrenal cortex, 213-214 mohammadi torbati p, zham h. epithelioid type of paratesticular leiomyosarcoma, 215-217 razi a. prostate cancer screening, yes or no? the current controversy, 240-245 tavangar sm, razi a, mashayekhi r. correlation between prostate needle biopsy and radical prostatectomy gleason gradings of 111 cases with prostatic adenocarcinoma, 246-249 mohseni mg, zand s, aghamir smk. effect of smoking on prognostic factors of transitional cell carcinoma of the bladder, 250-252 asgari ma, kaviani a, gachkar l, hosseini-nassab sr. is bladder cancer more common among opium addicts?, 253-255 hosseini sy, safarinejad mr. huge benign prostatic hyperplasia, 276-277 miscellaneous clinical application of computed tomography on prostate volume estimation in patients with lower urinary tract symptoms tae wook kang,1 jae mann song,1 kwang jin kim,1 hyun keun byun,1 young joo kim,1 hyun chul chung,1 yun byung chae,2 hong wook kim,3 jae hung jung1* purpose: to compare estimated prostate volume (pv) based on computed tomography (ct) scan and transrectal ultrasonography (trus) in patients with lower urinary tract symptoms (luts). materials and methods: between january 2010 and october 2012, 107 consecutive patients with luts were analyzed, retrospectively. pv measures were performed by the means of ellipsoid formula (pv = π/6 [width (cm) thickness (cm) length (cm)]) from trus (pvtrus) and ct (pvct ellipsoid). in addition, pv was calculated as the sum of the area of each slice and the ct slice interval using commercial software program (pvct 3d reconstruction). results: mean pvct ellipsoid was 40.63 ± 31.06 cm3 (range, 8.34-217.46). mean pvtrus and pvct 3d reconstruction were 39.20 ± 33.04 (range, 4.00-223.81) and 45.30 ± 32.98 (range, 8.90-248.30), respectively. pvct ellipsoid was highly correlated with pvtrus and pvct 3d reconstruction (r = 0.935, p < .001; r = .970, p < .001, respectively). moreover, there was very strong agreement for pv measurements with all three methods (intraclass correlation coefficient = 0.934, p < .001). conclusion: pvct ellipsoid is adequate method for quick volume assessment with reasonable accuracy. therefore, we can easily predict pv by ct scan using ellipsoid formula without performing additional trus in patients with luts. keywords: lower urinary tract symptoms; male; image enhancement; methods; prostate; anatomy; organ size; tomography; x-ray computed; ultrasonography. introduction s everal prostatic conditions including benign prostatic hyperplasia (bph), acute/chronic prostate inflammation, and prostate cancer represent a huge health problem in aging society.(1) to access these conditions, prostate volume (pv) measurement has come to be an important step in the diagnosis and management of both benign and malignant prostatic diseases.(2) during the last decade, many urologists had used imaging techniques for the differential diagnosis of lower urinary tract symptoms (luts). transrectal ultrasonography (trus) has been used as a common imaging modality to measure pv.(2,3) however, trus has the disadvantage of depending on the operators who require a set of special technical skills. recently, computed tomography (ct) scan as an alternative technique is performed for pv estimation in particular situation, such as external beam radiotherapy and interstitial brachytherapy implantation to deliver radiation.(4-6) nevertheless, 3d rebuilt images of prostate are needed for volume estimation using ct scan, 1 department of urology and radiology, yonsei university, wonju college of medicine, wonju, republic of korea. 2 department of urology, cheongju st. mary’s hospital, cheongju, republic of korea. 3 department of urology, konyang university, college of medicine, daejeon, republic of korea. *correspondence: department of urology, yonsei university, wonju college of medicine, 20 ilsan-ro, wonju 220-701, republic of korea. tel: +82 33741 0654. fax: +82 33741 1930. e-mail: geneuro95@yonsei.ac.kr. received april 2014 & accepted october 2014 and such procedure is time consuming. furthermore, there are only few reports about the comparability of these two diagnostic procedures in patients with luts. therefore, we compared estimated pv based on ct scan and trus. in addition, we evaluated whether the ellipsoid formula is able to substitute 3d reconstruction in the setting of ct scan. materials and methods between january 2010 and october 2012, 107 consecutive patients with luts were analyzed retrospectively. each patient underwent trus and ct scan over 14 days or less period. the individual images were interpreted independently by different urologist (j.h.j and h.k.b). pvs estimated by different modality were collected on independent data sheet, respectively. final data were combined during statistical analysis. the study was approved by the institutional review board (irb approved protocol number: ywmr-12-05-032). prostate volume estimation with trus and ct trus images were obtained with ultrasound system miscellaneous 1980 (aloka, tokyo, japan) using transrectal probe with the patient in lithotomy position. pv measured by trus (pvtrus) was calculated by the means of ellipsoid formula (pv = π/6 [width (cm) thickness (cm) length (cm)]). the width (right-left) and thickness (anterior-posterior) were estimated on the transverse plane, and length (cranial-caudal) was estimated on the sagittal plane. h.k.b measured pv using trus in real time. prostate images using ct scanner (phillips medical system, amsterdam, the netherlands) were obtained with the patient in supine position. ct axial images were scanned with 0.25 cm interval from visualized base of the gland to apex. the ct images were scanned into commercial software program (phillips medical system, amsterdam, the netherlands). prostate contours were drawn on each slice by one urologist who was unaware of pvtrus. the volume (pvct 3d reconstruction) was calculated as the sum of the area of each slice and the ct slice interval. in addition, pv measured by ct scan using the ellipsoid formula (pvct ellipsoid) was also calculated. j.h.j estimated pvct ellipsoid and pvct 3d reconstruction with 1 month interval only using patient’s id to avoid bias. statistical analysis pearson's and intraclass correlation coefficients (icc) of the exact type for the two-way mixed model were used for correlation of these two diagnostic procedures. all analyses were performed with statistical package for the social science (spss inc, chicago, illinois, usa) version 13.0 and two-tailed p value of less than .05 was considered statistically significant. results the mean age and prostate specific antigen (psa) of the patients were 64 years old (range, 34-93) and 7.00 ng/ml (range, 0.10-100), respectively. indication for ct scan included urological disorders (n = 45, 42.1%), such as hematuria, persistent pyuria, urolithiasis, and malignancy, medical health checkup (n = 45, 42.1%), gastrointestinal presentations (n = 10, 9.3%), solid organ malignancy (n = 5, 4.7%) and others (n = 2, 1.9%). eight patients (7.5%), among 19 patients (17.8%) with a psa level of 4 ng/ml or more, were diagnosed with prostate cancer. transurethral resection of prostate was performed in 12 patients (11.2%) with luts. pvtrus, pvct 3d reconstruction and pvct ellipsoid were 39.46 ± 32.87 cm3 (range, 9.36-223.81), 45.30 ± 32.98 (range, 8.90-248.30) and 40.63 ± 31.06 (range, 8.34-217.46), respectively. pvct ellipsoid was on average 8.4% (range, –52.0 – 197.0) larger than pvtrus. pvct 3d reconstruction was on average 23.5 % (range, –38.0 –136.0) larger than pvtrus. the pvtrus divided into quartiles are shown in table. table showed that the overestimation of pv by ct scan was greatest for smaller pv. pvct ellipsoid was highly correlated with pvtrus and pvct 3d reconstruction (r = .935, p < .001; r = .970, p < .001, respectively) (figure). moreover, there was very strong agreement for pv measurements with all three methods (icc = .934, p < .001). discussion imaging plays a key role in the diagnosis and management of urological disease. medical applications of ultrasonography (us) were first introduced in the 1960 and the use of us has increased dramatically in the past two decades.(7) with wide use of abdominal us, trus is a common clinical procedure for prostatic disease. trus has the capability to assess inflammatory disease, bph and cancer based on echogenicity and blood flow signal. (3,8) like us, ct scan have been used widely for trauma and unexplained abdominal symptoms. urological indications for ct scan include evaluation of hematuria, renal masses, urolithiasis, staging urological cancer, renal donor evaluation and characterization of incidental adrenal lesions.(7) although it is well known that ct is more sensitive than us in the evaluation of upper urinary tract, ct scan have been performed in brachytherapy and three dimensional conformal radiotherapy for the treatment of localized prostate cancer.(2,4,5) figure. correlation between prostate volumes measured by transrectal ultrasonography (pv trus) and computed tomography (pv ct). pvct ellipsoid was significantly correlated with pvtrus (a) and pvct 3d reconstruction (b). pvtrus quartile range (cm3) pvct ellipsoid/pvtrus pvct 3d reconstruction/pvtrus mean median mean median 1 9.36-21.12 1.15 1.09 1.38 1.41 2 21.13-25.71 1.08 1.08 1.27 1.23 3 26.13-46.19 1.02 1.02 1.13 1.11 4 46.66-223.81 0.99 1.01 1.07 1.17 abbreviations: pvct, prostate volume measured by computed tomography; pvtrus, prostate volume measured by transrectal ultrasonography. table. ratio of pvct ellipsoid and pvct 3d reconstruction to pvtrus by quartile pvtrus. prostate volume estimation by ct scan-kang et al vol 11. no 06 nov-dec 2014 1981 luts in men are common health problem that increases with age. bph causes luts that may affect quality of life and patient satisfaction.(1,3) according to american urological association guidelines, digital rectal examination should be performed to assess approximate size, consistency, shape and nodularity suggestive of prostate cancer. however, additional imaging of the prostate by us is needed to make a correct diagnosis when specific treatments including medicine and transurethral resection of prostate are planned.(9) pv has been measured through ellipsoid formula that was designed in accordance with geometric shape of the prostate.(2-6,8) for determining more accurate pv, step section planimetry may be also employed in patients with prostate cancer.(10,11) previous literatures reported an excellent reproducibility of pv measurements by planimetry.(11) however, it is difficult for urologist to estimate pv using time consuming step section planimetry and requires special equipment, specifically for screening purpose. in the present study, it takes about 15-30 min in the measurement of pvct 3d reconstruction for each patient. furthermore, it is not clear whether additional trus should be necessary or not, if the patient already underwent ct scan due to other causes. in addition, we determined whether the ellipsoid formula is able to replace with 3d reconstruction in the setting of ct scan. several investigators reported that volume determinations based on the formula were comparable to planimetry and real specimen volume.(2,11,12) although there are some discrepancies, ct scan defined volumes using 3d reconstruction method are closely correlated with those obtained by trus using step section planimetry.(4,5,11) however, ct scan consistently overestimated the prostate volume compared with trus by 17-50%.(4-6,10-12,14) in our study, a strong correlation was also found between ct scan and trus measurement of pv. pvct ellipsoid and pvct 3d reconstruction were 8.4% and 23.5% larger than pvtrus. this finding supports that ct overestimated pv. however, we reported just 8.4% and 23.5% differences between ct scan and trus in contrast to 50% of prior researches.(6,14) one explanation could be that ct scan imaging lacks the soft-tissue resolution required to distinguish prostate anatomy from adjacent structures, such as seminal vesicle, the bladder wall, the rectal wall, the puborectalis muscle, the anterior venous plexus and the muscles of pelvic floor. badiozamani and colleagues excluded these soft tissues from the volume and finally concluded that ct scan did not overestimate pv compared with trus. therefore, we followed badiozamani’s rules in tracing of prostatic margin. secondly, yang and colleagues delineated that increased slice thickness of the ct scan images usually reduces estimated pv because larger slice thickness cannot reproduce the correct contour of the prostate in the base and apex.(6) we performed ct scan with smaller slice interval of 0.25 cm in contrast with published reports with 0.5 cm interval. interestingly, our study suggests that simpler formula provided measurements were comparable to planimetry in prostate volume estimation by ct scan (figure, b). additionally, mean ratio of pvct ellipsoid to pvtrus was smaller than that of pvct 3d reconstruction. these results that prolate ellipsoid formula underestimated the prostate volume are consistent with those of other study.(12) thus, pvct ellipsoid may be more accurate than pvct 3d reconstruction because previous studies demonstrated a trend toward greater underestimation by trus in pv.(4-6,10-12,14) ct scan, with its inferior soft tissue contrast, compared to trus is not regarded as primary diagnostic modality for the prostate.(15) furthermore, we should concern radiation hazard and adverse reaction of contrast media when using ct scan. typical radiation exposures in directly irradiated organs are in the range of 20-30 millisievert (msv) for current diagnostic ct scan examination.(16) recently, despite of diagnostic ct scan, the potential for adverse consequences may arise with increasing ct scan utilization. the overall incidence of adverse reaction is about 5%. although most reactions are minor, cardiopulmonary and anaphylactoid reactions can be fatal.(16) however, with wide range of indications, for example medical health checkup, cancer staging, or gastrointestinal presentations, ct scan may be considered as an alternative in selected patients with pathology of the prostate. conclusion as a result, pv determination by ct scan using formula is effective method for quick volume measurement with reasonable accuracy. however, pvct 3d reconstruction that requires manual contouring of the consecutive is more time consuming. therefore, simple formula based on prostate diameters is preferable alternative in the clinics without performing additional trus in patients with luts. conflict of interest none declared. references 1. yoo tk, cho hj. benign prostatic hyperplasia: from bench to clinic. korean j urol. 2012;53:139 48. 2. park sb, kim jk, choi sh, noh hn, ji ek, cho ks. prostate volume measurement by trus using heights obtained by transaxial and midsagittal scanning: comparison with specimen volume fol lowing radical prostatectomy. korean j radiol. 2000;1:110-3. 3. abdi h, kazzazi a, bazargani st, djavan b, tele grafi s. imaging in benign prostatic hyperplasia: what is new? curr opin urol. 2013;23:11-6. 4. badiozamani kr, wallner k, cavanagh w, blasko j. comparability of ct-based and trus based prostate volumes. int j radiat oncol biol phys. 1999;43:375-8. 5. hoffelt sc, marshall lm, garzotto m, hung a, holland j, beer tm. a comparison of ct scan to transrectal ultrasound-measured prostate vol ume in untreated prostate cancer. int j radiat on col biol phys. 2003;57:29-32. 6. yang ch, wang sj, lin at, lin ca. factors af fecting prostate volume estimation in computed to mography images. med dosim. 2011;36:85-90. prostate volume estimation by ct scan-kang et al miscellaneous 1982 7. bueschen aj, lockhart me. evolution of urologi cal imaging. int j urol. 2011;18:102-12. 8. wasserman nf. benign prostatic hyperplasia: a re view and ultrasound classification. radiol clin north am. 2006;44:689-710. 9. mcvary kt, roehrborn cg, avins al, et al. up date on aua guideline on the management of be nign prostatic hyperplasia. j urol. 2011;185:1793 803. 10. kälkner km, kubicek g, nilsson j, lundell m, levitt s, nilsson s. prostate volume determina tion: differential volume measurements comparing ct and trus. radiother oncol. 2006;81:179-83. 11. gloi a, mccourt s, zuge c, goettler a, schlise s, cooley g. a bland-altman analysis of the bias between computed tomography and ultra sound pr ostate volume measurements. med dosim. 2008;33:234-8. 12. eri lm, thomassen h, brennhovd b, håheim ll. accuracy and repeatability of prostate volume measurements by transrectal ultrasound. prostate cancer prostatic dis. 2002;5:273-8. 13. terris mk, stamey ta. determination of prostate volume by transrectal ultrasound. j urol. 1991;145:984-7. 14. narayana v, roberson pl, pu at, sandler h, winfield rh, mclaughlin pw. impact of differen ces in ultrasound and computed tomography volu mes on treatment planning of permanent prostate implants. int j radiat oncol biol phys. 1997;37:1181-5. 15. talab ss, preston ma, elmi a, tabatabaei s. prostate cancer imaging: what the urologist wants to know. radiol clin north am. 2012;50:1015-41. 16. semelka rc, armao dm, elias j jr, huda w. im aging strategies to reduce the risk of radiation in ct studies, including selective substitution with mri. j magn reson imaging. 2007;25:900-9. prostate volume estimation by ct scan-kang et al vol 11. no 06 nov-dec 2014 1983 urol_v3_no2_001_editorial.qxd o r i g i n a l a r t i c l e s endourology and stone diseases extracorporeal shock wave lithotripsy and transureteral lithotripsy in the treatment of impacted lower ureteral calculi seyyed amir mohsen ziaee,* abbas basiri, mohammad nadjafi-semnani, saeed zand, armin iranpour urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: we compared the efficacy of extracorporeal shock wave lithotripsy (swl) with ureteroscopy followed by transureteral lithotripsy (tul) for the treatment of impacted distal ureteral calculi. materials and methods: a total of 96 patients with solitary impacted distal ureteral calculi were assigned into 2 groups of treatment with swl (42 patients) and tul (54 patients) with a 6.9-f semirigid ureteroscope. characteristics of the patients and the calculi, treatment parameters, clinical outcomes, and patients' satisfaction were assessed for each group as well as efficiency quotient. results: demographic characteristics of the patients in the 2 groups were similar as well as the sizes of the calculi. the stone-free rate, 2 months postoperatively, was 71.4% in the patients of the swl group and 88.9% in those of the tul group. the efficiency quotient was 56% and 81% for the swl and tul groups, respectively (p = .004). retreatment rate was 26.2% (11 patients) and 9.3% (5 patients) for the swl and tul groups, respectively (p = .027). thirty patients in the swl group (71.4%) and 52 in the tul group (96.3%) were satisfied with their treatment (p = .001). there were no major complications in neither of the groups. minor complications (pain and hematuria) were more common in the tul group. conclusion: based on the results of this study, tul seems to be more effective than swl in the treatment of impacted lower ureteral calculi sized smaller than 12 mm, and patients are more satisfied with this treatment method. key words: ureteral calculi, ureteroscopy, lithotripsy, shock wave, clinical trials 75 urology journal unrc/iua vol. 3, no. 2, 75-78 spring 2006 printed in iran introduction today, selection of the optimal surgical treatment for distal ureteral calculi remains one of the controversial topics in endourology.(1-3) treatment options vary and include expectant management, placement of ureteral stents, extracorporeal shock wave lithotripsy (swl), ureteroscopy with basket extraction or intracorporeal lithotripsy, and salvage procedures such as laparoscopic or open ureterolithotomy.(3) the likelihood of successful fragmentation of impacted ureteral calculi by swl is still a matter of debate.(4-10) some investigators have shown that impaction does not affect swl results and believe that it should be attempted as the firstline treatment.(5,8) to our knowledge, there is no report comparing transureteral lithotripsy (tul) received july 2005 accepted may 2006 *corresponding author: department of urology, shaheed labbafinejad medical center, 9th boustan st, pasdaran, tehran 1666679951, iran. tel: +98 21 2256 7222, fax: +98 21 2256 7282 e-mail: ziaee@hotmail.com shock wave versus transureteral lithotripsy for ureteral calculi and swl in the treatment of impacted lower ureteral calculi. in this clinical trial, we compared the efficacy and complications of swl with tul for the treatment of impacted distal ureteral calculi. materials and methods between september 2002 and march 2004, patients referring to our clinic with a single impacted lower ureteral calculus were evaluated to be enrolled in our study. intravenous urography (ivu) was performed in all patients and those with a single radio-opaque impacted lower ureteral calculus sized less than 12 mm were selected. patients with multiple ureteral calculi, solitary kidney, kidney dysfunction, ipsilateral ureteral stricture, plan for ipsilateral or contralateral renal or ureteral surgery, active urinary tract infection, transplanted kidney allograft, and uncorrected coagulopathy were excluded. impaction was defined as hydroureteronephrosis above the calculus and nonvisualized ureter below it on ivu or no changes in the location of the calculus on serial plain abdominal radiographies (kidney, ureter, and bladder [kub]) during the past 2 months. indication for and timing of surgical intervention versus observation was left to the discretion of the treating physician. patients who met the inclusion criteria and were eligible to undergo both swl and tul were enrolled in the study. all patients provided informed consent. they were assigned into either the swl or the tul group according to their preferences. shock wave lithotripsy was performed using a dornier compact delta lithotripter (dornier medtech europe gmbh, wessling, germany) and up to a total of 2400 shock waves were administered at a power adjusted between 15 w and 22 w. transureteral lithotripsy was performed under epidural anesthesia, with a 6.9f semirigid ureteroscope (richard wolf gmbh, knittlingen, germany), and all calculi were fragmented using ballistic lithoclast (swiss lithoclast, ems, geneva, switzerland). placement of ureteral stent at the end of the procedure was left to the discretion of the treating surgeon. physical examination was performed and kub and ultrasonography were obtained in all patients at 2 weeks and 2 months after the operation. in the presence of hydronephrosis and suspected residual calculi, ivu was also done. stone-free rate was defined as the percent with complete clearance or residual calculi sizes less than 2 mm. for a better comparison between the efficiency of both treatments, the efficiency quotient (eq) was calculated by the formula introduced by clayman and associates(11): [percent stone free/(100% + percent retreatment + percent auxiliary procedures)] × 100 patients with a failed treatment in each group underwent repeat procedure. patient's satisfaction was defined as recommendation of the treatment by the patients for their relatives or for themselves in a similar situation and was evaluated at the 2-month follow-up visit. statistical analyses were performed with fisher exact test, chi-square test, mann-whitney test, and student t test where appropriate. values less than .05 for p were considered statistically significant. results a total of 96 patients were studied, of whom 42 were treated by swl and 54 underwent tul. the patients' characteristics are summarized in table 1. there was no significant difference in patients' age, sex, and calculus size as well as the stone side between the 2 groups. the stone-free rate at 2-month follow-up was 71.4% in the patients of the swl group and 88.9% in those of the tul group (table 2). the eq was 56% and 81% for the swl and tul groups, respectively (p = .004). retreatment rate was 26.2% (11 patients) and 9.3% (5 patients) for the swl and tul groups, respectively (p = .027), and the number of treatment sessions per patient in the 76 table 1. characteristics of the patients and calculi in the shock wave lithotripsy (swl) and transureteral lithotripsy (tul) groups* *values in parentheses are percents. swl tul p value number of patients 42 (43.7) 54 (56.3) sex male 28 (66.6) 37 (68.5) female 14 (33.4) 17 (31.5) .84 stone side right 17 (40.5) 21 (38.9) left 25 (59.5) 33 (61.1) .87 mean stone size (mm) 7.6 ± 1.9 7.5 ± 2.4 .79 mean patients’ age (year) 46.02 ± 13 44.96 ± 12 .69 ziaee et al swl and tul groups were 1.26 and 1.09, respectively (p = .028). thirty patients in the swl group (71.4%) and 52 in the tul group (96.3%) were satisfied with their treatment (p = .001). there were no major complications in neither of the groups; however, minor complications (pain and hematuria) were more common in the tul group (table 2). discussion the choice of tul or swl for the treatment of lower ureteral calculi is still open to debate. the indications for ureteroscopic lithotripsy for the stones of all parts of the ureter have been expanded with the advent of smaller semirigid ureteroscopes, laser technology, and more robust flexible instruments.(12) it is stated that swl, even in its new generation formats, takes a back seat to more invasive endoscopic therapy.(13) previous swl failure, large calculi, hard calculi, and obstruction or impaction are clinical parameters that affect the outcomes of tul and even more the swl.(4) in this randomized clinical trial, we compared the efficacy of swl and tul for the treatment of impacted distal ureteral calculi. there are different definitions of impacted ureteral calculus in the literature. sinha and colleagues used a definition similar to one in our study except for they considered that the ureter below the stone should not be visualized in any ivu radiography up to 3 hours after the injection of the contrast.(5) roberts and coworkers defined impaction as ureteral calculi remaining unchanged in their location for at least 2 months,(14) while mugiya and colleagues defined it as calculi causing ureteral obstruction and not moving in response to manipulations such as ureteral catheterization.(15) regarding these different definitions of stone impaction in the literature, there are contradictory opinions that impacted stones may affect the treatment outcome. based on a critical analysis of the literature, segura determined pervious swl failure, large or hard calculi, obstruction or impaction, and certainty of results as the clinical parameters that are associated with a higher likelihood of swl failure.(4) sinha and colleagues investigated the effect of the failure to visualize the ureter distal to an impacted calculus on the successful lithotripsy. they concluded that complete clearance rates in the impacted as well as the nonimpacted calculi were both 76.7% and impaction seen on the ivu does not affect the results of swl.(5) in the report of endoscopic management of impacted ureteral stones using a small-caliber ureteroscope and a laser lithotripter, mugiya and coworkers showed that the stone-free rate with a single session of ureteroscopy was 96%.(15) this is comparable with the stone-free rates of 97% to 100% for the ureteral calculi generally reported in the literature for the treatment of lower ureteral calculi using a single procedure and laser lithotripsy without ureteral orifice dilatation.(16) generally, stone-free rates for swl and tul of the distal ureteral calculi are 50% to 99% and 86.4% to 100% in the literature, respectively; whereas, retreatment rates (in patients with treatment failure) are 7.1% to 50% and 0.8% to 19.8%, respectively.(1,17-21) the stone-free rate from a single procedure with ballistic lithotripsy is 74% to 100%.(22-28) in our study, the stone-free rate was 71.4% with swl and 88.9% with tul using ballistic lithotripsy, and retreatment rate was 26.2% and 9.3%, respectively (p = .027). in 1990, clayman and colleagues developed the eq to help compare the results of the different swl technologies that also takes into account the need for retreatment and auxiliary procedures. according to this formula, an ideal swl machine would have an eq of 100%, ie, all calculi are fragmented and passed without any retreatment or auxiliary procedure. in contrast, lithotripters with an eq of 50% or less would be largely inefficient since each patient would require a retreatment or auxiliary procedure to achieve a 100% stone-free rate.(11) in our study, the eq for tul and swl were 81% and 56.1%, respectively (p = .004), demonstrating the advantage of the former. there were no major complications in neither group and only minor 77 table 2. stone-free rates and complications in the patients of the shock wave lithotripsy (swl) and transureteral lithotripsy (tul) groups* *values in parentheses are percents. swl tul p value stone-free patients at 2 weeks 24 (57.1) 37 (68.5) .28 at 2 months 30 (71.4) 48 (88.9) .037 complications pain 14 (33.3) 25 (46.3) pain and hematuria 17 (40.5) 27 (50) total 31 (73.8) 52 (96.3) .006 shock wave versus transureteral lithotripsy for ureteral calculi temporary complications were noted which were more frequent in the patients treated with tul. however, the satisfaction rate, albeit assessed subjectively, was higher among the patients in the tul group. conclusion based on the results of this study, it seems that for the impacted calculi less than 12 mm in the distal ureter, ureteroscopy with intracorporeal lithotripsy is the preferred treatment method and patients are more satisfied with this option. references 1. turk tm, jenkins ad. a comparison of ureteroscopy to in situ extracorporeal shock wave lithotripsy for the treatment of distal ureteral calculi. j urol. 1999;161:45-6. 2. tiselius hg, ackermann d, alken p, et al. guidelines on urolithiasis. european association of urology urological guidelines. [updated june 2005]. available from: http://www.uroweb.org/index.php?structure_id=140#ea u_guidelines_online. 3. lingeman je, lifshitz da, evan ap. surgical management of urinary lithiasis. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 3361-451. 4. ramakumar s, segura jw. when not to use shock wave lithotripsy for ureteral stones. contemp urol. 2001;13:54-65. 5. sinha m, kekre ns, chacko kn, et al. does failure to visualize the ureter distal to an impacted calculus constitute an impediment to successful lithotripsy? j endourol. 2004;18:431-5. 6. gomha ma, sheir kz, showky s, abdel-khalek m, mokhtar aa, madbouly k. can we improve the prediction of stone-free status after extracorporeal shock wave lithotripsy for ureteral stones? a neural network or a statistical model? j urol. 2004;172:175-9. 7. nabi g, baldo o, cartledge j, cross w, joyce ad, lloyd sn. the impact of the dornier compact delta lithotriptor on the management of primary ureteric calculi. eur urol. 2003;44:482-6. 8. deliveliotis c, chrisofos m, albanis s, serafetinides e, varkarakis j,protogerou v. management and follow-up of impacted ureteral stones. urol int. 2003;70:269-72. 9. abdel-khalek m, sheir k, elsobky e, showkey s, kenawy m. prognostic factors for extracorporeal shockwave lithotripsy of ureteric stones--a multivariate analysis study. scand j urol nephrol. 2003;37:413-8. 10. abdel-khalek m, sheir kz, mokhtar aa, eraky i, kenawy m, bazeed m. prediction of success rate after extracorporeal shock-wave lithotripsy of renal stones--a multivariate analysis model. scand j urol nephrol. 2004;38:161-7. 11. clayman rv, mcclennan b, gavin t, denstedt jd, andriole gl. lithostar: an electromagnetic acoustic shock wave unit for extracorporeal lithotripsy. j endourol. 1989;3:307-10. 12. anagnostou t, tolley d. management of ureteric stones. eur urol. 2004;45:714-21. 13. clayman rv. editorial comment. j urol 2004;172:2105. 14. roberts ww, cadeddu ja, micali s, kavoussi lr, moore rg. ureteral stricture formation after removal of impacted calculi. j urol. 1998;159:723-6. 15. mugiya s, nagata m, un-no t, takayama t, suzuki k, fujita k. endoscopic management of impacted ureteral stones using a small caliber ureteroscope and a laser lithotriptor. j urol. 2000;164:329-31. 16. watterson jd, sofer m, wollin ta, nott l, denstedt jd. holmium: yag laser endoureterotomy for ureterointestinal strictures. j urol. 2002;167:1692-5. 17. bierkens af, hendrikx aj, de la rosette jj, et al. treatment of midand lower ureteric calculi: extracorporeal shock-wave lithotripsy vs laser ureteroscopy. a comparison of costs, morbidity and effectiveness. br j urol. 1998;81:31-5. 18. kupeli b, biri h, sinik z, et al. extracorporeal shock wave lithotripsy for lower caliceal calculi. eur urol. 1998;34:203-6. 19. park h, park m, park t. two-year experience with ureteral stones: extracorporeal shockwave lithotripsy v ureteroscopic manipulation. j endourol. 1998;12:501-4. 20. pardalidis np, kosmaoglou ev, kapotis cg. endoscopy vs. extracorporeal shockwave lithotripsy in the treatment of distal ureteral stones: ten years' experience. j endourol. 1999;13:161-4. 21. peschel r, janetschek g, bartsch g. extracorporeal shock wave lithotripsy versus ureteroscopy for distal ureteral calculi: a prospective randomized study.j urol. 1999;162:1909-12. 22. aghamir sk, mohseni mg, ardestani a. treatment of ureteral calculi with ballistic lithotripsy. j endourol. 2003;17:887-90. 23. de sio m, autorino r, damiano r, oliva a, perdona s, d'armiento m. comparing two different ballistic intracorporeal lithotripters in the management of ureteral stones. urol int. 2004;72:52-4. 24. keeley fx jr, pillai m, smith g, chrisofos m, tolley da. electrokinetic lithotripsy: safety, efficacy and limitations of a new form of ballistic lithotripsy. bju int. 1999;84:261-3. 25. leidi gl, berti gl, canclini l, et al. ureteroscopy and stone lithotripsy with lithoclast: personal experience. arch ital urol androl. 1997;69:181-3. 26. menezes p, kumar pv, timoney ag. a randomized trial comparing lithoclast with an electrokinetic lithotripter in the management of ureteric stones. bju int. 2000;85:22-5. 27. terai a, takeuchi h, terachi t, et al. intracorporeal lithotripsy with the swiss lithoclast. int j urol. 1996;3:184-6. 28. vorreuther r, klotz t, heidenreich a, nayal w, engelmann u. pneumatic v electrokinetic lithotripsy in treatment of ureteral stones. j endourol. 1998;12:233-6. 78 re: surgical treatment of erectile dysfunction and peyronie’s disease using malleable prosthesis peyronie’s disease (pd) is a growing problem in our community, and in contrast to the literature most patients affected with this disease are usually aged between 20 and 40 years. prevalence is 3-9% according to rochelle and levine report.(1) but according to my experience, pd is more prevalent. schwarzer and colleauges suggest an increasing incidence of pd.(2) may be, this increase is correlated and appears to coincide with the advent of phosphodiesterase-5 inhibitors and other erection-enhancing drugs. usta and colleagues(3) have demonstrated that erectile dysfunction (ed) is highly prevalent in patients with pd, ranging from 20% to 54%. most of the affected patients seek help in late phase of pd, when the plaques have involved nearly whole of the penis, and resulted in severe ed. nearly all of the patients in advanced stage of pd (when the plaques have already been calcified) suffer from some degree of ed. surgical techniques for the managing of pd are divided into 3 categories: procedures which shorten the convex, uninvolved side of the tunica albuginea, techniques which lengthen the concave, involved side, and penile prosthesis implantation (ppi). i agree with the authors that in advanced stage of disease, ppi provides the most promising outcome and the patients will be more probably to reserve potency than after conservative management. the penile curvature associated with pd can be effectively corrected by a nesbit procedure, but this can result in a considerable amount of penile shortening. to address this issue, plaque excision and grafting with some materials such as tunica vaginalis, temporalis fascia, dermis or synthetic material has been proposed. unfortunately, these procedures have high risk of ed after surgery. surgical treatments should be considered after pd has stabilized. surgical correction of the penile curvature in pd should not be performed until at least 12 months after the onset and after the symptoms have been stable for 6, and preferably, 12 months. when surgical management is indicated, it must be individualized, directing not only at returning penile function but also restoring as much as possible the prior status of the patient. erectile function evaluation is crucial to detect whether surgery is indicated or not, as well as determining the most suitable surgical technique. penile tumescence, or incomplete rigidity, is often mistaken for normal erection, and the objective measurement of erection by pharmacologically induced erection is vital prior each intervention, it may alter the therapeutic plan. ppi is an outstanding option for men with pd associated with ed. when surgery is selected for treatment of pd, the quality of erection is imperative in the selection of surgical procedure and its method. the quality of erection may be classified as good, impaired but satisfactory with use of a phosphodiesterase-5 inhibitor, or poor even with treatment. in this latter group, the ppi should be considered, because the results are excellent. plaque excision and dermal graft was the standard management modality until a decade ago, but this procedure may now be considered as outdated. substantial number of patients with advanced pd, has widespread fibrosis in corpora cavernosa. it should be highlighted that ppi into corpora cavernosa with severe fibrosis is a challenging and risky procedure. in present study, it is not clear how ppi has been done in patients with fibrosed corpora cavernosa. the blind use of surgical devices to excavation can give rise to perforation of the tunica albuginea or damage to the urethra. the most difficult task during implanting a prosthesis is dilatation of the corpora cavernosa, whether through or alongside the fibrotic tissue, while protecting the integrity of the tunica albuginea and keeping the urethra from being injured. this is very difficult action, bearing in mind that, dilatation mandates the use of force against resistance, generally in a blind manner. unexperienced surgeons should refrain from operating these cases and instead refer them to the tertiary referral centers with enough experiences. various surgical methods and devices have been developed to diminish difficulty and complication rate of the procedure, including specialized devices which permit controlled sharp resection instead of blunt dilatation, incisions that allow safer and easier access to the penile crura, or procedures that allow visual control of the process. ignored weakening of the tunica albuginea is the consequence of blind vigorous mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specializing in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com. editorial comments vol 12 no 06 november-december 2015 2434 sexual dysfunction and infertility 2435 dilatation with resultant posterior migration of the penile prosthesis despite initial absence of perforation.(4) this is the cause why none of the “blinded techniques” has a 100% ppi survival rate, and why they may end up with damages to the urethra, or with perforations whether proximal or distal. ultrasound guidance can be used to monitor and adjust any of the surgical instruments in the corpora cavernosa, thus avoiding perforation of the tunica albuginea and injury to the urethra.(5) similarly, ultrasound guidance allows safe use of sharp instruments, such as the otis urethrotome, laparoscopy trocar, and scissors.(5) principal aims after surgical correction of penile deformity include normal painfree erection, comfortable coitus both for patient and his partner, and curvature that do not hamper vaginal intromission. while postoperative satisfaction is vital, some of the adverse effects of surgical procedures are unacceptable for patients; such as significant residual penile curvature, sensation of bumps under the skin,(6) penile sensory altrations, penile shortening,(7) and etc. weaknesses of present study include a retrospective design, small sample size, and subjective evaluations of satisfaction and erectile function. future studies for the surgical management of pd are needed using objective measures for determining penile blood flow, such as penile dynamic color doppler ultrasonography, and objective modalities for determining accurate penile rigidity and tumescence, such as rigiscan® nocturnal penile tumescence test. references 1. gelbard mk, dorey f, james k. the natural history of peyronie’s disease. j urol. 1990;144:1376-9. 2. schwarzer u, sommer f, klotz t, braun m, reifenrath b, engelmann u. the prevalence of peyronie’s disease: results of a large survey. bju int. 2001;88:727-30. 3. usta mf, bivalacqua tj, tokatli z, et al. stratification of penile vascular pathologies in patients with peyronie’s disease and in men with erectile dysfunction according to age: a comparative study. j urol. 2004;172:259-62. 4. mulcahy jj. crural perforation during penile prosthetic surgery. j sex med. 2006;3:177-80. 5. shaeer o. penile prosthesis implantation in cases of fibrosis: ultrasound-guided cavernotomy and sheathed trochar excavation. j sex med. 2007;4:809-14. 6. gholami ss, gonzalez-cadavid nf, lin cs, rajfer j, lue tf. peyronie’s disease: a review. j urol. 2003;169:1234-41. 7. carrier s, lue tf. for peyronie’s disease, act conservatively. contemp urol. 1994;6: 3-65. penile prosthesis in peyronie’s disease-yavuz et al. 1642 | expression and function of muscarinic subtype receptors in bladder interstitial cells of cajal in rats yingbing wu,1 chang shi,2 jianping deng,1, xin zhang,1 bo song,1 longkun li1 corresponding author: longkun li, md, phd department of urology, second affiliated hospital, third military medical university, chongqing 400037, china. tel: +86 23 6875 5623 e-mail: lilongk@hotmail.com received july 2013 accepted april 2014 1 department of urology, second affiliated hospital, third military medical university, chongqing, 400037, china. 2 beijing institute of pharmacology and toxicology, beijing, 100850, china. cellular and molecular urology cellular and molecular urology purpose: to locate the muscarinic (m) m2 and m3 receptors in bladder interstitial cells of cajal (iccs) and to determine the effects of m2 and m3 agonists on bladder iccs. materials and methods: a total of 30 adult male sprague-dawley rats weighing 225-250 g were used in this study. double-labeled fluorescence of muscarinic receptors and c-kit was performed for co-localization. to evaluate the effect of muscarinic agents on the excitation of bladder iccs, we analyzed the inward current of bladder iccs using the whole-cell patch clamp. the effect of muscarinic agents on the carbachol-induced inward currents was evaluated with the whole-cell patch clamp. results: m2 and m3 receptors were confirmed in the stroma iccs in rats’ bladders with double-labeled immunofluorescence. spontaneous action potential was observed in freshly isolated bladder iccs. the carbachol-induced inward ca2+ current in iccs can be blocked by atropine. the m2 receptor antagonist methoctramine (1 µm) showed a weak inhibitory capability on the inward ca2+ current [from 74.8 ± 9.6 to 63.3 ± 13.8 pascal (pa), n = 12, p = .03]. while the m3 receptor antagonist 4-diphenyl-acetoxy-n-methyl-piperidine methiodide (4-damp) (1 µm) significantly inhibited the inward ca2+ current (from 78.4 ± 11.2 to 17.3 ± 7.9 pa, n = 12, p < .001). conclusion: bladder iccs express m2 and m3 cholinergic receptors. most muscarinic cholinergic receptor antagonists, especially the m3 antagonists, can effectively inhibit the carbamylcholine-induced inward current of bladder iccs. keywords: animals; interstitial cells of cajal; microscopy; rats; urinary bladder; muscle; smooth; receptors. 1643vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l muscarinic subtype receptors in bladder icc | wu et al introduction the excitation and contraction of the urinary bladder are believed to be regulated neurogenically and myogeni-cally. the bladder can autonomously contract, but it can also initiate contraction under voluntary control. moreover, independent contraction can be observed in isolated detrusor strips.(1) it is unclear how the neurogenic and myogenic interactions coordinate. whether other mechanisms, such as a pacemaker or other regulation center, are involved remains to be clarified. interstitial cells of cajal (iccs) are widely distributed in the visceral smooth muscle organs. they possess the ability to selfexcite and produce an action potential. iccs in the gastrointestinal tracts(2) and in the upper urinary tracts(3) are believed to behave as pacemakers. additionally, they can receive the innervation pulse.(4) in the bladder, iccs have been found among the detrusor smooth muscle bundles and are closely associated with bladder excitation and contraction.(5,6) changes of bladder iccs can impact the initiation of spontaneous electrical activity, which may result in homologous functional disturbances in bladder contraction.(7) our previous studies have found that there were some specific changes in the quantity and physiological characteristics of bladder iccs in bladder instability.(8) it is critical to clarify the interaction between bladder innervation and iccs. cholinergic nerves are the main neurogenic factors in bladder function. the muscarinic (m) m2 and m3 receptors are the two main subtypes of muscarinic receptors in the bladder. when stimulated by cholinomimetics in vitro, iccs generate transient calcium, which is mainly mediated by the m3 receptor agents. (9) however, the expression and function of muscarinic receptors in bladder icc, and its potential value for treatment are still unclear. based on our previous studies and article reports, we hypothesized that muscarinic receptors were expressed in bladder icc, and played important role in the bladder excitation regulation. in this study, the location of m2 and m3 receptors in bladder iccs were observed with immunofluorescence. the effects of m2 and m3 agonists on bladder iccs were also recorded with the patch clamp technique. materials and methods animals a total of 30 adult male sprague-dawley rats weighing 225250 g were used in this study. this study was approved by the research council and animal care and use committee of southwest hospital, third military medical university, china (approval no. syxk20070002). the experiments conformed to the guidelines for the ethical use of animals, and all efforts were made to minimize animal suffering and to reduce the number of animals used. all animals were similarly fed in a special pathogen-free room, with free access to food and water. their general states of health and activity were monitored closely during the experiment. the experimental unit for morphology was rat, and for functional study the unit was rat bladder iccs. all the experimental manipulations were standardized, and accomplished by an experience experimenter. double-labeled fluorescence for bladder iccs and m2, m3 receptors to observe the location of m2 and m3 receptors in bladder icc, 10 rats were used for this study. double-labeled fluorescence of muscarinic receptors and c-kit was performed for co-localization. a 25% urethane (1.1 g/kg) intraperitoneal injection was used for anesthesia. under sterile conditions, the bladder was exposed through a median abdominal incision, and the bilateral ureters were ligated. then 4% paraformaldehyde was injected into the bladder through a transurethral epidural catheter, and the bladder neck was ligated after the bladder was filled to 20 cmh2o. the bladder was harvested and immersed into 4% paraformaldehyde solution for 6 to 8 h for continuous fixing. under a dissecting microscope, the mucous membrane and its substratum were carefully removed. the bladder’s muscular layer was longitudinally cut to 3 × 4 mm and then thoroughly rinsed with 0.01 m phosphate buffered saline (pbs) for 5 min × 3 times, 0.03% h2o2/methanol sealing endogenous peroxidase at 370c for 30 min, then 0.01 m pbs for 5 min × 3 times. it was then incubated in 1% bovine serum albumin (bsa) for 30 min at room temperature. the incubation solution was removed, and anti-c-kit displaying icc (goat anti-rat monoclonal, 1:200, sigma) and m2 or m3 receptor antibodies (rabbit anti-rat monoclonal, 1:2000c sigma) were added. the samples were incubated in 40c anti-dilution for 12 h (negative control in 0.01 m pbs as collation), and secondary antibodies marked with alexa 488 (donkey-anti-goat polyclonal, 1:2000c molecular probes) and alexa 594 (donkey-anti-rabbit polyclonal, 1:200, molecular probes) was added for 12 h. the samples were then thoroughly rinsed with 0.01 m pbs for 5 min × 3 times and 1644 | cellular and molecular urology incubated with the secondary antibody at 370c for 1 h. then, 4',6-diamidino-2-phenylindole (dapi) was added for 10 min for nucleus fluorescence loading. after 3 times of rinses with 0.01 m pbs (30 min each for the first two rinses and 3 h for the last time), the glass was sealed with glycerol and subjected to laser confocal microscopy. the c-kit was labeled in green under an excitation wavelength of 488 nm, and m2 or m3 receptors were labeled in red under a wavelength of 560 nm. fresh isolation and culture of bladder iccs to evaluate the effect of muscarinic agents on the excitation of bladder iccs, we analyzed the inward current of bladder iccs using the whole-cell patch clamp. according to the sample size for self anterior-posterior contrast study, the number was set at 8 for atropine (effect size/estimated standard deviation = 5.12), and 12 for methoctramine and 4-diphenyl-acetoxy-n-methylpiperidine methiodide (4-damp) (effect size/estimated standard deviation = 0.89), with power of 90%, significance level of 5%. all the variables were continuous variables. referring to the method of mcclosky (mccloskey & gurney, 2002), the urothelium layer was carefully removed, and the rat bladder was chopped into small pieces of about 1 mm3. the pieces were then incubated in a digestion solution containing (mg/ml) 1.0 type ii collagenase, 2.0 bovine serum albumin, and 1.0 trypsin inhibitor (all from sigma) at 370c for 30 min. the supernatant was then removed, and the isolated cells were immersed into enzyme-free hanks’ balanced salt solution (hbs; r and d) and cultured at 370c in 5% co2 and 95% o2 in dulbecco’s modified eagle’s medium (dmem; gibco, grand island, ny, usa) with 10% fetal bovine serum and 25 ng/ml scf until proper adherence. iccs with typical morphology with many branches under visible light positive for c-kit staining were prepared for the subsequent patch clamp studies, as reported by mccloskey and colleagues.(10) effects of muscarinic receptor antagonists on the carbachol-induced inward current the effect of muscarinic agents on the carbachol-induced inward currents was evaluated with the whole-cell patch clamp. using a one-step method, soft, neutral, hollow glass tubes (sutter instrument, america) were drawn by a vertical puller to prepare a microelectrode with a heat value of 56. a microelectrode with a diameter of approximately 1 μm was selected for the patch clamp studies. the supernatant isolated cells was removed and the adhered recording chamber was constantly perfused with hanks solution at room temperature and addifigure 1. the identification of positive muscarinic (m) receptors in iccs of rats bladder. a: m2 receptors in rat bladder iccs; b: m3 receptors in rat’s bladder iccs. double-labeled immunofluorescence using anti-c-kit (green, a2) for icc, anti-m2 (red, a3) or anti-m3 (red, b3) for m2 or m3, and dapi (blue, a1 and b1) for nuclei. arrows: examples of iccs double-marked with the c-kit and m2 (a4) or c-kit and m3 (b4) receptors. 1645vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l tionally, the cell under study was continuously superfused by a close-delivery system. positive pressure was loaded into the microelectrode cavity. the electrode was proceeded to the iccs to attain negative pressure and create substantial impedance. to record the whole cell current, a pclamp (axon instruments, america) with a sampling frequency of 4 khz and a filtering frequency of 2 khz was used. the 3d manipulator was regulated to seal on contact, and the impedance was set to reach 1 gω. the cell membrane was sucked and broken to create a wholecell recording mode. whole-cell current recording was conducted in voltage clamp mode. all recorded data were analyzed and treated using clampfit 9.2 at the backstage. the membrane potential was set at -50 mv with the clamp. carbamylcholine (1 µm and 10 µm, sigma) was added to induce an icc inward ca2+ current, and various antagonists, including the mreceptor antagonist atropine (1 µm, sigma), the m3-receptor antagonist 4-damp (1µm, sigma), and methoctramine, were administered to investigate their functional effect on the carbachol-induced (10 µm, sigma) inward ca2+ current in iccs. statistical analysis all the quantitative data were confirmed to obey the normal distribution with homogeneity of variance by test of normality, and were presented as mean ± sd. student’s t-test was used for comparison [statistical package for the social science (spss inc, chicago, illinois, usa) version 13.0 software)], with p < .05 considered significant. all the data were double-blinded, randomized and analyzed using posteriori tests. results double-label fluorescence for m2 or m3 receptors and bladder iccs iccs were identified by their c-kit positivity and spindle shape. m2 (figure 1a) and m3 (figure 1b) receptors were confirmed in the stroma iccs in rats’ bladders with double-labeled immunofluorescence. effects of muscarinic receptor antagonists on carbacholinduced bladder contraction spontaneous action potential was observed in freshly isolated bladder iccs (figure 2). iccs can be activated with a dosedependent inward ca2+ current induced by carbachol. the peak current values in 1 µm and 10 µm of carbachol are 18.3 ± 8.7 pascal (pa) and 75 ± 10.9 pa, respectively, with statistical differences (n = 8, p <0.001; figures 3a and b). the carbacholinduced inward ca2+ current in iccs can be blocked by atropine. when the carbachol dose was set at 10 µm, 1 µm atropine could significantly reduce the peak current from 77.1 ± 10.0 pa to 5.8 ± 2.7 pa (n = 8, p < .001; figures 3c and d). the carbachol-induced inward ca2+ current in iccs can also be blocked by m2 and m3 receptors antagonists. the m2 receptor antagonist methoctramine (1 µm) showed a weak inhibitory capability on the inward ca2+ current (from 74.8 ± 9.6 to 63.3 ± 13.8 pa , n = 12, p = 0.03; figures 3e and f), while the m3 receptor antagonist 4-damp (1 µm) significantly inhibited the inward ca2+ current (from 78.4 ± 11.2 to 17.3 ± 7.9 pa, n = 12, p < .001; figures 3g and h). discussion many studies on detrusor myocytes, receptor expression, cellcell communication and cell phenotypic alteration have been conducted, but the mechanisms responsible for bladder excitation and contraction have not been well clarified.(11) iccs distributing submucously and among the smooth muscle bundles are thought to mediate signal transmission from neurons to smooth muscles.(12,13) in this study, we hypothesized and confirmed the expression and function of muscarinic cholinergic subtype receptors in iccs with double-labeled immunofluorescence. m2 and m3 receptors were confirmed in bladder iccs. in human and guinea pig bladder, the proportion of m2 and m3 is about 3:1, although the m3 subtype is dominant in the excitation of smooth muscle contraction via gq/11 activating hydrolysis of phosphoinositide, ip3 production, and elevation of intracellular ca2+. conversely, m2 receptors may indirectly enhance m3-mediated contraction, by opposing the normal effects of β-adrenoceptor g protein-coupled activation of adenylyl cyclase which lead to cyclic adenosine mono phosphate (camp) production and bladder relaxation.(14) the innervation methods of smooth muscles and skeletal muscles are different. muscarinic subtype receptors in bladder icc | wu et al figure 2. the spontaneous action potential of novel icc samples isolated from adult rat’s bladders. 1646 | in skeletal muscle organs, neural impulses can directly activate the muscle cells through neuromuscular synapses. in smooth muscle organs, there are no analogous structures connecting the cells and neural terminals. when the innervation impulse reaches the nerve terminal, the secretory vesicle releases neurotransmitters, which diffuse throughout the intercellular fluid and act on the target cells. many factors can affect excitation through this regulatory pathway. because iccs in the gastrointestinal tracts are considered pacemakers, iccs in the bladder might be presumed to facilitate signal transduction from nerve terminals to detrusor myocytes. because iccs express the specific cell membrane surface receptor kit, the c-kit receptor identification companion and its cell shape and phenotype have been acknowledged as the standards for iccs identification.(15) yamanishi and colleagues found that icc in the bladder have close structural relationships with cholinergic nerves. freshly dispersed detrusor iccs and iccs in situ respond to cholinergic stimulation by firing ca2+ transients.(8) among the innervation types in the nervous system, cholinergic nerves particularly muscarinic cholinergic receptors are the most important for bladder excitation and contraction. the parasympathetic impulse can trigger the neural transmitter and initiate bladder contraction via the muscarinic cholinergic receptor. different subtypes of muscarinic cholinergic receptors can be classified by specific selective receptor antagonists. the expression of m2 and m3 subtype receptors has been confirmed mainly in the bladder. muscarinic cholinergic receptors with a high affinity with af-dx 116 are defined as type m2, while those with a high affinity with 4-damp are defined as type m3. different blocking agents with relative selectivity for muscarinic receptors have been obtained. among these agents, triptiramine has been found to possess the highest affinity with m2 receptors, followed by afdx384 and imbacine. 4-damp possesses the highest affinity with m3 receptors, followed by darifenacin.(16) m2 receptors are more abundant than m3 receptors in the bladder, which may indirectly mediate detrusor contraction by deteriorating the detrusor dilatation mediated by the β adrenergic nerve.(17) although m3 receptors are less prevalent, they are believed to play a central role in mediating bladder contractions.(18) in the gastrointestinal tract, iccs in the gastric antrum and stomach can be stimulated by cholinergic neural pulses, and they can subsequently increase the slowwave frequency. this effect can be mediated by m3 receptors, indicating that cholinergic neurotransmitters can regulate icc excitation of the gastrointestinal tract and subsequently effect smooth muscle contraction.(19) it can be assumed that iccs in the urinary bladder can influence bladder excitation, which can be regulated by muscarinic cholinergic nerves, especially m3 receptors. in our functional studies, the results might indicate that bladder iccs are mainly excited by m3 receptors, as displayed by inward currents and depolarization. it is generally believed that m3 receptors may activate phosphoinositide hydroxylation by coupling with the gq /11 of g protein to produce ip3 and dag as second messengers, thereby mediating the increase of the calcium ions in cells. m3 receptors also directly induce detrusor contractions,(20) but the detailed signal pathway still needs to be clarified. the functional studies on the effect of cholinergic antagonists on the carbachol-induced icc inward current sugcellular and molecular urology figure 3. effects of carbachol, atropine, methoctramine and 4-damp to inward ca2+ currents of bladder iccs. a and b: carbachol-induced inward currents in bladder iccs. c and d: atropin’s inhibition of the inward current stimulated by carbachol. e and f: methoctramine’s inhibition of the inward current stimulated by carbachol. g and h: 4-damp’s inhibition of the inward current stimulated by carbachol. 1647vol. 11 | no. 03 | may june2014 |u r o lo g y j o u r n a l references 1. xiao cg, du mx, dai c, li b, nitti vw, de groat wc. an artificial somatic-central nervous system-autonomic reflex pathway for controllable micturition after spinal cord injury: preliminary results in 15 patients. j urol. 2003;1701237-41. 2. mccann cj, hwang sj, bayguinov y, colletti ej, sanders km, ward sm. establishment of pacemaker activity in tissues allotransplanted with interstitial cells of cajal. neurogastroenterol motil. 2013;25:e418-28. 3. mccloskey kd, gurney am. kit positive cells in the guinea pig bladder. j urol. 2002;168:832-6. 4. feldstein ae, miller sm, el-youssef m, et al. chronic intestinal pseudoobstruction associated with altered interstitial cells of cajal networks. j pediatr gastroenterol nutr. 2003;36:492-7. 5. mccloskey kd. characterization of outward currents in interstitial cells from the guinea pig bladder. j urol. 2005;173:296-301. 6. davidson ra, mccloskey kd. morphology and localization interstitial cells in the guinea pig bladder: structural relationships with smooth muscle and neurons. j urol. 2005;173:1385-90. 7. nakagawa t, misawa h, nakajima y, takaki m. absence of peristalsis in the ileum of w/w(v) mutant mice that are selectively deficient in myenteric interstitial cells of cajal. j smooth muscle res. 2005;41:141-51. 8. wang y, fang q, lu y, song b, li w, li l. effects of mechanical stretch on interstitial cells of cajal in guinea pig bladder. j surg res. 2010;164:e213-e9. 9. johnston l, carson c, lyons ad, davidson ra, mccloskey kd. cholinergic-induced ca2+ signaling in interstitial cells of cajal from the guinea pig bladder. am j physiol renal physiol. 2008;294:645-55. 10. mccloskey kd. interstitial cells in the urinary bladder-localization and function. neurourol urodyn. 2010;29:82-7. 11. li l, jiang c, hao p, li w, song c, song b. changes of gap junctional cell-cell communication in overactive detrusor in rats. am j physiol cell physiol. 2007;293:c1627-35. 12. sanders km, ordog t, ward sm. physiology and pathophysiology of the interstitial cells of cajal: from bench to bedside. iv. genetic and animal models of gi motility disorders caused by loss of interstitial cells of cajal. am j physiol gastrointest liver physiol. 2002;282:g747-56. 13. sui gp, rothery s, dupont e, fry ch, severs nj. gap junctions and connexin expression in human suburothelial interstitial cells. bju int. 2002;90:118-29. 14. yamanishi t, chapple cr, chess-williams r. which muscarinic receptor is important in the bladder? world j urol. 2001;19:299-306. 15. torihashi s, ward sm, nishikawa s, nishi k, kobayashi s, sanders km. c-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract. cell tissue res. 1995;280:97-111. 16. formey a, buscemi l, boittin fx, bény jl, meister jj. identification and functional response of interstitial cajal-like cells from rat mesenteric artery. cell tissue res. 2011;343:509-19. 17. braverman as, doumanian lr, ruggieri mr. m2 and m3 muscarinic receptor activation of urinary bladder contractile signal transduction. . denervated rat bladder. j pharmacol exp ther. 2006;316:75880. 18. staskin dr, macdiarmid sa. using anticholinergics to treat overactive bladder: the issue of treatment tolerability. am j med. 2006;119:9-15. 19. epperson a, hatton wj, callaghan b, et al. molecular markers expressed in cultured and freshly isolated interstitial cells of cajal. am j physiol cell physiol. 2000;279:c529-39. 20. igawa y. discussion: functional role of m(1), m(2), and m(3) muscarinic receptors in overactive bladder. urology. 2000;55:47-9. muscarinic subtype receptors in bladder icc | wu et al gest iccs’ important role in regulating bladder excitation from neurons to detrusor myocytes. conclusion bladder iccs may play an important role in regulating bladder excitation and contraction, presumably through the muscarinic cholinergic transmissions to the detrusor myocytes. bladder iccs express m2 and m3 cholinergic receptors. most muscarinic cholinergic receptor antagonists, especially the m3 antagonists, can effectively inhibit the carbamylcholine-induced inward current of bladder iccs. acknowledgements this study was supported by the national natural science foundation of china (no. 81230017, 81170705) and chongqing scientific fundation (cstc2010ba5005). the funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. yingbing wu and chang shi contributed equally. conflict of interest none declared. zhen-yu ou, jin-bo chen, zhi chen, min-feng chen, long-fei liu, xu zhou, yang-le li, lin qi, xiong-bing zu department of urology, xiangya hospital, central south university, changsha city, hunan province, china. corresponding author: xiong-bing zu, md department of urology, xiangya hospital, central south university, changshacity, hunan province, 410008, china. tel: +86 731 84327242 fax: +86 731 84327242 e-mail: whzuxb@163. com received june 2013 accepted june 2014 purpose: to report a modified retroperitoneoscopic dismembered pyeloplasty technique and its application in the treatment of ureteropelvic junction obstruction (upjo). materials and methods: from june 2010 to march 2012, retroperitoneoscopic dismembered pyeloplasty was performed in 46 patients with upjo. briefly, the renal pelvis was incised in the anterior aspect instead of the lateral aspect, and proximal ureter was spatulated with incision on its posterior wall. after adequately trimming, two layers of ureteropelvic anastomosis respectively lay on left and right side of one laparoscopic plane other than two different planes. in our refined procedure, the difficulty of intracorporeal suturing was greatly decreased. data from 19 months mean follow-up were analyzed to evaluate the surgical outcomes. results: all operations were completed without open conversion. the mean operative time, estimated blood loss, and postoperative hospitalization stay were 108 min (75 to 155 min), 30 ml (15 to 60 ml) and 4 days (2 to 9 days), respectively. no intraoperative complications were occurred. postoperative complications included 2 cases of minor abdominal wall hematoma and 1 case of transient postoperative anastomotic leakage for 8 days, which all were successfully treated by conservative management. a mean follow-up of 19 months (12 to 36 months) was performed which showed a success rate of 97.8%. one case (2.2%) underwent open surgery for persistence upjo two months later. conclusion: our modification to the retroperitoneoscopic dismembered pyeloplasty procedure is technically feasible and reliable with low complications. it could be implemented as a useful alternative technique to greatly decrease the difficulty of this procedure. keywords: hydronephrosis; surgery; laparoscopy; retroperitoneal space; treatment outcome; ureteral obstruction; kidney pelvis; reconstructive surgical procedures. laparoscopic urology retroperitoneoscopic dismembered pyeloplasty for ureteropelvic junction obstruction: modification of the procedure and our experience 1763 laparoscopic urology urology journal vol. 11 no. 04 july august 2014 1764 operative technique all patients received general anesthesia and were positioned in the lateral decubitus position with hyperextension. a four-port balloon-dissecting retroperitoneal laparoscopic approach was used. a 2 cm incision was first made beneath the 12th costal margin at the posterior axillary line. a hemostatic forceps was then used to divide fascia lumbodorsalis and a finger was inserted to separate the retroperitoneal fat and the retroperitoneal space. the creation of a working space in the retroperitoneum was performed by a homemade balloon dilator with 800-1000 ml air infused for 5 minutes. three ports were guided by index finger and placed at the subcostal anterior axillary line (5 mm trocar for surgeon) , 2 cm above the iliac crest (10 mm trocar for 30° telescope ) and midaxillary line at the level of 11th rib (5 mm trocar for assistant), respectively. also, a 10 mm trocar for surgeon was introduced through the initial incision. then a co 2 insufflation was performed at a pressure of 12 mmhg. after completing the retroperitoneal access, the extraperitoneal fat was dissected to reveal gerota’s fascia, which was then incised longitudinally close to the psoas magnum muscle. the perirenal fat was dissected to reveal the posterior surface of the kidney. the lower pole of the kidney was identified. surrounding fatty and connective tissues were bluntly dissected from the pelvis and upper ureter using the tip of the suction tube. the location of upjo could be identified after the pelvis and the upper ureter had been fully exposed. our technological innovation in the anderson-hynes procedure includes the modifications of incision and trim of the pelvis, ureter and intracorporeal suture. the anteriorly visible renal pelvis was incised using an endoscopic scissor. dilated renal pelvis was cut from proximal part to distal part until exceeding obstructed position. the transection of the ureter was made about 0.5 cm distal to the obstructed position. the proximal ureter was spatulated with a 1.0 cm longitudinal incision on its posterior wall (figure 1a and 1b). the stenotic segment of upj and redundant renal pelvis was cut down. then renal pelvis was cut into a trumpet shape, and bell mouth was towards surgeon, so that the shape resembled the shovel face which is formed by ureter backward (figure 1c and 1d). a single 4-0 absorbable monofilament stitch was placed from the most inferior point of the ureteral spatulation to the most dependent portion on the posterior wall of the trimmed pelvis (figure 2a and 2b). a double-j ureteral stent (6 french [f] or 7f for adults, 4f or 5f for children) was inserted in an antegrade fashion. this procedure was completed with the help of a suction tube. the surgeon passed the stiff end of a guide wire through a stent pusher (40 cm) and then through the open end of a double-j ureteral stent to straighten the close end of the stent. one artery forceps was applied to clamp the end of the pusher. a suction tube was sent to retroperitoneum through the trocar at the subcostal posterior axillary line. then, the stent was passed through the suction tube and the stent was allowed to project about 2 cm beyond the tip of the tube. under direct vision, the surgeon drew ureter with a grasping forceps, and guided stent with suction tube so as introduction aureteropelvic junction obstruction (upjo) is an obstruction or blockage at the junction of the kidney and ureter. when a upjo occurs, the amount of urine produced is more than the amount that can be drained through the ureter causing a ‘backup’ of urine. in 1949, anderson and hynes reported the technique of open dismembered pyeloplasty (anderson-hynes technique), and this technique had ever since been the gold standard for the treatment of upjo with an overall success rate greater than 90%.(1-4) with the development of minimally invasive surgical techniques, laparoscopic dismembered pyeloplasty through a transperitoneal or retroperitoneal route has been widely accepted by urologists.(5,6) in fact, laparoscopic pyeloplasty (lp) has now emerged as a favored surgical treatment option for surgical correction erson-hynes technique of upjo in the last two decades. it has a success rate equivalent to that of the open procedure and has advantages of minimal morbidity and significant reduction of hospital care costs.(7) however, the procedure demands extremely high laparoscopic surgical skills, especially in laparoscopic suturing and knot-tying. the successful rate of lp is still strongly limited by the challenge of the steep learning curve. in the present study, we report our experience with retroperitoneoscopic dismembered pyeloplasty for the treatment of upjo since 2008, with focus on modifications to this technology. materials and methods study subjects between june 2010 and march 2012, forty-six consecutive patients underwent retroperitoneal laparoscopic dismembered pyeloplasty at our center. our hospital is a public, teaching hospital and the largest medical center in our province. this study obtained ethics approval from the ethics committee at xiangya hospital, central south university, changsha, hunan province, china. also, we obtained informed consent from the adult participants or from the parents of the children participants in study. the informed consent was written and specified in the operative consent. the all procedures were performed by a single, experienced laparoscopic surgeon (xiong-bing zu). the mean age of patients was 21 years (range, 13 to 50 years), and of the 20 women and 26 men, 25 presented upjo on the right side and 21 on the left side. thirty-six (78%) cases had suffered from mild to moderate flank pain with a duration of 3 months to 2 years. the other 10 (22%) patients were asymptomatic and the upjo was discovered incidentally while receiving renal ultrasonography or computed tomography for different reasons. no patients had undergone previous renal operations. all patients were subjected to a preoperative evaluation (renal ultrasonography, diuretic renography, intravenous urography with high-volume contrast medium or computed tomography) to confirm the diagnosis and the degrees of hydronephrosis. the inclusion criteria were: an obstructive pattern on diuretic renal scan and impaired renal function, an increasing degree of hydronephrosis and symptoms such as recurrent urinary tract infection and flank pain. retroperitoneoscopic dismembered pyeloplasty-qu et al minor postoperative complications (clavien-dindo classification grade i)(8) occurred in 3 cases (6.5%). abdominal wall hematomas occurred in 2 patients which were resolved spontaneously. one patient developed urine leakage which was managed successfully through extending the drainage time up to 8 days. no major postoperative complications were observed. the mean follow-up in our series was 19 months (range, 12 to 36 months). at the first time of follow-up, 35 of 36 preoperative symptomatic patients reported a complete resolution of symptoms. all 10 preoperative asymptomatic patients didn’t have persistent flank pain after surgery. the overall success rate in the present study was 97.8%. only one (2.2%) patient had persistent flank pain, who presented a persistence of upjo with t1/2 > 20 min on the diuretic renal scan after treatment with retrograde insertion of a double-j ureteral stent for 2 months. this patient later underwent open dismembered pyeloplasty successfully. the obstruction reason was a fibrotic scar around the upj. the patients and operative characteristics are shown in table. discussion for decades, open anderson-hynes dismembered pyeloplasty has been regarded as the gold standard for the treatment of upjo due to its extensive use and high success rate. the development of laparoscopic instruments and refinement of laparoscopic techniques have enabled surgeons to perform technically more complex reconstructive surgery. in particular, the lp has emerged as a feasible and effective treatto insert stent into the distal end of ureter across the cut of ureter. the assistant promoted the pusher till the joint of the pusher and stent had only a distance of 1-2 cm from the cut of ureter so that the distal end of stent is ensured to enter bladder. the surgeon clamped the open end of stent with a forceps, and then the assistant extracted the guide wire and pusher. afterwards, the surgeon drew the proximal end of stent into renal pelvis. after placing the double-j ureteral stent, interrupted suture was used for the left ureteropelvic anastomosis. the suture was from the distant portion on the anterior wall of the pelvis to anterior surface of the proximal aspect of the ureter. the right ureteropelvic anastomosis was completed using similar suture. after the preceding procedures, two sutured anastomotic stomas were placed respectively on the left and right side in the same plane (figure 2c and 2d). then, the remaining pyelotomy was closed with a running suture (figure 3). all the sutures were placed and tied intracorporeally, with all knots located outside the lumen. during our procedure, a stick was used through the fourth trocar for minimizing the interference of the surrounding tissue in the operating field. if a crossing vessel was encountered during the dissection of the ureter, it was preserved. the ureter and the renal pelvis were transposed anteriorly to the vessels. the procedure was completed with a suction drain placed through the trocar above the iliac crest into the retroperitoneum. the foley catheter was removed on postoperative day 2 or 3. the drain was subsequently removed when the drainage was < 10 ml/24 h after foley catheter removal. the patient demographic data and perioperative outcomes were recorded. patients were followed up for an average of 19 months. intravenous urography with high-volume contrast medium and diuretic renography were performed after 3 months and yearly thereafter. success criteria were defined as adequate renal excretion (t1/2 < 20 min) on diuretic renal scan and improvement or stabilization in function, along with the complete resolution of presenting symptoms. results in the present study, all 46 patients underwent modified retroperitoneoscopic dismembered pyeloplasty successfully without conversion to open surgery. the underlying causes were determined intraoperatively, and included intrinsic upj stenosis in 33 cases and crossed vessel compression in 13 cases. the mean operative time was 108 min (range, 75 to 155 min). the mean estimated blood loss was 30 ml (range, 15 to 60 ml) and none of the patients required blood transfusion. no intraoperative complications occurred in the 46 procedures. mean hospital stay was 4 days (range, 2 to 9 days). an artery vessel crossing on the ventral side of the upj was encountered in 13 patients, all the vessels were preserved and the ureter and the renal pelvis are transposed anteriorly to the vessels. the double-j ureteral stent was removed 4 weeks postoperatively by a cystoscope. we observed if any complications happened until the double-j ureteral stent removed. after that, we assessed if late complications happened during follow-up. variables values age (mean, range) (years) 21 (13-50) gender (male/female) 26/20 side of obstruction (left/right) 21/25 symptoms, no. (%) asymptomatic 10 (22) flank pain 36 (78) operating time (mean, range) (min) 108 (75-155) estimated blood loss (mean, range) (ml) 30 (15-60) crossing vessels, no. (%) 13 (28.3) postoperative hospital stay (mean, range) 4 (2-9) (days) intraoperative complications, no. (%) (0.0) postoperative complications, no. (%) 3 (6.5) abdominal wall hematoma, no. (%) 2 (4.3) urine leakage, no. (%) 1 (2.2) follow-up time (mean, range) (months) 19 (12-36) table. demographic and clinical characteristics of study subjects and operative results. 1765 laparoscopic urology urology journal vol. 11 no. 04 july august 2014 1766 pleted on one two-dimensional plane. the inconvenience in operation due to the limitation of stereoscopic vision is thus overcome. in addition, an antegrade fashion for double-j ureteral stent insertion is used in the modified procedure. under the guidance of suction tube, the direction of stent is easily controlled after it is planted, allowing the stent to enter ureter smoothly. at the same time, the assistant can help push stent forward externally under the monitoring of the screen. thus, this procedure is easy and simple to carry out. in our procedure we did not have any migration of the ureteral stent in any patient which further demonstrated the effectiveness and reliability of the procedure. in the previous studies, the overall complication rate for the laparoscopic dismembered pyeloplasty were between 6% and 38%,(10,13,15-19) with most complications being related to hematoma formation or urine leakage. our overall complication rate in this study was 6.5% which was relatively low. only three patients presented minor postoperative complications which were resolved by conservative treatment. after the follow-up period of at least 12 months, our success rate was 97.8% which was similar to the previous experiences.(18-20) these results indicate that our innovative techniques are very valuable in enment alternative to open surgery, because it demonstrated a success rate similar to, or better than, that of open pyeloplasty but with lower morbidity, minimal invasion, less blood loss, shorter postoperative hospital stay and rapid recovery.(9,10) some previous series supported the view that lp had superseded open surgery as the new standard surgical management for upjo, with commensurate results and lower morbidity.(11-13) however, lp is a technically difficult procedure that needs considerable skills and expertise especially in intracorporeal suturing, and is hampered by its steep learning curve.(14) traditionally, the intracorporeal suturing has remained the most difficult part of lp. consequently, we present our personal experience and modifications of retroperitoneoscopic dismembered pyeloplasty to simplify the procedure. in this study,the authors created some technical innovations to the standard procedure, which included the modification of incising pelvis and ureter and simplification of anastomotic suture. in the new procedure, the renal pelvis is firstly incised in the anterior layer instead of the lateral aspect as described in the standard anderson-hynes technique. then the transected ureter is spatulated on its posterior wall. two spatulated inclined planes including forward pelvis slope and backward ureter slope, in similar shapes, are formed after trimming redundant pelvis and removing stenosis section. two left and right lateral anastomotic stomas were formed after suturing endpoints. in this way, we can transfer anterior and posterior anastomotic stomas (seen in standard anderson-hynes technique) (figure 4) to bilateral ones so as to greatly decrease difficulty of suturing (figure 3). laparoscopic surgery is generally a two-dimensional surgery which is lack of depth perception and spatial orientation in video vision. under such circumstance, it is very hard to incise and suture precisely two anastomotic stomas (one forward and the other one backward) on different planes. through our improvement, two edges of incision are placed on left and right side of one laparoscopic plane and bell mouth of renal pelvis is towards the surgeon. as a result, all sutures are comfigure 1. a and b: the proximal ureter was spatulated with a 1.0 cm longitudinal incision on its posterior wall; c and d: dilated renal pelvis was trimmed into a trumpet shape. figure 2. a and b: a single stitch was placed from the most inferior point of the ureteral spatulation to the most dependent portion on the posterior wall of the trimmed pelvis; c and d: two anastomotic stomas which were respectively on the left and right side of the same plane were formed (white arrows). figure 3. the remaining pyelotomy is closed with a running suture. retroperitoneoscopic dismembered pyeloplasty-qu et al son-hynes repair of ureteropelvic junction obstruction in 60 patients. j urol. 1989;142:704-6. 5. bauer jj, bishoff jt, moore rg, chen rn, iverson aj, kavoussi lr. laparoscopic versus open pyeloplasty: assessment of objective and sub jective outcome. j urol. 1999;162:692-5. 6. hao g, xiao j, yang p, shen h. laparoscopic retroperitoneal dismem bered pyeloplasty: single-center experience in china. j laparoendosc adv surg tech. 2013;23:38-41. 7. martina gr, verze p, giummelli p, et al. a single institute’s experience in retroperitoneal laparoscopic dismembered pyeloplasty: results with 86 consecutive patients. j endourol. 2011;25:999-1003. 8. dindo d, demartines n, clavien pa. classification of surgical compli cations: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 9. ben slama mr, salomon l, hoznek a, et al. extraperitoneal laparo scopic repair of ureteropelvic junction obstruction initial experience in 15 cases. urology. 2000;56:45-8. 10. zhang x, li hz, ma x, et al. retrospective comparison of retroperi toneal laparoscopic versus open dismembered pyeloplasty for ureteropel vic junction obstruction. j urol. 2006;176:1077-80. 11. eden cg, cahill d, allen jd. laparoscopic dismembered pyeloplasty: 50 consecutive cases. bju int. 2001;88:526-31. 12. symons sj, bhirud ps, jain v, shetty as, desai mr. laparoscopic py eloplasty: our new gold standard. j endourol. 2009;23:463-7. 13. moon da, el-shazly ma, chang cm, gianduzzo tr, eden cg. lapa roscopic pyeloplasty: evolution of a new gold standard. urology. 2006;67:932-6. 14. singh o, gupta ss, arvind nk. laparoscopic pyeloplasty: an analysis of first 100 cases and important lessons learned. int urol nephrol. 2011;43:85-90. 15. qadri sj, khan m. retroperitoneal versus transperitoneal laparoscopic pyeloplasty: our experience. urol int. 2010;85:309-13. 16. shoma am, el nahas ar, bazeed ma. laparoscopic pyeloplasty: a pro spective randomized comparison between the transperitoneal approach and retroperitoneoscopy. j urol. 2007;178:2020-4. 17. rassweiler jj, teber d, frede t. complications of laparoscopic pyelop lasty. world j urol. 2008;26:539-47. 18. inagaki t, rha kh, ong am, kavoussi lr, jarrett tw. laparoscopic pyeloplasty: current status. bju int. 2005;95:102-5. 19. blanc t, muller c, abdoul h, et al. retroperitoneal laparoscopic py eloplasty in children: long-term outcome and critical analysis of 10-year experience in a teaching center. eur urol. 2013;63:565-72. 20. jarrett tw, chan dy, charambura tc, fugita o, kavoussi lr. laparo scopic pyeloplasty: the first 100 cases. j urol. 2002;167:1253-6. suring high quality pelvis-ureter anastomosis with an ordinary two-dimensional vision. no comparison was carried out in this study between standard anderson-hynes technique and our modified technique. a full evaluation of our innovation necessitates more studies to compare the operative time, intracorporeal suturing time, complication rate, success rate and other perioperative data between the two procedures. conclusion in our experience, our modification to the standard retroperitoneoscopic dismembered pyeloplasty is technically ease and safe. thus, it might be a useful alternative to greatly decrease difficulty of this procedure. acknowledgement zhen-yu ou and jin-bo chen contributed equally to this work. conflict of interest none declared. references 1. o’reilly ph, brooman pj, mak s, et al. the long-term results of ander son–hynes pyeloplasty. bju int. 2001;87:287-9. 2. mikkelsen ss, rasmussen bs, jensen tm, hanghøj-petersen w, chris tensen po. long-term follow-up of patients with hydronephrosis treated by anderson-hynes pyeloplasty. br j urol. 1992;79:121-4. 3. clark wr, malek rs. ureteropelvic junction obstruction-observation on the classic types in adults. j urol. 1987;138:276-80. 4. nguyen dh, aliabadi h, ercole cj, gonzalez r. nonintubated anderfigure 4. two anastomotic stomas were respectively on the anterior and posterior plane in the conventional laparoscopic dismembered pyeloplasty. 1767 laparoscopic urology miscellaneus electrophysiological identification of central sensitization in patients with chronic prostatitis selda korkmaz,1* mert ali karadag,2 kemal hamamcioglu,3 mustafa sofikerim,4 murat aksu5 purpose: chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a chronic pain condition and a common problem in urology clinics. although many different etiologies and mechanisms exist, the exact cause of the disease has been unknown. central sensitization (cs) is defined as an augmentation of responsiveness of central cortical neurons to input from peripheral nociceptive structures. somatosensory evoked potentials (seps) is an electroneurophysiological method to assess cortical activity in somatosensory area of brain related to sensorial stimuli. we aimed to determine the presence of cs using the seps of dorsal penile nerve stimulation in patients with cp/cpps. materials and methods: seventeen male patients diagnosed cp/cpps and 17 male healthy controls were prospectively included in the study. for sep study, electrical stimulus was applied with penile ring electrodes. recording electrodes were placed as active to cz’ and reference electrode on fz’ according to the 10–20 international system. latency of n50 was defined as the second negative (upward) deflection of the w-shaped averaged cortical waveform. results: n50 latencies were significantly shortened in the patient group compared to the healthy controls (p < .001). conclusion: these results support the presence of central sensitization because of exaggerated transmission of pain sensation to the somatosensory cortex. therefore, normalization of transmission might be an important step in treatment of pain in patients with cp/cpps. this study can be counted as an important guiding on pathogenesis and treatment of disease. keywords: chronic pain; physiopathology; evoked potentials; somatosensory; neuropsychological tests; prostatitis; physiopathology. introduction chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a chronic pain condition and a common problem in urology clinics. according to the current national institutes of health (nih) definition, cp/ cpps is characterized by chronic pelvic pain symptoms that last for at least three of the prior six months, occur in the absence of a urinary tract infection or another identifiable cause such as malignancy, bacterial infection but in the presence of urinary symptoms or sexual dysfunction. the main complaint of cp is chronic pain that cannot be explained by any organic or morphological local change. cp/cpps is associated with a wide spectrum of symptoms including irritative and obstructive voiding symptoms, pain in the pelvic region, and sexual dysfunction like pain during ejaculation, depression, and psychosocial maladjustment.(1) it has been estimated that between 2% and 14% of men worldwide may have symptoms of cp/cpps.(2,3) although many proposed etiologies and mechanisms exist to explain the pathogenesis of cp/cpps,(4-9) neither cause of disease has been exactly known nor effective treatments have been identified.(10,11) central sensitization (cs) is defined as an augmentation of responsiveness of central cortical neurons to input from unimodal and polymodal receptors. the main cause of cs is the long-term potentiation or sensitization of nociceptive neurons and decreased activity in the antinociceptive system. here, the balance deteriorates to facilitate the formation of pain. although cs is usually an important factor in the modulation of pain sensation, in some conditions it can be the cause of chronic pain. the main complaint of cp/cpps is chronic pain that cannot be explained by any organic or morphological local change. therefore, cs might be the etiological factor for the pain sensation in cp/cpps. a previous study using thermal algometry as an indicator for the presence of cs in patients with cp/cpps demonstrated that noxious heat stimuliincreased pain sensitivity.(12) there are several methods, most of them electroneurophysiological, to determine presence of cs. somatosensory evoked potentials (seps) is an electroneurophysiological method that assesses cortical activity 1 nih/ninds human motor control section, bethesda, maryland, usa. 2 department of urology, kafkas university college of medicine, kars, turkey. 3 department of neurology, acibadem kayseri hospital, kayseri, turkey. 4 department of urology, acibadem kayseri hospital, acibadem university college of medicine, istanbul, turkey. 5 department of neurology, acibadem kayseri hospital, acibadem university college of medicine, istanbul, turkey. *correspondence: nih/ninds human motor control section, bethesda, maryland, usa. tel: +1 240 8010674. e-mail: korkmazs78@gmail.com. received january 2015 & accepted april 2015 vol 12 no 04 july-august 2015 2280 in the somatosensory area of brain related to sensorial stimuli.(13-15) sep recording of dorsal penile nerve stimulation is not a commonly used clinical test, however it is analogous to other sep studies in that it is a neurophysiological test to show the excitability of the sensorial cortex via a pathway from the dorsal penile nerve to brain. therefore, we studied the seps of dorsal penile nerve stimulation in cp/cpps and compared them with healthy control subjects to determine if cs increases in patients with cp/cpps. this increase in cs could explain the cause of pain for at least some patients with cp/cpps, thus this affirmation of this hypothesis could lead to alterations in the therapy modalities of cp/cpps patients who experience increased cs. materials and methods study subjects seventeen male patients with cp/cpps and 17 healthy male controls were prospectively included in the study between september 2012 and january 2014, after obtaining local ethics review committee approval and written informed consent forms. this study was performed in accordance with the helsinki declaration of the world medical association. the study group was constructed from patients diagnosed by the urology outpatient clinic of acibadem kayseri hospital. control group members were selected from subjects applying by the announcement. a total of 83 patients with pelvic pain from the outpatient clinic applied for participation in the study. exclusion criteria for all subjects were presence of ongoing urinary tract infection or uropathogen documented within the past year, chronic bacterial prostatitis after lower urinary tract localization studies, history of urinary tract malignancy, radiation therapy, postoperative pain, any known neurological abnormalities including spinal cord injury, previous cerebrovascular disease, neuropathy, and presence of medical treatment history with diagnosis of cp/cpps. all patients completed a national institutes of health-chronic prostatitis symptom index (nih-cpsi) (16) and likert scale pain index, and underwent detailed neurological/urologic examinations and laboratory tests that included urine analysis, semen and urine cultures, and expressed prostatic secretion (eps) after prostate massage. blood tests included a liver function test, kidney function test, thyroid function test, complete blood count, and vitamin b12 levels were normal in all. the patient group: 17 patients clinically diagnosed with cp/cpps. inclusion criteria included pelvic pain symptoms (i.e., perineum, rectum, testicles, penis, or lower back pain), presence or absence of pain during urination or ejaculation for three or more months and a desire for treatment, severe nih-cpsi and likert pain scale index scores (i.e., 20-29 and 7-10, respectively), negative urine, semen, and eps cultures, 26 to 52 years old, height in the range of 166 to 175 cm, weight in the range of 70 to 84 kg. the control group: 17 healthy volunteers men, no history of pelvic pain and any pain treatment, between the ages of 23 and 48, ranged in height from 165 to 177 cm, ranged in weight from 69 to 86 kg. blood tests including liver function test, kidney function test, thyroid function test, complete blood count, vitamin b12 levels were performed in all study subjects to exclude subjects with any systemic disorder that might cause neuropathy. procedure tests were performed in the neurophysiology laboratory in afternoon hours between three and five. all subjects are asked to forego sexual activities for 24 hours prior to test. before sep, a nerve conduction study was performed on all study subjects to exclude peripheral neuropathy. the room temperature was set to 23-centigrade degrees. for the sep study, stimuli were applied with penile ring electrodes. the cathode was placed 1 cm proximal to the anode. recording electrodes were placed as active to cz’ (i.e., 2 cm posterior to cz) and reference electrode on fz’ (i.e., midway positions between fz and fpz) according to the 10–20 international system (figure 1). before the sep recordings, the sensory threshold was determined in each subject. this was defined as the lowest stimulus intensity required to evoke sensory perception. in this procedure, the electrical stimulus is applied to all study subjects via stimulus electrodes, table 1. demographic and electroneurophysiological data of study groups. variables patients controls p value age, years 38.0 ± 8.5 34.6 ± 8.0 .2 height, cm 170.5 ± 2,7 170.8 ± 3,2 .7 weight, kg 77.6 ± 4.2 77.6 ± 4.2 .8 sensory threshold, ma 12.0 ± 3.8 12.8 ± 2.5 .5 n50 latency 44.7±3.9 59.1±5.8 <.0001 data are presented as mean ± sd. abbreviation: ne, not evocable. no. patients controls 1 40.64 ne 2 50.72 62.10 3 49.12 49.12 4 42.88 62.10 5 43.64 ne 6 ne 58.70 7 39.84 55.20 8 47.50 69.20 9 50.40 61.10 10 43.20 66.17 11 41.60 60.96 12 47.84 48.60 13 48.80 57.60 14 43.30 55.60 15 44.64 58.40 16 42.50 56.16 17 38.40 65.28 table 2. n50 latencies of patients and controls. miscellaneous 2281 central sensitization in patients with chronic prostatitis-korkmaz et al. beginning at 1ma (milliampere) intensity and 0.1 ms (millisecond) duration. stimulus intensity is gradually increased in 1 ma increments until the subject feels the stimulus sensation. this stimulus level was described as the subject’s sensory threshold and was used for the identification of stimulus severity. for the sep study, stimulus intensity was determined as two times the sensory threshold and we applied that ranges in all subjects. cutaneous stimulus parameters were set at 0.1 ms duration, frequency 4.1 hz. bandpass filter was set to 2 to 5000 hz and sweep time to 100 ms. an average of 300 stimuli were recorded, and the test was three times repeated to ensure repeatability. latency of n50 was defined as the second negative (upward) deflection of the w-shaped average cortical waveform. if the response could not be reproduced at least twice or if the cortical response could not be clearly identified, the n50 was classified as not evocable. n50 latencies of both patients and controls have been given in table 1. statistical analysis this study was designed to detect up a 40% difference in seps of dorsal penile nerve stimulation between control (healthy) and study (patients with cp/cpps) groups with 90% power, assuming a significant difference level of 0.05 and a two-sided statistical test. relying on the results of a pilot study performed in our department and lee et al.(17), we calculated the sufficient sample size for our study. the statistical package for social sciences (spss) version 16.0 was used for statistical analyses. all variables including age, weight, height, latency of n50, and sensory threshold were compared between patients and healthy control groups using two independent student’s t tests that were based on distribu-tion characteristics. the shapiro-wilk test was used to determine distribution characteristics. the impact of potential confounding variables such as age, height, and weight was assessed by analyses of covariance. results all results were reported as mean ± sd. mean age, height, and weight of patient and healthy control groups were (38.0 ± 8.5) versus (34.6 ± 8.0), (170.5 ± 2.7) versus (170.8 ± 3.2), (77.3 ± 3.7) versus (77.6 ± 4.2), respectively. sensory thresholds of patient and healthy control groups ranged from 6 to 20 ma (12.0 ± 3.8), 8 to 17 ma (12.8 ± 2.5), respectively. there were no significant differences between the two groups in terms of age, height, weight, and sensory threshold (p > .05). in one cp/cpps patient and two healthy subjects, sep responses could not be achieved. cortical latencies of n50 after dorsal penile nerve stimulation in the patient and healthy control groups were 44.7 ± 3.9 vs. 59.1 ± 5.8 respectively. n50 latencies were significantly shorter in the patient group compared to the healthy controls (p < .0001). none of the covariates including age, weight, and height indicated a significant impact on the latency of n50. all statistical results are presented in table 1. all demographic characteristics and n50 latencies of patients and control subjects are given in table 2. also, the sep of control number 10 has been shown on figure 2 to exemplify what n50 component of sep is. discussion peripheral pain sensation is carried to the somatosensory cortex by different fibers. whereas noxious stimulus is carried by thin myelinated aδ and unmyelinated c fibers, non-noxious stimulus is carried by thick myelinated aβ fibers. fibers that transmit pain reach the somatosensory cortex via the spinal cord and thalamus. during normal pain transmission, whereas aβ fibers have an inhibitory effect on pain transmission at the level of the spinal cord, aδ and c fibers have a stimulatory effect. in the presence of central sensitization, both aβ and aδ and c fibers affect stimulation at the same level. therefore, the total effect of transmission throughout those fibers, transmission of pain sensation is increased into the somatosensorial cortex. figure 1. illustration of recording and stimulating electrodes localization. figure 2. sample of n50 latency of control number 10. vol 12 no 04 july-august 2015 2282 central sensitization in patients with chronic prostatitis-korkmaz et al. cp/cpps is a clinical condition characterized by the presence of peripheral pain sensation even in the absence of a stimulus. therefore, we believe that central sensitization plays an important role in the pathogenesis of this disease. abnormal sep responses are not surprising in the presence of central sensitization. in this study, in terms of n50 latency there was a significant difference between patients with cp/cpps and healthy controls. in a previous study conducted in patients with cp/cpps, aδ and c fibers were assessed by thermal sensory analysis (tsa) and aβ fibers were assessed by seps and bulbocavernous reflex (bcr).(17) in this study, neither sep nor bcr showed any significant difference when compared with study subject’s normal laboratory values, yet the results of visual analog scale applied post-tsa were found to be higher for pain sensation. in this study, it was thought that the aδ and c fibers were responsible for the pain experienced by cp/ cpps patients. on the other hand, another study found no difference in tsa between cp/cpps patients and healthy controls, however sep was not used to evaluate pain.(18) in our study, we hypothesized that the central sensitization that occurs in chronic pain conditions such as cp/cpps will be shown by seps, as there may be a functional alteration in somatosensory pathway even if the pathway is structurally normal (i.e., similar to other conditions that also have central sensitization. while our previous study attempted to determine which type of fiber damage was responsible for pain in patients with cp/cpps by seps response, the aim of present study was to determine activity of pain related to the cortical area. the aims of these two studies were different although the same electroneurophysiological method was used. on the other hand the results of our study and the previous study contradict each other. although sep study is frequently conducted in urological disorders such as erectile dysfunction, this is only the second study assessing sep responses in cp/cpps patients. a change in somatosensorial transmission may be the principal mechanism responsible for the pain experienced by this patient group. all sensory stimuli including pain sensation are transmitted to same area in the cerebral cortex by somatosensorial nerve fibers. we suggest that hypersensitized nerve fibers that transmit the pain sensation cause an alteration in cortical responses. conclusions we concluded that latencies of sep responses are significantly shorter in patients with cp/cpps than in healthy controls. these results support the hypothesis of presence of central sensitization due to exaggerated transmission of pain sensation to the somatosensory cortex. therefore, normalization of transmission might be an important step in the treatment of pain in patients with cp/cpps. conflict of interest none declared. references 1. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama. 1999;282:236-7. 2. mehik a, hellstrom p, lukkarinen o, sarpola a, jarvelin m. epidemiology of prostatitis in finnish men: a population-based crosssectional study. bju int. 2000;86:443-8. 3. collins m, meigs jb, barry mj, walker corkery e, giovannucci e, kawachi i. prevalence and correlates of prostatitis in the health professionals follow-up study cohort. j urol. 2002;167:1363-6. 4. shahed ar, shoskes da. oxidative stress in prostatic fluid of patients with chronic pelvic pain syndrome: correlation with gram-positive bacterial growth and treatment response. j androl. 2000;21:669-75. 5. dunphy ej, eickhoff jc, muller ch, berger re, mcneel dg. identification of antigenspecific igg in sera from patients with chronic prostatitis. j clin immunol. 2004;24:492-502. 6. zermann dh, ishigooka m, doggweiler r, schmidt ra. neurourological insights into the eti-ology of genitourinary pain in men. j urol. 1999;161:903-8. 7. naslund mj, strandberg jd, coffey ds. the role of androgens and estrogens in the pathogenesis of experimental nonbacterial prostatitis. j urol. 1988;140:1049-53. 8. mehik a, hellstrom p, sarpola a, lukkarinen o, jarvelin mr. fears, sexual disturbances and personality features in men with prostatitis: a population-based cross-sectional study in finland. bju int. 2001;88:35-8. 9. shoskes da, albakri q, thomas k, cook d. cytokine polymorphisms in men with chronic prostatitis/chronic pelvic pain syndrome: association with diagnosis and treatment response. j urol. 2002;168:331-5. 10. zhu y, wang c, pang x, li f, chen w, tan w. antibiotics are not beneficial in the management of category iii prostatitis: a meta analysis. urol j. 2014;11:1377-85. 11. stamatiou kn, moschouris h. a prospective interventional study in chronic prostatitis with emphasis to clinical features. urol j. 2014;11:1829-33. 12. yang cc, lee jc, kromm bg, ciol ma, berger r. pain sensitization in male chronic pelvic pain syndrome: why are symptoms so difficult to treat? j urol. 2003;170:823-6. 13. lebrun p, manil j, colin f. formalin-induced central sensitization in the rat: somatosensory evoked potential data. neurosci lett. 2000;283:113-6. 14. melzack r, wall pd. textbook of pain. london: churchill livingston;1999. 15. apkarian av, baliki mn, geha py. towards a theory of chronic pain. prog neurobiol. 2009;87:81-97. 16. litwin ms, mcnaughton-collins m, fowler fj jr, et al. the national institutes of miscellaneous 2283 central sensitization in patients with chronic prostatitis-korkmaz et al. health chronic prostatitis symptom index: development and validation of a new outcome measure. j urol. 1999;162:369-75. 17. lee jc, yang cc, kromm bg, berger re. neurophysiologic testing in chronic pelvic pain syndrome: a pilot study. urology. 2001;58:246-50. 18. yılmaz u, ciol ma, berger re, yang cc. sensory perception thresholds in men with chronic pelvic pain syndrome. urology. 2010;75:34-7. vol 12 no 04 july-august 2015 2284 central sensitization in patients with chronic prostatitis-korkmaz et al. brief communication 123urology journal vol 6 no 2 spring 2009 urinary tract and other associated anomalies in newborns with esophageal atresia fatemeh eghbalian,1 alireza monsef,2 seyed habibollah mousavi-bahar3 esophageal atresia is often associated with other anomalies. hereditary and environmental factors may influence the incidence of associated anomalies, particularly of the urogenital system. we had 63 neonates with esophageal atresia admitted to 2 centers in hamadan, iran, from 2002 to 2008. they were 38 girls (60.3%) and 25 boy (39.7%). tracheoesophageal fistula was present in 54 neonates (85.7%), and other associated anomalies in 10 (15.9%). cardiac anomalies were found in 7 neonates; anorectal anomalies, in 4; urinary tract anomalies, in 2; and limb anomaly, in 1. urinary tract anomalies (3.2%) were bilateral polycystic kidney in 1 neonate and unilateral hydronephrosis due to ureteropelvic junction obstruction in another. both neonates with urinary tract anomalies were female and both had tracheoesophageal fistula, as well. many of the associated congenital abnormalities influence the management protocol of esophageal atresia, and therefore, should be detected as soon as possible after birth. urol j. 2009;6:123-6. www.uj.unrc.ir keywords: esophageal atresia, newborn infant, urinary tract, congenital abnormalities 1division of neonatology, department of pediatric, besat hospital, hamadan university of medical sciences, hamadan, iran 2department of pathology, besat hospital, hamadan university of medical sciences, hamadan, iran 3department of urology, shahid beheshti hospital, hamadan university of medical sciences, besat hospital, hamadan, iran corresponding author: fatemeh eghbalian, md department of pediatrics, besat hospital, hamadan, iran tel : +98 811 822 3978 fax : +98 811 251 7910 e-mail: eghbalian_fa@yahoo.com received january 2009 accepted april 2009 esophageal atresia can occur as an isolated entity or in association with one or more fistulas communicating between the abnormal esophagus and the trachea. the embryologic missteps leading to esophageal atresia are associated with varying components of the malformation constellation termed vacterl, which refers to anomalies of the vertebrae (v), atresias in the gastrointestinal tract (a), congenital heart lesions (c), tracheoesophageal defects (te), renal and distal urinary tract anomalies (r), and limb lesions (l).(1) if any of these anomalies are present, the presence of the others must be assessed.(2) thus, urinary tract abnormalities must be considered in all of neonates with esophageal atresia with or without tracheoesophageal fistula.(1,3,4) early ultrasonographic assessment is mandatory and useful to evaluate associated kidney or ureteral anomalies, or both.(1,3-5) in addition, the kidneys may be palpable on physical examination.(3,5) early recognition of newborns with no prospect of long-term survival (bilateral renal agenesis) will avoid unnecessary surgery on the esophagus.(1,3-5) the reported incidence of urinary tract anomalies associated with esophageal atresia has been varying between 4% and 64% in different studies.(3,6,7) hereditary and environmental factors may influence the incidence of associated anomalies, particularly of the urogenital system.(5-8) the initial reports documenting this spectrum of associated defects appeared over urinary tract anomalies in esophageal atresia—eghbalian et al 124 urology journal vol 6 no 2 spring 2009 30 years earlier, and the incidence of urinary tract and other associated anomalies has not been precisely quantified in recently.(5,9) multiple studies have shown that knowledge on the diagnosis of concomitant anomalies with esophageal atresia, especially urinary tract abnormalities, can improve prognosis of the patients.(5-10) we reviewed our hospital records for evaluation of the prevalence of urinary tract and other associated anomalies with esophageal atresia in neonates. this study was a retrospective investigation on hospitalized neonates at ekbatan and besat hospitals of hamadan university of medical sciences. neonates with esophageal atresia who had been admitted between 2002 and 2008 were identified. their documents were evaluated and data including age, sex, birth weight, diagnosed urinary tract anomalies, and other associated anomalies were collected. all of these neonates had drooling or excessive salivation and respiratory difficulties in the first few days of life. passing of a nasogastric tube had not been possible. in attempts to pass a nasogastric tube, chest radiography had shown the tube curling up in the upper esophageal pouch. the diagnosis of isolated esophageal atresia with no tracheoesophageal fistula had been made in case of no air in the gastrointestinal tract on chest radiography. in our two centers, the diagnostic management plan for evaluation of associated congenital anomalies had included the following: lateral lumbar radiography, for vertebral anomalies (multiple or single hemivertebrae, scoliosis, and rib deformities); rectal examination, for imperforate anus and anorectal anomalies; echocardiography, for congenital heart lesions (ventricular septal defects, atrial septal defects, and tetralogy of fallot); posteroanterior and lateral plain chest radiographies with nasogastric tube opaque line, for tracheoesophageal fistula and esophageal atresia; urinary tract ultrasonography, for urinary tract anomalies (renal agenesis, potter syndrome, bilateral renal agenesis or dysplasia, horseshoe kidney, polycystic kidneys, urethral atresia, and ureteral malformations); and limb radiography for limb anomalies (radial dysplasia, absent radius, syndactyly, polydactyly, and tibial deformities). also we had performed voiding cystourethrography and technetium tc 99m diethylenetriamine pentaacetic acid renal scintigraphy for the patients suspected to have urinary tract anomalies. we found that during the 6-year studied period, 63 neonates had been diagnosed with esophageal atresia. a female predominance was seen in these neonates; they were 38 girls (60.3%) and 25 boys (39.7%). the mean age of the neonates was 2.33 ± 1.90 days (range, 1 to 11 days) at diagnosis, and their mean birth weight was 2678.6 ± 511.3 g (range, 1350 g to 3600 g). tracheoesophageal fistula was present in 54 neonates (85.7%). ten neonates (15.9%) had other anomalies (regardless of having tracheoesophageal fistula or not), including cardiac anomalies in 7 neonates (ventricular septal defects and atrial septal defects), anorectal anomalies in 4 (imperforated anus), urinary tract anomalies in 2, and limb anomaly in 1 (absent radius). urinary tract anomalies were bilateral polycystic kidney in 1 neonate and unilateral hydronephrosis due to ureteropelvic junction obstruction in another. both neonates with urinary tract anomalies were female and both had tracheoesophageal fistula. in one of these patients, voiding cystourethrography revealed vesicoureteral reflux with unilateral hydronephrosis and technetium tc 99m diethylenetriamine pentaacetic acid renal scan showed ureteropelvic junction obstruction. both of the neonates had been referred to our hospital within the first 24 hours after birth. their weights were 3300 g and 2850 g. their laboratory tests and vital signs were normal at admission. esophagoplasty and fistulography had been performed for both of the newborns. five days after the operation, esophagography revealed no leakage or abnormality. after discharge, they were referred to a pediatric nephrologist for follow-up. esophageal atresia is a life-threatening malformation with unknown pathogenesis. management of acute and chronic problems related to the associated anomalies, especially those of the urinary tract, are crucial, because they are the main causes of death in newborns urinary tract anomalies in esophageal atresia—eghbalian et al urology journal vol 6 no 2 spring 2009 125 with esophageal atresia.(1-3,11) on the other hand, early recognition of urinary tract anomalies with no prospect of long-term survival (eg, bilateral renal agenesis) will avoid unnecessary surgeries.(9,10,12) in our study, 63 neonates with esophageal atresia referred to our centers during a 6-year period were evaluated for urinary tract and other associated anomalies. urinary tract anomalies were found in 3.2% of the patients who had bilateral polycystic kidney and unilateral hydronephrosis due to ureteropelvic junction obstruction. similar anomalies have been described in other studies on esophageal atresia.(3-7) the frequency of tracheoesophageal fistula in our study was 85.7%, which was consistent with the reported 80% to 90% incidence rates of tracheoesophageal fistula in patients with esophageal atresia.(1-11) in our study, 15.9% of the infants had been affected by other anomalies (with or without tracheoesophageal fistula). previous studies have shown a 40% to 57% incidence of associated anomalies.(2-7,9,11) chittmittrapap and colleagues reviewed their 8-year data and found that 48% of their patients with esophageal atresia had associated anomalies, as well.(6) van heurn and colleagues’ study compared the associated anomalies in neonates with esophageal atresia was between the asian and european neonates. there were no significant differences in the incidence of cardiovascular, anorectal, and musculoskeletal anomalies between the two populations. however, the european patients had a significantly higher incidence of urinary tract anomalies (26% versus 4%, p = .006).(7) the frequency of urinary tract anomalies has been varying in different reports. brown and colleagues documented a renal anomaly incidence of 16% in infants with esophageal atresia and tracheoesophageal fistula,(9) while muraji and mahour reported that 9 of 14 infants with esophageal atresia with or without tracheoesophageal fistula had urinary tract anomalies.(10) gunn and coworkers found urinary tract abnormalities is 14.3 per 1000 births with esophageal atresia.(13) overall, it has been shown that urinary tract abnormalities are the second most common associated defects with esophageal atresia after cardiac abnormalities.(1-5) hereditary factors may influence the incidence of associated anomalies in neonates with esophageal atresia, particularly of the urinary tract anomalies. however, environmental factors cannot be excluded.(6,7,10) significant discrepancies in reported incidence of urinary tract anomalies in previous studies warrants studies on larger samples with special attention to the genetic and environmental causal factors. many of the associated congenital abnormalities influence the way in which the esophageal atresia is managed, and therefore, should be detected as soon as possible after birth. thus, knowledge on the local epidemiology and etiologies is crucial. acknowledgment the authors would like to acknowledge the office of vice chancellor for research of hamadan university of medical sciences for financial support of this study. also, we would like to thank dr mh azimian, for his assistance in statistical analyses, and dr r eslah and the staff of neonatal ward for their collaboration. conflict of interest none declared. references 1. spitz l, kiely e, brereton rj. esophageal atresia: five year experience with 148 cases. j pediatr surg. 1987;22:103-8. 2. german jc, mahour gh, woolley mm. esophageal atresia and associated anomalies. j pediatr surg. 1976;11:299-306. 3. dobanovacki d, marinkovic s, jokic r, zivkovic d, stanic-canji d, borisev v. [urogenital abnormalities and atresia of the gastrointestinal tract]. med pregl. 2005;58:271-4. serbian. 4. quan l, smith dw. the vater association. vertebral defects, anal atresia, t-e fistula with esophageal atresia, radial and renal dysplasia: a spectrum of associated defects. j pediatr. 1973;82:104-7. 5. keckler sj, st peter sd, valusek pa, et al. vacterl anomalies in patients with esophageal atresia: an updated delineation of the spectrum and review of the literature. pediatr surg int. 2007;23:309-13. 6. chittmittrapap s, spitz l, kiely em, brereton rj. oesophageal atresia and associated anomalies. arch dis child. 1989;64:364-8. 7. van heurn lw, cheng w, de vries b, et al. anomalies associated with oesophageal atresia in asians and europeans. pediatr surg int. 2002;18:241-3. urinary tract anomalies in esophageal atresia—eghbalian et al 126 urology journal vol 6 no 2 spring 2009 8. iuchtman m, brereton r, spitz l, kiely em, drake d. morbidity and mortality in 46 patients with the vacterl association. isr j med sci. 1992;28:281-4. 9. brown ak, roddam aw, spitz l, ward sj. oesophageal atresia, related malformations, and medical problems: a family study. am j med genet. 1999;85:31-7. 10. muraji t, mahour gh. surgical problems in patients with vater-associated anomalies. j pediatr surg. 1984;19:550-4. 11. yang cf, soong wj, jeng mj, et al. esophageal atresia with tracheoesophageal fistula: ten years of experience in an institute. j chin med assoc. 2006;69:317-21. 12. beasley sw. influence of associated anomalies on the management of oesophageal atresia. indian j pediatr. 1996;63:743-9. 13. gunn tr, mora jd, pease p. antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 weeks’ gestation: incidence and outcome. am j obstet gynecol. 1995;172:479-86. 955 edited1.pdf 894 | miscellaneous evaluation of patency of arteriovenous fistula and its relative complications in diabetic patients seyed saeed mortaz,1 ali davati,1 maryam khan ahmadloo,1 hamid reza taheri,1 farzaneh golfam,1 azin tavakoli,2 ali reza khalaj1 purpose: materials and methods: t results: p p conclusion: keywords: corresponding author: ali reza khalaj, md department of surgery, faculty of medical sciences, shahed university, tehran, iran tel: +98 21 8897 7927 fax: +98 21 8896 3122 e-mail: arkhalaj@yahoo.com received april 2011 accepted august 2011 1department of surgery, faculty of medical sciences, shahed university, tehran, iran 2faculty of veterinary medicine, islamic azad university-garmsar branch, garmsar, iran miscellaneous 895vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l introduction materials and methods t p results table 1. location of the fistula and duration of patency. duration of patency (mean ± standard deviation), month number (%)location of the fistula 25.27 ± 15.7744.6 (58%) brachiocephalic left 24.0 ± 13.7616.2 (21%) right 170.8 (1%) radiocephalic left 15.2 ± 6.683.8 (5%) right 24.18 ± 18.1229.1 (38%) anatomical snuffbox area left 25.27 ± 15.775.4 (7%) right av fistula in diabetics | mortaz et al 896 | p p discussion st th conclusion conflict of interest table 2. duration of patency in different genders and number of complications in patients. variable number duration of patency (mean ± standard deviation) gender male female 65 65 23.64 ± 15.33 24.83 ± 16.34 complication yes no 7 123 19.85 ± 13.6 24.48 ± 15.92 table 3. rate of complications in different genders and location of the fistula. variable rate of complication, % gender male female 6.2 4.7 location of fistula brachiocephalic radiocephalic 7.7 16.7 miscellaneous 897vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l av fistula in diabetics | mortaz et al references 1. boyle jp, thompson tj, gregg ew, barker le, williamson df. projection of the year 2050 burden of diabetes in the us adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. popul health metr. 2010;8:29. 2. baska tv, nemcova j, martinka e, straka s, mad'ar r. [epidemiological characteristics of diabetes mellitus in slovakia, 1992-2002]. epidemiol mikrobiol imunol. 2006;55:68-72. 3. patel a, macmahon s, chalmers j, et al. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. n engl j med. 2008;358:2560-72. 4. wyatt sb, winters kp, dubbert pm. overweight and obesity: prevalence, consequences, and causes of a growing public health problem. am j med sci. 2006;331:166-74. 5. quinton w, dillard d, scribner bh. cannulation of blood vessels for prolonged hemodialysis. hemodial int. 2004;8:69. 6. brescia mj, cimino je, appell k, hurwich bj, scribner bh. chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. 1966. j am soc nephrol. 1999;10:193-9. 7. baker ld, jr., johnson jm, goldfarb d. expanded polytetrafluoroethylene (ptfe) subcutaneous arteriovenous conduit: an improved vascular access for chronic hemodialysis. trans am soc artif intern organs. 1976;22:382-7. 8. falk a. maintenance and salvage of arteriovenous fistulas. j vasc interv radiol. 2006;17:807-13. 9. srivastava a, sharma s. hemodialysis vascular access options after failed brescia-cimino arteriovenous fistula. indian j urol. 2011;27:163-8. 10. windus dw. the effect of comorbid conditions on hemodialysis access patency. adv ren replace ther. 1994;1:148-54. 11. lin sl, huang ch, chen hs, hsu wa, yen cj, yen ts. effects of age and diabetes on blood flow rate and primary outcome of newly created hemodialysis arteriovenous fistulas. am j nephrol. 1998;18:96-100. 12. sesso r, melaragno cs, luconi ps, et al. [survival of dialyzed diabetic patients]. rev assoc med bras. 1995;41:178-82. 13. tuka v, slavikova m, svobodova j, malik j. diabetes and distal access location are associated with higher wall shear rate in feeding artery of ptfe grafts. nephrol dial transplant. 2006;21:2821-4. 14. resic h, sahovic v, mesic e. [predictors of av fistula adequacy in haemodialysed patients]. med arh. 2005;59:177-8. 15. murphy gj, nicholson ml. autogeneous elbow fistulas: the effect of diabetes mellitus on maturation, patency, and complication rates. eur j vasc endovasc surg. 2002;23:4527. 16. ernandez t, saudan p, berney t, merminod t, bednarkiewicz m, martin py. risk factors for early failure of native arteriovenous fistulas. nephron clin pract. 2005;101:c39-44. 1703vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l appendico-vesical fistula in a woman farzaneh sharifiaghdas, mohammadali ghaed, mahboubeh mirzaei corresponding author: mahboubeh mirzaei, md urology and nephrology research center, no 44, boostan 9, pasdaran ave, tehran, iran. tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: mirzaeimahboubeh@yahoo. com received april 2013 accepted october 2013 department of urology, shaheed labbafinejad medical center, urology and nephrology research center, shaheed beheshti medical university, tehran, iran. case report keywords: appendix; pathology; urinary bladder fistula; diagnosis. introduction appendico-vesical fistula is a rare disease for which a precise diagnosis is often difficult to make.(1) the clinical presentation is recurrent urinary tract infections with or without gastro-intestinal symptoms.(2)as the symptoms are not specific, usually there is a large interval between the onset of symptoms and the final diagnosis.(3) the most accurate diagnosis tools are through imaging by cystography and cystoscopy and, or followed by computed tomography (ct) cystography.(4) case report a 30-year-old woman was referred to our clinic for evaluation and treatment of the unresolved bacteriuria. she complained of a chronic right lower abdominal pain for 5 years. meanwhile, she had a history of pneumaturia and fecaluria since 1 year ago. there was no other past medical or surgical disease. urine culture showed growth of escherichia coli (e. col). cystourethroscopy revealed a small opening on the right lateral wall of the bladder dome. passage of a guidewire through the fistula tract was unsuccessful. a ct cystography was requested which showed a suspicious communicating tract between the appendix and bladder and presence of air inside the bladder cavity (figurers 1 and 2). colonoscopy was done for rule out of bowel disease like crohn’s disease which was normal. 1704 | with an impression of appendico-vesical fistula, the patient was operated through an infra umbilical midline incision. the right lateral side of the bladder dome was strongly adhered to the distal part of the thick appendix with a fine fistulous tract. after the ligation of the appendicular base blood supply with 2-0 vicryl suture, the fistulous tract was resected. bladder was repaired in two layers with zero vicryl suture and omental flap was interposed between the cecum and bladder. postoperative period was uneventful and the patient was discharged after third post-op day .the foley catheter was removed in the 7th post-op day. the pathology of the specimen was chronic inflammation of appendix without malignancy. discussion appendico-vesical fistula is a very rare complication of appendicitis.(1) it occurs more common in males at the range of 10 and 40 years old.(1,5) the lower incidence in females is attributed to the interposition of the uterus between the bladder and the intestine.(2) although more than 100 cases figure 1. coronal view of cecum, bladder and fistula in computed tomography cystography. figure 2. transverse view of cecum, bladder and fistula in computed tomography cystography. case report 1705vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l appendico-vesical fistula in a woman | sharifiaghdas et al references 1. rainauli z, mekokishvili l, de petriconi r. 15-year history of spontaneous appendico-vesical fistula (case report). georgian med news. 2012 ;205:7-11. 2. abubakar am, pindiga uh, chinda jy, nggada ha. appendico-vesical fistula associated with hirschsprung's disease. pediatr surg int. 2006;22:617-8. 3. bigler me, wofford je, pratt sm, stone wj. serendipitous diagnosis of appendicovesical fistula by bone scan: a case report. j urol. 1989;142:815-6. 4. goldman sm, fishman ek, gatewood om, jones b, siegelman ss. ct in the diagnosis of enterovesical fistulae. ajr am j roentgenol. 1985;144:1229-33. 5. steel mc, jones it, webb d. appendicovesical fistula arising from appendiceal diverticulum suspected on barium enema. anz j surg. 2001;71:769-70. 6. afifi ay, fusia tj, feucht k, paluzzi mw. laparoscopic treatment of appendicovesical fistula: a case report. surg laparosc endosc. 1994;4:320-4. 7. athanassopoulosa, speakmanmj. appendicovesical fistula. int urol nephrol. 1995;27:705-8. 8. kawamura yj, sugamata y, yoshino k, et al. appendico-ileo-vesicalfistula. j gastroenterol. 1998;33:868-71. 9. albrecht k, schumann r, peitgen k, walz mk. laparoscopic therapy of appendicovesical fistula -two case reports. zentralbl chir. 2004;129:396-8. have been reported in the literature in last decades, only a few cases were female.(6,7) the most common symptoms of appendicovesical fistula are unresolved urinary tract infection, lower abdominal pain and pneumaturia.(2,8) as the symptoms are occasionally non-specific and the usual diagnostic tool cannot easily demonstrate the disease and the precise pre-operative diagnosis is difficult to make.(3) so that, it may be delayed for more than 1 years for definite diagnosis.(3,8) diagnostic tools are cystourethroscopy, cystography and ct scan. ct cystography has been introduced as the most accurate diagnostic test.(4) appendectomy and repair of the bladder wall is the principle treatment of appendicovesical fistula.(9) conflict of interest none declared. urol_v03_no3_001_editorial.indd miscellaneous urology journal vol 3 no 3 summer 2006 175 retrocaval ureter a study of 13 cases aliasghar yarmohammadi, mohamadali mohamadzadeh rezaei, behzad feizzadeh, hassan ahmadnia introduction: the aim of this study was to report our 23-year experience in the diagnosis and treatment of retrocaval ureter. materials and methods: data from 13 patients with retrocaval ureter were reviewed. intravenous urography and retrograde pyelography had been used for confirming the diagnosis. all of the patients had been symptomatic and undergone surgery. a control intravenous urography had been performed 6 months postoperatively. results: the mean age of the patients was 23 years (range, 12 to 37 years). twelve patients (92.3%) were men. the clinical manifestations were pyelonephritis in 7 (53.8%), right flank pain in 4 (30.8%), gross hematuria in 1 (7.7%), and ureteral calculus in 1 (7.7%). all of the patients had type 1 right-sided retrocaval ureter. associated anomalies were seen in none of the patients. the control intravenous urography showed improvement of renal function. conclusion: in our patients, the most common cause of referral was pyelonephritis. in symptomatic cases, operation is needed and can improve renal function. urol j (tehran). 2006;3:175-9. www.uj.unrc.ir keywords: ureter, retrocaval, ureteroureterostomy, urogenital abnormalities department of urology, qaem hospital, mashhad university of medical sciences, mashhad, iran corresponding author: aliasghar yarmohammadi,md qaem hospital, mashhad, iran tel: +98 511 841 7404 email: behzadfeizzadeh@yahoo.com received january 2006 accepted june 2006 introduction retrocaval ureter is a rare congenital abnormality in association with upper urinary tract obstruction and usually has an s-shape or fishhook appearance on intravenous urography (ivu) that is due to the passage of the ureter posterior to the inferior vena cava (ivc). congenital anomalies that result in the obstruction of the ureter are extremely rare; however, retrocaval ureter is the most common anomaly with a venous cause.(1) it is also called circumcaval or postcaval ureter.(2) the anomaly is usually observed in the right side and in some cases (such as patients with situs inversus) it may be left sided. the prevalence of the disease is reported to be 1 in 1000 live births.(1) although the anomaly is congenital, patients become symptomatic in their 3rd or 4th decade of life.(1) in symptomatic cases, surgical intervention is often required.(1-3) we report 13 patients with this anomaly during our 23year experience in the diagnosis and treatment of the retrocaval ureter. materials and methods medical records of 13 patients with retrocaval ureter who had been treated in qaem hospital (mashhad) between 1983 and 2005 were reviewed. the definite diagnosis was made by ivu and retrograde pyelography. the type of the retrocaval ureter was identified according to the classification by bateson and atkinson.(3) intravenous urography had been performed for all retrocaval ureter—yarmohammadi et al 176 urology journal vol 3 no 3 summer 2006 patients 6 months postoperatively, as well. all patients were symptomatic and had undergone surgery. age, sex, reason for referral, hospital staying, treatment modality, treatment outcome, and associated anomalies were collected from the patients’ data sheets. results a total of 13 patients had retrocaval ureter. the median age of the patients was 23 years (range, 12 to 37 years). twelve patients (92.3%) were men and 1 (7.7%) was a woman. the reason for seeking treatment was pyelonephritis in 7 patients (53.8%), right flank pain in 4 (30.8%), gross hematuria in 1 (7.7%), and ureteral calculus in 1 (7.7%). the mean hospital staying was 3.24 days (range, 3 to 4 days). no associated anomaly was seen in these patients. the retrocaval ureter was type 1 and right-sided in all of the patients. we performed end-to-end ureteroureterostomy through an extraperitoneal incision on the 12th rib in all patients. on the control ivu performed 6 months postoperatively, there were no remarkable findings and no complication occurred during the follow-up (figures 1 and 2). discussion retrocaval ureter was first reported by hochstetter in 1893.(4) normally, ivc originates from the supracardinal and subcardinal veins inferior and superior to the kidney, respectively. if the ivc inferior to the kidney is formed by subcardinal vein, it will be located anterior to the ureter and will form a retrocaval ureter. there are two types of retrocaval ureter: type 1 which is more prevalent and has an s-shape or fishhook appearance, and type 2 which is sickle shaped.(3) in radiographic studies, all of our patients had type 1 pattern of the retrocaval ureter. for editorial comment see p 179 abnormal development of the ivc is generally considered as the etiology of the retrocaval ureter; figure 1. left, intravenous urography before surgery for retrocaval ureter in a 12-year-old boy. severe dilatation and s-shape pattern of the ureter is seen in the right side. right, six-month postoperative ivu in the same patient. decreased hydronephrosis and correction of the ureter pathway is seen. retrocaval ureter—yarmohammadi et al urology journal vol 3 no 3 summer 2006 177 however, maternal exposure to diethylene glycol monomethyl ether (an industrial solvent) during fetal period is proposed to be a probable cause.(5) none of our patients had the history of such exposure. retrocaval ureter is almost always right sided; however, in cases with situs inversus or duplication of the ivc, it may be seen in the left side.(2,6) in our study, all of the patients had rightsided retrocaval ureters. the ratio of men to women is 2.8:1 in clinic.(7) in our patients, however, this rate was 12:1. patients usually present in their 3rd or 4th decades of life.(8) the median age of our patients was 23 years, similar to the age mentioned in the literature. retrocaval ureter may be asymptomatic or cause symptoms such as flank pain, urinary tract infection, hematuria, or calculus formation.(4,9) other disorders that have been reported to be associated with the retrocaval ureter are retroperitoneal fibrosis, carcinoma of the ureter, and renovascular hypertension.(10-12) the referral reasons in our patients were pyelonephritis (the most common manifestation), right flank pain, gross hematuria, and ureteral calculus. associated anomalies with retrocaval ureter are reportedly up to 21% and are mainly related to the cardiovascular and urogenital systems (including horseshoe kidney, ureteropelvic junction obstruction, congenital lack of the vas deferens, hypospadias, extra vertebra, diverticulum, anterior urethral calculus, kidney agenesis, syndactyly in both feet, intestinal malrotation, and goldenhar syndrome.(13-20) none of these anomalies was seen in our patients. retrocaval ureter has been previously diagnosed by ivu and retrograde pyelography, but nowadays, ct scan is the best modality for diagnosis.(4,21) diagnosis of the retrocaval ureter has also been reported by technetium tc 99m diethylenetriamine pentaacetic acid scan, technetium tc 99m methylene diphosphonate scan, and magnetic resonance imaging.(22-24) in our series, the diagnosis was made based on ivu and retrograde pyelography. asymptomatic cases of retrocaval ureter do not need surgery,(9) but symptomatic patients figure 2. left, intravenous urography before surgery for retrocaval ureter in a 24-year-old man. dilatation and hydronephrosis exist in the right side. right, postoperative ivu of the same patient. decreased dilatation and improved renal function is seen. retrocaval ureter—yarmohammadi et al 178 urology journal vol 3 no 3 summer 2006 generally need surgical intervention which is mainly ureteroureterostomy.(4) in all 13 patients, a moderate to severe hydronephrosis was present and all of them were symptomatic. thus, they all required surgical intervention. intravenous urography, performed 6 months after ureteroureterostomy, revealed considerable improvement. laparoscopic correction of the retrocaval ureter is also reported which may be transperitoneal or extraperitoneal.(23-25) in case of renal dysfunction, nephrectomy is mandatory.(4) conclusion of the most common causes of referral in the patients with retrocaval ureter is pyelonephritis. in symptomatic cases, surgical intervention should be performed and renal function improves after the operation. although the known associated anomalies must be considered, they seem not to be very common in retrocaval ureter. conflict of interest none declared. references 1. rubinstein i, cavalcanti ag, canalini af, freitas ma, accioly pm. left retrocaval ureter associated with inferior vena caval duplication. j urol. 1999;162:13734. 2. wang lt, lo hc, yu ds, sun gh, wu cc, fong cj. ureteral obstruction caused by a duplicated anomaly of inferior vena cava. int j urol. 2005;12:842-4. 3. bateson em, atkinson d. circumcaval ureter: a new classification. clin radiol. 1969;20:173-7. 4. hochstetter f. beitrage zur entwicklungsgeschichte des venen-systems der amnioten: iii. sauger morph jahrb. 1893;20:542. 5. karaman mi, gurdal m, ozturk m, kanberoglu h. maternal exposure to diethylene glycol monomethyl ether: a possible role in the etiology of retrocaval ureter. j pediatr surg. 2002;37:e23. 6. gramegna v, madaro a, pellegrini f, et al. a rare case of retrocaval ureter associated with persistent left vena cava. urol int. 2003;70:337-8. 7. schlussel rn, retik ab. anomalies of the ureter. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell’s urology. 7th ed. philadelphia: wb saunders; 1998. p. 1814–58. 8. feldman sl, dimarco er, tencer t, ross ls. retrocaval ureter: radiographic techniques directing surgical management. br j urol. 1982;54:212-5. 9. cao avellaneda e, server pastor g, lopez lopez ai, et al. [non obstructive retrocaval ureter]. actas urol esp. 2005;29:107-9. spanish. 10. arriola pm, el-droubi h, dahlen cp. combined retrocaval ureter and retroperitoneal fibrosis: report of a case. j urol. 1979;121:107-8. 11. fillo j, cervenakov i, mardiak j, szeiff s, kopecny m, labas p. retrocaval ureter with ureteral carcinoma. bratisl lek listy. 2003;104:408-10. 12. tanaka k, akimoto s, kozuma t, et al. [renovascular hypertension with a solitary kidney associated with retrocaval ureter: a case report]. nippon geka gakkai zasshi. 1984;85:849-54. japanese. 13. perimenis p, gyftopoulos k, athanasopoulos a, pastromas v, barbalias g. retrocaval ureter and associated abnormalities. int urol nephrol. 2002;33: 19-22. 14. shigeta m, nakamoto t, nakahara m, hiromoto n, usui t. horseshoe kidney with retrocaval ureter and ureteropelvic junction obstruction: a case report. int j urol. 1997;4:206-8. 15. baba y, ishizu k, nakamura k, ueno t, takihara h, sakatoku j. [congenital absence of the vas deferens associated with retrocaval ureter: a case report]. hinyokika kiyo. 1991;37:175-7. japanese. 16. friebel n, bolten m, fernandez de la maza s. [retrocaval ureter]. urologe a. 2004;43:708-10. german. 17. nonomura m, kanaoka t, soeda a, matsuo m. [anterior urethral diverticular stones and retrocaval ureter in male: a case report and review of literature in japan]. hinyokika kiyo. 1992;38:721-4. japanese. 18. altland h, molitor d. [retrocaval ureter with unilateral agenesis of the kidney]. rofo. 1983;138:106-9. german. 19. mitchell j, stahlfeld kr, cercone rg. retrocaval ureter with intestinal malrotation. urology. 2003;62: 142-3. 20. ishitoya s, arai y, waki k, okubo k, suzuki y. left retrocaval ureter associated with the goldenhar syndrome (branchial arch syndrome). j urol. 1997;158:572-3. 21. lin wc, wang jh, wei cj, chang cy. assessment of ct urography in the diagnosis of urinary tract abnormalities. j chin med assoc. 2004;67:73-8. 22. uthappa mc, anthony d, allen c. case report: retrocaval ureter: mr appearances. br j radiol. 2002;75:177-9. 23. bhandarkar ds, lalmalani jg, shivde s. laparoscopic ureterolysis and reconstruction of a retrocaval ureter. surg endosc. 2003;17:1851-2. 24. miyazato m, kimura t, ohyama c, hatano t, miyazato t, ogawa y. retroperitoneoscopic ureteroureterostomy for retrocaval ureter. hinyokika kiyo. 2002;48:25-8. 25. tobias-machado m, lasmar mt, wroclawski er. retroperitoneoscopic surgery with extracorporeal uretero-ureteral anastomosis for treating retrocaval ureter. int braz j urol. 2005;31:147-50. retrocaval ureter—yarmohammadi et al urology journal vol 3 no 3 summer 2006 179 editorial comment this is an interesting article demonstrating good number of cases with good results. it has recently been shown that during the management of the retrocaval ureter, removal of the retrocaval segment is not necessary.(1) also today, laparoscopic approach to the retrocaval ureter without removing the retrocaval segment seems preferable which results in less morbidity with less pain, shorter hospitalization, and better cosmetic results. nasser simforoosh department of urology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran reference 1. simforoosh n, nouri-mahdavi k, tabibi a. laparoscopic pyelopyelostomy for retrocaval ureter without excision of the retrocaval segment: first report of 6 cases. j urol. 2006;175:2166-9. reply by author the authors would like to express their gratitude to the editors of the urology journal for their meticulous appraisal of our paper. this series is a report of our experience within more than 2 decades. laparoscopic approach is a brand new technique which was not available at our center; however, we have started laparoscopic surgeries and hope to report our experiences in the laparoscopic management of the retrocaval ureter regarding such novel approaches in the future. behzad feizzadeh department of urology, qaem hospital, mashhad university of medical sciences, mashhad, iran review a meta-analysis of the relationship between testicular microlithiasis and incidence of testicular cancer tao wang,1,2 luhao liu,3 jintai luo,3 taisheng liu,4 anyang wei1* purpose: there are many recent observational studies on testicular microlithiasis (tm) and risk of testicular cancer. whether tm increases the risk of testicular cancer is still inconclusive. the objective of this updated meta-analysis was to synthesize evidence from clinical observational studies that evaluated the association between tm and testicular cancer. materials and methods: we identified eligible studies by searching the pubmed, embase and cochrane library before march 2014. adjusted relative risks (rr) with 95% confidence interval (ci) were calculated using random-or fixed-model. results: a total of 14 studies involving 35578 participants were included in the meta-analysis. on the basis of the newcastle ottawa scale systematic review, eleven studies were identified as relatively high-quality. tm was strong association with an increased incidence of testicular cancer (rr = 12.70, 95% ci: 8.18-19.71, p < .001), with significant evidence of heterogeneity among these studies (p for heterogeneity < .001, i2 = 82.1%). the subgroup and sensitivity analysis confirmed the stability of the results and no publication bias was detected. conclusion: the present meta-analysis suggests that tm is significantly associated with risk of testicular cancer. more researches are warranted to clarify an understanding of the association between tm and risk of testicular cancer. keywords: testicular diseases; complications; calculi; testicular neoplasms; carcinoma in situ; risk factors; testis; pathology. introduction in 1987 testicular microlithiasis (tm) was first described by doherty as “innumerable tiny bright echoes diffusely and uniformly scattered throughout their substance of the testicle”.(1) tm is a condition in which calcium deposits form in the lumen of seminiferous tubules,(2-4) or arise from the tubular basement membrane components.(5) it was categorized as limited testicular microlithiasis (ltm) if there was at least one image that showed fewer than five microliths, or as classic testicular microlithiasis (ctm) when five or more microliths existed. hobarth and colleagues(6) reported that a prevalence of testicular microlithiasis of 0.6% in a population referred for symptomatic scrotal sonography. while middleton and colleagues(7) reported incidence of 18.1% in referred patient. yee and colleagues(8) reported incidence of tm of 6% in adults and children. tm has been associated with male pseudohermaphroditi sm,(9) cryptorchidism,(9-11) subfertility,(12,13) infertility,(12,13) hypogonadism,(14) varicocele,(14) testicular torsion,(14) kli nefelter syndrome(14,15) and down syndrome.(9) testicular malignancy has an annual incidence of three case per 100,000 men and is the most common cancer in young men.(16,17) although a wide variety of factors have been studied for their connection with cancers, few are considered risk factors for the development of testicular cancer. currently, there are different opinions as to the clinical importance of tm in association with testicular cancer. many retrospective studies have reported a significant association between tm and risk of testicular cancer,(18-20) tm can no longer be regarded simply as a benign condition because of its association with testicular malignancy; however, some other studies failed to reach such associations.(21-23) nowadays, the issue whether testicular microlithiasis has to be regarded as a premalignant lesion or not is still controversial. given the high prevalence of tm across the globe and inconsistent finding about the association between tm and risk of testicular cancer, this study aimed to conduct here a meta-analysis of published literature to investigate whether an epidemiologic relationship, if any, existed between tm and risk of testicular cancer. materials and methods search strategy systematic literature search was conducted by two 1 department of urology, medical center for overseas patients, nanfang hospital, southern medical university, guangzhou, china. 2 department of urology, longjiang hospital of shunde district in foshan city, guangdong province, china. 3 department of urology, minimally invasive surgery center, the first affiliated hospital of guangzhou medical university, guangdong key laboratory of urology, guangzhou, china. 4 department of esophagus, mediastinal oncosurgery, the affiliated tumor hospital of guangzhou medical university, guangzhou, china. *correspondence: department of urology, medical center for overseas patients, nanfang hospital, southern medical university, guangzhou, china. tel: +86 20 6164 2231. fax: +86 20 6164 2231. e-mail: profwei@126.com. received september 2014 & accepted february 2015 vol 12. no 02 march-april 2015 2057 testicular microlithiasis and testicular cancer-wang et al vol 12. no 02 march-april 2015 2058 included studies country study period study design age, years no. of definition of follow-up cancer type of origin (range) participants microlithiasis (months) cast et al. 2000(36) uk 1996-1998 cohort study 37 (18-74) 4892 classic 9 nr skyrme et al. 2001(31) uk 1995-1998 cohort study 34 (23-78) 2215 classic 41 3 seminoma 2 teratoma bach et al. 2001(19) usa 1992-1998 cohort study 45 (18-87) 528 classic nr 8 nsgct 4 seminoma derogee et al. 2001(32) the 1993-1999 cohort study 35.4 (19-74) 1535 > 3mm 61.8 11 seminoma netherlands 19 non-seminoma middleton et al. 2002(7) usa 1996-1999 cohort study 44.4 (15-92) 1079 includes limited 42 8 seminoma 1 mgct 2 leydig cell tumor 1 embryonal cell carcinoma ahmad et al. 2007(35) uk 2000-2006 cohort study 42.6 (17-82) 4259 classic 33.9 nr lam et al. 2007(38) usa 1996-2005 case-control 32 (0.01-75) 274 includes limited 19 4 seminoma 3 mgct 1 choriocarcinoma miller et al. 2007(30) uk 1995-2000 cohort study 40 (18-91) 3279 includes limited nr nr sanli et al. 2008(29) turkey nr(5-year) cohort study 27.5 ± 10.1 (9–56) 4310 classic nr 10 seminomas 3 mgct 2 germ cell tumors 1 embryonal cell carcinoma 1 teratoma chen et al. 2010(34) taiwan jun-dec 2007 cohort study 54.32 (0.5-91) 513 includes limited nr 4 seminoma 3 mgct 1 serous carcinoma la vignera et al. 2012(33 ) italy 2005-2010 cohort study 43.3 ± 7.0 (0.25-87) 1056 includes limited nr 10 seminoma 8 leydig cell tumor 7 intratubular germ cell tumor cooper et al. 2014(18) usa 2003-2012 cohort study 11 (0.6-17.9) 3370 classic 50.4 1 seminoma 1 mgct 1 intratubular germ cell tumor heller et al. 2014(39) usa 1994-2011 case-control 41.3 6002 classic nr 52 seminoma 1 leydig cell tumor volokhina et al. 2014(37) usa 2000-2011 cohort study 7.9 (0.01-19) 2266 classic 8.8 1 mgct abbreviations: nsgct, non-seminomatous germ cell tumor; mgct, mixed germ cell tumor; nr, not reported. table 1. main characteristics of the included studies. review 2058 vol 12. no 01 jan-feb 2015 1997 independent reviewers (tao wang and luhao liu) in pubmed, the cochrane library and embase database for papers published before march 2014. the following keywords were used in our search strategy: microlithiasis, testicular microlithiasis, testicular calcification, testicular cancer, testicular neoplasms, testicular tumor, germ cell tumors, germ cell neoplasms, nonseminoma, and vol 12. no 02 march-april 2015 2059 seminoma. duplicate citations were then removed. in addition, the reference lists of selected articles were also manually examined to find relevant studies not discovered in the databases. the language was limited to english. study selection criteria the studies included in the meta-analysis must have met all the following inclusion criteria:(1) all available retrospective comparative studies (cohort or case-control studies) that had comparative data of the association between tm and testicular cancer; (2) one of the exposure of interest was tm; (3) one of the outcome interest was testicular cancer;(4) reported rate ratio, hazard ratio, or standardized incidence/mortality rate (sir/smr) with their 95% confidence intervals (cis), or provided sufficient information to calculate them and(5) the identified studies were reported in english. following studies were excluded:(1) case reports, editorials, review articles and animal experimental studies; (2) articles about association of tm and testicular cancer were excluded for which tm were included in both case and control groups without non-tm to compare; (3) duplicate data and (4) if they provided only an effect estimate with no means to calculate a ci. when multiple reports describing the same population were published, the most recent or complete report was used. data extraction two collaborators (tao wang and luhao liu) independently reviewed all of the articles and data included studies selection comparability outcome total scores ia ib ic id iia iib iiia iiib iiic cast et al. 2000(36) yes yes yes yes yes yes yes no no 7 skyrme et al. 2001(31) yes yes yes yes yes no yes yes yes 8 bach et al. 2001(19) yes yes yes yes yes yes yes no no 7 derogee et al. 2001(32) yes yes no yes yes no yes yes yes 7 middleton et al. 2002(7) yes yes no yes yes no yes yes yes 7 ahmad et al. 2007(35) yes yes yes yes yes yes yes yes no 8 lam et al. 2007(38) yes yes yes yes yes no yes yes yes 8 miller et al. 2007(30) yes yes yes yes yes yes yes no no 7 sanli et al. 2008(29) yes yes yes yes yes no yes yes yes 8 chen et al. 2010(34) yes yes no yes yes yes yes no no 6 la vignera et al. 2012(33) yes yes yes yes yes no yes no no 6 cooper et al. 2014(18) no yes yes yes yes yes yes yes yes 8 heller et al. 2014(39) yes yes yes yes yes yes yes no no 7 volokhina et al. 2014(37) no yes yes yes yes yes yes no no 6 table 2. newcastle-ottawa scale (nos) assessment of the quality of the studies. for cohort studies; ia: indicates that the exposed cohort was representative of the population; ib: indicates that the non-exposed cohort was drawn from the same population; ic: indicates that the exposure ascertainment was from secure records or a structured interview; id: indicates that testicular cancer was not present at start of study; iia: indicates that the cohorts were comparable for age and sex; iib: indicates that the cohorts were comparable on all additional factor(s) reported; iiia: indicates that testicular cancer was assessed from a secure record; iiib: indicates that follow-up was long enough for testicular cancer to occur; iiic: indicates that follow-up was complete. for case-control studies; ia: indicates cases with independent validation; ib: indicates consecutive or representative cases; ic: indicates community controls; id: indicates controls with no history of testicular cancer; iia: indicates that study controls were comparable for age and sex; iib: indicates that study controls were comparable on all additional factor(s) reported; iiia: indicates that the same method of ascertainment was used for cases and controls; iiib: indicates that assessment of exposure was from a secure record; iiic: indicates that the non-response rate was similar in both groups. figure 1. flow chart of study selection. testicular microlithiasis and testicular cancer-wang et al. disagreement was resolved by a third review or by consensus. the following information was extracted from each study: the first author, publication year, country of origin, study design, age of study population, number of patients in each group, duration of follow-up and tumor histology. when such data were not explicitly reported, they were derived from data provided in the articles or requested from the authors through personal contacts, wherever possible. statistical analysis the association of tm and testicular cancer was estimated by calculating pooled relative risk (rr) and 95% ci. the significant of pooled rr was determined by z test (p < .05 was considered statically significant). statistical heterogeneity between studies was assessed by using q-test with significance set at p < .10, and heterogeneity was quantified using the i2 statistic (significance level at i2 > 50%). the random-effects model was used if there was heterogeneity between studies; otherwise, the fixedeffects model was used.(24,25) we conducted subgroup analysis to explore heterogeneity across studies and the difference between subgroups was tested by meta-regression analysis. the methodological quality of observational studies was assessed by using the newcastle-ottawa scale (nos) systematic review method, with some modifications to match the needs of the present study.(26) the quality of studies was evaluated by examining three aspects of the study design: patient subgroups no. of studies rr (95% ci) i2 (%) p-value heterogeneity geographical region north america (usa) 6 9.43 (4.58-19.44) 83.4 .000 european countries 6 16.31 (11.12-23.94) 40.2 .137 asia 2 16.06 (10.04-25.69) 0.0 .882 study design cohort study 12 13.62 (8.08-22.96) 84.0 .000 case-control study 2 7.68 (5.54-10.64) 0.0 .967 age <18 2 13.04 (0.92-184.64) 82.5 .017 >18 12 12.11 (7.76-18.89) 82 .000 no. of participants ≤ 1000 3 6.58 (2.32-18.68) 52.1 .124 > 1000 11 14.80 (10.07-21.76) 69.8 .000 table 3. subgroup analysis of the association between testicular microlithiasis and testicular cancer. abbreviations: rr, relative risks; ci, confidence interval. testicular microlithiasis and testicular cancer-wang et al figure 2. forest plot of testicular microlithiasis and risk of testicular cancer. abbreviation: ci, confidence interval. review 2060 review 2061 selection, comparability of the groups, and assessment of outcomes. in this 9 scores system, studies scored greater than or equal to 7 were considered to be of high quality. sensitivity analysis was performed by sequential omission of individual studies under various contrasts to reflect the influence of the individual data to the pooled rrs and evaluate the stability of the results. we used the begg adjusted rank correlation test, and the egger regression asymmetry test to detect publication bias and p > .05 for both tests was considered to be no significant publication bias.(27,28) the stata 12.0 statistical software (stata corporation, college station, texas, usa) was used for all the statistical analyses. p values < .05 were considered statistically significant, and all the p values were two-sided. results search results our initial search identified 734 articles, and 676 articles were excluded by examining the titles and abstracts. by examining the full-texts of these articles, we excluded 44 studies because association of interest was not evaluated, requested data were not reported, or articles were not published in english. finally, a total of 14 articles were selected for our meta-analysis, including 12 cohort(7,18,19,29-37) and 2 case-control studies.(38,39) examination of the reference lists of these studies did not detect any further studies for evaluation. our search flow diagram was shown in figure 1. study characteristics and quality assessment the characteristics and information of the included studies were shown in table 1. the 14 selected studies contained 35578 participants (ranging from 274 to 6002) with 1493 cases of tm from different populations (6 studies originated from the united states and 2 studies from asia). the remaining 6 studies were from european countries, including: 4 from uk, 1 from italy and 1 from netherlands, with varied length of the follow-up period (ranging from 8.8 to 61.8 months). the results of quality assessment according to nos for included studies were shown in table 2. in this total 9 points evaluation system, the scores of included studies ranged from six to eight, while eleven of them were defined high-quality. results of meta-analyses we identified 14 observational studies that reported results on tm and testicular cancer incidence. as shown in figure 2, the summary rr was 12.70 (95% ci: 8.18-19.71) in a random-effects model for tm patients, compared with individuals without tm. there was significant heterogeneity among these studies (p < .001, i2 = 82.1%). to further elicit the association between tm and the risk of testicular cancer, subgroup analyses were adopted, according to stratification on geographical region, study design, age and numbers of participants (table 3). our data supported the hypothesis that tm is association with an increased incidence of testicular cancer. sensitivity analysis was performed to assess the influence of individual studies on the overall risk of testicular cancer by excluding each individual study and recalculating the figure 3. begg’s funnel plot for publication bias evaluating the association between testicular microlithiasis and testicular cancer. figure 4. influence of each individual study on the relative risks of testicular cancer in testicular microlithiasis patients as compared with individuals without testicular microlithiasis. testicular microlithiasis and testicular cancer-wang et al. vol 12. no 02 march-april 2015 2061 pooled rr. similar rr and 95% ci were generated with the exclusion of each study, indicating the high degree of stability of the results (figure 4). publication bias there was no funnel plot asymmetry for the association between tm and risk of testicular cancer (figure 3). p values for begg adjusted rank correlation test was 0.381 and the egger regression asymmetry test was 0.231, suggesting a low probability of publication bias. discussion in the last decade, several epidemiological studies have examined the association between tm and risk of testicular cancer but provided inconsistent results. based on data from 12 cohort studies and 2 case-control studies, the present study represents the meta-analysis quantitatively investigating the association between tm and risk of testicular cancer. we found that compared with non-tm or general population, individuals with tm might have more than 12-fold increased incidence of testicular cancer. further stratification for age demonstrated similar trends. our study recruited a total of 1493 tm cases and 34085 controls, which greatly improved the statistical power and the conclusions were more credible than those of individual studies. subgroup analyses were performed to explore the degree to which potential confounders might have influenced the findings, according to stratification on geographic location, study design and age. the sensitivity analysis further confirmed the stability of the conclusions. the mechanisms by which tm could affect the pathogenesis of testicular cancer remain largely unknown. tm is an incidental finding detected during ultrasonographic examination of the scrotum. owing to the use of higher-frequency ultrasound transducers resulting in enhanced spatial resolution and thus improved sensitivity, exquisite detail of testicular pathology can be demonstrated. moreover, an increased general knowledge of the association of tm with testicular cancer, more cases of tm have recently been reported. it is unclear if the high prevalence rate is a result of a true high incidence, because of a wide variety of ultrasound transducers used and different methods for identifying patients with tm.(14) although originally thought to be a rare abnormality, the reported frequency of detection of tm in relationship to the racial background of a healthy population was 4.2% white, 14.1% african american, 8.5% hispanic, 5.6% asian or pacific islander and 5.2% who did not claim a race affiliation.(21) in addition, testicular microlithiasis can be seen at all ages but is reported to be more common in childhood.(6) its relative prevalence has been reported in previous literature as 1/2100 for adults, 1/618 for boys and 1/15 for boys with cryptorchidism.(40) it is generally accepted that tm consists of calcified cores surrounded by concentric layers of collagen fibers located in the lumen of the seminiferous tubules.(41) however, some author believe that the microliths are located outside the tubules and have been present since early stage of testicular development.(5) the microcalcification may be initiated by sloughing of degenerated cells into the tubule. the major defect is believed to be in the breakage of the basement membrane of the seminiferous tubule.(10) almost all of the patients examined had tubular hyalinization in the tissue surround the testicular cancer, the same as reported by previous studies,(42,43) as a result not only of autoimmune processes but also of ischemic or obstructive events that may account for the development of a cancer in a predisposing environment. this is also supported by the fact microlithiasis and tubular hyalinization are absent in the only benign neoplasm,(44) while not excluding an environmental component. coffey and colleagues(45) noted that a higher degree of concordance for tm among testicular germ cell tumors cases and matched relative pairs than was expected by chance. therefore tm may be, at least in part, genetically determined and may have a joint etiology. given the current literature and our data, we can prove the hypothesis that tm is associated with an increased incidence of testicular cancer; but we cannot assess whether tm is a cause or risk factor for development of testicular cancer. as noted in the literature, because the clinical importance of tm is still in debate, the role of ultrasound and the recommendations for follow-up studies in patients with tm vary among different authors. some authors recommend annual physical examination and periodic self-examination, but no regular ultrasound follow-up.(7) decastro and colleagues(46) suggested that testicular cancer will not develop in the majority of men with tm (98.4%) during a 5-year follow-up. it is unlikely that an extensive screening program would benefit men at risk with any decreased burden of treatment or improved cure rate. because of a high prevalence of testicular cancer in infertile men, some authors recommend biopsy or follow-up ultrasound when tm is seen in an atrophic testis.(46) most studies had not found elevated tumor markers in those with incidental tm, monitoring of serum tumor marker was not appropriate. we advocate that the most prudent approach will be to instruct patients with incidental tm to perform testicular self-examination and annual physical exams by a primary care provider, while tm in patients with risk factors for developing testicular cancer to rely on monthly testicular self-exams, annual physical exams by a urologist and ultrasound follow-up. (22) the present meta-analysis has the following limitations that must be taken into account. first, the main limitation was that all the included studies were retrospective studies, which might not be prone to recall bias but were prone to selection bias. in the future, longitudinal prospective studies are required to validate the evidence of a parenchymal environment predisposing to the development of testicular cancer. second, we did not uncover unpublished studies and chose to collect only published articles in english, which could bring publication bias, despite there being no significant evidence of publication bias observed in egger’s test. third, great heterogeneity existed in terms of ethnicity, study design, age and definition of microlithiasis. use of the random-effect model for pooled data might minimize the effects of heterogeneity, but did not abolish them. the degree of heterogeneity fell for most outcomes with sensitivity analysis, but this difference was not significant. conclusion in conclusion, results of this meta-analysis suggest a potential hazardous effect of tm for developing testicular cancer. given its association with testicular cancer, we advocate that all tm patients are well informed and educated to practice regular self-examination of testes and annual physical exams. in future, large-scale and well-designed prospective studies are necessary to be testicular microlithiasis and testicular cancer-wang et al review 2062 vol 12. no 02 march-april 2015 2063 conducted to further elucidate the association between tm and risk of testicular cancer. acknowledgments we thank professor anyang wei and luhao liu for their excellent technical support. this study was supported by the national natural science foundation of china (81170566) and natural science foundation of guangdong province (s2012010009091). conflict of interest none declared. references 1. doherty fj, mullins tl, sant gr, drinkwater ma, ucci aj. testicular microlithiasis. a 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microlithiasis: prevalence and clinical significance in a population referred for scrotal ultrasonography. korean j urol. 2011;52:172-7. 9. bieger rc, passarge e, mcadams aj. testicular intratubular bodies. j clin endocrinol metab. 1965;25:1340-6. 10. vegni-talluri m, bigliardi e, vanni mg, tota g. testicular microliths: their origin and structure. j urol. 1980;124:105-7. 11. weinberg ag, currarino g, stone ij. testicular microlithiasis. arch pathol. 1973;95:312-4. 12. schantz a, milsten r. testicular microlithiasis with sterility. fertil steril. 1976;27:801-5. 13. pierik fh, dohle gr, van muiswinkel jm, vreeburg jt, weber rf. is routine scrotal ultrasound advantageous in infertile men? j urol. 1999;162:1618-20. 14. miller fn, sidhu ps. does testicular microlithiasis matter? a review. clin radiol. 2002;57:883-90. 15. bunge rg, bradbury jt. intratubular bodies of the human testis. j urol. 1961;85:306-10. 16. richie jp. detection and treatment of testicular cancer. ca cancer j clin. 1993;43:151-75. 17. dieckmann kp, boeckmann w, brosig w, jonas d, bauer hw. bilateral testicular germ cell tumors. report of nine cases and review of the literature. cancer. 1986;57:1254-8. 18. cooper ml, kaefer m, fan r, rink rc, jennings sg, karmazyn b. testicular microlithiasis in children and associated testicular cancer. radiology. 2014;270:857-63. 19. bach am, hann le, hadar o, et al. testicular microlithiasis: what is its association with testicular cancer? radiology. 2001;220:70-5. 20. tan ib, ang kk, ching bc, mohan c, toh ck, tan mh. testicular microlithiasis predicts concurrent testicular germ cell tumors and intratubular germ cell neoplasia of unclassified type in adults: a meta-analysis and systematic review. cancer. 2010;116:4520-32. 21. peterson ac, bauman jm, light de, mcmann lp, costabile ra. the prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. j urol. 2001;166:20614. 22. rashid hh, cos lr, weinberg e, messing em. testicular microlithiasis: a review and its association with testicular cancer. urol oncol. 2004;22:285-9. 23. serter s, gumus b, unlu m, et al. prevalence of testicular microlithiasis in an asymptomatic population. scand j urol nephrol. 2006;40:2124. 24. mantel n, haenszel w. statistical aspects of the analysis of data from retrospective studies of disease. j natl cancer inst. 1959;22:719-48. 25. dersimonian r, laird n. meta-analysis in clinical trials. control clin trials. 1986;7:17788. 26. wells ga, shea b, o’connell d, peterson’connell j, welch v, et al. the newcastle-ottawa scale (nos) for assessing the quality of nonrandomised studies in metaanalyses. a v a i l a b l e : h t t p : / / w w w . o h r i . c a / p r o g r a m s / clinical_epidemiology/oxford.asp. accessed 2103 nov 9. 27. begg cb, mazumdar m. operating characteristics of a rank correlation test for publication bias. biometrics. 1994;50:1088101. 28. egger m, davey sg, schneider m, minder c. bias in meta-analysis detected by a simple, graphical test. bmj. 1997;315:629-34. 29. sanli o, kadioglu a, atar m, acar o, nane testicular microlithiasis and testicular cancer-wang et al. i, kadioglu a. grading of classical testicular microlithiasis has no effect on the prevalence of associated testicular tumors. urol int. 2008;80:310-6. 30. miller fn, rosairo s, clarke jl, sriprasad s, muir gh, sidhu ps. testicular calcification and microlithiasis: association with primary intratesticular malignancy in 3,477 patients. eur radiol. 2007;17:363-9. 31. skyrme rj, fenn nj, jones ar, bowsher wg. testicular microlithiasis in a uk population: its incidence, associations and follow-up. bju int. 2000;86:482-5. 32. derogee m, bevers rf, prins hj, jonges tg, elbers fh, boon ta. testicular microlithiasis, a premalignant condition: prevalence, histopathologic findings, and relation to testicular tumor. urology. 2001;57:1133-7. 33. la vignera s, condorelli r, vicari e, d'agata r, calogero ae. testicular microlithiasis: analysis of prevalence and associated testicular cancer in central-eastern sicilian andrological patients. andrologia. 2012;44 suppl 1:295-9. 34. chen jl, chou yh, tiu cm, et al. testicular microlithiasis: analysis of prevalence and associated testicular cancer in taiwanese men. j clin ultrasound. 2010;38:309-13. 35. ahmad i, krishna ns, clark r, nairn r, alsaffar n. testicular microlithiasis: prevalence and risk of concurrent and interval development of testicular tumor in a referred population. int urol nephrol. 2007;39:1177-81. 36. cast je, nelson wm, early as, et al. testicular microlithiasis: prevalence and tumor risk in a population referred for scrotal sonography. ajr am j roentgenol. 2000;175:1703-6. 37. volokhina yv, oyoyo ue, miller jh. ultrasound demonstration of testicular microlithiasis in pediatric patients: is there an association with testicular germ cell tumors? pediatr radiol. 2014;44:50-5. 38. lam dl, gerscovich eo, kuo mc, mcgahan jp. testicular microlithiasis: our experience of 10 years. j ultrasound med. 2007;26:867-73. 39. heller ht, oliff mc, doubilet pm, o'leary mp, benson cb. testicular microlithiasis: prevalence and association with primary testicular neoplasm. j clin ultrasound. 2014;42:423-6. 40. mceniff n, doherty f, katz j, schrager ca, klauber g. yolk sac tumor of the testis discovered on a routine annual sonogram in a boy with testicular microlithiasis. ajr am j roentgenol. 1995;164:971-2. 41. holm m, lenz s, de meyts er, skakkebaek ne. microcalcifications and carcinoma in situ of the testis. bju int. 2001;87:144-9. 42. nistal m, mate a, paniagua r. granulomatous epididymal lesion of possible ischemic origin. am j surg pathol. 1997;21:951-6. testicular microlithiasis and testicular cancer-wang et al 43. trias i, algaba f, hocsman h. intratubular germ cell tumor. relation with 'burned-out' tumor and testicular germinal neoplasia. eur urol. 1991;19:81-4. 44. parenti gc, zago s, lusa m, campioni p, mannella p. association between testicular microlithiasis and primary malignancy of the testis: our experience and review of the literature. radiol med. 2007;112:588-96. 45. coffey j, huddart ra, elliott f, et al. testicular microlithiasis as a familial risk factor for testicular germ cell tumour. br j cancer. 2007;97:1701-6. 46. decastro bj, peterson ac, costabile ra. a 5-year followup study of asymptomatic men with testicular microlithiasis. j urol. 2008;179:14203. 47. von eckardstein s, tsakmakidis g, kamischke a, rolf c, nieschlag e. sonographic testicular microlithiasis as an indicator of premalignant conditions in normal and infertile men. j androl. 2001;22:818-24. review 2064 vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2479 endourology and stone diseases comparison of anesthesia methods in treatment of staghorn kidney stones with percutaneous nephrolithotomy ibrahim buldu,1* abdulkadir tepeler,2 mehmet kaynar,3 tuna karatag,1 muhammed tosun,2 tarik umutoglu,4 hakan tanriover,5 okan istanbulluoglu1 purpose: to compare the efficacy and safety of percutaneous nephrolithotomy (pnl) in the treatment of staghorn calculi (sc) under spinal anesthesia (sa) versus general anesthesia (ga). materials and methods: patients with sc who treated with pnl from 2011 to 2014 were retrospectively reviewed. in total, 100 patients were divided into 2 groups according to anesthesia type: sa (group 1, n = 47) and ga (group 2, n = 53). demographics, perioperative parameters, and postoperative analgesic requirements were compared between the two groups. results: there was no significant difference in terms of age, sex, american society of anesthesiologists score, body mass index, or stone size between the two groups (p = .40, .30, .18, .20, and .50, respectively). the mean procedure times were 84.7 and 87.5 min in the sa and ga groups, respectively (p = .68). the complication rates were similar in the sa and ga groups (19.1% vs. 13.2%, respectively; p = .421). the stone-free rates were also similar in the sa and ga groups (61.7% vs. 52.8%, respectively; p = .374). no statistically significant difference was found in analgesic requirements. conclusion: sa is a safe method without the risks of ga and may be used for conditions in which ga is contraindicated or in patients with concerns about ga. our outcomes indicated that sc can be treated safely and effectively under sa. keywords: kidney calculi; surgery; nephrostomy; percutaneous; adverse effects; complications; treatment outcome; anesthesia; methods. introduction staghorn calculi (sc) are branched kidney stones that fill part or all of the pelvicaliceal system and account for 27.7% of all cases of kidney stones.(1,2) because sc can cause urinary infections, they may be responsible for kidney damage and the development of life-threatening sepsis.(3,4) for many years, percutaneous nephrolithotomy (pnl) was the first option for treatment of large and staghorn kidney stones.(1) however, pnl may be difficult due to a number of factors, such as a prolonged operation time and hospitalization, requirement for more than one access route, an increased rates of intercostal access, and hemorrhage.(5-8) pnl can be performed with either spinal anesthesia (sa) or general anesthesia (ga). several studies have evaluated the advantages and disadvantages of sa versus ga.(9-14) these studies suggested that treatment of sc with standard pnl might be problematic under sa because of the prolonged operation time. due to a lack of previous clinical studies regarding this issue, we compared the efficacy and safety of pnl in the treatment of sc under sa versus ga. materials and methods patients with sc who underwent standard pnl by experienced urologists (a.t., o.i.) in two referral centers from 2011 to 2014 were retrospectively reviewed. we excluded patients 1) under the age of 18 years, 2) with a solitary kidney, 3) with bilateral kidney stones, and 4) undergoing additional surgical interventions for conditions other than kidney stones. in total, 100 patients were included in the study, and they were divided into 2 groups according to the type of anesthesia: sa (group 1) and ga (group 2). in a standard fashion, the patients 1 department of urology, faculty of medicine, university of mevlana, konya 42000, turkey. 2 department of urology, faculty of medicine, bezmialem vakif university, istanbul 34000, turkey. 3 department of urology, faculty of medicine, selcuk university, konya 42000, turkey. 4 department of anesthesiology, faculty of medicine, bezmialem vakif university, istanbul 34000, turkey. 5 department of anesthesiology, faculty of medicine, university of mevlana, konya 42000, turkey. *correspondence: department of urology, faculty of medicine, mevlana university, konya 42000, turkey. tel: +90 505 4553123. fax: +90 332 4424200. e-mail: ibrahimbuldu@yahoo.com. received april 2015 & accepted november 2015 endourology and stone diseases 2480 of the first center underwent the pnl procedures under sa (group 1), while pnl procedures were performed under ga in center 2 (group 2). demographic data, american society of anesthesiologists (asa) score, stone size and location, perioperative parameters (operation time, hemoglobin drop, stone-free and complication rates, mean access number, access location), and postoperative analgesic requirements were compared between the groups. all patients underwent routine urinalysis, urine culture, and blood chemistry as well as a physical examination. patients with positive urine cultures were also treated with appropriate antibiotics preoperatively. antibiotic drugs, including ciprofloxacin 200 mg and cefuroxime sodium 750 mg, were administered as prophylactic regimens intravenously for 24 h, and oral ciprofloxacin 500 mg (twice per day) was maintained until the patient was discharged. radiological evaluation was performed with kidney-ureter-bladder (kub) plain images, urinary ultrasonography, intravenous urography, and/or computed tomography (ct) scan for all patients. the largest diameter of the stone was determined using imaging (in mm), and in the presence of multiple stones, the sum of the largest diameters of all stones was calculated. spinal anesthesia technique all patients received 1000 ml of intravenous normal saline 20 to 30 min before surgery. following administration of midazolam (2 mg) for sedation, anesthesia was achieved with administration of 15 to 20 mg of bupivacaine (adjusted according to body mass index [bmi]) through intervertebral gap l3–l4 into the subarachnoid space with a 25-gauge needle. hypotension was controlled by ephedrine (5–10 mg) administration. anesthesia was provided up to the t4 dermatome level (up to the level of the nipple). general anesthesia technique initially, 2 mg/kg of propofol and 1 mg/kg of fentanyl were administered intravenously in the general anesthesia group. following these medications, oxygen containing 0.8% to 1.2% isoflurane and 50% n 2 o was applied. the ventilation rate was adjusted using an anesthesia machine ventilator with a tidal volume of 10 to 12 breaths/min (8–10 ml/kg). neuromuscular block was eliminated by applying 0.5 mg of atropine and 1 mg of neostigmine at the end of surgery. surgical technique the procedure was started with the insertion of a 6 french (f) open-ended ureteral catheter in the lithotomy position. the patient was then turned to the prone position. next, access to the desired calyx was performed under c-arm fluoroscopy. the tract was dilated up to 30 f using amplatz dilators over a guidewire, and a 30 f amplatz sheath was placed into the collecting system. stone disintegration was achieved using a pneumatic lithotripter through a 26 f nephroscope. stone fragments were removed with graspers. after assessment of stone clearance using fluoroscopy and endoscopy, a nephrostomy tube was inserted into the collecting system. the operation time was defined as the duration between the beginning of the pnl procedure after changing the position and inserting the nephrostomy tube. all patients were evaluated with kub and biochemical tests postoperatively. patients were discharged in the absence of any complications after removal of the nephrostomy tube on postoperative days 1 to 3. complications were classified according to the clavien classification system.(15) the success of the procedure was assessed with ct scan 4 weeks after surgery. statistical analysis data analysis was performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 20. patientand operation-related parameters were compared between the groups using the mann–whitney u test for numerical variables and the χ2 test for categorical variables. a p value of < .05 for the mann–whitney u test was considered statistically significant. table 1. demographic characteristics of study patients. variables group 1 group 2 p value patient number, no. 47 53 .435 mean age, years 48.5 ± 13.8 (19-78) 46.1 ± 16.6 (19-69) .3 sex, male/female 33/14 42/11 .215 mean bmi, kg/m² 28.7 ± 5.6 (18-46.1) 27.1 ± 6.6 (18-42.3) mean asa score 1.4 1.2 .188 mean stone size, mm 52.9 ± 15.4 (35-125) 50.6 ± 24.6 (36-184) .58 abbreviations: bmi, body mass index; asa, american society of anesthesiologists score. percutaneous nephrolithotomy and two different anesthesia methods – buldu et al. vol 13 no 01 january-february 2016 2481 results demographic characteristics of patients are summarized in table 1. in total, 100 patients (75 males and 25 females) were included in the study. the numbers of patients were 47 and 53 in groups 1 and 2, respectively. the mean age, bmi, asa score, and stone size were 48.5 and 46.1 years, 28.7 and 27.1 kg/m2, 1.4 and 1.2, and 52.9 and 50.6 mm in groups 1 and 2, respectively. there was no statistically significant difference in terms of age, sex, asa score, bmi, or stone size between the groups (p = .40, .30, .18, .20, and .50, respectively). the postoperative outcomes of the patients are summarized in table 2. the mean operation time was 84.7 (range, 55–200) min in group 1 and 87.5 (range, 40– 210) min in group 2 (p = .68). the mean access numbers were 1.19 and 1.21, the rates of intercostal access were 4.2% and 13.2%, and the mean hospitalization times were 2.3 and 2.7 days, respectively. these differences were not statistically significant. the stone-free rates were similar in both groups (61.7% vs. 52.8%, respectively; p = .374). no statistically significant difference was found regarding analgesic requirements. the mean opioid usage was 43.2 and 53.2 mg in groups 1 and 2, respectively. the mean doses of paracetamol were 2303 and 2604 mg, respectively (p = .201). the complication rates were similar in groups 1 and 2 (19.1% vs. 13.2%, respectively; p = .421). in total, nine patients in the sa group showed complications: hemorrhage requiring blood transfusion (clavien ii; n = 2), double-j ureteral catheter insertion due to prolonged urine drainage (clavien iiia; n = 2), atelectasis (clavien ii; n = 1), urinary tract infection (clavien ii; n = 1), perioperative hypotension (n = 1), and postoperative headache (clavien i; n = 2). the complications seen in the ga group were hemorrhage requiring blood transfusion (clavien ii; n = 2), urinary tract infection (clavien ii; n = 2), urosepsis (clavien iiia; n = 1), double-j ureteral catheter insertion due to prolonged urine drainage (clavien iiia; n = 1), and pneumothorax (clavien iiia; n = 1). two patients experienced pain toward the end of the pnl procedure in the sa group, but the procedures were completed successfully after injection of 1 mg of midazolam and 1 µg/kg of fentanyl citrate. no patient in the sa group required conversion to ga. discussion treatment of sc remains a problem for urologists despite recent technological refinements. pnl is recommended as the first option for the treatment of sc. all acute complications, such as transfusion requirement and death, are more common in cases of sc than othpercutaneous nephrolithotomy and two different anesthesia methods – buldu et al. variables group 1 group 2 p value mean perative time (range), min 84.7 ± 28.6 (55-200) 87.5 ± 37.2 (40-210) .684 mean access number 1.19 1.21 .86 intercostal access, no. (%) 2 (4.2) 7 (13.2) .12 mean hemoglobin drop, mg/dl 2.4 ± 1.5 1.9 ± 2.1 .283 complication, no. (%) 9 (19.1) 7 (13.2) .421 hemorrhage 2 (4.2) 2 (3.8) prolonged urine drainage 2 (4.2) 1 (1.9) pneumothorax 0 1 (1.9) atelectasis 1 (2.1) 0 urinary tract infection 1 (2.1) 2 (3.8) postoperative headache 2 (4.2) 0 perioperative hypotension 1 (2.1) 0 urosepsis 0 1 (1.9) mean analgesic requirement, doses/patient 4.2 ± 2.6 4.4 ± 2.0 .765 mean hospital stay, day 2.3 ± 1.3 2.7 ± 2.5 .432 outcome, no. (%) stone free 29 (61.7) 28 (52.8) .374 fragments < 4 mm 7 (14.9) 9 (17.0) .777 rest 11 (23.4) 16 (30.2) .448 table 2. the operative outcomes of patients are presented. endourology and stone diseases 2482 er types of kidney stones.(1) in a study by the clinical research office of endourological society (croes) group, the rates of postoperative fever, hemorrhage, perforation of the collection system, blood transfusion, and both operative and hospitalization times were higher, while the stone-free rate was lower in the sc group than in cases of non-sc.(2) many urologists prefer ga in the treatment of sc with pnl. despite its advantages, such as the ability to control the patient’s breathing and increased comfort for the surgeon, ga has several disadvantages for the patient, including an increased incidence of anaphylaxis due to multiple drug administration; pulmonary, vascular, and neurological complications; and the risk of problems related to endotracheal tubes while turning the patient to the prone position from the lithotomy position.(11,16) several studies have demonstrated that regional anesthesia can be performed safely and effectively in patients undergoing pnl for the treatment of kidney stones.(9-14) however, the efficacy of pnl under sa has not been investigated. to our knowledge, this is the first reported study comparing anesthesia methods for pnl of sc. in a randomized clinical study, nouralizadeh and colleagues(9) reported that both anesthesia methods had similar efficacy and complication rates. kuzgunbay and colleagues(10) found no significant difference with respect to operative time, amount of irrigation, fluoroscopy time, hemoglobin changes, hospitalization, or stonefree rates between combined epidural sa and ga. in another study, karacalar and colleagues(11) reported that patient satisfaction was higher and pain scores were lower in the spinal epidural block group than in the ga group. however, in a randomized controlled study comparing sa and ga in terms of efficacy and complication rates in pnl, mehrabi and colleagues(12) found no statistically significant difference in success rate or patient satisfaction. they reported that intraoperative hypotension, postoperative headache, and backache were more common with sa. moreover, they noted that sa was less costly while narcotic analgesia requirements were higher in ga on postoperative day 1.(12) cicek and colleagues(13) reported similar success rates but shorter durations of hospitalization, operation, and fluoroscopy in sa than ga in pnl. they also found significantly higher postoperative narcotic analgesia requirements and blood transfusion rates in the ga group.(13) in contrast, we found similar outcomes in the sa and ga groups with regard to complications (19.1% vs. 13.2%, respectively), stone-free rates (61.7% vs. 52.8%, respectively), and mean hemoglobin change (2.4 vs. 1.9 mg/dl, respectively). as mentioned in many previous studies, the most common side effects of sa are intraoperative hypotension and postoperative headache and backache due to the blockage of central venous pressure and vasodilatation. all of these conditions can be managed with intraoperative ephedrine injection, rest, and postoperative use of analgesic drugs.(12) intercostal access rates were higher in pnl surgery of patients with sc versus those with non-sc.(2) in one study, investigators evaluated patients undergoing supracostal access in sa and ga groups. they found similar complication and success rates, and no patients converted to ga. the average sensorial and motor block times were 120 ± 20 and 110 ± 40 min, respectively.(17) we found no significant difference with regard to the number of intercostal interventions (4.2% vs. 13.2%, respectively). in the sa group, two patients experienced pain and prolonged operation times of > 150 min, and they were managed by perioperative analgesic supplementation. the main limitations of this study are its retrospective nature and the lack of visual analog scale scores and perioperative blood pressure measurements. there may also be a need to convert to open surgery in cases of massive hemorrhage. there might also be wasted time in turning the patient to the lateral decubitus position following the insertion of an endotracheal tube. thus, it can be recommended to perform pnl under sa only with an experienced urologist and anesthesiologist. the outcomes reported here contribute to the literature in terms of the safety and efficacy of performing pnl under sa for the treatment of sc. conclusions sa is a safe method without the risks of ga and may be used for conditions in which ga is contraindicated or in patients with concerns about ga. the outcomes reported here indicated that staghorn kidney stones can be treated safely and effectively under sa. conflict of interest none declared. references 1. preminger gm, assimos dg, lingeman je, nakada sy, pearle ms, wolf js jr. aua nephrolithiasis guideline panel. chapter 1: aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005;173:19912000. percutaneous nephrolithotomy and two different anesthesia methods – buldu et al. vol 13 no 01 january-february 2016 2483 2. desai m, de lisa a, turna b, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: staghorn versus nonstaghorn stones. j endourol. 2011;25:1263-8. 3. koga s, arakaki y, matsuoka m, ohyama c. staghorn calculi--long-term results of management. br j urol. 1991;68:122-4. 4. soucy f, ko r, duvdevani m, nott l, denstedt jd, razvi h. percutaneous nephrolithotomy for staghorn calculi: a single center’s experience over 15 years. j endourol. 2009;23:1669-73. 5. turna b, nazli o, demiryoguran s, mammadov r, cal c. percutaneous nephrolithotomy: variables that influence hemorrhage. urology. 2007;69:603-7. 6. preminger gm. high burden and complex renal calculi: aggressive percutaneous nephrolithotomy versus multimodal approaches. arch it urol androl. 2010;82:3740. 7. akman t, sari e, binbay m, et al. comparison of outcomes after percutaneous nephrolithotomy of staghorn calculi in those with single and multiple accesses. j endourol. 2010;24:955-60. 8. ganpule ap, mishra s, desai mr. multiperc versus single perc with flexible instrumentation for staghorn calculi. j endourol. 2009;23:16758. 9. nouralizadeh a, ziaee sa, hosseini sharifi sh, et al. comparison of percutaneous nephrolithotomy under spinal versus general anesthesia: a randomized clinical trial. j endourol. 2013;27:974-8. 10. kuzgunbay b, turunc t, akin s, ergenoglu p, aribogan a, ozkardes h. percutaneous nephrolithotomy under general versus combined spinal-epidural anesthesia. j endourol. 2009;23:1835-8. 11. karacalar s, bilen cy, sarihasan b, sarikaya s. spinal-epidural anesthesia versus general anesthesia in the management of percutaneous nephrolithotripsy. j endourol. 2009;23:15917. 12. mehrabi s, mousavi zadeh a, akbartabar toori m, mehrabi f. general versus spinal anesthesia in percutaneous nephrolithotomy. urol j. 2013;10:756-61. 13. cicek t, gonulalan u, dogan r, et al. spinal anesthesia is an efficient and safe anesthetic method for percutaneous nephrolithotomy. urology. 2014;83:50-5. 14. singh v, sinha rj, sankhwar sn, malik a. a prospective randomized study comparing percutaneous nephrolithotomy under combined spinal-epidural anesthesia with percutaneous nephrolithotomy under general anesthesia. urol int. 2011;87:293-8. 15. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 16. barak m, putilov v, meretyk s, halachmi s. etview tracheoscopic ventilation tube for surveillance after tube position in patients undergoing percutaneous nephrolithotomy. br j anaesth. 2010;104:501-4. 17. moslemi mk, mousavi-bahar sh, abedinzadeh m. the feasibility of regional anesthesia in the percutaneous nephrolithotomy with supracostal approach and its comparison with general anesthesia. urolithiasis. 2013;41:53-7. percutaneous nephrolithotomy and two different anesthesia methods – buldu et al. 1392 | department of urology, dr d. mišović clinical center, belgrade, serbia. slaviša savić, vinka vukotić, miodrag lazić, nataša savić management of calculus anuria using ureteroscopic lithotripsy as a first line treatment: its efficacy and safety corresponding author: slaviša savić, md department of urology, dr. d. misovic hospital, h.m. tepica 1, 11000 belgrade, serbia. tel: +381 11 3630600 fax: +381 11 3672025 e-mail: drsavics@yahoo. com received may 2013 accepted december 2013 purpose:topresentourexperiencewithemergencyureteroscopiclithotripsy(ursl)forureteral calculiassociatedwithacutekidneyinjury(aki). materials and methods:weretrospectivelyevaluatedthe61patientsconsistedof90ureteralunits (uu),whounderwentursl.thecauseofanuriawasbilateralcalculusobstructionsin29cases, andunilateralcalculusobstructionwith,absent,nephrectomizedcontralateralkidneyin32cases. inthecaseofbilateralsynchronousuretericcalculisame-sessionbilateralureteroscopy(sbbu) wasdone.thedurationofanuriavariedbetween12to72hours.attheendoftheprocedure,ureteralstentwassystematicallyleftinplaceinallpatients.surgerywasperformed6-12hoursafter admissiontohospital.patientswerefollowedatleast1monthpostoperatively. results:thestonefreerates(sfr)weredeterminedasbaseline,onthefirstpost-operativeday, andasoverallonthe30daysafterprocedure.thegreatestsuccesswasachievedinthedistal localizationofstonesupto10mm(93%).renalfunctionreturnedin51(83.6%)patientswithin 7days.in18(29.5%)patients[18(20%)uu]weperformedsecondprocedureasextracorporeal shockwavelithotripsyin16.7%andopensurgeryin2.2%.in43(70.5%)patientsurslwasasuccessfultherapeuticapproachindealingwithpain,obstructionandcalculus. conclusion: calculusanuriaisamedicalemergencythatrequiresrapiddiagnosisandprompt treatmentforthepurposeofdecompression.urslisthepropermethodofchoiceforselected patientsandcanbeperformedsafelyandhashighsuccessrateswithminimalmorbidity. keywords: ureteralcalculi,surgery;ureteroscopy;lithotripsy;kidney,abnormalities;anuria,therapy;treatmentoutcome. endourology and stone disease endourology and stone disease 1393vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l introduction acutekidneyinjury(aki)hasbeendefinedinmul-tiplestudiesusingvaryingchangesinserumcre-atinine,urineoutput,needforrenalreplacement therapyandestimatedglomerularfiltrationrate.(1)acute reversiblekidneyinjury(arki)secondarytobilateralureteral obstruction(buo)isacommonurologicalproblemandthe underlyingetiologycanbemalignantorbenign.(2) postrenalanuriaisaurologicemergencythatmustbemanagedrapidlyandcarefully;otherwisetheglomerularfiltrationrate(gfr)willdeclinerapidly,withriseofbloodurea andserumcreatinineandwater-electrolytesimbalance.then aseriesofsymptomsinotherorganswillbeevidentand lastlymultipleorgansfailurewillresultandthepatient’slife will be threatened.(3)thepatientwhopresentswithacuteurinaryobstructionisinneedofurgentdrainageoftheurinary tracteitherbyureteralstentingorpercutaneousnephrostomy (pcn).timely decompression may result in complete recoveryofrenalfunction.(4)postrenalanuriaismostlydueto obstructionoftheurinarytractandthemostcommoncause ofurinaryobstructionisureteralcalculi.(5)calculusanuria isaurologicalemergencyandanuriacanbeduetobilateral uretericcalculusimpactionortounilateraluretericcalculus impactionofasolitarykidneyortoonlyasinglefunctioningkidney.acuteunilateralureteralobstructionduetostones isafrequentevent,affecting5%to15%ofthepopulation worldwide.(6) ureteroscopic lithotripsy (ursl) represents the golden standardforthetreatmentofuretericstonesinthecaseof bilateral synchronous ureteral calculi, and the options are a stagedorasynchronousurslprocedure.bilateralsamesessionureteroscopy(ssbu)canreduceinoveralloperative timeandhospitalstay,preventmultiplesurgicalprocedures andanesthesia,minimizethedurationofconvalescenceand also complications, provided that the surgeon has enough experienceinendoscopicprocedures.conversely,thetechniquewouldexposebothureters to injurythatcouldlead tosignificantmorbidity.gunlusoyandcolleaguesreported thatbilateralsingle-sessionpneumaticlithotripsycanbeperformedsafelyandhashighsuccessrateswithminimalmorbidity and short hospital stay.(7) patientswithasolitarykidneyneedtobecomestone-freeas soonaspossibleduetoriskofacuteobstructiverenalinsufficiency.sinceursloffersbothimmediaterelieffromsymptomsandstonefragmentationwithminimalcomplications, itmaybesuccessfullyusedforthemanagementofureteral calculiinpatientswithasolitarykidney. wereportourexperiencewithurgenturslandwithssbuurslasafirstlinetreatmentinconditionofacuteanuria causedbyobstructivecalculi.theprimaryendpointofthe studywastodeterminetheoutcomesoftreatmentforpatients withobstructiveanuria. material and methods patients and study design thisretrospectivechartanalysiswasconductedatthedepartmentofurology,dr.d.mišovićhospital,belgrade,serbia.fromamongnearly1234patientswhohadundergone urslinourclinic,betweenjanuary1998andjanuary2013, 61 patients presented clinically as acute calculus anuria and treatedurgentlywithurslorssbu.atotalof3surgeons performedtheseprocedures. thecauseofanuriawasbilateralobstructionbythecalculiin 29cases,andunilateralobstructionwith/absent/nephrectomizedcontralateralkidneyin32cases.inunilateralcasesnephrectomyhadbeenalreadydoneduetotumorin8patients, calculosisin19patientsandnon-functioningdiseasedkidney in5patients. retrospectively,thepatientsaregroupedonthebasisofthe durationofanuria.groupaincludedpatientswithanuria lastingupto48hoursandgroupbincludedpatientswith anuriaofover48hoursinduration.thesetwogroupsare compared with regard to post-operative recovery of renal function,atthe7thpost-operativeday.wedefinedrecovery ofrenalfunctiononthebasisofamountofpost-obstructive diuresisandlevelsofserumcreatinine.thus,wecompare therelationbetweenthedurationofanuriaandearlypostoperativerecoveryofrenalfunctionaftersuccessfulreliefof obstructionviaemergencyurslusingfisher’sexacttest. generallypatientswereselectedforssbubasedonsurgeon judgmentthateachsidecouldbetreatedsafelyandeffectively.urslwasinitiallystartedonthesideinwhichstonesize wassmallerandlowerlocalizationthantheother. clinical procedure allinterventionswerecarriedoutunderregionalorgeneral anesthesia, with a semi-rigid single channel olympus 9.8 management of calculus anuria using tul | savic et al 1394 | channel(ch)ureteroscope.anekl(electrokinetic)andelectrohydraulic(ehl)generator,lithotronwalzel-27compact(walz,germany)wasused. patientswereadmittedonanemergencybasis.onadmission,detailedhistoryofpain,urinaryoutput,fever,hematuria anduremicsymptomswithdurationswererecorded.urine outputbetween0-100ml/24hourswasregardedasanuria. generalphysicalexaminationandsystemicexaminationwith especialreferencetothegenitourinarytractwasperformed andpositivefindingswererecorded.investigationsincluded completehematologicexamination,bloodurea,serumcreatinine,serumelectrolytesincludingplasmapotassiumlevel. ultrasonography(us)andplainfilmoftheabdomenwere performedinallcasestoevaluatethesize,siteandnumber ofstones,degreeofhydronephrosis(uhn),echogenicity,renalcorticalthickness,andpresenceofeitherkidneysorsolitarykidney.beforesurgery(45min),thepatientsreceived asingledoseofantibioticsintravenously(cephalosporinor fluoroquinolone),whichwasthencontinuedduringthehospitalization. ursaccesswassuccessfullyachievedinallcaseswithout theneedforureteralorificedilatation.endoscopicinspection wasdoneattheendoftheproceduretoruleoutanyresidual calculi>2mmorureterallesion.operationtimewascalculatedfromthetimetheureteroscopewasintroducedintothe urethratothetimeoffinalremovaloftheendoscope.proximalanddistalureteralstonesweredefinedasthoseabove andbelowthepelvicbrim,respectively,assuggestedbyhollenbackandcolleagues.(8)pigtailureteral6frpolyurethane stentorureteralprobe6chweroutinelyplacedinallpatients.ureteralprobeshavebeenremovedatpostoperative days1-4(mean2.5). thedecisionondisplacementoftheureteralstentwasbased onclinicalandintraoperativecharacteristicsincludingdurationofanuria,thesizeandnumberofcalculi,thedegreeof calculusimpactionandmucosaledema,stonefreestatuson thefirstpost-operativedays,thevolumeofurineoutput,laboratoryanalysis.doublej(dj)ureteralstentswereremoved after2-4weeksunderlocalanesthesia.post-operatively,all patientswereevaluatedbymonitoringurineoutput,serum creatininebloodureaandplasmapotassiumdaily,untilnormaloracceptablelevelswereobtained.weused≥33%decreaseinserumcreatinineafterinterventionasconfirmation ofakri.(9)plainfilmoftheabdomenandultrasonography wereperformedatthefirstdaypost-operatively(toassess theinitialstone-freerateandtoconfirmthecorrectstentposition)andduringthefollow-upvisits(after2weeksand4 weeks).closecollaborationbetweenurological,nephrologicalandradiologicalserviceswasbeenrequired,andcarewas takentoavoidhypovolemiathatcouldpotentiallycausefurther injury. follow-up procedure forthesuccesscriteria(intraoperativesuccesswasdefined endoscopically),wedeterminedstonediameters≤2mmas stone-freerate(sfr).fragmentslessthan2mmwereleft, sincetheycanpass,butlargerfragmentswereextractedby endourology and stone disease table 1. clinical and stone characteristics of study population. variables anuria < 100 ml/24-hour, no. (%) duration, no. (%) 9 (14.8) 48-hour 38 (62.3) 72-hour 14 (23) hydronephrosis, no. (%) grade 1 23 (25.6) grade 2 48 (53.3) grade 3 19 (21.1) level of serum creatinine (µmol/l) 492 (range, 200-800) level of blood urea (mmol/l) 27 (range,11-39) plasma potassium level (mmol/l) 6 (range 5.76.9) stone size (mm) overall 9 (5-16) < 10 mm 56 (62.2%) >10 mm 34 (37.8%) stone number, no. (%) solitary 84 (93) multiple 6 (7) stone opacity (%) radiopaque 82 radiolucent 18 localization, no. (%) proximal ureter 27 (30) distal ureter 63 (70) time to operation (hour) 6-12 mean operative time (min) 34 (range, 19-65) mean hospitalization stay (day) 5.4 (2-12) basket / grasper / forceps use (per ureteral unit) 59 (65.5%) 1395vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l management of calculus anuria using tul | savic et al table 2. stone-free rates as function of stone location. stone free rate ureteral units stone localization stone size --------proximal n = 27 distal n = 63 < 10 mm n = 56 > 10 mm n = 34 postoperative 56 (62) 9 (33) 46 (73) 39 (70) 16 (47) overall, 30 days after operation 73 (81) 15 (56) 59 (94) 52 (93) 21 (62) *are presented as number (%). dormiasoundorstonegrasper. postoperativesuccess(overallstone-freestatus)wasdeterminedasnosignificantstonefragmentsgreaterthan2mmin diameteroninitialfollow-upradiographyandplainabdominalx-rayperformedatleast1monthaftersurgery,duetothe limited availability of non-contrast abdomino-pelvic computedtomography(ct)scanasgoldstandardinourcountry. intraoperative and postoperative complications associated with procedure were recorded and reported according to the clavien-dindoclassificationofsurgicalcomplications.(10) thisstudyprotocolwasapprovedbytheethicalcommittee ofthehospitaldragišamišovićandtheresearchwascarried outincompliancewiththehelsinkideclaration.allpatients gavewritteninformedconsentbeforeparticipationandthen underwent ureteroscopy. results inthe27(44%)menand34(56%)womenwithameanage of52yearsold(range34to81)atotalof88urgentursl weredone.percutaneousnephrostomywasperformedin2 (3.3%)patients,2(2.2%)ureteralunits(uu)withbilateral calculus,withseverely impactedharddistalstones.these patientswerecandidatesforopensurgery,ureterolithotomy, 6to8weeksaftertheprimaryintervention(ursl+pcn). thedurationofanuriavariedbetween1to3days.wedid notobserveanycasesofpyuriaduringtheprocedure.stone burdenwasdeterminedbymeasuringthemaximumstonedimension.incasesofmultiplestones,thesedimensionswere addedtogether.theclinicalandstonecharacteristicofour studypopulationareshownintable1.stone-freeratesare stratifiedbystonelocationintable2. stonemigrationtothekidney(push-back)occurredin12uu (12patients),in7uu(7patients)withunilateral,andin5uu (5patients)withbilateralobstructionduringupperureteric stonemanipulation,anddjstentswereleftintheseureters. migratedstonesweresubjectedtoextracorporealshockwave lithotripsy(swl)5-11daysafterursl,afternormalization ofserumcreatinine. attheendoftheprocedureureteralstentwasplacedbilaterallyin44uu(22patients)andunilaterallyin32uu(25 patientswithsolitarykidneyandin7patientswithbuo, ureteralstentplacedunilaterally).ninepatients,returnedto theemergencyroombecauseofpain24hoursafterremoving the ureteral stent. ultrasound showed uhn, and a dj stent wasplacedinordertosecureurinarydrainage.sixofthese patientshadasolitarykidney,andwerecomplementedby medicalexpulsivetherapy(met)treatmentwhileinthree patient, three ureteral units, the planned secondary procedure wasswl. post-operativemonitoringofpatientsisshownintable3. post-operative monitoring of urine volume revealed postobstructivediuresisorpolyuriainrecoveryphase,inallpatients, but the urine output gradually decreased to reach normallevelwithinthe1stweekpostoperatively.also,serum creatinine,bloodureaandplasmapotassiumlevelsreturned tonormaloracceptablelevelswithin7-10days. intable4,thepatientsaregroupedaccordingtotheduration ofanuria(upto48-hourandover48-hour).recoveryofrenal functionasindicatedbypost-obstructivediuresisandserum creatinineiscomparedinthesetwogroupsofpatientsusing fisher’sexacttest.itisseenthattherecoveryofrenalfunctionwaspoorerinthepatientswithlongerdurationofanuria. recoveryofrenalfunctionatdischargewasconfirmedin51 (83.6%)patients. in44(72%)patientsurslisasuccessfultherapeuticapproach for relief of obstruction and removal of calculus. 1396 | endourology and stone disease treatmentmodalitiesinrelationtouuareshownintable 5.asecondaryprocedurewasrequiredin17(18.9%)uu.a classification(modifiedclaviensystem)hasbeenproposed togradeperioperativecomplications(table6).majorcomplications(suchassepsis,perforation,andavulsion)werenot observedduringtheprocedure. urslprovokedsignificantmucosal lacerationwithguide wireatthesiteofimpactedureteralstonein5(8.2%)patients. totreatthiscomplicationureteralstentplacementwassufficient.stoneorfragmentmigrationwasseenat12(19.7%) patients, all in the upper stone localization, and that was the majorcauseoffailureoftheprocedure. mild macroscopic hematuria was observed in the first 24 hourswhichdidnotrequiretreatment.therewaspostoperativehighgradefeverin8(13.1%)patients.thebodytemperature returned to normal within 4 days after receiving maximum dose and intravenously injected 3rd generation cephalosporinantibiotic(urinefromureteralstentforurine culture-withpositiveurinecultureresults,escherichiacoli). postoperative “pain” (renal colic), was the most frequent complication, mandating a readmission in two patients (3.3%)withsolitarykidney,emergencydepartmentvisitin9 (14.8%)patients(ofwhom4patientshadbilateralstent),or re-instrumentationsecondurslin1(1.6%)patienttreated forlargebilateralcalculi>15mminonesession. minorcomplicationssuchaslowerurinarytractsymptoms (luts), mild hematuria, flank and pelvic pain improved withinoneweekafterstentremoval. discussion thestandardfirst-lineapproachinthemanagementofsymptomaticureteralstoneisreliefofobstructionbyinsertionofa nephrostomytubeoradjureteralstentandfragmentationof thestonesubsequently.insertionofanephrostomytubeunder localanesthesiaisrelativelylessinvasiveandisconsideredto bebetterifthereisevidenceofsepsisatthetimeofpresentation.nevertheless,itspotentialdisadvantagesareleakage, dislodgementofthetubeandtheneedtomanagethestoma.(11) ureteroscopy is a relatively complication-free procedure. however,ifcomplicationsdooccur,theymayberelatedto theprocedureitself.themainadvantagesofurslareimmediatereliefofsymptomsandstonefragmentation.quick ureteral stone removal may be important in patients with calculusanuria.ureteroscopyhasvariablecomplications(920%)includingbleeding,ureteralperforation,falsepassage, urinomaformation,stricturesand, inafewcases,ureteral avulsion.(12)leeandbaglyreportedthatureteroscopyshould besafewithregardtorenalfunction,thereisnopuncture, asinpercutaneousnephrolithotomy(pcnl),andnoshockwavesdirectedtorenalparenchyma,asinswl.however, table 3. postoperative monitoring of study population. monitoring pod 1 pod 3 pod 7 pod 10 ultrasonography + + distal n = 63 < 10 mm n = 56 plain abdominal film + 46 (73) 39 (70) postobstructive diuresis + ----59 (94) 52 (93) range, 2400-8300 ml/24-hour laboratory analysis mean complete blood count + + + ----serum creatinine + + + + blood urea + ----+ + plasma potassium + + + urine from ureteral stent for uc + --------keys: pod, postoperative day; uc, urine culture. * optional. 1397vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l management of calculus anuria using tul | savic et al otherpotentialmechanismsofinjuryduringurslsuchas excessiveirrigationmaygeneratesufficientpressureinthe kidneytocausepyelovenousbackflowanddamagetherenalparenchyma.thermalinjurymayalsooccurduetothe energyof the laser.however, this isunlikely,as frequent irrigation should dissipate the heat energy, so ureteroscopic laserlithotripsyhasnoharmfulimpactonrenalfunctionin patientswithmildtomoderaterenalinsufficiency.(13) someauthorsstatedthatincomparisonwithunilateralureteroscopy,nodifferencewasfoundwithbilateralsamesession ureteroscopywithregardtocomplicationrate(6.7%)orstonefreerate(80%)andconcludedthatbilateralsame-sessionureteroscopyisasafeandeffectiveprocedureinthemanagement ofbilateralureteralstones.bilateralsame-sessionureteroscopycanpreventfrequentsurgeriesandanesthesiaandreduce hospitalstay.properpatientselection,ampleexperienceofthe surgeon,andappropriateinstruments,allreducecomplications andincreasetreatmentsuccess.(14)initialoppositiontossbu arosefromconcernsthateachrenalunitcouldbecompromisedsimultaneously.whileitisrare,anuricrenalfailureafter atraumaticssbuhasbeenreported.(15) inthepresentstudy,90ureteralunitswithobstructiveureteral stones were evaluated. the intervention, ursl was implemented among patients without changes on 12-lead electrocardiography.(16)aftersingleendoscopicprocedure,a stone-freeratewasachievedin53(62%)ureteralunits.approximately70%ofthestoneswerelocatedinthedistalureter.theprocedurewassuccessfulfordistaluretericstonesin 73%.forpatientswithcalculilessthan10mmandgreater than10mm,theinitialstone-freerateafterureteroscopywas 70%and47%,respectively.aswasshownbytheresultsof ourstudy,thebestcandidatesforurgentandbilateralsamesession ureteroscopy are patients with distal ureteral stone. thirtydaysaftertheinitialprocedure,inureteralunitswith ureteralstonesupto10mmandlocalizedinthedistalureteralstones, thesfrwas93%.theamericanurological association(aua)ureteralstonesclinicalguidelinespanel andeuropeanassociationofurology(eau)guidelineson urolithiasishavereportedthaturslstone-freerates(97%) werebetterthanswlstone-freerates(86%)fordistalureteralstones<10mm.(17)ureteralstentingofpatientswith multipleunilateral (in twodistinct locations)andbilateral calculiappearstolessentheriskofapostoperativecomplication.protectingtheurinarytreeafterabilateralproceduredj ureteralstentplacementseemedimportanttous;andadded littleoperativetimetotheprocedure,althoughtherewasa slightincreaseinpostoperativediscomfortandhematuria.an importantcounterpointisprovidedbythefindingsofhollenbeckandcolleagues,whonotedthatpatientswere70%more likelytohavepostoperativecomplicationswhenaureteral stentwasnotplacedaftertreatmentforbilateralormultiple unilateral calculi.(18)auaandeauguidelinesonurolithiasis reportedthatstentingafteruncomplicatedurslisoptional, butsolitarykidneyisoneoftheindicationsforstentingafter ursl.(17)thus,whilestent-freeureteroscopyhasprovento besafeafteruncomplicatedunilateralprocedures,itsrolein ssbuislessdefined.(19) thetechniqueofureteroscopybasedonstonefragmentation table 4. indicators of recovery of renal function on the 7th post-operative day in relation to duration of anuria prior to admission.* variables group a group b p diuresis < 2500 ml/24-hour 40 5 .0007 ≥ 2500 ml/24-hour 7 9 serum creatinine (μmol/l) 50-110 44 6 .0001 ≥110 3 8 * group a, 47 (77%) patients with anuria time of < 48-hour; group b, 14 (23%) patients with anuria time of > 48-hour. 1398 | endourology and stone disease withtheelectropneumaticgenerator,lithotronwalzel-27 compactproduceslargerfragments(3-4mm)thatmaypotentiallycauseproblemsin termsofspontaneouspassage. someauthorsrecommendusingforcepstoreducere-treatmentrate.(20)similarly,inthisstudy,stoneforcepswereused toremovestonefragments≥2mmin59(65.5%)ofuuto reducetheriskofasecondorauxiliaryprocedure. ourattitudetoroutinelyplacementofureteralstent,primarilyfordrainageofurinemaybecorrectedinthefutureinthe sensethatthesurgeonisprovidedwithachoice,tostentor nottostentafterssbu.theselectiveuseofstentsaccordingtosurgeonpreferencemadeitchallengingtodetermine theirroleinssbu.however,thedecisiontostentplacement waslefttotheattendingurologist’sdiscretion.theperceived complexityofthecasewasundoubtedlyrelatedtothedecision to stent. opensurgerywasrequiredfortwoofourpatients(3.3%) with large,hardstones.pcnwasperformedasanurgent treatment.ureterolithotomywasdone(intwopatients,i.e. two units of bilateral ureteral calculi) 6 to 8 weeks after the primary intervention (ursl+pcn). sharma and colleagues(21)reportedthatopenmini-accessureterolithotomy isasafeandreliableminimally-invasiveprocedure;itsrole ismainlyconfinedtosalvageforfailedfirst-linestonetreatments.inselectedcases,however,whereapooroutcomecan bepredictedfromothermethods,itisanexcellentfirst-line treatment. calculusanuriaisaurologicalemergency.managementin formofurinarydiversionanddefinitesurgicaltreatmentcan savethepatientfromdevelopingchronicrenalfailure.(22) althoughtheneedforrapidmanagementofureteralstoneshas beenaccepted,thebestmodalityoftreatmentisstillamatter ofdebate.thebestproceduretochooseisdependentonseveralfactors,besidesstonesizeandlocation,includingtheoperator’sexperience,patientpreference,availableequipment and related costs.(23)finally,thereisstillnoconsensuson single-sessionurslforthemanagementofbilateralureteric stonesandtheuseofpostoperativestentsisstillcontroversial. limitationsofourstudyarethatitisretrospective,non-randomizedandthatnocomparisonwithacontrolgroupwas done.patientspresenting in thesamemanner (anuriadue toureteralstone)whowereinitiallymanagedwithpcnor stentsarenotagoodcomparisongroup,becausetheonlyaddressed anuria, not calculosis. conclusion thepresentedresultssuggestthaturgentureteroscopiclithotripsy,ursl,isthemethodofchoiceforpatientswithrenalcalculiandanuria.thereasonsforthisconclusionare, themethodpreservesrenalfunction,whichisachievedvia controlledreliefofobstructionwithestablishmentofprompt diuresis,itprovidesahighstone-freerateforpatientswith distalcalculuslocation,andthereissmallnumberofrelatively mild post-operative complications. the question is raisedastowhetherroutinestentplacementisindicatedpostprocedurally. table 5. treatment modalities in relation to ureteral units. type of treatment ureteral units, no. (%) ursl + ureteral stent 73 (81.1) ursl + dj stent + swl 15 (24.6) ursl + pcn + op 2 (2.2) keys: ursl, ureteroscopic lithotripsy; dj, double j; swl, extracorporeal shockwave lithotripsy; pcn, percutaneous nephrostomy; op, open surgery. table 6. complications classified according to the modified clavien system. ccs grade patients-ureteral units no. (%) grade 1 mucosal laceration 5 (8.2)-5 (5.6) stone/fragment migration 12 (19.7)-12 (13.3) fever 8 (13.1) hematuria 3 (4.9) renal colic 9 (14.8) grade 2 urinary tract infection 5 (8.2) pyelonephritis 2 (3.3) grade 3 stent migration 1 (1.6) key: ccs, clavien-dindo classification system. 1399vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l management of calculus anuria using tul | savic et al references 1. james m, pannu n. methodological considerations for observational studies of acute kidney injury using existing data sources. j nephrol. 2009;22:295-305. 2. allen dj, longhorn se, philp t, smith rd, choong s. percutaneous urinary drainage and ureteric stenting in malignant disease. clin oncol (r coll radiol). 2010;22:733-9. 3. praught ml, shlipak mg. are small changes in serum creatinine an important risk factor? curr opin nephrol hypertens. 2005;14:26570. 4. sood g, sood a, jindal a, verma dk, dhiman ds. ultrasound guided percutaneous nephrostomy for obstructive uropathy in benign and malignant diseases. int braz j urol. 2006;32:281-6. 5. scarpa rm, de lisa a, porru d, usai e. holmium: yag laser ureterolithotripsy. eur urol. 1999;35:233-8. 6. moe ow. kidney stones. pathophysiology and medical management. lancet. 2006;367:333-44. 7. gunlusoy b, degirmenci t, arslan m, et al. bilateral single-session ureteroscopy with pneumatic lithotripsy for bilateral ureter stones: feasible and safe. urol int. 2008;81:202-5. 8. hollenbeck bk, schuster tg, faerber gj, wolf js jr. comparison of outcomes of ureteroscopy for ureteral calculi located above and below the pelvic brim. urology. 2001;58:351-356. 9. macedo e, bouchard j, mehta rl. renal recovery following acute kidney injury. curr opin crit care. 2008;14:660-5. 10. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five year experience. ann surg. 2009;250:187-96. 11. joshi hb, obadeyi oo, rao pn. a comparative analysis of nephrostomy, jj stent and urgent in situ extracorporeal shock wave lithotripsy for obstructing ureteric stones. bju int. 1999;84:264-9. 12. alapont jm, broseta e, oliver f, pontones jl, boronat f, jiménezcruz jf. ureteral avulsion as a complication of ureteroscopy. int braz j urol. 2003;29:182-3. 13. lee di, bagley dh. long term effects of ureteroscopic laser lithotripsy on glomerular filtration rate in the face of mild to moderate renal insufficiency. j endourol. 2001;15:715-7. 14. el-hefnawy as, el-nahas ar, el-tabey na, et al. bilateral same-session ureteroscopy for treatment of ureteral calculi: critical analysis of risk factors. scand j nephrol urol. 2011;45:97-101. 15. bandi g, vicentini fc, triest ja. anuric renal failure after samesession bilateral atraumatic flexible ureteroscopy. int braz j urol. 2007;33:193-4. 16. clinical practice guidelines treatment of acute hyperkalemia in adults, uk renal association (2005 and 2007). accessed in: http:// www.renal.org/libraries/guidelines/treatment_of_acute_hyperkalaemia_in_adults_-_final_version_july_2012.sflb.ashx 17. preminger gm, tiselius hg, assimos dg, et al. 2007 guideline for the management of ureteral calculi. j urol. 2007;178:2418-34. 18. hollenbeck bk, schuster tg, faerber gj, wolf js jr. safety and efficacy of same-session bilateral ureteroscopy. j endourol. 2003;17:881. 19. haleblian g, kijvikai k, de la rosette j, preminger g. ureteral stenting and urinary stone management: a systematic review. j urol. 2008;179:424. 20. gonen m, cenker a, istanbulluoglu o, ozkardes h. efficacy of dretler stone cone in the treatment of ureteral stones with pneumatic lithotripsy. urol int. 2006;76:159-62. 21. sharma dm, maharaj d, naraynsingh v. open mini-access ureterolithotomy: the treatment of choice for the refractory ureteric stone? bju int. 2003;92:614-6. 22. westenberg a, harper m, zafirakis h, shah pj. bladder and renal stones: management and treatment. hosp med. 2002;63:34-41. 23. autorino r, osorio l, lima ea. rapid extracorporeal shock wave lithotripsy for proximal ureteral calculi in colic versus noncolic patients. eur urol. 2007;52:1264-5. acknowledgment theauthorswishtothankdrkarenbelkicforhercareful readingofthemanuscript. conflict of interest none declared. u j all final for web.pdf 774 | urological oncology department of urology, school of medicine, university of ankara, ankara, turkey evren süer, sümer baltaci, berk burgu, özgü aydoğdu, çağatay göğüş significance of tumor size in renal cell cancer with perinephric fat infiltration is tnm staging system adequate for predicting prognosis? corresponding author: evren süer, md department of urology, school of medicine, ankara university 06700, i̇bni sina hospital, samanpazarı, ankara, turkey tel: +90 312 508 22 58 fax: +90 312 311 21 67 e-mail: drevrensuer@ gmail.com received november 2011 accepted april 2012 purpose: materials and methods: performed in order to evaluate the prognostic factors. results: conclusion: into consideration for better prognostic analysis. keywords: renal cell carcinoma, prognosis, fatal outcome, humans urological oncology 775vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l predicting prognosis of rcc | süer et al introduction pathologic staging according to tnm staging system has been accepted as the most important prognos(rcc). (3) tions have been generated to increase the prognostic accuracy of this staging system. this tumor size system. value.(6) distinctly, these revisions did not include pt3a tunostic factor is still unclear.(7) recent studies demonstrated different results and achieved contrary conclusions. materials and methods nal computed tomography, abdominal ultrasonography, and ined for tumor size, fuhrman grade, and histological cell substaging. fuhrman grading system and heidelberg histologic st nd year, and annually thereafter. t compare the means of continuous and categorical variables, mortality due to rcc progression and estimated using the kaplan meier method. a receiver operating characteristic p results p patients (p analysis determined the optimal tumor size cutoff value as 7 table 1. multivariate analysis for disease-specific survival in patients with pt1-3an0m0 renal cell carcinoma. variable hazard ratio 95% confidence interval p age 1.578 0.776 to 3.208 .208 perinephric fat invasion 3.521 1.700 to 7.294 .001 grade (grades 1 to 2 vs grades 3 to 4) 5.239 2.418 to 11.353 < .001 tumor size (≤7 cm vs >7 cm) 1.624 0.806 to 3.272 .175 776 | (p p invasion (p only tumor grade and perinephric fat invasion as prognostic as an independent prognostic factor in multivariate analysis perinephric fat invasion using the 7 cm cutoff value (table p p to evaluate the prognostic effects of perinephric fat invasion tect perinephric fat invasion as a prognostic factor. unlikely, and multivariate analyses demonstrated perinephric fat invatable 2. clinicopathological parameters compared according to the 7 cm cutoff value, which was defined by the roc curve analysis.* tumor size >7 cmtumor size ≤7 cm ppfi (+)pfi (-)ppfi (+)pfi (-) 693220631no .18 40 (58%) 29 (42%) 23 (71.9%) 9 (28.1%) .062 131 (63.6%) 75 (36.4%) 25 (80.6%) 6 (19.4%) gender male female .30256.7 (± 10.11)59 (± 10.9).03155.6 (± 11.7)60.5 (± 10.5)mean age (± sd) .121 50 (73.5%) 13 (19.1%) 5 (7.4%) 30 (93.7%) 2 (6.3%) 0 (0%) .346154 (77.7%) 31 (15.6%) 13 (7.4%) 22 (75.8%) 6 (20%) 1 (4.2%) no cell type (%)£ clear cell papillary chromophobe .001 48 (69.6%) 21 (30.4%) 9 (28.1%) 23 (71.9%).126 159 (77.2%) 47 (22.8%) 20 (64.5%) 11 (35.5%) no grade (%) 1 to 2 3 to 4 .4710.71(± 2.86)10.01(± 1.79).5434.34 (± 1.49)4.48 (± 1.42)mean tumor size (± sd), cm .0017 (10.1%)12 (37.5%).04311 (5.4%)5 (16.1%)death by rcc *roc indicates receiver operating characteristic; pfi, perinephric fat invasion; sd, standard deviation; and rcc, renal cell carcinoma. £histologic subtypes besides clear cell. papillary and chromophobe subtypes were omitted for statistical accuracy and 327 patients were included for the analysis. urological oncology 777vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l discussion and involvement of the adjacent tissues. tumor size and perinephric fat invasion are basic features to classify the rcc according to the tnm staging system. although evolution included many variables in the tnm staging system of rcc, tients. unlike tumor size, perinephric fat invasion remained as a stable staging parameter regardless of tumor size. perinephric as pt3a tumor regardless of tumor size in all recent tnm invasion compared to tumor size is unclear. pt3a according to their clinicopathological features. the than perinephric fat invasion. siemer and associates, simithe cutoff value for tumor size, according to the dss. they have assigned 7 cm as a cutoff value. they have compared the staging of patients by merging all patients according to 7 a prognostic predictor, and proposed not to use perinephric fat invasion to assign t category.(7) predicting prognosis of rcc | süer et al table 3. significance of perinephric fat invasion at multivariate analysis. risk ratio (95% confidence interval) p tumors ≤4 cm no perinephric fat invasion perinephric fat invasion 1.0 1.65 (0.22 to 12.04) .618 tumors 4 to 7 cm no perinephric fat invasion perinephric fat invasion 1.0 8.3 (1.49 to 19.09) .016 tumors >7 cm no perinephric fat invasion perinephric fat invasion 1.0 5.01 (1.85 to 13.52) .001 disease-specific survival for renal cell carcinoma >7 cm and ≤7 cm. 778 | value of perinephric fat invasion. the univariate and multifavorable prognostic factor in all of the tumor size groups. they have concluded that utilizing tumor size for grouping pt3a is unnecessary. and pt3a patients in their recent study. they found out that large tumor burden. their suggestion is to include tumor size aforementioned studies revealed that utilization of perinephric fat invasion in tnm staging system and classifying are unclear. to evaluate the prognostic role of perinephric the 7 outcomes of siemer,(7) yoo, and murphy studies. gofrit and associates emphasized the heterogeneity of pt3a tumors and represented perinephric fat invasion as an insigapplies only tumor size and venous involvement. this inference is contrary to our results since perinephric fat invashared opinion of these authors is the prominent role of the tumor size on prognosis. in our study, the 7 cm cutoff value provided prognostic they suggested the consideration these groups. the univariate and multivariate analyses did not demonstrate any negative impact of perinephric fat invasion on dss in tive feature of this study and the relatively small number of conclusion although perinephric fat invasion is an accepted prognostic cacy in tnm staging system and help to differentiate patient studies are needed for higher level of evidence. conflict of interest none declared. references 1. belldegrun a, tsui kh, dekernion jb, smith rb. efficacy of nephron-sparing surgery for renal cell carcinoma: analysis based on the new 1997 tumor-node-metastasis staging system. j clin oncol. 1999;17:2868-75. 2. gettman mt, blute ml. update on pathologic staging of renal cell carcinoma. urology. 2002;60:209-17. urological oncology 779vol. 10 | no. 1 | winter 2013 |u r o lo g y j o u r n a l 3. international union against cancer (uicc): tnm classification of malignant tumours. 3 ed. geneva; 1978. 4. hermanek p, sobin lh. tnm classification of malignant tumours. berlin: springer-verlag; 1987. 5. sobin lh, fleming id. tnm classification of malignant tumors, fifth edition (1997). union internationale contre le cancer and the american joint committee on cancer. cancer. 1997;80:1803-4. 6. greene fl, page dl, fleming id, et al. ajcc cancer staging manual. vol 6: springer new york; 2002. 7. siemer s, lehmann j, loch a, et al. current tnm classification of renal cell carcinoma evaluated: revising stage t3a. j urol. 2005;173:33-7. 8. siddiqui sa, frank i, leibovich bc, et al. impact of tumor size on the predictive ability of the pt3a primary tumor classification for renal cell carcinoma. j urol. 2007;177:5962. 9. yoo c, song c, hong jh, kim cs, ahn h. prognostic significance of perinephric fat infiltration and tumor size in renal cell carcinoma. j urol. 2008;180:486-91; discussion 91. 10. steiner t, knels r, schubert j. prognostic significance of tumour size in patients after tumour nephrectomy for localised renal cell carcinoma. eur urol. 2004;46:327-30. 11. ficarra v, guille f, schips l, et al. proposal for revision of the tnm classification system for renal cell carcinoma. cancer. 2005;104:2116-23. 12. murphy am, gilbert sm, katz ae, et al. re-evaluation of the tumour-node-metastasis staging of locally advanced renal cortical tumours: absolute size (t2) is more significant than renal capsular invasion (t3a). bju int. 2005;95:27-30. 13. gofrit on, shapiro a, pizov g, et al. does stage t3a renal cell carcinoma embrace a homogeneous group of patients? j urol. 2007;177:1682-6. 14. lam js, klatte t, patard jj, et al. prognostic relevance of tumour size in t3a renal cell carcinoma: a multicentre experience. eur urol. 2007;52:155-62. 15. roberts ww, bhayani sb, allaf me, chan ty, kavoussi lr, jarrett tw. pathological stage does not alter the prognosis for renal lesions determined to be stage t1 by computerized tomography. j urol. 2005;173:713-5. predicting prognosis of rcc | süer et al endourology and stone disease the effect of stone localization on the success and complication rates of percutaneous nephrolithotomy goksel bayar,1 mustafa kadihasanoglu,2* mustafa aydin,3 umut sariogullari,1 orhan tanriverdi,4 muammer kendirci4 purpose: to evaluate the effect of stone localization on the success and complication rates of the percutaneous nephrolithotomy (pnl) procedure. materials and methods: five hundred seventy-eight pnl procedures that were performed in our clinic were retrospectively evaluated. the patients were divided into seven groups according to the localization of the renal stones as: group 1, patients having stones only in the upper calyx; group 2, patients having stones only in the pelvis; group 3, patients having stones only in the lower calyx; group 4, patients having partial staghorn stones; group 5, patients having multiple calyx stones; group 6, patients having stones in both the pelvis and lower calyx and group 7, patients having complete staghorn stones. the first three groups were defined as simple stones, and the other four groups were defined as complex stones. results: the mean stone clearance rate was 77% in simple stones and 53% in complex stones (p = .005). the complication rate was significantly higher only in the group with complex staghorn stones at a rate of 19.5% (p = .006). the difference between preoperative and postoperative hematocrit concentrations was the least in the group that had stones in the pelvis and this value was statistically significantly lower than the patients with complex staghorn stones (p = .027). the mean duration of the operation and the number of ports was higher in patients with complex stones. conclusion: the localization of stone affects the success and complication rates of the operation. keywords: kidney calculi; surgery; nephrostomy; percutaneous; treatment outcome; adverse effects. introduction the introduction of percutaneous nephrolithotomy (pnl) to the practice of urology and its becoming the gold standard in the treatment of large kidney stones occurred in a very short time period. in fact, with the use of this treatment, which first began to be interpreted as experimental in 1970s, the rate of open surgical procedures for renal stones decreased below 1% by 2002. (1,2) by means of the learning curve duration of 60 cases that could be assumed to be a short period, the interest of all urologists in this operation has increased and caused it to be a widely-used procedure.(3) pnl can be used safely in children under 3 years by avoiding disastrous complications and morbidities in open surgical treatment of kidney stones.(4) besides, pnl can be applied in prone position as well as supine and flank suspended supine position easily.(5) although at first, it was a method that was mostly used in the treatment of small renal stones in single localizations, it was later successfully used in the treatment of larger complete staghorn stones.(6) when the simple stones and complex stones are compared, it is known that the success rate in simple stones is higher and more than one kidney access and prolonged surgical duration increases the complications and similarly the presence of multiple or staghorn stones increases the risk of bleeding.(7-9) mousavi-bahar and colleagues described a new technique for displacing the complex stones from an inaccessible calyx to an accessible calyx by the single pre-existing tract.(10) it is thought that the presence of stones in the pelvis and major calyx suggest higher success rates than the presence of stones in the minor calyx and this is the reason for the low success rates in staghorn stones.(11) however, pnl has now become the first choice in the treatment of renal stones larger than 2 cm.(12) the current study aimed to evaluate the effect of the localization of stones on the intraoperative and postoperative outcome of the pnl procedure in patients with renal stones. materials and methods five hundred seventy-eights pnl procedures were performed in our clinic between 2004 and 2013, and 548 1 department of urology, sisli hamidiye etfal training and research hospital, sisli, istanbul, turkey. 2 department of urology, istanbul training and research hospital, fatih, istanbul, turkey. 3 department of urology, samsun training and research hospital, ilkadim, samsun, turkey. 4 department of urology, bahcesehir university, faculty of medicine, liv hospital, besiktas, istanbul, turkey. *correspondence: istanbul training and research hospital, fatih, istanbul, turkey. tel: +90 212 459 6000. fax: + 90 212 632 0060. e-mail: kadihasanoglu@gmail.com. received march 2014 & accepted october 2014 endourology and stone disease 1938 patients for which the data could be reached were retrospectively investigated. pnl procedures were performed with indications appropriate with the current guidelines.(11) these indications were the presence of stones larger than 2 cm or the presence of stones that were unresponsive to shock wave lithotripsy (swl) treatment. a 22 french (f) (wolf®, richard wolf, gmbh, germany) nephroscope and a 24 f (storz®, karl storz endoskope, tuttlingen, germany) rigid nephroscope were used for operations. in some pediatric patients, a 17 f miniperc (storz®, karl storz endoskope, tuttlingen, germany) was used and in some patients, a 14 f flexible nephroscope (storz®, karl storz endoskope, tuttlingen, germany) was used. the lithotripsy procedure was executed by using ultrasonographic, pneumatic, or combined (ultrasonic and pneumatic) methods. the operations were performed by urologists who were experienced in pnl or senior assistants who had assisted a sufficient number of operations under the guidance of an urologist. the patients were divided into seven groups according to the position of the renal stone or stones according to the vertical axis as: group 1, patients having stones only in the upper calyx; group 2, patients having stones only in the pelvis; group 3, patients having stones only in the lower calyx; group 4, patients having partial staghorn stones group 5, patients having multiple calyx stones; group 6, patients having stones in both the pelvis and lower calyx and group 7, patients having complete staghorn stones. the first three groups were defined as simple stones and the other four groups were defined as complex stones. we have excluded the patients with just middle calyx stone, pelvis and middle or upper calyx stone; because patients’ number was so small. we have excluded second and third pnl procedures too. all of patients were operated firstly pnl. the duration of hospital stay was accepted as the duration of hospital stay after the day of the operation. the surface area of the stones were calculated with [(height × width × π) / 4] formula. the change in hematocrit (hct) was calculated by the difference between the preoperative and the postoperative 24th hour values. in patients who had transfusion of erythrocyte suspensions, hct value before transfusion was accepted as the postoperative hct value. in patients who had erythrocyte transfusion during the perioperative period, the value was calculated by subtracting three units from the postoperative hct value for every unit of erythrocyte suspension. the starting of the surgery was accepted as the first introduction of the chiba needle to the skin after insertion of the urethral catheter in the prone position. the time of end of the surgery was accepted as the time of the removal of the amplatz tube following the insertion of the nephrostomy tube through the amplatz tube. the time in between was accepted as the surgical duration. the duration of fluoroscopy was calculated as the total pedaling time of the fluoroscopy pedal during the operation. the clearance of the stone was accepted as the complete absence of the stone or the presence of a maximum of one stone in one calyx not causing infection, obstruction, or pain and additional treatment requirement with maximum 4 mm diameter. the complications were graded according to clavien classifications. grade 1 complications were not included in the evaluation. the number of kidney accesses was accepted as the number of nephrostomy tubes inserted to the kidney after the operation and more than 1 access (angular y access) from a single access was accepted as single port. the patients in both groups were compared in terms of age, body mass index (bmi), duration of hospital stay, surface area of the stone, preoperative and postoperative hct differences, amount of blood transfusions, duration of operation and fluoroscopy, complication rates and stone clearance rates. for statistical analysis, fisher’s exact test, pearson’s chi square, kruskal-wallis and one way anova tests were used. for post-hoc analysis lsd (least significant difference) test was used. a value of p < .05 was accepted as significantly difference. results when the total 548 were examined, the number of males variables values patients number 538 total kidney units 578 mean age (years) (range) 41.6 ± 15.4 (3.5-81) sex (male/female) 240/298 mean body mass index (kg/m²) (range) 26.4 ± 5.6 (14-60) stone side (right/left) 208/330 table 1. clinical and demographic characteristics of study subjects. variables patients no. stone surface duration of access no. complication stone-free (mm²) operation (min) (%) rate (%) rate (%) simple stones upper calyx 53 715 ± 772 70 ± 56 1.09 ± 0.35 9.4 79.2 pelvis 132 560 ± 394 74 ± 52 1.05 ± 0.28 4.5 75.7 lower calyx 180 632 ± 445 84 ± 52 1.08 ± 0.37 6.1 79.4 complex stones partial staghorn 88 1021 ± 827 85 ± 52 1.46 ± 0.6 5.7 70.4 multiple calyx 32 966 ± 526 105 ± 50 1.96 ± 0.64 9.3 56.2 pelvis and lower calyx 47 1029 ± 1050 102 ± 52 1.44 ± 0.54 10.6 46.8 complete staghorn 46 1436 ± 641 116 ± 52 2.08 ± 0.91 19.5 39.1 table 2. operative value by stone localizations. effects of stone localization on pnl resultsbayar et al vol 11. no 06 nov-dec 2014 1939 was 308 and the number of females was 240. bilateral pnl was performed in 30 patients. a total of 578 pnl procedures were performed; 248 on the right kidney and 330 on the left kidney. the mean age of the patients was 41.6 years (range, 3.5-81 years), and mean bmi was 26.4 kg/m2 (range, 14-60 kg/m²) (table 1). while the mean duration of hospital stay was 5.3 days, the shortest duration of hospital stay was 2 days and the longest duration of hospital stay was 34 days. there was no difference between groups in terms of duration of hospital stay (p = .924). the surface area of the stone that was obtained by using the two dimensional size of the stone was accepted as the size of the stone. there was no difference between the upper calyx (715 mm²), pelvis (560 mm²) and lower calyx (632 mm²) groups (p > .05). the size of the stones in patients having partial staghorn (1021 mm²), multiple calyx (966 mm²) and combined pelvis and lower calyx stones (1029 mm²) was significantly larger than the first three groups (p = .005); it was significantly lower than the group with complete staghorn (1436 mm²) stones (p = .005) (table 2). the mean duration of operation in all patients was 86 ± 54 min. there was no difference in terms of duration of operation in groups with upper calyx (70 ± 56 min), pelvis (74 ± 52 min) and lower calyx (84 ± 52 min) (p > .05). the mean duration of operation was significantly longer in patients with multiple calyx (105 ± 50 min), combined pelvis and lower calyx stones (102 ± 5 min) and complete staghorn (115 ± 52 min) stones when compared with the first three groups (p = .01) (table 2). the mean duration of fluoroscopy in all patients was 6 min (range, 0-46 min) and there was no significant difference between groups (p = .077). the mean number of kidney accesses in all patients was 1.3 ± 0.6. there was no difference between the patients with upper calyx (1.09 ± 0.35 min), pelvis (1.05 ± 0.28) and lower calyx (1.08 ± 0.38) stones in terms of the mean number of accesses. the number of accesses in patients with partial staghorn (1.46 ± 0.6) and combined pelvis and lower calyx (1.44 ± 0.54) stones was significantly higher than the first three groups (p = .001); it was significantly lower than the patients with multiple calyx (1.96 ± 0.64) and complete staghorn (2 ± 0.91) stones (p = .001) (table 2). the preoperative and postoperative mean hct difference was 6.1 ± 4.4% (0.1-28.5%). the mean number of erythrocyte suspension units that was transfused was 0.3 ± 0.7 (range, 0-6). in the comparison of the groups, the decrease in hct in the group with pelvic stones (5.3 ± 3.6%) was significantly lower than that of the group with combined pelvic and lower calyx stones (7.3 ± 5.8%) (p = .006), partial (6.6 ± 4.8%) (p = .027) and complete staghorn stones (7.3 ± 3.9%) (p = .007). the stone clearance rates in patients with upper calyx, pelvis and lower calyx stones was 79.2%, 75.7%, and 79.4%, respectively (p = .403). the success rate in simple stones was 77%. the stone clearance rate in patients with partial staghorn, multiple calyx, combined pelvis and lower calyx, and complete staghorn stones was 70.4%, 56.25%, 46.8% and 39.1%, respectively. the mean success rate in complex stones was 53% and it was significantly lower than for simple stones (p = .01) (table 3). when all patients were considered, the complication rate was 7.6%. the lowest complication rate was in the group with pelvic stones (4.5%) and the highest complication rate was in the group with complete staghorn stones (19.5%). the complication rate in upper calyx stones was 9.4% and it was found to be high when compared with the simple stones, although not statistically significant (p > .05). in the comparison of the groups, the complication rate was significantly high only in the group with complete staghorn stones (p = .006). additionally, the mean complication rate in complex stones was 10.1% and it was significantly higher than for simple stones (p = .006) (table 3). the most frequent complication that was seen in the current series was hemorrhage. out of 41 patients with hemorrhage, nephrectomy was conducted in only one patient due to unpreventable hemorrhage and selective arterial embolization under angiography was conducted on 4 patients; in other patients hemorrhage was controlled with blood transfusions. pneumonia in 2 patients and cellulitis in the area of operation in 1 patient was treated with antibiotic therapy. a double j ureteral stent was inserted into the urethra in 2 patients with pelvis perforation and in 3 patients with persistent (longer than 24 hours) urine leakage and was treated by keeping the stent in place for 4 weeks. the hemothorax in 2 patients, which developed due to the intercostal approach, was treated by the insertion of a chest tube. the small intestinal perforation that developed in 1 patient was recognized during the operation and treated with primary repair under open surgery. the urosepsis that developed in 4 patients after pnl was treated with intense antibiotic and fluid therapy (table 4). discussion by using a nomogram called “s.t.o.n.e. nephrolithometry”, okhunov and colleagues attempted to predict the postoperative success and complications with the preoperative data before the pnl procedure.(13) those in which 1-2 calyx were affected were scored with “1” point, those in which 3 calyx were affected were scored with “2” points, and those with staghorn stones were scored with “3” points. with the increase in the total score, the stone clearance rate decreased and the complication rate increased. again in the same study, it was found that while the mean number of calyx that were affected was 1.8 in variables simple stones (n = 365) complex stones (n = 213) p stone surface (mm2) 618 ± 537 1090 ± 774 .001 duration of operation (min) 75 ± 53 98 ± 51 .02 access number 1.07 ± 0.34 1.68 ± 0.65 .003 complication rate (%) 6.6 10.1 .006 stone-free rate (%) 77 53 .005 table 3. comparison of simple and complex stones operative databases. effects of stone localization on pnl resultsbayar et al endourology and stone disease 1940 patients who were cleared from the stones, it was 3.3 in patients with residual stones, and the difference was statistically significant.(13) it seems that the highest success rate in patients with stones in single calyx localization and the lowest success rate in complete staghorn stones the current study is parallel to the aforementioned study. muslumanoglu and colleagues demonstrated in their study that the success rate in simple stones was 85% and was 52% in complex stones (p < .01).(7) similarly in our series, it was demonstrated that in 75% of the patients with complex renal stones, there is a need for more than 1 port and the complication rate in these patients is higher. in a study that graded the complications that develop during pnl according to the clavien classification, the “guy’s stone score” scoring system was used in the prediction of complications.(9) according to this study, the success rate of the operation in patients with staghorn stones, abnormal renal anatomy, and spinal deformities decreased and the complication rate increased. similarly, in patients with upper calyx stones, the success rate was lower and the complication rate was higher when compared with the patients with lower calyx and pelvis stones. the higher complication rate in upper calyx stones than pelvis or lower calyx stones and similarly the higher complication rate in staghorn stones in the current series also support the aforementioned study. lee and colleagues reported the rate of major complications during pnl procedure as 6%.(14) however, in their study they did not accept hemorrhage as a major complication. on the other hand, when segura and colleagues included the hemorrhage within the major complications, they reported the rate of major complication as 6.2%, and 3% of this was reported to be hemorrhage.(15) however, the low complication rate in this study could be contributed to the fact that it was performed in 1985 and at that time, fewer aggressive pnl procedures were performed. in the current study, the total complication rate was 7.6%, which is parallel to the literature. the literature review revealed that the rate of hemorrhage requiring angioembolization was 0.8-1.4% and the need for nephrectomy was 0.1-0.3%.(16,17) in the current series, hemorrhage requiring angiographic embolization occurred in 4 patients (0.7%) and in 1 patient, nephrectomy was required due to unpreventable hemorrhage (0.17%). one study concluded that the factors increasing the hemorrhage during pnl are staghorn stones, high bmi, increased load of stones, prolonged surgical duration and the absence of hydronephrosis.(18) the current study revealed that the least hemorrhage was found in patients with stones that were localized in the pelvis and the reason for this was the low load of stones, low number of calyx, and short duration of surgery. in the literature, it was reported that the incidence of intestinal damage was 0.7%, the incidence of double j ureteral stent requirement due to urine leakage was 1.1%, and the incidence of collecting system perforation was 0.4%.(15) in the current series, intestinal perforation that developed in only 1 patient (0.17%) was recognized in the early period and repaired perioperatively, urine leakage requiring double j ureteral stent insertion developed in 3 (0.5%) patients, and collecting system perforation developed in 2 (0.34%) patients. upon evaluation of the duration of hospital stay after pnl, olbert and colleagues reported the mean duration of hospital stay as 7 (3-26) days.(19) although they have demonstrated that with the decrease in bmi and with the increase in size of the stone, the duration of hospital stay increased, the current series reported the mean duration of hospital stay as 5.3 days and no correlation was found with the localization of the stone. the longest duration of hospital stay in the current series was 34 days. at first this patient underwent bilateral open nephrolithotomy and bilateral pnl was performed in the same session. however, as bleeding occurred after bilateral pnl, an erythrocyte transfusion was given. furthermore, a blood transfusion reaction developed in the patient, followed by pleural effusion and pneumonia, and the duration of hospital stay was prolonged. predictive factor of residual stones after pnl are complete staghorn stones and the presence of additional calyceal stones. complications are high if pnl is not performed by an experienced endourologist or if preoperative urine culture is positive.(20) the decrease in the success rate in complex stones in the current series can be attributed to the increase in stone load together with the localization of the stone. in fact, this situation is an inevitable result of the increase in volumes of complex stones. conclusion it is possible to predict the success and complication rates grade type of complication patients number treatment grade 2 serious bleeding 36 blood transfusion pneumonia 2 antibiotics cellulite on lumbar region 1 antibiotics grade 3a pelvis perforation 2 double j ureteral stent insertion for 4 weeks persistent urine leakage 3 double j ureteral stent insertion for 4 weeks hemothorax 2 insertion chest tube grade 3b upj stenosis 1 pyeloplasty perirenal hematoma 4 selective angioembolization grade 4a retractable bleeding 1 nephrectomy bowel perforation 1 primary repairing grade 4b urosepsis 4 antibiotics table 4. complications according to clavien classification. effects of stone localization on pnl resultsbayar et al abbreviation: upj, ureteropelvic junction. vol 11. no 06 nov-dec 2014 1941 before the pnl procedure according to the localization of the stone in the kidney. with the increase in the number of calyx that are affected by the stone, the success rate decreases and complication rate increases. although the success rate in upper calyx stones is parallel to the other simple stones, the complication rate in some is higher. all of these factors should be considered and the possible risks and the patient should be informed of the possibility of the requirement of additional procedures prior to the operation. conflict of interest none declared. references 1. alken p, hutschenreiter g, günther r, mar berger m. percutaneous stone manipulation. j urol.1981;125:463-6. 2. matlaga br, assimos dg. changing indica tions of open surgery. urology. 2002;59:490 4. 3. tanriverdi o, boylu u, kendirci m, kadiha sanoglu m, horasanli k, miroglu c. the lea rning curve in the training of percutaneous nephrolithotomy. eur urol. 2007;52:206-11. 4. zeng g, zhao z, zhao z, yuan j, wu w, zhong w. percutaneous nephrolithotomy in infants: evaluation of a single-center experi ence. urology. 2012;80:408-11. 5. pan tj, li gc, ye zq, wen hd, shen gq, zhang jq. flank suspended supine position for percutaneous nephrolithotomy. urologia. 2012;79:58-61. 6. aron m, yadav r, goel r, et al. multi-tract percutaneous nephrolithotomy for large com plete staghorn calculi. urol int. 2005;75:327 32. 7. muslumanoglu ay, tefekli a, karadag ma, tok a, sari e, berberoglu y. impact of per cutaneous access point number and location on complication and success rates in percuta neous nephrolithotomy. urol int. 2006;77: 340-6. 8. kukreja r, desai m, patel s, bapat s, desai m. factors affecting blood loss during percu taneous nephrolithotomy: prospective study. j endourol. 2004;18:715-22. 9. mandal s, goel a, kathpalia r, et al. prosp ective evaluation of complications using the modified clavien grading system, and of suc cess rates of percutaneous nephrolithotomy using guy’s stone score: a single-center ex perience. indian j urol. 2012;28:392-8. 10. mousavi-bahar sh1, ahanian a, borzouei b. needle manipulation for removing inaccessi ble stones in parallel calices during percutan eous nephrolithotomy. urol j. 2012;9:522-4. 11. jeong cw, jung jw, cha wh, et al. seoul national university renal stone complexity score for predicting stone-free rate after percutaneous nephrolithotomy. plos one. 2013;8:e65888. 12. türk c, knoll t, petrik a, et al. guidelines on urolithiasis. available from: www.uro web.org/gls/pdf/18_urolithiasis.pdf. 13. okhunov z, friedlander ji, george ak, et al. s.t.o.n.e. nephrolithometry: novel surgical classification system for kidney calculi. urology. 2013;81:1154-9. 14. lee wj, smith ad, cubelli v, et al. compli cations of percutaneous nephrolithotomy. ajr am j roentgenol. 1987;148:177-80. 15. segura jw, patterson de, leroy aj, et al. percutaneous removal of kidney stones: re view of 1,000 cases. j urol. 1985;134:1077 81. 16. kessaris dn, bellman gc, pardalidis np, smith ag. management of hemorrhage after percutaneous renal surgery. j urol. 1995;153:604-8. 17. shin ts, cho hj, hong sh, lee jy, kim sw, hwang tk. complications of percuta neous nephrolithotomy classified by the modified clavien grading system: a single center’s experience over 16 years. korean j urol. 2011;52:769-75. 18. lee jk, kim bs, park yk. predictive factors for bleeding during percutaneous nephro lithotomy. korean j urol. 2013;54:448-53. 19. olbert pj, hegele a, schrader aj, scherag a, hofmann r. preand perioperative pre dictors of short-term clinical outcomes in pa tients undergoing percutaneous nephrolithol apaxy. urol res. 2007;35:225-30. 20. el-nahas ar, eraky i, shokeir aa, et al. factors affecting stone-free rate and compli cations of percutaneous nephrolithotomy for treatment of staghorn stone. urology. 2012;79:1236-41. effects of stone localization on pnl resultsbayar et al endourology and stone disease 1942 kidney transplantation association of serum fetuin-a levels with allograft outcome in renal transplant recipients abdolrasoul mehrsai,1 gholamreza pourmand,1 hamed azhdari tehrani,2 hossein keyhan,2 mohamad reza rahmati,1 ayat ahmadi,3 sanaz dehghani,1 rahil mashhadi1* purpose: to determine serum fetuin-a pattern after renal transplantation and its association with graft outcome. materials and methods: in 41 renal transplant recipients, serum pretransplant fetuin-a levels and serum fetuin-a concentrations on days 7 and 30 after transplantation were measured using the enzyme-linked immunosorbent assay (elisa) method. also, the association between serum fetuin-a levels with clinical and laboratory parameters was evaluated. results: a significant decrease in serum fetuin-a levels was noted in the first week after transplantation (p < .001). subsequently, it started to increase and surpass pretransplant values during the first month (p < .001). pretransplant fetuin-a levels did not differ among patients with different diethylenetriamine pentaacetic acid (dtpa) results. in addition, serum fetuin-a levels did not significantly correlate with metabolic parameters. conclusion: in this prospective study there was no increase in serum fetuin-a levels during the first month and pretransplant fetuin-a levels are not predictive for allograft outcome in renal transplant recipients. keywords: kidney transplantation; postoperative complications; kidney failure; kidney function tests; prospective studies. introduction kidney transplantation is an important and effective treatment for most patients with end-stage renal disease, which confers a survival benefit compared to hemodialysis.(1) improved technical approaches, new advances in immunosuppression, antibody definition and improvements in the overall care of the transplant recipient during the past decades, have significantly increased the short-term kidney allograft survival rate.(2,3) in spite of these advances, long-term allograft survival after the first year has not improved, and the length of kidney allograft survival is still shorter than that of the recipient’s even with the use of immunosuppressive drugs in sufficient doses to prevent acute rejection.(2,3) reasons for allograft failure are not well understood. (2) renal allograft failure occurs by both immune and nonimmune mechanisms; for example, graft rejection, graft thrombosis, interstitial fibrosis and tubular atrophy (if/ta), infection, chronic inflammation, nephrotoxicity from calcineurin inhibitors and calcification of the allografts.(2) therefore, access to innovative risk-identifying strategies in order to increase the long-term allograft survival can be considered as the best target for studies.(4) in patients with end-stage renal disease (esrd) and chronic kidney disease (ckd), the risk of subsequent cardiovascular events is higher than the ageand sexmatched populations with normal kidney function.(5) recent observations have shown rapid progression of cardiovascular calcification in patients with ckd and esrd.(5) cardiovascular calcification is a tightly regulated process affected by multiple mechanisms and also several serum proteins.(6) although calcium and phosphate precipitation occur in several tissues due to multiple risk factors such as age or inflammation reactions, but some serum precipitation inhibitory proteins would not allow this process to proceed. a number of calcification inhibitors such as fetuin-a, have been identified in recent years.(5,6) fetuin-a is a vertebrate plasma protein, belongs to the cystatin superfamily. cystatins can inhibit cysteine peptidases and play key roles in inflammation.(7) fetuin-a (molecular weight of about 60 kda), also known as α-2 heremans-schmid glycoprotein (ahsg), is synthesized by hepatocytes and ubiquitously present in the serum.(8) fetuin-a serum concentrations are relatively high (0.5 and 1.0 g/l) in the healthy population.(9) fetuin-a has been recognized as a major serum-based inhibitor of vascular and soft-tissue calcification, limiting hydroxyapatite crystal formation and stabilizing calcium–phosphate in a complex, which enables its clearing by the phagocytic system. (9-11) in animal studies, fetuin a-deficient mice developed calcifications in soft-tissue and vessels, accelerated by a mineral-rich diet, as well as renal failure.(12) fetuin-a is a multifunctional molecule with several biologic functions such as inhibition of calcification-inducing effects of transforming growth factor-β, inhibition 1 urology research center, tehran university of medical sciences, tehran, iran. 2 department of urology, bouali hospital, islamic azad university, tehran medical branch, tehran, iran. 3 research development center, sina hospital, tehran university of medical sciences, tehran, iran. *correspondence: hassan-abad sq., urology research center, sina hospital, tehran, iran. tel: +98 21 66348560. fax: +98 21 66348560. e-mail: rh_mashhadi@yahoo.com. received october 2014 & accepted february 2015 kidney transplantation 2182 of insulin receptor autophosphorylation, tyrosine kinase activity and protease.(8) serum fetuin-a reacts as a negative acute phase glycoprotein and is down regulated in acute and chronic inflammatory states.(13) some studies permit consideration of fetuin-a deficiency as a new mortality risk factor in patients with chronic kidney disease (ckd).(4,9) in hemodialysis patients, serum levels of fetuin-a is significantly lower than controls.(14) in addition, lower fetuin-a is associated with increased vascular calcification and inflammation and consequently high cardiovascular mortality.(9,14) few data was available regarding effect of fetuin-a in renal transplant recipients. one study showed that fetuin-a levels increased after renal transplantation.(15) in another study, no association was found between fetuin-a levels and allograft rejection.(9) however, due to the reduction of serum fetuin-a levels during inflammation(16) and its inhibitory role in calcification and fibrosis,(8,17) fetuin-a serum levels may be considered as a predictor of allograft outcome and rejection episodes.(4) we assumed that serum fetuin-a levels would be related to the kidney function. therefore, the aim of this study was to determine serum fetuin-a pattern after renal transplantation and to examine whether fetuin-a is associated with graft outcome. materials and methods study subjects in this single-center prospective study, 65 patients (48 males) who had undergone kidney transplantation were included. of these patients, 41 were included in the final analysis and 24 were excluded due to incomplete data. transplantations were performed in sina hospital, iran, from october 2012 to may 2013. there were 30 (73%) deceased donor and 11 (27%) living donor. the following groups of recipients were excluded from the study: recipients of combined organs such as kidney/pancreas, children and patients with hepatitis b or c. the causes of renal failure were diabetic nephropathy (n = 7), hypertensive ischemic nephropathy (n = 16), reflux nephropathy (n = 10), nephrotic syndrome (n = 3), chronic nephrolithiasis (n = 3) and unknown etiology (n = 2). an informed consent was obtained from all patients prior to their inclusion in the study. this study was approved by the medical ethics committee of the tehran university of medical sciences. patients’ immunosuppressive protocols were based on calcineurin inhibitor (cyclosporine a, 6-7 mg/kg/day) along with mycophenolate mofetil hydrochloride (1200 mg/m2). additionally, all patients received prednisone prior to transplantation (methylprednisolone, 10 mg/kg prior to transplantation rapidly converting into prednisolone, tapering the dose over 12 weeks to the dose of 0.3 mg/kg); also, anti-thymocyte globulin (atg rabbit, 1-1.5 mg/kg) was given to 5 patients with possible renal allograft rejection. renal function was evaluated by measuring urine volume and serum creatinine before transplantation and on days 7 and 30 after transplantation (creatinine clearance was calculated using the cockcroft/gault formula). in order to evaluate renal perfusion and function, technetium-99 diethylenetriamine pentaacetic acid (99mtc-dtpa) scan was performed along with doppler ultrasonography at the end of the first week after renal transplantation. routine laboratory parameters were measured by standard clinical chemistry methods. serum fetuin-a five milliliters of venous blood were withdrawn from every patient. serum was collected after centrifugation at 2500 g for 20 min and stored at −80°c for subsequent analyses. serum fetuin-a levels were measured using the enzyme-linked immunosorbent assay (elisa, biovendor laboratory medicine, brno, czech republic) method according to manufacturer’s instructions. the intra and interassay coefficients of variation were both < 5.0%. statistical analysis categorical variables are expressed as frequencies and percentages and continuous variables are reported as mean ± standard deviation (sd). subgroups of dtpa were compared on serum fetuin-a at 7th and 30th days after transplantation using repeated measure analysis figure 1. individual course of fetuin-a levels from pretranspl antation up to day 30 after kidney transplantation. parameters values age, years 41.27 ± 12.6 sex, male % 73.17 body mass index, kg/m2 27.48 ± 2 smoking, % 51.2 serum albumin, g/l 4.16 ± 0.69 serum calcium, mg/dl 9.12 ± 0.79 serum potassium, mmol/l 4.47 ± 0.53 systolic blood pressure, mmhg 127.8 ± 21 diastolic blood pressure, mmhg 79.76 ± 13.69 serum fetuin levels, mg/l before transplantation 1543 ± 1372.09 day 7 465.99 ± 630.34 day 30 1878.38 ± 1556.11 serum creatinine levels, mg/dl before transplantation 5.49 ± 2.06 day 7 2.38 ± 1.5 day 30 1.68 ± 0.8 all continuous data are expressed as mean ± sd. table. demographic and clinical characteristics of study subjects. fetuin-a in renal transplant recipients-mehrsai et al. vol 12 no 03 may-june 2015 2183 of variance. to assess relationship between serum fetuin-a with age and serum creatinine levels the pearson correlation coefficient was used at different time points. results clinical and demographic characteristics of the patients are shown in table. based on dtpa scan results at the end of the first week after transplantation, the patients were divided into three subgroups. the first subgroup included 25 patients with fairly proper renal perfusion and function (dtpa-1). the second subgroup comprised of 11 patients with proper renal perfusion but decreased renal function and excretion (dtpa-2), and the third subgroup is composed of 5 patients who had decreased renal perfusion, function and excretion (dtpa-3). in the first week after transplantation, there was a significant decrease in serum fetuin-a levels (p < .001), it then started to increase and surpass pretransplant values on day 30 (p < .001) (figure 1). furthermore, pretransplant serum fetuin-a concentrations were correlated with serum fetuin-a levels on days 7 (r = 0.638, p < .001) and 30 (r = 0.438, p < .004). we evaluated serum levels of fetuin-a over time by tertile of dtpa subgroups (figure 2). subsequently, we found that changes in serum fetuin-a levels did not differ in patients with different dtpas (p = .541). in order to investigate whether pretransplant levels of serum fetuin-a can be a predictor of renal transplant outcome, the mean changes of pretransplant levels of serum fetuin-a in dtpa subgroups were statistically analyzed and there was no statistically significant difference (p = .461). also, we performed a correlation analysis in order to evaluate the correlation between serum fetuin-a levels and creatinine levels. there was no significant correlation between serum fetuin-a levels and creatinine. finally, we assessed the role of age in fetuin-a levels and no relationship was observed (figure 3). moreover, no association was found between serum fetuin-a levels and gender (p = .337) and type of donors (p = .987). discussion renal allograft failure is the result of cumulative damage caused by various stressors and factors(18) such as if/ta, chronic inflammation and calcification processes.(2) fetuin-a is one of the most potent calcification inhibitor.(19) since, soft tissue calcifications occurs in fetuin-a knockout mice,(12) and serum fetuin-a levels are reduced in uremic conditions, fetuin-a can be considered as an inhibitor of vascular calcification in healthy people as well as uremic patients.(20) mori and colleagues showed that serum fetuin-a levels are reduced in patients with esrd.(21) similarly, it has been shown that low serum fetuin-a levels are independently associated with higher overall cardiovascular mortality in patients with renal failure.(22) one of the reasons indicating an association between low serum fetuin-a levels and increased mortality can be due to down regulation of fetuin-a in inflammation.(23) previous studies have shown that renal transplantation leads to improved vascular function and increased serum levels of fetuin-a.(24) hence, it can be expected that improvement in renal function is associated with increased serum levels of fetuin-a after kidney transplantation.(9) therefore we hypothesized that serum fetuin-a concentrations increase by the time after renal transplantation. however, the results of our study did not demonstrate an increase of serum fetuin-a levels within the first post-transplant month. moreover, in the first week after transplantation, we observed a significant decrease in serum fetuin-a levels, although it started to increase and surpass pretransplant values on day 30. thus, there is an obvious disagreement between study results and study hypothesis. in line with our results, urbanova and colleagues in a study on 30 deceased donor kidney recipients showed that serum fetuin-a concentrations decreased 2 weeks after kidney transplantation.(9) similarly, argani and colleagues observed lower serum fetuin-a concentrations in renal transplant (rt) patients than hemodialysis (hd) patients.(8) in contrast, caglar and colleagues reported an increase in serum fetuin-a concentrations on days 30 and 90 after transplantation. (15) moe and colleagues studied calcification inhibitors and reported an increase in serum fetuin-a levels after kidney transplantation in 11 patients with a well-functioning allograft.(25) since serum fetuin-a is involved in inflammatory processes, and inflammation is assofigure 2. changes in serum fetuin-a levels from pretransplantation up to day 30 after transplantation by tertile of diethylenetriamine pentaacetic acid (dtpa) groups. figure 3. relationship between serum fetuin-a levels and age. a) before renal transplantation; b) one week after renal transplantation and c) one month after renal transplantation. fetuin-a in renal transplant recipients-mehrsai et al. kidney transplantation 2184 ciated with allograft outcome in renal transplant recipients,(26,27) we expected that serum fetuin-a pretransplant serum levels are associated with subgroups of dtpa. however, we found no significant correlation between pretransplant serum fetuin-a levels and dtpa results. this might be due to the few number of subgroups. one of the most important factors for explaining the differences observed in serum fetuin-a behaviors may be systemic inflammation in the early post-transplant period.(28) severe systemic inflammation may be caused by infection, surgical trauma and immune response against the graft in the early period after transplantation. (9) previous studies have shown that the down regulation of fetuin-a in inflammation or trauma.(13,28) in addition, serum fetuin-a reacts as a negative acute phase glycoprotein and has a negative association with concentration of the tumor necrosis factor α, c-reactive protein (crp) and inflammatory cytokines interleukin (il)-1 β , il-6,(4,28) supporting the hypothesis of inflammation-dependent down regulation of fetuin-a expression.(4) hence, one possible explanation for our findings could be the difference in age recipients, which leads to a difference in the intensity of postoperative inflammation and stress. the mean age of patients in our study and in urbanova and colleagues’ study(9) was higher than caglar and colleagues’ study(15) (41.3, 50.2 and 25.2, respectively). on the other hand, it has been recently shown that serum fetuin-a levels may decrease after a single hemodialysis session, that supports the hypothesis of dialysis-induced inflammation. therefore, serum fetuin-a levels can be affected by possible dialysis sessions.(29) another reason to explain the observed differences may be due to pharmacological interventions (for example, treatment with calcium-phosphate medication) that affect the fetuin-a levels.(30) coglar and colleagues showed that short-term sevelamer (phosphate binder) treatment significantly increases serum fetuin-a levels.(30) in this regard, we cannot ignore the possible impact of vitamin d preparations and the severity of glomerular dysfunction on the serum fetuin-a levels. conclusion our study demonstrated that fetuin-a levels decrease early after transplantation (day 7) and then start to increase in the first month. fetuin-a down regulation early after transplantation may be caused by inflammation and trauma after surgery. however, further studies are needed to better clarify fetuin-a patterns after renal transplantation. in addition, we could not find any evidence to confirm the association between fetuin-a pretransplant serum levels and allograft outcome. further investigations with larger sample sizes are required to elucidate the association between pretransplant serum fetuin-a levels and allograft outcome. acknowledgements this research has been sponsored by tehran university of medical sciences, tehran, iran. the authors wish to thank mrs. b. pourmand, mrs. f. heidari, dr. s. alatab, mrs. s. gholizadeh and research development center of sina hospital for valuable helps in this study. conflict of interest none declared. references 1. veroux m, corona d, veroux p. kidney transplantation: future challenges. minerva chirurgica. 2009;64:75-100. 2. el-zoghby zm, stegall md, lager dj, et al. identifying specific causes of kidney allograft loss. am j transplant. 2009;9:527-35. 3. matas aj, humar a, gillingham kj, et al. five preventable causes of kidney graft loss in the 1990s: a single-center analysis. kidney int. 2002;62:704-14. 4. roos m, heinemann fm, lindemann m, et al. fetuin-a pretransplant serum levels, kidney allograft function and rejection episodes: a 3-year posttransplantation follow-up. kidney blood press res. 2011;34:328-33. 5. ix jh, chertow gm, shlipak mg, brandenburg vm, ketteler m, whooley ma. fetuin-a and kidney function in persons with coronary artery disease: data from the heart and soul study. nephrol dial transplant. 2006;21:2144-251. 6. ketteler m, westenfeld r, schlieper g, brandenburg v, floege j. “missing” inhibitors of calcification: general aspects and implications in renal failure. pediatr nephrol. 2005;20:383-8. 7. jahnen-dechent w, heiss a, schafer c, ketteler m. fetuin-a regulation of calcified matrix metabolism. circ res. 2011;108:1494509. 8. argani h, ghorbanihaghjo a, panahi g, rashtchizadeh n, safa j, meimand sm. serum fetuin-a and pentraxin3 in hemodialysis and renal transplant patients. clin biochem. 2012;45:775-9. 9. urbanova m, kalousova m, zima t, skibova j, wohlfahrt p, viklicky o. fetuin-a early after renal transplantation. kidney blood press res. 2009;32:217-22. 10. turkmen k, gorgulu n, uysal m, et al. fetuin-a, inflammation, and coronary artery calcification in hemodialysis patients. indian j nephrol. 2011;21:90-4. 11. hausler m, schafer c, osterwinter c, jahnendechent w. the physiologic development of fetuin-a serum concentrations in children. pediatr res. 2009;66:660-4. 12. jahnen-dechent w, schinke t, trindl a, et al. cloning and targeted deletion of the mouse fetuin gene. j biol chem. 1997;272:31496503. 13. hermans mm, brandenburg v, ketteler m, kooman jp, van der sande fm, boeschoten ew. association of serum fetuin-a levels with mortality in dialysis patients. kidney int. 2007;72:202-7. 14. ketteler m, bongartz p, westenfeld r, et al. association of low fetuin-a (ahsg) concentrations in serum with cardiovascular mortality in patients on dialysis: a crosssectional study. lancet. 2003;361:827-33. fetuin-a in renal transplant recipients-mehrsai et al. vol 12 no 03 may-june 2015 2185 15. caglar k, yilmaz mi, saglam m, et al. endothelial dysfunction and fetuin a levels before and after kidney transplantation. transplantation. 2007;14:392-7. 16. marechal c, schlieper g, nguyen p, et al. serum fetuin-a levels are associated with vascular calcifications and predict cardiovascular events in renal transplant recipients. clin j am soc nephrol. 2011;6:974-85. 17. verma-gandhu m, peterson mr, peterson tc. effect of fetuin, a tgf beta antagonist and pentoxifylline, a cytokine antagonist on hepatic stellate cell function and fibrotic parameters in fibrosis. eur j pharmacol. 2007;572:220-7. 18. nankivell bj, chapmann bj. chronic allograft nephropathy: current concepts and future directions. transplantation. 2006;81:643-54. 19. jung jy, hwang yh, lee sw, et al. factors associated with aortic stiffness and its change over time in peritoneal dialysis patients. nephrol dial transplant. 2010;25:4041-8. 20. cozzolino m, mazzaferro s, pugliese f, brancaccio d. vascular calcification and uremia: what do we know? am j nephrol. 2008;28:339-46. 21. mori k, ikari y, jono s, et al. fetuin-a is associated with calcified coronary artery disease. coron artery dis. 2010;21:281-5. 22. moe sm, chen nx. inflammation and vascular calcification (review). blood purif. 2005;23:64-71. 23. wang ay, woo j, lam cw, et al. associations of serum fetuin-a with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients. nephrol dial transplant. 2005;20:1676-85. 24. van summeren mj, hameleers jm, schurgers lj, et al: circulating calcification inhibitors and vascular properties in children after renal transplantation. pediatr nephrol. 2008;23:98593. 25. moe sm, reslerova m, ketteler m, et al. role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (ckd). kidney int. 2005;67:2295304. 26. goldfarb-rumyantzev as, naiman n. genetic predictors of acute renal transplant rejection. nephrol dial transplant. 2010;25:1039-47. 27. ombrellino m, wang h, yang h, et al. fetuin, a negative acute phase protein, attenuates tnf synthesis and the innate inflammatory response to carrageenan. shock. 2001;15:1815. 28. lebreton jp, joisel f, raoult jp, lannuzel b, rogez jp, humbert g. serum concentration of human α2 hs glycoprotein during inflammatory process. evidence that α2 -hs glycoprotein is a negative acute-phase reactant. j clin invest. 1979;64:1118-29. 29. ciaccio m, bivona g, di sciacca r, et al. changes in serum fetuin-a and inflammatory markers levels in end-stage renal disease (esrd): effect of a single session haemodialysis. clin chem lab med. 2008;46:212-4. 30. caglar k, yilmaz mi, saglam m, et al. shortterm treatment with sevelamer increases serum fetuin-a concentration and improves endothelial dysfunction in chronic kidney disease stage 4 patients. clin j am soc nephrol. 2008;3:61-8. fetuin-a in renal transplant recipients-mehrsai et al. kidney transplantation 2186 miscellaneous effect of preoperative forced-air warming on hypothermia in elderly patients undergoing transurethral resection of the prostate youn yi jo, young jin chang, yong beom kim, sehwan lee, hyun jeong kwak* purpose: elderly patients under spinal anesthesia are vulnerable to hypothermia, leading to increased morbidity. the aim of this study was to investigate the effects of preoperative forced-air warming on perioperative hypothermia and shivering in elderly patients undergoing transurethral resection of the prostate (turp) under spinal anesthesia. materials and methods: patients (> 65-year-old) scheduled for turp under spinal anesthesia were randomly assigned to receive preoperative forced-air skin warming for 20 min (the pre-warmed group, n = 25) or not (control group, n = 25). core temperatures were measured at 15-min intervals after spinal anesthesia, and intraand post-operative shivering were also assessed. results: incidences of intraoperative hypothermia (< 36ºc) in the pre-warmed and control groups were not significantly different (10/25 [40%] vs. 15/24 [62.5%], p = .259). however, severities of hypothermia were significantly different (p = .019). no patient in the pre-warmed group showed moderate or profound hypothermia, whereas of patients in control group 21% and 13% did so, respectively. conclusion: this study demonstrated that a brief period of preoperative forced-air warming did not completely prevent intraoperative hypothermia or shivering, but it could significantly reduce its severity in elderly male patients under spinal anesthesia. keywords: anesthesia; spinal; body temperature; hypothermia; etiology; prevention & control; transurethral resection of prostate; adverse effects. introduction spinal anesthesia significantly impairs thermoregula-tion by inhibiting vasomotor and shivering responses(1) and the redistribution of body heat,(2) and predisposes patients to perioperative hypothermia. because elderly patients have a reduced shivering threshold,(3) they are at greatest risk of hypothermia,(4) which can lead to serious clinical complications such as, myocardial ischemia,(5) blood loss,(6) and surgical wound infection.(7) thus, it is important to monitor and control body temperature and prevent hypothermia in elderly patients under spinal anesthesia. in addition, shivering is a major problem for surgeons during transurethral resection of the prostate (turp). shivering may interfere with visual field for resectable prostate tissue and increase the risk of injury to the urethra, bladder, and rectum during the surgery. hypothermia frequently occurs during turp, because cold bladder irrigation fluid is an important source of heat loss and decreases core body temperature by 1-2°c. (8) in a previous study, isothermic irrigation fluid was found to significantly reduce body temperature more so than room temperature irrigation fluid.(9) however, it can difficult to warm a large volume of irrigation fluid. on the other hand, preoperative skin surface warming using a forced-air warmer for 2 h has been reported to reduce the temperature differential between the core and periphery and heat redistribution during epidural anesthesia in healthy young volunteers not undergoing surgery,(10) and in another study, pre-operative warming for 10 or 20 min reduced shivering and largely prevented hypothermia during general anesthesia in healthy adult patients.(11) a recent meta-analysis also showed that prewarming patients with forced-air warmer could effectively reduce the peri-operative hypothermia.(12) we hypothesized that preoperative surface warming using a forced-air warmer before spinal anesthesia might reduce perioperative hypothermia and shivering in elderly patients. thus, the aim of this prospective study was to investigate the effects of preoperative forced-air warming on perioperative hypothermia and shivering in elderly male patients undergoing turp under spinal anesthesia. materials and methods study population after obtaining approval by the institutional review board of gachon university gil medical center, written informed consent was obtained from all enrolled patients. fifty male patients aged over 65 years of ameridepartment of anesthesiology and pain medicine, gachon university, gil medical center, incheon, south korea. *correspondence: department of anesthesiology and pain medicine, gachon university, gil medical center, 1198 guwol-dong, namdong-gu, incheon 405-760, south korea. tel: +82 32 4603637. fax: +82 32 4696319. e-mail: hyun615@gilhospital.com. received march 2015 & accepted september 2015 miscellaneous 2366 can society of anesthesiologists physical status i-ii and scheduled to undergo elective turp were enrolled in this prospective randomized study. the exclusion criteria were a pre-anesthetic tympanic membrane temperature of > 37.5ºc or < 36ºc, uncontrolled hypertension or diabetes mellitus, and a condition requiring fluid restriction, such as, end-stage renal disease, peripheral vascular disease, uncompensated heart failure, or progressive respiratory disease. patients were not pre-medicated. procedure on arrival at the pre-anesthetic care unit, standard monitors were applied and tympanic temperature was measured using an infrared tympanic thermometer (thermoscan irt 1020; braun, germany). all patients were placed under a forced-air cover and pre-warming was performed using a forced-air warmer (warmtouch; mallinckrodt medical, st louis, mo, usa). patients were randomized to receive forced-air pre-warming at 38ºc for 20 min (the pre-warmed group, n = 25) or not (control group, n = 25) (figure 1). in the pre-anesthetic care unit, tympanic temperature was measured immediately after arrival in the pre-anesthetic care unit and 10 and 20 mins later (pre-t0, pre-t10 and pre-t20, respectively). all patients received 8-10 ml/kg/h of plasma solution for 20 min as pre-hydration, and ambient temperature in the pre-anesthetic care unit was maintained at 21-23ºc. after a 20-min stay in the pre-anesthetic care unit, patients were transferred to the operating room. room temperature was set at 24-25ºc, and warming mattress containing circulating water at 36ºc was applied on the operating table. spinal anesthesia was performed in the lateral decubitus position using 0.5% hyperbaric bupivacaine (10-12 mg intrathecally) by an anesthesiologist unaware of group identities. when systolic blood pressure fell to 80% below the baseline value or to lower than 90 mmhg, phenylephrine (50 μg) or ephedrine (5 mg) was given at 2 min intervals. room temperature plasma solution was infused at a constant rate of 6 ml/ kg/h. all patients were covered with one layer of surgical drapes over chest, thigh, and calves during turp. mean arterial pressure, heart rate, patient discomfort to temperature and the occurrence of shivering and of hypothermia were recorded immediately after arrival in the operation room. hypothermia was defined as a core temperature of < 36ºc. tympanic temperature was measured at 15-min intervals from spinal anesthesia in the operating room (t0) to 60 min (t60) and from arrival (post-t0) to 60 min after arrival (post-t60) in the post-anesthetic care unit. irrigation fluid for turp was not warmed. when tympanic temperature fell below 36.0ºc or a patient asked for warming, forced-air warming was supplied regardless of group identity. statistical analysis the sample size of 25 patients per each group was calculated using power analysis based on the findings of a previous study,(13) in which the overall incidence of hypothermia after neuroaxial anesthesia was found to be 77%. to detect a mean intergroup difference in the incidence of hypothermia, 23 subjects were required with type i error (an α error of 0.05) and type ii error (a β error of 0.2), and to account for possible losses, we included 25 patients per group. statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0 was used for the analysis. results are expressed as numbers of patients or as mean ± sd or median (interquartile range). the independent t-test or table 1. demographics and perioperative data of study subjects. variables pre-warmed (n = 25) control (n = 24) p value age (years) 73 ± 6 72 ± 4 .461 weight (kg) 63 ± 8 65 ± 6 .464 height (cm) 165 ± 5 167 ± 4 .282 sensory block level t8 (t6-t10) t8 (t6-t9) .185 operation time (min) 63 ± 22 55 ± 24 .360 total irrigation fluid (ml) 8000 (3000-13500) 8000 (3000-10000) 1.00 total infused fluid (ml) 400 (375-425) 400 (300-500) .335 data are expressed as mean ± sd or medians (interquartile ranges). figure 1. flow consort diagram preoperative forced-air warming for elderly patients-jo et al. vol 12 no 05 september-october 2015 2367 the chi-square test was used, as appropriate, to compare variables between the groups, and repeated measures anova was used to compare changes in core temperature between the pre-warmed and control groups. p values of less than .05 were considered statistically significant. results twenty-five patients were initially enrolled in each group, but one patient in the control group was excluded from the analysis, because the anesthetic technique was changed to general anesthesia (figure 1). patient characteristics and peri-operative data are presented in table 1. no significant differences were observed between the two groups in terms of sensory block level, volume of irrigation fluid, or total amount of intravenous fluid infused during turp. the incidences of intraoperative hypothermia (< 36ºc) in the pre-warmed and control groups were not statistically significant (10/25 [40%] vs. 15/24 [62.5%], p = .259). however, severities of hypothermia were significantly different (p = .019); no patient in the pre-warmed group showed moderate or profound hypothermia, whereas of patients in control group 21% and 13% did so, respectively. frequencies of rescue warming during and after surgery, and the incidences of intraand postoperative shivering were similar in the two groups (table 2). figure 2 illustrates observed changes in core temperature during the perioperative period. during preand postoperative periods, the changes in core temperature between the groups were not significantly different (both p values > .05). during the intraoperative period, a significant decrease in core temperature (p < .001) was observed in both groups, but these changes were not statistically significant (p = .763). mean core temperature was significantly higher in the pre-warmed group at pre-t20 and at t0 (immediately after spinal anesthesia). discussion in the present study, preoperative forced-air warming for 20 min did not completely prevent intraoperative hypothermia or shivering, but did significantly reduce table 2. incidences of hypothermia and shivering during the peri-operative period. variables pre-warmed (n = 25) control (n = 24) p value intra-operative period (in or) normothermia ( ≥ 36.0oc) 15 (60) 10 (41) .259 hypothermia (< 36.0oc) 10 (40) 14 (59) severity of hypothermia .019 mild (35.5-35.9oc ) 10 (40) 6 (25) moderate (35.0-35.4oc ) 0 (0) 5 (21) profound (34.5-34.9oc ) 0 (0) 3 (13) shivering 5 (20) 8 (33) .345 needing rescue warming 3 (12) 3 (13) .888 post-operative period (in pacu) hypothermia (< 36.0oc) on arrival 10 (40) 13 (54) .321 shivering 2 (8) 1 (4) .485 needing rescue warming 7 (28) 6 (25) .564 time required to normothermia (min) 44 ± 23 52 ± 13 .347 abbreviations: or, operating room; pacu, post-anesthetic care unit. data are expressed as mean ± sd or numbers of patients (%). figure 2. peri-operative changes in core temperature in patients who received forced-air warming for 20 min (pre-warmed group, ○) or not (control group, ●) during transurethral resection of the prostate. error bars represent standard deviations. pre-t0-20, from arrival to 20 min stay in the pre-anesthetic care unit; t0-60, immediately to 60 min after spinal anesthesia; post-t0-60, from arrival to 60 min stay in the post-anesthetic care unit. a significant decrease in core temperature was observed during the intraoperative period (p < .001). core temperature changes were not statistically significantly different in two study groups (p = .763). *p < .05, control group vs. pre-warmed group. preoperative forced-air warming for elderly patients-jo et al. miscellaneous 2368 its severity in elderly male patients undergoing turp under spinal anesthesia. several authors have reported that preoperative warming using a forced-air warmer, reduces the risk of core hypothermia and prevents post-anesthesia shivering after general anesthesia or an epidural block,(10,14) and suggested that effective skin surface warming helpfully increases body heat content and reduces the risk of redistribution hypothermia associated with anesthesia. a previous analysis of 19 studies with total 1451 patients suggested that as a single strategy, preoperative forced air warming had significant benefits than other warming methods.(15) however, studies on pre-warming prior to spinal anesthesia, which might prevent hypothermia or shivering during procedures requiring large volumes of cold irrigation are lacking. although during neuroaxial block (spinal/epidural anesthesia), heat loss from superficial tissue to the environment is less than during general anesthesia, due to a smaller temperature gradient, the temperature difference between core and superficial tissues is greater during neuroaxial block, and thus, core temperatures could fall due to heat redistribution.(10) accordingly, skin surface warming should theoretically reduce the core to superficial tissue temperature gradient and possibly prevent redistribution hypothermia.(10) kim and colleagues(16) demonstrated that skin surface warming during anesthetic preparation could significantly reduce the difference between core and skin temperatures in patients undergoing coronary artery bypass graft. in the present study, skin surface warming for 20 min significantly reduced the severity of hypothermia, but not its incidence. we believe this is probably due to age-related decreases in thermoregulatory functions, such as, vasoconstriction and shivering. in the elderly, reduced norepinephrine release and the down-regulation of α-adrenoreceptors impair vasomotor response to cold. furthermore, loss of lean body mass due to aging reduces shivering, and thus, metabolic heat generation.(17) in fact, with the exception of block level, an advanced age is the most significant predictor of core hypothermia during spinal anesthesia.(4) in the present study, we enrolled patients aged over 65 years old in view of the fact that the vasoconstrictive threshold is about 0.8oc lower in those aged 60-80 years than in those aged 30-50 years (35.0oc vs 35.8oc).(18) because of these thermoregulatory changes in elderly patients, pre-operative skin surface warming for 20 min is probably not sufficient to maintain a core body temperature of > 36oc during turp in the present study. furthermore, spinal anesthesia per se alters afferent thermal inputs and impairs thermoregulatory responses, and thresholds of shivering and vasoconstriction decrease by 0.5-0.9oc during spinal anesthesia.(1,19) in this study, we observed median maximal falls in core temperatures of 0.4oc and 0.5oc in the pre-warmed and control groups, respectively. furthermore, presumably because spinal anesthesia might decrease thermoregulatory thresholds further in the elderly, observed incidences of post-anesthesia shivering were relatively low (25% and 33% in the pre-warmed and control groups, respectively) as compared with those of intra-operative hypothermia (40% and 62.5% in the pre-warmed and control groups, respectively ). the restriction of the study population to elderly males is the main limitation of the present study. thermal responses to exogenous and endogenous heat losses differ between the sexes, because body surface to body mass ratios, subcutaneous fat contents, and exercise capacities differ.(20) furthermore, in a recent study, it was found that the incidence of postoperative shivering was higher in elderly females than in elderly males. (21) thus, our results cannot be generalized to elderly females, and further study is needed to elucidate the effect of pre-operative forced-air warming on hypothermia or shivering in female patients. another limitation in this study is that tympanic temperature alone might not guarantee the accurate core body temperature. gilbert and colleagues(22) demonstrated that additional use of digital oral thermometer to tympanic thermometer could provide valid patients’ temperature. however, another previous study has reported that oral or tympanic temperature frequently overor underestimate the rectal temperature.(23) additionally, if we have measure the skin temperatures on limbs and trunk in addition to core temperature, we could estimate mean body temperature and calculate total heat body content, based on previously reported formula.(24) however, we did not measure the skin temperatures, because applying forced air warming device would interfere with the accurate measurement of skin temperatures. meanwhile, we could calculate mean energy input in the pre-warmed group, since the heat capacity of human body is 0.812 kcal/kg oc,(25) which means that to change the body temperature of a 60 kg human by oc, 49 kcal is needed. in this study, mean patient weight was 63 kg, mean elevation in core temperature in the pre-warmed group was 0.2°c, and mean energy input in the pre-warmed group was about 10 kcal for 20 mins. conclusions in conclusion, in elderly male patients during turp under spinal anesthesia, pre-operative forced-air warming for 20 min significantly reduced the severity but not the incidence of intraoperative hypothermia. we suggest that only short-time skin surface warming could reduce somewhat the severity of redistribution hypothermia in elderly male patients. conflict of interest none declared. references 1. ozaki m, kurz a, sessler di, et al. thermoregulatory thresholds during epidural and spinal anesthesia. anesthesiology. 1994;81:282-8. 2. matsukawa t, sessler di, christensen r, ozaki m, schroeder m. heat flow and distribution during epidural anesthesia. anesthesiology. 1995;83:961-7. 3. vassilieff n, rosencher n, sessler di, conseiller c. shivering threshold during spinal anesthesia is reduced in elderly patients. anesthesiology. 1995;83:1162-6. 4. frank sm, el-rahmany hk, cattaneo cg, conseiller c. predictors of hypothermia during spinal anesthesia. anesthesiology. 2000;92:1330-4. 5. frank sm, beattie c, christopherson r, et al. unintentional hypothermia is associated preoperative forced-air warming for elderly patients-jo et al. vol 12 no 05 september-october 2015 2369 with postoperative myocardial ischemia. the perioperative ischemia randomized anesthesia trial study group. anesthesiology. 1993;78:468-76. 6. schmied h, kurz a, sessler di, kozek s, reiter a. mild hypothermia increases blood loss and transfusion requirements during total hip arthroplasty. lancet. 1996;347:289-92. 7. kurz a, sessler di, lenhardt r. perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. study of wound infection and temperature group. n engl j med. 1996;334:1209-15. 8. moorthy hk, philip s. turp syndrome current concepts in the pathophysiology and management. indian j urol. 2001;17:97-102. 9. pit mj, tegelaar rj, venema pl. isothermic irrigation during transurethral resection of the prostate: effects on peri-operative hypothermia, blood loss, resection time and patient satisfaction. br j urol. 1996;78:99103. 10. glosten b, hynson j, sessler di, mcguire j. preanesthetic skin-surface warming reduces redistribution hypothermia caused by epidural block. anesth analg. 1993;77:488-93. 11. horn ep, bein b, böhm r, steinfath m, sahili n, höcker j. the effect of short time periods of pre-operative warming in the prevention of peri-operative hypothermia. anaesthesia. 2012;67:612-7. 12. de brito poveda v, clark am, galvão cm. a systematic review on the effectiveness of prewarming to prevent perioperative hypothermia. j clin nurs. 2013;22:906-18. 13. arkiliç cf, akça o, taguchi a, sessler di, kurz a. temperature monitoring and management during neuraxial anesthesia: an observational study. anesth analg. 2000;91:662-6. 14. andrzejowski j, hoyle j, eapen g, turnbull d. effect of prewarming on post-induction core temperature and the incidence of inadvertent perioperative hypothermia in patients undergoing general anaesthesia. br j anaesth. 2008;101:627-31. 15. kim jy, shinn h, oh yj, hong yw, kwak hj, kwak yl. the effect of skin surface warming during anesthesia preparation on preventing redistribution hypothermia in the early operative period of off-pump coronary artery bypass surgery. eur j cardiothorac surg. 2006;29:343-7. 16. moola s, lockwood c. effectiveness of strategies for the management and/or prevention of hypothermia within the adult perioperative environment. int j evid based healthc. 2011;9:337-45. 17. frank sm, raja sn, bulcao c, goldstein ds. age-related thermoregulatory differences during core cooling in humans. am j physiol regul integr comp physiol. 2000;279:r34954. 18. ozaki m, sessler di, matsukawa t, et al. the threshold for thermoregulatory vasoconstriction during nitrous oxide/ sevoflurane anesthesia is reduced in the elderly. anesth analg. 1997;84:1029-33. 19. kurz a, sessler di, schroeder m, kurz m. thermoregulatory response thresholds during spinal anesthesia. anesth analg. 1993;77:7216. 20. gagnon d, kenny gp. does sex have an independent effect on thermoeffector responses during exercise in the heat? j physiol. 2012;590:5963-73. 21. conti d, ballo p, boccalini r, et al. the effect of patient sex on the incidence of early adverse effects in a population of elderly patients. anaesth intensive care. 2014;42:455-9. 22. gilbert m, barton aj, counsell cm. comparison of oral and tympanic temperatures in adult surgical patients. appl nurs res. 2002;15:42-7. 23. barnett bj, nunberg s, tai j, et al. oral and tympanic membrane temperatures are inaccurate to identify fever in emergency department adults. west j emerg med. 2011;12:505-11. 24. lenhardt r, sessler di. estimation of mean body temperature from mean skin and core temperature. anesthesiology. 2006;105:111721. 25. belani k, sessler di, sessler am, et al. leg heat content continues to decrease during the core temperature plateau in humans anesthetized with isoflurane. anesthesiology. 1993;78:856-63. preoperative forced-air warming for elderly patients-jo et al. miscellaneous 2370 introduction currently, prostate cancer is the most common cancer diagnosed in men and the second most common cause of death due to cancers after lung cancer.(1) its high prevalence, simple diagnostic methods, and definitive treatments have made early diagnosis essential. although there have been recent reports opposing the value of prostate-specific antigen (psa) as the best marker to detect prostate cancer, it remains one of the simplest ways of early diagnosis and followup of this disease.(1,2) prostate-specific antigen is not specific for prostate cancer and increases also in other conditions, such as benign prostatic hyperplasia, inflammation due to diagnostic and therapeutic manipulation, and prostatitis. however, the main role of psa is to screen patients with suspected prostate cancer.(1) since the introduction of psa as a diagnostic tool, there has always been a question of whether its normal value is influenced by other factors such as age and ethnicity. determining reference ranges for psa in all societies has been a significant challenge. early studies have shown that psa level in each society depends on age, race, and geographic characteristics of the region.(3) recently, attempts to determine the value of psa in different populations have been done.(2,4) the purpose of this study was to determine the normal serum psa levels in yasuj, a city in southwest iran. analysis of serum prostate-specific antigen levels in men aged 40 years and older in yasuj, iran sadrollah mehrabi,* hamidreza ghafarian shirazi, mahmoud rasti, babak bayat department of urology, faculty of medicine, yasuj university of medical sciences, yasuj, iran abstract introduction: serum prostate-specific antigen (psa) is still the simplest marker for early diagnosis and follow-up of prostate cancer. because racial differences in psa levels have been found, we performed this study to determine the reference level of serum psa for men in yasuj, in southwest iran. materials and methods: men aged 40 years and older who had been referred to any of the yasuj hospitals for a blood cell count for any reason were randomly selected. those with a history of prostate cancer, prostatitis, urinary tract infection, bladder outlet obstruction, or transurethral procedures were excluded. blood samples were taken, and psa levels were measured. results: prostate-specific antigen levels in the 95th percentile were 1.35 ng/ml, 1.85 ng/ml, 3.2 ng/ml, and 4.4 ng/ml for men aged 40 to 49, 50 to 59, 60 to 69, and older than 69 years, respectively. mean serum psa levels were 0.7 ng/ml, 0.9 ng/ml, 1.6 ng/ml, and 2.2 ng/ml, respectively. conclusion: a comparison of our results with those from studies in the united states and japan shows that the reference psa level in our society is significantly lower than that for white and black western men, and slightly lower than that for japanese men. although we examined men with no history of prostate cancer, cancer was not ruled out by diagnostic test; hence, our results may be overestimated. further investigations in iran are warranted. key words: prostate, serum prostate-specific antigen, yasuj 189 urology journal unrc/iua vol. 2, no. 4, 189-192 autumn 2005 printed in iran received january 2005 accepted june 2005 *corresponding author: shaheed labbafinejad medical center, 9th boustan, pasdaran, tehran 1666679951, iran. tel: ++98 917 341 4331, e-mail: mehrabi390@yahoo.com serum prostate-specific antigen in men from yasuj materials and methods in this cross-sectional study, between march 2003 and april 2004, 650 men aged 40 years and older who had been referred to any of the yasuj hospitals for a blood cell count for any reason were randomly selected. those with a history of prostate cancer, bladder outlet obstruction, bacterial prostatitis, urinary tract infection, any sign of inflammation (eg, pyuria), history of prostate surgery, or recent transurethral procedures were excluded. also, patients were excluded if their blood samples were being tested for prostate cancer. after obtaining informed consent, blood samples were taken, and 1 ml centrifuged serum was used for the serum psa test. an immunoradiometric assay using monoclonal antibodies (kavoshyar-iran, tehran, iran), which could measure psa levels to within 0.05 ng, was used. to identify age-specific ranges, participants were categorized into 4 groups: 40 to 49, 50 to 59, 60 to 69, and older than 69 years. the normal range for serum psa was defined as lower than the 95th percentile level. the borderline range was considered as those values falling between the 95th and 99th percentiles. data were analyzed using spss software (statistical package for the social sciences, version 10.0, spss inc, chicago, ill, usa). results blood samples were taken from 210, 180, 150, 110, respectively, in the age groups 40 to 49, 50 to 59, 60 to 69, and 70 years or older (n = 650 men). the mean serum psa level for men aged 40 to 49 years was 0.7 ng/ml. the normal level in this age group was 0 to 1.35 ng/ml, and the number of men with psa levels in this range was 198. there were 8 men with levels in the borderline range, the serum psa levels of whom were 1.35 ng/ml to 1.50 ng/ml. the mean serum psa level of men aged 50 to 59 years was 0.9 ng/ml. of 180 men, 167 had psa levels lower than or equal to those in the 95th percentile, ranging from 0 to 1.85 ng/ml. the psa levels of 10 men were in the borderline range, with psa levels between 1.85 and 2.25 ng/ml. men aged 60 to 69 years had a mean psa level of 1.6 ng/ml. the normal level in this age group was 0 to 3.2 ng/ml and was seen in 140 men. the borderline range was 3.2 ng/ml to 3.7 ng/ml and was seen in 8 men. finally, the mean psa level was 2.2 ng/ml in men older than 69 years. the normal and borderline levels were 0 to 4.4 ng/ml and 4.4 to 4.6 ng/ml in 102 and 6 men, respectively. a summary of these results in comparison with the results of other studies is shown in tables 1 and 2. discussion the comparison of this study with others (tables 1 and 2) shows that serum psa levels in our study population are lower than those in studies from the united states and japan. in fact, in all age groups over 40 years, the serum psa level in the normal and borderline ranges in our region was lower than those of other countries. however, our values are close to those of the japanese, corresponding to a probable difference between asians and americans and african-americans. in a study of 2119 residents of olmsted county, minnesota, in the united states, in 1994, osterling and colleagues reported that the maximum normal level of psa for different age groups was between 2.50 and 6.50 ng/ml, and psa levels of 2.60 ng/ml to 6.50 ng/ml were considered borderline. an important result of this 190 table 1. the 95th percentile of serum psa levels in the present study and studies from different regions psa levels (ng/ml) age group (years) current study oesterling et al (5) (minnesota) deantoni et al (6) (denver) oesterling et al (7) (japan) 40 to 49 1.35 2.50 2.00 1.50 50 to 59 1.85 3.50 3.80 2.00 60 to 69 3.20 4.50 4.20 3.40 ≥ 70 4.40 6.50 5.50 4.50 mehrabi et al study was that the normal psa level in different races was different; africans had a higher and asians had a lower psa level than did americans.(5) in another study of 286 healthy japanese men aged 40 to 79 years, it was shown that psa concentration was lower for the japanese than it was for the americans (p < .001). the studied population showed no evidence of prostate cancer by digital rectal examination and transrectal ultrasonography.(7) although the findings of our study are from a small province of iran and may not be generalizable to the entire country, it seems that psa levels in our study population are similar to those of the asian race rather than those of western society. morgan and colleagues measured serum psa in 3475 men (1802 white americans and 1673 african-americans) with no clinical evidence of prostate cancer and found reference serum psa levels of 2.1 ng/ml, 3.6 ng/ml, 4.3 ng/ml, and 5.8 ng/ml for white men and 2.4, 6.5, 11.4, and 12.5 ng/ml for african-american men in their 40s, 50s, 60s, and 70s.(8) it has been shown that african-american men are more likely to have inflammation, and this difference may contribute to elevated serum psa levels in african-american men compared with white men in the united states.(9) such differences may be the reason for racial differences in psa levels. studies in the united states have shown that the asian race has a lower psa level than do other races (african-americans and white americans). although the etiology of this effect is not known, it may be a result of lower serum androgen levels in asians; however, this remains to be elucidated.(10,11) benign prostate hyperplasia is another reason for slight increases in psa level. there is even a possibility that nutrition and geographic region, or distance from the equator, affect psa level, but none of the previous studies have compared these factors between different races.(2,12) in 2004, stamey and colleagues reviewed the psa levels of 1317 patients with prostate cancer in a retrospective study and mentioned that in the prior 5 years, serum psa was related only with benign prostatic hyperplasia. they concluded that there is an urgent need for another marker that will be more specific to screen for prostate cancer.(2) however, their sample was from patients with cancer and not from the general population. no new serum marker has been found that is better for screening for prostate cancer. therefore, serum psa level remains one of the best screening tools for detecting prostate cancer and following patients.(2,13) the limitations of this study may have led to our reporting even higher reference levels for serum psa than the actual values of the study population; patients were not examined for evidence of prostate cancer by digital rectal examination, transrectal ultrasonography, or biopsy, and there may have been cases of undiagnosed malignancies among our sample. also, if we were able to follow the patients with borderline psa levels, some would be excluded from the population of healthy men. consequently, we suggest that the reference psa level in our study sample may be even lower. conclusion this study shows that men older than 40 years in yasouj have lower normal levels of serum psa than do african-american and american men. comparison of psa levels in this study with 191 table 2. the 99th percentile of serum psa levels in the present study and studies from different regions psa levels (ng/ml) age group (years) current study oesterling et al (5) (minnesota) deantoni et al (6) (denver) oesterling et al (7) (japan) 40 to 49 1.50 2.60 2.40 1.70 50 to 59 2.25 4.50 4.10 2.40 60 to 69 3.70 5.10 5.00 3.90 ≥ 70 4.60 6.50 6.50 4.80 serum prostate-specific antigen in men from yasuj studies of japanese men and with those of western society shows that psa levels in asian men are lower. current study limitations preclude generalization of the results to the entire iranian population; however, owing to the significant differences of our results with the reference ranges used currently in iran, we suggest that a nationwide study be undertaken to better determine the age-specific reference serum psa levels in iranian men. exclusion of patients with any evidence of prostate cancer (by transrectal ultrasonography and other diagnostic tools) would be a requisite of such studies. references 1. carter hb, partin aw. diagnosis and staging of prostate cancer. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 3055-79. 2. stamey ta, caldwell m, mcneal je, nolley r, hemenez m, downs j. the prostate specific antigen era in the united states is over for prostate cancer: what happened in the last 20 years? j urol. 2004;172(4 pt 1):1297-301. 3. antonopoulos im, pompeo acl, de goes pm, chade j, sarkis as, arap s. racial differences in prostate cancer prevalence. braz j urol. 2002;28:214-20. 4. moul jw, sesterhenn ia, connelly rr, et al. prostatespecific antigen values at the time of prostate cancer diagnosis in african-american men. jama. 1995;274:1277-81. 5. oesterling je, jacobsen sj, chute cg, et al. serum prostate-specific antigen in a community-based population of healthy men. establishment of age-specific reference ranges. jama. 1993;270:860-4. 6. deantoni ep, crawford ed, oesterling je, et al. ageand race-specific reference ranges for prostate-specific antigen from a large community-based study. urology. 1996;48:234-9. 7. oesterling je, kumamoto y, tsukamoto t, et al. serum prostate-specific antigen in a community-based population of healthy japanese men: lower values than for similarly aged white men. br j urol. 1995;75:347-53. 8. morgan to, jacobsen sj, mccarthy wf, jacobson dj, mcleod dg, moul jw. age-specific reference ranges for serum prostate-specific antigen in black men. n engl j med. 1996; 335:304-10. 9. eastham ja, may ra, whatley t, crow a, venable dd, sartor o. clinical characteristics and biopsy specimen features in african-american and white men without prostate cancer. j natl cancer inst. 1998;90:756-60. 10. henderson rj, eastham ja, culkin dj, et al. prostatespecific antigen (psa) and psa density: racial differences in men without prostate cancer. j natl cancer inst. 1997;89:134-8. 11. abdalla i, ray p, ray v, vaida f, vijayakumar s. comparison of serum prostate-specific antigen levels and psa density in african-american, white, and hispanic men without prostate cancer. urology. 1998;51:300-5. 12. eastham ja, sartor o, richey w, moparty b, sullivan j. racial variation in prostate specific antigen in a large cohort of men without prostate cancer. j la state med soc. 2001;153:184-9. 13. fowler je jr, bigler sa, lynch c, wilson ss, farabaugh pb. prospective study of correlations between biopsydetected high grade prostatic intraepithelial neoplasia, serum prostate specific antigen concentration, and race. cancer. 2001;91:1291-6. 192 vol 13 no 02 march-april 2016 2590 review laparoendoscopic single-site adrenalectomy versus conventional laparoscopic adrenalectomy: an updated meta analysis shike wu,1* hao lai,1* jiangyang zhao,2* jiansi chen,1 xianwei mo,1 hongqun zuo,1** yuan lin1** purpose: previous meta-analyses that compared the outcome of laparoendoscopic single-site adrenalectomy (lessa) and conventional laparoscopic adrenalectomy (cla) have not shown consistent results. the aim of this meta-analysis was to reassess current evidence regarding the efficacy and safety of lessa versus cla. materials and methods: a literature search of pubmed, embase, medline, and the cochrane library was performed to identify eligible articles up until september 2015. quantitative variables were calculated using the weighted mean differences (wmds), and qualitative variables were pooled using odds ratios (ors). results: ten retrospective studies, including a total of 704 cases, were identified. patients in the lessa group benefitted from shorter length of hospital stay (95% confidence interval [ci]: -1.27 to -0.36, wmd: -0.81, p < .001) and better postoperative pain scores (95% ci: -1.51 to -0.99, wmd: 1.25, p < .001). there was no significant difference between the two techniques in operative time, estimated blood loss, resumption of oral intake, dose of analgesic required, perioperative complications, conversion, transfusion, or pain medications required. conclusion: based on current evidence, lessa appear to be a safe and feasible alternative to cla with a shorter length of hospital stay and lower postoperative pain scores in certain patients. we await high-quality, double-blind randomized clinical trials with long-term follow-up to confirm and update the findings of this analysis; future studies should focus on failure of technique, cosmesis, and cost. keywords: adrenal glands; surgery; adrenalectomy; methods; laparoscopy; treatment outcome; minimally invasive surgical procedures. introduction with the advent of laparoscopic surgery in the early 1980s, minimally invasive surgery has continued to evolve. since gagner first reported laparoscopic adrenalectomy (la) in 1992,(1) laparoscopic surgery for benign adrenal tumors has become the gold standard for treatment.(2,3) several studies have shown its advantages compared with open adrenalectomy, such as decreased complications, a shorter postoperative length of hospital stay, and reduced costs.(4-7) however, the ‘conventional’ laparoscopic approach requires three or four widely spaced access ports, and remains highly invasive. recently, with the development of laparoscopic techniques and instrumentation, as well as surgical experience, a minimally invasive surgery – socalled single-incision laparoscopic surgery (sils) – has gained popularity as a method of achieving a “scarless” abdomen through a single incision. in 2005, hirano and colleagues reported the first experience of a single-incision, retroperitoneoscopic, single-port adrenalectomy. (8) subsequently, laparoendoscopic single-site adrenalectomy (lessa) has been shown to be feasible for the treatment of benign adrenal tumors.(9-11) to date, many studies have been conducted to determine the advantages of surgical outcomes of lessa versus la.(12-20) two meta-analyses comparing conventional laparoscopic adrenalectomy (cla) and lessa were reported by hu and colleagues and wang and colleagues. in 2012,(21,22) 1 department of gastrointestinal surgery, affiliated tumor hospital of guangxi medical university nanning 530021, guangxi autonomous region, china. 2 department of clinical laboratory, children's hospital, maternal and child health hospital of guangxi zhuang autonomous region, nanning 530003, guangxi , china. *these authors contributed equally to this work and should be considered as co-first authors. **correspondence: department of gastrointestinal surgery, affiliated tumor hospital of guangxi medical university nanning 530021, guangxi autonomous region, china. tel: +86 0771 5644230. fax: +86 0771 5312000.e-mail: hongqunzuo@163.com. department of gastrointestinal surgery, affiliated tumor hospital of guangxi medical university nanning 530021, guangxi autonomous region, china. tel: +86 0771 5330708. fax: +86 0771 5312000. e-mail: doctoryuanlin@163.com. received october 2015 & accepted february 2016 which summarized and reviewed 171 cases of lessa compared with 272 cases of cla(12-20) and showed a longer operative time and lower postoperative visual analog pain score in lessa, and comparable results for complications, time to oral intake resumption, and estimated blood loss between the two groups. more recent publications were not investigated in these previous meta-analyses, which remain controversial.(23-25) thus, there is a need for an updated meta-analysis to reassess the safety and efficacy of the two procedures and to determine whether lessa is an acceptable alternative to cla for the treatment of benign adrenal tumors. materials and methods literature search a systematic literature search of the embase, cochrane, and pubmed databases was performed to identify studies comparing lessa with cla (to september 2015). the following medical subject heading (mesh) terms and words were used in the search, in all possible combinations: ‘laparoendoscopic,’ ‘single-site,’ ‘single port,’ ‘single incision,’ ‘single access,’ and ‘adrenalectomy.’ a second-level search included a manual search of the reference lists of all the relevant studies, systematic reviews, and previous meta-analyses to identify potentially eligible studies. inclusion and exclusion criteria titles and abstracts of all identified articles were screened and we included studies that satisfied the following criteria: (1) compared lessa and cla, (2) lessa performed using laparoscopic or retroperitoneoscopic techniques through a mono port or a single large port (the operative technique can be described as “laparoscopic,” “single-port,” “single-incision,” “mono port,” “single large port ,” “retroperitoneoscopic,” “conventional laparoscopic,” “3-port laparoscopic” or “4-port laparoscopic”), (3) applied the same approach in the cla and lessa group, (4) available in full-text, (5) written in english, and (6) reported at least one of the following outcomes: operative time, length of hospital stay, estimated blood loss (ebl), resumption of oral intake, postoperative pain scores, perioperative complications, conversion, cosmetic satisfaction score, recovery time, convalescence transfusion and pain medication requirement, dose of analgesic required, and interval to return to work/routine activity. if two studies from the same institution were identified, the most recent or most informative was selected (unless they were reports from clearly different periods or data from overlapping patients could be subtracted). outcome measures outcome variables were considered suitable for analysis if they met the following criteria: (1) continuous outcomes reported as means and standard deviations, and (2) identical variables reported by a minimum of two studies. outcome variables considered most suitable for analysis were as follows: operative time, length of hospital stay, ebl, resumption of oral intake, postoperative pain scores, doses of analgesic required, perioperative complications, conversion, transfusion, and pain medication required. if sufficient data were available, perioperative complications were subdivided into postoperative and intraoperative complications. if units used for the end points were not uniform, we attempted to convert them for ease of analysis. data extraction and quality assessment data were extracted from each study by two independent reviewers (shike wu and hao lai); agreement was achieved through discussion when necessary. we did not use any particular method for estimating standard deviations. the following data were extracted: first author, study period, study design, characteristics of study population, indications for surgery, number of subjects operated on with each technique, and perioperative outcomes. all studies were retrospective comparative studies and none was a randomized clinical trial (rct). according to the oxford 2011 levels of evidence,(26) the newcastle-ottawa quality assessment scale was used to assess the quality of studies.(27) this scale contains eight items, categorized into three dimensions, selection, comparability, and outcome. a study can be awarded a maximum of one star for each numbered item within the selection and outcome categories and two stars for comparability. a score of 0–9 (as stars) was allocated to each study: studies with a newcastle-ottawa score ≥ 6 were considered to be of high quality. statistical analysis statistical analyses were performed using stata software (version 12.0; stata corp., college station, tx, usa). for continuous variables, we calculated weighted mean differences (wmds) with 95% confidence intervals (cis). for dichotomous variables, we used odds ratios (ors) and a fixed-effects model. we used the χ² test and the i² statistic to assess heterogeneity between studies, with a p value of < .05 indicating statistical significance and the i² statistic > 50% was considered to represent significant heterogeneity. a random-effects model was used if there was significant heterogeneity. sensitivity and subgroup analyses were used to explore potential causes of heterogeneity. subgroup analyses were performed to examine whether results that comlaparoendoscopic single-site adrenalectomy-wu et al. review 2591 vol 13 no 02 march-april 2016 2592 pared lessa with cla varied by different approaches (transperitoneal and retroperitoneal). publication bias was evaluated by a funnel plot. results in total, 122 studies were identified by the electronic searches; no further study was identified through other sources. figure 1 depicts a preferred reporting items for systematic reviews and meta-analyses (prisma) flow chart for study inclusion and exclusion. after removing duplicate results, 116 records remained. of these, on reviewing the titles and abstract, 97 obviously irrelevant articles were rejected. thus, 19 relevant articles comparing lessa and cla were considered suitable for the pooled analysis. nine articles (seven with unavailable data and two repeated studies) were excluded by reading the full-text articles.(19,20,28-34) finally, 10 studies were included in the analysis.(12-18,23-25) the methodological quality of the included studies was relatively high, with a score of six or seven stars: the assessment of the included studies is shown in figure 2. study and patient characteristics the articles included in the quantitative synthesis were published between 2009 and 2014, with a total of 255 first author study design study period country lessa less cl number age (years) bmi (kg/m²) lessa cla procedures device device lessa / cla lessa / cla m / f m / f jeong, 2009 ra 2001-2009 korea lessa umbilicus through 3 or 4 ports 9 / 17 46.0 / 43.8 na 4 / 5 11 / 6 a 2-cm incision walz, 2010 ra 2000-2008 germany sara single-access approach 3 ports 47 / 47 43.3 / 42.2 25.1 ± 3.9 / 25.2 ± 3.9 17 / 30 17 / 30 tunca, 2012 ra 2006-2010 turkey sila through a 2-cm 3 ports 22 / 74 43.3 ± 10 / 43.4 ± 12.3 na 4 / 18 29 / 45 umbilical incision lin, 2012 ra 2006-2011 taiwan lessa with a 2.to 3-cm skin 3 or 4 ports 21 / 28 50.7 (34-74) / 51.7 (25-71) 25.6 / 24.6 12 / 9 14 / 14 incision just beneath the tip of the 12th rib wang, 2012 ra 2009-2011 china lessa a 2-3-cm through the na 13 / 26 47.2 ± 9.31 / 43.9 ± 10.27 24.9 ± 3.10 / 25.1 ± 4.16 8 / 5 10 / 16 umbilicus of 8 patients and a 2-3 cm subcostal incision of 5 patients shi, 2011 ra 2009 china less-ara a 2.5to 3-cm transverse skin 3 ports 19 / 38 57.0 / 57.0 29.8 / 29.0 8 / 11 21 / 17 incision made below the lower margin of the 12th rib kwak, 2011 ra 2008-2009 korea lamp at 2 fingerbreadths below the 3 ports 12 / 10 51.08 / 43.70 24.08 ± 4.01 / 26.17 ± 3.11 6 / 6 5 / 5 costal margin at the midclavicular line through a 2.5-cm incision. hirasawa, 2014 ra 2001-2013 japan lessa through the umbilicus or the side 3 or 4 ports 70 / 140 51.2 ± 11.5 / 50.9 ± 11.5 23.0 ± 3.6 / 23.1 ± 3.6 na na of the navel to approach the intraperitoneal space hora, 2014 ra 2008-2014 czech less ae quadport + in short pararectal na 15 / 15 59.3 ± 13.3 / 60.2 ± 11.9 26.9 ± 4.3 / 28.5 ± 2.0 na na incision or in the subcostal region, an additional 3 mm grasper wen, 2013 ra na taiwan lessra a 3-cm skin incision below the 3 ports 27 / 54 48.79 ± 1.69 / 49.62 ± 2.39 24.55 ± 6.37 / 25.20 ± 4.43 14 / 13 32 / 22 tip of the 12th rib table 1. characteristics of included studies. abbreviations: ra, retrospective analysis; less, laparoendoscopic single-site; cl, conventional laparoscopic; lessa, laparoendoscopic single-site adrenalectomy; lessae or less-ara or less ra, laparoendoscopic single-site retroperitoneoscopic adrenalectomy; lamp, laparoscopic adrenalectomy through mono port; sila, single-incision laparoscopic adrenalectomy; sara, single-access retroperitoneoscopic adrenalectomies; cla, conventional laparoscopic adrenalectomy; bmi, body mass index; m, male; f, female; na, not available; r, right; l, left. all values are number or mean ± sd or mean. laparoendoscopic single-site adrenalectomy-wu et al. patients treated with lessa and 449 patients treated with cla. the sample size of the trials ranged from 9 to 140. characteristics of the patients are summarized in table 1. for lessa, a commercially available multi-channel port device was used.(15-18,24,25) in one study, a home-made single-port device was inserted at the umbilicus through a 2-cm incision: a single-layered sterile surgical glove was then used.(13,23) one study used a single glove or commercially available multi-channel port. (14) the umbilicus or subcostal incision represented the most used access site. for cla, three or four ports were made. both transperitoneal and retroperitoneal access approaches were reported. histopathological data of the adrenal adenomas are summarized in table 2. outcome measurements operative time all included studies reported operative time;(12-18,23-25) three were not reported as means and standard deviations and were excluded.(12,14,15) subgroup analyses showed no significant difference in the retroperitoneal (re) group (95% ci: -13.18 to 17.85, wmd: 2.33, p = .768) or the transperitoneal (tr) group (p = .148). the overall pooled estimates also support this finding between the two groups (95% ci: -2.94 to 13.92, wmd: 5.49, p = .202; i² = 64.1%, p = .010 for heterogeneity; figure 3a). table 2. histopathological data of the adrenal adenomas. first author no. lessa / cla fa nfa cs ph hy apa csd metastasis ac myelolipoma mh pcs others jeong, 2009 9 / 17 na 3 / 6 1 / 2 5 / 9 na na na na na na na na 1 / 0 walz, 2010 47 / 47 na na 6 / 6 15 / 15 na na 20 / 20 na na na na na 6 / 6 tunca, 2012 22 / 74 na 3 / 17 7 / 18 8 / 26 na na na 0 / 3 0 / 3 na na na 4 / 7 lin, 2012 21 / 28 11/19 7 / 4 na 3 / 5 na na na na na na na na na wang, 2012 13 / 26 na 6 / 7 2 / 6 0 / 3 5 / 10 na na na na na na na na shi, 2011 19 / 38 na 5 / 7 4 / 11 3 / 5 7 / 15 na na na na na na na na kwak, 2011 12 / 10 3/5 na 3 / 1 2 / 0 1 / 4 na na 0 / 1 na 1 / 0 0 / 1 na na hirasawa 2014 70 / 140 na na 6 / 36 15 / 24 na 35 / 67 na na na na na na 14 / 13 hora, 2014 15 / 15 10/12 na na 3 / 2 na na na 2 / 1 na na na na na wen, 2013 27 / 54 na 11 / 12 4 / 7 0 / 1 na na 10 / 30 0 / 1 na na na na 2 / 3 abbreviations: no., numbers; fa, functional adenoma; nfa, nonfunctioning adenoma; cs, cushing’s syndrome; apa, aldosterone-producing adenoma; ph, pheochromocytoma; csd, conn’s syndrome; ac, adrenal cyst; hy, hyperaldosteronism; mh, medullary hyperplasia; pcs, pre-cushing’s syndrome; na, not available. figure 1. flow diagram of the literature search. figure 2. quality assessment of included studies with the newcastle-ottawa scale. laparoendoscopic single-site adrenalectomy-wu et al. review 2593 vol 13 no 02 march-april 2016 2594 length of hospital stay six studies reported the length of hospital stay.(13,1618,23,24) subgroup analyses showed significant differences in the re group (95% ci: -1.50 to -0.34, wmd: -0.92, p = .002); however, there was no significant difference in the tr group (95% ci: -1.59 to 0.35, wmd: 0.62, p = .221) the overall pooled estimates showed significant difference between the two groups (95% ci: -1.27 to -0.36, wmd: -0.81, p < .001; i² = 59.0%, p = .032 for heterogeneity; figure 3b). ebl five studies reported ebl.(16,18,23-25) subgroup analyses showed no significant difference in the re group (95% ci: -4.33 to -37.69, wmd: 16.68, p = .120) or the tr group (p = .341). the overall pooled estimates also supported this finding between the two groups (95% ci: -10.68 to 24.19, wmd: 6.76, p = .448; i² = 0.0%, p = .435 for heterogeneity; figure 3c). resumption of oral intake seven studies reported resumption of oral intake(12-15,18,23,24) of which four included standard mean difference values.(13,18,23,24) subgroup analyses showed no significant difference in the re group (95% ci: -0.05 to 0.05, wmd: -0.00, p = .867); however, there was a significant difference in the tr group (95% ci: -0.78 to -0.32, wmd: -0.55, p < .001). the overall pooled estimates showed no significant difference between the two groups (95% ci: -0.47 to 0.12, wmd: -0.17, p = .240; i² = 86.3 %, p < .001 for heterogeneity). postoperative pain scores two studies were available for analysis.(16,18) subgroup analyses showed significant differences in the re group (95% ci: -1.51 to -0.95, wmd: -1.23 p < .001) and the tr group (p < .001). the overall pooled estimates also supported this finding between the two groups (95% ci: -1.51 to -0.99, wmd: -1.25, p < .001; i² = 0.0%, p = .663 for heterogeneity; figure 3d). doses of analgesic required two studies reported the doses of analgesic required. (23,24) subgroup analyses showed no significant difference in the re group (95% ci: -0.41 to 0.41, wmd: 0.00, p = 1.000) or the tr group (p = .098). the overall pooled estimates also supported this finding between the two groups (95% ci: -0.44 to 0.10, wmd: -0,17, p = .210; i² = 14.5%, p = .279 for heterogeneity). pain medication requirement three studies including 183 patients reported pain medication requirements.(15,17,18) there were 41 patients who needed pain medication (51.90%) in the lessa group and 57 (54.81%) in the cla group. subgroup analyses showed no significant difference in the re group (95% ci: 0.65 to 2.83, wmd: 1.36, p = .414) or the tr group figure 3. a) forest plot of the comparison of lessa versus cla in terms of operative time; b) forest plot of the comparison of lessa vs. cla in terms of length of hospital stay; c) forest plot of the comparison of lessa vs. cla in terms of estimated blood loss (ebl); d) forest plot of the comparison of lessa vs. cla in terms of postoperative pain scores. abbreviations: lessa, laparoendoscopic single-site adrenalectomy; cla, conventional laparoscopic adrenalectomy; ebl, estimated blood loss. figure 4. a) forest plot of the comparison of lessa vs. cla in terms of perioperative complications; b) forest plot of the comparison of lessa vs. cla in terms of conversion; c) forest plot of the comparison of lessa vs. cla in terms of transfusion. abbreviations: lessa, laparoendoscopic single-site adrenalectomy; cla, conventional laparoscopic adrenalectomy. laparoendoscopic single-site adrenalectomy-wu et al. (p = .801). the overall pooled estimates also supported this finding between the two groups (95% ci: 0.16 to 4.88, or: 0.87, p = .875; i² = 72.2%, p = .027 for heterogeneity). perioperative complications the incidence of perioperative complication was reported in seven studies.(12-15,17,18,24) there were 13 complications (7.34%) in the lessa group and 22 (6.54%) in the cla group. subgroup analyses showed no significant difference in the re group (95% ci: 0.28 to 3.44, wmd: 0.99, p = .985) or the tr (p = .578). the overall pooled estimates also supported this finding (95% ci: 0.58 to 2.39, or: 1.17, p = .659; i² = 0.0%, p = .719 for heterogeneity; figure 4a). conversion three studies including 330 patients reported conversion events.(12,17,24) the conversion rate was 3.97% (5/126 patients) for lessa compared with 0.98% (2/202 patients) for cla. subgroup analyses showed no significant difference in the re group (95% ci: 0.51 to 187.87, wmd: 9.83 p = .129) or the tr group (p = .882). the overall pooled estimates also supported this finding between the two groups (95% ci: 0.70 to 13.55, or: 3.07, p = .139; i² = 0.0%, p = .458 for heterogeneity; figure 4b). transfusion three studies including 275 patients reported transfusion in the tr group only.(12,18,24) there was one (1.09%) transfusion in the lessa group and three (1.64%) in the cla group; a pooled analysis showed no significant difference (95% ci: 0.17 to 5.43, or: 0.96, p = .964; i² = 0.0%, p = .808 for heterogeneity) between the two groups (figure 4c). risk of publication bias a funnel plot of the studies included in our primary outcome of perioperative complications was prepared to explore publication bias. the scatter-distributed shapes of the funnel plots for operative time and perioperative complications were symmetrical, indicating no evidence of publication bias among the included studies (figures 5a and 5b; other data not shown). sensitivity analysis sensitivity analysis was conducted to assess the effect of study quality. a single study involved in the meta-analysis was deleted each time to reflect the influence of each individual data set on the pooled ors. the corresponding pooled ors were essentially unaltered, indicating that our results were statistically sound (figures 5c and 5d; other data not shown). discussion this meta-analysis of 10 retrospective comparative studies including 704 patients showed that lessa had similar outcomes to those of cla, without significant differences in terms of operative time, ebl, doses of analgesic required, perioperative complications, conversion, transfusion, resumption of oral intake, or pain medication requirement. lessa was also associated with reduced postoperative pain and a shorter length of hospital stay, despite controversies with respect to operative time and length of hospital stay in previous meta-analyses. indeed, previous meta-analyses demonstrated a significantly increased operating time for sils.(21,22) those results were inconsistent with the results of this analysis, which concluded that there was no difference between the two groups. in our meta-analysis, five studies reported a prolonged operating time in the lessa group,(13,17,18,24,25) but two showed the opposite.(16,23) a sensitivity analysis of the pooled studies showed a consistent result. however, different sides of surgery and the various designs of ports (transperitoneal and retroperitoneal) may have great impacts on operative time. only one study reported operative time on different sides,(25) so no subgroup analysis on different sides could be conducted. also, an additional trocar was required figure 5. a) funnel plot for operative time; b) funnel plot for perioperative complications; c) sensitivity analysis for operative time; d) sensitivity analysis for perioperative complications. laparoendoscopic single-site adrenalectomy-wu et al. review 2595 vol 13 no 02 march-april 2016 2596 for liver retraction in three studies,(16,18,25) which may have increased operative time. in addition, this difference in operative time may be due to the learning curve; unfortunately, only one study explicitly described the previous experience of the operating surgeons,(24) so a subgroup analysis could not be perform on this issue. furthermore, the sample size in each study was different. all these factors may have contributed to heterogeneity and influenced the results. thus, future rcts are needed to confirm the finding of this study. considering the similar operative times, which is a surprising result, confirming a clear learning-curve effect in the lessa treatment group, and the ability of surgeons in using the new devices for lessa, will likely reduce the technical difficulties.(35) postoperative pain is another important endpoint. less pain was expected in the lessa group for reduced trocars. however, the size of the fascial incision needed to accommodate the single-incision port may potentially increase pain, although there was no difference in the numbers of patients demanding pain medication and analgesics between the groups. only two studies provided adequate data on postoperative pain,(16,18) providing comparative evidence of limited importance. this observation should be regarded with caution because different or unclear postoperative analgesic protocols between groups may have led to bias in postoperative pain score assessment. additionally, a lack of evaluator and patient blinding may have influenced the results. the shorter length of hospital stay is an apparent advantage of lessa over cla, in contrast to a previous meta-analysis.(22) the result is encouraging, because it may reflect faster convalescence and less postoperative pain. in turn, this could decrease hospital costs and may be an important factor for recovery and an earlier return to work. only one study reported that patients could return to full activities earlier in the lessa group; more randomized trials are needed to confirm this.(18) the pooled studies showed no difference in ebl between the two groups.(16,18,23-25) four studies reported the resumption of oral intake, which showed no significant between the groups, although heterogeneity was observed. a study by wen and colleagues reported a shorter period before resumption of oral intake in the lessa group;(23) excluding this study from the analysis did not yield different results. surgical safety was evaluated in terms of perioperative complications, conversion, and transfusion. the complication rate is broadly considered as a surrogate for surgical competence. lessa is technically more difficult to perform and may be associated with increased complication rates. of the included eight studies, five showed a higher perioperative complication rate in lessa group,(12,13,15,18,25) although different approaches may have different impacts on perioperative complications. when we divided the surgeries into two approaches, transperitoneal and retroperitoneal, subgroup analyses showed no significant difference between the groups (p = .659), similar to the previous meta-analyses.(21,22) however, given the different sample sizes in each included study, this result should be viewed with caution; reduced triangulation, fog evacuation, clashing of instruments, and more complex procedures in the lessa group(36) – and the longer operative time – may also increase perioperative complications. the follow-up was insufficient in most of these studies for estimating late complications. future randomized trials with larger samples and longer-term follow-up are needed to evaluate the rate of complications accurately. conversion is considered to be a significant factor when counseling patients on the potential risks/benefits of any specific procedure.(37) technological difficulties may also be associated with conversion. the increasing conversion rate has considerably limited the use of lessa, although in the present study, the conversion rate was found to be similar for both techniques. bleeding requiring transfusion was reported in three studies; the pooled studies showed no difference in transfusion between the two techniques.(12,18,24) considering the perioperative complications, high-quality and double-blind rcts with long-term follow-up are required to assess the safety of the new technique. a previous meta-analysis demonstrated comparable cosmetic satisfaction between the two groups.(22) however, a recent study reported higher cosmetic satisfaction among young patients and female patients in the lessa group.(31) of the included studies, only one reported the outcomes as means and standard deviation,(18) so a meta-analysis of cosmetic satisfaction scores was not conducted. in the included studies, there was no significant difference between the lessa and cla groups in terms of basic data such as body mass index (bmi), age, gender, or tumor size, suggesting that our analysis may be more reliable than those of the former studies by reducing the influence of these confounding factors on the results. nevertheless, our present meta-analysis had several potential limitations. first, all included studies were retrospective analyses and most had a small sample size. second, a cost analysis to determine whether this new technique is more expensive could not be conducted due to insufficient data from the published relaparoendoscopic single-site adrenalectomy-wu et al. ports. third, heterogeneity was found in operative time, length of hospital stay, resumption of oral intake, and pain medication requirement, which may be attributable to matching criteria, operative techniques, single-port access devices, and different approaches; further studies are required to explore sources of heterogeneity. finally, the follow-up periods in most reports were insufficient; the studies analyzed here provided relatively short-term findings, so long-term outcomes of lessa compared with cla are required to confirm the safety and feasibility of this new technique. conclusions in conclusion, based on current evidence, lessa appear to be a safe and feasible alternative to cla with a shorter length of hospital stay and reduced postoperative pain scores in certain patients. we await high-quality, double-blind rcts with longer-term follow-up to confirm and update the findings of this analysis. future studies should focus particularly on rates of technical failure, cosmesis, and cost. acknowledgments shike wu, hao lai, and jiangyang zhao contributed equally to this work and should be considered as cofirst authors. conflict of interest none declared. references 1. gagner m, lacroix a, bolte e. laparoscopic adrenalectomy in cushing's syndrome and pheochromocytoma. n engl j med. 1992;327:1033. 2. smith cd, weber cj, amerson jr. laparoscopic adrenalectomy: new gold standard. world j surg. 1999;23:389-96. 3. arslan m, akin y, ates m, et al. changing surgical approaches for laparoscopic adrenalectomy: single-surgeon data of a 6-year experience. urol int. 2013;91:304-9. 4. bonjer hj, lange jf, kazemier g, de herder ww, steyerberg ew, bruining ha. comparison of three techniques for adrenalectomy. br j surg. 1997;84:679-82. 5. guazzoni g, montorsi f, bocciardi, a et al. transperitoneal laparoscopic versus open adrenalectomy for benign hyperfunctioning adrenal tumors: a comparative study. j urol. 1995;153:1597-600. 6. schell sr, talamini ma, udelsman r. laparoscopic adrenalectomy for nonmalignant disease: improved safety, morbidity, and costeffectiveness. surg endosc. 1999;13:30-4. 7. winfield hn, hamilton bd, bravo el, novick ac. laparoscopic adrenalectomy: the preferred choice? a comparison to open adrenalectomy. j urol. 1998;160:325-9. 8. hirano d, minei s, yamaguchi k, et al. retroperitoneoscopic adrenalectomy for adrenal tumors via a single large port. j endourol. 2005;19:788-92. 9. cindolo l, gidaro s, tamburro fr, schips l. laparo-endoscopic single-site left transperitoneal adrenalectomy. eur urol. 2010;57:911-4. 10. cindolo l, gidaro s, neri f, tamburro fr, schips l. assessing feasibility and safety of laparoendoscopic single-site surgery adrenalectomy: initial experience. j endourol. 2010;24:977-80. 11. inoue s, ikeda k, kajiwara m, teishima j, matsubara a. laparoendoscopic singlesite adrenalectomy sans transumbilical approach: initial experience in japan. urol j. 2014;11:1772-6. 12. jeong bc, park yh, han dh, kim hh. laparoendoscopic single-site and conventional laparoscopic adrenalectomy: a matched casecontrol study. j endourol. 2009;23:1957-60. 13. kwak hn, kim jh, yun js, et al. conventional laparoscopic adrenalectomy versus laparoscopic adrenalectomy through mono port. surg laparosc endosc percutan tech. 2011;21:439-42. 14. lin vc, tsai yc, chung sd, et al. a comparative study of multiport versus laparoendoscopic single-site adrenalectomy for benign adrenal tumors. surg endosc. 2012;26:1135-9. 15. shi tp, zhang x, ma x et al. laparoendosco pic single-site retroperitoneoscopic adrenalectomy: a matched-pair comparison with the gold standard. surg endosc. 2011;25:211724. 16. tunca f, senyurek yg, terzioglu t, iscan y, tezelman s. single-incision laparoscopic adrenalectomy. surg endosc. 2012;26:36-40. 17. walz mk, groeben h, alesina pf. single-access retroperitoneoscopic adrenalectomy (sara) versus conventional retroperitoneoscopic adrenalectomy (cora): a case-control study. world j surg. 2010;34:1386-90. 18. wang l, liu b, wu z, et al. comparison of single-surgeon series of transperitoneal laparoendoscopic singlesite surgery and standard laparoscopic adrenalectomy. urology. 2012;79:577-83. 19. ishida m, miyajima a, takeda t, et al. technical difficulties of transumbilical laparoendoscopic single-site adrenalectomy: comparison with conventional laparoscopic adrenalectomy. world j urol. 2013;31:199203. 20. vidal ó, astudillo e, valentini m, ginestà c, garcía-valdecasas jc, fernandez-cruz l. laparoendoscopic single-site adrenalectomy-wu et al. review 2597 vol 13 no 02 march-april 2016 2598 single-incision transperitoneal laparoscopic left adrenalectomy. world j surg. 2012;36:1395-9. 21. hu q, gou y, sun c, xu k, xia g, ding q. a systematic review and meta-analysis of current evidence comparing laparoendoscopic single-site adrenalectomy and conventional laparoscopic adrenalectomy. j endourol. 2013;27:676-83. 22. wang l, wu z, li m, cai c, liu b, yang q, sun y. laparoendoscopic singlesite adrenalectomy versus conventional laparoscopic surgery: a systematic review and meta-analysis of observational studies. j endourol. 2013;27:743-50. 23. wen sc, yeh hc, wu wj, chou yh, huang ch, li cc. laparoendoscopic singlesite retroperitoneoscopic adrenalectomy versus conventional retroperitoneoscopic adrenalectomy: initial experience by the same laparoscopic surgeon. urol int. 2013;91:297303. 24. hirasawa y, miyajima a, hattori s, et al. laparoendoscopic single-site adrenalectomy versusconventional laparoscopic adrenalecto my: a comparison of surgical outcomes and an analysis of a single surgeon's learning curve. surg endosc. 2014;28:2911-9. 25. hora m, urge t, stransky p, et al. laparoendoscopic single-site surgery adrenalectomy own experience and matched case-control study with standard laparoscopic adrenalectomy. wideochir inne tech malo inwazyjne. 2014;9:596-602. 26. oxford centre for evidence-based medicine (ocebm) levels of evidence working group, ‘‘the oxford 2011 levels of evidence,’’ oxford center for evidence-based medicine. available at: http://www.cebm.net/index. aspx?o=5653.accessed: march 3, 2013. 27. wells ga, shea b, o’connell d, et al. the newcastle-ottawa scale (nos) for assessing the quality if nonrandomised studiesin metaanalyses. available at: http://www.ohri.ca/ programs/clinical_epidemiology/oxford.asp accessed: march 3, 2013. 28. miyajima a, maeda t, hasegawa m, et al. transumbilical laparo-endoscopic single site surgery for adrenal cortical adenoma inducing primary aldosteronism: initial experience. bmc res notes. 2011;4:364. 29. hattori s, miyajima a, maeda t, et al. does laparoendoscopic single-site adrenalectomy increase surgical risk in patients with pheochromocytoma? surg endosc. 2013;27:593-8. 30. hasegawa m, miyajima a, jinzaki m, et al. visceral fat is correlated with prolonged operative time in laparoendoscopic singlesite adrenalectomy and laparoscopic adrenalectomy. urology. 2013;82:1312-8. 31. inoue s, ikeda k, kobayashi k, kajiwara m, teishima j, matsubara a. patientreported satisfaction and cosmesis outcomes following laparoscopic adrenalectomy: laparoendoscopic single-site adrenalectomy vs. conventional laparoscopic adrenalectomy. can urol assoc j. 2014;8:e20-5. 32. vidal o, astudillo e, valentini m, et al. single-port laparoscopic left adrenalectomy (sils): 3 years' experience of a single institution. surg laparosc endosc percutan tech. 2014;24:440-3. 33. yuan x, wang d, zhang x, cao x, bai t. retroperitoneal laparoendoscopic singlesite adrenalectomy for pheochromocytoma: our single center experiences. j endourol. 2014;28:178-83. 34. hirano d, hasegawa r, igarashi t, et al. laparoscopic adrenalectomy for adrenal tumors: a 21-year single-institution experience. asian j surg. 2015;38:79-84. 35. stamatakis l, mercado ma, choi jm, et al. comparison of laparoendoscopic single site (less) and conventional laparoscopic donor nephrectomy at a single institution. bju int. 2013;112:198-206. 36. kaouk jh, autorino r, kim fj, et al. laparoendoscopic single-site surgery in urology: worldwide multi-institutional analysis of 1076 cases. eur urol. 2011;60:9981005. 37. richstone l, seideman c, baldinger l, et al. conversion during laparoscopic surgery: frequency, indications and risk factors. j urol. 2008;180:855-9. laparoendoscopic single-site adrenalectomy-wu et al. clinical pathology case genital desmoplastic fibroblastoma (collagenous fibroma) department of urology, pathology, plastic surgery daegu catholic university medical center, daegu, republic of korea. corresponding author: jae shin park, md department of urology, daegu catholic university medical center, daegu, republic of korea. tel: +82 53 6504662 e-mail: jspark@cu.ac.kr received january 2014 accepted june 2014 jae shin park, kwon ho bae, hoon kyu oh, jae bok park, dae hwan park keywords: scrotum; genital neoplasms, male; diagnosis; fibroma; desmoplastic. introduction desmoplastic fibroblastomas (dfs) are rare fibrous soft tissue tumors that usually arise in subcuta-neous tissue or skeletal muscle in a variety of anatomical sites. this was first described by evans in 1995 and was classified as a distinctive form of benign fibrous soft tumor.(1) in 1996 the lesion was renamed as a “ collagenous fibroma” by nielsen and colleagues.(2) the arm or the shoulders are the most frequent sites of involvement. they have also been described in the neck, tongue, lacrimal gland and palate.(3-7) to the best of our knowledge, we report the first case of df (collagenous fibroma) occurring in genital area. case report a 71-year old man presented with a giant multiple globular mass in the scrotum which has grown slowly for figure 1. the 20 × 15 cm sized, homogeneous pearl-grey colored, firm globular mass in the scrotum has extended to adjacent penis and left inner thigh. penile glans was not appreciable. figure 2. computed tomography scan showed a 15 × 9 cm sized soft tissue mass in the scrotum (yellow arrow) and penis which has extended into the fascial area of left inner thigh (white arrows). penile glans (red arrow) is trapped in within the mass. 1849 clinical pathology case urology journal vol. 11 no. 04 july august 2014 1850 genital desmoplastic fibroblastoma-park et al discussion dfs also known as collagenous fibromas are benign soft tissue paucicellular tumors. they are usually well circumscribed and are composed of spindle to stellate shaped fibroblasts dispersed in a fibromyxoid or densely fibrous background stroma with low mitotic activity. so, miettinen and fetsch recommended the designation stellate cell fibroma. immunohistochemical and ultrastructural studies show that the tumor cells are predominantly fibroblastic in nature and typically positive for vimentin.(3) there is often focal reactivity for muscle actins (hhf-35) and α-smooth muscle actin.(3) scattered cd68-positive histiocytes and mast cells may be present, but the tumor cells are negative. there is no documented immunoreactivity for cd34, s-100 protein, desmin, or epithelial membrane antigen (ema). the lesion typically presents with a long history of a painless, slowly growing well-circumscribed subcutaneous mass occurring predominantly in males, with a median age of 50 years.(1,2) since 1995, approximately 94 cases of df have been reported in the literature with the largest case series of 63 patients being published by miettinen and fetsch.(3) it appears in a variety of peripheral sites with the most common location being the arm, shoulder, lower limb, back, forearm, hands, feet, neck and even in the tongue, lacrimal gland , palate and parotid gland.(3-8) conclusion in conclusion, the present case is the first description of a df that has involved the genital area. the clinical, gross and histologic features are those of a benign neoplasm. we highlight this peculiar lesion and wish to increase awareness of these rare lesions among urologists and pathologists alike. conflict of interest none declared. references 1. evans hl. desmoplastic fibroblastoma. a report of seven cases. am j surg pathol. 1995;19:1077-81. 2. nielson gp, o’connel jx, dickersin gr, rosenberg ae. collagenous fibroma (desmoplastic fibroblastoma): a report of seven cases. mod pathol. 1996;9:781-5. 3. miettinen m, fetsch jf. collagenous fibroma (desmoplastic fibroblasto ma): a clinicopathologic study of 63 cases of a distinctive soft tissue lesion with stellate-shaped fibroblasts. hum pathol. 1998;29:676-82. 4. watanabe h, ishida y, nagashima k, makino t, norisugi o, shimizu t. desmoplastic fibroblastoma (collagenous fibroma). j dermatol. 2008;35:93-7. 5. nonaka cf, de carvalho mv, de moraes m, de medeiros am, de fre itas ar. desmoplastic fibroblastoma (collagenous fibroma) of the tongue. j cutan pathol. 2010;37:911-4. 6. ahn m, osipov v, harris gj. collagenous fibroma (desmoplastic 4 years. on physical examination, a giant multiple globular mass in the scrotum has extended to adjacent penis and left inner thigh. penile glans was not appreciable (figure 1). he had no history of genital surgery. a pelvic computed tomography (ct) scan showed a soft tissue mass in the scrotum and penis which has extended into the fascial area of left inner thigh (figure 2). the patient underwent total excision of the mass in the scrotum, penis and left inner thigh. skin defect in penile shaft and scrotum were managed with penile skin graft and scrotoplasty (figure 3). on pathology, the resected penile and scrotal masses measures 17.5 × 11 cm and 12 × 8 cm, respectively, with vaguely circumscribed subcutaneous lesion with convoluted skin surface. the cut surface was whitish grey in color without hemorrhage or necrosis. microscopically, the mass was paucicellular and consists of widely spaced bland spindleto stellate-shaped fibroblasts embedded in a collagenous and myxocollagenous stroma (figure 4). cellular atypia or abnormal mitosis was absent. the immunohistochemical stains showed vimentin positive in stellated fibroblast, but, desmin, smooth muscle actin, s-100 protein, cd34, cd68, factor-8, myoglobin and neurofilament were negative. tumor recurrence was not observed for 12 months. figure 3. postoperative finding after excision of mass. penile glans is exposed. figure 4. microscopically, the tumor has been composed of hypocellular spindle to stellate shaped fibroblasts and myofibroblasts embedded in a prominent collagenous stroma (white arrows) (hematoxylin and eosin stains × 100). fibroblastoma) of the lacrimal gland. ophthalmic plast reconstr surg. 2009;25:250-2. 7. mesquita ra, okuda e, jorge wa, de arau´jo vc. collagenous fibroma (desmoplastic fibroblastoma) of the palate: a case report. oral surg oral med oral pathol oral radiol endod. 2001;91:80-4. 8. vinayak nagaraja, hedley g. coleman,gary j. morgan. desmoplastic fibroblastoma presenting as a parotid tumour: a case report and re view of the literature. head neck pathol. 2013;7:285-90. 1851 clinical pathology case urology journal unrc/iua 86 pediatric urology evaluation of meatal stenosis following neonatal circumcision hossein mahmoudi* department of surgery, naghavi hospital, kashan university of medical sciences, kashan, iran abstract introduction: meatal stenosis almost always develops following neonatal circumcision, and it usually does not become apparent until the child is toilet trained. the present study was conducted to determine the value of diagnostic ultrasonography in patients with meatal stenosis. materials and methods: a descriptive study was performed on 120 patients with meatal stenosis, referred to naghavi hospital, kashan, iran, from july 2000 to march 2002. symptoms and findings on physical examination were recorded for every patient, ultrasonography of the urinary tract, and urinalysis and urine culture were also performed. results: mean age of the patients was 2.5 years (range, 3 months to 6 years). the common symptoms were dysuria (35%), decreased urine caliber (33.3%), and bloody spotting (15%), while 26.6% of the patients were asymptomatic. paraclinical findings were microscopic hematuria (17.5%), bacteriuria (1.6%), and ureteral duplication (0.8%). no case of obstructive uropathy was detected by ultrasonography. conclusion: meatal stenosis rarely causes obstructive uropathy. hence, urinary tract ultrasonography is rarely necessary, unless symptoms persist after meatotomy. key words: meatal stenosis, circumcision, paraclinical evaluation vol. 2, no. 2, 86-88 spring 2005 printed in iran introduction meatal stenosis in males often develops following neonatal circumcision.(1) its prevalence is unknown.(2) some authors believe that fewer than 0.2% of circumcised patients acquire this complication.(3) several factors contribute to meatal stenosis such as severe balanitis following preputial detachment during circumcision,(1) frenular artery ligation and subsequent ischemia,(1,2) meatitis due to physical trauma to an uncovered glans,(2) and chemical dermatitis caused by urine.(4,5) meatal stenosis remains asymptomatic until urinary control is achieved and rarely leads to obstructive uropathy.(1) given the fact that the frequency of circumcision in our society is high, and that many patients with meatal stenosis come to urologic clinics, it is recommended that ultrasonography and physical examination be performed and a history be obtained.(1) the objective of this study was to determine how urinary tract ultrasonography helps in patient follow-up. materials and methods this was a descriptive study on 120 children with urinary problems or other complains (such as hernia, nocturia, hydrocele, etc), from july 2000 to march 2002, who were diagnosed on physical examination as having meatal stenosis. received january 2004 accepted february 2005 *corresponding author: department of urology, naghavi hospital, shaheed rajaee st., kashan, iran. tel: ++98 913 117 4182 e-mail: homahmoodi@yahoo.com mahmoudi 87 the criteria for diagnosis of meatal stenosis were based on the distortion of meatus from an ellipsoid to a pinpoint shape, and also an inability to pass a 6 f catheter into the urethra. only cases with stenosis secondary to circumcision were included; those secondary to surgery or hypospadias repair were excluded. patients' demographic characteristics and signs and symptoms, including decreased urinary caliber and dysuria, were recorded. urinalysis, urine culture, and urinary tract ultrasonography were done in all patients. data were collected and analyzed. results the mean age of the patients was 2.5 years (range 3 months to 6 years). the most prevalent age was 1 to 2 years old (figure 1). the most common symptoms were discomfort on voiding (dysuria) in 42 boys (35%), decreased urinary caliber and urinary deviation in 40 (33.3%), and blood in meatus in 18 (15%). thirtytwo (26.6%) of the patients were asymptomatic. twelve patients (10%) had more than one of the previously mentioned symptoms (figure 2). the paraclinical findings were microscopic hematuria in 21 patients (17.5%) and bacteriuria in 2 (1.6%). on sonography, only 1 case of ureteral duplication was seen, and no cases of obstructive uropathy were present. discussion in this descriptive study that was done on 120 children with meatal stenosis, the most prevalent symptoms were dysuria and narrowing of the urinary stream or urinary deviation (each in about one third of the patients). in another study by persad and coworkers, done on 12 cases of meatal stenosis following circumcision, the main symptoms were penile pain at the initiation of micturition (12 of 12); narrow, high speed stream (8 of 12); and the need to sit or stand back from the toilet bowl to urinate (6 of 12). traumatic meatitis of the unprotected postcircumcision urethral meatus and/or meatal ischemia following damage to the frenular artery at circumcision were possible causes suggested for meatal stenosis.(2) upadhyay and colleagues reported their 12 years' experience with 50 cases. the most common complaint among 34 symptomatic patients was decreased urinary caliber.(6) in another study by cartwright and colleagues, dysuria was reported as the most common symptom, which was consistent with our results.(7) furthermore, upadhyay and colleagues noticed that 32% of the patients (n = 50) had the diagnosis of meatal stenosis made incidentally.(6) this rate is similar to that of our study (26.6%). also, the median age at presentation of symptomatic children was 48 months (range 3 months to 13 years) following circumcision in their series; whereas the most prevalent age group in our study was 1 to 2 years. therefore, it can be concluded that symptomatic presentation of meatal stenosis after neonatal circumcision may be very late. ultrasonography was done in all the cases in our study, and no case of obstructive uropathy was found. a study on 280 children with meatal stenosis who were investigated by radiology revealed that only 1% had renal anomaly and no case of obstructive uropathy was reported.(1) none of the available literature has reported obstructive uropathy secondary to meatal stenosis, and while some recommend doing urinalysis and urinary tract ultrasonography,(1,5) others do not.(2,8) the laboratory and radiologic investigations in this study were not accomplished by one person, and the patients were not followed for a long time; however, it was the first study in this region, and the number of cases (compared with other studies) is considerable. many neonatal circumcisions are performed in our region; however, persons cannot always afford to pay for paraclinical fees for the follow-up. accordingly, performing ultrasonography may not be necessary in every patient, and it is suggested that patients be followed after meatotomy, and that radiologic fig. 1. age distribution of patients with meatal stenosis at presentation 0 5 10 15 20 25 30 <1 1 to 2 2 to 3 3 to 4 4 to 5 5 to 6 patients' age group p e rc e n ta g e meatal stenosis following neonatal circumcision88 studies be performed in cases of symptom continuation. conclusion the most common symptom of meatal stenosis is dysuria, which is mostly seen 1 year after neonatal circumcision. it should be noted, however, that many patients may be asymptomatic. obstructive uropathy is a rare complication; we did not detect any cases by ultrasonography in a relatively large sample. hence, performing ultrasonography may not be necessary in every patient. we suggest, therefore, that patients be followed after meatotomy, and that radiologic studies be performed in cases of symptom continuation. references 1. elder js. abnormalities of the genitalia in boys and their surgical management. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 2387-9. 2. persad r, sharma s, mctavish j, imber c, mouriquand pd. clinical presentation and pathophysiology of meatal stenosis following circumcision. br j urol. 1995 jan;75(1):91-3. 3. american academy of pediatrics. circumcision policy statement. american academy of pediatrics. task force on circumcision. pediatrics. 1999;103:686-93. 4. mcaninch jw. disorders of penis and male urethra. in: tanagho ea, mcaninch jw, editors. smith's general urology. 15th ed. new york (usa): lange medical books/mcgraw-hill; 2000. p. 661-75. 5. anderson je, anderson ka. what to tell parents about circumcision. roger knapp medical information. available from: http://www.rogerknapp.com/medical/circum.htm 6. upadhyay v, hammodat hm, pease pw. post circumcision meatal stenosis: 12 years' experience. n z med j. 1998;111:57-8. 7. van howe rs. meatal stenosis with bladder distention. circumcision [serial on the internet]. 1997;2(1). available from: http://faculty.washington.edu/gcd/circumcision/v2n 1.html 8. cartwright pc, snow bw, mcnees dc. urethral meatotomy in the office using topical emla cream for anesthesia. j urol. 1996;156:857-8. fig. 2. symptoms of meatal stenosis at presentation among 120 cases 35 33.3 26.6 15 10 0 5 10 15 20 25 30 35 40 dysuria urinary stream narrowing asymptomatic bloody spot complex of symptoms symptoms of meatal stenosis p e rc e n ta g e 133 urology journal unrc/iua vol. 1, no. 3, 133-147 summer 2004 printed in iran erectile dysfunction: clinical guidelines (1) safarinejad mr, hosseini sy urology/nephrology research center, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: according to a survey, the massachusetts male aging study, 52% of men beyond 40 years of age may have some degrees of erectile failure, and it is projected to affect 322 million men worldwide by 2025. we present a framework for the evaluation, treatment, and follow-up of the male patient who presents with erectile dysfunction. materials and methods: a comprehensive review of the literature was conducted using the medline database for all articles from 1975 through 2004 on male sexual dysfunction and the most pertinent articles are discussed. results: remarkable progress has been made in the treatment of erectile dysfunction (ed). erectile dysfunction is a common condition associated with aging, chronic illnesses and various modifiable risk factors. erectile dysfunction can be due to vasculogenic, neurogenic, hormonal, and/or psychogenic factors as well as alterations in the nitric oxide/cyclic guanosine monophosphate pathway or other regulatory mechanisms. the number of consultations from new patients presenting with erectile dysfunction and resulting costs for health care systems are increasing. urologist should be the evaluating physician who supervises the surgical, medical, and hormonal treatment and who refers the patient, as necessary, to other members of the multidisciplinary team. conclusion: erectile dysfunction has a significant negative impact on quality of life. male sexual dysfunction, especially erectile dysfunction, necessitates a comprehensive medical and psychologic evaluation involving both partners. all possible risk factors should be outlined and corrected, when feasible. key words: impotence, pathology, treatment outcome, penile erection, physiology introduction erectile dysfunction (ed) is defined as persistent or recurrent inability, for at least three months duration, to achieve and/or maintain an erection sufficient for satisfactory sexual performance.(1) erectile dysfunction is currently the preferred term instead of 'impotence' as the latter term lack specificity and has negative connotations.(2) ed does not refer to penile curvatures, spontaneous or drug-induced prolonged erections, and painful erections. ed must also be distinguished from other sexual disorders such as premature ejaculation, anorgasmia, and lack of desire, although ed may occur concurrently with these other sexual disorders. sexuality, including erection, is a complex biopsychosocial process. the physician and collaborating specialists should possess broad knowledge about human sexuality. in cases of erectile dysfunction, problems may be lifelong or acquired, and global or situational. adequate attention to these details during the history will educate the often-uninformed patient regarding the complex nature of sexuality, and prepare him for understanding treatment and outcome realities. cultural, social, ethnic, religious, and national/regional perspectives will significantly influence patient and partner expectations, needs, and priorities. the rational selection of therapy by patients is only possible following appropriate education, including information about sexuality and all treatments for erectile dysfunction. erectile dysfunction: clinical guidelines (1) although not always possible on the first visit, every effort should be made to involve the patient's sexual partner early in the therapeutic process. ed compromises overall quality of life and is associated with depression, anxiety and the loss of self-esteem.(3) this paper focuses on various aspects of erectile dysfunction. it reviews the epidemiology, physiology, causes, and treatments that have been shown to be effective, along with potential new therapies for this disease. impact of erectile dysfunction erectile dysfunction is a significant and common medical problem affecting many men worldwide. cause-specific assessment and treatment of male sexual dysfunction will require recognition by the public and the medical community that erectile dysfunction is a part of overall male sexual dysfunction. erectile dysfunction is a very common medical condition leading to fear, loss of image and self-confidence, and depression. the multifactorial nature of erectile dysfunction, comprising both organic and psychologic aspects, may often require a multidisciplinary approach to its assessment and treatment. this review addresses these issues, not only as isolated health problems, but also in the context of social and individual perceptions and expectations. erectile dysfunction is often assumed to be a natural concomitant of the aging process, to be tolerated along with other conditions associated with aging. this assumption may not be entirely correct. for the elderly and for others, erectile dysfunction usually occurs as a consequence of specific illnesses or of medical treatment for certain illnesses. physicians, health educators, and patients and their families are sometimes unaware of this potential complication. whatever the causal factors may be, the embarrassment among patients and health care providers in discussing sexual issues becomes a barrier to pursuing treatment. erectile dysfunction can be effectively treated with a variety of methods. many patients and health care providers are unaware of these treatments, and the dysfunction thus often remains untreated, compounded by its psychological impact. concurrent with the increase in the availability of effective treatment methods, new diagnostic procedures have developed that may help in the selection of an effective, cause-specific treatment. this review was designed to address these issues and to define the state of the art.(4) epidemiology historically, the prevalence of erectile dysfunction has been difficult to estimate due to the fact that it is not life threatening, patients often do not seek treatment, and literature terminology for the condition has been confusing. in the united states, the massachusetts male aging study, reported in 1994, provided data on the prevalence of erectile dysfunction in a general population of men who were 40 to 70 years of age.(5) the combined prevalence of all degrees of erectile dysfunction was 52% (fig. 1,2). the category with the highest prevalence was moderate erectile dysfunction with a rate of 25%, followed by minimal erectile dysfunction at 17% and complete erectile dysfunction at 10%.(5) as many as 50% of men between ages 40 and 70 are affected by transient ed and inadequate erections.(6) the incidence of ed is projected to increase sharply over the next 25 years. it may also be a biobehavioral marker for diabetes mellitus, depression, and/or cardiovascular disorders.(7) data from studies of the prevalence of erectile dysfunction in the general population based on 134 fig. 1. prevalence of erectile dysfunction in a general population, the massachusetts male aging study fig. 2. prevalence of erectile dysfunction with age in the massachusetts male aging study erectile dysfunction: clinical guidelines (1) surveys of samples of men indicate that the results are dependent on the definition used for erectile dysfunction. the period of data retrieval and the population surveyed also affect prevalence. it has been suggested that by age 45 many men will have experienced erectile dysfunction, and the results of a recent projection suggest that as many as 322 million men worldwide will have it by 2025.(8) large differences are present in the prevalence of ed between countries. for example, the prevalence of moderate to severe ed at ages 40 to 70 years was 34.8% in the united states, according to the massachusetts male aging study (mmas),(5) 39% in japan, 21% in italy, 15% in brazil, and 16% in malaysia.(9) the prevalence of ed in iranian men is 18.8%.(10) although the populations studied and methods used varied considerably, the results of recent epidemiologic studies indicate that erectile dysfunction is a common problem that is associated with age and has a significant impact on quality of life. further studies on the worldwide prevalence of erectile dysfunction with respect to racial, ethnic, socioeconomic, and cultural variability are needed. to our knowledge, the reasons for such large differences are unclear, but they may reflect medical and psychological factors, particularly in the setting of possible racial, socioeconomic, cultural, and racial differences. erectile physiology a normal erectile mechanism entails an intact nervous system and adequate blood supply to the penis and a competent veno-occlusive mechanism of the penis. penile erection and detumescence are homodynamic events that are regulated by corporal smooth muscle relaxation and contraction respectively. in the flaccid state, a dominant sympathetic influence prevails, and the arteries and corporal smooth muscle are tonically contracted. there is a constant but minimal blood flow into the lacuna spaces (sponge-like penile tissue). after sexual stimulation, parasympathetic activity increases resulting in vasodilatory effects. this decreases the peripheral resistance bringing about tremendous increase in blood flow through the cavernous and helicine arteries. relaxation of corporal smooth muscle increases compliance and the expansion of the lacuna spaces compresses the outflow veins (subtunical veins) resulting in maintenance of erection. detumescence occurs when sympathetic activity (following orgasm) increases the tone of the helicine arteries and the corporal smooth muscle. normal erectile process begins with sexual stimulation in the brain (perception, desire, etc) from where impulses are transmitted via the spinal cord and the pelvic nerve to the penile corpus cavernosum (corporal smooth muscle). corporal smooth muscle contraction is modulated by the sympathetic nervous system via the release of norepinephrine and activation of postsynaptic a1-adrenergic receptors. on the other hand, relaxation is mediated by acetylcholine released by the parasympathetic nervous system and a second neurotransmitter, nitric oxide (no), or a nitric oxide releasing substance.(11) nitric oxide increases intracellular levels of cyclic guanosine monophosphate (cgmp) in the corporal cavernosal smooth muscle (ccsm), which acts to relax cavernosal tissue, perhaps by activating protein kinase g and stimulating phosphorylation of proteins that regulate corporal smooth muscle tone. the actions of the parasympathetic nervous system, nitric oxide and cgmp permit rapid blood flow into the penis and the development of an erection.(12) the exact mechanisms that are involved in nitric oxide/cyclic guanosine monophosphate induced penile corporal smooth muscle relaxation are unknown. however, it has been proposed that cyclic guanosine monophosphate activates protein kinase g, leading to the phosphorylation of proteins regulating corporal smooth muscle tone.(10,13) causes of erectile dysfunction the two main categories of erectile dysfunction are psychologic and organic (fig. 3).(14,165) ed can occur as a result of a neurological disorder affecting the central nervous system or anywhere in the erection pathway, an arterial disorder, as in generalized arteriopathy or localized as seen after pelvic surgery or radiotherapy, or a defective veno-occlusive mechanism, either congenital or acquired. less commonly, ed can result from endocrinological factors (abnormal hormonal milieu) and penile or cavernosal factors (e.g. fibrosis and curvatures). psychological processes such as depression, anxiety, and relationship problems can impair erectile functioning by reducing erotic focus or otherwise reducing awareness of sensory experience. this may lead to inability in initiating or maintaining erection. in most patients with ed, both organic and psychogenic components exist. every man who has 135 erectile dysfunction: clinical guidelines (1) some problem with erectile function develops performance anxiety, and determining whether psychologic factors are the main problem or merely a minor accompaniment may be difficult. organic erectile dysfunction is due to vasculogenic, neurogenic, hormonal, medical, and pharmacologic or cavernosal smooth muscle abnormalities or lesions; whereas, psychogenic erectile dysfunction is due to central inhibition of the erectile mechanism without a physical injury. the most common cause of the organic component of erectile dysfunction is vascular (arterial or venous) abnormalities,(16) often associated with atherosclerosis and diabetes mellitus.(17-19) most of these causes affect the intrapenile vasculogenic mechanisms, either arterial or venous. another common finding is a decrease in local no, which is thought to be the main neurotransmitter in initiating the erectile process. fibrosis may also be present within the corpora cavernosa, which can limit their expandability, prevent the venules from compressing against the tunica albuginea, and thereby allow venous leakage from the penis. vascular causes vascular disease, in particular, is thought to be the most common cause of organic ed.(20) there are several pathophysiological mechanisms of vasculogenic ed, including impaired arterial inflow, impaired smooth muscle cavernosal relaxation, chronic ischemia induced increased cavernosal smooth muscle contraction, cavernosal fibrosis, veno-occlusive dysfunction, and chronic or episodic hypoxemia. if the corpora cavernosa cannot expand and fill with blood, decreased erectile firmness occurs. atherosclerotic disease is the cause of approximately 40% of erectile dysfunction in men older than 50 years.(21) thickening of the arterial walls results in a reduced blood flow throughout the body and can lead to impotence. arteriosclerosis is associated with aging and accounts for 50% to 60% of impotency cases in men above 60. risk factors for arteriosclerosis include hypertension, diabetes mellitus, smoking, and hyperlipidemia. smoking is the most significant risk factor for impotence related to arteriosclerosis.(22) although atherosclerotic plaques or damages by trauma or irradiation may decrease blood flow to the penis, vascular causes of ed are more often due to a failure of neural, muscular, or chemical factors. venous leakage occurs when incomplete filling of the corpora, or intracavernosal fibrosis, causes failure of the veins to be pressed shut against the tunica albuginea. therapeutic approaches to treating vasculogenic ed need to address these mechanisms. the following general pathophysiological mechanisms have been identified: veno-occlusive dysfunction. in the full erectile state increased blood volume and compression of the relaxed trabecular smooth muscle against the relatively rigid tunica albuginea lead to a reduction in venous outflow (referred to as the venoocclusive mechanism). a venous leak can result from injury, disease, or damage to the veins in the penis.(22) hypoxemia. hypoxia has profound effects on blood vessel tone (vasoconstriction) and induces production of various factors, such as plateletderived growth factor, endothelin-1 and vascular endothelial growth factor (vegf).(23) it is now well established that vascular diseases, including hypercholesterolemia,(24) atherosclerotic vascular occlusive disease,(25) blunt trauma,(26) radiation,(27) and diabetes mellitus,(28) can interfere with the intricate vascular mechanisms underlying normal erection. hypoxemia, sleep apnea, and respiratory failure are also increasingly recognized as causes of erectile dysfunction.(29) infrequent erections deprive the penis of oxygen-rich blood. without daily erections, collagen production increases and eventually may form a tough tissue that interferes with blood flow. the spontaneous erections in men while sleeping or awake may be a natural protection against this process. neurological causes erectile function can be impaired as a result of a cerebrovascular accident (cva or stroke), demyelinating diseases, or even seizure disorders. brain and spinal cord injuries or paraplegia can 136 fig. 3. underlying etiology of erectile dysfunction (pooled data) erectile dysfunction: clinical guidelines (1) cause ed when the transfer of nerve impulses from the brain to the penis is blocked. multiple sclerosis, parkinson's disease, epilepsy, stroke, guillain-barré syndrome, trauma and alzheimer's disease are other nerve disorders that sometimes also result in ed.(30,31) tumor and trauma to the spinal cord can also be causative factors of erectile dysfunction. trauma to the spinal cord or pelvic region can damage the veins and nerves needed for erection. autonomic and peripheral sensory nerves may be damaged by trauma or transurethral resection of the prostate. in a study on 1267 patients with ed by hatzichristou et al,(32) a neurological cause of impotence was recorded in 145 men (11.4%), of whom 54 (4.2%) had undergone major pelvic surgery, including radical prostatectomy in 27, radical cystectomy in 20 and rectal surgery in 7. a total of 34 patients (2.7%) had multiple sclerosis, 33 (2.6%) had paraplegia due to spinal cord injury, 12 (0.9%) had disc hernias, 5 (0.4%) had parkinson disease, and 7 (0.6%) had other causes of neuropathy. in 2 of the 12 patients with disc hernias who underwent surgery, erectile function was restored postoperatively. hormonal causes hormonal perturbations may contribute to sexual dysfunction, especially erectile dysfunction. adult males with severe androgen deficiency (hypogonadism) often experience loss of sexual interest, impaired seminal emission, and decreased frequency and magnitude of nocturnal erections. a progressive decline in testosterone occurs after the seventh decade, and testicular or hypothalamic-pituitary dysfunction is the etiology. hormone imbalances can result from kidney or liver disease.(22) hypothalamus has an essential role in integration and control of male reproductive and sexual functions.(33) the gonadotropin-releasing hormone (gn-rh) is synthesized and secreted in the median preoptic area (mpoa), and the hypothalamus controls pulsatile gonadotropin secretion and serum testosterone levels necessary to maintain spermatogenesis, libido and, at least in the rat, function of the corpus cavernosal smooth muscle and perineal muscles involved in penile erection.(34) most problems revolve around dysfunction of the hypothalamic-pituitary-gonadal axis and are associated with either excess prolactin or decreased testosterone levels. other endocrine disorders that may be suggested as the most likely associated with impairment of libido or erectile function include hypothyroidism, hyperthyroidism, adrenal insufficiency, or excessive levels of adrenal corticosteroids. in such cases, patients may experience a generalized fatigue or weakness from the effects of the illness. the attribution of a causal role of endocrine abnormalities to ed has ranged from 2% to 23%,(35) but current understanding of the erectile mechanisms seldom permits assignment of a single causative factor. however, it is commonly agreed that androgens profoundly affect male sexual function overall and erectile physiology specifically. hyperprolactinemia, which can be due to medications, hypothyroidism with increased thyrotropin, chest wall injuries, or compression of the pituitary stalk, can result in sexual problems. rarely, a patient may demonstrate an excess of a variant large prolactin molecule, macroprolactin, which is biologically inert and therefore incapable of causing sexual dysfunction. in a study of 4,803 asymptomatic men by miyake et al 14 patients (0.29%) had a serum prolactin of greater than 50 ng/ml.(36) the incidence of prolactinoma in men was estimated to be 1:1,600 in that study. about 80% of men with a prolactin level greater than 50 ng/ml complain of diminished libido and erectile dysfunction because excess prolactin can suppress secretion of gonadotropin-releasing hormone.(37) as men age, they undergo a number of hormonal changes, including a marked decrease in serum levels of testosterone and free testosterone.(38) aging was negatively correlated with bioavailable testosterone and positively correlated with luteinizing hormone levels. bioavailable testosterone and its ratio to luteinizing hormone showed a close association with sexual behavior, whereas total testosterone, estradiol and prolactin did not. although testosterone and free testosterone, like sexual function, decrease with age, the contribution of these hormonal changes to the development of erectile dysfunction is thought to be only minor.(39) any major medical illness or surgical procedure can suppress the central axis and cause secondary hypogonadism. primary hypogonadism due to autoimmune destruction of the testicles occurs in some men as they age. a related cause is unilateral mumps orchitis occurring during the early adult years, with later failure of the "good testis." congenital causes include klinefelter's syndrome, 137 erectile dysfunction: clinical guidelines (1) kallmann's syndrome, and myotonic dystrophy. the incidence of hypogonadism in patients with acquired immunodeficiency syndrome (aids) is quite high.(40) hypogonadism is defined as a free testosterone level that is below the lower limit of normal for young adult control subjects. previously, age-related decreases in free testosterone were accepted as "normal", but this concept has been challenged. similarly, several clinical conditions that were once accepted as normal age-related disorders are now thought to lead to medical problems, for example, hypertension, osteoporosis, and menopause.(41) medical causes any medical condition that can cause general debility has the potential to decrease sexual desire and performance. pain, shortness of breath, angina, muscle weakness, or a cerebrovascular accident may be responsible for the dysfunction. the most common medical conditions associated with sexual difficulties are diabetes mellitus and hypertension, possibly because of the microvascular and neurovascular changes that are inherent in these conditions. cigarette smoking can cause vascular insufficiency as well as a decrease in intrapenile no levels. smoking contributes to the development of impotence, mainly because it compounds the effects of other disorders of the blood vessels, including high blood pressure and atherosclerosis. for example, a study in 2001 concluded that among men with high blood pressure, smoking causes a 26-fold increase in erectile dysfunction.(42) ed in cases of diabetes may be associated with peripheral nerve damage but may involve diminished endothelial production of no as well.(43) chronic hyperglycemia associated with diabetes mellitus damages the nerves and small blood vessels throughout the body.(30) some antihypertensive medications, heart medications, tranquilizers, antidepressants, and sedatives contribute to or cause ed. given the age of the patient population, patients in ed trials also typically have a significant incidence of lower urinary tract symptoms, the presence of which is increasingly being recognized as an independent risk factor for ed.(44) the prevalence of benign prostatic hyperplasia (bph) increases with age, and the presence of bph increases the risk of erectile dysfunction.(45) namasivayam et al noted that more than half of a cohort of 140 men with bph also had some degree of erectile dysfunction.(46) however, it is not clear whether the presence of bph increases erectile dysfunction risk independent of age, or whether the increased risk is due to the fact that the prevalence of both conditions is increased in the elderly. current evidence appears to support the latter of these two possibilities.(47) in peyronie's disease, collagen tissue is converted to fibrous tissue for unknown reasons; hence, a palpable fibrous plaque is created in the tunica albuginea. the usual manifestation is a bending of the penis to one side during erection, which can occasionally be painful.(21) nutritional states associated with ed are malnutrition and zinc deficiency. blood diseases associated with ed are sickle cell anemia and leukemias. surgical causes surgery or irradiation of the prostate, bladder, colon, or rectum may damage the nerves and blood vessels involved in erection. procedures on the brain and spinal cord, retroperitoneal or pelvic lymph node dissection, aortoiliac or aortofemoral bypass, abdominal perineal resection, radical prostatectomy, transurethral resection of the prostate, cryosurgery of the prostate and cystectomy can also result ed. pharmacological causes both prescription and over-the-counter medications have been shown to be the cause of erectile problems in as many as 25% of cases.(48) common medications associated with ed are antidepressants, antipsychotics, antidepressants, tranquilizers, antihypertensives, antiulcer drugs such as cimetidine, hormonal medication such as, finasteride (proscar), or dutasteride (avodart), drugs that lower cholesterol, and mind-altering agents such as marijuana, heroin, and cocaine (table 1). the incidence of erectile dysfunction in patients receiving various types of antihypertensive drugs was examined in the treatment of mild hypertension study.(49) at 24 months the incidence of an inability to achieve an erection ranged from 2.8% in the doxazosin (α-blocker) group to 15.7% in the chlorthalidone (diuretic) group compared with 4.9% in the placebo group. the incidence of an inability to maintain an erection ranged from 4.2% in the doxazosin group to 17.1% in the chlorthalidone group versus 6.8% in the placebo group. 138 erectile dysfunction: clinical guidelines (1) 139 table 1. sexual side effects of common prescription medications ��������� ���������������������������� ���� �������������������������������� �������������������������� ���� ����������� �������� ��� ���� ��������� � � ���������� �� � ���������������������������������������������������������������� ���� ������ ������ ������ ��������������� �� ����� ��������� ��� 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�������� ��� � �� �� ����������������� � � � 4����� ����� � ������ ��� erectile dysfunction: clinical guidelines (1) although single medications can induce erectile dysfunction, the adverse effects of medications are often additive. this situation is particularly frequent in older men who are taking multiple medications, and partial or complete erectile dysfunction often results. a psychologic component can make partial erectile dysfunction progress to complete erectile dysfunction.(50) most psychotropic drugs can affect libido or erectile function, either through a direct action or by increasing prolactin or decreasing testosterone levels. although antidepressants may cause erectile dysfunction in susceptible patients, they may also be beneficial in improving libido in depressed men. antihypertensive medications may cause erectile dysfunction either by drug-specific effects or by decreasing the systolic blood pressure and thereby decreasing the intracavernosal penile pressure. this effect is especially prevalent in patients with diabetes or hypertension who have underlying microvascular disease. results of the massachusetts male aging study also indicated a higher probability of erectile dysfunction in association with certain treated medical conditions.(5) long-term use of alcohol and illicit drugs may affect the vascular and nervous systems and are associated with ed.(50) ketoconazole, aminoglutethimide, and similar drugs actually decrease the production of testosterone. most of the earlier antihypertensive agents—such as reserpine, guanethidine, and hydralazine—caused sexual dysfunction. some evidence suggests that exposure to estrogen-like chemicals, such as those found in ddt and other pesticides, may contribute to erectile dysfunction. some adrenergic blocking agents may cause sexual problems, but dysfunction with angiotensin-converting enzyme inhibitors or calcium channel blockers is less common. some drugs (spironolactone, cimetidine, flutamide, or cyproterone acetate) may block the peripheral androgen receptors. cimetidine may assume a greater importance because it can now be purchased without a prescription. drugs such as methyldopa, spironolactone, digoxin, and metoclopramide may raise prolactin levels. thiazide diuretics, finasteride, anticholinergic agents, and pain medications can cause erectile dysfunction.(51) psychological causes psychological impotence tends to develop rapidly and be related to a recent situation or event. the patient may be able to have an erection in some circumstances but not in others. being able to experience or maintain an erection upon waking up in the morning suggests that the problem is psychological rather than physical. it should be strongly noted that in virtually every case of impotence there are emotional issues that can seriously affect the man's self-esteem and relationship. depression, guilt, stress, and anxiety all contribute to a loss of libido and to ed.(30, 31) emotional causes anxiety. it has both emotional and physical consequences that can affect erectile function. generally, what we view as the psychogenic causes of ed have performance anxiety as their final common pathway. this anxiety may be present in just about any man who has once or twice been unable to sustain an erection. he starts thinking about performance whenever he gets into any kind of difficulty during sex, whether it's because he has an arterial diminishment in the flow to his cavernous artery or because he may feel guilty about something. impotence may be caused by depression. depression is strongly associated with erectile dysfunction. in depressed men, sexual problems (diminished libido, erectile dysfunction, and premature ejaculation) are common, but the antidepressant medications routinely prescribed to counter the manifestations of depression are themselves associated with a range of adverse effects on sexual function.(5) other psychological causes of ed are bereavement, tiredness, stress hang-ups for instance and guilt about sex. problems in relationships problems in a relationship may affect potency. partners of men with erectile dysfunction may feel rejected and resentful, particularly if the affected man does not confide his own anxieties or depression. both partners commonly experience guilt for what they each perceive as a personal failure. tension and anger frequently arise between people who are unable to discuss sexual or emotional issues with each other. it can be very difficult for the man to perform sexually when both partners harbor negative feelings. socioeconomic issues losing a job or having lower income or education increases the risk for impotence. 140 erectile dysfunction: clinical guidelines (1) evaluation and assessment of erectile dysfunction patients usually do not volunteer their problem with ed. screening should be employed if the doctor suspects that his patient has ed. screening is advised for males around 40 years of age, especially if they have risk factors such as: a. diabetes, b. hypertension, c. hyperlipidemia, d. heavy smoking, e. cardiac disease, and f. depression. standard questionnaires an acceptable screening tool using a 5-question questionnaire is as follows: (52, 53) 1. how often were you able to get an erection during sexual activity? almost never or never: 1, a few times (much less than half the time): 2, sometimes (about half the time): 3, most times (much more than half the time): 4, almost always or always: 5, 2. when you had erections with sexual stimulation, how often were your erections hard enough for penetration (entering your partner)? almost never or never: 1, a few times: (much less than half the time): 2, sometimes (about half the time): 3, most times (much more than half the time): 4, almost always or always: 5, 3. when you attempted intercourse, how often were you able to penetrate (enter) your partner? almost never or never: 1, a few times (much less than half the time): 2, sometimes (about half the time): 3, most times (much more than half the time): 4, almost always or always: 5, 4. during sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? almost never or never: 1, a few times (much less than half the time): 2, sometimes (about half the time): 3, most times (much more than half the time): 4, almost always or always: 5, 5. during sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? extremely difficult: 1, very difficult: 2, difficult: 3, slightly difficult: 4, not difficult: 5, all questions are preceded by the phrase ' over the past 4 weeks.' instructions for scoring: add the scores for each item 1-5 (total possible score =25). ed severity classification: total score 5-10 (severe); 11-15 (moderate); 16-20 (mild); 21-25 (normal). note: individuals who have been sexually active and have attempted sexual intercourse in the past three months should only complete the above questions. for sexually inactive individuals, the questionnaire may be answered for the last period of time (three months or longer), during which the individual was sexually active. should the patient be found to have ed from the above questionnaire (i.e. total score 20 or less), a subjective bothersome questionnaire may be useful:(54) if you were to spend the rest of your life with your erectile condition, the way it is now, how would you feel about that? very dissatisfied: 1, rather dissatisfied: 2, mixed, about equally satisfied: 3, rather satisfied: 4, very satisfied: 5. for patients suspected to be suffering from depression, a two-question screening tool may be useful:(55) • during the past month, have you often been bothered by feeling down, depressed or hopeless? • during the past month, have you often been bothered by little interest or pleasure doing things? although normal aging can result in a decline in sexual performance, persistent erectile dysfunction should be investigated. the appropriate evaluation of all men with erectile dysfunction should include a comprehensive sexual, medical and psychosocial history, physical examination and focused laboratory studies. evaluation of the couple ideally, the couple should undergo assessment together at the first visit or soon thereafter. a discussion about the partner is important. is the patient married, single, divorced, or widowed? because newer relationships may have adjustment problems, the duration of the relationship is important, as is the age disparity between the partners. the health of the partner is very important; 15% of men report a decreased sexual frequency or ability because of health problems that their partners are experiencing, and the men are infrequently aware of this connection.(56) in addition, potential psychosocial factors should be addressed to elucidate patient view of the erectile problem, which remains a relevant part in every evaluation.(57) the interviewer should determine whether any relationship problems exist between the partners or whether external stresses may be a predominant factor. using a goal-oriented evaluation can increase the value of self-reporting by cross-checking the reliability of patient reports 141 erectile dysfunction: clinical guidelines (1) with specific questions. clinically we could demonstrate that deterioration in erectile function is relevant and that patients report reliably. comprehensive sexual, medical and psychosocial history a sexual history is needed to accurately define the patient's specific complaint and to distinguish between true erectile dysfunction, changes in sexual desire, and orgasmic or ejaculatory disturbances. the patient should be asked specifically about perceptions of his erectile dysfunction, including the nature of onset, frequency, quality, and duration of erections; the presence of nocturnal or early morning erections; and his ability to achieve sexual satisfaction. psychosocial factors related to erectile dysfunction should be probed, including specific situational circumstances, performance anxiety, the nature of sexual relationships, details of current sexual techniques, expectations, motivation for treatment, and the presence of specific discord in the patient's relationship with his sexual partner. the sexual partner's own expectations and perceptions should also be sought since they may have an important bearing on diagnosis and treatment recommendations. other essential components of history taking should cover the following: • altered sexual desire • ejaculation • orgasm • sexual related genital pain • lifestyle factors • smoking • chronic medical illness: hypertension, diabetes mellitus, atherosclerosis, and cardio-vascular risk factors including hyperlipidemia, renal and hepatic dysfunction • pelvic / perineal / penile trauma: bicycling injury, motor vehicle accident, etc. • medications / recreational drug use: antihypertensives, antidepressants, alcohol, cocaine • past surgery: radical prostatectomy, laminectomy, vascular bypass surgery • neurological illnesses: spinal cord injury, multiple sclerosis, lumbosacral disc injury • endocrinological illnesses: hypogonadism, hyperprolactinemia, thyroid disease • sexually transmitted diseases: gonorrhea • psychiatric illnesses: depression, anxiety(4) psychosocial history should cover symptoms of depression, altered self esteem, past and present partner relationships, past and present sexual practices, history of sexual trauma/abuse, job and social position satisfaction, economic position and educational attainment. sample of psychosocial assessment questions: • "do you suffer from depression or other mood problems?" • "how are your relationships with family members and other important people in your life?" • "do you have any difficulties in your work situation?" (if applicable) • "how is your current relationship with your partner? how was it in the past?" • "were you ever the victim of sexual abuse (forced to have sex)? if yes, what effect did this have on you then or now?" sample of sexual history questions: • "many men of your age start to experience sexual difficulties, if you have such a problem, i would be happy to discuss this further": • "could you describe your sexual problem?" • "when did your erection problems begin?" "please describe the circumstances." • "how was your sexual functioning prior to this time?" • "how are your erections that you achieve with masturbation or those that occur with sleep or upon awakening early in the morning?" (the discussion of masturbation is a sensitive issue that is often influenced by cultural and religious perspectives). • "how strong is your desire for sex, now and in the past?" • "do you have difficulties in ejaculating, either too fast or slow, either now or in the past?" • "is your partner able to become aroused and reach climax when you have sex together?" • "what has been your partner's reaction to your current sexual difficulties?" • "what has been the effect of your sexual difficulties on your partner relationship?" • "what has been the effect of your sexual difficulties on your overall lifestyle?" (4) if nocturnal or morning erections are present and strong, it will direct the evaluation toward psychologic causes, or it may simply mean that a certain medication might have decreased its concentration (and its adverse effect) during the night.(58) physical examination medical examination of erectile dysfunction should first include a detailed medical and sexual history, as well as a complete physical exami142 erectile dysfunction: clinical guidelines (1) nation with attention paid to the cardiovascular, neurological and genitourinary systems. physical examination is directed toward possible signs of hypogonadism, hyperthyroidism, examination of the external genitalia to exclude penile and testicular pathology such as testicular atrophy, inflammation and cancer, and digital rectal examination of the prostate. blood pressure measurements with the patient supine and standing, and palpation of peripheral arteries of the lower extremities are part of the standard physical examination. in addition, a baseline neurological examination is done, consisting of motor activity, perineal and external genitalia sensation (light touch and pinprick) and reflexes (cremasteric, bulbocavernosus and plantar). the bulbocavernosus reflex is tested with the physician's finger in the rectum directed laterally to where the muscle is inserted. a moderate squeeze on the glans penis will cause the bulbocavernosus muscle to contract if the reflex arc is intact. a screening neurologic examination is necessary. diagnostic tests four diagnostic testing are used for evaluation of ed: 1blood tests 2vascular assessment 3sensory studies 4nocturnal penile tumescence and rigidity testing (rigiscan test) blood tests there is no consensus on the role of laboratory screening in men presenting with erectile dysfunction. chemistry testing should evaluate for anemia, increased plasma glucose levels, or impaired renal function. thyroid testing should be done if clinically indicated. other hormone screening should include serum testosterone and prolactin levels. the "normal" range for testosterone is controversial. the massachusetts male aging study confirmed that free testosterone decreases 1.2% per year and bioavailable testosterone decreases 1.0% per year, while the sex hormone-binding globulin increases 1.2% per year, between the ages of 40 and 70 years. for this reason, free or bioavailable testosterone assays are preferred over measurement of the total testosterone level. because of the diurnal variation of testosterone secretion, obtaining several morning samples or pooling of multiple samples is advisable. a minimum of two subnormal values should be obtained before treatment. if the testosterone level is low, or even borderline, a serum lh level should be obtained to distinguish primary from secondary hypogonadism. compensated primary hypogonadism is present when the testosterone level is normal but the lh level is increased. further testicular failure can be anticipated. whether to establish a follow-up schedule for the patient or to initiate treatment is an individual clinical decision.(59-61) routine screening of tsh, total serum cholesterol and hemoglobin a1c is warranted in men presenting with erectile dysfunction.(62) vascular assessment several diagnostic modalities have been used to evaluate vascular impotence to permit appropriate treatment and surgical intervention. penile color duplex ultrasonography: vascular flow to the corpora cavernosa may be quantified with the use of a penile doppler examination. lue et al pioneered sonographic evaluation of erectile dysfunction.(63) with the patient supine the duplex probe is placed on the ventral side at the base of the penis, and a baseline image of the penis is obtained in the longitudinal and transverse planes, including measurements of the blood flow in the cavernous arteries. a dose of 20-microgram prostaglandin e1 is injected intracavernously using a 27½ -gauge needle. the internal diameter of the cavernous arteries and flow parameters are measured 5, 10, 15 and 20 minutes thereafter, and 15 to 20 minutes after stimulation response are graded clinically by the aforementioned criteria. reference values for normal peak flow and end diastolic flow velocities were more than 30(64) and less than 5 cm per second,(65) respectively. three measurements of all parameters are made, with mean values use for calculations. shabsigh et al concluded that penile duplex ultrasonography with papaverine injection appeared to be a useful objective method to evaluate vasculogenic impotence, which correlated well with nocturnal penile tumescence monitoring.(66) the resistance index are calculated as (peak flow velocitydiastolic flow velocity)/peak flow velocity in the phases of evolving erection at 10 minutes and maximal erectile response at 20 minutes after injection.(67) clinically suspicion of venous leakage arises when the patient has an excellent arterial response to an injected vasodilator and greater than 30 cm. per second peak systolic velocity yet a high diastolic flow after self143 erectile dysfunction: clinical guidelines (1) stimulation. high diastolic flow indicates low intracavernous pressure and suggests venous leakage at this stage, which is accompanied by inadequate or transient rigidity after self-stimulation. quam et al found that venous leakage on cavernosometry was predicted when end diastolic flow was greater than 5 cm. per second.(68) if an erection capable of penetration is obtained, a physiologically significant vascular deficiency is excluded. it has also been suggested that endogenous epinephrine, generated by a patient's embarrassment, fear, or anxiety, can affect the validity of the test results. dynamic infusion pharmaco-cavernosometry: dynamic infusion pharmaco-cavernosometry has been established as a comprehensive approach in the diagnosis of cavernovenous leakage.(69) dynamic infusion pharmaco-cavernosometry is performed with the patient supine on an angiography table. a 19-gauge needle is inserted dorsolaterally in the right corpus cavernosum about halfway down the shaft and 20-micrograms prostaglandin e1 is injected. ten minutes after intracavernous injection, body temperature physiological saline solution is injected through the needle with a high flow mechanical pump.(69) the solution is injected with increasing flow rates starting at 40 ml. per minute and increases incrementally by 40 ml. per minute every minute until full rigid erection is achieved. rigid erection, evaluate subjectively by digital palpation, is found to be sufficient for easy vaginal penetration. the flow rates needed to induce and maintain erection are then recorded. a flow rate of less than 15 ml per minute to maintain erection was considered normal. montague et al concluded that infusion cavernosometry in the evaluation of impotence may be uncertain and limited, and should be considered together with nocturnal penile tumescence testing for an accurate diagnostic assessment.(70) patients are considered to have venous leakage at maintenance flow rate of greater than 15 ml. per minute. it was reported that a minimum maintenance rate of 25 ml per minute is required for operative candidates who complained of venogenic impotence.(71) pharmaco-cavernosography. cavernosography is performed with injection of a low osmolality contrast medium diluted 1:4 with 2,500 microns/l. heparinized saline solution to avoid any risk of thrombosis of the cavernous bodies. serial film is then taken with a 100-mm camera, and the corpora cavernosa and penile venous network are studied in oblique and anteroposterior projection. at the end of the procedure disconnecting the needle to clear the contrast material emptied the corpora. any venous leak can be demonstrated at obtained films.(72) penile brachial index. the penile brachial index (pbi) is a measurement that compares blood pressure in the penis with the blood pressure taken in the arm. problems with the arterial flow to the penis can be detected using this method. interestingly, investigators have suggested that a low pbi, which should indicate decreased penile blood flow, correlates better with coronary artery disease than it does with erectile dysfunction. routine measurement is not recommended. the one instance in which the pbi may be of value is in the pelvic steal syndrome. a minor blockage of a small artery may not cause symptoms in the relatively inactive state of foreplay; thus, an erection may be normal. after penetration and pelvic thrusting, however, shunting of the blood to the pelvic musculature may cause detumescence prematurely. this condition is diagnosed by obtaining a pbi before and after exercise on a treadmill or with multiple deep knee bends; a pbi decrease of 0.15 or more is presumptive evidence of the pelvic steal syndrome.(73) sensory studies the sensitivity of the skin of the penis to detect vibrations (biothesiometry) can be used as a simple office nerve function-screening test. this involves the use of a small vibrating test probe placed on the right and left side of the penile shaft as well as on the head of the penis. the strength of the vibrations is increased until patient can feel the probe vibrating clearly. although this test does not directly measure the erectile nerves, it serves as a reasonable screening for possible sensory loss and is simple to perform. more formal nerve conduction studies are only performed in selected cases monitoring night-time erections tests that monitor nighttime erections may be used to determine if the causes of erectile dysfunction are more likely to be psychological. neither of the following methods is helpful in determining a physical cause for erectile dysfunction. snap-gauge test. the snap-gauge test monitors the man's ability to achieve an erection during sleep. it is a very simple test. when the man goes 144 erectile dysfunction: clinical guidelines (1) to bed, he places bands around the shaft of his penis. if one or more breaks during the course of the night, it provides evidence of an erection. in this case, a psychological basis for the erectile dysfunction is likely. nocturnal penile tumescence monitoring. a noninvasive tool in the diagnosis of penile erectile capacity is the recording of nocturnal penile tumescence with the rigiscan device. it provides simultaneous continuous measurement of tumescence and rigidity. the measurement of nocturnal penile tumescence and rigidity is useful, especially to distinguish between psychologic and organic erectile dysfunction. a portable monitor for home use, called the rigiscan monitor, measures both penile rigidity and tumescence. it can be set up easily in the office of any interested physician. the test can help distinguish between organic and psychologic erectile dysfunction, either in the initial assessment of the patient or after organic medical factors have been corrected but the difficulty persists. severe psychoses may be associated with abnormal nocturnal penile activity, as may sleep apnea or nocturnal myoclonus. this type of testing is expensive, and some results are questionable because of the unfamiliar surroundings and the startle response. it is still regarded by some, however, to be the "gold standard" for distinguishing psychogenic from organic erectile dysfunction.(74,75) interpretation of nocturnal penile tumescence was based on multiple parameters, including duration of registration greater than 5 hours per night, frequency of tumescence 1 to 2 times per night, duration of erection 10 minutes or longer, increase in penile tip and base 2.5 cm or greater and penile rigidity 60 percent or greater at tip and base. according to these criteria nocturnal penile tumescence monitoring was evaluated as normal or abnormal.(76) others have demonstrated the role of nocturnal penile tumescence monitoring in the evaluation of vasculogenic impotence. nocturnal penile tumescence testing was compared to penile duplex ultrasonography to measure the integrity of the cavernous arteries as well as to pharmaco-cavernosometry to measure directly venous function.(70) normal nocturnal penile tumescence testing correlates well with duplex ultrasound and cavernosometry, and reflects probable normal function of penile arterial and venous systems. however, when nocturnal penile tumescence is abnormal, we cannot predict the results of vascular system functioning. in this case the nocturnal penile tumescence test should be regarded as only 1 important element in the comprehensive assessment of sexual dysfunction.(76) references 1. montague dk, barada jh, belker am, et al. clinical guidelines panel on erectile dysfunction: summary report on the treatment of erectile dysfunction. j urol 1996: 156: 2007-2011. 2. nih consensus development panel on impotence. impotence. jama 1993: 270(1): 83-90. 3. fugl-meyer ar, lodnert g, branholm ib, et al. on life satisfaction in male erectile 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clearance are employed. endourological approaches remain the mainstay of treatment in the management of the patient with an anatomically unique bladder but access can potentially traumatize a reconstructed tract with a conduit mechanism. therefore achieving complete stone removal while minimizing damage to a reconstructed bladder is difficult in this patient subgroup and the management of neuropathic patients has led to the development of innovative procedures that permit minimally invasive access. consequently, specific to the neuropathic patient with complex, long term bladder management issues any technique which (a) reduces complications and is (b) reproducible with minimal effects on aberrant anatomy is desirable. case report a 38 years old, wheelchair dependent, spina bifida female patient presented with multiple bladder stones (figure 1) which had been detected incidentally. her past history was remarkable for a clam ileocystoplasty, a mitrofanoff catheterizable stoma and a surgically ablated urethra. prior to definitive urinary diversion surgery she had been managed with a suprapubic catheter. she had referred by the colorectal team having been seen initially with a perineal fistula and pelvic radiology had detected multiple large bladder calculi. in her obstetric history she had an elective caesarian section which had been complicated by a retained suture which encroached upon the mitrofanoff channel. this had been subsequently removed with holmium laser treatment successfully in a different institution. physical examination of her abdominopelvic region revealed multiple scars, a catheterizable stoma, an ablated urethra and a perineal fistula. on reviewing her case notes it was evident that she had undergone over 30 abdominal procedures in multiple institutions since childhood but the operative details of all her surgeries were not available to us. technique and results under general anesthesia and antimicrobial coverage the patient was positioned supine. a standard percutaneous nephrolithotomy (pcnl) drape was used to cover the abdomen and the mitrofanoff stoma was exposed. a lawrence add-a-cath sheath® was back loaded onto a flexible cystoscope in order to achieve a rigid access sheath into the bladder. this permitted repeated passage of the flexible cystoscope into the bladder with concomitant basket retrieval of stone fragments whilst minimizing any damage to the mucosa of the mitrofanoff stoma. the use of a 265 µm laser fiber down the flexible cystoscope permitted fragmentation of large stones which were then removed with the zero tip basket. additionally, the tip of the sheath was angled towards the stone fragments and using gentle suprapubic pressure whilst withdrawing the cystoscope the stone fragments were expelled with the irrigant fountain using the back loaded amplatz sheath as a temporary catheter through the mitrofanoff stoma. (figures 2 and 3). this maneuver reduced operative time and the need for repeated stone retrieval. the entire procedure was performed by a single surgeon. on the first attempt the procedure took four hours and rendered the patient completely stone free. she was discharged the next day on 5 days of oral ciprofloxacin therapy and followed up with a repeat flexible cystoscopy after 2 months. discussion bladder calculi are a common complication of urinary reconstruction with an incidence of between 8 and 50%.(1-3) in patients with myelodysplasia urolithiasis remains a frequent cause of morbidity as the neurogenic bladder prevents complete physiological emptying, thus allowing urinary stasis and concomitant infection.(4) in the neuropathic enterocystoplasty patient the etiology of stone formation is multifactorial with urinary stasis, mucous production, bacteriuria and foreign bodies being predominant contributing factors.(3,5) traditionally these stones have been managed using either a transurethral, shockwave lithotripsy(6) or percutaneous approach.(7,8) neuropathic patients with an impassable or surgically ablated urethra present a unique challenge to the urologist as they do not have department of urology, michael heal unit, mid cheshire hospital nhs foundation trust, leighton hospital, crewe, cw1 4qj, united kingdom. *correspondence: department of urology, michael heal unit, mid cheshire hospital nhs foundation trust, leighton hospital, crewe, cw1 4qj, united kingdom. tel: +44 151 5293775. e-mail: nilbury@gmail.com. received august 2014 & accepted january 2015 vol 12. no 02 march-april 2015 2115 mitrofanoff cystolitholapaxy-floyd (jr) et al. dependent bladder drainage.(9) unfavorable anatomy such as kyphoscoliosis can be detrimental even when non interventional attempts at stone clearance, such as extracorporeal shock wave lithotripsy (swl), are used in neuropaths.(10) open cystolithotomy mandates a prolonged hospital stay and poses surgical difficulties regarding identification of stomas and preservation of previously reconstructed enterocystoplasties. this problem is compounded if repeat procedures are required as recurrent adhesions may complicate attempts at stone removal resulting in damage to a reconstructed tract. therefore, the presence of an existing suprapubic tract affords the urologist easy accessible to a reconstructed bladder. if no existing tract is present then stone size and burden, patient factors and surgically constructed anatomy must be considered when determining the optimal access approach. simple outpatient based procedures, such as flexible cystoscopy have been modified using guide wires to reduce urethral trauma in neuropathic bladder patients. (11) the first suprapubic combined approach to bladder calculi was described by gopalakrishnan and colleagues in 1988.(12) since then several modified techniques(13-16) have been described in an effort to achieve stone clearance endoscopically, percutaneously or using a combined approach in neuropathic patients. the potential advantages of any modified endoscopic procedure are the avoidance of open surgery in an already scarred abdomen, decreased hospital stay and reduced morbidity.(3) in spina bifida patients there are reports of urethral closure, formation of a continent vesicostomy via a benchekroun valve and development of recurrent bladder calculi.(17) subsequent removal of bladder calculi proved challenging with endoscopic access necessitating a suprapubic cystolithotomy. a repeat attempt at endoscopic access using a ureteroscope to access the benchekroun stoma was abandoned due to mucosal tears.(17) innovative “hybrid” techniques using a combined endoscopic and modified laparoscopic approach have been described.(7) an obvious benefit with this combined approach is that the previous suprapubic cystostomy site is used thus minimizing damage to the vascular supply of the conduit. separately as all stones are gathered in the entrapment bag “confined lithotripsy” can occur under direct vision. elder has described a separate technique in spina bifida patients using an endotracheal tube to dilate a suprapubic tract that did not permit large stone evacuation through the conventional amplatz sheath.(13) miller and colleagues have described a separate technique specific to the pediatric augmented bladder with calculi.(15) the use of a combined endoscopic and laparoscopic approach with an entrapment device positioned through a suprapubic laparoscopic port allowed stones to be removed on a day case basis. this technique is notable for avoiding a cystostomy and for reduced operative time but large stones required lithotripsy pre operatively. additionally this approach does avoid any instrumentation of a continent stoma but is not reproducible in patient with a surgically ablated urethra.(15) in a patient with stones in an indiana pouch a modified technique using a flexible cystoscope (to allow direct visualization) and a laparoscopic trocar introduced into the pouch, large stones have been entrapped, brought to the pouch entry site and fragmented with electrohydraulic devices.(18) use of the amplatz sheath has been described for dealing with large bladder calculi. hubscher and colleagues used a 30 french amplatz sheath inserted through an existing suprapubic tract and then introduced a combination of figure 1. a) plain x-ray of abdomen demonstrating multiple bladder calculi, distorted pelvic bony anatomy and clips in the right iliac fossa. b) computerized tomography revealing scoliosis and multiple bladder calculi. figure 2. clinical photographs demonstrating in a clockwise manner: a) standard percutaneous nephrolithotomy drape with mitrofanoff stoma exposed; b) flexible cystoscope and back loaded lawrence add-a-cath sheath through the mitrofanoff stoma permitting repeated atraumatic access; c) stone burden when removed; d) gentle suprapubic pressure allowing stone fragment expulsion through the access sheath following removal of the flexible cystoscope. figure 3. endoscopic views demonstrating in a clockwise manner. a) multiple bladder calculi in a mitrofanoff bladder; b) holmium laser fragmentation of bladder calculi with a 265µm fiber through the flexible cystoscope; c) stone free mitrofanoff bladder; d) stone fragment removal using the zero tip basket. point of technique 2116 either ultrasound or holmium laser to remove the calculi under direct vision with a nephroscope.(5) however in patients with an augment and catheterizable stoma they avoided the constructed conduit and used the native urethra instead. a combined approach using simultaneous transurethral and suprapubic cystolithotripsy has been described by sofer and colleagues.(8) although the procedure was effective in clearing large bladder stones and had a mean operative time of 56 minutes it required two operating surgeons and was not done on a day case basis. pietro and colleagues have described a technique in a 59 years old spina bifida patient with a mitrofanoff diversion and a renal transplant using a flexible ureteroscope, an amplatz sheath and combination ballistic and ultrasound lithotripsy. their approach differs from the one we describe as the patient was catheterized for 7 days post operatively and required a cystogram.(19) our technique, with the add-a-cath sheath acting as a protective mechanism permits repeated access while preserving mucosal integrity and allows repeated use of a basket for stone retrieval in a patient with a surgically inaccessible urethra. secondly as no suprapubic puncture is required the potential complication of peritoneal extravasation is avoided. unlike the procedure described by miller and colleagues, we were able to perform the procedure with a flexible cystoscope.(15) our procedure allows for full evacuation of small stone fragments but unlike van savage and colleagues, we did use the mitrofanoff conduit for stone evacuation thus avoiding a second suprapubic puncture.(14) since the establishment of percutaneous access for stone removal, significant work has been devoted to optimize retrieval devices and reduce urothelial trauma.(20) conclusion our approach allows atraumatic access to a reconstructed tract in spina bifida patients with a hostile abdomen or inaccessible urethra and is reproducible on a day case basis allowing bladders such as this to be maintained stone free. conflict of interest none declared. references 1. palmer ls, franco i, kogan sj, reda e, gill b, levitt sb. urolithiasis in children following augmentation cystoplasty. j urol. 1993;150:7269. 2. blyth b, ewalt dh, duckett jw, snyder hm 3rd. lithogenic properties of enterocystoplasty. j urol. 1992;148:575-7. 3. kronner km, casale aj, cain mp, zerin mj, keating ma, rink rc. bladder calculi in the pediatric augmented bladder. j urol. 1998;160:1096-8. 4. gros da, thakkar rn, lakshmanan y, ruffing v, kinsman sl, docimo sg. urolithiasis in spina bifida. eur j pediatr surg. 1998;8 suppl 1:68-9. 5. hubsher cp, costa j. percutaneous intervention of large bladder calculi in neuropathic voiding dysfunction. int braz j urol. 2011;37:636-41. 6. kilciler m, sümer f, bedir s, ozgök y, erduran d. extracorporeal shock wave lithotripsy treatment in paraplegic patients with bladder stones. int j urol. 2002;9:632-4. 7. lam pn, te cc, wong c, kropp bp. percutaneous cystolithotomy of large urinarydiversion calculi using a combination of laparoscopic and endourologic techniques. j endourol. 2007;21:155-7. 8. sofer m, kaver i, greenstein a, et al. refinements in treatment of large bladder calculi: simultaneous percutaneous suprapubic and transurethral cystolithotripsy. urology. 2004;64:651-4. 9. franzoni df, decter rm. percutaneous vesicolithotomy: an alternative to open bladder surgery in patients with an impassable or surgically ablated urethra. j urol. 1999;162:7778. 10. vaidyanathan s, johnson h, singh g, et al. atrophy of kidney following extra corporeal shock wave lithotripsy of renal calculus in a paraplegic patient with marked spinal curvature. spinal cord. 2002;40:609-14. 11. vaidyanathan s, soni b, singh g, hughes p, oo t. use of flexible cystoscopy to insert a foley catheter over a guide wire in spinal cord injury patients: special precautions to be observed. adv urol. 2011;2011:538750. 12. gopalakrishnan g, bhaskar p, jehangir e. suprapubic lithotripsy. br j urol. 1988;62:389. 13. elder js. percutaneous cystolithotomy with endotracheal tube tract dilation after urinary tract reconstruction. j urol. 1997;157:2298-300. 14. van savage jg, khoury ae, mclorie ga, churchill bm. percutaneous vacuum vesicolithotomy under direct vision: a new technique. j urol. 1996;156:706-8. 15. miller dc, park jm. percutaneous cystolithotomy using a laparoscopic entrapment sac. urology. 2003;62:333-6. 16. kusuma vr, reddy j, divella rk. endoscopic neo cystolithotripsy for multiple calculi in studer ileal neo bladder: a case report. urol j. 2011;8:159-62. 17. vaidyanathan s, soni bm, singh g, hughes pl, mansour p, oo t. complications of benchekroun vesicostomy in a spina bifida patient: severe stenosis requiring permanent suprapubic cystostomy, recurrent vesical calculi and abdominal hernia containing ileocystoplasty a case report. cases j. 2009;2:9371. 18. jarrett tw, pound cr, kavoussi lr. stone entrapment during percutaneous removal of infection stones from a continent diversion. j urol. 1999;162:775-6. 19. pietro g, antonio f, stefania f, et al. multiple stones in atypical heterotopic reservoir in a patient with renal transplant: endourologic mitrofanoff cystolitholapaxy-floyd (jr) et al. vol 12. no 02 march-april 2015 2117 point of technique 2118 resolution. urologia. 2011;78 suppl 18:49-53. 20. hoffman n, lukasewycz sj, canales b, botnaru a, slaton jw, monga m. percutaneous renal stone extraction: in vitro study of retrieval devices. j urol. 2004;172:559-61. mitrofanoff cystolitholapaxy-floyd (jr) et al. urology journal unrc/iua vol. 2, no. 3, 132-136 summer 2005 printed in iran 132 o r i g i n a l a r t i c l e s endourology percutaneous nephrolithotomy with and without retrograde pyelography: preliminary results of a randomized controlled trial ali tabibi,1 hamed akhavizadegan,1* kia noori mahdavi,1 mohammad najafi semnani,1 mojgan karbakhsh davari,2 ali reza niroomand1 1department of urology, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran 2department of community medicine, tehran university of medical sciences, tehran, iran abstract introduction: since the introduction of percutaneous nephrolithotomy (pnl), many modifications to entering the pyelocalyceal system have been made. one alternative is to insert a needle pointed to an opaque stone as a landmark. the aim of this study was to compare the outcomes of managing kidney calculi by pnl with and without retrograde pyelography. materials and methods: in this randomized controlled trial, 55 candidates for pnl with a single opaque kidney calculus in the calyx alone, the pelvis alone, or both the calyx and the pelvis were assigned into 2 groups. twenty-seven patients underwent pnl with a ureteral catheter, and 28 patients underwent pnl without a ureteral catheter. clinical outcomes were compared between the 2 groups using plain radiographs taken on the first day after the procedure. results: patients had similar distributions regarding sex, age, operative time, hospital stay, past surgical history on the kidneys, and stone size. there was a significantly greater decrease in postoperative hemoglobin level in patients having pnl with a ureteral catheter (p < 0 .001) than in those having the procedure without a ureteral catheter. no differences were seen among patients in the 2 groups in terms of stone-free rate, and number of patients with insignificant residue, and those needing extracorporeal shock wave lithotripsy, a second pnl procedure, or transurethral lithotripsy. conclusions: percutaneous nephrolithotomy without ureteral catheterization has specific benefits: urine leakage is lower and there is no need to perform cystoscopy. patients with a single kidney calculus are good candidates for pnl without previous ureteral catheter insertion. key words: percutaneous nephrolithotomy, retrograde pyelography, kidney calculi received may 2005 accepted september 2005 *corresponding author: shaheed labbafinejad hospital, 9th boustan st, pasdaran ave, tehran, iran. tel: ++98 21 2254 9010-16 e-mail: hamed_akhavizadegan@yahoo.com tabibi et al 133 introduction many modifications have been made since the introduction of percutaneous nephrolithotomy (pnl). with regard to the entrance to the pyelocalyceal system, different methods (such as inserting a needle pointed to an opaque stone as a landmark(1)) have been suggested as a substitute for the classic method of retrograde injection of air or a contrast medium.(2) both methods are widely used today, but to our knowledge, no randomized controlled trial has been done to compare the two. in the classic method, the surgeon must perform an additional procedure to insert a ureteral catheter. if the new method is as effective as the classic one with regard to elimination of stones, it would be wise to perform pnl without catheter insertion. in this study, we compared the clinical outcomes of kidney calculi management with and without retrograde pyelography. materials and methods in a randomized controlled trial between september 2003 and june 2004, 55 patients with a single opaque kidney calculus in the calyx alone, the pelvis alone, or both the calyx and the pelvis were studied. the study protocol was approved of by the research council of the urology and nephrology research center, shaheed beheshti university of medical sciences. all patients were candidates for pnl, and none of them had anatomic abnormalities in their intravenous pyelographies. informed consent was obtained from all patients. patients were randomly assigned into 2 groups. twenty-eight patients in the study group underwent pnl without placement of a ureteral catheter and 27 patients in the control group underwent the operation with placement of a ureteral catheter. data including age, sex, past surgical history on the kidneys, side of the involved kidney, postoperative decrease in hemoglobin level, postoperative fever, operative time, duration of radiation, hospital stay, and the surgical outcome were recorded for each patient. the outcome measures were stone-free rate, insignificant residue, need for extracorporeal shock wave lithotripsy, need for re-pnl, and need for transurethral lithotripsy. in patients in the control group, pnl was performed in the classic manner with insertion of the ureteral catheter, performance of retrograde pyelography (with air or a contrast medium), and then accessing the respective calyx. in patients in the study group, the pyelocalyceal system was approached by a small catheter guided toward the opaque stone without inserting a ureteral catheter. after entering the system with a needle, a contrast medium was injected, and if the first needle were not appropriately aligned (placed directly to the pelvis or between the 2 calyces), access to the enhanced system was attempted again in the proper direction. postoperative outcome was evaluated using plain radiographs performed on the morning of the first postoperative day. data analyses were performed using spss software (statistical package for the social sciences, version 11.5, ssps inc, chicago, ill, usa), with the kolmogorov-smirnov test, student t test, and mann-whitney u test, as appropriate. values for p less than 0.05 were considered statistically significant. results patients in the 2 groups had similar distributions with regard to sex, age, and past surgical history on the kidneys, except for the table 1. demographic and clinical characteristics of the patients in the two groups group control study p value sex (% male) 21 (77.8) 18 (64.3) .27 age (mean ± sd) 43.81 ± 13.78 45.93 ± 13.14 .56 history of surgical procedure on the kidneys (%) 25 (96.2) * 24 (85.7) .186 side of the involved kidney (% right) 21 (77.8) 13 (48.1) * .027 stone size (mean of 2 diameters ± sd) 3.2 ± 0.7 2.9 ± 0.5 .7 percutaneous nephrolithotomy without retrograde pyelography134 side of kidney stone. demographic features and other characteristics of the 2 groups are shown in table 1. there were no significant differences in stone location (the calyx alone, the pelvis alone, or both the calyx and the pelvis) between the 2 groups. the mean operative times were 73.20 ± 26.37 minutes and 62.86 ± 17.66 minutes in the control and study groups, respectively. the mean radiation durations were 2.66 ± 1.20 minutes and 2.58 ± 1.47 minutes, respectively. mean hospital stays were 2.7 ± 1.08 days and 2.93 ± 2.16 days, respectively. post-pnl fever was seen in 23.2% versus 18.5% of patients, respectively. no significant differences in any of the above variables were seen between the 2 groups. postoperative decreases in hemoglobin levels were significantly higher in patients undergoing pnl with a ureteral catheter compared with those undergoing pnl without a ureteral catheter (2.29 ± 1.25 mg/l vs 1.03 ± 0.9 mg/l, p < 0 .001). with regard to final outcomes, no significant differences were seen between the 2 groups (p = .136); 26 patients in the control (96.3%) and 22 patients in study group (78.6%) were stonefree on the first postoperative day. five patients in the control group and 1 patient in the study group needed extracorporeal shock wave lithotripsy. percutaneous pyeloplasty was required again in 1 patient in the study group. there was no difference between the 2 groups with regard to whether or not patients were stone-free at the end of the procedure (p = 0 .20). discussion to date, experience with pnl without a ureteral catheter has been limited to catheter insertion preoperatively and immediate removal afterwards.(3) in this study, in the study group, the catheter was not inserted from the beginning, and outcomes were compared with the classic pnl. in the classic approach to the pyelocalyceal system, the system is opacified with retrograde pyelography using air or a contrast medium.(2) in theory, using a catheter may facilitate access to the enhanced system (owing to some pyelocalyceal distension) in pnl,(4) although we did not find this to be true in the current study. in pnl with a catheter, constant access to the pelvis is provided and in case of any complications, successful management is more easily done. however, the rarity of complications, especially in operations on simple kidney stones, undermines any potential advantage. access to the enhanced system theoretically may reduce blood loss owing to entrance via a hypovascular region(5,6) and may decrease the incidence of residual stones, but our findings did not confirm this. it seems that targeting the stone from a point medial to the posterior axillary line (maximum 4-finger width lateral to the paravertebral muscle) preserves this hypovascular region. entering the system with antegrade pyelography has been widely used(1) and fluoroscopic evaluation of the collecting system during antegrade pyelography is probably the best technique to use;(7) however, in normal systems with simple stones (like those in our patients), retrograde pyelography is not necessary. in addition, the enhanced system may require less radiation exposure or may reduce the total operative time, although this was not apparent in our study. using balloon ureteral catheter insertion in pnl has some benefits (eg, inhibiting migration of stone particles to the ureter).(4) however, owing to financial limitations, it is not routine at our center to use it for pnl, and a simple ureteral catheter is used instead. nevertheless, migrated ureteral stones are infrequently seen in our patients. in the current study, there was no difference between the 2 groups regarding the rate of migrated ureteral stones necessitating transurethral lithotripsy. this is most likely due to the fact that the simple ureteral catheter in the control group did not provide any protection from migrated stones. use of a ureteral catheter may introduce bacteria from the lower urinary tract to the upper system, and its insertion requires that another procedure be imposed on patients. in addition to this potential complication, albeit rarely, an air embolism may occur during retrograde pyelography.(8) in this study, no difference was found between the 2 groups with regard to the rate of post-pnl fever. moreover, pnl without a ureteral catheter may reduce postoperative discomfort owing to decreased pain and less urine leakage, although this was not assessed in the current study. conclusion no differences were seen in the major clinical outcomes between pnl with and pnl without a tabibi et al 135 catheter. considering the other benefits of pnl without stent insertion (eg, no need to perform cystoscopy and lower amount of urine leakage as only 1 catheter is inserted into the urethra), this may be a preferred modality, especially if a balloon ureteral catheter is not readily available. selection of patients for pnl without a catheter, however, may be limited to those with opaque stones in the pelvis and/or in only 1 in the calyx. it is also a safe procedure for accessing the pyelocalyceal system in patients with problems in being appropriately positioned or with urethral stricture that impede cystoscopy. acknowledgment this research was funded by the urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran. the authors wish to thank dr. fereydoon khayyamfar and dr. esmaeel moosapour for their contributions to this study. references 1. biyabani sr, liew l, esuvaranathan k, li mk. evaluation of the current technique of percutaneous nephrolithotomy in a tertiary care urology setting in singapore. bju int. 2002;90 suppl 2:133. 2. kim sc, kuo rl, lingeman je. percutaneous nephrolithotomy: an update. curr opin urol. 2003;13:235-41. 3. karami h, gholamrezaie hr. totally tubeless percutaneous nephrolithotomy in selected patients. j endourol. 2004 ;18:4756. 4. mcdougall em, liatsikos en, dinlenc cz, smith ad. percutaneous approach to the upper urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.3323-4. 5. sampaio fj, aragao ah. anatomical relationship between the renal venous arrangement and the kidney collecting system. j urol.1990;144:1089-93. 6. sampaio fjb, mandarim-de-lacerda ca. 3-dimensional and radiological pelvicaliceal anatomy for endourology. j urol. 1988;140:1352-6. 7. leroy aj. percutaneous access. in: smith ad, badlani gh, bagley dh, et al, editors. smith's textbook of endourology. st louis: quality medical publishing; 1996. p.204. 8. varkarakis j, su lm, hsu th. air embolism from pneumopyelography. j urol. 2003;169:267. editorial comment the results of this study offer a modification of performing a less-invasive percutaneous nephrolithotomy. as the authors have mentioned, using a ureteral catheter or balloon has the following advantages: first, instillation of a contrast medium or air can reveal the kidney anatomy (especially the posteroinferior calyx, which is often the entry site); and second, if the stone is impacted, the caliceal system may be obstructed, precluding the introduction of the needle into the caliceal system. insertion of a catheter and injection of contrast medium or air prevents multiple puncturing and long exposure to radiographs. finally, a ureteral catheter may prevent passage of a stone to the ureter, later renal colics, and further interventions for extracting a ureteral stone. although the results of this study suggest no significant differences between the 2 groups regarding the abovementioned points, the relatively small sample size may have obscured any potential disadvantages. in addition, although no differences in the number of patients with stone migration to the ureter that needed transurethral lithotripsy were reported, no information regarding the total number of migrations was provided. the final point regards the preoperative intravenous pyelography results and the degree of hydronephrosis associated with a stone. intravenous pyelography results could be directly related to the results of the primary puncture in pnl without ureteral catheter. obviously, in the absence of hydronephrosis, access through a percutaneous puncture is not usually successful and in that case, a cystoscopy in the prone position and insertion of a ureteral catheter is warranted. this can be a great problem, especially when a flexible cystoscope is not available. abbas basiri urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran percutaneous nephrolithotomy without retrograde pyelography136 reply by author all of the mentioned comments by the editors are accepted in current textbooks of urology (references 4 and 7 of the article). however, many of these are not evidence-based and are only experts' opinions (references 2, 4, and 7 of the article). for example, a ureteral balloon catheter has been proven to decrease passage of stones to the ureter, but this is not true for simple ureteral catheters. when the stone is opaque and single and the anatomy of the kidney is normal (inclusion criteria for our project), retrograde pyelography has not been proven in any studies to be helpful. we introduce this technique only as an alternative to the classic method; thus, the number of patients was not a limiting factor in this study. ali tabibi department of urology, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran urol_v03_no3_001_editorial.indd urological oncology urology journal vol 3 no 3 summer 2006 145 prediction of prostatic involvement by transitional cell carcinoma of the bladder using pathologic characteristics of the bladder tumor ali tabibi, nasser simforoosh, mahmoud parvin, behrang abadpour, hamidreza abdi, sorayya khafri introduction: the aim of this prospective study is to determine the relationship between the pathologic characteristics of the transitional cell carcinoma (tcc) of the bladder and prostatic involvement. materials and methods: sixty men with bladder tcc underwent standard radical cystoprostatectomy and were enrolled in this study. vascular and perineural invasion, maximum diameter of the tumor, presence of carcinoma in situ, distance between the tumor and the bladder neck, and grade and local stage of the tumor were recorded and their relation with prostatic involvement was studied. in addition, hydronephrosis and age of the patients were included in the analysis. results: the mean age of the patients was 63.9 ± 11.1 years. of 60 men included in this study, 15 patients were found to have prostatic involvement with tcc (25%). univariate statistical analyses showed that vascular invasion and the distance between the tumor and the bladder neck were significantly related to the prostatic involvement (p = .007; p < .001). but, in the logistic regression, only the distance between the tumor and the bladder neck was significantly related to the prostatic involvement (p = .001). conclusion: this study suggests that the probability of prostatic involvement in patients with bladder tcc tumors near the bladder neck is high. prostate-sparing or capsule-sparing cystectomy should be avoided in such patients. urol j (tehran). 2006;3:145-9. www.uj.unrc.ir keywords: bladder, transitional cell carcinoma, prostate, prostatesparing cystectomy urology and nephrology research center & shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: behrang abadpour, md shaheed labbafinejad medical center, 9th boustan, pasdaran, tehran, iran tel: +98 912 543 0790 e-mail: abadpour@hotmail.com received march 2006 accepted june 2006 introduction transitional cell carcinoma (tcc) extending to the prostate was first reported in 1952 by melicow and hollowell who described carcinoma in situ (cis) of the prostate coexistent with tcc of the bladder as the bowen’s disease.(1,2) a close relation between tcc of the prostate and tcc of the bladder has been suggested.(3) prostatic tcc involvement has been reported in 7% to 48% of the patients undergoing radical cystoprostatectomy.(4,5) radical cystoprostatectomy remains the standard treatment of highrisk, superficial, recurrent, muscleinvasive bladder cancer. however, it can be associated with substantial morbidity.(6) some investigators have advocated prostate-sparing radical cystectomy. this approach obviates dissection distal to the bladder neck, leaving the neurovascular bundles and the sphincter entirely undisturbed. it has been associated with excellent functional results after neobladder reconstruction.(7,8) the vas deferens can also be spared, allowing preservation of fertility.(8) it has been prediction of prostatic involvement by transitional cell carcinoma—tabibi et al 146 urology journal vol 3 no 3 summer 2006 shown that nerve-sparing modifications does not compromise the control of the cancer.(9,10) finally, a new method of prostate capsule-sparing has also been described with similar results.(11) however, these approaches have raised the concern that the prostatic involvement may be neglected and we have to predict if cystoprostatectomy is required. in this study, we decided to find the relationship between different microscopic and macroscopic features of the tcc of the bladder and the risk of the prostatic involvement. materials and methods between january 2003 and november 2005, this prospective study was performed in shaheed labbafinejad medical center. the study was approved by the institutional review board of the urology and nephrology research center affiliated with shaheed beheshti university of medical sciences. all patients with proven bladder tcc who were candidates for radical cystectomy were included in this study. patients with a history of previous surgery on the bladder or prostate, systemic chemotherapy, and prior pelvic or lower abdominal radiotherapy were excluded. sixty patients met these criteria and entered the study. they underwent standard radical cystoprostatectomy with en bloc excision of the bladder, prostate, and seminal vesicles. on pathologic examination, mapping (macroscopic features) and microscopic characteristics of the bladder tumors were determined by a single pathologist. characteristics of the tumors including the number of the tumors (single or multiple), maximum diameter of the tumors in centimeter, distance of the tumors from prostatovesical junction (td), existence of cis, tumor grade (low or high), local stage (superficial, t2, t3, and t4), and vascular and perineural invasion were also recorded. involvement of the prostate by tcc was assessed by the same pathologist, as well. in addition, hydronephrosis was assessed by preoperative ultrasonography or ct scan and was included in the analyses. statistical analyses were performed by spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). we evaluated the relationship between each single factor and the prostatic involvement using the chi-square test. the differences in age and td between the patients with and without prostatic involvement were analyzed by the student t test and kolmogorov-smirnov test. all factors with a significant effect were analyzed using logistic regression (backward wald method) afterwards. the receiver operating characteristic (roc) curve was used to select a cutoff point with the best diagnostic accuracy for continuous variables. results the mean age of the patients was 63.9 ± 11.1 years at the time of surgical operation. of 60 men enrolled in this study, 15 (25%) had tcc in their prostates (table 1). of 15 patients with prostatic involvement, 6 (40%) had tcc in the urethra, 6 (40%) in the stroma, and 3 (20%) in both. the characteristics of the patients and the tumors in the 2 groups of prostatic involvement positives and prostatic involvement negatives are shown in table 2. univariate analysis demonstrated that from the 9 factors assessed, only vascular invasion (p = .007; odds ratio, 5.28; 95% confidence interval, 1.48 to 18.82) and td (p = .007; 95% confidence interval, 0.74 to 1.91) had significant relationships with the prostatic involvement. the results for age and td which had been analyzed by the student t test were confirmed by kolmogorovsmirnov test. in the second step, vascular invasion and td in addition to multifocality of the bladder tumor were entered in the logistic regression model. we first calculated multifocality in association with the other 2 factors because of its relatively low p value and the fact that it had been found to be a significant factor in some previous studies.(8,12) the logistic regression analysis showed that only td had a significant relation with the involvement of prostate by tcc (p = .001). the roc curve showed high sensitivity and specificity (area under the curve, 0.92) and the odds ratio for td was 0.021 (95% confidence interval, 0.002 to 0.219), but due to the tumors in patients number (%) evaluated cases 60 number of involved prostates 20 (32) adenocarcinoma 5 (7) tcc 15 (25) tcc in urethra 6 (40) tcc in stroma 6 (40) tcc in both 3 (20) table 1. prostatic involvement in patients with bladder cancer* *tcc indicates transitional cell carcinoma. prediction of prostatic involvement by transitional cell carcinoma—tabibi et al urology journal vol 3 no 3 summer 2006 147 limited number of patients, we did not specify the cutoff value for td (figure). discussion the incidence of primary tcc of the prostate is thought to be 1% to 4% of all prostate malignancies.(13,14) involvement of the prostate with bladder tcc is more common (7% to 43%).(4) spitz and colleagues performed prostate-sparing radical cystectomy on 4 patients for the first time,(15) vallancien and coworkers treated a larger series of men with bladder tcc using this method.(16) they used digital rectal examination, serum prostate specific antigen, and transrectal ultrasonography of the prostate for preoperative evaluation of the patients. if each of these factors was abnormal, they performed prostatic biopsy, and if carcinoma was found, prostate-sparing operation was abandoned. their study lacked evaluation of potential factors that may predict the involvement of the prostate by tcc. we designed this prospective study to determine the factors that might influence prostatic involvement. the parameters we considered were vascular invasion, perineural invasion, multifocality, size, grade, local stage, tumor distance from the bladder neck, cis, age, and hydronephrosis. the incidence of prostatic tcc involvement was 25%; similar to the results reported table 2. characteristics of patients and bladder tcc in relation to involvement of prostate* *tcc indicates transitional cell carcinoma; ci, confidence interval; td, tumor distance from bladder neck; and cis, carcinoma in situ. †values in parentheses are percents. prostatic involvement † factors positive negative p odds ratio 95% ci age, mean, y 63.2 ± 12.4 64.2 ± 10.8 .79 … -8.37 to 6.46 td, mean, cm 0.46 ± 0.35 1.79 ± 1.10 < .001 … 0.74 to 1.91 tumor stage noninvasive 15 (88.2) 2 (11.8) t2 20 (71.4) 8 (28.6) t3 8 (72.7) 3 (27.3) t4 2 (50) 2 (50) .37 … … cis 16 (73) 6 (27) .76 1.21 0.36 to 4.01 present vascular invasion 8 (50) 8 (50) .007 5.29 1.48 to 18.82 perineural invasion 7 (64) 4 (36) .34 1.97 0.48 to 8.00 multifocal disease 21 (66) 11 (34) .07 3.14 0.87 to 11.36 high grade disease 23 (72) 9 (28) .55 1.44 0.44 to 4.70 hydronephrosis 17 (77) 5 (23) .76 0.82 0.24 to 2.82 tumor diameter ≥ 2 cm 38 (76) 12 (24) .69 0.74 0.16 to 3.30 receiver operating characteristic curve shows the sensitivity and 1 specificity of the tumor distance from the bladder neck for the prostatic involvement by transitional cell carcinoma prediction of prostatic involvement by transitional cell carcinoma—tabibi et al 148 urology journal vol 3 no 3 summer 2006 in other studies (27% to 30%).(2,12) in multivariate analysis, only td was shown to be an influential factor on the involvement of the prostate. kefer and colleagues reported a retrospective study on the pathologic specimens of 70 men who had undergone radical cystoprostatectomy for bladder tcc.(8) they demonstrated that the existence of cis, multifocality of the tumor, and involvement of the bladder neck influence the involvement of the prostate by tcc. in 2003, liedberg and colleagues reported 2 factors related to the prostatic involvement in patients with tcc of the bladder: the existence of tcc or cis in the bladder neck and multifocality of the bladder tumor.(12) as seen, multifocality of the tumor was a significant factor in both previous studies. although this variable was not significantly related to the prostatic involvement in our study, its p value was reported to be .07 indicating that if assessed in a larger sample of patients, it might be more significant. kefer and colleagues described the cis related to prostatic involvement, but liedberg and colleagues reported cis to be significant only when it was present in the bladder neck. our results did not show this relationship, either. finally, the only factor that is shown to be related with tcc involvement of the prostate in all reports is the presence or absence of the tumor in the bladder neck. this factor was described as the distance of the tumor from the bladder neck in our study, which was shown to be closely related to the prostatic involvement. we determined a cutoff point of 0.55 cm for this factor; however, the clinical use of such a parameter requires larger studies. conclusion the distance of bladder tumor from the bladder neck has a potent relationship with the prostatic tcc involvement in patients with tcc of the bladder. also, multifocality of the bladder tumor may increase the probability of prostatic involvement. thus, it seems reasonable to avoid prostate-sparing or capsule-sparing cystectomy in patients with bladder tumors very close to the bladder neck and in those with multifocal tumors. acknowledgement the authors would like to thank mrs baharak sabahi for her tireless efforts in bringing this paper to completion. conflict of interest none declared. funding support this study was financially supported by the urology and nephrology research center affiliated with shaheed beheshti university of medical sciences. references 1. melicow mm, hollowell jw. intra-urothelial cancer: carcinoma in situ, bowen’s disease of the urinary system: discussion of thirty cases. j urol. 1952;68: 763-72. 2. njinou ngninkeu b, lorge f, moulin p, jamart j, van cangh pj. transitional cell carcinoma involving the prostate: a clinicopathological retrospective study of 76 cases. j urol. 2003;169:149-52. 3. schellhammer pf, bean ma, whitmore wf jr. prostatic involvement by transitional cell carcinoma: pathogenesis, patterns and prognosis. j urol. 1977;118:399-403. 4. wood dp jr, montie je, pontes je, vanderbrug medendorp s, levin hs. transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. j urol. 1989;141:346-9. 5. zincke h, utz dc, farrow gm. review of mayo clinic experience with carcinoma in situ. urology. 1985;26: 39-46. 6. schover lr, evans r, von eschenbach ac. sexual rehabilitation and male radical cystectomy. j urol. 1986;136:1015-7. 7. hart s, skinner ec, meyerowitz be, boyd s, lieskovsky g, skinner dg. quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit, cutaneous or urethral kock pouch. j urol. 1999;162:77-81. 8. kefer jc, voelzke bb, flanigan rc, wojcik em, waters wb, campbell sc. risk assessment for occult malignancy in the prostate before radical cystectomy. urology. 2005;66:1251-5. 9. colombo r, bertini r, salonia a, et al. nerve and seminal sparing radical cystectomy with orthotopic urinary diversion for select patients with superficial bladder cancer: an innovative surgical approach. j urol. 2001;165:51-5. 10. chiang ph, wu wj, chiang cp. nerve-sparing radical cystoprostatectomy: 3-year experience. kaohsiung j med sci. 1997;13:169-74. 11. ghanem an. experience with ‘capsule sparing’ cystoprostadenectomy for orthotopic bladder replacement: overcoming the problems of impotence, incontinence and difficult urethral anastomosis. bju int. 2002;90:617-20. prediction of prostatic involvement by transitional cell carcinoma—tabibi et al urology journal vol 3 no 3 summer 2006 149 12. liedberg f, chebil g, davidsson t, malmstrom pu, sherif a, mansson w. [transitional cell carcinoma of the prostate in cystoprostatectomy specimens]. aktuelle urol. 2003;34:333-6. german. 13. rubenstein ab, rubnitz me. transitional cell carcinoma of the prostate. cancer. 1969;24:543-6. 14. bates hr jr. transitional cell carcinoma of the prostate. j urol. 1969;101:206-7. 15. spitz a, stein jp, lieskovsky g, skinner dg. orthotopic urinary diversion with preservation of erectile and ejaculatory function in men requiring radical cystectomy for nonurothelial malignancy: a new technique. j urol. 1999;161:1761-4. 16. vallancien g, abou el fettouh h, cathelineau x, et al. cystectomy with prostate sparing for bladder cancer in 100 patients: 10-year experience. j urol. 2002;168: 2413-7. urological oncology management of nonpalpable incidental testicular masses: experience with 10 cases mohsen ayati,1 ali ariafar,2 hassan jamshidian,1 azadeh soleimani,1 faeze ghasemi,1 mohammad reza nowroozi1* purpose: to determine the proportion of benign and malignant testicular lesions among patients with nonpalpable incidental testicular masses. materials and methods: ten patients with nonpalpable incidental testicular masses underwent surgical exploration. surgery was performed via an inguinal approach with temporary cord occlusion and frozen section examination (fse) of the lesions. benign findings allowed for testicular sparing surgery (tss), whereas cancer prompted total orchiectomy. results: the lesions measured 6-19 mm in the largest diameter. four of the 10 lesions were benign (40%) and tss was accomplished in these cases. complete concordance was observed between the results of fse and permanent histopathology examination. of the six patients with cancer, four had pure seminoma and two were mixed germ cell tumor. surveillance was applied in four of these patients, radiotherapy was used in one patient with seminoma and retroperitoneal lymph node dissection was done in one patient with mixed germ cell tumor. with an average follow-up duration of 24 months, all patients were alive and free of disease. all four patients in whom tss was accomplished had an uneventful postoperative course, and after an average follow-up duration of 20 months, all had normal results in scrotal physical examination and ultrasound. conclusion: malignant lesion always should be considered in nonpalpable incidental testicular masses and surgical exploration is mandatory. tss is safe and effective in patients with small benign lesions. cancer is reliably detected by fse. keywords: testicular neoplasms; pathology; surgery; treatment outcome; urologic surgical procedures; palpation; prognosis. introduction the incidence of testis cancer is increasing with an incidence of approximately 3-10 new cases per 100,000 males per year in western countries.(1,2) about 90-95% of testicular tumors are malignant germ cell tumor and remaining of them are benign lesions or metastasis from other organs. most of these tumors are palpable and 95% of all palpable tumors are malignant. (1) with the general use of scrotal ultrasound in the evaluation of urologic problem such as infertility, scrotal pain or trauma, the incidentally detected nonpalpable testicular mass is increasing and most of these lesions are hypoechoic.(3-5) imaging study such as ultrasound or magnetic resonance imaging (mri) have high sensitivity in detection of these lesions but specificity is low and differentiation of benign from malignant lesions are impossible by these modalities.(4-6) so these finding are clinical dilemma and unlike the management of palpable testicular mass which is straightforward and radical orchiectomy remains the standard of care in these situation, treatment of incidentally impalpable testicular mass is controversial and is not well established.(1) impalpable testicular lesions have been studied in some case series and results of these studies were different and most of patients had benign lesion but some malignant lesion have also been reported and still there is controversy in management of these patients.(7-11) we here report a series of cases of incidentally impalpable testicular mass identified by ultrasound. materials and methods between april 2009 and may 2011 ten patients with nonpalpable testicular masses discovered by ultrasound were studied. patients underwent urological examination for reasons other than suspected testicular tumor. the indications for scrotal ultrasound were infertility evaluation in 4, orchalgia in 3 and scrotal trauma in 3 patients. ultrasonography was performed using a high-frequency linear-array transducer (8-13 mhz) and the testes were examined in at least two planes in the long and transverse axes. all patients had complete preoperative staging procedure, including abdominal computed tomography (ct) scan, chest x-ray and tumor markers measurements including α fetoprotein, β human chorionic gonadotropin (hcg) and lactate dehydrogenase. all patients underwent exploration with excision of the testicular mass using the inguinal approach without in1 uro-oncology research center, tehran university of medical sciences, tehran, iran. 2 department of urology, shiraz university of medical sciences, shiraz, iran. * correspondence: department of urology, uro-oncology research center, tehran university of medical sciences, tehran, iran. tel: +98 21 66903063; fax: +98 21 66903063. e-mail: mrnowroozi @tums.ac.ir. received september 2013 & accepted august 2014 urological oncology 1892 traoperative ultrasound. after inguinal exploration of the testis, ice slush solution was placed around the testis, and the spermatic cord vessels were occluded with a tourniquet. the tunica albuginea was incised in the relatively avascular region. the tumor was identified and excised leaving 2 to 3 mm borders of normal-appearing tissue around the mass. the lesion was sent for frozen section examination (fse) immediately. if a malignant germ cell tumor was found in the presence of a normal contralateral testis, radical orchiectomy was performed but if result of fse was benign organ-sparing surgery was done. results the patients’ characteristics are shown in table 1. the mean age at the time of diagnosis was 32.2 (range, 21-54) years. the mean tumor diameter was 10.6 (range, 6-19) mm and contralateral testicle was normal in all cases. tumor markers were within normal limits and abdominal ct scan and chest x-ray were unremarkable in all cases. all lesions were hypoechoic, and exploratory surgery with fse was performed for all of them. overall, the final histopathology examination revealed six (60%) malignant and four (40%) benign lesions. the diagnosis in malignant lesions include seminoma in four (40%) and mixed germ cell tumor in two patients (figure 1). the benign lesions were leydig cell tumor (n = 1), endodermal sinus tumor (n = 1), leiomyoma (n = 1) and intratesticular epidermoid cyst (n = 1) (figure 2). in four cases with benign lesions the testis sparing surgery was done, and negative margins were confirmed by biopsy. in five patients with malignant lesions detected on fse, radical orchiectomy was performed in the same procedure. result of one fse during operation revealed no evidence of malignancy and testis was preserved, but the final histological examination revealed seminoma. base of permanent pathology report radical orchiectomy was done subsequently. surveillance was applied in four of patients with malignant lesions, radiotherapy was used in one patient with seminoma and retroperitoneal lymph node dissection was done in one patient with mixed germ cell tumor. with an no. age at surgery (years) follow-up (months) reason for us tumor diameter (mm) final pathology 1 32 21 infertility 6 seminoma 2 26 23 orchalgia 12 leydig cell tumor 3 32 14 orchalgia 13 seminoma 4 34 21 infertility 9 leiomyoma 5 41 36 scrotal trauma 7 seminoma 6 54 25 scrotal trauma 10 mixed gct 7 35 20 infertility 5 endodermal sinus tumor 8 23 22 orchalgia 19 mixed gct 9 24 26 scrotal trauma 11 seminoma 10 21 16 infertility 14 epidermoid cyst table 1. the patients’ characteristics and final pathology diagnosis. abbreviations: us, ultrasonography; gct, germ cell tumor. authors year no. of patients size (range mm) no. benign lesions no. malignant lesions buckspan et al14 1989 4 3-6 4 0 corrie et al15 1991 4 9-27 4 0 horstman et al16 1994 9 3-15 7 2 comiter et al11 1995 15 4-32 4 11 pierik et al17 1999 6 nr 5 1 hopps et al18 2002 4 2-16 2 2 leroy et al19 2003 15 4-16 11 4 carmignani et al4 2003 10 4-16 10 0 carmignani et al20 2004 3 nr 3 0 sheynkin et al21 2004 9 nr 6 2 colpi et al22 2005 5 3-5 4 1 connolly et al23 2006 5 nr 3 2 muller et al7 2006 20 1-5 17 3 powell et al8 2006 4 5-6 2 2 rolle et al24 2006 7 2-16 6 1 assaf et al25 2006 6 4-20 2 2 avci et al26 2008 9 4-9 4 5 eifler et al9 2008 18 nr 17 1 hallak et al27 2009 5 6.7* 4 1 toren et al13 2010 8 4.3* 7 1 present study 2012 10 5-19 4 6 table 2. published series and hypoechoic nonpalpable testicular lesions. incidental testicular masses-ayati et al vol 11. no 05 sept-oct 2014 1893 average follow-up duration of 24 months, all were alive and free of disease. all four patients in whom tss was accomplished had an uneventful postoperative course, and with an average follow-up duration of 20 months, all had normal result in scrotal physical examination and ultrasound. discussion the studies analyzing the etiologies of nonpalpable testicular mass are contradictory; some reporting a high proportion of malignant lesions and other reported benign lesions.(3-5) nonpalpable incidental testicular masses detected by ultrasound is an increasing situation for urologists and pathologists and base of various reasons there is controversy in management of these lesions, either by radical orchiectomy or tss and in carefully selected patients surveillance with serial ultrasound.(12-27) the radical orchiectomy is over treatment for patients with a benign lesion. in the case of a malignant lesion, the risks of tss include alteration of the predictable pattern of lymphatic spread, a positive margin and unrecognized lesions or carcinoma in situ remaining in the testis. diagnosis at a higher stage of disease in the case of a malignant lesion is also risk for patients under surveillance. published studies documenting the pathological diagnosis of these lesions yielded different results. table 2 summarizes several series in the literature. horstman and colleagues(16) have reported a series of nine patients with tumors measured less than 2 cm that 78% (7/9) of cases were benign with a final diagnosis of leydig cell tumors 4 cases , sertoli cells tumors 2 cases and interstitial fibrosis one patient and only two tumors were malignant (1 seminoma and 1 teratocarcinoma).(16) also carmignani and colleagues studied 27 men with ultrasound-detected testicular lesions and reported an overall 51.8% prevalence of benign disease at permanent histology, which in the cases of nonpalpable lesions 80% were benign.(4) similarly, in a recent study, toren and colleagues reported of eight patients with incidentally discovered hypoechoic testicular lesions less than 10 mm, of which 7 cases were benign in final histopathology report. (13) it has been shown that the rate of benign lesions in smaller masses is high and there is a direct correlation between increasing the size and the rate of malignant lesions. connolly and colleagues showed that 3 of 13 cases (23%) in lesions ≤ 1 cm are malignant in contrast to 100% of lesions greater than 3 cm.(10,23) connolly and colleagues surveyed lesions less than 1 cm, and of the eight hypoechoic lesions with a mean size of 5.8 mm (range 3 to 9.8) only one showed interval growth, increased to a size of 1 cm during a short time and was diagnosed as seminoma on frozen section.(28) intraoperative ultrasound localization of nonpalpable testicular tumors has also been suggested and seems to be very useful for detection of nonpalpable tumor specially small ones.(12,18) we did not use intraoperative ultrasound so we had some problem in localization of small lesions in some cases. conclusion in any impalpable testicular masses malignancy should be excluded by exploratory surgery. references 1. stephenson aj md, gilligan td. neoplasms of the testis. in wein ja, kavoussi lr, novick ac, eds, campbell-walsh’s urology, 10th edn. philadelphia: wb saunders; 2011. p. 837-70. 2. huyghe e, matsuda t, thonneau p. increasing incidence of testicular cancer worldwide: a re view. j urol. 2003;170:5-11. 3. dogra vs, gottlieb rh, rubens dj, liao l. benign intratesticular cystic lesions: us featur es. radiographics. 2001;21:273-81. 4. coret a, leibovitch i, heyman z, goldwasser b, itzchak y. ultrasonography evaluation and clinical correlation of intratesticular lesions: a series of 39 cases. br j urol. 1995;76:216-9. 5. carmignani l, gadda f, gazzano g, et al. high incidence of benign testicular neoplasm diagno sed by ultrasound. j urol. 2003;170:1783-6. 6. kim w, rosen ma, langer je, banner mp, siegelman es, ramchandani p. us mr imagfigure 1. yolk sac tumor component in a patient with mixed germ cell tumor. figure 2. intratesticular epidermoid cyst. incidental testicular masses-ayati et al urological oncology 1894 ing correlation in pathologic conditions of the scrotum. radiographics. 2007;27:1239-53. 7. muller t, gozzi c, akkad t, pallwein l, bartsch g, steiner h. management of incidental intratesticular masses of < or = 5 mm in diame ter. bju int. 2006;98:1001-4. 8. powell tm, tarter th. management of nonpal pable incidental testicular masses. j urol. 2006;176:96-8. 9. eifler jr jb, king p, schlegel pn. incidental tes ticular lesions found during infertility evalua tion are usually benign and may be managed conservatively. j urol. 2008;180:261-4. 10. carmignani l, morabito a, gadda f, bozzini g, rocco f, colpi gm. prognostic parameters in adult impalpable ultrasonographic lesions of the testicle. j urol. 2005;174:1035-8. 11. comiter cv, benson cj, capelouto cc, et al. nonpalpable intratesticular masses detected so nographically. j urol. 1995;154:1367-9. 12. giannarini g, dieckmann kp, albers p, heid enreich a, pizzocaro g. organ-sparing surgery for adult testicular tumours: a systematic re view of the literature. eur urol. 2010;57:780 90. 13. toren pj, roberts m, lecker i, grober ed, jarvi k, lo kc. small incidentally discovered testicular masses in infertile men--is active sur veillance the new standard of care? j urol. 2010;183:1373-7. 14. buckspan mb, klotz pg, goldfinger m, stoll s, fernandes b. intraoperative ultrasound in the conservative resection of testicular neoplasms. j urol. 1989;141:326-7. 15. corrie d, mueller ej, thompson im. manage ment of ultrasonically detected nonpalpable tes tis masses. urology. 1991;38:429-31. 16. horstman wg, haluszka mm, burkhard tk. management of testicular masses incidentally discovered by ultrasound. j urol. 1994;151:1263 5. 17. pierik fh, dohle gr, van muiswinkel jm, vreeburg jtm, weber rfa. is routine scrotal ultrasound advantageous in infertile men? j urol. 1999;162:1618-20. 18. hopps cv, goldstein m. ultrasound guided needle localization and microsurgical explora tion for incidental nonpalpable testicular tumou rs. j urol. 2002;168:1084-7. 19. leroy x, rigot j-m, aubert s, ballereu c, gos selin b. value of frozen section examination for the management of nonpalpable incidental tes ticular tumors. eur urol. 2003;44:458-60. 20. carmignani l, gadda f, mancini m, et al. de tection of testicular ultrasonographic lesions in severe male infertility. j urol. 2004;172:1045 7. 21. sheynkin yr, sukkarieh t, lipke m, cohen hl, schulsinger da. management of nonpalpa ble testicular tumors. urology. 2004;63:1163-7. 22. colpi gm, carmignani l, nerva f, guido p, gadda f, castiglioni f. testicular-sparing micr osurgery for suspected testicular masses. bju int. 2005;96:67-9. 23. connolly ss, d’arcy ft, bredin hc, callaghan j, corcoran mo. value of frozen section anal ysis with suspected testicular malignancy. urol ogy. 2006;67:162-5. 24. rolle l, tamagnone a, destefanis p, et al. mi crosurgical ‘‘testis-sparing’’ surgery for nonpa lpable hypoechoic testicular lesions. urology. 2006;68:381-5. 25. assaf gj. non-palpable testicular lesion: the case for testicular preservation. can j urol. 2006;13:3034-8. 26. avci a, erol b, eken c, ozgok y. nine cases of nonpalpable testicular mass: an incidental finding in a large scale ultrasonography survey. int j urol. 2008;15:833-6. 27. hallak g, cocuzza m, sarkis as, athayde ks, cerri gg, srougi m. organ-sparing microsur gical resection of incidental testicular tumors plus microdissection for sperm extraction and cryopreservation in azoospermic patients: surgical aspects and technical refinements. urology. 2009;73:887-92. 28. connolly ss1, d’arcy ft, gough n, mccarthy p, bredin hc, corcoran mo. carefully selected intratesticular lesions can be safely managed with serial ultrasonography. bju int. 2006;98:1005-7. incidental testicular masses-ayati et al vol 11. no 05 sept-oct 2014 1895 urol_v3_no1_001_editorial.qxd 61 urology journal unrc/iua case reports coincidence of angiomyolipoma and pheochromocytoma majid aliasgari, alireza ghadian* department of urology, shaheed modarres hospital, shaheed beheshti university of medical sciences, tehran, iran key words: angiomyolipoma, pheochromocytoma, adrenal gland vol. 3, no. 1, 61-64 winter 2006 printed in iran introduction angiomyolipoma is a benign clonal neoplasm with a prevalence of 0.13% when screened by ultrasonography.(1) pheochromocytoma is the causative factor of hypertension in less than 1% of the hypertensive population.(2) each of these neoplasms may be accompanied by other tumors; however, to best of our knowledge, concomitant angiomyolipoma and pheochromocytoma has not been reported yet and our report is the first in this matter. case report a 40-year-old woman presented with hypertension, resistant to treatment for several years. the results of complete blood cell count, serum electrolytes laboratory tests, renal and liver function tests, and urinalysis were normal. on ultrasonography, a mass in the left adrenal gland and a hyperechoic mass, approximately 4.5 × 3.5 cm, in the right kidney were reported (figure 1). the 24-h urinary excretion of vanillylmandelic acid and homovanillic acid were in the reference range. a ct scan with oral and intravenous contrast media showed a left adrenal mass and a nonenhanced 5 × 5-cm mass with a small amount of fat in the lateral surface of middle lobe of right kidney (figure 2). magnetic resonance imaging revealed a low-signal-intensity mass in the left adrenal gland (figure 3) and a low-signal-intensity mass in the lateral surface of the middle lobe of the right kidney. the patient underwent left adrenalectomy through a left 12th costal incision. the patient's position was then changed to the right flank and partial nephrectomy was also performed. histopathologic examination showed pheochromocytoma of the left adrenal gland and angiomyolipoma of the right kidney. discussion angiomyolipoma is a benign clonal neoplasm. this tumor is found in 0.3% of all autopsies and in 0.13% of the population when screened by ultrasonography.(1) approximately 20% of angiomyolipomas are found in patients with tuberous sclerosis syndrome (an autosomaldominant disorder characterized by mental retardation, epilepsy, and adenoma sebaceum).(1,3) received april 2004 accepted december 2005 *corresponding author: department of urology, shaheed modarres hospital, sa'adatabad st, tehran, iran. tel: +98 912 319 7306 e-mail: alka1384@yahoo.com fig. 1. ultrasonography: a hyperechoic mass in the right kidney angiomyolipoma and pheochromocytoma62 angiomyolipoma's common signs and symptoms include flank pain, hematuria, palpable mass, and hypovolemic shock. the presence of even a small amount of fat within a renal lesion on ct scan (confirmed by hounsfield units ≤ 10) is characteristic for angiomyolipoma.(4) the typical but not diagnostic finding on ultrasonography is a well-circumscribed, highly echogenic lesion, often associated with shadowing.(5) pheochromocytoma is the causative factor of hypertension in less than 1% of the hypertensive population.(2) additional signs and symptoms are numerous but not specific. among these are headaches, sweating, pallor or flushing, palpitations, tachycardia, abdominal or chest pain, and postural hypotension. also common are weakness, nausea, emesis, and anorexia.(2) about 10% of pheochromocytomas are found in normotensive patients.(6) diagnosis is confirmed by demonstrating elevated levels of catecholamines in the blood or urine, which occur in 95% to 99% of patients with pheochromocytoma.(7) because of the severe consequences of the undiagnosed pheochromocytoma, it is recommended that hypertensive patients be screened. measurement of urinary catecholamines and metanephrines is adequate in most patients. rarely, the plasma and urinary concentrations of catecholamines and their metabolites are not elevated, especially if the patient is normotensive at the time of study,(2) as in our patient. to our knowledge, the coexistence of angiomyolipoma and pheochromocytoma has not been reported previously and our report was the first in this matter. it seems that the patient has had one of the following conditions: first, a renal tumor in the right kidney has developed metastases to the left adrenal gland--adrenal metastasis can be found in 9% of autopsies.(8) specifically, the adrenal glands have been found to be a site of metastasis in 40% of patients with renal cell carcinoma.(8) hypertension may be one of the paraneoplastic syndromes of renal tumor.(7,9) second, a pheochromocytoma in the left adrenal gland has given metastasis to the right kidney; hypertension is due to cathecoleamine release from pheochromocytoma. and, third, it has been the presence of 2 separate neoplasms in the right kidney and the left adrenal gland. the preferred procedure might be laparoscopic resection of tumors. however, after excision of adrenal mass, the patient's hemodynamic condition might become unstable; thus, we decided to perform adrenalectomy through the left 12th costal incision, and then if the patient's condition was appropriate, change the position and perform partial nephrectomy through a contralateral incision. fig. 3. magnetic resonance imaging revealed a hypoechoic mass in the left adrenal gland (arrows). fig. 2. ct scan with contrast-medium. a. a 2-cm tumor in the left adrenal gland, b. a mass on the external surface of the middle lobe of the right kidney aliasgari and ghadian 63 references 1. eble jn. angiomyolipoma of kidney. semin diagn pathol. 1998;15:21-40. 2. vaughan ed jr, blumenfeld jd, del pizzo j, schichman sj, sosa re. the adrenals. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 3507-69. 3. neumann hp, schwarzkopf g, henske ep. renal angiomyolipomas, cysts, and cancer in tuberous sclerosis complex. semin pediatr neurol. 1998;5:269-75. 4. bosniak ma, megibow aj, hulnick dh, horii s, raghavendra bn. ct diagnosis of renal angiomyolipoma: the importance of detecting small amounts of fat. ajr am j roentgenol. 1988;151:497-501. 5. siegel cl, middleton wd, teefey sa, mcclennan bl. angiomyolipoma and renal cell carcinoma: us differentiation. radiology. 1996;198:789-93. 6. scott hw jr, oates ja, nies as, burko h, page dl, rhamy rk. pheochromocytoma: present diagnosis and management. ann surg. 1976;183:587-93. 7. manger wm, gifford rw jr. pheochromocytoma. in: laragh jh, brenner bm, editors. hypertension: pathophysiology, diagnosis, and management. new york: raven press; 1990. p. 1639-59. 8. gross aj, wolff m, fandrey j, miersch wd, dieckmann kp, jelkmann w. prevalence of paraneoplastic erythropoietin production by renal cell carcinomas. clin investig. 1994;72:337-40. 9. willis ra. the spread of tumors in the human body. 2nd ed. st louis: mosby; 1952. p. 124. editorial comment the authors describe a case of coexisting contralateral adrenal pheochromocytoma and renal angiomyolipoma. this has been reported in at least 2 other patients to date.(1,2) both pheochromocytoma and angiomyolipoma are uncommon but not rate entities in the general population, approximating 1 per 100 in incidence. both are much more common in the setting of multiple endocrine neoplasm (men) type 1.(3) coexistence of these two entities is hence statistically expectable and has been pathologically documented by this and previous cases. one must also keep in mind that the conventional histologic appearance of angiomyolipoma, normal adrenal tissue, and adrenal pheochromocytoma plus normal cortical tissue, is mistakably similar. therefore, such findings must be correlated with the exact site of origin and whenever possible, with results of liberal immunostaining.(4) this propensity for multifocal extrarenal (including adrenal) involvement by angiomyolipoma must be borne in mind in coexisting lipid laden renal and adrenal masses.(5) finally, limitations imposed by availability and practice setting in this case are understandable. however, when conditions allow, one should approach the asymptomatic renal angiomyolipoma and symptomatic lesions less than 4 cm in diameter by angioinfarction.(6) pejman shadpour department of urology, hasheminejad kidney center (hkc), iran university of medical sciences, tehran, iran references 1. grigor'ev ba. [an unusual combination of primarymultiple apudomas and malignant angiomyolipoma of the kidney]. arkh patol. 1989;51:63-8. russian. 2. kragel pj, johnston ca. pheochromocytomaganglioneuroma of the adrenal. arch pathol lab med. 1985;109:470-2. 3. vortmeyer ao, lubensky ia, skarulis m, et al. multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors. mod pathol. 1999;12:919-24. 4. granter sr, renshaw aa. cytologic analysis of renal angiomyolipoma: a comparison of radiologically classic and challenging cases. cancer. 1999;87:135-40. 5. elsayes km, narra vr, lewis js jr, brown jj. magnetic resonance imaging of adrenal angiomyolipoma. j comput assist tomogr. 2005;29:80-2. 6. vaughan ed jr, blumenfeld jd, del pizzo j, schichman sj, sosa re. the adrenals. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 3507-69. reply by author two reports are available on the coexistence of angiomyolipoma and pheochromocytoma,(1,2) but some differences exist between them and our report: in both previous reports, patients had multiple endocrine neoplasm (men). in one of them (an unusual combination of primary multiple apudomas and malignant angiomyolipoma of the kidney),(1) the authors have suggested that pheochromocytoma represented metastases of a malignant carcinoid tumor. in the second one (pheochromocytoma-ganglioneuroma of the adrenal gland), the patient had a composite adrenal tumor composed of both pheochromocytoma and ganglioneuroma in association with elevated urinary and serum catecholamine levels. in this regard it seems that the presence of these tumors (pheochromocytoma angiomyolipoma and pheochromocytoma64 and angiomyolipoma) without other tumors and without elevated urinary and serum catecholamine levels (that suggest the presence of men or other syndromes) was seen in our case as first. references 1. grigor'ev ba. [an unusual combination of primarymultiple apudomas and malignant angiomyolipoma of the kidney]. arkh patol. 1989;51:63-8. russian. 2. kragel pj, johnston ca. pheochromocytomaganglioneuroma of the adrenal. arch pathol lab med. 1985;109:470-2. 1717vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l acute jejunal obstruction following laparoscopic nephrectomy albert abhinay kota,1 sukria nayak,1 rajiv paul mukha,2 nitin s kekre2 corresponding author: albert abhinay kota, md department of surgery iv, christian medical college and hospital, vellore, tamil nadu. 632004, india. tel: +91 416 228 2441 e-mail: albertkota@cmcvellore.ac.in received june 2013 accepted april 2014 1 department of surgery iv, christian medical college and hospital, vellore, india. 2 department of urology, christian medical college and hospital, vellore, india. case report keywords: intestinal obstruction; etiology; jejunum; kidney neoplasms; surgery; laparoscopy; nephrectomy; adverse effects. introduction in acute small bowel obstruction, internal hernias have an incidence of 1.9-3%. (1) most often, the clinical features are nonspecific and hence the diagnosis can be delayed causing increased morbidity and the risk of gangrene requiring resection. case report sixty five year old male incidentally detected to have left renal mass. he did not have any past surgeries. after discussion, he underwent laparoscopic transperitoneal radical left nephrectomy as he opted for the procedure. he was positioned in a modified right lateral decubitus position. we used the standard three port technique. pneumoperitoneum was created via open technique through a 10 mm port in the midclavicular line 2 cm lateral to the level of umbilicus, 10 mm port in the left subcostal region in the anterior axillary line and another 10 mm port in the anterior axillary line at the level of anterior iliac crest. the left colon was mobilized medially after incising the toldt’s line. the ureter and gonadal vein were identified and traced superiorly till the lower pole of the kidney. the lower pole was identified and elevated. the renal artery was dissected, isolated, clipped and divided. similarly the renal vein was divided. the gerota’s fascia at the upper pole was then incised and the adrenal glands 1718 | separated. the kidney was dissected posteriorly with the gerota intact. the ureter and gonadal vein were divided; the specimen was placed in an endobag and removed through a pfannenstiel incision. the procedure was done in 1 hour fifteen minutes and the intraoperative course was uneventful. histopathology of the nephrectomy specimen was reported as papillary carcinoma (pt1an0m0 fuhrman nuclear grade ii). on the fifth postoperative day, he developed abdominal distension, upper abdominal discomfort, nausea and bilious vomiting. examination was normal. on imaging, computed tomography (ct) scan revealed proximal small bowel obstruction with internal herniation of the jejunal loops in the left renal fossa bed (figures 1, arrow head) through the transverse mesocolon (arrow heads in figures 2). he underwent emergency operation involving laparoscopy converted into exploratory laparotomy due to dense adhesions. release of the internal herniated dilated jejunal loops and closure of the mesocolonic defect was done. the dilated jejunal loops were congested but recovered to normal color with arterial pulsations and peristalsis following the release of adhesions. after the procedure he recovered well. discussion small bowel obstruction (sbo) is a common surgical emergency. adhesive related small bowel obstruction is the most commonest cause of mechanical sbo.(2) internal hernias are rare. post-operative transmesenteric hernias are a common type of internal hernias.(3) they have been often reported following bariatric procedures like gastric bypass. (4) urological operations like nephrectomy have been rarely reported to cause intestinal obstruction. laparoscopic nephrectomies have reported complications like vascular injuries, bowel injuries, solid organ injuries, access related, renal artery pseudoaneurysm, bladder perforation.(5-7) our patient developed acute intestinal obstruction following left nephrectomy. in literature, there are only 8 case reports of the intestinal obstruction following nephrectomies, all of which were left sided.(4,8,9) the main mechanism of occurrence is thought be due to rent in the transmesocolic defect during medial mobilization of the left colon along the toldt’s line while preserving the gonadal vein and potential space in the renal fossa bed causing migration of the small intestinal loops, eventually leading to kinking and extrinsic obstruction. seldom do these loops of small bowel get strangulated. however if there was undetected prolonged obstruction, it can lead to gangrene and perforation requiring resection of small bowel. the presenting symptoms are often vague and vary from upper abdominal discomfort, bloating, nausea, vomiting with no abdominal signs. when the bowel becomes strangulated or gangrenous, then there can be signs like tenderness and localized guarding.(8) diagnosis is mainly based on imaging. abdominal plain x-rays may reveal dilated proximal small bowel figure 1. computed tomography scan (axial section) revealed revealed proximal small bowel obstruction with internal herniation of the jejunal loops in the left renal fossa bed. figure 2 . computed tomography scan (coronal section) revealed scan revealed proximal small bowel obstruction with internal herniation of the (arrow heads). case report 1719vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l jejunal obstruction following laparoscopic nephrectomy | kota et al loops. contrast enhanced computerized tomography is diagnostic. some have used small bowel series for diagnosis.(8) treatment involves emergency exploration, releasing the small bowel loops and closing the transmesocolic rent. this can be done laparoscopically or as an open procedure. this potential problem can be prevented by identifying the defect in the mesocolon intraoperatively and suturing appropriately. other techniques mentioned in literature to prevent the creation of the defect include, staying close to the gerotas fascia and staying lateral to the gonadal veins during dissection.(10) it is also prudent to remember that the splenic flexure is an important watershed area and injury to the marginal vessels can cause ischemic injury to the colon. conclusion acute small bowel obstruction following laparoscopic nephrectomy warrants an urgent imaging and exploration to prevent strangulation. care should be taken while dissecting the mesocolon to prevent causing any defect which can lead to this complication. conflict of interest none declared. references 1. ghosheh b, salameh jr. laparoscopic approach to acute small bowel obstruction: review of 1061 cases. surg endosc. 2007;21:1945-9. 2. miller g, boman j, shrier i, gordon ph. etiology of small bowel obstruction. am j surg. 2000;180:33-6. 3. ghiassi s, nguyen sq, divino cm, byrn jc, schlager a. internal hernias: clinical findings, management, and outcomes in 49 nonbariatric cases. j gastrointest surg. 2007;11:291-5. 4. wadhawan r, raul s, gupta m, verma s. management of intestinal obstruction following laparoscopic donor nephrectomy. j minim access surg. 2012;8:149-51. 5. maghsoudi r, azaripour a. bladder perforation during laparoscopic donor nephrectomy. urol j. 2007;4:123-4. 6. shakhssalim n, nouralizadeh a, soltani mh. renal artery pseudoaneurysm following a laparoscopic partial nephrectomy: hemorrhage after a successful embolization. urol j. 2010;7:12-4. 7. pareek g, hedican sp, gee jr, bruskewitz rc, nakada sy. meta-analysis of the complications of laparoscopic renal surgery: comparison of procedures and techniques. j urol. 2006;175:1208-13. 8. cox r, dalatzui n, hrouda d, buchanan gn. systematic review of internal hernia formation following laparoscopic left nephrectomy. ann r coll surg engl. 2009;91:667-9. 9. wong jf, ho hs, tan yh, cheng cw. rare cause of intestinal obstruction after laparoscopic radical nephrectomy: internal herniation via a mesenteric defect. urology. 2008;72:716.e13-4. 10. regan jp, cho es, flowers jl. small bowel obstruction after laparoscopic donor nephrectomy. surg endosc. 2003;17:108-10. ffinal-1282.pdf 903vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l a novel irrigation system in percutaneous renal surgery mohammad mehdi hosseini, mohammad amin afrasiabi, eskandar negahdari, alireza aminsharifi, saeed shakeri, alireza tadayon, ejaz ahmad, farhad manaheji keywords: percutaneous nephrolithotomy, kidney, treatment outcome, lithotripsy introduction percutaneous nephrolithotomy (pcnl) is known as an alternative for open surgery and a minimally-invasive modality for management of large or complex renal stones.(1) in this procedure, stone is fragmented with pneumatic, ultrasonic, or electrohydrolic devices and its particles are removed with irrigation.(2) may also result in contamination if the stone is infected (figure 1). we designed, manufactured, and used a closed system to overcome this problem during percutaneous renal surgeries, such as pcnl. case report between september 2005 and september 2012, 1137 adult patients, including 674 men and 463 women, with a mean age of 38.2 years (range, 19 to 67 years) and mean stone size of 25.5 mm (range,15 to 50 mm) underwent pcnl in our referral training center. of 1137 patients, 516 had right-sided and 621 had left-sided stones. most of the patients (64%) 1). all the patients were evaluated by our team, including a urologist, an anesthesiologist, and a cardiologist if needed. ney, ureters, and bladder x-ray), intravenous urography, or computed tomography scan. comcorresponding author: mohammad mehdi hosseini, md nephrology-urology research center, shahid faghihi hospital, shiraz university of medical sciences, shiraz, iran tel: +98 711 233 1006 fax: +98 711 233 0724 e-mail: mmhosseini@sums. ac.ir received december 2011 accepted january 2012 nephrology-urology research center, shiraz university of medical sciences, shiraz, iran point of technique *abstract of the preliminary study was presented as a video presentation in 25th wce, cancun, mexico, 2007. 904 | point of technique checked. patients with staghorn calculi or positive culture received admitted 6 to 12 hours before the operation, and received partechnique we designed and manufactured a closed system that can be connected to the external, free end of the amplatz sheath to 30f with or without two lock-washers for watertight connecthe open end of the amplatz sheath by a piece of a matched when this device is connected to the amplatz sheath, the fore, before this connection, the amplatz sheath should be shortened to match with the length of the nephroscope. durdraining port into the collection bottle passively with little volume used for irrigation during the surgery. in all (1137 patients) but 27 cases, the procedure was done 27 morbid obese patients, the standard amplatz sheath was were unable to mount the 3-way connector in this setting. discussion in the present study, we showed the feasibility of our hometable 1. demographic characteristics of the patients who underwent percutaneous nephrolithotomy with closed irrigation system. male/female 678/459 mean age (range), y 38.2 (19 to 67) mean stone size (range), mm 25.5 (15 to 50) right/left side 516/621 comorbidities solitary kidney diabetes mellitus hypertension heart diseases renal insufficiency morbid obesity 47 (4.1%) 44 (3.8%) 113 (9.9%) 74 (6.5%) 22 (2.0%) 27 (2.4%) figure 1. conventional irrigation system in percutaneous renal surgery. figure 2. elements of the connector used for closed irrigation system. 905vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l ful to measure the volume of the irrigation used for proceaware that this system converts an open irrigation system to a closed one. any obstruction in the draining port (eg, stone fragments) may lead to an increased intrarenal pressure. although we did not encounter any major complication with the closed irrigation system, a comparative study would be helpful to observe if this system affects the outcome of pcnl. conflict of interest none declared. irrigation in percutaneous renal surgery | hosseini et al table 2. results and complications of novel irrigation system. stone-free rate, n (%) 1029 (90.5%) mean operative time (range), min 75 (40 to 115) mean irrigation volume (range), l 11.5 (6 to 18) complications (clavien classification) grade i: fever (t: 38.3º), bleeding, pcs perforation 44 (23,18,11) grade ii: transfusion, ileus, pneumonia 23 (12,7,4) grade iii: redo pcnl, urs, late hematuria 7 (3, 2, 2) grade iv: myocardial infarction, sepsis 5 (4,1) grade v: death 2 pcs indicates pelvicaliceal system; pcnl, percutaneous nephrolithotomy; and urs, ureteroscopy. figure 3. closed irrigation system during percutaneous nephrolithotomy using our novel device. references 1. basiri a, ziaee sa, nasseh h, et al. totally ultrasonographyguided percutaneous nephrolithotomy in the flank position. j endourol. 2008;22:1453-7. 2. peterson gn, krieger jn, glauber dt. anaesthetic experience with percutaneous lithotripsy. a review of potential and actual complications. anaesthesia. 1985;40:460-4. urological oncology bladder paraganglioma: clinicopathology and magnetic resonance imaging study of five patients jiuping liang,1 hengguo li,1* likun gao,2 liang yin,3 lei yin,4 jiawen zhang5 purpose: to investigate the clinicopathology and magnetic resonance imaging (mri) features of bladder paraganglioma, an extremely rare clinical entity. materials and methods: five patients with bladder paraganglioma (3 males and 2 females, 27-52 years old) were retrospectively reviewed. all cases underwent baseline mri and contrast-enhanced scans, and three cases underwent diffusion weighted imaging (dwi) and cystoscopy. cases were immunohistochemically examined with neuroendocrine markers (chromogranin and synaptophysin) and ki-67, and histology was reviewed by a pathologist. results: three cases exhibited painless gross hematuria, including one case with hypertension, whereas two cases were asymptomatic. one of the three patients who underwent cystoscopy was negative. the tumors were round (n = 1) or oval (n = 4) and located in the anterior wall (n = 1), posterior wall (n = 1), lateral wall (n = 2) or trigone (n = 1). all tumors were located in the submucosal or lamina propria. four cases presented with well-circumscribed margins, whereas one case was poorly circumscribed. all tumors exhibited slight hyperintensity on t1-weighted images (t1wi) and hyperintensity with “salt and pepper” appearance on t2-weighted images (t2wi). dwi indicated strong hyperintensity, and all cases exhibited conspicuous enhancement after intravenous gadobenate dimeglumine (gd-dtpa) injection. pathological evaluation confirmed paraganglioma. conclusion: mri plays an important role in the preoperative diagnosis of bladder paraganglioma. this rare condition has a characteristic round or oval appearance, located in the submucosal area, with slight hyperintensity on t1wi and hyperintensity with “salt and pepper” appearance on t2wi. dwi indicated strong hyperintensity and conspicuous enhancement on contrast-enhanced scans. keywords: paraganglioma; diagnosis; urinary bladder neoplasms; humans; tomography x-ray computed; magnetic resonance imaging; differential. introduction bladder paraganglioma is extremely rare and ac-counts for 0.06% of all bladder tumors and 1% of extra-adrenal pheochromocytomas.(1,2-6) pheochromocytomas are secreting catecholamine tumors, which originate in the chromaffin cells of the sympathetic nervous system; tumors that originate from extra adrenal sites are referred to as paraganglioma.(1,2,7-10) the most common symptoms are intermittent painless gross hematuria, paroxysmal hypertension, and micturitional attacks.(2,3,11,12) however, approximately 17% patients are hormonally inactive,(13) which makes it notoriously difficult to confirm an actual preoperative diagnosis. (14) cystoscopy and biopsy may provoke a hypertensive crisis and are therefore not recommended.(5,14) furthermore, the biological behavior of bladder paraganglioma is uncertain, and the histological features are not reliable to distinguish malignant from benign tumors.(3,8,9,11,15,16) previous studies(11) suggest that tumor stage and complete resection are the most important prognostic variables in patients with bladder paraganglioma. thus, preoperative imaging plays a crucial role, and magnetic resonance imaging (mri) has the lowest false negative localization rate for the diagnosis of paraganglioma.(17) the rare prevalence of this disorder renders it substantially more difficult to complete a comprehensive study. therefore, this study summarizes the clinicopathology and mri characteristics of bladder paraganglioma in a series of case reports. to the best of our knowledge, this is the first study to report the clinicopathology and mri features of bladder paraganglioma. materials and methods study patients this retrospective study was approved by our local ethics committee, and all patients provided written in1 medical imaging center, the first affiliated hospital, jinan university, guangzhou 510630, china. 2 department of pathology, renmin hospital of wuhan university, wuhan, 430060, china. 3 department of radiology, shenzhen baoan hospital, southern medical university, shenzhen 518101, china. 4 department of radiology, provincial clinical college, fujian medical university, fuzhou 350001, china. 5 medical imaging center, nan fang hospital, southern medical university, guangzhou 510515, china. *correspondence: medical imaging center, the first affiliated hospital, jinan university, guangzhou 510630, china. tel: +86 20 38688583. e-mail: lhgjnu@263.net. received august 2015 & accepted march 2016 urological oncology 2605 vol 13 no 02 march-april 2016 2606 echo time [te], 19.995; repetition time [tr], 500); t2-weighted images (t2wi; te, 100; tr, 3624); fat saturated; and diffusion weighted imaging (dwi; te, 67.448; tr, 1130.7) with b values of 0 and 800 s/mm2. ge signa 1.5t: fov, 310-420 mm; mmatrix, 384 × 245; thickness, 4-7 mm; intersection gap, 1 mm; t1wi (te, 1.7-7.7; tr, 3.4-480); t2wi (te, 109-130; tr, 3200-3900); fat saturated; and dwi (te, 89.2-9; tr, 2950-3650) with b values of 0 and 800 s/mm2. ge signa 3.0t: fov, 340-400 mm; mmatrix, 384×224; thickness, 4-5 mm; intersection gap, 1 mm; t1wi (te, 1.8-7.5; tr, 180-500); t2wi (te, 135.2; tr, 40004140); and fat saturated. siemens verio 3.0t: fov, 228-370 mm; mmatrix, 320 × 320; thickness, 4-6 mm; intersection gap, 1 mm; t1wi (te, 11; tr, 721-826); t2wi (te, 70-98; tr, 4000-5190); and fat saturated. gadobenate dimeglumine (0.1 mmol/kg; bayer schering pharma ag, berlin-wedding, germany and consun, guangzhou, china) was intravenously injected via a rapid bolus injection at a rate of 2-3 ml/s with a power injector (spectris solaris mr injector system, medrad, incorporated, pittsburgh, pa, usa). all mri findings were independently analyzed by two radiologists (with 13 and 17 years of experience, respectively). pathological examination all specimens were investigated morphologically and immunohistochemically. all histological slides were retrospectively reviewed by a pathologist (with 8 years of experience) who was unaware of the mri findings. the patient follow-up data were acquired from case histories. formalin-fixed and paraffin-embedded specimens were cut into conventional 5-µm-thick sections, immunohistochemically stained, and examined. immunochemical analysis was performed using an avidin-biotin-peroxidase complex (abc) method. formed consent. five cases of bladder paraganglioma were enrolled at four hospitals from november 2011 to april 2014. the participants comprised 3 males and 2 females, with an age range of 27-52 years. the mean age of the participants was 39.80 ± 10.85 years. mri examination mri examinations were performed with a philips achieva 1.5t (philips, amsterdam, the netherlands), ge signa hdxt 1.5t and a 3.0t magnetic resonance scanner (signa excite, general electric, fairfield, ct, usa), and siemens verio 3.0t (siemens, munich, germany) mr scanners. the patients were placed in a supine position. a surface phased-array coil was used, and scanning was conducted with the following parameters. philips achieva 1.5t: field of view (fov), 370-82.8 mm; mmatrix, 320 × 256; thickness, 5.5-6.6 mm; intersection gap, 0.725 mm; t1-weighted images (t1wi; table 1. clinical features of bladder paraganglioma. case sex age (years) size (mm) blood pressure (mmhg) clinical symptoms cystoscopy findings preoperative diagnosis 1 male 52 60 152/87 intermittent painless gross hematuria, not performed carcinoma urinary frequency, urgency 2 male 37 35 118/70 intermittent urinary pain, neoplasm carcinoma painless gross hematuria 3 female 50 15 127/84 painless gross hematuria neoplasm carcinoma 4 female 33 40 114/82 asymptomatic not performed leiomyoma 5 male 27 35 118/80 asymptomatic no neoplasm isolated fibroma figure 1. the tumors were round or oval appearance, located in the submucosal area, with slight hyperintensity on t1wi (a) and hyperintensity with “salt and pepper” appearance on t2wi (b). diffusion weighted imaging indicated strong hyperintensity (c) and conspicuous enhancement on contrast-enhanced scans (d). clinicopathology and mri of bladder paraganglioma-liang et al. results clinical features three cases comprised painless gross hematuria (1 case with hypertension), whereas two cases were asymptomatic with an increased blood pressure (bp) of 200-240 mmhg (systolic bp: case 4, 240 mmhg; case 5, 200 mmhg) at the beginning of the resection. three cases underwent cystoscopy, in which 2 cases exhibited neoplasm and 1 case was negative. all cases underwent surgery. the detailed clinical profiles of the patients are summarized in table 1. mri features the tumors were round (n = 1) or oval (n = 4) and located in the anterior wall (n = 1), lateral wall (n = 2), posterior wall (n = 1), or trigone (n = 1). all tumors were located in the submucosa. all tumors demonstrated slight hyperintensity on the t1wi (figure 1a). furthermore, the tumors demonstrated hyperintensity and a “salt and pepper” appearance on the t2wi (figure 1b). dwi was conducted in three patients, which indicated strong hyperintensity (figure 1c). all tumors demonstrated conspicuous enhancement on the contrast-enhanced images (figure 1d). four tumors exhibited well-circumscribed margins, while one tumor (case 1) was poorly circumscribed and had invaded the pelvic wall. no lymph nodes or distant metastases were identified in any of the cases. pathology all tumors were round or oval, and all cases were located in the submucosa or lamina propria. the tumor cells were arranged in a “zellballen” pattern, round and acidophilic, and embedded in a fibrous septa, which was richly vascularized (figure 2a). nuclear pleomorphism and mitotic figures were occasionally identified. immunohistochemically, these cells were positive for vimentin, p53, and neuroendocrine markers, such as synaptophysin (syn), chromogranin (cga) (figure 2b), and neuronal cell adhesion molecules 56 (cd 56). case location morphology immunohistochemistry ki-67 s-100 syn cd56 p53 cga vimentin 1 submucosa tumor cells grew in “zellballen pattern” 50% + + + + (weakly) separated by elaborate vascular septa; increased number of mitotic figures and focal necrosis. 2 submucosal and tumor cells characterized by round cells 3% + + + + +/ muscularis propria arranged in “zellballen pattern” separated by fine vascular network; tumor cells contained abundant cytoplasm with an eosinophilic granular appearance; mitotic figures occasionally identified. 3 muscularis propria tumor cells grew in “zellballen pattern” 3% + + +++ +++ +++ embedded in a fibrous vascularized network; round cells contained abundant cytoplasm with an eosinophilic granular appearance; mitotic figures were not common. 4 submucosa tumor cells grew in “zellballen pattern” 2% + + +++ + (weakly) +++ embedded in a fibrous vascular network; cells exhibited mild atypia. 5 submucosal and tumor cells grew in “zellballen pattern” 5% + + + + + muscularis propria separated by elaborate vascular septa; tumor cells had abundant cytoplasm with an eosinophilic granular appearance; nuclei exhibited mild atypia; mitotic figures were inconspicuous; tumor capsule was incomplete; lymphatic invasion was identified. table 2. pathology of bladder paraganglioma. abbreviations: syn, synaptophysin; cga, chromogranin; s-100, sustentacular cell. clinicopathology and mri of bladder paraganglioma-liang et al. urological oncology 2607 vol 13 no 02 march-april 2016 2608 sustentacular cells were immunostained for s-100 protein (figure 2c). the ki-67 indices were low (< 5%) with the exception of one case. the detailed pathology features are summarized in table 2. discussion the diagnosis of bladder paraganglioma is often confirmed by increased levels of catecholamines and their urinary and serum metabolites.(12,18,19) biochemical investigations were not performed on all cases in this series of patients because bladder paraganglioma was not considered preoperatively given the lack of classical signs and symptoms. cystoscopy and biopsy were avoided, which may provoke a hypertensive crisis following insufficient preparation.(5,14) in this study, two cases exhibited a sudden hypertensive crisis at the beginning of resection, which was controlled by medical intervention. one of the three cases who underwent cystoscopy was negative as a result of the submucosal tumor location and the cover provided by an intact epithelium. therefore, a preoperative ultrasound, ct scan, and mri were important for a definitive therapy.(5) mri is superior to ct scan in diagnostic sensitivity and specificity for the submucosal origin of the tumor because of its inherent tissue contrast resolution and multiple parametric imaging.(2,9,10,12) however, reports regarding mri features of bladder pheochromocytoma are rare, and previous publications involve single or very small case reports.(2,4,9,12,20,21) bladder paraganglioma originates in the paraganglionic cells that migrate into the bladder wall.(3,13,22) li and colleagues(23) reported that approximately 40% of bladder paraganglioma tumors were located in the submucosa, which may represent a key ultrasound imaging characteristic of bladder paraganglioma. however, cheng and colleagues(11) reported that approximately 94% of tumors involved the lamina propria of the bladder wall. in this study, mri indicated the location of all the masses was the submucosal layer, which is consistent with previous studies.(6,8,13,14,19,20,23,24) furthermore, the pathology results also demonstrated that all masses were located in the submucosal or lamina propria. nevertheless, the anatomical site predilection has been controversial in previous reports.(3,11,23) there was no site predilection identified in this study, which is in accordance with a previous study.(25) in this study, all masses exhibited slight hyperintensity on the t1wi and fat saturation, which is consistent with previous research.(12) wang and colleagues(21) suggested that lesions that exhibit homogeneous hyperintensity on t1wi are the key mri features of bladder paraganglioma; however, the reason for the slight hyperintensity on t1wi remains unknown. electron microscopic studies have indicated the presence of dark brown intracytoplasmic granules(3,7,8,15) and melanin pigments(26) in tumor cells, which may explain the increased signal intensity on t1wi; however, these findings require further confirmation. while all tumors exhibited hyperintensity on t2wi and fat saturation, the “salt and pepper” appearance may be an important mri feature, which is consistent with the pathology results and the mr features of carotid body tumor and glomus jugular tumor.(27) in this study, all tumors exhibited conspicuous enhancement because of their vascularity, which is in accordance with previous studies.(14,21,23) furthermore, this enhancement is an important diagnostic feature that differentiates bladder paraganglioma from other bladder tumors.(24) wang and colleagues(21) reported that the mean adc values of bladder paraganglioma were lower than the values for bladder cancer. in this study, dwi was conducted in three patients and indicated strong hyperintensity, which may represent another mr imaging characteristic of bladder paraganglioma. it is very difficult to obtain an actual preoperative diagfigure 2. the tumor comprised large polygonal cells with clear cytoplasm in a typical “zellballen growth” pattern with elaborate vascular septa (a). immunostaining for the neuroendocrine marker chromogranin a was positive (b). sustentacular cells were highlighted on immunostaining for s-100 protein (c). clinicopathology and mri of bladder paraganglioma-liang et al. nosis in asymptomatic bladder paragangliomas. histological features and immunohistochemistry have been important for the differential diagnosis of other bladder tumors;(1,25) in some cases, these approaches are the only alternative. in this study, the tumor cells were round or polygonal epithelioid and arranged in a pattern of classic zellballen with elaborate vascular septa. however, this feature is not always conspicuous, and some tumors grow diffusely. individual tumor cells are most often polygonal with a moderate amount of granular, eosinophilic to amphophilic cytoplasm. some cells may morphologically mimic neuronal or ganglion cells. nuclear hyperchromasia and pleomorphism may be prominent features; however, these features are not reliable predictors of malignant behavior. these cells were characteristic of positive immunostaining for neuroendocrine markers, such as syn, cga, and cd56. positive nuclear staining for s-100 protein highlighted the sustentacular cells. in addition, two cases expressed the limited positivity of p53. the role of p53 in pheochromocytoma tumorigenesis is unclear. petri and colleagues(28) have reported that although there is frequent loss of the p53 locus on 17p, the p53 gene does not appear to play a major role in pheochromocytoma tumorigenesis. the antibody p53 (dako, do-7) reacts with the wild type and mutant type of the p53 protein. thus, we suggest that the limited positivity of p53 should be considered in wild type expression. the paraganglioma biological behavior is uncertain, and previous reports(3,8,9,11,15,16) have indicated that histological features were not reliable to distinguish malignant from benign tumors. the most recent world health organization classification of pheochromocytomas and paragangliomas defined malignancy as the presence of metastases, not local invasion.(29) in this study, the tumor capsule of case 5 was incomplete, and lymphatic invasion was identified, as local invasion is a poor predictor of aggressive behavior, and the absence of invasion does not obviate the development of metastasis.(30) thus, while we cannot view case 5 as malignant, the patient should be followed over time. necrosis and an increased number of mitotic figures have previously been associated with a more aggressive prognosis in patients with paraganglioma.(31) case 1 exhibited malignant biological behavior that suggested tumor necrosis, an increased mitotic index, and a high (50%) ki-67 index. this case required additional follow-up; however, no recurrence or metastases occurred in an 8 month follow-up period. kang and colleagues(8) reported that long term follow-up was required. microscopic sections may demonstrate what appears to be an invasion of lamina propria of the bladder wall; thus, the bladder paraganglioma may often be judged for malignant tumor prior to operation. the major differential diagnoses of bladder paraganglioma include the following: granulosa cell tumor, a nested variant of urothelial carcinoma, metastatic large-cell neuroendocrine carcinoma, and malignant melanoma.(11) awareness of these rare diseases is essential to prevent misinterpretation. the lack of a “zellballen growth” mode and fine vascular stroma, absence of a sustentacular staining pattern of s-100 protein, and negative immunostaining of neuroendocrine markers easily discriminate these tumors from bladder paraganglioma.(11) when some atypia and mitotic features are present, it is easy to understand how a misdiagnosis of conventional urothelial carcinoma may be made; however, specific immunohistochemical stains may be helpful. it should be pointed out that metastatic neuroendocrine tumors also express neuroendocrine markers; however, the histological characteristics, including necrosis, cellular anaplasia, and mitotic figures, and the absence of a sustentacular staining pattern of s-100 protein distinguish them from paraganglioma. furthermore, in uncommon cases, bladder paraganglioma contains melanin pigment, similar to malignant melanoma.(26) melanomas do not express neuroendocrine markers, which may differentiate each other. however, none of the current cases had melanin pigments. furthermore, a rare composite paraganglioma-ganglioneuroma may occur in the urinary bladder;(32) this tumor may contain a substantial component of ganglioneuroma that consists of mature ganglion and spindle cells that merge with the classical paraganglioma component. to identify unique components, such as ganglioneuroma, neuroblastoma, or ganglioneuroblastoma, a malignant peripheral nerve sheath tumor (mpnst; malignant schwannoma) in the tumor may facilitate the correct diagnosis of composite paraganglioma/pheochromocytoma. conclusions in conclusion, mri plays an important role in the preoperative diagnosis of bladder paraganglioma, with a relatively characteristic mr appearance, including a round or oval shape and submucosal location. t1wi exhibited slight hyperintensity, whereas t2wi indicated hyperintensity with a “salt and pepper” appearance. dwi exhibited strong hyperintensity and conspicuous enhancement. pathological evaluation suggested paraganglioma as the final diagnosis. however, several limitations must be considered in the interpretation of these clinical findings. first, because of the rare prevalence clinicopathology and mri of bladder paraganglioma-liang et al. urological oncology 2609 vol 13 no 02 march-april 2016 2610 of this disorder, this study comprised a small sample of patients. furthermore, a retrospective design was used. thus, a prospective and multicenter study is needed to elucidate the clinical findings revealed in these case reports. nevertheless, the current case report provides novel insights regarding the rare clinical condition of bladder paraganglioma. conflicts of interest none declared. references 1. bohn ol, pardo-castillo e, fuertes-camilo m. urinary bladder paraganglioma in childhood: a case report and review of the literature. pediatr dev pathol. 2011;14:32732. 2. wong-you-cheong jj, woodward pj, manning ma, davis cj. neoplasms of the urinary bladder: radiologic-pathologic correlation. radiographics. 2006;26:1847-68. 3. leestma je, price ebj. paraganglioma of the urinary bladder. cancer. 1971;28:1063-73. 4. ansari ms, goel a, goel s, durairajan ln, seth a. malignant paraganglioma of the urinary bladder. a case report. int urol nephrol. 2001;33:343-5. 5. dahm p, gschwend je. malignant nonurothelial neoplasms of the urinary bladder: a review. eur urol. 2003;44:672-81. 6. liu y, dong sg, dong z, mao x, shi xy. diagnosis and treatment of pheochromocytoma in urinary bladder. j zhejiang univ sci b. 2007;8:435-8. 7. lam ky, loong f, shek tw, chu sm. composite paraganglioma-ganglioneuroma of the urinary bladder: a clinicopathologic, immunohistochemical, and ultrastructural study of a case and review of the literature. endocrine pathol. 1998;9:363-73. 8. kang wy, chai cy, shen jt. paraganglioma of the urinary bladder: a case report. the kaohsiung j med sci. 2003;19:136-40. 9. halefoglu am, miroglu c, uysal v, mahmutoglu a. malignant paraganglioma of the urinary bladder. eur j radiol extra. 2006;58:53-8. 10. tsai cc, wu wj, chueh ks, et al. paraganglioma of the urinary bladder first presented by bladder bloody tamponade: two case reports and review of the literatures. kaohsiung j med sci. 2011;27:108-13. 11. cheng l, leibovich bc, cheville jc, et al. paraganglioma of the urinary bladder can biologic potential be predicted? cancer. 2000;88:844-52. 12. celiktaş m1, okur n, aikimbaev ks, binokay f, sert m, akgül e. bladder pheochromocytoma encountered on sonography. australas radiol. 2004;48:398400. 13. das s, bulusu nv, lowe p. primary vesical pheochromocytoma. urology. 1983;21:20-5. 14. xu df, chen m, liu ys, gao y, cui xg. non-functional paraganglioma of the urinary bladder: a case report. j med case rep. 2010;4:216. 15. dewan m, rasshid m, elmalik em, ansari ma, morad n. lessons to be learned: a case study approach paraganglioma of the urinary bladder. j r soc promot health. 2001;121:1938. 16. huang kh, chung sd, chen sc, et al. clinical and pathological data of 10 malignant pheochromocytomas: long-term follow up in a single institute. int j urol. 2007;14:181-5. 17. erickson d, kudva yc, ebersold mj, et al. benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. j clin endocrinol metab. 2001;86:5210-6. 18. whalen rk, althausen af, daniels gh. extra-adrenal pheochromocytoma. j urol. 1992;147:1-10. 19. al-zahrani aa. recurrent urinary bladder paraganglioma. adv urol. 2010:912125. 20. usuda h, emura i. composite paraganglioma– ganglioneuroma of the urinary bladder. pathol int. 2005;55:596-601. 21. wang h, ye h, guo a, et al. bladder paraganglioma in adults: mr appearance in four patients. eur j radiol. 2011;80:e217-20. 22. zimmerman ij, biron re, macmahon he. pheochromocytoma of the urinary bladder. n engl j med. 1953;249:25-6. 23. li y, guo a, tang j, et al. evaluation of sonographic features for patients with urinary bladder paraganglioma: a comparison with patients with urothelial carcinoma. ultrasound med biol. 2014;40:478-84. 24. athyal rp, al-khawari h, arun n, abul f, patrick j. urinary bladder paraganglioma in a case of von hippel-lindau disease. australas radiol. 2007;51:b67-b70. 25. menon s, goyal p, suryawanshi p, et al. paraganglioma of the urinary bladder: a clinicopathologic spectrum of a series of 14 cases emphasizing diagnostic dilemmas. indian j pathol microbiol. 2014;57:19-23. 26. moran ca, albores-saavedra j, wenig bm, mena h. pigmented extraadrenal paragangliomas: a clinicopathologic and immunohistochemical study of five cases. cancer. 1997;79:398-402. 27. lee ky, oh yw, noh hj, et al. extraadrenal paragangliomas of the body: imaging features. ajr am j roentgenol. 2006;187:492-504. 28. petri bj, speel ej, korpershoek e, et al. frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas. mod pathol. clinicopathology and mri of bladder paraganglioma-liang et al. 2008;21:407-13. 29. delellis, ronald a., ed. pathology and genetics of tumours of endocrine organs. vol. 8. iarc, 2004. 30. tischler as. pheochromocytoma and extraadrenal paraganglioma: updates. arch pathol lab med. 2008;132:1272-84. 31. lack ee, cubilla al, woodruff jm. paragangliomas of the head and neck region. a pathologic study of tumors from 71 patients. hum pathol. 1979;10:191-218. 32. chen ch, boag ah, beiko dt, siemens dr, froese a, isotalo pa. composite paraganglioma-ganglioneuroma of the urinary bladder: a rare neoplasm causing hemodynamic crisis at tumour resection. can urol assoc j. 2009;3:e45-8. clinicopathology and mri of bladder paraganglioma-liang et al. urological oncology 2611 1678 | biaxial mechanical properties of human ureter under tension aisa rassoli,1 mohammad shafigh,2 amirsaeed seddighi,3 afsoun seddighi,3 hamidreza daneshparvar,4 nasser fatouraee 1 corresponding author: nasser fatouraee, ph.d biological fluid mechanics research laboratory, biomedical engineering faculty, amirkabir university of technology (tehran polytechnic), tehran, iran. tel: +98 21 6454 2368 fax: +98 21 6646 8186 e-mail: nasser@aut.ac.ir received february 2014 accepted may 2014 1 biological fluid mechanics research laboratory, biomedical engineering faculty, amirkabir university of technology (tehran polytechnic), tehran, iran. 2 department of engineering, islamshahr branch, islamic azad university, tehran, iran. 3 functional neurosurgery research centre, shohada tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 4 legal medicine research center, legal medicine organization, tehran, iran. miscellaneous purpose: the mechanical properties of the ureteral wall may be altered by certain diseases such as megaureter. ureter compliance and wall tension alterations can occur, leading to some abnormalities such as reflex mechanisms. familiarizing with the mechanical properties of the ureter can help us advance in the understanding of urinary tract diseases. materials and methods: a constitutive model that can predict the mechanical response of ureteral tissue under complex mechanical loading is required. parameters characterizing the mechanical behaviour of the material were estimated from planar biaxial test data, where human ureter specimens were simultaneously loaded along the longitudinal and circumferential directions. results: the biaxial stress-stretch curve was plotted and fitted to a hyperelastic four-parameter fung type model and five-parameter mooney-rivlin model. the average strength in the longitudinal direction was 3.48 ± 0.47 mpa and 2.31 ± 0.46 mpa (p < .05) for the circumferential direction.in the fung model the value of parameter a2 (0.699 ± 0.17) was higher than a1 (0.279 ± 0.07), which may be due to the collagen fiber orientation’s preference along the longitudinal axis. conclusion: according to this study, it seems that ureter tissue is stiffer in the longitudinal than in the circumferential direction and maybe the collagen fiber are along the axial axes. also the specimens showed some degree of anisotropy. keywords: biomechanical phenomena; computer simulation; elasticity; ureter; physiology; models; biological; peristalsis; stress; mechanical. miscellaneous 1679vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l mechanical properties of human ureter introduction ureters are tubes that are made up of smooth mus-cle fibres, and their function is to transfer urine from the kidneys to the bladder.(1) in the adult, the ureter is usually 25-30 cm long and about 3-4 mm in diameter.(2-4) histologically, the ureter contains the muscle cover that causes the transmission of urine from the kidney to the bladder and alters its flexibility. megaureter is one of the most important abnormalities of the upper urinary tract,(5-9) which is classified by some urologists into those attributable to: reflux, obstruction, unrelated to reflux and unrelated to obstruction. a quantitative analysis characterizing peristaltic flow will further expand our knowledge of the ureter and also assist in the design of flow-aided devices to correct some abnormalities. the anatomical complexity of the ureter has considerable clinical importance, therefore, models that contain mechanical properties of the ureteral wall with actual modelling of peristaltic flow can yield applied results with accurate interpretations. hence, a constitutive model that can reliably predict the mechanical behaviour of the ureteral tissue is necessary. notwithstanding the physiological and clinical relationship of ureteral elasticity, insufficient data is available about the mechanical behaviour of ureteral wall. among the few studies, yin and fung performed uniaxial tensile tests on ureter from a variety of mammals and human foetus. important findings were that ureters exhibit an anisotropic, nonlinear and pseudo-elastic behaviour over finite strain, and that their behaviour differs with the region under strain.(10) sokolis investigated the biaxial properties of rabbit ureter by applying internal pressure through inflation and used the four-parameter fung-type sef model to describe them.(11) although the uniaxial tensile test data were presented comprehensively they were not sufficient to determine mechanical properties like nonlinear and anisotropic responses. moreover, the inflation tests lacked the adaptability of a planar test, in addition to the fact that the sample sizes in these tests were dependent on the pressure and size of the nozzle.(12) to the authors’ knowledge, experimental measurements obtained from the biaxial planar loading have so far not been considered in the development of constitutive models for the ureter. hence, the goal of this study was to develop an anisotropic constitutive model for the ureter wall. planar biaxial tests were performed on specimens by loadings applied along the circumferential and longitudinal directions. then, the data of the experimental tests were modelled by the anisotropic four-parameter fung-type model and the anisotropic modified mooney-rivlin model. materials and methods sample preparation human ureter was used in this study. before resecting the samples, written consent was obtained from the families of the deceased. they were asked to sign the consent form prepared by the legal medicine organization. eighteen ureter specimens were used in this study, extracted from 9 healthy upper urinary tracts. to protect the samples from dehydration, tissues were cleaned and stored in physiological saline 0.9%. the tests were performed within 10 hours after extraction. thickness measurements were taken from different regions of the samples by using a micrometre. out of necessity, the mean thickness was utilized for stress calculations. the central parts of the specimens were cut into segments, then cut along the longitudinal axis, and splayed to obtain square 6 × 6 mm2 samples for biaxial testing. during the test, the samples were stored in 0.9% physiological saline heated by a heater to 37°c. testing protocol device description: tests on each specimen were done by the planar biaxial testing system with strain controlled capability. the clamps of this system were able to directly hold samples with dimensions of ≥ 5 × 5 mm2 without damaging the tissue (figure 1). in order to preserve the mechanical properties, samples were kept wet at a temperature of 37◦c by using a temperature controlled water bath. tensile forces were measured by two umaa 2 kilogram-force (kgf) load cells (dacell co., ltd, korea corporation, korea). the required tensile forces, in this device, were applied by four micro stepper motors with a resolution of 0.36 degrees and with a nominal torque of 1.2 kg/cm (autonics corporation, gyeonggi-do, korea). four drivers were used to drive the stepper motors (autonics model md5-h14). to measure the tissue deformation, an universal serial bus (usb) digital microscope camera was used (300 × zoom, 30 hz and reso1680 | miscellaneous lution of 480 × 640). data sent by the controller were transferred to a computer and saved there. to synchronize the data, load cells and camera data were simultaneously saved at a frequency of 5 hertz (hz). loading protocols: after each specimen was placed on the testing system, a preload of 0.01 newton (n) was applied along both axes to obtain meaningful measurements. a low loading rate was considered for a quasi-static test by selecting the strain rate at 0.02 mm/s for all tests. force and displacement data were recorded at 0.2 second intervals (frequency of 5 hz).the digital microscope camera’s data were processed with the imagej package to obtain stretch in each direction. we could not use ink markers in stretch (displacement) measurement, because of the small dimensions of the samples. the initial distance between the ends of each clamp was considered as the reference measure for sample length in both directions. the stress-strain curve for each specimen was obtained in two axes [the (11) axes corresponding to the circumferential direction and the (22) axes corresponding to the longitudinal direction].the experimental stresses for the samples were computed as follows: where λl and λ2 are the stretch ratios, f11 and f22 are the forces measured by the load cells, t is the thickness of the samples, and l1 and l2 are the unloaded widths of the samples in the two directions. the unloaded widths of the samples in the two directions. constitutive model development in this study, ureter was modeled as an incompressible, homogeneous and hyperelastic material. these assumptions justify the existence of a strain energy function w which is the criterion for the stored energy in the materials as a result of the deformation. with the use of strain energy function, the stresses can be computed from the strains as follows:(13-15) where σij is the cauchy stress tensor, p is the lagrange multiplier introduced to enforce incompressibility, cij = fij t.fij is the right cauchy–green deformation tensor, eij = 0.5(cij-iij) is the green–lagrange strain tensor, iij is the identity unit tensor and fij is the deformation gradient tensor which can be described as f= ∂x/∂x' in which x' and x are the positions of material points in the reference and current configuration, respectively. note that in this study the shear strains were negligible and hence ignored in the subsequent data analysis. based on the strain energy function and hyperelastic models,(16-20) two appropriate constitutive models were chosen to express the mechanical properties of the ureter; as these models have been used previously for other soft tissues. the first model utilized was a fung-type model(16) able to describe the anisotropic behaviour of tissue. in the fung model, the strain energy density is given by: whereq(e) = a1e11 2+a2e22 2+2a3e11e22 , and c ,a1, a2 and a3 are constitutive parameters. the cauchy stress components in the two directions were then calculated as follows: the second model was the modified mooney-rivlin model which shows the anisotropic behaviour of the tissues and can also be implemented in many standard fe packages. the strain energy density function of this model is given by: are the model parameters(21). according to the strain energy function, cauchy stresses in the two axes are as follows: 1681vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l experimental data were then fitted to cauchy stress of each model by using genetic algorithm and the parameters of constitutive models were obtained for each data set. for the fung model, anisotropy was also calculated as follows: statistics the results of the experimental tests and constitutive models are presented as average ± sd. the two-tailed paired t-test was used to compare the longitudinal and circumferential directions stiffness with statistical package for the social science (spss inc, chicago, illinois, usa) version 22.0. significance was set at p < .05 results since some of the specimens were unsuitable for testing (some specimens were very soft or they had degenerated during the tests), ten samples were appropriate for the biaxial tests. figure 2 shows the cauchy stress-stretch curves obtained from the biaxial mechanical testing of all specimens in the circumferential (1-a) and in the axial (1-b) directions. it cannot be said that the axial direction was consistently the stiffer (or less stiff) direction. but on average, the specimens acted stiffer in the axial direction than in the circumferential direction. simultaneous loading in these two orthogonal directions also allowed us to conclude that the mechanical response in one direction was influenced by the characteristics of the other direction. then, these cauchy stress-stretch curves were fitted to the fung and modified mooney-rivlin constitutive equations through eqs.(5,6,8,9) table represents the fung and mooney-rivlin best-fit material parameters for all the existing data. the mean values calculated are presented in the last column. based on the calculated rms error (table), the mooney-rivlin model approximately provides the best qualitative fit to the data. by using these material constants, stretch-stress curves were extracted and plotted in figure 3. the mean biaxial stretchstress curve for ureter was also obtained from the average fung constants mentioned in table and plotted in figure 2 as well. to validate the fitting method, the experimental data and model curves obtained from the material constants were illustrated together in figures 4 and 5 for specimens. it can be seen that predicted models are in agreement with experimental data. figure 1. diagram of the biaxial tensile test system (1: the micro stepper motors; 2: the load cells) mechanical properties of human ureter 1682 | discussion this study provides a complete set of experimental planar biaxial data for human ureter fitted to the two anisotropic constitutive models to describe its mechanical characteristics. the reliance of the constitutive behavior on the specific position in the tissue was overlooked and a homogeneous response was presumed. this approach, although suitable for modelling the behavior of the ureteral tissue at the macroscopic level, cannot associate the observation made with the naked eye with the microstructure. the soft tissue walls include extracellular matrix proteins and cells, which give origin to a multi-layered composite material where each layer has specific composition, organization and mechanical property. stiffer behaviour in the longitudinal direction had been reported in earlier research on uniaxial tensile tests for dog ureter as well.(10) inflation tests on rabbit ureter(11) also showed stiffer characteristics in the axial direction. in this figure 2. stress-stretch data for human ureter. the left hand plots (a) show the stresses and stretches in the circumferential (11) direction while the right hand plots (b) show the stresses and stretches in the longitudinal (22) direction. figure 3. stress-stretch curves obtained from the fung constants in circumferential (a) and axial (b) directions (λ 1 = λ 2 = λ). miscellaneous 1683vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l study, samples showed maximum stiffness in the longitudinal direction. the average strength in the longitudinal direction was 3.48 ± 0.47 mpa and 2.31 ± 0.46 mpa p < .05 for the circumferential direction. the behavior of the soft tissue up to the rupture point in the longitudinal and circumferential direction depends on the exposure of collagen, elastin fiber network and smooth muscle cells in its different layers. elastin fibers are involved in the initial phase of stretching; then, collagen fibers also participate in stress tolerance. the higher stiffness of the ureteral tissue in the longitudinal direction than in the circumferential direction indicates that the collagen is more effective in this direction because the elastin fibers have low strength.(22) under high strain ratio, the role of collagen is more important than that of elastin. the current investigation’s limitation is its method of sample preparation, as it was not possible for us to do the experiments when the tissues were alive. so we cannot discuss the small muscle cells’ roles in the mechanical properties of the ureteral tissue because when the tissue is alive, smooth muscle cells and their tension also contribute to the development of overall wall tension. as aforementioned we chose two anisotropic constitutive models for our biaxial data, where both models are well established as soft tissue materials and widely cited within figure 4. comparison of stretch-stress curves of fung model and experimental data for all specimens in circumferential (a) and axial (b) directions. figure 5. comparison of stretch-stress curves of mooney-rivlin model and experimental data for all specimens in circumferential (a) and axial (b) directions. mechanical properties of human ureter 1684 | the pertinent literature. the fung-type exponential model has been used to describe the mechanical properties of arteries,(16) but it has also been applied for myocardium,(23) epicardium,(24) rabbit ureter(11) and porcine intestine.(25) the mooney-rivlin model formulations based on polynomials and exponentials of strain invariants are also common in the literature(26,27) and have been implemented in many standard fe packages. these constitutive models demonstrated mechanical anisotropy and nonlinearity of the tissues, and the data (table) present some degree of anisotropy for ureteral wall. as mentioned, on average, the specimens acted stiffer in the longitudinal direction than in the axial direction. in the fung model the value of parameter a2 (0.699 ± 0.17) was higher than a1 (0.279 ± 0.07), which may be due to the collagen fiber orientation’s preference along the longitudinal axis, as earlier justified by the extracellular matrix component of ureteral tissue.(11) all of the models presented in this study were nonlinear and anisotropic. in particular, the mooney-rivlin model is an anisotropic model which can be used for fluid-structure interaction (fsi) numerical analysis in finite element analyses (fea) packages (e.g. a fsi procedure in a commercial finite-element package named adina). although the two models considered in this paper are phenomenological, they may be helpful as research references, offering good descriptive capabilities. more research is required to determine the efficacy of small muscle cells on the mechanical properties of the ureter through in-vivo experiments. moreover, further experimental investigations are needed to compare the mechanical properties of different segments of the ureter using the planar biaxial tensile test, and to compare the strength of the left and right ureteral tissues. conclusion in this study the mechanical properties of human ureter have been determined by using a biaxial mechanical device. the resultant stretch-stress curves from the experimental data miscellaneous table parameters of the two constitutive models. fung c (mpa) a1 a2 a3 anisotropy rms (mpa) ureter 1 1.8955 0.1202 0.1590 0.0291 0.79 0.0165 ureter 2 1.0372 0.7139 0.5293 0.4299 0.84 0.0237 ureter 3 0.8891 0.5528 0.7477 0.4663 0.84 0.0244 ureter 4 0.1632 0.1383 0.2221 0.8551 0.92 0.0106 ureter 5 0.7525 0.2138 0.4090 0.2356 0.69 0.0291 ureter 6 0.9477 0.1944 1.8774 0.4231 0.27 0.0349 ureter 7 0.3262 0.3556 0.9223 0.1229 0.46 0.0331 ureter 8 0.6828 0.1432 1.1083 0.1471 0.23 0.0073 ureter 9 1.1357 0.0671 0.8423 0.2702 0.3 0.0215 ureter 10 0.1631 0.2947 0.1743 0.2203 0.77 0.0053 average 0.4056 0.7091 0.1856 0.8892 0.67 0.0083 mooney-rivlin c 1 (mpa) d 1 (mpa) d 2 k 1 (mpa) k 2 rms (mpa) ureter 1 0.0395 0.2223 0.3566 -0.0100 0.1058 0.0109 ureter 2 0.0203 0.1820 0.8502 0.0430 0.4023 0.0205 ureter 3 -0.7233 1.3778 0.4801 -0.0558 0.3676 0.0244 ureter 4 -0.2411 0.2714 0.4694 0.0515 0.1970 0.0091 ureter 5 -0.1136 0.2302 0.5595 -0.0276 0.3615 0.0204 ureter 6 -0.1082 0.7183 0.7736 -0.4032 0.9814 0.0255 ureter 7 -0.4796 0.5492 0.4839 -0.0559 0.7150 0.0185 ureter 8 -0.1623 0.4968 0.5679 -0.1416 0.8185 0.0046 ureter 9 -0.3702 1.1924 0.4526 -0.2232 0.4047 0.0154 ureter 10 -0.0754 0.1529 0.3494 0.0031 0.2423 0.012 average -0.1114 0.2050 0.6803 0.0402 0.9106 0.0039 1685vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l references 1. vahidi b, fatouraee n, imanparast a, nasiraei-moghaddam a. a mathematical simulation of ureter:effect of the model parameters on ureteral pressure/flow relations. j biomech eng. 2011;133:1-9. 2. jimenez lozano jn. peristaltic flow with application to ureteral biomechanics. ph.d. thesis in mechanical engineering, notre dame university, indiana, usa;2009 . 3. woodburne rt, lapides j. the ureteral lumen during peristalsis. am j anat. 1972;133:225-8. 4. walsh pc, wein aj, kavoussi lr, peters ca, novick ac. campbell's urology. (4 volume set), 8th edition, elsevier science;2002. 5. smith ed, cussen lj, glenn j, et al. report of working party to establish an international nomenclature for the large ureter. birth def. 1977;13:3-8. 6. shokeir aa, nijman rjm. primary megaureter:current trends in diagnosis and treatment. bju int. 2000;86:861-8. 7. keating ma, escala j, snyder 3rd h m, heyman s, duckett jw. changing concepts in management of primary obstructive megaureter. j urol. 1989;142(2 pt 2):636-40. 8. biserte j. surgical treatment of primary mega-ureter. j prog urol. 1997;7:112-9. 9. king lr. megaloureter: definition, diagnosis and management. j urol. 1980;123:222-3. 10. yin fcp, fung yc. mechanical properties of isolated mammalian ureteral segments. am j physiol. 1971;221:1484-93. 11. sokolis dp. multiaxial mechanical behavior of the passive ureteral wall: experimental study and mathematical characterization. comput methods biomech biomed engin. 2012;15:1145-56. 12. hung h, chong c, steinhart a, trexler j, billiar k. design of a biaxial test device for compliant tissue. bioengineering conference. proceedings of the ieee 31st annual northeast. 2005;april;200-201. 13. sun w, sacks ms, scott mj. numerical simulations of the planar biaxial mechanical behavior of biological materials. asme summer bioengineering, miami, fl. 2003. 14. humphrey jd, strumpf rk, yin fcp. determination of a constitutive relation for passive myocardium: a new functional form. j biomech eng. 1990;112:333-9. 15. humphrey jd, strumpf rk, yin fcp. determination of a constitutive relation for passive myocardium: ii. parameter estimation. j biomech eng. 1990;112:340-6. 16. fung yc, fronek k, patitucci p. pseudoelasticity of arteries and the choice of its mathematical expression. am j physiol. 1979;237:62031. 17. holzapfel ga, gasser tc, ogden rw. a new constitutive framework for arterial wall mechanics and a comparative study of material models. j elasticity. 2000;61:1-48. 18. holzapfel ga, eberlein r, wriggers p, weizsacker h. large strain analysis of soft biological membranes: formulation and finite element analysis. comput method appl m. 1996;132:45-61. 19. holzapfel ga, gasser tc, ogden rw. comparison of a multi-layer structural model for arterial walls with a fung-type model, and issues of material stability. j biomech eng. 2004;126:264-75. were fitted to the four-parameter fung-type model as well as the modified mooney-rivlin model, and the anisotropy values of the samples were calculated by the constitutive fung model parameters. the samples showed some degree of anisotropy. the curves, on average, also showed stiffer behaviour in the longitudinal direction than in the circumferential direction. to conclude, this study may be used as a reference for the numerical simulation of ureter. acknowledgements the authors would like to gratefully acknowledge the iranian legal medicine organization for their support throughout this project by providing the specimens. ethical standards as mentioned earlier in the methods section, the human samples used in this study were taken from cadavers preserved in the iranian legal medicine organization. the families of the deceased had given their informed consent prior to resection. moreover, authorization to use these specimens was granted by the iranian legal medicine organization to the research team under letter no. p/49751, dated 11/08/2013. therefore, the standards laid down in the declaration of helsinki have been adhered to. authors’ contribution rasooli contributed to the modeling, data analysis, and manuscript writing. she also performed the experiments. shafigh helped with the experiments, specimen acquiring, and manuscript writing. seddighi acted as the consultant in the medical aspects of the project and helped evaluate the results. daneshparvar collaborated with the group from the legal medicine organization and was responsible for all the procedures up to resection. and fatouraee supervised the project through protocol development and manuscript editing. all authors read and approved the final manuscript. conflict of interest none declared. mechanical properties of human ureter 1686 | 20. holzapfel ga. similarities between soft biological tissues and rubberlike materials. in constitutive models for rubber-proceedings, balkema. 2005;4:607. 21. yang c, bach rg, zheng j, et al. in vivo ivus-based 3-d fluid-structure interaction models with cyclic bending and anisotropic vessel properties for human atherosclerotic coronary plaque mechanical analysis. ieee trans bio med eng. 2009;56:2420-8. 22. sokolis dp, kefaloyannis em, kouloukoussa m, marinos e, boudoulas h, karayannacos pe. a structural basis for the aortic stress–strain relation in uniaxial tension. j biomech. 2006;39:1651-62. 23. yin fc, strumpf rk, chew ph, zeger sl. quantification of the mechanical properties of noncontracting canine myocardium under simultaneous biaxial loading. j biomech. 1987;20:577-89. 24. humphrey jd, strumpf rk, yin fcp. a constitutive theory for biomembranes: application to epicardial mechanics. j biomech eng.1992;114:461-6. 25. bellini c, glass p, sitti m, di martino es. biaxial mechanical modeling of the small intestine. j mech behav biomed. 2011;4:1727-40. 26. kural mh, cai m, tang d, gwyther t, zheng j, billiar kl. planar biaxial characterization of diseased human coronary and carotid arteries for computational modeling. j biomech. 2012;45:790-8. 27. tang d, yang c, kobayashi s, et al. 3d mri-based anisotropic fsi models with cyclic bending for human coronary atherosclerotic plaque mechanical analysis. j biomech eng. 2009;131:061010. miscellaneous pediatric urology combined dietary recommendations, desmopressin, and behavioral interventions may be effective first-line treatment in resolution of enuresis pietro ferrara,1* valentina del volgo,2 valerio romano,1 valentina scarpelli,3 laura de gara,3 giacinto abele donato miggiano4 purpose: nocturnal enuresis (ne) is a very common multifactorial pediatric disorder and in children without any other lower urinary tract symptoms is defined as monosymptomatic ne (mne). pharmacological, psychological/behavioral, and alternative interventions are commonly used and the first-line drug therapy for patients with mne is desmopressin (ddavp) but the response rate is less than 40-60% and the relapse rate is about 50-80% after treatment. many studies show that some foods and beverages can promote diuresis or bladder irritability, which in some people can exacerbate bladder symptoms and ne. the present study aimed to compare the efficacy of combined specific dietary advices and ddavp vs ddavp alone. materials and methods: we enrolled in the study 172 patients affected by mne between january 2013 and may 2014, of these 35 were excluded. the inclusion criterion was primary mne and exclusion criteria included non-mne, secondary mne and lactose intolerance. children were treated with ddavp at a dose of 120 µg a day and were randomized to receive dietary recommendations. they were asked to fill out a charter depicting their wet and dry nights for the period of treatment. sixty-seven patients were randomly assigned to receive ddavp and dietary advices (group a) and 70 patients to receive ddavp alone (group b). results: we included in our study 137 children, 102 (74.5%) male, and 35 (25.5%) female, aged between 5 and 14 years. our results show a higher response rate and a lower number of relapse in group a vs group b with 67.2% of responders in group a vs 58.6% in group b, after 3 months of therapy and 31.1% of relapse in group a vs 46.3% in group b one month, after the end of treatment. conclusion: our results show the effectiveness of specific dietary advices in the management of primary mne. however further studies are needed to determine whether the difference between therapy with combined dietary recommendations and ddavp vs ddavp alone. keywords: nocturnal enuresis; therapy; treatment outcome; deamino arginine vasopressin; drug therapy; remission; diet; nutrition policy. introduction nocturnal enuresis (ne) is a very common pediatric disorder. the estimated prevalence of ne is highly variable be¬cause there is a heterogeneity in diagnostic criteria. it is estimated to be approximately 10-15% at 5-year old, 5-10% at 7-year old, 3-8% at 10-year old children and 1-4% in adolescents with 0.5-2% in the untreated adults.(1) a multicenter italian study shown an overall prevalence of 3.8%, which progressively decreased from 8.1% in males and 9.6% in females at age 6 years to 1.2% at age 13 years.(2) according to recent international children’s continence society (iccs), ne is defined as intermittent incontinence occurs exclusively during sleeping periods. ne should not be used to refer to daytime incontinence.(3) in children without any other lower urinary tract symptoms and without a history of bladder dysfunction is defined as monosymptomatic ne (mne). according to diagnostic and statistical manual of mental disorders (dsm) 5 ne is defined as repeated voiding of urine into bed or cloche while asleep in children older than 5 years. ne is a multifactorial disorder with a genetic underpinning. it has 3 main pathophysiological determinants that are nocturnal polyuria, detrusor overactivity and failure to awaken in response to bladder sensations (high arousal thresholds).(3-7) otherwise rectal distension due to fecal retention in chronic functional constipation causes bladder distortion and may cause stimulation of detrusor stretch receptors resulting in detrusor overactivity. so constipation is another cause of detrusor overactivity.(8) when organic disease is not suspected, and children suffer from mne that they consider a significant problem it should be treated.(9) pharmacological, psychological/behavioral and other interventions such as homotoxicology are commonly used.(10) simple behavioral interventions are often used as a first attempt to improve ne and include reward systems such as star charts given for dry nights, lifting or waking the children at night to urinate and to involve the child in cleaning up after wetting, so that they can share the responsibility.(11) many studies show that some foods and beverages can promote diuresis or 1 institute of pediatrics, catholic university of sacred heart, rome, italy. 2 service of pediatrics, campus bio-medico university, rome, italy. 3 food sciences and human nutrition unit, campus bio-medico university, rome, italy. 4 service of clinical nutrition, catholic university of sacred heart, rome, italy. *correspondence: institute of pediatrics, catholic university of sacred heart, l.go francesco, vito 1, rome 00168, italy. tel: +39 06 30154348 & fax: +39 06 3383211. e-mail: pferrara@rm.unicatt.it. received february 2015 & accepted june 2015 vol 12 no 04 july-august 2015 2228 detrusor over-activity, which in some people can exacerbate overactive bladder symptoms and ne. these findings explain how behavioral therapy by reducing the consumption of foods and drinks containing caffeine, carbonated drinks and fluid intake after 6 p.m. (or approximately 3-4 h before bedtime) can often promote continence.(12-14) the first-line drug therapy for patients with mne associated with nocturnal polyuria and normal bladder function is desmopressin (ddavp) for a period of 3 months following by withdrawal.(15) ddavp is associated with a response rate of about 4060% however its effect may not be maintained on discontinuing treatment, and symptoms have been found to recur in about 50-80% after stopping treatment.(9,15,16) the present study aimed to compare the efficacy of combined specific dietary advices and ddavp vs ddavp alone in these patients. materials and methods study participants according to the iccs classification, we enrolled 172 children with ne referred to the pediatric ambulatory, ‘campus bio-medico’ university of rome, from january 2013 to may 2014, of these 35 were excluded. the inclusion criterion was primary mne and exclusion criteria included non-mne, secondary mne and lactose intolerance, in order to avoid bias, secondary to the exclusion of lactose-containing foods: fresh dairy products with the preference of ripened cheeses whose lactose content is almost zero. the children and their families were asked to participate in the study at the end of the clinical evaluation and, after a 3 months observation period. treatment protocols eligible children were randomly divided into 2 groups assigned to receive combined ddavp and dietary recommendations (group a) or to receive ddavp alone (group b). children were treated for a period of 3 months with ddavp at a dose of 120 µg a day and were open randomized to receive dietary recommendations or nonspecific dietary advices such as reducing fluid intake after 6 p.m. the list of dietary advices have been made reviewing literature and consisted in a list of recommended food, not recommended food at evening and not recommended food (table). nonspecific advices consisted in simple advices given to the child and to the parents such as to reduce the fluid intake at evening and to treat constipation if present. the parents were asked to fill out a charter depicting their wet and dry nights and an alimentary diary. during the 3 months follow up we called families to verify their adherence to alimentary recommendation and to the therapy and their response. outcome measures according to the iccs classification for initial success, the children were classified as non-responders if there was no or less than 50% decrease in wet nights compared to baseline; partial responders if there was 50% or more, but less than 99% decrease in wet nights compared to baseline; responders if there was a 100% of reduction.(3) statistical analysis data are presented as frequency and percentage. paired-samples t test and independent-samples t test were used for continuous variables; the χ2 test was used for categorical variables. the significance level was set at p < .05. results we enrolled 172 patients with bedwetting. of these 35 (20.3%) were excluded for the following reasons: 19 because of presence of daytime symptoms, 11 were lost to follow up, 3 had undergone therapy with ddavp in the last 6 months, 1 patient was diagnosed with diabetes insipidus, and 1 patient had secondary ne. so we included in our study 137 children, 102 (74.5%) male and 35 (25.5%) female, aged between 5 and 14 years (mean age 8.8 years). sixty-seven patients were randomly assigned to receive combined ddavp and dietary recommendations (group a) and 70 patients to receive ddavp alone (group b). there were no differences in gender, age, or number of wet nights/week between groups. the baseline severity of mne was similar in the two groups (mean 6/7 wet night in both groups). after the first 3 months of therarecommended food not recommended food at evening not recommended food vegetables yogurt salt (spinach, chard, cauliflower, chicory, cabbage, legumes, water chocolate, cocoa tomatoes, eggplant, peppers, beans, cucumbers, asparagus, fruit carbonated drinks celery, peas, beans, lettuce, kale) (pineapple, melon, apples, watermelon, tea apricot, banana) fruit juice fish milk (specially grapefruit and orange) (tuna, salmon, sardines, sea bream, sole, sea bass) cheese seafood (mozzarella, cottage cheese, soft cheese, chartreuse) dried fruits cereals (gems of oats, wheat buds, puffed rice, corn flakes, wheat bran, muesli) eggs table. list of dietary advises in children with nocturnal enuresis. pediatric urology 2229 combination therapy in nocturnal enuresis-ferrara et al. py a response was achieved in 45/67 (67.2%) in group a vs. 41/70 (58.6%) in group b (p > .05). in group a there was a full response in 40/45 (88.9%) and a partial response in 5/45 (11.1%). partial responders had a mean reduction of wet night of 75%. in group b there was a full response in 37/41 (90.2%) and a partial response in 4/41 (9.8%). partial responders had a mean reduction of wet night of 80%. one month after the end of treatment, relapse, defined as bedwetting occurring more than 2 night per month after the 1-month treatment-free period, occurred in 14/45 (31.1%) of group a vs. 19/41 (46.3%) of group b (p > .05) (figure). discussion many studies showed that some foods and beverages can promote diuresis or detrusor overactivity and have suggested that absorptive nocturnal hypercalciuria might be responsible for ne in some patients.(12-14,17) therefore diet changes and behavioral interventions are usually recommended in mne to reduce fluid intake before bedtime, to reduce the consumption of carbonate drinks and to treat constipation. however most provided dietary advices to treat mne are non-specific and provided before the beginning of therapy. excessive fluid intake can cause polyuria and exacerbate overactive bladder symptoms and incontinence. fluid restriction reduces the total overnight urine production which reduces the child’s need to void overnight. otherwise carbonated drinks may contribute to overactive bladder symptoms and there are evidences that eliminating this kind of fluid from the diet may promote continence.(14) caffeine in particular has been shown to have a diuretic effect and may increase overactive bladder symptoms by increasing detrusor pressure and by promoting detrusor muscle excitability, so it should be avoided in mne.(12-14) caffeine is a constituent of variety of beverages and foods such as coffee, tea, cocoa and chocolate and we advised against them. (14,17) there is also evidence to suggest that aspartame and other artificial sweeteners induce detrusor contraction, so we recommended avoiding these bladder irritants.(14,18) fresh fruit also contributes to fluid intake because contains lot of water, but it also contains important vitamins, so we recommended to take it during daytime (and to avoid it at evening). as far as other dietary factors are concerned hypercalciuria has been considered as an important pathogenic factor of ne. high levels of calcium in the urine seem to decrease the amount of aquaporin-2 (aqp2) detectable in the urine and urinary excretion of aqp2 in humans has been proposed to be a potential marker of collecting-duct responsiveness to vasopressin, indeed studies report that urinary aqp2 correlates with the severity of ne in children.(19) moreover several studies demonstrated a strong association between ddavp resistance and hypercalciuria, with ddavp responsiveness increasing when a calcium restricted diet was implemented.(19,20) however an adequate calcium intake is important for healthy growth. for these reasons we recommended fresh cheese such as mozzarella and ricotta (italian soft cheese) especially during daytime, and advised against ripened cheese, such as parmesan cheese, grana padano and pecorino (italian sheep cheese) at every meal because aged cheese are too rich in calcium. to advise against milk would be unhealthy so we recommended taking it before 6 p.m. we also recommended drinking a bottle of water with lower calcium level. in order to low calcium intake we also recommended vegetables rich in oxalate and phytate, such as spinach, chard, legumes, tomatoes, eggplants and peppers, because they have been reported to inhibit bowel calcium absorption in association with fresh cheese.(21) otherwise in a recent study vitamin b12 and folate levels were found significantly lower in enuretic children compared with the control group.(22) vitamin b12 and folate are effective on the neurogenic maturation and lack of them could cause maturational delay of the central nervous system connections necessary for nocturnal bladder control. according to this hypothesis the most commonly emphasized pathophysiologic theory of ne proposes a delayed functional maturation of the central nervous system control on the bladder at night. basing on this possible lack of vitamin b12 and folate in enuretic children we recommended foods rich in them such as meat (entrails, above all), fish (pilchard, mackerel, salmon), albumen and yolk, seafood (mussel) and cheese, which all supply vitamin b12; wheat germ, wheat bran, corn flakes, crisped rice, asparagus, turnip greens, chickpeas, spinach, muesli, chard which all supply folate. another recent study suggests omega-3 fatty acids may influence ne by regulation of prostaglandin e2 (pge2), nitric oxide (no) synthesis and brain signaling.(23) it is important, because children with ne have been shown to have higher mean serum and urine pge2 levels and higher nitrite excretion compared with healthy controls. in fact pge2 and no (nitrite is a stable end product of no) inhibit sodium and fluid reabsorption and decrease anti-diuretic hormone production. effects on brain signaling are important because it has been suggested that ne represents a functional immaturity of the cns. basing on this study we recommended foods rich in omega-3 fatty acids such as fish, especially tuna, salmon, trout, bass, sea bream, better if caught in their natural environment rather than from fish breeding, dried fruit and cereals as germ of oats and wheat. figure. study flow chart. vol 12 no 04 july-august 2015 2230 combination therapy in nocturnal enuresis-ferrara et al. finally ne often occurs concomitantly with constipation defined in accord to roma iii criteria. this association is probably due to the close anatomical communication between bladder and rectum, which share muscular structures of the pelvic floor: the distension of the rectum by stool impaction in constipated children presses on the bladder wall, causing bladder outflow obstruction as well as inducing detrusor over-activity. for this reason it is necessary treat constipation if present, in fact constipated children with ne often become dry when successfully treated for their constipation. standard treatment of constipation includes advice regarding sufficient fluid and dietary fiber intake and regular toilet habits (e.g., defecation every morning after breakfast).(24) therefore we advised to improve fiber intake by recommending wheat bran and vegetables. we can summarize our dietary recommendations in three groups: recommended food, not recommended food at evening, not recommended food. we evaluated the effectiveness of these specific dietary advices comparing the response rate to therapy with ddavp and dietary recommendations (group a) vs. response rate to ddavp alone (group b). our results show a higher rate response and a lower number of relapse in group a vs. group b (67.2% of responders full and partial in group a vs. 58.6% in group b and 31.1% of relapse in group a vs 46.3% in group b). also if our preliminary results aren’t statistically significant we suppose it’s due to the small sample size and is possible that specific dietary recommendations are effectiveness in the management of primary mne. it suggests the effectiveness of specific dietary advices in the management of primary mne. strength of our study is to advice healthy diet regardless ne. our diet advices, indeed, can be followed by every child because they respect healthy diet principles and this is mainly important for parents since they are able to cook the same food for the whole family, even for those who do not have health problems and this is a strength point which improves parent’s adherence to our advices. another strength point is to propose dietary advices instead diet which is considered too restrictive for children (it need to know exact quantity of food and complete adherence and has to be customized) and too difficult to follow for parents. conclusions in conclusion mne is a common pediatric condition and, despite several treatment options, a group of children remain not responders to pharmacological therapy and it can be inconvenient and distressing to both the child and their family and recent studies shown persistence of ne can have medical consequences.(25-27) because behavioral modifications in association with pharmacological therapy can be superior to pharmacological therapy alone in treatment of mne we believe that further studies with a larger sample size are needed to determine whether the difference between therapy with ddavp used alone and ddavp plus dietary recommendations may become statistically significant. conflict of interest none declared. references 1. nevéus t, sillén u. lower urinary tract function in childhood; normal development and common functional disturbances. acta physiologica. 2013;207:85-92. 2. chiozza ml, 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and stress incontinence: a longitudinal study in women. bju int. 2003;92:69-77. 14. wyman jf, burgio kl, newman dk. practical aspects of lifestyle modifications and behavioral interventions in the treatment pediatric urology 2231 combination therapy in nocturnal enuresis-ferrara et al. of overactive bladder and urgency urinary incontinence. int j clin pract. 2009;63:117791. 15. ferrara p, romano v, cortina i, ianniello f, fabrizio gc, chiaretti a. oral desmopressin lyophilisate (melt) for monosymptomatic enuresis: structured versus abrupt withdrawal. j pediatr urol. 2014;10:52-5. 16. monda jm, husmann da. primary nocturnal enuresis: a comparison among observation, imipramine, desmopressin acetate and bedwetting alarm systems. j urol. 1995;154:7458. 17. aryan la, myers dl, jackon nd. dietary caffeine intake and the risk for detrusor instability: a case-control study. obstet gynecol. 2000;96:85-9. 18. dasgupta j, elliott ra, doshani a, tincello dg. enhancement of rat bladder contraction by artificial sweeteners via increased extracellular ca2+ influx. toxicol appl pharmacol. 2006;217:216-24. 19. valenti g, laera a, pace g, et al. urinary aquaporin 2 and calciuria correlate with the severity of enuresis in children, j am soc nephorol. 2000;11:1873-81. 20. nikibaksh a, poostindooz h, mahmoodzadeh h, karamyyar m, ghareaghaji rr, sepehrvand n. is there any correlation between hypercalciuria and nocturnal enuresis? indian j nephrol. 2012;22:88-93. 21. bohn l, meyer as, rasmussen sk. phytate: impact on environment and human nutrition. a challenge for molecular breeding. j zhejiang univ sci b. 2008;9:165-91. 22. altunoluk b, davutoglu m, garipardic m, bakan v. decreased vitamin b(12) levels in children with nocturnal enuresis. isrn urol. 2012;2012:789706. 23. logan ac, lesperance f. primary nocturnal enuresis: omega-3 fatty acids may be of therapeutic value. med hypotheses. 2005;64:1188-91. 24. vande walle j, rittig s, bauer s, et al. practical consensus guidelines for the management of enuresis. eur j pediatr. 2012;171:971-83. 25. ferrara p, de angelis mc, caporale o, et al. possible impact of comorbid conditions on the persistence of nocturnal enuresis: results of a long-term follow-up study. urol j. 2014;11:1777-82. 26. shadpour p, shiehmorteza m. enuresis persisting into adulthood. urol j. 2006;3:11729. 27. guzelsoy m, demirci h, coban s, belkiz güngör b, ustunyurt e, isildak s. impact of urinary incontinence on quality of life among residents living in turkey. urol j. 2014;11:1447-51. vol 12 no 04 july-august 2015 2232 combination therapy in nocturnal enuresis-ferrara et al. monograph challenges and choices in prostate cancer irradiation: from the three dimensional conformal radiotherapy to the era of intensity modulated, image-guided and adaptive radiation treatment maria-aggeliki kalogeridi,1 george kyrgias,1 anna zygogianni,2 john kouvaris,2 kyriaki theodorou,1 nikolaos kelekis,3 vassilios kouloulias3 abstract in the last decades the status of radiotherapy was tremendously increased in terms of conformity to the target as well as image-guided techniques in conjunction with intensity-modulated radiotherapy (imrt). the technological improvement had a significant clinical outcome for better response and lower toxicity to the surrounding normal tissues. nowadays the incidence of rectal toxicity has been significantly decreased, especially with image guided radiation therapy (igrt), whereas the dose escalation to the prostate has driven the clinical practice to the fact that radical radiotherapy for low or intermediate risk prostate cancer is definitely equivalent to surgery. the treatment volume can be reduced by reducing the size of the necessary margins to count for inaccuracies in target position and patient setup. this can be achieved either by improving the daily localization of the target before treatment or by adapting the treatment in response to feedback. this is the goal of image-guided and adaptive radiotherapy, respectively. these techniques improve the accuracy of dose delivery with a significant impact on clinical outcome and toxicity. keywords: prostatic neoplasms; radiotherapy; humans; brachytherapy; treatment outcome. introduction the prostate is the most common male malignancy and the second cause of death from solid tumors in males. radiotherapy, in the form of either external beam radiotherapy (ebrt) or brachytherapy along with radical prostatectomy, endocrine therapy and new-age chemotherapy, constitutes the approved therapeutic approach to prostate cancer.(1) traditional techniques of ebrt (i.e. conventional radiotherapy) have been well overpassed by novel techniques with the aim to increase tumor dose as a means of enhancing local control. however, the maximum dose that can be delivered to the prostate tumor is restricted by the tolerance of normal tissues within the high dose volume and by the target motions as well. the treatment volume can be reduced by reducing the size of the necessary margins to account for inaccuracies in target position and patient setup. this can be achieved either by improving the daily localization of the target before treatment or by adapting the treatment in response to feedback. all those are goals of the newer techniques in order to enhance the delivered dose with a significant impact on clinical outcome while minimizing the probability of geographic miss and toxicity. challenges and choices dose escalation and related toxicity conventional radiotherapy using the “classical” four field technique (the so called “boxtechnique”) has been for long the standard radiotherapy approach and could safely deliver a total dose of 66.6-70 gy.(2) currently this dose is considered insufficient to provide satisfactory local control.(3,4) several studies have shown that dose escalation for radiotherapy of prostate cancer leads to an improved clinical outcome and biochemical control.(4-9) however, the higher dose to the prostate may lead to significant toxicity by increasing the dose to the organs at risk. this was the result of a multicenter, randomized trial comparing 68 gy to 78 gy for prostate cancer. the trial showed a considerably higher incidence of late rectal toxicity displayed with rectal bleeding in patients receiving 78 gy with conventional technique.(10) overall, the meta-analysis carried out in randomized studies of dose-escalation showed that late side effects increase with increasing total radiation therapy (rt) dose.(11) since there was a need to improve radiotherapy technique so that greater doses could be delivered without increasing normal tissue complications, conventional radiotherapy has largely been replaced by a more sophisticated form of ebrt, the so-called three-dimensional conformal radiotherapy (3d-crt).(12) the primary aim of 3d-crt is to provide dose distributions accurately shaped to the target, following a treatment planning which defines the tumor and healthy organs with a volumetric image-based approach. the evidence-based american society for ra1 department of radiotherapy, faculty of medicine, school of health sciences, university of thessaly, larissa, thessaly, greece. 2 first department of radiology, radiotherapy unit, medical school, kapodistrian university of athens, greece. 3 second department of radiology, radiotherapy unit, medical school, kapodistrian university of athens, greece. *correspondence: second department of radiology, radiotherapy unit, kapodistrian university of athens “attikon” university hospital of athens, haidari,greece. tel: +30 210 5831860. e-mail: vkouloul@ece.ntua.gr. received june 2014 & accepted october 2014 vol 11. no 06 nov-dec 2014 1925 diation oncology (astro) systematic review showed a decrease in acute toxicity by virtue of 3d-crt.(13) a further step of conformal radiotherapy is imrt which allows higher dose gradients(14,15) that improve dose conformity relative to tumor coverage and exposure of normal tissues (figure 1). moreover, imrt allows for “dose painting” by delivering different doses to different areas of the planning tumor volume (ptv). on the other hand, in the trials using imrt to deliver increased rt dose, having however a shorter follow-up, the late gastrointestinal (gi) toxicity reported is lower to the one reported by trials using 3d-crt technique.(11) with these advances in technology and more sophisticated treatment planning systems, more complex treatment plans with tightly conforming doses can be created. thus, it is possible to deliver escalated doses to the treatment volume without increasing toxicity. moreover, the dose distribution delivered to the site of interest can be highly conformal with steep dose gradients. organ motion, set-up errors and related problems a major concern in prostate cancer patients receiving radiotherapy is toxicity in relation to dose escalation. as mentioned above, the imrt technique partially fulfilling this issue. however, any variation in organ volume or position during treatment may significantly alter the actual dose delivered to both the target volume (geographic miss of the target) and surrounding normal tissues (organ motion’s related toxicity). when treating the prostate the potential disadvantage of these novel techniques is the risk of geographic miss due to tight margins and organ motion.(16) the position of the prostate within the pelvis from one treatment to another is affected by physiologic changes in the bladder filling and rectum volume.(17,18) moreover, during radiotherapy there is prostate deformation unrelated to differential rectum or bladder filling, but related to a prior transurethral resection of the prostate (p = .003).(19) even with the use of a variety of external immobilization devices, patient positioning by skin marks and lasers is not a precise way to target the prostate since the gland itself moves within the pelvis, as shown in figure 2. although efforts have been made to reduce prostate motion with the placement of an endorectal balloon, this method cannot reduce the interfraction prostate motion.(20) these variations in position and shape can be left unchanged and compensated with wide margins, or reduced by image guidance resulting in smaller irradiated volumes of normal tissues. since smaller margins are important to reduce the dose to the organs at risk, effort has been directed at reducing uncertainties with the use of image guidance that increases the precision of radiation dose delivery. as a result, although a safety margin of 8 mm laterally and 1 cm sagitally and coronally around the prostate is recommended without any image guidance(21,22) comparable optimal target coverage can be achieved with a reduction of margins in combination to image guided techniques. the use of a newer technique, the so-called image-guided radiotherapy (igrt) achieves the goal to reduce toxicity while maintaining dose escalation. igrt implies the use of a variety of imaging techniques in the treatment room to determine the location of target areas within the patient in the treatment position. there are many image guidance methods using ultrasound, x-ray systems, kilovoltage (kv)or megavoltage computed tomography (mvct) systems or even magnetic resonance imaging (mri) technologies.(23) mri-guided radiotherapy devices are not yet available for clinical use. however, their prototypes are being investigated as their routine use would allow image guidance without radiation exposure for image acquisition. the various image guidance devices may monitor soft tissue prostate anatomy or implanted markers. transabdominal ultrasound was the first widely used technique for daily prostate localization in the treatment room. ultrasound imaging of the prostate provides a setup tool for patients undergoing imrt radiotherapy for localized prostate cancer that takes into account real-time prostate position and may make it possible to decrease tumor margins.(24) morr and colleagues found that daily figure1. typical intensity-modulated radiotherapy plan for prostateand seminal vesicles irradiation (personal archive). figure2. uncertainties of target (prostate and seminal vesicles) dueto movements of pelvic organs such asrectum and bladder in 1 stand 4th week oftreatment. from 3dcrt to imrt/igrt for prostate cancer-kalogeridi et al monograph 1926 computed assisted ultrasound positional verification of the prostate can be successfully performed through the acquisition of high-quality images in most patients with only a modest increase in setup time.(25) nevertheless, in reports evaluating the acceptability of these images for target position verification in the setting of imrt for prostate cancer the rates of usable images varies significantly. in the study of morr and colleagues poor image quality was associated with patient inability to maintain a full bladder, large body habitus or other anatomic constrains.(25) moreover ultrasound probe itself may displace the prostate.(26,27) another widely studied imaging technique is the use of implanted markers in the prostate gland. markers can be implanted using a transrectal ultrasound-guided procedure, similar to prostate biopsy. these markers can be detected using kv x-rays or an electronic portal image device (epid) in the treatment room. although there is interfractional motion for both the patient’s prostate as well as bony anatomy, these move independently, so the pelvic bony anatomy should not be used as a surrogate for prostate position.(28) implanted markers could be the golden standard for position verification if they are stable within the prostate. according to poggi and colleagues, there is negligible seed migration within the prostate over the entire course of definite radiotherapy although there are small, detectable movements in individual seed locations perhaps resulting from topographic changes in the gland secondary to seed placement, anatomic changes in bladder or rectum and treatment itself.(29) daily portal imaging with implanted fiducials has improved the ability to localize the prostate in patients receiving imrt and is necessary for the reduction of the treatment margins. (30,31) nevertheless, these markers do not define the shape or volume of prostate during daily treatment, because of deformation or rotation of the gland. there is greater movement of the prostatic base and seminal vesicles than the apex and center of the gland with changes in rectal and bladder filling.(32) fiducial markers are unable to count for this variability which may result in exclusion of portions of the prostate and seminal vesicles from treatment fields with reduced treatment margins of imrt technique. another disadvantage is that the implantation of markers is an invasive procedure requiring the service of an interventional radiologist, while there is the possibility of complications such as urinary frequency, hematuria, rectal bleeding, dysuria or hematospermia in up to 13% of patients.(33) most symptoms are grade 1 or 2 in severity, but can last more than two weeks in 9% of patients.(32) despite these shortcomings, a recent study comparing prostate localization using three-dimensional ultrasound (3d-us) to a standard technique using implanted fiducial markers (fms) for prostate image-guided radiation therapy indicated that us cannot replace fms for prostate igrt since the latter can offer greater sparing of the rectum and bladder.(34) the limitations of marker-based strategies argue for the development of another imaging modality. linear accelerators equipped with kv cone-beam computed tomography (cbct) have gained popularity. they enable direct visualization of soft-tissue targets such as prostate gland and organs at risk immediately before treatment using a kv-x ray tube with detectors on-board on the linear accelerator. cbct permits the acquisition of 3d volumetric images of excellent quality while the patient is in the treatment position.(35) after acquiring a set of in-room ct images target alignment can be chosen to bone, soft tissues or implanted markers. igrt with cone-beam computed tomography for imrt prostate plans has the potential to improve target localization and to provide guidelines for margin definition.(36-38) an issue that needs further study is the need for daily cbct, since it increases the time between imaging and treatment, potentially increasing the impact of intrafraction motion. moreover, each cbct delivers and additional dose to the patient, ranging between 2 and 4 cgy centrally.(39) wu and colleagues studied the combination of online and offline processes to increase the confidence in the delivery of image-guided radiation therapy.(40) for the online process, treatment and planning cts were registered by matching the treatment ct image with the contours drawn on the reference ct. this was called image-based registration (ibr). for the offline process, treatment and reference cts were registered using contours on these cts. this was called contoured-based registration (cbr). this study indicated that offline compensation using imrt can effectively repair the dose deficit incurred during early fractions and therefore complements the online image guidance procedure and offers the potential to further reduce margins. compared with the single dose compensation at the end of the treatment course, dose compensation performed at weekly intervals is as effective and more biologically beneficial. in terms of quality assurance, the minimum requirements for the best treatment practice is authors patients no. dose (gy) technique acute gi toxicity acute gu toxicity late gi toxicity late gu toxicity (%) (%) (%) (%) (%) grade 2 grade 3 grade 2 grade 3 grade 2 grade 3 grade 2 grade 3 lips et al,44 331 76 imrt 30 0 47 3 9 1 21 4 martin et al,45 259 79.8 3d-crt 10.1 33.3 0 3.1 1.2 7.4 1.2 imrt ghadjar et al,46 102 80 imrt 2 0 43 5 5 0 21 1 guckenberger et al,47 100 76.23 imrt ≥ grade 2: 12 ≥ grade 2: 42 ≥ grade 2: 1.5 ≥ grade 2: 7.7 nath et al,48 100 76 imrt 11 0 90 0 2 0 17 0 eade et al,49 101 78.3-84 imrt ≥ rade 2: 6.9 ≥ grade :2 39 ≥ grade 2:2 ≥ grade 2: 3 table 1. toxicity of high dose image-guided radiotherapy for prostate cancer. abbreviations: gi, gastrointestinal; gu, genitourinary; 3d-crt, three-dimensional conformal radiotherapy; imrt, intensity-modulated radiotherapy. from 3dcrt to imrt/igrt for prostate cancer-kalogeridi et al vol 11. no 06 nov-dec 2014 1927 the weekly image-based registration and compensation of treatment planning. in a study by gill and colleagues,(41) it was reported that ≥ grade 3 urinary frequency and ≥ grade 2 diarrhea were significantly more common in the non-igrt group than the igrt group (23% vs. 7%, p = .0118 and 15% vs. 3%, p = .0174, respectively). overall, symptoms occurred later in the treatment course for igrt patients compared to non-igrt patients. the former group had also a sho duration of toxicity.(41) these results are in line with other studies reporting acceptable gi and genitourinary (gu) toxicity with daily image-guidance for the delivery of higher than conventional radiation doses (table 1). (42-47) there also available systems based on the application of megavoltage (mv) for ct acquisition. helical tomotherapy is the fusion of a linear accelerator with a helical mv fan beam ct that allows for daily ct-assisted positioning of the patient followed by a rotational imrt. helical tomotherapy has given encouraging results for prostate cancer radiation therapy.(48,49) it is highly effective in a simultaneous integrated boost scenario(50) as well as in hypofractionated postprostatectomy radiotherapy.(51) patient-specific approach the identification of treatment variations including setup errors, organ motion and deformation have increased the awareness of limitations in therapeutic gain using conventional radiation therapy (crt) and imrt.(52,32) as mentioned before, while appreciable margins need to be added to the target volume to account for these inaccuracies these margins increase normal tissue toxicity and hinder dose escalation. a reduction of these margins can be achieved if they are not based on population averages but they become patient-specific. in fact, this is the goal of adaptive radiotherapy (art) that introduces the use of patient-specific margins using image feedback of prostate location and patient setup position. the art process introduced in william beaumont hospital has been designed to improve accuracy of dose delivery, enhancing dose escalation.(53) there are two solutions for adaptive radiotherapy. an off-line solution to motion might include planning with somewhat larger margins initially, obtaining daily scans with the initiation of treatment for some number of treatment days, and then generating a margin that is specific to that patient and continues to be used from that point forward without much additional imaging. this strategy avoids systematic errors, primarily in patient positioning. an on-line solution might be to initiate therapy with small initial margins, image the patient daily and make daily positional adjustment for the patient. this is the best possibility avoiding both systematic and random errors, but the clinical workload will be dramatically greater.(54) martinez and colleagues(53) reported that there was a potential for dose escalation for prostate patients enrolled in the art process with an increase up to 10% (mean 5%) at the prescription dose level, in comparison to the conventional treatment process. this level could be further increased to 5-15% (mean 7.5%) when the imrt delivery was combined with the art process. moreover, the art process identified the group of patients for which the dose should not be escalated above conventional levels, due to the large variations in clinical target volume (ctv) position observed during treatment course. this is paramount to keep complication rates low.(53) brabbins and colleagues studying 280 patients undergoing art with crt or imrt technique for localized prostate cancer found that significant dose escalation can be achieved without increasing gu or gi toxicity.(55) nuver and colleagues(56) reported that the adaptive off-line procedure allows for reduction of the ptv margin to 7 mm (from 10 mm) without decreasing target coverage during treatment. by decreasing the treatment volume one also treats less of normal dose-limiting tissue. the same study concluded that the dose received by the rectal wall will be reduced using art and the number of patients who suffer from serious side effects, such as late rectal bleeding, is expected to be reduced. when imrt is applied for prostate cancer the irradiated treatment volume can be reduced by 29% leading to a significantly reduced probability by 19% and 16% for late rectal bleeding and fecal incontinence, respectively.(57) conclusion nowadays in the psa-screening era,(58) as recommended by national comprehensive cancer network (nccn),(59) to treat prostate cancer the use of a 3d-crt technique is minimally required, while the imrt technique should be preferred, as long as it is available. either way imrt/ igrt is required for doses ≥ 78 gy. overall, imrt/ igrt could become the standard of practice in dose-escalated radiotherapy since it can allow the delivery of higher doses while maintaining acceptable toxicity levels. (60-63) however, there is still considerable scope for further improvement of igrt systems. the ideal system would allow for precise daily imaging without significant extension of treatment time or patient exposure to additional radiation. and, when all is said and done, we think there is no better conclusion than the one stated by g. rodrigues in his recent commentary: “new innovations in radiotherapy technique need to be assessed for both treatment efficacy and for normal tissue toxicity to demonstrate improvements in the therapeutic ratio prior to widespread adoption”.(63) conflict of interest none declared. references 1. aus g, abbou cc, bolla m, et al. eau guide lines on prostate cancer. eur urol. 2005;48:546-51. 2. jereczek-fossa ab, orecchia r. evdence based radiation oncology: definitive, adju vant and salvage radiotherapy for non-met astatic prostate cancer. radiother oncol. 2007;84:197-215. 3. kupelian pa, mohan ds, lyons j, klein ea, reddy ca. higher than standard radia tion 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radiotherapy. radiat oncol. 2011;6:145. 42. lips im, dehnad h, van gils c, boeken kruger ae, van der heide ua, van vulpen m. high-dose intensity-modulated radi otherapy for using daily fiducial mark er-based position verification: acute and late toxicity in 331 patients. radiat oncol. 2008;3:15. 43. martin jm, bayley a, bristow r, et al. image guided dose escalated prostate radiotherapy: still room to improve. radiat oncol. 2009;4:50. 44. ghadjar p, gwerder n, manser p, et al. high dose (80 gy) intensity-modulated radiation therapy with daily image-guidance as prima ry treatment for localized prostate cancer. strahlenther onkol 2010;186:687-92. 45. guckenberger m, ok s, polat b, sweeney ra, flentje m. toxicity after intensitymod ulated image-guided radiotherapy for prost ate cancer. strahlenther onkol. 2010;186:535-43. 46. nath sk, sandhu ap, sethi ra, et al. target localization and toxicity in dose-escalated prostate radiotherapy with image-guided ap proach using daily planar kilovoltage imagi ng. technol cancer res treat. 2011;10:31-7. 47. eade tn, guo l, forde e, et al. image-guid ed dose-escalated intensity-modulated radia tion therapy for prostate cancer: treating to doses beyond 78 gy. bju int. 2012;109:1655-60. 48. longobardi b, berardi g, fiorino c, et al. anatomical and clinical predictors of acute bowel toxicity in whole pelvis irradiation for prostate cancer with tomotherapy. radiother oncol. 2011;101:460-4. 49. fiorino c, alongi f, broggi, et al. physics aspects of prostate tomotherapy: planning optimization and image-guidance issues. acta oncol. 2008;47:1309-16. 50. geier m, astner st, duma mn, et al. dose-escalated simultaneous integrated-boo st treatment of prostate cancer patients via h elical tomotherapy.strahlenther onkol. 2012;188:410-6. 51. cozzarini c, fiorino c, di muzio n, et al. hypofractionated adjuvant radiotherapy with helical to motherapy after radical prostatec tomy: planning data and toxicity results of a phase i-ii study. radi-other oncol. 2008; 88: 26-33. from 3dcrt to imrt/igrt for prostate cancer-kalogeridi et al monograph 1930 52. rudat v, schraube p, oetzel d, zierhut d, flentje m, wannenmacher m. combined er ror of patient positioning variability and pro state motion uncertainty in 3d conformal ra diotherapy of localized prostate cancer. int j radiat oncol biol phys.1996;35:1027-34. 53. martinez aa, yan d, lockman d, et al. im provement in dose escalation using the proc ess of adaptive radiotherapy combined with three-dimensional conformal or intensity modulated beams for prostate cancer. int j radiat oncol biol phys. 2001;50:1226-34. 54. kupelian p, meyer j. prostate cancer: image guidance and adaptive therapy. in: jl meyer ed. imrt, igrt, sbrt. advances in the tr eatment planning and delivery of radiother apy. karger; 2007. p. 302-3. 55. brabbins d, martinez a, yan d, et al. a dose-escalation trial with the adaptive radio therapy process as a delivery system in local ized prostate cancer: analysis of chronic tox icity. int j radiat oncol biol phys. 2005; 61: 61:400-8. 56. nuver tt, hoogman ms, remeijer p, van herk m, lebesque jv. an adaptive off-line procedure for radiotherapy of prostate cance r. int j radiat oncol biol phys. 2007;67:1559 67. 57. nijkamp j, pos f, nuver t, et al. adaptive radiotherapy for prostate cancer using kilo voltage conebeam computed tomography: first clinical results. int j radiat oncol biol phys. 2008;70:75-82. 58. stamatiou kn. elderly and prostate cancer screening. urol j. 2011;8:83-7. 59. nccn clinical practice guidelines in on cology (nccn guideline®: prostate cancer version 2.2014, available at www.nccn/org/ patients. 60. boda-heggemann j, lohr f, wenz f, flent je m, guckenberger m. kv cone-beam ct based igrt: a clinical review. strahlenther onkol. 2011;187:284-91. 61. zelefsky mj, kollmeier m, cox b, et al. im proved clinical outcomes with high-dose im age guided radiotherapy compared with non-igrt for the treatment of clinically loc alized prostate cancer. int j radiat oncol biol phys. 2012;84:125-129. 62. pinkawa m, piroth md, holy r, et al. com bination of dose escalation with technologi cal advances (intensity-modulated and im age-guided radiotherapy) is not associated with increased morbidity for patients with prostate cancer. strahlenther onkol. 2011;187:479-84. 63. rodrigues g. is intensity-modulated radio therapy for prostate cancer ready for prime time? can j urol. 2012;19:6381-2. from 3dcrt to imrt/igrt for prostate cancer-kalogeridi et al vol 11. no 06 nov-dec 2014 1931 editorial comments re: evaluation of microdissection testicular sperm extraction results in patients with non-obstructive azoospermia: independent predictive factors and best cutoff values for sperm retrieval the authors from turkey smartly show the predictive factors for successful sperm retrieval rate (srr) with mi-crodissection testicular sperm extraction (micro-tese), carried out on men with non-obstructive azoospermia (noa). in men with noa, retrieval of spermatozoa provides a chance for fatherhood, in spite of very scares sperm production. men go through assessment for infertility are found to have azoospermia in their ejaculate in up to 10% of the cases.(1) around 60% of these cases are due to noa.(2) men with noa need some type of sperm retrieval (sr) technique in combination with intra-cytoplasmic sperm injection (icsi) to have their own children. there are some methods for sr, including, percutaneous testicular biopsy, fine needle aspiration (fna), open testicular biopsy (testicular sperm extraction (tese), which includes multiple tese), and micro-tese. micro-tese is now one of the most popular sr techniques for men with noa. although the success of micro-tese compared to other sr techniques has been widely documented, a complete judgment of predicting preoperatively whom the technique is going to be successful is not totally clear and remains controversial. in addition reported srr can be biased either by including patients demonstrating nearly normal spermatogenesis, or by inclusion of patients without available testicular histology. therefore, successful srrs reported in the literature for noa men differ from around 30% to level more than 80%. in well-designed studies with well-defined men with noa, the reported successful srrs after a first tese attempt is about 50%. nonetheless, due to invasive nature of tese, men with noa want to have a well prediction of likelihoods of successful srr than tossing a coin. since testicular volume and serum follicle stimulation hormone (fsh) levels are routinely evaluated in men with azoospermia, these parameters are regularly used, alone or in combination, to predict successful sr. unfortunately, their predictive value remains restricted and is subject to the demographic and clinical characteristics of the studied patients with noa. idem ditto for the predictive parameters for successful sr has been published by boitrelle and colleagues.(3) the positive likelihood ratios for the stand-alone parameters are less than 2 and hereafter not of a great diagnostic power in predicting testicular srr. with a positive likelihood ratio of 3, a predictive score combining serum fsh concentration, testicular volume, and serum inhibin-b level, seems more favorable in their setting. nevertheless again, is this a strong predictive model appropriate to every men with noa? all seminiferous tubules (st) must be inspected to recognize small foci of normal spermatogenesis. the sts are extremely coiled within very fine septae. the dissection should be performed between tubules to permit access to deeper portions of the sts. the space between the tubules and the tunica is very vascular, thus hemorrhage that would be very difficult to control can happen if dissection is made in this plane. to avoid separation of sts from their blood supply and thus devascularization of the sts, unnecessary force during the dissection should be avoided. postoperative hemorrhage and hematoma formation after micro-tese can result in scar formation within the testis. cautious dissection and careful hemostasis, will minimize these complications. microdissection continues until sperm are found or all areas of both testes are examined. usually, small samples of 2-10 mg are taken. if sperm are not found in one testis, the process should be repeated in the contralateral testis. when sufficient sperm are obtained, hemostasis is accomplished using bipolar cautery. improvement of spermatogenesis before proceeding to sr should be tried in cases where the female age permits. hormonal therapy can increase endogenous testosterone (t) production and normalize the testosterone/estrogen ratio in men with documented hypogonadism. hormonal therapy includes administration of aromatase inhibitors, clomiphene citrate, and human chorionic gonadotropin (hcg). in patients with klinefelter's syndrome and low serum t level, when t increases to greater than 250 ng/dl with medical therapy, srr with micro-tese will be higher.(4) the rationale behind of such treatment based on the fact that most men with noa have small testes with reduced t production and hypogonadism. sufficient intratesticular androgen levels are vital to maintain normal spermatogenesis. in some cases with noa gonadotropins administration are worthwhile, these include mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specializing in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com. vol 12 no 06 november-december 2015 2444 men with noa and testicular histology demonstrating hypospermatogenesis, and men who had failed initial micro-tese.(5) men with noa may benefit from clomiphene citrate administration even with serum normal t level. up till now, there are yet no absolute preoperative predictive criteria for successful sr in men with noa. fsh, serum t levels and testes volume indicate global testicular function and are not indicator for presence of a site of normal spermatogenesis within a testis. despite the widespread use of tese, consistent clinical and laboratory prognostic factors of sr are lacking. in the literature there are many proposed prognostic factors including testis size, serum fsh, inhibin β, genetic alterations and the etiology of infertility; nevertheless, the histological testicular pattern remains the best predictor of sr, although with the awkwardness of a second invasive procedure. testicular histopathology examinations, in contrast, provide better prognostic factor compared with the aforementioned markers. srrs by micro-tese are considerably higher in hypospermatogenesis (93%) compared with maturation arrest (64%) and sertoli cell only syndrome (20%).(6) the best method to identify sperm-containing st is using from operating microscope. the best sensitivity and specificity for a positive result on sr is achieved with 250 µ slices. currently we need a novel techniques which can help us in the detection of sperm-producing st without the necessity of tissue removal. multiphoton microscopy has been used successfully to differentiate normal from abnormal spermatogenesis both in animal model and in humans.(7,8) confocal fluorescence microscopy has also been applied in a murine model of micro-tese.(9) in addition, full field optical coherence tomography, is a useful tool to simplify real-time visualization of spermatogenesis in an ex vivo rodent sco model.(10) there is no individual characteristic or factor that can absolutely predict the ability to sr during a surgical procedure. while preoperative factors still do not offer an accurate model to predict success of micro-tese, data on literature demonstrate that a combination of these factors can be used to counsel patients and help guide clinical decisions. testicular sr is a feasible and successful procedure. testicular spermatozoa can be retrieved from the testis even in men with testicular azoospermia and severe impaired spermatogenesis. but, surgical injury of the testis might also damage the interstitial compartment of the testis with testosterone deficiency as a result. therefore, endocrine follow-up is mandatory following micro-tese. references 1. irvine ds: epidemiology and aetiology of male infertility. hum reprod. 1998;13(suppl 1):3344. 2. willott gm: frequency of azoospermia. forensic sci int. 1982;20:9-10. 3. boitrelle f, robin g, marcelli f, et al. a predictive score for testicular sperm extraction quality and surgical intra-cytoplasmic sperm injection outcome in non-obstructive azoospermia: a retrospective study. hum reprod. 2011;26:3215-21. 4. ramasamy r, ricci ja, palermo gd, gosden lv, rosenwaks z, schlegel pn. successful fertility treatment for klinefelter's syndrome. j urol. 2009 ;182:1108-13. 5. aydos k1, unlü c, demirel lc, evirgen o, tolunay o. the effect of pure fsh administration in non-obstructive azoospermic men on testicular sperm retrieval. eur j obstet gynecol reprod biol. 2003;108:54-8. 6. verza s, esteves sc. microsurgical versus conventional single-biopsy testicular sperm extraction in nonobstructive azoospermia: a prospective controlled study. fertil steril. 2011;96:s53. 7. ramasamy r, sterling j, fisher es, et al. identification of spermatogenesis with multiphoton microscopy: an evaluation in a rodent model. j urol. 2011;186:2487-92. 8. najari bb, ramasamy r, sterling j, et al. pilot study of the correlation of multiphoton tomography of ex vivo human testis with histology. j urol. 2012;188:538-43. 9. smith rp, lowe gj, kavoussi pk, et al. confocal fluorescence microscopy in a murine model of microdissection testicular sperm extraction to improve sperm retrieval. j urol. 2012;187:1918-23. 10. ramasamy r, sterling j, manzoor m, et al. full field optical coherence tomography can identify spermatogenesis in a rodent sertolicell only model. j pathol inform. 2012;3:4. evaluation of microdissection testicular sperm extraction results-cetinkaya et al. sexual dysfunction and infertility 2445 reply by authors microdissection testicular sperm extraction (micro-tese) is the most popular and acceptable method for sperm retrieval (sr) according to our knowledge. yes we agree with you, the success rate of sr were found between 30% and 80% in several studies and also success rate in sr varies depending on the degree of disorder in testicular pathology. the most important thing is that to what percentage of the sperm found and which histologic subgroup. therefore, it’s more proper that we consider success rate into each subgroup instead of total success rate. if we have all patients with hypospermatogenesis, of course we will have high success rate, in contrast if we have done micro-tese in patients with just sertoli cell only syndrome we will have low success rate. in addition as you mentioned the success rate is around 50% in patients with non-obstructive azoospermia (noa) in well-defined studies. i would like to mention again azoospermia factor (azf) deletion should be evaluated in patients with noa in additional to routine parameters which you recommend. because, azf deletion were more common in patients with azoospermia and oligozoospermia and also azf deletions have diagnostic and predictive values. evaluation of y chromosome microdeletions in nao were strongly recommended by guidelines. in case of complete microdeletion of azfa or azfb micro-tese is not necessary due to unlikely sperm found.(1) urologist should avoid extreme dissection which can cause scar to preventimpaired testosterone production. we agree with what you said about hormone therapy. janosek-albright and colleagues reported that medical treatment was effective and recommended for men with hypogonadotropic hypogonadism; therefore, medical treatment can often obviate the need for sperm retrieval techniques.(2) the aim of hormonal manipulation was to increasing endogenous production of testosterone and normalizing the testosterone/estrogen ratio in men with clear hypogonadism. men with hypospermatogenesis, men who failed initial micro-tese but before a repeat micro-tese, might benefit from a trial of gonadotropins.(2) certainly, there were not predictive factors which clinically clarified. as you mentioned above the best predictive factor is testicular histology. we also would like to mention that, the fiberoptic confocal microscopic study on animalresults inhigher sr success rate and lower operation time. everaert and colleagues evaluated the effect of micro-tese on androgens in long term follow up and they found that de novo androgen deficiency occurred in 16% of the male patients following micro-tese, indicating that, in men with noa, long term hormonal follow up is recommended after micro-tese.long-term androgen deficiency is a potential risk of micro-tese and patients with noa need to be informed about this possible complication.(3) mehmet cetinkaya,1 kadir önem2 references 1. jungwirth a, diemer t, dohle gr, et al. european association of urology guidelines on male infertility. eur urol. 2014. 2. janosek-albright kjc, schlegel pn, dabaja aa. testis sperm extraction. asian j androl. 2015;2:79-84. everaert k, de croo i, kerckhaert w, et al. long term effects of micro-surgical testicular sperm extraction on androgen status in patients with non obstructive azoospermia. bmc urol. 2006;6:9. vol 12 no 06 november-december 2015 2446 review articles erectile dysfunction: clinical guidelines (2) safarinejad mr*, hosseini sy urology/nephrology research center, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: according to a survey, the massachusetts male aging study, 52% of men beyond 40 years of age may have some degrees of erectile failure, and it is projected to affect 322 million men worldwide by 2025. we present a framework for the evaluation, treatment, and follow-up of the male patient who presents with erectile dysfunction. materials and methods: a comprehensive review of the literature was conducted using the medline database for all articles from 1975 through 2004 on male sexual dysfunction and the most pertinent articles are discussed. results: remarkable progress has been made in the treatment of erectile dysfunction (ed). erectile dysfunction is a common condition associated with aging, chronic illnesses and various modifiable risk factors. erectile dysfunction can be due to vasculogenic, neurogenic, hormonal, and/or psychogenic factors as well as alterations in the nitric oxide/cyclic guanosine monophosphate pathway or other regulatory mechanisms. the number of consultations from new patients presenting with erectile dysfunction and resulting costs for health care systems are increasing. urologist should be the evaluating physician who supervises the surgical, medical, and hormonal treatment and who refers the patient, as necessary, to other members of the multidisciplinary team. conclusion: erectile dysfunction has a significant negative impact on quality of life. male sexual dysfunction, especially erectile dysfunction, necessitates a comprehensive medical and psychologic evaluation involving both partners. all possible risk factors should be outlined and corrected, when feasible. key words: impotence, pathology, treatment outcome, penile erection, physiology 227 urology journal unrc/iua vol. 1, no. 4, 227-239 autumn 2004 printed in iran treatment of erectile dysfunction the first step in the management of a patient with ed is to facilitate the patient's and his partner's (if available) understanding of the condition, the results of the diagnostic assessment and to identify the patient's and his partner's needs, expectations, priorities, and preferences. the identification and recognition of associated medical and psychological factors in the individual patient must be emphasized. clearly, the selection of therapy is strongly influenced by personal, cultural, ethnic, religious, and economic (affordability) factors. the presentation and stratification of therapies may therefore vary from individual to individual, culture-to-culture, religious persuasion to religious persuasion, and from one economic tier to another. sensitivity to these factors is important in determining the long-term success of any selected therapeutic course. prior to direct intervention, good medical practice recognizes the value of altering modifiable risk factors, and this step alone may be of some value in selected patients. the patient and his partner (if available) should *corresponding author: p.o. box: 19395-1849, tel: +98 912 109 5200, e-mail: safarinejad@unrc.ir erectile dysfunction be informed of all of the available and acceptable treatment options applicable to his clinical condition and the related benefits, risks, and costs of each modality. the development of ed can significantly affect the quality of life, but it is not a lifethreatening disease. consequently, it is reasonable to discuss the benefits, risks, and costs of the available treatment strategies with the patient and have the patient actively participate in the choice of therapy (shared decision making). an important issue prior to the institution of any therapy and the subsequent resumption of sexual activity is the overall cardiovascular condition of the patient. is this patient able to resume the exercise of sexual activity? if not, priority cardiovascular assessment and intervention may be appropriate. the partner's sexual function, if possible, should be considered prior to initiating therapy. the vast majority of patients will need to consider direct treatment options for ed. only those pharmacological treatments that have been thoroughly tested in randomized clinical trials, with subsequent publication of results in peerreviewed literature, should be considered for general use. long-term follow-up of all treatment options must be performed to demonstrate durability and continuous efficacy and safety as well as patient and partner acceptability. additionally, new treatment options that enter the arena not only will need to meet the above efficacy and safety criteria, but also should be compared to available therapies for cost-effectiveness. the treatment selected by a patient, will be influenced not only by issues such as efficacy and safety, but also by the patient's cultural, religious, and economic background. additionally, such factors as 1. ease of administration, 2. invasiveness, 3. reversibility, 4. cost and 5. the mechanism of action (peripheral vs. central, inducer vs. enhancer), and 6. availability, may critically influence the individual patient's selection of therapy. as previously mentioned, affordability is a prime factor in influencing patient acceptance and utilization of a specific therapy for ed.(1) any drugs that might be contributing to ed should be discontinued. in the case of antihypertensive agents, other drugs with a different mechanism of action should be considered. five basic types of therapy reported in the literature are potential options for treating organic erectile dysfunction: 1. oral drug therapy, 2. vacuum constriction device therapy, 3. intracavernous vasoactive drug injection and topical therapy, 4. penile prosthesis implantation, 5. venous and arterial surgery. oral drug therapy there is a wide range of treatments for erectile dysfunction. if organic problems seem to be dominant, the first step is to identify the medical risk factors and correct them, if possible. plasma glucose must be regulated in men with poorly controlled diabetes. medications for hypertension must be optimized. cessation of tobacco abuse is important. hyperlipidemia must be treated aggressively. intake of alcohol and illicit drugs should be discontinued. the central issue in understanding the patient with ed is not only understanding ed as a medical condition, but also understanding patient behavior and attitudes. it is important to remember that there is a broader context for treating ed. physicians need to avoid over-focusing on the genital response and consider the psychosocial consequences and obstacles of ed. a wide range of oral treatments have been used in men with erectile dysfunction, including sildenafil, apomorphine, oral phentolamine, isoxsuprine, trazodone, and yohimbine.(2) new drugs include several new phosphodiesterase type 5 inhibitors and agents with other mechanisms of action.(3,4) sildenafil (viagra) is now the first choice for treating erectile dysfunction and has helped men with a wide range of conditions. pharmacology: sildenafil facilitates erections associated with sexual stimulation. it will not act if the man is not sufficiently mentally aroused or his peripheral autonomic nerves are absent (e.g. radical prostatectomy). it acts by inhibiting phosphodiesterase isoenzyme 5 (pde-5), thus prolonging cyclic guanosine monophosphate (cgmp) activity in erectile tissue, and enhancing the vasodilating actions of nitric oxide, which is released in response to sexual stimulation. sildenafil is rapidly absorbed from the gut peaking 30 to 120 minutes after an oral dose. at peak effect, it lowers mean systolic supine blood pressure (8 mmhg) in healthy volunteers. the drug is eliminated by liver metabolism (cyp3a4) with a half-life of 3 to 5 hours. half-life is prolonged in patients over 65 years and in patients with renal or hepatic impairment. adverse effects: the most common adverse 228 safarinejad and hosseini effects, as absolute risk increase over placebo, were headache at 14%, flushing at 17%, dyspepsia at 4%, rhinitis at 4%, and visual disturbance at 1%. none of the studies assessed the effects of long-term sildenafil use. such studies are needed, particularly in patients with a history of retinal and cardiovascular disorders. serious rare side effects include priapism, severe hypotension, heart attack, stroke and death. contraindications: sildenafil is contraindicated in patients taking or at risk of requiring nitrates in any form, patients, in whom sexual activity is inadvisable because of their cardiovascular status (e.g. myocardial infarction or cerebrovascular accident within 6 months, heart failure, unstable angina, hypotension, uncontrolled hypertension, aortic stenosis, etc.), and patients with retinitis pigmentosa, anatomical deformities of the penis, conditions predisposing to priapism (e.g. sickle cell anemia, multiple myeloma), or receiving multiple antihypertensive drugs. precautions: there is no safety information on patients excluded from the trials (e.g. patients with alcoholism, active peptic ulcer, proliferative diabetic retinopathy, etc.). inhibitors of cyp3a4 such as erythromycin, ketoconazole, grapefruit juice, and others would be expected to increase the magnitude and duration of response to sildenafil. a relatively small number of deaths have been reported in association with sildenafil usage, but the specific relationship to the drug is uncertain. this underscores the need for cardiovascular assessment prior to the treatment of ed and regular follow-up. a small percentage of these deaths occurred with concomitant use of nitrates and are presumed to be due to severe hypotension that may ensue, following this combination.(5) in addition, patients with possible or active coronary heart disease or other significant cardiovascular diseases such as aortic stenosis should undergo cardiac evaluation and management prior to considering sildenafil usage.(5) to date, there is no physiological reason to indicate sildenafil exerts a direct effect on the myocardium. in general, sildenafil when prescribed appropriately has demonstrated broad efficacy and an acceptable safety profile. dosage and cost: the drug should be taken on an empty stomach 1 hour before intended sexual activity and no more than once daily. dose range is 25 to 100 mg. as with most drugs start with the lowest dose, 25 mg, and increase only if necessary. since the cost of each tablet is similar ($10 to $12), prescribing the higher dose tablets and dividing them can substantially reduce the cost. although sildenafil is currently the most widely used approach and has an excellent overall success rate (60% to 85%), a substantial portion of patients continue to have an inadequate response.(6) martinez-jabaloyas et al(7) recently evaluated risk factors for treatment failure with sildenafil and noted that diabetes, non-nerve sparing radical prostatectomy and high baseline disease severity, as reflected by sexual health inventory for men scores, were all predictors of a lower success rate for sildenafil therapy. oral sildenafil is a moderately effective treatment for erectile dysfunction in men with diabetes. the response rate was lower and cardiovascular events were higher than previously reported in nondiabetic patients.(8) currently, two other phosphodiesterase-5 inhibitors are available: tadalafil and vardenafil. early data indicate that there are differences among sildenafil, tadalafil, and vardenafil in pharmacokinetic properties, efficacy, potency, half-life, and adverse effect profiles.(9) tadalafil (cialis) is the latest of the three to be approved by the food and drug administration (fda).(10) this medication is a highly selective, potent, reversible inhibitor of phosphodiesterase type 5 (pde5).(11, 12) tadalafil differs from the other two products in that it stays in the body for a longer time, which is an advantage for men with ed.(10) compared with sildenafil, tadalafil has an extended terminal half life, 17.5 hours(13) versus 3.7 hours,(14) suggesting a lengthened period of responsiveness compared with sildenafil. the same cautions apply for these agents as they do for sildenafil. common side effects of this agent are similar to those of sildenafil and include flushing, dizziness, nasal congestion, upset stomach, and vision abnormalities. success rates have been significant in men suffering from erectile dysfunction of varying severity and from many causes. one study suggested, however, that, as with sildenafil, it may interact with nitrates. an assessment of the safety and effectiveness of tadalafil in patients older than 65 years of age versus younger patients indicated that it was safe and effective in both groups, with improved erections in up to 81% of men in the combined population.(15) simultaneous administration of tadalafil and 229 erectile dysfunction the alpha-adrenergic antagonists, except for 0.4 mg once-daily tamsulosin, is contraindicated. in a study of drug-drug interactions, 20 mg of tadalafil was administered to healthy subjects taking 8 mg of doxazosin mesylate daily. a significant increase in the blood pressure-lowering effect of doxazosin was observed.(16) the recommended starting dose for most patients is 10 mg, to be taken before anticipated sexual activity. the dose may be increased to 20 mg or decreased to 5 mg, depending on the agent's efficacy and patient's tolerability. for most patients, the maximum dosing frequency is once daily. unlike other available treatments, tadalafil may enable a patient to take a pill on a wednesday evening and have intercourse with his partner on a thursday night or a friday morning. this extended period of responsiveness afforded by tadalafil may lead to a new treatment paradigm for men with ed.(16,17) vardenafil (levitra), another novel selective phosphodiesterase type 5 inhibitor, has also been shown to be safe and effective for the treatment of erectile dysfunction in a 12-week, multicenter, randomized, double-blind, placebo-controlled trial that included 601 men with mild to severe erectile dysfunction.(18) for most patients, the recommended starting dose of vardenafil is 10 mg, taken orally approximately 60 minutes before sexual activity. the dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and side effects. the maximum recommended dosing frequency is once per day. vardenafil can be taken with or without food. sexual stimulation is required for response to treatment. studies evaluating vardenafil have determined it to be safe and effective at doses of 5 mg to 40 mg, including subjects with diabetes mellitus and subjects who have undergone radical prostatectomy. vardenafil has a pharmacokinetic profile similar to that of sildenafil, with an onset of action and half-life of 0.7 hours and 5 hours, respectively. vardenafil, like other pde5 inhibitors, is metabolized hepatically via the cytochrome p-450 system. the drug appears to be well tolerated. in clinical trials, headache, dyspepsia, and flushing were the most common adverse effects reported by subjects taking vardenafil. no adverse hemodynamic or visual effects have been reported during clinical trials of vardenafil; however, further investigation, including post-marketing surveillance, will be required to determine whether vardenafil will cause these adverse effects. in vivo, vardenafil has been found not to interact with nifedipine, nitroglycerin, digoxin, magnesium hydroxide/aluminum oxide, or ranitidine. only a small, clinically insignificant interaction was observed when vardenafil was given concurrently with cimetidine. further research and clinical experience with the newer pde-5 inhibitors (vardenafil and tadalafil) will be needed before their roles in the treatment of ed can be determined. patients taking nitrate drugs (used to treat chest pain) and those taking alpha-blockers (used to treat high blood pressure and benign prostatic hyperplasia) should not take selective enzyme inhibitors. common side effects of selective enzyme inhibitors include headache, reddening of the face and neck (flushing), indigestion, and nasal congestion. tadalafil may cause muscle aches and back pain, which usually resolve on their own within 48 hours. oral phentolamine. phentolamine is an agent that has been used in injections for achieving erection. phentolamine is an α-adrenergic blocking agent with both central and peripheral activity. an oral form of phentolamine (vasomax) has been developed that may be of some benefit for men with mild impotence. the drug is not as effective as sildenafil and it has more side effects. however, vasomax works faster and it does not interact with nitrates. studies suggest that it produces erections within 20 to 40 minutes in 40% to 50% of men with mild to moderate erectile dysfunction. side effects include nasal congestion, headache, light-headedness, low blood pressure, tachycardia and nausea. these events are minimal at the usual dose of 40 mg.(1) apomorphine (spontane, uprima), which is taken as a tablet under the tongue, causes a sexual signal in the brain to trigger an erection, although it is not an aphrodisiac. apomorphine is a dopaminergic agonist acting at the central nervous system level. it was initially administered subcutaneously. however intolerable adverse events prompted the development of a sublingual pill. apomorphine has shown efficacy in placebocontrolled fixed and dose escalation studies.(19) in responders, erection usually begins within 20 minutes. its principal adverse effect is nausea, which is usually minimal at lower dosages (2 mg and 4 mg). other adverse effects are dizziness, 230 safarinejad and hosseini sweating, somnolence and yawning as well as rarely, syncope.(1) studies report improved erectile function in 40% to 60% of men, with the better results occurring at the higher doses. high doses, however, also cause severe side effects, including nausea (in between 15% to a third of patients), yawning, fatigue, dizziness, sweating, excitability, and aggression. apomorphine appears to be safe for men with diabetes or stable heart disease, and is well tolerated by men with high blood pressure. opioid antagonists. opioid antagonists, such naltrexone (revia), are used to help maintain abstinence in alcoholism. naltrexone may be helpful for erectile dysfunction in men with inhibited sexual desire. the most common side effect of naltrexone is nausea, which is usually mild and temporary. high doses can cause liver damage. the drug should not be administered to anyone who has used narcotics within a week to 10 days. angiotensin-receptor blockers. recent drugs known as angiotensin-receptor blockers (arbs), also known as angiotensin ii receptor antagonists are being used to lower blood pressure in men with hypertension. in one study, after 12 weeks of treatment with an arb called losartan (cozaar), 88% of hypertensive males with sexual dysfunction reported improvement in at least one area of sexuality. the number of men reporting impotence declined from 75.3% to 11.8%. other arbs include candesartan (atacand), telmisartan (micardis), and valsartan (diovan). trazadone, a widely used antidepressant, has been associated with the development of priapism. trazodone, a serotonin antagonist and reuptake inhibitor, improved premature ejaculation and erectile function in men with psychogenic ed but had a marginal effect in men with organic ed.(20) this side effect has created interest for its potential use in men with impotence. doses of 150 mg per day have been used in most studies and case reports. the mechanism by which trazodone may help patients with impotence is unclear but is most likely a result of the drug's ability to block both serotonin and α2-adrenorceptors. whatever the mode of action, recent clinical studies seem to indicate that if trazodone does have a role in the treatment of erectile dysfunction, then its benefit may only be marginal. yohimbine, an alkaloid derived from the bark of the central african yohimbine tree, has been used as folk medicine for many years. the alkaloid has α2-adrenoreceptor blocking activity and produces a rise in sympathetic drive. yohimbine has no effect on erectile function when administered by intracavernous injection, and its action in relation to erectile dysfunction is thought to be almost entirely central. traditionally, extracts from the yohimbine bark have been used to treat all forms of impotence. most information available on the use of yohimbine comes from isolated reports and uncontrolled trials. only in the last 15 years have formal clinical studies been undertaken. a review of recent clinical trials indicates that the response rate to yohimbine is only 30-40%. the difference between responders to yohimbine and to placebo has not been clinically significant in many cases. it is clear that some patients, especially those without serious medical problems, demonstrate improvement in the quality, frequency or rigidity of erections but not always enough to restore satisfactory sexual function. side effects associated with the use of the drug include nausea, insomnia, nervousness, headache, and dizziness. large doses can increase blood pressure and heart rate but rarely do patients have to discontinue therapy subsequent to adverse effects. questions about the drugs long-term safety still remain. the most commonly used dose is 5.4 mg three times daily.(21,22) isoxsuprine is a vasodilator, acting by direct relaxation of vascular smooth muscle. its primary mechanism of action is by stimulation of betaadrenergic receptors. the commercially available form is a 10mg tablet. isoxsuprine is no better than placebo as a first line treatment for mixed type erectile dysfunction.(23) hormonal treatment endocrine disorders, such as hypogonadism, androgen abnormalities, growth hormone defects, thyroid disease and lipid disorders also play a significant role in ed physiology.(10) castration reduces intracavernous pressure following intracavernosal administration of adrenomedullin, calcitonin gene-related peptide, vasoactive intestinal polypeptide or nociceptin. all of these compounds lead to increases in camp. moreover, testosterone regulates the expression and activity of nos in some species. castration also inhibits the increase in intracavernous pressure following a nitric oxide (no) donor. these findings suggest that androgens influence the camp and cgmp pathways in addi231 erectile dysfunction tion to nos. although androgens may not directly augment the effects of cyclic nucleotides, these data argue that androgen replacement may be a prerequisite for pharmacological therapy to improve ed if an androgen deficiency exists. thus, in hypoandrogenic patients the combination of testosterone and pde-5 inhibition or intracavernous activation of adenylate cyclase may be indicated.(24) the hypothalamic-pituitary-gonadal axis has been shown to decrease functioning temporarily after acute medical events or surgical procedures; such an occurrence can cause low gonadotropin and testosterone levels. similarly, a temporary decrease in testosterone levels may occur as a result of less serious circumstances, such as anxiety, excessive intake of alcohol, use of multiple medications, or uncontrolled diabetes. patients with these causes are less likely to respond to testosterone replacement. stimulation of gonadotropins with clomiphene citrate and the subsequent increase in testosterone levels emphasize the functional and reversible nature of this phenomenon; short-term therapy with clomiphene citrate may help some patients. if the testicles are intact, testosterone can be stimulated by injections of human chorionic gonadotropin, but this technique is cumbersome and rarely used. hypogonadism is common in patients with diabetes, many of whom may respond to testosterone treatment.(25) appropriate therapy in the presence of a documented deficiency (e.g. androgen deficiency and hypogonadism), may not necessarily improve ed and thus one may need to consider direct intervention therapy even in this patient population. the issue of androgen replacement therapy is complicated. there is a statistical decline of testosterone levels, particularly free testosterone, in aging men. while this fall is only moderate, aging men show clinical signs of hypogonadism (loss of muscle mass/strength, reduction in bone mass and an increase in visceral fat). testosterone replacement or supplement therapy may improve bone mass, muscle mass, strength and frequently nocturnal erections as well in this age group. however, the effects on sexual function, mood and cognition are less clear but may be meaningful in certain men. the identification of that segment of the aging male population that might possibly benefit from androgen supplementation remains difficult. questions still remain regarding the magnitude and longevity of these potential beneficial effects. more importantly, the long-term risks of androgen therapy in this age group really are now known, especially in the areas of cardiovascular and prostate diseases.(26) despite increasing evidence that patients with subnormal or borderline normal levels of testosterone could be considered as candidates for testosterone treatment, until more information is available, testosterone and androgens in general should not be recommended as supplemental therapy.(1) testosterone replacement for hypogonadism may also correct sexual dysfunction, unless the patient has other comorbid illnesses. for decades, the standard has been a depot intramuscular injection of testosterone enanthate or cypionate every 2 or 3 weeks (200 mg or 300 mg, respectively). smaller doses and more frequent injections, however, are better at maintaining circulating testosterone levels of testosterone enanthate or cypionate intramuscularly at 7to 14-day intervals. an alternative approach is to administer 100 mg on days 1, 11, and 21 of each month, while allowing some flexibility of injection days. if testosterone levels are measured, they should be in the normal range just before the next injection. other forms of intramuscular testosterone preparations are also being evaluated. implantable testosterone pellets are now, but they are infrequently prescribed. oral forms of testosterone are not recommended because of the risk for liver damage when taken for long periods of time. the us food and drug administration (fda) have now approved testosterone scrotal and nonscrotal dermal patches. testosterone absorption is greater through scrotal skin. the scrotal patch was the first to be introduced. these patches are placed on the scrotal skin and are changed daily, in the morning. for many patients, weekly shaving of the scrotum is necessary. the patch increases testosterone levels to the low-normal range, with peak levels achieved 3 to 5 hours after application of the patch. because 5-a-reductase in scrotal skin is high, the dihydrotestosterone (dht) level in serum becomes quite high. the role of dht is currently being investigated. the nonscrotal patch (androderm), applied daily in the evening, may be worn in various sites on the skin. the manufacturer recommends that it not be used over bony prominences. the levels remain stable in the middle of the normal range, and the dht levels remain normal. skin irritation may develop and often responds to applica232 safarinejad and hosseini tion of corticosteroid cream. in a certain small percentage of patients, therapeutic blood levels of testosterone may not be achieved. another nonscrotal patch, testoderm, was associated with less skin irritation but was more likely to fall off; it has recently been withdrawn from the market. the fda for use in the united states has recently approved a 1% testosterone gel. it is more expensive than the testosterone patches. the blood levels of testosterone associated with use of the gel are dose dependent and vary less than with the testosterone patches. care must be exercised because the testosterone can be transferred to another person if skin-to-skin contact occurs. with any form of testosterone treatment, the patient may have a slow but steady increase in libido and erectile ability during a course of months. if no improvement is noted after three months, the hormone deficiency is probably not the only cause of the sexual dysfunction. a comorbid medical illness might be present, or perhaps performance anxiety is dominant. any patient treated with replacement androgens should be reassessed within 1 to 3 months after initiation of therapy and then at 6to 12month intervals to ensure that clinical problems have not developed or worsened during such treatment. prostate cancer and breast cancer are contraindications to androgen therapy, whereas sleep apnea, peripheral edema, erythrocytosis (hematocrit >52%), and benign prostatic hyperplasia are relative contraindications that may respond to adjustments in the medication or specific treatments (for example, use of continuous positive airway pressure or weight reduction).(27) intracavernous vasoactive drug injection and topical therapies intracavernosal injections. drugs for ed vary by not only class, but also route of administration. penile injections have now largely been replaced by oral medications, specifically sildenafil. nevertheless, injection and topical (skin) therapies employ various agents that have properties that help achieve erection, even in many men who do not succeed with sildenafil. alprostadil (caverject). this is the most widely used agent. alprostadil is derived from a natural substance, prostaglandin e1, and acts by opening blood vessels. it is an effective treatment for some men. it can be administered in three ways: by injection into the erectile tissue of the penis (caverject, edex), by a device that administers the drug through the urethra (muse system), and in a topical cream (topiglan, alprox-td) applied directly to the penis. regardless of how it is administered, alprostadil works in many men with a wide range of medical disorders related to erectile dysfunction, including the following: diabetes, prostate cancer treatments (early use of alprostadil injections after treatment, particularly when followed by oral sildenafil, may be very helpful for men being treated for prostate cancer), men who are taking nitrates and injury. alprostadil is not an appropriate choice for the following individuals: men with severe circulatory or nerve damage, men with bleeding abnormalities or men who are taking medications that thin the blood, such as heparin or warfarin and men with penile implants. the drug may have toxic effects if it reaches the fetus in pregnant women, so men should not use alprostadil for intercourse with pregnant women without the use of a condom or other barrier contraceptive device. it is effective in 70% to 80% of patients and has a low incidence of side effects. penile pain occurs in 15% to 50% of patients but is often not troublesome. the dose range is 5 to 20 mcg but some physicians will increase it further or use a combination with papaverine and phentolamine. priapism occurred in about 1% of patients and the incidence of penile fibrosis was 10% in a period of 3 years. about half of the cases with fibrosis resolved spontaneously. thymoxamine (moxisylyte hydrochloride) (erecnos, icavex). this agent, a selective α1 adrenergic receptor antagonist, has been licensed for use in erectile dysfunction and is used in a dosage of 10-20 mg. it is less effective in initiating erection but with sexual stimulation gives sufficient rigidity in some patients. it has a lower incidence of side effects such as penile pain and prolonged erection. papaverine (pavabid, cerespan). this was the first agent in general use and had the advantage of being cheap. it is not licensed for the treatment of ed and is not recommended because of the relatively high risk of priapism and penile fibrosis. papaverine and phentolamine mixtures (androskat). this is still used in some countries because of its efficacy and relatively low cost. it is more effective than papaverine alone. trimix (papaverine, phentolamine and alprostadil). this combination was introduced to 233 erectile dysfunction treat those patients who responded poorly to the papaverine/phentolamine mixture or alprostadil. it is unlicensed and is prepared by specialized pharmacies. vasointestinal polypeptide (vip) and phentolamine (invicorp). this is another preparation in an advanced phase of clinical development although it is not yet licensed except recently in denmark. the main side effect is facial flushing and tachycardia but it has the advantage over alprostadil of a lower incidence of pain. its effectiveness, compared to alprostadil has yet to be determined.(28) while intercavernosal injection therapy consistently produces erections in up to 87% of patients, there is a dropout rate of about 50%.(29) intraurethral suppository. prostaglandin e1 (alprostadil) (muse system), is also available as an intraurethral suppository. padma-nathan et al35 reported an at home successful sexual intercourse rate of approximately 60% in a large series of men, 20% of whom had diabetes. although pge1 is less invasive and easier to use than intracavernosal injection, it may reduce sexual spontaneity. men must remain standing after the pellet has been inserted to increase penile blood flow, and the time to erection is 15 to 30 minutes. patients may complain of penile pain (12%), minor urethral bleeding (5%), testicular pain, and dizziness. female partners may report vaginal burning or itching (6%) with use of the suppository. prostaglandin e1 is contraindicated in men with abnormal penile anatomy and those with hyperviscosity syndromes; men cannot take pge1 if they have intercourse with pregnant women who are not using barrier contraceptives.(30) reported success rates with intraurethral alprostadil have been around 50% but range widely. venous and arterial surgery impaired arterial inflow has been addressed in select cases by various penile revascularization procedures and attempts to induce neovascularization. of course, known risk factors, such as smoking, hyperlipidemia, diabetes, hypertension and obesity, should be controlled. penile revascularization. for men whose impotence is caused by damage to the arteries or blood vessels, vascular surgery might be an option. the best candidates for such surgery are young men with discrete blockage of an artery because of an injury to the crotch or fracture of the pelvis. the procedure is almost never successful in older men with widespread blockage. penile revascularization represents the only currently feasible cure of arteriogenic ed.(31,32) the revascularization procedure usually involves taking an artery from a leg and then surgically connecting it to the arteries at the back of the penis, bypassing the blockages and restoring blood flow. in a related procedure called deep dorsal vein arterialization, a penile vein is used for the bypass. young men with local sites of arterial blockage or those with pelvic injuries generally achieve the best results. in studies of selected patients there was improvement in erectile dysfunction in 50% to 75% of men after five years. in the virag type of procedures the epigastric artery is anastomosed to the deep dorsal vein at the base of the penis. blood flows retrograde through the veins and enters the corpora through the connecting posterior emissary veins.(33) direct anastomosis of the epigastric artery to the cavernosal artery is feasible but technically challenging.(34) direct epigastric artery to dorsal penile artery anastomosis in various modifications has also been described.(32,35) neovascularization. neovascularization is another emerging approach to reversal of impaired cavernosal artery flow. tissue hypoxia and the inflammatory response are major physiological stimuli to angiogenesis. the process is under the control of angiogenic growth factors, small proteins that induce proliferation and migration of endothelial and smooth muscle cells, and branching of the vascular tree. all growth factors are mitogens to endothelial cells and include basic fibroblast growth factor, vascular endothelial growth factor (vegf) and hypoxia inducible factor. in addition to direct stimulation of endothelial cell growth, some growth factors such as vegf possess the ability to stimulate production of no. intracavernosal injection of vegf in an ischemic rat model has recently been shown to stimulate endothelial nitric oxide synthase (nos) and inducible nos expression.(36) several recent animal studies have shown the feasibility of using local intracavernosal vegf injection. in vitro vegf treatment has been shown to ameliorate the effects of hypercholesterolemia on rabbit cavernosal smooth muscle.(37) in a rat model using acute arterial ligation, a single intracavernosal bolus of vegf improved penile erection.(38) regeneration of nerves and endothelial cells 234 safarinejad and hosseini lining the cavernous spaces was seen.(38) venous ligation. venous leak has been termed an "epiphenomenon" of cavernosal smooth muscle dysfunction.(15) thus, it does not appear to offer curative potential when addressed as an isolated phenomenon. venous ligation is performed when the penis is unable to store a sufficient amount of blood to maintain an erection. this operation ties off or removes veins that are causing an excessive amount of blood to drain from the erection chambers. the success rate is estimated at between 40% and 50% initially, but drops to 15% over the long term. it is important to find a surgeon experienced in this surgery. in a variation of this technique called venous ablation, ethanol is injected into the deep dorsal vein, the main vein that drains blood from the penis. the ethanol causes scarring that closes off smaller veins and prevents blood leakage, thereby bolstering erectile function. in a small trial in 10 men with severe impotence, half maintained erectile function two to three years after the procedure. recently, improved results were reported when patients were selected according to the presence of mild cavernous leak, more than 30% cavernous smooth muscle content, normal cavernosal electromyography results, and oxygen tension of more than 65 mm hg during erection, and age younger than 50 years. in this series of 23 men treated with venous ligation 74% had normal erections at 1 year and 50% beyond 1 year. venous ligation appears to have a role only in highly selected men with minimal cavernosal dysfunction.(34) the american urologic association stresses that vascular surgery is still investigative. vacuum constriction device therapy vacuum constrictor device. any system encouraging blood to flow into and be captured in the penis should produce an erection. this is the principle behind the vacuum constrictor device (vcd) now offered as a noninvasive means of restoring erections for some impotent men. vacuum devices, or external management systems, are effective, safe, and simple to use for all forms of impotence except when severe scarring has occurred from peyronie's disease. vacuum devices rely on first drawing blood into the penis, by means of an externally applied suction pump, and then retaining the resultant erection by means of an elastic ring applied to the base of the penis. provided it is used properly, the failure rate is very low and serious adverse effects are rare, although many patients find the method cumbersome. the band may only be kept on for 30 minutes and ejaculation may be obstructed. one small retrospective study shows that 81% of men stopped using the device over a one-year period.(39) a second study of 50 men suggested that only 27% preferred the vacuum device to intracavernosal injection therapy.(40) not only does vacuum-induced pressure in the vcd cause most men to experience penile discomfort, but the erection achieved by this means is inferior to a spontaneous erection in three significant aspects. once the vacuum has induced the erection, the rubber bands in place at the base of the penis choke off blood flow into the penis. this causes penile skin temperatures to fall to 35.5-centigrade degree. one-third of the female partners of men using vcds found the chilled penis displeasing during intercourse. another drawback is that as the penis becomes engorged and congested by the vcd-induced suction and inhibition of venous outflow, penile circumference increases more than it would during a normal erection. this gives the penis a sausage like appearance. third, the erection created by the vcd is rigid only from the point at which the rubber bands are affixed. this means that it is not fully upright and rigid like a normal erection, but flexible and capable of swiveling or pivoting at its base. the vcd also does not permit normal ejaculation. because the rubber bands remain in place throughout the sexual act, semen is trapped in the urethra and can be released only after the bands are removed. venous flow controllers. vacuum-less devices that trap blood within the penis are also available. they are called venous flow controllers or simple constricting devices. these devices are typically rubber or silicone rings or tubes (e.g., actis) that are placed at the base of the erect penis to trap the erection. men who can achieve erections but lose them easily can use them. these devices should not be used for longer than 30 minutes or lack of oxygen can damage the penis, and patients who have bleeding problems or are taking anticoagulants should not use them. penile prosthesis implantation implanted devices, known as prostheses, can restore erection in many men with ed. possible problems with implants include mechanical breakdown and infection, although mechanical problems have diminished in recent years because of 235 erectile dysfunction technological advances. malleable implants usually consist of paired rods, which are inserted surgically into the corpora cavernosa. the user manually adjusts the position of the penis and, therefore, the rods. adjustment does not affect the width or length of the penis. inflatable implants consist of paired cylinders, which are surgically inserted inside the penis and can be expanded using pressurized fluid. tubes connect the cylinders to a fluid reservoir and a pump, which are also surgically implanted. the patient inflates the cylinders by pressing on the small pump, located under the skin in the scrotum. inflatable implants can expand the length and width of the penis somewhat. they also leave the penis in a more natural state when not inflated. there appear to be no long-term immune problems related to the silicon or other materials in the devices. there are potential limitations with these devices. erectile tissue is permanently damaged when these devices are implanted and procedures are irreversible. although uncommon, mechanical breakdown can occur, or the device can slip or bulge, especially if the patient coughs or vomits vigorously after the operation. in addition, a less than optimal quality of erection may result. (using the muse system may restore or improve the function of a penile prosthesis in patients with a failed device.) infection is the major concern with these devices. redness and fever often accompany a full-blown infection. any intermittent pain that continues to occur after an implant may be an indicator of a low-grade infection. if the infection can be caught early enough, implant failure can be prevented. most infections are treated with antibiotics for at least 10 to 12 weeks. if antibiotics fail, a surgical exchange, in which the infected implant is simultaneously replaced with a new one, should be considered. this is a complex procedure, but some surgeons have reported a 90% success rate. coatings with specific antibiotics are being investigated and studies are reporting very low infection rates. miscellaneous therapy psychosexual counseling although widely recommended, there have been no controlled studies of the use of psychosexual counseling in erectile dysfunction. one questionnaire survey of 289 sex therapists suggested that they achieved a successful outcome in 25% of patients treated for impotence, although the nature of the patients referred is unclear.(41) in another study, 20 consecutive diabetic men with erectile dysfunction were referred for psychosexual assessment and treatment.(42) three of these achieved long-term improvement in sexual function, although it proved impossible to identify these responders from their pretreatment characteristics. a third study looked at a combination of treatment strategies in 145 men.(43) twenty-one per cent of those studied were able to have intercourse after psychotherapy alone. interestingly, those with clearly organic impotence benefited almost as much as those with psychogenic impotence (21% versus 32%). psychological counseling for patients with or without their partners are helpful in addressing the psychogenic and interpersonal factors associated with erectile dysfunction.(44) approaches include techniques to reduce anxiety and to enhance sexual stimulation, desensitization procedures, cognitive-behavioral interventions, and traditional counseling. these approaches may be used alone or in addition to other treatment interventions such as oral medication or the vacuum pump. such combination therapy may be particularly useful in situations of low sexual desire, problems of sexual initiation, other sexual dysfunction, and significant relationship problems.(45) psychosocial factors that contribute to men discontinuing therapy, despite its effectiveness, also can be addressed in psychological counseling or sex therapy sessions.(46) these factors include emotional readiness of each partner to resume sexual activity, the attitude of each partner toward using a medical intervention, the quality of the sexual relationship, unconventional arousal patterns, and the quality of the couple's sexual life before erectile dysfunction. sex therapy a significant number of men develop impotence from psychological causes that can be overcome. when a physiological cause is treated, subsequent self-esteem problems may continue to impair normal function and performance. qualified therapists (e.g. sex counselors, psychotherapists) work with couples to reduce tension, improve sexual communication, and create realistic expectations for sex, all of which can improve erectile function. 236 safarinejad and hosseini psychological therapy may be effective in conjunction with medical or surgical treatment. sex therapists emphasize the need for men and their partners to be motivated and willing to adapt to psychological and behavioral modifications, including those that result from medical or surgical treatment. lifestyles changes staying sexually active can help prevent impotence. frequent erections stimulate blood flow to the penis. it may be helpful to note that erections are firmest during deep sleep right before waking up. autumn is the time of the year when male hormone levels are highest and sexual activity is most frequent. cigarette smoking has been shown to be an independent risk factor for ed.(47) in one study the relative risk of developing internal pudendal artery atherosclerosis for each 10 pack-year smoked was 1.(48) the evidence linking smoking with ed is complex and it has been concluded that an association between smoking and ed is likely.(49) this finding is supported by some animal(50) and human(51) studies, which demonstrated a direct inhibitory effect of smoking on erection. however, direct evidence of restoration of erectile ability with smoking cessation is sparse(52,53) and there may be a point of no return after years of cigarette smoking. everyone should eat a diet rich in fresh fruits and vegetables, whole grains, and fiber and low in saturated fats and sodium. because erectile dysfunction is often related to circulation problems, diets that benefit the heart are especially important. foods that some people claim to have qualities that enhance sexual drive include chilies, chocolate, licorice, lard, scallops, oysters, olives, and anchovies. no evidence exists for these claims, and eating large amounts of some of these foods, such as licorice and lard, can be dangerous. nevertheless, as with hypercholesterolemia, advising our patients who are seeking improvement of erectile function to cease smoking is strongly recommended. obesity and sedentary lifestyle are also well-recognized risk factors that can be modified in an attempt to improve erectile ability.(52) a regular exercise program is extremely important. one study reported that older men who ran 40 miles a week boosted their testosterone levels by 25% compared to their inactive peers. another study found that men who burned 200 calories or more a day in physical activity (which can be achieved by two miles of brisk walking) cut their risk of erectile dysfunction by half compared to men who did not exercise. gene therapy defective smooth muscle is seen in the rat model of aging, when the corporal tissue becomes more fibrotic as the animal ages. what has also been shown in this aged animal model is a reduction in nos activity in the corporal tissue. in an attempt to overcome this dual hit to aged tissue, investigators have searched for ways to either regenerate the relatively noncompliant corporal tissue or to up-regulate the factors that promote smooth muscle relaxation. one of the ways to accomplish this is via the ca2+ sensitive k+ channel (maxi-k+) that regulates smooth muscle relaxation. christ et al used naked dna that encodes the maxi-k+ channel for injection into the penises of aged animals and was able to augment their erectile response in this manner. this gene therapy approach to overcome the processes that fail with certain disease states highlights what can be expected in the future for the treatment of patients who have erectile dysfunction that is refractory to medical therapy.(54) conclusion major advances have been made in the understanding of the pathophysiology of impotence and erectile dysfunction. the ability to relax and contract corporal smooth muscle with pharmacologic agents has led to the development of several new treatment options for men with impotence. the demand for safer and more effective treatments for erectile dysfunction will continue to foster research in this field. men with erectile dysfunction should be encouraged to overcome their reluctance to seek advice. the standard diagnostic assessment should include a detailed medical and sexual history and clinical examination of the patient. there are various treatment options available for the management of erectile dysfunction and each is associated with a different profile of efficacy, safety and patient satisfaction. most patients would prefer to regain their ability to have a normal spontaneous erection. this is however only possible when the problem is mainly psychological, hormonal, drug-dependent or in the rare men where arterial reconstruction is possible. all patients benefit from some psychosexu237 erectile dysfunction al counseling and it is important to remember that some patients prefer the option of having a satisfactory, non-penetrative, sexual relationship. it is customary to start with a non-invasive type of therapy and limit more invasive treatments to those patients with a special indication, for example arterial reconstruction, or those who do not respond to non-invasive methods by implanting a penile prosthesis. references 1. clinical practice guide in erectile dysfunction: malaysia urological association and medact. available from: http://www.acadmed.org.my/html/cpg. 2. padma-nathan h, giuliano f. oral drug therapy for erectile dysfunction. urol clin north am. 2001;28:321-9. 3. padma-nathan h, mcmurray jg, pullman we, et al. on-demand ic351 (cialis) enhances erectile function in patients with erectile dysfunction. int j impot res. 2001;13:2-9. 4. pryor jl, redmon b. new therapies and delivery 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and therapeutic response. j urol 2003; 170: s3-5. 10. u.s. food and drug administration. fda talk paper. fda approves third drug to treat erectile dysfunction, 2003 nov 21. available from: http://www.fda.gov/bbs/topics/answers/2003 /ans01265. 11. erectile dysfunction. national kidney and urologic diseases information clearinghouse. available from: http://kidney.niddk.nih.gov/kudiseases/pubs/impotence. 12. padman-nathan h. efficacy and tolerability of tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction. am j cardiol. 2003;92(9 suppl 1):19-25. 13. rosen rc, padma-nathan h, shabsigh r. cialis (ic351) provides prompt response and extended period of responsiveness for the treatment of men with erectile dysfunction (ed). proceedings of the 96th annual meeting of the american urological association, 2001 june 2-7. anaheim, california. 14. walker dk, ackland mj, james gc, et al. pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog, and man. xenobiotica. 1999;29:297-310. 15. brock gb, mcmahon cg, chen kk, et al. efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. j urol. 2002;168:1332-8. 16. cialis (tadalafil) prescribing information. indianapolis, in: eli lilly and company; november 2003. 17. porst h, padma-nathan h, giuliano f, et al. efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. urology. 2003;62:121-6. 18. porst h, rosen r, padma-nathan h, et al. the efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. int j impot res. 2001;13:192-8. 19. williams t, honeywell m, branch iii e, ghazvini p, king k. tadalafil in the treatment of erectile dysfunction. drug forecast. 2004;29:295-303. 20. meinhardt w, schmitz pi, kropman rf, de la fuente rb, lycklama a nijeholt aa, zwartendijk j. trazodone, a double blind trial for treatment of erectile dysfunction. int j impot res. 1997;9:163-5. 21. rowland dl, kallan k, slob ak. yohimbine, erectile capacity, and sexual response in men. arch sex behav. 1997;26:49-62. 22. vogt hj, brandl p, kockott g, et al. double-blind, placebo-controlled safety and efficacy trial with yohimbine hydrochloride in the treatment of nonorganic erectile dysfunction. int j impot res. 1997;9:15561. 23. safarinejad mr. therapeutic effects of high-dose isoxsuprine in the management of mixed-type impotence. urology. 2001;58:95-7. 24. steers wd. viability and safety of combination drug therapies for erectile dysfunction. j urol. 2003;170:s20-3. 25. handelsman dj. testicular dysfunction in systemic disease. endocrinol metab clin north am. 1994;23:839-56. 26. lei ccm, kim yc. hormonal therapy for erectile dysfunction. apsir book on erectile dysfunction. chapter 9. apsir; 1999. p.113-7. 27. american association of clinical endocrinologists medical guidelines for clinical practice for the evaluation and treatment of male sexual dysfunction: a couple's problem-2003 update. endocrine practice. 2003;9:77-95. 28. a physician guide to the management of erectile dysfunction: the european society for impotence research. available from: http://www.esir.com. 29. padma-nathan h. minimally invasive therapy for erectile dysfunction: intracavernosal, oral, transdermal/trans238 safarinejad and hosseini glanular, and intraurethral approaches. in: mulcahy jj, editor. topics in clinical urology: diagnosis and management of male sexual dysfunction. tokyo: igaku-shoin; 1999. p.182-5. 30. shepherd dj. evaluation and treatment of erectile dysfunction in men with diabetes mellitus. mayo clin proc. 2002;77:276-82. 31. hauri d. penile revascularization surgery in erectile dysfunction. andrologia. 1999;31 suppl 1:65-73. 32. virag r, bennett ah. arterial and venous surgery for vasculogenic impotence: a combined french and american experience. arch ital urol nefrol androl. 1991;63:95-102. 33. manning m, junemann kp, scheepe jr, braun p, krautschick a, alken p. long-term followup and selection criteria for penile revascularization in erectile failure. j urol. 1998;160:1680-7. 34. konnak jw, ohl da. microsurgical penile revascularization using the central corporeal penile artery. j urol. 1989;142:305-11. 35. zumbe j, drawz g, wiedemann a, grozinger k, engelmann u. indications for penile revascularization and long-term results. andrologia. 1999;31(suppl):83-8. 36. lin cs, ho hc, chen kc, lin g, nunes l, lue tf. intracavernosal injection of vascular endothelial growth factor induces nitric oxide synthase isoforms. bju int. 2002;89:955-61. 37. byrne rr, henry gd, rao ds, et al. vascular endothelial growth factor restores corporeal smooth muscle function in vitro. j urol. 2001;165:1310-5. 38. lee mc, el-sakka ai, graziottin tm, ho hc, lin cs, lue tf. the effect of vascular endothelial growth factor on a rat model of traumatic arteriogenic erectile dysfunction. j urol. 2002;167:761-7. 39. earle cm, seah m, coulden se et al. the use of the vacuum erection device in the management of erectile impotence. int j impot res 1996; 8: 237-40. 40. soderdahl dw, thrasher jb, hansberry kl. intracavernosal drug-induced erection therapy versus external vacuum devices in the treatment of erectile dysfunction. br j urol. 1997;79:952-7. 41. kilmann pr, boland jp, norton sp et al. perspectives of sex therapy outcome: a survey of aasect providers. j sex marital ther. 1986;12:116-38. 42. mcculloch dk, hosking dj, tobert a. a pragmatic approach to sexual dysfunction in diabetic men: psychosexual counselling. diabetic med. 1986;3:485-9. 43. segenreich e, israilov sr, shmueli j, et al. vacuum therapy combined with psychotherapy for management of severe erectile dysfunction. eur urol. 1995;28:47-50. 44. levine sb. erectile dysfunction: why drug therapy isn't always enough. cleve clin j med. 2003;70:241-6. 45. rosen rc. psychogenic erectile dysfunction. classification and management. urol clin north am. 2001; 28(2): 269-78. 46. althof se, cappelleri jc, shpilsky a, et al. treatment responsiveness of the self-esteem and relationship questionnaire in erectile dysfunction. urology. 2003;61:888-92. 47. mannino dm, klevens rm, flanders wd. cigarette smoking: an independent risk factor for impotence? am j epidemiol. 1994;140:1003-8. 48. rosen mp, greenfield aj, walker tg, et al. cigarette smoking: an independent risk factor for atherosclerosis in the hypogastric-cavernous arterial bed of men with arteriogenic impotence. j urol. 1991;145:759-63. 49. mcvary kt, carrier s, wessells h; subcommittee on smoking and erectile dysfunction socioeconomic committee, sexual medicine society of north america. smoking and erectile dysfunction: evidence based analysis. j urol. 2001;166:1624-32. 50. juenemann kp, lue tf, luo ja, benowitz nl, abozeid m, tanagho ea. the effect of cigarette smoking on penile erection. j urol. 1987;138:438-41. 51. hirshkowitz m, karacan i, howell jw, arcasoy mo, williams rl. nocturnal penile tumescence in cigarette smokers with erectile dysfunction. urology. 1992;39:101-7. 52. derby ca, mohr ba, goldstein i, feldman ha, johannes cb, mckinlay jb. modifiable risk factors and erectile dysfunction: can lifestyle changes modify risk? urology. 2000;56:302-6. 53. jeremy jy, mikhailidis dp. cigarette smoking and erectile dysfunction. j r soc health. 1998;118:151-5. 54. rajfer j. growth factors and gene therapy for erectile dysfunction. rev urol. 2000;2:34. 239 benign retroperitoneal schwannoma mimicking adrenal mass farid dadkhah*, mohammadreza salimi, ali kaviani department of urology, shaheed modarress hospital, shaheed beheshti university of medical sciences, tehran, iran key words: adrenal mass, retroperitoneal tumor, schwannoma, diagnosis 49 urology journal unrc/iua vol. 2, no. 1, 49-51 winter 2005 printed in iran benign retroperitoneal schwannoma is a rare tumor originating from the schwann cells in the myelinated neural sheath and mostly manifested as an adrenal mass.(1-7) however, there are reports of developing of this tumor within or in front of psoas muscle(8) or other parts of the body. we report a benign retroperitoneal schwannoma, incidentally detected through imaging, mimicking an adrenal mass. case report a 57-year-old female, weighed 85 kg at presentation, was referred to our center with a large abdominal mass, which was incidentally detected in right adrenal site through imaging. no history of right flank pain, gross hematuria, sweating, flushing, or tachycardia was reported. on physical examination, the mass was not palpable in the right flank. moreover, microscopic hematuria was not seen in the conducted tests, and laboratory studies for pheochromocytoma were negative. ct scan showed a large right adrenal mass with low density central area, indicating central necrosis together with enhanced septation (fig. 1). mri demonstrated a hyperintense lesion in t1 weighted image, which is seen in figure 2a, attached to the kidney, and in figure 2b, apart from the kidney with adrenal origin. right adrenal gland is seen in figure 2a. the hyperintense lesion was seen in t2 weighted image, as well (fig. 2c). the patient underwent exploration with the preoperative differential diagnoses of adrenal mass, retroperitoneal mass, and renal mass, respectively. a large mass apart from kidney was seen that had pushed the adrenal gland upward and could have been easily separated from the kidney and adrenal gland. the tumor was drained via a vein at a size of renal vein which was directly connected to inferior vena cava. the mass, measured 6 × 8 ×12 cm, was removed (fig. 3a). in figure 3b, necrotic and cystic changes in central areas are seen through a cut section from the mass. histologic examination confirmed that this giant tumor was a benign retroperitoneal schwannoma, predominantly anton a type (fig 4). in 1-year follow-up, no recurrence was observed and the patient had no complication. discussion retroperitoneal schwannoma is a rare tumor originating from the schwann cells in the myelinated sheath of nerves.(1) it has been mostly reported a benign tumor.(1-7) received january 2004 accepted june 2004 *corresponding author: shaheed modarress hospital, saadat abad, tehran, iran. e-mail: dr_fdadkhah@yahoo.com. fig. 1. abdominal ct scan showed a large mass with central necrosis at the right adrenal area. in a study carried out in japan, of all the cases of schwannoma 94 (72.3%) were benign and 36 (27.7%) were malignant.(2) schwannoma develops as an adrenal mass, as reported in most cases.(1-7) symptomatic patients have only vague flank pain. due to central necrosis, this tumor has a low density(2) or internal cystic schema(3) in ct scan. however, although the presence of cystic schema is highly indicative of schwannoma, this is not necessary for diagnosis.(3) exploration is often required for diagnosis of this tumor, since mere imaging would not be sufficient in most cases.(5) in our case, an internal cystic schema was seen. although the mass was separate from adrenal gland and kidney in most ct scan cuts, in some other cuts the mass seemed to have completely adrenal origin. also, it seemed that there was a complete adhesion to kidney, even originating from the kidney capsule. as a result, we could not determine its real origin preoperatively. during benign retroperitoneal schwannoma50 fig. 2. mri, a. t1 weighted image: a hyperintense tumor in the upper pole of the right kidney, b. t1 weighted image: the tumor appears to be separate from the kidney. c. t2 weighted image: the tumor is hyperintense. fig. 3. a. the extracted tumor, b. the tumor, longitudinally incised. a c b a b dadkhah et al 51 exploration, the mass was completely separated from kidney and adrenal gland, and our diagnosis was retroperitoneal mass. finally, pathologic diagnosis of benign schwannoma confirmed its retroperitoneal nature. references 1. ben moualli s, hajri m, ben amna m, et al. [retroperitoneal schwannoma. case report]. ann urol (paris). 2001;35:270-2. french 2. okamura k, ito k, aota y, suzuki y, shimoji t. [a case report of retroperitoneal malignant schwannoma]. hinyokika kiyo. 1984;30:1045-51. japanese 3. barrero candau r, ramirez mendoza a, morales lopez a, et al. [benign adrenal schwannoma]. arch esp urol. 2002;55:858-60. spanish 4. behrend m, kaaden s, von wasielewski r, frericks b. benign retroperitoneal schwannoma mimicking an adrenal mass. surg laparosc endosc percutan tech. 2003;13:133-8. 5. igawa t, hakariya h, tomonaga m. [primary adrenal schwannoma]. nippon hinyokika gakkai zasshi. 1998;89:567-70. japanese 6. hettiarachchi ja, finkelstein mp, schwartz am, johnson gb, konno s, choudhury ms. benign retroperitoneal schwannoma presenting as a giant adrenal tumor. urol int. 2003;71:231-2. 7. pittasch d, klose s, schmitt j, et al. retroperitoneal schwannoma presenting as an adrenal tumor. exp clin endocrinol diabetes. 2000;108:318-21. 8. perhoniemi v, anttinen i, kadri f, saario i. benign retroperitoneal schwannoma. scand j urol nephrol. 1992;26:85-7. fig. 4. pathologic view of the tumor texture, a benign retroperitoneal schwannoma, predominantly anton a type vol 13 no 02 march-april 2016 2590vol 13 no 02 march-april 2016 2640 miscellaneous prevention of urinary tract infection with oximacro®, a cranberry extract with a high content of a-type proanthocyanidins: a pre-clinical double-blind controlled study purpose: urinary tract infections (utis) are widespread and affect a large portion of the human population. cranberry juices and extracts have been used for uti prevention due to their content of bioactive proanthocyanidins (pacs), particularly of the a type (pac-a). controversial clinical results obtained with cranberry are often due to a lack of precise determination and authentication of the pac-a content. this study used oximacro® (biosfered s.r.l., turin, italy), a cranberry extract with a high content of pac-a, to prevent utis in female and male volunteers. materials and methods: the oximacro® pacs content was assayed using the brunswick laboratories 4-dimethylaminocinnamaldehyde (bl-dmac) method, and the dimer and trimer pacs-a and pacs-b percentages were determined via high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (hplc/esi-ms/ms). a balanced group of female (ranging from 19 to over 51 years) and male volunteers (over 51 years) was divided into two groups. the experimental group received 1 capsule containing oximacro® (36 mg pacs-a) twice per day (morning and evening) for 7 days, and the placebo group was given the same number of capsules with no pacs. results: analysis of oximacro® revealed a high total pac content (372.34 mg/g ± 2.3) and a high percentage of pac-a dimers and trimers (86.72% ± 1.65). after 7 days of oximacro® administration, a significant difference was found between the placebo and oximacro® groups for both females (mann-whitney u-test = 875; p < .001; n = 60) and males (mann-whitney u-test = 24; p = .016; n = 10). when the female and male age ranges were analysed separately, the female age range 31-35 showed only slightly significant differences between the placebo and oximacro® groups (mann-whitney u-test = 20.5; p = .095; n = 10), whereas all other female age ranges showed highly significant differences between the placebo and oximacro® groups (mann-whitney u-test = 25; p = .008; n = 10). furthermore, colony forming unit/ml counts from the urine cultures showed a significant difference (p < .001) between the experimental and the placebo groups (sd difference = 51688; df = 34, t = -10.27; dunn-sidak adjusted p < .001, bonferroni adjusted p < .001). conclusion: careful determination of the total pac content using the bl-dmac method and the authentication of pacs-a with mass spectrometry in cranberry extracts are necessary to prepare effective doses for uti prevention. a dose of 112 mg oximacro® containing 36 mg pacs-a was found to be effective in preventing utis when used twice per day for 7 days. keywords: urinary tract infections; prevention & control; plant extracts; pharmacology; humans; urinalysis; therapeutic use; vaccinium macrocarpon. introduction urinary tract infections (utis) are widespread and affect a large portion of the human population. approximately 13 million women in the united states and approximately 150 million people worldwide develop utis each year, with societal costs of approximately 3.5 billion usd per year in the usa alone.(1) an estimated 40% of women develop at least one uti during their lifetimes.(2) utis refer to the presence of a certain threshold number of bacteria in the urine (usually > 105/ml) and consist of cystitis (or lower utis, 1 department of life sciences and systems biology, university of turin, via quarello 15/a, turin, italy. 2 farmacia antoniana, viale cesare balbo, 3, 10040 san gillio (to), italy. *correspondence: department of life sciences and systems biology, university of turin, via quarello 15/a, 10135 turin, italy. tel: +39 011 6705967. fax: +39 011 2365967. e-mail: massimo.maffei@unito.it. received september 2015 & accepted february 2016 with bacteria in the bladder), urethral syndrome and pyelonephritis (or upper utis, with infection of the kidneys).(3) bacterial cystitis (also called acute cystitis) can occur in women and men, and the signs and symptoms include dysuria (pain on passing urine), frequency, cloudy urine, and occasionally haematuria (blood in the urine); bacterial cystitis is also often associated with pyuria (urine white cell count > 104/ml). some people also develop recurrent utis with an average of two to three episodes/year.(4) the berries of cranberry (vaccinium macrocarpon aiandrea occhipinti,1 antonio germano,2 massimo e. maffei1* ton) have been used for hundreds of years as a remedy for diseases of the urinary tract and have attracted attention due to their potential health benefits.(5,6) the beneficial mechanism of cranberry was historically thought to be due to the fruit’s acids causing a bacteriostatic effect in the urine. however, recently, a group of proanthocyanidins (pacs) with a-type linkages (pac-a) was isolated from cranberries and shown to exhibit bacterial antiadhesion activity against both antibiotic-susceptible and -resistant strains of uropathogenic p-fimbriated escherichia coli (e. coli) bacteria, including multidrug-resistant e. coli.(7-10) central in the efficacy of cranberry extract/juice is the determination of the optimum dose of pac-a, which is an essential requirement in establishing botanical supplements as viable supports to conventional therapies.(11) recent studies have revealed that cranberry extract regimens containing 72 mg pacs produce significant bacterial antiadhesion activity in human urine.(2,10) clearly, the dose of bioavailable pac-a is central to the issue of cranberry efficacy. currently, four methods are used to evaluate the content of cranberry pacs; two methods are based on the depolymerisation of pacs (e.g., the hydrochloric acid butanol method known as bates-smith and the european pharmacopoeia method), and two are colorimetric methods (a ultraviolet-visible [uv-vis] spectrophotometric method based on prussian-blue or folin-ciocalteu reagents and the brunswick laboratories 4-dimethylaminocinnamaldehyde [bl-dmac] method). the bl-dmac colorimetric method (an aldehyde condensation of 4-dimethylaminocinnamaldehyde) appears to be more accurate than the other methods and has been successfully used to quantify cranberry pacs.(12) in particular, the bl-dmac method is less likely to be subject to interference from cranberry components, such as anthocyanins, because the reaction is read at 640 nm. however, the bl-dmac method, although specific for pac quantification, is not able to distinguish between aand b-type pacs;(13) therefore, analytical methods, such as high-performance liquid chromatography (hplc) coupled to mass spectrometry or fluorescence detectors, are necessary for pacs-a authentication.(14) oximacro® is a cranberry extract with the highest content of pacs (according to the bl-dmac method) and the highest percentages of pac-a dimers and trimers (based on liquid chromatography [lc]/mass spectrometry [ms] identification) available on the market. here, we report on the chemical analysis of the pac content of oximacro® and its action in preventing utis based on a pre-clinical double-blind controlled study on male and female volunteers. materials and methods reagents oximacro®, a cranberry (vaccinium macrocarpon aiton) extract, was provided by biosfered s.r.l. (turin, italy) and produced from cranberries as a reddish powder with a total pac content > 360 mg/g (lot # cr0104-pd01). the coa of the product is available at the company web site (http://www.biosfered.com). extrasynthese (lyon, france) provided pure standards of pac-a and pac-b. the pure chemicals were dissolved in 96% v/v ethanol (sigma-aldrich, carlsbad, usa) at a final concentration of 100 µg/ml. aliquots of stock solutions were stored in 1.5-ml hplc vials at -80°c figure 1. spectral analysis of the bl-dmac reaction of pac-a (black line) and pac-b (red line). when tested at the same concentration (20 µg ml-1), pac-b showed a higher absorbance (at 640 nm) than pac-a. abbreviations: pac, proanthocyanidins; bl-damc, brunswick laboratories 4-dimethylaminocinnamaldehyde. prevention of urinary tract infection with oximacro®-occhipinti et al. miscellaneous 2641 vol 13 no 02 march-april 2016 2642 until use. the chemical purity and integrity of standard compounds was assessed (see below) prior to use. determination of the total pac content with the bl-dmac method the bl-dmac assay was performed according to the method of prior and colleagues(12) with minor modifications. extraction buffer was composed of acidified 75% v/v acetone (vwr international, milan) with 0.5% v/v acetic acid (sigma-aldrich, carlsbad, usa). acidified ethanol was composed of 72% v/v ethanol and hydrochloric acid (sigma-aldrich, carlsbad, usa) at a final concentration of 1.52 m. dmac solution was composed of 0.1% w/v 4-(dimethylamino)-cinnamaldehyde (dmac) (sigma-aldrich, usa) in acidified ethanol; this solution was freshly prepared prior to the assay. briefly, oximacro® (20-30 mg) was dissolved in 5 ml of extraction buffer. the powder was extracted in an ultrasonic bath at room temperature for 20 min and then shaken with an orbital shaker for 1 h. samples were centrifuged at 5,000 g for 10 min and then diluted in the extraction buffer prior to spectrophotometric assay. the colorimetric reaction was performed by mixing 0.84 ml dmac solution and 0.28 ml of a diluted sample in a 1.5-ml plastic cuvette. the total pacs were quantified via an external calibration curve made with a pure pac-a standard. the reaction kinetics of both pac standards (pac-a and pac-b) were determined using a time-course bl-dmac assay. a concentration of 20 µg/ml was tested for both standards. the reaction was incubated in the dark from 1 to 25 min to assess the dynamics of the dmac reaction, and the absorbance was read at 640 nm (cary60, agilent-technologies, california, usa) against a blank composed of acidified ethanol and dmac solution. the quantification was performed in triplicate within the linear range of calibration curves (5-30 µg/ml). oximacro® was then assayed exactly at 20 min, which corresponds to the maximum absorbance value for pac-a. to test the reactivity of pac-a and pac-b to dmac, 20 µg/ml solutions of pac-a and pac-b were tested with increasing percentages of pac-b (0, 25, 50, 75 and 100%). the final concentration of the tested mixtures was always 20 µg/ml. the absorption spectra were recorded between 350 and 800 nm, exactly 20 min after the beginning of the dmac colorimetric assay. authentication of the pac-a content in oximacro® pac-a and pac-b authentication of oximacro® were obtained via liquid chromatography (1200 hplc, agilent technologies, california, usa) equipped with a reverse phase (rp) c18 kinetex (2.6 µm, 100 × 3.0 mm, phenomenex, california, usa) column. the binary solvent system was a) milliq h 2 o (millipore, billerica, massachusetts, usa) with 0.1% v/v of formic acid and b) acetonitrile (vwr international, usa) with 0.1% v/v of formic acid. chromatographic separation was carried out at constant flow rate (200 µl/min) using the following conditions: linear gradient from 5% to 30% of b in 10 min and isocratic elution for 5 min and 20 min at 50% of b and 24 min at 90% of b at 24 min. the initial mobile phase was re-established for 10 min prior to the next injection. tandem mass spectrometry analyses were performed with a 6330 series ion trap lc-ms system (agilent technologies, california, usa) equipped with an electrospray ionization figure 2. time-course of the bl-dmac reaction of 20 µg ml-1 pac-a and pac-b. when used at the same concentration, pac-b (dotted line) reacts more rapidly and with a higher absorbance with respect to pac-a (solid line). metric bars represent standard deviation. abbreviations: pac, proanthocyanidins; bl-damc, brunswick laboratories 4-dimethylaminocinnamaldehyde. prevention of urinary tract infection with oximacro®-occhipinti et al. source (esi) operating in negative mode. the identification of pac-a (dimers and trimers) was performed via multiple reaction monitoring (mrm) by monitoring the following parental ions [m-h]-: 575, 577, 861, 863 and 865 m/z. study population and inclusion and exclusion criteria to assess the effect of oximacro®, we recruited participants from a population of volunteers (10 male and 60 female) involved in studies performed by the farmacia antoniana (san gillio, italy) under the supervision of medical doctors. informed consent was obtained. the inclusion criteria included any woman or man at least 18 years of age to over 51 years of age with at least 2 culture-documented symptomatic utis in the calendar year prior to recruitment. the choice of volunteers was completely balanced, and volunteers with known anatomical abnormalities (posterior urethral valves, neurogenic bladder, or any urinary obstruction) were excluded from this study. urinary infection was defined as a positive culture of a midstream sample with a uropathogenic bacterium at 105 colony forming unit (cfu)/ml in symptomatic volunteers with no more than two species of organisms present. we accepted lower counts (104 cfu/ml) if the volunteer had typical symptoms of uti and positive white blood cells and/or nitrites on urine analyses. specific symptoms and signs included pain before, during, or after micturition; increased frequency of micturition; pain in abdomen; haematuria; foul smell; and signs of common sickness (fever > 37.9°c or 1.5°c above baseline, temperature, chills, nausea, and vomiting). nonspecific symptoms were considered anorexia, fatigue and reduced mobility, and signs of delirium (e.g., confusion and deterioration in mental or functional status). asymptomatic bacteriuria was not considered an end point. after explaining the study and obtaining consent, patients were assigned to the placebo group or experimental randomized groups. the randomization was concealed. oximacro® administration and dosage capsules contained 500 mg of the product [112 mg oximacro® (equivalent to 36% pac-a), 383 mg mipercentage of a 20 µg ml-1 pac-a solution percentage of a 20 µg ml-1 pac-b solution total pacs, expressed as µg ml1 (± standard deviation) 100 0 20.49a (± 0.65) 75 25 22.65b (± 1.48) 50 50 25.49c (± 2.55) 25 75 28.18d (± 2.48) 0 100 31.29e (± 2.19) abbreviations: pac, proanthocyanidins. table 1. comparative analysis of total pacs content based on a pac-a calibration curve with an increasing percentage of pac-b (± standard error; n = 3). in the same column, different letters indicate significant (p < .05) differences. figure 3. bl-dmac spectral analysis of a 20 µg ml-1 solution of pac-a and pac-b used at increasing pac-b concentrations. increasing pac-b causes an absorbance increase at 640 nm. abbreviations: pac, proanthocyanidins; bl-damc, brunswick laboratories 4-dimethylaminocinnamaldehyde; abs, absorbency. prevention of urinary tract infection with oximacro®-occhipinti et al. miscellaneous 2643 vol 13 no 02 march-april 2016 2644 crocrystalline cellulose and 5 mg magnesium stearate]. the placebo was indistinguishable in colour, taste, and appearance, consisting of all elements above without oximacro® and coloured with azorubine. the experimental group (5 males and 30 females) received 1 capsule containing 36% pac-a twice per day (morning and evening) for 7 days, and the placebo group (5 males and 30 females) was given the same number of capsules with no pacs. a score (from 0, representing no effect, to 10, representing a maximum effect of oximacro® in preventing uti) was recorded for all volunteers. to obtain linearity, the logarithm of the scores (ln scores) was used. the dose was calculated based on previous clinical trials.(10) the administration was performed for 7 days; during this time, the volunteers were followed with alternating visits and telephone calls every 2 days. at the end of the treatment period, a urine sample was sent for urine analysis and urine culture. to avoid contamination, the volunteers were asked to not use antibiotics or any other cranberry products for the duration of the study, with the exception of the placebo group, in which volunteers were asked to immediately report on symptoms. in the latter case, they were asked to use the antibiotic prescribed by the medical doctor and to interrupt the placebo administration. the attending urologists, outcome assessor and statistician were all blinded to the group allocations. statistical analysis we performed fisher’s exact tests on the tabulated frequencies to assess the effect of the treatments. kolmogorov–smirnov tests were used to assess the distribution type for the continuous variable, i.e., the average value of the score. the data were log-transformed. accordingly, a non-parametric analysis of variance was used to assess the differences in the oximacro® and placebo groups according to the sex and age categories. the median, quartile, maximum and minimum score values are represented in boxplots; outliers are represented by asterisks. a binary logistic regression was performed to test the independent effects of age and sex on oximacro® outcomes. all statistical analyses were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 22.0. the intentable 2. volunteers baseline characteristics. variables experimental group, oximacro® administration, n = 35 placebo group, n = 35 demographics females, no (%) 30 (85.7) 30 (85.7) males, no (%) 5 (14.3) 5 (14.3) median age (range) 38 (19-61) 38 (19-63) age range 19-24 5 (f) 5 (f) 25-30 5 (f) 5 (f) 31-35 5 (f) 5 (f) 36-40 5 (f) 5 (f) 41-50 5 (f) 5 (f) > 51 5 (f), 5 (m) 5 (f), 5 (m) baseline characteristics acute uti, no (%) 35 (100) 35 (100) bladder and bowel dysfunction, no (%) 35 (100) 35 (100) average utis in years prior to treatment 2.5 2.6 number of capsules (days) 2 (7) 2 (7) volunteers not completing the study, no (%) 6 (17) 15 (43) females, no (%) 6 (17) 13 (43) males, no (%) 1 (20) 3 (60) abbreviations: m, male; f, female; uti, urinary tract infections. variables placebo oximacro® not recovered 35 7 recovered 0 28 fisher's exact test: p < .001 table 3. contingency table. prevention of urinary tract infection with oximacro®-occhipinti et al. tion-to-treat principle was followed. results one of the key points in uti prevention is the assessment of the content of bioactive pacs-a, which are contained in the capsule. total pac content can be quantitated using various methods, among which the bl-dmac method is generally recognised as the most accurate.(12,13) however, the bl-dmac assay is sensitive to the presence of both pacs-a and pacs-b. when we measured the standards of pac-a and pac-b using the bl-dmac method, we found that the same amount of pac reacted differently with various absorbance spectra (figure 1). in particular, a higher absorbance (at 640 nm) was found for pac-b than pac-a (figure 1). a time-course experiment was then performed by measuring the bl-dmac reaction of 20 µg/ml pac-a and pac-b. pac-b reached maximum absorbance after 11 min, whereas pac-a showed a maximum absorbance at 20 min (figure 2). pac-a and pac-b purity standards were analysed to assess purity and integrity; the results showed that the purity was identical to that declared by the supplier. to determine whether a mixture of pac-a and pac-b with increasing percentages of the two pacs could result in differing pac quantifications, we assayed the bl-dmac of the mixtures and found that the presence of pac-b increased the absorbance values measured at 640 nm (figure 3). finally, we calculated the total amount of pacs based on a calibration curve prepared with a pac-a standard using mixtures with increasing percentages of pac-b and decreasing percentages of pac-a at a final concentration of 20 µg/ ml, as calculated using the gravimetric method. table 1 shows that the total amount of pacs increased with increasing pac-b content despite a constant amount of total pacs used. these results indicate that the bl-dmac method is time-sensitive (in our analyses, the best timing for the pac-a reaction was 20 min) and that shorter reaction times may lead to overestimating the total pac content. the latter result may occur in cases of high amounts of pac-b. furthermore, our results confirm that the bldmac method does not distinguish between pac-a figure 4. hplc-esi-ms/ms analysis of oximacro®. a) hplc-esi-ms/ ms chromatogram of dimers and trimers of pac-a and pac-b. the mass spectrometry analysis performed in mrm mode shows the presence of pac-a dimers (black line) and trimers (blue line) and pac-b dimers (red line). b) ms2 spectra in negative mode of a typical pac-b dimer ([m-h]1 575 m/z). c) ms2 spectra in negative mode of a typical pac-a dimer ([m-h]-1 577 m/z). abbreviations: pac, proanthocyanidins; hplc-esi-ms/ms, high-performance liquid chromatography/electrospray ionization tandem mass spectrometry; mrm, multiple reaction monitoring. figure 5. boxplot representing the logarithm of the scores of the placebo and oximacro® groups in both females and males volunteers. females differences between placebo and oximacro®: mann-whitney = 875; p < .001; n = 60; males differences between placebo and oximacro®: mann-whitney = 24; p = .016; n = 10. prevention of urinary tract infection with oximacro®-occhipinti et al. miscellaneous 2645 vol 13 no 02 march-april 2016 2646 and pac-b and that even when a calibration curve is obtained with pac-a, an increased amount of pac-b eventually increases the absorbance at 640 nm, thereby affecting the total pac quantification. therefore, a high pac value obtained with the bl-dmac method does not necessarily indicate a high amount of pac-a even though a calibration curve is calculated with a pac-a standard. having assessed the best timing for pac determination, we next measured the total amount of oximacro® pacs. the bl-dmac method showed a total of 372.34 mg/g (± 2.3) pacs, in line with that declared by the producer. to our knowledge, and based on the bl-dmac method, this is the highest amount of pacs reported for a cranberry extract that is currently on the market. the bioactivity of cranberry against uti is dependent on the pac-a content(9,15,16) (particularly dimers and trimers);(17-19) thus, we analysed oximacro® via hplc followed by electrospray ionization (ei) and tandem mass spectrometry (esi-ms/ms). oximacro® was primarily composed of pac-a dimers followed by a lower amount of pac-a trimers (figures 4a and 4c). the total percentages of pac-a and pac-b based on hplc-esi-ms/ms were 86.72% (± 1.65) and 13.99% (± 1.03), respectively (figures 4a-c). the percentage of other pac polymers was below the threshold of detection. considering the total pacs (calculated using the bldmac method) and the percentage of pac-a dimers and trimers, oximacro® showed a total pac-a content of 322.89 mg/g (± 1.58). therefore, 112 mg of oximacro® contains 360 mg/g pac-a. following the assessment and authentication of the pac-a content of oximacro®, we prepared capsules containing 112 mg of oximacro® (which corresponds to 36% pac-a) and placebo capsules. in all volunteers, the infection prior to recruitment was due to e. coli in 85%, other enteric gram-negative bacilli in 10%, and more than 1 type of bacteria in 5% of the volunteers. table 2 shows the volunteers’ demographic and baseline characteristics. reasons for dropout in the experimental group included relocation (1), feeling better prior to the end of treatment (4), contrary advice from a family doctor (1), and a family perception of oximacro® ineffectiveness (1). reasons for dropout in the placebo group included acute pain (12), contrary advice from a family doctor (2), and a family perception of oximacro® ineffectiveness (1). the median follow-up time in both groups was 4 weeks. the mean capsule intake was 97% (95% ci: 96.6– 97.6%) and was similar between the experimental and placebo groups. after 7 days of oximacro® and placebo administration, a contingency table was calculated based on recovered vs. not recovered volunteers (table 3); this table showed a significant difference (fisher’s exact test: p < .001) between the oximacro® and placebo groups. a general mann-whitney u-test test further showed a highly significant difference between the placebo and oximacro® groups (1191; p < .001; n = 70), with most of the placebo group unable to recover from uti. eventually, all placebo volunteers had to be treated with antibiotics (monuril®, trometamol salt of fosfomycin) to reduce pain. figure 5 shows the boxplot of female and male scores; a significant difference was found between the placebo and oximacro® groups for both females (mann-whitney u-test = 875; p < .001; n = 60) and males (mann-whitney u-test = 24; p = .016; n = 10). significant differences were also found when the age ranges were analysed. in particular, between the placebo and oximacro® groups, the female age ranges of 19-24, 25-30, 36-40, 41-50 and over 51 years showed figure 6. boxplot representing the logarithm of the scores of the placebo and oximacro® groups in both females (left panel) and males (right panel) volunteers according to the age range. left panel, females age range-based (19-24, 25-30, 36-40, 41-50 and > 51 years) differences between placebo and oximacro®: for each age range, mann-whitney = 25; p = .008; n = 10; differences between placebo and oximacro® for the female age range of 31-3 years: mann-whitney = 20.5; p = .095; n = 10. right panel, differences between placebo and oximacro® for the male age range over 51: mann-whitney = 24; p = .016; n = 10. prevention of urinary tract infection with oximacro®-occhipinti et al. highly significant differences (for each age range: mann-whitney u-test = 25; p = .008; n = 10); the age range from 31-35 years showed barely significant differences (mann-whitney u-test = 20.5; p = .095; n = 10) (figure 6 left panel). for males, the only age range (over 51) showed a significant difference between the placebo and oximacro® groups as reported above (figure 6 right panel). finally, considering the cfu/ml counts from the urocultures, a significant difference (p < .001) was found in the comparison between the experimental group and the placebo group (sd difference = 51688; df = 34, t = -10.27; dunn-sidak adjusted p < .001, bonferroni adjusted p < .001). overall, these results show that the administration of oximacro® significantly ameliorated uti in the treatment group. when a multivariate binary logistic regression was performed to examine the independent effect of oximacro® on healing (dependent variable) based on sex and age (covariates), no significant effect (p > .900) for categorical variables was found for the treatment outcomes (data not shown). discussion the efficacy of cranberry in preventing utis remains controversial primarily due to contrasting results indicating either a nonsignificant effect (as in the case of cranberry juice drinking)(20-23) or an extended duration therapy requirement (e.g., 12 months of drinking cranberry juice).(24) in individuals with recurrent utis, low-dose antibiotic prophylaxis for several months is usually recommended.(25) however, extended use of antibiotics may lead to the development of antibiotic resistance. indeed, several e. coli isolates are resistant to antimicrobial treatment, and the interest in non-antibiotic methods for the prevention of utis is growing.(26) if the dosage of non-antibiotic methods is not standardized, the cost/effect ratio may be higher than antibiotic treatment, as recently shown with a cranberry prophylaxis regimen for preventing utis in which the pac-a treatment was far below (18.2 mg/day) the recommended dosage (72 mg). in this case, the cranberry treatment was less effective and more expensive than (dominated by) trimethoprim-sulfamethoxazole prophylaxis.(27) the use of concentrated cranberry extract with a high pac content has been successfully proven to prevent utis in women who are subject to recurrent infections.(7,9,10, 18,28-31) despite these positive results, one of the major concerns is the quantification of pacs-a, which are the only bioactive compounds thus far demonstrated to exert a significant uropathogenic bacterial anti-adhesion effect.(9,19) a recent survey on the pac content of some cranberry extract products via both bl-dmac and hplc found that bl-dmac values for the pac content per unit were below those declared by the manufacturers. in particular, some cranberry extract medicinal products showed a a-type pac content so low that they would have no chance of providing health benefits;(32) the availability of these extracts was likely the result of overestimation of the pac content provided by the bates-smith and the european pharmacopoeia methods. on the one hand, these methods grant a high percentage value; on the other hand, by overestimating the real pac content, these methods limit the health benefits of cranberry extracts. the cranberry industry is currently using bl-dmac as a standard method;(13) however, the bl-dmac method is unable to discriminate between aand b-type pacs.(13) it is thus important to combine accurate timing and the kinetics of the method with the hplc-ms authentication of pac types. the results of this work show that the presence of pac-b in cranberry extract can overestimate the total pac content based on a pac-a calibration curve. for instance, a cranberry extract with a high percentage of pac-b (as is typical in some cranberry cultivars) may yield a high total pac value with the bl-dmac method despite a pac-a standard calibration curve. furthermore, in our conditions (see the materials and methods), 20 min of reaction were required for an accurate pac-a determination (complete saturation of the reaction). therefore, the standardization of pacs using the bl-dmac method and the authentication of pac-a with lc-ms is a prerequisite in preparing cranberry dosages for the prevention of utis. our results showed that the cranberry extract oximacro® contains a high total pac content and a high percentage of bioactive pac-a dimers and trimers. when administered to volunteers, the extract was particularly suitable for uti prevention, and 112 mg oximacro® (equivalent of 36 mg pacs-a) twice per day for 7 days was significantly effective in reducing the total urobacterial cfu counts in both the female and male groups with respect to placebo. the age ranges were unaffected by treatment with the sole exception of the 31-35 year age range in the female group. this group did not differ in baseline characteristics with respect to the other age groups; thus, the reason for the reduced effect of oximacro® in this group requires further investigation. a literature search on age-related responses to cranberry treatment did not provide any reported cases, although further studies will focus on this aspect. conclusions prevention of urinary tract infection with oximacro®-occhipinti et al. miscellaneous 2647 vol 13 no 02 march-april 2016 2648 the results of this work are in agreement with previous randomized, double-blind versus placebo multicentre studies examining the effects of 72 mg of pac-standardized cranberry.(2,10,13) furthermore, our results show that 72 mg pac-a is highly effective, and we suggest the use of dosages based on pacs-a instead of the total pacs in uti treatment. due to the impossibility of bldmac in discriminating between pac-a and pac-b, the sole total pacs quantification may not be sufficient in providing the required amount of pac-a needed to significantly inhibit utis. further studies will assess the recurrence of utis in oximacro®-supplemented volunteers. aknowdledgements the authors would like to express their gratitude to dr. francesca barbero for the statistical analyses and for the revision of the manuscript. conflicts of interest none declared references 1. flores-mireles al, walker jn, caparon m, hultgren sj. urinary tract infections: epidemiology, mechanisms of infection and treatment options. nat rev microbiol. 2015;13:269-84. 2. micali s, isgro g, bianchi g, miceli n, calapai g, navarra m. cranberry and recurrent cystitis: more than marketing? crit rev food sci nutr. 2014;54:1063-75. 3. foxman b. urinary tract infection syndromes occurrence, recurrence, bacteriology, risk factors, and disease burden. infect dis clin north am. 2014;28:1-13. 4. fiore dc, fox cl. urology and nephrology update: recurrent urinary tract infection. fp essent. 2014;416:30-7. 5. jass j, reid g. effect of cranberry drink on bacterial adhesion in vitro and vaginal microbiota in healthy females. can j urol. 2009;16:4901-7. 6. jepson rg, williams g, craig jc. cranberries for preventing urinary tract infections. cochrane database syst rev. 2012;10:cd001321. 7. gupta k, chou my, howell a, wobbe c, grady r, stapleton ae. cranberry products inhibit adherence of p-fimbriated escherichia coli to primary cultured bladder and vaginal epithelial cells. j urol. 2007;177:2357-60. 8. stapleton ae, dziura j, hooton tm, et al. recurrent urinary tract infection and urinary escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. mayo clinic proc. 2012;87:143-50. 9. howell ab, reed jd, krueger cg, winterbottom r, cunningham dg, leahy m. a-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. phytochemistry. 2005;66:2281-91. 10. howell ab, botto h, combescure c, et al. dosage effect on uropathogenic escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. bmc infect dis. 2010;10:94. 11. gurley bj cranberries as antibiotics? arch int med. 2011;171:1279-80. 12. prior rl, fan e, ji h, et al. multi-laboratory validation of a standard method for quantifying proanthocyanidins in cranberry powders. j sci food agric. 2010;90:1473-8. 13. krueger cg, reed jd, feliciano rp, howell ab. quantifying and characterizing proanthocyanidins in cranberries in relation to urinary tract health. anal bioanal chem. 2013;405:4385-95. 14. prior rl, lazarus sa, cao gh, muccitelli h, hammerstone jf. identification of procyanidins and anthocyanins in blueberries and cranberries (vaccinium spp.) using high-performance liquid chromatography/ mass spectrometry. j agric food chem. 2001;49:1270-6. 15. la vd, howell ab, grenier d. antiporphyromonas gingivalis and antiinflammatory activities of a-type cranberry proanthocyanidins. antimicrob agents chemother. 2010;54:1778-84. 16. ou k, percival ss, zou t, khoo c, gu l. transport of cranberry a-type procyanidin dimers, trimers, and tetramers across monolayers of human intestinal epithelial caco-2 cells. j agric food chem. 2012;60:1390-6. 17. feliciano rp, shea mp, shanmuganayagam d, krueger cg, howell ab, reed jd. comparison of isolated cranberry (vaccinium macrocarpon ait.) proanthocyanidins to catechin and procyanidins a2 and b2 for use as standards in the 4-(dimethylamino) cinnamaldehyde assay. j agric food chem. 2012;60:4578-85. 18. feliciano rp, meudt jj, shanmuganayagam d, krueger cg, reed jd. ratio of "a-type" to "b-type" proanthocyanidin interflavan bonds affects extra-intestinal pathogenic escherichia coli invasion of gut epithelial cells. j agric food chem. 2014;62:3919-25. 19. foo ly, lu yr, howell ab, vorsa n. a-type proanthocyanidin trimers from cranberry that inhibit adherence of uropathogenic p-fimbriated escherichia coli. j nat prod. 2000;63:1225-8. 20. barbosa-cesnik c, brown mb, buxton m, zhang l, debusscher j, foxman b. cranberry juice fails to prevent recurrent urinary prevention of urinary tract infection with oximacro®-occhipinti et al. tract infection: results from a randomized placebo-controlled trial. clin infect dis. 2011;52:23-30. 21. cowan c, hutchison c, cole t, et al. a randomised double-blind placebo-controlled trial to determine the effect of cranberry juice on decreasing the incidence of urinary symptoms and urinary tract infections in patients undergoing radiotherapy for cancer of the bladder or cervix. clin oncol (r coll radiol). 2012;24:e31-8. 22. takahashi s, hamasuna r, yasuda m, et al. a randomized clinical trial to evaluate the preventive effect of cranberry juice (ur65) for patients with recurrent urinary tract infection. j infect chemother. 2013;19:112-7. 23. howell ab. updated systematic review suggests that cranberry juice is not effective at preventing urinary tract infection. evidencebased nurs. 2013;16:113-4. 24. jepson r, craig j. cranberries for preventing urinary tract infections. cochrane database syst rev. 2008;cd001321. 25. albert x, huertas i, pereiró ii, sanfélix j, gosalbes v, perrota c. antibiotics for preventing recurrent urinary tract infection in non-pregnant women. cochr datab syst rev. 2004;cd001209. 26. beerepoot m, geerlings s, van haarst e, van charante n, ter riet g. nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and metaanalysis of randomized controlled trials. j urol. 2013;190:1981-9. 27. bosmans je, beerepoot ma, prins jm, ter riet g, geerlings se. cost-effectiveness of cranberries vs antibiotics to prevent urinary tract infections in premenopausal women: a randomized clinical trial. plos one. 2014;9:e91939. 28. bailey dt, dalton c, daugherty f, tempesta ms. can a concentrated cranberry extract prevent recurrent urinary tract infections in women? a pilot study. phytomedicine. 2007;14:237-41. 29. blumberg jb, camesano ta, cassidy a, et al. cranberries and their bioactive constituents in human health. adv nutrit. 2013;4:618-32. 30. barnoiu o, sequeira-garcia del moral j, sanchez-martinez n, et al. american cranberry (proanthocyanidin 120mg): its value for the prevention of urinary tracts infections after ureteral catheter placement. act urologic espanol. 2015;39:112-7. 31. afshar k, stothers l, scott h, macneily a. cranberry juice for the prevention of pediatric urinary tract infection: a randomized controlled trial. j urol. 2012;188:1584-7. 32. chrubasik-hausmann s, vlachojannis c, zimmermann bf. proanthocyanin content in cranberry ce medicinal products. phytother res. 2014;28:1612-4. prevention of urinary tract infection with oximacro®-occhipinti et al. miscellaneous 2649 sexual dysfunction and infertility selective nuclear factor kappa b (nfκb) inhibitor, pyrrolidium dithiocarbamate prevents, long-term histologic damage in ischemia-reperfusion injuries after delayed testicular torsion levent ozcan,1* alper otunctemur,2 emre can polat,2 emin ozbek,2 sinan levent kirecci,3 adnan somay4 purpose: nuclear factor kapa b (nfkb) is a transcription factor that is required for cytokine-mediated induction of the human inducible nitric oxide synthase (inos) gene. recent studies have shown that in the pathophysiology of ischemia-reperfusion (ir) injuries nfkb is involved. in our study we aimed to determine the efficacy of the selective nfkb inhibitor, pyrrolidium dithiocarbamate (pdtc), on long-term histological damage in testicular ir injuries. materials and methods: twenty-one adult male wistar albino rats were divided into 3 equal groups. in groups 1-2, the left testes in rats underwent 4 hours of 720° experimental torsion. in group 2, pdtc (100 mg/kg) was administered intraperitoneally in the last 1 hour before detorsion; and group 3 underwent a sham operation. all rats underwent bilateral orchiectomy 45 days after the experiment. the testes weights were measured and compared to the other groups and their contralateral values. testes samples were fixed with bouin solution for histological (johnsen score) and immunohistochemical examination. immunohistochemically inos and an active subunit of nfkb, p65 were evaluated using mouse primary monoclonal antibodies and were evaluated semi quantitatively. results: testicular weights and johnsen scores in ipsilateral testes were 0.67 ± 0.85, 1.54 ± 0.11, 1.84 ± 0.64 and 1.63 (1-4), 6.94 (4-10), 5.29 (1-9) in the torsion, sham and pdtc groups, respectively. in contralateral testes the same values were 1.74 ± 0.84, 1.59 ± 0.13, 1.50 ± 0.54 and 5.38 (2-8), 7.17 (5-10), 6.30 (4-9). testicular weights and johnsen scores were significantly different in the ipsilateral torsion group (p < .05). in the pdtc group testicular weights and johnsen scores were similar with the control group (p > .05). immunohistochemically there was marked staining in the inos and p65 expressions in the torsion group compared with group 2 and 3. in rats administered pdtc, inos and p65 expressions were significantly reduced compared with the torsion group. there were no significant differences between the histological and immunohistochemical results of groups 2 and 3. conclusion: this data suggests that ir induces inos expressions through the activation of nfkb, p65. the nfkb pathway plays major role in testicular reperfusion injuries. it is possible to prevent reperfusion injuries using selective the nfkb inhibitor. keywords: torsion abnormality; reperfusion ınjury/pathology; rats, wistar; antioxidants/therapeutic use; testis/ blood supply; testis/metabolism. introduction testicular torsion (tt) is common urological emer-gency in infants and adolescents that can lead to testicular necrosis. the incidence of tt has been estimated to be 1 in 158 males by the age of 25 years or approximately 1 in 4,000 per annum in males.(1) to avoid testicular loss and eventual impaired fertility, rapid diagnosis and immediate surgical intervention are the most important issues for the treatment of these patients. testicular salvage rates with surgery have been reported to range from 42% to 88%.(2,3) surgical intervention within 6, 12 and 24 hours of beginning results in a salvage rate of 90%, 50% and less than 10%, respectively.(4) several experimental studies suggest the role of ischemia and reperfusion injuries in the pathophysiology of tt and the salvage of testicles from ischemia reperfusion induced testicular injuries, antioxidants and reactive oxygen species (ros) scavengers have been used widely in literature.(5-9) previous studies have demonstrated that nuclear factor kappa b (nfkb) is involved and is an important transcription factor during the inflammatory process and ischemia reperfusion. activation of nfkb by ros are responsible for several proinflammatory molecules including intercellular adhesion molecular-1, inducible nitric oxide synthase (inos), cyclooxygenase-2, interleukin-1β, interleukin-6, tumor necrosis factor-α, etc. (10-12) 1 department of urology, derince training and research hospital, kocaeli, turkey. 2 department of urology, okmeydani training and research hospital, istanbul, turkey. 3 department of urology, sisli etfal training and research hospital, istanbul, turkey. 4 department of pathology, fatih sultan mehmet training and research hospital, istanbul, turkey. *correspondence: department of urology, derince training and research hospital, kocaeli, turkey. tel: +90 262 3178000. fax: +90 262 2334641. e-mail: drleventozcan@yahoo.com. received november 2015 & accepted february 2016 vol 13 no 03 may-june 2016 2702 in this study we tested the preventive role of selective the nfkb inhibitor, pyrrolidium dithiocarbamate (pdtc) in testicular ischemia reperfusion ischemia induced testis damage in rats in the long term. materials and methods experimental procedure adult, male, wistar albino rats (230-250 g) were used. the animals were kept under standard laboratory conditions (12 h light/dark cycle, 26-28°c) for at least 1 week before the experiment and those conditions were preserved until the end of the experiment. animal cages were kept clean, and food and water were given regularly every day. all experiments in this study were performed in accordance with the guidelines for animal research issued by the national institutes of health and were approved by the local committee on animal research. the rats were divided into 3 groups containing 7 rats each, group 1: sham control; group 2: ischemia-reperfusion; group 3: ischemia-reperfusion + pdtc. all anesthesia was performed with sodium pentobarbital (50 mg/kg body weight, intraperitoneally). after anesthesia, the rats were kept in a supine position and underwent antisepsis of the scrotal region with 2% iodine alcohol. surgery was performed through a left scrotal incision. in group 2 and 3, unilateral testicular torsion was created by rotating the left testis 720° in a clockwise direction and fixed within hemiscrotum with a 3/0 silk suture and the incision was then closed using 2/0 silk suture.(8) torsion was maintained for 4 hours. at the end of 4 hours, anesthesia was repeated. then detorsion of the testis was performed in group 2 and a testis was placed into the scrotum and wound closed again. in group 3, pdtc (sigma-aldrich chemical corp, mo, usa; 100 mg/kg) was administered intraperitoneally in the last 1 hour before detorsion and then the testis was detorsioned and placed into scrotum and wound closed. the doses of pdtc were selected based on the results of recent studies in which the antioxidant and anti-inflammatory action of this agent were apparent.(13,14) pdtc was dissolved in 0.9% saline. all rats underwent bilateral orchiectomy 45 days after the experiment. contralateral testes were used as an internal control. testes weights were measured and compared to other groups and contralateral values. testes samples were fixed with bouin solution for histological (johnsen score) and immunohistochemical examinations. immunohistochemistry and johnsen scoring for the immunohistochemical evaluations, the specimens were processed for light microscopy and sections incubated at 60°c overnight and then de-waxed in xylene for 30 min. after rehydrating them in a decreasing series of ethanol, sections were washed with distilled water and phosphate-buffered saline (pbs) for 10 min. sections were then treated with 2% trypsin in a 50 mm tris buffer (ph 7.5) at 37°c for 15 min, and then washed with pbs. sections were delineated with a dako pen (dako, glostrup, denmark) and incubated in a solution of 3% h 2 o 2 for 15 min to inhibit endogenous peroxidase activity. then, sections were incubated with nf-κb/p65 (rel a) ab-1 (r-b-1638-r7, neomarkers, labvision, fremont, ca, usa) and inos ab-1 (r-b1605-r7, neomarkers, labvision, fremont, ca, usa) nfκb and torsion-ozcan et al. figure 1. haematoxylene eosine staining. a: g-i, there is only sertoli cells in tubular lumens (×400). b: g-i, seminifer tubules containing only sertoli cells (×100). c: g-i, there is moderate narrowing in seminifere tubules (×400). d-e: g-ii, active spermatagenesis, spermatids in seminifer tubules and spermatozoas (×400). f: g-ii, partially protected seminifer tubules (×400). sexual dysfunction and infertility 2703 antibodies. the ultra-vision (labvision, fremont, ca, usa) horseradish peroxidase/3-amino-9ethylcarbazole staining protocol was used at this stage. sections prepared for each case were examined by light microscopy. sections of rat lung were used as the control for immunohistochemical staining specificity, in accordance with data provided by the antibody manufacturer. the sections were evaluated for diffuseness and staining. testicular changes were evaluated according to the diffuseness and intensity of staining. for staining diffuseness, sections were graded as: 0, no staining; 1, staining < 25%; 2, staining 25-50%; 3, staining 50-75%; 4, staining > 75%. for staining intensity, sections were graded as: 0, no staining; 1, weak but detectable above control; 2, distinct; 3, intense.(14) immunohistochemical values were obtained by adding the diffuseness and intensity scores, and the results were compared using chi-square test. johnsen tubular testicular biopsy scores the johnsen score was used to assess testicular morphological damage as described above.(15) briefly, paraffin sections (4 mm thick) were cut and mounted on glass slides and then sections were defaraffinized and hydrated by processing them with xylene and a series of graded alcohols. the sections were stained by hematoxylin eosin were observed under a light microscope, and then seminiferous tubular sperm formation disorders were evaluated in each group following the johnsen score. to evaluate spermatogenesis, at least 40 seminiferous tubules were examined per slide, and each slide was scored using the johnson score. seminiferous tubules were scored on a scale of 1 to 10, with complete inactivity of tubules scored as 1 and those with maximum activity (≥ 5 spermatozoa in the lumen) scored as 10. statistical analysis testicular weights and johnsen biopsy scores in the table. testicular weights and johnsen score among the groups. parameters sham group torsion group pdtc + torsion group testicular weight/i (g) 1.54 ± 0.11 0.67 ± 0.85a 1.84 ± 0.64b testicular weight/c (g) 1.59 ± 0.13 1.74 ± 0.84 1.51 ± 0.54 johnsen score/i 6.94 ± 2.13 1.63 ± 1.12a 5.29 ± 2.92b johnsen score/c 7.17 ± 2.72 5.38 ± 1.86 6.3 ± 2.76 abbreviations: pdtc, pyrrolidium dithiocarbamate; i, ipsilateral; c, contralateral. values are expressed as mean ± sd for seven rats in each group. a significantly different from sham. b significantly different from torsion group (p < .05). figure 2. immunohistochemical staining. a: g-i, strongly positive staining p65 in seminiferous tubules (×400). b: g-iii, weak staining of p65 (×400). c: g-ii, weak inos staining in seminiferous tubules (×400). d: g-ii, moderate staining of p65 in seminiferous tubules (×100). e: g-i, strong inos staining in interstitial space (×400). f: g-iii, weak inos staining (×100). nfκb and torsion-ozcan et al. vol 13 no 03 may-june 2016 2704 groups are expressed as the mean ± sd. analysis of variance (anova) was used for statistical analysis of the data among the groups. the significance between two groups was determined by the tukey’s multiple comparison test and p < .05 was accepted as statistically significant value. results testicular weights and johnsen scores in the ipsilateral testes were 0.67 ± 0.85, 1.54 ± 0.11, 1.84 ± 0.64 and 1.63 (1-4), 6.94 (4-10), 5.29 (1-9) in torsion, sham and pdtc group, respectively. in contralateral testes the same values were 1.74 ± 0.84, 1.59 ± 0.13, 1.50 ± 0.54 and 5.38 (2-8), 7.17 (5-10), 6.30 (4-9). testicular weights and johnsen scores were significantly different in the ipsilateral torsion group (p < .05). in pdtc group testicular weights and johnsen scores were similar with the control group (p > .05) (table). immunohistochemically there was marked staining in inos and a p65 expression in the torsion group compared with group 2 and 3. in rats administered pdtc, inos and p65 expression were significantly reduced compared with torsion group (figures 1 and 2). there were no significant differences between the histological and immunohistochemical results of groups 2 and 3. discussion the severity of testicular damage is related to the duration and degree of torsion and reperfusion time.(16) increased reactive oxygen species after detorsion are the most important mediators in testicular damage. to prevent or minimize the ischemia reperfusion injuries, antioxidants are the most commonly used agents.(7,8) one of them nfkb, is a transcriptional factor and plays a significant role in the pathophysiology of ischemia reperfusion induced tissue damage. to prevent testicular damage after ischemia reperfusion injury several agents have been tested. ekici and colleagues have showed the protective effect of ozone and melatonin in tt.(8) in another study altunoluk and colleagues evaluated the protective effects of zofenopril on tt. according to their study treatment with zofenopril decreased damage in ipsilateral testis caused by ischemia/reperfusion. they also conducted clinical application of zofenopril which might be a new approach for the treatment of tt in addition to conventional detorsions.(17) in recently published study, the involvement of nfκb has been reported. according to this study the authors demonstrates that pdtc prevents testicular torsion-detorsion injury induced biochemical and histologic changes testicular tissues in the rat.(18) the protective role of nfκb, other antioxidants and ros scavengers has been used in tt for short time periods. but in this study we evaluated the protective role of selective nfκb inhibitors, pdtc, after a long time period. animal studies have known significant decreases in testicular weights and johnsen scores in ipsilateral testes, but there are some controversies about the possible deleterious effect of torsion on contralateral testis.(19-21) the present study showed that unilateral tt-detorsions caused significant loss in ipsilateral testicular weight in torsion group. ischemia-reperfusion of the testes results in increased testicular oxidative stress and germ cell apoptosis. in this study we evaluated spermatogenesis by johnsen scores. we showed that unilateral tt-detorsions caused significant loss in ipsilateral testicular johnsen score in the torsion group. one of the mechanisms involved in ischemia reperfusion injuries is the increased intratesticular nitric oxide levels the through activation of inos.(22) another of the most accepted possible mechanisms of nitric oxide is through increased peroxynitrite production.(23) excess amounts of nitric oxide production by inos react rapidly with the superoxide radicals that are produced during reperfusion injuries to form peroxynitrite which induces protein damage by forming nitrotyrosine.(24,25) wang and colleagues showed that natural phenolic antioxidant compound tyrosol administration attenuated ischemia-reperfusion-induced nfκb activations, inos expression and improved kidney functions. they proposed that that tyrosol may have a protective effect against acute kidney injury through inhibition of inos-mediated oxidative stress.(24) in immunohistochemical examination there was severe staining in inos and the active subunit of nfκb, p65, in the torsion group, however, there was weak staining in sham and pdtc treated group in this study. we propose that activation of nfκb by ir, activates inos expressions and this results in increased intratesticular nitric oxide and testicular injury. the limitation of this study is the biochemical parameters of ir injuries which were not analyzed and the lack of a vehicle group. conclusions this data suggest that ir induces inos expression through activation of the nfkb pathway which plays a major role in testicular reperfusion injuries. it is possible to prevent reperfusion injuries using the selective nfkb inhibitor. our study needs to be supported by further experimental and clinical studies. nfκb and torsion-ozcan et al. sexual dysfunction and infertility 2705 conflict of interest none declared. references 1. barada jh, weingarten jl, cromie wj. testicular salvage and age-related delay in the presentation of testicular torsion. j urol. 1989;142:746-8. 2. parker rm, robison jr. anatomy and diagnosis of torsion of the testicle. j urol. 1971;106:243-7. 3. cattolica ev, karol jb, rankin kn, klein rs. high testicular salvage rate in torsion of the spermatic cord. j urol. 1982;128:66-8. 4. ringdahl e, teague l. testicular torsion. am fam physician. 2006;74:1739-43. 5. prillaman hm, turner tt. rescue of testicular function after acute experimental torsion. j urol. 1997;157:340-5. 6. lee jw, kim ji, lee ya, et al. inhaled hydrogen gas therapy for prevention of testicular ischemia/reperfusion injury in rats. j pediatr surg. 2012;47:736-42. 7. romeo c, antonuccio p, esposito m, et al. raxofelast, a hydrophilic vitamin e-like antioxidant, reduces testicular ischemiareperfusion injury. urol res. 2004;32:367-71. 8. ekici s, doğan ekici ai, öztürk g, et al. comparison of melatonin and ozone in the prevention of reperfusion injury following unilateral testicular torsion in rats. urology. 2012;80:899-906. 9. tamamura m, saito m, kinoshita y, et al. protective effect of edaravone, a free-radical scavenger, on ischaemia-reperfusion injury in the rat testis. bju int. 2010;105:870-6. 10. shen b, li j, gao l, zhang j, yang b. role of cc-chemokine receptor 5 on myocardial ischemia-reperfusion injury in rats. mol cell biochem. 2013;378:137-44. 11. jia p, wang j, wang l, et al. tnf-α upregulates fgl2 expression in rat myocardial ischemia/reperfusion injury. microcirculation. 2013;20:524-33. 12. won jh, im ht, kim yh, et al. antiinflammatory effect of buddlejasaponin iv through the inhibition of inos and cox-2 expression in raw 264.7 macrophages via the nf-kappab inactivation. br j pharmacol. 2006;148:216-25. 13. tian xf, yao jh, li yh, et al. protective effect of pyrrolidine dithiocarbamate on liver injury induced by intestinal ischemiareperfusion in rats. hepatobiliary pancreat dis int. 2006;5:90-5. 14. tugcu v, ozbek e, tasci ai, et al. selective nuclear factor k-b inhibitors, pyrolidium dithiocarbamate and sulfasalazine, prevent the nephrotoxicity induced by gentamicin. bju int. 2006;98:680-6. 15. filho dw, torres ma, bordin al, et al. spermatic cord torsion, reactive oxygen and nitrogen species and ischemia-reperfusion injury. mol aspects med. 2004;25:199-210. 16. johnsen sg. testicular biopsy score count a method for registration of spermatogenesis in human testis: normal values and results in 335 hypogonadal males. hormones. 1970;1:2-25. 17. filho dw, torres ma, bordin al, et al. spermatic cord torsion, reactive oxygen and nitrogen species and ischemia-reperfusion injury. mol aspects med. 2004;25:199-210. 18. altunoluk b, söylemez h, bakan v, ciralik h, tolun fi. protective effects of zofenopril on testicular torsion and detorsion injury in rats. urol j. 2011;8:313-9. 19. kabay s, ozden h, guven g, et al. protective effects of the nuclear factor kappa b inhibitor pyrrolidine dithiocarbamate on experimental testicular torsion and detorsion injury. korean j physiol pharmacol. 2014;18:321-6. 20. jeong sj, choi ws, chung js, baek m, hong sk, choi h. preventive effects of cyclosporine a combined with prednisolone and melatonin on contralateral testicular damage after ipsilateral torsion-detorsion in pubertal and adult rats. j urol. 2010;184:7906. 21. lorenzini f, tambara filho r, gomes rp, martino-andrade aj, erdmann tr, matias je. long-term effects of the testicular torsion on the spermatogenesis of the contralateral testis and the preventive value of the twisted testis orchiepididymectomy. acta cir bras. 2012;27:388-95. 22. turner tt. on unilateral testicular and epididymal torsion: no effect on the contralateral testis. j urol. 1987;138:1285-90. 23. yagmurdur h, ayyildiz a, karaguzel e, akgul t, ustun h, germiyanoglu c. propofol reduces nitric oxide-induced apoptosis in testicular ischemia-reperfusion injury by downregulating the expression of inducible nitric oxide synthase. acta anaesthesiol scand. 2008;52:350-7. 24. mccord jm. oxygen derived free radicals in post ischemic tissue injury. n engl j med. 1985;312:159-63. 25. wang p, zhu q, wu n, siow yl, aukema h, o k. tyrosol attenuates ischemiareperfusion-induced kidney injury via inhibition of inducible nitric oxide synthase. j agric food chem. 2013;61:3669-75. 26. kinaci mk, erkasap n, kucuk a, koken t, tosun m. effects of quercetin on apoptosis, nf-κb and nos gene expression in renal ischemia/reperfusion injury. exp ther med. 2012;3:249-54. nfκb and torsion-ozcan et al. vol 13 no 03 may-june 2016 2706 urological oncology polyomavirus hominis 1(bk virus) infection in prostatic tissues: cancer versus hyperplasia afsoon taghavi,1,2 peyman mohammadi-torbati,3 amir hossein kashi,2,4 hanieh rezaee,5 maryam vaezjalali2,5 purpose: polyoma virus hominis 1, better known as bk virus (bkv) infection might be a predisposing factor for prostate cancer (pca). the aim of this study was to compare the frequency of bk virus infection in pathological specimens of patients with pca compared to patients with benign prostatic hyperplasia. materials and methods: from july 2011 to june 2012, paraffin-embedded tissue blocks of patients with pca (60 specimens) and also with benign prostatic hyperplasia (60 specimens) were investigated. after dna purification, existence of virus nucleic acid was assessed by polymerase chain reaction. results: viral dna was identified in 9 patients (15%) with bph and 17 patients (28%) with pca (p =.076). in patients with pca, viral dna was observed more often in those with lower total gleason scores (p = .045). conclusion: the frequency of bk virus infection in pca patients was higher than bph patients. bk virus was more often observed in patients with lower gleason scores. less detection of bk virus dna in overt cancer may prove the activity of the virus which paves the way for tumorigenic transformation at early stages of pca. keywords: bk virus; isolation; purification; polyomavirus infections; complications; prostate; virology; prostatic neoplasms; tumor virus infections. introduction polyomavirus hominis 1, better known as bk virus (bkv), is a polyomavirus which is widely spread in human populations. sero-epidemiological studies have confirmed the existence of bk virus antibodies in 60% to 80% of adults in the world.(1) therefore, bk virus can persist in the body and create asubclinical latent infection which can be activated in immune suppressed individuals and rarely in healthy people.(2) bk virus genome contains three different regions:(1) early coding region which codes the major tumor antigen (t-ag), minor tumor antigen (t-ag), and truncated tumor antigen (truncated t-ag) which has been discovered recently;(2) late coding region which codes viral proteins of the capsid (vp1, vp2, and vp3) and also agoprotein; and(3) the non-coding control region containing necessary initiation and regulation elements for the transcription of the two previous regions.(3,4) carcinogenic feature of bk virus is highly dependent on early coding region which codes a nuclear phosphoprotein of 97 kda named tag. this protein is homologue ofsimian virus 40 (sv40) tumor ag(tag) based on various biological and biochemical properties. sv40 tag is an adenosine triphosphatase (atpase) with helicase activity which binds to viral and cellular dna to activate their replication and is bound to products of p53 and retinoblastoma (rb) tumor-suppressing genes and deactivates their functions. current evidences demonstrate that the expression of tag and sv40 bk virus alters the integrity and stability of the host cellular genome and contributes to structural and numerical aberrations in the chromosome.(2) bk virus is known to produce persistent infection in kidney and ureter. therefore, bk virus-related urothelialcancers are highly probable.(5) among all urogenital tumors, prostate cancer (pca) is an important cause of mortality in men.(4) this cancer is the most prevalent malignancy in men and is the second cause of cancer deaths in aged men in the usa.(6,7) in a study by hossieni and colleagues, the prevalence of pca in iranians older than 40 yearsold was 3.4%.(8) the aim of this study was to investigate the relationship of bk virus infection with pca by comparing the frequency of bk virus dna in cancerous and non-cancerous pathological prostate specimens. materials and methods from july 2011 to june 2012, paraffin-embedded tissue blocks of patients with pca (60 specimens) and benign prostatic hyperplasia (bph) (60 specimens) who were operated in our center were evaluated. patients with pca were chosen as case study and those with bph as control group.all these patients were diagnosed at our center in tehran and were over 50 years old. the 1 cancer research center, shahid beheshti university of medical sciences, tehran, iran. 2 urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 3 department of pathology, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. 4 national elites foundation, tehran, iran. 5 department of microbiology, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. *correspondence: department of microbiology, faculty of medicine, shahid beheshti university of medical sciences, velenjak st., tehran, iran. tel: +98 21 23872556. fax: +98 21 22439964. e-mail: maryam.vaezjalali@sbmu.ac.ir. received december 2014 & accepted july 2015 vol 12 no 04 july-august 2015 2240 diagnosis of pc aand bph was confirmed by an experienced uro-pathologist. six 5-10 µm sections were obtained from paraffin-embedded blocks of tumor site. qia amp-dna formalin-fixed, paraffin-embedded (ffpe) tissue extraction kit (qiagen, dusseldorf, germany) was used to extract and purify bk viral dna of prepared sections. after dna extraction in specimens, presence of beta-globin dna was evaluated by polymerase chain reaction (pcr) method and specific primers (gh20 and pc04) based on saiki and colleagues report.(9) specific primers (vp1-327-1 and vp1-3272r) and pcr conditions for bk virus genes were derived from jin protocol.(10) accu power pcr premix (bioneer, seoul, south korea) which consisted of top dna polymerase (1 u), dntp (250 µm), tris-hcl (ph 9.0) (10 mm), kcl 30 (10 mm), mgcl2 (1.5 mm) with template dna (100 200 ng) and primers (10 pmol) were used for pcr reactions. also, thermal cycling with the following conditions, five minutes of denaturation at 94°c, followed by 35 rounds of an amplification cycle consisting of 35 seconds denaturation at 94°c, one minute annealing at 50°c for beta-globin and 55°c for bk virus and oneminute extension at 72°c, and a final extension cycle of fourminutes at 72°c, was used. statistical analysis two separate positive bk virus specimens from the urine of infected patients were used as positive controls. the statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0 was used for data analysis. nominal and ordinal variables were compared by chi square and mann-whitney tests, respectively. independent samples t-test was employed to compare continuous variables. results in this study the mean age of patients with prostate hyperplasia was 68 ± 8.9 years old (age range of 50 to 95 years old). also, the mean age of patients with pca was 67.14 ± 9.96 years old (age range of 40 to 95 years old). gleason score of tumor was categorized from 5 to 10. the highest score was 10, which was observed in 4.2% of the patients. characteristics of this score in patients with pca are summarized in table. pcr for beta-globin gene in paraffin blocks after dna extraction in specimens, presence of beta-globin dna was evaluated by pcr method with 368 bp pcr product. this test was considered as a control for next molecular steps, and results of all assessed specimens were positive. positive results demonstrated successful dna extraction. pcr for bk virus in paraffin blocks after performing pcr for bk virus, in which a 287 bp segment was expected, of all 120 tissue specimens, 26 (21.7%) specimens were positive for bk virus dna. from 60 pca tissue specimens, 17 specimens (28.3%) and from 60 studied bph tissue specimens, 9 specimens (15%) were positive for bk virus dna. there was no significant relationship between the presence of bk virus dna and the age of patients (p = .38) bk virus and pca there was no significant relationship between the presence of bk virus dna and pca of patients (p = .076). odds ratio rates of pca were 2.24 (0.9–5.5), measured according to presence of bk virus in studied patients. these rates in patients with pca and those with bph were 1.5 (0.8–2.7) and 0.7 (0.4–0.9), respectively (p = .076). however, there was a significant relationship between the presence of bk virus dna and gleason score (p = .045). so gleason scores were categorized into pca risk categories. gleason scores less than seven, seven and more than seven were grouped into low, moderate, and high risk categories, respectively. bk virus was discovered in eight (53%), five (25%) and four (16%) patients with low, moderate and high risk pca, respectively (p = .047). however, there was a significant relationship between the presence of bk virus dna and gleason score (spearman r = -0.26, p = .045) (figure). discussion in this study,bk virus dna was observed in 28% of pca patients and 15% of bph patients. these infection rates are of the highest reported rates. lauand colleagues studied 30 pca specimens. they stated that insitu hybridization test demonstrated the presence of bk virus in only two specimens (7%).(1)also, in a study figure. polymerase chain reaction products of bk partial genome derived from prostate cancer paraffin embedded tissues. 1) dna marker (100 base pair); 2) positive control; 3) negative control; 4) negative sample; 5,6) positive sample; 7,8,9) negative sample; 10) dna marker. urological oncology 2241 bk virus infection in patients with pca-taghavi et al. by akgüland colleagues in 2012, the presence of bk virus was verified in only 1 of 85 paraffin-embedded pca tissues.(11) in 2008, may and colleagues revealed that none of their 213 pca specimens had bk virus dna.(12) they reported that bk virus lacked any significant role in cancer pathogenesis. higher frequencies of infection have been reported by few other researchers. balis and colleagues reported the presence of bk virus in 19% of fresh frozen prostate tissues of 42 patients with pca.(13) russo and colleagues reported bk virus infection in 85% of specimens from pca patients.(14)a main reason for discrepancies between these studies might be due to various assessment methods for bk virus in pca specimens, since paraffin-embedded tissues enable fewer virus extractions compared to fresh frozen specimens. in other words, fresh frozen specimens contribute to more repeatable results and have higher sensitivity.(15) furthermore, various molecular methods have been usedin these studies. some studies have used nested pcr to extract more viral dna.(16) several studieshave suggested prostate as a suitable environment for the growth of infectious agents such as carcinogenic virus dna and pointed to potential role of these viruses (e.g. john cunningham (jc) virus) in incidence of pca.(15) they claim that bk virus has a role in progression of pca has been supported by other studies assessing the presence of viral tag and/or p53 gene mutations. for instance, immunohistochemistry analysis in a study demonstrated the position of tag and p53 in cytoplasm of cancer cells while in those cells negative for tag, p53 was located in the nucleus. this emphasized the role of bk virus as a co-factor in pathogenesis of pca. it suggested the role of bk virusin disruption of a cellular path way which may lead to cell cancer.(14) also, another study revealed that p53 was nuclear in negative tag cells.(17) furthermore, these cells had wild-type and mutant p53 genes. p53 in cells with tag were always cytoplasmic and locating these two proteins in the cytoplasm was not associated with the presence of mutations in their nuclear sequence.(18) considering these results together, researchers have suggested that wild-type p53 can be deactivated by tag in the cytoplasm. in addition, several studies have revealed that despite locating tag in carcinogenic cell cytoplasm, lack of viral vp1 expression in such cells implies lack of viral replication. it is not easy to understand the mechanisms underlying viral oncogenic activities and the methods they employ to organize tumor microenvironment.(19-21) the “hit and run hypothesis” seems the most valid theory to justify a co-factorial role of bk virus in pca onset and progression.(17) this hypothesis also helps to explain why bk virus is present in cancerous cells but is less present at the protein expression stage.(22) the ability of polyomavirus to interfere with the cell cycle could induce the infected cells to reach the critical point of no return during oncogenic transformation.(23)a meta-analysis on a total of 1106 cancer cases, ranging from 7 to 328, and 1068 control cases, ranging from 11 to 385, showed that the prevalence of bk virus was significantly higher in cancer tissues than in control tissues (p < .0001).(22) in the current study bk virus was observed in a higher frequency of pca patients compared to bph patients. bk virus dna was detectedin 28% of patients with pca which is almost twice the rate of infection in bph patients which was 15%. in our study, a significant relationship was found between low gleason scores and bk virus in cancerous specimens (p = .045). das and colleagues also noted the role of bk virus in early stages of pca, but failed to detect the presence of bk virus in advanced stages of cancer.(6) lower detection of the bk virus dna in overt cancerous cells may point to the activity of the virus which paves the way for tumorigenic transformation at early stages of pca. viral fitness in the tumor cells is no longer needed to charge the tumor causality to the virus itself.(22) however, russo and colleagues have reported a significant relationship between higher gleason scores and higher bk virus dna.they also reported a significant relationship between higher gleason scores and rates of mutant p53.(14) our study had a larger sample size compared to previous studies. since the method used for preparing paraffin-embedded tissue blocks can affect dna and even destruct it, a beta-globin test (similar with the size of considered segment) was designed as a control to detect proper viral dna purification. in this regard, only in one study, negative specimens for bk virus were considered as control for negative results.(15) incomplete deletion of paraffin from tissue blocks isasystematic error during pcr technique on beta-globin gene. we prepared deparaffinized solution and kept tissues in the heater for 24 hours. since some reports have demonstrated that obtained jc virus dna was higher in fresh frozen specimens compared to paraffin-embedded specimens, it is recommended to use fresh frozen specimens and needle-like specimens prepared from pca specimens along with paraffin-embedded blocks. (24) even so, delbue and colleagues(22) reported that the efficiency of detecting bk virus dna in ffpe tissue was significantly higher than frozen sections. they confirmed that quantitative real time pcr is the best gene assay method for detecting bk virus dna in tissues and it supports the use of ffpe tissue specimens for molecular-based testing. it seems that, problems such as tissue conservation table. characteristics of studied patients. groups values bph number of patients 60 age, (mean ± sd) years 68.0 ± 8.9 pca number of patients 60 age, (mean ± sd) years 67.1 ± 10.0 gleason score, no. (%) 5 2 (3) 6 13 (22) 7 20 (33) 8 9 (15) 9 11 (18) 10 5 (8) abbreviations: bph, benign prostatic hyperplasia; pca, prostate cancer; sd, standard deviation. vol 12 no 04 july-august 2015 2242 bk virus infection in patients with pca-taghavi et al. method, time duration before fixation of tissue, time duration in which the tissue is located in fixator, and finally lifetime of paraffin-embedded blocks can affect stability of viral dna and also produce different results from various laboratories.(24) however, detecting viral genes due to the complete disappearance of the virus in tumor cells may depend on test sensitivity. this is because the detection rate of bk virus dna in tumor tissues by quantitative real time pcr can be significantly higher than the rate obtained by both nested and regular pcr.(22) therefore, using a conventional pcr kit and working with paraffin-embedded specimens were limitations of our study in detecting bk virus dna. conclusions more bk virus infection was observed in pca specimens compared to bph specimens. also, bk virus infection was predominantly observed in cancerous specimens with lower total gleason scores. this may be in consistent to co factorial role of bkv in pca triggering and hit and run theory. simultaneous use of bk virus infection assessment methods, including serology tests for determining its antibody, measuring virus tag in the cell, and also assessing the number of virus in the blood plus viral dna in pca cell, are also suggested future researches. acknowledgements this study was supported by urology and nephrology research center of shahid beheshti university of medical sciences (grant number 415/12). the authors thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. references 1. lau sk, lacey sf, chen yy, chen wg, weiss lm. low frequency of bk virus in prostatic adenocarcinomas. apmis. 2007;115:743-9. 2. de mattei m, martini f, corallini a, et al. high incidence of bk virus large‐t‐antigen‐ coding sequences in normal human tissues and tumors of different histotypes. int j cancer. 1995;61:756-60. 3. fioriti d, videtta m, mischitelli m, et al. the human polyomavirus bk: potential role in cancer. j cell physiol. 2005;204:402-6. 4. abend jr, jiang m, imperiale mj. bk virus and human cancer: innocent until proven guilty. semin cancer biol. 2009;19:252-60. 5. chesters pm, heritage j, mccance dj. persistence of dna sequences of bk virus and jc virus in normal human tissues and in diseased tissues. j infect dis. 1983;147:67684. 6. das d, shah rb, imperiale mj. detection and expression of human bk virus sequences in neoplastic prostate tissues. oncogene. 2004;23:7031-46. 7. jemal a, murray t, ward e, et al. cancer statistics, 2005. ca cancer j clin. 2005;55:1030. 8. hosseini sy, moharramzadeh m, ghadian ar, hooshyar h, lashay ar, safarinejad mr. population‐based screening for prostate cancer by measuring total serum prostate‐specific antigen in iran. int j urol. 2007;14:406-11. 9. saiki rk, gelfand dh, stoffel s, scharf sj, higuchi r, horn gt, et al. primer-directed enzymatic amplification of dna with a thermostable dna polymerase. science. 1988;239:487-91. 10. jin l. molecular methods for identification and genotyping of bk virus. sv40 protocols: springer; 2001. p. 33-48. 11. akgül b, pfister d, knüchel r, heidenreich a, wieland u, pfister h. no evidence for a role of xenotropic murine leukaemia virusrelated virus and bk virus in prostate cancer of german patients. med microbiol immunol. 2012;201:245-8. 12. may m, kalisch r, hoschke b, et al. die detektion von papillomavirus-dna in der prostata. der urologe. 2008;47:846-52. 13. balis v, sourvinos g, soulitzis n, giannikaki e, sofras f, spandidos da. prevalence of bk virus and human papillomavirus in human prostate cancer. int j biol markers. 2006;22:245-51. 14. russo g, anzivino e, fioriti d, et al. p53 gene mutational rate, gleason score, and bk virus infection in prostate adenocarcinoma: is there a correlation? j med virol. 2008;80:2100-7. 15. zambrano a, kalantari m, simoneau a, jensen jl, villarreal lp. detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections. prostate. 2002;53:263-76. 16. shenagari m, ravanshad m, hosseini s, ghanbari r. detection and prevalence of polyoma virus bk among iranian kidney transplant patients by a novel nested-pcr. iran red crescent med j. 2010;12:631-35. 17. das d, wojno k, imperiale mj. bk virus as a cofactor in the etiology of prostate cancer in its early stages. j virol. 2008;82:2705-14. 18. delbue s, matei d-v, carloni c, et al. evidence supporting the association of polyomavirus bk genome with prostate cancer. med microbiol immunol. 2013;202:425-30. 19. dayaram t, marriott sj. effect of transforming viruses on molecular mechanisms associated with cancer. j cell physiol. 2008;216:309-14. 20. cader fz, vockerodt m, bose s, et al. the ebv oncogene lmp1 protects lymphoma cells from cell death through the collagen-mediated activation of ddr1. blood. 2013;122:423745. 21. ren c, cheng x, lu b, yang g. activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence urological oncology 2243 bk virus infection in patients with pca-taghavi et al. to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment. eur j cancer. 2013;49:3889-99. 22. delbue s, ferrante p, provenzano m. polyomavirus bk and prostate cancer: an unworthy scientific effort? oncoscience. 2014;1:296-303 23. dickmanns a, zeitvogel a, simmersbach f, et al. the kinetics of simian virus 40-induced progression of quiescent cells into s phase depends on four independent functions of large t antigen. j virol. 1994;68:5496-508. 24. albertsen pc. the prostate cancer conundrum. j natl cancer inst. 2003;95:930-1. vol 12 no 04 july-august 2015 2244 bk virus infection in patients with pca-taghavi et al. urological oncology the prevalence and prognostic significance of polyomavirus infection in patients with urothelial carcinoma of the bladder sheng-wen wu,1,2* jia-hung liou,3,4,5 kun-tu yeh,3,5 tung-wei hung,1,2 horng-rong chang1,5* purpose: human polyomaviruses (pv) has been associated with oncogenicity; however, the association between human bladder cancer and pv remains inconclusive. moreover, whether pv has the interaction with p53 in tumorigenesis and their prognostic significance on human bladder cancer has yet to be determined. materials and methods: bladder tumor specimens and clinical parameters from 74 patients with urothelial carcinoma were collected. immunohistochemical analysis using monoclonal antibodies specific to pv large tumor antigen (tag) and p53 protein was performed to investigate the involvement of pv in human bladder tumorigenesis and the prognostic significance of tag and p53 expressions using cox proportional hazards model. results: the mean age of the 74 patients at diagnosis was 64 years and 61 (82.4%) were male. the expression of pv tag protein was found in 45 (60.8%) tumor samples, but was not correlated with the expression of p53 (p = .280). the detection of pv tag was significantly associated with tumor stage (p = .001) but not decreased overall survival (os) or cancer-specific survival (css) (p = .661 and .738, respectively). however, the p53 overexpression was significantly associated with decreased css (p = .028). in multivariate cox proportional hazards analysis, age and p53 overexpression were predictors of os (p = .026) independently of tumor stage and css (p = .042), respectively. conclusion: we found that pv, which was detected in a significant percentage of tumor specimens, may be an important co-factor in the tumorigenesis of the bladder in humans. however, only p53 overexpression was associated with predicting css independently of tumor stage. keywords: bk virus; large t antigen; oncogenicity; polyomavirus; protein p53; survival; urinary bladder neoplasms introduction most humans become infected with human poly-omaviruses (pv) during childhood, which then establishes a life-long latent infection, particularly in the kidneys and urinary tract.(1) reactivation of the pv infection can occur in people with a compromised immune system, such as patients undergoing organ transplantation, which can lead to diseases like hemorrhagic cystitis and polyomavirus nephropathy.(2) pv, and mainly the bk virus (bkv), have been reported to be oncogenic viruses in many cell and animal studies. (3-5) the early region of pv encodes two known oncoproteins, large tumor antigen (tag) and small tumor antigen (tag), which may lead to transformation by interacting with cellular tumor suppression proteins, such as p53 and inhibiting protein phosphatase 2a, respectively.(6,7) although an increasing number of recent studies have investigated the potential association between pv and various human tumors, the results are still inconclusive.(8) bladder cancer is the most common malignancy involving the urinary system in developed countries, with urothelial carcinoma (ucc) being the predominant histologic type.(9) however, there is wide variation in the reported incidence in different regions.(10) furthermore, the incidence of bladder ucc is significantly higher in patients with chronic kidney disease and those undergoing renal transplants, particularly in asian countries.(11,12) these findings imply that the contributory factors for bladder tumorigenesis are complex. considering that pv is known to persist in the urinary tract and can be reactivated in immunocompromised people, it is reasonable to hypothesize that urinary tract carcinomas are likely to be associated with pv, particularly in asian countries. to date, few studies with a small number of patients have discussed the association between pv and the development of human bladder ucc and the interaction with p53 in tumorigenesis. in addition, it is unclear whether pv infection has an impact on tumor grade, tumor stage and clinical prognosis of bladder cancer. therefore, the aim of this study was to investigate the involvement of pv in human bladder tumorigenesis and clarify the prognostic significance of pv 1 school of medicine, chung shan medical university, taichung, taiwan. 2 division of nephrology, chung shan medical hospital, taichung, taiwan. 3 departments of pathology, changhua christian hospital, changhua, taiwan. 4 department of medical technology, jen-teh junior college, miaoli, taiwan. 5 the institute of medicine, chung shan medical university, taichung, taiwan. *correspondence: the school of medicine, chung shan medical university, taichung, taiwan. tel: +886 4 24739595. fax: +886 4 24739220. e-mail: s41111.tw@yahoo.com.tw. received january 2016 & accepted june 2016 urological oncology 2773 vol 13 no 04 july-august 2016 2774 tag and p53 expressions on human bladder cancer. materials and methods study population a total of 74 formalin-fixed and paraffin-embedded tumor samples were obtained from 74 patients with a diagnosis of ucc of the bladder at chung shan medical university and changhua christian hospital after the local institutional review board approved this study (cs11140). all tumors were retrospectively re-graded and re-staged according to the 2010 american joint committee on cancer (ajcc) staging system by an experienced pathologist.(13) the study included 61 male and 13 female patients with a mean age of 64.5 years. the mean follow-up period was 53 months. procedures paraffin-embedded tumor tissue sections (4-µm) on poly-1-lysine-coated slides were deparaffinized. after treatment with 3% h 2 o 2 in methanol, the sections were hydrated with gradient alcohol and pbs, incubated in 10 mm citrate buffer and finally heated at 100 °c for 20 minutes in pbs. the immunohistochemical procedure for the monoclonal antibody to sv40 tag (oncogen research products, cambridge, ma) followed standard immunoalkaline phosphatase methods and was preceded by pressure-cooked antigen retrieval for 5 min in ventana retrieval buffer (ph 10.0; ventana medical systems, tucson, az). diaminobenzidine tetrahydrochloride was used as a chromogen. the monoclonal antibody was used to detect epitopes unique to pv tag and shared by sv40, bk, and jc viruses. for p53 detection, the sections were heated in a microwave oven twice for 5 min in citrate buffer (ph 6.0), and then incubated with a monoclonal antihuman p53 antibody (dako, do7; at a dilution of 1:250) for 60 min at 25°c. the conventional streptavidin peroxidase method (dako, lsab kit k675) was used to develop signals, and the cells were counterstained with hematoxylin. evaluations the intensities of signals were evaluated independently by two observers. negative immunostaining for p53 protein was defined as 0% to 10% positive nuclei and >10% positive nuclei was defined as positive for immunostaining (overexpression).(14) in addition, any positive nuclear reaction to pv tag was defined as positive staining. positive control slides for p53 protein detection were purchased from dako and renal allograft tissues with bk virus infection were used as positive controls for pv tag. a neutralizing peptide was used to replace antibodies and served as a negative control. statistical analysis given a type i error (α) level of 0.05, type ii error (β) level of 0.20, the prevalence of human pv among patients with ucc of 0.17,(15) the prevalence of human p53 polyomavirus and urothelial carcinoma-wu et al. table 1. relationships between pv tag immunostaining, p53 expression and clinicopathological parameters in patients with urothelial carcinoma of the bladder. pv tag immunostaining variablesa total positive negative p value (n = 74) (n = 45) (n = 29) age at diagnosis (years) 64.5 ± 14.8 66.1 ± 12.1 62.2 ± 18.4 .325 gender male 61 (82.4%) 38 (84.4%) 23 (79.3%) .571 female 13 (17.6%) 7 (15.6%) 6 (20.7%) ever-smokerb 37 (54.4%) 23 (51.1%) 14 (48.2%) .812 tumor grade low 2 (2.8%) 0 (0.0%) 2 (6.9%) .074 high 72 (97.2%) 45 (100.0%) 27 (93.1%) tumor stage 0a or 0is 13 (17.5%) 4 (8.9%) 9 (31.0%) .001 i 33 (44.6%) 22 (48.9%) 11 (37.9%) ii 10 (13.5%) 3 (6.7%) 7 (24.1%) iii 14 (18.9%) 14 (31.1%) 0 (0.0%) iv 4 (5.5%) 2 (4.4%) 2 (6.9%) p53 immunostaining positive 56 (76%) 36 (80%) 20 (69%) .28 negative 18 (24%) 9 (20%) 9 (31%) abbreviations: pv tag, polyomaviruses large tumor antigen adata are shown as numbers with percentage or means ± standard deviation bdata in six patients were missing among patients with ucc of 0.37,(14) detectable relative risks of 3.5, the minimum sample size required for each group was calculated to be 30. additional subjects (nearly 20%) were recruited to avoid the loss to follow-up. finally, we recruited a total of 74 patients in this study. the patients’ age at diagnosis, gender, and smoking status were recorded. overall survival (os) was calculated as the period from the date of diagnosis to the date of death or the date of last follow-up. cancer-specific survival (css) was defined as death attributable to bladder ucc. for categorical and continuous variables, pearson chi-square and anova tests were used to determine association between pv tag expression and variables of interest. kaplan-meier analysis and the log-rank test/ gray’s test were used to evaluate the associations between the expression of pv tag and p53 with os and css. a cox proportional hazards model was used to evaluate the variables of interest in predicting os and css. the combined effect of human pv tag and p53 expressions on the survival of ucc patients was also evaluated. interaction was further assessed using the likelihood ratio test to calculate x2 and p values. in the test for interaction, the conditional logistic regression model with only main effects was compared to that with both main effect terms and interaction term. values were expressed as mean ± sd. p-values of less than 0.05 were considered to indicate statistical significance. all analyses were performed using spss software for windows version 12.0 (spss inc., chicago, il). results patients’ characteristics and clinical parameters the patients’ characteristics are shown in table 1. of the 74 patients, 25 (34%) received radial cystectomy with lymph node dissection. the final pathology of these 25 patients revealed that two had positive surgical margins, lymphovascular invasion, and positive lymph nodes; two had positive lymphovascular invasion and lymph node status; one had positive surgical margin; and one had positive lymphovascular invasion. at the end of study, 29 patients had died, of whom 20 had died from cancer-related deaths. pv tag immunohistochemistry and association with clinical parameters of the 74 bladder tumors, 45 (60.8%) had positive nuclear reactivity to pv tag, which was only expressed in the tumor cells as well as a few adjacent normal lymphocytes in the tumor tissues (figure 1). the relationships between the expression of pv tag and clinical parameters of the patients with bladder ucc are shown in table 1. the tumors that expressed pv tag tended to be of a higher tumor stage than those that did not (p = .001). however, neither tumor grade nor p53 protein expression was associated with the expression of pv tag (p = .258 and .280, respectively). the kaplan-meier curves for os and css, defined by the status of pv tag expression, are shown in figure 2a and 2b. the os and css between the patients with and without tag expression in their bladder tumors were not statistically different in the kaplan-meier analysis (p = .661 and .738, respectively). p53 immunohistochemistry and association with clinical parameters urological oncology 2775 figure 1. immunohistochemical analysis of the pv tag protein, using monoclonal antibody to sv40 tag, in urothelial cell carcinoma of the bladder and adjacent normal tissues. (a) negative results of pv tag immunostaining in high-grade tumor cells (×100); (b) pv tag protein expressed in renal allograft with pv nephropathy as a positive control (×100); (c) pv tag protein expressed focally in high-grade tumor cells (×200); (d) pv tag protein expressed diffusively in high-grade tumor cells (×200); (e) pv tag protein expressed in few adjacent normal lymphocytes in high-grade tumor tissues (×200); (f) negative control of tumor tissues using antibody dilution buffer to replace the antibodies (×200). figure 2. kaplan–meier post diagnostic survival curves. overall survival (a) and cancerspecific survival (b) among the patients with urothelial carcinoma of the bladder, defined by the status of pv tag expression. polyomavirus and urothelial carcinoma-wu et al. vol 13 no 04 july-august 2016 2776 although 56(76%) of the 74 bladder tumors demonstrated nuclear accumulation of p53 protein (figure 3), neither tumor grade nor tumor stage was associated with the expression of p53 (p = .568 and .539, respectively). the kaplan-meier curves with log-rank test for os and css, defined by the status of p53 expression, are shown in figure 4a and 4b. the patients with bladder ucc with p53 overexpression had significantly and borderline significantly worse css and os (p = .028 and .096, respectively). furthermore, the gray’s test was also used to compare the os among the pv tag-negative and pv tag-positive patients and we found the two curves to be no significantly different (gray’s test result: χ2 = 0.032, df = 1, p = .859). a similar result was also found among the p53-negative and p53-positive group (χ2 = 0.511, df = 1, p = .612). the prognostic significance of variables of interest in the cox proportional hazards model the cox proportional hazards model for predicting os and css was adjusted for age, gender, tumor grade, tumor stage, smoking status, and the status of pv tag and p53 expressions. the two independent factors predicting os were age (95% confidence interval [ci]: 1.11 to 5.80, hazard ratio [hr] = 2.54, p = .026) and tumor stage (95% ci: 1.81 to 8.04, hr = 3.81, p < .001). the two independent factors predicting css were p53 overexpression (95% ci: 1.08 to 61.93, hr = 8.16, p = .042) and tumor stage (95% ci: 2.26 to 16.03, hr = 6.01, p < .001). furthermore, no significant interaction between human pv tag and p53 expressions on the os of ucc patients was observed (χ2 = 0.23, p = .063). discussion bladder cancer has a significant impact on health and medical costs because of its high incidence and prevalence in chinese populations.(11,12) there are many established risk factors for bladder ucc, including male gender, smoking, exposure to various chemical carcinogens, and genetic factors.(16-20) some infections, including chronic cystitis and human papillomavirus (hpv), have been associated with bladder cancer, although the findings are not consistent across the studies.(21,22) even though pv is regarded to be an oncogenic virus because of its transformative behavior in vitro and in animal studies, few studies have reported an association between pv infection and the development of human bladder ucc.(15,23-30) in one italian study, monini et al.(24) reported that bkv dna was detected in 15 (58%) of 26 bladder tumor tissues using the polymerase chain reactions (pcr). however, the prevalence of pv observed in a study from the u.s. with a larger sample size (76 patients), also using pcr, was only 5%.(29) in contrast to these studies using pcr, another study in the us using the immunohistochemical study reported a prevalence of pv in the 24 patients of nearly 17%.(15) the current study is the largest to date to investigate pv in bladder tumor samples, using immunohistochemistry (ihc), and we found pv tagpositive rate in the bladder tumor samples of nearly 60%. the reason for this inconsistency in results between studies is unclear. in general, pcr has a greater degree of sensitivity than figure 3. immunohistochemical detection of p53 nuclear reactivity, using anti-p53 monoclonal antibodies in urothelial cell carcinoma of the bladder. (a) diffuse positive staining (> 50%) in highgrade urothelial cell carcinoma (×100); (b) heterogeneous positive staining (10 to 50%) in high-grade invasive urothelial cell carcinoma (×100); (c) scattered positive staining in high-grade tumor cells (<10%) (×100); (d) non-tumor sample with scattered positive staining as a normal control (×100) figure 4. kaplan-meier post-diagnostic survival curves. overall survival (a) and cancer-specific survival (b) among patients with urothelial carcinoma of the bladder, defined by the status of p53 expression polyomavirus and urothelial carcinoma-wu et al. ihc; however, it can also overestimate the prevalence of pv due to laboratory contamination. on the other hand, pcr may lead to the underestimation of the prevalence of pv due to the “hit-and-run” phenomenon. another important issue is that even though we used a newer immunohistochemical technique (a streptavidin-biotin system, less non-specific background staining than with the conventional avidin-biotin complex method) with good quality control, we cannot exclude the possibility that the high prevalence of pv tag positivity was caused, at least in part, by background staining. although methodological differences and small sample sizes most likely explain the inconsistencies in the reported prevalence rates of pv in bladder tumor tissues, it is possible that ethnic and genetic variations in the susceptibility to pv carcinogenesis may be another possible explanation. in light of the high prevalence of pv in our bladder tumors, pv may be an important cofactor in human bladder tumorigenesis in chinese patients. previous studies have reported that pv tag may exert its transformative activity by interacting with and functionally inactivating cellular p53 at a molecular level. (31,32) to elucidate whether tag affects the expression of p53, we determined the expression of p53 in bladder tumor tissues using ihc. we found the expression of tag was not associated with p53 expression, which implies that tag probably inactivates p53 by binding directly to p53 without down-regulating its expression in bladder tumor tissues. furthermore, we could not exclude the possibility that pv tag mediates bladder tumorigenesis through other mechanisms, such as inactivating retinoblastoma susceptibility protein (prb) or activating the insulin-like growth factor-i signaling pathway.(33,34) recently, alexiev et al. proposed that in the dysplastic background of p53 or prb inactivation in bkv-infected urothelium, a “time lapse” may play an important role in tumorigenesis of bladder urothelial , which is consistent with the concept of multiple carcinogenesis casade. (35) to the best of our knowledge, this is the first study to report the relationships between the expression of pv tag and clinical parameters of bladder ucc. the finding that the detection of pv tag was significantly associated with tumor stage implies that pv infection affects the aggressiveness of a tumor, although further studies are needed to elucidate the mechanism. however, it is somewhat surprising that no associations were found between the expression of pv tag and os and css in kaplan-meir analysis. it may be attributable to inadequate power due to an insufficient sample size or heterogeneity of the study population. further studies are needed to investigate the reasons for this discrepancy. it has been postulated that the overexpression of p53 implies a missense mutation of the p53 gene with a prolonged half-life, leading to nuclear accumulation of the mutant p53 protein, which can then be used as a prognostic predictor of bladder cancer.(14,36,37) consistent with this hypothesis, we found that the overexpression of p53 was significantly associated with decreased css and borderline significantly with decreased os in the kaplan-meir analysis. in the multivariate cox proportional hazards model, p53 overexpression was an independent predictor of css. however, it is interesting to note that age rather than p53 overexpression was an independent predictor of os. we think this may be explained by multiple comorbidities and poor performance in the elderly. therefore, in treating patients with bladder ucc, it is important to consider age when choosing the therapeutic strategy. conclusions in this study, pv was detected in a significant percentage of bladder cancer tissue samples, and may be an important cofactor in the tumorigenesis of human bladder and may also be associated with tumor stage. however, only the p53 overexpression was an independent predictor of css. acknowledgments this study was supported by a grant from chung shan medical university hospital, taichung, taiwan (csh-2012-c-013). references 1. nickeleit v, singh hk, mihatsch mj. polyomavirus nephropathy: morphology, pathophysiology, and clinical management. curr opin nephrol hypertens 2003; 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34: 201-3. 28. newton r, ribeiro t, casabonne d, et al. antibody levels against bk virus and prostate, kidney and bladder cancers in the epicoxford cohort. br j cancer 2005; 93: 1305-6. 29. rollison de, sexton wj, rodriguez ar, kang lc, daniel r, shah kv. lack of bk virus dna sequences in most transitional-cell carcinomas of the bladder. int j cancer 2007; 120: 1248-51. 30. roberts is, besarani d, mason p, turner g, friend pj, newton r. polyoma virus infection and urothelial carcinoma of the bladder following renal transplantation. br j cancer 2008; 99: 1383-6. 31. jiang d, srinivasan a, lozano g, robbins pd. sv40 t antigen abrogates p53-mediated transcriptional activity. oncogene 1993; 8: 2805-12. 32. segawa k, minowa a, sugasawa k, takano t, hanaoka f. abrogation of p53-mediated transactivation by sv40 large t antigen. oncogene 1993; 8: 543-8. 33. harris kf, christensen jb, imperiale mj. bk virus large t antigen: interactions with the retinoblastoma family of tumor suppressor proteins and effects on cellular growth control. j virol 1996; 70: 2378-86. 34. bocchetta m, eliasz s, de marco ma, rudzinski j, zhang l, carbone m. the sv40 large t antigen-p53 complexes bind and activate the insulin-like growth factor-i promoter stimulating cell growth. cancer res 2008; 68: 1022-9. 35. alexiev ba, randhawa p, vazquez martul e, et al. bk virus-associated urinary bladder carcinoma in transplant recipients: report of 2 cases, review of the literature, and proposed pathogenetic model. hum pathol 2013; 44: 908-17. 36. smith nd, rubenstein jn, eggener se, kozlowski jm. the p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer. j urol 2003; 169: 1219-28. 37. malats n, bustos a, nascimento cm, et al. p53 as a prognostic marker for bladder cancer: a meta-analysis and review. lancet oncol 2005; 6: 678-86. polyomavirus and urothelial carcinoma-wu et al. 165 urology journal unrc/iua vol. 2, no. 3, 165-168 summer 2005 printed in iran reconstructive surgery early versus delayed internal urethrotomy for recurrent urethral stricture after urethroplasty in children seyyed yousef hosseini, mohammad reza safarinejad* department of urology, shaheed modarress hospital, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: our aim was to evaluate the results of early versus delayed internal urethrotomy for management of recurrent urethral strictures after posterior urethroplasty in children. materials and methods: twenty boys with proven posterior urethral strictures were treated by perineal posterior urethroplasty. of these, 12 required internal urethrotomy. each radiograph demonstrated a patent but irregular urethra with a decrease in diameter at the point of repair (fair results). patients were then divided into 2 groups: 6 underwent early (within 6 weeks from urethroplasty), and 6 underwent delayed (after 12 weeks from urethroplasty), internal urethrotomy with the cold knife as a complementary treatment. the groups were comparable in terms of patient age, etiology of the primary urethral stricture, number of recurrences, length and site of the actual stricture, and preoperative maximum flow rate. mean follow-up was 5 years. results: kaplan-meier analyses showed that the stricture-free rate was 66.6% after early, and 33.3% after delayed, internal urethrotomy (p = .03). conclusion: early internal urethrotomy should be considered in boys with recurrent urethral stricture after urethroplasty. key words: urethral stricture, surgery, internal urethrotomy, children, treatment outcome introduction the management of urethral strictures in young boys has been a challenge for urologists. urethroplasty is still regarded as the gold standard for treatment of urethral stricture,(1) but recurrence of stricture with this technique is not uncommon. recurring strictures secondary to posterior urethroplasty are difficult to manage, especially in children. we reviewed the results of early versus delayed internal urethrotomy as a complementary treatment in these patients. materials and methods from january 1974 to july 1997, 100 patients underwent repair of urethral strictures by perineal urethroplasty in our center. of these patients, 20 were children between 5 and 14 years old. posturethroplasty follow-up was based on voiding function, urinary tract infection, and radiographic appearance. the overall results were classified as good if the patient required no further postoperative treatment and no stricture was identified radiographically, with no residual urine on a postvoid film; and fair if internal urethrotomy was required and radiography demonstrated a patent but irregular urethra with a decrease in diameter at the point of repair. received january 2005 accepted september 2005 *corresponding author: po box: 19395-1849, tel: ++98 912 109 5200, e-mail: safarinejad@unrc.ir internal urethrotomy for recurrent urethral stricture166 recurrent strictures were identified by peak flow rates less than 15 milliliters per second. the diagnosis was established by urethroscopy. of 20 boys, 12 (60%) had fair results (recurrent stricture) after primary posterior perineal urethroplasty. these children with recurrent urethral strictures were candidates for internal urethrotomy. the etiology of the primary stricture was trauma for all patients. they were divided into 2 groups according to the time of internal urethrotomy, following prior informed parental consent and assent from the children. six children (group 1) underwent early internal urethrotomy (within 6 weeks postoperatively), and the remaining 6 boys (group 2) underwent delayed internal urethrotomy (beyond 12 weeks postoperatively) with the cold knife as a complementary treatment. the mean patient age was 8 years (range, 5-14 years). the length of urethral stricture ranged from 0.5 to 1 cm in both groups. the strictures were situated in the bulbomembranous part of the urethra in all patients. the 2 groups were comparable, with no significant differences in patients' age, length, and site of actual stricture (p = .01). preurethrotomy evaluation included a complete history and physical examination, urethrography under radiographic fluoroscopy, uroflowmetry, and urethroscopy. the only study exclusion criterion was complete occlusion of the urethra on urethrography. therapeutically, all the patients underwent an identical endoscopic procedure(2) under general anesthesia. antibiotic prophylaxis was administered with intravenous injection of gentamycin, 40 mg. all patients were treated using the storz urethrotome. urethrotomy usually began by introducing a thin catheter, used for orientation, to bypass the stricture zone. the stricture was incised at the 12 o'clock position along its entire length and depth. a 2-way 12-f to 16-f foley catheter was left indwelling for 48 hours. on the second postoperative day, a nurse trained all patients' parents to perform a clean intermittent catheterization. catheters (14-f to 18-f) with a nelaton point were used, and parents were instructed on how to leave the catheter in situ for 5 minutes and to perform catheterization twice weekly for the first month postoperatively and once weekly for the 3 subsequent months. patients were evaluated after termination of clean intermittent catheterization. follow-up was scheduled for 3, 6, 9, 12, 24, 36, 48, and 60 months after the urethrotomy. at each follow-up session, the following data were collected or the procedure performed: history of voiding difficulties, calibrating the urethra, examining the urine for sensitivity, and performing uroflowmetric studies. a recurrence was defined as a maximum flow rate of less than 10 ml/s and a characteristic flow curve. data analyses were performed using spss software (statistical package for the social sciences, version 11.5, ssps inc, chicago, ill, usa). the kaplan-meier method was used to estimate survival function for the 2 groups (survival times were regarded as the time to stricture recurrence), and the log-rank test was used to compare the efficacy of urethrotomies. results both groups underwent internal urethrotomy without complications. clean intermittent catheterization did not pose complications in any of the patients. there were no significant differences with regard to patients' ages; etiologies of the stricture; clinical presentations; and number, length, and sites of the strictures between patients in the 2 treatment groups. incidences of complications and failure during performance of the procedure did not differ significantly between the groups. there was no significant difference between the 2 groups in the availability and duration of follow-up. kaplan-meier survival function analysis showed that the estimated stricture-free rate at 60 months was 66.6% after early internal urethrotomy and 33.3% after delayed internal urethrotomy (figures 1 and 2). the difference was statistically significant (p = .03). the median time to stricture recurrence was 14 months after early urethrotomy and 6 months after delayed urethrotomy. stricture-free survival, calculated from the time of urethrotomy, did differ significantly between the groups (p = .032). the median maximum flow rate at recurrence was 7.4 ml/s (range, 1 to 9.7 ml/s). postoperative complications including urethral bleeding, extravasation, chordee, and incontinence were not seen. discussion the incidence of posturethroplasty recurrent strictures in this study is high and probably due hosseini and safarinejad 167 to the fact that all patients were examined by voiding interview, uroflowmetry, and retrograde urethrography. urethral stenosis may occur at the level of the urethral anastomosis. therefore, a careful follow-up, based mainly on voiding symptoms and uroflowmetry, is necessary.(3,4) in the literature, most studies of urethral stricture treatment have only inconsistently reported stricture characteristics, such as length, location, and etiology, and have not presented the optimal time for internal urethrotomy. in our study, the 2 groups of patients were analyzed in combination to compare treatment results among those with identical etiologies that underwent identical procedures at different times. follow-up in both groups was sufficient (mean, 5 years). mean patient ages were comparable and all strictures had been treated previously by perineal urethroplasty. the primary investigations (urinary flow rate and retrograde urethrography) were comparable in both groups, with treatment success defined as no clinical symptoms and peak flow rate greater than 15 ml/s. the overall recurrence rate differed remarkably in both groups (33.3% in group 1 versus 66.6% in group 2) owing to the differences in urethrotomy time. risk of recurrence is higher with periurethral scarring.(5-7) it is agreed that every procedure causes a scar, and progressive scarring occurs with the passage of time. severe scar formation necessitates reconstructive urethroplasty with excision of the lesion. the only cofactor significantly associated with stricture recurrence in our study was the time of urethrotomy. the recurrence rate was 66.6% for delayed internal urethrotomies and 33.3% for early internal urethrotomies (p = .03). conclusion early internal urethrotomy is an efficient complementary method that consolidates the results obtained in the treatment of posterior urethral strictures in children. postponement of urethrotomy leads to progressive scar formation and is associated with higher recurrence rates. further studies with larger samples are necessary to evaluate the ultimate durability of internal urethrotomy in pediatric populations. references 1. yelderman jj, weaver rg. the behavior and treatment of urethral strictures. j urol. 1967;97:1040-4. 2. sachse h. [treatment of urethral stricture: transurethral slit in view using sharp section]. fortschr med. 1974;92:12-5. german. fig. 2. the same patient as in figure one, 4 years after early internal urethrotomy fig. 1. bulbourethral stricture in a 12-year-old boy after previous failed urethroplasty internal urethrotomy for recurrent urethral stricture168 3. brannan w. management of urethral strictures. j urol. 1985;133:442. 4. netto nr jr. the surgical repair of posterior urethral strictures by the transpubic urethroplasty or pullthrough technique. j urol. 1985;133:411-2. 5. pansadoro v, emiliozzi p. internal urethrotomy in the management of anterior urethral strictures: long-term followup. j urol. 1996;156:73-5. 6. steenkamp jw, heyns cf, de kock ml. internal urethrotomy versus dilation as treatment for male urethral strictures: a prospective, randomized comparison. j urol. 1997;157:98-101. 7. merkle w, wagner w. risk of recurrent stricture following internal urethrotomy. prospective ultrasound study of distal male urethra. br j urol. 1990;65:618-20. vol 13 no 04 july-august 2016 2750 endourology and stone disease percutaneous nephrolithotomy using split amplatz sheath: a randomized clinical trial ali tabibi,1 amir reza abedi,2 mohammad hadi radfar,1* mohammad reza kamranmanesh,6 hormoz karami,3 davoud arab,4 hamid pakmanesh5 purpose: to compare the outcome of percutaneous nephrolithotomy (pcnl) using split or intact amplatz sheath. materials and methods: seventy two patients who underwent pcnl were randomly divided into two groups; pcnl using intact (group 1) and split (group 2) amplatz sheath. preoperative data, operative time, largest extracted stone size, fluoroscopy and lithotripsy time, and serum biochemistry tests before and after pcnl were evaluated. results: preoperative features and stone size were not significantly different between the groups. there were no significant differences in complications and postoperative changes in hemoglobin and serum electrolytes. stone free rate in group 2 (88.1%) was insignificantly higher than group 1 (83.3%) (p = .05), but in staghorn stones and stones larger than 1000 mm2, stone free rate in group 2 was significantly higher than group 1 (82% vs. 72%). the mean extracted stone size in group 2 (150 ± 49mm2) was significantly larger than group 1 (40 ± 16 mm2) (p < .005). the mean operative, lithotripsy and fluoroscopy times were significantly longer in group 1. conclusion: using split amplatz sheath in pcnl facilitates extraction of larger stone fragments which could contribute to shorter fluoroscopy, lithotripsy and operative times. keywords: percutaneous nephrolithotomy; amplatz sheath; nephrolithiasis. introduction percutaneous nephrolithotomy (pcnl) is the standard procedure for the treatment of stones larger than 2 cm, staghorn calculi, and small stones refractory to shock wave lithotripsy (swl).(1-3) pcnl has the highest stonefree rate (sfr) among all renal stone treatment options. the sfr after one session of pcnl is more than 80%.(4) operative time is a key factor correlated with the postoperative and, indirectly with anesthesia-related complications.(5,6) a few studies have investigated factors that influence operative time during percutaneous nephrolithotomy. these studies have shown that a history of open surgery, stone size and surgical experience are correlated with operative time(6,7). in a study by el-nahas et al. stone size was found to be a predictive factor for both longer operative time and hospital stay.(8) we hypothesized that extraction of stones in larger fragments may decrease the need for stone fragmentation and consequently, shorten the operative time. hence, this study was done to compare the perioperative and postoperative outcome of pcnl using split and intact amplatz sheath. materials and methods between june and april 2014, 123 patients underwent pcnl in our department. the study was approved by our institutional ethical committee, and informed consent was sought from all patients. all patients who were candidate for pcnl were included except patients with the american society of anesthesiologists (asa) risk class iii or more, multiple stones and those requiring supracostal access. considering study power of 80%, sample size was calculated to be 36 patients in each group. we randomized patients into two groups; in group one pcnl was performed using intact amplatz sheath, and in group two longitudinally split amplatz sheath was used. to have a split amplatz sheath, a conventional amplatz sheath was simply cut longitudinally in its total length with a surgical knife. the randomization method was simple randomization using table of random numbers. figure 1 shows the consort chart of this study. preoperative evaluation included laboratory tests (complete blood count (cbc), coagulation tests, serum electrolytes, urine analysis and culture) and imaging studies (spiral abdominopelvic computed tomography (ct) scan and/or intravenous urography (ivu). all patients received prophylactic antibiotics preoperatively. data were collected prospectively by one of the authors blinded to the procedure. participants and care givers were also blinded to group assignment. 1urology and nephrology research center, shahid labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. 2urology and nephrology research center, shohadaye tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 3yazd university of medical sciences, yazd, iran. 4semnan university of medical sciences, semnan, iran. 5kerman university of medical sciences, kerman, iran. 6anesthesiology research center, shahid labbafinejad hospital, shahid beheshti university of medical sciences *correspondence: shahid labbafinejad hospital, 9th boostan, pasdaran avenue, tehran, iran. tel& fax: +98 212 258 8016. e-mail: mhadirad@yahoo.com received april 2016 & accepted july 2016 pcnl using split amplatz sheath-tabibi et al. in the lithotomy position and under spinal anesthesia, cystoscopy was performed to insert a 5f ureteral catheter. the position was changed to prone with a support under chest and pelvis. access to the kidney was obtained under fluoroscopic guidance; the tract was dilated to 30 fr using amplatz dilator with single-step dilation technique, and amplatz sheath (split or intact sheath) was placed. stone degradation was performed by pneumatic lithotripsy using lithoclast master system (ems, switzerland). we did not use flexible nephroscopy for our patients. an 18 fr nephrostomy tube was inserted at the end of procedure for all patients. all operations were supervised by an attending endourologist. cbc and serum electrolytes were checked on the first postoperative day. abdominal ultrasonography and plain abdomen x-ray were also performed on the first postoperative day. if there was no significant residual stone, nephrostomy tube was removed. ureteral catheter was removed when urinary leakage from nephrostomy removal site was less than 100 ml/day. patients with no residual stone or residual stone < 4 mm were considered stone free. stone free rate was the primary outcome evaluated in this study. secondary outcomes included operative time, the largest extracted stone size, fluoroscopy and lithotripsy times, blood tests before and after pcnl, ancillary procedures, hospital stay and complications. for statistical analysis, spss ver.21 software was used. quantitative and categorical variables were tested using student’s t-test and chi-square test, respectively. results seventy two patients (57 men and 15 women) with mean age of 43.45 ± 13.41 years were included in the study. the preoperative characteristics were not significantly different between the two groups. (table 1) the mean body mass index (bmi) was 29.2 ± 5.6 and 28.64 ± 6.1 kg/m2 in group one and two, respectively (p = .68). table 2 summarizes intraand table 1. stones characteristics. stone characteristics intact group split group total stone locationa upper calyx 1 1 2 lower calyx 4 3 7 pelvis 14 13 27 pelvis + one calyx 10 13 23 staghorn 6 7 13 mean stone sizeb (mm2) 950 ± 967 1165 ± 1424 1005.7 ± 23 astatistically insignificant difference between the groups. (p = .58) b p = .45 features intact group split group p value operative time (mean ± sd) min 70 ± 22.2 48.33 ± 17.32 .005 fluoroscopy time (mean ± sd) second 45.8 ± 14.66 25.63 ± 12.8 .005 extracted stone size (mean ± sd) mm2 40 ± 16 150 ± 49 .005 preoperative hemoglobin (mean ± sd) g/dl 14.32 ± 1.52 14.1 ± 1.2 .67 postoperative hemoglobin (mean ± sd) g/dl 11.8 ± 1.56 11.82 ± 2.7 .95 preoperative na (mean ± sd) mg/dl 141.7 ± 2.6 141.8 ± 2.6 .14 postoperative na (mean ± sd) mg/dl 141.1 ± 2.56 140.08 ± 3.2 .13 preoperative k (mean ± sd) mg/dl 4.23 ± 0.22 4.34 ± 0.42 .22 postoperative k (mean ± sd) mg/dl 4.11 ± 0.31 3.95 ± 0.36 .08 preoperative cr (mean ± sd) mg/dl 1.11 ± 0.22 1.11 ± 0.27 .9 postoperative cr (mean ± sd) mg/dl 1.13 ± 0.27 1.13 ± 0.35 .95 hospital stay (mean ± sd) days 3.5 ± 1.5 3.1 ± 1.2 .2 lithotripsy time (mean ± sd) second 61.9 ± 30.69 38.61±33.58 .003 access tracts (no. of patients) .005 1 34 33 2 2 3 table 2. intraand postoperative data. endourology and stone diseases 2751 vol 13 no 04 july-august 2016 2752 postoperative data. the mean operative, fluoroscopy and lithotripsy times in group one (intact sheath) were significantly longer than group two (split sheath). the mean size of extracted stone fragment in group one was significantly smaller than group two. (figure 2) hemoglobin change was not significantly different (p = .54) (2.52 ± 1.2 in the split group vs. 2.35 ± 1.07 in intact group). there was no significant difference in mean change of serum sodium (na), potassium (k), and creatinine between the two groups. (table 2) stone free rate was not significantly different between the two groups (83.3% vs. 88.1% in groups 1 and 2, respectively) (p = .5). however, in staghorn stones and stones larger than 1000 mm2, stone free rate in group 1 was significantly lower than group 2 (72% vs. 82%). the need for ancillary procedures was not significantly different between the two groups. swl was necessary in 6 patients (4 patients in group one and two patients in group two), ureteroscopy in two patients (one patient in each group), and repeat pcnl in two patients (one patient in each group). according to the modified clavien system, class ii complication (blood transfusion) was found in 3 patients in group one and 2 patients in group two (p = .56). class iiia complication (double-j stent insertion without general anesthesia because of prolonged urine leakage from nephrostomy removal site) occurred in two patients in group 1 and one patient in group 2. there were no perinephric collection (evaluated by ultrasonography) or major complications (clavien class iiib or higher) in our patients. discussion since the first report of pcnl in 1976, its instruments and techniques have evolved. pcnl is currently the standard of care for large renal stones (> 2 cm)(9). although pcnl is safe and effective, it is the most costly minimally invasive procedure for renal stone treatment. (10) the cost-effectiveness of pcnl correlates with operative time, stone burden, stone free rate, and major complications.(6) bleeding is one of the most common complications of pcnl, with an incidence rate of 1-55% in different studies.(11) operative time is an important factor that correlates with perioperative bleeding and cost-effectiveness of the procedure.(6) a few studies are available about factors affecting operative time of pcnl. olbert et al. reported on 109 patients who underwent pcnl and found out that stone size correlates with operative time and hospital stay(12). akman et al. showed that operative time for stones larger than 1000 mm2 was three times longer than for stones less than 1000 mm2. with increasing stone burden, the need for multiple access tracts increases and multiple tracts are correlated with more blood loss and longer hospital stay(6). bagrodia et al. found that increasing figure 1. consort chart of the study. figure 2. a large stone fragment is extracted from the split amplatz sheath. pcnl using split amplatz sheath-tabibi et al. stone size affects treatment related costs. larger stone burden is associated with longer operative time, longer hospital stay, more salvage procedures, and higher cost. they also showed that average operative time slowly decreases with increased experience of surgeon.(10) some authors have reported that the hydronephrosis grade could affect operative time. they described that a severely hydronephrotic kidney collapses after percutaneous access and detection of stone fragments could be difficult and take longer time.(6,12) correlation between stone size and operative time could be explained by longer time needed for stone fragmentation and extraction. since operative time affects complication rate and cost-effectiveness, any attempt to reduce it is of critical importance. our study compared the outcomes of pcnl using intact and split amplatz sheath in a randomized clinical trial. it showed that using split amplatz sheath allows for extracting significantly larger stone fragments which results in decrease of lithotripsy time and number of stone fragments. as the number of stone fragments is reduced, their detection and extraction could be performed easier, faster, and with less need for fluoroscopy. this could also explain higher stone free rate achieved in group 2, particularly for staghorn calculi and stones larger than 1000 mm2. a technical point of using split sheath was the risk of entrapment of stone fragments in the fascia. to avoid this risk, the fascia should be opened wider. blood transfusion and mean hb change was not significantly different between the two groups. there was concern about probable fluid leakage through the split sheath and the risk for electrolyte disturbances. our findings showed that electrolyte changes were not significantly different between the two groups and none of the patients had perinephric collection on postopearative ultrasonography. conclusion using split amplatz sheath during pcnl facilitates extraction of larger stone fragments which could contribute to shorter fluoroscopy time, lithotripsy time, and operative time. operative time is a key factor which correlates with intraand postoperative complications. it seems that the benefits of using spit amplatz sheath might be more considerable in large and staghorn stones. this should be confirmed in larger studies with more patients. acknowledgements the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. references 1. ziemba jb, matlaga br. guideline of guidelines: kidney stones. bju int. 2015; 116: 184-9. 2. skolarikos a, alivizatos g, de la rosette jj. percutaneous nephrolithotomy and its legacy. eur urol. 2005; 47: 22-8. 3. skolarikos a, de la rosette jj. prevention and treatment of complications following percutaneous nephrolithotomy. curr opin urol. 2008; 18: 229-34. 4. shin ts, cho hj, hong sh, lee jy, kim sw, hwang tk. complications of percutaneous nephrolithotomy classified by the modified clavien grading system: a single center's experience over 16 years. korean j urol. 2011; 52: 769–75. 5. falahatkar s, moghaddam kg, kazemnezhad e, et al. factors affecting operative time during percutaneous nephrolithotomy: our experience with the complete supine position. j endourol. 2011; 25: 1831-6. 6. akman t, binbay m, akcay m, et al. variables that influence operative time during percutaneous nephrolithotomy: an analysis of 1897 cases. j endourol. 2011; 25: 1269-73. 7. tugcu v, su fe, kalfazade n, sahin s, ozbay b, tasci ai. percutaneous nephrolithotomy (pcnl) in patients with previous open stone surgery. int urol nephrol. 2008; 40:881-4. 8. el-nahas ar, eraky i, shokeir aa, et al. factors affecting stone-free rate and complications of percutaneous nephrolithotomy for treatment of staghorn stone. urology. 2012; 79:1236-41. 9. fernstrom i, johansson b. percutaneous pyelolithotomy: a new extraction technique. scand j urol nephrol. 1976; 10:257–9. 10. bagrodia a, gupta a, raman jd, bensalah k, pearle ms, lotan y. predictors of cost and clinical outcomes of percutaneous nephrostolithotomy. j urol. 2009; 182: 58690. 11. lee jk, kim bs, park yk. predictive factors for bleeding during percutaneous nephrolithotomy. korean j urol. 2013; 54: 448-53. 12. olbert pj, hegele a, schrader aj, scherag a, hofmann r. preand perioperative predictors of short-term clinical outcomes in patients undergoing percutaneous nephrolitholapaxy. urol res. 2007; 35: 225-30. pcnl using split amplatz sheath-tabibi et al. endourology and stone diseases 2753 89 urology journal unrc/iua vol. 2, no. 2, 89-92 spring 2005 printed in iran urological oncology the effect of acute urinary retention on serum prostate-specific antigen level majeed aliasgari,* mohammad soleimani, seyyed mohammadmehdi hosseini moghaddam urology and nephrology research center, shaheed modarress hospital, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: our aim was to evaluate the effect of acute urinary retention on serum prostate-specific antigen (psa) level. materials and methods: men aged 50 years and older who presented with acute urinary retention were studied. patients with urethral stricture, neurogenic bladder, prostate cancer, and those with a history of recent instrumentation or prostate biopsy were excluded. blood samples for serum psa measurement were obtained (psa1), and an indwelling urethral catheter was inserted for 2 weeks. before catheter removal, a second blood sample for measurement of serum psa level (psa2) was obtained. in patients who were able to void, a third sample was obtained 3 weeks later (psa3). in the first and second visits, digital rectal examinations (dre1, dre2) were performed to assess prostate volume. mean psa levels (psa1, psa2, and psa3) and prostate volumes (dre1, dre2) were compared. results: forty-five patients with a mean age of 70.18 years (range 56 to 85 years) participated in this study. mean psa1 and psa2 levels were 9.8 ng/ml and 5.05 ng/ml, respectively (p < 0.001; medians, 6.2 and 4.2 ng/ml). mean prostate volumes at the time of retention and 2 weeks later were 43.4 ml and 37.8 ml, respectively (p < 0.001; medians, 45 and 40 ml). psa3 was measured in 31 patients 2 weeks after catheter removal. in this group of patients, mean psa2 and psa3 levels were 5.03 ng/ml and 4.97 ng/ml, respectively (p = 0.49; medians, 4.3 and 4.1 ng/ml). conclusion: acute urinary retention can increase serum psa levels by approximately 2 fold. in this series, we found that this effect may continue up to 2 weeks. key words: urinary retention, prostatic hyperplasia, prostate-specific antigen introduction prostate-specific antigen (psa) has been introduced as the most useful tumor marker in urology.(1) its accuracy for prostate cancer diagnosis has been demonstrated by several studies.(2) serum psa levels increase not only in prostate cancer, but also as a result of several urologic manipulations and benign conditions.(3) however, there are some reports about the inaccuracy of psa in detecting prostate cancer in the presence of acute urinary retention (aur).(4-6) to date, however, to the best of our knowledge, no study has precisely elucidated the duration received january 2005 accepted april 2005 *corresponding author: unrc, no 44, boustan 9th, pasdaran, tehran, iran 1666679951. tel: ++98 21 22567222, fax: ++98 21 22567282 e-mail: h_moghaddam@unrc.ir acute urinary retention on serum prostate-specific antigen level90 and magnitude of this effect. armitage and colleagues have observed that patients with aur have a higher level of serum psa,(2) and hicks has reported a case with a dramatic increase in serum psa level following aur.(5) in 7 patients with aur, semjonow and colleagues showed that psa levels at the time of retention are about twice as high as levels measured 24 to 48 hours after suprapubic catheterization.(4) the precise mechanism of this effect is unclear, although spiro et al have suggested that it is presumably secondary to prostatic infarction.(7) mcneill and hargreave evaluated the efficacy of psa for detecting prostate cancer in patients with aur and concluded that psa should not be measured at the time of aur.(6) since urinary retention is one of the most frequent indications for surgical intervention, and measuring serum psa levels is usually necessary before surgery, it is important to know the magnitude and duration of increase in serum psa levels following aur. given the preceding, in this prospective study, we aimed to more accurately assess the effect of aur on psa levels. materials and methods from october 2001 to september 2003, 136 men aged 50 years and older (mean age, 70.18 years; range, 56 to 85 years) with aur due to benign prostatic hyperplasia (bph) were referred to our center. forty-five patients were enrolled in this study. patients with urethral stricture, neurogenic bladder, prostate cancer, and those with a history of recent instrumentation or prostate biopsy were excluded. all cases were managed with an indwelling urethral catheter. a blood sample for psa was obtained (psa1), and a urethral catheter was left in place for 2 weeks. urine samples (obtained by catheterization) were sent for culture. prior to catheter removal, another blood sample for psa (psa2) was obtained. also, in patients who were able to void, a third blood sample was obtained 2 weeks later (psa3). the elisa test was used to measure serum psa levels. at the first and second visits, after taking blood samples, a digital rectal examination (dre1, dre2) was performed to assess prostate volume. patients were asked about their last ejaculation time to consider its effect on serum psa levels. surgical intervention was performed for patients who could not void after removal of the urethral catheter. if the last serum psa level was higher than 4 ng/ml, the patient was referred for a prostate biopsy. mean psa levels (psa1, psa2, and psa3) and prostate volumes (dre1 and dre2) were compared using nonparametric statistical methods (wilcoxon signed rank test), and p values less than 0.05 were considered statistically significant. results urine cultures performed at the time of retention were positive in 2 patients. none of the patients had a history of ejaculation within the preceding 48 hours. prostatic adenocarcinoma was diagnosed during follow-up in 3 patients. the mean psa level at the time of aur (psa1) was 9.8 ng/ml (median, 6.2 ng/ml; range, 0.3 to 39 ng/ml). the mean psa2 level was 5.05 ng/ml (median, 4.2 ng/ml; range, 0.2 to 17.5 ng/ml), significantly lower than the psa1 level (p < 0.001). the mean prostate volume at the time of dre1 (43.4 ml; median, 45 ml; range, 30 to 60 ml) was significantly higher than at dre2 (37.8 ml; median, 40 ml; range, 25 to 50 ml) (p < 0.001). malignancy was not suspected by dre in any of the patients. psa3 was measured in 31 patients 4 weeks after retention (2 weeks after catheter removal). in this group of patients, mean psa2 and psa3 levels were 5.03 ng/ml and 4.97 ng/ml, respectively (median, 4.3 and 4.1, respectively, p = 0.49). by excluding 2 patients with positive urine cultures and 3 patients with prostate adenocarcinoma, mean psa1, psa2, and psa3 levels were 9.8 ng/ml, 4.66 ng/ml, and 4.98 ng/ml, respectively (median: 6.5, 4.05, and 4.1 ng/ml). the difference was significant between psa1 and psa2 (p < 0.001), but not between psa2 and psa3 (p = 0.72). of 30 patients with psa1 levels greater than 4.0 ng/ml, 11 had a lower psa2 level and 2 had a lower psa3 level. of 40 patients with bph, 24 underwent surgery (turp or open prostatectomy) owing to recurrent retentions and 16 were able to void with medical therapy. in these 2 groups (surgical and medical therapy), the mean psa1 levels were 10.44 ng/ml and 8.81 ng/ml, respectively (median, 6.9 and 6.05 ng/ml; p = 0.49), and the mean prostate volumes at the time of retention were 45 ml and 42.2 ml, respectively (median, 45 and 42.5 ml; p = 0.48). overall, after 2 weeks of free drainage in these 40 patients, psa levels decreased in 38 patients, increased in 1, and remained unchanged in 1 (table 1). aliasgari et al 91 discussion in the present study, we showed that aur could increase serum psa levels more than 2 fold. since the half-life of serum psa is 2 to 3 days,(8) we evaluated patients at 2-week intervals—more than 5 half-life periods—which is sufficient for psa levels to return to normal values. in a study of 6 patients by semjonow and colleagues, psa levels decreased by 50% compared with those at the time of retention 24 to 48 hours after catheterization.(4) this indicates that free psa, which has a serum half-life of 2 to 3 hours,(9) may be the major factor for the increase seen in serum psa levels after aur. mcneill and hargreave have reported a significant difference between psa levels at the time of admission for 11 patients with aur and their respective followup psa levels; however, the interval between retention and follow-up psa is not clear in this article.(6) in our study, a nonsignificant difference between psa2 and psa3 suggests that the 2-week interval between retention and psa measurement is acceptable and can prevent unnecessary biopsies in more than one third of patients (11 out of 30); nonetheless, in 2 patients, it took 4 weeks for the psa level to decrease to lower than 4.0 ng/ml. we excluded all patients with a history of disease other than bph that could result in aur (ie, urethral stricture, neurogenic bladder, prostate cancer) and patients who had a condition or procedure that could affect serum psa levels (recent instrumentation, prostate biopsy, urinary tract infection, and ejaculation in the last 48 hours) to accurately evaluate the effect of aur due to bph. the effect of catheterization or presence of an indwelling urethral catheter on serum psa levels is controversial. by daily checking the psa level in 21 patients catheterized due to nonurologic problems, matzkin et al demonstrated that catheterization had no effect on serum psa levels.(10) in another study of 35 patients with aur, erdogan and coworkers managed patients with either a urethral or suprapubic catheter and found that there was no difference in serum psa levels between the two.(11) in 2 studies on 19 and 83 patients, respectively, dutkiewicz et al and batislam et al demonstrated that serum psa levels increased in patients catheterized owing to aur; these authors therefore concluded that catheterization, per se, could increase serum psa levels.(12,13) ignoring the effect of aur seems to be a major flaw of these studies, however. because we found no statistically significant difference between psa2 and psa3, we suggest that an indwelling urethral catheter has no effect on serum psa level. although it has been reported that serum psa concentration and prostate volume are powerful predictors of a need for surgery in men with bph,(14) we did not find significant differences in serum psa levels and prostate volumes between patients who needed surgery and those who did not. in our study, prostate volume increased at the time of aur and returned to its normal value after a period of time. we speculate that prostate congestion or inflammation is the factor responsible for both urinary retention and enhancement of serum psa levels. considering the shortcomings of dre, we recommend transrectal ultrasonography to more precisely evaluate prostate volume changes in future studies. since serum psa level is frequently recorded at the time of a patient's presentation with aur, ignoring its effect on serum psa levels could be associated with unnecessary and sometimes hazardous biopsies. conclusion acute urinary retention can increase serum psa levels by approximately 2 fold. this impact will disappear after 2 weeks. considering this effect, the clinician can prevent unnecessary biopsies in many patients. also, we recommend psa measurement at least 2 weeks after aur. given the decrease in prostate volume after the period of catheterization we observed in the current study, we suggest that the decision regarding treatment options (ie, turp or open prostatectomy) should not be made based on the findings of dre at the time of retention. table 1. number of patients in different psa level ranges psa levels (ng/ml) 0 to 4 4 to 10 10 to 20 > 20 psa1 10 (25%) 17 (42.5%) 8 (20%) 5 (12.5%) psa2 21 (52.5%) 16 (40%) 3 (7.5%) psa3 15 (48.4%) 14 (45.2%) 2 (6.4%) acute urinary retention on serum prostate-specific antigen level92 references 1. oesterling je. prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. j urol. 1991;145:907-23. 2. armitage tg, cooper eh, newling dw, robinson mr, appleyard i. the value of the measurement of serum prostate specific antigen in patients with benign prostatic hyperplasia and untreated prostate cancer. br j urol. 1988;62:584-9. 3. tchetgen mb, oesterling je. the effect of prostatitis, urinary retention, ejaculation, and ambulation on the serum prostate-specific antigen concentration. urol clin north am. 1997;24:283-291. 4. semjonow a, roth s, hamm m, rathert p. re: nontraumatic elevation of prostate specific antigen following cardiac surgery and extracorporeal cardiopulmonary bypass. j urol. 1996;155:295-6. 5. hicks rj. elevated prostate-specific antigen: a case report and analysis. j fam pract. 1993;37:284-8. 6. mcneill sa, hargreave tb. efficacy of psa in the detection of carcinoma of the prostate in patients presenting with acute urinary retention. j r coll surg edinb. 2000;45:227-30. 7. spiro lh, labay g, orkin la. prostatic infarction. role in acute urinary retention. urology. 1974;3:345-7. 8. oesterling je, chan dw, epstein ji, et al. prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. j urol. 1988;139:766-72. 9. partin aw, piantadosi s, subong en, et al. clearance rate of serum-free and total psa following radical retropubic prostatectomy. prostate suppl. 1996;7:35-9. 10. matzkin h, laufer m, chen j, hareuveni m, braf z. effect of elective prolonged urethral catheterization on serum prostate-specific antigen concentration. urology. 1996;48:63-6. 11. erdogan k, gurdal m, tekin a, kirecci s, sengor f. the effect of urethral catheterisation on serum prostatespecific antigen levels in male patients with acute urinary retention. yonsei med j. 2003;44:676-8. 12. dutkiewicz s, stepien k, witeska a. bladder catheterization and a plasma prostate-specific antigen in patients with benign prostatic hyperplasia and complete urine retention. mater med pol. 1995;27:71-3. 13. batislam e, arik ai, karakoc a, uygur mc, germiyanoglu rc, erol d. effect of transurethral indwelling catheter on serum prostate-specific antigen level in benign prostatic hyperplasia. urology. 1997;49:50-4. 14. roehrborn cg, mcconnell jd, lieber m, et al. serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. pless study group. urology. 1999;53:473-80. urol_v3_no2_001_editorial.qxd miscellaneous ethylenedicysteine versus diethylenetriamine pentaacetic acid as the carrier of technetium tc 99m in diuretic renography for patients with upper urinary tract obstruction hossein shahrokh, mansour movahhed, mohammad ali zargar shoshtari, amir mohammad orafa,* sepideh hekmat department of urology, hasheminejad hospital, iran university of medical sciences, tehran, iran abstract introduction: l,l-ethylenedicysteine (ec) is a new carrier of technetium tc 99m (99mtc) with a lower affinity to plasma albumin in comparison with diethylenetriamine pentaacetic acid (dtpa). we compared 99mtc-ec scan with 99mtc-dtpa scan in diuretic renography for patients with obstructive uropathy. materials and methods: thirty-three patients with upper urinary tract obstruction were randomly selected and underwent diuretic renographies by 99mtc-ec and 99mtcdtpa. the counts of radioisotope per pixel in the target (the kidney) and background tissues as well as the clearance half-life of these two radiopharmaceuticals were measured and compared. results: mean counts of radioisotope per pixel in the target tissue was not different between 99mtc-ec and 99mtc-dtpa scans, but in the background tissue, it was less for 99mtc-ec (p = .003). target-background ratio was higher for 99mtc-ec scan (3.80 ± 2.11 versus 2.48 ± 1.39; p < .001). renal clearance half-life of radioisotope was shorter for 99mtc-ec scan than 99mtc-dtpa scan (58.15 ± 15.17 minutes versus 78.65 ± 19.99 minutes; p = .033). the results were similar for uremic patients (with a serum creatinine level > 2mg/dl). conclusion: target-background ratio of radiopharmaceutical uptake rates in diuretic renography was a good indicator of the higher resolution of 99mtc-ec than 99mtc-dtpa scan. we also demonstrated the faster clearance of 99mtc-ec than 99mtc-dtpa. this results in less radiation that is especially useful in children. to our opinion, 99mtc-ec can better depict the kidneys in comparison with 99mtc-dtpa. key words: radioisotope renography, kidney function, diethylenetriamine pentaacetic acid, l,l-ethylenedicysteine, radiopharmaceutical, ureteral obstruction 97 urology journal unrc/iua vol. 3, no. 2, 97-103 spring 2006 printed in iran introduction today, the advanced urology is based on disease knowledge, the most cost-effective diagnostic methods, the simplest treatment modality with minimal tissue injury, and finally, the most efficient and economical methods for follow-up. in other words, the use of invasive and expensive methods is not popular anymore. diuretic renography plays a special role in the measurement of the kidney function and the location of obstruction in the upper urinary tract system. in iran and many other countries, the received july 2005 accepted september 2005 *corresponding author: imam sadegh hospital, meybod, yazd, iran tel: +98 913 153 0820 e-mail: aorafa2001@yahoo.co.uk technetium tc 99m ethylenedicysteine in renography standard radiopharmaceutical for diuretic renography is technetium tc 99m diethylenetriamine pentaacetic acid (99mtc-dtpa). but, notwithstanding its easy application and widespread clinical use, the background of images (especially in uremic patients and severely hydronephrotic kidneys) is obscured due to high uptake of radioactive substance by the liver and the spleen. consequently, it cannot provide sufficient anatomic resolution for clinical judgment and decision-making in some cases of upper urinary tract obstruction. for this reason, it is inevitable for physicians to use invasive methods, although they usually impose high expenses to patients by accepting the risk of anesthesia and iatrogenic damage to the urinary tract. the most important cause of obscured images on 99mtc-dtpa scans is a tight protein binding of 99mtc-dtpa to plasma albumin and its tendency to be absorbed in the gastrointestinal tract.(1) thus, it is reasonable to use radiopharmaceuticals with weaker protein binding and lower visceral uptake. one of these pharmaceuticals, which has recently been considered, is technetium tc 99m l,lethylenedicysteine (99mtc-ec)(1); however, sufficient clinical evidence of its efficacy is lacking.(1) in this study, we compared the results of diuretic renography using 99mtc-ec and 99mtcdtpa in a group of patients with upper urinary tract obstruction. materials and methods from april 2004 to march 2005, a total of 135 consecutive patients with upper urinary tract obstruction who had referred to hasheminajad hospital were initially evaluated by ultrasonography, intravenous urography, and, where required, retrograde and/or antegrade pyelography. serum creatinine level was measured and urinalysis and urine culture were done. after documentation of obstruction with radiologic findings, 33 patients who had no indications for urgent interventions (eg, acute pyelonephritis, high fever, and sepsis) were randomly selected. all of the patients gave written informed consent. this study was approved by the ethics committee of iran university of medical sciences. diuretic renography was performed by either 99mtc-ec or 99mtc-dtpa while a foley catheter was fixed and furosemide (in patients with normal serum creatinine levels, 20 mg; in those with impaired kidney function, 40 mg) was given 20 minutes after radiopharmaceutical injection (f+20 protocol). after a 2or 3-day interval, the other radiopharmaceutical was used in a second diuretic renography with the same method. bolus injections of 220 mbq to 300 mbq of 99mtc-ec and 450 mbq to 550 mbq of 99mtc-dtpa were administered. both radioisotopes were made by the iranian atomic energy organization. labeling was performed at the nuclear medicine department of the hospital in room temperature (hot lab). the kits were prepared rapidly and all at a same duration. kidney imaging was performed using a single gamma camera in supine position with the nearest possible distance from the body surface. after assuring that the patient is hydrated, dynamic imaging was performed in vascular and excretory phases (within 20 minutes after the radiopharmaceutical injection) and after diuretic administration (at 10, 15, and 20 minutes after the injection). delayed images were obtained up to 4 hours after the procedure, if necessary (in case of radiotracer in the pyelocaliceal system). a serum creatinine level higher than 2 mg/dl was considered as uremic. the examined parameters in this study were as follow: uptake rate of the radiopharmaceutical in the target tissue (kidney) and the background tissue (using count per pixel unit), target-background ratio of uptake, and clearance half-life of radiopharmaceutical from the kidneys. the collected data were analyzed using spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa). paired t test was used to compare the uptake parameters of each scan. continuous variables were demonstrated as means ± standard deviations and a p value less than .05 was considered significant. results thirty-three patients were enrolled in this study and 43 obstructive urinary tract units were evaluated. twenty of the patients were men and 13 were women. mean age of the patients was 54 ± 8 years. mean serum level of creatinine was 4.2 ± 1.2 mg/dl. the serum level of creatinine was 2 mg/dl or less in 12 patients (nonuremic) and greater than 2 mg/dl in 21 (uremic). mean counts of radioisotope per pixel in the target tissue was 85.91 ± 50.87 and 87.50 ± 55.27 in 99mtc-ec and 99mtc-dtpa scans (p = .802), and 98 shahrokh et al in the background tissue, it was 25.76 ± 11.12 and 41.64 ± 23.52, respectively (p = .003). mean counts of radioisotope per pixel in the target tissue were not significantly different between 99mtc-ec and 99mtc-dtpa scans neither in uremic nor in nonuremic patients. but, this rate in the background tissue was significantly lower for 99mtc-ec scan than 99mtc-dtpa scan in both groups of patients (table 1). target-background ratio was higher in 99mtc-ec scan (3.80 ± 2.11 versus 2.48 ± 1.39; p < .001). in both nonuremic and uremic patients, this ratio was significantly higher for 99mtc-ec scan (table 1, figure 1). renal clearance half-life of the radioisotope was shorter for 99mtc-ec scan than 99mtc-dtpa scan (58.15 ± 15.17 minutes versus 78.65 ± 19.99 minutes; p = .033). in nonuremic patients, renal clearance half-life of the radioisotope substance was shorter for 99mtc-ec scan (23 ± 7.17 minutes versus 26.80 ± 9.5 minutes; p = .087), and it was 72.83 ± 28.35 minutes versus 100.25 ± 38.68 minutes in uremic patients (p = .043) (figure 2). discussion technetium tc 99m dtpa is an appropriate radiopharmaceutical for the evaluation of the kidney and glomerular filtration by diuretic renography. of other characteristics of this radiopharmaceutical are low-dose radiation exposure to patient, reasonable cost, and availability. however, it is not suitable for the assessment of the renal cortex. technetium tc 99m ec is a tubular radiopharmaceutical with a n2s2 ligand. it is virtually a diacid derivative of a radiopharmaceutical used in brain scans called 99mtc-l,l-ethylenedicysteine diethylester. l,lethylenedicysteine easily binds to 99mtc in laboratory conditions and room temperature.(2) in this study, we showed that there is no significant difference between the uptake rate of the radioactive substance in the kidney tissue for 99mtc-ec and 99mtc-dtpa scans. in contrast, the mean rate of radioactive substance uptake in the background tissue was considerably less in 99mtcec scan; this could be due to the less protein binding and the weak binding of ec to red blood cells which eventually lead to a faster excretion of the radiopharmaceutical from the kidney (figure 3).(3) mean target-background uptake ratio of radioactive substance was greater for 99mtc-ec scan. this difference causes a higher resolution 99 table 1. counts of radioisotope per pixel in target (the kidney) and background tissues and targetbackground ratio for 99mtc-ec than 99mtc-dtpa scans *counts per pixel 99mtc-ec: technetium tc 99m l,l-ethylenedicysteine, 99mtc-dtpa: technetium tc 99m diethylenetriamine pentaacetic acid 99m tc-ec 99m tc-dtpa p value all patients target tissue * 85.91 ± 50.87 87.50 ± 55.27 .80 background tissue * 25.76 ± 11.12 41.64 ± 23.52 .003 target-background 3.80 ± 2.11 2.48 ± 1.39 < .001 patients with serum creatinine of 2 mg/dl or less target tissue 97.87 ± 53.21 118.19 ± 49.76 .11 background tissue 17.62 ± 10.97 32.62 ± 25.25 .086 target-background 5.97 ± 1.69 4.01 ± 1.68 .019 patients with serum creatinine greater than 2 mg/dl target tissue 81.08 ± 48.06 84.67 ± 58.42 .68 background tissue 29.15 ± 9.67 45.40 ± 22.82 .020 target-background 2.89 ± 1.55 1.85 ± 0.54 .007 technetium tc 99m ethylenedicysteine in renography100 fig. 1. comparison of target-background ratio of 99mtc-ec and 99mtc-dtpa uptakes according to the serum creatinine level 0 1 2 3 4 5 6 7 8 <=1.5 1.6 to 2.5 3.6 to 4.5 4.6 to 5.5 > 5.5 serum creatinine (mg/dl) t a rg e tb a c k g ro u n d r a ti o o f ra d io is o to p e u p ta k e dtpa ec fig. 2. comparison of 99mtc-ec and 99mtc-dtpa renal clearance half-life according to the serum levels of creatinine 0 20 40 60 80 100 120 140 160 <=1.5 1.6 to 2.5 3.6 to 4.5 4.6 to 5.5 > 5.5 serum creatinine (mg/dl) r e n a l c le a ra n c e h a lf -l if e dtpa ec shahrokh et al for imaging with 99mtc-ec compared to 99mtc-dtpa regardless of the serum levels of creatinine. das and colleagues compared 99mtc-ec scan and 99mtc-dtpa scan in a prospective study. in patients with a normal renal function, the results of these two scans were not significantly different, but 99mtc-ec scan had a higher imaging resolution and a faster clearance. in another group of patients who had an increased serum level of creatinine to a maximum of 3 mg/dl, reduction in glomerular filtration had confounded the background of the images and lack of sufficient resolution in images were significant in 99mtc-dtpa scan, whereas in 99mtc-ec scan, the images had a higher resolution, radioactive concentration in background tissue was less, and retention and concentration time of radioactive substance in the kidneys were shorter. they also studied a third group of patients who had a pathologic finding in the kidneys but were not uremic; there were no significant differences between the results of the two scans except for a higher resolution and a faster clearance of 99mtc-ec. their study demonstrated the superiority of imaging with 99mtc-ec pharmaceutical in uremic patients, but it lacked a quantitative measurement of the parameters.(4) in a study by eftekhari and colleagues,(5) 23 patients underwent diuretic renography with 99mtc-ec and 99mtc-dtpa. the mean serum creatinine level of the patients was 4.5 ± 4.11 mg/dl. in their study, mean target-background ratio of radioisotope uptake was greater for 99mtc-ec compared to 99mtc-dtpa. the mean counts of radioisotope per pixel in the background tissue was 3.31 ± 1.7 and 9.78 ± 2.76, respectively. furthermore, renal clearance halflife of the radioactive substance after diuretic administration was shorter for 99mtc-ec. this means that 99mtc-ec is excreted more rapidly compared to 99mtc-dtpa; consequently, the exposure of patients to 99mtc-ec scan is shorter. they also reported that measurements of uptake rate in the upper and lower backgrounds of the kidney are not significantly different, especially for 99mtc-ec scan. when we evaluated the variables categorized according to the serum levels of creatinine, the results were considerable; in both uremic and nonuremic patients, there was no remarkable difference between 99mtc-ec and 99mtc-dtpa in the mean uptake rate in the target tissue (the kidney). this finding shows that patient's creatinine level has similar effects on the absorption of these two radiopharmaceuticals, and what may actually cause a high resolution on imaging in 99mtc-ec scans, especially in uremic patients, is the lower hepatobilliary excretion of this radiopharmaceutical. in 1998, zakko and coworkers performed a study on 2213 people to evaluate the hepatobilliary excretion rate of 99mtc-ec. they reported that only 9 cases of gallbladder visualizations and/or biliary excretion were identified. in no case did biliary excretion affect the interpretation of the renal study. they concluded that hepatic uptake of this pharmaceutical is little; however, their measurement method was not quantitative.(6) although the background uptake rate of 99mtc-ec in both uremic and nonuremic patients was less, this difference was statistically significant only in uremic patients. in other words, the background on 99mtc-dtpa scan can make the image more unclear if the patient's creatinine level is greater than 2 mg/dl. in our patients, renal clearance half-life of 99mtc-ec was significantly shorter after diuretic 101 fig. 3. comparison of 99mtc-ec and 99mtc-dtpa scans in a 67-year-old patient with prostate cancer, 20 minutes after radiopharmaceutical injection (a) and 20 minutes after furosemide injection. the 99mtc-ec scan could rule out ureterovesical junction obstruction 20 minutes after diuretic injection, because more than 50% of the radiopharmaceutical was excreted, but 99mtc-dtpa scan findings showed equivocal obstruction and more invasive methods such as nephrostography was needed to rule out obstruction. technetium tc 99m ethylenedicysteine in renography administration. however, this difference between 99mtc-ec and 99mtc-dtpa was significant in uremic patients but not in nonuremic ones. renal clearance half-life as well as target-background ratio shows that in uremic patients, 99mtc-ec can be excreted from the kidneys more easily, hence creating a better anatomic visualization of the kidney. meanwhile, in uremic patients, the shorter clearance of 99mtc-ec in comparison with 99mtc-dtpa reduces radiation exposure. nowadays, 99mtc-mercaptoacetyltriglycine (99mtc-mag3) and iodine i 125 orthoiodohippurate (125i-oih) are known as favorable radiopharmaceuticals for assessing the obstructive systems, which were not available for us. stoffel and colleagues evaluated the safety and pharmacokinetics of iodine i 125 orthoiodohippurate (125i-oih), 99mtc-mag3, and 99mtc-ec. in their study, the clearance of 99mtc-ec and 99mtc-mag3 averaged 71% and 52% of that of 125i-oih, respectively. volumes of distribution of 125i-oih and 99mtc-ec were almost equal (%20 of body weight). the reasons were lower plasma protein binding (31% versus 50% to 70%), lower erythrocyte binding (%2 versus %5), and lower extrarenal clearance of 99mtc-ec which reduces its volume of distribution. these three factors result in equal volume of distribution for the two radiopharmaceuticals in uremic patients. clearance of 99mtc-ec was 10 ml/min to 15 ml/min, while it was 30 ml/min for 125i-oih. their study also showed that hepatobiliary clearance of 99mtc-ec was a bit less than 125ioih.(2) renal clearance of 99mtc-ec is fast.(1,7) verbruggen and colleagues performed a study on mice, and compared 4 carriers of radioactive substances: oih, dtpa, mag3, and ec. they found that ec has a faster renal clearance and less retention in the kidneys, liver, intestines, and blood than did 99mtc-mag3. they showed that renal excretion of ec is moderately more than mag3, while hepatobiliary absorption of ec is considerably lower. this can explain a more similarity between ec and oih.(1) another study has revealed that lack of maturity in renal glomerular tissue of children usually results in better images by radiopharmaceuticals with tubular excretion (eg, 99mtc-mag3 and 99mtc-ec) comparing with those with glomerular excretion (eg, 99mtc-dtpa).(8) it has been demonstrated that the resolution of 99mtc-ec scan is higher than 99mtc-mag3 scan because of its higher extraction fraction (70% versus 50%). this finding is mainly due to less background and hepatic absorption of 99mtc-ec.(8) taylor and coworkers published an article in 2004 in which they showed that the pharmacokinetic properties of 99mtc-mag3 is far different from 125i-oih and cannot be a substitute for it. thus, they introduced a combination of ec and mag3 named mercaptoacetamide-ethylene-cysteine (maec) for assessment of obstruction in the urinary tract. they showed that 99mtc-maec has a higher renal clearance compared to 99mtcmag3, providing a better image; however, 125ioih was still superior regarding clearance.(9) conclusion our study showed that target-background ratio of radiopharmaceutical uptake rates in diuretic renography can support the higher resolution of 99mtc-ec than 99mtc-dtpa scan. hence, renography with 99mtc-ec can be more contributory in surgeon's decision-making. we also revealed the faster clearance of 99mtc-ec than 99mtc-dtpa. this can help us reduce radiation, especially in children. comparing with the findings of previous studies on 99mtc-mag3 as the current standard radiopharmaceutical in diuretic renography, 99mtc-ec has a higher laboratory stability, significantly lower hepatobiliary absorption, and shorter renal clearance time. in addition, it is produced more easily. we believe that 99mtc-ec can better depict the kidney in comparison with 99mtc-dtpa and can be an alternative to 125i-oih. references 1. verbruggen am, nosco dl, van nerom cg, bormans gm, adriaens pj, de roo mj. technetium-99m-l,lethylenedicysteine: a renal imaging agent. i. labeling and evaluation in animals. j nucl med. 1992 ;33:551-7. 2. stoffel m, jamar f, van nerom c, et al. evaluation of technetium-99m-l,l-ec in renal transplant recipients: a comparative study with technetium-99m-mag3 and iodine-125-oih. j nucl med. 1994;35:1951-8. 3. kabasakal l, turoglu ht, onsel c, et al. clinical comparison of technetium-99m-ec, technetium-99mmag3 and iodine-131-oih in renal disorders. j nucl med. 1995;36:224-8. 4. das bk, misra m, gambhir s, mittal br, banerjee sn. comparative study of 99mtc-cystine and 99mtc-dtpa as renal agents. indian j nucl med. 1992;7:34-9. 5. eftekhari m, vakili a, alavi ms. clinical evaluation of 102 shahrokh et al 99m-tc ethylanedicystein for renal function study and comparison with 99m-tc dtpa. iran j nucl med.1380;3:6-11. 6. zakko s, mrhac l, al-bahri j, al-shamsi h, lootah s, benjamin rj. biliary excretion of tc-99m ec in renal studies. clin nucl med. 1998;23:417-9. 7. kabasakal l, halac m, yapar af, et al. prospective validation of single plasma sample 99mtcethylenedicysteine clearance in adults. j nucl med. 1999;40:429-31. 8. tripathi m, chandrashekar n, phom h, et al. evaluation of dilated upper renal tracts by technetium-99m ethylenedicysteine f+0 diuresis renography in infants and children. ann nucl med. 2004;18:681-7. 9. taylor at, lipowska m, hansen l, malveaux e, marzilli lg. 99mtc-maec complexes: new renal radiopharmaceuticals combining characteristics of (99m)tc-mag3 and (99m)tc-ec. j nucl med. 2004;45:885-91. 103 1442 | kidney sparing surgery for urothelial carcinoma of the pyelocalyceal system: is there a role for open techniques? results from a small series stefan latz, stefan hauser, stefan c. müller, guido fechner purpose: toevaluate individually tailoredopennephron-sparingsurgical techniquesfor urothelialcarcinomaofthepyelocalycealsystem(ucpcs). materials and methods:fourpatientsunderwentnephron-sparingsurgeryforucpcsincluding,openpartialresectionofthepyelonwithperitonealreconstruction,partialnephrectomy,openpartialresectionofthepyelonwithkidneyautotransplantation,combinedopen resection and calicoscopic laser coagulation. results:recurrence-freesurvivalwas24monthswithoutanyimpairmentofkidneyfunction in all patients. conclusion:opennephron-sparingsurgeryforucpcsshouldbetakenintoconsideration forselectedcases. keywords: carcinoma;transitionalcell;urothelium;organsparingtreatments;treatmentoutcome;neoplasmrecurrence;pelvicneoplasms. corresponding author: stefan latz, md department of urology, bonn university, sigmund-freud st. 25, 53127 bonn, germany. tel: +49 228 287 14180 fax: +49 228 287 19150 e-mail: stefan.latz@ukb.unibonn.de received june 2013 accepted january 2014 department of urology, bonn university, sigmund-freud st. 25, 53127 bonn, germany. urological oncology urological oncology 1443vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l introduction radicalnephroureterectomy(rnu)withexcisionofabladdercuffisconsideredasstandardtreat-ment for urothelial carcinoma of the pyelocalycealsystemforbestsurvival.(1)accordingtotheriskof potentialovertreatmentespeciallyinlowgradetumorsless invasive kidney-sparing strategies have been introduced successfully for selected cases.(2) both percutaneous and ureteroscopictreatmentcouldshowefficientcancercontrol butrelevantriskofrecurrenceandprogression.asaconsequence,cutressandcolleaguesconcludedfromasystematicreviewthatendoscopickidneysparingtreatmentshould belimitedtoimperativeindicationsinthecontextofthe patient'soveralllifeexpectancyandcompetingcomorbidity.(3) in contrast, in patients with distal ureteric urothelial carcinomarnuhasbeencompletelyreplacedbysegmental ureteric resection followed by ureteroneocystostomy. hereexcellentresultscomparabletornuareprovidedindependentoftumorstageandgrade.(4)wereportonasmall seriesofselectedpatientswithurothelialcarcinomaofthe pyelocalycealsystemandimperativeindicationsforkidney sparingsurgerywhounderwentopensurgerywithindividuallyadjustedtechniques. materials and methods case 1 a55yearsoldfemalepatientpresentedwithapapillarylesionoftherightrenalpelvisasmetachronousmanifestationof ucpcs.fiveyearsbefore,invasiveurothelialcarcinomaof theleftkidneywasdiagnosedandtreatedwithrnu.preoperativeserumcreatininewas1.0mg/dl.fortechnicalreasons ureteroscopiclasercoagulationwasonlypartiallyfeasible.we performedanopenresectionofthetumorbearingrenalpelvis (classifiedaslowgradeurothelialcarcinomaptainthefinal specimen)includingarightsidedcompleteureterectomyfollowedbyanautotransplantationoftherightkidneyintheleft iliacfossa.urinarydrainagewasachievedbydirectpyelovesicostomy.a14french(f)stentwasplacedinthepyelovesicostomyintraoperativelyandcouldberemovedonthe12th day aftersurgery.clinicalcoursewasuneventful.in2012thereis noevidenceofrecurrence.routinefollow-upisperformedby cystoscopyeasilypassingthepyelovesicostomyintoeachrenalcalyxwithaflexiblecystoscope(figure1). case 2 aftergrosshematuriatransitionalcellcarcinoma(tcc)of theupperurinarytractwasdiagnosedina60yearsoldmale patientwithasinglekidney40yearsafterleftsidednephrectomyfornephrolithiasis.ureteroscopygaveevidenceofa tccwithadiameterof3centimeterslocatedintherenalpelvis.incontrasttoitslargevolume,thetumorwasconsidered mostprobablyassuperficial.preoperativeserumcreatinine was1.3mg/dl.thereforeweperformedopenpartialpyelonicresectionfollowedbyfreeperitonealflapreconstructionsupportedbygreateromentum.aurinaryleakdemanded percutaneousdrainagecombinedwithuretericstentingfor8 weekspostoperatively.pathologistsdiagnosedalowgrade urothelialcarcinomaptainthefinalspecimen.in2012the patientisrecurrence-freewithoutanyfunctionalimpairment ofthekidney(figure2). case 3 the main reason for initial clinical presentation in a 61 yearsoldmanwasgrosshematuriacausedbybladdercancer.completetransurethralresectionwascarriedoutandas ahighgradept1urothelialcarcinomawasfound,asecond resectionwasplannedafter6weeks.surprisingly,multifocal tumorrecurrencewasdetected,includingurethraandupper urinarytractonbothsides(figure3).preoperativecreatinine was1.1mg/dl.thusradicalcystectomyincludingurethrectomywascarriedout.topreventthepatientfromhemodialysistherapy(andonhisstrongdemand),right-sidednephroureterectomycombinedwithleftsidedurethrectomywas performed.multifocalurothelialcarcinomaoftheleftpyelocalycealsystemwastreatedwithcombinedopenresection andintraoperativeopenpyeloscopiclasercoagulation.anilealconduitwassuturedtotheleftrenalpelvisforretrograde pyeloscopicfollow-up(figure4).a14fstentplacedinthe pyeloilealanastomosisintraoperativelywhichwasremoved after12days.postoperativecoursewasuneventful.inthefinalspecimenlowgradeptaurothelialcarcinomaoftherenal pelvisandurethrawerediagnosed,respectively.inthebladderpathologistsfoundalowgradeurothelialcarcinomapt1, lymphnodenegative.afterroutine3-monthlyretrogradepyeloscopyfor2yearsalesionofthelowercalyxsuspicious forcarcinomainsituwasdetected.fortechnicalreasonsa biopsywasnotpossible,butbarbotagecytologygaveevidenceofhighgradetcc.aweeklybacilluscalmette-guerin (bcg)installationviauretericstentwasstarted,followedby open nephron-sparing surgery for ucpcs | latz et al 1444 | bcgmaintenancetherapywhichisnowongoing. case 4 ina60yearsoldwomanlocalizedurothelialcarcinomain theuppercalyxoftherightkidneywasdiagnosed(figure5). duetoascheduledchemotherapyformetastaticbreastcancer,preservationofrenalfunctionwasmandatory.preoperativeserumcreatininewas1.3mg/dl.fortechnicalreasons ureteroscopiclasercoagulationwasimpossible.therefore, anupperpoleresectionofthekidneywasperformed(pathofigure 1. cystoscope passing pyelovesicostomy (edge in foreground) facing the renal pelvis and calyxes after autotransplantation. figure 2. retrograde uretreopyelography after partial resection of the renal pelvis and reconstruction with a peritoneal flap. figure 3. intravenous urography with panurothelial transitional cell carcinoma. figure 4. retrograde contrast filling of ileal conduit connected to the left renal pelvis. urological oncology 1445vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l open nephron-sparing surgery for ucpcs | latz et al logicaldiagnosisinthespecimenwaslowgradeurothelial carcinomapta).besidesaprolongedurinaryextravasation treatedwithuretericstentingfor4weeks,clinicalcoursewas uneventful.in2012therewasnoevidenceofupperurinary tracturothelialcarcinomarecurrencebutalowgradesuperficial bladder cancer was diagnosed and treated with transurethral resection. results inallpatientskidneysparingsurgeryforupperurinarytract tccwastechnicallyfeasibleandcouldbecarriedoutwithoutseverecomplications.nopatientreceivedanyapplicationofintracavitarydrugslikemitomycinintheearlypostoperativeperiod.forkidneysparingstrategyinallpatients intraoperative frozen section with evidence of superficial lowgradetccwaspresent.lowgradesuperficialtccwas confirmedinallpatientslaterinembeddedspecimen.mean recurrence-freefollow-upwas24months(range15-60).in3 single-kidneypatientsmeanserumcreatininevaluewas1.2 mg/dl(range0.9-1.4)oneyearpostoperatively.noobstructionsoftheupperurinarytractorsymptomaticurinarytract infectionswerereported. discussion endoscopictreatmentofupperurinarytracttcchasdisadvantages,especiallyinlowercalyxtumorstechnicallimitations(e.g.maximumendoscopebendingwithlaserprobe) aremet.follow-upisdifficultassensitivityofbothintravenousurographyandcomputedtomographyislowinsmall lesions.(5)incaseofsuspiciousresultsofimaging,ureteral instrumentationlikediagnosticpyeloscopyisnecessary.our mainaimintwopatientswithsinglekidneywastocreate aneasyaccesstotheupperurinarytractbothtofollow-up andforoccasionalendoscopictreatmentincaseoftumorrecurrence.inthesepatientstheaimhasbeenreachedbyautotransplantationwithpyelovesicostomyoranastomosisof anilealconduittotherenalpelvis,respectively.asamajor advantage,duringthefollow-upperiod,easyendoscopicaccesstotherenalpelvisorcalyceswaspossibleasanoutpatient procedure without general anesthesia. discussing oncologicalresultsofnephron-sparingsurgery,theideaoftumor cellseedinghastobetakenintoaccount.intransurethralresection,thishistorical(andtheoretical)hypothesisisaccused fortumorrecurrenceandmaybetransferredtoendoscopic ablationofucpcs.(6)inopenorlaparoscopicsurgeryfor urothelialcarcinomatumorcellseedingisafrequentlydiscussedissue.althoughworldwidesurgeonsareafraidofthis phenomenon,thereisonlylittleevidence.availabledataare restrictedtocasehistoriesdescribingextravesicaltumorimplantationorport-sitemetastasisaftersurgeryforurothelial carcinoma.(7-9)thereforetheclinicalrelevanceofthe`seeding-theory`remainsunclear.althoughourstudyislimited bythesmallnumberofpatientswewouldliketoencourage urologicalsurgeonsconsideringopensurgeryfortccofthe upper urinary tract in selected cases. conclusion transitionalcellcarcinomaoftheupperurinarytractisarare entity,butifdiagnosed,usuallytreatedwithnephroureterectomy.inselectedcasesnephronsparingsurgeryispossible. all4patientsreported,underwentvarioustailoredopenoperationswithexcellentcancercontrolandfunctionalresults keepingadequaterenalfunction. conflict of interest none declared. figure 5. transitional cell carcinoma of the right upper renal calyx in magnetic resonance imaging. 1446 | references 1. margulis v, shariat sf, matin sf, et al. outcomes of radical nephroureterectomy: a series from the upper tract urothelial carcinoma collaboration. cancer. 2009;115:1224-33. 2. bader mj, sroka r, gratzke c, et al. laser therapy for upper urinary tract transitional cell carcinoma: indications and management. eur urol. 2009;56:65-71. 3. cutress ml, stewart gd, zakikhani p, phipps s, thomas bg, tolley da. ureteroscopic and percutaneous management of upper tract urothelial carcinoma (utuc): systematic review. bju int. 2012;110:614-28. 4. jeldres c, lughezzani g, sun m, et al. segmental ureterectomy can safely be performed in patients with transitional cell carcinoma of the ureter. j urol. 2010;183:1324-9. 5. caoili em, cohan rh, inampudi p, et al. mdct urography of upper tract urothelial neoplasms. ajr am j roentgenol. 2005;184:187381. 6. weldon te, soloway ms. susceptibility of urothelium to neoplastic cellular implantation. urology. 1975;5:824-7. 7. herawi m, leppert jt, thomas gv, de kernion jb, epstein ji. implants of noninvasive papillary urothelial carcinoma in peritoneum and ileocolonic neobladder: support for "seed and soil" hypothesis of bladder recurrence. urology. 2006;67:746-50. 8. segawa n, azuma h, takahara k, et al. [port-site metastasis after retroperitoneoscopy-assisted nephroureterectomy and cystectomy for bladder cancer invading the ureter: a case report]. hinyokika kiyo. 2008;54:13-6. 9. via kj, burns km, lamm dl. tumor implantation: a rare but potentially preventable cause of death in cystectomy patients. can j urol. 2010;17:5216-8. urological oncology letter to editor i read with great interest the recently published article entitled “ureteroscopy: the first line treatment for distal lo-cated ureteral stones smaller than 10 mm” by kirac m et al.(1) this article highlights the superiority of ureteroscopy (urs) over observation, and medical expulsion therapy (met) with tamsulosin in managing distal ureteric stone smaller than 10 mm. in my opinion this is inappropriate comparison as urs is in the group of minimally invasive urology procedures, whereas the latter two are in non-invasive treatment method group. thus, the complications of these two groups of treatment option (minimally invasive vs. non-invasive) will be obviously different. all the possible complications should also be considered before deciding which is the best choice of treatment for any patient. on top of that, cost effective and availability of the services should also be considered. the most common comparison in many of the published literatures was between urs and extracorporeal shock wave lithotripsy (swl). these two procedures have almost equal risk of complication as well as cost.(2,3) besides that, in this paper there was no clear definition for stone expulsion time in urs group. based on the presented result, the expulsion time was obviously short (1.95 ± 2.2 days). most likely the authors calculated stone expulsion time in urs group starting from post-operative period onwards. whereas for the other two groups the expulsion time was calculated starting from the stone first diagnosed (in which usually medication started). in my opinion, similar starting point should be used to give better comparison of stone expulsion time between all 3 groups. thus, the stone expulsive time in urs group will be calculated starting from stone being diagnosed until post-operative imaging shows stone free. this will include pre-operative waiting period. in busy center with high work load the operation waiting list may up to a few months. thus, the finding of this paper not applicable for all urology center. the urs with simultaneous stone extraction or stone fragmentation was being an efficacious single session treatment. however it comes with complication and some limitation. thus, the final therapeutic decision should be individualized in each patient. mohd nazli kamarulzaman department of surgery, kulliyyah of medicine, international islamic university malaysia (iium) kuantan, malaysia. references 1. kiraç m, atkin ms, biri h, deniz n. “ureteroscopy: the first line treatment for distal located ureteral stones smaller than 10 mm. urol j. 2014;10:1028-34. 2. lingeman je1, mcateer ja, gnessin e, evan ap. shockwave lithotripsy: advance in technology and tech nique. nat rev urol. 2009;6:660-70. 3. papadoukakis s, stolzenburg ju, truss mc. treatment strategies of ureteral stones. eur urol. 2006:184–190. eau–ebu update series 4. letter to editor 1914 i took your letter about my published article entitled “ureteroscopy: the first-line treatment for distallylocated ureteral stones smaller than 10 mm”. firstly, thanks for your worthy opinion and criticisms about our article. according to the literature, there are different treatment options including, observation, medical expulsive therapy (met), ureteroscopy (urs) and extracorporeal shock wave lithotripsy (swl) in distally located ureteral stones.(1,2) in our study, it was investigated which treatment options were effective for distal ureteral stones. you may think that the comparison of an invasive method (urs) and a non-invasive method (met or observation) may be unreasonable. but this comparison is reasonable both theoretically and statistically. on the other hand, currently, urs has become a widely used technique and very low complication rate for treatment of distal ureteral stones. in my opinion, now, urs can be considered as a non-invasive technique. according to european association of urology (eau) guidelines, if there is indication of active stone removal, urs is the first choice for treatment of distal ureteral stones.(3) in our study, the stone expulsion time was calculated since the time of urs. yes, you are right. it must be calculated since the stone diagnosis. we did not include the patients who has long time waiting period before the surgery in the study. we had to specify this situation in our paper but we did not. recently, in most urology centers, urs has been selected as the first choice for the treatment distal ureteral stones because of technical and instrumental development. this study introduces our clinical results. our results must be exactly confirmed by other clinical results. mustafa kirac endourology department of koru hospital, ankara, turkey. references 1. perez castro e, osther pj, jinga v, et al. differences in ureteroscopic stone treatment and outcomes for distal, mid-, proximal, or multiple ureteral locations: the clinical research office of the endourological society ureteroscopy global study. eur urol. 2014;66:102-9. 2. yencilek f, sarica k, erturhan s, yagci f, erbagci a treatment of ureteral calculi with semirigid ureteros copy: where should we stop? urol int. 2010;84:260-4. 3. türk c, knoll t, petrik a, sarica k, seitz c, straub m. guidelines on urolithiasis, european association of urology. 2011. available at http://www.uroweb.org/guidelines/online-guidelines. response by author vol 11. no 05 sept-oct 2014 1915 pediatric urology 96 urology journal vol 6 no 2 spring 2009 vesicostomy as a protector of upper urinary tract in long-term follow-up alessandro prudente, leonardo oliveira reis, rodrigo de paula frança, márcio miranda, carlos arturo levi d’ancona introduction: the aim of this study was to analyze the results of vesicostomy in children as a protector of the upper urinary tract and assess the adjustments taken by the caregivers. materials and methods: twenty-one children who had undergone vesicostomy with the blocksom technique were evaluated. their mean age was 3.7 years (range, < 1 to 10 years). the evaluation consisted of kidney function tests, cystography, and analysis of complications. twenty parents or caregivers were interviewed about their attitudes towards vesicostomy and its outcomes. results: the main causes of the vesical dysfunction were posterior urethral valve in 7 (33.3%) and myelomeningocele in 5 patients (23.8%). ten children (58.8%) showed improvement and 7 (41,2%) showed cure. hydronephrosis observed in 17 children was alleviated or cured following the procedure. kidney function, tested by creatinine clearance calculation, remained stable or improved in 20 patients (95.2%). episodes of urinary tract infection and vesicoureteral reflux lowered in 8 of 21 (38.1%) and 10 of 14 patients (71.4%), respectively. subjective evaluation of 20 cases showed that 18 children (90.0%) remained dry during the day and 14 caregivers/parents (70.0%) felt they had acquired the skills necessary to handle a patient with vesicostomy. the mean global rate of satisfaction of the results of the surgery ranging from 0 (worst result) to 10 (best result) was 8.7. conclusion: vesicostomy is a simple surgery that protects the upper urinary tract, decreases hydronephrosis, and improves kidney function. there was adequate adjustment to vesicostomy and a positive global evaluation as reported by the parents and caregivers. urol j. 2009;6:96-100. www.uj.unrc.ir keywords: cystostomy, overactive detrusor, neurogenic urinary bladder, patient satisfaction, child, caregiver department of urology, state university of campinas, são paulo, brazil corresponding author: leonardo oliveira reis, md r votorantim, 51, apt 43, campinas-sp, brazil 13073-090 tel: + 55 19 3521 7481 fax: + 55 19 3521 7481 e-mail: reisleo@unicamp.br received september 2008 accepted january 2009 introduction voiding dysfunction in childhood, either neurogenic or functional, represents a great challenge for the physician. among the patients with neurological disease, over 90% will demand regular urological follow-up and between 20% and 30% may need associated operations such as bladder augmentation.(1) once voiding dysfunction is detected, the priorities are preservation of the upper urinary tract, promotion of continence, and reducing episodes of urinary tract infection (uti).(2) in order to achieve these, clinical measures are most frequently utilized. these include physiotherapy, clean intermittent catheterization (cic), and anticholinergic vesicostomy as a protector of upper urinary tract—prudente et al urology journal vol 6 no 2 spring 2009 97 drugs. surgery should be considered if clinical treatment has failed.(3) considering the infancy as a critical phase in kidney development with great susceptibility to renal scars and loss of kidney function, permanent diversion has been the first surgical option to permit renal maturing.(3) the use of vesicostomy in children was proposed by michie and colleagues and duckett in 1960s.(4,5) queipo zaragoza and associates studied 43 children with neurogenic bladder and vesicostomy.(6) they observed that 100% and 90% presented improvement in hydronephrosis and kidney function, respectively. on the other hand, 20% of the patients had urinary infection, calculus, or stenosis during follow-up. in another study, alexander and kay described children with cloacal anomalies submitted to vesicostomy after primary reconstruction. they observed that vesicostomy was technically simple to perform, easily reversed, and effectively preventive from urinary sepsis.(7) the upper urinary tract protection by vesicostomy and the caregiver’s opinions towards the procedure and its repercussions on the patient’s quality of life have been little explored in the current literature. this study’s purpose was to verify the results of vesicostomy on the upper urinary tract in patients affected by voiding dysfunctions as well as the caregiver’s lifestyle adjustments. materials and methods the charts of 21 children who had undergone vesicostomy between 1992 and 2007 were analyzed. vesicostomy had been done according to the technique proposed by blocksom.(8) the indication for applying this procedure was failure in clinical treatment defined by worsening hydronephrosis, recurrent uti, stable high-degree vesicoureteral reflux (vur), worsening kidney function, and noncompliance with cic and anticholinergics. in these situations, we always perform lower urinary tract diversion. if decrease in kidney function or recurrent uti occurs after the procedure, the upper tract diversion is considered. although those patients presenting with posterior urethral valve (puv) were submitted to previous valve ablation, bladder impairment was not avoided. ultrasonography, voiding cystourethrography, static renal scintillography, blood tests, and urine cultures were performed every 6 months during the follow-up period. reduction in grade of hydronephrosis or vur was considered as improvement. on the other hand, absence of disorders on evaluation was considered as cure. the antibiotic prophylaxis was discontinued in the absence of uti and vur. the creatinine clearance value was calculated by the following formula: k × h/c, where k is a constant (k = .55 for child, 0.45 for infant, and 0.7 for adolescent), h is height in centimeters, and c is serum creatinine concentration in mg/dl.(9) caregivers or their parents who were involved in the care of their children were interviewed at the last follow-up visit (before closure of the vesicostomy, if applicable) to complete a questionnaire for self-evaluation of the surgical procedure at the last follow-up (appendix). in one question we asked for a global score ranging from 0 (worst) to 10 (best) based on lickert scale. the questionnaires were originally designed by the investigators in portuguese. results twenty-one children with a mean age of 3.7 years (range, < 1 to 10 years) were evaluated. the most frequent diagnoses were puv in 7 (33.3%) and myelomeningocele in 5 patients (23.9%; table 1). before vesicostomy, 3 patients (14.3%) showed decrease in kidney function due to inadequate neobladder function after the correction of bladder extrophy. seventeen children (81.0%) had hydronephrosis on ultrasonography before the procedure. the mean follow-up was 6.9 years (range, 1 to 15 years), with only two children with less than 2-year follow-up. diagnosis patients (%) posterior urethral valve 7 (33.3) myelomeningocele 5 (23.9) vesical extrophy 3 (14.2) idiopathic hyperactive bladder 3 (14.2) sacral agenesis 1 (4.8) prune belly syndrome 1 (4.8) imperforated anus 1 (4.8) table 1. diagnoses in patients with voiding dysfunction vesicostomy as a protector of upper urinary tract—prudente et al 98 urology journal vol 6 no 2 spring 2009 ten children (58.8%) showed improvement and 7 (41,2%) showed cure. there was no worsened case. static renal scintillography with dimercaptosuccinic acid scan registered a kidney function deficit prior to the operation in 9 patients (42.9%), while there was no postoperative impairment in 20 children (95.2%). creatinine clearance was less than 90 ml/min/1.72 m2 in all the patients before the procedure, and it improved in 11 (52.4%) reaching more than 90ml/min/1.72m2. therefore, creatinine clearance stabilized in 9 (42.9%) and worsened in 1 (4.8%). urinary tract infection prior to surgery was frequent (more than 1 time per year) in all the children. after vesicostomy, 8 children (38.1%) demonstrated a decrease of this morbidity without suppressive antibiotic therapy. the others needed continuous antibiotic therapy because of more than 1 uti episodes per year. fourteen patients (66.7%) presented vur before the operation (10 bilateral and 4 unilateral), all with grades 3 or 4. complete resolution (cure) was observed in 4 unilateral cases and improvement to grades 1 or 2 in 6 bilateral cases. we observed no impairment in 4 bilateral cases which maintained grade 3 or 4. the complications of the surgery were stenosis in 8 patients (38.1%), dermatitis in 5 (23.8%), and mucosal prolapse in 6 (28.6%). among children with prolapse, 5 presented dermatitis. on the other hand, 3 patients with stenosis presented prolapse after surgical correction. we did not observe bladder or upper urinary tract calculus. all complications occurred around 6 months after the operation (range, 4 to 10 months). a total of 20 caregivers answered the survey at the last follow-up visit or the visit before closure of vesicostomy. they classified 18 children (90.0%) as dry (when the skin around the vesicostomy was parched and only the pad was continuously wet). fourteen (70.0%) caregivers considered vesicostomy to be manageable (table 2). when asked if the caregivers would like to close vesicostomy even if catheterization would be necessary, 12 (60.0%) answered “no” and 8 (40.0%) answered “yes.” the interviewees gave a mean global score of 8.7 (range, 3 to 10) to vesicostomy. six patients (28.6%) had their vesicostomies closed after a mean period of 2.4 ± 1.3 years. among these, 3 (14.2%) experienced augmentation enterocystoplasty and 1 required ureterovesical re-implant at the same time as vesicostomy closure. fifteen patients (71.4%) preserved their vesicostomies until the end of this study. the reasons for this were caregiver refusal in 5 (23.8%) or children being under school age in 10 cases (47.6%). discussion vesicostomy is considered a temporary urinary diversion. some authors suggested it be a permanent diversion, mainly in patients who refuse cic or those who choose an incontinent diversion.(10) while most of the studies only evaluate patients with neurological voiding dysfunctions, we evaluated a larger number of children that had urinary tract malformations such as puv.(11) this different sampling approach may have caused surfacing of infection and vur in these patients which in turn may justify the lower resolution and high complication rate. in spite of the high complication rates, most of these are minor and present modest impact on the quality of life. following vesicostomy, an objective improvement of hydronephrosis ranging from 85% to 100% and stabilization of kidney function, evaluated by scintillography, of around 88% have survey question main answer frequency (%) family income 1 to 5 minimum wage 18 (90) children’s level of education first-degree incomplete 14 (70) caregivers’ level of education first-degree incomplete 14 (70) social interpersonal relation with other children “get along with children of same age” 16 (80) state of the child during the majority of the day dry 18 (90) description of the work required “difficult, but i am used to do it” 14 (70) table 2. survey results applied to 20 children’s caregivers vesicostomy as a protector of upper urinary tract—prudente et al urology journal vol 6 no 2 spring 2009 99 been detected.(3,10-12) these were reproduced in our study by improving rates of 81% and 95%, respectively. however, reduction in frequency of utis and improvement of vur that were shown in this study were lower than the ones demonstrated up to this point (38% and 58%, respectively, versus 85% and 73%).(11) in a study comparing 2 groups of patients operated on in childhood and adolescence using blocksom technique with 5-year and 13-year follow-up periods, both groups presented a similar percentage of complications ranging between 15% and 25%.(10) in the present study, using the same surgical technique, the mean age of the patients at the time of surgery was 3.7 years with a scheduled follow-up not exceeding 15 years following the surgery; the percentage of complications was found to be between 23% and 38%. the complications described to date occurred in 20% to 35% of the cases and the most frequent ones are dermatitis, mucosal prolapse, and vesicostomy stenosis.(10,12) it is noteworthy that there were no cases of urinary tract lithiasis in our study. no observation of calculus formation may be due to the short length of follow-up. in the case of dermatitis, there is great variation in the incidence mainly because of difficulty in classifying its intensity. the blocksom technique emphasizes on the importance of dissecting vesical cupula after removing the urachus in tailoring the vesicostomy and lowering chances of postsurgical prolapse.(8) there is no study comparing complication rates between different techniques. by the way, all these complications have relatively simple solutions.(11) with regard to dermatitis, it is important to inform the patients of proper care of the stomas, and a topical treatment is usually sufficient. in the case of stenosis, dilations may be performed and a new surgery should be done only if all others fail. finally, the prolapse constitutes a technical problem and probably will require a surgical revision of the procedure. during the bibliographical review that supported this study, we were unable to identify any other study that had given credit nor evaluated caregivers’ opinions towards the procedure and its repercussions on the patients’ quality of life. even though we used a survey not yet generally accepted by the scientific community, we were able to observe the good receptivity of the method by caregivers once a dry state was achieved throughout the day. conclusion we conclude that vesicostomy is a simple urinary diversion, showing encouraging results towards safeguard of kidney function. furthermore, the procedure has received rave reviews from the caregivers, and therefore, it has become a viable choice for children with neurological or other voiding dysfunctions or those that do not respond to conservative treatment. conflict of interest none declared. appendix interview questionnaire of vesicostomy survey family income: (a) 1 minimum wage (b) 1 to 5 minimum wage (c) 6 to 10 minimum wage (d) 10 minimum wage level of education patient: (a) literate/illiterate (b) first degree complete/no formal education (c) second degree complete/incomplete (d) third degree complete/incomplete caregivers: (a) literate/illiterate (b) first degree complete/no formal education (c) second degree complete/incomplete (d) third degree complete/incomplete body weight? height? vesicostomy as a protector of upper urinary tract—prudente et al 100 urology journal vol 6 no 2 spring 2009 how is the patient’s social interaction with other children? (a) get along with children of same age (b) get along with older children (c) get along with younger children (d) unable to get along with other children how is the child in the majority of day? (a) dry, without signs of leaking outside the container (b) wet, with signs of leaking outside the container how do you (caregiver) evaluate taking care of a child with a vesicostomy? (a) daunting (b) difficult, but i am used to it and it does not mess up my daily activities (c) not difficult would you like the child to switch from vesicostomy to clean intermittent catheterization by closing the former? (a) yes (b) no (c) has already closed it what score would you give to this surgery (select between 0 and 10)? would you like to close vesicostomy? (a) yes (b) no references 1. agarwal sk, khoury ae, abramson rp, churchill bm, argiropoulos g, mclorie ga. outcome analysis of vesicoureteral reflux in children with myelodysplasia. j urol. 1997;157:980-2. 2. smith ed. urinary prognosis in spina bifida. j urol. 1972;108:815-7. 3. lee mw, greenfield sp. intractable high-pressure bladder in female infants with spina bifida: clinical characteristics and use of vesicostomy. urology. 2005;65:568-71. 4. michie aj, borns p, ames md. improvement following tubeless suprapubic cystostomy of myelomeningocele patients with hydronephrosis and recurrent acute pyelonephritis. j pediatr surg. 1966;1:347-52. 5. duckett jw jr. cutaneous vesicostomy in childhood. the blocksom technique. urol clin north am. 1974;1:485-95. 6. queipo zaragozá ja, domínguez hinarejos c, serrano durbá a, estornell moragues f, martínez verduch m, garcía ibarra f. [vesicostomy in children. our experience with 43 patients]. actas urol esp. 2003;27:33-8. spanish. 7. alexander f, kay r. cloacal anomalies: role of vesicostomy. j pediatr surg. 1994;29:74-6. 8. blocksom bh jr. bladder pouch for prolonged tubeless cystostomy. j urol. 1957;78:398-401. 9. white ca, huang d, akbari a, garland j, knoll ga. performance of creatinine-based estimates of gfr in kidney transplant recipients: a systematic review. am j kidney dis. 2008;51:1005-15. 10. hutcheson jc, cooper cs, canning da, zderic sa, snyder hm 3rd. the use of vesicostomy as permanent urinary diversion in the child with myelomeningocele. j urol. 2001;166:2351-3. 11. morrisroe sn, o’connor rc, nanigian dk, kurzrock ea, stone ar. vesicostomy revisited: the best treatment for the hostile bladder in myelodysplastic children? bju int. 2005;96:397-400. 12. lee mw, greenfield sp. intractable high-pressure bladder in female infants with spina bifida: clinical characteristics and use of vesicostomy. urology. 2005;65:568-71. urological oncology effects of previous or synchronous non-muscle invasive bladder cancer on clinical results after radical nephroureterectomy for upper tract urothelial carcinoma: a multi-institutional study bup wan kim,1 yun-sok ha,1 jun nyung lee,1 hyun tae kim,1 tae-hwan kim,1 jung keun lee,2 seok-soo byun,2 young deuk choi,3 ho won kang,4 seok-joong yun,4 wun-jae kim,4 young suk kwon,5 tae gyun kwon1* purpose: to evaluate the effects of the presence of previous or synchronous non-muscle invasive bladder cancer (nmibc) on the oncologic outcomes of radical nephroureterectomy in patients with upper tract urothelial carcinoma (utuc). materials and methods: in total, 505 patients with utuc were enrolled from four different institutions. the clinicopathologic parameters of patients with and without previous or synchronous nmibc were compared, and kaplan-meier estimates and multivariate cox regression analyses were performed. results: the median follow-up period was 38.4 months. in all, 408 patients had primary utuc, 45 (8.9%) had a history of nmibc, 59 (11.7%) had concomitant bladder cancer, and seven (1.4%) had experienced both. tumors in patients with associated nmibc were more commonly multifocal (p = .001) and associated with surgical margin positivity (p = .001). kaplan-meier estimates revealed that previous or synchronous nmibc was significantly associated with bladder recurrence (p < .001) and locoregional recurrence/ distant metastasis (p = .008). a multivariate cox regression model identified previous or synchronous nmibc as an independent predictor of bladder recurrence (p < .001). however, the presence of previous or synchronous nmibc was not a prognostic indicator of locoregional recurrence/distant metastasis. conclusion: in patients with utuc, previous or synchronous nmibc was significantly associated with an increased risk of cancer recurrences in the bladder after radical nephroureterectomy. the present findings suggest that a close monitoring should be required for the patients with previous or concomitant nmibc. keywords: neoplasm recurrence; nephrectomy; urinary bladder neoplasms; treatment outcome; urologic surgical procedures; urothelium; pathology; urologic neoplasms. introduction both synchronous and metachronous multifocal de-velopment and frequent recurrences are common in bladder cancer (bc).(1,2) in fact, it is estimated that upper tract urothelial carcinomas (utucs) develop in 2-4% of patients with bc.(3-5) conversely, the proportion of detected bc in patients with utuc varies from 15 to 75%.(6-8) while experts attribute these phenomena to defect cancerization and clonal expansion,(9,10) no consensus has been reached in understanding the precise mechanisms underlying the proposed theories. (11-13) it has been reported that the chances of a recurrent urothelial carcinoma in normal-appearing urothelium with similar oncologic characteristics are about 50-80% after the initial resection of non-muscle-invasive bc (nmibc) tumors.(1) although several factors may play a role in this adverse prognosis in utuc patients,(6,14,15) 1 department of urology, school of medicine, kyungpook national university, daegu, korea. 2 department of urology, seoul national university, bundang hospital, seongnam, korea. 3 department of urology and urological science institute, college of medicine, yonsei university, seoul, korea. 4 department of urology, college of medicine, chungbuk national university, cheongju, chungbuk, korea. 5 section of urologic oncology, rutgers cancer institute of new jersey and rutgers robert wood johnson medical school, new brunswick, nj, usa. *correspondence: department of urology, chilgok kyungpook national university hospital, 807 hoguk-ro, buk-gu, daegu 702-210, korea. tel: +82 53 2003027 & fax: +82 53 3213027. e-mail: tgkwon@knu.ac.kr. received november 2014 & accepted july 2015 few studies have reported the effect of previous nmibc on cancer recurrence and overall survival.(16) here, we investigated whether previous or synchronous nmibc were associated with poor oncologic outcomes for utuc patients following radical nephroureterectomy (rnu). materials and methods in total 505 utuc patients who underwent either open (n = 183) or laparoscopic rnu (n = 322) at four academic institutions in korea between march 2001 and december 2013 were included in our study and were retrospectively analyzed. patients with previous or concurrent muscle-invasive bc (mibc), those who received neoadjuvant chemotherapy, or those with the evidence of distant metastasis at the time of diagnosis were excluded in order to minimize the confounding errors in assessing survival estimates. after rnu, bladder urological oncology 2233 figure 1. effect of previous or concomitant non-muscle-invasive bladder cancer on bladder recurrence (a) and locoregional recurrence/distant metastasis (b) after radical nephroureterectomy. abbreviations: utuc, upper tract urothelial carcinoma; bc, bladder cancer. figure 2. effect of previous or concomitant non-muscle-invasive bladder cancer on cancer-specific survival (a) and overall survival (b) after radical nephroureterectomy. abbreviations: utuc, upper tract urothelial carcinoma; bc, bladder cancer. table 1. clinicopathological characteristics of patients with previous or synchronous nmibc and those without. parameters utuc without previous utuc with previous or p value synchronous nmibc (n = 408) synchronous nmibc (n = 97) age, (mean ± sd), y 66.2 ± 10.5 66.6 ± 10.4 .719 bmi, kg/m² 23.7 ± 3.1 24.0 ± 2.9 .364 gender, no. (%) .224 male 276 (67.6) 72 (74.2) female 132 (32.4) 25 (25.8) smoking status, no. (%) .893 no 262 (64.3) 63 (65.3) yes 146 (35.7) 34 (34.7) laterality, no. (%) 1.000 left 217 (53.2) 51 (52.6) right 191 (46.8) 46 (47.4) tumor size, (mean ± sd), mm 37.9 ± 22.7 41.8 ± 36.1 .316 tumor location, no. (%) <.001 renal pelvis 161 (39.5) 24 (24.7) ureter 206 (50.5) 46 (47.4) both 41 (10.0) 27 (27.8) bladder cuff resection, no. (%) .485 no 46 (11.3) 14 (14.4) yes 362 (88.7) 83 (85.6) multifocality, no. (%) .001 no 298 (72.5) 53 (54.6) yes 112 (27.5) 44 (45.4) pathologic t stage, no. (%) .146 ta, cis, t1–2 232 (56.9) 63 (64.9) t3−4 176 (43.1) 34 (35.1) pathologic n stage, no. (%) .748 nx 177 (43.4) 41 (42.3) n0 207 (50.7) 52 (53.6) n+ 24 (5.9) 4 (4.1) grade, no. (%) .374 low 141 (34.6) 39 (40.2) high 267 (65.4) 58 (59.8) concomitant cis, no. (%) .148 no 383 (93.8) 86 (88.9) yes 25 (6.2) 11 (11.1) lymphovascular invasion, no. (%) .468 no 335 (82.1) 76 (78.4) yes 73 (17.9) 21 (21.6) margin status, no. (%) .001 negative 394 (96.6) 85 (87.6) positive 14 (3.4) 12 (12.4) abbreviations: nmibc, non-muscle-invasive bladder cancer; utuc, upper tract urothelial carcinoma; cis, carcinoma in situ; sd, standard deviation; bmi, body mass index. vol 12 no 04 july-august 2015 2234 upper tract urothelial carcinoma after non-muscle invasive bladder cancer-kim et al. cuff resection was performed using standard procedures (i.e., an extravesical approach via a gibson incision) stipulated by each center. lymph node dissection was indicated if lymphadenopathy was suspected upon preoperative imaging or observed during surgery. a majority of patients with non-organ-confined disease received cisplatin-based adjuvant chemotherapy. tumors were staged according to the american joint committee on cancer (6th edition) staging system.(17) tumor grades were assessed according to the 1998 world health organization (who) classification system.(18) tumor multifocality was defined as the synchronous presence of two or more pathologically confirmed tumors in any location (renal pelvis or ureter).(19) follow-up regimen included cystoscopy, urine cytology, chest x-ray, and computed tomography (ct) of the chest. cystoscopy and urine cytology were performed at 3, 6 and 12 months post-surgery, and yearly thereafter. imaging analyses (chest x-ray and ct of chest) were performed at 3, 6 and 12 months after rnu, and then at every 6 months from 1 to 5 years post-surgery. scans were performed annually thereafter. elective bone scans, chest ct, or positron emission tomography (pet) scans were performed when clinically indicated. the median follow-up period was 38.4 months (interquartile range, 15.6–56.5). one hundred and nine patients (21.6%) received adjuvant systemic chemotherapy and 287 patients (56.8%) underwent lymph node dissection during rnu. four hundred-and-eight patients had primary utuc (no history of previous nmibc or concomitant nmibc), 45 (8.9%) had previous nmibc, 59 (11.7%) had concomitant nmibc, and seven (1.4%) had experienced both. thus, 97 patients (19.2%) had previous or concomitant nmibc. the demographic and clinical characteristics of the 505 patients are listed in table 1. utuc without nmibc was more likely to be associated with pathologic stage t3 or greater; however, the difference was not statistically significant. there were no significant differences between the two groups in terms of n stage, grade, lymphovascular invasion, and concomitant carcinoma in situ (cis). tumors with associated nmibc were more figure 3. bladder recurrence free survival between open and laparoscopic radical nephroureterectomy. abbreviations: op, operative, rnu, radical nephroureterectomy. parameters univariate analysis multivariate analysis hr (95%, ci) p value hr (95%, ci) p value age 1.000 (0.986−1.014) .962 1.003 (0.984−1.023) .748 gender (male vs. female) 1.043 (0.757−1.436) .797 1.199 (0.748−1.922) .451 smoking (no vs. yes) 0.771 (0.534−1.113) .771 0.878 (0.547−1.407) .587 tumor size 1.002 (0.996−1.008) .533 1.003 (0.996−1.011) .360 tumor location renal pelvis 1 ---- 1 ----ureter 1.599 (1.131−2.262) .008 1.088 (0.669−1.767) .735 both 2.017 (1.272−3.201) .003 0.804 (0.354−1.830) .603 bladder cuff resection (no vs. yes) 1.498 (0.867−2.588) .147 1.535 (0.722−3.264) .266 multifocality (no vs. yes) 1.071 (0.779−1.472) .675 1.318 (0.657−2.646) .437 pathologic t stage (ta, cis, t1–2 vs. t3–4) 1.035 (0.759−1.410) .830 1.350 (0.836−2.181) .219 pathologic n stage (nx, n0 vs. n+) 1.190 (0.607−2.332) .612 1.670 (0.714−3.906) .237 grade (low vs. high) 1.274 (0.898−1.807) .175 0.736 (0.435−1.245) .253 concomitant cis (no vs. yes) 1.280 (0.709−2.312) .413 0.866 (0.441−1.701) .676 lymphovascular invasion (no vs. yes) 1.027 (0.693−1.523) .895 0.901 (0.530−1.532) .700 margin status (no vs. yes) 1.281 (0.676−2.428) .448 0.586 (0.228−1.506) .267 previous or synchronous nmibc (no vs. yes) 2.440 (1.768−3.367) <.001 2.845 (1.811−4.470) <.001 table 2. univariate and multivariate cox regression analyses to identify predictors of bladder recurrence in patients with utuc. abbreviations: utuc, upper tract urothelial carcinoma; hr, hazard ratio; ci, confidence interval; cis, carcinoma in situ; nmibbc, non-muscle-invasive bladder cancer. urological oncology 2235 upper tract urothelial carcinoma after non-muscle invasive bladder cancer-kim et al. often multifocal (p = .001), related to a positive surgical margin (p = .001), and localized to both the ureter and renal pelvis (p < .001). to evaluate the outcomes, the enrolled utuc were allocated into two groups: those with previous or synchronous nmibc, and those without. the student’s t test and the chi-square test were used to examine the association between variables between the two groups. bladder recurrence-free survival, locoregional recurrence/distant metastasis-free survival, cancer-specific survival, and overall survival after rnu were estimated using the kaplan-meier method and the log rank test. multivariate cox regression analyses were performed to identify independent predictors of bladder recurrence and locoregional recurrence/distant metastasis. all statistical analyses were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0. all reported p values were 2-sided and significance was set at p < .05. results in total, 173 patients (34.3%) experienced bladder recurrences after a median follow-up time of 17.0 months (interquartile range, 8.4-36.0). bladder recurrence was significantly more common in patients with previous or concomitant nmibc than in those with isolated utuc (55.7% vs. 29.2%, respectively; p < .001). the kaplan-meier analysis revealed that bladder recurrence-free survival was significantly higher in men with a history of nmibc (figure 1, panel a, p < .001; log rank test). during the follow-up period, locoregional recurrence/distant metastasis were observed in129 patients (25.5%) after a median of 25.5 months (interquartile range, 12.0–51.4). locoregional recurrence/distant metastasis was also more commonly seen in patients with previous or concomitant nmibc than in those without (38.1% vs. 22.5%, respectively; p = .002). locoregional recurrence/distant metastasis-free survival was significantly lower in patients with previous or concomitant nmibc than in those without (figure 1, panel b, p = .008; log rank test). there were no significant differences in cancer-specific survival (figure 2, panel a, p = .634; log rank test) or overall survival (figure 2, panel b; p = .658; log rank test) between patients with previous or concomitant nmibc and those without. univariate cox analyses identified tumor localization in areas other than the renal pelvis [ureter, hazard ratio (hr): 1.599, p = .008; both ureter and renal pelvis, hr: 2.017, p = .003] and previous or synchronous nmibc (hr: 2.440; p < .001) as factors associated with bladder recurrence (table 2). multivariate cox regression analysis identified previous or synchronous nmibc as an independent predictor of bladder recurrence (hr: 2.845; p < .001; table 2). univariate analysis identified older age, larger tumor size, tumors located in both the ureter and renal pelvis, bladder cuff resection, worse pathologic t stage, pathologic n stage, grade, lymphovascular invasion, positive margin status, and previous or synchronous nmibc as factors significantly associated with locoregional recurrence/distant metastasis (table 3). multivariate analysis identified bladder cuff resection, worse pathologic t stage, pathologic n stage, lymphovascular invasion, higher grade, and positive margin status as independent predictors of locoregional recurrence/distant metastasis. previous or concurrent table 3. univariate and multivariate cox regression analyses to identify predictors of locoregional recurrence/distant metastasis in patients with utuc. parameters univariate analysis multivariate analysis hr (95%, ci) p value hr (95%, ci) p value age 1.020 (1.002−1.038) .025 1.009 (0.983−1.036) .506 gender (male vs. female) 0.951 (0.653−1.385) .795 0.791 (0.440−1.421) .432 smoking (no vs. yes) 0.952 (0.618−1.466) .823 0.677 (0.385−1.192) .177 tumor size 1.007 (1.001−1.012) .018 1.002 (0.995−1.009) .64 tumor location renal pelvis 1 ---- 1 ----ureter 1.176 (0.793−1.743) .42 0.874 (0.488−1.567) .652 both 1.847 (1.123−3.038) .016 0.840 (0.302−2.336) .738 bladder cuff resection (no vs. yes) 0.274 (0.195−0.917) .019 0.475 (0.236−0.956) .037 multifocality (no vs. yes) 1.180 (0.821−1.695) .371 1.284 (0.544−3.032) .568 pathologic t stage (ta, cis, t1–2 vs. t3–4) 3.274 (2.051−5.226) <.001 2.221 (1.630−2.367) .005 pathologic n stage (nx, n0 vs. n+) 5.845 (3.616−9.448) <.001 3.908 (1.919−7.959) <.001 grade (low vs. high) 4.992 (2.686−9.278) <.001 3.547 (1.305−9.639) .013 concomitant cis (no vs. yes) 0.999 (0.481−2.031) .975 1.135 (0.530−2.429) .745 lymphovascular invasion (no vs. yes) 4.069 (2.863−5.783) <.001 1.877 (1.087−6.750) .024 margin status (no vs. yes) 4.979 (3.054−8.116) <.001 3.045 (1.373−6.750) .006 previous or synchronous nmibc (no vs. yes) 1.664 (1.136−2.483) .009 1.571 (0.922−2.677) .097 abbreviations: utuc, upper tract urothelial carcinoma; hr, hazard ratio; ci, confidence interval; cis, carcinoma in situ; nmibc, non-muscle-invasive bladder cancer. vol 12 no 04 july-august 2015 2236 upper tract urothelial carcinoma after non-muscle invasive bladder cancer-kim et al. nmibc showed a marginal association with locoregional recurrence/distant metastasis (hr: 1.571; p = .097; table 3). discussion to the best of our knowledge, the cohort of 505 patients with utuc recruited from four academic centers in korea represents the largest of its kind in east asia to date. our results revealed that previous or synchronous nmibc was an independent predictor of bladder recurrence in patients with utuc, but this was not associated with locoregional recurrence/distant metastasis, cancer-specific survival, or overall survival. these results were consistent with previously published reports. (16,20) a study performed in serbia reported that a history of nmibc was significantly associated with bladder recurrence, but not with non-bladder recurrence and cancer-specific survival.(16) a recent multi-institutional study performed in france(20) found that patients with previous or synchronous bc were more likely to experience bladder recurrence; this study also excluded the patients with previous or concomitant mibc that was treated by cystectomy. the study also found that metastasis-free survival and cancer-specific survival rates were not significantly affected by the presence of associated bc. hence, the more frequent incidence of bladder recurrence in patients with previous or synchronous nmibc is likely attributed to the natural propensity of nmibc to recur, but this association does not adversely affect the prognosis of patents with utuc. in this current study, patients with previous or synchronous nmibc were more likely to show multifocality, and the tumors were localized in both the ureter and renal pelvis. thus, our results were consistent with the earlier studies on tumor location and multifocality as predictors of bladder recurrence.(19,21,22) in addition, patients with nmibc were also more likely to have a positive surgical margin than those with primary utuc (12.4% vs. 3.4%, respectively; p = .001). because positive margin status after rnu is associated with a poor prognosis and has a higher chance of developing metastasis,(23,24) it was likely that previous or synchronous nmibc was also associated with locoregional recurrence/distant metastasis based on univariate analysis. the effect of operative methods between laparoscopic versus open rnu on bladder recurrence was controversial.(25) in this study, there were no significant differences in bladder recurrence-free survival between open and laparoscopic procedures (p = .428) (figure 3). in contrast to previous studies, our current study, which was performed exclusively in east asia, displays several distinctive characteristics. in particular, the relatively low incidence of those with a history of nmibc should be noted. for example, the incidence of previous nimbc in the present study was 8.9%, compared to 12.5-28% reported in other prior studies.(16,20,26) similarly, with the inclusion of concomitant nmibc, we found that the rate of previous or synchronous nmibc was 19.2% when pignot and colleagues reported that 220 out of 662 patients (33.2%) had previous or synchronous nmibc.(20) these findings collectively indicate that ethnicity may play a role concerning the discrepancies as our study population is uniformly composed of koreans, as opposed to the earlier studies comprised of predominantly caucasian study participants. among the reported ethnic patterns in utuc, it was shown that the incidence of utuc was unusually high in taiwanese patients. also, the relative proportion of ureter tumors was higher among korean patients with utuc when compared to other ethnicities.(24,27) indeed, our current study supported that ureter tumors were more commonly observed than tumors in the renal pelvis. as matsumoto and colleagues highlighted some major differences in clinicopathological characteristics (gender distribution, pathologic stage, and grade) between caucasian and japanese patients,(28) race and ethnicity may account for the difference in the incidence rate of nmibc between our current study and the previous reports. even though this is the largest cohort of utuc patients in asia, the present study is not without its limitations. first and foremost were the limitations inherent in retrospective analyses, which inevitably resulted in selection bias. second, we were unable to obtain detailed clinicopathologic information on previous or concomitant nmibc, including t stage, grade, and tumor size and number. our data also lacked information on the clinical courses (e.g. number of recurrence and tumor progression) and types of treatments (e.g. intravesical therapy and radical cystectomy) in patients with bladder recurrence. because the data were gathered from four different institutions, we were unable to combine a multiple set of complex information into a uniform database. third, as we excluded patients with mibc, we were not able to examine the potentially different oncologic patterns between mibc and nmibc. for example, several studies that included mibc patients demonstrated that a history of bc has an adverse effect on the prognosis of utuc patients.(26,29) however, the inclusion would go beyond the scope of our current study. nonetheless, this may be an important investigation into which future prospective studies could possibly delve deeper. the prevention of bladder recurrence after rnu is an important task for clinicians. as recent prospective randomized ii study showed that a single intravesical instillation of anthracycline could reduce bladder recurrence after rnu,(30) our current study findings could provide useful information for clinicians to stratify patients and select patients who would most likely benefit from intravesical chemotherapy. conclusions our study findings demonstrated that the presence of a previous or synchronous nmibc is associated with increased risk of developing bladder recurrence after rnu. these findings may assist physicians to estimate the risk of bladder recurrences in individual and establish, a risk-stratified surveillance strategy. acknowledgement this research was supported by the kyungpook national university research fund, 2012. conflict of interest none declared. references 1. kakizoe t. development and progression of urothelial carcinoma. cancer sci. 2006;97:821-8. urological oncology 2237 upper tract urothelial carcinoma after non-muscle invasive bladder cancer-kim et al. 2. jeong p, min bd, ha ys, et al. runx3 methylation in normal surrounding urothelium of patients with non-muscle-invasive bladder cancer: potential role in the prediction of tumor progression. eur j surg oncol. 2012;38:1095100. 3. rabbani f, perrotti m, russo p, herr hw. upper-tract tumors after an initial diagnosis of bladder cancer: argument for long-term surveillance. j clin oncol. 2001;19:94-100. 4. solsona e, iborra i, ricos jv, dumont r, casanova jl, calabuig c. upper urinary tract involvement in patients with bladder carcinoma in situ (tis): its impact on management. urology. 1997;49:347-52. 5. latz s, hauser s, muller sc, fechner g. kidney sparing surgery for urothelial carcinoma of the pyelocalyceal system: is there a role for open techniques? results from a small series. urol j. 2014;11:1442-6. 6. hisataki t, miyao n, masumori n, et al. risk factors for the development of bladder cancer after upper tract urothelial cancer. urology. 2000;55:663-7. 7. miyake h, hara i, arakawa s, kamidono s. a clinicopathological study of bladder cancer associated with upper urinary tract cancer. bju int. 2000;85:37-41. 8. kang ch, yu tj, hsieh hh, et al. the development of bladder tumors and contralateral upper urinary tract tumors after primary transitional cell carcinoma of the upper urinary tract. cancer. 2003;98:1620-6. 9. garcia sb, park hs, novelli m, wright na. field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets. j pathol. 1999;187:61-81. 10. harris al, neal de. bladder cancer-field versus clonal origin. n engl j med. 1992;326:759-61. 11. miyake h, hara i, kamidono s, eto h. multifocal transitional cell carcinoma of the bladder and upper urinary tract: molecular screening of clonal origin by characterizing cd44 alternative splicing patterns. j urol. 2004;172:1127-9. 12. hafner c, knuechel r, zanardo l, et al. evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract. oncogene. 2001;20:4910-5. 13. goyal s, singh ur, sharma s, kaur n. correlation of mitotic indices, agnor count, ki-67 and bcl-2 with grade and stage in papillary urothelial bladder cancer. urol j. 2014;11:1238-47. 14. hall mc, womack s, sagalowsky ai, carmody t, erickstad md, roehrborn cg. prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. urology. 1998;52:594-601. 15. ehdaie b, shariat sf, savage c, coleman j, dalbagni g. postoperative nomogram for disease recurrence and cancer-specific death for upper tract urothelial carcinoma: comparison to american joint committee on cancer staging classification. urol j. 2014;11:1435-41. 16. milojevic b, djokic m, sipetic-grujicic s, et al. prognostic significance of non-muscleinvasive bladder tumor history in patients with upper urinary tract urothelial carcinoma. urol oncol. 2013;31:1615-20. 17. greene fl. the american joint committee on cancer: updating the strategies in cancer staging. bull am coll surg. 2002;87:13-5. 18. epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998;22:1435-48. 19. chromecki tf, cha ek, fajkovic h, et al. the impact of tumor multifocality on outcomes in patients treated with radical nephroureterectomy. eur urol. 2012;61:24553. 20. pignot g, colin p, zerbib m, et al. influence of previous or synchronous bladder cancer on oncologic outcomes after radical nephroureterectomy for upper urinary tract urothelial carcinoma. urol oncol. 2014;32:23. e1-8. 21. zigeuner re, hutterer g, chromecki t, rehak p, langner c. bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location. bju int. 2006;98:1181-6. 22. elalouf v, xylinas e, klap j, et al. bladder recurrence after radical nephroureterectomy: predictors and impact on oncological outcomes. int j urol. 2013;20:1078-83. 23. colin p, ouzzane a, yates dr, et al. influence of positive surgical margin status after radical nephroureterectomy on upper urinary tract urothelial carcinoma survival. ann surg oncol. 2012;19:3613-20. 24. lee jn, kwon sy, choi gs, et al. impact of surgical wait time on oncologic outcomes in upper urinary tract urothelial carcinoma. j surg oncol. 2014;110:468-75. 25. ni s, tao w, chen q, et al. laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies. eur urol. 2012;61:114253. 26. nuhn p, novara g, seitz c, et al. prognostic value of prior history of urothelial carcinoma of the bladder in patients with upper urinary vol 12 no 04 july-august 2015 2238 upper tract urothelial carcinoma after non-muscle invasive bladder cancer-kim et al. tract urothelial carcinoma: results from a retrospective multicenter study. world j urol. 2015;33:1005-13. 27. yang mh, chen kk, yen cc, et al. unusually high incidence of upper urinary tract urothelial carcinoma in taiwan. urology. 2002;59:6817. 28. matsumoto k, novara g, gupta a, et al. racial differences in the outcome of patients with urothelial carcinoma of the upper urinary tract: an international study. bju int. 2011;108:e304-9. 29. mullerad m, russo p, golijanin d, et al. bladder cancer as a prognostic factor for upper tract transitional cell carcinoma. j urol. 2004;172:2177-81. 30. ito a, shintaku i, satoh m, et al. prospective randomized phase ii trial of a single early intravesical instillation of pirarubicin (thp) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the thp monotherapy study group trial. j clin oncol. 2013;31:14227. urological oncology 2239 upper tract urothelial carcinoma after non-muscle invasive bladder cancer-kim et al. 1563vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l 1 department of urology, muğla university, medical faculty, muğla, turkey. 2 department of urology, şehitkamil state hospital, gaziantep, turkey. hasan deliktaş,1 onur yapici,2 utku özen,2 engin yalçin,2 hayrettin şahin1 can we reduce secondary surgical interventions and length of hospitalization in percutaneous nephrolithotomy? corresponding author: hasan deliktaş, md department of urology, muğla university, medical faculty, muğla, turkey. tel: +90 252 211 4868 fax: +90 252 211 1345 e-mail: hasandeliktas@mu.edu. tr received january 2013 accepted april 2014 purpose: to evaluate the success and complication rates of percutaneous nephrolithotomy (pnl) operations and to determine the effect of postoperative late removal of an open-end ureter catheter on hospital stay and on secondary interventions. materials and methods: the records of 198 patients (97 female, 101 male) who had pnl between may 2009 and february 2012 were retrospectively reviewed. the open-end ureter catheter which was placed during the operation was removed at the end of the operation in the first 53 patients ( group 1) and 12 hours after the nephrostomy catheter in 145 patients ( group 2). results: pnl intervention was performed in 198 patients with a mean age of 40.83 ± 13.64 years and mean stone load of 9.82 ± 5.37cm2 (range 2 to 26 cm2). when clinically insignificant stone pieces < 4 mm were accepted as successful, the total success rate was 80.80 % (79.2% in group1 and 81.4% in group 2, p = .50). the hospitalization period was significantly reduced in group 2 (3.45 ± 0.95 days vs. 2.61 ± 0.65 days; p = .006). while secondary surgical intervention was not necessary in any of the patients in group 2 (0.0%), but 4 patients (7.5%) required ureterorenoscopy plus double-j stent placement following the primary procedure in group 1 (p = .006). conclusion: pnl is a safe procedure with a high success rate and a short hospitalization period. there was a significant decrease in the hospitalization period and secondary surgical intervention rates with the postoperative late removal of the open-end ureter catheter. keywords: kidney calculi; surgery; nephrostomy; percutaneous; methods; treatment outcome; nephrolithiasis; retrospective studies. 17. ap evan, fl coe, je lingeman, et al. renal crystal deposits and histopathology in patients with cystine stones. kidney int. 2006;69:222735. endourology and stone disease 1564 | introduction the contemporary treatment of stone disease, which is a serious health problem, has made great pro-gress in recent years. in particular, because of the improvements in extracorporeal shock wave lithotripsy (swl), ureterorenoscopy (urs), intracorporeal lithotripsy and percutaneous surgery, only 0.7-4% of urinary system stones now need open surgery.(1,2) percutaneous nephrolithotomy (pnl), which is a minimal invasive surgical method, was first introduced in 1976 by fernström and johansson.(3) pnl is a method, the effectiveness and reliability of which has been proven in the treatment of kidney stones, thanks to developments in surgical instruments and technology along with an increase in surgical experience.(4) pnl is becoming a more preferred treatment method in stone surgery for reasons such as low morbidity and a short hospitalization period.(5) pnl has mostly replaced open surgery and in many centers pnl is recommended as the first choice in the treatment of kidney stones larger than 2 cm.(6,7) in this study, we aimed to evaluate the success and complication rates of percutaneous nephrolithotomy operations and to determine the effect on hospital stay and the rate of secondary interventions of the postoperative late removal of open-end ureter catheter which was placed during pnl operations for the visualization of the collecting system. materials and methods pnl intervention was performed in 198 patients (97 female, 101 male) with a mean age of 40.83 ± 13.64 years (range, 9 to 76 years). the open-end ureter catheter placed during the operation was removed at the end of the operation in the first 53 patients (group 1) and 12 hours after the nephrostomy catheter in 145 patients (group 2). the patients were evaluated routinely with full urine analysis, serum biochemistry, bleeding and coagulation time, direct urinary system graph (dus) and ultrasonography (usg). the patients with normal serum creatinine levels were evaluated with intravenous urography (ivu) and the patients with high serum creatinine levels were evaluated with non-contrast abdominal computerized tomography (ct) scan. the size of the stones was calculated by measuring the longest diameter and the diameter perpendicular to this and multiplying the values for a cm2 result. all patients with a sterile pre-operation urine culture were administered third generation cephalosporin as prophylaxis one hour before the operation and on the first day post-operatively, oral antibiotics were administered. patients with growth in the urine culture were discharged with a suitable treatment plan and when the urine culture was sterile, they were readmitted for the operation. pnl procedure following general anesthesia, a 6 french (f) open-end ureter catheter was placed in the lithotomy position. after fitting the ureter catheter, an appropriate calyx was entered with an 18 gauge percutaneous entrance needle (boston scientific, natick, ma, usa). amplatz mechanical dilatators were used for percutaneous tract dilatation (amplatz sheath, boston scientific, natick, ma, usa). a pneumatic lithotripter was used for in vivo lithotripsy in all cases. at the end of the operation, a 14 f nephrostomy tube was placed in the patients, except for those patients with significant bleeding to whom a 22 f pezzer drain nephrostomy was applied. the open-end ureter catheter that was placed during the operation to visualize the collecting system was removed either at the end of the operation or 12 hours after the nephrostomy catheter was removed. the nephrostomy tube of patients without hematuria was removed postoperatively on the first or second day. at the 1 and 3-month follow-up examinations, usg was performed. when usg imaging was insufficient, non-contrast abdominal ct was performed in 23 patients (6 patients in group 1 and 17 patients in group 2). the presence of a stone ≥ 4 mm was accepted as residue and pnl and/or swl was carried out at least one month later. statistical analysis statistical analyses were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 20.0. results were expressed as mean ± standard deviation (sd). the differences between the two groups for continuous variables (age, operation time, stone load, nephrostomy removal time and hospitalization time) were analyzed by independent samples t test and for categorical data (stone location, prolonged drainage, secondary surgical intervention, success rate and complication rates) by fisher’s exact test. a p value of ≤ .05 was considered statistically significant. endourology and stone disease 1565vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l results in total, the mean stone load was 9.82 ± 5.37 cm2 (range 2 to 26 cm2). stone localization was determined as only in the pelvis in 55 (27.8%) patients, only in the lower calyx in 58 (29.3%), only in the upper calyx in 10 (5.1%), in both pelvis and calyx in 41 (20.7%), in the calyx diverticulum in 7 (3.5%), in the proximal ureter in 9 (4.5%) and 18 (9.1%) patients had staghorn stones. the pre-operative characteristics of patients in group1 and group 2 are given in table 1. the mean operation time was 75.40 ± 16.05 min. while 183 patients were entered subcostally, in 15 patients supracostal entrance was preferred. when clinically insignificant stone pieces with the largest diameter of < 4 mm were accepted as successful, the total success rate was 80.8% (160/198). similar success rates were obtained in both groups (79.2% in group 1 vs. 81.4% in group 2; p = .50). one month following pnl, 38 (19.2%) patients were pnl and/or swl for residual stones. the pnl and/or swl rate was similar between the groups (p = .46). at the 3-month follow-up none of the patients had any stone residue. table 2 summarizes the operative features and post-operative results related to the pnl procedure in total and in both groups. prolonged drainage (> 24 hours) from the nephrostomy tract was observed in two patients in group 2. the drainage of the patients ceased after 36 hours without any intervention. no patient in this group needed a secondary surgical intervention. in group 1, on the other hand, prolonged drainage was observed in 5 patients (p = .018). while 1 patient did not need any extra intervention, the other 4 patients had urs under spinal anesthesia. in 2 of the urs patients a 3-4 mm stone was found in the distal ureter and removed by forceps. no pathology other than ureteral edema was encountered in the remaining 2 patients. a double-j stent was placed in 4 patients who had urs during the operation. while secondary surgical intervention was not necessary in any of the patients in group 2 (0.0%), 4 patients (7.5%) required urs plus double-j stent placement following the primary procedure in group 1 (p = .006). the hospitalization period was significantly reduced in group 2. the mean hospital stay was found to be 3.45 ± 0.95 days in group 1 and 2.61 ± 0.65 days in group 2 (p = .006). on postoperative day 25, one patient with a massive hemorrhage was referred to an advanced center. an a-v fistula was detected on the renal angiography of the patient and the hemorrhage ceased after the embolization of the a-v fistula. in one case with a proximal ureter stone, the ureter was perforated when the stone was being removed by forceps. this patient was fitted with an anterograde double-j stent and the double-j stent was removed in the postoperative third week. secondary surgical interventions and length of hospitalization in pnl | deliktaş et al table 1. the preoperative characteristics of both groups. variables group 1 group 2 p age (years), (mean ± sd) 38.69 ± 15.33 41.61 ± 12.93 .28 stone load (cm2), (mean ± sd) 9.78 ± 6.69 9.83 ± 4.82 .09 stone location, no. (%) pelvis 7 (13.2) 48 (33.1) .02 lower calyx 12 ( 22.6) 46 (31.7) .22 upper calyx 2 (3.8) 8 (5.5) .48 pelvis and calyx 13 (24.5) 28 (19.3) .32 calyx diverticulum 3 (5.7) 4 (2.8) .29 proximal ureter 8 (15.1) 1 (7.0) .00 staghorn 8 (15.1) 10 (6.7) .096 1566 | none of the patients had any abdominal organ damage or hydro-pneumothorax following the procedure. the complication rates are summarized according to the modified clavien system in table 3. discussion pnl was first introduced as a minimally invasive surgical method by fernström and johansson for the first time in 1976.(3) today, pnl is a method, the effectiveness and reliability of which has been proven in the treatment of kidney stones. pnl is replacing open surgery and is generally recommended as the first choice in the treatment of kidney stones larger than 2 cm.(6,7) pnl has applications as the first choice in complex kidney stones which have resulted in a dilated pelvicalyceal system due to obstruction, and also in kidney stones of large sizes and chemical structures that are not suitable for swl or stones that are located in the lower calyx, isolated calyx, diverticulum and those that are staghorn.(4) in pnl studies, the success rate of pnl surgery ranges from 72% to 98% in wide series.(8-10) factors such as differences in stone volume, dilatation in the collecting system, the presence of complex structures within the collecting system and the experience of the surgeon are all held responsible for the wide variation in the success rates.(11) the success rate in the current study, when the residual pieces with no clinical meaning are accepted as successful, was found to be 81% which conforms to literature. prolonged drainage from the nephrostomy tract is a commonly seen situation in pnl treatment. this situation lengthens the hospitalization period and increases the secondary intervention rates. in the study carried out by agrawal and colleagues, this rate was found to be 6.9%.(12) in the current series 3.5% of all patients had prolonged drainage from the nephrostomy tract. in group 1 patients this rate was 9.4% (5/53), while in group 2 only 1.4% (2/145) of cases showed prolonged drainage. prolonged drainage from the nephrostomy tract after removal of the nephrostomy tube, which necessitates a double-j stent placement, is considered to be a grade 3 complication according to the modified clavien system.(13) in the current study, double-j stent placement due to prolonged drainage was not required in any of the patients in group 2 but 4 patients in group 1 required double-j stent placement due to prolonged drainage. this procedure can be considered to minimize grade 3 complications in the modified clavien system. lee and colleagues reported 1.5% of patients in whom urine leakage persisted for more than 1 week from the percutaneous tract without a double-j stent placement.(9) in a study by binbay and colleagues, 4.3% of patients underwent double-j stent placement because of urine leakage persisting for more than 24 hours after removal of the nephrostomy tube.(14) in the current study, 4 (7.5%) patients from group 1 received double-j stent, while none from group 2 required this protable 2. the per-operative characteristics and post-operative results of the percutaneous nephrolithotomy procedure in all patients and in both groups. variables all patients (n = 198) group 1 (n = 53) group 2 (n =145) p* operation time (min), (mean ± sd) 75.40 ± 16.05 69.90 ± 17.96 77.41 ± 14.86 .45 nephrostomy removal (days), (mean ± sd) 1.24 ± 0.45 1.26 ± 0.48 1.22 ± 0.43 .16 prolonged drainage from nephrostomy, no. (%) 7 (3.5) 5 (9.4) 2 (1.4) .018 secondary surgical intervention, no. (%) 4 (2) 4 (7.5) 0 (0.0) .006 success rate, no. (%) 160 (80.8) 42 (79.2) 118 (81.4) .50 hospital stay (days), (mean ± sd) 2.83 ± 0.83 3.45 ± 0.95 2.61 ± 0.65 .006 reoperation, no. (%) 38 (19.2) 11 (20.8) 27 (18.6) .46 pnl/swl, no. 24/14 8/3 16/11 keys: pnl, percutaneous nephrolithotomy; swl, extracorporeal shockwave lithotripsy, * comparison between group 1 and group 2. endourology and stone disease 1567vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l cedure. the total stone burden has also been reported to affect the hospitalization period after pnl.(15) although the mean stone size was higher in group 2 in the current study, the hospital stay of those patients was significantly shorter. limb and bellman reported that the period of hospitalization was significantly shorter in patients undergoing tubeless pnl.(16) one of the most important disadvantages of the tubeless technique using a double-j stent for internal drainage is the need for postoperative cystoscopy to remove the stent. in the current study, when the method described here was used, there was no need either for cystoscopy or for secondary surgical interventions such as double-j stent removal. the late removal of the open-end ureter catheter not only provides urine drainage but also secures the resolution of post-operative edema in the ureter while at the same time helps dilatation of the ureter. as a result of this drainage and ureter dilatation the nephrostomy tract of those patients closes up early. in addition, the remaining stone pieces and the coagulations formed during the operation are easier to extract through the open-end ureter catheter. these seem to be the main reasons behind the shortened hospitalization period and the lesser need for secondary intervention with the late removal of the open-end ureter catheter. after frequent observation of prolonged drainage and secondary intervention rates from the nephrostomy tract following removal of the nephrostomy tube in the first 53 patients (group 1), we considered that late removal of the open-end ureter catheter could minimize the previously mentioned complications and we began our application. in patients, the late removed open-end ureter catheter not observed any obstructions in catheter lumen by clots and stone debris. we suggest that as in double-j stent obstructions, even open-end ureter catheter lumen is obstructed, passage can be maintained around the catheter. to the best of our knowledge, there are no similar studies in literature evaluating the hospitalization period and secondary interventions after pnl. although this is a first report, the results of our study showed the advantages of late removal of the open-end ureter catheter such as shortening the hospitalization period after pnl and a reduced need for secondary interventions such as ureterorenoscopy and double-j stent placement. therefore, it is our opinion that because of the above-mentioned advantages, this approach may be extensively used in clinics where pnl is widely applied. the limitations of this study are the small number of patients and the retrospective chart review. however, further prospective, randomized and controlled studies are needed to prove the assertion of the present study. table 3. the complication rates of percutaneous nephrolithotomy in both groups according to the modified clavien system. modified clavien grading system group 1 (n = 53) group 2 (n = 145) p grade 1: hemorrhage not requiring transfusion (n = 32), postoperative high fever > 38 °c (n = 16)), [no (%)] 12 (22.7) 36 (24.9) .6 grade 2: hemorrhage requiring transfusion (n = 8), [no (%)] 4 (7.6) 4(2.8) .14 grade 3a: ureter perforation (n = 1), hydropneumothorax (n = 0), double j stent placement for urine leakage > 24h (n = 4), no. (%) 5 (9.4) 0 .001 grade 3b: arteriovenous fistula, no. (%) 0.0 1(0.6) 0.7 grade 4a: no. (%) 0.0 0.0 --grade 4b: no. (%) 0.0 0.0 --grade 5: no. (%) 0.0 0.0 --pnl/swl, no. 24/14 8/3 --keys: pnl, percutaneous nephrolithotomy; swl, extracorporeal shockwave lithotripsy. * comparison between group 1 and group 2. secondary surgical interventions and length of hospitalization in pnl | deliktaş et al 1568 | endourology and stone disease conclusion pnl can be carried out safely by trained urologists with a short hospitalization period, high stoneless rates and acceptable side effects. in this study, we showed that the hospitalization period and requirement for secondary surgical interventions decreased with the postoperative late removal of open-end ureter catheter. acknowledgement the resources of sehitkamil state hospital, gaziantep, turkey were used in this study. conflict of interest none declared. references 1. matlaga br, assimos dg. changing indications of open stone surgery. urology. 2002;59:490-4. 2. kane cj, bolton dm, stoller ml. current indications for open stone surgery in an end urology center. urology. 1995;45:218-21. 3. fernström i, johannson b. percutaneous pyelithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 4. akinci m, esen t, tellaloğlu s. urinary stone disease in turkey: an updated epidemiological study. eur urol. 1991;20:200-3. 5. tanriverdi o, boylu u, kendirci m, kadihasanoglu m, horasanli k, miroglu c. the learning curve in the training of percutaneous nephrolithotomy. eur urol. 2007;52:206-11. 6. tiselius hg1, ackermann d, alken p, buck c, conort p, gallucci m; working party on lithiasis, european association of urology. guidelines on urolithiasis. eur urol. 2001;40:362-71. 7. preminger gm, clayman rv, curry t, redman hc, peters pc. outpatient percutaneous nephrolithotomy. j urol. 1986;136:355-7. 8 .segura jw, patterson de, leroy aj. percutaneous removal of kidney stones. review of 1000 cases. j urol. 1985;134:1077-81. 9. lee wj, smith ad, cubelli v, et al. complications of percutaneous nephrolithotomy. ajr am j roentgenol. 1987;148:177-80. 10. goldwasser b, weinerth jl, carson cc, dunnick nr. factors effecting the success rate of percutaneous nephrolithotripsy and the incidence of retained fragments. j urol. 1986;136:358-60. 11. lam hs, lingeman je, baron m, et al. stag-horn calculi: analysis of treatment results between initial percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy immunotherapy with reference to surface area. j urol. 1992;147:1219-25. 12. agrawal ms, agrawal m, gupta a, bansal s, yadav a, goyal j. a randomized comparison of tubeless and standard percutaneous nephrolithotomy. j endourol. 2008;22:439-42. 13. tefekli a, ali karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008;53:184-90. 14. binbay m, sari e, tepeler a, et al. characteristics of patients requiring double-j placement because of urine leakage after percutaneous nephrolithotomy. j endourol. 2009;23:1945-9. 15. lingeman je, coury ta, newman dm, et al. comparison of results and morbidity of percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy. j urol. 1987;138:485-90. 16. limb j, bellman gc. tubeless percutaneous renal surgery: review of first 112 patients. urology. 2002;59:527-31. urological oncology the rate of neoadjuvant chemotherapy use in muscle invasive bladder cancer and the approach of urologists in turkey oktay ucer1*, ali can albaz1, elif atağ2, aziz karaoğlu2, talha muezzinoglu1 purpose: to investigate the proportion of neoadjuvant chemotherapy (nac) use in patients with muscle invasive bladder cancer before radical cystectomy and the approach of urologists to this subject. materials and methods: we invited 242 urologists during the 12th international urooncology congress in turkey to answer a self-administered questionnaire. the questionnaire included questions related to radical cystectomy, lymph node dissection and neoadjuvant chemotherapy that had been performed in patients with muscle invasive bladder cancer by the urologist. results: the median number of radical cystectomy operations was 20 per year. 122 (50.5 %) of 242 urologists had used neoadjuvant chemotherapy for the treatment of muscle invasive bladder cancer before radical cystectomy. the mean rate of neoadjuvant chemotherapy use by these urologists (n=122) was 28.46 %. the most common reasons for not using neoadjuvant chemotherapy by urologists in turkey were as follows: (i) neoadjuvant chemotherapy might lead to a decrease in the cure rate of radical cystectomy due to delayed surgery (ii) complication rate of radical cystectomy might be elevated and the surgery might be complicated by nac use. conclusion: although the european association of urology (eau) guidelines panel on muscle invasive bladder cancer recommends using nac in t2-t4a bladder, the rate of neoadjuvant chemotherapy use was still found to be low in our country because urologists have concerns about adverse effects nac on radical cystectomy. keywords: bladder cancer; chemotherapy; neoadjuvant treatment introduction bladder cancer (bc) is a worldwide problem, as being the fourth most common cancer in men and the eighth one in women and 80% of all bc patients are males (1). worldwide estimates suggest that approximately 330,000 cases are diagnosed with bc each year, and 123,000 patients will die due to this cancer(2). the most common histological types of bcs are transitional cell or urothelial carcinoma, constituting 90% of all bcs and 30% of these casesmare muscle invasive bladder cancer (mibc) at the time of initial diagnosis. radical cystectomy (rc) and pelvic lymph node dissection are considered to be the gold standard treatment for mibc (3). although this treatment may be curative, a large proportion of the patients will harbor micrometastatic disease, contributing to recurrence rates of up to 40% at 5 years(4). an early study of southwest oncology group demonstrated that radiotherapy before rc did not change the results(5). therefore systemic chemotherapy has been investigated as a treatment option in both neoadjuvant and adjuvant settings since the 1980s. although the data supporting adjuvant chemotherapy are insufficient, neoadjuvant chemotherapy (nac) that includes cisplatin-based combination therapy is recommended for mibc by the guidelines for muscle invasive and metastatic bladder cancer of the european association of urology(6). although according to the american national cancer database records, only 1.2 % of patients with mibc received neoadjuvant chemotherapy between 1998 and 2003(7), this rate was reported as 12 % by feifer et al. in 2011(8). despite the recommendation of nac use in mibc and the outcomes of randomized trials, the rate of patients receiving nac has increased only quite a little(6). the aim of the present study was to investigate the rate of nac use in patients with mibc before radical cystectomy and the approach of urologists to this subject in turkey. materials and methods three hundred and ten urologists, who participated in 12th international urooncology congress (total number of participants was about 750) between 18th and 22nd of november 2015 in antalya-turkey, filled out a self-administered questionnaire. two hundred and forty two of the 310 participants who were working in turkey were enrolled in the study. 68 urologists were excluded from the study either because they did not perform radical cystectomy in their clinics or did not completely fill in the questionnaire form. the study questionnaire was developed by the study team and consisted of three parts as follows:(1) socio-demographic data;(2) five questions about how the urologists performed radical cystectomy procedure in their clinics;(3) four questions about their preference for nac use for the treatment of mibc. if they 1celal bayar university, faculty of medicine, department of urology, manisa, turkey. 2dokuz eylül university, faculty of medicine, department of medical oncology, izmir,turkey. *correspondence: celal bayar university, faculty of medicine, department of urology, manisa turkey. tel: +905052114618. e-mail: uceroktay@yahoo.com. receiveed february 2016 & accepted august 2016 urological oncology 2841 answered that they did not choose to give nac then they were asked why they did not prefer to use it. statistical analysis was performed using spss 16.0 (spss inc., chicago, il, usa). the demographic data and responses to the questions were statistically evaluated. the participants were divided into two groups according to whether they used nac or not and into three groups according to their responses (yes, no or i do not know) to the question "do medical oncologists recommend nac in your hospital?" the groups were statistically compared by using the chi-square test. statistical significance was considered at p < .05. results two hundred and forty two of the 310 participants were enrolled in the study. 68 urologists (21.9%) were excluded from the study either because they did not perform radical cystectomy in their clinics or did not completely fill in the questionnaire form. the demographic data of urologists in this study is presented in table 1. the median number of radical cystectomy operations was 20 (2-200) per year. all the participants performed lymph node dissection during radical cystoprostatectomy. the rate of lymph node dissection during radical cystectomy was 100 %. the mean rate of extended lymph node dissection was 65.05 ± 3.64 (0-100). 122 of 242 urologists performed nac before radical cystectomy for the treatment of mibc. the mean rate of nac use was 28.46 % ± 24.39 % (5-100%). 120 urologists, who did not use nac were asked, why they did not use nac. the distribution of responses to this question is summarized in table 2. the responses to two questions about their urooncologic council and medical oncologists’ approach in their hospital are summarized in table 3. logistic regression was used to assess the effect of potentially relevant factors on the nac use. we found that the participants who worked with medical oncologist that recommended nac used nac 3.24 (2.19 4.79) times more than other participants. discussion the risk of recurrence following rc for the treatment of mibc is high and correlates with pathologic staging(9). although rc is gold standard, it provides 5-year survival only in approximately 50 % of patients(6). despite this gold standard treatment, patients with mibc face a 50% chance of recurrence(10). some authors suggested that the predominant cause of this high recurrence rate was occult micro-metastases present at the time of rc(1). nac has been investigated for last three decades for their effect in mibc. there are many advantages of nac for the patients with mibc, including: (1) chemotherapy is delivered at the earliest time-point and allows for earlier exposure of micro-metastatic cells to chemotherapeutic agents;(2) we can determine the chemosensitivity of tumor cells in vivo; and(3) patient compliance and tolerability are better before rc than after it(6). the most recent meta-analysis with updated results from 11 randomized trials (n = 3005) detected a significant survival benefit associated with platinum based combination chemotherapy for the treatment of mibc before rc(11). the results of this meta-analysis showed a 5 % absolute improvement in survival at 5 years. similarly, the nordic combined trial showed an 8 % absolute improvement chemotherapy in bladder cancer in turkey-ucer et al. table 1. demographic data of urologists in the study age (years) n % 20-30 38 15.7 31-40 66 27.2 41-50 76 31.5 51-60 45 18.6 > 60 17 7.0 degree urology specialists 55 22.7 assistant professor 32 13.2 associated professor 68 28.1 professor 87 36.0 institution university 153 63.2 training and research hospital 68 28.1 private hospital 21 8.7 no responses to the question n % 1 it may decrease the chance of cure because of delayed rc 21 17.5 2 it may complicate rc and increase the complications of surgery 21 17.5 3 adjuvant chemotherapy is more effective than neoadjuvant 12 10 4 i do not believe in the effectiveness of neoadjuvant chemotherapy 7 5.8 5 1+2 35 29.2 6 1+3 5 4.1 7 1+4 5 4.1 8 others 14 11.8 total 120 100 abbreviation: rc, radical cystectomy table 2. responses to the question “why not do you use neoadjuvant chemotherapy before radical cystectomy for the treatment of muscle invasive bladder cancer”. vol 13 no 05 september-october 2016 2842 in survival at 5 years and 11 % in the ct3 disease(3). the largest randomized trial with a median follow–up of 8 years confirmed these results. this trial showed that nac (cisplatinum, metotrexate and vinblastine) increased the 10 years survival rate from 30% to 36%(12). despite these benefits of platinum based nac, most urologists still do not use it before surgery(8). actually use of nac has been rising in the last decades globally, but it still remains underutilized. in a retrospective study, krabbe la et al. reported that the usage of cisplatin-based nac increased from 17% to 35% between 2008 and 2012(13). in a larger data set from national cancer database in usa, it was reported that use of nac in mibc increased from 13% in 2007 to 21% in 2010(14). in our study, the mean rate of nac administration by urologists was found to be 28.4%. this result is higher than the rates reported in the older studies(7,8), but it is similar to some contemporary series(13,14). we do not have any historical data for use of nac in our county. therefore we could not compare our result with any historical turkish series. in this study we found a good rate for nac in mibc but this rate is still low. the two most common reasons that urologists claim for not using nac are as follows: (i) it may decrease the chance of cure because of delayed rc and (ii) it may complicate rc and increase the complications of surgery. 72.4% of the urologists participating in this study chose one of these two responses to the question “why don’t you use nac ? ”. in fact, the results of the combined nordic trial responded to the concern of urologists regarding the adverse effect of nac on rc(3). the results showed that nac did not have any major influence on the percentage of performable rc. the cystectomy frequency in all patients allocated to the nac arm was 86% and in the control arm was 87%. three studies that investigated the effect of nac on perioperative mortality and morbidity were published in 2014(15-17). the findings of these studies showed that nac was not associated with an increase in perioperative complications or death. the other most common concern of urologists in our study was that it might decrease the chance of cure because of delayed rc. european association of urology guidelines on muscle-invasive and metastatic bladder cancer reported a significant survival benefit of nac for the treatment of mibc and recommend it for t24a, n0m0 bladder cancer. delayed rc may influence only patients, who are not sensitive to chemotherapy. however, there are no studies, which show that delayed rc due to nac, can have a negative impact on survival(6). therefore, the fears of urologists, who did not use nac before rc are unwarranted in fact. the main problem regarding the use of nac is actually risk of overtreatment. however, none of the urologists in our study mentioned this as a concern for not using nac. bimanual palpation, computerized tomography and magnetic resonance imaging are often used for diagnosis of bladder cancer. clinical staging using these modalities may result in both over and under-staging and lead to a staging accuracy of only 70%(18,19). thus, overtreatment or undertreatment is possible for some cases. in the present study, we also assessed the effects of medical oncologists and regular meetings of multidisciplinary urooncologic council on the preference of urologists with regard to nac use. there was no significant relationship between the preferences of urologists and regular meetings of multidisciplinary urooncologic council, on the other hand there was a significant relationship between the preference of urologists and the recommendation of medical oncologists (table 3). the recommendations of medical oncologists that worked in the same hospital with urologists who preferred to use nac and who did not, were 85.2% and 34.4%, respectively (p < .001). also the results of logistic regression indicated that the nac use frequency of participants who worked with medical oncologist who recommended nac was 3.24 (2.19 4.79) fold higher than those who did not. this result shows that recommendation of medical oncologists plays an important role in the preference of urologists regarding nac. a limitation of our study was that the rate of nac use was only determined according to the written statement of urologists. if this rate was calculated with data obtained from hospital archives, the results could be more reliable. conclusions the findings of our study shows that the rate of nac use before rc in our country was low despite the strong recommendations of urology guidelines. the reasons for the reluctance to use nac are found to be concerns about: a) the fear that nac may decrease the chance of cure due to delayed rc and b) increase in surgical mortality and morbidity. there are many evidences showing that nac does not lead to these situations in the literature. we suggest that it should be emphasized that these concerns about nac are unurological oncology 2843 table 3. the comparison of the responses to the two questions about their urooncologic council and aspect of medical oncologists in their hospital. do you use neoadjuvant chemotherapy? n (%) p value yes no total does an urooncology council regularly meet in your hospital? n (%) yes 91 (74.5) 79 (64.7) 170 (70.2) 0.51 no 31 (25.5) 41 (35.3) 72 (29.8) total 122 (100) 120 (100) 242 (100) do medical oncologists recommend neoadjuvant yes 104 (85.2) 42 (34.4) 146 (60.4) < 0.001 chemotherapy before radical cystectomy in your hospital? n (%) no 3 (2.4) 45 (36.8) 48 (19.8) i do not know1 5 (12.4) 33 (28.8) 48 (19,8) total 122 (100) 120 (100) 242 (100) chemotherapy in bladder cancer in turkey-ucer et al. warranted and the recommendations of the current guidelines by urology associations should be reminded in congresses or via internet. in addition, we recommend that urologists and medical oncologists should be working in collaboration for the treatment of mibc. references 1. grossman hb, natale rb, tangen cm, et al. neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. n engl j med 2003; 349: 859-66. 2. jemal a, bray f, center mm, et al. global cancer statistics. ca cancer j clin 2011; 61: 69-90. 3. sherif a, holmberg l, rintala e, et al. neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two nordic studies. eur urol 2004; 45: 297-303. 4. hautmann re, de petriconi rc, pfeiffer c, et al. radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. eur urol 2012; 61: 1039-47. 5. smith ja jr, crawford ed, paradelo jc, et al. treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: a phase iii intergroup study. j urol 1997; 157: 805-7. 6. witjes ja, compérat e, cowan nc, et al. eau guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. eur urol 2014; 65: 778-92. 7. david ka, milowsky mi, ritchey j, et al. low incidence of perioperative chemotherapy for stage iii bladder cancer 1998 to 2003: a report from the national cancer data base. j urol 2007; 178: 451–4. 8. feifer a, taylor j, shouery m, et al. multiinstitutional quality-of-care initiative for nonmetastatic, muscle-invasive, transitional cell carcinoma of the bladder. j clin oncol 2011;29 (suppl 7; abstr 240). 9. stein jp, skinner dg. radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. world j urol 2006; 24: 296-304. 10. porter mp, kerrigan mc, donato bm, et al. patterns of use of systemic chemotherapy for medicare beneficiaries with urothelial bladder cancer. urol oncol 2011; 29: 252-8 11. advanced bladder cancer (abc) metaanalysis collaboration. neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and metaanalysis of individual patient data advanced bladder cancer (abc) meta-analysis collaboration. eur urol 2005; 48: 202-205 12. international collaboration of trialists; medical research council advanced bladder cancer working party (now the national cancer research institute bladder cancer clinical studies group); european organisation for research and treatment of cancer genito-urinary tract cancer group, et al. international phase iii trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the ba06 30894 trial. j clin oncol 2011; 29: 2171-7. 13. krabbe lm, westerman me, margulis v et al. changing trends in utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer. can j urol. 2015; 22: 7865-75. 14. zaid hb, patel sg, stimson cj et al. trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: results from the national cancer database.urology. 2014; 83: 75-80. 15. johnson dc, nielsen me, matthews j, et al. neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity. bju int 2014; 114: 221-8. 16. gandaglia g, popa i, abdollah f, et al. the effect of neoadjuvant chemotherapy on perioperative outcomes in patients who have bladder cancer treated with radical cystectomy: a population-based study. eur urol 2014; 66: 561-8. 17. tyson md, bryce ah, ho th, et al. perioperative complications after neoadjuvant chemotherapy and radical cystectomy for bladder cancer. can j urol 2014; 21: 7259-65. 18. sternberg cn, pansadoro v, calabrò f, et al. can patient selection for bladder preservation be based on response to chemotherapy? cancer 2003; 97: 1644-52. 19. herr hw, scher hi. surgery of invasive bladder cancer: is pathologic staging necessary? semin oncol 1990; 17: 590-7. chemotherapy in bladder cancer in turkey-ucer et al. vol 13 no 05 september-october 2016 2844 case report isolated urethral rupture related to sexual intercourse in male and literature review hung-chieh chiu,1 chao-hsiang chang,1,2 po-fan hsieh1* introduction penile fracture is defined as blunt trauma resulting in a tear of tunica albuginea surrounding the corpus caverno-sum and rapidly expanding hematoma during erection.(1) concomitant penile fracture with urethral rupture has been reported from 10% to 20% in all penile fracture cases.(2) however, isolated urethral injury during sexual inter courseis extremely rare. in females, intercourse-related urethral injury might occur after rape, sexual abuse, müllerian anomalies, or intraurethral intercourse.(3) among males, only 5 cases have been described in the literature. (4-6) we report a patient suffering from penile trauma during sexual intercourse and urethral rupture without penile fracture as demonstrated on surgical exploration. case report a 51-year-old heterosexual married male had penile trauma while attempting to penetrate his partner’s vagina in the missionary position. sharp penile shaft pain developed suddenly, followed by detumescence and penile swelling. he also suffered from gross hematuria, difficulty in urination and weak stream thereafter. initially, he did 1 department of urology, china medical university hospital, taichung, taiwan. 2 school of medicine, china medical university, taichung, taiwan. *correspondence: department of urology, china medical university hospital, no. 2, yu-der rd, taichung, taiwan. tel: +886 4 22052121, ext 4439. fax: +886 4 22052121, ext 6399. e-mail: phdoublem@yahoo.com.tw. received february 2015 & accepted november 2015 figure 1. ecchymosis, extended from penis to scrotum and perineum without penile deformity. figure 2. contrast medium extravasation at proximal penile urethra in retrograde urethrography. vol 12 no 06 november-december 2015 2462 not take the symptoms seriously. because of progressive penile shaft pain, he visited the outpatient urology clinic 3 days later. physical examination showed flaccid and mildly swelling penis, as well as ecchymosis on penis, scrotum and perineum. there was some bloody discharge over urethral meatus. no penile deformity was observed (figure 1). under the suspicion of penile fracture with concomitant urethral rupture, he was subjected to retrograde urethrography with subsequent surgical exploration. contrast medium extravasation at proximal penile urethra was demonstrated and flexible urethroscopy showed a urethral tear over the penobulbous junction (figures 2 and 3). a subcoronal circumferential incision with penile degloving was made but there was no tunica albuginea injury surrounding the corpus cavernosum nor peritunical hematoma. we identified the rupture of the urethra over the penobulbous junction (figure 4). the wound edge debridement was done and the length of rupture was measured as 1 cm. the circumferential defect involved up to five-sixths of the urethra. primary anastomosis with 5-0 vicryl was done, and the patient was discharged with 16 french foley catheter on the next day. foley catheter was removed 3 weeks later and urethral stricture was noted during follow-up. he kept regular sounding for urethral stricture in the first 4 months and then he had no more voiding difficulty. uroflowmetry revealed fair urinary maximum flow rate (20.3 ml/s) with acceptable residual urine amount (59 ml) in the fourth month follow-up. there was no fistula for mation. international prostate symptom score (ipss) was 3 (1 score in intermittency, 1 score in frequency and 1 score in weak stream), international index of erectile function (iief) was 25 in the sixth month follow-up. discussion the classic presentation of penile fracture is a cracking or snap sound , followed by sharp pain, detumescence, penile swelling, deformation and ecchymosis.(7) furthermore, if bloody discharge over urethral meatus or difficulty in urination occurs, concomitant urethral injury should be taken into consideration.(8) the frequency of combined penile fracture and urethral injury is variable, ranging from 0% to 3% in asia to 20~30% in europe and the united states.(7,8) it is believed that greater force results in greater injury, and bilateral corporal injury with concomitant urethral injury is more often seen compared with unilateral corporal injury. the site of urethral injury is usually the same table. summary of reports of isolated male urethral injury. study year patient number site of injury position mohapatra et al.3 1990 3 fossa navicularis reverse position de mendonça et al.4 2009 1 fossa navicularis reverse position patel et al.5 2010 1 penobulbous junction missionary position present case 2015 1 penobulbous junction missionary position urethral rupture due to sexual intercourse-chiu et al. figure 3. urethroscopy showed urethral rupture over proximal urethra. figure 4. proximal penile urethral injury was detected and repaired. case report 2463 level as corporal injury.(8,10) isolated urethral injury without penile fracture during coitus is extremely rare. based on the literature, only five male patients have been reported. mohapatra and colleagues described 3 cases of fossa navicularis injury on the reverse position.(4) mendonça and colleagues reported 1 case of fossa navicularis injury on the reverse position.(5) patel and colleagues reported an isolated urethral injury over the penobulbous junction in missionary position (table).(6) in the present case, the injury was over penobulbous junction while the patient adopted the missionary position. to the best of our knowledge, this is the sixth case of isolated male urethral injury in the literature. from an anatomical aspect, the hypothesis is that corpus spongiosum is overlain by the rigid tunica albuginea of the corpus cavernosa except for the glans and bulb of the penis. at the penile base, the corpus cavernosa diverts beneath the pubis and has inserted placement into the bilateral pubic ramus, leaving the bulb of the penis unsupported and vulnerable. on the other hand, in the missionary position, the penis is relatively dorsiflexed with more ventral force encountered; therefore, the proximal penile and bulbous urethra along with the adjacent corpus spongiosum might be injured by this ventral force, resulting in isolated urethral rupture. for partial urethral injury, diverting cystostomy or urethral catheterization has been described in some reports.(11) but the recent literature advocates surgical treatment for penile fracture and/or urethral injury as soon as possible as this appears related to fewer complications and better outcomes.(8,12) in our case, although urethral stricture was identified in the post-operative first 4 months, there was no erectile dysfunction or fistula formation. conclusions physicians should remain alert to urethral injury when patients present with gross hematuria or voiding difficulty after sexual intercourse, even though there is no typical feature of penile fracture. the main stream treatment for penile fracture with concomitant urethral injury or isolated urethral injury is early surgical exploration and repair. conflict of interest none declared. references 1. mydlo jh, hayyeri m, macchia rj. urethrography and cavernosography imaging in a small series of penile fractures: a comparison with surgical findings. urology. 1998;51:616-9. 2. bertero eb, campos rsm, mattos jr d. penile fracture with urethral injury. braz j urol. 2000;26:295-7. 3. zargham m, abbasi h, alizadeh f, et al. intra urethral intercourse: a report of two cases. urol j. 2014;11:1343-6. 4. mohapatra tp, kumar s. reverse coitus: mechanism of urethral injury in male partner. j urol. 1990;144:1467-8. 5. de mendonca rr, bicudo m c, sakuramoto pk, bezerra c a, pompeoa c, wroclawski er. isolated anterior urethral trauma in man after coitus: a case report. einstein. 2009; 7(4 pt 1):503-5. 6. patel a, kotkin l. isolated urethral injury after coitus-related penile trauma. j trauma. 2010;68:e89-90. 7. tsang t, demby am. penile fracture with urethral injury. j urol. 1992;147:466-8. 8. el-assmy a, el-tholoth hs, mohsen t, ibrahiem el hi. long-term outcome of surgical treatment of penile fracture complicated by urethral rupture. j sex med. 2010;7:3784-8. 9. zargooshi j. penile fracture in kermanshah, iran: report of 172 cases. j urol. 2000;164:3646. 10. fergany af, angermeier kw, montague dk. review of cleveland clinic experience with penile fracture. urology. 1999;54:352-5. 11. maharaj d, naraynsingh v. fracture of the penis with urethral rupture. injury. 1998;29:483. 12. raheem aa, el-tatawy h, eissa a, elbahnasy ah, elbendary m. urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption. arch ital urol androl. 2014;86:159. urethral rupture due to sexual intercourse-chiu et al. vol 12 no 06 november-december 2015 2464 urological oncology correlation between apoptosis and histological grade of transitional cell carcinoma of urinary bladder jalali nadoushan mr, peivareh h, azizzadeh delshad a department of pathology, medical faculty, shahed university, tehran, iran abstract purpose: to evaluate the relationship between histological grade and apoptotic index (ai) in transitional cell carcinoma (tcc) of urinary bladder. materials and methods: formalin-fixed and paraffin-embedded tissue blocks from 75 patients with tcc, who undergone transurethral resection (tur) were studied. one 3-micron section was provided from each tur samples. in one section after hematoxylin and eosin (h&e) staining, tumor grade was determined according to world health organization/international society of urology and pathology (who/isup) criteria. the apoptotic cells were determined using a terminal deoxynucleotidyl transferase (tdt) mediated dutp biotin nick end labeling (tunel) technique. apoptotic index was then obtained as the percent of tunel positive cells from observations of at least 1000 cells in each section. results: forty-nine patients were men and 26 were women. mean age was 56.34±9 years. mean ai was 2.30±0.50. the relationship between grade and ai was significant (p=0.000, r=0.551); a higher grade was associated with a higher ai. conclusion: apoptosis index has a positive correlation with bladder tcc's grade. further studies are needed to better determine the effect of apoptosis index on prognosis. key words: transitional cell carcinoma, grade, apoptotic index, tunel 177 urology journal unrc/iua vol. 1, no. 3, 177-179 summer 2004 printed in iran introduction transitional cell carcinoma (tcc) of urinary bladder is the second most common genitourinary cancer.(1) patient's prognosis depends on several clinicopathological findings. some of the related variables are stage, histological grade, age, site of the tumor, and simultaneous mucosal lesions in bladder.(2) it is well known that the growth of tumor is determined by cell proliferation and cell loss (apoptosis). recent studies revealed important role for apoptosis in the tumor progression and the prediction of patient survival in a variety of cancers,(3,4,5) but little is known concerning the role of tumor apoptosis in tcc of urinary bladder. in the current study, we investigated the frequency of apoptosis by terminal deoxynucleotidyl transferase (tdt) dutp biotin nick end labeling (tunel) technique, and evaluated the relationship between apoptosis and tumor grade. materials and methods formalin-fixed and paraffin-embedded tissue blocks from 75 patients with tcc of urinary bladder who had undergone transurethral resection (tur) were studied retrospectively. none of the patients had any treatment before tur. the tissue blocks were cut into 3-micron thick sections. representative sections were stained with routine hematoxylin and eosin (h&e) and evaluated. histological grading was done using the who/isup criteria. for the detection of apoptotaccepted for publication in april 2004 correlation between apoptosis and histological grade of transitional cell carcinoma of urinary bladder ic cells, in 3-micron thick sections of the formalin-fixed and paraffin-embedded tissue, the tunel method was used according to the procedures included in the in situ cell detection kit, pod (roche diagnostics gmbh).(6) in brief, after deparaffinization and blocking steps, the sections were exposed to trypsin (0.25 gr) in 100 ml hcl (0.01 normality) and incubated for 30 minutes at 37 degrees centigrade. incubation with 50 microliters tunel reaction mixture (50 microliters terminal deoxynucleotidyl transferase with 450 microliters nucleotide mixture) was performed in a moist chamber for 60 minutes at 37 degrees centigrade, followed by exposure to 50 microliters converter-peroxidase for 30 minutes at 37 degrees centigrade. the sections were then exposed to diaminobenzidine tetrahydrochloride. for negative controls, tdt was omitted.(6) the apoptotic index (ai) was obtained as the ratio of tunelpositive cells to the total number of counted tumor cells and calculated from observations of at least 1000 cells in each section. spearman's rho test was used to analyze the data by spss 9.0 package. results we studied 75 samples from patients with tcc of the urinary bladder, of whom 49 were men and 26 were women. the median age was 56 (range 39 to 80) years. the frequency of the samples' grades is shown in figure 1. mean ai was 2.30±0.50 (range 1.10 to 3.60) percent. mean ai in each grade is shown in figure 2. ai ranged from 1.10% to 2.30% in low malignant potential (lmp) grade, from 1.40% to 3.60% in low grade, and from 1.80 to 3.20% in high grade tumors. ai was significantly related to the tumor grade (p=0.000, r=0.551). discussion most previous studies have demonstrated significant relationship between the presence of apoptosis and tumor grade in tcc of the bladder,(7,8,9) using the tunel method. these studies reported that a higher tumor grade was associated with a higher percent of ai. our study also agrees with this finding. however, lavezzi et al reported an opposite result.(10) they observed a worse prognosis in the presence of low or absent apoptosis. their study involved 177 patients, which were more than the current and previous studies.(7,8,9,11) zhang et al reported a mean value of 2.26% for ai.(9) our report agrees with their study. nevertheless, according to shiina et al,(8) mean ai was 0.96%. the tunel method was used for detecting apoptotic cells in these studies, so the differences in performing several steps of the tunel technique is probable. korkolopoulou et al demonstrated that the assessment of apoptotic potential is more informative than standard prognostic factors in predicting overall survival in patients with tcc of the urinary bladder.(11) for more comparable results our patients are needed to be followed up for long-term. the advantage of this study, compared with the previous ones,(7-11) is the usage of who/isup criteria in histological grading, which is the newest suggested grading criteria. conclusion we demonstrated a close association between apoptosis and tumor grade in tcc of urinary bladder. we believe that the evaluation of apoptosis may be useful in predicting prognosis of the tcc of the urinary bladder. other prospective studies are needed for better determination of the correlation between apoptosis and tumor grade in tcc of bladder. references 1. carroll pr. urothelial carcinoma: cancers of the bladder, ureter, and renal pelvis. in: tanagho ea, mcaninch jw, editors. smith's general urology.15th ed. mcgraw hill; 2000. p. 355-357. 178 fig. 1. frequency of different histological grades fig. 2. mean apoptotic index (ai) in different grades 18.7 46.7 34.7 0 10 20 30 40 50 low malignant potential low grade high grade p e rc e n t 0 0.5 1 1.5 2 2.5 3 low malignant potential low grade high grade a p o p to ti c i n d e x correlation between apoptosis and histological grade of transitional cell carcinoma of urinary bladder 2. kenneth wb, nelson go, richard db, bilbao jm, rosenblum mk. rosai ju. ackerman's surgical pathology. 8th ed. missouri: mosby; 1996. p. 1203-1204. 3. koivisto p,visakorpi t,rantala i. increased cell proliferation activity and decreased cell death are associated with the emergence of hormone-refractory recurrent prostate cancer. j pathology 1997; 183: 51-56. 4. ito y, matsuura n, sakon. m. both cell proliferation and apoptosis significantly predict shortened disease-free survival in hepatocellular carcinoma. br j cancer 1999; 81: 747-751. 5. boohner b, cote r, weidner n. angiogenesis in bladder cancer relationship between microvessel density and prognosis. j national cancer inst 1995; 87: 1603-1612. 6. roche diagnostic gmbh. in situ cell death detection kit, pod. germany: roche; 2003 jaunary. 7. koyuncuoglu m, kargi a, cingoz s, kirkali z. investigation of p53, c-erbb-2, pcna immunoreactivity, dna content, agnor and apoptosis in bladder carcinoma as prognostic parameters. cancer lett 1998 apr; 126(2): 143-8. 8. shiina h, igawa m, shigeno k, yamasaki y, urakami s, yoneda t, et al. clinical significance of mdm2 and p53 expression in bladder cancer. a comparison with cell proliferation and apoptosis. oncology 1999 apr; 56(3): 239-47. 9. zhang x, kong c, takenaka i. evaluation of cell prolifration, apoptosis, and angiogenesis in transitional cell carcinoma of the renal pelvis and ureter. urology 2001 may; 51(5): 981-5. 10. lavezzi am, biondo b, cazzullo a, girdano f, pallotti f, turconil p, et al. the role of different biomarkers (dna, pcna, apoptosis, and karyotype) in prognostic evaluation of superficial transitional cell bladder carcinoma. anticancer res 2001 mar-apr; 21(213): 1279-84. 11. korkolopoulou p, konstantinidou ae, christodoulou p, patsouris e, thomas t, kapralos p, et al. apoptosis in bladder carcinomas detected with monoclonal antibody to single-stranded dna relation to cell cycle regulators and survival. urology 2000 sep; 56(3): 516-20. 179 urol_v03_no3_001_editorial.indd urological oncology 150 urology journal vol 3 no 3 summer 2006 diagnosis of bladder cancer by urine survivin, an inhibitor of apoptosis a preliminary report seyed amirmohsen ziaee,1 seyed javad moula,2 seyed mohammadmehdi hosseini moghaddam,3 darioush eskandar-shiri1 introduction: survivin is an inhibitor of apoptosis that is expressed in undifferentiated tissues like tumors. detection of survivin in urine has been proposed as a diagnostic marker for bladder cancer. we evaluated the urine samples of patients with bladder cancer for survivin and compared them with healthy controls. materials and methods: the urine specimens of 20 patients with transitional cell carcinoma (tcc) of the bladder (group 1) and 18 controls without cancer (group 2) were collected before cystoscopy and assessed for survivin by reverse transcriptase polymerase chain reaction. results: all patients except 1 in group 1 were men. urine specimens were positive for survivin in 18 (90%) and 9 (50%) patients of groups 1 and 2, respectively (p = .007). sixteen patients with tcc had urine cytology, of which 6 (37.5%) were positive. urine survivin was positive in all 10 patients with negative cytology. nine patients in this group had low-grade tumors. conclusion: urine survivin seems to have a higher sensitivity than urine cytology, especially in low-grade bladder cancer. the quantitative measurement of survivin in urine by advanced techniques may provide a better diagnostic and prognostic tool. however, the clinical use of survivin and its association with different stages and grades of tcc still requires more studies. urol j (tehran). 2006;3:150-3. www.uj.unrc.ir keywords: transitional cell carcinoma, bladder, survivin, tumor marker, cytology, urine 1department of urology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran 2department of genetics, tarbiat-emodarress university, tehran, iran 3urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: seyed amir mohsen ziaee, md department of urology, shaheed labbafinejad medical center, 9th boustan st, pasdaran, tehran 1666679951, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: ziaee@hotmail.com received june 2006 accepted july 2006 introduction although we lack a precise statistic, it can be estimated that bladder cancer is the most common urogenital cancer among the iranian men. early diagnosis is crucial and patients with bladder cancer must be followed every 3 to 6 month. the current modalities for diagnosis and follow-up of the bladder cancer are cystoscopy and urine cytology; one an invasive high-cost method and the other a low-sensitive and operator dependent method.(1) to date, many tumor markers have been proposed for bladder cancer, but none have had the potential of surpassing the conventional methods. bladder tumor antigen (bta), nuclear matrix protein-22, telomerase, and hyaluronic acid hyaluronidase are some of the markers which were proposed.(2,3) suboptimal diagnostic accuracy, technology dependency, and high costs have made them abandoned. an ideal bladder tumor marker requires being feasible and easily and rapidly interpreted, like the prostate-specific antigen in the prostate cancer. apoptosis is a genetic cell death program regulated by 3 families of proteins: b-cell leukemia/lymphoma 2 urine survivin and bladder cancer—ziaee et al urology journal vol 3 no 3 summer 2006 151 (bcl2), flice-like inhibitory proteins (flips), and inhibitor of apoptosis proteins (iaps).(1,4) the latter consists of 9 apoptosis regulating proteins, one of which is survivin.(5) survivin was first discovered by ambrosini in 1997.(5) it is a 16.5-kd protein expressed by the birc5 gene at chromosome 17q25.(5) survivin is expressed during embryonic and fetal periods, but it is undetectable in normal adult tissue.(5) it has been shown that survivin is overexpressed in tumoral tissue, reportedly in neuroblastoma, b-cell lymphomas, and the lung, breast, colon, esophagus, and bladder cancers.(6-12) smith and colleague first described urine survivin as a marker of bladder cancer in 2001.(13) the subsequent reports, however, have indicated varying diagnostic accuracies.(14) in this study, we evaluated the accuracy of urine survivin in diagnosing the bladder cancer. materials and methods patient selection in a case-control study, we collected urine samples of the patients with bladder cancer and healthy controls to test for urine survivin. forty-two patients suspected to have bladder cancer underwent cystoscopy. a papillary tumor in the bladder was detected in 20 patients. none of the tumors had involved the bladder neck. they underwent transurethral resection (tur) or tur-biopsy, and pathologic examination confirmed transitional cell carcinoma (tcc) of the bladder. the exclusion criteria were a positive urine culture for infection; primary involvement of the upper urinary tract or the urethra by the tumor; and a positive history of intravesical chemotherapy, systemic chemotherapy, or pelvic and abdominal radiotherapy. all 20 patients were eligible to be enrolled in the study. a urine specimen was obtained before cystoscopy which was used for detection of survivin. a group of controls was selected from among patients who underwent cystoscopy for other reasons and had not any evidence of malignancy in their physical examination, laboratory studies, and cystoscopic examination. urine detection of survivin fifty-ml urine specimens were sent to the genetics laboratory of tarbiat-e-modarres university in tehran, to be tested for survivin by reverse transcription polymerase chain reaction (rt-pcr). extraction of the total rna was performed using rnx-plus solution (cinnagen, tehran, iran) according to the manufacturer’s instructions. the extracted rna was stored in -80°c for use. single-stranded complementary dna (cdna) was synthesized using 5 µg of rna and mmlv reverse transcriptase (gibco brl, germany) with oligo (dt)18 priming in a 20 µl reaction as described elsewhere.(15) the synthesized cdna was amplified using specific primers designed for survivin. the designed primers as well as the oligo (dt)18 primer were synthesized by mwg biotech company (ebersberg, germany) as highly purified salt-free grade. polymerase chain reaction analysis was performed using 5 µl of synthesized cdna with 1.25 u of taq polymerase (promega, madison, wi, usa). the amplification was performed for 25 to 35 cycles. the cycling conditions were as follows: 94°c for 30 seconds, 55°c for 30 seconds, 72°c for 1 minute, and a final extension at 72°c for 10 minutes. the pcr products were then separated on a 1.5% agarose gel and visualized by ethidium bromide staining. statistical analyses the results of survivin in the 2 groups were compared using the chi-square test and a value of less than .05 for p was considered significant. results a total of 20 patients with papillary bladder tumor (group 1) and 18 controls (group 2) were tested for urine survivin. demographic and clinical characteristics of the subjects are summarized in table 1. urine survivin was positive in the specimens of 18 (90%) and 9 (50%) patients in groups 1 and 2, respectively (p = .007). the results of urine cytology were available in 16 patients of group 1, of which 6 (37.5%) were positive for malignancy. all of the patients with a positive cytology had high-grade tumors. urine survivin was detectable in 5 out of 6 patients with positive cytology. furthermore, urine survivin was positive in all 10 patients with negative cytology. nine patients in this group had low-grade tumors (table 2). finally, the 2 patients who were negative for survivin had stage t1 tumors. urine survivin and bladder cancer—ziaee et al 152 urology journal vol 3 no 3 summer 2006 discussion we performed the present study to assess the value of urine survivin in the diagnosis of bladder cancer. as a member of apoptosis inhibitor proteins, survivin is overexpressed in undifferentiated cells associated with a high potential of cell proliferation.(5) survivin is also reported to be highly expressed in cancerous cells.(6-12) following the introduction of survivin by ambrosini in 1997,(5) the first study on bladder cancer that revealed survivin overexpression was done by swana and colleagues in 1999.(12) they found that survivin expression could be documented in 78% of bladder tumor specimens; 65%, 90%, and 100% of grade 1, grade 2, and grade 3 tumors were positive for survivin expression. recurrence of tcc was more frequent among patients with detectable survivin. they also showed that survivin was not expressed in normal transitional cells. however, survivin expression was reported in normal bladder mucosa by lehner and associates in 2002.(16) later on, low rates of survivin expression (13% to 30%) in tumoral cells were demonstrated.(17,18) our previous experience with survivin was indicative of a positive survivin expression in only 50% of tumors.(19) we also studied survivin-∆ex3–a variant product of survivin gene which was reported in renal cell carcinoma.(20) it was more strongly associated with bladder cancer than survivin. detection of survivin in urine specimens of patients with bladder cancer was first studied by smith and colleagues in 2001.(13) they evaluated healthy subjects and patients with benign urogenital disorders; prostatic, renal, vaginal, or cervical tumors; newly diagnosed bladder cancer; and treated bladder tumors. the sensitivity and specificity of urine survivin for the diagnosis of bladder cancer were 100% and 95%, respectively. they used the bio-dot microfiltration detection system for all and the rt-pcr analysis for 20 samples of each group of patients. shariat and coworkers compared 117 patients with bladder cancer and 92 controls and reported that higher levels of urine survivin are associated with bladder cancer and high-grade tumors.(14) we performed a study with 2 phases; the expression of survivin in tumoral cells of bladder cancer was confirmed in the first phase.(19) in the present study (phase 2), we assessed urine survivin. the sensitivity and specificity of urine survivin were lower than those reported by smith and colleagues (90% and 50%, respectively). it may be due to the limited sample sizes and unequal groups in both studies (31 and 16 patients in the subject and control groups of smith and colleagues’ study). furthermore, we excluded any factor that might lead to false-positive results for urine survivin (urinary tract infection, primary upper urinary tract disorders, chemotherapy, etc). we compared the results of urine survivin and urine cytology and their relation with tumor grade. although the number of the patients is too small for table 2. pathology and cytology results in patients with transitional cell carcinoma cytology and pathology survivin positives survivin negatives urine cytology positive 5 1 negative 10 0 tumor stage ta 6 0 t1 9 2 t2 3 0 tumor grade low 10 1 high 8 1 table 1. demographic and clinical characteristics of patients with tcc and controls* *tcc indicates transitional cell carcinoma. †ellipses indicate not applicable. characteristics patients with tcc (group 1) controls (group 2) † median age, y 60 (17 to 82) 43 (24 to 81) male/female 19/1 18/0 cause of referral obstructive and irritative symptoms 0 12 removal of stent 0 6 gross hematuria 18 0 microscopic hematuria 2 0 diagnosis papillary tcc 20 0 bph 0 4 urethral stricture 0 5 bladder calculus 0 1 normal 0 8 tumor stage ta 6 … t1 11 … t2 3 … tumor grade low 11 … high 9 … urine survivin and bladder cancer—ziaee et al urology journal vol 3 no 3 summer 2006 153 a precise conclusion, we can note that urine survivin seems to be more sensitive for diagnosis of bladder cancer, especially high-grade tumors. this test, itself or in combination with cytology, may be useful in the workup of the patients and provide a high sensitivity. for clinical application of survivin, a quantitative test would be more useful. new techniques have been studied recently to determine the levels of survivin in urine,(14) and we have planned a third phase for our study to test the level of survivin in patients with suspected bladder cancer and in patients with treated cancer. also, a comprehensive comparison of urine survivin and urine cytology in different stages and grades is necessary. conclusion the preliminary results of the studies on the expression of survivin have shown that it can be a valuable marker for bladder cancer. we found that urine survivin provides a higher sensitivity compared to urine cytology in low-grade tumors. more studies are required for better clarifying the diagnostic value of urine survivin in bladder cancer. conflict of interest none declared. funding support this study was financially supported by the urology and nephrology research center affiliated with shaheed beheshti university of medical sciences. the laboratory facilities were provided by the tarbiate-modarres university. references 1. sharp jd, hausladen da, maher mg, wheeler ma, altieri dc, weiss rm. bladder cancer detection with urinary survivin, an inhibitor of apoptosis. front biosci. 2002;7:e36-41. 2. lokeshwar vb, soloway ms. current bladder tumor tests: does their projected utility fulfill clinical necessity? j urol. 2001;165:1067-77. 3. stein jp, grossfeld gd, ginsberg da, et al. prognostic markers in bladder cancer: a contemporary review of the literature. j urol. 1998;160:645-59. 4. o’driscoll l, linehan r, clynes m. survivin: role in normal cells and in pathological conditions. curr cancer drug targets. 2003;3:131-52. 5. ambrosini g, adida c, altieri dc. a novel antiapoptosis gene, survivin, expressed in cancer and lymphoma. nat med. 1997;3:917-21. 6. monzo m, rosell r, felip e, et al. a novel antiapoptosis gene: re-expression of survivin messenger rna as a prognosis marker in non-small-cell lung cancers. j clin oncol. 1999;17:2100-4. 7. tanaka k, iwamoto s, gon g, nohara t, iwamoto m, tanigawa n. expression of survivin and its relationship to loss of apoptosis in breast carcinomas. clin cancer res. 2000;6:127-34. 8. kawasaki h, altieri dc, lu cd, toyoda m, tenjo t, tanigawa n. inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. cancer res. 1998;58:5071-4. 9. kato j, kuwabara y, mitani m, et al. expression of survivin in esophageal cancer: correlation with the prognosis and response to chemotherapy. int j cancer. 2001;95:92-5. 10. adida c, haioun c, gaulard p, et al. prognostic significance of survivin expression in diffuse large bcell lymphomas. blood. 2000;96:1921-5. 11. islam a, kageyama h, takada n, et al. high expression of survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. oncogene. 2000;19:617-23. 12. swana hs, grossman d, anthony jn, weiss rm, altieri dc. tumor content of the antiapoptosis molecule survivin and recurrence of bladder cancer. n engl j med. 1999;341:452-3. 13. smith sd, wheeler ma, plescia j, colberg jw, weiss rm, altieri dc. urine detection of survivin and diagnosis of bladder cancer. jama. 2001;285:324-8. 14. shariat sf, casella r, khoddami sm, et al. urine detection of survivin is a sensitive marker for the noninvasive diagnosis of bladder cancer. j urol. 2004;171:626-30. 15. sambrook j, russel dw. molecular cloning: a laboratory manual. 3rd ed. new york: cold spring harbor laboratory press; 2001. 16. lehner r, lucia ms, jarboe ea, et al. immunohistochemical localization of the iap protein survivin in bladder mucosa and transitional cell carcinoma. appl immunohistochem mol morphol. 2002;10:134-8. 17. gazzaniga p, gradilone a, giuliani l, et al. expression and prognostic significance of livin, survivin and other apoptosis-related genes in the progression of superficial bladder cancer. ann oncol. 2003;14:85-90. 18. nakanishi k, tominaga s, hiroi s, et al. expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract. virchows arch. 2002;441:559-63. 19. mowla sd, emadi bayegi m, ziaee sam, nikpoor p. evaluating expression and potential diagnostic and prognostic values of survivin in bladder tumors: a preliminary report. urol j (tehran). 2005;2: 141-7. 20. mahotka c, wenzel m, springer e, gabbert he, gerharz cd. survivin-deltaex3 and survivin-2b: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. cancer res. 1999;59:6097-102. 896 edited1.pdf 906 | case report renal replacement lipomatosis with coexistent papillary renal cell carcinoma, renal tubulopapillary adenomatosis, and xanthogranulomatous pyelonephritis an extremely rare association and possible pathogenetic correlation prerna arora,1 seema rao,1 nita khurana,1 vinod kumar ramteke2 keywords: pyelonephritis, papillary renal cell carcinoma, lipomatosis introduction renal replacement lipomatosis (rrl) is a rare condition, which is characterized by diffuse replacement of renal parenchyma, sinus, and hilum with adipose tissue.(1) it is thought to be associated with physiological as well as several pathological (2,3) in the present case, we found coexistence of rrl with papillary renal cell carcinoma (prcc). furthermore, renal tubulopapillary adenomatosis, xanthogranulomatous pyelonephritis (xgp), and multiple renal calculi were also found. a brief review of literature along with probable pathogenesis of such a rare coexistence is presented. case report years. physical examination was unremarkable. urinalysis showed 30 to 35 red blood cells/ hpf and 20 to 25 pus cells/hpf. an abdominal ultrasonography revealed multiple calculi in the right kidney along with a hypoechoic mass near the upper pole with alteration of vascularity, suggestive of rcc or adrenal mass. contrast-enhanced computed tomography revealed small contracted right kidney. the perinephric fat was proliferating and compressing patissue mass was seen at the superior pole suggestive of rcc or oncocytoma. left kidney was normal in morphology and echotexture. corresponding author: seema rao, md department of pathology, maulana azad medical college, new delhi, 110002, india tel: +91 986 855 1374 fax: +91 2658 8641 e-mail: seemarao1974@ yahoo.co.in received february 2011 accepted july 2011 1department of pathology, maulana azad medical college, new delhi, 110002, india 2department of surgery, maulana azad medical college, new delhi, 110002, india case report 907vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l by adipose tissue with small foci of residual atrophied renal parenchyma (figure 1). there was dilatation of pelvicalyceal system with presence of multiple stones in the calytiple small yellow-colored nodules, largest one of which microscopic examination from yellow nodules showed foci of tubulopapillary adenomatosis (figure 2). sections from papillary area showed prcc (figure 3a). adjacent areas revealed thyroidization of tubules along with diffuse interand xanthoma cells, suggestive of xgp (figures 2 and 3b). discussion renal replacement lipomatosis is a benign condition where renal parenchyma, which in turn becomes atrophic. it can involve the renal sinus, renal hilum, and perirenal space to variable extent.(1) hilum, and/or perirenal space include obesity, cushing’s syndrome, corticosteroid excess, or be idiopathic. however, the preservation of renal parenchyma in such cases distinguishes these entities from rrl.(4,5) renal replacement lipomatosis is usually secondary to renal calculus and renal tuberculosis, occasionally occurs after renal infarction or may be idiopathic. there was no history suggestive of cushing syndrome or corticosteroid and anti-tuberculosis drug intake. diagnosis in rrl and is considered to be superior to ultrasonography, which is not very sensitive for detecting fatty proliferation.(7) furthermore, ct scan is considered to be the best imaging modality to differentiate rrl from other fat-rich lesions, such as renal angiomyolipoma, retroperitoneal lipoma, and liposarcoma.(8) renal replacement lipomatosis is frequently associated with xgp. both share several similarities in terms of possible coexistent of lipomatosis with rcc | arora et al figure 1. gross photograph of the kidney showing fatty replacement of renal tissue, renal calculi (single arrow), and part of atrophic cystic kidney (double arrows); inset: solid foci of papillary rcc (arrow). figure 2. microphotograph of the kidney showing multiple foci of tubulopapillary adenomatosis along with changes of chronic pyelonephritis (hematoxylin and eosin stain, ×4). figure 3. (a) microphotograph showing papillary rcc with psammomatous calcification (hematoxylin and eosin stain, 10×); (b) kidney showing xanthogranulomatous pyelonephritis comprising foamy cells along with inflammatory cells (hematoxylin and eosin stain, ×20) 908 | induction of fatty proliferation, which in turn compensates the loss of renal tissue, thus leading to rrl.(9,10) although there are only limited data available, it is known that the kidneys harboring rcc could reveal various premalignant lesions ranging from dysplasia to adenoma.(11,12) in prcc. in a study of 542 nephrectomy specimens, 7% showed papillary adenoma, out of which 47% arose in the setting of prcc and 15.7% in association with clear cell rcc.(12) adenomas associated with prcc are usually multiple.(12) the present subject had prcc with presence of multiple tubulopapillary adenomatosis, thereby corroborating adenoma-carcinoma sequence. furthermore, our patient had the unique coexistence of rrl with xgp, probably secondary to renal calculi. in conclusion, apart from the novelty of being a rare case, predisposing factors and pathogenesis of rrl and prcc. we hope more urologists, radiologists, and pathologists become aware of this unique entity for its early diagnosis and proper management. conflict of interest none declared. references 1. setty nha, uma k, narvekar vn, desai rs. bilateral idiopathic replacement lipomatosis of the kidney with posterior mediastinal lipomatosis. indian j radiol imaging. 2002;12:251-2. 2. kuthman a. replacement lipomatosis of the kidney. surg gynecol obstet. 1931;52:690-701. 3. kiris a, kocakoc e, poyraz ak, dagli f, boztosun y. xanthogranulomatous pyelonephritis with nephrocutanous fistula and coexisting renal replacement lipomatosis: the report of a rare case. clin imaging. 2005;29:356-8. 4. ambos ma, bosniak ma, gordon r, madayag ma. replacement lipomatosis of the kidney. ajr am j roentgenol. 1978;130:1087-91. 5. hurwitz rs, benjamin ja, cooper jf. excessive proliferation of peripelvic fat of the kidney. urology. 1978;11:448-56. 6. peacock ah, balle a. renal lipomatosis. ann surg. 1936;103:395-401. 7. kocaoglu m, bozlar u, sanal ht, guvenc i. replacement lipomatosis: ct and mri findings of a rare renal mass. br j radiol. 2007;80:e287-9. 8. waligore mp, stephens dh, soule eh, mcleod ra. lipomatous tumors of the abdominal cavity: ct appearance and pathologic correlation. ajr am j roentgenol. 1981;137:539-45. 9. sakata y, kinoshita n, kato h, yamada y, sugimura y. coexistence of renal replacement lipomatosis with xanthogranulomatous pyelonephritis. int j urol. 2004;11:44-6. 10. prasad kk, pandey r, kathuria m, pradhan pk. co-existent massive renal replacement lipomatosis and xanthogranulomatous pyelonephritis--a case report. indian j pathol microbiol. 2003;46:674-5. 11. van poppel h, nilsson s, algaba f, et al. precancerous lesions in the kidney. scand j urol nephrol suppl. 2000;13665. 12. wang kl, weinrach dm, luan c, et al. renal papillary adenoma--a putative precursor of papillary renal cell carcinoma. hum pathol. 2007;38:239-46. case report case report delayed diagnoses of retroperitoneal cystic adenocarcinoma mimicking renal cyst myung-geun noh,1 sang soo shin,2 yoo duk choi,1 taek won kang3,4* keywords: adenocarcinoma/diagnosis; retroperitoneal neoplasms; treatment outcome. introduction primary retroperitoneal cystadenocarcinomas are extremely rare.(1) in the english literature, only 28 cases of primary retroperitoneal cystadenocarcinoma have been published.(2-8) because of the rarity of these tumors, it is hard to determine their exact origin and define an optimal treatment regimen. when this type of lesion is adjacent to the kidney, it can mimic a renal cyst. preoperative diagnosis is difficult because the condition can be mistaken for renal cystic disease.(9) with the increasing availability and use of abdominal imaging tools, cystic renal disease has become a very common finding and the detection of complex cystic masses in the kidney has increased dramatically.(10) however, there is no agreed upon follow-up schedule for complex cystic lesions of the kidneys. we report our experience with a patient with delayed diagnosis of primary retroperitoneal cystadenocarcinoma involving hepatic metastasis that mimicked a renal cyst. it is our hope that physicians will be made more aware of this type of tumor and include it in their differential diagnoses. case report a 67-year-old woman was admitted to our hospital with left flank discomfort and a palpable mass. her medical history included an extracorporeal shock wave lithotripsy (swl) procedure for a urinary stone in the left ureterovesical junction 14 years earlier. at that time, she had a 12 × 9 cm left renal cyst and cytology following cystic aspiration was negative. after 7 years, another left renal cyst, 7.4 cm in size, was detected; cytology following cystic aspiration in that instance was also negative. she failed to appear at a follow-up appointment. when she presented to our hospital, physical examination was unremarkable. she was afebrile and normotensive, her pulse was 96 beats/min, and her respiratory rate was 20 breaths/min. routine laboratory findings including urinalysis results were normal. a chest x-ray and electrocardiogram showed no remarkable findings. abdominal computed tomography (ct) scan demonstrated a retroperitoneal multi-septated cystic lesion with a solid enhancing mass in the left lower pole of the kidney, which met the criteria for a bosniak category iif cyst (figure 1a). magnetic resonance imaging (mri), performed to evaluate the cause of the patient’s symptoms, showed a 7 × 6.5 × 5.1 cm well-defined lobulated hemorrhagic cystic mass abutting the lower pole of the left kidney, which was in agreement with the diagnosis of a bosniak category iif cyst. the patient visited our outpatient clinic for a follow-up every six months, and there was no significant change in the cystic lesion except for an increase in size (the cyst grew from about 7 cm to 8.8 cm over 2 years), as determined by ultrasound imaging. given that the cyst significantly increased in size and flank discomfort persisted, surgery was considered. an abdominal ct scan revealed a 8.4 × 7.3 × 5.5 cm septated cystic mass with solid enhancing portions in the left retroperitoneum abutting the lower pole of the left kidney and the descending colon, suggesting a malignant cystic tumor, several variable-sized peripheral enhancing mass lesions in the liver, suggesting metastases, and several small (1 cm or smaller) lymph nodes in the para-aortic space (figures 1b and 1c). the patient underwent ultrasound-guided 18g needle biopsy of the left hepatic lobe and the retroperitoneal cystic 1 department of pathology, chonnam national university medical school, gwangju 61469, korea. 2 department of radiology, chonnam national university medical school, gwangju 61469, korea. 3 department of urology, chonnam national university medical school, gwangju 61469, korea. 4 center for aging and geriatrics, chonnam national university medical school, gwangju, 61469, korea. *correspondence: department of urology, chonnam national university hospital and medical school, 42 jebong-ro, donggu, gwangju 61469, south korea. tel: +82 62 2206703. fax: +82 62 2271643. e-mail: sydad@hanmail.net. received december 2015 & accepted april 2016 case report 2729 lesion. both pathological exams were consistent with adenocarcinoma, so it was clear that metastasis had occurred (figure 2). for lesions not amenable to surgery, chemotherapy is the treatment of choice. discussion cystic renal disease is very common and the rate of detection of complex cystic lesions in the kidney has increased dramatically over the last few decades because of the increased availability of cross-sectional imaging tools.(10) cysts may be complicated by hemorrhage or infection and develop calcification, septation, wall thickening, or high attenuation, which are all features that are shared by cystic tumors. to characterize these lesions and provide an approach for their management, the bosniak classification system based on ct features is used by urologists and radiologists in clinical practice. category i lesions require no follow-up or other intervention. category ii lesions are considered benign and also do not require follow-up. where there is some ambiguity, however, about the extent or character of the septation, calcification, or other features, follow-up with repeat imaging studies at 3 months, 6 months, and 1 year is recommended. category iii lesions can be either malignant or benign tumors. because it is difficult to accurately distinguish between different kinds of multilocular renal masses, such lesions must be surgically removed. if clinical and imaging features suggest multilocular cystic nephroma, kidney-sparing surgery can be performed. category iv lesions have more obvious malignant characteristics and are regarded as unequivocally malignant, requiring surgical management. (11) in the case of our patient, the lesion was determined to be a category iif, which requires annual follow-up studies. however, in the 7 years after the patient saw a specialist for the first time, the lesion was evaluated only once. after 14 years, the lesion had evolved into an adenocarcinoma with liver metastases. retroperitoneal adenocarcinomas are extremely rare. (1) because of the rarity of these tumors, it is hard to determine their exact origin and decide on an optimal treatment regimen. preoperative diagnosis is difficult because such lesions are easily mistaken for renal cystic disease.(9) the ability to differentiate between benign and malignant tumors represents a major challenge. the clinical course may appear to be indolent; however, these tumors can become aggressive. overall, the prognosis and pathophysiology of such tumors are uncertain because of their rarity and the lack of long-term follow-up studies. the longest reported follow-up study was done over the course of 6 years.(12) of the 26 female patients in that study, 4 died of metastatic disease, which involved the lungs, liver, adrenal gland, peritoneum, and regional lymph nodes. adjuvant chemotherapy was attempted in 6 patients with limited success. three patients died within 4–18 months after surgery, 1 experienced recurrence after 21 months, and 2 others were retroperitoneal cystic adenocarcinoma-noh et al. figure 1. computed tomography (ct) scan. a) a bosniak category iif cystic lesion in the lower pole of the left kidney. b) multiple heterogenous masses in the liver. c) a cystic mass in the retroperitoneum, which is invading the psoas muscle. figure 2. a) histological evaluation of the retroperitoneal mass, demonstrating adenocarcinoma (hematoxylin and eosin staining, ×10). b) histological evaluation of the hepatic mass, demonstrating adenocarcinoma (hematoxylin and eosin staining, ×10). vol 13 no 03 may-june 2016 2730 free from recurrence at 18 and 33 months.(4) mucinous cystadenocarcinomas can also occur in the liver, pancreas, and ovaries. our patient had a renal cystic mass and several hepatic masses. preoperative evaluation could not exclude benign renal cystic disease as the origin of the cystic retroperitoneal mass. renal lymphangiomas can also present as slow-growing flank or abdominal masses that take an indolent clinical course; in those cases, imaging reveals large perirenal and peripelvic cysts. parasitic cysts or renal hydatidosis are uncommon conditions but should also be considered.(7,14) diagnosis can often only be made through surgical excision.(13) needle biopsy may be of use in these situations because a biopsy may reveal adenocarcinoma, which implies that a tumor, such as a primary retroperitoneal adenocarcinoma, is likely to exist. however, needle biopsy is not a good tool for identifying malignancy in cystic tumors. physicians should consider primary retroperitoneal adenocarcinoma in the differential diagnosis of large retroperitoneal cystic lesions, because such lesions are often mistaken for renal cysts. the tumors usually present with mass effects, as in our patient, take an indolent course, and can become very large before they cause clinical problems. preoperative diagnosis is difficult, and in most cases, a laparoscopic procedure is the best method for diagnosis and treatment. aspiration and cytology of the cystic lesion was not effective in this case. however, needle tract seeding is a rare event; the incidence is estimated to be less than 1 in 10,000 biopsies. only eight cases of needle tract seeding during a renal mass biopsy have been described in the medical literature.(15) conclusions even though a cyst may not progress rapidly, it can display aggressive clinical behavior, and the appropriate treatment regimen has yet to be defined. to date, extirpative surgery appears to be the treatment of choice, and the role of adjuvant radiation or chemotherapy has yet to be determined. acknowledgements this study was supported by a grant (cri15002-1) chonnam national university hospital biomedical research institute. conflict of interest none declared. references 1. suzuki s, mishina t, ishizuka d, fukase m, matsubara yi. mucinous cystadenocarcinoma of the retroperitoneum: report of a case. surg today. 2001;31:747-50. 2. carabias e, garcia muñoz h, dihmes fp, lópez pino ma, ballestín c. primary mucinous cystadenocarcinoma of the retroperitoneum. report of a case and literature review. virchows arch. 1995;426:641–5. 3. kessler tm, kessler w, neuweiler j, nachbur bh. treatment of a case of primary retroperitoneal mucinous cystadenocarcinoma: is adjuvant hysterectomy and bilateral salpingooophorectomy justified? am j obstet gynecol. 2002;187:227–32. 4. mikami m, tei c, takehara k, komiyama s, suzuki a, hirose t. retroperitoneal primary mucinous adenocarcinoma with a mural nodule of anaplastic tumor: a case report and literature review. int j gynecol pathol. 2003;22:205–8. 5. park u, han kc, chang hk, huh mh. a primary mucinous cystoadenocarcinoma of the retroperitoneum. gynecol oncol. 1991;42:64–7. 6. seki h, shiina m, nishihara m, et al. primary retroperitoneal mucinous cystadenocarcinoma: report of a case. radiat med. 1990;8:164–7. 7. shahait m, saoud r, el hajj a. laparoscopic treatment of giant renal cystic echinococcosis. int j infect dis. 2016;42:58-60. 8. tangjitgamol s, manusirivithaya s, sheanakul c, leelahakorn s, thawaramara t, kaewpila n. retroperitoneal mucinous cystadenocarcinoma: a case report and review of literature. int j gynecol cancer. 2002;12:403–8. 9. green jm, bruner bc, tang ww, orihuela e. retroperitoneal mucinous cystadenocarcinoma in a man: case report and review of the literature. urol oncol. 2007;25:53-5. 10. mcguire bb and fitzpatrick jm. the diagnosis and management of complex renal cysts. curr opin urol. 2010;20:349-54. 11. curry ns. atypical cystic renal masses. abdom imaging. 1998;23:230-6. 12. uematsu t, kitamura h, iwase m, et al. ruptured retroperitoneal mucinous cystadenocarcinoma with synchronous gastric carcinoma and a long postoperative survival: case report. j surg oncol. 2000;73:26–30. 13. honma i, takagi y, shigyo m, et al. lymphangioma of the kidney. int j urol. 2002;9:178–82. 14. gogus c, safak m, baltaci s, turkolmez k. isolated renal hydatidosis: experience with 20 cases. j urol. 2003;169:186–9. case report 2731 retroperitoneal cystic adenocarcinoma-noh et al. 15. chang dt, sur h, lozinskiy m, wallace dm. needle tract seeding following percutaneous biopsy of renal cell carcinoma. korean j urol. 2015;56:666-9. retroperitoneal cystic adenocarcinoma-noh et al. vol 13 no 03 may-june 2016 2732 urology journal vol. 11 no. 04 july august 2014 1772 laparoscopic urology laparoendoscopic single-site adrenalectomy sans transumbilical approach: initial experience in japan shogo inoue, kenichiro ikeda, mitsuru kajiwara, jun teishima, akio matsubara department of urolgy, hiroshima university graduate school of bio medical sciences, hiro shima, japan. corresponding author: shogo inoue, md department of urology, hiroshima university graduate school of biomedical sciences, 1-2-3 kasumi, minami-ku, hiroshima, 7348551, japan. tel: +81 82 257 5242 fax: +81 82 257 5244 e-mail: inosyogo@hiro shima-u.ac.jp received july 2013 accepted february 2014 purpose: the use of laparoendoscopic single-site (less) surgery has been increasing. the less procedure has been done for various urological diseases and studies have shown that it results in less pain, shorter hospital stays and excellent cosmetic outcomes. materials and methods: we describe our initial experience with less adrenalectomy without the use of the transumbilical approach. the participants were 16 consecutive patients who underwent less adrenalectomy using a sils porttm (covidien, mansfield, ma, usa) at hiroshima university hospital. various parameters including the insufflation time, estimated blood loss, resumption of oral intake and complications were analyzed. results: the adrenalectomy was completed successfully with no major intraoperative complications in 15 of the patients. one less adrenalectomy was converted to a conventional laparoscopic adrenalectomy by placement of two additional 12 mm trocars; this patient was therefore excluded from the study. the mean (range) patient age was 53.8 (35-69) years, body mass index (bmi) was 23.5 (20.7-27.2) kg/m2, tumor size was 19.8 (9-45) mm, insufflation time was 188.0 (95-340) min and estimated blood loss was 36.3 (10-80) ml. in all cases articulating instruments were used for satisfactory dissection and triangulation. one bowel injury (serosal) occurred and was repaired in the open laparotomy before sils porttm insertion. all patients at the follow-up visit were satisfied and pleased with their scars. conclusion: we found less adrenalectomy to be apparently safe, effective and minimally invasive for adrenal diseases. in our opinion, less adrenalectomy without using the transumbilical approach is feasible and easy to introduce. keywords: adrenalectomy; laparoscopy; methods; standards; postoperative complications; quality improvement. by co 2 gas insufflation to 8 mmhg. the surgical strategy followed that for a conventional transperitoneal adrenalectomy.(5) specifically, the toldt line and the typical vascular landmarks (inferior vena cava and renal vein for rightand left-sided adrenal tumor, respectively) were dissected and exposed using a bent laparoscopic instrument (roticulator endo dissecttm, covidien, mansfield, ma, usa) and straight standard instruments (figure 1). the adrenal veins were identified, controlled with two 5 mm polymer locking clips (hem-o-lok, teleflex medical, research triangle park, n.c., usa), one proximally and one distally and then divided. a 5 mm ligasuretm (covidien, mansfield, ma, usa) was used to complete the adrenal gland dissection. then hemostasis was ensured, the entire adrenal gland involving the tumor was freed within the abdomen and placed in an endocatch goldtm (covidien, mansfield, ma, usa) inserted through the 12 mm instrument channel. the specimen was retrieved together with the sils porttm without any further skin incision in all cases. a surgical suction drain was left in place through the surgical port. all patients underwent transperitoneal less adrenalectomy. results the patient demographics and surgical outcomes are shown in tables 1 and 2. the mean (range) patient age was 53.8 years and mean body mass index (bmi) was 23.5 kg/m2. there was no conversion to open surgery for any patient. one patient, however, was switched to a conventional laparoscopic adrenalectomy by the placement of two additional 12 mm trocars. this patient was slightly obese (bmi 27.2 kg/ m2), resulting in a very small working space, which made handling the instruments very difficult. this indicates that the patient selection criteria were less stringent than expected. for the remaining 15 patients, the less adrenalectomy was completed successfully without any intraoperative complications. with growing experience, indications can be expanded to include more challenging cases. in all cases, the sils porttm was easily inserted, and the articulating instruments facilitated satisfactory dissection and triangulation. the mean (range) insufflation time was 188.0 (95-340) min, and there was learning curve (figure 2). the mean estimated blood loss was 36.3 (10-80) ml, and the dissected tumor weight was 21.2 (8-58) g. the mean insufflation time and estimated blood loss were not significantly different for left side tumors (212.3 min; 27.5 ml) and right side tumors (141.3 min, p = .07; 22.9 ml, p = .66). a minor serosal injury occurred in patient #1 during open laparotomy and was in situ repaired with intermittent sutures before sils porttm insertion. none of the patients required blood transfusion. the mean vas was 2.5 on the first postoperative day (pod) and 0.4 on the seventh. mean length of hospital stay was 7.9 (5-12) days. all patients at the follow-up visit were satisfied and pleased with their scars (figure 3). discussion introduction since the early 1990s, laparoscopic adrenalectomy has become a standard procedure for the majority of patients with a surgical adrenal tumor.(1) the conventional laparoscopic adrenalectomy uses three or four ports, most commonly one 12 mm and two or three 5 mm. a paradigm shift in the field of minimally invasive surgery is now underway, as laparoscopy progresses toward scar less techniques. with the advent of multichannel single ports as well as curved and articulating instruments, the possibility of complex laparoscopy through a single incision has been reported. as a result, the use of laparoendoscopic single-site (less) surgery has increased. over the last few years there has been increasing enthusiasm for and growing interest in this novel minimally invasive surgical procedure.(2) less surgery has been done for various urological diseases, and studies have shown that it results in less pain, shorter hospital stays and excellent cosmetic outcomes.(3) however, evaluation of less cosmesis has largely entailed subjective operator assessment, with objective evaluation limited by small sample sizes and evaluation as a secondary endpoint. less adrenalectomy through the umbilical access can be extremely challenging due to the angle of approach and difficult organ retraction. there have been few reports on the use of less adrenalectomy without using the transumbilical approach for japanese patients. in this report, we describe our initial experience with less adrenalectomy in japanese patients using a multichannel single port without using the transumbilical approach. materials and methods participants between november 2009 and january 2011, sixteen consecutive patients with an adrenal tumor (12 primary aldosteronism, 2 cushing syndrome, and 2 preclinical cushing syndrome) underwent transperitoneal less adrenalectomy by two surgeons (a.m. and s.i.) at hiroshima university hospital. all patients consented to less adrenalectomy and additional incisions if necessary. the surgeons had previously undergone animal lab training. various parameters including the insufflation time, estimated blood loss, pain scale, resumption of oral intake and complications were analyzed. convalescence was measured by using a visual analogue pain scale (vas) from 0 (negligible pain) to 10 (severe discomfort). surgical technique under general anesthesia, the patients were placed in the 60° modified flank position; the operators stood facing the abdomen, between the arcus costalis on the ipsilateral side and the umbilicus. a 2 cm skin incision and an access into the peritoneal cavity were made by open laparotomy. then, a multichannel port (sils porttm, covidien, mansfield, ma, usa) was placed in the incision. an additional port was used in right-sided adrenal tumor for liver traction.(4) a 5-mm trocar is inserted in the right lateral abdomen for a snake-retractor to pull up the lateral segment of the liver and prevent liver injury. to minimize instrument collision, a flexible 5 mm 0° high-definition laparoscope (olympus, tokyo, japan) was used. pneumoperitoneum was induced 1773 laparoscopic urology urology journal vol. 11 no. 04 july august 2014 1774 laparoendoscopic single-site adrenalectomy-inoue et al initial experience, the insufflation time trended down as the surgeons became more experienced with the articulating instruments. until now, the main benefit of less surgery over conventional lapa roscopic surgery has been the improved cosmetic outcome. few studies have been conducted comparing less surgery with conventional laparoscopic surgery. addition of working port risks morbidity from bleeding, hernia and internal organ damage.(13) in addition to the cosmetic advantage, less has the potential to minimize or eliminate other complications due to surgical incision. all 15 patients underwent surgery safely without major complications. while less surgery is more difficult than conventional laparoscopic surgery, the patients in our study made a fast and relatively painless recovery. the first successful less adrenalectomy was reported by cindolo and colleagues(14) for the excision of a 4 cm non-functional left adrenal mass using a 3 cm incision. over the last 2 years, several series of less adrenalectomy have been reported, so that available evidence on this surgical procedure is larger.(15) one of our less adrenalectomy patients had a relatively high bmi (27.2 kg/m2) and although he had a great deal of fat tissue, the operation was successfully performed in two hours. although it has been reported that a high bmi might be a contraindication for less,(16) we believe that selection of our subcostal approach might reduce the difficulty of less adrenalectomy in patients with high bmi. the most common position for access in less surgery has been the umbilicus for cosmetic reasons. however, less adrenalectomy through the umbilical access is extremely challenging due to the angle of approach and difficult organ retraction. moreover, as the target area for dissection becomes more cranial, dissection with the transumbilical less procedure will become extremely difficult. our subcostal approach allowed a wider working space for instrumetion than the retroperitoneal approach and more direct and shorter access to the tumor compared with the transumbilical approach.(17) there is also the laparoscopic adrenalectomy has become the gold standard for the treatment of adrenal tumors, and it has various approaches.(6) many investigators have developed and reported techniques for reducing the number of ports required to perform safe laparoscopic surgery.(7) although several efforts have been made to further reduce invasiveness in laparoscopic adrenalectomy, an incision is ultimately required for specimen retrieval.(8) the sils porttm (figure 1) has three legs, each 5 mm in diameter, and one insufflation line and requires only a 20 mm longitudinal incision. air leaks at the operative sites can be avoided by using a sils porttm. three instruments with diameters of 5 mm or less can be used simultaneously by inserting each one through a port leg. alternatively, two 5 mm port legs can be replaced with one 12 mm port leg, enabling the surgeon to use a 10 mm instrument, such as an endocatch goldtm, by passing it through the 12 mm channel. the sils porttm allowed us to perform the whole procedure up until the final incision for specimen retrieval. a key problem with the use of the less procedure is the inability to triangulate the positions of the instruments, which are inserted in parallel.(9) we had difficulty driving the instruments and avoiding internal and external collisions. these limitations are typical of all less procedures, reflecting the small space between the hands of the surgeon and those of the assistant. the introduction of advanced equipment and technical modifications obscured the concept of an essential triangulation in favor of less.(10) cooperation between the surgeons requires skilled camera driving and constant coordination.(11) these skills can be honed through laboratory training.(12) to achieve optimal dissection and triangulation, we used articulating instruments. there is room for technological improvement in the trocars, cameras and instruments.(4,9) further development of ergonomically shaped handles designed for less would help promote wide adoption of this technique. in this variables values no. of patients 16 gender, no. (%) male 10 (62.5) female 6 (37.5) age, year, mean (range) 53.8 (35-69) bmi, kg/m2, mean (range) 23.5 (20.7-27.2) preoperative diagnosis, no. (%) primary aldosteronism 12 (75.0) preclinical cushing’s syndrome 2 (12.5) cushing’s syndrome 2 (12.5) laterality, no. (%) right 8 (50.0) left 8 (50.0) variables values conversion, no. (%) 1 (6.3) tumor size, mean (range) (mm) 19.8 (9-45) insufflation time, mean (range) (min) 188.0 (95-340) estimated blood loss, mean (range) (ml) 36.3 (10-80) dissected tumor weight, mean (range) (g) 21.2 (8-58) transfusion, no. (%) 0.0 (0.0) resumption of oral intake, pod, mean 1.0 complications, no. (%) 1.0 (6.3) vas, mean (range) pod 1 2.5 (0-6) pod 7 0.4 (0-1) table 1. patients demographics. abbreviation: bmi, body mass index. abbreviations: vas, visual analog scale; pod, post-operative day. table 2. surgical outcomes. resulting in fewer scars. in our opinion, less adrenalectomy without using the transumbilical approach is feasible and easy to introduce, but experience in standard laparoscopy should be accumulated, and patients should be accurately and rigorously screened prior to undergoing less adrenalectomy. conflict of interest none declared. references 1. guazzoni g, cestari a, montorsi f, et al. current role of laparoscopic adrenalectomy. eur urol. 2001;40:8-16. 2. autorino r, cadeddu ja, desai mm, et al. laparoendoscopic single-site and natural orifice transluminal endoscopic surgery in urology: a critical analysis of the literature. eur urol. 2011;56:26-45. 3. kaouk jh, autorino r, kim fj, et al. laparoendoscopic single-site sur gery in urology: worldwide multi-institutional analysis of 1076 cases. eur urol. 2011;60:998-1005. 4. gettman mt, box g, averch t, et al. consensus statement on natural orifice transluminal endoscopic surgery and single-incision laparoscopic surgery: heralding a new era in urology? eur urol. 2008;53:1117-20. 5. zacharias m, haese a, jurczok a, stolzenburg ju, fornara p. transperiquestion of whether our subcostal approach to less adrenalectomy provides more benefits than the transumbilical approach. this question remains for future research. there were limitations to this study. the small sample size (15 patients) makes it impossible to state any general conclusion. few studies have compared less surgery with conventional laparoscopic surgery. a more extensive randomized comparison between less surgery and conventional laparoscopic surgery using tools designed to detect differences in morbidity and assess cosmetic benefits will ultimately determine the future of less surgery.(18) we believe that continuing advances in less technology will improve this procedure in the near future.(8) less surgery should still be explored with the greatest consideration of all ethical and methodological issues. in our opinion, less adrenalectomy without using the transumbilical approach is a safe procedure, with the additional benefit of being minimally invasive; however, long-term follow-up is necessary. conclusion even though these first cases represent only our initial experience with less adrenalectomy, we have found that this procedure is apparently safe, effective and minimally invasive for adrenal diseases. less adrenalectomy has great potential as a new laparoscopic procedure figure 1. laparoendoscopic single-site adrenalectomy; (a) multi-channel sils porttm, (b) outside view and (c) inside view during laparoendoscopic single-site adrenalectomy, (d) separation of left adrenal tumor using roticulator endo dissecttm and ligasuretm device. figure 2. insufflation time in minutes; black is operator a and gray is operator b. figure 3. postoperative appearance of laparoendoscopic single-site surgical incision. 1775 laparoscopic urology urology journal vol. 11 no. 04 july august 2014 1776 toneal laparoscopic adrenalectomy: outline of the preoperative manage ment, surgical approach, and outcome. eur urol. 2006;49:448-59. 6. mccauley lr, nguyen mm. laparoscopic radical adrenalectomy for cancer: long-term outcomes. curr opin urol. 2008;18:134-8. 7. han wk, park yh, jeon hg, et al. the feasibility of laparoendoscopic single-site nephrectomy: initial experience using home-made sin gle-port device. urology. 2010; 76: 862-5. 8. cindolo l, gidaro s, neri f, tamburro fr, schips l. assessing feasibil ity and safety of laparoendoscopic single-site surgery adrenalectomy: initial experience. j endourol. 2010;24:977-80. 9. stolzenburg ju, kallidonis p, hellawell g, et al. technique of lapro scopic-endoscopic single-site surgery radical nephrectomy. eur urol. 2009;56:644-50. 10. canes d, desai mm, aron m, et al. transumbilical single-port surgery: evolution and current status. eur urol. 2008;54:1020-9. 11. cindolo l, berardinelli f, bellocci r, schips l. laparoendoscopic sin gle-site unclamped nephron-sparing surgery: a case report. eur urol. 2010;60:591-4. 12. kaouk jh, haber gp, goel rk, et al. single-port laparoscopic surgery in urology: initial experience. urology. 2008;71:3-6. 13. raman jd, cadeddu ja, rao p, rane a. single-incision laparoscopic surgery: initial urological experience and comparison with natural-ori fice transluminal endoscopic surgery. bju int. 2008;101:1493-6. 14. cindolo l, gidaro s, tamburro fr, schips l. laparoendoscopic sin gle-site left transperitoneal adrenalectomy. eur urol. 2010;57:911-4. 15. rane a, cindolo l, schips l, de sio m, autorino r. laparoendoscopic single site (less) adrenalectomy: technique and outcomes. world j urol. 2012;30:597-604. 16. miyajima a, hattori s, maeda t, et al. transumbilical approach for lap aro-endoscopic single-site adrenalectomy: initial experience and short term outcome. int j urol. 2012;19:331-5. 17. wang l, liu b, wu z, et al. comparison of single-surgeon series of tran speritoneal laparoendoscopic single-site surgery and standard laparo scopic adrenalectomy. urology. 2012;79:577-83. 18. desai mm, berger ak, brandina r, et al. laparoendoscopic single-site surgery: initial hundred patients. urology. 2009;74:805-12. laparoendoscopic single-site adrenalectomy-inoue et al vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2014 urological oncology novel approach for pain control in patients undergoing prostate biopsy: iliohypogastric nerve block with or without topical application of prilocaine-lidocaine: a randomized controlled trial fatih hizli,1* güldeniz argun,2 fatih özkul,1 oğuz güven,1 ali ihsan arik,1 sinan başay,1aydin köşüş,3 halil günaydin,1 halil başar1 purpose: to investigate the efficacy of a novel anesthetic technique called iliohypogastric nerve block (inb) for pain control in patients undergoing prostate biopsy. materials and methods: a total of 59 consecutive patients who underwent transrectal ultrasound guided prostates biopsies were included in the study. patients were randomized into four groups: (1) control, no method of anesthesia was administered, (2) intrarectal prilocaine-lidocaine cream application, (3) inb and (4) inb + intrarectal prilocaine-lidocaine cream application (combined group). patients were asked to use a scale of 0-10 in a visual analogue scale (vas) questionnaire about pain during probe insertion (vas 1) and prostate biopsy (vas 2). results: the mean vas 1 and vas 2 scores were 0.7 and 4.9 for controls, 0.5 and 1.8 for inb, 0.5 and 2.6 for the intrarectal cream group, and 0.4 and 1.8 for the combined group. the mean vas 1 scores were not different between groups. however, the mean vas 2 scores were significantly lower in inb, prilocaine-lidocaine cream and combined groups compared to the control group (p < .001). in addition, the inb group had significantly lower vas 2 scores compared to the cream application group (p = .03). on the other hand, there was no difference between the inb and combined groups (p = .8). conclusion: any form of anesthesia was superior to none. however, inb alone seemed to be superior to prilocaine-lidocaine cream application in patients undergoing prostate biopsy. addition of prilocaine-lidocaine cream application to inb may not provide better analgesia. keywords: anesthetics; local; administration; lidocaine; pain management; methods; prostate treatment; outcome. introduction prostate biopsy is considered to be an invasive procedure and is likely painful, requiring some form of anesthesia.(1) transrectal probe insertion and multiple punctures of the anterior rectal wall, periprostatic soft tissue and prostate capsule may cause the pain. the gold standard for the best pain control during prostate biopsy is to use periprostatic infiltration of lidocaine.(2-10) however, the periprostatic injection itself may cause pain and makes the entire biopsy procedure more uncomfortable.(11) it has been shown that preventive topical anesthesia combined with periprostatic infiltration is successful in achieving more complete pain control during the biopsy procedure. previously, it was shown that a lidocaine-prilocaine mixture as a topical anesthetic had a pain control advantage versus placebo when the prostate capsule was punctured.(12) the efficacy of topical prilocaine-lidocaine cream was reported by other authors as well.(13-15) during the last decade, the use of ultrasound-guided regional anesthesia has increased, and developments in ultrasound technology have enabled direct visualization of peripheral nerves.(16) a technique for ultrasound-guided iliohypogastric nerve block (inb) has been described in adults.(16-18) in pediatric patients, ultrasound-guided blocks have been associated with a higher success rate and a lower volume of local anesthetic needed, compared with conventional landmark based techniques.(19,20) it has been shown that the use of inb for patients undergoing herniorrhaphy resulted in a shorter time-to-home readiness, quicker oral intake postsurgery, and no need for recovery room care.(21) in light of these findings, primary outcome of the study was to investigate the efficacy of a novel anesthesia technique called inb and the secondary outcome was to determine whether application of local anesthetics enhance the pain relief in patients undergoing prostate biopsy. materials and methods patients and study design after obtaining approval from the local ethics committee, a total of 59 consecutive patients who underwent transrectal ultrasound guided biopsies were included in this single blind randomized prospective study. all participants were informed and written consents were taken. the random allocation procedure was determined by opening a sequentially numbered envelope, thereby determining whether the patients should receive(1) no 1 department of urology, oncology training and research hospital, ankara, turkey. 2 department of anesthesiology, oncology training and research hospital, ankara, turkey. 3 department of obstetrics and gynecology, faculty of medicine, turgut ozal university, ankara, turkey. *correspondence: department of urology, oncology training and research hospital, 06530 demetevler, ankara, turkey. tel: +90 312 336 0909 4943. fax: +90 312 345 4979. e-mail: fatihhizli33@yahoo.com. received august 2014 & accepted january 2015 method of anesthesia,(2) intrarectal prilocaine-lidocaine cream (emla®, astrazeneca inc, macclesfield, cheshire uk) application,(3) inb or(4) inb + intrarectal prilocaine-lidocaine cream application (combined group). this random sequence was generated by computer, and the investigator was unaware of the sequence. consort flow diagram of the trial is shown in figure 1. physician performing prostate biopsy and evaluating vas scores, was blind to the patient’s group assignment. iliohypogastric nerve block (inb) once the target nerves had been identified in a crosssectional view, the following measurements were made: distance from the anterior superior iliac spine to the ilioinguinal nerve, distance between the ilioinguinal and iliohypogastric nerves, depth of the ilioinguinal and iliohypogastric nerves relative to the skin and distance from the ilioinguinal nerve to the peritoneum. following aseptic preparation of both the puncture site and the ultrasonographic probe, the nerve block was performed using an insulated 22-gauge 40-mm needle with a facette tip needle and an injection line. initially, the anterior superior iliac spine was palpated and a mark made 2 cm medial and 2 cm superior from it (figure 2). the needle was then visualized by ultrasound (figure 3). a loss of resistance was appreciated as the needle passed through the muscle to lie between the muscle and the internal oblique. after the initial loss of resistance and negative needle aspiration of blood, the needle was placed in an optimal position relative to the nerves, and a single injection of lidocaine 0.2% was administered under realtime ultrasound control until both nerves were surrounded by the local anesthetic. the needle was then inserted further to encounter another resistance, which was the internal oblique muscle. a further loss of resistance was appreciated once the needle passed through the internal oblique to lie between it and the transversus abdominis muscle. after the second loss of resistance, another 2 ml of local anesthetic was administered. the needle was then withdrawn to the skin and redirected at a 45-degree angle medially to again pierce the external and then the internal oblique muscles (figure 4). after each loss of resistance, 10 ml of local anesthetic was again administered. the needle was then returned to the skin and inserted 45 degrees laterally, and the procedure repeated. thus, a total of 20 ml of local anesthetic was placed in a fan-like distribution between the external and internal oblique and the internal oblique and transversus abdominis muscles. note: in patients with little abdominal wall musculature, the internal oblique muscle may be too thin to appreciate a loss of resistance as it is penetrated. to prevent entering the abdomen after piercing the external oblique muscle, the author limits further abdominal wall penetration without loss of resistance to 1.5 cm. lower abdominal skin or inguinal region is checked for the maintenance of anesthesia. pain score patients were asked to use a scale of 0-10 to complete a visual analogue scale (vas) questionnaire about pain during probe insertion (vas 1) and prostate biopsy (vas 2) (figure 5). prostate biopsy procedure variables group 1 group 2 group 3 group 4 p value patients number 14 16 14 15 age, years, mean ± sd 60.2 ± 5.6 60.5 ± 5.2 63.3 ± 11.7 65.0 ± 5.7 .100 prostate volume, ml mean ± sd 41.5 ± 10.2 49.1 ± 6.6 50.5 ± 24.6 49.9 ± 8.3 .100 serum psa, (ng/ml) mean ± sd 8.2 ± 3.5 8.2 ± 1.9 13.0 ± 15.7 8.5 ± 3.4 .700 vas 1 0.7 ± 0.5 0.5 ± 0.5 0.5 ± 0.6 0.4 ± 0.5 .300 vas 2 4.9 ± 0.7 2.6 ± 1.0 1.8 ± 0.5 1.9 ± 0.4 < .001 abbreviations: psa, prostate specific antigen; vas, visual analogue scale, sd, standard deviation. table 1. demographic and clinical characteristics of study groups. figure 1. consort flow diagram for patients who were brought into trial. figure 2. the application of ultrasound-guided iliohypogastric nerve block. pain control during trus-guided prostate biopsy-hizli et al urological oncology 2015 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2016 included in the study were 59 consecutive patients with concerning elevated prostate-specific antigen (psa) values or suspicious digital rectal exam (dre) results, and/ or who underwent transrectal ultrasound (trus)-guided needle biopsy of the prostate. exclusion criteria included lidocaine allergy, hemostasis disorders, anticoagulant therapy, prediagnostic unbearable pain, chronic pelvic pain syndrome, or anorectal pathologies. prophylaxis was carried out by oral administration of ciprofloxacin 500 mg twice a day, starting the evening before sampling until 3 days after the procedure. for bowel cleaning, fleet-enema was self-administered on the morning of the biopsy. biopsies were performed in left lateral decubitus position; an 18g tru-cut core needle biopsy gun was used. for all patients, 12 core biopsy samples were taken. two prostate cores were randomly obtained from each peripheral side, and from the apical margin or basement (figure 6). statistical analysis power analysis of the study showed that a total 57 patients were needed to gain 80% power when alpha error was set at 0.05, beta error at 0.20 and effect size at 0.50. groups were controlled in terms of conformity to normal distribution by graphical check and shapiro-wilk test. the groups were distributed normally and mean and sd parameters were used. anova with bonferroni correction was used for comparison of four independent groups, respectively. analysis of pearson correlation was performed to examine the correlation between parameters and vas scores may be effective. ordinal regression analysis was performed in order to determine parameters that could be effective in predicting vas scores. p value of < .05 was taken as of significant. the statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0 was used for statistical analysis. table 2. ordinal regression results of effective factors for estimating the values of vas 1 and vas 2. variables score estimate se p value 95% confidence interval lower upper vas 1 prostate volume 0.005 0.020 .809 -0.034 0.043 age -0.028 0.038 .453 -0.103 0.046 bmi -0.293 0.133 .028 -0.555 -0.032 group 0 0 . . . . 1 -1.250 0.782 .110 -2.783 0.282 2 -1.091 0.812 .179 -2.682 0.500 3 -0.753 0.792 .342 -2.305 0.799 vas 2 prostate volume 0.035 0.021 .099 -0.007 0.076 age -0.068 0.040 .089 -0.146 0.010 bmi -0.106 0.126 .401 -0.353 0.141 group 0 0 . . . . 1 -5.265 1.296 < .001 -7.805 -2.725 2 -7.405 1.468 < .001 -10.282 -4.529 3 -7.107 1.463 < .001 -9.975 -4.238 abbreviations: bmi, body mass index; vas, visual analogue scale, se, standard error. variables group 1 group 2 group 3 group 4 gross hematuria 1 1 1 1 rectal bleeding 5 2 2 3 dysuria 1 1 1 gross hematuria 2 1 1 + high fever rectal bleeding 1 + hematuria total 8 5 5 6 table 3. complications seen after prostate biopsy. figure 3. iliohypogastric nerve block application shown by in a patient. pain control during trus-guided prostate biopsy-hizli et al results the median age of the 59 men was 62.0 (range 47-87) years. the median prostate volume and psa levels were 47.8 (range 20-103) ml and 9.4 (range 3.6-60.3) ng/ ml, respectively. the mean vas 1 and vas 2 scores were 0.7 and 4.9 for controls, 0.5 and 1.8 for inb, 0.5 and 2.6 for the intrarectal cream group, and 0.4 and 1.9 for the combined group. characteristics of patients are shown in table 1. the mean vas 1 scores were not different between groups. however, the mean vas 2 scores were significantly lower in inb, prilocainelidocaine cream and combined groups compared to the control group (p < .001). in addition, the inb group had significantly lower vas 2 scores compared to the cream application group (p = .03). on the other hand, there was no difference between the inb and combined groups (p = .8). age and prostate volume were not correlated with vas 1 and vas 2 scores (p > .05). regression results on the effective factors to estimate the values of vas 1 and vas are shown in table 2. ordinal regression analysis showed that increasing body mass index (bmi) decreased vas 1 scores significantly (p = .028). there was no significant effect in predicting vas 1 scores by including other parameters (p > .05). among all the groups and the control group, prediction of vas 1 scores was found to be significantly no different from using other methods (p > .05). no significant differences were detected in vas1 score between inb and the combined method and emla (p = .412 and p = .774, respectively), or between inb and the combined method (p = .649). when vas 2 values were examined, compared with the control group, the combined method was 7.1 times decreased, the inb group 7.4 times decreased and the emla group 5.4 times decreased (p < .001). between inb and the combined method and emla, a significant difference was detected in terms of predicting vas 2 scores (p = 0.039 and p = .016, respectively). compared to the emla group there was 1.9 times the combined method in pain scores, which were reduced 2.2-fold in the inb group. comparing the inb and the combined group in terms of estimating vas 2 scores, no significant differences were detected (p = .798). a detailed summary of complications after prostate biopsy are presented in table 3. no complication was detected during inb application. discussion it is intuitive that a potentially painful procedure such as prostate biopsy should require some form of anesthesia. recently, the superiority of combined local lidocaineprilocaine for intrarectal anesthesia in controlling pain during all phases of the biopsy procedure has been demonstrated.(22) several studies have shown that topical prilocaine-lidocaine application was more efficient than placebo(12) and the formulation of this synergistic mixture yields a higher concentration (approximately 80%) of active substance, compared with the commonly used lidocaine gel, which yields approximately 20%.(23) this property leads to a better penetration of the drug and better anesthetic effect. it has been shown that preventive topical anesthesia combined with periprostatic infiltration is successful in achieving more complete pain control during the entire prostate biopsy procedure.(24) inb is also widely used for postoperative pain relief because it is free of many side effects, such as motor block of the lower limbs and urinary retention. indications for inb include anesthesia for any somatic procedure involving the lower abdominal wall/inguinal region such as inguinal herniorrhaphy(18,21) and for analgesia after surgical procedures using a pfannenstiel incision as for cesarean section(16) and abdominal hysterectomy. (25) these blocks do not provide visceral anesthesia and thus cannot be used as the sole anesthetic for procedures figure 4. needle insertion of ultrasound-guided iliohypogastric nerve block. figure 5. visual analogue scale score questionnaire. figure 6. transrectal prostate biopsy after iliohypogastric nerve block application. pain control during trus-guided prostate biopsy-hizli et al urological oncology 2017 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2018 such as lower intra-abdominal surgery. when used for inguinal herniorrhaphy, the sac (containing peritoneum) must be infiltrated with local anesthetic by the surgeon to complete anesthesia for the procedure. there are no specific contraindications for these blocks apart from the generic contraindications for performance of any regional block, such as infection at the procedure site, allergy to local anesthetics, indeterminate neuropathy and so on. inb has several advantages and limited complications because since the block is limited to the lower abdominal wall and inguinal region, any hemodynamic changes would be unusual. as with other blocks, the patient is advised to protect the anesthetized area from trauma. although periprostatic nerve blockade is a commonly used method for this purpose, the equally painful process of fibrosis is a disadvantage of repeated injection. during trus-guided prostate biopsies, sedation is also performed. for this purpose entonox (50% nitrous oxide in 50% oxygen), intravenous propofol, and intravenous ketorolac have been used. usually, rapidacting and rapidly failing anesthetic agents are used in outpatient cases, but they cannot be applied to all patients. in our patients, no complications such as bleeding, hematoma, or micturition-defecation disorder were seen. significant numbers of studies have been done to develop an efficient program for local anesthesia during prostate biopsy to date. however, this is the first article that evaluated the efficacy of inb for pain control in patients undergoing prostate biopsy in the english literature. according to our results, both inb with or without topical anesthesia and use of topical anesthesia alone were effective for pain control when compared to the control group. however, addition of topical anesthesia to inb did not provide better analgesia. on the other hand, the main limitation of our study was the small patient population. moreover, vas is not a precise and reproducible tool, but currently there is no better way than vas to compare anesthetic effects during prostate biopsy. to increase the reliability of vas scores, the same operator questioned the patients to obviate interobserver variability for reliable results. the other limitation of the study was, this study was not double blinded. the patients were aware of the anesthetic method that they will receive, so the results may be influenced by this awareness. conclusion in conclusion, inb may be an easily applicable and minimally invasive method with effective pain control for patients undergoing prostate biopsy. addition of topical anesthesia may not have benefit for pain relief. subsequent prospective, double-blind, randomized studies in a larger number of patients are required to support our results. acknowledgements special thanks to associated professor dr. aydin köşüş for his valuable analysis and support in this paper’s statistical analysis and comment. conflict of interest none declared. references 1. irani j, fournier f, bon d, gremmo e, doré b, aubert j. patient tolerance of transrectal ultrasound-guided biopsy of the prostate. br j urol. 1997;79:608-10. 2. nash pa, bruce je, indudhara r, shinohara k. transrectal ultrasound guided prostatic nerve blockade eases systematic needle biopsy of the prostate. j urol. 1996;155:607-9. 3. soloway ms, obek c. periprostatic local anesthesia before ultrasound guided prostate biopsy. j urol. 2000;163:172-5. 4. lynn nn, collins gn, brown sc, o’reilly ph. periprostatic nerve block gives better analgesia for prostatic biopsy. bju int. 2002;90:424-6. 5. rodriguez a, kyriakou g, leray e, lobel b, guillé f. prospective study comparing two methods of anaesthesia for prostate biopsies: apex periprostatic nerve block versus intrarectal lidocaine gel: review of the literature. eur urol. 2003;44:195-200. 6. leibovici d1, zisman a, siegel yi, sella a, kleinmann j, lindner a. local anesthesia for prostate biopsy by periprostatic lidocaine injection: a double-blind placebo controlled study. j urol. 2002;167:563-5. 7. berger ap, frauscher f, halpern ej, et al. periprostatic administration of local anesthesia during transrectal ultrasound-guided biopsy of the prostate: a randomized, doubleblind, placebo-controlled study. urology. 2003;61:585-8. 8. walker ae1, schelvan c, rockall ag, rickards d, kellett mj. does pericapsular lignocaine reduce pain during transrectal ultrasonographyguided biopsy of the prostate? bju int. 2002;80:883-6. 9. seymour h, perry mj, lee-elliot c, dundas d, patel u. pain after transrectal ultrasonographyguided prostate biopsy: the advantages of periprostatic local anaesthesia. bju int. 2001;88:540-4. 10. kaver i, mabjeesh nj, matzkin h. randomized prospective study of periprostatic local anesthesia during transrectal ultrasound-guided prostate biopsy. urology. 2002;59:405-8. 11. luscombe cj, cooke pw. pain during prostate biopsy. lancet. 2004;363:1840-1. 12. raber m, scattoni v, roscigno m, rigatti p, montorsi f. perianal and intrarectal anesthesia before transrectal biopsy of the prostate: a prospective, randomized study assessing lidocaineprilocaine cream versus placebo. bju int. 2005;96:1264-7. 13. de maria m, mogorovich a, giannarini g, manassero f, selli c. lidocaine prilocaine administration during transrectal ultrasound guided prostatic biopsy: a randomized, singleblind, placebocontrolled trial. j endourol. 2006;20:525-9. 14. galosi ab, minardi d, dell’atti l, yehia m, muzzonigro g. tolerability of prostate transrectal biopsies using gel and local anesthetics: results of a randomized clinical trial. j endourol. 2005;19:738-43. pain control during trus-guided prostate biopsy-hizli et al 15. adamakis i, mitropoulos d, haritopoulos k, alamanis c, stravodimos k, giannopoulos a. pain during transrectal ultrasonography guided prostate biopsy: a randomized prospective trial comparing periprostatic infiltration with lidocaine with the intrarectal instillation of lidocaine-prilocaine cream. world j urol. 2004;22:281-4. 16. sakalli m, ceyhan a, uysal hy, yazici i, başar h. the efficacy of ilioinguinal and iliohypogastric nerve block for postoperative pain after caesarean section. j res med sci. 2010;15:6-13. 17. vallejo mc, steen tl, cobb bt, et al. efficacy of the bilateral ilioinguinal-iliohypogastric block with intrathecal morphine for postoperative cesarean delivery analgesia. scientificworld journal. 2012;2012:107316. 18. aveline c, le hetet h, le roux a, et al. comparison between ultrasound-guided transversus abdominis plane and conventional ilioinguinal/iliohypogastric nerve blocks for day-case open inguinal hernia repair. br j anaesth. 2011;106:380-6. 19. abdellatif aa. ultrasound-guided ilioinguinal/ iliohypogastric nerve blocks versus caudal block for postoperative analgesia in children undergoing unilateral groin surgery. saudi j anaesth. 2012;6:367-72. 20. seyedhejazi m, daemi or, taheri r, ghojazadeh m. success rate of two different methods of ilioinguinal-iliohypogastric nerve block in children inguinal surgery. afr j paediatr surg. 2013;10:255-8. 21. santos gde c, braga gm, queiroz fl, navarro tp, gomez rs. assessment of postoperative pain and hospital discharge after inguinal and iliohypogastric nerve block for inguinal hernia repair under spinal anesthesia: a prospective study. rev assoc med bras. 2011;57:545-9. 22. başar h1, başar mm, ozcan s, akpinar s, başar h, batislam e. local anesthesia in transrectal ultrasound-guided prostate biopsy: emla cream as a new alternative technique. scand j urol nephrol. 2005;39:130-4. 23. ehrenstrom reiz gm, reiz sl. emla-a synergistic mixture of local anaesthetics for topical anaesthesia. acta anaesthesiol scand. 1982;26:596-8. 24. raber m, scattoni v, roscigno m, et al. topical prilocaine-lidocaine cream combined with peripheral nerve block improves pain control in prostatic biopsy: results from a prospective randomized trial. eur urol. 2008;53:967-73. 25. yucel e, kol io, duger c, kaygusuz k, gursoy s, mimaroglu c. ilioinguinal-iliohypogastric nerve block with intravenous dexketoprofen improves postoperative analgesia in abdominal hysterectomies. braz j anesthesiol. 2013;63:3349. pain control during trus-guided prostate biopsy-hizli et al urological oncology 2019 urology journal vol. 11 no. 04 july august 2014 1800 female urology combination of sacral neuromodulation and tolterodine for treatment of idiopathic overactive bladder in women: a clinical trial hua tang, jian chen, yongfu wang, ting yu, changping guo, xiaoqi liao department of urinary sur gery, the second hospital of sanming, yong’an, 366000, fujian province, china. corresponding author: hua tang, ms department of urinary surgery, the second hospital of sanming. no. 86 yan jiang east road, yong’an, 366000, fujian province, china. tel: +86 598 8823242 fax: +86 598 8823136 e-mail: tanghuabm@163. com received august 2013 accepted july 2014 purpose: to evaluate the efficacy of intermittent percutaneous needle sacral nerve stimulation (ipn-sns) in women with idiopathic overactive bladder (ioab) treated with tolterodine. materials and methods: a total of 240 female patients diagnosed with ioab were randomized to receive tolterodine only treatment (group 1, n = 120) or tolterodine combined with ipn-sns (group 2, n = 120). each group included 120 participants, who were divided into subgroups depending on whether they had dry oab (urinary frequency and urgency) or wet oab (urinary frequency and urgency with urgency incontinence). in the treatment group, patients received percutaneous ipn-sns plus tolterodine (2 mg once daily), while in the control group, only tolterodine (2 mg once daily) was administered for 3 months. the voiding diary and urodynamic parameters were monitored, and patients’ psychological depression and anxiety scores were recorded before and after treatment. results: there were significantly greater improvements in the conditions of first desire to void (fdv), maximum cystometric capacity (mcc), and daily average volumes, as well as the daily single maximum voided volumes in group 2 (p = .001) than in group 1. in addition, there were significantly greater decreases in self-rating depression scale (sds) and self-rating anxiety scale (sas) scores in group 2 compared with group 1 (p < .001). conclusion: combined treatment with tolterodine plus ipn-sns can not only improve the symptoms of voiding dysfunction but can also reduce the concomitant depression and anxiety in women with ioab, thereby improving patients’ quality of life. keywords: electric stimulation therapy; electrodes, implanted; urinary bladder; neurogenic; complications; overactive; therapy. ticipants. female patients from the department of urinary surgery of the hospital who were between 18 and 70 years old and had been diagnosed with oab, with symptoms persisting for more than 6 months, were included in this prospective trial. the exclusion criteria were as follows: 1) 24-h average urine voided volume more than 200 ml or average urinary frequency less than 8 times; 2) pregnancy, breast-feeding or planned pregnancy; 3) bladder outlet obstruction; 4) abnormal liver or kidney function; 5) urinary infection and 6) contraindication or hypersensitivity to anticholinergic agents. from january 2004 to january 2011, a total of 240 female patients aged 33-65 years old, with an average age of 49.6 years, who met the inclusion and exclusion criteria were chosen for randomization into 2 groups. before treatment, all patients underwent urinary examinations to exclude urinary tract infection (uti), urine cytology to exclude urinary carcinoma, urinary ultrasound to determine residual urine, intravenous urography to exclude urolithiasis, as well as cystoscopy and urodynamic examinations to exclude lower urinary tract obstruction and to evaluate detrusor function. none of the patients had a history of stroke, spinal cord injury, or parkinson’s disease. in the tolterodine only group (group 1, n = 120), among 120 patients, 45 had dry idiopathic overactive bladder (ioab) for an average of 33 ± 16 months and 75 had wet ioab for an average of 30 ± 16 months. in the ipn-sns plus tolterodine treatment group (group 2, n = 120), of 120 patients, 47 had dry ioab for an average of 31 ± 9 months and 73 experienced wet ioab for an average of 29 ± 12 months. treatment period in both groups was 3 months (figure). ipn-sns methods all patients received tolterodine ((lientai®, sichuan dikang sci. & tech. pharmaceutical industry co., ltd, chengdu, sichuan, china) and ipn-sns was performed by physicians at the department of urinary surgery. for each treatment session, the patient undergoing surgery was placed in the prone position, with 1 or 2 pillows placed under the lower abdomen and trunk, while the lower limbs were spread at a 30° angle. an insulated needle (suzhou medical instrument co., ltd, zhangjiagang city, jiangsu, china) was introduced percutaneously into the s 3 foramen, located at about 2 cm from the midpoint connection between the superior border line of the sacrum and the coccyx, at a 60° angle with the body surface. a computerized nerve and muscle stimulator (smy-10a, shanghai bang cheng industrial co., ltd, shanghai, china) was used with a stimulating voltage of 10 v and a pulse frequency of 20-200 hz, while ensuring that the current intensity could be tolerated by the patients. the duration of each ipnsns treatment session was 30 min. the criteria for choosing appropriate currents were as follows: 1) anal contractions; 2) the big toe in the same side bending towards the planter center and 3) the region of the labia having a feeling of tremor. the treatment frequency was once every 2 days in a cycle of 3 months. at the same time, tolterodine (2 mg once daily) was administered, and the control group received only tolterodine (2 mg once daily) for the same period of 3 months. in our hospital, 2 mg is the standard dose of tolterodine, since the recommended dose of 4 mg per day would be too high for the typical body introduction overactive bladder (oab) syndrome is characterized by urinary urgency accompanied by frequency and nocturia, with or without urgent urinary incontinence, in the absence of urinary tract infection (uti) or other obvious pathology.(1) in our country entering an era of an aging population, the incidence of diabetes mellitus, cerebral thrombosis and other neurologically damaging diseases is increasing. at the same time, there is also, a growing number of individuals affected by oab; therefore, there is a great need to find effective treatments for oab. studies show that the incidence of oab in europe is over 17% in persons over 40 years of age, which is a higher rate than that of alzheimer’s disease and osteoporosis.(2) while in china, the incidence of oab in adults ( > 18 years of age) is 5.2%.(3) the pathogenesis of oab is mainly thought to be related to idiopathic or neurogenic detrusor overactivity. neurogenic overactivity is often caused by confirmed neurologic disease, whereas idiopathic detrusor overactivity may be due to a nonspecific infection of the bladder itself, as well as radiation cystitis, interstitial cystitis, bladder outlet obstruction, or various psychological factors. oab in turn can lead to depression, so patients’ overall quality of life may be negatively affected by the disease. tyagi and colleagues have reported that oab patients’ social activities are largely restricted because most of them are unwilling to accept the diagnosis and undergo treatment, so they are prone to suffer from depression and anxiety.(4) antimuscarinic drugs (m receptor antagonists) exert their effect by blocking cholinergic m receptors, which mediate the contraction of the detrusor, and by inhibiting acetylcholine–m receptor signaling, thereby blocking the involuntary contraction of the detrusor and reducing the overactivity of the bladder. anti-muscarinic drugs are widely used in the treatment of oab,(5,6) but have a number of undesirable side effects. tolterodine, which is a non-selective and potent m receptor antagonist with similar clinical efficiency but better tolerance, is an alternative choice for treating oab.(5,7) beside medications, oab can also be treated with implantation of permanent s 3 sacral nerve electrodes coupled to pulse generators for sacral nerve stimulation to electrically stimulate non-muscular afferent sacral somatic nerve fibers, thereby modulating sensory processing and micturition reflex pathways in the spinal cord. (8,9) as an alternative to the permanent implantation of electrodes, an intermittent percutaneous needle sacral nerve stimulation (ipn-sns) method has been developed in china, which is a temporary ambulant treatment without surgical intervention and serves the same purpose as the conventional sns. in this prospective clinical trial, we compared the outcomes of tolterodine only treatment and tolterodine plus ipnsns, and hypothesized that ipn-sns can further enhance the effects of oab medication. materials and methods study patients the research was approved by the ethics committee of the second hospital of sanming, and informed consent was obtained from all par1801 female urology urology journal vol. 11 no. 04 july august 2014 1802 tolterodine and sacral nerve stimulation-tang et al variables group 1 (n = 120) group 2 (n = 120) p value age, years 52 ± 11 54 ± 13 > .05 duration of symptoms (months) 33 ± 16 30 ± 11 > .05 urine test data bacterial culture negative negative 1.0 fungal culture negative negative 1.0 cytology negative negative 1.0 residual urine, ml 0.0 0.0 1.0 urodynamic study no obstructive disease no obstructive disease 1.0 intravenous urography normal normal 1.0 cystoscopy normal normal 1.0 table 1. demographic and clinical data of study subjects. daily average urination frequency, daily average single voided volume, daily single maximum voided volume, fdv, mcc, qmax and psychological scores of patients’ depression and anxiety before and after treatment were compared, and prism 5 was used for statistical analysis. analysis of variance (anova) was utilized for comparing multiple groups and the bonferroni t-test was used for the comparison of 2 groups (groups before and after treatment, control group and treatment group). p value < .05 was considered statistically significant. results patients’ general characteristics no obvious differences were observed regarding age, course of disease and urine examination data, including urinary bacterial culture and urinary fungal culture or urine cytology, while urodynamic examinations showed no obstructive diseases in any of the patients. both the intravenous urography and cystoscopy data were normal, indicating the comparability of the 2 groups (table 1). efficacy of the combined ipn-sns and tolterodine treatment in women with ioab results showed that the daily average single voided volume, the daily maximum volume of a single urination, fdv and mcc improved significantly (p = .001) with both nolterodine treatment ioccyx)as treatments. the daily average urination frequency and qmax values also improved in both treatment groups, but without statistical significance. when comparing the outcomes of the 2 different treatments after 3 months, the combination therapy was significantly superior (p = .001) for the daily average single voided volume, the daily maximum single volume of urination, as well as for fdv and mcc, compared to treatment by tolterodine only (table 2). efficacy of the combined ipn-sns plus tolterodine treatment for improving depression we compared self-rating depression scale (sds) and self-rating anxiety scale (sas) scores before and after treatment. the normal standard score for sds is 53; if the score is higher than 53, the patient is likely to be affected by depression. the normal standard score for sas is weight of our female patients. outcome measures the physician in charge noted the medical records, including the patients’ general information, changes in illness state and adverse drug reactions. data were collected before and at 3 months after the start of the trial. primary outcome measures were daily average frequency of micturition (times/day), daily average single voided volume (ml/ micturition), daily single maximum voided urine volume (ml/micturition), first desire to void (fdv, ml), maximum cystometric capacity (mcc, ml) (urodynamic catheter, laborie medical technologies inc., ontario, canada) and maximum flow rate (qmax, ml/s). secondary outcome measures were the psychological scores of patients’ self-rating depression scale (sds) and self-rating anxiety scale (sas) before and after treatment, which were determined as described else where.(10) statistical analysis figure. study flow chart. nificantly greater extent than tolterodine alone (table 3). no obvious recurrence was noticed after 12 months of follow-up among patients in group 2. discussion our hospital has been carrying out ipn-sns and tolterodine treatments since 2004. among the 240 female patients admitted to our hospital, urinary frequency, average voided volume, and single maximum void50; if the score is higher than 50, the patient is likely to be affected by anxiety. the results showed that the sds and sas scores were significantly lower (p <.001) after treatment than before in both groups, but the combined treatment led to statistically significantly better outcomes (p < .001) than the medication only treatment (table 3). taken together, these results indicate that the combined treatment with ipnsns plus tolterodine has improved patients’ quality of life to a sig table 2. outcome measures in both study groups. variables ipn-sns plus tolterodine tolterodine only dry ioab wet ioab dry ioab wet ioab (n = 47) (n = 73) (n = 45) (n = 75) urinary frequency (times/day) before treatment 23 ± 10 22 ± 11 23 ± 11 23 ± 10 after treatment 10 ± 7 10 ± 7.5 20 ± 12 18 ± 11 effect size -1.30 -1.09 0.27 -0.5 single voided urine volume before treatment 119 ± 71 126 ± 84.5 117 ± 75 121.5 ± 74.5 (ml/times) after treatment 245 ± 47* 245.5 ± 69* 150 ± 77*♦ 157 ± 63.5♦ effect size 1.77 1.47 0.44 0.48 maximum single voided urine before treatment 154 ± 34 146 ± 43.5 161 ± 86 148.5 ± 60.5 volume (ml/times) after treatment 315 ± 77* 323 ± 61.5* 212 ± 44*♦ 206 ± 61*♦ effect size 4.73 4.07 0.59 0.95 first desire to void (ml) before treatment 116 ± 47 113 ± 57.5 108 ± 50 110 ± 52.5 after treatment 176 ± 64* 187 ± 63* 142 ± 44*♦ 140 ± 52*♦ effect size 1.28 1.29 0.68 0.57 maximum cystometric capacity before treatment 166 ± 69 157 ± 61.5 164 ± 60 160 ± 52 (ml) after treatment 265 ± 46* 287.5 ± 45* 203 ± 50*♦ 193 ± 42.5*♦ effect size 1.43 2.11 0.65 0.63 maximum flow rate (ml/s) before treatment 12.8 ± 5.1 12.2 ± 4.3 12.9 ± 4.8 11.9 ± 3.9 after treatment 20.1 ± 3.3 21.2 ± 3 18.1 ± 2.9 18 ± 3.2 effect size 1.41 2.09 1.08 1.56 abbreviations: ipn-sns, intermittent percutaneous needle sacral nerve stimulation; ioab, idiopathic overactive bladder. *p < .001 when compared with pre-treatment. ♦ p < .001 when compared with ipn-sns plus tolterodine. table 3. efficacy comparison of tolterodine plus ipn-sns and tolterodine only treatments for improving depression. abbreviations: ipn-sns, intermittent percutaneous needle sacral nerve stimulation; ioab, idiopathic overactive bladder. *p < .001 when compared with pre-treatment. ♦ p < .001 when compared with ipn-sns plus tolterodine. psychological measures ipn-sns plus tolterodine tolterodine only dry ioab wet ioab dry ioab wet ioab (n = 47) (n = 73) (n = 45) (n = 75) self-rating depression scale before treatment 61 ± 5.2 60 ± 5.1 61 ± 5.5 59.8 ± 5.8 after treatment 33 ± 6.2* 32.3 ± 6.6* 44.0 ± 5.9*♦ 43.1 ± 5.6*♦ effect size -5.38 -5.43 -3.09 -2.88 self-rating anxiety scale before treatment 60.6 ± 7.7 59.6 ± 7.9 60.4 ± 7.0 61 ± 7.5 after treatment 30.3 ± 4.4* 32.6 ± 5.3* 41.3 ± 4.4*♦ 43 ± 6*♦ effect size -3.93 -3.42 -2.73 -2.40 maximum flow rate (ml/s) before treatment 12.8 ± 5.1 12.2 ± 4.3 12.9 ± 4.8 11.9 ± 3.9 after treatment 20.1 ± 3.3 21.2 ± 3 18.1 ± 2.9 18 ± 3.2 effect size 1.41 2.09 1.08 1.56 1803 female urology urology journal vol. 11 no. 04 july august 2014 1804 and that such combined treatment can lead to improved outcomes when compared to treatment by tolterodine only. acknowledgment this work was supported by a grant from the natural science foundation of fujian province (2012j01434). conflict of interest none declared. references 1. haylen bt, de ridder d, freeman rm, et al. an international urogy necological association (iuga)/international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. neurourol urodyn. 2010;29:4-20. 2. van voskuilen ac, oerlemans dj, weil eh, de bie ra, van kerrebroe ck pe. long term results of neuromodulation by sacral nerve stimulation for lower urinary tract symptoms: a retrospective single center study. eur urol. 2006;49:366-72. 3. wang y, xu k, hu h, et al. prevalence, risk factors, and impact on he alth related quality of life of overactive bladder in china. neurourol urodyn. 2011;30:1448-55. 4. tyagi s, thomas ca, hayashi y, chancellor mb. the overactive blad der: epidemiology and morbidity. urol clin north am. 2006;33:433-8. 5. abrams p, freeman r, anderstrom c, mattiasson a. tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. br j urol. 1998;81:801-10. 6. zinner n. darifenacin: a muscarinic m3-selective receptor antagonist for the treatment of overactive bladder. expert opin pharmacother. 2007;8:511-23. 7. harvey ma, baker k, wells ga. tolterodine versus oxybutynin in the treatment of urge urinary incontinence: a meta-analysis. am j obstet gy necol. 2001;185:56-61. 8. bosch jl, groen j. sacral nerve neuromodulation in the treatment of patients with refractory motor urge incontinence: long-term results of a prospective longitudinal study. j urol. 2000;163:1219-22. 9. chancellor mb, chartier-kastler ej. principles of sacral nerve stimula tion (sns) for the treatment of bladder and urethral sphincter dysfun ctions. neuromodulation. 2000;3:16-26. 10. li l, liu f, zhang h, wang l, chen x. chinese version of the post partum depression screening scale: translation and validation. nurs res. 2011;60:231-9. 11. kabay s, kabay sc, yucel m, et al. the clinical and urodynamic re sults of a 3-month percutaneous posterior tibial nerve stimulation treat ment in patients with multiple sclerosis-related neurogenic bladder dys function. neurourol urodyn. 2009;28:964-8. 12. kohli n, patterson d. interstim therapy: a contemporary approach to overactive bladder. rev obstet gynecol. 2009;2:18-27. 13. leong rk, de wachter sg, van kerrebroeck pe. current information on sacral neuromodulation and botulinum toxin treatment for refractory idi opathic overactive bladder syndrome: a review. urol int. 2010;84:245 53. 14. peters km, macdiarmid sa, wooldridge ls, et al. randomized trial ed volume in the 2 groups treated with tolterodine improved statistically significantly, but these outcomes were statistically significantly superior for patients treated with ipn-sns plus tolterodine. sns involves an interventional technique, which continually delivers short electric pulses to stimulate specific sacral nerves (s 3 or s 4 ) in order to disrupt psychologically misleading electric signals generated by nerve cells. the external stimulation serves to artificially activate excitatory and inhibitory neural pathways, to disturb an abnormal sacral nerve reflex arc, and to affect and mediate the behavior of effector organs dominated by the sacral nerves of the bladder, urethral sphincter, and pelvic floor, thus providing neuromodulation.(8) it has been reported that urinary frequency and urgency syndrome, as well as urgent incontinence, are often associated with detrusor overactivity, which can be inhibited by stimulating the ano-rectal branch of the pelvic floor nerve, pudendal nerve and lower limb nerves. in addition, the spinal cord inhibitory pathway can also be activated through stimulating s 3 afferent nerves.(11) stimulation of the pelvic floor sensory afferent nerve pathway can restrain impulses of the detrusor motor neurons at the spinal cord level, so that micturition reflexes or unstable contractions of the detrusor are inhibited.(12-14) sns treatment of oab is considered to be safe, as well as feasible and with the improved technology of therapy devices, sns is increasingly applied for the treatment of oab.(9,15,16) moreover, sns is a bridge connecting a conservative treatment with radical invasive techniques and has already become a widely accepted treatment for oab.(17) up to now, there have been few reports describing the combined use of sns and oab medications. the common application of sns is the surgical implantation of a permanent electrode in one of the sacral foramen, which is connected to a subcutaneously placed pulse generator via an extension lead. in our clinical experience, many patients, particularly those who are middle-aged, cannot accept this procedure. as an alternative, we developed the ipn-sns treatment, in which the electrical stimulation is periodically applied in the hospital without surgical intervention. the disadvantage of this approach is the relative long period without electrical stimulation between treatments. at present, tolterodine is the number one choice for the medical treatment of oab, but there is room for improvement. (18) in our study, we found that the addition of ipn-sns to tolterodine could substantially improve treatment outcomes, leading to significantly reduced sds and sas scores after 3 months of combination therapy. a limitation of our study is the relatively small number of patients used; therefore, the results need further validation by larger trials. in addition, the ipn-sns treatment is laborious and requires a lot of work by clinical staff, particularly for large patient groups. furthermore, the results cannot be generalized to all patient groups, especially in view of the reduced tolterodine dosage used in our specific settings. conclusion in summary, our study has demonstrated that it is safe and feasible to adopt a combination treatment of ipn-sns plus tolterodine for oab, tolterodine and sacral nerve stimulation-tang et al of percutaneous tibial nerve stimulation versus extended-release tolte rodine: results from the overactive bladder innovative therapy trial. j urol. 2009;182:1055-61. 15. leong rk, marcelissen ta, nieman fh, de bie ra, van kerrebroeck pe, de wachter sg. satisfaction and patient experience with sacral neuromodulation: results of a single center sample survey. j urol. 2011;185:588-92. 16. yoong w, ridout ae, damodaram m, dadswell r. neuromodulative treatment with percutaneous tibial nerve stimulation for intractable det rusor instability: outcomes following a shortened 6-week protocol. bju int. 2010;106:1673-6. 17. siddiqui ny, wu jm, amundsen cl. efficacy and adverse events of sacral nerve stimulation for overactive bladder: a systematic review. neurourol urodyn. 2010;29 suppl 1:s18-23. 18. roberts r, bavendam t, glasser db, carlsson m, eyland n, elinoff v. tolterodine extended release improves patient-reported outcomes in ove ractive bladder: results from the impact trial. int j clin pract. 2006;60:752-8. 1805 female urology endourology and stone disease comparison of safety and efficacy of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in patients with renal pelvic stones: a randomized clinical trial abbas basiri, ali tabibi, akbar nouralizadeh, davood arab, gholam hossein rezaeetalab, seyed hossein hosseini sharifi, mohammad hossein soltani* purpose: a randomized clinical trial was designed to compare the efficacy, success rate and surgical complications of percutaneous nephrolithotomy (pcnl) and laparoscopic pyelolithotomy (lp). materials and methods: sixty patients with renal pelvic stones larger than 2 cm were randomly divided into two groups of lp and pcnl. all patients were followed up to three months after surgery using renal diethylenetriaminepentaaceticacid (dtpa) scan and determining the glomerular filtration rate (gfr). results: mean operation time (149 ± 31 vs. 107 ± 26 min) and mean hospital stay (3.4 vs. 2.16 days) were significantly higher in lp, but mean hemoglobin drop (0.85 vs. 1.88 g/dl) and the rate of blood transfusion were significantly lower. stone free rate was 90% and 86.6% for lp and pcnl, respectively (p =.59), while the changes in gfr were not statistically significant 3 days after surgery between two groups. those in lp group showed better improvement in gfr at three months postoperatively. improvement of the affected split kidney function was significantly higher in lp group (p =.04). no major complications were observed in both groups according to clavien grading system. conclusion: pcnl remains the gold standard treatment for most large kidney stones, nevertheless, laparoscopic pyelolithotomy can be considered for selected cases especially in whom maximal preservation of renal function is necessary. keywords: kidney calculi; surgery; laparoscopy; nephrostomy; percutaneous; treatment outcome. introduction percutaneous nephrolithotomy (pcnl) is accepted as the gold standard surgery for most patients suf-fering from large renal calculi. despite the progressive advances in percutaneous approach, some concerns still remain about its complications such as immediate or late hemorrhage (due to arteriovenous fistula or pseudo aneurism), parenchymal loss and injury to the adjacent organs.(1) on the other hand, the effect of pcnl on renal function needs to be better clarified.(2,3) while, some studies have indicated that the effect of pcnl on glomerular filtration rate (gfr) and isotope uptake was not significant and there is no renal parenchymal injury,(2-6) more comparative studies with control groups (i.e. other surgical modalities) are still needed to evaluate this opinion. with the evolution of laparoscopy, a new era in the field of stone removal surgery is developing. according to the findings of the previous studies that have assessed the outcomes and adverse effects of laparoscopic pyelolithotomy (lp), the definite indications for laparoscopic surgery of kidney stones have been limited to the following situations: 1) stones in extra-renal pelvis 2) failed pcnl and 3) stones associated with congenital renal anomalies such as ureteropelvic junction obstruction (upjo).(7) theoretically, lp is assumed to preserve functional renal parenchyma, and there is a limited risk for immediate or late renal hemorrhage. therefore, it might be an alternative for the patients in whom maximal preservation of renal parenchyma is necessary. in present study we aimed to compare the success rate and perioperative complications of lp versus pcnl. the main specific goal of the present study was to investigate the effect of these two modalities on renal function, as assessed by renal isotope scan and laboratory tests in short term follow-up period. materials and methods study subjects a randomized clinical trial was conducted in the patients with renal calculi referred to labbafinejad medical center from september 2009 to february 2012. the study population consisted of 60 patients with one to 3 stones larger than 2 cm in extra-renal pelvis who were randomly divided into two groups of pcnl and lp. simple randomization approach was used. the cutoff of 2 cm was considered appropriate for surgical intervention considering the literature.(8) all patients with a history of diabetes mellishahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences (sbmu), tehran, iran. *correspondence: shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences (sbmu), tehran, iran. tel: +98 21 2258 8016. e-mail: mhsoltani60@gmail.com. received september 2014 & accepted november 2014 endourology and stone disease 1932 tus, extracorporeal shock wave lithotripsy (swl), retroperitoneal surgery and those with separate stone burden in different calyces or intra-renal pelvis were excluded from the study. all patients provided written informed consent before the study and the medical ethics committee of iranian urology and nephrology research center approved the study protocol. all patients underwent routine laboratory tests including complete blood count, blood chemistry and urine analysis and urine culture preoperatively. to evaluate the impact of surgery on renal function, glomerular filtration rate (gfr) was measured preoperatively, at day 3 and three months after surgery. estimated gfr was calculated using cockcroft-gault formula. to assess selective renal function, kidney scintigraphy with single–shot diethylenetriaminepentaacetic acid (dtpa) was done before operation and at three months postoperatively. all perioperative and post-operative complications up to 3 months were recorded and classified according to the clavien grading system.(9) stone-free result (as the primary end point of the study) was defined as no residual fragments or a residual fragment smaller than 4 mm on the postoperative imaging profiles (ultrasonography and kidney-ureter-bladder x-ray). surgical techniques all pcnls were performed under general anesthesia. first, a 5 french (f) ureteral stent was inserted using a semirigid cystoscope in lithotomy position. desired calyces were then punctured using triangular method, under the guidance of fluoroscopy in the prone position. oneshot dilation technique was used as the regular approach for tract dilation up to 30 f and a pneumatic lithotripter was applied to break the calculi. a 16 f nephrostomy tube was inserted into the calyceal system at the end of the surgery and one-shot nephrostography would confirm that pyelocalyceal system was unharmed. at the first postoperative day, the nephrostomy tube was removed and if no urinary leakage was observed at the site of surgery, the ureteral stent was also withdrawn the day after. lp was also performed under general anesthesia in modified lateral decubitus position. first, a 12 mm port was inserted at the umbilicus using open access approach.(10) then three 5 (sub xiphoid), 10 (para rectal region parallel to umbilicus) and 5 mm (2 cm medial to anterior superior iliac spine) ports were inserted under direct vision. whenever necessary, another 5 mm port was used for liver retraction in the patients with right kidney stones. all lps were performed via a transperitoneal approach. after medial mobilization of colon and once renal pelvis and ureteropelvic junction were exposed, a longitudinal or circular incision was made on the renal pelvis, depending on the location and shape of the stone. stones were removed from renal pelvis using grasper forceps and delivered via an endobag. after suctionirrigation of renal pelvis (to wash out further tiny stone particles), a double j ureteral stent was passed through renal pelvis to the bladder. finally, pelvis was closed using a 4-0 absorbable polyglactin suture in a running fashion. foley catheter was removed 48 h after operation. drain was removed when its daily output reached lower than 25 ml. double j ureteral stent was removed under local anesthesia 4 weeks later. statistical analysis regarding the power factor of 80% for the study and 95% confidence level, a sample size of 60 patients was calculated. the hypothesis of this study was that lp is as effective as pcnl in the selected group of patients. thus, the primary end point of this study was to measure the mean success rate of the two groups and compare them together. up to 20% difference in stone free rate of the two groups was accepted according to the previous studies. multivariate analysis was used to reduce the effect of confounding factors. independent sample t-test was used to compare quantitative values and all qualitative factors were analyzed using chi-squared and mann-whitney u test. statistical analysis was performed by statistical package for the social science (spss inc, chicago, illinois, usa) version 20.0. p value less than.05 was considered statistically significant. results the demographic characteristics of the patients are shown in table 1. mean age of patients in lp and pcnl groups were 38 ± 15.9 (range, 15-61) and 42 ± 14.3 (range, 1772) years, respectively (p = .114). mean stone size (as the largest diameter of the stone on computed tomography scan) was 3.6 cm and 3.3 cm in lp and pcnl groups, respectively (p = .356). staghorn calculi (defined as stone burden in renal pelvis with extension to at least two calvariables laparoscopy pcnl p value mean age (year) 38.5 ± 15.9 42.1 ± 14.3 .114 bmi (kg/m2) 26.1 ± 6.7 25.8 ± 7.3 .830 side, no. left 20 13 .426 right 10 17 mean stone size (cm) 3.6 (2.8-4.4) 3.3 (2.7-4.2) .356 stone feature, no. staghorn 12 9 .417 non-staghorn 18 21 abbreviations: pcnl, percutaneous nephrolithotomy; bmi, body mass index. table 1. demographic characteristics of the study groups. laparoscopic pyelolithotomy vs. pcnl-basiri et al vol 11. no 06 nov-dec 2014 1933 yceal groups) were observed in 12 patients in lp group and 9 patients in pcnl group (p = .417). table 2 shows the intraoperative and postoperative parameters and surgical complications. mean operation time was significantly higher in lp group than pcnl group (149 ± 31 min vs. 107 ± 26 min respectively, p = 0.01). mean hospital stay was also lower in pcnl group than lp group (2.16 vs. 3.4 days; p = .025). the mean hemoglobin drop was significantly lower in lp group than in pcnl group (0.85 ± 0.5 vs. 1.88 ± 1.2 g/dl; p = .001). of all patients, 5 required blood transfusion during surgery or after that. among them 1 was in the lp group and 4 were in pcnl group (p = .001). conversion to open surgery occurred in one patient in lp group due to injury to a branch of renal vein. stone free rate was 90% for lp group and 86.6% for pcnl group which did not indicate statistically significant difference (p = .59). three patients in lp group had residual fragments that were managed with swl. four patients in pcnl group had residual fragments. two patients underwent swl and two other patients with complete staghorn stone underwent two sessions of pcnl. mean changes in gfr three days after the operation were 5.2 ± 2.3 and 7.2 ± 3.9 ml/min for lp and pcnl groups, respectively (p = .379). however, after 3 months the mean changes in gfr demonstrated a significant difference between two groups (+ 14 ± 8.1 ml/min for lp and + 6 ± 3.7 ml/min for pcnl group; p = .05). dtpa scan revealed that the mean increase in split function of the operated kidney 3 months after surgery was significantly higher in lp group (5.7 ± 1.9%) than pcnl group (4.4 ± 1.3%) (p = .04). no major complications were seen in both groups. there was no case of urinary leakage in lp group. but in the pcnl group three patients needed to undergo double j ureteral stenting due to prolonged leakage of urine from the site of nephrostomy tube. in four patients in laparoscopic group, it was not possible to place a double j ureteral stent intra operatively, so they were followed as stentless pyelolithotomy, but since we did not observe any case of urinary leakage or other side effects, no further intervention was needed. discussion although pcnl is considered as the gold standard treatment modality for most of large renal stones, with global increase in experience of laparoscopic surgery, there is an upward trend toward the usage of laparoscopy in stone removal surgery. however, sufficient findings regarding the efficacy and safety of laparoscopic pyelolithotomy are lacking. on the other hand, pcnl still has limitation in some situations like retrorenal colon and skeletal anomalies.(1) nowadays, lp can be recommended for confined pelvic stones without extension to several renal calyces as an alternative to pcnl. it is a fact that introduction of pcnl has led to a revolution in the field of stone surgery, but some concern still remains regarding its side effects. colon injury and damage to the large blood vessels are some of the rare (less than 1%), but important pcnl complications. immediate or late hemorrhage (4-20% and 1%, respectively) may also happen. blood transfusion and prolonged hospital stay, or rehospitalization may occur due to the hemorrhage, which impose extra cost on the patient and the variables laparoscopy pcnl p value mean operation time (min) 149 ± 31 107 ± 26 .01 mean hemoglobin drop (g/dl) 0.85 ± 0.5 1.88 ± 1.2 .001 blood transfusion, no. 1 4 .001 conversion to open surgery, no. 1 0 .32 mean hospital stay (day) 3.4 ± 1.2 2.16 ± 0.7 .025 stone free rate (%) 90 86.6 .593 postoperative complications grade i 2 0 grade ii 1 4 grade iiia 0 2 .225 grade iiib 1 0 grade iv 0 0 mean change in total gfr (ml/min) 3 days after operation -5.2 ± 2.3 -7.2 ± 3.9 .379 3 months after operation +14 ± 8.1 +6 ± 3.7 .05 split function in dtpa scan preoperative split function 42.5 ± 17.7 39.7 ± 8.6 .539 postoperative split function 48.2 ± 15.2 43.5 ± 9.2 .741 differential split function (post – pre) 5.7 ± 1.9 4.4 ± 1.3 .04 table 2. intra operative and postoperative parameters and surgical complications in study groups. abbreviations: pcnl, percutaneous nephrolithotomy; gfr, glomerular filtration rate; dtpa, diethylenetriaminepentaacetic acid. laparoscopic pyelolithotomy vs. pcnl-basiri et al endourology and stone disease 1934 health care system.(1) radiation exposure during pcnl is another hazard for both the patient and physician.(11,12) basiri and colleagues have reported few cases of neurologic complications including paraplegia and hemiplegia following pcnl.(13) despite the fact that some of this hazards may happen during laparoscopy too (like visceral and great vessels injury), some urologists have proposed it as an appropriate alternative to pcnl in selected cases. (14) however, due to the potential side effects of laparoscopy, safety of lp needs to be assessed and compared to standard pcnl. earlier studies suggested lp for limited conditions such as solitary stone in extra renal pelvis and coexistence of congenital anomalies such as upjo and pelvic kidney. (14-16) in 2005, nambirajan and colleagues reported 18 patients with kidney stones who underwent laparoscopy. several patients had coexisting anomalies such as upjo, calyceal diverticulum and horse shoe kidney. despite the relatively prolonged mean hospital stay in this case series (10.5 days) and small to moderate stone size (mean 1.3 cm length), nambirajan and colleagues concluded that laparoscopic surgery would be effective for complex kidney stones and it could be an alternative to pcnl.(17) as laparoscopic surgery has been developing, several studies have reported a higher success rate for lp in extraction of more complex and staghorn stones.(18) nouralizadeh and colleagues. al have reported 13 patients with large stones in extra renal pelvises who had underwent lp. mean stone size and mean hospital stay were 5.1 cm and 4 days, respectively. overall success rate was 84.6% and there was no major complication.(19) another advantage of lp is that often stone is extracted in whole form, in contrast to pcnl, in which tiny stone particles can become a nidus for future stone formation. several studies have compared success rate, operation time, hospital stay and surgical complications of lp and pcnl. study of 16 patients who had undergone lp by meria and colleagues showed that operation time was longer in lp, but success rate and mean hospital stay were not significantly different between two groups.(20) in a cohort study by tefekli and colleagues on two groups including 26 patients in each arm, operation time and hospital stay were significantly higher in lp group, but mean hemoglobin drop was less (p = .024). stone free rate was similar between two groups.(21) recently, aminsharifi and colleagues have carried out another cohort study on 60 patients to compare lp and pcnl for solitary pelvic stones larger than 3 cm. according to their results, mean operation time was significantly higher in lp group (p = .01); but stone free rate and average treatment cost were significantly lower in lp group. in this study, no significant difference in mean hemoglobin drop was noted between lp and pcnl groups.(22) there is a paucity of randomized clinical trials in the field of lp in the current literature. wang and colleagues have reviewed 7 trials and a total of 176 and 187 patients who had undergone lp and pcnl for single pelvic stones. (23) they concluded that operation time and hospital stay were shorter in pcnl group; but decrease in hemoglobin level and rate of fever were lower in patients treated with lp. similar to our results, the stone free rate was not different between two groups. similar findings have been reported by haggag and colleagues who compared a group of 10 lp cases with 40 pcnl cases.(24) regarding the fact that all trials that were included in wang’s meta-analysis were not necessarily randomized, our study presents same results regarding the operation time, hospital stay, stone free rates and mean hemoglobin drop by conducting a randomized controlled research. our study showed a better improvement in renal function following lp at 3 months after surgery. it is believed that stone removal may result in renal function improvement due to several mechanisms. stone extraction may lead to the improvement of postoperative renal function by relieving of urinary tract obstruction, possible infection and inflammation. also, several studies have reported significant increase in gfr after pcnl,(2,4,6) but it can be assumed that this improvement is due to the resolution of stone burden rather than pcnl itself. in other words, all surgical approaches with acceptable success rate would have such impact on renal function. so, the effect of various surgical modalities (including pcnl and lp) on kidney function should be compared to withdraw a better conclusion. this is specially a matter of concern in the patients whose renal function is already impaired or maximal renal performance is necessary (those who are single kidney). theoretically, pcnl may cause harm to the kidney parenchyma. this can happen by either direct injury to the renal tissue during tract dilation and lithotripsy, or indirect mechanisms like massive hemorrhage and vasoconstriction of kidney vessels. moskovitz and colleagues has carried out a study on a series of 88 patients who had undergone pcnl by doing dimercaptosuccinic acid (dmsa) scan before and after pcnl. this study showed a decrease in functional volume of the treated kidney after pcnl (p = .011). nevertheless, total isotope uptake was not significantly reduced.(3) unsal and colleagues have reported a rate of 18% new focal cortical defects after pcnl. however, they reported that kidney function would preserve or often improve after pcnl.(5) giving the fact that total gfr is resultant of function of both kidneys and does not specifically show the impact of surgery on the affected kidney, we performed a dtpa scan before and after surgery in order to compare changes in split renal function. in both groups, gfr reduced within 3 days after surgery. this effect can be attributed to the impact of anesthetics, medications, intra and postoperative hemorrhage and parenchymal injury. three months after surgery, while the burden of stone is removed and the effect of surgery and medications are nearly resolved; gfr increased and renal split function showed improvement in both groups. this is similar to the previous studies that indicated an improvement in renal function following pcnl. nevertheless, our study shows that mean changes in total gfr and split function of the operated site were significantly higher in lp group at three months after surgery. hence, lp can be assumed as a reasonable alternative for pcnl in the patients for whom preservations of renal performance is a matter of utmost importance. although the study population was not large enough to assess probable but rare complications, no major side effects were observed up to 3 months according to clavien classification except that hemoglobin level and blood transfusion rate were higher in pcnl group. larger and staghorn stones were independent risk factors for perioplaparoscopic pyelolithotomy vs. pcnl-basiri et al vol 11. no 06 nov-dec 2014 1935 erative hemorrhage in both groups. there was one patient in lp group who underwent open surgery due to injury to the renal vein branch. our study has several limitations. the nature of laparoscopy prevents all stones from being extracted via pyelolithotomy. in fact only some kidney stones inside extra renal pelvis can be operated using lp. so we excluded many patients who had multiple staghorn stones in intra renal pelvis. with nowadays experiences with lp it can be solely recommended for selected cases. another limitation is the small number of study population. it is necessary to carry out larger multi center studies to get more accurate results. conclusion pcnl remains the gold standard treatment for most large kidney stones. nevertheless, lp can be considered for selected cases in which maximal preservation of renal function is needed. while mean operation time and hospital stay is longer in lp, decline in hemoglobin level and rate of blood transfusion is significantly lower than pcnl. lp is not associated with radiation exposure and its success rate is comparable to pcnl. further large scale studies are needed to get more accurate results, especially about the complications. conflict of interest none declared. references 1. stuart wolf j. urinary lithiasis: percutaneo us approaches to the upper urinary tract coll ecting system. in wein aj, kavoussi lr campbell-walsh urology 10th ed. philadel phia, elsevier; 2012. p.1348-54. 2. nouralizadeh a, sichani mm, kashi ah. impacts of percutaneous nephrolithotomy on the estimated glomerular filtration rate duri ng the first few days after surgery. urol res. 2011;39:129-33. 3. moskovitz b, halachmi s, sopov v, et al. effect of percutaneous nephrolithotripsy on renal function: assessment with quantitative spect of (99m) tc-dmsa renal scintigrap hy. j endourol. 2006;20:102-6. 4. chatham jr, dykes te, kennon wg, schwartz bf. effect of percutaneous nephro lithotomy on differential renal function as measured by mercaptoacetyl triglycine nucl ear renography. urology. 2002;59:522-5. 5. unsal a, koca g, reşorlu b, bayindir m, korkmaz m. effect of percutaneous nephr olithotomy and tract dilatation methods on renal function: assessment by quantitative single-photon emission computed tomogra phy of technetium-99m-dimer captosuccinic acid uptake by the kidneys. j endourol. 2010;24:1497-502. 6. bayrak o, seckiner i, erturhan sm, mizrak s, erbagci a. analysis of changes in the glo merular filtration rate as measured by the co ckroft-gault formula in the early period after percutaneous nephrolithotomy. korean j urol. 2012;53:552-5. 7. al-hunayan a, khalil m, hassabo m, hanafi a, abdul-halim h. management of solitary renal pelvic stone: laparoscopic retroperito neal pyelolithotomy versus percutaneous nephrolithotomy. j endourol. 2011;25:975 8. 8. matlaga b, lingeman j. surgical manage ment of upper urinary tract calculi in ka voussi l, novick a, partin a, peters c, edi tors. campbell-walsh urology. 10th ed. philadelphia: wb saunders; 2012. p. 1360 75. 9. dindo d, demartines n, clavien pa. classi fication of surgical complications: a new pro posal with evaluation in a cohort of 6336 pa tients and results of a survey. ann surg. 2004;240:205-13. 10. simforoosh n, soltani mh, ahanian a, lashay a. initial series of minilaparoscopic live donor nephrectomy using a novel techn ique. complications of laparoscopic access techniques in urology: open access versus b lind access. 30th world congress of endour ology & swl; wce 2012. istanbul, turkey. 2012. mp 18-04. 11. majidpour hs. risk of radiation exposure during pcnl. urol j. 2010;7:87-9. 12. mettler fa jr, koenig tr, wagner lk, kelsey ca. radiation injuries after fluoro scopic procedures. semin ultrasound ct mr. 2002;23:428-42. 13. basiri a, soltani mh, kamranmanesh m, et al. neurologic complications in percutane ous nephrolithotomy. korean j urol. 2013;54:172-6. 14. nadu a, schatloff o, morag r, ramon j, winkler h. laparoscopic surgery for renal stones: is it indicated in the modern endourol ogy era? int braz j urol. 2009;35:9-17. 15. ramakumar s, lancini v, chan dy, parsons jk, kavoussi lr, jarrett tw. laparoscopic pyeloplasty with concomitant pyelolithoto my. j urol. 2002;167:1378-80. 16. nadu a, schatloff o, morag r, ramon j, winkler h. laparoscopic surgery for renal stones: is it indicated in the modern endourol ogy era? int braz j urol. 2009;35:9-17. 17. nambirajan t, jeschke s, albqami n, abuk ora f, leeb k, janetschek g. role of laparos copy in management of renal stones: single center experience and review of literature. j endourol. 2005;19:353-9. 18. lee jw, cho sy, yeon js, et al. laparosco pic pyelolithotomy: comparison of surgical outcomes in relation to stone distribution within the kidney. j endourol. 2013;27:592 7. laparoscopic pyelolithotomy vs. pcnl-basiri et al endourology and stone disease 1936 19. nouralizadeh a, simforoosh n, soltani mh, et al. laparoscopic transperitoneal pyelolith otomy for management of staghorn renal c lculi. j laparoendosc adv surg tech a. 2012;22:61-5. 20. meria p, milcent s, desgrandchamps f, mongiat-artus p, duclos jm, teillac p. management of pelvic stones larger than 20 mm: laparoscopic transperitoneal pyelolitho tomy or percutaneous nephrolithotomy? urol int. 2005;75:322-6. 21. tefekli a, tepeler a, akman t, et al. the comparison of laparoscopic pyelolithotomy and percutaneous nephrolithotomy in the treatment of solitary large renal pelvic stones. urol res. 2012;40:549-55. 22. aminsharifi a, hosseini mm, khakbaz a. laparoscopic pyelolithotomy versus percuta neous nephrolithotomy for a solitary renal pelvis stone larger than 3 cm: a prospective cohort study. uro lithiasis. 2013;41:493-7. 23. wang x, li s, liu t, guo y, yang z. lapa roscopic pyelolithotomy compared to percu taneous nephrolithotomy as surgical manage ment for large renal pelvic calculi: a meta-an alysis. j urol. 2013;190:888-93. 24. haggag ym, morsy g, badr mm, al emam ab, farid m, etafy m. comparative study of laparoscopic pyelolithotomy versus percuta neous nephrolithotomy in the management of large renal pelvic stones. can urol assoc j. 2013;7:e171-5. laparoscopic pyelolithotomy vs. pcnl-basiri et al vol 11. no 06 nov-dec 2014 1937 female urology the effect of valsalva leak point pressure on outcomes of the needleless ®system in female stress urinary incontinence seung bum han, joon chul kim, dong hwan lee, hyo sin kim, jun sung koh, won sok hur, kang jun cho* purpose: this study aimed to investigate the effects of preoperative valsalva leak point pressure (vlpp) on the outcomes of the single-incision midurethral sling procedure (needleless® system) in female stress urinary incontinence (sui). materials and methods: we evaluated 112 patients who underwent midurethral sling placement for sui using the needleless® system. patients were divided into two groups according to their preoperative vlpp values: vlpp > 90 cmh 2 o (group 1) and vlpp 60-90 cmh2o (group 2). after the postoperative period, sui status and satisfaction were compared between the two groups. subjective cure was defined as the absence of any episodes of urinary incontinence associated with conditions that increase intra-abdominal pressure in daily life. treatment satisfaction was analyzed according to patient responses as ‘satisfied’, ‘neutral’, and ‘dissatisfied’. postoperative other lower urinary tract symptoms except sui were compared between the two groups too. results: there were no significant differences in age, body weight, and urodynamic parameters (except vlpp) between the two groups. the mean vlpps were 105.9 ± 12.3 cmh 2 o (range, 93.6–118.2 cmh2o) in group 1 and 75.4 ± 10.5 cmh2o (range, 65–85.9 cmh2o) in group 2. the overall subjective cure rates were 65.0% in group 1 and 62.5% in group 2 (p = .744). the overall satisfaction rates were 58.8% in group 1 and 68.8% in group 2 (p = .600). complication rates did not differ between the two groups. conclusion: when stratified as > 90 cmh2o or ≤ 90 cmh2o, preoperative vlpp did not affect needleless ® system outcomes in female sui patients. keywords: urinary incontinence; stress; surgery; treatment outcome; urodynamics; female; suburethral slings. introduction midurethral slings that utilize synthetic polypro-pylene monofilament mesh have been established to be safe and effective in the treatment of female stress urinary incontinence (sui). this treatment strategy is based on petros and ulmsten’s(1) suggestion that the main pathophysiology of sui involves weakening of the pubourethral ligaments and the impairment of midurethral function and anterior urethral wall support. midurethral sling techniques have progressed rapidly, and they can be classified into three generations, with retropubic transvaginal tape (tvt) representing the first generation, and transobturator tape (tot) representing the second generation. the third generation technique is the single-incision mini-sling (sims), which utilizes a shorter sling and a single vaginal incision to minimize morbidity by avoiding blind passage in the retropubic space or obturator foramen. although the sims offers a shorter operative time and a lower risk of postoperative pain, debate remains over its clinical efficacy compared to standard midurethral slings. a meta-analysis by mostafa and colleagues(2) found no evidence of significant differences in cure rate between sims and standard midurethral slings at a mean follow-up of 18 months, excluding the tvt-secure (gynecare, sommerville, nj, usa). the tvt-secure was inferior to standard midurethral slings and has already been withdrawn from clinical use. while there has been insufficient evidence to reveal a difference in outcome between sims and standard midurethral slings, sims has been considered inferior to standard midurethral slings.(3,4) various fixation mechanisms and preoperative risk factors may influence the outcomes of sims placement. adequate patient selection would be beneficial in situations in which the efficacy of sims is uncertain. valsalva leak point pressure (vlpp), an objective parameter of sui severity, is a risk factor for the failure of surgical treatment. patients with a low vlpp in the preoperative urodynamic study (uds) are considered to have a greater risk of treatment failure. some studies found that patients with a low vlpp had a lower subjective cure rate after tvt, but there was no significant difference in outcomes after tot.(5,6) however, there is a lack of data regarding the relationship between vlpp and sims outcomes. we therefore investigated the effects of preoperative vlpp on sims outcomes using the needleless® system (neomedic international, spain) in female sui. materials and methods study subjects after institutional review board approval, we retrodepartment of urology, college of medicine, the catholic university of korea, seoul, korea *department of urology, the catholic university of korea, bucheon st. mary`s hospital, 327 sosa-ro, wonmi-gu, bucheon-city, gyeonggi-do, 420-717, korea. tel: +82 32 3407730. fax: +82 32 3402124. e-mail: gift99@catholic.ac.kr. received april 2015 & accepted july 2015 female urology 2251 spectively reviewed the clinical data of women who underwent sims using the needleless® system for sui in two centers from march 2010 to august 2012 and could be followed up by telephone interview. those who previously underwent other surgeries for sui, had neurologically caused incontinence, or had stage 3 or greater pelvic organ prolapse were excluded. techniques of anti-incontinence surgery in patients without exclusion criteria were chosen by surgeon’s preference in our institute. patients were divided into two groups according to their preoperative vlpp values: vlpp > 90 cmh2o (group 1), vlpp 60-90 cmh 2 o (group 2). evaluations all the women underwent clinical evaluations, including complete history taking, physical examination, and uds. uds was performed with a 6-french (f) dual-lumen vesical catheter and a 12-f rectal balloon catheter. the bladder was filled with 30–50 ml/min saline with the patient in the sitting position. patients were asked to void prior to the examination, at which point the maximum flow rate in the sitting position, voiding volume, and postvoid residual urine volume were recorded. during bladder filling, the patients were simply instructed to report their sensations to the examiner. total bladder capacity was recorded during filling cystometry. a urethral pressure profile was performed, and the detrusor pressure at the maximum flow rate in the voiding phase and the maximum urethral closure pressure were recorded. with the subject seated after 150 ml of filling, vlpp was determined by asking the subject to perform a valsalva maneuver until urine loss was directly observed. if there was no leakage at this volume, the test was repeated after each additional 50 ml of filling. the lowest measured vlpp was recorded. surgical technique placement of the midurethral sling (needleless® system) was performed by one of two experienced urologists (jck, dhl) under spinal or general anesthesia. the intervention consisted of placing a polypropylene monofilament mesh measuring 114 mm in length and 12 mm in width under the midurethra; a pocket positioning system was located in the lateral sides of the mesh, anchoring the sling. the patient was positioned in the lithotomy position, and a 16 f foley catheter was inserted into the bladder for drainage and identification of the bladder neck. a longitudinal 2 cm incision was made in the anterior vaginal wall at the level of the midurethra. lateral to this incision, the para-urethral spaces were dissected bluntly at 2 and 10 o’clock positions to easily accept the fully extended mesh, but only up to the descending ramus of the pubic bone. a pair of surgical forceps was then introduced inside the pocket positioning system at the edge of the mesh. we hyperextended the jaws of the forceps and closed them to create an arrow with the mesh. the mesh was then introduced through the dissected para-urethral space. we continued pushing the forceps in the 10 o’clock direction, perforating the urogenital diaphragm and into the internal obturator muscle. the forceps were opened widely to extend the pocket inside the muscle. we then withdrew the forceps, semi-closing them. to control the penetration of the tip of the forceps and the mesh, the surgeon could hold the central portion of the mesh by means of a blue centering suture affixed to the middle of the mesh for this purpose. the process was repeated on the contralateral side towards the 2 o’clock direction. once the sling was placed, it could be adjusted to further support the urethra by introducing the tip of the forceps into the pocket positioning system and pushing the tip of the mesh up to the desired support level. to reduce the mesh urethral support level, the surgeon could pull the blue centering suture on the mesh. after achieving proper positioning, the blue centering suture was removed from the mesh with a single cut on one side of the suture while maintaining traction on the suture. finally, the vaginal incision was closed using 2-0 rapidly absorbable sutures in a running fashion. all patients were discharged on the same day after voiding. outcome measures after the postoperative period, sui status and treatment satisfaction were compared between the two groups. subjective patient outcomes were defined as follows: “cure” was defined as the absence of any episodes of urinary incontinence associated with conditions that increase intra-abdominal pressure in daily life, “improvement” was defined as reduced frequency and amount of urine leakage, and all other outcomes were regarded as “failure”. treatment satisfaction was analyzed according to patient responses as ‘satisfied’, ‘neutral’, and ‘dissatisfied’. other lower urinary tract symptoms newtable 1. comparison of preoperative clinical characteristics and urodynamic parameters between group 1 and group 2. variables group 1 (n = 80) group 2 (n = 32) p value age (years) 54.4 ± 6.9 54.5 ± 8.9 .748 body weight (kg) 61.9 ± 9.8 58.4 ± 2.8 .274 mixed ui 33 (41.2) 12 (37.5) .715 qmax (ml/s) 20.9 ± 7.5 22.5 ± 7.2 .550 pvr (ml) 28.2 ± 35.1 30.0 ± 27.0 .510 vlpp (cmh 2 o) 105.9 ± 12.3 75.4 ± 10.5 <.001 pdetqmax (cmh 2 o) 31.7 ± 15.9 21.3 ± 8.3 .095 mucp (cmh 2 o) 60.0 ± 25.9 49.1 ± 11.4 .364 cmg bladder capacity (ml) 329.8 ± 64.1 311.6 ± 60.2 .530 abbreviations: ui, urinary incontinence; qmax, maximum urinary flow rate; pvr, postvoid residual volume; pdet qmax, detrusor pressure on maximumflow; mucp, maximum urethral closure pressure; vlpp, valsalva leak point pressure; cmg, cystometrography. data are presented as mean ± standard deviation or as no. (%). vol 12 no 04 july-august 2015 2252 effect of vlpp on outcome of needleless in sui-han et al. ly detected during follow-up were recorded and compared between the two groups. urgency incontinence was evaluated with urinary sensation scale. statistical analysis all statistical analyses were carried out using ibm statistical package for the social science (spss) version 20.0 (ibm corp., armonk, ny, usa). continuous variables were reported as the mean ± standard deviation and categorical variables were expressed as frequencies with percentages. continuous variables were evaluated using student t-test. categorical variables were evaluated with the chi-square test. a p value < .05 was considered statistically significant. results a total of 112 patients were enrolled in the study. table 1 presents the preoperative clinical and urodynamic characteristics of group1 (n = 80) and group 2 (n = 32). the mean follow-up was 28.1 ± 4.9 months (range 25– 40) for group 1 and 27.8 ± 3.5 months (range 24–36) for group 2. no significant differences were found between the two groups in terms of age, body weight, mixed urinary incontinence rates and urodynamic parameters (except vlpp). the mean vlpp values were 105.9 ± 12.3 cmh2o (range, 93.6-118.2 cm h2o) in group 1 and 75.4 ± 10.5 cm h2o (range, 65-85.9 cm h2o) in group 2. the overall subjective cure rates were 65.0% in group 1 and 62.5% in group 2 (p = .744). the overall satisfaction rates were 58.8% in group 1 and 68.8% in group 2 (p = .600) (table 2). twenty-five patients (31.3%) in group 1 and nine patients (28.1%) in group 2 complained of voiding symptoms, such as a weak stream, straining to void, and intermittency, but there were no severe voiding difficulties requiring urethral catheterization (p = .745). overall 45 (40.1%) patients had mixed urinary incontinence preoperatively, whereas, 29 (25.9%) patients had urge incontinence at follow up for more than 24 months. five patients (6.2%) in group 1 and six patients (18.8%) in group 2 complained of postoperative de novo urgency incontinence (p = .073). there was not any other early or late postoperative complication such as vaginal tape erosions and urinary tract infection related with anti-incontinence surgery. discussion we found that preoperative vlpp did not affect cure rate, satisfaction, or postoperative de novo urinary symptoms after sims using the needleless® system in female sui patients with a preoperative vlpp > 60 cmh 2 o. a vlpp ≤ 60 cmh2o in sui is suggestive of an intrinsic sphincter deficiency etiology.(7) some authors demonstrated a correlation between vlpp and risk factors for standard midurethral sling success(5,8) while others have not.(6,9) the vlpp threshold reported in the literature is generally 60 cmh 2 o. some studies with varying vlpp thresholds used vlpp values of 60 and 90cmh2o. (6,10) in a study seeking to identify preoperative factors affecting the sims cure rate, a vlpp < 60 cmh2o was associated with a lower cure rate for the tvt-secure (11) and severe incontinence was a risk factor for failure of the mini-arc (american medical systems, minnetonka, mn, usa).(12) a previous study of needleless® system outcomes by amatand colleagues(13) did not include patients with intrinsic sphincter deficiency, defined as a vlpp < 60 cmh2o and the absence of urethral hypermobility. although we did not propose the exclusion of patients with a vlpp < 60 cmh2o initially, all patients enrolled in our study had vlpp values ≥ 60 cmh2o. this indicates that surgeons tend to avoid using sims in patients with intrinsic sphincter deficiency. thus, we used a vlpp of 90 cmh 2 o as the threshold for investigating the effect of preoperative vlpp on needleless® system outcomes. a vlpp ≥ 90 cmh2o is usually not associated with intrinsic sphincter damage and is related to urethral hypermobility, while a vlpp of 60-90 cmh2o indicates the possible coexistence of intrinsic sphincter damage and urethral hypermobility.(14) agarwal and colleagues(15) reported no significant differences in quality of life and incontinence assessment tools at both 6 and 12 months postoperatively when comparing tot outcomes by stratifying preoperative vlpp as 60-90 or > 90 cmh2o. however, sims procedures such as the needleless® system have basic anchoring mechanisms different from those of standard midurethral sling procedures such as tot. simss have a shorter trajectory of mesh insertion and need to be soundly anchored to the obturator internus muscle with a strong post-insertion pullout force.(2) we hypothesized that these different anchoring mechanisms could influence sims outcomes when comparing patients with a preoperative vlpp of 60-90 versus > 90 cmh2o. however, we did not find any significant differences in needleless® system cure rate between the two groups. rather, the treatment satisfaction rate seemed to be higher when the vlpp was lower (68.8% vs. 58.8%), although the difference of satisfaction rate was not significant. patients with a lower vlpp, which is associated with more severe sui, were more satisfied by a relatively minor improvement of their symptoms through surgical treatment. in this study, the total cure rate and total satisfaction rate for the overall study cohort more than 24 months after the needleless® system procedure were 64.3% (72/112) and 61.6% (69/112), respectively. amat and table 2. comparison of subjective outcomes between group 1 and group 2. variables group 1 (n = 80) group 2 (n = 32) p value cured 52 (65.0) 20 (62.5) .744 improved 22 (27.5) 9 (28.1) failed 6 (7.5) 3 (9.4) satisfied 47 (58.8) 22(68.8) .600 neutral 25 (31.2)) 6 (18.8) dissatisfied 8 (10.0) 4 (12.4) all data are presented as no. (%). female urology 2253 effect of vlpp on outcome of needleless in sui-han et al. martinez franco (13,16) reported outcomes for sui women who underwent the needleless® system procedure. in their study, 87.5% of patients were cured, 39.7% were very satisfied, and 53.4% of patients were satisfied at 12 months after treatment. in addition, 84.7% of patients were cured, 40.5% were very satisfied, and 52.7% were satisfied at 36 months after treatment. the outcomes for the needleless® system were not different to those of the tvt-o. the differences in cure and satisfaction rates between our study and previously reported studies may be due to these studies’ exclusion patients who had symptoms of urgency before surgery that persisted after surgery. among the most troublesome outcomes following anti-incontinence surgery is the development of voiding dysfunction. a long-term study of the needleless® system showed that 8.4% of patients experienced de novo urgency and 0.8% experienced voiding difficulty.(16) a study of sims utilizing the ophira mini sling (promedon, cordoba, argentina) found that 7.3% of patients experienced de novo urgency and 3.2% experienced voiding difficulty.(17) in our study, 9.8% (11/112) of patients experienced de novo urgency and 30.3% (34/112) experienced voiding symptoms, and there were no significant differences in de novo voiding dysfunction between groups 1 and 2. although urgency incontinence prior surgery would influence the outcomes of anti-incontinence surgery, overactive bladder symptoms could decrease significantly by surgical treatment for sui.(18) our study showed the similar results. our study has some limitations. first, this study was a retrospective study and the outcomes were entirely based on patient self-reports of incontinence rather than objective outcomes. this had a relatively small sample size that did not have statistical power sufficient to show the relationship of vlpp with outcome of sims. further prospective research with adequate power and improved design are needed to provide more information. in addition, there is a lack of consensus regarding the specific threshold of vlpp that correlates with the surgical outcomes of sims. we acknowledge that selecting slightly different vlpp thresholds could result in slightly different outcomes. conclusions although we could not identify preoperative factors for adequate sims patient selection, preoperative vlpp stratified as 60-90 cmh 2 o or > 90 cmh 2 o did not affect outcomes after sims performed using the needleless® system. further studies are necessary to confirm these data and to identify preoperative factors predicting the outcome of sims. conflict of interest none declared. references 1. petros pe, ulmsten ui. an integral theory and its method for the diagnosis and management of female urinary incontinence. scand j urol nephrol suppl. 1993;153:1-93. 2. mostafa a, lim cp, hopper l, madhuvrata p, abdel-fattah m. single-incision minislings versus standard midurethral slings in surgical management of female stress urinary incontinence: an updated systematic review and meta-analysis of effectiveness and complications. eur urol. 2014;65:402-27. 3. cornu jn, sebe p, peyrat l, ciofu c, cussenot o, haab f. midterm prospective evaluation of tvt-secur reveals high failure rate. eur urol. 2010;58:157-61. 4. nambiar a, cody jd, jeffery st. singleincision sling operations for urinary incontinence in women. cochrane database syst rev. 2014;6:cd008709. 5. kawasaki a, wu jm, amundsen cl, et al. do urodynamic parameters predict persistent postoperative stress incontinence after midurethral sling? a systematic review. int urogynecol j. 2012;23:813-22. 6. ryu jg, yu sh, jeong sh, et al. transobturator tape for female stress urinary incontinence: preoperative valsalva leak point pressure is not related to cure rate or quality of life improvement. korean j urol. 2014;55:265-9. 7. mcguire ej, fitzpatrick cc, wan j, et al. clinical assessment of urethral sphincter function. j urol. 1993;150:1452-4. 8. iancu g, peltecu g. predicting the outcome of mid-urethral tape surgery for stress urinary incontinence using preoperative urodynamics a systematic review. chirurgia (bucur). 2014;109:359-68. 9. costantini e, lazzeri m, giannantoni a, bini v, del zingaro m, porena m. preoperative mucp and vlpp did not predict long-term (4-year) outcome after transobturator midurethral sling. urol int. 2009;83:392-8. 10. feldner pc, jr., bezerra lr, de castro ra, et al. correlation between valsalva leak point pressure and maximal urethral closure pressure in women with stress urinary incontinence. int urogynecol j pelvic floor dysfunct. 2004;15:194-7. 11. han jy, park j, choo ms. efficacy of tvtsecur and factors affecting cure of female stress urinary incontinence: 3-year follow-up. int urogynecol j. 2012;23:1721-6. 12. oliveira r, botelho f, silva p, resende a, silva c, dinis p, et al. single-incision sling system as primary treatment of female stress urinary incontinence: prospective 12 months data from a single institution. bju int. 2011;108:1616-21. 13. amat itl, martinez franco e, laillavicens jm. contasure-needleless compared with transobturator-tvt for the treatment of stress urinary incontinence. int urogynecol j. 2011;22:827-33. 14. prieto chaparro l, garcia lopez f, llorens martinez f, et al. [valsalva minimal leak point pressure: a useful approximation to type iii female urinary incontinence]. arch esp urol. 1998;51:783-9. vol 12 no 04 july-august 2015 2254 effect of vlpp on outcome of needleless in sui-han et al. 15. agarwal a, rathi s, patnaik p, et al. does preoperative urodynamic testing improve surgical outcomes in patients undergoing the transobturator tape procedure for stress urinary incontinence? a prospective randomized trial. korean j urol. 2014;55:821-7. 16. martinez franco e, amattardiu l. contasureneedleless(r) single incision sling compared with transobturator tvt-o (r) for the treatment of stress urinary incontinence: longterm results. int urogynecol j. 2015;26:213-8. 17. palma p, riccetto c, bronzatto e, castro r, altuna s. what is the best indication for singleincision ophira mini sling? insights from a 2-year follow-up international multicentric study. int urogynecol j. 2014;25:637-43. 18. ciftci s, ozkurkcugil c, ustuner m, yilmaz h, yavuz u, gulecen t. comparison of transobturator tape surgery using commercial and hand made slings in women with stress urinary incontinence. urol j. 2015;12:2090-4. female urology 2255 effect of vlpp on outcome of needleless in sui-han et al. urology journal unrc/iua vol. 1, no. 4, 282-283 autumn 2004 printed in iran 282 successful medical treatment of emphysematous pyelonephritis asgari sa* departement of urology, razi hospital, gilan university of medical sciences, rasht, iran key words: emphysematous pyelonephritis, percutaneous nephrostomy, nephrectomy, medical treatment introduction emphysematous pyelonephritis (epn) is a rare life threatening condition. it usually happens in diabetic patients. its mortality is as high as 75% and urgent nephrectomy has been highly recommended.(1) however, recent advancements in imaging techniques and new stronger antibiotics can make medical treatment an acceptable alternative for radical surgery. we report a diabetic patient with epn, who was managed successfully with medical treatments. case report a 45-year-old woman with a history of fever for 10 days, persistent left flank pain, nausea, vomiting, and loss of appetite was referred to our medical center. she was also complaining of irritative urinary symptoms. hematuria or pneumaturia was not present. she had non-insulin dependent diabetes mellitus for 12 years, which was under control with glibenclamide and metformine. she had also a history of myocardial infarction 3 months earlier. on admission, she was cachectic and ill. the conjunctiva was pale and the other vital signs were as follows: blood pressure: 130/85 mmhg, pulse rate = 90/min, and temp = 38.1°c. on physical examination, the left flank was tender and a moderately mobile and soft mass was palpable. the right kidney was also palpable, but without tenderness. laboratory studies revealed leukocytosis, anemia, serum creatinine 2.5 mg/dl, pyuria, and microscopic hematuria. left kidney calyxes were outlined in kub. on intravenous pyelography that had been taken in another center, the left kidney was not visible, but there was air in the collecting system and the resultant air pyelogram and ureterogram were apparent (fig. 1). ultrasonography revealed diffuse echogenic foci in the left kidney, together with hydronephrosis and dirty shadow. in addition, there was a 17-mm echogenic focus behind the bladder in the left side (suggestive of stone). due to the history of myocardial infarction 3 months earlier, the risk of surgery was high, and we decided to attempt medical treatment. ct scan without contrast enhancement revealed an enlarged left kidney with air density in collecting system (fig. 2). under intravenous sedation with neuroleptic agents and antibiotic coverage, cystoscopy and ureteroscopy were done. there was not any obstruction in the left ureter, but after lifting a mucosal fold, a purulent discharge was seen. left percutaneous nephrostomy was performed and a ureteral stent was placed in the left ureter. after received february 2003 accepted may 2004 *correspondng author: department of urology, razi hospital, sardar-e-jangal st., rasht, iran. tel: +98 911 132 0117, e-mail: s-a-asgari@gums.ac.ir. fig. 1. air pyelogram and ureterogram in the collecting system was detected by intravenous pyelography. asgari 283 24 hours, nephrostomy tube was removed due to cessation of discharge. antibiotic therapy consisted of metronidazole 500 mg, iv, tid, ceftriaxone 1 gr, iv, bd. after seven days of medical treatment, the patient's fever was alleviated and serum creatinine level decreased to normal level. the patient was discharged in the tenth day of admission with a good general condition and oral antibiotic (ciprofloxacin 500mg, po, bd) for additional five days was priscribed. discussion emphysematous pyelonephritis was first described in 1898 as an acute perirenal narcotizing parenchymal infection that is produced by gas forming uropathogen. patients with epn are very ill and septic and some have associated liver insufficiency.(1) mostly it is unilateral, but in 10% of cases, both kidneys are involved. four factors have been proposed to have a role in the development of epn: gas producing bacteria, high blood glucose level, damaged tissue perfusion, and impaired immune response. in a report of 48 patients with epn, 96% were diabetics and 22% had urinary obstruction. the most common causative microorganisms are: escherichia coli, klebsiella pneumoniae, proteus mirabilis, pseudomonas aeruginosa, aerobacter aerogenes, citrobacters, and rarely fungi.(2) emphysematous pyelonephritis can be fatal if left untreated. traditionally the consensus is that mere medical treatment is ineffective and prompt nephrectomy is necessary. mortality rate in patients who are treated only with antibiotics is 40%. treatment is successful in 66% of patients who are treated with percutaneous nephrostomy and antibiotics, and in 90% of those with nephrectomy. man et al have divided the epn into two types.(3) in type one that is a classic from of epn, the gas is disseminated throughout the kidney in the form of streaky or mottled pattern and there is associated tissue destruction and little or nil fluid.(4) in type two, there is fluid collection in renal or perirenal tissues with gas accumulation in collecting system (fig. 1). in type one, due to severe tissue destruction, the prognosis is poor and it is recommended that nephrectomy must be done. in type two, like our patient, prognosis is better and one can expect appropriate response to medical therapy.(5,6) based on our findings, it seems that nephrectomy is not a preferred treatment for all of the epn cases. nowadays, there are growing reports of successful medical treatment of epn. references 1. eloubeidi ma, fowler vg jr. images in clinical medicine. emphysematous pyelonephritis. n engl j med. 1999;341:737. 2. gervais da, whitman gj. emphysematous pyelonephritis. ajr am j roentgenol. 1994;162:348. 3. man yl, lee ty, bullard mj, tsai cc. acute gas-producing bacterial renal infection: correlation between imaging findings and clinical outcome. radiology. 1996;198:433-8. 4. huang jj, tseng cc. emphysematous pyelonephritis: clinicoradiological classification, management, prognosis, and pathogenesis. arch intern med. 2000; 160: 797805. 5. best cd, terris mk, tacker jr, reese jh. clinical and radiological findings in patients with gas forming renal abscess treated conservatively. j urol. 1999;162:1273-6. 6. evanoff gv, thompson cs, foley r, weinman ej. spectrum of gas within the kidney. emphysematous pyelonephritis and emphysematous pyelitis. am j med. 1987;83:149-54. fig. 2. enlarged edematous left kidney with air density in the collecting system was observed in ct scan without contrast enhancement. urology journal vol. 11 no. 04 july august 2014 1752 does the use of smaller amplatz sheath size reduce complication rates in percutaneous nephrolithotomy? ayhan karakose, ozgu aydogdu, yusuf ziya atesci department of urology, izmir university school of medicine, izmir, turkey. corresponding author: ayhan karakose, md department of urology izmir university school of medicine, izmir, turkey. tel: +90 23 2399 5050-2113 e-mail: drayhankarakose@ gmail.com recevied september 2013 accepted april 2014 purpose: to evaluate the effect of amplatz sheath size used in percutaneous nephrolithotomy (pcnl) on postoperative outcomes, bleeding and renal impairment rates. materials and methods: we retrospectively evaluated the records of 91 patients who had undergone pcnl. we divided the patients into 2 groups according to amplatz sheath size (22 and 30 french [f]) used in the pcnl procedure. groups were retrospectively compared in terms of preand postoperative hemoglobin and renal function, mean nephrostomy time, mean nephrostomy tube diameter, mean operative time, mean hospitalization time and mean scopy time. results: mean operative time, mean preoperative hemoglobin and serum creatinine values were similar in 2 groups. the mean stone diameter of patients in group 1 (22f) and group 2 (30f) were 38.47 ± 11.51 mm and 37.69 ± 12.33 mm, respectively. preand postoperative hemoglobin (hb) levels were 14.52 ± 1.5 g/dl and 13.51 ± 1.4 g/dl, respectively in group 1. preand postoperative hb level were 14.23 ± 1.6 g/dl and 10.73 ± 1.7 g/dl, respectively in group 2. there was a significant difference between the two groups in terms of mean scopy time (p = .023), postoperative hb (p = .027), postoperative creatinine (p = .032), mean nephrostomy duration (p = .019), mean nephrostomy diameter (p = .028) and hospitalization time (p = .034). there was significant difference between the two groups in bleeding requiring blood transfusion (p = .023) and residual stone (p = .035). conclusion: the smaller the amplatz sheath used in pcnl, the lower kidney hemorrhage and renal function impairment happens. keywords: kidney calculi; surgery; nephrostomy, percutaneous; adverse effects; postoperative complications; treatment outcome; retrospective studies. endourology and stone disease following the procedure for hemostasis and re-opened at the postoperative 2nd hour unless the patient experienced pain. nephrostomy tube was removed if the color of the urine had become clear and all patients were discharged 12 hours following the nephrostomy tube removal if there was no urinary leak. we accepted the patients with residual stones ≤ 4 mm as stone free. two groups were retrospectively compared in terms of preand postoperative hemoglobin and renal function, nephrostomy time, nephrostomy tube diameter, operative time, hospitalization time and scopy time. clinical and laboratory data were analyzed with statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0 and data were displayed as mean ± standard deviation (sd). the two groups were analyzed and compared by using independent t-tests and paired t-tests. a 5% level of significance was used for all statistical testing. a p value < .05 was considered significant. results mean age of the patients was 44.35 ± 13.79 (range, 24-71) years and mean stone diameter was 37.56 ± 9.58 (range, 10-55) mm. mean operative and scopy time were 109.81 ± 42.43 (range, 50-202) min and 14.43 ± 9.61 (range, 3-27) min, respectively. the mean stone diameter of patients in group 1 (22f) and group 2 (30f) were 38.47 ± 11.51 mm and 37.69 ± 12.33 mm, respectively. fifty-eight patients presented with multiple stones (27 and 31 patients in groups 1 and 2, respectively). thirty-two patients presented with staghorn stone (15 and 17 patients in groups 1 and 2, respectively). table 1 includes patients’ characteristics and stones’ properties. there was no statistical difference between 2 groups in terms of age, male to female ratio, mean maximum stone diameter, number of stones and side. preoperative and postoperative hemoglobin (hb) levels were 14.52 ± 1.5 g/dl and 13.51 ± 1.4 g/dl, respectively in group 1. preoperative and postoperative hb levels were 14.23 ± 1.6 g/dl and 10.73 ± 1.7 g/ dl, respectively in group 2. there was a significant difference between the two groups in terms of mean scopy time (p = .023), postoperative hb (p = .027), postoperative creatinine (p = .032), mean nephrostomy duration (p = .019), mean nephrostomy diameter (p = .028) and hospitalization time (p = .034). postoperative mean hb level was significantly lower and postoperative mean serum creatinine level was significantly higher in patients who were treated with 30f amplatz sheath when compared to 22f amplatz sheath. it was observed that nephrostomy time and nephrostomy tube size significantly increased as the amplatz sheath size increased. mean operative time, mean preoperative hb and serum creatinine values were similar in all 2 groups. results are summarized in table 2 and figure. eight patients presented with postoperative infection (clavien grade 1) (3 and 5 patients in 22f and 30f groups, respectively), 11 patients developed bleeding requiring blood transfusion (clavien grade 2) (3 and 8 patients in 22f and 30f groups, respectively), residual stone was observed in 7 patients (5 and 2 patients in 22f and 30f groups, respectively), and 6 patients had antegrade placement of a 6f double-j introduction in recent years urolithiasis has become one of the most import-ant disorders affecting the daily life of patients and percutaneous nephrolithotomy (pcnl) has become a standard procedure in the surgical treatment of larger renal or proximal ureteral stones.(1-3) since the procedure was firstly described, several efforts have been made to improve the outcome and decrease the complication rates.(2,4) although the procedure has various advances, some issues associated with pcnl remain matter of debate.(3) recently there have been several reports in the literature investigating the effect of nephrostomy tube size on the success, bleeding, renal function impairment and postoperative urinary leak rates.(1-3) in addition there are many trials comparing the nephrostomy drainage with no nephrostomy (tubeless) drainage following pcnl.(1-3,5, 6) in most of the previous studies a 26 to 30 french (f) amplatz sheath was positioned into the renal collecting system.(1,3) none of these reports include any data presenting the effect of amplatz sheath size on surgical outcomes and perioperative findings. in the recent study we retrospectively evaluated the effect of amplatz sheath size used in pcnl on postoperative outcomes, bleeding, and renal impairment. nephrostomy tube size and duration, operative time, hospitalization time, and scopy time were also compared. materials and methods the records of 91 patients (56 males and 35 females) who have undergone pcnl by two different surgeons between november 2011 and june 2013 were retrospectively evaluated. previously 30f amplatz sheath was routinely used in all patients who underwent pcnl in our clinic regardless of the stone size. in our clinical experience we observed that the intraoperative bleeding following serial renal dilatation increased after 24f renal dilatator, although there was no significant bleeding with renal dilatators smaller than 24f. therefore we began to use 22f amplatz sheath routinely in all patients regardless of stone diameter after october 2012. we divided the patients into 2 groups according to amplatz sheath size (22f and 30f) used in the pcnl procedure. patients with abnormal preoperative renal function and pyonephrosis were excluded from the study. all patients were operated in prone position through a percutaneous access following retrograde ureteral catheterization under general anesthesia. initial percutaneous renal access to either the lower or the middle calyx was performed by the operating surgeon under radiologic assistance using x-ray in combination with retrograde intra-renal contrast injection. once access was obtained, a sensor guidewire (boston scientific®, cimed, inc., minnesota, usa) was inserted and preferably maneuvered toward the ureter. a 22f or 30f amplatz sheath was positioned in the renal collecting system following progressive dilation of the tract using serial dilators under fluoroscopic control. the stones were disintegrated with pneumatic lithotripsy and removed using foreign body grasper. the nephrostomy tube was introduced under fluoroscopic control. the nephrostomy tube was closed 1753 endourology and stone disease urology journal vol. 11 no. 04 july august 2014 1754 amplatz sheath size and complication rates in pcnl-karakose et al system following pcnl.(2) in a previous study 3 different nephrostomy tube types including 24f re-entry tube, 8f pigtail catheter and double j stent plus 18f councill-tip catheter were compared.(19) the authors noted no statistical difference in terms of pain scores, hematocrit change and hospital stay. in a recent study, the effect of nephrostomy tube size (22f versus 12f) on perioperative outcomes of pcnl was investigated.(3) this study showed that a small bore nephrostomy tube can safely be used instead of a larger size tube following uncomplicated pcnl procedure since the size of the nephrostomy tube does not affect blood loss and hospital stay. in a similar study the authors explored the relationship between nephrostomy tube size and results of pcnl.(2) the authors concluded that large bore nephrostomy tube reduce bleeding and overall complication rate. previous studies have not discussed the potential impact of amplatz sheath size on surgical outcomes of pcnl procedure. to the best of our knowledge the recent study represents the first trial investigating the effect of amplatz sheath size on surgical outcomes and perioperative findings of pcnl. we tried to evaluate the effect of amplatz sheath size used in pcnl on postoperative outcomes, bleeding, and renal impairment. we also compared nephrostomy tube size and duration, operative time, and scopy time. postoperative mean hb level was significantly lower and postoperative mean creatinine level was significantly higher in the patients who were treated with larger amplatz sheath when compared to smaller size. we think that although pcnl is a minimally invasive procedure to the skin, the technique is still invasive for the kidney. the findings of the recent study proved that the use of small size amplatz sheath is less harmful for the kidney resulting in less bleeding and less renal impairment. although we have not objectively evaluated the postoperative pain status of the patients, we observed that the use of small size amplatz sheath decreased the postoperative patient discomfort. however further studies investigating postoperative pain with valid pain scoring systems are needed. ureteral stent (22f and 30f groups, respectively). there was significant difference between the two groups in bleeding requiring blood transfusion (p = .023) and residual stone (p = .035). none of the patients presented with postoperative prolonged urinary leak and no patient required any ancillary procedures. postoperative results are summarized in table 3. discussion morbidity associated with the open surgery for larger renal and proximal ureteral calculi has significantly decreased by the use of pcnl. (1) although pcnl is a well-defined procedure, surgical technique is still changing since most of the clinicians are trying to optimize the outcomes and minimize the complications and patients’ discomfort related with the procedure.(2,3) previous studies mainly discussed pcnl exit strategy including nephrostomy drainage versus no nephrostomy drainage (tubeless) and nephrostomy tube type and size if used.(1-3,7-10) there has been increasing evidence that the drainage method used in pcnl may significantly affect the outcomes and complications including hospital stay, patients’ discomfort, bleeding, prolonged urinary leak and renal impairment.(1, 2) previous studies mainly discussed pcnl postoperative outcomes, complications, bleeding, and renal impairment. recently tubeless pcnl has been advocated by various trials in short and uncomplicated cases with minimal bleeding, fewer complications and reduced hospital stay.(1-3,9-18) desai and colleagues prospectively compared postoperative outcomes among tubeless, conventional large bore and small bore nephrostomy drainage.(1) they concluded that tubeless pcnl is associated with the least postoperative pain, urinary leakage and hospital stay. in contrast several studies demonstrated that nephrostomy tube placement is mandatory providing hemostatic tamponade for the percutaneous renal tract, continuing access to the renal collecting system if a second look procedure is required and avoiding urinary extravasation.(2,3) there are conflicting findings associated with the type and size of the nephrostomy tube used to drain the renal collecting table 1. demographic and clinical characteristics of study groups. variables group 1 (22f) group 2 (30f) patients, no. 47 44 age, years, mean ± sd 44.3 ± 13.61 45.17 ± 12.71 (min-max) (25-67) (24-71) male:female, no. 29:18 27:17 right:left side, no. 22:25 21:23 stone diameter, mm, mean ± sd 38.47 ± 11.51 37.69 ± 12.33 (min-max) (10-50) (15-55) multiple stones, no. 27 31 staghorn stone, no. 15 17 abbreviations: sd, standard deviation; f, french. the recent study has some limitations including the retrospective design which might introduce some selection bias. our findings demonstrated that stone free rate is negatively related with the amplatz sheath size. this might possibly because we have only used pneumatic lithotripsy device for fragmentation of stones. we suppose that our stone free rates would potentially be better if we could use both pneumatic and ultrasonic lithotripsy devices. we compared two (22f, 30f) amplatz sheath size and inserted nephrostomy tube to all patients. further prospective and randomized studies including different sized nephrostomy tube drainage and no nephrostomy drainage (tubeless) groups would probably demonstrate the effect of amplatz sheath size on perioperative outcomes more objectively. in contrast to the results of the study reported by cormio and colleagues, our findings showed that nephrostomy tube size and bleeding significantly increased as the amplatz sheath size increased.(2) we think that the amplatz sheath size is more crucial than the size of nephrostomy tube used to drain the renal collecting system in terms of bleeding and renal impairment. although the impact of percutaneous tract dilatation in terms of intraoperative bleeding was not prospectively evaluated in the recent study, in our clinical experience we observed more intraoperative bleeding following 24f or larger dilatators. in a recent study the authors advocated that the size of nephrostomy tube does not affect blood loss and hospital stay.(3) in contrast our findings showed that the use of small size amplatz sheath significantly decreased the nephrostomy tube size, bleeding, nephrostomy time hospital stay. table 2. perioperative findings in study groups.* variables group 1 (22f) group 2 (30f) p value operative time, min 101.31 ± 32.1 118.36 ± 48.5 .082 (min-max) (50-115) (62-202) scopy time, min 18.72 ± 3.2 12.13 ± 5.9 .023 (min-max) (5-25) (3-27) preoperative hb, g/dl 14.52 ± 1.5 14.23 ± 1.6 .092 (min-max) (11.3-16.2) (10.9-16.5) postoperative hb, g/dl 13.51 ± 1.4 10.73 ± 1.7 .027 (min-max) (10.3-15.2) (8.5-12.7) preoperative creatinine, mg/dl 0.9 ± 0.53 0.85 ± 0.42 .079 (min-max) (0.4-1.66) (0.4-1.39) postoperative creatinine, mg/dl 0.9 ± 0.31 1.62 ± 0.43 .032 (min-max) (0.5-1.4) (0.9-2.1) nephrostomy duration, day 1 ± 0.53 3.95 ± 1.23 .019 (min-max) (1-4) (3-7) nephrostomy diameter, mm 12.52 ± 1.41 16.64 ± 2.56 .028 (min-max) (10-14) (12-20) hospitalization stay, days 1.7 ± 0.43 2.7 ± 0.72 .034 abbreviations: hb, hemoglobin; f, french. * data are presented as mean ± standard deviation. table 3. postoperative findings in study groups.* variables group 1 (22f) group 2 (30f) p value postoperative infection 3 (6.38) 5 (11.36) .061 bleeding requiring blood transfusion 3 (6.38) 8 (18.18) .023 residual stone 5 (10.63) 2 (4.54) .035 6 fr double-j stent 2 (4.25) 4 (9.09) .053 * data are presented as number percent. 1755 endourology and stone disease urology journal vol. 11 no. 04 july august 2014 1756 amplatz sheath size and complication rates in pcnl-karakose et al less percutaneous renal surgery. j urol. 1997;157:1578-82. 8. lojanapiwat b, soonthornphan s, wudhikarn s. tubeless percutaneous nephrolithotomy in selected patients. j endourol. 2001;15:711-3. 9. shah hn, sodha hs, khandkar aa, kharodawala s, hegde ss, bansal mb. a randomized trial evaluating type of nephrostomy drainage after percutaneous nephrolithotomy: small bore v tubeless. j endourol. 2008;22:1433-9. 10. crook tj, lockyer cr, keoghane sr, walmsley bh. a randomized controlled trial of nephrostomy placement versus tubeless percutaneous nephrolithotomy. j urol. 2008;180:612-4. 11. limb j, bellman gc. tubeless percutaneous renal surgery: review of first 112 patients. urology. 2002;59:527-31. 12. crook tj, lockyer cr, keoghane sr, walmsley bh. totally tubeless percutaneous nephrolithotomy. j endourol. 2008;22:267-71. 13. de cógáin mr, krambeck ae. advances in tubeless percutaneous neph rolithotomy and patient selection: an update. curr urol rep. 2013;14:130 7. 14. mehrabi s, karimzadeh shirazi k. results and complications of spinal anesthesia in percutaneous nephrolithotomy. urol j. 2010;7:22-5. 15. mousavi-bahar sh, mehrabi s, moslemi mk. percutaneous nephroli thotomy complications in 671 consecutive patients: a single-center expe rience. urol j. 2011;8:271-6. 16. sharifiaghdas f, simforoosh n, ozhand a. a complication after percuta neous nephrolithotomy. urol j. 2010;7:199-200. 17. etemadian m, soleimani mj, haghighi r, zeighami mr, najimi n. does bleeding during percutaneous nephrolithotomy necessitate keep ing the nephrostomy tube? a randomized controlled clinical trial. urol j. 2011;8:21-6. 18. basiri a, najjaran toussi v, mohammadi sichani m, ardestani zadeh a. spontaneous resolution of severe hemorrhagic intrarenal pseudoaneu rysm after percutaneous nephrolithotomy. urol j. 2010;7:10-1. 19. marcovich r, jacobson ai, singh j, et al. no panacea for drainage after percutaneous nephrolithotomy. j endourol. 2004;18:743-7. conclusion the use of small bore amplatz sheath in pcnl procedure seems to reduce bleeding, renal impairment rates, and patients’ postoperative discomfort. further prospective, high numbered and randomized studies are needed to support our findings. conflict of interest none declared. references 1. desai mr, kukreja ra, desai mm, et al. a prospective randomized comparison of type of nephrostomy drainage following percutaneous nephrostolithotomy: large bore versus small bore versus tubeless. j urol. 2004;172:565-7. 2. cormio l, preminger g, saussine c, et al. nephrostomy in percutaneous nephrolithotomy (pcnl): does nephrostomy tube size matter? results from the global pcnl study from the clinical research office endou rology society. world j urol. 2013;31:1563-8. 3. de sio m, autorino r, quattrone c, giugliano f, balsamo r, d’armien to m. choosing the nephrostomy size after percutaneous nephrolithotmy. world j urol. 2011;29:707-11. 4. fernström i, johansson b. percutaneous pyelolithotomy. a new ex traction technique. scand j urol nephrol. 1976;10:257-9. 5. borges cf1, fregonesi a, silva dc, sasse ad. systematic review and meta-analysis of nephrostomy placement versus tubeless percutaneous nephrolithotomy. j endourol. 2010;24:1738-46. 6. ni s, qiyin c, tao w, et al. tubeless percutaneous nephrolithotomy is associated with less pain and shorter hospitalization compared with stan dard or small bore drainage: a meta-analysis of randomized, controlled trials. urology. 2011;77:1293-8. 7. bellman gc, davidoff r, candela j, gerspach j, kurtz s, stout l. tubefigure. mean scopy time, nephrostomy duration, nephrostomy tube diameter, postoperative hemoglobin, hospitalization time and serum creatinine values were significantly different among groups. 169 urology journal unrc/iua vol. 2, no. 3, 169-170 summer 2005 printed in iran case reports synchronous renal fossa recurrence with bladder metastases due to renal cell carcinoma hooman djaladat,1* abdorrasoul mehrsai,2 hamid nasseh,2 gholamreza pourmand2 1department of urology, mohammadi hospital, hormozgan university of medical sciences, bandarabbas, iran 2urology and renal transplant research center, department of urology, sina hospital, tehran university of medical sciences, tehran, iran key words: renal cell carcinoma, bladder, metastasis introduction renal cell carcinoma (rcc) accounts for 3% of all malignancies in adults. it is the most lethal urologic cancer.(1) common sites of distant metastatic disease are the adrenal gland (ipsilateral and contralateral), lung, liver, bones, subcutaneous tissues, and brain.(2) guinan and coworkers have found a direct correlation between solid tumor size and its metastatic potential.(3) we report a rare metastasis of rcc, detected in a patient after radical nephrectomy. case report a 54-year-old male farmer presented to our clinic with gross hematuria. three years earlier, he had been referred owing to right flank pain and intermittent hematuria. a renal mass (16 × 9 × 8 cm) occupying the upper pole of the right kidney had been found, and further investigations had shown no metastases. at that time, he had undergone right radical nephrectomy. pathologic examination showed a papillary-type rcc invading the perinephric fat (t3an0m0) (figure 1). from then until the current presentation, he had been well until the recurrence of hematuria. he had no history of cigarette smoking, diabetes mellitus, hypertension, or any other medical disease. radiologic investigation revealed a solid cystic mass in the right renal fossa measuring about 7 × 6 cm. imaging studies showed the remainder of the right ureter to be free of metastases. however, there was a suspected mass in the bladder. cystoscopy revealed a frondlike tumor just over the right ureterovesical junction. the specimen resected for biopsy demonstrated papillary rcc (figure 2). results of biopsy specimens of other parts of the bladder were normal. results of urine cytology were negative. further investigation demonstrated no other metastases. palliative transurethral resection (tur) was performed. immunohistological studies (cd10 and cytokeratin 20) performed on both the nephrectomy and tur specimens received may 2004 accepted april 2005 *corresponding author: urology and transplant research center, sina hospital, hassanabad sq, tehran 1995345432, iran. tel: ++98 21 6671 7447, fax: ++98 21 6671 7447 e-mail: hoomanj@hums.ac.ir fig. 1. pathologic appearance of papillary-type renal cell carcinoma (hematoxylin-eosin, × 10) renal fossa recurrence with bladder metastases due to renal cell carcinoma170 revealed the same histologic result (papillary rcc). the patient subsequently underwent immunotherapy. two years later, the patient died owing to distant metastases. discussion metastases to the bladder from rcc are extremely rare. the review of the literature and other case reports indicates that these metastases are usually diagnosed 2 to 3 years after initial diagnosis of primary renal tumor. the prognosis is poor and seems not to depend on the type of treatment. most patients die within 1 year of diagnosis. treatment should be as conservative as possible.(4) asynchronous metastasis is much more common than synchronous metastasis.(5) morphologically, rcc can be confused with transitional cell carcinomas, especially those exhibiting clear cell features, as well as with other bladder tumors such as paragangliomas and metastatic melanomas.(6) in our patient, both the primary and metastatic pathology were papillarytype rcc. this characteristic also represents the majority of cases reported in the literature. additionally, simultaneous recurrence in the primary fossa and bladder is quite unique. the mechanism of spread to the bladder in our case seems to be direct extension and implantation. other mechanisms such as a retrograde venous embolism of tumoral cells from a renal vein into numerous venous connections of the left renal vein (which is why we there are more left-sided renal tumors leading to bladder secondaries than right-sided tumors) and lymphatic spreads also have been proposed.(6) interestingly, this case was a right-sided renal tumor metastasized to the right side of the bladder. different treatments have been proposed including bacillus calmette-guerin,(7) ureterectomy with cuff cystectomy,(8) transurethral resection,(4) and even radical cystectomy.(9) overall, the prognosis is poor. references 1. novick ac, campbell sc. renal tumors. in: walsh pc, retik ab, vaughan ed. et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 2672-731. 2. patel a, kernion j. diagnosis and staging of renal cell carcinoma. in: oesterling je, richie jp, editors. urologic oncology. 1st ed. philadelphia: wb saunders; 1997. p. 147-73. 3. guinan pd, vozelgang nj, fremgen am, et al. renal cell carcinoma: tumor size, stage and survival. members of the cancer incidence and end results committee. j urol. 1995;153:901-3. 4. gallmetzer j, gozzi c, mazzoleni g. [solitary synchronous bladder metastasis from renal cell carcinoma treated bytransurethral resection]. urologe a. 2000;39:52-4. german. 5. ziade j, cipolla b, robert i, et al. [synchronous bladder metastasis of a clear-cell adenocarcinoma of the kidney]. acta urol belg. 1994;62:45-8. french. 6. sim sj, ro jy, ordonez ng, park yw, kee kh, ayala ag. metastatic renal cell carcinoma to the bladder: a clinicopathologic and immunohistochemical study. mod pathol. 1999;12:351-5. 7. vecchioli scaldazza c, giacomini g. [repeated bladder metastases from renal cell carcinoma. report of a case with particular attention to the use of immunomodulators]. minerva urol nefrol. 2000;52:215-8. italian. 8. chiu ky, ho hc, chen jt, et al. renal cell carcinoma metastasized to the ureteral stump. zhonghua yi xue za zhi (taipei). 2001;64:64-8. 9. chinegwundoh fi, khor t, leedham pw. bladder metastasis from renal cell carcinoma.br j urol. 1997;79:650-1. fig. 2. pathologic appearance of bladder metastases (hematoxylin-eosin, × 10) 1527vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l complete supine tubeless percutaneous nephrolithotomy siavash falahatkar, alireza farzan, aliakbar allahkhah, nadia rastjou herfeh, samaneh esmaeili corresponding author: siavash falahatkar, md urology research center, guilan university of medical sciences, rasht, iran. tel: +98 131 5525259 e-mail: falahatkar_s@yahoo.com urology research center, school of medicine, guilan university of medical sciences, rasht, iran. video introduction although,percutaneousnephrolithotomy(pcnl)hasbeenusuallyperformedinthepronepositionbutrecentlyotherpositionslikesupineandcompletesupinehavebeenrecommendedbysomeendourologists.(1-8)thepronepositionhasnumerous disadvantagesbutalotofpublisheddatahavedenotedsomeadvantagesofthesupinepcnl, including less patient handling, easier access to the urethra, position changing in spinal or regionalanesthesiaiseasier,betteraccesstotheairwayofthepatients,easieraccesstothe uppercalyces,evacuationofstonefragment,feasibilityofsimultaneousureteroscopy,puncturesiteisfarfromthefluoroscopytube,shorteroperativetime,morecomfortforthepatient, lessriskofcoloninjuryandhighertoleranceforpulmonaryorcardiovasculardisease.(1,7-8) weaimedtoshareourexperienceofthecompletesupinepercutaneousnephrolithotomy (cspcnl)withothersbyavideopresentationwiththedetailsofthetechnique. keywords:nephrostomy;percutaneous;methods;humans;kidneycalculi;surgery. 1528 | video surgical technique thismoviepresentscompletesupinepcnlina52-year oldmanwithmultiplestonesinhisrightkidney.afterureteral catheterization, the patient is drawn toward the edge ofthebed.itisnotnecessarytodrawthepatientmore,becausethemetaldensityofthebedmightinterfereduringthe access.flankelevationorchangingthepositionoflegisn’t neededincompletesupineposition. thepuncturesitesareselectedbetweenmidandposterior auxiliarylineunderthe12thrib(figure) thesubcostalupperpoleaccessisfeasibleincspcnlwith sometechnicalmaneuvers.(7) during the deep inspiration, thekidneymovestoinalowerpositionandtheuppercalyx achievementbysubcostalapproachisfeasible.(7)incompletesupinepositionthefluoroscopytubeisfarfromthe surgeryfieldandthesurgeongetsawidespaceforworking. thekidneymovementisthemarkerthattheneedleisonthe posteriorsurfaceofthekidney.then,thesurgeonchooses thebestangleforachievingthecalyx.becausethefluid maydrenchthesurgeon’slowerlimbsduetothesittingpositionincompletesupine,waterproofcoverisusedbythe surgeon. oneofthemostimportantdifferencesbetweenthecompletesupinepositionandthepronepositionforpcnlis evacuationofstonefragments.wehavefrequentlyseenthe evacuationofstonefragmentsduringthesurgery.(1)ouroptionforallpatientsistubelesspcnlunlessthepresence ofsignificantresidualstoneorseverehemorrhageorsignificantextravasation.(2)theanesthesiatimeinthesupine positionissignificantlyshorterthantheproneposition. conflict of interest none declared. conclusion aswehaveshowninthemoviethatcspcnlisfeasibleand thesurgeoncandecidewhetheranephrostomytubeshould beinsertedornot? figure . (a) shows mid auxiliary line, the 11th and the 12th ribs and the iliac crest. the puncture site in complete supine percutaneous nephrolithotomy is usually placed in an area between mid-auxiliary line and posterior auxiliary line under the 12th rib, (b) demonstrates the puncture site. references 1. falahatkar s, moghaddam aa, salehi m, nikpour s, esmaili f, khaki n. complete supine percutaneous nephrolithotripsy comparison with the prone standard technique. j endourol. 2008;22:2513-7. 2. falahatkar s, farzan a, allahkhah a. is complete supine percutaneous nephrolithotripsy feasible in all patients? urol res. 2011;39:99104. 3. rana am, bhojwani jp, junejo nn, das bhagia s. tubeless pcnl with patients in supine position: procedure for all seasons?-with comprehensive technique. urology. 2008;71:581-5. 4. steele d, marshall v. percutaneous nephrolithotomy in the supine position: a neglected approach? j endourol. 2007;21:1433-7. 1529vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l tubeless pcnl | falahatkar et al 5. basiri a, mohammadi sichani m, hosseini sr, et al. x-ray-free percutaneous nephrolithotomy in supine position with ultrasound guidance. world j urol. 2010; 28:239-44. 6. de sio m, autorino r, quarto g, et al. modified supine versus prone position in percutaneous nephrolithotomy for renal stones treatable with a single percutaneous access: a prospective randomized trial. eur urol. 2008; 54:196-202. 7. falahatkar s, enshaei a, afsharimoghaddam a, emadi sa, allahkhah aa. complete supine percutaneous nephrolithotomy with lung inflation avoids the need for a supracostal puncture. j endourol. 2010;24:213-8. 8. valdivia-uria jg, valle gerhold j, lopez lopez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol. 1998;160:1975-8. introduction a complete duplex kidney is not an uncommon congenital anomaly of the urinary tract and has a prevalence of 1/125. it is usually associated with ureteroceles, vesicoureteral reflux and ectopic ureters accompanied by a poorly functioning upper pole segment. (1,2) it manifests with urinary tract infections (uti), urinary incontinence and voiding dysfunction during childhood, whereas flank pain or recurrent uti might be signs of the disease when undiagnosed until adulthood. the standard treatment for the duplicated system is upper pole heminephrectomy with ureterectomy when needed, which used to be performed with a flank incision. since the first laparoscopic upper pole heminephrectomy with ureterectomy in a pediatric patient was reported by jordan and winslow in 1993, urologists tend to perform this surgery using the laparoscopic technique.(2) the published reports on laparoscopic heminephrectomy are limited and occasionally confined to the pediatric population.(1,35) we report our results and experience in laparoscopic upper pole heminephrectomy for the treatment of duplex kidneys in adults. materials and methods study population the endourological databases of two high-volume urology clinics (department of urology, school of medicine in hacettepe and çukurova universities) were retrospectively reviewed to analyze the results of laparoscopic heminephrectomy. between april 2005 and march 2010, six males and four females within the age range of 27–54 years underwent laparoscopic upper pole heminephrectomy for duplicated collecting systems. five and 4 patients had a duplicated system on the right and left sides, respectively, while one patient had a bilateral duplicated system. ipsilateral kidney stones were detected in 2 patients, one of them, in which the stone was in the affected system, was treated laparoscopically during heminephrectomy and the other one who had the stone in the healthy lower pole was managed with an internal stent to facilitate further treatment modalities. all patients had ectopic ureters, additionally an ureterocele was revealed in 2 patients who had a history of previous endoscopic ureterocele incision in the duplicated region site and 1 patient had a cecal ureterocele. the main complaint on admission was side or abdominal pain in all patients. eight patients had a history of recurrent uti, two of them presented with high fever and required long-term antibiotic therapy and one required nephrostomy drainage. preoperative imaging evaluation was done using ultrasonography, computed tomography laparoscopic urology laparoscopic upper pole heminephrectomy in adults for treatment of duplex kidneys muhammet irfan dönmez,1* mustafa sertaç yazici,1 deniz abat,2 önder kara,1 yildirim bayazit,2 cenk yücel bilen1 purpose: to present our results of laparoscopic upper pole heminephrectomy in adult patients with duplex kidney. materials and methods: a total of 10 patients with an age range of 27 to 54 years old underwent laparoscopic upper pole heminephrectomy for complete duplication of the renal collecting system. the key point of the technique included the placement of a catheter in the normal ureter at the beginning of the procedure. the patient was positioned in a 45-90 degrees lateral decubitus position and a 4-port transperitoneal or 3-port retroperitoneal technique was applied followed by the mobilization of the upper pole ureter away from the renal hilum. afterwards, the vasculature supplying the upper pole was precisely identified and ligated. followed by transection of the ureter and its transposition cephalad to the hilum, the upper pole moiety was fully transected using the harmonic scalpel. results: eight patients were operated on using the transperitoneal approach and 2 using the retroperitoneal technique. one patient required preoperative percutaneous drainage due to pyonephrosis. the operation time ranged between 150 to 350 min with minimal blood loss (0-200 ml). hemostasis was achieved with an argon laser in one patient. the lower pole calyceal system was perforated in one patient and repaired intracorporally. no major intraoperative complications occurred. all of the patients except two had their drains removed in 72 h after the operation and were generally discharged on postoperative day 3. conclusion: laparoscopic upper pole heminephrectomy for an ectopic ureter is safe and reproducible and offers benefits of laparoscopic surgery even in patients with complicated urinary tract infection. keywords: kidney; abnormalities; surgery; laparoscopy; nephrectomy; methods; postoperative complications. 1 department of urology, school of medicine, hacettepe university, sihhiye/ankara, turkey. 2 department of urology, school of medicine, çukurova university, balcali/adana, turkey. *correspondence: department of urology, school of medicine, hacettepe university, sihhiye/ankara, turkey. tel: +90 312 305 1969. fax: +90 312 311 2262. e-mail: m_irfan83@yahoo.com. received june 2014 & accepted march 2015 laparoscopic urology 2074 vol 12. no 02 march-april 2015 1995vol 12. no 02 march-april 2015 2075 and voiding cystourethrography when necessary (figure 1). surgical technique after the induction of general anesthesia, cystoscopy was carried out routinely in all patients and a 6 french (f) open-ended catheter was placed into the normal ureter under fluoroscopic guidance. the urethral foley catheter was left in situ. thereafter, the patient was positioned in a 45-90 degrees lateral decubitus position and the transperitoneal technique (retroperitoneal in 2 patients) was performed. we applied a similar technique as first performed by wang and colleagues in 2004.(6) no bowel preparation was used routinely in our patients; however, all of them were wearing either pneumatic whole leg compressors or surgical stockings. peritoneal access is obtained using a veress needle inserted at the umbilicus and the abdomen is insufflated up to 15 mm hg. all trocars were placed under direct vision. a threeport transperitoneal technique is utilized with a 10 mm trocar at the umbilicus, a 10 mm port in the midclavicular line just below the umbilicus, and a third 5 or 10 mm port subcostally. an optional fourth port (5 mm) was placed just above the umbilical level in the midaxillary line when needed. four trocars were used in six patients, 3 trocars in two patients whereas 5 trocars were used in another two patients. after moving the colon medially, the kidney and the duplicated ureters were identified with blunt and sharp dissection. the normal lower pole ureter was identified by the previously placed catheter, which helped the operators to precisely dissect it away from the effected upper pole ureter. then, the upper pole ureter was fully mobilized away from the renal hilum (posterior and cephalad). because duplicated systems are mostly accompanied by vascular anomalies, the upper pole ureter dissection must be performed carefully. close dissection to the serosa of the upper pole ureter will be protective against harming unexpected vascular structures. during dissection, the artery and vein supplying the upper pole were precisely identified and ligated. after transection of the ureter and its transposition cephalad to the hilum, dissection of the upper pole moiety was performed using harmonic scalpel through the demarcation line, which is easily distinguished. hook electrocautery is used in some cases to mark the renal capsule between the upper pole and the lower pole. hemostasis was achieved using bipolar and monopolar electrocautery. no adjuvant coagulative agent was used. indigo blue injected through the ureteral catheter showed extravasation from the lower pole collecting system in only one patient. a drain was placed in the surgical field before removal of the trocars (figure 2 a and b). results patient characteristics are summarized in table. no conversion to open surgery or re-operation was required. in one patient, the collecting system of the lower pole was opened and the defect was sutured intracorporeally by using 3.0 vicryl suture. no other intraoperative complications occurred. the mean blood loss volume was minimal (0-200 ml) and the mean operation time was 230 min (150-350 min). dissection of the upper pole was technically difficult in the two cases with uti as expected. laparoscopic upper pole heminephrectomy in adults-dönmez et al. figure 1. three dimensional reconfiguration of computed tomography demonstrating the non-functioning upper pole moiety. figure 2. a) fine dissection of upper pole ureter from the lower pole ureter and identification and preparation of renal vasculature; b) precise identification of multiple renal veins draining the normal lower pole of the right kidney; c) transection of the upper pole ureter; d) suspension of the renal vein and transposition of the upper pole ureter through the renal vasculature; e and f) the upper pole ureter is completely mobilized and transposed, the vascular supply of the upper pole was identified and controlled using clips and vascular sealing devices when appropriate; g and h) resection of the upper pole and repair of the lower pole perforation. the ureteral catheters were removed before removing the patient from the operating room. the urinary catheters were removed 24 h after surgery in all patients while drains were generally removed on postoperative day 2. the mean hospital stay after surgery was around 60 h excluding the 2 patients with prolonged hospital stay. patients were not discharged in the case of absent flatus. subsequently, none of our patients showed delayed flatus. pathology reports revealed active chronic inflammatory fibrosis and granulation tissue in all patients. hemostasis was achieved with bipolar and monopolar cautery. argon laser was used in one patient with pyonephrosis on lower pole moiety through the dissection line to control oozing from the inflammatory parenchyma. the ureters of the effected system were dissected as far as possible and ligated; however, in one case, in which a refluxing cecal ureterocele was present, the ureter was adequately dissected and left open. dissection was not continued in the pelvis to prevent the disruption of neurogenic and vascular structures that would cause voiding problems. two patients with uti received antibacterial therapy for 10 days. the postoperative period was uneventful except for two patients. both presented with extensive drainage. one showed minimal extravasation from the normal ureter on post-operative day 1, which was thought to be injured during dissection and was successfully managed with an internal stent (double j ureteral stent) insertion, the patient was discharged the other day. patient number 10 had a huge dilated upper pole segment and presented with an abdominal mass. although an extensive dissection was performed, the vascular supply could not be identified. due to the prolonged urine drainage and the lack of vascular supply visualization preoperatively, a selective renal angiography was planned. the angiography revealed two extra renal segmental arteries arising from the main renal arteries, which were embolized at the same time. subsequently, drainage decreased and the patient was discharged after removal of the drain (figure 3). none of the patients required blood transfusions. discussion in adults, treatment of the non-functioning upper pole of complete duplex kidneys is indicated in patients with recurrent uti and/or side or abdominal pain. since the first laparoscopic heminephrectomy by jordan and winslow,(3) there has been a high incidence of pediatric use of laparoscopy in treatment of duplex systems. nevertheless, there are limited data and studies focusing on heminephrectomy in adults. this study was conducted to increase the amount of data available in laparoscopic upper pole heminephrectomies in duplex kidneys. laparoscopy offers better visualization of the vasculature and parenchyma, shorter hospital stay and diminished postoperative pain. regardless from the approach, both retroperitoneal and transperitoneal heminephrectomy offers classical advantages of laparoscopic surgery. the advantages of transperitoneal approach are as follows: having a larger working space, better exposure of the hilum and easy manipulation of the ureter when necessary. figure 3. successful angioembolization of the upper pole artery. patients age/gender side/symptom approach operation time (min) drain removal time complications management / trocar number / discharge time (h) (clavien grade) 1 42/m r/abdominal pain retroperitoneal / 4 150 26/30 ---- ----2 36/f r/abdominal pain-uti transperitoneal / 5 300 40/96 ---- ----3 53/m l/abdominal pain transperitoneal / 4 255 36/72 ---- ----4 50/f r/abdominal pain retroperitoneal / 3 270 16/20 ---- ----5 27/m r/abdominal pain transperitoneal / 4 150 72/96 chest pain (grade i) conservative 6 44/m l/abdominal pain transperitoneal / 3 150 24/26 --------7 42/f l/abdominal pain transperitoneal / 4 225 72/96 lower pole perforation intracorporeal (grade iii) suture 8 36/f r/abdominal pain-uti transperitoneal / 5 350 72/336 uti (grade ii) antibiotics 9 28/m l/abdominal pain transperitoneal / 4 180 44/48 urinary extravasation double j ureteral (grade iii) catheter insertion 10 54/m l/abdominal pain transperitoneal / 4 270 440/460 prolonged drainage angioemboliza (grade iii) tion table. characteristics of patients who have undergone laparoscopic upper pole heminephrectomy for treatment of duplex kidney. abbreviations: m, male; f, female; r, right; l, left; uti, urinary tract infection. laparoscopic upper pole heminephrectomy in adults-dönmez et al. laparoscopic urology 2076 vol 12. no 02 march-april 2015 1995 the retroperitoneal heminephrectomy has its own benefits, such as less dissection to reach the renal pedicle, reduced risk of intra-abdominal organ injury and shorter bowel movement recovery time; however, it has a limited working space compared to the transperitoneal approach. with regard to duplex kidneys, transperitoneal approach was thought to be better in anatomically complicated and/ or infected systems, which were preoperatively diagnosed using imaging modalities and in patients with massive hydronephrosis. surely, in patients without these factors, retroperitoneal approach is feasible without an increase in complications. reported postoperative complications in the literature are prolonged urinary drainage, urinoma, recurrent uti due to incomplete excision of the ureteric stump, loss of function of the lower pole and hypertension regardless from the approach. we encountered a 50% complication rate. although we did not perform complete ureteral excision, none had urinoma formation or extravasation. in the literature, it is not recommended to manipulate infected systems; however, our approach is to insert a percutaneous nephrostomy preoperatively to reduce the risk of postoperative sepsis in patients with pyonephrosis. as shown in table, the patients who had uti prior to surgery, had the longest operation time, which were also done by five trocars. it should be remembered that surgery of infected organs requires meticulous dissection because antibiotic treatment might not eliminate adhesions. an anomalous urinary tract suggests an anomalous vasculature; therefore, preoperative appropriate evaluation of the vascular supply of the kidney should be performed to reduce both intra and postoperative complications and it should be remembered that a transperitoneal approach will be easier to recognize the vasculature in these cases. even the arteries, which seem non-vital, must be carefully dissected and ligated to minimize the risk for bleeding. ureters with vesicoureteral reflux should be followed up to the bladder and ligated to prevent a source for recurrent uti; otherwise, ureteric dissection should be performed as far as possible without compromising the comfort of the surgeon. we use preoperative insertion of a ureteral catheter to identify the normal ureter however different alternatives have been suggested for preserving the ureter.(7) different techniques regarding hemi/partial nephrectomies have been suggested in the literature.(8) this study is a retrospective review of our results rather than a technical analysis. we aimed to publish our operative findings with regard to a rare operation in adult age group. the relatively high complication rate indicates the difficult nature of the procedure. furthermore, infected urinary system prior to surgery might be challenging in some cases. the negative aspect of our study is the lack of long term follow-up and post-operative imaging regarding the function of the residual kidneys. although the data on long-term follow-up in the literature is limited on adult laparoscopic heminephrectomies, it still provides classical advantages of laparoscopic surgery. nevertheless, the complexity of the technique of heminephrectomy requires a sufficient laparoscopy expertise. conclusion as previously proven for the pediatric population, laparoscopic upper-pole heminephrectomy for ectopic ureter in duplex kidneys is safe, reproducible and offers typical preoperative and postoperative benefits of laparoscopic surgery in adults with acceptable complications. these advantages are obvious even in patients with complicated uti. conflict of interest none declared. references 1. janetschek g, seibold j, radmayr c, bartsch g. laparoscopic heminephroureterectomy in pediatric patients. j urol. 1997;158:1928-30. 2. malek rs, kelalis pp, stickler gb, burke ec. observations on ureteral ectopy in children. j urol. 1972;107:308-13. 3. jordan gh, winslow bh. laparoendoscopic upper pole partial nephrectomy with ureterectomy. j urol. 1993;150:940-3. 4. prabhakaran k, lingaraj k. laparoscopic nephroureterectomy in children. j pediatr surg. 1999;34:556-8. 5. yao d and poppas dp. a clinical series of laparoscopic nephrectomy, nephroureterectomy and heminephroureterectomy in the pediatric population. j urol. 2000;163:1531-5. 6. wang ds, bird vg, cooper cs, austin jc, winfield hn. laparoscopic upper pole heminephrectomy for ectopic ureter: initial experience. can j urol. 2004;11:2141-5. 7. kumar s, singh sk, pandya s, acharya n, mandal a. laparoscopic pyeloureterostomy in ureteral duplication with lower polar ureteropelvic junction obstruction: easy and effective. j laparoendosc adv surg tech a. 2007;17:785-8. 8. nouralizadeh a, ziaee sa, basiri a, et al. transperitoneal laparoscopic partial nephrectomy using a new technique. urol j. 2009;6:176-81. laparoscopic upper pole heminephrectomy in adults-dönmez et al. vol 12. no 02 march-april 2015 2077 case report acute urinary retention due to a prostatic cystadenoma: a case report eduard pandi1, laurian stefan maxim³, adrian cristian¹, mircea daniel hogea¹, corina maria dochit², camelia cornelia scarneciu5* , ioan scarneciu 3**, aurel mironescu4 key words: acute urinary retention; prostatic disease; cyst;surgical treatment; benign lesion. introduction papillary cystadenoma of the prostate is a rare benign tumor that affects the prostate gland(1,2). it is usually a large size tumor and is located between the rectum and the urinary bladder. the benign nature of the tumor is suggested by the clear delimitation from vicinity organs. the patient usually presents with obstructive voiding symptoms, like: urinary intermittency, poor stream, a sensation of incomplete emptying and straining. defecation symptoms might be present due to the compression of the prostatic tumor on the lower gastrointestinal tract. imaging provides valuable information about localization and relation of the tumor with adjacent organs, it might also offer information about the nature of the tumor. therefore, imaging information proves to be very helpful in planning surgical management which usually is complete excision. we report the case of a prostatic cystadenoma in a male patient who presented himself to the emergency unit with symptoms of acute urinary retention. case report a 61-year-old male patient, from the urban area, was admitted to our clinic for sudden onset pain in the lower region of the abdomen with fever (38°c), and inability to urinate from 12 hours prior to admission. the patient complained of urgency, frequency, inability to completely empty his bladder with an evolution of around 5 months prior to admission. the patient had never received urological treatment. physical examination revealed a feverish patient (38°c) with palpatory tenderness in the lower abdomen, a mass which extended from the umbilicus to the pubis of approximately 10 cm in diameter, which was painful both spontaneously and at palpation and revealed characteristics of fluid content at percussion. an 18 fr urinary catheter was inserted and approximately 1 3rd general surgical unit, emergency clinical county hospital, brasov, 500365, romania. 2 department of pathology, emergency clinical county hospital, brasov, 500365, romania. 3 department of urology, emergency clinical county hospital, brasov, 500365, romania. 4 pediatric surgical unit, clinical children’s hospital, brasov, 500365, romania. 5 department of internal medicine transylvania university of brasov, faculty of medicine. **correspondence: department of urology , emergency clinical county hospital, brasov, 500365 romania. tel: +40 722 332622. e-mail: urologie_scarneciu@yahoo.com. *correspondence: department of internal medicine transylvania university of brasov, faculty of medicine romania. tel: +40 723 644424. fax: +40268414441. e-mail: scarneciu.camelia@gmail.com. received november 2015 & accepted february 2016 case report 2797 figure 1. pelvic cystic mass of uncertain origin with thin walls with fluid densities figure 2. histological examination vol 13 no 04 july-august 2016 2798 2 liters of puddled urine was evacuated. subsequently to the evacuation of urine, tumor mass and pain disappeared. rectal examination revealed an enlarged prostate of normal consistency and a tumoral formation of uncertain origin, with increased consistency and fluid content that could be palpated through the anterior rectal wall. rectal mucosa was normal in palpation and the tumoral mass was mobile, thus demonstrating its extrarectal origin. laboratory findings were normal except for leukocytosis (17000/mm3). psa level was normal. transabdominal ultrasound was performed revealing an anechoing cystic mass in the retrovesical space with multiple thin, echogenic internal septations. a contrast-enhanced ct followed the ultrasound exam showing a pelvic cystic mass of uncertain origin with thin walls and with fluid densities, without iodine caption and with fine septum of 14.6/13.2 cm in diameter. the mass had displaced the bladder anteriorly and was compressing it. a separation plan was visualized between the cystic mass and the bladder. the rectum was not invaded by the tumoral mass. ( figure 1 a-d). even if it would have supported a better description of topography of the lesion, no rmn was performed. the patient received antibiotics (cyprofloxacinum 400mg/12 hours ), painkillers ( metamizolum 1g/6 hours ), antipyretics ( paracetamolum 1g/8 hours ) and electrolyte rebalancing treatment. not being sure about the origin of the lesion and not having experience with the conservative treatment of these lesions, we decided to proceed with surgery the day after hospitalization. we performed a midline umbilical-pubic incision. we incised the retrovesical peritoneum and penetrated into the retroperitoneal space, where we identified a 16 cm cystic wide grayish tumor mass, apparently of prostatic origin. the tumor mass compressed the bladder and the inferior rectum. the left ductus deferens was anteriorly dislocated. the tumor mass detached itself from the posterior wall of the bladder. in the lower part it was adherent to the prostate, which showed callous area on the contact surface with the cystic mass. dissection continued laterally, highlighting the ureters. posterior dissection cleared the tumor mass from the superior rectum. in order to obtain a better access to the prostate, the tumor mass was punctured, followed by partial evacuation of clear, sero-citrine liquid, without fetid odor (no sampling for histopathological examination was performed). the remaining tumor mass was difficultly detached from the prostate during which accidental injury to the anal canal happened. the cyst was completely excised, without macroscopic highlighting of any tumor remnants. the anal canal injury required rectoraphy with protective colostomy (“loop colostomy”). postoperatively, the patient’s recovery was slow but favorable, with discharge on the 20th day after admission. two months later, the patient underwent surgery for restoration of the large bowel continuity. macroscopically the tumour could be described as a 12 cm unilocular lesion. the walls were consistent with an area of thickening of 2.5 / 2 cm .the pathological examination revealed, amid benign prostatic hyperplasia (figure 2a), a cystic lesion with fibrous structure (figure 2b), lined by acinar type epithelium that included adenomatous proliferation (figure 2 c – detail ) with papillary extensions projected intraluminally (figure 2d). immunohistochemical staining was performed for vim, cd34, p53, 34betae12, cd30, ck7, but was positive only for psa (figure 3) discussion prostatic cystadenoma is a rare condition with less than 20 cases reported in the literature(3). it is a benign tumour that can reach large sizes without embedding the pelvic organs. it is usually located between the urinary bladder and rectum and it may originate from the prostatic tissue, the seminal vesicles, or the ejaculatory ducts. histologically, this lesion is made out of cysts lined by cuboidal or columnar epithelium and prostatic glands are arranged in a fibrous stroma. immunohistochemically, the membrane of the epithelial cells presents prostatic-specific antigen thus proving the prostatic origin of the lesion. because of the large size of the lesion the patient presents with symptoms of obstruction of the urinary flow and sometimes a palpable mass in the lower abdomen. in some cases, the first symptom of this condition is primary infertility with azoospermia.(4) to the practitioner, the prostatic cystadenomas presents a number of diagnostic and therapeutic challenges. the differential diagnosis is made with other prostatic lesions such as mȕllerian duct cysts and prostatic utricle cysts, ejaculatory duct cysts, retention cysts, benign prostatic hyperplasia with cystic degeneration, cavitary prostatitis, prostatic abscess, other rare cystic lesions (echinoccocus cyst, bilharzial cyst, cystic carcinoma) (5). because of their midline development, the mȕllerian cyst and the prostatic utricle cyst are discovered incidentally through ultrasonography. they are usually located at the base of the prostate, in the back of the urinary bladder neck and they do not contain seminal fluid. the retention cysts and cystic degeneration develop laterally, they do not contain sperm cells and are generally asymptomatic in benign prostatic hyperplasia and are usually endorectal ultrasound findings. the vas deferens cyst is located on the median line, it contains seminal fluid and it is associated to an increased rate of infertility in men. prostatic cysts and cavitary prostatitis occur in a patient with signs and symptoms of infection. cavitary prostatitis and prostatic abscess manifest themselves clinically by pain with dysuria, by interrupting the urine stream, and even by acute figure 3. immunohistochemical staining retention due to prostatic cystpandi et al. retention. the patient is feverish, his general state of health is altered and signs of sepsis with low blood pressure may occur. the diagnosis of echinococcosis or schistosomiasis may be easily established, based on clinical suspicions, by observing eggs of schistosoma in patient’s urine or specific igg antibody for echinococcosis in patient`s serum. likewise, high levels of eosinophils are specific for both pathologies. papillary cystadenoma of the prostate should be included in the differential diagnosis of retroperitoneal masses and prostatic cysts (teratoma, lymphangioma, cystic sarcoma, and multilocular peritoneal inclusion cysts). because of its obstructive voiding symptoms the cystadenoma of the prostate usually imitates benign prostatic hyperplasia. despite the extensive radiological assessment (ct, mri, endorectal sonography), the diagnosis is histologically confirmed after a complete excision or biopsy. the natural evolution of cystadenoma of prostate is unknown. faced with a pelvic mass, a surgical treatment is recommended although there are some authors who recommend that complete surgical excision might not be necessary.(6) despite its benign nature maluf et al. reported a case of cystic lesion recurrence in a 41-yearold male patient 12 months after incomplete surgical excision. recurrence is treated by mass excision(7) or by pelvic exenteration(8). in case of recurrence, datta et al. proposed treatment by gonadotropin-releasing hormone antagonists(9). there are numerous authors who have used laparoscopic surgical treatment for treating mȕllerian cysts while we identified a single author who used this technique for treating a papillary cystadenoma with solid consistency and reduced size (7.5x5.4x2.2 cm).(10) even if we are not experienced with the laparoscopic treatment of this type of lesion, we appreciate that this type of treatment is superior to the classic approach, by allowing a more elaborate dissection and thus by avoiding complications (lesion of the anal tract in our case). conclusions prostatic papillary cystadenoma, a benign lesion, should be included in the differential diagnosis of the retroperitoneal and retrovesical cystic lesions in all male patients with signs of acute urinary retention. acknowledgments we hereby acknowledge the structural funds project pro-dd (pos-cce, 0.2.2.1., id 123, smis 2637, no 11/2009) for providing infrastructure used in this work. references 1. eble j n, sauter g, epstein ji , sesterhenn ai .world health organization classification of tumours. pathology and genetics of tumours of the urinary system and male genital organs. 2004; chapter 3:213 2. maluf hm, king me, deluca fr, navarro j, talerman a, young rh. giant multilocular prostatic cystadenoma: a distinctive lesion of the retroperitoneum in men—a report of two cases. am j surg pathol 1991; 15:131-135 3. r sarvanandan, r thangaratnam. giant multilocular prostatic cystadenoma in a 15year old: radical surgery not necessary.the internet journal of surgery. 2009;volume 22, number 1 4. asharaf a. mosharafa, mohammed h. torky, yasser ragab, nader dahba.prostate cystadenoma presenting with obstructive azoospermia. journal of andrology. 2011; 32(4):364-366 5. nghiem ht, kellman gm, sandberg sa, craig bm. cystic lesions of the prostate. radiographics 1990; 10:635-650 6. matsumoto k, eqawa s, iwabuchi k, baba s. prostatic cystadenoma presenting as a large multilocular mass. int j urol 2002;9:410–2 7. rusch d, moinzadeh a, hamawy k, larsen c. giant multilocular cystadenoma of the prostate. ajr am j roentgenol. 2002;179:1477–1479 8. levy da, gogate pa, hampel n. giant multilocular prostatic cystadenoma: a rare clinical entity and review of the literature. j urol. 1993;150:1920–1922 9. datta mw, hosenpud j, osipov v, young rh. giant multilocular cystadenoma of the prostate responsive to gnrh antagonists. urology. 2003;61:225 10. hwang ec, park jb, jung si, im cm, kim so, kang tw, kwon dd, park k, ryu sb, choi c. retrovesical multilocular prostatic cystadenoma mimicking a pelvic cavity tumor.korean j urol. 2009;50(12):12621264 retention due to prostatic cystpandi et al. case report 2799 endourology and stone diseases effect of malva neglecta wallr on ethylene glycol induced kidney stones jamileh saremi,1 hossein kargar-jahromi,2 mohammad pourahmadi3* purpose: the aim of this study was to investigate the anti-urolithiasis effects of aqueous extracts of malva neglecta wallr on ethylene glycol and ammonium chloride induced kidney stones in a rat model. materials and methods: a total number of 64 male wistar rats were randomly divided into eight groups equally: group i (normal control), group ii (disease control), groups iii and iv (sham), groups v and vi (preventive groups), and groups vii and viii (curative groups). group i received tap drinking water, groups iii and iv were given intra-peritoneal injections of 200 and 800 mg/kg aqueous extracts for 28 days. groups ii, v, vi, vii, and viii received 1% ethylene glycol plus 0.25% ammonium chloride in drinking water for 28 days. groups v and vi were given intraperitoneal injections of 200 and 800 mg/kg aqueous extracts for 28 days and groups vii and viii received intra-peritoneal injections of 200 and 800 mg/kg aqueous extracts from the 14th day of the experiment. after 28 days the kidneys were removed and observed for calcium oxalate (caox) deposits and tubulointerstitial changes. results: the extract significantly decreased caox deposits and tubulointerstitial damage in the preventive groups (p < .001). in curative groups, a low dosage of extract, reduced kidney oxalate deposits and tubulointerstitial damage (p < .05). in addition a significant decrease was observed in crystal deposition and tubulointerstitial damage in high dosed group (p < .001). however, high dosed preventive and curative groups seemed to be more effective (p ≤ .001). conclusion: malva neglecta wallr has beneficial effects on preventing and treating caox deposition and decreasing tubulointerstitial damage on a dosage dependent manner. these effects may be due to the components presented in this plant such as saponins, flavonoids, mucilage, and phenolic compounds. keywords: animals; calcium oxalate; ethylene glycol; kidney/drug effects; kidney tubules/pathology; rats; treatment outcome; urolithiasis/chemically induced; drug therapy. introduction urolithiasis is still a worldwide problem. despite numerous methods for its treatment, there is still no satisfactory drug to prevent and treat kidney stones. malva neglecta wallr commonly known as “panirak” is extensively used in folk medicine for urolithiasis. kidney stones are the third prevalent disorder in the urinary system.(1) in 2005, prevalence of urolithiasis in iran was 5.7%, affecting 6.1% of men and 5.3% of women.(2) the average recurrence rate was 16% after one year, 32% after five years and 53% after 10 years.(2) about 8085% of stones are mainly composed of calcium oxalate (caox). kidney stones cause renal colic, urinary tract obstruction, hydronephrosis, infection, hematuria and loss of renal function.(1) surgical operation, extracorporeal shock wave lithotripsy, transureteral lithotripsy and laparoscopy are widely used to remove the stones. (1) even though these techniques have been improved in recent years, using these invasive procedures may also lead to severe complications not considering their high costs. in this regard, it seems reasonable to replace these treatments with a low side-effect herbal medication since many plants have been traditionally used in management of urolithiasis. malva neglecta wallr is a plant that is used as food and medication.(3) in traditional medicine, it is used for treating kidney stones and urinary disorders.(4) it has been reported to have anti-ulcerogenic,(5) antioxidant,(6) and antibacterial(7) properties. however, no scientific data is available to validate the beneficial effect of this plant on kidney stones. this study aimed to evaluate the effect of aqueous extracts of malva neglecta wallr on ethylene glycol and ammonium chloride induced kidney stones in rats. materials and methods study animals this was an animal experimental study. sixty four adult male wistar rats (200 ± 10 g) were housed at 25 ± 2°c temperature on a standard diet and tap drinking water.(8) they maintained on 12 hours light/12 hours dark cycle. the experiments were in accordance with the guidelines 1 department of anatomy and histology, faculty of medicine, jahrom university of medical sciences, jahrom, iran. 2 zoonosis research center, jahrom university of medical sciences, jahrom, iran. 3 research center for noncommunicable diseases, faculty of medicine, jahrom university of medical sciences, jahrom, iran. *correspondence: research center for noncommunicable diseases, faculty of medicine, jahrom university of medical sciences, motahari blvd, jahrom, iran. tel: +98 71 54336085. fax: +98 71 54340405. e-mail: zahed1340@yahoo.com. received january 2015 & accepted november 2015 endourology and stone diseases 2387 for the care and use of laboratory animals and were approved by the ethics committee of jahrom university of medical sciences (jums. rec. 1392. 042). the malva neglecta wallr was collected in spring from the zarghan garden (shiraz, iran) and was identified by amir borjian (phd of plant systematic, jahrom islamic azad university, jahrom, iran). the leaves were thoroughly washed under tap water, dried under shade, and then powdered by mechanical grinder. the powders were soaked in distilled water. after 72 hours, the extract was filtered and then condensed by a rotary evaporator under vacuum at 50°c temperature. urolithiasis was induced by 1% ethylene glycol and 0.25% ammonium chloride in the experimental animals. all animals were fed with a standard rat chow diet and they were randomly divided into eight groups equally: group i (normal control): received tap drinking water for 28 days. group ii: (disease control): received drinking water containing 1% ethylene glycol and 0.25% ammonium chloride for 28 days to induce urolithiasis. sham groups (iii and iv): received intra-peritoneal injections of 200 mg/kg (group iii) and 800 mg/kg (group iv) aqueous extract for 28 days. preventive groups (v and vi): received drinking water containing 1% ethylene glycol and 0.25% ammonium chloride plus intra-peritoneal injections of 200 mg/kg (group v) and 800 mg/kg (group iv) aqueous extract for 28 days. curative group (vii and viii): received drinking water containing 1% ethylene glycol and 0.25% ammonium chloride for 28 days plus intra-peritoneal injections of 200 mg/kg (group vii) and 800 mg/kg (group viii) aqueous extract from the 14th day until the end of the experiment. histopathological analysis of the kidney at the end of the experiment (the 29th day), the rats were killed by carbon dioxide inhalation. thereafter the right and left kidneys were isolated, cleaned, and weighed. kidneys were fixed in 10% formalin, dehydrated in a gradient of ethanol, embedded in paraffin, cut into 5 µm tick sections and stained with hematoxylin and eosin (h & e) and periodic acid-schiff (pas). the slides were examined under a light microscope (10 × magnification). ten slides containing five sections from each kidney were prepared. caox crystal deposits were counted in 10 microscopes filed.(9) tubulointerstitial changes such as tubular cell necrosis, dilation, interstitial inflammation, hyaline cast and tubular atrophy were graded according to semiquantative system on scale of 0-4: 0 = none, 1 = trace (< 10%), 2 = mild (10-25%), 3 = moderate (26-50%) and 4 = marked (˃ 50%).(10) statistical analysis the results were expressed as mean ± standard error (se). caox deposits and tubulointerstitial changes were normally distributed as tested by kolmogorov-smirnov test. the differences between groups were compared using one way analysis of variance (anova) and analyzed by statistical package for the social science (spss inc, chicago, illinois, usa) version 17. post hoc least significant difference test was used for inter-group comparisons. p value less than .05 was considered significant. results pathologic examination was done to detect caox deposits and tubulointerstitial damage in the kidney. the sediments were visible as transparent crystals in the renal tubules with an optical microscope. in group i, the examination of the kidney sections revealed no caox deposits or other abnormalities in different segments of the nephrons. in group ii, a high number of caox deposits were found inside the proximal tubules, loops of henle, distal tubules and collecting ducts. considerable tubulointerstitial changes such as tubular atrophy, dilation, hyaline cast, tubular cell necrosis and interstitial inflammation were observed in renal tissue. in sham groups (iii and iv), no caox deposits were seen and tissue damage was nearly same as group i (figure, table). a significant decrease was detected in the preventive group v, in crystal deposition in comparison to groups ii (p < .001) and vii (p = .005). in addition, tubulointerstitial damage in group v showed a significant decrease compared to groups ii (p < .001), vii (p = .003) and viii (p = .009). in group vi, a few crystals of caox were observed when compared with groups malva neglecta wallr and kidney stones-saremi et al. vol 12 no 06 november-december 2015 2388 table. effect of malva neglecta wallr on calcium oxalate deposits and tubulointerstitial changes in urolithiasis induced rat. variables group i group ii group iii group iv group v group vi group vii group viii (normal (disease (sham 200 (sham 800 (preventive (preventive (curative (curative 8 control) control) mg/kg) mg/kg) 200 mg/kg) 800 mg/kg) 200 mg/kg) 00 mg/kg) calcium oxalate 0 19.9 ± 1.9 0 b*** 0 b*** 9.7 ± 1.25 4.15 ± 1.18 14.27 ± 1.82 6.75 ± 1.18 a*** a*** b*** a* a*** a*** b*** b*** b* tubulointerstitial 0.01 ± 0.01 1.91 ± 0.12 0.01 ± 0.01 0 0.99 ± 0.1 0.4 ± 0.1 1.35 ± 0.130. 67 ± 0.1 damage a*** b*** b*** a*** b*** a** b*** a*** a*** b*** b* values are expressed as mean ± standard error (n = 8). *** p < .001, ** p < .01, * p < .05. a: comparisons made with normal control group (group i). b: comparisons made with disease control group (group ii). ii (p < .001), v (p = .001) and vii (p < .001). tubulointerstitial damage significantly decreased in group vi compared to groups ii (p < .001), v (p < .001), vii (p < .001), and viii (p = .033). in the kidney specimen of curative groups, group vii showed a significant decrease in crystal deposition (p = .033) and tubulointerstitial damage (p = .023) compared to group ii. the number of caox crystals in group viii was significantly different from that of groups ii and vii (p < .001). in addition, a significant decrease was found in tubulointerstitial tissue in group viii compared with groups ii and vii (p < .001). discussion studies indicate that administration of ethylene glycol and ammonium chloride can induce renal caox deposition in rats(9,11) as a model to mimic the kidney stone formation in humans. based on traditional use of malva neglecta wallr in kidney stones, this model was used to evaluate the effects of aqueous extracts of malva neglecta wallr on ethylene glycol and ammonium chloride induced kidney stones in male rats. microscopic examination of kidney sections showed extensive renal damage and caox deposits in calculi induced rats. in our study malva neglecta wallr had a preventive and treatment effect on caox calculus formation and tubulointerstitial damage with a dosage dependent manner. in prophylactic and curative treatment groups, low and high dosages of extract reduced the number of caox calculi and tubulointerstitial damage, although a high dosages of extract seemed to be more effective. the exact mechanisms involved in the effect of malva neglecta wallr on caox calculi remain unclear. studies reveal that malva neglecta wallr contains k, na, p, ca, mg, fe, mn(12) alkaloids, flavonoids, saponins,(13) phenolic compounds(6) and mucilage content.(14) phenolic compounds and flavonoids have antioxidant activities.(6) caox crystals and high levels of oxalate in the nephrons can damage the epithelial cells so that, the cells may produce some product as well as free radicals, which induce heterogeneous crystal nucleation and result in aggregation of crystals.(15) therefore, it is speculated that malva neglecta wallr prevents the formation of caox calculi and tubulointerstitial damage due to its antioxidant(6) and anti-inflammatory(5) effects. saponins have antiviral, antifungal, antioxidant and cholesterol lowering effects.(16) earlier studies have reported that plants rich in saponin have protective effects on the renal oxidative stress and renal interstitial fibrosis in rats induced by unilateral ureteral obstruction.(17) they plays an important role in preventing ethylene glycol induced urolithiasis.(18) thus, anti-urolithiatic effects of malva neglecta wallr may be because of saponin content presented in this plant. nano bacteria mediate apatite nucleation and crystal growth. they may trigger renal pathology involving damage to tubular epithelium, biomineralization, and perhaps tubule obstruction and chronic infection resulting in defective tissue repair and stone formation. (19) antibacterial activity of malva neglecta wallr has been reported previously.(7) therefore, this plant may be effective for both prevention and cure of caox urolithiasis. the mucous lining of the urinary tract serves as a defense against caox crystal adherence.(20) malva neglecta wallr contains mucilage content that can play a role to prevent crystals adherence. conclusions aqueous extracts of malva neglecta wallr is effective on ethylene glycol and ammonium chloride induced kidney stones in male rats. the extract has beneficial effects on preventing and treating caox calculi and reducing tubulointerstitial damage in the rat kidney depending on the dosage. the anti-urolithiatic activity of this plant might be the result of its components such as saponins, flavonoids, mucilage, and phenolic compounds. further studies are necessary to elucidate the chemical constituents of malva neglecta wallr responsible for anti-urolithiatic activity. acknowledgments the authors are grateful to jahrom university of medical sciences for their financial support (grant no. 2262/d/p). they would like to thank seyed muhammed hussein mousavinasab and mohammad hadi sameni for their sincere cooperation in editing this text. conflict of interest none declared. references 1. stoller m, bolton d. urinary stone diseases. in: tanagho ea, mcaninch jw, editors. smith's general urology: mcgraw-hill medical new figure. photomicrographs of the rat kidney stained with hematoxylin and eosin and periodic acid-schiff: a (×10), c (× 10), d (× 40), e (× 10), j (× 40), l (× 40), u (× 40), and x (× 40). histological changes visualized by hematoxylin and eosin (h & e): b (× 40), f (× 10), g (× 10), h (× 40), i (× 10), k (× 10), m (× 10), n (× 10), o (× 40), p (× 10), q (× 40), r (× 40), s (× 10), t (× 40), v (× 10), and w (× 40). histological changes visualized by periodic acid-schiff (pas): group i (a and b), group ii (c-h), group iii (i and j), group iv (k and l), group v (m-o), group vi (p-r), group vii (s-u), and group viii (v-x). multiple tubular stones (white arrows), tubulointerstitial damage (tubular atrophy, dilation, hyaline cast, tubular cell necrosis and interstitial inflammation) (black arrows). malva neglecta wallr and kidney stones-saremi et al. endourology and stone diseases 2389 york; 2008. 2. safarinejad mr. adult urolithiasis in a population-based study in iran: prevalence, incidence, and associated risk factors. urol res. 2007;35:73-82. 3. akcin oe, ozbucak tb. morphological, anatomical and ecological studies on medicinal and edible plant malva neglecta wallr. (malvaceae). pak j biol sci. 2006;9:2716-9. 4. kianmehr h. tashkhise giyahaneh darooii [recognition of medical herbs]. tehran: aiij publications; 2008. [in persian] 5. gürbüz i, özkan am, yesilada e, kutsal o. anti-ulcerogenic activity of some plants used in folk medicine of pinarbasi (kayseri, turkey). j ethnopharmacol. 2005;101:313-8. 6. dalar a, türker m, konczak i. antioxidant capacity and phenolic constituents of malva neglecta wallr. and plantago lanceolata l. from eastern anatolia region of turkey. j herb med. 2012;2:42-51. 7. seyyednejad sm, koochak h, darabpour e, motamedi h. a survey on hibiscus rosasinensis, alcea rosea l. and malva neglecta wallr as antibacterial agents. asian pac j trop biomed. 2010;3:351-5. 8. hadjzadeh m-a-r, khoei a, hadjzadeh z, parizady m. ethanolic extract of nigella sativa l seeds on ethylene glycol-induced kidney calculi in rats. urol j. 2009;4:86-90. 9. khalili m, jalali mr, mirzaei-azandaryani m. effect of hydroalcoholic extract of hypericum perforatum l. leaves on ethylene glycol-induced kidney calculi in rats. urol j. 2012;9:472-9. 10. cho hj, bae wj, kim sj, et al. the inhibitory effect of an ethanol extract of the spores of lygodium japonicum on ethylene glycolinduced kidney calculi in rats. urolithiasis. 2014;42:309-15. 11. divakar k, pawar a, chandrasekhar s, dighe s, divakar g. protective effect of the hydroalcoholic extract of rubia cordifolia roots against ethylene glycol induced urolithiasis in rats. food chem toxicol. 2010;48:1013-8. 12. iqbal b, hussain t, shah h, manan s. chemical composition of malva neglecta grown in kalam district swat [pakistan]. sarhad j agric. 1994;10:125-9. 13. mojab f, kamalinejad m, ghaderi n, vahidipour hr. phytochemical screening of some species of iranian plants. iran j pharm res. 2003;2:77-82. 14. pakravan m, abedinzadeh h, safaeepur j. comparative studies of mucilage cells in different organs in some species of malva, althaea and alcea. pak j biol sci. 2007;10:2603-5. 15. khan s, thamilselvan s. nephrolithiasis: a consequence of renal epithelial cell exposure to oxalate and calcium oxalate crystals. mol urol. 1999;4:305-12. 16. francis g, kerem z, makkar hp, becker k. the biological action of saponins in animal systems: a review. br j nutr. 2002;88:587605. 17. xie x-s, liu h-c, yang m, zuo c, deng y, fan j-m. ginsenoside rb1, a panoxadiol saponin against oxidative damage and renal interstitial fibrosis in rats with unilateral ureteral obstruction. chin j integr med. 2009;15:133-40. 18. patel pk, patel ma, vyas ba, shah dr, gandhi tr. antiurolithiatic activity of saponin rich fraction from the fruits of solanum xanthocarpum schrad & wendl (solanaceae) against ethylene glycol induced urolithiasis in rats. j ethnopharmacol. 2012;144:160-70. 19. kajander eo, ciftcioglu n, aho k, garciacuerpo e. characteristics of nanobacteria and their possible role in stone formation. urol res. 2003;31:47-54. 20. smith cl. calcium oxalate crystal adherence in the rat bladder: restoration of anti-adherence after acid treatment. j urol. 2004;171:882-4. vol 12 no 06 november-december 2015 2390 malva neglecta wallr and kidney stones-saremi et al. urological oncology prostate cancer antigen 3 gene expression in peripheral blood and urine sediments from prostate cancer and benign prostatic hyperplasia patients versus healthy individuals hemen moradi sardareh,1,2 mohammad taghi goodarzi,1,2 reza yadegar-azari,2,3 jalal poorolajal,4 seyed habibollah mousavi-bahar,5 massoud saidijam2,3* purpose: to determine the expression of prostate cancer antigen 3 (pca3) gene in peripheral blood and urine sediments from patients with prostate cancer (pca) and benign prostatic hyperplasia (bph) and normal subjects. materials and methods: a total number of 48 patients [24 with biopsy proven prostate cancer (pca) and 24 with benign prostate hyperplasia (bph)] were studied. twenty-four healthy individuals were also recruited as control group. after blood and urine sampling, total rna was extracted and cdna was synthesized. expression of pca3 gene was assessed by quantitative reverse transcription polymerase chain reaction. results: comparison of pca3 gene expression between control and bph groups indicated no statistically significant differences in both urine and blood samples. patients with pca demonstrated an increased pca3 gene expression rate compared to control and bph groups (10.64 and 7.17 folds, respectively). the rate of fold increased pca3 gene expression in urine was 20.90, 20.90, and 20.35 in patients with pca, bph and normal subjects, respectively. conclusion: evaluation of pca3 gene expression can be considered as a reliable marker for detection of pca. increased level of this marker in urine sediments is more sensitive than blood for distinguishing between cancerous and non-cancerous groups. keywords: prostatic neoplasms; diagnosis; tumor markers; biological; blood; urine; gene expression regulation; oncogene proteins. introduction prostate cancer (pca) is a common neoplasm in de-veloped countries and its incidence has increased in the past few years in iran, too.(1,2) the available information in recent years shows that among various neoplasms, pca has the highest estimated new cases in men. after lung and bronchus cancers, the most estimated deaths rate belong to pca in the same years.(3,4) for the first time in 1986, us food and drug administration (fda) approved the prostate specific antigen (psa) test for monitoring pca patients.(5) subsequently in 1994, it was accepted as a screening tool for detection of pca. (6) today, the benefits of psa screening are accepted but its usage has some limitations such as low specificity.(7) in this respect, ghafoori and colleagues concluded that results obtained from serum psa test solely is not valid for detection of pca since it lacks enough sensitivity and specificity.(8) also, yoon and colleagues studied the serum psa levels in men for detecting pca. however, no significant difference was observed in cancer detection rates according to serum psa levels between their studied groups.(9) despite of 3 ng/ml value(7) as threshold of serum psa level to differentiate healthy men from pca patients, the rate of negative biopsy is 70-80%.(7) in a 7-year study on healthy men less than 55 years old based on serum psa level less than 3 ng/ml and normal digital rectal examination (dre), thompson and colleagues concluded that there was no threshold of serum psa levels to differentiate between healthy individuals and pca patients. also, they demonstrated that there was a risk of pca in all levels of serum psa.(10) moreover, mehrabi and colleagues evaluated the serum psa levels in an iranian population and compared it with studies in united states and japan. they observed that the serum reference psa level in iranian men is significantly lower.(11) therefore, more specific tests are needed to detect pca, particularly in men with a previous negative biopsies.(12) prostate cancer antigen 3 (pca3) gene is located on 9q21.2 chromosome and expresses exclusively in prostate tissue.(13) recent studies have shown that pca3 gene expresses in prostate epi1department of biochemistry and nutrition, school of medicine, hamadan university of medical sciences, hamadan, iran. 2 research center for molecular medicine, hamadan university of medical sciences, hamadan, iran. 3 department of genetics and molecular medicine, hamadan university of medical sciences, hamadan, iran 4 research center for modeling of non-communicable diseases, department of epidemiology and biostatistics, school of public health, hamadan university of medical sciences, hamadan, iran. 5 urology and nephrology research center, hamadan university of medical sciences, hamadan, iran. *correspondence: research center for molecular medicine, hamedan university of medical sciences, hamadan, iran. tel: + 98 81 38380462. fax: + 98 81 38380464. e-mail: sjam110@yahoo.com. received october 2013 & accepted april 2014 urological oncology 1952 thelial cells. however, no cytoplasmic protein is created from its translation. pca3 expresses significantly in more than 95% of primary and metastatic pca samples,(14) but no significant correlation has been observed between the expression of pca3 and tumor stage or gleason score.(15) pca3 expression was surveyed primarily in prostate tissue samples,(15) then the expression of this marker was also checked in urine(13,16) and blood.(15) several studies have shown different sensitivity and specificity for pca3 tests. the aim of this study was to assess the expression of pca3 in urine and blood simultaneously and to compare the results in the same conditions. to achieve this goal the laboratory methods were modified to get more accurate results. materials and methods this was a frequency matched case-control study. among the patients who were referred to our urology center in hamadan city, iran, during january 2011 to december 2012, 48 cases were selected and categorized into two groups: pca (group 1, n = 24 and benign prostatic hyperplasia (bph), group 2, n = 24). all participants had pathologic diagnosis. twenty-four healthy men (group 3) were also included as control group. the participants of the three groups had no significant differences based on age. blood and urine samples were collected from pca and bph patients one month after the pathologic examination confirmation. all participants in pca group were diagnosed less than one year before the beginning of the study. the excluding criteria were doing hormone therapy, chemotherapy and radiation therapy. patients whose pca was definitively ruled out according to tissue pathology were included in the bph group. for this group the excluding criteria were having a history of cancer, taking finasteride or the other anticancer drugs more than one month or having prostate tissue pathology results suspected being prostatic intraepithelial neoplasia. all participants were aware of their participation and had willingly signed a consent form. the study protocol was approved by the medical ethics committee of hamedan university of medical sciences. blood sampling immediately after blood sampling, 2.5 ml blood was added to ethylenediaminetetraacetic acid (edta) containing tubes and kept at 4°c in the box of ice. then, rna extraction and cdna synthesis were performed in less than 2 hours later. for rna extraction from whole blood, lysis solution was prepared containing 10 mm tris-hcl, 320 mm sucrose, 5 mm mgcl 2 and triton x100 1% solution. the ph was adjusted to 8. based on the protocol,(17) lysis solution was added to the blood about 4 times of the volume of the sample. after centrifugation for 20 min at 4000 rpm, supernatant was discarded. then the sediment was mixed with phosphate buffered saline and was stirred in order to unfold the clot completely. subsequently, the samples were centrifuged for 10 min at 3000 rpm and supernatant was discarded again. the prepared sediment contained white blood cells along with the cancer cells. to ensure complete removal of hemoglobin, an inhibitor of the polymerase chain reaction (pcr), lysis buffered solution and phosphate buffered saline washing solution were added and the process was repeated. finally, the sediment (which should have been transparent as much as possible) entered the main phase of rna extraction which was carried out according to the manufacturer protocol. urine sampling urine cells integrity is affected by ph, temperature and concentration of urine and the time interval between sampling and testing. on the other hand, urine cells contain a great amount of ribonuclease that can degrade the urine rna rapidly if these cells are destroyed. to harvest high-quality rna and prevent its degradation in urine, the key-points are protecting urine cells from destruction in pre-extraction rna, decreasing the temperature and reducing the time between sampling and extraction. the scientific and practical findings led us to prepare a mixed solution, including chaotropic agents, detergent, phosphate buffered saline and 2-mercaptoethanol. then the ph of solution was checked and adjusted on 7. the mixed solution was kept at 4°c for protection from deterioration. immediately after the dre, 20-25 ml of the primary urine samples was collected in sterile containers.(16) then the collected urine was added to the equal volume of prepared cold mixed solution. rna extraction and cdna synthesis were accomplished within 2 hours. rna extraction and cdna synthesis total rna was isolated from peripheral blood and urine in accordance to standard procedures and manufacturer manuals using rneasy mini kit (qiagen, hilden, germany). the purity and quantity of all extracted rna were evaluated by nanodrop spectrophotometer (epoch, biotek, winooski, vermont 05404-0998, usa), and the ratio of a260/a280 was measured. then rna integrity was checked by agarose gel electrophoresis (1%), 1× tris-borate-edta (tbe). subsequently, 1µg of extracted rna was subjected to cdna synthesis kit (qiagen, hilden, germany). cdna was stored at -80°c after production. to confirm the success of reverse transcription and absence of contamination before performing quantitative pcr, 18s rrna gene expression was checked as an internal control. real-time reverse transcription polymerase chain reaction (rt-pcr) test was performed using cfx96 real time thermocycler system (biorad, hercules, ca, usa) and quantifast sybr green pcr kit (qiagen, hilden, germany). the reaction was incubated at 95°c for 5 min, followed by 40 cycles of 15s at 94°c, 30s at annealing temperature, 30s at 72°c and then fluorescence was measured. primers, designed by software alleleid 7.6, were: pca3-f (5’-caatataatgtctaagtagt-3’), pca3-r (5’-ttaaggaacacatcaat-3’), 18s rrna-f (5’-gtaacccgttgaaccccatt-3’), 18s rrna-r (5’-ccatccaatcggtagtagcg-3’). relative expression of the studied genes was calculated by measuring the delta threshold cycle value (δct) for each sample. delta threshold cycle value for each sample was determined as the average of a triplicate assay. statistical analysis was done by stata 11 software with 95% confidence intervals (ci). receiver operating characteristic (roc) curve was drawn using the sensitivity and specificity to compare pca3 expression in blood and urine. in this analysis, the specificity (true negative) and pca3 gene expression in patients with pca and bph-moradi sardareh et al vol 11. no 06 nov-dec 2014 1953 sensitivity (true positive) was plotted on the x and y axes, respectively. roc curve was used to determine a cutoff point to differentiate between cancerous patients from non-cancerous one (control subjects and bph group). results the mean of participants’ age was 66.17 ± 12.72 years (range, 47-87 years) in control group, 66.62 ± 6.39 years (range, 58-79 years) in bph group and 64 ± 5.11 years (range, 56-75 years old) in pca group. there were no significant differences between the mean age of the three groups (p = .542). also, the three groups showed no significant differences in terms of body mass index (bmi) (p = .396). evaluation of 18s rrna gene expression as an internal control average threshold cycle values (ct) of 18s rrna in the blood was 25.63 ± 0.93 in the control group, 25.37 ± 1.35 in bph group and 25.55 ± 0.91 in the pca group that showed no statistically significant differences (p = .713). also, average threshold cycle values in the urine were 25.92 ± 0.53, 25.71 ± 1.46 and 25.91 ± 1.02 in the control, bph and pca groups, respectively (p = .798). the participants were divided into two groups based on the mean age (< 66 and ≥ 66 years old) and mean bmi (< 23 and ≥ 23 kg/m2). expression of the internal control in blood and urine of these groups showed no statistically significant differences (table 1). for more documentation, all participants were divided into 5 subgroups based on their age (41-50, 51-60, 61-70, 71-80 and more than 81 years old). analysis of variance among these five groups in both blood and urine samples showed no statistically significant differences in gene expression rate. pca3 gene expression in the urine and blood the δct value of pca3 marker was determined in urine and blood samples using the formula [ct value of marker ct value of internal control]. the mean δct in blood was 7.18 ± 1.02, 6.61 ± 2.09 and 3.77 ± 1.0 in control, bph and pca groups, respectively. there was no statistically significant difference between control and bph groups (p = .273). however, in cancer group the difference was statistically significant compared to the control (p = .001) and bph (p = .001) groups. the mean δct in control, bph and pca groups were 7.40 ± 0.76, 7.41 ± 2.51 and 3.20 ± 1.10, respectively. again there was no statistically significant differences between control and bph groups, but differences between control and bph groups compared with pca group was significant (p = .001). then, pca3 expression was compared among the five age subgroups (41-50, 51-60, 61-70, 7180 and more than 81 years old). there was no statistically significant difference, however the 51-60 years old men figure 1. receiver operating characteristic (roc) analysis of the dd3 gene expression in blood: area under the roc curve (aur): 0.937. figure 1. receiver operating characteristic (roc) analysis of the dd3 gene expression in urine: area under the roc curve (aur): 0.981. sample risk factors no. mean standard deviation p bmi < 23 29 25.6476 1.17550 .134 ≥23 23 26.0870 0.81795 urine < 66 30 25.6510 1.43299 .839 age ≥66 27 25.5789 1.20965 blood bmi < 23 41 25.4437 1.10123 .528 ≥23 25 25.6192 1.07195 age < 66 34 25.5691 1.05127 .694 ≥66 33 25.4642 1.12007 table 1. comparison of ct value for 18s rna in different age and body mass index (bmi) groups. pca3 gene expression in patients with pca and bph-moradi sardareh et al urological oncology 1954 had the highest expression rate. we did not observed any relationship between the pca3 expression in urine and blood with weight. pca3 expression was also investigated in the pca group based on gleason score. patients with pca was classified into two subcategories according to gleason score (< 7 and ≥ 7). the mean δct of pca3 in patients’ blood with gleason < 7 and ≥ 7, were 5.05 and 6.57, respectively, which did not show statistically significant differences (p = .14). also, in the urine samples this difference was not significant. based on δct value of pca3 marker, the cut-off point in urine and blood samples were determined with ci of 95%. based on these data, the sensitivity and specificity of the pca3 marker were 94.74% and 81.82% in blood, and 100% and 86.36% in urine, respectively. comparing the rate of increasing pca3 expression between the three groups revealed that the mean of urinary pca3 expression in pca group vs. control group was 20.90 fold and for the bph group, was 20.35 fold while the expression of this marker in urine of bph group was only 1.02 fold vs. control group. increasing rate of pca3 expression in blood of pca group was 10.64 and 7.17 fold compared to control and bph groups, respectively. furthermore, the expression level of this gene in bph vs. control participants was only 1.48. the sensitivity and specificity of pca3 marker in blood and urine is shown in table 2. according to these results, roc curve was plotted and area under the curve (auc) was calculated (figures 1 and 2). roc curve was used to determine a cutoff level. the cutoff values were 4.81 and 4.46 in blood and urine samples, respectively (arrows in figures 1 and 2). however with greater cutoff values the sensitivity did not increase. according to the achieved data from pca3 primers-blast (basic local alignment search tool), they were exclusively attached to the various variants of pca3 mrna that are in genbank. the pcr product produced by these primers had 430bp lengths. also, the length of the pcr product for 18s rrna was 151 bp. to confirm these results the generated products by reverse transcription pcr (rt-pcr) were subjected on agarose gel electrophoresis 1% (figure 3). discussion pca diagnosis is currently based on abnormal psa test following biopsy. however, a number of factors affect srum psa levels.(18,19) therefore this test has so many false results. psa production is controlled by androgenic and some non-androgenic factors such as obesity and prostate disease. factors such as age and prostatitis affect psa production, too. likely, obesity is associated with low levels of psa.(18,19) on the other hand, obesity leads to increasing the size of the prostate. assuming 3 ng/ml as the cutoff value for psa, the rate of negative biopsies will increase up to 70-80%.(7) according to thomson and colleagues, a borderline could not be considered for psa test in pca diagnosis.(20) in second half of 1990s, pca3 gene was detected in a collaborated study by the johns hopkins hospital in baltimore and radboud university in the netherlands,(21) which was called dd3.(22) at first, this gene was used in differential diagnosis between bph and pca, particularly in the prostate tissue, and then it was isolated from urine sediments and yielded acceptable results.(14-16) hessels and colleagues and van gils and colleagues studied pca3 gene in urinary sediments after dre and concluded that the presence of pca3 in urine sediment is beneficial as a diagnostic test for pca.(22,23) these studies also revealed that uses of this test might raise the specificity of diagnosis of pca. so it can prevent unnecessary prostate biopsies.(16,23) therefore, in addition to better detection, using this test sample cancerous non-cancerous p number percent number percent blood present 18 94.74 08 18.18 .001 absent 01 05.26 36 81.82 urine present 18 100.00 06 13.64 .001 absent 00 000.00 38 86.36 table 2. sensitivity and specificity of the dd3 gene expression in blood and urine. references no. pca (%) sensitivity (%) specificity (%) auc van gils et al(23) 534 33.0 65 66 0.66 marks et al(29) 226 26.5 58 72 0.68 hessels et al(16)** 108 28.0 67 83 0.72 tinzel et al(13)** 201 39 82 76 0.87 present study* 72 33.3 94.74 81.82 0.93 present study** 72 33.3 100 86.36 0.98 abbreviations: pca3, prostate cancer antigen 3; pca, prostate cancer; auc, area under the curve. *blood **urine table 3. sensitivity and specificity of the pca3 marker in some studies. pca3 gene expression in patients with pca and bph-moradi sardareh et al vol 11. no 06 nov-dec 2014 1955 may prevent invasive diagnostic procedures such as prostate biopsy. hara and colleagues concluded that prostate biopsy may lead to spread of prostate cells in the blood. so biopsy leads to tumor metastasis in pca patients probably.(24) bussemakers and hessels`s reports indicated that unlike psa, pca3 value is not affected by patients’ age, the size of prostate and other prostate diseases.(14,22) our results on age and pca3 expression in blood and urine confirmed these previous findings. this result suggests that although age is a risk factor for pca, it has no effect on pca3 expression. previously, the correlation between gene expression and gleason score has been studied. for instance, mofid and colleagues investigated the association of her-2 gene expression and the gleason score but they did not find any correlation between them.(25) so we studied a novel marker. the pca3 expression was evaluated in cancer patients based on gleason score as an indicator of cancer development and progression. this comparison did not show any significant differences in blood and urine. these results confirmed the finding of hessels and colleagues in which they did not observe a significant association between pca3 expression (after dre) and prognostic parameters such as gleason score or tumor size.(26) their results was also confirmed by van gils and colleagues.(27) however, the results obtained by vlaeminck-guillem and colleagues don’t agree with our results.(12) they observed meaningful correlation between pca3 gene expression, gleason score and tumor volume.(12) nakanishi and colleagues also observed a significant correlation between pca3 and tumor volume.(28) these findings supported by marks and colleagues who stated that, higher levels of pca3 are seen in men with gleason score more than seven.(29) also, whitman and colleagues found that the rate of pca3 is associated with pathological finding such as tumor size.(30) over 30% of american adults are obese. obesity is associated with a number of cancers such as breast and colon cancers,(31) but its association with pca is not known. although a number of studies have found that increasing bmi is related to more detection of pca,(32) other researchers have not found any relationship.(33,34) interestingly, about one-third of pca patients are obese. in most cases, when the disease is detected, it is in an advanced stage. hence, obese men are the greatest victims of this disease.(35) in the present study no significant relationship was observed between the pca3 expression in blood and urine with weight. with the changes done in the laboratory method of this study, a significant increase in the sensitivity and specificity of the used test was provided. the sensitivity and specificity of the pca3 marker obtained in our study (in blood 94.74, 81.82%, respectively, and in urine 100, 86.36% respectively) have been compared to the other reports (table 3). the limitations of this study were small sample size and lack of uniformity in stage of cancer. conclusion evaluation of pca3 gene expression could be considered as a reliable marker for detection of pca. increased expression of this marker in urine sediments is more sensitive than blood for differentiating subjects with pca and non-cancerous subjects. acknowledgments the authors appreciate all staff and experts of urology department of shahid beheshti hospital of hamadan, the staff of laboratories in departments of molecular medicine and genetics and biochemistry of hamadan university of medical science. also they express special thanks to prof. virginie vlaeminck-guillem for helpful comments during the process and prof. shukmei ho and prof. jun ying for helping in methodology and responding to our questions. in addition, they would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. this report was based on a msc thesis and was supported by research and technology deputy, hamadan university of medical sciences (grant no. 9004141495). conflict of interest none declared. references 1. fallah m. cancer incidence in five provinces of iran ardebil, gilan, mazandaran, golestan and kerman, 1996 – 2000. finland: universi ty of tampere; 2007:23-25. 2. malekzadeh r, editor. incidences of different cancers in iran [persian]. the 16th internati onal congress of geographic; 2003; shiraz, iran. dec 1-4: medicine shiraz university of medical sciences. 3. jemal a, siegel r, xu j, ward e. cancer sta tistics, 2010. ca cancer j clin. 2010;60:277 300. 4. siegel r, naishadham d, jemal a. cancer statistics, 2013. ca cancer j clin. 2013;63: 11-30. figure 3. agarose gel electrophoreses of reverse transcription polymerase chain reaction products: (a) lane 1, molecular weight standards; lanes 2 and 3, prostate cancer antigen3 products of blood sample from two cancer patients; lane 4, 18s rna product of blood; (b) lane 1, molecular weight standards; lanes 2 and 3, prostate cancer antigen3 products of urine sample from the same two cancer patients; lane 4, 18s rna product in urine. pca3 gene expression in patients with pca and bph-moradi sardareh et al urological oncology 1956 5. fitzpatrick j. “psa screening for prostate cancer.” urol news. 2004;9:6-9. 6. donovan jl, hamdy fc, neal de. screenin g for prostate cancer. the case against. ann r coll surg engl. 2005;87:90-1. 7. hessels d, verhaegh gw, schalken ja, wit jes ja. applicability of biomarkers in the ea rly diagnosis of prostate cancer. expert rev mol diagn. 2004;4:513-26. 8. ghafoori m, varedi p, hosseini sj, asgari m, shakiba m. value of prostate-specific an tigen and prostate-specific antigen density in detection of prostate cancer in an iranian population of men. urol j. 2009;6:24-30. 9. yoon bi, shin ts, cho hj, et al. is it effec tive to perform two more prostate biopsies according to prostate-specific antigen lev el and prostate volume in detecting prostate cancer? prospective study of 10-core and 12-core prostate biopsy. urol j. 2012;9:491 7 . 10. thompson im, ankerst dp, chi c, et al. op erating characteristics of prostate-specific antigen in men with an initial psa level of 3.0 ng/ml or lower. jama. 2005;294:66-70. 11. mehrabi s, ghafarian shirazi h, rasti m, bayat b. analysis of serum prostate-spe cific antigen levels in men aged 40 years and older in yasuj, iran. urol j. 2009;2:189-92. 12. vlaeminck-guillem v, ruffion a, andré j, devonec m, paparel p. urinary prostate cancer 3 test: toward the age of reason? urol ogy. 2010;75:447-53. 13. tinzl m, marberger m, horvath s, chypre c. dd3” pca3” rna analysis in urine–a new perspective for detecting prostate can cer. eur urol. 2004;46:182-7. 14. bussemakers mj, van bokhoven a, verhae gh gw, et al. dd3: a new prostate-specific gene, highly overexpressed in prostate ca ncer. cancer res. 1999;59:5975-9. 15. de kok jb, verhaegh gw, roelofs rw, et al. dd3pca3, a very sensitive and specific marker to detect prostate tumors. cancer res. 2002;62:2695-8. 16. hessels d, klein gunnewiek jm, van oort i, et al. dd3 “pca3” based molecular urine analysis for the diagnosis of prostate can cer. eur urol. 2003;44:8-16. 17. yadegarazari r, hassanzadeh t, majlesi a, et al. improved real-time rt-pcr assays of two colorectal cancer peripheral blood mrna biomarkers: a pilot study. iran bi omed j. 2013;17:15. 18. dahle se, chokkalingam ap, gao y-t, deng j, stanczyk fz, hsing aw. body size and serum levels of insulin and leptin in re lation to the risk of benign prostatic hyperp lasia. j urol. 2002;168:599-604. 19. hammarsten j, högstedt b. hyperinsulinae mia as a risk factor for developing benign prostatic hyperplasia. eur urol. 2001;39:151 8. 20. thompson im, pauler dk, goodman pj, tan gen cm, lucia ms, parnes hl, et al. prev alence of prostate cancer among men with a prostate-specific antigen level≤ 4.0 ng per milliliter. n engl j med. 2004;350:2239-46. 21. schalken j. interview with jack schalken. pca3 and its use as a diagnostic test in pros tate cancer. interview by christine mckillop. eur urol. 2006;50:153-4. 22. 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parameters in radical prostatectomy specimens and pca3 urine test results. pros tate. 2008;68:1215-22. 28. nakanishi h, groskopf j, fritsche ha, et al. pca3 molecular urine assay correlates with prostate cancer tumor volume: implica tion in selecting candi-dates for active surve illance. j urol. 2008;179:1804-10. 29. marks ls, fradet y, lim deras i, et al. pca3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. urology. 2007;69:532-5. 30. whitman ej, groskopf j, ali a, et al. pca3 score before radical prostatectomy predicts extracapsular extension and tumor volume. j urol. 2008;180:1975-8. 31. bray ga. the underlying basis for obesity: relationship to cancer. j nutr. 2002;132: 3451s-5s. 32. engeland a, tretli s, bjørge t. height, body mass index, and prostate cancer: a follow-up of 950 000 norwegian men. br j cancer. 2003;89:1237-42. pca3 gene expression in patients with pca and bph-moradi sardareh et al vol 11. no 06 nov-dec 2014 1957 33. schuurman ag, goldbohm ra, dorant e, van den brandt pa. anthropometry in relat ion to prostate cancer risk in the netherlands cohort study. am j epidemiol. 2000;151: 541-9. 34. whittemore as, kolonel ln, wu ah, et al. prostate cancer in relation to diet, physical activity, and body size in blacks, whites, and asians in the united states and canada. j natl cancer inst.1995;87:652-61. 35. sonoda t, nagata y, mori m, miyanaga n, takashima n, okumura k, et al. a case‐con trol study of diet and prostate cancer in japan : possible protective effect of traditional jap anese diet. cancer sci. 2004;95:238-42. urological oncology 1958 pca3 gene expression in patients with pca and bph-moradi sardareh et al laparoscopic urology laparoscopic radical prostatectomy after previous transurethral resection of the prostate in clinical t1a and t1b prostate cancer: a matched-pair analysis yi yang,1* yun luo,1* guo-liang hou,2 qun-xiong huang,1 min-hua lu,1 jie si-tu,1 xin gao1** purpose: to analyze and compare surgical, oncological and functional outcomes of laparoscopic radical prostatectomy (lrp) in patients with and without previous transurethral resection of the prostate (turp). materials and methods: in total, 785 men underwent lrp at our institution from january 2002 to december 2012. turp had been performed previously in 35 of these patients (turp group). a matched-pair analysis identified 35 additional men without previous turp who exhibited equivalent clinicopathological characteristics to serve as a control group. perioperative complications and surgical, functional, and oncological outcomes were compared between the two groups. results: the groups were similar in age, body mass index, serum prostate-specific antigen level, and preand post-operative gleason scores. patients in the turp group had greater blood loss (231 vs. 139 ml), longer operative times (262 vs. 213 min), a greater probability of transfusion (8.6% vs. 0%), and a higher rate of complications (37.1% vs. 11.4%) compared with the control group. the positive surgical margin rate was higher in the turp group, but this difference was not statistically significant (p = .179). the continence rates at one year after surgery were similar, but a lower continence rate was identified in the turp group (42.9% vs. 68.6%) at 3 months. biochemical recurrence developed in 17.1% and 11.4% of the patients in the turp and control groups, respectively, after a mean follow-up of 57.6 months. conclusion: lrp is feasible but challenging after turp. lrp entails longer operating times, greater blood loss, higher complication rates and worse short-term continence outcomes. however, the radical nature of this cancer surgery is not compromised. keywords: laparoscopy; prostatectomy; methods; prostatic neoplasms; surgery; blood loss; operative time; transurethral resection of prostate; postoperative complications; adverse effects; treatment outcome. introduction it is fairly common for patients with clinically local-ized prostate cancer (pca) to undergo transurethral resection of the prostate (turp) for benign prostatic hyperplasia (bph). the rate of pca that is detected on histopathological examination of turp chips using normal range age-specific serum prostate-specific antigen (psa) levels and negative digital rectal examination findings is 6.4%.(1) it is considered that the presence of periprostatic fibrosis, scar tissue and inflammation after previous turp may hinder optimal outcomes for radical prostatectomy.(2) historically, open retropubic radical prostatectomy (rrp) after previous turp was associated with poor surgical, pathological, and functional outcomes. (3) during the past years, laparoscopic radical prostatectomy (lrp) has become a more commonly performed procedure for the treatment of localized pca. (4,5) lrp has the advantages of clearer fields of vision, better preservation of anatomical structures, a shorter period of convalescence and less blood loss compared with rrp, and it seems ideal for the navigation of difficult tissue planes in a previously treated surgical field.(6,7) menard and colleagues(1) showed that lrp could be performed after prior turp without compromising the oncological results but with worse intraoperative and postoperative outcomes. however, several studies have shown no difference in complication rates or morbidity, and the opportunity for surgical cure was comparable to patients without previous turp, although lrp was technically more difficult.(8) there are a few published data of a limited number of patients exploring the influence of previous turp on lrp, but no consensus has been reached. limited reports are available on the long-term oncological and functional results in patients with a history of turp who undergo lrp. to our knowledge, there is a lack of published data on outcomes of lrp in patients with previous turp in china. in this retrospective review, we assessed the perioperative, oncological and functional outcomes of patients with a history of turp who underwent lrp. materials and methods study design a total of 785 men underwent lrp at our institution from january 2002 to december 2012. all of their 1department of urology, the third affiliated hospital, sun yat-sen university, guangzhou, 510630, china. 2 department of urology, foshan first municipal people’s hospital, foshan, 528000, china. *authors contributed equally. **correspondence: department of urology, the third affiliated hospital, sun yat-sen university, tianhe road 600, guangzhou, 510630, china. tel: +86 20 85252990. fax: +86 20 85252678. e-mail: urogx@hotmail.com received june 2015 & accepted june 2015 laparoscopic urology 2154 clinical data were recorded in our database. a prior conventional turp for bladder outlet obstruction had been performed in 35 patients. the turp group consisted of patients with pca that was incidentally diagnosed following turp (stage t1a, t1b). this group included patients who had undergone preoperative transrectal ultrasound-guided systematic 12core prostate biopsy because of elevated serum psa levels, but the histopathology showed only bph. a match-paired analysis was performed using our database to identify men without a history of turp with equivalent clinicopathological characteristics to serve as the control group (non-turp group). matching criteria included, age, body mass index (bmi), american society of anesthesiology (asa) score, preoperative serum total psa level, preoperative gleason score, and pelvic lymph node dissection. the patients in the control group had all undergone transrectal ultrasound-guided biopsies demonstrating pca. the 2002 american joint committee on cancer (ajcc) tnm staging of pca was used for both clinical and pathologic staging. gleason score was evaluated by dedicated pathologist according to the international society of urological pathology (isup) 2005 guidelines.(9) treatment plan a single surgeon (x.g.) performed all of the lrps using a transperitoneal or extraperitoneal approach as described previously.(10) pelvic lymph node dissection was performed in all patients with a serum psa level > 10 ng/ml and/or a gleason score > 6. complications were evaluated according to the clavien-dindo classification.(11) all of the patients underwent cystography 7-10 days after surgery. anastomotic leakage was defined as the presence of extravasation on cystography. the catheter was removed if no extravasation was recorded. follow-up a 3-monthly follow-up was conducted to assess longterm oncological and functional outcomes. the mean follow-up period was 57.6 months (range 30–107). continence was evaluated using the international continence society (ics) questionnaire. a requirement for > 1 pad daily with normal physical activity was considered incontinence. biochemical recurrence was defined as 2 consecutive detectable serum psa levels > 0.2 ng/ ml. no patients received adjuvant hormonal therapy or radiotherapy without a psa level higher than 0.2 ng/ml. match-paired analysis preoperative clinicopathological characteristics (age, bmi, prostate size, clinical stage, serum psa level, preoperative gleason score, and continence), intraoperative characteristics (neurovascular bundle [nvb] preservation, lymph node dissection, estimated blood loss, need for transfusion, operative time, and intraoperative complications), postoperative oncological characteristics (gleason score, pathological stage, positive surgical margin [psm] and positive lymph nodes), postoperative complications, biochemical recurrence, and continence were compared between the turp and control groups. statistical analysis we compared the two groups using one-way analysis of variance or student’s t test for numeric values and a chi-squared test for non-numeric values. the univariate and multivariate models were performed for urinary function in combination with time of continence with a correction in imbalance factors. pearparameters turp control p value group group patients (n) 35 35 age (years) .56 mean 69.9 68.9 range 54-82 51-79 bmi (kg/m2) .883 mean 23.2 23.2 range 22-25.5 20.2-25.6 asa score (n) .597 1 26 24 2 9 11 prostate volume (ml) < .001 mean 19.2 ± 5.6 34.4 ± 15.5 range 10.3-37.1 11.6-76.7 biopsy gleason score .773 mean 6.5 6.6 range 4-9 4-9 psa (ng/ml) .474 mean 9.21 10.49 range 0.624-20.73 1.73-26.67 clinical t stage (n) t1a 5 t1b 30 t1c 19 t2a 14 t2b 2 interval between turp and lrp (weeks) mean 7.5 range 1-12 access (n) .003 transperitoneal 15 27 extraperitoneal 20 8 operative time (min) < .001 mean 262 213 range 165-370 120-305 estimated blood loss (ml) .002 mean 231 139 range 100-800 50-300 transfusions (n) 3 0 lymphadenectomy (n) 1.0 yes 30 30 no 5 5 nerve sparing (n) .001 none 26 (74.3) 14 (40) unilateral 3 (8.6) 4 (11.4) bilateral 6 (17.1) 17 (48.6) complications (n) 13 (37.1) 4 (11.4) .012 minor (clavien i-ii) 9 2 anastomosis leakage 9 2 urinary infection 3 0 major (clavien iii-iv) 4 2 rectal injury 2 0 anastomotic stricture 4 2 abbreviations: bmi, body mass index; psa, prostate specific antigen; asa, american society of anesthesiology; turp, transurethral resection of prostate; lrp, laparoscopic radical prostatectomy. data in parentheses are percentages. the level of statistical significance was defined as p < .05. table 1. comparison of perioperative parameters between the 2 study groups. matched-pair analysis of laparoscopic radical prostatectomy after previous turp-yang et al. vol 12 no 03 may-june 2015 2155 son’s contingency coefficient test was performed for a correlation analysis between continence (n) and biochemical recurrence (n). the data were analyzed using statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. a p value < .05 was considered statistically significant. results patient characteristics this study was conducted in accordance with the guidelines of the ethics committee of the third affiliated hospital of sun yat-sen university. comparative data on the two groups are provided in table 1. both groups were similar in age, bmi, preoperative gleason score, serum psa level, and the requirement for lymphadenectomy. a significant difference was observed between prostate volume in the turp group vs. the control group (19.2 ± 5.6 vs. 34.4 ± 15.5 ml, p < .001). the mean time interval between turp and lrp was 7.5 weeks and ranged from 1 to 12 weeks (table 1). the mean operative time was 49 min longer for the turp group than the control group (262 vs. 213 min, p < .001). intraoperative blood loss data were obtained from the anesthesia records. the mean estimated blood loss was 231 ml in the turp group compared with 139 ml in the control group (p < .001). the intraoperative blood transfusion rate was 8.6% in the turp group, and no patient needed transfusion in the control group. a nerve-sparing procedure was performed in only 25.7% of patients in the turp group (unilaterally in 3 and bilaterally in 6) compared with 60% of patients in the control group (unilaterally in 4 and bilaterally in 17) (p = .001). fourteen patients (40%) in the control group chose to maximize oncological safety, and they did not undergo a nerve-sparing procedure. the days of drainage (dd), catheterization (dc), and hospital stay (hs) was 3~5, 7~10 and 10~14 in both groups, respectively. no perioperative mortality was observed in either group. complications a statistically significant difference in the complication rate was observed between the turp group and the control group (37.1% vs. 11.4%, p = .012). the most common complication was anastomosis leakage, which was significantly higher in the turp group than the control group (34.3% vs. 5.7%, p = .003). rectal injury occurred in 2 men in the turp group. three patients in the turp group developed urinary infections. anastomotic strictures developed in 4 patients in the turp group and in 2 patients in the control group. however, the stricture rate between the groups was not significantly different. these patients underwent bladder neck incision as and when the stricture developed, and good outcomes were achieved. oncological results pathological results and follow-up information are shown in table 2. no significant difference in post-operative gleason scores was observed between the two groups. the percentage of gleason scores ≥ 8 in the turp group was somewhat higher than the control group, but this difference was not significantly different. psm was defined as the presence of tumor cells at the inked surface of the resected specimen. the overall psm rate was 34.3% for the turp group compared with 20% for the control group (p = .179). eight patients in the turp group had positive nodes compared with 4 patients in control group. these patients were immediately started on hormonal ablation. there were no biochemical recurrence cases in 3 months postoperatively. biochemical recurrence occurred in 6 and 4 patients in the turp group and control group, respectively, after a mean follow-up of 57.6 months (range 30–107). only 1 patient in the turp group died of pca. parameters turp group control group p value post-operative gleason score .569 mean 6.9 6.7 range 4-9 4-9 gleason score group .466 ≤ 6 14 (40) 14 (40) 7 8 (22.9) 12 (34.3) ≥ 8 13 (37.1) 9 (25.7) psm (n) 12 (34.3) 7 (20) .179 pt2 2 3 pt3a 5 3 pt3b 3 1 pt4 2 0 nodes positive (n) 8 (22.9) 4 (11.4) .205 pathological t stage (n) .127 t2 25 (71.4) 30 (85.7) t3a 5 (14.3) 3 (8.6) t3b 3 (8.6) 1 (2.9) t4 2 (5.7) 1 (2.9) biochemical recurrence (n) 6 (17.1) 4 (11.4) .495 prostate cancer-specific mortality (n) 1 0 1.0 continence at last follow-up (n) 30 (85.7) 33 (94.3) .428 abbreviations: psm, positive surgical margin; turp, transurethral resection of prostate. data in parentheses are percentages. the level of statistical significance was defined as p < .05. table 2. pathological results and follow-up information of the 2 study groups. matched-pair analysis of laparoscopic radical prostatectomy after previous turp-yang et al. laparoscopic urology 2156 functional results all of the patients were continent preoperatively. the continence rates at 3 months were significantly higher in the control group than in the turp group (68.6% vs. 42.9%, p = .03). however, no statistically significant difference was found between the 2 groups at 12 months after lrp. at last follow-up, continence was achieved in 85.7% of patients in the turp group and in 94.3% of patients in the control group. univariate (hazard ratio [hr] = 1.355, 95% confidence interval [ci]: 0.823-2.232, p = .233) and multivariate (hr = 1.324, 95% ci: 0.6542.677, p = .435) analysis showed that there were no significant difference in urinary continence between the 2 groups. besides, pearson’s contingency coefficient test showed that the correlation was not significant between urinary continence and biochemical recurrence status. discussion the relative paucity of pca patients who have undergone a previous turp makes any comparative analysis somewhat difficult. however, several studies on this subject have been reported. most of these studies have focused only on histopathological or surgical results rather than long-term oncological results and functional outcomes. our literature review did identify few studies that addressed lrp after previous turp in chinese patients. the present study used a matched-pair design to compare the perioperative, oncological, and functional results of lrp in chinese patients with and without previous turp. turp results in periprostatic edema, inflammation and fibrosis, and distortion of the proper surgical plane, which increases the difficulties of subsequent procedures. therefore, the optimal time interval between turp and lrp is theoretically when the reactive inflammation and fibrosis is lightest. elder and colleagues(12) recommended performing surgery either during the first month after turp or to wait until 4 months after turp. zugor and colleagues(6) suggested a time interval between turp and rp of at least 3 months in an attempt to decrease the amount of possible postoperative inflammation. the mean time interval between turp and lrp was 7.5 weeks (range 1 to 12 weeks) in this study, which is a shorter interval than the time recommended previously. we found that the periprostatic edema in this interval was indeed severe in some cases. however, the optimal time interval was impossible to evaluate in this study because no lrp was performed later than 3 months after turp. several studies reported that surgical procedures after turp are challenging.(2,8,13,14) to our experience, there are several concerns during the procedure with respect to the post turp scenario. (i) it is difficult to identify the prostatovesicular junction after the removal of prostatic tissue during turp. (ii) urethrovesical anastomosis becomes technically difficult after previous turp because of rigidity of the bladder neck and the loss of elasticity in the urethra.(13) (iii) the need for bladder neck reconstruction is increased because preservation of the bladder neck after turp is difficult. katz and colleagues(13) did not attempt to preserve the bladder neck but instead made a wide incision and redesigned the bladder neck in the form of a racket handle to increase the distance between the ureteral orifices and the region of the urethrovesical anastomosis. (iv) posterior dissection is difficult, which increases the risk of rectal injury because of periprostatic adhesions and fibrosis. (v) the tumor that is diagnosed by turp chips was usually located in the transitional zone. therefore, seminal vesicular involvement may be increased because a transitional zone tumor may spread easily via the ejaculatory ducts. (vi) the risk of anastomotic leakage and incontinence may be increased because the bladder neck becomes thickened, fibrotic, and rigid after previous turp. (vii) the nvbs were less dissociable from the prostatic capsule after previous turp because of periprostatic adhesions. the influence of previous prostate surgery on the outcome of radical prostatectomy remains controversial, except for the intraoperative difficulties.(8,15) one proposed hypothesis is that previous turp increases intraoperative and postoperative morbidity and complicates oncological and functional outcomes in patients undergoing lrp because of the difficult dissection resulting from the obscured planes caused by periprostatic inflammation and fibrosis. the existing literature suggests that relatively poorer outcomes are achieved in men with previous prostatic surgery.(16,17) one study of 117 patients reported that patients with a history of turp who underwent lrp had worse outcomes of operative time, overall complication rate, and functional outcomes.(2) however, several previous studies demonstrated that although surgery may be technically more difficult, overall morbidity and long-term functional or oncological outcomes are not compromised.(1,7,13,18) our study encountered longer operative times, greater intraoperative blood loss, and higher blood transfusion rates in the turp group. these results may be attributed to the extravasation of blood and fluid irrigation during turp, which resulted in periprostatic fibrosis and obscured the proper planes between tissues. the preoperative biopsy also induces some inflammatory and fibrotic reactions in and around the prostate, but these reactions are much lighter than turp-induced reactions.(19) anastomotic leakage rates were much higher in the turp group. jaffe and colleagues(2) found that patients with previous turp had a significantly higher rate of anastomotic leakage (15.1%) following lrp than patients without previous surgery (6.7%). one possible explanation is that the scarring and fibrosis of the previously resected bladder neck complicates healing at the anastomosis. some studies demonstrated that nvb preservation was technically feasible in approximately 33% to 56.5% of lrp patients after turp.(1,18) the isolation and preservation of nvb in our study was technically feasible in only 25.7% of patients in the turp group compared to 60% in the control group. as reported by colombo and colleagues,(19) this reduced preservation may result from the more difficult dissection of the nvbs because of periprostatic fibrosis. nerve-sparing techniques maybe have a significant effect on urinary continence because the autonomic nerve fibers from the pelvic plexus innervate the sphincteric mechanism.(20,21) do and colleagues(22) investigated a series of 100 patients who had undergone lrp after previous turp and showed that 93% of patients were continent at 12 months, but data of nvb preservation were not shown. teber and colleagues demonstrated that previous turp was associated with a lower continence rate than the control group at 3 months (49.1% vs. 61.8%).(23) similar outcomes were encountered in our study. therefore, patients with a history of turp should be informed of the potential risk of delayed continence before surgery. matched-pair analysis of laparoscopic radical prostatectomy after previous turp-yang et al. vol 12 no 03 may-june 2015 2157 several studies reported higher psm rates (21.8%– 34.2%) in patients who underwent lrp after turp. (2,8) katz and colleagues(8) noted positive margins in 12 of 35 patients who underwent lrp after previous turp, including 22.2% of patients with pt2 and 75% of patients with pt3. jaffe and colleagues(2) reported a greater overall psm rate after turp, but they did not detail the pathological stage. in contrast, other studies did not detect these differences.(1) our study found no significant difference between the two groups. one possible explanation for the somewhat higher psm rate in the current series is the difficulty in the identification of the proper surgical planes because of periprostatic inflammation and fibrosis after turp. (24) psms were associated with biochemical progression in 21% to 30.8% of patients, depending on the location of the positive margins.(25) our study found a higher biochemical recurrence rate in the turp group than the control group (17.1% vs. 11.4%, respectively, p = .495) after a mean follow-up of 57.6 months, but this difference was not statistically significant. this result may be explained by the higher psm rate, higher lymph-positive rate, and the greater percentage of cases with gleason scores ≥ 8 in the turp group. these findings should be interpreted within the context of the limitations of our study. there was a statistically significant difference in clinical stage between the two groups. however, 94.3% of patients in the control group had a t stage ≤ t2a. this difference could potentially limit the study. however, we believe that the results were not affected, because t stage ≤ t2a would be grouped as low risk according to the d’amico classification. the time interval between turp and lrp was not standardized because this study was a retrospective review. this factor may limit the results of the study. the procedural approach is another potential limitation of the study. lrp was transperitoneally performed in 42.9% and 77.1% of patients in the turp group and control group, respectively. however, a previous study reported that these two techniques exhibited equivalent perioperative, oncological and functional results.(26) therefore, this fact does not likely limit the findings in this study. still, we have to acknowledge that a matchedpair analysis has certain limitations in this study and a relatively low number of total patients in both groups also may reduce the persuasion of research results. besides, quality of life questionnaire (such as continence) for patients was also influenced by many factors. conclusion previous turp may cause technical difficulties during lrp. lrp after turp is associated with a longer operating time, greater blood loss, difficult nvb preservation, a higher rate of anastomosis leakage and worse short-term continence outcomes compared to turp naïve cases. the follow-up data suggest that lrp after turp can be safely performed without compromising the radical nature of cancer surgery and long-term continence rate. however, patients should be informed of these potential risks before undergoing lrp. acknowledgments the authors acknowledge financial support received from the national natural science foundation of china (81201694), the reserve personnel plan of the third affiliated hospital of sun yat-sen university, the science and technology planning project of guangdong province (2014a020212160) and the specialized research fund for the doctoral program of higher education of china (20120171120059). conflicts of interest none declared. references 1. menard j, de la taille a, hoznek a, et al. laparoscopic radical prostatectomy after transurethral resection of the prostate: surgical and functional outcomes. urology. 2008;72:593-7. 2. jaffe j, stakhovsky o, cathelineau x, barret e, vallancien g, rozet f. surgical outcomes for men undergoing laparoscopic radical prostatectomy after transurethral resection of the prostate. j urol. 2007;178:483-7. 3. bandhauer k, senn e. radical retropubic prostatectomy after transurethral prostatic resection. eur urol. 1988;15:180-1. 4. ficarra v, novara g, artibani w, et al. retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. eur urol. 2009;55:1037-63. 5. hanchanale vs, mccabe je, javlé p. radical prostatectomy practice in england. urol j. 2010;7:243-8. 6. zugor v, labanaris ap, porres d, witt jh. surgical, oncologic, and short-term functional outcomes in patients undergoing robot-assisted prostatectomy after previous transurethral resection of the prostate. j endourol. 2012;26:515-9. 7. suzuki y, matsuzawa i, hamasaki t, kimura g, kondo y. retrospective study of laparoscopic radical prostatectomy for localized prostate cancer after transurethral resection of the prostate compared with retropubic radical prostatectomy at the same institution. j nippon med sch. 2012;79:41621. 8. katz r, borkowski t, hoznek a, salomon l, gettman mt, abbou cc. laparoscopic radical prostatectomy in patients following transurethral resection of the prostate. urol int. 2006;77:216-21. 9. epstein ji, allsbrook wc jr, amin mb, egevad ll; isup grading committee. the 2005 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma. am j surg pathol. 2005;29:1228-42. 10. gao x, pu xy, si-tu j, huang wt. singlecentre study comparing standard apical dissection with a modified technique to facilitate vesico-urethral anastomosis during laparoscopic radical prostatectomy. asian j androl. 2011;13:494-8. 11. dindo d, demartines n, clavien pa. matched-pair analysis of laparoscopic radical prostatectomy after previous turp-yang et al. laparoscopic urology 2158 classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 12. elder js, gibbons rp, correa rj, jr., brannen ge. morbidity of radical perineal prostatectomy following transurethral resection of the prostate. j urol. 1984;132:557. 13. yazici s, inci k, yuksel s, bilen cy, ozen h. radical prostatectomy after previous prostate surgery: effects on surgical difficulty and pathologic outcomes. urology. 2009;73:8569. 14. gupta np, singh p, nayyar r. outcomes of robot-assisted radical prostatectomy in men with previous transurethral resection of prostate. bju int. 2011;108:1501-5. 15. kanno h, umemoto s, izumi k, et al. [prostate cancer development after transurethral resection of the prostate--histopathological studies of radical prostatectomy specimens]. nihon hinyokika gakkai zasshi. 2006;97:64959. 16. stolzenburg ju, ho km, do m, rabenalt r, dorschner w, truss mc. impact of previous surgery on endoscopic extraperitoneal radical prostatectomy. urology. 2005;65:325-31. 17. bujons tur a, montlleo gonzalez m, pascual garcia x, rosales bordes a, caparros sariol j, villavicencio mavrich h. [radical prostatectomy in patients with history of transurethral resection of the prostate]. arch esp urol. 2006;59:473-8. 18. eden cg, richards aj, ooi j, moon da, laczko i. previous bladder outlet surgery does not affect medium-term outcomes after laparoscopic radical prostatectomy. bju int. 2007;99:399-402. 19. colombo r, naspro r, salonia a, et al. radical prostatectomy after previous prostate surgery: clinical and functional outcomes. j urol. 2006;176:2459-63. 20. kessler tm, burkhard fc, studer ue. nervesparing open radical retropubic prostatectomy. eur urol. 2007;51:90-7. 21. sfoungaristos s, perimenis p. bilateral cancer in prostate biopsy associates with the presence of extracapsular disease and positive surgical margins in low risk patients: a consideration for bilateral nerve sparing radical prostatectomy decision. urol j. 2013;10:966-72. 22. do m, haefner t, liatsikos e, et al. endoscopic extraperitoneal radical prostatectomy after previous transurethral resection of prostate: oncologic and functional outcomes of 100 cases. urology. 2010;75:1348-52. 23. teber d, cresswell j, ates m, et al. laparoscopic radical prostatectomy in clinical t1a and t1b prostate cancer: oncologic and functional outcomes--a matched-pair analysis. urology. 2009;73:577-81. 24. ramon j, rossignol g, leandri p, gautier jr. morbidity of radical retropubic prostatectomy following previous prostate resection. j surg oncol. 1994;55:14-9. 25. pettus ja, weight cj, thompson cj, middleton rg, stephenson ra. biochemical failure in men following radical retropubic prostatectomy: impact of surgical margin status and location. j urol. 2004;172:129-32. 26. cathelineau x, cahill d, widmer h, rozet f, baumert h, vallancien g. transperitoneal or extraperitoneal approach for laparoscopic radical prostatectomy: a false debate over a real challenge. j urol. 2004;171:714-6. matched-pair analysis of laparoscopic radical prostatectomy after previous turp-yang et al. vol 12 no 03 may-june 2015 2159 urology journal unrc/iua vol. 2, 36-39 spring 2004 printed in iran 36 management of peyronie's disease by dermal grafting nikoobakht mr, mehrsai a, pourmand gh, jaladat h, nasseh hr department of urology, sina hospital, tehran university of medical sciences, tehran, iran abstract purpose: to evaluate the results of plaque excision and dermal grafting in peyronie's disease. materials and methods: twenty seven patients were scheduled to undergo plaque excision and dermal grafting for peyronie's disease. potency, bending of erected penis, and having painful erection were evaluated in patients before and after operation. to evaluate erectile dysfunction, we used international index of erectile function (iief) by interviewing the patients and filling questionnaires by their partners. doppler ultrasonography was used to determine the vascular competence of penis before and after operation in 15 patients. results: the disease was more prevalent between the ages of 40 and 60 years. plaques were located as follows: dorsal in 18, right lateral in 6 and left lateral in 3. mean plaque size was 11 (range 5 to 18) mm. after plaque excision and dermal grafting, penile deformity, erectile dysfunction, and painful erection had remained yet in 4 (15%) out of 27, 3 (16%) out of 19, and 3 (14%) out of 22, respectively. doppler ultrasonographic study in 15 patients revealed improvement in peak systolic velocity (p<0.01). in addition, a decrease in end diastolic velocity was noted also that was not significant statistically (p=0.26). resistive index did not improve after operation. conclusion: this procedure showed significant improvement in penile deformity (85% of cases), erectile dysfunction (84% of cases) and painful erection (86% of cases). we recommend plaque excision and dermal grafting as an effective procedure in treating peyronie's disease. key words: impotence, dermal grafting, peyronie's disease introduction the incidence of symptomatic peyronie's disease is estimated to be 1% and its asymptomatic prevalence is between 0.4% and 1%. in 100 autopsies from previously asymptomatic individuals, 22 cases of peyronie's like lesions were found. moreover, it seems that the incidence of the disease is in progress.(1) thus, finding an appropriate therapy is getting more crucial. it is suggested that trauma is the trigger event.(2) the result is a plaque formation, which impede dilation of tunica albuginea during the erection.(1) changes in the appearance and the tissue of tunica albuginea is the characteristic pathology. induration may occur within the tunica albuginea with or without lymphocyte infiltration.(3) this disease can lead to painful erection, bending of erected penis, and in advanced stages, erectile dysfunction (43%).(4) according to various studies, improvement occurs spontaneously in 13% of the patients. in 47%, complications persist and in 40% progress gradually.(5) several therapeutic options are available: medical treatments such as orgotein (an anti-inflammatory drug)(6), vitamin e(7), tamoxifen(8), verapamil(9), cholchicine(10), and intralesional triamcinolone(11) and even radiotherapy or surgical approaches. various surgical procedures have been used to date. one of the increasingly accepted methods is dermal grafting.(1) in a study of 20 patients who underwent plaque excision and dermal grafting, ample erection for satisfactory intercourse was achieved postoperatively in 4 of 4 patients (100%) with erectile dysfunction.(12) considering the high prevalence of peyronie's disease and its impact on accepted for publication in july 2003 management of peyronie's disease by dermal grafting patients' quality of life, and regarding the outcomes of the studies on dermal grafting in other countries, we decided to investigate the results of plaque excision and dermal grafting in iranian patients. materials and methods thirty five patients were evaluated between september 1992 and february 1998 at sina hospital. twenty-four of them had the indication for surgery and underwent plaque excision with dermal grafting by a single surgeon. we used a hairless area in the superio-lateral side of iliac crest of the abdominal skin for obtaining dermis. epidermis was removed and derma was grafted. mean followup was 12 (range 9 to 72) months. each patient who met these criteria was included: a minimum of 1-year unsuccessful medical treatment, age of less than 65, and the location of plaque on the inferior or lateral surface of penis. a written consent was signed by the patients preceded with explaining the procedure and its complications. patients who were over 65, had no plaque, were not interested in surgical therapy, or were given medical treatment less than one year were excluded. data were collected through interview, questionaires filled out by the patient and his sexual partner, and physical examination before and after the procedure. erectile dysfunction, painful erection, and bending erected penis were evaluated using international index of erectile function (iief). in order to quantify postoperative symptoms, we graded the patients based on the surgeon and patient's point of view as follows: grade 1: only one symptom resolved or all the symptoms remained. grade 2: two symptoms were relieved. grade 3: no symptom remained. statistical analysis was performed by spss software, using paired t test. the p value of less than 0.05 was regarded significant. results twenty seven out of 35 were selected to undergo the operation. they were classified by age (table 1). mean age was 56 (range 36 to 64) years. similar to the results of other studies, peyronie's disease was more prevalent in the patients between 40 and 60 years old. all the patients underwent plaque excision with dermal grafting. plaque was located right-laterally in 6, posteriorly in 18, and left laterally in 34. mean plaque size was 11 (range 5 to 18) mm. nineteen patients had erectile dysfunction (70%), based on the iief scoring, 22 (81%) had painful erection, and all of the cases (100%) suffered from bending erected penis. postoperatively, penile deformity, erectile dysfunction, and painful erection were found in 4 (15%) out of 27, 3 (16%) out of 19, and 3 (14%) out of 22, respectively (tables 2,3). the remainder were improved (p<0.001). doppler ultrasonography was performed in 15 cases; peak systolic velocity increased significantly (p<0.01) and end diastolic velocity had slight decrease which was not statistically significant (p=0.26). resistive index did not improve after the surgery (table 4). according to our grading, 23 patients had no unresolved symptom (grade 3). one case of bending erected penis remained unresolved (grade 2) and 3 patients still had painful erection, erectile dysfunction, and bending erected penis (grade 1). discussion peyronie's disease is not a rare condition. despite of its self-limiting nature and the availability of a series of non-invasive treatments, in some cases with failure of conservative therapies and 37 table 1. patients' age distribution age number (percent) <40 years 3 (11.3%) 40-60 years 18 (66.4%) >60 years 6 (22.3%) total 27 (100%) table 2. iief results before and after dermal grafting in 27 patients underwent the surgery mild: 5-7 scores, moderate: 8-16 scores, severe: 1721 scores table 3. the effect of plaque excision and dermal grafting on painful erection, erectile dysfunction, and erected penis bending before the operation after the operation erectile dysfunction intensity number (percent) number (percent) mild 3 (16%) 0 (0%) moderate 7 (37%) 2 (66.7%) severe 9 (47%) 1 (33.3%) painful erection erectile dysfunction erected penis bending before the operation 22 (87%) 19 (70%) 27 (100%) after the operation 3 (11%) 3 (11%) 4 (15%) p value <0.001 <0.001 <0.001 management of peyronie's disease by dermal grafting severe deformity and erectile dysfunction, surgical correction would be warranted. the most common surgical methods are nesbit's tucking technique, its excision-plication type, and free dermal grafting introduced by devine and horton.(13) in this study, 27 patients needed surgical intervention and dermal grafting of whom 70% had erectile dysfunction, similar to those in previous reports.(14-16) the rate of erectile dysfunction was reduced to 11% (3 cases) after the procedure (p 15 mm had a lower treatment success rate by swl compared to flexible urs and pnl. various factors predict unfavorable results of swl for lower calyceal stones. the european association of variables multivariate analysis odds ratio 95% ci p value age 0.993 (0.909-1.084) .870 gender 0.267 (0.033-2.164) .216 stone size 3.009 (1.372-6.597) .006 operation time 0.996 (0.927-1.070) .909 fluoroscopy time 1.283 (0.902-1.825) .166 opaque or non-opaque 4.732 (0.119-187.696) .408 left or right kidney 0.667 (0.095-4.695) .684 table 3. logistic regression analysis results according to treatment success rate. abbreviation: ci, confidence interval. flexible ureterorenoscopy for opaque and non-opaque renal stones-tanik et al endourology and stone disease 2007 vol 12. no 01 jan-feb 2015 1995vol 12. no 01 jan-feb 2015 2008 urology (eau) guidelines recommend flexible urs or pnl for lower calyceal stones > 15 mm.(19) in our study, the treatment success rate was affected by stone size (multivariate logistic regression analysis), as has been reported previously.(20,23,24) as stone burden increased, the stone-free rate by flexible urs decreased. sener and colleagues reported a 100% stone-free rate for upper urinary tract stones < 1 cm.(25) flexible urs treatment for stones > 2 cm has high treatment success rates with acceptable complication rates.(26) we treated stones < 2 cm in our study. the improvement of flexible urs and developments in intracorporeal lithotripsy techniques, has allowed effective and safe operations. as mentioned in the 2012 guidelines of the eau, urs is a good option for small-to-moderate sized kidney stones(15) access sheath placement was preferred whenever possible in this study. access sheath placement reduces intra-pelvic pressure, the need for fluoroscopy, residual stone rate and operation time.(12,27) we placed access sheaths in 86 (91.5%) patients. flexible urs was also performed in patients in whom a ureteral access sheath could not be inserted. as the number of patients in whom a ureteral access sheath was not inserted was insufficient, no statistical comparison was performed. fluoroscopy time was shorter in patients in the non-opaque stone group compared to the opaque stone group (p < .001). stone location was determined by direct vision because the stones were radiolucent. conclusion our results demonstrate that flexible urs was successful for treatment of non-opaque and opaque renal stones. furthermore, radiolucency did not affect the operative measures. however, these preliminary results should be confirmed by high-volume, randomized, prospective studies. conflict of interest none declared. references 1. stamatelou kk, francis me, jones ca, nyberg lm, curhan gc. time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003;63:1817-23. 2. hesse a, brandle e, wilbert d, kohrmann ku, alken p. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2003;44:709-13. 3. skolarikos a, laguna mp, alivizatos g, kural ar, de la rosette jj. the role for active monitoring in urinary stones: a systematic review. j endourol. 2010;24:923-30. 4. scales cd, jr., krupski tl, curtis lh, et al. practice variation in the surgical management of urinary lithiasis. j urol. 2011;186:146-50. 5. bader mj, eisner b, porpiglia f, preminger gm, tiselius hg. contemporary management of ureteral stones. eur urol. 2012;61:764-72. 6. matlaga br, jansen jp, meckley lm, byrne tw, lingeman je. treatment of ureteral and renal stones: a systematic review and metaanalysis of randomized, controlled trials. j urol. 2012;188:130-7. 7. breda a, ogunyemi o, leppert jt, schulam pg. flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. eur urol. 2009;55:1190-6. 8. riley jm, stearman l, troxel s. retrograde ureteroscopy for renal stones larger than 2.5 cm. j endourol. 2009;23:1395-8. 9. mariani aj. combined electrohydraulic and holmium:yag laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. j urol. 2007;177:168-73. 10. karlsen sj, renkel j, tahir ar, angelsen a, diep lm. extracorporeal shockwave lithotripsy versus ureteroscopy for 5to 10-mm stones in the proximal ureter: prospective effectiveness patient-preference trial. j endourol. 2007;21:2833. 11. weld lr, nwoye uo, knight rb, et al. fluoroscopy time during uncomplicated unilateral ureteroscopy for urolithiasis decreases with urology resident experience. world j urol. 2015;33:119-24. 12. mandeville ja, gnessin e, lingeman je. imaging evaluation in the patient with renal stone disease. semin nephrol. 2011;31:254-8. 13. halabe a, sperling o. uric acid nephrolithiasis. miner electrolyte metab. 1994;20:424-31. 14. karadag ma, demir a, cecen k, et al. flexible ureterorenoscopy versus semirigid ureteroscopy for the treatment of proximal ureteral stones: a retrospective comparative analysis of 124 patients. urol j. 2014;11:1867-72. 15. türk c, knoll t, petrik a, sarica k, straub m, seitz c. guidelines on urolithiasis. european association of urology. 2012;1-102. 16. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 17. prabhakar m. retrograde ureteroscopic intrarenal surgery for large (1.6-3.5 cm) upper ureteric/renal calculus. indian j urol. 2010;26:46-9. 18. grasso m, conlin m, bagley d. retrograde ureteropyeloscopic treatment of 2 cm. or greater upper urinary tract and minor staghorn calculi. j urol. 1998;160:346-51. 19. girman cj. natural history and epidemiology of benign prostatic hyperplasia: relationship among urologic measures. urology. 1998;51:812. 20. pearle ms, lingeman je, leveillee r, et al. prospective, randomized trial comparing shock wave lithotripsy and ureteroscopy for lower pole caliceal calculi 1 cm or less. j urol. 2005;173:2005-9. 21. el-anany fg, hammouda hm, maghraby ha, flexible ureterorenoscopy for opaque and non-opaque renal stones-tanik et al elakkad ma. retrograde ureteropyeloscopic holmium laser lithotripsy for large renal calculi. bju int. 2001;88:850-3. 22. fabrizio md, behari a, bagley dh. ureteroscopic management of intrarenal calculi. j urol. 1998;159:1139-43. 23. perlmutter ae, talug c, tarry wf, zaslau s, mohseni h, kandzari sj. impact of stone location on success rates of endoscopic lithotripsy for nephrolithiasis. urology. 2008;71:214-7. 24. geavlete p, seyed aghamiri sa, multescu r. retrograde flexible ureteroscopic approach for pyelocaliceal calculi. urol j. 2006;3:15-9. 25. sener nc, imamoglu ma, bas o, et al. prospective randomized trial comparing shock wave lithotripsy and flexible ureterorenoscopy for lower pole stones smaller than 1 cm. urolithiasis. 2014;42:127-31. 26. aboumarzouk om, monga m, kata sg, traxer o, somani bk. flexible ureteroscopy and laser lithotripsy for stones >2 cm: a systematic review and meta-analysis. j endourol. 2012;26:125763. 27. miernik a, wilhelm k, ardelt pu, adams f, kuehhas fe, schoenthaler m. standardized flexible ureteroscopic technique to improve stone-free rates. urology. 2012;80:1198-202. flexible ureterorenoscopy for opaque and non-opaque renal stones-tanik et al endourology and stone disease 2009 refractory haematuria resulting from peritoneal dissemination of metastatic gastric cancer: radiation therapy for a nodule infiltrating the urinary bladder introduction bladder metastases from distant primary sites are believed to account for only 1.5% of all bladder tumours(1,2,3). we describe a patient suffering from refractory haematuria in the form of a nodule resulting from peritoneal dissemination infiltration of the urinary bladder, which was clearly detected on imaging and by cystoscopy. following local radiation therapy for this nodule, vesical bleeding stopped as the nodule was markedly diminished. there are no previous reports on radiation therapy performed for haematuria caused by a nodule resulting from peritoneal dissemination of a primary tumour. case report a 64-year-old man became aware of tarry stools and subsequently gastric and rectal tumours were discovered. tumour biopsy revealed poorly differentiated and moderately differentiated adenocarcinoma, respectively. according to immunostaining, the primary gastric and rectal cancer were ck-7 (+) plus ck-20 (-) and ck-7 (-) plus ck-20 (+), respectively, indicating different primary tumours. as rectal stenosis was suspected, a colostomy was performed. intraoperatively, nodules representing peritoneal dissemination were identified under the abdominal incision and removed for biopsy. the biopsy of one of these nodules indicated carcinoma and immunostaining revealed them to be ck-7 (+), while were almost ck-20 (-). multiple peritoneal dissemination nodules were found in the dome of the bladder. on whole-body computed tomography (ct), no other primary lesion was detected, so the diagnosis was peritoneal dissemination of gastric cancer. the patient became aware of gross haematuria eight months after the initial examination. on ct, a nodule infiltrating the dome of the bladder was identified which was strongly contrast-enhanced (figure 1). magnetic resonance diffusion-weighted imaging confirmed the same nodule (figure 2). a cystoscopic examination revealed that the nodule, which was clearly extramural, had infiltrated the dome of the urinary bladder wall, resulting in bleeding (figure 3). subsequently, the haematuria increased and the number of blood transfusions increased. we planned for biopsy of the extramural nodule on cystoscopy and definitive haemostasis was attempted, but it was not possible to observe the inside of the urinary bladder because it was filled with haematoma. therefore, radiation therapy was planned to control vesical bleeding. radiation was delivered to the nodule with a 1cm margin. as the patient’s general condition was poor, the irradiation dose was 3 gy/fraction for a total of 30 gy. the extramural nodule at the dome of the urinary bladder and the haematuria resolved one week after the completion of radiation therapy (figure 4) and the patient’s anaemia was improved with no further blood transfusions. the patient died with malignant ascites after 20 days after the completion of radiation therapy, during this short follow-up period, bladder bleeding did not recur. discussion bladder metastases from distant primary sites are described to account for only 1.5% of all bladder tumours(1,2,3). 1department of radiology, 2department of urology, 3department of digestive surgery, nihon university school of medicine, itabashi, tokyo, japan. *correspondence: department of radiology, nihon university school of medicine, 30-1, oyaguchi kami-cho itabashi-ku, tokyo 1738610, japan. tel.: +81 339728111, fax: +81 339582454, e-mail: ishibashi.naoya@nihon-u.ac.jp. received may 2016 & accepted december 2016 naoya ishibashi1*, toshiya maebayashi1, takuya aizawa1, masakuni sakaguchi1, osamu abe1, tsuyoshi matsui2, megumu watanabe3 keywords: haematuria; gastric cancer; metastases; peritoneal dissemination; radiotherapy. bladder metastases from remote primary sites are rarely reported. we present a case of haematuria caused by infiltration of the urinary bladder wall by a nodule resulting from peritoneal dissemination of a primary gastric tumour. the nodule was detected by computed tomography, magnetic resonance imaging and cystoscopy. transarterial embolization or haemostasis could not be performed because of the haematuria, thus the vesical bleeding was treated with a low irradiation dose of 3 gy/fraction for a total of 30 gy administered to the dome of the urinary bladder. no adverse effects occurred, and the gross haematuria and nodule resolved within 1 week. thus, radiotherapy should be considered for treatment of visceral bleeding caused by peritoneal dissemination of gastric cancer when other methods of haemostasis cannot be performed. case report vol 14 no 01 january-february 2017 2982 furthermore, peritoneal dissemination is reportedly common in melanoma, breast cancer and gastric cancer(4). there are three reports describing peritoneal dissemination detected as protuberances with bladder metastases from gastric cancer on ct or cystoscopy(5,6,7). two cases were not treated and one underwent partial cystectomy. our present report is the first, to our best knowledge, describing a case for which radiation therapy was performed. peritoneal dissemination of digestive tract malignancies including gastric cancer for which whole abdominal cavity irradiation (12 gy/3 fr) was performed has been reported(8). in general, the sensitivity of gastric cancer to radiation is considered to be poor, but there are cases with lymph node relapses who received radiation therapy, and shrinkage was observed in some cases(9). there is only one case report on peritoneal dissemination from gastric cancer for which local radiation therapy was performed, a lesion infiltrating the rectum at a total dose of 40 gy, which ameliorated rectal stenosis(10). our present case also received a total dose of 30 gy and the nodule resolved. as our present case has shown, radiation therapy is effective for treating vesical bleeding caused by peritoneal dissemination when haemostasis via a cystoscopic approach is difficult. radiotherapy for a dissemination infiltrating the urinary bladder-ishibashi et al. figure 2. mri with diffusion-weighted image showing high signal intensity of the lesion depicted in ct (white arrow). figure 3. cystoscopy image showing the nodule, which was clearly extramural, had infiltrated the dome of the urinary bladder wall, resulting in slow bleeding (arrows). figure 4. cystoscopy image taken 1 week after the completion of radiation therapy. the extramural nodule at the dome of the urinary bladder and the hematuria had resolved. figure 1. (a) whole body enhanced computed tomography (ct) and pelvic ct (b) showing a strongly contrast-enhanced nodule at the base of the abdominal cavity on the bladder dome (white arrow). case report 2983 references 1. melicow mm. tumors of the urinary bladder: a clinico-pathological analysis of over 2500 specimens and biopsies. j urol 1955; 74: 498521. 2. ganem ej, batal jt. secondary malignant tumors of the urinary bladder metastatic from primary foci in distant organs. j urol. 1956; 75: 965-72. 3. goldstein ag. metastatic carcinoma to the bladder. j urol. 1967; 98: 209-15. 4. bates aw, baithun si. the significance of secondary neoplasms of the urinary and male genital tract. virchows arch. 2002; 440: 6407. 5. saba nf, hoenig dm, cohen si. metastatic signet-ring cell adenocarcinoma to the urinary bladder. acta oncol. 1997; 36: 219-20. 6. lim ek, lin v.c.h, shu ct, yu tj, lu k. gastric cancer with bladder metastasis: case report and literature review. urol sci. 2011; 22: 80-2. 7. vigliar e, marino g, matano e, imbimbo c, rossella de c, insabato l. signet-ringcell carcinoma of stomach metastatic to the bladder: a case report with cytological and histological correlation and literature review. int j surg pathol. 2013; 21: 72-5. 8. sugahara s, ohara k, todoroki t, et al. whole abdominal irradiation for peritoneal dissemination of alimentary tract cancers. nihon igaku hoshasen gakkai zasshi. 1995; 55: 751-6. 9. nishijima k, minatoya g, itoh h, et al. effects of radiation therapy for paraaortic lymph node involvement and recurrent lymph node metastases from gastric cancer. gan to kagaku ryoho. 2004; 31: 1351-5. 10. shirai j, cho h, fujikawa h, et al. a case of rectal stenosis due to peritoneal dissemination from gastric cancer that was treated with chemoradiation therapy gan to kagaku ryoho. 2013; 40: 2268-70. radiotherapy for a dissemination infiltrating the urinary bladder-ishibashi et al. vol 14 no 01 january-february 2017 2984 urol_v03_no3_001_editorial.indd case report 180 urology journal vol 3 no 3 summer 2006 polyorchidism a case report and review of literature seyed mohammad hadi kharrazi, mohammad reza rahmani, majid sakipour, saeed khoob urol j (tehran). 2006;3:180-3. www.uj.unrc.ir keywords: testis, urogenital abnormalities, ultrasonography, magnetic resonance imaging department of urology, shohada-etajrish hospital, shaheed beheshti university of medical sciences, tehran, iran correspondence author: mohammad reza rahmani, md shohada-e-tajrish hospital, tajrish sq, tehran, iran tel: +98 912 293 9946 e-mail: urorahmanireza@yahoo.com received april 2006 accepted june 2006 introduction polyorchidism is an extremely rare congenital anomaly of the urogenital system and refers to the presence of more than two testicles. about 100 cases of this disease have been reported in the english literature, so far.(1) its most common presentation is triorchidism.(2) the left side is predominantly affected. approximately 50% of the cases are detected between 15 and 25 years of age.(3) the majority of patients are asymptomatic or present with painless inguinal or scrotal masses, undescended testis, and rarely, torsion of the supernumerary testis.(4) we report triorchidism in a 24-year-old man. case report a 24-year-old man presented with a dull pain in the left hemiscrotum. he did not have any previous history of urogenital complaints. physical examination of the left scrotum revealed 2 ovoid, nontender, soft, mobile lumps which were homogeneous in consistency. the right testis was normal in palpation. no lymphadenopathy was detected. laboratory tests including the serum levels of α-fetoprotein, β-human chorionic gonadotropin, folliclestimulating hormone, luteinizing hormone, and testosterone were within the reference range. semen analysis showed no abnormality. for editorial comment see p 182 ultrasonography revealed the presence of 2 testes within the left hemiscrotum with complete septation, a similar echotexture, and a vascular flow pattern similar to the vascular flow of the normal right testis (figure 1). a mild hydrocele was also noted on the right side. the right testis measured approximately 4 × 3 × 2 cm, and the 2 soft-tissue structures of the left side measured 2.5 × 2 × 2 cm and 2 × 2 × 1.5 cm. there was no focal abnormal echogenicity suggesting malignancy. scrotal mri confirmed 2 soft-tissue structures in the left hemiscrotum with normal signal intensity at t1w and t2w images. both testes had a tunica albuginea with low-signal intensity (figure 2). figure 1. ultrasonography of the left scrotum showed 2 softtissue structures with complete septation and similar echotexture to the normal right testis in the transverse section. polyorchidism—kharrazi et al urology journal vol 3 no 3 summer 2006 181 the findings were compatible with the diagnosis of testicular duplication. the patient was followed up conservatively. discussion polyorchidism is a rare congenital anomaly and 100 cases have been reported in the literature, to date.(2) testicular duplication may be due to the duplication of the genital ridge or longitudinal or transverse division of it before the 8th week of the gestation period.(3,5) a functional classification is reported by thum based on the embryonic development as follows: type 1, the supernumerary testis does not have epididymis and vas deferens; type 2, the supernumerary and the regular testes are linked to each other with a common epididymis and they both have a common vas deferens (incomplete division); and type 3, the supernumerary testis has its own epididymis but its vas deferens is shared with the regular testis (complete division).(6) our case falls into the type 3 category of this classification with complete left testicular duplication. the most common anomalies associated with polyorchidism are inguinal hernia (30%), maldescended testis (15% to 30%), testicular torsion (13%), hydrocele (9%), varicocele (< 1%), hypospadias (< 1%), anomalous urogenital union (< 1%), and malignancy (< 1%).(5) to date, a few cases of polyorchidism associated with malignancy have been reported in the literature, but there is no evidence supporting the idea of a relation between these two entities.(7) assessment of the true malignancy potential of polyorchidism is difficult due to its low incidence and frequent association with other risk factors, such as cryptorchidism.(8) the appropriate management of polyorchidism remains unclear. careful evaluation is necessary in every suspected testicular or scrotal finding to avoid misdiagnosis. however, if there is not any coexistent disorder, testicular tumor markers are negative for malignancy, and tumors can be ruled out by ultrasonography or mri, surgical exploration or biopsy is not necessary. consequently, these patients can be followed up conservatively.(7) splenogonadal fusion is a rare anomaly due to abnormal connection of the splenic tissue to the gonad or the mesonephric structures during embryonic development. typically, the malformation manifests as a testicular mass such as polyorchidism. ultrasonography demonstrates an ovoid structure attached to the testicle which has a homogeneous echogenicity similar to the echogenicity of the testicle. thus, the differentiation of splenogonadal fusion and polyorchisism cannot be made solely on the basis of ultrasonographic findings. some authors have described the use of technetium tc 99m sulfur colloid scintigraphy to identify the areas of ectopic splenic activity, and thereby, adding information to the imaging diagnosis.(9) magnetic resonance imaging also helps distinguish between the testicular and extratesticular pathologic processes and determine the solid and cystic lesions.(10) references 1. sheah k, teh hs, peh oh. supernumerary testicle in a case of polyorchidism. ann acad med singapore. 2004;33:368-70. 2. woodward pj, schwab cm, sesterhenn ia. from the archives of the afip: extratesticular scrotal masses: radiologic-pathologic correlation. radiographics. 2003;23:215-40. 3. spranger r, gunst m, kuhn m. polyorchidism: a strange anomaly with unsuspected properties. j urol. 2002;168:198. 4. haddock g, burns hj. polyorchidism. postgrad med j. 1987;63:703-5. 5. leung ak, wong al, kao cp. duplication of the testis with contralateral anorchism. south med j. 2003;96: 809-10. 6. thum g. polyorchidism: case report and review of literature. j urol. 1991;145:370-2. 7. berger ap, steiner h, hoeltl l, bartsch g, hobisch a. occurrence of polyorchidism in a young man. urology. 2002;60:911. figure 2. coronal plane magnetic resonance imaging demonstrated 2 testes in the left hemiscrotum. polyorchidism—kharrazi et al 182 urology journal vol 3 no 3 summer 2006 8. pomara g, cuttano mg, romano g, bertozzi ma, catuogno c, selli c. surgical management of polyorchidism in a patient with fertility problems. j androl. 2003;24:497-8. 9. pomara g. splenogonadal fusion: a rare extratesticular scrotal mass. radiographics. 2004;24: 417. 10. akbar sa, sayyed ta, jafri sz, hasteh f, neill js. multimodality imaging of paratesticular neoplasms and their rare mimics. radiographics. 2003;23:1461-76. editorial comment we read, with great interest, the article by dr kharrazi and colleagues. polyorchidism is an unusual abnormality of the genital tract in which supernumerary testicles are present, usually within the scrotum. it can be located in the scrotum, inguinal region, or in the abdomen. this anomaly is usually associated with inguinal hernia, testicular torsion, hydrocele, cryptorchidism, and testicular cancer. the exact embryological explanation of this anomaly is not fully understood in spite of several theories proposed to explain the different anatomical types.(1) three main theories have been proposed. the first suggests initial longitudinal and the second suggests transverse division of the genital ridge, either through some local accident or by development of the peritoneal bands. the result of longitudinal division may be a complete duplication of the vas, epididymis, and testis, as it is present on the both sides in this case. the more common form of polyorchidism is associated with transverse division in the genital ridge resulting in the duplication of the testis with a single epididymis, vas deferens, and tunica albuginea.(1,2) another hypothesis of 2-fold primordial glands on either side is supported by 8 previously reported cases,(3) where there are 2 testes with 2 separate epididymides and their vas deferens. polyorchidism is a very rare congenital disorder with fewer than 100 cases reported in medical literature.(3) only one case has been reported from our country.(3) the most common form is triorchidism or tritestes in which 3 testes are present. the condition is usually asymptomatic, but can increase the risk of testicular cancer. leung described the anatomical variations on the possible embryological basis. polyorchidism occurs in several forms(4): type 1: the supernumerary testis lacks an epididymis and vas deferens and has no connection to the other testes. type 2: the supernumerary testis shares the epididymis and the vas deferens of the other testes. type 3: the supernumerary testis has its own epididymis and shares a vas deferens. type 4: complete duplication of the testis, epididymis, and vas deferens is seen. type 2 is the most common form of polyorchidism, and types 2 and 3 together account for more than 90% of the cases. except in type 1, the supernumerary testis is usually reproductively functional. the supernumerary testis is most often found in the left scrotal sac. similarly, singer and associates suggested an anatomical as well as functional classification of polyorchidism.(5) type 1: supernumerary testes attached to the draining epididymis and vas deferens with reproductive potential (leung, type 2, 3, and 4). type 2: testes with lack of such an attachment without having any reproductive potential (leung, type 1). each of these 2 types are again subdivided into 2 groups (a and b) depending on their location in the scrotum (orthotopic) or outside the scrotal sac (ectopic), respectively. combining this classification with knowledge of potential complications, they proposed a management strategy. polyorchidism is generally diagnosed via an ultrasonographic examination of the testes. however, the advent of ultrahigh-frequency probes with vastly expanded dynamic ranges makes monographic evaluation a safe, inexpensive, and highly accurate modality to accomplish the diagnosis. color flow and power doppler can help accurately diagnose abnormalities of the vascular supply in most cases; ie, torsion. but other scrotal pathologies must be considered as a differential diagnosis of this entity. in all of the reported cases (except for few with ultrasonographic diagnosis but not surgical confirmation) the final diagnoses were confirmed by surgical exploration. polyorchidism was suspected by ultrasonography, but follow-up ultrasonographic studies showed a decrease in the echogenicity of the scrotal structure. surgical exploration revealed the testis and epididymis to be completely separated, with no duplicated testis.(6) polyorchidism—kharrazi et al urology journal vol 3 no 3 summer 2006 183 references 1. mcvary kt, maizels m. duplex testes (polyorchidism): report of 2 cases, review of the literature, and proposal of a classification system. j urol. 1988;139:500a, abstract 1346. 2. nocks bn. polyorchidism with normal spermatogenesis and equal sized testes: a theory of embryological development. j urol. 1978;120:638-40. 3. gardiner ra, samaratunga ml, gwynne ra, clague a, seymour gj, lavin mf. abnormal prostatic cells in ejaculates from men with prostatic cancer--a preliminary report. br j urol. 1996;78:414-8. 4. leung ak. polyorchidism. am fam physician. 1988;38:153-6. 5. singer br, donaldson jg, jackson ds. polyorchidism: functional classification and management strategy. urology. 1992;39:384-8. 6. zuppa aa, nanni l, di gregorio f, visintini f, buonuomo v, pintus c. complete epididymal separation presenting as polyorchidism. j clin ultrasound. 2006;34:258-60. abdolmohammad kajbafzadeh,1 hamid arshadi2 1pediatric urology research center, children’s hospital medical center, tehran university of medical sciences, tehran, iran 2department of urology, tehran university of medical sciences, tehran, iran urology journal unrc/iua 256 kidney transplantation a comparative study on the effect of lidocaine and furosemide on urinary output and graft function after renal transplantation razzaghi mr*, heidari f department of urology, shohada-e-tajrish hospital, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: renal transplantation is an ideal treatment for patients with chronic renal failure. it was demonstrated that despite the adhesion to surgical and anesthetic principles, urinary output is not satisfactory after transplantation. it seems that microvascular spasm of renal vasculature is responsible for this phenomenon. we designed a study to investigate whether lidocaine injection into renal artery can relieve vasospasm and subsequently improve output and graft function better than furosemide. materials and methods: in a randomized clinical trial, from july 2002 to november 2003, 100 consecutive patients who were referred to our center for kidney transplantation were recruited in this study. after obtaining written informed consent, they were divided blindly into two groups. in group 1, lidocaine was injected into renal artery, before arterial anastomosis, and group 2 received furosemide as the conventional intervention. urine volume within 1, 4, and 24 postoperative hours and serum creatinine levels in the first three weeks were recorded and compared between the two groups. results: urine volumes at 1, 4, and 24 hours after transplantation were higher significantly in lidocaine group (p <0.001). serum creatinine levels were lower significantly in the first postoperative day and also 21 days after transplantation in group 1 (p <0.001). conclusion: comparing to furosemide, it seems that lidocaine can cause a more effective vasodilation in renal arteries of kidney allograft, resulting in a better diuresis. this may have a role in the betterment of graft function. key words: kidney transplantation, lidocaine, vasospasm, graft function, urinary output vol. 1, no. 4, 256-258 autumn 2004 printed in iran introduction vasospasm is a common problem in vascular surgeries that can cause hypoperfusion and subsequent organ dysfunction. many studies have been conducted to introduce a safe vasodilator to use in surgical operations. there is a consensus that the ideal agents for relieving vasospasm are those effecting locally and improving flap blood flow.(1) among these drugs are: papaverine,(1) lidocaine,(1) nicardipine,(1) verapamil,(2) and capsaicin.(3) lidocaine had been extensively studied on various organs and animal models and its efficacy has been proved. vasodilation can be induced by lidocaine doses higher than 40 µg/ml.(4) on the other hand, is has been demonstrated that a better diuresis in time zero and received march 2004 accepted august 2004 *corresponding author: shohada-e-tajrish hospital, tajrish sq., tehran, iran. e-mail: rezarazaghi@yahoo.com. razzagi and heidari 257 within three days after transplantation (early polyuria) is associated with a better graft function.(5) the conventional diuresis induction method is to administer a large amount of intravenous fluid (5 to 7 liters) and diuretics, most commonly furosemide (5 mg/kg).(6) however, this method is not always effective; furosemide acts on the thick ascending limb of henle's loop, so that it must enter glomerular blood flow and then be excreted by proximal tubular cells in order to reach its action site.(7) it means that, without a good perfusion, diuretics cannot be effective. furthermore, furosemide can cause hyponatremia, hypokalemia, hyperglycemia, and metabolic alkalosis.(7) heretofore, the vasodilatory effect of lidocaine has been demonstrated on rabbit's carotid vessels,(8) porcine's epicardial arteries,(9) and rat's cremasteric vessels.(4) in human models, its effect on femoral(10) and retrobulbar vessels(11) has been showed. in this study, we used lidocaine, as an intravenous injection to renal arteries of kidney allograft and compared its vasodilatory effect with furosemide. materials and methods a total of 100 consecutive patients who were referred to shohada-e-tajrish hospital for renal transplantation were enrolled in this randomized clinical study. using a questionnaire, the following data were collected from patients: age, sex, weight (in the operation day morning), etiology of renal failure, hemodialysis duration, and time interval between disease diagnosis and the need for hemodialysis. the patients were randomly divided into two groups, each with 50 cases. all of the patients underwent renal transplantation, while the surgeon was blind to the random numbers based assignment of the patients by the operation time. during the operation, blood pressure in declamping time, fluid intake, and vital signs were recorded. in group 1, lidocaine 2%, 2 mg/kg, was injected into renal artery prior to anastomosis and then it was clamped with a bulldog. end to side anastomosis of renal vein to external iliac vein and then, end-to-end anastomosis of renal artery to internal iliac artery were performed. before declamping, vital signs were recorded and the urine flow in the ureter was observed. if there was not enough diuresis within three minutes, a diuretic would be administered and the patient would be excluded from the study. nevertheless, it did not happen in neither of the patients who received lidocaine. in group 2, furosemide, 3 to 5 mg/kg was administered before declamping and the remaining process was the same as that in group 1. the ureter was anastomosed over a double j stent into bladder with lich method. fascia was sutured with 0.0 nylon, after the insertion of a drain and skin was sutured with 2.0 nylon. after the closure of the wound, a nurse who was blind to the study groups recorded the urinary output volume, hourly. the urine volume within 1, 4, and 24 postoperative hours and was also calculated. serum creatinine level was measured daily, for three weeks. statistic analysis was done using t, chisquare, and repeated measurements tests. results from july 2002 to november 2003, 100 consecutive patients were enrolled in this study. of patients, 68% and 32% were male and female in group 1 and 66% and 34% were male and female in group 2, respectively. mean age of the patients was 36.8 ± 12.3 years in group 1 and 40.61 ± 11.1 years in group 2. there were not any significant differences regarding age and gender between the two groups. the etiologies for renal failure in group 1 were diabetes mellitus 40%, glomerulonephritis 22%, polycystic kidney disease 8%, hypertension 6%, and idiopathic 24%. in group 2, these were as follows: diabetes mellitus 44%, glomerulonephritis 8%, polycystic kidney disease 8%, hypertension 8%, and idiopathic 24%. chisquare test showed no significant difference between the two groups. the mean hemodialysis duration was 1.6 and 2 years in groups 1 and 2, respectively. the time interval between diagnosis of renal insufficiency and the need for hemodialysis was 3.9 and 3.2 years in groups 1 and 2, respectively (p = ns). at declamping time, the mean systolic blood pressure in group 1 (13.12 ± 1.05 mmhg) was not different from that in group 2 (13.22 ± 1.13 mmhg) and the mean diastolic blood pressure in group 1 (7.4 ± 1.08 mm/kg) and group 2 (7.9 ± 1.05 mmhg) were not different significantly. urine volume in the first hour after transplantation (v1) was 694 ± 299 ml and 348 ± 204 ml in groups 1 and 2, respectively, and the independent t test showed a significant difference between the two groups (p <0.001). the urine volume in the first 4 hours after transplantation (v2) was significantly different between group 1 (3980 ± 1547 ml) and group 2 (2575 ± 1187 ml) (p <0.001). in addition, urine volume in the first 24 hours after transplantation (v3) was signifieffect of lidocaine on urinary output and graft function258 cantly higher in group 1(18590 ± 5379 ml) in comparison with group 2 (11078 ± 7698 ml) (p <0.001). as the urine volumes of v2 and v3 were obtained from the summation of previous hourly urine outputs, we used repeated measurement test to evaluate the results; it was shown that urine volumes were statistically different between the two groups (p <0.001, f = 5.22). the urine volume in every three measurements in group 1 was higher than that in group 2. fluid intake during the surgery in group 1 (3.42 ± 0.57 liters) was significantly lower than that in group 2 (4.48 ± 0.5 liters) (p <0.001). serum creatinine level in the first postoperative day (cr1) was 6.07 ± 1.09 in group 1 and 6.1 ± 1.44 mg/dl in group 2. but, serum creatinine level in the second postoperative day (cr2) was significantly lower in group 1 (2.1 ± 0.8 mg dl) than in group 2 (3.1 ± 1.5 mg/dl) (p <0.001). likewise, serum creatinine level, 21 days after transplantation (cr3), was significantly lower in group 1 (1.18 ± 0.9 mg/dl) than in group 2 (1.7 ± 1.6 mg/dl) (p = 0.0027). discussion to our knowledge, this study has been done for the first time worldwide and there was not any similar study for comparison. experimental animal studies have shown vasodilatory effect of lidocaine. the obscure fact is effective vasodilatory dose of lidocaine. in animal studies, doses higher than 30 to 40 mg/ml have been used.(4) in one study on cadaver kidney transplantation, the dose of 2 mg/kg has been effective.(12) we also used this dose of lidocaine. the safe dose of lidocaine for local anesthesia is 2 to 4 mg/kg.(13) we also did not observe any side effect with the used dosage. with this dosage, the graft function was better after transplantation. conclusion lidocaine is a safe and effective drug for prevention of vasospasm in vascular surgeries. in this study, we demonstrated that it improves renal perfusion and results in better diuresis and graft function. references 1. evans gr, gherardini g, gurlek a, et al. drug-induced vasodilation in an in vitro and in vivo study: the effects of nicardipine, papaverine, and lidocaine on the rabbit carotid artery. plast reconstr surg. 1997;100:1475-81. 2. dawidson i, rooth p, lu c, et al. verapamil improves the outcome after cadaver renal transplantation. j am soc nephrol. 1991;2:983-90. 3. verdick gm, abbott pv. blood flow changes in human dental pulps when capsaicin is applied to the adjacent gingival mucosa. oral surg oral med oral pathol oral radiol endod. 2001;92:561-5. 4. johns ra, difazio ca, longnecker de. lidocaine constricts or dilates rat arterioles in a dose-dependent manner. anesthesiology. 1985;62:141-4. 5. matteucci e, carmellini m, bertoni c, boldrini e, mosca f, giampietro o. urinary excretion rates of multiple renal indicators after kidney transplantation: clinical significance for early graft outcome. ren fail. 1998;20:325-30. 6. solonynko i, loba m, orel j, kobza i, zhuk r, yeliseev g. renal transplantation--choice of anesthesia. wiad lek. 1997;50:447-8. 7. smith c, reynard a. textbook of pharmacology. wb saunders; 1992. p.554-88. 8. gherardini g, gurlek a, cromeens d, joly ga, wang bg, evans gr. drug-induced vasodilation: in vitro and in vivo study on the effects of lidocaine and papaverine on rabbit carotid artery. microsurgery. 1998;18:90-6. 9. perlmutter ns, wilson ra, edgar sw, sanders w, greenberg bh, tanz r. vasodilatory effects of lidocaine on epicardial porcine coronary arteries. pharmacology. 1990;41:280-5. 10. van der molen hr. vasoactive intra-arterial therapy in peripheral occlusive arterial disease (with follow-up after 6.5 years). angiology. 1980;31:221-9. 11. gombos gm. retinal vascular occlusions and their treatment with low molecular weight dextran and vasodilators: report of six years' experience. ann ophthalmol. 1978;10:579-83. 12. schulak ja, novick ac, sharp wv, ford e. donor pretreatment with lidocaine decreases incidence of early renal dysfunction in cadaver kidney transplantation. transplant proc. 1990;22:353-4. 13. catterall wa, mackie k. local anesthetics. in: hardman jg, limbird le, editors. goodman & gilman's the pharmacological basis of therapeutics. 10th ed. wb saunders 2001. p.379-8. 1724 | uretero-caval fistula after radical cystectomy with bricker ileal conduit: a case report cristian vincenzo pultrone,1 riccardo schiavina,1 eugenio brunocilla,1 caterina gaudiano,2 matteo renzulli,2 valerio vagnoni,1 fiorenza busato,2 marco borghesi,1 giuseppe martorana1 corresponding author: marco borghesi, md. palagi 9 street, 40138 bologna, italy. tel: +39 051 636 2733 fax: +39 051 636 2743 e-mail: mark.borghesi@gmail.com received july 2013 accepted january 2014 1 department of urology, azienda ospedaliero-universitaria, policlinico s. orsolamalpighi, bologna, italy. 2 department of radiology, azienda ospedaliero-universitaria, policlinico s. orsolamalpighi, bologna, italy. case report keywords: urinary fistula; vena cava; inferior; ureter; urinary diversion; cystectomy; methods; postoperative complications. introduction radical cystectomy represents the gold standard treatment for muscle-invasive blad-der cancer and ileal conduit (ic), first described by bricker in 1950, continues to be one of the most common forms of urinary diversion. nevertheless, the rate of early (infections, fistulas and bleeding) and late (parastomal hernia, ureteral/ileal stenosis, urolithiasis and deterioration of kidney function) reaches up to 66%.(1) in the literature, the uretero-arterial fistulas, as well as the aorto/iliac-ureteral fistula, are reported as complications of pelvic surgery or radiotherapy,(2) and ureteral or endovascular stenting.(3,4) ishibashi and colleagues(5) described a case of aorto-ileal-conduit fistula but, to our knowledge, this is the first case of fistula between ureter and inferior vena cava (ivc). case report we report the case of a 68-year-old woman who has underwent cystectomy and pelvic lymphadenectomy with bricker ic for a muscle-invasive-high grade urothelial bladder cancer. computed tomography-urography (ctu) performed for the onset of fever forty days after surgery, revealed a thrombus in the lumen of the ivc at the level of right ureteral anastomosis (figure 1a) with a urinary fistula between the ureter and ivc (figure 1b; arrow indicates the case report 1725vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l uretero-caval fistula with bricker ileal conduit | pultrone et al passage of iodinated urine in the lumen of the ivc through the fistula). the examination excluded abdominal fluid collections; pulmonary microembolism was also present. due to the high surgical risk, we decided to perform a conservative treatment to allow the complete exclusion of the urinary system and the treatment of ivc thrombosis and pulmonary microembolism. therefore, nephrostomy and anterograde ureteral stent were positioned in addition to the anticoagulant/antimicrobial therapy. after one month, the ctu performed prior to the ureteral stent removal demonstrated the complete healing of the ivc wall (figure 2a, arrow) and the absence of the passage of iodinated urine in the lumen of the vein (figure 2b). the anterograde pyelography, carried out without ureteral stent, confirmed the complete resolution of the fistula with regular flow of the iodinated urine in the ic (figure 3). discussion notably, our case stands out because the patient did not show the typical sign of a urinary-vascular fistula, i.e. hematuria, but only nonspecific clinical sign such as fever; this presentation made the clinical diagnosis more challenging. it has been shown that pelvic lymph node dissection (plnd) has a staging and, maybe, therapeutic role in the treatment of muscle-invasive bladder cancer;(6,7) in this case, we performed an extended plnd up to the ivc, which was probably damaged in its wall during the dissection. endoluminal thrombosis, as a result of an ulcer in the wall of the vein, prevented the bleeding in the ureter (avoiding the hematuria) and limited the spreading of the urine through the fistula. conflict of interest none declared. figure 1. inferior vena cava with thrombus in the lumen at the level of right ureteral anastomosis, arrow highlights the urinary fistula between the ureter and inferior vena cava. figure 2. computed tomography-urography performed prior to the ureteral stent removal, note the complete healing of the inferior vena cava wall. figure 3. anterograde pyelography without ureteral stent, complete resolution of the fistula. 1726 | references 1. madersbacher s, schmidt j, eberle jm, et al. long-term outcome of ileal conduit diversion. j urol. 2003;169:985-90. 2. santarpia l, creta m, bracale um, et al. ureteroiliac artery fistula in a young woman with short bowel syndrome for radiation enteritis. case rep med. 2010;2010:287034. 3. dangle pp, bahnson r, patel a. ureteral stent-related aortoureteric fistula: case report and literature review. can urol assoc j. 2009;3:84-6. 4. aarvold a, wales l, papadakos n, munneke g, loftus i, thompson m. arterio-ureteric fistula following iliac angioplasty. cardiovasc intervent radiol. 2008;31:821-3. 5. ishibashi h, ohta t, sugimoto i, et al. successful treatment of an aorto-ileal-conduit fistula with an endovascular stent graft: report of a case. surg today. 2007;37:305-7. 6. palmieri f, brunocilla e, bertaccini a, et al. prognostic value of lymphovascular invasion in bladder cancer in patients treated with radical cystectomy. anticancer res. 2010;30:2973-6. 7. brunocilla e, pernetti r, martorana g. the role of pelvic lymph node dissection during radical cystectomy for bladder cancer. anticancer res. 2011;31:271-5. case report vol 12. no 02 march-april 2015 1995 endourology and stone disease randomized double blinded placebo controlled trial comparing diclofenac and piroxicam in management of acute renal colic and its clinical implications gokul vignesh kandaswamy,1* ananda kumar dhanasekaran,2 aravindhan elangovan,3 bobby john,4 bobby viswaroop,5 kandasami sangam vedanayagam6 purpose: to compare the efficacy of sublingual piroxicam 40 mg with intramuscular diclofenac 75 mg in treatment of acute renal colic. the secondary objective was to look for factors that can affect the severity of the pain and pain relief in acute renal colic. materials and methods: one hundred patients with acute renal colic were randomized into two groups. group a (n = 50) received intramuscular diclofenac and sublingual methylcobalamin. group b (n = 50) received sublingual piroxicam 40 mg and intramuscular distilled water. pain severity was measured using visual analog scale (vas) and verbal and facial response scales. they were followed up for 3 h. intramuscular injection of pentazocine 30 mg with promethazine 25 mg were used as rescue drugs. results: both groups were comparable for age, sex distribution, body mass index (bmi), and pain duration before presentation. significant pain relief was noticed in both groups. sixteen percent in group a and 18% in group b had complete pain relief within 30 min (p = .75). fifteen patients in group a and 13 patients in group b needed rescue drugs, 84% of group a and 76% of group b had complete pain relief at the end of 3 hours (p = .25). decrease in pain by each scoring method was also comparable (p = .75). in multiple regression analysis, increasing age, positively affects the severity of pain and pain relief while increasing bmi negatively affect the initial pain relief. acute renal colic seems to affect men more commonly than women, 81% of the study population were men. patients with low initial pain score did not require any additional pain relief. average pain duration before presenting to hospital is 260 min. sixty percent of renal colics are due to stones below pelvic brim. conclusion: the results show that sublingual piroxicam is as effective as intramuscular diclofenac. it can be easily self-administered and it overcomes the morbidity and time delay in getting intramuscular diclofenac. keywords: double-blind method; drug combinations; emergency treatment; adverse effects; pain measurement; renal colic; drug therapy. introduction the incidence and prevalence of urinary stone disease is reported widely as increasing across the world. stone formation is multifactorial. persistent high temperature is positively correlated to the increased stone and colic episodes. acute renal colic episodes seem to affect people who work outdoors mostly in these extreme conditions.(1) acute renal colic episodes, typically described by patients as ‘coming out of the blue’, do cause severe distress and warrant emergency medical attention. these patients are treated with opioids and non-steroidal anti-inflammatory drugs (nsaids) to relieve pain in the acute setting. most patients suffer with this sudden acute pain while waiting for medical help, as these drugs are more effective parenterally or per-rectally. the primary objective of this study was to compare the efficacy of sublingual piroxicam with intramuscular diclofenac in relieving pain associated with acute renal colic. the secondary objective was to look for factors that can affect the severity of the pain and pain relief after treatment in acute renal colic. also few underreported parameters in renal colic are looked into, such as pain severity and duration at presentation, site of stones in patients with renal colic and etc. materials and methods study population this study was performed in a single high volume stone center in south india. these cohorts of patients were seen in emergency department in a dedicated tertiary referral center for urology. one hundred non-consecutive patients, who presented with acute renal colic, were enrolled for 1 dudley group hospitals nhs foundation trust, dudley-dy1 2hq, west midlands, uk. 2 queen elizabeth university hospital, birmingham, uk. 3 dharan hospital, salem, india. 4 department of urology malankara orthodox syrian church medical college, kolenchery, india. 5 vedanayagam hospital private limited, coimbatore, india. 6 department of urology vedanayagam hospital, private limited, coimbatore, india. *correspondence: dudley group hospitals nhs foundation trust, dudley-dy1 2hq, west midlands, uk. tel: +44 012 15376070. e-mail: kgvignesh@yahoo.com. received decmber 2014 & accepted april 2015 vol 12. no 02 march-april 2015 2069 the study after obtaining informed verbal consent. the inclusion criteria for the study were presentation with acute renal colic with stone confirmed on imaging, willingness to participate and no analgesic intake in the last 24 h. presence of stone was confirmed with one or a combination of kidney-ureter-bladder (kub) x-ray, ultrasonography (us) or computed tomography (ct) scan. the hospital policy is to offer kub x-ray as the first line investigation followed by us and then ct scan if still a diagnosis cannot be made. us is done directly in known recurrent radiolucent stone formers. in the study cohort, kub x-ray was the predominant mode of diagnosis while some had diagnosis confirmed in us. few patients had investigations done elsewhere like ct scan but if had presented with renal colic was also considered for study. the exclusion criteria were contraindication or hypersensitivity to nsaids, declined to participate, signs of infection like fever or positive urine dipstick, no stones on imaging, unable to wait for investigations such as ct scan and anatomic abnormality of the urinary tract (figure 1). once patients were included in the study, computergenerated random numbers, randomized patients in to 2 groups. pain was assessed by visual analog scale (vas), verbal scale and facial grimace scale (fgs) (figure 2). patients scored their pain in the visual and verbal scales and the author scored their pain using fgs. patients in group a received diclofenac 75 mg intramuscularly with methylcobalamin 1500 µg sublingually as placebo and in group b patients received piroxicam 40 mg sublingually with distilled water 0.2 ml intramuscularly. the investigator and the patients were blinded for the group they belong to. the nurse administering the drugs is not blinded for safety reasons. after initial pain scoring and administration of drugs, patients were followed up at 30, 60 and 180 min for further pain scoring in all 3 scales, administration of further analgesics if needed, monitoring vital signs, recording adverse effects and data collection. patients who needed further pain relief were given pentazocine 30 mg with promethazine 25 mg intramuscularly as rescue drugs starting from 30 min onwards as per patient’s request. the following definitions were used for the study. severity of pain is graded as mild, (1-4) moderate (5-7) and severe (8-10) based on the vas score. complete pain relief is defined as no pain experienced by the subject at that point. significant pain relief is defined as reduction in pain by 3 units in vas score or from one group to other in verbal scale. the need for rescue drugs was defined as study failure i.e., failure of either drugs to provide effective pain relief. demographic and clinical characteristic of patients such as age, sex distribution, bmi, duration of pain, prior treatment if any, rescue drugs if given and its time of administration were recorded. statistical analysis the homogeneity of the descriptive variables of the two treatment groups was examined by student’s t-test and chi-square test. percentage of pain improvement was analyzed with z-test for proportions. pain scores of two treatment groups were analyzed with friedman variables group a group b p value age group (years) (mean ± sd) 20-60, (33.86 ± 9.5) 19-65, (37.02 ± 9.9) .11 male to female ratio 39:11 42:8 .61 bmi (kg/m2), range (mean ± sd) 14.42-33.33, (23.57 ± 3.9) 17.26-48.47, (25.18 ± 4.8) .073 duration of pain (min), range, (mean ± sd) 40-720, (284.1 ± 151.24) 20-725, (238.2 ± 133.94) .111 side of pain, right-left, (%) 22-28, (44-56) 26-24, (52-48) .42 site of stone, uu-mu-lu-uvj 13-7-12-18 15-5-13-17 .55 vas score at presentation, range, (mean ± sd) 4-10, (7.3 ± 1.59) 4-10, (7.2 ± 1.64) .805 table 1. demographic and clinical characteristics of study groups. abbreviations: sd, standard deviation:; bmi, body mass index; uu, upper ureter, above sacroiliac joint; mu, middle ureter, between upper and lower ends of sacroiliac joint; lu, lower ureter, below sacroiliac joint; uvj, ureterovesical junction; vas, visual analog scale. results group a (n = 50) group b (n = 50) p value z value complete pain relief at 30 min 8/16, (6-26) 9/18, (8-28) .79 0.84 complete pain relief at one hour** 11/22, (11-33) 16/32, (19-45) .26 1.27 complete pain relief at 3 hours** 42/84, (74-94) 38/76, (64-88) .32 1.00 significant pain relief at 30 min*** 27/54, (40-68) 29/58, (44-72) .41 0.4 rescue drugs 15/30, (17-43) 13/26, (14-38) .67 0.44 prior treatment 9/18, (7-29) 10/20, (9-31) .80 0.26 table 2. study outcomes in both study groups.* * data are presented as no/% (95% confidence interval). **excluding complete pain relief at 30 min. ***excluding complete pain relief. diclofenac and piroxicam in management of renal colic-kandaswamy et al. vol 12. no 02 march-april 2015 2070endourology and stone disease 2070 vol 12. no 02 march-april 2015 1995 test and mann-whitney u test. agreement between two scoring systems was checked with chi-square test. multiple regression analysis was done to find any association between severity of pain and other observed variables. data are presented as means with standard deviations (sd). all analyses were done using statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. the power of the study was calculated retrospectively. for a difference of 1, 2 and 3 unit on the vas score the power was 61%, 92% and 99%, respectively. the alpha error was kept at 0.05. a difference of 3 units was set in initial definitions, which means the power of study is 99%. results the results are summarized in tables 1 and 2. no significant difference was seen between the two groups in terms of age, sex, bmi, duration and severity of pain at presentation, side of pain and site of stone (table 1). table 2 demonstrates the outcome analysis, following medication administration in both groups. the drop in pain scores recorded in the regular intervals in all 3 scales and in both groups was uniformly very significant (p = .00). however between the two groups there is no statistically significant difference in all 3 scales in terms of pain relief recorded at each interval. this confirms both groups showed similar pain relief and in a similar comparable pattern. the number of patients having pain relief either complete or partial and the rate of pain relief are similar in both groups. significant pain relief was noticed in both groups, 16% had complete pain relief within 30 min in group a as against 18% in group b (p = .75). fifteen (30%) patients in group a and 13 (26%) in group b needed rescue drugs. eighty-four percent of group a and 76% of group b had complete pain relief at the end of 3 h including patients who received rescue drugs (p = .25). decrease in pain by each scoring method was also comparable (p = .75). no significant adverse effects noticed in both groups. the duration of pain before presentation seems to make a difference. table 3 shows that both groups did not have any significant difference in degree of pain irrespective of the difference in the duration of pain in advance, however patients with longer duration of pain before presentation had better pain relief with diclofenac intramuscularly when compared to piroxicam sublingually. between two groups it took 261 minutes on average for people with renal colic to seek medical attention. comparison of patient reported pain score and the physicians’ record of pain by fgs is shown in the figure 3. even though physicians’ assessment closely follows the patient reported score, it tends to underscore albeit not statistically significant, and supporting the use of standardized and validated patient reported scales unless this can be further studied. multiple regression analysis was done to find any relation between severity of pain and other factors i.e. age, sex, correlation between prior duration of pain and pain on visit: • group a, r = -0.166; t value = 1.17; p = .249 • group b, r = -0.235; t value = 1.68; p = .1 correlation between prior duration of pain and pain after 1 h: • group a, r = -0.353; t value = 2.61; p = .012 • group b, r = -0.127; t value = 0.89; p = .378 table 3. correlation between prior duration of pain and pain relief. diclofenac and piroxicam in management of renal colic-kandaswamy et al. figure 2. the 3 different pain scoring scales used in the study. abbreviations: vas, visual analog scale; fgs, facial grimace scale. figure 1. study flowchart. abbreviations: nsaids, non-steroidal anti-inflammatory drugs; ct, computed tomography; us, ultrasonography; uti, urinary tract infection. vol 12. no 02 march-april 2015 2071 bmi, previous illness, presence of red blood cell (rbc) in urine, type of pain relief received (diclofenac or piroxicam) and site of calculus. after adjusting for other variables only age was found to be positively correlated with severity of pain (r = 0.32). it was statistically significant (p = .001). however it could explain only 9% of the variance (adjusted r2 = 0.09). the final regression model provided by the stepwise regression is the linear equation: pain score = 5.41 + 0.05 × age there was no multicollinearity in r (tolerance = 1.0). this meant that older patients presented with more severe pain and also showed better pain relief. another analysis was done to find any relation between decrease in pain score at different intervals and other factors i.e. age, sex, bmi, previous illness, urine rbc, type of pain relief received (diclofenac or piroxicam) and site of calculus. after adjusting for other variables only bmi was found to be negatively correlated with decrease in pain score after 30 min (r = .24). it was statistically significant (p = .015). however it could explain only 5% of the variance (adjusted r2 = 0.05). the final regression model provided by the stepwise regression is the linear equation: decrease in pain score = 6.4 – 0.124 × bmi there was no multicollinearity in r (tolerance = 1.0). this means that patients with larger bmi had lesser pain relief at 30 min but at 60 min and later they matched that of patients with lesser bmi. the drugs given in the study are standard doses and not weight adjusted. whether it is due to fewer doses per unit body volume or delay in absorption or distribution remains to be elucidated. for instance in diclofenac arm if part of the drug is injected subcutaneously due to thicker fat layer might contribute to any delay in pain relief. discussion different group of drugs have been studied and reported for the use of pain relief in acute renal colic. opioids have remained the mainstay of treatment of acute renal colics until the turn of the century, but with significant side effects such as nausea, vomiting, constipation and drowsiness. in addition larger doses can cause respiratory depression and hypotension. however in vitro studies comparing it with nsaids regarding ureteric tone and pressure changes showed conflicting results for opioids which generally produced increased or no ureteric activity and favoring nsaids which produced abrupt inhibition. (2) nsaids is still the first line drug recommended and used widely. analgesia can be provided by oral, parenteral or rectal nsaids; these can be given to treat an acute exacerbation of pain or more regularly to provide background analgesia.(3) nsaids enjoys grade a recommendation by the european association of urology (eau) panel while national institute for health and care excellence (nice) in uk specifically recommends diclofenac 75 mg intramuscular as first line medication.(4,5) even though few studies proved that 50 mg of diclofenac given three times a day has no morphine sparing effect, it is still the first drug of choice.(6) many nsaids are available; the main differences between them are the incidence and type of adverse events, predominantly gastric irritation and ulceration. selective inhibition of cyclooxygenase-2 (cox)-2 improves gastrointestinal tolerance but still has a detrimental effect on renal and cardiac function in those with pre-existing disease. typically, cox-2 is up regulated locally in response to an inflammatory stimulus, and therefore drugs able to selectively inhibit cox-2 should limit their effects to the affected area. although selective cox-2 inhibitor reduces ureteric contractility as effectively as non-selective cox-2 inhibitor in vitro, its efficacy in treating renal colic remains to be elucidated,(7) and since they are orally administered they have a delayed onset of action. there are two studies where piroxicam has been investigated as an alternative to intramuscular diclofenac and it was known to be effective and comparable in both intramuscular and sublingual route in both the studies.(8,9) this study has also confirmed the efficacy of piroxicam in sublingual form. sublingual route will bypass liver metabolism and helps attaining early therapeutic blood levels. even though present study is not a longitudinal or a population-based study, the small cohort of 100 patients in this study gives some interesting observations about the pattern of acute renal colics and its management. this study has also thrown few insights into stone colic presentation in southern india. even though there are widespread reports and estimates that stone disease in females are increasing, if not matching men, in the study cohort, the incidence of acute renal colic, is 4 times more common in men than women. the role of obesity in urolithiasis is inconclusive. epidemiologic studies have shown that the incident of stone risk, increases with increasing bmi, and no further increase in risk is noticed when the bmi > 30 kg/m2.(10) kadlec and colleagues concluded in their study of 590 patients that obesity has little effect on stone composition until a very high (> 40 kg/m2) bmi is reached.(11) obesity seems be a risk factor for urolithiasis but the mean bmi in the study group is within the normal range. it either means bmi is not a significant factor in indian stone formers or at least it is not predictive factor for acute renal colic in indian men. however increasing bmi seems to affect initial pain relief in this study population. acute renal colic seems to affect both sides almost equally with no preference to any particular side. while there is no side predilection in the study cohort, there is definitely a site predilection. we showed that 35% of acute renal colics are due stones lodged in ureterovesical junction, while another 25% of acute renal colics are due to lower ureteral stones. while it is known that acute renal colic causes severe pain, there is paucity of studies documenting this in a measurable scale. in this study the figure 3. comparison of patient reported and physician recorded pain scores. abbreviation: vas, visual analog scale. diclofenac and piroxicam in management of renal colic-kandaswamy et al. endourology and stone disease 2072 vol 12. no 02 march-april 2015 1995vol 12. no 02 march-april 2015 2073 average vas core is just above 7 out of a scale of 0 to 10, where ten being the maximum pain patient is aware of and zero being no pain. we did not actually find any difference in severity of pain between men and women or the laterality of stone. but patients who had acute renal colics and stones in the past seem to present earlier. almost all patients who have recorded a pain score of 4 and 5 on the numeric scale have had stones and renal colics in the past and had presented earlier this time. an even more interesting finding is that, because of their early presentation and intervention, none of these patients needed rescue drugs. their pain scores became zero in 30 min in most of them and none had any pain at one hour. in the era of proms (patient reported outcome measures), the physicians recording of patients pain (pertaining to pain recording) still closely parallels patients own recording, albeit marginally underscored. this can have practical implications. some patients find it annoying when questioned about the scale of pain, as was observed in this study as well, and any compassionate healthcare personnel can clearly understand the physical suffering of a patient. a good relevance for this study lies in the fact that many patients present late as seen in table 1, sometimes as late as 12 h. the delay is not due low severity of pain in most of these patients. patients take an average of 4-5 h overall to seek medical help and in the study scenario it is due to factors like, distance from hospital, arranging travel, cover for work, family and etc. considering the last two observations i.e. early intervention relieves pain quicker with no need for rescue drugs and multiple factors causing delay for medical attention, a case for using sublingual piroxicam as a patient initiated management for acute renal colic, at least in known stone formers can be made. the morbidity of intramuscular diclofenac is not very well documented and is in fact under reported. the peak serum concentration is seen in 2-4 h with both diclofenac and piroxicam, but the latter has a half-life of about 45-50 h against 1-2 h of the former. so whether piroxicam can provide pain free episodes over a longer duration, in addition to relieving acute pain remains to be evaluated. we do acknowledge certain limitations of the study. the size of the stones was not recorded and quite a lot of patients were excluded before randomization itself as per the criteria. the power of the study was calculated retrospectively but given a good sample size it remains at 99%. we also did not do any subgroup analysis, however that was not the original objectives of the study. conclusion acute renal colics still seem to be affecting men more commonly and early treatment seems to improve pain faster. sublingual piroxicam is as effective as intramuscular diclofenac. it has the advantage of ease of self-administration and overcomes the morbidity and time delay in getting access to intramuscular diclofenac. it could be considered for self-start pain relief treatment in known stone former patients with no contraindications. this study strengthens evidence supporting the use of sublingual piroxicam in acute renal colics. conflict of interest none declared. references 1. abbagani s, gundimeda sd, varre s, ponnala d, mundluru hp. kidney stone disease: etiology and evaluation. ijabpt. 2010;1:17582. 2. lennon gm, bourke j, ryan pc, fitzpatrick jm. pharmacological options for the treatment of acute ureteric colic. br j urol. 1993;71:401-7. 3. whitfield hn. the management of ureteric stones. part ii: therapy. bju int. 1999;84:91621. 4. holdgate a, pollock t. nonsteroidal antiinflammatory drugs (nsaids) versus opioids for acute renal colic. cochrane database syst rev. 2004;cd004137. 5. türk c, knoll t, petrik a, sarica k, straub m, skolarikos a, seitz c. guidelines on urolithiasis. arnhem, the netherlands: european association of urology (eau); 2014. 6. engeler ds, ackermann dk, osterwalder jj, keel a, schmid hp. a double blind, placebo controlled comparison of the morphine sparing effect of oral rofecoxib and diclofenac for acute renal colic. j urol. 2005;174:933-6 7. nakada sy, jerde tj, bjorling de, saban r. selective cyclooxygenase inhibitors reduce ureteral contraction in vitro: a better alternative for renal colic? j urol. 2000;163:607-12. 8. supervía a, pedro-botet j, nogués x, et al. piroxicam fast-dissolving dosage form vs. diclofenac sodium in the treatment of acute renal colic: a double blind controlled trial. br j urol. 1998;81:27-30. 9. al-waili ns, saloom ky. intramuscular piroxicam versus intramuscular diclofenac sodium in the treatment of acute renal colic: double-blind study. eur j med res. 1999;4:236. 10. ahmed mh, ahmed ht, khalil aa. renal stone disease and obesity: what is important for urologists and nephrologists? ren fail. 2012;34:1348-54. 11. kadlec ao, greco k, fridirici zc, hart st, vellos t, turk tm. metabolic syndrome and urinary stone composition: what factors matter most? urology. 2012;80:805-10. diclofenac and piroxicam in management of renal colic-kandaswamy et al. pictorial urology 232 urology journal vol 5 no 4 autumn 2008 retroperitoneal ganglioneuroma urol j. 2008;5:232. www.uj.unrc.ir a 45-year-old man was diagnosed with retroperitoneal ganglioneuroma. the tumor was a large encapsulated mass of firm consistency with a homogeneous, solid, grayish white-cut surface, having a focally edematous appearance (figures, top). microscopically, the overall appearance of ganglioneuroma resembled that of a neurofibroma (it is designated as a schwannian steroma-dominant tumor) except for the presence of numerous collections of abnormal but fully mature ganglion cells, often with more than one nucleus (figures, bottom). neuroblastic tumors constitute 4 basic morphologic categories: neuroblastoma; ganglioneuroblastoma, intermixed; ganglioneuroma; and ganglioneuroblastoma, nodular.(1) ganglioneuromas are fully differentiated and invariably benign, mostly seen in the elderly. they can be multiple and/or associated with other independent types of neural/neuroendocrine neoplasms. their most common location is the posterior mediastinum and the retroperitoneum. although catecholamine synthesis is an almost constant feature of all the neurogenic tumors, ganglioneuromas rarely lead to symptoms.(1) thorough microscopic examination is crucial; areas of different colors or consistency are particularly suspicious for harboring less differentiated foci, namely ganglioneuroblastoma. if there is a minor component of scattered collections of differentiating neuroblasts and/or maturing ganglion cells, the tumor is named maturing subtype,(2) which blends with the intermixed subtype of ganglioneuroblastoma, from which it differs in that the immature foci do not form distinct microscopic nests. exceptionally, the schwann cell component of the ganglioneuroma may show features of a malignant nerve sheath tumor.(3) samad zare, mahmood parvin, seyed mohammad ghohestani departments of urology and pathology, shahid labbafinejad medical center, shahid beheshti university (mc), tehran, iran e-mail: drzaree@yahoo.com references 1. shimada h, ambros im, dehner lp, hata j, joshi vv, roald b. terminology and morphologic criteria of neuroblastic tumors: recommendations by the international neuroblastoma pathology committee. cancer. 1999;86:349-63. 2. umehara s, nakagawa a, matthay kk, et al. histopathology defines prognostic subsets of ganglioneuroblastoma, nodular. cancer. 2000;89:1150-61. 3. geoerger b, hero b, harms d, grebe j, scheidhauer k, berthold f. metabolic activity and clinical features of primary ganglioneuromas. cancer. 2001;91:1905-13. epidemiologic study of 284 patients with urogenital trauma in three trauma center in tehran salimi j, nikoobakht mr, zareei mr trauma and surgery research center, sina hospital, tehran university of medical sciences, tehran, iran abstract purpose: to perform an epidemiologic study of urogenital injuries in traumatic patients who were referred to three traumatic centers in tehran during one year. materials and methods: this study included a part of data of national trauma registries, which was performed within one year. questionnaires were completed by trained staff in three different geographical regions of tehran: shohada-e-tajrish hospital (north of tehran), sina hospital (south of tehran), and shaheed faiazbakhsh (west of tehran). results: two hundred and eighty four (5%) out of 57367 patients who were referred to the above mentioned centers had genitourinary trauma, of whom, 145(42%) were hospitalized. males with a frequency of 92% (258 patients) were the most injured group. patients mean age was 25±14 years, mostly between 20 and 29 years (33.6%) followed by 10-19 years age group with a frequency of 25.6%. non-penetrating trauma with a frequency of 96% was the most common type and accident was the most mechanism of trauma. one hundred and one patients out of the studied population had associated injuries. the most frequent injuries were occurred in extremities (40%) and the less in head and neck (7%). there were 22 (21.7%) intra-abdominal organ injuries. sixty nine percent of patients developed mild injury (iss<7), 20% developed severe injury and (iss>12), and 4.2% of patients died. the most common injured organ was kidney (3.3%) and the least one was ureter, as no ureteral injury was reported. conclusion: although a low percentage of traumatic patients develop urogenital injuries, disregarding these injuries may lead to serious complications and it is recommended to consider these injuries while dealing with such patients. considering the fact that these complications which could be preventable, are mostly developed in the youth, making solution for such problem is recommended. key words: urogenital system trauma, epidemiology, tehran, injury severity 47 urology journal unrc/iua vol. 2, 47-50 spring 2004 printed in iran introduction trauma is considered as the main reason for mortality in the ages between 1 and 44 years in the united states, and some believe that it is the first reason of mortality for this age group worldwide. the rate of injuries leading to disability is 2.5 times as many as the mortality caused by trauma.(1) urogenital system injuries are seen in 10% of traumatic patients and mostly in patients with multiple trauma and severe trauma of lower parts of abdomen or pelvis. the prevalence of uretrogenital injuries has been reported between 10 and 30% in adults and less than 3% in children.(1) blunt trauma is the cause of more than 90% of such injuries(2,3) and damages caused by sports and accidents are among common causes of such injuries. penetrating trauma caused by knife and gunshut comprises the highest percentage of injuries factors.(3) renal injury is the most common injury in uretrogenital system. renal trauma in traumatic patients who were referred to hospital comprises 3% and is detected in 8-10% of patients with accepted for publication in august 2003 epidemiologic study of 284 patients with urogenital trauma in three trauma center in tehran abdominal trauma.(4) ninety percent of renal injuries are due to blunt trauma. accidents, falling and being hit are the most frequent of non-penetrating injuries, whereas bullet and stab wounds are the most common cause for penetrating injuries.(5) there is no need for surgical exploration in 80% of blunt trauma; while, penetrating trauma mostly needs surgery.(5,6) etiologically, most ureteral injuries are caused by penetrating trauma which are mostly resulted from stab wound or gunshot.(5,6,7) bladder injuries are rarely caused by trauma and mostly developed by pelvic fracture. in 5-10% of pelvic fractures, urinary tract injuries are seen.(8) although such traumas are not mostly life threatening, they can lead to sexual dysfunction or urinary tract disorders; surely, the study of these organs has a great importance, when patient's vital signs are unstable.(2,3) at the evaluation of patients with multiple traumas, the probability of urogenital injuries should be considered in all cases, so that they could be detected at early stages.(5) in this article the frequency of urogenital injuries and their etiologies were studied in three medical centers. materials and methods the data of this article are based on the approved national proposal of demographic study and evaluation of injury severity in traumatic patients according to iss (injury severity score) and general success rate of medical measures which were carried out multicenterally at tehran. this prospective cross-sectional study was performed at three medical centers: shohada-etajrish, sina, and faiazbakhsh hospitals in 1996 in accordance with trauma and registry of american college of surgeons (tracs) and national trauma data bank (ntdb). the reason for choosing these three centers was the pattern of patients referral in tehran, as patients at the north of tehran are referred to shohada-e-tajrish hospital, at the south are referred to sina hospital and at the west are referred to faiazbakhsh hospital. data collection was carried out according to a designed questionnaire form and by trained physicians who filled in the forms of whole referred traumatic patients to the above mentioned centers, 24 hours a day. direct observation and interview were the method of data collection. the trained physicians became familiar with data collection process during several sections. a total of 57367 patients were referred to these centers within one year, 4497 of whom were hospitalized. those traumatic patients whose urogenital injury was detected by paraclinical investigations and physical examinations, were enrolled in this study and those whose urogenital injury was not proved definitely, were excluded from the study. finally, 284(5%) patients with urogenital injury entered the study. the collected data included demographic characteristics, trauma mechanism, type of injury, severity of injury and associated injuries. these data were collected in a designed data bank and were analysed with spss 10.01. t test was used to compare the means of constant quantitative variables and chi-square test or fisher's exact test were used to compare qualitative variables. results from a total of 57363 traumatic patients who were referred to the above mentioned hospitals, 4497(7%) patients were hospitalized and 52780(93%) were followed outpatiently. genital injury was seen in 284(5%) patients, 125(44%) of whom were hospitalized, which consisted of 2.8% of the total hospitalized traumatic patients. two hundred sixty one (92%) patients were males and 23(8%) were females (p<0.01). patients mean age was 25±14 years. the highest incidence (33.6%) was seen in 20-29 years age group followed by 25.6% in 10-19 age group and 13.4% in 30-39 age group (fig. 1). the frequency of blunt trauma was 96% and penetrating was 4%. non-penetrating trauma, the most common mechanism of trauma, was observed in 139 (48.9%) of cases, vehicle accidents in 75(26.5%) the most common of which were passenger accidents (39%), and falling from a high level in 39 (12.9%) (table 1). of the patients, 43.1% were injured of street and 25.4% at their work. (table 2). 48 fig. 1. the distribution of age group in the studied urogenital injured patients 0 20 40 60 80 100 10 20 30 40 50 60 70 age group f r e q u e n c y epidemiologic study of 284 patients with urogenital trauma in three trauma center in tehran mean iss was 7±3.1. mild injury (iss<7) was seen in 69%, moderate injury (712) in 20% of patients. one hundred and one (35.5%) patients had associated injuries, as well. extremities injuries were seen in 41(40%) patients, organs and abdominal viscera injuries in 22(21.7%), chest injury in 18(17.8%), vertebral column injury in 13(12.8%) and head injury in 7(6.9%). the cause of injury was accident in 84(29.6%) patients and conflict and hitting others in 51(81%) (fig. 2). renal traumas was reported in 94(33%) of patients, scrotal trauma in 91(32%) and urethral trauma in 16(5.6%), 2 of whom developed complete urethral rupture (table 3). twelve (4.2%) patients died (iss>r) in whom renal injury was the most common genital injury, reported in 7(40%). discussion according to the obtained results from this study, urogenital injuries develop in a little portion of traumatic patients. this is similar to the findings of other studies. the considering point is that 20-30 years age group was the most common age group was the most common age group included in this study, may be because of trauma pattern which mostly affects the youth, though no difference is seen in the outcome of disease. however, since these injuries may lead to urogenital dysfunction, neglecting them could cause serious sequelae.(2) regarding gender, males were enrolled 11 times more than females in this study which might be because of socio-cultural condition of the patients, as females mostly spend their time at home. statistically, the rate of mortality and temporary disability in the studied patients in different age groups was not statistically different. trauma was blunt in 96% of patients which is almost similar to other studies;(3,4) moreover, kidney was the most common injured organ. according to the type of trauma in renal and scrotal injuries, there was a significant difference between injured organs and the reason of trauma, injuries were mostly caused by blunt trauma (p<0.05). moreover, ureteral injuries were the less 49 table 1. the distribution of frequency of trauma mechanism in the studied patients with urogenital injuries trauma mechanism no. percentage accident falling from high level non-penetrating objects penetrating objects bullet others 75 36 139 10 1 20 26.5 13.8 48.9 3.5 0.4 7 total 284 100 fig. 2. the distribution of frequency of urogenital injury according to the cause of accident in the studied traumatic patients 0 5 10 15 20 25 30 kidney scrotum bladder urethra uterus testis penis others accident conflict type of injury cause of trauma n u m b e r table 2. the distribution of place of accident frequency according to the gender of the studied urogenital injured patients gender place of accident male frequency (%) female frequency (%) total frequency (%) home street place of work general places others 51(20.1%) 109(42.9%) 70(27.6%) 3(1.2%) 21(8.3%) 9(40.9%) 10(45.5%) -- -- 5(22.5%) 60(21.7%) 119(43.1%) 70(27.6%) 3(1.2%) 26(8.7%) total 254(100%) 24(100%) 278(100%) table 3. the distribution of urogenital injuries frequency in the studied traumatic patients place of injury frequency (%) renal injury renal contusion with hematuria subcapsular hematoma without laceration renal parenchymal laceration 94(33.1) 81 6 7 bladder injury contusion and hematoma bladder laceration 9(3.2) 3 6 scrotum contusion, scratching, superficial cutting vast rupture 91(32) 89 2 urethra contusion superficial injury without extravasation superficial rupture with extravasation complete rapture of urethra 16(5.6) 10 2 2 2 testis 19(6.7) male genital organ contusion superficial laceration vast and deep laceration 26(9.2) 14 6 6 female genital organ 5(1.8) others 24(8.5) total 284(100) epidemiologic study of 284 patients with urogenital trauma in three trauma center in tehran common injuries caused by blunt traumas, this was similar to foreign studies results (5,6). injury of external genitalia in scrotum had a considerable incidence and there was a significant difference between accident and hitting others according to the reason of trauma (p<0.05). due to unavailability of gunshot and heavy punishment for illegal use of them, penetrating injury rate is low and gunshot consists of the lowest mechanism of trauma. only 20% of patients developed severe injury (iss>12), low percentage out of whom needed surgical exploration, this finding was similar to the findings of other studies.(5,6) conclusion although according to the conclusion of our and other studies, urogenital injuries comprise a low percentage of injuries of traumatic patients, disregarding these injuries may lead to serious complications and it is recommended to consider these injuries while dealing with such patients. in regard to the fact that these complications are mostly developed in youth and they could be preventable, making solution for this problem is recommended. references 1. mc aninch jw. genitourinary trauma. world urol 1999 17: 95-96. 2. dreitlein aa, snner s, basler j. genitourinary trauma. emery med clin north am 2001 19(3): 599-90. 3. mattox kl, feliciano dv. trauma. 4th ed. new york: mcgraw-hill; 2000. p. 839-580. 4. peterson ne. gurrent management of acut renal trauma. urology annual 1991; 151-179. 5. palmer ls, rosenbaum rr, gershbaum md. penetrating ureteral trauma at an urban trauma center. urology 1999 54(1): 34-36. 6. siemer s, russ f, mutschler w, zwergel t. injuries of the urinary system and management in multiple trauma cases. urology 1997 36(6): 513-22. 7. dobrowolski z, kusionowicz j, derwniak t. renal and ureteric trauma: diagnosis and management in poland. bju int 2002 89:748-751. 8. walsh pc, et al. genitourinary trauma. in: campbell's urology.8th ed. new york: saunders; 2002. p. 3707-3732. 50 transcutaneous ultrasound guided nephrolithotomy: the first report from iran etemadian m, amjadi m, simforoosh n department of urology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: to evaluate the safety and efficacy of transcutaneous ultrasound guided nephrolithotomy. materials and methods: from december 1999 to december 2000, 12 patients with renal stone were selected for pcnl. six patients had failed eswl and the remainder had multiple and large stones in pelvis and lower calyx. ultrasonography was used in 11 patients during the entrance to the system and dilatation of the tract. entrance to the system was impossible in one case for which open surgery with dorsal lumbotomy was performed. results: the stone was removed by just one session of pcnl in 8 and the residual stone was less than 1 cm in the 3 other cases. repeated pcnl from the same tract was performed in one case and eswl was carried out in the other 2 cases. after three months, all of the 11 patients were stone free. conclusion: it seems that ultrasonography could replace fluoroscopy in patients with dilated collective urinary system and a single large stone in calyx or pelvis. key words: percutaneous nephrolithotomy, ultrasonography, renal stone 19 urology journal unrc/iua vol. 2, 19-21 spring 2004 printed in iran introduction despite its short age, the scope of endourology has been widened and its success rate has increased by medical engineering.(1) the development of imaging was essential in the progression of endourology as the innovation and progression of pcnl was impossible without fluoroscopy.(2) the use of fluoroscopy to enter collective system and dilatation could expose patients and physicians to x-ray irradiation. since endourologists are highly exposed to x-ray irradiation during endourologic surgeries, the use of alternative methods for the entrance into collective system and dilatation of tract could be safe and less expensive. ultrasonography is one of the substitutional methods.(2-5) in this study 12 patients with renal stone underwent pcnl by the use of ultrasonography. materials and methods from december 1999 to december 2000, 12 patients with renal stone were selected for pcnl. routine blood and urine tests were carried out and medical conditions were studied. patients were enrolled in pcnl if normal tests and negative urine culture were achieved. cystoscopy was carried out under general anesthesia and a 5 f ureteral catheter was inserted into the kidney. patients were positioned prone and then appropriate position for pcnl. thirty to 60 ml (based on the dilation of collective system) normal saline was infused into the kidney through ureteral catheter. thus, a complete dilatation of collective urinary system was performed. then, by using ultrasonography and the observation of dilated system at the stone site, the tract and the site of needle entrance was detected after which the needle was inserted into the system by ultrasonography. then a 0.038 inches guide wire was inserted into the kidney, the needle was removed, and the exact distance between the skin and the accepted for publication in may 2002 transcutaneous ultrasound guided nephrolithotomy: the first report from iran system was measured. the tract was dilated by elastic semirgid dilatators to 12 f and then, by telescopic metallic dilatators to 27 f, using ruler and accurate measurement of tract. during dilatation, besides the measurement and ultrasonographic control of dilatators, normal saline was always infused, so that it should have been drawn from around the dilatators. thus, the surgeon could assure the insertion of dilatators in the urinary system. next, a 28 f amplatz sheet was placed by which nephroscopy was performed and the observed stone was fragmented by lithoclast and extracted by forceps. by the end of surgery, the kidney was irrigated and a 24 f nephrostomy was placed and fixed to the skin and clamped for 4 hours. kub was conducted 24 hours later for control and if there was no residual stone, nephrostomy catheter would be removed 48 to 72 hours later and ureteral catheter would be removed 1 to 3 days after the removal of nephrostomy tube if there was no leakage from the site of nephrostomy. finally, the patient would be discharged. in the presence of any urine leakage ureteral catheter would be preserved until the complete stop of leakage. results twelve patients (8 males and 4 females) with a mean age of 39 (range 11 to 67) years were selected for this study. the stone location was the right kidney in 4 patients and the left kidney in 8. the reasons for performing pcnl were: a large pelvic stone associated with a lower calyx stone in 3 cases, 2 pelvic stones in 2 cases, and obstructive stone in upj in one. six patients had a pelvic stone sized more than 2 cm with failed eswl (table 1). puncture of system was easily performed in 11 cases and entrance into the system was impossible in one case for which dorsal lumbotomy was carried out in prone position and the stone was removed by nephrotomy, following pcnl, a residue of less than 1 cm was present in 3 patients which was removed by repeated pcnl using the same tract in one case and by eswl in 2. no stone was seen in the control kub taken 3 months postoperatively in all of the patients. mean duration of the patients' hospitalization was 4 (range 2 to 6) days. no blood transfusion was needed and no visceral, vascular, pleural injury, or long term urinary leakage was seen. discussion as a world wide and regional common disease, urinary stones are one of the recurrent diseases and if we consider surgery as its solely possible treatment, it will lead to limitations in treatment and may practically cause serious risks during multiplied surgeries. researchers have tried to introduce more noninvasive methods consisting of endoscopic methods to prevent such risks and ease urinary stones treatment.(1) the first percutaneous nephrostomy for stone removal was performed by fernstom and johannson in 1976. in 1981, alke et al from germany and in 1983, wiekham et al from england extracted the stones percutaneously.(1,5,6) to date, pcnl is considered as a routine technique in treating upper urinary tract stones in most urologic clinics. fluoroscopy is required for pcnl. long-term xray exposure may cause deleterious effects for both patient and physician. to decrease irradiation, in addition to taking some general interventions, many instruments were also developed. using c-arm fluoroscopies in which radiation producing tube is located under the bed, leads to the reduction of received radiation by 40 times for physician and by 150 times for patient.(7) ultrasonography could be of help in collective system puncture,(3,4,5,7) which is easily practical in dilated systems.(4,5) however, dilatation needs more accuracy and it is preferable to be conducted by fluoroscopy guidance and contrast media. dilatation could also be performed under ultrasonography direction, by using accurate measurement of the distance between the skin and the collective system. in this study normal saline was frequently injected through ureteral catheter to produce hydronephrosis, prevent collapse of system and facilitate dilatation. the leakage of fluid around metallic dilatators indicated the right tract. the accession of system and dilatation of tract was carried out with no particular problem in 11 patients. the entrance to the system was impossible in one; thus, the patient underwent dorsal lumbotomy in prone position. no loss of tract or unusual hemorrhage was occurred in our patients. 20 cases no. pelvic and calyx stones 3 multiple pelvic stones 2 upj stone 1 failed eswl 6 table 1. the reasons for performing pcnl transcutaneous ultrasound guided nephrolithotomy: the first report from iran no large vessels or visceral injury was observed. the use of ultrasonography prevents the exposure of patient and physician to x-ray. however, performing pcnl by the guidance of ultrasonography needs more attention and experience and the surgeon should be familiar with the ultrasonographic anatomy of kidney. in the cases that the system is not dilated or the pelvis is intra-sinus and there are multiple calices, the use of ultrasonography may practically lead to incorrect tract or unusual hemorrhage. in such cases it is preferable to apply an ultrasonographic prob which has an opening on it for the entrance to system; otherwise, fluorscopy should be used. in general, for dilated systems which have relatively large pelvic stone and not so many calices, the use of this method is more appropriate and less expensive. since endourologic beds are so expensive and it is impossible to use them in all urologic centers, it seems that those who are completely familiar with pcnl could perform it by the use of ultrasonography in which there is no need for endourologic beds. eight out of 11 patients became stone-free by just one session of pcnl. repeated pcnl was performed in 1 and eswl was carried out in 2. three months later, all of the patients were stone-free. hydronephrosis facilitates the observation of collective system and ultimately eases its availability via ultrasonography. more care should be taken in choosing patients for ultrasonographic pcnl. sever hydronephrosis, few calices, and single and large pelvic stone could increase success rate and facilitate the accessibility of stone and tract dilatation. those kidneys with multiple major and minor calices in collective system, intra-sinus pelvis, and mild hydronephrosis are not good candidates for ultrasonographic pcnl. conclusion in some selected cases (dilated systems and single pelvic stones) classic pcnl could be replaced by ultrasonographic pcnl for reducing the physician and patient exposure to x-ray and avoiding the need to endourology beds. a large stone in a relatively dilated pelvis is the best case for ultrasonographic pcnl. other stone cases could be treated by this method as well, but with less success rate. experienced physician, accurate system entrance, and right tract dilatation are needed for ultrasonographic pcnl. references 1. basiri a, et al. endourology till now. iranian journal of urology 1994; 1: 3-18. 2. clayman rv. endouorology of the upper urinary tract. in: walsh pc, retik ab. campbell's urology. 7th ed. wb saunders; 1998. p. 2789-2790. 3. grasso m. techniques for percutaneous renal access. in: sosa re. textbook of endourology. 1st ed. wb saunders; 1997. p. 101-102. 4. korth k. percutaneous surgery of kidney stones. 1st ed. berlin: springe verlay; 1984. p. 25-27. 5. trade t, hatzinger m, rassweiler j. ultrasound in endourology. j endourol 2000; 15:3-15. 6. darabi mr, kianian hr. the treatment of kidney stones by pcnl. iranian journal of urology 1987; 4(15-16): 2737. 7. clayman rv. endourology of the upper urinary tract. in: walsh pc, retik ab. campbell's urology. 7th ed. wb saunders; 1998. p. 2794-2796. 21 editorial comment editorial comment to: prostate cancer antigen 3 gene expression in peripheral blood and urine sediments from prostate cancer and benign prostatic hyperplasia patients versus healthy individuals i read with great interest the manuscript entitled “prostate cancer antigen 3 gene expression in peripheral blood and urine sediments from prostate cancer and benign prostatic hyperplasia patients versus healthy individuals”. this manuscript has some important shortcoming and drawbacks which should be clarified for readers. i summarize them, otherwise it take lots of thorough notes. 1. the most important one is study sample size. the authors have acknowledged this issue, but the study sample size is very small to draw any conclusion. the minimum requirement sample size for gene expression study is 150.(1) in present study the total number of patients with prostate cancer (pca) is 24. even this number of patients has been categorized into five subgroups, which made the obtained results totally questionable. factors that affect power and sample size calculations include variability of the population, the desired detectable differences, the power to detect the differences and an acceptable error rate. calculating of sample size and reporting the study power are mandatory in each gene expression study. (see: http://www.cscu.cornell.edu/news/statnews/stnews41.pdf). usually we are interested in calculating the sample size needed to have the effect size (or odds ratio) in the range of 1.5-2.0 with at least 80 percent power under a dominance model. quanto can compute the required sample size. the following link has an example to see how quanto works. http://www.cscu.cornell.edu/news/statnews/stnews71quantoexample.pdf 2. the study lacks of even scientific short literature review. there are some nationwide studies regarding the prevalence of pca in iranian men.(2,3) none of them has been cited in present study. relying only for two congress abstracts(4,5) is not acceptable in scientific era. the authors claimed that, the incidence of pca has been increased in iran during last decade. there is no reference for this statement. indeed according to the two nationwide population based studies(2,3) the incidence of pca in iran is much lower than that in europe and america and even some asian countries. 3. the cancer gene expression study should comply with standards. the most important one is “strengthening the reporting of genetic association studies (strega)". none of the criteria which have mentioned in strega recommendation has been addressed in present paper. the scientific background and rationale for the investigation is not clear. the issue of prostate cancer gene 3 (pca3) expression in prostatic diseases and in normal individuals already has been studied in more than one hundred scientific papers with large sample sizes.(6-10) i don’t know which new data has been added to the literature by this paper. 4. classic statistical issues such as appropriate, study sample size, replicate structure, statistical significance and outlier determination are important issues in the planning and analysis of gene expression studies. the authors claimed that, 95% confidence interval (ci) has been calculated. but, indeed there is any 95% ci reported in this manuscript. an analysis solely based on fold change does not allow the assessment of significance of expression differences in the presenceof biological and experimental variation, which may differ from gene to gene. this is the main reason for using statistical tests to assess differential expression. generally, one might look at various properties of the distributions of a gene’s expression levels under different conditions. the authors mentioned that, relying the results of this study, may omit the necessity of prostate biopsy for detecting pca. i think this recommendation is absolutely impractical. up to now the expression and frequencies of more than 100 genes have been studied regarding pca.(11-17) but none of them can be replaced by prostate biopsy. i have a question. does a 60 years old men with serum psa level of 8 ng/ml, and negative pca3 gene expression need prostate biopsy or not? in addition a linear regression model should be used to adjust confounding factors such as age, body mass index, occupational status, educational level, smoking status and etc. all of them should put in a multiple regression analysis model. what is more important in gene association study is correlation between gene single nucleotide polymorphisms (snp) and related disease. regarding pca3, one should calculate pca3 scores. pca3 score is generated from the ratio of pca3 mrna level to prostate specific antigen (psa) mrna level, through which pca3 expression is normalized with the psa expression used as a housekeeping gene. presently, the first discovery of genetic determinants based on a genome-wide study for pca3, which has been performed by chen et al.(18) they included 1371 men in their study. "two snps, rs10993994 in β-microseminoprotein at 10q11.23 and rs10424878 in kallikrein-related peptidase 2 at 19q13.33, were associated with pca3 score at genome-wide significance level (p = 1.22 x 10-9 and 1.06 x 10-8, respectively). men carrying the rs10993994 “t” allele or rs10424878 “a” allele had higher pca3 score compared with men carrying rs10993994 “c” allele or rs10424878 mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specialized in urological and andrological genetics, tehran, iran. e mail: info@safarinejad.com vol 11. no 06 nov-dec 2014 1959 “g” allele (β = 1.25 and 1.24, respectively)." 5. rt-pcr methods can provide quantitative information regarding mrna expression levels, and individual gene identities can be detected. the major drawback is that it would be difficult for academic laboratories to automate, and there is always some uncertainty regarding the detection of each gene being investigated. high-throughput sequencing technology is rapidly becoming the standard method for measuring rna expression levels (aka rnaseq).(19) the results of present study should be interpreted very cautiously. genome-wide association studies (gwas) are needed to identify snps that are associated with the urine and blood levels of pca3. references 1. bashalkhanov s, pandey m, rajora op. a simple method for estimating genetic diver sity in large populations from finite sample sizes. bmc genet. 2009;10:84-9. 2. hosseini sy, moharramzadeh m, ghadian ar, hooshyar h, lashay ar, safarinejad mr. population-based screening for prostate cancer by measuring total serum prostate-sp ecific antigen in iran. int j urol. 2007;14:406 11. 3. safarinejad mr. population-based screening for prostate cancer by measuring free and to tal serum prostate-specific antigen in iran. ann oncol. 2006;17:1166-71. 4. fallah m. cancer incidence in five provinc es of iran ardebil, gilan, mazandaran, go lestan and kerman, 1996 – 2000. finland: university of tampere; 2007:23-25. 5. malekzadeh r, editor. incidences of different cancers in iran [persian]. the 16th internati onal congress of geographic; 2003; shiraz, iran. dec 1-4: medicine shiraz university of medical sciences. 6. drayton rm1, rehman i2, clarke r, et al. identification and diagnostic performance of a small rna within the pca3and bmcc1 gene locus that potentially targets mrna. cancer epidemiol biomarkers prev. 2014 nov 12. pii: cebp.0377.2014. [epub ahead of print] 7. wei jt1, feng z2, partin aw, et al. can uri nary pca3 supplement psa in the early de tection of prostate cancer? j clin oncol. 2014 nov 10. pii: jco.2013.52.8505. [epub ahead of print] 8. wang y, liu xj, yao xd. function of pca3 in prostate tissue and clinical research progr ess on developing a pca3 score. chin j can cer res. 2014;26:493-500. 9. vedder mm1, de bekker-grob ew2, lilja hg, et al. the added value of percentage of free to total prostate-specific antigen, pca3, and a kallikrein panel to the erspc risk calculator for prostate cancer in pres creened men. eur urol. 2014 aug 25. pii: s0302-2838(14)00753-2. doi: 10.1016/j. eur uro.2014.08.011. [epub ahead of print] 10. luo y, gou x1, huang p, mou c. the pca3 test for guiding repeat biopsy of prostate can cer and its cut-off score: a systematic review and meta-analysis. asian j androl. 2014;16:487-92. 11. safarinejad mr, safarinejad s, shafiei n, safarinejad s. g protein β3 subunit gene c825t polymorphism and its association with the presence and clinicopathological characteristics of prostate cancer. j urol. 2012;188:287-93. 12. safarinejad mr, safarinejad s, shafiei n, safarinejad s. effects of the t-786c, g894t, and intron 4 vntr (4a/b) polymorphisms of the endothelial nitric oxide synthase gene on the risk of prostate cancer. urol oncol. 2013;31:1132-40. 13. liu l, dong x. complex impacts of pi3k/ akt inhibitors to androgen receptor gene expression in prostate cancer cells. plos one. 2014;9:e108780. 14. safarinejad mr, safarinejad s, shafiei n, sa farinejad s. estrogen receptors alpha (rs2234693 and rs9340799), and beta (rs4986938 and rs1256049) genes polymor phism in prostate cancer: evidence for asso ciation with risk and histopathological tumor characteristics in iranian men. mol carcinog. 2012;51suppl 1:e104-17. 15. zazzeroni f, nicosia d, tessitore a, et al. kctd11 tumor suppressor gene expression is reduced in prostate adenocarcinoma. bio med res-int. 2014;2014:380398. 16. safarinejad mr, shafiei n, safarinejad s. relationship of insulin-like growth factor (igf) binding protein-3 (igfbp-3) gene pol ymorphism with the susceptibility to devel opment of prostate cancer and influence on serum le-vels of igf-i, and ig fbp-3. growth horm igf res. 2011;21:146-54. 17. goksel g, bilir a, uslu r, akbulut h, guv en u, oktem g. wnt1 gene expression alte rs in heterogeneous population of prostate cancer cells; decreased expression pattern observed in cd133+/cd44+ prostate cancer stem cell spheroids. jbuon. 2014;19:207 14. 18. chen z1, sun j, kim st, genome-wide as sociation study identifies genetic determin ants of urine pca3 levels in men. neoplasia. 2013;15:448-53. 19. mortazavi a, williams ba, mccue k, schaeffer l, wold b. mapping and quantify ing mammalian transcriptomes by rna-seq. nat methods. 2008;5:621-8. urological oncology 1960 pca3 gene expression in patients with pca and bph-moradi sardareh et al radical cystoprostatectomy in patients with behçet’s disease: the report of four cases and review of the literature introduction behçet's disease (bd) is a chronic, relapsing, multisystemic inflammatory disease that is character-ised by recurrent oral and genital ulceration with skin and ocular lesions. bd affects other areas of the body, including the joints, blood vessels, nervous system and gastrointestinal system(1). a bd diagnosis is based on clinical criteria, such as the criteria proposed by the international study group for bd and, more recently, the international team for the revision of the international criteria for bd(2,3). according to the relationship between malignancy and bd, fırat et al. found no difference in the incidences of malignancies in relation to bd compared to the incidences of malignancies in the normal population of turkey.(4) with regard to the association of bd with bladder cancer, there is only one reported case with a previous history of prolonged cyclophosphamide therapy(5). therefore, it is very difficult to determine whether or not bd is related to the pathogenesis of bladder cancer. also, the relationship of genitourinary cancer with bd is not yet known. there are only a few studies that refer to radical surgery in bd patients, and there is only one case report about radical cystoprostatectomy in a bd patient. therefore, it is still not well known whether or not pelvic surgery in patients with bd is safe. a radical cystoprostatectomy is a routine surgery performed in our clinic. in this paper, we present our experience with four bd patients who underwent a radical cystoprostatectomy with pelvic lymph node dissection. cases description four patients with bd who underwent a radical cystoprostatectomy with pelvic lymph node dissection were retrospectively examined. in our clinic, 457 radical cystoprostatectomies with pelvic lymph node dissection were performed between 2000 and 2015. all of the operations were performed by the same two senior surgeons. following protocol, each patient was held in the intensive care station for one or two days after the operation. the mean time for the occurrence of bd was 14 years (11-18 years). all patients (n = 4) were treated with colchicine after diagnosis until the time of operation. additionally, three of the patients took prednisolone for an interval of 2-5 years. none of the patients had a history of cyclophosphamide consumption, which is a known cause of bladder cancer. the mean age of the patients was 51.5 years. the first patient was a female consuming cholchicine intermittently until 4 months before surgery. clinical manifestations were oral aphthous stomatitis, genital ulcer, erythema nodosum and maculopustular lesions. the second and third patient were males who presented with oral ulcer, genital ulcer, arthritis and erythema nodosum as clinical manifestations of bd. the medical therapy with cholchicine and methylprednisolone was quitted approximately one year before surgery in the second patient and approximately three months before surgery in the third patient. the fourth patient presented with oral ulcer, genital ulcer and skin lesions. treatment with cholchicine and prednisolone was concluded two months before operation. none of the patients had indication or history for neurological, vascular and/or gastrointestinal manifestation of bd. three patients had a history of occupational exposure to carcinogens, and two of the patients had a history of tobacco smoking. no comorbidity, especially any affecting the cardiovascular system, or cardiovascular diseases were present in the patients. the asa score was 2 in all of the patients. none of the patients had a history of prior surgery and other systemic diseases. the routine preoperative evaluation included an abdominal computed tomography (ct). this pre-evaluation was done for all of the patients with invasive bladder cancer in our clinic. ct results revealed no signs of vascular dysfunction or any pathological indication in the vascular system caused by bd. further evaluation was not necessary. the perioperative and postoperative periods of the tur-b operations progressed uneventfully. the patients were referred to rheumatologists for rheumatologic approval. all of the patients were assessed for disease activity by evaluation of the erythrocyte sedimentation rate (esr), c-reactive protein (crp) and by clinical examination. none of the patients were in the active phase of bd. intravenous methylprednisolone therapy was started 72 hours before surgery and was continued until the seventh postoperative day, thereafter oral methylprednisolone therapy was started for two weeks. routine preoperative bowel preparation with a rectal enema was performed on both the night before and the morning of the opera1medicana international hospital istanbul. 2kolan international hospital, 3istanbul training and research hospital. *correspondence: kolan international hospital istanbul, kaptanpaşa mh. darülaceza cd. no:14, okmeydanı, şişli-istanbul, 34384, turkey. e mail: ozkaptanorkunt@gmail.com. received april 2016 & accepted september 2016 case report cuneyd sevinc1, orkunt özkaptan2*, muhsin balaban1, ugur yucetaş3, tahir karadeniz1 keywords: behçet’s disease; bladder cancer; ileal ischaemia; patch closure; radical cystoprostatectomy; vascular involvement. case report 2871 vol 13 no 05 september-october 2016 2872 tion. patient characteristics are listed in table 1. additionally, we determined our first 100 patients as the control group of this study and presented mortality rate, vascular and gastrointestinal complications of the control group in table 2. information about patient characteristics and complications was obtained retrospectively through chart review by medical doctors. the perioperative and postoperative processes of the four patients were as follows: the first patient was a 57-year-old female with an invasive tumour diagnosed during the patient’s initial tur-b operation (pt2g3). the perioperative period of the first operation was uneventful. the final pathology after a cystectomy was pt2g3n0 (n14/0). acute ischaemia occurred during preparation of an ileal conduit in this patient. this part of the ileum had to be re-anastomosed, and an ureterocutanostomic diversion had to be performed. total blood loss was 500 ml. the postoperative period was uneventful, and the patient was discharged after 11 days. the patient was admitted to our clinic because of urinary infection in the third month after the operation and stayed for four days. nephrological follow-up was suggested for the patient because of ascending creatinine levels after 48 months. the patient will be observed for 60 months after the operation. histopathological evaluation of the resected ileum was diagnosed as vasculitis. figure 1 shows gross pathologic and microscopic section specimens. the second patient was a 44-year-old male diagnosed with an invasive transitional cell carcinoma after the first tur-b operation. a radical cystoprostatectomy with a studer neobladder was performed. blood loss was 850 ml. the postoperative period was uneventful, except for prolonged lymph drainage caused by lymphocele and hypoalbuminemia. albumin replacement was done for the patient. the patient was discharged seventeen no age/gender bd medication duration of risk factor of cancer pathology complication diagnosis medication in years duration 1 57/female 13 cholchicine 13 shoe manufacture pt2g3n0 ileal ischemia 2 44/male 11 cholchicine/prednisolone 3 silver foundry pt3g3n3 no 3 53/male 18 cholchicine/prednisolone 5 aluminum production, pt2g3n1 common iliac smoking 36 packs/year ci̇s + arter 4 52/male 14 cholchicine/prednisolone 14 smoking 39 packs/year pt3g3n0 common iliac arter table 1. patients' characteristics mortality 4 cases age asa score 55 2 pulmonary embolism 62 2 septicaemia 81 3 heart failure 60 3 pulmonary embolism gastrointestinal complications 8 cases evisceration 2 subileus 4 ileal fistula 1 rectum injury 1 cardiovascular complications 7 cases external iliac injury 1 deep venous thrombosis 3 pulmonary embolism 2 heart failure 1 table 2. mortality rate, gastrointestinal and vascular complications of the first 100 patients (mean age: 60.7 years) who were operated in our clinic. figure 1. gross pathology specimen and microscopic section specimen radical cystectomy in behcet disease-sevinc et al. days after the operation. adjuvant chemotherapy with carboplatin/gemcitabine was administered after the operation. no complications related to bd were observed in this patient. this patient died after 12 months due to tumour progression. figure 1 shows gross pathologic specimen and microscopic specimen of this patient. the third patient was diagnosed with an invasive urothelial carcinoma (pt2g3) of the bladder after the first tur-b operation. this male patient underwent a radical cystectomy with an orthotopic neobladder. the right common iliac artery started to bleed spontaneously after lymph node removal. a cardiovascular surgery consultation was requested, and the arterial tear was repaired using a dacron patch. hypokalemia was determined in the first postoperative day and wound infection occurred in the third day. on the seventh postoperative day, spontaneous bleeding occurred from the drain. urgent operative intervention was carried out. acute bleeding was detected from the right common iliac artery and resulted in patient's death. the source of the bleeding was the injured segment of the iliac artery where the patch was placed. the patch was separated partially from the iliac artery. a pathological evaluation of the common iliac artery revealed an obliterative vasculitis of the vaso vasorum. for the fourth patient, a radical cystectomy with an ileal conduit was planned. the tur-b pathology of this patient was pt2g3. the final pathology was pt2g3n0. on the first postoperative day, hypotension and tachycardia were observed, requiring urgent operative intervention. cardiovascular surgeons were called for operation who used a dacron patch on the patient. afterwards, the patient was transferred to the intensive care station. ileus and evisceration occurred on the fifth postoperative day. subsequently, acute spontaneous bleeding occurred. the patient died during urgent operative intervention. the patch was separated from the common iliac artery. information about complications and the classification of postoperative complications with the clavien-dindo score is presented in table 3. discussion bd was described by hulusi behçet in 1937; its incidence is higher in the middle east, japan and mediterranean countries. currently, it is believed that the pathological basis of the disease is systemic vasculitis affecting both small and big vessels(6). both sexes are equally affected, but the syndrome is more severe in young men(7). the authors have reported an increased morbidity in bd patients compared to patients without bd(8). in contrast, cengiz et al. reported that the surgical treatment of malignancies in the presence of bd appeared to be safe(9). regarding the safety of radical cystoprostatectomy in bd patients, there is only one publication. baltacı et al. concluded that a radical cystoprostatectomy is safe in patients with bd(10). they presented the first case of sporadic bladder cancer with bd. this case was a grade 3 transitional cell carcinoma with perivesical invasion and lymph node metastasis (pt3bn1m0). the patient died 6 months after surgery due to tumour progression. gastrointestinal involvement of bd varies in different populations, and it is reported to be common in japan; however, the exact prevalence of gastrointestinal involvement in bd is still unknown. symptoms of gastrointestinal involvement include anorexia, vomiting, dyspepsia, diarrhoea and abdominal pain(11). the presence of gastrointestinal involvement in bd is not commonly accompanied by clinical symptoms. köklü et al. reported that only three out of nine patients with ileum ulcers complained of gastrointestinal symptoms. moreover, they diagnosed abnormal microscopic findings as vasculitis and ileitis in 23 patients without macroscopic findings. the findings of vasculitis and ileitis were significantly higher than in patients without bd. they concluded that ileal visualisation should be performed during colonoscopic examinations in clinical practices to document intestinal involvement(12). in our case where ileal ischaemia occurred, there was no visible sign of an ulcer or any other pathology during the preparation of the ileum. likewise, the patient did not complain about any gastrointestinal symptom before the surgery. the reason for acute ischaemia may have been the involvement of the arteries feeding the ileum. we came to the conclusion that the reason for ileal ischaemia was bd involvement; the patient had no other factors, such as cardiovascular disease or atherosclerosis, that could have predisposed the patient to ischaemia. further, the patient was not one of our first cases, so we can exclude inexperience as a probable factor for this complication. it is known that arteries can cause bleeding, infarction and limb ischaemic symptoms despite immunosuppressant or steroid medication(13). it should be noted that our patient was only consuming colchicine at the time of the operation and was not in case blood loss/ml transfusion units perioperative postoperative clavien-dindo duration of surgery/minutes complication complications classification score 90 < days 1 500 no ileal ischemia, urinary infection i 380 2 850 1 es/iu none prolonged lymph ii 350 drainage, hypoalbuminemia 3 2850 7 es/iu acute bleeding acute bleeding, v (death; acute bleeding) 440 wound infection, hypokalemia 4 3000 7 es/iu none acute bleeding v (death; acute bleeding) 410 table 3. perioperative and postoperative complications radical cystectomy in behcet disease-sevinc et al. case report 2873 vol 13 no 05 september-october 2016 2874 the active phase of bd. a colonoscopic evaluation and concomitant biopsy before surgery may be useful in these patients to predict gastrointestinal involvement and the probable risk for perioperative complications. regarding vascular manifestations in bd, arterial involvement and aneurysm formation are the most serious complications(13). the most common site of aneurysm formation is the aorta, followed by the pulmonary and femoral arteries(13). cigarette smoking is reported to be a possible risk factor for arterial disease in patients with bd(14). recent studies of patients confirm that males and patients with a younger age of disease onset are at a higher risk for vascular involvement(15). fatal complications may occur in patients with arterial involvement more frequently than with venous involvement(13-14). the occurrence of an aneurysm is, together with a mortality rate of up to 60% if it is not treated(16). in the two cases in our report in which spontaneous vascular bleeding occurred on the common iliac arteries, the time since bd diagnoses was 7 and 11 years. there were no signs of an aneurysm or any visible pathology on the artery during lymph node dissection around the iliac vessels. it should be noted that further evaluation of the cardiovascular system, including ct angiography, mr angiography or doppler ultrasound, may be helpful in diagnosing vascular disease. in our study, only an enhanced abdominal ct, which revealed no evidence for vascular disease, was requested for our patients. common iliac artery was probably involved in our two cases, and inflammation caused the vascular wall to weaken without the formation of an aneurysm. the pathology and pathogenesis of the arterial involvement in bd has been documented by matsumoto et al. they described it as an inflammatory obliterative endarteritis of the vasa vasorum, most likely brought about by immune deposition. it causes destruction of the tunica media and fibrosis, weakening and predisposing arterial wall to aneurysm formation and eventually aneurysm rupture(17). smoking cigarettes is another predisposing factor for vascular disease. both of the patients were long-time smokers. manipulation of the vessels during lymph node dissection could have stimulated the rupture of these weak vessel walls. another important point is that during lymph node dissection, the surgeon did not observe evidence of injury to the vessels. regatding the treatment of vascular complications in bd, various endovascular or surgical interventions have been performed in patients with bd. nevertheless, the outcomes of endovascular and surgical intervention are still unfavorable(18,19). kwon et al. presented their results of surgical treatment for abdominal aneurysms in bd. they concluded that resection and interposition grafting revealed much better results than a patch closure. the recurrence rate of patch closure (62.5%) was significantly higher than the rate of an interposition graft (14.3%). at least one patient with a patch closure died due to a recurrent aneurysm after 4 months. authors declared that surgical treatment for arterial involvement of bd is highly associated with postoperative complications; therefore, the surgical treatment should not be applied in the active phase of the disease, and systemic therapy, including aspirin and corticosteroids, should be considered for all patients(20). furthermore, another study reported that remission using glucocorticoid before surgical intervention can decrease the incidence of postoperative anastomic complications(21). interestingly, none of our cases were in the active phase of bd, and the patients were on prednisolone therapy. nevertheless, acute bleeding occurred, and the patches were separated spontaneously from the common iliac arteries. after our experience with four bladder cancer patients with concomitant bd, we conclude that radical cystoprostatectomy shows higher morbidity and mortality in these patients. it should be emphasised that all patients were in the inactive phase of the disease. in this context, detailed preoperative evaluation related to bd should be performed. ileal visualisation, including microscopic evaluation, could be done to determine potential ileal involvement (if an ileal reservoir is planned to be used). ct angiography or doppler ultrasonography are preferred modalities for vascular evaluation. we suspect that the sufficiency of these methods to establish vascular involvement is efficient because we are able to detect pathology on the arteries during operation or on ct. strict cooperation with the rheumatology department and cardiovascular surgeons is required before deciding for an intervention on bd patients. references 1. sakane t, takeno m, suzuki n, inaba g. behçet's disease. n engl j med 1999; 341: 1284-91. 2. international study group for behçet’s disease. criteria for diagnosis of behçet’s disease. lancet 1990; 335:1078-80. 3. international team for the revision of the international criteria for behcet’s disease revision of the international criteria for behcet’s disease (icbd): clin exp rheumatol 2006; 24(suppl 42): s14–s15. 4. fırat d, hayran m. in cancer statistics in turkey and in the world (1990-1992). ankara: i̇z matbaacılık 1995. 5. çelik , altunda k, erman m, batalı e. cyclophosphamideassociated carcinoma of the urinary bladder in behçet’s disease. nephron. 1999; 81: 239. 6. kotsis t, moulakakis kg, mylonas s, andrikopoulos v. vascular manifestations in behcet’s disease. phlebology 2011; 26: 24953. 7. yazici h, tüzün y, pazarli h, yurdakul s, ozyazgan y, ozdoğan h, et al. influence of age of onset and patient’s sex on the prevalence and severity of manifestations of behçet’s syndrome. ann rheum dis 1984; 43: 783-9. 8. sayek i, aran o, uzunalimoglu b, hersek e: intestinal behçet’s disease. surgical experience in seven cases. hepatogastroenterology 1991; 38: 81–3. 9. cengiz m, altunda mk, zorlu af, güllü ih, özyar e, atahan il. malignancy in behçet’s disease: a report of 13 cases and a review of the literature. clin. rheumatol. 2001; 20: 239– 44. 10. baltaci, s, gogus c, karamursel t, tulunay o. invasive bladder carcinoma in a patient with behcet's disease. int j urol 2003; 10: radical cystectomy in behcet disease-sevinc et al. 669-71. 11. yurdakul s, tuzuner n, yurdakul i, hamuryudan v, yazici h. gastrointestinal involvement in behcet’s syndrome: a controlled study. annals of the rheumatic diseases 1996; 55: 208–10. 12. köklü s, yüksel o, onur i, unverdi s, biyikoğlu i, akbal e, et al. ileocolonic involvement in behçet’s disease. endoscopic and histological evaluation 2010; 81: 214-7. 13. iscan zh, vural km, bayazit m. compelling nature of arterial manifestations in behcet disease. j vasc surg 2005; 41:53–58. 14. calamia kt, cohen md, o’duffy jd. large vessel involvement in behçet’s disease (a). proceedings of the eighth international congress on behçet’s disease. italy: reggioemilia; 70, 1998. . 15. tursen u, gurler a, boyvat a. evaluation of clinical findings according to sex in 2313 turkish patients with behcet’s disease. int j dermatol 2003; 42: 346-51. 16. reiter bp, marin ml, teodorescu vj, mitty ha. endoluminal repair of an internal carotid artery pseudoaneurysm. j vasc interv radiol 1998; 9: 245-8. 17. matsumoto t, uekusa t, fukuda y. vasculobehc¸et’s disease: nevera pathologic study of eight cases. hum pathol 1991; 22: 45-51. 18. kwon tw, park sj, kim hk, yoon hk, kim ge, yu b. surgical treatment result of abdominal aortic aneurysm in beh-cet’s disease. eur j vasc endovasc surg 2008; 35: 173–80. 19. koksoy c, gyedu a, alacayir i, bengisun u, uncu h, anadol e. surgical treatment of peripheral aneurysms in patients with behcet’s disease. eur j vasc endovasc surg 2011; 42: 525–30. 20. saadoun d, asli b, wechsler b, houman h, geri g, desseaux k, et al. long-term outcome of arterial lesions in behçet disease: a series of 101 patients. medicine (baltimore) 2012; 91: 18–24. 21. kalko y, basaran m, aydın u, kafa u, basaranoglu g, yasar t. the surgical treatment of arterial aneurysms in behçet’s disease:a report of 16 patients. j vasc surg 2005; 42: 673-7. radical cystectomy in behcet disease-sevinc et al. case report 2875 transplantation urology living unrelated versus related kidney transplantation: a 25-year experience with 3716 cases nasser simforoosh,1* abbas basiri,1 alitabibi,1 babak javanmard,1 amir hossein kashi,1,2 mohammad hossein soltani,1 khalid obeid1 purpose: to evaluate the results of transplantation from living unrelated donors (lurd) versus living related donors (lrd) with a long term follow-up of 25-30 years. materials and methods: from 1984 to 2015, a total of3716 kidney transplantations (411 lrds and 3305 lurds) were enrolled to the study. long-term survival of grafts and patients as well as the association between relation state and patients or grafts surveillance were the outcomes. results: a total of 3716 live donor kidney transplants (lrd, n = 411; lurd, n = 3305) were carried out over this period. the mean age of donors was 28 ± 54 years in the lurd group and 34.4 ± 11.7 years in lrd (p < . 001), while the mean age of the recipients was 35.6 ± 15.6 years and 27.6 ± 10.1 years for the two groups, respectively. donor age was the only statistically significant predictor of graft survival rate (hazard ratio = 1.021, 95% confidence interval: 1.012-1.031). between 1984 and 2015, patient survival and graft survival improved significantly also patient survival and graft survival was similar in lurds compared with lrds. conclusion: it seems that the outcome of lurd and lrd is comparable in terms of patient and graft survival. therefore, transplants from lurds may be proposed as an acceptable management for patients with end stage renal disease. keywords: donor selection; humans; kidney transplantation; living donors; organ transplantation; risk assessment; risk factors. introduction renal transplantation is still an excellent treatment for patients with end stage renal disease (esrd). (1,2) considering the growing number of esrd patients, the widening gap between the demand and supply of donor kidneys has led to a call for an expansion in the potential donor pool such as using unrelated living kidney donors.(3-7) therefore, living unrelated donors (lurd) transplantation faced a revival and experienced 100% increase between 1994 and 1996, similarly the proportion of transplantation from lurds is still growing worldwide.(8) although human leukocyte antigen (hla) matching of unrelated donors might not be expected to be opium, previous studies showed comparable results between lurds and living related donors (lrds).(1,7,9-13) however, short term follow-up, the patients’ fall during the study and low sample sizes are the major limitations of these literatures. we believe that iran has the largest experience with lurd transplantation. the first planned unrelated renal transplantation was performed on a spouse.(13) in iran, donation from lurds is strictly supervised by governmental agencies. kidney transplantation has recently been restricted to university hospitals and donation is only possible to iranian natives. using the iranian model by combining lrds, lurds, and cadaveric donors to form a donation pool, the waiting list for kidney transplantation has been shortened despite the growing number of patients waiting for transplantation. therefore, there is currently a shorter waiting time for kidney transplantation in iran compared to many other countries. we had previously published medium term follow-up of lurds versus lrds in 2006.(2) here, we provide longer term follow-up together with inclusion of newer transplantations from 2006 to 2014, including 3739 living donor transplantations. materials and methods patients and setting 1 urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2 national elites foundation, tehran, iran. *correspondence: urology and nephrology research center, 9th boostan street, pasdaran ave, tehran, iran. tel: +98 21 22541185. fax: +98 21 22541185. e-mail: simforoosh@iurtc.org.ir. received: september 2016 & accepted: december 2015 transplantation urology 2546 vol 13 no 01 january-february 2016 2547 this study was conducted from june 1984 to november 2015 in the department of urology at labbafinejad university hospital (referral center, shahid beheshti university of medical sciences) in tehran, iran. with the collaboration of the collaborative transplant study (cts), data of 3716 transplant patients, donors and annual follow-ups was used for this study. the study was approved by the ethics committee of shahid beheshti university of medical sciences, and each patient was given an informed consent prior to the study, which was performed in accordance with the ethical standards of the 1964 declaration of helsinki as revised in 2000. as part of the adopted lurd renal transplant program, during the evaluation of a renal transplant candidate, the transplant physician emphasized on the advantages of an lrd compared with lurd transplantation, such as longer graft survival rates and fewer acute rejection episodes, and recommended transplantation from an lrd. if the patient had no lrd or the potential donor is not willing to donate a kidney, the patient is referred to the dialysis and transplant patients association (datpa) to find a suitable lurd. the datpa is the site where those who wish to volunteer sign up as lurds. the volunteers registered at datpa underwent an evaluation in the foundation clinics. permission from the parents in younger and single adults or the spouse to register was mandatory. the potential donors were required to be in complete health and a consent was obtained from each donor prior to the introduction to the potential recipients. most of the members of datpa are esrd patients. they receive no financial incentives to find an lurd or to refer the patient and donor to a transplant team. there was no role for a middleman or agency in this program. all transplant teams were affiliated with university hospitals and the government is responsible for all hospital expenses of transplantation. after transplantation, the lurd received an award from the government and a majority of the lurds also received a rewarding gift from the recipient (or were arranged a reward by datpa). transplant teams received no inunrelated and related kidney transplantation-simforoosh et al. table 1. characteristics of transplantations from living related donors versus living unrelated donors. variables lurds lrds p value donor age, years, mean ± sd 28.0 ± 5.4 34.4 ± 11.7 < .001 recipient age, years, mean ± sd 35.6 ± 15.6 27.6 ± 10.1 < .001 donor gender, no (%) male 2736 (93) 208 (7) < .001 female 516 (72) 198 (28) recipient gender, no (%) male 2164 (89) 270 (11) .81 female 1136 (89) 138 (11) transplantation years, no (%) 1984-1999 849 (74) 302 (26) < .001 2000-2015 2456 (96) 109 (4) abbreviations: lrd, transplantation from living related donors; lurd, transplantation from living unrelated donors; sd, standard deviation. variables 1 year 3-year 5-year 10-year 15-year 20-year 25-year graft survival rate lrd 89.0 77.4 70.2 54.9 40.0 31.5 31.5 lurd 90.0 85.6 81.6 71.1 55.6 38.6 38.6 patient survival rate lrd 94.5 88.5 84.0 80.2 74.2 72.4 67.9 lurd 95.2 93.9 92.5 88.5 83.1 65.9 65.9 * data are presented as percent. abbreviations: lurd, living unrelated renal donor; lrd, living related donor. table 2. distribution of graft and patient survival rate during follow-ups.* centives from the rewarding gifts or the governmental awards. the rewarding gifts has been limited to a range that enables the majority of patients of a poor socioeconomic class to afford with the help of charity foundations. this program was under the close observation of the iranian ministry of health and medical education. according to a recent rule for transplantation in iran, kidney transplantation to a foreign citizen is forbidden except neighbor countries that do not have transplantation programs (e.g. afghanistan). in these cases, the donors have to be a native from the recipient country.(14) surgical and laboratory interventions our technique was standard retroperitoneal flank approach for open donor nephrectomy until 1997. since 1997, the standard approach in our department has been laparoscopic donor nephrectomy including right side nephrectomy and inverted kidney transplantation.(15-17) to evaluate the recipient, we limited our donor laboratory tests to abo compatibility and preliminary cross-matching. these patients underwent: renal ultrasound, voiding cystourethrography (if needed), chest x-ray, ear-nose-throat examination, dental examination, complete blood count, blood coagulation tests, stool examination, venereal disease research laboratory, human immune deficiency antibody, human t-lymphotropic virus-1 antibody, hepatitis b surface antigen, hepatitis c virus antibody, urinalysis, urine culture, and sometimes renal biopsy. other tests like gastrointestinal endoscopy were done when necessary. immunosuppression was similar for the two groups, and patients received cyclosporine-based immunosuppression. the allograft transplant was performed by anastomosis of the renal artery to the internal iliac artery or to the external or common iliac arteries when the internal was not suitable. the renal vein in almost all patients was anastomosed to the external iliac vein, and in some cases, to the common iliac vein. aorta and inferior vena cava were the sites of vascular anastomosis in small pediatric recipients. suture material was prolene 6-0 and 5-0 for vascular anastomosis. ureteral anastomosis was done within modified lich technique using ureteral stent. all transplantations were performed by the team led by three transplantation urologists (n.s., a.b. and a.t.). graft and patient surveillances were our primary outcomes. secondary outcomes included the association of baseline characteristics, transplant year and the type of relation as well. statistical analysis data entry and statistical analysis was performed employing stata software version 11.0 (statacorp, texas, usa). chi-square test was used to compare nominal baseline variables in the two groups (lrd and lurd). independent samples t-test was used to compare numeric baseline variables between lurd and lrd recipients. graft and patient survival were estimated by the kaplan–meier method and compared across levels of nominal variables by the log-rank test. bonferroni correction was used for the number of testing for each predictor variable (6 testing correcting p value for statistical significance at .008). statistically significant variables were introduced into a cox regression model. the cox proportional regression model was used to examine the influence of relation status on graft and patient survival adjusting for the effects of donor age, recipient age and stratified on transplantation year categories (1984-1999 and 2000-2015). stratification of transplantation year categories was based on the different distribution of donor types (related, unrelated and cadaveric) in 1984-1999 compared to after 2000. results from 1984 to 2015, 3716 living transplantations were performed in our center consisting of 3305 lurd and 411 lrd transplants. baseline characteristics of the patients are shown in table 1. graft and patient survivals rates during the follow-ups are shown in table 2. in univariate log rank tests, graft or patient survival were not distinctive across different genders of donors or recipients (all p values > .05) but graft or patient surfigure 1. kaplan-meier curve for patient survival in transplantation from living related and unrelated donors. solid line indicates transplantation from related donor, dashed line indicates transplantation from unrelated donor. unrelated and related kidney transplantation-simforoosh et al. transplantation urology 2548 vol 13 no 01 january-february 2016 2549 vival were dissimilar across different age groups of donors and recipients, different transplantation years and donor relationship status (lrd versus lurd). in the cox proportional hazard model, donor age, recipient age and relation status (related versus unrelated) were introduced into the model and the model was stratified based on transplantation year categories (1984-1999 and 2000-2015). stratification was employed to remove the confounding effect of transplantation time as lrds were performed more often prior to 1999, while after 2000 there was a relatively constant proportion of lrds to lurds. donor age was the only statistically significant predictor of graft survival in the cox model (hazard ratio [hr] = 1.021, 95% confidence interval [ci]:1.012-1.031). the same modeling was used to investigate the variables influencing the patient survival. in the latter model, donor age (hr = 1.020, 95% ci: 1.006-1.034) and recipient age (hr = 1.029, 95% ci: 1.021-1.037) were statistically significant predictors of the patient survival. in neither models the relation status (lrd versus lurd) was a significant predictor of graft (hr = 1.046, 95% ci: 0.862-1.268) or patient (hr = 0.991, 95% ci: 0.737-1.334) survival (figures 1 and 2). discussion the most important finding of this study was comparable patient or graft survival rates for lurds compared with lrds. donor and recipient gender was not associated with graft or patient survival rates (all p values > .05) but donor age, recipient age, transplantation year and relationship (lrd versus lurd) were statistically significant predictors of graft and/or patient survival rates. transplantation from living donors is increasingly becoming popular because of its excellent outcomes compared with cadaveric transplantations.(3,6) previous studies showed acceptable results for lurd kidneys. we recently published the largest series reported from a single center including 2155 cases with excellent results.(13) gjertson and cecka reported a 5-year graft survival of 72% based on the analysis of united network for organ sharing (unos) registry from 1987 to 1998.(6) ahmad and colleagues reported an excellent 3-year graft survival of 93.7% in their series of lurds from st. mary hospital of london during 2001 to 2004. (1) furthermore, a 5-year survival of 82% has been reported from the university of wisconsin series.(18) in korea, the 5-year survival rate of lurts was 86.9% similar to one-haplotype disparate living transplants.(19) the 5-year graft survival in the current study for 3305 lurds was 81.6%. the introduction of laparoscopic donor nephrectomy (ldn) has also resulted in a better motivation for potential donors.(3) we reported that ldn improved donor satisfaction without impairing graft outcome when compared to open donor nephrectomy.(15) currently, almost all donor nephrectomies in our center are performed through laparoscopy. since the adoption of this policy, we have had an increasing number of living donor transplantations in the past decade. in this study, a great proportion of donors in the lrd group were parents who volunteered for kidney donation to their offspring. hence, the average age for donors in the lrd group is higher than the lurd group. older age is regarded as a risk factor for a higher rejection rate(3,10) observed in the lrd group. employing multivariate analysis and adjusting for the effect of age, graft and patient survival in the lurd group is seen to be closely similar to the lrd group (figures 1 and 2). analysis of transplantation data by opelz on the cardio thoracic systems registries revealed that hla mismatches have an important role in the outcome of transplantation.(20) nevertheless, many single center studies have reported equal or even better short, medium and long term outcomes of transplantation in lurd series compared with lrds.(1,2,7,9,11) it seems that the extremes of hla mismatch influence the outcomes of transplantation as the best survivals have been reported with hla-identical grafts. the 5-year graft survival reported for patients with moderate degrees of mismatch (1-4 antigen mismatch) is roughly equal in the range of 69% to 71.2%.(3) in this study, the crude outcome figure 2. kaplan-meier curve for graft survival in transplantation from living related and unrelated donors. solid line indicates transplantation from related donor, dashed line indicates transplantation from unrelated donor. unrelated and related kidney transplantation-simforoosh et al. of transplantation in terms of graft and patient survival was better in the lurd group; however, when analysis was performed this difference was no longer statistically significant in terms of transplantation year categories (figures 1 and 2). regarding the best survival figures reported with hla-identical transplantations or relatives with less hla-mismatches,(3,6) the first choice for a living donor is still the patient's sibling or a hla identical donor. if such a donor is not available, lurds represent an alternative source of donation. results of the current study with a long term follow-up moves in parallel with the results reported before. interestingly, graft and patient survival was not worse in lurds compared with lrds. this observation has previously been reported,(1,2,7,9) while the reasons have not been fully defined. motivation and induction medication for lurds have been proposed as some of the possible reasons. when long term follow-up of lurds provide acceptable and consistent results in terms of graft function, survival and patient survival, ethical issues are still an impediment for full employment of lurds as a potential source of kidney donation in many countries. in iran, donation from lurds is strictly supervised by governmental agencies. kidney transplantation has recently been restricted to university hospitals and donation is only possible to iranian natives. using the iranian model by combining lrds, lurds, and cadaveric donors to form a donation pool, the waiting list for kidney transplantation has been shortened despite the growing number of patients waiting for transplantation. by this strategy, the mortality of patients who are in kidney waiting list decreased, whereas, in the usa, 4,270 patients died while waiting for a kidney transplant in 2014. another 3,617 people became too sick to receive a kidney transplant.(4) spouses constitute a potential population of motivated lurds. previous reports point to the excellent long term results of graft survival from spouses. mittal and colleagues compared the graft survival from spouses relative to lrds. no inferior functions of grafts from spouses were observed in comparison with relatives.(9) in another study yoon and colleagues reported equal graft survival from spouses versus lurds in spite of higher donor age and greater hla mismatches in the spouse group.(12) unos registry data reveals that during 1987 to 1997, 62% of lurds were spouses.(8) chung and colleagues reported increasing frequency of donation from spouses from 5.1% in 1990s to 8.1% after 2000(23) and spouses constitute 15-20% of all kidney donations in india.(24) in conclusion, the results of living unrelated kidney transplantation in our long-term follow-up with a large number of cases show that living unrelated kidney transplantation is as good as living related kidney transplantation. the organ shortage can be alleviated by using living unrelated kidney transplantation with successful results similar to living related kidney transplantation. furthermore, by using living unrelated kidney transplantation the waiting time for patients was decreased, hence, the mortality of some patient in the waiting period is prevented. conclusions it seems that outcome of lurd and lrd is comparable in terms of patient and graft survival. therefore, transplants from lurds may be proposed as a good therapeutic alternative for management of patients with esrd. conflict of interest none declared. references 1. ahmad n, ahmed k, khan ms, et al. living-unrelated donor renal transplantation: an alternative to living-related donor transplantation? ann r coll surg engl. 2008;90:247-50. 2. simforoosh n, basiri a, fattahi mr, et al. living unrelated versus living related kidney transplantation: 20 years' experience with 2155 cases. transplant proc. 2006;38:422-5. 3. knoll g. trends in kidney transplantation over the past decade. drugs. 2008;68:3-10. 4. panchal h, muskovich j, patterson j, schroder pm, ortiz j. expanded criteria donor kidneys for retransplantation united network for organ sharing update: proceed with caution. transpl int. 2015;28:990-9. 5. sankari br, wyner lm, streem sb. living unrelated donor renal transplantation. urol clin north am. 1994;21:293-8. 6. gjertson dw, cecka jm. living unrelated donor kidney transplantation. kidney int. 2000;58:491-9. 7. humar a, durand b, gillingham k, payne wd, sutherland de, matas aj. living unrelated donors in kidney transplants: better long-term results than with non-hla-identical living related donors? transplantation. 2000;69:1942-5. 8. suzuki mm, cecka jm, terasaki pi. unrelated living donor kidney transplants. br med bull. 1997;53:854-9. 9. mittal t, ramachandran r, kumar v, et al. outcomes of spousal versus related donor kidney transplants: a comparative study. indian j nephrol. 2014;24:3-8. unrelated and related kidney transplantation-simforoosh et al. transplantation urology 2550 vol 13 no 01 january-february 2016 2551 10. park yh, min sk, lee jn, lee hh, jung wk, lee js, lee jh, lee yd. risk factors on graft survival of living donor kidney transplantation. transplant proc. 2004;36:2023-5. 11. voiculescu a, ivens k, hetzel gr, et al. kidney transplantation from related and unrelated living donors in a single german centre. nephrol dial transplant. 2003;18:41825. 12. yoon he, song jc, hyoung bj, et al. comparison of long-term outcomes between spousal transplants and other living unrelated donor transplants: single-center experience. nephron clin pract. 2009;113:c241-9. 13. simforoosh n, bassiri a, amiransari b, gol s. living-unrelated renal transplantation. transplant proc. 1992;24:2421-2. 14. einollahi b. iranian experience with the nonrelated renal transplantation. saudi j kidney dis transpl. 2004;15:421-8. 15. simforoosh n, basiri a, tabibi a, shakhssalim n, hosseini moghaddam sm. comparison of laparoscopic and open donor nephrectomy: a randomized controlled trial. bju int. 2005;95:851-5. 16. simforoosh n, soltani mh, basiri a, et al. evolution of laparoscopic live donor nephrectomy: a single-center experience with 1510 cases over 14 years. j endourol. 2014;28:34-9. 17. simforoosh n, zare s, basiri a, tabibi a, samzadeh m, soltani mh. pediatric kidney transplant with laparoscopic donor nephrectomy. exp clin transplant. 2014;12:391-5. 18. d'alessandro am, pirsch jd, knechtle sj, et al. living unrelated renal donation: the university of wisconsin experience. surgery. 1998;124:604-10. 19. park k, kim ys, lee em, lee hy, han ds. single-center experience of unrelated livingdonor renal transplantation in the cyclosporine era. clin transpl. 1992:249-56. 20. opelz g. impact of hla compatibility on survival of kidney transplants from unrelated live donors. transplantation. 1997;64:1473-5. 21. moosa m. renal transplantation in developing countries. moris p. kidney transplantation: principles and practice. 5th ed. philadelphia, usa: wb saunders; 2001:659-91. 22. simforoosh n. kidney donation and rewarded gifting: an iranian model. nat clin pract urol. 2007;4:292-3. 23. chung bh, jung mh, bae sh, et al. changing donor source pattern for kidney transplantation over 40 years: a single-center experience. korean j intern med. 2010;25:288-93. 24. dash sc, bhowmik d. the wife as kidney donor: current indian scenario. kidney int. 2001;59:801. unrelated and related kidney transplantation-simforoosh et al. kidney transplantation frequency of infectious skin lesions in kidney transplant recipients masoomeh alimagham,1* saeed amini-afshar,1 siamak farahmand,2 aydin pour-kazemi,1 fatemeh pour-reza-gholi,3 sara masood1 1department of infectious diseases, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran 2department of surgery, imam hossein medical center, shaheed beheshti university of medical sciences, tehran, iran 3department of nephrology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran abstract introduction: this study was performed to evaluate the frequency of skin lesions in kidney transplant recipients. materials and methods: a total of 681 kidney transplant recipients were followed at shaheed labbafinejad transplant center in tehran, iran. skin lesions were evaluated, and diagnoses were made clinically and confirmed by lesion smear, tissue biopsy, tissue culture, and serologic examinations, as indicated. results: skin lesions were found in 54 patients (7.9%), and their frequencies were as follows: dermatomal herpes zoster (18 patients, 2.6%, 13 men and 5 women), herpes simplex infection of face and lips (15 patients, 2.2%, 5 men and 10 women), chickenpox (6 patients, 0.9%, 5 men and 1 woman), kaposi's sarcoma (5 patients, 0.7%, 3 men and 2 women), warts (4 women, 2 of whom had genital warts), pyoderma gangrenosum (1 man, 0.14%), multiple fungal abscesses of the leg (1 man, 0.14%), mucormycosis (1 man, 0.14%), and molluscum contagiosum (1 man, 0.14%). moreover, 2 women (0.3%) had generalized herpes simplex lesions. conclusions: frequencies of herpes zoster (3.5%), herpes simplex (2.5%), and human papillomavirus (0.6%) infections in our kidney transplant recipients were low. we recommend that all kidney transplant candidates be evaluated and immunized for herpes zoster virus before transplantation, all herpetic-form lesions of these patients be reported to physicians (even mild lesions), and finally, that all human papillomavirus lesions be diagnosed and treated promptly to prevent more serious lesions such as malignancies. key words: skin lesion, kidney transplantation, varicella-zoster virus, herpes simplex, chickenpox, kaposi's sarcoma 193 urology journal unrc/iua vol. 2, no. 4, 193-196 autumn 2005 printed in iran introduction cutaneous lesions are usually a significant problem in kidney transplant recipients. factors such as climate and the patient's skin type have received february 2005 accepted september 2005 *corresponding author: department of infectious diseases, shaheed labbafinejad medical center, tehran, iran. tel: ++98 21 2254 6026 e-mail: dr.mahnazaalimagham@yahoo.com infectious skin lesions after kidney transplantation been implicated as factors that influence clinical manifestations.(1) immunosuppressive therapy, although it contributes to successful kidney transplantation outcomes, also increases the rate of nonmalignant and malignant skin lesions.(2,3) there is also a correlation between duration of the immunosuppressive therapy and risk of acquiring squamous cell skin cancer and common viral warts, the latter of which is reported in up to 55% of patients with kidney allografts.(2) also, it has been suggested that human papilloma virus, the cause of warts, has a role in the etiology of squamous cell carcinoma in kidney allograft recipients.(4) the risk of neoplasia in the first 10 years after transplantation is 14%, increasing to 40% after 20 years.(5) thus, any infectious skin disease should be taken seriously to reduce the risk of transformation into malignancy. the prevalence and clinical characteristics of cutaneous lesions and their relation to malignancies in kidney transplant recipients, although previously reported in many studies, have not been elucidated in our region. in this study, we assess the prevalence and clinical spectrum of infectious lesions at shaheed labbafinejad medical center in tehran, iran. materials and methods a total of 681 kidney allograft recipients were assessed retrospectively. they had undergone kidney transplantation and were followed from april 2000 to march 2002 at shaheed labbafinejad medical center in tehran, iran. follow-up was performed by the center's nephrologists and, in case of skin lesions, by infectious diseases specialists. consultation with a dermatologist was on an as-needed basis. cases of skin lesions were evaluated, and diagnoses were made clinically. diagnoses were confirmed by lesion smear, tissue biopsy, tissue culture, and serologic examinations, as indicated. the patients' clinical and demographic characteristics were collected and analyzed. results of 681 patients, 243 were female (35.7%), and 438 were male (64.3%; age range, 3 to 78 years). overall, 54 patients (7.9%) had skin lesions. the frequencies of skin lesions were as follows: dermatomal herpes zoster (18 patients, 2.6%, 13 men and 5 women), herpes simplex infection of face and lips (15 patients, 2.2%, 5 men and 10 women), chickenpox (6 patients, 0.9%, 5 men and 1 woman), kaposi's sarcoma (5 patients, 0.7%, 3 men and 2 women), warts (4 women, 2 of whom had genital warts), and pyoderma gangrenosum (1 man, 0.14%), multiple fungal abscesses of the leg (1 man, 0.14%), mucormycosis (1 man, 0.14%), and molluscum contagiosum (1 man, 0.14%). moreover, 2 women (0.3%) had generalized herpes simplex lesions. table 1 summarizes the time of onset, age at diagnosis, and treatments for the various lesions. discussion skin infections are common after transplantation but are rarely life-threatening. they constitute a significant nuisance to the transplant recipient and may be an indication of a serious systemic infection. the most frequent pathogens in infectious skin lesions include staphylococcus aureus, herpes simplex virus, varicella-zoster virus, papillomaviruses, candida species, and dermatophytes.(6) the frequency of skin lesions in this study was 7.9%, of which 0.7% was due to kaposi's sarcoma. the findings of this study disagree with those of other studies; for 194 table 1. time of onset, age at diagnosis, and treatments of the main lesions kaposi’s sarcoma herpes zoster chickenpox herpes simplex number of patients (%) 5 (0.7) 18 (2.6) 6 (0.9) 15 (2.2) age (range, year) 40 to 67 30 to 59 20 to 50 8 to 47 sex (male/female) 3/2 13/5 5/1 5/10 time of onset after transplantation (months) 6 to 11 1 to 15 3 to 11 1 to 11 treatment discontinuing or decreasing of immunosuppressives acyclovir acyclovir acyclovir alimagham et al example, cohen and colleagues have reported a prevalence of 12% skin lesions in 580 kidney transplant recipients, most of which were squamous cell carcinoma and human papillomavirus infections.(7) the most common viral skin infections are those caused by herpes simplex virus and varicella-zoster virus.(8) the frequency of varicella-zoster virus infections in this study was 3.5%, which is lower than that of other studies, which have reported rates of 7% to 16%.(6,9,10) this may be due to the different follow-up durations (about 2 years in our study versus an average of 5 years in other studies). the onset time of herpes zoster rash is reported to be 1 to 3 months after transplantation,(8) while we had cases with onset after the 10th month. the frequency of herpes simplex in this study was significantly lower when compared with other reports (2.5% versus 60%).(8) this may be due to the rather short (2-year) follow-up of our study. in addition, transient and minimal lesions were not considered in our evaluation.(8) the papillomavirus infection rate in this study was 0.6%. however, bar and colleagues found this infection in 77% of patients with a graft survival of more than 5 years, and in 20% of those patients with a graft survival of less than 5 years.(4) the low incidence of papillomavirus infection in our patients can be attributed to the low prevalence of this disease in our country, as well as to the short length of this study. an association of papillomavirus dna and squamous cell skin carcinoma has been found in the majority of kidney allograft recipients with squamous cell skin carcinoma.(11) therefore, it seems that early diagnosis and treatment of human papillomavirus infection would prevent development of such serious lesions in these patients. shuttleworth and colleagues have reported cutaneous fungal lesions in 15% of kidney transplant patients,(12) while a much lower prevalence (< 0.5%) was seen in this study. this may be due to differing geographic distributions of fungal infections. chickenpox was one of the more common diseases (with skin manifestations) in our patients. chickenpox, which is reported in approximately 15% to 18% of patients,(13,14) is associated with significant morbidity and mortality in immunocompromised children and adults. it is recommended that prior to transplantation, patients be evaluated serologically, and vaccinated against varicellazoster virus, if necessary. conclusion our data show that the prevalence of infectious skin lesions in our patients in iran differs from that of other regions and necessitates further investigations. although the rates were relatively low, we recommend that first, all patients with symptoms be examined for human papillomavirus infection (particularly genital warts) to prevent malignant deteriorations. second, all patients should be informed and sufficiently educated with regard to herpetic infections (even minor ones like a cold sore) and should report them to their physician immediately. lastly, prior to transplantation, patients must be evaluated serologically and vaccinated against varicellazoster virus, when appropriate. references 1. lugo-janer g, sanchez jl, santiago-delpin e. prevalence and clinical spectrum of skin diseases in kidney transplant recipients. j am acad dermatol. 1991;24:410-4. 2. blohme i, larko o. skin lesions in renal transplant patients after 10-23 years of immunosuppressive therapy. acta derm venereol. 1990;70:491-4. 3. mclelland j, rees a, williams g, chu t. the incidence of immunosuppression-related skin disease in long-term transplant patients. transplantation. 1988;46:871-4. 4. barr bb, benton ec, mclaren k, et al. human papilloma virus infection and skin cancer in renal allograft recipients. lancet. 1989;1:124-9. 5. london nj, farmery sm, will ej, davison am, lodge jp. risk of neoplasia in renal transplant patients. lancet. 1995;346:403-6. 6. dummer js. infectious complications of transplantation. cardiovasc clin. 1990;20:163-78. 7. cohen eb, komorowski ra, clowry lj. cutaneous complications in renal transplant recipients. am j clin pathol. 1987;88:32-7. 8. dummer js, ho m. infection in solid organ transplant recipients. in: mandell gl, bennett je, dolin r, editors. mandell, douglas and bennett's principles and practice of infectious diseases. 5th ed. philadelphia: churchill livingstone; 2000: p. 3153. 9. broyer m, tete mj, guest g, gagnadoux mf, rouzioux c. varicella and zoster in children after kidney transplantation: long-term results of vaccination. pediatrics. 1997;99:35-9. 10. rifkind d. the activation of varicella-zoster virus infections by immunosuppressive therapy. j lab clin med. 1966;68:463-74. 195 infectious skin lesions after kidney transplantation 11. euvrard s, chardonnet y, hermier c, viac j, thivolet j. [warts and epidermoid carcinoma after renal transplantation]. ann dermatol venereol]. 1989;116:20111. french. 12. shuttleworth d, philpot cm, salaman jr. cutaneous fungal infection following renal transplantation: a case control study. br j dermatol. 1987;117:585-90. 13. whitley rj. varicella-zoster virus. in: mandell gl, bennett je, dolin r, editors. mandell, douglas and bennett's principles and practice of infectious diseases. 5th ed. philadelphia: churchill livingstone; 2000: p. 1580-6. 14. feldman s, hughes wt, daniel cb. varicella in children with cancer: seventy-seven cases. pediatrics. 1975;56:388-97. 196 miscellaneous relationship between metabolic syndrome and predictors for clinical benign prostatic hyperplasia progression and international prostate symptom score in patients with moderate to severe lower urinary tract symptoms sicong zhao,1 chao chen,1 zongping chen,1 ming xia,1 jianchun tang,2 sujun shao,3 yong yan1* purpose: to investigate the association between metabolic syndrome (mets) and the predictors of the progression of benign prostatic hyperplasia (bph) and the corresponding frequency and severity of lower urinary tract symptoms (luts). materials and methods: a total of 530 men with moderate to severe international prostate symptom score (ipss) > 7 were recruited in the present study. the predictors for clinical bph progression were defined as the total prostate volume (tpv) ≥ 31 cm3, prostate-specific antigen level (psa) ≥ 1.6 ng/ml, maximal flow rate (qmax) < 10.6 ml/s, postvoid residual urine volume (pvr) of ≥ 39 ml, and age 62 years or older. luts were defined according to the ipss and mets with the national cholesterol education program-adult treatment panel iii guidelines. the mantel-haenszel extension test and the multivariate logistic regression analyses were used to statistically examine their relationships. results: the percentage of subjects with ≥ 1 predictors for clinical bph progression, the percentage of subjects with a tpv ≥ 31 cm3, the percentage of subjects with a pvr ≥ 39 ml, and the percentage of subjects with a qmax < 10.6 ml/s increased significantly with the increasing in the number of mets components (all p < .05). after adjusting for age and serum testosterone level, the mets were independently associated with the presence of tpv ≥ 31 cm3 (or = 17.030, 95% ci: 7.495-38.692). moreover, mets was positively associated with the severity of luts (p < .001) and voiding scores (p < .001), and each individual mets component appeared as an independent risk factor for severe luts (ipss > 19, all p < .001). conclusion: our data have shown that the mets significantly associated with the predictors for clinical bph progression and the frequency and severity of luts, especially the voiding symptoms. the prevention of such modifiable factors by promotion of dietary changes and regular physical activity practice may be of great importance for public health. keywords: metabolic syndrome x/complications; prostatic hyperplasia/pathology; humans; male; prostate/pathology; urination. introduction benign prostatic hyperplasia (bph) and secondary lower urinary tract symptoms (luts) are high prevalence public health problems that have been well described in elderly men. bph, which is characterized by enlargement of prostatic glandular tissue and narrowing of the urethra, affects 70% of us men at the age of 60-69 years and 80% of those at the age of 70 years.(1) the clinical progression of bph could results in acute urinary retention, renal insufficiency, recurrent urinary tract infection, urinary incontinence, and the need for 1 department of urology, beijing shijitan hospital, capital medical university, beijing 100038, china. 2 department of cardiology, beijing shijitan hospital, capital medical university, beijing 100038, china. 3department of physical examination center, beijing shijitan hospital, capital medical university, beijing 100038, china. *correspondence: department of urology, beijing shijitan hospital, capital medical university, 10 tieyi road, haidian district, beijing 100038, china. tel: +86 010 63926667. fax: +86 010 60298651. e-mail: yyshijitan@126.com. received september 2015 & accepted february 2016 bph-related surgery.(2,3) apparently these complications can affect the quality of life and increase the medical expenses of the elderly. metabolic syndrome (mets) is a cluster of metabolic disorders that increased the risk of cardiovascular diseases and type 2 diabetes mellitus, which associated with central obesity, dyslipidemia, hyperglycemia, elevated blood pressure, and insulin resistance.(4) recent years, emerging studies have suggested that mets is correlated with bph/luts in different countries.(5,6) to date, a positive correlation between mets and prostate volume miscellaneus 2717 growth rate has been emphasized in clinical series.(7,8) however, little is known about the relationship between mets and the progression of bph. furthermore, most studies exclusively focused on the correlation between mets and prostate volume or prostate growth rate, without exploring the corresponding frequency and severity of luts with mets. a recent systematic review identified eight eligible studies showing the role of mets in the development of bph.(9) unfortunately, only the correlation between mets and prostate volume has been assessed, without strong available evidence regarding the severity of luts. in order to investigate the association between mets and the predictors of the progression of bph and the corresponding frequency and severity of luts, we carefully assessed the relationship between mets and the predictors for clinical bph progression and the overall ipss in patients with moderate to severe luts in chinese male population. we believe a better understanding of these relationships could lead to a better prevention of prostate diseases. materials and methods study subjects the institutional review board of the beijing shijitan hospital approved the present study in september 2014. from october 2014 to december 2014, 871 community elderly male residents who had an international prostate symptom score (ipss) > 7, and had consecutively participated in prostate health examinations at the beijing shijitan hospital were recruited in the present study. to minimize potential confounding factors and bias, the participants who had a former history of prostate or urethral surgery and those who had been diagnosed with urologic diseases, including urethral stricture, urologic infections, malignancy, or neurogenic bladder or who had been administrated drugs including anticholinergics, 5α-reductase inhibitors, phosphodiesterase-5 inhibitors and hormone replacement therapy, were excluded from the study. in summary, 86 men suffered one or several of the above conditions. sixteen men refused to undergo a transrectal ultrasound examination of the prostate. eleven men did not finish the ipss questionnaire. moreover, 196 patients taking bph-related medications and 32 patients were diagnosed with prostate cancer by prostate biopsy. finally, the remaining 530 participants were included in the present study. the dedicated informed consents were obtained from all subjects before enrolling. bph/luts assessment the subjects' medical histories were collected using a standardized structured questionnaire. the chinese version of the international prostate symptom score (ipss) was administered to the subjects to evaluate urinary symptoms. as proposed in the boston area community health (bach) survey,(5) ipss was both considered as a continuous and categorical variable, stratifying subjects as none/mild (0-7), moderate(8-19), and severe (20-35). luts were further categorized as voiding (incomplete emptying, weak stream, intermittency, straining) and storage (frequency, urgency and nocturia) and dichotomized as 5 or greater vs. less than 5 for voiding and 4 or greater vs. less than 4 for storage. the postvoid residual urine volume (pvr) and total prostate volume (tpv) were measured using transrectal ultrasonography, and tpv was calculated using the prolate ellipse formula (transverse × anteroposterior × cephalocaudal diameter × π/6). the maximum urinary flow rate (qmax) was determined by uroflowmetry at a voided volume of > 150 ml. the serum prostate-specific antigen (psa) levels were collected in the morning after an overnight fast and determined using radioimmunoassay. the serum testosterone was determined by automatic electrochemiluminescence immunoassay. all subjects underwent digital examinations of the rectum to exclude palpable prostatic nodules. according to results from the placebo-arm study of the medical therapy of prostatic symptoms study (mtops),(10) the defined predictors for clinical bph progression including a tpv ≥ 31 cm3, qmax < 10.6 ml/s, psa ≥ 1.6 ng/ ml, pvr ≥ 39 ml and age 62 years or older. definition of metabolic syndrome anthropometric measurements were measured by trained nurses using a standardized protocol. the waist circumference (wc) was measured from midway between the lowest rib and the iliac crest to the nearest 0.1 cm. two blood pressure (mm hg) measurements were obtained 5 minutes apart using a mercury sphygmomanometer on the right arm and the values were averaged. body weight (kg) and height (cm) were measured. body mass index (bmi) was calculated by dividing the weight (kg) by the square of height (m). blood specimens were obtained with the subjects in the fasting state at the same time as psa and serum testosterone levels. the biochemical analyses included fasting plasma glucose (fpg), triglycerides, high-density lipoprotein cholesterol (hdl-c), low-density lipoprotein cholesterol (ldl-c), and total cholesterol (tc). all laboratory parameters were measured on fresh serum obtained after a 12-hour overnight fast, when the patient had been sedentary in a sitting or supine position for 15 minutes. the mets was diagnosed using the 2005 national chovol 13 no 03 may-june 2016 2718 relationship between metabolic syndrome and clinical bph progression-zhao et al. lesterol education program-adult treatment panel iii (ncep-atp iii) criteria for asian americans.(11) the modified ncep-atp iii has defined the mets as the simultaneous occurrence of at least 3 of the following 5 risk factors: (1) waist circumference ≥ 90 cm, (2) triglycerides ≥ 150 mg/dl or drug treatment for elevated triglycerides, (3) high-density lipoprotein cholesterol (hdl-c) < 40 mg/dl or drug treatment for reduced hdl-c, (4) blood pressure ≥130/85 mmhg or antihypertensive drug treatment with a history of hypertension, (5) fasting plasma glucose (fpg) ≥ 100 mg/dl or drug treatment for elevated glucose. statistical analysis evaluation of data distribution showed a skewed distribution of the data set. differences between groups of subjects in medians (iqr) for quantitative variables and differences in distributions for categorical variables were tested with the kruskal-wallis 1-way analysis of variance and chi-square tests. we stratified subjects into 6 groups according to the number of metabolic components they met (0, 1, 2, 3, 4 and 5). the mantel-haenszel extension and chi-square tests were introduced to determine whether the percentage of subjects who were positive of predictors for clinical bph progression increased with the increasing in the number of metabolic components. multivariate logistic regression analyses adjusted for potential confounders (age and serum testosterone level) were performed to table 1. patients’ characteristics according to the presence or absence of metabolic syndrome. variables overall (n = 530) mets (n = 200) non-mets (n = 330) p value age (yeas) 65 (58-75) 61 (54-73) 67 (60-76) < .001* testosterone (ng/ml) 3.4 (3.2-3.7) 3.2 (3.0-3.3) 3.6 (3.4-3.8) < .001* bmi (kg/m2) 25.1 (23.3-27.1) 27.2 (25.3-29.0) 24.0 (22.2-25.6) < .001* waist (cm) 88 (82-94) 94 (90-99) 85 (80-89) < .001* sbp (mmhg) 136 (126-147) 139 (131-149) 134 (122-146) < .001* dbp (mmhg) 81 (74-87) 84 (76-90) 79 (72-84) < .001* fpg (mg/dl) 96.5 (89.3-109.8) 104.6 (94.4-116.3) 93.4 (88.2-101.5) < .001* triglycerides (mg/dl) 110.3 (81.9-169.6) 180.5 (124.6-234.7) 93.5 (69.7-122.8) < .001* hdl-c (mg/dl) 47.2 (40.0-55.2) 39.6 (35.3-46.0) 51.8 (44.8-59.6) < .001* ldl-c (mg/dl) 110.5 (88.1-131.8) 114.0 (94.3-132.8) 109.2 (86.2-131.1) .167 tc (mg/dl) 183.0 (158.6-204.6) 186.7 (165.0-204.6) 181.3 (156.0-204.1) .347 mets (%) 37.7 (200/530) tpv (cm3) 26.6 (23.1-31.2) 32.6 (28.4-36.8) 23.9 (22.1-26.4) < .001* ipss total score 13 (11-16) 16 (13-17) 12 (11-14) < .001* 8-19 (%) 94.2 (499/530) 85.5 (171/200) 99.4 (328/330) < .001 20-35 (%) 5.8 (31/530) 14.5 (29/200) 0.6 (2/330) voiding 8 (6-12) 11 (8-13) 7 (5-9) < .001* ≥ 5 (%) 89.2 (473/550) 97.0 (194/200) 84.5 (279/330) < .001 storage 5 (3-7) 5 (3-7) 5 (3-7) .912 ≥ 4 (%) 68.7 (364/550) 67.5 (135/200) 69.4 (229/330) .649 qmax (ml/s) 16.9 (7.7-18.8) 17.1 (7.7-18.8) 16.8 (7.7-18.8) .763 psa (ng/ml) 0.73 (0.43-1.06) 1.16 (1.00-1.58) 0.50 (0.34-0.68) < .001* pvr (ml) 34.6 (29.5-40.5) 37.8 (31.7-42.5) 32.6 (27.2-39.5) < .001* abbreviations: bmi, body mass index; sbp, systolic blood pressure; dbp, diastolic blood pressure; fpg, fasting plasma glucose; hdl-c, high-density lipoprotein cholesterol; ldl-c, low-density lipoprotein cholesterol; tc, total cholesterol; mets, metabolic syndrome; tpv, total prostate volume; ipss, international prostate symptom score; qmax, maximum urinary flow rate; psa, prostate-specific antigen; pvr, postvoid residual urine volume; aur, acute urinary retention. * kruskal-wallis 1-way analysis of variance. ∙chi-squared test. p value < .05 was considered statistically significant. miscellaneus 2719 relationship between metabolic syndrome and clinical bph progression-zhao et al. assess the association of mets and its components with each predictor for clinical bph progression, and the association between each individual mets component and the severity of luts and the specific risk of voiding and storage symptoms. multivariate-adjusted odds ratios (ors) and 95% confidence intervals (cis) were simultaneously estimated by logistic regression analyses. differences were considered statistically significant by a two-tailed p value of < 0.05. statistical analyses were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 13.0 for windows (spss inc., chicago, il, usa). results patients characteristics the characteristics of our study population are listed in table 1. the median age was 65 years (iqr, 5875 years), and the median serum testosterone level was 3.4 ng/ml (iqr, 3.2-3.7 ng/ml). the median bmi was 25.1 kg/m2 (iqr, 23.3-27.1 kg/m2) and approximately 16.2% (86/530) were obese (bmi ≥ 28 kg/m2). of the 530 patients, 37.7% (200/530) had mets. luts were considered as moderate and severe in 94.2% (499/530) and 5.8% (31/530) of subjects, respectively. the median voiding and storage scores were 8 (iqr, 6-12) and 5 (iqr, 3-7), respectively. bmi, ipss, tpv, pvr, and psa levels were higher and serum testosterone levels were lower in the mets group than in the non-mets group (all p < .001). we found a strong positive association between the present of mets and luts severity for overall ipss and voiding scores. the median ipss was greater by approximately 4 points in subjects with mets, and men more frequently had severe luts symptoms in subjects with mets (p < .001). voiding scores were increased by 57% in subjects with mets as compared with those without mets, and men more frequently had a voiding score ≥ 5 in subjects with mets (p < .001). however, there were no statistically significant association between mets and qmax and storage scores. association between number of mets components and predictors for clinical bph progression as shown in table 2. a total of 474 patients (89.4%) had at least 1 predictors of the risk of clinical progression of bph. the percentage of subjects with ≥ 1 predictors for clinical bph progression, the percentage of subjects with a tpv ≥ 31 cm3 and the percentage of subjects with a pvr ≥ 39 ml, all significantly increased as the number of mets components increased (all p < .001). on the other hand, although the median qmax was not associated with the presence of mets, the percentage of subjects with a qmax < 10.6 ml/s also increased significantly with the increase in the number of mets components (p = .032). notably, even for patients who did not meet the criteria of mets diagnosis (with < 3 mets components), a significant difference in the percentage of subjects with ≥ 1 predictors for clinical bph progression was also observed among patients with 1 or 2 components compared with those without any components of mets (0 vs. 1-2, 73.5% vs. 86.1%; chi-square test, p = .025; data not shown). however, the percentage of subjects with a psa ≥ 1.6 ng/ml or age ≥ 62 years did not associated with the number of mets components. association of mets and its components with each predictor for clinical bph progression after adjusting for age and serum testosterone level, the mets, waist circumference and fpg level were independently associated with the presence of tpv ≥ 31 cm3 (or = 17.030, 95% ci: 7.495-38.692; or = 1.101, 95% ci: 1.014-1.195; and or = 1.011, 95% ci: 1.0011.021, respectively, (table 3). in addition, the presence of pvr ≥ 39 ml showed an independent positive assotable 2. association between number of metabolic components and predictors for clinical bph progression. predicators overall components of metabolic syndrome (n) p value* (n = 530) 0 (n = 49) 1 (n = 148) 2 (n = 133) 3 (n = 121) 4 (n = 55) 5 (n = 24) ≥ 1 predictor (%) 89.4 73.5 81.1 91.7 96.7 all all < .001† age ≥ 62 years (%) 58.9 63.3 57.4 57.9 59.5 63.6 50.0 .865 tpv ≥ 31 cm3 (%) 25.7 12.2 16.2 18.8 37.2 40.0 58.3 < .001† qmax <10.6 ml/s (%) 31.5 18.4 26.4 33.8 33.9 41.8 41.7 .032† psa ≥ 1.6 ng/ml (%) 9.2 none none none 28.9 23.6 16.7 .410 pvr ≥ 39 ml (%) 33.8 6.1 10.8 26.3 56.2 63.6 91.7 < .001† abbreviations: tpv, total prostate volume; qmax, maximum urinary flow rate; psa, prostate-specific antigen; pvr, postvoid residual urine volume. * mantel-haenszel extension test. † statistically significant difference (p < .05). vol 13 no 03 may-june 2016 2720 relationship between metabolic syndrome and clinical bph progression-zhao et al. ciation with waist circumference (or = 1.075, 95% ci: 1.009-1.145). association of each mets component with the severity of luts the association between each individual component of mets and luts is shown in table 4. there was a positive association between each individual mets component and the presence of severe luts (ipss>19, all p < .001). moreover, blood pressure and fpg level were independently associated with a voiding scores ≥ 5 (or = 2.993, 95% ci: 1.539-5.820; and or = 3.074, 95% ci: 1.419-6.657, respectively) in multivariate logistic regression analyses. however, there was no statistically significant association between any individual mets component and a storage scores ≥ 4. discussion this is the first study to investigate the association between mets and the predictors for clinical bph progression and overall ipss in patients with moderate to severe luts in chinese male population. we found that the percentage of subjects with predictors for the progression of bph significantly increased as the number of mets components increased, and the specific mets component were independently associated with predictors of bph progression after adjusting for age and serum testosterone level. we also found a strong positive association between the present of mets and luts severity for overall ipss and voiding scores, and there was a positive association between each mets component and the presence of severe luts. moreover, blood pressure and fpg level were independently associated with a voiding scores ≥ 5. mets is a complex and widespread epidemic disorder with a high socio-economic impact, due to its association with increased morbidity and mortality. to date, a positive link between mets and prostate volume growth rate has been emphasized in clinical series.(7,8) although the exact pathophysiology linking mets and bph/ luts remains unknown, there are several hypotheses were introduced to depict this association, including the insulin growth factor pathway, leading to prostate cells growth and proliferation, the chronic prostatic inflammation, leading to the development of bph nodules, and pelvic atherosclerosis, leading to chronic ischemia of the bladder and prostate, which can result in structural and functional impairment.(12) these mechanisms might still exist after bph/luts development and could continuously affect the clinical progression of bph. therefore, it is important to identify whether and how the mets-related events contribute to the clinical progression of bph. in the present study, we found that fasting glucose level and central obesity (waist circumference) were associated with a tpv ≥ 31 cm3. these results are in close agreement with numerous former studies. initially, hammarsten and colleagues(13) found correlations between the annual prostate growth rates, mets, and fasting plasma insulin levels and concluded that bph might be an insulin resistance-related disorder, and this founding is supported by the study of dahle and colleagues,(14) that a high correlation was found between hyperinsulinemia and the median prostate growth rate in a 280 patients’ cohort. a recent report demonstrated that diet-induced insulin resistance and compensatory elevated plasma insulin resulted in increased cellular proliferation, prostate enlargement and reduced prostate table 3. association of metabolic syndrome and its components with each predictor for clinical benign prostatic hyperplasia progression. tpv ≥ 31 cm3 qmax ＜ 10.6 ml/s psa ≥ 1.6 ng/ml pvr ≥ 39 ml factors or 95% ci p value* or 95% ci p value* or 95% ci p value* or 95% ci p value* wc 1.101 1.014-1.195 .021† 1.010 0.950-1.074 .748 0.968 0.882-1.061 .485 1.075 1.009-1.145 .025† sbp 1.008 0.987-1.028 .458 1.007 0.992-1.022 .369 1.004 0.981-1.029 .712 1.002 0.987-1.017 .775 dbp 1.002 0.974-1.031 .875 0.983 0.961-1.005 .119 0.975 0.941-1.010 .164 1.005 0.983-1.027 .659 fpg 1.011 1.001-1.021 .031† 0.999 0.992-1.007 .864 0.988 0.986-1.011 .815 1.003 0.996-1.010 .447 tg 1.000 0.998-1.002 .998 0.999 0.997-1.002 .496 1.000 0.996-1.004 .970 1.000 0.998-1.002 .978 hdl-c 0.980 0.951-1.009 .172 0.997 0.978-1.016 .752 1.008 0.980-1.038 .571 0.998 0.979-1.018 .837 mets 17.030 7.495-38.692 <.001† 0.998 0.572-1.742 .995 0.473 0.192-1.161 .102 1.670 0.962-2.900 .068 abbreviations: or, odds ratio; ci, confidence interval; wc, waist circumference; sbp, systolic blood pressure; dbp, diastolic blood pressure; fpg, fasting plasma glucose; tg, triglycerides; hdl-c, high-density lipoprotein cholesterol; mets, metabolic syndrome; qmax, maximum flow rate; tpv, total prostate volume; psa, prostate-specific antigen; pvr, postvoid residual urine volume. * multivariate logistic regression analysis, adjusted for age and serum testosterone. † statistically significant difference (p < .05). miscellaneus 2721 relationship between metabolic syndrome and clinical bph progression-zhao et al. atrophy and apoptosis in rats.(15) as considered to be the core pathophysiology of mets, insulin resistance leads to secondary hyperinsulinemia in order to maintain glucose homeostasis. increased fasting glucose levels are likely to be accompanied by hyperinsulinemia which stimulates the liver and then, results in an increase in free biologically active igf-1 (insulin-like growth factor, a known prostatic mitogen) levels and induces a cluster of disorders such as central obesity, increased igf-1 favor prostate gland growth and lead to prostatic enlargement.(16) on the other hand, central obesity may play a key role in the pathogenesis of mets. although the pathophysiology is incompletely understood, the role of fatty adipose tissue has been assumed by the fact that an excess of fatty acids and cytokines may induce insulin resistance and compensatory hyperinsulinemia. in a retrospective study of 409 men aged ≥ 40 years, as the waist circumference increased from < 90 cm to 9099 cm to ≥ 100 cm, the likelihood of an increased prostate volume was greater after adjusting for age (or = 1.39, p = .01).(17) moreover, parsons and colleagues(18) have confirmed that men above the 50th percentile of waist circumference (i.e. 96.5 cm) had increased risk of prostate enlargement compared with those below this threshold (or = 1.58; 95% ci: 1.06-2.36), in addition, they also found that men with increased fasting glucose levels were three times more likely to have prostate enlargement than those with normal levels. in accordance with the aforementioned results, our data confirms that insulin resistance is an important etiologic link between mets and the increased risk of bph. additionally, we found that central obesity (waist circumference) correlated with a pvr ≥ 39 ml. a recent epidemiological study(19) from europe of 4666 participants showed a positive correlation between waist circumference and ipss. however, no data concerning the pvr were included in that study. to our knowledge, this is the first study suggesting an association between waist circumference and pvr. there is a pathophysiology known to be associations between central obesity and pvr. central obesity can affect the androgen-estrogen conversion process, so that obese patients often have relatively lower levels of testosterone.(20) ehrén and colleagues(21) has suggested that nitric oxide may influence the dilation of the bladder neck. testosterone modulates nitric oxide (nos) activity; thus we can speculate that low levels of testosterone may possibly inhibit bladder neck dilation by regulating the nos metabolism. consequently, this mechanism might influence the relationship between central obesity and a pvr ≥ 39 ml in patients with moderate to severe luts in the present study. recent data(22,23) have, indeed, suggested that low testosterone might be an additional mets component that induces urinary tract diseases, and this hypothesis is also supported by our data (3.2 vs. 3.6 ng/ml, p < .001; kruskal-wallis 1-way analysis of variance). unfortunately, despite the importance of the public table 4. association of each metabolic syndrome component with the severity of luts. variables waist circumference sbp ≥ 130 mmhg and/or fasting plasma glucose ≥ triglycerides ≥ high-density lipoprotein ≥ 90 cm dbp ≥ 85 mmhg 100 mg/dl 150 mg/dl cholesterol < 40 mg/dl yes, no, p value∙ yes, no, p value∙ yes, no, p value∙ yes, no, p value∙ yes, no, p value∙ % % % % % % % % % % pipss < .001† < .001† < .001† < .001† < .001† 8-19 88.2 98.7 91.8 100 89.4 97.4 86.1 97.8 83.3 97.5 20-35 11.8 1.3 8.2 0 10.6 2.6 13.9 2.2 16.7 2.5 voiding or = 1.926 or = 2.993 or = 3.074 or = 2.508 or = 0.945 ≥ 5* 95% ci: 0.762-4.870 95% ci: 1.539-5.820 95% ci: 1.419-6.657 95% ci: 0.951-6.611 95% ci: 0.388-2.298 p = .166 p = .001† p = .004† p = .063 p = .900 storage or = 0.725 or = 1.076 or = 0.862 or = 1.150 or = 1.192 ≥ 4* 95% ci: 0.402-1.307 95% ci: 0.689-1.680 95% ci: 0.568-1.308 95% ci: 0.681-1.941 95% ci: 0.713-1.993 p = .285 p = .747 p = .485 p = .601 p = .04 abbreviations: or, odds ratio; ci, confidence interval; sbp, systolic blood pressure; dbp, diastolic blood pressure; ipss, international prostate symptom score. ∙ chi-squared test. * multivariate logistic regression analysis, adjusted by age, serum testosterone level, body mass index, total prostate volume, postvoid residual urine volume and serum prostate-specific antigen level. † statistically significant difference (p < .05). vol 13 no 03 may-june 2016 2722 relationship between metabolic syndrome and clinical bph progression-zhao et al. health impact of these two pathologies, correlation between mets and bph/luts has not been thoroughly studied. a recent systematic review identified eight eligible studies showing the role of mets in the development of bph,(9) whereas only the correlation between mets and prostate volume has been assessed, without strong available evidence regarding the frequency and severity of luts. theoretically luts are considered as a substitute for the course of bph and often resulting from an enlarged prostate and heightened tone of the prostate and bladder smooth muscle. to our knowledge, we have firstly evaluated the relationship between mets and the overall ipss in patients with moderate to severe luts. in addition we also investigated the role of each individual mets component in this potential relationship. in the present study, participants with mets had a higher ipss score and voiding score (p < .001; p < .001, respectively), and there was a positive association between each individual mets component and the presence of severe luts (ipss > 19, all p < .001). moreover, blood pressure and fasting glucose level were independently associated with a voiding score ≥ 5 (or = 2.993, 95% ci: 1.539-5.820; and or = 3.074, 95% ci: 1.419-6.657, respectively). in the third national health and nutrition examination study (nhanes iii),(24) where of 2372 male participants, those with at least 3 components of mets were at 80% increased risk for luts defined as a report of 3 or 4 urologic symptoms in men aged ≥ 60 years compared with those without any components (or = 1.6; 95% ci: 1.0-2.6). similarly, bach survey(5) showed a statistically significant association between mets and mild to severe luts (multivariate or = 1.68, 95% ci: 1.21-2.35), the prevalence of mets were lowest (about 20%) for men reporting no symptoms or 1 symptom and increased with mild luts (aua-si) to approximately 40%, and a statistically significant association was also observed between mets and a voiding score ≥ 5 (multivariate or = 1.73, 95% ci: 1.06-2.80) but not for a storage score ≥ 5 (multivariate or = 0.94, 95% ci: 0.66-1.33). results of the present study strengthen the evidences that mets correlates with the severity of luts, especially the voiding symptoms. possible pathophysiological mechanisms to explain the relationship between mets and luts include the influence of sustained hyperglycemia on the viability of parasympathetic neurons in the pelvic ganglion. animal studies have shown that long-term increased serum glucose induces neuronal apoptosis that favors parasympathetic neuron compared to sympathetic neuron.(25) such an unbalanced loss of autonomic neurons might induce an oversupply of sympathetic tone compared to parasympathic efferent activity. in addition, hypertension is also known to be associated with increased sympathetic tone and α1-adrenoceptor function.(26,27) therefore, it is presumed that an increased sympathetic tone may result in increased bladder neck obstruction and reduced bladder power. taken together, these changes could collaboratively culminate in increased voiding symptoms as reported in the present study. in addition, the rho kinase system plays an important role in prostate contractility by modifying the calcium sensitivity of the contractile muscles.(28,29) higher levels of interleukin (il)-8 and of the vasoconstrictor endothelin-1, which are usually observed in men with mets, may lead to an increased activity of the rho kinase system that in turn may result in prostate contractility, including voiding symptoms.(30-32) in a former clinical study, doxazosin, an α-blocker used for symptomatic prostatic hyperplasia treatment, was shown to increase insulin sensitivity and reduce insulin levels.(33) however, a few studies do not support the association between mets and luts. gao and colleagues(34) retrospectively evaluated the effect of mets on the severity of luts with data from a healthy and examination survey project in china, they concluded that no significant were found in the severity of luts in men with or without mets. however, their study is difficult to compare with our results as they took the whole man population as the study objects, regardless of whether or not there was a concomitant bph existed, and their subjects are younger (median age were 39 vs. 65 of the present study) and less symptomatic (92.1% participants with mild luts). even so, their study found moderate or severe storage symptoms were inversely correlated with mets. the same considerations are also valid for similar studies performed in an asian population where no significant differences were found in the severity of luts between the mets and non-mets group.(35) our finding certainly need further confirmatory studies, but once confirmed, would raise a number of questions regarding the different components of mets such as central obesity, diabetes and hypertension, multiple serum hormone alterations including testosterone, and insulin resistance that may promote the development and progression of bph and specifically the voiding symptoms in patients with moderate to severe luts. our data suggests that improved clinical attention, including finding the bph progression, prescribing a combination of α-blockers and 5α-reductase inhibitors to reduce bph progression, and more detailed counseling concerning the prognosis of bph/luts, is needed for miscellaneus 2723 relationship between metabolic syndrome and clinical bph progression-zhao et al. patients with the mets and bph/luts. the sixth national census of china in 2010 showed that 13.26% of the chinese population was older than 60 years. with the arriving of aging society, the predicted increase in the proportion of elderly people in future years means that the prevalence of bph/luts and costs of treatment will continue to increase, thus chinese urologists confronted with challenges of applying early intervention or cost-effective approaches for urinary tract diseases at a relatively low medical expenses. a recent meta-analysis of eleven studies found that physical activity decreases the risk of bph by as much as 25% relative to a sedentary lifestyle.(36) indeed, gacci and colleagues(37) have suggested that mets could be regarded as a new determinant of bph/luts. despite the best efforts, some potential limitation in the present study should be considered. first, we acknowledge that the results of our study are only hypotheses generated, and we have already organized a multicenter longitudinal confirmatory study with other urology centers involved in china. second, a potential selection bias was present because our study included only subjects from a single institution, which could also be improved by performing the multicenter study in the future, which is in progress indeed, as conducted by the department of urology research institute of peking university. another possible limitation was the use of self-report ipss questionnaires for assessing the severity of luts. this may introduce a potential response bias, as respondents may inaccurately report their urinary symptoms. however, the questionnaires selected for this study have all been formerly validated in clinical and nonclinical samples and are used worldwide. finally, we did not evaluate insulin levels and insulin resistance indexes, while former studies have suggested a significant association of insulin resistance or hyperinsulinemia with the prostate volume.(6,33) conclusions at the present of time, this is the largest contemporary prospective series evaluating the association between mets and the predictors for clinical bph progression and the overall ipss in patients with moderate to severe luts. we found that mets significantly associated with the predictors for clinical bph progression and the corresponding frequency and severity of luts, especially the voiding symptoms. the prevention of such modifiable factors by promotion of dietary changes and regular physical activity practice may be of great importance for public health. further investigations with long-term follow-up are needed to better understand the role of mets as a potential risk factor for bph/luts progression and to identify new possible therapeutic targets and open novel strategies for the management of bph/luts. acknowledgements this work was supported by funding from beijing municipal science & technology commission (no. z141100002114005) and china railway corporation (no.2014z005-c). conflict of interest none declared. references 1. wei jt, calhoun e, jacobsen sj. urologic diseases in america project: benign prostatic hyperplasia. j urol. 2008;179(5 suppl):s75-80. 2. fitzpatrick jm. the natural history of benign prostatic hyperplasia. bju int. 2006;97(suppl 2):3-6. 3. emberton m, cornel eb, bassi pf, fourcade ro, gómez jm, castro r. benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. int j clin pract. 2008;62:107686. 4. grundy sm, hansen b, smith sc jr, cleeman ji, kahn ra. clinical management of metabolic syndrome: report of the american heart association/national heart, lung, and blood institute/american diabetes association conference on scientific issues related to management. circulation. 2004;109:551-6. 5. kupelian v, mcvary kt, kaplan sa, et al. association of low urinary tract symptoms and the metabolic syndrome: results from the boston area community health survey. j urol. 2013;189:s107-s16. 6. zhang x, zeng x, liu y, dong l, zhao x, qu x. impact of metabolic syndrome on benign prostatic hyperplasia in elderly chinese men. urol int. 2014;93:214-9. 7. hammarsten j, högstedt b, holthuis n, mellström d. components of the metabolic syndrome-risk factor for the development of benign prostatic hyperplasia. prostate cancer prostatic dis. 1998;1:157-62. 8. ozden c, ozdal ol, urgancioglu g, koyuncu h, gokkaya s, memis a. the correlation between metabolic syndrome and prostatic growth in patients with benign prostatic hyperplasia. eur urol. 2007;51:199203. 9. gacci m, corona g, vignozzi l, et al. metabolic syndrome and benign prostatic enlargement: a systematic review and metavol 13 no 03 may-june 2016 2724 relationship between metabolic syndrome and clinical bph progression-zhao et al. analysis. bju int. 2015;115:24-31. 10. crawford ed, wilson ss, mcconnell jd, et al. baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo. j urol. 2006;175;1422-6. 11. grundy sm, cleeman ji, daniels sr, et al. diagnosis and management of the metabolic syndrome: an american heart association/national heart, lung, and blood institute scientific statement. circulation. 2005;112:2735-52. 12. de nunzio c, aronson w, freedland sj, giovannucci e, parsons jk. the correlation between metabolic syndrome and prostatic diseases. eur urol. 2012;61:560-70. 13. hammarsten j, högstedt b. hyperinsulinemia as a risk factor for developing benign prostatic hyperplasia. eur urol. 2001;39:1518. 14. dahle se, chokkalingam ap, gao yt, deng j, stanczyk fz, hsing aw. body size and serum levels of insulin and leptin in relation to the risk of benign prostatic hyperplasia. j urol. 2002;168:599-604. 15. vikram a, jena g, ramarao p. insulinresistance reduces botulinum neurotoxin-type a induced prostatic atrophy and apoptosis in rats. eur j pharmacol. 2011;650:356-65. 16. hammarsten j, damber je, karlsson m, et al. insulin and free oestradiol are independent risk factors for benign prostatic hyperplasia. prostate cancer prostatic dis. 2009;12:16065. 17. lee rk, chung d, chughtai b, te ae, kaplan sa. central obesity as measured by waist circumference is predictive of severity of lower urinary tract symptoms. bju int. 2012;110:540-5. 18. parsons jk, carter hb, partin aw, et al. metabolic factors associated with benign prostatic hyperplasia. j clin endocrinol meta. 2006;91:2562-8. 19. pashootan p, ploussard g, cocaul a, gouvello a, desgrandchamps f. association between metabolic syndrome and severity of lower urinary tract symptoms (luts): an observational study in a 4666 european men cohort. bju int. 2015;116:124-30. 20. kristal ar, arnold kb, schenk jm, et al. race/ethnicity, obesity, health related behaviors and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. j urol. 2007;177:1395-400. 21. ehrén i, iversen h, jansson o, adolfsson j, wiklund np. localization of nitric oxide synthase activity in the human lower urinary tract and its correlation with neuroeffector responses. urology. 1994;44:683-7. 22. corona g, rastrelli g, vignozzi l, mannucci e, maggi m. testosterone, cardiovascular disease and the metabolic syndrome. best pract res clin endocrinol metab. 2011;25:337-53. 23. vignozzi l, morelli a, sarchielli e, et al. testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. j endocrinol. 2012;21:71-84. 24. rohrmann s, smit e, giovannucci e, platz ea. association between markers of the metabolic syndrome and lower urinary tract symptoms in the third national health and nutrition examination survey (nhanes iii). int j obes (lond). 2005;29:310-6. 25. cellek s, rodrigo j, lobos e, fernández p, serrano j, moncada s. selective nitrergic neurodegeneration in diabetes mellitusa nitric oxide-dependent phenomenon. br j pharmacol. 1999;128:1804-12. 26. goldstein ds. plasma catecholamines and essential hypertension: an analytical review. hypertension. 1983;5:86-99. 27. michel mc, brodde oe, insel pa. peripheral adrenergic receptors in hypertension. hypertension. 1990;16:107-20. 28. rees rw, foxwell na, ralph dj, kell pd, moncada s, cellek s. y-27632, a rho-kinase inhibitor, inhibits proliferation and adrenergic contraction of prostatic smooth muscle cells. j urol. 2003;170:2517-22. 29. takahashi r, nishimura j, seki n, et al. rhoa/rho kinase-mediated ca2+ sensitization in the contraction of human prostate. neurourol urodyn. 2007;26:547-51. 30. zozuliñska d, majchrzak a, sobieska m, wiktorowicz k, wierusz-wysocka b. serum interleukin-8 level is increased in diabetic patients. diabetologia. 1999;42:117-8. 31. khan za, chakrabarti s. endothelins in chronic diabetic complications. can j physiol pharmacol. 2003;81:622-34. 32. penna g, fibbi b, amuchastegui s, et al. the vitamin d receptor agonist elocalcitol inhibits il-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the rhoa/rho kinase and nf-kappab pathways. prostate. 2009;69:480-93. 33. shieh sm, sheu wh, shen dc, fuh mm, chen yd, reaven gm. glucose, insulin, and lipid metabolism in doxazosin-treated patients with hypertension. am j hypertens. 1992;5:827-31. 34. gao y, wang mj, zhang hy, et al. are metabolic syndrome and its components associated with lower urinary tract symptoms? results from a chinese male population survey. urology. 2012;79:194201. 35. park hk, lee hw, lee ks, et al. relationship between lower urinary tract symptoms and metabolic syndrome in miscellaneus 2725 relationship between metabolic syndrome and clinical bph progression-zhao et al. a community based elderly population. urology. 2008;72:556-60. 36. parsons jk, kashefi c. physical activity, benign prostatic hyperplasia, and lower urinary tract symptoms. eur urol. 2008;53:1228-35. 37. gacci m, vignozzi l, sebastianelli a, et al. metabolic syndrome and lower urinary tract symptoms: the role of inflammation. prostate cancer prostatic dis. 2013;16:101-6. vol 13 no 03 may-june 2016 2726 relationship between metabolic syndrome and clinical bph progression-zhao et al. urol_v3_no1_001_editorial.qxd review articles current management of renal cell carcinoma and targeted therapy a erdem canda,1 ziya kirkali2* 1manisa sarigol state hospital, manisa, turkey 2department of urology, dokuz eylul university school of medicine, izmir, turkey abstract introduction: the aim of this review is to provide an update on the current management of renal cell carcinoma (rcc) and targeted molecular therapy for metastatic rcc. materials and methods: a pubmed database search was performed using the keywords "renal cell carcinoma, treatment, management, localized disease, metastatic disease and targeted therapy" covering 1995 to 2006. the most recent articles published having clinical relevance were reviewed for the preparation of this paper. results: surgery is considered as the only curative treatment for localized rcc. currently, open radical nephrectomy is mainly performed in patients with large tumor size, locally advanced tumors and tumor thrombus extending into the vena cava. nephron sparing surgery (nss) is the most commonly performed procedure with excellent local cancer control in small, resectable renal tumors. increasingly, laparoscopy is being performed and now recommended for early-stage rccs unsuitable for nss. laparoscopic radical nephrectomy seems to be providing long-term cancer control comparable to open radical nephrectomy. laparoscopic nss is now available particularly in patients with a relatively small and peripheral renal tumor. the current therapy for metastatic rcc is inadequate and surgery is an important component of the treatment with combined immunotherapy in which response rates remain at about 15% to 25%. in the past several years, significant advances in the underlying biological mechanisms of rcc development have permitted the design of new molecularly targeted therapeutics such as antibodies, tumor vaccines, anti-angiogenesis agents and small molecule tyrosine kinase inhibitors in order to improve treatment options. conclusion: surgery is the only curative treatment for localized rcc and nss cures most of the patients with early-stage disease. currently laparoscopy is recommended for early-stage rccs unsuitable for nss. better understanding of the molecular pathways of carcinogenesis in rcc leads to the discovery of new drugs which can prolong survival in metastatic rcc. key words: renal cell carcinoma, treatment, management, localized disease, metastatic disease, targeted therapy 1 urology journal unrc/iua vol. 3, no. 1, 1-14 winter 2006 printed in iran *corresponding author: department of urology, school of medicine, dokuz eylul university, izmir 35340, turkey. tel: +90 232 278 7477, fax: +90 232 278 7477 e-mail: ziya.kirkali@deu.edu.tr introduction renal cell carcinoma (rcc) accounts for 3% of adult solid tumors, and each year more than 30000 new cases in the united states and 20000 in the european union are detected. the highest renal cell carcinoma and targeted therapy2 incidence of rcc is detected between 50 and 70 years of age and men are affected twice as often as women.(1) due to the widespread use of imaging modalities such as ultrasonography and computed tomography, most kidney tumors are being detected incidentally with a smaller size, leading to the increased incidence of rcc.(2) in the pathogenesis of conventional rcc, mutations leading to inactivation of the von hippel-lindau tumor suppressor gene (vhl) have been detected in the hereditary and up to 80% of sporadic forms of clear cell rcc, and premalignant lesions in the kidney such as renal intra-epithelial neoplasms have been described which seem to be sharing similar genetical changes with rcc.(3,4) there are limited independent predictors of survival in patients with rcc. although there are promising clinical, histological, molecular, and cytogenetic parameters, none of them has yet been shown to have an independent prognostic value. tumor stage, tumor grade, and patient performance status are the currently known prognostic indicators.(5) presence of necrosis is also considered as a prognostic marker for rcc and has been recommended to be routinely reported and used in clinical assessments.(6) diagnosis, staging, and treatment of patients with rcc have improved significantly during the last 2 decades; however, despite advances in biological and immune-based therapies, response rates for patients with metastatic rcc remain at about 15% to 25%.(7) the number of patients who will benefit from cytokine-based therapy with interleukin-2 (il-2) and/or interferon alfa (ifnalpha) is limited, and currently, there is no proven effective therapy in patients who do not respond or relapse after this treatment. therefore, treatment alternatives other than cytokine-based therapy are being developed in order to improve treatment options in the management of metastatic rcc, particularly in those who are unable to tolerate or who are resistant to systemic immunotherapy. treatment of localized disease open surgery open radical nephrectomy. radical nephrectomy (rn) cures most of the patients with localized early-stage disease,(8) but half of the patients with localized disease progress after rn.(1) currently, open rn is mainly performed in patients with a large tumor which is not amenable to nephron sparing surgery (nss) and can not be dealt with laparoscopy, in the presence of complicated tumor thrombus extension into the vena cava and when there is need for surgery for other diseases (eg, renal artery stenosis) or single organ metastases when metastasectomy is being performed. due to the low incidence of unsuspected lymph nodes and the rarity of the lymph node involvement without distant metastases, lymph node sampling is currently recommended in case of suspicion. adrenalectomy seems to be unnecessary unless there is involvement on imaging studies or at the time of operation and in tumors not involving the upper pole. the 5-year patient survival rates have been reported to be 75% to 95% for organ-confined disease, 65% to 80% for perinephric fat or adrenal involvement, 40% to 60% for vena cava thrombus, 10% to 20% for lymph node involvement, and 0% to 5% for metastatic disease after rn.(9) open partial nephrectomy. although rn was the standard treatment of kidney tumors in the past,(10) recently, due to similar cancer-specific survival rates detected for patients undergoing rn or nss for small kidney masses (< 4 cm), nss is considered as the treatment of choice in most kidney tumors.(11-13) because of the increased prevalence of incidentally detected rccs with smaller sizes, nss is increasingly being performed with a successful cancer control and preservation of the renal parenchyma. the tumor(s) has to be removed very carefully with a minimal safety margin, and in case of doubt, ultrasonography or biopsy of the tumor bed may be used.(14) wedge resection and polar nephrectomy are the surgical techniques of choice. water-jet resection is a recently developed technique that holds some promise. although tumor enucleation might be associated with an increased risk of positive surgical margin,(15) some authors suggest enucleation as a lessinvasive alternative to ordinary nss for small rccs by using microwave tissue coagulation or laser for the tumor and tumor bed.(16) the disease-free survival has been detected to be decreased in patients undergoing nss for lesions larger than 4 cm compared to those with a tumor smaller than 4 cm and those who undergo rn; therefore, nss is recommended for peripherally located tumors smaller than 4 cm in size (table 1).(17) recently, no significant differences in cancer specific survival and distant canda and kirkali metastases-free survival were detected between patients with 4to 7-cm rccs treated by nss and rn. thus, nss is recommended for 4-cm to 7-cm rccs, because it results in an excellent outcome in appropriately selected patients.(18) there is controversy regarding the cutoff size of the kidney tumors for elective nss and kidney tumors smaller than 7 cm have been considered suitable only in carefully selected patients.(13) the reported local recurrence after elective nss is as low as 1% which demonstrated that nss can be cured with an excellent local control.(19) indications for open partial nephrectomy (pn) are summarized on table 2. tumor size, location, surgical margin, multifocality, and pathologic variables affect the outcome in elective nss.(13,18) increased tumor size, pt2 or higher stages, presence of vascular invasion, and papillary or mixed histology are associated with an increased risk of multifocality.(15) lower tumor stages, lower nuclear grades, papillary or chromophobe histology, and incidentally detected tumors are considered as good prognostic pathologic factors after pn.(18) currently, nss is considered as the most commonly performed procedure in the management of kidney tumors, particularly with smaller sizes which are frequently diagnosed incidentally. minimally invasive surgery laparoscopic radical nephrectomy. laparoscopy has gained popularity in the management of urologic malignancies and rn can be safely performed for rcc by laparoscopy or retroperitoneoscopy leading to a less morbidity and a better patient acceptance. laparoscopic rn (lrn) is now considered as the treatment of choice for early-stage (t1n0m0) rccs unsuitable for nss (table 3).(21,22) the advantages of lrn are reduced blood loss, decreased postoperative pain, earlier recovery, decreased total time of convalescence, and decreased length of hospital stay, whereas, the cost and the need for a highly skilled operating team are the major limitations.(22) a 5-year recurrence-free survival of 91% and a 5-year cancer-specific survival of 98% have been reported for lrn, which is comparable to open rn in terms of providing long-term cancer control. similar complication 3 table 1. disease-free survival rates in 3 groups of patients with partial nephrectomy according to the tumor size five-year disease free survival (%) number of patients tumor < 4 cm tumor 4 cm to 7 cm tumor > 7 cm elective surgery (%) lee and colleagues (19) 79 95 47 hafez and colleagues (16) 485 96 86 9 belldegrun and colleagues (20) 108 100 90 66 58 lerner and colleagues (17) 54 91 100 table 2. indications for open partial nephrectomy(13) absolute tumors in a solitary kidney bilateral synchronous kidney tumors severe renal insufficiency relative presence of a pre-existing kidney disease in the contralateral side nephrolithiasis recurrent pyelonephritis mild to moderate renal insufficiency ureteropelvic junction obstruction vesicoureteral reflux presence of diseases predisposing to renal insufficiency diabetes mellitus hypertension presence of a known multifocal disease or underlying genetic syndromes papillary renal cell carcinoma von hippel-lindau disease elective kidney tumors smaller than 4 cm peripherally located lesions in the kidney healthy young individuals renal cell carcinoma and targeted therapy rates for open rn, hand-assisted rn, and lrn have been detected (10%, 17%, and 12%, respectively), and currently laparoscopic approach is recommended for the majority of patients with stage t1 and stage t2 tumors.(23) laparoscopic partial nephrectomy. laparoscopy is a minimally invasive approach which is emerging as an effective surgical alternative to open surgery for small and peripheral kidney tumors. laparoscopic partial nephrectomy (lpn) is suggested for kidney tumors particularly smaller than 4 cm which offers advantages similar to lrn, such as earlier hospital discharge, more rapid convalescence, reduced postoperative narcotic use, and effective cancer control with acceptable complication rates (table 4).(20, 24-26) ablative treatments. ablative techniques for the treatment of rcc are an extension of nss and include minimally invasive treatments such as cryoablation, radiofrequency ablation (rfa), and high-intensity focused ultrasonography (hifu) which have been introduced recently. these might decrease morbidity by treating kidney tumors in situ rather than extirpation. cryosurgery is the most studied of the ablative approaches, and clinical studies have demonstrated promising short-term results and a remarkable safety profile. long-term studies, however, are needed in order to determine the appropriate selection criteria and to confirm a response as durable as that for pn and rn. they might have advantages compared with conventional open kidney surgery such as shorter convalescence, improved cosmetic results, reduced postoperative pain, and kidney preservation.(27) treatment of metastatic disease surgery and immunochemotherapy renal cell carcinoma is resistant to chemotherapeutic agents due to the presence of multidrug resistance-1 gene and one-third of patients with rcc present with metastatic disease.(1,28) the current best therapy for metastatic rcc is inadequate and surgery is an important component of the treatment due to the potential for improving the effectiveness of adjuvant therapy and possibly stimulating regression of metastases with combined immunochemotherapy using ifn-alpha, il-2, and 5-fluorouracil (5-fu).(28) nephrectomy in metastatic rcc should be recommended to those patients with a good performance status before immunotherapy.(29) on the other hand, initial 4 table 3. the expanding indications for laparoscopic radical nephrectomy in selected patients(20) larger tumors (> 7 cm, pt2) level 1 renal vein tumor thrombus cytoreductive nephrectomy limited locally invasive tumors into psoas or diaphragm muscle concomitant lymphadenectomy for small volume disease morbid obesity with renal cell carcinoma laparoscopic approach in the previously operated abdomen table 4. comparison of laparoscopic versus open nephron-sparing surgery (nss) in patients with a solitary kidney tumor of 7 cm or smaller in size in a study by gill and colleagues*(25) *no significant differences in the overall postoperative complications were detected between two groups. major intra-operative complications 5% 0% 0.02 renal/urological complications 11% 2% 0.01 median operative time (hours) 3 3.9 < 0.001 blood loss (ml) 125 250 < 0.001 mean warm ischemia time (minutes) 27.8 7.5 < 0.001 median analgesic requirement (morphine sulfate equivalents, mg) 20.2 252.5 < 0.001 hospital stay (days) 2 5 < 0.001 median convalescence (weeks) 4 6 < 0.001 median preoperative serum creatinine level (mg/dl) 1.0 1.0 0.52 median postoperative serum creatinine level (mg/dl) 1.1 1.2 0.65 canda and kirkali treatment with immunotherapy and delayed adjuvant nephrectomy has been proposed to avoid the morbidity of nephrectomy only in those who respond.(28) distinct genetic abnormalities affecting different molecular pathways result in the development of rcc leading to different clinical courses that respond differently to therapy.(30) determination of the molecular profile of each tumor might improve treatment and guide patient selection for targeted therapies. recently, a wide range of new agents are being introduced in the treatment of metastatic rcc. recently, promising response to a combination of 13-cis-retinoic acid with ifn-alpha-2a has been detected in patients with progressive metastatic rcc by the european organization for research and treatment of cancer genitourinary tract cancer group.(31) new drugs such as gemcitabine, capecitabine, or taxane-based chemotherapeutics may show promising antitumor activity in combination with targeted therapy.(32-34) current research is being focused on identification of novel agents and treatment modalities with a better antitumor activity such as antibodies, tumor vaccines, anti-angiogenesis agents, small molecule inhibitors, virus mediated gene transfer, and some other drugs. the hypoxia-inducible pathway and rcc the hypoxia-inducible pathway is important in angiogenesis, ph control, glucose metabolism, invasion/metastasis, and epithelial proliferation of malignant cells (figure 1); therefore, it might play a role in the adaptation of cancer cells to a hypoxic environment and their resistance to radiation and chemotherapy.(35,36) the vhl gene encodes vhl protein (pvhl) and in normoxia and a normal vhl gene function, pvhl targets hypoxia-inducible factor (hif) for proteolysis.(37,38) hypoxia-inducible factor is composed of hif-1α, hif-2α, hif-3α, and hif-1β. although hif-1β is constitutively expressed, biosynthesis and posttranslation of hif-1α is regulated. biosynthesis of hif-1α is induced by several growth factors such as insulinlike growth factor-i (igf-i), igf-ii, and epidermal growth factor (egf).(39) hypoxia controls hif-1α at the posttranslational level via pvhl.(37) under normoxic conditions, the hif-α subunit is hydroxylated at 2 proline residues by an oxygen5 fig. 1. the hypoxia inducible pathway(30) hif-1: hypoxia inducible factor-1, vhl: von hippel-lindau gene, tgfa: transforming growth factor-α, igf: insulin-like growth factor hif-1α wild type vhl hif degeneration hypoxia vhl loss/dysfunction hif accumulation target gene induction vegf angiogenesis ca metabolism ph regulation glut-1 glucose transport tgfa/igf growth survival other genes regulating cell cycles, apoptosis renal cell carcinoma and targeted therapy dependent mechanism. however, in hypoxia or defective pvhl function, due to the dysfunctional interaction between pvhl and hif-1α, hif-1α is not degraded and moves into the nucleus, dimerizes with hif-1β, and activates expression of hypoxia-inducible genes (table 5).(42,43) defective ubiquitination of hif subunits also occurs due to mutation, deletion, or hypermethylation of the vhl gene.(37,44) mutations leading to inactivation of the vhl have been detected in the hereditary and sporadic forms of clear cell rcc.(45) loss or mutation of the vhl is detected in 50% to 80% of sporadic clear cell rccs which suggests vhl-hif tumorigenic pathway for clear cell rcc.(40,41,44--46) therefore, vhl inactivation seems to cause vascular endothelial growth factor (vegf) overexpression, thus leading to tumor angiogenesis in the majority of clear cell rccs. molecular therapeutic approaches targeting vhl gene pathway and genes regulated by hif such as vegf, platelet-derived growth factor (pdgf), or the transforming growth factor-α/epidermal growth factor receptor (tgfa/egfr) autocrine loop are potential approaches in the treatment of rcc.(47) role of carbonic anhydrase ix in rcc carbonic anhydrase ix (ca9) is one of the genes that is regulated by hif-1.(48) the vhl gene dysfunction can lead to the accumulation of hif-1α and increased ca9 expression.(49) the ca9 gene is important in regulating intracellular and extracellular ph. therefore, it may be important for the accommodation of tumors to an acidic and hypoxic environment leading them to further proliferate and metastasize. it has been shown that normal fetal or adult kidney specimens do not express ca9, which suggests that it might be a product of tumor biology.(50) because ca9 is highly expressed by rcc, it might be used for vaccine development and as a target for immunotherapy.(50) low ca9 staining was found to be an independent prognostic factor of poor survival in patients with metastatic rcc, and complete response to il-2 immunotherapy has been detected to correlate with high ca9 expression.(51) targeted therapy antibodies. the antibodies selectively interact with the antigens expressed on malignant cells; therefore, guiding toxic substances or radionuclides to the tumor might have therapeutic effects (table 6). g250 (wx-g250) is a chimeric monoclonal antibody developed for rcc for both therapeutic and diagnostic purposes.(6) bleumer and colleagues administered intravenous g250 weekly to 36 patients with a metastatic rcc which was safe and well tolerated. eleven patients achieved stable disease including 1 complete response and 1 partial regression.(52) bevacizumab (avastin) is a recombinant human monoclonal antibody developed against vegf which binds and neutralizes all biologically active isoforms of vegf targeting the vhl/hif/vegf pathway.(53) yang and coworkers administered bevacizumab to 116 patients with a metastatic rcc. significant prolongation of time-toprogression was detected in patients receiving high-dose antibody versus placebo although survival was not significantly different.(54) no lifethreatening toxicities or deaths were detected. hypertension and asymptomatic proteinuria were detected particularly in patients who received high-dose bevacizumab antibody. all toxicities were reversible with cessation of therapy. vegf-trap is a combination of vegf receptor1 immunoglobulin (ig) domain 2 and vegf receptor-2 ig domain 3 fused to human igg1 which binds vegf with a 100-fold greater affinity 6 table 5. activation of genes and their products due to hif-1α accumulation(36,44,45) genes encoding growth and angiogenic factors vascular endothelial growth factor (vegf) erythropoietin (epo) platelet-derived growth factor (pdgf) transforming growth factor-α (tgfa) and its receptor epidermal growth factor receptor (egfr) genes encoding enzymes involved in glucose uptake and metabolism glucose transporter 1 (glut-1) phosphoglycerate kinase (pgk) ph regulation carbonic anhydrase ix (ca9) tissue-matrix metabolism matrix metalloproteinases canda and kirkali than bevacizumab.(55) in a phase 1 study vegftrap was administered to 9 patients with metastatic rcc and no objective responses were observed. drug-related grade 3 adverse events included hypertension and proteinuria.(56) erlotinib is a small-molecule egfr inhibitor and in a clinical trial conducted in patients with a metastatic rcc, intravenous bevacizumab (10 mg/kg, every 2 weeks) was administered with oral erlotinib (150 mg, daily); a 25% partial response rate was reported.(57) the egfr is expressed up to 85% in rcc, 7 table 6. current strategies for metastatic renal cell carcinoma treatment ca9: carbonic anhydrase ix, vegf: vascular endothelial growth factor, egfr: epidermal growth factor receptor, ctla-4: cytotoxic t-lymphocyte associated-4, bfgf: basic fibroblast growth factor pdgfr: platelet derived growth factor receptor, flt3: fms-like tyrosine kinase 3, pi3k-akt-mtor: phosphatidylinositol 4,5bisphosphate-akt-mtor, dcs: dendritic cells, hsppc-96: heat shock protein peptide complex 96 agent class mechanism of action/molecular target antibodies wx-250 targets ca9 bevacizumab targets vegf panitumumab, abx-egf targets egfr cetuximab, imc-c225 targets egfr mdx-010 targets ctla-4 to block lymphocyte activity suppression anti-angiogenesis agents thalidomide immunomodulatory agent, inhibits vegf + bfgf thalidomide analogues (cc5013) similar to thalidomide endothelin-1 receptor antagonists (atrasentan, abt-627) selective endothelin-1 receptor antagonist indolinone (su-011248) inhibits vegfr, pdgfr + flt3 signal transduction + c-kit tyrosine kinase vegfr + egfr inhibitors (zd 6474) targets vegfr and egfr vegfr inhibitors (ptk 787) selectively targets vegfr 1, vegfr-2 + vegfr-3 tyrosine kinases thrombospondin-1 mimetics (abt-510) synthetic peptide that mimics thrombospondin-1 antiangiogenic activity small molecule inhibitors rapamycin + rapamycin analogues cci-779, rad001 inhibits pi3k-akt-mtor signal transduction pathway raf kinase inhibitors bay 43-9006 targets raf kinase + vegfr-2 proteasome inhibitors bortezomib, ps-341 inhibits 26s proteasome catalytic activity, prevents proteolysis egfr tyrosine kinase inhibitors gefitinib, zd1839 erlotinib, osi 774 inhibits egfr tyrosine kinase tumor vaccines dcs potent antigen presenting cells that can be pulsed or gene modified with tumor antigens such as ca9, tumor lysate, rna, mutated vhl peptides, etc hsppc-96 activates t cells, induces innate immune response + induces dc maturation renal cell carcinoma and targeted therapy correlated with an aggressive disease.(58) cetuximab (erbituxe) and abx-egf (fremont) target the egfr. cetuximab (c225) and gefitinib (iressa, zd1839) are egfr tyrosine kinase inhibitors. gefitinib is recently approved by the food and drug administration (fda) for locally advanced or metastatic non--small-cell lung cancer. although egf expression is common in rcc, these agents have shown no activity.(6) in a phase 2 trial including patients with a metastatic disease, 2 of 31 patients who had failed or were unable to receive il-2/ifn-alpha achieved objective responses and 58% had minor responses or stable disease to abx-egf therapy.(59) antictla-4 (mdx-010) antibodies augment the immune system by blocking the suppression of lymphocytic activity.(6) tumor vaccines. it has been demonstrated that ca9-derived cd8+ and cd4+ t-cell epitopes can induce ca9-specific t cells in vitro.(50) both primary and metastatic rcc deposits can be targeted by monoclonal antibodies (mab) against ca9.(6) the ca9-transduced peripheral blood monocytes have been shown to generate cytotoxic t cell lymphocytes which lyse ca9 expressing kidney cancer cells.(60) vaccines based on ca9, such as granulocyte macrophage colonystimulating factor and ca9 (gmca9) fusion protein vaccine are being developed in order to increase the immunogenicity of ca9 (table 6).(48) a combination of radioisotopes with antibodies directed against ca9 (sodium iodine i 131mg250) in order to target rcc lesions are also being developed.(61) imaging of lesions greater than 2 cm were successfully detected in early phase 2/3 clinical trials and there was an apparent improvement in survival compared to historical trials.(62) several tumor cell-based and dendritic cell (dc)based vaccines for rcc are currently in clinical trials.(6) heat shock proteins (hsps) are known to induce dc activation and the significance of hsps and their expression in rcc has been evaluated recently.(63) the hsp-peptide complex96 (hsppc-96) is currently in phase 3 trials.(64) assikis and colleagues administered hsppc-96 vaccine to 61 patients. response to the treatment was seen in 21 patients and no significant toxicity was observed.(64) of 16 patients whose disease progressed while on vaccine, 7 achieved disease stability after adding il-2. the median progression-free survival was 18 weeks for all patients who received the vaccine, and 25 weeks for patients who also received il-2. anti-angiogenesis agents. vascular endothelial growth factor is the most potent proangiogenic tumor-secreted cytokine with critical importance in both normal and tumorassociated angiogenesis. cytokines, growth factors, hormones, hypoxia, and tumor suppressor genes regulate the expression of vegf.(65) inactivation of the vhl gene leads to the increased expression of vegf which is detected in the majority of rccs.(65) vascular endothelial growth factor receptors have been identified not only on endothelial cells, but also on the surface of kidney neoplasm cells which suggests that vegf might stimulate tumor growth.(65) therefore, targeting vegf is a logical therapeutic alternative in rcc (table 6). thalidomide is known as a potent angiogenesis inhibitor and inhibits endothelial cell proliferation via reducing mrna and protein expression of basic fibroblast growth factor (bfgf) and vegf.(65) it also reduces tumor necrosis factor-a production from macrophages, induces g1 cell cycle arrest/apoptosis, and modulates natural killer and t-cell activity; therefore, it has both antiangiogenetic and antitumor effects.(65) low-dose and high-dose thalidomide have been evaluated as a single agent therapy in metastatic rcc. in a study on its low dose, 18 patients with metastatic rcc were administered oral thalidomide (100 mg/d), which was well tolerated.(66) three patients (17%) achieved partial responses and 3 (17%) had a stable disease for at least 3 months after a median follow-up of 36 months.(66) in a study on high-dose thalidomide, 25 patients with a metastatic rcc were titrated to a planned dosage of 600 mg per day.(67) although 60% of patients were not able to reach the target dose due to toxicity (lethargy, constipation, and neuropathy), thalidomide (400 mg/d) was well tolerated. after a median follow-up of 20 months, 2 out of 22 patients (9%) who could be evaluated had partial responses and 12 (55%) had a stable disease. the median survival in these two studies was 9 months. daliani and associates investigated the efficacy of thalidomide in 20 metastatic rcc patients with disease progression after immunotherapy.(68) eighteen patients (90%) achieved the 1200-mg target dose. peripheral neuropathy, grade 3/4 deep vein thrombosis, and pulmonary embolism were the complications. a partial response was seen in 2 out of 19 patients 8 canda and kirkali (11%) who were evaluated after 7 and 11 months of therapy, with responses lasting for 16 and 31 months. a stable disease was detected in 9 patients (47%) lasting for a median of 14 months. all patients progressed eventually and the median progression-free survival was 4.6 months. the median survival was 18.1 months. motzer and coworkers administered thalidomide to 26 patients with a metastatic rcc.(69) thalidomide was started at a dosage of 200 mg per day and titrated to a planned dosage of 800 mg. sixtynine percent of the patients received thalidomide, 400 mg or 600 mg, and due to the toxicity (grade 3 dyspnea and neurologic toxicity), only 19% were able to receive a dose of 800 mg. although 16 patients (64%) had a stable disease, none of the 25 patients with a complete evaluation had partial responses. the progression-free survival at 6 months was 32%, and 57% of patients were alive at 1 year. a combination of thalidomide and standard cytokine therapy has also been investigated. thalidomide (300 mg/d) and low-dose interferon (1.2 million international units [miu], 3 times per day) were administered to 30 patients with untreated, metastatic rcc.(70) six cases of partial response and no complete response were observed in the patients. subcutaneous il-2 (9.0 mu/m2, days 1 through 5, weekly) and thalidomide (100 mg/d) were administered to 31 patients in a phase 1 study and 2 objective responses (6.5%) were detected.(71) amato and colleagues administered a combination of lowdose thalidomide and ifn-alpha to patients with a metastatic rcc in a phase 2 study. of the 14 patients evaluated, 3 (21.4%) achieved a partial response and 7 (50%) obtained a stable disease. the overall nonprogression rate was 71.4% and the overall survival was 17.4 months.(72) the combination of il-2 and thalidomide has also been evaluated in another phase 2 study(73); of 36 patients evaluated, there was 1 patient with a complete response, 14 with a partial response, and 11 who achieved a stable disease. the treatment was well tolerated. in a phase 1/2 trial including 8 patients, thalidomide was combined with 5-fu, ifn-alpha, and il-2. the overall response rate was 14% and the mean time to progression was 161 days. one patient achieved radiographically complete response of the bone and pulmonary lesions.(74) the new immunomodulatory analogs of thalidomide have also been studied in metastatic rcc. ae-941 (neovastat) is produced from shark cartilage, and like thalidomide, it has antiangiogenic effects. ae-941 inhibits endothelial cell migration, vasculogenesis, vascular permeability (via competitive binding with vegf receptor-2), and matrix metalloproteinases.(75) batist and colleagues evaluated ae-941 in patients with a refractory rcc, and the median survival of 14 patients treated with high-dose ae941 (neovastat) was detected to be significantly longer than that in 8 patients treated with its low doses (14.4 months versus 7.1 months), and the therapy was well tolerated.(76) however, the study was not randomized and the number of patients was too small for definite conclusions to be drawn. small molecule inhibitors. small-molecule tyrosine kinase inhibitors inhibit both vegf receptor and other receptors in the split kinase domain superfamily of tyrosine kinase receptors such as pdgf receptor which is expressed in pericytes. therefore, an alternative approach to vegf inhibition involves small-molecule tyrosine kinase inhibitors (table 6). inhibition of the signal transduction pathway of phosphatidylinositol 3-kinase-akt-mammalian target of rapamycin (pi3k-akt-mtor) slows down tumor growth and adaptation to hypoxia. rapamycin and rapamycin analogs such as cci779 inhibit mtor activation that causes tumor growth arrest and inhibition of hif-1α synthesis.(77) antitumor activity has been demonstrated by cci-779 administration in patients with an advanced rcc in a phase 2 trial which was well tolerated.(78) phosphatase and tensin homolog (pten) gene mutations have been detected to make tumors dramatically more responsive to treatment with cci-779 than tumors with a normal pten.(79) the ras/raf signaling pathway is important in tumor cell proliferation and angiogenesis. activated ras leads to cell proliferation via the raf/mek/erk pathway by binding to and activating raf kinase. bay 43-9006 is an orally bioavailable raf kinase inhibitor that inhibits tumor cell proliferation by both inhibiting c-raf and b-raf. it also inhibits angiogenesis by acting on vegf receptor 2 and pdgf receptor-β. after a 12-week induction phase with bay 43-9006, 89 of 106 patients with rcc had a response and 37 experienced tumor shrinkage of more than 25% and 13 had their tumors shrunk by at least 50% in a phase 2, randomized, placebo-controlled 9 renal cell carcinoma and targeted therapy trial.(80) sti-571 (gleevec) inhibits pdgf receptor and it has a specificity for c-kit pathway. high c-kit expression has been demonstrated in sarcomatoid rcc; therefore, sti-571 might be useful in the treatment of these tumors.(81) su-011248 is an orally bioavailable indolinone that works as a signal transduction inhibitor of the vegf receptor, pdgf receptor, and c-kit tyrosine kinase. motzer and colleagues administered su-011248 orally in a phase 2 study to 63 patients with a metastatic rcc who had failed standard therapy.(82) a partial response was achieved in 33% of patients; while, 37% had a stable disease for less than 3 months. at 6 months, 22% had a partial response. toxicities were most commonly grade 1 or grade 2 including fatigue/asthenia, nausea, diarrhea, and stomatitis. grade 3/4 toxicities included lymphopenia, and elevated serum levels of lipase, amylase, and phosphorus. ptk787/zk222584 (ptk787) is an oral, selective inhibitor of vegf receptor-1, vegf receptor-2, and pdgf receptor-β tyrosine kinases.(53) in a phase 1/2 trial, ptk787 was administered to 45 patients with a metastatic rcc. among 41 patients evaluated, 2 (5%) partially responded. minor responses (25% to 50% tumor shrinkage) were detected in 6 patients (15%) and therapy was well tolerated.(83) another potential anticancer strategy is the use of drugs that work on the ubiquitin/proteasome system. bortezomib (ps-341) is a small molecular weight reversible inhibitor of the intracellular 26s proteasome, a large protein (enzyme) complex that may target hif-1. it may respond to proteasome inhibition and is recently approved by fda for multiple myeloma and rcc.(6) drucker and coworkers administered bortezomib (ps-341) to patients with a metastatic disease and of the 32 patients evaluated, 3 achieved a partial response (9%) and the remaining had either stable or progressive disease. all responders had progressed with cytokine therapy. most of the adverse events were grade 2/3.(84) hif-1α is associated with the molecular chaperone, hsp90. geldanamycin is an hsp90 antagonist and promotes degradation of hif-1α in both normoxia and hypoxia.(85) therefore, direct inhibition of the hif activity causes targeting the vhl pathway. yc-1 is an antiangiogenic anticancer agent which blocks hif-1α expression at the posttranscriptional level.(86) yc-1 has been demonstrated to decrease the growth of caki-1 renal carcinoma xenografts in immunodeficient mice.(86) histone deacetylase (hdac) inhibitors are agents which reverse the repression of genes responsible for the regulation of cell cycle and apoptosis. depsipeptide (fr901228) is a hdac inhibitor with cytotoxic activity and a response has been demonstrated in a small phase 1 trial in patients with rcc.(87) gti-2040 is an antisense compound that targets the ribonucleotide reductase (rnr) r2 subunit, which is an essential enzyme for dna synthesis and repair. gti-2040 is being studied in combination with capecitabine and has shown potential against rcc.(88) bay 59-8862 is a second-generation taxane and exhibits antiangiogenic activity by downregulating both vegf and bfgf. in a phase 2 study, 42 patients were evaluated who were administered bay 59-8862 and there were no complete or partial responders. stable disease was detected in 6 patients with a median duration of 4.5 months.(89) epothilone ep0906 is a microtubular stabilizer that inhibits cell growth. in a phase 2 study, epothilone ep0906 was administered to 52 patients with advanced rcc. partial response was detected in 2 patients (at 3 months and 5 months) and 24 patients had a stable disease at 16 weeks of therapy.(90) summary and future perspectives the incidence of kidney cancer is increased all around the world. renal cell carcinoma is the most lethal of the common urological malignancies with 40% eventually dying of cancer progression and the chance of cure in advanced and metastatic cancer is low. due to the widespread use of imaging modalities, many tumors are diagnosed incidentally with an earlier stage which can be cured by surgery.(91) currently, surgery is considered as the only curative treatment for localized rcc in which rn and nss cure most of the patients with an earlystage disease. laparoscopy is increasingly being performed in the surgical management of kidney tumors particularly for early-stage disease unsuitable for nss. laparoscopic rn seems to provide long-term cancer control comparing to open rn. the typical rcc is a highly vascular tumor with 10 canda and kirkali an extremely poor prognosis in the presence of metastases.(92) the current therapy for metastatic rcc is inadequate and surgery is an important component of the treatment with combined immunotherapy. there has been a tremendous development in oncological urology in the last couple of years, particularly in the treatment of advanced and metastatic cancer. although chemotherapy was the standard treatment for all advanced urological malignancies, better understanding of the molecular pathways of carcinogenesis individualized targeted and biological treatments.(91) the field of rcc is rapidly undergoing a revolution led by molecular markers and therapies based on molecular targeting. the use of genetic and molecular markers might predict an individual tumor's behavior which could lead to shifting from nonspecific treatments to designing and targeting therapies in selected populations of patients. the hypoxia-inducible pathway plays an important role in epithelial proliferation, cell migration, apoptosis, glucose transport, glycolysis, ph control, and angiogenesis; therefore, it seems to be responsible for the adaptation of rcc to a hypoxic environment, thus, their resistance to radiation and chemotherapy. inactivation of the vhl gene leads to accumulation of 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progressive metastatic renal cell carcinoma. cancer. 2002 aug 15;95(4):758-65. 69. motzer rj, berg w, ginsberg m, et al. phase ii trial of thalidomide for patients with advanced renal cell carcinoma. j clin oncol. 2002 jan 1;20(1):302-6. 70. tomlinson ip, alam na, rowan aj, et al. germline mutations in fh predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. nat genet. 2002;30:406-10. 71. vissers jl, de vries ij, engelen lp, et al. renal cell carcinoma-associated antigen g250 encodes a naturally processed epitope presented by human leukocyte antigen-dr molecules to cd4(+) t lymphocytes. int j cancer. 2002;100:441-4. 72. sella a, sternberg c, yarom n, et al. phase ii study of low dose thalidomide and interferon-alfa in metastatic renal cell carcinoma [abstract]. proc am soc clin oncol. 2003;22:402. 73. amato rj, schell j, thompson n, et al. phase ii study of thalidomide + interleukin-2 (il-2) in patients with metastatic renal cell 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[molecular pathways of tumour angiogenesis and new targeted therapeutic approaches in renal cancer]. prog urol. 2005;15:1021-9. french. 14 urol_v3_no1_001_editorial.qxd urology journal unrc/iua 44 miscellaneous radiofrequency-induced thermotherapy in benign prostatic hyperplasia mohammad ali zargar shoshtari,* majid mirzazadeh, masoud banai, meysam jamshidi, kaveh mehravaran department of urology, hasheminejad hospital, iran university of medical sciences, tehran, iran abstract introduction: we evaluated the efficacy and safety of radiofrequency-induced thermotherapy of the prostate in patients with benign prostatic hyperplasia (bph). materials and methods: radiofrequency-induced thermotherapy of the prostate was performed under local anesthesia in 24 patients (median age, 67 years) with bph. the international prostate symptom score (ipss), maximum flow rate, postvoid residual urine volume, and prostate volume were measured preoperatively and 4 months postoperatively. results: nine patients (37.5%) had urinary retention preoperatively. one patient (4.2%) required transurethral resection of the prostate due to retention despite improved symptoms, and 2 (8.3%) needed an α-blocker, postoperatively. the success rate was 87.5% after 4 months follow-up. all patients were catheter-free after the procedure. the mean ipss decreased from 26.08 ± 3.9 to 13.33 ± 4.69 (p < .001), and the mean maximum flow rate increased from 4.63 ± 4.4 ml/s to 13.21 ± 4.28 ml/s (p < .001). the mean prostate volume and mean residual urine volume were 46.38 ± 16.8 ml and 160 ± 57 ml, which decreased to 39.6 ± 16 ml (p = .009) and 61.46 ± 17.45 ml (p = .003), respectively. fever, dysuria, and perineal pain (in 9 patients; 37.5%) were improved with conservative therapy. retrograde ejaculation, erectile dysfunction, and urinary incontinence were not reported. conclusion: radiofrequency-induced thermotherapy of the prostate is a new, safe, and effective treatment for bph. this technique is carried out under local anesthesia and mild sedation with little bleeding. it is especially appropriate for patients who present as high risk for general anesthesia. key words: benign prostatic hyperplasia, radiofrequency, thermotherapy vol. 3, no. 1, 44-48 winter 2006 printed in iran introduction several different medical and surgical treatments exist for benign prostatic hyperplasia (bph). one of the minimally invasive procedures for the management of bph is radiofrequencyinduced thermotherapy of prostate (rfitt). by increasing temperature, thermotherapy causes necrosis of the prostate tissue and reduces outlet resistance and prostate volume. the aim is to increase prostate tissue temperature to a range between 60°c and 100°c. transurethral needle ablation (tuna) of the prostate is also used. in this procedure, radiofrequency energy with low amplitude waves are applied to the prostate tissue by a special needle, causing localized intraprostatic necrotic lesion.(1-4) the advantage received august 2004 accepted october 2004 *corresponding author: hasheminejad hospital, vanak sq, tehran, iran. tel: +98 912 115 0504, fax: +98 21 8879 6540 zargar shoshtari et al 45 of tuna is that it yields a controlled necrotic lesion and can be used under local anesthesia.(1-3) following the food and drug administration approval and approval for medicare coverage, tuna has gained popularity worldwide.(5) technology has had a great role in treatment of urinary stones and has influenced the practice of urology worldwide. it is time to search for minimally invasive procedures instead of transurethral resection of prostate (turp) for the treatment of bph. bipolar rfitt of the prostate is a new procedure that is a variation of tuna. a bipolar needle with 470-khz waves is used to create an intraprostatic necrotic lesion. new systems with bipolar electrodes minimize injury to contiguous organs, and transrectal ultrasonography is not required to evaluate the location of the needle tip. also, the needle tip has a thermometer that continuously shows the central temperature of necrotic cavity. few studies regarding this new system exist; therefore, we performed the current study to evaluate the efficacy of rfitt in the treatment of bph. materials and methods between july 2003 and october 2003, 24 patients (median age, 67 years; range, 57 to 78 years) with bph and severe lower urinary tract symptoms who were to undergo rfitt of the prostate were selected to take part in a nonrandomized prospective study at hasheminejad hospital. inclusion criteria were at least a 3-month duration of symptoms and failed medical therapy with α-blocker drugs. patients with any evidence of prostatic carcinoma, according to the clinical and laboratory findings, were excluded. all patients had concomitant cardiovascular disease (14 had congestive heart failure and poor exercise tolerance, 6 had chronic obstructive pulmonary disease, and 4 were receiving anticoagulant therapy), which put them at high risk (preoperative american society of anesthesiologists classes ii and iii) for general or regional anesthesia. therefore, they were not candidates for turp or open prostatectomy. patients were informed of alternative treatments, and informed consent was obtained. nine patients had urinary retention, and a foley catheter was placed 3 to 24 days before the procedure. digital rectal examination and transabdominal ultrasonography of the kidneys, bladder, and prostate were performed for all patients before rfitt of the prostate, and serum prostate-specific antigen (psa), serum creatinine, postvoid residual urine volume, maximum flow rate, and international prostate symptom score (ipss) score were measured. serum psa was determined by enzyme-linked immunosorbent assay method, and ultrasonography was performed by a single experienced radiologist. in all patients, rfitt was performed under local anesthesia by lidocaine 2% gel. the bipolar rfitt® (celon ag, berlin, germany) was used. patients received midazolam during the procedure. a 14-f suprapubic catheter was inserted, and the patient was fixed in a lithotomy position. a cystoscope with a 30-degree lens and a 6-f working channel was used. the rfitt electrode was introduced through the working channel of cystoscope until its tip was seen. irrigation of bladder was accomplished with dextrose 5% or normal saline during the operation. the tip of the cystoscope was moved from the verumontanum toward the bladder neck, and the electrode was inserted into the prostatic tissue at a 45-degree angle. puncturing was done only at the 2 o'clock to 4 o'clock and the 8 o'clock to 10 o'clock positions of the lateral lobes. the first puncture was made adjacent to the verumontanum, and the needle was inserted at least to the level of black marks (at 21 mm to 26 mm) on the electrode. then, the system's power was set at 6 w. the temperature of the tip of the electrode was monitored. the temperature reached 115°c to 120°c, and then it took 1 minute to 3 minutes for the tissue to be coagulated completely. afterwards, the electrode was withdrawn and moved 1 cm toward the bladder neck to make another puncture for coagulation. for every 5 g of prostate tissue, 1 puncture was required. in the median lobe, the electrode was inserted directly and coagulation was carried out. the lesion size for every puncture was 20 mm × 10 mm. after the procedure had been carried out, an 18-f 2-way foley catheter was inserted in all patients, and they were discharged the following day. oral cephalexin (500 mg) was prescribed every 6 hours for 3 days. the urethral catheter was removed on the seventh postoperative day, and the suprapubic catheter was removed after a voiding trial, 10 to 14 days postoperatively. at the fourth postoperative month, the ipss, prostate volume, postvoid residual urine volume, maximum flow rate, serum psa, and serum thermotherapy in benign prostatic hyperplasia46 creatinine levels of the patients were measured and compared with those values before the operation. continuous variables are shown as means ± standard deviation, and the paired t test was used to compare them before and after rfitt. a value for p less than .05 was considered significant. results the mean serum psa was 3.23 ± 0.96 ng/ml, preoperatively. two patients had psa levels greater than 4 ng/ml, and transrectal ultrasonography-guided biopsy of the prostate was carried out, the pathology results of which demonstrated a benign tumor. this also was found in 1 patient with abnormal digital rectal exam results. the mean ipss, prostate volume, maximum flow rate, and postvoid residual urine volume were 26.08 ± 3.9, 46.38 ± 16.8 ml, 4.63 ± 4.4 ml/s, and 160.60 ± 57 ml, before the procedure. the mean number of punctures for each patient was 10.5 ± 3.2. the mean operative time was 25 ± 15 minutes, and the mean volume of irrigation fluid used intraoperatively was 5.6 ± 1.6 l. the measured parameters 4 months after rfitt are shown in table 1. the ipss, prostate volume, and postvoid residual urine volume showed a significant decrease compared with these values before treatment (p < .001; p = .009; p = .003). the maximum flow rate increased remarkably (p < .001), but no significant changes were seen in serum psa and creatinine. all patients were catheter-free 4 months after the treatment. minor complications were fever (3 patients; 12.5%), dysuria (4 patients; 16.6%), and perineal pain (2 patients; 8.3%) all of which subsided with conservative therapy. retrograde ejaculation, erectile dysfunction, and urinary incontinence were not seen. one patient among those with preoperative retention required turp despite the improvement of symptoms. two patients (8.3%) required an α-blocker postoperatively. the success rate was 87.5% at 4 months follow-up. bleeding was not remarkable, and bladder irrigation was not necessary after the operation. discussion transurethral resection of prostate remains the gold standard for treatment of bph; however, it is probably less attractive from the patient's perspective, especially when minimally invasive techniques with a good tolerability are available.(6) radiofrequency-induced thermotherapy is a cost-effective and quick procedure with a short hospitalization. radiofrequency ablation has been utilized in several different clinical applications, ranging from cardiac dysrhythmia to primary and metastatic liver lesions, as well as tumors of the nervous system and bone. urologists have used this technology to treat bph through a transurethral approach and to treat prostate cancer through a transperineal approach. thanks to bipolar rfitt technology, the current flow is confined to the treatment area. the use of a return electrode is not required, making the procedure safer compared to monopolar systems (tuna). the probe carries an alternating current of high-frequency radio waves that causes the local ions to vibrate, and table 1. measured parameters before and 4 months after rfitt in all patients and those with and without preoperative urinary retention psa: prostate-specific antigen, ipss: international prostate symptom score before operation four months after operation all patients all patients patients with urinary retention patients without urinary retention number of patients 24 24 9 15 psa (ng/ml) 3.23 ± 0.96 3.04 ± 0.91 3.78 ± 1.1 2.61 ± 0.67 maximum flow rate (ml/s) 4.63 ± 4.4 13.21 ± 4.69 11.67 ± 3.43 14.83 ± 4.88 prostate volume (ml) 46.38 ± 16.8 39.67 ± 16 33.23 ± 16.83 38.89 ± 15.13 ipss 26.08 ± 3.9 13.33 ± 4.69 14.11 ± 5.1 13.87 ± 4.47 postvoid residual urine volume (ml) 160.60 ± 57 61.46 ± 17.45 71.11 ± 21.94 55.67 ± 15.63 creatinine (mg/dl) 1.3 ± 0.8 1.5 ± 0.9 1.5 ± 0.6 1.4 ± 1.0 zargar shoshtari et al 47 the resistance in the tissue creates heat to the point of desiccation (thermal coagulation). temperature sensor in the tip of the probe controls applicator placement and the procedure. the real time 3-d-impedance feedback constantly adjusts the power output to the tissue impedance and takes care of automatic termination of the coagulation procedure (automatic power control). this allows optimal energy deposition combined with a minimized procedure time preventing overdosing and carbonization. microscopic examination immediately after radiofrequency ablation reveals intense stromal and epithelial edema with marked hypereosinophilia and pyknosis. this is replaced in the matter of days to weeks by coagulative necrosis with concentric zones of inflammatory infiltrate, hemorrhage, and fibrosis.(7) the whole procedure can be performed under local anesthesia. most of our patients are at high risk to undergo anesthesia because of cardiac or other medical problems. consequently, radiofrequency ablation is a safe technique for high-risk patients. minardi and colleague have recently reported the results of a comparison of turp with minimally invasive treatments of bph (transurethral electrovaporization, tuna, interstitial laser coagulation, and water-induced thermotherapy) in 212 patients. in a 24-month follow-up, they showed that turp achieved the highest decrease in prostate volume (48.8%), the best increase of maximum flow rate (75.3%), and the highest decrease of residual urine volume (89.8%) compared with the other methods. in addition, a marked decrease of ipss and quality of life (qol) scores was observed for all the procedures after 6 months, up to 76.7% for tuna.(6) cimentepe and coworkers have shown that the tuna procedure, compared with turp, is an effective and safe, minimally invasive treatment for selected patients with symptomatic bph. in 2003, they carried out a study on 59 patients older than 40 years with bph (26 treated with tuna and 33 with turp). improvements in maximum flow rate, prostate volume, ipss, and qol score were statistically significant for both groups at 3 and 18 months' follow-up. there were no complications associated with the tuna procedure, while 16 retrograde ejaculation, 4 erectile impairment, 2 urethral stenosis, and 1 urinary incontinence cases were observed after turp.(3) in a study on 26 patients with bph, the ipss of the patients decreased from 21.2 to 10.5, and the maximum flow rate increased from 10.9 ml/s to 13.7 ml/s after tuna.(1) in hill and colleagues' study of a comparison between tuna and turp, 121 men were evaluated (56 underwent turp and 65 were treated with tuna). for patients treated with tuna or turp, significant improvements from baseline were found for ipss, postvoid residual urine volume, and maximum flow rate; however, the turp group reported a 41% retrograde ejaculation, while the tuna group reported none. the incidence of erectile dysfunction, incontinence, and stricture formation was also greater in patients undergoing turp than in those undergoing tuna with significantly fewer adverse events for those treating with tuna than for those receiving turp.(4) in our study, similar results were obtained; significant improvement in ipss, postvoid residual urine volume, and maximum flow rate were seen after rfitt (48%, 61%, and 220%), although these were relatively lower than those in reported turp cases. however, owing to the general anesthesia risks, our patients could not benefit from turp. besides, no major complications occurred in our series, which is in agreement with other studies' outcomes. conclusion radiofrequency-induced thermotherapy is a fast procedure with low costs and short hospitalization. it is very useful for patients with bph who have concomitant cardiac diseases, coagulative disorders, or other medical problems which preclude general or regional anesthesia. the therapeutic results are good with few complications. radiofrequency-induced thermotherapy is a new variation of tuna, but is easier to perform with fewer complications and better results. hence, it can be considered as an alternative in patients with bph. references 1. daehlin l, gustavsen a, nilsen ah, mohn j. transurethral needle ablation for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia: outcome after 1 year. j endourol. 2002;16:111-5. 2. zlotta ar, giannakopoulos x, maehlum o, ostrem t, schulman cc. long-term evaluation of transurethral needle ablation of the prostate (tuna) for treatment of symptomatic benign prostatic hyperplasia: clinical thermotherapy in benign prostatic hyperplasia48 outcome up to five years from three centers. eur urol. 2003;44:89-93. 3. cimentepe e, unsal a, saglam r. randomized clinical trial comparing transurethral needle ablation with transurethral resection of the prostate for the treatment of benign prostatic hyperplasia: results at 18 months. j endourol. 2003;17:103-7. 4. hill b, belville w, bruskewitz r, et al. transurethral needle ablation versus transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia: 5-year results of a prospective, randomized, multicenter clinical trial. j urol. 2004;171:2336-40. 5. braun m, mathers m, bondarenko b, engelmann u. treatment of benign prostatic hyperplasia through transurethral needle ablation (tuna). review of the literature and six years of clinical experience. urol int. 2004;72:32-9. 6. minardi d, galosi ab, yehia m, et al. transurethral resection versus minimally invasive treatments of benign prostatic hyperplasia: results of treatments. our experience. arch ital urol androl. 2004;76:11-8. 7. bishoff jt, baughman sm. novel tissue ablation technology. in: graham sd, editor. glenn's urologic surgery. 6th ed. philadelphia: lippincott williams & wilkins; 2004. p. 1042-3. vol 12. no 01 jan-feb 2015 1995 case report syndrome of spigelian hernia and cryptorchidism: new evidence pertinent to pathogenic hypothesis ufuk ates, gonul kucuk, gulnur gollu, aydin yagmurlu* keywords: cryptorchidism; hernia; ventral; complications; inguinal canal. introduction lateral ventral hernia (spigelian hernia) is a rare surgical condition in children. the cases are commonly seen in adult population. it arises because of weakness in fascia. preperitoneal fatty tissue, intraabdominal organs may herniate through hernial sac. strangulation or incarceration may rarely occur. frequency of undescended testis was found much higher in cases with spigelian hernia than normal population.(1-3) a one-month old boy who had testis in spigelian hernial sac was found to have gubernaculum and inguinal canal opposing previously described “spigelian-cryptorchidism syndrome”. the aim of this study is to describe details of this case. case report one month-old boy had left inguinal-lower quadrant swelling and left nonpalpable testis. physical examination revealed spigelian hernia and left nonpalpable testis (figure 1). diagnostic laparoscopy which was performed through umbilicus revealed spigelian hernia with left testis inside hernial sac and open bilateral internal rings (figure 2). after termination of laparoscopy, left oblique incision was used and hernial sac was found (figure 3). testis was liberalized after gubernaculum was cut, upon protecting spermatic cord and vessels. spermatic cord had sufficient length to bring the testis into the scrotum through the inguinal canal. hernial sac was excised and defect was repaired. left testis was descended through inguinal canal and positioned into supra dartos pouch. contralateral inguinal hernia was repaired. there were no complications. discussion spigelian hernia is a ventral interstitial hernia which occurs as a result of weakness of aponeurosis between semilunar line and lateral edge of rectus abdominis muscle.(1-6) external oblique abdominis muscle and its aponeurosis are usually intact whereas transversalis fascia and internal oblique abdominis muscle are weak. spigelian hernia is rare in children and 40 cases of childhood spigelian hernia have been reported in the literature.(1,3-5) co-occurrence of spigelian hernia and cryptorchidism has been reported only in thirty cases in the literature. there are some theories on coexistence of spigelian hernia and cryptorchidism. discussions are on whether undescended testes contribute to the development of congenital spigelian hernia or weakness in abdominal wall somehow department of pediatric surgery, school of medicine, ankara university, ankara, turkey. *correspondence: ankara universitesi, tip fakultesi cocuk cerrahisi, ad dikimevi, ankara, turkey. tel: +90 312 5956227. fax: +90 312 5956563. e-mail: ayagmurlu@gmail.com. received june 2014 & accepted november 2014 figure 1. physical examination revealed spigelian hernia and left nonpalpable testis. figure 2. a schema of the laparoscopic view. vol 12. no 01 jan-feb 2015 2040 interrupts normal testicular descent and causes testis to settle down in hernial sac.(2,3) according to generally held view, spigelian aponeurosis is weak point and undescended testis takes path of least resistance, coming to rest in hernial sac and accounting for coexistence.(1,3,7) another view describes ectopic descent of testis as main problem. while descending to ectopic site, analogous to its descent into scrotum, testis may stimulate formation of processus vaginalis and this peritoneal processus accompanying ectopic testis forms potential sac.(5) according to rushfeldt and colleagues, spigelian herniacryptorchidism syndrome arises from inability of testis to descend into scrotum because of failure in development of gubernaculum and inguinal canal. spigelian herniacryptorchidism consists of 4 congenital ipsilateral elements: defect in the spigelian fascia, hernial sac containing testis, absence of gubernaculum and absence of inguinal canal.(3) existence of gubernaculum and inguinal canal in this presented case has failed to support rushfeldt and colleagues hypothesis. although infantile spigelian hernia are very rare, they are indeed congenital in nature and there is cause and effect relationship with undescended testis, although this relationship is not yet elucidated.(2) physical examination is main diagnostic factor in spigelian hernia however the intact overlying muscle and aponeurosis can lead to diagnostic challenges. in these cases where hernia is suspected but cannot be demonstrated, ultrasonography can be used to show hernial sac. once diagnosed, spigelian hernia should be repaired because of high rate of incarceration.(2,7,8) these defects are repaired primarily, however in unusually large defects, mesh may be required for the repair. spigelian hernia is rare condition in childhood. the incidence of cryptorchidism is much higher in cases with spigelian hernia with respect to normal population and the testis is frequently found in the hernial sac. repair of the hernia and orchiopexy can be easily performed due to the sufficient length of testicular vessels. conflict of interest none declared. references 1. singal ak, ravikumar vr, kadam v, jain v. figure 3. left testis inside the spigelian hernial sac (informed consent was taken from the parent for the photographs). undescended testis in spigelian hernia-a report of 2 cases and review of the literature. eur j pediatr surg. 2011;21:194-6. 2. durham mm, ricketts rr. congenital spigelian hernias and cryptorchidism. j pediatr surg. 2006;41:1814-7. 3. rushfeldt c, oltmanns g, vonen b. spigeliancryptorchidism syndrome: a case report and discussion of the basic elements in a possibly new congenital syndrome. pediatr surg int. 2010;26:939-42. 4. ilce z, ozcan r, elicevik m, tekant g. çocuklarda nadir görülen cerrahi patoloji; lateral ventral fıtık (spigelian fıtık): olgu sunumu. çocuk cerrahisi dergisi. 2007;21:104-7. 5. raveenthiran v. congenital spigelian hernia with cryptorchidism: probably a new syndrome. hernia. 2005;9:378-80. 6. fascetti-leon f, gobbi d, gamba p, cecchetto g. neonatal bilateral spigelian hernia associated with undescended testes and scalp aplasiacutis. eur j pediatr surg. 2010;20:123-5. 7. al-salem ah. congenital spigelian hernia and cryptorchidism: cause or coincidence? pediatr surg int. 2000;16:433-6. 8. levy g, nagar h, blachar a, ben-sira l, kessler a. preoperative sonographic diagnosis of incarcerated neonatal spigelian hernia containing the testis. pediatr radiol. 2003;33:407-9. spigelian hernia and cryptorchidism syndrome-ates et al case report 2041 comparison of flexible ureterorenoscopy and laparoscopic ureterolithotomy methods for proximal ureteric stones greater than 10 mm idris kivanc cavildak,1 ismail nalbant,2* can tuygun,2 ufuk ozturk,2 hasan nedim goksel goktug,2 hasan bakirtas,3 muhammed abdurrahim imamoglu4 purpose: to examine the outcomes and compare the effectiveness of laparoscopic ureterolithotomy and flexible ureterorenoscopy (furs) in patients with proximal ureteral stones larger than 10 mm in diameter. materials and methods: in total, 150 patients who underwent laparoscopic ureterolithotomy and furs because of ureteral stones in our urology clinic from january 2010 to june 2015 were retrospectively analyzed. the patients were divided into 2 groups: 70 patients who underwent laparoscopic ureterolithotomy (group 1) and 80 patients who underwent furs (group 2). success rates and complications were compared. results: the success rates were 95.7% and 90.0% in groups 1 and 2, respectively; there was no statistically significant difference between the groups. no statistically or clinically significant complications occurred in either group. conclusion: laparoscopic ureterolithotomy and furs are both effective and reliable for the treatment of proximal ureteral stones. however, considering the shorter operation and hospitalization times and the management of situations that require secondary interventions, we suggest that furs, as a minimally invasive method, may be the first choice in the treatment of proximal ureteral stones. keywords: ureteral calculi; surgery; laparoscopy; adverse effects; lithotripsy; postoperative complications; ureterolithiasis; treatment outcome; ureteroscopy; methods. introduction ureteral stones are seen in approximately 15% of the population and are responsible for 20% of cases of urolithiasis.(1) the aim of treatment of ureteral stones is to achieve complete stone removal with minimal morbidity. standard treatment methods for upper ureteral stones include extracorporeal shock wave lithotripsy (swl), ureterorenoscopy (urs), ureterolithotomy, and antegrade percutaneous nephrolithotomy. although the rates of laparoscopic treatment for large and impacted ureteral stones seem to have decreased with the development of flexible urs (furs) and fine-tipped laser lithotripsy, laparoscopy still has high success rates in the treatment of ureteral stones that cannot be treated by swl and endoscopic methods.(2) in this study, we examined the outcomes and compared the effectiveness of laparoscopic ureterolithotomy and furs in patients with proximal ureteral stones larger than 10 mm in diameter. materials and methods after obtaining approval from the local ethics committee at our hospital, the medical files of 150 patients who underwent laparoscopic ureterolithotomy and furs because of ureteral stones in our urology clinic from january 2010 to june 2015 were retrospectively analyzed. the patients were divided into 2 groups: 70 patients who underwent laparoscopic ureterolithotomy (group 1) and 80 patients who underwent furs (group 2). patients with proximal ureteral stones larger than 1 cm in diameter were included in the study. patients with a solitary kidney, ureteropelvic junction obstruction, pelvic kidney abnormalities, non-opaque and multiple stones, and a history of open or percutaneous surgery or swl were excluded. preoperatively, all patients underwent a complete blood count, serum urea and creatinine measurement, bleeding and coagulation profile analysis, urinalysis and urine culture, intravenous urography, and computed toendourology and stone diseases endourology and stone diseases 2484 1 department of urology, 29 mayis state hospital, ankara 06450, turkey. 2 department of urology, diskapi training and research hospital, ankara 06110, turkey. 3 department of urology, special memorial hospital, ankara 06450, turkey. 4 department of urology, medical faculty, bozok university, yozgat 66000, turkey. *correspondence: dişkapi training and research hospital, clinics of urology, irfan bastug street, diskapi/altindag/ankara, turkey. tel: +90 312 5962000. fax: +90 312 3186690. e-mail: nalbant60@yahoo.com. received august 2015 & december 2015 vol 13 no 01 january-february 2016 2485 mography without contrast, if needed. the success rates and complications in groups 1 and 2 were compared. residual stones and stone-free rates were evaluated by urinary tract radiography and ultrasonography 4 to 6 weeks after surgery. cases involving detection of small fragments (< 4 mm) and the absence of stones were considered successful. cases involving symptomatic and/or residual fragments greater than 4 mm or stone clearance achieved with an auxiliary procedure were deemed technique failures. double j (dj) ureteral stents in the stone-free patients were removed 2 weeks after furs. we first compared the success rates of the procedures and then compare the hospitalization and operation times and complication rates. three trocars (10–12 mm) were used for laparoscopic ureterolithotomy. the initial port was placed by the open method at the junction of the 12th rib and posterior axillary line. in the open method, a 1.5 cm incision was made in the fascia of the external oblique muscle. the retroperitoneal space was accessed by puncturing the fascia of the transversus abdominis muscle with a blunt clamp. first, an 800-ml space was created with a finger and then with a balloon dissector while the peritoneum was shifted medially at the same time. the second port was placed 1 cm anterior to the 11th rib. the third port was placed at the anterior axillary line, 2 cm superior and 2 cm medial to the spina iliaca anterior superior. after expansion of the retroperitoneum and opening of gerota’s fascia, the ureter was identified over the psoas muscle. protuberance of the stone was noted, and the stone was grasped with a babcock clamp. after stabilization of the stone, the ureter was incised vertically with a wedge-tipped endoscopic scalpel. the stone was extracted with right-angle forceps. it was placed in an endobag, and a 26 cm antegrade dj ureteral catheter was inserted. the ureteral incision was closed using 4/0 vicryl suture. a hemovac drainage catheter was placed in the periureteric area near the second port site. the dj catheter was left in place for 7 days.(3) in the furs procedure, a 9.5to 11.5 french (f) access sheath (elit flex, ankara, turkey) was placed in all patients in the lithotomy position. standard retrograde furs was applied with a 7.5 f flexible ureteroscope (flex x2; karl storz gmbh, tuttlingen, germany). stone fragmentation was achieved using a 4to 30 w holmium laser (medilas h20; dornier med-tech gmbh, wessling, germany) with 200or 365 µm laser fibers at 5 to 10 hz and 0.2to 3.0 joule (j) intervals. the fragments were collected in a 1.9 f basket (zero tip; boston scientific, marlborough, ma, usa) and sent for stone analysis. residual stones were checked on postoperative day 1 with x-rays and ultrasonography, and the stone-free status was confirmed on x-ray, ultrasonography, and non-contrast computed tomography 2 weeks after surgery.(4) treatment of large proximal ureteral stones-cavildak et al. parameters group 1 (n = 70) group 2 (n = 80) p value median age, years (range) 49 (20-70) 46 (16-76 ) . 459 gender, n (%) . 781 male 32 (45.71) 44 (55) female 38 (54.28) 36 (45) side, n (%) . 624 right 33 (47.14) 31 (38.75) left 37 (52.85) 49 (61.25) median bmi, kg/m2 (range) 25.77 (23.63-30.42) 25.87 (23.18-29.15) . 894 table 1. demographic and clinical characteristics of study participants. abbreviation: bmi, body mass index. variables group 1 (n = 70) group 2 (n = 80) p value median stone diameter, mm (range) 17 (14-30) 15.5 (10-20) .074 median hospitalization time, days (range) 3 (2 13) 1 ( 0.5 3) < .001 median operational time, min (range) 80 (40-150) 45 (35-85) .001 stone-free rate, n (%) 67 ( 95.7) 75 (93.75) .081 table 2. operation parameters. statistical analysis the statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0 was used for statistical analysis of the data. numerical variables are expressed as mean ± standard deviation. because there were two groups, the significance of differences in medians was tested with the mann–whitney u test. nominal variables were tested with pearson’s χ2 test or fisher’s exact test. p values of < .05 were considered to indicate statistical significance. results demographic characteristics of the patients (table 1) and stone sizes (table 2) were similar in both groups. the mean operation time in groups 1 and 2 was 80.71 ± 2.90 and 49.18 ± 1.39 min, respectively, and the mean hospitalization time in groups 1 and 2 was 3.08 ± 0.17 and 1.19 ± 0.06 days, respectively. the operation time and hospitalization time were shorter in group 2, and the differences were statistically significant (table 2). the grade of hydronephrosis was similar between the two groups (table 3). in group 1, the surgical procedure was ended laparoscopically in 67 of 70 (95.7%) patients. we returned to open surgery after incision of the ureter laparoscopically in three patients. we could not perform percutaneous nephrolithotomy or furs because of gonadal vein injury in one patient and the possibility of extravasation and failure to provide clear vision in two. although the patients were stone-free after the open procedure, these cases were considered unsuccessful. in group 2, 75 of 80 patients (93.75%) became stonefree, and the fluoroscopy time was 22.09 ± 4.21 s. stone fragments migrated into the lower calices in five patients, and because furs was not able to reach the lower calix, these patients needed swl postoperatively to obtain complete stone clearance. these five cases were considered furs failures. in three patients, we could not reach the proximal ureter using a flexible ureterorenoscope because of stricture of the distal ureter; thus, we placed a dj catheter. two weeks later, these patients were treated with furs. furs after placement of dj was described as a part of the procedure, so these three cases were considered furs successes. there was no significant difference in success rates between the groups (table 2). no statistically significant differences were observed in the total number of complications or grade of complications by the clavien classification (table 4). we observed no renal failure or increased creatinine levels in any patient in the preoperative or postoperative period. we placed a percutaneous nephrostomy tube on postoperative day 7 in one patient in group 1 because of prolonged urine extravasation, although a dj stent was placed intraoperatively. the patient was discharged on postoperative day 13 after the leakage stopped, and no clinical pathology was observed. a postoperative fever was detected in three patients in group 2, but the fever resolved with conservative treatment. these three patients were discharged successfully. no preoperative stone analysis was performed in these patients. we did perform postoperative stone analyses of 17 patients in group 1 and found calcium oxalate in 9 patients, calcium phosphate in 6, and struvite in 2. postoperative stone analysis of 13 patients in group 2 revealed calcium oxalate in 8 patients and calcium phosphate in 5. we recommended specific suggestions for patients with stone analyses and general suggestions for the patients without analyses. discussion while some ureteral stones may pass readily through the urinary tract, some require surgical procedures to provide a stone-free status. the location and size of the stone, presence of hydronephrosis, and initial renal function play important roles in determining the type of surgery. when these factors are taken into consideration, treatment options include medical treatment, swl, urs, antegrade urs, and laparoscopic and open ureterolithotomy. success of swl for proximal ureteral stones ranges from 57% to 96%.(5-7) it is generally considered a firstline therapy because it has no need for anesthesia or surgical intervention and is a noninvasive outpatient endourology and stone diseases 2486 hydronephrosis group 1 (n = 70) group 2 (n = 80) p value grade 0 1 (1.42) 6 (7.5) grade 1 29 (41.42) 36 (45) .550 grade 2 31 (44.28) 32 (40) grade 3 9 (12.85) 6 (7.5) * data are presented as n (%). table 3. grade of hydronephrosis in patients.* treatment of large proximal ureteral stones-cavildak et al. vol 13 no 01 january-february 2016 2487 procedure. however, swl may be insufficient for large stones and hard stones, such as cystine and calcium oxalate, and it has a risk of renal parenchymal damage. thus, alternative treatment methods are needed for some patients.(8) for these reasons, minimally invasive methods, such as laparoscopic approaches and furs, are taking the place of swl. recently, based on developments in urs and lithotripsy, furs with holmium-yag laser lithotripsy is becoming preferred to a semi-rigid urs with lithotripsy in the endoscopic treatment of ureteral stones. furs can reach migrated stones because of its high mobility. however, it may not be possible to perform furs or place a ureteral access sheath because of stricturing of the ureteral orifice. thus, secondary procedures may still be needed.(9,10) in the present study, eight patients required additional interventions. the stone-free rate for urs in proximal ureteral stones larger than 1 cm ranges from 77% to 85%.(11,12) in their series of 58 patients with this type of stone, potis and colleagues(13) reported a stone-free rate of 84%. chen and colleagues(14) reported a stone-free rate of 84% for proximal ureteral stones of > 2 cm. in our study, the success rate of furs was 90%, consistent with the current literature. prabhakar and colleagues(15) performed furs in their series of 30 patients. they reported a mean stone diameter of 25 mm, a mean hospitalization time of 1 day, and a mean operational time of 92 min. in their series of 100 patients, hatipoğlu and colleagues(16) reported a mean stone diameter of 15.26 mm, a mean hospitalization time of 1.3 days, and a mean operational time of 52.72 min. in the present study of 80 patients, we found a mean stone diameter of 15.8 mm, a mean hospitalization time of 1.19 days, and a mean operational time of 49.1 min, consistent with the current literature. furs has some minor complications, such as hematuria, fever, and ureteral laceration, with rates ranging from 0% to 35%.(17,18) the most common postoperative complication is fever at a rate of 1.8%.(19) in the present study, postoperative fever occurred in three patients, and the complication rate was 3.75%. furs is performed under direct vision, and the device has a thin, flexible nature; thus, major complications are rare. serious complications include ureteral stricture and ureteral avulsion. no major complications occurred in this study. the first application of laparoscopic surgery in stone disease is ureterolithotomy. european urology guidelines state that laparoscopic ureterolithotomy has higher success rates than swl or urs if performed with correct indications, such as the presence of large and impacted ureteral stones that cannot be treated by endoscopic methods or swl.(2) laparoscopic ureterolithotomy may be performed via transperitoneal or retroperitoneal techniques. in both, the subsequent procedure is similar once the ureter is reached. the most important difference is that to reach the transperitoneal space, mobilization of the colon is required, which can lead to significant injuries and morbidity. the most important advantages of retroperitoneal laparoscopic ureterolithotomy are the direct access to retroperitoneal organs, less frequent abdominal contamination and infection due to urinary leakage, and the absence of peritoneal irritation. (20) thus, we prefer a retroperitoneal approach in all of our cases. the success rate for laparoscopic ureterolithotomy is > 90%.(21,22) the largest series of laparoscopic ureterolithotomies (123 cases) reported a stone-free rate of 96.7%.(23) only one patient in this series required open surgery due to migration of the stone. the stone-free rate was 96% among 24 patients in the series by bayar table 4. complication rates according to clavien classification. clavien complication grade group1 (n = 70), no group 2 (n = 80), no p value 1 0 3 (fever) 2 0 0 .491 3a 1( percutaneous nephrostomy) 5 (swl) 3b 3 ( open operation) 0 total, n (%) 4 (5.71) 8 (10) .334 abbreviation: swl, extracorporeal shock wave lithotripsy. treatment of large proximal ureteral stones-cavildak et al. and colleagues(24) in the present study, the success rate was 95.7%. in their series of eight patients, demirkesen and colleagues(25) reported a mean stone diameter of 17 mm, a mean hospitalization time of 3.25 days, and a mean operational time of 150 min. in their series of 24 patients, bayer and colleagues(24) reported a mean stone diameter of 15 to 20 mm and a mean hospitalization time of 3.4 days. in their series of 101 patients, gaur and colleagues(26) reported a mean stone diameter of 16 mm, a mean hospitalization time of 3.5 days, and a mean operational time of 79 min. the present study showed similar results. the complication rate of laparoscopic ureterolithotomy is low; even in the study with the highest reported rate of 17.6%, the most common cause was ureteral urinary leakage.(27) in the present study, the urinary leakage rate was 1.4%, and the leakage was treated by percutaneous nephrostomy. to prevent the development of ureteral stenosis, another complication, it is important to protect the blood supply of the incised portion of the ureter during the operation. nouira and colleagues(28) reviewed the literature and reported a ureteral stenosis rate of 2.5%. in the present study, we found no complications that could be attributed to ureteral stenosis. overall, we found that the furs and laparoscopic ureterolithotomy had similar success rates for the treatment of proximal ureteral stones. open surgery seems to be the only way to manage complications when endoscopic procedures are not sufficient for laparoscopic ureterolithotomy. however, the management of complications in furs can be less invasive than laparoscopy. conclusions laparoscopic ureterolithotomy and furs are both effective and reliable in the treatment of proximal ureteral stones. however, when considering the short operational and hospitalization times and the management of situations that require secondary interventions, we suggest that furs, as a minimally invasive method, may be the first choice in the treatment of proximal ureteral stones. conflict of interest none declared. references 1. dellabella m, milanese g, muzzonigro g. randomized trial of efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi. j urol. 2005;174:167-72. 2. türk c, petřík a, sarica k, seitz c, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2015 sep 4. 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the endourological society ureteroscopy global study: indications, complications, and outcomes in 11,885 patients. j endourol. 2014;28:131-9. 20. shao y, wang d , lu g, et al. retroperitoneal laparoscopic ureterolithotomy in comparison with ureteroscopic lithotripsy in the management of impacted upper ureteral stones larger than 12 mm. world j urol. 2015;33:1841–5. 21. skrepetis k, doumas k, siafakas i, lykourinas m. laparoscopic versus open ureterolithotomy. a comparative study. eur urol. 2001;40:32-6. 22. you-qiang fang, jian-guang qiu, de-juan wang, hai-lun zhan, jie situ. comparative study on ureteroscopic lithotripsy and laparoscopic ureterolithotomy for treatment of unilateral upper ureteral stones. acta cir bras. 2012;27:266-70. 23. simforoosh n, basiri a, danesh ak, et al. laparoscopic management of ureteral calculi: a report of 123 cases. urol j. 2007;4:138-41. 24. bayar g, sarioğullari u, acinikli h, et al. the comparison of ureteroscopy and ureterolithotomy fort the treatment of large and impacted ureteral stones in the middle and upper part of ureter. med bull şişli etfal hosp. 2014;:119-23. 25. demirkesen o, kural ar, atatus s, özkan b, yalçin v, akpinar h. laparoscopic ureterolithotomy: our initial experiences. j turk urol. 2004;30:457-60. 26. gaur dd, trivedi s, prabhudesai mr, madhusudhana hr, gopichand m. laparoscopic uretrolithotomy: technical considerations and long-term follow-up. bju int. 2002;89:339-43. 27. wang y, hou j, wen d, ouyang j, meng j, zhuang h. comparative analysis of upper ureteral stones (>15 mm) treated with retroperitoneoscopic ureterolithotomy and ureteroscopic pneumatic lithotripsy. int urol nephrol. 2010;42:897-901. 28. nouira y, kallel y, binous my, dahmoul h, horchani a. laparoscopic retroperitoneal ureterolithotomy initial experience and review of literature. j endourol. 2004;18:557-61. treatment of large proximal ureteral stones-cavildak et al. case report adrenocortical carcinoma with renal vein tumor thrombus extension saeid haghdani,1 reza kafash nayeri,1 homayoun zargar,2* mohammad ali zargar1 keywords: adrenal cortex neoplasms; humans; neoplasm invasiveness; renal veins. introduction adrenocortical carcinoma (acc) is a rare malignancy with an incidence rate of 0.5-1 per million per year. (1) tumor thrombus in this setting has been described but it represents an exceedingly rare surgical entity. however in one retrospective acc series was reported in 25% of cases.(1) similar to other acc tumors, up to 50% of tumors with thrombus extension are functional at diagnosis.(2) non-functional tumors are diagnosed due to mass effect or incidentally. depending on the tumor thrombus level, patients can present with varicocele,(3) lower limb edema(1) or pulmonary embolus.(1) apart from extension to renal vein and vena cava, extension to right atrium, splenic vein,(4) hepatic vein(5) and invasion into vena cava(6) have also been reported. herein we report a case of acc with left renal vein thrombosis in a male patient. case report a 60-year-old man presented with a 3 month history of left hemi-scrotal pain. the patient did not report any urinary or systemic symptoms. physical examination was unremarkable. scrotal ultrasonography (us) was normal. abdominal us demonstrated normal kidneys and a 10.7 × 8.5 cm heterogeneous mass in the upper pole of the left kidney. color doppler us identified left adrenal vein thrombosis with extension into the left renal vein. laboratory examinations including cbc (hemoglobin 15.7 g/dl), liver function tests (aspartate transaminase16 u/l, alanine aminotransferase 26 u/l, alkaline phosphatase 133 u/l, total bilirubin 0.43 mg/dl), serum creatinine (1.1 mg/dl) and electrolytes (na 143 mmol/l, k 3.9 mmol/l), and 24-hour urine collection (vanillylmandelic acid 1.5 mg/day, cortisol 15 µ/day) were within the normal ranges. computed tomography (ct) scan with contrast (figure 1a, 1b) confirmed the us findings. it demonstrated a 10 cm heterogeneous mass with hounsfield (hu) density of 30 on non-contrast imaging. the tumor had washout of < 50% with attenuation of > 30 hu, 15 minutes after contrast media injection (figure 1c, 1d, 1e). tumor thrombus was seen extending into the left renal vein on the ct scan images. chest ct was not suggestive of metastatic disease. after counseling, our patient elected to undergo adrenalectomy using the flank approach. intra-operatively a large adrenal mass with adhesion to the upper pole of left kidney along with adrenal vein thrombosis was observed (figure 2a). the tumor thrombus extended into the renal vein and inferior vena cava junction. adrenalectomy with en bloc radical nephrectomy and adrenal vein tumor thrombus excision was performed (figure 2b). the estimated blood loss was 700 ml and the patient required two units of intra-operative blood transfusion. no post-operative 1 department of urology, hasheminejad kidney center, iran university of medical sciences, tehran, iran. 2 glickman urological and kidney institute, cleveland clinic, cleveland, usa. *correspondence: glickman urological and kidney institute, cleveland clinic, q10, 9500 euclid ave. cleveland, ohio 44195 usa. tel: +1 216 526 6139. e-mail: homi.zargar@gmail.com. received january 2014 & accepted december 2014. figure 1. (a and b) computed tomography scan with coronal view. arrows demonstrate tumor thrombus extension into the left renal vein; (c, d and e) computed tomography with axial view demonstrating large heterogeneous adrenal lesion. figure 2. (a) intra-operative image demonstrating the left renal vein filled with the tumor thrombus; (b) gross pathology, the tumor thrombus within the renal vein is isolated after en bloc removal. case report 2037 vol 12. no 01 jan-feb 2015 2038 complications occurred. the histopathology confirmed acc with tumor thrombosis of the left adrenal vein. on histopathology assessment the tumor had 7 out of 9 criteria of weiss scoring for acc.(7) these included high fuhrman nuclear grade (3/4), mitotic counts > 5/50 per high power field, less than 25% clear cells composing tumoral cells, diffuse architecture in more than 1/3 of tumor, presence of necrosis, venous invasion and invasion of sinusoid structure. there was no evidence of renal involvement, and surgical margins were negative (pt3). the patient received adjuvant chemotherapy (mitotane 4g/day) post operatively and currently remains on this treatment. at the follow up time of 5 months, the patient remains free of local/systemic recurrence. discussion acc is a rare malignancy and acc with tumor thrombus extension is a rare presentation of this malignancy. depending on the extent of the tumor thrombus, patients can present with a variety of sign and symptoms.(3-6) after initial office assessment, laboratory assessment should include comprehensive endocrine evaluation. acquisition of ct scan of chest and abdomen (adrenal protocol with delayed contrast media washout phase) is universal to all acc staging. with regards to the tumor thrombus, magnetic resonance imaging (mri) is a better modality for assessing the extent of the thrombus extension.(8) further imaging (bone scan, head ct) is performed according to degree of clinical suspicion. complete surgical resection with a negative margin (r0 resection) is the only curative option for localized disease.(9) on retrospective review of 275 patients with acc undergoing primary tumor resection, r0 resection was associated with 25% reduction of local recurrence (hazard ratio 0.74).(2) presence of the tumor thrombus adds to the complexity of the surgery. the level of the tumor thrombus is an important factor for determining the surgical approach and type of incision. although laparoscopic adrenalectomy in the setting of acc with tumor thrombus has been described,(10) an open approach remains the gold standard surgical modality. depending on the extent of the tumor thrombus, open surgery can be performed via flank, subcostal, chevron or thoracoabdominal approach. the principle of surgery is early proximal and distal vascular control followed by tumor thrombectomy. where the inferior vena cava wall is invaded by the tumor, if r0 resection is possible complete excision and reconstruction of the cava should be performed. for the tumors extending into the atrium, cardiopulmonary bypass and cardiothoracic surgical assistance is necessary. kidney sparing surgery should be performed where possible but one must have a low threshold for en bloc nephrectomy if renal invasion is suspected. there are no explicit recommendations to differentiate benign and malignant adrenocortical tumors. a few systems incorporating histological criteria have been proposed. the most frequently cited is the weiss criteria revised by aubert.(7) our case satisfied 7 out of the 9 criteria, which is beyond the threshold of 3 suggestive of malignant tumor behavior. it is noteworthy to mention that the morphological criteria for diagnosis of benign and malignant adrenocortical tumors are different between adult and pediatric populations.(11) furthermore in both populations, when adrenocortical tumors are composed exclusively or predominantly of oncocytes (oncocytic adrenocortical neoplasms) morphological criteria for predicting clinical behavior are different from those applied in tumors with non-oncocyte morphology and linweiss-bisceglia score system is more appropriate.(12) the decision for administration of adjuvant therapy is made based on the tumor stage, resection status and the presence of ki-67 proliferation marker.(13) adjuvant therapy with mitotane has been shown to prolong overall survival and disease free survival. (14,15) close follow-up with 3 monthly ct scan imaging of the chest and the abdomen for the first 2 years is of importance, as the risk of recurrence remains high. conclusion acc is a rare condition and tumor thrombus represents a relatively uncommon presentation for this condition and where suspected needs to be further studied during the pre-operative work up. complete resection with negative margins represents the best chance of cure for the patient. adjuvant chemotherapy can be considered depending on final histopathology assessment and has been shown to improve survival. conflict of interest none declared. references 1. chiche l, dousset b, kieffer e, chapuis y. adrenocortical carcinoma extending into the inferior vena cava: presentation of a 15-patient series and review of the literature. surgery. 2006;139:15-27. 2. ayala-ramirez m, jasim s, feng l, et al. adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center. eur j endocrinol. 2013;169:891-9. 3. cheungpasitporn w, horne jm, howarth cb. adrenocortical carcinoma presenting as varicocele and renal vein thrombosis: a case report. j med case rep. 2011;5:337. 4. stein jp, selby rr, cote rj, hopkins b, figueroa aj, skinner dg. adrenal cortical carcinoma associated with a splenic vein tumor thrombus. scand j urol nephrol. 1998;32:1402. 5. reyes ma, ciancio g, singal r, manoharan m. adrenocortical carcinoma with tumor thrombus in the right hepatic vein. int j urol. 2006;13:1233-5. 6. yavascaoglu i, yilmaz m, kordan y. cardiac and caval invasion of left adrenocortical carcinoma. urol int. 2008;81:244-6. 7. aubert s, wacrenier a, leroy x, et al. weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. am j surg pathol. 2002;26:1612-9. 8. mueller-lisse ug, mueller-lisse ul, meindl t, et al. staging of renal cell carcinoma. euro radiol. 2007;17:2268-77. 9. fassnacht m, libe r, kroiss m, allolio b. adrenocortical carcinoma: a clinician’s update. nat rev endocrinol. 2011;7:323-35. adrenocortical carcinoma with renal vein tumor thrombus-haghdani et al 10. kim jh, ng cs, ramani ap, et al. laparoscopic radical adrenalectomy with adrenal vein tumor thrombectomy: technical considerations. j urol. 2004;171:1223-6. 11. magro g, esposito g, cecchetto g, et al. pediatric adrenocortical tumors: morphological diagnostic criteria and immunohistochemical expression of matrix metalloproteinase type 2 and human leucocyte-associated antigen (hla) class ii antigens. results from the italian pediatric rare tumor (trep) study project. hum pathol. 2012;43:31-9. 12. wong dd, spagnolo dv, bisceglia m, havlat m, mccallum d, platten ma. oncocytic adrenocortical neoplasms--a clinicopathologic study of 13 new cases emphasizing the importance of their recognition. hum pathol. 2011;42:489-99. 13. berruti a, fassnacht m, baudin e, et al. adjuvant therapy in patients with adrenocortical carcinoma: a position of an international panel. j clin oncol. 2010;28:e401-2. 14. menaa f, menaa b. development of mitotane lipid nanocarriers and enantiomers: two-inone solution to efficiently treat adreno-cortical carcinoma. curr med chem. 2012;19:5854-62. 15. terzolo m, angeli a, fassnacht m, et al. adjuvant mitotane treatment for adrenocortical carcinoma. n engl j med. 2007;356:2372-80. adrenocortical carcinoma with renal vein tumor thrombus-haghdani et al case report 2039 case report 2122 case report giant bladder calculi: a case report emre can polat,1* levent ozcan,2 alper otunctemur,3 emin ozbek4 keywords: case reports; urinary bladder calculi; urologic diseases; radiography. introduction bladder calculi account for 5% of all urinary system calculi.(1) they are usually seen in older men and occur because of infravesical obstructions such as prostate hyperplasia, neurogenic bladder, urinary tract infection (uti), foreign bodies, but anti-incontinence surgery in woman and rarely pregnancy can also be predisposing factors for bladder calculus.(2,3) bladder stones could also be seen in patients who had undergone radical cystectomy for invasive bladder cancer with neo-bladder reconstruction.(4) bladder stones may cause unilateral or bilateral hydronephrosis.(5) in this case report we present a 50 years old man who had giant bladder stone. case report a 50 years old man was admitted to the our clinic with lower abdominal pain, dysuria and pollakiuria. the patient came from mountainous rural area where the typical foods eaten by inhabitants contain high levels of oxalate and animal protein, such as sweet potatoes, mushrooms, spinach and red meat. the patient had no history of inflammatory bowel disease or surgery. he had several utis in his medical history. physical examination revealed mild tenderness in the lower abdomen. on digital rectal examination prostate was normal. routine hemogram test was normal and blood urea nitrogen and serum creatinine levels were 70 mg/dl and 2.3 mg/dl, respectively. patient urine culture was sterile before surgery. plain abdominal radiography showed a large and regular bladder stone measuring 10.1 × 7.5 cm (figure 1). ultrasonography revealed bilateral hydroureteronephrosis and a large bladder stone. preoperative neurological examination was normal and there were no signs of neurogenic bladder. therefore, videourodynamic evaluation was not performed preor post-operatively. patient underwent diagnostic cystoscopy before open surgery on the same operative day. no anatomical urethral obstruction was observed and there wasn't any suspicion for bladder cancer. then, we performed an open cystolithotomy under the diagnosis of bladder stone. during the operation, digital rectal manipulation was needed to remove the stone, which was adherent to the bladder mucosa. the stone weighed 500 gr and measured 9.9 × 8.9 × 7.1 cm in size (figure 2). x-ray crystallography showed calcium oxalate monohydrate stone composition. he was evaluated in the outpatient clinic on the first month after the operation. the patient had decreased hydroureteronephrosis on follow-up ultrasonography, and blood urea and serum creatinine levels were improved. uroflowmetry study was normal. also metabolic evaluation protocol showed hyperoxaluria with low urine ph. the patient gave an informed consent for publishing of data. 1 department of urology, istanbul medipol university, istanbul, turkey. 2 department of urology, derince training and research hospital, kocaeli, turkey. 3 department of urology, okmeydani training and research hospital, istanbul, turkey. 4 department of urology, istanbul training and research hospital, istanbul, turkey. *correspondence: department of urology, istanbul medipol university, istanbul, turkey. tel: +90 532 714 9604. e-mail: dremrecan@hotmail.com;ecpolat@medipol.edu.tr. received january 2015 & accepted march 2015 figure 1. giant bladder calculi seen in plain radiography. figure 2. extracted giant bladder stone by open cystolithotomy. vol 12. no 02 march-april 2015 1995vol 12. no 02 march-april 2015 2123 discussion massive or giant bladder calculus is a rare entity in the recent urological practice. males are more affected than females. bladder calculi are usually observed secondary to bladder outlet obstruction. these patients generally present with recurrent uti, hematuria or urinary retention. (6) our patient was admitted with recurrent utis. bladder stones are commonly observed with renal or ureteral calculi, but in our case there wasn’t any upper urinary tract calculus.(7) although bladder cancer is associated with upper and lower urinary tract stones,(8) we did not seen any suspicious lesions in terms of bladder cancer on cystoscopy. hyperoxaluria, hypercalciuria and a low urine calcium-oxalate ratio are implicated in calcium oxalate urinary stone formation.(9) although our patient had several utis history, no struvite and carbonate apatite existed in the stone analysis. in our case, dietary hyperoxaluria and low urinary ph due to high intake of animal protein may resulted in bladder stone formation. boonstra and colleagues reported a patient with acute abdominal pain and a palpable mass in the lower abdomen. after laparotomy they found bladder rupture caused by a giant vesical calculus and small intestine and sigmoid colon perforations due to pressure necrosis.(10) conclusion in conclusion, this case report emphasis that, in a patient with lower abdominal pain and recurrent utis, a bladder stone must be considered and the patient must be evaluated with radiological investigations. as a second finding after reviewing the related literature on this topic, we believe that large bladder stones should be viewed as a different clinical presentation than small bladder stones, especially regarding the cause of their formation. conflict of interest none declared. references 1. schwartz bf, stoller ml. the vesical calculus. urol clin north am. 2000;27:333-46. 2. oğuz u, şenocak c, kara c, bozkurt o.f, unsal a. [giant bladder calculus in a young and healthy man: a case report]. ankara univ med j. 2009; 62:183-5. 3. escobar-del barco l, rodriquez-colorado s, duenas-garcia of, avilez-cevasco jc. giant intravesical calculus during pregnancy. int urogynecol j pelvic floor dysfunct. 2008,19:1449-51. 4. picozzi s, macchi a, carmignani l. giant bladder stones. urol j. 2014;10:1027. 5. ciftci h, savas m. unilateral hydronephrosis secondary to giant bladder stone. turk j urol. 2008;34:261-3. 6. aydogdu o, telli o, burgu b, beduk y. infravesical obstruction results as giant bladder calculi. can urol assoc j. 2011;5:e77-8. 7. hammad ft, kaya m, kazim e. bladder calculi: did the clinical picture change? urology. 2006;67:1154-8. 8. michaud ds. chronic inflammation and bladder cancer. urol oncol. 2007;25:260-8. 9. xia p, zhang j, chen w. a huge bladder calcium oxalate stone. urolithiasis. 2015;43:97-8. 10. boonstra rh, blok ac, van der veen jh, silvis r. acute abdomen caused by a large vesical cystine calculus. ned tijdschr geneeskd. 2006;150:2800-4. giant bladder calculi-polat et al. urol_v3_no1_001_editorial.qxd urology journal unrc/iua 32 sexual dysfunction and infertility correlation of sperm nuclear chromatin condensation staining method with semen parameters and sperm functional tests in patients with spinal cord injury, varicocele, and idiopathic infertility nasser salsabili,1* abdorasoul mehrsai,2 babak jalalizadeh,2 gholamreza pourmand,2 shohreh jalaie3 1department of in vitro fertilization, mirza kouchack khan hospital, tehran university of medical sciences, tehran, iran 2urology research center, sina hospital, tehran university of medical sciences, tehran, iran 3department of biomedical statistics, faculty of rehabilitation, tehran university of medical sciences, tehran, iran abstract introduction: our aim was to investigate sperm nuclear chromatin condensation and its correlation with semen parameters and vitality test in infertile patients with spinal cord injury (sci), varicocele, and idiopathic infertility. materials and methods: sperm chromatin condensation was determined by aniline blue staining in 22 sci-injured infertile men, 20 with varicocele, and 28 with idiopathic infertility. the results were compared with the semen analysis parameters and the hypo-osmotic swelling test results. three grades of staining for sperm heads were distinguished: unstained, showing sperm maturity (g0); partially stained (g1); and completely stained, showing sperm immaturity (g2). the total score was calculated as: (g0 × 0) + (g1 × 1) + (g2 × 2). results: in all groups, the total staining score was higher than 75%, corresponding to a high degree of immaturity of sperm. patients with sci had a less sperm nuclear chromatin condensation and chromatin stability than patients with idiopathic infertility and varicocele (total scores, 98% versus 89% and 88%, respectively; p < .01). all of the patients had normal hypo-osmotic swelling test results. sperm counts for all patients were within the reference range. the mean percentages for normal motility and morphology of the sperm were 15.5% and 15% for patients with sci, 43% and 15% for patients with varicocele, and 62.5% and 54% for patients with idiopathic infertility. there was no correlation between sperm nuclear chromatin condensation and semen analysis parameters. conclusion: aniline blue staining for sperm nuclear chromatin condensation is a method independent of semen analysis and demonstrates the internal structural defects of sperm. this method may have a predictive value in assessing fertility. key words: sperm chromatin condensation, sperm count, sperm morphology, sperm motility, male infertility vol. 3, no. 1, 32-37 winter 2006 printed in iran received july 2004 accepted july 2005 *corresponding author: mirza kouchack khan hospital, 323 north ostad nejatollahy ave, tehran, iran. tel: +98 912 309 9140, fax: +98 21 8890 4172 e-mail: nsalsabili56@yahoo.com salsabili et al 33 introduction assessing sperm morphology, motility, and concentration is the best way to investigate male fertility. these are the 3 most important factors in male reproduction potential.(1,2) however, these parameters have not been proven useful in predicting the results of assisted reproductive technology (art).(3) therefore, more sensitive diagnostic techniques to identify subfertility amenable to the therapeutic options must be developed,(4) especially in patients with idiopathic infertility, blood vessels diseases, and nervous system disorders. bedford and colleagues have stated that the existence of subtle sperm abnormalities that are unrecognized by conventional semen analyses may explain reproduction failures.(5) such structural or biochemical defects are thought to be associated with chromatin packaging in the sperm nucleus.(5) poor chromatin packaging and possible dna damage may contribute to a failure of sperm decondensation and subsequently, fertilization failure or habitual abortion following fertilization.(6,7) the degree of chromatin condensation can be assessed with acidic aniline blue staining, which discriminates lysine-rich histones from arginine-rich and cysteine-rich protamines.(8) histone-rich nuclei of immature spermatozoa are rich in lysine and consequently, take up the blue stain. conversely, protamine-rich nuclei of mature spermatozoa are rich in arginine and cysteine, and contain relatively low amounts of lysine(9,10); thus, they do not stain with aniline blue. accordingly, evaluation of sperm chromatin condensation may be a good predictor of art results. this study was carried out to compare the results of sperm chromatin condensation with semen analysis parameters to assess male infertility in patients with spinal cord injury (sci), varicocele, and idiopathic infertilities, and to determine the influence of external structure and parameters on the internal structure of sperm cells. materials and methods this prospective study was performed on infertile men who had been referred to sina hospital, mirza kouchak khan hospital, and koassar fertility and impotency center, in tehran, iran. from september 2002 to september 2003, 22 patients with sci, 20 with varicocele, and 28 with idiopathic infertility and their partners were enrolled in the study. informed consent was obtained from the subjects and their partners. to confirm the diagnoses, clinical and paraclinical assessments (hormone profile, antisperm antibodies, and ultrasonography) were performed in all 3 patient groups. the patients' partners also were examined to rule out female-factor infertility. group 1 included 3 patients with thoracic sci (t1 to t10) and 19 patients with lumbar sci (t10 to l2). all of these patients had a complete sci and a history of paralysis of between 11 and 18 years' duration. in group 2, diagnosis of varicocele was made by physical examination and doppler ultrasonography. group 3 was composed of 28 infertile men with normal semen analysis results according to the criteria of the world health organization guidelines for semen analysis and kruger and colleagues' strict criteria (volume, > 2 ml; ph, 7.2 to 7.8; sperm count, > 20 × 106/ml; sperm motility, > 25%; sperm morphology, > 14%),(11,12) and no diseases were identified in clinical and paraclinical assessments (hormone profile, antisperm antibodies, ultrasonography), corresponding to men with idiopathic infertility. in all patients, semen samples were obtained in an antegrade fashion. in sci patients, the bladder was emptied with a catheter first. then, a seager model 14 electroejaculator (dalzell medical system, the plains, va, usa) was used, and the semen was obtained into a sterile container. semen volume, density, and ph; sperm count, morphology, and motility; and white blood cell count in the semen were determined according to the world health organization guidelines for semen analysis.(11) sperm count was measured in a grade pattern using a neubauer hemocytometer. sperm motility was defined as the percentage of sperm demonstrating flagellar motion, categorized as a (significant rapid progressive motility), b (slow progressive motility), c (nonprogressive motility), and d (no motility). sperm morphology was interpreted by the strict criteria defined by kruger and colleagues.(12) the degree of chromatin condensation was assessed using staining with aniline blue as previously described.(13) after sperm preparation, 5 µl of prepared spermatozoa was spread onto a glass slide and air-dried. smears were fixed in 3% buffered glutaraldehyde in phosphate buffered sperm nuclear chromatin condensation34 saline for 30 minutes. slides were then stained with 5% aqueous aniline blue mixed with 4% acetic acid (ph, 3.5) for 5 minutes. a total of 100 to 200 sperm cells were evaluated, and the percentage of stained sperm heads was calculated. three grades of staining for sperm heads were identified: unstained, showing sperm maturity (g0); partially stained (g1); and completely stained, showing sperm immaturity (g2). the total score was calculated according to the number of sperm heads with any of the 3 grades of staining by this formula: (g0 × 0) + (g1 × 1) + (g2 × 2).(14) the hypo-osmotic swelling (hos) test was performed in all 3 groups to evaluate sperm vitality and sperm wall integrity. one aliquot of 0.1 ml liquefied semen was added to 1 ml of hypo-osmotic solution. after incubation for 60 minutes at 37°c, samples were examined by a single technician using a phase-contrast microscope. the score was defined based on the 7 morphologic types of tail swelling (a, no change; b-g, various types of tail swellings). the hos test was considered abnormal for a semen sample if fewer than 50% of the spermatozoa were swollen.(11) collected data were compared between the 3 groups of patients using a 1-way analysis of variance and the tukey test. the pearson correlation coefficient was used to study the relationship between semen parameters and sperm chromatin nuclear staining, and between semen parameters and hos test types. results mean ages of men with sci (group 1), varicocele (group 2), and idiopathic infertility (group 3) were 34 ± 4.6 years, 32 ± 2.2 years, and 34 ± 1.6 years. the mean age of their partners was 30.7 ± 2.3 years, and no cause of infertility was found in them. the results of semen analyses for all patients are summarized in table 1. the sperm count was within the reference range for the patients of the 3 groups, but the mean sperm count was higher for the patients in group 1 than it was for patients in groups 2 and 3 (p < .05). the mean percentage of sperm with normal motility was the lowest in patients in group 1 and highest in patients in group 3 (p < .05). the mean percentage of sperm with a normal morphology was significantly higher in patients in group 3 (p < .01). the seminal fluid ph was significantly higher in men in group 2 than it was for men in group 3 (p < .05). the mean number of white blood cells in the seminal fluid of patients in group 1 was significantly higher than it was in patients in groups 2 and 3 (p < .01). the other seminal fluid components and sperm parameters were not significantly different between patients of the 3 groups. the total score of chromatin staining (representing sperm immaturity) in all 3 groups was higher than 75% (table 2). no correlation was found between chromatin condensation and sperm parameters (table 3). patients in group 1 had lower chromatin condensation and stability (higher total score) when compared with patients in groups 2 and 3 . the level of g0 chromatin condensation was significantly lower in patients in group 1 when compared with patients in the other 2 groups (p < .01), while the level of g1 chromatin was higher in patients in group 1 than it was in patients in group 2 (p < .01); however, this level was not significantly higher than the level in patients in group 3. no significant differences were seen in the level of g2 between the 3 groups. results of the hos test were table 1. results of seminal fluid and sperm parameters in the 3 groups of patients *significant difference between the patients of groups 2 and 3 (p < .05) †significant difference between the patients of groups 1 and 3 (p < .001) ‡significant difference between the patients of groups 1 and 2 (p < .01) number of patients volume (ml) ph sperm count (× 10 6 /ml) sperm motility (%) sperm morphology (%) white blood cells ( × 10 6 /ml) group 1 (spinal cord injury) 22 2.5 ± 1.87 7.74 ± 0.26 110.11 ± 88.48 † 15.63 ± 11.99 †‡ 15.06 ± 10.21 31.95 ± 21.78 †‡ group 2 (varicocele) 20 3.21 ± 1.64 8.01 ± 0.60 * 56.1 ± 44.09 * 43.1 ± 21.33 *‡ 15.45 ± 11.51 8.6 ± 13.02 ‡ group 3 (idiopathic infertility) 28 3.42 ±1.87 7.55± 0.29 * 78.92 ± 40.14 *† 62.57 ± 12.66 *† 53.93 ± 16.65 5.39 ± 11.21 † salsabili et al 35 normal in all patients (less than 50% type a spermatozoa). significant differences were found between the 3 groups, especially with regard to some types of tail defects (table 4). type a was more frequent in patients in group 3. differences also were significant in types c, d, and g. in the patients of group 2, seminal ph had a inverse relationship with tail defects, although this relationship was not significant. in the patients of group 2, seminal ph had a direct relation with sperm motility and a inverse relation with tail defects (p < .05). discussion as indicated by who protocol, the high prevalence of a male factor for infertility mandates a complete andrologic examination that must include functional sperm parameters and an hos test.(11) in this study, a significant difference was found between sperm parameters in patients with sci, varicocele, and idiopathic infertility, especially with regard to sperm count, motility, and morphology. these 3 factors are important, but none of them seem to play a major role in the outcome of intracytoplasmic sperm injection (icsi).(13) using other sperm functional tests, such as chromatin condensation, is still under debate.(15,16) in this study, using aniline blue staining, a relatively high proportion of immature sperm was found, while no correlation was found between chromatin condensation (aniline blue staining) and semen analysis. the hos test results and most semen analysis parameters were normal in all patients. thus, semen analyses and table 3. correlation between sperm chromatin condensation and sperm morphology, count, and motility, in the 3 groups of patients table 4. results of hos test in the 3 groups of patients *significant difference between the patients of groups 1 and 3 (p < .05) †significant difference between the patients of groups 1 and 2 (p < .05) type a (%) type b (%) type c (%) type d (%) type e (%) type f (%) type g (%) group 1 (spinal cord injury 11.45 ± 1.14 *† 21.86 ± 2 11.72 ± 1.69 * 5.4 ± 1.68 *† 13.81 ± 1.56 13.4 ± 1.36 21.45 ± 1.26 † group 2 (varicocele 13.7 ± 2.38 † 22.6 ± 1.78 12.9 ± 1.65 3.7 ± 1.8 † 12.25 ± 1.74 12.3 ± 1.65 23.35 ± 3.06 † group 3 (idiopathic infertility 14.35 ± 1.68 * 23.10 ± 1.79 13.10 ± 1.89 * 2.96 ± 1.57 * 12.64 ± 1.63 12.32 ± 1.74 22.89 ± 1.85 pearson r (p value) groups sperm morphology sperm count sperm motility group 1 (spinal cord injury 0.07 (.52) 0.16 (.18) 0.27 (.51) group 2 (varicocele 0.03 (.77) 0.09 (.43) 0.37 (.77) chromatin condensation (total score) group 3 (idiopathic infertility 0.09 (.59) 0.41(.91) 0.35 (.71) table 2. nuclear maturity and chromatin condensation categories in the 3 groups of patients g0: not stained showing sperm maturity, g1: partially stained, g2: completely stained showing sperm immaturity, total score = (g0 × 0) + (g1 × 1) + (g2 × 2) *significant difference between the patients of groups 1 and 3 (p < .01) †significant difference between the patients of groups 1 and 2 (p < .01) g0 (%) g1 (%) g2 (%) total score (%) group 1 (spinal cord injury) 11.04 ± 5.31 *† 78.68 ± 9.55 † 9.59 ± 5.55 97.86 ± 50.59 *† group 2 (varicocele) 22.25 ± 8.08 † 67.20 ± 10.52 † 11.05 ± 7.45 89.30 ± 12.16 † group 3 (idiopathic infertility) 19 ± 11.98 * 74.1 ± 13.41 6.89 ± 6.40 87.82 ± 13.74 * sperm nuclear chromatin condensation36 the hos test failed to show any defect that might impact the results of icsi. the association of abnormal sperm chromatin condensation with male infertility has been previously described.(6,13,15) consequently, sperm chromatin condensation may indicate a defect in the sperm of infertile men with normal semen analyses that may lead to icsi failure. some authors have investigated aniline blue staining as a marker for sperm chromatin defects to predict art results. haidl and schill have found a strong correlation between normal chromatin condensation and fertilization rate in in vitro fertilization (ivf). they have recommended that this method be performed prior to ivf because of the significant correlation between fertilization rate of spermatozoa in ivf and normal chromatin condensation.(7) however, hammadeh and colleagues have found different results in their studies.(13,17-19) in a study in 1996, they demonstrated that chromatin condensation has no predictive value for icsi outcomes. they compared the outcome of icsi between patients with 0% to 29% stained spermatozoa with aniline blue and those with more than 29% stained spermatozoa and found pregnancy rates of 18.5% and 35.5%, respectively.(13) in another study of 96 infertile men, they compared the fertilization rate after ivf between men with 20% or fewer stained spermatozoa and those with more than 20%. the fertilization rates were 79.9% versus 58.8%, respectively.(17) hammadeh and colleagues performed research similar to ours and found no correlation between sperm morphology, chromatin condensation, and sperm count either in the fresh or in the processed semen samples.(18) later, in 2001, these authors designed a case-control study to determine the value of sperm chromatin condensation to assess male fertility. a total of 165 semen samples from 90 patients and 75 healthy donors (control) were examined for chromatin condensation by aniline blue staining. a lower percentage of the samples from infertile patients was unstained by aniline blue (p < .001). however, no correlation was found between sperm chromatin condensation and morphology, count, and motility. the authors concluded that chromatin condensation constitutes a valuable parameter in assessing male fertility, independent of conventional sperm parameters. the inclusion of chromatin condensation in routine laboratory investigations of semen prior to assisted reproduction is strongly recommended by this group.(19) sperm chromatin packaging quality has been assessed by the chromomycin a3 (cma3) fluorochrome and the presence of dna damage in spermatozoa, using in situ nick translation, as well. sakkas and coworkers have shown that normal men present sperm parameters with a normal morphology of > 20%, cma3 fluorescence of < 30%, and exhibit endogenous nicks in < 10% of their spermatozoa. when they separated patients according to these values, no difference was observed in fertilization rates after icsi. when the unfertilized icsi oocytes were examined, they found that patients with cma3 fluorescence of < 30% and nicks in < 10% of their spermatozoa had only 21.6% of their unfertilized oocytes containing spermatozoa that remained condensed. in contrast, patients with higher cma3 and nick values had a significantly higher percentage, 48.9%, of their unfertilized oocytes containing condensed spermatozoa. sperm morphology showed no such pattern. the percentage of spermatozoa that had initiated decondensation in unfertilized oocytes was not influenced by morphology, cma3 fluorescence, or nicks. they postulated that poor chromatin packaging and/or damaged dna may contribute to failure of sperm decondensation after icsi and result in failure of fertilization.(3) controversial reports on the practical use of sperm nuclear condensation assessment warrant further studies. however, it seems that semen assessment for sperm chromatin condensation may be useful in the icsi procedure,(3) where much of the natural selection mechanism involved in fertilization is bypassed. the absence of a correlation between chromatin condensation and sperm functional tests in our results indicates that they are independent parameters. the last step of fertilization is determined by chromatin decondensation in spermatozoa, in which the histones are replaced by protamine.(3) the ratio of replacement can be determined by aniline blue staining or other methods and may be of good prognostic value in male fertility. conclusion aniline blue staining for chromatin condensation of sperm nuclear is an independent factor from sperm functional parameters. thus, it may be a good means of assessing the fertilization potential by demonstrating internal structural defects in the fertility potential of salsabili et al 37 sperm. we recommend that it be included in routine laboratory investigations of semen prior to assisted reproduction. however, the efficacy of this test must be evaluated by further studies in the future. references 1. ombelet w, pollet h, bosmans e, vereecken a. results of a questionnaire on sperm morphology assessment. hum reprod. 1997;12:1015-20. 2. liu dy, du plessis yp, nayudu pl, johnston wi, baker hw. the use of in vitro fertilization to evaluate putative tests of human sperm function. fertil steril. 1988;49:272-7. 3. sakkas d, urner f, bianchi pg, et al. sperm chromatin anomalies can influence decondensation after intracytoplasmic sperm injection. hum reprod. 1996;11:837-43. 4. aitken rj. evaluation of human sperm function. br med bull. 1990 jul;46(3):654-74. 5. bedford jm, bent mj, calvin h. variations in the structural character and stability of the nuclear chromatin in morphologically normal human spermatozoa. j reprod fertil. 1973;33:19-29. 6. zamboni l. sperm structure and its relevance to infertility. an electron microscopic study. arch pathol lab med. 1992;116:325-44. 7. haidl g, schill wb. assessment of sperm chromatin condensation: an important test for prediction of ivf outcome. arch androl. 1994;32:263-6. 8. hofmann n, hilscher b. use of aniline blue to assess chromatin condensation in morphologically normal spermatozoa in normal and infertile men. hum reprod. 1991;6:979-82. 9. calvin hi. comparative analysis of the nuclear basic proteins in rat, human, guinea pig, mouse and rabbit spermatozoa. biochim biophys acta. 1976;434:377-89. 10. gusse m, sautiere p, belaiche d, et al. purification and characterization of nuclear basic proteins of human sperm. biochim biophys acta. 1986;884:124-34. 11. world health organization. laboratory manual for the examination of human semen and semen-cervical mucus interaction. 4th ed. new york, ny: cambridge university press; 1999. 12. kruger tf, acosta aa, simmons kf, swanson rj, matta jf, oehninger s. predictive value of abnormal sperm morphology in in vitro fertilization. fertil steril. 1988;49:112-7. 13. hammadeh me, al-hasani s, stieber m, et al. the effect of chromatin condensation (aniline blue staining) and morphology (strict criteria) of human spermatozoa on fertilization, cleavage and pregnancy rates in an intracytoplasmic sperm injection programme. hum reprod. 1996;11:2468-71. 14. dadoune jp, mayaux mj, guihard-moscato ml. correlation between defects in chromatin condensation of human spermatozoa stained by aniline blue and semen characteristics. andrologia. 1988;20:211-7. 15. razavi s, nasr-esfahani mh, mardani m, mafi a, moghdam a. effect of human sperm chromatin anomalies on fertilization outcome post-icsi. andrologia. 2003;35:238-43. 16. agarwal a, said tm. role of sperm chromatin abnormalities and dna damage in male infertility. hum reprod update. 2003;9:331-45. 17. hammadeh me, stieber m, haidl g, schmidt w. association between sperm cell chromatin condensation, morphology based on strict criteria, and fertilization, cleavage and pregnancy rates in an ivf program. andrologia. 1998;30:29-35. 18. hammadeh me, nkemayim dc, georg t, rosenbaum p, schmidt w. sperm morphology and chromatin condensation before and after semen processing. arch androl. 2000;44:221-6. 19. hammadeh me, zeginiadov t, rosenbaum p, georg t, schmidt w, strehler e. predictive value of sperm chromatin condensation (aniline blue staining) in the assessment of male fertility. arch androl. 2001;46:99-104. introduction of patients with pelvic fractures, 4% to 14% also have posterior urethral rupture (pur), which is associated with considerable morbidities such as incontinence, erectile dysfunction, and urethral stricture.(1) management of pur continues to evolve. some urologists advise initial placement of a suprapubic cystostomy followed by delayed urethroplasty 3 to 6 months later, while others suggest immediate realignment.(2) the definition of primary realignment of urethral distraction injury has changed over the years. the current definition of primary realignment refers to immediate stenting of urethral distraction with a catheter without pelvic dissection or suture.(3) in the present study, we review our experience with primary realignment of pur and report its outcome and complications. materials and methods between march 2002 and august 2004, there were 25 men (mean age, 33.5 ± 14.5 years; range, 18 to 70 years) with pur due to injury who underwent primary realignment in our medical center. posterior urethral ruptures were diagnosed and confirmed by history, physical examination, and retrograde urethrography. we prospectively selected those patients with no visceral injuries to undergo primary realignment. surgical technique. a lower midline abdominal incision is made. if the patient is hemodynamically stable with no other genitourinary tract injuries, a vertical cystotomy incision is made under direct vision, and a urethral foley catheter is gently passed in a retrograde fashion. if the catheter is easily primary realignment of posterior urethral rupture mehdi salehipour, abdolaziz khezri, rashid askari,* parham masoudi department of surgery, division of urology, faghihi hospital, shiraz university of medical sciences, shiraz, iran abstract introduction: we report the results of treatment of posterior urethral rupture (pur) by primary realignment with some modifications of the technique. materials and methods: in this prospective study, 25 patients (mean age, 33.5 years; range, 18 to 70 years) in whom pur had been proved underwent primary urethral realignment. all patients were evaluated postoperatively for urinary incontinence, erectile dysfunction, and urethral stricture. they were followed for a mean of 20 months (range, 9 to 27 months). results: in 20 of 25 patients (80%), posterior urethral rupture was associated with pelvic fractures and in 2 (8%), bladder rupture was also present. none of the patients had urinary incontinence. six patients (24%) had evidence of postoperative stricture that required urethral dilatation and/or direct vision internal urethrotomy in 2 or 3 procedures under local anesthesia. erectile dysfunction was reported by 4 patients (16%) as a decreased quality of erection, all of whom responded to sildenafil. conclusion: we believe that primary realignment of pur is a simple procedure associated with low morbidity. it is recommended for patients who are stable and have no other significant intra-abdominal and pelvic organ injuries. key words: urethra, urethral distraction, urethroplasty, injuries, primary realignment 211 urology journal unrc/iua vol. 2, no. 4, 211-215 autumn 2005 printed in iran received january 2005 accepted july 2005 *corresponding author: department of urology, faghihi hospital, zand ave, shiraz, iran. tel: ++98 711 233 0724, ++98 711 235 5397, fax: ++98 711 233 0724 e-mail: rashidaskari@yahoo.com primary realignment of posterior urethral rupture brought into the bladder, its tip is sewn to the tip of a nelaton catheter using a nonabsorbable suture, and the latter catheter is brought out from the bladder and the anterior abdominal wall and fixed to the abdominal wall. a suprapubic tube is placed in the dome of the bladder and the bladder is closed in 2 layers using a standard technique (figure 1a). if retrograde catheter placement fails, a 20-f nelaton catheter is gently passed from the urethral meatus to the urethral disrupted area and the space of retzius. a second 18-f nelaton catheter is also gently passed from the bladder neck and the prostatic urethra to the disrupted area and the space of retzius, in an antegrade fashion. the ends of these catheters are tied together, and the antegrade catheter is manipulated through the anterior urethra by pulling the retrograde catheter back to the urethral meatus. subsequently, the antegrade catheter is secured to a foley catheter by a nonabsorbable suture, which is then pulled back into the bladder. the antegrade catheter is brought out the anterior wall of the bladder and abdominal wall and fixed to the skin. the foley catheter balloon is filled with 20 ml fluid. a suprapubic cystostomy tube is placed using a standard technique as previously described. no traction is applied on the foley catheter. the foley catheter is left in place for 4 weeks and replaced by another one based on the guidance of the antegrade catheter. the foley catheter is retracted until the tip of the antegrade catheter are seen via the urethral meatus. the suture is removed from tips of both catheters, and a new foley catheter is sewn to the tip of the antegrade catheter. the antegrade catheter is retracted through the bladder and the abdominal wall and removed by cutting the sutures (figure 1b). the new foley catheter is retracted gently while its balloon is filled with 20 ml fluid (figure 1c). the new foley catheter is left in place for another 4 weeks and removed when a retrograde urethrography around the foley catheter shows no extravasation of contrast medium. the suprapubic cystostomy is clamped, but left in place. if the patient voids normally and without difficulty, the cystostomy tube may be removed 2 weeks later. follow-up. after the removal of catheters, the patients were followed at 3, 6, and 12 postoperative months with physical examination, uroflowmetry studies, and, if needed, retrograde urethrography and/or a voiding cystourethrography. potency and continence were evaluated subjectively by interviews with the patients. patients were considered potent if they were able to have intercourse with vaginal penetration. if the patients had decreased firmness of erection compared with the preinjury status, this was considered decreased potency. continence was defined as no requirement to use a pad to protect against urine loss. eventually, the need for additional urologic procedures was assessed. 212 fig. 1. primary realignment of posterior urethral rupture, a. a 20-f foley catheter is inserted, its tip is sewn to a nelaton catheter, and cystostomy is placed. b and c. after 4 weeks, the foley catheter is exchanged with another one, and the nelaton catheter is retracted from the bladder and abdominal wall and removed. a foley catheter is placed for another 4 weeks. salehipour et al results mean follow-up was 20.0 ± 5.6 months (range, 9 to 27 months). twenty patients (80%) had pelvic fractures, and 2 (8%) had both pelvic fracture and bladder rupture. they had no visceral injury. all patients underwent surgical operation within 12 hours after injury. twenty-one patients were followed for more than 12 months. the most common mechanisms of injury in our patients, in order of frequency, are shown in table 1. on follow-up, 19 patients (76%) had no symptoms or radiologic evidence of urethral stricture. all patients reported good urinary continence with no need for a pad. six (24%) had strictures that were treated with urethral dilatation and/or direct vision internal urethrotomy. of these, 3 patients required 3 procedures, and 3 required 2 procedures. none required open urethroplasty. twenty-one (84%) patients reported a normal erection, while 4 (16%) had decreased firmness of erection (all of which responded to sildenafil, 50 mg to 100 mg, daily). the mean operative time for primary realignment was 50 ± 3 minutes (range, 45 to 60 minutes). the estimated blood loss was 300 ml to 700 ml, and 3 patients received 500 ml blood transfusion. discussion the pur is one of the worst types of genitourinary trauma with 3 significant complications: erectile dysfunction, urethral stricture, and urinary incontinence. management of pur remains controversial. in the present study, we showed that primary realignment was associated with no urinary incontinence, a low rate of erectile dysfunction, and a relatively low rate of urinary tract strictures that were treated successfully. some studies have shown that initial suprapubic cystostomy and delayed urethroplasty, 3 to 6 months later produces less complication than does primary realignment, while other studies have shown the opposite. in 1972, morehouse and colleagues(4) reported high impotence and incontinence rates in patients treated with primary realignment. webster and coworkers(5) have compared delayed urethroplasty and primary realignment in the treatment of pur and noted a significant advantage with delayed urethroplasty. on the other hand, follis and colleagues(6) have compared the operative outcomes of complete prostatomembranous disruptions in 20 men with delayed repair and 13 with immediate realignment. they reported potency rates of 50% and 80%, respectively, and an increased need for a secondary operation when the repair was delayed. elliott and barrett(3) analyzed the longterm (10-year) results of treatment of pur with primary realignment in 57 men and showed that primary realignment resulted in low incidence of erectile dysfunction (21%, mostly mild), incontinence (3.7%), and stricture (34%, but with no requirement for intervention). the main disadvantages of delayed urethroplasty are urethral stricture (in approximately 100% of patients(1)) and the need for a second operation with its potential complications such as impotence and incontinence. conversely, primary realignment reduces the requirement for secondary open urethroplasty, and in addition, the majority of strictures can be treated with urethral dilatation and/or direct vision internal urethrotomy as an outpatient procedure. compared with other studies,(3,6) the rate of urethral stricture in our study was relatively low. we think that the low urethral stricture rate is probably due to the minor modifications we made in our procedure. we connect the tip of the retrograde catheter to the tip of the antegrade nelaton catheter for 2 reasons: first, because it can prevent unwanted disconnection of the retrograde catheter that acts as a stent and is important to the healing processes; and second, because passage of the nelaton catheter after 4 weeks (when we change the retrograde foley catheter with another one, while the antegrade catheter is connected to it) 213 table 1. mechanisms of posterior urethral rupture in 25 patients mechanisms of injury number of patients (%) car accident 12 (48) falling 5 (20) crushing 4 (16) motorcycle accident 3 (12) tractor rollover 1 (4) total 25 (100) primary realignment of posterior urethral rupture may result in mild urethral dilatation. urinary continence depends on intact internal and external urethral sphincters. in pur, the bladder neck is separated from the urethra, and so it seems that continence is dependant on the external sphincter function. during urethroplasty, the possibility of damage to the external urethral sphincter is high. consequently, the rate of incontinence is higher than that in primary realignment. the reported rate of urinary incontinence with delayed urethroplasty has been 2% to 8%.(4-6) in 2 studies on primary realignment, urinary incontinence was present in 0% and 3.7% of the patients, and none of the patients in the latter study needed treatment.(3,6) we had no cases of incontinence. thus, is seems that primary realignment can be done with no serious impact on the patient's continence. we speculate that this is due to less manipulation of the external sphincter during primary realignment and repair of bladder neck and prostatic urethra with a good exposure. in addition, we used no traction on the urethral foley catheter, which prevents ischemic damage to the internal urethral sphincter, which is very important in maintaining continence.(7) causes of erectile dysfunction following pur are not understood. dhabuwala and associates have noted that impotence is caused by the original injury and is not due to the urethral repair.(8) in a report by tunc and colleagues,(9) erectile dysfunction was attributed to delayed urethral reconstruction in 16.2% of patients. it is likely that injury to the autonomic plexus in patients with pelvic fractures, or injury to the nervi erigentes in the neurovascular bundles dorsolateral to the prostatomemberanous urethra contributes to erectile dysfunction.(6) in our study, no patient developed permanent erectile dysfunction, and 4 patients with decreased firmness of erection responded to sildenafil and gradually improved significantly. we suppose that minimal manipulation of pelvic viscera and a low incidence of hematomas contributed to the low rate of erectile dysfunction in our study. the complication rates of primary realignment in our study and some other studies are shown in table 2. conclusion we believe that primary realignment of pur is a simple procedure associated with low morbidity. this technique is useful for patients who are stable with no other significant intra-abdominal or pelvic organ injuries. acknowledgement we gratefully acknowledge ms. mersedeh feradoni for her drawings in this article. we would also like to thank the office of research development of nemazee hospital and dr. hooman yarmohammadi for his editorial assistance. references 1. mcaninch jw, santucci ra. genitourinary trauma, in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 3707-44. 214 table 2. results of primary realignment versus delayed urethroplasty of posterior urethral rupture in different studies study technique number of patients stricture no. (%) incontinence no. (%) erectile dysfunction no. (%) elliott and barrett (3) pr 57 18 (34) 2 (3.7) 12 (21) webster and colleagues (5) pr 19 18 (95) 1 (5.2) 10 (53) follis and colleagues (6) pr/du 20/13 3/11 (15/85) 0/1 (0/8) 4/5 (20/39) tunc and colleagues (9) du 77 77 (100) 7 (9.1) 7/58 (16.2) patterson and colleagues (10) pr 29 11(38) 1 (3.4) 4 (14) husmann and colleagues (11) du 17 16 (94) 2 (12) 8 (47) the present study pr 25 6 (24) 0 (0) 4 (16) salehipour et al 2. koraitim mm. pelvic fracture urethral injuries: the unresolved controversy. j urol. 1999;161:1433-41. 3. elliott ds, barrett dm. long-term follow-up and evaluation of primary realignment of posterior urethral disruptions. j urol. 1997;157:814-6. 4. morehouse dd, belitsky p, mackinnon k. rupture of the posterior urethra. j urol. 1972;107:255-8. 5. webster gd, mathes gl, selli c. prostatomembranous urethral injuries: a review of the literature and a rational approach to their management. j urol. 1983;130:898-902. 6. follis hw, koch mo, mcdougal ws. immediate management of prostatomembranous urethral disruptions. j urol. 1992;147:1259-62. 7. mcaninch jw. traumatic injuries to the urethra. j trauma. 1981;21:291-7. 8. dhabuwala cb, hamid s, katsikas dm, pierce jm jr. impotence following delayed repair of prostatomembranous urethral disruption. j urol. 1990;144:677-8. 9. tunc hm, tefekli ah, kaplancan t, esen t. delayed repair of post-traumatic posterior urethral distraction injuries: long-term results. urology. 2000;55:837-41. 10. patterson de, barrett dm, myers rp, deweerd jh, hall bb, benson rc jr. primary realignment of posterior urethral injuries. j urol. 1983;129:513-6. 11. husmann da, wilson wt, boone tb, allen td. prostatomembranous urethral disruptions: management by suprapubic cystostomy and delayed urethroplasty. j urol. 1990;144:76-8. 215 urology journal unrc/iua vol. 1, no. 4, autumn 2004 printed in iran 290 author index to volume 1 afshar r, salimi j, sanavi sr, modaghegh mh, niazi f, fallah n. one-year efficacy of expanded polytetraflouroethylene vascular graft in eightythree hemodialysis patients, 188 aghah m, falihi a. the efficacy of acupuncture in extracorporeal shock wave lithotripsy, 195 aghamir smk, mohseni mg, ardastani a. the application of kub for detecting of submucosal ureteral stones, 32 aghamir smk, see mohseni mg, 250 ahmadnia h, younesi rostami m. treatment of renal colic using intracutaneous injection of sterile water, 200 ahmadnia h, see simforoosh n, 77 ahmadnia h, see younesi m, 126 ahmadi gh, see dadkhah f, 273 amir-zargar ma, yavangi m, ja'fari m, mohseni mj. primary tuberculosis of glans penis, 278 amjadi m, see etemadian m, 82 ardastani a, see aghamir smk, 32 asgari ma, kaviani a, gachkar l, hosseini-nassab sr. is bladder cancer more common among opium addicts? 253 asgari sa. successful medical treatment of emphysematous pyelonephritis, 282 asl zare m, see younesi m, 126 a'yanifard m, see tadayon a, 170 azadi sh, see nasehi a, 128 azizzadeh delshad a, see jalali nadoushan mr, 177 bagheri chime ar, see kazemeyni sm, 157 baharnoori m, see kajbafzadeh am, 218 bardideh ar, see rezaei m, 180 barzegarnejad a, see darabi mr, 131 basiri a, maghsoudi r, shadpur p. laparoscopicassisted ureterocystoplasty , 123 basiri a, simforoosh n, khoddam r, hoseini moghaddam mm, shayani nasab h. a comparison of augmentation cystoplasty before and after renal transplantation with the control group, 45 basiri a, simforoosh n, nikoobakht mr, hoseini moghaddam mm. the role of ureteroscopy in the treatment of renal transplantation complications, 27 basiri a, see simforoosh n, 10 basiri a, see simforoosh n, 165 basiri a, see ziaee sam, 174 dadfar mr, mostofi ne. adrenal myelolipoma, 211 dadkhah f, nahabidian a, ahmadi gh. the correlation between semen parameters in processed and unprocessed semen with pregnancy rate in intrauterine insemination in the treatment of male factor infertility, 273 danesh ak, see simforoosh n, 165 danesh ak, see ziaee sam, 174 darabi mr, barzegarnejad a. bilateral cryptorchid malignancy with persistent mullerian duct , 131-132 djaladat h , see nikoobakht mr, 99 djaladat h, see mehrsay a, 191 ebadzadeh mr, see tadayyon f, 204 emami m, see zargar ma, 263 etemadian n, amjadi m, simforoosh n. transcutaneous ultransound nephrolithotomy: the first report from iran , 82 falihi a, see aghah m, 195 fallah n, see afshar r, 188 fanaie a, see khatami m, 213 gachkar l, see asgari ma, 253 haberal ma. living donor kidney transplantation: how far should we go?, 148 hajebrahimi s, madaen sk, sheikhzadeh p. effects of thyrotropin-releasing hormone on urethral closure pressure in females with voiding dysfunction, 35 heidari f, see karami, 280 heidari f, see razzaghi mr, 256 heidari m, see irani d, 107 heidari n, see irani d, 90 heidary ar, see kazemeyni sm, 157 hesse a, see mehrsay a, 191 hoseini moghaddam mm, see basiri 27 hoseini moghaddam mm, see basiri a. 45 hosseini j, soltanzadeh k. a compatative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran, 94 hosseini sy, safarinejad mr. huge benign prostatic hyperplasia, 276 hosseini sy, see safarinejad mr, 227 hosseini sy, see safarinejad mr, 133 hosseini-moghaddam smm, see simforoosh n, 165 hosseini-nassab sr see asgari ma, 253 irani d, heidari n, khezri aa. the efficacy and safety of intravesical bacillus-guerin in the treatment of female patients with interstitial cystitis: a doubleblinded prospective placebo conrtolled study, 90 irani d, zeighami sh, khezri aa. results of dermal patch graft in the treatment of peyronie's disease, 103 irani d, heidari m. results of modified gil-vernet antireflux surgery in the treatment of vesicoureteral reflux, 107 ja'fari m, see amir-zargar, 278 jalali m, see nikravesh, 268 jalali nadoushan mr, peivareh h, azizzadeh delshad a. correlation between apoptosis and histological author index to volume 1 291 grade of transitional cell carcinoma of urinary bladder, 177 jamshidi m, see zargar ma, 263 kajbafzadeh am, baharnoori m. renal malakoplakia simulating neoplasm in a child, 218 karami h, heidari f. pseudoaneurysm following percutaneous nephrolithotomy, 280 kaviani a, see asgari ma, 253 kazemeyni sm, bagheri chime ar, heidary ar. woldwide cadaveric organ donation systems (transplant organ procurement), 157 kazemnejad a, see rezaei m, 180 khatami m, fanaie a, mehrvarz sh, kosari f. large adenocarcinoma of the right adrenal cortex, 213 khezri aa, see irani d, 103 khezri aa, see irani d, 90 khoddam r, see basiri a. 45 kosari f, see khatami m, 213 lesan pezeshki m. the newest medications in kidney transplantation and their mechanisms of action, 19 madaen sk, see hajebrahimi s, 35 maghsoodi r see simforoosh n, 10 maghsoudi r, see basiri a, 123 mahdavi r, mehrabi m. incisional hernia after renal transplantation and its repair with propylene mesh, 259 mahdavi r, rahmani m. cabernous hemangioma of the bladder, 49 mahdavi r. preparing live donor for kidney donation, 71 mahmoudi m, see rezaei m, 180 mansoori d, see mehrsai a, 85 mansoori d, see tadayon a, 170 mashayekhi r, see tavangar sm, 246 mehrabi m, see mahdavi r, 259 mehrsai a, mansoori d, taheri mahmoodi m, sina a, seaji a, pourmand gh. a comparison between clinical and pathologic staging in patients with bladder cancer, 85 mehrsai a, taghizadeh afshra a, zohrevand r, djaladat h, steffes hj, hesse a, pourmand gh. evaluation of urinary calculi by infrared spectrosopy, 191 mehrsai a, see nikoobakht mr, 99 mehrvarz sh, see khatami m, 213 modaghegh mh, see afshar r, 188 mohammadi torbati p, zham h. epithelioid type of paratesticular leiomyosarcoma, 215 mohammadzadeh rezaee ma. endoscopic resection of lower ureter in upper urinary tract tumors, 208 mohseni mg, zand s, aghamir smk. effect of smoking on prognostic factors of transitional cell carcinoma of the bladder, 250 mohseni mg, see aghamir smk 32 mohseni mj, see amir-zargar, 278 mombini h. the relationship between weight as well as the kind of prostate hypertrophy and the response to tamsulosine, a specific?-blocker, 115 mo'menzadeh s, see razavi ss, 40 mostofi ne, see dadfar mr, 211 nahabidian a, see dadkhah f, 273 najafi semnani m. a case of primary urethral carcinoma and inguinal lymphatic metastasis eith partial penectomy and limited inguinal lymphadenectomy, 52 nasehi a, azadi sh. elephantiasis of penis and scrotum, 128 nasehi a, see ziaee sam, 174 nasseh hr , see nikoobakht mr, 99 niazi f, see afshar r, 188 nikoobakht mr, mehrsai a, pourmand gh, djaladat h, nasseh hr. management of peyronie's disease by dermal grafting, 99 nikoobakht mr, see basiri, 27 nikoobakht mr, see salimi j, 117 nikravesh mr, jalali m. the effect of camphor on the male mice reproductive system, 268 nooralizadeh a, see simforoosh n, 165 nooralizadeh a, see simforoosh n, 24 nouralizadeh a, see tabibi a, 121 peivareh gh, see jalali nadoushan mr, 177 pourmand gh, see mehrsai a, 85 pourmand gh, see mehrsay a, 191 pourmand gh, see nikoobakht mr, 99 rahmani m, see mahdavi r, 49 razavi ss, shaeghi s, shiva h, mo'menzadeh s. a comparison between acetaminophen suppository and caudal anesthesia in relieving pain after pediatric surgery, 40 razi a. prostate cancer screening, yes or no? the current controversy, 240 razi a, see tavangar sm, 246 razzaghi mr, heidari f. a comparative study on the effect of lidocaine and furosemide on urinary output and graft function after renal transplantation, 256 rezaei m, kazemnejad a, bardideh ar, mahmoudi m. factors affecting survival in kidney recipients at kermanshah, 180 safarinejad mr, hosseini sy. erectile dysfunction: clinical guidelines(1), 133 safarinejad mr, hosseini sy. erectile dysfunction: clinical guidelines (2), 227 safarinejad mr, see hosseini sy, 276 salimi j, nikoobakht mr, zareei mr. epidemiologic study of 284 patients with urogenital trauma in three trauma centers in tehran, 117 salimi j, see afshar r, 188 sanavi sr, see afshar r, 188 seaji a, see mehrsai a, 85 shadpur p, see basiri a, 123 shaeghi s, see razavi ss, 40 shafi h, see simforoosh n, 10 shahbazian h. kaposi sarcoma in kidney transplanted patients, 111 sharifi-aghdas f, see simforoosh n, 165 sharifi-aghdas f, see ziaee sam, 174 shayani nasab h, see basiri a, 45 author index to volume 1292 shayani nasab h, see simforoosh n, 24 sheikhzadeh p, see hajebrahimi s, 35 shiva h, see razavi ss, 40 simforoosh n, ahmadnia h. laparoscopic adrenalectomy : a report of the first experiment in iran, 77 simforoosh n, basiri a, maghsoodi r, shafi h. modern status of laparoscopic surgery in the urology of iran and world, 10 simforoosh n, tabibi a, nooralizadeh a, shayani nasab h. laparoscopic ureteropelvic junction decompression for the management of obstruction, 24 simforoosh n, basiri a, tabibi a, danesh ak, sharifiaghdas f, ziaee sam nooralizadeh a, hosseinimoghaddam smm. a comparison between laparoscopic and open pyeloplasty in patients with ureteropelvic junction obstruction, 165 simforoosh n, see basiri, 27 simforoosh n, see basiri a, 45 simforoosh n, see etemadian m, 82 simforoosh n, see ziaee sam, 174 soltanzadeh k, see hosseini j, 94 steffes hj, see mehrsay a, 191 tabibi a, nouralizadeh a. diverticulocystoplasty in a case with decreased bladder capacity, 121 tabibi a, see simforoosh n, 165 tabibi a, see simforoosh n, 24 tabibi a, see ziaee sam, 174 tadayon a, a'yanifard m, mansoori d. endoscopic renal cyst ablation, 170 tadayyon f, yazdani m, ebadzadeh mr. a comparison study between theophylline and placebo in passage of ureteral stones, 204 taghizadeh afshra a, see mehrsay a, 191 taheri mahmoodi m, see mehrsai a, 85 tavangar sm, razi a, mashayekhi r. correlation between prostate needle biopsy and radical prostatectomy gleason gradings of 111 cases with prostatic adenocarcinoma, 246 yavangi m, see amir-zargar, 278 yazdani m, see tadayyon f, 204 younesi m, ahmadnia h, asl zare m. an unusual foreign body in the bladder and percutaneous removal, 126 younesi rostami m, see ahmadnia h, 200 zand s see mohseni mg, 250 zareei mr, see salimi j, 117 zargar ma, emami m, zargar k, jamshidi m. the results of grade iv cystocele repair using mesh, 263 zargar k, see zargar ma, 263 zeighami sh, see irani d, 103 ziaee sam, abdollah nasehi, basiri a, simforoosh n, danesh ak, sharifi-aghdas f, tabibi a. pcnl in the management of lower pole caliceal calculi, 174 ziaee sam, see simforoosh n, 165 zohrevand r, see mehrsay a, 191 403 forbidden
acute urinary retention in children seyyed alaeddin asgari1*, mandana mansour ghanaie2, nasser simforoosh3, abdolmajid kajbafzadeh4, alireza zare'1 1department of urology, razi hospital, gilan university of medical sciences, rasht, iran 2department of gynecology, azzahra hospital, gilan university of medical sciences, rasht, iran 3department of urology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran 4department of urology, pediatrics medical center, tehran university of medical sciences, tehran, iran abstract purpose: acute urinary retention in children is a relatively rare entity. there are a variety of causes that are poorly defined in the literature. we review our cases of acute urinary retention in children at three major pediatrics centers in iran. materials and methods: between 1996 and 2003, children (up to 14 years old) who had been referred due to acute urinary retention were examined. urinary retention was defined as inability to empty the bladder volitionally for more than 12 hours with a urine volume greater than expected for age or a palpably distended bladder. all data from the patients' past medical history, physical examination, and laboratory and radiographic assessments were collected. also, cystourethroscopy and urodynamic procedures had been carried out according to patient's conditions. patients with secondary urinary retention, including those with surgical history, immobility or chronic neurological disorders, mental retardation, and drugs or narcotics consumption were excluded from study. results: there were 86 patients meeting the inclusion criteria, consisting of 58 males with a median age of 4 years (range 1 month to 14 years) and 58 females with a median age of 4 years (range 4 month to 14 years). etiologies were lower urinary tract stone in 27.9%, neurological disorders in 10.4%, trauma in 10.4%, local inflammatory causes in 9.1%, urinary tract infection in 7.4%, ureterocele in 7.4%, benign obstructing lesions in 5.8%, iatrogenic in 5.8%, constipation in 4.6%, imperforated hymen in 3.5%, and large prostate utricle, urethral foreign body, and rhabdomyosarcoma each in 1 case (1.1%). conclusion: the most common cause of acute urinary retention was lower urinary tract stone in our pediatric cases. ureterocele and stone were the main findings in girls and boys, respectively, and urinary retention in boys was twice as prevalent as that in girls. key words: urinary retention, children, bladder, urethra 23 urology journal unrc/iua vol. 2, no. 1, 23-27 winter 2005 printed in iran introduction acute urinary retention (aur) always requires timely evaluation, management, and occasionally, hospitalization. otherwise, it would lead to the damage of kidney and urinary tract. although aur in men due to benign prostatic hyperplasia is well known and recognized, but in women and especially in children, it is rare, and as a result, it is not well studied in these populations. aur in children has mostly been described as few case received february 2004 accepted april 2005 *corresponding author: razi hospital, rasht, iran. tel: ++98 131 669 0006, e-mail: s-a-asgari@gums.ac.ir acute urinary retention in children reports.(1-4) in this study, we describe the causes of aur among children in three urology centers in iran. materials and methods in a retrospective study, we reviewed the hospital records of all of the children younger than 14 years old who presented with aur. data of the cases referred between 1997 and 2003 were collected from three main urological centers comprising shaheed labbafinejad, pediatrics medical center in tehran, and razi hospital in rasht. aur was defined as: inability to void and associated suprapubic pain and agitation that lasts more than 12 hours; or distended palpable bladder associated with pain. in all the patients, aur had been relieved with urethral catheterization or suprapubic cystostomy, and then they had undergone history taking, physical examination, laboratory tests and imaging modalities. if necessary, cystourethroscopy and urodynamic studies had also been done. patients with secondary urinary retention were excluded from the study, according to the exclusion criteria including surgical history, immobility or chronic neurological disorders, mental retardation, and drugs or narcotics consumption. results a total of 86 patients were studied, including 58 males with a median age of 4 years (range 1 month to 14 years) and 58 females with a median age of 4 years (range 4 month to 14 years). causes of aur, in descending order, were lower urinary tract stone in 24 (27.9%), neurological disorders in 9 (10.4%), trauma in 9 (10.4%), local inflammation in 8 (9.1%), urinary tract infection in 6 (7.4%), and ureterocele in 6 (7.4%) (table 1). causes of urinary retention in boys were lower urinary tract stones in 38%, neurological disorders in 12%, and local inflammation in 10%; while in girls, these were ureterocele in 21.4%, trauma in 17.8% and imperforated hymen in 10.7%. the incidence of lower urinary tract stones was 5.5-fold in boys (38.5% versus 7%). the rates of trauma and constipation were nearly equal in boys and girls. benign obstructive lesions, prostatic utricle, urethral foreign body, and prune belly syndrome were seen solely in boys, and ureterocele, imperforated hymen, and hinman syndrome all were seen merely in girls. in cases with lower urinary tract stone, the locations of stones were bladder neck, penile urethra, meatus, and urethral diverticulum. neurologic diseases were seen in 9 patients including spinal cord injuries with detrusor sphincter dyssynergia (dsd), ewing sarcoma, and sacrocoxygeal teratoma. genital and urethral traumas were seen in 9 patients. local inflammation included balanoposthitis, labial adhesion, and vulvitis, which were the causes of urinary retention in 5 male and 2 female 24 table 1. acute urinary retention in children etiology boys (no.) age range (mean) year girls (no.) age range (mean) year total (%) lower urinary tract stones 22 3-14 (7.2) 2 6-11 (8.5) 24 (27.9) neurologic problems 7 2.5-6 (4) 2 3-4.5 (3.75) 9 (10.4) trauma 4 2-7 (5) 5 4-13 (7.4) 9 (10.4) local inflammation 6 1.5-4 (2.5) 2 3-3.5 (3.25) 8 (9.1) urinary tract infection 4 0.5-2.5 (1.16) 2 0.5-1 (0.75) 6 (7.4) ureterocele 6 4-13 (7.33) 6 (7.4) benign obstructive lesions 6 0.8-1 (0.9) 5 (5.8) iatrogenic 3 1-5 (3.2) 2 4-6 (5) 5 (5.8) constipation 2 4-5 (4.5) 2 6 4 (4.6) imperforated hymen 3 12-13 (12.5) 3 (3.5) prostatic utricle 2 4-14 (9) 2 (2.3) hinman syndrome 1 10 1 (1.1) urethral foreign body 1 13 1 (1.1) urethral cyst 1 0.8 1 (1.1) prune belly syndrome 1 0.8 1 (1.1) rhabdomyosarcoma 1 2.5 1 (1.1) asgari et al patients. urinary tract infection was seen in 6 patients. ureterocele and benign obstructive lesions were seen in 6 girls and 6 boys, respectively. iatrogenic causes including urethral ligation, stiff dressing following circumcision, and vcug, were seen in 5 patients. four patients developed urinary retention due to constipation as the only abnormal finding. imperforated hymen associated with amenorrhea and abdominopelvic pains were seen in three girls. large prostatic utricle was seen in 2 boys, associated with urinary tract infection in one. in one boy, intentionally inserted foreign body into the urethra was the cause of urinary retention. other rare reasons were paraurethral cyst and rhabdomyosarcoma. discussion urinary retention is not common in children. in adults, it is defined as inability to void voluntarily despite a full bladder. children cannot express the sensation of bladder fullness or their inability to void, so that we defined urinary retention as the inability to void for at least 12 hours. in normal children, voiding intervals more than 12 hours is rare. furthermore, urine volume in the first 48 hours of the infant's life is low. in this study, we defined the full bladder as: extended palpable bladder or a urine volume greater than expected for bladder capacity in that age,(5) which was calculated with the using of two formulas: bladder capacity in children (≤2 years) = [2 × age (year) + 2] × 30 bladder capacity in children (>2 years) = [age (year) / 2 + 6] × 30 the study population was all of the pediatric inpatients or outpatients with aur who were referred to three medical centers in iran. in our study, the most common cause of urinary retention in children was lower urinary tract stones. this finding disagrees with others, in which the most common cause has been reported to be neurological disorders.(6,7) in one study, of 53 children with urinary retention, consisting of 37 boys, only one case of meatus stone was found.(6) in our study, of 86 patients, 24 (22 boys and 2 girls) had lower urinary tract stone, in which the most common location was urethral meatus (75%). often, urethral stone in males are originated from bladder. primary urethral stones can also be formed in the setting of urethral stricture, urethral diverticula, or urethral pouch.(8) primary urethral stones may be painless, due to their slow growing nature in the lumen or diverticula, but migratory stones usually have symptoms such as, dysuria, weak urine flow, and urinary retention. almost two third of urethral stones in adults are located in posterior and one third in anterior urethra.(9) in our study, urethral stone had induced urinary retention in 20 patients, most common site of which was meatus. most of the patients had a history of dysuria, obstructive urinary symptoms, and terminal dribbling. in most of them, the primary site of stone formation was bladder (70%) and the remainder 30% had a passage of ureteral stone. neurological disorders and genital trauma were in subsequent ranks after lower urinary tract stones. neurological causes, due to serious and progressive natures, necessitate special attention. of 9 patients with neurological etiology, 5 had spinal cord injury with detrusor sphincter dyssynergia manifestations. in 4 of them, no apparent pathology was found, though tethered cord and occult dysraphism had been considered as differential diagnoses. in our study, 9 patients (4 boys and 5 girls) had genital trauma. in girls, blunt direct trauma to external genitalia had caused urinary retention, of which only one had meatal laceration. in four other girls, urethra was intact and urinary retention was the result of pain and emotional effects, treated with urethral catheterization. the etiology of urinary retention in all the 4 boys was serious injury and urethral rupture, which were managed appropriately. this is contrary to the results of other studies, wherein, trauma as a cause of urinary retention has been seldom reported. this is presumably due to high prevalence of trauma in our country, especially in the north region. local inflammation had caused physical obstruction in 7 patients (5 boys and 2 girls), which were diagnosed simply with external genitalia examination. these lesions are often associated with dysuria and frequency, and urinary retention is uncommon. in our study, all of the 5 boys had balanoposthitis associated with sever glans and prepuce edema, which were treated with dorsal slit, urethral catheterization, and subsequent circumcision. of 2 girls with local inflammation, one had vulvitis and another one had labial adhesion; conservative treatment was successful in both. urinary tract infection was found as the etiology in 4 boys and 2 girls. except 25 acute urinary retention in children for one 2.5-year-old boy, they were younger that one year. in contrary to the textbooks in which cystitis is cited as the cause for urinary retention in patients with urinary tract infection (uti), in our study all of the patients had severe complicated uti, associated with purulent urine. the actual mechanism of urinary retention following uti is not well known. it may result from physical obstruction, impaired contractility due to edema or neuritis, and avoiding from voiding due to dysuria.(10) obstructive lesions, other than lower urinary tract stones, were found in 5 boys. they included 4 neonate boys with posterior urethral valve (puv) and one with bulbomembranous urethral stricture. patients with puv had distended abdomen, resulting from completely full bladder, of which one also had abdominal ascites. in neonates and infants, obstructive symptoms are more common than infectious symptoms. one 5-year-old patient with bulbomembranous urethral stricture had a history of encephalitis and long lasting urethral catheterization 1.5 years ago. ureterocele was seen in 6 girls with the age range of 4 to 13 years. one had bilateral ureterocele and 2 had concurrent uti. in our study, the most common cause of urinary retention in girls was ureterocele. although the common manifestation of ureterocele after birth is uti,(11-13) prolapsed ureterocele can cause bladder outlet obstruction, and this is the most common reason for urethral obstruction in girls.(14) iatrogenic etiology was found in 5 patients (3 boys and 2 girls) with urinary retention. in boys the reasons for urinary retention were urethral ligation in 1 and stiff dressing following circumcision in 2. in 2 girls, urinary retention had developed following vcug. urinary retention is an early complication of circumcision. it has been reported between 0.2% and 4.3%. it is mostly due to compressive dressing for prevention of bleeding.(15-17) complications of vcug are uti, irritative symptoms, and urinary retention. association of constipation with voiding dysfunction has been well described,(18,19) but its pathophysiology is not clear. association between constipation and urinary retention is present in the period of achieving voluntary urinary continence in children. pelvic diaphragm is responsible for stool and urinary continence, and when stool control is obtained, the child can subsequently control voiding. also vice versa is right.(19) in addition, filled rectum can displace bladder and its trigone anteriorly and impair urinary flow.(20) also, dysfunction in central and urethrovesical reflex in patients with chronic constipation has been proposed.(21) in our study, in 4 (4.6%) patients with urinary retention, constipation was the only abnormal finding, while in other reports, constipation comprises 13% of cases with urinary retention. imperforated hymen had caused urinary retention in 3, of whom 2 had hydrocolpos and one had hematocolpos with hematometra. these patients mostly complain from vague cyclic lower abdominal pain, but urinary retention is also common. in one report, of 26 patients with imperforated hymen, 12 (46%) manifested with urinary retention.(22) urinary retention in these patients is mostly due to pressure effect on urethra and bladder.(23) ultrasonography is the diagnostic choice to rule out mullerian duct malformations.(19) of other rare causes of urinary retention in this study were large prostatic utricle, hinman syndrome, paraurethral cyst, prune belly syndrome, foreign body, and pelvic rhabdomyosarcoma.(6) rare etiologies for urinary retention in other studies are hypomagnesaemia, bladder diverticula, ovarian cysts, appendiceal abscess, and strangulated hernia. conclusion in conclusion, the most common cause of urinary retention in our study was lower urinary tract stone, while in other studies, neurological problems and occasionally uti are mentioned as the most common causes. ureterocele and stone were the main findings in girls and boys, respectively, and urinary retention in boys was twice as prevalent as that in girls. references 1. walker rd. presentation of genitourinary disease and abdominal masses. in: kelalis p, king l, belman a, editors. clinical pediatric urology. 3rd ed. philadelphia: wb saunders; 1992. p.219. 2. rauch mk, martin el, cromie wj. rectal duplication as a cause of neonatal bladder outlet obstruction and hydronephrosis. j urol. 1993;149:1085-6. 3. mathews r, jeffs rd, maizels m, palmer ls, docimo sg. single system ureteral ectopia in boys associated with bladder outlet obstruction. j urol. 1999;161:1297300. 26 asgari et al 4. zia-ul-miraj m. congenital bladder diverticulum: a rare cause of bladder outlet obstruction in children. j urol. 1999;162:2112-3. 5. kaefer m, zurakowski d, bauer sb, et al. estimating normal bladder capacity in children. j urol. 1997;158:2261-4. 6. gatti jm, perez-brayfield m, kirsch aj, smith ea, massad hc, broecker bh. acute urinary retention in children. j urol. 2001;165:918-21. 7. peter jr, steinhardt gf. acute urinary retention in children. pediatr emerg care. 1993;9:205-7. 8. menon m, resnick mi. urinary lithiasis: etiology, diagnosis, and medical management. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.3288-9. 9. jenkins ad. calculus formation. in: gillenwater jy, grayhack jt, howards ss, mitchell me, editors. adult and pediatric urology. 4th ed. philadelphia: lippincott williams & wilkins; 2002. p.383. 10. koff sa, wagner tt, jayanthi vr. the relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. j urol. 1998;160:1019-22. 11. monfort g, guys jm, coquet m, roth k, louis c, bocciardi a. surgical management of duplex ureteroceles. j pediatr surg. 1992;27:634-8. 12. coplen de, duckett jw. the modern approach to ureteroceles. j urol. 1995;153:166-71. 13. cooper cs, snyder hm. ureteral duplication, ectopy, and ureteroceles. in: gearhart jp, rink rc, mouriquand pde, editors. pediatric urology. philadelphia: wb saunders; 2001. p.434. 14. christakis da, harvey e, zerr dm, feudtner c, wright ja, connell fa. a trade-off analysis of routine newborn circumcision. pediatrics. 2000;105:246-9. 15. wiswell te, geschke dw. risks from circumcision during the first month of life compared with those for uncircumcised boys. pediatrics. 1989;83:1011-5. 16. cuckow pm, nyirady p. male genital abnormalities. in: gearhart jp, rink rc, mouriquand pde, editors. pediatric urology. philadelphia: wb saunders; 2001. p.710. 17. chircop r. a case of retention of urine and haematocolpometra. eur j emerg med. 2003;10:244-5. 18. de paepe h, hoebeke p, renson c, et al pelvic-floor therapy in girls with recurrent urinary tract infections and dysfunctional voiding. br j urol. 1998;81 suppl 3:109-13. 19. loening-baucke v. urinary incontinence and urinary tract infection and their resolution with treatment of chronic constipation of childhood. pediatrics. 1997;100:228-32. 20. o'regan s, yasbeck s, shick e. constipation and the urinary system. in: o'donnell b, koff sa, editors: pediatric urology. 3rd ed. oxford: butterworthheinemann; 1997. p.197-8. 21. kerrigan dd, lucas mg, sun wm, donnelly tc, read nw. idiopathic constipation associated with impaired urethrovesical and sacral reflex function. br j surg. 1989;76:748-51. 22. yu tj, lin mc. acute urinary retention in two patients with imperforate hymen. scand j urol nephrol. 1993;27:543-4. 23. blask ar, sanders rc, rock ja. obstructed uterovaginal anomalies: demonstration with sonography. part ii. teenagers. radiology. 1991;179:84-8. 27 vol 13 no 04 july-august 2016 2794 breif communication prevention of stricture recurrence following urethral internal urethrotomy: routine repeated dilations or active surveillance? ye tian1 , romel wazir2, jianzhong wang3, kunjie wang4*, hong li 4 abstract strictures of the urethra are the most common cause of obstructed micturition in younger men and there is frequent recurrence after initial treatment. currently, routine repeated dilations, including intermittent self-catheterisation (isc) are prescribed by urologists to prevent urethral stricture recurrence. there is, however, no high level evidence available supporting the effectiveness of practicing these painful techniques. balancing efficacy, adverse effects and costs, we hypothesize that active surveillance is a better option for preventing stricture recurrence as compared with routine repeated dilations. however, well designed, adequately powered multi-center trials with comprehensive evaluation are urgently needed to confirm our hypothesis. introduction the term urethral stricture refers to the reduction of the urethral lumen from a scarring process, which could result from trauma, localized inflammation and iatrogenic or idiopathic pathologies. the estimated urethral stricture prevalence in the uk ranges from 10/100,000 to 100/100,000 and even higher in the usa, putting heavy financial burden on patient and the health services.(1, 2) when the maximum urinary fiow rate is < 5 ml/s, urethral stricture is always associated with particularly troublesome progressive voiding symptoms and urinary tract infections (utis).(3) open urethroplasty is regarded as the gold standard treatment of urethral strictures.(4) however, internal urethrotomy (iu) and urethral dilatation are still widely performed all over the world(5,6) even when the risk of recurrence is estimated to be high. the most common complication of urethral reconstructive surgery is recurrence of stricture. currently, routine repeated dilations including intermittent self-catheterisation (isc) are routinely prescribed by most urologists for urethral stricture recurrence prevention. despite this routine gained widespread acceptance, as far as we know, there is no high level supportive evidence from randomized clinical trials regarding this practice. in several studies, postoperative isc seem to reduce the stricture recurrence rate, (7) but due to the flaws of the nonrandomized design, the lack of information, the non-considerable follow-up times, the non-comprehensive evaluation and the retrospective case-control analysis, we should not jump to conclusions. furthermore, a prospective randomized study conducted by matanhelia et al.(8) suggested that there were no stricture recurrence prevention effects in patients pretreated with internal urethrotomy. there is also evidence that repeated dilations do not significantly reduces the risk of hospitalization or the need for ‘surgical’ dilatation or urethrotomy in case of recurrent strictures,(9) and instead, it even exacerbates scar formation, thus adding to stricture length and severity.(10) 1 department of urology surgery, guizhou provincial hospital, guiyang, p.r. china. 2 field hospital, mari petroleum company limited, daharki, district ghotki, sindh, pakistan. 3 department of urology, the first affiliated hospital of anhui medical university, hefei, p.r. china. 4 department of urology, west china hospital, sichuan university, chengdu, p.r. china. *correspondence: guoxue alley #37, chengdu, sichuan, p.r. china. postcode: 610041 phone: +86 1360 8017793. fax: +86-28-8542 2451. e-mail: wangkj@scu.edu.cn. received january 2016 & accepted june 2016 our hypothesis is that active surveillance with close follow-ups could be a better option than routine repeated dilations for preventing stricture recurrence following urethral internal urethrotomy. there is scientific evidence for supporting our hypothesis: challenges for practicing dilation routine repeated dilations following urethral internal urethrotomy are mostly performed by patients or their relatives, which can impose both physical and emotional challenges. it evokes a variety of embarrassment and shock as men are usually unfamiliar with and sometimes fearful of the concept when initially introduced to isc. they are worried about causing damage to themselves. (11) in addition, manual dexterity, cognitive ability and patient’s general health are important for practicing isc, many patients simply stop using it because of the sheer inconvenience,(8) indicating that not all the patients should be recommended to implement this procedure. each structure of the urethral lumen after reconstruction has its unique features. even for the well-trained surgeons, the practice of blind passage of filiforms and blind dilations without knowledge of the anatomy of the urethral stricture is indeed worrying. for the patients, severe damage could be introduced by blind isc. routine repeated dilations destroy the wound healing process the primary change after urethral reconstruction is metaplasia of the urethral epithelium from its normal pseudo-stratified columnar type to stratifed squamous epithelium,(12) which is a more fragile epithelium. considering this process, urethral reconstruction is usually performed 3-6 months later to give time for healing of the initial assault for which the patient had seeked treatment. shearing force caused by repeated dilations tends to split the urethral epithelium. these fissures or ulcers lead to focal extravasation of urine on voiding that in turn leads to subepithelial fibrosis.(3) bleeding is often present during dilations. if bleeding occurs, the stricture has been unfortunately torn rather than stretched, further injuring the involved area and producing further scarring. immediate difficulty with urination or development of acute urinary retention after dilations are commonly seen in daily clinical practice, and is mostly attributed to local tissue edema, implicating dilations, impairing the stricture area or even increasing the degree of scarring. complications caused by repeated dilations septicemia after dilatation was once the main risk in treated patients in the 20th century. with the development and wide application of antibiotics, the incidence and mortality of these septic episodes have decreased dramatically. but still, utis or asymptomatic bacteruria are familiar complications after dilation/catheterization by the healthcare workers. this complication can logically be observed more often when conducted by patients with improper or poor sterile techniques. as invasive blind operation, dilation/isc was also often associated with other complications including pain, haemorrhage, haematoma, false passage, extravasation, urethral perforation, rectal injury, sexual dysfunction and knotting/breaking/bending of the filiform leader.(13-15) long-term evaluation and cost-effectiveness although endoscopic treatments such as urethral dilation can transiently improve urinary fiow, repeated instrumentation exacerbates scar formation, thus adding to stricture length and severity. recurrent urethral stricture after repeated interventions is usually more complex with worsening conditions; making a more difficult and definitive open repair approach inevitable. a number of studies showed that the success of reconstruction is diminished by multiple prior urethral dilations and internal urethrotomy. (10,13) for most patients in whom dilations have failed, urethroplasty is usually the only curative option. as we know, there is still no cost-effectiveness analysis of active surveillance versus repeated dilations regarding urethral stricture recurrence prevention. considering the costs of inpatient and outpatient medical care, including the complications caused by repeated dilations and the more difficult and definitive open repair approach following repeated failed dilations, together with the socio-economic burden, we believe that active surveillance might be more cost-effective. voiding improvement might be achieved with repeated urethral dilations by causing the urethral lumen to be temporarily maintained. however, this improvement is maintained at the expense of extending the stricture longitudinally, and decreasing the calibre of the urethral lumen by the fibrotic process as dilations stop abruptly. although there is a lack of evidence, unfortunately, routine repeated dilations are still widely recommended. unless there is a significant improvement after repeated dilations, we believe active surveillance with close follow-up, together with urodynamic studies might be a better option for urethral stricture prevention. when a weaker urinary stream occurs, an attempt of a few dilations by experienced surgeons can be an option before urethroplasty, but should not be overused. in most cases, urethroplasty should be selected. active surveillance can save stable patients from unnecessary lifelong iscs and also the patients who needed urethroplasties from dilation-caused worsening conditions. anyway, well designed, adequately powered trials are needed for answering the relevant clinical questions more than just stricture recurrence rate, and more importantly, to understand which intervention is better for urethral stricture recurrence prevention considering the balance of efficacy, adverse effects and costs. conflict of interest none declared. references 1. mcmillan a, pakianathan m, mao jh, macintyre cc. urethral stricture and urethritis in men in scotland. genitourin med. 1994; 70: 403-5. 2. santucci ra, joyce gf, wise m. male urethral stricture disease. j urol. 2007; 177: 1667-74. 3. mundy ar, andrich de. urethral strictures. bju int. 2011; 107: 6-26. 4. barbagli g, lazzeri m. urethral reconstruction. curr opin urol. 2006; 16: 391-5. 5. liu js, hofer md, oberlin dt, et al. practice patterns in the treatment of urethral stricture among american urologists: a paradigm change? urology. 2015; 86: 830-4. 6. palminteri e, maruccia s, berdondini e, di pierro gb, sedigh o, rocco f. male urethral strictures: a national survey among urologists in italy. urology. 2014; 83: 477-84. 7. lauritzen m, greis g, sandberg a, wedren h, ojdeby g, henningsohn l. intermittent self-dilatation after internal urethrotomy for primary urethral strictures: a case-control study. scand j urol nephrol. 2009; 43: 220-5. 8. matanhelia ss, salaman r, john a, matthews pn. a prospective randomized study of selfdilatation in the management of urethral strictures. j r coll surg edinb. 1995; 40: 2957. 9. greenwell tj, castle c, andrich de, macdonald jt, nicol dl, mundy ar. repeat urethrotomy and dilation for the treatment of urethral stricture are neither clinically effective nor cost-effective. j urol. 2004; 172: 275-7. 10. waxman sw, morey af. management of urethral strictures. lancet. 2006; 367: 137980. 11. mcconville a. patients' experiences of clean intermittent catheterisation. nurs times. 2002; 98: 55-6. 12. chambers rm, baitera b. the anatomy of the urethral stricture. br j urol. 1977; 49: 545-51. 13. heyns cf, steenkamp jw, de kock ml, whitaker p. treatment of male urethral strictures: is repeated dilation or internal urethrotomy useful? j urol. 1998; 160: 356-8. 14. gelman j, liss ma, cinman nm. direct vision balloon dilation for the management of urethral strictures. j endourol. 2011; 25: 124951. 15. krebs j, wollner j, pannek j. urethral strictures in men with neurogenic lower urinary tract dysfunction using intermittent catheterization repeated dilations or surveillance-tian et al. breif communication 2795 vol 13 no 04 july-august 2016 2796 for bladder evacuation. spinal cord. 2015; 53: 310-3. repeated dilations or surveillance-tian et al. 93 urology journal unrc/iua vol. 2, no. 2, 93-96 spring 2005 printed in iran kidney transplantation kidney transplantation in older adults: does age affect graft survival? hassan ahmadnia,* ali shamsa, aliasghar yarmohammadi, mohammadreza darabi, mohammad asl zare department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran abstract introduction: there is a paucity of data on long-term patient and graft survival in the older kidney recipients. our aim was to evaluate the long-term outcomes of kidney transplantation in patients aged 50 years and older and compare them with outcomes in younger recipients. materials and methods: forty-seven recipients aged 50 years and older and 47 recipients aged younger than 50 years were randomly assigned to two groups (groups 1 and 2, respectively). patients who had received a cadaveric kidney allograft were excluded from the study. data including demographic and clinical characteristics, early complications, early mortality, and actuarial patient and graft survival rates were collected, and the two groups were compared, accordingly. results: the rates of early complications and mortality were not different between the two groups. patient survival rates at 1, 3, 5, and 7 years were 72%, 58%, 41%, and 41% for patients in group 1 and 95%, 86%, 86%, and 86% for patients in group 2, respectively (p = 0.007). graft survival rates were 72%, 58%, 41%, and 41% for patients in group 1 and 95%, 85%, 85%, and 85% for patients in group 2, respectively (p = 0.006). graft loss due to patient death was 33.33% in group 1 compared with 4.25% in group 2 (p < 0.001). conclusion: kidney transplantation should be considered in patients older than 50 years, since the graft survival rate is acceptable in this population, and early mortality and complications in this group are not different than those of younger recipients. although older patients have a shorter life expectancy, they benefit from renal transplantation in ways similar to younger kidney transplant recipients. key words: elderly, end-stage renal disease, kidney transplantation, survival introduction kidney transplantation today is widely known as the best treatment for patients requiring renal replacement therapies.(1) among the growing population of dialysis-dependent patients, those aged older than 60 years now account for more than 53% of the population requiring renal replacement therapies.(2) hemodialysis, the most commonly used modality in these patients, is associated with significant morbidity and mortality compared with kidney transplantation.(3) it has been shown that kidney transplantation in older patients can be performed safely and successfully.(4) therefore, it is not surprising that the demand for donor received january 2005 accepted april 2005 *corresponding author: 136 farhang lane, tehran st, mashhad 91366, iran. tel: ++98 511 859 5880, fax: ++98 511 841 7404 e-mail: ahmadnia2001@yahoo.com kidney transplantation in older adults94 organs has been steadily rising.(1) however, little long-term follow-up data exist regarding elderly transplant recipients.(2) the purpose of this study was to evaluate graft and patient survival in firsttime kidney transplant recipients aged 50 years and older. materials and methods from november 1983 to september 2004, 485 kidney transplantations were performed in ghaem medical center in mashhad, iran. in this historical cohort study, 47 recipients aged 50 years and older (group 1) and 47 recipients aged younger than 50 years (group 2) were randomly selected. the preoperative management was similar in both groups. patient evaluation before admission was standardized and included a medical history, physical examination, routine biochemical and hematological studies, blood grouping, white blood cell cross-match, viral studies (hepatitis b, hepatitis c, cytomegalovirus, and human immunodeficiency virus), electrocardiogram, and chest-radiograph. additional tests such as echocardiography, exercise test, and angiography were performed if a history of ischemic heart disease with or without diabetes mellitus or hypertension were present. all transplants were performed at a single center. patients who had received cadaver kidney allografts were excluded from the analysis. standard initial immunosuppressive therapy consisted of cyclosporine, prednisolone, and azathioprine. postoperative management and follow-up were done by the same team. data including demographic and clinical characteristics, serum creatinine levels, systolic and diastolic blood pressures before and after transplantation, early complications (wound infection, bleeding, urinary leak, and arterial and venous thromboses), early mortality (within 1 postoperative week), and actuarial patient and graft survival rates were collected, and the two groups were compared, accordingly. data analyses were performed using spss software (statistical package for the social sciences, version 11.5, ssps inc, chicago, ill, usa), with a chi-square test, student t test, and fisher exact test, as appropriate. also, kaplanmeier method and log-rank test were used for survival analyses. graft loss (death-censored) was considered the graft survival endpoint. values for p less than 0.05 were considered statistically significant. results in group 1, 2 patients were excluded because their data were incomplete. the mean ages for patients in groups 1 and 2 were 53.93 ± 3.67 years and 25.23 ± 6.76 years, respectively. both groups had similar sex ratios (13 women in each group). the mortality rate within the first week was 6.7% in group 1 (3 patients) and 2.1% in group 2 (1 patient) (p = 0.28). early complications were seen in 7 patients (15.6%) in group 1 and in 7 patients (14.9%) in group 2 (p = 0.93). the number of living-donor kidney recipients in groups 1 and 2 were 23 (51.1%) and 40 (85.1%), respectively (p < 0.001). there were no between-group differences regarding the patients' systolic and diastolic blood pressures, either before or after the procedure (pretransplant, p = 0.58, p = 0.7; posttransplant, p = 0.34, p = 0.1, respectively). the mean serum creatinine levels for patients in groups 1 and 2 before the operation were 5.21 ± 1.63 mg/dl and 4.87 ± 1.32 mg/dl, respectively (p = 0.27). the mean serum creatinine levels at the time of discharge from the hospital were 1.96 ± 1.39 mg/dl and 1.86 ± 0.99 mg/dl (p = 0.7) for patients in groups 1 and 2, respectively. patient survival rates at 1, 3, 5, and 7 years were 72%, 58%, 41%, and 41% in group 1 versus 95%, 86%, 86%, and 86% in group 2 (p = 0.007). the two main causes of death for patients in group 1 were related to cardiovascular events and infections. graft survival rates at 1, 3, 5, and 7 years were 72%, 58%, 41%, and 41% for patients in group 1 versus 95%, 85%, 85%, and 85% for patients in group 2 (p = 0.006). graft loss due to patient death was 33.33% in group 1 compared with 4.25% in group 2 (p < 0.001). discussion the purpose of renal replacement therapy is to prolong and maintain the quality of life for patients with end-stage renal disease (esrd) in whom the risks of undergoing transplantation is equal to or less than that of remaining on dialysis. kidney transplantation is the preferred method of therapy for most patients with esrd because it is more cost-effective,(5) and it allows return to a more-normal lifestyle than does maintenance dialysis therapy.(6) advanced age is often assumed to be a contraindication to kidney transplantation based on the fact that older patients may respond badly ahmadnia et al 95 to immunosuppression, may be at risk from anesthesia and surgery, and may be particularly prone to posttransplant complications. prior to the 1980s (the earlier years of kidney transplantation), it was reasonable to have such a negative attitude.(7) from 1981 on, however, there have been several reports of acceptable results of cadaveric kidney transplantation in older patients. lauffer and colleagues studied on 507 patients, of whom 63 (12.4 per cent) were over 55 years old at the time of operation, received first cadaver renal transplants. despite serious complications, actuarial graft survival for the population over 55 years of age was no worse than for those patients receiving first cadaver grafts who were under 55 years old, although patient survival was poorer in the former group (p = 0.027).(7) when analyzing mortality in older transplant recipients, the key question is to compare the risk of death with that seen in patients on long-term dialysis treatment. a study based on proportional hazard methodology for unequal group analysis on 389 patients treated for esrd was performed in the united kingdom, between 1974 and 1985. the authors concluded that no meaningful differences were noted between the relative risk of death for patients on continuous ambulatory peritoneal dialysis, those on hemodialysis, and those who had received a kidney transplant.(8) in several reports, it has been shown that the mortality rate in elderly patients is not significantly different from that observed in younger recipients. hestin et al reported no statistically significant differences in 3-year graft survival rates between the older and younger groups in their study. it is interesting to note that in that study, death or nephrectomy represented the exclusive cause of graft loss in elderly patients, whereas chronic rejection was the main cause of graft loss in younger recipients.(9) although we found a significant difference in graft survival rates between recipients 50 years of age and older (group 1) and those under 50 years of age (group 2) in the current study, this was due to more deaths in group 1; in group 1, 33.33% of graft losses were due to death, compared with 4.25% in group 2. many centers, including ours, remain reluctant to accept older patients on kidney transplantation lists owing to their shorter life expectancies. we hope, however, that our results, as well as those from other researchers, may convince more centers that age is not a contraindication to kidney transplantation.(2) we should be able to increase the number of kidney transplantations performed in patients older than 50 years by considering every patient older than 50 years as a potential recipient. their survival rates can be improved by careful selection and thorough assessment of cardiac and infection risks, as well as tailored immunosuppression.(2) conclusion kidney transplantation should be considered in patients aged older than 50 years, since graft survival in this population is excellent, and early mortality and complication rates in this group are no different than those of younger persons. although these patients have a shorter life expectancy, they benefit from kidney transplantation in ways similar to younger kidney transplant recipients. acknowledgement the authors wish to thank drs. habibollah esmaili and saed farzanefar for their wholehearted help and assistance, without which this article could not have been completed. references 1. saudan p, berney t, goumaz c, morel p, martin py. renal transplantation with donors aged over 50: a longterm, single centre experience. swiss med wkly. 2001;131:117-21. 2. saudan p, berney t, leski m, morel p, bolle jf, martin py. renal transplantation in the elderly: a long-term, single-centre experience. nephrol dial transplant. 2001;16:824-8. 3. wolfe ra, ashby vb, milford el, et al. comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. n engl j med. 1999;341:1725-30. 4. lufft v, kliem v, tusch g, dannenberg b, brunkhorst r. renal transplantation in older adults: is graft survival affected by age? a case control study. transplantation. 2000;69:790-4. 5. evans rw, kitzmann dj. an economic analysis of kidney transplantation. surg clin north am. 1998;78:149-74. 6. dew ma, switzer ge, goycoolea jm, et al. does transplantation produce quality of life benefits? a quantitative analysis of the literature. transplantation. 1997;64:1261-73. 7. lauffer g, murie ja, gray d, ting a, morris pj. renal kidney transplantation in older adults96 transplantation in patients over 55 years old. br j surg. 1988;75:984-7. 8. burton pr, walls j. selection-adjusted comparison of life-expectancy of patients on continuous ambulatory peritoneal dialysis, haemodialysis, and renal transplantation. lancet. 1987;1:1115-9. 9. hestin d, frimat l, hubert j, renoult e, huu tc, kessler m. renal transplantation in patients over sixty years of age. clin nephrol. 1994;42:232-6. point of technique diverticulocystoplasty in a case with decreased bladder capacity tabibi a, nouralizadeh a department of urology, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences,tehran, iran key words: diverticulocystoplasty, diverticulum, bladder capacity 51 urology journal unrc/iua vol. 2, 51-52 spring 2004 printed in iran introduction bladder diverticula are often asymptomatic, but in some cases they become symptomatic and lead to calculus formation, urinary tract infection, vesicoureteral reflux, and urethral obstruction. surgical intervention and diverticulectomy is required in such cases.(1) we described our experience in the treatment of a patient with large diverticulum. case report a 17-year-old boy with a chief complaint of discomfort in hypogastrium and urinary retention was evaluated. he had a history of frequency, urgency, and nocturia, without urinary infection or incontinence. physical examination revealed a relatively large palpable mass, in the lower abdominal area, from the umbilicus to the pelvis. biochemical laboratory studies were normal. ultrasonography showed normal kidneys, but a thickened bladder wall and a cystic mass with smooth wall containing liquid. the bladder was longitudinally stretched and had a large diverticulum in vcug (fig. 1). vesicoureteral reflux was not present. a large amount of residual urine in the diverticulum was seen in the post void film. cystoscopy was performed and showed a severe trabeculated and low-capacity bladder. furthermore, 2 cm above the right ureteral orifice a diverticulum opening measured 1.5 cm × 1.5 cm was seen. cystometry was not applicable due to low capacity bladder which was influenced by diverticulum pressure and the resultant pop off mechanism. indwelling urethral could not reduce the size of the diverticulum. due to the lowered bladder capacity, we decided to perform augmentation cystoplasty using diverticulum. the bladder was accessed with a lower midline incison. the bladder was opened longitudinally and 500cc urine was drained from the diverticulum. afterwards, the bladder and diverticulum were incised longitudinally on the adjacent walls and they were sutured to each other preceding by cystostomy and urethral catheter fixation. finally, a spherical vesicle was achieved. the patient was discharged after two weeks. urethral catheter was removed after three weeks. urinary residue was checked following proper voiding which was not significant; thus, the cystostomy was removed too. vcug was done three months later (fig. 2). follow-up has been continued accepted for publication in july 2003 fig 1. low capacity bladder with a large diverticulum on its right side (vcug) diverticulocystoplasty in a case with decreased bladder capacity every six months by renal and vesical ultrasonography, and biochemistry studies. the patient has been using intermittent catheterization in order to drain urine since then. discussion most bladder diverticula in young adults are single and associated with a small bladder. voiding disorders are common in bladder diverticulum.(1) they are often located laterally above the ureter orifice. diagnosis is made by cystography, particularly with post void film. surgery is warranted if recurrent infection, urethral and ureteral obstruction, or reflux develops. diverticulum can be secondary to obstructive neurogenic bladder. several treatments have been introduced for diverticula including laparoscopic, endoscopic, and open surgical approaches.(2-4) izquierdo and colleagues performed urodynamic studies in 11 cases with congenital bladder diverticulum of whom 8 had vesicoureteral dysfunction. urodynamics were normal in all following operation, so that they concluded that functional changes were due to diverticulum and reflux.(5) because of urinary retention and a large mass in the pelvis and abdomen, surgical approach was necessary in this patient. on the other hand, diverticulectomy could possibly lead to higher bladder pressure, incontinence, and upper tract damages since the bladder had a lowered capacity and thickened trabeculated wall. hence, we decided to perform augmentation using diverticulum itself, taking into account its advantages compared to intestinal tissue. to our knowledge, we have reported the first case of diverticulocystoplasty, and according to the last follow-up outcomes, it was successful. references 1. gearhart pj. exstrophy, epispadias and other bladder anomalies. in: walsh pc, retik ab, editors. campbell's urology. philadelphia: wb saunders; 2002. p. 2189. 2. porpiglia f, tarabuzzi r, cossu m, et al. sequential transurethral resection of the prostate and laparoscopic bladder diverticulectomy: comparison with open surgery. urology 2002; 60(6): 1045-9. 3. yu tj. extravesical deverticuloplasty for repair of a paraureteral diverticulum and the associated refluxing ureter. j urol 2002; 168(3): 1135-7. 4. martov ag, moskalev aiu, et al. endoscopic treatment of bladder diverticula. urologiia 2001;(6):40-4. 5. izuierdo mcr, mialdea lr, navascues aj, et al. functional changes in the bladder of children with primary bladder diverticulum. arch esp urol 1997 jul-aug; 50(6): 661-7. 52 fig 2. vcug three months after diverticulocystoplasty endourology and stone disease flexible ureterorenoscopy versus semirigid ureteroscopy for the treatment of proximal ureteral stones: a retrospective comparative analysis of 124 patients mert ali karadag,1* aslan demir,1 murat bagcioglu,1 kursat cecen,1 ramazan kocaaslan,1 fatih altunrende2 purpose: to investigate and compare the stone clearence and complication rates of flexible ureteroscopy (urs) with semirigid urs in patients having proximal ureteral stones. materials and methods: the data of 124 patients with proximal ureteral stones who underwent semirigid or flexible ureterorenoscopic lithotripsy between march 2008 and december 2012 were retrospectively investigated. the patients were divided into 2 groups according to the operation types. group 1 included 63 patients who were treated with semirigid urs and group 2 was consisted from 61 patients who underwent flexible urs. each group was compared in terms of stone diameter, successful access to the stone, operation time, reoperation rates, stone free status at postoperative 1st and 3rd month and complications. results: successful access was achieved in 48/63 (76%) of the cases in group 1 and 57/61 (93%) of the patients in group 2 (p < .05). initial stone free status was 63.4% (40/63) and 86.8% (53/61) in groups 1 and 2, respectively (p < .05). third month radiologic investigations revelaed a stone free rate of 77.7% (49/57) in group 1 and 93.4% (57/61) in group 2 (p < .05). reoperation was required in 20.6% (13/63) of cases in group 1 and this value was only 6% (4/61) in group 2 (p < .05). there was not any statistically significant difference between 2 groups in terms of complication rates (p > .05). conclusion: flexible urs is a favorable option for patients having proximal ureteral stones with higher stone free rate; on the other hand semirigid urs seems a less successful alternative for treatment of proximal ureteral stones. keywords: ureteral calculi; surgery; ureteroscopes; ureteroscopy; lithotripsy; retrospective studies; treatment outcome; complications. introduction proximal ureteral stones can be managed by various techniques including extracorporeal shock wave lithotripsy (swl), ureterorenoscopy (urs) with semirigid or flexible instruments, laparoscopic approaches, antegrade ureterolithotripsy and open surgery. the decisions about the choice of therapy depends on the stone factors like localization, size, density and radiolucency, anatomical factors, obstruction, technical capacity of the department, patient’s preference and surgeon’s skills.(1,2) swl and urs have been accepted as the initial treatment alternatives for proximal ureteral stones having low probability of spontaneous passage. swl has been considered as the first line treatment alternative for patients having proximal ureteral stones < 10 mm due to noninvasiveness and lower complication rates.(3) the major disadvantages of swl are long duration of treatment and requirement for auxillary procedures. with the miniaturization and advancements in the designs of ureterorenoscopes, stone disintegration systems and endourologic techniques, most of the ureteral stones can be managed by urs now1 department of urology, kafkas university, faculty of medicine, kars, turkey. 2 department of urology, istanbul bilim university, faculty of medicine, istanbul, turkey. *correspondence: kafkas üniversitesi tıp fakültesi hastanesi, üroloji a.b.d, kars, türkiye. tel: +90 532 5584324. e-mail: karadagmert@yahoo.com. received march 2014 & accepted october 2014. adays. usage of holmium:yag laser during urs makes the stone clearence better in a single session even for the proximal ureteral stones > 10 mm.(4) many studies to date have investigated the superiority and outcomes (in terms of complication rates and stone free status) of swl, retrograde intrarenal surgery and laparoscopy over each other for the treatment of proximal ureteral stones.(5,6) to the best of our knowledge, there has been no published article investigating and comparing the outcomes of flexible urs (f-urs) against semirigid urs for treatment of proximal ureteral stones. in the present study, we investigated and compared the stone clearence and complication rates of f-urs against semirigid urs in patients having proximal ureteral stones. materials and methods the medical files of 228 patients with solitary proximal ureteral stones who underwent semirigid urs or f-urs in kars state hospital, kafkas university, faculty of medicine and acibadem kayseri hospital between vol 11. no 05 sept-oct 2014 1867 march 2008 and december 2012 were reviewed and database of the study was formed. semirigid urs was performed in 108 patients and 120 underwent f-urs. according to the data searched, a total of 124 patients with solitary proximal stones who underwent semirigid urs or f-urs with holmium:yag laser were enrolled in this study. inclusion criteria of the study was patients who were operated for solitary proximal ureteral stones with semirigid or f-urs and who had postoperative 1st and 3rd month radiological investigations for assessment of stone free status in the medical records. patients with ureteral calculi who were previously operated or treated with swl, cases with ureteropelvic junction obstruction, solitary kidneys or multiple stones and the patients under 18 years old were excluded from the study. semirigid urs group included the patients who were operated in kars sate hospital and kafkas university, faculty of medicine. f-urs group consisted of the patients who were operated in acibadem kayseri hospital. review of the complete medical records of the patients for our study was approved by local ethics committee of kafkas university, faculty of medicine and performed in accordance with the helsinki declaration of the world medical association. proximal ureteral stones were defined as the stones located between the superior margin of the sacroiliac joint and the ureteropelvic junction. all of the patients were preoperatively evaluated with a detailed history, physical examination, laboratory tests including renal function tests, urine analysis and urine culture. the imaging investigations were plain x-ray of the kidneys, ureter and bladder (kub), urinary ultrasonography and non contrast computed tomography (ct) scan of the abdomen in patients with radioluscent stones. stone status was assessed intraoperatively and with postoperative 1st and 3rd month plain x-ray of the kub, urinary ultrasonography and non contrast ct scan of the abdomen in patients having radioluscent stones. success was accepted as patients with no stones or clinically insignificant residual fragments (< 4 mm) observed at initial postoperative evaluation and 1st/3rd month radiologic investigations. stone size was measured by using the longest axis of the stone viewed on plain film or sagittal section of ct scan. surgical procedures all of the patients were operated under general anesthesia at the lithotomy position. cephazolin sodium 1 gr intravenous was administered for preoperative antibiotic prophylaxis. semirigid urs was performed by using a 6.0/7.5 french (f) ureteroscope (richard wolf, knittlingen, germany). first, we introduced a safety guide wire (microvasive, boston scientific corp, natick, ma, usa) to the ureter with stone, then the semirigid ureterorenoscope was inserted into the ureter over guide wire under direct vision. after reaching the stone, disintegration was completed by using 20 w holmium:yag laser (lumenis, santa clara, ca, usa). a 200-µm laser fiber with an energy output of 0.8-1.5 joule at 8-12 hertz was used; but the joule and hertz of energy could be changed during the operation according to the stone hardness and efficacy of lithotripsy. the main goal was to disintegrate the stones until the fragments were smaller than 4 mm under direct vision or completely extraction of the stone fragments with basket (zero tip™, boston scientific corp, natick, ma, usa). f-urs was performed using a 7.5 f flexible ureterorenoscope (karl storz, tuttlingen, germany). after the insertion of a 9/11 f access sheath (cook urological, spencer, indiana, usa) over a sensor guide wire (microvasive, boston scientific corp, natick, ma, usa) under c arm fluoroscopy, we inserted the f-urs into the ureter and completed the stone disintegration and extraction like in the semirigid urs procedure. for both treatment groups, we inserted 26 cm 4.8 f double j ureteral catheters over the guide wires at the end of the procedures. it is a routine application in our department and urology department of acibadem kayseri hospital after the treatment of proximal ureteral stones. statistical analysis results are presented as the mean ± standard deviation (sd). the data were analyzed by statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. categorical variables were analyzed using chi-square test and statistical analyses of the means of continuous variables were performed with the student’s t-test. a p value of < .05 was considered statistically significant. each group treated with semirigid urs and f-urs for proximal ureteral stones were compared in terms of stone diameter, successful access to the stone, operation time, reoperation rates, stone free status at 1st and 3rd month and complications like fever, bleeding and perforation. reoperation was defined as requirement of same modality in patients with residual stones or stones > 4 mm in radiologic evaluation. bleeding was accepted as hemorrhage that disrupted the endoscopic vision of the surgeon and ureteral injury was defined as mucosal trauma that was observed during urs applications. bleeding and ureteral injury were decided by the urologists who performed the operations. results patients’ characteristics and demographics of 2 groups were summarized in table. there was not any statistically significant difference between two groups in terms of age, gender, stone size and opacity (p > .05). as expected, the mean operation time of group 1 was significantly shorter than group 2. with regards to success rate of reaching to the stone, we could make a successful access and reach to the stone in 48/63 (76%) of the cases in group 1 and 57/61 (93%) of the patients in group 2. this value was statistically significant (p = .008) and showed the superiority of f-urs in reaching to the proximal ureteral stones. in patients of group 1 with unsuccessful access to the stones (n = 9) (5 tortuosity, 2 narrow caliber of the ureter and 2 serious stenosis) and stone migration into the kidneys (n = 6), we inserted 26 cm 4.8 f double j catheters and operations were terminated. they were referred to another center for swl or f-urs applications and excluded from the study in terms of stone free achievement. in patients of group 2 with unsuccessful access to the stone (n = 4), same aforementioned modality was preferred. the reason of unsuccessful access in these patients was narrow caliber of the ureters (summarized in the flow chart). flexible ureterorenoscopy vs. semirigid ureteroscopy-karadag et al endourology and stone disease 1868 initial stone free status which was achieved after disintegration of the stones < 4 mm or complete extraction of the fragments decided by the surgeon at the end of the procedure was 63.4% (40/63) and 86.8% (53/61) in groups 1 and 2, respectively. this result was statistically significant (p = .003). this rate increased to 71.4% (45/63) in group 1 and 90.1% (55/61) in group 2 (p = .008) at 1st month radiologic controls. third month radiologic investigations revelaed a stone free rate of 77.7% (49/63) in group 1 and 93.4% (57/61) in group 2 (p = .013). all these results showed us the superiority of f-urs in terms of achieving a stone free status. reoperation rates of 2 groups were compared in our study. we required reoperation in cases who had rest stones or stones > 4 mm in radiologic evaluations. reoperation was required in 13/63 (20.6%) of cases in group 1 this value was only 6% (4/61) in group 2. reoperation rate of group 2 was statistically lower than group 1 (p = .023). complications were classified according to the modified clavien grading system.(7) no major intraoperative complications (grade 4 or 5) like avulsion or septicaemia were observed. ureteral perforation (grade 3b) below the ureteropelvic junction occured in 1 patient from f-urs group and managed conservatively with insertion of a 26 cm 4.8 f double j ureteral catheter. the complication rates of 2 groups in terms of fever, bleeding and ureteral injury were compared. postoperative fever (grade 1) was observed in 7 (11.1%) patients from group 1 and 8 (13.1%) patients from group 2 (p = .732). bleeding (grade 1) was noted in 13 (20.6%) and 5 (9.8%) patients from group 1 and 2, respectively (p = .095). ureteral injury (grade 1) occured in 4 (7.9%) and 2 (3.2%) cases from groups 1 and 2, respectively (p = .261). there was not any statistically significant difference between 2 groups in terms of complication rates. discussion the success rate of swl in proximal ureteral stones larger than 10 mm varies between 57-96% in the literature. (8,9) patient’s and urologist’s preference of swl therapy mainly depend on the advantage of less invasiveness with lower complication rates.(3) in our department, we also have a swl machine and therapy choice of proximal ureteral stones are decided after explaination of the options and discussion with the patients. all of the patients who were included in our study preferred ureterorenoscopic procedures as therapeutic modality. recent developments in the market about miniaturization of semirigid and f-urs and holmium:yag laser in urs applications attracted the attentions’ of the urologists and markedly improved the success rates of treating proximal ureteral and renal stones. atis and colleagues investigated the efficacy of semirigid urs against f-urs in treatment of renal pelvis stones.(10) the study included 47 patients with isolated renal pelvis stones. successful access with semirigid urs was achieved in 25 of 47 patients and the stones were fragmented using holmium:yag laser. f-urs was performed in remaining 22 patients. variables semirigid urs flexible urs p value no. of patients 63 61 mean age (year)* 38.2 ± 9.85 36.2 ± 7.38 .214 stone diameter (mm)* 11.6 ± 2.20 11.01 ± 2.24 .107 sex** .697 female 29/63 25/61 ---- male 34/63 36/61 ----laterality** .474 right 34/63 29/61 left 29/63 32/61 radioluscent** 7/63 6/61 .817 operation time (min)* 64.71 ± 16.11 84.06 ± 16.7 .001 table. demographic and clinical characteristics of study groups. abbreviation: urs, ureteroscopy. *student t-test (p > .05) **chi-square test (p > .05) flexible ureterorenoscopy vs. semirigid ureteroscopy-karadag et al flow chart vol 11. no 05 sept-oct 2014 1869 the authors revealed no significant differences among 2 groups in terms of stone free rates, complication rates and hospitalization. an approximately success rate of 50% improved to 90% in the treatment of proximal ureteral stones after development of small caliber urs and holmium:yag laser.(11-14) the major disadvantage of holmium:yag laser seems to be the cost; but we also prefer to use holmium:yag laser for treating patients with proximal ureteral stones as energy source in our department. in a recent study from india, 90 patients having upper ureteral stones < 2 cm were treated with shockwave lithotripsy and semirigid urs and outcomes were compared. (15) ureteroscopy and stone disintegration were performed by using an 6/7.5 f semirigid urs with holmium:yag laser. the average stone size of urs group was 12.5 mm and the overall 3rd month stone free rate was 86.6%. in our study, the mean stone size of patients treated with semirigid urs was 11.6 mm and 3rd month success rate of this group was 77.7%. the average stone diameter of 2 studies were similar; but the other group’s success rate was higher. this may attribute to the experience of the other group in treating proximal ureteral stones and technical armamentarium of the clinics. in our opinion, if we had f-urs, stone-cone® or n-trap® basket in the clinics of kars state hospital and kafkas university faculty of medicine, the success rate of semirigid urs group would be higher. after introduction of flexible systems into urology, the stone free rate was significantly increased for the treatment of the patients having proximal ureteral stones.(16,17) in a recent study, liu and colleagues investigated the outcomes of 187 patients with proximal ureteral stones who were treated with ureteroscopic lithotripsy using holmium:yag laser.(18) they reported that with the aid of f-urs and n-trap® basket, the success rate improved to 88.9% and achievement of a stone free state after semirigid urs procedures would be possible. endourological society ureteroscopy global study group recently published their article dealing with differences in ureteroscopic stone treatment and outcomes in patients with distal, mid, proximal, or multiple ureteral locations.(19) of 9681 patients, 2656 received ureteroscopy treatment for stones locataed in the proximal ureter. semirigid urs with laser or pneumatic lithotripsy were used in the majority of cases. they revealed a stone free rate of 84.5% for proximal ureteral stones. similar to our study, failure and retreatment rates were significantly higher for semirigid urs, when compared to f-urs. a new study from korea investigated the effectiveness of flexible ureteroscopic stone removal for treating ureteral and ipsilateral renal stones.(20) the study included 74 ureteral stones of which 46 located in the upper ureter, 10 in the middle ureter and 18 in the lower ureter. they achieved a stone free rate of 100% for ureteral stones; but the mean size of the ureteral stones was not reported in the study. instead of average stone size term, they used cumulative stone burden which also included the sizes of ipsilateral renal stones. in our study, the initial success rate of f-urs group was 86.8% and this rate increased to 93.4% at the end of 3rd month. the overall success rate of f-urs group was statistically higher than semirigid urs group. in our opinion, the treatment of patients of semirigid urs group having unsuccessful access to the stone or stone migration into the kidneys could be completed by using f-urs. unfortunately, the urology departments of kars state hospital and kafkas university, faculty of medicine had not had f-urs until 2012. nowadays, we have capability of using f-urs in patients with proximal ureteral or renal stones. most of the urologists prefer to dilate the ureter “optically’’ by using a semirigid urs prior to f-urs. besides this, we did not perform optical dilatation before flexible procedures in our study and they were performed after insertion of 9/11 f access sheaths over the guide wires. instead of switching to f-urs in the operation, we rather prefer to start the procedure with flexible instrument and disintegrate the stone with the same modality. stone access rates in our study showed us that f-urs was statistically superior against semirigid urs (93% vs. 76%). this difference may be attributable to the use of access sheath prior to the flexible procedure. the application of ureteral access sheath carries many advantages like outflow of irrigation fluid which facilitates clear vision for the surgeon, avoiding of high renal pressure which could decrease septicemia risk and obtain expulsion of stone fragments, preventing mucosal trauma during the procedure and prolonging the active life of f-urs.(18) except of 4 cases with narrow caliber of ureters, we introduced access sheaths to all patients prior to the flexible procedures and we did not face with any difficulties in application of the access sheaths over guide wires. in our opinion, factors that complicate access to stones like tortuousity of the ureter, angulations and serious edema at the stone site could be defeated by using access sheath and f-urs. retreatment rate of semigid urs varies between 4% and 23% in the literature.(21-23) our study revealed a reoperation rate of 20.6% for semirigid urs group. this result was similar with the rate of basiri’s and nikoobakht’s studies.(22,23) basiri and colleagues found reoperation rate in their study as 22%; on the other hand salem and colleagues(21) revealed a reoperation rate of 4%. in our opinion, the heterogenity in reoperation rates depends on the mean stone sizes of the studies. the mean stone size of patients who were treated with semirigid urs in salem’s study was approximately 7 mm; but the average stone size of the patients in basiri’s study was 1.8 ± 0.2 cm. lee and colleagues reported a reoperation rate of 42% with f-urs for the patients having large upper third ureteral stones.(17) in our study, reoperation rate of f-urs group was only 6%. this disparity could be explained again with the difference in average stone diameters of the studies. the mean stone size in lee’s study was 1.8 ± 0.3 cm, on the other hand our study’s average stone size of patients treated with f-urs was 11.01 mm. it seems that the requirement for auxillary treatments increases with the increase in the ureteral stone diameter. the most important and serious complications of ureteroscopic lithotripsy are ureteral avulsion and perforation. (18) in the literature, the incidence of ureteral perforation is between 0-1%.(18,20,24) only in 1 patient from f-urs group, a 2 cm ureteral perforation occured at the edematous site below the ureteropelvic junction during tracing a stone which migrated into the kidney. the operation was terminated after insertion of a 26 cm 4.8 f double j ureteral catheter and left for 6 weeks. after 6 weeks he was reoperated for migrating stone. the comparison between complication rates in terms of fever, bleeding and ureflexible ureterorenoscopy vs. semirigid ureteroscopy-karadag et al endourology and stone disease 1870 teral injury revealed no significant difference between 2 groups. these minor complications were treated conservatively and disappeared after 2-3 days. bleeding and ureteral injury were more common in patients treated with semirigid urs. we did not terminate any operations due to bleeding or ureteral injury in any cases. we think that it was due to surgeon’s forced forward pushing of semirigid ureteroscope in some cases having angulations, tortuousity of the ureter and serious edema at the stone site. in our opinion, these difficulties in reaching the proximal ureteral stones could be defeated by using f-urs with the advantages of deflexion and rotation. there are several limitations of our study. first of all, our study had a retrospective nature and based on a small sample size. in the literature, the “stone free status’’ and clinically insignificant residual fragments (cirf) terms have not been defined and standardized yet. in our study, we preferred to use cirf term for stones < 4 mm. there are 3 institutions involving in this study; but procedures were performed by only 3 surgeons. kc performed semirigid ureteroscopies, whereas mak and ms performed flexible procedures. it should be kept in mind that surgical skills may vary from surgeon to surgeon and for this reason making standardization about studies dealing with surgical interventions is very difficult. conclusion ureteroscopic management of proximal ureteral stones can be achieved by using semirigid or f-urs. f-urs is a favorable option for patients having proximal ureteral stones with higher stone free rate; on the other hand semirigid urs seems a less successful alternative for treament of proximal ureteral stones. the semirigid urs should be preferred for management of proximal ureteral stones, if f-urs is involved in department’s armamentarium due to the fact that with the aid of f-urs, success rate of the semirigid procedures will be higher. conflict of interest none declared. references 1. kijvikai k, haleblian ge, preminger gm, de la rosette j. shock wave lithotripsy or ureterosco py fort he management of proximal ureteral cal culi: an old discussion revisited. j urol. 2007;178:1157-63. 2. maltaga br. contemporary surgival managem ent of upper urinary tract calculi. j urol. 2009;181:2418-34. 3. segura jw, preminger gm, asssimos dg, et al. ureteral stones clinical guidelines panel sum mary report on the management of ureteral calculi. the american urological association. j urol. 1997;158:1915-21. 4. wu cf, shee jj, lin wy, lin cl, chen cs. comparison between extracorporeal shock wave lithotripsy and semirigid ureterorenoscope with holmium:yag laser lithptripsy for treating large proximal ureteral stones. j urol. 2004;172:1899-902. 5. ozturk u, sener nc, goktug g, gucuk a, nal bant i, imamoglu a. the comparison of laparos copy, shock wave lithotripsy and retrograde int rarenal surgery for large proximal ureteral stones. can urol assoc j. 2013;7:e673-76. 6. lam js, greene td, gupta m. treatment of proximal ureteral calculi: holmium:yag laser ureterolithotripsy versus extracorporeal shock wave lithotripsy. j urol. 2002;167:1972-6. 7. dindo d, demartines n, clavien pa. classific ation of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 8. liong ml, clayman rv, gittes rf, lingeman je, huffman jl, lyon es. treatment options for proximal ureteral urolithiasis: review and recommendations. j urol. 1989;141:504-9. 9. demirbas m, samli m, karalar m, kose ac. extracorporeal shockwave lithotripsy for ureter al stones: twelve years of experience with 2836 patients at a single center. urol j. 2012;9:557 61. 10. atis g, gurbuz c, arikan o, canat l, kilic m, caskurlu t. ureteroscopic management with laser lithotripsy of renal pelvic stones. j endou rol. 2012;26:983-7. 11. slam j, tricia d: greene and mantu gupta. treatment of proximal ureteral calculi: holmi um yag laser ureterolithotripsy versus extra corporeal shock wave lithotripsy. j urol. 2002;167:1972-6. 12. ching-fang w, shee jj, lin wy, lin cl, chen cs. yag laser lithotripsy for treating large proximal ureteral stones. j urol. 2004;172:1899 902. 13. razzaghi mr, razi a, mazloomfard mm, tak limi ag, valipour r, razzaghi z. safety and efficacy of penumatic lithotripters versus holmi um laser in management of ureteral calculi: a randomized clinical trial. urol j. 2013;10:762 6. 14. tawfiek er, bagley dh. management of upper urinary tract calculi with ureteroscopic techniq ues. urology. 1999;53:25-31. 15. kumar a, nanda b, kumar n, kumar r, vasu deva p, mohanty nk. a prospective randomiz ed comparison between shockwave lithotrip sy and semirigid ureteroscopy for upper uret eral stones < 2 cm: a single center experience. j endourol. 2013; sep 12. [epub ahead of print] 16. best sl, nakada sy. flexible ureteroscopy is effective for proximal ureteral stones in both obese and non obese patients: a two year, sin gle-surgeon experience. urology. 2011;77:36-9. 17. lee yh, tsai jy, jiaan bp, wu t, yu cc. pro spective randomized trial comparing shockwave lithotripsy and ureteroscopic lithotripsy for the management of large upper third ureteral stones. urology. 2006;67:480-4. 18. liu dy, he h, wang j, et al. ureteroscopic lith otripsy using holmium laser for 187 patients with proximal ureteral stones. chin med j. 2012;125:1542-6. 19. perez castro e, osther pj, jinga v, et al. differ ences in ureteroscopic stone treatment and outcomes for distal, mid, proximal, or multiple flexible ureterorenoscopy vs. semirigid ureteroscopy-karadag et al vol 11. no 05 sept-oct 2014 1871 ureteral locations: the clinical research office of the endourological society ureteroscopy global study. eur urol. 2014;66:102-9. 20. lee sh, kim th, myung sc, et al. effective ness of flexible ureteroscopic stone removal for treating ureteral and ipsilateral renal stones: a single-center experience. korean j urol. 2013;54:377-82. 21. salem hk. a prospective randomized study comparing shockwave lithotripsy and semirig id ureteroscopy for the management of proximal ureteral calculi. urology. 2009;74:1216-21. 22. basiri a, simforoosh n, ziaee a, shayaninasab h, moghaddam sm, zare s. retrograde, antegr ade, and laparoscopic approaches for the manag ement of large, proximal ureteral stones: a rand omized clinical trial. j endourol. 2008;22:2677 80. 23. nikoobakht mr, emamzadeh a, abedi ar, moradi k, mehrsai a. transureteral lithotripsy versus extracorporeal shock wave lithotripsy in management of upper ureteral calculi: a com parative study. urol j. 2007;4:207-11. 24. taie k, jasemi m, khazaeli d, fatholahi a. prevelance and management of complications of ureteroscopy: a seven-year experience with introduction of a new maneuver to prevent uret eral avulsion. urol j. 2012;9:356-60. flexible ureterorenoscopy vs. semirigid ureteroscopy-karadag et al endourology and stone disease 1872 urology journal unrc/iua vol. 2, no. 1, 52-53 winter 2005 printed in iran 52 choriocarcinoma presenting as bilateral renal tumor: a case report alireza kheradmand* department of urology, golestan hospital, jundishapour (ahwaz) medical university, ahwaz, iran key words: choriocarcinoma, renal tumor, gestational trophoblastic diseases, hematuria introduction gestational trophoblastic diseases (gtds) are disorders with abnormal growth of the placenta. they are always associated with a conception.(1) choriocarcinoma that is a malignant type of gtd, can spread virtually anywhere in the body through hematogenous or lymphatic route, but it most commonly spreads to lung, lower genital tract (cervix, vagina, and vulva), brain, and liver.(2) we report a case of choriocarcinoma, presented with bilateral renal masses. case report a 28-year-old woman presented with painless gross hematuria, fatigue, and pallor for three months without any complaint of abnormal bleeding or history of coagulopathy, medication, or trauma. she had no pregnancy and no abnormal medical history except for an abortion in the 6th week of pregnancy, 7 years ago. on physical examination, she was pale and a mobile mass was palpated on her right flank. vaginal examination revealed no abnormal finding. laboratory tests showed severe anemia (hb = 7.2 mg/dl), elevated esr, and normal renal and liver function tests. ultrasonography demonstrated bilateral renal masses, suggestive for angiomyoma or renal cell carcinoma. ct scan revealed bilateral renal masses without fat component (fig. 1,2). on angiography, bilateral hypervascular renal masses without any arteriovenous malformation was seen, suggestive for angiomyolipoma. she underwent right radical nephrectomy with received january 2004 accepted october 2004 *corresponding author: urology department, golestan hospital, jundishpur (ahwaz) medical university, ahwaz, iran. tel & fax: ++98 611 334 9293, e-mail: kheradmand_a@yahoo.com fig. 1. ct scan with oral and iv contrast showed a large tumor in the right kidney. fig. 2. another cut of ct scan with oral and iv contrast showed bilateral renal tumors. kheradmand 53 primary differential diagnoses of bilateral renal cell carcinoma and angiomyolipoma. pathologic examinations revealed choriocarcinoma of kidney without extension to gerota fascia. serum betahcg level after radical nephrectomy was 1625 iu and investigations of brain, chest and internal genitalia were unremarkable. she was referred to oncologist for chemotherapy for the contralateral renal mass, but she did not accept. six weeks later, she developed a seizure attack, resulting in cardiopulmonary arrest, and died. her family refused autopsy. discussion choriocarcinoma is the most malignant tumor of gestational trophoblastic neoplasia. it grows rapidly and metastasizes to lung, liver, and, less frequently, brain.(3) renal involvement is rare and primary renal choriocarcinoma is scarce. its primary presentation with hematuria and renal mass is even less common.(2) ogunbiyi reported two young nigerian women in 1986, who presented with profuse haematuria and renal enlargement secondary to metastatic infiltration from choriocarcinoma in the absence of primary malignant uterine foci.(4) soper reported eight cases of renal metastases of gestational trophoblastic disease with primary uterine tumors,(5) and wang presented a clinicopathological study on 31 cases of renal metastases of choriocarcinoma in 1991.(6) tai reported one case of renal choriocarcinoma diagnosed by magnetic resonance imaging (mri) and proposed that mri is a useful modality to image the affected tissue.(3) altiparmak reported one case of choriocarcinoma manifested as nephritic syndrome with biopsy-proven glomerulopathy. before his report, only two cases of trophoblastic tumor manifesting as nephritic syndrome had been reported in literature.(7) our patient is the first case of choriocarcinoma that presented with bilateral renal masses without previous proven involvement of uterus. we must notice that although our patient had no apparent source of choriocarcinoma in our evaluations, it is possible that she is actually an unusual presentation of an occult primary trophoblastic tumor with an isolated metastasis to her kidneys. special attention should be given to puerperant women with unusual clinical presentation of hematuria.(8) in young women, with gross hematuria, menstrual irregularity, and atypical renal tumor, choriocarcinoma of the kidney should be suspected.(9) chemotherapy and/or surgery must be performed immediately after diagnosis, since they both cure the malignancy.(10) references 1. robboy si, duggan ma, kurman rj. the female reproductive system. in: rubin e, farber il, editors. pathology. 3rd ed. philadelphia: lippincott williams & wilkins; 1999. p.962-1026. 2. li mc. trophoblastic disease: natural history, diagnosis, and treatment. ann intern med. 1971;74:102-12. 3. tai ks, chan fl, ngan hy. renal metastasis from choriocarcinoma: mri appearance. abdom imaging. 1998;23:536-8. 4. ogunbiyi oa, enweren eo, ogunniyi jo. unusual renal manifestations of choriocarcinoma. afr j med med sci. 1986;15:93-7. 5. soper jt, mutch dg, chin n, clarke-pearson dl, hammond cb. renal metastases of gestational trophoblastic disease: a report of eight cases. obstet gynecol. 1988;72:796-8. 6. wang ye, song hz, yang xy, dong sy, gan n. renal metastases of choriocarcinoma. a clinicopathological study of 31 cases. chin med j (engl). 1991;104:716-20. 7. altiparmak mr, pamuk on, pamuk ge, ozbay g. membranous glomerulonephritis in a patient with choriocarcinoma: case report. south med j. 2003; 96:198-200. 8. hanna nh, ulbright tm, einhorn lh. primary choriocarcinoma of the bladder with the detection of isochromosome 12p. j urol. 2002 apr;167(4):1781. 9. devasia a, nath v, abraham b, gopalkrishnan g, nair s. hematuria, renal mass and amenorrhea: indicators of a rare diagnosis. j urol. 1994;151:409-10. 10. hopper j jr. editorial: tumor-related renal lesions. ann intern med. 1974;81:550-1. case report mandibular mass as an only presentation of metatatic renal cell carcinoma for four years: a case report shahram gooran1, alimohammad fakhr yasseri1, negar behtash1*, arash karimi1, masoud khalili1, mahboobeh asadi2 keywords: mandibular mass; metastasis; oral cavity; renal cell carcinoma. renal cell carcinoma is one of the most common tumors of the urinary tract. this tumor may appear as para neoplastic syndromes or distant metastasis. metastases in uncommon areas are one of the characteristics of renal tumors. one of the uncommon metastatic renal masses areas is the mandible. in different studies, patient survival after metastasis diagnosis is usually one year or less. in this study we introduce a patient with mass of the right mandible which existed four years before his referral, and in examinations it was diagnosed as metastasis with renal origin. introduction renal cell carcinoma is one of the most common tumors of the urinary tract. metastasis to the oral cavity is very rare and constitutes less than 1% of neoplasms of this area. extensive metastases to the mandible can be evaluated by ct and mri, although in some cases a definitive diagnosis is not possible. however, biopsy is necessary to confirm the diagnosis in all cases(1-3). case report the patient was a 74-year old man who complained of swelling in the right side of the face, fever, nausea and vomiting. patient’s nausea and vomiting and fever had started one month before his referral. but swelling of the right lower jaw started four years before referral and increased gradually. also, the patient complained of difficult breathing in the past few months (figure 1). the patient mentioned no history of medical diseases, previous surgeries, occupational exposure and taking medications except using 30 packs of cigarettes per year. the patient had been using dentures for almost 10 years. he had referred to physician four years before referral due to pain and swelling of mandible and was diagnosed with inflammation and infections resulting from the dentures and received antibiotic therapy. since the symptoms persisted after antibiotic therapy, the patient was advised to perform x-ray and lesion biopsy which the 1urology research center, sina hospital, tehran university of medical sciences, hassan-abad sq., tehran, iran. 2 department of otorhinolaryngology head and neck surgery, shahid beheshti university of medical sciences, taleghani hospital,tehran, iran. *correspondence: department of urology, tehran university, sina hospital, tehran, iran. tel: +98 912 2361 163. office: +98 21 6312 484 email: negar_behtash@yahoo.com. received june 2016 & accepted january 2017 figure 1. gross pathology of tumor figure 2. mandibular tumor case report 2979 patient did not accept. after a few years, the patient referred to the clinic and mandibular lesion biopsy was performed. pathology report was highly suggestive of metastatic carcinoma, clear cell type, most probably of renal origin. after ihc the primary source was revealed to be the kidney. ct scan with contrast injection of the head and neck, lungs, abdomen, and pelvis was done for the patient. a large hypervascular mass with thinning of the lateral wall of the right maxillary sinus and also destruction of mandible ramos and trunk were reported in the head and neck ct. an enhancing lesion with approximate dimensions of 33 × 33 mm in the lower left kidney bridge and also generalized osteopenia was reported in the abdomen and pelvis ct (figure 2). in patient’s bone scan, abnormal activity in the right mandible and right maxillary bones suggesting tumoral invasion, was reported. the patient underwent left radical nephrectomy. (figure 3) the final pathology reported unifocal clear cell rcc with no sarcomatoeid features and no lymphovascular invasion. the patient was referred to otolaryngology clinic again for mandible lesion resection. since the lesion was extensive and non-respectable, the patient was introduced to oncologists for chemo-radiotherapy. currently the patient is under chemo-radiotherapy. discussion rcc bone metastases are osteolytic metastasis and usually observed in axial bones specially t2 to l5. these metastases are often seen on the same side of the primary tumor(4). jaw invasions are usually detected in ages of 50-70(5). mandible trunk invasion is 4 to 5 times more common than maxillary bone invasion(2,6). mandibular metastasis is from renal origin in 16% of its metastasis(7-9) . metastasis in oral soft tissue is associated with worse prognosis(10,11). the majority of patients die one year after metastasis of head and neck while our patient had the history of lower jaw lesion four years before referral. most researchers have accepted radical nephrectomy for limited disease and even for kidney tumor with distant metastases and believe that this therapeutic approach improves the quality of life and survival of these patients. in different studies with single metastasis of oral cavity, surgery after nephrectomy improved survival for two years (in 43% of patients) and 5 years (in 13% of patients)(12,13). although rcc is usually resistant to radiotherapy and chemotherapy, but using these therapies is recommended for the relief of metastatic lesions in the oral cavity. researchers believe that using local radiotherapy may relieve patients’ local symptoms for a short time(7,8). using chemotherapy (interleukin-2, interferon-alpha and 5-fluorouracil) may be helpful in some cases(10). in some studies, using immunotherapy after radical nephrectomy improves survival in patients with distant metastasis. in patients with synchronous metastases, cytoreductive nephrectomy and systemic immunotherapy has been more effective than immunotherapy alone(7). references 1. pick jb, wagner rm, indresano at. initial appearance of renal cell carcinoma as a metastatic mass in the mandible. j am dent assoc. 1986;113:759-61. 2. sastre j, naval l, munoz m, gamallo c, diaz fj. metastatic renal cell carcinoma to the mandible. otolaryngol head neck surg. 2005;132:663-4. 3. shibahara t, nomura t, cui nh, noma h. a study of osteoclast-related cytokines in mandibular invasion by squamous cell carcinoma. int j oral maxillofac surg. 2005;34:789-93. 4. shetty sc, gupta s, nagsubramanium s, hasan s, cherry g. mandibular metastasis from renal cell carcinoma. a case report. indian j dent res. 2001;12:77-80. 5. vallejo j. metastases in the mandible: clear cell carcinoma of a horseshoe kidney. international journal of oral and maxillofacial surgery. 2011;40:1184-5. 6. quinn jh, kreller js, carr rf. metastatic renal cell carcinoma to the mandible: report of case. j oral surg. 1981;39:130-3. 7. ahmadnia h, amirmajdi nm, mansourian e. renal cell carcinoma presenting as mandibular metastasis. saudi j kidney dis transpl. 2013;24:789-92. 8. will ta, agarwal n, petruzzelli gj. oral cavity metastasis of renal cell carcinoma: a case report. j med case rep. 2008;2:313. 9. ebert cs, jr., dubin mg, hart cf, chalian aa, shockley ww. clear cell odontogenic carcinoma: a comprehensive analysis of treatment strategies. head neck. 2005;27:53642. 10. maestre-rodriguez o, gonzalez-garcia r, mateo-arias j, et al. metastasis of renal clearcell carcinoma to the oral mucosa, an atypical location. med oral patol oral cir bucal. 2009;14:e601-4. 11. ellis gl, jensen jl, reingold im, barr rj. malignant neoplasms metastatic to gingivae. oral surg oral med oral pathol. 1977;44:23845. mandibular mass as an only presentation of metatatic rcc-gooran et al. figure 3. computed tomography of renal tumor vol 14 no 01 january-february 2017 2980 case report 2981 12. hatziotis jc, constantinidou h, papanayotou ph. metastatic tumors of the oral soft tissues. review of the literature and report of a case. oral surg oral med oral pathol. 1973;36:54450. 13. makos cp, psomaderis k. a literature review in renal carcinoma metastasis to the oral mucosa and a new report of an epulis-like metastasis. journal of oral and maxillofacial surgery. 2009;67:653-60. mandibular mass as an only presentation of metatatic rcc-gooran et al. miscellaneous preparation of rat whole-kidney acellular matrix via peristaltic pump rongfu liu,1* jiasheng gao,2 yufeng yang,1 weixin zeng1 purpose: to design a whole-kidney a cellular matrix scaffold using peristaltic pump perfusion and to ascertain the retention of extra cellular proteins by the scaffold. materials and methods: male sprague-dawley (sd) rats weighing 200-250 g were used. intravenous catheters were inserted into the renal artery followed by perfusion of decellularization solution using a peristaltic pump. after decellularization, the acellular matrix was observed under a microscope after hematoxylin and eosin (h&e) staining and a fluorescence microscope after 4′,6-diamidino-2-phenylindole (dapi) staining. immunohistochemistry was used to identify the composition of kidney acellular matrix. results: the result of h&e and dapi staining demonstrate the removal of cellular material in kidney a cellular matrix. immunohistochemistry confirmed the conservation of the natural expression of extra cellular matrix proteins including collagen types i and iv, fibrin and laminin. conclusion: peristaltic pump perfusion enables successful preparation of renal a cellular matrix, to retainthe criticalproteins of natural extra cellular matrix. the resulting kidney a cellular matrix represents an ideal natural scaffold for renal tissue engineering. keywords: disease models, animal; kidney; metabolism; rats; in vitro techniques; infusion pumps. 1 department of urology, the first affiliated hospital of xiamen university, xiamen 361003, china. 2 department of urology, the first people hospital of jiujiang city, jiujiang 332000, china. *correspondence: department of urology, the first affiliated hospital of xiamen university, no.55 zhenhai road, xiamen 361003, china. tel: +86 592 2139714. e-mail: lliurf@126.com. received may 2015 & accepted november 2015 miscellaneous 2457 introduction acute or chronic renal failure is associated with high morbidity and mortality.(1,2) current treatments include hemodialysis and renal transplantation. however, dialysis only partly compensates for the loss of renal functionat a high medical cost. the biggest challenge with kidney transplantation is the shortage of human organs,(3) which warrants development of new strategies for intervention. currently, renal tissue engineering represents a feasible approach. the key challenge in renal tissue engineering is to build ascaffold, which contains the essential functional composition for transplantation. a scaffold comprising natural biological tissues accurately removes all the cellular precursors but still retains the necessary signals for the extra cellular matrix generation. acellular matrix refers to the reservoir of extra cellular matrix (ecm) with its three-dimensional structural integrity and biological activity after depleting the cellular components. the acellular process can be completed using detergents such as sodium dodecyl sulfate (sds) or tritonx-100, which cause membrane rupture or fracture of the connection between the cell and ecm. until now a variety of acellular tissues or organ matrices have been successfully used in clinical or preclinical studies including the dermis,(4) heart,(5) small intestinal submucosa,(6) ligament(7) and bladder.(8,9) this study adopts peristaltic pump perfusion for the preparation of rat whole-kidney acellular matrix and simultaneously identifies the matrix composition. the identification focuses on retention of the main natural protein ingredients of ecm by the scaffold. the ingredients may play a key role in cell adhesion, migration, and proliferation for cell implantation. materials and methods 1. experimental materials 1.1 animalresources twenty male sprague-dawley (sd) rats (male, 200250 g) were purchased from the experimental animal center of people's liberation army military academy of medical sciences. 1.2 reagents 1% sds, 3% triton x 100, 5 mm calcium chloride, 5 mm magnesium chloride, 4′,6-diamidino-2-phenylindole (dapi) staining solution, type i collagen, type iv rat whole-kidney acellular matrix-liu et al. collagen, fibrin, laminin protein and four types of antibodies were obtained from wuhan boster biological technology co. ltd. (wuhan city, china). 1.3 equipment the bt600l traffic intelligent peristaltic pump was acquired from the baoding rafer fluid technology co. ltd (baoding city, china), along with 24 gauge (0.7 mm × 19 mm) indwelling needle, ophthalmic surgical instruments, and microscope. 2. experimental methods 2.1 kidney samples and renal artery catheter rats were anesthetized by intraperitoneal injection of 0.5 ml of 2% sodium pentobarbital and fixed to a surgical platform to remove and disinfect the skin. the abdominal cavity was opened along the midline, and the left kidney was stripped of the surrounding fat using a small forceps. after freeing the entire left kidney and the renal pedicle, it was stripped bluntly again along the renal pedicle till the abdominal aorta to identify the ureter, renal artery, and renal vein. the tiny renal artery and vein were distinguished from the rear of the kidney. the pulsating renal artery, with its thick white wall, was located in the front. the renal artery was separated from the renal vein with the tweezers from the middle and gently lifted for intubation. the micro-peristaltic pump was started to let the liquid flow from the catheter at a speed of 2 ml per minute. the catheter was then slightly and slowly replaced into left renal artery from the beginning. a part of the kidney suddenly changed from brownish red to white, indicating successful renal artery intubation. a thin string was used to ligate the place of cannulation to hold the needle in position. finally, we divided the joint between ureter, renal vein, renal artery, and abdominal aorta and then fixed the kidney above the glassware for perfusion. 2.2 micro-peristaltic pump perfusion the perfusion fluid on the left side of the micro-peristaltic pump was connected with the kidney on the right with a hose. the micro-peristaltic pump was opened and the flow speed was adjusted at an average level of 2 ml per minute. the perfusion was performed in the following sequence: heparinized phosphate buffered saline (pbs) solution for 30 min; 3% triton x-100 solution for 30 min; deionized water for 15 min; 5 mm calcium chloride and 5 mm magnesium chloride solution for 30 min, respectively; deionized water for 15 min; 3% triton x-100 solution for 30 min again; deionized water for 15 min; 1% sds for 12 h; deionized water for15 min followed by pbs-containing penicillin and streptomycin for 48 h. the shape of the kidney color was observed. when the perfusion was conducted with 1% sds alternating with pbs, the perfusion fluid was changed every 4h. 2.3 detection of the scaffold of renal acellular matrix during the preparation of renal acellular matrix, the specimen was initially removed and the left kidney of the same sd rat as acellular matrix group was used while the right kidney served as a control. the acellular matrix was perfused in the order mentioned above and the control group was stored in pbs solution containing green streptomycin. the cell matrix group and the control group specimens were transferred into 4% paraformaldehyde and fixed for 48 h. different gradients of alcohol were used for dehydration for 2 h, respectively. the specimens were placed into i and ii cylinders of xylene for 20 min, respectively, and then immersed in wax for 2 hat 60°c, followed by slicing of the paraffin-embedded specimens. 2.4 h&e staining the h&e staining protocol requires dewaxing of the sample slices with xylene, and then dehydration using graded ethanol followed by washing using distilled water. the sections were sequentially transferred and washed after each step as follows: into hematoxylin-stained nucleus for 1 min; 1% hydrochloric acid solution for 10 s; 1% ammonia complex blue for 30 s; and 0.5% eosin solution for 2 min. after subjecting to ethanol dehydration the specimens were mounted and the acellular matrix micro structure was visualized under the microscope to ensure the absence of residual cell debris. five non-overlapping cortical and medullary views of each specimen were randomly selected and photographed (×200). 2.5 dapi staining the paraffin sections were dewaxed with xylene, dehydrated with graded ethanol, washed three times with pbs and diluted with dapi staining solution at a ratio of 1:1000. the specimens were visualized under a fluorescence microscope after dapi staining to ensure the absence of nuclear remnants in the acellular matrix. 2.6 detection and identification of acellular matrix components by immunohistochemistry (ihc) paraffin sections were placed in xylene for dewax ingandin graded ethanol for dehydration. after addition of 0.3% h 2 o 2 for 10 min to remove endogenous peroxidase, they were transferred to a container filled with citrate buffer, followed by microwave heating (92°c-95°c, 10 min). after addition of goat serum for 30 min, and diluted primary antibody solution (collagen type i, collagen iv, fibrin, and laminin from rabbit, diluted at the ratio of 1: 200 respectively) the specimens vol 12 no 06 november-december 2015 2458 were incubated overnight at 4°c. a goat anti-rabbit secondary antibody solution was added and left for 30 min at 37°c. after washing with pbs, horse radish peroxidase (hrp) was used to label the fluid for 30 min at 37°c. after washing the sample slices, 3,3'-diaminobenzidine (dab) chromogenic substrate solution was added for 5 min. it was followed by hematoxylin staining of the nucleus, and sealing by resin, and stored at room temperature. five random fields were selected from each specimen and photographed (× 200 times). results 1. general observation of acellular matrix after 12 h, the color of the kidney invitro changed from bright red to milky white (figure 1). at 24 h, it gradually turned into translucent white with a segmented and lobulated internal structure. at 36 h, the whole kidney was translucent with a clear branch-like structure. after the perfusion was completed, the acellular matrix was soft and flexible under gentle pressure. 2. histology of acellular matrix figure 2 illustrates the microstructure of the h&estained acellular matrix. no residues of cells or nuclear debris were seen in the renal cortex and medulla of the acellular matrix group. the three-dimensional network structure of the acellular matrix was closely connected. the structure of the glomerular vascular basement membrane and tubular base membrane of the internal stripped cells remained intact. the nucleus and the normal renal structure were clear. the results demonstrate that the micro-peristaltic pump perfusion at a low flow rate removed the cells and nuclei of kidney but still retained the integrity of the ecm structure. 3. dapi staining of nucleus figure 3 shows the result of dapi staining. after the appearance of blue fluorescence in acellular matrix, the figure 1. altered kidney color after sequential perfusion of acellular fluid. 12 h: color of the kidney invitro changes from bright red to milky white; 24 h: the kidney gradually turns translucent white with a segmented and lobulated internal structure; 36 h: the whole kidney is translucent white with a clear branch-like renal structure. figure 2. hematoxylin and eosin staining of renal cortex and renal medulla (20×10). the figure shows the absence of cellular residues and nuclear debris in the renal cortex and renal medulla of the acellular matrix group and the mesh structures of the glomerular tubule remain intact. the following diagram illustrates the renal cortex and medulla of the normal control group. the glomerular structure, tubular organization and the nucleus are clear. rat whole-kidney acellular matrix-liu et al. miscellaneous 2459 basement membrane was connected to network structure. the control group was covered by cells with a strong blue fluorescence. 4. ihc of acellular matrix components immunohistochemical staining shows the key protein expression in ecm including the type i and iv collagen, fibrin, and laminin (figure 4). the expression of four proteins was similar to the natural acellular tissue. the type i and iv collagens show significant expression in glomerular vascular basement membrane but less in the tubular basement membrane. fibrin and laminin were highly expressed in both glomerular and tubular basement membrane, revealing the ecm network. immunohistochemical results show that the acellular matrix retained the key component of the natural ecm. discussion using invitro studies of rat kidney acellular matrix and identification of the components of the 3d kidney scaffold, the sequential perfusion of detergent 3% tritonx-100, 5 mm calcium chloride and magnesium chloride and 1% sds with micro-peristaltic pump completely removed kidney cells. the identification of acellular matrix composition by ihc confirms the expression of the main components of ecm including collagen type i, collagen type iv, laminin, and fibrin. renal tissue engineering includes seed cells and scaffolds. the selection of an ideal material for scaffold is an important step in kidney tissue engineering. an ideal material for scaffold is characterized by the following properties: 1. good biocompatibility to ensure regeneration of host tissue without immune rejection; 2. three-dimensional structure, which is similar to the shape of the internal organs; 3. cellular adhesion and growth; and 4. biodegradation. acellular matrix scaffold represents such an ideal scaffold since it retains the natural expression of proteins in the ecm and contains an internal structure that matches the target organ. the key step in the study is to develop a full kidney acellular matrix scaffold. the report of nakayama and colleagues(10) confirmed that acellular rhesus monkey kidney stent was an ideal scaffold. their results suggest that the kidney was sliced into layers and the best acellular method was selected. the most efficient acellular process appeared with 1% sds solution at 4°c. ross and colleagues(11) demonstrated that rat kidney acellular matrix can be successfully prepared through the sequential perfusion of 3% triton x-100, dna nuclease, followed by 3% triton x-100 and 4% sds. liu and colleagues(12) reported that the acellular matrix of the whole kidney can be prepared through the sequential perfusion of 1% sds and 1% triton, which confirms the success of renal acellular matrix from a histological perspective. our experiment uses a new autoperfusion method to prepare the decellularized scaffolds by sequential perfusion of 3% triton x-100, 5 mm calcium chloride and magnesium chloride (to remove endogenous nuclease), 1% sds at a flow rate of 2 ml/min with micro-peristaltic pump. the results of h&e and dapi staining show that preparation of the whole kidney acellular matrix scaffold was successful, without retaining any residual cellular organelles except for the figure 3. 4′,6-diamidino-2-phenylindole (dapi) staining of nuclei (40×10). after the appearance of blue fluorescence in acellular matrix, a faint blue fluorescence can be seen without any round blue nuclei following dapi staining. the control group was covered by cells with a strong blue fluorescence. figure 4. immunohistochemical identification of acellular matrix components (40×10). type i and iv collagens were prominently expressed in glomerular vascular basement membrane but less prominently in the tubular basement membrane. fibrin and laminin were highly expressed in both glomerular and tubular basement membrane, and the network structure of the extracellular matrix was clearly seen. rat whole-kidney acellular matrix-liu et al. vol 12 no 06 november-december 2015 2460 original cells and the ecm meshwork. ecm is present in all tissues and organs as a reticularnetwork of fibrin, collagen, glycoproteins (laminin), and proteoglycans (basement membrane). ecm not only provides mechanical support, but also mediates cell signaling, cytokine and growth factor activity, playing an important role in cellular repair and regeneration. (13) the report of rossand colleagues(11) shows that ec m maintains a complex anatomical structure and plays a key role in cell differentiation. vaccination of the acellular kidney with embryonic stem cells (es) confirms that ecm induced es cells to differentiate into renal cells. our study also confirms acellular matrix expression of collagen type iv, laminin, and fibrin by ihc and also the conservation of important ecm proteins, which play a key role incellular adhesion, proliferation, and differentiation. conclusions experiments show that the whole kidney acellular matrix scaffold, which retains the natural extra cellular matrix protein, can be successfully prepared using a micro-peristaltic pump perfusion. it provides the best possible micro-environment for adhesion, proliferation, and differentiation of seeded cells for further studies. in conclusion, the acellular matrix scaffold represents an idealnatural scaffold for renal tissue engineering. conflict of interest none declared. references 1. humes hd, szczypka ms. advances in cell therapy for renal failure. transpl immunol. 2004;12:219-27. 2. friedericksen dv, van der merwe l, hattingh tl, nel dg, moosa mr. acute renal failure in the medical icu still predictive of high mortality. s afr med j. 2009;99:873-5. 3. hammerman mr. xenotransplantation of developing kidneys. am j physiol renal physiol. 2002;283:601-6. 4. kolker ar, brown dj, redstone js, scarpinato vm, wallack mk. multilayer reconstruction of abdominal wall defects with acellular dermal allograft (alloderm) and component separation. ann plast surg. 2005;55:36-41. 5. ott hc, matthiesen ts, goh sk, et al. perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. nature. 2008;14:213-21. 6. ferguson re jr, pu ll. repair of the abdominal donor-site fascial defect with small intestinal submucosa (sugrisis) after tram flap breast reconstruction. ann plast surg. 2007;58:95-8. 7. wang h, chen xs, zhou sy, huang jj, cai ty. biocompatibility and superiority of lyophilized acellular ligament scaffolds. j clin rehabil tissue eng res. 2011;15:5334-8. 8. el-kassaby a, abou shwareb t, atala a. randomized comparative study between buccal mucosal and acellular bladder matrix grafts in complex anterior urethral strictures. j urol. 2008;179:1432-6. 9. lu mj, wang z, zhou gd, liu w, caoly. construction sandwich structure of bladder wall in vitro by tissue engineering approach. chinesej urol. 2007;28:82-5. 10. nakayama kh, batchelder ca, lee ci, tarantal af.decellularized rhesus monkey kidney as a three-dimensional scaffold for renal tissue engineering. tissue eng. 2010;16:2207-16. 11. ross ea, williams mj, hamazaki t, et al. embryonicstem cells proliferate and differentiate when seeded into kidney scaffolds. j am soc nephrol. 2009;20:233847. 12. liu cx, liu sr, xu ab, kang yz, zheng sb, li hl. preparation of whole-kidney acellular matrix in rats by perfusion. nan fang yi ke da xue xue bao. 2009;29:979-82. 13. badylak sf. the extracellular matrix as a scaffold for tissue reconstruction. semin cell dev biol. 2002;13:377-83. rat whole-kidney acellular matrix-liu et al. miscellaneous 2461 laparoscopic urology quality of life survey following laparoscopic and open radical nephrectomy cenk acar,1 cenk bilen,2 yıldırım bayazıt,3 güven aslan,4 artan koni,2 erem başok,5 mustafa kaplan6 purpose: to compare the quality of life (qol) of renal cancer patients following laparoscopic and open radical nephrectomy. materials and methods: seventy-two (64.9%) patients who were treated with open radical nephrectomy (orn group) and 39 (35.1%) patients who were treated with laparoscopic radical nephrectomy (lrn group) were included in this study. qol was evaluated by short form-36 (sf-36) physical domain scores obtained before surgery, 1 and 6 months after surgery. analgesic requirement and visual analog scale (vas) pain scores following surgeries were recorded. results: the demographic features of the groups were similar. there was a significant difference in tumor size between the orn group (71.59 ± 29.83 mm) and lrn group (57.08 ± 19.33 mm) (p = .011). in the lrn group there was less blood loss, a lower transfusion rate, earlier ambulation, more rapid convalescence and shorter hospitalization; however, the difference in surgical duration between the orn group (122.86 ± 36.8 min) and lrn group (140.17 ± 50.71 min) was not significant (p = .383). analgesic requirement and vas pain scores were similar in both groups. in terms of sf-36 physical domain scores, the general health perception score in the lrn group was higher than that in the orn group at pre-surgery, 1 and 6 months after surgery. sf-36 physical functioning and general health perception scores in both groups were significantly lower in 1 month after surgery and were higher in 6 months after surgery, as compare to before surgery. bodily pain scores in lrn group did not change significantly after surgery (p = .376). conclusion: lrn exhibited some technical advantages, including less blood loss, shorter hospitalization and more rapid recovery. although the orn patients had relatively larger tumors, analgesic requirement, postoperative complications, body pain, and physical functioning weren't significantly different between the groups. qol was higher 6 months after surgery than before surgery in both groups. keywords: kidney diseases; surgery; nephrectomy; methods; treatment outcome; kidney neoplasms; laparoscopy; quality of life. introduction renal cell carcinoma (rcc) is the third most com-mon malignancy of the genitourinary tract and accounts for 2-3% of all cancers.(1) open radical nephrectomy (orn) has been accepted as the standard curative treatment for resectable renal tumors for many years. with the advent of minimally invasive surgery, laparoscopic radical nephrectomy (lrn) has become a feasible treatment alternative for localized rcc, following the first report of its use by clayman and colleagues in 1991. according to the findings of long term oncological studies, lrn is associated with a cancer-free survival rate similar to that of orn.(2,3) following worldwide acceptance of the kidney function preservation concept, nephron-sparing surgical techniques (open, laparoscopic and robotic) have emerged as viable options for the treatment of small renal tumors (< 4 cm and t1a) in cases with a normal contralateral kidney. according to recently published guidelines, lrn is recommended as the standard of care for patients with localized rcc and a small renal mass that can’t be treated with nephron-sparing surgery.(4) studies that compared orn and lrn reported that lrn has some advantages with regard to all perioperative morbidity indexes, including blood loss, postoperative analgesic requirement, duration of hospitalization and convalescence.(5-7) patients should be counseled concerning the course of disease, treatment options, oncological outcome and treatment complications, as well as the effects on quality of life (qol) of each treatment option. to date, health-related quality of life (hrqol) has had only a marginal impact on the decision-making process of patients with kidney tumors. specifically, qol questionnaires are essential for determining the extent of a 1 department of urology, acibadem university faculty of medicine, istanbul, turkey. 2 department of urology, hacettepe university faculty of medicine, ankara, turkey. 3 department of urology, cukurova university faculty of medicine, adana, turkey. 4 department of urology, dokuz eylul university faculty of medicine, izmir, turkey. 5 department of urology, goztepe educational and research hospital, istanbul, turkey. 6 department of urology, trakya university faculty of medicine, edirne, turkey. *correspondence: department of urology, hacettepe university school of medicine, cankaya, ankara, turkey. tel: +90 312 305 1885. fax: +90 312 305 1969. e-mail: cybilen@yahoo.com. received february 2014 & accepted august 2014 laparoscopic urology 1944 variables open nephrectomy (n = 72) laparoscopic nephrectomy (n = 39) p value demographic features age (year) (mean ± sd) 55.79 ± 10.82 54.33 ± 11.9 .512 gender, no (%) male 47 (65.3) 23 (59) .511 female 25 (34.7) 16 (41) body mass index (kg/m2) (mean ± sd) 28.16 ± 3.46 27.86 ± 4.54 .841 asa scores, no (%) 1 38 (60.3) 23 (60.5) .05 2 23 (36.5) 9 (23.7) 3 2 (3.2) 6 (15.8) comorbid diseases, no (%) 1 19 (26.4) 12 (30.8) .466 2 8 (11.1) 1 (2.6) 3 4 (5.6) 2 (5.1) tumor characteristics clinical tumor size (mm) (mean ± sd) 71.59 ± 29.83 57.08 ± 19.33 .011 tumor side, no (%) right 36 (51.4) 28 (73.7) .025 left 34 (48.6) 10 (26.3) clinical t stage, no (%) 1a 6 (8.3) 7 (17.9) .119 1b 28 (38.9) 18 (46.2) 2a 22 (30.6) 10 (25.6) 2b 12 (16.6) 1 (2.6) 3a 2 (2.8) 0 (0) 3b 0 (0) 0 (0) 4 0 (0) 1 (2.6) missing 2 (2.8) 2 (5.1) clinical n stage, no (%) n0 66 (91.7) 35 (89.7) .816 n1 5 (6.1) 2 (5) missing 2 (2.8) 2 (5.1) pathological t stage, no (%) 1a 6 (9.2) 2 (6.4) .001 1b 19 (29.2) 21 (68) 2a 18 (27.7) 4 (12.8) 2b 6 (9.2) 0 (0) 3a 8 (12.3) 2 (6.4) 4 8 (12.3) 2 (6.4) pathological n stage, no (%) n0 62 (95.4) 30 (96.7) .194 n1 3 (4.6) 1 (3.3) pathology, no (%) renal cell carcinoma 65 (93) 31 (79.4) .114 oncocitoma 1 (1.4) 4 (10.3) others 4 (4.9) 4 (10) histology, no (%) clear cell 40 (61.5) 23 (74.2) .416 papillary 10 (15.3) 2 (6.5) chromophobe 8 (12.3) 3 (9.7) mixed 1 (1.6) 1 (3.2) other 5 (7.7) 1 (3.2) non-classified 1 (1.6) 0 (0.0) missing 0 (0.0) 1 (3.2) fuhrman grade, no (%) 1 10 (14.9) 1 (3.3) .074 2 36 (53.7) 24 (80) 3 14 (20.9) 5 (13.4) 4 7 (10.5) 1 (3.3) table 1. comparison of demographic features and tumor characteristics of the patients. abbreviation: asa, american society of anesthesiologists. quality of life survey in laparoscopic radical nephrectomy-acar et al vol 11. no 06 nov-dec 2014 1945 patient’s usual or expected physical, emotional and social well-being following the diagnosis of a medical condition and/or its treatment;(8) however, few researchers have studied post-surgical hrqol in patients with kidney tumors.(9-14) in addition, survey analyses of diseases or interventions provide more accurate information about patient health by assessing every individual patient on their health condition. only a few studies, which determined the post-operative course of renal tumors on hrqol compared with baseline values, were conducted. most such studies were limited by biases, including the absence of baseline hrqol assessment, small patient population,(14) retrospective design and low treatment response rates.(12,15) the present multicenter prospective study aimed to evaluate whether different techniques (lrn and orn) of radical nephrectomy might affect hrqol based on qol survey in patients with non-metastatic renal cancer. secondarily, we aimed to assess the effect of surgical techniques on perioperative morbidity indices. materials and methods patient selection this prospective study consecutively included 152 patients with non-metastatic rcc that underwent orn or lrn between 2007 and 2010 at 5 different hospitals. patients with clinically determined t4 disease, vena cava thrombus, cognitive dysfunction, neuromuscular diseases and history of abdominal or retroperitoneal surgery were excluded from the study. patients with metastatic disease during post-surgery follow-up [5 (3.1%)], incomplete or missing short form-36 (sf-36) questionnaires [17 (11.1%)] and lost to follow-up [19 (12.5%)] were also excluded. in all, 72 (64.9%) patients that underwent orn (orn group) and 39 (35.1%) patients that underwent lrn (lrn group) were analyzed. tumor, node, and metastasis (tnm)-2009 classification was used for staging the patients based on preoperative thoracic and abdominal computed tomography (ct) scan. systemic comorbid diseases of the patients were recorded including diabetes mellitus, chronic heart failure, hypertension, asthma and hypo/hyperthyroidism . they grouped as number of comorbidities, which existed in particular patients. surgery lrn was performed using a standard transperitoneal or retroperitoneal approach.(16) specimens were removed intact without using morcellation through a 5-7 cm oblique lower abdominal incision (gibson). orn was performed via a transperitoneal or retroperitoneal approach, with a subcostal incision.(17) experienced academic surgeons performed all surgeries according to the standard criteria for orn (each surgeon had performed ≥ 150 orns as the lead surgeon) and lrn (each moderately experienced surgeon performed ≥ 75 lrns). type of surgery (open or laparoscopic), length of subcostal and gibson incisions and trocar placement for lrn were determined based on patient characteristics, tumor characteristics, and surgeon preference. all specimens were analyzed according to standard pathology procedures in each of the hospitals in which the surgery was performed. tumor nuclear grading was performed according to fuhrman classification. no central pathologic slide review was performed; however, a senior pathologist at each hospital confirmed the pathological slides. patient demographic characteristics, including age, gender, body mass index and american society of anesthesiologists (asa) score, were recorded. tumor characteristics and surgical variables were also analyzed and compared. the sf-36 questionnaire general hrqol was measured using the sf-36 health survey.(18) sf-36 consists of 8 subscale scores that are the weighted sums of the questions in each section. each subscale is directly transformed into a 0-100 scale based on the assumption that each question carries equal weight. in the present study, qol was evaluated by self-administered sf-36 questionnaire obtained preoperatively and the end of first and 6th months after surgery. physical domains were used to compare the effects of surgery on qol, including physical functioning (pf), bodily pain (bp) and general health perception (ghp). to optimize analgesic usage, paracetamol infusion (10 mg/ml) was administered 3 times (8 hours apart) during the first 24h post-surgery; afterwards, patient-controlled analgesia (pca) was used according to need by preparing 400 mg pethidine hydrochloride in 100 ml saline with a dose of 10-15 mg infusion per hour. analgesic requirement was defined as necessity of using pca by the patients. pain was assessed using a visual analog scale (vas) 48h post-surgery (0 = no pain and 10 = extreme pain). postoperative complications were graded using the clavien-dindo classification system.(19) statistical analysis statistical analysis was performed using a computer-based statistical program. the mann-whitney u test and kruskal wallis test were used for continuous variables, and the chi-square test was used for categorical variables. correlations between age and sf-36 physical domain scores were analyzed based on spearman’s correlation coefficient. friedman variance analysis was used for dependent variables. multiple linear regression was run to predict sf-36 pf, bp and ghp scores from gender, age, tumor size, tumor stage, preoperative and postoperative hemoglobin (hb) and serum creatinine levels, bmi, asa, number of comorbidities, complications and hospital readmission in 6-month postoperatively. the level of statistical significance was set at p < .05. results mean age of the patients was 55.27 ± 11.19 years (range: 27-80 years); 70 (63.1%) of the patients were male and 41 (36.9%) were female. demographic features and tumor characteristics of the patients in both groups are shown in table 1. in the lrn group 28 (71.8%) patients were treated via a transperitoneal approach, 10 (25.6%) via a retroperitoneal approach and only one (2.6%) via a hand-assisted technique, whereas all surgeries in the orn group were performed via anterior subcostal incision. there was a statistically significant difference in mean tumor size between the orn (71.59 ± 29.83 mm) and lrn (57.08 ± 19.33 mm) groups (p = .011). according to pathological t (pt) staging, there were more patients in the lrn group with pt1 tumors than in the orn group (p = .001). quality of life survey in laparoscopic radical nephrectomy-acar et al laparoscopic urology 1946 pathological examination in all patients with pt4 disease showed adrenal involvement of the tumors. in all, 5 patients (6.9%) in the orn group and 2 patients (5.1%) in the lrn group that were clinically diagnosed as n1 disease underwent para-aortic lymph node dissection. in the lrn group there was significantly less blood loss, a lower transfusion rate, earlier ambulation, shorter hospitalization and more rapid convalescence (p < .001, p = .007, p = .023, p < .001 and p < .001, respectively) (table 2). none of the patients was needed to admit intensive care unit during convalescence period. the 30 days hospital readmission rates are shown in table 2. none of the patients in lrn group admitted to the hospital while 9 of 39 patients hospitalized due to wound infection [5 (12.8%)], retroperitoneal hematoma [1 (2.5)], low hb level [1 (2.5%)], incisional hernia [1 (2.5)] and appendicitis [1 (2.5%)]. none of the patients died during follow-up. the difference in surgical duration between the orn (122.86 ± 36.8 min) and lrn (140.17 ± 50.71 min) groups was not significant (p = .383). analgesic requirement and vas pain scores were similar in both groups (p = .536 and p = .900, respectively). in terms of sf-36 physical domains, ghp scores in the lrn group were higher than in the orn group pre surgery, 1 and 6 months after surgery (table 3). preoperative pf and ghp scores in the male patients were higher than those in the female patients (p = .003 and p = .011, respectively). there was not a correlation between age and preoperative sf-36 physical domain scores (pf: p = .149, r = -0,132; bp: p = .132, r = -0,138; ghp: p = .561, r = -0.05). pf and ghp scores were significantly lower in 1 month after surgery and higher in 6 months after surgery than pre surgery in both groups (figure). the changes in bp scores in the lrn group were not statistically significant in both first and 6th months after surgery when compared with baseline values (p = .376) whereas the changes of pf and ghp scores in lrn group and, pf, bp and ghp scores in orn group was significantly different (figure, a). according to multiple linear regression analysis, the factors that predicting low sf-36 pf scores were female gender [odds ratio (or) = 14.2, 95% confidence interval (ci): 23.78-4.64; p = .004], low preoperative hb (or = 4.5, 95% ci: 8.68-0.39, p = .033) and high t stage (or = 2.16, 95% ci: 4.2-0.08; p = .042). for sf-36 bp, the model was not found statistically significant (p = .061). the performing lrn (or = 13.1, 95% ci: 6.09-20.2; p < .001) and young age (or = 0.39, 95% ci: 0.65-0.122; p = .005) were the factors that positively affected the sf-36 ghp scores. discussion the present findings show that physical aspects of hrqol were significantly lower in 1 month after surgery and improved in 6 months after surgery in patients that underwent orn and lrn. indeed, investigated sf-36 domain scores at 6 months after surgery were higher than at baseline. lrn was not better than orn in terms of analgesic requirement and vas pain score at 48h post-surgery, even though mean tumor size and pathological t stage were higher in the orn group. nevertheless, ghp scores were higher in the lrn group and bp scores in the lrn group didn’t change significantly both in 1 and 6 months after surgery. lrn was better than orn in terms of perioperative indices, including blood loss, the transfusion rate, ambulation, duration of hospitalization and convalescence; however, surgical duration and the postoperative complication rate did not differ significantly between the groups. the literature contains insufficient data concerning hrqol in rcc patients treated lrn and orn, as most of the relevant studies were retrospective and cross-sectional in design. it may be more advantageous to conduct survey studies to determine the exact value of lrn, because the factors affecting baseline hrqol in patients with renal tumors vary patient by patient; therefore, the present study prospectively evaluated qol in patients that underwent orn and lrn. the present study in particular could show the alterations and differences in hrqol after the radical nephrectomy techniques with its prospective design. recently, 2 prospective studies compared radical nephrectomy (rn) and other treatment options in terms of hrqol in rcc patients.(9,14) onishi and colleagues reported that radiofrequency ablation had significantly less of an effect on hrqol than lrn during the first week post-surgery;(14) however, the study included 37 patients figure. variance analyses of short form-36 (sf-36) physical domains in open nephrectomy group (a) and laparoscopic nephrectomy group (b). quality of life survey in laparoscopic radical nephrectomy-acar et al vol 11. no 06 nov-dec 2014 1947 and evaluated only patients with tumors < 4 cm. novara and colleagues evaluated hrqol in patients that underwent open partial nephrectomy (opn) and rn 12 months after surgery, and investigated the prognostic factors predictive of post-surgical hrqol.(9) at 6 months post-surgery 59-81% of the patients’ scores returned the baseline values across the different domains. they reported that new york hearth association class in the role physical functioning (rpf) domain, mode of presentation in the ghp domain, indications for nephron-sparing surgery in the pf domain and tumor histology in the bp domain were significantly associated with recovery of baseline sf-36 scores 6 months after surgery. other retrospective study focused primarily on hrqol. gratzke and colleagues reported that patients with postoperative complications (regardless of the type of surgery) tended to have lower qol scores (especially ghp) than patients without complications.(13) on the other hand, clark and colleagues did not observe any significant differences in sf-36 physical or mental domain scores according to type of surgery. (15) parker and colleagues evaluated the general and cancer specific qol of 172 patients with renal tumors who underwent laparoscopic/open radical and partial nephrectomy with a follow-up of 12 months. they used sf-36 for general qol and the cancer rehabilitation evaluation system-short form for cancer specific qol. they demonstrated that qol scores of the patients treated with laparoscopy is higher than open surgery and better cancer specific qol was reported in patients who underwent radical nephrectomy. they concluded there were significant differences in qol and psychosocial adjustment outcomes during 1 year in patients treated with all kind of renal surgery. finally, they stated the qol outcomes must be evaluated in the context of tumor characteristics, cancer specific outcomes and renal function. in the present study sf-36 ghp scores in the lrn group were higher than those in the orn group, which may have been due smaller mean tumor size and the presence of more pt1 tumors in the lrn group, whereas age, body mass index, gender and asa scores did not differ significantly between the groups. in multiple linear regression analysis, performing lrn and young age are the predicting factors for high sf-36 ghp scores. in addition, female gender and higher t stage had worse outcome for sf-36 pf. we can explain the effect of gender that we found high preoperative pf and ghp scores in the male patients than those in the female patients. furthermore, we think that the positive impact of cancer treatment on physical and general qol may have led to improvement in sf-36 physical domain scores between baseline and 6 months post-surgery. studies that evaluated pain following orn and lrn reported that analgesic requirement was significantly lower in the lrn group;(7) however, the present findings indicate that analgesic requirement and vas pain score at 48h post-surgery were similar in the orn and lrn groups. in our study all orns were performed via subcostal incision, so as to standardize the patients. it may well be speculated that morbidity associated with subcostal incision might be low in the orn group. indeed, novara and colleagues reported that flank incision was associated with a higher morbidity rate than anterior incision.(9) as compared to baseline, bp scores in the present study’s orn group were significantly lower in one month after surgery and higher in 6 months after surgery, whereas in the lrn group the change in bp was not significant. on the other hand postoperative vas pain scores and analgesic requirement were similar in the orn and lrn groups, which might show be indicative of the positive effect of short convalescence period of the laparoscopic variables open nephrectomy (n = 72) laparoscopic nephrectomy (n = 39) p value hemoglobin (g/dl) preoperative 13.21 ± 1.92 13.19 ± 1.79 .887 postoperative 11.87 ± 1.66 12.12 ± 1.67 .733 creatinine (mg/dl) preoperative 1.04 ± 0.38 0.96 ± 0.33 .268 postoperative 1.42 ± 1 1.13 ± 0.3 .051 operative time (min) 122.86 ± 36 .8 140.17 ± 50.71 .383 blood loss (ml) 359 ± 416.1 150 ± 177.7 < .001 blood transfusion (unit) 0.4 ± 0.816 0.08 ± 0.35 .007 analgesic requirement, no (%) no 18 (28.1) 10 (34.5) .536 yes 55 (71.9) 16 (65.5) ambulation (hour) 16.97 ± 10.29 13.79 ± 2.52 .023 time to start oral intake (hour) 23.98 ± 13.36 19 ± 10.94 < .001 time to removal of drain (day) 3.71 ± 1.73 1.85 ± 0.53 < .001 hospitalization (day) 6.26 ± 3 3.36 ± 1.34 < .001 convalescence time (week) 3.24 ± 1.04 1.71 ± 0.69 < .001 clavien-dindo grade (30 days), no (%) 1 8 (9.9) 0.0 < .001 2 1 (1.2) 0.0 3b 2 (2.5) 1 (2.5) 30 days hospital readmission, no (%) 9 (23) 0.0 .02 table 2. comparison of operative variables of the study groups according to surgery type.* * data are presented as mean ± sd. quality of life survey in laparoscopic radical nephrectomy-acar et al laparoscopic urology 1948 approach on bp. the present study’s findings might be useful for counseling patients before surgery concerning the probability of and time necessary to return to preoperative hrqol. the present study also evaluated perioperative morbidity indices, including operative variables, pathological features, postoperative course and complications associated with orn and lrn. as previously reported, the lrn group of present study had significantly less blood loss, a lower transfusion rate, earlier ambulation, more rapid convalescence and shorter hospitalization than the orn group. studies reported that mean duration of hospitalization and convalescence time were significantly shorter in the lrn group than in the orn group.(7,13) blood loss and the transfusion rate were also found to be significantly lower in the lrn group.(4) although the surgical complication rate found to be low in the lrn group, there wasn’t a difference in such complications as surgical site infection, pneumonia, hemorrhage, or postoperative mortality.(4) the present study has several limitations. first, it employed a prospective, non-randomized design; however, randomization is very difficult with multicenter studies that are affected by such factors as patient characteristics, tumor characteristics and surgeon experience. we realized that the number of orn has been increased over lrn during the study period due to the patient and/or surgeon preferences. during run-in period of the patients, some clinics had only performed orn that changed distribution of the patients in the study groups. it could affect the sample size and statistical power because the sample size assumed as 50 patients to each group according to the priori statistical power analysis of the study. second, longer follow-up of hrqol might yield more information and more accurately indicate the natural history of cancer after surgery, even though disease progression probably impairs qol components. on the other hand, the present study investigated hrqol in patients with a good-intermediate prognosis in whom disease-free survival is really high. another important limitation was use of sf-36 instead of a disease-specific qol questionnaire. although sf-36 can measure both physical and mental qol, a specific questionnaire for rcc might have more accurately indicated the effect of each surgical technique on qol. on the other hand, kim and colleagues evaluated hrqol outcome after renal surgery with 2 patient-reported hrqol instruments, convalescence and recovery evaluation (care), and sf-12 in 71 patients. the care pain, gastrointestinal (gi) and activity domain scores and the sf-12 physical composite score (pcs) were sensitive to changes in hrqol. interestingly, they found postsurgical hrqol effects detected by the questionnaires were most evident at 2 weeks and, 74% and 50% of patients returned to within 90% of baseline 4 weeks after radical and partial nephrectomy, respectively. they concluded that the activity, pain and gi domains of care and pcs sub scores of the sf-12 are sensitive measures of hrqol outcome of renal surgery and they recommended these questionnaires for appropriate measures of hrqol in renal surgery.(20) finally, the functional assessment of cancer therapy kidney symptom index (fksi-15) was recently developed for this purpose,(21) but this questionnaire was designed for evaluating advanced and recurrent kidney cancer and was not considered appropriate for use in the present study. conclusion the investigated qol parameters didn’t differ significantly between the lrn and orn groups, except for the ghp domain score. minor changes in sf-36 bp scores in the lrn group could be considered indicative of the superiority of lrn. although the patients in the orn group had relatively larger tumors and/or higher pathologic stage, these factors had no effect on analgesic requirement, postoperative complications, or physical functioning. the higher physical and general qol scores at 6 months post-surgery in both groups let us think the positive impact of cancer treatment, regardless the type of surgical treatment. lastly, lrn exhibited explicit technical advantages over orn, including less blood loss, shorter hospitalization and more rapid recovery. acknowledgements all authors are members of turkish uro-oncology society and the present study was conducted under approval of general council of the society. variables open nephrectomy (n = 72) laparoscopic nephrectomy (n = 39) p value postoperative vas scores at 48 hours 3.92 ± 1.49 3.9 ± 1.57 .900 preoperative sf-36 physical domains physical functioning 71.74 ± 25.27 70.87 ± 25.23 .896 bodily pain 70.56 ± 20.57 69.56 ± 23.47 .980 general health 58.78 ± 15.85 70.31 ± 19.38 < .001 postoperative 1 month sf-36 physical domains physical functioning 58.19 ± 23.9 64.64 ± 23.44 .230 bodily pain 58.42 ± 19.59 66.56 ± 1.55 .058 general health 58.24 ± 15.17 67.05 ± 15.97 .011 postoperative 6-month sf-36 physical domains physical functioning 74.11 ± 16.74 73.9 ± 24.21 .521 bodily pain 77.43 ± 17.44 72.15 ± 20.33 .440 general health 64.81 ± 14.45 72.44 ± 15 .55 table 3. comparison of vas scores and sf-36 physical domains of the patients according to surgery type.* abbreviations: vas, visual analog scale; sf-36, short form-36 questionnaire. * data are presented as mean ± sd. quality of life survey in laparoscopic radical nephrectomy-acar et al vol 11. no 06 nov-dec 2014 1949 conflict of interest none declared. references 1. jemal a, siegel r, ward e, et al. cancer statis tics, 2008. ca cancer j clin. 2008;58:71-96. 2. berger a, brandina r, atalla ma, et al. lapa roscopic radical nephrectomy for renal cell car cinoma: oncological outcomes at 10 years or more. j urol. 2009;182:2172-6. 3. gabr ah, gdor y, strope sa, roberts ww, wolf js jr. approach and specimen handling do not influence oncological perioperative and long-term outcomes after laparoscopic radical nephrectomy. j urol. 2009;182:874-80. 4. maclennan s, imamura m, lapitan mc, et al. systematic review of oncological outcomes fol lowing surgical management of localised renal cancer. eur urol. 2012;61:972-93. 5. dunn md, portis aj, shalhav al, et al. lapar oscopic versus open radical nephrectomy: a 9-year experience. j urol. 2000;164:1153-9. 6. gill is, meraney am, schweizer dk, et al. laparoscopic radical nephrectomy in 100 pati ents: a single center experience from the united states. cancer. 2001;92:1843-55. 7. hemal ak, kumar a, kumar r, wadhwa p, seth a, gupta np. laparoscopic versus open radical nephrectomy for large renal tumors: a long-term prospective comparison. j urol. 2007;177:862-6. 8. khanna d, tsevat j. health-related quality of life--an introduction. am j manag care. 2007;13 suppl 9:s218-23. 9. novara g, secco s, botteri m, de marco v, artibani w, ficarra v. factors predicting health-related quality of life recovery in patients undergoing surgical treatment for renal tumors: prospective evaluation using the rand sf-36 health survey. eur urol. 2010;57:112-20. 10. dillenburg w, poulakis v, skriapas k, et al. retroperitoneoscopic versus open surgical rad ical nephrectomy for large renal cell carcinoma in clinical stage ct2 or ct3a: quality of life, pain and reconvalescence. eur urol. 2006;49:314-22. 11. poulakis v, witzsch u, de vries r, moeckel m, becht e. quality of life after surgery for localized renal cell carcinoma: comparison be tween radical nephrectomy and nephron-sparing surgery. urology. 2003;62:814-20. 12. ficarra v, novella g, sarti a, et al. psycho-so cial well-being and general health status after surgical treatment for localized renal cell carci noma. int urol nephrol. 2002;34:441-6. 13. gratzke c, seitz m, bayrle f, et al. quality of life and perioperative outcomes after retrope ritoneoscopic radical nephrectomy (rn), open rn and nephron-sparing surgery in patients with renal cell carcinoma. bju int. 2009;104:470-5. 14. onishi t, nishikawa k, hasegawa y, et al. as sessment of health-related quality of life after radiofrequency ablation or laparoscopic surgery for small renal cell carcinoma: a prospective study with medical outcomes study 36-item health survey (sf-36). jpn j clin oncol. 2007;37:750-4. 15. clark pe, schover lr, uzzo rg, hafez ks, rybicki la, novick ac. quality of life and psychological adaptation after surgical treatme nt for localized renal cell carcinoma: impact of the amount of remaining renal tissue. urolo gy. 2001;57:252-6. 16. desai mm, strzempkowski b, matin sf, et al. ospective randomized comparison of transpr peritoneal versus retroperitoneal laparoscopic radical nephrectomy. j urol. 2005;173:38-41. 17. robson cj. radical nephrectomy for renal cell carcinoma. j urol. 1963;89:37-42. 18. ware je jr., sherbourne cd. the mos 36-item short-form health survey (sf-36). i. conceptual framework and item selection. med care. 1992;30:473-83. 19. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009;250:187-96. 20. kim sb, williams sb, cheng sc, sanda mg, wagner aa. evaluation of patient-reported quality-of-life outcomes after renal surgery. urology. 2012;79:1268-73. 21. cella d, yount s, du h, et al. development and validation of the functional assessment of can cer therapy-kidney symptom index (fksi). j support oncol. 2006;4:191-9. quality of life survey in laparoscopic radical nephrectomy-acar et al laparoscopic urology 1950 review articles invasive bladder cancer: the role of bladder preserving therapy seyyed yousef hosseini* department of urology, shaheed modarress hospital, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: to evaluate the reported outcomes of multimodality therapy with organ preservation in invasive bladder cancer and assess it as an alternative for radical cystectomy in selected cases. materials and methods: all the articles on multimodality therapy with organ preservation in invasive bladder cancer, published from 1974 to 2004, were reviewed and the results were compared with the outcome of radical cystectomy in cases with invasive bladder cancer. results: multimodality therapy is transurethral resection of the bladder tumor (turbt) combined with chemoradiation therapy. it yields a 36% to 48% 5-year survival rate, when the bladder is preserved, and an overall rate of 48% to 63%. this method takes a long time for treatment and is accompanied by significant morbidity and mortality. cystectomy will be required in 34% to 45% of the patients, during the treatment course, and in 28%, repeat turbt will be performed due to recurrence of superficial tumors. conclusion: organ preserving in multimodality therapy of invasive bladder cancer can have acceptable results in some special situation, provided that a close cooperation between urologist, radiotherapist, and oncologist exists. however, radical cystectomy is still considered the standard treatment for invasive bladder cancer. key words: bladder neoplasm, bladder preservation, chemotherapy, radiation therapy, cystectomy 1 urology journal unrc/iua vol. 2, no. 1, 1-7 winter 2005 printed in iran introduction since 1990s, the main aim of treatment in patients with cancer has been organ preservation with chemoradiation, with or without limited local surgery. this approach has gained footage in breast, esophageal, larynx, lung, and anal cancers. yet, radical cystectomy in invasive bladder cancer has its own place as the standard treatment. the treatment results of these tumors, when radiotherapy, turbt, or chemotherapy is used alone in order to preserve bladder, have been disappointing. but trimodality bladderpreserving therapy, using combined transureteral resection of the bladder tumor (turbt), radiotherapy, and chemotherapy, has brought hope on the horizon in some special cases. in clinically staged groups of patients, trimodality bladder-preserving therapy has had comparable outcomes with radical cystectomy. eighty percent of these patients who survived for at least five years enjoyed their own normal bladder, while in 20% of whom, transureteral resection (tur) had been required again due to superficial tumors relapses.(1) these tumors, like the primary ones, are sensitive to intravesical *corresponding author: urology and nephrology research center, no. 44, 9th boustan, pasdaran, tehran, iran. tel: ++98 912 354 2496, e-mail: info@unrc.ir bladder preserving therapy for invasive bladder cancer installation of bacillus calmette guerin (bcg). bladder function studies have shown that 70% of these patients are able to void normally and nearly 50% of them have normal erection. trimodality bladder-preserving therapy, notwithstanding that it cannot surpass radical cystectomy, could be offered as an alternative approach to the patients. the need for multimodality approach single modality treatment of invasive bladder tumors with turbt, radiotherapy, or chemotherapy has not been successful. barnes et al have reported 27% 5-year survival in 85 patients with well to moderately differentiated t2 bladder tumors who had undergone turbt.(2) herr studied on highly-selective patients treated with turbt and found that survival at 5 years was 76%.(3) chemotherapy has also discouraging results as a single therapy in invasive bladder cancer. robert and colleagues used methotrexate and cisplatin for the treatment of t3 and t4 bladder tumors; complete response was seen in 5 patients (11%) and partial response in 15 (34%).(4) radiotherapy has been used in europe and canada as monotherapy in invasive bladder cancer. duncan and quilty performed a study in edinburgh to evaluate external beem radiotherapy in 699 patients with invasive bladder cancer. the overall 5-year survival was 30%.(5) in toronto, canada, gospodarowicz et al reported 31.6% overall 5year survival in 121 cases treated with radiotherapy.(6) unfavorable outcomes of these approaches have urged physicians to consider multimodality approach, since its results in other cancers have been encouraging. the usage of turbt and radiotherapy is to locally control the tumor and chemotherapy is helpful mainly for systemic therapy. previous reports indicate that complete response can be achieved in 45% of cases using radiotherapy and tur.(6-8) a proportion of patients who undergo radical cystectomy may have undetectable micrometastases, which are the most common cause of mortality within the three postoperative years.(9) combining turbt and radiotherapy with chemotherapy eliminates such micrometastases, in addition to local therapy. in consequence, chemotherapy with methotrexate, cisplatin, and vinblastine (mcv) is administered before or after radiotherapy. also in some protocols cisplatin and/or 5-fluorouracil is used simultaneously with radiotherapy. although the therapeutic effects of this method has not been examined yet, cisplatin and 5-fluorouracil has proven effective as radiosensitizer in oropharyngeal carcinomas.(10,11) patient selection in multimodality approach all patients who require radical cystectomy are eligible to undergo multimodality method, subject to their acceptance and cooperation. however, patients with tumors sized 6 cm or larger, and those with hydronephrosis due to ureteral orifice obstruction by tumor, are not appropriate candidates. furthermore, bladder-sparing therapy would not be an appropriate approach in the presence of white blood cell count <4000/µl, platelet count <100000/µl, serum creatinine >1.7 mg/dl, creatinine clearance <60 ml/min, severe irritative bladder symptoms, and diffused carcinoma in situ of bladder. therapeutic method in multimodality approach in this method the optimum possible turbt is performed and treatment is continued with chemotherapy and radiotherapy. afterwards, patients receive 2400 to 4000 rad radiotherapy and undergo 2 to 3 sessions of chemotherapy with mcv. at the end of this stage, namely induction therapy, re-evaluation of bladder at the primary tumor site is done using cystoscopy, cytology, and tur resection. any report of tumor remainders is considered as failure and radical cystectomy would be done. but if no tumor is detected (response to treatment) patients undergo additional chemotherapy and radiotherapy as consolidation therapy, in order to establish the resultant effects. at the end of the treatment period, when complete response is achieved, a strict follow-up consisting of cystoscopy, biopsy of suspected areas, and urinary cytology, is pivotal. follow-up is recommended to be done every three months for the first two years, every 6 months for the subsequent 3 years, and yearly, afterwards. a summary of the treatment schema is shown in figure 1. in a study by housset et al from paris, induction therapy with 2400 rad radiotherapy combined with cisplatin and 5-flurouracil was performed in 120 cases.(12) in 18 patients with 2 hosseini stage t2 to t4 tumors who had responded to induction therapy, radical cystectomy and lymphadenectomy of pelvis were done before consolidation therapy. histological assessment of bladder and lymph nodes showed no tumor. a total of 77% of the patients had complete response and their treatment course was continued with 2000 rad radiotherapy, twice a day and combination of cisplatin and 5fluorouracil. patients who did not respond, underwent cystectomy following induction therapy and tumor recurrence. survival at 5 years was 63%. fellin and colleagues reported the outcomes in 56 patients with stage t2 to t4 tumors who underwent turbt and two courses of mcv, following with 4000 rad radiotherapy and concomitant cisplatin. complete response was achieved in 50% of patients after induction therapy. they were maintained on 2400 rad radiotherapy and cisplatin as complementary treatment. overall 5-year survival rate was 55% and it was 41% in cases with bladder preservation.(13) paclitaxel, cisplantin, and 5-fluorouracil can increase the sensitivity of tumoral cells to radiotherapy, leading to better tumor removal. the other advantage of combining radiotherapy with chemotherapy is the potential effects on micrometastases not visualized with the current staging devices. to promote the effect of radiotherapy, a twice daily bifractional plan is recommended in some protocols.(12-14) the rationale behind administering two sessions a day with 12-hour intervals is that tumoral cells will be removed more rapidly with shorter intervals between radiotherapy sessions. in a study by noslund and coworkers on 168 cases of bladder tumor, it was shown that the result of local control at 10 years was better with hyperfractionation with 1 gy 3 times a day, comparing to standard treatment.(15) 3 fig. 1. multimodality bladder-preserving treatment of invasive bladder cancer(1) biopsy-proven invasive bladder cancer transurethral resection of the whole visible tumor (turb-t) induction therapy with external beam radiation and radiosensitizing chemotherapy (weeks 1 to 3) repeat cystoscopy with transurethral biopsy (week 7) complete pathologic response (pt0, ta or tcis) residual tumor or new site of tumor (t1 or greater) proceed with consolidation therapy (week 8 to 9) radical cystectomy (week 9) repeat cystoscopy with transurethral biopsy (week 17) adjuvant chemotherapy complete response superficial persistence muscle-invasive disease long-term cystoscopic intravesical therapy or radical cystectomy bladder preserving therapy for invasive bladder cancer results of bladder preserving protocols the results of bladder saving in a series of studies are as follows: in a study by the radiation therapy oncology group (rtog), they started chemoradiation with radiotherapy combined with 5-flurouracil and cisplatin.(16) of 34 cases, twothird had complete response and were eligible for commencing consolidation therapy. kachnic et al, from massachusetts general hospital (mgh), used two courses of chemotherapy with mcv combined with radiotherapy at a dose of 4000 rad and cisplatin, as well as turbt, and in those with complete response they completed the treatment with 2400 rad radiotherapy and cisplatin. sixty-six percent of the patients had complete response after induction therapy. overall and bladder-saving survivals at 5 years were 52% and 43%, respectively.(17) in mgh group, 190 cases were followed up from 1986 to 1998; 121 of those (63%) had complete response and entered the consolidation therapy period.(18) in a study by sauer and colleagues, of 181 patients, 145 (80%) had complete response,(19) and in rtog studies, they achieved 75%(20) and 59%(21) complete response. one of the concerns after complete response and ending the treatment is the tumor relapse, either an invasive or a superficial form. longterm follow-up by mgh group in 121 patients had shed light on this issue(22); of 121 cases, 73 had no recurrence during 6.7 years follow-up. thirtytwo of 48 recurrence cases were superficial tumors and 16 were invasive tumors. the latter cases were treated with radical cystectomy and superficial ones received local therapies such as tur and intravesical bcg. the outcomes of delayed cystectomy were the same as those of primary cystectomy. furthermore, 15% of the 72 patients in the rtog phase iii with complete response experienced invasive tumor recurrence within 5-year follow-up.(20) consequently, longterm follow-up is strongly recommended. neoadjuvant chemotherapy there exists controversy in the effects of neoadjuvant chemotherapy, preceding radical cystectomy and trimodality bladder preservation therapy. in a study by the european organization for research and treatment of cancer and the medical research council, half of 976 patients underwent chemotherapy prior to radical cystectomy and the other half had no chemotherapy before cystectomy or radiotherapy. complete response was seen in 33% and 12% of the patients with and without chemotherapy, respectively.(1) the effect of neoadjuvant chemotherapy before the treatment protocol of trimodality bladder preservation therapy has not been desirable. in rtog trial, 123 patients were divided into two groups after turbt, one was started on trimodality therapy and the other received two courses of mcv chemotherapy preceding trimodality therapy. five-year survival was not different in the two groups and the possibility of bladder preservation was 36% in the first and 40% in the second group.(20) accordingly, it seems that neoadjuvant therapy is not a recommendable method in bladder preservation protocols. position of bladder preservation although the results of bladder preservation have improved in the last 15 years, radical cystectomy has reserved its place as the standard treatment among urologists. this approach demands a close cooperation of the specialists team members, including oncologist, radiotherapist, and urologist. consequently, it is still unclear whether we can achieve a favorable survival in comparison with the survival rates after radical cystectomy or not. on the other hand, improvement in surgical methods has provided a better outcome with low morbidity rate for patients who undergo radical cystectomy. this method is not associated with local and systemic complications seen in bladder preservation protocols. comparing the effectiveness of multimodality approach with radical cystectomy it has been claimed that the overall 5-year survival of the patients with multimodality therapy is comparable to that in primary radical cystectomy. in 5 years, the local control is 90% after primary radical cystectomy and survival rate is between 40% to 60%.(23,24) however there is no prospective randomized control trial to compare long-term survival rates. given et al from florida university have reported a better outcome for radical cystectomy. in this study on 94 patients, 5-year survival rate was higher in patients who had undergone radical cystectomy 4 hosseini during the follow-up comparing to those in whom bladder was preserved (65% vs. 40%).(25) some believe that delayed cystectomy in the patients undergone this protocol may lower the survival. in a proportion of patients, cystectomy will be required at the end of induction therapy, due to incomplete response or recurrence during followup period. hautman compared 210 cases of primary cystectomy with 88 cases of delayed cystectomy.(26) reasons for delay were radiotherapy, neoadjuvant chemotherapy, treatment of stage pt1 tumor with bcg installation, and repeat turbt. in primary cystectomy group, 26% of the patients had a tumor with stage pt3b or higher and 12% had positive lymph nodes; while in delayed cystectomy group, 42% had stage pt3b or higher and 26% had positive lymph nodes. the difference was statistically significant. abratt et al studied on 46 patients, in whom salvage cystectomy had been performed, following radiotherapy. survival at 5 years was better in those with cystectomy due to incomplete response to radiotherapy than to recurrence in follow-up (50% vs. 32%).(27) the above findings suggest that early cystectomy is associated with a better 5-year survival. however, some other researchers have shown that delay in cystectomy does not impact long-term outcome. some researchers have reported that 90-day postpone of cystectomy after diagnosis to perform neoadjuvant chemotherapy prior to surgery has no difference with prompt cystectomy.(28,29) on the other hand, it has been disputed that pathologic staging is not available in bladder preservation. lynch et al did cystectomy due to irritative bladder symptoms in 5 patients with bladder preservation. subsequently, tumor was detected in all pathologic samples.(30) quality of life and complications in bladder preservation protocols those who support bladder preservation emphesize the better quality of life. however, improvement in surgical methods of cystectomy has made this advantage trivial. continence can be achieved in 91% of the patients during the day time and 80% to 87.5% at night, when orthotopic method is used as the first choice.(31,32) clean intermittent catheterization is required in less that 5% of the patients. also, potency is restored in 64% of cases with cavernosal nerves preservation method.(25) cox et al and also lynch and colleagues reported that patients who had undergone chemoradiation had normal bladders, but radiotherapy could aggravate symptoms of those who had low capacity bladder or urge incontinence.(30,33) multimodality bladder preservation therapy is an expensive and time consuming procedure. zietman et al, from massachusetts general hospital, demonstrated that in order to complete this procedure, cooperation of three specialist groups during a 6 months period is required.(14) shiply et al believe that specific centers with the requisite discipline are needed to perform the protocol.(34) radical cystectomy costs $22900, while bladder preservation methods cost $41268.(14) external beam radiation therapy and systemic chemotherapy have serious local and systemic complications. in a rtog's study, 38% of patients could tolerate only one course of chemotherapy with mcv and 4% died during induction therapy.(20) in a report by mgh group in 1997, 20% of patients underwent changes in induction therapy due to severe complications. mortality rate in this study was 4%.(17) in a study by skinner et al, mortality rate among patients younger than 70 years old was reported as 2% and it was 2.8% in those older than 70.(35) main complications of bladder preservation are associated with chemotherapy. incomplete response or recurrence warrants cystectomy in some patients who were candidates for bladder preservation. during the follow-up, 45% of patients in rtog phase iii(20) and 34% in mgh group(17) underwent cystectomy; these patients had undertaken complications of chemotherapy, as well. most urologists believe that chemoradiation seriously impacts normal bladder function. in three studies bladder function following chemoradiation has been assessed.(36-38) in one of those, mgh study, urodynamic tests were used as well as a questionnaire to assess bladder function in patients with chemoradiation and they were compared with the results in a control group matched for age and gender. it was shown that in 7 out of 31 patients, bladder compliance had decreased and other parameters had been normal. data extracted from questionnaires were in accordance with urodynamic findings, corresponding to 74% satisfaction from bladder function. rectal symptoms in this study were not common, but the rate of symptoms related to 5 bladder preserving therapy for invasive bladder cancer small intestine was 22%. recently, radiotherapy has been limited to a less extensive area of lymph nodes, so that such complications are seen less. in mgh study, most men reported satisfaction with their sexual activity and only 8% were dissatisfied. women preferred not to respond to the questions concerning this issue.(38) the damage to the potency of patients with radiotherapy due to bladder cancer is less in comparison with prostate cancer, which is because of the lower dose needed in bladder cancer and that the cavernous nerves are away from the radiotherapy area. plans for the future in the recent years, remarkable results have been reported for using molecular biomarkers such as p53 and prb as a prognostic factor and a guide to select patients for chemotherapy. several studies have shown that p53 and prb are the factors indicating poor prognosis.(39-41) studies from southern california demonstrated that patients with invasive bladder cancer and abnormal nuclear p53 accumulation benefit from adjuvant chemotherapy.(42) it seems that in the future, these markers will be helpful hints to select patients eligible for chemoradiation and bladder preservation. conclusion treatment of invasive bladder cancer with trimodality bladder-preserving therapy method is highly dependent on a close cooperation of the urologists, oncologists, and radiotherapists as a unanimous team, and the patients should be selected carefully and be completely informed of the procedure. this approach needs a 6 months period to perform and a 5-year intense follow-up, as well as complementary treatments, if needed. notwithstanding all the above considerations, 40% of patients will eventually undergo cystectomy. references 1michaelson d, zietman a. invasive bladder cancer: the role of bladder-preserving therapy. in: american society of clinical oncology. 2004 educational book. proceedings of the 40th asco annual meeting; 2004 june 5-8; new orleans, la. p.457-65. 2barnes rw, dick al, hadley hl, johnston ol. survival following transurethral resection of bladder carcinoma. cancer res. 1977;37:2895-7. 3herr hw. conservative management of muscleinfiltrating bladder cancer: prospective experience. j urol. 1987;138:1162-3. 4roberts jt, fossa sd, richards b, et al. results of medical research council phase ii study of low dose cisplatin and methotrexate in the primary treatment of locally advanced (t3 and t4) transitional cell carcinoma of the bladder. br j urol. 1991;68:162-8. 5duncan w, quilty pm. the results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage x-ray therapy. radiother oncol. 1986;7:299-310. 6gospodarowicz mk, hawkins nv, rawlings ga, et al. radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. j urol. 1989;142:1448-53. 7jenkins bj, caulfield mj, fowler cg, et al. reappraisal of the role of radical radiotherapy and salvage cystectomy in the treatment of invasive (t2/t3) bladder cancer. br j urol. 1988;62:343-6. 8quilty pm, duncan w. primary radical radiotherapy for t3 transitional cell cancer of the bladder: an analysis of survival and control. int j radiat oncol biol phys. 1986;12:853-60. 9skinner dg, daniels jr, russell ca, et al. the role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. j urol. 1991;145:459-64. 10horiot jc, le fur r, n'guyen t, chenal c, schraub s, alfonsi s, gardani g, van den bogaert w, danczak s, bolla m, et al. hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the eortc cooperative group of radiotherapy. radiother oncol. 1992 dec;25(4):231-41. 11herskovic a, martz k, al-sarraf m, et al. combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. n engl j med. 1992 jun 11;326(24):1593-8. 12housset m, maulard c, chretien y, et al. combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. j clin oncol. 1993;11:2150-7. 13fellin g, graffer u, bolner a, ambrosini g, caffo o, luciani l. combined chemotherapy and radiation with selective organ preservation for muscle-invasive bladder carcinoma. a single-institution phase ii study. br j urol. 1997;80:44-9. 14zietman al, shipley wu, kaufman ds, et al. a phase i/ii trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer. j urol. 1998;160:1673-7. 15naslund i, nilsson b, littbrand b. hyperfractionated radiotherapy of bladder cancer. a ten-year follow-up of a randomized clinical trial. acta oncol. 1994;33:397-402. 16kaufman ds, winter ka, shipley wu, et al. the initial results in muscle-invading bladder cancer of rtog 9506: phase i/ii trial of transurethral surgery plus 6 hosseini radiation therapy with concurrent cisplatin and 5fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response. oncologist. 2000;5:471-6. 17kachnic la, kaufman ds, heney nm, et al. bladder preservation by combined modality therapy for invasive bladder cancer. j clin oncol. 1997;15:1022-9. 18shipley wu, kaufman ds, zehr e, et al. selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. urology. 2002;60:62-7. 19sauer r, birkenhake s, kuhn r, wittekind c, schrott km, martus p. efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer. int j radiat oncol biol phys. 1998;40:121-7. 20shipley wu, winter ka, kaufman ds, et al. phase iii trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of radiation therapy oncology group 89-03. j clin oncol. 1998;16:3576-83. 21tester w, caplan r, heaney j, et al. neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of radiation therapy oncology group phase ii trial 8802. j clin oncol. 1996;14:119-26. 22zietman al, grocela j, zehr e, et al. selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of ta, t1, and tis recurrence within the retained bladder.urology. 2001;58:380-5. 23pagano f, bassi p, galetti tp, et al. results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification. j urol. 1991;145:45-50. 24waehre h, ous s, klevmark b, et al. a bladder cancer multi-institutional experience with total cystectomy for muscle-invasive bladder cancer. cancer. 1993;72:3044-51. 25given rw, parsons jt, mccarley d, wajsman z. bladder-sparing multimodality treatment of muscleinvasive bladder cancer: a five-year follow-up. urology. 1995;46:499-504. 26hartmann re. complications and results after cystectomy in male and female patients with locally invasive bladder cancer. eur urol. 1998;33 suppl 4:23-4. 27abratt rp, wilson ja, pontin ar, barnes rd. salvage cystectomy after radical irradiation for bladder cancerprognostic factors and complications. br j urol. 1993;72:756-60. 28sell a, jakobsen a, nerstrom b, sorensen bl, steven k, barlebo h. treatment of advanced bladder cancer category t2 t3 and t4a. a randomized multicenter study of preoperative irradiation and cystectomy versus radical irradiation and early salvage cystectomy for residual tumor. daveca protocol 8201. danish vesical cancer group. scand j urol nephrol suppl. 1991;138:193-201. 29schultz pk, herr hw, zhang zf, et al. neoadjuvant chemotherapy for invasive bladder cancer: prognostic factors for survival of patients treated with m-vac with 5-year follow-up. j clin oncol. 1994;12:1394-401. 30lynch wj, jenkins bj, fowler cg, hope-stone hf, blandy jp. the quality of life after radical radiotherapy for bladder cancer. br j urol. 1992;70:519-21. 31christiano ap, yang x, gerber gs. malignant transformation of renal angiomyolipoma. j urol. 1999;161:1900-1. 32stenzl a, colleselli k, poisel s, feichtinger h, pontasch h, bartsch g. rationale and technique of nerve sparing radical cystectomy before an orthotopic neobladder procedure in women. j urol. 1995;154:2044-9. 33cox jd, guse c, asbell s, rubin p, sause wt. tolerance of pelvic normal tissues to hyperfractionated radiation therapy: results of protocol 83-08 of the radiation therapy oncology group. int j radiat oncol biol phys. 1988;15:1331-6. 34shipley wu, kaufman ds, heney nm, althausen af, zietman al. an update of selective bladder preservation by combined modality therapy for invasive bladder cancer. eur urol. 1998;33 suppl 4:32-4. 35skinner dg, stein jp, lieskovsky g, et al. 25-year experience in the management of invasive bladder cancer by radical cystectomy. eur urol. 1998;33 suppl 4:25-6. 36caffo o, fellin g, graffer u, luciani l. assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. a survey by a self-administered questionnaire. cancer. 1996;78:1089-97. 37henningsohn l, wijkstrom h, dickman pw, bergmark k, steineck g. distressful symptoms after radical radiotherapy for urinary bladder cancer. radiother oncol. 2002;62:215-25. 38zietman al, sacco de, skowronski ue, et al. organ conservation as an alternative to radical cystectomy for invasive bladder cancer: urodynamic and quality of life evaluation of patients treated by trimodality therapy. int j radiat oncol biol phys. 2003. [in press] 39sarkis as, bajorin df, reuter ve, et al. patient-reported impotence and incontinence after nerve-sparing radical prostatectomy. j clin oncol. 1995;13:1384-90. 40esrig d, elmajian d, groshen s, et al. accumulation of nuclear p53 and tumor progression in bladder cancer. n engl j med. 1994;331:1259-64. 41cote rj, dunn md, chatterjee sj, et al. elevated and absent prb expression is associated with bladder cancer progression and has cooperative effects with p53. cancer res. 1998;58:1090-4. 42cote rj, esrig d, groshen s, jones pa, skinner dg. p53 and treatment of bladder cancer. nature. 1997;385:123-5. 7 urology journal unrc/iua vol. 1, no. 3, 208-210 summer 2004 printed in iran 208 point of technique endoscopic resection of lower ureter in upper urinary tract tumors mohammadzadeh rezaee ma department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran abstract purpose: to evaluate the efficacy and safety of endoscopic resection of lower ureter in upper urinary tract tumor cases. materials and methods: five patients with transitional cell carcinoma (tcc) of the upper urinary tract were enrolled in this study. nephrectomy was carried out through a flank incision and distal ureter with a cuff of bladder, which was removed using endoscopic approach. complications and recurrence rate were evaluated. results: a total of 5 patients with upper urinary tract tumor underwent the endoscopic resection of lower ureter. all the patients had grade i transitional cell tumor. two patients had suffered from bladder tcc treated previously. during the follow-up two cases developed bladder tumor: one, 18 months and another, one year postoperatively, both in the base of bladder, which was managed successfully by transurethral resection (tur). conclusion: endoscopic resection of lower ureter in selected patients with upper urinary tract tumors can lead to lower morbidity, shorter operation time, and higher patient's satisfaction. despite the minority of cases in this study, it seems that this method is applicable in selected cases. key words: transitional cell carcinoma, upper urinary tract, treatment introduction upper urinary tract tumors constitute 5% of urothelial tumors. the standard treatment is nephroureterectomy along with the resection of a cuff of bladder in the vesicoureteral junction.(1) to do so, a long incision from flank to pelvic area or two incisions, one in flank and another as a gypsone incision, is indispensable. moreover, a midline incision in order to remove kidney, ureter, and a portion of bladder is another option.(2) all these procedures lead to long incisions and various complications. we introduce endoscopic resection of lower ureter in these cases, which is less invasive and brings about a better outcome. to our knowledge, this method has not been reported at least in our country. materials and methods five patients with transitional cell carcinoma (tcc), who required nephroureterectomy were referred to our urology department of ghaem hospital, at mashhad. nephrectomy was carried out through a flank incision and distal ureter with a cuff of bladder was removed endoscopically. technique the patient was secured in lumbar position and kidney was removed through a flank incision (intercostals 11 and 12). ureter was dissected adjacent to iliac vessels or bladder, if possible, using blunt dissection. consequently, ureter was freed. an 8 f nelaton catheter was placed in the ureter and pushed into the bladder. afterwards, the end of the catheter was cut and the end of accepted for publication in july 2003 endoscopic resection of lower ureter in upper urinary tract tumors 209 the ureter was fixed to it with a nylon 2.0 suture (fig. 1). flank incision was then sutured in three layers preceded by establishing a drain. in order to endoscopically resect the ureter, patient was secured in lithotomy position. the endoscopic sheet was advanced into bladder and the tip of ureteral catheter was found and grasped, allowed to gently pull the catheter and cystoscope together toward urethra and finally excising from the urethral meatus (fig. 2). a 24 f resectoscope was inserted into bladder parallel to the catheter, while it was pulling by assistant surgeon. then, bladder mucosa and muscles in an area 1.5 cm around the ureteral orifice was incised by coagulation using electro hook. this process was done with the bladder filled with an adequate volume of liquid. nelaton catheter was, then, pulled gently under the supervision from inside the bladder, yielding the inversion of the ureter, which was fixed to the end of the catheter. as a result, the ureter along with a cuff of bladder in vesicoureteral junction consisting of ureteral muscles and waldeyer sheath were resected and removed. the operation ended by inserting a foley catheter to provide bladder drainage. in the second or third follow-up day, drain was removed and so was the urethral catheter in the sixth or seventh post-operative day. results a total of 5 patients with upper urinary tract tumor underwent the endoscopic resection of lower ureter, whose mean age was 56 (range 45 to 68) years. all the patients had grade i tcc (four in renal pelvis and one in ureter). two patients had suffered from bladder tcc, treated before the operation. during the follow-up, two patients developed bladder tumor: one, 18 months and another, one year postoperatively, both in the base of bladder, which were managed successfully by tur. discussion as this method is not a standard approach, it can be only compared with the current standard methods in order to discuss its advantages and complications. however, mcdonald reported this surgical approach in 1952 for the first time.(3) this method had not been reported in authentic journals until laparoscopic nephrectomy was popularized, and endoscopic resection of distal ureter became a common approach.(2,4) fig. 1. placing the catheter and fixing the end of the ureter to the catheter fig. 2. inserting the endoscopic sheet in order to grasp the catheter and gently pulling the catheter and cystoscope together toward the urethra endoscopic resection of lower ureter in upper urinary tract tumors 210 intraand post-operative complications consist of extravasation, intraperitoneal rupture of bladder, tumor implantation on cuff resection site, and retroperitoneal tumor implantation due to temporal cells seeding.(1,5) recurrent tumors have been reported at a rate of 20% to 30% in open surgical operations, 80% of them within one to two years.(1) fortunately, none of our cases had tumor recurrence in the site of resected bladder cuff and recurrent tumor in the operated side was observed in one patient 18 months after the operation. patients with high grade and invasive tumors or lower ureter tumors are not good candidates for this surgical method. moreover, cases with simultaneous bladder and pelvis tumors, pelvic infectious diseases (pid), previous pelvic radiotherapy, retroperitoneal fibrosis, and previous surgical manipulation in the respective site are not appropriate candidates for endoscopic resection of ureter using this method.(1) laguna et al reported a comparison of 19 patients with nephroureterectomy using one incision with 15 patients who underwent nephroureterectomy using two incisions. they found that operation time, bleeding, hospitalization stay, analgesic administration, and the overall morbidity were lower in endoscopic resection group than that in two-incisional approach. however, complications in the two groups were similar.(6) conclusion endoscopic resection of lower ureter in patients with upper urinary tract tumors can lead to lower morbidity, shorter operation time, and higher patient's satisfaction. nonetheless, patients should be meticulously selected, as all the cases are not eligible for this method; low grade caliceal or upper ureter tumors, particularly in females and in whom nephrectomy is performed laparoscopically, are the most appropriate cases for this surgical method. our study, albeit with few cases, showed that endoscopic resection of lower ureter is an appropriate method, when indicated. references 1. hetherington jw, ewing r, philips nh. modified nephroureterectomy: a risk of tumor implantation. br j urol 1986; 58: 368-370. 2. logadottir y. single incision nephroureterectomy. bju int 2001; 88(1): 124-127. 3. mcdonald hp, upchurch we, sturdevant ct. nephroureterectomy: a new technique. j urol 1952; 67: 804-9. 4. fadden pt, nakada sy. hand-assisted laparoscopic renal surgery. urol clin north am 2001; 28(1): 1023-1030. 5. seaman ek, lawin km, benson mc. treatment options for upper tract transitional call carcinoma. urol clin north am 1993; 20: 349. 6. laguna mp, de la rosette jj. the endoscopic approach to the distal ureter in nephroureterectomy for upper urinary tract tumor. j urol 2001 dec; 166(6): 2017-22. urology journal unrc/iua 118 bilateral emphysematous pyelonephritis: a case report mohammadreza darabi,* maliheh keshvari department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran key words: emphysematous pyelonephritis, necrotizing infection, renal parenchyma vol. 2, no. 2, 118-119 spring 2005 printed in iran introduction emphysematous pyelonephritis is a rapidly progressive acute necrotizing infection of the kidney parenchyma caused by gaseous anaerobic bacteria.(1-3) it is almost always seen in diabetic patients (more than 90% of cases) and is sometimes associated with urinary obstruction induced by renal stone, papillary necrosis, chronic infections, or kidney dysfunction.(1,3) it is bilateral only in 10% of cases.(3) here, we report a patient with bilateral emphysematous pyelonephritis. case report a 31-year-old woman with flank pain and fever of 3 days' duration was referred to our emergency department. the flank pain was vague and had increased in intensity over time. results of a physical examination revealed bilateral costovertebral angle tenderness and a distinct mass. the patient had a 9-year history of diabetes mellitus, which was under control by nph insulin, administering 32 units in the morning and 16 units in the evening (fasting blood glucose = 160 mg/dl). her family history was unremarkable. urinalysis revealed a ph of 6, glucose of 3+, 10 to12 wbc/hpf, and 13 to 16 rbc/hpf. results of a urine culture were positive for escherichia coli. results of a blood culture were negative. complete blood count (cbc) showed a wbc of 8600/µl with 83% neutrophils, 15% lymphocytes, 1% eosinophils, and 1% monocytes. hematocrit, aspartate aminotransaminase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, creatine phosphokinase, blood urea nitrogen, and creatinine were 24%, 14 iu/l, 8 iu/l, 1240 iu/l, 102 iu/l, 475 iu/l, 36 mg/dl, and 1.5 mg/dl, respectively. a kidney, ureter, and bladder plain radiograph (kub) was performed and revealed a gaseous pattern in the region of both kidneys, in which the psoas muscle was blurred. on computed tomography (ct) scan, severe destruction of the left kidney, accompanied by multifocal gas accumulations, was seen, with extension to the perirenal tissue (figure 1). decreased renal function of the right kidney and multifocal gas accumulations (less than those received august 2003 accepted july 2003 *corresponding author: school of medicine, mashhad university of medical sciences, mashhad, iran. tel: ++98 511 843 0734 fig. 1. ct scan demonstrating severe destruction of the left kidney, accompanied by multifocal gas accumulations, with extension to perirenal tissue darabi and keshvari 119 seen in the left kidney) were found in the right kidney, as well. a dimercaptosuccinic acid (dmsa) scan demonstrated a nonfunctional left kidney and right kidney with severely decreased function. the patient was treated with ceftriaxone and metronidazole and subsequently, underwent left nephrectomy because she had no response to medical treatment. grossly, a huge kidney with several necrotic foci was seen. combined treatment with ceftriaxone and metronidazole was started, postoperatively. the patient's general condition improved, her vital signs became stable, and results of a urine culture became negative. on postoperative ct scan, gas density disappeared completely in the left side and extremely decreased in the right side. the patient was discharged in good general condition on a regimen of ciprofloxacin. serum creatinine was 1.3 mg/dl, on discharge. on 5-month follow-up ct scan, complete recovery in the right kidney was seen. the patient underwent close monitoring of blood sugar and urine culture, afterwards. discussion bilateral emphysematous pyelonephritis is a rapidly progressive infection of the kidney parenchyma that is usually seen in diabetic women; juvenile diabetes mellitus has no role in its pathogenicity.(3) patients may have a prolonged history of urinary tract infection, urologic operations, or chronic pyelonephritis.(1,3,4) its symptoms are similar to those of acute pyelonephritis but are more severe, as improvement is not achieved after a 3-day course of antibiotic therapy. almost all patients experience fever, nausea, vomiting, and flank pain.(1,3,5) pneumaturia will be seen if a collecting system is involved.(3) dic, hyperglycemia, and/or diabetic ketoacidosis may be present.(6) a detectable mass may be one of the signs of the disease.(3,6) a cbc usually reveals leukocytosis with a shift to the left (immature myeloid cells), and results of urine and blood cultures may be positive.(3) confirmation of the diagnosis is radiologic (eg, gas accumulation in parenchymal, subcapsular [crescent sign], or pararenal site on ct scan, kub, or ultrasonography).(3) the kidney often has little or no function on intravenous pyelography.(3,7) ultrasonography reveals several hyperechoic foci, demonstrating the presence of gas.(3,7) ct scan is used to determine the stage of the disease, and renal scan is performed to evaluate kidney function.(3,7) three radiologic stages are observed in this disease: stage 1, blurred lucency along the kidney pyramids; stage 2, gas in the kidney parenchyma limited to gerota's fascia in a bubbled pattern; and stage 3, gas in the kidney parenchyma beyond gerota's fascia and retroperitoneum in a diffused pattern. these patients should immediately undergo wide-spectrum antibiotic therapy and careful blood sugar control. if obstructive uropathy is present, it must be relieved.(3) however, most patients do not respond to medical treatment.(8) the persistence of gas despite medical treatment demonstrates treatment failure, and other procedures (eg, surgical drainage or nephrectomy) are needed.(2) percutaneous drainage has been reported to be useful.(3) emphysematous pyelonephritis is an extremely destructive disease of the kidney, which is curable if diagnosed and treated rapidly; however, if it is unresponsive to medical treatment, then surgical drainage or nephrectomy is necessary.(2,3) in our patient, her right kidney disease was cured, but left nephrectomy was performed due to unresponsiveness to medical treatment. references 1. stamm we. urinary tract infections and pyelonephritis. in: braunwald e, fauci as, kasper dl, hauser sl, longo d, jameson jl, editors. harrison's principles of internal medicine. 15th ed. mcgraw-hill; 2001. p. 1620-7. 2. sathyanathan vp, gomathy s, potty rn, george j, pisharody r. emphysematous pyelonephritis. j assoc physicians india. 1998;46:562-3. 3. schaeffer aj. infections of the urinary tract. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 573-4. 4. goldman l, bennett jc, editors. cecil textbook of medicine. 21st ed. wb saunders; 2000. p. 613-7. 5. mcrae sn, dairiki shortliffe lm. bacterial infections of the genitourinary tract. n: tanagho ea, mcaninch jw, editors. smith's general urology. 15th ed. new york (usa): lange medical books/mcgraw-hill; 2000. p. 246-8. 6. kunin cm. urinary tract infections: detection, prevention, and management. 5th ed. baltimore: lippincott williams & wilkins; 1997. p. 202-4. 7. dunnick nr, sandler cm, newhouse jh, amis jr es. textbook of uroradiology. 3rd ed. philadelphia: lippincott williams & wilkins; 2001. p. 162-3. 8. kanjaa n, el hijri a, harrandou m, et al. [emphysematous pyelonephritis: a case report]. ann urol (paris). 2000;34:158-60. french. miscellaneous safety and efficacy of bipolar versus monopolar transurethral resection of the prostate: a comparative study erkan hirik,1 aliseydi bozkurt,1 mehmet karabakan,1* huseyin aydemir,2 binhan kagan aktas,3 baris nuhoglu1 purpose: transurethral resection of the prostate (turp) is considered gold standard for surgical treatment of benign prostatic hyperplasia (bph). in this study, we aimed to compare post-operative clinical outcomes and adverse effects between monopolar and bipolar turps. materials and methods: the study included 590 patients who underwent turp by a single urologist (e.h.) between june 2006 and june 2014 with a diagnosis of bph. patients were divided into two groups as monopolar turp (group 1, n = 300) and bipolar turp (group 2, n = 290). patients receiving oral anticoagulants or aspirin and those with prostate cancer diagnosis were not included in the study. data regarding pre-operative age, international prostate symptom score (ipss), maximum urinary flow rate (qmax), post voiding residual urine volume (pvr), serum prostate specific antigen (psa) levels and prostate volume (vp) of the patients were gathered from medical records. groups were compared in terms of catheterization, operation time, hemoglobin (hb) decrease, and ipss, qmax, and pvr values at post-operative 12th month follow-up visit. results: from pre-operative to post-operative period, ipss, qmax and pvr showed significant improvements within both groups (p < .001). when groups were compared with each other, bipolar turp group had significantly lesser catheterization time and hemoglobin decrease than monopolar turp group, while no significant differences were detected regarding all other variables. conclusion: bipolar and monopolar turps are both effective and safe treatment modality for bph. bipolar turp is superior to conventional monopolar turp in terms of catheterization time and hb decrease. keywords: prostatic hyperplasia; surgery; prospective studies; transurethral resection of prostate; methods; electrosurgery; adverse effects; hot temperature; electrocoagulation; instrumentation. introduction benign prostatic hyperplasia (bph) is one of the most common urological diseases seen in aging men. the objectives of most of the methods used in the treatment of bph are to eliminate lower urinary tract symptoms (luts), prevent disease progression, and reduce any complications that may emerge in the longterm.(1) surgical treatment is recommended for patients unresponsive to medical therapy or those who have developed bph-related complications.(2) given the longterm results of randomized controlled trials (rcts),monopolar transurethral resection (m-turp) has been considered the gold standard for surgical treatment of bph.(3) this surgical technique involves endoscopic removal of inner prostate gland using a diathermy unit. although high success rates of m-turp have been demonstrated with symptom score, urine flow rate, and other functional parameters, it is associated with 1 department of urology, mengucek gazi training and research hospital, erzincan university, erzincan, turkey. 2 department of urology, sakarya education and training hospital, sakarya, turkey. 3 department of urology, ankara numune education and training hospital, ankara, turkey. *correspondence: department of urology, mengucek gazi training and research hospital, erzincan university, basbaglar mah., mengucek gazi hospital, no. 7, erzincan, turkey. tel: +90 446 212 2222. fax: +90 446 212 2211. e-mail: mkarabakan@yandex.com. received april 2015 & accepted september 2015 significant morbidities, including perioperative and post-operative bleeding, tur syndrome, extended hospitalization and even urinary incontinence, retrograde ejaculation and erectile dysfunction.(4) therefore, several minimally invasive techniques using a variety of energy sources for resection, ablation or vaporization of the prostate have been developed in order to reduce the rates of turp complications. these techniques are thought to be similar to m-turp in terms of efficacy and safety but differ from it on some issues, such as the risk of developing tur syndrome, requirement for blood transfusion, sexual function, and urinary incontinence rates.(5) unlike the conventional m-turp system, in bipolar energy system, tur is performed after generating a high-frequency current between two electrodes. these systems are referred to as plasmakinetic resection or bipolar turp (b-turp), and their most important disvol 12 no 06 november-december 2015 2452 monopolar vs. bipolar turps-hirik et al. tinctive feature is elimination of tur syndrome risk due to the use of isotonic fluid, instead of the irrigation fluid used in conventional turp.(6) in this study, we aimed to compare post-operative clinical results and side effects of monopolar and bipolar turps. materials and methods study population of 916 patients diagnosed with bph who underwent turp performed by a single urologist (e.h.) in 3 different hospitals located in the province of erzincan from june 2006 to june 2014, 590 patients whose records were accessible were studied. patients were divided into two groups as m-turp (group 1, n = 300) and b-turp (group 2, n = 290). patients diagnosed with cancer based on pathological results, those with a history of previous prostate surgery, neurogenic lower urinary tract dysfunction and those receiving oral anticoagulants or aspirin were excluded from the study. upper limit criterion for weight of prostate wasn’t used. required ethical permissions of the study have been obtained from ethics committee of erzincan university, mengucek gazi training, and research hospital. evaluations and procedures data regarding pre-operative age, international prostate symptom score (ipss), maximum urinary flow rate (qmax), post voiding residual urine volume (pvr), serum prostate specific antigen (psa) levels, and prostate volumes (vp) of the patients were obtained from medical records. all patients received spinal anesthesia. storz resectoscope (karl storz gmbh, tuttlingen, germany) with 26 french (f) sheath was used for all patients who underwent m-turp, while gyrus plasmakinetic system resectoscope (gyrus medical ltd., bucks, uk) with 26 f sheath was used for b-turp patients. groups were compared in terms of urethral catheterization and operation time, decrease in hemoglobin (hb), and ipss, qmax, and pvr values at post-operative 12th month follow-up visit. statistical analysis statistical analysis was performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0 for windows. comparison was done using chi-square test for independent variables and the mann-whitney u test. a power analysis and multivariate regression analysis were also performed and added into the study. results there were no statistically significant differences between the two groups in terms of demographic characteristics. when intragroup pre-operative and post-operative data were compared, both groups were found to have significant improvements in ipss, qmax, and pvr (p < .001). when the groups were compared with each other, b-turp group was found to have signififigure 1. multiple regression analysis of preoperative prostate volume and hemoglobin decrease and catheterization time in monopolar turp method. abbreviations: vp, prostate volume; preop, preoperative, hb, hemoglobin; se, standard error; ci, confidence interval; r, correlation coefficient. miscellaneous 2453 cantly shorter catheterization time (b-turp 3.4 days, m-turp 3.1 days, p = .001), and less hemoglobin decrease (b-turp 16.9%, m-turp 18.5%, p = .006) as compared to m-turp group. twelve patients (4%) from monopolar group and 3 (9%) patients from bipolar group required transfusion. no differences were detected in terms of all other variables (operation time, post-operative ipss, post-operative pvr, and post-operative qmax) (table). tur syndrome as dilutional hyponatremia was observed in 2 patients (0.6%) in monopolar group, where as none of the patients from bipolar group developed tur syndrome. figure 2. multiple regression analysis of preoperative prostate volume and hemoglobin decrease and catheterization time in bipolar turp method. abbreviations: vp, prostate volume; preop, preoperative, hb, hemoglobin; se, standard error; ci, confidence interval; r, correlation coefficient. variables monopolar turp (n = 300) bipolar turp (n = 290) p value age (years) 65.3 ± 9.3 66.4 ± 9.2 .154 pre-operative ipss (0-35) 23.7 ± 4.3 23.9 ± 4.5 .632 pre-operative qmax (ml/s) 5.8 ± 2.4 5.8 ± 2.4 .840 pre-operative pvr (ml) 333.4 ± 212.3 309.1 ± 195.0 .149 pre-operative vp (ml) 63.7 ± 13.7 63.8 ± 14.1 .970 pre-operative psa (ng/ml) 3.2 ± 1.2 3.1 ± 1.3 .451 post-operative ipss (0-35) 6.1 ± 1.4 6.2 ± 1.3 .597 post-operative qmax (ml/s) 20.4 ± 2.4 20.1 ± 2.6 .254 post-operative pvr (ml) 71.8 ± 42.5 68.9 ± 40.6 .390 operation time (min) 60.6 ± 9.3 59.6 ± 9.4 .201 catheterization time (days) 3.4 ± 0.8 3.1 ± 0.7 .001 percentage change in post-operative ipss -73.6 ± 7.2 -73.4 ± 7.5 .760 percentage change in post-operative qmax 251.3 ± 118.2 234.6 ± 105.1 .085 percentage change in post-operative pvr -68.6 ± 33.1 -68.5 ± 31.6 .971 percentage change in post-operative hb -17.9 ± 7.2 -16.9 ± 6.0 .006 abbreviations: turp, transurethral resection of the prostate; ipss, international prostate symptom score; qmax, maximum urinary flow rate; pvr, post voiding residual urine volume; vp, prostate volume; hb, hemoglobin; psa, prostate specific antigen. table. comparison of data between the two study groups. monopolar vs. bipolar turps-hirik et al. vol 12 no 06 november-december 2015 2454 the sample numbers that describe catheterization time and the level of the percentage change in hb were selected by the order minimum 171 and 213 (n2/n1: 1, β = 0.20 vs α = 0.05). therefore, in accordance to the number of samples, the power indicator numbers were calculated by the order 0.961 and 0.915 in this study. upon the analysis through multiple regression between prostate scales and the length of catheterization time and also the change of %hb (independent parameter), it was obtained that 24% of the patients were under influence of such relevance (p < .001). additionally, results of spearman correlation analysis showed that there is a higher correlation between vp and catheterization time as well as the change of %hb in b-turp method than monopolar method (p < .001) (figures 1 and 2). discussion surgical treatment is recommended for patients who do not benefit from medical treatment or those who have developed complications due to bph (recurrent urinary retention, recurrent urinary tract infections, recurrent hematuria, renal failure, bladder stones, and etc.).(7) the goal of bph treatment is to improve the quality of life, reduce symptoms and minimize adverse effects.(8) tur syndrome is the greatest cause of morbidity arising during operation. it may lead to clinical conditions, including headache, restlessness, confusion, cyanosis, dyspnea, arrhythmias, hypotension, convulsion, along with dilutional hyponatremia, and may even be fatal. (9) particularly in conventional monopolar systems, glycine solution causing tur syndrome is used as irrigating fluid, while isotonic saline solution is used for the same purpose in bipolar systems. the use of isotonic irrigation fluid theoretically may lead to decreased serum na levels to a lesser extent and prevent the development of tur syndrome. however, regardless of the type of irrigation fluid, it should be noted that fluid absorption to systemic circulation is not eliminated during the operation.(6) there is no report of tur syndrome with b-turp in the literature.(10,11) in our study, tur syndrome as dilutional hyponatremia developed in 2 patients (0.6%) in the monopolar group, whereas tur syndrome was not observed in any of the patients in bipolar group. if monopolar energy will be used, it is recommended to take precautions to prevent tur syndrome such as avoiding extension of resection time (60 min), minimizing fluid pressure, and keeping the height of the fluid bag below 50 cm. a lot of work has reported that the bipolar system is reliable in terms of dilutional hyponatremia.(10-13) despite its reduction with the use of bipolar techniques, one of the turp complications is bleeding, which is seen in 5% of cases.(6) in a meta-analysis by mamualakis and colleagues(12) evaluating 12 studies, no significant difference was found between b-turp and m-turp in terms of the requirement for transfusion. similarly, ahya and colleagues(18) did not identify any significant difference in terms of the requirement for transfusion in their meta-analysis covering 10 studies; similar results were also reported in other studies.(12,14,15) there are also studies indicating that the requirement for transfusion is less in the case of b-turp group.(16,17) in the meta-analysis of mamualakis and colleagues,(12) in which they evaluated pre-operative and post-operative hemoglobin change, there was no difference between the two systems in nine studies. other studies in the literature did not identify statistically significant differences between the groups in terms of hemoglobin change.(11,13) in our study, it was revealed that the bipolar group had less hemoglobin loss, as compared to the monopolar group and 12 patients (4%) from monopolar group and 3 (9%) patients from bipolar group required transfusion. in randomized controlled trials performed in terms of catheterization time, b-turp method appears to be advantageous. however, it is not easy to compare catheterization times reported in the literature. some of the studies reported catheter removal at 24 hours after irrigation became clear, whereas some reported catheter removal in all patients immediately when irrigation became clear or on post-operative day 1, making it difficult to evaluate the results.(13,15,18) however, ahya and colleagues(18) compared catheterization times in their meta-analysis and found that b-turp has slightly shorter catheterization time. in our study, we identified that b-turp group had significantly shorter catheterization times as compared to m-turp group. in our study, mean operation times for m-turp and b-tur-p were 60.6 ± 9.3 min and 59.6 ± 9.4 min, respectively and there was no statistically significant difference between them. there was no statistical difference between the two groups, and yet a variety of findings on this issue were also reported in the literature. erturhan and colleagues(16) found shorter operation times for bipolar group. ho and colleagues(15) reported similar operation times for both groups. in a study by michielsen and colleagues,(13) bipolar group had significantly longer operation times. the reported results vary depending on factors, including the experience of the surgeon, the loop size used, the amount of resected tissue, and etc. however, in our study, all patients underwent surgery by the same surgeon, making this study valuable and meaningful in this respect. monopolar vs. bipolar turps-hirik et al. miscellaneous 2455 conclusions according to our results, b-turp and m-turp systems were found to have similar outcomes in the post-operative period. both methods proved to be effective and safe in the treatment of bph. we determined that b-turp is superior to conventional m-turp in terms of catheterization time and hb decrease. conflict of interest none declared. references 1. wilt tj, n’dow j. benign prostatic hyperplasia. part 2-management. bmj. 2008;336:206-10. 2. kaplan sa. update on the american urological association guidelines for the treatment of benign prostatic hyperplasia. rev urol. 2006;8(suppl4):s10-s7. 3. aua practice guidelines committee. aua guideline on management of benign prostatic hyperplasia (2003). chapter 1: diagnosis and treatment recommendations. j urol. 2003;170:530-47. 4. reich o, gratzke c, stief cg. techniques andlong-term results of surgical procedures for bph. eur urol. 2006;49:970-8. 5. autorino r, damiano r, di lorenzo g. fouryear outcome of a prospective randomised trial comparing bipolar plasmakinetic and monopolar transurethral resection of the prostate. eur urol. 2009;55:922-31. 6. rassweiler j, schulze m, stock c, teber d, de la rosette j. bipolar transurethral resection of the prostate-technical modifications and early clinical experience. minim invasive ther allied technol. 2007;16:11-21. 7. guidelines on benign prostatic hyperplasia; european association of urology guidelines, 2014. 8. lowe fc. goals for benign prostatic hyperplasia therapy. urology. 2002;59:1-2. 9. mebust wk, holtgrewe hl, cockett at, peters pc. transurethral prostatectomy: immediate and postoperative complications. a cooperative study of 13 participating institutions evaluating 3,885 patients. j urol. 2002;167:999-1003. 10. issa mm. technological advances in transurethral resection of the prostate: bipolar versus monopolar tur-p. j endourol. 2008;22:1587-95. 11. issa mm, young mr, bullock ar, bouet r, petros ja. dilutional hyponatremia of tur-p syndrome: a historical event in the 21st century. urology. 2004;64:298-301. 12. mamoulakis c, ubbink dt, de la rosette jj. bipolar versus monopolar transurethral resection of the prostate: a systematic review and meta-analysis of randomized controlled trials. eur urol. 2009;56:798-809. 13. michielsen dp, debacker t, de boe v, et al. bipolar transurethral resection in salinean alternative surgical treatment for bladder outlet obstruction? j urol. 2007;178:2035-9. 14. de sio m, autorino r, quarto g, et al. gyrus bipolar versus standard monopolar transurethral resection of the prostate: a randomized prospective trial. urology. 2006;67:69-72. 15. ho hs, yip sk, lim kb, fook s, foo kt, cheng cw. a prospective randomized study comparing monopolar and bipolar transurethral resection of prostate using transurethral resection in saline (turis) system. eur urol. 2007;52:517-24. 16. erturhan s, erbagci a, seckiner i, yagci f,ustun a. plasmakinetic resection of the prostate versus standard transurethral resection of the prostate: a prospective randomized trial with 1-year follow-up. prostate cancer prostatic dis. 2007;10:97100. 17. bhansali m, patankar s, dobhada s, khaladkar s. management of large (>60 g) prostate gland: plasma kinetic superpulse (bipolar) versus conventional (monopolar) transurethral resection of the prostate. j endourol. 2009;23:141-6. 18. ahyai sa, gilling p, kaplan sa, et al. meta analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. eur urol. 2010;58:384-97. monopolar vs. bipolar turps-hirik et al. vol 12 no 06 november-december 2015 2456 retained surgical gauze presenting with gross hematuria: a case report babak javanmard, mohammad reza yousefi, behrouz fadavi, morteza fallah karkan * keywords: gossipyboma; prostatectomy; surgical gauze; gross hematuria. urology department, shohadaye tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology resident, urology department, shohadaye tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. tel: +98-9111863352. e mail: mortezafallah.md@gmail.com. received october 2016 & accepted june 2017 gossipyboma is a mass which is made around a cotton sponge or abdominal compress retained in a patient during surgery accidentally. patients manifest with either acute or chronic symptoms due to complications. here in we reported an 89-year-old man case of transvesical migration of gossipyboma who presented with gross hematuria with a history of transvesical prostatectomy 6 years ago. patient underwent exploratory laparotomy with repairing of the bladder and peritoneum. he had no complications during surgery and was subsequently discharged. introduction gossipyboma (textiloma, cottonoid, gauzoma, and muslinoma) is a mass which is made around a cotton sponge or abdominal compress retained in a patient during surgery accidentally(1,2). its incidence during surgical procedures, reported in several case reports, is of about 1/1000–1500 procedures on average(3). patients manifest with either acute or chronic symptoms due to complications. each foreign body poses a challenge to the urolocase report figure 1. plain abdominal x-ray shows a retained surgical gauze (black arrow) in the abdominal cavity. figure 2. gross appearance of the retained gauze. vol 14 no 05 september-october 2017 5027 retained surgical gauze with gross hematuria-javanmard et al. gist and treatment has to be individualized according to the size and its nature and age of the patient(4). other manifestations are either exudative like granuloma around the surgical sponge/gauze, abscess formation or aseptic complications such as adhesions or encapsulation months to years after surgery(5). although open surgery is the most common approach in the treatment of gossipyboma, endoscopic extraction or other minimal invasive surgery has also been reported(6-8). herein we reported a case of transvesical migration of gossipyboma presented with gross hematuria. case description an 89-year-old man was hospitalized with chief complaint of gross hematuria for 2 days. physical examination, showed a hypogasteric tenderness and firmness in abdomen. laboratory findings were within normal limits. other examinations were normal. he had a history of open prostatectomy and bilateral hernioraphy at another hospital 6 years before admission. computed tomography scan revealed a foreign body with heterogeneous margin in the pelvis that was surrounded by bladder tissue. gauze retention in the posterior vesical fossa with migration into the bladder and peritoneal cavity was noted (figure 1). patient underwent exploratory laparotomy with repairing of bladder and peritoneum under spinal anesthesia. during operation, a gossipyboma formation, about 8 cm in size, was noted with penetration into the bladder and abdominal cavity, the gauze was embedded in the granulation tissue surrounding the gossipyboma. the gauze was removed successfully (figure 2), and the penetrated bladder and abdominal fascia was repaired. there was no complication during and after surgery, and the patient was discharged after making an uneventful recovery. discussion leaving gauze or rarely instruments behind after any surgery is a misadventure and is solely iatrogenic(9). swabs, packs, towels, or other instruments may be left in the body cavities after surgery(10). rafique in a case series mentioned that 5 of 16 patients reviewed had retained surgical gauze (31.25%) in pakistan(7). gawande et al. found that the incidence of gossipyboma and retained instruments varied from 1/8801 to 1/18760 of inpatient operations at general hospitals and it has been estimated that more than 1500 cases of retained foreign bodies occur annually in the usa(11). change in operating room staff, an emergency operation, an unexpected change in procedure, inadequate number of staff, long duration operations, hurried sponge counts, inexperienced staff, patients’ unstable conditions, obesity of patients, excessive blood loss in trauma patients, and a failure to count surgical instruments and sponges are risk factors for leaving gauze or other instruments in body cavity (11,12). the three most important risk factors are emergency surgery, unplanned change in the operation, and body mass index (2,13). here we reported a gossipyboma in vesical wall after prostatectomy which had been performed 6 years before which manifested by gross hematuria. nishikawa et al. reported a case of bladder tamponade caused by a foreign body (gauze) in the bladder of a 24-year-old man treated with the lambotte wire and screw for repair of pubic bone fracture caused by traffic accident. their case manifested after one year with gross hematuria(14). plain abdominal radiography, sonography, fistulography, ct scan and mri are useful for diagnoses(2,11). time to presentation of gossipyboma can be early or very late after surgery and with different manifestations. patients undergoing multiple abdominal surgeries with chronic abdominal pain must undergo imaging including abdominal radiography which must be considered carefully to see the surgical gauze line. in conclusion; although several cases of retained surgical gauze have been reported previously, here we presented a migration of gauze to urinary bladder which is rare and to our knowledge there is no previous reported case after prostatectomy. in our case, the chronic inflammation around the gauze made a gossipyboma that rubbed out into the urinary bladder and presented as gross hematuria. small symptom following surgeries even after many years should considered as an important clue to find the gossipyboma. it is recommended that patients are followed up carefully to decrease later mismanagement and lower the rate of gossipyboma. acknowledgement patient permission we took a written consent from patient to report his images for promotion of knowledge. references 1. zantvoord y, van der weiden rm, van hooff mh. transmural migration of retained surgical sponges: a systematic review. obstetrical & gynecological survey. 2008;63:465-71. 2. erdil a, kilciler g, ates y, et al. transgastric migration of retained intraabdominal surgical sponge: gossypiboma in the bulbus. internal medicine. 2008;47:613-5. 3. dhillon js, park a. transmural migration of a retained laparotomy sponge. the american surgeon. 2002;68:603-5. 4. van ophoven a, de kernion jb. clinical management of foreign bodies of the genitourinary tract. the journal of urology. 2000;164:274-87. 5. govarjin hm, talebianfar m, fattahi f, akbari me. textiloma, migration of retained long gauze from abdominal cavity to intestine. journal of research in medical sciences. 2009;15:54-7. 6. younesi m, ahmadnia h, asl zare m. an unusual foreign body in the bladder and percutaneous removal. urology journal. 2009;1:126-7. 7. rafique m. intravesical foreign bodies: review and current management strategies. urology journal. 2008;5:223-31. 8. lv y-x, yu c-c, tung c-f, wu c-c. intractable duodenal ulcer caused by transmural migration of gossypiboma into the duodenum-a case report and literature review. bmc surgery. 2014;14:1. case report 5028 9. cheng t-c, chou as-b, jeng c-m, chang p-y, lee c-c. computed tomography findings of gossypiboma. journal of the chinese medical association. 2007;70:565-9. 10. szentmariay if, laszik a, sotonyi p. sudden suffocation by surgical sponge retained after a 23-year-old thoracic surgery. the american journal of forensic medicine and pathology. 2004;25:324-6. 11. gawande aa, studdert dm, orav ej, brennan ta, zinner mj. risk factors for retained instruments and sponges after surgery. new england journal of medicine. 2003;348:22935. 12. sümer a, carparlar ma, uslukaya ö, et al. gossypiboma: retained surgical sponge after a gynecologic procedure. case reports in medicine. 2010;2010. 13. cruz jr rj, de figueiredo lfp, guerra l. intracolonic obstruction induced by a retained surgical sponge after trauma laparotomy. journal of trauma and acute care surgery. 2003;55:989-91. 14. nishikawa k, ohyama a, kan e, et al. [case report: a foreign body (gauze) in the bladder]. hinyokika kiyo. 1991;37:287-9. retained surgical gauze with gross hematuria-javanmard et al. vol 14 no 05 september-october 2017 5029 sexual dysfunction and infertility the effect of testicular cryoablation on testosterone level in rats: an experimental model of histopathological orchiectomy serkan ozcan,1 emre huri,1 omer gokhan doluoglu,2* tolga karakan,1 elif ozer,2 vildan fidanci,3 muzaffer eroglu,1 sema hucumenoglu1 purpose: to determine whether testicular cryoablation caused histopathological orchiectomy, and to show its effects on serum total testosterone (t-testosterone) levels in rats. materials and methods: a total of 12 wistar albino male rats were used in this study. the animals were divided into two groups, as cryoablation (9 rats) and control (3 rats) groups. bilateral cryoablation was performed in the cryoablation group. t-testosterone levels were measured in both groups before scrotal exploration. bilateral orchiectomy was performed in both groups 10 days after the cryoablation procedure. t-testosterone was measured immediately before orchiectomy. mann-whitney u test was used for intergroup comparisons. results: baseline t-testosterone levels were 1.31 (0.78-2.45) ng/ml and 0.98 (0.91-2.05) ng/ml in the cryoablation and the control groups, respectively (p = .92). t-testosterone levels were 0.23 (0.07-1.12) ng/ml and 2.87 (0.63-3.06) ng/ml in the cryoablation and the control groups, respectively, in the blood samples obtained at the time of orchiectomy (p = .03). histopathological examination of rat testes revealed varying degrees of paratesticular inflammation and necrosis in 13 of 18 testes in the cryoablation group. none of 6 testes showed necrosis in the control group. conclusion: our study showed that histopathological orchiectomy could be obtained by cryoablation in rat testes. keywords: disease models; animal; male; orchiectomy; adverse effects; rats, wistar; testosterone. introduction prostate cells physiologically depend on androgens for stimulation of their growth, function, and proliferation. testosterone is essential for the growth and perpetuation of tumor cells.(1) testis is the source of most androgens, and adrenal biosynthesis provides only 5-10% of them. this is why androgen deprivation therapy (adt) has been the main treatment option in advanced prostate cancer (pca) after huggins and colleagues.(2,3) adt can be provided through medical and surgical (bilateral orchiectomy) approaches. surgical castration has still been accepted as the gold standard when compared to the other treatment options. it provides a significant decrease in the testosterone level, and causes hypogonadism at the castration level. however, both treatment options have disadvantages. the most important disadvantage of the surgical castration is its negative psychological effect. some men may perceive this as an insult to their masculinity. the most important drawback of medical adt is its cost and its burden to national health assurance since the treatment is administered for a long time. this is why it is logical to investigate new treatment modalities that do not necessitate orchiectomy, and reach the castration level after just one intervention or procedure. in this study, we investigated whether testicular cryoablation resulted in histopathological orchiectomy, and showed its effects on total testosterone levels in rats. materials and methods study animals after the approval of local ethics committee, the study was performed in ankara education and research hospital’s animal experiment laboratory, ankara, turkey, between august 1-20, 2013, in accordance with the directives on “rules and principles of animal experiment laboratories” (nih publication no. 85-23, revised 1985). a total of 12 wistar albino male rats, weighing 250-350 g were used in this study. the rats were housed in a room at 20-24°c with a moisture of 60-70%. twelve-hour light-darkness cycle (dark: 07:00 pm 07:00 am) was provided. standard pellets were used to feed the rats, and tap water was used as drinking water. the rats were divided into two groups, as cryoablation (9 rats) and control (3 rats) groups. first, scrotal exploration was performed in both groups. blood was drawn to measure total testosterone (t-testosterone) levels in both groups before scrotal exploration. procedures the genital regions of the rats were shaved and washed with diluted benzalkonium chloride solution before surgery. the surgical field was washed with povidone iodine. a single dose of intraperitoneal ketamine was used for anesthesia, at a dose of 30 mg/kg. later, a vertical skin and subcutaneous tissue incision was done at the midline of scrotum. testes were removed after freeing gubernaculum. only scrotal exploration was departments of urology,1 pathology,2 and biochemistry,3 ankara training and research hospital, ankara, turkey. *correspondence: department of urology, ankara training and research hospital, sukriye mahallesi ulucanlar caddesi. tel: +90 533 215 7809. fax: +90 312 362 4933. e-mail: drdoluoglu@yahoo.com.tr. received november 2014 & accepted april 2015 vol 12 no 04 july-august 2015 2256 performed in the control group. scrotal exploration was done immediately before cryoablation in the cryoablation group, then bilateral cryoablation was performed using brymill cry-ac portable cryo device (figure 1). tissue freezing procedure was done with liquid nitrogen. a 21g, green, 0.8 × 38 mm injector needle was placed on the device (figure 1). the needle was stabbed to the testis, and the device was run for 5 minutes until an ice ball was generated. after 15-minutes of thawing, a second nitrogen application was performed. formation of the ice ball was seen and palpated. the testes were put back, and the incision was sutured. bilateral orchiectomy was performed in both groups 10 days after the cryoablation procedure. t-testosterone level was measured immediately before orchiectomy. a third blood sample was obtained from the survived rats for t-testosterone measurement 72 hours after orchiectomy (figure 2, flowchart). after macroscopic examination, removed testes were fixed in 10% neutral formalin solution. tissues were stained with hematoxylin & eosin, and examined by an experienced uropathologist (eo) in pathology clinic of ankara training and research hospital. according to our experiences and observations, the tissues were analyzed for necrosis, inflammation, hyperemia, and edema on histopathological examination, and they were graded as 0, 1+, 2+, or 3+ for active inflammation, hyperemia, edema and paratesticular inflammation, and necrosis (0: none, 1+: ≤ 10% of the included tissue, 2+: 10-49% of the included tissue, 3+: ≥ 50% of the included tissue). the blood samples were stored at -20°c until t-testosterone measurement. t-testosterone measurement was done using siemens advia centaur xp (siemens; erlangen, germany) device, with direct chemiluminescence immunoassay method. the normal range of total testosterone was 0.66-5.4 ng/ml for the male rats in this device. statistical analysis data analysis was performed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 11.5. mann-whitney u test was used for the intergroup analysis of continuous variables. categorical variables were analyzed with chi square test. pearson correlation coefficient were used to compare testosterone and degree of necrosis. p values < .05 were considered as statistically significant. results baseline median t-testosterone levels were 1.31 (0.782.45) ng/ml and 0.98 (0.91-2.05) ng/ml in the cryoablation and the control groups, respectively (p = .92). the median t-testosterone levels measured at the time of orchiectomy (10 days after cryoablation) were 0.23 (0.07-1.12) ng/ml and 2.87 (0.63-3.06) ng/ml in the cryoablation and the control groups, respectively (p = .03) (tables 1 and 2). six rats survived after orchiectomy, and their median t-testosterone levels were 0.05 (0.04-0.43) ng/ml in cryoablation group (4 rats) and 0.01 (0.01-0.01) ng/ml in the control group (2 rats) (p = .38). histopathological examination of the rat testes revealed various degrees of paratesticular inflammation and necrosis in 13 of 18 testes in cryoablation group. necrosis was seen in 100% of 10 testes. necrosis was not found in any of the 6 testes in the control group. there was a negative correlation between testosterone levels and the degree of inflammation and necrosis (p = .02, r = 0.74). in the control group, there were no significant findings except mild hyperemia in 3, and mild to moderate edema in 3 testes. however, high degrees of active inflammation, hyperemia, and edema were seen in cryoablation group (table 3) (figures 3 and 4). discussion androgens are needed for growth and proliferation of the prostate cells. although testosterone is not tumorigenic, tumor cells need it to proliferate and survive. androgens are mainly produced by testes. ninety to ninety-five percent of androgens are produced in testes, and 5-10% is released by the adrenal glands. apoptosis occurs in prostate cells if androgenic stimulation of the prostate cells is blocked (programmed cell death). any treatment modality that suppresses androgenic stimulation is called as adt. adt can be performed both by suppression of androgen release and by decreasing the effects of circulating androgens (androgen blockage). the treatment is called as complete androgen blockage if both methods are used simultaneously. the standard castration level is determined as < 50 ng/ml for testosterone. current chemiluminescence tests have found the mean testosterone level as 15 ng/ml after surgical castration. therefore, castration level was accepted as 20 ng/ml. adt is the primary treatment choice in advanced pca. table 1. comparison of total testosterone (t-testosterone) levels in cryoablation and the control groups. variables cryoablation group (9 rats) control group (3 rats) p value total testosterone levels before cryoablation (ng/ml) 1.31 (0.78-2.45) 0.98 (0.91-2.05) .92 total testosterone levels at the time of orchiectomy (ng/ml) 0.23 (0.07-1.12) 2.87 (0.63-3.06) .03 total testosterone levels 72 hours after orchiectomy (ng/ml) 0.05 (0.04-0.43) 0.01 (0.01-0.01) .38 variables rat 1 rat 2 rat 3 rat 4 rat 5 rat 6 rat 7 rat 8 rat 9 total testosterone levels in 0.065 0.23 0.076 0.67 0.13 0.29 0.12 0.38 1.12 cryoablation group (ng/ml) total testosterone levels in 0.63 2.87 3.06 _____ _____ _____ _____ _____ _____ the control group (ng/ml) table 2. total testosterone (t-testosterone) levels at the time of orchiectomy in the cryoablation and the control groups. sexual dysfunction and infertility 2257 testicular cryoablation and testosterone level-ozcan et al. (2,4) adt can be performed by medical or surgical methods. bilateral orchiectomy has currently been accepted as the gold standard among other adt methods. the advantages of orchiectomy are its low cost, and easy application under local anesthesia. however, some men may perceive this operation as an insult to their masculinity.(5) long acting luteinizing-hormone releasing hormone (lh-rh) agonists are the primary agents used for medical adt. continuous stimulation of the receptors by these agents caused downregulation of lh-rh receptors, and hence, testosterone levels are suppressed. (6) however, the castration levels cannot be reached in approximately 10% of the patients. if castration level is accepted as 20 ng/ml, this value reaches to 15%. (7) flare phenomenon can be seen at the initiation of this treatment, leading to increased bone pain, bladder output obstruction, kidney obstruction and spinal cord compression. long term use of these agents brings a large economic burden to national health insurance. in europe, the money spent for the pca patients diagnosed in 2006 was 106.7-179.0 million euros. a formal meta-analysis estimated the cost-effectiveness of different adt methods in advanced pca. this study showed that the most cost-effective treatment for adt was bilateral orchiectomy. the cost-effectiveness of medical hormone therapies was found worse.(8) therefore, it may be logical to investigate cost-effective, new treatment modalities that do not necessitate orchiectomy, and reach the castration level after just one intervention or procedure. testicular cryoablation has not been performed before in order to suppress androgens. cryotherapy freezes and kills the cells. cell death occurs by protein denaturation due to dehydration, direct laceration of the cell membrane by ice crystals, and ischemia caused by vascular stasis and microthrombi. (912) cryotherapy was first used by gonder and colleagues in the field of urology in 1964 for benign prostatic hyperplasia and pca.(13) this modality has been the preferred method for treatment of localized pca in elderly patients with comorbidities.(14) in our study, normal testicular tissue was tried to be destructed by cryoablation, and the histological and biochemical results of cryoablation were analyzed. the t-testosterone level measured at the time of orchiectomy was 0.23 (0.07-1.12) ng/ml in the cryoablation, and 2.87 (0.63-3.06) ng/ml in the control groups. the values obtained in the cryoablation group have suggested that t-testosterone level can be significantly reduced after cryoablation. histopathological examination revealed varying degrees of paratesticular inflammation and necrosis in 13 of 18 rat testes in the cryoablation group. one hundred percent of 10 testes showed necrosis. necrosis is followed by fibrosis. since fibrotic testes will remain in their position, the patients will not have a perception of “testicular absence”. our results suggest that cryoablation can result in histopathological orchiectomy. when cryotherapy is used for cancer, it is important to preserve neighboring tissues while destructing the cancerous tissue. since there are no neighboring structures of testes, we suppose that cryotherapy may be a suitable option for adt. systemic inflammatory response may develop after cryoablation,(15,16) and may cause hypotension, respiratory distress, multi-organ dysfunction and intravascular coagulation due to cytokine production.(17) this response usually develops after cryoablation of masses with large table 3. histopathological findings in study groups. variables active inflammation hyperemia edema paratesticular inflammation and necrosis group 0 +1 +2 +3 0 +1 +2 +3 0 +1 +2 +3 0 +1 +2 +3 cryoablation (n = 18) 0 4 2 12 0 5 8 5 0 4 13 1 5 1 1 11 control (n = 6) 5 1 0 0 3 3 0 0 3 2 1 0 6 0 0 0 p value .0001 .001 .003 .004 figure 1. brymill cry-ac portable cryo device. figure 2. study flowchart. vol 12 no 04 july-august 2015 2258 testicular cryoablation and testosterone level-ozcan et al. volumes. none of the rats died after cryotherapy, until the time of orchiectomy in our study. conclusions our study showed that histopathological orchiectomy could be obtained in testes by cryoablation. in our opinion, cryoablation can be an alternative to medical and surgical (orchiectomy) castration in patients with advanced pca. since orchiectomy is not performed, the perception of orchiectomy as an insult to masculinity may not appear. in addition, the economic burden of the disease to national health assurance may decrease since castration levels can be reached by a single procedure, and the patients do not have to use lh-rh analogs for a long time. cryoablation can be performed in the office, under local anesthesia. as we have done, if cheap and easy-to-use systems can be made available, we suppose that cryoablation can be a logical option to achieve castration. our study is the first study one on this topic, and prospective randomized studies on a larger subject figure 3. extensive necrosis and normal histological findings in testis (hematoxylin and eosin stain × 10). figure 4. findings of mild (a), moderate (b), and severe necrosis (c). (d) extensive necrosis and severe inflammation (hematoxylin and eosin stain × 40). group are needed to further clarify this issue. conflict of interest none declared. references 1. berman dm, rodriguez r, veltri rw. development, molecular biology and physiology of the prostate. campbell-walsh urology. 10th edn. in:wein aj, kavoussi lr, novick ac et al (eds). elsevier 2012. p. 253369. 2. huggins c, stevens re jr, hodges cv. studies on prostate cancer. ii. the effect of castration on advanced carcinoma of the prostate gland. arch surg. 1941;43:209-23. 3. sharifi n, gulley jl, dahut wl. androgen deprivation therapy for prostate cancer. jama. 2005;294:238-44. 4. huggins c, hodges cv. studies on prostatic cancer. i. the effect of castration, of estrogen and of androgen injection on serum phosphatase in metastatic carcinoma of the prostate. j urol. 2002;167:948-51. 5. kordan y. hormone therapy in metastatic prostate cancer. turk urol sem. 2010;1:195200. 6. klotz l, boccon-gibod l, shore nd et al. the efficacy and safety of degarelix : a 12-month, comparative, randomized, open-label, parallelgroup phase iii study in patients with prostate cancer. bju int. 2008;102:1531-38. 7. morote j, planas j, salvador c, raventos cx, cetalan r, reventos j. individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy. bju int. 2009;103:332-35. 8. bayoumi am, brown ad, garber am. costeffectiveness of androgen supression therapies in advanced prostate cancer. j natl cancer inst. 2000;92:1731-39. 9. fahmy we, bissada nk. cyrosurgery for prostate cancer. arch androl. 2003;49:397407. 10. rees j, patel b, macdonagh r, persad r. cryosurgery for prostate cancer. bju int. 2004;93:710-14. 11. han kr, belldegrun as. third-generation cryosurgery for primary and recurrent prostate cancer. bju int. 2004;93:14-8. 12. beerlage hp, thüroff s, madersbacher s, et al. current status of minimally invasive treatment options for localized prostate carcinoma. eur urol. 2000;37:2-13. 13. kim jm, luo l, zikrin br. caspase-3 activation is required for leydig cell apoptosis induced by ethane dimethanesulfonate. endocrinology. 2000;5:1846-53. 14. batur af, acar c, sozen s. cryoablation in sexual dysfunction and infertility 2259 testicular cryoablation and testosterone level-ozcan et al. prostate cancer. turkiye klinikleri j urol. 2008;1:79-89. 15. chapman wc, debelak jp, blackwell ts, et al. hepatic cryoablation-induced acute lung injury: pulmonary hemodynamic and permeability effects in a sheep model. arch surg. 2000;135:667-72. 16. washington k, debelak jp, gobbell c, et al. hepatic cryoablation-induced acute lung injury: histopathologic findings. j surg res. 2001;95:1-7. 17. seifert jk, stewart gj, hewitt pm, bolton ej, junginger t, morris dl. interleukin-6 and tumor necrosis factoralpha levels following hepatic cryotherapy: association with volume and duration of freezing. world j surg. 1999;23:1019-26. vol 12 no 04 july-august 2015 2260 testicular cryoablation and testosterone level-ozcan et al. female urology gender preferences for urologists: women prefer female urologists sun-ouck kim*, taek won kang, dongdeuk kwon purpose: to investigate patients’ preferences for the gender of their urologist. materials and methods: patients who visited a urologic center were asked to complete a self-administered questionnaire on the preferences for the gender of their urologist as well as on their age, education level and employment status. results: of 270 respondents, 144 subjects (53%) had a preference for the gender of their urologist, whereas 126 subjects (47%) had no preference. among 154 female respondents, 56 (36.4%) patients had no preference; 96 (62.3%) patients had preferences for female urologists; and only 2 (1.3%) patient preferred male urologists. among 116 male respondents, 70 (60.3%) patients had no preference; 30 (25.9%) patients had preferences for male urologists; and 16 (13.8%) preferred female urologists. of patients that did express a preference, 87.5% (126/144) preferred the same gender urologist, with 65.2% (30/46) of male patients preferring male urologists and 97.9% (96/98) of female patients preferring female urologists (p < .001). however, age and education level were not correlated with gender preference. conclusion: more than half the female participants had a preference for the same gender of urologist, whereas the majority of male participants expressed no preference for the gender of their urologist. furthermore, gender preference was not correlated with age and education level. keywords: gender; preference; urologist. introduction in korea, urology remains a male-dominated profes-sion. however, in urology in korea, the number of women applying for residency positions has increased over the recent years. in 2013, 7 of 235 urology residents (2.98 %) and 3 of 96 board certified urologists (3.13 %) were female. many patients show preferences towards the gender of their health-care physician. for instance, some studies have shown patients’ preferences for the gender of their doctors of different specialties including primary care medicine, gynecology and breast surgery.(1-3) in most previous studies, among patients who did have a preference for the gender of their physician, females were more likely to prefer the same gender doctor.(1-3) in another study, women were shown to prefer women physicians for breast, genital, or anal examinations, because they feel that they would be less embarrassed with women.(1,4) however, on the contrary, there have been reports showing that the majority of patients have no preference for the gender of their doctors.(4-7) because urology consultations usually include a pelvic examination, it is expected for female patients to prefer urologists of the same gender. nowadays, patients have shown a growing interest in their choice of the gender of their urologist who will perform the urology examination and treatment. physician sensitivity to this issue is extremely important because gender preferences have been shown to possibly impact patients’ compliance with urology procedures. tempest et al. identified whether patients in uk express preferences for the gender of their urologist and showed that the majority of patients had no preference.(6) we evaluated patients’ preference for the gender of their urologist according to occupation, age, education, and gender in korea which is a country with a different cultural basis from european countries and with a smaller number of women urologists. nowadays, an increasing number of female residents are working in the department of urology than ever before in korea. this is the first analysis of gender preferences for urologists in our country, and this could be useful in estimating the potential future demand for female urologists. materials and methods study design the study was conducted from january 2015 to december 2015 at outpatient urology clinics in chonnam national university hospital. research staff gave questionnaires to patients who visited urologic clinics. most patients complained of voiding difficulty as the main symptom. after an interview with the investigator, patients were orally instructed about study objectives and gave informed consent before completing the questionnaire. patients unwilling to complete the survey were excluded. research staff was present to assist patients department of urology, chonnam national university medical school, gwangju, korea. *correspondence: department of urology, chonnam national university hospital and medical school 8, hak-dong, dong-ku, gwangju #501-757, south korea. telephone: +82-62-220-6702. fax: +82-62-227-1643. e-mail: seinsena@hanmail.net. received july 2016 & accepted january 2017 female urology 3018 with completion of the questionnaire if they could not read/write the korean language. all participants provided written informed consent with data collection and received approval from the local ethics committee and the institutional review board of chonnam national university hosptial. the procedure of this study complied with the guidelines provided by the declaration of helsinki. questionnaire patients were asked regarding their gender, age, occupation and educational level. the question, “if you can choose the doctor at the medical consultation, who do you want to see?” gave three options for the gender preference of their urologist – male, female or no preference. each patient was asked about their gender preference for who will perform the next urology medical treatment. moreover, each patient was asked about their gender preference for who will perform their next urology surgical treatment. in total, 7 responses were required in the questionnaire (see appendix). statistics statistical analysis of data was performed using spss 11.5 software, and differences in urologist-gender preference were analyzed using the ≥2 tests and t-tests. univariate analysis was used to study the independent effect of different variables. for age, results are expressed as mean and standard error (±se). a p value < 0.05 was considered statistically significant. variables n(%) gender female 154 (57) male 116 (43) age (years) 20-29 34 (12.6) 30-39 70 (25.9) 40-49 48 (17.8) 50-59 50 (18.5) 60-69 68 (25.2) education 4 weeks apart) which were carried out as described in the world health organization (who) manual (who 1999).(11) hormone analyses blood samples were taken from antecubital vein at morning in fasting situation. hormones were measured using commercially available kits. serum fsh concentrations were measured by an immunoenzymatic assay with two monoclonal antibodies (immuno 1; technicon, bayer, tarrytown, ny, usa), and the data were expressed in terms of international reference preparations (irp)78/549. the sensitivity of the assay was 0.1 iu/l, and the inter-assay coefficient of variation was 2.7%. plasma testosterone was analyzed by a radioimmunoassay (diagnostic products ltd, wales, uk), according to the manufacturer’s instructions. dimeric inhibin b was measured by a solid-phase sandwich enzyme-linked immunosorbent assay, which used two monoclonal antibodies (serotec, oxford, uk). fluorescent polymerase chain reaction (flpcr) four multiplex fl-pcr formats were developed, including a total of 28 different primer pairs to screen different loci dispersed on azf a, b, and c, sry, zfx/ zfy and the y distal heterochromatin region. pcr was performed on genomic dna extracted from peripheral blood cells, and the products were visualized by agarose gel electrophoresis as previously described.(12) microdissection tese the microtese procedure was performed under a 20 to 40 × magnification operating microscope. an attempt was made to identify individual seminiferous tubules that were larger and more opaque than other tubules in the testicular parenchyma. small samples (15–20 mg from each testis) were excised from the larger, more opaque tubules. sperm retrieval each sample was placed in a petri dish filled with 0.5 ml of human tubal fluid (htf) medium, minced and shredded using sterile glass slides. then, each sample was examined immediately by placing a small droplet figure 1. percentage of positive testicular sperm extraction (tese) according to the histologic classification. figure 2. family history as an independent predictive factor for sperm retrieval. abbreviation: tese, testicular sperm extraction. of the dispersed tissue suspension on a slide under a phase microscope using 200 × magnification for the presence of testicular sperm. a small sample was taken for histological diagnosis. histopathology tissue sections were fixed in bouin's solution, stained with hematoxylin andeosin, and examined by the same expert pathologist under the microscope. testicular histology was classified as previously reported into hypospermato genesis, maturation arrest (ma) and sertoli cell only (sco).(13) the testicular histology was scored on a scale of 1-10 according to the method of johnson. (14) statistical analysis the statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0 was used for the statistical analysis. power analysis was performed. the clinical factors were analyzed with the independent sample t-test, mann whitney u, chi-square, multivariate regression analysis, and fisher’s exact tests. the receiver operating characteristic (roc) curve analysis was used to determine the best cutoff values. a value of p < .05 was considered statistically significant. results a total of 191 patients underwent microtese. the sample size was adequate for a power size of 80% and alpha of 0.05 according to the power analysis for regression (n = 191). the mean age of the patients was 34.4 ± 5.6 years; the mean age was 33.8 ± 5.4 years in the unsuccessful group and 34.9 ± 5.8 years in the successful group. the sperm retrieval was successful in 104 patients and unsuccessful (no sperm found) in 87 patients. the overall sperm retrieval rate was 54.5%. table 1. characteristics of study subjects variables microdissections testicular sperm extraction p value all patients unsuccessful group (n = 87) successful group (n = 104) age (years) 34.4 ± 5.6 33.8 ± 5.4 34.9 ± 5.8 .203 duration of infertility (years) 7.8 ± 5.1 7.56 ± 4.8 8.1 ± 5.3 .512 testicular size (ml) 9.74 ± 8.09 7.22 ± 6.1 11.7 ± 8.9 .001* endocrine profile fsh (miu/ml) 21.1 ± 15.1 24.9 ± 15.2 17.5 ± 14.1 .001* lh (miu/ml) 8.9 ± 6.5 11.0 ± 7.5 7.1 ± 4.9 .001* free testosterone (pg/dl) 13.1 ± 8.4 11.1 ± 7.2 14.7 ± 8.9 .004* total testosterone(ng/ml) 420.3 ± 265.1 367.5 ± 258.7 468.7 ± 263.7 .023* prolactin (ng/dl) 13.2 ± 18.1 11.3 ± 7.4 14.9 ± 24.1 .617 inhibin-b (pg/dl) 134.5 ± 144.7 114.4 ± 139.5 153.5 ± 148.1 .078 histopathology (johnsen score) 4.0 ± 2.8 2.5 ± 1.5 5.4 ± 3.1 .000* y-chromosome microdeletions, % no 89.7 99.0 yes 10.3 1.0 .006* patient with varicocele, % no 83.5 83.7 yes 16.5 16.3 .982 previous inguinal and scrotal surgery no 52.9 54.8 yes 47.1 45.2 .672 family history negative 73.6 82.8 positive 26.4 17.2 .144 abbreviations: lh, luteinizing hormone; fsh, follicle stimulating hormone. * statistically significant. evaluation of microdissection testicular sperm extraction results-cetinkaya et al. vol 12 no 06 november-december 2015 2438 according to the histological evaluation, the frequency of sco, ma and hypospermatogenesis was 48.7%, 22.7%, and 28.6%, respectively (figure 1). comparison between the successful and unsuccessful outcomes the values for the 13 clinical factors, which were analyzed using student’s t-test, mann whitney u, chisquared and fisher’s exact tests are shown for the successful and unsuccessful microtese groups in table 1. seven factors, which were testicular size (volume), johnson score, y chromosome microdeletion, and serum fsh, lh, ft and tt levels, were significantly different between the groups according. however, the varicocele, previously inguinal and scrotal surgery, and family history ratios were similar between the groups (table 1). the karyotype analysis of the patients (191) revealed that 6 patients had klinefelter syndrome (47xxy). remaining patients had normal karyotypes (46-xy). sperm was found in one patient (20%) with klinefelter syndrome. the y chromosome microdeletion screen of the 191 sexual dysfunction and infertility 2439 patients revealed that 10 (5.2%) patients had a y chromosome microdeletion (azf deletion). one of these patients was in the successful group, and the other nine were in the unsuccessful group. the distribution of the azf deletion regions was 5 azf-c, 1 azf-b, 2 azfbc, 1 azf-abc, and 1 azf-ac. best cutoff predicted probability with respect to sensitivity and specificity with roc curve of the seven clinical factors, the y chromosome microdeletion results were excluded, and the roc analysis was performed for 6 clinical factors. these analyses are shown in table 2. the best cutoff value of the serum fsh concentration for discriminating between successful and unsuccessful tese was 15 miu/ml (sensitivity 75%, specificity 51.2%, p = .001), with an area under the curve (auc) of 0.656. the best cutoff value of the serum lh concentration for discriminating between successful and unsuccessful tese was 7.5 miu/ml (sensitivity 63.1%, specificity 63.9%, p = .001), with an auc of 0.666. the best cutoff value of the serum ft concentration for discriminating between successful and unsuccessful tese was 11 pg/dl (sensitivity 66.7%, specificity 63.4%, p = .004), with an auc of 0.355. the best cutoff value of the serum tt concentration for discriminating between successful and unsuccessful tese was 400 ng/ml (sensitivity 52.2%, specificity 60%, p = .023), with an auc of 0.648. the best cutoff value of the testicular size for discriminating between successful and unsuccessful tese was 10 ml (sensitivity 77.8%, specificity 49%, p = .002), with an auc of 0.658. the best cutoff value of the johnson score (range 1 to 10) for discriminating between successful and unsuccessful tese was 2 (sensitivity 71.2%, specificity 74.7%, p = .001), with an auc of 0.79. multivariate analysis independent predictive factors were detected by multivariate and regression analyses for the presence of table 2. best cutoff predicted probability with respect to sensitivity and specificity with receiver operating characteristic curve. variables auc (95% ci) best cutoff value sensitivity % specificity % p value ppv npv ln+ lntesticular size (ml) 0.658 10 77.8 49 .002 0.62 0.38 1.65 1.60 fsh (miu/ml) 0.656 15 75 51.2 .001 0.60 0.40 1.52 1.47 lh (miu/ml) 0.666 7.5 63.1 63.9 .001 0.50 0.49 1.03 1.00 free testosterone (pg/dl) 0.652 11 66.7 63.4 .004 0.52 0.48 1.08 1.05 total testosterone (ng/ml) 0.648 400 52.2 60 .023 0.47 0.53 0.89 0.86 histopathology 0.790 2 71.2 74.7 .000 0.49 0.50 0.99 0.96 (johnsen score) abbreviations: lh, luteinizing hormone; fsh, follicle stimulating hormone; ppv, positive predictive value; npv, negative predictive value; lr+, positive likelihood ratios; lr−, negative likelihood ratios; auc, area under the curve; ci, confidence interval. figure 3. the sperm-found ratios according to the testicular histology. abbreviations: tese, testicular sperm extraction; sco, sertoli cell only syndrome; sa, spermatogenesis arrest. evaluation of microdissection testicular sperm extraction results-cetinkaya et al. sperm in the tese. two different models were used for the analysis. the first model included all parameters (fsh, lh, testicular volume, inhibin b, family history, tt, ft, azf deletions, prolactin, varicocele presence, and patient age) for the unknown testicular pathologic evaluation. in addition to the above mentioned parameters, model two included the testicular johnson score and histology of the patients who previously underwent testicular biopsy. according to model one, fsh, tt, family history, and y chromosome microdeletions were independent predictive parameters for sperm retrieval (table 3). furthermore, in model two for patients who previously underwent testicular biopsy, the johnson score, tt, family history, and y chromosome microdeletions (except for the azf c microdeletion) were determined to be independent predictive factors for sperm found (table 3). a positive family history was also found to be an independent predictive factor for sperm retrieval (figure 2). according to the testicular histology, the sperm-found ratios were 36%, 48.6%, and 95.5% in the sco, ma and hypospermatogenesis groups, respectively (figure 3). discussion the first treatment modality of cases with noa is tese combined with icsi. the success rates were between 24% and 81% in patients with noa.(13) unsuccessful microtese can cause psychological, financial and physical distress in couples. therefore, determining predictive factors for successful sperm retrieval has become important. similar studies were conducted previously to determine predictive factors in patients with noa, and different formulas were developed by various authors.(10) in many studies, the testicular size, endocrine profile, testicular histology, patient history, and genetic evaluation were considered to be predictive factors.(8,10) in terms of sperm retrieval techniques, the success of microtese compared with conventional tese has been reported in the literature.(4,15) there was a negative correlation between elevated fsh and lh levels and spermatogenesis. increasing fsh and lh levels were found to have poor predictive values for successful tese.(8) in our study, we found statistical differences in the serum fsh and lh levels between the successful and unsuccessful groups (table 1). the best cutoff points for fsh and lh were calculated to be 15 mul/ml (sensitivity 75%, specificity 51.2%, p = .001) and 7.5 mul/ml (sensitivity 63.1%, specificity 63.9%, p = .001), respectively. in contrast, similar studies did not suggest these results.(9,16,17) additionally, lh was not found to be predictive factor for tese in each regression model. however, fsh was determined to be an independent predictive factor for sperm found in regression model one, which did not include testicular histology. in model two, fsh did not affect the success of tese because the fsh was already reflected in the testicular histology and was highly correlated with the johnson score. the total testosterone level was found to be an independent predictive factor for sperm found in published studies.(10) in the present study, we also found that total testosterone was an independent predictive factor for sperm retrieval in each regression model, and we detected significantly different levels between the groups in the chi-square test (table 1). inhibin b is accepted as reflecting spermatogenesis. it is secreted primarily from sertoli cells, and the serum inhibin b level reflects the function of the seminiferous tubules. it also has a negative feedback regulatory role between hypophysis and the gonads.(18) published studabbreviations: lh, luteinizing hormone; fsh, follicle stimulating hormone;ci, confidence interval; tt, total testosterone. models factor coefficients 95% ci p value model 1 constant .757 .535 .980 .000 r square 0.42 fsh -.013 -.020 -.006 .000 tt .001 .000 .001 .005 positive family history -.387 -.624 -.149 .002 y chromosome microdeletion -.440 -.795 -.085 .016 model 2 constant .360 .051 .668 .023 r square 0.68 johnson .220 .109 .332 .000 positive family history -.355 -.562 -.149 .001 y chromosome microdeletion -.472 -.813 -.131 .008 tt .001 .000 .001 .024 table 3. regression analysis models and independent predictive factors that reflect possibility of sperm retrieval. evaluation of microdissection testicular sperm extraction results-cetinkaya et al. vol 12 no 06 november-december 2015 2440 ies indicate that serum inhibin b combined with fsh is a more sensitive marker than either serum fsh or inhibin b alone for disturbed spermatogenesis in men.(8,16,19) some studies confirm that when inhibin b is used alone or together with fsh, it cannot predict sperm retrieval from testicular tissue samples.(10) however, inhibin b values cannot predict the type of spermatogenic damage. in addition, many studies have shown that in cases with focal sco, the inhibin b and fsh rates are normal.(16,19,20) meachem and colleagues found that using inhibin b alone or in combination with fsh cannot be helpful to decide whether to perform tese on a patient. (21) in a study conducted by ballesca and colleagues, inhibin b could discriminate between successful and unsuccessful tese.(22) the difference between successful and unsuccessful tese in cases with noa compared with the control group, as determined by roc analysis, was 40 pg/ml inhibin b, with a sensitivity of 90% and specificity of 100%. pierik and colleagues also reported that serum inhibin b levels were significantly correlated with testicular biopsy scores and argued that inhibin b was the best available spermatogenetic serum marker. (23) bellesca and colleagues reported that it is necessary to evaluate inhibin b in addition to the fsh level and karyotype analysis before performing tese on a man with noa.(22) in contrast, many studies showed that inhibin b did not have any role in predicting the presence of sperm before the tese.(16,24) in our study, the mean inhibin b levels were 153.5 pg/ ml and 114.4 pg/ml in the successful and unsuccessful groups, respectively. there was no significant difference between the successful and unsuccessful groups in terms of the mean serum inhibin b level (table 1). in the multivariate regression analysis, inhibin b was not found to be an independent predictive factor and thus cannot reflect sperm retrieval in either model. in our study, the inhibin b levels were different between each histopathological group (kruskal-wallis test p = .01). the inhibin b level appeared to reflect testicular histopathology, but the distribution of the inhibin b level was non-parametric, meaning a wide variety and irregular distribution. for this reason, the inhibin b level may not be an independent predictive factor in the regression model. the published data support this interaction between inhibin b and testicular histology. erkardstein and colleagues detected different inhibin b levels according to the testicular histology.(16) therefore, the sperm found rate was approximately 68% explained by model two. the y chromosome microdeletion is a reason for the spermatogenesis failure that causes male infertility. after klinefelter syndrome, y chromosome microdeletions are the second most common genetic reason for male infertility.(25) over the last ten years, many studies that defined microdeletions in infertile patients have been performed, and the molecular diagnosis of deletions has been a routine diagnostic test for male infertility. the incidence of y chromosome microdeletions ranges widely, between 1% and 55%. this rate has been reported as 15-20% in males with noa. the highest deletion rate is reported for the azoospermic patient group.(26,27) in our study on patients with noa (n = 191), ten patients (5.2%) had a y chromosome microdeletion, with only one (1%) of these individuals in the successful tese group and nine (10.7%) in the unsuccessful group. between these two groups, there was a significant difference (p = .006) with respect to genetic damage. in one patient with a deletion (azf-c deletion), sperm was found. in addition to the existence of a deletion, the location of the deletion is also important because sperm can be retrieved in those patients with an azf-c deletion.(28) recently, tese has not been advised for patients with azf-a or azf-b deletions. y chromosome microdeletion analysis has been suggested as a routine test before tese for azoospermic or severe oligozoospermic patients.(28,29) additionally, a positive family history (e.g., aborted, dead, malformed, mentally retardation children) was detected in 28% of the infertile population relatives.(30) positive family history means: if the patients relatives have infertility history or death, aborted, and mentally retarded child. that means abnormal reproduction. however, a positive family history was not evaluated as an independent predictive factor for the success of microtese. in this study, we determined that a positive history was an independent predictive factor for sperm retrieval (table 3). sperm was most likely present in patients without a positive family history (figure 2). the chi-squared test for family history was insignificant, but in multivariate analysis, a negative family history was an independent high positive predictive factor for the sperm found group. this study is the first to demonstrate that family history is an independent predictive factor for the success of microtese using multivariate analysis. underlying genetic abnormalities other than y chromosome microdeletions should affect spermatogenesis because the multivariate analysis showed that both azf microdeletions and family history were found to be predictive factors for sperm retrieval. in this study, we concluded that genetic abnormalities significantly affect the tese results except for azf microdeletions or karyotype. there was a relationship between testicular volume and evaluation of microdissection testicular sperm extraction results-cetinkaya et al. sexual dysfunction and infertility 2441 spermatogenesis. however, this relationship between testicular volume and pathology was not correlated under some conditions because topographic changes can occur.(10) previous studies demonstrated that testicular volume was not an independent predictive factor for sperm retrieval.(7,9) in the present study, we found that the testicular volume was higher in the successful group than in the unsuccessful group but that the testicular volume was not an independent predictive factor in the multivariate analysis. in a recent study, the best cutoff value for testicular volume was calculated to be 10 ml. ziaee and colleagues reported that testicular volume was a predictive factor for sperm retrieval and that the best cutoff value was 9.5 ml.(8) although there were testicular topographic differences, this observation did not alter our significant differences between testicular volume and sperm retrieval. testicular histology was one of the most important predictive factors for sperm retrieval.(31) the published data demonstrated that the probability of finding mature spermatozoa during tese was significantly affected by the testicular histology. the best sperm retrieval rates occurred in patients with hypospermatogenesis, and low rates were found in patients with sco.(32) in our study, we demonstrated similar findings: histology and the johnson score were determined to be predictive factor for sperm retrieval according to our multivariate analysis. but we don’t recommend testicular biopsy before microtese. because bad testicular histology is not contraindication for micro tese. known testicular histology can help to predict outcomes and we can share our predictions to the family. and also based on testicular histology, redo microtese can be recommended if first microtese was negative. conclusions according to our results, fsh and tt levels, family history, and y chromosome microdeletion are independent predictive factors for sperm retrieval. furthermore, previous testicular biopsy, johnson score, tt level, family history, y chromosome microdeletions, and inhibin b are independent predictive factors for sperm found. for the first time, we demonstrated that family history is a novel independent predictive factor for microtese. conflict of interest none declared. references 1. hamada aj, esteves sc, agarwal a. a comprehensive review of genetics and genetic testing in azoospermia. clinics (sao paulo). 2013;68 suppl 1:39-60. 2. craft i, bennett v, nicholson n. fertilising ability of testicular spermatozoa. lancet. 1993;342:864. 3. schoysman r, vanderzwalmen p, nijs m, segal-bertin g, van de casseye m. successful fertilization by testicular spermatozoa in an invitro fertilization programme. hum reprod. 1993;8:1339-40. 4. tsujimura a, matsumiya k, miyagawa y, et al. conventional multiple or microdissection testicular sperm extraction: a comparative study. hum reprod. 2002;17:2924-9. 5. silber sj, van steirteghem ac, devroey p. sertoli cell only revisited. hum reprod. 1995;10:1031-2. 6. devroey p, liu j, nagy z, et al. pregnancies after testicular sperm extraction and intracytoplasmic sperm injection in nonobstructive azoospermia. hum reprod. 1995;10:1457-60. 7. tsujimura a. microdissection testicular sperm extraction: prediction, outcome, and complications. int j urol. 2007;14:883-9. 8. ziaee sa, ezzatnegad m, nowroozi m, jamshidian h, abdi h, hosseini moghaddam sm. prediction of successful sperm retrieval in patients with nonobstructive azoospermia. urol j. 2006;3:92-6. 9. tunc l, kirac m, gurocak s, et al. can serum inhibin b and fsh levels, testicular histology and volume predict the outcome of testicular sperm extraction in patients with nonobstructive azoospermia? int urol nephrol. 2006;38:629-35. 10. tsujimura a, matsumiya k, miyagawa y, et al. prediction of successful outcome of microdissection testicular sperm extraction in men with idiopathic nonobstructive azoospermia. j urol. 2004;172:1944-7. 11. world health organization. who laboratory manual for the examination of human semen and sperm-cervical mucus i̇nteraction. 4 th ed. cambridge: cambridge university press; 1999. 12. karadayı h, ozkan s, saglam y, et al. outcome of 732 infertile men for y chromosome microdeletions and karyotype analysis. paper presented at: 13th world congress on invitro fertilization assisted reproduction & genetics. istanbul, turkey, may 26-29, 2005. 13. ezeh ui, moore hd, cooke id. a prospective study of multiple needle biopsies versus a single open biopsy for testicular sperm extraction in men with non-obstructive azoospermia. hum reprod. 1998;13:3075-80. 14. johnsen sg. testicular biopsy score count--a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. hormones. 1970;1:2-25. 15. schlegel pn. testicular sperm extraction: evaluation of microdissection testicular sperm extraction results-cetinkaya et al. vol 12 no 06 november-december 2015 2442 microdissection improves sperm yield with minimal tissue excision. hum reprod. 1999;14:131-5. 16. von eckardstein s, simoni m, bergmann m, et al. serum inhibin b in combination with serum follicle-stimulating hormone (fsh) is a more sensitive marker than serum fsh alone for impaired spermatogenesis in men, but cannot predict the presence of sperm in testicular tissue samples. j clin endocrinol metab. 1999;84:2496-501. 17. ramasamy r, lin k, gosden lv, rosenwaks z, palermo gd, schlegel pn. high serum fsh levels in men with nonobstructive azoospermia does not affect success of microdissection testicular sperm extraction. fertil steril. 2009;92:590-3. 18. pineau c, sharpe rm, saunders pt, gerard n, jegou b. regulation of sertoli cell inhibin production and of inhibin alpha-subunit mrna levels by specific germ cell types. mol cell endocrinol. 1990;72:13-22. 19. bohring c, krause w. serum levels of inhibin b in men with different causes of spermatogenic failure. andrologia. 1999;31:137-41. 20. foresta c, bettella a, rossato m, la sala g, de paoli m, plebani m. inhibin b plasma concentrations in oligozoospermic subjects before and after therapy with follicle stimulating hormone. hum reprod. 1999;14:906-12. 21. meachem sj, nieschlag e, simoni m. inhibin b in male reproduction: pathophysiology and clinical relevance. eur j endocrinol. 2001;145:561-71. 22. ballesca jl, balasch j, calafell jm, et al. serum inhibin b determination is predictive of successful testicular sperm extraction in men with non-obstructive azoospermia. hum reprod. 2000;15:1734-8. 23. pierik fh, vreeburg jt, stijnen t, de jong fh, weber rf. serum inhibin b as a marker of spermatogenesis. j clin endocrinol metab. 1998;83:3110-4. 24. vernaeve v, tournaye h, schiettecatte j, verheyen g, van steirteghem a, devroey p. serum inhibin b cannot predict testicular sperm retrieval in patients with non-obstructive azoospermia. hum reprod. 2002;17:971-6. 25. simoni m, bakker e, krausz c. eaa/emqn best practice guidelines for molecular diagnosis of y-chromosomal microdeletions. state of the art 2004. int j androl. 2004;27:240-9. 26. van der ven k, montag m, peschka b, et al. combined cytogenetic and y chromosome microdeletion screening in males undergoing intracytoplasmic sperm injection. mol hum reprod. 1997;3:699-704. 27. foresta c, ferlin a, garolla a, et al. high frequency of well-defined y-chromosome deletions in idiopathic sertoli cell-only syndrome. hum reprod. 1998;13:302-7. 28. simoni m, tuttelmann f, gromoll j, nieschlag e. clinical consequences of microdeletions of the y chromosome: the extended munster experience. reprod biomed online. 2008;16:289-303. 29. omrani md, samadzadae s, bagheri m, attar k. y chromosome microdeletions in idiopathic infertile men from west azarbaijan. urol j. 2006;3:38-43. 30. maiburg m, alizadeh b, kastrop p, lock m, lans s, giltay j. does the genetic and familial background of males undertaking icsi affect the outcome? j assist reprod genet. 2009;26:297-303. 31. abdel raheem a, garaffa g, rushwan n, et al. testicular histopathology as a predictor of a positive sperm retrieval in men with non-obstructive azoospermia. bju int. 2013;111:492-9. 32. weedin jw, bennett rc, fenig dm, lamb dj, lipshultz li. early versus late maturation arrest: reproductive outcomes of testicular failure. j urol. 2011;186:621-6. evaluation of microdissection testicular sperm extraction results-cetinkaya et al. sexual dysfunction and infertility 2443 female urology neuronal nitric oxide synthase expression in the anterior vaginal wall of patients with stress urinary incontinence levent ozcan1*, emre can polat2, efe onen1, alper otunctemur2, emin ozbek2, adnan somay3, nurver ozbay3 purpose: stress urinary incontinence (sui) and pelvic organ prolapse (pop) are common medical problems, particularly among older women. in this study, we aim to explore the relationship between the neurotransmitter nnos in the vaginal epithelium, and the occurrence of sui and changes of nnos levels according to menopausal status. matherials and methods: fourty women were enrolled. the patients were divided into four groups according to menstruaiton status and sui. the vagina specimens were taken during transobturator tape application. the specimens were examined pathologically in terms of n-nos expression. nnos expression was compared between sui and control groups. the results were evaluated statistically. result: epithelial total nnos score in group 1 and group 3 were 2.4 ± 0.5 and 1.4 ± 0.5 respectively (p = .003). stromal total nnos score was found 2.2 ± 0.4 in group 1 and 1.3 ± 0.5 in group 3 (p = .001). epithelial total nnos score in group 2 and group 4 were 4.4 ± 0.5 and 3.5 ± 0.5 respectively (p = .003). stromal total nnos score was found 4.4 ± 0.5 in group 2 and 3.6 ± 0.5 in group 4 ( p = .006). conclusion: our results show that expression of nnos in the anterior vaginal epithelium decreased significantly in the sui group. altough our findings indicate important results, well designed further studies are needed to comprehend the role of nos pathways better in sui pathophysiology. key words: human vaginal tissue; nitric oxide; pathophysiology; pelvic floor disorders; stress urinary incontinence introduction stress urinary incontinence (sui) and pelvic organ prolapse (pop) are common medical problems, particularly among older women. they can have a significantly negative impact on the quality of life, and yet less than half of women with urinary incontinence seek medical attention. these two diseases have an etiologically close relationship.(1)pelvic floor tissues, including vaginal wall tissues, are rich in nerve fibers and functionally protect the normal position of pelvic organs.(2) the effects of pelvic support weakness may induce the development of sui.(3) changes in some neuropeptides in the pelvic floor tissue have been observed in sui and pop patients.(4) vasoactive intestinal peptide (vip) is one of the neuropeptides widely distributed in the vaginal wall that serves as a local neurotransmitter or neuromodulator. however, the underlying neuropathophysiology of sui is unclear. nitric oxide (no) is an anorganic free-radical gas that stimulates soluble guanylyl cyclase activity and creates smooth muscle relaxation.(5) there are three nos isoforms:, neuronal (nnos), endothelial (enos) and inducible (inos). neuronal nos (nnos) is present in neuronal tissues; neuronal excitation increases ca+2 concentration within nerves, which leads to synthesis of no from l-arginine. elucidation of the physiologic role of no and nitric oxide synthase (nos) is not only of research interest but may also provide a basis for therapeutic interventions in patients with lower urinary tract dysfunction. it is also important as a me1derince training and research hospital, department of urology, kocaeli, turkey. 2okmeydani training and research hospital, department of urology, istanbul, turkey. 3fatih sultan mehmet training and research hospital, department of pathology, istanbul, turkey. *correspondence: derince training and research hospital, department of urology, 41900 derince, kocaeli, turkey. tel: (+90) -262-317 8000. fax: (+90)262233 4641. e-mail: drleventozcan@yahoo.com. received may 2016 & accepted december 2017 diator in the female and male reproductive tracts.(6-8) in this study, we aim to explore the relationship between the neurotransmitter, nnos in the vaginal epithelium, and the occurrence of sui and changes of nnos levels according to menopausal status. patients and methods study population institutional review board approval was obtained and all participants signed an informed consent before being enrolled in the study. patients who attended our clinic with the complaints of incontinence and were detected to have sui were included in the study. to evaluate incontinence, detailed incontinence history, age, body mass index (bmi), number of deliveries and previous surgical history were recorded. on physical examination, we accessed the women for sui at gynecologic position, and we performed cough stress test. fourty women were enrolled. the patients were categorized into four groups according to menstruaiton status and sui. premenopausal sui formed group 1, premenopausal controls formed group 2 and postmenopausal sui formed group 3, postmenopausal controls formed group 4. each group had 10 cases. the vagina specimens were taken during transobturator tape application. the specimens were examined pathologically in terms of n-nos expression. the results were evaluated statistically. control groups were choosen among healty women who had surgery for benign reasons such as female urology 280 vol 15 no 05 september-october 2018 281 ureterorenoscopy or urethral caruncle. excluded from the study were women who had previous endometriosis, adenomyosis, uterine fibroids, connective tissue disorders, pelvic inflammatory conditions, or pelvic surgery. none of the patients took hormonal drugs during the 3 months before surgery. and none of the patients had pop. immunohistochemistry the tissue sections were fixed in 10% buffered formalin for about 24 h, embedded in paraffin, and 5 µm sections were then deparaffinized. then the sections were immersed in antigen retrival solution (biogenex) and treated in microwave oven for 10 minutes. after cooling, the sections were washed with phosphate buffered solution (pbs). the incubation with the primary antibody was done in a solution of 0.8% bsa and 20 mm nan3 in pbs containing the nnos–specific mouse antibody (1:100 dilution) for 1 h at room temperature. after rinsing with pbs the sections were incubated with the secondary biotinylated goat antimouse antibody for 30 min at room temperature. then, an alkalene phosphatase complex was utilized as a detection system (1:200 dilution) for another 1 hr. finaly, the staining was developed for 15 min with fast red solution and counterstained with mayer’s hematoxylin. negative controls sections were incubated in the absence of the primary antibody. the nnos immunoreactivity of the specimens were rated according to a score that was calculated using intensity and area scores. the intensity of staining was on the following scale: 0, no staining of nnos in the vagina; 1+, mild staining; 2+, moderate staining and 3+, marked staining. the area of staining was evaluated as follows: 0, no staining of in the vagina in any microscopic field; 1+, 0-25% of the vagina stains positive; 2+, 25-50% staining positive; 3+, 50-75% staining positive; 4+, 75-100% staining positive. statictical analysis all statistical analysis was performed by using spss ver. 15.0 (spss inc., chicago, il, usa). epithelial and stromal scores of nnos were compared in four groups using kruskal-wallis h test and mann-whitney u test. in all comparisons of values, p-values of less than 0.05 were considered to be statistically significant. results there were no significant differences in age, bmi (calculated as weight in kilograms divided by height in meters squared), or parity among the four groups. characteristics features of the patients are shown in table 1. nnos immunostainings were shown in the anterior vaginal wall in all groups. nnos immunostainings at different density were observed , as demonstrated by a mild, moderate, or marked staining accordingly. in women with sui, only scattered nnos with weak staining was observed. (figures 1, 2 and 3). however, in postmenopausal women without sui, the intensity and distribution of nnos decreased and showed dispersed and moderate staining (figures 4 and 5). marked epithelial and stromal staining with nnos was observed in a premenopausal patient without sui (figures 6,7). comparison of nnos expression is shown in table 1. as shown in table 1, the group with the most decreased table 1. characteristics of patients and comparison of nnos expression among the four groups. group1 group2 group3 group4 p age 47.1 ± 5.1 46.5 ± 4.1 50.2 ± 2.7 49.6 ± 2.9 .126 paritiy 3.2 ± 1.1 2.8 ± 1.4 3.2 ± 1.3 2.9 ± 1 .781 bmi (kg/m2) 30.5 ± 3.3 27.8 ± 2.9 29.6 ± 1.3 28.3 ± 2.5 .126 nnos epithelial 2.4 ± 0.5 4.4 ± 0.5 1.4 ± 0.5 3.5 ± 0.5 .001 nnos stromal 2.2 ± 0.4 4.4 ± 0.5 1.3 ± 0.5 3.6 ± 0.5 .001 nnos epithelial 2.4 ± 0.5 1.4 ± 0.5 .003 nnos stromal 2.2 ± 0.4 1.3 ± 0.5 .001 nnos epithelial 4.4 ± 0.5 3.5 ± 0.5 .003 nnos stromal 4.4 ± 0.5 3.6 ± 0.5 .006 figure 1. mild epithelial staining (1+) with nnos in a patient premenopausal with sui immunostaining x100 figure 2. mild epithelial staining (1+) with nnos in a patient postmenopausal with sui immunostaining x40 stress urinary incontinence and nnos-ozcan et al. expression of nnos is group 3. epithelial total nnos scores in group 1 and group 3 were 2.4 ± 0.5and 1.4 ± 0.5, respectively with statistically significant differences between the two groups (p = .003). stromal total nnos score was found to be 2.2 ± 0.4 in group 1 and 1.3 ± 0.5 in group 3. there were statistically significant differences between the two groups ( p = .001) (table 1) (figures 1,5) epithelial total nnos score in group 2 and group 4 were 4.4 ± 0.5and 3.5 ± 0.5, respectively with statistically significant differences between the two groups (p = .003). stromal total nnos score was found to be 4.4 ± 0.5 in group 2 and 3.6 ± 0.5 in group 4. there were statistically significant differences between the two groups ( p = .006) (table 1) (figures 3,4). discussion pelvic floor disorders (pfd),including pop and sui, are major health problems in women. the causes of pfd are multifactorial, including defect in the pelvic floor musculature and connective tissue weaknesses.(9) another study has suggested that damage to the innervation of the pelvic floor can be an important factor in the etiology of sui.(10) neuropeptides, which are considered a marker of nerve damage, are used in the study of pelvic floor dysfunction. a neuropeptide is a peptide released by different tissues, that acts as a neural messenger. neuropeptides act as neurohormones, neurotransmitters, or neural modulators. neuropeptides are widely distributed in the central and peripheral nervous system and in many areas of the human body, including the gut, pancreas, heart, lung, and genital tract.(11) neuropeptides are well-represented in the innervation of the human female reproductive tract. neurons that contain vasoactive intestinal polypeptide (vip) are abundant in the vagina, where they innervate blood vessels and smooth muscle in the vaginal wall, and form a plexus beneath the epithelial layer.(12) neuropeptide y (npy) is also abundant in neurons in the human female genital tract, and is contained in nerves innervating blood vessels, as well as in nerves that form a subepithelial plexus.(13) previous studies have shown that vip levels were significantly decreased in the anterior vaginal wall in premenopausal and postmenopausal sui or pop patients. hu et al. found that the expression of vip in the vaginal epithelium significantly decreased in pop patients.(14) in figure 5. moderate stromal staining (2+) with nnos in a patient postmenopausal without sui immunostaining x100 figure 6. marked epithelial staining (3+) with nnos in a patient premenopausal without sui immunostaining x100 figure 3. mild stromal staining (1+) with nnos in a patient postmenopausal with sui immunostaining x100 figure 4. moderate epithelial staining (2+) with nnos in a patient postmenopausal without sui immunostaining x100 stress urinary incontinence and nnos-ozcan et al. female urology 282 vol 15 no 05 september-october 2018 283 another study, falconer et al. showed that women with sui have a significantly lower total innervation of the paraurethral vaginal epithelium than controls without incontinence.(15) alm et al.(16) reported the existence of vasoactive intestinal peptide (vip) containing nerves in the vaginal wall. vip-containing nerves have been described throughout the human female genital tract, and are most abundant in the vagina, cervix, and clitoris.(2) from studies on laboratory animals it has been suggested that no may also function as a neurotransmitter in male and female genital organs, including the uterus and vagina.(17-20) and can mediate neurogenic vasodilatation. hoyle et al. reported that nerves that utilise nitric oxide, npy, vip, or cgrp as a neurotransmitter may play a role in controlling blood flow and capillary permeability in the human vagina.(21) nerve and supportive tissue injury caused by prior pregnancy and delivery increasingly deteriorates as the patients ages.(22) as a component of the “hammock” according to the theory presented by delancey(23), the anterior vaginal wall with decreased neurotransmitter content might alter the tension of the hammock, which contributes to the pathogenesis of sui. in light of previous studies we hypothesized that nos secreted by the neuropeptidergic fiber terminals take part in the pathogenesis of sui. in the present study we investigated nnos expression in the anterior vaginal wall because the anterior vaginal wall plays a more important role than the posterior vaginal wall in the etiology of sui(11). our results confirmed that nnos levels decreased significantly in the anterior vaginal wall in sui patients, supporting the possible role of nnos in the pathophysiologic process of sui. another result of this study is that, nnos expressions are related to menopausal status. compared to premanopausal control patients with postmenopausal control patients, nnos levels decreased in postmenopausal period. this result shows clearly nnos expressions is decrease in postmenopausal period. the precise mechanism for the decrease of nnos remains unclear. lower nnos in patients with sui may either be related to the lower neuronal production of nos or to age-induced nerve degeneration. another possible explanation is that nnos alterations affect the pathophysiological process via the local blood supply and nutrition state. figure 7. marked stromal staining (3+) with nnos in a patient premenopausal without sui immunostaining x100 in summary, the present study constituted a specific assessment of the relationship between nnos expression and the development of sui. the present data could not determine whether differences in nnos innervation are the cause of sui or whether they result from the pathological changes caused by sui. conclusions in sui patients, pelvic support tissue becomes weakened with age, and has a stronger correlation with nnos containing nerves. however, the underlying neuropathophysiology of sui is still unclear. the lack of western blotting analysis is a limitation of our study. well designed further studies are needed to comprehend the role of nnos pathways in sui pathophysiology. conflict of interest none declared. references 1. molander u, milsom i, ekelund p, mellström d. an epidemiological study of urinary incontinence and related urogenital symptoms in elderly women. maturitas. 1990; 12:51–60. 2. hong x, huang l, song y. role of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide in the vaginal wall of women with stress urinary incontinence and pelvic organ prolapse. int urogynecol j pelvic floor dysfunct. 2008; 19:1151–7. 3. smith ar, hosker gl,warrell dw. the role of partial denervation of the pelvic floor in the aetiology of genitourinary prolapse and stress 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41, 1103-1111, 1989. 13. jorgensen jc, sheikh sp, forman a, norgard m, schwartz tw, ottesen b. neuropeptide y in the human female genital tract: localization and biological action. american journal of physiology. 1989; 257, e220-e227. 14. hu jm, cheng x, wang l, zhu jn, zhou lh. vasoactive intestinal peptide expression in the vaginal anterior wall of patients with pelvic organ prolapse.taiwan j obstet gynecol. 2013;52:233-40. 15. falconer c, ekman-ordeberg g, hilliges m, johansson o: decreased innervation of the paraurethral epithelium in stress urinary incontinence women. eur j obstet gynecol reprod biol.1997; 72:195–198. 16. alm p, alumets j, hakanson r et al. vasoactive intestinal polypeptide nerves in the human female genital tract. am j obstet gynecol. 1980; 136:349–51. 17. kummer w, fischer a, mundel p et al. nitric oxide synthase in vip-containing vasodilator nerve fibres in the guinea-pig. neuroreport. 1992; 3, 653-655. 18. ding y-q, wang y-q, qin b-z, li j-s. the major pelvic ganglion is the main source of nitric oxide synthase-containing nerve fibers in penile erectile tissue of the rat. neuroscience letters. 1993; 164, 187-189. 19. grozdanovic z, mayer b, baumgarten hg, brutning g. nitric oxide synthase-containing nerve fibers and neurons in thegenital tract of the female mouse. cell and tissue research. 1994; 275, 355-360. 20. lincoln j, hoyle chv, burnstock g: transmission: nitric oxide. in autonomic neuroeffector mechanisms (ed. burnstock g, hoyle chv), pp. 509-539. chur: harwood academic, 1995. 21. hoyle ch, stones rw, robson t, whitley k, burnstock g.innervation of vasculature and microvasculature of the human vagina by nos and neuropeptide-containing nerves.j anat jun;188 ( pt 3):633-44, 1996. 22. kerns jm, damaserms, kane jm et al. effects of pudendal nerve injury in the female rat. neurourol urodyn. 2000; 19:53–69. 23. delancey jol: structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. am j obstet gynecol. 1994; 170:1713–23. stress urinary incontinence and nnos-ozcan et al. female urology 284 endourology and stone diseases combined use of pyelolithotomy and endoscopy: an alternative surgical treatment for staghorn urolithiasis in children beata jurkiewicz,1* tomasz ząbkowski,2 katarzyna jobs,3 joanna samotyjek,1 anna jung3 purpose: to present a combining pyelolithotomy and endoscopy, an alternative approach for treating staghorn calculi in children. materials and methods: we treated 1414 children (age, 10 months to 17 years) with urolithiasis between 2009 and 2013 in the pediatric surgery department and in the pediatrics and nephrology department, military institute of medicine in warsaw. most patients were treated conservatively. in 162 cases, an extracorporeal shockwave lithotripsy (swl) procedure was needed. surgery was only used in patients who had failed swl. we performed minimally invasive procedures, ureterolithotripsy using semi-rigid and flexible ureterorenoscopes or percutaneous nephrolithotomy (pcnl) in 126 patients. results: in the most serious cases of staghorn or multifocal calculi, we performed a combined operation of pyelolithotomy with endoscopic removal of concrements from all calyces of the diseased kidney. in 15 out of the 18 combination treatments (83.3%), concrements were completely removed from the kidney in a single procedure. in three cases, fine concrements (5 to 6 mm) remained after the procedure, and these were candidate for swl. in one case, a boy aged 4 years, symptoms of infection in the urinary tract occurred 2 days after the procedure. conclusion: combining pyelolithotomy with endoscopy to remove concrements clears the diseased kidney without causing parenchymal damage in one procedure. the method is safe in children, does not require blood transfusion, and helps maintain kidney function. keywords: child; kidney calculi; surgery; treatment outcome; urologic surgical procedures. introduction urolithiasis is a well-known and widespread dis-ease. the prevalence in europe is 5–10% in adults and approximately 2% in children. the number of new cases has increased over the past few years, especially in much younger patients, particularly those aged < 1 year.(1,2) the disease is chronic, and regression occurs within 15 years in 30 –50% of affected patients.(1,3) the management of cases with new concrement formation is especially very problematic. according to data from the medical literature, approximately 80% of concrement created in the urinary system can be excreted spontaneously.(1,4) such stones are typically 4–5 mm in diameter; however, in children, the spontaneous excretion of stones that are 9–10 mm of diameter is possible, possibly as a result of the greater elasticity of the urinary tract.(2) the duration that the concrement is present in the same location is a factor that determines its passage; after 4 weeks, the probability of spontaneous excretion is low.(5) the procedure for active concrement removal may obstruct the flow of urine from the kidney and make an individual susceptible to infection, obstruction of urine outflow from only one kidney, urinary system defects, stymied urine outflow, and inefficient analgesic treatment.(1) therefore, the need for concrement removal using one of available method performs in about 25% of all group of patients and until in half of these patients with clinical symptoms.(1) the most severe form of urolithiasis is staghorn urolithiasis with metabolic disorders which results in concrements in urinary tracts. typical stones include all calyces of the kidney and renal pelvis creating a typical ‘cast’ of tracts carrying urine from the kidney. the treatment of this type of urolithiasis is a challenge for a surgeon. the aim of the study was to present an alternative, efficient method of concrement removal from the kidney 1department of pediatric surgery, children's hospital, marii konopnickiej street 65, 05-092 dziekanów lesny, warsaw, poland. 2department of urology, military medical institute, szaserów street, 128,04-349 warsaw, poland. 3department of pediatric and nephrology, military medical institute, szaserów street, 128,04-349 warsaw, poland. *correspondence: department of urology, military medical institute, szaserów street 128,04-349, warsaw, poland. tel:+48 791 533555. e-mail: urodent@wp.pl. received september 2015 & accepted march 2016 endourology and stone diseases 2599 vol 13 no 02 march-april 2016 2600 which is possible to use within staghorn urolithiasis in children. materials and methods study population a total of 1414 patients aged 10 months to 17 years with urolithiasis were treated in the pediatric surgery department and pediatrics and nephrology department of the military institute of medicine between 2009 and 2013. of whom 1111 (78.57%) patients were treated conservatively. procedures an extracorporeal shockwave lithotripsy (swl) procedure was needed in 162 (11.45%) cases. a total of 141 (9.97%) patients with different types of urolithiasis were treated using other surgical procedures. surgical treatment was used only in the patients who were not suitable to undergo swl procedure for many different reasons. in most of these patients, minimally invasive procedures (ureterolithotripsies) were performed using semi-rigid and flexible ureterorenoscopes (urs); percutaneous nephrolithotomy (pcnl) procedures were performed in 126 (17.82%) patients. in certain serious cases of staghorn or multifocal urolithiasis including renal pelvis and at least 3 calyces (most of concrements were from 11 mm to 50 mm), we performed a combination of pyelolithotomy and endoscopic removal of concrements from all calyces of each diseased kidney (figures 1-4). inclusion and exclusion criteria the inclusion criteria were: a lack of renal stones evacuation using minimally invasive procedures, or concrements in major and distal calyces including renal pelvis. in 2009–2013, 15 (1.06%) patients aged 1.5–10 years (mean age, 6.7 years; 10 boys, 5 girls) with staghorn urolithiasis underwent pyelolithotomy with endoscopic concrement removal. there were 4 children aged under 2 years of life. twelve of these patients had unilateral urolithiasis, whereas the other three had bilateral urolithiasis (figure 2). evaluations the dominant symptom of these patients was pain in the lumbar area. recurrent urinary tract infections, urosepsis, and urinary retention were also common. before a decision on the surgical approach was made, the patients’ conditions were precisely evaluated and assessed to detect metabolic changes that may be related to the cause of the urolithiasis. the diagnoses included hyperoxaluria type i in three cases, cystinuria in four cases, and hypercalciuria in the remaining cases. the patients with cystinuria were initially qualified to conservative treatment using tiopronin and captopril with urine alkalization by potassium citrate over 7.5 ph. the children with hyperoxaluria were given vitamin b6 with high fluid intake, the urine alkalization was also used. unfortunately, this management did not protect the patients against the new concrements formation. the following basic examinations were performed in all patients: blood cell count, ionogram, urea and creatinine concentration test, urinalysis and urine culture, and assessment of urinary crystalloid excretion in urine collection samples. the presence of concrements within the urinary tract was assessed using ultrasonography. the radiological examinations included plain abdominal radiography, urography, or computed tomography with contrast. before the procedure, dynamic scintigraphy was performed to determine the excretory and secretory function of the kidneys. the conducted history results that in the majority of figure 1. the treatment’s methods used in children with urolithiasis (n =1414). abbreviations: eswl, extracorporeal shockwave lithotripsy; pcnl, percutaneous nephrolithotomy; ursl, ureterorenoscopy with lithotripsy. combined use of pyelolithotomy and endoscopy-jurkiewicz et al. children the minimally invasive procedures were earlier performed. in 9 children, swl procedures were repeatedly performed (from 2 to 5 times), in 3 cases pcnl was performed, in 4 cases retrograde intrarenal surgery (rirs) was performed. in 4 children, different possibilities of minimally invasive treatment’s ways were used, from swl procedures to urs lithotripsy (ursl), rirs and pcnl. unfortunately, these procedures were ineffective, and in the kidneys were still big concrements. the size of the concrements ranged from 11 mm to 3 -5 cm, and the concrements were numerous, varied in size, and were located in several calyces and in the pelvis. in 3 cases, staghorn urolithiasis was accompanied by hydronephrosis as well as obstruction of the urine outlet in the ureteropelvic junction. in the case of sub-pelvic stenosis, the stenosis was excised using the hynes-anderson method and pyelotomy, during which the nephroscope was introduced into the kidney. after concrement removal, plastic reconstruction of the ureteropelvic junction was performed. the pyelolithotomy procedure with endoscopic concrement removal consisted of several stages. stage 1: the kidney was accessed using lumbotomy and exposure of the renal pelvic and ureteropelvic junction. the entire kidney was not released from concretions with surrounding tissues; instead, a slanted 1–1.5 cm long incision was made in the renal pelvis to expose the concrements (figure 3). stage 2: a staghorn concrement within the renal pelvis was crushed by a pneumatic lithotripter wolf and the fragments of the concrement were removed using forceps via a small perforation made in the renal pelvis (figure 3). stage 3: after the concrements were removed from the renal pelvis, their locations within the calyces were determined using a 9 french (f) nephroscope wolf or 4.5 f ureteroscope (figure 3). stage 4: these concrements were then crushed in stages using a pneumatic, laser and ultrasound waves. the calyces were sequentially ‘cleaned’ until all of the concrements were removed from the diseased kidney. stage 5: all calyces were assessed using a nephroscope, and the catheter pig -tail was placed from the renal pelvis to the urinary bladder to ensure appropriate outflow from the kidney. the incisions made in the renal pelvis were closed by using a running suture. a drainage tube was left near the kidney. the integuments were closed lamellarly. after the procedure, the patients received secondgeneration cephalosporin within 3 days. the pig-tail catheter was removed 10 days after the procedure with the patient receiving brief intravenous anesthesia. after the procedures, blood cell count, ionogram, creatinine concentration test were performed. after the procedures, ultrasonography and plain abdominal radiography were repeated performed. these follow-up examinations were performed 1 week, 2 weeks, and 1 month after the procedure. in all children, renoscintigraphy was performed after 3 months to assess renal function after procedure. statistical analysis for the statistical analysis, the number of procedures was calculated for the retrospective (before the perfigure 2. bilateral cystine urolithiasis in boy aged 2.5 years of life. figure 3. stage 1: pyelolithotomy and concrement’s removal from renal pelvis. stage 2: concrement’s removal from upper and interior calyces. stage 3: concrement’s removal from lower calyces. combined use of pyelolithotomy and endoscopy-jurkiewicz et al. endourology and stone diseases 2601 vol 13 no 02 march-april 2016 2602 formance of this procedure) and prospective (after the performance of this procedure) phases of the study. continuous variables were compared using the wilcoxon rank-sum test. the number of procedures in residual concrements was analyzed using a kaplan-meier survival function. differences in continuous variables were expressed as mean difference (md) with 95% confidence intervals (ci). results in 15 (83.3%) cases, the concrements were completely removed from the kidney within a single procedure. the duration of procedures ranged from 90 to 300 minutes (mean, 160 minutes). in the other 3 (16.7%) cases, concrements of 5–6-mm in size remained after the procedure and required swl. symptoms of generic infection in the urinary tract occurred in only 1 patient, a 4-year-old boy, on the second day after procedure. escherichia coli was detected during culture of a urine sample. pharmacological therapy consisted of an aminoglycoside (amikacin) and a carbapenem (meropenem). none of the patients required a blood transfusion because of blood loss within surgical procedure or after it. follow-up after procedures ranged from 1 year to 5 years. at the same time, in all children, isotopic examinations of kidneys, creatinine concentration test and blood pressure were performed (table). renoscintigraphy revealed that the renal function had figure 4. intraoperative photos, the concrements in calyces of the kidneys. no. type of urolithiasis 1 day before procedure 3 months after procedure urosepsis procedures in follow-up after diagnosed in creatinine blood pressure creatinine blood pressure residual concrements procedure (months) metabolic examinations (mg/dl) (mmhg) (mg/dl) (mmhg) 1 hypercalciuria 0.22 94/60 0.2 90/60 (-) none 27 2 cystinuria 0.3 103/69 0.3 110/70 (-) none 21 3 hypercalciuria 0.32 95/60 0.42 110/65 (-) none 61 4 hypercalciuria 0.49 120/75 0.47 117/70 (-) none 29 5 hyperoxaluria 0.6 120/60 0.65 124/65 (-) none 62 6 cystinuria 0.6 125/70 0.7 115/70 (-) none 50 cystinuria 0.75 120/75 0.9 109/72 (-) swl 22 7 hyperoxaluria 0.3 90/60 0.22 92/60 e. coli none 29 8 hyperoxaluria 0.7 90/60 0.5 100/65 (-) none 58 9 cystinuria 0.5 124/82 0.6 122/80 (-) none 28 cystinuria 0.92 108/65 0.79 127/75 (-) none 23 10 hypercalciuria 0.39 92/64 0.3 90/60 (-) none 63 hypercalciuria 0.39 94/60 0.36 97/60 (-) none 29 11 hypercalciuria 0.8 127/70 0.77 125/72 (-) swl 18 12 hypercalciuria 0.23 90/63 0.26 92/63 (-) none 16 13 hypercalciuria 0.5 109/70 0.6 100/60 (-) swl 58 14 hypercalciuria 0.6 115/78 0.5 115/82 (-) none 16 15 cystinuria 0.31 110/65 0.34 110/70 (-) none 23 abbreviation: swl, extracorporeal shockwave lithotripsy. table. clinical characteristics of study patient. combined use of pyelolithotomy and endoscopy-jurkiewicz et al. not worsened in any of the children 3 months after the procedure. in ultrasound examinations, it was not diagnosed any concrements in the urinary tracts. all patients are under the care of nephrology clinic. discussion swl is the most minimally invasive surgical procedure for urolithiasis at present.(6) however, the success rates of complete concrement removal within the first procedure are 70–94%.(7) other minimally invasive methods for achieving concrement removal include urs and pcnl. concrement within the ureters can be removed via lithotripsy using rigid, semi-rigid, and flexible ureterorenoscopes.(8) however, in certain cases, concrement in the kidneys are removed using pcnl and mini-pcnl in children; the diameter of the nephroscope is 15 f. rirs is a recently established urological procedure that removes concrements from the kidney using a flexible ureterorenoscope and the holmium:yag laser.(9) all health centers treating urolithiasis in children aim to minimalize the extent of the surgical procedures and the risk related to surgical treatment.(10) nevertheless, in certain clinical situations, unconventional treatment might be required. despite being efficient and safe, minimally invasive methods have certain limitations, including early or late post-surgical complications. however, there is some group of patients, for whom open surgery is only one appropriate and safe procedure. according to el-husseiny and buchholz, despite the fact that open surgery is currently rarely used, it is still one of the treatment’s way of urolithiasis in adults and children.(11) the more complicated type of urolithiasis with anatomical anomalies, the more recommended is the use of surgical techniques.(11) in the health centers in the world provided with the right equipment, having a big experience and a team of experts, about 1-5.4% of patients with urolithiasis are operated.(12) according to sumit and colleagues, 10% of children treated operatively required open surgery.(13,14) in the most recent european urology association guidelines (2011) prepared by knoll and pearle regarding the treatment of children with urolithiasis, surgical procedures are allowed in certain cases, primarily those involving staghorn urolithiasis and children at a very young age.(12) in some health centers, all children under 1 year of life are operated and efficiency of procedures ranges from 90% to 100%.(15) bartoletti and cai described very precisely indications for open surgery in adults and they also highlighted the necessity to use minimally invasive methods as a treatment of choice in most cases.(16) complex procedure: pyelolithotomy combined with endoscopic concrement removal is able to remove all concrements from a diseased kidney within a single procedure, but without causing parenchymal damage. in this procedure, all defects of the upper urinary tract may be fixed, and the inhibition of urine flow from the kidney may be resolved.(17) this method is safe for children, does not involve blood transfusions, and facilitates the preservation of kidney function. the identification of disorders such as cystinuria is especially important in cases of severe chronic kidney failure, as certain metabolic disorders may damage the renal parenchyma (especially hyperoxaluria type i), or cases with a very high frequency of new concrement formation (for example in cystinuria). in the literature there are descriptions of “combined” methods used in adults.(18,19) these methods combine open surgery with minimally invasive methods at the same time. however, a described method was not used in children so far. conclusions primary surgical treatment of urolithiasis is minimally invasive endoscopic treatment. however, in complicated, select cases there is an opportunity to use surgical methods. open surgery is required only for the urolithiasis which is difficult to treat. the new presented combination of open surgery and endoscopic technique used in complicated cases of staghorn urolithiasis is a safe and effective method, and it can be an alternative to the traditional methods. conflict of interest none declared. references 1. akimoto m, higashihara e, kumon h, masaki z, orikasa s. treatment of urolithiasis. germany: springer-verlag; 2001. p. 12-6. 2. straub m, gschwend j, zorn c. pediatric urolithiasis: the current surgical management. pediatr nephrol. 2010;25:1239-44. 3. bastug f, dusunsel r. pediatric urolithiasis: causative factors, diagnosis and medical management. nat rev urol. 2012;9:138-46. 4. dincel n, resorlu b, unsal a, et al. are small residual stone fragments really insignificant in children? j pediatr surg. 2013;48:840-4. 5. hesse a, tiselius hg, jachnen a. urinary stones. general aspects. in: hesse a, tiselius hg, jahnen a: urinary stones. diagnosis, treatment and prevention of recurrence. 2002:11-43. 6. gnessin e, chertin l, chertin b. current combined use of pyelolithotomy and endoscopy-jurkiewicz et al. endourology and stone diseases 2603 vol 13 no 02 march-april 2016 2604 management of paediatric urolithiasis. pediatr surg int. 2012;28:659-65. 7. stamatiou kn, heretis i, takos d, papadimitriou v, sofras f. extracorporeal shock wave lithotripsy in the treatment of pediatric urolithiasis: a single institution experience. int braz j urol. 2010;36:724-30. 8. oktar t, sanli o, acar ö, tefik t, karakus s, ziylan o. retroperitoneoscopic ablative renal surgery in children: the feasibility of using three trocars. urol j. 2014;10:1040-5. 9. au, wing-hang. "retrograde intrarenal surgery (rirs)-ureterorenoscopic lithotripsy for renal stones." medical bulletin. 2009;14.10. 10. resorlu b, unsal a, tepeler a, et al. comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in children with moderate-size kidney stones: results of multi-institutional analysis. urology. 2012;80;519-23. 11. turk c, knoll t, petric a, et al. guidelines on urolithiasis, european association of urology. 2011:69-76. 12. knoll t, pearle m. clinical management of urolithiasis; 2013 isbn 978-3-642-287312 springer; pediatic stones; 14,7 surgical treatment; 145. 13. sumit d, khoury ae, braga l, walid a. single-institutional study on role of ureteroscopy and retrograde intrarenal surgery in treatment of pediatric renal calculi. urology. 2008;72:1018–21. 14. zargooshi j. open stone surgery in children: is it justified in the era of minimally invasive therapies? bju int. 2001;88: 928-31. 15. zhu j, phillips tm, mathews ri. operative management of pediatric urolithiasis. indian j urol. 2010;26:536-43. 16. bartoletti r, cai t. surgical approach to urolithiasis: the state of art. clin cases miner bone metab. 2008;5:142-4. 17. nuño de la rosa i, palmero jl, miralles j, pastor jc, benedicto a. a comparative study of percutaneous nephrolithotomy in supine position and endoscopic combined intrarenal surgery with flexible instrument. actas urol esp. 2014;38:14-20. 18. nabbout p, slobodov g, culkin dj. surgical management of urolithiasis in spinal cord injury patients. curr urol rep. 2014;15:408. 19. moslemi mk, safari a. a huge left staghorn kidney, a case report of inevitable open surgery: a case report. cases j. 2009;2:8234. combined use of pyelolithotomy and endoscopy-jurkiewicz et al. 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran history of immunosuppressive therapies the first immunosuppressive therapeutic method was initiated by applying a total body irradiation. azathioprine was discovered at the beginning of 1960s. treatment with azathioprine together with prednisolone was administered as an immunosuppressive protocol for many years. polyclonal antithymns (atg) and antilymphocyte antibodies (alg) were introduced at the middle of 1970s. with azathioprine and prednisolone based protocols and by the use of atg and alg in treating steroid resistant rejections, success rate of kidney transplantation reached 50% during one year and mortality rate decreased to almost 10-20%. a great revolution was made by the discovery of cyclosporine from toly pocladium inflatum fungus by which survival in kidney transplantation was increased to 80%. the decrease of corticosteroid usage and the improvement of medical review article the newest medications in kidney transplantation and their mechanisms of action lesan pezeshki m division of nephrology, imam khomeini hospital, tehran university of medical sciences, tehran, iran abstract purpose: in recent years, many new immunosuppressive drugs have been discovered and developed for clinical use in transplantation. this review focuses on new drugs and novel strategies that have been shown to have immunosuppressive activity in patients. materials and methods: the literature was reviewed. results: the introduction of cyclosporine in the early 1980s improved renal allograft survival by approximately 15 percent at one year post transplant. however, cyclosporine failed to enhance long term graft survival. in addition, transplant recipients are at risk of significant side effects due to immunosuppression, including infection, cardiovascular disease, hypertension and malignancy. the limitations constitute the rational for the continued development of new immunosuppressive agents. conclusion: the therapeutic armamentarium for transplant immunosuppression continues to broaden and become more complex, as does the variety of potential drug combinations or protocols. further studies in a large number of individuals is required to clarify the role of new immunosuppressive agents and novel strategies in transplant recipients. key words: new immunosuppressive agents, transplantation accepted for publication the newest medications in kidney transplantation and their mechanisms of action services, considerably reduced mortality rate. the therapeutic protocol was changed to triple therapy with cyclosporine, prednisolone and azathioprine. in spite of positive effects of cyclosporine, its chronic and acute nephrotoxic effects were gradually manifested. in 1985, okt3 was introduced as the first monocolonal antibody and it was used in the treatment of first onset of rejection as well as in rejections resistant to steroid and as an induction therapy. at the beginning of 1990s, these treatment modalities led to the increase of oneyear survival of transplant to 90% and to a considerable decrease of mortality. later progresses included the discovery of tacrolimus and mycophenolate mofetile (mmf). tacrolimus was initially used in liver transplantation and then in kidney transplantation as cyclosporine substitute. as a more effective drug, mmf was gradually used instead of azathioprine. daclizumab and basiliximab, which are two newer monocolonal antibodies, have been administered in kidney transplantation in recent years. they proved to be effective in reducing the incidence of acute rejection and delaying it, as well as in treating acute rejection. sirolimus was added to immunosuppressive medications at the end of 1999, some other new medications which were also studied will be discussed later on. 1. mycophenolate mefetile (mmf or cellcept®): this medication which is more effective than imuran in preventing acute rejection in kidney recipients from cadaver was added to transplant medications in 1995 after some clinical studies.(1) mycophenolic acid (mpa) is the active ingredient of this drug. mechanism of action: mmf is a reversible inhibitor of inosinate monophosphat dehydrogenase (impdh) enzyme. this enzyme has a role in porine biosynthesis and is more effective than inosin in guanosin nucleotides production. the decrease of guanosine nucleotides has elective antiproliferative effects in lymphocytes.(2) in fact, this medication has specific antimetabolite effects. contrary to calcinosin inhibitors (such as cyclosporine and tracrolimous) and sirolimus, mmf has no impact on cytokine production and in contrast with azathioprine, it has no effect on lymphocytes and neutrophils. mmf reduces the adhesion of molecules to lymphocytes and consequently decreases their adhesion to the vessels' endothelial cells. it inhibits mononuclear cells migration to the rejection area by which it could be effective in treating the rejection episodes. it also prevents proliferative arteriolopathy by which it could prevent chronic rejection.(3) the most important adverse effect of mmf is on gastrointestinal system, as it causes diarrhea in 30% of the cases. the decrease of dosage can often prevent diarrhea. it should not be used with antiacids and cholestyramine. 2sirolimus: this medication is a macrolid antibiotic that is structurally similar to tacrolimus. it was clinically introduced to the world of transplant in 1999 after a series of clinical studies. together with cyclosporine and prednisolone, it considerably reduces acute rejection incidence at the beginning of transplantation. it has the same immunosuppressive power of cyclosporine, yet, more effective than mmf with more side effects.(4) mechanism of action: sirolimus is linked to a protein (fk binding protein) in cytoplasm. this complex has an inhibitor effect on the target of rapamycine (tor). the inhibition of tor could reduce cytokine related cellular proliferation at g1 to s cellular division phases. thus, this mechanism affects hematopoetic and non-hematopoetic cells.(5) sirolimus together with tacrolimus could form a much more effective regimen that could be administered with a lower dosage. sirolimus is metabolized in the liver by cyp3a and p-glycoprotein. its renal excretion is low, so that in case of renal function impairment there would be no need of reducing dosage; however, it should be adjusted in liver function impairment. like cyclosporine, sirolimus has interaction with calcium channel blockers, antifungal, anticonvulsive, and antituberculosis drugs. its two important side effects are hyperlipidemia and thrombocytopenia. patients with considerable preoperative hyperlipidemia are not good candidates to receive sirolimus. in addition, its tubular toxic effect could lead to hypokalemia and hypomagnesemia. 3humanized anti-tac monoclonal 2 the newest medications in kidney transplantation and their mechanisms of action antibodies: these drugs include basiliximab and daclizumab, which act against alpha-chain of interleukine 2 (tl2). this receptor only increases in activated t cells. following its link with the antibody, the reaction caused by tl2 is blocked. these drugs complete the effect of calcinorin inhibitors, which reduce intercolin-2 production, and their most important effect is to prevent acute rejection onset. murine monoclonal antibody is the origin of both drugs. human igg was substituted for 75% of the molecule in basiliximab and for 90 % in daclizumab. regarding that the immunogenisity of these medications is low and no considerable amount of antibodies is produced against them, their half-life would be higher (more than 7 days) and no first-dose reaction would be seen.(6) new immunosuppressive medications new considerable medications have been produced. little changes have been induced in some to decrease side effects and improve therapeutic index. some others could cause significant changes in immunosuppressive therapies in near future, if clinically approved. modifications of available drugs 1. rad: this drug is derived from sirolimus and structurally similar to it, but with more oral absorption. rad could be used together with cyclosporine, while sirolimus should be administered with an interval of 4 hours after cyclosporine. besides, rad has a shorter half life than sirolimus.(7) 2. erl080a: this drug is enteric-coated type of mycophenolate with lower gastrointestinal side effects and it could be administered with a lower dose. 3. fty 720: it is a new immunosuppressive drug, which reduces b and t cells in the peripheral blood, while it increases them in lymph nodes and peyer's patch by affecting lymphocyte chemokine receptors. thus, lymphocyte infiltration is inhibited in allograft and long lymphopenia is developed. fty080a has no effect on the amount and function of granulocytes. it promotes immunosuppressive effect of cyclosporine. new monoclonal antibodies 1hum291: this drug is a humanized okt3. it is a human and hybrid provided by the transmission of complementary determining region of okt3 to human igg and mutation of single amino acids. this variant of okt3 does not activate human t cells; however, it has strong immunosuppressive effects.(9) regarding that the immunogenisity of this medication is much lower than okt3, its half-life would be longer, approximately 142 hours.(10) 2t10b9.1a: this murine monoclonal antibody reacts against an epitope located on t lymphocyte receptor (alpha/beta-heterodimer). since it is not a mitogen, it does not have the complications caused by cytokine, which are seen by okt3 use. additionally, it accelerates the improvement of rejection episodes that lead to renal failure.(11) regarding murine origin of this drug, there is a high possibility of antibody formation against it; however, since there is a little interaction between t10b9.1a and okt3, it could be used in patients who do not respond to okt3.(12) 3anti-icam-1 antibody (enlimomab): a considerable number of adhesion molecules take part in the interaction between t cells, antigen presenting cells, and target cells. among these the reaction between leukocyte function associated molecules (lfa-1) in lymphocytes and intercellular adhesion molecule-1 in cells that provide antigen is of great importance.(13) primary experimental studies indicated that murine monocolonal antibodies which are produced against icam-1 could delay but not prevent acute rejection. a multicentral randomized placebo controlled study was conducted on 262 cadaver renal recipients. enlimomab was administered in enlimomab group for 6 days. this group was compared with placebo.(14) all patients received cyclosporine, azathioprine, and prednisolone. no significant difference was observed between the two groups, regarding clinical purposes. hence, the useful role of these antibodies is not definitely clear and further studies are needed to determine whether this role would be useful for just high risk groups or all groups. 4odulimomab: this antibody is formed 3 the newest medications in kidney transplantation and their mechanisms of action against alpha-chain of lfa-1. the effect of this antibody was compared with rabbit atg in a multi-central study. clinical tolerance for this medication was better than atg, while rejection onsets at the first 10 days were more in odulimomab group. however, the incidence and severity of acute rejection onsets at the first three months, survival of transplanted kidney at the first year, and the incidence and severity of infection in both groups were similar.(15) 5alemtuzumab (campath-1h): this human monoclonal antibody is formed against cd52 of lymphocytes. it is a very effective drug by which patient would have a proper status with a low dose of cyclosporine only as an immunosuppressive drug. in a study, 31 cadaver recipient patients receive 20mg iv dose of this drug together with 500mg methylprednisolone at the day of surgery, this dose was repeated on the following day. afterwards, cyclosporine was started 72 hours postoperatively. during 21 months follow-up 6 patients developed acute rejection episodes, which were treated by steroids and one patient, died of cardiac ischemia. twenty seven out of 29 patients with normal renal function received only a low dose of cyclosporine.(16) 6okt 4a: a murine monoclonal antibody is formed against cd4. it inhibits co-stimulatory function of cd4 molecule. the decrease of rejection incidence and low toxicity were reported in phase i trial studies.(17) t-cell co-stimulatory blockers among tolerance inducer methods, affecting signals that lead to t cell activity are of a considerable importance. co-stimulatory signals are needed to complete t cell response following antigen detection. this is accomplished by t cell surface accessory molecules. among these, costimulatory, cd28: b7, and cd154: cd40 are of great importance. ctla-4-ig is a fusion protein and a cd28 homolog. when it binds to b7 molecule, its interaction with cd28 is blocked.(18) administering this protein and anit-cd154 in experimental studies proved to be effective in preventing rejection.(19) together with this drug, sirolimus could improve graft tolerance by producing apoptosis signals. these observations are of great clinical importance because they provide selective immunosuppression instead of global immunosuppression. immune modulation in these methods, non-specific changes in the immune system facilitate graft acceptance with no impact on effector cells. 1donor-specific bone marrow infusion: in this method short-term non-specific immunosuppression leads to long survival of graft with no need to any immunosuppressive. thus, donor-specific bone marrow cells provide a signal for tolerance. 2blood transfusion: this method is of useful impact in increasing survival of transplanted kidney. microchimerism is one of the mechanisms of bone marrow cell infusion and blood transfusion. the existence of donor cells in recipient blood circulation even in a very low amount is an important factor in tolerance stability. 3ivig infusion: it leads to the production of antiidiotyic antibodies and the decrease of anti hla antibodies if administered prior to transplantation. 4photopheresis: it is one of the new treatments in extracorporeal photochemotherapy. it was used in the treatment of t cell cutaneous lymphomas and some autoimmune diseases. in this method, peripheral mononuclear cells were separated by aphresis. these separated cells are exposed to 8-methoxy psoralen and ultraviolet light extracorporeally and again infused to the body. this method had been used in resistant rejections of transplanted heart and kidney and in some types of lung rejection.(20) in one study, four patients with rejected transplanted kidney, which were resistant to conventional treatments, were treated by photopheresis for six months. all rejections were improved and corticosteroid dosages were reduced in three.(12) in the future, new treatments can considerably increase survival of transplanted organ, and patients will have a hopeful life. references 1. cho s, danovitch g, deierhoi m, et al. 4 the newest medications in kidney transplantation and their mechanisms of action mycophenolate mofetil in cadaveric renal transplantation. am j kidney dis 1999; 34:292. 2. halloran p, mathew t, tomlanovich s, et al. mycophenolate mofetil in renal allograft recipients. transplantation 1997; 63: 39. 3. ojo a, meier-kriesche h, hanson ja, et al. mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. transplantation 2000; 69: 2405. 4. groth cg, backman l, morales j, et al. sirolimus (rapamycin)-based therapy in human renal transplantation. transplantation 1999: 67: 1036. 5. sehgal sn. rapamune: mechanism of action and immunosuppressive effect results from blockade of signal transudation and inhibition of cell cycle progression. clin biochem 1998: 31: 335. 6. nashan b, light s, hardie ir, et al. reduction of acute renal allograft rejection by daclizumab. transplantation 1999; 67: 110. 7. kahan bd, kaplan b, loyber mi, et al. rad in denovo renal transplantation. transplantation 2001; 71: 1400. 8. troncoso p, stepkowski sm, wang m, et al. prophylaxis of acute renal allograft rejection using fty 720 in combination with subtherapeutic doses of cyclosporine. transplantation 1999; 67: 145. 9. alegre ml, peterson lj, xu d, et al. a nonactivating 'humanized` anti-cd3 monoclonal antibody retains immunosuppressive properties in vivo. transplantation 1994; 57: 1537. 10. cole ms, stellrecht ke, shi jd, et al. hum 191, a humanized anti-cd3 antibody is immunosuppressive to t cells while exhibiting reduced mitogenicity in vitro. transplantation 1999; 68: 568. 11. brown sa, lucas ba, waid th, et al. t10 b9 (medi-500) mediated immunosuppression: studies on the mechanism of action. clin transplant 1996; 10: 607. 12. waid th, lucas ba, thompson js, et al. treatment of renal allograft rejection with t10 b9. 1a31 or okt3. transplantation 1997; 64: 274. 13. rabb h, bonventre jv. leukocyte adhesion molecules in transplantation. am j med 1999; 107: 157. 14. salmela k, wrammer l, ekberg h, et al. a randomized multi-center trial of the antiicam-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation. transplantation 1999; 67: 729. 15. hourmant m, bedrossian j, durand d, et al. a randomized multi-center trial comparing leukocyte function-associated antigen-i monoclonal antibody with rabbit antithymocyte globulin treatment in first kidney transplantations. transplantation 1996; 62: 1562. 16. calne r, moffatt sd, friend pj, et al. campath 1 h allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. transplantation 1999; 68: 1613. 17. delmonico fl, cosimi ab, colvin r, et al. murine okt4 immunosuppression in cadaver donor renal allograft recipients. transplantation 1997; 63: 1243. 18. gudmundsdottir h, turka la. t cell costimulatory blockade: new therapies for transplant rejection. j am soc nephrol 1999; 10: 1356. 19. kirk ad, burkly lc, batty ds, et al. treatment with humanized monoclonal antibody against cd154 prevents acute renal allograft rejection in non-human primates. nature med 1999; 5: 686. 20. salerno ct, park sj, kreykes ns, et al. adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. j thorac cardiovasc surg 1999; 117: 1063-69. 21. dall' amico r, murer l, montini g, et al. successful treatment of recurrent rejection in renal transplant patients with photopheresis. j am soc nephrol 1998; 9: 121. 5 sexual dysfunction and andrology 6020 does preoperative use of dutasteride decrease bleeding during open prostatectomy? purpose: to investigate whether use of dutasteride, a 5-alpha reductase inhibitor, for at least four weeks preoperatively affected the blood loss during open prostatectomy (op). materials and methods: retrospective analysis was made of the data of 110 patients who had undergone op. group i comprised 50 patients that used dutasteride for 4 weeks preoperatively, and group ii comprised 60 patients that did not use the drug. the groups were compared in respect of age, total prostate specific antigen (tpsa) levels, prostate volumes, preoperative hemoglobin (hgb) and hematocrit (hct) levels, postoperative reduction of hgb and hct, percentage reduction in hgb and hct, and the administration of postoperative blood products. results: no differences were determined between the two groups in respect of prostate volumes, tpsa, preoperative hgb and hct levels (p = .813, p = .978, p = .422, p =.183, respectively). postoperative hgb reduction was 2.19 ± 1.36 g/dl in group i, and 2.5 ± 1.47 g/dl in group ii (p = .260). hgb reduction was calculated as 16.4 ± 9.7% in group i and 17.6 ± 9.7% in group ii (p = .505). reductions in hct were 5.8 ± 3.7% in group i, and 7.3 ± 4.4% in group ii, and percent reductions were 14.8 ± 9.4% in group i and 17.3 ± 10.2% in group ii (p = .068, p = .182, respectively). conclusion: the use of dutasteride before op did not affect blood loss during surgery, therefore surgery should not be delayed for the administration of dutasteride to patients. keywords: prostate; open prostatectomy; dutasteride; bleeding introduction benign prostatic hyperplasia (bph) is a histo-pathological condition that causes lower urinary tract symptoms (luts) and bladder outlet obstruction (boo) in elderly males. although bph is evident histologically in most males aged > 40 years, it does not always cause symptoms or boo(1-4). the etiology of bph consists of an increase of glandular-epithelial and stromal cells, and a decrease in apoptosis resulting from various factors, including androgens(4). dihydrotestosterone (dht) is the main androgen of prostate. it is produced in the prostate from free testosterone by 5-alpha reductase (5ar) enzyme, and free testosterone is taken into the prostate cells through diffusion from plasma. 5ar has two isoforms, and type 2 5ar is the major one found in the prostate(1). finasteride inhibits only type 2-5ar, but dutasteride inhibits both type 1 and type 2-5ar, and the guidelines of the european association of urology have recommended it for patients with a prostate volume of > 40 ml and moderate or severe luts, with an evidence level of 1b(5). transurethral prostatectomy (tur-p) is the gold standard treatment method for patients with a prostate volume of 30-80 milliliters (ml), when there are concomitant conditions of benign prostatic obstruction (bpo) requiring surgery, such as significant luts unresponsive to medical treatment, recurrent urine retention and 1department of urology, ankara training and research hospital, ankara, turkey. 2department of urology, çanakkale 18 mart university, canakkale, turkey. 3department of urology, bezmialem university, istanbul, turkey. *correspondence: ankara training and research hospital, ankara, turkey. phone: +905322500072 received september 2016 & accepted october 2017 urinary infection, persistent hematuria, renal dysfunction due to boo and similar upper urinary tract alterations, and bladder stones secondary to obstruction. in cases of prostate volume >75-80 ml, the recommended surgical options are open prostatectomy (op), and holmium laser enucleation of prostatectomy (holep). op is the most invasive treatment method of bpo. even though op may be thought to be rarely performed nowadays, in developing countries it is still a frequently applied operation (14%-40%), even for prostates <80ml in volume(5,6,7). there are a number of studies that have investigated dutasteride, a type 1 and type 2 5ar inhibitor causing reduction in prostate vascularity and volume, and its effect on bleeding during surgery when used in the preoperative period, particularly before tur-p procedure. in this study, an investigation was made of the use of dutasteride before op, and its effect on bleeding during surgery. methods after obtaining institutional review board approval for the study, the data of the patients with boo due to bph, and had op because of prostate volume in three centers in turkey between 2013 and 2014 were analyzed retrospectively. use of preoperative dutasteride was searched for in the hospital records, and confirmed arif demirbas1*, berkan resorlu1, murat tolga gulpinar2, sina kardas3, omer gokhan doluoglu1, ,abdulkadir tepeler3, muhammet fatih kilinc1, tolga karakan1, serkan ozcan1 miscellaneous miscellaneous 48 by examining the patients’ records in the national pharmacy database. group i comprised 50 patients administered with dutasteride for at least 4 weeks preoperatively. group ii comprised 60 patients with no dutasteride use. for each patient, a record was made of age, total prostate specific antigen (tpsa) levels, prostate volumes measured transrectally, preand postoperative hemoglobin (hgb) and hematocrit (hct) levels, postoperative transfusion of blood products, and the histopathological results of the op specimens. patients with serum tpsa levels > 4 ng/ml had transrectal ultrasonography guided (trusg) prostate biopsies, and a benign result was obtained (31 in group i, 33 in group ii). op was applied directly, without any biopsies, to 10 patients between the ages of 78 and 86 years, taking the 10-year life expectancy into consideration. it was noted that all op specimens were reported as benign. postoperative hgb and hct levels were obtained from peripheral blood samples collected within 2 hours after surgery, in all three clinics. preoperative hgb and hct levels were obtained from the complete blood counts ordered preoperatively, when consulting the patient to the anesthesiologist. op was performed using a suprapubic prostatectomy approach (freyer procedure) in all three clinics, and none of the patients had a retropubic prostatectomy procedure. no antiaggregants or anticoagulants were used on any patient during the surgical procedure, or within 1 week preoperatively. the patients in groups i and ii were compared in respect of age, tpsa levels, prostate volumes, the difference between preoperative and postoperative hgb and hct levels (reduction of hgb and hct) used to determine bleeding, the ratio of reduction in hgb and hct to preoperative hgb and hct (reduction percentage), and postoperative transfusion of blood products. in addition, the correlation between age and bleeding parameters was investigated, independently of the other parameters. statistical analysis the data analysis was performed using spss for windows, version 11.5 software (spss inc., chicago, il, united states). the normality of the distribution of data was tested with p-p plot and kolmogorov-smirnov tests. all data were determined to conform to normal distribution. descriptive statistics were shown as mean ± standard deviation for the variables with normal distribution. the student’s-t test was used for the intergroup analysis of continuous variables. data were analyzed with ancova, corrected for age and bleeding parameters. a value of p < .05 was considered statistically significant. results the mean age of the patients was 74.64 ± 5.25 years in group i and 65.48 ± 7.27 years in group ii (p < .001). the mean preoperative prostate volume as measured with trusg was 129.22 ± 40.40 ml in group i, and 127.51 ± 34.86 ml in group ii. the difference between the two groups was not significant (p = .813) (table 1). the mean tpsa levels were 8.1 ± 6 ng/dl and 8.14 ± 6.78 ng/dl in groups i and ii, respectively (p = .978) (table 1). preoperative hgb was 13.25 ± 1.8 g/dl and hct was 39.4 ± 5.2% in group i, and those values were 13.91 ± 1.5 g/dl and 41.66 ± 4.5%, respectively in group ii. no significant difference was seen between the groups in respect of hgb and hct levels (p = .422 and p = .183, respectively) (table 1). postoperative hgb was 11.05 ± 1.8 g/dl and hct was 33.52 ± 5.5% in group i, and those levels were 11.41 ± 1.5 g/dl and 34.31 ± 4.9%, respectively in group ii. analysis of the parameters used to determine the amount of bleeding during surgery showed hgb reduction of 2.19 ± 1.36 g/dl in group i and 2.5 ± 1.47 g/dl in group ii, with no significant difference between the groups (p = .260) (table 2). hct reduction was 5.8 ± 3.7% in group i, and 7.3 ± 4.4% in group ii (p = .068). no significant differences were determined between the groups in respect of hgb and hct reduction (p = .505, p = .182, respectively) (table 2). the correlation between age and hgb and hct reduction percentages were analyzed with spss-ancova test since there was a statistically significant difference between the groups for age (p < .001). age was not correlated with hgb reduction (p = .599) or hct reduction (p = .309) or with hgb reduction percentage (p = .757) or hct reduction percentage (p = .627). thus, no correlation was found between age and the parameters indicating bleeding amount during surgery. postoperative transfusion of blood products was necessary in 11 (10%) of 110 patients that had op. each patient was administered 1 unit of erythrocyte suspension (es). the distribution of the 11 patients that had es transfusion was equal in groups i and ii [5 patients (10%) in group i, and 6 patients (10%) in group ii]. discussion benign prostatic hyperplasia (bph) is a frequently seen histopathological condition in males, and epidemiologdutasteride effect on bleeding in open prostatectomy-demirbas et al. table 1. the descriptive characteristics of the patients that had open prostatectomy due to bph. group i (n=50) group ii (n=60) p-value mean age 74.64 ± 5.25 65.48 ± 7.27 < 0.001 prostate volume (ml) 129.22 ± 40.40 127.51 ± 34.86 0.813 total psa (ng/dl) 8.1 ± 6 8.14 ± 6.78 0.978 preoperative hgb (g/dl) 13.25 ± 1.8 13.91 ± 1.5 0.422 preoperative hct (%) 39.4 ± 5.2 41.66 ± 4.5 0.183 group i (n=50) group ii (n=60) p-value hgb reduction (g/dl) 2.19 ± 1.36 2.5 ± 1.47 0.260 hct reduction (%) 5.8 ± 3.7 7.3 ± 4.4 0.068 hgb reduction percentage 16.4 ± 9.7 17.6 ± 9.7 0.505 hct reduction percentage 14.8 ± 9.4 17.3 ± 10.2 0.182 table 2. the parameters measured to determine the amount of blood loss in the groups. vol 15 no 01 january-february 2017 49 miscellaneous 50 ical studies have reported that its prevalence increases with aging. it is histopathologically evident in 50% of cases at 50 years of age, and in 88% of cases after the age of 80 years. autopsy studies have shown that the increasing prevalence was not associated with race or geographic characteristics, but only with age (8-10). other than the histopathological changes, the main problem is enlargement of the prostate, which has been specified as the natural course of the disease, resulting in boo and related to a decrease in urine flow rate, and decreased quality of life (11,12). boo related to bph needs treatment after the development of complications. op is a safe treatment option when non-invasive or minimally invasive and endoscopic treatment options are not suitable due to the volume of the prostate(13-15). although the op procedure has low morbidity and mortality, perioperative bleeding and urinary retention that develop due to clots in the early postoperative period are important problems (13,16). there have been some randomized, controlled studies and a meta-analysis on bleeding during tur-p and type 1 and type 2 5ar inhibitors that were supposed to decrease this bleeding, but there have been few studies on op, which is a more invasive procedure(17). the hypothesis that the use of 5ar inhibitors before tur-p could cause less bleeding is based on histopathological studies showing interaction of dht with some factors such as vascular endothelial growth factor (vegf), insulin-like growth factor (igf), and transforming growth factor (tgf-beta), and decrease of arterial and venous microvessels in prostate tissue in patients who have been administered those agents(4,18, 19). some other studies have claimed the opposite, and reported that the use of dutasteride did not result in any difference in prostatic microvessel density when compared with the control groups(20, 21). pastore et al.(22) performed a randomized controlled study on 142 patients that had tur-p, and reported that dutasteride use for 6 weeks decreased bleeding significantly. the authors found hgb reduction to be 1.29 ± 0.81 g/dl in the dutasteride group and 1.83 ± 1.25 g/ dl in the control group (p < .0027), hct reduction was determined as 5.67 ± 2.58% in the dutasteride group, and 6.50 ± 2.40% in the control group (p = .0491). in 2015, a study from korea conducted on 83 patients reported similar findings, and hgb reduction was found to be 0.65 ± 1.27 g/dl in the dutasteride group despite use of the drug for 2 weeks, and hgb reduction was found to be 1.16 ± 0.73 g/dl in the control group (p = .019). in the same study, hct reduction was 1.89 ± 3.83% in the dutasteride group, and 3.47 ± 2.09% in the control group (p = .016). the authors recommended preoperative use of dutasteride for 2 weeks before tur-p to decrease bleeding. the authors also reported that the duration of urethral catheter and hospital stay were shorter due to less bleeding in patients that used dutasteride(23). in 2007, hahn et al.(20) conducted a randomized, controlled study on 213 patients from 6 countries scheduled for tur-p. use of dusteride preoperatively for 28-32 days resulted in 88% reduction in dht compared to the placebo group, although the groups did not show any significant differences in respect of the amount of hgb determined in the irrigation fluid, clot retention, need for transfusion, or development of acute urinary retention. in a meta-analysis of all randomized controlled studies performed before 2015, the effect of 5ar inhibitors on bleeding during tur-p was analysed, and no difference was found between the dutasteride and control groups in respect of calculated blood loss, hgb reduction, removed tissue weight, prostate volume, need for transfusion, or duration of surgery(17). only one study performed on a small number of patients reported less bleeding in relation to the removed tissue/grams in the dutasteride group(24). to date, only one study has investigated the use of dutasteride before op. that retrospective study was performed in 2015, included a total of 218 patients, 46 of whom used dutasteride. the effect of dutasteride was investigated by taking only hgb reduction into consideration. the patients were administered dutasteride preoperatively for 6 weeks, and the difference between the study and the control groups for hgb reduction was found to be significant (2.72 g/dl vs. 1.93 g/dl, p = .01). however, there was a significant difference between the preoperative hgb levels of the groups (p = .002). in addition, the hct value that shows the ratio of total erythrocyte volume to total blood volume was not taken into consideration when comparing the blood loss between the groups(25). the descriptive statistics of the current study groups are presented in table 1. taking those data into consideration, prostate volume (p = .813), tpsa (p = .978), preoperative hgb (p = .422), and preoperative hct (p = .183) were similar in both groups, but there was a significant difference between group i and group ii for age (p < .001). however, the ‘spss-ancova’ test was applied to analyze the hypothesis that age could have an effect on bleeding. it was determined that age and hgb reduction, hct reduction, and hgb and hct reduction percentages were not correlated, independently of the other parameters (p = .599, p = .309, p = .757, p = .627, respectively). hemoglobin reduction, hct reduction, and hgb and hct reduction percentages that show a proportional decrease postoperatively compared to the preoperative levels, were used as the parameters to determine blood loss during op in the current study, and these were compared between the two groups (table 2). no significant differences were determined between the dutasteride and control groups in respect of those four parameters (p = .260, p = .068, p = .505, p = .182, respectively) (table 2). there was a need for blood transfusion after the surgical procedure in 11 (10%) patients, and each patient was transfused 1 unit erythrocyte suspension. of those patients 5 (10%) were in the dutasteride group, and 6 (10%) were in the control group. there was no significant difference between the groups. limitations of this study are that it was retrospective in nature and different surgeons performed the surgical procedures. however, as there are only a few studies in literature, that more parameters were examined in this study, and comparisons were made of similar groups can be considered to be the strengths of this research. conclusions in conclusion, the data obtained in this study showed that the use of preoperative dutasteride by patients planned to undergo op did not reduce the amount of bleeding caused by op. although there are many randomized, controlled studies and meta-analyses related to a reduced amount of bleeding with the use of dutasteride effect on bleeding in open prostatectomy-demirbas et al. dutasteride before tur-p, there has been no previous study on this subject related to op. therefore, there is a need for further studies to support the evidence-based medical requirement of the opinions determined in this study. conflict of interest the authors declare that they have no competing interests. references 1. berman dm, rodriguez r, veltri rw. development, molecular biology and physiology of the prostate. in: wein aj, editor. campbell-walsh urology. 10’th edition; 2012, p. 2533-2569. 2. chung bi, sommer g, brooks jd. anatomy of the lower urinary tract and male genitalia. in: wein aj, editor. campbell-walsh urology. 10’th edition; 2012, p. 33-72. 3. flocks rh: the arterial distribution within the prostate gland: its role in transurethral prostatic resection. j urol 1937. 4. roehrborn cg. benign prostatic hyperplasia: etiology, pathophysiology, epidemiology, and, natural history. in: wein aj, editor. campbell-walsh urology. 10’th edition; 2012, p. 2570-2613. 5. gravas s, bach t, bachmann a, drake m, gacci m, gratzke c, et al: management of non-neurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo). eau guidelines 2015: 5-70 6. modder jk, mcvary kt: suprapubic prostatectomy. hinman’s atlas of urologic surgery. 3’th edition: 472-481. 7. simforoosh n, abdi h, kashi ah, zare s, tabibi a, danesh a, basiri a, ziaee sa.open prostatectomy versus transurethral resection of the prostate, where are we standing in the new era? a randomized controlled trial. urol j. 2010 fall;7:262-9. 8. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol 1984;132:474479. 9. oesterling je. the origin and development of benign prostatic hyperplasia an agedependent process. journal of andrology 1991;12:348-55. 10. carter hb, coffey ds: the prostate: an increasing medical problem. the prostate 1990;16:39-48. 11. roberts ro, jacobsen sj, jacobson dj: longitudinal changes in peak urinary flow rates in a community based cohort. j urol 2000; 163: 107-13. 12. kirby rs: the natural history of benign prostatic hyperplasia: what have we learned in the last decade? urology 2000; 56: 3-6 13. han m, partin aw: retropubic and suprapubic open prostatectomy. campbellwalsh urology. 10’th edition: 2695-2702. 14. tubaro a, carter s, hind a, vicentini c, miano l. a prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. j urol 2001; 166: 172-6. 15. varkarakis i, kyriakakis z, delis a, protogerou v, deliveliotis c. long-term results of open transvesical prostatectomy from a contemporary series of patients. urology 2004; 64: 306–10. 16. moody ja, lingeman je. holmium laser enuclation for prostate adenoma greater than 100 gm: comparison to open prostatectomy. j urol 2001; 165: 459-62. 17. zhu yp, dai b, zhang hl, shi gh, ye dw. impact of preoperative 5α-reductase inhibitors on perioperative blood loss in patients with benign prostatic hyperplasia: a meta-analysis of randomized controlled trials. bmc urol. 2015; 15: 47. 18. foley sj, bailey dm. microvessel density in prostatic hyperplazia. bju int 2000; 85: 70-3. 19. zaitsu m, tonooka a, mikami k, hattori m, takeshima y, uekusa t, et al. a dual 5α-reductase inhibitor dutasteride caused reductions in vascular density and area in benign prostatic hyperplasia. isrn urol 2013: 863489. 20. hahn rg, fagerström t, tammela tlj, trip ovv, beisland ho, duggan a, et al: blood loss and postoperative complications associated with transurethral resection of the prostate after pretreatment with dutasteride. bju international 2007; 99: 587–94. 21. ku jh, shin jk, cho mc, myung jk, moon kc paick js. effect of dutasteride on the expression of hypoxia-inducible factor1α, vascular endothelial growth factor and microvessel density in rat and human prostate tissue. scand j urol nephrol 2009; 43: 445– 53. 22. pastore al, mariani s, barrese f, palleschi g, valentini am, pacini l, et al. transurethral resection of prostate and the role of pharmacological treatment with dutasteride in decreasing surgical blood loss. j endourol 2013; 27: 68-70. 23. kim ks, jeong ws, park sy, kim yt, moon hs. the effect of two weeks of treatment with dutasteride on bleeding after transurethral resection of the prostate. world j mens health 2015; 33: 14–9. 24. tuncel a, ener k, han o, nalcacioglu v, aydin o, seckin s, et al: effects of shortterm dutasteride and serenoa repens on perioperative bleeding and microvessel density in patients undergoing transurethral resection of the prostate. scand j urol nephrol 2009; 43: 377–82. dutasteride effect on bleeding in open prostatectomy-demirbas et al. vol 15 no 01 january-february 2017 51 miscellaneous 52 25. gokce mi, kerimov s, akinci a, hamidi n, faraj a, yaman o. effect of dutasteride treatment on reducing blood loss and in perioperative period of open prostatectomy. turkish journal of urology. 2015; 41: 24–6. dutasteride effect on bleeding in open prostatectomy-demirbas et al. urology journal unrc/iua vol. 2, no. 4, 216-221 autumn 2005 printed in iran 216 miscellaneous the effect of voiding position on uroflowmetry findings of healthy men and patients with benign prostatic hyperplasia seyyed mohammadkazem aghamir, mohammadghasem mohseni, saeed arasteh* department of urology, sina hospital, tehran university of medical sciences, tehran, iran abstract introduction: we assessed the effect of different positions of voiding on uroflowmetry findings in healthy men and in patients with benign prostatic hyperplasia (bph). materials and methods: ten men with symptomatic bph and 10 healthy men were enrolled in this study. urodynamic study was done for each subject in 3 positions: standing, crouching (the position used in the iranian style toilets), and sitting. the following urodynamic parameters were studied: voided urine volume, residual urine volume, total flow time, flow time, maximum flow rate, average flow rate, delay to start voiding, and maximum flow time. results: there were no significant differences between the 3 voiding positions and urodynamic parameters of healthy men. in men with bph, the postvoid residual urine volume was significantly lower in the sitting position compared with the crouching and standing positions (67 ml versus 130 m/l and 130 ml; p < .001). the median average flow rate was 2.5 ml/s in the crouching, 3.5 ml/s in the sitting, and 3 ml/s in the standing positions (p = .016). also, delay to start voiding was longest in the crouching position (6.5 seconds, 6 seconds, and 5 seconds in the crouching, sitting, and standing positions; p = .011). voided urine volume, total flow time, flow time, maximum flow rate, and maximum flow time were not different among the 3 positions. conclusion: in patients with bph, voiding position may affect urodynamic parameters and the physician's decisions. further studies are needed to elucidate the effects of voiding position on urodynamic parameters. key words: uroflowmetry, voiding position, crouching, postvoid residual volume, average flow rate introduction the lower urinary tract system is one of the few body systems controlled by both voluntary and autonomic nervous systems. this results in a complexity of function.(1,2) the lower urinary tract is associated with a nonlinear, multivariable, dynamic system that depends on internal alterations (convulsions, dysfunctions, infections, etc) and external alterations (coughing, sneezing, exercise, listening to running water, fear, cold, etc). several models have been introduced to explain the mechanical properties of the urinary tract, but none of them address of all the system's aspects.(3) voiding position is a parameter thought to influence urodynamic studies. this may alter the uroflowmetry findings affecting angles and crosssectional area of the meatus. as yet however, no study has addressed the effect of voiding positions on uroflowmetry findings. in this study, received september 2003 accepted february 2005 *corresponding author: sina hospital, hassanabad sq, tehran, iran. tel: ++98 912 205 7898, e-mail: arastehs@sina.tums.ac.ir aghamir et al 217 we investigated the uroflowmetry findings of 3 different voiding positions in healthy men and patients with benign prostatic hyperplasia (bph). materials and methods between january 2003 and march 2003, we studied on the uroflowmetry findings of 10 men with bph (mean age, 69.5 years; range, 58 to 76 years) who were candidates for open prostatectomy or transurethral resection of the prostate for reasons other than urinary retention. also, urodynamic study was performed in 10 healthy volunteers (mean age, 23.6 years; range, 19 to 32 years). the patients were informed of the study parameters and informed consent was obtained. the study design was approved by the bioethics board of tehran university of medical sciences. urodynamic study was done 3 times for each patient and each healthy volunteer. each was asked to urinate in 3 positions: standing, crouching (the position used in iranian style toilets), and sitting (the position used in european style toilets). in each position, urodynamic findings including voided urine volume, residual urine volume, total flow time, flow time, maximum flow rate, average flow rate, delay to start voiding, and maximum flow time were measured using a dantec ud 5500 mk2 urology cystometer uroflowmetry (dantec, denmark). changes in uroflowmetry parameters in each group were analyzed using the friedman and wilcoxon signed rank tests, and the 2 groups' results were compared using the mann-whitney u test. continuous variables are presented as medians (interquartile range), and a p values less than .05 were considered statistically significant. data were analyzed using spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). results the voided urine volume, maximum flow rate, and average flow rate were significantly lower in men with bph than in healthy men. patients with bph had longer total flow time and flow time, a greater postvoid residual urine volume, and a longer delay to start voiding, but maximum flow time was not different between the 2 groups. urodynamic findings in the 2 groups are summarized in table 1. there were no significant differences between the 3 voiding positions regarding the urodynamic parameters of healthy men. in men with bph, the postvoid residual urine volume was significantly lower in the sitting position compared with crouching and standing positions (67 ml versus 130 ml and 130 ml; p < .001; figure 1). the average flow rate was slightly different in this group of patients when they changed their voiding position; the median fig. 1. postvoid residual urine volume in 10 men with benign prostatic hyperplasia in 3 voiding positions voiding position and uroflowmetry findings218 average flow rate was 2.5 ml/s in the crouching, 3.5 ml/s in the sitting, and 3 ml/s in the standing positions (p = .016; figure 2). also, the delay to start voiding was longest in the crouching position (6.5 seconds, 6 seconds, and 5 seconds in crouching, sitting, and standing positions; p = .011; figure 3). other parameters including voided urine volume, total flow time, flow time, maximum flow rate, and maximum flow time were not different in the 3 positions in men with bph (p = .90, p = .33, p = .27, p = .22, and p = .10, respectively). comparing sitting and standing positions in this group of patients, the postvoid residual urine volume was less, and the delay to start voiding was longer in the sitting position (p = .005, p = .012), but the average flow rate was not significantly different. discussion the physiology of voiding is dependent on mechanical characteristics of the detrusor muscle, mechanical characteristics of meatus, shape of meatus, and hydrodynamics of elastic tubes.(4) various models have been introduced to describe the mechanical and neurologic characteristics of the lower urinary system. in the hydrodynamic model, meatus is characterized as a heterogenous elastic tube in which urinary flow depends on time, cross-sectional area, and pressures of its segments. this model shows that table 1. urodynamic findings in healthy men and patients with bph, in crouching, sitting, and standing positions, reported as medians (interquartile ranges) position variable healthy men men with bph p value voided urine volume (ml) 316 (96) 220 (90) .003 total flow time (second) 18.5 (9) 87.5 (24) < .001 flow time (second) 17.5 (8.5) 85 (23.5) < .001 residual urine volume (ml) 0 (0) 130 (113) < .001 maximum flow rate (ml/s) 25 (6.1) 6.7 (2.3) < .001 average flow rate (ml/s) 16.5 (2.3) 2.5 (2) < .001 delay to start voiding (second) 1 (1) 6.5 (8) < .001 crouching maximum flow time (second) 9.5 (2.25) 9 (7.25) .988 voided urine volume (ml) 288 (27) 209 (101) .026 total flow time (second) 18 (4.5) 81.5 (37.5) < .001 flow time (second) 17 (4) 80 (37.5) < .001 residual urine volume (ml) 0 (0) 67 (82) < .001 maximum flow rate (ml/s) 25.5 (4.7) 7.2 (2.7) < .001 average flow rate (ml/s) 17 (1.5) 3.5 (2) < .001 delay to start voiding (second) 1 (1) 6 (8.25) < .001 sitting maximum flow time (second) 8.5 (2.25) 8.5 (2.75) .847 voided urine volume (ml) 307 (57) 235 (54) .001 total flow time (second) 20.5 (6) 88 (23.5) < .001 flow time (second) 19 (6) 86.5 (24.5) < .001 residual urine volume (ml) 0 (0) 130 (77) < .001 maximum flow rate (ml/s) 25 (5) 7 (3.6) < .001 average flow rate (ml/s) 17 (2.3) 3 (2) < .001 delay to start voiding (second) 1 (0.25) 5.5 (7.25) < .001 standing maximum flow time (second) 8 (5.25) 7.5 (8) .493 aghamir et al 219 the initial and final flows of micturition are influenced by the bladder neck, and midurinary flow (plateau phase) is produced by prostatic meatus.(5) urinary flow curve is also affected by sex and urinary volume in the bladder. in men with symptomatic bph, another parameter, pressure changes on the prostatic meatus and bladder neck from an enlarged prostate, impacts the uroflometry parameters.(4) another model for description of lower urinary tract function is the myocybernetic model. this model introduces 3 variables: volume of bladder contents, normalized activity of the detrusor muscle, and normalized activity of the sphincter. normalized activity of the detrusor is influenced by detrusor innervation, dynamics of smooth muscles, and changes in bladder geometrics. normal sphincter activity is affected by sphincter innervation, dynamics of striated muscles, and amount of changes to the meatal geometry.(5) fig. 2. average flow rate in 10 men with benign prostatic hyperplasia in 3 voiding positions fig. 3. delay to start voiding in 10 men with benign prostatic hyperplasia in 3 voiding positions voiding position and uroflowmetry findings different positions may alter these factors, and subsequently, urodynamic characteristics. voiding position has been studied in healthy persons, but the findings are controversial. riehmann and colleagues have shown that the urinary flow rate decreases in the recumbent position.(6) in 1999, yamanishi and coworkers studied 5 voiding positions in 21 healthy men aged 24 to 40 years. they reported that the maximum flow rate was 20.7 ± 6.59 ml/s with voided volume of 262 ± 77.8 ml in the lateral, 22.1 ± 7.05 ml/s with a voided volume of 309 ± 130 ml in the supine, 25.0 ± 8.25 ml/s with a voided volume of 287 ± 122 ml in the sitting, 27.1 ± 8.89 ml/s with voided volume of 263 ± 102 ml in the standing, and 28.7 ± 10.6 ml/s with voided volume of 303 ± 98 ml in the prone positions.(7) unsal and cimentepe studied sitting and standing positions in 44 healthy men and found no significant differences in uroflowmetry parameters and postvoid residual volume.(8) we found no differences in urodynamic parameters of healthy men in crouching, sitting, and standing positions. the crouching position also has been investigated by unsal and cimentepe. they evaluated 36 men and reported that the mean maximum flow rate, average flow rate, voided volume, and postvoid residual volume values in the sitting, crouching, and standing positions in men were not significantly different. they also studied 36 women in sitting and crouching positions and reported no differences in this group, either.(9) however, moore and colleagues, in 80 healthy british women, have shown that the crouching position causes a 21% reduction in average flow rate and a 149% increase in residual urine volume compared with the sitting position.(10) benign prostatic hyperplasia may have an additional effect on voiding position. this, however, has not been studied extensively. in unsal and cimentepe's study,(8) 44 patients with symptomatic bph were also evaluated in sitting and standing positions. their results are as follows: the mean maximum flow rate values for the standing and sitting positions in the patient group were 10.2 ± 0.49 ml/s and 9.5 ± 0.55 ml/s, respectively, and the mean average flow rate values were 4.7 ± 0.25 ml/s and 4.7 ± 0.31 ml/s, respectively. the mean voided volume values for the standing and sitting positions in the patient group were 292.6 ± 17.19 ml and 271.1 ± 15.51 ml, respectively, and the mean postvoid residual volume values were 82.2 ± 10.97 ml and 85.5 ± 12.46 ml, respectively. they found no differences in this group of patients, but in our patients, the postvoid residual urine volume was less, and the delay to start voiding was longer in sitting position. to our best knowledge, there is no study examining the effect of voiding positions of patients with bph on the angle and cross-sectional area of different segments of meatus, and consequently, on uroflowmetry findings. the present study, albeit on a small sample size of patients, indicates an apparent effect of the crouching position in the urodynamic findings of patients with bph, making consideration of this factor necessary when uroflowmetry is performed. conclusion it seems that different voiding positions in healthy people do not influence uroflowmetry findings and residual urine volume. however, in patients with bph, though trivial, these parameters may be affected by standing and crouching positions. in patients whose lower urinary tract function is borderline (eg, patients with bph), a more obtuse angel between the bladder and the urethral axes while sitting might be better for bladder emptying. the crouching position is the most common voiding position among iranian patients. thus, it may affect the urodynamic findings and physician's decision to treat. sitting at micturition may decrease the need for medical or surgical therapy or may postpone it. nevertheless, further studies are warranted. references 1. yoshimura n, de groat wc. neural control of the lower urinary tract. int j urol. 1997;4:111-25. 2. kinder mv, bastiaanssen eh, janknegt ra, marani e. neuronal circuitry of the lower urinary tract; central and peripheral neuronal control of the micturition cycle. anat embryol (berl). 1995;192:195-209. 3. paya as, chamizo jmg, pico fi, perez fm. urodynamic model of the lower urinary tract. proceedings of the international conference on computational intelligence for modelling control and automation (cimca'99); 1999 february; viena, austria. available from: http://www.ua.es/i2rc/cimca99ing.pdf 4. bastiaanssen eh, van leeuwen jl, vanderschoot j, redert pa. a myocybernetic model of the lower urinary tract. j theor biol. 1996;178:113-33. 5. valentini fa, besson gr, nelson pp, zimmern pe. a mathematical micturition model to restore simple flow 220 aghamir et al recordings in healthy and symptomatic individuals and enhance uroflow interpretation. neurourol urodyn. 2000;19:153-76. 6. riehmann m, bayer wh, drinka pj, et al. positionrelated changes in voiding dynamics in men. urology. 1998;52:625-30. 7. yamanishi t, yasuda k, sakakibara r, et al. variation in urinary flow according to voiding position in normal males. neurourol urodyn. 1999;18:553-7. 8. unsal a, cimentepe e. effect of voiding position on uroflowmetric parameters and postvoid residual urine volume in patients with benign prostatic hyperplasia. scand j urol nephrol. 2004;38:240-2. 9. unsal a, cimentepe e. voiding position does not affect uroflowmetric parameters and postvoid residual urine volume in healthy volunteers. scand j urol nephrol. 2004;38:469-71. 10. moore kh, richmond dh, sutherst jr, imrie ah, hutton jl. crouching over the toilet seat: prevalence among british gynaecological outpatients and its effect upon micturition. br j obstet gynaecol. 1991;98:569-72. 221 endourology and stone disease safety and efficacy of percutaneous nephrolithotomy in patients with severe skeletal deformities seyed habibollah mousavi-bahar, shahriar amirhasani,* maede mohseni, rezgar daneshdoost purpose: treatment of renal calculi in patients with severe skeletal deformities can be challenging. we present our experience in order to provide an assessment of technical difficulties, associated complications, and outcomes of percutaneous nephrolithotomy (pcnl) as a treatment option in this special patient group. materials and methods: our study included eight patients treated with pcnl for renal stones. all had severe skeletal deformities including six with severe kyphoscoliosis, one with osteogenesis imperfecta, and another with rickets. after pre-operative evaluation the procedure was performed under fluoroscopic and/or ultrasonic guidance. in all but one case, pcnl was performed with the patient in the prone position. silicone rolls and soft padded bolsters were used to obtain the best positioning for the procedure. clearance rates and complications were assessed. results: complete stone-free rate was achieved in six patients (75%) after first-pcnl. the two patients with residual stones underwent a second-look pcnl, after which one was completely cleared. the overall complete stone-free rate after second pcnl was 87%. only minor complications were seen in two patients (25%). conclusion: we found pcnl to be safe and effective for managing kidney stones in patients with severe skeletal deformities. keywords: kyphoscoliosis; osteogenesis imperfecta; percutaneous nephrolithotomy; renal calculi; rickets. introduction performing surgical, anesthesiologic, and technical procedures in patients with skeletal deformations can be very challenging.(1) percutaneous nephrolithotomy (pcnl) is well established in the modern era as the treatment of choice for large renal calculi even in cases with risk factors such as renal anatomical abnormality, morbid obesity, and a past history of renal surgery.(2, 3) there are few reports in the literature regarding the management of renal stones in patients with skeletal abnormality and most are focused on morbidly obese patients or patients with spinal cord injury.(4, 5) the aim of this study was to present our experience of technical difficulties, associated complications, and outcomes of pcnl in patients with skeletal abnormalities and renal stones. we present our experience to provide an assessment of technical difficulties, associated complications, and outcomes to evaluate pcnl as an option for urolithiasis treatment in this patient population. patients and methods study population our study included eight patients treated with pcnl for renal stones. pcnl was performed by one surgeon in our hospital between the years 2008 and 2014. all patients had severe skeletal deformities including six with severe kyphoscoliosis, one with osteogenesis imperfecta, and another with rickets. the mean age of our patients was 43.2 years (range: 6-58) and three patients were female (table 1). one patient had history of failed shockwave lithotripsy (swl), two patients had past history of ureteroscopy and open nephrolithotomy. pre-operative diagnostic imaging of the urinary tract, including intravenous urography (ivu), was performed in all patients to evaluate urinary tract abnormalities and to identify the anatomic location of the stones. for evaluation of intra abdominal organs, spinal deformity and assessing percutaneous approach we used computed tomography (ct scan) and ultrasound. prior to surgery, all patients were evaluated by an anesthesiologist who used the mallampali score to predict intubation comfort. prophylactic antibiotics (firstor second-generation cephalosporin or fluoroquinolone ) were administrated to all patients and all procedures were performed with the patient under general anesthesia. we estimated the stone burden via ct-scan with coronal section reconstruction. the entire procedure was performed by an experienced endourologist. inclusion criteria inclusion criteria were patients with renal stone and skeletal deformities. exclusion criteria exclusion criteria consisted of pregnancy, untreated coagulopathy and any contraindication for anesthesia. pcnl procedure cystoscopy was performed on all patients; a 5-f ureurology & nephrology research center, hamadan university of medical sciences, hamadan, iran. *correspondence: urology & nephrology research center, hamadan university of medical sciences, hamadan, iran. tel : +98-813838704, +98-9188127721. e-mail: shahriar_amirhassani@yahoo.com. received december 2016 & accepted april 2017 vol 14 no 03 may-june 2017 3054 teric catheter was advanced up to the renal pelvis then ureteral catheter was fixed to a foley catheter (1016f). in all but one patient, pcnl was performed in the prone position. soft padded bolsters and silicone rolls were used to obtain the best position for the procedure (figure 1). we used fluoroscopic guidance to obtain percutaneous access in all patients; in one case we needed to perform pcnl under ultrasonic guidance in combination with fluoroscopy. under direct fluoroscopic-guidance (ultrasound), an 18-gauge needle was used to puncture the collecting system; a hydrophilic guidewire (0.038 inch) was then pushed through the needle until it reached renal system. depending on the existence of hydronephrosis, the working tract was dilated using alken dilators or the one-shot technique. (6–8) nephroscopy was performed using a rigid nephroscope (standard nephroscope 26f) in the all cases; a flexible nephroscope was available for the last 2 cases (number: 7, 8). a pneumatic device (swiss litho clast master, ems, nyon, sz) was used for lithotripsy. grasping forceps were used for removal of stone fragments. stone-free status was evaluated at the end of the procedure by fluoroscopy;(9) then a double-j was inserted antegradely if necessary. reentry nephrostomy (22f) were placed. evaluations symptoms, physical examination, lab-data and ultrasound were used to evaluate complications. patients had a follow-up via kidney-ureter-bladder (kub) x-ray and ultrasound 2 to 6 months after the procedure. the nephrostomy tubing was removed when patients were discharged, after we ruled out residual stones via kub or ultrasound. statistical analysis for our study, we collected and analyzed the clearance and complication rates. the necessary data was analyzed with spss software (the statistical package for the social sciences, version 16.0, spss inc, chicago, illinois,usa). table 1. detailed parameters of patients number 1 2 3 4 5 6 7 8 age; year 56 6 47 53 41 47 38 58 sex f f f m m m m m stone location multiple proximal of renal renal renal renal pelvis renal pelvis & renal stones ureter pelvis pelvis pelvis & lower calyx lower calyx pelvis hydronephrosis severe moderate mild mild mild moderate mild mild clearance after initial pcnl yes yes yes yes yes yes no no stone residue (mm) ------ ------------ 10 14 clearance after redopcnl ------ ------------ yes no stone burden (mm2) 216 55 272 132 750 456 190 572 operative time (min) 60 75 95 30 210 180 125 120 abbreviations: f, female; m, male. figure 1. prone position safety and efficacy of percutaneous nephrolithotomy-mousavi-bahar et al. endourology and stone diseases 3055 results patients parameters are summarized in table 1. we collected and evaluated patient demographic data from the medical records. percutaneous renal access was achieved via upper-pole tract (n:1), mid-pole tract (n:1) and lower-pole tract (n:6). complete stone clearance was achieved in 6 patients (75%) after the first-pcnl; two patients had residual stones. these two underwent a second-look pcnl that resulted in complete stone clearance in one case. the complete stone-free rate after second pcnl was 87% (table 2). the mean operative time was 111.8 min (range, 30–210 min) and the mean hospital stay was 3 days (range, 2–5 days). there were no anesthetic complications and no admissions to the intensive care unit. we evaluated surgical complications by using a modified clavien grading system.(10) overall, we had 2 complications in 8 pcnls (25%). the first was a patient with transient fever (t: 38.2ºc oral) who only required routine antibiotics (grade 1 clavien). the second complication was a patient with acute blood loss requiring one unit of blood transfusion (grade 2 clavien). no instances of vascular trauma, bowel injury, hematoma formation or septicemia were evident. the mean hemoglobin drop was 1.5 mg/dl (range, 0.8–2.2). with the exception of one patient who was treated by an anterior approach, pcnl was performed in prone position. five patients underwent antegrade ureteric double-j placement. the left kidney was affected in two patients and the right in six. post-operatively, one patient (number: 8) underwent swl. one patient (number: 5) underwent tubeless pcnl while the remaining patients had nephrostomy tubes placed. a second procedure was performed for remnant stones in 2 cases (numbers: 7 and 8). we present the imaging from case number 7. he had 190 mm2 stones in the renal pelvis and lower calyx (figure 2); his first pcnl was performed under fluoroscopic guidance. the renal pelvis was cleared but the lower calyx was not (figure 3); therefore, we performed redo-pcnl with flexible nephroscope from another tract, resulting in complete clearance (figure 4). discussion severe skeletal anomaly is a problem that affects the quality of life. spinal deformities including scoliosis and kyphosis impair respiratory function,(11) and these patients present a challenge during surgical, anesthesiological and technical procedures.(12) before the introduction of pcnl and swl, open surgery was the only method of therapy with major complications including paralytic ileus and wound infection.(13) patients with skeletal deformities often have other comorbidities for example renal stone formation. on the other hand, interventional treatment in these patients is a large challenge for urologists. in normal populations without skeletal deformities we have several non-medical therapeutic methods available for surgical treatment of renal stones, for example: nephrolithotomy, swl, ureteroscopy and pcnl. in patients with skeletal deformities, open surgery and retroperitoneal approach is difficult and the risk of wound infection is high and the time for wound repair is longer than other patients. the other commonly used method is swl; swl is often unsuccessful and with high re-treatment rate in this patient population since proper positioning is hard to achieve makeing wave focus on target difficult. even if swl is feasible and successful, the endourologist is faced with the problem of how to remove stone fragments because fragment passage can be hindered by aberrant renal locations. passage of the stone fragments from the ureter is challenging since ureteroscopy, especially rigid table 2: stone burden and clearance rate after pcnl study number mean average clearance clearance require required nephronever cleared complication (%) of patients patient stone after first after redo swl (%) ureteroscopy (%) or lost age (year) burden pcnl (%) pcnl(%) follow-up (%) (mm2) our study 8 43.2 330 75 87 12.5 0 0 25 alisinnawi 5 28 940 60 80 20 0 0 100 et al. (15) kara et al.(16) 5 36.8 475 60 80 0 20 0 60 goumas et al.(2) 9 46 372 55.5 66.6 22 11 11 41 symons et al.(3) 29 44 13 had 62 ----13 6.8 24 48 (10 spina staghorn bifida ) safety and efficacy of percutaneous nephrolithotomy-mousavi-bahar et al. vol 14 no 03 may-june 2017 3056 figure 2. stones in the left renal pelvis and lower calyx ureteroscopy, is difficult. our research has found that in these conditions the best method for treatment of renal stones in patients with severe skeletal deformities is pcnl. open surgery and ureteroscopy (urs) have difficult restrictions due to anatomic variations. patients with musculoskeletal deformity, such as kyphosis and scoliosis, can have associated urinary tract problems including infection and stone formation.(14) prolonged anesthesia in the prone position, combined with the respiratory and cardiac dysfunction, necessitates detailed monitoring of the respiratory and cardiovascular system during surgery.(15) in our study, all patients required a single tract access in first pcnl. all patients had a ct scan of the abdomen & pelvis before the procedure to avoid colonic injury and to delineate anatomy. it is also useful to plan the choice of calyx and the orientation of the tract. in an active endourology department that performs many pcnl procedures each week, a wide variety of patients undergo pcnl; the endourologist should consider the individual when making decisions about treatment. the prone position, if possible with the patient's body habitus, may offer a wider space for percutaneous access. the patient's position is crucial for pcnl; in our cases the desired positioning was accomplished by using pillows to maintain upper body support. stabilization of the patients head and cervical spine was achieved with a horseshoe head support and the table was tilted to a reverse trendelenburg position to avoid cerebral edema. pcnl as monotherapy assists in eradicating large stones and yields excellent results with minimal morbidity even in difficult cases such as those involving renal anatomic variations, children, and morbidly obese patients. there are few reports about the management of kidney calculi in patients with skeletal abnormalities. alsinnawi et al.(11) reported clearance rate of 60% with complication rate of 100% (clavien 1&2). goumas-kartalas et al.(2) reported a 44% complication rate and clearance rate of 55.5%. kara et al. (12) reported a first-pcnl clearance rate of 60% with a complication rate of 60% in their 5 patients. symons et al.(3) reported 39 pcnl procedures in 29 patients with 48% complication rate including 2 post-operative deaths. in our study, the stone clearance rate was 75% after one session pcnl and 87% after redopcnl and complication rate was 25%. conclusions the restricted number of cases makes it impossible to get definitive conclusions and recommendations. however, our research has found pcnl to be safe and effective for managing renal stone disease in patient with severe skeletal deformities. in the end, respiratory and cardiac dysfunctions are common in patients with skeletal deformities; therefore, an extensive analysis should be performed. acknowledgement we thank to contributors for analysis and interpretation of the data. also, members of staff of the records section of shahid beheshti hospital for their help with the data collection. all authors have read and approved the final manuscript. all authors are employees of hamadan university of medical sciences, hamadan, iran. this study was approved by urology & nephrology research center, hamadan university of medical sciences, hamadan, iran and also by chancellor of research and technology of hamadan university of medical sciences. these institutes had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. conflict of interest the authors of this manuscript have no conflicts of interest to disclose as described by the urology journal. safety and efficacy of percutaneous nephrolithotomy-mousavi-bahar et al. endourology and stone diseases 3057 figure 3. renal pelvis was cleared. figure 4. complete clearance after redo-pcnl. references 1. ozyurt g, basagan-mogol e, bilgin h, tokat o.spinal anesthesia in a patient with severe thoracolumbar kyphoscoliosis. tohoku j exp med. 2005;207:239–42. 2. goumas-kartalas i, montanari e. percutaneous nephrolithotomy in patients with spinal deformities. j endourol. 2010;24:1081–9. 3. symons s, biyani cs, bhargava s, et al. challenge of percutaneous nephrolithotomy in patients with spinal neuropathy. int j urol. 2006;13:874–87. 4. gofrit on, shapiro a, donchin y, et al. lateral decubitus position for percutaneous nephrolithotripsy in the morbidly obese or kyphotic patient. j endourol. 2002;16:383–86. 5. culkin dj, wheeler js, nemchausky ba, et al. percutaneous nephrolithotomy: spinal cord injury vs. ambulatory patients. j am paraplegia soc. 1990;13:4–6. 6. alken p. the telescope dilators. world j urol. 1985;3:7–10. 7. amirhassani s, mousavi-bahar sh, iloon kashkouli a, et al. comparison of the safety and efficacy of one-shot and telescopic metal dilatation in percutaneous nephrolithotomy: a randomized controlled trial. urolithiasis. 2014;42:269. 8. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899–906. 9. mousavi-bahar sh, mehrabi s, moslemi mk. the safety and efficacy of pcnl with supracostal approach in the treatment of renal stones. int urol nephrol. 2011; 43:983-7. 10. tefekli a, ali karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008;53:184–90. 11. patel j, walker jl, talwalkar vr et al. correlation of spine deformity, lung function, and seat pressure in spina bifida. clin orthop relat res. 2011;469:1302–7. 12. papatsoris a, masood m, el-husseiny t, et al. improving patient positioning to reduce complications in prone percutaneous nephrolithotomy. journal of endourology. 2009;23: 831-2. 13. donovan wh, carter re, bedbrook gm, et al. incidence of medical complications in spinal cord injury: patients in specialised, compared with non-specialised centres. paraplegia. 1984; 22:282–90. 14. beals rk, robbins jr, rolfe b. anomalies associated with vertebral malformations. spine. 1993;18:1329–32. 15. alsinnawi m, torreggiani wc, flynn r, et al. percutaneous nephrolithotomy in adult patients with spina bifida, severe spinal deformity and large renal stones. ir j med sci. 2013;182:357–61. 16. kara c, resorlu b, ozyuvali e et al. is percutaneous nephrolithotomy suitable for patients with scoliosis: single-center experience. urology. 2011;78:37–42. safety and efficacy of percutaneous nephrolithotomy-mousavi-bahar et al. vol 14 no 03 may-june 2017 3058 urology in history 138 urology journal vol 6 no 2 spring 2009 avicenna’s canon of medicine and modern urology part iii: other bladder diseases seyed mohammad ali madineh in the third part of this article on avicenna’s canon of medicine, diseases of the bladder other than bladder calculus are reviewed. avicenna covers topic on bladder infection, pelvic abscess, urethritis, cystitis, prostatitis, bladder tumors, bladder dysfunction, urinary retention, and neurogenic bladder. the interesting point is that 10 centuries ago, avicenna had described almost all diseases of the blabber. avicenna’s canon of medicine is a comprehensive book on semiology of bladder diseases. his approach to diagnoses complies with the modern methodology, and even in some interventions such as routes of drug administration and catheterization, his points are astonishing. urol j. 2009;6:138-44. www.uj.unrc.ir urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: seyed mohammad ali madineh, md mostafa khomeini hospital, italia st, tehran, iran tel: +98 21 6643 8140 fax: +98 21 6690 7895 e-mail: madinehurologist@yahoo.com introduction avicenna has had a great influence on the medical knowledge of the world by writing the canon of medicine. in the previous two parts of these articles, i reviewed chapters of avicenna’s book on bladder anatomy and diseases with modern urological findings.(1,2) in this part of these article series, review of book iii, part 19 is completed by covering chapters 7 to 15 which are on bladder inflammation, infections, tumors, and neurogenic bladder. materials and methods this study is the comparison of modern urology with the urological chapters of avicenna’s canon of medicine. i used the canon in its original language (arabic),(3) along with its persian translation.(4) part 19 of the 3rd book contains subjects related to a vast range of bladder diseases such as tumors, infection, and bladder dysfunction. i compared the text to the current urological findings. selected topics from the canon are presented and a brief discussion follows each subject. a translation from the arabic version and comparison with the persian translation was done to present an accurate text. the domain of traditional and herbal medicine in avicenna’s book was skipped here. these subjects were beyond the aim of this paper, and i was only engaged to the items that the current modern medicine obviously and clearly proceeds with them. it should be noted that this paper is a revised version of an article by the author in persian which was published in the iranian journal of urology in 1996.(5) discussion book iii, part 19, treatise 1, chapter 7 “warm inflammation and abscess avicenna’s canon of medicine—madineh urology journal vol 6 no 2 spring 2009 139 in bladder” is the title of this chapter, which is on bladder infection: less frequently, there is warm inflammation in the bladder that is accompanied by the excretion of blood,... . this often affects children, but it can affect adults too. bladder calculus can cause this condition. calculus scratches the bladder and leads to pain and warm inflammation. its signs are fever, urinary retention or difficult voiding, and urinary dribbling. the patient cannot void in the flank position and only amount of urine is excreted in the standing position. occasionally, the concentrated urine may be trapped in the bladder. there is inflammation in the flank and suprapubic area. there is pain in the flank area that is similar to needle insertion. it is sometimes throbbing accompanied by redness in the perirenal area. another sign is that pain is alleviated if you bandage the area. symptoms of warm inflammation in bladder are: (1) severe thirst, (2) vomiting of bile, (3) dyspnea similar to that of asthma, (4) cold extremities, (5) delirium, (6) blackness of tongue, (7) worsening of disease by any astringent and diuretic food, and (8) relation of the disease and the patient’s age. the worst signs of warm inflammation in the bladder are severe persistent fever, retention of urine, fecal impaction, severe constipation, and worsening pain…. if warm inflammation of the bladder converts to abscess, it is much more dangerous, but if urinary sediment of the patient is clear, there is hope of recovery. otherwise, cloudy sediment is a sign of patient’s death. in bladder abscess, there are several types of rigor, various types of fevers, and signs similar to those described for kidney abscess. if the abscess bursts into the bladder, its sign is the pus that passes through urine. if the abscess … does not burst, the patient dies in 1 week. discharges of bladder in abscess often appear in bladder neck and occasionally may flood to other surrounding tissues. bladder abscess can be opened and drip its content to the abdominal cavity or places other than the abdomen.(3,4) discussion 1. warm inflammation and abscess in the bladder to which avicenna points is indeed severe bacterial infection of the bladder, pyovesica, and prostatic abscess. bladder infection itself is a frequent disease that is prevalent, especially in women. pyovesica, however, is relatively rare and is often secondary to infravesical obstruction. it is especially associated with diabetes mellitus, chronic kidney failure, and immunocompromised conditions. this is now obvious that urethral instrumentation, chronic indwelling catheter, foreign bodies, and bladder calculi can aggravate bladder inflammation. in the ancient area with no antibiotics, it can be anticipated that the prevalence of bacterial infection of the low urogenital tract had been higher than that in the modern area.(6) discussion 2. the symptoms and signs that avicenna lists in his book are fever, urinary retention, difficult voiding, dribbling, and concentrated urine. he describes signs of kidney abscess including inflammation in the flank and redness of that area due to renal or perirenal abscess, and signs of urinary retention, such as suprapubic bulging, that are a predisposing factor of pyovesica. bulging of the suprapubic area as the sign of paravesical and prostatic abscess can lead to septicemia and septic shock. in the final stage, there is coldness of the extremities, confusion, cyanosis, vomiting, and acute respiratory distress syndrome with associated symptoms such as dyspnea. severe thirst can be a symptom of hypotension and early stages of septic shock. also, diabetes mellitus that induces thirst is a predisposing factor for severe urinary tract infection and abscess. neurogenic bladder due to diabetes mellitus can be another predisposing factor for urinary tract infection in these patients. fever and rigor can be induced in the presence of perivesical abscess, pyovesica, and prostatic, renal, or perirenal abscess.(6) discussion 3. bladder perforation can be induced by multiple causes. one of them which is the most frequent is trauma.(7) occasionally, spontaneous perforation of the bladder is induced in some diseases such as bladder cancer or thinning of the bladder wall due to any causes.(7) perforation of the bladder, as avicenna states here, can be intraperitoneal or extraperitoneal,(7) avicenna’s canon of medicine—madineh 140 urology journal vol 6 no 2 spring 2009 and if it is associated with purulent urine, it can induce infectious peritonitis or perivesical abscess. book iii, part 19, treatise 1, chapter 8 in this chapter, named “management of bladder inflammation,” avicenna first describes some of the therapeutic methods which are outdated and i have to pass them aside. then, he points to 4 of the important therapeutic methods that he uses for bladder inflammation in addition to oral drugs. in early stages of the disease, inject these drugs transurethrally into the bladder by a hollow cylindrical instrument, if the patient can tolerate [drugs list is omitted here]. if the pain of the inflammated bladder aggravates to a severe level that could induce [shock and] death, you must prescribe narcotics. you can prescribe it locally by rubbing onto the skin over the bladder or inject it into the bladder. you should know that asking the patient to sit in sitz bath is always useful even if the patient wants to void in the water. let the patient do this because it is therapeutic and useful. there are some solutions that are compatible and useful for patients with bladder inflammation. there are solutions that are mixed with various drugs. and this method relieves the pain due to inflammation. you must dissolve these drugs in water and soak a handkerchief in it until the handkerchief absorbs the drug, and then, insert the handkerchief into the patient’s anus until he pain is alleviated. the patient will immediately sleep. in this stage, if the patient tolerates, inject some of these narcotics through penile urethra with a hollow cylindrical instrument into the bladder. at this time, if you rub the narcotics on the patient’s bladder topically you can boost the effects of these drugs.(3,4) discussion 1. in this chapter, avicenna points out to 4 important routes of drug administration in bladder disease: (1) transurethral injection of drugs by a hollow instrument, (2) rubbing the drug onto the skin over the bladder or topical administration of drugs, (3) sitting the patient in sitz bath, and (4) transrectal administration of analgesics. it is notable how avicenna was familiar with intravesical drug injection. today in modern urology, this method is prescribed in the local treatment superficial transitional cell carcinoma of the bladder.(8) also, some drugs are prescribed by this method in the treatment of interstitial cystitis.(9) avicenna also names local drug therapy that is the cornerstone of iontophresis in drug prescription.(10) iontophresis is a noninvasive method of propelling high concentrations of a charged substance, medications, or bioactive agents transdermally by repulsive electromotive forces using a small electrical charge. today it can be used in peyronie’s disease.(10) another interesting point is avicenna’s indication of the use of sitz bath in some disease. in modern urology, hot sitz bath is used for the treatment of some disorders such as amicrobic cystitis and chronic prostatitis.(11) finally, avicenna points to rectal route of drug administration. this is astonishing that he was familiar to all of these methods of drug administration. discussion 2. today, urologists prescribe anticholinergics, acetaminophen, nonsetroidal anti-inflammatory drugs, antidepressants, and selective bladder analgesics such as phenazopridine for bladder pain. in case of severe and intolerable pain, especially in inoperable highgrade and high-stage bladder tumors and even in chronic painful bladder syndrome, opiates are prescribed orally or parenterally.(9) book iii, part 19, treatise 1, chapter 9 avicenna describes a second type of bladder inflammation in this chapter entitled “hard inflammation in bladder”: causes of hard inflammation in the bladder are the same as causes of hard inflammation in the kidney, which are often induced by heat, trauma, and falling down to the ground on the suprapubic area. occasionally, it is a complication of bladder surgery. hard inflammation in the bladder has distinctive signs by which it can be diagnosed; (1) difficult voiding and difficult defecation is seen; (2) some signs and symptoms of hard inflammation of the kidney such as fecal retention, numbness of the lower leg, confusion, and debility are present (sometimes hard inflammation of bladder can lead to dropsy avicenna’s canon of medicine—madineh urology journal vol 6 no 2 spring 2009 141 [estesga in arabic] ); (3) it has less severe symptoms in comparison with hard inflammation of the kidney; (4) the site of inflammation is compatible with the bladder location and not the kidneys (bladder inflammation is in the bladder in which the urine accumulates); and (5) the pain and other signs in hard inflammation of the bladder begins from a site more inferior than those of the kidneys. management of hard inflammation in the bladder is the same as that of the kidneys: (1) some ointments must be rubbed on suprapubic area; (2) drinking solutions that are combined with diuretic herbal seeds is recommended; (3) sitz bath is useful the same as in hard inflammation of the kidney; and (4) catheters [gasathir in arabic] should be used. the latter are instruments by which drugs are injected from down to up. this treatment is specific for bladder inflammation, and in this method, the therapeutic drugs and solutions are injected into the bladder.(2,3) discussion. apparently, hard inflammation of the bladder is chronic cystitis and chronic prostatitis, and avicenna prescribes the above mentioned methods for treatment of these disorders. book iii, part 19, treatise 1, chapter 10 this chapter is on bladder ulcers: causes of bladder ulcer are probably the same as the causes of kidney ulcers. bladder ulcer is often due to abrasion and desquamation induced by calculi. it is probable that there had already been inflammation in the bladder that has burst or there had been a boil that has become purulent and ultimately converted into ulcer. if a person has severely astringent urine for a long time, it can induce bladder ulcer. management of bladder ulcer is more difficult than management of kidney ulcer because the bladder has been created from fibrous tissue. curability of the ulcers originated from fibrous tissue is more difficult than of ulcers originated from fleshy material. in these patients, if the bladder is perforated or torn, death is the most probable event. during surgery, if some parts of the bladder tear, they will not heal except in states that the scalpel hits to fleshy part of bladder during operation in which state it may be cured. bladder ulcer symptoms : bladder ulcer can induce urinary retention or difficult urination and suprapubic and flank pain. in bladder ulcer, whitish scales are excreted in urine. if large, their origin is from bladder ulcer and if small, their origin is from ureteral ulcer. bladder ulcer can be mutilating type and we discussed them in chapter on kidney ulcer. symptoms of bladder ulcer are the same as symptoms of kidney ulcer and include blood in urine, pus in urine, frequency, and intermittency. also signs of bladder and kidney ulcers are similar and include signs of inflammation or mass, mutilation [khoreh in persian], and bladder cracking and perforation.(3,4) discussion 1. studying the avicenna’s descriptions in this chapter and the chapter of kidney ulcer reveals that bladder ulcer in the canon means bladder cancer or malignancy. in the chapter of kidney ulcer, he specifies that kidney ulcer is malignant, but its malignancy is less severe than the malignancy of bladder and ureteral ulcers. he accurately discusses their signs.(3) discussion 2. bladder and renal pelvis malignancies both have a same origin and a same etiology as avicenna mentions. bladder and renal pelvis urothelial chronic injury and irritation by calculi and chronic infection can be a predisposing factor of cancer in these organs, especially of squamous cell carcinoma of the bladder. avicenna points to the role of bladder calculi in bladder carcinoma. today, carcinogenic agents in urine, of course are the most important factors in the industrialized era (not at avicenna’s era) in the etiology of bladder cancer.(12) discussion 3. avicenna, at the end of this chapter, describes 3 types of bladder cancer: inflammatory (mass and association with stone), mutilating (infiltrative), and ulcerative (perforative). today there is no place for perforative bladder cancer in its classification, but bladder cancer can be a cause of spontaneous perforation of the bladder,(7) to which avicenna points, too. in the canon’s classification of bladder cancer, avicenna indicates the 2 major types of bladder cancer: papillary (exophytic) and infiltrative ulcerative or sessile types.(13) avicenna’s canon of medicine—madineh 142 urology journal vol 6 no 2 spring 2009 discussion 4. avicenna discusses one important issue: postoperative urinary fistula. this complication, which rarely occurs today, is induced by unhealed bladder tissue and it can even cause tumoral tract and extension of tumor to the abdominal wall. today in bladder cancer operations, the urologist must try as far as possible, not to insert cystostomy tube to prevent this complication.(14) discussion 5. avicenna points to urinary retention and difficult urination as signs of bladder cancer. these signs are prevalent in tumors near the bladder neck. he also points to suprapubic and flank pain. flank pain can be induced by ureteral obstruction and hydronephrosis due to bladder tumor.(12) discussion 6. excretion of whitish scales in urine to which avicenna points can in fact be necrotic papillary particles in cauliflower bladder tumors. cancerous cells in urine was the basis of modern oncourological cytology and flowcytometric techniques.(12) discussion 7. avicenna indicates astringent urine in ulcers. painful bladder syndrome/interstitial cystitis—named at times as a pseudonym hunner’s ulcer—can be induced by urinary abnormalities. this theory, which is similar to astringent urine theory of avicenna in bladder ulcer, is based on toxicity of interstitial cystitis urine.(11) book iii, part 19, treatise 1, chapter 11 chapter 11 of the canon of medicine is on bladder pustules or desquamation [jarab in arabic]: when a patient has dysuria, malodorous urine, severe suprapubic pain, itching around the bladder, and bran-like urinary sediment, the diagnosis is bladder pustules. the purulent material due to inflammation can induce bladder pustules. in this disorder, the patient urinates blood instead of urine occasionally.(3,4) discussion. in this chapter, avicenna does not give us additional information about pustules. by studying this disease in other organs such as the kidney in the canon, we suppose that the bladder pustules is in fact urethritis. book iii, part 19, treatise 1, chapter 12 chapter 12 is on blood coagulation (clotting) [jomoud dod dam in arabic] in the bladder: occasionally, blood can be clotted in the bladder and remain there in coagulated form. symptoms of blood clotting in the bladder are: (1) the patient is severely depressed; (2) sometimes, the patient faints; (3) on palpation, the extremities are cold; (4) the patient has short respirations; (5) the patient’s pulse is weak and rapid; (6) the patient has cold perspiration; (7) the patient has nausea; (8) sometimes, hematuria and fever or rigor are seen; (9) sometimes, blood clots in the bladder after trauma due to direct hit to the bladder or falling down on the bladder.(3,4) discussion 1. please note that how accurate is avicenna’s description of intravesical hematoma and signs or symptoms of hemorrhagic and septic chock due to hematoma. his notes are comparable to the modern medicine. avicenna describes shock and its signs such as restlessness, depression of body functions, tachypnea, hypoperfusion of the extremities and coldness, accelerated pulse, and cold perspiration.(15) discussion 2. severe hematoma is one of the predisposing factors of urinary tract infection and septicemia, especially with urinary tract manipulation and catheterization. today, this complication has been reduced by antibiotics and aseptic manipulation and surgical techniques. discussion 3. avicenna points out to one of the causes of bladder hematoma, ie, bladder and urethral trauma and 2 mechanisms of injury: direct hit to the bladder and straddle injury.(16) book iii, part 19, treatise 1, chapter 13 this chapter of the book is on neurogenic bladder using the terms “bladder luxation or displacement” and “laxity”[esterkha in arabic]: bladder displacement or descending is a state in which the bladder moves or descends from its natural anatomic place. bladder laxity is a state in which urine rushes without patient’s willing and control. one of the causes of descended bladder is trauma to back. sometimes bladder displacement or bladder laxity causes difficult avicenna’s canon of medicine—madineh urology journal vol 6 no 2 spring 2009 143 voiding or dribbling, depending to the condition of the muscle that can be extended and dilated. if displacement of the bladder is due to back trauma, its treatment is difficult. bladder displacement or laxity can be due to paralysis or convulsion.(3,4) discussion. it is noteworthy that how avicenna briefly points to neurogenic bladder and its two spastic and flaccid types. spinal cord injury is a frequent cause of neurogenic bladder that, especially in modern era, is due to car accidents. difficult voiding, frequency, dribbling, and urinary incontinence occur in this situation. convulsion, especially due to space occupying lesions and also diseases that cause paralysis (eg, cerebrovascular accident), can induce neurogenic bladder and voiding symptoms, too. avicenna knew these etiologies 10 centuries ago.(17) neurogenic bladder is one of the main complicated urological diseases in modern urology that despite all advances, its therapeutic methods are controversial, yet. book iii, part 19, treatise 1, chapter 14 interestingly, avicenna reviews all causes of pain in the bladder area [oojaol mathana in arabic] after all chapters on specific bladder diseases: bladder pain can be due to one of the causes listed below: (1) abnormal temperament, (2) bladder calculus, (3) bladder ulcer, (4) bladder pustules, (5) inflammation, (6) wind or gas, and (7) other disorders that affect the bladder. bladder pain often occurs in seasons with northern wind blowing. then avicenna discusses a case report about pain in the bladder area: it is said that if a patient has bladder pain and after several days, a mass grows in his left subaxillary area and he will dye after 15 days, especially if after growing the subaxillary mass, he has lethargy. in this situation, death is indispensable.(3,4) discussion. as you note in this chapter, avicenna reviews some vesical causes of suprapubic pain. the most prevalent of them is cystitis (or bladder inflammation as avicenna cites). also, avicenna indicates some other main causes of pain including bladder calculi, bladder tumors (or bladder ulcer as avicenna cites), and urethritis (or bladder pustules as avicenna cites). book iii, part 19, treatise 1, chapter 15 chapter 15 is named “bladder weakness”: bladder can become weak due to abnormal temperament, hard inflammation, bladder laxity, or bladder displacement. cold weather is a cause too. bladder weakness may be so severe that it cannot tolerate excessive urine, and thus, it expels it out. the bladder muscle can be so weak that it cannot expel the urine out. in these two conditions that both bladder and its muscles are weak, occasionally but not frequently and not regularly, there may be dribbling.(3,4) discussion. as you notice, avicenna points to bladder dysfunction and atony, the most important cause of which is neurogenic bladder. two important progressive stage of this condition to which avicenna points are overflow incontinence and urinary retention. in overflow incontinence, as avicenna cites, the bladder weakness is severe, but it can expel the urine out. however, in the final stage, as he cites, the bladder muscle is so weak that it cannot expel the urine out. especially in the first stage (overflow incontinence), there is urinary dribbling as he indicates. conclusion ten centuries ago, avicenna had described almost all diseases of the blabber. although treatment methods and medications had not been developed enough, avicenna’s canon of medicine is a comprehensive book on semiology. his approach to diagnosis complies with the modern methodology, and even in some interventions such as routes of drug administration and catheterization, his points are astonishing. references 1. madineh sma. avicenna’s canon of medicine and modern urology. part i: bladder and its diseases. urol j. 2008;5:284-93. 2. madineh sma. avicenna’s canon of medicine and modern urology. part ii: bladder calculi. urol j. 2009;6:63-8. avicenna’s canon of medicine—madineh 144 urology journal vol 6 no 2 spring 2009 3. ibn sina. al-qanun fi al-tibb. rome: typgraphia mediciea; 1593. p. 539-43. 4. abu ali sina. qanun [translated into persian by sharafkandi ar]. tehran: soroush; 2004. book iii, p. 155-60. 5. madineh sma. avicenna’s canon of medicine and modern urology. part ii: bladder and its diseases. iran j urol. 1996;3:3-10. 6. nguyen ht. bacterial infections of the genitourinary tract. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 16th ed. new york (usa): mcgrawhill medical; 2004. p. 220. 7. mcaninch jw. injuries to the genitourinary tract. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 16th ed. new york (usa): mcgraw-hill medical; 2004. p. 291-310. 8. jones js, campbell sc. non-muscle-invasive bladder cancer. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2455. 9. hanno pm. painful bladder syndrome/interstitial cystitis and related disorders. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 331-64. 10. barry bw. novel mechanisms and devices to enable successful transdermal drug delivery. eur j pharm sci. 2001;14:101-14. 11. tanagho ea. specific infections of the genitourinary tract. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 16th ed. new york (usa): mcgrawhill medical; 2004. p. 236. 12. messing em. urothelial tumor of the bladder. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2415-31. 13. grossfeld gd, carroll pr. urothelial carcinoma: cancers of the bladder, ureter & renal pelvis. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 16th ed. new york (usa): mcgraw-hill medical; 2004. p. 326. 14. hinman f. atlas of urologic surgery. 2nd ed. philadelphia: wb saunders; 1998. p. 503. 15. mandell gl, bennett je, dolin r, editors. mandell, douglas, and bennett’s: principles and practice of infectious diseases. 6th ed. philadelphia: churchill livingstone; 2005. p. 915-6. 16. morey af, rozanski ta. genital and lower urinary tract trauma. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2655-6. 17. wein aj. lower urinary tract dysfunction in neurologic injury and disease. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2014-5. urological oncology 243urology journal vol 5 no 4 autumn 2008 urine concentration of nuclear matrix protein 22 for diagnosis of transitional cell carcinoma of bladder hassan jamshidian,1 kianoush kor,2 mahmoud djalali3 introduction: the aim of this study was to determine the diagnostic value of urine nuclear matrix protein 22 (nmp22) level in detection of transitional cell carcinoma (tcc) of the bladder. materials and methods: a total of 76 patients with newly-diagnosed or recurrent tcc and 75 controls without urinary tract disorders participated in this study. a urine sample was obtained for measurement of the nmp22 level using the enzyme-linked immunoabsorbent assay. the resulted values were evaluated in comparison with the results of pathologic examination. results: a total of 76 patients with tcc of the bladder and 75 volunteers without tcc were enrolled in the study. the mean level of urine nmp22 had an increasing trend associated with tumor grade (p = .01) and tumor stage (p < .001). in participant without tcc, the mean urinary nmp22 level was 5.48 ± 6.34 u/ml, while this value was 25.01 ± 35.33 u/ml in patients with tcc of the bladder (p < .001). the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of urine nmp22 for detection of tcc were 75.5%, 86.7%, 85.1%, 77.4%, and 80.8%, respectively. the sensitivity of nmp22 in detecting stage ta tumors appeared to be low (31.3%), but for grade 1 tumors, the sensitivity was 66.7%. conclusion: measurement of urine nmp22 is a noninvasive, highly sensitive, and specific method for detecting tcc of the bladder and estimating its grade and stage. further studies can be helpful to determine whether it can be used in clinical practice. urol j. 2008;5:243-7. www.uj.unrc.ir keywords: transitional cell carcinoma, bladder neoplasms, diagnosis, nuclear matrix proteins, tumor markers 1urology research center, sina hospital, tehran university of medical sciences, tehran, iran 2department of urology, imam khomeini hospital, tehran university of medical sciences, tehran, iran 3department of nutrition and biochemistry, institute of public health research, tehran university of medical sciences, tehran, iran corresponding author: kianoush kor, md department of urology, imam khomeini hospital, tohid sq, tehran, iran tel: +98 911 375 0135 e-mail: kianoushkor@yahoo.com received august 2007 accepted august 2008 introduction transitional cell carcinoma (tcc) accounts for the majority of bladder tumors.(1) currently, the standard methods for detecting, staging, and tracking the progress of bladder cancer include urine cytology, cystoscopy, biopsy of the suspected mass, and excretory urography.(2) urine cytology is easy to perform but not sensitive for detection of grade 1 and grade 2 tumors,(3) while it is very important to diagnose the disease prior to invasion in order to improve the prognosis of the patients. in addition, since tcc of the bladder frequently recurs, close follow-up after the successful treatment of the initial tumor is mandatory.(4) as referenced above, cytology of urine is not sensitive enough for low-grade tumors, and on the other hand, the gold-standard cystoscopy and biopsy are invasive methods, and they are both costly and uncomfortable for the patient.(5) therefore, the need for an in vitro, noninvasive, diagnostic urine nuclear matrix protein 22 in bladder cancer diagnosis—jamshidian et al 244 urology journal vol 5 no 4 autumn 2008 test for providing objective quantitative results to be used in conjunction with the currently accepted diagnostic methods is beyond question. employing this methodology would significantly improve the urologist’s ability to make clinical decisions regarding the status of the disease and effectiveness of the treatment, especially in patients with low-grade tumors. nuclear matrix proteins (nmps) are parts of the internal structural framework of the cell nucleus.(6) they are known to play important roles in dna replication, transcription and processing of rna, and regulation of the gene expression.(6) additionally, it has been demonstrated that the intracellular nmp22 concentration is at least 25 times greater in the bladder cancer tumoral cells than in the normal bladder cells.(7-10) in this study we aimed to determine the diagnostic value of urine nmp22 in detection of transitional cell carcinoma (tcc) of the bladder. materials and methods we selected patients with tcc of the bladder referred to imam khomeini hospital in tehran, iran, between december 2005 and april 2007. assigned as group 1, they were either newlydiagnosed or had recurrence of tcc. the patients were visited in the clinic or admitted to the hospital for follow-up after treatment of the bladder tumor. a control group was selected from among admitted patients who had no evidence of bladder tumor and joined the study voluntarily (group 2). patients with urinary tract infection, urinary calculi, and any malignancy in other parts of the urinary tract were excluded. for this reason, the health status of the control group was confirmed by medical examination, urinalysis, and sometimes, ultrasonography of the urinary tract system. we obtained informed consent from the participants in both groups. a total of 151 urine samples were collected. in group 1, a single-voided urine sample from each participant was collected just prior to cystoscopy. biopsy was taken from any visible tumor or suspected lesion. the biopsies were evaluated using the tnm staging system and the world health organization’s grading. a urine collection kit, containing urine stabilizers, was used for urine sample collection for the nmp22 test, and the urine was immediately stored at under -20°c. demographic information including date of birth, sex, and pathology report of the biopsy were recorded. for both groups, the urine samples were sent to the laboratory with an identification number without any detailed demographic information. the nmp22 was determined by 2-step-sandwich enzyme-linked immunoabsorbent assay (matritech, newton, usa). all samples were processed according to the written instructions provided by the kit manufacturer. diluted urine samples were added to microplates which were antibody coated. after washing the captured nmp22 antigen, we allowed the antigen to react to a second antibody which was labeled by digoxigenin. the excessive digoxigenin was washed and a new antidigoxigenin antibody, which was coupled with horseradish peroxidase, was added. the remaining antibody was also washed and the sandwich was detected using o-phenylenediamine substrate. for stopping the reaction, 2 mol/l of sulfuric acid was added. the nmp22 concentration was proportional to the developed color intensity, and its level was calculated from the standard curve. the reference cutoff level of nmp22 had been set to be 10 u/ ml by the manufacturer. data were analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). the chi-square test and the t test were used for comparisons between the two groups. diagnostic value of the nmp22 was tested by calculation of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. in addition, the receiver operating characteristic curve was used for obtaining threshold values. correlations between the level of the nmp22 and tumor grade and stage were evaluated by the kendall’s tau-b test. a p value less than .05 was considered significant. results a total of 76 patients with tcc of the bladder and 75 volunteers without tcc were enrolled in the study. the patients with tcc (group 1) urine nuclear matrix protein 22 in bladder cancer diagnosis—jamshidian et al urology journal vol 5 no 4 autumn 2008 245 and the volunteers (group 2) were comparable in terms of age and sex distribution (table 1). histopathological data of group 1 is shown in table 2. the patients in group 1 had a significantly higher mean urinary nmp22 level than those in group 2 (25.01 ± 35.33 u/ml versus 5.48 ± 6.34 u/ml, p < .001). the data obtained on the mean urinary nmp22 levels of each study individual was analyzed with the kruskal-wallis nonparametric test as shown in table 2, which revealed an increasing trend in urine nmp22 values associated with tumor grade (p = .01) and tumor stage (p < .001). also, using the kendalls’ tau-b test, it was shown that the urine nmp22 values correlated significantly with the tumor stages (r = 0.37, p < .001). the diagnostic profile of nmp22 was evaluated using the receiver operating characteristic curve analysis. the optimal combination, defined by the largest area under the roc curve (0.88; 95% confidence interval, 0.83 to 0.95), obtained a sensitivity of 75.0% and a specificity of 86.7%, taking a threshold value of 10.1 u/ml for nmp22 level in urine which is nearly the same as the manufacturer’s recommendation (10 u/ml). based on the cutoff point of 10.1 u/ml, the nmp22 was positive in 5 (31.3%), 27 (90.0%), 6 (66.7%), and 18 (90.0%) of the patients with ta, t1, t2, and t3 bladder tumors, respectively (p < .001). overall, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of nmp22 for detection of tcc were 75.0%, 86.7%, 85.1%, 77.4%, and 80.8%, respectively. as shown in table 3, the tumor class sensitivity, % specificity, % positive predictive value, % negative predictive value, % accuracy, % stage ta 31.3 86.7 33.3 85.5 76.9 t1 90.0 86.7 73.0 95.6 76.6 t2 66.7 86.7 37.5 95.6 84.5 t3 90.0 86.7 64.3 97.0 87.4 grade 1 66.7 86.7 72.2 83.3 79.8 2 81.8 86.7 37.5 97.0 86.0 3 84.6 86.6 68.7 94.2 86.1 superficial tcc 70.2 86.7 76.7 82.3 80.3 tcc (overall) 75.0 86.7 85.1 77.4 80.8 table 3. diagnostic value of urine nuclear matrix protein 22 level in transitional cell carcinoma (tcc) of bladder tumor class patients (%) mean nmp22, u/ml nmp22 range, u/ml stage cis 1 (1.3) 11.00 … ta 16 (21.1) 8.17 ± 3.87 2.5 to 17.0 t1 30 (39.5) 17.81 ± 16.91 4.5 to 76.5 t2 9 (11.8) 39.39 ± 38.37 5.5 to 105.0 t3 20 (26.3) 43.50 ± 55.39 3.7 to 232.0 grade 1 39 (51.3) 14.01 ± 15.25 2.5 to 76.5 2 11 (14.5) 34.50 ± 33.37 5.0 to 105.0 3 26 (34.2) 37.48 ± 50.54 2.5 to 232.0 table 2. grade and stage of transitional cell carcinoma and urine nuclear matrix protein 22 (nmp22) levels in each tumor grade and stage cis indicates carcinoma in situ. characteristic group 1(n = 76) group 2 (n = 75) p mean age, y 66.5 ± 11.3 65.7 ± 10.5 .84 sex male 61 (80.3) 62 (82.7) female 15 (19.7) 13 (17.3) .85 table1. age and sex distribution of patients with transitional cell carcinoma (group 1) and participants without bladder cancer (group 2)* *values in parentheses are percents. urine nuclear matrix protein 22 in bladder cancer diagnosis—jamshidian et al 246 urology journal vol 5 no 4 autumn 2008 sensitivity of urine nmp22 to detect stage ta tumors appeared to be only 31.3%. on the other hand, the sensitivity for grade 1 tumors was 66.7%. discussion although cystoscopy is the “gold standard” method for detecting bladder cancer, it is invasive and expensive.(11) on the other hand, urine cytology is not sensitive enough for the lowgrade disease; therefore, a noninvasive tool is necessary to be introduced to help the urologist in diagnosis and treatment planning in patients with bladder tumor. several tumor markers have been employed for this purpose with different accuracy levels, including bladder tumor antigen, urinary bladder cancer antigen, telomerase, hyaluronic acid, and hyaluronidase.(12-14) however, none of these markers are sensitive enough to be recommended for daily practice.(14) the use of nmp22 as a marker in urine for diagnosis of tcc has been proposed by a few studies.(15-20) our study revealed that the mean level of urine nmp22 in the patients with active bladder tumor was 5 times higher than that in individuals with an intact urinary tract. a significant relationship was also found between the level of urine nmp22 and stage and grade of the tumor. in terms of diagnostic accuracy, we found acceptable sensitivity and specificity. table 4 highlights the results of the diagnostic value of urine nmp22 in several studies. soloway and colleagues(15) found a sensitivity of 100% for invasive disease and 70% overall and a negative predictive value of 86% by urine nmp22. shariat and associates(16) studied nmp22 in 209 patients and controls and determined a sensitivity of 50% and a positive predictive value of 81%. zippe and colleagues(17) studied 18 patients with biopsy confirmed bladder cancer and 312 with benign conditions of the bladder and found the highest sensitivity of 100% and specificity of 85%. however, the positive predictive value was low (29%) in this study. there are also some other published studies on urine nmp22 with various reports of sensitivity (48.5% to 85%).(18-20) the current study yielded diagnostic test values above 75%; however, it was also shown that the urine nmp22 test had significantly low sensitivity for detection of the tumors with ta stage. conclusion we found that measurement of urine nmp22 is a noninvasive, highly sensitive, and specific method for detecting tcc of the bladder and evaluating its grade and stage. however, this test cannot be trusted in detection of superficial bladder cancer, especially stage ta cancer. the promising results for this tumor marker make its further evaluation for clinical usage beneficial. conflict of interest none declared. references 1. johansson sl, cohen sm. epidemiology and etiology of bladder cancer. semin surg oncol. 1997;13:291-8. 2. kriegmair m, baumgartner r, knuchel r, stepp h, hofstadter f, hofstetter a. detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. j urol. 1996;155:105-9. 3. badalament ra, hermansen dk, kimmel m, et al. the sensitivity of bladder wash flow cytometry, bladder wash cytology, and voided cytology in the detection of bladder carcinoma. cancer. 1987;60:1423-7. 4. mufti gr, singh m. value of random mucosal biopsies in the management of superficial bladder cancer. eur urol. 1992;22:288-93. study participants sensitivity, % specificity, % positive predictive value, % negative predictive value, % current study 151 75.0 86.7 85.1 77.4 soloway et al(15) 90 78.5 75.9 57.5 86.1 shariat et al(16) 209 50.0 50.0 81.0 57.0 zippe et al(17) 330 100 85.0 29.0 100 atsu et al(18) 202 78.1 66.0 59.5 82.5 eissa et al(19) 168 85.0 91.3 89.5 87.5 stampfer et al(20) 231 48.5 91.8 65.3 84.9 table 4. reported diagnostic value of urine nuclear matrix protein 22 level in literature urine nuclear matrix protein 22 in bladder cancer diagnosis—jamshidian et al urology journal vol 5 no 4 autumn 2008 247 5. berezney r, coffey ds. identification of a nuclear protein matrix. biochem biophys res commun. 1974;60:1410-7. 6. pardoll dm, vogelstein b, coffey ds. a fixed site of dna replication in eucaryotic cells. cell. 1980;19:52736. 7. zeitlin s, parent a, silverstein s, efstratiadis a. premrna splicing and the nuclear matrix. mol cell biol. 1987;7:111-20. 8. kumara-siri mh, shapiro le, surks mi. association of the 3,5,3’-triiodo-l-thyronine nuclear receptor with the nuclear matrix of cultured growth hormone-producing rat pituitary tumor cells (gc cells). j biol chem. 1986;261:2844-52. 9. nakayasu h, berezney r. mapping replicational sites in the eucaryotic cell nucleus. j cell biol. 1989;108:111. 10. keesee sk, briggman jv, thill g, wu yj. utilization of nuclear matrix proteins for cancer diagnosis. crit rev eukaryot gene expr. 1996;6:189-214. 11. lotan y, roehrborn cg. cost-effectiveness of a modified care protocol substituting bladder tumor markers for cystoscopy for the followup of patients with transitional cell carcinoma of the bladder: a decision analytical approach. j urol. 2002;167:75-9. 12. zargar m, soleimani m, moslemi m. comparative evaluation of urinary bladder cancer antigen and urine cytology in the diagnosis of bladder cancer. urol j. 2005;2:137-40. 13. shimetani n, mori m. [urinary bta (bladder tumor antigen)]. nippon rinsho. 2005;63 suppl 8:782-4. japanese. 14. glas as, roos d, deutekom m, zwinderman ah, bossuyt pm, kurth kh. tumor markers in the diagnosis of primary bladder cancer. a systematic review. j urol. 2003;169:1975-82. 15. soloway ms, briggman v, carpinito ga, et al. use of a new tumor marker, urinary nmp22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. j urol. 1996;156:363-7. 16. shariat sf, zippe c, ludecke g, et al. nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with ta, t1 or cis transitional cell carcinoma of the bladder. j urol. 2005;173:1518-25. 17. zippe c, pandrangi l, agarwal a. nmp22 is a sensitive, cost-effective test in patients at risk for bladder cancer. j urol. 1999;161:62-5. 18. atsu n, ekici s, oge oo, ergen a, hascelik g, ozen h. false-positive results of the nmp22 test due to hematuria. j urol. 2002;167:555-8. 19. eissa s, swellam m, sadek m, mourad ms, el ahmady o, khalifa a. comparative evaluation of the nuclear matrix protein, fibronectin, urinary bladder cancer antigen and voided urine cytology in the detection of bladder tumors. j urol. 2002;168:465-9. 20. stampfer ds, carpinito ga, rodriguez-villanueva j, et al. evaluation of nmp22 in the detection of transitional cell carcinoma of the bladder. j urol. 1998;159:394-8. case report bilateral laparoscopic adrenalectomy in a pregnant woman with cushing’s syndrome mohammad aslzare,1 mohammad alipour,2 morteza taghavi,3 alireza ghoreifi4* keywords: adrenal cortex neoplasms; adrenalectomy; cushing syndrome; pregnancy; laparoscopy. introduction cushing’s syndrome (cs) occurs rarely during pregnancy.(1) surgical treatment is the principal therapy for cs in pregnancy, with medical treatments constituting the second choice. the most common cause of cs in pregnancy is adrenal gland adenoma that may be treated by unilateral adrenalectomy during gestation.(2,3) herein we present a 31 years old pregnant woman with cs who underwent bilateral laparoscopic adrenalectomy in her 18th week of pregnancy. our medline search revealed that this is the first “bilateral” laparoscopic adrenalectomy during pregnancy which has been reported. case report a 31-year old primigravid woman was referred to our clinic at 4 months gestation following the diagnosis of cs from about three months ago. she has been treated medically but her blood pressure was not well controlled. the patient also had a history of cardiac ablation because of paroxysmal supraventricular tachycardia about 4 months ago when she was unaware of her pregnancy. her laboratory data showed urine free cortisol level of 730 µgr/24hr (normal range, 10-100) and her late-night salivary cortisol level was 60 nmol/l (normal range, 6.2-19.4). ultrasonography showed increased size of adrenals with an 18 weeks normal fetus (figure 1). abdominal magnetic resonance imaging (mri) showed adrenal hyperplasia (figure 2) but brain mri was normal. we decided to perform bilateral laparoscopic adrenalectomy. laparoscopy was done under general anesthesia with anterior transperitoneal approach using three working trocars. after extraction of left adrenal gland (figure 3) the position was changed to right lateral decubitus and right adrenal gland was similarly excised successfully (figure 4). the time of surgery was about 4.5 hours. post-operative view of the abdomen is shown in figure 5. the operation was uneventful and the patient and fetus were well during post-operative period. the patient was discharged after 4 days with oral medications. after surgery baseline serum cortisol level decreased from 60 to 2.8 nmol/l, and 24-hour urine cortisol decreased from 730 to 29 µg. after 3 months the patient underwent cesarean section because of fetoplacental abnormality. a preterm infant with intrauterine growth retardation (iugr) without any malformation was born. the patient was discharged without any complication but her infant was remained under observation in neonatal intensive care unit (nicu) for figure 1. ultrasonography of the patient. figure 2. magnetic resonance imaging of the patient. departments of urology1, anesthesiology2 and endocrinology3, ghaem hospital, mashhad university of medical sciences, mashhad, iran. 4 department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran. * correspondence: imam reza hospital, mashhad university of medical sciences, mashhad, iran. tel: +98 511 8022553. e-mail: aghoreifi@yahoo.com. received february 2014 & accepted june 2014 vol 11. no 05 sept-oct 2014 1911 40 days. the baby had good condition after discharge and remained normal during his two years follow up. discussion pregnancy is rare in women with cs, with fewer than 150 cases reported in the literature. it is because that the hyperandrogenism and hypercortisolism status during pregnancy suppress pituitary secretion of gonadotropins. (4,5) however, because cs results in increased fetal and maternal complications, its early diagnosis and treatment are critical.(1,2) the etiology of cs in pregnant women is different from that in of non-pregnant women. adrenal adenomas cause approximately 40-50% and 17-29% of cs in pregnant and non-pregnant women, respectively. (4,6,7) in contrast, cushing disease is less common in pregnancy; with rates of 63-72% in the general population compared with 33% in pregnant women.(4,6) the etiology of cs in our case was bilateral adrenal hyperplasia. there are many overlapping features between normal pregnancy and cs, so the clinical diagnosis of cs in pregnancy may be difficult and unfortunately is often not detected until 12-26 weeks of gestation.(4,6,7) the biochemical diagnosis of cs in pregnancy is difficult because of the normal hypercortisolism during pregnancy.(6) adrenal ultrasonography or mri can be safely performed during pregnancy for detection of adrenal tumor. mri can also be useful in locating pituitary tumors.(3) when cs is diagnosed during pregnancy, therapeutic options depend on the underlying etiology, including, surgical treatment, conservative management, medical treatment, and delay of surgery until after delivery. (5) when contemplating surgical treatment for a pregnant patient with suspected adrenocortical adenoma, the surgical approach and the optimal time for surgery need to be determined. surgery is the treatment of choice for cs in pregnancy, except perhaps late in the third trimester, with medical treatment being a second choice. there is no rationale for supportive treatment alone.(4) the commonest cause of cs in pregnancy, adrenal gland adenoma, may be treated by unilateral adrenalectomy during gestation. open or laparoscopic methods have been performed in practice. the end of the first trimester and the first half of the second trimester are considered the best time for surgery. in the third trimester, conservative treatment and early delivery are preferred. however aishima and colleagues and sammoura and colleagues successfully treated their patients with cs at this gestational stage by retroperitoneal laparoscopic adrenalectomy.(5,8) we found 24 cases of adrenalectomy in literature due to cs caused by adrenocortical adenoma in pregnancy, but we didn’t find a case of bilateral laparoscopic adrenalectomy in a pregnant woman. in our case, laparoscopy was done by transperitoneal approach. although the patient was obese with a history of severe hypertension and cardiac ablation, she didn’t have any complication perioperatively. conclusion we demonstrated that bilateral laparoscopic adrenalectomy is possible during pregnancy and may be considered safe and minimally invasive in selected patients. conflict of interest none declared. references 1. kita m, sakalidou m, saratzis a, ioannis s, avramidis a. cushing’s syndrome in pregnanfigure 3. laparoscopic views. left: the pregnant uterus. right: the adrenal during excision. figure 5. abdomen at the end of surgery. figure 4. adrenal specimens after excision. bilateral laparoscopic adrenalectomy in pregnancy-aslzare et al case report 1912 cy: report of a case and review of the literature. hormones (athens). 2007;6:242-6. 2. lindsay jr, jonklaas j, oldfield eh, nieman lk. cushing’s syndrome during pregnancy: personal experience and review of the literature. j clin endocrinol metab. 2005;90:3077-83. 3. bednarek-tupikowska g, kubicka e, sicińs ka-werner t, et al. a case of cushing’s syn drome in pregnancy. endokrynol pol. 2011;62:181-5. 4. vilar l, freitas mda c, lima lh, lyra r, kater ce. cushing’s syndrome in pregnancy: an over view. arq bras endocrinol metabol. 2007;51:1293-302. 5. sammour rn, saiegh l, matter i, et al. adre nalectomy for adrenocortical adenoma causing cushing’s syndrome in pregnancy: a case report and review of literature. eur j obstet gynecol reprod biol. 2012;165:1-7. 6. lindsay jr, nieman lk. the hypothalamic pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. endocr rev. 2005;26:775-99. 7. buescher ma, mcclamrock hd, adashi ey. cushing’s syndrome in pregnancy. obstet gy necol. 1992;79:130-7. 8. aishima m, tanaka m, haraoka m, naito s. retroperitoneal laparoscopic adrenalectomy in a pregnant woman with cushing’s syndrome. j urol. 2000;164:770-1. bilateral laparoscopic adrenalectomy in pregnancy-aslzare et al vol 11. no 05 sept-oct 2014 1913 urology journal unrc/iua vol. 2, 22-26 spring 2004 printed in iran 22 urological oncology a comparison between clinical and pathologic staging in patients with bladder cancer mehrsai a1, mansoori d2, taheri mahmoodi m1, sina a1, seraji a1, pourmand gh1 1department of urology, sina hospital, tehran university of medical sciences, tehran, iran 2department of urology, shaheed mohammadi hospital, bandarabbass university of medical sciences, bandarabbass, iran abstract purpose: to determine the accuracy of clinical staging methods of bladder cancer and turbt results in estimating the pathologic stage of tumor. materials and methods: thirty two patients who had undergone radical cystectomy were studied in this retrospective survey. the results of bimanual examination, cystoscopy, turbt pathology report and the tumor contour in ct scan, (size, infiltrative deepness, pelvic lymph nodes involvement and hydronephrosis) were recorded. the type of surgery and pathologic report of cystectomy sample were analyzed as well. then the results of bimanual examination, tumor size, hydronephrosis and ct scan findings including tumor infiltrative deepness, pelvic lymph adenopathy and turbt findings were compared to pathologic results of cystectomy sample. results: seven patients were females and 25 were males. their mean age was 62 (range 36 to 80) years. gross hematuria and irritative urinary symptoms were the most common complaints. the duration between symptom manifestation and patient's referral was 5 days to 72 months (mean 12 months). bimanual examination in estimating the extravesical involvement of tumor had a specificity of 82%, sensitivity of 46%, positive predictive value of 70% and negative predictive value of 63%. the size of tumor in determining extravesical involvement had a specificity of 41%, sensitivity of 93%, and positive predictive value of 58% and negative predictive value of 87%. hydronephrosis was present in 15 patients of whom, 14(93%) had bladder muscle involvement. ct scan specificity was 70%, and sensitivity was 46% regarding pelvic lymph adenopathy and perivesical fat involvement. in turbt report no muscle sample was observed in 11 cases, so that the interpretations of results were impossible. the reported grade of tumor was lower than pathologic sample of cystectomy in 4 patients. conclusion: clinical staging in invasive bladder cancers has not high accuracy regarding the involvement of bladder surrounding fats and pelvic adenopathies. a tumor sized more than 5 cm could be sensitive in estimating extravesical involvement. positive predictive value of hydronephrosis is considerable regarding bladder muscle involvement. tumor understaging by turbt is happened in high percentage of patients with invasive bladder cancer. key words: bladder cancer , bimanual palpation, hydronephrosis, tumor size, turbt accepted for publication in april 2003 a comparison between clinical and pathologic staging in patients with bladder cancer introduction radical cystectomy is considered as a standard treatment in muscle invasive urothelial bladder tumors. before such treatment, clinical staging is done by physical examination, imaging, liver function tests, bladder endoscopy, bimanual examination under anesthesia, tumor biopsy, and turbt; however, pathologic staging which is the most important factor in patient prognosis is done ultimately following the study of the full thickness of bladder wall and lymphatic glands, that is after radical cystectomy.(1,2) there is always a risk of error in clinical staging of patients with bladder cancer which may even exceed to 50%.(3) bimanual examination of the bladder is used to detect palpable extravesical mass. palpable mass particularly after turbt affects patient survival.(4) ct scan is a common method in clinical staging. its sensitivity in estimating extravesical involvement of tumor is between 57% and 96% and its specificity is reported to be between 60% and 93%.(5,6,7) hydronephrosis is a sign of ureteral obstruction and is regarded as an important factor in staging .it is associated with muscle invasion in 70-90% and distant metastasis in 55%.(8) the size of tumor is also considered as an effective factor in patients' prognosis(9) and finally turbt is regarded as one of the most important methods of clinical staging and determining biologic characteristics of tumor; however, there is a risk of error in estimating infiltrative deepness of tumor and its grade and understaging could be occurred even in more than 50% of cases.(10) muscle invasion is indicated in more than 95% of high grade tumors in patients who underwent cystectomy; while, the deepness of high grade tumors is mostly estimated lower than its actual amount via turbt.(2) the efficiency of the following items has been studied in this survey: 1. bimanual examination, 2. ct scan findings including tumor size, hydronephrosis, infiltrative deepness of tumor regarding prevesical fat involvement, and pelvic adenopathy, 3. turbt report to estimate pathologic stage of bladder cancer. materials and methods thirty two patients with bladder cancer who had undergone surgical radical cystectomy from 1999 to 2001, were enrolled in this retrospective survey. patients' preoperative evaluations were as follows: history taking, physical examination, chest x-ray, cbc, bun, cr, electrolytes, liver function tests, ct scan, bone scan, and barium enema or colonoscopy for patients who were candidates for urinary diversion, in order to rule out any colorectal lesion. the following data were collected from each patient: the results of bimanual bladder examination, cystoscopy, turbt or tumor biopsy report, tumor site and size in pelvic ct scan, regarding size, infiltrative deepness, hydronephrosis, pelvic lymph nodes involvement as well as type of surgery and pathologic report of radical cystectomy. in this survey, the efficiency of bimanual examination, infiltrative deepness, tumor size in ct scan, hydronephrosis, and turbt or biopsy report in estimating pathologic stage of bladder tumor were studied. tumor staging was performed according to tnm classification (edition 1997) and tumor grading was conducted in accordance with who classification (grade i to iii). results seven out of 32 studied patients were females and 25 were males. patients mean age was 61 (range 36 to 80) years. a history of gross hematuria was reported in 29 patients, irritative urinary symptoms in 15, and obstructive urinary symptoms in 6 and suprapubic pain in 3. one patient suffered form anuria. mean duration between the disease manifestation and referral time was 12 (range 5 to 72) months. the tumor was palpable by bimanual examination in 11 patients. table 1 shows the results of comparing palpable tumor and final pathology. the specificity of bimanual examination in this study was 82%, sensitivity was 46%, positive predictive value was 70%, and negative predictive value was 63%. according to cystoscopy and ct scan, the tumor was located on the left wall in 11 patients, right in 8, bladder base in 7, diffuse in 23 total no extravesical tumor involvement (t1 , t2) extravesical tumor involvement (t3 , t4) 10 3 7 palpable cases 22 14 8 no-palpable cases 32 17 15 total table 1. results of bimanual examination of tumor and their comparison to pathologic results of radical cystectomy samples a comparison between clinical and pathologic staging in patients with bladder cancer the bladder in 4, at the bladder dome in 1, and in the bladder diverticulum in 1. trigone involvement was not present in 7 patients, while it was observed via cystoscopy in the remained patients. tumor size (the largest dimension of tumor) was measured in ct scan. it was compared to final pathologic results (table 2). tumor size specificity in determining extravesical involvement was 41% and its sensitivity was 93%. its positive productive value was 58% and negative productive value was 87%. unilateral or bilateral hydronephrosis were seen in 15 patients. table 3 shows the relationship between hydronephrosis and pathologic findings of surgical samples. the specificity of hydronephrosis in determining the involvement of bladder muscle was 75%, its sensitivity was 50%, its positive productive value was 93%, and its negative productive value was 17%. table 4 shows the involvement of perivesical fat or pelvic lymph adenopathy in ct scan and its comparison to final pathology. the specificity of ct scan in determining perivesical fat involvement or pelvic adenophathy was 70%, its sensitivity was 46%, its positive productive value was 58% and its negative productive value was 60%. in the turbt report of patients who underwent cystectomy, no muscular sample was seen in biopsy of 11 patients and only mucosal layer involvement with tumor was reported. tumor grade was lower than radical cystectomy sample in 4 cases. clinical evidences of muscular involvement including turbt or ct scan results were the indication of radical cystectomy in 29 cases. surgical operation was performed in 3 cases considering big size of tumor or the presence of bladder diverticulum's, despite the lack of evidence of bladder muscular involvement. figures 1 and 2 show types of used urinary diversion and final report of patients pathology. in situ carcinoma was also simultaneously reported in 5 patients. discussion the stage of bladder cancer has been reported in several reports as the most important criterion of prognosis and patient's survival.(11,12) despite the innovation of modern methods of imaging, clinical staging of bladder cancer has a high percentage of errors.(13) a comparison has been conducted between the accuracy of different methods of clinical staging and final pathologic staging. bimanual examination of bladder particularly under anesthesia and following turbt is regarded as an important staging tool. in a study conducted on 276 swedish patients, 5-year patient survival was 24 table 2. a comparison between of tumor size and pathologic reports of radical cystectomy samples total no extravesical involvement (t1 or t2 , n0) extravesical involvement (t3 or t4 or n+) 24 10 14 tumor lager than 5 cm 8 7 1 tumor smaller than 5 cm 32 17 15 total table 3. a comparison between hydronephrosis and pathologic reports of radical cystectomy samples table 4. a comparison between ct scan findings and pathologic reports of radical cystectomy samples total no muscular involvement (t1) muscular involvement (t2 , t3 , t4) 15 1 14 hydronephrosis 17 3 14 without hydronephrosis 32 4 28 total total no extravesical involvement (t1 or t2 , n0) extravesical involvement (t3 or t4 or n+) 12 5 7 presence of perivesical fat involvement or pelvic adenopathy in ct scan 20 12 8 no extravesical involvement in ct scan 32 17 15 total fig. 1. types of urinary diversion surgeries in patients fig. 2. results of pathologic report of cystectomy samples of patients 0 2 4 6 8 10 12 14 16 1st qtr mainz ii mitrofanoff ileal conduit ureterosigmoidostomy ucla pouch camey ii pouch indiana pouch 0 2 4 6 8 10 12 14 t1 n0 m 0 t2 n0 m 0 t3 or t 4 or n +,m 0 tcc scc adeno a comparison between clinical and pathologic staging in patients with bladder cancer reduced from 83% (in not palpable cases) to 50% in the cases of palpable mass.(4) the specificity of this examination was acceptable in the prognosis of extravesical tumor involvement; sensitivity was low, only about 46%. the reason might be bimanual examination without anesthesia, which led to lack of complete relaxation of abdominal muscles. patient obesity, unavailable bladder tumor as well as small size of tumor are regarded other influencing factors for false negative results in this examination, as it mentioned in references. previous pelvic surgical history, radiotherapy and inflammatory lesions of rectosigmoid are among false positive reasons.(2) the size of tumor is considered as a prognostic factor in bladder tumors. in a study conducted on 64 patients who underwent radical cystectomy, the size of tumor, as an independent factor, affected on 10-year cancerspecific survival.(9) in this study 14 out of 15 patients whose pathologic stages were t3 or higher, had a tumor larger than 5 cm which indicated the necessity of invasive treatment in large tumors particularly high grade ones. hydronephrosis is regarded as a prognostic criterion in bladder tumors by which muscular involvement is reported to be between 70% and 90%.(8) no deference has been seen between unilateral and bilateral hydronephrosis in most performed studies considering the relationship between the stage of cancer and obstruction,(14,15) though, some believe that bilateral hydronephrosis has worsen prognosis.(8) ct scan is conducted to determine the infiltrative deepness of tumor in bladder muscle and the involvement of surrounding soft tissue; however, these changes could be inflammatory and noninfiltrative. in addition, if ct scan is performed after bladder tumor tur, these changes might be due to extravasation of fluid. in a survey, the similarity between ct scan findings and pathologic staging was reported in 86% of 50 patients who underwent radical cystectomy.(16) in another study this rate was 68% in 60 patients.(17) in a retrospective study carried out on 82 patients, final result showed that ct scan was unable to detect microscopic involvement or little extravesical extension of tumor and lymphatic metastasis; moreover, it had a high understaging rate and lacked the effect on surgical treatment of patients.(18) in this study ct scan specificity was 70% and sensitivity was 46% which insure the unreliability of this method in tumor staging. turbt is one of the most important approaches in bladder cancer staging; however, the difference of surgeons' experience and the variety of deepness of removed tissue as well as problem in pathologic interpretation of samples decreases the accuracy of this method in determining the stage of tumor. if the sample is so small or if just a biopsy of tumor was taken, a high percentage of error would be occurred in determining infiltrative deepness of tumor and its grade. in a survey performed on 105 patients, understaging of tumor was reported via turbt in 55 patients.(10) in this study no muscular sample was seen in turbt samples in 11(34%) patients of mainly, the lack of muscular sample in bladder biopsy is considered a risk factor in understaging bladder tumor.(19) tumor grade was lower than final pathology in 4 other patients. conclusion this survey which was conducted to assess the efficacy of clinical methods for staging of invasive bladder invasive tumors showed that bimanual palpation lacks adequate sensitivity for determining extravesical involvement of tumor but it is mostly specified. a tumor lager than 5 cm could lead to high sensitivity in predicting extravesical involvement of tumor, but it has not a high specificity. regarding bladder muscle involvement, hydronephrosis has a high positive predictive value and ct scan has low accuracy in determining the involvement of surrounding bladder tissue and pelvic lymphadenopathy. furthermore, understaging with turbt or biopsy is occurred in high percentage of patients, specially, when no bladder muscular tissue is seen in tur samples. finally, it seems that none of the current common methods is adequately credible for clinical staging of bladder cancer in the prognosis of pathologic stage. probably, using molecular markers or modern methods of imaging like spiral ct scan and mri may be more accurate in staging. it is recommended to perform prospective study with more samples and with modern imaging modalities and using molecular markers to predict pathologic stage of invasive bladder tumors. references 1. messing em, catalona w. urothelial tumors of the urinary tract. in: walsh pc, retik ab, vaughan ed, editors. campbell's urology. wb saunders company; 1998. p. 23272410. 2. droller mj, gospodarowicz mk. staging of bladder cancer. 25 a comparison between clinical and pathologic staging in patients with bladder cancer in: vogelzang nj, scardino pt, shipley wu, editors. comprehensive textbook of genitourinary oncology. lippincott williams wilkins; 2000. p. 343-355. 3. skinner dg, tift jp, kaufman jj. high dose, short coarse preoperative radiation therapy and immediate single stage radical cystectomy with pelvic node dissection in the management of bladder cancer. j urol 1982; 127: 671. 4. wijkstrom h, norming u, lagerkvist m, nilsson b, naslund j, wiklund p. evaluation of clinical before cystectomy in transitional cell bladder carcinoma: a long-term follow-up of 276 consecutive patients. br j urol 1998 may; 81(5): 686-91. 5. see wa, fuller jr. staging of advanced bladder cancer: current concepts and pitfalls [review] urol clin north am 1992; 19: 663-683. 6. voges ge, tauschke e, stockle m, et al. computerized tomography: an unreliable method for accurate staging of bladder tumors in patients who are candidates for radical cystectomy. j urol 1989; 142: 927-974. 7. barentsz jo, witjes ja, rujis jh. what is new in bladder cancer imaging. urol clin north am 1997; 24: 583-602. 8. haleblian ge, skinner ec, dickinson mg, lieskovsky g, boyd sd, skinner dg. hydronephrosis as a prognostic indicator in bladder cancer patients. j urol 1998; 160(6): 2011-2014. 9. cheng l, neumann rm, scherer bg, weaver al, leibovich bc, et al. tumor size predicts the survival of patients with pathologic stage t2 bladder carcinoma: a critical evaluation of the depth of muscle invasion cancer 1999 jun 15; 85(12): 2638-47. 10. cheng l, neumann rm, weaver al, cheville jc, leivovich bc, ramani dm, et al. grading and staging of bladder carcinoma in transurethral resection specimens. correlation with 105 matched cystectomy specimens. am j clin pathol 2000 feb; 113(2): 275-9. 11. thrasher jb, frazier ha, robertson je, dodge rk and paulson df. clinical variables which serve as predictors of cancer-specific survival among patients treated with radical cystectomy for transitional cell carcinoma of the bladder and prostate. cancer 1994; 73: 1708. 12. narayana as, loening sa, slymen dj and culp da. bladder cancer: factors affecting survival j urol 1983; 130: 56. 13. holzbeierlein jm, smith jr. management of superficial ta/t1 tis bladder cancer. vogelzang nj, scardino pt, shipley wu, editors. in: comprehensive textbook of genitourinary oncology. lippincott williams and wilkins; 2000. p. 384-393. 14. hatch tr, barry jm. the valve of excretory urography in staging bladder cancer. j urol 1986; 135: 49. 15. lange ek. the roentgenographic assessment of bladder tumors. a comparison of the diagnostic accuracy of roentgenographic techniques. cancer 1969; 23: 717. 16. liu d, chen q, tang a. the evaluation of clinical staging by preoperative ct examination in patients with bladder cancer. zhonghua wai ke za zhi 1996 may; 34(5): 283-5 [abstract]. 17. nurmi m, katevuo k, puntala p. reliability of ct in preoperative evaluation of bladder carcinoma scan. j urol nephrol 1988; 22(2): 125-8. 18. paik ml, scolieri mj, brown sl, spirnak jp, resnick mi. limitation of computerized tomography in staging invasive bladder cancer before radical cystectomy. j urol 2000 jun; 163(6): 1693-6. 19. dutta sc, smith ja jr, shappell sb, coffey cs, chang ss, cookson ms. clinical understaging of high risk nonmusele invasive urothelial carcinoma treated with radical cystectomy. j urol 2001 aug; 166(2): 490-493. 26 case report inflammatory pseudotumour of urinary bladder a management dilemma: a rare case report gaurav prakash,* bhupendra pal singh, satya narayan sankhwar, ankur jhanwar keywords: urinary bladder diseases; humans; inflammation; pathology; male. department of urology, king george medical university, lucknow-226003, india. *correspondence: department of urology, king george medical university, lucknow-226003, india. tel: +91 737 6540487. fax: 0522 2256543. e-mail: gaurav.kgmc08@gmail.com. received october 2015 & accepted february 2016 introduction inflammatory pseudotumor (ipt) is known in the lung and orbit, but other organs of body can be involved.(1) ipt of urinary bladder is a benign mass of uncertain malignant potential. it is described as non-epithelial, proliferative lesion of the sub mucosal stroma. different names have been given like inflammatory myofibroblastic tumor, plasma cell granuloma, xanthomatous pseudotumor, pseudosarcomatous myofibroblastic proliferation, inflammatory myofibroblastic proliferation and myofibroblastoma. it is very difficult to differentiate this tumor from malignant lesion on endoscopic or radiological examination. so it must be differentiated by histopathological examinafigure 1. ultrasonography showing bladder mass. figure 2. histopathological examination showing spindle cell proliferation. figure 3. follow up cystoscopy view (at 6 months). case report 2727 tion from malignant lesions to avoid radical surgeries. most common presentations are hematuria and storage lower urinary tract symptoms (luts). inflammatory pseudotumor has been described at almost any location, in both sexes and at all ages.(2) the pathogenesis of ipt is not clearly known, some have postulated that the lesion develops in response to infection, inflammation, or malignancy, but the causative relationship has not yet been proven.(3) there is no clear cut guidelines regarding management and follow up for this tumor. various management options have been described including transurethral resection of bladder tumor and partial cystectomy.(4) these tumors are locally aggressive but stop progression after complete removal. we are reporting a case of 62 years old male diagnosed to have ipt of urinary bladder which was managed endoscopically with complete transurethral resection and has been on regular and satisfactory follow up. case report a 62-year old man presented with storage luts and intermittent hematuria with passage of clots for last 6 months. ultrasonography and kidney ureter and bladder region (kub) showed a 20 × 17 mm mass at left lateral wall near left ureteric orifice with normal upper tracts (figure 1). cystoscopy confirmed two cm polypoidal growth with surrounding bullous edema and hemorrhagic patches at left lateral wall near ureteric office. urine culture was sterile and urine for malignant cytology was also negative. he underwent transurethral resection of mass (complete resection) with multiple random biopsies from surrounding area. histopathology showed proliferation of large spindle cells mixed with chronic inflammatory cells, lymphocyte, and plasma cells confirming diagnosis of inflammatory pseudotumor (figure 2). considering it to be a benign lesion with unknown malignant potential, patient was followed up every 3 months with cystoscopy and urine cytology. at last follow up of 6 months, no recurrence was observed with healthy scar at previous resection site. (figure 3) urine cytology was negative. discussion reactive, non-neoplastic proliferations arising within the bladder have been well documented and described in the literature. inflammatory pseudotumor is most commonly used to describe this entity. roth in 1980 first described this benign lesion as pseudo sarcoma.(5) world health organization has put this mass lesion under benign category with unknown malignant potential. earlier this lesion has been misdiagnosed as sarcoma and led to radical surgery. so it is crucial to know the exact diagnosis, management and follow up. various management options have been described including transurethral resection of bladder tumor (turbt) and partial cystectomy for such cases. to the best of our knowledge there are few cases of recurrences, but no cases of metastasis has been reported in literature.(6,7) we managed this patient by turbt and as there are reports of recurrence so it is better to keep patient for longer follow up. no recurrence was observed till last follow up. conclusions inflammatory pseudotumor of bladder is a benign lesion with a potential of recurrence it is essential for both urologist and pathologist to get a correct diagnosis to avoid radical surgery of bladder. turbt (complete resection) is the best way of management. long term follow up is must to rule out any recurrence. conflict of interest none declared. references 1. coffin cm, watterson j, priest jr, dehner lp. extra pulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinic pathologic and immunohistochemical study of 84 cases. am j surg pathol. 1995;19:859-72. 2. sugita r, saito m, miura m, yuda f. inflammatory pseudotumour of the bladder: ct and mri findings. br j radiol. 1999;72:809-11. 3. narla ld, newman b, spottswood ss, narla s, kolli r. inflammatory pseudotumor. radiographic. 2003;23:719-29. 4. harik lr, merino c, coindre jm, amin mb, pedeutour f, weiss sw. pseudosarcomatous myofibroblastic proliferations of the bladder: a clinicopathologic study of 42 cases. am j surg pathol. 2006;30:787-94. 5. roth ja. reactive pseudosarcomatous response in urinary bladder. urology. 1980;16:635-637. 6. difiore jw, goldblum jr. inflammatory myofibroblastic tumor of the small intestine. j am coll surg. 2002;194:502-6 7. harik lr, merino c, coindre jm, amin mb, pedeutour f, weiss sw. pseudosarcomatous myofibroblastic proliferations of the bladder: a clinicopathologic study of 42 cases. am j surg. pathol. 2006;30:787-94. inflammatory pseudotumor of urinary bladder-prakash et al . vol 13 no 03 may-june 2016 2728 urological oncology comparison of non-hilar clamping simple enucleation and enucleo-resection of exophytic renal tumors mehmet balasar,1* emrullah durmuş,2 mehmet mesut pişkin,1 giray karalezli,1 recai gürbüz,1 mehmet kilinç1 purpose: to retrospectively evaluate our institutional experience with non-hilar-clamping simple enucleation (se) and enucleoresection (er) for the treatment of exophytic renal tumors regarding their oncological outcomes. materials and methods: we retrospectively evaluated patients treated between 2006 and 2013 for clinical exophytic t1-t2a renal tumors using open nephron-sparing surgery. results: a total of 33 patients underwent se and 39 underwent er. the mean tumor size was 38.7 mm. none of the patients had positive surgical margins. no local recurrences were observed during the postoperative follow-up period (mean 40.7 ± 23.4 months); however, ipsilateral adrenal and contralateral kidney metastasis was detected in one of the patients. there was no statistically significant difference in the r.e.n.a.l nephrometry score, operative time, or intraoperative blood loss in the non-hilar-clamping se and er groups (p > .05). during the third postoperative month, the estimated glomerular filtration rate (egfr) levels in the se group were significantly reduced compared with the preoperative egfr levels (p = .046). conclusion: se and er with non-hilar clamping are safe, acceptable approaches for treating exophytic renal tumors. keywords: carcinoma, renal cell; surgery; follow-up studies; kidney neoplasms; mortality; nephrectomy; adverse effects; organ sparing treatments; methods; glomerular filtration rate. introduction during recent decades, modern imaging techniques have facilitated the use of nephron-sparing surgery (nss) to protect intact tissue when treating small renal tumors, with oncological outcomes similar to those accomplished with radical nephrectomy.(1,2) the current gold standard for addressing renal tumors is nss that includes enucleoresection (er). with this procedure, the tumor is removed, along with an adequate safety margin of healthy parenchyma.(3) as reported in various studies, a minimal tumor-free surgical margin is considered sufficient to avoid the risk of local recurrence and allow the possible use of simple enucleation (se), a nephron-sparing procedure with oncological effectiveness.(4) the aims of nss are total resection of the tumor with as little intraoperative hemorrhage as possible and leaving as much intact functional parenchyma as possible. minimal hemorrhage is achieved by clamping the hilar vessels in either a warm or cold ischemia condition. the maximum warm ischemia time during nss without leading to permanent damage in the kidney is reported to be 30 minutes.(5) however, recent studies have decreased this time to 20 minutes. various studies have claimed that every minute during ischemia, even if it is less than 20 minutes, damages kidney function.(6) the aim of the present study was to analyze the patients’ preoperative, intraoperative, and postoperative conditions; positive surgical margins; and the pathological outcome data of 72 patients who underwent non-hilar clamping se or er. materials and methods a total of 72 patients who underwent se and er from 2006 to 2013 due to exophytic t1-t2a renal tumors were included in this retrospective study. two surgical teams performed the operations. one team exclusively performed se, and the other team exclusively performed er. the preoperative evaluation of all patients included ultrasonography of the kidney, ureter, and bladder, abdominal computed tomography with contrast enhancement, and chest radiography. to determine the location of the tumor in the kidney, we calculated the r.e.n.a.l nephrometry score (radius, exophytic or endophytic nearness to the collecting system or sinus, and anterior or posterior location relative to polar lines). 1 department of urology, necmettin erbakan university, meram medical school, konya, turkey. 2 department of urology, bulanık state hospital, muş, turkey. *correspondence: department of urology, necmettin erbakan university, meram medical school, konya 42080, turkey. tel: +90 532 5174613. fax: +90 332 2236522. e-mail: drbalasar@gmail.com. received february 2015 & accepted november 2015 vol 12 no 06 november-december 2015 2410 urological oncology 2411 (7) the e-score of the r.e.n.a.l nephrometry was 1 point for all patients recruited to the study. all patients were considered to be free from distant metastases prior to surgery. technique the participants provided written consent before the surgical intervention. an anterior subcostal approach was used in all patients. a direct approach to the kidney was preferred before the kidney was totally separated from the perirenal fat to extricate the exophytic renal tumor that had been detected earlier by imaging. for safety reasons, the renal pedicle was carefully isolated and then suspended with umbilical tape but not clamped. in the patients who underwent se, the renal capsule at the edges of the mass was denoted using electrocautery. the natural cleavage was opened using clamps. the natural cleavage plane between the tumor and normal parenchyma enabled a 360° turn with the index finger. the mass was totally excised without tumor bed ablation. for hemostasis, the renal parenchyma around the enucleation site was compressed using the thumb and index finger. the renal parenchymal defect was closed with hemostatic material and parenchymal horizontal mattress sutures. in the er group, using gyrus open forceps (gyrus medical pk system seal; gyrus international, berkshire, uk), the mass was resected along with 1 to 5 mm of intact parenchyma around the tumor (figures table 1. patient and event characteristics. variables group se (simple enucleation) group er (enucleo-resection) p value patients, no 33 39 age, years, mean ±sd 55.5 ± 11.0 54.6 ± 12.9 .76 gender, no (%) .85 male 21 (63.6) 24 (61.5) female 12 (36.4) 15 (38.5) tumor side, no (%) .83 right 17 (51.5) 18 (46.1) left 16 (48.5) 21 (53.9) tumor localization, no (%) .67 upper pole 8 (24.2) 13 (33.3) mid-kidney 4 (12.1) 5 (12.8) lower pole 21 (63.7) 21 (53.9) tumor size, mm, mean ±sd 36.8 ± 13.3 40.4 ± 15.2 .17 r.e.n.a.l nephrometry score, mean ± sd 4.55 ± 0.87 4.64 ± 0.78 .39 pt stage, no (%) pt1a 21 (63.6) 23 (58.9) pt1b 11 (33.4) 15 (38.5) pt2a 1 (3) 1 (2.6) rcc grade, no (%) g1 2 (6.9) 1 (2.5) g2 16 (55.1) 18 (46.1) g3 10 (34.5) 18 (46.1) g4 1 (3.5) 2 (5.2) operative time (min), mean ± sd 100.0 ± 13.2 106.7 ± 14.1 .61 estimated blood loss (ml), mean ± sd 286.7 ± 143.1 313.8 ± 169.7 .47 hb drop (g/dl), mean ± sd 1.55 ± 1.20 1.07 ± 1.58 1.19 follow-up (months), mean ± sd 40.5 ± 21.5 41.5 ± 24.3 .6 local recurrences / metastasis 0/0 0/1 abbreviations: sd, standard deviation; rcc, renal cell carcinoma; hb, hemoglobin renal tumor and nephron sparing surgery-balasar et al. 1-3). the renal parenchymal defect was closed with hemostatic material and parenchymal horizontal mattress sutures. we observed no parenchymal hemorrhage that necessitated digital compression of the parenchyma due to the thermal effect of the gyrus open forceps. in both groups, the operation was conducted without clamping the renal artery. the operation time, intraoperative blood loss, preoperative and postoperative hemoglobin (hb) levels, serum creatinine levels, estimated glomerular filtration rate (egfr), and r.e.n.a.l nephrometry score were evaluated in all patients undergoing the nss techniques (se and er). glomerular filtration speed was calculated using the chronic kidney disease epidemiology collaboration formula.(8) pathological tumor size, 2010 tnm (tumor, node, metastasis) stage, the surgical margin in the specimens, and histological subtypes according to the world health organization (who) classifications were recorded. during the postoperative follow-up, all patients underwent radiological reevaluations for local recurrence and metastasis. the study was presented to the local ethics committee. this study followed the declaration of helsinki statement on medical protocol and ethics. statistical analysis the statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0 was used for statistical analysis. the data are recorded as the mean ± standard deviation (sd) and percentage values. for the parameters with a normal distribution, student’s t-test was used to compare the two groups. comparisons of categorical data were made using a χ² test. variant analyses were used to test the difference in the gfr and creatinine levels in repetitive measurements. bonferroni’s correction was used to determine differences between the groups. p = .05 was considered to indicate statistical significance. results patient characteristics the data obtained from 72 patients were evaluated. when the two groups (se and er) were compared, the mean ages of the patients were 55.5 ± 11.0 and 54.6 ± 12.9 years, respectively (p = .76). the male/female ratios were 21 (63.6%) and 24 (61.5%) for males and 12 (36.4%) and 15 (38.5%) for females in the se and er groups, respectively (p = .85; table 1). event characteristics the mean tumor size was 36.8 ± 13.3 mm in the se group and 40.4 ± 15.2 mm in the er group (p = .17). the mean r.e.n.a.l nephrometry score was 4.55 ± 0.87 (range 4-6 points) in the se group and 4.64 ± 0.78 (range 4-6 points) in the er group (p = .39). in terms of localization of the mass in the kidneys, 17 (51.5%) and 18 (46.1%) lesions were on the right side in the se and er groups, respectively, whereas 16 (48.5%) and 21 (53.9%) lesions were on the left side in the se and er groups, respectively (p = .83). the numbers of histological types of tumors (clear cell renal cell carcinoma [rcc], papillary rcc, chromophobe rcc, other rcc, non-rcc) were 16 (48.5%), 8 (24.3%), 2 (6%), 3 (9.1%), and 4 (12.1%), respectively, in the se group and 25 (64.1%), 7 (18%), 5 (12.8%), 2 (5.1%), and 0, respectively, in the re group. in the se group, four non-rcc tumors were noted, two of which were angiolipomas and two were oncocytomas. the histopathological analysis of the surgical specimens revealed negative surgical margins in all specimens. the tnm 2010 classifications (pt1a, pt1b, and pt2a) table 2. preoperative and postoperative renal function results. variables preoperative egfr (ml/min/1.73 m²) postoperative 3rd month egfr (ml/min/1.73 m²) p value group se 103.6 ± 24.1 96.0 ± 23.8 .046 group er 89.5 ± 26.4 85.6 ± 30.5 .636 abbreviations: egfr, estimated glomerular filtration rate; se, simple enucleation; er, enucleo-resection figure 1. exophytic tumor located at the lower pole of the kidney. renal tumor and nephron sparing surgery-balasar et al. vol 12 no 06 november-december 2015 2412 were assigned to the lesions as follows: 21 (63.6%), 11 (33.4%), and 1 (3%), respectively, in the se group and 23 (58.9%), 15 (38.5%), and 1 (2.6%), respectively, in the re group. the average operation durations for the se and er groups were 100.0 ± 13.2 and 106.7 ± 14.1 minutes (p = .61), respectively. the average blood loss volumes were 286.7 ± 143.1 and 313.8 ± 169.7 ml (p = .47), respectively, and the average hb drop measurements were 1.55 ± 1.20 and 1.07 ± 1.58 mg/dl (p = 1.19), respectively. the intraoperative blood loss ranged between 50 and 750 ml. blood transfusion was performed in three patients in whom the preoperative hb level of 10 mg/ dl decreased postoperatively to 8 mg/dl (two in the se group and one in the er group). the preoperative and 3-month postoperative egfr values in the se group were 103.6 ± 24.1 and 96.0 ± 23.8 ml/min/1.73 m2, respectively (p = .046). the corresponding egfr values in the er group were 89.5 ± 26.4 and 85.6 ± 30.5 ml/min/1.73 m2 (p = .636). significant differences were noted between the preoperative and 3-month egfr values in the se group (table 2). the drains were removed on the third postoperative day. prolonged urinary drainage (6 days) was observed in one patient in the er group. one patient in the se group had gross hematuria for 7 days that resolved spontaneously during the follow-up. the mean follow-up was 40.5 ± 21.5 months after se and 41.5 ± 24.3 months after er (p = .6). the median follow-up was 19 months (2-80 months) for the se group and 41 months (1-95 months) for the er group. the patients were re-evaluated during the postoperative follow-up period for local recurrence and metastasis. two years after the operation, ipsilateral adrenal and probable contralateral kidney metastases were detected in one patient in the er group who had a history of histologically diagnosed papillary rcc. no local recurrence or metastasis was observed in any other patients. discussion czerny first described nss for treating renal tumors in 1890.(9) in 1950, vermooten proposed that peripheral encapsulated renal neoplasms could be excised locally by leaving a margin of normal parenchyma around the tumor.(9,10) although radical nephrectomy (rn) has been a proven effective treatment modality since the 1950s, nss has only limited applications. many researchers have published their results after kidney-preserving surgical interventions and have demonstrated the validity of this approach in cases in which rn could not be conducted. moreover, various retrospective studies have demonstrated that survival is enhanced with nss due to preserved renal function.(11) the european organization for research and treatment of cancer randomized trial 30904 demonstrated that nss has a reduced overall survival rate compared with rn. the study also demonstrated that nss reduced the incidence of moderate renal failure.(12,13) in line with the recent increase in incidental tumor diagnosis, the focus on nss has also increased. today, according to european association of urology guidelines, nss has become the standard treatment modality for tumors < 4 cm.(14) the aim of nss is total resection of the renal tumor while retaining as much functional parenchyma as possible.(15) several tumor-related factors, i.e., renal tumor urological oncology 2413 figure 2. enucleated tumor. figure 3. the tumor bed after resection. renal tumor and nephron sparing surgery-balasar et al. size, location, and depth, are visible on preoperative imaging and can affect the tumor resection technique. hence, various nss techniques are available. the most common nss technique is clamping the renal artery with or without the renal vein and sharply excising the renal mass. the time frame during which a vessel is clamped is called the “warm ischemia time.” a safe warm ischemia time is still under discussion; however, it is generally accepted to be 20 to 30 minutes.(6,16) removing a 1-cm margin of normal parenchyma may lead to complications, such as increased hemorrhage risk, potential renal hilum injury, collecting system injury, the need for renal vessel clamping, and prolonged ischemia time.(17) when the concept of an nss surgical technique was initiated, it involved excising a 1-cm margin of peritumor normal renal parenchyma to ensure a negative surgical margin. in recent decades, however, various authors have demonstrated that intact parenchyma surrounding the tumor can be limited to a few millimeters while preserving the oncological safety of nss.(18) despite the fact that the mean thickness of the safety margin surrounding the tumor ranges from 2.5 to 5.0 mm, various studies have demonstrated that the minimum thickness of the safety margin is 0 to 1 mm, which is most important at the bottom of the tumor. various recent studies have assumed no association between margin size during nss of small renal masses and the recurrence of rcc.(2) with nss, especially in single, small (< 4 cm) tumors limited to the kidney, oncological outcomes are similar to those of rn outcomes, whereas renal function is better preserved. this finding is especially important for patients with a solitary functioning kidney. most of these patients had pre-existing renal insufficiency. thus, their quality of life, i.e., having dialysis-free and tumor-free renal function, is positively affected.(19) the 5-year disease-specific survival rates can increase up to 97%, differentiating nss from rn.(20) although the upper tumor size limit for elective nss is defined as 4 cm, tumors up to 7 cm might be appropriate for treatment using nss in cautiously selected patients.(14,21,22) following these developments, se and er techniques have been used.(14,21) small rccs may frequently be well bordered and have a pseudocapsule. these are not true capsules, however, and might be invaded by the tumor. therefore, if a small portion of the healthy parenchyma surrounding the renal tumor is not excised, it may lead to incomplete resection because of microscopically sized residual tumors. therefore, in the case of simple tumor enucleation, frozen section analysis from the resection borders and the coagulation of the tumor bed is suggested.(23) alternatively, as with the er technique, the mass is debulked with a cautery dissection 1 to 5 mm away from the peritumoral capsule. with se, the tumor is excised with blunt dissection following the natural cleavage plane between the peritumoral capsule and the renal parenchyma, leaving behind a visible border of healthy renal tissue. evaluations of progression-free and cancer-specific survival (css) data revealed that renal tumor enucleation is a more oncologically sound procedure than nss.(24) lapini and colleagues reported on the results of enucleation of small rccs (median 2.5 cm) combined with tumor bed coagulation with diathermy spray coagulation or an argon beam. the 107 patients were followed for a mean of 88.3 months. the authors reported 99% 5-year and 97.8% 10-year css rates for this patient series. the 5and 10-year progression-free survival rates were 98.1% and 94.7%, respectively.(25) however, recent data suggested that enucleation of rccs without tumor bed ablation may produce similar oncological outcomes. minervini and colleagues reported the results of a series of consecutive patients undergoing enucleation without ablation of the renal tumor surgical bed. according to their report, all of the patients had positive surgical margins, but only 3 of the 164 patients (1.8%) developed a local recurrence, of which only one (0.6%) was a true local recurrence in the enucleation bed. to date, this study is the largest consecutive series of rccs treated with enucleation with no ablation of the surgical bed.(24) in the present study, only 1 of the 72 patients who underwent either se or er had a positive surgical margin and developed metastasis and/or local recurrence during the mean 40.7-month follow-up. two years after the operation, ipsilateral adrenal and contralateral kidney metastases were detected in this patient, who was in the er group and was formerly diagnosed with histologically diagnosed papillary rcc. despite the fact that our mean postoperative follow-up period was short (40.7 months), neither of the surgical techniques was superior to the other in terms of survival rates. three anatomical classification and scoring systems are used to identify the predictive characteristics of renal tumors and can be used to identify the risk of a prolonged warm ischemia time or surgical complications: the r.e.n.a.l nephrometry score, padua score, and c (centrality) index.(16) r.e.n.a.l nephrometry scores impact the preoperative approaches to kidney tumors. according to one retrospective study, this scoring system is a useful tool when using nss to remove a ct1 renal tumor and nephron sparing surgery-balasar et al. vol 12 no 06 november-december 2015 2414 renal cancer.(26) in another study on the predictive value of the r.e.n.a.l nephrometry score in regard to performing robotic partial nephrectomy, a strong positive relation was observed between the r.e.n.a.l nephrometry score and the warm ischemia time.(27) to decrease hemorrhage during nss, the renal pedicle is frequently clamped. however, recent studies have claimed that warm ischemia of > 20 minutes might lead to serious kidney damage. the increased popularity of laparoscopic nss with a prolonged operation time among nss procedures exposes the kidney to more ischemia, leading to long-lasting harm. thompson and colleagues. demonstrated that a prolonged ischemia time in patients with solitary kidneys has undesirable long-term effects on renal function.(28) despite the fact that the use of nss has been described with open, laparoscopic, and robotic methods, the most important point for the patient is to preserve renal function.(29) marszalek and colleagues reported that when open nss (onss) is compared to laparoscopic surgery the warm ischemia time is shorter with onss, although the hemorrhage levels are the same.(30) lucas and colleagues, in a study of 96 patients with kidney tumors with a mean size of 2.3 cm and a nephrometry score of 6, reported that renal function preservation, complication rates, and surgical margin positivity were comparable for all three methods.(31) the mean operation time was 147 minutes in the onss group, which included a significantly shorter (12 minutes) warm ischemia time. however, the hemorrhage amount was > 250 ml. in the same study, a decrease of > 10% in the egfr levels of 44 patients was significant. in the 72 nss cases in this study, the mean tumor size was 36.8 mm in the se group and 40.4 mm in the er group, respectively. the r.e.n.a.l nephrometry scores were 4.55 ± 0.87 and 4.64 ± 0.78, respectively. the mean hemorrhage amount during the intervention was 301.4 ± 157.5 ml, which is consistent with the findings in the literature. the pedicle was not clamped in any of the patients during the operation, and the kidney was not exposed to warm ischemia. during the se procedure, while the tumor was enucleated and the parenchyma sutured, the enucleation site and surrounding parenchyma were compressed between the thumb and index finger for homeostasis. during the er procedure, gyrus open forceps were used, and some intact tissue was excised together with the tumor. there was some concern that the gyrus open forceps might affect the egfr by its thermal energy. we did not observe any egfr change at the 3-month follow-up evaluation in the er group (p = .636). however, we identified a significant change in the se group from the preoperative egfr level (p = .046). although the compression time and compression force applied to the parenchyma were not clear, we thought that the decrease in the egfr scores at the 3-month follow-up might be attributed to the renal parenchymal compression that was achieved using the thumb and index finger, perhaps causing mechanical or ischemic stress. the small sample size, short follow-up period, and retrospective nature of the study design are the limitations of this study. hence, there is need for well-designed prospective studies. conclusions non-hilar clamping se and er are safe, acceptable approaches for treating exophytic renal tumors. no statistically significant differences were noted in the r.e.n.a.l nephrometry scores, operative times, or intraoperative blood loss in the non-hilar clamping se and er groups. conflict of interest none declared. references 1. haddad rl, patel mi, vladica p, kassouf w, bladou f, anidjar m. percutaneous radiofrequency ablation of small renal tumors using ct-guidance: a review and its current role. urol j. 2012;9:629-38. 2. ficarra v, galfano a, cavalleri s. is simple enucleation a minimal partial nephrectomy responding to the eau guidelines’ recommendations? eur urol. 2009;55:1315-8. 3. uzzo rg, novick ac. nephron sparing surgery for renal tumors: indications, techniques and outcomes. j urol. 2001;166:618. 4. minervini a, rosaria raspollini m, tuccio a, et al. pathological characteristics and prognostic effect of peritumoral capsule penetration in renal cell carcinoma after tumor enucleation. urol oncol. 2014;32:50.e15-22 5. margreiter m, marberger m. current status of open partial nephrectomy. curr opin urol. 2010;20:361-4. 6. shikanov s, lifshitz d, chan aa, et al. impact of ischemia on renal function after laparoscopic partial nephrectomy: a multicenter study. j urol. 2010;183:1714-8. 7. kutikov a, uzzo rg. the r.e.n.a.l. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. j urol. 2009;182:844-53. 8. levey as, stevens la, schmid ch, et al. a new equation to estimate glomerular filtration urological oncology 2415 renal tumor and nephron sparing surgery-balasar et al. rate. ann intern med. 2009;150:604-12. 9. czerny he. cited by herczele: ueber nierenexstirpation. beitr z klin. 1890;6:4846. 10. vermooten v. indications for conservative surgery in certain renal tumors: a study based on the growth pattern of the cell carcinoma. j urol. 1950;64:200-8. 11. weight cj, lieser g, larson bt, et al. partial nephrectomy is associated with improved overall survival compared to radical nephrectomy in patients with unanticipated benign renal tumours. eur urol. 2010;58:2938. 12. van poppel h, da pozzo l, albrecht w, et al. a prospective, randomised eortc inter group phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. eur urol. 2011;59:543-52. 13. scosyrev e, messing em, sylvester r, campbell s, van poppel h. renal function after nephron-sparing surgery versus radical nephrectomy: results from eortc randomized trial 30904. eur urol. 2014;65:372-7. 14. ljungberg b, cowan nc, hanbury dc, et al. eau guidelines on renal cell carcinoma: the 2010 update. eur urol. 2010;58:398-406. 15. miyamoto k, inoue s, kajiwara m, teishima j, matsubara a. comparison of renal function after partial nephrectomy and radical nephrectomy for renal cell carcinoma. urol int. 2012;89:227-32. 16. krebs rk, andreoni c, ortiz v. impact of radical and partial nephrectomy on renal function in patients with renal cancer. urol int. 2014;92:449-54. 17. li ql, guan hw, zhang qp, zhang lz, wang fp, liu yj. optimal margin in nephron sparing surgery for renal cell carcinoma 4 cm or less. eur urol. 2003;44:448-51. 18. sutherland se, resnick mi, maclennan gt, goldman hb. does the size of the surgical margin in partial nephrectomy for renal cell cancer really matter? j urol. 2002;167:61-4. 19. fergany af, hafez ks, novick ac. longterm results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup. j urol. 2000;163:442-5. 20. patard jj, shvarts o, lam js, et al. safety and efficacy of partial nephrectomy for all t1 tumors based on an international multicenter experience. j urol. 2004;171:2181-5. 21. canda ae, kirkali z. current management of renal cell carcinoma and targeted therapy. urol j. 2006;3:1-14. 22. bayrak o, seckiner i, erturhan s, cil g, erbagci a, yagci f. comparison of the complications and the cost of open and laparoscopic radical nephrectomy in renal tumors larger than 7 centimeters. urol j. 2014;11:1222-7. 23. steinbach f, stöckle m, hohenfellner r. current controversies in nephron-sparing surgery for renal-cell carcinoma. world j urol. 1995;13:163-5. 24. minervini a, serni s, tuccio a, et al. local recurrence after tumour enucleation for renal cell carcinoma with no ablation of the tumour bed: results of a prospective single-centre study. bju int. 2011;107:1394-9. 25. lapini l, serni s, minervini a, masieri l, carini m. progression and long-term survival after simple enucleation for the elective treatment of renal cell carcinoma: experience in 107 patients. j urol. 2005;174:57-60. 26. yasuda y, yuasa t, yamamoto s, et al. evaluation of the renal nephrometry scoring system in adopting nephron-sparing surgery for ct1 renal cancer. urol int. 2013;90:179-83. 27. boylu u, güzel r, turan t, lee br, thomas r, gumus e. predictive value of r.e.n.a.l. nephrometry score in robotic assisted partial nephrectomy. turk j urol. 2011;37:81-5. 28. thompson rh, lane br, lohse cm, et al. comparison of warm ischemia versus no ischemia during partial nephrectomy on a solitary kidney. eur urol. 2010;58:331-6. 29. leslie s, goh ac, gill is. partial nephrectomycontemporary indications, techniques and outcomes. nat rev urol. 2013;10:275-83. 30. marszalek m, meixl h, polajnar m, rauchenwald m, jeschke k, madersbacher s. laparoscopic and open partial nephrectomy: a matched-pair comparison of 200 patients. eur urol. 2009;55:1171-8. 31. lucas sm, mellon mj, erntsberger l, sundaram cp. a comparison of robotic, laparoscopic and open partial nephrectomy. jsls. 2012;16:581-7. renal tumor and nephron sparing surgery-balasar et al. vol 12 no 06 november-december 2015 2416 urology journal unrc/iua vol. 1, no. 4, 240-245 autumn 2004 printed in iran 240 prostate cancer screening, yes or no? the current controversy razi a* department of urology, shariati hospital, university of medical sciences, tehran, iran abstract purpose: the increasing incidence of prostate cancer and different viewpoints of medical authorities to it, has lead to conversion of preliminary plan of screening test to a requisite. the objective of this study is to clarify the obscure aspects of this subject using the literature review. materials and methods: we reviewed the following items in the literature: prostate cancer screening, introduction of relevant tests, screening criteria according to world health organization, screening experience in different countries, community notification, specialists training in order to establish an integrated approach and treatment, anxiety relief, and promotion of patient awareness in this field. results: it has been shown that, except in china, programmed and official screening of prostatic cancer has not been accepted by concordant responsible authorities, neither in developed countries nor in developing ones. however, it is performed informally in different parts of the world. conclusion: there is no unanimous consensus about performance of screening for prostate cancer. continuing voluntary referral of men above 50 years old for performing prostatic specific antigen (psa) test has been accepted universally and is being done potentially, defined as "opportunistic screening". key words: prostate cancer, screening, incidence introduction prostate cancer is a universal and serious health threatening disease. it is seen mainly in the aged and its occurrence is very rare under the age 50. its incidence has increased significantly in the recent years, but its mortality has not followed this trend. it might be due to physicians' attention to this disease, its diagnosis in early stages, and appropriate treatments. some authorities believe that this success is indebted to performance of prostatic specific antigen (psa) test.(1,2) prostate cancer is the most common malignancy, diagnosed in the united states and generally in western men.(3,4) although in some reports it has the second rank after skin cancer, it is the second cause of death from malignancy. factors such as a positive family history, black race, and the presence of prostate intraepithelial neoplasia in previous biopsies increase the risk of its occurrence.(2,5) it has been observed that the chance of positive results of malignancy in the performed biopsies is increasing in young age group. for instance, in one study in the united states the rate of diagnosed prostate cancer by biopsy in patients aged 50 to 59 years has increased from 11% in 1995 to 16% in 2002; whereas, in those of 70 to 74 years old, this rate has declined from 46% in 1995 to 34% in 2004.(6) these studies show that the need for performing screening test has converted to a requisite, specially due to increment in education level and awareness of population and improvement in their socioeconomic status, their request to do screening test has increased. although it is rarely seen that the health service of a country accepts screening test for prostatic cancer as a health policy, the opposite is happening in the world; the *corresponding author: shariati hospital, north karegar st., tehran, iran. e-mail: arazi@tums.ac.ir razi 241 daily rate of psa tests performed indicates informal performance of this test despite compile programs, and free referral of people to do these tests confirms their acceptance.(7) there is another point that, a large distance has been created between opinion and action due to high demands for these tests. in theory, at present, there is a unanimous consensus not to perform psa test for patients over 75 years old, due to accepted reasons. the high incidence of histological cancer, low life-expectancy, and the presence of co-morbidities, of which, some are more fatal in this age group, has lead to this agreement.(7) however, for these patients, psa test is practically done according to patient demand and physician's recommendation. for example, in a national research in 2000 in the united states, 7889 old men were interviewed, showing that 34% had done psa test after the age 75 years old, of which 86% was due to physician's recommendation and in 12%, patient's demand was involved.(8) this rate is comparable to the rate of pap smear application for cervical cancer in females, but less than that of stool occult blood test for colorectal carcinoma.(8) on the other hand, at least there is no consensus that screening test can affect present treatment and subsequently, mortality and morbidity due to prostate cancer(7,9,10-13) and also there is no consensus that early diagnosis of the disease reduces early mortality. at present, 3% of mortality rate in western men over 55 is due to this disease.(4) some authorities believe that screening test is even harmful, because it may disclose those tumors which might never become clinically considerable, otherwise, patient will dye "with" the disease, not "of" the disease and if diagnosed, the patient will suffer from being aware of his illness and should undergo different stages of investigation and treatment, which might be accompanied by significant morbidities (i.e. incontinency, impotency, intestinal complications, etc.).(2,14-17) accordingly, they reserve psa test until obtaining a written informed consent from the patient(13) and not a verbal one. in the other end of the spectrum, some believe that not performing this test may increase a serious risk of reducing longevity and quality of life in men. in a study done in quebec, canada, it has been shown that mortality rate due to prostate cancer in screened group is one third of that in controls.(14) on the other hand, the sight of society and asking for screening is understandable; people believe that the same level of care for breast or cervical cancer in females should be done for malignancies in males, as mammography, pap smear, or ultrasonography in normal pregnancies are routinely done in some countries worldwide, such as belgium, the netherlands, japan, australia, the united states, etc.(16,18-20) finally, as we enter the post-genomic century, introducing biomarkers and molecular-based prognostic markers will clarify psa test obscurities and identifies those patients who have a great potential for malignancy, so that the story of screening test will get more evident. who is responsible for screening tests? is world health organization (who) responsible or ministry of health, medial professionals such as specialists or general practitioners, or medical universities? actually, in iran, it seems that urologists, despite ministry of health and universities' responsibility, informally should undertake this duty and accompany people's will. which types of screening are being performed? there are different types of screening, performing for different diseases and each of them has its own condition. 1mass screening: in this type of screening which is performed in a specific population or group, the goal is to detect the disease in its primary stage, when the treatment is practically most viable.(2) 2selected screening: it is a screening of a selected group of people such as those who are placed in a high-risk category (positive family history, black race, etc.)(1,2,5) 3case finding: this type of screening, which is done in periodic check-ups (each 6 months or 12 months), is based on an obligation. for example, a person who is employee in an organization is to participate in periodic obligatory check-up programs and give his/her health reports to the system.(2) 4opportunistic screening: it refers to a situation in which the physician uses any opportunity to perform screening test. the request for performing this test is based on physician's preference or patient's willingness.(2) all the above-mentioned methods are used in the management of prostate cancer, but the opportunistic screening is more common.(14,16,18-20) prostate cancer screening242 who criteria for screening tests who has specified a series of criteria for performing screening tests in the management of any disease:(2) 1the target disease should pose as a health problem. 2the latent form of the disease or at least its clinical form in early stages should be diagnosable. 3the natural history of the disease and its transition from latent to clinical form should be known. 4there should be acceptable treatment for those who are diagnosed. 5there should be known laboratory test and physical examination for diagnosing the disease. 6the test should be accepted by the community. 7there should be an approved policy (or unanimous strategy) for the treatment of patients. 8available facilities for diagnosis and treatment should be present. 9case finding expenses should be equivalent to medical care expenses. 10case finding process should be consistent. adaptation of who criteria for prostate cancer it is believed that screening test for prostate cancer has some concordances and incongruities as compared to who criteria: 1the disease should pose a health problem: this is true for prostate cancer. the incidence of disease is increasing, but first, the mortality and morbidity rates have remained constant and second, the disease belongs to old ages and if it is not screened, the danger for the patient is less than that of lung, colorectal, and breast carcinoma.(1,2,14,20-22) it means that the priority is not given to prostate cancer. 2the latent form of the disease or at least its clinical form in early stages should be diagnosable: although we are able to diagnose the latent form of prostate cancer, we are unable to differentiate the non-progressive disease from its fatal form.(1,7,12,14,16,23) prostate cancer has a low fatal potency. many of the patients die of other diseases rather than prostate cancer. it is probable that screening test may diagnose a benign form of disease, not requiring treatment, which will impose unnecessary measures on patients.(1,5,8,11,15,16,23) 3the natural history of the disease and its transition from latent to clinical form should be known: there is not much information about the nature of prostatic cancer and the studies performed in this filed has not achieved definite results. despite the broad studies, which have been performed on age, nutritional regimen, body mass, physical status, genetic factors, and vasectomy, the risk factors of prostate cancer are not known yet.(1,2,20) 4there should be acceptable treatment for those who are diagnosed: although there are acceptable treatments such as radical prostatectomy, radiotherapy, and watchful-waiting available for prostate cancer, there is a question whether these treatments will alter the natural course of preclinical disease or not, which is not answered yet. radical prostatectomy for organ confined form of the disease is the best treatment, but nobody has used the term "treatment of choice" for it. some advocate radiotherapy, specially in old patients. but, both of these treatments have complications such as urethral stenosis, injury to intestine, incontinency, and impotence, which are intolerable and problematic for those patients who have the histological form of the disease, but not its clinical form. robeca ferrini, a member of the american college of preventive medicine, refers to these as a reason for objection to screening tests.(1) watchful-waiting, although not an active treatment, is accepted as a treatment strategy, in those patients who are monitored closely and any treatment is aimed to appearance of the signs of disease. the mean time from diagnosis to the need for treatment is 10 years, making the early treatment of prostate cancer questionable.(2) 5there should be known laboratory and physical examinations for diagnosing the disease: digital rectal examination (dre) test has been being used for a long time, but it is helpful in diagnosis of the palpable form of disease and the result of test is different among physicians. the sensitivity of test is different from 18% to 68%, which is due to the different sensitivity of examiners' fingers.(1,2) in the united states and canada, dre is a part of screening test and along with psa, form the first line of screening.(1,14) however, there are controversies about this screening method in other parts of the world.(20) in a study, it has been shown that one case of razi 243 prostate cancer is detected in each 96 rectal examinations, which might not be a clinically significant form, and 289 rectal examinations should be performed to diagnose one case of clinically significant prostate cancer.(24) the principal screening test for prostate cancer is psa test, which was discovered in 1979 and could make a revolution in early diagnosis of the disease, otherwise known as psa-era or psa revolution. however, there is high variation in sensitivity and specificity.(2,25,26) its sensitivity is 27% to 80%, being higher for aggressive cancers.(27) its cut-off point value is controversial and although 4 ng/ml is acceptable, the amount of 4.1-10 ng/ml is considered as gray zone by all authorities. there are different cut-off points in different parts of the world; in japan, those with psa<2 ng/ml are excluded from annual control(28) and in the united states, some believe that the cut-off point should be psa=2.5 ng/ml. however, measurement of free psa, age adjustment, and determination of psa velocity and psa density can help to determine the cut-off point.(25,27) performing biopsy in those with a psa between 4.1 and 10 ng/ml will lead to diagnosis of cancer in 25%.(29) finally, psa is accompanied with high false positive results, which its psychological burden would be a matter of attention and it is necessary for the results to be confirmed with second line tests such as transrectal ultrasound (trus) or transrectal ultrasound-guided biopsy (trus-gb). but these tests are invasive and can not be used as a screening test; whereas, psa is eligible to be a screening test according to who criteria.(2,16) 6the test should be accepted by the community: there is no study regarding the community acceptance and to show how much the people are satisfied with screening test, but in many communities such as the iranian, the patients have embarrassment with dre and the cost of psa may be high for some patients. 7there should be an approved policy for the treatment of patients: there is no such agreement about prostate cancer. in addition there is no agreement that early diagnosis can reduce mortality rate with appropriate treatment. two large randomized and multicenter study in the united states and europe are in process, publishing the results in the future.(2) in a study done in quebec, canada, 80137 men above 50 years old underwent dre and psa. in case of abnormal results for each test, trus was performed and in doubtful cases, biopsy was done. these patients were compared with 38000 unscreened controls. the mortality rate from prostate cancer decreased dramatically in screened patients (5/100000 vs. 48.7/100000).(14) there are also many studies such as the one done by barry and colleagues from massachusetts hospital, that disagrees the above. they believe that there is no study that confirms the role of prostate cancer screening in reducing mortality and morbidity of the cancer. although over-treatment is not always associated with increased mortality, unawareness of benefits and harms of invasive treatment of patients diagnosed via screening and its high cost should be taken into account.(23) 8available facilities for diagnosis and treatment should be present: certainly, performance of screening test for prostate cancer needs more facilities and human and financial resources, which is not enough at the moment. 9case finding expenses should be equivalent to medical care expenses: it is not true for prostate cancer because expenses comprise both human and financial resources and screening expenditure is much higher than medical care expenses. mass screening is estimated to cost 12 to 28 billion dollars in the united states, that means such equilibrium is not present.(1) 10case finding process should be consistent: due to constant dispute about screening test in prostate cancer,(7,9,10-13) time intervals for its performance have not been determined. as a result screening test for prostate cancer is not concordant with who criteria and it is not documented whether it can improve the health condition of the population or not. hence, screening test for prostate cancer may not be introduced formally, but its opportunistic form which is now performed in practice, can be justified. how is the screening status in different countries? the united states prostate cancer is the second most commonly diagnosed malignancy after skin cancer and the prostate cancer screening244 second most common cause of death due to malignancy after lung cancer. there is one death for each five diagnosed prostate cancer annually.(1) the opportunistic form of screening is performed in this country. it means that the patients who demand to perform this test themselves and those who refer for other prostatic disease such as bph are evaluated and among the tests, dre and psa are performed as the first line tests and trus and biopsy are in the second line for those whose one or both test results are abnormal. american urological association (aua) and american council of radiology (acr) have advised that all men above 50 years old should undergo psa test and dre annually and for high risk and afro-american men it should be performed at 40 years old. american cancer association has limited these tests to those who have at least 10-year life expectancy.(1) but american college of physicians (acp) and office of technologic assessment (ota) object to annual follow-up and believe that people should be informed, so that they decide themselves. in summary, the united states preventive service task force (uspstf), who is responsible for general examination in regular periods is against screening for prostate cancer and believes that there is not enough evidence in favor of or against screening and because of few reports on effectiveness of early intervention in prostate caner, there is no reason to expose the patients to factors such as anxiety, biopsy and complications of treatment.(1) the netherlands in the netherlands, preventive medicine takes priority in the government's point of view and health technology assessment (hta) is of special importance. based on this country's rules, which is unique all over the world, screening test should be thoroughly investigated and its efficacy and ethical, legal and social aspects should be considered. researchers and experts have performed studies on psa test for prostate cancer, mammography for breast cancer, and ultrasonography for normal pregnancies as screening tests. different studies has led to acceptance of mammography, but for screening with psa and ultrasonography only their opportunistic forms are accepted.(15) belgium numerous studies have been performed regarding psa for prostate cancer, mammography for breast cancer, and ultrasonography for normal pregnancies in belgium. published articles, performed researches, unpublished manuscripts and different interviews with experts have been reviewed. as a result, only in flandre area mammography is being used as screening for breast cancer and a final agreement is not reached for other screening tests.(20) australia australian health technology advisory committee (ahtac) has performed an extensive study on advantages, risks, and costs of screening for prostate cancer. they concluded that it can not be recommended and only opportunistic screening has been advised and supported.(2) austria only opportunistic screening has been accepted in this country.(29) china mass screening for men above 50 years old is performed in this country and they believe that, it is the only way to diagnose the disease in its early stages.(30) new zealand although screening with psa test has not been accepted and is not performed in this country, many of male population without signs or symptoms are referred for psa test and dre. however, this rate is less than that in australia.(31) need for educational programs and ethical consideration there is no doubt that there is not any consensus regarding screening test for prostate cancer. on the other hand, it is a health problem and there is a general demand in this regard. therefore, it is necessary that the problem should be clarified for the society, medical professionals, and responsible organizations through an educational program. prostate disease patient outcome research team (pdpdrt) in the united states has accepted the responsibility to prepare appropriate educational material for physicians and patients. an educational pamphlet, which provides complete information, is distributed widely among people and medical professionals are educated via continuous medical education program. in addition, ethical burden resulted from screening tests should also be considered and enough care must be taken to that the result of screening does not affect employment or insurrazi 245 ance facilities for immigrants. conclusion psa screening test cannot be imposed to the health system of a country as a complied program. people's demand for performing psa test and available opportunities should definitely be used for its performance. references 1. ferrini r, woolf sh. american college of preventive medicine practice policy. screening for prostate cancer in american men. am j prev med. 1998;15:81-4. 2. australian health technology advisory committee. prostate cancer screening. commonwealth department of health and family services. available from: http://www7.health.gov.au/pubs/ahtac/prostate.htm. 3. crawford ed. epidemiology of prostate cancer. urology. 2003;62(6 suppl 1):3-12. 4. chakravarti a, zhai gg. molecular and genetic prognostic factors of prostate cancer. world j urol. 2003;21:265-74. 5. hsieh k, albertsen pc. population at high risk for prostate cancer. urol clin north am. 2003;30:669-76. 6. lowe fc, gillbert sm, kahane h. evidence of increased prostate cancer detection in men aged 50 to 59: a review of 324, 684 biopsies performed between 1995 and 2002. urology. 2003;62:1045-9. 7. richter f dudley aw jr, irwin rj jr, sadeghi-nejad h. are we ordering too many psa test? prostate cancer diagnosis and psa screening patterns for a single veterans affairs medical cancer. j cancer educ. 2001;16:38-41. 8. lu-yao g, stukel ta, yao sl. prostate-specific antigen screening in elderly men. j natl cancer inst. 2003;95: 1792-7. 9. berger ap, volgger h, rogatsch h, et al. screening with low psa cutoff values result in low rates of positive surgical margins in radical prostatectomy specimens. prostate. 2002;53:241-5. 10. mcgregor m. psa screening: correlating noise with noise? cmaj. 2002; 167:340. 11. mccarthy m. psa screening said to reduce prostate-cancer deaths, or does it? lancet. 1998; 351:1563. 12. de koning hj, schroder fh. psa screening for prostate cancer: the current controversy. ann oncol. 1998;9:1293-6. 13. federman dg, goyal s, kamina a, peduzzi p, concato j. informed consent for psa screening: dose it happen? eff clin pract. 1999;2: 152-7. 14. labrie f, candas b, dupont a, et al. screening decreases prostate cancer death: first analysis of the 1988 quebec prospective randomized controlled trial. prostate. 1999;38:83-91. 15. benta hd, oortwiin w. health technology assessment and screening in the netherlands: case studies of mammography in breast cancer, psa screening in prostate cancer, and ultrasound in normal pregnancy. int j technol assess health care. 2001;17: 369-79. 16. us preventive services task force update, 2002 release. guide to clinical preventive services. 3rd ed. periodic update cancer; 2002. 17. horninger w, rogatsch h, reissigl a, et al. correlation between preoperative predictors and pathologic features in radical prostatectomy specimens in psa-based screening. prostate. 1999;40:56-61. 18. wild c. screening in austria: the cases of mammography, psa testing and routine use of ultrasound in pregnancy. int j technol assess health care. 2001;17:305-15. 19. kurokawa k, suzuki k, okazaki h, et al. usefulness of psa screening in outpatients with bladder cancer: preliminary results. int j urol. 2002;9:237-40. 20. vermeulen v, coppens k, kesteloot k. impact of health technology assessment on preventive screening in belgium: case studies of mammography in breast cancer, psa screening in prostate cancer, and ultrasound in normal pregnancy. int j technol assess health care. 2001;17:316-28. 21. nakanishi h, nakao m, nomoto t, et al. the investigation of age-specific psa reference range as the cut-off values in the mass screening for prostatic cancer. nippon hinyokika gakkai zasshi. 1999;90:853-8. 22. hakama m, auvinen a, stenman uh, talmela t. about psa-screening. duodecim. 1996;112:1314-6. 23. barry mj. psa screening for prostate cancer: the current controversy--a viewpoint. patient outcomes research team for prostatic diseases. ann oncol. 1998;9:1279-82. 24. vis an, hoedemaeker rf, roobol m, van der kwast th, schrroder fh. tumor characteristics in screening for prostate cancer with and without rectal examination as an initial screening test at low psa (0.0-3.9 ng/ml). prostate. 2001;47:252-61. 25. gretzer mb, partin aw. psa markers in prostate cancer detection. urol clin north am. 2003;30:677-86. 26. so a, goldenberg l, gleave me. prostate specific antigen: an updated review. can j urol. 2003;10:2040-50. 27. h. ballentine curter, a lon w partin, campbell's urology eighth edition. volume 4; 3061-63. 28. uozumi j, tokuda y, fujiyama c, et al. annual psa tests are not necessary for men with a psa level below 2 ng/ml: findings of the imari prostate cancer screening program. int j urol. 2002;9:334-9. 29. ishidoya s, ogata y, inaba y, et al. screening of prostate cancer with psa and transprineal six sextant biopsy. nippon hinyokika gakkai zasshi. 1999;90:579-85. 30. zhao xj, kong xb, wang wh. mass screening for prostate cancer is the best approach to early diagnosis and treatment of prostate cancer. zhonghua nan ke xue. 2003;9:563-5,568. 31. sneyd mj, cox b, paul c, skegg dc. psa testing and digital rectal examination in new zealand. aust n z j public health. 2003;27:502-6. vol 12. no 02 march-april 2015 2065 introduction treatment options for lower pole renal calculi (lpc) depending on the stone size are extracorporeal shock wave lithotripsy (swl), percutaneous nephrolithotomy (pnl) and retrograde intrarenal surgery (rirs).(1) swl is a non-invasive procedure and can be performed as an outpatient setting under local anesthesia or sedation. swl has been accepted as a standard treatment for renal stones measuring less than 2 cm. however, lower success rates have been reported for lpc.(2) the first application of flexible ureteroscopy was reported by marshal in 1964. a 9 french (f) fiberscope manufactured by american cystoscope makers (pelham manor, ny, usa) was passed into the ureter to visualize an impacted ureteral calculus. downsizing of flexible ureterorenoscope from 9.8 f to 7.5 f and improvement in its deflection capacity while maintaining the same 3.6 f working channel has allowed urologists to reach renal calyces easily. this event has opened up a new era in the treatment of renal stones and rirs became a treatment option for renal stones smaller than 20 mm, in cases with an unsuccessful swl.(3) furthermore, depending on operator skills, it has been found to be safe and effective procedure even in stones larger than 2 cm.(4) despite technological improvements in flexible ureteroscopy, insertion of the laser probe may cause loss of def lection ability of the flexible ureterorenoscope within lower pole calyces and result in difficulties in access. this may be more crucial in patients with unfavorable anatomy. besides difficulties in access, calyceal unfavorable anatomy may also influence on the stone clearance rate by the effect of gravity after rirs. there are few studies assessing the effect of lower pole anatomical characteristics (lpacs) on the success rates of rirs.(5-7) the impact of intrarenal anatomy on stonefree rates after rirs is not completely clear yet. in our study, we tried to reveal the unfavorable anatomical factors influencing the success of rirs for lpc. materials and methods study population a total of 36 patients with radio opaque or non-opaque lower pole renal stones, who underwent rirs as a primary treatment for lpc between october 2012 and october 2013 were included in the study. the patients who had stones in other localizations than lower pole were excluded. before surgery, all patients were evaluated routinely with urinalysis, urine culture, coagulation tests, complete blood count, serum biochemistry and intravenous urography (ivu). stone length was calculated on preoperative kidney-ureter-bladder (kub) x-ray by two experienced urologists. in case of multiple stones, the stone size was calculated by adding the length of the longest axis of each endourology and stone disease unfavorable anatomical factors influencing the success of retrograde intrarenal surgery for lower pole renal calculi hakan kilicarslan,1 yurdaer kaynak,2* yakup kordan,1 onur kaygisiz,1 burhan coskun,1 kadir omur gunseren,1 feyzi mutlu kanat1 purpose: to determine the unfavorable factors, related to lower pole anatomical characteristics (lpacs), influencing the success of retrograde intrarenal surgery (rirs) for lower pole renal calculi (lpc). materials and methods: we reviewed the data of 36 patients who underwent rirs for lpc between october 2012 and october 2013. the infundibulopelvic angle (ipa), infundibular length (il) and infundibular width (iw) were measured on preoperative intravenous urographies. on follow-up stone-free status was defined as complete clearance at the first month kidney-ureter-bladder x-ray and computed tomography if necessary. results: the median stone size was 10 mm (range, 5-35). the stone-free rates according to lpacs at the first month follow-up were 100% (n = 17), 57.9% (n = 11), 90% (n = 18), 62.5% (n = 10), 90.5% (n = 19) and 60% (n = 9) for patients with ipa ≥ 70°, ipa < 70º, il < 3 cm, il ≥ 3 cm, iw ≥ 5 mm and iw < 5 mm, respectively. while ipa and iw were associated with success of rirs for lpc in multivariate analysis (p = .003 and p = .046, respectively), only iw was found to be a significant factor after applying multivariate analysis (p = .05). conclusion: the results of our study demonstrated that only iw had a significant effect on the success rate of rirs for lpc. keywords: kidney calculi; surgery; kidney calculi; therapy; nephrostomy; percutaneous; ureteroscopy; treatment outcome; kidney calculi. 1 department of urology, faculty of medicine, uludag university, bursa, turkey. 2 department of urology, state hospital, eskisehir, turkey. *correspondence: department of urology, eskisehir state hospital, 26020 eskisehir, turkey. tel: +90 542 292 77 84. fax: +90 222 237 6134. e-mail: yurdaerkaynak@hotmail.com. received september 2014 & accepted february 2015 stone. the infundibulopelvic angle (ipa), infundibular length (il) and infundibular width (iw) were measured by two experienced urologists on ivu. the ipa of lower calyx was measured as the inner angle formed at the intersection of the ureteropelvic and central axis of the lower pole infundibulum. the il was measured from the most distal point at the bottom of infundibulum to a mid-point at the lower lip of the renal pelvis. the iw was measured at the narrowest point along the infundibular axis as defined by elbahnasy and colleagues.(7) lower pole ipa, il and iw were measured and recorded for each patient as shown in the figure. stonefree and nonstone-free patients were analyzed according to their ipa < 70°, ipa ≥ 70º, il ≥ 3 cm, il < 3 cm, and iw < 5 mm and iw ≥ 5 mm. perioperative variables including age, gender, stone size, duration of operation and residual stone were recorded. surgical technique all patients were operated under general anesthesia by one experienced surgeon. patients were placed in a modified combined trendelenburg (head down approximately 20°) lithotomy position.(8) storz flexxtm 2 (karl storz, tutlingen, germany) flexible ureterorenoscope (7.5 f) was used in the operations. the instrument has continuous controlled dual deflection with increased downward and upward deflection up to 270 degrees in both directions. before insertion of flexible ureteroscope a semi-rigid ureterorenoscope was inserted into the bladder under endoscopic vision. a guide wire (polytetrafluoroethylene [ptfe] coated, 0.0035 inch) was inserted into ureter through a working channel. the semi-rigid ureterorenoscope was placed into the ureter under the guidance of the guide wire. once the ureterorenoscope had been in the ureter, the second guide wire (sensitive, 0.0035 inch) was inserted through the other working channel of the ureterorenoscope. then, the rigid ureterorenoscope was withdrawn and the access sheath (9.5 f) was inserted over the ptfe coated guide wire under fluoroscopy. the flexible ureterorenoscope was inserted. the visual image was coordinated with a fluoroscopy image to enter appropriate calyces.(9) a 270 micron laser fiber was used for lithotripsy. the holmium laser was set at an energy level of 0.5-1.2 joule and a rate of 10-25 hz. the stones were dusted with a holmium yag laser, however, when it was not possible to dust a stone (in case of a hard stone) the stone was fragmented smaller than 3 mm diameter. a ureteral double j (dj) ureteral stent (4.8 f) was placed at the end of the procedure. the dj ureteral stents were withdrawn four weeks after the procedure when kub x-ray shows complete clearance of stone fragmentation. the patients were advised to drink 2.5 l of water daily. kub x-ray was used to determine stone clearance at the first month follow-up for radio-opaque stones. the stone free statues of the non-opaque stone were evaluated with computed tomography scan (ct) scan. the success was defined as stone-free status which means complete clearance of the stone fragments. statistical analysis the normality was tested with shapiro-wilk test. student’s t-test was used for the homogeneous variables. mannwhitney u test was used for non-homogeneous variables. logistic regression test was used for multivariate analysis. the statistical evaluation of nominal variables was made by chi-square and fischer exact tests. statistical analysis was done with statistical package for the social science (spss inc, chicago, illinois, usa) version 20.0. the level of significance used was set at p < .05. results the mean age of the patients was 46.11 ± 10.46 years. among 36 patients 20 (55.6%) were male and 16 (44.4%) unfavorable factors influencing the success of retrograde intrarenal surgery-kilicarslan et al. variables stone free non stone free univariate multivariate (n = 28) (n = 8) p value p value odds ratio 95% ci mean age (year)1 45.96 ± 9.83 46.63 ±13.17 .877 _____ _____ _____ median stone size (mm)2 10.00 (5-35) 12.00 (5-15) .825 _____ _____ _____ median operation time (min)2 60 (12-210) 45 (14-90) .668 _____ _____ gender3 n (%) male 13 (62.3) 7 (36.8 ) .053 _____ _____ _____ female 15 (93.8) 1 (6.2 ) ipa3 n (%) ≥ 70º (n = 17) 17 (100) 0 (0) .003* _____ _____ _____ < 70º (n = 19) 11(57.9) 8 (42.1) il3 n (%) ≥ 3 cm (n = 16) 10 (62.5) 6 (37.5) .103 _____ _____ _____ < 3 cm (n = 20) 18 (90) 2 (10) iw3 n (%) ≥ 5 mm (n = 21) 19 (90.5) 2 (9.5) .046* .050 8 1.001-63.963 < 5 mm (n = 20) 9 (60) 6 (40) table. overall outcomes of retrograde intrarenal surgery. abbreviations: ipa, infundibulopelvic angle; il, infundibular length; iw, infundibular width; ci, confidence interval. * statistically significant; 1 homogeneous variables; 2 non-homogeneous variables; 3 nominal variables. endourology and stone disease 2066 vol 12. no 02 march-april 2015 2067 were female. the median stone size was 10 mm (range, 5-35). the median duration of operation was 60 minutes (range, 12-210). two patients underwent simultaneous ureterorenoscopy for ipsilateral ureteral calculi. we used the basket catheter to relocate the lower pole stone into renal pelvis in 4 cases because of difficulties in deflection. the success rate was 77.8% (n = 28) after a single session of rirs. comparison of age, stone size and length of operation between patients who were stone free and who were not, demonstrated statistically significant differences (p = .877, p = .808 and p = .668, respectively). complications observed in this study were, urinary tract infection in 5 and urosepsis in 1 patient. all of these patients were treated with appropriate antibacterial therapy. there was no significant difference in terms of stone free rate (sfr) between patients with > 3 cm and < 3 cm infundibular length (p = .103). for patients who had ipa < 70º and ipa ≥ 70º, sfr was 57.9% (n = 11) and 100% (n = 17), respectively. when patients with iw < 5 mm and w ≥ 5 mm were compared, sfr was 60% (n = 9) and 90.5% (n = 19), respectively. both ipa and iw were associated with stone-free status (p = .003, p = .046, respectively). however, iw was the only independent factor after performing multivariate analysis (p = .050). all findings were summarized in the table. discussion unfavorable anatomical characteristics of the lower pole (such as ipa, il and iw) have been reported to influence sfr in patients who underwent swl for lpc. thus, these parameters should also be taken into consideration before planning treatment.(10,11) there are a few reports assessing the effects of these aforementioned factors on success of rirs for lpc.(6,7) in the present study, we evaluated unfavorable anatomical factors influencing the success of rirs for lpc. both iw and ipa were found to be important factors for sfr in after univariate analysis. however, only iw was found to be statistically significant after multivariate analysis. there is no clear definition of sfr in literature. resorlu and colleagues defined sfr as no residual fragments or residual fragments smaller than 4 mm on non-contrast ct scan at the second month follow-up. they reported 80.6% of sfr.(6) ito and colleagues described it as no residual fragments on the postoperative first day and at the third month on plain kub films. they reported a sfr of 50.8% for the postoperative first day. in their study, the stones were at different localizations in the kidney and the mean stone size was larger than ours (stone-free and non-stone-free were 16.92 ± 10.22 cm and 36.42 ± 18.51 cm, respectively).(12) recent studies have reported 85% of sfrs for lpc.(12-16) in the present study, sfrs was 77.8% which was in accordance with other studies. scopes with higher deflection and double deflection ability may have higher stone free rates and success. resorlu and colleagues reported that the age was not an influencing factor as well.(17) in our study we also found that patient’s age was not a significant factor influencing the success in the treatment of lpc in our adult patients (p = .877). the mean stone size was slightly higher for patients with residual stones, but it was not statistically significant (p = .808). contrary to our results, resorlu and colleagues reported the stone size as a significant factor on sfr.(6) however, in their study, stone-free status was accepted as either when there were no stone or stone fragments smaller than 4 mm on the first month follow up with non-contrast ct. ito and colleagues using the same sfr definition with us, also found that stone size affects the sfrs after rirs for lpc.(12) in these two studies their mean cumulative stone sizes were higher than ours. these could be the reasons why stone size did not reach to statistical significance in our study. the duration of operation has been found to be longer in non-stone free patients than stone free patients.(12) stone size seems to influence the stone free status and the operation time. in our study we didn’t find any statistical difference in regards to the duration of the operation between stone free and non-stone free patients. this could also be attributed to the stone size since our cumulative stone size was smaller than the reported study. many studies have paid attention to the importance of unfavorable lower pole anatomy on the success of swl in patients with lpc.(7,18) after these reports, it has been emphasized to be of importance for the success of swl in patients with lpc.(1) however, there are a few reports evaluating unfavorable lower pole anatomy on the success of rirs in patients with lpc. in case of steep ipa, access to lower pole calyx may be difficult and it might make stone clearance complicated. in univariate analysis, we found that ipa was associated with stonefree status after rirs for lpc (p = .003). however this was not significant in multivariate analysis. an ipa ≥ 70º was found to be significant in a study by elbahnasy and colleagues.(7) resorlu and colleagues reported the similar result in terms of ipa,(6) but their cutoff value for favorable ipa was ≥ 45º. in a recent study, an acute ipa (< 30°) also was found to have significant influence.(19) geavlete and colleagues reported that the success rate was 87.5% (7/8 patients) in patients with infundibulopelvic angle wider than 90 degrees, 74.3% (26/35 patients) when this angle ranged between 30 and 90 degrees and 0% (0/4 patients) in patients with infundibulopelvic angle smaller than 30 degrees.(20) the narrow infundibulum may cause hemorrhage hampering the vision when ureterorenoscope is advancing in the narrowest part of it. the bleeding may become the figure. measurements of the infundibulopelvic angle (ipa), the infundibular length (il) and the infundibular width (iw). unfavorable factors influencing the success of retrograde intrarenal surgery-kilicarslan et al. access failed. in spite of good stone fragmentation, injured calyceal wall may deteriorate passive stone clearance after rirs. iw has been reported to be important for the patients who undergo swl for lpc.(7) in our study, the results of the multivariate analysis showed that iw (iw ≥ 5 mm) was the most important favorable anatomical factor influencing stone clearance for the patients who underwent rirs for lpc (p = .046). contrast to our study, resorlu and colleagues have reported that, iw not to be a predictive factor on sfrs.(6) the il has shown to be able to affect the results in patients with lpc undergoing swl.(7) we found il to be statistically an insignificant factor for the stone-free status, similar to the report by resorlu and colleagues.(6) the limitation of the present study was that our study consisted of 36 patients which were relatively small to draw an absolute conclusion. further large scale studies are needed to evaluate the effect of these factors in rirs treatment of lpc. conclusion the results of our study demonstrated that iw ≥ 5 mm had a significant effect on the success of rirs for lpc. il, ipa stone size, age and gender were not predictors of unsuccessful rirs for lpc. rirs can be safely and effectively used in the treatment of lpc in selected patients having favorable anatomical characteristics. conflict of interest none declared. references 1. türk c, knoll t, petrik a, sarica k, skolarikos a, straub m, seitz c. eau guidelines on urolithiasis. 2013:1-100. available at: http:// www.uroweb.org/gls/pdf/21_urolithiasis_ lrv2.pdf. 2. ghoneim ia, ziada am, elkatib se. predictive factors of lower caliceal stone clearance after extracorporeal shock wave lithotripsy (eswl): a focus on infundibulopelvic anatomy. eur urol. 2005;48:296-302. 3. fuchs am, fuchs gj. retrograde intra-renal surgery for calculus disease: new minimally invasive treatment approach. j endourol. 1990;4:337-45. 4. aboumarzouk om1, monga m, kata sg, traxer o, somani bk. flexible ureteroscopy and laser lithotripsy for stones >2 cm: a systematic review and meta-analysis. j endourol. 2012;26:125763. 5. grasso m, ficazzola m. retrograde ureteropyeloscopy for lower pole caliceal calculi. j urol. 1999;162:1904-8. 6. resorlu b, oguz u, resorlu eb, oztuna d, unsal a. the impact of pelvicaliceal anatomy on the success of retrograde intrarenal surgery in patients with lower pole renal stones. urology. 2012;79:61-6. 7. elbahnasy am, shalhav al, hoenig dm, et al. lower caliceal stone clearance after shock wave lithotripsy or ureteroscopy: the impact of lower pole radiographic anatomy. j urol. 1998;159:676-82. 8. portis aj, rygwall r, holtz c, pshon n, laliberte m. ureteroscopic laser lithotripsy for upper urinary tract calculi with active fragment extraction and computerized tomography follow up. j urol. 2006;175:2129-33. 9. honey rj, bagley dh, moran me, teichman jmh. flexible ureteroscopy for renal stones. aua postgraduate hands on course 03 dl. 2007. 10. sahinkanat t, ekerbicer h, onal b, et al. evaluation of the effects of relationships between main spatial lower pole calyceal anatomic factors on the success of shock-wave lithotripsy patients with lower pole kidney stones. urology. 2008;71:801-5. 11. danuser h, muller r, descoeudres b, dobry e, studer ue. extracorporeal shock wave lithotripsy of lower calyx calculi: how much is treatment outcome influenced by the anatomy of the collecting system? eur urol. 2007;52:53946. 12. ito h, kawahara t, terao h, et al. the most reliable preoperative assessment of stone burden as a predictor of stone-free status after flexible ureteroscopy with holmium laser lithotripsy: a single center experience. urology. 2012;80:5248. 13. breda a, ogunyemi o, leppert jt, lam js, schulam pg. flexible ureteroscopy and laser lithotripsy for single intrarenal stones 2 cm or greater-is this the new frontier? j urol. 2008;179:981-4. 14. mariani aj. combined electrohydraulic and holmium: yag laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. j urol. 2007;177:168-73. 15. galvin dj, pearle ms. the contemporary management of renal and ureteric calculi. bju int. 2006;98:1283-8. 16. breda a, ogunyemi o, leppert jt, schulam pg. flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. eur urol. 2009;55:1190-7. 17. resorlu b, unsal a, gulec h, oztuna d. a new scoring system for predicting stone-free rate after retrograde intrarenal surgery: the "resorluunsal stone score". urology. 2012;80:512-8. 18. sampaio fj. renal collecting system anatomy: its possible role in the effectiveness of renal stone treatment. current opin urol. 2001;11:359-66. 19. jessen jp, honeck p, knoll t, wendt-nordahl g. flexible ureterorenoscopy for lower pole stones: influence of the collecting system's anatomy. j endourol. 2014;28:146-51. 20. geavlete p, multescu r, geavlete b. influence of pyelocaliceal anatomy on the success of flexible ureteroscopic approach. j endourol. 2008;22:2235-9. unfavorable factors influencing the success of retrograde intrarenal surgery-kilicarslan et al. endourology and stone disease 2068 sexual dysfunction and infertility 260 urology journal vol 5 no 4 autumn 2008 sexual dysfunction in aging men with lower urinary tract symptoms darab mehraban, gholam hossein naderi, seyed reza yahyazadeh, mahdi amirchaghmaghi introduction: our aim was to evaluate the relationship between lower urinary tract symptoms (luts), age, and sexual dysfunction in the iranian men aged 50 to 80 years. materials and methods: a total of 357 men aged 50 to 80 years presenting at the urological clinic were enrolled in this study. the international prostatic symptom score (ipss) and the international index of erectile function (iief) questionnaires were used to assess the luts and sexual function, respectively. the questionnaires were completed by face-to-face interview. logistic regression model was used for multivariate analysis of the risk factors of sexual dysfunction and its domains assessed by the iief. results: of the patients, 332 (93%) were sexually active with a median sexual attempts of 4.6 times per month. frequency of sexual attempts was inversely related to luts severity (p < .001). advanced age was positively associated with luts severity (r = 0.534, p < .001). sexual dysfunction, defined as iief score of 20 and less, was present in 68.2% of the patients. all iief domain scores and the overall score were correlated with age (p < .001) and the ipss (p < .001). in a multivariate analysis, age, diabetes mellitus, and the ipss were strong independent predictors of the overall iief score. conclusion: sexual activity as an important component of the quality of life continues in the majority of men over 50 years. however, their sexual function can be severely affected by luts and its severity. urol j. 2008;5:260-4. www.uj.unrc.ir keywords: sexual dysfunction, prostatic hyperplasia, aged, urination disorders department of urology, shariati hospital, tehran university of medical sciences, tehran, iran corresponding author: department of urology, shariati hospital, karegar st, tehran, iran tel: +98 912 119 6097 fax: +98 21 8863 3039 e-mail: darabm@gmail.com received april 2008 accepted july 2008 introduction lower urinary tract symptoms (luts), mainly caused by benign prostatic hyperplasia (bph), and sexual dysfunction (sd) are highly prevalent urologic problems among the aging male population. both conditions have significant impact on the overall quality of life.(1) the massachusetts male aging study showed that 34.8% of 40to 70year-old men suffer from moderate to severe erectile dysfunction. in iran, impotence was reported in 47% of men aged between 60 and 70 years.(2) the condition is strongly related to age, cardiovascular diseases, depression, and diabetes mellitus.(2) although evidence on the relationship between luts and sd are controversial,(3,4) some have shown luts to be an independent risk factor of sd. results of a recent study indicated improvement in luts following the treatment of sd.(5) sexual dysfunction is a complex phenomenon not limited only to erectile dysfunction. it is well sexual dysfunction and lower urinary tract symptoms—mehraban et al urology journal vol 5 no 4 autumn 2008 261 established from several clinical studies that ejaculatory disorders are as prevalent as erectile dysfunction, affecting half of men aged over 50 years.(6) moreover, recent data from the multinational survey of the aging male (msam-7), conducted in the united states and 6 european countries, revealed that 46% of men had a reduced amount of ejaculate, and 59% of these men considered it to be a problem.(6) in addition, it was found that ejaculatory disorders significantly increased with the severity of luts.(7) reports from different countries have shown a wide range of incidence of sd in different populations.(8) meanwhile, some mechanisms such as activation of the noradrenergic system in bladder outlet obstruction or local effects of the enlarged prostate on cavernosal nerves have been proposed to explain this coexistence, but the exact pathophysiology of this relation is unknown.(6) we conducted a cross-sectional study to provide a preliminary sketch of basic epidemiologic data on the frequency of sexual dysfunction and lower urinary tract symptoms in our aging patients and to assess their relationship. materials and methods between june 2004 and december 2006, we enrolled 357 men aged 50 to 80 years in this study. data were collected from the patients referring to the outpatient urological clinic at shariati hospital. those with documented history of bladder calculus, urethral stricture, bladder tumor, prostate cancer, and those with indwelling catheters were excluded. during the outpatient visits, demographic characteristics, comorbidities (diabetes mellitus, hypertension, and hyperlipidemia), life style factors (smoking, alcohol consumption), and history of any pelvic surgery, related traumas, or treatment were asked. sexual dysfunction and luts were assessed by the international index of erectile function (iief) and the international prostatic symptom score (ipss) questionnaires, respectively, completed by face-to-face interview.(9,10) the interviews were performed by trained urology residents in this center. both questionnaires were linguistically validated using translation and back-translation process. the ipss questionnaire, is a validated 8-item questionnaire for assessment of the severity of luts. the first 7 questions are scored from zero to 5 with an overall score of zero to 35. the severity of symptoms is classified as “mild,” “moderate,” and “severe” for scores of 7 and less, 8 to 19, and more than 20, respectively. the iief questionnaire, as the gold standard method for assessment of sexual function in clinical trials, scores separate domains of erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. we analyzed the relation of the patients’ iief and ipss scores. statistical analyses were done using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). for comparisons between groups, the chisquare test and the kruskal-wallis test were used. correlations were tested with the spearman rho test. multivariate analysis using logistic regression model was used to measure the relationship between luts and sexual dysfunction, adjusted for confounding factors. two-sided test with type 1 error of 5% and 95 % confidence interval was used. results all of the approached 357 eligible patients consented to participate in the study. the mean age of the patients was 64.1 ± 7.4 years (range, 50 to 80 years). table 1 summarizes the clinical characteristics of the respondents. the median ipss score was 15 and in terms of severity, 68 (19.0%), 188 (52.7%), and 98 (27.5%) patients had mild, moderate, and severe luts, respectively. logistic regression analysis showed characteristics patients (%) missed data (%) comorbidities diabetes mellitus 49 (13.7) 1 (0.3) hypertension 96 (26.9) 12 (3.4) hyperlipidemia 48 (13.7) 7 (1.9) life style factors smoking 102 (28.6) 1 (0.3) alcohol consumption 3 (0.8) 0 history of pelvic trauma 13 (3.6) 40 (11.2) history of pelvic surgery 18 (5.0) 44 (12.3) table 1. characteristics of patients with lower urinary tract symptoms (n = 357) sexual dysfunction and lower urinary tract symptoms—mehraban et al 262 urology journal vol 5 no 4 autumn 2008 a significant association between the age and severity of luts (r = 0.534, p < .001). the association of other variables with the ipss are shown in table 2. of the participants, 332 (92.9%) were sexually active, reporting a median monthly sexual attempts of 4.6 times. this rate was significantly lower in those with severe luts (p < .001); the median frequency of sexual attempts was 6.4 times per month for the patients with mild symptoms compared to 3.3 times per month for those with severe luts. the overall frequency of sexual dysfunction, defined as iief scores of 20 or less, was 68.2%. there was a strong relationship between all iief domain scores and the severity of luts irrespective of other comorbidities such as diabetes mellitus, hypertension, and hyperlipidemia. similar relations were observed for the age (tables 3 and 4). univariate logistic regression analysis revealed that the ipss (p < .001), age (p < .001), smoking (p < .013), diabetes mellitus (p < .001), and hypertension (p = .001) were associated with the overall iief scores. however, on multivariate analysis, only age, diabetes mellitus, and the ipss were remained in the model. discussion lower urinary tract symptoms and sexual dysfunction are age-related conditions that are commonly seen during the routine urologic visits. it has been shown that the prevalence of histologic bph increases from 8% in the 4th decade to 82% in the 8th decade of life.(11) there might be differences in the prevalence of luts in different cultures. a greater rates of luts were reported in japan and the united states in comparison to those in france or scotland.(12) there has been notable differences in the prevalence of moderate to severe luts between men in singapore (14%) and philippines (56%).(13) lower urinary tract symptoms risk factors mild moderate severe p smoking yes 16 (15.8) 48 (47.5) 37 (36.6) no 52 (20.6) 140 (55.3) 61 (24.1) .06 diabetes mellitus yes 4 (8.2) 28 (57.1) 17 (34.7) no 64 (21.0) 160 (52.5) 81 (26.6) .09 hypertension yes 8 (8.4) 50 (52.6) 37 (38.9) no 57 (23.0) 135 (54.4) 56 (22.6) .001 history of surgery yes 2 (11.1) 2 (38.9) 9 (50.0) no 61 (20.8) 156 (53.2) 76 (25.9) .11 history of trauma yes 1 (7.7) 9 (69.2) 3 (23.1) no 62 (20.5) 62 (51.3) 85 (28.1) .45 table 2. severity of lower urinary tract symptoms stratified by risk factors* *numbers in parenthesis are percents. iief domains scores associated factors overall overall satisfaction intercourse satisfaction sexual desire orgasmic function erectile function ipss score -0.655 -0.539† -0.487 -0.450 -0.439 -0.659 age -0.504 -0.458† -0.330 -0.350 -0.323 -0.516 table 3. correlation coefficients for association of iief domains with ipss and age* *iief indicates the international index of erectile function and ipss, the international prostatic symptom score. †p < .001; spearman rho test. lower urinary tract symptoms domains mild moderate severe p erectile function 25 (5 to 30) 20 (8 to 29) 13 (1 to 25) < .001 orgasmic function 8 (4 to10) 6 (0 to 10) 5 (0 to 10) < .001 sexual desire 7 (3 to 10) 6 (2 to 10) 5 (2 to 9) < .001 intercourse satisfaction 11 (1 to 15) 9 (4 to 14) 6 (0 to 13) < .001 overall satisfaction 9 (2 to 10) 7 (2 to 10) 5 (2 to 10) < .001 overall 59 (24 to 68) 47 (24 to 70) 34 (5 to 64) < .001 table 4. scores of iief domains according to severity of lower urinary tract symptoms* *values are medians (ranges). sexual dysfunction and lower urinary tract symptoms—mehraban et al urology journal vol 5 no 4 autumn 2008 263 in a recent report from sweden, ströberg and coworkers demonstrated that 45% of the individuals with luts had moderate to severe degree of problems.(14) the current study showed that the prevalence of moderate to severe luts was 80.1% which was significantly higher than that in other studies. discrepancies in the luts prevalence might be due to cultural differences and the willingness to seek medical help for luts and sexual dysfunction. moreover, our sample was collected from a tertiary center population, leading to a selection bias. moreover, there has been significant correlation between age and ipss score which is in accordance with reggio and colleagues’ study.(14) recently, several investigations have examined the association of the components of metabolic syndromes with bph and suggested that metabolic profile of men constitute a risk factor of the development of bph. a prospective study showed that only categorized parameters of fasting blood glucose, serum triglyceride, and serum high-density lipoprotein cholesterol correlated with the severity of luts. in addition, the researchers did not find any association of luts with hypertension, smoking, hyperlipidemia, alcohol consumption, and diabetes mellitus.(16) we did not find such relations between these variables and the ipss, either. sexual activity remains high in iranian men aged 50 to 80 years. this prevalence is rather high compared with men in the southeast of asia (93% versus 73%).(13) in the msam-7, 52% of men aged 40 to 70 years had some degrees of erectile dysfunction ranging from 39% in men aged 40 years to 67% in those aged 70 years.(6) other studies demonstrated different incidences of sexual dysfunction among different countries. for example, men in japan (34%) and malaysia (22%) had higher incidences of moderate to complete erectile dysfunction in comparison with those in italy (17%) and brazil (15%).(8) erectile dysfunction was reported by 68.2% of the men in our study that was significantly higher than these reports. previous cross-sectional studies have shown that the prevalence of sexual dysfunction is independently increased with the luts severity. in a large cohort study on 6000 french men with luts, lukacs and colleagues reported that impairment of patients’ sexual activity was related to both age and severity of the luts, which is in accordance with other studies.(17) the msam-7 showed that ipss score was a highly significant predictor of all the iief domain scores. they also showed an independent effect of age and other comorbidities (diabetes, hypertension, cardiac disease, and hyperlipidemia), as well as tobacco use and alcohol consumption, on all the iief domain scores. the strongest predictor was age followed by the ipss score. likewise, we found a significant association between the luts severity and all of the iief domain scores. in the present study, in line with the other studies, the ipss score, age, and diabetes mellitus were strong independent predictors of the overall iief score. although, epidemiological studies provide clear evidence that luts and sexual dysfunction are strongly linked, a causal relationship cannot be established by the data from these studies. even these associations from epidemiological studies must have plausible biochemical explanations to be widely accepted. reduced production of nitric oxide/nitric oxide synthase in the pelvis and the activation of autonomic system due to bladder outlet obstruction have been proposed as potential mechanisms.(6) however, the exact mechanism has not been understood yet. we could not assess the ejaculatory problems because of lack of validated questionnaires. limitations of the present study are a rather small sample size compared to similar studies, a selection bias due to recruitment of the patients from a tertiary center, and finally, the crosssectional nature of this study which limits its strength to establish a causal relationship. on the other hand, data in our study were collected by face-to-face interview. this method increases the reliability of our data. to our knowledge, this is the first study examining sexual dysfunction in relation to luts in the middle east. conclusion elderly men, especially those with luts, should be routinely asked about their sexual function. erectile dysfunction is prevalent in these patients sexual dysfunction and lower urinary tract symptoms—mehraban et al 264 urology journal vol 5 no 4 autumn 2008 and is also strongly related to the severity of the symptoms. sexual dyfunction should be considered when treating aging men with luts. financial support this study was supported by a medical research grant from tehran university of medical sciences. conflict of interest none declared. references 1. van dijk l, kooij dg, schellevis fg, kaptein aa, boon ta, wooning m. nocturia: impact on quality of life in a dutch adult population. bju int. 2004;93:1001-4. 2. safarinejad mr. prevalence and risk factors for erectile dysfunction in a population-based study in iran. int j impot res. 2003;15:246-52. 3. braun mh, sommer f, haupt g, mathers mj, reifenrath b, engelmann uh. lower urinary tract symptoms and erectile dysfunction: co-morbidity or typical “aging male” symptoms? results of the “cologne male survey”. eur urol. 2003;44:588-94. 4. akkus e, kadioglu a, esen a, et al; turkish erectile dysfunction prevalence study group. prevalence and correlates of erectile dysfunction in turkey: a population-based study. eur urol. 2002;41:298-304. 5. mcvary kt. sexual function and alpha-blockers. rev urol. 2005;7:s3-11. 6. rosen r, altwein j, boyle p, et al. lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (msam-7). eur urol. 2003;44:637-49. 7. mcvary kt. sexual dysfunction in men with lower urinary tract symptoms and benign prostatic hyperplasia: an emerging link. bju int. 2003;91:770-1. 8. nicolosi a, moreira ed jr, shirai m, bin mohd tambi mi, glasser db. epidemiology of erectile dysfunction in four countries: cross-national study of the prevalence and correlates of erectile dysfunction. urology. 2003;61:201-6. 9. barry mj, fowler fj jr, o’leary mp, et al. the american urological association symptom index for benign prostatic hyperplasia. the measurement committee of the american urological association. j urol. 1992;148:1549-57. 10. rosen rc, cappelleri jc, gendrano n 3rd. the international index of erectile function (iief): a stateof-the-science review. int j impot res. 2002;14:226-44. 11. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol. 1984;132:474-9. 12. girman cj, jacobsen sj, tsukamoto t, et al. healthrelated quality of life associated with lower urinary tract symptoms in four countries. urology. 1998;51:428-36. 13. li mk, garcia la, rosen r. lower urinary tract symptoms and male sexual dysfunction in asia: a survey of ageing men from five asian countries. bju int. 2005;96:1339-54. 14. reggio e, de bessa j jr, junqueira rg, et al. correlation between lower urinary tract symptoms and erectile dysfunction in men presenting for prostate cancer screening. int j impot res. 2007;19:492-5. 15. ströberg p, boman h, gellerstedt m, hedelin h. relationships between lower urinary tract symptoms, the bother they induce and erectile dysfunction. scand j urol nephrol. 2006;40:307-12. 16. paick js, yang jh, kim sw, ku jh. are age, anthropometry and components of metabolic syndrome-risk factors interrelated with lower urinary tract symptoms in patients with erectile dysfunction? a prospective study. asian j androl. 2007;9:213-20. 17. lukacs b, leplège a, thibault p, jardin a. prospective study of men with clinical benign prostatic hyperplasia treated with alfuzosin by general practitioners: 1-year results. urology. 1996;48:731-40. urology journal unrc/iua vol. 2, no. 1, 8-12 winter 2005 printed in iran 8 o r i g i n a l a r t i c l e s endourology bilateral same-session ureteroscopy: its efficacy and safety for diagnosis and treatment mohammadreza darabi*, maliheh keshvari department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran abstract purpose: to report the results of bilateral same-session ureteroscopy in patients with bilateral pathologies in urinary system. materials and methods: from among nearly 3000 patients who had undergone diagnostic or therapeutic ureteroscopy in our center, 23 (13 females and 10 males) were treated with bilateral same-session ureteroscopy. pathologies included bilateral ureteral stone in 19, hematuria of unknown etiology in 3, and bilateral obstructive uropathy in 1. hospital and follow-up records of the patients were reviewed in this study. results: of 19 patients with bilateral ureteral stone, 11 had anuria and increased serum creatinine. ureteroscopy was successful in 9, and the stones were fragmented. ureteroscopy insertion was not successful in 1, and in 1 another, upper ureteral stone was pushed into the kidney. six patients had normal urine output and normal serum creatinine. in 5 of them, ureteroscopy was done and the stones were fragmented, but due to ureteral stricture, ureteroscopy was impossible in 1. in 2 patients with oliguria and increased serum creatinine, bilateral ureteral stones were extracted successfully. of 3 patients with hematuria of unknown origin, 2 had normal ureteroscopy, and 1 had a small non-opaque stone that was extracted successfully. in 1 patient with obstructive uropathy and the diagnosis of obstructive megaureter, bilateral ureteroscopy was done and bilateral ureteral stents were placed. finally, from 23 patients, 21 had successful bilateral same-session ureteroscopy. postoperative complications included pyrogenic infection in 2 and gross hematuria in 4, all of which were resolved with medical treatment. conclusion: bilateral same-session ureteroscopy is an appropriate therapeutic and diagnostic option, with its own specific indications. it can reduce hospital stay, prevent multiple anesthesias, and alleviate the costs. we recommend this approach in patients with bilateral ureteral pathologies, provided that they are amenable to ureteroscopy. key words: urolithiasis, hematuria, bilateral ureteroscopy, obstructive uropathy received december 2004 accepted march 2005 *corresponding author: school of medicine, mashhad university of medical sciences, mashhad, iran. tel: ++98 511 843 0734 darabi and keshvari 9 introduction endoscopic procedures on ureter were first done by two distinguished urologists; in 1912, yang passed a rigid cystoscope into ureter in a patient with posterior urethral valve.(1,2) in 1964, marshal passed a 3-mm fiberscope into distal ureter to observe a distal ureteral stone.(2) gradually, with technical advancements, more sophisticated flexible and rigid ureteroscopes were introduced. today, ureteroscopy, as an ideal approach for a series of diagnostic and therapeutic measures, is one of the daily urologists' practices, and it accounts for great achievements in ureteral surgeries.(2,3) bilateral same-session ureteroscopy can reduce hospital stay and prevent multiple surgical procedures and anesthesia, and also its complications in patients with bilateral ureteral pathologies are minimized, provided that the surgeon has enough experience in endoscopic procedures. in this study, we report the results of bilateral samesession ureteroscopy in patients with bilateral pathologies. materials and methods from among nearly 3000 patients who had undergone ureteroscopy or transureteral lithotripsy (tul) at our center, between september 1995 and september 2002, 23 (13 females and 10 males) were treated with bilateral same-session ureteroscopy. their age range was 4 to 78 years. pathologies included bilateral ureteral stone in 19, hematuria of unknown etiology in 3, and bilateral obstructive uropathy in 1. symptoms and signs in patients with bilateral ureteral stones were anuria with increased blood urea nitrogen (bun) and creatinine in 11 patients (creatinine range 4.2 mg/dl to 18 mg/dl), oliguria with slightly increased bun and serum creatinine in 2 patients, and normal urine output with normal serum bun and creatinine in 6. patients with hematuria complained only of periodical flank pain in addition to microscopic hematuria. the patient with obstructive uropathy had recurrent urinary infections, growth disorder, and impaired serum creatinine and bun. all patients with increased creatinine and bun, and anuria or oliguria were initially evaluated with ultrasonography and kub. in patients with normal serum creatinine and urine output, ultrasonography, kub and/or intravenous urography (ivu) were done. patients with hematuria were evaluated with ultrasonography, ivu, urinalysis, and urine culture. in one of them ct scan was also done. the patient with bilateral obstructive uropathy underwent ultrasonography, vcug and ivu. laboratory evaluations, consisting of urine analysis, urine culture, biochemistry, and hematology were taken either during hospitalization or afterwards. therapeutic measure. all of the patients with ureteral stone underwent bilateral same-session uretertoscopy and tul. all the patients were started on intravenous cephalothin 1gr. under general anesthesia, first, cystoscopy was done in lithotomy position. thereafter, a 0.038-inch floppy tip guidewire was inserted into the ureter and then with a 8 f wolf or 10.5 f storz ureteroscope, ureteroscopy was done. in the presence of stone, lithotripsy was performed. in patients with hematuria, thorough evaluation of ureter was done with ureteroscope, in order to detect the cause of hematuria, tumor, or any other potential pathology. in the patient with bilateral obstructive uropathy, due to severe tortoises of ureters, double j ureteral stents were placed with ureteroscope. results of 11 (47.8%) patients with bilateral ureteral stone, anuria, and increased serum creatinine and bun, 9 (39.1%) had successful ureteroscopy and stone fragmentation. bilateral ureteroscopy was impossible in 1 patient and the upper ureteral stone was pushed into renal pelvis in 1. ureteroscopy was successful in 2 patients with oliguria and increased serum creatinine and bun. in 6 (26%) patients with normal urine output and normal serum creatinine and bun level, bilateral same-session ureteroscopy was done successfully in 5 (21.7%), and in 1 patient, due to ureteral stricture, ureteroscopy was impossible in one side. overall, there were 38 ureters (in 19 patients, 82.6%) with ureteral stone, in 35 of which ureteroscopy was successful (bilateral in 16 patients and unilateral in 3 patients, 76%). in patients with anuria, after tul, ureteral catheter was inserted bilaterally (fig. 1,2). postobstructive diuresis was observed in a volume range of 6 to 19 liters in the first 24 hours and serum creatinine level returned back to nearly normal level within 4 to 12 days. in patients with oliguria and increased serum creatinine and bun, after successful lithotripsy, bilateral ureteral catheterization was done. bilateral same-session ureteroscopy10 fig. 1. bilateral ureteroscopy in a patient with bilateral ureteral stone, a. before the procedure, b. after the procedure fig. 2. bilateral ureteroscopy in a patient with bilateral ureteral stone, a. before the procedure, b. after the procedure subsequent diuresis was less remarkable than that in anuric patients (volume range 4 to 6 liters in 24 hours). serum creatinine level reached to nearly normal level after 2 weeks. in patients with normal urine output and normal serum creatinine and bun levels, stones were fragmented and bilateral catheterization was done. this was done unilaterally in one patient. darabi and keshvari 11 bilateral same-session ureteroscopy was also done in 3 (13%) patients with hematuria of unknown origin. no pathologic finding was detected in 2 of them, and 1 had a small nonopaque ureteral stone. obstructive megaureter was the diagnosis made with ureteroscopy in the patient with obstructive uropathy, and bilateral double j ureteral stents were placed using ureteroscope (fig. 3). ultimately, of 23 patients with bilateral ureteral pathology, 21 (91.3%) had successful bilateral same-session ureteroscopy. complications were seen in 3 cases, including pyrogenic infection in 2 and gross hematuria without requiring transfusion in 4. discussion in 1912, yang was the first urologist to use endoscopic approach for ureteral disorders; he passed a rigid cystoscope into ureter in a patient with posterior urethral valve.(1,2) in 1964, marshal passed a 3-mm fiberscope into distal ureter to observe a distal ureteral stone.(2) gradually, with technical advancements, more sophisticated flexible and rigid ureteroscopes were introduced. in 1960 hopkins cylindrical lens systems were introduced to market.(2) today, ureteroscopy is one of the daily urologists' practices.(3) ureteroscopy can be used for several diagnostic and therapeutic measures. diagnostic measures include evaluation of pyelocaliceal filling defects, upper urinary tract hematuria, and unilateral positive cytology, and also surveillance of patients with upper urinary tract malignant tumors that had been treated endoscopically. therapeutic measures include treatment of stones, ureteral strictures, localized low-grade and low-stage upper urinary tract urothelial tumors, and foreign bodies in upper urinary tract.(2-7) also ureteroscopy can be used for placement of ureteral stent in cases in which stent insertion is not possible with cystoscope.(7) with increasing usage of ureteroscopic procedures, the rate of complications, such as ureteral strictures, ureteral perforation, and ureteral avulsion increases, as well.(8,9) predisposing factors such as inexperienced surgeon, using rigid instruments with large diameter, negligence, and lack of insight into the anatomy can lead to complications.(10) indications of bilateral same-session ureteroscopy are similar to those of unilateral ureteroscopy. with increasing usage of ureteroscopy, bilateral ureteroscopy has been also used for more cases with bilateral pathologies.(8) fig. 3. bilateral ureteroscopy in a patient with obstructive megaureter, a. before ureteroscopy and dj stent insertion, b. after ureteroscopy and dj stent insertion bilateral same-session ureteroscopy12 the best candidates for bilateral same-session ureteroscopy are patients with bilateral distal ureteral stone. this approach can be used as an appropriate diagnostic and therapeutic tool, provided that the rate of ureteral complications is reduced. it can decrease number of anesthesia and surgical sessions, and hospital stay.(3,11) however, the surgeons' concern about intraoperative complications may make them evade bilateral same-session ureteroscopy, but a correct patient selection and appropriate use of instruments can minimize the complication.(3,11) in one report, bilateral same-session ureteroscopy had been used for diagnosis of bilateral pyeloureteritis cystica.(12) in another report, bilateral fibroepithelial polyp in a child was treated by this method.(5) also, it has been recommended for treatment of obstructive uropathy following radiotherapy, percutaneous nephrostomy, and ureteroscopy.(13) in this study, we used bilateral same-session ureteroscopy for the treatment of bilateral ureteral stone in 19 patients, hematuria of unknown origin in 3, and bilateral obstructive uropathy in 1. sixteen patients with bilateral stones and 3 patients (3 ureters) with unilateral ureteral stones (35 ureters), became stone free (90.3%). among 3 patients with hematuria of unknown origin, 2 had normal ureters, and 1 had a small non-opaque stone, detected in the right ureter and treated successfully. severe complication did not occur; however, in 2 patients, pyrogenic fever developed, which was alleviated using medical treatment, and in 4 patients, gross hematuria occurred, but transfusion was not needed. complications of ureteroscopy are perforation, avulsion, stricture, false passage, rupture of balloon dilator, hemorrhage, and sepsis, occurring in 2% to 20% of cases.(2,14,15) with advancements in less invasive therapeutic measures, postoperative morbidity has decreased and treatment success rate has increased.(8,11,15) complications such as perforation and stricture are directly associated with ureteroscope diameter.(2) we had not such complications in our patients. to reduce complications, we should use safety guidewire in all of the cases and in those with excessive manipulation, ureteral stents are recommended.(2) conclusion bilateral same-session ureteroscopy can prevent frequent surgeries and anesthesia and reduce hospital stay. proper patient selection, ample experience of surgeon, and appropriate instruments, all reduce complications and increase treatment success. reference 1. young hh, mckay rw. congenital valvular obstruction of the prostatic urethra. surg gynecol obstet. 1929;48:509. 2. su lm, sosa re. ureteroscopy and retrograde ureteral access. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.3306-18. 3. camilleri jc, schwalb dm, eshghi m. bilateral same session ureteroscopy. j urol. 1994;152:49-52. 4. bhalla rs, schulsinger da, wasnick rj. treatment of bilateral fibroepithelial polyps in a child. j endourol. 2002;16:581-2. 5. franco i, eshghi m, bruder j, et al. endourological management of 40 ureteral strictures. j urol. 1988;139(pt 2):201 a. 6. kasmaoui eh, ghadouane m, jira h, alami m, ouhbi y, abbar m. [treatment of ureteral calculi with rigid ureteroscopy. report of 67 cases]. ann urol (paris). 2001;35:207-9. french. 7. schwalb dm, eshghi m, franco i, fernandez r, addonizio jc. expanding the role of the ureteroscope. j urol. 1990;143:485-8. 8. stackl w, marberger m. late sequelae of the management of ureteral calculi with the ureterorenoscope. j urol. 1986;136:386-9. 9. hollenbeck bk, schuster tg, faerber gj, wolf js jr. safety and efficacy of same-session bilateral ureteroscopy. j endourol. 2003;17:881-5. 10. flam ta, malone mj, roth ra. complications of ureteroscopy. urol clin north am. 1988;15:167-81. 11. deliveliotis c, picramenos d, alexopoulou k, christofis i, kostakopoulos a, dimopoulos c. one-session bilateral ureteroscopy: is it safe in selected patients? int urol nephrol. 1996;28:481-4. 12. yamada h, asano k, abe k, et al. [bilateral pyeloureteritis cystica: a case report]. hinyokika kiyo. 2003;49:427-9. japanese. 13. zeng gh, li x, wu kj, chen wz. [endoscopic management of bilateral ureteral obstruction after radiotherapy]. ai zheng. 2004;23:108-9. chinese. 14. huffman jl, bagley dh, lyon es, morse mj, herr hw, whitmore wf jr. endoscopic diagnosis and treatment of upper-tract urothelial tumors. a preliminary report. cancer. 1985;55:1422-8. 15. heney nm, nocks bn, daly jj, blitzer ph, parkhurst ec. prognostic factors in carcinoma of the ureter. j urol. 1981;125:632-6. case report a rare case of prostatic brucellosis mimicking prostate cancer mehmet karabakan,1* serkan akdemir,2 alp ozgur akdemir,2 akif ersoy erkmen,2 uner kayabas3 keywords: brucellosis; microbiology; differential; humans; prostatitis; diagnosis. introduction brucellosis, with 500,000 new cases occurring annually is one of the most common zoonotic diseases in the world.(1) in turkey its incidence is 0.59/100000 and seropositivity rate is 1.8% in the healthy population.(2) in-cidence of the disease is high among the people who live in rural areas, consume raw milk and dairy products, livestock raisers, farmers, veterinarians, butchers and laboratory workers. the clinical features of brucellosis depend on the stage of the disease, and the organs and systems involved. brucella has been reported to compromise the central and peripheral nervous system, and the gastrointestinal (gi), hepatobiliary, genitourinary (gu), musculoskeletal, cardiovascular and integumentary systems.(3) osteoarticular involvements are the most common complications of human brucellosis. osteoarticular manifestations (sacroiliitis, spondylitis, peripheral arthritis and osteomyelitis) account for over half of the focal complications. gu complications (epididymo-orchitis, prostatitis, glomerulonephritis and renal abscesses) can be found in about 1-22 % of patients. epididymo-orchitis is the most common presentation of gu involvement due to brucellosis.(4) brucellosis as a cause of prostatitis is quite rare, it is only reported as a few case reports in the literature.(5) in this case report diagnoses and treatment of prostatitis cases of brucellosis are discussed. case report a 50 years old male patient who is dealing with the slaughterhouse livestock sector, with no previously known disease and no history of surgical procedure, with almost 3 months low back pain, left-sided chest pain, loss of appetite, weight loss, intermittent fever heights, and for the last one month with complaints of dysuria, pollakiuria, nocturia, and difficulty in urination applied to our clinic. physical examination revealed, international prostate symptom score (ipss) of 17, prostate volume on transrectal ultrasonography (trus) 40 ml, digital rectal examination grade 1 positive and there was a 1 × 1 cm nodule in the right lobe, and normal vital signs. laboratory investigations revealed, serum total/free prostate specific antigen (psa) level of 9.1/1.19, white blood cell 9800/mm3, c-reactive protein, 17 mg/dl, erythrocyte sedimentation rate 51 mm/h, alkaline phosphatase 185 u/l and blood chemistry and urine examination were normal. transrectal ultrasound-guided 10 cores prostate needle biopsies were taken from the patient. pathologic examination demonstratedhyperplastic prostate aciniwith widely stromal lymphocyte infiltration (benign prostatic hyperplasia). at 12th hour after prostate biopsy patient developed fever (39oc) and consultation with an infectious diseases specialist was requested. blood cultures which analyzed using an automated system (organon tecnica bact/ alert biomerieux, france) and urine cultures were taken by infectious diseases specialist’s recommendation, then the meropenem therapy was started. the patient's urine culture was negative, but gram-negative coccobacilli yielded in the blood cultures at the 4th day. the bacterium was identified as brucella spp. by conventional laboratory methods.(6) the patient’s serum sample was tested by wright agglutination test using b. abortus s99 antigen (pendik veterinary institute, istanbul, turkey) for brucellosis. sample dilutions started from 1/10 for wright agglutination test. patient’s wright agglutination test was positive at 1/640 titer.the patient was transferred to the infectious diseases clinic with the diagnosis of brucellosis. as the results, meropenem was stopped and then doxycycline 100 mg (twice daily) and rifampin 600 mg (once in a day) were started per orally and his fever begin to reduce. abdominal ultrasonography and lumbar magnetic resonance imaging (mri) were performed because the patient had low back pain. abdominal ultrasound showed no pathology other than hepatomegaly. in the lumbar mri, at the range of l1-l2, was suspicious for discovertebral infection and an 8 mm abscess in the left psoas wasseen. streptomycin 1 g (once in a day) intramuscularly was added to the treatment because of abscess in the psoas. due to the lack of follow-up problem, the outpatient antibiotic therapy was planned as doxycycline and rifampin for 3 months and streptomycin for three weeks. the patient was discharged by infectious diseases clinic with planning the control by urology and infectious diseases clinics after 3 months. 1 erzincan university, mengucek gazi education and training hospital, department of urology, erzincan, turkey. 2 ankara numune education and training hospital, department of urology. ankara, turkey. 3 department of infectious diseases and clinical microbiology, inonu university, malatya, turkey. *correspondence: erzincan university, mengucek gazi education and training hospital, urology clinic, erzincan, turkey. tel: +905367678034. fax: +904462122200. e-mail: mkarabakan@yandex.com. received june 2014 & accepted october 2014 vol 11. no 06 nov-dec 2014 1987 discussion brucellosis is endemic in turkey; especially it has a higher incidence of people who live in rural areas, consume raw milk and dairy products, livestock raisers, farmers, veterinarians, butchers and laboratory workers. disease transmission shape is usually unpasteurized dairy products and infected animal products. nonspecific symptoms such as fatigue, weight loss, headache, loss of appetite and night sweats are seen. histologically, they cause the non-caseified granulomatous inflammation. the world health organization criteria for the diagnosis of brucellosis with the symptoms are brucella standard tube agglutination test of ≥ 1/160 titers or growth of bacteria in blood or bone marrow cultures.(5) also in our patient, we diagnosed with the presence of brucella spp. in blood cultures and determination of 1/640 titers at agglutination tube test. because of the course of multisystem involvement and the emergence of different clinical manifestations, the diagnosis of brucellosis may be difficult. genitourinary system involvement in brucellosis is between 1-22%, most frequently in the form of epididymo-orchitis.(4) in our patient, as stated by colmenero and colleagues(7) there are symptoms such as fever, arthralgia, loss of appetite with the genitourinary system involvement but no statement of epididymo-orchitis. serum psa level, the most widely used diagnostic marker for prostate cancer (pca) beside prostatic carcinoma, the prostatitis case is the one of the benign factors that can increase serum psa levels.(8) as in the case of our patient, brucella-induced prostatitis may be considered in the differential diagnosis of pca that is a rare condition.(9,10) in rectal examination nodularity was palpated in our patient, the ratio of total/free serum psa values was 9.1/1.19, and serum psa density was 0.26 ng/ml, therefore according to the normal serum psa level for patient’s age (0-3 ng/ml), the presence of pca should be ruled out. prostate biopsy was done by taking 10 coresfrom prostate. there was no pca in pathologic examination. after prostate biopsy patient developed fever. also, blood cultures confirmed brucellosis induced prostatitis. prostate discharge culture or tissue culture has not been done, but the brucellosis was detected by agglutination tests and in blood culture. treatment with doxycycline and rifampicin improved signs of infection and fever. with this case introduction, in areas such as turkey, which brucellosis is endemic, both in the differential diagnosis of prostatitis and in the cases in which prostatic carcinoma is investigated because of the rise of psa, by taking a detailed history of the patient, on the clinical suspicion case, because of fact that the brucellosis infection can rarely cause this condition, brucellosis possibility should not be ignored in differential diagnosis. conclusion the most common manifestation of brucellosis in urogenital systemis epididiymo-orchitis and should be considered in differential diagnosis of prostatitis. conflict of interest none declared. references 1. pappas g, papadimitriou p, akritidis n, christou l, tsianos ev. the new global map of human brucellosis. lancet infect dis. 2006;6:91-9. 2. mert a, ozaras r, tabak f, et al. the sensitivity and specificity of brucella agglutination tests. diagn microbiol infect dis. 2003;46:241-3. 3. franco mp, mulder m, gilman rh, smits hl. human brucellosis. lancet infect dis. 2007;7:775-86. 4. buzgan t, karahocagil mk, irmak h, et al. clinical manifestations and complications in 1028 cases of brucellosis: a retrospective ev aluation and review of the literature. int j in fect dis. 2010;14:469-78. 5. rosales leal jl, tallada buñuel m, espejo mal donado e, et al. acute prostatitis as the 1st symptom of brucellosis. arch esp urol. 2003;56:527-9. 6. lindquist d, chu cm, probert sw. francicella and brucella. in: murray pr, barron ej, jor gensen jh, landry ml, pfaller ma, eds. manual of clinical microbiology. 9th ed. washington: asm press; 2007. p. 815-34. 7. colmenero jd, muñoz-roca nl, bermudez p, plata a, villalobos a, reguera jm. clin ical findings, diagnostic approach, and out come of brucel lameliten sisepididymo-orch itis. diagn microbiol infect dis. 2007;57:367 72. 8. morote j, lopez m, encabo g, de torres im. effect of inflammation and be nign prostatic enlargement on total and per cent free serum prostatic specific antigen. eur urol. 2000;37:537-40. 9. aksoy f, aksoy hz, sözen ee, yilmaz g, köksal i. a case of brucella prostatitis mis diagnosed as prostate carcinoma. mikrobiyol bul. 2009;43:493-7. 10. hakko e, oldsmar m, turkoglu s, calangu s. acute prostatitis as an uncommon presen tation of brucellosis. bmj case rep. 2009; 2009. brucellosis prostatitis-karabakan et al case report 1988 1575vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l department of urology, military hospital avicenna, marrakech, morocco. youness el harrech, najib abakka, jihad el anzaoui, omar goundale, driss touiti one-shot dilation in modified supine position for percutaneous nephrolithotomy: experience from over 300 cases corresponding author: youness el harrech, md service d’urologie, hôpital militaire avicenne, marrakech, maroc. tel: +212 661 32 6160 e-mail: youness.elharrech@ gmail.com received may 2013 accepted april 2014 purpose: to evaluate the feasibility, safety and efficacy of one-shot dilation (osd) in modified supine position percutaneous nephrolithotomy (pcnl). materials and methods: a total of 320 pcnl in a total of 291 patients were performed between october 2008 and july 2011. there were no specific exclusion criteria. patients with kidney anomalies or solitary kidney, with history of renal surgery or extracorporeal shockwave lithotripsy (swl), those with staghorn calculi or needing more than one access, were eligible for inclusion. data collected included patient demographics and stone characteristics, access time, radiation exposure, total operating time, preoperative and postoperative hemoglobin concentrations, tract dilatation failures, complications and transfusions. results: mean stone size was 38 mm (16-110 mm). the mean time access was 2.1 min (range 0.7-6.2 min). tract dilatation fluoroscopy time was 25 ± 17 sec. the targeted calix could be entered with a success rate of 97.81%. the mean hemoglobin decrease was –1.17 g/dl ± 0.84. there were no visceral, pleural, collecting systems or vascular injuries. major complications included, transfusion in 4 (1.25%) patients, pseudoaneurysm with persistent bleeding necessitating nephrectomy in 1 (0.3%) patient and two deaths (0.62%) after surgery. there was no significant difference in successful access and complications between patients with and without previous open surgery and in those with or without staghorn stones (p > .05). conclusion: the use of one shot and modified supine position combines the advantages of these both methods including less radiation exposure and shorter access and operative time. the one shot dilation is safe, easy to learn, cost effective and offers a potential alternative to the standard devices particularly in developing countries. keywords: dilatation; nephrostomy; percutaneous; methods; punctures; feasibility studies; urinary calculi; surgery; postoperative complications. endourology and stone disease 1576 | introduction one of the most fundamental steps of percutaneous nephrolithotomy (pcnl) is the creation of the ne-phrostomy access. it can be done with serial polyurethane co-axial dilators (amplatz dilators), balloon dilators and telescoping metallic co-axial dilators (alken dilators). use of an amplatz dilator set or metal incremental dilators is time consuming and requires longer exposure to fluoroscopy. (1) more recently, to reduce access time and radiation exposure during access, and to reduce cost, a single-step technique involving the use of an amplatz serial dilator over a metallic telescopic dilator (‘‘one-shot’’) has become accepted as a safe and effective technique.(1-3) starting in 2004, we routinely adopted the modified supine position to perform pcnl in patients affected by large and/ or complex urolithiasis.(4) this position has been considered by the second consultation on urolithiasis in 2007 as safe and effective.(5) we designed a prospective study in two different centers to evaluate the feasibility, safety and efficacy of one-stage dilation (osd) in modified supine position. to our knowledge, no published clinical trials have used this dilation technique in supine position. materials and methods a prospective chart and database was done of all patients undergoing pcnl using one shot dilation between october 2008 and july 2011 in one center. during this period, we performed 320 procedures in a total of 291 patients. there were no specific exclusion criteria. all adult candidates for pcnl were considered for enrollment consecutively. patients with kidney anomalies or solitary kidney, with history of renal surgery or extracorporeal shockwave lithotripsy (swl), those with staghorn calculi or needing more than one access, were eligible for inclusion. the purpose of the study was explained to all patients, and their informed consent was obtained. the parameters collected were patient demographics and stone (size, location and type) characteristics, total operating time, preoperative and postoperative hemoglobin concentrations, the number of transfusions, the number of tracts required, tract dilatation failures (inability to visualize the targeted calix by nephroscope) and injury of neighboring organs. the main study endpoints included access time (from needle puncture to the start of nephroscopy), radiation exposure during access (the number of seconds of x-ray exposure elapsed from the access needle to the placement of the amplatz sheath). operations were performed by eight different urologists with vast experience in the field of endourology. statistical analysis the continuous variables were analyzed using parametric (student’s t-test) and nonparametric (mann-whitney u test) statistical methods. categorical variables were analyzed using the pearson chi square test. a logistic model was used to determine the odds ratios for statistically significant parameters affecting complications. data were expressed as mean ± standard deviation. a p value of < .05 was considered significant. data were analyzed with the statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. technique pcnl was performed in the modified supine position according to techniques previously described.(4) in brief, the patient received general anesthesia and a single dose of antibiotic was administered intravenously. with the patient in the lithotomy position, a 5 french (f) ureteral catheter was inserted transurethrally. the patient was then placed in the modified supine position with the legs extended and the ipsilateral leg crossed over the contralateral leg. a cushion was placed below the ipsilateral flank to provide a 45-degree inclination. for patients with concomitant ureteral stones or depending on the surgeon preference, the split-leg modified lateral position was used. the patient was maintained in the lithotomy position with a 30-degree flank inclination.(6) the ipsilateral arm was over the thorax and the contralateral arm was used for intravenous infusion. an 18 gauge needle was horizontally introduced through the flank in the posterior axillary line into the collecting system. renal access was achieved under fluoroscopic guidance after visualization of the pelvicaliceal system by retrograde injection of diluted contrast through the ureteral catheter. an attempt, even if not always successful, was made to introduce the wire down the ureter. the skin over the puncture site and the fascial layers were incised. after the needle was removed, the alken guide was replaced under fluoroscopic guidance (figures 1 and 2). then, a single 25f amplatz dilator was pulled in on the alken endourology and stone disease 1577vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l one shot dilatation in pcnl | harrech et al guide (figure 3). this single passage allowed the insertion of the 30f amplatz sheath over the amplatz dilator (figure 4). fluoroscopy was used in all steps of tract dilation and sheath placement. after the correct position of the amplatz sheath was verified, the complex of amplatz dilator and alken guide were removed keeping the amplatz sheath and working guidewire in situ. in patients with horseshoe or pelvic kidney a nephrostomy tube was placed pre operatively under scan guidance or we used laparoscopy to guide puncture. results the preoperative patient and stone characteristics are summarized in table 1. mean age was 50.4 years (range 11 to 81 years). mean stone size was 38 mm (16-110 mm). of study subjects 28 patients had anatomical or functional solitary kidney. two patients had horseshoe kidneys, 5 patients had pelvic kidney, 31 patients had a history of ipsilateral open nephrolithotomy and 57 patients had staghorn stones. calyceal diverticula have been noted in 6 cases. in 76 procedures, access was obtained via an upper pole access, while in the other access was achieved through a middle or lower pole. totally tubeless surgery was performed in the 41 last procedures. intraoperative data, postoperative values and procedural outcomes are shown in table 2. mean operative time was 54.8 min (range 25 to 137 min). the mean time required for the access was 2.1 min (range 0.7-6.2 min). tract dilatation fluoroscopy time was available for 190 procedures and was 25 ± 17 seconds. the total x-ray exposure was 142 ± 54 seconds. mean postoperative hospital stay was 3.67 days (range 2 to 12 days). by applying a one-stage technique, the targeted calix could be entered with a success rate of 97.81%. conversion to alken dilation method was not needed in any instance. there was no significant difference in successful calix entrance in those with and without previous open surgery (success rate of 96.6% and 98.1%, respectively) and in those with or without staghorn stones (success rate of 97.2% and 98.6%, respectively). in three patients (two with a history of open surgery), renal access dilatation failed because heavy resistance of the fascial prevented the amplatz dilator from advancing over the guidewire. kidney hypermobility caused the failure of four dilatation procedures. visual clarity during pcnl was quantified as bad and surgery had to be abandoned in nine cases (2.81%). the procedure was deferred in all these patients. a comparison of the preoperative and postoperative hemoglobin was available for 148 procedures. the mean hemoglobin decrease was 1.17 g/dl ± 0.84. four patients required blood transfusions (1.25%). in regard to staghorn stones, no significant difference was noted in the hb drop (1.38 g/dl for staghorn stones vs. 1.08 g/dl for patient without staghorn stones, p = .13). no major complications, such as visceral, pleural, or vascular injuries, were seen except in three patients. one patient with multiple medical problems and complete complex calculi presented postoperatively a severe hemorrhage from a nephrostomy tube and received several blood transfusions before being returned to operatory room for nephrectomy. the patient was admitted in the intensive care unit postoperatively and died due to multi organ failure. another patient had nephrectomy for persistent bleeding due to a pseudo aneurysm. the embolization was not accessible in our center. the third elderly patient was with a medical history of diabetes and hypertension. he returned on the 6th postoperative day with severe sepsis and received reanimafigure 1. one shot dilation set. 1578 | tion. the ultrasonography showed a dilation of renal cavities. a double pigtail stent was placed. the patient died 48 hours later from septic shock. no urinary fistula in both groups (nephrostomy tube or tubeless procedure) was recorded. our perioperative complications are summarized in table 2 according to the dindo-modified clavien system proposed as a grading system for perioperative complications in general surgery.(7) at the time of this writing, the cost of the one shot set (figure 3) in our country is approximately 50 $us. discussion the dilation of the nephrostomy track is a central step of pcnl and is usually performed by three dilation methods: semirigid fascial dilators (amplatz) over an 8f guide catheter, metal telescopic dilators (alken telescopic dilators: atd) or nephrostomy balloon dilators (bd). each dilation method has advantages and disadvantages and there have been many attempts and modifications to obtain the best results with minimal kidney damage.(8-11) balloon dilatation is regarded as the gold standard.(12,13) although the balloon dilation system has advantages, such as the short dilatation and fluoroscopy time, tamponing of the tract, application of radial forces only and no risk of forward perforation,(14) its routine application has been limited because of its relatively high cost especially in centers with limited resources.(15) the use of multiple dilators was time-consuming and with each pass of the dilator injury to the collecting system can result.(12) also, there is a risk of significant bleeding when a sequential dilator is removed to allow placement of the larger one, because tract is left open, and there is no sheath in place to tamponed the bleeding. to improve dilation results, some authors.(8,16) proposed single-increment dilation and demonstrated its safety and feasibility. travis and colleagues(16) performed percutaneous nephrostomy in dogs with an open approach using a 6f dilator. a comparison of the degree of damage resulting from multi-increment amplatz dilation, a single increment 24f dilator, metal dilators, and balloon dilators was done. this study proved that single-increment dilatation was as safe as conventional techniques with minimal hemorrhage or parenchymal damage and healing at 6 weeks by a fine linear scar. frattini and colleagues.(2) who first described the one shot dilation technique, compared atd, bd and osd. they showed that mean (standard deviation [sd]) total radiation exposure with telescopic, balloon, and one-shot dilation was 310 (216), 179 (90) and 262 (173) seconds, respectively and found a reduction in the fluoroscopy time during the dilation procedure from 60 to 35 and 20 seconds in the mtd, the bd, and the osd group, respectively. in our study we observed that tract dilation fluoroscopy time was 25 ± 17 seconds and that total radiation exposure 142 ± 54 seconds. this is similar to the results of other teams using a similar osd technique. amjadi and colleagues(3) could reduce the tract dilation fluoroscopy time from 81 ± 53 seconds in the mdt group to 27 ± 15 seconds in the osd group. ziaee and colleagues(15) found a mean time of radiation exfigure 2. the alken guide (arrow) is placed under fluoroscopic guidance (b). figure 3. the single 25f amplatz dilator (dark arrow) is pulled in on the alken guide (white arrow) (a) under fluoroscopic control (b). endourology and stone disease 1579vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l posure during the whole access of 0.63 ± 0.71 minutes. in our study, mean access time calculated from getting access by needle to the positioning of the working sheath required 2.1 minutes (range 0.7-6.2). this is about 50% decrease in insertion time reported by amjadi and colleagues(3) (5.72 ± 1.75 min for one-shot dilation vs. 10.47 ± 2.97 min for gradual dilation, p = .00) and by ziaee and colleagues(15) (6.07 ± 4.37 min with no impact of open previous surgery). this shorter time access is probably due to the long experience acquired in ours departments in pcnl since 1997. a much longer access time of 11.2 minutes for bd, respectively, was recorded by safak and colleagues.(13) the mean operative time in the present study was 54.8 minutes (range 25 to 137 min). although balloon dilation is generally thought to be associated with shorter operating times,(12,13,17) in a recent pcnl global study including 5537 patients,(18) the median operating time with telescopic/serial dilation was 60 minutes vs. 94 minutes for balloon dilation. our operative time shorter than this reported in the literature was an expected finding. first, because it has been shown that a dilation technique requiring only limited passages or a single step may be less time consuming.(8,16) secondly, the modified supine position is less time-consuming than the prone position with no need for a position change from the lithotomy to the prone position during the procedure, knowing that this repositioning is time consuming, more demanding for the surgical team and include occupational risk due to shifting of heavy loads, especially in case of obese patients. (4,6) another advantage of this position is reducing the x-ray exposure because puncture and dilation of the nephrostomy tract are quite perpendicular to the body and the operator’s hands are outside the fluoroscopic field.(19) we believe that combination of one shot dilation and modified supine position permit the association of advantages of both of these techniques for the patient and for the urologist. anesthesiological advantages to the modified supine position include absence of cardiovascular, respiratory, neuroendocrine and pharmacokinetic problems typical of the prone position, particularly in obese patients.(20) urological advantages include easier puncture of the kidney, creation of a 2-tiered field to respect aseptic conditions and allowed simultaneous antegrade and retrograde endoscopic approach to urinary tract. one shot dilation in modified supine position permits improving radiation safety for both urologist and patient. bleeding and blood transfusions are common complications of pcnl. balloon dilation is generally considered to cause significantly less blood than did the other techniques.(12) however, in the pcnl global study,(18) bleeding was significantly higher with balloon at 9.4% compared with telescopic/serial dilation at 6.7%, and transfusions were significantly more common with balloon than telescopic/serial dilation at 7.0% and 4.9%, respectively. figure 4. a: insertion of the 30f amplatz sheath (dark arrow) over the amplatz dilator (white arrow). b: fluoroscopic guidance allowing the correct placement of the amplatz sheath in pelvicaliceal system. one shot dilatation in pcnl | harrech et al table 1. preoperative patient and stone characteristics. number of patients 291 mean age (years) (range) 50.4 (11 81) male/female 187/104 number of procedures 320 solitary kidney 28 congenital renal abnormalities horseshoe kidneys 2 pelvic kidney 5 calyceal diverticula 6 previous open surgery 31 mean stone size (mm) (range) 38 (16-110) stone location, no. (%) renal pelvis 135 (42.1) middle calix 87 (27.1) lower calix 83 (25.9) upper calix 45 (14.0) diverticular calculi 6 (1.8) staghorn 57 (17.8) 1580 | our 1.25% transfusion rate does not differ significantly from studies using osd. in the clinical study by frattinni and colleagues(2) one-shot dilation did not lead to more hemorrhagic complications than multiple incremental technique and was statistically less affected by blood losses than pneumatic dilation. in two others studies, falahatkar and colleagues(1) and amjadi and colleagues(3) one-shot and telescopic dilation had a similar hematologic safety profiles. the mortality in our series was 0.62%. one patient died from urosepsis despite adequate antibiotic treatment and urine drainage. sepsis rates reported in the literature vary from 0.97%(21) to 4.7%.(22) another patient died from multi organ failure due to bleeding despite controlling hemostasis after nephrectomy. postoperative death has been reported in 0.1-0.7% of patients undergoing pcnl.(23) our mortality rate, even if considered in the range of those reported in the literature, is probably due to the high proportion of difficult cases procedures or ‘‘difficult to treat’’ patients (the american society of anesthesiologists score iii and iv patients, renal anomalies, solitary kidneys, complex calculi and etc.). the presence of comorbidity, such as renal insufficiency, diabetes, morbid obesity, and pulmonary or cardiovascular, has been reported to increase the risk of complications during or after pcnl.(24) the success rate of tract dilation in our study using osd was 97% at the first procedure. all the attempts during the second procedure and using the same technique were successful witch raises the rate to 100%. in four patients, failure occurred because of kidney hypermobility. in three others patients (two with history of open nephrolithotomy), the failure of dilatation has been attributed to the heavy resistance of the fascial layers that prevented the passage of the amplatz dilator. in our positioning method, the kidney mobility is similar to what has been reported in the supine position.(25,26) however, we can ask the assistant to perform an extra-abdominal compression, during dilation to block the kidney displacement. besides, we need to make sure we well incise the skin to avoid projection movement during dilation. the dilator consistency and the rotational movement of the sheath during gradual advancement decrease the risk of kidney migration. (15) these mechanisms together, might explain the significantly different failure rates between one-shot dilation (7%) and balloon dilation (17% and would increase to 25% in patients with previous renal surgery).(13,27) in our study, the dilation failures have been managed by the same osd in a second procedure with no need to the mtd. this is different to the choice of amjadi and colleagues(3) who applied the mdt successfully in 4 cases of failure in 17 osd cases. ziaee and table 2. intraoperative data, postoperative values and procedural outcomes. mean operative time (range) 54.8 minutes (25-137) mean access time (range) 2.1 minutes (0.7-6.2) tract dilatation fluoroscopy time 25 ± 17 seconds total x-ray exposure 142 ± 54 seconds success rate of access, (%) (p > .05) 97.81 previous open surgery 96.6 no previous open surgery 98.1 staghorn stones 97.2 no staghorn stones 98.6 puncture site, no. (%) lower calyx 166 (51.8) middle calyx 128 (40) upper calyx 78 (24.3) number of tracts, no. (%) 1 276 (86.2) 2 36 (11.2) 3 8 (2.5) postoperative nephrostomy/tubeless 279/41 surgery abandoned due to bad visual clarity (%) 9 (2.81%) mean hemoglobin decrease, g/dl (p = .13) 1.17 ± 0.84 staghorn stones 1.38 no staghorn stones 1.08 blood transfusions, no (%) 4 (1.25) injury of neighboring organs 0 hydrothorax/ pneumothorax 0 collecting system injury necessitating stent 0 postoperative urinary tract infection, no (%) 10 (3.12) pseudoaneurysm, no (%) 1 (0.31) death, no (%) 2 (0.62) clavien grading, (%) i 12.50 ii 10.93 iiia 3.12 iiib 0.93 iva 0.31 ivb 0.00 v 0.62 endourology and stone disease 1581vol. 11 | no. 03 | may june 2014 |u r o lo g y j o u r n a l colleagues(15) also reported seven (7%) failures—three with and four without previous surgery—that were managed by using an mtd. no perforation of the collecting system happened during dilation in our study. safak and colleagues(13) observed perforations of the collecting system in 11.2% of the cases with bd and 16.6% of those with ad. one-shot dilation also reduces the costs of the pcnl as it is less expensive than bd (the cost of the nephromax bd system was for about 300 $us) and as the amplatz dilator can be desterilized, according to our experience. previous studies also confirm these findings.(17) in ‘‘developing countries,’’ there may less access to bd and with budget restrictions, the treating urologist might move directly to osd. we believe that there are potential advantages of osd compared to standard techniques for percutaneous access. our findings clearly show that the one-shot procedure is feasible and effective in modified supine position. it is applicable for almost all patients with minimal potential complications. the advantages of this dilation technique combined to those of modified supine position include reduced radiation exposure time and access time, a shorter operative time, lesser risk for injury to the collecting system and neighboring organs. a limitation of the present study was its observational nature and the absence of control group. this is because this technique is now the first choice for tract dilation for pcnl in adult patients in our department. indeed, in 2002, mcculloch and colleagues(28) proposed that ‘‘detailed prospective audit data collection is essential for surgical research’’ as there are many obstacles to performing randomized controlled trials (rcts) of surgical techniques, meaning that the quantity and quality of clinical research in surgery is limited, and general surgical practice is less likely to be based on rct evidence than general medical practice.(28-31) conclusion percutaneous access can be safely and successfully obtained by one shot dilation even in modified supine position. the use of this dilation technique in modified supine position combines their both advantages including less radiation exposure and shorter access and operative time. it is applicable in almost every adult patient regardless of kidney anomalies, previous open renal surgery or staghorn calculi. the one shot dilation is also cost effective, easy to learn and offers a potential alternative to the standard devices particularly in developing countries. further analysis and comparative studies are necessary to confirm these results. conflict of interest none declared. references 1. falahatkar s, neiroomand h, akbarpour m, emadi sa, khaki n. oneshot versus metal telescopic dilation technique for tract creation in percutaneous nephrolithotomy: comparison of safety and efficacy. j endourol. 2009;23:615-8. 2. frattini a, barbieri a, salsi p, et al. one shot: a novel method to dilate the nephrostomy access for percutaneous lithotripsy. j endourol. 2001;15:919-23. 3. amjadi m, zolfaghari a, elahian a, tavoosi a. percutaneous nephrolithotomy in patients with previous open nephrolithotomy: oneshot versus telescopic technique for tract dilatation. j endourol. 2008;22:423-5. 4. el harrech y, ghoundale o, zaini r, moufid k, touiti d. la nlpc en décubitus dorsal modifié : notre expérience. can urol assoc j. 2011;5:261-5. 5. saussine c, lechevallier e, traxer o. pcnl: technical variations. prog urol. 2008;18:897-900. 6. lezrek m, ammani a, bazine k, et al. the split-leg modified lateral position for percutaneous renal surgery and optimal retrograde access to the upper urinary tract. urology. 2011;78:217-20. 7. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 8. rusnak b, castañeda-zuñiga w, kotula f, herrera m, amplatz k. an improved dilator system for percutaneous nephrostomies. radiology. 1982;144:174. 9. patil av. a novel 5-part percutaneous access needle with guidewire technique (5-pang) for percutaneous nephrolithotomy: our initial experience. urology. 2010;75:1206-8. 10. baldwin dd, maynes lj, desai pj, jellison fc, tsai ck, barker gr. a novel single step percutaneous access sheath: the initial human experience. j urol. 2006;175:156-61. 11. maynes lj, desai pj, zuppan cw, barker bj, zimmerman gj, baldwin dd. comparison of a novel one-step percutaneous nephrolithotomy sheath with a standard two-step device. urology. 2008;71:2237. 12. davidoff r, bellman gc. influence of technique of percutaneous tract creation on incidence of renal hemorrhage. j urol. 1997;157:1229-31. 13. safak m, gogus c, soygur t. nephrostomy tract dilation using a balloon dilator in percutaneous renal surgery: experience with 95 cases and the comparison with the fascial dilator system. urol int. 2003;71:382-4. 14. wezel f, mamoulakis c, rioja j, michel ms, de la rosette j, alken p. two contemporary series of percutaneous tract dilation for percutaneous nephrolithotomy. j endourol. 2009;23:1655-61. one shot dilatation in pcnl | harrech et al 1582 | endourology and stone disease 15. ziaee sa, karami h, aminsharifi a, mehrabi s, zand s, javaherforooshzadeh a. one-stage tract dilation for percutaneous nephrolithotomy: is it justified? j endourol. 2007;21:1415-20. 16. travis dg, tan hl, webb dr. single-increment dilatation for percutaneous renal surgery: an experimental study. br j urol. 1991;68:144-7. 17. gönen m, istanbulluoglu om, cicek t, ozturk b, ozkardes h. balloon dilatation versus amplatz dilatation for nephrostomy tract dilatation. j endourol. 2008;22:901-4. 18. lopes t, sangam k, alken p, barroilhet bs, saussine c, shi l, de la rosette j. clinical research office of the endourological society percutaneous nephrolithotomy study group. the clinical research office of the endourological society percutaneous nephrolithotomy global study: tract dilation comparisons in 5537 patients. j endourol. 2011;25:755-62. 19. valdivia uria jg, valle gerhold j, lopez lopez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol. 1998;160:1975–8. 20. ibarluzea g, scoffone cm, cracco cm, et al. supine valdivia and modified lithotomy position for simultaneous anterograde and retrograde endourological access. bju int. 2007;100:233-6. 21. aron m, yadav r, goel r, et al. multi-tract percutaneous nephrolithotomy for large complete staghorn calculi. urol int. 2005;75:32732. 22. vorrakitpokatorn p, permtongchuchai k, raksamani eo, phettongkam a. perioperative complications and risk factors of percutaneous nephrolithotomy. j med assoc thai. 2006;89:826-33. 23. unsal a, resorlu b, atmaca af, et al. prediction of morbidity and mortality after percutaneous nephrolithotomy by using the charlson comorbidity index. urology. 2012;79:55-60. 24. labate g, modi p, timoney a, et al, rosette on behalf of the croes pcnl study group j. the percutaneous nephrolithotomy global study: classification of complications. j endourol. 2011;25:1275-80. 25. valdivia-uria jg, valle j, villarroya s. why is percutaneous nephroscopy still performed with patient prone? j endourol. 1990;4:269-72. 26. de sio m, autorino r, quarto g, et al. modified supine versus prone position in percutaneous nephrolithotomy for renal stones treatable with a single percutaneous access: a prospective randomized trial. eur urol. 2008;54:196-202. 27. joel ab, rubenstein jn, hsieh mh, chi t, meng mv, stoller ml. failed percutaneous balloon dilation for renal access: incidence and risk factors. urology. 2005;66:29-32. 28. mcculloch p, taylor i, sasako m, lovett b, griffin d. randomised trials in surgery: problems and possible solutions. bmj. 2002;324:144851. 29. farrokhyar f, karanicolas pj, thoma a, et al. randomized controlled trials of surgical interventions. ann surg. 2010;251:409-16. 30. ellis j, mulligan i, rowe j, sackett dl. inpatient general medicine is evidence based. a-team, nuffield department of clinical medicine. lancet. 1995;346:407-10. 31. howes n, chagla l, thorpe m, mcculloch p. surgical practice is evidence based. br j surg. 1997;84:1220-3. urology journal vol. 11 no. 04 july august 2014 1834 patient satisfaction in urology: effects of hospital characteristics, demographic data and patients’ perceptions of received care tonio schoenfelder,1 tom schaal,1 joerg klewer,2 joachim kugler1 1department of public health, dresden medical school, uni versity of dresden, fetscher strasse 74, 01307 dresden, germany. 2department of public health and health care management, university of applied sciences, dr.-friedrichs-ring 2a, 08056 zwickau, germany. corresponding author: tonio schoenfelder, phd, mph department of public health, dresden medical school, university of dresden, fetscherstrasse 74, 01307 dresden, germany. tel: +49 151 2270 2233 fax: +49 3761 186720 e-mail: tonio.schoenfelder@gmx. de. received august 2013 accepted january 2014 purpose: to identify factors that are significantly associated with patient satisfaction in urology and to assess the extent to which satisfaction ratings might be related to hospital and patient characteristics. materials and methods: data used in this study were obtained from 1040 randomly selected urology patients discharged from nine hospitals who responded to a mailed survey. bivariate and multivariate techniques were used to reveal relations between patient assessments of received care, hospital and patient characteristics. results: bivariate analysis showed a strong association between satisfaction scores and length of stay, provider status, work load of nurses and hospital size, with weaker findings pertaining to type of hospital (teaching versus non-teaching) and patient demographics. the multivariate analysis identified nine variables which are associated with overall satisfaction. strong factors were treatment outcome, the interpersonal manner of medical practitioners and nurses, as well as hotel aspects like accommodation and quality of food. variables reflecting information receiving about the undergoing treatment were not found to have a significant influence on patient satisfaction. conclusion: this study identified variables that are related to satisfaction in a urological setting and delivers information about aspects of the hospital stay that are not perceived as relevant by patients. these findings support healthcare professionals with valuable information to meet needs and preferences of patients in urology. keywords: hospitals; standards; professional-patient relations; quality improvement; medical staff; patient care team; patient satisfaction; hospital costs. miscellaneous voluntary. the study has been performed in accordance with the ethical standards laid down in the declaration of helsinki. surveys were accompanied by a cover letter informing the participants about the purpose, voluntary nature and anonymity of the study and their consent to participation when sending back the questionnaire. a total number of 3200 post-paid surveys were distributed; 1240 were finally completed, resulting in an initial response rate of approximately 39%. hospitals were excluded from the data set if number of respondents fell below 30; patients were excluded if they did not answer the question concerning overall satisfaction and failed to answer more than 25% of the items. in total, 1040 questionnaires from patients of nine hospitals were analyzed, resulting in a net response rate of approximately 33%. measures patient satisfaction, socio-demographic data and visit characteristics were assessed using a previously validated survey comprising of 37 items.(14) patient satisfaction concerning medical and service aspects of care were collected through 15 items using a six-point ordinal rating (very poor, poor, acceptable, fair, good and excellent). one item collected information concerning overall satisfaction with the hospital stay in general using the same six response category. additional data collected included patients’ age (categories with ten year intervals from 21 to > 80), gender, occurrence of post-discharge complications (in terms of physical complaints, pain, infections), perceived length of stay (los), number of prior hospitalizations and source of admission (e.g., specialist, self-admission and emergency). hospital characteristics were abstracted from quality assessment reports hospitals are obliged to publish in germany biennially. characteristics included hospital size as the number of beds (< 400, 400-799 and ≥ 800), teaching status (teaching versus non-teaching), provider status (public, non-profit, for-profit), and work load as the number of patients per medical practitioner and per nurse (full-time), per year. statistical analysis descriptive statistics and frequencies were computed. for data analyses, the highest ratings were coded with ‘6’ and the lowest with ‘1’. the level of significance was set at p ≤ .05 throughout the study. data was analyzed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. bivariate analyses the distribution of the satisfaction scores was skewed toward higher satisfaction, which is why non-parametric tests were performed. general associations between overall satisfaction and hospital and patie characteristics were investigated with x²-tests, fisher’s exact test in case cell counts were small, and kruskal-wallis tests with bonferroni adjustments in case of multiple comparisons. for the purpose of data analysis, the work load per medical practitioner and per nurse was categorized into the two groups high and low work load (‘high’ ^ above median of analyzed hospitals and ‘low’ ̂ below median), respectively. mann-whitney u tests were used for all patient perceptions variables. for that purpose, variables were dichotomized (median split). since introduction the assessment of patient satisfaction as a complement to other health care quality measures has gained increased recognition in a variety of settings and is viewed as a quality indicator for many health problems.(1,2) patients provide a unique opportunity to supply healthcare professionals with valuable information about specific areas in which care could be improved and in which care excelled that cannot be obtained from any other source.(1,3) in urology, patient satisfaction data is particularly salient since only a minority of urology patients, for a variety of reasons, seek medical attention,(4) which may negatively affect health-related quality of life and psychological wellbeing.(5,6) however, studies conducted in urology and other healthcare contexts point to a significant association between patients’ treatment-seeking behavior and positive or negative experiences with their illness and satisfaction with received care.(4,7) therefore, information about which aspects of health services contribute most to increase satisfaction can be helpful to improve the quality of care. patient satisfaction is a multidimensional concept which is not yet fully defined.(8) part of that concept are patients’ perceptions of health service quality and aspects which are not under the control of healthcare professionals such as various hospital characteristics like teaching status and size(9,10) as well as patient demographics.(11) study results further indicate that factors associated with satisfaction also vary according to setting,(12,13) which implies results cannot easily be generalized to urology. however, in an increasingly competitive market environment with many choices for patients, it is important for healthcare professionals in urology to understand whether factors associated with patient satisfaction are alterable by allocation of resources or whether variables that are outside the control of healthcare organizations are the most influential determinants. this information can be used to adjust for such factors when comparing the performance of individual physicians or hospitals based on patient satisfaction data. therefore, the objective of this study was to identify factors that are significantly associated with patient satisfaction in urology and to assess the extent to which satisfaction ratings might be related to hospital and patient characteristics. materials and methods patients and setting the study population consisted of randomly selected urology patients aged 21 years and older discharged in 2009 from 22 hospitals of a metropolitan area in germany with a total population of approximately 1.65 million (2009). the study data was obtained through a self-administered, post-visit questionnaire. survey participants were policy holders of four statutory health insurances, which together have a market share of approximately 80% of the area’s total population (2009). contact to participants was established by their health insurance rather than by the hospitals which rendered the services in order to avoid a selection of patients. participation was completely anonymous and 1835 miscellaneous urology journal vol. 11 no. 04 july august 2014 1836 patient satisfaction in urology-schoenfelder et al admission, number of prior hospitalizations, age, and gender were not statistically significantly related to patients’ overall satisfaction rating (table 1). the multivariate analysis identified nine variables which are associated with overall satisfaction (table 3). the strongest factors were: the degree to which the patient was satisfied with treatment outcome [odds ratio (or): 5.13], kindness of nurses (or: 3.46) and medical practitioners (or: 3.33), followed by individualized medical care (or: 1.95), accommodation (or: 1.90) and quality of food (or: 1.87). variables reflecting information receiving such as the quality of instructions given to the patient (e.g., clear information about medication or undergoing operations) were not included in the regression model. the patient (perceived los, complications) and hospital characteristics (provider status, work load per nurse and hospital size), statistically significantly related to the dependent variable in the bivariate analyses, were also excluded. discussion this study identified nine predictors of overall satisfaction of the hospitalization in urology, which partially differ from other settings. findings indicate that variables which are under the control of healthcare organizations have greater impact on satisfaction than patient demographic data and hospital characteristics. effects of patient assessments findings of prior studies highlighted the essential role of communication between hospital staff and patients in various settings and its contribution to satisfaction.(7,15,16) the results of the present study concur with these findings. the interaction between medical practitioners, nurses and patients had highly positive effects on overall satisfaction with the hospital stay. the results of this study also highlight the importance of providing comprehensible information at home after discharge. yet, the intensity of the relation was rather small in comparison to the other variables in the regression model as also found by other studies.(15,17) organization of the admitting procedure formed another predictor. a smoothly running admission by which the patient feels guided through the initial stages apparently has positive effects on satisfaction. study findings show that some hotel aspects of care are influential attributes on patients’ overall satisfaction in urology. a potential explanation for the relevance of quality of food and accommodation could be that patients look for surrogate indicators of treatment they are able to judge to measure their own satisfaction.(18) authors underlined that patients want to feel informed about tests, procedures and operative processes.(16,19) however, results of this study only partly agree on these findings. although patients were highly satisfied with information about anesthesia and operations, the analysis shows a rather weak association with overall satisfaction. however, these findings do not necessarily indicate that the feeling of being well informed is not an essential aspect of satisfaction, but perhaps patients were not able or did not feel qualified to judge whether the received information was appropriate. for example, prior studies revealed a patients may report greater satisfaction than they actually feel,(7) the two highest ratings (‘excellent’ and ‘good’) were considered satisfied, whereas ratings of ‘fair’ to ‘very poor’ were considered dissatisfied. multivariate analysis for the multivariate analysis, stepwise backward logistic regression was performed using all variables significant at p ≤ .05 level in bivariate analyses as predictors of patients’ overall satisfaction. the bivariate screening was performed due to the limited sample size in order to create sparse models with a small number of degrees of freedom. as for the bivariate analyses, the dependent variable was dichotomized into ‘fair/acceptable/poor/very poor’ versus ‘excellent/good’. for the purpose of the logistic regression, missing data of the performance of care measures were substituted with the average rating of the respective item in the questionnaire in order to have the largest possible set of data. results the majority of the study sample was male, aged 71-80, and reported 1-2 hospitalizations within the prior five years. about 78.7% of all subjects were admitted by a specialist, approximately 10.3% were sent to hospital by their general practitioner, and 7.6% because of emergency. approximately 75% of the sample assessed los to be appropriate, about 8% perceived their hospital stay to be too short and 4.5% to be too long. a minority of respondents (14.1%) reported post-discharge complications. most of the institutions were teaching hospitals with public providers and a capacity of 400-799 beds (table 1). in total, 905 (85%) patients rated their complete hospital stay either ‘excellent’ or ‘good’ (grouped median: 5.13). patients were most satisfied with kindness of the hospitals’ nurses (5.46) and medical practitioners (5.43), followed by ‘cleanliness’ (5.36). the lowest scores related to ‘discharge procedures and instructions’ (4.82) and ‘clear information about medication’ (4.92) (table 2). all 15 performance of care measures were statistically significantly (p < .001) related to patients’ overall satisfaction in the bivariate analyses (table 2). the patient characteristics perceived los and occurrence of complications as well as the hospital characteristics provider status, work load per nurse, and hospital size were also associated with the dependent variable (p < .001) (table 1). service users who perceived their hospital stay as appropriate were more satisfied (5.25) than patients who judged their hospital stay as too short (4.71), too long (4.58), or could not judge (4.72). patients reporting post-discharge complications were less satisfied (4.68) than patients without (5.19). for-profit providers received slightly higher scores (5.35) than non-profit (5.28) or public (5.06) hospitals. patients hospitalized in clinics with a lower work load per nurse were more satisfied (5.17) than patients in hospitals with a higher work load per nurse (5.03). the most satisfied patients were those hospitalized in clinics with less than 400 beds (5.28) and 400 to 799 beds (5.21), while study participants treated in hospitals with more than 800 beds were least satisfied (4.98). hospital teaching status, work load per medical practitioner, source of acteristics on assessment scores are often equivocal and sometimes contradictory; prior research also implies setting-related differences. in the investigated sample, demographic variables were found to be unrelated to patients’ overall satisfaction, which is consonant with other studies in urology.(22,23) occurrence of complications and los showed relations with overall satisfaction in the bivariate analysis. considerable lack of knowledge on the part of the patient (e.g., relating to the operation or anesthetic).(20,21) therefore, healthcare professionals should attach importance to the provision of comprehensible information about the different aspects of treatment. effects of patient characteristics study findings regarding the magnitude and direction of patient charvariable patients no. (%) satisfaction ratings* p value gender 714 (100) .105a male 616 (86.3) 5.12 female 98 (13.7) 5.10 missing cases 326 ---- age (year) 1040 ---- .066b 21-30 36 (3.5) 4.79 31-40 27 (2.6) 5.10 41-50 59 (5.7) 5.13 51-60 125 (12.0) 5.07 61-70 348 (33.5) 5.10 71-80 370 (35.6) 5.19 > 80 75 (7.2) 5.22 missing cases 0 ---- quantity of hospitalizations** 1014 (100) ---- .267b 1-2 627 (61.8) 5.14 3-5 286 (28.2) 5.09 > 5 101 (10) 5.16 missing cases 26 ---- source of admission 1040 (100) ---- .822c specialist 819 (78.8) 5.11 general practitioner 107 (10.3) 5.13 emergency 79 (7.6) 5.17 self-admission 25 (2.4) 5.26 transfer from another clinic 10 (1) 5.56 missing cases 0 ---- perceived length of stay 1026 (100) ---- < .001c appropriate 768 (74.9) 5.25 too short 82 (8.0) 4.71 too long 46 (4.5) 4.58 do not know 130 (12.7) 4.72 missing cases 14 ---- occurrence of complications 1019 (100) ---- < .001c yes 144 (14.1) 4.68 no 875 (85.9) 5.19 missing cases 21 ---- number of beds 1040 (100) ---- < .001b < 400 183 (17.6) 5.28 400-799 392 (38.0) 5.21 ≥ 800 462 (44.4) 4.98 provider status 1040 (100) ---- < .001c for-profit 87 (8.4) 5.35 non-profit 183 (17.6) 5.28 public 770 (74.0) 5.06 teaching status 1040 (100) ---- .061c teaching 903 (86.8) 5.11 non-teaching 137 (13.2) 5.22 work load per nurse 1040 (100) ---- high 396 (38.1) 5.03 < .001a low 644 (61.9) 5.17 median (range) 101 (55-132) ---- work load per medical practitioner 1040 (100) ---- .321a high 721 (69.3) 5.11 low 319 (30.7) 5.13 median (range) 244 (180-327) ---- table 1. relation between patient and hospital characteristics of the study sample and overall patient satisfaction (n = 1040). a mann-whitney u test. b kruskal-wallis test. c chi-squared test. * grouped median. ** within the prior five years. 1837 miscellaneous urology journal vol. 11 no. 04 july august 2014 1838 patients reporting complications (e.g., physical complaints, pain and infections) and those perceiving their hospital stay as too long were significantly less satisfied. while other studies also show that patients experiencing a longer visit length have a tendency to be more dissatisfied than patients with shorter visits.(13,24) borghans and colleagues found no evidence that los affects patient satisfaction ratings.(25) effects of hospital characteristics the conducted study found a rather weak influence of hospital characteristics on overall satisfaction ratings in comparison to performance of care measures. although hospital size, work load per nurse and provider status were statistically significantly associated with patient perceptions in bivariate analyses, this association faded when performing the multivariate logistic regression. study findings indicate that patients staying in for-profit hospitals with less than 400 beds tend to yield slightly better overall satisfaction ratings. as regards the effect of hospital size several studies found patients to be more dissatisfied in larger hospitals.(10,26) prior research suggests that work load has only satisfaction measure* all patients** satisfied patients† dissatisfied patients‡ organization of admitting procedure 5.23 5.32 (544) 4.50 (289) medical practitioner’s knowledge of 5.21 5.28 (473) 4.53 (257) patient anamnesis and pathogenesis clear reply of inquiries by medical practitioners 5.23 5.33 (543) 4.52 (266) individualized medical care 5.19 5.33 (559) 4.02 (203) clear information about undergoing operations 5.36 5.46 (513) 4.59 (250) clear information about anesthesia 5.40 5.47 (486) 4.89 (299) clear information about medication 4.92 5.04 (432) 4.14 (227) organization of procedures and operations 5.09 5.21 (527) 4.13 (229) discharge procedures and instructions 4.82 4.98 (525) 3.45 (195) kindness of the nurses 5.46 5.55 (551) 4.79 (228) kindness of the medical practitioners 5.43 5.54 (559) 4.52 (212) accommodation 5.15 5.25 (548) 4.44 (290) cleanliness 5.36 5.42 (543) 4.82 (313) quality of food 5.03 5.12 (543) 4.38 (315) treatment outcome 5.27 5.41 (562) 4.06 (192) table 2. satisfaction ratings of single items. * differences between satisfied and dissatisfied patients were significant. p < .001 mann-whitney u test. ** grouped median. † overall satisfaction of excellent and good; grouped median (mean rank). ‡ overall satisfaction of fair, acceptable, poor and very poor; grouped median (mean rank). variables odds ratio (95% ci) p value treatment outcome 5.13 (3.39-7.79) < .001 kindness of the nurses 3.46 (2.05-5.84) < .00 kindness of the medical 3.33 (2.01-5.51) < .001 practitioners individualized medical care 1.95 (1.35-2.80) < .001 accommodation 1.90 (1.31-2.76) < .001 quality of food 1.87 (1.35-2.60) < .001 discharge procedures and instructions 1.53 (1.12-2.59) .008 organization of procedures 1.72 (1.16-2.56) .007 and operations organization of admitting .46 (1.05-2.03) .024 procedure table 3. factors associated with overall satisfaction of the hospital stay (logistic regression). abbreviation: ci, confidence interval. statistics model: nagelkerke-r² = 0.74; x² hosmer-lemeshow goodness-of-fit-statistic = 3.858,8 df, p = .87; 94.6% of cases were correctly classified. patient satisfaction in urology-schoenfelder et al conflict of interest none declared. references 1. cleary pd, edgman-levitan s, roberts m, et al. patients evaluate their hospital care. a national survey. health aff (millwood). 1991;10:254 67. 2. pons me. patient satisfaction in treatment of overactive bladder. eur urol rev. 2008;3:54-6. 3. epstein kr, laine c, farber nj, nelson ec, davidoff f. patients’ per ceptions of office medical practice. judging quality through the patients’ eyes. am j med qual. 1996;11:73-80. 4. marschall-kehrel d, roberts rg, brubaker l. patient-reported outco mes in overactive bladder: the influence of perception of condition and expectation for treatment benefit. urology. 2006;68(supplement 2a):29 37. 5. heidrich sm, wells tj. effects of urinary incontinence: psychological well-being and distress in older community-dwelling women. j gerontol nurs. 2004;30:47-54. 6. avery jc, stocks np, duggan p, et al. identifying the quality of life effects of urinary incontinence with depression in an australian popula tion. bmc urol. 2013;13:11. 7. sitzia j, wood n. patient satisfaction: a review of issues and concepts. soc sci med. 1997;45:1829-43. 8. crow r, gage h, hampson s, et al. the measurement of satisfaction with health care: implications for practice from a systematic review of the literature. health technol assess. 2002;6:1-244. 9. finkelstein bs, singh j, silvers jb, neuhauser d, rosenthal ge. patient and hospital characteristics associated with patient assessments of hospi tal obstetrical care. med care. 1998;36(8 suppl):as68-78. 10. young gj, meterko m, desai kr. patient satisfaction with hospital care: effects of demographic and institutional characteristics. med care. 2000;38:325-34. 11. hall ja, dornan mc. patient sociodemographic characteristics as pre dictors of satisfaction with medical care: a meta-analysis. soc sci med. 1990;30:811-8. 12. nguyen thi pl, briancon s, empereur f, guillemin f. factors determi ning inpatient satisfaction with care. soc sci med. 2002;54:493-504. 13. boudreaux ed, ary rd, mandry cv, mccabe b. determinants of pa tient satisfaction in a large municipal ed: the role of demographic va riables, visit characteristics, and patient perceptions. am j emerg med. 2000;18:394-400. 14. schoenfelder t, klewer j, kugler j. determinants of patient satisfaction: a study among 39 hospitals in an in-patient setting in germany. int j qual health care. 2011;23:503-9. 15. mira jj, tomás o, virtudes-pérez m, nebot c, rodríguez-marín j. pre dictors of patient satisfaction in surgery. surgery. 2009;145:536-41. 16. juhra c, hensen p, pühse g, wollert s, roeder n. internal quality ma nagement: use of a patient questionnaire in a urological university clinic. results of a pilot project. urologe a. 2005;44:1463-8. a minor effect on patient assessments.(12,28) the conducted study mainly corresponds to those findings. teaching status was not related to overall satisfaction which is consonant with findings of other research.(10,26) conversely, finkelstein and colleagues examining data of gynecology patients and brédart and colleagues examining data of hospitalized cancer patients reported higher satisfaction scores among patients in non-teaching hospitals.(9,26) study limitations in interpreting the study findings, several methodic limitations must be acknowledged. first, as the baseline characteristics of non-respondents were not available, it is not possible to evaluate differences between respondents and non-respondents and its potential impact on patient assessments of received care and services. relating to this, literature reports inconsistent findings. while a study conducted by rubin suggest that respondents might evaluate care better than non-respondents,(29) ware and davies reported that those who were satisfied with the quality of care were more likely to not respond.(30) however, lasek and colleagues found that the impact of non-response bias on satisfaction surveys of hospitalized patients might be relatively small. (31) due to these ambiguous results, a limitation of the study findings caused by response bias due to the net response rate of 33% cannot be excluded. second, a sample of patients from nine hospitals of one geographical area in germany was analyzed. the number of institutions might limit the study results according to the effect of hospital characteristics. the generalizability of the findings to other regions or areas outside germany, particularly those that differ according to hospital characteristics, remains to be established. third, due to the fact that the majority of participants were satisfied, as in most patient satisfaction studies, the cell sizes for dissatisfied patients for some variables were very small. these unbalanced cell sizes may have negatively influenced the statistical analysis. however, the r² statistic indicates that the regression model is useful in predicting patient satisfaction and the hosmer-lemeshow test shows that the model adequately fits the data. conclusion findings indicate that subjective experiences of received care and services of patients have greater impact on overall satisfaction than hospital and demographic characteristics, variables which cannot be substantially influenced by health care professionals. specifically the patients’ evaluation of treatment outcome, assessment of communication with hospital staff, organizational aspects such as the organization of operations, and the perception of hotel aspects has strong predictive utility for overall satisfaction. variables predicting satisfaction found in this study can be altered through optimization of service processes and, therefore, should be focused on to increase patients’ evaluation of received care in urology. acknowledgements the authors thank the patients and the health professionals who contributed to this study. 1839 miscellaneous urology journal vol. 11 no. 04 july august 2014 1840 17. thompson da, yarnold pr, williams dr, adams sl. effects of actual waiting time, perceived waiting time, information delivery, and expres sive quality on patient satisfaction in the emergency department. ann emerg med. 1996;28:657-65. 18. otani k, kurz rs, harris le. managing primary care using patient satis faction measures. j healthic manag. 2005;50:311-24. 19. dawes pj, davison p. informed consent: what do patients want to know? j r soc med. 1994;87:149-52. 20. williams oa. patient knowledge of operative care. j r soc med. 1993;86:328-31. 21. sahai a, kucheria r, challacombe b, dasgupta p. video consent: a pilot study of informed consent in laparoscopic urology and its impact on pa tient satisfaction. jsls. 2006;10:21-5. 22. ramsey sd, zeliadt sb, blough dk, et al. complementary and alter native medicine use, patient-reported outcomes, and treatment satisfacti on among men with localized prostate cancer. urology. 2012;79:1034 41. 23. yossepowitch o, aviv d, wainchwaig l, baniel j. testicular prosthe ses for testis cancer survivors: patient perspectives and predictors of long-term satisfaction. j urol. 2011;186:2249-56. 24. quintana jm, gonzález n, bilbao a, et al. predictors of patient satisfa ction with hospital health care. bmc health serv res. 2006;6:102. 25. borghans i, kleefstra sm, kool rb, westert gp. is the length of stay in hospital correlated with patient satisfaction? int j qual health care. 2009;24:443-51. 26. hekkert kd, cihangir s, kleefstra sm, van den berg b, kool rb. pa tient satisfaction revisited: a multilevel approach. soc sci med. 2009;69:68-75. 27. brédart a, coensb c, aaronsonc n, et al. determinants of patient satis faction in oncology settings from european and asian countries: pre liminary results based on the eortc in-patsat32 questionnaire. eur j cancer. 2007;43:323-30. 28. fan vs, burman m, mcdonell mb, fihn sd. continuity of care and ot her determinants of patient satisfaction with primary care. j gen intern med. 2005;20:226-33. 29. rubin hr. patient evaluations of hospital care: a review of the literatu re. med care. 1990;28(suppl 9):3-9. 30. ware je, davies ar. behavioral consequences of consumer dissatisfac tion with medical care. eval program plann. 1983;6:291-7. 31. lasek rj, barkley w, harper dl, rosenthal ge. nonresponse bias on patient satisfaction surveys. med care. 1997;35:646-52. patient satisfaction in urology schoenfelder et al urological oncology 101urology journal vol 6 no 2 spring 2009 expression of survivin and its spliced variants in bladder tumors as a potential prognostic marker nazila nouraee,1 seyed javad mowla,1 ardalan ozhand,2 mahmoud parvin,2 seyed amir mohsen ziaee,2 nasim hatefi1,2 introduction: survivin, a novel inhibitor of apoptosis, is re-expressed in a vast majority of human cancers and is widely considered as a diagnostic marker of cancers. survivin protein regulates both cell division and apoptosis. there are at least 5 spliced variants of the gene with different subcellular localization and anti-apoptotic property. we examined the expression pattern of survivin and its 2 spliced variants, survivin-δex3 and survivin-2b, and their prognostic values in archival collections of formalin-fixed paraffin-embedded samples of bladder tumors. materials and methods: total rna from formalin-fixed paraffinembedded samples (51 samples from 30 patients with bladder cancer and 5-year follow-up) were extracted and analyzed by semiquantitative reverse transcriptase polymerase chain reaction technique. tissue distribution and subcellular localization of survivin protein in tumor tissues was also examined by immunohistochemistry. results: the expression of survivin, survivin-δex3, and survivin-2b were detected in 66.6%, 47.8%, and 54.7% of the specimens, respectively. the expression of survivin and survivin-δex3 were preferentially elevated in tumors with higher grades, whereas survivin-2b expression was lower in highgrade tumors (p = .04). a reverse correlation was observed between survivin2b expression and high-grade tumors. immunohistochemistry results also confirmed the nuclear localization of survivin protein within tumoral cells. conclusion: we were successful in detecting the expression of survivin and its variants in formalin-fixed paraffin-embedded bladder samples. furthermore, our results showed that overexpression of survivin and survivin-δex3 in bladder tumors correlates with poor prognosis of bladder cancer. we suggest that survivin and its variants are suitable prognostic markers of bladder tumors. urol j. 2009;6:101-8. www.uj.unrc.ir keywords: survivin protein, apoptosis, bladder neoplasms, reverse transcriptase polymerase chain reaction 1department of genetics, faculty of basic sciences, tarbiat modarres university, tehran, iran 2urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university (mc), tehran, iran corresponding author: seyed javad mowla, phd department of genetics, faculty of basic sciences, tarbiat modarres university, tehran, po box: 14115-175, iran tel: +98 21 8288 3464 fax: +98 21 8288 3463 e-mail: sjmowla@modares.ac.ir received june 2008 accepted december 2008 introduction similar to other types of tumors, bladder cancer initiates and progresses from genetics and epigenetic events affecting the delicate regulations imposed on cell proliferation and programmed cell death (apoptosis).(1) a tightly regulated balance between the presence of pro-apoptotic and anti-apoptotic regulators would determine the survival/death fate of each cell. deregulated expression of inhibitors of apoptosis may lead to the prolonged survival of transformed cells, and hence, tumor initiation, progression, or metastasis.(2,3) there are 2 major protein families involved in regulating the rate of apoptosis: b-cell cll/lymphoma 2 protein and inhibitors of apoptosis proteins expression of survivin in bladder tumors—nouraee et al 102 urology journal vol 6 no 2 spring 2009 (iaps).(4-6) the iaps are a group of evolutionary conserved proteins characterized by the presence of 1 to 3 domains known as baculoviral iap repeat domains, which are believed to be responsible for the anti-apoptotic function of the iaps.(5) survivin, a unique member of the iap family, is known to be involved in both regulation of apoptosis and control of cell division.(7) it is highly expressed during normal tissue development, but is absent in most terminally differentiated cells of adult tissues. recent identification of several functionally divergent survivin variants in mouse and human increases the complexity of survivin action as well as its regulation. at least, 5 different spliced variants of survivin have been reported so far in human.(8,9) loss of exon 3 in survivinδex3 results in a truncated baculoviral iap repeat domain and a frameshift of the cooh-terminal. in survivin-2b, partly retention of intron 2, as a cryptic exon, inserts 23 additional amino acids into the baculoviral iap repeat domain at essentially the same position.(8) despite these profound structural alterations, the anti-apoptotic potential of survivin-δex3 was largely preserved, while survivin-2b exhibited a loss of anti-apoptotic potential. the overexpression of survivin and survivin-δex3 in almost all human malignancies, and low or no expression in most normal tissues, suggests that it could be a good diagnostic and prognostic marker of cancers as well as an ideal target for cancer-directed therapy.(10,11) considering the necessity of using new molecular markers for assessing prognosis of bladder tumors, and also because of the potential application of survivin and its variants as specific tumor markers for cancers in general, we evaluated the prognostic value of expression of survivin and its two major variants, survivin-δex3 and survivin2b, in formalin-fixed paraffin-embedded (ffpe) samples of patients with bladder cancer, by means of reverse transcriptase polymerase chain reaction (rt-pcr) and immunohistochemistry techniques. materials and methods sampling human samples were obtained from the ffpe archival collections of shahid labbafinejad medical center in tehran. tissues with known 5-year follow-up history records were selected for further analysis. all of the ffpe samples were sectioned and deparaffinized with xylene and stained with hematoxylin-eosin, in order to confirm their previously determined stages and grades. rna extraction a total number of 51 specimens from 30 patients were collected and 3 to 5 sections of each block were prepared for rna extraction process. the sections were deparaffinized with xylene and alcohol, and the tissues were treated with proteinase k (fermentase, vilnius, lithuania). then, the pellets were treated with the rnx plus solution (cinnagen, tehran, iran) according to the manufacturer’s instructions, as described previously.(12) reverse transcriptase polymerase chain reaction specific primers of human beta-2-microglobulin (b2m; as an internal control), human survivin, survivin-δex3, and survivin-2b were designed using the gene runner software, version 3.6 (hastings software, hastings, new york, usa). the sequences of the designed primers and the accession numbers of genes are as follow: survivin (accession number: nm_001168.2): external forward primer: 5´-tggcagccctttctcaag-3´ external, reverse primer: 5´-gttcctctatggggtcgtc-3´ these primers amplified a 202-bp segment of human survivin complementary dna. internal, forward primer: 5´-accaccgcatctctacattc-3´ internal, reverse primer: 5´-gaagaaacactgggccaag-3´ these primers amplified a 131-bp segment from human survivin complementary dna. survivin-δex3 (accession number: nm_001012270.1): forward primer: expression of survivin in bladder tumors—nouraee et al urology journal vol 6 no 2 spring 2009 103 5´-atgacgaccccatgcaaag-3´ external, reverse primer: 5´-acaggaaggctggtggcac-3´ these primers amplified a 184-bp segment of human survivin complementary dna. for a heminested rt-pcr reaction, we used an internal reverse primer with the same forward one. internal reverse primer: 5´-cctggaagtggtgcagcc-3´ this primer together with the forward primer amplified a 153-bp segment. survivin-2b (accession number: nm_001012271.1): forward primer: 5´cggatcacgagagaggaac -3´ external, reverse primer: 5´ctttctccgcagtttcctc -3´ these primers amplified a 181 bp segment of human survivin complementary dna. internal reverse primer: 5´tttcttcttattgttggtttcc -3´ this primer together with the forward primer amplified a 156 bp segment. beta-2-microglobulin (accession number: nm012512): forward primer: 5´-ctactctctctttctggcctg-3´ reverse primer: 5´-gacaagtctgaatgctccac-3´ the product of amplification with these primers was a 191-bp segment from human b2m complementary dna. the primers were synthesized by mwg-biotech (ebersberg, germany) as high purified saltfree grade. all designed primers were blasted with human genome to make sure they are not complementary to other regions of the genome.(13) complementary dna synthesis reactions were performed using 11-μl rna and m-mulv reverse transcriptase (fermentas, vilnius, lithuania) with random hexamer priming in a 20-μl reaction, as previously described.(14) polymerase chain reaction assay was performed using 2 μl of synthesized complementary dna with 0.2 μl of taq polymerase (5 u/μl, cinnagen, tehran, iran), as described elsewhere.(18) the pcr amplification was performed for 20 to 35 cycles. the cycling conditions were as follows: 94°c for 40 seconds, 57°c for 45 secconds (for survivin external primers; for other primers see the results), 72°c for 1 minute, and a final extension at 72°c for 10 minutes. the pcr products were then separated on a 2% agarose gel and visualized by ethidium bromide staining. for a semiquantitative comparison of survivin expression among different samples as well as their different recurrences, we used b2m as an internal control. for each sample, the rt-pcr was performed under similar conditions (except for the number of cycles and the annealing temperature, see the results), but in 4 separate tubes for b2m, survivin, survivin-δex3, and survivin-2b. the band intensity for each gene was determined with uvitech software (cambridge, uk) and the expression levels were measured in relation with the b2m expression level for each sample. the data were statistically analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa). immunohistochemistry using a polyclonal antisurvivin antibody (novus biologicals, littleton, colorado, usa), we examined the subcellular localization of survivin protein in bladder tissues using immunohistochemistry. sections of samples with proved survivin-negative and survivinpositive expression at mrna level were further examined by immunohistochemistry. in these samples, expression or no expression of survivin was confirmed by rt-pcr reaction, according to the expression of b2m. briefly, the ffpe tissue sections (5 μm) were deparaffinized with xylene, rehydrated in descending concentrations of ethanol, and boiled for 15 minutes in citrate buffer (9 mm, ph 6.0) for antigene retrieval. then, endogenous peroxidase activity was suppressed with 3% h2o2 for 20 minutes. the slides were serum-blocked (with normal goat serum) and incubated with survivin’s primary expression of survivin in bladder tumors—nouraee et al 104 urology journal vol 6 no 2 spring 2009 antibody (1:500 dilution) at 4°c for overnight. the sections then incubated with the secondary antibody (vector, burlingame, california, usa), a biotinilated antirabbit antibody (1:250 dilution), for overnight at 4°c. the sections were then processed and stained with a complex of diaminobenzidine/h2o2 (1:1000). in negative control, all the conditions were kept the same, except that the first antibody was eliminated. results polymerase chain reaction optimization to find the optimal annealing temperature for each pair of primers, pcr reactions in a gradient of temperatures from 55°c to 65°c were performed for each round of pcr. the optimum annealing temperature for the survivin primers was 57°c and 62°c for the first and second round of pcr reaction, respectively. for survivin-δex3 primers, the annealing temperature was 61°c for both rounds of pcr. finally, 55°c was determined as the optimum annealing temperature to amplify survivin-2b, for both rounds of pcr (data not shown). the same strategy was used to find the best concentrations of magnesium chloride (2 mm), to optimize the pcr reactions (data not shown). owing to the weak intensity of the signal in the first round of pcr, a second round (nested) of pcr was performed on the product of the first round, using internal primers for 10 to 30 cycles for survivin and 25 to 40 cycles for the survivin variants. for survivin, the optimal number of cycles was determined as 35 and 18 for the first and second round of pcr, respectively. the optimal cycle numbers for survivin-δex3 were 35 and 37 for the first and second round of pcr, respectively. finally, for amplifying survivin-2b, the number of cycles was 35 for both rounds of pcr reaction. for b2m amplification, the annealing temperature of 57°c and the cycle number of 35 were similarly determined (data not shown). differential expression of survivin and its spliced variants overall, 51 tumor specimens from 30 patients were studied. clinicopathological characteristics of all patients were further confirmed by an expert urologist (table). to assure that equal amounts of rna were used for each rt-pcr, we used b2m as an internal control and compromise the relative survivin expression of each sample with its own b2m expression. for each specimen, the rt-pcr was performed under similar conditions within 4 separate tubes, for b2m and for survivin and its variants. as expected, b2m was expressed in all tumor specimens (figure 1). furthermore, the nested or heminested rt-pcr results on the same specimens amplified an expected 131-bp band for survivin and 2 bands of 153 bp and 156 bp for survivin-δex3 and survivin-2b, respectively (figure 1). the experiments were repeated at least twice for all specimens. overall, expression of survivin was detected in 34 out of 51 tumor tissues (66.7%), while survivin-δex3 and survivin2b were detected in 11 of 23 (47.8%) and 23 of 42 (54.8%) ffpe tissues, respectively. after performing rt-pcr for all the samples and determining the band intensity for each gene, statistical analysis of the correlation between the expression of survivin, survivin-δex3, and survivin-2b and different clinical and pathological characteristics of the cases was performed. the characteristic value number of patients 30 mean age at diagnosis, y 62.4 (31 to 84) cystectomy radical 9 (30.0) partial 1 (3.3) number of specimens 51 tumor grade at diagnosis 1 5 (16.7) 2 20 (66.7) 3 5 (16.7) tumor stage a 29 (96.7) b 1 (3.3) metastasis 8 (26.7) follow-up no tumor 10 (33.3) recurrence 12 (40.0) lost to follow up 8 (26.7) death 6 (20.0) clinicopathological features of patients with bladder cancer* *values in parenthesis are percents, except for age, which is range. expression of survivin in bladder tumors—nouraee et al urology journal vol 6 no 2 spring 2009 105 samples were classified according to the age and sex of the patients, 5-year survival rate, stage, grade of malignancy, and recurrences. there was a significant correlation between the expression level of survivin and the 5-year survival rate (odds ratio, 9.15; p = .04; figure 2). in low-survivin and high-survivin expression groups (expression above the median was considered as high, and below the median, as low), elevation in survivin expression correlated with a decrease in the survival rates of the patients by 6 times (odds ratio, 6.0). moreover, our data demonstrated that survivin expression was higher in high-grade tumors; however, the difference was not significant (spearman rho test; figure 3). there was no significant correlation between the expression level of survivin and the stage of the tumors. elevated expression of survivin-δex3 was observed in higher stages and in the 2nd and 3rd recurrences of the tumor, but this finding was not significant. furthermore, there was no significant correlation between the relative overexpression of survivin-2b and the survival rate of the patients. however, the data showed that with 1 unit of overexpression, survival rate would increase 2.3 figure 1. reverse transcriptase polymerase chain reaction analysis of the expression of (a) b2m (191 bp) and survivin (131 bp), and (b) b2m, survivin-∆ex3 (153 bp), and survivin-2b (156 bp). the a, b, c, and d indicate subsequent recurrences of the same patient. figure 2. proportional survivin expression levels (high expression and low expression) in dead and alive patients. those with high expression level of survivin had lower survival rate compared to the group having low or no expression of survivin. figure 3. proportional survivin expression levels in bladder tumors with different grades. expression of survivin in bladder tumors—nouraee et al 106 urology journal vol 6 no 2 spring 2009 times (odds ratio, 2.3). our results also revealed that in high-grade tumors, and also in the 2nd and 3rd recurrences of the tumors, survivin-2b was downregulated. however, these observations were not statistically significant. identity of survivin and its variants the identities of the amplified segments of the complementary dnas corresponding to the survivin, survivin-δex3 and survivin-2b were confirmed by direct sequencing (data not shown). intracellular localization of survivin in bladder tumors a survivin-positive sample (according to the rt-pcr results) was used for optimizing the experiment and choosing the required dilution of the primary and secondary antibodies. then, the immunohistochemistry was performed on tissue sections of 3 survivin-positive and 2 survivin-negative specimens. a specific signal was visualized in the nuclei of the survivinpositive tumor cells, while no immunoreactivity was observed in survivin-negative samples. for confirming the fidelity of immunoreactivity, we also employed negative controls, which were incubated in similar conditions, except for the absence of primary antibody (figure 4). discussion the main aim of the present study was to examine the potential correlation between the expression of survivin variants and the degree of malignancy, pathological behavior, patient survival rate, and the recurrence of bladder cancer. there are rich reservoirs of ffpe samples for molecular studies in the archive of hospitals and clinical centers. these samples can be used in retrospective studies of patients with cancer and could provide valuable prognostic information for further therapeutic strategies. the routine procedures to study paraffinized samples such as immunohistochemistry provide limited information on the biological nature of tumors. recent application of pcr and rt-pcr techniques on ffpe samples would provide more accurate diagnostic and prognostic data with higher sensitivity and specificity.(15) the current methods for rna extraction from ffpe samples are achieved by expensive commercial extraction kits, which increase the efficiency of the procedure. in the present study, we were successful to extract reliable rna from ffpe samples by changing the routine procedures figure 4. immunohistochemistry results showing the tissue distribution and subcellular distribution of survivin. top, a survivin-positive specimen (positive in reverse transcriptase polymerase chain reaction). arrows show the signal within nuclei. middle, a survivin-negative specimen. bottom, a specimen of negative control, processed in the absence of the first antibody. expression of survivin in bladder tumors—nouraee et al urology journal vol 6 no 2 spring 2009 107 for rna extraction from fresh samples. using this procedure, we were able to demonstrate the expression of survivin in 66.6%, survivin-δex3 in 47.8%, and survivin-2b in 54.7% of the ffpe specimens. previous studies on different human tumors such as breast, esophagus, lung, bladder, and gastric tumors have shown a correlation between overexpression of survivin and/or survivin-δex3 and high stages and grades of the tumor(16-20); whereas, a reverse correlation was reported for survivin-2b. furthermore, the overall survival rate of the patients declines with overexpression of survivin and survivin-δex3, and these variants are involved in malignant behavior and therapeutic resistance of the tumors. in accordance with the previous reports,(16-20) our study demonstrated that the overexpression of survivin and survivin-δex3 occurred mostly in tumors with high grades and stages. furthermore, our results revealed that the death risk of the patients increased with the elevated expression of survivin and survivin-δex3, and decreased with overexpression of survivin-2b. we failed to document any significant correlations between the levels of expression of survivin variants and other clinicopathological characteristics of the patients, which might be due to our small sample size. our available data suggest that increasing the number of samples would probably reveal such potential correlations more accurately. seven of the 30 patients (23.3%) died and 8 patients (26.7%) had undergone partial or radical cystectomy, and therefore, their specimens were omitted from the group of follow-up. another problem we faced during this project was the incomplete 5-year follow-up records of the patients. lack of a precise, uniform, and regular follow-up registry for most of the patients is a challenge for these kinds of research. precise recording of the patients’ information and regular follow-up in hospitals would provide a more reliable reservoir for future retrospective studies. conclusion we developed an economical procedure for evaluating the expression of survivin and its splicing variants with no need for expensive kits and techniques. here, we demonstrated that overexpression of survivin and survivin-δex3 correlated with the malignant outcome and recurrence of bladder cancer, while for survivin2b, a reverse correlation was seen. conflict of interest none declared. references 1. spruck ch, 3rd, ohneseit pf, gonzalez-zulueta m, et al. two molecular pathways to transitional cell carcinoma of the bladder. cancer res. 1994;54:784-8. 2. thompson cb. apoptosis in the pathogenesis and treatment of disease. science. 1995;267:1456-62. 3. lowe sw, lin aw. apoptosis in cancer. carcinogenesis. 2000;21:485-95. 4. rossi d, gaidano g. messengers of cell death: apoptotic signaling in health and disease. haematologica. 2003;88:212-8. 5. salvesen gs, duckett cs. iap proteins: blocking the road to death’s door. nat rev mol cell biol. 2002;3:401-10. 6. adams jm, cory s. the bcl-2 protein family: arbiters of cell survival. science. 1998;281:1322-6. 7. o’driscoll l, linehan r, clynes m. survivin: role in normal cells and in pathological conditions. curr cancer drug targets. 2003;3:131-52. 8. mahotka c, wenzel m, springer e, gabbert he, gerharz cd. survivin-deltaex3 and survivin-2b: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. cancer res. 1999;59:6097-102. 9. caldas h, honsey le, altura ra. survivin 2alpha: a novel survivin splice variant expressed in human malignancies. mol cancer. 2005;4:11. 10. span pn, tjan-heijnen vc, manders p, van tienoven d, lehr j, sweep fc. high survivin predicts a poor response to endocrine therapy, but a good response to chemotherapy in advanced breast cancer. breast cancer res treat. 2006;98:223-30. 11. mowla sj, emadi baygi m, ziaee sam, atlasi y, nikpoor p. evaluation of sensitivity and specificity of urine survivin as a new molecular marker in diagnosis of bladder tumors. iran j biotechnol. 2005;3:163-9. 12. nikpoor p, mowla sj, movahedin m, ziaee sa, tiraihi t. catsper gene expression in postnatal development of mouse testis and in subfertile men with deficient sperm motility. hum reprod. 2004;19:124-8. 13. national center for biotechnology information [home page on the internet]. blast human sequences [cited april 1, 2009]. available from: http://www.ncbi.nlm.nih. gov/genome/seq/blastgen/blastgen.cgi?taxid=9606 14. sambrook j, russel dw. molecular cloning a laboratory manual. 3rd ed. new york: cold spring harbor laboratory press; 2001. 15. babaei e, mowla sj, shariat torbaghan s, emadi expression of survivin in bladder tumors—nouraee et al 108 urology journal vol 6 no 2 spring 2009 bayegi m. detection of survivin gene expression in formalin-fixed paraffin-embedded tissues of human osteosarcoma: its potential usefulness in diagnosis and prognosis of bone tumors. iran biomed j. 2006;10:39-45. 16. vegran f, boidot r, oudin c, defrain c, rebucci m, lizard-nacol s. association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer. oncogene. 2007;26:290-7. 17. mccabe ml, dlamini z. the molecular mechanisms of oesophageal cancer. int immunopharmacol. 2005;5:1113-30. 18. shen m, rothman n, berndt si, et al. polymorphisms in folate metabolic genes and lung cancer risk in xuan wei, china. lung cancer. 2005;49:299-309. 19. mowla sd, emadi baygi m, ziaee sa, nikpoor p. evaluating expression and potential diagnostic and prognostic values of survivin in bladder tumors: a preliminary report. urol j. 2005;2:141-7. 20. meng h, lu c, mabuchi h, tanigawa n. prognostic significance and different properties of survivin splicing variants in gastric cancer. cancer lett. 2004;216:14755. new section in urology journal fillers fillers are materials, including text and image, to be published in the blank spaces of the journal. the subject is not restricted, but those related directly or indirectly to medicine and urology are preferred. quotations, interesting pictures, historical notes, and notice on events are some examples. please contact the editorial office via e-mail (urol_j@unrc.ir) to send fillers. epca2.22: a silver lining for early diagnosis of prostate cancer gholamreza pourmand1, majid safavi1, ayat ahmadi1, elaheh houdeh2, mohammad noori1, rahil mashhadi1, farimah alizadeh1, elaheh salimi1, fariba heydari1, abdolrasoul mehrsai1, naghmeh pourmand1* purpose: to investigate whether epca-2 (a prostate matrix nuclear protein) can be a more helpful marker in prostate cancer diagnosis. materials and methods: 176 patients enrolled in this study had abnormal prostate specific antigen (psa) or digital rectal examination and were candidates for prostate needle biopsy. blood samples were obtained from each patient prior to biopsy and the samples were frozen for epca-2 measurement. patients diagnosed with cancer were assigned to the case group and those with benign prostate hyperplasia (bph) were included in the control group. univariate and multivariable analyses were done to assess the relationship between different independent variables with cancer diagnosis. the diagnostic power of epca-2 for cancer was estimated at different levels of psa according to the roc curve. results: the mean(± sd) age of cancer cases was 70.33(± 9.02) years while it was 63.34(± 9.47) years for bph cases (p < .01). epca-2 and psa were also significantly different between cancer and bph cases (p < .001). the multivariable logistic regression showed that epca-2 has a significant relationship with cancer diagnosis (or=1.009, p = .021). after controlling other variables following stratification for psa, it was shown that epca-2 and cancer were correlated just when psa was >10 (p < .001). auc was 0.694 for cancer prediction by epca-2 when psa was >10 ng/ml. conclusion: epca-2 has the power of differentiating bph from cancer in prostate cancer suspects. this suggests that epca-2 can be helpful in diagnosing prostate cancer and can be a preventive test to avoid unnecessary biopsies considering psa and age of the patient. keywords: epca; prostate cancer diagnosis; psa introduction the discovery and increasing use of psa, as a screening test since 1980, has lifted prostate cancer (pca) to the most frequent neoplasia in men of developed countries. it is estimated that 900,000 new cases of pca leading to 258,000 pca-related deaths worldwide in 2008 are diagnosed; it proposed a rise to 1.7 million diagnoses and an annual mortality rate of 0.5 million men in 2030(1). prostate cancer incidence in europe is estimated at 416,700 new cases in 2012 resulting in 92,200 cancer deaths per year(2). in usa, it was estimated that 233,000 new cases would be diagnosed and 29,480 cancer deaths would occur during 2014(3). in iran, the incidence rate of pca (11.25: 100,000) is lower than the western countries(4) and this might be attributed to the nutrition pattern of the country consuming less red meat (36.3kg/year) than the world's average per capita rate (41.90 kg/year) according to current worldwide annual meat consumption per capita. notwithstanding its revolutionary role in prostate cancer diagnosis, psa is a tissue marker with restrictions due to its lack of specificity for pca cells, the serum level of which may change following inflammation, infection or manipulation of the prostate. racial and geographical variations of serum psa level should be added to the limitations of interpreting its 1urology research center, tehran university of medical sciences, tehran, iran. 2sana medical laboratory, tehran, iran. *correspondence: urology research center, sina hospital, hassan-abad sq., tehran, iran. 1136746911 tel/ fax: +98-21-66348560. e-mail: n.pourmand@yahoo.com. received march 2016 & accepted june 2016 results, as well. it is inevitable to investigate a tumor marker with high specificity to avoid unnecessary biopsies in cases with elevated prostate specific antigen (psa) and normal digital rectal examination (dre). epca (early prostate cancer antigen), primarily introduced by dhir et al.(4), is a nuclear matrix protein that has shown to be associated with prostate cancer and may be used as a specific tumor marker rather than a tissue marker for prostate cancer diagnosis individually or in combination with psa. they were able to measure anti-epca antibodies in prostate biopsies with negative results to predict prostate cancer development after 5 years. further immunohistochemical analyses documented a sensitivity and specificity of >80% for detecting prostate cancer(4,5). there are two unrelated types of nuclear matrix proteins found in serum, assisting urologists with diagnosing prostate cancer; the proteins are called epca and epca-2 due to their date of discovery, respectively(6). three epitopes including epca-2.22, epca-2.19, and epca-2.24 are defined for epca-2(7). it was observed that serum levels of epca-2.22 higher than 30 ng/ml were associated with a sensitivity of 94% for pca diagnosis while maintaining 92% specificity(8,9). besides differentiating bph from pca, epca2.19 and epca-2.22 assays were able to diagnose and localize prostate cancer from the metastasis(10,11). urological oncology urological oncology 2845 this study was conducted to investigate the efficacy of epca-2.22 as an epitope of epca2 in differentiating pca from benign prostate hyperplasia (bph) in candidates of prostate biopsy due to elevated psa and/or abnormal dre. materials and methods 176 prostate biopsy candidates with elevated psa and/or abnormal dre were enrolled in the study. blood samples were obtained from patients (5cc) to measure serum epca-2 and psa levels. the serum level of epca-2.22 epitope of epca-2 was measured using elisa method (cusabio kit). after measuring epca-2, all patients underwent transrectal ultrasound guided biopsy of the prostate using the 10 core biopsy method (standard method in our center). according to pathology reports, patients were divided into bph (n = 107 patients) and pca (n = 69 patients) groups. paraclinical and physical examination results as well as demographic information of the patients were gathered. statistical analysis the relationship between different independent variables and the outcome (pca versus bph) was estimated using univariate tests (chi 2, fisher exact, t-test). different independent variables were applied in a multivariate logistic regression and remained in the final model based on the backward method using wald test (entry: 0.05, removal: 0.1).the roc curve and auc as well as sensitivity, specificity, positive and negative predictive values were used for estimating the diagnostic power of epca-2. results pathology reports revealed 107 bph and 69 pca diagnosed cases. the mean( ± sd) age of the patients was 63.34 ( ± 9.47) years and 70.33( ± 9.02) years in bph and cancer groups, respectively. the mean difference of age between the two groups was significantly higher in the cancer group (p < .01). the mean serum level of epca-2 and psa was significantly higher in the cancer group (p < .001). other variables which were significantly higher in the bph group included hemoglobin and platelet count (hb: 14.99 versus 14.2; and for platelet: 23.46 versus 21.32 in controls and cases, respectively). table 1 shows other clinical characteristics of the patients according to their final diagnosis. the multivariable analysis of the association between different independent variables and cancer diagnosis showed that age and epca-2 have a significant association with cancer diagnosis (p < 0.001 and p = 0.21, respectively). table 2 shows the result of the logistic regression for variables remaining in the model using backward method with wald test. the roc curve of epca-2, psa and age was calculated for cancer diagnosis and demonstrated that the association between these three factors and the outcome is statistically significant (p = .001 for psa and p < .001for epca-2 and age). the frequency of cancer and bph was calculated following stratification of the patients based on psa (psa < 10, and psa > 10). about half of the patients with psa levels lower than 10(50.06%) were found with table1: clinical characteristics of patients according to their final diagnosis. risk factors outcomes or(ci) p-value bph; n (%) cancer; n (%) cardiovascular diseases 23(21.5) 14(20.6) 0.94(0.44 – 1.99) 0.88 diabetes 13(12.1) 11(15.9) 1.37(0.57 – 3.26) 0.47 hypertension 28(26.2) 19(27.5) 1.07(0.54 – 2.12) 0.84 renal failure 3(2.8) 5(7.2) 2.70(0.62 -11.71) 0.16 foot fracture 4(3.7) 4(5.8) 1.58(0.38 6.55) 0.52 colon surgery 0(0) 2(2.9) 0.07 prostate surgery 5(4.7) 6(8.7) 1.94(0.56 -6.63) 0.28 history of prostatitis 4(3.7) 0(0) 0.10 urinary tract infection 2(1.9) 0(0) 0.25 medication 49(48.0) 29(46.8) 0.95(0.50 -1.78) 0.87 family history of prostate disorder 50(46.7) 26(37.7) 0.68(0. 37 – 1.27) 0.23 urinary tract obstruction 33(30.8) 14(20.3) 0.57(0.27 – 1.16) 0.12 hematuria 27(25.2) 20(29.0) 1.20(0.61 – 2.38) 0.58 fever 9(8.4) 7(10.1) 1.22(0.43 – 3.47) 0.69 abbreviations: ci, confidence interval; n, number b s.e. or(exp b) p-value age .077 .024 1.080 .00 medication in use -.061 .39 .941 .87 prostate in family -.145 .396 .865 .713 epca .009 .004 1.009 .021 psa -.007 .015 0.993 .62 epca-2 in pca diagnosis-pourmand et al. table2: multivariable logistic regression results; dependent variable: cancer vs bph vol 13 no 05 september-october 2016 2846 bph diagnosis. in this group, cancer diagnosis was not associated with epca -2 values. however, the relation between epca-2 and cancer diagnosis showed that epca-2 and cancer diagnosis are significantly related when psa > 10 (p < .001). in this group (patients with psa > 10) higher epca-2 levels were significantly associated with a higher gleason score (mean epca was 196.6 for gleason score >= 7 in comparison to 90.52 for gleason score < 7; p = .034) while it was not the same in the other group of the patients (psa < 10). area under the curve (auc) was calculated for epca-2 and cancer diagnosis (figure 2) for those with psa > 10. according to the results of auc, different validity indices (sensitivity, specificity, positive and negative predictive values) were calculated for different cut-off points of epca-2 for cancer diagnosis in this psa stratum. table 3 shows the estimated validity indices for epca2. discussion psa was detected in serum in 1980 and revolutionized pca management. but soon, hopes disappeared, since it was found that psa is a tissue marker rather than tumor marker and some conditions like benign prostatic hyperplasia, infection and manipulation will affect the serum levels of psa(13). on the other hand, racial and geographical variations in serum psa level was another problem in interpreting it and defining a definitive cut off point for cancer diagnosis; for example, in usa and europe, a cutoff point of 2.5 ng/ml is offered to diagnose cancer while in iran, it was estimated to be 7.85 ng/ml in one report(14). when psa is elevated, several factors propose the need to seek other cancer specific biomarkers to diagnose pca and reduce unnecessary biopsies. it has been shown that epca is a nuclear matrix protein known to be expressed by pca cells showing 84% and 92% sensitivity versus 85% and 94%specificity for pca detection when assayed by immunohistochemical or eliza methods respectively(4,15,16). it was observed that age, psa and epca2.22 level are associated with pca diagnosis. in the current study, epca 2.22 was evaluated by eliza method to investigate if it is useful to diagnose prostate cancer and prevent unnecessary biopsies. when sensitivity and specificity for different cutoff points were calculated at 28.55ng/ml, epca2.22 diagnosed cancer with 74.1% sensitivity, 50% specificity, and 49.69% ppv; however, it was previously observed that serum levels higher than 30ng/ml have 94% sensitivity and 92% specificity for pca diagnosis(8, 9). in this study, epca2.22 did not predict pca diagnosis as good as previous reports, especially for the specificity index. to define the best diagnostic effect of epca2.22, patients were stratified into two groups (psa=< 10, psa>10). it was observed that epca2.22 can predict cancer diagnosis only when psa>10 (89.2% sensitable 3: test validity indices for differentiating cancer from bph according to different cut-off points of epca-2 when psa>10 cut-off sensitivity (%) specificity (%) ppv (%) npv (%) 3.23 100 0 49.33 30.1 89.2 23.7 53.23 69.26 43.79 75.7 39.5 54.92 62.53 55.62 70.3 50 57.78 63.35 119.41 51.4 86.8 79.12 64.71 133.98 40.5 94.7 88.15 62.04 164.54 35.1 97.4 92.93 60.65 375.38 10.8 100 100 53.51 figure 1: roc curve of epca-2, psa and age for cancer diagnosis figure2: roc curve of epsa-2 for prostate cancer diagnosis when psa>10 epca-2 in pca diagnosis-pourmand et al. urological oncology 2847 tivity, 23.7% specificity, 53.23% ppv and 69.26% npv in the cut-off point 30.1), and in these patients, higher epca2.22 level is associated with a higher gleason score (gleason score >=7 in comparison to gleason score < 7; p = .034). this may be rooted in the lower diagnostic power of epca2.22 in lower psa levels and probably localized and low-risk pca. it was documented that epca 2.22 in contrast to psa was highly accurate in differentiating localized from extra-capsular disease(17). we observed that in patients with psa>10, higher epca 2.22 levels are associated with a higher gleason score (gleason score >=7) which expresses its promising role in defining high risk patients; however, further studies are needed. although the specificity of epca and predictive values are not proofs recommending epca as a diagnostic measure, high sensitivity values for epca, that are almost the same in different studies show that it could be a good measure for ruling out cancer diagnosed-patients without biopsy. conclusions epca-2 has a notable power of differentiating bph from cancer in prostate cancer suspects. however, its result must be considered in combination with psa result and patient’s age. this suggests that epca-2 can be helpful in diagnosing pca and can be a preventive test to avoid unnecessary biopsies in patients who are supposed to do biopsy because of the high value of psa like when psa>10. acknowledgements this research has been sponsored by tehran university of medical sciences and health service grant no.15494. the authors thank mrs. bita pourmand for the careful edit of the manuscript. references 1. center mm, jemal a, lortet-tieulent j, et al. international variation in prostate cancer incidence and mortality rates. eur urol. 2012;61:1079-92. 2. ferlay j, steliarova-foucher e, lortet-tieulent j, et al. cancer incidence and mortality patterns in europe: estimates for 40 countries in 2012. eur j cancer. 2013;49:1374–1403. 3. salem s, salahi m, mohseni m, et al. major dietary factors and prostate cancer risk: a prospective multicenter case-control study. nutr cancer. 2011;63:21-7. 4. siegel r, ma j, zou z, jemal a. cancer statistics, 2014. ca cancer j clin. 2014;64:929. 5. dhir r, vietmeier b, arlotti j, et.al. early identification of individuals with prostate cancer in negative biopsies. j urol. 2004;171:1419-23. 6. uetsuki h, tsunemori h, taoka r, haba r, ishikawa m, kakehi y. expression of a novel biomarker, epca, in adenocarcinomas and precancerous lesions in the prostate. j urol. 2005;174:514-8. 7. pal rp, maitra nu, mellon jk, khan ma. r. defining prostate cancer risk before prostate biopsy. urol oncol. 2013;31:1408-18. 8. uetsuki h, tsunemori h, taoka r, haba r, ishikawa m, kakehi y. expression of a novel biomarker, epca, in adenocarcinomas and precancerous lesions in the prostate. j urol. 2005;174:514-8. 9. steuber t, o'brien mf, lilja h. serum markers for prostate cancer: a rational approach to the literature. eur urol. 2008;54:31-40. 10. you j, cozzi p, walsh b, et al. critical reviews in innovative biomarkers for prostate cancer early diagnosis and progression. crit rev oncol hematol. 2010;73:10-22. 11. leman es1, cannon gw, trock bj, et.al. epca-2: a highly specific serum marker for prostate cancer. urology. 2007;69:714-20. 12. oterojr, gomezbg, juanateyfc, et.al; prostate cancer biomarkers:anupdate, oncology: seminar sand original investigations. 32 (2014)252-260. 13. diamandis ep. point: epca-2: a promising new serum biomarker for prostatic carcinoma? clin.biochem. 2007; 40:1437–9. 14. stephan c, ralla b, jung k. review: prostatespecific antigen and other serum and urine markers in prostate cancer. biochim biophys acta. 2014;1846:99-112. 15. pourmand g, ramezani r, sabahgoulian b, et.al. preventing unnecessary invasive cancer-diagnostic tests: changing the cutoff points. iran j public health. 2012;41:4752. 16. you j, cozzi p, walsh b, et.al, innovative biomarkers for prostate cancer early diagnosis and progression. crit rev oncol hematol. 2010;73:10-22. 17. paul b, dhir r, landsittel d, hitchens mr, getzenberg rh. detection of prostate cancer with a blood-based assay for early prostate cancer antigen. cancer res. 2005; 65:4097100. 18. leman es1, magheli a, cannon gw, mangold l, partin aw, getzenberg rh. analysis of second epca-2 epitope as serum test for prostate cancer. prostate. 2009;69:1188-94. epca-2 in pca diagnosis-pourmand et al. vol 13 no 05 september-october 2016 2848 laparoscopic urology comparison of the efficacy and safety of laparoendoscopic single-site surgery with conventional laparoscopic surgery for upper ureter or renal pelvis stones in a single institution: a randomized controlled study juhyun park1, seung bae lee1, sung yong cho1, chang wook jeong2, hwancheol son1, yong hyun park3, hyeon hoe kim2, islahmunjih ab rashid4 , hyeon jeong1* purpose: to evaluate the utility and safety of laparoendoscopic single-site surgery (less) in comparison with conventional laparoscopic (cl) surgery for the treatment of upper urinary tract stones. material and methods: between june 2011 and may 2012, 20 patients with upper urinary tract stones were included in this prospective randomized study. the patients were assigned into the less group or cl group in a one-on-one manner using a random table. the clinical parameters were evaluated in the immediate postoperative period, and the stone clearance rate was evaluated via non-contrast computer tomography at one month postoperatively. results: there were no significant differences in patient demographics or preoperative stone sizes between the two groups. the perioperative parameters, including operative time, estimated blood loss, postoperative pain scores, length of hospital stay, and changes in renal function, were comparable. no transfusions or open conversions were required in either group. the incidence of residual stones was lower in the less group (1 case) than in the cl group (2 cases). however, this difference was not statistically significant. conclusions: for large and impacted upper ureteral stones, the effectiveness and safety of less were equivalent to those of cl. further randomized control trials with larger sample sizes are needed to strengthen the conclusions of this study. keywords: urinary calculi; ureteral calculi; kidney calculi; laparoscopy; prospective studies introduction less invasive techniques, such as extracorpore-al shock wave lithotripsy (eswl), percutaneous nephrolithotomy (pcnl) and ureteroscopic lithotripsy (urs), have recently become mainstream in the treatment of urinary stones.(1,2) however, despite the development and advances of these excellent techniques, invasive surgical procedures are still used for certain cases, such as those with large stone burdens, difficult stone positions, or coexisting obstructions. in such cases, laparoscopic surgery for urolithiasis can be a good alternative to open surgery, which is a very invasive proposition.(3-5) in contrast, the recently introduced laparoendoscopic single-site surgery (less) method uses only one port for the laparoscopic instrument manipulation and can thereby prevent internal organ damage and reduce the risk of bleeding from the initial blind trocar insertion.(6) less is known to provide better cosmetic outcomes and less postoperative pain than conventional laparoscopic (cl) surgery.(7) the feasibility of less for urinary stones has been proven in several studies;(8-10) however, few prospective randomized controlled studies comparing less with cl for urinary stone have been undertaken. therefore, we intended to examine the utility and safety of less for large upper urinary tract stones through a prospective randomized controlled trial in which the less procedure was compared with cl. materials and methods study population between june 2011 and may 2012, 20 patients with upper ureteral stones were included in the study. the indications for the operations were obstructive or impacted ureteral stones larger than 15 mm in the upper part of the ureter following previous eswl failure (figure 1). patients were randomly assigned in a one-on-one manner into the less or cl group via the use of a randomization table. the surgeons were informed of the type of laparoscopic urology 2759 1department of urology, seoul metropolitan government seoul national university boramae medical center, seoul, korea. 2department of urology, seoul national university hospital, seoul, korea. 3department of urology, seoul st. mary’s hospital, seoul, korea. 4urology unit, department of surgery, international islamic university malaysia, kuala lumpur, malasyia. *correaspondence: department of urology, seoul metropolitan government seoul national university boramae medical center, 20 boramae-ro 5-gil,dongjak-gu, seoul, 07061, korea. tel: +82 2870 2392. fax: +82 2870 3863. e-mail: drjh@brm.co.kr. received january 2016 & accepted june 2016 vol 13 no 04 july-august 2016 2760 laparoscopic procedure when the patient was admitted to the hospital. patients with anatomical abnormalities of the urinary tract, such as a horseshoe kidney and ureteropelvic junction (upj) obstruction, were excluded from the study. patients with history of previous abdominal surgery were also excluded from the study. ethical standards this study design and the use of patients’ information that was stored in the hospital database were approved by the institutional review board (irb) at the seoul metropolitan government-seoul national university boramae medical center. the approval number is 06-2011-46. the planned study was explained to the patients in detail, and written informed consent was obtained from each patient. our study was conducted according to the ethical standards delineated in the 1964 declaration of helsinki and its later amendments. surgical procedures all patients were positioned in a modified flank position that is typical of any laparoscopic kidney surgery. all of the procedures were performed under general anesthesia, and the kidneys were approached transperitoneally in both the less and cl procedures. in less, we utilized the commercially available access port (octoporttm, dalimsurgnet corp, seoul, korea) to gain access to the peritoneal cavity.(11) pre-bent instruments were applied through these access devices to optimize comparison of less and conventional laparoscopic stone surgery-park et al. the range of motion. a 3-cm incision was made at the umbilicus for the placement of the octoporttm (figure 2). meanwhile, a veress needle was used to create the initial pneumoperitoneum prior to the insertion of the first port in cl. the camera port was placed 2 cm below the umbilicus at the lateral margin of the rectus muscle. under direct laparoscopic guidance, two instrument ports were inserted: a 12-mm port at the anterior axillary line at the level of the umbilicus and a 5-mm port 7-8 cm cephalad to the camera port. the subsequent laparoscopic procedures were similar in both groups. the colon was reflected medially along the anatomical white line of toldt to expose the kidney. we followed the course of the ureter as a guide in the identification of the upj. subsequently, a vertical incision was made at the hydronephrotic ureter above the stone level to gain access to the main stone. if there were any calyceal stones besides the upper urinary tract stone, the flexible nephroscope was used to localize and remove them (figure 3). a ureteral stent was laparoscopically inserted into each patient at the completion of the procedure. the ureterotomy or pyelotomy incision was interruptedly closed using 4/0 polyglycolic acid suture. finally, a drain was placed in the perirenal space. clinical parameters the patients’ clinical parameters, including body mass table 1. comparison of preoperative parameters between less and cl groups. lessa cla p value no. of patients 10 10 age (years) 57.7 ± 13.2 51.8 ± 17.0 .393 gender 1.0 male 9 9 female 1 1 diabetes mellitus 4 3 .999 hypertension 5 4 .999 height (cm) 167.8 ± 8.2 167.9 ± 7.4 .969 weight (kg) 75.3 ± 12.5 73.9 ± 15.0 .821 bmi (kg/m2) 26.6 ± 3.2 26.1 ± 4.2 .796 preoperative hb (g/dl) 14.2 ± 1.5 14.1 ± 1.8 .970 preoperative scr (mg/dl) 1.10 ± 0.35 1.04 ± 0.23 .940 preoperative egfr (ml/min) 73.6 ± 20.0 76.6 ± 20.2 .821 stone location .999 no. of renal pelvis stone 6 5 no. of upper ureter stone 4 5 no. of concomitant calyceal stone 8 7 .999 max size of stone (mm) 23.5 ± 7.7 20.5 ± 5.4 .383 stone volume (mm3) 2804.3 ± 1883.3 2084.9 ± 1219.9 .326 preoperative pain score (vas) 4.9 ± 3.7 4.3 ± 2.5 .684 abbreviations: less, laparoendoscopic single-site surgery; cl, conventional laparoscopy; bmi, body mass index; hb, hemoglobin; scr, serum creatinine; egfr, estimated glomerular filtration rate; vas, visual analog scale; max, maximum adata is presented as mean ± sd or absolute numbers index (bmi), serum creatinine (scr), estimated glomerular filtration rate (egfr), hemoglobin, maximal stone size and volume, and pain scores, were determined preoperatively. the operative time, flexible nephroscope use time, estimated blood loss, pain scores, and intraoperative complications were recorded on the operative day. the operative time was measured from skin incision to skin closure including the flexible nephroscope use time. the duration of the hospital stay and the pain scores were noted and recorded at the discharge of the patient from the hospital. the postoperative hemoglobin, scr and egfr were checked two weeks after surgery when the ureteral stents were removed. non-contrast computed tomography (ncct) was performed at one month postoperatively. stone-free status was judged at that time, and was defined by the absence of residual stone or the presences of residual stones ≤ 2 mm. statistical analysis the continuous data are presented as the mean ± the sd. the mann-whitney u test and the fisher’s exact test were used to investigate several parameters and identify significant differences between the two groups. two-sided p < .05 was considered statistically significant. the data were analyzed using commercially available software (spss version 20.0, ibm spss statistics, chicago, il, usa). results a total of 20 patients were included in this study and divided equally into two groups. there were no signiflaparoscopic urology 2761 icant differences between the less and cl groups in any of the preoperative parameters (table 1). the intraoperative parameters were also comparable between the less and cl groups (table 2). neither transfusion nor open conversion was required in any case in either group. there were no additional procedures for the residual stones because the patients were asymptomatic, and the sizes of all residual stones were smaller than 2 mm, i.e., they were limited to clinically insignificant residual fragments. discussion in this era of less invasive surgical techniques, urs and pcnl were the first treatment options for large upper tract stones.(12,13) however, for upper tract stones larger than 2 cm, the efficacy of urs decreases, whereas its complication risk increases.(14) pcnl also has a risk of complications, such as renal parenchymal injury, bleeding, and even urosepsis, during the pcnl tract formation.(15) therefore, we were forced to choose from invasive surgical procedures for the upper tract stones in our study. in these situations, we found that laparoscopic surgery can be a good alternative to very invasive treatments for urolithiasis.(3-5) with the rapidly increasing frequency of the application of laparoscopy in the field of urology, the acceptance of laparoscopic stone surgery as an alternative to open stone surgery is growing. whereas the 2007 european urological association guidelines on urolithiasis considered laparoscopic stone surgery to be table 2. comparison of perioperative parameters between less and cl groups. lessa cla p value operative time (min) 167.4 ± 80.2 190.3 ± 135.8 .850 time using flexible nephroscopes (min) 15.0 ± 18.4 19.0 ± 22.3 .745 estimated blood loss (ml) 51.0 ± 96.6 64.0 ± 102.7 .606 postoperative hospital stay (day) 3.9 ± 1.7 3.5 ± 1.6 .672 postoperative hb (g/dl) 13.9 ± 1.4 13.7 ± 1.5 .970 postoperative serum cr (mg/dl) 1.07 ± 0.31 0.98 ± 0.18 .733 change in serum cr -0.07 ± 0.17 -0.08 ± 0.16 .912 postoperative egfr (ml/min) 79.3 ± 19.3 81.6 ± 21.9 .940 change in egfr 4.7 ± 14.3 5.6 ± 11.2 .739 pain scores on operative day (vas) 6.9 ± 2.0 6.4 ± 2.5 .631 pain scores at discharge (vas) 2.4 ± 0.5 2.3 ± 0.8 .684 postoperative complication .255 no complication 6 8 hematuria 1 0 fever 3 1 ureteral stent reposition or reinsertion 1 1 no. of patient with residual stone 1 2 .999 stone free rate (%) 90% 80% .999 abbreviations: less, laparoendoscopic single-site surgery; cl, conventional laparoscopy; hb, hemoglobin; scr, serum creatinine; egfr, estimated glomerular filtration rate; vas, visual analog scale adata is presented as mean ± sd or absolute numbers comparison of less and conventional laparoscopic stone surgery-park et al. vol 13 no 04 july-august 2016 2762 ‘option’(16), this procedure was ‘highly recommended’ in the 2009 version, and upgraded to ‘preferred’ relative to open stone surgery in the 2016 version, given that the surgeon has sufficient experienced.(17) indeed, laparoscopic surgery is known to be superior to pcnl in terms of the risks of complications such as bleeding.(3,5,18) laparoscopic surgery has the advantage of being harmless to the renal parenchyma and a presumed lower risk of intraoperative bleeding.(3,18) tefekli et al. reported the results of a matched comparative analysis between laparoscopic pyelolithotomy and pcnl for renal stone surgery. these authors found that the operative time and hospital stay were shorter in pncl group, but the postoperative hemoglobin decrease and transfusion rate were lower in the laparoscopic surgery group.(19) al-hunayan et al. also reported similar results base on their randomized figure 1. simple x-ray image of impacted upj stone with multiple calyceal stones. this patient was assigned into less group. controlled study. in that study, even the stone-free rate was superior in the laparoscopic surgery group.(20) less has attracted attention as the latest laparoscopic technique. less generally uses only one port for laparoscopic instrument manipulation and thus can minimize port site-related problems and prevent the risk of initial blind trocar insertion, which is an essential procedure during cl. less is also better than cl in terms of cosmetic outcomes and postoperative pain control.(5, 7, 10) cosmetic appearance should be an area of interest in less pyelolithotomy because urinary stones do affect young female patients for whom aesthetic outcome is a particular concern.(21,22). white et al. reported superior cosmetic outcomes in a less group in his study of less abdominal sacrocolpopexy.(21) raybourn and his colleagues also reported better cosmetic outcomes in patients who underwent less simple nephrectomy.(22) furthermore, less for urinary stones does not require a large incision for the removal of the specimen, which may further improve the cosmetic outcome (figure 4). however, our study did not demonstrate any significant differences in postoperative pain or the length of hospital stay between the less and cl groups. we assume the surgery type resulted in these unexpected findings. for example, whereas laparoscopic nephrectomy requires an additional skin incision for tissue retrieval, pyelolithotomy does not require an additional skin incision for stone retrieval, even in cases of cl pyelolithotomy.(3,4) this difference is a possible reason for the lack of significant differences between the two groups in terms of postoperative pain and hospitalization. less is performed through a single port through which the telescope and the dissecting surgical instruments enter the abdominal cavity through the same incision. this procedure can lead to the loss of triangulation and distance, a clash of the surgical instruments, difficulty in the overall performance of the surgery, and consequently a presumably longer operative time.(7) however, in our series, we observed that the operative time was shorter in the less group than in the cl group, although this difference did not reach statistical significance. raman et al. compared less and cl for nephrectomy procedures and found no difference in the operative times.(23) stein et al. also reported no statistically significant difference in the operative times for less and cl pyeloplasty.(24) we assume that the advent of new endoscopic techfigure 2. octoporttm, access port for less ureterolithotomy was placed at the umblilicus. it has a camera port of 5/10 mm, a 5/12 mm port and two 5 mm ports. figure 3. removed upj stone and calyceal stone comparison of less and conventional laparoscopic stone surgery-park et al. nologies and instruments has eased the performance and shortened the duration of less surgery. furthermore, we also believe that once the learning curve has reached a plateau and the surgeon has become sufficiently experienced with the less technique, there should be no difference in the operative times of less and cl. in our study, we demonstrated that less, at least as performed by an expert, is as efficacious as cl surgery in the removal of upper ureter stones. our study provides good evidence supporting the use of less for urolithiasis. because the present study was prospective, we admit the inherent weakness of our study due to the small number of patients. patients with large stone burdens, stones greater than 15 mm and those with multiple accompanying calyceal stones are not common. the continuous evolution and development of telescopes and dissecting instruments for less promises the continued evolution of this technique. conclusion our results demonstrated that when performed by skillful surgeons, the effectiveness and safety of less are equivalent to those of cl in the surgical treatment of upper urinary tract stones. further randomized control trials with larger sample sizes are needed to strengthen the conclusions of this study. conflict of interest nothing to declare reference 1. wright ae, rukin nj, somani bk. ureteroscopy and stones: current status and future expectations. world j nephrol. 2014;3:243-8. 2. rosa m, usai p, miano r, et al. recent finding and new technologies in nephrolitiasis: a review of the recent literature. bmc urol. 2013;13:10. 3. simforoosh n, aminsharifi a. laparoscopic management in stone disease. curr opin urol. 2013;23:169-74. 4. skolarikos a, papatsoris ag, albanis s, laparoscopic urology 2763 assimos d. laparoscopic urinary stone surgery: an updated evidence-based review. urol res. 2010;38:337-44. 5. wang x, li s, liu t, guo y, yang z. laparoscopic pyelolithotomy compared to percutaneous nephrolithotomy as surgical management for large renal pelvic calculi: a meta-analysis. j urol. 2013;190:888-93. 6. bove p, iacovelli v, de nunzio c, et al. critical review of laparoendoscopic singlesite surgery versus multiport laparoscopy in urology. arch esp urol. 2012;65:348-56. 7. kallidonis p, kontogiannis s, kyriazis i, et al. laparoendoscopic single-site surgery in kidney surgery: clinical experience and future perspectives. curr urol rep. 2013;14:496505. 8. tugcu v, simsek a, kargi t, polat h, aras b, tasci ai. retroperitoneal laparoendoscopic single-site ureterolithotomy versus conventional laparoscopic ureterolithotomy. urology. 2013;81:567-72 9. lee jy, kang dh, chung jh, jo jk, lee sw. laparoendoscopic single-site surgery for benign urologic disease with a homemade single port device: design and tips for beginners. korean j urol. 2012;53:165-70. 10. wen x, liu x, huang h, et al. retroperitoneal laparoendoscopic single-site ureterolithotomy: a comparison with conventional laparoscopic surgery. j endourol. 2012;26:366-71. 11. koo dh, park yh, jeong cw, jeong h, kim hh, lee sb. feasibility of laparoendoscopic single-site partial nephrectomy in a porcine model. korean j urol. 2011;52:44-8. 12. antonelli ja, pearle ms. advances in percutaneous nephrolithotomy. urol clin north am. 2013;40:99-113. 13. preminger gm, tiselius hg, assimos dg, et al. 2007 guideline for the management of ureteral calculi. j urol. 2007;178:2418-34. 14. aboumarzouk om, kata sg, keeley fx, mcclinton s, nabi g. extracorporeal shock wave lithotripsy (eswl) versus ureteroscopic management for ureteric calculi. cochrane database syst rev. 2012;(5):cd006029. 15. de la rosette j, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol. 2011;25:11-7. 16. preminger gm, tiselius hg, assimos dg, et al. 2007 guideline for the management of ureteral calculi. eur urol. 2007;52:1610-31. 17. türk c, petřík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 18. lee jw, cho sy, jeong cw, et al. comparison of surgical outcomes between laparoscopic pyelolithotomy and percutaneous figure 4. the postoperative wound of less ureterolithotomy. the patient is left with only a small invisible scar at the umbilicus. comparison of less and conventional laparoscopic stone surgery-park et al. vol 13 no 04 july-august 2016 2764 nephrolithotomy in patients with multiple renal stones in various parts of the pelvocalyceal system. j laparoendosc adv surg tech a. 2014;24:634-9. 19. tefekli a, tepeler a, akman t, et al. the comparison of laparoscopic pyelolithotomy and percutaneous nephrolithotomy in the treatment of solitary large renal pelvic stones. urol res. 2012;40:549-55. 20. al-hunayan a, khalil m, hassabo m, hanafi a, abdul-halim h. management of solitary renal pelvic stone: laparoscopic retroperitoneal pyelolithotomy versus percutaneous nephrolithotomy. j endourol. 2011;25:975-8. 21. white wm, goel rk, swartz ma, moore c, rackley rr, kaouk jh. single-port laparoscopic abdominal sacral colpopexy: initial experience and comparative outcomes. urology. 2009;74:1008-12. 22. raybourn jh, 3rd, rane a, sundaram cp. laparoendoscopic single-site surgery for nephrectomy as a feasible alternative to traditional laparoscopy. urology. 2010;75:100-3. 23. raman jd, bagrodia a, cadeddu ja. singleincision, umbilical laparoscopic versus conventional laparoscopic nephrectomy: a comparison of perioperative outcomes and short-term measures of convalescence. eur urol. 2009;55:1198-204 24. stein rj, berger ak, brandina r, et al. laparoendoscopic single-site pyeloplasty: a comparison with the standard laparoscopic technique. bju int. 2011;107:811-5. comparison of less and conventional laparoscopic stone surgery-park et al. diagnostic yield and complications using a 20 gauge prostate biopsy needle versus a standard 18 gauge needle: a randomized controlled study urological oncology jianlong wang,1 ben wan,1 chao li,2 jianye wang,1 weixin zhao,4 qiang fu,3* kaile zhang3** purpose: to compare and evaluate whether a 20 gauge (20g) biopsy needle maintains a similar detection rate as that of the commonly used 18g needle for transrectal ultrasound-guided prostate biopsy (truspb) aimed at assessing prostate cancer (pca) and decreasing pain and complications. materials and methods: a total of 122 cases with indications of pca were randomly allocated into two groups for this randomized controlled study. truspb was performed randomly using either an 18g or 20g needle for core biopsies (62 cases with 18g and 60 cases with 20g). detection rate, pain, and complications were assessed after the procedure. results: the cancer detection rate in the 18g group (40.3%) did not differ from that in the 20g group (35.0%). however, the number of patients with pain was significantly lower in 20g group (p < .05). the number of patients with self-limiting hematuria decreased in both groups after the biopsy procedure (18g: 38 cases; 20g: 16 cases; p < .0001). hematochezia occurred in 11 cases (9 cases [14.5%] in the 18g group; 2 cases [3.4%] in the 20g group). the number of patients with infection, dysuria, and urinary retention tended to be lower in 20g group. conclusion: use of a 20g needle for truspb yielded a comparable cancer detection rate to that of an 18g needle and led to less local injury, pain, and complications. a larger and more sensitive study is needed to verify our results. keywords: prostatic neoplasms; diagnosis; biopsy; large-core needle; humans; ultrasonography; interventional; image-guided biopsy. introduction prostate cancer (pca), particularly locally advanced/castration-resistant pca, is one of the most common, life-threatening, malignant diseases in elderly men.(1) transrectal ultrasound-guided prostate biopsy (truspb) and the gleason score (gs) are the primary approaches for diagnosing pca early. there is a correlation between the number of biopsy specimens and the detection rate.(2,3) therefore, many factors, such as the number of samples and the size of the needle groove, affect the pca detection rate. many factors that increase the pca detection rate and decrease the complications of truspb have been researched, and the studies indicate that the results of the initial prostate biopsy should be used rather than taking more cores, which would increase the complication rate.(4) current evidence indicates that an initial saturation biopsy scheme is more efficient than an extended scheme for detecting pca, particularly in men with lower serum levels of prostate specific antigen (psa), higher prostate volume (pv), or lower psa density, without increasing complications and the amount of insignificant cancer.(5) bjurlin and colleagues(6,7) suggested that 12-core biopsies ensure the highest detection rate, avoid duplicate sampling, and also provide an adequate diagnosis or differential diagnosis of prostate tissue. however, it is unknown whether the size of the biopsy sample affects the detection rate and grading accuracy. prostate biopsies are usually performed with an 18 gauge (g) needle because a sufficient amount of tissue can be acquired; however, the sizes of truspb biopsy needles have not been standardized.(8,9) cicione and colleagues(10) compared 16g and 18g needles, and reported that needle size did not affect the concordance between biopsy and pathological gs. in the present study, we evaluated whether a smaller 1 department of urology, beijing hospital, beijing, china. 2 department of urology, tongji hospital, shanghai, china. 3 department of urology, affiliated sixth people’s hospital, shanghai jiaotong university, shanghai, china. 4 wake forest institute for regenerative medicine, winston-salem, north carolina, usa. *correspondence: department of urology, affiliated sixth people’s hospital, shanghai jiaotong university, shanghai, china. tel: +86 136 61685257. fax: +86 021 37723037. e-mail: great_z0313@126.com. **correspondence: department of urology, affiliated sixth people’s hospital, shanghai jiaotong university, shanghai, china. tel: +86 021 64369181. fax: +86 021 64369189. email: jamesqfu@aliyun.com. received may 2015 & accepted september 2015 vol 12 no 05 september-october 2015 2329 (20g) needle could achieve similar detection rates, pain scores, and complications compared to the standard 18g needle. a prospective, single-blinded, and randomized controlled study was conducted to compare the outcomes of patients biopsied using 18g or 20g needles to detect pca. materials and methods study subjects this randomized controlled study was approved by the ethics committee of beijing hospital, china. patients with suspicious pca were referred exclusively to our hospital’s outpatient clinical department of urology. the indications for truspb were from the 2014 chinese guidelines of urology: psa > 4 ng/ml,(2) presence of a prostatic nodule on digital rectal examination (dre) with a particular psa level, and an imaging abnormality on ultrasound, computed tomography scan, or magnetic resonance imaging with a particular psa level. all eligible patients gave informed consent. in all, 12 patients were excluded from the study for various reasons, and 122 who were suspected to have pca were randomly assigned into two groups. the randomization was performed using the closed-envelope selection method, and the envelopes were kept in the operating room before the procedures. sixty-two patients were assigned to group 1 (18g needles), and sixty patients were assigned to group 2 (20g needles). a flow diagram for the study is displayed in figure 1. age, psa level, pv, and dre-positive rates were not different between the two groups (table 1). all eligible patients underwent a preoperative coagulation test to exclude those with coagulation abnormalities and other related diseases. a feasible truspb procedure was performed only for patients who had stopped taking aspirin at least 1 week before the operation and had stopped clopidogrel (plavix) at least 2 weeks preoperatively. procedures after routine preoperative preparation, the patient was placed on the left hip, with knees and hips flexed 90°. a dre was performed and the perianal skin and rectum were disinfected with iodine. lidocaine gel was placed in the rectum. a medical ultrasound probe was covered with a condom, and the prostate biopsies were taken as systematic 12-core biopsies and an extra one or two core needle biopsy specimens were added during the trus-guided biopsy if any abnormal sites were detected by ultrasound. the 12 cores were evenly distributed table 1. clinical characteristics of study patients. variables 18g (n = 62) 20g (n = 60) t value p value age (year) 69.27 ± 10.62 68.03 ± 8.55 0.710 .258 psa (ng/ml) mean (sd) 55.42 ± 188.86 29.60 ± 82.87 0.972 .069 median (range) 20.6 (0.713-78.26) 22.3 (2.755-366.61) pv (ml) 51.65 ± 34.65 52.42 ± 27.47 0.136 .173 dre positive rate, % 40.5 38.9 0.223 .824 abbreviations: psa, prostate specific antigen; pv, prostate volume; dre, digital rectal examination. abbreviations: psa, prostate specific antigen; bph, benign prostate hyperplasia; pca, prostate cancer. data are presented as numbers (%). variables 18g (n = 62) 20g (n = 60) t value p value bph pca bph pca psa < 4 ng/ml 9 (75.0) 3 (25.0) 11 (91.7) 1 (8.3) 1.076 .294 4.1-10 ng/ml 14 (66.7) 7 (33.3) 18 (72.0) 7 (28.0) 0.384 .703 10.1-20 ng/ml 12 (66.7) 6 (33.3) 10 (71.4) 4 (28.6) 0.280 .782 > 20 ng/ml 2 (18.2) 9 (81.8) 0 (0) 9 (100) 1.342 .198 total 37 (59.7) 25 (40.3) 39 (65.0) 21 (35.0) 0.602 .548 gleason score 6 17 (68) 14 (66.6) 0.273 .604 ≥ 7 8 (32) 7 (33.3) 0.043 .835 table 2. prostate cancer detection rate in the groups. prostate biopsy needle: 20g vs. 18g-wang et al. urological oncology 2330 around four vertical planes: right lateral, right medial, left medial, and left lateral. three biopsy cores from each plane were located at the apex, middle, and base of the prostate, respectively.(11,12) the prostate tissue specimens were fixed in 10% formalin and labeled with the biopsy site. one experienced pathologist reviewed all histological specimens and determined the gs scores. a pain and bleeding questionnaire(13) was administered single-blindly to patients 20 min after truspb. a dre was performed, the rectal biopsy site was pressed for 5 min, and iodine gauze was packed into the rectal puncture points. the patients were requested to remove the gauze 4–6 h after the biopsy. all patients received prophylactic antibiotic (levofloxacin) according to the american urological association best practice policy. (14) further symptomatic treatment was provided if postoperative body temperature was > 37.5°c, or symptoms such as severe hematuria, hematochezia, urine retention, or obvious discomfort were observed. statistical analysis dichotomous variables were analyzed with the chisquare test, and continuous variables were compared to student’s t-test using statistical package for the social science (spss inc, chicago, illinois, usa) version 14.0. p-values < .05 were considered significant. results detection rate a total of 122 patients were recruited; 46 (37.7%) cases were diagnosed with pca (25 [40.3%] in the 18g group and 21 [35.0%] in the 20g group) (table 2). pca detection rate was not different between the two groups (p > .05). pain pain was assessed immediately after the puncture according to the wong–baker facial expression scale (table 3). mean pain score was 1.821 ± 1.372 in the 18g group and 2.11 ± 1.580 in the 20g group. the differences in the three marks were significant in both groups (p < 0.05). complications gross hematuria occurred in 54 cases (44.3%): 38 patients (61.3%) in the 18g group and 16 (26.7%) in the 20g group (p = .0001). it usually occurred in the first urination after the biopsy, but all cases were self-limiting. no cases of severe bleeding were detected. no differences in blood hemoglobin or red blood cell count were observed between the first postoperative examination in the early morning and that at admission (p > .05). all cases received routine antibiotics (quinolones) postoperatively; seven cases (5.7%) developed infection accompanying a positive blood culture and/or a positive urine culture (6 [9.7%] in the 18g group and 1 [1.7%)] in the 20g group; p = .0572). five cases (4.1%) developed fever (mean, 39°c; mean white blood cell count, 15.46 × 109/l; 4 [6.5%] in the 18g group and 1 [1.7%] in the 20g group; p = .1826), and all cases progressed to sepsis. fever often developed within the first 3 days after biopsy. severe infection symptoms were fever, chills, sweating, fatigue, accelerated heart rate, loss of appetite, and muscle aches. there were no cases of systolic blood pressure < 90 mmhg. five patients recovered from infection after receiving 4–9 days of carbapenems or teicoplanin. no septic shock or death occurred. eleven cases (9.0%) developed hematochezia (9 [14.5%] patients in the 18g group and 2 [3.4%] in the 20g group; p = .0311). five cases (4.1%) developed dysuria. one case (1.6%) in the 18g group developed urinary retention (4 [6.5%] in the 18g group and one [1.7%] in the 20g group; p = .1826). the number of infectious complications was significantly different between the groups (p < .05) (table 4). discussion truspb is the primary approach for preoperative pathological diagnosis of pca. truspb images all prostate tissue clearly and simultaneously monitors the entire puncture process, allowing doctors to accurately obtain target tissue.(15) in this study, we prospectively evaluated results after using a smaller biopsy needle (20g) compared to the 18g needle, which is widely used for truspb. the 18g needle had a diameter of 1.3 mm, length of 25 cm, and specimen slots of 1.9 cm. it can harvest 25.21 mm3 of prostate tissue. in contrast, table 3. evaluation of pain using facial expressions and the wong–baker facial expression scale. marks 18g (n = 62) 20g (n = 60) χ² value p value 0-4 49 58 8.793 .003 5-7 9 2 4.887 .027 8-10 4 0 4.002 .045 data are presented as numbers (%). variables 18g (n = 62) 20g (n = 60) χ² value p value hematuria 38 (61.3) 16 (26.7) 14.82 .0001 infection 6 (9.7) 1 (1.7) 3.62 .0572 fever (> 37.5°c) 4 (6.5) 1(1.7) 1.78 .1826 hematochezia 9 (14.5) 2 (3.4) 4.65 .0311 dysuria 4 (6.5) 1 (1.7) 1.7762 .1826 table 4. complications in both study groups. prostate biopsy needle: 20g vs. 18g-wang et al. vol 12 no 05 september-october 2015 2331 a 20g biopsy needle has a diameter of 1.1 mm, length of 20 cm, sampling groove of 1.9 cm, and is also used for lung and thyroid biopsies. it samples less tissue, which could avoid unnecessary injury and complications. in the present study, all patients underwent the same procedure with different needles, and both procedures yielded satisfactory tissue samples. the 12-core puncture results showed an overall pca detection rate of 37.7%, which is comparable to a retrospective truspb analysis of patients in our medical center from 1996 to 2007 in which the pca detection rate was 39.8%. in the present study, the detection rates of the 18g and 20g groups were 40.3% and 35.0%, respectively (p > .05). thus, the smaller needle did not significantly decrease the detection rate. mean gs was also similar between the two groups. a moderate direct linear relationship has been reported between biopsy scores and prostatectomy specimens. however, underestimates of the actual gs of a radical prostatectomy specimen are common in low-grade tumors.(16) in our study, we found no differences in the gs during prostatectomy between the groups. most of the 122 cases complained of piercing-like pain after the truspb procedure. thirteen patients complained of pain but completed the procedure. these symptoms were relieved after a short break and without providing additional analgesics.(17) the pain scores were significantly different between the groups (p < .05). truspb pain was mainly caused by the insertion of the probe, penetration of the rectal mucosa with the biopsy needle, and stimulation of the prostate nerve when the needle punctured the prostate capsule. (17) common postoperative complications of truspb are hematuria, blood in the stool, acute urinary retention, blood in the sperm, and a vagal reflex.(18) therefore, it might be necessary to minimize local injury with more careful handling, including using a thinner biopsy needle. infections were the most serious complication. lee and colleagues(19) reported that most surgical complications during truspb are mild and without sequelae. despite the preoperative bowel preparation, a small biopsy needle could introduce bacteria into the prostate or blood. we found significant differences in the frequencies of hematuria and hematochezia between the two groups (p < .05). the most frequent complication was gross hematuria, which was self-limiting and occurred mostly during the first urination but recovered after observation or symptomatic treatment. the incidence of gross hematuria was 44.3%, which may have been related to older age, anticoagulant use, inefficient pressure hemostasis, and the different puncture techniques. postoperative infection-related complications of truspb include asymptomatic bacteriuria, urinary tract infection, febrile urinary tract infection, and sepsis.(20) postoperative prophylactic antibiotics reduce the majority of infections, but rectal bacteria entering the blood can cause sepsis. in this study, seven cases (5.7%) developed serious infections, and all cases developed sepsis. however, no case proceeded to septic shock. our results suggest that a 20g biopsy needle might reduce the incidence of postoperative infection compared to the commonly used 18g needle. truspb using a 20g needle is a safe, simple, and less invasive way to improve early diagnosis and differential diagnosis of pca from prostate disease. it not only maintained the pca detection rate but reduced rectal and prostate injury, compared to the 18g needle. it could potentially decrease the incidence of complications, including hematuria, pain, and infection. this is the first study to evaluate a 20g needle for truspb. we discovered that the pca detection rate was maintained using this needle. however, a few limitations of this study should be mentioned. first, the gs in both groups was determined only by the biopsy sample and was not verified with a sample taken during prostatectomy to confirm the accuracy of biopsies with different needles. second, chinese men appear to have lower pca detection rates compared to western men when using a psa cutoff value > 4 ng/ml, which may have influenced the positive rate. however, no specific psa level has been validated for chinese men. third, the number of patients in this study was small. although the detection rates were 25% vs. 8% in the group with psa < 4 ng/ml, the difference was not significant. last, although the indicators for randomization including psa level, pv, and dre-positive rate were not different in this study (p > .05), the detection rate may not be a valid outcome in a series of patients with high-risk pca (mean psa > 55 ng/ml), in which cancer volume is sure to be high. conclusions a 20g biopsy needle had a comparable pca detection rate during truspb compared to the 18g biopsy needle. it also decreased local injury, pain, and complications. further controlled studies with larger sample sizes and a more precise randomization methods are needed to draw a final conclusion. acknowledgment jianlong wang and ben wan contributed equally to this study. conflict of interest none declared. references 1. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part ii: treatment of advanced, relapsing, and castration-resistant prostate cancer. eur urol. 2014;65:467-79. 2. ekin rg, zorlu f, akarken i, et al. anterior apical cores in the initial prostate biopsy does not increase detection of significant prostate cancer. urol j. 2015;12:2084-9. 3. gleason df, mellinger gt. prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. j urol. 1974;111:58-64. 4. yoon bi, shin ts, cho hj, et al. is it effective to perform two more prostate biopsies according to prostate-specific antigen level and prostate volume in detecting prostate cancer? prospective study of 10-core and 12core prostate biopsy. urol j. 2012;9:491-7. 5. jiang x, zhu s, feng g, et al. is an initial saturation prostate biopsy scheme better than an extended scheme for detection of prostate cancer? a systematic review and metaprostate biopsy needle: 20g vs. 18g-wang et al. urological oncology 2332 prostate biopsy needle: 20g vs. 18g-wang et al. analysis. eur urol. 2013;63:1031-9. 6. bjurlin ma, carter hb, schellhammer p, et al. optimization of initial prostate biopsy in clinical practice: sampling, labeling and specimen processing. j urol. 2013;189:203946. 7. eichler k, hempel s, wilby j, myers l, bachmann lm, kleijnen j. diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. j urol. 2006;175:1605-12. 8. divrik rt, eroglu a, sahin a, zorlu f, ozen h. increasing the number of biopsies increases the concordance of gleason scores of needle biopsies and prostatectomy specimens. urol oncol. 2007;25:376-82. 9. divrik rt, eroglu a, sahin a, zorlu f, ozen h. extended prostate needle biopsy improves concordance of gleason grading between prostate needle biopsy and radical prostatectomy. urol oncol. 2007;25:376-82. 10. cicione a, cantiello f, de nunzio c, tubaro a, damiano r. needle biopsy size and pathological gleason score diagnosis: no evidence for a link. can urol assoc j. 2013;7:e567-71. 11. xu g, yao m, wu j, et al. diagnostic value of different systematic prostate biopsy methods in the detection of prostate cancer with ultrasonographic hypoechoic lesions a comparative study. urol int. 2015;95:183-8. 12. miyoshi y, furuya m, teranishi j, et al. comparison of 12and 16-core prostate biopsy in japanese patients with serum prostatespecific antigen level of 4.0-20.0 ng/ml. urol j. 2014;11:1609-14. 13. garra g, singer aj, domingo a, thode hc jr. the wong-baker pain faces scale measures pain, not fear. pediatr emerg care. 2013;29:17-20. 14. bhanot n, sahud ag, sepkowitz d. best practice policy statement on urologic surgery antimicrobial prophylaxis. urology. 2009;74:236-7. 15. hossack t1, woo hh. acceptance of repeat transrectal ultrasonography guided prostate biopsies with local anaesthesia. bju int. 2011;107 suppl 3:38-42. 16. tavangar sm, razi a, mashayekhi r. correlation between prostate needle biopsy and radical prostatectomy gleason gradings of 111 cases with prostatic adenocarcinoma. urol j. 2004;1:246-9. 17. hizli f, argun g, özkul f, et al. novel approach for pain control in patients undergoing prostate biopsy: iliohypogastric nerve block with or without topical application of prilocainelidocaine: a randomized controlled trial. urol j. 2015;12:2014-9. 18. hwang ec, jung si, seo yh, et al. risk factors for and prophylactic effect of povidone-iodine rectal cleansing on infectious complications after prostate biopsy: a retrospective cohort study. int urol nephrol. 2015;47:595-601. 19. lee sh, chen sm, ho cr, chang pl, chen cl, tsui kh. risk factors associated with transrectal ultrasound guided prostate needle biopsy in patients with prostate cancer. chang gung med j. 2009;32:623-7. 20. shakil j, piracha n, prasad n, et al. use of outpatient parenteral antimicrobial therapy for transrectal ultrasound-guided prostate biopsy prophylaxis in the setting of communityassociated multidrug-resistant escherichia coli rectal colonization. urology. 2014;83:710-3. vol 12 no 05 september-october 2015 2333 urological oncology anterior apical cores in the initial prostate biopsy do not increase detection rate of significant prostate cancer rahmi gokhan ekin,1* ferruh zorlu,1 ilker akarken,1 zubeyde yildirim,2 huseyin tarhan,1 gokhan koc,1 ulku kucuk,2 umit bayol2 purpose: to examine the effect of routine sampling anterior apical cores in the initial prostate biopsy among patients that 14-cores of prostate biopsy (pb) planned. materials and methods: five-hundred twenty-eight patients with increased prostate-specific antigen (psa) levels and/or abnormal digital rectal examination underwent transrectal ultrasound and initial pb between november 2012 and october 2013. we performed routine 12-cores extended pb, plus 2 anterior apex samples that were taken from the junction of urethra and apex of the prostate. site-specific and unique cancer detection rate, tumor characteristics, the presence of clinically insignificant prostate cancer (pca) (clinical stage ≤ t1, serum psa level of < 10 ng/ml, biopsy gleason score ≤ 6, number of positive biopsy cores ≤ 3 and no core with > 50% involvement) and biopsy-related pain were evaluated. results: pca was detected in 147 of 451 patients (32.6%). the lateral base of the prostate was the most affected area with 128 of 451 patients (28.3%), followed by unique cancer detection, with 17 of 40 patients (43.5%). anterior apex (n = 6) was in third place after the lateral apex (n = 8). the patients diagnosed by anterior apex cores were all clinically insignificant pca. the cancer diagnosis rate would be 31% if 12-cores biopsy was used, but the rate was found to be 32.6% in 14-cores biopsy (p = .016). average biopsy pain, right anterior apex biopsy pain, and left anterior apex biopsy pain were found to register at 0.61, 1.06 and 1.08 points in the visual analog scale pain score, respectively. when right and left anterior apex biopsy pain is compared to average biopsy pain, the pain level was found to be statistically significantly higher in the biopsies of right and left anterior apex (p = .040 and p = .042, respectively). conclusion: the gold standard for the diagnosis of pca is at least 8 cores pb. according to our results, although most pca diagnosis is carried out with 14-cores pb, it should not be forgotten that these patients might have clinically insignificant pca. keywords: prostatic neoplasms; diagnosis; biopsy; needle; methods; prostate; pathology. introduction there were 679,000 new cases of prostate cancer (pca) worldwide in 2002.(1) estimated age-standardized incidence rates were 119.9 and 61.6 per 100,000 male population in the united states and europe, respectively. (1) transrectal ultrasound guided (trus) prostate biopsy (pb) is suggested as the gold standard for the diagnosis of pca.(2,3) at least 8 cores pb is recommended by european association of urology (eau) guidelines, and there is no consensus about the number of optimal cores.(2) performing pb with a greater number of cores is considered to increase the cancer detection rate, despite increasing the rate of adverse effects. however, this hypothesis is controversial, as it is the first pb, and has not yet been verified.(1,4-8) the examination of radical prostatectomy and cystoprostatectomy specimens has proved that the detection of pca is more related to the location of the cores than the number of the cores conducted in pb.(9,10) for this reason, many authors recommend that the peripheral zone, in which most cases of pca develop, be sampled appropriately.(9,11,12) it was advocated that the traditional sextant pb yields poor sampling for anterior of prostate.(13) several studies have recommended anterior apex sampling to increase pca detection rate.(14) during a digital rectal examination (dre), there may be difficulties in palpating the apical anterior cancers that extend and develop at the apex of the peripheral prostate zone from anteriorly to the distal prostatic urethra.(14,15) instead of passing through the rectum, the apical core biopsies may transverse the anus, which is sensitive to pain because of the sensorial pain fibers, therefore these biopsies are considered as more painful, and as a result, some urologists might avoid this procedure to minimize pain.(16) in this study, the primary aim was to examine the effect of taking cores of anterior apical on the initial diagnosis of pca among patients waiting to undergo 14-cores of trus pb. the secondary aim was to determine the pain levels that related to additional anterior apical biopsies. materials and methods study participants departments of urology1 and pathology,2 tepecik teaching and research hospital, izmir, turkey. *correspondence: tepecik teaching and research hospital, gaziler caddesi, 35000, yenisehir, izmir, turkey. tel: +90 505 3157091. fax: +90 232 4330756. e-mail: gokhanekin@gmail.com. received october 2014 & accepted march 2015 urological oncology 2084 vol 12. no 02 march-april 2015 2085 all 4052 patients, who underwent trus pb between september 2007 and june 2014, were included in a prospectively collected database. the study, conducted between november 2012 and october 2013, included 528 patients with the serum prostate specific antigen (psa) level over 2.5 ng/ml, or with an abnormality in dre, and who were waiting to undergo trus pb for the first time. thirteen patients aged over 70 years and with serum psa level under 10 ng/ml, 8 patients with the life expectancy of less than 10 years and 56 patients with the serum psa level over 50 ng/ml were excluded from the study (figure). the life expectancy was determined by the nomogram for pca.(17) the demographic and tumor-related data of the patients were assessed. pb was conducted with an 18-gauge core biopsy needle in an appropriate outpatient operation room and under appropriate antibiotic prophylaxis, by using the end fire ultrasound probe and after performing periprostatic nerve block with 10 ml 1% of lidocaine. all trus pb was performed by the same experienced urologist. each core was put into tubes containing 10% of formaldehyde, and labeled with locations from which they were taken. each core was evaluated by the same experienced pathologist (ub), according to the gleason grading system. clinically insignificant pca was defined as clinical stage ≤ t1, psa < 10 ng/ml, biopsy gleason score ≤ 6, number of positive biopsy cores ≤ 3, and no core with > 50% involvement. the study protocol was approved by the local ethics committee, and informed consents were provided by all patients. prostate biopsy procedure three cores from lateral apex, mid-gland, and base of the prostate in the lateral plane and 3 cores from lateral apex, mid-gland, and base of the prostate in the parasagittal plane were taken from the right side of all patients. then the same procedure was performed on the left side. following this, the anterior apex samples were taken from the junction of urethra and apex. firstly, right anterior apical core was taken and the same procedure was performed on the left side. in order to evaluate the biopsy-related pain, 10 points of linear visual analog scale (vas) were used by the physician during the variables total benign cancer p value number of patients (%) 451 304 (67.4) 147 (32.6) _____ patients’ age (year), mean ± sd (range) 63.33 ± 6.27 62.13 ± 6.11 65.81 ± 5.88 < .05 (40-75) (40-75) (49-75) ipss, mean ± sd (range) 10.30 ± 6.88 10.09 ± 6.65 10.71 ± 7.32 .377 (0-33) (0-27) (0-33) serum psa (ng/ml), mean ± sd (range) 9.84 ± 7.74 8.41 ± 5.60 12.80 ± 10.32 < .05 (1.16-47.5) (1.16-37.3) (2.66-47.5) psa subgroups < 10 ng/ml, n (%) 308 (68.3) 232 (51.4) 76 (16.9) 10-20 ng/ml, n (%) 88 (19.5) 47 (10.4) 41 (9.1) < .05 21-50 ng/ml, n (%) 55 (12.2) 25 (5.5) 30 (6.7) prostate volume (cm3), mean ± sd (range) 45.20 ± 25.16 49.35 ± 26.49 36.60 ± 19.62 < .05 (10.39-216.25) (12.57-216.25) (10.39-129.44) dre abnormality, n (%) yes 69 (15.3) 25 (5.5) 44 (9.8) < .05 no 382 (84.7) 279 (61.9) 103 (22.8) total cores length (mm), mean ± sd (range) 18.30 ± 3.24 18.03 ± 3.26 18.84 ± 3.12 .012 (6.60-29.10) (6.60-29.10) (9.90-26.10) table 1. demographic and clinical characteristics of study subjects. abbreviations: psa, prostate-specific antigen; dre, digital rectal examination; ipss, international prostate symptom score; sd, standard deviation. variables total benign cancer p value* dre 1.15 ± 1.83 1.15 ± 1.74 1.14 ± 2.00 .920 probe insertion 3.03 ± 2.63 3.04 ± 2.46 3.00 ± 2.95 .872 periprostatic 0.47 ± 1.11 0.48 ± 1.11 0.46 ± 1.11 .875 nerve block 12-core biopsy 0.61 ± 1.23 0.59 ± 1.19 0.65 ± 1.30 .604 right anterior 1.06 ± 1.49 1.12 ± 1.49 0.93 ± 1.49 .215 apex biopsy left anterior 1.08 ± 1.55 1.16 ± 1.58 0.90 ± 1.48 .100 apex biopsy table 2. comparison of vas scores between prostate cancer and benign groups. abbreviations: vas, visual analog scale; dre, digital rectal examination. * p values between prostate cancer and benign groups. anterior apical cores in the initial prostate biopsy-ekin et al. variables total unique anterior apex other tumors p value number of patients with adenocarcinoma (%) 147 6 (4.1) 141 (95.9) _____ serum psa (ng/ml), mean ± sd (range) 12.80 ± 10.32 4.92 ± 1.37 13.13 ± 10.4 < .05 (2.66-47.5) (3.06-6.67) (2.66-47.50) prostate volume (cm3), mean ± sd (range) 36.60 ± 19.62 41.81 ± 4.51 36.38 ± 19.98 .045 (10.39-129.44) (34.56-47.98) (10.39-129.44) number of positive cores, mean ± sd 4.97 ± 4.32 1 ± 0.0 5.13 ± 4.34 < .05 total cores length (mm), mean ± sd (range) 18.84 ± 3.12 19.26 ± 2.06 18.83 ± 3.16 (9.90-26.10) (17.60-22.90) (9.90-26.10) .740 tumor length (mm), mean ± sd (range) 2.82 ± 4.03 (1.00) 0.15 ± 0.17 2.94 ± 4.08 < .05 (0.07) (1.08) gleason score of patients (n) 3+3 97 6 91 3+4 13 13 4+3 17 17 4+4 10 10 4+5 7 7 5+4 3 3 table 3. comparison of tumors between located unique anterior apex and other tumors. abbreviations: psa, prostate-specific antigen; sd, standard deviation. variables number of positive core number of unique positive core 14-core biopsy scheme right lateral apex 53 (11.8) 7 right lateral mid 61 (13.5) 1 right lateral base 60 (13.3) 7 right medial apex 36 (8.0) _____ right medial mid 50 (11.1) 2 right medial base 46 (10.2) _____ left lateral apex 51 (11.3) 1 left lateral mid 57 (12.6) 2 left lateral base 68 (15.1) 10 left medial apex 49 (10.9) 2 left medial mid 62 (13.7) _____ left medial base 49 (10.9) 1 right anterior apex 46 (10.2) 3 left anterior apex 42 (9.3) 3 unified biopsy site lateral apex 104 (23.0) 8 lateral mid 118 (26.1) 3 lateral base 128 (28.3) 17 medial apex 85 (18.8) 2 medial mid 112 (24.8) 2 medial base 95 (21.0) 1 anterior apex 88 (19.5) 6 table 4. frequency of prostate cancer detection among all biopsy sites.* * data are presented as no (%). urological oncology 2086 anterior apical cores in the initial prostate biopsy-ekin et al. vol 12. no 02 march-april 2015 2087 procedure. the pain caused by the rectal probe entrance during the periprostatic block, and during the standard 12-cores biopsy conduction was evaluated. in addition, the pain levels during the right and left anterior apical cores conduction were recorded separately. statistical analysis for the parametric conditions, student’s t-test for nonparametric conditions mann-whitney u test and for qualitative data the χ² test or fisher exact test were used. the possibility of the biopsy diagrams detecting pca was conducted with mcnemar’s test. p value < .05 was considered as statistically significant. all data were analyzed using statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. results four-hundred fifty-one patients were included in the study. trus pb and basic data of the study group is shown in the table 1. the average age of patients was 63.33 years (range, 40-75). the average international prostate symptom score (ipss) of patients were found as 10.30 (range, 0-33). nine patients had urethral catheters, therefore their ipss could not be evaluated. the average serum psa value was 9.84 ng/ml (range, 1.16-47.5), and the average prostate volume was determined as 45.20 cm³ (range, 10.39-216.25). the average probe pain was determined as 3.03, the average biopsy pain following periprostatic nerve block was determined as 0.61, and there was statistically significant difference between the conditions (p < .05). the average anterior apex biopsy pain was 1.06 on the right side and 1.08 on the left. when both were compared separately to average biopsy pain, pain levels were found to be higher and statistically significant (p = .040 and p = .042). there was no statistically significant difference in vas scores between detected pca and benign groups (table 2). the total core of trus pb length was identified as 18.30 mm (range, 6.60-29.10). of the total number of patients undergoing biopsy, 147 (32.6%) were diagnosed with pca (table 3). pca was detected in an average of 4.97 (range, 1-14) cores. serum psa values of 147 (32.6%) patients were examined in pca detected group, and it was seen that 76 (51.8%) were under 10 ng/ml, and 41 (27.8%) were between 10-20 ng/ml and 30 (20.4%) were between 20-50 ng/ml. when a subgroup of the patients diagnosed with pca was examined, it was found that the gleason score of 64 patients (43.5%) was 6 and the serum psa level was under 10 ng/ml. according to the 14 cores pb diagram, cancer was detected in the left lateral base core in 69 of the 451 patients, and this area has the highest pca detection rate, with 15.1% (table 4). the cancer detection rate was to be found 10.2% for the right anterior apex, and 8.3% for the left. when biopsy sites were assessed in combination, the contribution of the lateral cores to pca diagnosis found that the highest and most important was the lateral base core, with 28.3%. the contribution of anterior apex to diagnosis was found to be 19.5%. in 88 of 450 patients diagnosed pca in the anterior apex cores, the gleason score of anterior apex cores were correlated with other detected cancer cores. there was no upgraded the gleason score due to the anterior apex biopsy. thirty-nine patients (8.6%) were detected with unique pca involvement when one core was examined, and among these, the left lateral base yields the highest rate of detecting pca, with a total of ten patients. when the results are examined according to the unified biopsy site, while the lateral base (n = 17) was found the highest in diagnosing, anterior apex (n = 6) remained in third place after the lateral apex. in addition, in one patient, pca was detected in both left and right anterior apex. thirty-seven patients (94.8%) were diagnosed with unique pca, and gleason score was 3+3 pca. for the other two patients, gleason score was found as 4+3 pca. lateral base core had the highest rate of detecting unique pca (n = 17). if a 12-cores pb was conducted, pca diagnosis rate would be 31%, and by adding the anterior apex pb, this rate increased to 32.6%, which was found to be statistically significant (p = .016). for all 6 patients diagnosed by anterior apex cores, gleason score was found 6, and average serum psa value was 7.53 ± 7.01 ng/ml (range, 3.06-21.18). for the patient diagnosed with pca by both anterior apex, serum psa value was found to be 21.18 ng/ml, the maximum percentage of pca in the core was 70%, and the gleason score was 3+3. this patient underwent radical retropubic prostatectomy, and gleason score was raised to 4+3. when the seven patients diagnosed with pca by only anterior apex were compared with another 140 patients diagnosed with pca, there were no statistically significant differences in age (p = .154), serum psa level (p = .167), dre findings (p = .675), prostate volume (p = .730), vas score, total average of core length (p = .976) and gleason score (p = .096), the only significant difference was in the ipss (3.71 vs. 11.07, p < .05). when comparing the patients diagnosed with pca in anterior apex with other patients diagnosed with pca in standard 12-core, there were no statistically significant differences in variables. discussion figure. prostate biopsy cohort flow chart. anterior apical cores in the initial prostate biopsy-ekin et al. the diagnosis of pca depends on adequately sampling the zones in which cancer is mostly located. early and decisive diagnosis rate has considerably risen in the last 20 years due to sextant biopsy protocol. two basic modalities, i.e. the change of biopsy location and increase of total biopsy cores, have been applied in order to prevent high false-negative.(1,8) nowadays, even if there is no consensus about the ideal schema for the initial pb, most authors recommend minimum 8-cores pb.(1,2,8,12) it is considered that core location is more important for detection of pca. according to our knowledge, apical anterior gland was not sampled in past biopsy regimens. anterior compartment of prostate includes anterior horns of the peripheral, anterior transitional and fibromuscular zones. chen and colleagues tested biopsy strategies with a computer simulation model using 180 radical prostatectomy specimens. according to this, the highest pca detection rate was found in the anterior horn.(18) the study of bott and colleagues investigated over 547 radical prostatectomy specimens, and indicated that 21% of pca was found to have mainly anterior distribution. (19). many other studies also have confirmed that clinically significant pca exists in the anterior of the prostate. takashima and colleagues examined tumor maps of 62 japanese patients, whose clinical stage was t1c using a computer-assisted imaging technique.(13) even though an equal distribution of pca between anterior and posterior was found, the authors indicated that nonpalpable lesions are denser on the apex, and the primary extent of these tumors was in the anterior half of the prostate. they found that the efficiency of traditional sextant pb is low for determination of pca settling as anterior. eskicorapci and colleagues presented pca detection rates in different zones of prostate, and 42.6% involvement in the prostate apex was detected.(20) wright and ellis proposed anterior apical biopsy because it increases total cancer detection, and they found that unique cancer detection rate of anterior apical biopsy was 17%.(21) this was a retrospective study with 12-cores pb, and also included first or repeating biopsy. however, apical biopsies have been conducted from under 3-5 mm of the prostatic apex. in contrast to our study, clinically significant pca was detected by unique anterior apical biopsy, and no differences could be found in terms of serum psa level, gleason score, prostate volume and clinical stage.(21) although apical anterior sampling results in a slight increase in total pca diagnosis, which has no statistical significance, meng and colleagues stated that it was possible to diagnose 2% of patients with only apical anterior biopsy.(22) this contribution has become prominent in men whose prostate volume was under 50 cc, serum psa value was low and had a normal dre. orikasa and colleagues examined the first or repeating pb data of 931 japanese patients retrospectively, and in 252 patients who had undergone their first pbs, pca detection rate was 51% on the apical anterior peripheral zone. despite only a slight increase in total pca diagnosis detected with apical anterior biopsy, this increase was approximately 5.2% in first biopsy patients.(23) this effect has been found statistically significant in patients with a prior negative and normal dre. patient groups of these studies must be examined carefully, because the significance of the anterior apex might be different in the first and repeating biopsy. supporting this view, presti states that even in the case that apex and lateral apex are sampled using extended pb, these additional cores are important, especially in repeating biopsies.(24) moussa and colleagues have prospectively evaluated 181 patients whose initial pb was performed. they indicated that 14-cores pb determined significantly greater levels of pca than 12-cores pb (47.5% vs. 44.2%). they found that the tumor features of pca, which were detected to a limited extent on anterior apex, were similar to other pca. (14) in another study, sazuka and colleagues evaluated factors that predict preoperative tumor on prostate apex via radical prostatectomy specimen in 158 japanese patients. psa value, gleason score, tumor stage and total tumor volume were not found to be preoperative factors that predict positive pb on the apex.(25) in another recently published retrospective study, gleason score ≥ 7 was found to be more likely to be detected with 14-cores pb.(26) we showed increased cancer detection rate with 14-cores pb, and unlike other studies, we detected clinically insignificant pca with additional anterior apical cores. on the other hand, 37 of the 39 patients (94.8%) with unique pca were clinically insignificant pca. in patients with a unique pca, pca is often in small volume (< 0.5 ml), therefore these cases tend to be insignificant. most urologists believe that apical pb is more painful, due to the pain fibers of the inferior rectal nerve below the dentate line. in a study involving 60 patients, jones and zippe have indicated that avoiding this nerve with rectal sensation test significantly decreases vas score (1.25 vs. 2.28) of apical pb.(16) meng and colleagues stated that anterior apical biopsy is tolerated well, and anterior apical sampling causes no increase in pain levels. (22) however, in this study, no method for evaluating pain, such as vas, was used. in contrast, in our study, it was found that anterior apical biopsy vas score was almost 55% greater than normal biopsy vas (p < .05). limitations of our study include its retrospective nature, the use of a single tertiary institution and a single racial group. in this study, the complication rate has not been examined. pain assessment was performed during procedure. the duration of the pain was not taken into consideration. for patients on whom pca was detected, it is not clear whether or not these cancers are clinically significant, as radical prostatectomy was not performed on all. however, in the literature, study population in this area focuses on japanese and american populations, therefore, this study presents different patients from a different racial background. although the addition of anterior apex to initial pb increases the diagnosis of pca, patients who were diagnosed with pca with anterior apical cores in the first pb were clinically insignificant pca. conclusion according to our results, although greater levels of more detailed/accurate pca diagnosis can be achieved with 14-cores pb, it should not be forgotten that patients who were diagnosed pca with anterior apical cores in the first pb, potentially may have clinically insignificant pca. it should also be kept in mind that the addition of anterior apex cores to routine 12-cores pb increases the pain of the pb procedure. conflict of interest none declared. references 1. miyoshi y, furuya m, teranishi j, et al. urological oncology 2088 anterior apical cores in the initial prostate biopsy-ekin et al. vol 12. no 02 march-april 2015 2089 comparison of 12and 16-core prostate biopsy in japanese patients with serum prostatespecific antigen level of 4.0-20.0 ng/ml. urol j. 2014;11:1609-14. 2. heidenreich a, bellmunt j, bolla m, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and treatment of clinically localised disease. eur urol. 2011;59:61-71. 3. stamatiou kn. elderly and prostate cancer screening. urol j. 2011;8:83-7. 4. irani j, blanchet p, salomon l, et al. is an extended 20-core prostate biopsy protocol more efficient than the standard 12-core? a randomized multicenter trial. j urol. 2013;190:77-83. 5. ankerst dp, till c, boeck a, et al. the impact of prostate volume, number of biopsy cores and american urological association symptom score on the sensitivity of cancer detection using the prostate cancer prevention trial risk calculator. j urol. 2013;190:70-6. 6. ukimura o, coleman ja, de la taille a, et al. contemporary role of systematic prostate biopsies: indications, techniques, and implications for patient care. eur urol. 2012;63:214-30. 7. scattoni v, zlotta a, montironi r, schulman c, rigatti p, montorsi f. extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature. eur urol. 2007;52:1309-22. 8. yoon b il, shin ts, cho hj, et al. is it effective to perform two more prostate biopsies according to prostate-specific antigen level and prostate volume in detecting prostate cancer? prospective study of 10-core and 12-core prostate biopsy. urol j. 2012;9:491-7. 9. stamey ta. making the most out of six systematic sextant biopsies. urology. 1995;45:212. 10. abdollahi a, ayati m. frequency and outcome of metaplasia in needle biopsies of prostate and its relation with clinical findings. urol j. 2009;6:109-13. 11. ravery v, goldblatt l, royer b, blanc e, toublanc m, boccon-gibod l. extensive biopsy protocol improves the detection rate of prostate cancer. j urol. 2000;164:393-6. 12. presti jc, chang jj, bhargava v, shinohara k. the optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. j urol. 2000;163:163-6. 13. takashima r, egawa s, kuwao s, baba s. anterior distribution of stage t1c nonpalpable tumors in radical prostatectomy specimens. urology. 2002;59:692-7. 14. moussa as, meshref a, schoenfield l, et al. importance of additional “extreme” anterior apical needle biopsies in the initial detection of prostate cancer. urology. 2010;75:1034-9. 15. presti jc. prostate biopsy strategies. nat clin pract urol. 2007;4:505-11. 16. jones js, zippe cd. rectal sensation test helps avoid pain of apical prostate biopsy. j urol. 2003;170:2316-8. 17. walz j, gallina a, saad f, et al. a nomogram predicting 10-year life expectancy in candidates for radical prostatectomy or radiotherapy for prostate cancer. j clin oncol. 2007;25:3576-81. 18. chen me, troncoso p, johnston da, tang k, babaian rj. optimization of prostate biopsy strategy using computer based analysis. j urol. 1997;158:2168-75. 19. bott srj, young mpa, kellett mj, parkinson mc. anterior prostate cancer: is it more difficult to diagnose? bju int. 2002;89:886-9. 20. eskicorapci sy, baydar de, akbal c, et al. an extended 10-core transrectal ultrasonography guided prostate biopsy protocol improves the detection of prostate cancer. eur urol. 2004;45:444-8. 21. wright jl, ellis wj. improved prostate cancer detection with anterior apical prostate biopsies. urol oncol. 2006;24:492-5. 22. meng m v, franks jh, presti jc, shinohara k. the utility of apical anterior horn biopsies in prostate cancer detection. urol oncol. 2003;21:361-5. 23. orikasa k, ito a, ishidoya s, saito s, endo m, arai y. anterior apical biopsy: is it useful for prostate cancer detection? int j urol. 2008;15:900-4. 24. presti jc. repeat prostate biopsy--when, where, and how. urol oncol. 2009;27:312-4. 25. sazuka t, imamoto t, namekawa t, et al. analysis of preoperative detection for apex prostate cancer by transrectal biopsy. prostate cancer. 2013;2013:705865. 26. elshafei a, kartha g, li y, et al. low risk patients benefit from extreme anterior apical sampling on initial biopsy for prostate cancer diagnosis. prostate. 2014;74:1183-8. anterior apical cores in the initial prostate biopsy-ekin et al. review 215urology journal vol 5 no 4 autumn 2008 surgical repair of posterior urethral defects review of literature and presentation of experiences jalil hosseini, kamyar tavakkoli tabassi introduction: the main objective of the present review article was to study the different aspects of reconstructive surgery for posterior urethral defects by reviewing the published articles and presentation of our experiences in the reconstructive urology division at shohada-e-tajrish hospital. materials and methods: the medline was searched with the keywords of posterior urethroplasty, end-to-end anastomosis, excisional urethroplasty, anastomotic urethroplasty, pelvic fracture, bulboprostatic anastomosis, and urethral repair. the search was limited to papers published from 1980 to september 2008. we selected the relevant published articles in this database and also presented our experience at our reconstructive urology division. results: of over 5000 search results, we selected 38 relevant articles with substantial contribution to the subject. pelvic fracture due to accidents was the most common etiology of pelvic fracture urethral distraction defect that usually involved the membranous urethra. surgical treatment of this disorder with perineal anastomotic urethroplasty was accompanied by a success rate of 82% to 95% in different studies. the most important complications of this surgery include urinary incontinence and impotence; however, the incidence of these complications has been reduced by using new surgical techniques. conclusion: complete preoperative assessment, the use of suitable reconstructive techniques, and in particular, the use of flexible cystoscopy can lead to acceptable outcomes of the surgical repair of pelvic fracture urethral distraction defects. urol j. 2008;5:215-22. www.uj.unrc.ir keywords: reconstructive surgical procedures, urethral diseases, pelvic fracture, posterior urethral stricture reconstructive urology division, department of urology, shohadae-tajrish hospital and infertility and reproductive health research center, shahid beheshti university (mc), tehran, iran corresponding author: seyed jalil hosseini, md department of urology, shohada-etajrish hospital, tajrish sq, tehran, iran tel: +98 21 2271 8001 fax: +98 21 8852 6901 e-mail: jhosseinee@gmail.com introduction strictures and defects of the posterior urethra in men is one of the challenging clinical problems for urologists. because of the special anatomical structure of this region, especially in complicated cases, the stricture site is not easily accessible for surgeons. also surgical repair can lead to several postoperative complications such as urinary incontinence and impotence (erectile dysfunction). when the urethral continuity is totally destructed, the term of urethral distraction defect will be used.(1) the treatment of choice for this condition, that can frequently involve the membranous urethra, is perineal anastomotic urethroplasty.(2-5) in the present article, we reviewed the outcome and complications of different treatment methods for this defect with the emphasis on perineal anastomotic urethroplasty on the basis of a comprehensive review of the published studies on the treatment methods of surgical repair of posterior urethral defects—hosseini and tavakkoli tabassi 216 urology journal vol 5 no 4 autumn 2008 posterior urethral strictures in men. the medline was searched with the keywords of posterior urethroplasty, end-to-end anastomosis, excisional urethroplasty, anastomotic urethroplasty, pelvic fracture, bulboprostatic anastomosis, and urethral repair. the search was limited to papers published from 1980 to september 2008. of over 5000 search results, we selected 38 relevant articles with substantial contribution to the subject. we also presented our 15-year experience at the reconstructive urology division of the urology department in shohada-e-tajrish hospital as a referral center for the whole country. this division is the first reconstructive urology division accredited for the training of reconstructive urology fellowship program. definition following a pelvic bone fracture with the destruction of posterior urethral continuity, a surrounding hematoma-fibrosis complex will be formed between the two urethral ends.(1) therefore, instead of “stricture,” the term of “defect” is usually used for the posterior urethra. (1) the posterior urethra and then the liver and the spleen are the most commonly injured organs after a traumatic pelvic fracture.(6) the prevalence of posterior urethral injuries in pelvic fractures had been estimated to be 5% to 10% in the earlier reports.(7) in the latest studies, it has been estimated to be between 3% and 25%, and the concomitant injuries of abdominal organs have been also reported in 27% of them.(8) the incidence of double injuries of the urethra and bladder in men has been reported between 10% to 20%.(9) however, since a number of these injuries are incomplete, complete urethral defects are relatively uncommon.(1) it is generally believed that the posterior urethral injuries can be caused by disruption of the membranous urethra after pelvic fracture.(10) however, mundy showed that the disorder is accompanied by avulsion of the bulbomembranous junction in two-thirds of the cases and avulsion of the proximal bulbar urethra in one-third.(1) urethral injuries in these patients are often accompanied by butterfly fracture of symphysis pubis with or without diastasis of one sacroiliac joint.(11) after puberty, this defect rarely involves the prostatic urethra; however, before puberty, this disorder can involve both the prostatic urethra and the bladder neck.(12) previously, colapinto and mccallum classified posterior urethral injuries into 3 categories on the basis of radiological appearance.(13) recently, a new classification of posterior urethral injury in patients with fractured pelvis was proposed. the new classification scheme allows us to compare different therapeutic strategies and their outcomes (table).(14) etiology the most common etiologies of strictures or defects of the posterior urethra are motor vehicle accidents.(15-19) in a study on 82 patients undergoing posterior urethroplasty, the main causes of pelvic fracture were car to pedestrian in 40%, car to motorcycle in 26%, and falling down and crash injuries in 26% of the cases.(19) in another study on 21 patients with complex posterior urethral disruption, the most common reported etiology was explosive blast in 12 men. (15) another common cause of posterior urethral defects in men is gunshot independent of pelvic fracture.(16,17) in one study, gunshot was the main cause of defect in 2 of 60 cases, and in another survey, this etiology was the cause of defect in 1 of 155 patients. furthermore, in a large study in shohada-e-tajrish hospital on 320 patients with posterior urethral defects (unpublished data), class definition i the posterior urethra stretched but intact ii tear of the prostatomembranous urethra above the urogenital diaphragm iii partial or complete tear of both anterior urethra and posterior urethra with disruption of the urogenital diaphragm iv bladder injury extending into the urethra iva injury of the bladder base with periurethral extravasation simulating posterior urethral injury v partial or complete pure anterior urethral injury classification of urethral defects by goldman and colleagues(14) surgical repair of posterior urethral defects—hosseini and tavakkoli tabassi urology journal vol 5 no 4 autumn 2008 217 the most common etiologies of these defects were motor vehicle crashes (63%), falling (10%), getting trapped under the debris (12%), kicking (2.2%), iatrogenic (2.5%), infection (0.6%), and penetrating trauma (3.8%). preoperative evaluation before each interventional procedure, the exact determination of the anatomy of the injured organ is necessary.(1,15-17,20-26) in almost all previous studies, it has been recommended to perform retrograde urethrography and antegrade cystourethrography for the determination of stricture severity and other anatomical information. a combination of the two above techniques guided by fluoroscopy not only can determine the length of posterior urethral defect, but also describes coronal displacement of the prostatic urethra. if the posterior urethra is not filled by contrast medium on cystourethrography, it is imperative to repeat cystourethrography before and during anesthesia.(16) however, some researchers concluded to perform static cystography and then concomitant retrograde urethrography and cystourethrography.(18) if the neck of the bladder is opened, it may lead to postoperative urinary incontinence more often. (27,28) a combination of retrograde urethrography and cystourethrography can determine not only the length of the posterior urethral defect, but also the opening of the bladder neck during urination.(18) furthermore, some experts consider it useful to perform secretary retrograde urethrography and/or complete abdominal and pelvic ultrasonography.(16,26) the role of magnetic resonance imaging in this condition is controversial. some investigators believe that the information provided by magnetic resonance imaging is not particularly useful.(12) others, however, believe magnetic resonance imaging can provide additional information on the lateral displacement of the prostate and the severity of the posterior urethral defect.(19,29) in addition, this technique can detect bone fragments between the two ends of the urethra after pelvic fracture.(12,29) some researchers have used the flexible suprapubic cystoscopy and urethroscopy for the assessment of the bladder neck condition and its anatomical details. in addition, flexible suprapubic endoscopy can guide anatomic reconstructive urethroplasty by showing the true proximal urethral end to prevent false passage or malalignment.(20,23,30) in a previous study on 111 patients suffering from posterior urethral rupture, we recommended flexible suprapubic cystoscopy as a useful technique for the assessment of the bladder, bladder neck, and posterior urethra.(30) this modality can reveal the exact anatomy after the trauma with any suggestion for urethral end deviation and also the complications related to previous managements. in our center, the patient is first visited in the clinic, his clinical information is collected, and undergoes physical examination. then, concurrent retrograde urethrography and cystography is performed. in another visit, the patient undergoes anterior urethra cystoscopy and flexible suprapubic cystoscopy. by this protocol, the anterior urethra, bladder, bladder neck, ureteral orifices, and prostatic urethra are assessed, and the length of defects is determined. based on the results of these studies, the procedure of choice and time of operation are determined. surgical operation methods grafts and flaps, used commonly for the repair of anterior urethral stricture, are less useful for the defects of the posterior urethra. therefore, end-to-end anastomosis should be usually performed.(31) after injection of antibiotics, the patient is placed in the lithotomy or the exaggerated lithotomy position.(20) through an inverted y-shaped perineal incision or a straight midline perineal incision,(23) the bulbar urethra is mobilized and transected at the point just distal to the stricture or obliteration (figure 1). we have a 15-year experience in shohada-e-tajrish hospital as a referral center and as the first reconstructive urology fellowship training center for the whole country. our selected method is operation in the lithotomy position and setting of small cotton or gelatinize pillow under the thigh and then straight perineal incision on the median raphe. other centers explain their experiences in this stage by guidance of a sound.(16,20) the proximal end of the stricture or obliteration is determined surgical repair of posterior urethral defects—hosseini and tavakkoli tabassi 218 urology journal vol 5 no 4 autumn 2008 via passing of a 20-f van buren sound through the suprapubic cystostomy tract.(20) if the tip of the sound is not palpable in the perineal point, the use of flexible cystoscopy is recommended to locate the proximal end of the stricture.(5,20) we use flexible cystoscopy routinely for all patients. in this technique, a cystoscope is passed through the bladder neck from the prostatic urethra and the tip of the cystoscope is placed on the end of the stricture (figure 2). fibrotic tissue is removed under the guidance of cystoscope light. then, a needle is passed through the perineum into the proximal urethral end under the guidance of the flexible cystoscope light (figure 3). using the light of the flexible cystoscope versus a 20-f van buren sound for the determination of the true end of the urethra has 2 benefits: first, it dose not allow creation of false passage. second, the true end point of the urethra is opened, and opening of the urethra proximal to the point of obstruction is avoided. furthermore, by using a flexible cystoscope, it is possible to determine abnormal and nonanatomical placement of the proximal end of the urethra and its deviation to the rectum, laterals, and behind the pubis.(30) after the incising of the two ends of the urethra, fibrotic tissues should be completely removed. tractional sutures on these fibrotic tissues are useful.(20) for prevention of intensive tension on the point of the anastomosis, creation of spaces between the two corpora, inferior pubectomy by using a bone nibbling forceps, or rerouting of the corpus spongiosum around the corpus cavernosum can be performed.(23) according to one study and the anatomical feature of the vessels and nerves, for preservation of erection and potency, it was recommend that during the repair of the distal end of the urethra, dissection be performed only inside the bulb and without disturbing the area outside the bulb (cutting within the bulb).(22) also, during the exposure of the prostatic urethra, dissection in the lateral surface of the prostate is not recommended and it is preferred only in the anterior surface of the prostate.(22) after the removal of the scar and fibrotic tissue, the proximal end of urethra is spatulated in the position of 12 o’clock (figure 4), so that a 24-f to 32-f metallic sound can pass through the urethra. the distal end of urethra is also spatulated in the opposite direction (figure 5).(12,20) figure 1. the bulbar urethra is mobilized. figure 2. light of the flexible cystoscope. figure 3. a needle is passed through the perineum into the proximal urethral end under the guidance of cystoscope light. surgical repair of posterior urethral defects—hosseini and tavakkoli tabassi urology journal vol 5 no 4 autumn 2008 219 to achieve better mucus-to-mucus anastomosis, some surgeons fix the proximal end of the urethra to the lateral section of the urethra with 4 to 6 sutures after spatulation.(16,25) anastomosis of the two ends of the urethra is performed mucus to mucus around the urethra on a urethral catheter, with 6 to 12 sutures (figure 6). for this purpose, absorbable single-filament threads with the diameters of 6-0 to 3-0 are used.(15,16,20,21) after the anastomosis of the urethra, to reduce tension on the suture line, bulbar urethra is fixed to the perineal fascia with 3 chromic sutures with the diameters of 3-0.(26) during anastomosis, a loupe can be used for magnification.(24) the operation can be finished after setting the cystostomy sound, washing the wound, setting the drain, and closing the layers. in our experience, there is no need for a drain and we rarely use rerouting. in complex disruption of the posterior urethra (stricture gap exceeding 3 cm) or the presence of a previous history of perineal urethroplasty, some surgeons recommend abdominal transpubic perineal urethroplasty.(15) in this surgery, patients are placed in the standard lithotomy position. through a midline perineal incision, the anterior urethra is dissected and the firotic tissue of the stricture is completely excised. a midline subumbilical incision is made that extends over the symphysis. the attachments of the rectus abdominis muscles are cleared off of the outer surface of the pubis using a periosteal elevator approximately 2 cm from each side of the symphysis pubis. a wedge of bone is removed from the superior surface of the pubis using an osteotome. the depth of osteotomy varies according to the required exposure. the prostate is freed from the retropubic callus. the prostatic apex and distal urethra are spatulated anteriorly. a tension-free end-to-end anastomosis is performed using 6 to 8 sutures of 4-0 polyglactin over an 18-f catheter. furthermore, in children, anastomosis of the two ends of posterior urethra after symphysiotomy has been described in place of transpubic method.(34) turner-warwick proposed the concept of engaged bladder neck by fibrotic tissue during traumatic pelvic fracture healing that make the bladder neck open and increase the risk of incontinence.(35) then, in suspicious cases for open bladder neck and the risk of incontinence after urethroplasty, he proposed perineoabdominal approach to release the bladder neck from fibrotic tissue during figure 4. spatulation of the distal end of the urethra. figure 5. proximal end of the urethra after spatulation. figure 6. anastomosis over a urethral stent. surgical repair of posterior urethral defects—hosseini and tavakkoli tabassi 220 urology journal vol 5 no 4 autumn 2008 urethroplasty. we use this concept in complicated cases of pelvic fracture urethral distraction defect to decrease the incontinence. after the operation, the patient is kept completely bed rest for 24 to 48 hours. we recommend even longer bed rest. three to 4 weeks after the operation, the urethral catheter is removed and a voiding cystourethrography is done through the suprapubic tract. if extravasation is absent, the suprapubic catheter is clamped and removed 5 to 7 days later.(12) some surgeons perform urethrography before bringing out the urethral sound.(15) we recommend the same method. outcome and complications of surgery in different studies, different results of posterior urethra repair have been obtained due to various definitions of surgical success, follow-up duration, age of the patients, and the previous history of surgery. in some of these studies, successful operation has been defined as the absence of relapse of stricture or defect. the need for reoperation, urethrotomy, or dilation has been defined as failure. thus, in different studies, the success rate of this surgery ranged between 82% and 95%.(15,16,19,20,22,25,26,28,36) our unpublished results are also in this range. in some other studies, the absence of relapse of the defect after one urethrotomy was also defined as successful surgery. based on this definition, a success rate of 93% to 97% was achieved.(19,32) in a study by culty and boccon-gibod, it was found that the success rate of the operation during 1-, 5-, and 10-year follow-up was 63%, 55%, and 43%, respectively, while half of their patients had a history of open or endoscopic surgery. including 1 or 2 internal urethrotomies in the treatment, these rates reached to 84%, 80%, and 76%, respectively.(21) the authors noticed that a history of previous operation notably reduced the success rate. in mundy’s study, the rate of relapse one year after the operation was 7% and this rate was estimated as 12% after 5-year follow-up. in that study, the relapse rate was constant during 10 years after the operation.(3) in 2 studies on children with posterior urethral defect, aged 11.9 years and 9.8 years on average, complete success rate was 70% and 89%, respectively.(17,23) in the fist survey, 6 of 10 patients were operated with the technique of abdominal transpubic perineal urethroplasty. in contrast, in one study on the elderly patients (older than 65 years old), complete success rate of posterior urethroplasty was 84% that confirmed the safety of this procedure in the elderly.(24) koraitim determined factors that contribute to an unsuccessful results and proposed guidelines to reduce failures. the essential operative details of posterior urethroplasty included complete excision of scar tissue involving the membranoprostatic region, lateral fixation of pliable prostatic mucosa, and creation of a tension-free anastomosis.(25) in his study, previous repair, a long distraction defect, and urinary infection did not preclude successful posterior urethroplasty.(25) the most common complications of posterior urethroplasty include urinary incontinence and erectile dysfunction. the incidence of urinary incontinence is about 10% in some reports, the majority of which are reversible(15,23); however, in some other studies, the incidence of this complication was much lower.(12,19) in some reports, opening of the bladder neck in static cystostography before operation resulted in a higher incidence of urinary incontinence.(27,28) furthermore, in mundy’s study, the incidence of persistent erectile dysfunction was about 7%.(3) however, in recent studies, the incidence of impotence has been lower. for example in one study, only 2 of 155 patients suffered from impotence. in another study, among 22 studied patients only 3 cases of impotence was found, one of which was persistent impotence.(16,22) in koraitim’s study on 155 patients undergoing posterior urethroplasty, 110 patients had normal sexual activity before trauma. this normal activity was preserved only in 66 patients after the trauma. twenty-nine patients of this group regained their sexual ability postoperatively, while 2 suffered from impotence.(16) other less common complications of posterior urethroplasty include rectal injury, fistula formation, wound infection, perineal nerve injury, and recurrent urinary infection.(16-18,22,26) surgical repair of posterior urethral defects—hosseini and tavakkoli tabassi urology journal vol 5 no 4 autumn 2008 221 acknowledgement we appreciate the team of reconstructive urology at shohada-e-tajrish hospital for their cooperation, and we would like to especially thank dr reza rezaei, resident of urology, for his special assistance. conflict of interest none declared. references 1. mundy ar. transperineal bulbo-prostatic anastomotic urethroplasty. world j urol. 1998;16:164-70. 2. koraitim mm. the lessons of 145 posttraumatic posterior urethral strictures treated in 17 years. j urol. 1995;153:63-6. 3. mundy ar. urethroplasty for posterior urethral strictures. br j urol. 1996;78:243-7. 4. turner-warwick r. principles of urethral reconstruction. in: webster g, kirby r, king l, goldwasser b, editors. reconstructive urology. cambridge: blackwell; 1993. p. 609-42. 5. webster gd, macdiarmid sa. posterior urethral reconstruction. in: webster g, kirby r, king l, goldwasser b, editors. reconstructive urology. cambridge: blackwell; 1993. p. 687-702. 6. demetriades d, karaiskakis m, toutouzas k, alo k, velmahos g, chan l. pelvic fractures: epidemiology and predictors of associated abdominal injuries and outcomes. j am coll surg. 2002;195:1-10. 7. cass as, godec cj. urethral injury due to external trauma. urology. 1978;11:607-11. 8. chapple c, barbagli g, jordan g, et al. consensus statement on urethral trauma. bju int. 2004;93:1195202. 9. carlin bi, resnick mi. indications and techniques for urologic evaluation of the trauma patient with suspected urologic injury. semin urol. 1995;13:9-24. 10. pokorny m, pontes je, pierce jm, jr. urological injuries associated with pelvic trauma. j urol. 1979;121:455-7. 11. koraitim mm, marzouk me, atta ma, orabi ss. risk factors and mechanism of urethral injury in pelvic fractures. br j urol. 1996;77:876-80. 12. jordan gh, schlossberg sm. surgery of the penis and urethra. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1054-84. 13. colapinto v, mccallum rw. injury to the male posterior urethra in fractured pelvis: a new classification. j urol. 1977;118:575-80. 14. goldman sm, sandler cm, corriere jn, jr., mcguire ej. blunt urethral trauma: a unified, anatomical mechanical classification. j urol. 1997;157:85-9. 15. pratap a, agrawal cs, tiwari a, bhattarai bk, pandit rk, anchal n. complex posterior urethral disruptions: management by combined abdominal transpubic perineal urethroplasty. j urol. 2006;175:1751-4; discussion 4. 16. koraitim mm. on the art of anastomotic posterior urethroplasty: a 27-year experience. j urol. 2005;173:135-9. 17. das k, charles ar, alladi a, rao s, d’cruz aj. traumatic posterior urethral disruptions in boys: experience with the perineal/perineal-transpubic approach in ten cases. pediatr surg int. 2004;20:44954. 18. corriere jn. 1-stage delayed bulboprostatic anastomotic repair of posterior urethral rupture: 60 patients with 1-year followup. j urol. 2001;165:404-7. 19. morey af, mcaninch jw. reconstruction of posterior urethral disruption injuries: outcome analysis in 82 patients. j urol. 1997;157:506-10. 20. kizer ws, armenakas na, brandes sb, cavalcanti ag, santucci ra, morey af. simplified reconstruction of posterior urethral disruption defects: limited role of supracrural rerouting. j urol. 2007;177:1378-81; discussion 81-2. 21. culty t, boccon-gibod l. anastomotic urethroplasty for posttraumatic urethral stricture: previous urethral manipulation has a negative impact on the final outcome. j urol. 2007;177:1374-7. 22. al-rifaei ma, zaghloul s, al-rifaei am. bulboprostatic anastomotic urethroplasty with preservation of potency: anatomical study, operative approach and clinical results. scand j urol nephrol. 2005;39:163-8. 23. hafez at, el-assmy a, sarhan o, el-hefnawy as, ghoneim ma. perineal anastomotic urethroplasty for managing post-traumatic urethral strictures in children: the long-term outcome. bju int. 2005;95:403-6. 24. santucci ra, mcaninch jw, mario la, et al. urethroplasty in patients older than 65 years: indications, results, outcomes and suggested treatment modifications. j urol. 2004;172:201-3. 25. koraitim mm. failed posterior urethroplasty: lessons learned. urology. 2003;62:719-22. 26. aghaji ae, odoemene ca. one-stage urethroplasty for strictures: nigerian experience. int j urol. 2001;8:380-5. 27. corriere jn, jr., rudy dc, benson gs. voiding and erectile function after delayed one-stage repair of posterior urethral disruptions in 50 men with a fractured pelvis. j trauma. 1994;37:587-9; discussion 9-90. 28. macdiarmid s, rosario d, chapple cr. the importance of accurate assessment and conservative management of the open bladder neck in patients with post-pelvic fracture membranous urethral distraction defects. br j urol. 1995;75:65-7. 29. hosseini j, kaviani a, golshan ar. magnetic resonance urethrography versus other modality in posterior urethroplasty. the 11th congress of the iranian urological association. tehran; 2008. 30. hosseini sj, kaviani a, jabbari m, hosseini mm, hajimohammadmehdi-arbab a, simaei nr. diagnostic surgical repair of posterior urethral defects—hosseini and tavakkoli tabassi 222 urology journal vol 5 no 4 autumn 2008 application of flexible cystoscope in pelvic fracture urethral distraction defects. urol j. 2006;3:204-7. 31. hosseini sj, soltanzadeh k. a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran. urol j. 2004;1:94-8. 32. cooperberg mr, mcaninch jw, alsikafi nf, elliott sp. urethral reconstruction for traumatic posterior urethral disruption: outcomes of a 25-year experience. j urol. 2007;178:2006-10. 33. zhou zs, song b, jin xy, xiong eq, zhang jh. operative techniques of anastomotic posterior urethroplasty for traumatic posterior urethral strictures. chin j traumatol. 2007;10:101-4. 34. basiri a, shadpour p, moradi mr, ahmadinia h, madaen k. symphysiotomy: a viable approach for delayed management of posterior urethral injuries in children. j urol. 2002;168:2166-9. 35. turner-warwick r. the surgery of some strictureas and stenoses. some principles of the surgical treatment of strictures and stenoses of the urinary tract. ann r coll surg engl. 1972;50:318-20. 36. aydos mm, memis a, yakupoglu yk, ozdal ol, oztekin v. the use and efficacy of the american urological association symptom index in assessing the outcome of urethroplasty for post-traumatic complete posterior urethral strictures. bju int. 2001;88:382-4. new section in urology journal pictorial urology pictorial urology is a section for publishing interesting images of medical conditions. any kind of images (pictures, radiological images, pathologic images, etc) that show a typical, unique, or rarely seen variety of a condition related to urology, or those with a highly educational value can be submitted to this section. however, the section is not a place for case reports. only high-quality images that are not submitted or published elsewhere will be considered for publication. to submit an image, please send the materials via e-mail (urol_j@unrc.ir) and notice “pictorial urology” in your e-mail title. a maximum of 4 images can be submitted. a short title and accompanied by a legend of no more than 200 words is required. a short description of the case and images, as well as a brief discussion on the images should be provided in the text. no more than 3 references can provided for the text. for photographs of an identifiable patient, a written consent is required. no more than 3 authors can be listed for this section. 1738 | erratum erratum erratum the authors of the article entitled “effect of low dose dopamine on early graft function in living unrelated kidney donors” published in volume 9 no. 1, winter 2012 issue of the urology journal would like to correct the name of the second author to "samad ej golzari". the names of the authors should have read as follows: hamzeh hosseinzadeh, samad ej golzari, mohammad abravesh, ata mahmoodpoor, davood, aghamohammadi, afshar zomorrodi, parisa hosseinzadeh. 1490.pdf 837vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l purpose: to review the acute and chronic pathological effects of sulfur mustard on the genitourinary system and male fertility. materials and methods: related to the sulfur mustard-induced genitourinary effects and male infertility. information in the abstracts of non-english related papers as well as those in the proceedings of congresses on sulfur mustard were reviewed as well. results: in acute phase after sulfur mustard exposure, evidences are in favor of microscopic and macroscopic renal lesions, very low androgen levels, and impaired spermatogenesis. several years following sulfur mustard exposure, the long-term pathological effects vary from the renal function impairment to the gonadal damage, in particular, the spermatogenesis. nevertheless, carcinogenic effect of sulfur mustard on the genitourinary system as well as the prevalence of male infertility among sulfur mustard-exposed veterans in the chronic post-exposure phase is still unclear. conclusion: sulfur mustard causes both acute and chronic injuries to different parts of the genitourinary system. keywords: mustard gas, urogenital system, infertility 1chemical injuries research center, baqiyatallah university of medical sciences, tehran, iran 2tuberculosis and lung disease research center, tabriz university of medical sciences, tabriz, iran 3young researchers club, tabriz branch, islamic azad university, tabriz, iran 4pediatric health research center, tabriz university of medical sciences, tabriz, iran 5cardiovascular research center, tabriz university of medical sciences, tabriz, iran 6chronic kidney disease research center, tabriz university of medical sciences, tabriz, iran 7physical medicine and rehabilitation research center, tabriz university of medical sciences, tabriz, iran 8medical philosophy and history research center, tabriz university of medical sciences, tabriz, iran yunes panahi,1 mostafa ghanei,1 kamyar ghabili,2,3 khalil ansarin,2 saeid aslanabadi,4 zohreh poursaleh,1 samad eslam jamal golzari,5 jalal etemadi,6 majid khalili,7 mohammadali mohajel shoja8 review acute and chronic pathological effects of sulfur mustard on genitourinary system and male fertility corresponding author: kamyar ghabili, md tuberculosis and lung disease research center, tabriz university of medical sciences, tabriz, iran tel: +98 914 410 6136 fax: +98 411 337 8093 e-mail: kghabili@gmail.com received may 2012 accepted august 2012 838 | review introduction first used by the german military at ypres in septem-ber 1917 during the world war i, [bis (2-chloroethyl) is an alkylating chemical agent causing many casualties among enemy forces and civilians upon exposure.(1) later, sm was employed by the iraqi forces against iranian military and civilians, resulting in thousands of medical casualties in the period of 1983 to 1988.(2) sulfur mustard exerts direct toxic effects on the eyes, skin, and respiratory system, with subsequent systemic effects on physiological systems.(1) apart from its acute effects, sm induces a wide range of long-term pathological effects on the skin, eyes, respiratory tract, and immune system, and in some cases on the gastrointestinal tract, cardiovascular, nervous, and genitourinary systems.(3) this review will focus on the acute and chronic pathological effects of sm on the genitourinary system as well as male fertility. materials and methods we searched pubmed and google scholar from 1980 to rinary complications and male infertility using the following terms: “mustard gas, sulfur mustard, vesicant gas, genitourinary, urology, urological, testicular, testes, infertility, fertility, sterility, urinary, kidney, and renal”. information in the abstracts of non-english related papers as well as those in the proceedings of congresses on sm were reviewed as well. checking the search results and their references, we found 39 full-text articles (31 in english, 6 in persian, 1 in japanese, and 1 in german), 9 abstracts, and 1 book. the articles included original animal and human studies and few case reports. herein, all the observations and inferences we discuss apply to the sm, but not analogous mustard, etc.(4) kidney injury animal studies effects of exposure to sm on the renal tissue have been investigated in a number of animal studies. both percutaneous and inhalation exposure to sm at doses of 1 to 2 ld50 (42.3 to 84.6 mg/m3) resulted in renal lesions characterized by congestion and hemorrhage. histopathologically, these lesions included vascular granular degeneration with perinuclear clumping of the cytoplasm of renal parenchymal cells.(5,6) furthermore, exposure to sm via intraperitoneal injection caused tubular necrosis and urinary epithelial cell sloughing in rats in a timeand dose-dependent manner.(7) it is believed that oxidative stress or imbalance between the antioxidant enzymes and products of oxidative reactions plays a key role in the pathogenesis of both acute and chronic effects of sm exposure.(4,8) few studies have investigated the oxidants/antioxidants status in the kidney tissues of the animals exposed to sm. mouse kidneys showed changes in glutathione metabolism and oxidative stress after subcutaneous levels of reduced and oxidized glutathione fell markedly, and after one hour, there was evidence for decreased lipid peroxidation; glutathione peroxidase and glutathione s-transferase activities increased.(9) the imbalanced oxidants/antioxidants status in sm-exposed animals has been recently corroborated by boskabady and colleagues.(10) two weeks after exposure to 100 mg/m3 inhaled sm, guinea pigs treated with vitamin e and/or dexalogical alterations in the kidneys.(10) in contrast, activities of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase in the renal tissues of the sm-exposed rats, were comparable to those of the control group twenty-four hours after dermal application of a 0.5 ld50 dose of sm in rats.(11) apart from the histopathological and biochemical changes in the kidneys following sm exposure through inhalation, variables as well. a timeand dose-dependent increase was noted both in blood and excretion of urinary uric acid following inhaled sm exposure in mice. however, creatine and manner only at higher inhaled sm doses.(12) in contrast, oral administration of sm at doses up to 0.3 mg/kg/day did not result in alterations in the levels of blood urea nitrogen and serum creatinine.(13) 839vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l human studies a few studies have addressed at the renal complications of sm exposure in human victims. most of the studies revealing the early effects of sm toxicity on the human kidneys were performed during the period that the iraqi forces used ter sm exposure, only mild transient glycosuria, hematuria, proteinuria, and urobilinogen were detected in urinalysis. in this phase, the patients might complain of oliguria and hematuria.(14) in contrast, a recent clinical survey on workers in louisiana exposed to sm failed to detect any abnormalities in post-exposure urinalysis of these subjects.(15) in few cases of severe sm exposure, some degrees of renal failure determined by elevated blood urea and creatinine were notable. nevertheless, the sm victims had no complaints except urinary inurinalysis two months after exposure.(16) interestingly, renal pathology at autopsy of sm victims in the acute phase of toxicity was indicative of edema and spotty hemorrhage in the renal glomeruli, desquamation of the renal tubular epithelial cells, acute hemorrhagic nephritis, and tubules containing casts.(14,17) several years after sm exposure (chronic phase), no charactaken 19 to 26 years after high-dose sm exposure. accordingly, soroush and coworkers reported a positive history of urinary calculi (17%), recurrent urinary tract infections (9%), benign prostatic hyperplasia (2%), and renal failure (1%) in 289 veterans. they highlighted that the frequency of nephrolithiasis and recurrent urinary tract infections in these individuals was high compared with the normal population. they failed to detect any association between recurrent urinary tract infections, urinary calculi, and other variables, such as age, time interval from exposure to the study, and type or dose of medications. nevertheless, their study was biased in favor of several medications (eg, systemic corticosteroids), numerous hospitalizations and interventions, and the selfreported nature of the survey.(18) on the other hand, in a case-series study, taghaddosinejad and colleagues further delineated the renal pathology several years after sm exposure. based on the autopsy studies, simple renal cyst and membranoproliferative glomerulonephritis tory changes in the calyces, and chronic renal failure.(19) as mpgn is an immune-mediated glomerulonephritis usually presenting in childhood or young adulthood, presentation of mpgn in sm victims older than 40 years might be attributed to this chemical warfare agent. interestingly, multiple intrarenal abscesses have been reported in an sm victim who received a living-unrelated renal transplant.(20) sulfur mustard-induced immunosuppression was deemed as a factor predisposing to renal abscess formation in this patient. carcinogenesis literature indicates that sm may have carcinogenic effects in humans, but it is not a potent carcinogen, and perhaps its carcinogenesis depends on the duration of exposure.(1) although increased risk of renal cell carcinoma in men occupationally to 12.5) was reported by hu and associates,(21) no history of urogenital malignancies was stated among iranian victims almost 20 years after high-dose sm exposure.(18) nevertheless, several years after occupational exposure to sm.(22) therefore, urogenital carcinogenicity of sm in humans is still ambiguous. reproductive hormones animal studies effects of sm exposure on the reproductive hormones in animals have been less studied. in a study by kooshesh and coworkers on male rats, intraperitoneal injection of sm (5 rum levels of testosterone and estradiol ten days after exposure.(23) dependent decrease and increase in the serum testosterone and estradiol levels, respectively.(23) further similar investigations with higher doses of sm exposed in different routes pathological effects of sulfur mustard on genitourinary system | panahi et al 840 | review human studies iranian sm victims have been studied for hormonal abnormale sm victims a week after the exposure, serum levels of follicle-stimulating hormone (fsh) and luteinizing hormone (lh) did not change compared with the unexposed creased total and free serum testosterone and dehydroepian(24-26) a long-term study by azizi and colleagues on young sm-exposed men showed the drop in serum levels of total exposure and the normalization of these values by the 12th week after injury.(26) cant increase in the serum level of lh by the 3rd week and that of fsh by the 5th week after sm exposure.(26) further assessments in these patients delineated that administration of gonadotropin-releasing hormone (gnrh) caused no sigwithin three months after the sm exposure, serum levels of (26) patterns of alterations in the serum levels of total and free testosterone and dhes in the sm victims between 1 to 12 weeks after exposure are illustrated in figure 1. these studies are indicative of a transient malfunction in the leydig cells resulting in primary testicular failure following exposure to sm. during the period between 1 to 3 years after sm exposure, few studies aimed at assessing the reproductive hormonal status of the iranian sm victims. in a study by azizi and associates on 42 moderately to severely sm-exposed men aged 18 to 37 years, serum levels of testosterone, fsh, and lh were normal compared with those of the normal individuals. (26) on the contrary, amini and hosseinpour found markedly decreased serum levels of testosterone, but not fsh and lh alteration, in the sm victims three years after exposure.(27) the long-term effects of sm exposure on the reproductive hormones have been recently analyzed. amirzargar and colleagues found normal serum testosterone and lh levels in 64 sm-exposed men twenty years after mild to severe injury. nonetheless, the exposed men had higher serum levels of fsh compared with unexposed individuals in their study.(28) although these studies lacked accurate drug history of sm it seems that serum levels of the reproductive hormones are within the normal range in sm-exposed men several years after the injury. semen indices animal studies the effects of sm exposure on the semen indices have been studied by sasser and colleagues(29) and kooshesh and associates.(23) oral administration of sm at dose of 0.5 mg/kg in the total number of abnormal sperm heads and a reduction in percentage of normal sperm with unchanged percentage of sperm motility and concentration.(29) furthermore, kooshesh and coworkers found that intraperitoneal injection of sm at the sperm count compared with the sham group.(23) however, this semen index was not different between the two studied sm doses.(23) human studies data addressing the acute and subacute effects of sm exposure on semen indices and related abnormalities are lacking. one to three years following moderate to severe sm exposure, the mean total sperm count of 42 sm victims aged 18 to 37 years was 84 × 106/ml.(26) azizi and colleagues also detected oligozoospermia (total sperm count <20 × 106/ml) in approximately one-third of the sm-exposed young men. (26) however, screening of iranian veterans four years after infertility rate among sulfur mustard-exposed and unexposed veterans. no. reference time from exposure infertility rate (exposed) infertility rate (unexposed) 1* amirzargar et al.(28) 4 years 22.2% 2* ketabchi(39) 8 years 23.3% 1.6% 3* shakeri et al.(30) 10 years 35% 4* ghanei et al.(50) 12 years 17.1% 15.1% 5 ghanei et al.(31) 15 years 8.3% 6* amirzargar et al.(28) 20 years 22.6% 4.9% 7 soroush et al.(51) 20 years 2.5% *these studies reported the male infertility rate. 841vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l mild to severe sm exposure revealed the mean total sperm count of 172 × 106/ml.(28) this difference might be attributed to an enhanced spermatogenesis four years after sm exposure; however, the latter study included the mild sm-exposed victims as well, which might contribute to such discrepancy. long-term effects of sm exposure on the semen indices have been investigated in few studies. at least ten years after suspicious sm exposure, the results of semen analysis in 56 individuals were indicative of the sperm abnormalities in 38% of the sm victims aged <55 years.(30) shakeri and associates reported that the most common semen abnormalities were abnormal sperm morphology (54%) and decreased sperm motility (48%).(30) fifteen years post exposure, 10% of the sm victims had oligospermia.(31) twenty years after mild to severe sm exposure, azoospermia and oligozoospermia were reported in nearly 30% of the exposed subjects.(28) decrease in all the semen indices, including ejaculate volume, sperm concentration, total sperm count, and sperm motility and morphology between four and twenty years after sm exposure. they also found that except for the sperm motility, than in unexposed casualties twenty years after exposure to sm.(28) in a recent study on sm-injured and non-sm-injured inferin semen values (sperm concentration, total sperm count, and sperm motility and morphology) of infertile sm victims twenty years after exposure.(32,33) interestingly, fertile compared with their non-sm-injured fertile peers.(32) furthermore, among sm-exposed infertile patients, an inverse correlation was found between the severity of sm exposure and sperm concentration, sperm motility, and sperm with normal morphology.(32) of the gonadotoxicity of sm in the chronic phase. it is generally agreed that the major cytotoxic effect of sm arises from dna damage.(4) in a recent study orchestrated to investigate an association between sm exposure and sperm dna damage two decades after injury, safarinejad performed sperm chromatin structure assay (scsa) on sm-injured and non-sm-injured infertile and fertile men. accordingly, a sigsm fertile and infertile casualties in comparison with matched controls. in other words, spermatozoa from sm-injured subjects had more abnormal chromatin than their non-sm-injured counterparts.(32) nerability to congenital abnormalities and genetic defects in sm-exposed veterans’ offspring created by intra-cytoplasmic sperm injection technique.(32) through intra-cytoplasmic sperm injection technique, the natural progression of sperm selection is bypassed that might result in direct access of weaker or damaged sperms to a fertile egg.(34) semen indices and reproductive hormones pathological effects of sulfur mustard on genitourinary system | panahi et al figure 1. serum levels of total and free testosterone and dehydroepiandrosterone sulphate (ds) in patients injured by sulfur mustard (sm) 1, 3, 5, and 12 weeks after exposure. the vertical bars indicate ± standard error of the mean (sem). *p < .001, as compared to normal controls. +p < .001, as compared to values in the 1st week after sm injury. modified from azizi and colleagues’ manuscript.(26) 842 | serum levels of testosterone, fsh, and lh between the smexposed subjects with (total sperm count <20×106/ml) or without oligozoospermia (total sperm count >20×106/ml). (26) in their study one to three years after sm exposure, of 29 men who had oligozoospermia, 20 had total sperm counts above 60 × 106/ml. comparing this subgroup of patients with those with oligozoospermia revealed that serum fsh terone and lh were not different between these two groups. (26) interestingly, intensity of sm exposure and level of fsh were found as independent factors associated with the logsperm count.(35) twenty years after sm exposure, low sperm concentration associated with a high fsh level. additionally, sperm concentration and sperm counts were positively correlated with the testosterone level in these subjects.(28) dicate that a reduced sperm count is attributable to a primary testicular injury; a proof supporting the idea of sm gonadotoxicity. furthermore, arrest of spermatogenesis in testicular biopsies of sm-exposed veterans with oligozoospermia or azoospermia (see below) rules out other pathologic causes of low semen volume, such as ejaculatory duct obstruction. testicular histology animal studies intravenous injection of sm in male mice resulted in damage to the testes with inhibition of spermatogenesis.(3) in an investigation applying intraperitoneal injection of sm in male rats, ghahari and associates found dose-dependent alterations in the testicular tissue integrity.(36) eight weeks after sm injection, increased distance between the seminiferous tubules, presence of necrotic forms of spermatocytes, and necrotic cells with picnotic nuclei in the lumen were detected in the sm-treated rats.(36) in another similar study, kooshesh and coworkers reported dose-dependent decrease in the testis weight and johnsen’s score (indicative of the maturation of the seminiferous tubules) following intraperitoneal injection of sm in the male rats.(23) human studies a week after sm exposure, postmortem needle sampling of testicular tissue revealed normal histology.(16) one to three years later, azizi and coworkers performed testicular biopsy in six young sm victims with oligospermia. the results showed testicular atrophy and complete or partial arrest of spermatogenesis.(26) at least three years after sm exposure, infertile victims showed almost total atrophy of the seminiferous epithelium with intact interstitial cells. furthermore, the infertile azoospermic sm victims appeared to have a sertoli cell only pattern in the testicular biopsy (figure 2).(35) several years after sm exposure, amirzargar and colleagues ans.(28) altogether, it seems that spermatogenesis is the main target of gonadal injury caused by sm. sexual dysfunction loss of libido was complained by 25% of iranian sm victims three years after exposure.(16) however, their complaint of the loss of libido increased to 52% one year later.(37) interestingly, an increase of libido was recorded in 9.7% of the sm victims, which had not been previously reported in the medical literature.(37) in a survey of 800 iranian men exposed to sm, 35% and 1% of men reported decreased and increased libido, respectively.(38) eight years after chemical warfare agent exposure mostly to sm, loss of libido was reported in unexposed veterans.(39) several years following the sm exposure, erectile dysfuncreview figure 2. testicular biopsy from an azoospermic patient exposed to sulfur mustard. testicular tubule is lined by sertoli cells only. groups of leydig cells are present in the interstitial tissue. from safarinejad,(35) reproduced with permission from elsevier. 843vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l tion or impotence was detected in 9% of the victims.(37,39) common among the sm-exposed victims than the unexposed individuals (23.6% versus 4.3%).(39) while erectile dysfunction can be related to the decreased serum testosterone level, the premature ejaculation in sm-exposed veterans seems to be secondary to posttraumatic stress disorder. in other words, psychiatric complications of sm exposure might give rise to a wide range of sexual dysfunctions in sm victims.(40) genital lesions sulfur mustard-induced skin lesions present with erythema and subepidermal blisters within hours after exposure.(41,42) when large blisters rupture, full-thickness skin loss followed by ulceration and formation of a necrotic layer or eschar on the affected skin surface develops within a few days.(1,41) these skin lesions usually end with hyper and/or hypopigalong with scarring.(42,43) genital area is one of the anatomical locations associated with severe sm-induced lesions and shorter time to onset of symptoms.(1) the natural characteristic of genitalia gives rise to this susceptibility; moisture covers the thin skin with more hair follicles, leading to a facile penetration by sm.(44) figure 3 shows the bulla formation on the genital area produced by sm within hours after exposure in 1984. hyperpigmentation, xerosis, and scars at the sites of previous sm-induced skin injuries were the most frequent objective (45-47) the sm-induced scar, incapacitating particularly in the genital area, has been reported to cause stenosis of (figure 4).(48,49) male infertility prevalence of infertility there is still a debate on the prevalence of infertility among sm-exposed veterans in the chronic post-exposure phase. table summarizes the results of different studies in this regard. months of unprotected intercourse after marriage, the longterm prevalence of infertility among sm victims ranged from 2.5% to 35%.(28,30,31,39,50,51) the divergence of infertility rates among the sm victims might stem from numerous factors. ketabchi studied chemical victims exposed to numerous chemical warfare agents, such as sm, hydrogen cyanide, and nerve agent, among which sm constituted the most commonly exposed agent (85%).(39) shakeri and colleagues found male infertility rate of 35% among the victims who had suspicious sm exposure, but also lacked the infertility rate among unexposed individuals to be compared with that of the exposed patients.(30) ghanei and associates concluded that their calculated infertility pathological effects of sulfur mustard on genitourinary system | panahi et al figure 4. hyperpigmentation, depigmentation, and meatal stenosis with ventral meatotomy on the glans of penis in a sulfur mustard victim several years after exposure. from emadi and associates,(49) reproduced with permission from john wiley and sons. figure 3. bulla formation on the genitalia 4 hours after sulfur mustard exposure in the battlefield, 1984. from emadi and associates,(49) reproduced with permission from john wiley and sons. 844 | rate of 8.3% among sm-exposed couples was comparable to the overall 8% prevalence of infertility among the general iranian population.(31) furthermore, it is believed that these in the extent of sm exposure of the study subjects;(27) the gonadotoxic effects of sm mostly occur in more severe sm injuries.(35) further similar studies targeting at the infertility rate among sm victims with particular attention to the extent of sm exposure together with inclusion of the unexposed individuals seem crucial prior to reaching any reliable conclusions in this regard. infertility and reproductive hormones the subject of reproductive hormonal status in infertile smexposed men has been of some researchers’ interest. in the following reports, infertility has been regarded as failure to conceive after 12 months of unprotected intercourse after marriage. in a study on 81 infertile men who had been exposed to sm at least three years previously, safarinejad per limit of normal. however, the serum levels of testosterone and lh were within the normal range. furthermore, the spermic (sperm count <2 × 106/ml) or azoospermic infertile subjects suffering from severe sm injuries than infertile subjects with moderate and mild injuries.(35) recent studies by amirzargar and colleagues and safarinejad that infertile sm-exposed men had higher serum levels of fsh than fertile sm victims.(28,32) moreover, dramatically low serum values of testosterone were not observed more frequently in infertile versus fertile sm-exposed men in the study of amirzargar and associates.(28) ply the relative resistance of the leydig cells to sm toxicity along with the seminiferous tubule damage twenty years after sm exposure. conclusion sulfur mustard causes both acute and chronic injuries to different parts of the genitourinary system. in acute phase after sm exposure, evidences are in favor of microscopic and macroscopic renal lesions, very low androgen levels due to transient malfunction in the leydig cells, and impaired spermatogenesis. several years following sm exposure, the long-term pathological effects vary from the renal diseases to the gonadal injury, in particular the spermatogenesis. nevertheless, carcinogenic effect of sm on the genitourinary system as well as the prevalence of male infertility among sm-exposed veterans in the chronic post-exposure phase is still unclear. apart from the long-term pathological effects of sm on the eyes, skin, and respiratory tract, clinicians should consider persistent consequences of sm poisoning on the genitourinary system when evaluating a patient with history of sm exposure. nevertheless, there is a need for further detailed clinical studies focusing on the long-term effects of sm on the genitourinary system and male fertility. for instance, how sm victims have been monitored and treated over years, the effect of age after exposure, the correlation between dose and time of sm exposure with complications, and morbidity rates can constitute indispensable steps towards drawing any conclusions with regard to the chronic genitourinary complications of sm toxicity. furthermore, information about the abortion rate, teratogenicity, and mutagenicity among infertile sm-exposed men’s sibling, if sm victims achieve a pregthis regard. conflict of interest none declared. review references 1. ghabili k, agutter ps, ghanei m, ansarin k, shoja mm. mustard gas toxicity: the acute and chronic pathological effects. j appl toxicol. 2010;30:627-43. 2. ghanei m, poursaleh z, harandi aa, emadi se, emadi sn. acute and chronic effects of sulfur mustard on the skin: a comprehensive review. cutan ocul toxicol. 2010;29:269-77. 3. balali-mood m, mousavi s, balali-mood b. chronic health effects of sulphur mustard exposure with special reference to iranian veterans. emerg health threats j. 2008;1:e7. 4. ghabili k, agutter ps, ghanei m, ansarin k, panahi y, shoja mm. sulfur mustard toxicity: history, chemistry, pharmacokinetics, and pharmacodynamics. crit rev toxicol. 2011;41:384-403. 845vol. 10 | no. 2 | spring 2013 |u r o lo g y j o u r n a l 5. pant sc, vijayaraghavan r. histomorphological and histochemical alterations following short-term inhalation exposure to sulfur mustard on visceral organs of mice. biomed environ sci. 1999;12:201-13. 6. sharma m, pant sc, pant jc, vijayaraghavan r. nitrogen and sulphur mustard induced histopathological observations in mouse visceral organs. j environ biol. 2010;31:891905. 7. mirshafiee gh, sadraei sh, bahadoran h. effect of sulfur mustard on the epithelial cell necrosis of urinary duct of kidney in rat [in persian]. iran j mil med. 2011;12:203-9. 8. ghabili k, shoja mm, agutter ps, agarwal a. hypothesis: 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m, shakoor a. autopsy findings on iranian victims of chemical warfare. abstracts of the first international medical congress on chemical warfare agents in iran. vol 31. mashhad: mashhad university of medical sciences; 1988. 15. iyriboz y. a recent exposure to mustard gas in the united states: clinical findings of a cohort (n = 247) 6 years after exposure. medgenmed. 2004;6:4. 16. balali m, seddigh m, akhavian f. report of second study on late toxic effects of sulfur mustard poisoning. abstracts of the first international medical congress on chemical warfare agents in iran. vol 64. mashhad: mashhad university of medical sciences; 1988. 17. papirmeister b, feister af, robinson si, ford rd. medical defense against mustard gas toxicity: mechanisms, pharmacology, implications. boca raton, fl: crc press; 1991. 18. soroush mr, ghanei m, assari s, khoddami vishteh hr. urogenital history in veterans exposed to high-dose sulfur mustard: a preliminary study of self-reported data. urol j. 2009;6:114-9; discussion 9. 19. taghaddosinejad f, fayyaz af, behnoush b. pulmonary complications of mustard gas exposure: a study on cadavers. acta med iran. 2011;49:233-6. 20. shoja mm, ardalan mr, etemadi j, tubbs rs, varshochi m. renal allograft abscesses following transplant: case report and literature review. exp clin transplant. 2007;5:720-3. 21. hu j, mao y, white k. renal cell carcinoma and occupational exposure to chemicals in canada. occup med (lond). 2002;52:157-64. 22. weiss a, weiss b. [carcinogenesis due to mustard gas exposure in man, important sign for therapy with alkylating agents]. dtsch med wochenschr. 1975;100:919-23. 23. kooshesh l, dashtnavard h, bahadoran h, karimi a, jafari m, asadi mh. evaluation of sulfur mustard effect on the spermatogenesis process of mature male rats [in persian]. j iran anat sci. 2007;5:27-36. 24. azizi f, elyasi h, sohrabpour h, jalali n, nafarabadi m. serum concentrations of various hormones following exposure to chemical weapons containing sulfur mustard. med j islam repub iran. 1989;3:105-7. 25. azizi f, jalali n, nafarabadi m. the effect of chemical weapons on serum concentrations of various hormones. iran j med sci. 1989;14:46-50. 26. azizi f, keshavarz a, roshanzamir f, nafarabadi m. reproductive function in men following exposure to chemical warfare with sulphur mustard. med war. 1995;11:34-44. 27. amini m, hosseinpour m. late complications of chemical warfare gases on pituitary-gonadal axis [in persian]. j faculty med, shahid beheshti univ med sci. 1998;21:27-31. 28. amirzargar ma, yavangi m, rahnavardi m, jafari m, mohseni m. chronic mustard toxicity on the testis: a historical cohort study two decades after exposure. int j androl. 2009;32:411-6. 29. sasser lb, cushing ja, dacre jc. dominant lethal study of sulfur mustard in male and female rats. j appl toxicol. 1993;13:359-68. pathological effects of sulfur mustard on genitourinary system | panahi et al 846 | 30. shakeri s, yazdani m, kheradpezhouh e. long-term effect of exposure to mustard gas on male infertility. iran red crescent med j. 2007;9:59-62. 31. ghanei m, rajaee m, khateri s, alaeddini f, haines d. assessment of fertility among mustard-exposed residents of sardasht, iran: a historical cohort study. reprod toxicol. 2004;18:635-9. 32. safarinejad mr. sperm chromatin structure assay analysis of iranian mustard gas casualties: a long-term outlook. curr urol. 2010;4:71-80. 33. ghabili k, shoja mm, golzari se, ansarin k. serium testosteron level and semon indices in sulfur mustard exposed men: comment on "sperm chromatin structure assay analysis of iranian mustard gas casualties: a long-term outlook". curr urol. 2012;6:112. 34. nasr-esfahani mh, deemeh mr, tavalaee m. new era in sperm selection for icsi. int j androl. 2012;35:475-84. 35. safarinejad mr. testicular effect of mustard gas. urology. 2001;58:90-4. 36. ghahari l, safarinejad mr, moradi a, markazi-moghadam n, dadpey m. the evaluation of histopathologic effects of mustard gas on testis parenchyma in rats [in persian]. j army univ med sci i r iran. 2004;2. 37. balali m, moodi jr. report of third study on late toxic effects of sulfur mustard poisoning. abstracts of the first international medical congress on chemical warfare agents in iran. vol 65. mashhad: mashhad university of medical sciences; 1988. 38. pour-jafari h, moushtaghi aa. alterations of libido in gased iranian men. vet hum toxicol. 1992;34:547. 39. ketabchi a. urogenital and fertility complications in victims of chemical war residing in kerman province. j kerman univ med sci. 1998;5:72-7. 40. balali-mood m, balali-mood b. sulphur mustard poisoning and its complications in iranian veterans. iran j med sci. 2009;34:155-71. 41. shakarjian mp, heck de, gray jp, et al. mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure. toxicol sci. 2010;114:5-19. 42. kehe k, thiermann h, balszuweit f, eyer f, steinritz d, zilker t. acute effects of sulfur mustard injury--munich experiences. toxicology. 2009;263:3-8. 43. kehe k, balszuweit f, steinritz d, thiermann h. molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering. toxicology. 2009;263:12-9. review 44. hefazi m, maleki m, mahmoudi m, tabatabaee a, balalimood m. delayed complications of sulfur mustard poisoning in the skin and the immune system of iranian veterans 16-20 years after exposure. int j dermatol. 2006;45:1025-31. 45. balali-mood m, hefazi m, mahmoudi m, et al. long-term complications of sulphur mustard poisoning in severely intoxicated iranian veterans. fundam clin pharmacol. 2005;19:713-21. 46. panahi y, moharamzad y, beiraghdar f, naghizadeh mm. comparison of clinical efficacy of topical pimecrolimus with betamethasone in chronic skin lesions due to sulfur mustard exposure: a randomized, investigator-blind study. basic clin pharmacol toxicol. 2009;104:171-5. 47. emadi sn, mortazavi m, mortazavi h. late cutaneous manifestations 14 to 20 years after wartime exposure to sulfur mustard gas: a long-term investigation. arch dermatol. 2008;144:1059-61. 48. momeni az, enshaeih s, meghdadi m, amindjavaheri m. skin manifestations of mustard gas. a clinical study of 535 patients exposed to mustard gas. arch dermatol. 1992;128:775-80. 49. emadi sn, hosseini-khalili a, soroush m, et al. external urethral stenosis: a latent effect of sulfur mustard two decades post-exposure. int j dermatol. 2009;48:960-3. 50. ghanei m, allameh z. effect of chemical warfare agents on fertility. j med chem. 2003;1:1. 51. soroush mr, modirian e, khateri sh. long-term effects of exposure to mustard gas on male infertility. iran red crescent med j. 2008;10:344-5. xivol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l prostate cancer (pca) screening via serum prostate specific antigen (psa) measurement is controversial. a reliable and valid screening test for a specific disease should be cost-effective, be easy to perform, and have a statistically acceptable sensitivity and specificity. a 2011 study(1) demonstrated that "after 20 years of follow-up the rate of death from prostate cancer did not differ significantly between men in the screening group and those in the control group". finally the united states preventive services task force (uspstf) recommended against psa screening in healthy men.(2,3) the uspstf's investigations demonstrate that 80 per cent of men with increased serum psa levels have a false-positive result, but they undergo a prostate biopsy which can have serious complication. the uspstf recommendation isn't a mandate. the uspstf stresses that men who want to get a psa test still can get one, but only after the physician explains the limitations and uncertainties. in this case, the uspstf concluded that the benefit of the psa test in preventing mortality from pca was minimal and was more than counteract by the complications of surgery or radiotherapy to treat cancers that would never have killed the patient. the leader of the uspstf denoted that, for every 1000 men screened for pca, maximum one will avoid a cancer death during a decade.(3) in that same group, two to three will have a serious complication resulted from pca treatment such as a blood clot, myocardial infarction, stroke, or even death, and up to 40 will have urinary incontinence, erectile dysfunction or both. so, if screening doesn't save lives and may result in potentially severe complications, why do it at all? also owen sharp, chief executive of the charity prostate cancer uk, believes that: “although recent research does suggest that screening for prostate cancer may reduce the number of deaths from this disease, we still believe that the potential negative impact of screening outweighs its potential positives. as screening can potentially lead to over-diagnosis and unnecessary treatment we do not currently support the introduction of a national screening program.(4)” but the american urological association (aua) blasted the uspstf recommendations saying that the uspstf was “doing men a great disservice disparaging what is now the only widely available test for prostate cancer.(5)” in additions many urologists reacted angrily. they state that the test is a "best practice" for decades. they note that pca remains the second-leading cause of cancer deaths in american men, and that mortalities from pca have dropped by up to 40 percent since the psa screenings came on the urology armamentarium two decades ago. and they swear to tell everyone they know to mohammad reza safarinejad m.d associate editor editorial prostate cancer screening: yes or no? xii | editorial overlook the recommendation of the uspstf. treating patients with pca is a highly profitable business in some communities especially in the united states, and much of the urological practice is dedicated to this issue. indeed some viewpoints are ‘commercial” not “scientific”. if men no longer get screened for pca routinely, urologists will encounter a steady steep decline in patient visits and income. in addition pharmaceutical companies, medical industries, and private sector of health care have also great benefits from diagnostic procedures and treatment modalities for pca. on the other hand governmental sector of health care should allocate significant amount of its resources for diagnosis and treatment of insignificant pca. this is an important issue especially in communities with poor resources for health care. as otis brawley, chief medical officer of the american cancer society, noted in the annals of internal medicine, the task force is “ideally suited to provide an objective, unbiased assessment” because its members, unlike many of their critics, “have no emotional, ideological or financial conflicts of interest.(6)” the uspstf is an independent group of health care professionals which provides medical advice to the federal government and the public, too, on preventing diseases and health problems. i also favor the uspstf recommendations, but i do understand why the urologists have their opinion. the present routine screenings for pca too often bring flawed results and have resulted to a wide speared of anxiety, unnecessary surgery, overtreatment and treatment related complications. i applaud the uspstf decision against the psa testing because there is certainty that the screening has no net benefit, or even worse that the harms outweigh the benefits. men treated for pca often suffer from complications that affect adversely their quality of life such as urinary incontinence, erectile dysfunction and even bowl problems. yet prostate biopsy bears potential risks of hospitalization, urinary tract infections such as prostatitis and other potentially fatal complications for instance septicemia. while pca screening does help to determine more cancers, it has little or no effect on the rate of fatality from the cancer. the main problem with psa test in addition to significant false positive results is that, it cannot differentiate between aggressive and non-aggressive cancers. in other words, although screening results in pca being detected earlier, it does not inform us which cases ultimately will become aggressive. the prostate health index (phi) was approved by the food and drug administration in june 2012 and now it is available. the advantage of the phi is that it yields more precise risk assessment. it has been used in europe since 2010. the phi can reduce the number of biopsies done and, as a result, the number of men needlessly treated for slow-growing pca. using phi physicians can evaluate the risk of pca far more accurately than the serum psa level alone. what should physicians and health care providers do? how should patients set this controversy into outlook? currently, many medical associations and government task forces have released their recommendations regarding pca screening. these recommendations range from proposing screening not at all to suggesting annual screening starting at age 40. we should remember that some men have higher risk for developing pca such as african-american men and those with a family history of pca and may want to undergo regular psa tests. i believe that we cannot recommend a single global advice for the entire world. each society, ethnic group, region, specific population and community has own needs. it is the responsibility of the government task forces, ministries of heath, and scientific associations to provide necessary recommendations for related population. references 1. sandblom g, varenhorst e, rosell j, löfman o, carlsson p. randomised prostate cancer screening trial: 20 year followup. bmj. 2011;342:d1539. 2. moyer va on behalf of the u.s. preventive services task force. screening for prostate cancer: u.s. preventive services task force recommendation statement. annals of internal medicine 2012; 157:120-134. 3. http://www.uspreventiveservicestaskforce.org/prostatecancerscreening/prostatefinalrs.htm 4. the independent thursday 07 february 2013, http://www. independent.co.uk/news/science/controversial-test-canstop-prostate-cancer-7986020.html 5. http://www.hisandherhealth.com/component/content/ article/662-center-aua-speaks-out-against-uspstf-recommendations 6. brawley ow. prostate cancer screening: what we know, don’t know, and believe. ann intern med. 2012;157:135-6. treatment of renal colic using intracutaneous injection of sterile water ahmadnia h1, younesi rostami m2 1department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran 2department of urology, imam hospital, mazandaran university of medical sciences, sari, iran abstract purpose: to evaluate the intracutaneous injection of sterile water in the treatment of renal colic. patients and methods: one hundred patients with renal colic were randomly divided into two groups of 50 patients and underwent the treatment. in the first (study) group 0.5 ml of sterile water and in the control group, 0.5 ml of normal saline was intradermally injected. the severity of pain was assessed by visual analogue scale (vas) system before and 30 and 90 minutes after the injection. patients in whom the presence of stone was not proved were excluded from the study. results: before the treatment mean pain severity in the study group was 9.86±0.4 and in the control group was 9.96±0.19, so that the difference was not statistically significant (p=0.12). thirty and 90 minutes after the injection, the means were 0.76±2.3 and 1.02±2.63 in study group and 5.94±4 and 6.7±4.19 in control group, respectively. the results in 30 and 90 minutes between the two groups were statistically significant (p=0.000 and p=0.000, respectively). pain in all patients in the study group was relieved; however, only %34 of the patients in the control group reported a decrease in pain. there was no complication among the patients of both groups and only a severe and transient pain during injection was reported by the patients. conclusion: this study along with many other existing studies indicates the efficacy of intradermal injection of sterile water for the treatment of severe pain syndromes such as renal colic. the advantages of this method are its efficacy, availability, cost benefits, and easy application. we recommend the use of this approach for the treatment of renal colic. key words: sterile water, renal colic, normal saline urology journal unrc/iua vol. 1, no. 3, 200-203 summer 2004 printed in iran 200 introduction renal colic is a common urology emergency that is quite intolerable. women who have experienced renal colic compare it to the labor pain, and this reflects the severity of pain in renal colic. the first step, according to the literature is the use of narcotic drugs, but their complications such as fatigue, drowsiness, vomiting , and nausea as well as their unavailability, especially in small medical centers and far-off clinics, illegal abuse, and administration limits in patients with asthma and pregnancy has placed a restriction on their use.(1) using sterile water in the treatment of back pain especially during labor has been successful.(2) in this study, which is a random and double-blinded clinical trial, the result of renal colic treatment by intradermal injection of sterile water is discussed. materials and methods one hundred patients with renal colic were enrolled in this random, double-blinded clinical trial. none of the patients had received analgesics before they were referred to our center. the age of the selected patients was kept in the range of accepted for publication in january 2004 treatment of renal colic using intracutaneous injection of sterile water 201 21 to 55 years, firstly, because measuring the severity of pain was more reliable on the basis of these patients' statements and secondly, because of the lower incidence of diseases and the special medical conditions of this age group. hence, it was more possible to analyze renal colic separately. the panticipants were divided into two groups by random numerical table. in the first group the treatment was done by using 0.5 ml sterile water and in the second group, which was the control group 0.5 ml normal saline was used as a placebo. in both groups injections were done using 1 ml insulin syringe in prone position. after cleansing the injection area with alcohol, 0.5 ml of sterile water or normal saline was injected in the most painful area of the flank, so that bleb was created at the injection site. before injection, 30 and 90 minutes after the injection the severity of pain was measured using visual analog scale (vas) on the scale of 0 to 10, in that zero indicates the painless status and 10 indicates the severest pain that the patient has ever experienced. the patients were asked to record the time immediately after the pain would be relived. the diagnostic criteria of renal colic were based on history, physical examination, urinalysis for the presence of hematuria, and ultrasonography from the urinary tract for the presence of stone. if necessary, ivp was also done. patients in whom the presence of stone was not proved by imaging modalities were excluded from the study. all the process of the study was explained for the patients and informed consents were obtained. statistical analysis was done, using chisquare test, t test, and mann-whitney u test by spss 9.01 software package. results seventy-two percent of the patients were men and 28% were women. mean age was 35.46 (range 21 to 55) years. in the study group the mean age was 35.26±9.16 years and in the control group was 33.90±9.96; the difference was not statistically significant. pain was in the right side in 44% and 36% of the study and control group and in the left side in 56% and 64%, respectively. the difference was not statistically significant (p=0.41). in 92% of the patients in the study group and 88% in the control group hematuria was present in urinalysis (p=0.79). twenty-four percent of the patients in the study group and 20% in the control group had a previous experience of stone passage (p=0.62). mean stone size was 7.14±1.76 mm and 7.20±1.85 mm in the study and control groups, respectively. this difference was not statistically significant (p=0.878). the mean of vas before treatment in the study and control groups were 9.86±3 (range 8 to 10) and 9.96±19 (range 9 to 10), respectively (p=0.12). mean vas from the point of pain severity, thirty minutes after treatment was 0.76±2.3 (range 0 to 10) in the study group and 5.94±4 (range 0 to 10) in the control group (p=0.0000). mean vas, ninety minutes after treatment in the study group was 1.02±2.63 (range 0 to 10) and in the control group was 6.7±4.19 (range 0 to 10) and the difference was statistically significant (p=0.000). it is important to say that in all treated patients with sterile water, pain was relieved after injection (in 100% of cases); however, two patients, thirty minutes after injection and one patient, fifteen minutes after injection had severe pain for whom narcotics were used for pain relief (the severity of pain was recorded 10 based on vas). however, only 17 patients (34%) in the control group had pain relief after injection (p= 0.00000). the average time of pain relief after injection of sterile water was 1.93±0.93 (range 1 to 6) minutes in the study group and 2.4±1.23 (range 1 to 4) minutes in the control group. the difference was not statistically significant (p=0.063). none of the patients in the two groups reported any special complications at the site of the injection. the only complication observed in this study was severe pain at the site of injection which lasted 20 to 30 seconds. discussion after presentation of gate control theory by melzack and wall in 1965, a lot of physiological, pharmacological, and psychological researches were conducted in order to find new approaches to pain relief.(3) regarding the role of different pain stimuli in activating the anti-pain network in the cns, using these stimuli in order to control pain has been an ultimate goal from a long time ago. different theories such as hyperstimulation or counter-irritation, and dnic (diffuse noxious inhibitory control) have been proposed to explain the mechanism of action of these stimuli. some of these mechanisms are acupuncture, tens (transcutaneous electrical nerve stimulation) and intracutaneous or subcutaneous injection of sterile water.(1,3-6) mechanisms of these methods are treatment of renal colic using intracutaneous injection of sterile water 202 fully understood by gate control theory.(1,3) some of the uses of these methods are the use of tens for the treatment of labor pain and pain due to peripheral neuropathy, the use of acupuncture in the treatment of renal colic, and injection of sterile water for the treatment of different pain syndromes such as neck and shoulder pain in whiplash syndrome, chronic myofascial pain syndrome, and back pain as a result of labor pain.(1,3-6) in four studies pain relief has been reported in low back pain during labor.(2,7-9) in labrecque's study, 34 women with low back pain during labor were divided into three groups. one group was treated with subcutaneous injection of sterile water, another group with tens, and the third group with the standard treatment. they reported that only patients who received sterile water had pain relief. in this group the pain rapidly decreased with the injection of sterile water.(6) in a controlled randomized double blinded trial by bengtsson and colleagues in denmark (1981), renal colic was treated with the injection of sterile water in 4 sites. the reported response rate was 89%.(10) two explanatory mechanism have been proposed for intracutaneous injection of sterile water. the first includes endrofinergic mechanisms. short-term painful stimulation can cause opioid analgesic effects that can be restored by opioid antagonists. the second explanatory mechanism is the activation of pain regulatory mechanisms of the cns because of painful stimulus. it has been determined that severe and long-lasting stress will result in the activation of pain control networks in cns and exerts its non-opioid analgesic effect. the analgesic effect of painful stimuli is understood by gate control theory and dnic.(1,3) it is clear that the injection of sterile water can cause inflation in the skin and this inflation will activate both mechanical and pain (nociceptors) receptors. activation of large fibers by affecting dorsal horn gate will raise the threshold of pain sensation.(3) intracutaneous injection of sterile water, with providing local stimulation, will cause a strong sensory stimulation in skin, at the side of injection, approximately for 30 seconds. the origin of the resultant analgesia by this stimulation might be the midbrain or on the basis of gate control theory, it may originate from spinal cord. strong stimulation of a particular area of the skin can influence the pain sensation in the viscera and result in referred analgesia. according to the gate control theory, when injection is done on renal and ureteral nerve dermatomes in renal colic, the pain is relieved.(2) as it was mentioned above, only 34% of patients in the control group reported pain relief, the same as that in other studies.(2,10) the reason is unknown, but it might be related to the fact that the intracutaneous injection of the sterile water causes both osmotic stimulation and inflation of compact layers of the skin while the injection of normal saline can only cause the dilation in the compact layers of skin.(3) now, we are conducting another study in that the effect of morphine is compared with sterile water in the treatment of renal colic and it is in its final stages. conclusion this study and all other available researches indicate the high efficacy of intracutaneous injection of sterile water for the treatment of sever pain syndromes such as renal colic. the advantages of this approach are effectiveness, availability, cost benefits, and easy application. it has no important complication and the only associated complication is a severe and transient pain resulting from intracutaneous injection, thus, physicians should inform the patient before the injection is done. it might be treatment of choice for renal colic especially in remote centers, where narcotics and nsaids (non-steroid anti inflammatory drugs) are not available and also in pregnant and asthmatic patients. references 1. reynolds jl. intracutaneous sterile water for back pain in labour. can fam physician 1994; 40: 1785-1792. 2. trolle b, moller m, kronborg h, thomsen s. the effect of sterile water blocks on low back labor pain. am j obstet gynecol 1991; 164: 1277-81. 3. martensson l, wallin g. labour pain treated with cutaneous injection of sterile water: a randomized controlled trial. br j obstet gynaecol 1999; 106: 633-637. 4. bym c, borenstein p, linder le. treatment of neck and shoulder pain in whiplash syndrorme with intracutaneous sterile water injections. acata anaesthesiol scand 1991; 35: 52-53. 5. wreje uc, brosson b. a multicenter randomized controlled trial of injection of sterile water and saline for chronic myofascial pain syndromes. pain 1995; 61: 441444. 6. labrecque m, nouwen a, bergeron m. a randomized controlled trial of non-pharmacologic approaches for treatment of renal colic using intracutaneous injection of sterile water 203 relief of lower back pain during labor. j fam pract 1999; 48: 259-263. 7. ader l, hansson b, wallin g. parturition pain treated by intracutaneous injections of sterile water. pain 1990; 41: 133-8. 8. lytzen t, cederberg l, moller-nielen j. relif of low back pain in labor by using intracutaneous nerve stimulation(ins) with sterile water papules. acta obstet gynecol scand 1989; 68: 341-3. 9. dahl v, aames t. sterile water papulae for analgesia during labor. tidsskr nor laegeforen 1991; 111: 14847. 10. bengtsson j, worning am, gertz j, et al. urolithiasissmerter behandler med intrakutne sterlivandspapler (pain duo to urolithiasis treated by intracutaneous injection of sterile water). ugeskrlaeger 1981; 143: 3463-5. vol 13 no 05 september-october 2016 2744 the effect of antibiotic prophylaxis on post-operative infection in patients undergone flexible cystos-copy miguel ángel arrabal-polo1,2*, maría del carmen cano-garcía1,2, miguel arrabal-martín2, sergio merino-salas3 purpose: the aim of this study is to determine whether antibiotic prophylaxis is required in this outpatient procedure. materials and methods: a non-randomised, prospective observational study that included 184 patients subjected to flexible cystoscopy divided into three groups: group 1:60 patients with prophylaxis of 500 mg of ciprofloxacin; group 2:62 patients with prophylaxis of 3 g of phosphomycin; and group 3:62 without antibiotic prophylaxis. prior to inclusion in the study, absence of infection was checked by means of a urine culture obtained 7 days before the procedure. an analysis was made of urinary infection after 7 days, the cystoscopy indications and its diagnosis, the presence of comorbidities, and the urinary symptoms during the following 7 days. results: the mean age of the patients in group 1 was 65.3 (sd: 12.5) years, 66.7 (10.8) years in group 2, and 66.9 (10.8) years in group 3 (p = .7). bacteriuria was present in 15% of the patients in group 1, compared to 22.6% in group 2, and 12.9% in group 3, with the differences not statistically significant. in multivariate analysis, it was observed that there was no association with the appearance of bacteriuria between the groups for age (p = .8), diabetes (p = .2), smoking (p = .4), lower urinary tract symptoms (p = .7), or immunosuppression (p = .6). conclusion: the use of ciprofloxacin or phosphomycin as prophylaxis does not appear to be indicated in flexible cystoscopy in our health area. keywords: ciprofloxacin; flexible cystoscopy; prophylaxis; phosphomycin; urinary infection. introduction antibiotic prophylaxis in urological surgery contin-ues to be a subject of debate years after the first publications that recommended the use of beta-lactams only, or in combination with aminoglycosides, and placing special emphasis on patients of advanced age and with certain comorbidities(1,2). subsequent studies continue to indicate that more studies are required in order to optimize and establish the correct prophylaxis in urological procedures performed on outpatients, as well as in those that require hospital admission(3,4). the increase in the performing of transurethral procedures has led to the need to find a more suitable plan of action as regards antibiotic prophylaxis, since although some authors recommend its use in high risk procedures, they do not believe it is indicated in low risk procedures, such as flexible cystoscopy(5). as regards the use of antibiotic prophylaxis, two recent reviews recognized that there is low-moderate scientific evidence that lead us to the option of not giving prophylactic antibiotic treatment, although they mention that more well-designed studies are required to compare the use of antibiotic prophylaxis against not using it(6,7). different types of antibiotics have been used in the prophylaxis of out1 urology department. la inmaculada hospital. huercal overa. spain.. 2 ibs granada. spain. 3 urology department. poniente hospital. almería. spain. *correspondence: urology department. la inmaculada hospital. huercal overa. spain. adress: plaza ciudad de los carmenes, 6, pz 18013. granada. received august 2016 & accepted january 2017 patient procedures such as cystoscopy. these include quinolones that, although some authors defend their use in decreasing bacteriuria and urinary infection(8,9), this point must be clarified, as we have previously seen in recent reviews(6,7). as can be seen from the current scientific evidence and from usual clinical practice, there are no protocols on the use or not of antibiotic prophylaxis in flexible cystoscopy, nor is there a consensus on whether or not it is appropriate. the justification for this study is based mainly on this, in the interest that it contributes to increasing the scientific evidence on whether there is a need or not to give antibiotic prophylaxis. the interest of this study is that is a clinical study without intervention, but with a well designed method in clinical habitual practice comparing two antibiotic prophylaxis with no prophylaxis. as different studies(1-3,8,9) have used quinolones and phosphomycin as prophylaxis in flexible cystoscopy, asserting its usefulness in the reduction of bacteriuria and infection, we established that the main objective of this study is to analyse the role of ciprofloxacin and phosphomycin versus not carrying out any prophylactic treatment in patients subjected to flexible cystoscopy, evaluating the presence of urinary tract infections, bacteriuria, as well as other variables that will be mentioned in the following section. endourology and stone disease vol 14 no 03 may-june 2017 3050 materials and methods the prospective non-randomised study included 184 patient candidates for flexible cystoscopy. these were performed by 3 different urologists according to their usual individual clinical practice, with one of them using 500 mg ciprofloxacin as antibiotic prophylaxis, another with 3 g of phosphomycin as prophylaxis, and another without using any prophylaxis. all patients had a urine culture performed to check for the absence of urinary infection before inclusion in the study. the patients were divided into 3 groups: group 1: 60 patients, who took 500 mg ciprofloxacin 1 hour before being subjected to flexible cystoscopy. group 2: 62 patients, who took 3 g phosphomycin 1 hour before being subjected to flexible cystoscopy. group 3: 62 patients, with no prophylaxis before being subjected to flexible cystoscopy. · inclusion criteria: males and females aged over 18 years in whom a flexible cystoscopy according to routine clinical practice was indicated (presence of hematuria, voiding symptoms, bladder tumour revision). · exclusion criteria: patients with a bladder catheter or antibiotic prophylaxis in flexible cystoscopy-arrabal-polo et al. endourology and stone diseases 3051 table 1. characteristics of patients performed flexible urethrocystoscopy with antibiotic prophylaxis with ciprofloxacin 500 mg (group 1), phosphomycin 3 gr (group 2) and without (group 3). group 1 group 2 group 3 p sex 0.62 men 73.3% 77.4% 80.6% women 26.7% 22.6% 19.4% smoking 0.03 yes 35% 14.5% 19.4% no 30% 25.8% 25.8% ex-smoking 35% 59.7% 54.8% bladder instillations 0.16 yes 35% 41.9% 25.8% no 65% 58.1% 74.2% diabetes mellitus 0.99 yes 28.3% 27.4% 27.4% no 71.7% 72.6% 72.6% immunosuppression 0.21 yes 10% 16.1% 6.5% no 90% 83.9% 93.5% luts* 0.31 yes 38.3% 41.9% 51.6% no 61.7% 58.1% 48.4% indication 0.59 tumor follow-up 63.3% 62.9% 51.6% haematuria 16.7% 19.4% 16.1% mictional symptoms 8.3% 6.5% 14.5% others 11.7% 11.2% 17.8% diagnosis 0.001 normal 56.7% 58.1% 38.7% bladder tumor 25% 35.5% 27.4% urothelial edema 10% 1.6% 0% strength bladder 6.7% 0% 6.5% others 1.6% 4.8% 27.4% *luts: lower urinary tract symptoms suprapubic drainage line, patients who had a urinary infection in the previous month, patients with a ureteral catheter or nephrostomy line, and patients with urethral stenosis. · primary variables analyzed: urinary infection symptoms during the 7 days after the cystoscopy, attending an emergency department or primary care clinic due to infection symptoms, bacteriuria (by urine culture at 7 days), and the type of microorganism present in cases of infection. · secondary variables: age, gender, concomitant diseases, presence of prior lower urinary tract symptoms, reason for cystoscopy, result of the cystoscopy, and bladder instillations. · statistical analysis: the proportions and means of the variables recorded in the study was analyzed first, followed by a statistical analysis of the results, by applying an anova test for the analysis of the qualitative-quantitative variables, and the chi-squared test for the analysis of the qualitative variables. the normality of the variables was checked using the kolmogorov-smirnov test, and the analysis of variance with the levene test. a multivariate analysis was performed using binary logistic regression. p≤.05 was considered significant. the analysis was performed using the program spss 17.0 for windows. · calculation of sample size: at least 180 patients needed to be included in the study, considering a beta error of 80% and alpha error of 5%, in order to obtain a statistically significant difference between the groups, and taking into account an estimated percentage loss of 5% and a precision of 3%. the patients were included in each following routine clinical practice of each urologist that perform cystoscopy. · ethics: all patients were informed about the study and gave their informed consent to participate in it. the ethics committee of our health area approved the conducting of the study. in this study urologists for 3 different hospitals have participated. each urologist has assessed and checked the patients in our health area for urinary tract infection after flexible cystoscopy. if urinary tract infection was present after the procedure a correct antibiotic treatment and follow up has been practiced. results the mean age of the patients in group 1 was 65.3 (12.5) years, 66.7 (10.8) years in group 2, and 66.9 (10.8) years in group 3, which was not statistically significant (p=.7). table 1 summarizes the variables recorded: gender, smoking, bladder instillations, as well as the presence of diabetes mellitus, immunosuppression and lower urinary tract symptoms, the reason for cystoscopy, and its results. the analysis of the urine culture performed 7 days after cystoscopy showed the presence of bacteriuria in 15% of the patients in group 1, compared to 22.6% in the patients of group 2, and 12.9% of group 3 patients, with no statistically significant differences (p = .31). the microorganisms isolated in 13% of the previously indicated group 1 patients were: e. coli (n = 3), k. pneumoniae (n = 1), e. faecalis (n=1), s. epidermidis (n = 1), and p. mirabilis (n = 3); while in 22.6% of group 2 they were: e. coli (n = 2), k. pneumoniae (n=6), e. faecalis (n = 3) and others (n = 2), and in 12.9% of group 3 they were: e. coli (n = 2), e. faecalis (n = 1), p. mirabilis (n = 1) and others (n = 4). only 1 patient in group 2 went to the emergency department due to symptoms of a urinary infection arising from the flexible cystoscopy, and only 1 patient from group 1 went to primary care due to urinary infection symptoms. a multivariate analysis was performed to determine the relationship between different factors and the appearance of bacteriuria, which included age (p = .8), smoking (p = .4), presence of diabetes (p = .2), immunosuppression (p = .6), and lower urinary tract symptoms (p = .7), observing a lack of relationship between these and the appearance of bacteria in the urine. discussion the use of antibiotic prophylaxis in flexible cystoscopy is controversial. despite the european urology association clinical guidelines(10) recommending its use only in high risk patients, in usual clinical practice it depends to a great extent on the preferences of the urologist. manson, in a study with 138 patients, stated that the routine use of an antibiotic did not prevent the appearance of bacteriuria and thus, was not indicated(11). rané et al.(12), on the other hand showed that the use of gentamicin in a single dose decreased the rate of urinary infection after flexible cystoscopy, and administering it as a prophylactic would be indicated. karmouni et al.(13), after conducting a study with 126 patients, stated that the use of antibiotic prophylaxis did not decrease the incidence of urinary tract infection and therefore, it would not be necessary to use it. on the other hand, trinchieri et al. stated that the use of levofloxacin reduced the incidence of urinary infection after endoscopic procedures in the urinary tract(9). however, wilson et al.(14) did not observe a benefit in the administration of norfloxacin in patients subjected to flexible cystoscopy in terms of urinary infection incidence. on the contrary to this last study, johnson et al.(8) did observe a benefit of another quinolone, ciprofloxacin, in the prevention and reduction of bacteriuria after flexible cystoscopy. however, in our study, after analyzing the different variables and comorbidities, we observe that the use of prophylaxis with ciprofloxacin did not reduce the presence of bacteriuria or the urinary infection symptoms, suggesting, according to our results, that its use is not recommended. for their part, cam et al.(15) and jiménez et al.(16), did not observe any benefit of antibiotic prophylaxis with phosphomycin in a population with no risk factors and appropriately selected; although they stated that further studies are necessary to establish the real risk in these types of patients. in a study by garcía-perdomo et al.(17), using 500 mg levofloxacin compared to placebo, no statistically significant decrease in bacteriuria or urinary infection was observed between both groups. therefore, they did not recommend the use of this antable 2: results of urinary culture after flexible cystocospy. no statistically differences were observed between groups (p = 0.31). group 1 group 2 group 3 urinary culture positive 15% 22.6% 12.9% urinary culture negative 85% 77.4% 87.1% antibiotic prophylaxis in flexible cystoscopy-arrabal-polo et al. vol 14 no 03 may-june 2017 3052 tibiotic as prophylaxis, unlike other studies(8,9) that did recommend the use of quinolones as prophylactics. we are in accordance with the study by garcía-perdomo, in that the use of quinolones as a prophylactic does not reduce the presence of bacteriuria. the recent studies by herr(18,19), with a very large cohort of patients, showed that antibiotic therapy before cystoscopy does not appear to be necessary in patients who do not have signs or symptoms of a urinary tract infection, although these results cannot be extrapolated to another health area, and the responsibility for whether to use it or not falls uniquely on the urologist. as can be observed in the data presented here, and in the literature, as well as that indicated by mossanen et al.(20), there is a wide variability in antibiotic prophylaxis in urological procedures. therefore, it is important to perform further studies in order to achieve a better understanding of the reasons for this variability in prophylaxis, with the aim of decreasing complications and improving the outcomes of the procedures routinely performed by urologists. conclusions as a conclusion, despite the limitations of our study, due to the number of patients and not being a clinical trial, it is clear on looking at the results, that we do not believe that the use of ciprofloxacin or phosphomycin is routinely indicated as antibiotic prophylaxis in the performing of flexible cystoscopy regardless of other concomitant factors. references 1. larsen eh, gasser tc, madsen po. antimicrobial prophylaxis in urologic surgery. urol clin north am. 1986; 13: 591-604. 2. fujita k, matsushima h, nakano m, kaneko m, munakata a. prophylactic oral antibiotics in urethral instrumentation. nihon hinyokika gakkai zasshi. 1994; 85: 802-5. 3. kraklau dm, wolf js jr. review of antibiotic prophylaxis recommendations for officebased urologic procedures. tech urol. 1999; 5: 123-8. 4. bootsma am, laguna pes mp, geerlings se, goossens a. antibiotic prophylaxis in urologic procedures: a systematic review. eur urol. 2008; 54: 1270-86. 5. dasgupta r, sullivan r, french g, o´brien t. evidence-based prescription of antibiotics in urology: a 5-year review of microbiology. bju int. 2009; 104: 760-4. 6. alsaywid bs, smith ghh. antibiotic prophylaxis for transurethral urological surgeries: systematic review. urol ann. 2013; 5: 61-74. 7. mirone v, franco m. clinical aspects of antimicrobial prophylaxis for invasive urological procedures. j chemother. 2014; 26 suppl 1: s1-s13. 8. johnson mi, merrilees d, robson wa et al. oral ciprofloxacin or trimethoprim reduces bacteriuria after flexible cystoscopy. bju int. 2007; 100: 826-9. 9. trinchieri a, mangiarotti b, lizzano r. use of levofloxacin in the antibiotic prophylaxis for diagnostic procedures in urology. arch ital urol androl. 2002; 74: 33-9. 10. grabe m, bjerklund-johansen te, botto h et al. eau guideline on urinary tract infection. 2010. 11. manson al. is antibiotic administration indicated after outpatient cystoscopy. j urol. 1988; 140: 316-7. 12. rané a, cahill d, saleemi a, montgomery b, palfrey e. the issue of prophylactic antibiotics prior to flexible cystoscopy. eur urol. 2001; 39: 212-4. 13. karmouni t, bensalah k, alva a, patard jj, lobel b, guillé f. role of antibiotic prophylaxis in ambulatory cystoscopy. prog urol. 2001; 11: 1239-41. 14. wilson l, ryan j, thelning c, masters j, tuckey j. is antibiotic prophylaxis required for flexible cystoscopy? a truncated randomized double-blind controlled trial. j endourol. 2005; 19: 1006-8. 15. cam k, kayikci a, erol a. prospective evaluation of the efficacy of antibiotic prophylaxis before cystoscopy. indian j urol. 2009; 25: 203-6. 16. jimenez-pacheco a, lardelli-claret p, lópezluque a, lahoz-garcia a, arrabal-polo ma, nogueras ocaña m. randomized clinical trial on antimicrobial prophylaxis for flexible urehtrocystoscopy. arch esp urol. 2012; 65: 542-9. 17. garcía-perdomo ha, lópez h, carbonell j, castillo d, cataño jg, serón p. efficacy of antibiotic prophylaxis in patients undergoing cystoscopy: a randomized clinical trial. world j urol. 2013; 31: 1433-9. 18. herr hw. should antibiotics be given prior to outpatient cystoscopy? a plea to urologist to practice antibiotic stewardship. eur urol. 2014; 65: 839-42. 19. herr hw. the risk of urinary tract infection after flexible cystoscopy in patients with bladder tumor who did not receive prophylactic antibiotics. j urol. 2014. doi: 10.1016/j. juro.2014.07.015. 20. mossanen m, calvert jk, holt sk et al. overuse of antimicrobial prophylaxis in community practice urology. j urol. 2014. doi: 10.1016/j.juro.2014.08.107. endourology and stone diseases 3053 antibiotic prophylaxis in flexible cystoscopy-arrabal-polo et al. 211 urology journal unrc/iua vol. 1, no. 3, 211-212 summer 2004 printed in iran introduction adrenal myelolipoma is a rare benign tumor of adrenal glands characterized by fatty tissue and bone marrow resembling elements in microscopy.(1) we report a case of such tumors and discuss clinical manifestations, paraclinical evaluations, intraoperative findings, and microscopic features. case report an 18-year-old man was referred to our hospital for an abdominal mass. the patient suffered from pain, dullness of right side and an increase in abdomen size, which had begun two weeks before and increased gradually. the patient had no history of gastrointestinal symptoms, except for a decrease in appetite. no history of fever, weight loss, urinary symptoms, change in urine color, or hematuria was reported. he also suffered from thalassemia major. the patient had had abdominal surgery almost one year before for lymph nodes and liver biopsies, but the results were obscure. no history of drug intake was reported. in physical examination, normal vital signs, dark face, pale mucosae and icteric sclera in both eyes were observed. a non-tender mass with smooth edges, extending down to pelvis was palpable. this mass had crossed the midline and its auscultation was unremarkable. in blood chemistry, anemia, hyperbilirubinemia, hypocalcemia, hyperphosphatemia, and increased transaminases were detected. sonography revealed a solid mass at right adrenal site, sized 20 × 15 cm, which caused the downward displacement of right kidney, while a distinguishable capsule separated it from liver. abdominal ct scan confirmed the ultrasonographic findings (fig. 1). furthermore, necessary laboratory studies for pheochromocytoma and neuroblostoma were also done. via a thoracoabdominal incision the right adrenal mass was excised. pathologic diagnosis report was myelolipoma (fig. 2,3). discussion adrenal myelolipoma is a benign tumor without hormonal function, which is diagnosed by the presence of bone marrow and fatty tissue in adrenal gland.(1) this tumor was first described in 1905 by case reports adrenal myelolipoma dadfar mr1*, mostofi ne2 1department of urology, imam khomeini hospital, ahwaz university of medical sciences, ahwaz, iran 2department of pathology, imam khomeini hospital, ahwaz university of medical sciences, ahwaz, iran key words: adrenal, myelolipoma, surgical removal accepted for publication in august 2003 *corresponding author: email: mdadfar@yahoo.com fig. 1. abdominal ct scan. a 15×12×20 cm mass with fat contents, located between the liver and kidney adrenal myelolipoma qiraul. since then, only about 100 cases have been reported. mostly, these tumors are smaller than 5 cm in diameter and patients are male and obese, with the main symptom of flank pain.(2) this tumor is rarely calcified and has no hormonal activity; however, hormonal studies are recommended because of probable association with cortical adenoma.(3) the cause of this tumor is unknown, but in 1950, seyle and stone succeeded in producing myelolipoma tissue in reticular layer of adrenal cortex in mouse by injecting undeveloped extract of hypophysis and testosterone.(4) this is a slow growing tumor and surgical removal is not recommended, provided that the patient has no symptoms due to the size of tumor.(5) if this tumor is detected with ct scan features and the patient has no symptom, further intervention is not required.(6) however, huge tumors, which need differential diagnosis from adrenal adenocarcinomas, can lead to clinical symptoms and surgical exploration and removal is indicated.(7) the indication for surgery in our patient was the huge abdominal mass. in summary, surgical removal in small size adrenal myelolipoma is not recommended, but it must be differentiated from adrenal adenocarcinoma. preoperative diagnosis is of great importance and imaging modalities are helpful. references 1. papavasiliou c, gouliamos a, deligiorgi e. masses of myeloadipose tissue: radiological and clinical considerations. int j radiot oncol boil phys 1990; 19 : 985-993 2. sanders r, bissada n, curry n. clinical spectrum of adrenal myelolipoma: analysis of 8 tumors in 7 patients. j urol 1995; 6: 1791-1793. 3. vyberg m, sestoft l. combined adrenal myelolipoma and adenoma associated with cushing's syndrome. am j clin pathol 1986; 86: 541-5. 4. selye h, stone h. hormonally induced transformation of adrenal into myeloid tissue. am j pathol 1950; 26: 211-233. 5. han m, burnett al, fishman ek. the natural history and treatment of adrenal myelolipoma. j urol 1997; 157: 1213-1216. 6. casey lr, cohen aj, wile ag, dietrich rb. giant adrenal myelolipomas: ct and mri findings. abdom imaging 1994; 19: 165-167. 7. wilhelmus jl, schrodt gr, alberhasky mt, alcorn mo. giant adrenal myelolipoma: case report and review of the literature. arch pathol lab med 1981; 105: 532-5. 212 fig. 3. pathology showed mature fat lobes, containing active ingredients of bone marrow, along with large areas with hemorrhage. fig. 2. a large mass, weighed 1200 gr, was excised. urology journal unrc/iua vol. 1, no. 3, 180-187 summer 2004 printed in iran 180 kidney transplantation factors affecting survival in kidney recipients at kermanshah rezaei m1*, kazemnejad a2, bardideh ar3, mahmoudi m4 1department of medical statistics, kermanshah university of medical sciences, kermanshah, iran 2 department of biostatistics, tarbiat modarres university, tehran, iran 3department of kidney transplantation, kermanshah university of medical sciences, kermanshah, iran 4department of medical statistics, tehran university of medical sciences, tehran, iran abstract purpose: to evaluate patient and graft survivals in kidney recipients and factors impacting on survival rates at kermanshah. materials and methods: this study was done on 712 kidney transplants from 1989 through 2001 in kermanshah. one of the most important applications of survival analysis is assessing the role of explanatory factors in the studied event. in this study kaplan-meier method was used to calculate patient and graft survivals and in order to determine the factors affecting survival, cox proportional hazard model was used. the iterations in cox model was four times and the inclusion and exclusion criteria, calculated by forward conditional method were less than 5% and 10%, respectively. results: of the recipients, 47.6% were female and most of them (94.4%) had received kidneys from living unrelated donors. one-year patient survivals in recipients from living unrelated donors (lurd) and living related donors (lrd) were 89.4% and 100%, 3-year survivals were 82% and 97.4%, and 10-year survivals were 61.4% and 72%, respectively. in addition, graft survival rates in one year were 85.6% and 97.4%, in three years were 77.2% and 92.3%, and in 10 years were 33.3% and 60.6% in lurd and lrd, respectively. in cox model, four factors, including the presence of surgical or other complications, known primary disease, and donor-recipient relationship had significant association with patient survival and seven factors, including the presence of surgical complications, known primary disease, donor-recipient relationship, gender, weight, same side transplanted kidney, and donor's age had significant relationship with graft survival. conclusion: in summary, it can be concluded that patient and donor demographic characteristics and transplantation conditions may affect patient and graft survival. with the use of multivariate regression analysis methods, the characteristics that have high probability for survival can be determined. controlling these situations, where they have high survival probability, effectively help better treatment and high survival rate. key words: kidney transplantation, survival rate, cox regression, affecting factor, log rank test accepted for publication in august 2003 *corresponding author: po box:14115-331, tehran, iran. email: rezaei39@yahoo.com factors affecting survival in kidney recipients at kermanshah 181 introduction the 1980s has been named organ transplantation decade. significant advances which has occurred in immunosuppressive therapy has lead to performance of more transplantations and increase in patients and graft survival.(1) the prevalence and incidence of end stage renal disease (esrd) was 15000 and 3175 cases in 60 million iranian people per year, respectively.(2) the first kidney transplantation in iran was done in 1967, in shiraz. from 1967 through 1985 about 100 transplantations were performed. there is no national center for recording short-term and long term results of renal transplants in iran. in 2000, the rule of officially recognizing brain death and cadaveric transplantation was established in the parliament.(2,3) kidney transplantation has two periods in iran: first period (1967-1988), which was living related donor (lrd) transplant era and transplantation was less than the expected demand, and second period (1367-1379), in which living unrelated donor transplant (lurd) was established. in the past 12 years more than ten thousand kidney transplantations have been done and the waiting list was eliminated in 1999. diabetes mellitus and hypertension were the two main causes of esrd. few cadaveric transplantations have been performed in iran (less than 1%) and most donors are unrelated and males (64.7%).(4) little information is available about kidney transplantation activity in developing countries.(5) the initial organ transplant was from living related donors in 1954. in 1997, the correction of transplant rules for unrelated donors in germany got approved.(4) besides 81% of recipients from living unrelated donors had living related donors, but they didn't do so. living unrelated donor program can prevent the development of uncontrolled commercial and illegal transplantation which in the absence of cadaver is the single choice.(2,3) demand for resources and social management of patients who require renal replacement therapy is one of the health care service problems in all nations. performance of transplantation and dialysis programmes are related not only to art and medical knowledge but to the socio-economic status of the nations as well. due to above-mentioned reasons the inclusion criteria to these programmes differs from one country to the other. the prevalence of patients who undergo renal replacement therapy in iran is identical to eastern european countries, such as poland and is more when compared to the previous soviet union and less than high prevalence reported in the united states, japan, and western europe.(4) the comparison of survival between dialysis and transplanted patients is not correct because of their differences. even if we consider those patients who are in waiting list (as they have similar conditions to be in waiting list), the conditions that lead to transplantation in some and dialysis in the others are not identical. due to these reasons, the differences in patient survival may correspond to patient differences. in these situations, the consideration of the factors affecting survival such as immunity, gender, age, race, and socioeconomic status and controlling these factors can enable us to make the survival of the two above-mentioned groups comparable. the differentiation between two groups according to the presence or absence of only one risk factor might not be possible with simple statistical analysis.(6) the majority of studies, which have been done in our country were based mainly on the clinical aspects of transplantation and no study was found about determination of the factors affecting survival in kidney recipient patients, so this study might be the first assessment regarding this subject. in kermanshah, kidney transplantation was initiated in 1989. the determination of patient survival after transplantation and clarifying the role of affecting factors on survival is of specific importance. the purpose of this study was clarifying the role of the factors that affect patient and graft survival from 1989 through 2001 at the forth-shaheed-e-mehrab hospital in kermanshah. materials and methods seven hundred and twelve patients who had undergone kidney transplantation since 1368 (the time of initiation of transplantation in kermanshah), until 1380, were enrolled in this study. patients had been usually hospitalized for two weeks after operation and visited daily. afterwards, they asked to refer to the transplant center, weekly in the first month, twice a month up to 3 months, and then every other month for physical examination and performing laboratory tests. with the usage of patients' hospital records, forms for collecting data about the past history of recipients and donors were filled. laboratory tests and patients' follow-up, which had been factors affecting survival in kidney recipients at kermanshah182 recorded in their clinic files, were also considered. the transplantation ward staff cooperated in these procedures. in this study, kaplan-meier method was used to calculate patient and graft survivals, cox proportional hazard model with forward conditional method to determine the factors affecting survival, and pearson's correlation coefficient to evaluate correlation between continuous variables and survival time.(6,7,8) spss 9.0 and spss 10.0 under windows program were the software packages used for analysis. patient survival was defined as the interval between transplantation and death or the last follow-up. graft survival was considered from transplantation until irreversible graft failure (defined as returning to long-term dialysis or second transplant), or the last follow-up with a graft still functioning, or death time. thus, in this study, death while functioning graft was considered as graft failure.(7) the patients had received one of the three immunosuppressive regimens listed below: two-drug regimen (cyclosporine+prednisolone) three-drug regimen (cyclosporine+prednisolone+azathioperine) three-drug regimen (cyclosporine+prednisolone+cellcept) total transplantations from the beginning of transplantation to the time of the study were 800 cases and all the transplanted patients since 1989 up to the present time who has been transplanted in the forth shahid-e-mehrab in kermanshah were enrolled in this study. only 88 patients who were followed for less than one year were excluded from the study. for determination of the relationship between potential affecting factors and patient and graft survival time in cox model, a series of variables were considered, including: height (cm), weight (kg), body mass index (bmi) (kg/m2), donor and recipient age (year), difference between donor and recipient age (year), donors and recipient gender, donor-recipient sex matching, blood group matching, ph matching, donor's and recipient's rh, rh matching, rh and blood group matching, familial relationship, the side of donor's and recipient's kidney, same sided kidney transplantation, primary renal disease, presence of concomitant diseases, dialysis duration (month), date of transplantation, date of birth, residence region (defined as kermanshah, far way cities, and nearby cities), surgical complications, other complications, and number of previous transplants. cox model converged after four iterations and variables were entered to removed from the model using forward conditional method by 5% and 10 % probability, respectively. results most of the recipients were 217 cases (30.5%) from kermanshah, 135 (19%) from other cities of kermanshah province, 135 (19%) from kordestan province, 68 (9.6%) from eilam province, 59 (8.3%) from lorestan province, and 46 (6.5%) from hamedan province. three hundred and thirty-nine cases out of total number of recipients were female (47.6%), while only 191 cases (26.8%) were females in the donors. log rank test did not show any significant difference in survivals between the two genders (p=0.621). regarding the familial relationship between donors and recipients, most of the donors were unrelated (94.4%) and only 40 cases where related, from which 16 cases (2.2%) were sibling, 11 cases were offspring (1.5%), 8 cases (1.1%) were parent, and 5 cases (0.7%) were spouse. a total of 153 deaths (21.5%) occurred in this study, from which 21.9% were recipients from living-unrelated donors (lurd) and 15% from living-related donors (lrd). log rank test showed a significant difference between the two related and unrelated groups' survival and it was more in lrd group (p=0.0056). the most common known primary diseases among kidney recipients, in descending order, were glomerulonephritis in 277 cases (38.9%), hypertension in 136 (19.1%), nephrolithiasis in 46 (6.5%), polycystic kidney disease in 24 (3.4%), pyelonephritis in 20 (2.8%), post partum hemorrhage in 18 (2.5%), and diabetes mellitus in 11 (1.5%). as a whole, 61 cases (8.6%) of the recipients had a concomitant disease that their frequency was as follows: hypertension in 19 (2.7%), diabetes mellitus in 12 (2.2%), congestive heart failure (chf) in 6 (0.8%), and tuberculosis (tb) in 4 (0.6%). fifty-four cases (7.6%) out of the total number of transplantations, performed in kermanshah, had surgical complications and 131 cases (18.4%) had other complications. surgical complications were mostly ureter fistula in 17 cases (2.4%), hemorrhage in 13 (1.8%), and venous thrombosis in 6 (0.8%). among other complications, the most commons were as follow: liver factors affecting survival in kidney recipients at kermanshah 183 table 1. mean graft and patient survival time (months) according to recipient and donor characteristics and transplant condition ��������� ��� ��� ������ ���� ��� ��� �� � ���� �� � �� � ��� ��� � ��� ��� �� �������� ������� � ��� �� � !"� � !#� � $#�%� �"�!� &�' �� �� ��� �!%� �"��� $(�%� !��#� $��#� �"�!� ���� ����� '�� � �� �((� !��"� $ ��� !(��� $%��� !%�%� � '���� �� �� �� $%� %� � !"�%� �"�"� !"�%� �"�"� �� ��� '�� � �� �#� ���� $ � � � �%� $ � � � �%� �������� ��) *� �� �$� !�$� $$�$� !��!� $%��� !��#� +�)��,�� �$#� �"�(� $#��� ! �#� $#�(� !$�%� � � � �� �����* � �� � -����� (��� �##� $$�#� !$�%� $$��� !$��� � �� � �� �%� ���� $!�%� !��%� $!�%� !��%� &�' �� �� ��� �"� ��(� ( �(� ���!� ( �(� ���!�.����'��� ���* � �� � / �����* � �� �� %�� ��%� %#��� !��$� %#�$� !��!� & ������� � �!� ���� ����� !���� ���$� !��#� +� � ����� ������ �(� ��$� #�%� $��(� !�%� $#������� �������'� ��� ���� / ��������'� ��� ���� $� (�%� !"��� $ �"� $���� $$�(� ��������� ����* ���* ��� ��� �� � ($�(� $#��� ($�(� $#��� '� ���� �� �!� ���� !���� !"�#� !���� !"�#� 0 ������ �� �$� ��#� ��$� !%�"� ��$� !%�"� /�� �����'� ��� ���� � / ��������'� ��� ���� �!�� ���$� $%�$� !��!� $%�(� !���� 1 ��� � !!"� $(�%� $ ��� !$�%� $ �(� !$��� 2 � ' ��3��� �* �� ��� � !(!� ��$� $!��� !$�%� $$�#� !$�!� 1 ��� � �"�� �%��� $#��� !��%� $#�%� !���� �����3��� �* �� ��� � ��� (���� $ �%� ! �$� $%�$� ! �#� 0 ��� ��� �� � !���� ���!� !���� ���!� -����'���� *�� * � 2 ���� %"�� "(��� $$� � !$�"� $ ��� !$�$� 0 ��� %%� ("� � $%�(� !$� � $(�$� !$��� ������� '�� ������� * � 2 ���� ��%� ���#� !!� � �"�"� !$�%� �"�%� 4 ��������� ��(� !#� � $%�$� ! �"� $(�#� ! � � � ����� ���� � �� � !� ��� � $!��� !��%� $$� � !���� � 5 � 6 �� 1���,���� � �� !$�� $��#� $���� !$�(� $!�%� !$�!� 0+2�� %(�� "$�$� $���� !!�(� $��"� !!��� �����7� � ' ���� ��� ���� '� 02�� $#� �%� ( �"� ! �!� (%��� !$�"� � �� � ��� !� (�$� ��#� !���� �� � !(�%� 2�����'�� � � ��� 8* �� ���� % �� "��%� $!�!� !!�"� $$��� !!� � � �� � ��� $#� �%� $%��� ! �$� $%�!� ! ��� 9���*�����'������ ��� 8* �� ���� %%"� "$�#� $$�#� !$�$� $$�(� !$�#� � �� � ��� !!%� $(��� $%�"� ! �%� $(� � ! ��� � �* ������� ��� 8* �� ���� !(!� ��$� $��%� !!�!� $��$� !���� � �� � ��� !� ((�(� $(�#� !$�(� $(�%� !$�!� 4 *� ��� * ������ ��� 8* �� ���� �!�� �"�$� !!�(� �"�$� !$��� �"��� � �� � ��� �%� ����� $"�%� !(��� #�#� !(�$�5����� �����2����*� ����*�����'������ ��� 8* �� ���� %�!� �(� � $!�$� !$�#� $$��� !!� � -����� (��� �##� $$�#� !$�%� $$��� !$��� factors affecting survival in kidney recipients at kermanshah184 cancer in 17 cases (2%), pneumonia in 13 (1.8%), psychological disorders in 11 (1.5%), myocardial infarction in 9 (1.3%), cirrhosis of the liver in 8 (1.1%), kaposi sarcoma in 8 (1.1%), cytomegalovirus infection in 7 (10%), chf in 6 (0.8%), and tb in 5 (0.7%). out of the total number of patients only 5 cases (0.7%) had received two-drug regimen (cyclosporine+prednisolone) and the majority (664 cases or 93.3%) had received triple therapy (cyclosporine+prednisolone+azathioperine), and 43 cases (6%) had been treated with cyclosporine+prednisolone+cellcept. the differences in mean survival rate (p<0.001), graft survival rate (p<0.001), donors' age (p=0.008), and duration of dialysis (p=0.026) were significant between lrd and lurd groups. one-year patient survivals in lurd and lrd were 89.4% and 100%, 3-year survivals were 82% and 97.4%, and 10-year survivals were 61.4% and 72%, respectively. in addition, graft survival rates in one year were 85.6% and 97.4%, in three years were 77.2% and 92.3%, and in 10 years were 33.3% and 60.6% in lurd and lrd, respectively. considering the similarities in recipients and donors characteristics, the least patient and graft survivals were associated with the same sided kidney transplantation and the most were related to lurd and rh mismatched groups. according to donor and patient age, the least survival rate was associated with female donor and the most with male donor. left-sided kidney transplantation in recipient was associated with lower survival rate; whereas, left-sided donor nephrectomy was associated with higher survival rate (table 1). according to primary disease, post partum hemorrhage and nephrolithiasis were associated with the lowest and hypertension with the highest survival rates. patients having concomitant hypertension had the highest patient and graft survivals and hemorrhage was associated with the lowest and psychological disorders with highest survival time among complications. transplantation date showed the highest inverse correlation with patient survival (r=-0.477) and graft survival (r=-0.47) using pearson's correlation coefficient (table 2). due to insignificant association of height, donor age, blood group matching, rh matching, blood group and rh compatibility, donor and recipient rh, duration of dialysis, and number of previous transplantations with survival rates after primary analysis, these variables were deleted from the list of explanatory variables for cox regression model. of 712 transplant cases, 43 cases of transplant survival data and 17 cases of patient survival data had been missed and consequently, were omitted. thus, 669 and 695 transplant cases were studied in the two regression analyses, respectively. in these cases, 226 (33.8%) graft rejection and 150 (21.6%) patient deaths have occurred. the remaining 17 variables were enrolled in cox model to describe patient and graft survivals. of 17 variables, seven, including weight, donor's age, recipient gender, donor-recipient familial relationship, same sided kidney transplantation, known primary renal disease, and presence of surgical complications had significant relationship with graft survival and other ten variables had no significant relationship. furthermore, of the 17 above-mentioned variables, familial relationship, known primary renal disease, and presence of surgical and other complications had shown significant relationship with the patient survival and the other 13 variables didn't show any significant relationship (table 3). cox regression equations are as follows: for grafts: -0.89 (if lrd) +0.60 (if surgical complications occurred) -0.45 (if female recipient) +0.41 (if same sided kidney transplanted) 0.40 (if primary disease was known) +0.02 (donors age) -0.01(patients weight) for patients: +0.94 (if surgical complications occurred) +1.30 (if other complications occurred) -0.89 (if lrd) -0.54 (if primary disease was known) table 2. correlation between numerical variables and survival rates (pearson's correlation coefficient) ��������� ��� ��� ������ ���� ��� � ���� �� ��� �� � ���� � ���� ��� ��� �� �� � ��� �� ��� � ���� ��� ��� �� �� � ��� �� ��� � ���������� � �� ���� ���� ��� � ��!� � ��� "� ��!#�� $ � % ������� � �� ���� ! � &�� "'� ������ &�� (� ������ ) ��*�+�� � ! � ������ ������ &���� � ���!�� ,� �+ �� � �� � ���� &�� "� ���� � &�� ""� ������ -����%�����+�� � ! #� &��(!� ������ &��(!!� ������ . �*������� ! #� ��� '� ���#(� ���#(� ��� �� / �*���0��� ���� ����'� ���!� ���!�� ���('� �� � 10���)23� ���� ���'�� ���#"� ���� � ��� �� � ���� ��+���� ��� �����*��� ! #� �� " � ������ �� #�� ���� � factors affecting survival in kidney recipients at kermanshah 185 discussion this study was done on 712 renal transplant patients. after calculating patient and graft survival rates, the association of 27 variables with survival was evaluated. in our country, limited number of investigations has been performed on renal transplant patients' survival. of course, more investigations have been done on other fields, but all have considered the clinical aspects of transplant in the absence of survival analysis. in this study, patient survival rate had significant relation with donor-recipient relationship, known primary kidney disease, and presence of surgical and other complications. other 13 variables hadn't significant relation with patient survival. graft survival had also significant association with weight, donor's age, recipient gender, same sided kidney transplantation, known primary kidney disease, and presence of surgical complications. the factors including presence of surgical complications, known primary kidney disease, and donor-recipient relationship were enrolled in cox models for graft and patient survivals, but other complications was only related to patient survival and the four factors of recipient gender, weight, same sided kidney transplantation, and donor's age were only related to graft survival. there is a wide variety of suggestions about factors affecting kidney transplanted patients' survival. in shaheed hasheminejad hospital, tehran, 1020 renal transplantations were done, from which 571 cases were from lrd and 449 cases from lurd and 65.9% were male donors between ages 8 and 86 years. graft survival was significantly higher in lrd group when compared to lurd ones (p<0.005). but there was no significant difference in patient survival between the two groups. log rank test showed a significant correlation between patient survival and age group (p<0.002) and donor-recipient relationship (p<0.02); however, no correlation between patient survival and recipient's or donor's age was observed.(9) the result of this study in some cases such as the correlation of donor-recipient relationship with graft survival was similar to the results of kermanshah study, but not in other aspects. the reason might be that tehran study hasn't used regression method, as survival can related to patients differences. in these situations considering the factors affecting survival in a multivariate analysis can measure each variable effect in the presence of the other factors. these effects can not be differentiated with simple statistical analysis according to the presence or absence of only one risk factor. in the united states, one-, five-, and ten-year survival for patients above 60 years oldwas 98%, 78%, and 44%, and for patients less than 60 years old was 97% ,93%, and 81%, respectively (p<0.0001), but graft survival was not different between the two age groups and no significant correlation with the donor's age was present.(10) besides, another study was designed in the united kingdom from 1992 through 1994 to signify the factual rate of renal damage in organ harvesting and to measure its effect on graft survival. patients' age was an important factor in one-year and three-year survivals (p<0.001).(11) nonetheless, in kermanshah study, they were related to donors' age. also, in the united kingdom, 6363 cadaveric transplants were followed up to 1 and 5 years after transplantation and were analysed with multivariate and cox proportional hazard model. date of transplantation, donor's age, recipient's age, and recipient diabetes mellitus had significant correlation in multivariate analysis, but gender, blood groups, primary disease of kidney, table 3. factors affecting survivals in cox regression model ��������� ��� ������ � ������� ��� ������ ������� ��������� �������� � � � �������� ���� �� ���������� � ����� ������� ��� ����� ���� ����� ���� !�"��# �����! $���%� &��� ! ��� "" &����'# ��(') "�( )) ��� "� ����*������ ��� �� &��!" ) ���� ) &���"" ��)�) ���)�# ���� " ���+��, ������ &��!��( ��� � &���!�( ��))( "�'"") ��� "" �����&����*���� ���������%�* &��''( ����)� &���!) ��!! (�!��� ����� -� ��, �� � +���%��� ��! �� ��� �( ����(# �" � "�) �� ��� #( � � � � �� � � � � � � .������� ��+*��������� ��"(" ����"' ���!)# �' � )�"('! ��� �� ���+��, ������ &��"�(� ����!� &���"') ��"'� #�!# ����)� �����&����*���� ���������%�* &��''#) ����)� &����)" ��! "�# ��� )( .������� ��+*��������� ��(!!) ����� ���'#� ��"# ��#!"( �����! � � � � �� � � � � � � /�%�� ��+*��������� ��(# ������ �� '�! ��)"' ")�!(�( ������ � factors affecting survival in kidney recipients at kermanshah186 waiting period until transplantation, and side of kidney were not significantly associated.(12) with increasing age of recipient and donor, the risk of transplant failure increased, that agrees with our study in kermanshah and few differences may be due to differences in donors (cadaver and live) in the two studies. patient survival determinants after transplantation has been incompletely understood and different reports have been published. these differences might be due to differences in the time of patient selection, post transplant management, and immunosuppressive therapy. leiden renal transplant database (lrtd) is the analysis of data from the first renal transplant done in leiden, holland, between 1966 and 1994. on 86 living donors and 916 cadaveric donors, the effect of time passed from transplantation, gender, age at the time of transplantation, cause of graft failure, immunosuppressive regimen, type and duration of dialysis before transplantation, hypertension, diabetes mellitus, smoking, and cause of death has been studied. after adjusting for age and gender, relative risk of mortality rate for living donor transplants versus cadaveric donors was 0.5 (p<0.06). mortality risk in the first year for those who received their first graft from cadaver had improved significantly, which was associated with the introduction of cyclosporine. mortality rate after the first year was higher in older patients (age>40), males, smokers, and patients with diabetes or hypertension, but individual characteristic factors had little effect. type and duration dialysis was not associated with patient's mortality rate. also, in this study, time dependent variations in patient management were responsible for improvement of one-year survival.(13) the little effect of individual characteristic factors and ineffectiveness of type and duration of dialysis, was similar to the finding of our study and differences might be due to more cadaveric transplantations in leiden analysis. a study was done on 608 patients in sweden between 1991 and 1997. five-year survival in recipients from living donors and cadaveric donors were 94% and 81%, respectively, and for all diabetics was 78%. date of birth, date of initial dialysis, diagnosis of primary disease, date of transplantation, and date of death or missing were the studied variables,(14) but the number of variables were more in our study. non-diabetic patients (287 cases), who were in waiting list for cadaveric donor were enrolled in a study from 1998 through 1999. the health status (according to nephrological evaluation) was divided into four groups (1: high risk, 2: normal, 3: good, 4: excellent). the relative significance of clinical score, age, and age at dialysis initiation in patient survival were overviewed by univariate and multivariate cox regression model. survival had significant difference in the four above-mentioned clinical groups (mantel cox, p<0.0001). ten-year survival declined from 100% in group 4 to almost 40% in group 1. according to cox model, the best model for predicting patient survival included age and clinical score (p<0.0001). age at dialysis initiation had negative relation, but was diluted in the presence of age and clinical score.(6) unfortunately, clinical evaluation hasn't been done in our study, but if supposed to be equivalent to primary disease and concomitant diseases, the results of our study agree with these findings. in a study, factors correlated with higher survival in recipients from their spouse were evaluated using kaplan-meier analysis for calculating survival rates. three-year survival in spouses who didn't have blood transfusion before operation was 81% and for those who had 1 to 10 transfusion before operation was 40% (p=0.008). higher survival rate was not associated with better hla matching, white race, younger donor's age, or shorter time of ischemia, except for damage during the shock before harvesting the kidney from cadaver.(15) in our study, hla matching was not measured because hla matching is rarely done, due to rarity of cadaveric or lrd transplantation in iran. in geneva university hospital, 310 renal transplantation was done in 283 patients, between 1983 and 1999, from which 49 transplants were done in 48 patients >60 years old. as a whole, multivariate logistic regression analysis showed that patients' and donors' age were not predictors of graft survival.(10) the result of above-mentioned study was similar to ours; however, in our study, recipients age did not show any relation with survival rates. conclusion in summary, it can be concluded that patient and donor characteristics and transplantation conditions may affect patient and graft survival. with the use of multivariate regression analysis methods, the characteristics that have high probability for survival can be determined. factors affecting survival in kidney recipients at kermanshah 187 controlling these situations, where they have high survival probability, effectively help better treatment and higher survival rate. acknowledgement the authors hereby appreciate doctor mohammadreza meshkani, professor of shaheed beheshti university, doctor gholamreza babaei rouchi, associate professor of tarbiat-e-modarres university, and doctor dariush raeesi, assistant professor of kermanshah university of medical sciences, for their great help and valuable advice. also, we should thank ms. fatemeh namaki ravesh and mr. mohammadkazem nasseri from the forth-shaheed-e-mehrab hospital in kermanshah for their painstaking cooperation. references 1. simforoosh n, asgari ma, safarinejad mr. post-transplantation pregnancy. iranian urology j 1999; 2: 1-15. 2. haghighi an, broumand b, d'amico m, locatelli f, ritz e. the epidemiology of end-stage renal disease in iran in an international perspective. nephrol dial transplant 2002 jan; 17(1): 28-32. 3. sesso r, ancao ms, draibe sa, sigulem d, ramos ol. survival analysis of 1563 renal transplants in brazil: report of the brazilian registry of renal transplantation. nephrol dial transplant 1990; 5: 956961. 4. ghods aj. renal transplantation in iran. nephrol dial transplant 2002; 17: 222-228. 5. ghods aj, ossareh s, savaj s. results of renal transplantation of the hashemi nejad kidney hospital-tehran. clin transpl 2000; : 203-10. 6. vianello a, spinello m, palminteri g, brunello a, calconi g, maresca mc. are the baseline chances of survival comparable between the candidates for kidney transplantation who actually receive a graft and those who never get one? nephrol dial transplant 2002; 17: 1093-1098. 7. ebpg expert group on renal transplantation. european best practice guidelines for renal transplantation. section iv: long-term management of the transplant recipient. iv.13 analysis of patient and graft survival. nephrol dial transplant 2002; 17 suppl 4: 60-7. 8. sadri gh, mahjoub h. essentials of epidemiology and statistics in epidemiology. 1st ed. hamedan university of medical sciences; 2001. p. 139. 9. porooshani a, ganji m, porooshani f, ghods aj. results of 1020 renal transplantation: single center experience. acta medica iranica 2001; 39(1): 17-19. 10. saudan p, berney t, leski m, morel p, bolle jf, martin py. renal transplantation in the elderly: a long term, single center experience. nephrol dial transplant 2001; 16: 824-828. 11. wigmore sj, seeney fm, pleass hcc, et al. kidney damage during organ retrieval: data from uk national transplant database. lancet 1999 oct 2; 354: 1143-1146. 12. morris pj, johnson rj, fuggle sv, belger ma, riggs jd. analysis of factors that affect outcome of primary cadaveric renal transplantation in the uk. hla task force of the kidney advisory group of the united kingdom transplant support service authority (uktssa). lancet 1999 oct 2; 354: 1147-52. 13. arent s, mallat m, westendorp r, vander woud f, van esl. patient survival after renal transplantation: more than 25 years follow up. nephrol dial transplant 1997; 12: 1672-1679. 14. medin c, elinder cg, hylender b, blom b, wilczek h. survival of patients who have been on a waiting list for renal transplantation, nephrol dial transplant 2000; 15 (5): 701. 15. terasaki pi, cecka jm, gjertson dw, takemoto s. high survival rates of kidney transplants from spousal and living unrelated donors. n engl j med 1995; 333: 333-6. pictorial urology 162 urology journal vol 6 no 3 summer 2009 adrenal lipoma complicated by perinephric abscess a 51-year-old man presented with fever, chills, and significant weight loss of 6 months’ duration. three months earlier, the patient had undergone percutaneous nephrolithotomy for right-sided kidney calculus. computed tomography revealed an 11.6 × 14.9 × 14.9-cm encapsulated multiseptated hypodense mass with enhancing walls and septa and areas of fat density and air in the right suprarenal region, displacing the inferior vena cava. laparotomy revealed a cystic retroperitoneal mass adhered to the liver, duodenum, and transverse colon. there was a 9 × 8-cm solid mass within the cavity arising from the adrenal gland. histological examination showed adrenal lipoma. the patient’s symptoms could be explained by the presence of right perinephric abscess, which possibly resulted in after percutaneous nephrolithotomy. perinephric abscess is a rare complication of percutaneous nephrolithotomy.(1) adrenal lipoma was an incidental finding complicated by perinephric abscess, which led to a presentation like a large tumor. although lipomas are benign tumors, surgical excision is recommended even for asymptomatic lesions because of the risk of developing malignancy.(2) manoj gupta, disha sood, amanjeet singh department of surgical gastroenterology, sir ganga ram hospital, new delhi, india e-mail: dramanarora03@yahoo.com references 1. liu yd, yuan j, li x, luo jt, zeng gh, wu kj. [complications of minimally invasive percutaneous nephrolithotomy]. zhonghua wai ke za zhi. 2008;46:200-2. chinese. 2. lam ky, c y lo. adrenal lipomatous tumours: a 30 year clinicopathological experience at a single institution. j clin pathol. 2001;54:707-12. urol j. 2009;6:162. www.uj.unrc.ir primary report of totally tubeless percutaneous nephrolithotomy despite pelvi-calyceal perforations seyed mohammad kazem aghamir1, alborz salavati1*, morteza hamidi2, asghar fallahnejad1 purpose: nephrostomy tube insertion and/or a ureteral stent placement is advised when pelvi-calyceal perforations are encountered during percutaneous nephrolithotomy (pnl) nevertheless totally tubeless pnl is a possible exit strategy in percutaneous renal surgery therefore case series on the short term clinical outcomes of noninvasive management of iatrogenic pelvicalyceal perforations encountered during pnl is presented. patients and methods: during retrospective analysis of 1271 pnl procedures, 25 incidents of accidental ureteral catheter/ jj stent dislodgement during first 24 post-operative hours were identified in patient who had pelvi calyceal perforations and had no nephrostomy tube (tubeless). thirteen patients could not be re-stented nor a nephrostomy tube could have been placed for them mainly due to patient refusal or comorbid conditions. the main outcome was rate of successful noninvasive management. results: eighteen patients bearing mucosal tears (grade i trauma) or visible peri-pelvic fat (grade ii) successfully recovered without need for ureteral stenting or nephrostomy (72.0%). in seven (28.0%) cases of extension of the perforation into the peri-pelvic fat (grade iii), either nephrostomy insertion or jj stenting was needed for resolution of fever and urinoma. the major limitation was the necessity to exclude patients and manage them in the standard fashion according to clinical guidelines. conclusion: iatrogenic perforations of the collecting system are quite diverse in terms of severity that result in different natural histories and not all might need urinary diversion via nephrostomy or ureteral stenting. low grade perforations may be successfully managed in totally tubeless fashion nevertheless further prospective investigations seem warranted. keywords: percutaneous nephrolithotomy; iatrogenic renal trauma; collecting system perforation; renal pelvis injury; urinary diversion introduction percutaneous nephrolithotomy (pnl) is the current mainstream procedure in nephrolithiasis management yet perforations of the collecting system are major complications which are routinely managed by nephrostomy and ureteral stent placement; except for the intra-peritoneal perforations that need more aggressive interventions. incidence of such complications are reported to be about 3.4 % according to large scale studies(1). over advancement of dilators further than the calyx , kinks in the guide wire, vigorous sheath manipulation in the vicinity of the pelvi-ureteral junction are known risk factors of collecting system perforation(2). current literature suggests intra renal free drainage which in most cases incorporates nephrostomy placement and/or double j ureteral stent (dj) insertion; as quoted in european guideline on renal trauma : “termination of pcnl if the renal pelvis is torn or ruptured is a safe choice. management requires close monitoring, placement of an abdominal or retroperitoneal drain, and supportive measures.”(3) the totally tubeless technique has been used at the end of a uncomplicated pnl which does not incorporate use of any ureteral stent or nephrostomy tube and relies on physiologic function of the ureter(4,5) as the natural drain. in many trials carried out in the beginning era of totally tubeless pnl the perforation of the collecting system was an exclusion(6). in our center, any violation of pelvi-calyceal integrity is managed by ureteral stenting (or dj), depending on the severity and nephrostomy is not a routine, therefore, there have been few unfortunate cases of ureteral stent or dj dislodgement in post pnl settings bearing collecting system perforations and in many instances the patient fully recovered not requiring any urinary diversion (neither nephrostomy nor a ureteral stent) despite the pelvi-calyceal perforation. such observation inspired us to investigate characteristics of iatrogenic pelvis perforations to identify patients who might not need any invasive intervention and would recover without either nephrostomy or dj stent (totally tubeless); according to the ongoing trial’s protocol, details on complications were recorded and used to form a grading system for collecting system perforations during pnl to help the surgeon identify those who could safely benefit from a totally tubeless pnl. 1sina hospital , imam khomeyni ave, tehran university of medical sciences , tehran , iran. 2imam reza hospital , fatemi ave. tehran , iran. *correspondence: tehran university of medical sciences, sina hospital, imam khomeyni ave, tehran university of medical sciences , tehran , iran. tel: +98 21 63120(481). e mail: alb_salavati@razi.tums.ac.ir. received september 2016 & accepted june 2017 endourology and stone disease vol 14 no 04 july-august 2017 4020 endourology and stone diseases 4021 patients and methods study population during february 2003 and june 2015 data on more than 1200 pnls at sina hospital a referral urology center of the tehran university of medical sciences, iran were gathered and retrospectively analyzed which identified 49 cases of collecting system perforations during pnl. cases in whom nephrostomy tube was inserted at the end of operation (standard pnl technique) were excluded. the remaining 26 had either undergone tubeless pnl (no nephrostomy but a ureteral stent inserted) or had been planned to have a total tubeless pnl (no nephrostomy and no ureteral stent) as a part of another clinical trial(7) but had been converted to tubeless pnl with ureteral catheter insertion because of pelvicalyceal perforations during operation ; both groups had left the operation room bearing a ureteral/ dj stent ; these cases were included in this case series. study design a retrospective re-analysis of totally tubeless percutaneous nephrolithotomy database(7,8) identified cases of iatrogenic pelvi-calyceal perforations that had been managed without use of nephrostomy tube or ureteral stents and data on baseline characteristics including depth of the perforation and short term clinical outcome of these patients were gathered to seek any correlation between the severity of the perforation and the clinical outcomes. the aghamir-salavati grading (table 1) for pelvi-calyceal perforation during pnl (based on nephroscopic direct visual assessment of perforation site) is used to categorize patients in three subgroups and need for further urinary diversion was assessed in these subgroups. patients in the observation group (n=13) were closely monitored by repeated abdominal examination every 6 hour checking for generalized abdominal tenderness or guarding and ultraonographic examination for expanding urinoma every 12 hours; adequate intravenous antibiotics were administered at full therapeutic dose (mainly cephalosporins plus aminoglycoside). in case of positive findings in abdominal examination or expanding urinoma, emergent intervention was contemplated (ureteroscopy and dj insertion). all patients (n= 25) had indwelling bladder catheters with free drainage until discharge. outcomes : clinically significant urinomas as identified by local tenderness, localized peritoneal irritation signs, signs of systemic inflammatory response or sepsis (pulse rates over 100/min, blood pressure less than 100mmhg, temperatures above 38.0 c ) and leukocytosis (wbc > 7500). the main outcome measure was rate of successful noninvasive management (full recovery in the same admission without re-stenting or the ureter or nephrostomy tube placement). statistical analysis odds of successful conservative management of perforations in different perforation grades were investigated in control and totally tubeless observation groups using pasw v.18 software using crosstab. results there was 49 pelvi-calyceal perforations in 1271 pnl operations (3.9%). twenty-three of them had undergone standard pnl (with nephrostomy tube and ureteral stent) so the early dislodgement of ureteral stent did not change their clinical course. one patient underwent immediate laparotomy and repair beside nephrostomy, dj and peritoneal drain placement. the remaining 25 perforations with early stent dislodgement had either undergone tubeless pnl (only ureteral stent or dj placed at the end of surgery) or were intended to have a totally tubeless pnl but were converted to tubeless and an externalized ureteral stent or dj was placed at the end of their surgery because of a perforation in the renal pelvis or calyces. a grade iii perforation was present in 7 (28.0%), there were 7 (28.0%) grade ii and eleven (44.0 %) grade i injuries. among these 25 perforation cases with ureteral stent dislodgement in the first 24 postoperative hours, 12 underwent immediate ureteroscopy and stenting (the totally tubeless pnl after pelvis perforations-aghamir et al. grade 1 a laceration limited to detached mucosa and submucosa with no visible fat tissue. grade 2 the adipose tissue is visible but no intrusions has been made. grade 3 the nephroscope or dilator has protruded into the peri-pelvic fat( a visible tract or space inside fat tissue is visible). table 1. the aghamir-salavati grading for pelvi-calyceal perforations during pnl (based on nephroscopic assessment ) perforation grading observation group immediate re-intervention total needing later dj insertion g1 6 0 (0%) 5 11 (44%) g2 4 0 (0%) 3 7 (28%) g3 3 3 (100%) 4 7 (28%) total 13 3 (23%) 12 25 table 2. frequency of different trauma grades in observation and re-stenting groups. control group) ; there were 4 ( 33.3 % ) grade iii , three (25.0%) grade ii and 5 (41.6%)grade i perforations (table 1).the remaining 13 patients were not fit for immediate intervention due to comorbid conditions (six ( 46.1 %) had grade i , four (30.7%) had grade ii and three (23.0%)had grade iii perforations) were considered as the case group. out of 13 patients in the no drainage group, six patients with grade i injury (46.2%) and four patients with grade ii injury (30.8%) were successfully managed conservatively without further need for intervention (77%) (p=.003; ci, 0.000-0.030). the longest hospital stay was 7 days. all grade iii patients (23.0%) developed abdominal guarding and expanding urinoma on ultrasonographic exam and underwent ureteroscopy and stenting between 3rd 5th postoperative days and were discharged on the 9th or 10th postoperative days. discussion in this retrospective study, data on conservative management ( no drainage ) of accidental early ureteral stent dislodgement in pnl patients with iatrogenic pelvi-calyceal system perforations were gathered and compared with a similar group of patients in whom immediate re-insertion of a dj stent was performed to describe different natural history of injuries of different depths. considering the possible ethical issues in designing a prospective study to observe the natural history of pelvi-calycea perforations of different severity, retrospective analysis of such cases is being presented comprising 13 cases of no drainage versus another group of 12 patient who had immediately undergone ureteroscopy and dj insertion after stent dislodgement. ten (77%) out of 13 totally tubeless (no drainage catheter) patients fully recovered without the need for re-stenting or nephrostomy; only three (23%) of them needed ureteroscopy and dj insertion for control of the urinoma and other adverse clinical conditions. all these three had grade iii aghamir-salavati pelvicalyceal trauma (visible fat at the trauma site which the nephroscope or grasper or lithotripter had intruded inside). six patient s bearing grade i (mucosal laceration/flap) and 4 grade ii (visible but intact fat at trauma site) finally recovered without need for re-intervention. the pnl procedure is a grade iv sharp renal trauma that in many instances could be managed without any ureteral stent or nephrostomy tube(9,10); it is proposed that the tract is sealed off by the recoil of the renal parenchyma and clot formation. currently totally tubeless percutaneous nephrolithotomy is considered a safe variant in selected cases(8,11) and perforations in the collecting system have been a known exclusion criteria to such exit strategy during pnl . in a retrospective large scale pnl complication reports(12) perforation rates were reported to be around 2% and peri-renal hematoma were observed in 7.5 % of pnl cases. not all perforations are clinically symptomatic. unfortunately reliable uniform data on conservative management of extra peritoneal iatrogenic pelvicalyceal perforations are rare in contrast to gasterointestinal complications of pnl(13) albeit there is a large body of evidence on conservative management of blunt and closed high grade renal traumas(2,14). similar reports of successful management of traumatic urinomas are available in pediatric trauma patients(15,16). it has been mentioned that many of these blunt traumatic cases needed angiographic intervention for bleeding control(17) but urinomas rarely needed any intervention other than antibiotics. unfortunately, these type of studiesmostly case reportsconsider dj stenting as a conservative approach and does not clarify the outcome of the group of patients who underwent stenting versus those that despite a urinoma had not undergone ureteral stenting or percutaneous drainage. the grading proposed here is based on results of the current case series that is a mere initial step toward differentiating those iatrogenic closed collecting system perforations which would not result in clinically symptomatic urinomas and therefore could be managed in a totally tubeless setting. ethical issues hindered us from designing an interventional human or animal survey nevertheless this observational study implicates that all iatrogenic perforations during pnl does not share the same natural history and if further investigated and correctly categorized might be managed differently according to the severity. such approach might relieve the need for dj stent placement after all perforations occurred during pnl. further investigations are warranted to clarify natural history of different types of iatrogenic pelvi-calyceal trauma which is the beginning of a change in post pnl complication management. conclusions iatrogenic perforations of the collecting system during pnl are quite diverse in terms of severity that result in different natural histories and not all might need urinary diversion via nephrostomy or ureteral stenting. low grade perforations may successfully be managed in totally tubeless fashion nevertheless further prospective investigations seem warranted. acknowledgements authors wish to thank kind support of all colleagues at "mizrah" department, and the "research development center" of sina hospital. conflict of interest the authors report no conflict of interest. references 1. de la rosette j, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol.25:11-7. 2. summerton dj, kitrey nd, lumen n, serafetinidis e, djakovic n. eau guidelines on iatrogenic trauma. eur urol.62:628-39. 3. taneja m, tan kt. renal vascular injuries following nephron-sparing surgery and their endovascular management. singapore medical journal. 2008;49:63-6. 4. aghamir sm, salavati a, aloosh m, farahmand h, meysamie a, pourmand g. feasibility of totally tubeless percutaneous nephrolithotomy under the age of 14 years: a randomized clinical trial. j endourol.26:621-4. 5. aghamir sm, hamidi m, aloosh m, totally tubeless pnl after pelvis perforations-aghamir et al. vol 14 no 04 july-august 2017 4022 mohammadi a, nikoobakht mr, meysamie a. efficacy and morbidity following pcnl in patients with renal anomalies: the outcome from a randomized study comparing different imaging modalities for assessment. minerva urol nefrol.63:207-12. 6. aghamir sm, modaresi ss, aloosh m, farahmand h, hosseini sh, meysamie a. which is access suitable for a solitary upper pole renal stone? a possible novel criterion. minerva urol nefrol.64:1-6. 7. aghamir sm, hosseini sr, gooran s. totally tubeless percutaneous nephrolithotomy. j endourol. 2004;18:647-8. 8. aghamir sm, elmimehr r, modaresi ss, salavati a. comparing bleeding complications of double and single access totally tubeless pcnl: is it safe to obtain more accesses? urol int. 9. aghamir sm, modaresi ss, aloosh m, tajik a. totally tubeless percutaneous nephrolithotomy for upper pole renal stone using subcostal access. j endourol.25:583-6. 10. ozturk h. tubeless versus standard pcnl in geriatric population. actas urol esp.39:494501. 11. jou yc, lu cl, chen fh, et al. contributing factors for fever after tubeless percutaneous nephrolithotomy. urology.85:527-30. 12. semins mj, bartik l, chew bh, et al. multicenter analysis of postoperative ct findings after percutaneous nephrolithotomy: defining complication rates. urology.78:291-4. 13. akbulut f, ucpinar b, savun m, et al. a major complication in micropercutaneous nephrolithotomy: upper calyceal perforation with extrarenal migration of stone fragments due to increased intrarenal pelvic pressure. case rep urol.2015:792780. 14. basiri a, mehrabi s, kianian h, javaherforooshzadeh a, kamranmanesh mr. blind puncture in comparison with fluoroscopic guidance in percutaneous nephrolithotomy: a randomized controlled trial. urol j. 2009;4:79-85. 15. kikuchi m, kameyama k, horie k, et al. [conservative management of symptomatic or asymptomatic urinoma after grade iii blunt renal trauma: a report of three cases]. hinyokika kiyo.60:615-20. 16. ho ym, schuetz m. grade 4 renal injury: current trend of management and future directions. chin j traumatol.14:120-2. 17. salem hk, morsi ha, zakaria a. management of high-grade renal injuries in children after blunt abdominal trauma: experience of 40 cases. j pediatr urol. 2007;3:223-9. totally tubeless pnl after pelvis perforations-aghamir et al. endourology and stone diseases 4023 sexual dysfunction and infertility 255urology journal vol 5 no 4 autumn 2008 effect of saffron on semen parameters of infertile men mohammad heidary,1 jahanbakhsh reza nejadi,2 bahram delfan,2 mehdi birjandi,2 hossein kaviani,3 soudabeh givrad4 introduction: we conducted this study to determine the effects of saffron (crocus sativus) on the results of semen analysis in men with idiopathic infertility. materials and methods: in this clinical trial, 52 nonsmoker infertile men whose problem could not be solved surgically were enrolled. they were treated by saffron for 3 months. saffron, 50 mg, was solved in drinking milk and administered 3 times a week during the study course. semen analysis was done before and after the treatment and the results were compared. results: the mean percentage of sperm with normal morphology was 26.50 ± 6.44% before the treatment which increased to 33.90 ± 10.45%, thereafter (p < .001). the mean percentage of sperm with class a motility was 5.32 ± 4.57% before and 11.77 ± 6.07% after the treatment (p < .001). class b and c motilities were initially 10.09 ± 4.20% and 19.79 ± 9.11% which increased to 17.92 ± 6.50% (p < .001) and 25.35 ± 10.22% (p < .001), respectively. no significant increase was detected in sperm count; the mean sperm count was 43.45 ± 31.29 × 106/ml at baseline and 44.92 ± 28.36× 106/ml after the treatment period (p = .30). conclusion: saffron, as an antioxidant, is positively effective on sperm morphology and motility in infertile men, while it does not increase sperm count. we believe further studies on larger sample sizes are needed to elucidate the potential role and mechanism of action of saffron and its ingredient in the treatment of male infertility. urol j. 2008;5:255-9. www.uj.unrc.ir keywords: male infertility, crocus sativus, antioxidants, sperm motility, sperm count 1department of urology, lorestan university of medical sciences, khorramabad, iran 2department of anesthesiology, lorestan university of medical sciences, khorramabad, iran 3shohada-e-ashayer hospital, lorestan university of medical sciences, khorramabad, iran 4urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: mohammad heidary, md urology and nephrology research center, no 44, 9th boustan st, pasdaran ave, tehran, iran phone: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: drheidary@yahoo.com received february 2008 accepted july 2008 introduction approximately, 8% of the iranian couples suffer from infertility after 2 years of attempting conception.(1) where the issue lies with the male partner, 2 groups of patients are seeking treatment, namely those suffering from idiopathic infertility and those in whom the etiology of infertility is known. various therapeutic agents including clomiphene citrate, tamoxifen, kallikreins, and antioxidant agents such as vitamin e and glutathione are used to help these patients; nevertheless, none is a definite treatment.(2-4) this necessitates utilization of other alternative agents. recent studies have investigated the role of reactive oxygen species (ros) on sperm. even though, small amounts of ros are necessary for sperm activation, these agents can cause damage to the sperm in higher concentrations.(5-7) increased levels of ros are related to decreased motility of the spermatozoa and dna damage, and may even lead to germ cell apoptosis.(8-12) in fact, studies have shown that more than saffron and semen parameters of infertile men—heidary et al 256 urology journal vol 5 no 4 autumn 2008 40% of infertile men have augmented levels of ros in their seminal plasma.(13) therefore, many studies have focused on antioxidant agents in order to prevent this damage on sperm metabolism, motility, morphology, and as a consequence, fertilizing capacity. crocus sativus (saffron) is a perennial herb of the iridaceae family with antioxidative prosperities.(14-16) it is widely cultivated in iran, india, greece, spain, and france. its dried red stigma is commercially used as a food spice. saffron has also been widely used in folk medicine as an antispasmodic, eupeptic, pain killer, anticatarrhal, carminative, diaphoretic, expectorant, stimulant, stomachic, aphrodisiac, and emmenagogue.(17,18) in some countries such as india, spain, and china, saffron has been used to treat infertility and impotence from long ago.(19,20) we undertook this study to investigate the effect of saffron on semen parameters and infertility. materials and methods between 2006 and 2007, we evaluated infertile men referring to the urology clinic of shohadae-ashayer hospital in khorramabad, iran. all patients were initially interviewed and questioned about their sexual behavior, history of prior surgical interventions or childhood diseases such as cryptorchidism that affect fertility, and family history of infertility. complete drug history was obtained; the patients were specifically asked about administration of sulfasalazine, cimetidine, marijuana, cocaine, and tobacco. moreover, history of contact with chemicals and ionizing radiation was acquired. all patients were then assessed for systemic diseases such as fever, viremia, and acute infections (eg, mumps). finally, the participants underwent full urologic examination. smokers and patients whose problems could be solved surgically were excluded. eligible patients provided informed consent and entered the study. the study protocol was approved by the ethics committee of the urology and nephrology research center, shahid beheshti university (mc). before initiating the treatment with saffron, semen analysis was performed. samples were obtained 48 to 72 hours after the patient’s last sexual contact. analyses were performed by the aid of the computer-assisted sperm analysis in less than 1 hour after sample collection. using this method, sperm motility was determined in 4 classes defined by the world health organization.(21) these 4 classes are characterized as follows: class a, fast progressively motile sperm (4th degree); class b, progressively motile sperm (3rd degree); class c, nonprogressively motile sperm (2nd degree); and class d, immotile sperm (1st degree). by the end of initial evaluation and semen analysis, the patients were asked to administer 50 mg of saffron solved in milk, 3 times a week for 3 months. a specific brand of the available saffron in khorramabad was obtained for all the patients. the amount to be used was weighed and divided in separate doses by the trained research assistants. no other treatment options were considered during the study period. after finishing the treatment course, semen analysis was again carried out by computer-assisted sperm analysis method. results were compared and analyzed by paired t test. results a total of 52 eligible patients were enrolled in the study, all of whom finished the study course and underwent a secondary semen analysis. the mean age of the patients was 31.0 ± 4.6 years (range, 21 to 48 years). the mean percentage of sperm with normal morphology was 26.50 ± 6.44% before the treatment which increased to 33.90 ± 10.45%, thereafter (p < .001), which corresponded to a 7.4% improvement in this index. significant increases were also seen in the percentages of class a to class c morphology of the sperm. the mean percentage of sperm with class a motility was 5.32 ± 4.57% before and 11.77% ± 6.07% after the treatment (p < .001). class b and c motilities were initially 10.09 ± 4.20% and 19.79 ± 9.11% which increased to 17.92 ± 6.50% (p < .001) and 25.35 ± 10.22% (p < .001), respectively. overall, 6.4%, 7.8%, and 5.6% increases were detected in the percentage of sperm with class a, b, and c motility, respectively. we could not detect a significant increase in terms of sperm count with saffron therapy; the mean sperm count was saffron and semen parameters of infertile men—heidary et al urology journal vol 5 no 4 autumn 2008 257 initially 43.45 ± 31.29 × 106/ml which changed to 44.92 ± 28.36× 106/ml, afterwards (p = .30). discussion about 8% of the iranian couples are infertile, and male factor accounts for nearly 40% of infertility cases.(1,22) recent advances in fertility medicine are indicative of ros, which impairs sperm function, as one of the reasons behind this dilemma.(1,8-13,23) as mentioned earlier, in contrast to the semen of a healthy man, seminal plasma of up to 40% of infertile men shows increased amounts of ros.(13) thus, reducing the ros may help in the treatment of male-factor infertility. pursuing this hypothesis, we examined saffron stigma as an antioxidant and found that semen parameters improved after a period of saffron administration. reactive oxygen species consist of a wide range of molecules including radicals, nonradicals, and oxygen derivatives.(22) a small amount of ros is necessary for the function of cells including germ cells. however, in increased levels, these molecules are capable of damaging cell membranes and genetic content. polyunsaturated fatty acids found in the sperm cell membrane are one of the primary targets of ros due to their lipid nature. reactive oxygen species cause lipid peroxidation in the sperm cell membrane, and as a result, impair sperm motility and its ability to fuse with the oocyte.(24,25) moreover, ros may induce dna damage, which in turn will result in poor fertilization. this dna damage happens through modification of all bases, production of base-free sites, deletions, frame shifts, dna cross links, and chromosomal re-arrangements. also, they may induce high frequencies of singlestrand and double-strand dna breaks.(11,12,24) finally, high levels of ros disrupt the inner and outer membranes of the mitochondria; as a consequence, cytochrome c is released and caspases are activated which lead to apoptosis.(24) antioxidants preserve fatty acids from oxidation, and therefore, may play an important role in male fertility.(25) many studies have investigated the role of different antioxidants on infertility. in an investigation by lenzi and colleagues, it was shown that utilizing glutathione (600 mg/d for 2 months) had a significant effect on increasing sperm motility and morphology.(26) they carried out another study in 1993 on 20 infertile men and re-established the role of glutathione in improving sperm motility and morphology.(27) in 1996, suleiman and coworkers determined the role of vitamin e in the treatment of infertile men. they treated 82 infertile men with vitamin e and demonstrated that sperm motility increased from 31.1% to 48.9%, compared to a slighter increase from 30.6% to 35.9% in the control group of infertile men.(28) in the group receiving vitamin e, 11 pregnancies took place, 9 of which led to birth; however, no pregnancies happened in the control group. in another research project, martin-du pan and sakkas treated 14 infertile men with vitamin e and gave another 20 infertile men glutathione.(29) they concluded that vitamin e improved sperm count, while glutathione increased sperm motility. five years later, ibrahim and colleagues investigated the effect of vitamin e on 65 infertile men.(30) sperm motility and sperm count increased from 32.46% and 11.9 × 106/ml to 37.2% and 12.15 × 106/ml in their patients, respectively. eskenazi and associates performed another study on 96 healthy male participants in california university in 2005.(31) they established the fact that using antioxidants (vitamin e, vitamin c, l-carnitine, and beta carotene) had beneficial effects on concentration and motility of the sperm; especially, class a motility. increased absorption of antioxidants led to increased effect on concentration and motility of the sperm. therefore, those with higher absorption, had 80 × 106/ml more sperm than those with lower absorption; furthermore, the number of sperm with class a motility was 36 × 106/ml more in those with a high absorption rate.(32) crocetin and dimethylcrocetin are derived from crocin which is a water-soluble carotenoid found in the stigmas of saffron.(16) their antioxidant effect has been documented in several studies.(14-16) we tested this effect on the sperm of infertile men and found no significant change in sperm count after a period of treatment with saffron; however, significant alterations were observed in sperm morphology and motility. the normal morphology of the sperm increased from a mean of 26.5% to 33.9%; class a motility was initially saffron and semen parameters of infertile men—heidary et al 258 urology journal vol 5 no 4 autumn 2008 5.3% that later increased to 11.8%. as for class b and c motility, the preliminary amounts of 10.1% and 19.8% changed to 17.9% and 25.4% after the treatment course, respectively. overall, the introductory amount of motile sperm (35.2%) increased to the final amount of 55.1%. although the study did not have the strength of a randomized controlled trial, results were promising and the effect of saffron on semen parameters was documented. this can be a basis of further investigation on saffron ingredients in infertility research. conclusion saffron has a positive effect on semen parameters in terms of sperm motility in men suffering from idiopathic infertility. it comprises several ingredients and even though its antioxidative effect may be the reason behind its positive value on spermatic parameters, further studies are required to define its exact mechanism of action. moreover, we acknowledge the need for further studies on larger groups of patients. we also believe that a longer period of follow-up, possibly up to 1 year, will be more beneficial in determining the role of saffron on seminal fluid. conflict of interest none declared. references 1. safarinejad mr. infertility among couples in a population-based study in iran: prevalence and associated risk factors. int j androl. 2008;31:303-14. 2. isidori am, pozza c, gianfrilli d, isidori a. medical treatment to improve sperm quality. reprod biomed online. 2006;12:704-14. 3. kumar r, gautam g, gupta np. drug therapy for idiopathic male infertility: rationale versus evidence. j urol. 2006;176:1307-12. 4. schiff jd, ramírez ml, bar-chama n. medical and surgical management male infertility. endocrinol metab clin north am. 2007;36:313-31. 5. de lamirande e, gagnon c. capacitationassociated production of superoxide anion by human spermatozoa. free radic biol med. 1995;18:487-95. 6. de lamirande e, gagnon c. a positive role for the superoxide anion in triggering hyperactivation and capacitation of human spermatozoa. int j androl. 1993;16:21-5. 7. ford wc. regulation of sperm function by reactive oxygen species. hum reprod update. 2004;10:387-99. 8. agarwal a, said tm. oxidative stress, dna damage and apoptosis in male infertility: a clinical approach. bju int. 2005;95:503-7. 9. wang x, sharma rk, sikka sc, thomas aj jr, falcone t, agarwal a. oxidative stress is associated with increased apoptosis leading to spermatozoa dna damage in patients with male factor infertility. fertil steril. 2003;80:531-5. 10. rao av, shaha c. role of glutathione s-transferases in oxidative stress-induced male germ cell apoptosis. free radic biol med. 2000;29:1015-27. 11. barroso g, morshedi m, oehninger s. analysis of dna fragmentation, plasma membrane translocation of phosphatidylserine and oxidative stress in human spermatozoa. hum reprod. 2000;15:1338-44. 12. kemal duru n, morshedi m, oehninger s. effects of hydrogen peroxide on dna and plasma membrane integrity of human spermatozoa. fertil steril. 2000;74:1200-7. 13. zini a, de lamirande e, gagnon c. reactive oxygen species in semen of infertile patients: levels of superoxide dismutaseand catalase-like activities in seminal plasma and spermatozoa. int j androl. 1993;16:183-8. 14. pham tq, cormier f, farnworth e, tong vh, van calsteren mr. antioxidant properties of crocin from gardenia jasminoides ellis and study of the reactions of crocin with linoleic acid and crocin with oxygen. j agric food chem. 2000;48:1455-61. 15. botsoglou na, florou-paneri p, nikolakakis i, et al. effect of dietary saffron (crocus sativus l.) on the oxidative stability of egg yolk. br poult sci. 2005;46:701-7. 16. kanakis cd, tarantilis pa, tajmir-riahi ha, polissiou mg. crocetin, dimethylcrocetin, and safranal bind human serum albumin: stability and antioxidative properties. j agric food chem. 2007;55:970-7. 17. basker, d, negbi, m. uses of saffron crocus sativus. econ bot. 1983;37:228-36. 18. ríos jl, recio mc, giner rm, máñez s. an update review of saffron and its active constituents. phytotherapy research. 1996;10:189-93. 19. chatterjee s, poduval tb, tilak jc, devasagayam tp. a modified, economic, sensitive method for measuring total antioxidant capacities of human plasma and natural compounds using indian saffron (crocus sativus). clin chim acta. 2005;352:155-63. 20. abdullaev fi. cancer chemopreventive and tumoricidal properties of saffron (crocus sativus l.). exp biol med (maywood). 2002;227:20-5. 21. world health organization. laboratory manual for the examination of human semen and semen-cervical mucus interaction. 4th ed. new york, ny: cambridge university press; 1999. 22. giudice lc. infertility and the environment: the medical context. semin reprod med. 2006;24:129-33. 23. agarwal a, prabakaran sa. oxidative stress and antioxidants in male infertility: a difficult balance. iran j of reprod med. 2005;3:1-8. saffron and semen parameters of infertile men—heidary et al urology journal vol 5 no 4 autumn 2008 259 24. agarwal a, makker k, sharma r. clinical relevance of oxidative stress in male factor infertility: an update. am j reprod immunol. 2008;59:2-11. 25. bolle p, evandri mg, saso l. the controversial efficacy of vitamin e for human male infertility. contraception. 2002;65:313-5. 26. lenzi a, lombardo f, gandini l, culasso f, dondero f. glutathione therapy for male infertility. arch androl. 1992;29:65-8. 27. lenzi a, culasso f, gandini l, lombardo f, dondero f. placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility. hum reprod. 1993;8:1657-62. 28. suleiman sa, ali me, zaki zm, el-malik em, nasr ma. lipid peroxidation and human sperm motility: protective role of vitamin e. j androl. 1996;17:530-7. 29. martin-du pan rc, sakkas d. is antioxidant therapy a promising strategy to improve human reproduction? are anti-oxidants useful in the treatment of male infertility? hum reprod. 1998;13:2984-5. 30. ibrahim om, al-azab ga, kolkaila aa, hegazy sk. clinical & biochemical study on the role of free radicals & antioxidants in male infertility. j pan-arab league dermatol. 2004;15:211-7. 31. eskenazi b, kidd sa, marks ar, sloter e, block g, wyrobek aj. antioxidant intake is associated with semen quality in healthy men. hum reprod. 2005;20:1006-12. 32. verma sk, bordia a. antioxidant property of saffron in man. indian j med sci. 1998;52:205-7. new section in urology journal fillers fillers are materials, including text and image, to be published in the blank spaces of the journal. the subject is not restricted, but those related directly or indirectly to medicine and urology are preferred. quotations, interesting pictures, historical notes, and notice on events are some examples. please contact the editorial office via e-mail (urol_j@unrc.ir) to send fillers. review urinary tract endometriosis anna kołodziej,1 wojciech krajewski,1* łukasz dołowy,1 lidia hirnle2 recently, occurrence of urinary tract endometriosis (ute) is more frequently diagnosed. according to literature, it refers to approximately 0.3 to even 12% of all women with endometriosis. the pathogenesis of ute has not been clearly explained so far. the actually proposed hypotheses include embryonic, migration, transplantation, and iatrogenic theory. most frequently ute affects bladder, less often ureters and kidneys. one-third of patients remains asymptomatic or exhibits only minor manifestations. in symptomatic patients main complaints include dysuria, urinary urgency, and/or frequency, painful micturition, and burning sensation in the urethra and discomfort in the retropubic area. treatment of ute is challenging and can be pharmacological, surgical or can be a combination of both methods. in this paper we present a review of the literature concerning the ute, its diagnosis and treatment. keywords: endometriosis; complications; diagnosis; urinary bladder; ureter. introduction endometriosis, the presence of endometrial tissue outside the uterine cavity, affects 5-15% of premenopausal females.(1) it is usually classified, according to the depth of invasion and anatomic location. one of the divisions differs 3 categories: peritoneal, ovarian, and deep infiltrating endometriosis.(2) deep infiltrating endometriosis (die) is defined as the implantation of endometrial glandular epithelium, and/or stroma and smooth muscle, penetrating walls of any pelvic organs or/and the retroperitoneal space to a depth of at least 5 mm.(1) recent studies have reported that foci of endometriosis may be supplied by nerves, lymphatic vessels, and blood vessels.(3,4) in recent years occurrence of urinary tract endometriosis (ute) has been more frequently diagnosed.(5) according to literature, ute refers to approximately 0.3 to 12% of all women with endometriosis.(6-9) most frequently ute affects bladder (80% of cases), less often ureters (14%) and kidneys (4%).(10) it is shown that in patients with die, involvement of the urinary tract can reach more than 52% of patients.(11) ute generally affects women of childbearing age. due to the regression of estrogen-dependent endometrial tissue, postmenopausal endometriosis is extremely rare. endometriosis during premenarchal period is occasional and only several cases have been documented in literature.(12,13) ute may be primary or secondary. the primary appears spontaneously in urinary tract and pertains to about 11% of women with die. the secondary occurs after pelvis surgeries such as caesarean section or hysterectomy.(14-16) approximately 50% of patients with endometriosis of the bladder or ureter underwent pelvis surgeries in the past. ute is often multifocal, and usually develops from the outer layer of bladder or ureter, penetrating deeper toward the mucosa. bladder trigone and bladder apex are the most often affected locations. the pathogenesis of ute has not been clearly explained so far. the actually proposed hypotheses include em1 department of urology, wrocław medical university, ul. borowska 213, 50-556 wrocław, poland. 2 department of gynaecology, wrocław medical university, ul. t. chałubińskiego 3, 50-368 wrocław, poland. *correspondence: wrocław medical university, borowska 213, wrocław, poland. tel: +71 7331010. e-mail: wk@softstar.pl. received november 2014 & accepted july 2015 bryonic, migration, transplantation, and iatrogenic theory. the first one is associated with the presence of remnants of the mullerian ducts, located mainly in the vesicouterine and vesicovaginal septum.(8,15) the migration theory, called also the reflux theory, claims the existence of menstrual blood regurgitation through the fallopian tubes into the pelvis and implantation of endometrial cells in the urinary system. this phenomenon is facilitated by the position of vesicouterine pouch.(17,18) at present, the most accepted is the theory of transplantation, according to which, endometrium cells are displaced through the lymphatic and circulatory system and implanted in the urinary system.(17,18) intraoperative iatrogenic spread of endometrial cells during operations is the basis of the last, the iatrogenic theory.(6,15) recently the case of scar related abdominal endometriosis in patient after bladder exstrophy reconstruction was reported.(19) urinary bladder endometriosis endometrial lesions affect mainly detrusor muscle in bladder trigone and bladder apex. symptoms depend on the location and size of changes.(15,20,21) one-third of patients remains asymptomatic or exhibits only minor complaints. diagnosis is made incidentally during periodic inspections or during the investigation into causes of infertility. in these asymptomatic cases, endometrial changes in bladder usually do not exceed 1-2 cm. in symptomatic patients main complaints include dysuria, urinary urgency, and/or frequency, painful micturition, and burning sensation in the urethra and discomfort in the retropubic area. these symptoms are recurrent in 40% of patients, usually occur in pre-menstruation period, and are often confused with symptoms of urinary tract infections. hematuria, which is widely regarded as the dominant symptom of ute, in fact concerns only 20-30% of patients. it is due to the fact, that endometriosis rarely infiltrates deep enough to cause ulceration of the urothelial mucosa.(22,23) differential diagnosis review 2213 includes chronic inflammation of bladder and overactive bladder. it is also vital to involve urinary bladder malignancies in differential diagnosis. bladder cancer can mimic endometriosis symptoms and may lead to therapeutic errors.(24) bimanual examination may reveal large foci of die. transabdominal, transvaginal, and transrectal ultrasonography (usg) might be useful in detecting smaller lesions and additionally hydroureteronephrosis can be shown. the specificity of well-performed usg is high and reaches almost 100%. unfortunately, detection of lesions smaller than 3 cm is often difficult, especially if the patient has undergone surgical procedures and sensitivity does not exceed 50%. cystoscopy is a mandatory test in suspected ute, although the cystoscopy may not be able to reveal shallow penetrating endometriosis. magnetic resonance imaging (mri) is considered to be the "gold standard" in ute diagnosis. according to the latest reports, if examination is performed on 3-tesla mri system, the sensitivity reaches 88% and specificity is higher than 98%.(25-28) urine examination performed to disclose possible hematuria is also recommended. recent study comparing three-dimensional color doppler usg with magnetic resonance imaging and cystoscopy in the diagnosis of bladder endometriosis showed that usg seems to be superior to cystoscopy and is at least as effective as mri in diagnosing and planning the surgery for bladder endometriosis.(29) morphology of endometrial changes can vary depending on phase of menstrual cycle. the most characteristic changes, observed just before and during menstruation, have irregular, nodal shape of different color (bluish-red, bluish-black or/and bluish-brown). during cystoscopy it is necessary to determinate distance between endometrial lesions and ureters openings. pathological changes situated closer than 2 cm from ureters openings may require replantation of ureter. it is also obligatory to perform biopsy, normally by transurethral resection of the bladder (turb), to exclude presence of bladder carcinoma, mesenchymal bladder tumor or/and uterine fibroids. treatment of bladder endometriosis there are no substantial guidelines for the treatment of ute due to the rarity of the disease, and the inability to conduct randomized trials. isolated reports of case series treatment are not entirely reliable, because of the different therapeutic success criteria adopted by the authors. treatment of ute depends on many factors, such as age of patients, extent of the disease, the severity of urinary tract symptoms and presence of other foci of endometriosis in the abdomen. in some cases fertility preferences should be taken into consideration. treatment of bladder ute can be pharmacological, surgical or can be a combination of both methods. pharmacological therapy of bladder ute is in fact designed to achieve regression of endometrial tissue. the ideal candidate for this procedure is menopausal female with single, small (less than 5 mm) endometrial focus in the bladder. the most commonly used drugs include gonadotropin releasing hormone (gnrh) analogues, gestagens, and combined oral contraceptive therapy. unfortunately almost 50% of patients with die do not respond to this therapy. additionally, side effects are frequent during pharmacological treatment. they include hot flashes, sleep disturbance and vaginal dryness when gnrh analogues are used, and breakthrough bleeding, weight gain, fluid retention, skin changes, hot flashes and loss of libido in case of gestagens therapy. relapses of symptoms are common when pharmacological therapy is discontinued. ability of endometric cells to migrate, metastasize, invade, and induce angiogenesis makes them similar to malignant cells. therefore, various anticancer drugs are being tested in the ute treatment. so far, only a combination of aromatase inhibitors with gestagens or gnrh analogues has proven its effectiveness, but because of the high complication rates and the large costs, it is not used in clinical practice.(30) surgery is the only treatment that gives a chance for a complete cure. there are many possibilities for surgical management of bladder endometriosis, ranging from endoscopic procedures such as turb and laparoscopic partial resection of the bladder to the total cystectomy. transurethral resection is contraindicated in die, since lesions infiltrate bladder from the outside toward mucosa and cannot be removed through the urethra. it is therefore essential to perform appropriate imaging and endoscopic visualization procedures. moreover, accurate evaluation of the size and location of endometric lesions in the bladder, including their relation to ureteral openings and the assessment of the upper urinary tract is very important. the most crucial task is to exclude neoplastic lesions. the therapeutic success can be achieved only by radical elimination of endometric tissue. incomplete removal of lesions is associated with relapses.(15,31,32) partial resection of the bladder, which is an excision of endometriotic lesions together with the entire thickness of the bladder wall and surrounding margin of normal tissue, is a procedure that allows maintaining the proper function of the bladder. there are several reports of high efficiency of both laparoscopic and classic partial cystectomy in alleviation of symptoms, improving the quality of life and recurrence-free survival.(6,7,15,20,31) the authors emphasize the desirability of double j ureteral catheter implantation preoperatively or intraoperatively if endometrial lesions are situated closer than 2 cm from the opening of the ureter. reconstruction of bladder in patients with multiple die foci in pelvis is very difficult and often requires multidisciplinary team compound of a gynecologist, an urologist, and not infrequently a surgeon of gastro-intestinal tract. nezhat and colleagues presented experience with robot-assisted laparoscopy in treatment of one patient with bladder endometriosis and two patients with urethral endometriosis. authors prove that this therapy can be feasible and safe option in patients with ute.(33) one of the major risk factors for treatment failure is the age of the patient. the younger is the patient, the greater is the risk of recurrence. endoscopic procedures (e.g. turb) associated with hormonal therapy are a satisfactory option in young patients willing to preserve fertility. however, failure indicator reaches 25-35%. (1,6,10) older patients approaching menopause may also benefit from this minimally invasive treatment option, as endometriosis is often spontaneously regressing after menopause.(12) ureteral endometriosis endometriosis of the ureter is second most common manifestation of ute. disease most often affects distal urinary tract endometriosiskołodziej et al. vol 12 no 04 july-august 2015 2214 part of left ureter, less commonly middle part and sporadic the proximal segment. bilateral manifestation of ureters is rare, occurs in 10-20% of patients.(6,8,10,14,15,17,34) interestingly, the proportion of left-oriented gonadal and ureteral lesions are remarkably similar (63% and 64%, respectively). this asymmetry in the endometriosis appearance seems to be consistent with the reflux theory and with existence of anatomical differences in the left and right sides of the abdomen. there are two main ureter endometriosis types the intrinsic and the extrinsic. the second type occurs four times more frequently. in the extrinsic ureter endometriosis, pathological tissue invades only the outer layer of the ureter, and in some cases may lead to obstruction of the ureter.(8,10,14) in case of inner ureter endometriosis lesions invade muscle layer, basement membrane and finally ureter lumen. these two pathological forms may coexist with each other. it is often impossible to determine which form of endometriosis is present in a particular patient before performing surgery. degree of ureter endometriosis invasion is specified and confirmed by examining histopathological samples. recently seracchioli and colleagues tried to evaluate the histological pattern of ureteral endometriosis (endometriotic or fibrotic ureteral endometriosis) on large group of patients. they proved that endometriotic pattern was more often occurring than fibrotic pattern. additionally, authors showed that endometriotic pattern was significantly more often associated with the presence of hydroureteronephrosis.(35) endometrial tissue located in ureter undergoes the same hormone-dependent periodic changes as normal uterine endometrium. this causes cyclical bleeding, desquamation of a lesion, necrosis, or fibrosis, which are followed by development of ureteral stenosis. ureter endometriosis usually gives non-specific symptoms associated with obstruction of the ureter, such as renal colic, back pain and in some cases hematuria. more than half of the patients report dyspareunia, dysmenorrhea, and pelvic pain. seracchioli and colleagues found that only 40% of the endometriotic patients were suspected of having ureteric endometriosis preoperatively based on clinical symptoms, ultrasound, and intravenous urography.(36) furthermore, exists a big group of completely asymptomatic patients.(11) there is a limited correlation between severity of symptoms and the degree of obstruction of the ureter. high degree of obstruction may proceed for a long time without symptoms (so-called silent obstructive uropathy), consequently leading to deterioration of renal function. loss of renal function occurs even in 2545% of cases. due to lack of specific symptoms for ureter endometriosis and the high risk of silent kidney function loss, ultrasound control is strongly recommended. usg should be performed in all patients with endometriosis, before and after surgery, and during pharmacological therapy. unfortunately, both ultrasound and other imaging tests (uro-ct, mri, intravenous pyelogram, urography) have limited value in providing accurate information about the extent of the disease and the degree of tissue infiltration. recent study conducted by sillou and colleagues endometriotic comparing mri with intraoperative and histological findings showed that mri may to be an efficient, non-invasive means of investigation for diagnosing urinary tract endometriosis. authors tried to predict whether the urinary tract lesions are intrinsic or extrinsic basing on mri imaging. they stand that mri is more sensitive than surgery (91% vs. 82%), but less specific (59% vs. 67%) in diagnosing intrinsic disease for ureteric sites of disease.(37) it should be remembered that endometriosis can mimic other pathologies, what most important, malignancy.(38) ureterorenoscopy with biopsy remains a most precise diagnostic option for patients with endometrial changes located in the ureter. this procedure allows confirming the diagnosis and often makes the endoscopic ablation of endometrial tissue possible.(39) treatment of ureteral endometriosis the choice of treatment for ureter endometriosis is subject of controversy. the main goal of treatment is to remove obstacles and allow free flow of urine through the ureter. results of the application of only hormonal therapy are often not satisfactory. it causes reduction of endometrial tissue but the existing obstacle, as a result of tissue fibrosis and existing adhesions, rarely disappears. hormonal therapy as the sole treatment option may be considered in young patients, who wish to become pregnant quickly. during this treatment active ultrasonographic urinary tract surveillance is strongly recommended to prevent appearance of hydroureteronephrosis, obstructive uropathy, and renal function loss. however, hormonal therapy can also be a valuable treatment option in patients with no significant scarring and/or fibrosis of the ureter. for years, surgery has been the preferred treatment form, especially for extensive and advanced ureter endometriosis. ureterolysis, which consist of exposing the ureter and freeing it from external lesions or adhesions, ureteroneocystostomy or ureterectomy with end-to-end anastomosis are basic methods of ureteric endometriosis treatment. all of those procedures can be successfully performed by laparoscopic way. this is due to the fact, that modern advanced laparoscopes provide very good visibility and allow exposure of endometrial nodules. additionally, laparoscopic procedures are much less invasive than open surgery. however, it is believed that ureterolysis is effective only when endometrial foci are small (less than 3 cm) and located superficially.(40) in cases of ureter die and in lesions closing the ureter lumen treatment failure rates are high. if hydroureteronephrosis maintains despite of performed ureterolysis, stenosis removal and re-anastomosis of ureteral ends is indicated.(40) in some cases it is necessary to perform ureteroneocystostomy, which is reimplantation of ureter into the bladder. it was shown in large retrospective study that ureteral reimplantation is a suitable technique in cases of severe distal ureteral stenosis, extensive ureteral involvement, or when ureterolysis or ureterectomy with end-to-end anastomosis are not feasible. authors proved that ureteral reimplantation gives good long term results, with no need for repeat surgical treatment.(41) after these procedures insertion of double j ureteral catheter is mandatory. isolated reports of successful of intrinsic ureteral endometriosis treatment by endoscopic laser ablation are available, however, that method requires confirmation in a larger number of surveys. relapse rate after non-radical removal of lesions is very high and reaches 30% of patients.(42) proper preoperative classification, determination of surgery extension, and experience in gynecological and urological laparoscopy is necessary to ensure therapeutic success and avoid complications. urinary tract endometriosiskołodziej et al. review 2215 conflict of interest none declared. references 1. olive dl, pritts ea. treatment of endometriosis. n engl j med. 2001;345:26675. 2. cordeiro gonzalez p, punal pereira a, blanco gomez b, lema grille j. bladder endometriosis: report of 7 new cases and review of the literature. arch esp urol. 2014;67:646-9. 3. mechsner s, schwarz j, thode j, loddenkemper c, salomon ds, ebert ad. growth-associated protein 43-positive sensory nerve fibers accompanied by immature vessels are located in or near peritoneal endometriotic lesions. fertil steril. 2007;88:581-7. 4. hsiao ky, chang n, lin sc, li yh, wu mh. inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis. hum reprod. 2014;29:2747-55. 5. hosseini sy, safarinejad m. endometriosis of the urinary tract: a report of 3 cases. urol j. 2005;2:45-8. 6. collinet p, marcelli f, villers a, et al. management of endometriosis of the urinary tract. gynecol obstet fertil. 2006;34:347-52. 7. nezhat c, nezhat f, nezhat ch, nasserbakht f, rosati m, seidman ds. urinary tract endometriosis treated by laparoscopy. fertil steril. 1996;66:920-4. 8. yohannes p. ureteral endometriosis. j urol. 2003;170:20-5. 9. razzaghi mr, rahjoo t, golshan a. endometriosis with pure urinary symptoms. urol j. 2009;6:132-4. 10. comiter cv. endometriosis of the urinary tract. urol clin north am. 2002;29:625-35. 11. knabben l, imboden s, fellmann b, nirgianakis k, kuhn a, mueller md. urinary tract endometriosis in patients with deep infiltrating endometriosis: prevalence, symptoms, management, and proposal for a new clinical classification. fertil steril. 2015;103:147-52. 12. maeda t, uchida y, nakajima f. vesical endometriosis following the menopause. int urogynecol j pelvic floor dysfunct. 2009;20:1515-7. 13. ebert ad, fuhr n, david m, schneppel l, papadopoulos t. histological confirmation of endometriosis in a 9-year-old girl suffering from unexplained cyclic pelvic pain since her eighth year of life. gynecol obstet invest. 2009:67:158-61. 14. chapron c, chopin n, borghese b, et al. deeply infiltrating endometriosis: pathogenetic implications of the anatomical distribution. hum reprod. 2006;21:1839-45. 15. donnez j, van langendonckt a, casanasroux f, et al. current thinking on the pathogenesis of endometriosis. gynecol obstet invest. 2002;54 suppl 1:52-8. 16. somigliana e, vercellini p, gattei u, chopin n, chiodo i, chapron c. bladder endometriosis: getting closer and closer to the unifying metastatic hypothesis. fertil steril. 2007;87:1287-90. 17. vercellini p, busacca m, aimi g, bianchi s, frontino g, crosignani pg. lateral distribution of recurrent ovarian endometriotic cysts. fertil steril. 2002;77:848-9. 18. vercellini p, frontino g, pisacreta a, de giorgi o, cattaneo m, crosignani pg. the pathogenesis of bladder detrusor endometriosis. am j obstet gynecol. 2002;187:538-42. 19. floyd ms, jr., mistry r, burrows ct, baird ad. abdominal endometriosis arising in an exstrophy patient. urol j. 2014;11:1844-6. 20. nezhat ch, malik s, osias j, nezhat f, nezhat c. laparoscopic management of 15 patients with infiltrating endometriosis of the bladder and a case of primary intravesical endometrioid adenosarcoma. fertil steril. 2002:78:872-5. 21. villa g, mabrouk m, guerrini m, et al. relationship between site and size of bladder endometriotic nodules and severity of dysuria. j minim invasive gynecol. 2007;14:628-32. 22. fauconnier a, chapron c, dubuisson jb, vieira m, dousset b, breart g. relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. fertil steril. 2002;78:719-26. 23. westney ol, amundsen cl, mcguire ej. bladder endometriosis: conservative management. j urol. 2000;163:1814-7. 24. genc m, genc b, karaarslan s, solak a, saracoglu m. endometriosis localized to urinary bladder wall mimicking urinary bladder carcinoma. arch ital urol androl. 2014;86:233-4. 25. balleyguier c, chapron c, dubuisson jb, et al. comparison of magnetic resonance imaging and transvaginal ultrasonography in diagnosing bladder endometriosis. j am assoc gynecol laparosc. 2002;9:15-23. 26. chamie lp, blasbalg r, pereira rm, warmbrand g, serafini pc. findings of pelvic endometriosis at transvaginal us, mr imaging, and laparoscopy. radiographics. 2011;31:e77-100. 27. manganaro l, fierro f, tomei a, et al. feasibility of 3.0t pelvic mr imaging in the evaluation of endometriosis. eur j radiol. 2012;81:1381-7. urinary tract endometriosiskołodziej et al. vol 12 no 04 july-august 2015 2216 28. saba l, sulcis r, melis gb, et al. endometriosis: the role of magnetic resonance imaging. acta radiol. 2015;56:355-67. 29. thonnon c, philip ca, fassi-fehri h, et al. three-dimensional ultrasound in the management of bladder endometriosis. j minim invasive gynecol. 2015;22:403-9. 30. bulun se. endometriosis. n engl j med. 2009;360:268-79. 31. seracchioli r, mabrouk m, montanari g, manuzzi l, concetti s, venturoli s: conservative laparoscopic management of urinary tract endometriosis ute. surgical outcome and long-term follow-up. fertil steril. 2010;94:856-61. 32. takamura m, koga k, osuga y, et al. postoperative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. hum reprod. 2009;24:3042-8. 33. nezhat c, hajhosseini b, king lp. roboticassisted laparoscopic treatment of bowel, bladder, and ureteral endometriosis. jsls. 2011;15:387-92. 34. karadag ma, aydin t, karadag oi, et al. endometriosis presenting with right side hydroureteronephrosis only: a case report. j med case rep. 2014;8:420. 35. seracchioli r, raimondo d, di donato n, et al. histological evaluation of ureteral involvement in women with deep infiltrating endometriosis: analysis of a large series. hum reprod. 2015;30:833-9. 36. seracchioli r, mabrouk m, manuzzi l, et al. importance of retroperitoneal ureteric evaluation in cases of deep infiltrating endometriosis. j minim invasive gynecol. 2008;15:435-9. 37. sillou s, poiree s, millischer ae, chapron c, helenon o. urinary endometriosis: mr imaging appearance with surgical and histological correlations. diagn interv imaging. 2015;96:373-81. 38. babu sm, sandeep p, pathade a, nagaraj hk. bleeding ureter: endometriosis mascarading as a ureteral malignancy a case report. j clin diagn res. 2014;8:nd10-11. 39. castaneda cv, shapiro ey, ahn jj, et al. endoscopic management of intraluminal ureteral endometriosis. urology. 2013;82:30712. 40. mu d, li x, zhou g, guo h. diagnosis and treatment of ureteral endometriosis: study of 23 cases. urol j. 2014:11:1806-12. 41. schonman r, dotan z, weintraub ay, et al. long-term follow-up after ureteral reimplantation in patients with severe deep infiltrating endometriosis. eur j obstet gynecol reprod biol. 2013;171:146-9. 42. fedele l, bianchi s, zanconato g, bergamini v, berlanda n, carmignani l. longterm follow-up after conservative surgery for bladder endometriosis. fertil steril. 2005;83:1729-33. urinary tract endometriosiskołodziej et al. review 2217 urological oncology determination of the safe surgical margin for t1b renal cell carcinoma kan zhang, wen lian xie* purpose: to determine the rational surgical margin for pathological t1b renal cell carcinoma (rcc). materials and methods: this retrospective study included surveys of 60 patients with t1bn0m0 rcc who underwent radical nephrectomy (rn, n = 40) or partial nephrectomy (pn, n = 20) between october 2008 and december 2014 at the sun yat-sen memorial hospital affiliated with zhongshan university. specimens were collected from 6 sites at the tumour periphery for rn and pn, and at suspected sites on the tumour surface for pn in addition. the histological subtype, pathological grade, surgical margin, pseudocapsule completeness, distribution of satellite foci, and largest distance between the extra-pseudocapsule lesion and primary tumour (dep) were evaluated. this paper will analyse the relationships between these factors. results: the positive surgical margin rate was 10% in patients undergoing pn. the study found no significant relationships between the incidence of satellite foci and tumour diameter, fuhrman grade, or histological subtype (all p > 0.05). however, male sex, positive surgical margins, and an incomplete pseudocapsule were associated with the incidence of satellite foci (p < 0.05). cases with satellite foci tended to show positive surgical margins. the dep was <1.0 mm for all tumours, but there were no significant relationships between the dep and the tumour diameter, pathological grade, or histological subtype (p > 0.05). conclusion: in t1b rcc, a 1-mm surgical margin would be sufficient to attain integrated resection of the primary tumour and its cancerous tissue beyond the pseudocapsule. pn was insufficient to prevent a positive surgical margin, most likely due to the presence of satellite foci. keywords: renal cell carcinoma; partial nephrectomy; distance of extra-pseudocapsule lesion; satellite tumours; safe surgical margin introduction presently, for t1a renal cell carcinoma (rcc) (< 4 cm in diameter), partial nephrectomy (pn) is recommended by the experts' consensus. however, pn is increasingly being used for resection of t1b rcc tumours (diameter, 4–7 cm). in the 2010 national comprehensive cancer network kidney cancer guidelines, pn and radical nephrectomy (rn) were suggested as standard surgical procedures for t1b rcc,(1) although the application of pn for t1b rcc remains controversial. the greatest concern for applying pn is the possibility of residual tumours. chen et al.(2) compared t1a and t1b rcc patients who underwent pn, and found that the pseudocapsule incompleteness rates and the incidence rates of lesions beyond the pseudocapsule were significantly higher in patients with t1b rcc, suggesting that pn is not very efficacious for eradication of t1b rcc. another concern is that pn is associated with operative complications, such as renal parenchyma damage and intrarenal arteries and collecting system lesion, which can cause urinary leak and bleeding(3) .pn also carries the postoperative risk of positive surgical margins. currently, there is no consensus(4–7) on whether positive surgical margins are a risk factor for rcc recurrence. similarly, there is no consensus on the rational management for patients with positive surgical margins after pn.(8) therefore, in order to avoid a positive surgical margin, it is imperative to excise all cancerous tissues completely during pn. as the practice of pn evolved and minimal invasive techniques were developed to maintain long-term renal function, the traditional surgical margin width was reduced from 1 cm to 0.5 cm for small local rcc tumours. in 2008, the chinese diagnosis and treatment of urological disease guide recommended a 0.5–1-cm surgical margin.(9) as early as 2003, li et al.(10) proposed that a 0.5-cm surgical margin was sufficient to eradicate lesions beyond the pseudocapsule in t1a rcc tumours. however, other studies have suggested that there were no relationships between surgical margin width and rcc progression, recurrence, or survival rates.(11–12) therefore, it is likely that a histologically confirmed tumour-free margin of resection, irrespective of margin width, is sufficient to achieve complete local excision of rcc. however, during pn, surgeons attempt to persist the normal renal parenchyma surrounding the tumour, which tends to make the surgical margin larger than desirable. to achieve a clear surgical margin, imaging modalities such as computed tomography and magnetic resonance imaging are used to locate the tumour and surrounding cancerous tissues. in addition, ultrasonography is used to locate suspected satellite foci urology surgery, sun yat-sen memorial hospital, sun yat-sen university, guangzhou, china. *correspondence: urology surgery, sun yat-sen memorial hospital, sun yat-sen university, guangzhou, china. tel: +86 13318868013. fax: +86 020 34070447. e-mail: wenlianxie@126.com. received august 2016 & accepted january 2017 urological oncology 2961 during pn,(12) but the risk of a positive surgical margin also depends on the surgeon’s perioperative predictions of pseudocapsule completeness and normal renal parenchyma capsule completeness around the tumour, which could result in widening margin during the surgery.(13) previous studies on the safe surgical margin for pn have mostly considered t1a rcc, but this may not translate well to t1b rcc.(14-15) this retrospective study aims to evaluate the rational margin for pn of t1b rcc tumours based on clinicopathological tumour features such as tumour size, pseudocapsule morphology, tumour histology, and the incidence of satellite foci. patients and methods study population in this retrospective study, we analyzed the data from patients with histological confirmed t1b rcc who underwent pn or rn (all operations were laparoscopic by two surgeons) at the sun yat-sen memorial hospital affiliated with zhongshan university between october 2008 and december 2014. after reviewing the patients’ medical records, we reviewed the patients’ medical records and identified 469 patients who met the following criteria: the presence of a single primary renal tumour; the absence of metastasis, as determined by preoperative computed tomography (ct) or magnetic resonance imaging (mri); and common histological rcc subtypes such as clear-cell, papillary-cell, and chromophobe-cell carcinomas. finally, we analyzed the data from 60 patients, 40 of whom underwent rn and 20 of whom underwent pn. histopathological analysis in order to determine the maximum tumour diameter, we fixed the 60 excised tumour tissues in 10% formalin and cut along the coronal plane of the kidney. for each tumour specimen, 6 circular specimens from the tumour surface measuring 1.4 × 1.4 × 0.4 cm3 were collected. these specimens were obtained from the centre of tumour and consisted of the primary tumour, tumour margins, and the normal renal parenchyma surrounding the primary tumour (figure 1). during the study period, the surgical margin apart from the tumour in pn was at least 0.5cm. for the 20 pn-excised tumours, suspected sites (without surrounding of normal renal parenchyma by naked eye) at the surgical margin were sampled to determine the surgical margin status. a total of 398 table 1: tumour-associated characteristics t1b rn pn pseudocapsule (n, %) complete 25 (41.7) 16 (64.0) 9 (36.0) non-infiltrating 6 (10) infiltrating 19 (37.1) incomplete 35 (58.3) 24 (68.6) 11 (31.4) no tumour invasion 16 (26.6) tumour invasion 13 (21.7) no pseudocapsule 6 (10) margin status (n, %)a positive 2 (10) negative 18 (90.0) satellite foci (n, %) positive 17 (28.3) 13 (76.5) 4 (23.5) negative 43 (71.7) 27 (62.8) 16 (37.2) abbreviations: rn, radical nephrectomy; pn, partial nephrectomy a margin status was evaluated in patients who underwent pn alone. dep(mm) t1b percentage% accumulative percentage % 0 16 55.2 55.2 0.01-0.50 7 24.1 79.3 0.51-1.00 6 20.7 100.0 *when pseudocapsule existed and was incomplete table 2. frequency distribution of dep vol 14 no 01 january-february 2017 2962 safe surgical margin for t1b rcc-zhang et al. specimens were paraffin-embedded, sectioned, and subjected to haematoxylin and eosin staining. slides were evaluated using a light microscope with a camera attachment. all the specimens were examined by one dedicated pathologist. tumour characteristics characteristic tumour features are shown in figure 2. a complete pseudocapsule was defined as being present when all tumour samples from the same patient had a pseudocapsule that continuously separated the tumour from the normal renal parenchyma. incomplete pseudocapsules was defined where is was found with : no tumour invasion (figure 2a), with tumour invasion beyond the pseudocapsule (figure 2b), or as a complete absence of pseudocapsule (figure 2c). the distance of the extra-pseudocapsule lesion (dep) was defined as the maximal distance from the outermost margin of the primary tumour to the outermost layer of the pseudocapsule, as measured to a precision of 0.01 mm (figure 2d). the dep was defined as 0 mm when incomplete pseudocapsule had no tumour invasion. the status of the surgical margin was described as positive if tumour cells were present, and was described as negative if they were not. satellite foci were defined as small distinct focal points of tumour cells outside the pseudocapsule and departed from the primary tumour (figure 2e).(1617) outcome assessment spss®, version 19.0 (ibm, armonk, ny, usa) and excel® 2010 (microsoft, redmond, wa, usa) were used for all statistical analysis. differences between the rn and pn groups were evaluated using student’s t-test or the chi-square test. differences among factors possibly affecting dep were evaluated using the analysis of variance (anova). relationships between variables were evaluated using a pearson’s correlation test. the two-sided alpha level of 0.05 and a p-value of < 0.05 were considered statistically significant. all procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. results histopathological tumour-associated characteristics safe surgical margin for t1b rcc-zhang et al. table 3: frequency of dep according to tumour diameter, fuhrman grade, and histological subtype dep p value n x ± sd tumour diameter (cm)a 4.1–5.0 7 0.61 ± 0.17 5.1–6.0 3 0.37 ± 0.24 .015 6.1–7.0 3 0.18 ± 0.11 .006 fuhrman grade a .070 high differentiation 7 0.58 ± 0.15 moderate differentiation 4 0.24 ± 0.15 low differentiation 2 0.43 ± 0.47 histological type a na clear-cell 13 0.45 ± 0.25 papillary-cell 0 0 chromophobe-cell 0 0 abbreviations: dep, distance of the extra-pseudocapsule lesion; sd, standard deviation; na, non-applicable a analysis of variance (anova) figure 1. diagrammatic representation of tumour sampling regions the tumour edge close to the pelvis (a), the tumour edge close to the renal parenchyma and medulla (c, d, e, and f), and the tumour edge close to the renal capsule (b). urological oncology 2963 the pseudocapsule morphologies, margin statuses, and existence of satellite foci are shown in table 1, both for the overall patient cohort and groups according to the surgical procedure. there was no significant difference in rates of pseudocapsule completeness according to surgical modality. the majority of patients did not have satellite foci.in the pn group, the majority of patients had negative surgical margins. factors affecting the dep distribution of dep was shown in table 2. dep varied significantly as tumour diameter increased. this appeared to indicate an association between increasing tumour size and decreasing dep which failed to achieve statistical significance. in addition, there were no significant correlations between dep and pathological grade. all cases of rcc infiltrating beyond the pseudocapsule into normal parenchyma were clear-cell carcinomas (table 3). factors associated with the incidence of satellite foci we evaluated the relationship between clinicopathological parameters and the incidence of satellite foci (table 4). in 17 cases of positive satellite foci, the distances between the primary tumour and the satellite focus ranged from 0.5 mm to 5.2 mm. the presence of satellite foci was not associated with tumour diameter, fuhrman grade, or histological subtype (p > 0.05), but was associated with sex and pseudocapsule completeness (p < 0.05). male patients and patients with an incomplete pseudocapsule were more likely to have satellite foci. discussion numerous clinical studies have indicated that pn and rn have comparable effective local control and disease-specific survival rates in patients with t1b rcc. (18–19) the major concern for the application of pn is the risk of incomplete tumour excision because of tumour extension beyond the pseudocapsule or the presence of satellite foci, which are difficult to detect both by using imaging modalities. in addition, discrepancies concerning the appropriate surgical margin width have been a cause for concern.(20–21) the traditional tumour excision margin of 5–10 mm was applied. however, without a reference point, it was impossible to excise the thick parenchyma that surrounds the primary tumour evenly, because the bottom of the margin was usually thinner than the rest of the margin.(24) in addition, thicker surgical margins are difficult to achieve by laparoscopic pn within 20–30 min of hot ischemia, which can lead to an increased risk of complications. all deps in the present study were well within the traditional surgical margin width. based on the dep, a 1-mm surgical margin would be sufficient to attain table 4: factors associated with the incidence of satellite foci variable satellite foci p value negative positive sex a male 29 (64.4) 16 (35.6) .032 female 14 (93.3) 1 (6.7) tumour diameter (cm) a 4.1–5.0 21 (80.8) 5 (19.2) .385 5.1–6.0 14 (63.6) 8 (36.4) 6.1–7.0 8 (66.7) 4 (33.3) fuhrman grade a high differentiation 28 (77.8) 8 (22.2) .433 moderate differentiation 12 (63.2) 7 (36.8) low differentiation 3 (60.0) 2 (40.0) margin status a negative 16 (88.9) 2 (11.1) .003 positive 0 (0.0) 2 (100.0) histological subtype a clear-cell 35 (71.4) 14 (28.6) .988 papillary-cell 5 (71.4) 2 (28.6) chromophobe-cell 3 (75.0) 1 (25.0) pseudocapsule a complete 22 (88.0) 3 (12.0) .018 incomplete 21 (60.0) 14 (40.0) a chi-square test vol 14 no 01 january-february 2017 2964 safe surgical margin for t1b rcc-zhang et al. integrated resection of the primary tumour and its cancerous tissue beyond the pseudocapsule. however, this margin was not sufficient for two patients who did show positive surgical margins, most likely because those patients had satellite foci. this suggests that, although pn with a surgical margin <1 mm might be useful for preventing positive surgical margins by removing residual tumour, it might not be sufficient for preventing positive margins caused by satellite foci. in the present study, the incidence rate of satellite foci was 28.3%, in this study, the satellite foci incidence rate was higher than the positive surgical margin rate of 10.0%. a similar finding was reported in a previous study of local rcc after pn; the satellite foci incidence rate was 15.7% and the positive surgical margin rate was 0.0–7.0%.(11,22) it is likely that some correlation exists between satellite foci and positive surgical margin. in 17 cases, the distance between satellite foci and the primary tumour was 0.5–5.2 mm. however, because the measured distance was limited by pathological sampling, only those foci in proximity to the tumour could be observed. this may result in false negative findings. in 32 cases of multicentric foci, li et al.(11) found that 23 cases were < 8 mm from the primary tumour, but 9 cases were about 30 mm (range:15–60 mm) . loran et al. indicated that the distance between multicentric foci and the primary tumour was more than 20mm.(25) taken together, these results suggest that the traditional surgical margin width of 5–10 mm would not be sufficient to remove satellite foci. local recurrence after pn is more likely attributable to satellite foci, rather than (in any substantial sense) residual tumour caused by incomplete removal of the primary tumour. some researches show positive surgical margins have been shown to increase the recurrence risk after pn, but did not affect the survival of patients. however, others proved positive surgical margins did not affect local recurrence or metastases risks after pn.(22) there are a number of factors that may explain why having a positive surgical margin did not appear to affect clinical efficacy in these studies.(23) as mentioned above, because either ectomy does not completely clear up the satellite foci, it makes no obvious difference to overall survival no matter whether the surgical margin is positive or negative. in general, a narrow surgical margin width is recommended in t1a rcc, but we do not advocate tumour enucleation for t1b rcc. in the present study, the incomplete pseudocapsule rate in patients with t1b rcc was much higher than that reported for t1a rcc.(2) even if the pseudocapsule was complete, tumour invasion of the pseudocapsule was prevalent(76%). besides, there is a risk of disrupting the pseudocapsule during tumour enucleation, which could lead to tumour dissemination. both minervini et al.(26) and ficarra et al.(21) demonstrated that cancer cells could be separated from the surgical margin by a thin layer of chronically inflamed tissues. however, some sites with incomplete pseudocapsule did not show an inflammatory layer enveloped (figure 2b). these results may narrow applications of tumour enucleation, especially for highly malignant t1b rcc or tumours with an incomplete pseudocapsule. there were some limitations in this study: 1) to meet the inclusion of this study and to match paired groups demand, it can only recruit 60 patients in all, the number of patients is relatively small; 2) although the presence of satellite foci and their exact location could be better evaluated in a radical nephrectomy specimen rather than a partial specimen, more and more patients choose to use partial nephrectomy. so there is great significance to explore the relationship between satellite foci and surgical margin in partial nephrectomy; 3) the follow-up is not long enough to study the long term prognosis. conclusions in t1b rcc, a 1-mm surgical margin was sufficient to excise the primary tumour and its residual tissue beyond the pseudocapsule. however, the presence of satfigure 2. histological tumour features (a) incomplete pseudocapsule with no tumour invasion (b) incomplete pseudocapsule with tumour invasion (c) incomplete pseudocapsule with a complete absence of tumour capsule (d) the dep (e) satellite foci ps, pseudocapsule; t, tumour; st, satellite foci; dep, distance of the extra-pseudocapsule lesion urological oncology 2965 safe surgical margin for t1b rcc-zhang et al. ellite foci might cause a positive surgical margin. the incidence of satellite foci was associated with male sex and an incomplete pseudocapsule in patients who underwent laparoscopic pn. therefore, we conclude that laparoscopic pn is not sufficient to remove satellite foci in patients with t1b rcc. acknowledgement this study was approved in department of urology surgery, sun yat-sen memorial hospital affiliated with zhongshan university, as a research project. the authors would like to thank dr. wenlian xie and appreciate his support for the preparing of this manuscript. conflict of interest the authors report no conflict on interests. references 1. motzer rj, jonasch e, agarwal n, et al. kidney cancer, version 2.2014. j natl compr canc netw. 2014;12:175–82. 2. chen xs, zhang zt, du j, bi xc, sun g, yao x. optimal surgical margin in nephronsparing surgery for t1b renal cell carcinoma. urology. 2012;79:836–9. 3. becker a, ravi p, et al. laparoscopic radical nephrectomy vs laparoscopic or open partial nephrectomy for t1 renal cell carcinoma: comparison of complication rates in elderly patients during the initial phase of adoption. urology. 2014;83:1285–91 4. halpem ej, mitchell dg, wechsler rj, outwater ek, mortiz mj, wilson ga. preoperative evaluation of living renal donors: comparison of ct angiography and mr angiography. radiology. 2000;216:434–9. 5. peycelon m, hupertan v, comperat e, et al. long-term outcomes after nephron sparing surgery for renal cell carcinoma larger than 4 cm. j urol. 2009;181:35–41. 6. marszalek m, meixl h, polajnar m, rauchenwald m, jeschke k, madersbacher s. laparoscopic and open partial nephrectomy: a matched-pair comparison of 200 patients. eur urol. 2009;55:1171–8. 7. yossepowitch o, thompson rh, leibovich bc, et al. positive surgical margins at partial nephrectomy: predictors and oncological outcomes. j urol. 2008;179:2158–63. 8. bensalah k, pantuck aj, rioux-leclercq n, et al. positive surgical margin appears to have negligible impact on survival of renal cell carcinomas treated by nephron-sparing surgery. eur urol. 2010;57:466–71. 9. marszalek m. positive surgical margins after nephron-sparing surgery. eur urol. 2012;61:757–63. 10. na yanqun. diagnosis and treatment of urological disease guide (2008, chinese edition). beijing, china: people's medical publishing house; 2008. 11. li ql, guan hw, zhang qp, zhang lz, wang fp, liu yj. optimal margin in nephronsparing surgery for renal cell carcinoma 4 cm or less. eur urol. 2003;44:448–51. 12. piper ny, bishoff jt, magee c, et al. is a 1-cm margin necessary during nephronsparing surgery for renal cell carcinoma? urology. 2001;58:849–52. 13. castilla ea, liou ls, abrahams na, et al. prognostic importance of resection margin width after nephron-sparing surgery for renal cell carcinoma. urology. 2002;60:993–7. 14. wang h, gao zl, lin ch, et al. laparoscopic partial nephrectomy for t1a renal tumors is safe and feasible. chin med j (engl). 2011;124:2243–7. 15. méjean a. how far should partial nephrectomy be extended for renal cell carcinoma? ann urol (paris). 2006;40 suppl 3:s68–s71. 16. fang xie. intraoperative ultrasonic monitoring to assist nephron sparing surgery for solitary kidney renal carcinoma. j clin urology (china). 2013;28:1–5. 17. dimarco ds, lohse cm, zincke h, cheville jc, blute ml. long-term survival of patients with unilateral sporadic multifocal renal cell carcinoma according to histologic subtype compared with patients with solitary tumors after radical nephrectomy. urology. 2004;64:462–7. 18. sorbellini m, bratslavsky g. decreasing the indications for radical nephrectomy: a study of multifocal renal cell carcinoma. front oncol. 2012;2:84. 19. leibovich bc, blute ml, cheville jc, lohse cm, weaver al, zincke h. nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. j urol. 2004;171:1066–70. 20. thompson rh, siddiqui s, lohse cm, leibovich bc, russo p, blute ml. partial versus radical nephrectomy for 4 to 7 cm renal cortical tumors. j urol. 2009;182:2601–6. 21. ficarra v, galfano a, cavalleri s. is simple enucleation a minimal partial nephrectomy responding to the eau guidelines' recommendations? eur urol. 2009;55:1315– 8. 22. li ql, guan hw, zhang qp, et al. study of the genesis of multicentricity in renal cell carcinoma. chinese j urol. 2003;24:232–34. 23. stephens r, graham sd jr. enucleation of tumor versus partial nephrectomy as conservative treatment of renal cell carcinoma. cancer. 1990;65:2663–7. 24. blackley sk, ladaga l, woolfitt ra, schellhammer pf. ex situ study of the effectiveness of enucleation in patients with renal cell carcinoma. j urol. 1988;140:6–10. 25. loran ob, seregin av, tsyganove se. vol 14 no 01 january-february 2017 2966 safe surgical margin for t1b rcc-zhang et al. a multicentric variant of renal carcinoma growth. urologiia. 2003;5:13–15. 26. minervini a, di cristofano c, lapini a, et al. histopathologic analysis of peritumoral pseudocapsule and surgical margin status after tumor enucleation for renal cell carcinoma. eur urol. 2009;55:1410–8. urological oncology 2967 safe surgical margin for t1b rcc-zhang et al. robotic or open radical prostatectomy in men with previous transurethral resection of prostate mahmoud mustafa,¹ john w davis,² sacit nuri gorgel,³ louis pisters² purpose: to assess and compare the surgical, oncological and functional outcomes of robotic and open radical prostatectomy (rp) in patients with history of transurethral resection of prostate (turp). material and methods: total of 48 patients with mean ± sd age of 64.5 ± 6.0 years who had undergone turp prior to rp were included. thirty-one (64.58%) patients underwent robotic rp (group i) and 17 patients underwent open rp (group ii). variables evaluated included demographic characteristics, perioperative complications, functional and oncological outcomes. biochemical recurrence (bcr) was defined as a detectable level of serum psa after rp. continence was defined as being pad free and potency as erection with or without medication enough for penetration. results: all patients had undetectable psa after rp. four patients (12.9%) from group i and 2 patients (11.8%) from group ii had positive margins (p = .9). the rates of continence were 70% and 80.81% for group i and group ii respectively (p = .47). potency rate was 68.2% in group i and 46.1% in group ii (p = . 31). the psa value at the last follow-up was undetectable except in 2 patients who had psa values of 0.2 and 1ng/ml respectively. conclusion: robotic or open rp can be performed safely and effectively after turp without compromising the oncological results. the outcomes of robotic rp are comparable to that of open rp. the patients who undergo robotic or open rp should be informed about increased likelihood of intra operative complications and worse post operative functional outcomes with respect to continence and erectile function. keywords: prostate; prostate cancer; radical prostatectomy; robotic surgical procedures; transurethral resection of prostate. introduction both, lower urinary tract symptoms as a result of prostate enlargement and prostate cancer are common in elderly men. therefore, it is not uncommon for men to be diagnosed of cancer on transurethral resection of prostate (turp) chips or to develop prostate cancer after having undergone turp for benign prostatic enlargement. such men present different outcomes on radical prostatectomy (rp) compared to those who have no previous intervention. the relative paucity of the number of patients who underwent a previous turp makes any comparative study analysis somewhat difficult and also is a reflection of the few available studies on his subject in the literature. it is considered that previous prostatic resection may hinder optimal outcomes for radical prostatectomy in several ways(1-5). several studies have suggested that the outcomes of rp in men who have previously undergone pelvic or prostate surgeries are relatively poorer than those who have not undergone such surgery(6-8). in a recent study we had evaluated the feasibility and safety of open or robotic rp after previous pelvic surgery and we concluded that open or robotic rp can be done safely and effectively in patients who have previously undergone pelvic surgery(7). to our knowledge there is no study comparing the safety and efficacy of robotic or open rp in patients with prior turp. the objective of the present study was to assess and compare the periand postoperative outcomes of patients with a history of turp who underwent robotic or open rp for prostate cancer. materials and methods the study population consisted of a consecutive series of 2400 men who had rp for prostate cancer between january 2007 and january 2011 at the university of texas md anderson cancer center. in all, 48 patients with mean ± sd age of 64.5 ± 6.0 years who underwent open or robotic rp after prior turp were identified. thirtyone (64.6%) patients (group i) underwent robotic rp and 17 patients (35.4%) (group ii) underwent open rp. the medical records of both groups were evaluated and compared in term of preoperative, intraoperative parameters and the oncological and functional outcomes. thirty-five patients 74.9% had standard tur and 13 (27.1%) patients had laser prostatectomy (p =. 34). the patients who underwent robotic rp usually had low stage and grade. the mean period between prior turp and rp was 54.4 ± 68.6 months (range; 2-336). the mean values of preoperative psa for group 1an-najah national university, faculty of medicine and health science, urology department, nablus, west bank, palestine. 2anderson cancer center, urology department, university of texas, houston, texas, united states. 3izmir katip celebi university, medical school, urology department, izmir, turkey. *correspondence: department of urology, an-najah university hospital, nablus-west bank, palestine. tel: 009-72-02390390. fax: 009-72-02390316. mobile;009-069-662988. dr_mahmoud681@yahoo.com. received may 2016 & accepted december 2016 laparoscopic urology laparoscopic urology 2955 i and group ii were 5.5+4.3 ng/ml and 2.9+2.3 ng/ ml respectively (p = .73) (table1). thirteen patients (27.1%) were diagnosed by tur while the remaining patients were diagnosed by transrectal ultrasound biopsy. the performance of neurovascular bundle (nvb) preservation and pelvic lymph node dissection (plnd) were dependent on the patient’s preoperative serum psa levels, clinical stage of prostate cancer and gleason score. the extended lymph adenectomy included obturator, hypogastric, and external iliac lymph nodes. ethical approval from md anderson cancer center was obtained and the study was carried out in compliance with the helsinki declaration. biochemical recurrence (bcr) after rp was defined as a detectable level of serum psa after rp. patients were considered to be continent if they were pad free or small liner daily for security purposes only. patients were considered to have erectile function if they could achieve erections with or without medication that were adequate enough for penetration intercourse. the mean hospitalization for group i and group ii were 3 ± 2.6 and 4.5 ± 3.4 days respectively (p = .19). the mean follow-up periods for group i and group ii were 15.5 ± 1.8 and 18.5+1.6 months respectively (p = .99). spss ver. 10.0 (spss inc., chicago, il, usa) was used for the statistical analysis. a p-value of greater than 0.05 was accepted as insignificant. comparison between the parameters of subgroups was calculated by use of student t-test, the mann whitney u test, and chisquare tests. radical prostatectomy after turp-mustafa et al. results none of the robotic rp patients needed open conversion. the mean operative time for group i and group ii were 277.4 ± 518.6 and 324.6 ± 159.0 minutes respectively (p = .33). blood loss for patients in group i and group ii were 250.7± 324.0 and 911+785.3 ml respectively (p = .01). intraoperative findings, functional and oncological outcomes are shown in table 2. blood transfusion was done for 1 patient (3.2%) in group i and for 2 patients (17.6%) in group ii. plnd was done for all patients in group ii and for 20 patients (64.5%) in group i (p = .005). nvb preservation were performed for 18 patients (58.1%) and 8 patients (47.1%) in group i and group ii respectively (p = .46). the numbers of lymph node yields were equal for both groups (p = .24). two patients had positive lymph nodes involvements (6.4%) in group i and 1 patient (5.9%) in group ii (p = .67). rectal injury occurred in 1 patient (3.2%) from group i and in 1 patient (5.9%) from group ii. two patients had ureter transaction from the series of open rp. no urethral stricture was observed. positive surgical margins (psm) were detected in 4 patients (12.9%) from group i and in 2 patients (11.8%) from group ii (p = .9). post operative serum psa level was undetectable in all patients. biochemical recurrence occurred in 1 patient (3.2%) from group i and in 3 patients (17.5%) from group ii (p = .02). the median values of psa at bcr were 0.3 ng/ml (range, 0.2-0.4). three patients received salvage radiotherapy and 1 patient received salvage hormonal therapy. continence data at table 1. the pre-operative demographic characteristics. variable a robotic rp open rp total p patients 31(64.58) 17 (35.41) 48(100) age year, (mean+ sd) 66.2 ± 5.5 64.7 ± 5.8 64.5 ± 6.0 0.74 standard turp 24/31(77.41) 13/17 (76.47) 35/48 (72.91) 0.34 laser turp 7/31(22.58) 6 (35.29) 13/48 (27.08) interval between tur and rp month (mean+sd) 76.11 ± 7.1 30.5 ± 3.3 54.4 ± 68.6 0.025 volume of prostate ml (mean+sd) 38.3 ± 2.89 40.4 ± 2.7 37.2 ± 21.6 0.59 initial psa ng/ml , (mean+sd) 6.4 ± 4.1 6.4 ± 4.8 5.7 ± 4.1 0.91 preoperative psa ng/ml (mean+sd) 5.5 ± 4.3 2.9 ± 2.3 4.4 ± 3.3 0.73 gleason (score) 0.03 6 12 (38.7) 3 (17.64) 15 (31.25) 7 16 (51.61) 8 (47.05) 24 (50) 8 2 (6.4) 2 (11.76) 4 (8.33) 9 1(3.22) 3 (17.64) 4 (8.33) 10 0 1(5.88) 1(2.1) clinical stages 0.23 t1c 26 (83.87) 9 (52.94) 35 (72.91) t2 5 (16.12) 7(41.17) 12(25) t4 0 1(5.88) 1(2.1) abbreviations: rp, radical prostatectomy; psa, prostate specific antigens; turp, transurethral resection of prostate. a data are presented as no. of patients (%) unless otherwise indicated. vol 14 no 01 january-february 2017 2956 6 months follow up were available for 31 patients; the rates of continence in group i and group ii were 70% and 81.8% respectively (p = .47). erection function data were available on 35 patients. twenty-one patients (60%) were able to achieve erection with or without medical aid (i.e phosphodiesterase-5 inhibitors, intracavernous injection or vacuum). the psa value at the last follow-up was undetectable in all patients in group i. three patients in group ii had detectable psa level at last follow up; 0.2, 0.6 and 1 ng/ml respectively. postoperative complications were mild and did not mandate surgical intervention except in one patient who developed hematuria due to benign polpoid mass at the vesico-urethral anastomosis which underwent transurethral resection. three patients developed lymphocele which resolved spontaneously and one patient had prolonged leakage on the cystogram. perioperative data and complications using the clavien classification system were illustrated in table 3. discussion the rate of prostate cancer detection revealed by transurethral resection of prostate or prostatectomy in patients with both negative psa levels and negative digital examination findings is 6.4%(9). the reports are conflicting as to whether or not previous turp worsen the prognosis after radical prostate surgery as a result of fibrous scaring and altering tissue layers associated with difficult surgical procedures. some authors considered prior turp as a risk factor for anastomotic stricture, erectile dysfunction, and urinary incontinence, although several studies have not demonstrated any increased morbidity or detrimental effect on the oncological or functional results(6,8,10,11). the outcomes of robotic rp are comparable to that of open rp with acceptable oncological results and worse post-operative functional outcomes with respect to continence and erectile function. there are different results from different series of laparoscopic rp (lrp), and robot-assisted rp(rarp) after turp. while colombo et al. reported that open rp could be safely performed after previous turp, jaffe et al. and gupta et al. reported worse surgical outcomes with high perioperative complications(1,4,10). menard et al. and zugor et al. reported that lrp and rarp resulted in worse perioperative outcomes and higher complication rates without compromising the oncological outcomes(11,12). martin et al. reported no higher complication rate and similar oncological outcomes after rarp(13). in the study of elden et al., lrp resulted in no difference of complication rate and comparable pms and bcr with delay incontinence and no difference in erection rate(14). in our study, the operative time, hospitalization period and the number of lymph nodes yield were identical in both groups; however, the blood loss was less for patients in group i than those in group ii. pelvic lymph nodes dissection was done for all patients in group ii. table 2. intraoperative findings and postoperative outcomes. variable a robotic rp open rp total p nvb preservation 18/31 (58.06%) 8 (47.05%) 26 (54.16) 0.46 patients had lymph nodes dissection 20/31(64.51) 17/17(100) 37 (77.08) 0.005 hospitalization day (mean+sd) 3.0 ± 2.6 4.5 ± 3.4 2.7 ± 2.1 0.19 psm 4 (12.90) 2 (11.76) 6 (12.5) 0.9 seminal vesicle involvement 1(3.22) 2 (11.76) 3 (6.25) 0.24 lymph node yields (mean+sd) 11.4 ± 4.3 11.7 ± 8.0 12.4 ± 7.6 0.24 lymph node involvement 2(6.45) 1 (5.88) 3 (6.25) 0.67 gleason score at specimen (median, range) 7 (6-9) 7 (6-9) 7 (6-9) 0.26 bcr 1(3.22) 3(17.64) 4 (8.33) 0.03 pathologic stages 0.23 t2 26 (83.87) 10 (58.88) 36 (75) t3 5 (16.12) 5 (29.41) 10 (20.83) t4 0 1(5.88) 1(2.1) t0 0 1(5.88) 1(2.1) continenceb 14/20 ( 70) 9/11 (80.81) 23/31, 74.19* 0.47 erection with or without medication c 15/22, 68.18% 6/13, 46.15% 21/35, 60% 0.31 follow up month , (mean+sd) 15.5 ± 1.8 18.5 ± 1.6 17.3 ± 15.2 0.99 abbreviations: rp, radical prostatectomy; psa, prostate specific antigens; nvb, neurovascular bundle; psm, positive surgical margins; bcr, biochemical recurrence. a data are presented as no. of patients (%) unless otherwise indicated. b continence data were available for 20 patients of 31 patients who underwent robotic rp, and 11 of 17who underwent open rp. c erection function data were available for 22 of the 31 patients who underwent robotic rp, and 13 of 17 patients who underwent open rp. radical prostatectomy after turp-mustafa et al. laparoscopic urology 2957 the higher blood loss in group ii may be due to the advance clinical stages of the prostate cancer; half the patient in group ii had stage t2 and t4, while half of the patient in group i had stage t1c. the preoperative parameters in term of gleason score, clinical stages and the interval between turp and rp were not homogenous. the long operative time in group ii was due to the high grade and stage of the patients who underwent open rp (table1). rectal injury occurred in 2 patients and the primary repair was enough for both of them; one of these patients had two previous turs and the last turp was done 4 months before the open rp. thus such patient is under high risk of rectal injury even in open surgery. the second patients who had rectal injury had robotic rp after laser prostatectomy. ureter transaction occurred in two patients with open rp after prior standard turp; one of them had two previous turps. during turp capsular perforation and extravasations of the irrigation fluid, causes peri prostatic fibrosis(4). therefore waiting at least 3 months after turp is recommended(11). we believe that number of turps is important in increasing the incidence of intra operative complications. as half of patients who had intraoperative complications had two standard turps. all intra operative complications occurred in patients who had standard turp except for one patient who had laser prostatectomy. this also may be due to the fact that laser is a less invasive procedure and usually is done by more experienced surgeons in well qualified medical centers, thus capsular perforation and periprostatic fibrosis may be less likely than in the standard turps. these intra operative findings demonstrated that open or robotic rp with bilateral plnd can be done safely and effectively in patients who have previously undergone prostate surgery. because of fibrosis surrounding the adhesion, it is difficult to identify nvb(4). suardi et al. evaluated the feasibility and safety of nerve sparing procedure during robotic rp in patients who had other invasive prostatic treatments e.g. holmium laser enuculeation, turp or open prostatectomy(15). the authors could preserve nvb in all patients who had holmium laser, and 86.6% of those who had turp and 73.3% of those who had open prostatectomy(15). palisaar et al. could preserve the nvb in 25 patients (40%) out of 60 who underwent open rp after previous turp(16). out of 25 patients, 15 (60%) could achieve sexual intercourse(11). in our study we could preserve nvb for 58.1% of patients in group i and for 47.1% of patients in group ii. the potency rates in group i was similar to the reported rates, however potency rate was low in group ii. the preoperative erectile function was compromised, 71% (10/14) of those who were impotent after rp had pre operative erectile dysfunction and their median value of international index for erectile function (ieef) score was 9.5. in group ii 53.84% (7/13) of the patients had erectile dysfunction before rp. out of 14 patients who had nvb preservation in group i, 10 patients (71.4%) could achieve enough erection and out of 7 patients who nvb preservation in group ii, 4 patients (57.1%) could achieve enough erection. preservation of nvb after laser turp is a challenging issue. saurdi et al. was the first to report the feasibility of nvb preservation in patients with history of laser turp (15), we could achieve nvb preservation in 7 patients (53.82%) out of 13 who had laser prostatectomy. although, nvb preservation in open or robotic/ laparoscopic rp after previous turp is difficult and challenging; it is possible and feasible. incontinence rate is expected to be higher after rp in patients with previous turp because surrounding periprostatic adhesions and fibrosis make it difficult to preserve sufficient urethra to perform a proper urethrovesical anastomosis. in our study the overall continence rate was 74.2% at six months follow up with no pad usage. katz et al. reported similar functional results after laparoscopic rp; 76% of their patients were completely continent(3). colombo et al. reported the highest table 3. perioperative data and complications using the clavien classification system variable a robotic rp open rp total p operative period minute (mean+sd) 277.4 ± 518.6 324.6 ± 159.0 255.8 ± 385.7 0.33 blood loss ml (mean+sd) 250.7 ± 324.0 911.5 ± 785.3 450.5 ± 585.7 0.01 blood transfusion 1(3.22) 2 (17.64) 3(6.25) rectal injury 1(3.2) 1(5.88) 2(4.16) hematuria 0 1(5.8) 1(2.1) lymphocele 2 (6.44) 1(5.88) 3 (6.25) leakage of urine 1(3.2) 0 1(2.1) ureter transaction 0 2 (11.7) 2(4.16) complications 5 (16.12) 5 (29.41) 10 (20.83) clevien grade i 3 (9.67) 1(5.88) 4(8.33) clevien grade ii 1(3.22) 0 1(2.1) clevien grade iiia 1(3.22) 3(17.64) 4(8.33) a data are presented as no. of patients (%) unless otherwise indicated. radical prostatectomy after turp-mustafa et al. vol 14 no 01 january-february 2017 2958 rate (86%) of continence(4). in similar series, the rates of continence were reported to be 81% and 75% after open or robotic rp(10,16). in our study continence rate after robotic or open rp are encouraging and identical to the reported rates of other series. higher psm rates have been reported after robotic rp (17). some studies suggested that there is no difference in oncological efficacy(11). gupta et al. reported rate of 22.2% of psm after robotic rp in patients with previous turp and 12.9% in patients without previous turp(10). other studies reported 19% and 26% rates of psm after open or robotic rp respectively(11,16). in the present study, psm was low in both groups and even similar to patients who underwent rp without history of prostate surgery. the rate of positive surgical margins was 12.9% and 11.76 % for group i and group ii respectively. all patients had undetectable psa after surgery. biochemical recurrence occurred in 4 patients, with psa values less than 0.5 ng/ml. after salvage therapy, the last psa values were undetectable in 2 of these patients and the remaining patients had psa less than or equal to 1 ng/ml. the high rate of bcr in our study especially in group ii may be due to poor preoperative oncologic features (clinical stage, gleason score). the advanced pathologic stages on the specimen, and involvement of seminal vesicle in 3 patients at pathologic specimens may also justify the early recurrence of the prostate cancer after surgery. our data show that the oncological outcomes in term of psm and bcr are acceptable and comparable to those reported by other series(10). the majority of the postoperative complications were clinically insignificant and were resolved spontaneously with conservative approach. table 3 shows postoperative complications according to clavien classification system. conclusions performing robotic or open rp for prostate cancer in patients who had previous turp is a technically demanding issue. the outcomes of robotic rp are comparable to that of open rp with acceptable oncological results. the patients should be informed about the potential intra operative complications and worse post operative functional outcomes with respect to continence and erectile function. conflict of interest none declared. references 1. jaffe j, stakhovsky o, cathelineau x, barret e, vallancien g, rozetet f. surgical outcomes for men undergoing laparoscopic radical prostatectomy after transurethral resection of the prostate. j urol 2007; 178: 483–7. 2. bernstein aj, eun d, katz mh. robotic assisted laparoscopic prostatectomy after turp: a multi-institutional analysis of oncologic and quality of life outcomes. j urol 2008; 179: 347–351. 3. katz r, borkowski t, hoznek a salomon l, gettman mt, abbou cc. laparoscopic radical prostatectomy in patients following transurethral resection of the prostate. urol int 2006;77: 216–221. 4. colombo r, naspro r, salonia a et al. radical prostatectomy after previous prostate surgery: clinical and functional outcomes. j urol 2006; 176: 2459–63. 5. leewansangtong s, taweemonkongsap t. is laparoscopic radical prostatectomy after transurethral prostatectomy appropriated? j med assoc thai 2006;89:1146–9. 6. stolzenburg ju, ho km, do m, rabenalt r, dorschner w, truss mc. impact of previous surgery on endoscopic extraperitoneal radical prostatectomy. urology 2005; 65: 325-331. 7. mustafa m, pettaway ca, davis jw. pisters l. robotic or open radical prostatectomy after previous open surgery in the pelvic region. korean j urol 2015; 56:131-7. 8. bhayani sb, pavlovich cp, strup se et al. laparoscopic radical prostatectomy: amultiinstitutional study of conversion to open surgery. urology 2004; 63: 99-102. 9. zigeuner re, lipsky k, riedler i et al. did the rate of incidental prostate cancer change in the era of psa testing? a retrospective study of 1127 patients. urology. 2003; 62:451-5. 10. gupta np, singh p, nayyar r. outcomes of robot-assisted radical prostatectomy in men with previous transurethral resection of prostate. bju int. 2011;108:1501-5. 11. menard j, de la taille a, hoznek a et al. laparoscopic radical prostatectomy after transurethral resection of the prostate: surgical and functional outcomes. urology. 2008;72:593-7. 12. zugor v, labanaris ap, porres d, witt jh. surgical, oncologic, and short-term functional outcomes in patients undergoing robot-assisted prostatectomy after previous transurethral resection of the prostate. j endourol 2012;26:515-9. 13. martin ad, desai pj, nunez rn et al. does a history of previous surgery or radiation to the prostate affect outcomes of robotassisted radical pros¬tatectomy? bju int 2009;103:1696-8. 14. eden cg, richards aj, ooi j, moon da, laczko i. previous bladder outlet surgery does not affect medium-term out¬comes after laparoscopic radical prostatectomy. bju int 2007; 99:399-402. 15. suardi n, scattoni v, briganti a et al. nervesparing radical retropubic prostatectomy in patients previously submitted to holmium laser enucleation of the prostate for bladder outlet obstruction due to benign prostatic enlargement. eur urol. 2008 ;53:1180-5. 16. palisaar jr, wenske s, sommerer f, hinkel a, noldus j. open radical retropubic prostatectomy gives favorable surgical and functional outcomes after transurethral resection of the prostate. bju int. 2009 radical prostatectomy after turp-mustafa et al. laparoscopic urology 2959 ;104:611-5. 17. hampton lj, jacobsohn k, nelson ra. patients with prior turp undergoing robotic assisted laparoscopic radical prostatectomy have higher positive surgical margin rates. j urol 2008; 179 (suppl.): 606. radical prostatectomy after turp-mustafa et al. vol 14 no 01 january-february 2017 2960 1491vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l intra urethral human papillomavirus related warts following urinary tract instrumentation morkos iskander, nina patrick, rahul mistry st helen's and knowsley teaching hospital nhs trust, england. corresponding author: morkos iskander, md st helen's and knowsley teaching hospital nhs trust, england. tel: +44 0151 280 3006 e-mail: morkos.iskander@doctors. org.uk received august 2012 accepted july 2013 st helen's and knowsley teaching hospital nhs trust, england. a 68yearsoldmanwithahistoryofag3pt1transitionalcellcarcinoma(tcc)withacarcinomainsitucomponentofhisbladderwasnotedtohaveintraurethraltumoronfollow-upflexiblecystoscopy(figures1and2),withthesuspicionofrecurrenceofhistccbeingraised.theselesionswereresectedviarigidcystoscopyandexamined inhistopathology,whereadiagnosisofpapillarysquamouswartswasmade.itsubsequentlytranspiredthatthispatienthada historyofcondylomataaccuminata.henowundergoescystoscopicsurveillanceforhistccaswellasintraurethralcondylomataaccuminata,andhashadalaserablationtorecurrentcondylomataaccuminata. casesofcondylomataaccuminataofthelowerurinarytracthavepreviouslybeendocumentedinliterature(1)andcausativelinkbetween humanpapillomavirus(hpv)infectionandcarcinomasofthelowerurinarytracthaverecentlybeensuggested,(2) particularly in the younger population.(3)previously,casesinvolvingintravesicalcondylomataaccuminataweredescribedinimmunosuppressedpatients. (4)wesuggestroutinelyincludingenquiryfullgenitourinaryhistorywhenconsideringadiagnosisofurothelialcarcinoma,particularly in a young patient. pictorial references 1. guo cc, fine sw, epstein ji. noninvasive squamous lesions in the urinary bladder: a clinicopathologic analysis of 29 cases. am j surg pathol. 2006;30:883-91. 2. kawaguchi s, shigehara k, sasagawa t, et al. a case study of human papillomavirus-associated bladder carcinoma developing after urethral condyloma acuminatum. jpn j clin oncol. 2012;42:455-8. 3. alonso fv, campos rb, sanz ip, et al. conservative management of unusual keratinising squamous metaplasia of the bladder in a 28-year-old female and overview of the literature. case rep urol. 2012;2012:940269. 4. chrisofos m, skolarikos a, lazaris a, bogris s, deliveliotis ch. hpv 16/18-associated condyloma acuminatum of the urinary bladder: first international report and review of literature. int j std aids. 2004;15:836-8. pictorial urology 87urology journal vol 6 no 2 spring 2009 leiomyomatous angiomyolipoma of kidney a 24-year-old man was diagnosed with a mass in the left kidney on abdominal computed tomography (figure a). nephrectomy specimen showed a smooth-surfaced tumor, sized 9 × 6 × 6 cm, attached to the hilar area, which was homogenous, well-circumscribed, grayish white, and solid, compressing the renal parenchyma, but not invading it (figure b). microscopic examination showed spindle cells arranged in whorls, rich in blood vessels (figure c). on immunohistochemistry, the tumor cells expressed smooth muscle actin, vimentin, desmin, and hmb-45 (figure d). a diagnosis of leiomyomatous angiomyolipoma was made. leiomyomatous angiomyolipoma is a benign mesenchymal tumor which is typically composed of a mixture of vessels, smooth muscle, and fat. in addition, it contains clear or pale epithelioid cells, currently known as the perivascular epithelioid cells,(1) which show positivity for hmb-45 in addition to expected smooth muscle markers. on computed tomography, leiomyomatous angiomyolipoma shows a characteristic appearance because of abundant adipose tissue, the lack of which pose a problem. microscopically, leiomyomatous angiomyolipomas with predominant spindle cells of smooth muscle type may look like leiomyomas, leiomyosarcoma, or gastrointestinal stromal tumors.(2) the presence of perivascular epithelioid cells in tumoral tissue, which shows reactivity to melanocytic markers such as hmb-45 in addition to smooth muscle markers, clinches the diagnosis.(1) kavita munjal,1* shyam agrawal,2 saroj munjal1 1department of pathology, sri aurobindo institute of medical sciences, indore, india 2department of urology, geeta bhawan trust hospital, manoramaganj, indore, india *e-mail: kavita_munjal@rediffmail.com references 1. bonetti f, pea m, martignoni g, et al. the perivascular epitheloid cell and related lesions. adv anat pathol. 1997;4:343-58. 2. nonomura a, minato h, kurumaya h. angiomyolipoma predominantly composed of smooth muscles cells: problems in histological diagnosis. histopathology. 1998;33:20-7. urol j. 2009;6:87. www.uj.unrc.ir urology journal unrc/iua vol. 1, no. 4, 284-285 autumn 2004 printed in iran 284 letter to the editor re: treatment of renal colic using intracutaneous injection of sterile water ahmadnia h, younesi rostami m urology journal. 2004;1;3:200-203 to the editor. pain relief of acute renal colic is usually achieved by administration of narcotics(1) because of its severity, which is comparable to labor pain.(2) although not asserted in the article, it seems that this trial(1) had been performed on "acute" renal colic as the pain score had been between 8 to 10 before treatment according to visual analogue scale. the investigators had explained to the patients that they were receiving either sterile water or saline for their pain and they had consented to enter the trial. at the end of the trial, 63% of the control group had suffered from pain for as long as one and a half hours. it is asserted in ethical considerations of clinical trials that when there is a known therapy of value, it is unethical to use a placebo.(3) talking of acute renal colic, both normal saline and sterile water are considered "placebos". nearly all the published papers on implementation of sterile water for pain relief are in areas in which either application of known analgesics is more harmful than beneficial, e.g. in labor pains,(4-9) or there is no evidence based remedy e.g. chronic pains.(10,11) from a methodological viewpoint, performance of this trial was justifiable in cases with any contraindications of narcotic administration (acute asthma, pregnancy,…). otherwise, denying an analgesic from the patients for 90 minutes without any exclusion criteria (e.g. if the pain was not bearable, the patient being excluded) does not sound to be advisable. other methodological considerations like choice of statistical tests (friedman two-way anova by ranks or repeated measures in case of normality of distributions) are discussed elsewhere,(12) and thus not elaborated here. respectfully, akhavizadegan h department of urology, shaheed labbafinegad hospital, shahid beheshti university of medical sciences, tehran, iran e-mail: hamed_akhavizadegan@yahoo.com karbakhsh davari m department of community medicine, tehran university of medical sciences, tehran, iran references 1. menon m, resnick mi. urinary lithiasis: etiology, diagnosis, and medical management. in: walsh pc, retik ab, vaughan ed, et al, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p.3272. 2. ahmadnia h, younesi rostami m. treatment of renal colic using intracutaneous injection of sterile water. urology journal. 2004;1:200-3. 3. rothman kj, michels kb. the continuing unethical use of placebo controls. n engl j med. 1999;331:394-8. 4. martensson l, wallin g. labour pain treated with cutaneous injections of sterile water: a randomised controlled trial. br j obstet gynaecol. 1999;106:633-7. 5. reynolds jl. intracutaneous sterile water for back pain in labour. can fam physician. 1994;40:1785-8, 1791-2. 6. dahl v, aarnes t. sterile water papulae for analgesia during labor. tidsskr nor laegeforen. 1991;111:1484-7. 7. ader l, hansson b, wallin g. parturition pain treated by intracutaneous injections of sterile water. pain. 1990;41:133-8. ahmadnia h, younesi rostami m 285 8. balsbaugh ta. cutaneous injections of sterile water for the relief of labor pain. j fam pract. 1999;48:746-7. 9. trolle b, moller m, kronborg h, thomsen s. the effect of sterile water blocks on low back labor pain. am j obstet gynecol. 1991;164:1277-81. 10. wreje u, brorsson b. a multicenter randomized controlled trial of injections of sterile water and saline for chronic myofascial pain syndromes. pain. 1995;61:441-4. 11. byrn c, borenstein p, linder le. treatment of neck and shoulder pain in whip-lash syndrome patients with intracutaneous sterile water injections. acta anaesthesiol scand. 1991;35:52-3. 12. dawson b, trapp rg. basic and clinical biostatistics. 3rd ed.new york: mcgraw-hill; 2001. p.179. reply by authors. although using narcotics is the treatment of choice in renal colic, a proportion of patients do not respond and re-administration of narcotics or substitution by nsaids would be required. repeated injection usually is done after a 30-minute interval. in addition, pain relief is achieved 10 to 30 minutes after intramuscular injection. consequently, ethical conflict is not the issue; the effect of intramuscular morphine begins 10 to 30 minutes later and the optimum effect is achieved 30 to 60 minutes afterwards. a pilot study was set up before doing this research and 10 patients with renal colic, not responded to narcotics and nsaids, volunteered to receive intradermal sterile water injection and in all of them, pain was relieved in a short time. as a result, and according to its therapeutic mechanism described in a series of studies,(1,2,3,4) it seems that sterile water is justified to use. furthermore, bengtsson and colleagues have reported a similar study, which is published in denmark.(4) it is noteworthy that the proposal of this study has been approved by the disserations and ethics committees of mashhad university of medical sciences. eventually, we have not denied pain killers for 90 minute. all the patients were controlled for 90 minutes and, as mentioned in the article, two patients were excluded after 30 minutes and received narcotics due to severe pain and also one after 15 minutes. once again herein, we recommend using sterile water as the intradermal injection for the treatment of renal colic. references 1. reynolds jl. intracutaneous sterile water for back pain in labour. can fam physician. 1994;40:1785-92. 2. trolle b, moller m, kronborg h, thomsen s. the effect of sterile water blocks on low back labor pain. am j obstet gynecol. 1991;164:1277-81. 3. martensson l, wallin g. labour pain treated with cutaneous injection of sterile water: a randomized controlled trial. br j obstet gynaecol. 1999;106:633-7. 4. bengtsson j, worning am, gertz j, et al. urolithiasissmerter behandler med intrakutne sterlivandspapler (pain duo to urolithiasis treated by intracutaneous injection of sterile water). ugeskr laeger. 1981;143:3463-5. sexual dysfunction and infertility comparison of sexual functions in pregnant and non-pregnant women mustafa aydin,1 neval cayonu,2 mustafa kadihasanoglu,3* lokman irkilata,1 mustafa kemal atilla,1 muammer kendirci4 purpose: the physiology and anatomy of pregnant women change during pregnancy. pregnancy is an anatomically and physiologically amended process experienced by women and as a result of these changes, sexual life of pregnant women alters during pregnancy. we aimed to compare sexual functions of pregnant and non-pregnant women. materials and methods: sexually active 246 pregnant women were included into this cross-sectional controlled study. a total of 210 non-pregnant women were served as control. both groups were compared in terms of age, gestational age, presence of urinary incontinence, body mass index, and obstetrical history. sexual functions of the women were evaluated with female sexual function index (fsfi). data were analyzed using chi-square, mann-whitney u, fisher’s exact, shapiro wilk, kruskal wallis and dunnett’s tests where appropriate. the p values < .05 were considered statistically significant. results: mean age in both groups were comparable (p = .053). median total fsfi scores in the pregnant women were significantly lower than those non-pregnant (18.9 vs. 22.7; p < .05). additionally, the subgroup analyses of the fsfi scores were found that, total fsfi score is significantly lower in the pregnant group compared to non-pregnant group (p < .05). furthermore, rate of sexual dysfunction in pregnant women was significantly higher than those non-pregnant women (91.08% vs. 67.61%, p = .0001). however, in pregnant women, no meaningful difference in rate of sexual dysfunction was found according to the trimesters (p = .632). moreover, gravidity and parity exhibited negative impacts on the sexual functions. but number of abortions did not affect sexual function. conclusion: these data demonstrate that pregnancy significantly diminishes sexual function in women. we believe that, couples need to be counseled regarding the impact of pregnancy on sexual functions. keywords: prospective studies; sexual behavior; female; physiology; psychology; sexuality. introduction sexuality is defined as "although not vital, a necessity and a basic instinct needed to survive and to continue human species". female sexual dysfunction (fsd) is a common health problem affecting 20% to 50% of population and prevalence of this condition correlates with age.(1,2) pregnancy is an anatomically and physiologically amended process experienced by women. as a result of these changes, sexual life of pregnant women alters during pregnancy.(3) although 86%-100% of couples have been reported to be sexually active during pregnancy period, majority of pregnant women showed decrease in sexual intercourse and sexual desire.(4-6) sexual health plays an important role for the quality of life. decrease in sexual function affects a woman's mood of well-being and social relations with others. in parallel with this effect, sexual dysfunction often leads to emotional stress. studies indicate a strong correlation between sexual dysfunction and physical and emotional status.(7) physicians generally do not give sufficient attention on this subject when interviewing with couples. 1 department of urology, samsun training and research hospital, samsun 55000, turkey. 2 department of gynecology and obstetrics, igdir state hospital, igdir 76000, turkey. 3 department of urology, istanbul training and research hospital, fatih, istanbul 34000, turkey. 4 department of urology, medical faculty, bahcesehir university, besiktas, istanbul 34000, turkey. *correspondence: department of urology, liv hospital ulus', istanbul training and research hospital, fatih, istanbul 34000, turkey. tel: +90 212 4596000. fax: +90 212 4536000. e-mail: kadihasanoglu@gmail.com. received december 2014 & accepted june 2015 sexuality arises as a problem during a distressing pregnancy, and pregnancy can be a cause of temporary discontinuation of sexual life. in present study, we aimed to evaluate sexual function in pregnant and non-pregnant women. materials and methods study population between april 2012 and december 2013, we designed a non-interventional, observational, prospective, cross-sectional, and single-center study in 246 pregnant women and in 210 age-matched healthy non-pregnant women. the hospital’s ethics committee approved the study and all the participants provided written informed verbal consent. a total of 246 sexually active pregnant women, who had normal sexual function before pregnancy and had been sexually active in the last 4 weeks, and 210 sexually active non-pregnant and healthy women in reproductive age recruited from contraceptive clinic included in this study. evaluations vol 12 no 05 september-october 2015 2339 detailed medical history and basic socio-demographic information were collected from all participants including: age, educational level, occupational status, monthly income, urinary continence status, and obstetric data (gravidity, parity, abortion, gestational week) and the complications faced like abortus imminens, preeclampsia, hellp syndrome ["hellp" is an abbreviation of the three main features of the syndrome, hemolysis, elevated liver enzymes, low platelet count] early membrane rupture and preterm birth. women with hypertension, hyperlipidemia, liver failure, endocrinologic disorders such as thyroid dysfunction and diabetes mellitus, chronic renal insufficiency, gynecological malignancies, primary ovarian failure, hypothalamic amenorrhea, psychiatric disorders such as depression and anxiety and women taking hormone replacement therapy were excluded from the study. questionnaire the sexual function of women were assessed using turkish version of female sexual function index (fsfi), which has been previously validated in turkish language by turkish society of andrology,(8,9) in six domains including: 1. desire (questions 1 and 2); 2. arousal (questions 3,4,5 and 6); 3. lubrication (questions 7,8,9 and 10); 4. orgasm (questions 11,12 and 13); 5. satisfaction (questions 14,15 and 16); 6. pain (questions 17,18 and 19). we scored turkish version of fsfi as follows: the items 1 to 16 had five likert-type answers from “never” (score 1) to “very much” (score 5) and the items 16 to 18 were leveled from “very much” (score 1) to “never” (score 5). adding the score of individual items that comprise the domain and multiplying the sum by domain factor obtained individual domain score. factors were 0.6 for desire, 0.3 for arousal and lubrication, and 0.4 for orgasm, pain, and satisfaction. the total-scale score range was from 2 to 36. cutoff value was 26.55; equal or below this point, was assumed as sexual dysfunction.(8) a cutoff total score of ≤ 26.55 on the fsfi is the current standard for diagnosing sexual dysfunction in women across a wide range of ages (18-74 years) and lifestyles.(10) we used the same cutoff value for fsfi to diagnose fsd in this study. according to a previous report,(11) to estimate the presence or sexual difficulty in each domain, a score of 40% or less of the maximum value of the desire domain (≤ 2.4) and a score of less than 60% of the maximum value of the other five domains (< 3.6) were selected as the cutoff, respectively. outcome measures the primary outcome of this study was to evaluate the female sexual function of pregnant women and compare sexual function in pregnant and non-pregnant-women. on the basis of previous studies,(3,4,6,12-16) we calculated that 100 patients per group would be required to detect a 20% difference in proportions with a power of 90% at a 0.05 level of significance. in anticipation of case failtable 1. demographic characteristics of pregnant and non-pregnant groups. variables pregnant women (n = 246) non-pregnant women (n = 210) p value age, year (range) 29.74 ± 11.6 (16-49) 32.03 ± 13.6 (18-51) .0529 bmi, kg/m2 (range) 24.39 ± 10.12 (15-42) 23.1 ± 9.85 (11-41) .17 percentage of patients with urinary incontinence 48.37 51.42 .237 educational level, no. elementary or none educated 131 122 secondary school 69 51 .559 high or above 46 37 percentage of employed women 33.7 48.57 .0013 monthly income > 1000 tl, (%) 53.7 64.6 .016 abbreviations: bmi, body mass index; tl, turkish lira. pregnant women non-pregnant women domains no. median (min-max) no. median (min-max) p value sexual desire 246 3 (1.2-6) 210 3.6 (1.2-6) < .05 sexual arousal 246 3 (1.2-6) 210 3.6 (1.2-6) < .05 lubrication 246 3.3 (1.2-6) 210 3.9 (1.2-6) < .05 orgasm 246 3.2 (1.2-6) 210 4 (1.2-6) < .05 satisfaction 246 3.2 (1.2-6) 210 4 (1.2-6) < .05 pain 246 3.2 (1.2-6) 210 3.6 (1.2-6) < .05 total score 246 18.9 (7.2-36) 210 22.7 (7.2-36) < .05 table 2. female sexual function index scores in pregnant and non-pregnant groups. pregnancy and sexual function-aydin et al. sexual dysfunction and infertility 2340 table 3. sexual dysfunction in pregnant women regarding to trimester, gravidity, parity, and abortion. presence of fsd absence of fsd p value characteristics no (%) no (%) total, no (%) trimester 1st trimester 51 (89.47) 6 (10.52) 57 (100) 2nd trimester 64 (90.14) 7 (9.86) 71 (100) .632 3rd trimester 110 (93.2) 8 (6.8) 118 (100) gravidity 1 39 (78) 11 (22) 50 (100) ≥ 2 178 (90.81) 18 (9.19) 196 (100) .013 parity primiparous 42 (79.24) 11 (20.76) 53 (100) multiparous 181 (93.78) 12 (6.22) 193 (100) .001 abortion 0 112 (89.6) 13 (10.4) 125 (100) ≥ 1 113 (93.4) 8 (6.6) 121 (100) .287 abbreviation: fsd, female sexual dysfunction. abbreviations: fsd, female sexual dysfunction; bmi, body mass index; tl, turkish lira. variables presence of fsd absence of fsd values characteristics no (%) no (%) total, no (%) p value age (years) 16-30 144 (92.3) 12 (7.7) 156 (100) 31-45 66 (85.71) 11 (14.29) 77 (100) ≥46 11 (84.61) 2 (15.39) 13 (100) .238 bmi (kg/m2) underweight 57 (91.9) 5 (8.1) 62 (100) normal 65 (97.01) 2 (2.99) 67 (100) overweight or obese 104 (88.8) 13 (11.2) 117 (100) .152 urinary incontinence yes 157 (89.2) 19 (10.8) 176 (100) no 61 (87.1) 9 (12.9) 70 (100) .645 educational level elementary or none educated 112 (85.5) 19 (14.5) 131 (100) secondary school 56 (81.1) 13 (18.9) 69 (100) high or above 34 (73.9) 12 (26.1) 46 (100) .304 occupational status employed 157 (95.15) 8 (4.85) 165 (100) unemployed 70 (86.4) 11 (13.6) 81 (100) .016 monthly income < 1000 tl 98 (93.3) 7 (6.7) 105 (100) ≥ 1000 tl 119 (84.4) 22 (15.6) 141 (100) .032 table 4. sexual dysfunction in pregnant women according to age, bmi, urinary incontinence, educational level, and occupational status. pregnancy and sexual function-aydin et al. vol 12 no 05 september-october 2015 2341 ure, we included approximately 200 admitted patients in each group. statistical analysis statistical analysis was performed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. the data were analyzed using chi-square, mann-whitney u, fisher exact, shapiro wilk, kruskal wallis, dunnett’stests, and student t-test. results were expressed as median (minimum-maximum) and a p value < .05 was considered as statistically significant. results the demographic characteristics of study groups are presented in table 1. mean age was 29.74 ± 11.6 years in pregnant and 32.03 ± 13.6 years in non-pregnant group, no statistical significance between two groups was noted (p = .0529). besides, no statistical significance was noted in comparison of body mass index (bmi) between pregnant and non-pregnant groups (p = .17). the median total fsfi score of pregnant womenwas lower than non-pregnant women [18.9 (range, 7.236) vs. 22.7 (range, 7.2-36), p < .05] (table 2). pregnant women had lower scores than non-pregnant women in all fsfi domains (sexual desire, sexual arousal, lubrication, orgasm, satisfaction, pain) (p < .05). using the established cutoff score of 26.55, 91.08% of pregnant women were classified as having fsd. however, the prevalence rate of fsd in non-pregnant women was 67.61%. sexual dysfunction in pregnant women was greater than non-pregnant women (p < .0001). sexual functions were similar during pregnancy in women. the number of pregnant women with sexual dysfunction was not statistically different among trimesters (p = .632). gravidity and parity were different between pregnant women with and without fsd, but the number of abortion were not different between pregnant women with and without fsd. higher gravidity and parity were associated with sexual dysfunction (table 3). variability of domains according to trimesters revealed no statistically significant differences between subscales. age, bmi, and educational level were not different between pregnant and non-pregnant women with fsd and without fsd. the pregnant and non-pregnant women with and without urinary incontinence had similar sexual function. however, employed pregnant and non-pregnant women and pregnant women with higher monthly income expressed lesser sexual dysfunction (tables 4 and 5). patients with lower bmi showed significantly poorer lubrication than normal weighted and obese women (p < .05). in non-pregnant women, lubrication seemed significantly better in age group between16-30 years old than age group ≥ 46 years old (p = .001). table 5. parameters influencing female sexual dysfunction in non-pregnant women. presence of fsd absence of fsd variables no (%) no (%) total, no (%) p value age (years) 16-30 62 (68.8) 28 (31.2) 90 (100) 31-45 72 (69.9) 31 (30.1) 103 (100) ≥46 15 (88.2) 2 (11.8) 17 (100) .258 bmi (kg/m2) underweight 52 (74.3) 18 (25.7) 70 (100) normal 39 (61.9) 24 (38.1) 63 (100) overweight or obese 52 (67.5) 25 (32.5) 77 (100) .307 urinary incontinence yes 48 (76.2) 15 (23.8) 63 (100) no 97 (66) 50 (34) 147 (100) .142 educational level elementary or none educated 83 (68) 39 (32) 122 (100) secondary 34 (66.6) 17 (33.4) 51 (100) high or above 22 (59.5) 15 (40.5) 37 .546 occupational status employed 77 (74.8) 26 (25.2) 103 (100) unemployed 66 (61.7) 41 (38.3) 107 (100) .041 monthly income < tl 1000 55 (76.4) 17 (23.6) 72 (100) ≥ tl 1000 91 (65.9) 47 (34.1) 138 (100) .373 abbreviations: fsd, female sexual dysfunction; bmi, body mass index; tl, turkish lira. pregnancy and sexual function-aydin et al. sexual dysfunction and infertility 2342 however, no statistically significant difference was determined between 16-30 years old and 31-45 years old age groups (p = .258). discussion this study demonstrated sexual dysfunction in 91.08% of pregnant women, and 67.61% of control subjects. in our study, we examined the relation between the status of sexual function during pregnancy in terms of fsfi total score and fsfi subscales (table 2). we found higher sexual dysfunction rates for both pregnant and non-pregnant women considering some other studies. oksuz and colleagues revealed 48.3% sexual dysfunction in non-pregnant women and bartellas and colleagues found 49% sexual dysfunction in pregnant women.(4,17) in another study from turkey by güleroğlu and beşer, the median fsfi score of pregnant women was 21.1, and 63.4% of them had sexual dysfunction. (18) in a population based study lauman and colleagues indicated that sexual dysfunction was very prevalent in both sexes which ranged between 10%-52% in men and 25%-63% in women.(7) our somewhat higher rates may indicate turkish women's attitude to stay away from sexuality issues in their entire life due to general tendency taught by parents. we analyzed various parameters influencing sexual function in pregnant and non-pregnant women. trimester, gravidity, parity, and abortion seemed to influence sexual function in different ways. physiological and psychological alterations experienced a woman during pregnancy period has impact on sexual life. on the first trimester, sexuality is to be influenced due to the many symptoms that often accompany the beginning of pregnancy such as fatigue, breast tenderness, nausea and vomiting along with pregnancy and adaptation efforts by couples to somewhat a new period. gökyildiz and colleagues demonstrated that sexual desire increased from the first to the second trimester, and then decreased again.(3) however, some authors suggested that sexual desire and satisfaction reduced in pregnant women.(19) on the second trimester, pregnancy is generally accepted and sexual life is better than first trimester. (15,20) khamis and colleagues and ryding demonstrated that nearly half of women had better sexual satisfaction during the second trimester of pregnancy due to reduction of the early symptoms of pregnancy such as fatigue, nausea, and vomiting.(20,21) however, on the third trimester sexual function deteriorates due to advancing pregnancy period and fetus. pregnant women fear for abortion and pre-term birth due to sexual act, and therefore, are reluctant for sexual activity.(12,14) moreover, other causes of reduction of sexual desire during pregnancy are discomfort like breathlessness, fatigue, increased size of fetus, and downward pressure as the baby settles into the pelvis.(4,21,22) we found no statistically significant difference between trimesters considering sexual dysfunction and a significant decline in sexual function for all trimesters was noted. however, in the study by yildiz, the percentage of participants experiencing sexual dysfunction before pregnancy, according to the fsfi cutoff values, was 25.4%, whereas this figure increased significantly during pregnancy, beginning in the first trimester and reaching a peak in the third trimester.(23) we found that, gravida and parity influenced sexual function, but, the number of abortion did not. similarly, eryilmaz and colleagues revealed that, the number of previously abortion and curettage had no effect on sexual activity, but, increased numbers of pregnancy and births affected negatively coital frequency in pregnancy period.(15) besides, eryilmaz and colleagues found out that, the more educational level of pregnant women the more decline in coital frequency in pregnancy period as a result of awareness of pregnant women about possible risks.(15) in a study from iran 52.9% of the pregnant women believed that intercourse during pregnancy results in abortion and 52.9% considered it as the reason for fetal infections.(16) however, we found no clear effect of educational level on sexual function. planned or not, couples carry some concerns about pregnancy as to whether it poses economic burden and about how to cope with this newly situation. in a non-planned pregnancy, couples may show a trend to accuse themselves and may experience difficulties in their sexual life arising from pooreconomic conditions.(13) we found that, employment status and monthly income affected sexual function, a notably finding differently from the study by eryilmaz and colleagues.(15) we also investigated the different domains of fsfi and how these domains were changed according to age, bmi, and urinary incontinence in both pregnant and non-pregnant women. kolotkin and colleagues found that, obesity affected negatively sexual functions in pregnant women, just as decline in sexual desire and performance.(24) however, we did not find any effect of age and bmi on sexual function in pregnant and non-pregnant women (tables 4 and 5). we found that, lubrication was significantly increased in obese pregnant women with bmi ≥ 25 kg/m2 and better than pregnant women with bmi ≤ 18 kg/m2. the percentage of urinary incontinence for pregnant and non-pregnant women was 48.37% and 51.42%, respectively (p = .237). in the literature, it was indicated that urinary incontinence affects between 42% and 71% of women. (25) however, we did not find any impact of urinary incontinence on female sexual function of pregnant and non-pregnant women (table 4). conclusions sexual functions are affected considerably in pregnancy period and a significant, more serious sexual dysfunction in an increased manner may appear. sexual function decreases through out pregnancy, getting worse as thepregnancy progresses. therefore, it is important to inform women that sex is safe during pregnancy from the first day to the last day if they have no medical risk. conflict of interest none declared. references 1. coskun b, coskun bn, atis g, ergenekon e, dilek k. evaluation of sexual function in women with rheumatoid arthritis. urol j. 2013;10:1081-7. 2. hosseini l, iran-pour e, safarinejad mr. sexual function of primiparous women after elective cesarean section and normal vaginal delivery. urol j. 2012;9:498-504. 3. gökyildiz s, beji nk. the effects of pregnancy on sexual life. j sex marital ther. pregnancy and sexual function-aydin et al. vol 12 no 05 september-october 2015 2343 2005;31:201-15. 4. bartellas e, crane jm, daley m, bennett ka, hutchens d. sexuality and sexual activity in pregnancy. bjog. 2000;107:964-8. 5. orji eo, ogunlola io, fasubaa ob. sexuality among pregnant women in south west nigeria. j obstet gynaecol. 2002;22:166-8. 6. aslan g, aslan d, kizilyar a, ispahi c, esen a. a prospective analysis of sexual functions during pregnancy. int j impot res. 2005;17:154-7. 7. laumann eo, paik a, rosen rc. sexual dysfunction in the united states: prevalence and predictors. jama. 1999;281:537-44. 8. rosen r, brown c, heiman j, et al. the female sexual function index (fsfi): a multidimensional self-report instrument for the assessment of female sexual function. j sex marital ther. 2000;26:191-208. 9. cayan s, akbay e, bozlu m, canpolat b, acar d, ulusoy e. the prevalence of female sexual dysfunction and potential risk factors that may impair sexual function in turkish women. urol int. 2004;72:52-7. 10. wiegel m, meston c, rosen r. the female sexual function index (fsfi): cross-validation and development of clinical cutoff scores. j sex marital ther. 2005;31:1-20. 11. jiann bp, su cc, yu cc, wu tt, huang jk. risk factors for individual domains of female sexual function. the j sex med. 2009;6:336475. 12. adinma ji. sexuality in nigerian pregnant women: perceptions and practice. aust n z j obstet gynaecol. 1995;35:290-3. 13. bogren ly. changes in sexuality in women and men during pregnancy. arch sex behav. 1991;20:35-45. 14. byrd je, hyde js, delamater jd, plant ea. sexuality during pregnancy and the year postpartum. j fam pract. 1998;47:305-8. 15. eryilmaz g, ege e, zincir h. factors affecting sexual life during pregnancy in eastern turkey. gynecol obstet invest. 2004;57:103-8. 16. jamali s, mosalanejad l. sexual dysfunction in iranian pregnant women. iran j reprod med. 2013;11:479-86. 17. oksuz e, malhan s. prevalence and risk factors for female sexual dysfunction in turkish women. j urol. 2006;175:654-8. 18. tosun guleroglu f, gordeles beser n. evaluation of sexual functions of the pregnant women. j sex med. 2014;11:146-53. 19. tolor a, digrazia pv. sexual attitudes and behavior patterns during and following pregnancy. arch sex behav. 1976;5:539-51. 20. khamis ma, mustafa mf, mohamed sn, toson mm. influence of gestational period on sexual behavior. j egypt public health assoc. 2007;82:65-90. 21. ryding el. sexuality during and after pregnancy. acta obstet gynecol scand. 1984;63:679-82. 22. oboro vo, tabowei to. sexual function after childbirth in nigerian women. int j gynaecol obstet. 2002;78:249-50. 23. yildiz h. the relation between prepregnancy sexuality and sexual function during pregnancy and the postpartum period: a prospective study. j sex marital ther. 2015;41:49-59. 24. kolotkin rl, binks m, crosby rd, ostbye t, gress re, adams td. obesity and sexual quality of life. obesity (silver spring). 2006;14:472-9. 25. thiagamoorthy g, srikrishna s, cardozo l. sexual function after urinary incontinence surgery. maturitas. 2015;81:243-7. pregnancy and sexual function-aydin et al. sexual dysfunction and infertility 2344 case report no suspicion, no disease! renal infarction: case series sinan karacabey,1 hilal hocagil,2 erkman sanri,3 abdullah cuneyt hocagil,2* senol ardic,4 enes suman5 keywords: kidney; blood supply; renal artery obstruction; diagnosis; thrombosis. introduction a bdominal and flank pain with sudden onset is one of the most common patient presentations to emergency departments (ed). renal infarction is a rare cause of abdominal and flank pain. usually the symptoms of renal infarction are nonspecific, so the diagnosis is frequently missed or delayed.(1) especially if a patient has a disease such as nephrolithiasis and pyelonephritis, the possibility of delay or a misdiagnosis will increase. this may lead to irreversible loss of renal function. diagnosis requires high degree of suspicion.(2) in other words, ‘no suspicion, no disease’. renal infarction was first described in 1940 by hoxie and kogan.(2) although it is uncommon, it is responsible for considerable morbidity and mortality.(3) in this case series, we aim to increase awareness of this condition and decrease the delay and misdiagnosis of renal infarctions. case report case 1 a 47-year old male applied to the clinic with flank pain. his pain was localized in his right flank area and started a few hours prior to his arrival to ed. when the patient’s medical history was obtained, it was found that he had been diagnosed with nephrolithiasis and cardiomyopathy. the patient’s vital signs were as follows: body temperature of 36.7°c, blood pressure (bp) of 200/110 mmhg, heart rate (hr) of 75/min and rhythmic, respiratory (rr) of 17/min and his physical examination signs were all normal except for a costovertebral angle tenderness on the right side. the patient’s laboratory values indicated white blood cell (wbc) count of 11,000/µl in his blood results, and in his urine analysis, protein + and red blood cells (rbc) +++ were present. urine analysis and ultrasonography (usg) was performed, but no calculus was seen. thus, contrast enhanced abdominal computed tomography (ct) scan was performed. there was no contrast infiltration in the right kidney. then, renal doppler usg was carried out, and it was found that there was no blood flow in the right kidney. after consulting with the cardiovascular surgeons, the patient was admitted for surgery. total occlusion of the renal artery made the surgeons choose the surgical intervention. during the surgery, anatomic bypass surgery was done. the circulation was restored after the surgery. after a period of one month, the patient was admitted to the nephrology clinic. none of the complications of renal infarct were revealed. case 2 an 81-year old female was admitted to ed with abdominal pain. her abdominal pain was severe, and it started suddenly 4 hours prior to her arrival to ed. her medical history was significant for coronary arterial disease and atrial fibrillation. besides, her surgical history indicated cholecystectomy. physical examination showed the vital signs as follows: body temperature of 37.7°c, bp of 240/120 mmhg, hr of 85/min and rr of 16/min. upon palpation, the abdomen was found to be tender in the upper right abdominal quadrant. the remainder of the examination was normal. the patient’s laboratory values indicated wbc count of 11,000/µl in her blood results, and in her urine analysis, protein + and rbc +++ were present. diclofenac sodium intramuscular injection was administered to the patient for pain management. after a 30 min waiting period, there was no regression in the pain, so contrast enhanced abdominal ct scan was performed. there was no contrast infiltration in the right kidney, so right renal infarction was diag1 department of emergency medicine, bozok university, faculty of medicine, yozgat, turkey. 2 department of emergency medicine, bülent ecevit university, faculty of medicine, zonguldak, turkey. 3 department of emergency medicine, sanliurfa mehmet akifinan education and research hospital, şanliurfa, turkey. 4 department of emergency medicine, trabzon kanuni education and research hospital, trabzon, turkey. 5 department of emergency medicine, receptayyip erdogan university, education and research hospital, rize, turkey. *correspondence: beü faculty of medicine, esenköy-kozlu 67600, zonguldak, turkey. tel: +90 37 2261 2086. e-mail: drhocagil@yahoo.com.tr. received march 2014 & accepted october 2014 case report 1984 nosed. after consulting with the cardiovascular surgeons, the patient was admitted for surgery. because of the total occlusion of the renal artery, the surgeons chose the surgical intervention. during the surgery, anatomic bypass surgery was performed. the circulation was restored after the surgery. after a period of two months, the patient was admitted to the nephrology clinic. none of the complications of renal infarct were revealed. case 3 a 48-year old male was presented with left flank pain. the patient’s vital signs were all within normal limits, and his physical examination signs were also all normal except for a costovertebral angle tenderness on the left side. the patient’s laboratory values indicated wbc count of 16,000/µl, hemoglobin (hb) of 15.0 g/dl, hematocrit (htc) of 44.8%, minimal protein was present in his urine analysis. contrast enhanced abdominal ct scan was performed, and as a result, renal infarction on the left kidney was diagnosed. after consulting with the cardiovascular surgeons, the patient was admitted for thrombolytic medication. the patient received follow-ups by the nephrology clinic for a period of four months. no complication of renal infarction was identified. case 4 a 48-year old male was admitted to ed with right flank pain started 10 hours prior to his arrival to ed. there was no disease in the patient’s past history. his vital signs were all normal, and his physical examination signs were also all normal except for a costovertebral angle tenderness on the right side. the patient’s laboratory values indicated wbc count of 19,000/µl, hb of 15.4g/dl, htc of 45.2%, aspartate transaminase (ast) of 56.5 units/l alanine transaminase (alt) of 75.9 units/l and minimal protein, minimal rbc were present in his urine analysis. abdominal ct scan was performed, and renal infarction was diagnosed. after consulting with the cardiovascular surgeons, the patient was admitted for thrombolytic medication. the patient received follow-ups by the nephrology clinic for a period of four months. no complication of renal infarction was identified case 5 a 46 year old male came to ed with pain in the left flank area. there was no disease in his medical history. his vital signs were as follows: body temperature of 36.5°c, bp of 186/105 mmhg, hr of 92/min and rhythmic and rr of 18/min. on physical examination, left costovertebral angle tenderness was found. the patient was first diagnosed as renal colic. on laboratory examination, the results of the renal function tests, complete blood count and urine analysis were normal. noncontrast abdominal ct scan result was normal. patient’s pain didn’t respond to painkillers. contrast-enhanced abdominal ct scan revealed renal infarction in the left kidney. thrombus resources were evaluated, and hematological and cardiac pathology could not be detected. idiopathic renal infarction was considered, and the patient was discharged with oral warfarin treatment to prevent further complications. the patient was followed up by the nephrology clinic for 2 months, and no complications were encountered. discussion renal infarction is emerged when an embolus from a distant origin, suddenly ceases the renal blood flow. it has been reported that the postmortem incidence of renal infarction is 1.4% and its clinically significant incidence is in the order of 0.007% of hospitalized patients.(4) renal infarction is typically seen in patients with atrial fibrillation, ischemic heart disease, cardiomyopathy and cardiac valve diseases. ischemic events are not rare in these patients.(5) but they are rarely seen in trauma patients, patients with polyarthritis nodosa, cocaine abuse, lupus erythematosus or it may be idiopathic.(6-10) according to the literature reviews, the age of the patients can vary but the average age is sixth decade, and clinically, they are presented with abdominal, flank and back pain. in laboratory tests, leukocytosis is usually present. serum creatinine may be elevated, but it is unclear if it is a direct result of the renal infarction or not. in 2/3 of the patients, microscopic hematuria is present. the absence of hematuria shows hypo perfusion of the infarcted area with resulting reduction of glomerular filtration and urine production.(2) serum lactate dehydrogenase (ldh) is the most sensitive marker, but it has poor specificity. urinary ldh may be more specific than the other tests. in renal infarction, ldh which is originated in the kidneys is found to be high in the urine analysis due to the increased excretion. it is not possible to measure ldh in ed of our hospital so we could not obtain the ldh levels of the patients. there are many ways for diagnosing renal infarction such as radioisotope renography, excretion urography, renal angiography and contrast enhanced ct scan. although the sensitivity of radioisotope renography and excretion urography is high, they are rarely used. the sensitivity of renal angiography is also high, but it is an invasive procedure. for this reason, it is not the first choice.(3) abdominal ct scan and magnetic resonance imaging (mri) are usually preferred for parenchymal evaluation of the kidney. renal infarction can be easily diagnosed by contrast enhanced ct scan and t1-weighted gadolinium enhanced mri. the most suitable strategy for the patient presented with renal colic is to perform an unenhanced helical ct scan to rule out nephrolithiasis, and then to perform a contrast enhanced ct scan to observe the renal infarction.(11) the standard management for the renal infarction is anticoagulant and/or thrombolysis. anticoagulant therapy starts with intravenous heparin and oral warfarin. cornerstones of conservative treatment are analgesics, regoutcomes patient(%) normal renal function 57.7 mild renal impairment 16.7 moderate renal impairment 15.4 severe renal impairment/esrd 10.2 death within 1 year* 14.3 embolic disease 50.0 myocard ınfarction 25.0 sepsis 25.0 abbreviation: esrd, end stage renal disease. *severe renal dysfunction or esrd in 58.3% table. outcomes in renal artery embolism.(2) renal infarction-karacabey et al vol 11. no 06 nov-dec 2014 1985 ulation of blood pressure and systemic heparinization. a thrombolytic therapy should be considered; the decision depends on the extent of infarction and the remaining renal function and clinicians’ decision. this therapy prevents other thromboembolic events from happening. perfusion is provided by thrombolysis or surgical revascularization.(12) in our case 1 and 2, total occlusion of the renal artery made surgeons choose the surgical intervention. but in the other cases, anticoagulation or thrombolytic treatment was chosen because there weren’t revealed total occlusions. renal insufficiency may arise in a great deal of patients with renal infarction in acute period, but in most of these cases, their renal functions return to their baseline. hemodialysis is required in those whose renal functions do not return to their baseline. when hemodialysis is necessary, the rate of mortality is higher. death in these patients is usually caused by either ischemic events or heart diseases when compared to renal complications. in the studies, the early diagnosis of renal infarction prevents the complications and morbidity of the renal infarction. (13,14) in our patients, we diagnosed renal infarction in the early period of the infarction and no complications were observed. the literature on renal embolism subject is limited. in a few of the reported case studies, the epidemiology and clinical characteristics of this entity are described. conclusion renal infarction should always be considered among the differential diagnosis of a patient who is presented to ed with abdominal and/or flank pain and have risk factors. advanced imaging should be performed to confirm the diagnosis. conflict of interest none declared. references 1. huang cc, lo hc, huang hh, et al. ed pres entations of acute renal infarction. am j emerg med. 2007;25:164-9. 2. kansal s, feldman m, cooksey s, patel j. renal artery embolism: a case report and review. j gen intern med. 2008;23:644-7. 3. hazanov n, somin m, attali m, et al. acute renal embolism. forty-four cases of renal infarction in patients with atrial fibrillation. medicine (balti more) 2004;83:292-9. 4. korzets z, plotkin e, bernheim j, zissin r. the clinical spectrum of acute renal infarction. isr med assoc j. 2002;4:781-4. 5. domanovits h, paulis m, nifkardjam m, et al. acute renal infarction. clinical characteristics of 17 patients. medicine. 1999;78:386-94. 6. lichtenheld fr, franklin ss, serenati qj. renal infarction due to trauma. j urol. 1961;85:710-3. 7. ambrosio mr, rocca bj, ginori a, et al. renal infarction due to polyarthritis nodosa in a patient with angioimmunoblastic t-cell lymphoma: a case report and a brief review of the literature. diagn pathol. 2012;7:50. 8. goodman pe, rennie wp. renal infarction sec ondary to nasal insufflation of cocaine. am j emerg med. 1995;13:421-3. 9. hernández d1, dominguez ml, diaz f, et al. re nal infarction in a severely hypertensive patient with lupus erythematosus and antiphospholipid an tibodies. nephron. 1996;72:298-301. 10. braun dr, sawczuk is, axelrod sa. idiopathic re nal infarction. urology. 1995;45:142-5. 11. kawashima a, sandler c, ernst r, tamm e, gold man s, fishman e. ct evaluation of renovascular disease. radiographics. 2000;20:1321-40. 12. amilineni v, lackner df, morse ws, srinivas n. contrast enhanced ct for acute flank pain cau sed by renal artery occlusion. ajr am j roent genol. 2000;174:105-6. 13. lumerman jh, hom d, eiley d, smith ad. heightened suspicion and rapid evaluation with ct for early diagnosis of partial renal infarction. j endourol. 1999;13:209-14. 14. chu pl, wei yf, huang jw, chen s, chu ts, wu kw. clinical characteristics of patients with segm ental renal infarction. nephrology (carlton). 2006;11:336-40. renal infarction-karacabey et al case report 1986 urological oncology lower urinary tract symptoms and efficacy of anticholinergic drugs in patients remaining diseasefree after radical retropubic prostatectomy. seung woo yang,1 yong gil na,1 ki hak song,1 ju hyun shin,1 young seop chang,2 jong mok park,1 chung lyul lee,1 jae sung lim1* purpose: this study was conducted to evaluate lower urinary tract symptoms (luts) change in patients with localized prostate cancer after radical retropubic prostatectomy (rrp) and examine the efficacy of anticholinergic drugs to treat patients suffering from storage symptoms. materials and methods: among 50 patients who underwent rrp for prostate cancer, 40 who did not undergo additional treatment that might affect their urination pattern were included in the analysis. the international prostate symptom score (ipss), quality of life (qol) score, and uroflowmetry were analyzed prior to rrp and 12 months after rrp. twelve months after rrp, patients desiring improvement of storage symptoms were administered anticholinergic drugs for 6 months; the effects of such treatments were analyzed 3 and 6 months later. results: preoperatively and at 12 months after surgery, the mean ipss for patients were 10.9 ± 6.7 and 9.2 ± 5.7, respectively. the mean ipss for patients desiring improvement of storage symptoms before and after administration of medication were 9.7 ± 5.9 and 9.0 ± 4.4, respectively. in particular, the mean storage symptom composites improved significantly after administration of medication. there were no statistically significant differences in frequency between baseline and 3-month, but frequency was improved significantly after 6 months. urgency and nocturia were improved significantly after 3 months. conclusion: in patients undergoing rrp, urinary symptoms change over time, with worsening storage symptoms. our results suggest that, in patients who had discomfort with storage symptoms after rrp, anticholinergic drugs significantly improved symptoms and qol. keywords: lower urinary tract symptoms/etiology; prospective studies; prostatectomy/methods; postoperative complications; prostatic neoplasms/surgery; quality of life; urination disorders/drug therapy. introduction prostate cancer is the second most common cause of cancer-related deaths and the most common malignancy diagnosed in the united states.(1) there are many treatment options for early stage prostate cancer including watchful waiting, radical prostatectomy, radiotherapy, and hormonal therapy depending upon each patient’s performance status, demands, and the doctor – patient relationship. despite many years of treating prostate cancer, there is no gold standard in terms of efficacy. however, radical prostatectomy is most frequently used to treat localized prostate cancer because this technique can lead to complete removal of cancer cells.(2) indeed radical prostatectomy can lead to secondary effects, such as sphincter dysfunction, that require clinical management. radical prostatectomy removes the prostate and divides the trigone and posterior urethra, thereby inducing denervation and ischemic change.(3) it is well known that storage and voiding symptoms are common in men with prostate cancer who undergo radical prostatectomy, significantly affecting their quality of life (qol).(4) because many of these patients have bladder outlet obstruction (boo) and detrusor overactivity before treatment, it is important to understand the impact of radical prostatectomy on lower urinary tract symptoms (luts) and urinary incontinence.(5) according to the european association of urology guidelines, a trial of antimuscarinic drugs is the appropriate medical approach for post-radical prostatectomy patients with mixed urinary incontinence symptoms and/or urgency. (6) because of increasing awareness of health and qol for patients with luts, the patient-reported health-related qol has become an important barometer when evaluating the effect of treatment for people who suffer 1 department of urology, chungnam national university school of medicine, daejeon, korea. 2 department of urology, konyang university college of medicine, daejeon, korea. *correspondence: department of urology, chungnam national university hospital, 282 monwha-ro, jung-gu, daejeon 35015, korea. tel: +82 42 2807779. fax: +82 42 2570966. e-mail: uro17@cnu.ac.kr. received november 2015 & accepted march 2016 vol 13 no 03 may-june 2016 2684 from urinary symptoms.(7) here, we present the results of a longitudinal study to clarify the effect of radical retropubic prostatectomy (rrp) on luts, except pure stress urinary incontinence. the aim of this study was to evaluate changes in luts and the efficacy of anticholinergic drugs in patients remaining disease-free after rrp. materials and methods medical records were collected prospectively for all patients who underwent rrp in our hospital between january 2009 and january 2012 (mean age 66.5 years, mean prostate specific antigen [psa] 12.3 ng/ml). this study was approved by the chungnam national university hospital institutional review board (irb no. cnuh 1007-86), and all participants signed informed consent forms. all patients were suspected of having prostate cancer based on positive results from digital rectal examinations, serum psa, and transrectal ultrasonography (trus). all patients underwent trus-guided prostate biopsy, and prostate cancer was confirmed by pathology after rrp. all patients were < 75 years old and had serum psa < 50 ng/ml. we included patients who agreed not to seek or use any other form of treatment for bladder dysfunction during the study. exclusion criteria included prior treatment with radiation therapy, concomitant use of medications with antiandrogenic activity, prior history of cancer, biochemical recurrence, or severe renal or hepatic impairment. we also excluded patients with active or recurrent urinary tract infections, uncontrolled diabetes, or pure stress urinary incontinence. fifty patients were initially enrolled in the study; however, 10 had undergone adjuvant or salvage radioand/or hormonal therapy during or up to 12 months after rrp, and were therefore excluded from the study since such additional therapies may impact luts. a total of 40 patients were enrolled in the study. luts was assessed based on the international prostate symptom score (ipss) and the ipss qol score, which are both validated.(8) the ipss is a self-administered seven-item questionnaire surveying incomplete emptying, intermittency, weak stream, and straining (voiding symptom composites), and frequency, urgency, and nocturia (storage symptom composites). each question is scored separately from 0 to 5, with a higher score representing a worse outcome. the ipss ranges from 0 to 35, with scores of 0, 1 to 7, 8 to 19, and 20 to 35 indicating absent, mild, moderate, and severe symptoms, respectively. the ipss qol score quantifies the qol for specific luts, and is scored from 0 to 6, with a higher score indicating worse health. the urinary flow rates (only voids > 150 ml were included) and ipss were recorded before and at each visit 12 months after rrp. residual urine was determined by transabdominal ultrasonography. out of 40 patients, 34 who desired further improvement of storage symptoms were medicated by anticholinergic drugs (solifenacin 5 mg, once daily) for 6 months. the urinary flow rates, ipss, qol, the international consultation on incontinence questionnaire-short form (iciq-sf),(9) and the king’s health questionnaire (khq)(10) were recorded at 3 and 6 months after administration of medication. the iciq-sf and khq were self-completed by the patients. the iciq-sf assesses and scores frequency of urine loss (0–5), severity (0–6), and urine leakage interfering with daily life (0–10), and also includes an unscored self-diagnostic question. the scores are added (score range from 0 to 21), with a higher score indicating a worse qol. the khq is a measure of health-related qol that includes two single-item domains (general health perception and incontinence impact), seven multi-item domains (role limitations, physical limitavoiding patterns after prostatectomy-yang et al. table 1. clinical characteristics of the patients (n = 40). characteristics values mean age (years) 66.5 ± 5.8 age (years) < 60 6 (15) 60~69 18 (45) ≥ 70 16 (40) mean psa at diagnosis (ng/ml) 12.3 ± 8.5 psa at diagnosis (ng/ml) < 4 2 (5) 4~10 18 (45) > 10 20 (50) gleason score ≤ 6 19 (47.5) 7 14 (35) ≥ 8 7 (17.5) clinical tumor classification t1 24 (60) t2 16 (40) prostate volume (ml) < 20 4 (10) 20 40 32 (80) > 40 4 (10) abbreviation: psa, prostate-specific antigen. values are presented as mean ± standard deviation and number (percentage). urological oncology 2685 tions, social limitations, personal relationships, emotional problems, and sleep/energy disturbances), and a multi-item severity measure.(9) the two single item domains and the seven multi-item domains of the khq are scored on a scale from 0 (best) to 100 (worst). reported adverse events during the treatment period were also analyzed. statistical analysis all statistical analyses were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0. parametric numeric data were analyzed with the paired t-test and nonparametric data were assessed using the wilcoxon’s signed rank test. values are expressed as the mean ± standard deviation table 2. comparison of uroflowmetry and international prostate symptom score prior to and 12 months after surgery (n = 40). variables before rrp after rrp p value maximal flow rate (ml/sec) 17.9 ± 5.3 18.6 ± 6.4 .162 residual urine (ml) 31 ± 29.5 27 ± 19.1 .160 total ipss 10.9 ± 6.7 9.2 ± 5.7 .075 voiding 6.7 ± 4.5 4.4 ± 3.6 b .003 storage 4.2 ± 2.9 4.8 ± 2.8 .136 incomplete emptying 1.4 ± 1.4 0.8 ± 1.0 a .010 frequency 1.7 ± 1.2 1.6 ± 1.0 .618 intermittency 1.8 ± 1.5 1.2 ± 1.2 a .033 urgency 0.9 ± 1.2 1.5 ± 1.5 a .027 weak stream 2.3 ± 1.5 1.4 ± 1.1 b .005 straining 1.3 ± 1.5 1.0 ± 1.1 .208 nocturia 1.6 ± 1.3 1.7 ± 1.2 .570 quality of life 2.0 ± 1.3 2.5 ± 1.1 a .020 abbreviations: ipss, international prostate symptom score; rrp, radical retropubic prostatectomy. values are presented as mean ± standard deviation. a p < .05, b p < .01 versus before rrp. variables baseline 3-month 6-month p value a p value b maximal flow rate (ml/sec) 18.7 ± 6.7 18.5 ± 6.4 18.1 ± 4.8 .661 .439 residual urine (ml) 26.8 ± 20.2 28.8 ± 17.9 28.5 ± 17.4 .256 .439 total ipss 9.7 ± 5.9 9.3 ± 5.3 9.0 ± 4.4 c .082 .026 voiding 4.6 ± 3.6 4.7 ± 3.4 4.8 ± 2.8 .292 .353 storage 5.2 ± 2.9 4.6 ± 2.4 d 4.2 ± 2.1 d .001 .001 incomplete emptying 0.8 ± 1.0 0.8 ± 0.9 0.9 ± 0.7 .325 .254 frequency 1.7 ± 1.1 1.6 ± 1.0 1.4 ± 0.8 c .160 .027 intermittency 1.2 ± 1.2 1.2 ± 1.2 1.3 ± 0.9 .571 .414 urgency 1.7 ± 1.5 1.4 ± 1.2 d 1.4 ± 1.1 d .006 .008 weak stream 1.5 ± 1.1 1.5 ± 0.9 1.4 ± 0.9 .661 .254 straining 1.1 ± 1.1 1.1 ± 1.1 1.2 ± 1.1 .160 .096 nocturia 1.7 ± 1.2 1.5 ± 1.0 c 1.4 ± 1.0 d .017 .003 quality of life 2.6 ± 1.2 2.6 ± 1.1 2.3 ± 1.0 c .325 .016 abbreviation: ipss, international prostate symptom score. values are presented as mean ± standard deviation. a compares values between the baseline and 3 months of therapy; b compares values between the baseline and 6 months of therapy; c p < .05 versus baseline; d p < .01 versus baseline. table 3. comparison of uroflowmetry and international prostate symptom score prior to administration of medication, and 3 and 6 months after medication (n = 34). voiding patterns after prostatectomy-yang et al. vol 13 no 03 may-june 2016 2686 (sd), with p < .05 considered significant. results characteristics of the 40 patients at the time of diagnosis are presented in table 1. at diagnosis the mean psa value was 12.3 ng/ml (range 3.2 – 43.6 ng/ml) and the median prostate volume was 28.6 cm3 (range 16 – 56 cm3). the overall mean total ipss, which was 10.9 ± 6.7 before rpp, decreased over time after rpp to 9.2 ± 5.7 at 12 months after surgery, a difference that did not reach the level of significance. the overall mean ipss qol score increased with time after rpp, and the difference reached the level of significance at 12 months after rrp, while the change in ipss did not. individual analysis of each question reflected in the ipss demonstrated that the symptoms of incomplete emptying, intermittency, and weak stream were significantly relieved after surgery, while the symptom of urgency significantly worsened after rrp (table 2). the overall mean total ipss in the patient population seeking medication to relieve luts, which was 9.7 ± 5.9 before medication, was reduced significantly to 9.0 ± 4.4 at 6 months after medication. the overall mean ipss qol score decreased with time after medication in parallel with the ipss, and the difference from baseline reached the level of significance at 6 months after medication. no significant change was noted in any of the four voiding symptom composites. however, all three of the storage symptom composites decreased significantly at 6 months after medication. the results of the uroflow test before and after medication showed that maximal uroflow changed from 18.7 ± 6.7 ml/sec to 18.1 ± 4.8 ml/ sec, and residual urine changed from 26.8 ± 20.2 ml to 28.5 ± 17.4 ml, neither of which reached the level of significance (table 3). the iciq-sf score improved from 4.9 ± 1.8 to 4.6 ± 1.4 at 6 months after medication, which did not reach the level of significance. the khq score significantly improved from 25.6 ± 7.1 to 23.5 ± 6.6 at 6 months after medication (table 4). the overall incidence of adverse events was 35.3% (12/34 patients), and all were mild in intensity. no patients experienced severe hepatic dysfunction, renal failure, or cardiovascular effects. dry mouth was the most frequently reported adverse event (23.5% or 8/34), followed by constipation in 14.7% (5/34). no patients discontinued treatment due to adverse events (table 5). discussion prostate cancer is likely to remain one of the most important issues in men’s health for the foreseeable future. opinions differ regarding the optimal management of prostate cancer. in men > 70 years of age, or in those with appreciable co-morbidity, a conservative management approach is generally accepted. however, healthy younger men are more likely to live long enough to experience disease progression; therefore, radical prostatectomy and radiotherapy, as well as "watchful waiting", are options in this group. use of radical prostatectomy has been increasing in patients with early stage disease, and is indicated for men with a life expectancy of > 10 years.(11) the first surgical management of prostate cancer was performed by millin and colleagues in 1947.(12) since then, several improved operative methods have been established. surgical management of the dorsal vein complex and a procedure effective for preserving the neurovascular bundle were described by walsh and colleagues(13) consequently, the incidence of postoperative complications has been decreasing. however, postoperative luts continue to occur at a constant rate and negatively affect the qol of the patients. thus, qol issues need to be considered when deciding on the best treatment option. relief of obstruction by radical prostatectomy has been reported by several investigators to diminish luts. schwartz and colleagues indicated, in patients with moderated or high degree symptoms, that radical prostatectomy significantly reduces the total ipss and positively affects luts.(14) our investigation further extended knowledge of the impact of rrp on luts, demonstrating that rrp provides major benefits for men with luts. namiki and colleagues reported that storage symptoms, such as frequency and nocturia, do not improve after radical prostatectomy, or are exacerbated in some cases.(15) results from the present study were similar, in that overall urinary symptoms significantly improved after operation, yet patients’ qol progressively worsened. specifically, progressively table 4. comparison of questionnaire scores prior to, and 3 and 6months after medication (n = 34). variables baseline 3-month 6-month p value a p value b iciq-sf score 4.9 ± 1.8 4.8 ± 1.4 4.6 ± 1.4 .404 .154 khq score 25.6 ± 7.1 24.8 ± 6.2 23.5 ± 6.6 c .263 .019 abbreviations: iciq-sf, international consultation on incontinence questionnaire-short form; khq, king’s health questionnaire. values are presented as mean ± standard deviation. a compares values between the baseline and 3 months of therapy; b compares values between the baseline and 6 months of therapy; c p < .05 versus baseline. voiding patterns after prostatectomy-yang et al. urological oncology 2687 deteriorating storage symptom composites negated the improvements in voiding symptom composites, resulting in worsened qol. this information is important when counseling patients about treatment options for localized prostate cancer. the improvement of luts is probably mostly attributable to obstruction relief by rrp. it is well known that benign prostatic hypertrophy can cause boo, secondary bladder overactivity, and reduction in functional bladder capacity, which may result in storage symptoms.(16) conversely, these symptoms can be reversed with obstruction relief by prostatectomy.(17) several investigators have also reported ipss improvement concurrent with an increase in urinary flow rate after rrp in patients with moderate to severe luts.(18) although our study lacked urodynamic data, these findings suggest an association between boo relief by rpp and ipss improvement. rrp increased urgency and nocturia (not significantly) in our study. in contrast, namiki and colleagues(19) reported that nocturia did not return to the baseline level within 2 years after surgery. gomha and colleagues(20) reported that, following radical prostatectomy, a substantial proportion of patients were affected by detrusor overactivity, impaired detrusor contractility, decreased compliance, and sphincter weakness. bladder denervation during surgery has been suggested as one reason for these abnormalities. wide anatomical dissection around the prostate and bladder neck may disrupt regional afferent and efferent innervation, causing outlet lethargy and partial denervation of the detrusor muscle.(21) also, jung and colleagues(22) demonstrated that leakage of urine into the proximal urethra could increase bladder activity by stimulating urethral afferents, which in turn modulate the micturition reflex and induce detrusor instability. thus, bladder denervation during surgery and postoperative urine incontinence may be implicated in the deterioration of storage symptoms, even though recovery from urinary incontinence after rpp is considerable. for patients with luts, these adverse effects may exacerbate urgency or nocturia. the reversal of detrusor overactivity by relief of boo might have been dampened by adverse effects such as bladder denervation or subtle urine leakage. in patients with preoperative luts, communicating that voiding symptoms can be improved after radical prostatectomy will be important to promoting qol. in our study, bladder storage symptoms aggravated after prostatectomy. we believe that an irritated urethra caused by urine leakage due to nerve or sphincter injury during prostatectomy caused decreased bladder compliance and detrusor overactivity. also, extensive incisions during prostatectomy can damage the efferent and afferent nerves of the bladder trigone, bladder neck, and detrusor muscle. therefore, storage symptoms may be aggravated as opposed to voiding symptoms after prostatectomy.(22) in general, storage symptoms are managed with anticholinergic drugs, since detrusor contractions are mediated by cholinergic receptor stimulation. the results of the current study show that anticholinergic drugs act not only on detrusor muscle but also on muscarinic receptors located on bladder afferent nerve terminals and on urothelium.(23) recent pharmacologic advancements have produced anticholinergic drugs with an increased duration of action and fewer side effects, such as dry mouth and constipation. in our study, taking anticholinergic drugs significantly improved storage symptoms after radical prostatectomy. our findings supplement subjective questionnaire-based reports of decreased urgency and frequency reported in trials of solifenacin.(24,25) our study will help clarify treatment options for patients with localized prostate cancer who consider refusing prostatectomy due to not wanting changes in luts. limitations of our study are its small sample size and short follow-up period after medication, which allows for potential selection bias. long-term follow-up data on this patient population is needed. to clarify the mechanism of luts improvement, further investigation including urodynamic studies and overactive bladder symptoms score, will be needed. further large prospective studies and long-term follow-up will be required to fully evaluate the drug efficacy results. conclusions postoperative luts is a common adverse effect of rrp, potentially leading to a significantly diminished qol. however, the exact cause of postoperative luts was not determined. although our study was relatively small, it provides important and detailed information about the impact of rrp on luts and luts-related qol. it also supports the benefits of anticholinergic drugs as treatment for postoperative luts. we hope table 5. adverse events due to anticholinergic drugs (n = 34). adverse events 3-month 6-month dry mouth 6 (17.6) 8 (23.5) constipation 3 (8.8) 5 (14.7) blurred vision 0 (0) 1 (2.9) headache 2 (5.9) 1 (2.9) dizziness 1 (2.9) 1 (2.9) values are presented as number (percentage). voiding patterns after prostatectomy-yang et al. vol 13 no 03 may-june 2016 2688 that our findings will assist patients, families, and doctors in their discussions about treatment expectations and outcomes. ackowledgements this work was supported by chungnam, national university hospital research fund, 2011. conflict of interest none declared. references 1. siegel r, ma j, zou z, jemal a. cancer statistics, 2014. ca cancer j clin. 2014;64:9-29. 2. jani ab, hellman s. early prostate cancer: clinical decision-making. lancet. 2003;361:1045-53. 3. song c, lee j, hong jh, choo ms, kim cs, ahn h. urodynamic interpretation of changing bladder function and voiding pattern after radical prostatectomy: a longterm follow-up. bju int. 2010;106:681-6. 4. hollenbeck bk, lipp er, hayward ra, montie je, schottenfeld d, wei jt. concurrent assessment of obstructive/ irritative urinary symptoms and incontinence after radical prostatectomy. urology. 2002;59:389–93. 5. masters jg, rice ml. improvement in urinary symptoms after radical prostatectomy: a prospective evaluation of flow rates and symptom scores. bju int. 2003;91:795–7. 6. bauer rm, gozzi c, hubner w, et al. contemporary management of postprostatectomy incontinence. eur urol. 2011;59:985-96. 7. babic u, santric-milicevic m, terzic z, et al. impact of voiding and incontinence symptoms on health-related life quality in serbian male population. urol j. 2015;12:2196-203. 8. barry mj, fowler fj jr, o’leary mp, et al. the american urological association symptom index for benign prostatic hyperplasia. the measurement committee of the american urological association. j urol. 1992;148:1549–57. 9. avery k, donovan j, peters tj, shaw c, gotoh m, abrams p. iciq: a brief and robust measure for evaluating the symptoms and impact of urinary incontinence. neurourol urodyn. 2004;23:322-30. 10. kelleher cj, cardozo ld, khullar v, salvatore s. a new questionnaire to assess the quality of life of urinary incontinent women. br j obstet gynaecol. 1997;104:1374–9. 11. sriprasad s, feneley mr, thompson pm. history of prostate cancer treatment. surg oncol 2009;18:185-91. 12. millin t. retropubic prostatectomy. j urol. 1948;59:267–80. 13. walsh pc. anatomic radical prostatectomy: evolution of the surgical technique. j urol. 1998;160:2418–24. 14. schwartz ej, lepor h. radical retropubic prostatectomy reduces symptom scores and improves quality of life in men with moderate and severe lower urinary tract symptoms. j urol. 1999;161:1185–8. 15. namiki s, saito s, ishidoya s, et al. adverse effect of radical prostatectomy on nocturia and voiding frequency symptoms. urology. 2005;66:147–51. 16. de nunzio c, franco g, rocchegiani a, iori f, leonardo c, laurenti c. the evolution of detrusor overactivity after watchful waiting, medical therapy and surgery in patients with bladder outlet obstruction. j urol. 2003;169:535–9. 17. giannantoni a, mearini e, di stasi sm, et al. assessment of bladder and urethral sphincter function before and after radical retropubic prostatectomy. j urol. 2004;171:1563–6. 18. kumar v, toussi h, marr c, hough c, javle p. the benefits of radical prostatectomy beyond cancer control in symptomatic men with prostate cancer. bju int. 2004;93:507–9. 19. namiki s, ishidoya s, saito s, et al. natural history of voiding function after radical retropubic prostatectomy. urology. 2006;68:142–7. 20. gomha ma, boone tb. voiding patterns in patients with post-prostatectomy incontinence: urodynamic and demographic analysis. j urol. 2003;169:1766–9. 21. giannantoni a, mearini e, di stasi sm, et al. assessment of bladder and urethral sphincter function before and after radical retropubic prostatectomy. j urol. 2004;171:1563–6. 22. jung sy, fraser mo, ozawa h, et al. urethral afferent nerve activity affects the micturition reflex; implication for the relationship between stress incontinence and detrusor instability. j urol. 1999;162:204–12. 23. andersson ke, yoshida m. antimuscarinics and the overactive detrusor which is the main mechanism of action? eur urol. 2003;43:1–5. 24. santos jc, telo er. solifenacin: scientific evidence in the treatment of overactive bladder. arch esp urol. 2010; 63:197–213. 25. vardy md, mitcheson hd, samuels ta, et al. effects of solifenacin on overactive bladder symptoms, symptom bother and other patient reported outcomes: results from vibrant a double-blind, placebo-controlled trial. int j clin pract. 2009;63:1702–14. voiding patterns after prostatectomy-yang et al. urological oncology 2689 urology journal unrc/iua 148 vol. 1, no. 3, 148-156 summer 2004 printed in iran accepted for publication in july 2003 *corresponding author: taskent caddesi no. 77, kat 4, bahcelievler 06490 ankara, turkey. email: rektorluk@baskent-ank.edu.tr kidney donation: state of the art living donor kidney transplantation: how far should we go? haberal ma* department of transplantation, baskent university, ankara, turkey abstract purpose: to describe the work that the bașkent university faculty of medicine has done to increase kidney donors' number in turkey and also to discuss the major effects that donor-organ shortage is currently having worldwide. materials and methods: from 1975 through 2003, our transplantation team at hacettepe university hospital and later at the bașkent university transplantation center (butc) performed 1451 kidney transplantations. cadaver donation and patient and graft survival rates for various groupings of transplantation types were compared. results: of all the renal transplantations completed in turkey from 1975 to january 2004, 20% were performed by our team in our center. for the years 1990 through 2003, the 1-, 3-, and 5-year patient survival rates in the first-degree-living-related kidney transplantation group were 96%, 93%, and 91%, respectively, and the corresponding graft survival rates were 93%, 84%, and 81%. in the second-degree living-related group, the 1-, 3-, and 5-year patient survival rates were 94%, 90%, and 87%, respectively, and the corresponding graft survival rates were 93%, 86%, and 84%. for living-unrelated transplantations, the 1-, 3and 5-year patient survival rates were 93%, 90%, and 83%, respectively, and the corresponding graft survival rates were 83%, 78%, and 76%. in the cadaver-kidney transplantation group, the 1-, 3and 5-year patient survival rates were 85%, 78%, and 70%, respectively, and the corresponding graft survival rates were 82%, 64%, and 53%. during this same period, the 1-, 3-, and 5-year graft survival rates for our cadaver donors and living donors older than 55 years of age were 80%, 52%, 46% and 88%, 69%, 61%, respectively. conclusion: vigorous efforts by our group at bașkent university and by other transplant surgeons across the nation have increased the numbers of transplantations performed each year. as well, since the ncc was established in 2001, the number of cadaver-kidney transplantations has more than doubled. the initial results with this new nationwide organ-sharing system are promising, and there is every indication that this approach will continue to raise the number of transplant operations performed across turkey each year. key words: kidney transplantation, living donor, cadaver, turkey living donor kidney transplantation: how far should we go? 149 introduction for several years after the first successful transplantation of a kidney from one twin to another in 1954, living-related donors were the most frequent source of kidneys for renal transplantation. over the past few decades, the concept of brain death has been introduced, immunosuppressive therapy has improved, and exciting progress has been made with many transplantrelated clinical, biological, and immunological problems. as a result of these advancements, cadaveric organ transplantation has become the predominant mode of treatment for end-stage renal disease (esrd). greater success with kidney transplantation has led to increased numbers of patients on waiting lists and a growing demand for donor organs. however, the shortage of cadaver organs remains a crippling problem that educational changes, legislative efforts, and international cooperation have not yet solved. at the march 2002 national conference on the waiting list for kidney transplantation, it was reported that, from 1990 to mid-2002, the kidney transplant waiting list in the united states had expanded from approximately 15,000 to 55,000 patients, while the number of cadaveric kidneys transplanted annually had remained stable at approximately 9,000.(1) as a result, the median waiting time between listing and renal transplantation in the united states has been extended from 19 months (as of a decade ago) to more than 3 years for patients listed in 1999.(2) it is projected that, by the year 2010, the waiting list for kidney transplants in that country will comprise 100,000 patients and the average waiting time will be nearly 10 years.(3) currently, more than 40,000 patients are registered on waiting lists in western europe, and the list grows by several hundred patients each month. the scenario is similar throughout the world. the consequences of this are serious: lower quality of life, poorer rehabilitation, increased numbers of deaths, and higher costs of renal replacement therapy for patients awaiting kidneys compared to costs for transplant recipients.(4) in turkey, solid-organ transplantation began in 1969 with two heart transplantations that, unfortunately, were unsuccessful. by the early 1970s, our team had initiated experimental studies on kidney and liver transplantation.(5) this team performed the country's first livingrelated kidney transplantation (lrkt) in november 3, 1975.(6) today, the supply of cadaver kidneys in turkey lags far behind the demand, and the number of potential transplant recipients has dramatically increased with the rising incidence of esrd. these factors have spurred the expansion of lrkt in our country, and our current kidney transplantation program is still largely dependent on firstand second-degree relatives and spouses. this article describes the work that the bașkent university faculty of medicine has done to increase kidney-donor numbers in turkey. it also discusses the major effects that donor-organ shortage is currently having worldwide. materials and methods from 1975 through 2003, our transplantation team at hacettepe university hospital and later at the bașkent university transplantation center (butc) performed 1451 kidney transplantations. of these, 1106 (76%) involved living donors and 345 (24%) involved cadaver organs. the total number of kidney transplantations carried out in turkey during the same period was 6082, with 4572 (75%) of these transplants coming from living donors and 1510 (25%) coming from cadavers. the bașkent university team has also performed re-transplantations of kidneys in 55 cases.(7) two of these patients received three renal transplants, and the other 53 received two grafts. in turkey, any individual related or married to the recipient who is free of chronic disease and willing to donate a kidney is informed about the risks, benefits, and procedures involved in livingdonor transplantation. care is taken to ensure the person feels no obligation to donate. multiple ureters, multiple veins, multiple arteries, renal cysts, and ectopic kidneys are not considered contraindications, though we prefer to harvest kidneys that have a single long arterial pedicle. briefly, our surgical technique for arterial and ureteral anastomosis involves a combination of the parachute technique and the four-quadrant running suture technique, and we prefer to anastomose the renal artery to the external iliac artery. we have also adopted the lich-gregoir technique as part of our standard procedure, and this involves placement of a temporary stent that is removed before ureteral re-implantation is completed.(8,9,10) recently, in efforts to improve patient compliance with surgery and to reduce postoperative discomfort, we have changed our protocol for recipients from general anesthesia to epidural anesthesia, and have introduced comliving donor kidney transplantation: how far should we go?150 bined spinal-epidural anesthesia for donors.(11) for lrkt, we use standard triple-drug immunosuppression. our initial regimen was 1 mg/kg prednisolone, 5 mg/kg cyclosporine a, and 2 mg/kg azathioprine daily in the postoperative period. in 1999, we modified our protocol by replacing azathioprine with mycophenolate mofetil (mmf) and, in selected cases (steroid resistant acute rejection and cyclosporine toxicity), replacing cyclosporine with tacrolimus. azathioprine (or mmf) and prednisolone are started 3 days prior to the surgery. prednisolone is tapered to the maintenance dose of 10 mg/day at two months post-transplantation, and is tapered further to 5 mg/day if the patient develops problems such as diabetes, aseptic necrosis, or obesity. cyclosporine or tacrolimus doses are adjusted according to serum levels, and doses of azathioprine (or mmf) are altered according to leukocyte count and results of liver function testing. episodes of acute rejection are treated with intravenous bolus doses of methylprednisolone (250-500 mg/day) for three consecutive days, and steroid-resistant cases are treated with monoclonal antibody (okt3) and plasmapheresis. the severe shortage of kidney donors in turkey has forced us to expand our list of criteria for donor eligibility. in 1985, we began to use organs from cadaveric and living donors older than 55 years of age(11) after 1985, our group also started to perform cadaver-kidney transplantations with cold ischemia times longer than 100 hours,(12) and in 1987 we began to carry out aboincompatible kidney transplantations.(13) in addition, in may 1992 we harvested multiple organs (segmental liver and kidney) from one living donor, and performed simultaneous liver and kidney transplantation with these grafts.(14) currently, we also perform kidney transplantations between living-related donors and recipients with one or two hla matches if there is no other donor candidate with a better match. in order to reduce problems with cadaver-donor identification/management and maximize cadaver donor numbers, in january 2001 the ministry of health gathered all transplantation centers in turkey under an umbrella organization called the national coordination center (ncc). for this report, we calculated and compared the cadaver donation rates prior to and after the ncc was established. we also compared patient and graft survival rates for various groupings of transplantation types (i.e. first-degree living-related, second-degree living-related, unrelated, abo-incompatible, and others). all statistical analysis was done using the log-rank test and the software program spss for windows. results of all the renal transplantations completed in turkey from 1975 to january 2004, 20% were performed by our team in our center. figure 1 lists the yearly distribution of livingand cadaverdonor renal transplantations carried out by our team from 1975 through 2003. figure 2 summarizes similar data compiled from 29 other transplantation centers in turkey from 1990 through 2003. for the years 1990 through 2003, the 1-, 3-, and 5-year patient survival rates in the first-degree-living-related kidney transplantation group were 96%, 93%, and 91%, respectively, and the corresponding graft survival rates were 93%, 84%, and 81%. in the second-degree living-related group, the 1-, 3-, and 5-year patient survival rates were 94%, 90%, and 87%, respectively, and the corresponding graft survival rates were 93%, 86%, and 84%. for living-unrelated transplantations, the 1, 3and 5-year patient survival rates were 93%, 90%, and 83%, respectively, and the corresponfig. 1. the distributions of livingand cadaver-donor renal transplantations performed at the butc from 1975 through 2003 fig. 2. the distributions of livingand cadaver-donor renal transplantations performed at 29 other transplantation centers in turkey from 1990 through 2003. cadaver and living donor numbers are not available before 1994. living donor kidney transplantation: how far should we go? 151 ding graft survival rates were 83%, 78%, and 76%. in the cadaver-kidney transplantation group, the 1-, 3and 5-year patient survival rates were 85%, 78%, and 70%, respectively, and the corresponding graft survival rates were 82%, 64%, and 53%. the 1-, 3-, and 5-year patient and graft survival rates for first-degree, second-degree, unrelated, and cadaver-donor kidney transplantations are presented in figures 3 and 4. during this same period, the 1-, 3-, and 5-year graft survival rates for our cadaver donors and living donors older than 55 years of age were 80%, 52%, 46% and 88%, 69%, 61%, respectively. these rates were slightly lower than those for the transplantations done with grafts from younger donors, but we found that patient survival rates were similar in the older and younger donor age groups. the graft survival rates for transplants from our donors older than 55 years are presented in figure 5. the respective 1-, 3-, and 5-year graft survival rates for the abo-incompatible transplantations performed during this time were 66.7%, 52.4%, and 47.6%. these rates were slightly lower than the corresponding figures for the abo-compatible transplantations. we also analyzed graft survival in relation to numbers of hla mismatches. comparison of the findings showed that zero-mismatch cases had significantly higher graft survival rates than cases with one, two, three, four or five mismatches; however, there were no significant differences among the rates for the latter five groups (fig. 6). it has been three years since the ncc was established. although the current levels of organ donation and procurement in turkey still do not meet the need, rates have risen during this period. in the first year after the ncc was formed, the number of cadaver-kidney transplantations increased from 92 to 162. this figure rose to 189 in the second year, and the total number was 177 in the third year. table 1 shows the numbers of different types of cadaver-organ transplantations performed in our country from 2001 through 2003. fig. 3. patient survival rates for kidney transplantations carried out at the butc from 1990 through 2003 �� �� �� �� ��� ��� � ��� � ��� � ��� ��� �� �� � � � � ������ �� �� � � � ��� � � � � � � ��� fig. 4. graft survival rates for kidney transplantations carried out at the butc from 1990 through 2003 �� �� �� �� �� �� ��� � �� � �� � � �� � �� ������ �� ������ ���������� �� ������ �� ������ ������ �� fig. 5. overall graft and patient survival rates, and graft survival rates in donors over 55 years of age for kidney transplantations carried out at the butc from 1990 through 2003 � �� �� �� �� ��� � ��� � ��� � �� � � �� ��������� � �� ��������� � �� ��������� �� � fig. 6. comparison of findings with grafts grouped according to hla matching showed that cases with zero mismatches (mm) had the best graft survival rates. the 5-year graft survival rate was poorest in the cases with five mismatches, but there were no statistically significant differences among the groups with one, two, three, four or five mismatches. � �� �� �� �� �� �� �� � � ��� ������ ������� ������ ��� ��� ��� ��� ��� ��� � �� heart valve liver kidney cornea before ncc (jan 2001) 63 70 212 989 6259 2001 27 25 68 162 1267 2002 20 15 82 189 1538 2003 23 24 87 177 1060 total 133 134 449 1517 10124 table 1. cadaver-organ transplantation activities in turkey before and in the years since the national coordination center (ncc) was established living donor kidney transplantation: how far should we go?152 discussion in turkey, the leading cause of chronic renal failure is chronic glomerulonephritis. in the year 2000, the cadaver donation rate in our country was 0.9 per million people, the lowest rate in europe. according to year 2002 data from the registry of the turkish nephrology association, the prevalence and incidence of esrd are 395 per million and 70 per million, respectively. this registry listed a total of 25,397 esrd patients in turkey as of 2002, with 7086 new cases diagnosed in that year alone.(15) however, of the 6060 patients who were placed on renal transplant center waiting lists in 2002, only 550 (9%) received a graft kidney that year. in our country, many people with esrd remain unaware of the possibility of renal transplantation, and the number of patients who receive transplants is far less than the number who could benefit from transplantation. there is a great need to inform this group that kidney transplantation is the most efficient mode of renal replacement therapy. also, aside from the general problems of organ supply and demand, there is a specific issue with pediatric transplantation in turkey. although pediatric esrd patients are given priority over adults, very few of these children are registered on transplant waiting lists by their parents. as of 1999, only 118 pediatric esrd patients in turkey had undergone renal transplantation. forty-two (36%) of these children were transplanted at butc.(15) why living donation? the worldwide medical literature on various aspects of living donation indicates that postoperative mortality in living kidney donation is approximately 1 in 3,000 cases.(16) long-term follow-up investigations of donors have shown that the risks of progressive renal failure, hypertension, and proteinuria are not increased by nephrectomy per se, and that these problems occur occasionally due to other causes.(17) overall, the findings suggest that unilateral nephrectomy is not harmful in healthy individuals. in addition, there are other valid reasons to expand living donation: 1) the demand for cadaveric donor kidneys far exceeds the supply; 2) the quality of kidneys from living donors is better due to shorter ischemia time, lack of effects from the agonal phase, and lack of effects from cytokine release after brain death; 3) better results with kidney transplants from living donors compared to grafts from cadaver donors in the cyclosporine era (and this also appears to hold for grafts from unrelated living donors despite hla incompatibility); and 4) pre-emptive transplantation with an organ from a living donor not only avoids the risks, cost, and inconvenience of dialysis, but is also associated with better graft survival than transplantation after a period of dialysis (particularly within the live-donor cohort). at our center, only first-degree (father, mother, sibling, offspring) and second-degree (aunt, uncle, cousin, nephew, grandmother, grandfather) relatives are considered "related" donors. the only "unrelated" donors we accept in our program are those legally married to the recipient. interestingly, although unrelated donor-recipient pairings invariably have poorer hla matches than is typical of living-related pairings, we have found that graft and patient survival rates are comparable. the current percentages of living donors are near 12% in europe, 35% in the united states, 50% in latin america, 90% in asia, and 75% in turkey. expanding the organ pool in turkey as noted above, in order to increase the numbers of organs available for transplantation at our center we raised the acceptable donor age range for both cadaver and living-related donors. also, in the 1980s we began to use cadaver grafts with longer ischemia times. this strategy added a new dimension to the field, and reports of renal transplantations involving cold ischemia times of 48-72 hours started to appear in the worldwide literature.(12) in 1987, we also broke barriers related to major histocompatibility complex and blood type compatibility, transplanting abo-incompatible kidneys after donor-specific skin grafting. initially, we performed both splenectomy and plasmapheresis in these cases; however, we later adopted a strategy of using plasmapheresis until the recipient's anti-a immunoglobulin igg/igm or anti-b igg/igm titers dropped to 1:16 or lower.(14) we also adopted the policy of accepting donorrecipient pairs with few hla matching if a more suitable donor was unavailable. the safety and value of organ sharing in a donor-recipient pair with zero hla mismatches are undisputed, and policies of accepting higher numbers of hla mismatches when selecting recipients for available organs are much criticized. however, awarding points for donor-recipient matching at the hla a locus has already been eliminated from the algoliving donor kidney transplantation: how far should we go? 153 rithm for waiting list allocation (unos policy 3.5.11.2), and it is also proposed that b locus mismatching should be eliminated from the unos sharing algorithm.(18) in the future, as more potent and selective immunosuppressive drugs and methods become available, tissue typing may be totally eliminated from the donor-recipient selection protocol. when treating a patient with multiple organ failure, in order to maximize the use of a living donor who has given consent we prefer to harvest multiple organs (e.g. one kidney and a segment of liver). to date, we have completed two such transplantations. governmental policies related to cadaver donation have also been important in terms of the organ pool. in turkey, the initial law on organ/tissue harvesting, storage, grafting and transplantation (turkish law 2238) was enacted on june 3, 1979, much earlier than similar legislation in many other countries. according to this law buying and selling of organs and tissues for a momentary sum or other gain is forbidden, and all advertisement in connection with the harvesting and donation of organs and tissues is forbidden. harvesting organs and tissues from person under age of 18 or who are not of sound mind is forbidden. on january 2, 1982, new articles were added to law 2238 that make it possible to harvest organs when a person dies due to accident or natural causes and there are no next of kin.(13) according to a recent study in the united states, problems with donor identification and/or management (42%), and family or coroner refusals (26%) account for most cases in which brain-dead donors' organs are not used.(19) to minimize these problems and maximize the use of available donor organs nationwide, in early 2001 turkish parliament founded a new national organ-sharing organization (the above-mentioned ncc) under the auspices of the turkish ministry of health. under this system, the country is divided into six regions, each with its own regional coordination center (rcc).(20) every transplant center has a transplant team comprising a transplant coordinator, clinicians (nephrologists, gastroenterologist, and pathologist), and surgeons. the transplant coordinator works in a role that is completely separate from the clinical departments and other members of the transplantation team. this person's primary responsibilities are to promote organ donation and procurement; to organize interviews with donor families; to maintain contact with national and international organ-sharing organizations on a 24-hour on-call basis; and to train all personnel involved in the transplantation process. since 2001, the number of transplantation procedures performed per year throughout turkey has risen by more than 30%, and the proportion of cadaver-donor organs has increased significantly, from 21% to 50%. this rise likely reflects increased collaboration among transplantation centers, as well as a change in turkish people's attitudes toward organ donation. the latter has been achieved through the dedicated efforts of staff at transplantation centers and the ministry of health and through persuasive speeches by officials in the department of religious affairs, who have explained that organ donation is not forbidden in islamic belief. as table 1 shows, the numbers of all forms of solid-organ transplantation in turkey have risen since the ncc was founded. the world situation there is much ethical debate about certain aspects of transplantation, but alternatives to directed donation (donors who are biologically or emotionally connected to the recipient) are growing. today, the options include non-directed donation (e.g., permitting a volunteer to donate a kidney to an anonymous recipient), donor-recipient pair exchanges (a donor who is better matched to another recipient is switched and donates to that other recipient), and list-paired donation (an hla-mismatched directed donor is paired with a stranger on the cadaver waiting list, which means that the intended recipient moves to the top of the list). a report from the organ procurement and transplantation network (optn) stated that, for the first time, in 2001 the number of living donors in the united states (6371; preliminary data from the optn as of february 8, 2002) surpassed the number of cadaveric donors (6070; preliminary data as of the same date). between 1990 and 2000, the total number of living-donor kidney transplants in the united states more than doubled, from 2095 to 5304. while this increase for living donors biologically related to kidney recipients was impressive (more than twofold), the number of living-unrelated donors increased nearly 15-fold, from 87 to 1243. in contrast, the increase in cadaver-donor kidney transplants was only 10.5%, and this was largely attributed to acceptance of more donors through living donor kidney transplantation: how far should we go?154 expanded criteria.(21) today, very few countries are able to reduce the numbers of patients on transplantation waiting lists. however, iran has completely eliminated its renal transplant waiting list by implementing a new model called "controlled living-unrelated transplantation." as of the end of the year 2000, a total of 10,957 renal transplantations (involving 2,468 living-related donors and 8,404 living-unrelated donors) had been performed in iran.(22) living-unrelated transplantation is currently gaining popularity in many parts of the world, and some experts are presenting this as a viable solution for organ insufficiency. still, it is of major concern that unrelated transplantation (that in which the donor is not a relative or spouse) is not strictly controlled in countries where it is practiced. along with the impressive results that have been made in living-donor transplantation, there has also been some distressing news. debates about providing incentives for organ donors, and reports on the sale of human organs for transplantation as means of motivating living donation are two examples. news items about organ removal after executions, uncontrolled commercial renal transplantation, and the black market for organs show the ugly face of transplantation.(23,24,25) in general, experience with living-unrelated donation indicates that this practice leads to commercialism. paid unrelated living donors may be found in places such as india, iraq, and even the united states. sale of organs has been banned universally, but some countries, such as israel, are now deliberating about lifting this ban. the argument in favor of this is based on humanitarian considerations for people who are dying due to lack of transplantable organs, or due to the lack of funds to pay for transplantation surgery. however, societies with large low-income populations will be unable to avoid commercialism of organ trading. we agree with the statement made by drs. hasan rizvi and anwar naqvi: "being an optimist, one has great faith in the goodness of human nature and the human desire to live longer, which may be for even just one month. this flame is difficult to extinguish".(26) the will to live is extremely strong; if the spark of living-unrelated kidney donation (excluding that between spouses) is permitted to burn, it will be impossible to prevent the sale of other organs. the less privileged countries of the world will be transformed to universal donors, with poor masses and oppressed groups as the most widely exploited victims. there are also health-related arguments to be made against living-unrelated organ donation. although current data on kidney donation indicate that donor nephrectomy is safe, this procedure is not without risks. as of february 2002, 56 individuals in the united states who had previously been kidney donors were identified as listed for cadaveric kidney transplantation.(21) a survey of live donors conducted by the american society of transplant physicians in 1995 reported 0.03% mortality and a 0.23% rate of serious complications.(27) the same report noted that 15 donors (0.15%) developed advanced renal disease after donation (4 cases of renal insufficiency and 11 cases of esrd). in another study of 1800 live donors, 7 (0.4%) developed esrd.(18) the consensus statement on the live organ donor concluded that, "the benefits to both donor and recipient must outweigh the risks associated with the donation and transplantation of the livingdonor organ".(28) current data from around the world suggest that both shortand long-term follow-up is mandatory for living donors. considering all the societal and health risks, and the costs connected with living-unrelated donation, we believe that it is not wise to expand living organ donation to include individuals who are not married or blood relatives. in our opinion, the most logical way to tackle the organ shortage problem is to expand cadaver donation, although living-donation is feasible option for patient with chronic liver and kidney diseases, there are also among of these who needs lung, heart, cornea, pancreas, and skin transplantation. various nations around the globe have established different systems for donating organs, such as "opt-in" policies (consent is required) and "opt-out" policies (consent is presumed). four european nations with opt-in policies (denmark, the netherlands, the united kingdom and germany) have much lower cadaver donation rates than countries with opt-out policies (austria, belgium, french, hungary, poland, portugal and sweden). changing a country's standard policy on organ donation can result in striking differences in organ donation. the studies done by eric johnson and daniel goldstein at columbia university in the united states have shown that donation rates can rise significantly under opt-out conditions.(29) living donor kidney transplantation: how far should we go? 155 conclusion today, turkish organ donors and recipients are being cared for with the most advanced scientific and medical techniques available in the world. vigorous efforts by our group at bașkent university and by other transplant surgeons across the nation have increased the numbers of transplantations performed each year. newly developed, effective immunosuppressive protocols are prolonging graft and patient survival. as well, since the ncc was established in 2001, the number of cadaver-kidney transplantations has more than doubled. the initial results with this new nationwide organ-sharing system are promising, and there is every indication that this approach will continue to raise the number of transplant operations performed across turkey each year. we suggest that turkish citizens should consider changing our national policies on organ donation. opt-out policies can increase the pool of cadaverorgan transplants. in addition to increasing cadaver donation, we feel that living-related donation restricted to firstand second-degree relatives and acceptable non-blood-related donors (such as spouses) is the best path to expanding kidney transplantation worldwide. references 1. united network for organ sharing. richmond va; 2002. 2. united states scientific renal transplant registry (srtr). annual report. 2001. 3. xue jl, ma jz, louis ta, et al. forecast of the number of patients with end-stage renal disease in the united states to the year 2010. j am soc nephrol 2001; 12: 2753-2758. 4. kahan bd, ponticelli c. selection and operative approaches for cadaveric and living donors. in: kahan bd, ponticelli c, editors. principles and practice of renal transplantation. london: martin dunitz ltd; 2000. p. 145-190. 5. haberal m, gulay h, buyukpamukcu n, et al. liver transplantation in turkey. transplant proc 1991; 23: 2563. 6. haberal m, sert s, aybastı n, et al. living donor kidney transplantation. transplant proc 1988: 20:353. 7. bilgin g, karakayalı h, moray g, demirağ a, arslan g, akkoç h, turan m. outcome of renal transplantation from elderly donors. transplant proc 1998; 30: 744. 8. haberal m, karakayali h, bilgin n, moray g, arslan g, büyükpamukçu n. four-quadrant running-suture arterial anastomosis technique in renal transplantation: a preliminary report. transplant proc 1996; 28: 2334. 9. moray g, bilgin n, karakayalı h, haberal m. comparison of outcome in renal transplant recipients with respect to arterial anastomosis: the internal versus the external iliac artery. transplant proc 1999; 31: 2839-40. 10. haberal m. böbrek transplantasyonu. in: haberal m, editor. doku ve organ transplantasyonları. haberal eğitim vakfı 1993; 159. 11. haberal m, emiroglu r, arslan g, apek e, karakayali h, bilgin n. living-donor nephrectomy under combined spinal-epidural anesthesia. transplant proc 2002; 34(6): 2448-9. 12. haberal m, sert s, aybasti n, et al. cadaver kidney transplantation cases with a cold ischemia time of over 100 hours. transplant proc. 1987 oct;19(5):4184-8. 13. karakayalı h, moray g, demirağ a, turan m, bilgin n, haberal m. long-term follow-up of abo-incompatible renal transplant recipients. transplant proc 1999; 31: 256-257. 14. haberal m, moray g, karakayalı h, bilgin n. transplantation legislation and practice in turkey: a brief history. transplant proc 1998; 30: 3644. 15. erek e, süleymanlar g, serdengeçti k. türkiye'de nefroloji-dializ ve transplantasyon. registry, istanbul; 2002. 16. narkun-burgess dm, nolan cr, norman je, page wf, miller pl, meyer tw. forty-five year follow-up after uninephrectomy. kidney int 1993; 43: 1110-1115. 17. hartmann a, fauchald p, westlie l, brekke ib, holdaas h. the risk of living kidney donation. nephrol dial transplant 2003; 18: 871-873. 18. gaston rs, danovitch gm, adams pl, et al. the report of a national conference on the wait list for kidney transplantation. am journal transplant 2003; 3: 775-785. 19. wight c, cohen b, beasley c. donor action: a systemic approach to organ donation. transplant proc 1998: 30:2253-2254. 20. haberal m. development of transplantation in turkey. transplant proc 2001; 33: 3027. 21. ellison md, mcbride ma, taranto se, et al. living kidney donors in need of kidney transplants: a report from the organ procurement and transplantation network. transplantation 2002; 74 (9): 1349-1354. 22. ghods aj, savaj s, khosravani p. adverse effects of a controlled living-unrelated donor renal transplant program on living-related and cadaveric kidney donation. transplant proc 2000; 32: 541. 23. friedlaender mm. the right to sell or buy a kidney: are we failing our patients? lancet 2002; 16 (359): 971-3. 24. cameron js, hoffenberg r. the ethics of organ transplantation reconsidered: paid organ donation and the use of executed prisoners as donors. kidney int 1999; 55: 724-732. 25. mufson s. chinese doctor tells of organ removals after executions. washington post 2001 june 27; sect. a:1. 26. rizvi sah, naqvi saa. our vision on organ donation in developing countries. transplant proc 2000; 32: 144-145. living donor kidney transplantation: how far should we go?156 27. bia mj, ramos el, danovitch gm, et al. evaluation of living renal donors: the current practice of us transplant centers. transplantation 1995; 60: 322-327. 28. abecassis m, adams m, adams p, et al. consensus statement on the live organ donor: live organ donor consensus group. jama 2000; 284: 2919-2926. 29. johnson ej, goldstein d. do defaults save lives? science 2003 nov 21; 302(5649): 1338-9. vol 13 no 05 september-october 2016 2744 comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery in treating 20-40 mm renal stones gokhan atis1*, meftun culpan1, eyup sabri pelit2, cengiz canakci1, ismail ulus1, bilal gunaydın1, asıf yildirım1, turhan caskurlu1 purpose: to compare the outcomes of percutaneous nephrolithotomy (pcnl) and retrograde intrarenal surgery (rirs) in treating renal stones between 20 and 40 mm in diameter. materials and methods: 146 patients, who were treated with rirs and 146 patients, who were treated with pcnl for renal stones between 20 and 40 mm in diameter were compared retrospectively using a matched-pair analysis. the operative and post-operative outcomes of both groups were analyzed retrospectively. results: the mean age, gender, body mass index and stone laterality were similar between the groups. the mean stone size was 28.39 ± 4.67 mm for the pcnl group and 25.08 ± 6.07 mm for the rirs group (p =.21). the mean operative times were statistically longer in the rirs group, whereas the fluoroscopy times, hospitalization times and post-operative visual analogue scores were statistically higher in the pcnl group. the stonefree rates (sfr) after a single procedure were 91.7% in the pcnl group and 74% in the rirs group (p = .04). after auxiliary procedures, the overall sfrs reached 94.4% for the pcnl group and 92.3% for the rirs group (p = .52). no major complications were observed for both groups. minor complication (clavien 1–3) rates were 6.8% and 3.4% for the pcnl and rirs group, respectively (p =.18). conclusion: rirs has some advantages over pcnl such as shorter hospitalization times, shorter fluoroscopy times and less post-operative pain in treating renal stones between 20 and 40 mm in diameter. however, pcnl has a higher sfr with only a single session. keywords: percutaneous nephrolithotomy; nephrolithiasis; retrograde intrarenal surgery introduction the management of patients with renal stone has been changing with the advances in laser technology and instruments miniaturization. today; percutaneous nephrolithotomy (pcnl), retrograde intrarenal surgery (rirs), shock-wave lithotripsy (swl) and laparoscopic stone surgery are the most preferable treatment choices for renal stones(1). the recommendation of the eau guideline revealed pcnl as a first line treatment choice for renal stones > 2 cm and rirs and swl for renal stones < 2cm(2). despite the recommendations of the eau guideline on management of renal stones, rirs has been widely used to treat renal stones > 2 cm by several investigators and has been associated with lower complications than pcnl(3-5). the stone-free rate (sfr) of rirs has been reported as 77% to 96.7% with staged procedures for renal stones > 2 cm(6). rirs is becoming a safe alternative procedure for renal stones > 2 cm(3-6). at the other side, pcnl achieves higher sfr when compared with rirs after a single session, however, some major complications such as bleeding requiring embolization, sepsis, urinoma and organ injury after 1 istanbul medeniyet university goztepe training and research hospital, urology, istanbul, tr. 2 harran universitesi school of medicine, urology, sanliurfa, tr. *correspondence: istanbul medeniyet university goztepe training and research hospital, urology, istanbul, tr. adress: istanbul medeniyet university goztepe training and research hospital, urology, istanbul, tr received august 2016 & accepted january 2017 pcnl may occur(2). in this study, we aimed to compare the outcomes of pnl and rirs in treating renal stones between 20 and 40mm in diameter using a match-paired analysis. to our knowledge, our study group is one of the largest patient series in the literature. patients and methods study population a total of 292 patients with renal stones ranging between 20 – 40 mm in diameter who were treated in our clinic with rirs (n:146) or pcnl (n:146) were included. the choice of treatment modality was made according to the patient and surgeon preferences. the data of both groups were analysed retrospectively. demographic parameters including age, sex, size-number-laterality-location of the stones, operative time, flouroscopy time, hospitalization time were recorded. pre-operative evaluation of the patients included intravenous urography (ivu), and/or non-contrast computed tomography (ncct), urine culture, coagulation tests, platelet counts, hemoglobin measurements and serum biochemistry. all patients had sterile urine culendourology and stone disease vol 14 no 02 march-april 2017 2995 ture before the surgery. stone size was determined as the longest diameter on plain radiography or ncct. patients with renal abnormalities, pediatric patients and patients who had small stones (< 2 cm) were not included in the study. surgical technique pcnl technique after induction of general anesthesia, a 6 f open-end ureteral catheter was placed with cystoscope after then patients were turned to the prone position. renal collecting system access was performed via 18 gauge diamond tip needle from lower or middle calyx under fluoroscopic guidance. a guidewire was pushed forward to the collecting system through the needle and tract was dilated with amplatz renal dilatators up to 28 f-30 f. fragmentation and aspiration of the stones were accomplished using ultrasonic and/or pneumatic lithotripter through 26 f nephroscope. some stone fragments were taken out with basket catheter for stone analysis. a 12 f re-entry catheter inserted to the renal pelvis as a nephrostomy tube after fragmentation completion. operation time was calculated from inserting ureteral catheter to the nephrostomy tube placement. rirs technique after induction of general anesthesia, we performed semirigid ureteroscopy (8,5 / 11,5 f ,wolf, knittlingen, germany ) for ureteral dilation and placing a hydrophilic guidewire to the renal pelvis. rirs was performed by using a 7.5 f flexible ureteroscope (karl storz flex-x2, tutlingen, germany) through the ureteral access sheath (uas). 9.5/11.5 fr uas placement was attemped through the ureter in all patients. in failing of the uas, rirs was performed without using the uas. holmium laser was used with a 273 µm fiber for disintegration of the stone. holmium laser energy was set to 0.6 -1.5 j and frequency was set to 10-15 hz. a basket catheter was used for taking some stone fragments for stone analysis. at the end of the procedure, a double-j stent was placed and was removed after two weeks. outcome assessment operation time was calculated from the beginning of the semirigid ureteroscopy to the urethral catheter placement. in follow-up, plain radiography and ncct were performed to determine sfrs at the first postoperative day and 3 month following the surgery, respectively. patients were considered stone-free in the absence of residual fragments. the re-treatment decision was made in the presence of residual fragments on ncct performed at 3 month following the surgery. no pre-operative analgesics were given prior to the surgery, however, analgesics were given to the patients who complained from pain post-operatively. postoperative first day visual analogue score was recorded for all patients before analgesic medication. complications were divided into two groups as minor and major complications. minor complications involved clavien-dindo grades 1-2-3 and major complications involved grade 4-5(7-8). spss software, version 20,0 (ibm, armonk, ny) was used to perform statistical analysis. distribution of variables normality was checked with kolmogorov-smirnov test. numeric variables were analysed with student ’s t test and mann–whitney u test. to compare categorical variables, chi-square test or fisher’ s exact test were used. statistical significance was set at p < .05. results in this study, there were 146 patients in the pcnl group and 146 patients in the rirs group. the baseline demographic data were similar between the two groups, in terms of age, gender, stone laterality and locations (table 1). the mean stone size differences was not statistically significant between the two groups, 25.08 ± 6.07mm for the rirs group and 28.39 ± 4.67mm for the pcnl group (p = .21). the mean fluoroscopy times, hospitalization times and visual analogue scores (vas) at post-operative day 1 were statistically higher in the pcnl group (table 2). the mean operative time for pcnl and rirs groups were 55.36 ± 17.93 and 66.86 ± 12.82, respectively (p = .002). sfrs were 74% in the rirs group and 91.7% in the pcnl group after a single procedure (p = .04). in the rirs group, 38 (26%) patients underwent an additional rirs procedure because of the residual stone fragments > 4 mm. 12 (8.3%) patients in the pcnl required auxiliary procedure, 5 of whom were treated with rirs and the remaining 7 patient underwent swl due to the residual stone fragments > 4mm. the re-treatment rate was significantly higher in the rirs group than the pcnl group (p < .001). after auxiliary procedures, the overall sfrs reached to 94.4% in the pcnl group and to 92.3% in the rirs group (p = .52). two patients in the pcnl group and 3 patients in the rirs group with residual stones < 4 mm were followed up. no major complications were observed in both group. minor complication rates were 6.8% (10 patients) and 3.4% (5 patients) for the pcnl and rirs groups, respectively (p = .18). blood transfusion was required in 3 (2%) patients in the pcnl group. intravenous antibiotic therapy was required in 4 (2.7%) patients because of the urinary tract infection postoperatively in the pcnl group. double j catheter was inserted to 3 (2%) patient due to urine leakage after removal of the nephrostomy tube. in the rirs group, none of the patients received blood transfusion. four (2.7%) patients were treated with antibiotic therapy for urinary infection postoperatively. rigid ureteroscopy was performed for 1 (0.6%) patient due to steinstrasse after removal of dj stent. discussion pcnl is recommended as a first-line treatment modality for renal stones > 2 cm according to eau guidelines (2). this procedure has been associated with high sfr, however, major complications after this procedure may still occur(2). at the other side, with advances of flexible ureterorenoscopes and holmium laser technology, rirs has been also used in treating renal stones > 2 cm by several investigators in the management of these renal stones despite the requirement of the repeated procedures(9-11). although some authors have compared the safety and efficiency of the pcnl and rirs, in current literature the present study has the highest case number. we also compared the outcomes of pcnl and rirs in treating renal stones between 20-40 mm in diameter to investigate the advantages and disadvantages of both procedures. the sfr of rirs for renal stones > 2 cm varies from comparison of pcnl and rirs in 20-40 mm renal stones-atis et al. endourology and stone diseases 2996 77% to 96.7% in the published articles after repeated procedures(6). on a comparative study, akman et al. reported sfrs of 91.2% and 73.5% after a single procedure for pcnl and rirs. in their study, sfr was reported to reach to 88.2% for rirs after a second procedure, which was similar to the sfr of pcnl(9). in the study of bryniarski et al., it was demonstrated that pcnl had higher efficacy (94%) in comparison with rirs (75%) in a single session(10). on the other hand palmero et al. reported that the pcnl procedure was associated with a higher success rate than rirs (80.6% vs. 73.6%); however the difference was not statistically significant (p = .40) and sfrs after repeated sessions were almost same for pcnl and rirs (94.3% vs. 93.5%, respectively, p = .88)(11). similarly, in the study of koyuncu et al. that compared rirs and pcnl for lower pole stones greater than 2 cm, the sfrs after pcnl and rirs were similar even after single procedures (96.1% vs 90.6, respectively, p = .26)(12). in the present study, the sfrs were 74% and %91.7 after a single procedure in the rirs and pcnl groups respectively, and after auxiliary procedures, these rates reached to 92.3% for the rirs group and 94.4% for the pcnl group. the difference of the reported sfrs in the literature may be resulted from complexity of the stones, patients' characteristics or surgeons experience. stone localization can be considered a predictive factor for stone-free status. in the present study, although there were no statistically significant differences in stone locations between the two groups, the upper calyceal localizations of the stones were higher in the rirs group, which are easier for rirs and more difficult for pcnl procedures. it may also affect the sfrs after the procedures. the complications following pcnl includes transfusion (7%), embolization (0.4%), urinoma (0.2%), fever (10.8%), sepsis (0.5%), thoracic complication (1.5%) and organ injury (0.3%)(2). post-operative complications such as febrile urinary tract infection, acute urinary retention, subcapsular hematoma, fever, steinstrasse, pyelonephritis and bleeding may also be seen after rirs, however, most of these complications are minor and can be treated conservatively(13,14). aboumarzouk et al. conducted a metanalysis of nine studies with 445 patients who were treated with rirs for renal stones > 2 cm and reported an overall complication rate of 10.1% (6). in the present study, although there was no statistically difference in complication rates among the two groups, minor complication rates were higher in the pcnl group. additionally, 2 % of patients in the pcnl group required blood transfusion, whereas none of the patients received blood transfusion in the rirs group. according to the findings of the present study, rirs is more advantageous in terms of complication rate for treating renal stones when compared to pcnl. for renal stones > 2cm, the reported mean operative time for rirs and pcnl varies from 28 to 215 and 58 to 112 minutes in the non-comperative and comperative articles respectively(6,15). in the present study, the mean operative times for rirs and pcnl were 66.86 ± 12.82 and 55.36 ± 17.93 minutes, respectively (p = .002). our reported operative times are in concordence with the published articles in the literature. post-operative pain after renal stone surgery is a major problem, that may lead the patient to use post-operative narcotic analgesics because of the discomfort. this has been associated with nephrostomy tube or double-j stent placement post-operatively by several investigators(16,17). in the present study, we placed a nephrostomy tube after pcnl and a double-j stent after rirs in all patients and found lower post-operative pain scores after rirs. similarly, in the study of bryniarski et al., the post-operative vas and narcotic analgesics use of patients in the pcnl group were higher than patient in the rirs group(10). to our best knowledge, post-operative pain is important and may affect the hospitalization time and comfort of the patients. the present study has some limitations. first, the prestable 1. patients characteristics of the groups pcnl groupa rirs groupa p value no. patient (n) 146 146 age(years) 46.33 ± 12.34 47.23 ± 15.16 0.780 gender 0.327 male (n) 104 98 female (n) 42 48 stone size (mm) 28.39 ± 4.67 25.08 ± 6.07 0.214 stone laterality 0.752 right (n) 76 80 left (n) 70 66 stone location 0.165 lower calyx 108 90 middle calyx 30 35 upper calyx 8 21 adata is presented as mean ± sd or numbers. comparison of pcnl and rirs in 20-40 mm renal stones-atis et al. vol 14 no 02 march-april 2017 2997 ent study is a retrospective analysis of patients who were treated with pcnl or rirs in a single center. second, the cost analysis of each procedure was not evaluated which may be an important factor on decision of the surgical technique. therefore, studies with large population of patients in a prospective-randomized design are needed to assess the best treatment option in this group of patients. conclusions both of rirs and pcnl are safe and effective treatment options for large size renal stones. according to our findings, rirs has some advantages such as less post-operative pain, shorter hospitalization and fluoroscopy time in treating 20-40 mm renal stones. however, pcnl poses a higher sfr only with a single session. the treatment modality should be decided with patients by discussing advantages and disadvantages of each procedure. conflict of interest the authors report no conflict on interest. references 1. romero v, akpinar h, assimos dg. kidney stones: a global picture of prevalence, incidence, and associated risk factors. rev urol. 2010;12:e86-96 2. turk c, knoll t, petrik a, et al. guidelines on urolithiasis, 2015: 1–71. available at: http://uroweb.org/wp-content/uploads/eauguidelines-urolithiasis-2015-v2.pdf 3. resorlu b, unsal a, ziypak t, et al. comparison of retrograde intrarenal surgery, shockwave lithotripsy, and percutaneous nephrolithotomy for treatment of mediumsized radiolucent renal stones. world j urol. 2013 ;31:1581-6. 4. wiesenthal jd, ghiculete d, d'a honey rj, pace kt. a comparison of treatment modalities for renal calculi between 100 and 300 mm2: are shockwave lithotripsy, ureteroscopy and percutaneous nephrolithotomy equivalent? j endourol 2011;25:481-5. 5. bozkurt of, resorlu b, yildiz y, can ce, unsal a. retrograde intrarenal surgery versus percutaneous nephrolithotomy in the management of lower-pole renal stones with a diameter of 15 to 20 mm. j endourol 2011; 25:1131-5. 6. aboumarzouk om, monga m, kata sg, traxer o, somani bk. flexible ureteroscopy and laser lithotripsy for stones > 2 cm: a systematic review and meta-analysis. j endourol 2012; 26: 1257-63. 7. clavien pa, sanabria jr, strasberg sm. proposed classification of complications of surgery with examples of utility in cholecystectomy. surgery 1991;111:518-26 8. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg 2004;240:205-13. 9. akman t, binbay m, ozgor f, et al. comparison of percutaneous nephrolithotomy and retrograde flexible nephrolithotripsy for the management of 2-4 cm stones: a matchedpair analysis. bju int. 2012;109:1384-9. 10. bryniarski p, paradysz a, zyczkowski m, kupilas a, nowakowski k, bogacki r. a randomized controlled study to analyze the safety and efficacy of percutaneous nephrolithotripsy and retrograde intrarenal surgery in the management of renal stones more than 2 cm in diameter. j endourol. 2012 jan;26:52-7. 11. palmero jl, durán-rivera aj, miralles j, pastor jc, benedicto a. comparative study for the efficacy and safety of percutaneous nefhrolithotomy (pcnl) and retrograde intrarenal surgery (rirs) for the treatment of 2-3,5 cm kidney stones. arch esp urol. 2016;69:67-72. 12. koyuncu h, yencilek f, kalkan m, bastug y, yencilek e, ozdemir at. intrarenal surgery vs percutaneous nephrolithotomy in the table 2. perioperative and postoperative data of the groups pcnl groupa rirs groupa p value operative times (min) 55.36 ± 17.93 66.86 ± 12.82 0.002 sfr after a single procedure (%) 134 (91.7%) 108 (74%) 0.040 re-treatment rate (%) 12 (8.3%) 38 (26%) 0.001 sfr after additional procedures (%) 138 (94.4%) 135 (92.3%) 0.520 fluroscopy time (sec) 161.4 ± 107.4 4.85 ± 3.71 0.0001 hospitalization time (day) 3.97 ± 1.92 1.41 ± 1.16 0.0001 visual analogue scores 4.69 ± 1.39 2.41 ± 1.43 0.0001 minor complication rates 10 (6.8%) 5 (3.4%) 0.18 adata is presented as mean ± sd or number(percent). comparison of pcnl and rirs in 20-40 mm renal stones-atis et al. endourology and stone diseases 2998 management of lower pole stones greater than 2 cm. int braz j urol. 2015;41:245-51. 13. hyams es, munver r, bird vg, uberoi j, shah o. flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burdens that measure 2 to 3 cm: a multi-institutional experience. j endourol 2010; 24: 1583-8. 14. breda a, ogunyemi o, leppert jt, schulam pg. flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. eur urol 2009; 55: 1190–6. 15. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015;67:125-37. 16. agrawal ms, agrawal m, gupta a, bansal s, yadav a, goyal j. a randomized comparison of tubeless and standard percutaneous nephrolithotomy. j endourol 2008; 22: 439– 42. 17. knoll t, wezel f, michel ms, honeck p, wendt-nordahl g. do patients benefit from miniaturized tubeless percutaneous nephrolithotomy? a comparative prospective study . j endourol 2010; 24: 1075–9. comparison of pcnl and rirs in 20-40 mm renal stones-atis et al. vol 14 no 02 march-april 2017 2999 case report 223urology journal vol 6 no 3 summer 2009 angiosarcoma of kidney a case report and review of literature vaios d papadimitriou, konstantinos n stamatiou, dimitrios m takos, vasilios m adamopoulos, ioannis e heretis, frank a sofras urol j. 2009;6:223-5. www.uj.unrc.ir keywords: kidney neoplasms, hemangiosarcoma, multicystic kidneys department of urology, university of crete, crete, greece corresponding author: stamatiou n konstantinos, md 2 salepoula st, 18536, piraeus, greece tel: +30 210 453 9744 e-mail:stamatiouk@yahoo.com received march 2008 accepted september 2008 introduction angiosarcoma is a rare high-grade malignant tumor accounting for less than 2% of the soft tissue sarcomas.(1) they originate from the endothelium of the blood and lymphatic vessels and can be primary or metastatic, and localized or multicentric. most angiosarcomas develop in the skin or soft tissue, and others, in the breast, liver, and bones.(2) commonly, metastases occur in the liver, lungs, and bones. those involving the kidney usually represent metastasis from the skin or the primary visceral lesions. on the contrary, primary angiosarcoma of the kidney is a very rare neoplasm with less than 30 cases reported in the literature to date. (3,4) to our knowledge, all previous reports described the origin of angiosarcoma in a normal kidney. we report a unique case of primary renal angiosarcoma arising from a multicystic kidney. case report a 68-year-old man, who was a farmer, presented with a history of mild persistent left flank pain, nocturia, dysuria, and 2 episodes of macroscopic hematuria, starting 1 month earlier. on physical examination, blood pressure was 135/80 mm hg. palpation of the lower left quadrant of the abdomen caused diffuse pain and revealed a palpable mass at the left costovertebral angle. on admission, his leukocyte count was 14.5 × 109/l, 85% of which were granulocytes. serum levels of sodium and potassium levels were 135 meq/l and 3.1 meq/l (reference ranges, 135 meq/l to 145 meq/l and 3.5 meq/l to 5.5 meq/l), respectively. kidney function tests showed a blood urea nitrogen of 49 mg/dl (reference range, 17 mg/dl to 53 mg/dl) and a serum creatinine of 1.3 mg/ dl (reference range, 0.7 mg/dl to 1.5 mg/dl). erythrocyte count and hemoglobin concentration were also within normal ranges. ultrasonography revealed a complex mass of 10 am in diameter at the normal anatomic position of the left kidney, consisting of cysts with thickened irregular walls and a solid dense central area, suggesting a renal tumor. abdominal computed tomography with endovenous contrast medium confirmed the above findings. no lymphadenopathy or metastatic diseases were noted. preoperative diagnosis of cystic renal tumor was made and left nephrectomy was carried out. the macroscopic appearance of the mass was that of a large solid tumor angiosarcoma of the kidney—papadimitriou et al 224 urology journal vol 6 no 3 summer 2009 mixed with recently clotted blood, replacing four-fifths of the organ (figure). diagnosis was made on a morphologic basis, proven by the immunohistochemical study. according to the pathology report, the central area of the mass consisted of irregular vascular spaces, covered by discretely pleomorphic cells with large, hyperchromatic nuclei. immunohistochemical study showed that malignant cells were positive for anti-cd31 and anti-cd34 antibodies which are specific for angiosarcoma. the patient was discharged 10 days after the surgery and was scheduled for chemotherapy with cisplatin and isofamide and shortinterval follow-ups, despite the absence of detectable metastases at diagnosis. discussion predisposing factors for angiosarcoma include kidney transplantation and exposure to arsenic, thorium dioxide, vinyl chloride, and radiation after the treatment of lymphedema, while the causes of primary angiosarcoma in the kidney are still unknown.(1,5) occurrence of primary angiosarcoma in a multicystic kidney is intriguing. in fact, this neoplasm is common in both congenital and acquired human renal cystic diseases. an unusual case of mixed wilms tumor and angiosarcoma in a 38-year-old woman has recently been reported.(6) fewer than 30 cases of primary kidney angiosarcoma have been reported to date, and therefore, the natural history of the disease is unknown. the most important prognostic factor is the tumor size and presence or absence of metastases at diagnosis.(7,8) in tumors larger than 5 cm, the 5-year survival rate is 13%, while this rate is 32% in smaller tumors.(9) if metastasis is present, survival rates diminish dramatically.(10) despite the progress in chemotherapy, patients’ mean survival rate after diagnosis of metastatic disease remains as low as 13 weeks.(11) local recurrence after radical nephrectomy is frequent in angiosarcomas, since in most of the reported cases, micrometastases had already occurred before diagnosis.(3) the usual treatment of localized disease includes wide resection followed by adjuvant radiotherapy, which shows a response rate between 44% and 71%. the role of radiotherapy is controversial.(12,13) given the paucity of published cases, it is difficult to standardize treatment of the local disease; it seems however, that the best treatment consists of radical surgery associated with systemic chemotherapy.(7) chemotherapy regimens have been used according to the results obtained in other types of sarcomas or in angiosarcomas of other locations. the standard treatment of metastatic disease remains an isofamide-based regimen (cisplatin and isofamide or doxorubicin and isofamide); however, this management provides a median progression-free survival and a median overall survival of about 4 and 8 months, respectively.(14) taxanes (paclitaxel or docetaxel) may be more efficient in the treatment of metastatic renal angiosarcomas. paclitaxel has unique activity in angiosarcomas of the face and the scalp; however, its use in angiosarcomas originating from other sites is less well defined. saroha and colleagues and skubitz and haddad showed that paclitaxel was efficient in angiosarcomas originating from other sites (although not statistically superior to nontaxane regimens), while penel and coworkers reported a 78% nonprogression rate and a 10% complete histological response in patients with unresectable or metastatic angiosarcomas of various origins.(15-17) we still do not know the best primary angiosarcoma arising from a multicystic kidney. angiosarcoma of the kidney—papadimitriou et al urology journal vol 6 no 3 summer 2009 225 option for patients with metastatic angiosarcoma of the kidney. due to nonspecific symptoms and clinical presentation (pain in the flank in 81%, hematuria in 38%, and palpable mass in 31% of the cases), the differential diagnosis is difficult. these tumors are frequently hemorrhagic, and therefore, are able to mimic a retroperitoneal hematoma or cause massive hematuria and anemia.(18) since they are commonly associated with a renal mass, pathologic examination of the nephrectomy specimen is the only effective method to diagnose angiosarcoma of the kidney. conflict of interest none declared. references 1. fata f, o’reilly e, ilson d, et al. paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. cancer. 1999;86:2034-7. 2. lee ch, park ku, nah dy, won ks. bilateral spontaneous pneumothorax during cytotoxic chemotherapy for angiosarcoma of the scalp: a case report. j korean med sci. 2003;18:277-80. 3. costero-barrios cb, oros-ovalle c. [primary renal angiosarcoma]. gac med mex. 2004;140:463-6. spanish. 4. lopez bc, perez if, alvarez jac, et al. renal angiosarcomas. clin transl oncol. 2008;9:806-10. 5. ahmed i, hamacher kl. angiosarcoma in a chronically immunosuppressed renal transplant recipient: report of a case and review of the literature. am j dermatopathol. 2002;24:330-5. 6. yau t, leong ch, chan wk, chan jk, liang rh, epstein rj. a case of mixed adult wilms’ tumour and angiosarcoma responsive to carboplatin, etoposide and vincristine (ceo). cancer chemother pharmacol. 2008;61:717-20. 7. martínez-piñeiro l, lópez-ferrer p, picazo ml, martínez-piñeiro ja. primary renal angiosarcoma. case report and review of the literature. scand j urol nephrol. 1995;29:103-8. 8. leggio l. primary angiosarcoma of the kidney: size is the main prognostic factor. int j urol. 2007;14:777. 9. mark rj, poen jc, tran lm, fu ys, juillard gf. angiosarcoma. a report of 67 patients and a review of the literature. cancer. 1996;77:2400-6. 10. akkad t, tsankov a, pelzer a, peschel r, bartsch g, steiner h. early diagnosis and straight forward surgery of an asymptomatic primary angiosarcoma of the kidney led to long-term survival. int j urol. 2006;13:1112-4. 11. tsuda n, chowdhury pr, hayashi t, et al. primary renal angiosarcoma: a case report and review of the literature. pathol int. 1997;47:778-83. 12. terris d, plaine l, steinfeld a. renal angiosarcoma. am j kidney dis. 1986;8:131-3. 13. mordkin rm, dahut wl, lynch jh. renal angiosarcoma: a rare primary genitourinary malignancy. south med j. 1997;90:1159-60. 14. leggio l, addolorato g, abenavoli l, et al. primary renal angiosarcoma: a rare malignancy. a case report and review of the literature. urol oncol. 2006;24:30712. 15. saroha s, litwin s, von mehren m. retrospective review of treatment for angiosarcoma at fox chase cancer center over the past 15 years. j clin oncol. 2007;25:10034. 16. skubitz km, haddad pa. paclitaxel and pegylatedliposomal doxorubicin are both active in angiosarcoma. cancer. 2005;104:361-6. 17. penel n, lansiaux a, adenis a. angiosarcomas and taxanes. curr treat options oncol. 2007;8:428-34. 18. souza oe, etchebehere rm, lima ma, monti pr.primary renal angiosarcoma. int braz j urol. 2006;32:448-50. urological oncology core length: an alternative method for increasing cancer detection rate in patients with prostate cancer omer gokhan doluoglu,1* cem nedim yuceturk,1 muzaffer eroglu,1 berat cem ozgur,1 arif demirbas,1 tolga karakan,1 selen bozkurt,2 berkan resorlu1 purpose: we determined whether the lengths of benign and malignant cores affect cancer detection rates in patients with prostate cancer (pca). materials and methods: we evaluated retrospectively 512 patients in our clinic who had undergone 12 core transrectal ultrasound (trus)-guided prostate biopsies. the cores were divided into two groups: one with cancer (group 1) and one without cancer (group 2). we also classified gleason scores as poorly differentiated (scores of 7-10) and moderately differentiated (scores of 5-6); these scores were compared with each other in terms of the core length. the core lengths of the groups were compared using a student’s t-test. a p value of less than .05 was considered to be statistically significant. results: of the 512 patients, 76 (15%) had pca. in total, we evaluated 912 cores of prostate biopsy samples from the 76 patients. since 92 cores included insufficient tissue and rectal mucosa, we were not able to evaluate them. the remaining 820 cores were divided into two groups. cancer was detected in 302 cores; 518 cores were benign in nature. the average core length in group 1 was 11.9 ± 4.4 mm, and the average core length in group 2 was 11.1 ± 5.1 mm (p = .015). the core lengths of poorly differentiated and moderately differentiated cancers were similar: 12.3 ± 4.2 mm and 11.7 ± 4.5 mm, respectively (p = .25). conclusion: increasing cancer detection rates in cores may be related to core length in trus-guided prostate biopsies in pca patients. keywords: biopsy; needle; standards; instrumentation; prostatic neoplasms; diagnosis; ultrasonography; prospective studies. introduction prostate needle biopsy, used for diagnosing prostate cancer (pca), is usually performed using transrectal ultrasound guidance (trus). after hodge and colleagues described the sextant biopsy method in 1989, trus-guided needle biopsy has played an important role in the diagnosis of pca.(1) although the random systematic six-core prostate biopsy method has significantly improved the cancer detection rate, some reports have demonstrated that 15-31% of pca cases can be missed by this method.(2,3) therefore, to enhance the cancer detection rate, various strategies were advised by clinicians, like increasing the number of cores and collecting more lateral cores.(4-6) thus, sampling more prostate sites and consequently obtaining more prostate tissue can increase the cancer detection rate. the length of the cores sampled during prostate biopsy can also affect the pca detection rate.(7,8) the core lengths and quality of obtained prostate tissue are the main parameters for cancer diagnosis. on the other hand, few studies have assessed the effect of needle core length on cancer diagnoses. some studies specified that core lengths need to be more than 10 mm for a correct histological evaluation;(8,9) otherwise, the accuracy of prostate needle biopsy may be questionable and have no diagnostic value.(9) in this study, we analyzed the lengths of the needle cores sampled during 12-core trus-guided prostate biopsy in patients with cancer. our aim was to detect whether there was a correlation between the lengths of benign and malignant cores and cancer detection. secondly, we tried to find out any relationship between the core length, gleason score, and percentage of tumors in the cores of pca patients. materials and methods study population after obtaining the institutional review board’s approval for the study, we retrospectively evaluated 512 patients who underwent trus-guided prostate biopsy in our department between 2008 and 2012. twelve cores were sampled in every patient (sextant biopsy from each the right and left prostate lobes). 1 department of urology, clinic of ankara training and research hospital, ankara, turkey. 2 department of biostatistics and medical informatics, faculty of medicine, akdeniz university, antalya, turkey. *correspondence: department of urology, clinic of ankara training and research hospital, sukriye mahallesi, ulucanlar caddesi, ankara, turkey. tel: +90 533 2157809. fax: +90 312 3624933. e-mail: drdoluoglu@yahoo.com.tr. received march 2015 & accepted september 2015 urological oncology 2324 biopsy procedure biopsy was performed with the patient in the lateral decubitus position and, in all cases, an anesthetic block of the periprostatic plexus was performed by administering 0.2% prilocaine. a 25 cm 18 gauge, side-notch cutting (tru-cut®) needle was used in each case (general electric, log-13, 41123ws1 ultrasonography equipment with a 6.5 mhz biplane transrectal probe). biopsies were obtained under trus guidance in the sagittal plane, by two urologists that specialized in this subject (tk, ad), using automatic gun biopsy (maxicore mcs 01090026, geotek medical devices, ostim, ankara, turkey). every specimen was removed from the needle carefully and the quality of the cores was observed macroscopically by the urologist. if we obtained inadequate specimens, like fragmented or small tissues or those of suspect quality, additional specimens were taken immediately from the same sites. sample evaluation each sampled core was numbered, identified by site and prostate lobe, and then sent for pathological examination. the pathology report described the length of each core in millimeters (mm) and any percentage of cancer in the biopsy specimen. we recorded and analyzed the length of the longer core and disregarded the fragmented and smaller cores.the tumor’s grade of differentiation was assigned with the gleason grading and scoring system. for homogenization, patients with a prostate-specific antigen (psa) level higher than 20 ng/ml, prior prostate biopsy, presence of any urinary tract infections, suspicious digital rectal examinations (dre), pathology reports (including atypical small acinar proliferation and high-grade prostatic intraepithelial neoplasia), or specimens containing only periprostatic tissue or rectal mucosa were excluded from the study. all patients included in the study had normal dre. all patients were diagnosed with pca after 12-core biopsies were obtained with trus, which was performed due to high serum psa levels (> 2.5 ng/dl). the sampled biopsy cores were divided into two groups: cores including cancer (group 1) and those without cancer (group 2). we compared the benign and malignant core lengths of patients diagnosed with cancer and their effects on the cancer detection rate. we also determined tumor grade differentiation with the gleason score system as poorly differentiated (scores of 7-10) or moderately differentiated (scores of 5 or 6) tumors. statistical analysis the data analysis was performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. descriptive statistics for variables with a normal distribution, non-normal distribution, and categorical variables were shown as mean ± standard deviation (sd), median (min-max), and the number of cases and (%), respectively. student’s t-test and the mann-whitney u test were used for the intergroup analyses of continuous variables. categorical variables were analyzed with chi-square test. the p value < .05 was considered statistically significant. results biopsy was performed for 512 patients. the mean age of the patients diagnosed with cancer was 67.1 ± 7.5 years, the average core length was 12.9 ± 5 mm, and the average prostate volume was 36 ± 22 ml. the average serum psa level was 9.4 ± 4.6 ng/ml. pathology reports of the 512 patients revealed cancer in 76 (15%) men; the other 436 cases were benign. a total of 912 prostate biopsy cores were evaluated from 76 pca patients. ninety-two cores contained inadequate prostate tissue or rectal mucosa and were thus excluded from the analysis; the remaining of 820 cores were included in the study. pathology reports revealed that out of 820 cores, cancer was detected in 302 cores and the other 518 cores were benign tissue. the average core lengths in groups 1 and 2 were 11.9 ± 4.4 mm and 11.08 ± 5.1 mm, respectively (p = .015) (table 1). in the figure, the lengths of cores with andwithout cancer are shown in pca patients. of the 76 patients with a cancer diagnosis, the needle core lengths of poorly differentiated (12.3 ± 4.2 mm) and moderately differentiated (11.7 ±4.5 mm) tumors were not statistically significantly different (p = .25). distribution of cancer cores along the prostate regions and the comparison of average core lengths with and without cancer are shown in table 2. the only statistically significant difference was observed between the core lengths at the right lateral apex (p = .02). additiontable 1. comparison of core lengths with and without cancer in patients with prostate cancer. variables core length p value cores with cancer (n = 302) 11.9 ± 4.4 mm .015* cores without cancer (n = 518) 11.08 ± 5.1 mm *statistically significant. 1: right base, 2: right midgland, 3: right apex, 4: right lateral base, 5: right lateral midgland, 6: right lateral apex, 7: left base, 8: left midgland, 9: left apex, 10: left lateral base, 11: left lateral midgland, 12: left lateral apex. *statistically significant. variables 1 2 3 4 5 6 7 8 9 10 11 12 core length with cancer (mm) 12.6 ± 3.3 12.9 ± 3.7 12.1± 4.1 10.3± 4.6 12 ± 4.6 11.3± 4.7 13.6± 5.07 12.6 ± 4.8 10.5 ± 3.3 11.6 ± 4.1 13.5 ± 4.1 10.9 ± 4.8 core length without cancer (mm) 13.1 ± 5.9 12.1 ± 5.3 10.2 ± 5.08 9.9 ± 3.9 10.9 ± 4.5 8.8 ± 3.8 11.4 ± 5.08 12.4 ± 5.6 11.6 ±5.6 10.4 ± 5.2 12.1 ± 4.4 9.9 ± 4.5 p value .57 .56 .09 .81 .62 .02* .09 .82 .46 .31 .26 .40 cancer percentage 29/9.6 25/8.2 22/7.2 33/10.9 13/4.3 30/9.9 29/9.6 29/9.6 26/8.6 24/7.9 11/3.6 31/10.2 in core regions, n /% table 2. distribution of cores with and without cancer according to prostate regions, average core lengths, and average tumor percentages in cores with cancer. core length and prostate cancer-doluoglu et al. vol 12 no 05 september-october 2015 2325 ally, when the cores with cancer were divided by the lengths, into < 10 mm and >10 mm groups, the average percentages of cancer detected in the cores were 37% ± 28 vs. 37% ± 26, respectively, and no statistically significant difference was found (p = .93) (table 3). discussion pca is still a major health problem among males all over the world. histopathological examination of the tissue obtained from prostate biopsy is significant for a definite diagnosis of pca. so the question is, “how can urologists improve the prognostic capability of prostate biopsy for cancer detection?” from this point of view, the main concern is increasing the number of cores, which enables increased sampling of prostate sites and prostate tissue. various efforts have been applied for this purpose, like sextant biopsy, 8-15 core collection, or saturation biopsies.(6,10-14) the diagnostic value of sextant prostate biopsy is 43% higher than that of two or fewer biopsies.(1,15,16) biopsy of 12 sites identified 29% more cancers than the sextant approach.(10) after performing saturation biopsies (14 45 sites) on patients who previously had a negative sextant biopsy, cancer was identified in 34% of them.(14) ultrasound-targeted biopsies and an additional four far-lateral peripheral zone or posterolateral biopsies have also optimized the diagnostic yield of prostate biopsy.(12,13) guichard and colleagues found that the cancer detection rates of 6-, 12-, 18-, and 21-core biopsies were 31.7%, 38.7%, 41.5%, and 42.5%, respectively.(17) in a study including 1086 cases, 12-core biopsy was significantly superior to sextant biopsy.(18) similarly, in the study by ceylan and colleagues, the cancer detection rates of 8-, 10-, 12-, 16-, and 21-core prostate biopsies were 18.3%, 14.8%, 24%, 22.1%, and 30.3%, respectively.(6) addition of the lateral peripheral zone to biopsies was 25.5% more advantageous than the sextant biopsy technique in determining pca.(19) although it seems that sampling more anatomic sites can enhance the cancer detection rate, this may not be a valid way of thinking every time; in the study by naughton and colleagues, there was no diagnostic yield of a 12-core biopsy above that of a sextant biopsy.(20) the lengths of sampled needle cores can also influence the pca detection rate.(8) in the study by baccon-gibodand colleagues, an average of 10 mm of prostate tissue was accepted as the shortest available length for adequate prostate biopsy. from their point of view, core lengths shorter than 10 mm might be inadequate for a correct pathologic result and diagnosis.(9) iczkowskiand colleagues observed that the lengths of the cores obtained from the midgland and base of the prostate were much longer than the apex,(7) and when sampling longer single cores, cancers were better detected at the apex. ficarra and colleagues revealed the advantage of a transperineal approach, which allowed better and more sensitive sampling at the prostate apex than at the midgland and base.(21) in our study, cores with cancer were much more longer in all regions of the prostate except the right base and left apex. we consider that the biopsy needle length and method of transferring the tissue to the container are the main factors that affected core lengths. however, when the cores were evaluated separately, significant differences were detected only in region 6; we believe this was due to the declining number of samples when the cores were divided into subgroups (type ii error). additionally, while obtaining cores from the right and left apexes in the lateral decubitus position, pushing the probe forward, a short apex, and the difficulty of curling the right wrist laterally may explain the shorter core lengths in this region than the other regions.in the present study, when cores were divided into two groups, <10 mm and >10 mm, we determined no difference in the percentages of tumors detected in the cores. a possible explanation could be that after the tumor was captured, much longer lengths may be required to show a large amount of core invasion. if we were able to obtain cores longer than 20 mm, increasing the core lengths would provide high tumordetection percentages. for this reason, efforts should be focused on prospective randomized studies that include table 3. division of cores by lengths, <10 mm and >10 mm and comparison of average tumor percentages in cores. core length with cancer cancer percentages in cores p value <10 mm 37 ± 28 .93 ≥ 10 mm 37 ± 26 figure: length distribution of benign and malignant cores. core length and prostate cancer-doluoglu et al. urological oncology 2326 the evaluation of different core lengths. similar to our results, a newly published study by öbekand colleagues demonstrated a significance between needle core length and cancer detection rate, including all biopsy cores and all prostate sites.(22) in cancer patients, we proved that the average length of the cores in groups showed a statistically significant difference (p = .015), meaning an increased cancer detection rate. in the present study, the mean length of the cores was longer than 10 mm, strongly supporting our findings. öbek and colleagues determined that a core length greater than 11.9 mm was associated with a high possibility of cancer detection; they found cancer detection rates for cores under and over 11.9 mm of 23% and 39%, respectively. we did not try to find a cutoff value, but that might be necessary for obtaining more accurate results and increasing cancer detection. our mean core lengths in groups 1 and 2 were close to the detected cutoff value, increasing the value of our study. additionally, only pca patients were included in our study and their cores were examined; this is different from the other studies in the literature. even in patients with diagnosed cancer, the length of malignant cores was longer than benign ones, which suggests a strong correlation between core length and cancer detection. reis and colleagues found that, among patients who underwent radical prostatectomy, the mean core length in those presenting an underestimated gleason score upon biopsy was 11.61 mm (± 2.5, median 11.40), compared to 13.52 mm (± 3.2, median 13.70) in those with perfect gleason score agreement between the biopsy and radical prostatectomy (p < .001).(23) the lengths of cores might be influenced by several factors. the needle, transrectal, or transperineal biopsy procedures, sending the cores to the pathology department regularly, the techniques of pathological analysis, and the urologist who performs the biopsy may affect the diagnostic value of a prostate biopsy.(8,9) in our study, to reduce the impact of these factors, we made a standardized protocol that made every attempt to maximize the quality of the obtained prostate biopsy. all biopsies were performed transrectally by the same urologists (tk, ad) using the same ultrasound machine and biopsy needle. our assistants transferred the specimens to the pathology department properly. the same uropathologist evaluated the histopathological result of the biopsy cores. from the beginning of the study, efforts were made to raise the power of the study and prevent missing any cancer cases. the method of performing the biopsy can influence core lengths and the sampling of prostate anatomic sites. the transperineal prostate biopsy method is more effective and selective than the transrectal route when sampling the prostate peripheral and anterior zones.(2426) in the study by emiliozzi and colleagues, the core lengths obtained by transperineal and transrectal sextant biopsy overlapped.(25) ficarra and colleagues found that the transperineal approach allows better sampling at the prostate apex than the other prostate sites.(19) öbek and colleagues obtained effective results by transrectal biopsy and concluded that core length was an important indicator for the cancer detection rate. in our clinic, to support the quality of prostate biopsy, transrectal guidance is preferred. we try to obtain adequate prostate tissue; if not, a second attempt from the same anatomic site is done to avoid missing any pca case. nevertheless, when we examined the biopsy records, 92 cores with insufficient tissue were excluded from the study. this may be due to fragmented tissues, not paying enough attention while removing each core from the biopsy needle properly, or a delay in sending biopsy specimens for pathological evaluation; the rest of the cores were suitable for the study. reis and colleagues. reported that pathologists often receive more cores than the number sampled by the urologist, and suggested that these changes are due to core fragmentation. fragmentation of biopsy cores may skew the interpretation of biopsy results. therefore, we disregarded the fragmented and smaller cores in the present study.(27) although our study was retrospective and this seemed to be a limitation, it was one of the few studies that indicated the effect of core lengths on cancer detection. even in pca patients, the difference in core lengths between cores with and without cancer demonstrated the importance of core lengths as much as core numbers. not assessing the whole prostate glandafter radical prostatectomy was the other limitation of our study. multiple prospective studies should be done to determine adequate core lengths. conclusions our results suggest that needle core length is related with the cancer detection rate in cores of pca patients. biopsy tissue length is at least as influential as the number of sites sampled. all efforts should be focused on sampling longer tissue lengths. conflict of interest none declared. references 1. hodge kk, mcneal je, terris mk, stamey ta. random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. j urol. 1989;142:71-4. 2. singh h, canto ei, shariat sf, et al. improved detection of clinically significant, curable prostate cancer with systematic 12-core biopsy. j urol. 2004;171:1089-92. 3. durkan gc, sheikh n, johnson p, hildreth aj, greene dr. improving prostate cancer detection with an extended-core transrectal ultrasonography-guided prostate biopsy protocol. bju int. 2002;89:33-9. 4. eskew la, bare rl, mccullough dl. systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. j urol. 1997;157:199-202. 5. terris mk, wallen em, stamey ta. comparison of mid-lobe versus lateral systematic sextant biopsies in the detection of prostate cancer. urol int. 1997;59:239-42. 6. ceylan c, doluoglu og, aglamis e, baytok o. comparison of 8, 10, 12, 16, 20 cores prostate biopsies in the determination of prostate cancer and the importance of prostate volume. can urolassoc j. 2014;8:e81-5. 7. iczkowski ka, casella g, seppala rj, et al. needle core length in sextant biopsy influences prostate cancer detection rate. core length and prostate cancer-doluoglu et al. vol 12 no 05 september-october 2015 2327 urology. 2002;59:698-703. 8. van der kwast th, lopes c, santonja c, et al. members of the pathology committee of the european randomised study of screening for prostate cancer. guidelines for processing and reporting of prostatic needle biopsies. j clin pathol. 2003;56:336-40. 9. boccon-gibod l, van der kwast th, montironi r, boccon-gibod l, bono a. european society of uropathology; european society of pathology uropathology working group. handling and pathology reporting of prostate biopsies. eur urol. 2004;46:177-81. 10. brössner c, bayer g, madersbacher s, kuber w, klingler c, pycha a. twelve prostate biopsies detect significant cancer volumes (> 0.5 ml). bju int. 2000;85:705-7. 11. norberg m, egevad l, holmberg l, sparén p, norlén bj, busch c. the sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. urology. 1997;50:562-6. 12. chang jj, shinohara k, bhargava v, presti jc jr. prospective evaluation of lateral biopsies of the peripheral zone for prostate cancer detection. j urol. 1998;160:2111-4. 13. epstein ji, walsh pc, carter hb. importance of posterolateral needle biopsies in the detection of prostate cancer. urology. 2001;57:1112-6. 14. stewart cs, leibovich bc, weaver al, lieber mm. prostate cancer diagnosis using a saturation needle biopsy technique after previous negative sextant biopsies. j urol. 2001;166:86-91. 15. shaw eb, wofford ed, carter j. processing prostate needle biopsy specimens for 100% detection of carcinoma. am j clin pathol. 1995;103:507-10. 16. shaw eb, daniel bw, wofford ed, carter jb. prostate biopsies: optimized cancer detection and staging. j s c med assoc. 1996;92:261-6. 17. guichard g, larré s, gallina a, et al. extended 21-sample needle biopsy protocol for diagnosis of prostate cancer in 1000 consecutive patients. eur urol. 2007;52:4305. 18. chiang in, chang sj, pu ys, huang kh, yu hj, huang cy. comparison of 6and 12-core prostate biopsy in taiwanese men: impact of total prostate-specific antigen, prostate-specific antigen density and prostate volume on prostate cancer detection. urol int. 2009;82:270-5. 19. eskicorapci sy, baydar de, akbal c, et al. an extended 10-core transrectal ultrasonography guided prostate biopsy protocol improves the detection of prostate cancer. eur urol. 2004;45:444-8. 20. naughton ck, miller dc, mager de, ornstein dk, catalona wj. a prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. j urol. 2000;164:388-92. 21. ficarra v, martignoni g, novella g et al. needle core length is a quality indicator of systematic transperineal prostate biopsy. eur urol. 2006;50:266-71. 22. obek c, doganca t, erdal s, erdoğan s, durak h. core length in prostate biopsy: size matters. j urol. 2012;187:2051-5. 23. reis lo, sanches bc, de mendonça gb, et al. gleason underestimation is predicted by prostate biopsy core length. world j urol. 2015;33:821-6. 24. vis an, boerma mo, ciatto s, hoedemaeker rf, schröder fh, van der kwast th. detection of prostate cancer: a comparative study of the diagnostic efficacy of sextant transrectal versus sextant transperineal biopsy. urology. 2000;56:617-21. 25. emiliozzi p, corsetti a, tassi b, federico g, martini m, pansadoro v. best approach for prostate cancer detection: a prospective study on transperineal versus transrectal six-core prostate biopsy. urology. 2003;61:961-6. 26. satoh t, matsumoto k, fujita t, et al. cancer core distribution in patients diagnosed by extended transperineal prostate biopsy. urology. 2005;66:114-8. 27. reis lo, reinato ja, silva dc, matheus we, denardi f, ferreira u. the impact of core biopsy fragmentation in prostate cancer. int urol nephrol. 2010;42:965-9. core length and prostate cancer-doluoglu et al. urological oncology 2328 urology journal unrc/iua vol. 2, 40-43 spring 2004 printed in iran 40 results of dermal patch graft in the treatment of peyronie’s disease irani d, zeighami sh, khezri aa department of urology, shaheed faghihi and namazi hospitals, shiraz university of medical sciences, shiraz, iran abstract purpose: to investigate the efficacy of “dermal patch graft” in surgical management of peyronie’s. materials and methods: eighteen of peyronie’s disease cases, with a mean age of 49 and a history of penile curvature and painful erection were enrolled in this study. diagnosis was made clinically by plaque palpation. all of them were in the chronic stage of disease with symptom duration of at least 6 months. we also evaluate their potency through brief sexual function inventory (bsfi) questionnaire before and after the operation, meanwhile the degree of penile curvature was measured with goniometry while artificial erection status was induced. results: mean penile curvature, before and after the operation (58 and 5 degrees respectively), showed significant improvement (p<0.001). the improvement of curvature was irrespective of the plaque size. all of our patients suffered from inability to intercourse due to significant penile curvature but after the procedure 11 of them (66.1%) could do so. also the bsfi score improved significantly in this subgroup (p<0.05). the remaining 7 cases (39%) already suffered from erectile dysfunction despite of operation; however, the penile curvature improved significantly in them. six of this latter group had a plaque size greater than 4 cm2 and bsfi score was not significantly improved. conclusion: dermal patch graft as a cost effective method in the management of peyronie’s disease significantly corrects the curvature irrespective of plaque size and curvature severity. we found that if the fibrous plaque is less than 4 cm2 and the patient has no severe erectile dysfunction, this procedure will significantly improve his potency; however, if the patient suffers from a plaque sized greater than 4 cm2 and/or severe erectile dysfunction, to reach satisfactory erection, implantation of penile prosthesis or applying other methods of artificial erection in addition to dermal patch graft is suggested. key words: peyronie’s disease, dermal graft, penile curvature introduction peyronie’s disease was first described by francois de-la peyronie in 1743.(1) this disease causes penile curvature by forming fibrous plaque on penile tunica albuginea.(2) according to the most recent studies, its prevalence is approximately 3% and most of the patients are 40 to 60 years old. despite of the introduction of the disease about 250 years ago and its high prevalence, not only the etiology and mechanism of peyronie’s disease is unknown, but also there is no approved available standard therapy.(3) however, a few theories have been proposed to explain the pathogenesis: microtraumas during intercourse (the most accepted theory),(4) vascular inflammation and its resultant fibrous,(5) genetic factors such as hla-dq5.(6) accepted for publication in august 2003 results of dermal patch graft in the treatment of peyronie’s disease peyronie’s disease has two clinical phases: acute phase with painful erection, inflammation, and deformity of the penis, and chronic phase in which the pain reduces and persistent penile curvature, plaque calcification, and erectile dysfunction is established. diagnosis is made by history and physical examination. a palpable plaque on tunica albuginea, curvature, and painful erection are characteristic for this disease. the treatment of choice in the acute phase is conservative therapy using oral antioxidants (vitamin e, potaba),(7,8) colchicine, intralesional injection of drugs (verapamil, steroids, collagenase)(9,10,11), and any type of energy transmitters (ultrasound, extracorporeal shockwave therapy, laser therapy, x-ray).(3,7,12) appropriate response to medical therapies in this phase is of low probability and surgical intervention is warranted. to the present time several surgical approaches have been suggested, often based on the incision or removal of plaque accompanied with plication or grafting of dermis, tunica vaginalis, venous wall, dacron, pericardium, or fascia to the plaque region.(13) after 30 years of the innovation of dermal patch grafting method, it has remained one of the best approaches due to low complication, cost-effective material used, availability, and maintaining the length of penis. nonetheless, dermal patch graft has not been used in our center before this study and its outcome and indications are not well defined. moreover, to the authors’ knowledge, no study has been done to investigate the relation of surgical response and the size of fibrous plaque. thus, our study is a unique one to re-evaluate a known surgical procedure and suggests useful notes for treatment decisions. materials and methods dermal patch graft surgery was performed in 18 males, referred to shaheed faghihi and motahhari urology clinics between 1999 and 2002. the mean age of the patients was 49±4.45 (range 41 to 60) years. in all of the patients, it had been 6 months since the beginning of the symptoms and they were all in the chronic phase. they had received one to three types of medications with no significant response. penile curvature had been established according to the patients’ report and the presence of plaque was confirmed by the urologist examination. no additional paraclinic assessment was required for diagnosis. primary evaluations consisted of disease history taking, filling out a brief sexual function inventory (bsfi) questionnaire, determining the location and size of the plaque, and measuring the degree of penile curvature. erection was induced using papaverin with a minimum dosage of 10 mg, increased gradually to achieve complete erection. afterwards, the degree of deviation was measured using goniometry. bsfi questionnaire had three main parts of frequency of erection, hardness of erection, and overall satisfaction. each part had 0 to 4 scores, making bsfi sum together.(14) kelami classification(15) was used for grouping the patients according to the plaque size. this classification method (kelami’s) is a standard method to classify penile curvatures: class i: plaque size < 2 cm2 class ii: plaque size 2-4 cm2 class iii: plaque size <4 cm2 the operation included the stages of tunica albuginea dissection with sparing posterior neurovascular bundle of the penis, plaque removal, and dermal patch grafting. the dermal patch was obtained from the superior region of iliac crest skin, after separating the epidermis and subcutaneous adipose layer. the outcomes were recorded 3 and 6 months after the surgery using bsfi and deviation measurement of the artificially erected penis. finally, data analysis was done by wilcoxon signed ranks test and paired t test with the help of spss 10 software. results none of the 18 patients was able to have intercourse due to penile curvature or erectile dysfunction preoperatively. penile curvature trend was dorsal in 61%, lateral in 28% and ventral in 11%. mean penile curvature degree was 58±19 (range 25 to 90) degrees. deviation decreased to 5±6 (range 0 to 20) degrees postoperatively which was significant (p=0.0005). peyronie’s plaque was in the median one-third of the penis in 50%, distal one-third in 28%, and proximal one-third in 22%. mean plaque volume was 3.3±2.1 (range 1 to 9) cm2. according to kelami classification, 28% (5) of the patients were in class i (plaque size<2 cm2), 38% (7) in class ii (2-4 cm2), and 33% (6) in class iii (> 4 cm2). mean bsfi score was 4.4±1.7, which improved to 7.3±1.4 after the procedure. this significant improvement was also seen in each part of bsfi questionnaire (p=0.01). analysis of the results of 6 cases with a plaque 41 results of dermal patch graft in the treatment of peyronie’s disease size of greater than 4 cm (kelami class iii) revealed that postoperative bsfi cumulative score and the ones for each part did not differ significantly (p=0.5). however, changes in the degree of penile curvature was statistically significant (p=0.0005). in patients with a plaque volume of greater than 4 cm3, surgery was only effective in the correction of penile curvature. none of the patients had satisfactory intercourse before the operation, but the overall complete or moderate satisfaction was achieved in 61% (11 patients) postoperatively. six out of 7 patients, who were impotent postoperatively, had a plaque size of greater then 4 cm2. preoperative painful erection (40%), declined to 11% ( 2 patients) following the surgical therapy. as a complication, two cases of superficial ecchymosis were seen, which were improved spontaneously. discussion devin and horton were the first who described plaque excision and dermal patch graft with successful results in 1974.(16) since then various materials were used as a graft such as tunica vaginalis and venous wall. artificial materials were also introduced such as dacron and polyglicolic acid.(11,17,18,19) every method had its own limitation, for example, venous wall could be used only in small plaques. furthermore, synthetic materials did not result in desirable outcomes because of the lack of flexibility and being foreign body.(20) as well as the access to a natural low cost material, using derma has the advantage of no plaque size limitation and no risk of hypersensitivity reaction. in this study all the patients were in the fifth or sixth decade of life and had an average age of 49 years which is comparable to the epidemiologic data of the disease in most parts the world.(21) spontaneous improvement or response to medical therapy is probable in the acute phase. thus, surgical intervention must be performed at least 6 months after the beginning of the symptoms or in case of complete calcification of the plaque.(22) as we considered this condition, the chance of recovery without invasive intervention was trivial. bsfi questionnaire was preferred because of its flexibility and simplicity in comparison with other questionnaires such as iief (international index of erectile function) that is complicated with much more items.(23) although the range of deviation was wide (25° to 90°) surgery was effective in lowering the penile curvature; mean degree of the angle declined from 58° to 5° which was a significant change (p=0.0005). plaque size did not affect the correction of penile deviation. consequently, results are indicative of the benefits of using dermal graft in the correction of severe deviations despite of the large size of plaque. conversely, other methods like plication have not been effective in severe deviation and have led to shortening of penis.(24) none of the patients had been able to have effective intercourse preoperatively, but 61% had satisfactory results proved by the significant rise of bsfi and its components scores (p=0.01). reassessment of the remaining 7 patients, who still were complaining of erectile dysfunction and unsatisfactory intercourse, revealed that 6 of them had plaques size greater than 4 cm2 and their chief complaint had been inability to achieve erection before the operation. in this group of patients bsfi changes were not significant either (p=0.5). regarding these findings, it seems that this approach is not effective in the treatment of sexual dysfunction when the plaque size is greater than 4 cm2 (kelami class iii) or when severe erectile dysfunction is present before the operation. plaque excision and using dermal patch graft can only correct penile deviation in these cases. however, further studies are needed to confirm our findings. accordingly, it is suggested that these patients become aware of the risk of failure and be proposed to use prosthesis, drugs, or devices of erection induction. conclusion dermal grafting is a cost-effective and useful method for penile curvature correction regardless of the severity of the curvature or the plaque size. the results of this study indicate that this method is successful if the plaque size is less than 4 cm2 and erectile dysfunction is not severe. thus, it is recommended to use prosthesis or artificial erection methods as well as the operation in patients with a larger volume of plaque and complete impotence. since peyronie’s disease leads to severe physical and psychological complications and due to its prevalence, further studies are warranted. 42 results of dermal patch graft in the treatment of peyronie’s disease references 1. dunsmuir wd, kirby rs. francois de lapeyronie (16781747) the man and the disease he described. bju 1996: 78: 613-22. 2. gelbard mk, dorey f, james j. the natural history of peyronie's disease. j urol 1990: 144: 1376-9. 3. hamm r, mclerty e, ashodown j. peyronie's disease the plymouth experience of extracorporeal shockwave treatment. bju 2001; 87: 849-852. 4. devine cj jr, somers kd, wright gl jr, et al. a working model for the genesis of peyronie's disease derived from its pathobiology. j urol 1988: 139:286 a (abst 495). 5. smith bh. peyronie's disease. am j clin pathol 1966: 45: 670. 6. nachtsheim da, rearden a. peyronie's disease is associated with an hla class ii antigen hla dq5 implying an autoimmune aetiology. j urol 1996: 156: 1330-4. 7. rodriques cl, njo kh, karim ab. results of radiotherapy and vitamin e in the treatment of peyronie's disease. int j radiat oncol biol phys 1995: 31: 571-6. 8. zarafonetis cj, horran tm. treatment of peyronie's disease with potassium paraaminobenzoate (potaba). j urol 1959: 81: 770-3. 9. desanctis pn, furey ca jr. steroid injection therapy for peyronie's disease a 10-year summary and review of 38 cases. j urol 1967; 97: 114-6. 10. levine la. treatment of peyronie's disease with intralesional verapamil injection. j urol 1997; 158: 1395-9. 11. rehman j, benet a, melman a. use of intralesional verapmil to dissolve peyronie's disease plaque: a long-term single-blind study. urology 1998; 51: 620-6. 12. heslop rw, oakland dj, maddox bt. ultrasonic therapy in peyronie's disease. bju 1967; 39: 415-9. 13. levine la, lenting el. a surgical algorithm for the treatment of peyronie's disease. j urol 1997; 158: 2149-52. 14. mathias sd, leary mp, henning jm, pasta dj, fromm s, rosen rc. a comparison of patient and partner responses to a brief sexual function questionnaire. j urol 1999; 162: 1999-2002. 15. kelami a. classification of congenital and acquired penile deviation. urol int 1983; 38: 229. 16. devine cj jr, and horton ce. surgical treatment of peyronie's disease with a dermal graft. j urol 1974; 111: 44. 17. das s. peyronie's disease: excision and autografting with tunica vaginalis. j urol 1980; 124: 818. 18. lowe d h, ho pc, parsons cl, schmidt jd. surgical treatment of peyronie's disease with dacron graft. urology 1982; 19: 609. 19. bazeed ma, thuroff jw, schmidt ra, tanagho fa. new surgical procedure for management of peyronie's disease. urol 1983; 21: 501. 20. fitkin j. peyronie's diseasecurrent management. american family physician 1999; 60: 549-54. 21. scharzer u, sommer f, klota t. the prevalence of peyronie's disease: result of large survey. bju 2001; 88: 727-730. 22. williams g, green na. the non-surgical treatment of peyronie's disease. bju 1980; 52: 392-5. 23. rosen rc, cappalleri jc, smith md, lipsky j, pena bm. development and evaluation of an abridged. 5-item, version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j import res 1999; 11: 31-25. 24. goldstein m, laungani g, abrahams j, waterhous k. correction of adult penile curvature with a nesbit operation. j urol 1984; 131: 56. 43 female urology comparison of transobturator tape surgery using commercial and hand made slings in women with stress urinary incontinence seyfettin ciftci,1* cuneyd ozkurkcugil,1 murat ustuner,1 hasan yilmaz,1 ufuk yavuz,1 turgay gulecen2 purpose: to compare the complications and success rates of hand-made sling with commercial sling used in transobturator tape (tot) surgery. materials and methods: from 2008 to 2010, hand-made slings were used in tot surgery, whereas commercial slings were used from 2010 to 2013 in our clinic. overall 102 patients were included in the study. patients were categorized into 2 groups: group 1 had hand-made (polypropylene monofilament) slings, while group 2 had commercial slings (polypropylene monofilament). we retrospectively reviewed 1-year follow-up results of the whole cohort. ages, body mass indexes, menopausal status, operation time, cost of sling, success of operation and complications were recorded. all these data were compared between the 2 groups. results: there were 41 patients (54.29 ± 9.88 years) in group 1 and 61 patients (52.82 ± 9.85 years) in group 2. menopausal status and body mass index (28.1 vs. 29.2 kg/m² respectively) were similar for both groups. previous history of incontinence or pelvic organ prolapse surgery (p = .046), mean duration of the procedure (p = .001), and vaginal extrusion rate (p = .016) were significantly lower in group 2. the cost of the sling was higher in group 2 than in group 1. there was no significant difference in success of operation between the groups (p = .319). conclusion: according to our results, hand-made mesh is a viable option in tot surgery with similar efficacy, but surgeons should be careful in terms of vaginal extrusion. keywords: suburethral slings; urinary incontinence; stress; surgery; treatment outcome; urologic surgical procedures; adverse effects. introduction stress urinary incontinence (sui) is the urine leakage through the urethra resulting from increased abdominal pressure and urethral occlusion mechanism dysfunction in the absence of detrusor muscle contraction. (1) the prevalence of sui increases with age and reaches 45% at 60 years of age.(2) since sui is a common problem, many surgical techniques have been described for management, including conventional open surgeries and minimally invasive techniques that use organic or synthetic materials to support the mid-urethra, known as slings. suburethral slings have become the preferred technique for the treatment of sui.(3) in 2001, delorme(4) described a new method of tension-free mid-urethral tape, referred to as the transobturator tape (tot), in which the tape is introduced through the obturator foramen and the retropubic space is not violated. with mid-urethral sling techniques, a number of synthetic materials were developed and impressive reductions in surgical morbidity have been achieved. the use of synthetic meshes reduced operating time and eliminated the possibility of morbidity at the autologous graft harvest site.(5) the characteristics of different meshes differ in terms of their fibers, weave, porosity and flexibility. these properties affect tissues response and the capacity for incorporation into the host’s tissues or for fighting infection; however, the cost of the meshes used in the tot procedure is expensive, especially in developing countries. the objective of this study was to compare low-cost, hand-made polypropylene slings with the more expensive commercial slings in sui management. materials and methods from 2008 to 2010, hand-made slings (covidien ilc, 15 hamsphire street, mansfield, ma, usa) were used in tot surgeries in our clinic. commercial slings were used for the same purpose in from 2010 to 2013. a total of 135 patients underwent the tot procedure during the study period; however, 21 patients were lost during the followup and 12 patients did not complete the 12-month followup period. the remaining 102 women who underwent tot surgery with the complaint of pure sui or mixed sui in that period were retrospectively evaluated. oneyear follow-up data of all patients were recorded. medical history, demographic characteristics, body mass indexes (bmi), and menopausal status of patients were recorded. physical examination, urinalysis and urodynamic evaluations were performed on all patients preoperatively. 1 department of urology, school of medicine, university of kocaeli, kocaeli, turkey. 2 department of urology, hakkari state hospital, hakkari, turkey. *correspondence: department of urology, university of kocaeli, campus of umuttepe, 41380, kocaeli, turkey. tel: +90 262 303 8708. fax: +90 262 303 8003. e-mail: seyfettinciftci@yahoo.com; seyfettin.ciftci@kocaeli.edu.tr. received september 2014 & accepted march 2015 female urology 2090 vol 12. no 02 march-april 2015 2091 urodynamic analysis was performed as described in the international continence society (ics) guidelines with 2 lumens 8 f urethral catheters, one lumen for infusion of fluid and the other for bladder pressure measurement, and a 4.5 f rectal catheter. the valsalva maneuver was used to provoke sui. patients with confirmed sui via physical examination and urodynamic studies underwent the tot procedure. before the operation, all patients were evaluated with ultrasonography, but none had bladder lithiasis or any other bladder pathology. before 2010, commercial slings were not covered by the general health insurance of turkey. thus, use of handmade slings was emphasized in an informed consent form that was routinely received before the operation from all group 1 patients. placement of the sling to the midurethra was done by a single surgeon (co) in the outsidein manner as described previously by delorme.(4) as antibiotic prophylaxis, cefazolin (1 gr) was intravenously administered 30 minutes before the procedure. the time taken for the surgical procedure and the cost of slings were also recorded and noted for every patient. group 1 was treated with a hand-made sling consisting of a polypropylene monofilament mesh measuring 15 cm in width and 30 cm in length. the cost of this sling was 45 us dollars. initially, we divided this large sling into 15 pieces 1 cm in width and 30 cm in length in sterile condition. we used one piece in the operation and the remaining 14 pieces were packaged separately and resterilized using the ethylene technique. thus, we used a single sling in 15 patients, corresponding to a cost of 3 us dollars per patient in group 1. in contrast, in group 2, the commercial betamix® bss vaginal tape system (betatech medical corporation, istanbul, turkey) (http:// www.betatechmedical.com) was used. the cost of this sling was 300 us dollars per patient. both types were monofilament polypropylene macroporous slings. we prepared a hand-made sling after passing silk sutures through both edges of the mesh. other sites of the silk sutures were passed through holes at the end of the introducers (figure). we used specially-designed introducers for group 1. the vaginal mucosa was closed with continuous 2.0 absorbable polyglactin 910 sutures material. the urethral catheters were removed and patients were discharged at postoperative day 1. after removal of urethral catheters, post-void residual volumes were measured in all patients. less than 100 ml residual urine was accepted as normal and considered as absence of urethral obstruction. exclusion criteria included history of major pelvic surgery, radiation therapy to the pelvis, chronic retention, and pure intrinsic sphincter deficiency. patients with active urinary infections were treated and then included variables group 1 group 2 p value no. of patients 41 61 _____ mean age (years) (sd) 54.29 (9.88) 52.82 (9.85) .537 mean bmi (kg/m2) (sd) 28.1 (3.7) 29.2 (4.52) .210 mixed ui * 15 (36.6) 17 (27.9) .237 pure sui * 26 (63.4) 44 (72.1) premenopausal * 15 (36.6) 30 (49.2) .209 postmenopausal * 26 (63.4) 31 (50.8) previous ui or pop surgery * 11 (26.8) 7 (11.5) .046 mean duration of surgery (min) 40.6 30.9 .001 table 1. demographic and clinical characteristics of patients who underwent sling procedures using hand-made or commercial slings. abbreviations: bmi, body mass index; sd, standard deviation; ui, urinary incontinence; sui, stress urinary incontinence; pop, pelvic organ prolapse. * data are presented as no. (%). complications group 1 (n = 41) group 2 (n = 61) grade** p value*** vaginal extrusion 6 (14.6) 1 (1.6) grade 3 .016 bladder pprforation 0 (0) 1 (1.6) grade 3 .598 de novo urgency 2 (4.9) 0 (0) grade 2 .159 uti 1 (2.4) 2 (3.3) grade 2 .647 obstruction 1 (2.4) 1 (1.6) grade 2 .645 abbreviation: uti, urinary tract infection. * data are presented as no. (%). ** according to clavien-dindo classification of surgical complications grade *** fisher’s exact test. table 2. comparison of complication rates between two study groups.* figure. demonstration of hand-made sling with two silk sutures and introducers. comparison of commercial with hand-made slings-ciftci et al. in the study. all patients were assessed at the 30th day and 3, 6, and 12 months after surgery. pre, early post-, and late post-operative complications were recorded. all complications were graded according to the 2004 clavien– dindo grading system.(6) the follow-up visit included a detailed medical interview, clinical examination, urine analysis and post-void residual volume determination. at follow-up visits, they were specifically asked about the relief of symptoms for which they underwent surgery. the cure of sui was defined as no urine leakage at cough test (negative stress test) and not reporting any event of urinary incontinence. only 1 or 2 episodes of sui were accepted as relief of symptoms. patients who did not meet these criteria were considered to have “failed” treatment. at the first follow-up visit, the patients who had negative stress test but had urgency or urge incontinence were treated with anticholinergic treatment for 12 weeks and then re-evaluated in terms of incontinence. we repeated the stress test at the following visit and evaluated in terms of urgency and urge incontinence. our cure criteria were applied to these patients after that. statistical analysis all collected data were entered and analyzed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0. the independent sample t-test, fisher’s exact, and chi-squared tests were used. statistical significance was set at a p value < .05. results retrospective analysis identified 102 patients achieving minimum 12-month follow-up; 41 (40.2%) patients in group 1 and 61 (59.8%) patients in group 2. mean ages, bmis, urodynamic proven sui, and mixed urinary incontinence rates were similar in both groups (table 1). overall, 32 (31.4%) patients had urodynamic proven mixed type incontinence, whereas, at followup, 24 (23.5%) patients had urge incontinence and needed anticholinergic treatment (p = .027). there was a significant decrease in terms of overactive bladder symptoms, which did not depend on the type of sling used (p = .570). there was no significant difference between the groups regarding menopausal status. mean operative time was higher in group 1. medical history of incontinence or pelvic organ prolapse surgery (pop) was significantly higher in group 2 (table 1). bladder perforation was seen in only one patient and, after closure of the bladder, we performed the obturator sling procedure. her urethral catheter was removed at postoperative day 7. there was a need for urethral catheter post-surgery due to obstruction in 2 patients, 1 in group 1 and the other in group 2. after 2 weeks, catheters were removed and were no longer required. vaginal extrusion occurred more often in group 1 than in group 2 (table 2). overall, the vaginal extrusion rate was 6.8% (n = 7) and all were seen in the first 6 months of follow-up. all patients were treated initially with topical estrogen cream and then with partial removal of the extruded sling. even with partial removal of the sling and re-approximation of the vaginal mucosa, continence was maintained in 6 patients, all of which were in group 1; however, the patient in group 2 was incontinent before and after partial removal of the sling. de novo urgency and urinary tract infection (uti) occurred in 2 and 3 patients, respectively without statistically significance, all of them were managed successfully with conservative treatments. there was not any other early or late postoperative complication. all complications are summarized in table 2. we accepted no episode of incontinence as success of the operation. partial improvement was defined as 1 or 2 episodes of incontinence per day. at the end of the study, there was no significant difference between the groups in terms of success of operation (p = .319) (table 3). furthermore, we achieved the same result among patients with pure stress incontinence after exclusion of 32 patients (15 in group 1, 17 in group 2) who had mixedtype incontinence (p = .477). discussion sub-urethral synthetic slings, like tot, have been described as the most popular surgery for management of female sui.(7) some types of materials, such as alloplastic, autologous and synthetic, were described as sub-urethral slings.(3) natalin and colleagues compared the autologous and synthetic sling materials in terms of success rate and bladder outlet obstruction;(8) the authors found similar success rates for both sling materials, though, bladder outlet obstruction was common in the autologous sling group. mustafa and wadie defined a new technique for placement of an in situ anterior vaginal wall sling in 11 patients.(9) the authors used this autologous sling with a good success rate and low incidence of complications. the perfect graft material has not yet been created. polypropylene, monofilament mesh with a large pore size (type 1 mesh) is the ideal mesh for the sling procedures. (10) both types of slings that we used in the procedures were type 1. synthetic sling materials are commonly used in the treatment of sui, but synthetic sling materials are much more expensive and increase the cost of surgery. in this study, we used 2 types of synthetic slings; lowcost hand-made slings and expensive commercial slings to support the mid-urethra for the management of sui. rechberger and colleagues reported that successful surgical sui management did not depend on the bmis of patients.(11) in contrast, age and menopausal status affected the success rate of operation. they found that tot surgery appears to be more effective in premenopausal women than in postmenopausal. they also reported that age has an unfavorable effect on the table 3. comparison of operation success rates between two study groups.* surgical outcome group 1 (n = 41) group 2 (n = 61) p value successful 31 (75.6) 51 (83.6) .319 improvement 4 (9.8) 5 (8.2) .525 failed 6 (14.6) 5 (8.2) .304 * data are presented as no. (%). female urology 2092 comparison of commercial with hand-made slings-ciftci et al. vol 12. no 02 march-april 2015 2093 success of the operation. in our study, there was not a statistically significant difference between the 2 groups in terms of age, menopausal status, or bmi of patients; these data were similar for the 2 groups. in the literature, mean operative time ranged from 16-51 minutes.(12,13) our operation time was measured from the opening to the closing of the vaginal wall. there was a significantly shorter operative time in group 2, likely due to the time spent preparing the hand-made sling. on the other hand, operation times of both groups were in the range described in the literature. although bladder perforation is a common complication that is seen in tension-free vaginal tape (tvt), the tot technique reduces this risk by avoiding violation of the retropubic space. however, needles may injure the bladder. in the literature, bladder perforation during the tot procedure was between 0-1.52%.(14,15) abdel-fettah and colleagues compared the outside-in (n = 241) and inside-out techniques (n = 148) in terms of bladder and urethral injuries.(16) they reported 2 (0.5%) bladder and 2 (0.5%) urethral injuries, all of which were outside-in tot group with no significant difference between techniques. we report only 1 (0.9%) case of bladder perforation during the procedure without significance between the groups. in terms of postoperative complications, de novo urgency and uti were seen in 3 and 2 patients, respectively, without statistically significance. it is known that the tot procedure results in high chronic groin pain,(17) however, none of our patients complained of chronic groin pain at the end of the follow-up. vaginal extrusion refers to fnding exposed sling material in the vaginal canal postoperatively. conservative treatment, including the application of topical estrogen creams, may manage the small extrusions; however, larger extrusions should be managed with removal of all infected materials and re-approximation of the vaginal mucosa with a combination of appropriate antibiotics. some patients with large extrusions may benefit from excision and removal of the extruded portion of the sling and closure of the vaginal wall. reported rates of vaginal mesh extrusion change from 0 to 13.8% in transobturator slings.(18,19) our overall vaginal extrusion rate is (6.8%) in the acceptable range in the literature. the vaginal extrusion rate was significantly high in the hand-made group. ignjatovic and colleagues used self-created and commercial slings in 67 and 47 patients, respectively.(20) they reported vaginal extrusion in 1.4% and 4.2% of the self-created and commercial groups, respectively. brito and colleagues used hand-made slings in 19 patients and commercial slings in 20 patients.(13) they did not observe any evidence of erosion of the urinary system or vaginal extrusion. however, they used the tvt technique, in contrast to us. long and colleagues reported that the vaginal extrusion rate is higher in the tot procedure compared with tvt, but it was not statistically significant.(17) furthermore, it does not explain the higher vaginal extrusion rate of the hand-made group compared with the commercial group in our study. aside from this, we did not see any urethral or bladder erosion of the sling. overall, our success rate was 80.4% (n = 82). patients had no episode of incontinence after the procedure until the last follow-up visit. there was no difference between the hand-made and commercial groups in success rate. furthermore, the study that compared the hand-made and commercial slings reported that success rate does not depend on the type of sling used.(13) in our study, we confirmed the results of brito and colleagues. the main different outcome of these 2 studies was the vaginal extrusion rate. they did not report any case of vaginal extrusion, whereas we found 7 cases, which was significantly high, in the hand-made group. furthermore, we did not clarify any complication after the 6th month of follow-up; all vaginal extrusions were seen in the first 6-month period after the procedure. it was most likely the result of re-sterilization of hand-made slings. the other most probable cause might be the significantly high medical history of previous incontinence or pop surgery in group 1. extrusion of material may also be related to infection or the physical properties of the implanted material. nevertheless, no additional factors could be established as the reason for higher vaginal extrusion in the hand-made group. more recently, a study was performed to compare selfcutting slings (n = 67) with commercial slings (n = 47). (20) in this prospective study, the authors compared the two groups and concluded that self-cut slings do not have inferior results in terms of success rate and complication rate. we confirmed this result in our retrospective study. our results also support the use of hand-made slings with a similar success rate to commercially-available slings. the main difference between the 2 studies is the vaginal extrusion rate. although other complications were statistically similar between the 2 groups, vaginal extrusion was higher in the hand-made group in the present study. the present study is not free of limitations. the main limitation in our study was the low number of patients in both groups. the retrospective character of the present study was another limitation. another limitation was the high number of mixed ui in whole cohort; however, after exclusion of the 32 patients who had mixed ui, the difference in success rates between the 2 groups remained insignificant. on the other hand, we only evaluated the 1-year follow-up result of our study, but the 1-year followup period may be short to make a final comparison. conclusion in conclusion, use of hand-made slings is a reasonable option in the management of sui. however, hand-made slings’ cost may increase when the cost of erosions and sterilization are added, leading to underestimation of the cost for group 1. in addition, physicians should be careful, in terms of vaginal extrusion, when they use hand-made slings. significant vaginal extrusion necessitates an evaluation of the medicolegal aspects of hand-made slings. further studies with a larger number of patients and long-term follow-up results should be carried out to elucidate these results. conflict of interest none declared. references 1. haylen bt, de ridder d, freeman rm, et al. an international urogynecological association (iuga)/international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. neurourol urodyn. 2010;29:4-20. 2. hunskaar s, lose g, sykes d, voss s. the prevalence of urinary incontinence in women in four european countries. bju int. 2004;93:324comparison of commercial with hand-made slings-ciftci et al. 30. 3. niknejad k, plzak ls, 3rd, staskin dr, loughlin kr. autologous and synthetic urethral slings for female incontinence. urol clin north am. 2002;29:597-611. 4. delorme e. [transobturator urethral suspension: mini-invasive procedure in the treatment of stress urinary incontinence in women]. prog urol. 2001;11:1306-13. 5. norris jp, breslin ds, staskin dr. use of synthetic material in sling surgery: a minimally invasive approach. j endourol. 1996;10:227-30. 6. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 7. jonsson funk m, levin pj, wu jm. trends in the surgical management of stress urinary incontinence. obstet gynecol. 2012;119:84551. 8. natalin ra, riccetto c, nardi pedro r, prudente a, salvador navarrete g, rodrigues palma pc. [autologous versus synthetic sling procedure: success rate and bladder outlet obstruction rates]. actas urol esp. 2009;33:154-8. 9. mustafa m, wadie bs. in situ anterior vaginal wall sling for treatment of stress urinary incontinence: extended application and further experience. urol j. 2009;6:35-9. 10. roth cc, holley td, winters jc. synthetic slings: which material, which approach. curr opin urol. 2006;16:234-9. 11. rechberger t, futyma k, jankiewicz k, adamiak a, bogusiewicz m, skorupski p. body mass index does not influence the outcome of anti-incontinence surgery among women whereas menopausal status and ageing do: a randomised trial. int urogynecol j. 2010;21:8016. 12. trivedi p, d'costa s, shirkande p, kumar s, patil m. a comparative evaluation of suburethral and transobturator sling in 209 cases with stress urinary incontinence in 8 years. j gynecol endosc surg. 2009;1:105-12. 13. brito lm, sousa ade p, de figueiredo neto ja, duarte tb, pinheiro gdo l, chein mb. comparison of the outcomes of the sling technique using a commercial and handmade polypropylene sling. int braz j urol. 2011;37:519-27. 14. barber md, kleeman s, karram mm, et al. transobturator tape compared with tension-free vaginal tape for the treatment of stress urinary incontinence: a randomized controlled trial. obstet gynecol. 2008;111:611-21. 15. juma s, brito cg. transobturator tape (tot): two years follow-up. neurourol urodyn. 2007;26:37-41. 16. abdel-fattah m, ramsay i, pringle s. lower urinary tract injuries after transobturator tape insertion by different routes: a large retrospective study. bjog. 2006;113:1377-81. 17. long cy, hsu cs, wu mp, liu cm, wang tn, tsai em. comparison of tension-free vaginal tape and transobturator tape procedure for the treatment of stress urinary incontinence. curr opin obstet gynecol. 2009;21:342-7. 18. gilchrist as, rovner es. managing complications of slings. curr opin urol. 2011;21:291-6. 19. domingo s, alama p, ruiz n, perales a, pellicer a. diagnosis, management and prognosis of vaginal erosion after transobturator suburethral tape procedure using a nonwoven thermally bonded polypropylene mesh. j urol. 2005;173:1627-30. 20. ignjatovic i, potic m, basic d, et al. selfcreated transobturator tape treatment of stress urinary incontinence without prior urodynamic investigation. eur j obstet gynecol reprod biol. 2014;182:76-80. comparison of commercial with hand-made slings-ciftci et al. female urology 2094 editorial comments re: the effect of testicular cryoablation on testosterone level in rats: an experimental model of histopathological orchiectomy in this issue of the urology journal, ozcan and colleagues reported on the efficacy of testicular cryoablation for providing castrate level of serum total testosterone in rats. the beneficial effects of androgen deprivation therapy (adt) on prostate cancer (pca) have been known for more than a half century.(1) to achieve the castrate level of testosterone usually two types of treatment methods, luteinizing-hormone releasing hormone (lh-rh) analogue administration or bilateral orchiectomy are used. the first comes at a cost with own disadvantages and the later has psychologic burden. therefore the authors should congratulate for their study to finding alternative treatment modality for advanced pca. cryoablation is used for treatment of different cancer as primary treatment. cryoablation is also used to relieve the pain of many different types of cancer that metastasize the bone or other organs. the adverse events associated with lh-rh analogs administration are well characterized.(2) an adverse event that is commonly overlooked, yet, is the failure to decrease or maintain serum levels of testosterone that would be achieved with lh-rh agonists administration. in addition the testosterone surge that occurs after initial administration of lh-rh agonists can cause cancer flare in up to 63% of patients with advanced pca.(3) in certain men with advanced pca, these flares are accompanied by serious adverse events that can result in urinary retention and spinal cord compression, which can lead to paralysis and, rarely, death.(4) testosterone breakthrough and the acute-on-chronic effects of lh-rh analog administration may cause serum testosterone concentrations to periodically increase, sometimes to non-castrate levels. the goal of adt should be consistent achievement and maintain the castrate levels of testosterone without significant side effects. inadequate suppression of serum testosterone concentration is currently poorly known and may possibly have an effect of pca mortality. so the important question today is, "is there a best castration therapy"? this is study is the first one addressing the effectiveness of testicular cryoablation to achieve castrate level of testosterone. animal study, particularly that relating to pharmaceuticals, may be a poor predictor of human experience. before clinical trials are performed, the efficacy and safety of new drugs or treatment modalities are usually investigated in animal models. some believe, however, that the results from animal researches are not applicable to humans because of biological differences between the species. one reason why animal researches usually do not translate into replications in human trials(5) is that many animal studies are poorly designed, performed and analyzed. another possible explanation to failure to replicate the results of animal experiment in humans is that reviews and extraction of evidence from animal research are methodologically inadequate.(6) despite significant limitations of animal studies, there are many cases in which the results of carefully and well designed experiments using animals have contributed significantly to medicine progress and consequently benefited humans. do cryoablation for adt really work? more scientific researches are needed of the subject to respond this question. references 1. huggins c, hodges cv. studies on prostatic cancer: i. the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. j urol. 2002;168:9-12. 2. faris je, smith mr. metabolic sequelae associated with androgen deprivation therapy for prostate cancer. curr opin endocrinol diabetes obes. 2010;17:240-6. 3. labrie f, dupont a, belanger a, lachance r. flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist. j urol. 1987;138:804-6. 4. el-rayes bf, hussain mh. hormonal therapy for prostate cancer: past, present and future. expert rev anticancer ther. 2002;2:37-47. 5. hackam dg, redelmeier da. translation of research evidence from animals to humans. jama. 2006;296:1731-2. 6. mignini le, khan ks. methodological quality of systematic reviews of animal studies: a survey of reviews of basic research. bmc med res methodol. 2006;6:10. mohammad reza safarinejad, md clinical center for urological disease diagnosis and private clinic specializing in urological and andrological genetics, tehran, iran. e-mail: info@safarinejad.com editorial comment 2289 reply by authors first of all we are pleasure because of what you say about our issue. as you say, in this research, we reported on the efficacy of testicular cryoablation for providing castrate level of serum total testosterone in rats. may be animal researches are not applicable to humans because of biological differences between the species. but despite significant limitations of animal studies, there are many cases in which the results of carefully and well-designed experiments using animals have contributed significantly to medicine progress and consequently benefited humans. you asked “do cryoablation for adt really work?” we can say ‘yes’, but more scientific researches are needed of the subject to respond this question. and finally again we would like to say thank you. serkan ozcan md omer gokhan doluoglu md vol 12 no 04 july-august 2015 2290 female urology double tension adjustments with novel modification on tension-free vaginal tape mahmoud mustafa* objective: to evaluate the results of novel modifications on tensionfree vaginal tape (tvt) for the treatment of women with stress urinary incontinence (sui). materials and methods: sixteen female patients (average age 49.29 years, range: 31-78) who underwent anti-incontinence surgery to correct their sui in the period between june 2010 and august 2014 were included in the study. in situ anterior vaginal wall sling was prepared, and monofilament polypropylene tape passed below the in situ-sling and standard tvt procedure was performed. both ends of the mesh in the suprapubic region were labeled with vicryl sutures and left outside the wound. the middle of the mesh in the vaginal region were labeled with similar suture and left outside the vagina. foley catheter was removed on the third postoperative day. the average period of follow-up was 8 months (range: 5-17). results: all patients benefited from the surgery; 15 (94%) of them completely cured and one patient clinically improved. urinary retention was observed in one patient where the tension of the tape was reduced using adjustment sutures. no vaginal mesh erosion was detected during the gynecological examination postoperatively. no significant post-voiding residue was detected after catheter removal. conclusion: this technique gives feasible option to adjust the tension of the mesh in the early post-operative period in case of urinary retention. presence of intervening in situ sling reduces the risk of vaginal erosions. long-term success is expected because dislocation of the mid-urethral sling is less likely. keywords: female; quality of life; urinary incontinence; surgery; stress; outcome assessment; postoperative period; prospective studies. introduction since the initial description of tension-free vaginal tape (tvt) in 1995 by ulmsten and petros(1) for the treatment of stress urinary incontinence (sui) in women, many approaches have been evolved.(2) tvt which based on mid-urethral polypropylene, have become the most accepted technique for the treatment of type i and type ii sui in females.(3) the cure rate of mid-urethral sling (mus) appeared to decrease over time with an associated increase in the sui recurrence rate.(5) the overall 5-year cure rate for anti-incontinence surgery was reported to be 76.8%.(6) nilsson and colleagues reported excellent long-term success of 81.3% at 7 years follow-up.(7) there is no definite cause for this reduction in the success rate of tvt over long-term follow-up. many expected mechanisms may cause the reduction in long-term efficacy as the tape being loose, so that it becomes slacked with time or misplacement of mid-urethral tape.(8-10) loss of tensile property and relaxation of tvt tape are among the expected causes of reduction in the success rate at long-term follow-up. (11) beside reduction in long-term success rate, mus related complications are also present. deng and colleagues investigated the incidence of mus sling related complications in the american population and found they were underreported.(12) there was a significant variation between the scientific reports in english literature and food and drug administration (fda), which collect four times as many as major complications.(12) in a recent study we had introduced novel modification on tvt to overcome the dilemma of the reduction in long-term success rate and the results were promising. (13) here in we introduced further novel surgical modifications on tvt to achieve long-term success and avoid some complications of mus, including; mesh erosion and postoperative urinary obstruction or incontinence. materials and methods study population sixteen women (average age 49.3 years, (range: 3171) who were diagnosed with genuine sui underwent anti-incontinence surgery. six patients were operated between june 2010 and august 2010 in osmaniye state hospital in turkey and another 10 patients were operated in an-najah national university hospital in palestine, between april 2013 and august 2014. sui department of urology, faculty of medicine and health science, an-najah national university, nablus, west bank, palestine. *correspondence: department of urology, faculty of medicine and health science, an-najah national university, nablus, west bank, palestine. tel: +972 023 90390. fax: +972 023 90316. e-mail: dr_mahmoud681@yahoo.com. received january 2015 & accepted august 2015 female urology 2334 was defined as unintentional loss of urine on physical movement or activity such as coughing, sneezing, or heavy lifting. the urodynamic evaluation showed stable bladder with normal volume and no detrusor overactivity. all cases were primary, except 3 patients who had antiincontinence surgeries previously (the exact nature of the previous anti-incontinence surgeries was unclear). one of them had two previous unsuccessful anti-incontinence surgical interventions (vaginal approach without mesh), and another one had multiple pelvic surgeries with bladder and urethra rupture due to road traffic accident. this patient had severe form of sui, with low bladder capacity (300 ml), and low leak point pressure at urodynamic study. anti-cholinergic therapy was given for all patients before surgery and no benefit was seen. evaluations any patient who suffered from urodynamically documented urge incontinence was excluded from the study. baden-walker classification was used to evaluate the degree of cystocele.(14) cystocele was observed in only 4 patients: two patients with grade iii and two patients with grade ii. surgical procedure the patients were operated under spinal or general anesthesia. in the lithotomy position, an 18 french (f) foley catheter was inserted to evacuate the bladder. in the anterior vaginal wall placard incision was done (figure 1) and dissection was carried out to prepare a mid-urethral in situ anterior vaginal wall sling (figure 2). according to the degree cystocele the length of midline incision at anterior vaginal wall was determined. enough dissection at the lateral sides of in situ sling was performed till the index finger could be felt from the suprapubic region. no cauterization was done in the vaginal region. monofilament polypropylene mesh (vizcare, istanbul, turkey) passed through retropubic space as in the standard tvt operation and the mesh was passed between the mid-urethra and the in situ vaginal sling (figure 3), doing so dislocation of the tape was avoided. both ends of the tape in the suprapubic region were labeled with 2-0 vicryl sutures and left outside the skin to increase the tension of the mesh in the early postoperative period in case of incontinence presence. similarly the middle of the tape beside the in situ sling in the vaginal region was labeled with the same sutures and left outside the vagina to decrease the tension of the tape in the early post-operative period in case of urinary retention presence (figure 4). cystoscopy was done intra-operatively to rule out bladder or urethral perforation. the bladder was inflated with 300 ml normal saline and hand pressure was applied on the suprapubic region to define valsalva leak point pressure and accordingly the tension of the tape was adjusted. the placard incision edges were sutured tightly over the in situ sling, leaving the tension adjustment sutures outside the wound (figure 4). at the end of the surgery vaginal sponge with betadine solution and antibacterial cream was placed and left for one night. post-operative period oral quinolones antibiotics (500 mg twice/day) were given for one week postoperatively. all patients were hospitalized for one day. an 18 f foley catheter was left for average of 3 days. the operative time varied from 30-45 minutes. sexual intercourse and lifting heavy loads were avoided for 2 months postoperatively. the postoperative follow-up schedule was 0.5, 1, 3, 6 months, and then every 6 months; including clinical history for possible urinary leakage, pelvic physical examination, stress test, and estimation of the post-voiding residue (pvr) volume (50 ml or less was considered insignificant). real abdominal ultrasound was used to measure the pvr during the postoperative follow up. the patient was considered to be cured after surgery when there is absence of leakage with or without stress testing. improvement was considered when there is no urine loss on stress plus patients report of some leakage but overall satisfaction. therapeutic failure was defined as sustained sui. figure 1. schematic illustration of placard incision at the anterior vaginal wall. figure 2. in situ sling prepared form anterior vaginal wall is shown. novel modifications on tvt-mustafa. vol 12 no 05 september-october 2015 2335 results all patients benefited from the surgery; 15 (94%) of them completely cured and one patient clinically improved (78 year-old, grade iii cystocele, history of cerebrovascular accident). some urinary leakage occurred but satisfied overall. one patient (6%) had urinary retention (she had history of two anti-incontinence surgeries) after removal of foley catheter. so a foley catheter was re-inserted for one week more, but still the patient had urinary retention after the second removal of foley catheter. therefore a tension reduction of the sutures by pulling down external suspension suture (suture placed at the mid of the tape below the mid-urethra in the vagina (figure 4) was enough to resolve urinary retention. denovo urgency was performed in two patients, one of them had history of urgency symptoms before surgery and the other one was 71 years old and over obese. one of them gave a good response to anticholinergic therapy for three weeks; the other one (71-year old) partially benefited from anti-cholinergic therapy. no vaginal erosion was observed in any patient. there was no clinically significant pvr urine detected by real time abdominal ultrasound after catheter removal. the tension adjustment sutures were cut after one month postoperatively. the average follow-up period was 8 months (range: 5-17). discussion the safety and efficacy of tvt have been extensively investigated.(15) however few studies have mentioned about the true incidence and prevalence of complications(12) and even with their managements.(3) beside reduction in the long-term success rate,(5) postoperative obstruction, bladder erosion, vaginal erosion, urethral erosion and denovo urgency are among the most common complications of anti-incontinence surgery. in the current description two modifications were adopted; passing the tvt mesh below the in situ vaginal sling to prevent the dislocation or misplacement of the tape and decrease the risk of vaginal erosion, the second modification was labeling the upper ends and the lower middle of mesh by vicryl, thus the adjustment of the tape tension may be possible. in our study we tried to introduce solutions for the mechanisms that may cause decrement in the success rate on long-term follow-up. dislocation of the tape from the mid-urethra was avoided by passing the tape below the in situ sling (figure 3), so a long-term success is expected. in our recent published work, where mesh fixation with in situ sling were done, none of the patient who was continent after surgery suffered from any leakage at midterm follow-up. (13) low risk of vaginal erosion is also an expected result of the present technique. we had neither vaginal nor urethral mesh erosion. generally 66% of erosions are discovered within the first 3 months after surgery, although recent series demonstrated the ongoing risk of vaginal surgery erosions even 5 years after surgery. then we believe that our patients passed the critical period without having vaginal erosion as all patients were followed-up for more than 3 months. passing the tape below the in situ sling, makes vaginal erosion less likely to occur because of the presence interposition vaginal mucosa. about 35% of the vaginal erosions present with no symptoms and usually discover on routine follow-up and not during symptomatic check. similarly kobashi and colleagues reported that in 90 women who had anti-incontinence surgery using polypropylene mesh, developed vaginal erosions but only one patient had symptoms such as pain during sexual intercourse. (16) surgical approach ranges from partial excision of the exposed mesh to surgical exploration for total graft refigure 3. (a) dissection below the in situ sling to pass the tape; (b) mid urethral tape passing below the in situ vaginal sling. figure 4. tension adjustment sutures indicated by arrows in the suprapubic region and vagina. novel modifications on tvt-mustafa. female urology 2336 moval. some authors believe that mesh erosion should be treated with complete mesh removal and regardless to erosion site, width, or local tissue.(17) vaginal erosion of synthetic material such as polyester and silicon slings should be also treated with mesh removal because epithelization over these materials rarely occur.(12,18,19) in a recent study, a higher risk of vaginal erosion was found to be associated with hand-made sling (14.6%) than with commercial sling (1.6%).(20) in contrary to vaginal erosion, bladder erosion is serious complication, it is symptomatic and usually ends with calculus formation over the mesh. we do recommend intra-operative cystoscopy to verify the integrity of bladder. open surgery was the valid management for the calcified eroded mesh in the bladder. we were the first who introduced the usage of the standard transurethral resection of the mesh as safe and simple way for the management of mesh bladder erosion,(21) which was used and approved by many authors in a lot of publications.(22,23) urethral erosion following tape surgery is rare (0.03% to 0.8%) but potentially serious and symptomatic.(24) surgical intervention is mandatory, but there is no consensus regarding the optimal management. the reconstructive procedures include: endoscopic tape removal and vaginal removal with urethral reconstruction with or without interposition of vascularized autologous tissue. (24) it is clear that tape anti-incontinence surgeries do have serious and sophisticated complications without standard approaches for management. therefore save the patients from such complications is of utmost clinical value. postoperative urinary retention is a challenging complication of anti-incontinence surgery and there is no consensus-based approach for the management. in one of the largest studies, kuuva and nilsson reported that urinary retention after anti-incontinence surgery was 2.3%.(25) in our present study we had one patient (6.2%) with urinary obstruction after catheter removal and it was managed easily by reducing the tension of the mesh utilizing the adjustment suture at outpatient clinic. we believe that adjustment sutures are of much benefit especially for the beginner surgeons in the field of female anti-incontinence surgery. it is difficult to make definite comment regarding real possibility of adjusting the tension of the sutures as we have used it in one patient only. early transient post-operative urinary retention may require intermittent sterile catheterization and in the majority of cases, urinary retention tends to solve within 12 weeks. if urinary retention persist for more than 12 weeks or significant pvr is present, then transvaginal urethrolysis may be done. klutke and colleagues performed tape transaction without mesh resection for the treatment of postoperative persistent urinary retention.(3) similarly volkmer and colleagues reported that women with persistent postoperative urinary retention stayed continent after mesh transaction, suggesting that mesh resection could damage the scar that replace the urethropubic ligaments and might result in urinary incontinence.(26) either clean intermittent catheterization or sling transaction, they are not accepted procedure by the patients. in our technique, tension adjustment sutures give feasible option and fast solution for postoperative urinary retention. we believe that patients with high risk factors for persistence of incontinence such as, obesity, old age, and high grade cystocele, history of failed anti-incontinence surgery, diabetic, or presence of overactive bladder may be in need of tape tension adjustment. therefore tension adjustment sutures may improve the success rate and expand the patients group who may benefit from anti-incontinence surgery. our technique seems to be valid for secondary or complicated cases; none of the patients with history of previous vaginal or anti-incontinence surgery had recurrence of incontinence. however preparing vaginal in situ sling should be done carefully in such case as it is more difficult than in virgin cases. standard mus with these new modifications will keep it superior to all other kinds of anti-incontinence surgeries including vaginal sling and the new introduced single incision mini sling. in one of the recent meta-analysis of effectiveness and complications of mus and mini slings, there was no evidence of significant difference in patients reported and objective cure rate between mini sling and mus at midterm follow-up.(27) mini sling was shown to have several complications similar to that of mus.(28) also tvt secure has already been withdrawn from clinical use and it is inferior to standard mus.(29) conclusions our modifications do improve the superiority of tvt and offer feasible solution for severe complications after anti-incontinence surgery including urinary retention and leakage of urine. vaginal erosion is less likely to occur. long-term success is expected as no dislocation of tape from the mid urethral is expected. yet larger number of patients with longer follow up period is needed before final result can be drawn. conflict of interest none declared. references 1. ulmsten u, petros p. intravaginal slingplasty (ivs): an ambulatory surgical lprocedure for the treatment of female urinary incontinence. scand j urol nephrol. 1995;2975-82. 2. delorme e. transobturator urethral suspension: mini-invasive procedure in the treatment of stress urinary incontinence in women. prog urol. 2001;11:1306-13. 3. klutke c, siegel s, carlin b, paszkiewicz e, kirkemo a, klutkej. urinary retention after tension-free vaginal tape procedure: incidence and treatment. urology. 2001;58:697-701. 4. laurikainen e, valpas a, aukee p, et al. fiveyear results of a randomized trial comparing retropubic and transobturator midurethral slings for stress incontinence. eur urol. 2014;65:1109-14. 5. han jy, park j, choo ms. long-term durability, functional outcomes, and factors associated with surgical failure of tensionfree vaginal tape procedure. int urol nephrol. 2014;46:1921-7. 6. doo ck, hong b, chung bj, et al. fiveyear outcomes of the tension-free vaginal tape procedure for treatment of female stress urinary incontinence. eur urol. 2006;50:3338. 7. nilsson cg, falconer c, rezapour m. sevennovel modifications on tvt-mustafa. vol 12 no 05 september-october 2015 2337 year follow-up of the tension-free vaginal tape procedure for treatment of urinary incontinence. obstet gynecol. 2004;104:125962. 8. lo ts, horng sg, liang cc, lee sj, soong yk. ultrasound assessment of mid-urethra tape at three-year follow-up after tension-free vaginal tape procedure. urology. 2004;63:6715. 9. poon c, zimmern p. when the sling is too proximal: a specific mechanism of persistent stress incontinence after pubovaginal sling placement. urology. 2004;64:287-91. 10. lo ts, lee sj. treatment of recurrent genuine stress incontinence by shortening previously implanted tension-free vaginal tape. acta obstet gynecol scand. 2004;83:1005-6. 11. zorn kc, spiess pe, singh g, orvieto ma, moore b, corcos j. long-term tensile properties of tension-free vaginal tape, suprapubic arc sling system and urethral sling in an in vivo rat model. j urol. 2007;177:11958. 12. donna d, rutman m, raz s, rodriguez lv. presenting and management of major complications of mid-urethral slings: are complications under-reported. neurourol urodynam. 2007;26:46-52. 13. mustafa m. how to achieve long-term success in the treatment of female urinary stress incontinence? novel modification on vaginal sling. korean j urol. 2011;52:184-8. 14. baden wf, walker ta. statistical evaluation of vaginal relaxation. clin obstet gynecol. 1972;15:1070-2. 15. delorme e. transobturator urethral suspension: mini invasive treatment procedure in the treatment of stress urinary incontinence in women. prog urol. 2001:11;1306-13. 16. kobashi kc, govier fe. management of vaginal erosion of polypropylene mesh slings. j urol. 2003;169:2242-3. 17. sweat sd, itano nb, clemens jq, et al. polypropylene mesh tape for stress urinary incontinence: complications of urethral erosion and outlet obstruction. j urol. 2002;168:1447. 18. duckett jra, constantine g. complications of silicone sling insertion for stress urinary incontinence. j urol. 2000;163:1835-7. 19. stanton sl, brindley gs, holmes dm. silastic sling for urethral sphincter incompetence in women. br j obstet gynaecol. 1985;92:74750. 20. ciftci s, ozkurkcugil c, ustuner m, yilmaz h, yavuz u, gulecen t. comparison of transobturator tape surgery using commercial and hand made slings in women with stress urinary incontinence. urol j. 2015;29:2090-4. 21. mustafa m, wadie bs. bladder erosion of tension free vaginal tape presented as vesical stone; management and review of literature. int urol nephrol. 2007:39;453-5. 22. huwyler m, springer j, kessler tm, burkhard fc. a safe and simple solution for intravesical tension-free vaginal tape erosion: removal by standard transurethral resection. bju int. 2008;102:582-5. 23. oh th, ryu ds. transurethral resection of intravesical mesh after midurethral sling procedures. j endourol. 2009;23:1333-7 24. sinha s, sinha r, reddy jb, sirigiri sr, kanakamedala sk. urethral erosion with recurrent stress incontinence following transobturator tape surgery: urethral repair with simultaneous pubovaginal sling. urol j. 2012;9:436-8. 25. kuuva n cg. a nationwide analysis of complication associated with the tension free vaginal tape (tvt) procedure. acta obst geynecol scand. 2002:81;72-7. 26. volkmer bg, nesslauer t, rinnab l, schradin t, hautmann re, gottfried hw. surgical intervention for complications of tension-free vaginal tape procedure. j urol. 2003;169:5704. 27. mostafa a , lim cp, hopper l, madhuvrata p, abdel-fattah m. single-incision minislings versus standard midurethral slings in surgical management of female stress urinary incontinence: an updated systematic review and meta-analysis of effectiveness and complications. eur urol. 2014;65:402-27. 28. coskun b, lavelle rs, alhalabi f, lemack ge, zimmern pe. mini-slings can cause complications. int urogynecol j. 2015;26:55762. 29. nambiar a, cody jd, jeffery st. singleincision sling operations for urinary incontinence in women. cochrane database syst rev. 2014 6:cd008709. novel modifications on tvt-mustafa. female urology 2338 272 urology journal vol 5 no 4 autumn 2008 case report an unusual case of birt-hogg-dube syndrome with renal involvement andreas janitzky,1 frank reiher,2 markus porsch,1 christian grube,1 matthias evert,3 uwe-bernd liehr1 urol j. 2008;5:272-4. www.uj.unrc.ir keywords: birt-hogg-dube syndrome, renal cell carcinoma, pneumothorax, skin neoplasms, folliculin 1department of urology, otto-vonguericke-university, magdeburg, germany 2department of urology, sana ohre-hospital, haldensleben, germany 3department of pathology, otto-von-guericke-university, magdeburg, germany corresponding author: andreas janitzky, md department of urology, otto-vonguericke university, magdeburg leipziger strasse 44, 39120 magdeburg, germany tel: +49 391 671 5039 e-mail: ajanitzky@aol.com received april 2007 accepted october 2007 introduction recent investigations of the underlying pathophysiology of renal cell carcinoma (rcc) has resulted in the identification of involved molecular pathways, including the inactivation of the von hippel-lindau gene in most sporadic cases of rcc.(1) they are characterized by one specific histological type. in contrast, kidney tumors in patients with birt-hogg-dube syndrome (bhd) consist of a variety of histological types.(2) we report a patient with multiple renal cell tumors in one kidney with a history of spontaneous pneumothorax, but without skin lesions which are typical signs of bhd syndrome. case report a 67-year-old woman was admitted to our institution with a left-sided kidney tumor highly suspicious for rcc. the patient mentioned an open right-sided thoracotomy in her medical history due to a spontaneous pneumothorax. recurrent leftsided flank pain was mentioned, as well. typical skin lesions were not detected. the family history was unremarkable, with the notable exception of recurrent spontaneous pneumothoraxes in the patient’s son. computed tomography scan showed a highdensity tumor formation (4.9 cm in diameter, dorsal) along with a deformed kidney caused by multiple mixed hyperdense and hypodense cystic structures (figure 1). since the patient was allergic to contrast medium, magnetic resonance imaging was performed and revealed 2 more suspicious 3.2-cm and 1.7-cm lesions. the contralateral kidney was hypoplastic with multiple small cysts. bone scan did not reveal bone metastases. radical nephrectomy was performed because of multiple kidney tumors and suspicion of infiltration of the renal pelvis during the operation. pathologic examination of the kidney revealed numerous cystic and solid tumors measuring 5 mm to 4.5 cm in diameter. histologically, they were of various subtypes of renal cell tumors including clear cell carcinomas, papillary adenomas and carcinomas, chromophobe carcinomas, and oncocytomas, sometimes composed as hybrid tumors. in addition, many clear cell preneoplastic tubules were noted (figure 2). birt-hogg-dube syndrome was diagnosed on the basis of these remarkable pathologic findings and the patient’s history; renal cell carcinoma in birt-hogg-dube syndrome—janitzky et al urology journal vol 5 no 4 autumn 2008 273 the patient’s son also mentioned spontaneous pneumothoraxes in his history. the family was cared by the urologists to screen for urinary tract tumors. to date, no renal tumors in family were found. discussion the birt-hogg-dube syndrome is a rare autosomal dominant condition usually characterized by a triad: skin tumors (fibrofolliculomas, trichodiscomas, and acrochordons), kidney neoplasms, and spontaneous pneumothoraxes. in some patients, skin lesions as a typical hallmark of this syndrome cannot be found.(3) since first described in 1977 by birt and colleagues,(4) the gene has been mapped on chromosome 17p11.2, expressing folliculin on protein level.(5-7) although the function of this protein is not fully understood, mutations on its gene are linked to rcc in animal models and in the families with bhd syndrome.(3,8) in our patient, clinical signs of the bhd syndrome were not completely developed. typical skin lesions were not detected, making it even more difficult to include bhd syndrome in the differential diagnoses. in the literature, patients with missing typical skin lesions are described, as well.(3) the diagnosis was made retrospectively, combining all the information on pathology, patient’s history, and family history. this clearly shows the necessity of precise clinical information for the investigating pathologist. conclusion in cases of kidney tumors associated with spontaneous pneumothorax and/or skin lesions, bhd syndrome should be considered as a differential diagnosis. intense follow-up of the families with members who have bhd syndrome should include genetic screening, ultrasonography of the kidneys, and other radiographic methods. conflict of interest none declared. references 1. jennings sb, gnarra jr, walther mm, zbar b, linehan wm. renal cell carcinoma. molecular genetics and clinical implications. surg oncol clin n am. 1995;4:219-29. 2. adley bp, schafernak kt, yeldandi av, yang xj, nayar r. cytologic and histologic findings in multiple renal hybrid oncocytic tumors in a patient with birthogg-dubé syndrome: a case report. acta cytol. 2006;50:584-8. figure 1. magnetic resonance imaging showed multiple kidney tumors with different signal activities on the left side and a hypoplastic right kidney with multiple small cysts. figure 2. typical histological aspect of renal cell carcinoma in birt-hogg-dube syndrome. a very early clear cell carcinoma (upper left arrow), a chromophobe carcinoma (right arrow), and a clear cell preneoplastic tubular lesion (lower left arrow) was noted (hematoxylin-eosin). renal cell carcinoma in birt-hogg-dube syndrome—janitzky et al 274 urology journal vol 5 no 4 autumn 2008 3. pavlovich cp, grubb rl 3rd, hurley k, et al. evaluation and management of renal tumors in the birt-hogg-dubé syndrome. j urol. 2005;173:1482-6. 4. birt ar, hogg gr, dubé wj. hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. arch dermatol. 1977;113:1674-7. 5. nickerson ml, warren mb, toro jr, et al. mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the birt-hogg-dubé syndrome. cancer cell. 2002;2:157-64. 6. murakami t, sano f, huang y, et al. identification and characterization of birt-hogg-dubé associated renal carcinoma. j pathol. 2007;211:524-31. 7. da silva nf, gentle d, hesson lb, morton dg, latif f, maher er. analysis of the birt-hogg-dubé (bhd) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. j med genet. 2003;40:820-4. 8. kouchi m, okimoto k, matsumoto i, tanaka k, yasuba m, hino o. natural history of the nihon (bhd gene mutant) rat, a novel model for human birt-hogg-dubé syndrome. virchows arch. 2006;448:463-71. miscellaneous different strains of bk polyomavirus: vp1 sequences in a group of iranian prostate cancer patients maryam vaezjalali1, 2, helia azimi1,3, seyed masoud hosseini3, afsoon taghavi4, hossein goudarzi2* purpose: bk virus (bkv) has a worldwide seroprevalence in humans. based on sequences of the major capsid proteins, i.e. viral protein 1 (vp1), there are four bkv genotypes. each genotype has its own subtypes, and was shown to be circulating independently in the human population. the aim of this study was to determine bkv genotypes and subtypes among iranian patients with prostatic cancer, benign prostatic hyperplasia, and kidney transplantation. materials and methods: bkv dna was extracted from prostatic cancers and benign prostatic hyperplasia blocks and also urine of kidney transplantation patients. bkv (vp1) gene was amplified partially (327nt) by homemade polymerase chain reactions and subjected for sequencing and phylogenetic analysis. bioedit version 7.0 and mega version 5.0 were used for sequence analysis and for comparing the results with world-driven bkv sequences. results: all of bkv vp1 genes which were derived from iranian patients were classified with subtype 1b2 strains from germany and turkey. predicted amino acid sequences from the studied region of vp1 showed that all of these nucleotide diversities could change amino acid sequence numbers 60, 68, 72, 73 and 82 among vp1. conclusion: the interesting point was that genetic analysis of derived sequences showed a different feature of genetic diversity among iranian sequences. this feature has not been reported yet. this characteristic feature of iranian bkv vp1 gene provides a unique cluster of sequences in phylogenetic tree. keywords: bk virus; agnoprotein; genotype; prostate cancer; benign prostatic hyperplasia. introduction bk virus (bkv), a member of polyomaviridae, is ever-present among humans(1). in western countries, bkv infects children asymptomatically(2,3). about 50% of children have bkv antibodies by four years old. by the age of 10 years old, 90-100% of them have seroconverted. bkv may persist in kidney tissue(4,5) and its contribution to human cancers is controversial. this virus has a double-stranded circular dna genome of about 5 kbp packaged within a capsid of 45-50 nm in diameter(6). the bkv genome is divided into regulatory, early, and late regions, and encodes five major proteins(7,8). the capsid contains three proteins: viral proteins (vp) 1, 2 and 3. vp1 gene is responsible for coding vp1, a major structural protein that comprises approximately 80% of the total viral capsid protein. the vp1 protein has important domains which interact with viral receptors on host cells. a single amino acid change in vp1 protein can increase pathogenicity of mouse polyomavirus(9). diversities of vp1 gene lead to significant variation among bk viruses worldwide(10). bkv isolates are classified into four subtypes (i-iv) worldwide using serological and genotyping methods (1,11). subtype i is prevalent throughout the world, sub1 urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 2 department of microbiology, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. 3 department of microbiology, faculty of biological sciences, shahid beheshti university, tehran, iran. 4 department of pathology, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. *correspondence: department of microbiology, faculty of medicine, shahid beheshti university of medical sciences, velenjak st., tehran, iran. postal code: 1985717443. tel: +98 21 23872556. fax: +98 21 22439972. mobile: +98 9126194134. e mail: hossein.goudarzi@sbmu.ac.ir. received january 2017 & accepted october 2017 type iv is in asia and part of europe, and subtypes ii and iii are rare in the world. these four genotypes correlate well with four serogroups, and were shown to be circulating independently in the human population. there are three reasons for researching about bkv genotypes and subtypes: 1) there is little information about the geographical circulation of bkv subtypes and subgroups. the effect of each genotype or subtype on clinical implications has previously been suggested (12,13); 2) some researchers had reported that characterization of bk virus' genetic mutations has biological and clinical implications(14). this data may be needed to follow potential relationships between bkv genotype and clinical disease in future; and 3) diagnostic virology laboratories need the sequencing data of bkvs to ensure correct detection of all naturally occurring viral strains(15). this study tried to explain phylogenetic characterization of bkv strains among iranian population and analyze its different polymorphisms clinically. the bkv vp1 region was studied among iranian patients with prostatic cancer, benign prostatic hyperplasia, and kidney transplantation. materials and methods twenty-five samples from our previous work on bkv miscellaneus 44 were studied in this investigation(16). all patients were referred to a central hospital in tehran. each test was done considering one specimen as one patient. this study was approved by the ethics committee of the urology and nephrology research center (unrc approval number 12-22 on 2012/3/12) and is in accordance with the helsinki declaration of 1964. dna extraction, gene amplification and sequencing dna was extracted from urine samples with qiaamp® dna mini kit (qiagen, hilden, germany) and also from paraffin-embedded tissue blocks with qiaampdna ffpe tissue extraction kit (qiagen, duesseldorf, germany). the protocols for working on the samples were followed based on our previous study (16). briefly amplification of beta-globin was done for all samples to control dna extraction. then bkv amplification was done with specific primers(16). all experiments were done in a contamination-free environment. for each round of polymerase chain reaction (pcr), positive and negative controls were considered. pcr program included five minutes of denaturation at 94°c, followed by 35 rounds of an amplification cycle consisting of 35 seconds denaturation at 94°c, one minute annealing at 50°c for beta-globin and 55°c for bk virus and one minute extension at 72°c, and a final extension cycle of four minutes at 72°c. beta-globin and bkv positive samples were detected with gel electrophoresis and etidium bromide dying of 268 and 327 bp pcr product, respectively. one separate bk virus positive specimen from the urine of infected patients was used as positive control. one beta-globin and all bkv pcr products were purified by qiaquick pcr purification kit (qiagen, duesseldorf, germany). then, they were subjected for direct sequencing (genetic analyzer abi3130 dna sequencer, fostercity, ca, usa) with 10 pmol of related pcr primers bi-directionally. phylogenetic analysis sequences derived from samples were read by chromas software and aligned with reference sequences by bioedit version 7. their phylogenetic tree was drawn by mega 5.0 software. the evolutionary history was inferred using the neighbor joining method. the bootstrap consensus tree inferred from 1000 replicates was taken to represent the evolutionary history of the analyzed taxa. the evolutionary distances were computed using the kimura two-parameter method and were in the units of the number of base substitutions per site. a neighbor joining phylogenetic tree was reconstructed from the typing-region sequences obtained from iranian patients plus 88 reference sequences, using sa12 (a primate polyomavirus related to bkv) as the outgroup. results the patients from whom the samples were driven were from 10 provinces of iran. all of them were men with a mean age of 68.0 ± 8.9 years old (range: 50 to 95 years old). nephropathy of bkv was not reported. also, derived sequences from one beta-globin pcr product confirmed the presence of beta-globin gene. among 25 positive bkv samples, 15 samples were successfully sequenced. nine samples were derived out from prostatic cancer tissues and five were derived out from benign prostatic hyperplasia tissues. also, one sample was derived from a patient with kidney transplantation who was receiving immunosuppressive med kp221578.1 kp221577.1 kp221579.1 kp221580.1 kp221581.1 kp221582.1 kp221583.1 kp221584.1 kp221585.1 kp221586.1 kp221587.1 kp221588.1 kp221589.1 kp221590.1 kp221591.1 ab276243.1turkey ab276242.1turkey 213493172subtype1b2china 213493180subtype1b2china kf468300.1germany kf468289.1germany jx195576.1germany 138996528subtype1b2finland 213493186subtype1b2usa 213493184subtype1b2usa 213493192subtype1b2usa 213493188subtype1b2usa 118561556subtype1b1china 118561601subtype1b1china 118561595subtype1b1china 213493202subtype1b1usa 213493196subtype1b1usa 213493174subtype1b1usa 213493228subtype1b1usa 118561549subtype1b1china 118561615subtype1b1china 118561634subtype1cchina 118561613subtype1cchina 118561626subtype1cchina 118561617suype1cchina 118561632subtype1cchina ab213286.1subtype1cchina 118561558subtype1cchina 118561636subtype1cchina 118561575subtype1cchina 118561565subtype1cchina 118561624subtype1cchina 118561622subtype1cchina 118561607subtype1cchina 118561593subtype1cchina 118561580subtype1cchina 118561603subtype1cchina 83281137subtype 1cjapan 83281130subtype1c-japan 83281158subtype 1c-japan 213493220subtype1cusa jn794032.1-subtype 1afrance jn794016.1-subtype 1afrance kc412484.1-subtype 1abrazil kc412483.1-subtype 1abrazil kc412462.1-subtype 1abrazil 52839633subtype4-japan 118561554subtype4china 118561611subtype4china 118561597subtype4china 118561620subtype4china 109638401subtype4china 109638429subtype4vietnam 213493226subtype4usa 138996952subtype4philippines 118561630subtype4-china 138996860subtpye4myanmar 52839611subtype4japan 138997113subtype4italia 118561628sabtype4china 118561609subtype4china 118561605subtype4china 213493222subtype4usa 213493194subtype4usa 213493190subtype4usa 213493176subtype4usa 83281144subtype4-japan 138996586subtype4greece 109638167subtype4japan 52839547subtype4japan 82524372-simian virus 12 74 60 81 85 67 84 89 89 67 55 32 34 74 98 98 70 55 79 62 51 73 70 20 70 67 71 98 69 40 52 79 75 68 0.05 figure 1. phylogenetic tree of bkv vp1gene partial sequence constructed using 15 isolates from this study along with genbank reference sequences. sa12 (a primate polyomavirus related to bkv) was considered as the outgroup. bk virus genotypes among iranian patients-vaezjalali et al. vol 15 no 02 march-april 2018 45 ications. in the resulted tree (figure 1), typing-region sequences were divided into clusters corresponding to subtype i and all of iranian bkv strains were clustered with subtype 1b2 strains from germany, turkey and usa. it was apparent that iranian bkv sequences are classified as a different cluster among other subtype 1b2 strains. the sequences derived from this study have been submitted to genbank by accession numbers: kp221577kp221591. in this study nucleotides 118-393 and therefore predicated amino acid 40-132 of vp1 were investigated. iranian strains alignment with reference sequence (accession number: jx195576.1) showed that five nucleotides were different among the derived vp1 region, 180, 202, 215, 218 and 244. the predicted amino acid sequences from the studied region of vp1 showed that all of these nucleotide diversities could change amino acid sequence numbers 60, 68, 72, 73 and 82 among vp1. discussion in this study, phylogenetic analysis was done on 327 nucleotides of bkv vp1 region derived out from 15 patients. there were two remarkable findings. one was that phylogenetic analysis of these sequences established one cluster for designated iranian sequences. this cluster was classified with high bootstrap value with bkv sequences subtype 1b2 from turkey and germany. subtype 1b2 is of type 1 which had been reported in europe previously(15). subtypes a, b1 and c are other subgroups of subtype 1 which are most prevalent in africa, south-east asia and north-east asia, respectively(17-20). two previous studies in iran had detected bkv subtypes among kidney transplant recipients by restriction fragment length polymorphism polymerase chain reaction (rflp-pcr). in 2012, researchers reported bkv subtype 1 among 12 iranian-azeri people from north-west of iran(12). in 2015, researchers reported bkv subtype 1 from east of iran(21). from 51 bkv samples in that study, 94.11% were subtype i and 5.89% were subtype iv using the rflp method. none of the patients' urine samples were positive for subtypes ii and iii. one reason for achieving different results in our study might be because of fewer samples, ethnicity or different clinical samples. however, sequencing is the standard test for genotyping which can help researchers analyze viral sequences sufficiently. on the other hand, in a new study, bkv subtype 1b2 was reported among iranian hiv-infected patients(22). the other significant point was that our studied sequences were obtained from different clinical sources and geographical regions of iran. despite controlling pcr conditions and preventing dna contamination, no difference was observed between strains derived from patients with prostate cancer, benign prostatic hyperplasia and kidney transplantation. all of the derived sequences belonged to bkv subtype 1 in this study. previous studies had reported that despite different clinical samples, subtype 1 was predominant around the world (23-25). since bkv subtype i was geographically prevalent, some researchers had suggested that there is no significant correlation between bkv subtypes and geographical regions(17). however, it seems that different research design of studies might be the cause of this theory. previous studies had reported 287 bp of vp1 as a remarkable region for bkv genotyping. two articles reported that full genome sequencing can detect viral genotypes more powerfully with 5% higher probability for bootstrap subgroup classification(26,27). however, these two reports asserted that the 287 bp typing region is useful to classify isolates into subtypes i to iv. totally, sequencing of the whole vp1 region or first part of the ltag is required to classify isolates into subgroup ib-1 or ib-2, supporting findings in previous reports(14,27). zheng and colleagues analyzed 30 typing regions and also full genome sequencing of bkvs derived out from different geographical areas of the world(19). they reported that the phylogenetic analysis based on complete dna sequences supports not only the subtype classification of bkv isolates, but also the sub-classification of subtype i isolates. in addition, this phylogenetic analysis allowed sub-classification of subtype iv into its subgroups. also, they suggested that host-linked evolution is the general mode of polyomavirus (jc and bk viruses) evolution(19). additionally, their results indicated certain unique aspects of the relationship between bkv and humans. this was a theory for tracing the geographical origins of unidentified cadaver based on bk genotype in a report from ikegaya and colleagues(28). zhong and colleagues(20) studied bkv genotypes of american, european, and asian populations. they reported the highest frequency of subtype i in all populations compared to subtype iv which was variable among populations. subgroup i/c was prevalent in native japanese but was rare in the second generation of this population(19,20). this observation can also be reconciled with the co-migration hypothesis. this hypothesis assumes that the children of migrant japanese have acquired bkv infection not from their parents, but from european americans living in their local community(19,20). therefore, it seems that prevalence of bkv subgroups among a geographical region might not be related to ethnicity. by aligning the derived sequences with the reference sequence (accession number: jx195576), we found vp1 gene mutations which were different from other reports. all amino acid variations in this study (positions 60, 68, 72, 73 and 82) localize to the bc loop. on the other hand, subtypes are determined by the vp1 sequence between amino acids 61 and 83, which is the variable antigenic region and maps to the bc1 and bc2 loops. (29) therefore, it was apparent that the variations were not randomly distributed but seemed to be arranged in “vp1 hotspots.” amino acids at positions 60, 68, 72, 73 and 82 in the vp1 protein showed an interesting pattern of changes(14). some researchers had suggested that amino acid substitutions at these five locations might result in type-determining changes in three-dimensional protein configurations(14). since the bc loop is believed to interact with the cellular receptor of bkv, it would be speculated that the genotype specific amino acid changes might alter bkv tissue tropism(14). however, the finding of pastrana and colleagues proved that different bkv genotypes have different cellular tropisms and pathogenic potentials in vivo(30). recently, two published data have pointed that like rna, bkv viruses are able to produce quasispecies. a study had found that sequencing of bkv isolates subcloned from bkv in nephropathy patients revealed a high percentage of variants in the urine (40%) in the vp1 subtyping region(31). in vitro analysis of several vibk virus genotypes among iranian patients-vaezjalali et al. miscellaneus 46 ral variants revealed that all variants which recovered from the urine of bkv associated nephropathy patients produced infectious viral particles. studied bkvs were replication-competent in cell culture while some of the variants induced cytopathic changes in infected cells compared to the major bkv subtype and vp1 subtype i. these results suggest that rare bkv vp1 variants are more frequently associated with disease and that some variants could be more cytopathic than others in kidney transplant recipients(31). no phylogenetic analysis reports of bkv genome were found among patients with prostate cancers and benign prostatic hyperplasia tissues. in our study 93% of studied samples were derived out from patients with prostate cancers and benign prostatic hyperplasia tissues. this remarkable vp1 gene diversity of bkv may have an implication role for clinical diagnostics. bkv can cause malignancy in animal models. still conclusive evidence is lacking regarding a causal connection between bkvs and human cancer(30). our study had some limitations. we used relatively few samples. therefore, the results cannot be generalized to the iranian population. nevertheless, we consistently reported five new mutations in all studied patients which were not previously reported in iranian patients which add to the value of our findings. also as stated above we had no information regarding the serological tests of bkv infection in our patients. conclusions phylogenetic analysis of the vp1 gene sequences in our study supports the existence of genotypes 1b2 in the studied sample of iranian patients in this study. finding bkv subtype 1 in iran was consistent with other iranian studies, which had reported bkv among iranian kidney transplanted patients. our data documented the phylogenetic diversity of iranian bkv and established the existence of clades not previously recognized in the literature. in this study bkv sequence of iranian strains showed five mutations within the vp1 (positions 60, 68, 72, 73 and 82) which distinguished these strains from other type 1b2 sequences. iranian bkv strains do not form distinct clusters from each other. however, they were classified as a unique cluster among 1b2 subtype sequences. conflict of interest none declared. acknowlegement this study has been supported by urology and nephrology research center, shahid beheshti university of medical sciences. the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. references 1. knowles wa. propagation and assay of bk virus. methods mol biol. 2001;165:19-31. 2. jozpanahi m, ramezani a, ossareh s, et al. bk viremia among iranian renal transplant candidates. iran j pathol. 2016;11:210-5. 3. konietzny r, fischer r, ternette n, et al. detection of bk virus in urine from renal transplant subjects by mass spectrometry. clin proteomics. 2012;9:4. 4. chesters pm, heritage j, mccance dj. persistence of dna sequences of bk virus and jc virus in normal human tissues and in diseased tissues. j infect dis. 1983;147:67684. 5. heritage j, chesters pm, mccance dj. the persistence of papovavirus bk dna sequences in normal human renal tissue. j med virol. 1981;8:143-50. 6. dorries k. molecular biology and pathogenesis of human polyomavirus infections. dev biol stand. 1998;94:71-9. 7. frisque rj, bream gl, cannella mt. human polyomavirus jc virus genome. j virol. 1984;51:458-69. 8. pipas jm. common and unique features of t antigens encoded by the polyomavirus group. j virol. 1992;66:3979-85. 9. freund r, garcea rl, sahli r, benjamin tl. a single-amino-acid substitution in polyomavirus vp1 correlates with plaque size and hemagglutination behavior. j virol. 1991;65:350-5. 10. morel v, martin e, francois c, et al. a simple and reliable strategy for bk virus subtyping and subgrouping. j clin microbiol. 2017;55:1177-85. 11. krumbholz a, bininda-emonds or, wutzler p, zell r. evolution of four bk virus subtypes. infect genet evol. 2008;8:632-43. 12. motazakker m, bagheri m, imani m. subtyping of bk virus in iranian turkish renal transplant recipients by rflp-pcr. maedica (buchar). 2012;7:10-3. 13. wang zy, hong wl, zhu zh, et al. phylogenetic reconstruction and polymorphism analysis of bk virus vp2 gene isolated from renal transplant recipients in china. exp ther med. 2015;10:1759-67. 14. sharma pm, gupta g, vats a, shapiro r, randhawa p. phylogenetic analysis of polyomavirus bk sequences. j virol. 2006;80:8869-79. 15. luo c, bueno m, kant j, randhawa p. biologic diversity of polyomavirus bk genomic sequences: implications for molecular diagnostic laboratories. j med virol. 2008;80:1850-7. 16. taghavi a, mohammadi-torbati p, kashi ah, rezaee h, vaezjalali m. polyomavirus hominis 1(bk virus) infection in prostatic tissues: cancer versus hyperplasia. urol j. 2015;12:2240-4. 17. takasaka t, goya n, tokumoto t, et al. subtypes of bk virus prevalent in japan and variation in their transcriptional control region. j gen virol. 2004;85:2821-7. 18. ikegaya h, saukko pj, tertti r, et al. identification of a genomic subgroup of bk polyomavirus spread in european populations. bk virus genotypes among iranian patients-vaezjalali et al. vol 15 no 02 march-april 2018 47 miscellaneus 48 j gen virol. 2006;87:3201-8. 19. zheng hy, nishimoto y, chen q, et al. relationships between bk virus lineages and human populations. microbes infect. 2007;9:204-13. 20. zhong s, randhawa ps, ikegaya h, et al. distribution patterns of bk polyomavirus (bkv) subtypes and subgroups in american, european and asian populations suggest comigration of bkv and the human race. j gen virol. 2009;90:144-52. 21. kaydani ga, makvandi m, samarbafzadeh a, shahbazian h, hamidi fard m. prevalence and distribution of bk virus subtypes in renal transplant recipients referred to golestan hospital in ahvaz, iran. jundishapur j microbiol. 2015;8:e16738. 22. akhgari s, mohraz m, azadmanesh k, et al. frequency and subtype of bk virus infection in iranian patients infected with hiv. med microbiol immunol. 2016;205:57-62. 23. krumbholz a, zell r, egerer r, et al. prevalence of bk virus subtype i in germany. j med virol. 2006;78:1588-98. 24. jin l, gibson pe, knowles wa, clewley jp. bk virus antigenic variants: sequence analysis within the capsid vp1 epitope. j med virol. 1993;39:50-6. 25. agostini ht, brubaker gr, shao j, et al. bk virus and a new type of jc virus excreted by hiv-1 positive patients in rural tanzania. arch virol. 1995;140:1919-34. 26. drew rj, walsh a, laoi bn, crowley b. phylogenetic analysis of the complete genome of 11 bkv isolates obtained from allogenic stem cell transplant recipients in ireland. j med virol. 2012;84:1037-48. 27. luo c, bueno m, kant j, martinson j, randhawa p. genotyping schemes for polyomavirus bk, using gene-specific phylogenetic trees and single nucleotide polymorphism analysis. j virol. 2009;83:2285-97. 28. ikegaya h, motani h, saukko p, sato k, akutsu t, sakurada k. bk virus genotype distribution offers information of tracing the geographical origins of unidentified cadaver. forensic sci int. 2007;173:41-6. 29. dugan as, gasparovic ml, tsomaia n, et al. identification of amino acid residues in bk virus vp1 that are critical for viability and growth. j virol. 2007;81:11798-808. 30. pastrana dv, ray u, magaldi tg, schowalter rm, cuburu n, buck cb. bk polyomavirus genotypes represent distinct serotypes with distinct entry tropism. j virol. 2013;87:1010513. 31. tremolada s, akan s, otte j, et al. rare subtypes of bk virus are viable and frequently detected in renal transplant recipients with bk virus-associated nephropathy. virology. 2010;404:312-8. bk virus genotypes among iranian patients-vaezjalali et al. letter to editor re: sancar s, demirci h, guzelsoy m, et. al. fear of circumcision in boys considerably vanishes within ten days of procedure. urol j. 2016 mar 5-2541:(1)13;5. i read the article by sancar and colleagues(1) with interest. the authors mentioned in conclusion that circumcision is recommended for boys six years of age or older. however, they said fear of circumcision does not persist, it considerably vanishes within ten days. firstly, the study did not include younger children than 3 years. if they made inferences about the circumcision age, they should include all ages of boys. we do not know about fear of circumcision for neonatal and first 2 years of age. childhood circumcision is a psychological trauma in all interventions. also, infantile circumcision may effects lesser on behavioral changes than older ages.(2) circumcision recommended in conclusion after 6 years of age or older by authors, but in this age group children need general anesthesia or sedation during circumcision. because of this, they are also exposed to anesthetic materials and their side-effects. some authors advised that circumcision should be performed at the first year of life. (3) according to study in 2012, cüceloğlu and colleagues found that the risk of premature ejaculation is higher in children circumcised after age 7 years.(4) in another study in 2014, armağan and colleagues demonstrated that circumcision in phallic period does not affect psychosexual functions.(5) on the other hand, i want to learn why the authors measured children’s fear scale and venham picture test on the tenth day, why not seventh or fifteenth day. zülfü sertkaya md i̇stanbul medipol university, i̇stanbul, turkey. references 1. sancar s, demirci h, guzelsoy m, et. al. fear of circumcision in boys considerably vanishes within ten days of procedure. urol j. 2016;13:2541-5. 2. goldman r. the psychological impact of circumcision. bju int. 1999;83:93–102. 3. el bcheraoui c, zhang x, cooper cs, rose ce, kilmarx ph, chen rt. rates of adverse events associated with male circumcision in u.s. medical settings, 2001 to 2010. jama pediatr. 2014;168:625–34. 4. cuceloglu ea, hosrik me, ak m, bozkurt a. the effects of age at circumcision on premature ejaculation. turk psikiyatri derg. 2012;23:99–107. 5. armagan a, silay ms, karatag t, et al. circumcision during the phallic period: does it affect the psychosexual functions in adulthood? andrologia. 2014;46:254–7. letter 2735 reply by author we appreciate the comments on our paper entitled “fear of circumcision in boys considerably vanishes within ten days of procedure”.(1) in the study, our goal was to measure fear of circumcision in boys aged 3–11 years just before, immediately after, and on the 10th day after the operation. our study was aimed to determine whether fear disappeared within ten days. we did find that it decreased significantly within ten days. the reason we did not include boys younger than three years old was the validity of the test we used (venham picture test) was obtained for children ≥3 years old.(2) we mentioned reports on pain due to circumcision in our original text and we were able to measure fear in this age group with the instruments we used. we did not conclude in our study: ‘do not circumcise boys before the age of 3 years’, but we only recommended it would be reasonable to perform circumcision for boys at ≥ 6 years, evaluating ‘the fear’ measured. the author claimed that after six years of age anesthesia risk appears. i should express that all of the boys in our study underwent anesthesia before the operation. so it would not add additional anesthetic risk for the boys we treated. in addition to this, it would be addressed in a prospective study which type of anesthesia would be more suitable for different age groups, considering ‘the fear’ in various age groups. the authors commented that premature ejaculation (pe) was more common in older boys and they referenced a study claiming that pe was more common after the age of seven.(3) in the summary section of the study, it was uncertain if pe was more or less common at 7 years of age (there might be a typing error). and there is a study citing the referenced study claiming that in a larger population with more specific scales, they had findings opposing the referenced study.(4) the study also argued that pe was not more commonly seen in adolescent boys compared to younger ones. our study was not on pe. we only studied ‘the fear’ but reports on pe seem to have no opposing conclusions. we still insist on our conclusion that ‘it seems reasonable to recommend circumcision for boys six years of age or older'.(1) and for the last question related to the 10th-day evaluation, this was the day we checked wound healing. it could have been the 7th or 15th day, but we decided to check the participants on the 10th day for wound healing and invited them for examination. meanwhile, we collected the data related to ‘the fear’ of the boys. the scales we used measured situational fear and their fear from circumcision disappeared by the 10th day. references 1. sancar s, demirci h, guzelsoy m, et al. fear of circumcision in boys considerably vanishes within ten days of procedure. urol j. 2016;13:2541-5. 2. venham ll, gaulin-kremer e. a self-report measure of situational anxiety for young children. pediatr dent.1979;1:91-6. 3. cuceloglu ea, hosrik me, ak m, bozkurt a. the effects of age at circumcision on premature ejaculation. turk psikiyatri derg. 2012;23:99–107. 4. armagan a, silay ms, karatag t, et al. circumcision during the phallic period: does it affect the psychosexual functions in adulthood? andrologia. 2014;46:254-7. vol 13 no 03 may-june 2016 2736 urological oncology 182 urology journal vol 6 no 3 summer 2009 value of prostate-specific antigen and prostatespecific antigen density in detection of prostate cancer in an iranian population of men mahyar ghafoori,1 peyman varedi,1 seyed jalil hosseini,2 mojgan asgari,3 madjid shakiba4 introduction: the objective of this study was to evaluate the value of serum prostate-specific antigen (psa) and prostate-specific antigen density (psad) in the diagnosis of prostate cancer. materials and methods: a total of 330 consecutive patients suspected of having prostate cancer due to either abnormal digital rectal examination or elevated serum psa levels underwent transrectal ultrasonography-guided sextant biopsy of the prostate. the psa and psad values were assessed based on the biopsy results. results: one hundred and twenty-one patients (36.7%) had prostate cancer. in this group, the mean psa was 31.60 ± 30.85 ng/ml (range, 1.9 ng/ml to 166.0 ng/ml) and the mean psad was 0.83 ± 1.01 (range, 0.04 ng/ml/ cm3 to 6.38 ng/ml/cm3). in those without prostate cancer the mean psa and psad levels were 13.80 ± 18.72 ng/ml (range, 0.4 ng/ml to 130.0 ng/ ml; p < .001) and 0.24 ± 0.32 (range of 0.01 ng/ml/cm3 to 2.29 ng/ml/ cm3; p < .001). the receiver operating characteristic curve analysis revealed that the discriminating power of serum psa for detecting prostate cancer, as estimated by the area under the curve, was 0.74 while that for psad was 0.81 (p < .001). for the psa range of 3.5 ng/ml to 41 ng/ml (gray zone) the areas under the curve was 0.68 for psa, while it was 0.78 for psad (p < .001). conclusion: the use of psad instead of psa in the diagnosis of prostatic cancer improves the diagnostic accuracy. urol j. 2009;6:182-8. www.uj.unrc.ir keywords: prostate-specific antigen, predictive value of tests, prostatic neoplasms, roc curve 1department of radiology, hazrate-rasoul akram university hospital, iran university of medical sciences, tehran, iran 2department of urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran 3department of pathology, shahid hasheminejad hospital, iran university of medical sciences, tehran, iran 4research unit, medical imaging center, tehran university of medical sciences, tehran, iran corresponding author: mahyar ghafoori, md department of radiology, hazrat rasoul akram university hospital, niyayesh st, shahrara, tehran 1445613131, iran tel: +98 21 6650 9057 fax: +98 21 6651 7118 e-mail: mahyarghafoori@gmail.com received may 2008 accepted july 2009 introduction prostate cancer is one of the most common malignancies among men. increasing mortality rates due to prostate cancer have been observed worldwide.(1,2) this disease usually progresses imperceptibly; for this reason, screening programs aiming at early detection have been developed.(3,4) serum prostatespecific antigen (psa) test is today among the best screening tools available in medicine, as it is recognized as the best marker for early detection of prostate cancer. (5,6) however the lack of specificity is an important limitation of psa test.(7,8) increased psa concentrations are found not only in patients with prostate cancer, but also in patients with benign prostatic diseases.(1) several methods have been proposed to improve the specificity of psa test, including measurement prostate-specific antigen density in prostate cancer—ghafoori et al urology journal vol 6 no 3 summer 2009 183 of psa density (psad), transitional zone psa density, age-specific psa, psa velocity, freetotal psa ratio, and psa isoforms.(8-13) in the early 1990s, benston and colleagues introduced the psad to correct the psa levels for prostate volumes, on the basis of the fact that prostate cancer releases more psa per unit of volume in to the circulation than benign prostate hypertrophy (bph).(14) thus, it is suspected that the psad, as a quotient of total psa and prostate volume, is higher in patients with prostate cancer than in patients with bph.(1,14,15) this study was designed to evaluate the diagnostic value of psad for the detection of prostate cancer. our goal was to determine whether psad was a more accurate predictor of prostate cancer than psa. since there are no studies describing the accuracy of psa and psad in the iranian population, the aim of the present study was also to evaluate the utility of psa and psad for discrimination between benign and malignant prostate disease in iranian men. materials and methods from august 2005 to april 2006, a total of 330 consecutive men were referred to ultrasonography department of hasheminejad hospital, as part of investigations to rule out prostate cancer due to either abnormal findings on digital rectal examination or elevated psa levels. the objectives and methods of the study were explained to all of these men and written informed consent was obtained for participation in the study. the protocol for the research project was approved by the ethics committee of the iran university of medical sciences, which conforms to the provisions of the declaration of helsinki (as revised in edinburgh, 2000). prior to ultrasonography, blood was collected for serum psa assay. the assay was performed using the enzyme immunoassay method (drg instruments gmbh, marburg, germany). in all cases, transrectal ultrasonography was performed to monitor prostate echo texture and to calculate prostate volume using a technus mp machine (esaote, genoa, italy) with an endocavitary multifrequency 3to 9-mhz transducer (model ec123). volume of prostate was calculated using the prolate ellipse formula and the three main diameters of the gland, in which the volume equals 0.52 × (l × w × h), where l is the maximum length obtained from the longitudinal sonography, w is the maximum width obtained from the transaxial view and h is the maximum height obtained transaxially. the psad was calculated as psa (ng/ml) divided by prostate volume (ml). transrectal biopsies of the prostate were taken by an experienced radiologist with a 18-gauge automatic tru-cut biopsy needle (tsk, tokyo, japan) under transrectal ultrasonography guidance. our 12-core-based biopsy strategy was as follows: 2 specimens were obtained from the base of the prostate gland in each side and 2 from the apex of the gland in each side. the middle of the gland was divided into upper-mid and lowermid sections in each side and 4 biopsies were performed from each section, 2 from more medial and 2 from more lateral areas. if any suspicious lesion was detected in the peripheral or central zone, additional biopsies of that area were also performed. in all of the patients with a negative pathology results for prostate cancer who had a psa level higher than 10 ng/ml, systematic biopsy was repeated and the final results were considered in the study. pathologic evaluation of the biopsy specimens were performed by one experienced pathologist. statistical analyses the statistical analyses of the collected data were performed by the spss software (statistical package for the social sciences, version 11.0, spss inc, chicago, illinois, usa). the values of continuous variables were demonstrated as mean ± standard deviation. comparisons of variables (age, prostate volume, psa, and psad) between the patients with and without prostate cancer were done with the t test. for evaluation of the accuracy of psa and psad in detection of cancer cases, we used the receiver-operating characteristics (roc) curve analysis and the areas under the curve (auc) for these two curves were compared. p values less than.05 were considered significant. prostate-specific antigen density in prostate cancer—ghafoori et al 184 urology journal vol 6 no 3 summer 2009 results a total of 330 patients with a mean age of 67.6 ± 9.8 years (range, 43 to 90 years) were studied. the mean serum psa level was 20.40 ± 25.33 ng/ ml (range, 0.4 ng/ml to 166.0 ng/ml) and the mean psad was 0.46 ± 0.72 ng/ml/cm3 (range, 0.01 ng/ml/cm3 to 6.38 ng/ml/cm3). the mean volume of the prostate was 55.0 ± 28.4 ml (range, 12 ml to 220 ml). prostate cancer was diagnosed in 121 patients (36.7%) and benign lesions comprising bph with or without prostatitis, in 209 (63.3%). among patients without prostate cancer, the most common pathology was chronic prostatitis (79 of 209; 37.8%). patients with prostate cancer had a significantly smaller prostate, while they had higher psa and psad levels compared to those without cancer. data on age, prostate volume, psa, and psad of patients with and without prostate cancer are shown in table 1. in the patients without prostate cancer, the maximum serum psa level was 130 ng/ml, and the psa was equal or more than 40 ng/ml in 12 patients (5.3%). among 118 patients who had a prostate volume equal to or less than 40 ml, 61 (51.7%) had cancer, and among 212 patients who had a prostate volume greater than 40 ml, 60 (28.3%) had cancer; the sensitivity and specificity for diagnosis of cancer based on the prostate volume cutoff point of 40 ml were 50.4% and 72.7%, respectively. the roc curve analysis was performed to depict diagnostic accuracy of psa and psad for diagnosis of prostate cancer (figure 1). the discriminating power of serum psa for detecting prostate cancer, as estimated by the auc, was 0.74 (95% confidence interval [ci], 0.68 to 0.80; p < .001), while that was 0.81 (95% ci, 0.76 to 0.86; p < .001) for psad. comparison between the roc curves of psa and psad for the detection of prostate cancer showed that the use of psad improves the auc up to 7% (p < .001). according to these two roc curves, the diagnostic indexes of the psa and psad in different cutoff points are demonstrated in table 2; in the similar sensitivities, the specificity of the psad is better than that of psa. a cutoff point of 0.11 ng/ml/cm3 for psad had a 97.5% sensitivity and a 34% specificity for detecting prostate cancer. concerning the range of 4 ng/ml to 10 ng/ ml for psa level that is traditionally accepted as the gray zone, the psa level of 4 ng/ml had a sensitivity of 93.4% and a specificity of 15.3% and the psa level of 10 ng/ml has a sensitivity of 72% and a specificity of 59% for detection of prostate cancer. the roc curve analysis was performed for patients with serum psa levels of 4 ng/ml to 10 ng/ml (figure 2). the discriminating power of serum psa for figure 1. the receiver operating characteristics curve analyses for depicting the accuracy of prostate-specific antigen (psa) and prostate-specific antigen density (psad) for diagnosis of prostate cancer. participants parameter with prostate cancer without prostate cancer p age, y 68.1 ± 10.7 (43 to 90) 67.3 ± 9.3 (45 to 90) .47 prostate volume, cm3 43.5 ± 17.8 (15 to 92) 61.7 ± 31.1 (12 to 220) < .001 psa, ng/ml 31.60 ± 30.85 (1.9 to 166) 13.80 ± 18.72 (0.4 to 130.0) < .001 psa density, ng/ml/cm3 0.83 ± 1.01 (0.04 to 6.38) 0.24 ± 0.32 (0.01 to 2.29) < .001 table 1. mean age, prostate volume, and prostate-specific antigen (psa) parameters in patients with and without prostate cancer prostate-specific antigen density in prostate cancer—ghafoori et al urology journal vol 6 no 3 summer 2009 185 detecting prostate cancer in this range was 0.61 (95% ci, 0.48 to 0.73; p = .08), while that of psad was 0.76 (95% ci, 0.68 to 0.85; p < .001). the difference between these two aucs was significant (p = .03) a psa level of 3.5 ng/ml with a sensitivity of 95% and a specificity of 12% was considered as the lower cutoff point and a psa level of 41 ng/ ml with a specificity of 95% and a sensitivity of 26%, as the upper cutoff point of our gray zone. figure 2. the receiver operating characteristics curve analyses for depicting the accuracy of prostate-specific antigen (psa) and prostate-specific antigen density (psad) for diagnosis of prostate cancer in patients with a psa level between 4 ng/ml and 10 ng/ml. figure 3. the receiver operating characteristics curve analyses for depicting the accuracy of prostate-specific antigen (psa) and prostate-specific antigen density (psad) for diagnosis of prostate cancer in patients with a psa level between 3.5 ng/ml and 41 ng/ml. cutoff points sensitivity specificity ppv npv plr nlr psa, ng/ml 1.7 100 2.4 33.0 100 1.0 ... 3.0 97.5 9.6 38.4 87.0 1.1 1.8 6.0 89.3 29.2 36.4 60.6 1.0 0.9 8.0 79.3 47.8 46.8 80.0 1.5 2.3 10.0 71.1 61.7 51.8 78.7 1.9 2.1 14.0 62.0 77.5 61.5 77.9 2.6 2.0 25.0 42.1 89.0 68.9 72.7 3.8 1.5 40.0 27.3 94.7 75.0 69.2 5.2 1.3 130.0 1.7 100 100 63.7 … 1.0 psad, ng/ml/cm3 0.04 100 2.4 37.2 100 1.0 … 0.11 97.5 34.0 46.1 96.0 1.5 13.7 0.14 89.3 45.9 48.9 88.1 1.7 4.3 0.21 79.3 65.1 56.8 84.5 2.3 3.1 0.27 71.1 76.6 63.7 82.1 3.0 2.6 0.33 63.6 81.3 66.4 79.4 3.4 2.2 0.60 43.0 94.7 82.5 74.2 8.2 1.7 1.00 28.9 96.7 83.3 70.1 8.6 1.4 2.30 5.7 100 100 64.7 … 1.0 table 2. diagnostic indexes of prostate-specific antigen and prostate-specific antigen density for differentiating prostate cancer* *values in columns 2 to 7 are percents. ppv indicates positive predictive value; npv, negative predictive value; plr, positive likelihood ratio; and nlr, negative likelihood ratio. prostate-specific antigen density in prostate cancer—ghafoori et al 186 urology journal vol 6 no 3 summer 2009 the roc curve analysis for this range (figure 3) showed that the discriminating power of serum psa for detecting prostate cancer was 0.68 (95% ci, 0.61 to 0.75; p < .001), while that of the psad was 0.78 (95% ci, 0.72 to 0.84; p < .001). the difference between these two aucs was significant (p < .001). different ranges of serum psa that are mostly indicated in the literature were considered in the analyses. the frequency of cancer cases detected in different ranges of serum psa is shown in table 3. it shows that most of the cancers were detected with the psa levels equal or greater than 20 ng/ml, and the least of the cancers were detected with the psa levels less than 4 ng/ml. discussion in our study, statistical analyses showed that there was a significant difference in serum psa and psad levels between the patients with and without prostate cancer. this finding is compatible with previous reports.(3,16) a serum psa threshold of 4 ng/ml is usually an indication for prostate biopsy, and psa levels between 4 ng/ ml and 10 ng/ml, which is considered as gray zone, are shown to have a low sensitivity, but values above 10 ng/ml have a high sensitivity for prostate cancer. the sensitivity even reaches 100% if we consider values higher than 15 ng/ ml.(11,17) in our study, the lower cutoff point of 4 ng/ml for psa had a sensitivity of 93.4% and a specificity of 15.3%. we had 7 patients (2.1%) diagnosed with prostate cancer who had psa levels below 4 ng/ml. this means that if we do not continue following up patients with psa levels less than 4 ng/ml, we will miss some patients with prostate cancer. in addition, we had 85 patients (25.7%) with psa levels equal or greater than 10 ng/ml and 12 (5.3%) with psa levels equal or greater than 40 ng/ml who did not have prostate cancer. the highest recorded level of psa in patients with benign disease was 130 ng/ml. the roc curve analysis of the traditional gray zone showed that the auc for psa was 0.61 (p = .08). in this range, the psad had a larger auc (0.76; p < .001). the roc curve analysis of a gray zone of 3.5 ng/ml to 41 ng/ml showed that the auc for psa is 0.68 (p < .001) that is better than the gray zone of 4 ng/ml to 10 ng/ml. in this range also, the psad provided a better accuracy (p < .001) for diagnosis of prostate cancer. considering the above results, the gray zone of 3.5 ng/ml to 41 ng/ml is better suited for our population than the gray zone of 4 ng/ml to 10 ng/ml. our great dilemma remained in the serum psa range of 3.5 ng/ ml to 41 ng/ml, in which a large portion of our population (79.1%) had both benign and malignant lesions. the roc curve analysis showed that also in this range, the use of psad improves the accuracy up to 10%, which is considerable in practice. in a study on arab men,(11) sheikh and colleagues reported benign disease with the psa levels up to 50 ng/ml. our study and the others from asian countries(18,19) show that bph with prostatitis is a common cause of psa elevation greater than 10 ng/ml that is in contrary to the reports from western countries,(17) where prostate cancer is the most common cause of psa levels greater than 10 ng/ml. in order to eliminate the effect of other diseases such as bph, benston and colleagues introduced psad as a useful tool to increase specificity in the detection of prostate cancer,(14) and many studies have supported this indicator ever since; however, some did not confirm this advantage and reported that psad could not surpass psa.(20,21) table 2 shows that in our study, in all the given sensitivities, the specificity of psad is more than that of psa. for instance, a psad threshold of 0.11 ng/ml/cm3 has a 97.5% sensitivity and a 34% specificity for detecting prostate cancer. the roc curve analysis to depict diagnostic accuracy of psa and psad in prostate psa range total number prostate cancer <4 36 7 (19.4) ≥ 2 and < 4 29 6 (20.7) ≥ 4 and < 10 121 26 (21.5) ≥ 10 173 88 (50.9) ≥ 10 and < 20 78 23 (29.5) ≥ 20 95 65 (68.4) ≥ 2 and < 10 150 32 (21.3) ≥ 2 and < 20 228 55 (24.1) table 3. frequency of prostate cancer cases detected with different ranges of prostate-specific antigen (psa)* *values in parentheses are percents. prostate-specific antigen density in prostate cancer—ghafoori et al urology journal vol 6 no 3 summer 2009 187 cancer showed that the auc for psad is 7% larger than that of psa, which means psad is more accurate than psa in detecting prostate cancer. in a study on 1809 patients,(1) stephan and associates reported a significant difference in age between the patients with prostate cancer and the patients with bph; however, we did not find any significant difference in age between the patients with and without prostate cancer, which is compatible with the study of sheikh and coworkers.(11) we also found out that there was a significant difference in the volume of the prostate between the patients with and without prostate cancer; it means that the patients with prostate cancer have smaller prostates in comparison with patients without prostate cancer.(1) conclusion we conclude that serum psa per se does not have sufficient sensitivity and specificity to be useful in the routine evaluation of patients with prostate disease, and it is not accurate enough to include or exclude patients with prostate cancer. the use of psad, however, increases the accuracy and improves the sensitivity and specificity for detection of cancer. financial support this study was founded by a medical research grant received from the research deputy of iran university of medical sciences, tehran, iran. conflict of interest none declared. references 1. stephan c, stroebel g, heinau m, et al. the ratio of prostate-specific antigen (psa) to prostate volume (psa density) as a parameter to improve the detection of prostate carcinoma in psa values in the range of < 4 ng/ml. cancer. 2005;104:993-1003. 2. pfister c, basuyau jp. current usefulness of free/total psa ratio in the diagnosis of prostate cancer at an early stage. world j urol. 2005;23:236-42. 3. brawer mk. screening for prostate cancer. semin surg oncol. 2000;18:29-36. 4. pelzer ae, tewari a, bektic j, et al. detection rates and biologic significance of prostate cancer with psa less than 4.0 ng/ml: observation and clinical implications from tyrol screening project. urology. 2005;66:1029-33. 5. konstantinos h. prostate cancer in the elderly. int urol nephrol. 2005;37:797-806. 6. kobayashi t, kamoto t, nishizawa k, mitsumori k, ogura k, ide y. prostate-specific antigen (psa) complexed to alpha1-antichymotrypsin improves prostate cancer detection using total psa in japanese patients with total psa levels of 2.0-4.0 ng/ml. bju int. 2005;95:761-5. 7. heijmink sw, van moerkerk h, kiemeney la, witjes ja, frauscher f, barentsz jo. a comparison of the diagnostic performance of systematic versus ultrasound-guided biopsies of prostate cancer. eur radiol. 2006;16:927-38. 8. sozen s, eskicorapci s, kupeli b, et al. complexed prostate specific antigen density is better than the other psa derivatives for detection of prostate cancer in men with total psa between 2.5 and 20 ng/ml: results of a prospective multicenter study. eur urol. 2005;47:302-7. 9. aslan g, irer b, kefi a, celebi i, yorukoglu k, esen a. the value of psa, free-to-total psa ratio and psa density in the prediction of pathologic stage for clinically localized prostate cancer. int urol nephrol. 2005;37:511-4. 10. brassell sa, kao tc, sun l, moul jw. prostatespecific antigen versus prostate-specific antigen density as predictor of tumor volume, margin status, pathologic stage, and biochemical recurrence of prostate cancer. urology. 2005;66:1229-33. 11. sheikh m, al-saeed o, kehinde eo, sinan t, anim jt, ali y. utility of volume adjusted prostate specific antigen density in the diagnosis of prostate cancer in arab men. int urol nephrol. 2005;37:721-6. 12. veneziano s, pavlica p, compagnone g, martorana g. usefulness of the (f/t)/psa density ratio to detect prostate cancer. urol int. 2005;74:13-8. 13. kefi a, irer b, ozdemir i, et al. predictive value of the international prostate symptom score for positive prostate needle biopsy in the lowintermediate prostate-specific antigen range. urol int. 2005;75:222-6. 14. benson mc, whang is, pantuck a, et al. prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. j urol. 1992;147:815-6. 15. benson mc, mcmahon dj, cooner wh, olsson ca. an algorithm for prostate cancer detection in a patient population using prostate-specific antigen and prostate-specific antigen density. world j urol. 1993;11:206-13. 16. polascik tj, oesterling je, partin aw. prostate specific antigen: a decade of discovery--what we have learned and where we are going. j urol. 1999;162:293-306. 17. morgan to, jacobsen sj, mccarthy wf, jacobson dj, mcleod dg, moul jw. age-specific reference ranges for prostate-specific antigen in black men. n engl j med. 1996;335:304-10. prostate-specific antigen density in prostate cancer—ghafoori et al 188 urology journal vol 6 no 3 summer 2009 18. kehinde eo, sheikh m, mojimoniyi oa, et al. high serum prostate-specific antigen levels in the absence of prostate cancer in middle-eastern men: the clinician’s dilemma. bju int. 2003;91:618-22. 19. tan yh, tan ky, foo kt. the role of a trial of antibiotics in asymptomatic patients with elevated prostate specific antigen – an asian perspective. bju int. 2000;86(suppl 3):104. 20. dincel c, caskurlu t, tasci ai, cek m, sevin g, fazlioglu a. prospective evaluation of prostate specific antigen (psa), psa density, free-to-total psa ratio and a new formula (prostate malignancy index) for detecting prostate cancer and preventing negative biopsies in patients with normal rectal examinations and intermediate psa levels. int urol nephrol. 1999;31:497-509. 21. ohori m, dunn jk, scardino pt. is prostate-specific antigen density more useful than prostate-specific antigen levels in the diagnosis of prostate cancer? urology. 1995;46:666-71. 1530 | same session transureteral lithotripsy and laparoscopy: a case of ureteral stone with abdominal forgotten gauze after four years seyyed habibollah mousavi bahar, adel eslami corresponding author: adel eslami, md urology and nephrology research center, hamedan university of medical science, hamedan, iran. tel: +98 9125153705 fax: +98 8118237568 e-mail: adeleslami@yahoo.com urology and nephrology research center, shaheed beheshti hospital, hamedan university of medical sciences, hamedan, iran. video introduction forgottenorretainedsurgicalgauzeorpadintheabdominalorpelviccavityafteranoperationisnamedgossypiboma.theothersynonymsforgossypibomaaretexti-loma,cottonoid,gauzomaandmuslinoma.(1,2)removalofsurgicalgauzesorinstrumentsbylaparoscopicsurgeryhasalreadybeendoneandreported.(3-7) herein, we present a caseofabdominalgossypibomafouryearsafterhysterectomy.weperformedlaparoscopyas the surgical option. keywords:laparoscopy;methods;lithotripsy;ureteralcalculi;surgery;treatmentoutcome; abdomen;surgicalsponge;foreignbodies. case report a53-years-oldwomanpresentedwithacuterightrenalcolic.aftermedicationandpain mitigation,radiologicinvestigationsweredone.a10-mmstoneintherightdistalureter video 1531vol. 11 | no. 02 | marchapril 2014 |u r o lo g y j o u r n a l same session tul and laparoscopy | mousavi bahar et al andaforgottensurgicalgauzeintheleftsideofthepelvis wereobservedonkidney-ureter-bladder(kub)x-rayand confirmedbyintravenousurography(ivu)andcomputed tomography (ct) scan.the size of foreign body on ct scanwasmeasured5×3.5cmwhichhasbeenencircledby thesmallintestineandthecolon.transureterallithotripsy (tul)andlaparoscopywerescheduled. surgical technique undergeneralanesthesiaandlithotomypositiontulwas performedandcalculusparticleswereremoved.thereafter laparoscopywassettledinsupinepositionwithone12-mm infra-umbilicalportandtwo5-mmportsintheleftandright lowerquadrantsandthegauzewasseparatedfromthesurroundingtissuesandbroughtoutfromtheabdomenbyan endo-catchbag.thepatientwasdischargedonthefourth postoperativeday. discussion forgettingorleavinggauzesorinstrumentsinthebodycavitiesafteranyoperationismerelyiatrogenicandconsidered as malpractice.(1,8,9) gawande and colleagues studied 61 patients.theyreportedthepresenceofsurgicalspongein 69%ofcases.(10)rodrigues and colleagues described a case ofintra-abdominalforgottenribbonmalleableretractor(33 ×5cm)since14yearsago. theincidenceofgossypibomawasestimatedfrom1:8801 to1:18760ofsurgeriesbyandcolleagues.(10)severalrisk factorshavebeenreportedforleavingspongeandinstrumentsinoperationfield,includinganemergencyoperation andlongdurationofoperation.(2,10,11)somegossypibomas aresymptomaticandtheothersareasymptomatic.(3) in any case,itisrecommendedtoberemovedsurgicallyorlaparoscopically.(11) acaseof laparoscopicdiagnosisandremovalofsponge 14daysaftersurgerywasreportedalsobysinghandcolleagues,(3) in the meanwhile olivier and devriendt describedacaseoflaparoscopicremovalofagauzewhich hadbeenforgottenintheabdomenofapatientaslongas 22 years.(5) ourcase,presentedwithrenalcolicandtheretainedgauze inherabdomenwasdetectedaccidentally.afterradiologic studies,weremovedtheureteralstoneandforgottengauze inthesamesessionanesthesia,andaccomplishedbothsurgeries endoscopically. conclusion according to our experience and other reports, it seems laparoscopicsurgerycanbeappropriateoptionforremoval offorgottenpadsorinstruments,andcanbeperformedin early or delayed diagnosed cases. conflict of interest none declared. references 1. cheng tc, chou as, jeng cm, chang py, lee cc. computed tomography findings of gossypiboma. j chin med assoc. 2007;70:565-9. 2. bani-hani ke, gharaibeh ka, yaghan rj. retained surgical sponges (gossypiboma). asian j surg. 2005;28:109-15. 3. singh r, mathur rk, patidar s, tapkire r. gossypiboma: its laparoscopic diagnosis and removal. surg laparosc endosc percutan tech. 2004;14:304-5. 4. sharifiaghdas f, mohammad ali beigi f, abdi h. laparoscopic removal of a migrated intrauterine device. urol j. 2007;4:177-9. 5. olivier f, devriendt d. laparoscopic removal of a chronically retained gauze. acta chir belg. 2003;103:108-9. 6. rodrigues d, perez ne, hammer pm, webber jd. laparoscopic removal of a retained intra-abdominal ribbon malleable retractor after 14 years. j laparoendosc adv surg tech a. 2006;16:369-71. 7. ibrahim im. retained surgical sponge. surg endosc. 1995;9:709-10. 8. sharma d, pratap a, tandon a, shukla rc, shukla vk. unconsidered cause of bowel obstruction-gossypiboma. can j surg. 2008;51:e34-5. 9. szentmariay if, laszik a, sotonyi p. sudden suffocation by surgical sponge retained after a 23-year-old thoracic surgery. am j forensic med pathol. 2004;25:324-6. 10. gawande aa, studdert dm, orav ej, brennan ta, zinner mj. risk factors for retained instruments and sponges after surgery. n engl j med. 2003;348:229-35. 11. erdil a, kilciler g, ates y, et al. transgastric migration of retained intraabdominal surgical sponge: gossypiboma in the bulbus. intern med. 2008;47:613-5. sexual dysfunction and andrology diagnostic value of plasma pentraxin3level for diagnosis of erectile dysfunction ali erhan eren, ahmet reşit ersay, emrah demirci, cabir alan*, gökhan basturk purpose: erectile dysfunction (ed) is a sexual dysfunction described as the inability to develop or maintain an erection of the penis adequate for sexual intercourse, and its prevalence increases with age. seen as a common sexual disorder worldwide, organic causes are the underlying reason for 80 percent of ed cases, with the most characteristic pathology responsible for organic ed being atherosclerosis. this study investigates the diagnostic value of plasma ptx-3 levels in arterial ed. materials and methods: this study included a total of 45 patients who were admitted to the urology and cardiology outpatient clinics of the medical faculty of canakkale onsekiz mart university (comu) and consented to participate in this study. patients were categorized into three equal groups in number: (1) patients with ed diagnosed with coronary artery disease (cad) (15 patients in total); (2) patients with ed not having coronary artery disease or any other equivalent diseases (diabetes mellitus, hypertension and hyperlipidemia) (15 patients in total); and (3) ordinary patients with no ed (15 patients in total). an interview was conducted at the andrology polyclinic with each patient in order to ascertain detailed information on their medical and sexual history and on demographic characteristics. all patients were also administered the international index of erectile function (iief) questionnaire. result: the findings from this study investigating the diagnostic value of plasma ptx-3 levels in ed were statistically significant for two comparisons: the differences between the peripheral blood and cavernous blood values of the patient groups (group 1 and 2) and the control group (group 3), and the differences between the peripheral blood and cavernous blood values of group 2 (patients with ed who do not have cad) and the control group (group 3). conclusion: as ptx-3 is more specific than the formerly recognized biochemical markers in endothelial dysfunction, it can be used in the diagnosis of vascular originated ed. keywords: atherosclerosis; coronary artery disease; erectile dysfunction; pentraxin-3 (ptx-3); sexual function. introduction erectile dysfunction (ed) is a sexual disorder in-volving the inability to have an erection for the purpose of engaging in sexual intercourse and/or the inability to maintain an erection for the same purpose(1,2). ed increases with age and is a widespread health problem throughout the world(3). the etiology of ed includes organic (vascular, neurogenic, hormonal, cavernosal) and psychological reasons(1,4,5). organic causes are responsible for approximately 80% of ed cases, and among these causes, atherosclerotic disease of the penile arteries ranks first(6). in studies conducted over the last twenty years, disorders of endothelial functions have been shown to be the main cause behind the development of complications related to atherosclerotic plaques(7,8). smoking, hypertension (ht), diabetes mellitus (dm), hypercholesterolemia, age, obesity and sedentary lifestyle are the biggest risk factors for ed and also serve as common risk factors associated with atherosclerosis(9,10). for this reason, ed and vascular diseases are believed to be related with each other at the endothelium level(11). as a result of endothelial dysfunction, endothelial nitric oxide (no) decreases, and decreased no activity plays an impordepartment of urology, canakkale onsekiz mart university hospital, kepez, canakkale 17000, turkey. *correspondence: department of urology, canakkale onsekiz mart university hospital, kepez, canakkale 17000, turkey. tel: +90 5052658651. e-mail: cabir1@yahoo.com. received june 2017 & accepted november 2017 tant role in the pathogenesis of ed(12). ed and atherosclerosis thereby originate as a result of endothelial dysfunction(13). the studies conducted in recent years have sought to secure early detection of the endothelial dysfunction, which results in atherosclerosis. one of the best known markers used for this purpose are acute phase proteins. accumulation of c-reactive protein (crp) has been detected within atherosclerotic lesions and has been shown to be correlated with an increase in cardiovascular diseases, in both healthy and high risk individuals. crp belongs to the pentraxin family of proteins, whose members have a characteristic pentameric structure(14,15,16). crp is synthesized in the liver as a response to the inflammatory process, and it functions as a non-specific marker of inflammation(17,18). consequently, pentraxin-3 (ptx-3) has been commonly studied recently as a new marker. ptx-3, the foremost representative member of the long pentraxin group of the pentraxin family, is synthesized in endothelial cells, fibroblasts and smooth muscle cells. these cells, which are sources of pentraxin, are structures that have a direct role in atherosclerosis and are therefore thought to be a more specific marker for the development of atherosclerosis(17,18). vol 15 no 04 july-august 2018 199 in this study, the importance and role of ptx-3 level in the diagnosis of arterial ed has been investigated. in the literature review, there were no studies found that used the level of ptx-3 to aid in the diagnosis of ed. this study, therefore, is the first of its kind on this subject. materials and methods study population a total of 45 patients, who had presented to urology and cardiology outpatient clinics of comu faculty of medicine between 2013 and 2014, were included in this study. inclusion and exclusion criteria patients were divided into three groups, with group 1 composed of patients with ed who had been diagnosed with coronary artery disease, group 2 composed of patients with ed who had neither coronary artery disease nor equivalent diseases (dm, ht, hyperlipidemia), and group 3 composed of normal patients, who had no ed. the patients were selected from among those who had presented to urology and cardiology outpatient clinics during the dates indicated above. to give a clearer picture of the participants, group 1 included patients diagnosed with cad and ed who were receiving routine follow-up care at the cardiology outpatient clinic; group 2 included patients with ed, but for whom tests administered for diagnosis of cad were shown to be negative; and group 3 included patients with no ed who were presenting to the urology outpatient clinic. procedures a coronary angiography was performed on patients with anginal chest pain complaints and high risk of apparent ischemia and cardiovascular event, as indicated by the stress test results. exclusion criteria for this study included diagnosis of a rheumatologic disease, diagnosis of a malignant disease, previous treatment for ed, acute infectious disease, and chronic renal insufficiency. a detailed examination of the medical and sexual history of the patients who agreed to participate in the research was conducted. additionally, information on the demographic characteristics of the patients was obtained, and all patients were administered the iief questionnaire. peripheral blood samples were obtained from brachial vein with standard vaccinator, while cavernosal blood samples were taken with insulin injector in order to measure their levels of pentraxin-3. the blood samples were centrifuged in 3000 cycles for 10 minutes and then kept at a temperature of -20°c until the day of evaluation. radiologic evaluation; a penile color doppler ultrasonography was performed on the patients in the radiology clinic after they were administered an intracavernosal injection of 1 cc (60 mg) papaverin at intervals of 5, 10, 15 and 20 minutes by taking doppler samples from bilateral cavernosal artery lumina. the cut-off value for maximum peak systolic speed was 35 cm/s. measurements under this value were evaluated as having arterial insufficiency. the patients who were diagnosed with arterial insufficiency were included in the study. ptx-3 measurement; pentraxin-3 levels were measured by using a biocer elisa kit. the testing principle was based on the method of quantitative sandwich enzyme assay. a streptavidincovered plate was incubated with biotinized monoclonal antibodies specific to pentraxin-3. after washing the plate, (the standards were washed at an earlier time), the plasma samples were placed into the holes and ptx-3 was attached to biotinized antibodies. following the washing of the unattached proteins, specific enzyme-linked conjugate was added for ptx-3. next, a rewashing was performed and the substrate was then added. the color changed according to the concentration of ptx-3, and this process was stopped by adding acidic solution. the density of the color was measured in 450 nm. absorbances were in direct proportion to the concentration of ptx-3. a standard curve was drawn with the values table 1. the median age, bmi values and iief scores of the study groups group 1 group 2 group 3 age (yr) 63,8 (55-76) 62,0 (50-71) 52,8 (55-70) bmi ( kg/m2) 28,8 (24,4-34,6) 28,7 (22,4-36,0) 25,2 (22,6-29,1) iief score 5,6 (5-7) 5,7 (5-7) 24,1 (22-25) abbreviations: bmi, body mass index; iief, international index of erectile function. group 1 group 2 p median ± standart median ± standart deviation deviation cavernous 1,8 ± 2,9 1,4 ± 2,3 0,575 peripheric 2,2 ± 3,4 1,5 ± 2,4 0,300 p: mann whitney u test table 2. comparison of ptx-3 values between the patient groups all patients control p median ± standart median ± standart deviation deviation cavernous 1,6 ± 2,6 0,3 ± 0,0 < 0,001 peripheric 1,8 ± 0,0 0,3 ± 0,0 0,009 table 3. comparison of ptx-3 values between the patient groups and the control group p: mann whitney u test figure 1. pentraxin family coronary artery disease and sexual function-eren et al. sexual dysfunction and andrology 200 of absorbance corresponding to the concentrations of ptx-3, whose samples were calculated in nanogram/ ml by using the standard curve. statistical analysis the analyses of collected data were performed with the spss19-version software package. the suitability of the variables to the normal distribution was examined using the shapiro-wilk test. for the presentation of the defining data, the median, standard deviation, minimum values and maximum values were used. the mann-whitney u test was used for non-parametric data in the comparison of variables between groups, while for comparison of the variables of measurement within the groups, the wilcoxon test was used. kruskall-wallis variance analysis was applied for the comparison of the median values of the three groups. p-values below 0.005 were accepted as statistically significant. results the median age of all patients participating in the study was 52.3 years. further breaking it down, the median age of the patients in group 1 was 63.8 ± 7.0 (min-max: 55-76), 62.0 ± 7.1 (min-max: 50-71) in group 2, and 52.8 ± 2.4 (min-max: 55-70) years in group 3 (control group). in all patients (group 1 and group 2), arterial ed was confirmed with penile doppler ultrasonography and a psw < 35cm/s. the iief-5 test was between 5-7 for all the patients, meaning that they had severe ed, while for the control group, iief-5 was between 22-25, indicating that there was no ed (table 1). the bmi of the patients in group 1 was 28.8 ± 2.6 (min-max: 24.4-34.6), 28.7 ± 3.3 (min-max: 22.4-36) in group 2, and 27.2 ± 1.3 (min-max:23.6-29.1) in the control group (table 2). when the patients were evaluated in terms of ptx-3, there was statistically significant difference between the ptx-3 values in the cavernous and peripheral blood samples of the patients in group 1 and in group 2 (p < .05) (table 3). in comparing the ptx-3 values in the cavernous and peripheral blood samples of the patient groups to those in the patients of the control group, the values in the former were significantly higher statistically (p < .05) (table 4). in group 1, the ptx-3 value in cavernous and peripheral blood samples was higher than that of the patients in the control group and a statistically significant difference was detected (p = .05). in group 2, the ptx-3 value in cavernous and peripheral blood samples was significantly higher statistically than that of the patients in the control group (p < .05) (table 5). in comparing the patients in group 1 to those in group 2 in terms of the values of ptx-3 in cavernous and peripheral blood samples, there was no significant difference (p = 1.000) (table 6,7). lastly, when the values of ptx-3 were compared according to bmi, there was no significant difference in the cavernous and peripheral blood samples between normal weight patients and obese patients (p > .05) (table 8). discussion vasculogenic, neurogenic, anatomic, hormonal, psychologic and drug-related factors play a role in the pathophysiology of ed(19). although a dysfunction in any one of these factors suffices for the occurrence of ed, the event is generally multifactorial. changes in the blood flow of the penis in vasculogenic ed cause cavernosal artery insufficiency, while changes in backflow cause corporal veno-occlusive problems. in both situations, the endothelium and the endothelium-derived mediators, which function actively in penile vascularisation, play the basic role. as a result, despite the patient’s libido being normal, they are either unable to have an erection or to maintain one. atherosclerosis and atherosclerotic plaques are the main factors responsible for the development of complications in disorders of endothelium functions. ed and vascular diseases are therefore related with each other at the endothelium level. considering that the endothelial structure is located throughout the entirety of the body, studies focusing on this subject have aimed to provide early detection of this process. for this purpose, pentraxin-3 (ptx-3), which is a member of a new pentraxin family of proteins, has been examined. ptx-3 is the prototypical member of the long pentraxins of the pentraxin family, which also includes crp (figure1)(20,21). in the vascular endothelium cells, group 2 control p median ± standart median ± standart deviation deviation cavernous 1,4 ± 2,3 0,3 ± 0,0 < 0,001 peripheric 1,5 ± 2,4 0,3 ± 0,0 0,001 p: mann whitney u test table 4. comparison of ptx-3 values between the patients having ed but no cad and the control group cavernous peripheric p median ± standart median ± standart deviation deviation group 1 1,8 ± 2,9 2,2 ± 3,4 1,000 table 5. comparison of ptx-3 values in cavernous and peripheric blood samples of group 1 cavernous peripheric p group 2 median ± standart median ± standart deviation deviation 1,4 ± 2,3 1,5 ± 2,4 0,061 table 6. comparison of ptx-3 values in cavernous and peripheric blood samples of group 2 normal obese median ± standart median ± standart p deviation deviation cavernous 2,1 ± 3,1 0,5 ± 0,2 0,416 peripheric 2,5 ± 0,1 0,4 ± 0,1 0,226 table 7. comparison of ptx-3 values in cavernous and peripheric blood samples between groups of normal and obese patients coronary artery disease and sexual function-eren et al. vol 15 no 04 july-august 2018 201 fibroblasts and smooth muscle cells, ptx-3 is locally synthesized. these cells are structures that have a direct role in atherosclerosis. because ptx-3 is locally synthesized and not effected by a first pass through the liver, it is thought to be more specific than crp.(17,18) suliman et al. asserted that ptx-3 was an independent marker for endothelial dysfunction and peripheral injury(21,22). similarly, inoue et al. suggested that the level of plasma ptx-3 was independent of the risk factors of cardiovascular disease, such as high cholesterol, smoking, hba1c, gender and obesity(23). in the present study, however, there was no association between obesity and the levels of ptx-3. ptx-3 has been investigated more recently in the diagnosis of cad and has begun to be recognized as a more specific marker. for example, ustundag et al. reported that ptx-3 plasma levels had risen in a more specific manner than cardiac troponin values six hours after chest pain(24). additionally, fibrizia et al. suggested that ptx-3 was an important acute phase protein for atherosclerosis in cardiovascular diseases, acute coronary syndrome and peripheral vascular diseases(25). in 2014, gerald et al. reported that ed and coronary artery cad were different clinical appearances of the same disease(26). three groups were formed in the present study: group 1 included patients with cad and ed, group 2 included patients with ed but no cad; and group 3, the control group, included patients who had neither ed nor cad. no difference was found between the cavernosal blood values of ptx-3 and the peripheral blood values of ptx-3 within group 1 and group 2. although no statistical difference was detected in these values for group 1, the p value result of 0.061, being so close to the significant value established in this study, could gain greater significance in new studies conducted with a wider range of groups than that used in the present study, which was conducted with relatively small groups. when the ptx-3 values of the peripheral and cavernosal blood samples taken from group 1 and group 2 were compared with those taken from group 3, the ptx-3 values of both the peripheral and cavernosal blood samples of the group 1 and 2 were statistically found to be significantly high. . this finding was similar to the results obtained in the comparison between the control group (group 3) and the patients who had been diagnosed with cad. the ptx-3 value of both the peripheral and cavernosal blood samples of group 2 patients, those who had only ed but neither cad nor an equivalent of cad, was statistically significantly higher than that of the patients in the control group (group 3), the results of which show that findings derived from cad that had been determined to be significant were relevant for patients with ed. ptx-3 values also rise in peripheral endothelial dysfunction. when group 1 and group 2 were evaluated individually, no significant difference was found between the levels of ptx-3 in cavernosal blood samples and those in peripheral blood samples. conclusions since ptx-3 is more specific than the formerly employed biochemical markers, ptx-3 can be used for the diagnosis of arterial ed patients. given that the results can be further proven with a wider series, ptx-3 may be utilized in routine medical practice prior to applying the penile color doppler ultrasonography, which is a more invasive and relatively more expensive tool. future studies should be improved by involving more groups with different medical conditions, particularly focusing on patients with iief scores lower than those indicating arterial ed. acknowledgement none declared conflict on interest none declared references 1. nih. impotence. jama 1993; 270:83-90. 2. montague dk, barada jh, belker am, et al. clinical guidelines panel on erectile dysfunction: summary report on the treatment of organic erectile dysfunction. the american urological association. j urol 1996;156:200711. 3. laumann eo, paik a, rosen r:sexual dysfunction in the united states: prevelance and predictors. jama 1999; 21: 53744. 4. banet ae, melman a. the epidemiology of erectile dysfunction. urol clin north america 1995; 1995:699-709. 5. seth el, arnold m, george j, christ. a review of erectile dysfunction. new insights and more questions. the j. urology 1993; 149:1246-55. 6. sullivan me, keoghane sr, miller ma. vascular risk factors and erectile dysfunction. bju int 2001; 87:838-45. 7. ross r. atherosclerosis; an inflammatory disease. n engl j med 1999; 340: 115-26. 8. kinlay s, ganz p. role of endothelial dysfunction in coronary artery disease and implications for therapy. am j cardiol 1997; 80: 116. 9. maas r, schwedhelm e, albsmeier j, boger rh. the pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function. vasc med 2002; 7: 21325. 10. ganz p. erectile dysfunction: pathophysiologic mechanisms pointing to underlying cardiovascular disease. am j cardiol 1996; 96(suppl): 8m12m. 11. dayan l, greunwald i, vardi y, jacob g. a table 8. ptx-3 values in cavernous and peripheric blood samples cavernous peripheric median ± standart deviation median ± standart deviation group 1 1,8 ± 2,9 2,2 ± 3,4 group 2 1,4 ± 2,3 1,5 ± 2,4 group 3 0,3 ± 0,0 0,3 ± 0,0 all patients 1,6 ± 2,6 1,8 ± 0,0 normal bmi 2,1 ± 3,1 2,5 ± 0,1 obese 0,5 ± 0,2 0,4 ± 0,1 coronary artery disease and sexual function-eren et al. sexual dysfunction and andrology 202 new clinical method for the assessment of penile endothelial function using the flow mediated dilation with plethysmography technique. j urol 2005; 173:1268-72. 12. sullivan me, thompson cs, dashwood mr, et al. nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease? cardiovasc res 1999; 43:658-65. 13. billups kl. erectile dysfunction as an early sign of cardiovasculsar disease. international journal of impotence research 2005; 17:19 24. 14. garlanda c, bottazzi b, bastone a, mantovani a. pentraxins at the crossroads between innate immunity,inflammation, matrix deposition, and female fertility. annu rev immunol. 2005;23:337–66. 15. steel dm, whitehead as. the ana acute phase reactants: c-reactive protein, serum amyloid p component and serum amyloid a protein. immunol today. 1994; 15: 81–8. 16. bottazzi b, vouret-craviari v, bastone a, de gioia l, matteucci c, peri g, et al. multimer formation and ligand recognition by the long pentraxin ptx3. similarities and differences with the short pentraxins c-reactive protein and serum amyloid p component. j biol chem. 1997; 272: 32817–23. 17. spagnoli lg, bonanno e, sangiorgi g, mauriello a. role of inflammation in atherosclerosis. j nucl med 2007;48:1800– 15. 18. jenny ns, arnold am, kuller lh, tracy rp, psaty rm. in the elderly, interleukin-6 plasma levels and the −174g>c polymorphism are associated with the development of cardiovascular disease. arteriosclerosis, thrombosis, and vascular biology 2002; 22: 2066-71. 19. lewis rw. epidemiology of erectile dysfunction. urol clin north am 2001 may;28(2):209-16 20. saygı s, kırılmaz b, tengiz i̇, önsel türk u, yıldız h, tüzün n, alioğlu e, sönmez tamer g, ercan e. long pentraxin-3 measured at late phase associated with grace risk scores in patients with non-st elevation acute coronary syndrome and coronary stenting 21. suliman me, yilmaz mi, carrero jj, et al. novel links between the long pentraxin 3, endothelial dysfunction, and albuminuria in early and advanced chronic kidney disease. clinical journal of the american society of nephrology. 2008;3:976–85. 22. kunes p, holubcova z, kolackova m, krejsek j. pentraxin 3(ptx 3): an endogenous modulator of the inflammatory response. mediators of inflammation. 2012;2012:920517 23. k. inoue, a. sugiyama, p. c. reid et al., “establishment of a high sensitivity plasma assay for human pentraxin3 as a marker for unstable angina pectoris,” arteriosclerosis, thrombosis, and vascular biology, vol. 27, no. 1, pp. 161–167, 2007. 24. ustündağ m, orak m, güloğlu c, sayhan mb, alyan o, kale e. comparative diagnostic accuracy of serum levels of neutrophil activating peptide-2 and pentraxin-3 versus troponin-i in acute coronary syndrome. anadolu kardiyol derg. 2011;11:588–94 25. bonacina f, baragetti a, catapano al, norata gd. long pentraxin 3: experimental and clinical relevance in cardiovascular diseases. mediators of inflammation. 2013;2013:725102 26. brock g. diagnosing erectile dysfunction could save your patient’s life.canadian urological association journal. 2014;8(7-8 suppl 5):s151-s152. coronary artery disease and sexual function-eren et al. vol 15 no 04 july-august 2018 203 vol 13 no 04 july-august 2016 2788 six years’ experience of laparoscopic varicocelectomy using bipolar electrosurgery and its effect on semen parameters sexual dysfunction and infertility hossein karami*, amin hassanzadehadad, morteza fallahkarkan purpose: to evaluate postoperative results of laparoscopic varicocelectomy using bipolar electrosurgery and analyze semen according to the grade of varicocele after surgery. materials and methods: in a six-year period, 416 men with clinical varicocele and impaired semen parameters or infertility underwent laparoscopic varicocelectomy using bipolar electrosurgery. all patients were assessed for hydrocele and recurrence of varicocele six months and one year after the procedure. semen analyses were obtained before and after the surgery and were compared according to the clinical grade of varicocele. results: seven patients (1.7%) had right side, 391 (94%) had left side and 18 (4.3%) had bilateral varicoceles. varicocele grades i, ii and iii were detected in 113 (27.1%), 232 (55.7%) and 71 (17%) patients respectively. abdominal wall emphysema and pneumoscrotum were developed in 19 (4.5%) and 11 (2.6%) cases. recurrence rate was significantly higher in grade iii varicocele (p < .001). in patients with varicocele grades of i and ii, sperm concentration, motility and morphology significantly improved six months after surgery (p < .05). in patients with grade iii varicocele, only sperm concentration improved (p < .05). sperm motility and morphology did not show any significant change after one year. conclusion: laparoscopic varicocelectomy using bipolar cautery is a safe, feasible and cost-effective technique with few complications. it significantly improves sperm parameters. a follow up program for at least one year after the surgery seems reasonable to detect recurrent cases. the study shows that increase in clinical varicocele grade can cause irreversible deleterious effects on sperm motility and morphology. so, earlier treatment is recommended. keywords: varicocelectomy; bipolar cautery; varicocele; semen analysis introduction the abnormal dilatation of pampiniform venous plexus in the spermatic cord is called varicocele. its prevalence is 12% in the general population and 25% to 40% in infertile men.(1,2) multiple factors play role in male infertility. however, varicocele is the most common finding which is observed in 45-81% of men having secondary infertility.(3,4) the adverse effect of varicocele on male fertility is clearly manifested by testicular atrophy which is generally associated with this condition.(2) using scrotal ultrasound, it has been demonstrated that in men with left varicocele, the left testicular volume is less than the right testicular volume.(5) varicocele is associated with hypogonadism in some infertile men. also, varicocelectomy significantly improves serum testosterone levels.(6) the most common abnormality in the spermiogram of individuals who are suffering from varicocele is decreased sperm motility, which can be observed in 90% of patients.(7) in addition, abnormality in the shape of sperm cells is very common in them. currently no relationship has been found between varicocele grade, pathology of testicles and spermiogram abnormality. whenever clinical varicocele is undetectable and three dilated veins are found in the regular scrotal ultrasound, with at least one vein more than 3 mm in diameter, the patient is known to have subclinical varicocele.(8) urology department, shohadaye tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology ward, shohadaye tajrish hospital, tajrish sq, tehran, iran. postal code: 1989934148. tel: +98 21 22736386. fax: +98 21 22736386. mobile: +98 9121142080. email: karami_hosein@yahoo.com. received january 2016 & accepted august 2016 varicocele is also known as the most surgically correctable cause of male infertility. its repair is the most commonly performed surgical procedure in order to correct male infertility.(9) the standard varicocele surgery is the microscopic sub-inguinal procedure. sub-inguinal refers to the location of the incision.(10) varicocelectomy is cost-effective by itself or in conjunction with in vitro fertilization when compared to other fertility techniques.(11,12) there are several approaches for varicocelectomy. they include retroperitoneal and conventional inguinal open techniques, microsurgical inguinal and subinguinal approaches, laparoscopic varicocelectomy and radiographic embolization.(13,14) the microsurgical varicocelectomy is the standard technique because it is associated with the lowest risk of complications including varicocele recurrence, hydrocele formation and testicular atrophy.(14,15) in the inguinal approach, an incision is made on the groin above and lateral to the ipsilateral pubic tubercle, extending laterally along the skin lines of the inferior abdominal wall. the external oblique fascia is sharply incised to expose the spermatic cord covered with cremasteric fibers. they are incised along with the external spermatic fascia to provide access to vascular structures within. generally, the vas deferens should be identified and preserved along with its artery, vein and lymphatic vessels. venous structures, including the internal spermatic, cremasteric, external spermatic, gubernacular and periarterial veins (venae comitantes) have all been described to be part of the body of varicoceles and should be identified and dissected for ligation. arteries and lymphatic vessels should be clearly identified and preserved to avoid complications.(16) percutaneous embolization of the gonadal vein was originally described three decades ago. nowadays, percutaneous embolization procedures for varicocele include the traditional retrograde occlusion and the more recently described anterograde technique.(17) the recurrence/persistence rates, the complication rates, duration of procedure, the costs and clinical outcomes on the various treatment modalities vary. well-designed, large-scale comparatives studies evaluating the results of the various varicocele treatment options remain scarce in the recent literature.(14,18) previous studies have shown abnormalities in sperm count, motility, and morphology in varicocele patients. still a significant improvement has been seen in these parameters after surgical correction. this study evaluated the postoperative outcomes of laparoscopic varicocelectomy during a six-year period. the results of semen analyses were also compared before and after the surgery for all patients. materials and methods between march 2006 and may 2012, laparoscopic varicocelectomy was performed on 416 men diagnosed with varicocele. patients were older than 18 years and were included in the study by consecutive sampling. varicocele diagnosis was confirmed by doppler ultrasound. patients were infertile or had impaired semen parameters. all other patients without infertility were treated but were not enrolled in this study (figure 1). varicocele was defined on doppler ultrasound as spermatic venous dilatation of more than 3 mm with venous reflux. exclusion criteria were previous abdominal operation for infertility or subfertility due to other causes. in physical examination varicocele was graded according to dubin and ambler’s classification. a basic infertility evaluation including detailed history, physical examination and semen analysis were carried out before treatment. follow up and surgical assessment surgical assessment included the operation duration (from beginning of the operation until skin closure), major intraoperative complications such as vascular or bowel injury, emboli, cardiovascular complications, early and late postoperative complications including subcutaneous emphysema, pneumoscrotum, recurrence and hydrocele formation. patients were discharged from hospital the day after surgery. they were visited one week later to check the wound and look for possible complications. follow up program consisted of physical examination, doppler ultrasound study in suspicious cases of recurrence and semen analysis six months and one year after surgery. semen analysis was performed based on the latest world table 1. late postoperative complication according to the grade of varicocele grade of varicocele no. of recurrences p value number of hydrocele p value first follow up visit grade i 0 .03 6 .09 grade ii 0 4 grade iii 2 6 second follow up visit grade i 1 .001 1 .7 grade ii 1 1 grade iii 6 0 total grade i 1 <.001 7 .2 grade ii 1 5 grade iii 8 6 mean ± sd of sperm mean ± sd of sperm mean ± sd of normal varicocele grade concentration (number/million) motility (%) sperm morphology (%) before first second before first second before first second surgery follow up follow up surgery follow up follow up surgery follow up follow up grade i 21.5 ± 4.1 40.1 ± 4.4 40.3 ± 4.8 35.8 ± 4.3 49.2 ± 4.3 51.3 ± 4.6 40.6 ± 3.6 66.3 ± 3.8 69.5 ± 3.7 p = .01 p = .03 p = .01 grade ii 20.8 ± 4.3 40.5 ± 4.7 41.3 ± 5.1 37.7 ± 4.1 58.9 ± 5.2 59.7 ± 5 40.5 ± 3.3 65.1 ± 3.7 67.9 ± 3.8 p = .01 p = .01 p = .01 grade iii 14.7 ± 5.7 37.7 ± 6.4 39.4 ± 6.8 31.2 ± 4 37.7 ± 4.2 37.9 ± 4.2 38.3 ± 3.4 41.1 ± 3.3 4.8 ± 3.4 p < .01 p = .1 p = .3 note: p-value compares semen analysis before the surgery and at the second visit. there was no significant difference in sperm parameters between first and second follow up visits table 2. sperm parameters before surgery and in the first and second follow up visits laparoscopic varicocelectomy using bipolar electrosurgery-karami et al. sexual dysfunction and infertility 2789 vol 13 no 04 july-august 2016 2790 health organization (who) manual for the examination and processing of human semen. volume, ph, sperm density, morphology and motility were evaluated. normal semen parameters according to the who manual for semen analysis were as follows:(19) volume of semen in adult males: 1.5 ml, sperm concentration: 15×106, sperm morphology (normal forms): 4%, progressive and non-progressive motility: 40%, and progressive: 32%. surgical technique general anesthesia with endotracheal intubation was used in all patients. after placing the patient in a modest trendelenburg position, a 10 mm trocar was inserted using open access technique through an above umbilical incision. the abdomen was insufflated up to 12 mmhg with co 2 . a zero degree laparoscope was inserted. under laparoscopic vision, two 5 mm operating trocars were placed in the lower right and left quadrants of the abdominal wall along the lateral border of each abdominal rectus muscle. a retroperitoneal incision was made in the lateral aspect from a point 3 cm superior to the internal inguinal ring along the testicular vessels to expose them. the accompanying lymphatics and testicular artery were preserved from the spermatic veins. the veins were coagulated by a bipolar electrosurgery apparatus. each coagulated vein was transected by endoscissors. when the procedure was completed, the intraperitoneal pressure was reduced to 5 mmhg to check the surgical site and ensure absence of bleeding. the trocars were subsequently removed. fascia at the supraumbilical incision was sutured and the 5 mm incisions were closed by simple skin sutures. statistical analysis all data were analyzed by the statistical package for social sciences (spss) software version 16.0 (chicago, il, usa). the kolmogorov-smirnov test was used to determine whether the study population followed the normal distribution. all the nonparametric comparisons were performed by chi-square and mann-whitney u tests. the difference between preand post-operative seminal data was analyzed using a paired wilcoxon signed rank test. the mean of quantitative variables was reported with mean ± standard deviation. p values less than .05 were considered statistically significant. results a number of 416 men with mean age of 24.7 ± 9.2 years entered the study. there were seven cases (1.7%) of right sided, 391 cases (94%) of left sided and 18 cases (4.32%) of bilateral varicocele. 32 (7.6%) men had a history of inguinal varicocelectomy and recurrence after surgery. forty five men were infertile (10.8%). varicocele grades i, ii and iii were detected in 113 (27.1%), 232 (55.7%) and 71 (17%) men, respectively. the means ± sd of operation duration were 25.7 ± 16.5 and 37.1 ± 27.8 minutes for unilateral and bilateral cases, respectively. the study population had no normal distribution (p > .05). there were no major intraoperative complications. abdominal wall emphysema and pneumoscrotum were observed in 19 (4.5%) and 11 (2.6%) cases, respectively. at the first visit one week after the surgery, subcutaneous emphysema and pneumoscrotum resolved in all patients. however, three men (0.7%) still complained of scrotal pain and swelling. epididymitis was diagnosed with physical examination to check for enlarged lymph nodes in the groin and an enlarged testicle on the affected side. doppler ultrasound confirmed the diagnosis. these patients were treated by antibiotic and anti-inflammatory drugs without any further complications. the total number of hydrocele formations and recurrences after one year were 18 (4.3%) and 10 (2.4%), respectively. six months after surgery 21 (5%) patients were lost at the first follow up visit. hydrocele was detected in 16 patients (3.8%) and recurrence occurred in two cases (0.4%). in the second follow up visit, 24 patients (5.7%) were lost. hydrocele and recurrence were diagnosed in two (0.4%) and eight (1.9%) patients, respectively (table 1). sperm concentration, motility and morphology improved six months after surgery in patients with varicocele grades of i and ii. however, in grade iii varicocele only sperm concentration improved while motility and morphology did not change significantly. no significant improvement was detected in sperm parameters from the first to the second follow up visits (table 2). the increase in clinical varicocele grade caused irreversible deteriorational effects on sperm motility and morphology. at follow up visits patients were examined and doppler ultrasound was requested to confirm varicocele in cases which were suspicious of recurrence. both recurrent cases in the first follow up visit (six months after the surgery) had grade iii varicocele preoperatively. at the second follow up visit (one year after surgery) eight cases of recurrence were detected. all these cases had preoperative grade iii varicocele. recurrence rate was higher in varicocele grade iii compared to other grades (p < .001). discussion laparoscopic varicocelectomy is equally effective as open varicocelectomy.(20) laparoscopy has been shown to have the same intraoperative safety, shorter hospital stay and less postoperative complications.(21) it provides better magnification which is more helpful to preserve the testicular artery.(22) there are two main approaches for laparoscopic varicocelectomy. one is mass ligation of spermatic vessels and the other is just ligation of the veins and sparing lymphatics and testicular artery. mass ligation can be a safe approach with significantfigure1. flow diagram of the study laparoscopic varicocelectomy using bipolar electrosurgery-karami et al. ly lower recurrence and higher successful rates.(22) on the other hand, this technique is associated with more post-operative discomfort(23) and hydrocele formation.(24) the risk of hydrocele formation after mass ligation of spermatic vessels ranges from 3% to 25%. (22,25) as the laparoscopic approach may facilitate the identification of lymphatics, it is believed that sparing the lymphatics during the procedure may reduce the incidence of post-operative hydrocele.(26) misseri and colleagues observed very good outcomes after lymphatic sparing varicocelectomy.(27) they compared post-operative hydrocele formation of the two techniques and reported a significantly higher rate of hydrocele formation after mass ligation. kocvara and colleagues reported 17.9% hydrocele formation with conventional laparoscopic varicocelectomy and 1.9% after lymphatic vessel preservation.(28) in our study we performed the artery and lymphatic sparing approach and encountered 18 cases (4.3%) of hydrocele formation during one year follow up after surgery. it has been hypothesized by infertility experts that varicoceles are associated with progressive deleterious effects on testicular function.(29,30) barry and colleagues randomized 80 patients into two groups for laparoscopic and open inguinal varicocelectomies and compared their results.(26) they found a lower rate of recurrence with the laparoscopic approach (two versus seven). they also observed that recurrence would increase progressively with the increase of varicocele grade. among nine patients with recurrence, six had varicocele grade iii, preoperatively. in our series we used bipolar cautery to coagulate spermatic veins. standard bipolar diathermy technology may have some disadvantages in sticking and thermal spread.(31-33) simforoosh and colleagues compared laparoscopic varicocelectomy using bipolar cautery to open high ligation approach for 100 men who were randomly allocated into two groups.(33) they observed that using bipolar cautery is a safe technique and can reduce costs compared to endoclips. méndez-gallart and colleagues used ligasure technology to ligate spermatic veins for 63 men. they reported that using this system allows the surgeon to improve coagulation with minimal thermal spread to the surrounding tissues. still, the initial cost and learning curve may be its disadvantage.(34) semen analysis six months after surgery showed a significant improvement in concentration and quality (motility and morphology) of sperms in varicocele grades i and ii. for varicocele grade iii, only concentration improved and semen quality did not show any significant changes. no significant improvement was observed at the second visit in sperm concentration and quality. kang and colleagues compared testicular artery and lymphatic preservation versus complete testicular vessel ligation in 80 patients. they found significant improvement in sperm parameters after both procedures.(35) al-kandari and colleagues compared postoperative results of semen analysis of 120 men who were randomized into three groups for laparoscopic, open inguinal and subinguinal microscopic varicocelectomies.(36) no significant improvement was observed in sperm morphology in any group. our study with the advantage of one year follow up for most patients showed a significant improvement in sperm parameters after laparoscopic varicocelectomy. testicular artery, lymphatic preserving approach and using bipolar cautery were associated with a low rate of post-operative complications. the lack of data for pregnancy rate was a shortcoming of our study. besides measuring testicular size, studying the rate of catch up growth can be more informative. conclusion many approaches have been proposed for varicocele management. however, recent evidence supports the premise that the microsurgical technique is the standard technique. although in a number of studies, it has been shown that microsurgical varicocelectomy is superior to non-microsurgical procedures with respect to the development of postoperative complications such as hydrocele or recurrence. in this study we showed that laparoscopic varicocelectomy using bipolar electrosurgery is a safe and feasible technique, with a low rate of postoperative complications that can be an alternative for the standard microsurgical varicocelectomy. it significantly improves sperm parameters. a follow up program for at least one year after the surgery seems reasonable to detect recurrent cases. this study reveals that increase in clinical varicocele grade can cause irreversible deleterious effects on sperm motility and morphology, leading to a higher probability of recurrence after laparoscopic varicocelectomy. thus, earlier treatment seems reasonable when the disease has not progressed much. acknowledgement the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. references 1. redmon jb, carey p, pryor jl. varicocele-the most common cause of male factor infertility? hum reprod update. 2002;8:53-8. 2. [no authorlisted]. the influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. world health organization. fertil steril. 1992;57:1289-93. 3. cocuzza m, cocuzza ma, bragais fmp, agarwal a. the role of varicocele repair in the new era of assisted reproductive technology. clinics. 2008;63:395-404. 4. agarwal a, deepinder f, cocuzza m, et al. efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach. urology. 2007;70:532-8. 5. zini a, buckspan m, berardinucci d, jarvi k. the influence of clinical and subclinical varicocele on testicular volume. fertil steril. 1997;68:671-4. 6. zohdy w, ghazi s, arafa m. impact of varicocelectomy on gonadal and erectile functions in men with hypogonadism and infertility. j sex med. 2011;8:885-93. 7. twiss c, grasso m. abdominal pain associated with an intra-abdominal gonad in an adult. rev urol. 2000;2:178-81. laparoscopic varicocelectomy using bipolar electrosurgery-karami et al. sexual dysfunction and infertility 2791 vol 13 no 04 july-august 2016 2792 8. zini a, buckspan m, berardinucci d, jarvi k. loss of left testicular volume in men with clinical left varicocele: correlation with grade of varicocele. arch androl. 1998;41:37-41. 9. abdel-maguid a-f, othman i. microsurgical and nonmagnified subinguinal varicocelectomy for infertile men: a comparative study. fertility and sterility. 2010;94:2600-3. 10. khera m, lipshultz li. evolving approach to the varicocele. urol clin north am. 2008;35:183-9, viii. 11. diegidio p, jhaveri jk, ghannam s, pinkhasov r, shabsigh r, fisch h. review of current varicocelectomy techniques and their outcomes. bju int. 2011;108:1157-72. 12. lee hs, seo jt. advances in surgical treatment of male infertility. world j mens health. 2012;30:108-13. 13. murray rr, jr., mitchell se, kadir s, et al. comparison of recurrent varicocele anatomy following surgery and percutaneous balloon occlusion. j urol. 1986;135:286-9. 14. cayan s, kadioglu tc, tefekli a, kadioglu a, tellaloglu s. comparison of results and complications of high ligation surgery and microsurgical high inguinal varicocelectomy in the treatment of varicocele. urology. 2000;55:750-4. 15. grober ed, o'brien j, jarvi ka, zini a. preservation of testicular arteries during subinguinal microsurgical varicocelectomy: clinical considerations. j androl. 2004;25:7403. 16. chan p. management options of varicoceles. indian j urol. 2011;27:65-73. 17. lima ss, castro mp, costa of. a new method for the treatment of varicocele. andrologia. 1978;10:103-6. 18. al-said s, al-naimi a, al-ansari a, et al. varicocelectomy for male infertility: a comparative study of open, laparoscopic and microsurgical approaches. j urol. 2008;180:266-70. 19. who laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 5 ed. cambridge, uk: cambridge university press; 2010. 20. donovan jf, winfield hn. laparoscopic varix ligation. j urol. 1992;147:77-81. 21. abdulmaaboud mr, shokeir aa, farage y, abd el-rahman a, el-rakhawy mm, mutabagani h. treatment of varicocele: a comparative study of conventional open surgery, percutaneous retrograde sclerotherapy, and laparoscopy. urology. 1998;52:294-300. 22. esposito c, monguzzi gl, gonzalez-sabin ma, et al. laparoscopic treatment of pediatric varicocele: a multicenter study of the italian society of video surgery in infancy. j urol. 2000;163:1944-6. 23. nyirady p, kiss a, pirot l, et al. evaluation of 100 laparoscopic varicocele operations with preservation of testicular artery and ligation of collateral vein in children and adolescents. eur urol. 2002;42:594-7. 24. marte a, sabatino md, borrelli m, et al. ligasure vessel sealing system in laparoscopic palomo varicocele ligation in children and adolescents. j laparoendosc adv surg tech a. 2007;17:272-5. 25. podkamenev vv, stalmakhovich vn, urkov ps, solovjev aa, iljin vp. laparoscopic surgery for pediatric varicoceles: randomized controlled trial. j pediatr surg. 2002;37:727-9. 26. barry j, nady m, ragab g, el-khalaf b, abdallah a, imich am. five mm laparoscopic varicocelectomy versus conventional varicocele ligation in young men with symptomatic varicocele: a randomized clinical study. african journal of urology. 2012;18:12-5. 27. misseri r, gershbein ab, horowitz m, glassberg ki. the adolescent varicocele. ii: the incidence of hydrocele and delayed recurrent varicocele after varicocelectomy in a long-term follow-up. bju int. 2001;87:494-8. 28. kocvara r, dvoracek j, sedlacek j, dite z, novak k. lymphatic sparing laparoscopic varicocelectomy: a microsurgical repair. j urol. 2005;173:1751-4. 29. cozzolino dj, lipshultz li. varicocele as a progressive lesion: positive effect of varicocele repair. hum reprod update. 2001;7:55-8. 30. witt ma, lipshultz li. varicocele: a progressive or static lesion? urology. 1993;42:541-3. 31. guerrieri m, crosta f, de sanctis a, baldarelli m, lezoche g, campagnacci r. use of the electrothermal bipolar vessel system (ebvs) in laparoscopic adrenalectomy: a prospective study. surg endosc. 2008;22:141-5. 32. harold kl, pollinger h, matthews bd, kercher kw, sing rf, heniford bt. comparison of ultrasonic energy, bipolar thermal energy, and vascular clips for the hemostasis of small-, medium-, and largesized arteries. surg endosc. 2003;17:1228-30. 33. simforoosh n, ziaee sa, behjati s, beygi fm, arianpoor a, abdi h. laparoscopic management of varicocele using bipolar cautery versus open high ligation technique: a randomized, clinical trial. j laparoendosc adv surg tech a. 2007;17:743-7. 34. mendez-gallart r, bautista-casasnovas a, estevez-martinez e, rodriguez-barca p. bipolar electrothermal vessel sealing system and 5-mm 2 expandable trocar approach in pediatric laparoscopic varicocelectomy: a successful time-effective technical refinement. surg laparosc endosc percutan tech. 2011;21:e256-9. laparoscopic varicocelectomy using bipolar electrosurgery-karami et al. 35. kang dh, lee jy, chung jh, et al. laparoendoscopic single site varicocele ligation: comparison of testicular artery and lymphatic preservation versus complete testicular vessel ligation. j urol. 2013;189:2439. 36. al-kandari am, shabaan h, ibrahim hm, elshebiny yh, shokeir aa. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology. 2007;69:417-20. laparoscopic varicocelectomy using bipolar electrosurgery-karami et al. sexual dysfunction and infertility 2793 urological oncology coincidental bladder cuff transitional cell carcinoma in nephroureterectomy specimens: risk factors, prognosis and clinical implementation mohamed mohamed elawdy1* ,yasser osman2, diaa-eldin taha3, samer el-halwagy1, mohsen el-mekresh4 purpose: there is a lack of reporting of the bladder cuff pathology in the literature and ongoing debate regarding the role of bladder cuff excision (bce) in the prognosis in patients with upper tract urothelial carcinoma (utuc). we aimed to know the risk factors, the survival, and the clinical course of such pathology. materials and methods: the study was retrospective, from 1983-2013 on 305 patients who had diagnosed with utuc. patients were managed by radical open/ laparoscopic nephroureterectomy with bladder cuff excision. the tumor was staged using 1997 tnm classification and the 3-tiered who grading system was used for grading. patients who found to have a malignant bladder cuff on the final pathology were further analyzed for the risk factors for such disease and its effect on survivaltheir outcomes. results: 13/ 281 (4.6%) cases were found to have malignant bladder cuff. regarding tumor stage; one case was diagnosed with tis, eight had t1 and four cases had t2 malignant bladder cuff. all cases were with pure ureteric or multifocalcentric tumors, and none had pure pelvicalyceal tumors (p = .001). local recurrence at the surgical site and distant metastasis were significantly higher among patients with malignant bladder cuff (p = .001 and .002 respectively), and the last sustained its significance in multivariate analysis. those patients had a poor prognosis when compared to non-malignant bladder cuff cases (log rank test, p = .001) conclusion: ureteric tumor is the only independent risk factor for malignant bladder cuff at the final pathology and is associated with increased risks for invasive bladder tumor, distant metastasis and poor survival in comparison with non-malignant bladder cuff. in a clinical implementation, bce is considered as a mandatory step in management of ureteric tumors, while it could be omitted in pure and low grade renal pelvis tumors. keywords: urologic neoplasms; kidney pelvis neoplasms; ureteral neoplasms; nephroureterectomy; bladder cuff; bladder cuff excision . introduction upper tact urothelial carcinoma (utuc) arises from the urothelial lining of the urinary tract from the renal calyces to the ureteral orifice. they comprise 10 % of all renal tumors and 5% of all urothelial malignancies(1). while pathological criteria of utuc were mentioned in detail in some series(2,3), there is a lack of reporting on bladder cuff pathology. although krogh et al. reported a 19 % ureteric stump recurrence after conservative resection(4), a recent multi-institutional retrospective analysis of 4,210 patients with renal pelvic utuc, comparing the oncologic outcome between patients who underwent nephroureterectomy (nu) with or without bladder cuff excision (bce), concluded that nu without bce can be considered for patients with renal pelvic utuc with pt1and pt2(5). the lack of reporting of bladder cuff pathology, and the ongoing debate in the literature, compelled us to review 1sohar hospital, ministry of health, sultanate of oman 2urology and nephrology centre, mansoura university, egypt 3faculty of medicine, kafr elsheikh university, egypt 4mafraq hospital, united arab emirates *correspondence: sohar hospital, sohar, sultanate of oman tel: 0096891441050. e-mail address: mmelawdy@gmail.com received july 2017 & accepted december 2017 the final pathology in our series with 305 patients. we aimed to determine the risk factors and how malignant bladder cuff in the final pathology might affect the clinical course and the survival. materials and methods after institutional review board approval, from 1983 to 2013, a retrospective analysis was conducted on 305 patients registered in an electronic database with utuc at the final pathology. all the pathological reports were carefully reviewed for bladder cuff pathology. those who were found to have a malignant bladder cuff in the final pathology were further analyzed for risk factors and their outcomes. preoperative radiologic workup / operative procedures: the pre-operative evaluation included a complete history, physical examination, and standard routine laboratory, as well as radiological investigations (ct and/ or mri). in the majority of patients, cystoscopy & retrograde uretropyelography and/or diagnostic ureterosurological oncology 256 vol 15 no 05 september-october 2018 257 copy were done in separate sessions; any concomitant bladder tumors were resected, and when feasible, upper tract tumors were biopsied. most of the patients were treated by one stage standard radical open nu +bce, but 24 cases were done laparoscopically. renal sparing surgeries (ureterectomy and boari flap / ureteroureterostomy) were done for 15 cases, mostly for solitary functioning renal units. tumor characteristics and pathologic evaluation: surgical specimens were processed according to the standard pathological procedure. the tumor was staged according to the 1997 tnm classification, and the most traditional 3-tiered who grading system was used for pathological grading by different pathologists. postoperative follow-up: in our study, the follow-up was calculated on the analysis from the time of surgery till the time of last follow-up. the postoperative regimen in the first two years included a cystoscopy every three months and contrast-enhanced ct every 6 months. from the third to fifth year, a cystoscopy every 6 months and a ct annually; thereafter, clinical examination, urine analysis and cytology were ordered annually. patients with incidentally discovered malignant bladder cuff were put under strict surveillance and follow up. patients who developed bladder tumors were treated with trans-urethral resection and intra-vesical chemoimmunotherapy. in our protocol, alternating schedule of bcg and epirubicin is given for 6 weeks, and then followed by check cystoscopy. patients with no recurrence were given the same protocol, monthly for nine months. those who were found to have recurrence, were given the 6 weeks protocol again. radical cystectomy was offered to invasive bladder tumor or any recurrence beyond the scope of endoscopic resection. statistical methods data was collected using a spss® version 21, spreadsheet. for continuous data with normal distribution, bladder tcc in nephroureterectomy-elawdy et al. table 1. bivariate analysis of risk factors for coincidental malignant bladder cuff post surgical management of utuc variable malignant bladder cuff, n (%), total number (281) p value no yes gender male 238 (96) 10 ( 4) 0.1 female 30 (90) 3 (10) hx of bladder tumor (pre-operative) no yes 230 (95) 11 (5) 0.9 38 (95) 2 (5) concomitant bladder tumor no yes 199 (96) 7 (4) 0.15 69 (92) 6 (8) side of the tumor right left 120 (96) 5 ( 4) 0.6 148 (95) 8 ( 5) surgical approach open nu lap. nu 244 (95) 13 (5) 0.2 24 (100) site of the tumor kidney (pelvi-calyceal) 120 (100) ureter 102 (96) 4 (4) 0.001 kidney and ureter 46 (84) 9 (16) ureteric tumor no 120 (100) 0.001 yes 148 ( 92) 13 (8) tumor site within the ureter no 120 (100) proximal 38 ( 97) 1 ( 3) 0.001 distal 88 ( 90) 8 (10) multifocal 22 ( 85) 4 (15) presence of cis no 256 (96) 11 (4) 0.07 yes 12 (86) 2 (14) tumor grade grade i tcc 11 (100) -grade ii tcc 168 ( 96) 6 ( 4) 0.2 grade iii tcc 89 (92) 7 ( 8) tumor stage non muscle invasive 172 (96) 7 (4) 0.4 muscle invasive 96 (94) 6 (6) *decimals were removed & percentage was given for rows & a statistically significant (p < .05) with mean + sd were used for expression and median, and range for abnormally-distributed data. for categorical and nominal variables, frequency and percentage were used for expression, and chi-square test was used for analysis. cancer specific survival was estimated using kaplan-meier methods and the event was identified as death from the tumor or diagnosed with metastasis or local recurrence at the time of the last follow-up. logrank test was used to study the effect urs on survival. cox proportional hazards regression was used for multivariate analysis in a forward-selection strategy. in all tests, the p value was 2-sided, and significance was set at p < .05. results among the 305 patients with utuc, 8 cases had nontcc on the final histopathology, 15 cases were treated with renal-sparing surgeries, and 1 case with non-inclusive pathology report. those were eliminated from the study leaving 281 patients for review. the mean age of our patient population was 59+11 years, and 88 % were male with a median follow-up period of 34 months (range, 6-300 months). thirteen among 281 total cases (4.6%) were found to have malignant bladder cuff, comprising 8% among the total ureteric tumor cases (13/152). regarding tumor stage, one case had tis, eight had t1 and four cases had t2 malignant bladder cuff. all cases were with pure ureteric or multifocal tumors, and none had pure pelvicalyceal tumors (p = .001). there was a high incidence of malignant bladder cuff in distal ureteric compared to proximal ureteric tumors (p = .001). table 1 coincidental malignant bladder cuff was not a significant risk factor for bladder recurrence post-surgical management of utuc; however, it was associated with high incidence of invasive bladder tumor (p = .01). local recurrence at the surgical site and distant metastasis were significantly higher among patients with malignant bladder cuff (p = .001, table 2). distant metastasis sustained its significance in multivariate analysis and cox regression models (p = .01, table 3). those patients had a poor survival when compared to non-malignant bladder cuff cases on short, intermediate, and long-term follow up (breslow, tarone-ware, and log rank tests, p = .001, figure 1) regarding the 4 patients with t2 pathological staging in the bladder cuff specimen, 2 patients were advised to receive cystectomy and urinary diversion as a radical treatment. both refused but accepted to receive adjuvant intravesical therapy. both patients presented with treatment failure. the remaining 9 patients with noninvasive pathology of the bladder cuff received full course of adjuvant therapy. three patients showed local pelvic recurrence within 6 months of the surgery and died of the disease. discussion to the best of our knowledge, our review is the first to study the risk factors and the survival that may be associated with malignant bladder cuff. also, we aimed to determine its influence on the potential outcome. rnu with bce is known as the standard method of treattable 2. bivariate analysis of recurrence after surgical management of utuc with bladder cuff pathology* characteristics coincidental malignant bldder cuff, n (%) pvalue recurrent bladder tumor no yes no 143 (95) 7 (5) 0.9 yes 125 (95) 6 (5) recurrent invasive bladder tumor no 260 (96) 11 (4) 0.01 yes 8 (80) 2 (20) contra-lateral recurrence no 266 (95) 13 5 0.7 yes 2 (100) --uretheral recurrence no 261 (95) 12 (5) 0.2 yes 7 (88) 1 (12) local recurrence no 257 (96) 9 (4) 0.001 yes 11 (73) 4 (27) distant metastasis no 251 (97) 8 (3) 0.001 yes 17 (77) 5 (23) 95% ci exp(b) p-value recurrent invasive bladder tumor ---0.6 local recurrence ---0.07 distant metastasis 6.9 24.1 12 0.01 table 3. multivariate analysis and cox regression models figure 1. kaplan-meier curve of cancer-specific survival stratified by bladder cuff pathology bladder tcc in nephroureterectomy-elawdy et al. urological oncology 258 vol 15 no 05 september-october 2018 259 ment for utuc(6). different methods were described for bce; tansvesical, extravesical and endoscopic with no difference in terms of recurrence free survival, cancer specific survival, and overall survival among these methods. whatever technique is used, bce is an additional procedure that requires extra time, and another incision or patient's repositioning − all of which add to the complexity of the surgery and the overall morbidity(7). tumor location is the only significant risk factor for malignant bladder cuff in our series. when tumor location was grouped as ureteric and non-ureteric, all cases were with pure ureteric or multifocal tumors and none had pure pelvicalyceal tumors (p = .001). moreover, the more distal the ureteric tumors, the higher the chance of malignant bladder cuff. the majority (9/13, 70%) were with distal ureteric tumors (p = .001). ureteral tumor location was proved to be significantly associated with an increased risk of disease recurrence and cancer-specific death after surgery for utuc compared with renal pelvis tumors. also, ureteric tumors are associated with a high incidence of bladder tumor recurrence(4,8). in our review, female gender was more liable to have coincidental malignant bladder cuff with marginal significance (p = .05). similarly, chou et al who reported a more aggressive course of utuc in female than male(9). there is an ongoing debate regarding the role of bce and its influence on survival. it was reported that there is a high incidence of recurrence with inadequate bladder cuff excision(4,10). however, bce omission increased cancer specific mortality (csm) only in patients with pt3n0/x, pt4n0/x and pt (n1-3) with no compromise in patients with renal pelvic utuc with pt1 and pt2(11). in editorial comment, zlotta(12) stated that such a finding in the patients with the advanced utuc may be a confounder as one would expect patients with more advanced disease and more aggressive tumors to die from metastatic disease rather than from recurrence at the bladder level(12). the findings from our series support this opinion. all utuc cases of grade i had no malignant bladder cuff. conservative management of utuc either by endoscopic maneuvers(13) or segmental ureterectomy(14) has been established for low grade, low stage disease. conservative management does not involve bce and is done with preservation of the entire urinary unit. the main drawback for omitting bladder cuff excision is inability to accurately survey the ureteral stump during follow-up period˗ this should be put into consideration. on deciding to do distal ureterectomy as a conservative treatment for urothelial cancer in the distal ureter, our results support complete bladder cuff excision because there is a high incidence of coincidental tcc in the bladder cuff in such cases. from the results, no coincidental malignant bladder cuff cases were noticed in the laparoscopy arm. when the surgical approach was correlated with tumor location, we found that the majority of laparoscopic cases were pure renal-pelvic (17 cases) and only 7 were only pure ureteric tumors. in our series, while coincidental malignant bladder cuff was not a significant risk factor for the development of overall bladder recurrence, however, it was a risk factor for development of invasive bladder tumor, local recurrence at the surgical site as well as distant metastasis. in this investigation, patients with t2 bladder tumor bladder tcc in nephroureterectomy-elawdy et al. staging of the bladder cuff had a dismal outcome with disease dissemination in 3 out of 4 patients whilst the remaining patient died within 8 months of an unrelated cause. interestingly, patients with noninvasive pathology of the bladder cuff but with positive margin showed the same poor prognosis. on the other hand, patients with noninvasive pathology and negative margin were well-controlled under adjuvant therapy and surveillance. even those who developed later muscle invasive disease were non-metastatic at time of diagnosis and we could proceed to radical cystectomy with intent to cure. coincidental malignant bladder cuff was associated with high local recurrence at the surgical site and distant metastasis (p = .001), and the last sustained its significance in multivariate analysis and cox regression models (table 3). although the bladder cuff was excised, this finding may suggest a more aggressive nature of the disease in those patients or urothelial instability in the rest of bladder mucosa(12). there are many risk factors for local recurrence which were reported by mellouli et al. and kim et al(15,16). in a clinical implementation of our study, pure renal pelvis tumors, especially those with low grade, can be managed without bce with low chance of recurrence on the bladder cuff level. however, bce is indicated for ureteric tumors and it could be considered as a mandatory step for distal ureteric tumors. regardless their pathologic staging, patients with coincidental malignant bladder cuff have very poor survival when compared with those who have free bladder cuff. although our research was a retrospective; however, this could be accepted in rare diseases like utuc, and very rare findings like coincidental malignant bladder cuff. moreover, this topic is seldom mentioned in the literature− that adds to the power of our report. conclusions ureteric tumor is the only independent risk factor for malignant bladder cuff at the final pathology which associated with increased risks for invasive bladder tumor, distant metastasis and poor survival in comparison to non-malignant bladder cuff. in a clinical implementation, bce is considered as a mandatory step in management of ureteric tumors, while it could be omitted in pure and low grade renal pelvis tumors. patients with positive bladder cuff staged as t2 need immediate, aggressive surgical approach and adjuvant treatment. conflict of interest the authors report no conflict of interest. refrences 1. jemal a sr, ward e, murray t, xu j, thun mj. cancer statistics,. ca cancer j clin. janfeb 2007;57:43-66.. 2. elawdy mm, taha de, elbaset ma, abouelkheir rt, osman y. histopathologic characteristics of upper tract urothelial carcinoma with an emphasis on their effect on cancer survival: a single-institute experience with 305 patients with longterm follow-up. clin genitourin cancer. 2016;14:e609-e15. 3. hall mc, womack s, sagalowsky ai, carmody t, erickstad md, roehrborn cg. bladder tcc in nephroureterectomy-elawdy et al. prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. urology. 1998;52:594-601. 4. krogh j, kvist e, rye b. transitional cell carcinoma of the upper urinary tract: prognostic variables and post-operative recurrences. br j urol. 1991;67:32-6. 5. lughezzani g sm, perrotte p, shariat sf, jeldres c, budaus l, alasker a, duclos a, widmer h, latour m, guazzoni g, montorsi f, karakiewicz pi. should bladder cuff excision remain the standard of care at nephroureterectomy in patients with urothelial carcinoma of the renal pelvis? a populationbased study. eur urol. 2010 jun;57:956-62. 6. roupret m, zigeuner r, palou j, et al. [european guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. european association of urology guideline group for urothelial cell carcinoma of the upper urinary tract]. actas urol esp. 2012;36:2-14. 7. xylinas e eai. impact of distal ureter management on oncologic outcomes following radical nephroureterectomy for upper tract urothelial carcinoma. eur urol. 2012. 8. yafi fa, novara g, shariat sf, et al. impact of tumour location versus multifocality in patients with upper tract urothelial carcinoma treated with nephroureterectomy and bladder cuff excision: a homogeneous series without perioperative chemotherapy. bju int. 2012;110:e7-13. 9. chou yh, chang wc, wu wj, et al. the association between gender and outcome of patients with upper tract urothelial cancer. kaohsiung j med sci. 2013;29:37-42. 10. kang m ea. the characteristics of recurrent upper tract urothelial carcinoma after radical nephroureterectomy without bladder cuff excision. yonsei med j. 2014;56:37581,. 11. lughezzani g, sun m, perrotte p, et al. should bladder cuff excision remain the standard of care at nephroureterectomy in patients with urothelial carcinoma of the renal pelvis? a population-based study. eur urol. 2010;57:956-62. 12. zlotta ar. should urologists always perform a bladder cuff resection during nephroureterectomy, and which method should they use? eur urol. 2010;57:970-2. 13. pak rw me bd. what is the cost of maintaining a kidney in upper-tract transitional-cell carcinoma? an objective analysis of cost and survival. j endourol. 2009;mar;23:341-6. 14. colin p, ouzzane a, pignot g, et al. comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large french multicentre study. bju int. 2012;110:1134-41. 15. kim bw, ha ys, lee jn, et al. effects of previous or synchronous non-muscle invasive bladder cancer on clinical results after radical nephroureterectomy for upper tract urothelial carcinoma: a multiinstitutional study. urol j. 2015;12:2233-9. 16. mellouli m, charfi s, smaoui w, et al. prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract. urol j. 2017;14:500812. urological oncology 260 miscellaneous patient-reported goal achievement after treating male benign prostatic hyperplasia with alphaadrenergic antagonist: a -12week prospective multicenter study bum soo kim1, tae-hwan kim1, ki ho kim2, byung hoon kim3, ji yong ha3, deok hyun cho4, gun nam kim4, yoon hyung lee5, jae soo kim5, hyun-jin jung6, hong seok shin6, phil hyun song7, jong hyun yoon8, jae ho kim8, eun sang yoo1* purpose: the study was designed to assess and predict patient-reported goal achievement after treatment of benign prostatic hyperplasia (bph) patients with tamsulosin. materials and methods: from november 2013 to october 2015, 272 patients initially diagnosed with bph were prospectively enrolled in nine different centers. before the treatment, subjective final goals were recorded by all patients. every four weeks, the treatment outcomes were evaluated using international prostate symptom score (ipss) and uroflowmetry, and adverse events were recorded. patient-reported goal achievements were assessed after 12 weeks of treatment. results: of the enrolled patients, 179 patients completed the study. the pretreatment patients’ goals included the frequency improvement, nocturia improvement, residual urine sense improvement, well voiding, hesitancy improvement, weak urine stream improvement, urgency improvement, and voiding-related discomfort improvement. of the 179 patients, 129 patients (72.1%) reported that they achieved their primary goals after three months of medical therapy. logistic regression analysis revealed that pretreatment quality of life (or = 8.621, 95% ci: 2.154-9.834), and improvement of quality of life (or = 6.740, 95% ci: 1.908-11.490) were independent predictors of patient-reported goal achievement after tamsulosin monotherapy. conclusion: overall patient-reported goal achievement after medical therapy for bph was high and the scores of pretreatment quality of life and improvement of quality of life can be important factors to predict the achievement of treatment goals. keywords: prostatic hyperplasia; adrenergic alpha-antagonists; drug therapy; lower urinary tract symptoms; patient outcome assessment introduction benign prostatic hyperplasia (bph) is a common disease, which is present in 50% of men older than 50 years and in approximately 80% of men 80 years of age or older.(1,2) lower urinary tract symptoms (luts) are the most common and bothersome problems of bph. the luts due to bph include hesitancy, a weak urine stream, incomplete voiding, frequent urination, nocturia, and urgency. in the past, luts due to bph were usually managed by catheterization or surgery. however, over the past several decades, the management concept for bph has transitioned from an acute 1 department of urology, school of medicine, kyungpook national university, daegu, korea. 2 department of urology, college of medicine, dongguk university, gyeongju, korea. 3 department of urology, college of medicine, keimyung university, daegu, korea. 4 department of urology, gumi cha medical center, cha university, gumi, korea. 5 department of urology, daegu fatima hospital, daegu, korea. 6 department of urology, daegu catholic university medical center, daegu, korea. 7 department of urology, college of medicine, yeungnam university, daegu, korea. 8 department of urology, soonchunhyang university gumi hospital, gumi, korea. *correspondence: department of urology, kyungpook national university hospital, 130 dongdeok-ro, jung-gu, daegu, korea postal code: 41944 telephone: +82 53 200 5845. fax: +82 53 421 9618. e-mail: uroyoo@knu.ac.kr. received december 2016 & accepted december 2017 surgical condition to a chronic medical condition.(3) the development of alpha-adrenergic blockers (α-blockers) changed the treatment patterns of bph. it has been reported that most patients who were newly diagnosed with bph in the usa underwent watchful waiting or medical therapy, and monotherapy with α-blockers was the most common first-line medical therapy, constituting about 80% of the treatments.(4) the physiological function of α-blockers is the relaxation of smooth muscles in the prostate and bladder neck, thereby reducing the resistance to urinary flow and improving luts. first-generation α-blockers urology journal/vol 16 no. 4/ july-august 2019/ pp. 386-391. [doi: http://dx.doi.org/10.22037/uj.v0i0.3784] were non-selective agents, and their use was associated with frequent cardiovascular and gastrointestinal side effects. second-generation α-blockers, including terazosin and doxazosin, showed reduced side effects but required dose titration due to various vascular sequelae, such as hypotension, dizziness, fainting, and postural hypotension. more recently, third-generation α-blockers, including tamsulosin, alfuzosin, and silodosin, have been developed, which have a high affinity and selectivity for alpha-1a adrenergic receptors in the prostate and a lower affinity for the receptors in blood vessels. currently, these agents are widely used for the medical therapy of bph and have been reported to effectively improve luts with a low risk of vascular side effects.(5) tamsulosin, which is one of the most popular α-blockers, is an alpha-1a and alpha-1d selective adrenoceptor antagonist, and its efficacy and safety have been well established in many studies.(6-10) several clinical tools, such as the international prostate symptom score (ipss), american urological association symptom score (auass), peak flow rate (qmax), and post-void residual urine (pvr), have been used to evaluate the improvement of luts in bph patients. although these tools have been considered good measurement indices, it is still difficult to assess patients’ treatment goal achievement using these tools. therefore, we tried to evaluate the patients’ goal achievement with medical therapy for bph and performed a prospective multicenter study to assess and predict the patient-reported goal achievement after treatment with tamsulosin. materials and methods study design and sample size from november 2013 to october 2015, 272 patients initially diagnosed with bph were prospectively enrolled in nine different centers (at least 30 patients in each center). all patients were informed about the purpose and protocol of this study and provided consent. this study was approved by the institutional review board of each hospital (no. 2013-12-022). the primary endpoint of this study was the score of the patient-reported goal achievement after 12 weeks of treatment, and the secondary endpoints were the changes of the total ipss, voiding subscore, storage subscore, quality of life (qol), qmax, and pvr at 4, 8, and 12 weeks of treatment compared to the baseline. study population the inclusion criteria of this study were as follows: male patients with the age of 40 years or older, a baseline total ipss of ≥ 8, a bother score of qol of ≥ 3, initially diagnosed patients with bph without a history of prior ≥-blocker medication for the recent 12 weeks and no history of prior 5-alpha-reductase inhibitor (5-ari) medication for the recent 12 weeks. patients requiring surgery, those with suspicious hypersensitivity or a contraindication for ≥-blockers, a prior history of prostatic surgery, moderate or severe liver or renal function impairment, moderate or severe cardiovascular disorder, postural hypotension, hypotension, a history of senile dementia, combined urinary tract infection, underlying neurological disease, underlying urogenital malignancy, urethral stricture, chronic prostatitis or chronic pelvic pain syndrome, and serum prostate-specific antigen (psa) of ≥ 4 ng/ml were excluded from this study. variables and follow up period before the treatment, all patients underwent medical history taking, physical examination, including blood pressure and digital rectal examination, a serum psa test, urinalysis with urine culture, transrectal ultrasound, uroflowmetry, and ipss with qol determination. in addition, all patients were asked about their subjective final goals of treatment for bph. since tamsulosin 0.2 mg is recommend as initial treatment dose in east asian patients with bph, tamsulosin was initiated at 0.2 mg once daily, and the treatment continued for 12 weeks. after four weeks of treatment, if the parameters of uroflowmetry or ipss were not improved, or patients were not satisfied with their voiding status, the dose of tamsulosin was escalated up to 0.4 mg. other medications that could affect patients’ luts, such as cholinergic drugs, anticholinergic drugs, 5-aris, desmopressins, and other ≥-blockers, were not permitted throughout the study period. every four weeks, the treatment outcomes were evaluated using ipss and uroflowmetry, and adverse events were recorded. after 12 weeks of treatment, patient-reported goal achievements were assessed. the scoring of the goal achievement was set by 1 (completely unachieved), 2 (unachieved), 3 (neither achieved nor unachieved), 4 (achieved), and 5 (completely achieved). in addition, all patients were divided into two groups according to the goal according score; lower score (1, 2 and 3) and higher score (4 and 5), and risk factors for lower score of goal achievement were assessed using logistic regression analysis. statistical methods statistical analyses were performed using spss 18.0 (spss, chicago, il, usa). continuous variables, such as ipss, qol score, qmax and pvr were compared by student’s t-test and these variables of each time point (0, 4, 8 and 12 weeks) were compared by one-way analysis of variance (anova). when the value was found to be significant after an assessment using the anova statistical test, the tukey’s post-hoc comparison was performed. univariate and multivariate analyses were performed to determine the risk factors for tamsulosin dose escalation and lower score of patient-reported goal achievement. a p value of less than 0.05 was considered statistically significant. results of the enrolled patients, 179 patients completed the goal achievement for management of bph-kim et al. table 1. baseline patients’ characteristics. characteristics valuesa no. of patients 179 mean age (years) 62.0 ± 8.4 mean serum psa (ng/ml) 1.7 ± 2.6 mean prostate volume (g) 31.7 ± 12.2 patients’ goal setting nocturia improvement (n = 63) wus improvement (n = 52) frequency improvement (n = 34) rus improvement (n = 27) hesitancy improvement (n = 22) well voiding (n = 21) urgency improvement (n = 11) voiding related discomfort improvement (n = 2) a data are presented as mean±sd or number abbreiations: psa, prostate-specific antigen; rus, residual urine sense; wus, weak urine stream miscellaneus 387 vol 16 no 04 july-august 2019 388 study and reported their goal achievement score after 12 weeks of tamsulosin monotherapy. the reasons for dropping out of the study included a treatment failure (n = 14), adverse events (n = 6), a follow-up loss (n = 65), and psa elevation (n = 8). the adverse events that occurred in the dropped-out patients were one case of each dizziness, fever, vomiting, and general weakness and two cases of ejaculatory disorders. the mean age, mean serum psa level, and mean prostate size of the patients who completed the study are recorded in table 1. of the 179 patients, 42 patients set multiple goals (32 patients with 2 goals, 9 patients with 3 goals and 1 patient with 4 goals) and the goals set by the patients included the nocturia improvement (n = 63), weak urine stream improvement (n = 52), frequency improvement (n = 34), residual urine sense improvement (n = 27), hesitancy improvement (n = 22), well voiding (n = 21), urgency improvement (n = 11), and voiding-related discomfort improvement (n = 2). after four weeks of treatment, the mean qmax, and total ipss values, as well as the mean qol score, significantly improved, and the tamsulosin dose was escalated to 0.4 mg for 74 patients. the logistic regression analysis showed that less improvement in qmax [odds ratio (or) = 1.1, 95% confidence interval (ci): 1.0–1.2, p = .043] and that in pvr (or = 1.0, 95% ci: 1.0–1.0, p = .017) were independent risk factors for tamsulosin dose escalation. after 8 and 12 weeks of treatment, all the parameters further improved (table 2). after 12 weeks of treatment, the scores of patient-reported goal achievements were as follows: 5 in 21 patients (11.7%), 4 in 108 patients (60.3%), 3 in 33 patients (18.4%), 2 in 7 patients (3.9%), and 1 in 10 patients (5.6%). higher score group had shorter mean duration of luts (16.4 vs 36.6 months, p = .002), lower pretreatment total ipss (15.7 vs 18.6, p = .017), lower pretreatment ipss voiding subscore (9.3 vs 11.4, p = .014), and lower pretreatment qol score (3.8 vs 4.1, p = .028) than lower score group. post-treatment total, voiding and storage subscores of ipss and qol were also significantly lower in higher score group compared to lower score group. improvement of total, voiding and storage subscores of ipss and qol were significantly higher in higher score group. however, mean age, mean psa level, mean table 2. changes in symptom scores including quality of life and uroflowmetric parameters after 12 weeks treatment of tamsulosin. variablesa baseline 4-week treatment 8-week treatment 12-week treatment p valueb ipss (total) 17.5 ± 7.0 13.6 ± 6.7 12.5±6.4 11.0 ± 6.4 < 0.001 voiding subscore 10.4 ± 4.8 7.9 ± 4.4 7.4 ± 4.1 6.2 ± 4.1 < 0.001 storage subscore 6.9 ± 3.4 5.7 ± 3.2 5.2 ± 2.9 4.8 ± 2.9 0.001 qol 4.0 ± 1.0 3.1 ± 1.2 2.8 ± 1.2 2.5 ± 1.2 < 0.001 qmax (ml/sec) 12.5 ± 5.8 14.8 ± 6.4 15.3 ± 5.2 16.3 ± 5.8 0.001 pvr (ml) 36.5 ± 55.0 27.5 ± 43.7c 26.8 ± 44.7c 17.9 ± 26.7 < 0.001 a data are presented as mean ± sd or number a continuous variables were compared by independent samples t-test b p value was determined by anova test c these values were not statistically different compared with that of baseline by tukey’s post-hoc analysis (p > 0.05) abbreviations: ipss, international prostate symptom score; qol, quality of life; qmax, peak flow rate; pvr, post-void residual urine table 3. comparisons of demographic, medical and voiding characteristics between higher and lower score groups. variablesa higher score (n=129) lower score (n=50) p value age (years) 60.1 ± 8.3 62.6 ± 7.1 0.063 duration of luts (months) 16.4 ± 23.4 36.6 ± 43.8 0.002 prostate volume (g) 32.3 ± 10.4 33.0 ± 13.0 0.745 psa (ng/ml) 1.6 ± 2.0 1.8 ± 1.8 0.688 pretreatment qmax (ml/s) 13.4 ± 6.4 11.8 ± 5.3 0.142 pretreatment pvr (ml) 30.3 ± 51.9 35.3 ± 40.7 0.537 pretreatment ipss (total) 15.7 ± 6.4 18.6 ± 6.9 0.017 pretreatment ipss (voiding) 9.3 ± 4.2 11.4 ± 5.4 0.014 pretreatment ipss (storage) 6.3 ± 3.3 7.1 ± 3.6 0.198 pretreatment qol 3.8 ± 0.9 4.1 ± 0.8 0.028 no. of goals 1.3 1.4 0.096 posttreatment qmax (ml/s) 15.6 ± 6.0 14.2 ± 6.9 0.252 posttreatment pvr (ml) 22.3 ± 33.9 25.7 ± 24.8 0.509 posttreatment ipss (total) 11.5 ± 5.9 15.8 ± 6.7 < 0.001 posttreatment ipss (voiding) 6.7 ± 3.8 9.3 ± 4.6 < 0.001 posttreatment ipss (storage) 4.8 ± 2.7 6.5 ± 3.5 0.002 posttreatment qol 2.6 ± 1.1 3.7 ± 1.0 < 0.001 δ qmax (ml/s) 3.9 ± 5.1 3.5 ± 6.3 0.754 δ pvr (ml) -12.9 ± 42.1 -18.8 ± 37.3 0.447 δ ipss (total) -7.2 ± 5.6 -2.9 ± 6.1 < 0.001 δ ipss (voiding) -4.7 ± 3.9 -2.3 ± 4.9 0.006 δ ipss (storage) -2.6 ± 2.6 -1.2 ± 2.8 0.007 δ qol -1.9 ± 1.2 -0.6 ± 1.1 < 0.001 cases of dose escalation 40 (31.0%) 19 (38.0%) 0.103 a data are presented as mean ± sd or number abbreviations: luts, lower urinary tract symptoms; psa, prostate-specific antigen; qmax, peak flow rate; pvr, post-void residual urine; ipss, international prostate symptom score; qol, quality of life goal achievement for management of bph-kim et al. prostate volume, preand post-treatment uroflowmetric parameters, the presence of underlying diseases, the number of goals, and the sorts of goals were not significantly different between higher and lower score groups (table 3). multivariate analysis revealed that pretreatment quality of life (or = 8.6, 95% ci: 2.2-9.8) and improvement of quality of life (or = 6.7, 95% ci: 1.911.5) were independent predictive factors of patient-reported goal achievement (table 4). the most common adverse event was low blood pressure (systolic pressure < 110 mmhg) in 11 patients, and dizziness and ejaculatory disorder occurred in one patient each. discussion although there is strong evidence for the benefit of combination therapy (α-blocker with 5-ari), supported by several randomized, controlled trials, in terms of the symptom control, disease progression, and risk of bph-related surgery,(11,12) monotherapy still constitutes the largest portion of medical therapy for bph.(13,1416) among the drugs used as a monotherapy, ≥-blockers are the most common agents.(13,14-16) the availability of tamsulosin has been a major breakthrough for medical therapy of patients with bph, due to comparable efficacy, fewer side effects, and a more optimal dose compared to previously existing α-blockers. with these advantages, monotherapy using α-blockers became more common after tamsulosin had been introduced to the clinical practice.(3) the efficacy of α-blockers, including tamsulosin, has been usually evaluated by uroflowmetry and specially designed questionnaires, such as ipss and auass, in many bph-related studies.(17-20) although these evaluation tools are well validated and objectively reflect the change of luts, they have limitations in evaluation of patients’ subjective satisfaction and initial goal achievement after treatment. since bph is a chronic and refractory disease and medical therapy became a standard treatment for most bph patients with mild to moderate luts, adherence to and persistence with therapy are considered important factors for the success of the treatment.(5,21) therefore, assessment and prediction of the patient-reported goal achievement can be a useful indicator to predict patients’ adherence to and persistence with medical therapy. schoenfeld et al. reported that only about 40% of the patients with bph who initiated α-blocker monotherapy continued medication for six months, and about onethird of the patients continued it for one year.(5) however, shortridge et al. reported that 63.5% of the patients who initiated combination therapy with α-blockers and 5-aris persisted with their medications for more than four years.(21) this can be explained by the fact that the addition of 5-aris can be more helpful in improving luts subjectively as well as objectively. currently, anticholinergic agents and phosphodiesterase type 5 inhibitors are also available for medical therapy of bph, and several studies have proven their efficacy.(1,22) in this situation, physicians should decide whether they will continue ≥-blocker monotherapy or add or change to other drugs after a short-term follow-up. although several evaluating tools, such as uroflowmetry, ipss, and voiding diary, can be helpful, patients’ treatment goals and subjective satisfaction may also have important roles in determining the strategy. as seen in this study, patients with bph have various treatment goals, including not only voiding symptoms but also storage symptoms. however, the currently available bph-related evaluation tools, such as uroflowmetry and ipss, may not reflect or assess patients’ main treatment goals. continuing the same medical therapy, with only improvements of uroflowmetric parameters and ipss, regardless of patients’ treatment goals and/or subjective satisfaction, can lead to early discontinuation of medical therapy and dropout of overall treatment. nocturia improvement was the most common treatment goal (27.2%) in this study, followed by the weak urine stream improvement (22.4%). seventy-eight patients (43.6%) wanted to improve their storage symptoms as initial treatment goals. this indicates that not a few patients with bph want to improve their storage symptoms. traditionally, tamsulosin was considered to provide more effect on voiding symptoms, but recent studies have shown that tamsulosin monotherapy also has effects on storage symptoms.(23,24) in this study, more than 70% of all patients achieved scores of 4 or 5, and among the patients whose initial goals were the storage symptom improvement, nearly 70% also achieved scores of 4 or 5. in addition, the mean storage subscore of ipss was also significantly improved by the medication over time. this demonstrated that tamsulosin monotherapy is effective for storage symptoms as well as for voiding symptoms in patients with bph. although only patients with a mildto moderate-sized prostate were enrolled in the present study, this study confirmed that more than 70% of the patients with bph were able to achieve their treatment goals (scores 4 or 5) after 12 weeks of tamsulosin monotherapy, regardless of their primary treatment goals. in addition, every parameter, including the total ipss, voiding subscore, storage subscore, qol, qmax, and pvr, was significantly improved over time with tamsulosin monotherapy. however, nearly 30% of the patients did not table 4. logistic regression analysis to determine the predictive factors of patient-reported goal achievement (higher score). univariate analysis multivariate analysis odds ratio (95% ci) p value odds ratio (95% ci) p value pretreatment ipss 0.8 (0.2-1.8) 0.284 0.8 (0.2-1. 9) 0.169 pretreatment qol 10.0 (2.5-10.1) 0.001 8.6 (2.2-9.8) 0.002 duration of luts 1.0 (0.9-1.0) 0.372 1.0 (0.7-2.0) 0.155 posttreatment ipss 1.1 (1.0-1.1) 0.230 1.3 (0.8-2.5) 0.113 δ ipss (total) 1.0 (1.0-1.0) 0.859 1.0 (0.8-1.4) 0.967 δ ipss (voiding subscore) 1.0 (0.9-1. 2) 0.889 1.0 (0.5-1.1) 0.948 δ ipss (storage subscore) 0. 9 (0.8-0.9) 0.872 1.0 (0.6-2.0) 0.996 δ qol 7.6 (2.0-10.5) <0.001 6.7 (1.9-11.5) 0.001 abbreviations: ci, confidence interval; ipss, international prostate symptom score; qol, quality of life; luts, lower urinary tract symptoms goal achievement for management of bph-kim et al. miscellaneus 389 vol 16 no 04 july-august 2019 390 achieve their primary treatment goals, even with dose escalation, although their objective parameters, such as ipss, qmax, and pvr, improved compared to the pretreatment state. based on several previous studies, a relatively low dose of tamsulosin (0.2 mg daily) was recommended as the standard regimen for the treatment of luts in asian patients with bph.(7,9,25) however, recent studies have shown that tamsulosin at 0.4 mg once daily can be more effective for the patients who do not respond to 0.2 mg once daily, especially for the improvement of qmax without any increase in cardiovascular events.(10,26) therefore, all patients started tamsulosin at 0.2 mg daily as the initial dose, and the dose was escalated to 0.4 mg after four weeks of treatment if the patients did not demonstrate their luts improvement in this study. by the analysis of risk factors for dose escalation, our study showed that patients with less improvement of qmax and pvr could have higher risks for dose escalation. for the rest of the patients, who did not achieve their treatment goals (scores 1 or 2), a change in their treatment strategies needs to be considered, such as the addition or change of drugs, according to the state of their luts, even if their ipss or uroflowmetric parameters significantly improved; otherwise, there may be a higher risk of discontinuation of treatment. thus, the patient-reported goal achievement can be used to determine a change or addition of other drugs after initial treatment of patients with bph/luts. however, this evaluating tool also has disadvantages. the patient-reported goal achievement usually reflects changes of patients’ subjective symptoms. although ipss and uroflowmetric parameters tend to correlate with changes of subjective symptoms, some patients may complain about less improvement of their voiding symptoms even if their ipss, qmax, and pvr were significantly improved, or vice versa. therefore this patient-reported goal achievement cannot be used alone for the evaluation of objective changes in patients with bph/luts. in addition, this study demonstrated that patients with higher pretreatment qol and less improvement of qol may have fewer chances of goal achievement after medical therapy. therefore, close monitoring will be needed for these patients, and changing the treatment strategy should be considered. there are several limitations in this study. although this study was performed prospectively based on multi-institutional patient enrollment, a case-controlled trial or comparative study with other bph drugs was not conducted. in addition, patients with only mildto moderate-sized prostate were enrolled, even though this was not intended. a relatively high dropout rate due to a follow-up loss and the lack of long-term follow-up results, can also be limitations of this study. however, to the best of our knowledge, this is the first trial to assess the patient-reported goal achievement after the treatment with tamsulosin monotherapy for patients with bph. it can be the base of a new evaluation tool to increase the adherence to and persistence with medical therapy for bph/luts. based on the results of this study, a larger, population-based, longer-term follow-up and randomized controlled trial with/without other bph drugs will be needed for the future study. conclusions in conclusion, medical therapy with tamsulosin is safe and effective as an initial treatment for patients with bph. nocturia and a weak urine stream are the most common lower urinary tract symptoms that patients with bph want to be relieved by the treatment. more than 70% of our patients reported satisfactory goal achievement after 12 weeks of tamsulosin monotherapy, regardless of the patients’ treatment goals. this study demonstrated that the scores of pretreatment quality of life and improvement of quality of life can be important factors to predict the achievement of treatment goals. conflict of interests this work was conducted by the urostar study group and supported by astellas korea. this research was also supported by the basic science research program through the national research foundation of korea (nrf), which is funded by the ministry of science, ict & future planning (2015r1c1a1a01053509). references 1. van asseldonk b, barkin j, elterman ds. medical therapy for benign prostatic hyperplasia: a review. can j urol. 2015;22 suppl 1:7-17. 2. yamanishi t, kaga k, fuse m, shibata c, kamai t, uchiyama t. six-year follow up of silodosin monotherapy for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: what are the factors for continuation or withdrawal? int j urol. 2015;22:1143-8. 3. filson cp, wei jt, hollingsworth jm. trends in medical management of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. urology. 2013;82:138692. 4. erickson ba, lu x, vaughan-sarrazin m, kreder kj, breyer bn, cram p. initial treatment of men with newly diagnosed lower urinary tract dysfunction in the veterans health administration. urology. 2014;83:3049. 5. schoenfeld mj, shortridge ef, gelwicks sc, cui z, wong dg. treatment patterns in alpha-blocker therapy for benign prostatic hyperplasia. am j mens health. 2014;8:26772. 6. abrams p, schulman cc, vaage s. tamsulosin, a selective alpha 1c-adrenoceptor antagonist: a randomized, controlled trial in patients with benign prostatic 'obstruction' (symptomatic bph). br j urol. 1995;76:32536. 7. dunn cj, matheson a, faulds dm. tamsulosin: a review of its pharmacology and therapeutic efficacy in the management of lower urinary tract symptoms. drugs aging. 2002;19:135-61. 8. lepor h. phase iii multicenter placebogoal achievement for management of bph-kim et al. goal achievement for management of bph-kim et al. controlled study of tamsulosin in benign prostatic hyperplasia. urology. 1998;51:892900. 9. lyseng-williamson ka, jarvis b, wagstaff aj. tamsulosin: an update of its role in the management of lower urinary tract symptoms. drugs. 2002;62:135-67. 10. chung jw, choi sh, kim bs, et al. efficacy and tolerability of tamsulosin 0.4 mg in patients with symptomatic benign prostatic hyperplasia. korean j urol. 2011;52:479-84. 11. mcconnell jd, roehrborn cg, bautista om, et al. the long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. n engl j med. 2003;349:238798. 12. roehrborn cg, barkin j, siami p, et al. clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (bph) by baseline characteristics: 4-year results from the randomized, doubleblind combination of avodart and tamsulosin (combat) trial. bju int. 2011;107:946-54. 13. bishr m, boehm k, trudeau v, et al. medical management of benign prostatic hyperplasia: results from a population-based study. can urol assoc j. 2016;10:55-9. 14. cindolo l, pirozzi l, fanizza c, et al. actual medical management of lower urinary tract symptoms related to benign prostatic hyperplasia: temporal trends of prescription and hospitalization rates over 5 years in a large population of italian men. int urol nephrol. 2014;46:695-701. 15. lukacs b, cornu jn, aout m, et al. management of lower urinary tract symptoms related to benign prostatic hyperplasia in real-life practice in france: a comprehensive population study. eur urol. 2013;64:493-501. 16. hollingsworth jm, hollenbeck bk, daignault s, kim sp, wei jt. differences in initial benign prostatic hyperplasia management between primary care physicians and urologists. j urol. 2009;182:2410-4. 17. roehrborn cg. efficacy of alpha-adrenergic receptor blockers in the treatment of male lower urinary tract symptoms. rev urol. 2009;11:s1-8. 18. wilt tj, howe rw, rutks ir, macdonald r. terazosin for benign prostatic hyperplasia. cochrane database syst rev 2002:cd003851. 19. wilt tj, mac donald r, rutks i. tamsulosin for benign prostatic hyperplasia. cochrane database syst rev 2003:cd002081. 20. moon kh, song ph, yang dy, et al. efficacy and safety of the selective alpha1aadrenoceptor blocker silodosin for severe lower urinary tract symptoms associated with benign prostatic hyperplasia: a prospective, single-open-label, multicenter study in korea. korean j urol. 2014;55:335-40. 21. shortridge e, donatucci c, donga p, marcus m, wade rl. adherence and persistence patterns in medication use among men with lower urinary tract symptoms/benign prostatic hyperplasia. am j mens health. 2017;11:1649. 22. karami h, hassanzadeh-hadad a, fallahkarkan m. comparing monotherapy with tadalafil or tamsulosin and their combination therapy in men with benign prostatic hyperplasia: a randomized clinical trial. urol j. 2016;13:2920-6. 23. ko k, yang dy, lee wk, et al. effect of improvement in lower urinary tract symptoms on sexual function in men: tamsulosin monotherapy vs. combination therapy of tamsulosin and solifenacin. korean j urol. 2014;55:608-14. 24. aikawa k, kataoka m, ogawa s, et al. elucidation of the pattern of the onset of male lower urinary tract symptoms using cluster analysis: efficacy of tamsulosin in each symptom group. urology. 2015;86:349-53. 25. kawabe k, ueno a, takimoto y, aso y, kato h. use of an alpha 1-blocker, ym617, in the treatment of benign prostatic hypertrophy. ym617 clinical study group. j urol. 1990;144:908-11;discussion 11-2. 26. kim jj, han dh, sung hh, choo sh, lee sw. efficacy and tolerability of tamsulosin 0.4 mg in asian patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia refractory to tamsulosin 0.2 mg: a randomized placebo controlled trial. int j urol. 2014;21:677-82. miscellaneus 391 urological oncology 237urology journal vol 5 no 4 autumn 2008 mutations of ras gene family in specimens of bladder cancer navaz karimianpour,1 parisa mousavi-shafaei,1 abed-ali ziaee,1 mohammad taghi akbari,2 gholamreza pourmand,3 amirreza abedi,3 ali ahmadi,4 hossein afshin alavi5 introduction: studies have shown different types of ras mutations in human bladder tumors with a wide range of mutation frequencies in different patient populations. this study aimed to assess the frequency of specific-point mutations in the ras gene family of a group of iranian patients with bladder cancer. methods: we examined the tumor specimens of 35 consecutive patients with transitional cell carcinoma. the dna samples were evaluated for the occurrence of hras, kras, and nras activation using a polymerase chain reaction-restriction fragment length polymorphism technique. results: none of the patients had mutations in the ras gene family “hot spots” including codons 12, 13, and 61. conclusion: we failed to find ras mutations in our bladder tumor samples. these observations may reflect the involvement of different etiological factors in the induction of bladder tumor of which ras mutation might not be present in all populations. urol j. 2008;5:237-42. www.uj.unrc.ir keywords: bladder neoplasms, oncogenes, ras genes, codon, polymerase chain reaction, restriction fragment length polymorphism 1institute of biochemistry and biophysics, tehran university, tehran, iran 2medical genetics laboratory, tehran, iran 3urology research center, tehran university of medical sciences, tehran, iran 4department of pathology, sina hospital, tehran university of medical sciences, tehran, iran 5department of pathology, day hospital, tehran, iran corresponding author: abed-ali ziaee, phd institute of biochemistry and biophysics, tehran university, tehran131451384, iran tel: +98 21 6695 6975 fax: +98 21 6640 4680 e-mail: aaziaee@ibb.ut.ac.ir received may 2008 accepted october 2008 introduction bladder cancer is responsible for the death of 130 000 people annually worldwide.(1) studies performed by the american cancer society in 2000 estimated that 63 210 new cases of bladder cancer would be found in the united states during 2005, and about 13 180 people would die of the disease.(2) statistical analyses also showed that early detection of bladder cancer could increase the chance of survival.(3) at the molecular level, the ras activating mutations were first discovered in t24 cell line of bladder cancer.(4) the ras gene family consisting of 3 functional genes, harvey ras (hras), kristen ras (kras), and neuroblastoma ras (nras), encode highly similar and conserved proteins with a molecular weight of 21 kda (p21).(5) this protein is localized in the internal part of the cell membrane and has gtpase activity. mutations in the hotspot codons 12, 13 (exon1), or 61 (exon2) cause specific amino acid substitutions and result in the loss of gtpase activity.(6) it is well documented that guanosine triphosphates are molecular switches in signal transduction, and different kinds of extracellular signals stimulate conversion of ras-gdp to ras-gtp active conformation. the main function of the ras protein is to induce activation of downstream kinase cascades that results in continuous mitogenic signaling and transformation of immortalized cells.(7) mutation of ras in bladder cancer—karimianpour et al 238 urology journal vol 5 no 4 autumn 2008 many studies have detected different types of ras mutations in human bladder tumors.(8-14) the results from these studies show a wide range of mutation frequencies. it is not clear whether these differences are related to the different life styles of the studied populations, exposure to different suspected environmental carcinogens, or to the sensitivity of ecogenetic relationships. according to these observations, the present study was aimed to investigate the frequency of specific point mutations of the ras gene family in a group of iranian patients suffering from bladder cancer. materials and methods sample collection surgical specimens from 35 patients with histologically confirmed transitional cell carcinoma were collected and stored at -74°c. the patients were consecutively selected from among admitted patients to sina hospital. age, sex, and smoking history of the patients were obtained from their hospital records. dna extraction genomic dna was extracted from the tumoral tissues using proteinase k and phenol extraction methods, and then, it was stored at 4°c.(15) polymerase chain reaction-restriction fragment length polymorphism matched and mismatched oligonucleotide primers were designed or selected from previous studies for amplifying sequences around codon 12 of hras, codons 12 and 13 of kras, and codon 61 of nras in order to generate subfragments only from wild-type polymerase chain reaction (pcr)amplified ras genes (mutant-type destroys the created restriction site).(16) the primer sequences used were as follows: hras: 5’-gacggaatataagctggtgg-3’ and 5’-aggcacgtctccccatcaat-3’ kras: 5’-actgaatataaacttgtggtag ttggacct-3’ and 5’-ttctccatcaattactacttgctt cctgta-3’ nras: 5’-gacatactggatacagctggc-3’ and 5’-cctgtcctcatgtattggtc-3’ the dna samples were amplified in a total volume of 50 μl of 10 × pcr buffer (5 μl), dntp mix (10 mm, 1 μl), each primer (0.5 μl with final concentration of 40 pmol each) and taq polymerase (fermentas, burlington, canada). amplification of fragments of the studied genes was carried out with a thermal cycler pcr (geniu system, boehringer mannheim, germany) using the following thermal profile: 95°c for 5 minutes, 32 cycles; hras: 95°c for 40 seconds, 6°c for 40 seconds, and 72°c for 45 seconds; kras: 94°c for 40 seconds, 60°c for 40 seconds, and 72°c for 50 seconds; nras: 94°c for 30 seconds, 60°c for 40 seconds, 72°c for 30 seconds, followed by a final extension at 72°c for 2 minutes. enzyme digestion restriction endonucleases mspi, bstni, hphi, and msci (fermentas, burlington, canada) digested codons 12 (hras), 12 and 13 (kras), and 61 (nras), respectively. any mutation at these codons disrupts the restriction site for the related restriction enzyme. digestion was carried out in a total volume of 30 ul that contained 12 ul of pcr amplicon and 10 iu of restriction endonuclease. buffers and incubation conditions (overnight at 37°c) were applied as recommended by the manufactures. the digested fragments were electrophoresed on a 6% polyacrylamide gel (1:59 bis-acrylamide for hras and kras genes, and 1:19 for nras gene) in 0.5 × tbe at 200 v for 1 hour and gels were stained in ethidium bromide. in this work, different sizes of dna fragments of hras, nras, and kras genes (genbank accession numbers: nm_005343, nm_002524 and nm_004985, respectively) were obtained by means of pcr amplification. results patients the mean age of the patients was 65.8 ± 11.8 years (range, 34 to 85 years), and 74.3% of them were older than 60 years. twenty-nine patients were men (82.8%) and 18 were smokers (51.4%). analysis of the pathological grades showed that mutation of ras in bladder cancer—karimianpour et al urology journal vol 5 no 4 autumn 2008 239 23 specimens (65.7%) were low grade (2 low malignant potential, 21 low grade, and 12 high grade). polymerase chain reaction amplification the lengths of the ras amplified fragments according to the designed primers were 420 bp, 65 bp, 144 bp for hras, nras, and kras genes, respectively. restriction enzyme digestion of hras codon 12 to determine any point mutation at codon 12 of hras, the restriction enzyme mspi was used. only the wild-type amplicon containing the endonuclease recognition site could be cut off and give rise to 390-bp and 30-bp fragments. no point mutation on codon 12 of hras was found (figure 1). restriction enzyme digestion of nras codon 61 the restriction enzyme msci was used for digestion of the codon 61 of nras. the proper cutting site (tgg↓cca) was created with the help of the forward primer, which led to a single nucleotide change just before codon 61. in case of any mutation, the restriction enzyme msci would be unable to cut the pcr fragment to 21-bp and 44-bp oligonucleotides (figure 2). restriction enzyme digestion of kras codons 12 and 13 the restriction enzyme bstni was used for codon 12 of kras gene digestion. a primer was designed, so that the cutting site was created just before codon 12. only the wild-type kras pcr product would be cut by bstn1, yielding 2 fragments around 115-bp and 29-bp oligonucleotides. for codon 13, ggtga7/8↓ is the recognition site for hphi and is cut off by the enzyme. this site does not exist naturally, but it would appear in any type of mutation. digestion reaction was carried out for each sample and no mutation was detected for kras (figure 3). discussion studies on a variety of tumors have demonstrated some “hot spots” in ras gene family that are susceptible to point mutations. the frequent mutations are changes of glycine to valine at codon 12, glycine to cysteine at codon 13, and glutamine to arginine/lysine/leucine at codon 61.(17) the incidence of ras mutation varies and is figure 1. hras gene product analysis in bladder cancer by polymerase chain reaction-restriction fragment length polymorphism. a, undigested dna from a healthy person (420-bp); ad, mspi-cut polymerase chain reaction product of the healthy person (390-bp and 30-bp); lanes 15 and 18, undigested dna of patients 15 and 18, respectively; and lane 15d and 18d, digested products of patients 15 and 18, respectively. figure 2. nras gene product analysis in bladder cancer by polymerase chain reaction-restriction fragment length polymorphism. a, undigested dna from a healthy person (65-bp); ad, msci-cut polymerase chain reaction product of the healthy person (44-bp and 21-bp); lane 8 and 9, undigested dna of patients 8 and 9, respectively; and lane 8d and 9d, digested products of patients 8 and 9, respectively. mutation of ras in bladder cancer—karimianpour et al 240 urology journal vol 5 no 4 autumn 2008 greatly dependent on the tissue or cell type from which the cancer cells are derived. although ras mutations occur in 75% to 95% of pancreatic carcinomas and 50% of colon carcinomas, they are rare in several other neoplasms.(18-20) the hras mutation was first detected in the human bladder cancer cell line t24.(7) subsequent studies demonstrated that hras mutations were more frequently observed in urinary tract tumors than the kras or nras genes.(21) this initial expectation has been materialized, since later analysis of uncultured bladder tumors showed that only about 10% of the samples contained a mutated hras.(22-24) however, later reports showed higher frequencies. while fitzgerald and associates reported mutations in the hras gene in 44% of urine sediments from bladder cancer patients,(9) czerniak and coworkers observed hras mutation specifically in connection to codon 12 in 45% of the bladder cancers.(10) also, in a recent study by jebar and colleagues on 98 bladder tumors and 31 bladder cell lines, ras mutation was detected in 13% of both types of samples.(11) in total, there were 10 mutations in hras, 4 in kras, and 4 in nras. on the other hand, various levels of ras mutation at codon 12 have recently been reported in bladder cancer. while zhu and associates and buyru and coworkers showed 46.7% and 39% point mutation of hras at codon 12, respectively,(3,12) cattan and associates detected only 1% of such alterations.(13) furthermore, przybojewska and colleagues found the hras mutation in 84% of patients with bladder cancer using a pcr-restriction fragment length polymorphism assay.(16) in contrast to the above discussed investigations showing ras activation, our study detected no mutation in the ras gene family in any grades of bladder cancer in the 35 studied patients. it should be mentioned that the ras protein dysfunction may occur not only as a result of mutations in the ras gene, but also due to changes in the protein level. quantitative alterations in the expression due to gene amplification or overexpression could lead to continuous proliferative signals needed for cell propagation. previous studies demonstrated increased expression of ras protein in carcinoma in situ and high-grade tumors, but not in hyperplasia or low-grade tumors when immunohistochemical technique was applied.(14) vageli and associates reported an increase in ras transcripts in about 40% of the bladder cancers, as well.(25) all these studies indicate that the precise frequency of ras mutations in human bladder cancer is still unclear. the observed discrepancies in the mutation pattern of ras gene family among different populations suffering from bladder cancer may either reflect different etiological mechanisms involved in disease progression or alternative ras dysfunction such as gene amplification and/or overexpression.(14,25) notably, it is not surprising that iranian patients have a specific mutation pattern for p53 gene as it has been reported for esophageal cancer.(26) ecogenetic relationships and cultural conditions of may somehow explain the absence of ras gene family mutation in our patients. although the results so far reported still remain controversial, activation of the ras oncogene by point mutation or overexpression may be important in the carcinogenesis and progression of human bladder cancer. smoking is an established risk factor for bladder figure 3. kras gene product analysis in bladder cancer by polymerase chain reaction-restriction fragment length polymorphism. a, undigested dna from a healthy person (144-bp); ad, bstni-cut polymerase chain reaction product of the healthy person (115-bp and 29-bp); lane 27, undigested dna from patient 27; and lane 27d, the digested product from patient 27. mutation of ras in bladder cancer—karimianpour et al urology journal vol 5 no 4 autumn 2008 241 cancer.(27) consistent with the epidemiological evidence for an association between bladder cancer and smoking, we found that about 51% of our patients were smokers, which shows a direct correlation between smoking and the incidence of bladder cancer. however, the group under our investigation is too small in number to be considered for epidemiological conclusions. the other related risk factor of bladder cancer is age. our data showed nearly three-fourth of our patients were over 60 years of age. this is in accordance with the previous data showing more than 65% of bladder cancer patients in the united states were older than 65 years.(28) conclusion we failed to find ras gene mutation in our patients with bladder tumors. this observation may reflect the involvement of different etiological factors in the induction of this tumor. due to the reported studies and possibility of the involvement of various etiological factors, it is interesting to study the situation among iranian patients suffering from bladder cancer with various pathological low-grade and high-grade tumors regarding the status of these three genes. conflict of interest none declared. references 1. borden ls, jr., clark pe, hall mc. bladder cancer. curr opin oncol. 2003;15:227-33. 2. jemal a, murray t, ward e, et al. cancer statistics, 2005. ca cancer j clin. 2005;55:10-30. 3. buyru n, tigli h, ozcan f, dalay n. ras oncogene mutations in urine sediments of patients with bladder cancer. j biochem mol biol. 2003;36:399-402. 4. bos jl. ras oncogenes in human cancer: a review. cancer res. 1989;49:4682-9. 5. varras mn, koffa m, koumantakis e, et al. ras gene mutations in human endometrial carcinoma. oncology. 1996;53:505-10. 6. shinohara n, koyanagi t. ras signal transduction in carcinogenesis and progression of bladder cancer: molecular target for treatment? urol res. 2002;30:273-81. 7. capon dj, chen ey, levinson ad, seeburg ph, goeddel dv. complete nucleotide sequences of the t24 human bladder carcinoma oncogene and its normal homologue. nature. 1983;302:33-7. 8. oxford g, theodorescu d. the role of ras superfamily proteins in bladder cancer progression. j urol. 2003;170:1987-93. 9. fitzgerald jm, ramchurren n, rieger k, et al. identification of h-ras mutations in urine sediments complements cytology in the detection of bladder tumors. j natl cancer inst. 1995;87:129-33. 10. czerniak b, cohen gl, etkind p, et al. concurrent mutations of coding and regulatory sequences of the ha-ras gene in urinary bladder carcinomas. hum pathol. 1992;23:1199-204. 11. jebar ah, hurst cd, tomlinson dc, johnston c, taylor cf, knowles ma. fgfr3 and ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. oncogene. 2005;24:521825. 12. zhu d, xing d, shen x, liu j. a method to quantitatively detect h-ras point mutation based on electrochemiluminescence. biochem biophys res commun. 2004;324:964-9. 13. cattan n, saison-behmoaras t, mari b, et al. screening of human bladder carcinomas for the presence of ha-ras codon 12 mutation. oncol rep. 2000;7:497-500. 14. viola mv, fromowitz f, oravez s, deb s, schlom j. ras oncogene p21 expression is increased in premalignant lesions and high grade bladder carcinoma. j exp med. 1985;161:1213-8. 15. raply r. the nucleic acid protocols hand book. totowa, new jersey: human press; 2000. 16. przybojewska b, jagiello a, jalmuzna p. h-ras, k-ras, and n-ras gene activation in human bladder cancers. cancer genet cytogenet. 2000;121:73-7. 17. levesque p, ramchurren n, saini k, joyce a, libertino j, summerhayes ic. screening of human bladder tumors and urine sediments for the presence of h-ras mutations. int j cancer. 1993;55:785-90. 18. almoguera c, shibata d, forrester k, martin j, arnheim n, perucho m. most human carcinomas of the exocrine pancreas contain mutant c-k-ras genes. cell. 1988;53:549-54. 19. smit vt, boot aj, smits am, fleuren gj, cornelisse cj, bos jl. kras codon 12 mutations occur very frequently in pancreatic adenocarcinomas. nucleic acids res. 1988;16:7773-82. 20. vogelstein b, fearon er, hamilton sr, et al. genetic alterations during colorectal-tumor development. n engl j med. 1988;319:525-32. 21. rabbani f, cordon-cardo c. mutation of cell cycle regulators and their impact on superficial bladder cancer. urol clin north am. 2000;27:83-102, ix. 22. fujita j, srivastava sk, kraus mh, rhim js, tronick sr, aaronson sa. frequency of molecular alterations affecting ras protooncogenes in human urinary tract tumors. proc natl acad sci u s a. 1985;82:3849-53. 23. knowles ma, williamson m. mutation of h-ras is infrequent in bladder cancer: confirmation by singlestrand conformation polymorphism analysis, designed restriction fragment length polymorphisms, and direct sequencing. cancer res. 1993;53:133-9. mutation of ras in bladder cancer—karimianpour et al 242 urology journal vol 5 no 4 autumn 2008 24. saito s, hata m, fukuyama r, et al. screening of h-ras gene point mutations in 50 cases of bladder carcinoma. int j urol. 1997;4:178-85. 25. vageli d, kiaris h, delakas d, anezinis p, cranidis a, spandidos da. transcriptional activation of h-ras, k-ras and n-ras proto-oncogenes in human bladder tumors. cancer lett. 1996;107:241-7. 26. sepehr a, taniere p, martel-planche g, et al. distinct pattern of tp53 mutations in squamous cell carcinoma of the esophagus in iran. oncogene. 2001;20:736874. 27. dolin pj. an epidemiological review of tobacco use and bladder cancer. j smoking rel dis. 1991; 2 : 129143 . 28. jung i, messing e. molecular mechanisms and pathways in bladder cancer development and progression. cancer control. 2000;7:325-34. clinical trial registration the iranian registry of clinical trials (irct) has been launched (http://www.irct.ir/) thanks to the sponsorship by the iranian ministry of health. we strongly encourage researchers who would like to publish reports of their clinical trial in urology journal to register their studies in the irct or other registries that are proposed by the world health organization and the international committee of medical journal editors. registration of clinical trials before starting the research project is now considered a primary requirement by these organizations, and it is also emphasized by the world medical association declaration of helsinki. this helps to ensure that decisions about healthcare are informed by all of the available evidence, ensure that a trial and its results are publicly disclosed, avoid unnecessary duplication, facilitate recruitment of participants, identify gaps in research, encourage collaboration among researchers, and make it possible to identify potential problems and improve clinical trials. the links below would help you to find clinical trial registries and useful information on this issue: www.icmje.org/clin_trialup.htm www.icmje.org/faq.pdf www.irct.ir/ www.wma.net/e/policy/b3.htm case report response to cabazitaxel beyond 20 cycles in a patient with penile metastasis of prostate cancer: a case report elif atag1, huseyin salih semiz1, seher nazli kazaz1, emine burcin tuna2, ozhan ozdogan3, ozan bozkurt4, omer demir4, aziz karaoglu1 penile metastases are extremely rare events and generally occurs at a late stage of primary disease. they mostly originate from prostate and bladder in the genitourinary tract. penile metastases have a dismal prognosis and very low survival rates. we report a case of penile metastasis in 70-year-old geriatric male patient with prostatic adenocarcinoma who was treated with cabazitaxel chemotherapy beyond 20 cycles with a good response and acceptable minimal toxicity. keywords: cabazitaxel; penile metastasis; prostate cancer. introduction despite the rich and complex vascularization of the penis, metastasis to the penis is a very rare event(1). about 75% of the secondary penile tumors originate from the organs of the genitourinary tract. the most common primary malignancies which metastasize to penis are prostate and bladder carcinomas, followed by the rectosigmoid and renal carcinomas(2,3). despite various treatment options, prostate cancer patients with penile metastasis still have a poor prognosis(4). median survival has been reported 6 months in patients with penile metastasis of prostatic cancer in the literature(1-3). however in the last decade, treatment options for metastatic castration-resistant prostate cancer (mcrpc) have expanded with promising many new therapeutic agents. in this report, we present a case of prostate carcinoma spreading to the penis, who was treated with 21 cycles of cabazitaxel and had a good response with minimal toxicities. 1dokuz eylul university, faculty of medicine, department of medical oncology, izmir, turkey. 2dokuz eylul university, faculty of medicine, department of pathology, izmir, turkey. 3dokuz eylul university, faculty of medicine, department of nuclear medicine, izmir, turkey. 4dokuz eylul university, faculty of medicine, department urology, izmir, turkey. *correspondence: dokuz eylul university, faculty of medicine, department of medical oncology, 35210, balcova, izmir , turkey. tel: +90 232 412 48 01. fax: +90 232 277 23 03. e-mail:elifatag@gmail.com. received september 2016 & accepted december 2016 figure 1. 1a: axial images of an fluorine-18 fdg pet/ct show penile metastases before cabazitaxel treatment; 1b: axial images of an fluorine-18 fdg pet/ct show response after 6 cycles of cabazitaxel treatment. (fdg pet/ct: fluoro-deoxy glucose positron emission tomography-computed tomography) figure 2. histopathological specimen of the penile skin. tumor cells show psa reactivation (x400) case report 2985 case report a 70-year-old man was diagnosed with stage 2a (pt1cn0m0) prostate adenocarcinoma in 2001. gleason score was 3+3 and serum prostate specific antigen (psa) level was 14.2 ng/ml at that time. the patient was treated with definitive radiation therapy (rt) to the prostate-bed. after the rt, disease was stable for 4 years. in 2005, serum psa level increased and anti-androgen therapy was started with bicalutamide 50 mg/ day. psa levels reduced below to the normal range (0-4 ng/ml). however, in january 2011 serum psa level increased from 2.1 ng/ml to 6.7 ng/ml. bicalutamide dose was increased to 150 mg/day. in january 2012, multiple bone metastases occurred and serum psa level was 23.15 ng/ml. the patient was treated with intermittent subcutaneous injections of a leutenising hormone-releasing hormone agonist (goserelin 10.8 mg every 3 months), anti-androgen (bicalutamide 150 mg/ day), and zoledronic acid (4 mg every 28 days). in november 2012, bone metastases progressed. the patient was diagnosed with mcrpc and docetaxel (75 mg/m2 every 3 weeks) plus prednisone (10 mg/day) were started. serum psa level was decreased to 0.79 ng/ml and bone metastases were stable with six cycles of therapy. we gave three more cycles of docetaxel regimen and it was stopped at the ninth cycle due to adequate disease control. after the chemotherapy, bilateral orchiectomy was performed upon the patient’s requisition in december 2013. in may 2014, psa level was increased to 4.48 ng/ml and bone metastases progressed. abiraterone acetate, a selective inhibitor of cyp17 enzyme was started. after two months, the patient was applied to the our clinic with painless reddish solitary nodules on the penis and mons pubis. serum psa level was increased to 4.57 ng/ml. 18f-fluoro-deoxy glucose positron emission tomography-computed tomography (fdg pet/ ct) scan revealed a linear line f-18 fdg uptake on the penis (suv max: 5.8) and metastatic lesions on the bilateral pubic bones, right acetabulum, left ischial bone (figure 1a). a magnetic resonance imaging (mri) showed a 3.5x6.5 mm dermal nodule on the dorsolateral region of the penis and a mass throughout the corpus spongiosum. he underwent to the skin biopsy from the lesion on the glans penis. histological analysis revealed a poorly differentiated adenocarcinoma. diffuse staining of the neoplastic cells with keratin and psa at the immunohistochemistry demonstrated that the origin of the metastasis was prostate adenocarcinoma (figure 2). the patient’s karnofsky performance status was 90 and cabazitaxel (25 mg/m2 iv every 21 days) plus prednisone (10 mg/day) were started in july 2014. patient also received primary granulocyte colony stimulating factor (g-csf) prophylaxis after each cycle of cabazitaxel. psa level was decreased to 1.33 ng/ml and most of the skin lesions disappeared after 6 cycles (figure 3). fdg pet/ct scan showed a good partial response to therapy (suv max: 3.1) (figure 1b). bone metastases were stable. the patient tolerated the cabazitaxel regimen with minimal toxicities. we decided to continue the cabazitaxel regime until progression or intolerable toxicity. after 12th cycle, psa decreased to a nadir of 1.05 ng/ml and all skin lesions were disappeared. the treatment was well tolerated through 21 cycles. after 21 cycles, psa level increased to 3.48 ng/ ml, his imaging evaluations showed a progression of bone metastases, new pelvic metastatic lymph nodes and two skin lesions on the penis. cabazitaxel therapy was stopped and a sal vage chemotherapy regimen with weekly paclitaxel (80 mg/m2) was started, because patient still had a good performance status. discussion in prostate cancer, penile metastasis is extremely rare, with an incidence of less than 0.3%(4). possible mechanisms of metastasis to the penis are direct invasion, implantation, dissemination through the blood stream or dissemination through the lymphatic ducts(5). typically, penile metastasis of prostate adenocarcinoma figure 3. psa levels during the cabazitaxel treatment. cabazitaxel in metastatic prostate cancer-atag et al. vol 14 no 01 january-february 2017 2986 presents a painless nodule as in our case. kotake et al. have reported 25 cases with penile metastasis of prostate carcinomas and in their series, the main complaint of penile tumors were reported as penile nodule (80%), priapism (20%), painful erection (8%) and dysuria (4%). in the same study, penile metastasis appeared in castration-ressitant period in 15 cases (60%) as in our case(6). in the literature, there is also incidentally diagnosed penile metastasis with pet-ct in patients with no complaints. pet ct imaging was recommended as a noninvasive imaging technique for detection of the penil metastasis(7). psa is a reliable tumor marker that widely used in both diagnosis and follow-up for prostate cancer and typically correlate with tumor activity. however, patients with penile metastasis without psa increase has been reported in the literature(8-10). in this case serum psa level was elevated when admitted with penile metastasis. current treatment options include local excision, partial or total penile amputation, androgen blockage therapy, radiotherapy and chemotherapy. penile amputation is an undesirable option due to it’s negative psycological effects for the loss of sexual organ and operative complications. therefore surgical therapy is generally recommended as an option after other treatments have failed. radiotherapy is an another effective treatment option reducing a lesion’s size as well as improving patient’s symptoms with limited side effects; however, it can cause ulceration of the glans penis and urethral strictures(2,6,7). many systemic chemotherapeutic agents and regimens have used for treatment of penile metastases from primary prostate cancer until now. vinorelbine, cyclophosphamide, estramustine, gemcitabine, mitomycine, carboplatin-based combinations have showed minimal efficacy without any survival benefit(7,9,11). despite all of these agents and treatment modalities, prognosis is poor in these patients and median survival time has been reported only 6 months(1,6,9,12). to our knowledge, this case report is the first manuscript in the literature that showed a good response with systemic chemotherapy in penile metastasis from prostate cancer. in addition, this report describe firstly the role of cabazitaxel in this metastasis site. cabazitaxel, a semisynthetic antimicrotubule agent derived from taxanes, is the first fda-approved agent for second-line chemotherapy in mcrpc after treatment with docetaxel. in the phase iii tropic trial, median survival was 15.1 months who received cabazitaxel arm compared with 12.7 months in mitoxantrone arm (p < .001)(13). in our case, time to progression (ttp) was 14 months and overall survival was 25 months from july 2014 until june 2016 on the cabazitaxel therapy. in addition, we report a good tolerance to the cabazitaxel through the 21 cycles. although our case was in geriatric age group, he reported minimal toxicities (grade 1 or 2) through cabazitaxel cycles. we didn’t detected any neutropenic fever. pivotal tropic trial reported a high rate neutropenia (grade ≥3 82%) and neutropenic fever (8%). however the study had been allowed to use of prophylactic growth factor. ozguroglu et al. reported that the appropriate and timely use of g-csf reduces the occurrence of neutropenia in men receiving cabazitaxel(14). especially patients who have high risk factors need primary g-csf prophylaxis. therefore our patient received primary g-csf prophylaxis. in the tropic study, the cabazitaxel chemotherapy duration was limited to 10 cycles because of a comparable exposure with mitoxantrone arm. but some small series and case reports suggested that beyond to 10 cycles of cabazitaxel chemotherapy can be given until progression with minimal toxicities. we administered 21 cycles of cabazitaxel chemotherapy without any severe myelosuppression or other toxicities. pal sk et al. reported a 73-year-old prostate cancer patient could be received cabazitaxel therapy for a total of 24 cycles and they reported no toxicity in association with therapy(15). in a case series, the toxicity profile of four crpc patients who have been used over 10 cycles of cabazitaxel was reported. in this trial, noronha et al. found that peripheral neuropathy was the only clinically significant toxicity associated with cumulative doses. clinically significant neuropathy occurred after 15-17 cycles and it was partially reversible. another remarkable case was recently reported by lorenzo gd et al.(16) a patient who has metastatic crpc had refused continuation of cabazitaxel beyond the 10th cycles despite showing response to treatment. rapidly agressive progression was developed and the patient died with hepatic failure two months after discontinuation cabazitaxel chemotherapy. although there is no conclusive trial investigating the optimal duration of cabazitaxel therapy, it seems safe. in conclusion, penile metastasis of prostate cancer is very rare and it is associated with a poor prognosis. we report a successful treatment, using cabazitaxel chemotherapy in mcrpc with penile metastasis. the importance of our report is highlighting a few points. firstly, a patient who has penile metastasis from prostate cancer was successfully treated. psa decreased to a nadir of level and all skin lesions were disappeared. secondly, we could use prolonged cabazitaxel chemoterapy with a good response until 21 cycles. thirdly, we showed that cabazitaxel chemotherapy can be used for a long time with acceptable and manageable toxicities. extended using of cabazitaxel chemotherapy has no increased toxicity profile. lastly, our report suggested that extended cycles of cabazitaxel chemotherapy can be also used effectively and safely in geriatric patients. references 1. ansari h, prashant r, franks a. prostatic carcinoma metastasis to the penis – an uncommon site. lancet oncol 2003;4:705-6. 2. cante d, franco p, sciacero p, et al. penile metastasis from prostate cancer: a case report. tumori. 2014;100:14-6. 3. chaux a, amin m, cubilla al, young rh. metastatic tumors to the penis: a report of 17 cases and review of the literature. int j surg pathol. 2011;19:597-606. 4. tu sm, reyes a, maa a, et al. prostate carcinoma with testicular or penile metastases. clinical, pathologic, and immunohistochemical features. cancer.2002;94:2610-7. 5. abeshause bs, abeshause ga. metastatic tumors of the penis: a review of the literature and a report of two cases. j urol. 1961;86:99112. 6. kotake y, gohji k, suzuki t, et al. metastases cabazitaxel in metastatic prostate cancer-atag et al. case report 2987 to the penis from carcinoma of the prostate. int j urol. 2001;8:83-6. 7. spinapolice eg, fuccio c, rubino b, et al. penile metastases from bladder and prostate cancer detected by pet/ct: a report of 3 cases and a review of literature. clin genitourin cancer. 2014;12:e155-9. 8. cai t, salvadori a, nesi g, et al. penile metastasis from a t1b prostate carcinoma. onkologie. 2007;30:249-52. 9. pierro a, cilla s, digesù c, morganti ag. penile metastases of recurrent prostatic adenocarcinoma without psa level increase: a case report.j clin imaging sci. 2012;2:44. 10. kobashi-katoh r, tanioka m, takahashi k, miyachi y. skin metastasis of prostate adenocarcinoma to glans penis showing no correlation with serum prostate-specific antigen level. j dermatol. 2009;36:106-8. 11. powell fc, venencie pc, winkelmann rk. metastatic prostate carcinoma manifesting as penile nodules. arch. dermatol.1984;120:1604-6. 12. ghosh b, dorairajan ln, kumar s, basu d. penile nodule with inguinal lymphadenopathy: prostatic adenocarcinoma masquerading as penile cancer. indian j urol. 2013;29:56-8. 13. de bono js, oudard s, ozguroglu m, et al. prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. lancet. 2010;376(9747):1147-54. 14. ozguroglu m, oudard s, sartor a. o, et al. effect of g-csf prophylaxis on the occurrence of neutropenia in men receiving cabazitaxel plus prednisone for the treatment of metastatic castration-resistant prostate cancer (mcrpc) in the tropic study. j clin oncol 29: 2011 (suppl 7; abstr 1443). 15. pal sk, stein ca. prolonged therapy with cabazitaxel in an octogenarian with metastatic castration-resistant prostate cancer. clin genitourin cancer. 2012;10:274-6. 16. di lorenzo g, buonerba c, de placido s. rapidly progressive disease in a castrationresistant prostate cancer patient after cabazitaxel discontinuation. anticancer drugs. 2015;26:236-9. 17. noronha v, joshi a, prabhash k. beyond ten cycles of cabazitaxel for castrate-resistant prostate cancer. indian j cancer. 2014;51:3635. cabazitaxel in metastatic prostate cancer-atag et al. vol 14 no 01 january-february 2017 2988 vol 15 no 05 september-october 2018 285 sexual dysfunction and andrology is there any association between regular physical activity and ejaculation time?. yildiray yildiz*, muhammet fatih kilinc , omer gokhan doluoglu purpose: premature ejaculation (pe) is a prevalent disorder in males leading to sequelae such as lack of self-confidence, anxiety, depression and unsatisfactory intercourse for these men and their partners. the aim of this study was to evaluate the relationship between ejaculation and physical activity. materials and methods: group 1 comprised 112 participants who took regular physical activity and group 2 comprised 126 participants with a sedentary lifestyle. the participants were 18-45 years old, same ethnic origin, in same location and had regular sexual activity for at least 6 months. a comparison was made by metabolic equivalents (met), premature ejaculation diagnostic tool (pedt) and intravaginal ejaculatory latency time (ielt). result: the mean age of groups 1 and 2 was 25.34 years (range, 18-41 years) and 28.49 years (range, 19-45 years), respectively (p = .21). the mean pedt score was 6.18 in group 1, and 10.02 in group 2. significant differences were found between groups 1 and 2 (p = .001). the mean met score of group 1 was 3448.23 metmin/week (3012-4496 metmin/week) while the met score of group 2 was 201.87 metmin/week (66-744 metmin/week) (p = .001). the mean ielt of groups 1 and 2 were 316.42 s (120-1530 s) and 189.32 s (20-450 s), respectively. the mean ielt was significantly higher in group 1 (p = .001). conclusion: the study results demonstrated that pe was less frequent in men that perform regular physical activity compared to those with a sedentary lifestyle. it can be assumed that regular physical activity may be effectual in gaining a sexual life of higher quality. prospective studies with longitudinal data are needed to further understand the potential relationship between regular physical activity and premature ejaculation. keywords: intravaginal ejaculatory latency time; metabolic equivalents; premature ejaculation; premature ejaculation diagnostic tool; regular physical activity. introduction premature ejaculation (pe) is the most frequent sex-ual dysfunction in males, and its prevalence has been reported as 21-33% (1,2). currently, there are no universal criteria for the diagnosis, or treatment strategies or approaches for pe. lack of observational studies directed to pe makes comprehension of this sexual dysfunction difficult(3,4). the common point for definition of pe is a short duration between penetration and ejaculation, little or no control of the voluntary control of ejaculation, and the frustration and negative effect of this condition on the individual(5). there are various treatment methods since ejaculation physiology and neuroanatomy has not yet been clearly demonstrated(3). it has been shown that trace elements necessary in the body composition, such as magnesium, have an important effect in the pathophysiology of premature ejaculation(6) . according to the neurobiological hypothesis of waldinger(4), a dysfunction in the serotonin pathway of the central system such as serotonin-2c hyposensitivity and/or serotonin-1a receptor hypersensitivity is a possible cause of lifelong pe. these experimental animal models showed that serotonergic activity at the hypothalamic level inhibited the ejaculation reflex. based on this physiological effect, selective serotonin reuptake inhibitors (ssri), and serotonin agonists increase intradepartment of urology, ankara training and research hospital, ankara, turkey. *correspondence: department of urology, ankara training and research hospital, 06340, ankara, turkey. tel: +90 312 595 3000 fax: +90 312 363 3396 e-mail: dryildiray71@gmail.com. received june 2017 & accepted february 2018 vaginal ejaculation latency time (ielt). a number of studies have shown that exercise increased the functional effect of serotonin in the human brain(7). the effects of physical activity level on human health have attracted interest worldwide. lack of physical activity forms the basis of various health problems, whereas regular physical activity contributes to the prevention and treatment of a number of disorders(8). the results of studies investigating the effect of physical exercise on ejaculation are controversial. aloosh m et al.(6) claimed that long-term exercise caused premature ejaculation by reducing the extracellular magnesium level. on the other hand, kilinc et al.(9) recently reported that physical activity might be an alternative treatment for patients with lifelong pe. in the current study, a comparison was made of ejaculation control, ielt, and the prevalence of pe in men undertaking regular physical activity, and those with a sedentary lifestyle. material and methods study population approval for the study was granted by the local ethics committee. the study was conducted between november 2016 and january 2017 and included 112 males who regularly performed callisthenic and/or fitness exercise in a sports center for at least 6 months, and 126 individuals with a sedentary lifestyle who were staff in our hospital. all participants were living in ankara, turkey and all of them were same ethnic origin (caucasian). informed consent was obtained from all individual participants included in the study. this trial was registered with clinicaltrials.gov, number nct02984592. the exclusion criteria were the presence of chronic systemic disorders such as diabetes or hypertension, use of narcotic/hypnotic drugs or stimulants, anabolic steroids, selective serotonin receptors inhibitors (ssri) and previous diagnosis and treatment for pe. urinalysis and urine cultures were obtained from all the participants, and those with urinary infection were excluded. the participants were questioned about the presence of chronic pelvic pain and dysuria and those with suspected chronic prostatitis were not included in the study. the enrolment algorithm for the participants is illustrated in figure 1. patient selection and evaluation the voluntary participants were informed about the subject and context of the study. the participants included in the study were 18-45-years old, sexually active, heterosexual,without erectile dysfunction, and had a sexual partner for at least six months, and sexual intercourse at least twice a week. all participants completed the international index of erectile function (iief) questionnaire(10). none of the participants had erectile dysfunction. the ielt value was taken according to the duration determined by the sexual partner with the stopwatch method, and < 1 minute was considered as pe. either one of the couple was allowed to be responsible for handling the stopwatch, although it was requested that the same person remained responsible for each ielt measurement for the duration of the study. the instructions stated that the duration of ielt is calculated from time of vaginal penetration until ejaculation of semen. all calibrated stopwatches were provided by the researchers before the study. participants were instructed not to use a condom, lubricant gel or any other medication during sexual intercourse. the economic status of the family was estimated by taking into account the limits for hunger and poverty line announced annually by the turkish statistical institute. families with an income below the hunger limit were considered to have a low economic status, an income between the hunger and poverty limits was considered moderate, and those with an income above the poverty limit were considered to have a high economic status(11). the participants that met the inclusion criteria completed the premature ejaculation diagnostic tool (pedt) (12) and international physical activity questionnaire (ipaq)(13). the turkish version of pedt(14) , as validated by serefoglu, and ipaq(15), as validated by karaca, were used in this study. sexual partner satisfaction and performance status were assessed with the premature ejaculation profile, as validated by serefoglu.(16) measurement of ielt was explained to the participants, and the durations were recorded in the second interview. in the short form of the ipaq,(13) the following equations were used to calculate metabolic equivalent of task (met)-min/week scores in relation to the physical activity status and durations of the participants (table 1).the participants were divided into two groups. group 1 included those who performed regular sporting activities such as fitness and callisthenic exercise and were at least in the minimally active category of the ipaq classification (table 1) . the participants in group 2 had a sedentary lifestyle and were in the inactive category of the ipaq classification. the minimum sample size was estimated using an a priori power analysis based on a confidence level of 0.95 and a power of 0.80. the mean of the significant differences was based on the data of the first 88 participants. the 2 groups were compared in respect of mean ielt, met scores and pedt scores. the data analysis was performed using spss for windows, version 11.5 software (spss inc., chicago, il, united states). descriptive statistics for variables with a non-normal distribution and categorical variables were shown as median (min-max) and the number of cases (n) and percentage (%), respectively. the mann whitney u test was used for the intergroup analysis of continuous variables. categorical variables were analyzed with the chi square test. the relationships between pedt, ielt and met were evaluated with pearson bivariate correlation analysis. a value of p < .05 was considered statistically significant. results of the total 258 participants, a prospective analysis was made of 238 who met the inclusion criteria. group 1 comprised 112 participants and group 2, 126 (table 2). a total of 20 participants were excluded from the study.(figure 1) the individuals in group 1 stated that they had participated in regular exercise programs for the previous 6 months. the participants in group 2 stated that they had not performed any regular exercise in the previous 6 months. the mean age of group 1 (sportsmen group) was 25.34 years (range, 18-41 years) and the mean age of group 2 (sedentary group) was 28.49 years (range, 19-45 years). the distribution of age was similar in groups 1 and 2 (p = .21). the mean met scores were 3448.23 metmin/week figure 1. flow diagram of the study effect of exercise on ejaculation-yildiz et al. sexual dysfunction and andrology 286 vol 15 no 05 september-october 2018 287 (3012-4496 metmin/week) and 201.87 metmin/ week (66-744 metmin/week) in groups 1 and 2, respectively. the met score of group 1 was significantly higher than group 2 (p = .001). the mean ielt was 314.39 s (120-1530 s) in group 1, and 186.29 s (20450 s) in group 2. the mean ielt was significantly longer in group 1 (p = .001). ielt was not shorter than 60 secs in any of the participants in group 1, whereas 34 subjects (26.98%) in group 2 reported ielts shorter than 60 secs. the mean pedt score was 6.18 in group 1, and 10.02 in group 2. the pedt scores of group 1 were significantly lower than those of group 2 (p = .001). none of the participants in group 1 had a pedt score ≥ 11, whereas 32.53% of the participants in group 2 had pedt scores ≥ 11. in group 1, 79.47% (89) of the participants found their sexual performance adequate, but 20.53% (23) felt that their sexual performances were not adequate. those rates were 64.28% (81) and 35.72% (45), respectively, in group 2. there was a significant correlation between ielt and met (p > .001 r : 0.368). there was a significant negative correlation between pedt and met (p > .001 r : -0.383). the participants in groups 1 and 2 were asked whether their sexual partners were completely satisfied with the sexual intercourse. in group 1, 75.90% (85) of the participants thought that their partners were completely satisfied, 14.28 % (16) thought that their partners were partially satisfied, and 9.82% (11) thought that their partners were not completely satisfied. those rates were 56.35% (71), 25.40% (32), and 18.25% (23), respectively in group 2. none of the participants in group 1 were diagnosed with pe, whereas 24.60% (31) of group 2 were diagnosed with pe (table 2). discussion in this study, a comparison was made of participitants with high met scores that employed regular physical activity in their daily lives, with men with sedentary lifestyles. the group who undertook sport was found to have longer ielt, and lower pedt scores. it was also demonstrated that pe was less frequent in men with regular exercise compared to the sedentary individuals. premature ejaculation is a quite frequent sexual dysfunction, which significantly affects quality of life and the sexual lives of the partners(17) . the current definition of pe according to the international society of sexual medicine (issm) is: “ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration (lifelong pe), or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired pe), the inability to delay ejaculation on all or nearly all vaginal penetrations, negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy”(18) . this guideline describes secondary (acquired) premature ejaculation as a clinically significantly short time to ejaculation after vaginal penetration; this duration is usually shorter than 3 minutes, ejaculation cannot be delayed, and this condition causes stress, discomfort, distress, and/or avoidance of sexual intercourse in the individual. pedt is a psychometric test developed to diagnose pe. it was developed by symond et al.(12) and validated in turkish by serefoglu et al.(14) this test measures the control of the individual over ejaculation, whether it occurs with a low level of stimulus, the frequency of the condition, and whether it causes stress and discomfort to the individual. pe is not present if the test score is ≤ 8, a score 9-10 indicates probable pe, and a score ≥ 11 indicates pe. the participants in this study were given the short-ipaq, which is a questionnaire used to determine the physical activity and sedentary lifestyles of adults. the physical activity is divided into 3 basic classes in the survey: 1) vigorous physical activity (football, basketball, aerobics, fast cycling, weightlifting, heavy lifting, etc.); 2) moderate physical activity (carrying light weights, normal-speed cycling, folk dancing, dancing, bowling, table tennis etc.); 3) walking. the final question of the questionnaire queries the duration of activities performed without moving (sitting, lying down, etc.). the level of physical activity is calculated with the metabolic equivalent (met) method. one met equals energy consumption in ml/ kg/min while sitting still. in an average adult, 1 met table 1. categories of physical activity inactive (category 1) conditions that cannot be included in category 2 and 3 are considered as inactive <600 met-min/week minimally active (category 2) • ≤ 3 days of rigorous activity for at least 20 minutes 600-3000 met-min/week • ≤ 5 days of moderate activity or daily walking for at least 30 minutes • ≤ 5 days of walking and moderate activity combination providing a minimum of 600 met-min/week highly active ( category 3) • rigorous activity providing a minimum of 1500 met-min/week for at least 3 days >3000 met-min/week • ≤7 days of walking combined with moderate or rigorous activity providing a minimum of 3000 met-min/week group 1 group 2 p value mean age (years) 25.34 ± 5.56 (18-41) 28.49 ± 6.22 (19-45) p = .21 mean body mass index (kg/m2) 23.45 ± 6.34 25.12 ± 9.19 p = .16 mean number of sexual intercourse(weekly) 3.08 ± 1.61 2.73 ± 1.01 p = .22 economic status low 37 (%33) 43 (%34.1) p = .32 medium 54 (%48.2) 58 (%46) high 21(%18.7) 25 (%19.8) met score (met-min/week) 3448.23 ± 357.27 (3012-4496) 201.87 ± 152.66 (66-744) p = .001 ielt (seconds) 316.42 ± 187.59 (120-1530 ) 189.32 ± 112.26 (20-450 ) p = .001 pedt score 6.18 ± 1.75 10.02 ± 3.56 p = .001 pe (%) 0 24.60% table 2. participants characteristics effect of exercise on ejaculation-yildiz et al. = 3.5 ml/kg/min. this value may be used to determine resting o 2 and energy consumption rates. a number of studies have investigated a correlation of erectile dysfunction and exercise(18). erectile dysfunction has been associated with individuals with a sedentary lifestyle, and daily exercise of less than 200 kcal. the risk of erectile dysfunction has been reported to decrease by 70% in those who increased regular physical activity in their daily lives(19,20). a study performed on a young and healthy population reported that regular physical activity improved erectile function, and sexual dysfunction was more frequent in young males with sedentary lifestyles(21). serotonin (5-hydroxytriptamin) plays a very important role in ejaculation activity(22). serotonergic fibers are found among the sensory axons and motor neurons in the spinal cord that play a role in ejaculation. they are found in the dorsal and ventral horns, dorsal commissural gray and thoracolumbar intermediolateral cell column, and sacral parasympathetic nucleus of the lumbosacral spinal cord(23). however, serotonergic postsynaptic receptors are found in the lumbar spinothalamic region, suggesting that serotonin plays a role in ejaculation through possible connections in the spinal cord. serotonergic neurons in nucleus paragigantocellularis that is situated in the ventrolateral medulla of the brain stem innervate bulbospongiosus muscles that play a role in the inhibition of ejaculation(24). ssris are used in the treatment of pe based on the effect of serotonin on ejaculation. ssris block 5-ht transporters in synapses, stop axonal reuptake of serotonin, increase neurotransmission of 5-ht, stimulate 5-ht2c receptors in the post-synaptic membrane, and delay ejaculation(25). post et al.(26) increased the physical activities of the patients with depression, and measured the levels of biogenic amines in cerebrospinal fluid before and after this intervention. physical activity was seen to increase the level of 5-hydroxyindoleacetic acid (5-hiaa). chaouloff et al.(27) performed a study on rats, and showed that tryptophan and 5-hiaa levels increased in the brain ventricles of the rats with increased physical activity. intracerebral dialysis studies have shown that exercise increased extracellular serotonin and 5-hiaa levels in various regions of the brain, such as the hippocampus and cortex(28-30). jacobs et al.(31) suggested two mechanisms to explain the increase of serotonin levels with exercise. motor activity increases the activity of serotonin neurons, and hence synthesis and release of serotonin increase. the other mechanism suggests an increase of a serotonin precursor, tryptophan, after exercise(32). a recent, prospective, sham-controlled study was the first clinical study to demonstrate an association between regular exercise and premature ejaculation(9). 105 patients diagnosed with pe were divided into three groups; 35 were treated with dapoxetine, 35 performed moderate exercise, and 35 performed minimal exercise (sham). at the end of the study, when comparison was made of the premature ejaculation diagnostic tool (pedt) and intravaginal ejaculatory latency time (ielt), there was a statistically significant decrease in pedt scores, and increase in ielt in the dapoxetine and moderate exercise groups compared to the sham group. it was emphasized that regular exercise of longer than 30 min at least 5 times a week leads to ejaculation delay and may be an alternative treatment for pe. the main limitation of the current study is that it was a cross-sectional study. therefore, there are no data of the long-term follow-up of these participants. self-reporting of the subjects is a limitation of this study. self-reported ielt tends to be more inaccurate than stopwatch-recorded ielt and pe status based on pedt score. some authors have argued that the specificity of pedt is relatively low to be a reliable tool in diagnosing pe(33). conclusions the results of this study showed that pe was less frequent in men who performed regular physical exercise compared to those with a sedentary lifestyle, and it can be assumed that regular physical exercise may be effectual in gaining a sexual life of a higher quality. prospective studies with longitudinal data are needed to further understand the potential relationship between regular physical activity and premature ejaculation. acknowledgements we express our gratitude to mrs. caroline jane walker for her support in the proofreading the manuscript. conflict of interest the authors have no conflicts of interest. references 1. rowland d, perelman m, althof s, barada j, mccullough a, bull s. self‐reported premature ejaculation and aspects of sexual functioning and satisfaction. j sex med 2004; 1: 225-32. 2. laumann eo,paik a,rosen rc.sexual dysfunction in the united states:prevalence and predictors. jama 1999;281:537-44. 3. carson c, gunn k. premature ejaculation:definitio and prevalence. int j impot res 2006;18 (suppl 1):s5-s13. 4. waldinger md. the neurobiological approach to premature ejaculation. j urol 2002;168:2359-67. 5. mcmahon cg, abdo c, incrocci l, et al. disorders of orgasm and ejaculation in men. j sex med 2004;1:58–65. 6. aloosh m, hassani m, nikoobakht mr. seminal plasma magnesium and premature ejaculation: a case-control study. br j urol 2006;98: 402-4 7. simon n. young. how to increase serotonin in the human brain without drugs. j psychiatry neurosci 2007;32:395. 8. bulut s. sağlıkta sosyal bir belirleyici; fiziksel aktivite. turk hij den biyol derg, 2013;70: 205-14. 9. kilinc mf, aydogmus y, yildiz y, doluoglu og. impact of physical activity on patient self-reported outcomes of lifelong premature ejaculation patients: results of a prospective, randomised, sham-controlled trial. andrologia. 2017 mar 6. doi: 10.1111/and.12799. [epub ahead of print] effect of exercise on ejaculation-yildiz et al. sexual dysfunction and andrology 288 vol 15 no 05 september-october 2018 289 10. rosen rc, riley a, wagner g, .et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology 1997;49:82230. 11. turkish statistical institute, turkish statistical institute website, 2017. http://www.tuik. gov.tr/pretablo.do?alt_id=1013. accessed october 27, 2017 12. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol 2007;52:565–73 13. craig cl, mashall al, sjöström m, et al. international physical activity questionnaire: 12country reliability and validity. med sci sports exerc, 2003; 35: 1381-95. 14. serefoglu ec, cimen hi, ozdemir at, symonds t, berktas m, balbay md. turkish validation of the premature ejaculation diagnostic tool and its association with intravaginal ejaculatory latency time. int j impot res 2009;21:139–44 15. karaca a and turnagöl hh. ipaq anketinin geçerlilik ve güvenirlilik çalışması. hacettepe üniversitesi spor bilimleri dergisi 2007, 18, , 68-84. 16. serefoglu ec, yaman o, cayan s et al. the comparison of premature ejaculation assessment questionnaires and their sensitivity for the four premature ejaculation syndromes: results from the turkish society of andrology sexual health survey. j sex med 2011; 8: 1177-85. 17. gurkan l, oommen m, hellstrom wjg. premature ejaculation: current and future treatments. asian j androl 2008;10:102–5 18. serefoglu ec, mcmahon cg, waldinger md, et al. an evidence-based unified definition of lifelong and acquired premature ejaculation: report of the second international society for sexual medicine ad hoc committee for the definition of premature ejaculation. j sex med 2014; 11:1423-41. 19. derby ca, mohr ba, goldstein i, feldman ha, johannes cb, mckinlay jb. modifiable risk factors and erectile dysfunction:can lifestyle changes modify risk? urology 2000;56:302–6 20. feldman ha, johannes cb, derby ca, et al. erectile dysfunction and coronary risk factors: prospective results from the massachusetts male aging study. prev med 2000;30:328– 38. 21. hsiao w, shrewsberry ab, moses ka, et al. exercise is associated with better erectile function in men under 40 as evaluated by the international index of erectile function. j sex med 2012;9:524–30 22. oliver b,chan js, pattij t, et al. psychopharmacology of male rat sexual behaviour: modeling human sexual effect of exercise on ejaculation-yildiz et al. dysfunctions? int j impot res 2006;18(suppl 1): s14-s23 23. maxwell l, maxwell dj, neilson m, kerr r. a confocal microscopic survey of serotoninergic axons in the lumbar spinal cord of the rat: colocalization with glutamate decarboxylase and neuropeptides. neuroscience 1996,75:471-80 24. marson l, mckenna ke. a role for 5-hydroxytryptamine in descending inhibition of spinal sexual reflexes. exp brain res 1992; 88:313-20 25. mcmahon cg. dapoxetine: a new option in the medical management of premature ejaculation. ther adv urol 2012;4:233-51. 26. post rm, goodwin fk. simulated behavior states: an approach to specificity in psychobiological research. biol psychiatry 1973;7:237-54 27. chaouloff f, elghozi jl, guezennec y, laude d. effects of conditioned running on plasma, liver and brain tryptophan and on brain 5-hydroxytryptamine metabolism of the rat. br j pharmacol 1985;86: 33-41. 28. wilson wm, marsden ca. in vivo measurement of extracellular serotonin in the ventral hippocampus during treadmill running. behav pharmacol 1996;7:101-4. 29. gomez-merino d, béquet f, berthelot m, chennaoui m, guezennec cy. site-dependent effects of an acute intensive exercise on extracellular 5-ht and 5-hiaa levels in rat brain. neurosci lett 2001;301:143-6. 30. meeusen r, piacentini mf, kempenaers f, et al. brain neurotransmitter levels during exercise. dtsch z sportmed 2001;52:361-8 31. jacobs bl, fornal ca. activity of serotonergic neurons in behaving animals. neuropsychopharmacology 1999;21:9s-15s 32. chaouloff f, laude d, guezennec y, elghozi jl.motor activity increases tryptophan, 5-hydroxyindoleacetic acid, and homovanillic acid in ventricular cerebrospinal fluid of the conscious rat. j neurochem 1986;46:1313-6. 33. serefoglu ec, yaman o, cayan s, et al. the comparison of premature ejaculation assessment questionnaires and their sensitivity for the four premature ejaculation syndromes: results from the turkish society of andrology sexual health survey. j sex med 2011;8:1177– 85. endourology and stone diseases x-ray free minimally invasive surgery for urolithiasis in pregnancy abbas basiri,1 akbar nouralizadeh,1* amir h kashi,1,2 mohammad hadi radfar,1 mahmoodreza nasiri,1 mahdi zeinali,1 reza sarhangnejad,1 seyed-hossein hosseini-sharifi1 purpose: our goal was to present our experience with ultrasound guided supine or prone percutaneous nephrolithotomy in three pregnant women under spinal anesthesia. materials and methods: three pregnant women in the 16th, 20th and 28th weeks of pregnancy presented with symptomatic large renal stone in the first patient and multiple renal stones in the second and third patients which were unresponsive to conventional medical therapy. they requested a definitive stone treatment. the operations were done in november 2012, june 2014 and february 2015. data was gathered prospectively. all steps of gaining access to the pyelocalyceal system including needle insertion, tract dilation, and amplatz sheath placement were performed under ultrasonography guidance. tract was dilated with a single shot technique. the first two procedures were performed in supine position and the third procedure was performed in lateral flank position. results: two patients were stone-free postoperatively and one patient had only an asymptomatic 4 mm residual stone. they were discharged on the 2nd postoperative day and had an uneventful postoperative course. no fever, bleeding or renal colic was noticed during postoperative hospitalization. all patients delivered their fetuses at term without any abnormality reported by the examining pediatric specialist after their birth. conclusion: ultrasonography can be used as an imaging modality guiding all steps of obtaining percutaneous access in pregnant women. supine or flank ultrasound guided percutaneous nephrolithotomy can be offered to pregnant women in whom conservative measures fail to the patients’ wellbeing. keywords: percutaneous nephrolithotomy, ultrasonography, pregnancy, supine, flank. introduction since the first percutaneous nephrolithotomy (pcnl) which was performed in 1976, pcnl technique has evolved substantially.(1) traditionally, pcnl was performed under general anesthesia and fluoroscopy guidance in prone position. in recent years, various positions and imaging techniques with high success rates have been applied in pcnl. pcnl has been performed in supine, flank, and prone-flexed positions using x-ray, ultrasonography (us), computed tomography (ct) scan, or blind access techniques.(2-7) in pregnancy, 70-80% of symptomatic calculi pass spontaneously with conservative management leaving no sequelae. however; fever, infection, uncontrolled pain and progressive hydronephrosis, occurring in 30% of the patients, are indications for surgical intervention. (8) the current recommended interventions for symptomatic pregnant women with renal calculi are placement of nephrostomy or ureteral catheter. however in some patients, it becomes necessary to implement a definitive intervention or the patients ask for a definitive intervention. the concerns about percutaneous management of renal stones in a pregnant woman are anesthesia, prone positioning, and delivery of hazardous x-ray. we previously reported the use of totally us-guided pcnl in supine and flank positions(9, 10) and the use of spinal anesthesia for pcnl.(11) we used this method in three pregnant women who presented to our center. to our knowledge, there is limited prior experience in this field.(12,13) patient 1 a 26-year-old pregnant woman presented with severe left flank pain, nausea, and vomiting in the 16th weeks of pregnancy. the patient had history of previous stone passage. us revealed a 2.4 cm stone in the pelvis of the left kidney with mild to moderate hydronephrosis. analgesic and serum therapy were given to the patient. urine culture was positive and the patient was given 1 urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2 hasheminejad kidney center, tehran, iran. *correspondence: urology and nephrology research center, shahid labbafinejad medical center, 9th boostan street, pasdaran avenue, tehran, iran. tel: +98 21 22588016. e-mail: nouralizadeh@yahoo.com. received october 2015 & received december 2015 endourology and stone diseases 2496 vol 13 no 01 january-february 2016 2497 ultrasound-guided supine pcnl in pregnancy-basiri et al. antibiotics for 7 days and a repeat urine culture was negative. conservative measures were continued for 3 weeks but she still experienced severe pain. nephrostomy or double-j (dj) stent insertion was suggested to the patient, but she refused and requested for a definitive stone treatment. after consultation with her obstetrician and anesthesiologist, we suggested performing supine us-guided pcnl. potential risks of the procedure were explained to the patient and her family, and informed consent was obtained. the patient was operated on the 10th of november 2012. after spinal anesthesia, the patient was placed in supine position. cystoscopy was performed and a 5 french (f) ureteral catheter was inserted. access to the lower calyx was obtained under us guidance. all steps of tract dilation and 28 f amplatz sheath insertion were controlled with us avoiding x-ray exposure. nephroscopy was performed, and the stone was fragmented using pneumatic lithoclast and removed from the kidney. residual stones were checked with us. ureteral catheter was then removed and dj ureteral stent inserted anterogradely. no nephrostomy tube was inserted at the end of procedure. operation duration was 45 minutes. the patient was stone free on the first postoperative day us, and was discharged on the second postoperative day. no fever, gross bleeding or renal colic was noticed during postoperative hospitalization. dj was removed after 4 weeks. the patient was followed until delivery and the after birth neonatal examination by the pediatric specialist revealed no abnormality. patient 2 a 25-year-old female was referred by a urologist suffering from intractable renal colic in the 20th week of pregnancy. she had history of kidney stones. conservative management strategies (nephrostomy or dj) had been offered to the patient but she had requested for a definitive modality and hence referred to the office of one figure 1. ultrasonography demonstrates kidney stones in the second patient. figure 2. applying needle-holder under ultrasonography guidance to enter the proper calyx. the red line indicates the needle path denoted by its echogenicity. of the authors (a.b). us revealed 4 stones on the right side (15 mm, 9 mm, 4 and 3 mm) with mild-moderate hydronephrosis (figure 1). mri was requested which confirmed mild to moderate hydronephrosis of the right kidney. the patient was consulted about the potential risks of supine us-guided pcnl and informed consent was obtained. she was operated on the 4th of june 2014. the operation was performed in supine position. ureteral catheter was fixed by cystoscopy. the middle calyx was punctured under us guidance (figure 2) and guide wire inserted. then the tract was dilated under us guidance (figure 3) up to 30 f and drainage of urine from the tip of dilation instruments was confirmed at each step. nephroscopy was performed and the large stone was extracted by forceps and smaller stones were removed by irrigation and/or forceps. operation duration was 51 minutes. nephrostomy was fixed at the end of operation which was removed on the second postoperative day. ureteral catheter was removed on the first postoperative day. the patient did not experience fever or renal colic after the operation. she only experienced minor abdominal cramps after the operation for one day duration around her umbilicus. we requested a gynecologic consultation which reported no obstetric complication and the patient was given analgesics. the patient was uneventful at follow-up and a follow-up us one week after the operation only revealed an asymptomatic 4 mm stone in the right kidney. the patient was followed until delivery and the examination of her baby was normal after birth. patient 3 a 34-year-old pregnant woman presented with severe left flank pain, nausea, and vomiting in the 28th week of pregnancy. the patient had no history of previous stone passage. us revealed one 20 mm stone in the pelvis, one 12 mm stone in the upper pole, and one 10 mm stone in the lower pole of the right kidney with severe hydronephrosis and three 10 mm stones in distal ureter. analgesic and serum therapy were given to the patient. nephrostomy was placed for the patient under us guidance. the patient suffered from sustained flank discomfort despite insertion of percutaneous nephrostomy and requested for definitive stone treatment. mri was requested which confirmed severe hydroureteronephrosis of the right kidney (figure 4). after consultation with her obstetrician and anesthesiologist, we suggested perfigure 3. ultrasonography from the anterior abdominal wall guided the tract dilation step. the red arrow indicates the tip of amplatz sheath in the renal collecting system. figure 4. magnetic resonance imaging revealed stones in the right kidney and distal ureter (red arrow). ultrasound-guided supine pcnl in pregnancy-basiri et al. endourology and stone diseases 2498 vol 13 no 01 january-february 2016 2499 forming flank us-guided pcnl. potential risks of the procedure were explained to the patient and her family, and informed consent was obtained. the patient was operated on the 19th of february 2015. after spinal anesthesia, the patient was placed in supine position. ureteroscopy was performed and ureteral stones were fragmented using pneumatic lithoclast and removed from ureter and a 5 f ureteral catheter was inserted. then the patient was placed in right flank position (figure 5). access to the lower calyx was obtained under us guidance. all steps of tract dilation and 30 f amplatz sheath insertion were controlled with us avoiding x-ray exposure. nephroscopy was performed, and the stones were fragmented using pneumatic lithoclast and removed from the kidney. residual stone presence was checked with us. ureteral catheter was removed and a dj stent inserted anterogradely. nephrostomy was fixed at the end of operation which was removed on the second postoperative day. operation duration was 65 minutes. the patient was stone free on the first postoperative us, and was discharged on the second postoperative day. no fever, gross bleeding or renal colic was noticed during postoperative hospitalization. dj was removed after 4 weeks. the patient was followed until delivery and the examination of her baby was normal after birth. discussion the actual incidence of urinary stones in pregnancy is similar to non-pregnant women.(8,14) because of limitations and special concerns raised by pregnancy, urolithiasis is a particular diagnostic and therapeutic challenge in pregnancy.(15) approximately 70-80% of stones presented during pregnancy will pass spontaneously; therefore a trial of conservative management should be given to most of the patients, if possible.(16) urinary diversion via dj stent or percutaneous nephrostomy tube should be applied when the patient has refractory pain, urinary tract infection, or an obstructed single kidney. (17,18) these interventions are unpleasant to some patients due to the requirement for their periodic exchange (6-8 weeks).(19) besides, carrying a nephrostomy tube is uncomfortable for many patients and many are bothered by the irritative lower urinary symptoms associated with dj stents.(19) furthermore, encrustation of the dj stent is another concern which in some cases necessitated a pcnl operation to remove the proximal encrusted end of the catheter.(20) percutaneous nephrolithotomy is not generally advocated during pregnancy because of considerations regarding the length of anesthesia, need for fluoroscopy, and prone positioning.(8) nevertheless many publications in recent years reported the feasibility and safety of totally us-guided pcnl in supine, prone and flank positions,(10,21-25) basiri and colleagues reported their experience with x-ray free supine pcnl in 19 patients.(9) others have used various us types (doppler, b-mode) and positions (supine, flank, prone).(26,27) agarwall and colleagues used ultrasonography as a guide for the puncture step, and fluoroscopy for the rest of surgery. they concluded that us-guided puncture helps decrease radiation exposure and increase puncture accuracy.(12) furthermore, advances in anesthesia has made it less problematic for pregnant women and there is an increasing trend for the use of definitive interventions requiring regional anesthesia (e.g. ureteroscopy) in pregnancy(28-30) so that ureteroscopy is now offered as an alternative treatment strategy together with nephrostomy or ureteral stent for ureteral stones in pregnancy in european association of urology (eau) and american figure 5. lateral flank position of the patient (image taken after the operation). ultrasound-guided supine pcnl in pregnancy-basiri et al. urological association (aua) guidelines.(31,32) there have been reports on the feasibility and safety of pcnl under regional anesthesia including our previous publications.(11,33,34) shah and colleagues described their experience in a 33-year-old pregnant woman presented with right-sided pyonephrosis due to a 1.8 cm renal calculus obstructing the ureteropelvic junction. pcnl was carried out at 14 weeks of gestation with 6 seconds of radiation exposure confined to the right kidney.(35) toth and colleagues published a report on a 31-year-old, 11 weeks pregnant woman with an 8 mm stone who underwent successful pcnl in prone position under spinal anesthesia and us guidance.(36) feregonesi and colleagues reported a 24-year-old woman with symptomatic 2.7 cm right renal stone in the 22nd weeks of pregnancy who was successfully treated by supine us-guided pcnl.(13) our experience also supports the feasibility of supine us-guided pcnl for definitive treatment of renal stones in patients who are candidates for a definitive intervention. in this study we did not encounter any obstetric problem during operation or after operation until delivery. the nephrostomy and ureteral catheter which were inserted for the second patient were removed on postoperative days 1 and 2 and caused only a short time discomfort for the patient. dj was inserted for the 1st and 3rd patients as they were the first experiences of the attending surgeons (a.b and a.n respectively) as we preferred to be conservative and have a medium term drainage catheter in case of any unpredicted problem. all patients were followed up until after delivery. no abnormality was reported in their after birth neonatal examination carried out by the pediatric specialists; however this study included a limited number of patients. we think that the following tips will help to perform a safe pcnl in pregnancy. applying needle-holder under us guidance results in higher accuracy in entry to the selected target calyx (figure 2). us also allows for checking the depth of dilator insertion precisely. we dilated the tract with a single shot technique, while us from the anterior abdominal wall guided the procedure (figure 3). conclusions in conclusion, we suggest that pcnl can be more freely offered to pregnant women with renal stone who are unwilling to undergo several sessions of nephrostomy or dj stent exchange and prefer to receive definitive treatment especially if conservative measures fail to the patients’ wellbeing. acknowledgements the authors would like to thank iran's national elites foundation for their help and support. conflict of interest none declared. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. basiri a, mehrabi s, kianian h, javaherforooshzadeh a. blind puncture in comparison with fluoroscopic guidance in percutaneous nephrolithotomy: a randomized controlled trial. urol j. 2007 ;4:79-83. 3. gamal wm, hussein m, aldahshoury m, et al. solo ultrasonography-guided percutanous nephrolithotomy for single stone pelvis. j endourol. 2011;25:593-6. 4. roy op, angle jf, jenkins ad, schenkman ns. cone beam 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2010;28:239-44. 10. basiri a, ziaee sa, nasseh h, et al. totally u l t r a s o n o g r a p h y g u i d e d p e r c u t a n e o u s nephrolithotomy in the flank position. j endourol. 2008;22:1453-7. 11. nouralizadeh a, ziaee sa, hosseini sharifi sh, et al. comparison of percutaneous nephrolithotomy under spinal versus general anesthesia: a randomized clinical trial. j endourol. 2013;27:974-8. 12. agarwal m, agrawal ms, jaiswal a, kumar d, yadav h, lavania p. safety and efficacy of ultrasonography as an adjunct to ultrasound-guided supine pcnl in pregnancy-basiri et al. endourology and stone diseases 2500 vol 13 no 01 january-february 2016 2501 fluoroscopy for renal access in percutaneous nephrolithotomy (pcnl). bju int. 2011;108:1346-9. 13. fregonesi a, dias fg, saade rd, dechaalani v, reis lo. challenges on percutaneous nephrolithotomy in pregnancy: supine position approach through ultrasound guidance. urol ann. 2013;5:197-9. 14. drago jr, rohner tj, jr., chez ra. management of urinary calculi in pregnancy. urology. 1982;20:578-81. 15. mcaleer sj, loughlin kr. nephrolithiasis and pregnancy. curr opin urol. 2004;14:1237. 16. loughlin kr, ker la. the current management of urolithiasis during pregnancy. urol clin north am. 2002;29:701-4. 17. jarrard dj, gerber gs, lyon es. management of acute ureteral obstruction in pregnancy utilizing ultrasound-guided placement of ureteral stents. urology. 1993;42:263-7. 18. kavoussi lr, albala dm, basler jw, apte s, clayman rv. percutaneous management of urolithiasis during pregnancy. j urol. 1992;148:1069-71. 19. osman m, wendt-nordahl g, heger k, michel ms, alken p, knoll t. percutaneous nephrolithotomy with ultrasonography-guided renal access: experience from over 300 cases. bju int. 2005;96:875-8. 20. pais vm, jr., chew b, shaw o, et al. percutaneous nephrolithotomy for removal of encrusted ureteral stents: a multicenter study. j endourol. 2014;28:1188-91. 21. alan c, kocoglu h, ates f, ersay ar. ultrasound-guided x-ray free percutaneous nephrolithotomy for treatment of simple stones in the flank position. urol res. 2011;39:20512. 22. desai m. ultrasonography-guided punctureswith and without puncture guide. j endourol. 2009;23:1641-3. 23. falahatkar s, neiroomand h, enshaei a, kazemzadeh m, allahkhah a, jalili mf. totally ultrasound versus fluoroscopically guided complete supine percutaneous nephrolithotripsy: a first report. j endourol. 2010;24:1421-6. 24. fu ym, chen qy, zhao zs, et al. ultrasoundguided minimally invasive percutaneous nephrolithotomy in flank position for management of complex renal calculi. urology. 2011;77:40-4. 25. karami h, rezaei a, mohammadhosseini m, javanmard b, mazloomfard m, lotfi b. ultrasonography-guided percutaneous nephrolithotomy in the flank position versus fluoroscopy-guided percutaneous nephrolithotomy in the prone position: a comparative study. j endourol. 2010;24:135761. 26. lu mh, pu xy, gao x, zhou xf, qiu jg, si-tu j. a comparative study of clinical value of single b-mode ultrasound guidance and b-mode combined with color doppler ultrasound guidance in mini-invasive percutaneous nephrolithotomy to decrease hemorrhagic complications. urology. 2010;76:815-20. 27. tzeng bc, wang cj, huang sw, chang ch. doppler ultrasound-guided percutaneous nephrolithotomy: a prospective randomized study. urology. 2011;78:535-9. 28. lifshitz da, lingeman je. ureteroscopy as a first-line intervention for ureteral calculi in pregnancy. j endourol. 2002;16:19-22. 29. ulvik nm, bakke a, hoisaeter pa. ureteroscopy in pregnancy. j urol. 1995;154:1660-3. 30. watterson jd, girvan ar, beiko dt, et al. ureteroscopy and holmium:yag laser lithotripsy: an emerging definitive management strategy for symptomatic ureteral calculi in pregnancy. urology. 2002;60:383-7. 31. eau/aua nephrolithiasis guideline panel; preminger gmt, h.g, asimos dg, alken p, buck ac, gallucci m. ureteral calculi; 2007 guideline for management of ureteral calculi: european association of urology and american urological association research and education; 2007. available from: http:// www.auanet.org/education/guidelines/ ureteral-calculi.cfm. 32. turk ck, c., petrick a, sarica k, skolarikos a, straub m. guidelines on urolithiasis. in: members ego, editor. european association of urology guidelines; 2014 edition: european association of urology; 2014. p. 54-5. 33. kuzgunbay b, turunc t, akin s, ergenoglu p, aribogan a, ozkardes h. percutaneous nephrolithotomy under general versus combined spinal-epidural anesthesia. j endourol. 2009;23:1835-8. 34. singh v, sinha rj, sankhwar sn, malik a. a prospective randomized study comparing percutaneous nephrolithotomy under combined spinal-epidural anesthesia with percutaneous nephrolithotomy under general anesthesia. urol int. 2011;87:293-8. 35. shah a, chandak p, tiptaft r, glass j, dasgupta p. percutaneous nephrolithotomy in early pregnancy. int j clin pract. 2004;58:80910. 36. toth c, toth g, varga a, flasko t, salah ma. percutaneous nephrolithotomy in early pregnancy. int urol nephrol. 2005;37:1-3. ultrasound-guided supine pcnl in pregnancy-basiri et al. vol 13 no 01 january-february 2016 2471 review effect of obesity on prone percutaneous nephrolithotomy outcomes: a systemic review faruk ozgor,* burak ucpinar, murat binbay purpose: with decreased physical activity, growing sedentary lifestyle, and high fat diet, obesity has become a pandemic disease all over the world. in this review, we aim to assess the effect of obesity on prone percutaneous nephrolithotomy. (pnl) outcomes. materials and methods: we performed a comprehensive review of the published articles in pubmed®, medline, scopus, cochrane database from january 1, 2004 through june 31, 2015, using the key words; body mass index, obesity, morbid obesity, super obese, urolithiasis, nephrolithiasis, percutaneous nephrolithotomy and percutaneous lithotripsy. original research articles published in english language with accessibility to the full text article were analyzed for our review. results: at the end of the evaluation, we found 12 articles in english language, analyzing the effect of obesity on prone pnl outcomes. except one study, eleven studies were evaluated in this review had a retrospective nature without randomization. stone free status of patients was in a wide range between 49%-90% in obese patients and 41%-90% in morbid obese patients. conclusion: pnl is a safe and effective treatment modality for renal stone(s) in obese and morbid obese patients. however, effect of body mass index on pnl outcomes including operation time, fluoroscopy screening time, hospitalization time, complications and stone free status are still debatable. keywords: kidney calculi; complications; surgery; length of stay; nephrostomy; percutaneous; adverse effects; obesity; morbid; operative time; overweight; prospective studies. introduction according to world health organization.(who), obesity is described as a body mass index. (bmi) greater than or equal to 30 kg/m2.(1) with decreased physical activity, growing sedentary lifestyle and high fat diet, prevalence of obesity has doubled over last decades and obesity has become a pandemic disease, not only in developed countries, but also all over the world.(2,3) its well known that, obesity is associated with comorbid conditions such as diabetes mellitus, hypertension and nephrolithiasis.(4,5) additionally, anesthetic and surgical complications are higher in obese patients when compared with normal weight patients.(6) percutaneous nephrolithotomy (pnl) is a preferred treatment option for renal stone(s) larger than 2 cm and staghorn calculi.(7,8) although its' minimally invasive nature, pnl procedure has potential serious complications including; bleeding, adjacent organ injuries and urosepsis.(9,10) moreover, in obese patients, pnl has some technical difficulties.(11) excessive fat tissue decrease image quality of fluoroscopy screening and reduce the accuracy of defining the appropriate calyx or stone during access. besides, identifying a landmark at the beginning of the operation is complicated in obese patients. also, accessing to the pelvicaliceal system and dilating the tract is more challenging. additionally, inadequate length of working sheath and working instruments in obese patients affects adversely on pnl outcomes.(12-14) in this review, we aim to assess the effect of obesity on prone pnl outcomes and try to lead the way for urologists who are planning to perform pnl on obese patients. materials and methods before writing this review, we performed a comprehensive pubmed®, medline, scopus, cochrane database investigation of articles published from january 1, 2004 through june 31, 2015, using the key words; bmi, obesity, morbid obesity, super obese, urolithiasis, nephrolithiasis, percutaneous nephrolithotomy and percutaneous lithotripsy. all terms are in acordance with department of urology, haseki research and training hospital, fatih, istanbul, turkey. *correspondence: department of urology, haseki training and research hospital, fatih, istanbul, turkey. tel: +90 212 5294400. fax: +90 212 5896229. e-mail: md.farukozgor@yahoo.com. received: june 2015 & accepted: september 2015 table 1. preoperative characteristics in different study. studies body mass index patients mean bmi age, years male asa ≥ 3 stone size(cm) single stone multiple stones previous surgery alyami et al.(29) normal (< 25) 39 na 55 23 na 2.3 na na 17 overweight 24 na 60 10 na 2.3 na na 9 obese (30-39) 41 na 60 15 na 2.2 na na 19 morbid obese 10 na 53 5 na 2.4 na na 4 p value .1* .2** .9* .5** bagrodia et al.(21) normal (< 25) 26 na 58 na 8 1.7 13 13 10 overweight 44 na 54 na 13 1.6 14 30 33 obese (30-39) 51 na 53 na 19 1.8 19 32 31 morbid obese 29 na 45 na 12 2.3 11 18 18 p value .06 .7 .61 .51 .03 fuller et al.(22) normal (< 25) 1394 na na 755 98 na 581 813 na overweight 1568 na na 970 108 na 683 885 na obese (30-39) 650 na na 335 123 na 260 390 na super (≥ 40) 97 na na 32 60 na 37 60 na p value < .001 < .001 .591 el-assym et al.(30) normal (< 25) 270 na 46.5 ± 10.9 176 na 2.5 ± 0.8 98 172 na overweight 235 na 47 ± 10.9 220 na 2.5 ± 0.7 121 204 na obese (30-39) 468 na 46.9 ± 10.5 302 na 2.4 ± 0.8 172 296 na morbid obese 92 na 46.5 ± 10 43 na 2.5 ± 0.8 44 48 na p value .75 .003 .76 .43 keheila et al.(15) super (≥ 50) 17 57.2 54.8 6 2.7 3.3 na na na p value koo et al.(23) normal (< 25) 65 22.1 50 35 7 na na na na overweight 79 27.5 56 54 13 na na na na obese (30-39) 67 33.8 56 55 7 na na na na morbid obese 12 43.9 51 6 4 na na na na p value kuntz et al.(14) normal (< 25) 55 22.40 58 22 21 na 18 26 na overweight 74 27.40 51 37 19 na 23 27 na obese(30-35) 67 32 52 35 28 na 26 31 na morbid obese 72 40.5 29 31 34 na 23 43 na p value < .001 .123 0.47 < .001 0.01 ortiz et al. (28) normal (< 25) 77 22.70 51.9 ± 15.8 40 na na 70 7 10 overweight 93 27.30 56.2 ± 13.3 56 na na 84 9 10 obese (30-39) 75 33.7 54.7 ± 12.1 40 na na 64 11 7 morbid obese 10 44.1 58.4 ± 11.2 3 na na 7 3 2 p value < .01 .24 .24 .72 .1 sergeyev et al.(16) normal (< 25) 15 22.65 57.93 na na na na na na overweight 33 27.60 52.82 na na na na na na obese (≥ 30) 37 36.28 52.46 na na na na na na p value .41 shohab et al. normal (< 24) 47 na 43.29 ± 1.69 na na 2.546 ± 0.89 na na na overweight (24-30) 56 na 47.08 ± 1.29 na na 2.801 ± 0.84 na na na obese (≥ 30) 26 na 43.61±1.25 na na 2.684 ± 0.74 na na na p value simsek et al. normal (< 25) 849 na 38.19 ± 14.1 490 215 na 375 474 na overweight 883 na 46.39 ± 12.9 510 205 na 392 491 na obese (30-39) 334 na 49.52 ± 12.8 217 83 na 121 213 na morbid obese 36 na 50.22 ± 11.1 20 10 na 15 21 na p value .001 .102 .896 .059 tomaszewski et al. normal (< 25) 61 na 52.6 na na 3.6 na na na overweight 45 na 57.4 na na 3.1 na na na obese (30-34.9) 43 na 53 na na 3.7 na na na morbid obese 38 na 53 na na 3.9 na na na p value .34 .70 *anova, **logistics regression analysis review 2472 obesti and pcnl outcome-ozgor et al. vol 13 no 01 january-february 2016 2473 table 2. operative characteristics in different studies. obesti and pcnl outcome-ozgor et al. studies body mass index patients operation time complications, % multiple accesses alyami et al. normal (< 25) 39 44.6 7 na overweight 24 43.4 8 na obese (30-39) 41 47 2 na morbid obese 10 55 0 na p value .3 .55 bagrodia et al. normal (< 25) 26 na 26 4 overweight 44 na 11 7 obese(30-39) 51 na 19 5 morbid obese 29 na 17 5 p value .42 .76 fuller et al. normal (< 25) 1394 na 5 112 overweight 1568 na 7 112 obese (30-39) 650 na 5 44 super (≥ 40) 97 na 4% 6 p value 2/0, /5.8* < .001 el-assym et al. normal (<25) 270 69.8 ± 32.4 na na overweight 235 71.4 ± 28.7 na na obese (30-39) 468 68.5 ± 29.6 na na morbid obese 92 77.2 ± 32.4 na na p value .45 keheila et al. super (≥ 50) 17 106 na 7 p value koo et al normal (< 25) 65 75.2 7 na overweight 79 68.8 8 na obese (30-39) 67 68.5 14 na morbid obese 12 81.4 16 na p value .35 kuntz et al. normal (< 25) 55 na na 5 overweight 74 na na 6 obese (30-35) 67 na na 3 morbid obese 72 na na 3 p value .664 ortiz et al. normal (< 25) 77 101.7 ± 48.1 0 na overweight 93 96.6 ± 41.1 3% na obese (30-39) 75 110.2±46.2 4% na morbid obese 10 116.0 ± 49.8 0% na p value .2 .34** sergeyev et al. normal (< 25) 15 na na na overweight 33 na na na obese (≥ 30) 37 na na na p value shohab et al. normal (< 24) 47 128.4 ± 48.61 na na overweight (24-30) 56 126.62 ± 59.75 na na obese 26 129.42 ± 48.61 na na p value simsek et al. normal (< 25) 849 66.44 ± 26.93 3 184 overweight 883 65.74 ± 28.69 4 147 obese (30-39) 334 66.13 ± 28.42 5 56 morbid obese 36 68.20 ± 24.66 5 7 p value .638 .313 tomaszewski et al. normal (< 25) 61 na na na overweight 45 na na na obese (30-34.9) 43 na na na morbid obese 38 na na na p value * failed access/perforation/hydrothorax, respectively. ** failure to get access. table 3. postoperative characteristics in different studies. studies body mass index patients stone free rate, % complications hospital stay second procedure hb drop alyami et al.(29) normal (< 25) 39 90.0 5 1.6 (0.3) 0 1 overweight 24 87.0 2 1.9 (0.3) 1 1.8 obese (30-39) 41 90.0 9 1.5 (0.2) 3 1.2 morbid obese 10 80.0 20 1.7 (0.3) 1 1.5 p value .8 .1 .59 .3 .13 bagrodia et al.(21) normal (< 25) 26 46.0 na 3 11 na overweight 44 50.0 na 2 19 na obese (30-39) 51 53.0 na 3 18 na morbid obese 29 41.0 na 2 11 na p value .21 .86 fuller et al.(22) normal (< 25) 1394 77.5 1 na 12 na overweight 1568 79.7 2 na 9 na obese (30-39) 650 78.9 18 na 98 na super (≥ 40) 97 65.6 21 na 27 na p value .009 .707 < .001 el-assym et al.(30) normal (< 25) 270 83.70 6 3.4 ± 2.6 70 1.3 ± 1.4 overweight 235 86.70 9 3.3 ± 3 75 1.1 ± 1.3 obese (30-39) 468 84.80 5 3.3 ± 2.5 114 1.3 ± 1.4 morbid obese 92 84.70 7 3.1 ± 2 16 1.1 ± 1.4 p value .38 .66 .38 .6 .13 keheila et al.(15) super (≥ 50) 17 76.0 23 4.5 4 1.2 p value koo et al.(23) normal (< 25) 65 79.0 10 5.4 na 1.1 overweight 79 76.0 13 6.5 na 1.4 obese (30-39) 67 79.0 8 6.1 na 1.1 morbid obese 12 83.0 8 5.1 na 1.5 p value .93 .91 .17 kuntz et al.(14) normal (< 25) 55 45.0 18 na na na overweight 74 36.0 21 na na na obese (30-39) 67 49.0 19 na na na morbid obese 72 41.0 16 na na na p value .864 .89 ortiz et al.(28) normal (< 25) 77 76.60 31 5.2 ± 3.4 9 1.9 ± 1.9 overweight 93 68.80 35 5.7 ± 4.1 16 2.2 ± 2.0 obese (30-39) 75 78.70 29 5.2 ± 4.6 15 1.4 ± 1.4 morbid obese 10 90.0 10 5.3 ± 3.1 2 1.0 ± 1.4 p value .29 .39 .84 .59 .02 sergeyev et al.(16) normal (< 25) 15 93.0 na 5.40 1 2.31 overweight 33 100.0 na 3.64 0 2.25 obese (≥ 30) 37 89.0 na 3.70 4 2.29 p value .01 .98 shohab et al. normal (< 24) 47 91.18 6 3.00 ± 1.04 na na overweight (24-30) 56 89.62 8 3.00 ± 1.17 na na obese 26 90.23 23 3.03 ± 1.82 na na p value simsek et al. normal (< 25) 849 83.0 1 2.86 ± 1.56 na na overweight 883 80.9 1 2.90 ± 1.93 na na obese (30-39) 334 80.2 1 1.70 ± 1.58 na na morbid obese 36 86.1 2 2.81 ± 0.98 na na p value tomaszewski et al. normal (< 25) 61 80.6 na 3.4 na 6.2 (htc) overweight 45 76.9 na 2.4 na 7.3 (htc) obese (30-34.9) 43 77.0 na 3 na 6.5 (htc) morbid obese 38 78.9 na 2.6 na 5.3 (htc) p value .82 .53 .22 review 2474 obesti and pcnl outcome-ozgor et al. abbreviations: hb, hemoglobin; htc, hematocrit; na, not applicable. vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2475 the definitions reported in the prisma statement for reviewers (figure). two collaborators (fo and bu) independently reviewed all of the articles and data disagreement was resolved by a third reviewer or by consensus. original research articles published in english language with accessibility to the full text article were analyzed for our review. studies evaluating only the adult population were enrolled to our review. additionally, we excluded expert opinions, editorials comments, studies evaluating the effect of supine pnl on obese patients, letters to the editor and case reports from our review. additional citations were identified cautiously by reviewing reference lists of pertinent articles. at the end of the evaluation, we found 12 articles in english language, analyzing the effect of obesity on prone pnl outcomes. parameters like; total number of patients, bmi, age, male: female ratio, maximum stone diameter or stone burden, american society of anesthesiologists (asa) score and history of previous renal stone surgery were taken into account. perioperative parameters including operation time, fluoroscopy screening time, requirement of multiple access and peroperative complications were evaluated. also, length of hospital stay, stone free rates, requirement of additional procedures and complications were collected. results all studies were evaluated in this review had a retrospective nature without randomization except clinical research office of endourology society (croes) study which had a prospective data collecting design. additionally, reviewed original articles had different study designs which made it difficult to obtain a certain conclusion about the effect of obesity on pnl outcomes. nine of the twelve articles were divided patients into four groups; normal weight, overweight, obese and morbid obese. kuntz and colleagues and tomaszewski and colleagues accepted obesity range bmi between 30 and 35 kg/m2.(14,15) however, remaining seven articles defined obesity as bmi in the range of 30-39 kg/m2. one study was interested with only results of pnl in super obese patients and super obese was defined as bmi > 50 kg/m2.(16) another two studies categorized patients who underwent pnl into three groups (normal weight, overweight, obese) and did not analyze morbid obese patients.(17,18) additionally, the mean bmi of each groups were calculated in only five of these studies and as expected, the mean bmi was significantly higher in morbid obese patients. the asa score of the patients was mentioned in five comparative studies and in two articles the asa score was significantly higher in obese and morbid obese patients. the mean operation times and means fluoroscopy screening times were given in six and in one comparative studies, respectively, without any statically significant difference (tables 1 and 2). stone free status of patients was in wide range between 49%-90% in obese patients and 41%-90% in morbid obese patients. however, when each study evaluated in their own study groups, there was no statistically significant difference in stone free rates. similarly, post-operative complications were not significantly different in morbid obese and obese patients when compared with normal weight and over weight patients. the results of the included studies from the literature for our review are summarized in table 3. discussion with increasing bmi, metabolic disorders such as hypercalciuria, hyperoxaluria, hyperinsulinemia and low urine volume are more commonly seen and these conditions are also strong risk factors for stone formation.(19) because of all these, obese and morbid obese patients are more likely to face with renal stone disease. although, extracorporeal shock wave lithotripsy (swl) is accepted as one of the first line treatment modalities for kidney stones < 20 mm, according to the guidelines, obesti and pcnl outcome-ozgor et al. figure. prisma chart. longer skin to stone distance (ssd) and difficulties in focusing the stone under ultrasonography or fluoroscopy guidance reduces swl success rates in obese patients.(20) on the other hand, several studies mentioned that effectiveness of flexible ureterorenoscopy (f-urs) was decreased and requirement of second intervention is increased with the increase in stone size.(21,22) multiple interventions may lead to more anesthetic usage and surgical complications in obese patients. recently, pnl still remains one of the most important treatment options for renal stone treatment. in obese patients, anesthetic and pre-surgical problems can be challenging for urologists. five studies evaluated the asa score of patients who underwent pnl and two of them had demonstrated patients with > 3 asa score were more common in obese and morbid obese patients.(14,23-26) also, complications including atelectasis, venous thromboembolism and longer recovery period may be associated with higher asa scores.(27) conversely, other two studies failed to show significant difference between groups according to their bmi's. additionally, changing patients from lithotomy position to prone position requires special attention and more trained personnel, especially in obese patients. being a center with high stone patients volume, may have resulted in increased experience of surgeons, anesthetists and personnel that prevent unfortunate pre-operative events. complete clearance of the stone after pnl operation is the most pleasing condition for urologist and also for the patient. stone free status after pnl in obese patients was surprisingly in a wide range (49%-90% in obese patients and 41%-90% in morbid obese patients) according to the studies in the literature. these differences may due to different defining criteria for the term ‘success’ among different articles. stone free status accepted as complete clearance of stone and presence of residual fragments by some authors. other studies neglect the presence of residual stone fragments < 5 mm and define these conditions as stone free. moreover, some authors evaluated stone free status by abdominal computerized tomography and others used intravenous urography (ivu) or ultrasonography.(14,23) it is clear that imaging modalities have different sensitivities in detecting stone(s) and this difference may lead to misinterpretation of the results.(28,29) however, when each study is evaluated on its own, no difference was detected in groups with different bmi's. the mean operation time was given in four comparative studies and all of them demonstrated significantly longer operation time in morbid obese patients. however, the differences were not statically significant. moreover, none of these studies had given an exact definition of operative time. to our knowledge, some authors accepted operation time from beginning of anesthesia to nephrostomy tube placement but others accepted operative time from access attempt to nephrostomy tube placement.(30) this difference in calculations can lead to confusion when assessing the effect of bmi on pnl operation time. we believe that, calculating the operation time from anesthesia induction to the end of the operation is a more reliable approach to identify the effect of high bmi on pnl operation time. deterioration of image quality of stone and target calyx due to extensive fat tissue in obese patients was mentioned above. in the light of this information, fluoroscopy screening time is expected to be influenced by bmi. however, only ortiz and colleagues. discussed fluoroscopy screening time and found that the fluoroscopy screening time became longer with increasing bmi but their findings were not statistically significant. (31) radiation exposure to the surgical team and patients is an important issue. because of high recurrence risk of nephrolithiasis and technical difficulties of pnl in obese patients, longer fluoroscopy screening times are expected and this issue must be assessed carefully in further studies. the mean hospitalization time was similar in six comparative studies. only sergeyev and colleagues had demonstrated a significant difference in between groups according to their bmi's.(17) surprisingly, patients with normal weight had longer hospitalization times when compared with overweight and obese patients. we believe that longer hospitalization time is associated with operative or post operative complications such as bleeding, fever, adjacent organ injuries instead of technical difficulties. sergeyev and colleagues and and colleagues did not mention about their complications after pnl in details. the hospitalization time was longer in koo and colleagues and ortiz and colleagues studies and as expected, their complication rates were higher when compared with other studies.(25,31) requirement of additional procedures was discussed in five studies. alyami and colleagues reported 8% and 10% re-admission rates in obese and morbid obese patients, respectively, but they did not mention about the additional procedures in detail.(32) sergeyev and colleagues only mentioned about second-look pnl after initial procedure and they performed it only in five of their patients (1/15 in normal weight patients and 4/37 in morbid obese patients).(17) in bagrodia's study, need for a second look pnl rates were 35% and 38% in review 2476 obesti and pcnl outcome-ozgor et al. vol 13 no 01 january-february 2016 2477 obese and morbid obese patients, respectively, much higher when compared with sergeyev and colleagues study.(23) however, there was no statistically significant difference in between groups. similarly, requirement of second procedures including pnl, urs and swl, were similar between groups in both el-assmy and colleagues and ortiz and colleagues studies.(31,33) bleeding is one of the most serious complications of pnl procedure, 2%-45% and 0.8% of patients required blood transfusion and angioembolization, respectively.(34) all studies analyzed the hemoglobin drop after pnl procedure and there was no association between bleeding rates and bmi values of the patients. obesity seems to be a technical challenge for urologists while performing access into the calyceal system. we believe that bleeding complication rates are associated with the experience of the surgeon, applying multiple accesses into the system and history of previous surgeries, instead of technical difficulties during pnl surgery. it is quite complicated to assess the effect of obesity and morbid obesity on prone pnl complications due to different classification systems in different studies. ortiz and colleagues used clavien complication classification to categorize complications.(31) however, koo and colleagues classified their complications as minor and major complications.(25) differently, el-assmy did not categories the complications under subgroups, instead, they listed all the complications separately.(33) due to this different classification system, it is quite difficult to assess all the studies and come up with a certain result. however, when we assess all the studies separately, complication rates were not statistically significant between different bmi groups. conclusions pnl is a safe and effective treatment modality for renal stone(s) in obese and morbid obese patients. however, effect of body mass index on pnl outcomes including operation time, fluoroscopy screening time, hospitalization time, complications and stone free status are still debatable. role of obesity on pnl outcomes must be investigated by further prospective, randomized studies with larger patient volumes. conflict of interest none declared. references 1. de simone g, devereux rb, chinali m, et al. prognostic impact of metabolic syndrome by different definitions in a population with high prevalence of obesity and diabetes: the strong heart study. diabetes care. 2007;30:1851-6. 2. krzysztoszek j, wierzejska e, zielińska a. obesity. an analysis of epidemiological and prognostic research. arch med sci. 2015;11:24-33. 3. flegal km, carroll md, ogden cl, johnson cl. prevalence and trends in obesity among us adults, 1999 –2000. jama. 2002;288:1723-7. 4. taylor en, stampfer mj, curhan gc. diabetes mellitus and the risk of nephrolithiasis. kidney int. 2005;68:1230-5. 5. cappuccino fp, strazzullo p, and mancini m. kidney stones and hypertension: population based study of an independent clinical association. bmj 1990;12:1234. 6. choban ps, flancbaum l. the impact of obesity on surgical outcomes: a review. j am coll surg. 1997;185:593–603 7. de la rosette jj, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications and outcomes in 5803 patients. j endourol. 2011; 25:11. 8. skolarikos a, alivizatos g, de la rosette jjmch. percutaneous nephrolithotomy and its legacy. eur urol. 2005;47:22–8. 9. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899– 906. 10. matlaga br, shah od, zagoria rj et al: computerised tomography guided access for percutaneous nephrostolithotomy. j urol. 2003;170: 45. 11. wu sd, yilmaz m, tamul pc, et al. awake endotracheal intubation and prone patient self-positioning: anesthetic and positioning considerations during percutaneous nephrolithotomy in obese patients. j endourol . 2009;23:1599. 12. gofrit on, shapiro a, donchin y, et al. lateral decubitus position for percutaneous nephrolithotripsy in the morbidly obese or kyphotic patient. j endourol. 2002;16:383–6. 13. nguyen ta, belis ja. endoscopic management of urolithiasis in the morbidly obese patient. j endourol. 1998;12:33–5. 14. kuntz nj, 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influence of body mass index on outcome. j urol. 2012;188:138-44. 25. koo bc, burtt g, burgess na. percutaneous stone surgery in the obese: outcome stratified according to body mass index. bju int. 2004 ;93:1296-9. 26. şimşek a, özgör f, akbulut mf, küçüktopçu o, berberoğlu ay, sarılar ö, binbay m, müslümanoğlu ay. does body mass index effect the success of percutaneous nephrolithotomy? turk j urol. 2014;40:1049. 27. khoury w, stocchi l, geisler d. outcomes after laparoscopic intestinal resection in obese versus non-obese patients. br j surg. 2011;98:293-8. 28. ozden e, suer e, gulpinar b, gulpınar o, tangal s . comparison of imaging modalities for detection of residual fragments and prediction of stone related events following percutaneous nephrolitotomy. int braz j urol. 2015 jan;41:86-90. 29. sountoulides p, metaxa l, cindolo l. is computed tomography mandatory for the detection of residual stone fragments after percutaneous nephrolithotomy? j endourol. 2013;27:1341-8. 30. akman t, binbay m, akcay m, et al. variables that influence operative time during percutaneous nephrolithotomy: an analysis of 1897 cases. j endourol. 2011;25:1269-73. 31. torrecilla ortiz c, meza martínez ai, vicens morton aj, et al. obesity in percutaneous nephrolithotomy. is body mass index really important? urology. 2014;84:538-43. 32. alyami fa, skinner ta, norman rw. impact of body mass index on clinical outcomes associated with percutaneous nephrolithotomy. can urol assoc j. 2012;15:1-5. 33. el-assmy am, shokeir aa, el-nahas ar, et al. outcome of percutaneous nephrolithotomy: effect of body mass index. eur urol. 2007;52:199-204. 34. kefer jc, turna b, stein rj, desai mm. safety and efficacy of percutaneous nephrostolithotomy in patients on anticoagulant therapy. j urol. 2009;181:1448. review 2478 obesti and pcnl outcome-ozgor et al. 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran introduction pain relieving is regarded as one of the basic issues in pediatric anesthesia during the operation and postoperatively. pain is one of the major factors of children's agitation immediately after surgery, a matter which is particularly seen in infants and little children who are unable to communicate properly and do not receive an appropriate dosage of analgesic drugs.(1) postoperatively, pain would be followed by some physiologic complications manifested in human body systems and organizations. pain, under the age of five could affect physical and mental status and even might associate with a high level of somatization.(2) acetaminophen has an active metabolite known as phenacetin that provides analgesic and antipyretic effects. the mechanism of action is not well known. the analgesic effect of acetaminophen may be due to its fair inhibition of prostaglandin in cns.(3) this drug has no anti-inflammatory effects, and heightening pain threshold is considered as its analgesic mechanism.(3) its normal dosage is 30-40 mg/kg used in divided dosages but in children under 12 years old is 1.5 gr/ m2/day. hypersensitivity to this medication is known as its contradiction. in case of rectal bleeding, the drug should not be administered. the use of narcotics, regional anesthetics, analgesics such as nsaids, and probably non-pharmaceutical ways are considered as pain relieving methods during and after surgery.(4) since even one dose of narcotics could increase postoperative vomiting and may followed by some complications such as sedation and respiratory depression, it is necessary to avoid prescription of even one dose of narcotics.(5) in addition to their limited effect in controlling a comparison between acetaminophen suppository and caudal anesthesia in relieving pain after pediatric surgery razavi ss*, shaeghi s, shiva h, mo'menzadeh s department of anaesthesia, mofeed children hospital, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: our aim was to provide a simple, non-invasive, low cost, and practical method to be used by nurses and technicians in a low hazardous, safe, and painlessness anesthesia. materials and methods: in a prospective blind clinical trial 40 children between 4 and 6 months who were candidated for subumbilical elective surgeries were recruited. they were randomly divided into two groups. bupivacain 0.25% was prescribed in the control group according to armitage formula (0.51 ml/kg); while, supp. acetaminophen was administered in the subject group by a dosage of 30-40 mg/kg. results: there was no statistically significant difference in the pain score of the two groups within 2 hours postoperatively, but higher pain score was reported in subject group during the third and forth hours. conclusion: caudal anesthesia with bupivacaine has better painless period postoperatively. key words: acetaminophen suppository, caudal anesthesia, pediatric surgery accepted for publication pain, nsaids have their own specific complications such as gi bleeding and exacerbation of asthmatic crises. among regional approaches, painlessness by caudal anesthesia is regarded as the most common method in pediatric anesthesia, which is mostly applied in circumcision, hypospadiasis, club foot, herniorrhaphy, urogenital, and anal surgeries, and also generally subumbilical operations.(6) despite its advantages, caudal method has several disadvantages including: an experienced specialist is needed to perform this method. nonetheless, approximately 10% of cases ended in failure.(6) this method cannot be practical in the case of regional infection.(1) painlessness would be obtained just for a limited time. it is impractical in major malformations of sacrum, myelomeningocele and meningitis.(6) among local anesthesia methods, toxicity risk of local drugs in this method (preceded by intercostal method) would be higher than other methods which is due to intravenous or intraosseous injections.(6) intrathecal injection can also be done but hypotension can also occur in less than 8year-old children.(6) postoperative urination might be delayed and vomiting is reported in 30% of cases.(6) accordingly, there has not been any ideal method for children painlessness during and after anesthesia. in this study, we attempted to find a simple and practical method to be used by nurses and technicians in a low cost, less hazardous, and safe anesthesia with little pain. meterials and methods forty children between 6 month and 4 years who were candidated for subumbilical elective operations with asa class i and ii were included in this blind clinical trial regardless of sex. those with cns disorders, excessive hemorrhage, and tachycardia during the surgery and those who received narcotics postoperatively were excluded from the study. patients were connected to ecg monitoring device and pulse oxymeter for the detection of probable hypoxia, arrhythmia due to intravascular injection of bupivacaine, and tachycardia caused by pain, which indicates the failure of procedure. precordial stethoscope was also fixed for them. all patients were given similar premedication and oral midazolam (0.3 mgr/kg) and atropine (0.02 mgr/kg) were prescribed 30 minutes before surgery. all patients were anesthetized deeply by sodium thiopental (6mg/kg), halothane with a maximum concentration of 2%, and n2o gas 50% to 70% without muscle relaxants. laryngeal mask airway was applied appropriately to their age and patients were randomly selected using random table assignment. supp. acetaminophen 40 mg/kg was given in the subject group and caudal anesthesia in lateral position was applied to the other. a maximum of 20 cc of bupivocaine 0.25% was used according to armitage formula 0.5-1 ml/kg to induce blockage to high lumbarhigh sacral areas (single-shot caudal block). niddle number 23 gauge was used in all the cases accurately. patients' breathing was automatic, although, they were given assisted ventilation occasionally. postoperatively, patients' pain score was evaluated every one hour for four hours by a trained nurse who was unaware of the used method of anesthesia and painlessness. flcac pain score was used to estimate the pain (table 1). 2 table 1. pain score (flcac) pain score giterion o i 2 f(face) no special mood or laughing could be seen sometimes he frowns and pulls himself back he frowns repeatedly and press his mandibles on each other l(legs) normal position of legs in rest he is unease and agitated and he contracts his legs a little he kicks his legs & moves up and down c( crying) no crying (conscious, sleepy) he moans or cry's and sometimes sufferers from pain he always moans & cry's or screams a (activity) he sleeps calmly with normal activity and moves with ease he moves toward back & forth , right & left & feels uncomforted his limbs are bent & his muscles are contracted with sudden movement c(consol ability) he is calm & comfort he becomes calm by embracing and pampering him it is difficult to console him & make him comfort results six girls and 14 boys were included in the subject (acetaminophen) group and 6 girls and 14 boys comprised the control (caudal) group (fig.1). the mean ages were 19 months and 21 months in subjects and control groups respectively. at the first hour the maximum level of pain score in both groups did not exceed 4. four patients had 2-4 score in the case group; while, 3 cases felt 2-4 score in the control group. eighty two percent of patients had no remarkable pain at the first hour but 18% of them felt little pain that eased off (fig. 3, 4). at the second hour a significant number of patients had <2 pain scores in both groups and there was no statistical difference between them and one patient in the subject group had a score in the range of 2-4 (fig. 2, 4). fifteen percent in the case group and 5% in the control group had 2-4 pain scores in the third hour postoperatively (fig. 3). as indicated in table 2, patients gained a cumulative score of 16 in the subject group and 3 in the control group from which a significant statistical difference between the two groups could be notified that might be due to the decrease of plasma level of acetaminophen regarding its half-life. thirty percent of subject group had 2-4 pain score and 5% felt >4 pain score, while, 90% of control group had <2 score (table 2). total score of 20 studied patients was 28 in the case group and 8 in the control group, which indicates a significant discrepancy between the two groups and emphasizes that decreasing plasma level of acetaminophen has resulted in higher pain scores. discussion in accordance with previous studies, bupivocaine 0.25% compared to its lower concentrations provides a better painlessness and is of no risk in subumbilical surgeries; hence, the same concentration was used in this study.(7) earlier studies show that prophylactic acetaminophen could decrease pain in surgical procedures mild to moderately.(10, 11) in this study, the same finding was observed too. in a study comparing diclofenac to bupivocaine, pain incidence and intensity in diclofenac group were higher than bupivocaine group at the first hours; however, in this study no difference was noted at first hours, but pain 3 fig. 1. the frequency of genders in the subject and control groups 0 2 4 6 8 10 12 14 16 control study n u m b e r male female fig. 2. the frequency of <2 pain scores at the first to the fourth postoperative hour in the subject and the control group 0 5 10 15 20 25 1st hour 2nd hour 3rd hour 4th hour n u m b e r control study table 2. pain score table of the subject and control groups at the four postoperative hours fourth hour third hour second hour first hour control group fourth hour third hour second hour first hour subject group 0 5 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 4 0 0 0 4 0 0 0 0 0 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 4 1 5 0 0 0 0 3 0 0 0 1 0 4 3 0 0 4 3 0 3 1 2 1 0 0 0 3 0 3 0 1 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 1 0 3 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 4 0 4 0 0 3 4 0 0 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 0.4 0.15 0 0.7 1.4 0.75 0.25 0.8 mean x 1.273 0.67 0 1.04 1.82 1.07 0.695 1.58 standard deviation 8 3 0 10 28 16 5 16 total incidence and intensity increased more in case group later on.(8) regarding that in an investigation painlessness duration in surgical operations with caudal anesthesia exactly before the beginning of short period surgeries did not differ, in this study caudal anesthesia was performed before the beginning of surgery in this study. regarding the results obtained from statistical analysis of both groups and their pain score comparison at the first and the fourth hours, and also considering the resultant p value, we can conclude that there was statistically no significant difference in the pain score of both groups at the first and the second hours. moreover, it can be hypothesized that there is no difference between using caudal anesthesia and supp. acetaminophen concerning postoperative pain intensity at the first and the second hours. however, considering p value in the comparison of both groups' pain score at the third and the fourth hours, it can be concluded that pain level in the subject group was higher than the one in the control group. conclusion generally, it can be concluded that the children who received caudal marcaine for postoperative painlessness, experienced a better and longer painlessness; yet, if caudal anesthesia is impossible (due to anatomic problems of sacrum, local infection, medication lackness, etc.), at least a supp. of acetaminophen could be helpful in pain relieving at the first few postoperative hours. references 1. davis, moyotoma. smiths' anesthesia for infant and children. 3rd ed. w. b. saunders; 1996. p. 316. 2. sumner, edward, hatch dj. pediatric anesthesia. 4th ed. churchill livingstone; 1999. p. 148, 268. 3. katzong bg. basics of clinical pharmacology. 5th ed. p. 506. 4. houck cs, berde cb, anand kjs. pediatric pain management. in: gregory, editor. pediatric anesthesia. new york: churchill livingstone;1994. p. 743. 5. weinstein ms, nicolas sc, schreimner ms. a single dose of morphine increases the incidence of vomiting. anesthesiology 1994; 81: 572. 6. miller, roland. anesthesia. 5th ed. churchill livingstone; 2000. p. 1560-1561. 7. grunter jb, dann cm, bennie jb, et al. department of anesthesiology. washington university school medicine medline; 1991. 8. moors ma, wandless jg, fell d. comparison of caudal block using bopivacaine and diclofenac supp in children for ilioingoinal herniotomy. department of anesthesia, leicester royal infirmity 1999 feb. 9. rice lg, pudimat ma, hannallah rs. management of post operative pain in children with caudal anesthesia. department of anesthesiology, children's national medical center, washington, d.c 1990 may. 4 fig. 3. the frequency of 2-4 pain scores at the first to the fourth postoperative hour in the subject and the control group fig. 4. the frequency of >4 pain scores at the first to the fourth postoperative hour in the subject and the control group 0 2 4 6 8 10 12 14 16 1st hour 2nd hour 3rd hour 4th hour n u m b e r control study 0 2 4 6 8 10 12 14 16 1st hour 2nd hour 3rd hour 4th hour n u m b e r control study 10. romej m, veepel-lewis t, reynold pi. effect of preemptive acetaminophen on postoperative pain score and oral intake in pediatric tonsillectomy patient. aana journal 11996 dec; 64 (6): 535-540. 11. postoperative pain relief in children with acetaminophen comparison with thramadol. european journal of anesthesiology 1999 july; 16 (7): 473-478. 5 case report 280 urology journal vol 5 no 4 autumn 2008 persistent multiple vesicocutaneous fistulas or watering-can abdomen shanmugasundaram rajaian, santosh kumar, ganesh gopalakrishnan urol j. 2008;5:280-3. www.uj.unrc.ir keywords: urinary blabber fistula, cutaneous fistula, suprapubic cystostomy department of urology, christian medical college, vellore, tamilnadu, india corresponding author: ganesh gopalakrishnan, md department of urology, christian medical college, vellore, tamilnadu, india 632 004 tel: +91 416 228 2111 fax: +91 416 223 2035 e-mail: ganesh@cmcvellore.ac.in received december 2008 accepted april 2008 introduction vesicocutaneous fistula (vcf) is a known complication of longstanding suprapubic cystostomy tract. we report the first case of neglected urethral stricture with rectourethral fistula following pelvic trauma presenting as “watering-can abdomen” due to multiple vesicocutaneous fistulas following suprapubic cystostomy. case report a 24-year-old man referring from a remote village presented with the history of passing urine through multiple openings in the anterior abdominal wall. at presentation, his kidney function and the urinary tract were normal. he had a history of urethral injury due to pelvic trauma following accidental fall of heavy metal object while playing at the age of 4 years. as initial management, he immediately underwent suprapubic cystostomy. the suprapubic cystostomy catheter slipped out spontaneously and was not replaced. meanwhile, he was voiding via the urethra along with the leakage of urine through the rectum. two months later, he developed retarded urinary stream, and the leakage of urine through the rectum increased. he did not present for followup, and 6 years after the trauma, he developed a firm globular subcutaneous mass in the suprapubic area with the size of 10 × 10 cm and multiple punctuated openings through which he was voiding almost the entire volume of the urine (figure 1). he also had intermittent leakage of the urine through the rectum. rectal examination revealed palpable comminuted healed fracture of the pubis and superiorly displaced prostate across the anterior rectal wall. ascending urethrography figure 1. suprapubic mass—”watering-can abdomen”—reveals multiple urine and pus discharging tracts. persistent multiple vesicocutaneous fistulas—rajaian et al urology journal vol 5 no 4 autumn 2008 281 showed bulbomembranous urethral stricture and rectourethral fistula. fistulography and micturating cystourethrography showed multiple arborizing tracts, opacification of the vesicocutaneous fistula, and dilated posterior urethra along with the leakage of the contrast into the rectum (figure 2). t2-weighted magnetic resonance imaging further confirmed the wellestablished tract between the urinary bladder and the nodular swelling in the anterior abdominal wall (figure 3). the mass and the vcf tract were excised and bladder was closed in layers. a new suprapubic cystostomy was created away from the fistulous tract. transverse loop colostomy was done to divert the feces away from the fistula. chronic inflammation around and within the fistulous tracts was seen on histological evaluation of the mass. six weeks later, the patient underwent anastomotic urethroplasty and correction of the rectourethral fistula along with gracilis flap interposition with our described technique successfully.(1) three weeks thereafter, urethral and suprapubic cystostomy catheters were removed. during the follow-up, he was voiding with a good stream of urine, and there was no leakage of urine through the rectum. the figure 2. left, ascending urethrography shows bulbomembranous stricture (arrow) and opacification of the rectum. middle, fistulography shows arborizing tracts within the mass (arrows). right, micturating cystourethrography shows vesicocutaneous fistula (arrow) entering the “watering-can abdomen” and the rectum filled with the contrast medium. figure 3. left, t2-weighted sagittal magnetic resonance imaging shows the fistula (arrow) between the urinary bladder and the “watering-can abdomen.” right, t2-weighted axial magnetic resonance imaging reveals the same communication (arrow). persistent multiple vesicocutaneous fistulas—rajaian et al 282 urology journal vol 5 no 4 autumn 2008 suprapubic cystostomy site healed well as shown in the postoperative photograph taken 8 months after the operation (figure 4). postoperative micturating cystourethrography showed normal urethra and bladder and completely healed rectourethral fistula (figure 5). then, colostomy closure was planned. discussion the term “watering-can perineum” is often used to describe multiple urethrocutaneous fistulous tracts caused by periurethral abscesses and fistulas complicating urethral stricture. the term “watering-can abdomen” explains the voiding pattern of our patient through multiple suprapubic vesicocutaneous fistulas presenting as a mass following suprapubic cystostomy. a review of the english literature shows this to be the first case of its kind. vesicocutaneous fistula occurs due to various causes such as infection, neoplasm, bladder calculus, and bladder diverticulum or following procedures such as open prostatectomy and total hip arthroplasty.(2-7) however, in routine urological practice, the most common cause is persistent vcf after longstanding suprapubic cystostomy. it could be a troublesome complication for many urological diseases including untreated bladder outflow obstruction due to urethral stricture and benign prostatic enlargement. vesicocutaneous fistula often persists when the tract is well-epithelialized or infected, or when it is affected by foreign bodies or neoplasms. in our case, the vcf persisted and resulted in a keloidal mass in the suprapubic region because of the bladder outflow obstruction due to neglected urethral stricture and infection due to rectourethral fistula. excision of the longstanding suprapubic cystostomy tract along with treatment of the causes predisposing to the persistence of the vesicocutaneous fistula is mandatory in order to avoid complications like what we noticed in this case. voiding through multiple openings in the presence of urethral stricture and rectourethral fistula makes our case a unique one. conflict of interest none declared. figure 4. postoperative photograph shows healed suprapubic scar and spouting transverse colostomy. figure 5. postoperative micturating cystourethrography shows normal contour bladder with well-healed patent urethral anastomosis and no leakage of the contrast medium into the rectum. persistent multiple vesicocutaneous fistulas—rajaian et al urology journal vol 5 no 4 autumn 2008 283 references 1. gupta g, kumar s, kekre ns, gopalakrishnan g. surgical management of rectourethral fistula. urology. 2008;71:267-71. 2. deshmukh as, kropp ka. spontaneous vesicocutaneous fistula caused by actinomycosis: case report. j urol. 1974;112:192-4. 3. gupta np, singh i, nabi g, ansari ms, mandal s. marjolin’s ulcer of the suprapubic cystostomy site infiltrating the urinary bladder: a rare occurrence. urology. 2000;56:330. 4. kobori y, shigehara k, amano t, takemae k. vesicocutaneous fistula caused by giant bladder calculus. urol res. 2007;35:161-3. 5. kishore ta, bhat s, john pr. vesicocutaneous fistula arising from a bladder diverticulum. indian j med sci. 2005;59:265-7. 6. jaiswal p, challacombe b, dasgupta p. groin abscess: a vesico-cutaneous fistula to the groin. a rare complication of open prostatectomy. int j clin pract suppl. 2005;:113-4. 7. gallmetzer j, gozzi c, herms a. vesicocutaneous fistula 23 years after hip arthroplasty. a case report. urol int. 1999;62:180-2. case report median raphe cyst of the penis hasan deliktas*, hayrettin sahin, ozgur ilhan celik, omer erdogan keywords: diagnosis; differential; epidermal cyst; penile diseases; cysts; pathology. introduction median raphe cysts (mrc) are rarely seen cysts that develop from the median raphe in the male external genital region. these cysts might develop in any area, including the parameatus, glans penis, penile shaft, scrotum and perineum on the ventral surface of the genital region.(1,2) a differential diagnosis must be made from other lesions such as glomus tumors, dermoid cysts, pilonidal cysts, epidermal inclusion cysts, urethral diverticula and steatocytomas that originate in the genital region.(2) case report a 26-year-old male presented with a mass on the penis that had been growing slowly for 3 years; although the mass was painless, it caused discomfort during urination and sexual relations. in the physical examination, a penile mass 20 × 20 mm in size with regular borders was determined to be extremely close to the external meatus (figure 1a). except for the penile lesion, the physical and abdominal examinations were normal. the full urine test and full blood count results were normal. by penile ultrasonography, a cystic mass, 10 × 20 × 20 mm in size, was determined. under spinal anaesthesia, the mass was excised, and meatoplasty was performed (figure 1b, c, d). the patient was discharged on postoperative day 1. in the pathology examination, there was cyst formation ın the hematoxylin-eosin staining, with a lining of pseudostratified columnar epithelium in the deep dermis under a normal epidermis (figure 2a). focal squamous metaplasia in the pseudostratified columnar epithelium could be observed. in the immunohistochemical study, the epithelial cells of the cyst lining were stained positive with cytokeratin (ck) 7 (figure 2b) and carcinoembryonic antigen (cea) (figure 2c) and negative with cytokeratin 20 (figure 2d). the lesion was diagnosed as an mrc from these findings. at the 1-month follow-up, the complaints department of urology, school of medicine, mugla sitki kocman university, mugla, turkey. *correspondence: mugla sitki kocman university, school of medicine, department of urology, mugla, turkey. e-mail: hasandeliktas@mynet.com. received march 2015 & accepted june 2015 figure 1. (a) the cyst at the parameatus of the penis of a 26-year-old patient. (b) the image of the cyst after the complete excision. (c) the image of the meatoplasty. (d) the image of the penis after the catheter removed. figure 2. (a) cyst formation with a lining of pseudostratified columnar epithelium (hematoxylin-eosin, original magnification × 40). (b) the epithelial cells of the cyst lining were stained positive with cytokeratin 7 (original magnification × 200). (c) the epithelial cells of the cyst lining were stained positive for carcinoembryonic antigen (original magnification × 200). (d) the epithelial cells of the cyst lining were stained negative with cytokeratin 20 (original magnification × 200). case report 2287 of discomfort during urination and sexual relations had resolved. no recurrence or narrowing of the meatus was determined during the 1-year follow-up period of the patient. discussion median raphe cysts are cysts that develop on the median line in the male genital region any area from the anus to the external meatus.(2) the vast majority develop on the penile shaft and in the parameatal section.(3) median raphe cysts are hypothesised to originate from a defect that is created during the embryological development of the male urethra.(2,4) in the histopathological differential diagnosis, an mrc should be distinguished from apocrine cystadenomas, mucinous cysts and epidermal cysts. in an mrc, the lining primarily consists of pseudostratified, 1to 4-cell-thick columnar epithelium. immunohistochemically, the epithelial cells are ck 7 and cea positive and ck 20 negative.(5) in our case, the cyst lining was entirely composed of pseudostratified columnar epithelium that had positive staining with ck 7 and cea and negative staining with ck 20; it was diagnosed as mrc. although the majority of median raphe cysts are present from birth, they remain undetectable until adolescence or adulthood. because the lesions are generally asymptomatic, there is no impairment of urinary or sexual function.(2) median raphe cysts could be followed up without surgical excision in asymptomatic patients, particularly in children.(6) however, in some patients, they cause pain with urination and haematuria 3. in addition, pain might occur in the event of trauma or infection.(7) treatment should be applied to patients who experience symptomatic or cosmetic discomfort. because the lesion had a parameatal location in the current case, it was causing discomfort during urination and sexual relations. in the treatment of symptomatic median raphe cysts, the mass should be excised, and the patient must be followed up for the evaluation of recurrence.(3) aspiration alone is not recommended in the treatment of median raphe cysts. in the treatment of large cysts and those with a deep localisation, marsupialisation and de-roofing are performed. this surgical procedure results in cosmetically undesirable open-ended sinuses. when possible, this surgical procedure should be avoided.(4) in in a literature review, except for a limited number of patients in which an urethrocutaneous fistula occurred, there are no reports of surgical complications when appropriate mass excision is applied.(3) parameatal-located median raphe cysts might cause problems such as discomfort during sexual intercourse, difficulty with urination and cosmetic discomfort. meatoplasty might be applied safely if the cyst is near the external meatus. in the treatment of median raphe cysts, complete excision is a safe and effective treatment choice. conflict of interest none declared. references 1. romani j, barnadas ma, miralles j, curell r, de moragas jm. median raphe cyst of the penis with ciliated cells. j cutan pathol. 1995;22:378-81. 2. nagore e, sanchez-motilla jm, febrer mi, aliaga a. median raphe cysts of the penis: a report of five cases. pediatr dermatol. 1998;15:191-3. 3. shao ih, chen td, shao ht, chen hw. male median raphe cysts: serial retrospective analysis and histopathological classification. diagn pathol. 2012;7:121. 4. shiraki iw. parametal cysts of the glans penis: a report of 9 cases. j urol. 1975;114:544-8. 5. calonje e, brenn t, lazar a, mckee ph. mckee's pathology of the skin. 4th edition ed. elsevier, saunders, boston; 2012: 486-8 and 1508-10. 6. soyer t, karabulut aa, boybeyi o, gunal yd. scrotal pearl is not always a sign of anorectal malformation: median raphe cyst. turk j pediatr. 2013;55:665-6. 7. soendjojo a, pindha s. trichomonas vaginalis infection of the median raphe of the penis. sex transm dis. 1981;8:255-7. vol 12 no 04 july-august 2015 2288 median raphe cyst of the penis-deliktas et al. vol 13 no 02 march-april 2016 2590vol 13 no 02 march-april 2016 2656 acute urinary retention in a female following bladder tumor resection due to a stone in a urethral diverticulum pictorial osama z abusanad, michael s floyd (jr),* altaf qadir khattak a 56 years old female smoker presented with recurrent urinary tract infections but no hematuria. pelvic exam revealed an indurated area on the anterior vaginal wall. magnetic resonance imaging (mri) revealed a suspicious area around the urethra which was thought to be tumor extension from a bladder cancer (figure 1). rigid cystoscopy demonstrated a tight urethra and a bladder tumor. histology confirmed adenocarcinoma. the patient developed acute urinary retention following catheter removal and commenced intermittent catheterization. due to the aggressive histology and concerns over urethral involvement, a repeat mri (figure 2) was performed to permit local staging with a view to exenteration. this was preferred over a transvaginal scan as resection had confirmed a neoplastic process. when compared to the initial mri a stone was seen, which had initially been suspected to be direct tumor extension, but no adenopathy. repeat cystoscopy showed a large stone in a urethral diverticulum and recurrent bladder tumor. the stone was dislodged and treated with laser lithotripsy. the patient was treated with pelvic exenteration and adjuvant chemotherapy for a pt4 n2 bladder cancer. urethral diverticulum stones may cause recurrent urinary tract infections in females.(1) laser lithotripsy and diverticulum repair have been described. (2) mri has limitations when assessing female urethral pathology.(3) references 1. shim js, oh mm, kang ji, ahn st, moon du g, lee jg. calculi in a female urethral diverticulum. int neurourol j. 2011; 15:55-7. 2. susco bm, perlmutter ae, zaslau s, kandzari sj. female urethral diverticulum containing a calculus: a case report. w v med j. 2008;104:15-6. 3. chung de, purohit rs, girshman j, blaivas jg. urethral diverticula in women: discrepancies between magnetic resonance imaging and surgical findings. j urol. 2010;183:2265-9. department of urology, whiston hospital, st. helens and knowsley teaching hospitals, nhs trust, merseyside, l35 5dr, uk. *correspondence: department of urology, whiston hospital, st helen's and knowsley hospital nhs trust, merseyside, l35 5dr, uk. tel: + 44 151 4261600. fax: + 44 151 4301405. e-mail: nilbury@gmail.com. received march 2015 & accepted october 2015 figure 1. magnetic resonance imaging (mri) demonstrating a suspicious area around the urethra. figure 2. repeat magnetic resonance imaging (mri) demonstrating a stone when compared to the initial mri. does systemic disease aggravate the severity of dry mouth by anticholinergics in overactive bladder patients? keon-cheol lee1*, bong-mo seong2 purpose: in overactive bladder (oab) patients with systemic diseases, dry mouth tends to be more prominent owing to the effects of systemic diseases or related medications. we evaluated how systemic diseases affect dry mouth before and after anticholinergic treatment. materials and methods: oab patients were enrolled in this study. the patients were divided according to the presence or absence of systemic diseases. patients with systemic diseases were sub-grouped by the number of systemic diseases (only one or more than one disease). oab symptoms score (oabss), visual analogue scale (vas) score for dry mouth, and body mass index (bmi) were measured. the statistical assessments were done with independent t-tests and ancovas. results: one hundred and four oab patients were enrolled in this study. seventy (67.3%) patients had systemic diseases and thirty-four (32.7%) patients did not. age and bmi were higher in the systemic diseases group. the baseline vas score of oab in the systemic diseases group (15.9 ± 19.5) was higher than that in the oab without systemic diseases group (4.1 ± 6.4) (p = .002). even after age and bmi adjustment, the difference was significant. the follow-up vas score was also different (p = .028), but the change in vas score was not different (p = .280). in a sub-analysis, the change in vas score in the group with two or more systemic diseases (23.6 ± 18.1) was higher than that in the group with only one systemic disease (12.5 ± 13.2) (p = .012). conclusion: the severity of xerostomia after treatment with anticholinergics in oab increases in patients with one systemic disease parallel to its severity before starting treatment. however, in patients with two or more systemic disease the magnitude of change in xedrostomia score is higher that we would expect in patients with no or one systemic diasese. keywords: body mass index; cholinergic antagonists; systemic diseases; urinary bladder, overactive; xerostomia 1 department of urology, inje university school of medicine, ilsanpaik hospital, goyang, korea. 2 department of urology, comwel incheon hospital, incheon, korea. *correspondence: department of urology, inje university ilsanpaik hospital, 2240, daehwa-dong, goyang, gyeonggi, korea. postal code : 10380 tel: +82 31 9107230. fax: +82 31 9107239. e-mail: kclee@paik.ac.kr. received october 2016 & accepted march 2017 introduction anticholinergics are very useful and are current-ly the most commonly prescribed medication in overactive bladder (oab) patients. however, they have a well-known side effect profile that includes dry mouth, constipation, voiding difficulty, and so on.(1) dry mouth is the most common side effect; it occurs in 8-87% of oab patients after administration of various anticholinergics depending on the particular formulation of each anticholinergic agent.(2-5) anticholinergics work by blocking muscarinic receptors in the bladder, and dry mouth caused by anticholinergics appears to be the result of blocking muscarinic receptors in salivary glands. many systemic diseases appear to be related to dry mouth through various mechanisms. for example, diabetes, which is a common disease of the endocrine system, has a high dry mouth rate, up to 40-60%, even in children,(6) and the mechanisms are thought to be multifactorial and include dehydration, polyuria, and miscellaneous autonomic abnormalities.(7) the medications used to treat systemic diseases also frequently cause dry mouth. (8) therefore, patients with systemic diseases could already be predisposed towards a risk of dry mouth before treatment with anticholinergics. also, it may be that underlying systemic disease status affects side effect profiles in oab patients treated with anticholinergics. the interaction between anticholinergics and some drugs that interfere with the cytochrome p450 pathway has been reported to potentiate the side effects of anticholinergics.(9) however, clinical reports proving this hypothesis are rare. we can assume that underlying systemic diseases make some patients more vulnerable to the adverse effects of anticholinergics. therefore, we evaluated how systemic diseases affect dry mouth before and after anticholinergic treatment in oab patients. patients and methods oab patients were enrolled in this study. the institutional review board (irb) of inje university, ilsanpaik vol 14 no 02 march-april 2017 3035 were made again. to exclude the effects of age and bmi because age and bmi could be the risk factor of dry mouth, statistical adjustment for age and bmi was made and the data were re-analyzed. the group with two or more systemic diseases was compared with the group with only one systemic disease for the above mentioned clinical parameters. the statistical program used was spss 12.0 for windows and the normality of any variables was confirmed before running statistical comparison. employed statistical methods were independent t-tests and ancovas. p values less than 0.05 were regarded as statistically significant. results between june 2012 and february 2013, a total of one hundred and four oab patients were enrolled in this study. there were 40 (38.5%) male patients and 64 (61.5%) female patients in the studied group of patients. the mean age of the patients was 64.1 ± 10.2 years (range: 43-82) in the oab with systemic diseases group and 56.6 ± 11.6 years (range: 38-80) in the oab without systemic diseases group (p = .001). oab symptom duration before study was 83.5 ± 68.8 months (range: 3-240) for the oab with systemic diseases group and 49.3 ± 44.7 months (range: 3-120) for the oab without systemic diseases group (p = .003). baseline oabss of the oab with systemic diseases group (6.8 ± 3.5, range: 3-15) was not different from that of the oab without systemic diseases group (6.5 ± 4.2, range: 3-14). both groups showed significant improvements in oabss after treatment. all patients completed three-month follow-up. the follow-up oabss of oab with systemic diseases group (4.5 ± 2.8, range: 0-12) was also not different from that of the oab without systemic diseases group (3.9 ± 4.2, range: 0-14) (table 1). the baseline vas scale of the oab with systemic diseases group (15.9 ± 19.5, range: 0-50) was higher than effect of systemic diseases on dry mouth-lee et al. hospital approved this study (ib-1108-037). it follows the guidelines of the declaration of helsinki and all patients provided written informed consent. inclusion criteria were: age older than 20 years, total overactive bladder symptoms score (oabss) more than three, including question 3 score more than two, without the presence of any exclusion criteria, such as narrow angle glaucoma, urinary retention, gastro-intestinal slow transit, myasthenia and any anticholinergics use during last three months. the patients were divided into two groups according to the presence or absence of systemic diseases. a systemic disease is one that affects a number of organs and tissues, or affects the body as a whole and usually is dealt with in the internal medicine department. after thorough chart review, we used following categories as systemic diseases in this study (hypertension, endocrinologic diseases including diabetes, coronary artery diseases, cerebrovascular conditions, auto-immune conditions, hepato-biliary diseases, etc.). seventy (67.3%) patients had systemic diseases and thirty-four (32.7%) patients did not. patients with systemic diseases were sub-divided into two groups, those with only one systemic disease and those with two or more systemic diseases. drugs taken by the patients for the treatment of those systemic diseases were recorded via a full chart review or by asking the patients. before anticholinergic treatment, oabss and visual analogue scale (vas) score ranging from 0 to 100 for dry mouth was examined using self-administered questionnaire forms. body weight and height of the patients were measured in order to calculate body mass index (bmi). the clinical parameters of the systemic diseases group were compared with those of the non-systemic disease group. all patients received solifenacin 5 mg for the treatment of oab. after 3 months of solifenacin treatment, vas for dry mouth and oabss were measured again and comparisons between the two groups variables oab with systemic diseases(n=70) oab without systemic diseases(n=34) p-value age, year, mean ± sd 64.1 ± 10.2 56.7 ± 11.6 0.001 male(%) 45.7(32/70) 23.5(8/34) female(%) 54.3(38/70) 76.5(26/34) oab-ss mean ± sd baseline 6.8 ± 3.5 6.5 ± 4.2 0.453 follow-up 4.5 ± 2.8 3.9 ± 4.2 0.258 symptom duration, month, mean ± sd 83.5 ± 68.8 49.3 ± 44.7 0.010 bmi, kg/m2, mean ± sd 23.8 ± 3.5 22.3 ± 1.9 0.024 baseline vas, mean ± sd 15.9 ± 19.5 4.1 ± 6.4 0.002 age-adjusted difference 0.023 bmi-adjusted difference 0.002 follow-up vas, mean ± sd 33.1 ± 26.4 21.8 ± 20.1 0.028 changes of vas, mean ± sd 17.0 ± 16.2 13.2 ± 14.1 0.280 table 1. patient demographics and comparisons of vas score between the group of patients with oab and systemic diseases and the group with oab without systemic diseases before and after anticholinergic treatment. abbreviations: oab, overactive bladder; oab-ss, oab-symptoms score; bmi, body mass index; vas, visual analogue scale. miscellaneous 3036 that of the oab without systemic diseases group (4.1 ± 6.4, range: 0-20) (p = .002). even after age-adjustment, the difference in baseline vas scale between the two groups was still significant (p = .023). the follow-up vas scale score of the oab with systemic diseases group (33.1 ± 26.4, range: 0-90) remained higher than that of the oab without systemic diseases group (21.8 ± 20.1, range: 0-60) (p = .028). however, the extent of change in vas score in the oab with systemic diseases group (17.0 ± 16.2, range: 0-60) was not different from that of the oab without systemic diseases group (13.2 ± 14.1, range: 0-50) (p = .280). the bmi of the oab with systemic diseases group (23.8 ± 3.5, range: 16.431.6) was higher than that of the oab without systemic diseases group (22.3 ± 1.9, range: 17.6-26.5) (p = .024) and, after adjustment for bmi, the vas score of the oab with systemic diseases group was still higher than that of the oab without systemic diseases group (p = .002) (table 1). the mean number of systemic diseases in each patient in the systemic disease group was 1.7 ± 1.0 (range: 1-4) and the mean number of drugs prescribed for the treatment of systemic diseases was 3.8 ± 2.5 (range: 1-11). hypertension was the most common systemic disease (60%, 42/70), followed by diabetes (24/70), coronary artery diseases (20/70), cerebrovascular accidents (16/70), liver cirrhosis (8/70), autoimmune diseases (8/70), and end stage renal disease (2/70). in the sub-divided group comparison, the number of drugs prescribed for the treatment of systemic diseases in the two or more systemic diseases group (5.8 ± 2.6) was higher than that for the one systemic disease group (2.5 ± 1.3) (p = .000). although the baseline vas score was comparable between the two groups, the change in vas score of the two or more systemic diseases group (23.6 ± 18.1) was significantly higher than that of the one systemic disease group (12.5 ± 13.2) (p = .012) (table 2). discussion dry mouth, or xerostomia, is the subjective feeling experienced by patients suffering from hypofunction of the salivary glands.(10) in the elderly, the prevalence of xerostomia is 12-47%, which is higher than in the younger population, and age appears to be directly proportional to dry mouth.(11,12) in this study, the patients with systemic diseases and more severe dry mouth were older than the patients in the group without systemic diseases. so, we performed age-adjustment with statistical methods, and found that the severity of dry mouth of the oab with systemic diseases group was still significantly higher than that of the oab without systemic diseases group. the causes of dry mouth have been attributed to the use of medications, chronic disorders, and radiation therapy of the head and neck region.(13) dry mouth can cause dental and oral diseases such as dental caries, periodontal diseases, and problems with dentures, and can be accompanied by alterations in taste, speech, eating, and swallowing, so, it is an important problem that should not be overlooked.(14) various systemic diseases or medications used to treat those diseases can cause dry mouth. for example, endocrine diseases, infections, autoimmune or granulomatous diseases, end-stage renal disease, and parkinson’s disease are known to be related with hypofunction of the salivary glands and subjective feelings of xerostomia via various mechanisms.(15) various systemic diseases could have different effect profiles on xerostomia, so, some diseases could have more effect and some less. we analyzed one systemic disease group patients in this study and failed to find any difference among various systemic diseases. but, we think more profound analysis including patients with many types of systemic diseases would reveal this important hypothesis. patients with systemic diseases usually take many different types of drugs, some of which have anticholinergic effects. the summation of the anticholinergic effects of these drugs could be an important factor in dry mouth in systemic disease patients.(16) overactive bladder is a complex of symptoms including increased frequency, urgency, and nocturia, and it has a profoundly negative impact on the psychosocial functioning and quality of life of patients.(17) anticholinergics are the first-line agents used to treat overactive bladder(18) and have some side effects. of these side effects, dry mouth is the most common problem and tends to be the most annoying to patients and doctors. the side effects as well as efficacy of anticholinergics increase with increased dosage,(19) so, a fixed single dose is preferable for proper analysis in studies of anticholinergics. although recently introduced oab drugs, such table 2. comparisons between the group with only one systemic disease and that with two or more systemic diseases before and after anticholinergic treatment. variables one systemic disease (n=42) two or more systemic diseases (n=28) p-value age, year, mean ± sd 62.5 ± 11.4 66.6 ± 7.7 0.104 symptom duration, month, mean ± sd 67.0 ± 59.8 108.2 ± 74.9 0.013 bmi, kg/m2, mean ± sd 24.1 ± 3.8 23.2 ± 2.9 0.327 number of drugs for systemic diseases, mean ± sd 2.5 ± 1.3 5.8 ± 2.6 0.001 baseline vas, mean ± sd 12.5 ± 17.8 20.9 ± 21.1 0.120 follow-up vas, mean ± sd 28.6 ± 25.4 40.0 ± 26.7 0.075 changes of vas, mean ± sd 12.5 ± 13.2 23.6 ± 18.1 0.012 abbreviations: vas, visual analogue scale; bmi, body mass index. effect of systemic diseases on dry mouth-lee et al. vol 14 no 02 march-april 2017 3037 as beta-3 agonists, have a low incidence of dry mouth compared with previous drugs that act through anticholinergic mechanisms,(20,21) anticholinergic agents are still the main treatment tools used to manage overactive bladder and dry mouth is still the main concern. in this study, the severity of dry mouth in the group of oab patients with systemic diseases was higher than in the group of oab patients without systemic diseases before administration of anticholinergics, and the difference in the severity of dry mouth was maintained after 3 months of anticholinergic use. this could be because of the effects of the drugs used to treat systemic diseases or because of the diseases themselves. when we subdivided the systemic diseases group, the accumulated number of systemic diseases had a significant effect on dry mouth severity. the group with two or more systemic diseases showed increased dry mouth severity compared with the group with only one systemic disease. the number of drugs taken for systemic diseases was also greater in the group with two or more systemic diseases, which could result in those patients being more susceptible to the side effects of anticholinergics. oab patients with systemic diseases had higher baseline and follow-up dry mouth severity after anticholinergic treatment than did oab patients without systemic diseases even after adjusting for the effects of age and bmi. in addition to the well-known age factor, systemic diseases themselves affect baseline dry mouth, and this already high baseline xerostomia is accompanied by significantly more severe dry mouth after anticholinergic treatment in oab patients with systemic diseases. although the changes in the severity of dry mouth were not different between the systemic diseases group and the non-systemic diseases group, sub-classification of the systemic diseases group revealed an association between the number of systemic diseases and the changes in dry mouth after anticholinergic treatment. compared with the patients with only one systemic disease, those with two or more systemic diseases appear to be more susceptible to aggravation of dry mouth by anticholinergics. therefore, when administering anticholinergics to oab patients with systemic diseases, especially those with two or more systemic diseases, it is necessary to prepare for the aggravation of dry mouth. this study has several limitations. firstly, age was not comparable between the systemic diseases group and the no systemic diseases group. age is known to be directly proportional with the rate of dry mouth, so, this difference could have caused a bias in our results. all else being equal, it is reasonable to assume that patients with systemic diseases would generally be older and in worse condition. we did not make intentional efforts to select patients as long as all inclusion criteria and no exclusion criteria were met. simple allocation to groups was made according to the presence or absence of systemic diseases. we attempted to overcome this age discrepancy with statistical age-adjustment. second limitation of this study is that accurate sample size was not calculated before study with the simple goal of at least 30 patients in each group for the proper statistical comparison including normality and the number of patients were not the same among groups. another limitation of this study is that gender distribution is not even in oab without systemic disease group compared with oab with systemic disease group. male predominance in oab without systemic disease group might have the possibility of gender difference bias in xerostomia although gender difference in xerostomia was not generally proven. conclusions the severity of xerostomia after treatment with anticholinergics in oab increases in patients with one systemic disease parallel to its severity before starting treatment. however, in patients with two or more systemic disease the magnitude of change in xerostomia score is higher that we would expect in patients with no or one systemic disease. acknowledgement “ this work was supported by the grant from astellas ”. all authors have contributed significantly and all authors are in agreement with the content of this manuscript. conflict of interest the authors declare no conflict of interest. references 1. herbison p, hay-smith j, ellis g, moore k. effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. bmj. 2003;326:841-4. 2. cardozo l, lisec m, millard r, van vierssen trip o, kuzmin i, drogendijk te, huang m, ridder am. randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. j urol. 2004;172:1919-24. 3. chapple cr, arano p, bosch jl, de ridder d, kramer ae, ridder am. solifenacin appears effective and well tolerated in patients with symptomatic idiopathic detrusor overactivity in a placeboand tolterodine-controlled phase 2 dose-finding study. bju int. 2004;93:71-7. 4. halaska m, ralph g, wiedemann a, primus g, ballering-bruhl b, hofner k, jonas u. controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability. world j urol. 2003;20:392-9. 5. anderson ru, mobley d, blank b, saltzstein d, susset j, brown js, oros oxybutynin study group. once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. j urol. 1999;161:180912. 6. busato ims, ignácio sa, brancher ja, grégio amt, machado mân, azevedo-alanis lr. impact of xerostomia on the quality of life of adolescents with type 1 diabetes mellitus. oral surg oral med oral pathol oral radiol endod. 2009;108:376-82. 7. vasconcelos acu, soares msm, almeida effect of systemic diseases on dry mouth-lee et al. miscellaneous 3038 pc, soares tc. comparative study of the concentration of salivary and blood glucose in type 2 diabetic patients. j oral sci 2010;52:293-8. 8. miranda-rius j, brunet-llobet l, lahor-soler e, farré m. salivary secretory disorders, inducing drugs, and clinical management. int j med sci. 2015;12:811-24. 9. oefelein mg. safety and tolerability profiles of anticholinergic agents used for the treatment of overactive bladder. drug saf. 2011;34:73354. 10. thomson wm, chalmers jm, spencer aj, williams sm. the xerostomia inventory: a multi-item approach to measuring dry mouth. community dent health. 1999;16:12-7. 11. thomson wm. issues in the epidemiological investigation of dry mouth. gerodontology. 2005;22:65-76. 12. murray thomson w, poulton r, mark broadbent j, al-kubaisy s. xerostomia and medications among 32-year-olds. acta odontol scand. 2006;64:249-54. 13. ouanounou a. xerostomia in the geriatric patient: causes, oral manifestations, and treatment. compend contin educ dent. 2016;37:306-11. 14. turner m, jahangiri l, ship ja. hyposalivation, xerostomia and the complete denture. a systematic review. jada 2008;139:146-50. 15. mortazavi h, baharvand m, movahhedian a, mohammadi m, khodadoustan a. xerostomia due to systemic disease: a review of 20 conditions and mechanisms. ann med health sci res. 2014;4:503-10. 16. reppas-rindlisbacher ce, fischer hd, fung k, gill ss, seitz d, tannenbaum c, et al. anticholinergic drug burden in persons with dementia taking a cholinesterase inhibitor: the effect of multiple physicians. j am geriatr soc. 2016;64:492-500. 17. liberman jn, hunt tl, stewart wf et al: health-related quality of life among adults with symptoms of overactive bladder: results from a u.s. community-based survey. urology. 2001;57:1044. 18. krhut j, gärtner m, petzel m, sykora r, nemec d, tvrdik j, et al. persistence with first line anticholinergic medication in treatmentnaïve overactive bladder patients. scand j urol. 2014;48:79-83. 19. preik m, albrecht d, o'connell m, hampel c, anderson r. effect of controlledrelease delivery on the pharmacokinetics of oxybutynin at different dosages: severitydependent treatment of the overactive bladder. bju int. 2004;94:821-7. 20. andersson ke, martin n, nitti v. selective β-adrenoceptor agonists for the treatment of overactive bladder. j urol. 2013;190:1173-80. 21. imran m, najmi ak, tabrez s. mirabegron for overactive bladder: a novel, first-in-class β3-agonist therapy. urol j. 2013;10:935-40. effect of systemic diseases on dry mouth-lee et al. vol 14 no 02 march-april 2017 3039 case report brain metastasis of penile angiosarcoma ozgur kardes1, fatih aydemir2, halil ibrahim suner1*, emre durdag1, soner civi1, kadir tufan1, fazilet kayaselcuk3 keywords: angiosarcoma; penis; metastasis; brain. angiosarcoma is a rare malignancy originating from vascular endothelial cells. brain metastasis of aniosarcomas are uncommon up to the literature. penile angiosarcomas are also seldom among all anjiosarcomas. a case with penile angiosarcoma with confirmed brain metastasis is aimed to be reported and contribute to the literature for similar cases. 1department of neurosurgery, baskent university, faculty of medicine, ankara, turkey. 2department of neurosurgery, medical park hospital, bursa, turkey. 3department of pathology, baskent university, faculty of medicine, ankara, turkey. *correspondence: baskent university department of neurosurgery, adana dr. turgut noyan application and research center dadaloglu mh. sirinevler 2591. sok. no: 4/a 01250 yuregir adana/turkey. tel: +90 505 921 54 94. fax: +90 322 327 12 74. e-mail: h.ibrahimsuner@hotmail.com. received june 2016 & accepted september 2017 introduction angiosarcoma is a very rare, agressive malignancy originating from vascular endothelial cells. it can be pri-marily seen on the head, face, liver, skin and other soft tissues.(1) penile located angiosarcoma is very rarely seen.(2,3) its treatment is generally surgical with adjuvant chemotherapy or radiotherapy.(4) brain metastasis is an unusual condition in angiosarcomas, therefore very few cases have been described.(1) our aim is to present a rare case of penile angiosarcoma with brain metastasis. the case contributes to the literature on the diagnosis, treatment and treatment process. case report a 35-year-old male patient was admitted to the urology clinic with infiltrative mass on the glans penis. on inifigure 1. t2 and t1 weighed enhanced axial mr images showing metastatic mass lesions. largest one is localized on the left parietal cortical-subcortical area and all masses are heterogeneously enhanced with hemorrhagic content and concominant vasogenic edema. figure 2. a. atipical tumoral cells forming vascular structures within large hemorrhagic areas (h&e x100), b. closer look of the tumoral cells; large sytoplasms, aripically appearing cells (h&e x200), c. cd31 positive stained tumoral cells (ihc x200). (h&e : hematoxylin and eosine, ihc: immunohistochemistry). vol 15 no 01 january-february 2017 53 case report 54 tial presentation of the patient, pet ct was performed for general screening purposes. no spread anywhere except the penis was found. the laboratory examinations were also normal. the histopathological evaluation of the incisional biopsy was reported as epitheloid angiosarcoma. on the excisional biopsy, the surgical margines of the mass were intact, however intravascular tumor thrombi were detected. after diagnosis the patient received adjuvant chemotherapy (ctx). in the chemotherapy protocol; carboplatin dose calculated using auc 2 was administered for 12 weeks and paclitaxel was given in a dose of 80mg / m2 . the patient was followed up with ultrasonograohy and chest x-ray every 3 months. five years later he admitted to the emergency department with altered mental status and somnolence. on his neurological examinationi decline in the level of consciousness and quadriparesia were detected. on the cranial magnetic resonance imaging (mri); mass lesions on both parietooccipital areas were observed. the largest one was about 8x30 mm in diameter, with prominent peripheral vasogenic edema, with hemorraghic component, with heterogeneously contrast enhancement (figure 1). laboratory and other imaging studies were normal in this application. metastases were not present in other parts of the body. the patient was operated. microsurgical technique was used and total resection of the mass at the parietal lobe was performed. the patient had good postsurgical recovery period and was transfered to the oncology department. 300 cgy / fr total 30 gy, 2 areas, complex plan, palliative radiotherapy was applied. one month after radiotherapy, the patient died because of general condition deterioration and septicemia. pathological findings the tumors from the penile and cerebral biopsy showed identical morphological and immune staining properties. from the slices prepared of the 2.5x2x2 cm lesion excised at the occipital area; epitheloid-like atipical cells, with large cytoplasms, within large hemorrhagic areas were observed. immunohistochemically (ihc), the atipic cells showed positive staining with cd31, cd32 and vimentin, and negative ck20 staining. focal positive staining was observed with pas staining. based on the morphological, immunohistochemical findings and the patients clinical history the lesion was reported as metastasis of epitheloid angiosarcoma (figure 2). discussion angiosarcomas generally constitute less than 1% of all head, face, liver, skin and soft tissue sarcomas.(5) up to our knowledge almost 30 penile angiosarcomas have been reported in the literature so far.(3) exposure to vinyl chloride and arsenic, and chronic lymphedema may be accountable as risk factors.(6) treatment generally consists of radical surgery and adjuvant ctx and rt.(4) in the current literature limited data exist regarding the metastatic behaviour of angiosarcomas. there are few case reports of primary and secondary cerebral angiosarcoma. metastatic cerebral angiosarcomas are more common compared to primary cerebral angiosarcomas, and generally originate from the right atrium.(5,7) angiosarcomas metastatizing to the brain are reported to be localized generally in the thorax or abdomen (66%) and cardiac angiosarcomas are reported to metastasize more commonly to the brain.(1,8) in the literature, 2 of 6 splenic angiosarcomas are reported to have metastatize to the brain. beside being rare, only few cases reporting brain metastasis of penile angiosarcoma are present.(9) brain metastasis is most frequently found on the parietal (30,7%) and frontal (23%) lobes.(1) the localization of the metastasis in our case also supported these findings. cerebral metastasis of angiosarcoma is characterized by hemorrhagic transformation with perilesional edema in ct; and on mri, partial contrast enhancement is present beside hemorrhagia and perilesional edema. it may be confused with cavernous hemangioma due to its hemorrhagic appearance, and with other intracranial tumors due to the peritumoral edema.(5,10,11) in general, angiosarcomas have very poor prognosis. tipically, 5 year survival rate is 12%, and metastasis and relaps is seen during the first 2 years.(4) the prognosis may vary due to the primary location of the tumor, surgical resection and tumor size on presentation.(6,12) particularly in angiosarcomas with brain metastasis the overall survival rate is 2-6 months. in our case; we have achieved better results in terms of survival rate from the literature and life time after metastasis was consistent with the literature. after the excision of the primary angiosarcoma, ctx and rt may be useful in the prevention of brain metastasis. ctx in cases with brain metastasis is not effective due to the impermeability of the chemotherapeutic agents used in sarcoma treatment.(13) angiosarcomas have poor prognosis due to their malignant and aggressive course. our case can also be shown as an example of poor prognosis of angiosarcoma. conventionally, sarcoma, renal cell carcinoma and melanomas are accepted as radioresistant tumors. in the past, in sarcoma cases with brain metastasis, primary and fractioned whole brain radiotherapy (wbrt) was used in order to achieve local control, and the average survival was limited to 3 months.(13) classic treatment methods have been applied in our case and long-term survival after metastasis has not been achieved. therefore, radiation-resistant brain metastases should be treated more aggressively with stereotactic radiosurgery. references 1. shweikeh f, bukavina l, saeed k, et al. brain metastasis in bone and soft tissue cancers: a review of incidence, interventions, and outcomes. sarcoma 2014;2014:475175. 2. gogoi d, hazra s, ghosh b, pal d. angiosarcoma of penis. bmj case rep. 2013;18:bcr2013200878. 3. wasmer jm, block nl, politano va, tejada f. penile angiosarcoma presenting in bladder. urology 1981;18:179-80. 4. chami tn, ratner le, henneberry j,smith dp, hill g, katz po. angiosarcoma of the small intestine: a case report and literature review. am j gastroenterol. 1994;89:5:797– 800. 5. jung sh, jung ty, joo sp, kim hs. rapid clinical course of cerebral metastatic angiosarcoma from the heart. j korean brain metastasis of penile angiosarcoma-kardes et al. neurosurg soc 2012;51:47-50. 6. liassides c, katsamaga m, deretzi g, koutsimanis v, zacharakis g. cerebral metastasis from heart angiosarcoma presenting as multiple hematomas. j neuroimaging. 2004;14:1:71–3. 7. matsuno a, nagashima t, tajima y, sugano i. a diagnostic pitfall: angiosarcoma of the brain mimicking cavernous angioma. j clin neuro¬sci. 2005;12 : 688-91. 8. angrish k, manchanda sc,shankar sk, chopra p. primary angiosarcoma of the heart. japanese heart journal 1979;20:3:375-80. 9. zhu xw, guo jp, chen h, et al. deep sarcoma of the penis: a report of 2 cases and review of the literature. zhonghua nan ke xue 2007;13:915-7. 10. araoz pa, eklund he, welch tj, breen jf. ct and mr imaging of pri¬mary cardiac malignancies. radiographics 1999;19:142134. 11. gallo p, dini li, saraiva ga, sonda i, isolan g. hemorrhage in cerebral metastasis from angiosarcoma of the heart : case report. arq neurop¬siquiatr. 2001;59:793-6. 12. plotnik an, schweder p, tsui a, kavar b. splenic angiosarcoma metastasis to the brain. j clin neurosci. 2008;15:8:927-9. 13. españa p, chang p, wiernik ph. increased incidence of brain metasta¬ses in sarcoma patients. cancer 1980;45:377-80. brain metastasis of penile angiosarcoma-kardes et al. vol 15 no 01 january-february 2017 55 laparoscopic urology laparoscopic varicocelectomy with single incision in children qimin chen, liang zhong, shaofeng wu, yang sun, guanqun ju, jie sun* purpose: single-port laparoscopic varicocelectomy has recently been introduced. as an instrument with three ports was too large for use in children, a modified technique using a single incision with two trocars was attempted in our department. this study was designed to compare the new method with the traditional laparoscopic method involving three ports. materials and methods: twelve boys with a total of 14 varicoceles were admitted for laparoscopic varicocelectomy through a single incision with two trocars. thirty-two patients with 33 varicoceles were treated using traditional three-port laparoscopy, and were reviewed as controls. data were collected to compare the two groups. results: all procedures were completed successfully in both groups. there were no significant differences in terms of patients’ age, operative time, blood loss, analgesic requirement, hospital stay, and complications. conclusion: the technique of laparoscopic varicocelectomy through a single incision with two trocars is safe, effective, and cosmetically acceptable. keywords: laparoscopy; adolescent; vascular surgical procedures; methods; postoperative complications; treatment outcome; urologic surgical procedures. introduction adolescent varicocele is a common condition that is often encountered by pediatric urologists. the prevalence of the disease in the pediatric population is about 10% to 15%.(1) although many factors are involved in the genesis of a varicocele, primary renospermatic reflux is the most common cause of the disease. as this can create both testicular and sperm damage leading to testicular atrophy and oligozoospermia, many pediatric urologists are recommending varicocelectomy in children.(2) several surgical techniques for treatment have been described, and controversy still surrounds the advantages and disadvantages of the different options.(3) with decreased postoperative pain, improved cosmetic appearance, and reduced hospital stay and convalescence, laparoscopic varicocele surgery is an accepted procedure in china. recently, single-port laparoscopic surgery via the umbilicus to repair varicoceles has been reported.(4) the concealed scar of this “scarless” technique has led to wider use. however, a special port with three inserts was too large for use in children. a modified single incision with two trocars is used by our department. compared to other means of surgical access, the wound is more suited to the shape of the umbilicus. materials and methods patients from march 2011 to february 2012, 12 boys aged 9 to 18 years (mean age 13.6 years) were admitted to our hospital for the treatment of varicocele. twelve patients had varicoceles on the left side only, while two patients had bilateral varicoceles. four had grade ii varicoceles and the other 10 had grade iii varicoceles. this study was conducted in accordance with the declaration of helsinki. this study was conducted with approval from the ethics committee of shanghai jiao tong university. written informed consent was obtained from all participants’ guardians. all the clinical diagnoses were verified by a doppler study and a retroperitoneal location was excluded. laparoscopic procedure the patient was placed in the supine position. an infraumbilical incision of about 10 mm was made. after dissection with mosquito clamps and varicocele hooks, the peritoneum was opened under direct vision. two 5 mm trocars were inserted into the abdominal cavity through the single incision (figure). after carbon didepartment of urology, shanghai children’s medical center affiliated to shanghai jiao tong university school of medicine, shanghai 200127, china. *correspondence: department of urology, shanghai children’s medical center affiliated to shanghai jiao tong university school of medicine, shanghai 200127, china. tel: +86 021 38625709. fax: +86 021 58393915. e-mail: jiesundoc@126.com. received january 2015 & accepted november 2015 vol 12 no 06 november-december 2015 2400 laparoscopic varicocelectomy with single incision-chen et al. oxide insufflation, a 5 mm laparoscope was used for visualization, and a straight working instrument was inserted. the patient was maintained in the trendelenburg position and rotated slightly to the contralateral side of the operated vessels. the spermatic vessels were identified in the retroperitoneum. the peritoneum was then opened alongside the spermatic vessels as high as possible above the internal inguinal ring. the vessels were dissected free and divided with a harmonic scalpel. no attempt was made to spare the testicular artery or adjacent lymphatics. all patients were discharged on the 2nd postoperative day and returned to the hospital for scheduled follow-up. a group of 32 patients with 33 varicoceles was treated using traditional three-port laparoscopy between 2009 and 2010, and was served as control group. statistical analysis data on age, operative time, blood loss, analgesic requirement, hospital stay, and complications were collected. the unpaired t-test with mean and standard deviations (sd) was used for comparisons. a value of p < .05 was considered to be significant. results the average operating time was 25.0 minutes, and there was no significant blood loss during any operations. no postoperative complications were observed after 1 year of follow-up; complications were defined as wound infection, dehiscence, hydrocele, testicular atrophy, or recurrence. each incision was hidden well within the umbilicus. after the wound healed, the cosmetic result was excellent. all procedures were completed successfully using either the modified single incision with two trocars or the three-port technique. there were no significant differences between the two groups in terms of patients’ age, operative time, blood loss, analgesic requirement, hospital stay, or complications (table). discussion about 30% of patients with a varicocele are subfertile.(5) however, repair of adult varicocele in infertile men does not always result in fertility. many urologists therefore advocate performing varicocelectomy in children.(6) in our hospital, significant varicocele is routinely treated to preserve future fertility. several types of procedures are currently used to treat varicocele, including interventional radiologic vein embolization, inguinal microscopic testicular artery-sparing varicocelectomy, spermaticoepigastric venous anastomosis, and palomo varicocele ligation.(3,7-12) evolving laparoscopic techniques are mostly based on the palomo procedure. several reports have described laparoscopic extraperitoneal treatment for varicocele.(1,13,14) the principal disadvantages with this method are insufficiency of retroperitoneal space and difficulty in orientation, which are more significant in children. the transperitoneal approach was chosen, as we previously noted the ease of access and minimal invasiveness with this technique. a single incision with two trocars was used 2 years previously by the authors of this study. many surgeons have reported the use of a single port while performing laparoscopic varicocelectomy. in this process, a specially manufactured port with three inserts was necessary. (15-17) although the device was innovative, it is not suitable for use in children. the high cost of instruments for laparoendoscopic single-site surgery has also hindered update of traditional endoscopic ports in pediatric specialty hospitals in china. two 5 mm trocars could be inserted into the peritoneum through a single small infraumbilical incision with minimal or no gas leakage. pneumoperitoneum was induced with carbon dioxide to a pressure of 13 mmhg. both the laparoscope and working instruments used in the operation were straight. the spermatic vessels could be identified at the internal ring of the inguinal canal where the vas deferens joins the spermatic cord. the spermatic vessels were divided as high as possible. when feasible, vessels were coagulated with a harmonic scalpel without using hemoclips. although some spermatic veins have been reported to merge, this antable. clinical data analysis of varicocele with different laparoscopic treatments.* variables single incision with two trocars (12 patients, n = 14) traditional three ports (32 patients, n = 33) p value age (years) 13.6 ± 2.6 15.3 ± 3.7 .126 operative time (minutes) 25.0 ± 5.7 28.9 ± 10.2 .187 blood loss (ml) 0 0 > .05 analgesic requirement 0 1 .82 hospital stay (days) 2.1 ± 0.6 3.1 ± 1.2 .26 complications 0 1 hydrocele .82 * data are presented as mean ± sd. laparoscopic urology 2401 atomical variant was not observed in our study.(18) all vessels were therefore carefully isolated. we have no experience with the artery-sparing technique, but most surgeons believe that there is a higher risk of varicocele recurrence with techniques that preserve lymphatic or arterial supply.(19,20) therefore, surgeons who perform lymphatic or arterial preservation need to employ strategies to ensure venous collaterals are ligated.(21) the high division of both the testicular artery and vein resulted in a satisfactory outcome with no incidence of testicular atrophy in any of the patients we treated. with conventional laparoscopic equipment, the bilateral spermatic vessels can be inspected simultaneously. in our study, two patients underwent bilateral varicocelectomy. based on our experience, the two trocar insertion sites were placed in a line perpendicular to the midline of the body (figure), and the position of the laparoscope was closer to the dilated vessels, making it more convenient to observe and operate. follow-up was performed for an entire year. as shown in the table, there were no significant differences when compared to the three-port technique, including operative time, blood loss, and hospital stay. the cosmetic appearance was not scientifically evaluated. the surgeon’s subjective assessment was that single-port incisions were cosmetically superior. conclusions laparoscopic varicocelectomy through a single incision with two trocars involves only a small modification in technology. the learning curve was very short for a senior laparoscopic urologist, after the main challenge of performing without triangulation was overcome. acknowledgments we are grateful to the national natural science foundation of china and science and technology commission of shanghai municipality for the financial support (grant no. 81270689 & 12zr1419200). conflict of interest none declared. references 1. cobellis g, mastroianni l, cruccetti a, amici g, martino a. retroperitoneoscopic varicocelectomy in children and adolescents. j pediatr surg. 2005;40:846-9. 2. li f1, chiba k, yamaguchi k, et al. effect of varicocelectomy on testicular volume in children and adolescents: a meta-analysis. urology. 2012;79:1340-5. 3. cimador m, pensabene m, sergio m, caruso am, de grazia e. focus on paediatric and adolescent varicocoele: a single institution experience. int j androl. 2012;35:700-5. 4. barone jg, johnson k, sterling m, ankem mk. laparoendoscopic single-site varicocele repair in adolescents-initial experience at a single institution. j endourol. 2011;25:16058. 5. lee hj, cheon sh, ji yh, et al. clinical characteristics and surgical outcomes in adolescents and adults with varicocele. korean j urol. 2011;52:489-93. 6. hidalgo-tamola j, sorensen md, bice jb, lendvay ts. pediatric robot-assisted laparoscopic varicocelectomy. j endourol. 2009;23:1297-300. 7. gazzera c, rampado o, savio l, di bisceglie c, manieri c, gandini g. radiological treatment of male varicocele: technical, clinical, seminal and dosimetric aspects. radiol med. 2006;111:449-58. 8. al-said s, al-naimi a, al-ansari a, et al. varicocelectomy for male infertility: a comparative study of open, laparoscopic and microsurgical approaches. j urol. 2008;180:266-70. 9. camoglio fs, cervellione rm, bruno c, et al. microsurgical spermatico-epigastric venous anastomosis in the treatment of varicocele in children: assessment of long-term patency. eur j pediatr surg. 2003;13:256-9. 10. nees sn, glassberg ki. observations on hydroceles following adolescent varicocelectomy. j urol. 2011;186:2402-7. 11. lisle r, mahomed a. lymphatic sparing laparoscopic palomo varicoelectomy. j pediatr surg. 2010;45:285. 12. gulino g, d'onofrio a, palermo g, et al. is microsurgical technique really necessary in figure. a schematic figure from the sites of trocar insertion. laparoscopic varicocelectomy with single incision-chen et al. vol 12 no 06 november-december 2015 2402 inguinal or sub-inguinal surgical treatment of varicocele? arch ital urol androl. 2011;83:6974. 13. demirci d, gülmez i, hakan na, ekmekçioğlu o, karacagil m. comparison of extraperitoneoscopic and transperitoneoscopic techniques for the treatment of bilateral varicocele. j endourol. 2003;17:89-92. 14. agarwal bb, manish k. endoscopic varicocelectomy by extraperitoneal route: a novel technique. int j surg. 2009;7:377-81. 15. hao w, chan ih, liu x, tang pm, tam pk, wong kk. early post-operative interleukin-6 and tumor necrosis factor-α levels after singleport laparoscopic varicocelectomy in children. pediatr surg int. 2012;28:281-6. 16. kaouk jh, palmer js. single-port laparoscopic surgery: initial experience in children for varicocelectomy. bju int. 2008;102:97-9. 17. kawauchi a, kamoi k, soh j, naitoh y, okihara k, miki t. laparoendoscopic singlesite urological surgery: initial experience in japan. int j urol. 2010;17:289-92. 18. nagappan p, keene d, ferrara f, et al. antegrade venography identifies parallel venous duplications in the majority of adolescents with varicocele. j urol. 2015; 193:286-90. 19. kass ej, marcol b. results of varicocele surgery in adolescents: a comparison of techniques. j urol. 1992;148:694-6. 20. link ba, kruska jd, wong c, kropp bp. two trocar laparoscopic varicocelectomy: approach and outcomes. jsls. 2006;10:1514. 21. keene dj and cervellione rm. intravenous methylene blue venography during laparoscopic paediatric varicocelectomy. j pediatr surg. 2014;49:308-11. laparoscopic varicocelectomy with single incision-chen et al. laparoscopic urology 2403 endourology and stone disease efficacy of silodosin dose in medical expulsive therapy for distal ureteral stones: a retrospective study cem nedim yuceturk,1 mumtaz dadali,*2 muhammed sahin bagbanci2 , berat cem ozgur1 , yasin aydogmus3, yildiray yildiz1 , muhammet fatih kilinc1 purpose: we aimed to investigate the efficacy of silodosin 4 mg/day and 8 mg/day for medical expulsive therapy (met) of lower ureteral stones. materials and methods: we retrospectively analyzed the medical records of 161 patients admitted to urology clinics of ahi evran university medical faculty and ankara training and research hospital with distal ureteral stones and treated with met with different doses of silodosin between january 2013 and august 2015. 81 patients were treated with silodosin 4mg/day in group-1 and 80 patients with silodosin 8mg/day in group-2. age, gender, complaints on admission, stone size, the distance between the stone and ureterovesical junction, stone passage rate, duration of stone passage after starting met, and adverse effects were noted from the charts of the patients, and the groups were compared. results: there were 81 patients in group-1, and 80 patients in group-2. two groups were similar for age (p = .38) and gender (p = .92). spontaneous stone passage was seen in 41 (50.9%) patients in group-1, and in 59 (73.8%) patients in group 2. the groups were different for spontaneous stone passage rate (p = .002). in group-1, 10 (25%) patients that could not pass their stones spontaneously and were treated with extracorporeal shockwave lithotripsy (swl), and 30 (75%) of them were treated with ureterolithotripsy. eight (38%) patients that could not undergo ureterolithotripsy and/or anesthesia and were not able to pass their stones were treated with swl, and 13 (62%) patients were treated with ureterolithotripsy in group-2. all of the patients were stone free at the end of the treatment. conclusion: a dose of 8 mg/day should be preferred if silodosin is to be preferred for met in lower ureteral stones. key words: adrenergic α-blockers; lower ureteral stones; medical expulsion therapy; nephrolithiasis; silodosin; urolithiasis introduction urolithiasis is one of the most frequent diseases of the urinary tract. it has a multifactorial etiology and affects approximately 12% of the population. currently, minimally invasive techniques are used for surgical treatment of urinary stones in every level of the urinary system. technological advances provided progress in the surgical treatment of urinary stones, however, the same developments could not be achieved when medical treatment options are considered.(1,2) demonstration of alphaadrenergic receptors in distal one-thirds of the ureter, and evidence regarding the effects of those receptors on smooth muscle contraction showed that they played an important role in the ureter physiology.(3) understanding those physiologic factors enabled the use of alpha receptor blockers for medical treatment of distal ureteral stones. eau guidelines recommended use of alpha receptor blockers for medical expulsive therapy (met) of distal ureteral stones.(4) alpha blockers such as tamsulosin and doxazosin have been used in several studies for met in distal ureteral stones.(5) silodosin is a new molecule used for the treatment of benign prostate hyperplasia, and it has been used for met.(6,7) there is no consensus on the dose or duration of treatment for those agents. in our study, we compared the effectiveness of 4 mg/day and 8 mg/day silodosin used for met. materials and methods study population after obtaining ethical permission in local ethical committee of ankara training and research hospital we retrospectively analyzed the medical records of 161 patients admitted to urology clinics of ahi evran university medicine faculty and ankara training and research hospital with distal ureteral stones and treated with medical expulsive therapy (met) with different doses of silodosin between january 2013 and august 2015. 1department of urology, ankara training and research hospital, altındağ, ankara, 06000turkey. 2department of urology, medical faculty, ahi evran university, kırşehir 04000 turkey. 3department of urology, etimesgut military hospital, ankara 06000 turkey. *correspondence: department of urology, medical faculty, ahi evran university, kırsehir, turkey. phone: +90 505 3344603. fax: +90 386 280 39 17. e-mail: mumtazdadali@gmail.com. mumtazdadali@ahievran.edu.tr. received august 2016 & accepted december 2016 vol 14 no 01 january-february 2017 2944 medical expulsive therapy for ureteral stonesyücetürk et al. procedure from the patients’ records ,we extracted 161 patients who had undergone met, 81 patients were treated with silodosin 4mg/day in group-1 and 80 patients with silodosin 8mg/day in group-2. all patients had received silodosin therapy for four weeks. evaluation in our study, lower ureter was considered as the part of the ureter between the ureterovesical (uv) junction and the place where ureter crossed iliac vessels. the patients that had a solitary stone in this part of the ureter, and treated with 4 mg/day or 8 mg/day oral silodosin for met were included in the study. the exclusion criteria were the presence of a stone or another disorder in other parts of the ureter, bilateral lower ureteral stones, need for an early surgical intervention, high fever, and septic findings. the patients that stopped met by their own wills (may be due to the side effects like hypotension and retrograde ejaculation) and who preferred other treatment methods were not also included in the study. in two medical center, all medical records were selected randomly. we were not able to find detailed information in some medical records. so we did not take them into consideration and they were not included in our study. the records that we selected were the best kept ones. urinalysis, blood urea and creatinine levels, and complete blood counts of all patients were obtained on admission, and during treatment. kidney-ureter and bladder (kub) x-ray and spiral computerized tomography (ct) without contrast were used as imaging modalities on admission. the patients that had met were called for weekly follow-ups, and kub x-ray and/or urinary ultrasonography (usg) was used to determine the degree of hydronephrosis. urinalysis was used to determine hematuria and urinary infection. the stone size was considered as the longest diameter of the stone. the size of the stone, the distance of the stone to the uv junction, presence of hydronephrosis, and any other additional disorders were analyzed on ct. age, gender, complaints on admission, stone size, the distance between the stone and uv junction, duration of stone passage after starting met, stone passage rate, and adverse effects were noted from the charts of the patients, and the groups were compared. the additional therapies used in patients with unsuccessful met were evaluated. the patients in group-1 were administered 4 mg/day silodosin, and the ones in group-2 were administered 8 mg/day silodosin. all patients were recommended oral hydration. analgesics were given to be used when needed. antibiotics were added to the treatment in case of urinary infection. any patients who were not stone free after 4 weeks of follow-up with met were treated with swl or ureteroscopy. success was considered as the passage of stone during met, and the duration of treatment was noted. statistical analysis spss 21.0 package program was used for data analysis. normality of distribution was analyzed with kolmogorov-smirnov and shapiro-wilk tests. skewness and kurtosis values were also measured. “independent samples t-test” was used for pairwise comparisons with a normal distribution, and “mann-whitney u” test without normal distribution. “pearson’s chi-square” test was used to compare the categorical variables. p < .05 was considered as statistically significant. results patients and stone characteristics in groups were summarized in table 1. the groups did not show significant differences for age (p =.38) or gender (p =.92). endourology and stone diseases 2945 variables group-1 group-2 p value (n= 81) (n= 80) age,years mean ± sd (range) 37.9 ± 14.6 ( 17-71) 36.1 ± 13.2 (17-72) .38 gender, no(%) male 39 41 .92 female 42 39 stone size ,mm mean ± sd (range) 5.0 ± 2.1 (2-10) 5.1 ± 1.8 (2-9) .90 stone size < 5 mm 45 48 .56 (< or > 5 mm) 5-9 mm 36 32 table1. patient and stone characteristics group-1 group-2 p successful n(%) 41 (50.9 %) 59 (73.8 %) .002 unsuccessful n(%) 40 (59.1 %) 21 (26.2 %) the time of spontaneous stone passage , day mean± sd (range) 16.49 ± 6.67 (6 – 28) 16.02 ± 6.73 (5 – 28) .73 the number of analgesic usage mean ± sd (range) 2.26 ± 1.11 (0-5) 2.01 ± 1.00 (0-4) .14 table 2. outcomes of medical expulsive therapy with different doses of silodosin in groups (table 1) patient and stone characteristics and outcomes of medical expulsive therapy with different doses of silodosin in groups were summarized in tables 1 and 2, respectively. the duration for stone passage ranged between 6 and 28 days (16.49 ± 6.67 days) in group-1 while this duration was between 5 and 28 days (16.02 ± 6.73 days) in group-2. there was no statistically significant difference between the groups for the duration of stone passage (p = .73). (table 2) the need for analgesics during treatment was between 0 and 5 times (2.26 ± 1.11 times) in group-1, and between 0 and 4 times (2.01 ± 1.00 times) in group-2. the groups were similar for the need for analgesics (p =.14). the mean stone size was 4.05 ± 1.80 mm in the ones that passed their stones spontaneously, and 6.10±1.95 mm in the ones that could not pass their stones spontaneously in group-1, (95% ci: -2.97 to -1.32, or= -2.14, p < .001). those values were 4.61 ± 1.52 mm and 6.43 ± 1.63 mm, respectively, in group-2, (95%ci: -2.62 to -1.04, or= -1.83), p < .001). there was a statistically very significant association between stone size and ability to pass the stone spontaneously in both groups. the distance between the stone and uv junction was between 0 and 34 mm (16.73 ± 7.49 mm) in patients that passed their stones spontaneously, and between 8 and 32 mm (19.18 ± 7.39 mm) in patients that could not pass their stones spontaneously in group-1 (p =.33). those distances were between 0 and 32 mm (17.49 ± 8.25 mm), and between 8 and 32 mm (19.33 ± 6.65 mm), respectively in group-2 (p =.16). there was no significant association between the distance of the stone to uv junction and spontaneous passage of the stone in neither groups. retrograde ejaculation occurred in 4 (5%) and 7 (9%) patients in groups-1 and 2, respectively. hypotension did not occur in any of the patients in group-1, however, hypotension was seen in 3 (4%) patients in group-2. in group-1, 10 (25%) patients that could not pass their stones were treated with swl, and 30 (75%) patients were treated with ureterolithotripsy. six patients that were first treated with swl had ureterolithotripsy later. the stones were cleared in all patients. eight (38%) patients that could not pass their stones were treated with swl, and 13 (62%) patients were treated with ureterolithotripsy in group-2. five patients that were first treated with swl had ureterolithotripsy later. all of the patients were stone free at the end of the treatment. in our study groups, we did not encounter any complications higher than grade ii according to the clavien classification. discussion in our study, we retrospectively analysed patients with distal ureteral stones who were treated by different doses of silodosin in two medical centers. our aim was to find out an answer to the efficacy of silodosin dose in met. in our study, the groups did not show significant differences for age (p = .38), gender (p = .92) or stone size (p = .90). the main result of our study was in the stone expulsion rate. a significant statistical difference was noted between the two groups (50.9% vs 73.8%)( p = .002) the other significant statistical difference was obtained from the stone size in both groups. in each group, spontaneous stone passage was higher in stones with < 5 mm.(group 1, p < .001)(group 2, p < .001). although in stones with < 5 mm, watchful waiting is a therapeutic option, α 1 blockers in met reduce analgesic usage by decreasing the frequency of contractions in the ureter that means reducing the episodes of ureteral colic.(8) in our study, two different silodosin doses was efficacious for reducing pain and decreasing the amount of analgesic administered. the groups were similar for the need for analgesics (p = .14). in addition, expulsion time was similar in both groups and showed no statistically significant difference (p = .73). edema and the shape of the stones are the main factors influencing expulsion time and stone expulsion rate even in stones with <5 mm in diameter.(9) to overcome this problem, an alternative but an effective therapeutic approach; ureteroscopy can be safely performed. (10) in our study, in some of the patients with no stone passage after met, we treated them by ureteroscopy. in the ureteroscopic interventions, we saw that there was a severe inflammatory reaction of stone impacted mucosa with edematous changes. therefore, patients who were not stone free after 4-week follow-up by medical therapy, stones were most likely impacted and needed a different alternative approach. different treatment options such as ureterolithotomy, ureterolithotripsy, and swl have been employed in the treatment of lower ureteral stones. a wait-and-see approach may be used as an option in patients that do not prefer surgery as the first treatment option. in the literature, spontaneous passage of lower ureteral stones was reported as 68%, and this rate was reported as 2553% in the stones sized between 5 and 10 mm .(11,12) the possibility of spontaneous passage is lower in ureteral stones bigger than 10 mm since they are impacted to the ureter, therefore surgery should be preferred as the first treatment option in those cases.(13) adding α-adrenergic receptor blockers to treatment increases stone passage rate in patients who are followed up for spontaneous stone passage. placebo-controlled studies have been performed to investigate use of α-blockers for met in the case of ureteral stones .(6) although the presence of α -1 adrenergic receptors have been shown in the proximal and medial parts of the ureter, distal ureter has the highest concentration for α-1 adrenergic receptors.(14) the α-1d, -α-1a and α-1b subtypes of α-1 adrenergic receptors are found in the distal ureter, in rank order.(15) this is why met is most efficient in the case of distal ureteral stones. in literature, 0.4 mg tamsulosin and 8 mg silodosin have been used for met in case of distal ureteral stones. the studies that compared tamsulosin with a control group reported the success rate as 79-90% in tamsulosin group, and as 53-58% in the control group .(16-19) the studies that compared silodosin and tamsulosin reported better success rates with silodosin in distal ureteral stones .(20-21) silodosin 8 mg/day was compared with the control group, and a significantly higher success rate was reported with silodosin.(22) in the same study, it was reported that use of tamsulosin for the expulsion of stones sized ≥ 5 mm resulted in a better success rate when compared to the control group (75.9% vs. 17.9%). however, the expulsion rate was higher in the control group when compared to tamsulosin group in medical expulsive therapy for ureteral stonesyücetürk et al. vol 14 no 01 january-february 2017 2946 case of the stones sized < 5 mm (92.9% vs. 69.2%).a multicenter, randomised, placebo-controlled trial by pickard et al. demonstrated that tamsulosin and nifedipine were not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients and found no difference in spontaneous passage during 4 weeks treatment between groups.(23) however many prospective randomized studies should be done not only with these drugs but with the other α-blockers in order to support this comment. in our study, we compared 4 mg/day and 8 mg/day silodosin for met. we determined a significantly higher success rate in 8 mg/ day silodosin group. the success rate with 4 mg/day silodosin was found as 50.9% in our study. the success rates of the control groups in the studies that compared α-blockers for met with the control groups are similar to the success rate we obtained with 4 mg/day silodosin in our study.(17,18,21) in these studies, patients’ included criteria and demographics of those control groups may be different than the patients in our silodosin 4 mg group that’s why stone expulsion rate may be similar. in the literature, it was reported that the stone passage rate was shorter in patients that were given silodosin for met when compared to the control group in case of lower ureteral stones (9.29 ± 5.91 days vs.13.40 ± 5.90 days).(21) in our study, the duration for stone passage in case of spontaneous stone passage was between 6 and 29 days (mean: 16.49 ± 6.67 days) in group 1, and between 5 and 28 days (mean: 16.02 ± 6.73 days) in group 2. alpha 1d adrenoreceptors are predominate, particularly in the distal ureter. silodosin is 56-fold and 583fold more selective for α-1a when compared to α-1d and α-1b, respectively. the hypotensive effect of alpha receptor blockers decreases as their selectivity increases. however, an increase is seen in the frequency of retrograde ejaculation. a meta-analysis that reported silodosin as more effective than placebo and tamsulosin in the case of distal ureteral stones found only an insignificant increase in abnormal ejaculation.(22) in our study, we found higher rates of hypotension and retrograde ejaculation in the group that used a higher dose of silodosin, although those findings did not reach statistical significance. the adverse effect rate expectedly increases as the dose of alphareceptor blockers increases. in group 1 hypotension did not occur in any of the patients and retrograde ejaculation in 4 patients lower than group 2. from that point of view, silodosin 4 mg may be preferred when patients do not withstand these side effects. in our study, most likely urologists used lower dose of silodosin for met in distal ureteral stones for this reason. however, 8 mg silodosin was much more effective in stone expulsion and although there were side effects, all patients in this group completed the study. the patients should be closely followed up during met for the adverse effects that could develop due to obstruction in the case of distal ureteral stones. in case of severe pain, urinary infection, pyonephrosis, and rupture of the fornix, met should be stopped, and surgery should be planned. in our study group, there were no complications necessitating cessation of met. the patients were treated with other interventions when they could not pass their stones spontaneously. there are some limitations in our study. at first, its design is retrospective.the absence of a control group may seem to be a problem but our aim is to evaluate the efficacy of silodosin in the met for distal ureteral stones and want to examine whether the lower dose of silodosin is effective or not. the data obtained from two urology departments pointed out that lower dose of silodosin had been used by many urologists for distal ureteral stones. starting from this point of view, we designed our study and to our knowledge, it may be probably the first study on different doses of silodosin on distal ureteral stones. we believe that our results could help in guiding the urologists to review their preferences on the dose of silodosin for distal ureteral stones ≤ 10 mm. the stone expulsion percentage between men and women may be the other limitation. however, the objective of the present study was to observe stone expulsion rate. conclusions in our study, we concluded that for treatment of lower ureteral stones sized 2-10 mm, met with silodosin 8 mg is quite an effective method in patients when watchful waiting approach is appropriate. this option may be used safely in patients that may tolerate pain and do not prefer surgery as the first treatment option. due to the low incidence of side effects, low dose of silodosin may be used but when considering expulsion rates, silodosin 8 mg can be the reason for preference among urologists. conflict of interest the authors declare that they have no conflict of interest. references 1. tiselius hg. epidemiology and medical management of stone disease. bju int. 2003; 91:758-67. 2. stamatelou kk, francis me, jones ca, nyberg lm, curhan gc. time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003; 63:1817-23. 3. sigala s, dellabella m, milanese g, et al. evidence for the presence of alpha1 adrenoceptor subtypes in the human ureter. neurourol urodyn. 2005; 24:142-8. 4. türk c, petrik a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016; 69:468-74. 5. zehri aa, ather mh, abbas f, biyabani sr. preliminary study of efficacy of doxazosin as a medical expulsive therapy of distal ureteric stones in a randomized clinical trial. urology. 2010; 75:1285-8. 6. kumar s, jayant k, agrawal mm, singh sk, agrawal s, parmar km. role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: a randomized trial (a pilot study). urology. 2015; 85:59-63. 7. sur rl, shore n, l’esperance j, et al. silodosin to facilitate passage of ureteral stones: a multi-institutional, randomized, endourology and stone diseases 2947 medical expulsive therapy for ureteral stonesyücetürk et al. double-blinded, placebo-controlled trial. eur urol. 2015; 67:959-64. 8. wang cj, tsai pc, chang ch. efficacy of silodosin in expulsive therapy for distal ureteral stones: a randomized doubleblinded controlled trial. urol j. 2016; 13:2666-71. 9. porpiglia f, destefanis p, fiori c, fontana d.effectiveness of nifedipine and deflazacort in the management of distal ureter stones. urology. 2000; 56:579-82. 10. kiraç m, atkin ms, biri h, deniz n. ureteroscopy: the first-line treatment for distally located ureteral stones smaller than 10 mm .urol j. 2014; 10:1028-34. 11. giannarini g, autorino r. recommending medical expulsive therapy for distal ureteric calculi: a step back? eur urol. 2009; 56:413-5. 12. pedro rn, hinck b, hendlin k, feia k, canales bk, monga m. alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study. j urol. 2008; 179:2244-7. 13. shokeir aa.renal colic: pathophysiology, diagnosis and treatment. eur urol. 2001; 39:241-9. 14. malin jm jr., deane rf, boyarsky s. characterisation of adrenergic receptors in human ureter. br j urol. 1970; 42:171-4. 15. itoh y, kojima y, yasui t, tozawa k, sasaki s, kohri k. examination of alpha 1 adrenoceptor subtypes in the human ureter. int j urol. 2007; 14:749-53. 16. gupta s, lodh b, singh ak, somarendra k, meitei ks, singh sr. comparing the efficacy of tamsulosin and silodosin in the medical expulsion therapy for ureteral calculi. j clin diagn res. 2013; 7:1672-4. 17. parsons jk, hergan la, sakamoto k, lakin c. efficacy of alpha-blockers for the treatment of ureteral stones. j uro.l 2007; 177:983-7. 18. wang cj, huang sw, chang ch. efficacy of an alpha1 blocker in expulsive therapy of lower ureteral stones. j endourol. 2008; 22:41-6. 19. yilmaz e, batislam e, basar mm, tuğlu d, ferhat m, basar h. the comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. j urol. 2005; 173:2010-12. 20. dell'atti l. silodosin versus tamsulosin as medical expulsive therapy for distal ureteral stones: a prospective randomized study. urologia. 2015; 82:54-7. 21. itoh y, okada a, yasui t, et al. administration of the selective alpha 1a-adrenoceptor antagonist silodosin facilitates expulsion of size 5-10 mm distal ureteral stones, as compared to control. int urol nephrol. 2013; 45:675-8. medical expulsive therapy for ureteral stonesyücetürk et al. 22. huang w, xue p, zong h, zhang y. efficacy and safety of silodosin in the medical expulsion therapy for distal ureteral calculi: a systematic review and meta-analysis. br j clin pharmacol. 2016; 81:13-22. 23. pickard r, starr k, maclennan g, et al. medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. lancet. 2015; 386:341-9. vol 14 no 01 january-february 2017 2948 mesalazine: a novel etiology for drug-induced urinary calculi introduction mesalazine or 5-aminosalicylic acid (5-asa) is an anti-inflammatory agent used in inflammatory bowel dis-ease management such as: ulcerative colitis, crohn's disease, proctosigmoiditis, and ulcerative proctitis(1,2). the marketing authorization in france has been issued in 1987 for the rectal route and in 1990 for the oral route(1). due to 5-asa’s short half-life (1 hour), very few side effects have been reported(1-3). 5-asa is metabolized into n-acetyl-5-aminosalicylic acid in the liver and the intestine(1,3). approximately 60% of the mesalazine is absorbed after oral ingestion, leaving the remainder available for topical action and excretion in the feces(1,3). the absorbed n-acetyl-5-asa is eliminated by the kidney(1,3). urinary side effects are rare (< 1:10000) and include renal insufficiency, acute or chronic interstitial nephritis, nephrotic syndrome and urine discoloration(1,4,5). we report, thereafter, the case of a 23-year-old woman treated by mesalazine for ulcerative colitis who developed recurrent renal colic due to the formation of mesalazine stones in the urine. this side effect is not listed in the drug’s characteristics(1,4). only one previous case has been described in 2013(6). case report a 23-year-old woman diagnosed for an ulcerative colitis 4 years ago was treated daily by prednisone 10 mg, oral mesalazine 4 g, rectal mesalazine 500 mg, potassium chloride and calcium carbonate. she had no history of other diseases and especially no urolithiasis. after two years of mesalazine treatment, she presented with an acute coldepartment of urology, angers university hospital, angers, france. *correspondence: department of urology, angers university hospital 4, rue larrey 49933 angers cedex 09, france. tel: 02 41 35 53 16. fax: 02 41 35 53 23. e-mail: thibautculty@yahoo.com. received march 2017 & accepted july 2017 blaise corbery, souhil lebdai, shahed borojeni, pierre bigot, abdel-rahmène azzouzi, thibaut culty* we report the case of a 23-year-old woman treated by mesalazine for ulcerative colitis and who subsequently presented recurrent renal colic due to mesalazine urinary stones. this is the second case described in the literature. mesalazine stones are soft, friable and have an orange-beige color. they are not visible on non-contrast computed tomography (ct). their diagnosis is based on morpho-constitutional analysis and ct-urography. patients treated by mesalazine who present renal colic should undergo ct-urography in order to make the diagnosis. case report keywords: urolithiasis; mesalazine; renal colic; etiology; drugs. figure 1. macroscopic appearance of mesalazine stone. case report 54 vol 15 no 03 may-june 2018 55 icky pain of the left flank radiating to the groin without any antalgic position. the patient was nauseous and remained afebrile. the pain regressed with non-steroidal anti-inflammatory (nsaid) and antispasmodic treatments. non-contrast enhanced computed tomography (ncct) was normal (no dilatation of the renal tract and no visible stone). one year later, she presented a recurrence of the left renal colic. another ncct was performed and did not show any dilatation of the renal tract and no visible stone. the blood exams were normal except a mild thrombocytosis and a mild crp increase (47 mg/l), relating to her inflammatory bowel disease. the creatinine level was 84µmol/l (ckd-epi clearance = 84 ml/min/1.73 m2). eventually, she spontaneously expulsed a stone in her urine. the stone was soft, crumbly and orange-beige color (figure 1). morphological analysis and infrared spectrophotometry were performed by biomnis laboratory (lyon, france). the infrared spectrum revealed a 100% mesalazine composition. hyperhydration was recommended to the patient. mesalazine treatment was continued. eleven month later, there was no recurrence. discussion the incidence of urolithiasis is increasing in industrialized countries. its prevalence in france is estimated at 10% (7). drug-induced stones represent more than 1% of renal stones in france(8) but their frequency is probably underestimated in other papers(9). two mechanisms can explain their constitution(8,9). the first is the metabolic disorders induced by the drug, which can lead to a urinary environment more favorable for lithiasis formation. the second is the crystallization of the metabolites of the drug in the urine. the inducers of urolithiasis by crystallization are sulfasalazine(10), triamterene, sulphonamides, ciprofloxacin, but the most often involved drug is indinavir, an anti-protease used in anti-hiv triple therapy(11). the first case of mesalazine urinary stone was reported in 2013(6). the patient was a 32-year-old woman diagnosed with ulcerative colitis. several weeks after the initiation of the mesalazine treatment, she presented with recurrent renal colic. no stone and no dilatation of the renal cavities were visible on the ncct. the analysis of the stone revealed mesalazine lithiasis. urinary symptoms disappeared after mesalazine discontinuation. mesalazine stones are radiotransparent on both radiography and ct. their soft consistency may explain the absence of complete obstruction of the urinary tract and therefore the absence of dilation of the renal cavities on the ct. a ct-urography might be the most appropriate imaging to confront the lack of opacification. indeed, other examinations are possible like intravenous pyelography, retrograde ureteropyelography, or even the ureteroscopy, however, they are likely to delay the diagnosis and, for the last two, have surgical and anesthetic risks. rare cases of acute and chronic interstitial nephritis caused by mesalazine have been reported(4). it could be an extra-intestinal manifestation of the inflammatory bowel disease(12). a drug may cause kidney failure by different mechanisms but their responsibility is difficult to prove(13). the pathophysiology of these interstitial nephritides is unknown. this observation suggests that precipitation of mesalazine in renal tubules may play a role in their occurrence. conclusions mesalazine can precipitate in urine and induce repeated renal colic. mesalazine stones are not visible on ncct and may not cause any renal dilatation. patients treated by mesalazine should undergo ct-urography in case of renal colic. subsequently, infrared spectrophotometry will confirm the nature of stone. references 1. [no authorlisted]. vidal 2017: the dictionary. 93th ed. issy-les-moulineaux: vidal france; 2017:2114-7. 2. watanabe m, nishino h, sameshima y, ota a, nakamura s, hibi t. randomised clinical trial: evaluation of the efficacy of mesalazine (mesalamine) suppositories in patients with ulcerative colitis and active rectal inflammation -a placebo-controlled study. aliment pharmacol ther. 2013;38:264-73. 3. klotz u, maier ke. pharmacology and pharmacokinetics of 5-aminosalicylic acid. dig dis sci. 1987;32:46s-50s. 4. gisbert jp, gonzalez-lama y, mate j. 5-aminosalicylates and renal function in inflammatory bowel disease: a systematic review. inflamm bowel dis. 2007;13:629-38. 5. sacks a, davis mk. a curious case of redbrown urine in a child taking mesalamine. j pediatr gastroenterol nutr. 2013;56:e38-9. 6. jacobsson h, eriksen j, karlen p. mesalazineinduced renal calculi. am j case rep. 2013;14:551-3. 7. daudon m, traxer o, lechevallier e, saussine c. [epidemiology of urolithiasis]. prog urol. 2008;18:802-14. 8. hess b. drug-induced urolithiasis. curr opin urol. 1998;8:331-4. 9. daudon m. [drug-induced urinary calculi in 1999]. prog urol. 1999;9:1023-33. 10. de koninck as, groen la, maes h, verstraete ag, stove v, delanghe jr. an unusual type of kidney stone. clin lab. 2016;62:235-9. 11. schwartz bf, schenkman n, armenakas na, stoller ml. imaging characteristics of indinavir calculi. j urol. 1999;161:1085-7. 12. vasanth p, parmley m, torrealba j, hamdi t. interstitial nephritis in a patient with inflammatory bowel disease. case rep nephrol. 2016;2016:4260365. 13. mehta rl, awdishu l, davenport a, et al. phenotype standardization for drug-induced kidney disease. kidney int. 2015;88:226-34. mesalazine induced urolithiasiscorbery et al. urology journal unrc/iua vol. 1, no. 3, 188-190 summer 2004 printed in iran 188 one-year efficacy of expanded polytetrafluoroethylene vascular graft in eighty-three hemodialysis patients afshar r1, salimi j2, sanavi sr3, modaghegh mh2, niazi f, fallah n4 1department of nephrology, shahed university, tehran, iran 2department of surgery, tehran university of medical sciences, tehran, iran 3department of nephrology, shaheed hasheminejad hospital, iran university of medical sciences, tehran, iran 4department of biostatistics, shahed university, tehran, iran abstract purpose: to evaluate the patency and efficacy of expanded polytetrafluoroethylene (eptfe) vascular graft in hemodialysis patients. materials and methods: in a prospective study from january 1999 to january 2001 at sina hospital 41 patients underwent implantation of 6-mm vascular grafts and 42 underwent implantation of 8-mm grafts in order to make vascular assess for hemodialysis. they were followed up to 12 months, observing the complications. results: mean patients' age was 52.2 years. thirty-seven of them were females and 46 were males. over a 12 months period of follow-up, 12 cases of graft infection (14.5%), 21 cases of thrombosis (25.3%), 7 cases with both complications (8.4%), and 1 case of pseudoaneurism (1.2%) were observed. one-year patency rate was 34.9%. diabetes was the only factor associated with lower patency rate (27% versus 57%, p<0.05). conclusion: eptfe vascular graft seems to be an appropriate substitute for arteriovenous fistula as a vascular assess in hemodialysis patients. educating patients and good care can decrease the rate of infection, thrombosis, and other complications, resulting in a better patency and lower morbidity rate. key words: eptfe, hemodialysis, patency rate introduction developed in the mid 40's, hemodialysis rescued patients with end stage renal disease, but it accompanied with the challenging problem of finding a method to provide vascular assess. quinton and colleagues developed extracorporeal shunts in 1960.(1) using arteriovenous fistula (avf) was first introduced by brescia et al in 1966.(2) in spite of many remarkable advantages of av fistula, atherosclerosis can make avf useless in many patients. thus, investigators have tried innovative approaches in order to connect arteries and veins, which are distal to each other, and have offered the usage of bovine carotid artery,(3) dacron grafts,(4) saphenous vein, and umbilical vein.(5) synthetic prostheses made of polytetrafluroethylene (eptfe) were first introduced in 1970.(6) nowadays, they are the most common exogenous prostheses used for providing vascular access. they are also increasingly implementing in our country. however, evaluating the patency rate and the causal factors of graft failure can help selecting patients and promoting methods of graft care. this study aimed to evaluate demographic factors associating with patency rate of graft and to define the incidence of complications and risk factors in two types of grafts with different sizes. materials and methods as a prospective study, hemodialysis patients accepted for publication in august 2003 one-year efficacy of expanded polytetrafluoroethylene vascular graft in eighty-three hemodialysis patients 189 with non-functioning avf, in whom providing a new fistula was not feasible, were selected. eighty-three patients were referred to the vascular surgery department of sina hospital to implant vascular graft between january 1999 and january 2001. vascular graft of eptfe (goretex®) was used for 83 patients who were randomly assigned into two groups in order to receive either 6-mm or 8-mm grafts in the upper arm. preceding hospitalization, demographic factors including age, gender, times of dialysis per week, and history of diabetes and hypertension were taken using a questionnaire. patients with primarily non-functioning grafts or who underwent transplantation during the period of the study were excluded. the remained patients, in whom a thrill was palpable in the graft location and a proper function was achieved, completed the study. they were followed up by the questionnaires sent to the respective dialysis wards or by regular visits; cases of non-functioning grafts and complications such as thrombosis, infection, and pseudoaneurism were recorded. as none of the recanalization methods were used after the first surgery, all the records were indicative of primary patency rate. follow-up period was 12 months for all the patients and the cumulative time of the study was 24 months. statistical analysis was done by kaplan-meier and log rank tests using spss software. results a total of 83 patients were evaluated, whose mean age was 52.2 (range 12 to 91) years. thirtyseven of them (44.6%) were female and 46 were male (55.4%). six-mm grafts were used in 41(49.4%) and 8-mm grafts in 42(50.6%). hemodialysis had been carrying out three times a week in 53 patients (63.9%), twice a week in 25 (30%), and once a week in 5 (6%). hypertension, diabetes, or both were the present risk factors for atherosclerosis in 25 (30%), 11 (13%), and 20 (24.1%) of the patients, respectively. during a 12-month follow-up, 12 (14.5%) cases of graft infection, 21(25.3%) cases of thrombosis, 7 (8.4%) cases with both thrombosis and infection, and 1 (1.2%) case of pseudoaneurism were observed. according to kaplan-meier analysis, patency rate after 0, 1, 3, 6, 9 and 12 months were 85.5%, 78.5%, 65%, 49%, 40%, and 34.9%, respectively (fig. 1). using log rank test, the impact of age, gender, hypertension, diabetes, graft size, and times of dialysis per week on patency rate and on the type and rate of complications were evaluated; none of the above-mentioned factors had a meaningful association with 1-year patency rate or incidence of complications, except for diabetes, in which 1-year patency rate was 56% in non-diabetic and 27% in diabetic patients (p<0.05), corresponding to a lower patency in diabetic ones. discussion due to the progresses in diagnostic and therapeutic methods, the number of hemodialysis patients has increased. most of them are at risk of vascular diseases, because of elderliness, diabetes, hyperlipidemia, hypertension, and early atherosclerosis. subsequently, avf may not work properly in all patients and in case of the disruption of avf, no appropriate vascular access would be available. regarding its special advantages such as low thrombogenicity, ample durability, and the availability of its different diameters, eptfe grafts could be a connector of arteries and veins distal to each other, providing an appropriate vascular access. considering the high costs of vascular grafts and difficulties of vascular surgeries, preserving the implanted grafts is of high essence. one-year efficacy of grafts has been reported as 83% in a study on 46 cases.(7) two other reports have indicated a rate of 36% in 62 and 49% in 83 cases,(8,9) in which only the age of 60 or more was associated with lower patency rate (p<0.05).(9,10,11) however, our study did not support this finding. the average patency rate cited in different studies seems to be roughly 62%.(7,10) accordingly, all the studies have reported a higher patency rate than that in our study. such differences can be fig. 1. graft patency rate in 12 months � �� �� �� �� �� �� �� � � � � � � �� ������ � � �� � � � �� ���� one-year efficacy of expanded polytetrafluoroethylene vascular graft in eighty-three hemodialysis patients 190 due to a series of factors: 1. surgeon's experience, 2. usage of grafts with different diameters at each end, resulting in the ability of connecting various arteries and veins, 3. the staff experience in iv injections and haemostasis after dialysis, and 4. regular graft care services. in contrast to the studies reviewed, recanalization of grafts had not performed in any of our patients.(10-14) it seems that on-time referral had not been done, leading to lose the golden time for treatment. since recanalization is reported in almost 42.5% of obstruction cases in various studies and secondary patency rate could be raised up to 80%, educating the patients to have regular visits is very demanding. the most common complication, leading to graft loss was thrombosis in our study, the same as that in other studies, and stenosis in the venous anastomotic site is the most important cause of thrombosis. according to the suggestion of national kidney foundation, follow-up for graft surveillance technique should contain calculation of recirculation percent, graft blood flow rate, and venous line pressure.(12) considering such items helps early diagnosing of grafts with low blood flow rate, which is indicative of a stenosis. surgical intervention, then, can increase the graft patency. conclusion it is suggested that graft surveillance technique could help finding at risk cases and promoting graft patency as well as educating dialysis ward staff and patients about graft care. furthermore, elimination and control of risk factors such as smoking, diabetes, hypertension, and hyperlipidemia seems to be effective. references 1. quinton we, dillard d, scribner bh. cannulaticn of blood vessels for prolonged hemodialysis. trans am soc artif intern organs 1960; 6: 104-113. 2. brescia mj, cimmino je, apple k, hurwich bj. chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. n engl j med 1966; 6: 10891092. 3. oakes dd, spees ek jr, light ja. a three year experience using modified patients requiring hemodialysis. ann surg 1978; 187: 423-429. 4. burdick jf, scott w, cosimi b. experience with dacron graft arteriovenous fistulas for dialysis access. am surg 1978; 187: 262-266. 5. dardik h, ibrahim im, dardik i. arteriovenous fistula constructed with modified human umbilical cord vein graft. arch surg 1976; 111(1): 60-2. 6. baker ld jr, johnson jm, goldfarb d. expanded ptfe subcutaneous arteriovenous conduit: an improved vascular access for chronic hemodialysis trans. am soc artif intern organs 1976; 22: 382-387. 7. henrich wl. principles and practice of dialysis. lippincott williams & wilkins; 1999. p. 45-47. 8. daguirdas jt, blake pg, ing ts. handbook of dialysis. 3rd ed. lippincott williams & wilkins; 2001. p. 86-90. 9. tellis va, kohlberg wi, bhat dj, driscoll b, veith fj. eptfe fistula for chronic hemodialysis. ann surg 1979; 189(1): 101-5. 10. chen cy, teoh mk. graft rescue for haemodialysis arterio-venous grafts: is it worth doing and which factors predict a good outcome? j r coll surg edinb 1998 aug; 43(4): 248-50. 11. cinat me, hopkins j, wilson se. a prospective evaluation of ptfe graft patency and surveillance technique in hemodialysis access. ann vasc surg 1999 mar; 13(2): 191-8. 12. nkf doqi guideline for vascular access. am j kidney dis 2001; 37(supple 1): 5137. 13. munda r, first r, alexander w, linneman cc. ptfe graft survival in hemodialysis. jama 1983; 249: 219. 14. schwab sy. vascular access for hemodialysis. kidney int 1999; 55: 2078. review role of oxidative stress in male reproductive dysfunctions with reference to phthalate compounds sapna sedha,1 sunill kumar,1 shruti shukla2* purpose: a wide variety of environmental chemicals/xenobiotics including phthalates have been shown to cause oxidative stress targeting the endocrine system and cause reproductive anomalies. the present review describes various issues by oxidative stress causing male reproductive dysfunctions. here in this review, the importance and role of phthalate compounds in male reproductive dysfunction has been well documented. materials and methods: one class of environmental endocrine disruptors is phthalates. phthalate compounds are mostly used as plasticizers, which increase the flexibility, durability, longevity, and etc. of the plastics. large-scale use of plastic products in our daily life as well as thousands of workers engaged in the manufacture of plastic and plastic products and recycling plastic industry are potentially exposed to these chemicals. further, general population as well as vulnerable groups i.e. children and pregnant women are also exposed to these chemicals. phthalates are among wide variety of environmental toxicants capable of compromising male fertility by inducing a state of oxidative stress in the testes. they may also generate reactive oxygen species (ros) that may affect various physiological and reproductive functions. results: the available data points out that phthalate compounds may also induce oxidative stress in the male reproductive organs mainly testis and epididymis. they impair spermatogenic process by inducing oxidative stress and apoptosis in germ cells or target sertoli cells and thereby hamper spermatogenesis. they also impair the leydig cell function by inducing ros, thereby decreasing the levels of steroidogenic enzymes. conclusion: thus in utero and postnatal exposure to phthalate compounds might lead to decreased sperm count and various other reproductive anomalies in the young male. keywords: reproduction; spermatozoa; oxidative stress; prenatal exposure delayed effects; oxidative stress; physiology. 1. overview humans have always been exposed to certain per-sistent chemicals, some pesticides, heavy metals, solvents especially organic solvents, illicit drugs, tobacco smoking, and etc. which are reported to have reproductive toxic potential for both sexes depending upon the dose and duration of the exposure of the toxicants. naturally occurring environmental chemicals (e.g., phytoestrogens and estrogenic mycotoxins) induce infertility in domestic animal species and may alter human reproductive function.(1) exposure to synthetic chemicals such as dichlorodiphenyltrichloroethane (ddt) and its metabolites, alkylphenol ethoxylates, polychlorinated biphenyls (pcbs) and dioxins, produces reproductive problems in a variety of vertebrate species via endocrine mechanisms.(2,3) concern regarding the adverse effects of various environmental contaminants on the male reproductive system has been growing nowadays. a wide variety of environmental chemicals/xenobiotics including phthalates have been shown to cause oxidative stress, which potentially target the endocrine system and cause reproductive anomalies. free radicals such as reactive oxygen species (ros) are generated by exogenous agents (e.g., radiations, chemicals, and hyperoxia) or via endogenous processes such as in normal cellular metabolism. a number of studies indicate that ros are a double-edged sword: they have a role in pathological processes but can also serve as key signal molecules in physiological processes. when ros are present at certain levels, they greatly overwhelm the capacity of endogenous cellular antioxidant defense system, thus cause oxidative stress. the resulting damage to cells and organs may induce and/or accelerate disease processes. oxidative stress has been implicated in cancer, aging, atherosclerosis, ischemic injury, inflammation, and neurodegenerative diseases. (4,5) a major factor in the etiology of male infertility is oxidative stress. ros attack can induce lipid peroxidation and dna fragmentation disrupting both the motility of the cells and their ability to support normal embry1 reproductive and cytotoxicology department, national institute of occupational health (icmr), meghani nagar, ahmedabad-380016, gujarat, india. 2 department of food science and technology, yeungnam university, 280 daehak-ro, gyeongsan-si, gyeongsangbuk-do 712-749, republic of korea. *correspondence: department of food science and technology, yeungnam university, 280 daehak-ro, gyeongsan-si, gyeongsangbuk-do 712-749, republic of korea. tel: +82 53 8103590. fax: +82 53 8104662 . e-mail: shruti.shukla15@yahoo.com received april 2015 & accepted august 2015 review 2304 onic development at spermatozoon level. at the level of the testes, oxidative stress is capable of disrupting the steroidogenic capacity of leydig cells as well as the capacity of the germinal epithelium to differentiate normal spermatozoa. although experimental data in animal models demonstrating a causal relationship between the induction of oxidative stress in the testes and the impairment of male reproductive functions are available, the causative mechanism remains unresolved. there are so many factors (physical, chemical, and pathological) capable of inducing oxidative stress in the testes strongly suggesting that this is a vulnerable tissue which is both highly dependent on oxygen to drive spermatogenesis and yet highly susceptible to the toxic effects of reactive oxygen metabolites.(6) phthalates are one of the classes of environmental endocrine disruptors (eds), which are used as plasticizers for polyvinyl chloride plastics. recently, attention has been paid to these chemicals because the prenatal phthalate exposure to rats can cause testicular dysgenesis like syndrome (tds) in male offspring postnatally.(7,8) the use of plastics has increased several-folds worldwide. phthalate compounds, which are used as plasticizers for the manufacture of plastics, leach in to the surrounding medium. they are ubiquitously distributed in the environment and might have toxic potential to all the living beings. the physicochemical properties that impart usefulness as plasticizers also permit migration and leaching of phthalates from polymer substrates. this potential for leaching from products manufactured from plastics combined with a well-recognized toxicity profile for some phthalate esters has led to concern over potential health impacts particularly from use in consumer products where widespread public exposure to phthalate esters is possible. large-scale use of plastic products in our daily life as well as thousands of workers engaged in the manufacture of plastic and plastic products and recycling plastic industry are potentially exposed to these chemicals. further, general population as well as vulnerable groups i.e., children and pregnant women are also exposed to these chemicals. structurally, phthalate esters are characterized by a diester structure consisting of a benzenedicarboxylic acid head group linked to two ester side chains. the phthalate esters panel high production volume (hpv) testing group (2001) derived three categories of phthalates based on their use, physicochemical and toxicological properties.(9) they are low molecular weight phthalates, transitional phthalates and high molecular weight phthalates. low molecular weight phthalates were defined as those produced from alcohols with straightchain carbon backbones of ≤ c3 [e.g., dimethyl phthalate (dmp), diethyl phthalate (dep), dialkyl phthalate (dap), dimethylethyl phthalate (dmep), and diisobutyl phthalate (dibp)]. whereas high molecular weight phthalates were defined as those produced from alcohols with straight-chain carbon backbones of ≥ c7 or ring structure [e.g., diisononyl phthalate (dinp), dinonyl phthalate (dnp), and diisodocyl phthalate (didp)]. on the other hand, transitional phthalates are defined as those produced from alcohols with straight-chain carbon backbones of c4-6 [e.g., dibutyl phthalate (dbp), benzyl butyl phthalate (bbp) and di (2-ethylhexyl) phthalate (dehp)]. lower molecular weight phthalates are often associated with uses as solvents, whilst the higher molecular weight phthalates are associated with uses as plasticizers. the transitional phthalates are used as both plasticizers and solvents.(10) some of the transitional phthalates such as dibutyl phthalate (dbp), benzyl butyl phthalate (bbp) and di(2-ethylhexyl) phthalate (dehp) are known to interfere with male reproductive development in rats, and due to their reproductive toxicity, they have been banned for use in toys and other consumable products. dibp has similar properties as dbp however less toxic in nature, hence used in place of dbp wherever required.(11) while dinp is replacing dehp nowadays due to its process ability, durability and availability.(12) recently wang and colleagues determined whether phthalate levels in semen were associated with infertility.(13) using semen samples from 107 infertile and 94 fertile men, the presence and quantity of five phthalate esters were measured using high-performance liquid chromatography (hplc).(13) the cumulative levels of the measured phthalate esters were significantly higher in the infertility group as compared to the control group (p < .05). concentrations of the five phthalate esters in men varied by age with older men showing higher cumulative levels. the presence of phthalates may contribute to male infertility.(13) dadkhah and colleagues determined the relation of semen parameters in processed and unprocessed semen samples with pregnancy rate in intrauterine insemination (iui) in the treatment of male factor infertility and found that there was an inverse relationship between pregnancy rate and duration of infertility.(14) iui is a valuable method for the treatment of male factor infertility. the higher number of sperms, total motile sperms and iui sessions, and lower duration of infertility, all have a positive relationship with pregnancy rate.(14) nikoobakht and colleagues evaluated the effect of hypothyroidism on erectile function using international index of erectile function (iief-5) and sperm parameters and observed that hypothyroidism adversely affects erectile function and sperm parameters, including sperm count, morphology, and motility.(15) in patients with sperm abnormalities and erectile dysfunction, measurement of thyroid hormones is recommended.(15) the literature was collected through searching various databases such as pubmed, medline, toxline, google, and certain other web sites and consulting relevant reproductive toxicity journals. this review is divided into different sections such as the route of exposure and metabolism of phthalates, mode of action of phthalates, oxidative stress, genotoxic, and reproductive potential as well as developmental toxicity due to phthalate exposure. 2. route of exposure and metabolism phthalates can easily leach out of products to contaminate the external environment because they are not chemically bound to the plastic matrix or to other chemicals in formulations.(16) as a result of the ubiquitous use of phthalates in personal care and consumer products, human exposure is widespread. exposure through ingestion, inhalation and dermal contact are considered important routes of exposure for the general population. (17,18) ingestion exposure includes household goods (food packaging such as meat, fish, eggs, baby milk and milk products), phthalate-contaminated water, child soft toys (teethers and rattles), and certain medical procedures. oxidative stress in male reproductive dysfunctions-sedha et al. vol 12 no 05 september-october 2015 2305 whilst inhalation exposure may occur via household goods/dust [off-gassing of polyvinyl chloride (pvc) flooring], medical inhalation therapy (tubing inserted into throat for forced-air ventilation), and occupational exposure (heated/melted products that can emit phthalate vapors). on the other hand, dermal exposure may occur via clothing (raincoats and gloves), personal care products (soap, shampoo, nail polish, fragrance bases for perfumery and cosmetic products) including direct injection exposure through the use of medical bags and tubes-products used in hospitals made of pvc. after exposure, they are rapidly metabolized and excreted in the urine and feces. they undergo phase i biotransformation, that is, the diesters are primary metabolized into their hydrolytic monoesters by hydrolysis of one of their ester bonds plus free alcoholic group. then the second ester bond gets further hydrolyzed to phthalic acid. further enzymatic oxidation of the alkyl chain occurring in some of the phthalates, results in more hydrophilic oxidative metabolites. monoesters and the oxidative metabolites of phthalates may continue to undergo phase ii biotransformation to produce glucuronide conjugates with increased water solubility. (19) general metabolic pathway of phthalates is shown in figure 1. although phthalates do not bio-accumulate in the body like dioxins and other chemicals, their ubiquitous presence in the environment and the size of the population exposed suggest that the potential impact of phthalate exposure could be very large.(20) phthalates have also been measured in residential indoor environments in both house dust and indoor air as well as in foods, milk, and drinking water. however, the relative contribution from the various sources and routes of exposure to phthalates is unknown.(21,18) few studies also have investigated the carcinogenic effect of sulfur mustard exposure on the genitourinary system as well as the prevalence of male infertility. recent studies by amirzargar and colleagues on iranian victims 20 years after sulfur mustard (sm) exposure confirmed that infertile sm-exposed men had higher serum levels of fsh than fertile sm victims.(22) moreover, dramatically low serum values of testosterone were not observed more frequently in infertile versus fertile sm-exposed men in the study of amirzargar and colleagues.(22) these findings imply the relative resistance of the leydig cells to sm toxicity along with the seminiferous tubule damage twenty years after sm exposure.(23) hauser and colleagues estimated the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific endocrine-disrupting chemicals (edc) such as phthalate compounds exposures in the european union (eu).(24) in this study, the expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618,000 additional assisted reproductive technology procedures, costing €4.71 billion annually.(24) edcs may contribute substantially to male reproductive disorders and diseases, with nearly €15 billion annual associated costs in the european union (eu). these estimates represent only a few edcs for which there were sufficient epidemiological studies and those with the highest probability of causation. lagos-cabré and moreno, critically discussed the available information regarding the effect of various derivatives of phthalate compounds such as bisphenol a [2,2-bis(4-hydroxyphenyl) propane] (bpa), 4-nonylphenol (np) and di(2-ethylhexyl) phthalate (dehp), and its metabolite mono-2-ethylhexyl phthalate (mehp) upon mammalian spermatogenesis, a major target of endocrine disruptors (eds) and observed that germ cell sloughing, disruption of the blood-testis-barrier and germ cell apoptosis are the most common effects reported in the available literature.(25) the output and quality of sperm are useful tools to measure the effect of exogenous compounds on spermatogenesis.(25) a high correlation has been observed between urine bpa (phthalate compound) levels and semen quality in chinese men (including motility, viability, sperm count and sperm concentration), which also correlated with the educational level and longer employment history; men with better education and a long history of employment had lower levels of bpa since they were not in contact with eds, unlike men who worked in factories.(26) a recent study demonstrated that dehp-contaminated air was associated with an increase in sperm dna fragmentation and a decrease in sperm motility in pvc factory workers.(27) as in the case of dehp exposed workers, air bpa-exposed workers also show reduced sexual desire, accompanied by erectile dysfunction and ejaculation difficulties.(28) although high phthalate exposures have been evaluated among susceptible populations such as women of childbearing age, high-risk occupational groups have not been well studied. potential high-risk occupational groups include workers in pvc plants, massage therapists, and nail and beauty salon employees.(29) occupational health nurses should be aware of these high risk occupational groups and their potential for adverse reproductive effects. occupational health nurses can figure 1. general metabolic pathway for phthalates (adopted from frederiksen et al. 2007). oxidative stress in male reproductive dysfunctions-sedha et al. review 2306 educate high-risk occupational groups to use phthalate-free products, available alternatives found in retail stores. these products are labeled “phthalate-free.” occupational health nurses can advocate for legislation mandating workplace safety inspections among susceptible populations.(30) once the sources, extent, and routes of phthalate exposures are understood, specific environmental controls may be instituted to reduce them. workplace accommodation may play a role in preventing adverse effects among workers at high risk for phthalate exposure.(29) since there is the increasing evidence that exposure to phthalates may affect human health, therefore, the literature on exposure to phthalates, reproductive outcome and children health has been reviewed herein. 3. actions of phthalates on leydig cells there is a building consensus that phthalates are anti-androgenic. however, phthalates and their mono-phthalate metabolites do not bind to the androgen receptor (ar) in vitro at concentrations of up to 10 μm indicating that phthalates are not direct ar antagonists.(31) in fact, phthalate toxicity toward leydig cells depends on the dosage and time of exposure during development. leydig cells are the primary source of testosterone production in males, and differentiation of leydig cells in the testes is one of the primary events in male sex differentiation, puberty, and fertility.(32) one possible mechanism is that phthalate metabolites bind to peroxisome proliferator-activated receptors (ppars). (33) the ppar family contains three subtypes such as peroxisome proliferator-activated receptor α (pparα), pparβ and pparγ.(34) rat fetal leydig cells (flcs) express pparα and pparγ.(35) phthalates have been known to induce the actions of pparα and pparγ.(36-38) however, the action of phthalates on leydig cells cannot be explained entirely by a pparα-mediated pathway, because pparα-knockout mice remain sensitive to phthalate-mediated reproductive toxicity. another signaling pathway in leydig cells that might be affected figure 2. general mechanism by which oxidative stress alters cellular function (adopted from wells et al. 2009). compound name (abbreviation) metabolite name (abbreviation) actions of all listed phthalates di-(2-ethylhexyl) phthalate (dehp) mono-ethyl hexyl phthalate (mehp) agonists of peroxisome dibutyl phthalate (dbp) mono-butyl phthlalate (mbp) proliferator-activated receptor α butyl benzyl phthalate (bbp) mono-butyl benzyl phthlalate (mbzp) (pparα) and pparγ (mehp, mbp, mbzp) di-isononyl phthalate (dinp) mono-isononyl phthalate (minp) di-isodecyl phthalate (didp) mono-isodecyl phthalate (midp) leydig cell aggregation (dehp, dbp) dioctyl phthalate (dop) mono octyl phthlalate (mop) dihexyl phthalate (dhp) mono hexyl phthlalate (mhp) inhibition of testosterone and insl3 diethyl phthalate (dep) mono ethyl phthlalate (mep) production (dehp, dbp) table. working actions of various phthalates (adopted from hu et al. 2009). oxidative stress in male reproductive dysfunctions-sedha et al. vol 12 no 05 september-october 2015 2307 by phthalates is that of the aryl hydrocarbon receptor. in fact, fetal testes from animals treated with phthalates have increased expression levels of aryl hydrocarbon receptor and its downstream gene cytochrome cyp1b1. (39) inhibition of the cellular function of the leydig cells may perturb testosterone and insl3 synthesis resulting in disturbances in the normal development of the male reproductive tract whilst interference with sertoli cells may result in failure to proliferate with subsequent depleted germ cells.(10) diverse action of various phthalates is shown in the table. mono-(2-ethylhexyl) phthalate (mehp) directly alters the expression of leydig cell genes and cyp17 lyase activity in cultured rat fetal testis.(40) exposure to phthalates in utero alters fetal rat testis gene expression and testosterone production, however much remains to be done to understand the mechanisms underlying the direct action of phthalates within the fetal testis. chauvigné and colleagues investigated the direct mechanisms of action of mehp on the rat fetal testis, particularly focusing on leydig cell steroidogenesis. exposure to mehp led to a dose-dependent decrease in testosterone production.(40) moreover, the production of 5 alpha-dihydrotestosterone (5α-dht) (68%) and androstenedione (54%) was also inhibited by 10 μm mehp. these findings indicate that under in vitro conditions known to support normal differentiation of the fetal rat testis, the exposure to mehp directly inhibits several important leydig cell factors involved in testis function and that the cyp17a1 gene is a specific target to mehp explaining the mehp-induced suppression of steroidogenesis observed.(40) recently, savchuk and colleagues reported that mehp inhibits lh/human chorionic gonadotropin (hcg)-stimulated androgen production by both isolated rat leydig cells and ma-10 mouse tumor leydig cells. (41-43) however, a little has been known about the relationship between the steroidogenic potential of leydig cells and their sensitivity to phthalate exposure. recently 2 mouse genotypes, cba/lac and c57bl/6j, were identified whose leydig cells showed high and low androgen production potential.(44) savchuk and colleagues demonstrated for the first time that the sensitivity of mouse leydig cells to these monophthalates was not associated to their capacity to produce androgens.(41) mehp was found to be the only phthalate that caused a biological effect on mouse leydig cell steroidogenesis and mitochondrial function.(41) the mechanism(s) by which mehp can stimulate steroidogenesis in the leydig cells is under debate. recently svechnikova and colleagues reported that mehp stimulated basal steroidogenesis associated with increased star protein expression in rat progenitor leydig cells and immature granulosa cells.(45) in addition, zhou and colleagues showed that incubating leydig cells with mehp resulted in reductions of luteinizing hormone (lh)-stimulated cyclic adenosine monophosphate (camp) and progesterone productions. camp did not decrease in response to mehp when the cells were incubated with cholera toxin or forskolin. incubation of mehp-treated cells with dibutyryl-camp, 22-hydroxycholesterol or pregnenolone inhibited the figure 3. xenobiotic-enhanced ros formation (adopted from wells et al. 2009). oxidative stress in male reproductive dysfunctions-sedha et al. review 2308 reductions in progesterone.(43) increased levels of reactive oxygen species (ros) occurred in response to mehp. these results indicate that mehp inhibits leydig cell steroidogenesis by targeting lh-stimulated camp production and cholesterol transport, and that a likely mechanism by which mehp acts is through increased oxidative stress.(43) 4. mechanism of oxidative stress oxidative stress is a cellular condition in which damage to cellular macromolecules occurs as a result of excessive amounts of ros. ros such as hydrogen peroxide and hydroxyl radicals are formed via a variety of physiological and pathophysiological reactions (figure 2) and ros formation can be enhanced by radiation and xenobiotics, including drugs and environmental chemicals. these short-lived ros can play physiological roles in signal transduction, however they can contribute to the mechanisms of disease when produced excessively by dysregulation of signal transduction and/ or by oxidative damage to cellular macromolecules (lipids, proteins, dna, rna, carbohydrates) that exceeds the cellular capacity for regeneration or repair. this can also lead to embryo toxicity.(46) at the embryonic level, most antioxidative enzyme activity (figure 3) is around only 5% of maternal activity. (47) early organogenesis stage embryos are particularly sensitive to toxic insult during the transition phase from anaerobic to aerobic metabolism coinciding with the maturation of mitochondrial structure and function. this may reflect the observations that low levels of antioxidant enzyme activities increase as organogenesis proceeds, and that early in organogenesis the embryo may not be able to respond as effectively to oxidative imbalances.(48,49) phthalate-induced oxidative stress results in decreasing the antioxidant capacity, especially in gpx (glutathione peroxidase) and gst (glutathione s-transferase).(50) moreover, increase in lipid peroxidation, cat (catalase) and sod (cu/zn superoxide dismutase) activity was observed.(50) ros can affect peroxisome proliferator (pp) leading to parenchymal cell proliferation. it is mentioned that kupffer cells are a potential oxidant in rodent liver.(51) in fact, phthalates induce toxicity not only via affecting the antioxidant enzymes activity but also through gene expression. and colleagues assessed the effect of dehp on gene expression of antioxidant enzymes. a decrease in sod1 expression was noted. (52) also, wang and colleagues evaluated the effects of mehp on the gene expression.(52) the results revealed that sod1 and gpx expression decreased at 100 μg/ ml. decrease of anti-apoptotic factor (bcl-2) expression and increase of pro-apoptotic factor (bax) expression were noted at three doses of 1, 10 and 100 μg/ml. moreover, expression of cell cycle genes decreased at the same doses.(52) one of the most important mechanisms for phthalates toxicity is defined regarding oxidative stress. the most common ros are superoxide and h2o2 that can be converted into h2o and o2 by antioxidant enzymes such as sod, gpx and cat.(53) phthalates are demonstrated to alter the expression and activity of these enzymes leading to disruption of the cell function.(52) although there are several reports demonstrating the role of oxidative stress in this regard, the presence of a clear relationship between phthalate toxicity in some organs and oxidative stress as the main cause is still under question.(50) however, an additional mechanism of interest which has been understudied is the action of phthalates through induction of oxidative stress. the ability of phthalates to bind and activate peroxisome proliferator activated receptors (ppars) has been well-characterized.(54) binding may cause increased intracellular oxidative stress by overly activating certain enzymes involved in ros generation but only slightly activating those involved in their degradation.(55) this action may lead to systemic increases in oxidative stress which could have a range of downstream effects. for example, this mechanism could lead to altered metabolism, obesity, and development of type ii diabetes.(50) these outcomes have been linked to phthalate exposure in a handful of epidemiologic studies.(56) therefore, the goal of the present study is to systematically review the related reports and papers published in the valid and credible journals to confirm phthalate toxicity and oxidative stress causes infertility. 5. effects of phthalate induced oxidative stress most environmental chemicals are hormonally active compounds that target the endocrine system and cause reproductive anomalies.(57) an increase in these environmental contaminants impair testicular functions by disturbing the pro-oxidant/ antioxidant balance of testicular cells, thereby activating associated downstream pathways such as apoptosis.(58) for the normal functioning of the testes, physiological levels of ros and apoptosis are required however an imbalance or pathological levels may cause deleterious effects. spermatogenesis and steroidogenesis occur within the seminiferous tubules and interstitium of the testes. these two compartments are functionally connected however they differ morphologically. several intra and extra testicular regulatory processes are involved in the regulation of normal spermatogenesis. the ros that are generated during normal testicular function also play an important role in regulating the function of the testis. although ros are known to have damaging effects, controlled and low levels of ros play a beneficial role in normal testicular function.(57) to overcome the effect of ros, the testis is equipped with a very potent antioxidant system that protects it from the damaging effects of ros. the glutathione family of proteins, superoxide dismutase, catalase and several non-enzymatic antioxidants help the testis by counteracting any oxidative impact.(6) several environmental toxicants induce apoptosis in germ cells, thereby resulting in defective spermatogenesis. phthalates are among wide variety of environmental toxicants that are capable of compromising male fertility by inducing a state of oxidative stress in the testes, in addition to endocrine disruption. at the level of testes, oxidative stress is capable of disrupting the steroidogenic capability of leydig cells as well as the capacity of the germinal epithelium to differentiate normal spermatozoa. laboratory experiments implicate a role for oxidative stress in phthalate-stimulated liver tumorigenesis, male reproductive toxicity and developmental toxicity.(59-62) in a recent study, epididymal weight, activities of epididymal alpha-glucosidase and glutathione peroxidase (gsh-px) were significantly decreased in rats of oxidative stress in male reproductive dysfunctions-sedha et al. vol 12 no 05 september-october 2015 2309 500 mg/kg dbp exposure group than control.(60) the activity of superoxide dismutase (sod) was significantly decreased while the level of malondialdehyde (mda) was significantly increased in the epididymal tissue of the 250 and 500 mg/kg dbp exposure groups as compared to control group. this showed that dbp exposure alters the epididymal structure and functions by inducing oxidative stress in epididymis of adult rats. dehp led to a significant decrease in gsh/gssg redox ratio (> 10-fold) and marked increase in tbars levels. thus found to induce oxidative stress in rat testis.(63) epidemiologic studies have reported relationships between biomarkers of phthalate exposure and increased levels of the oxidative stress markers malondialdehyde (mda) and 8hydroxydeoxyguanosine (8-ohdg).(64,65) in a study, the activities of sod and gsh-px in dibp treated groups were significantly lower while the mda and 8-ohdg contents were significantly higher than the control group, indicating that oxidative stress induced by diisobutyl phthalate can decrease the activities of antioxidative enzymes and results in oxidative damage of tissues.(66) a study by hong and colleagues indicated that environmental chemicals, such as polycyclic aromatic hydrocarbons, volatile organic compounds, bisphenol a and phthalates exposure is associated with oxidative stress in urban adult populations.(64) nikravesh and jalali, evaluated the effect of camphor on histopathological changes of reproductive system in young male mice of balb/c racial type.(67) administration of camphor and its effects on male mice reproductive system may result in significant structural changes, including vascularization and proliferation of sexual cells.(67) this can affect maturation of seminiferous tubules and subsequently reproductive function of testes in mice. also continuous administration of low doses of camphor can affect the development and differentiation of testicular tissue and reduce its spermatogenesis activity.(67) lee and colleagues compared the effects of di (n-butyl) phthalate (dbp) on the oxidative damage and antioxidant enzymatic activity in testes of hyperthyroid rats. (68) hyperthyroidism was induced in pubertal male rats by intraperitoneal injection of tri-iodothyronine (t3, 10 μg/kg body weight) for 30 days. an oral dose of dbp (750 mg/kg) was administered simultaneously to normal or hyperthyroid (t3) rats over a 30-day period. no changes in body weight were observed in the hyperthyroid groups (t3, t3 + dbp) compared with controls. there were significantly higher serum t3 levels observed in the hyperthyroid rats than in the control, however the serum thyroid stimulating hormone levels were markedly lower in the hyperthyroid rats. dbp significantly decreased the weight of the testes in the normal (dbp) and hyperthyroid (t3 + dbp) groups. the serum testosterone concentrations were significantly lower in only dbp group. dbp significantly increased the 8-hydroxy-2-deoxyguanosine (8-ohdg) level in the testes, whereas the dbp-induced 8-ohdg levels were slightly higher in t3 + dbp group. superoxide dismutase and glutathione peroxidase activities were significantly higher in the testes of the dbp or t3 + dbp groups. catalase (cat) activity was significantly higher in the dbp treatment group, however the t3 + dbp group showed slightly lower dbp-induced cat activity. the testicular expression of thyroid hormone receptor alpha-1 (tralpha-1) was significantly higher in the dbp groups, and androgen receptor (ar) expression was not detected in the dbp treatment group. in addition, dbp significantly increased the peroxisome proliferator-activated receptor-r (ppar-r) levels in the testis. these results suggest that hyperthyroidism can cause a change in the expression level of ppar-r in testes, and may increase the levels of oxidative damage induced by the metabolic activation of dbp. farombi and colleagues carried out a study to evaluate the ameliorative effects of kolaviron (a biflavonoid from the seeds of garcinia kola) and curcumin (from the rhizome, curcuma longa) on the di-n-butylphthalate (dbp)-induced testicular damage in rats.(69) administration of dbp to rats at a dose of 2 g/kg for 9 days significantly decreased the relative testicular weights compared to the controls, while the weights of other organs remained unaffected. curcumin or kolaviron did not affect all the organ weights of the animals. while only dbp treatment significantly increased the testicular malondialdehyde level and gamma-glutamyl transferase activity (gamma-gt), whereas markedly decreased glutathione level, the testicular catalase, glucose-6-phosphate dehydrogenase, superoxide dismutase, sperm gamma-gt activities and serum testosterone level compared to the control group. data on cauda epididymal sperm count and live/dead ratio were not significantly affected in the dbp-treated rats. alone, dbp treatment resulted in a 66% decrease in spermatozoa motility and a 77% increase in abnormal spermatozoa in comparison to control. dbp-treated rats showed marked degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. the dbp-induced injuries in biochemical, spermatological parameters, and histological structure of testis were recovered by treatment with kolaviron or curcumin. the pattern in the behavior of these compounds might be correlated with their strucfigure 4. proposed mode of action of phthalate monoesters in the developing fetal leydig cells [source: david (2006)]. oxidative stress in male reproductive dysfunctions-sedha et al. review 2310 tural variations. their results indicate that kolaviron and curcumin protect against testicular oxidative damage induced by dbp. the chemoprotective effects of these compounds may be due to their intrinsic antioxidant properties and as such may prove useful in combating phthalate-induced reproductive toxicity. dbp exposure may affect the sperm motility and the anti-oxidative systems. the testis is a vital target organ influenced by dbp since dbp showed inhibitory effect on sod activities in the testis, and it was significant in the highest exposure group i.e. 1000 mg/kg in peanut oil compared with the control (p < .05).(69) in another study, gshpx activities in the serum and gsh levels in the testis homogenate showed a decreasing tendency, however gshpx activities increased markedly in the testis homogenate (p < .05), after 2-week dbp exposure at dosages of 0, 250, 500 and 1000 mg/kg.(70,71) after 4-week dbp exposure, alkaline phosphatase (alp) activities in the serum revealed an increasing tendency; sorbitol dehydrogenase (sdh) activities were inhibited significantly in both the serum and the testis homogenate at the dosage of 1000 mg/kg compared with the control group (p < .01). furthermore, gsh contents in the serum were also affected at this dose (p < .05). a study by kasahara and colleagues indicated that administration of dehp increased the generation of ros and selectively decreased gsh and ascorbic acid in the testes leading to apoptosis of spermatocytes to cause testicular atrophy.(68) results of so and colleagues. indicated that dbp and mbup induced developmental toxicity in rat embryonic limb bud cells and suggested that this effect of dbp might be exerted through oxidative stress.(72) from the above studies, it can be concluded that phthalates may induce oxidative stress by reducing the levels of anti-oxidative enzymes, testosterone and increasing the levels of mda and 8-ohdg in the male reproductive tissues such as testes and epididymis. thus they interfere with the normal spermatogenesis process leading to testicular atrophy and oxidative stress. several other studies have demonstrated that ros involve in neurological and psychiatric disorders, especially in depression.(73) likewise, phthalates could induce these disorders as a result of imbalance in antioxidants and ros levels.(74) moreover, the accumulation of ros has been related to a variety of neurodegenerative diseases.(75) on the other hand, ros cause impairment in learning behavior and reduce motor activity.(76) furthermore, oxidative stress might be considered as a main factor in neurotoxicity of phthalates, a factor by which disruption of neuronal systems may lead to neurobehavioral abnormalities.(77) zhang and colleagues. observed that di-(2-ethylhexyl) phthalate (dehp) is the most widely used plastizer in the world and can suppress testosterone production via activation of oxidative stress.(78) genistein (gen) is one of the isoflavones ingredients exhibiting weak estrogenic and potentially antioxidative effects.(78) in this study, dehp and gen were administrated to pre-pubertal male sprague-dawley rats by gavage from postnatal day 22 (pnd22) to pnd35 with vehicle control, gen at 50 mg/kg body weight (bw)/day (g), dehp at 50, 150, 450 mg/kg bw/day (d50, d150, d450) and their mixture (g + d50, g + d150, g + d450). on pnd90, general morphometry (body weight, agd, organ weight, and organ coefficient), testicular redox state, and testicular histology were studied. results indicated that dehp could significantly decrease sex organs weight, organ coefficient, and testicular antioxidative ability, which largely depended on the dose of dehp. (78) however, co-administration of gen could partially alleviate dehp-induced reproductive injuries via enhancement of testicular antioxidative enzymes activities, which indicates that gen has protective effects on dehp-induced male reproductive system damage after pre-pubertal exposure and gen may have promising future in its curative antioxidative role for reproductive disorders caused by other environmental endocrine disruptors.(78) 6. phthalate induced testicular dysgenesis is also a result of oxidative stress developmentally toxic phthalate esters target multiple pathways in the developing fetal testis. in fetal leydig cells, molecular pathways associated with lipid and cholesterol synthesis and transport and steroidogenesis are reduced, resulting in a dramatic reduction in testosterone (t) synthesis. insulin-like 3 (insl3) production by fetal leydig cells is also reduced and this reduction is likely involved in phthalate-induced cryptorchidism. (79) insl3 is involved in testicular descend. a reduction in alpha-inhibin production likely plays a role in altered sertoli cell maturation and function; this altered maturation together with phthalate-induced disruption in sertoli-gonocyte interaction likely plays a role in the development of multinucleated gonocytes (figure 4). free radical formation is a normal occurrence during steroidogenesis and it is likely that the reduction in expression of genes associated with protecting the cell from oxidative stress such as glutathione transferase and superoxide dismutase is due to a reduction in oxidative stress following reduction of testosterone synthesis leading to reduced fertility.(80) low molecular weight phthalates such as dmp and dep have no developmental effects, however dibp has some developmental effects. endocrine endpoints were studied in offspring at gestation day (gd) 19 or 21. dibp, butylparaben and rosiglitazone reduced plasma leptin levels in male and female offspring. dibp and rosiglitazone additionally reduced fetal plasma insulin levels. in males, dibp reduced anogenital distance, testosterone production and testicular expression of insl-3 (insulin-like factor 3) and genes related to steroidogenesis. pparα mrna levels were reduced by dibp at gd 19 in testis and liver.(81) pregnant wistar rats were gavage feeded from gd7 to gd 19 or 20/21 with either vehicle (corn oil) or 600 mg/ kg bw/day of dibp.(82) administration of dibp resulted in significant reduction in anogenital distance (agd) in male pups (and increased agd in female pups) at gd 20/21 together with reduction in body weights of male and female fetuses and reductions in testicular testosterone production and testicular testosterone content in the male offspring. testicular pathological changes such as clustering of small leydig cells on gd19 or gd20/21 and vacuolization of sertoli cells on gd20/21 were also noted. in another study, pregnant wistar rats were exposed from gestation day (gd) 7–21 to di-isobutyl phthalate (dibp), butylparaben, perfluorooctanoate, or rosiglitazone (600, 100, 20, or 1 mg/kg bw/day, respectively). dibp decreased fetal weight and increased the incidence of undescended testes at 500 mg/kg dose.(83) oxidative stress in male reproductive dysfunctions-sedha et al. vol 12 no 05 september-october 2015 2311 also, in male fetuses at term, dibp decreased testicular testosterone production ex vivo and testosterone levels in testes and plasma, decreased agd and induced pathological changes in the testes including clustering of small leydig cells and vacuolization of sertoli cells. (84) transitional phthalates produce antiandrogen effects by inhibiting fetal testosterone production and insl3. gestational exposure to bbp, dbp or dehp induced a decrease in expression of insl3 in rat fetal testes(79) perhaps explaining the increased incidence of cryptorchidism. serum testosterone was reduced following gestational treatment with bbp, dehp or dbp.(85-87,31) thus, the above studies indicate that phthalates might be inducing oxidative stress by disrupting the steroidogenic pathways leading to reduced testosterone synthesis and insl3 production by the fetal leydig cells which is likely to cause cryptorchidism. the molecular mechanism of dehp toxicity has been attributed to the toxicological properties of its metabolite mono (2-ethylhexyl) phthalate (mehp), formed by cytochrome p450 oxidation.(88) there is a general agreement that male reproductive organs are particularly susceptible to the deleterious effects of ros and lipid peroxidation (lpo) which ultimately lead to impaired fertility.(89) in utero exposure to dehp exerts both short-term and long-lasting suppressive effects on testosterone production in the rat.(90) recently, it was stated that mehp primary metabolite of dehp affects the steroidogenesis in rat leydig cells by provoking ros perturbation.(91) sekaran and colleagues tried to find out the impact of lactational exposure of dehp in testes of first filial generation (f1) progeny male rat postnatal day (pnd)-60. the results of the study showed that lactational exposure of dehp caused dose-dependent changes in testicular sertoli cells (sc) of male offspring through ros-induced apoptosis and perturbation of the tight junctional proteins.(88) 7. genotoxicity the data on genotoxicity of individual phthalate vary widely i.e., some have no data on genotoxicity, some have only in vitro genotoxic potential while some have both in vitro and in vivo genotoxic potential. data on the genotoxic potential of dibp indicate that it has low genotoxic potential since it exhibited genotoxic activities in one or more in vitro assays or in vivo dominant lethal assays.(10) moreover, oxidative stress has been suggested as the etiologic link for reported relationships between urinary phthalate metabolites of dehp and dep with increased dna damage in human sperm.(92,93) kleinsasser and colleagues used the alkaline micro gel electrophoresis assay to detect single-strand breaks in the dna following incubation with di-butyl phthalate (dbp) and di-isobutyl phthalate (dibp). they reported that both dbp and dibp induce the dna damage in oropharyngeal and nasal mucosa, though the effect of dibp was more pronounced than that of dbp.(94) recently, ahbab and colleagues evaluated possible genotoxicity of di-n-hexyl phthalate (dhp) and dicyclohexyl phthalate (dchp) at different concentrations using comet assay in male rat pups.(95) the researchers administered dchp and dhp to the pregnant rats by gavage at the doses of 0 (vehicle), 20, 100 and 500 mg/ kg/day from gestational day 6 (gd6) to gd19. male rats were allowed to grow till different ages (pre-pubertal, pubertal and adulthood) after delivery. erkekoglu and belma kocer-gumusel, postulate that fair intake of trace elements and vitamins with diet can be protective against the genotoxic and carcinogenic potentials of environmental chemicals, particularly against phthalates. (96) in addition, the results demonstrated genotoxic effects of phthalates on human mucosal cells of the upper aerodigestive tract, in contrast to earlier findings in animal models. later ma and colleagues investigated the oxidative damage induced by di-isobutyl phthalate (dibp) in mice treated with dibp (0, 50, 250, 500 and 1000 mg/kg).(66) by the end of the 8th week, the comet assay of blood was tested. the comet assay showed that the oxidative damage of dna in dibp groups was significant in comparison to the control group. it was investigated that dibp induced oxidative damage in mice treated with dibp. while dinp was reported to be non-genotoxic in a battery of bacterial and mammalian cell assays.(97) thus, due to insufficient available data, less is known about the in vivo genotoxic potential of phthalate compounds.(29,30) these studies suggest that some phthalates have the potential to induce dna damage however; further research is needed to fully characterize whether the genotoxic effect of phthalates is due to oxidative stress or not. 8. conclusions based on the available data, it can be inferred that exposure to phthalates might lead to oxidative stress in the male reproductive organs mainly testis and epididymis and causes disruption of the normal spermatogenesis and steroidogenesis. they impair spermatogenic process by inducing oxidative stress and apoptosis in germ cells or target sertoli cells and thereby hamper spermatogenesis. phthalates also decrease the leydig cell function by inducing ros, thereby decreasing the levels of steroidogenic enzymes. thus in utero and postnatal exposure to phthalate compounds might lead to decreased sperm count and various other reproductive anomalies in the young ones. conflicts if interest none declared. references 1. cain jc. miroestrol: an oestrogen from plant pueraria mirifica. nature. 1960;188:774-77. 2. adams nr. phytoestrogens in toxicants of plant origin. 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2002 16:19-28. 88. sekaran s, balaganapathy p, parsanathan r, et al. lactational exposure of phthalate causes long-term disruption in testicular architecture by altering tight junctional and apoptotic protein expression in sertoli cells of first filial generation pubertal wistar rats. human exp toxicol. 2015;34:575-90. 89. williams k, frayne j, mclaughlin ea, hall l. expression of extracellular superoxide dismutase in the human male reproductive tract, detected using antisera raised against a recombinant protein. mol hum rep. 1998;4:235–42. 90. culty m, thuillier r, li w, et al. in utero exposure to di-(2-ethylhexyl) phthalate exerts both short-term and long-lasting suppressive effects on testosterone production in the rat. biol rep. 2008;78:1018-28. 91. zhao y, ao h, chen l, et al. mono(2-ethylhexyl) phthalate affects the steroidogenesis in rat leydig cells through provoking ros perturbation. toxicol vitro. 2012;26:950-5. 92. hauser r. urinary phthalate metabolites and semen quality: a review of a potential biomarker of susceptibility. int j androl. 2008;31:112-7. 93. duty sm, singh np, silva mj, et al. the relationship between environmental exposures to phthalates and dna damage in human sperm using the neutral comet assay. environ health perspect. 2003;111:1164-9. 94. kleinsasser nh, kastenbauer er, weissacher h, muenzenrieder rk, harreus ua. phthalates demonstrate genotoxicity on human mucosa of the upper aerodigestive tract. environ mol mutagen. 2000;35:9-12. 95. ahbab ma, ündeğer ü, barlas n, başaran n. in utero exposure to dicyclohexyl and di-nhexyl phthalate possess genotoxic effects on testicular cells of male rats after birth in the comet and tunel assays. hum exp toxicol. 2014;33:230-9. 96. erkekoglu p, kocer-gumusel b. genotoxicity of phthalates. toxicol mech methods. 2014;24:616-26. 97. zeiger e, haworth s, mortelmans k, speck, w. mutagenecity testing of di (2-ethylhexyl) phthalate and related chemicals in salmonella. environ mutagen. 1984;7:213-32. review 2316 female urology which surgical technique should be preferred to repair benign, primary vesicovaginal fistulas? abdullah gedik,1* hasan deliktas,2 nurettin celik,1 devrim kayan,3 mehmet kamuran bircan3 purpose: to evaluate and compare the outcomes of benign, primary vesicovaginal fistulas (vvfs) treated using the transabdominal transvesical technique and the transvaginal technique without tissue interposition. materials and methods: a total of 53 consecutive women with vvf who were treated between september 1999 and october 2014 were evaluated retrospectively. patients with a malignant etiology and/or prior irradiation were excluded because they required a more complex repair. in the first group, the repair was performed using the transabdominal transvesical technique (n = 28). after one of our fellows had completed his urogynecology training, he began to perform the repairs using the transvaginal technique (n = 25). all included vvf patients were treated without a tissue interposition. results: vesicovaginal fistula repair was performed in 53 patients, with a mean age of 41.4 ± 15.2 years. there was no significant difference in terms of the patients’ age, fistula size, and the number of deliveries between the groups. all cases failed in terms of conservative management. the size of the fistulas ranged from 15 to 20 mm. the admission time was between 3 days and 21 years, and it was longer in less educated patients. the success rate was 96.4% (27/28) in the transabdominal transvesical group and 100% (25/25) in the transvaginal group (p = 1.00). the hospitalization period and complications were significantly reduced in the transvaginal group (p = .00 and p = .004, respectively). no patients converted from a transvaginal to a transabdominal repair. there was only one recurrence in the transabdominal transvesical group.the patients were followed up for 1 year. conclusion: transvaginal repair of benign, primary vvfs is more advantageous than transabdominal transvesical repair. there was a significant decrease in the hospitalization period and complications rates using the transvaginal technique without tissue interposition. keywords: vesicovaginal fistula; surgery; retrospective studies; treatment outcome; gynecologic surgical procedures; methods. introduction vesicovaginal fistula (vvf) is the most frequent type of acquired fistulas and causes both physical and psychosocial morbidity. in underdeveloped countries, vvfs occur due to obstetric complications when there is limited access to prenatal and obstetric care. in industrialized countries, vvfs usually occur as a complication of gynecological, urological or abdominal pelvic surgeries; other causes include malignant illnesses and radiotherapy of the pelvis.(1,2) the overall incidence of vvf because of gynecologic surgery is estimated to be 1 of every 1200 hysterectomies and 1 of every 455 laparoscopic hysterectomies.(3) it is estimated that more than 2 million women have untreated obstetric fistulas. there is an incidence of 50000–100000 new cases annually.(2) it is an ancient disease and has been described since 2050 bc as a large vesicovaginal fistula and laceration of the perineum, which is most likely due to birth trauma.(4) the first basic principles of vvf repair were described by hedrick in 1663, and in 1852, maram sims carried out the first successful vvf repair.(2) however, there are still many controversies in the type of treatment (conservative or surgical), in the optimum time of treatment (early or late), in the type of surgical technique (transvesical, transvaginal, laparoscopic or robotic), in the use of tissue interposition and in the type of urinary diversions used postoperatively (urethral catheter with or without cystostomy). the approach is dependent on many factors, particularly on the experience of the surgeon. in general, simple fistulas are treated using the vaginal approach, whereas complex fistulas are commonly treated using an abdominal approach.(5-7) in the literature, the success rate 1 department of urology, medical faculty, dicle university, diyarbakir 21000, turkey. 2 department of urology, medical faculty, mugla sitki kocman university, mugla 48000, turkey. 3 department of urology, memorial hospital, diyarbakir 21000, turkey. *correspondence: department of urology, medical faculty, dicle university, diyarbakir 21000, turkey. tel: +90 4122488001. fax: +90 4122488440. e-mail: gedikabd@gmail.com. received may 2015 & accepted november 2015 vol 12 no 06 november-december 2015 2422 position under general anesthesia. access to the bladder was achieved through an infra-umbilical incision, and the bladder was incised to expose the fistulous orifice. fistula catheterization was performed in all patients with a 12 french (f) urethral foley catheter, depending on the fistula size. the fistulous orifice was carefully surrounded with delicate dissection. after adding stay sutures to each side of the fistula, we removed the catheter. first, we closed the anterior vaginal wall with vicryl 2-0. the bladder wall was closed in two layers: the mucosa and muscle layers were closed with 4-0 and 2-0 vicryl sutures, respectively. before closure, a 14f foley was replaced as the suprapubic catheter, and an 18f foley was used as a urethral catheter. we inserted a povidone-iodine soaked sponge in the vagina and removed it on the following day. we removed the cystostomy on the third postoperative day and discharged the patient after the drainage stopped from the cystostomy tract and the urine became clear by prescribing antibiotics and anticholinergics, and called the patients back to by the 14th postoperative day to remove the urethral catheter. we stopped the anticholinergics one day prior to the catheter removal. transvaginal repair the patient was operated on in the dorsal lithotomy position. first, we inserted a guide wire through the fistula cystoscopically. fistula catheterization was performed transvaginally in all patients with a 12f foley catheter over the guide wire, depending on the fistula size. to drain the bladder, a16f foley catheter was used. routinely, we do not use suprapubic catheters. the fistulous orifice was carefully surrounded with delicate dissection. the bladder and perivesical tissue were sutured by 3-0 and 2-0 vicryl. after the closure of the second layer, the presence of leakage by filling the bladder was evaluated with 300 ml of saline dyed with blue methyl. if the sutures were secure and watertight, then we suture the vaginal layer of the fistula tract with 2-0 vicryl. we inserted a povidone-iodine soaked sponge to the vagina and removed it on the following day; the patient was discharged after the urine became clear by prescribing antibiotics and anticholinergics. all of the patients were called back on the 10th postoperative day to remove the urethral catheter. we stopped the anticholinergics one day before the catheter removal. statistical analysis statistical analyses were performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 15.0. the differences between the groups for continuous variables were performed using the independent sample t test and the categorical data vesicovaginal fistulas repair-gedik et al. female urology 2423 for simple vvfusing the transabdominal technique is 87.5% and is 87.0% using the transvaginal technique. (8-10) compared with the vaginal approach, the transabdominal approach to vvf repair is associated with a longer recovery time and patient hospitalization, greater blood loss, more cosmetic deformity, and in general, greater morbidity.(11,12) in this study, we retrospectively evaluated our treatment modalities in benign, primary vesicovaginal fistulas to assess and compare the outcomes of our treatment modalities and preferences that changed over the years. materials and methods study subjects this study was approved by the local ethics committee. patients who underwent surgery for vvfs between september 1999 and october 2014 were evaluated retrospectively. the study included 53 patients with vvf swho underwent a transabdominal transvesical repair (n = 28) or atransvaginal repair (n = 25). only primary benign fistulas were included in this study. recurrent vvfs and vvfs as a complication of malignant diseases or radiotherapy were excluded. we performed physical and vaginal examinations, and to detect the localization and size of fistula, we performed cystoscopy under local anesthesia in all patients with involuntary urine discharge from the vagina. in six patients, we could not see the fistula using cystoscopy. in these patients, we applied methylene blue via the urethral catheter and localized the fistula by vaginal examination. in all patients, we carried out the repair 12 weeks after the fistula formation. patients who arrived before 12 weeks were treated conservatively and maintained on a perurethral foley catheter for 12 weeks. in patients who failed to improve from conservative treatment at the end of 12 weeks, fistula repair was performed. until 2008, the repair of 28 patients was carried out using the transabdominal transvesical technique. after 2008, when one of our fellows (ag) completed his urogynecology training, he started to do the repairs by transvaginal technique. after then, in vaginal examination and cystoscopy, ureteral orifices are involved in the fistula and ureteral reimplantation is required, fistula size greater than 20 mm or in recurrent fistula, repair is done by transabdominal transvesical technique. fistula size smaller than 20 mm and in the uncomplicated fistula, even if the fistula located supratrigonal, repair is done by transvaginal technique. surgical techniques transabdominal transvesical repair the patients were operated on in the horizontal supine were compared using fisher’s exact test and chi-square test. a p value of < .05 was considered statistically significant. results vesicovaginal fistula repair was performed in 53 patients with amean age of 41.4 ± 15.2 years. there were no significant differences in terms of patient age, fistula size, and number of deliveries between the groups. all cases failed in terms of conservative management. the success rate was 96.4% (27/28) in the transabdominal transvesical group and 100% (25/25) in the transvaginal group (p = 1.00). the hospitalization period and complications were significantly reduced in the transvaginal group (p = .00 and p = .004, respectively). all of the included patients had a nonirradiated vvf and did not have an underlying malignant disease; further, in all of these patients, the repair was the primary procedure. all repairs were done by the same surgeon (ag) without tissue interposition. the patient and fistula characteristics are shown in table 1. the size of the fistulas ranged from 15 to 20 mm. the application time differed between 3 days and 21 years, and it was longer in undereducated patients. all fistula repairs were carried out after 12 weeks. the repair was performed immediately in patients who arrived later than 12 weeks. no patients converted from a transvaginal to a transabdominal repair. there was only one recurrent fistula in the transabtable 1. patient and fistula characteristics. surgical methods transabdominaltransvesical (n = 28) transvaginal (n = 25) p value mean age (years), (mean ± sd) 43.4 ± 15 40.3 ± 12 .07 number of deliveries, (mean ± sd) 4.4 ± 3.1 3.7 ± 4.6 .63 fistula size (mm), (mean ± sd) 18 ± 11 14 ± 13 .42 fistula localization, no supratrigonal 26 20 .23 trigonal/infra trigonal 2 5 etiology, no .45 normal delivery 4 2 caesarian section 11 14 total abdominal hysterectomy 13 9 variables transabdominal-transvesical (n=28) transvaginal (n=25) p value hospitalization time (day) (mean ± sd) 4.89 ± 2.46 1.12 ± 0.43 .00 success rate, no. (%) 27 (96.4) 25 (100) 1.00 follow up time (month) 12 12 recurrence, no 1 0 1.00 complications, no major complications* 0 0 minor complications 14 3 fever >38°c 3 1 hematuria 2 1 vaginal bleeding 0 1 prolonged drainage (> 24 hours) from the cystostomy tract 4 0 .004 infection in the cystostomy tract 1 0 opening of the incision 2 0 infection in incision area 1 0 scarring causing cosmetic problems in incision area 1 0 *defined as clavien class 2 or greater. table 2. results and complications. vesicovaginal fistulas repair-gedik et al. vol 12 no 06 november-december 2015 2424 dominal transvesical group. there were no major complications, as defined by clavien class 2 or greater, in either group. there were no bladder, bowel, ureteral or nerve injuries. the minor complications, according to clavien class 1, are shown in table 2. discussion though maram sims carried out the first successful repair of vvf in 1852,(13) there are still many controversies about the type of treatment (conservative or surgical), the optimum time of treatment (early or late), the surgical technique (transvesical, transvaginal, laparoscopic or robotic), the use tissue interposition and the type of urinary diversions (urethral catheter with or without cystostomy). in this study, we retrospectively evaluated our treatment modalities in benign, primary vesicovaginal fistulas to assess and compare the outcomes of our treatment modalities and preferences that changed over the years. there are controversies about the optimum timing of vvf surgery. early fistula repair is often followed by a relapse because of tissue necrosis. early surgery is indicated only in intra operatively discovered fistulas. phsak and colleagues reported that when they repaired fistulae earlier than 6 weeks, they found the repair to be significantly more difficult than necessary.(3) additionally, altaweel and colleagues(14) noted that when they carried out the repair earlier as recommended by bettez and colleagues,(15) their patients had major morbidities. (14,15) phsak and colleagues(3) said that a 6-week minimum between surgeries is sufficient to allow the inflammation to lessen and that waiting longer than 6-8 weeks is rarely needed for fistula repairs, regardless of whether it is primary or recurrent. similar to hadzi-djokic and colleagues(16) and altaweel and colleagues,(14) we think that the optimum time for surgery is 3 months after the formation of the fistula, i.e., after the healing response is complete.(14-16) in cases arriving to the hospital later than 12 weeks, we performed the repair immediately. the approach is dependent on many factors, particularly the surgeon’s experience. the most commonly used approaches are vaginal, transvesical, retroperitoneal, transperitoneal, and recently, laparoscopic and robotic approaches.(16-19) the abdominal approach may be used to treat all types of vvf as it is the preferred approach in complex situations when the fistula is large (wider than 4 cm), or when ureteral orifices are involved in the fistula and ureteral reimplantation is required. the biggest drawback of the abdominal approach is that it requires laparotomy and is associated with other morbidities and a longer recovery period. between september 1999 and october 2014, 53 patients with vvfs were treated in our clinic. until 2008, the repair of 28 patients was carried out using the transabdominal transvesical technique. after 2008, when one of our fellows (ag) completed his urogynecology training, he started performing repairs using the transvaginal technique. after observing his technique, we recognized how anuro gynecology fellowship is valuable and effective. the vaginal approach is less aggressive and is well accepted by patients. it involves the tension-free closure of the fistula. the postoperative patient comfort is higher, and the hospital stay is shorter. additionally, patients are free of abdominal incisional complications. although the transvesical approach was the most popular approach in the early period of this study, because there isno statistically significant difference in the success rates, we now recommend and prefer the vaginal approach in noncomplicated fistulas. there are no randomized control trials to suggest which approach is superior. although each approach has its benefits, the decreased length of stay, pain, and morbidity makes the transvaginal approach preferable.(6) in our practice, the transvesical approach is rarely required today and is used only in complex cases with large fistulas and in situations in which an additional surgical procedure, e.g., an ureteroneocystostomy, is required. incontinence as a result of vvf is one of the most disturbing conditions present in the female population. the aim of the treatment is to quickly stop the involuntary discharge of urine and to enable complete urinary and genital functions. surgical success is therefore necessary. tissue interposition in genitourinary fistula repairs can be accomplished with vascularized flaps, such as the labial fibrofatty tissue (martius flap), a pediculated vaginal wall flap, the peritoneum, the omentum, gluteus muscle, rectus abdominus muscle, or gracilis muscle.(1,20-22) nonautologous grafts, namely, small intestinal submucosa and human dura grafts, have also been used to treat benign recurrent vvfs.(23,24) it is generally accepted that the first repair has the highest chance of success, and there is little doubt that tissue interposition has allowed for the reconstruction of many complex vvfs. however, interpositional flaps are not without their complications, including hematomas, wound separations, painand deformities.(25) there is no doubt that tissue interposition can be used in complex vvfs. however, in benign vvfs, there is doubt about whether an interpositional flap is truly needed. therefemale urology 2425 vesicovaginal fistulas repair-gedik et al. fore, the risks and benefits of tissue interposition must be considered carefully. we believe that nonirradiated, primary vvfs differ from complex fistulas that typically require tissue interposition, as previously suggested. in fact, our cure rate of vvfs suggests that the risk and time associated with tissue interposition may be avoided in many patients with benign vvfs. additionally, there is debate about the use of urinary diversion. is it necessary to replace a cystostomy with a urethral catheter? it is generally well accepted that replacing a cystostomy with a urethral catheter increases the cure rate. however, cystostomies are not free of complications, and their use is relatively contraindicated in some pathologies such as previous lower abdominal or pelvic surgery and pelvic cancer, with or without a history of irradiation and coagulopathy. cystostomies also have short-term complications such as damage to the bowel or other surrounding structures, infection, bleeding, blood clots, and catheter migration into the ureteral orifice, which can lead to hydronephrosis andpotentially requiring a repeat procedure. cystostomies also have long-term complications such as urinary infection, stones in the urinary bladder, renal calculi, hematuria and neoplastic changes in the urinary bladder, at the site of the cystostomy or in the suprapubic tract. (26) these complications may increase the morbidity and stress of patients and physicians alike. therefore, the use of cystostomies must be evaluated carefully. as we faced some of these complications, we noticed that the postoperative care of cystostomies is not easy in cases in which we performed the repair transvaginally, and we did not replace the cystostomy. our results confirm our choice, and in our practice, if the method of repair is transvaginal, we never use a percutaneous cystostomy as a diversion. however, for the transabdominal transvesical technique, we advise and routinely use cystostomies as diversions. one of the other controversies concerns the removal time of the urinary diversion. the clinically acceptable duration of bladder catheterization in postfistula repair patient is unknown, and a randomized controlled trial to compare shorter and longer durations of the postoperative catheterization period is needed. in our first cases, we kept the catheter in for 21 days. in their retrospective study of 212 transvaginal repairs, nardos and colleagues removed the urethral catheters at three different time points: in the first group, the catheter was removed on the10th day; in the second group, the catheter was removed on the 12th day; and in the third group, the catheter was removed on the 14th day. in their study, they suggested that postoperative catheterization for 10 days is sufficient for the management of simple vesicovaginal fistula.(27,28) in transvaginal cases, we kept the catheter in for only ten days. similar to a cystostomy, a urethral catheter has its own disadvantages and should be removed as soon as possible. altaweel and colleagues(14) reported a 95% of success rate in all 26 cases repaired using the suprapubic, transvesical o’connor technique, and they drained the bladder continuously with only a urethral catheter for 10 days. they noted that the shorter duration of catheterization resulted in similar treatment outcomes and significant reductions in infection and cost.(14) following the repairs, the contracted bladder reacts to catheters. this reaction increases patient discomfort and involuntary contractions, which develop urinary discharge around the catheter. this complication increases the stress of the patient. to prevent these complications, we prescribed a scheduled dose of anticholinergics to all of our patients. in the postoperative period, however, we advised all patients to rest and asked them to avoid pelvic examination and intercourse for 6 weeks. conclusions the transvaginal repair of benign, primary vvfs is more advantageous than transabdominal transvesical repairs. there was a significant decrease in the hospitalization period and cystostomy or incision-related complication rates such as infection in the incision area, scarring causing cosmetic problems, prolonged drainage (> 24 hours) from the cystostomy tract, and an opening of the incision using the transvaginal technique without tissue interposition. we concluded that the best approach is the technique with which the surgeon feels safest and most confident. surgeons involved in fistula repair should be skilled in both abdominal and vaginal approaches, should have completed urogynecology fellowships, and should have experience in deciding the most appropriate procedure for each individual patient. conflict of interest none declared. references 1. singh o, gupta ss, mathur rk. urogenital fistulas in women: 5-year experience at a single center. urol j. 2010;7:35-9. 2. milicevic s, krivokuca v, ecim-zlojutro v, jakovljevic b. treatment of vesicovaginal fistulas: an experience of 30 cases. med arch. 2013;67:266-9. 3. pshak t, nikolavsky d, terlecki r, flynn bj. is tissue interposition always necessary vesicovaginal fistulas repair-gedik et al. vol 12 no 06 november-december 2015 2426 in transvaginal repair of benign, recurrent vesicovaginal fistulae? urology. 2013;82:70712. 4. zambon jp, batezini ns, pinto er, skaff m, girotti me, almeida fg. do we need new surgical techniques to repair vesico-vaginal fistulas? int urogynecol j. 2010;21:337-42. 5. woo hh, rosario dj, chapple cr. the treatment of vesicovaginal fistulae. eur urol. 1996;29:1-9. 6. eilber ks, kavaler e, rodriguez lv, rosenblum n, raz s. ten-year experience with transvaginal vesicovaginal fistula repair using tissue interposition. j urol. 2003;169:1033-6. 7. hadley hr. vesicovaginal fistula. curr urol rep. 2002;3:401-7. 8. mondet f, chartier-kastler ej, conort p, bitker mo, chatelain c, richard f. anatomic and functional results of transperitonealtransvesical vesicovaginal fistula repair. urology. 2001;58:882-6. 9. raut v, bhattacharya m. vesical fistulae-an experience from a developing country. j postgrad med. 1993;39:20-1. 10. sharifi-aghdas f, ghaderian n, payvand a. free bladder mucosal autograft in the treatment of complicated vesicovaginal fistula. bju int. 2002;89:54-6. 11. angioli r, penalver m, muzii l, et al. guidelines of how to manage vesicovaginal fistula. crit rev oncol hematol. 2003;48:295304. 12. urinary tract fistula. in: rovner es, ed. campbell-walsh urology. 9th ed. saunders, philadelphia, pa, usa 2007:2323-40. 13. riley vj, spiurlock j. vesicovbaginal fistula. (online) 2006. 14. altaweel wm, rajih e, alkhudair w. interposition flaps in vesicovaginal fistula repairs can optimize cure rate. urol ann. 2013;5:270-2. 15. bettez m, breault g, carr l, tu le m. early versus delayed repair of vesicouterine fistula. can urol assoc j. 2011;5:52-5. 16. hadzi-djokic j, pejcic tp, acimovic m. vesico-vaginal fistula: report of 220 cases. int urol nephrol. 2009;41:299-302. 17. singh v, mandhani pa, mehrotra s, sinha rj. laparoscopic repair of vesicouterine fistula: a brief report with review of literature. urol j. 2011; 8:149-52. 18. chibber pj, shah hn, jain p. laparoscopic o'conor's repair for vesico-vaginal and vesico-uterine fistulae. bju int. 2005;96:1836. 19. sundaram bm, kalidasan g, hemal ak. robotic repair of vesicovaginal fistula: case series of five patients. urology. 2006;67:9703. 20. reynolds ws, gottlieb lj, lucioni a, rapp de, song dh, bales gt. vesicovaginal fistula vesicovaginal fistulas repair-gedik et al. repair with rectus abdominus myofascial interposition flap. urology. 2008;71:1119-23. 21. ninkovic m, dabernig w. flap technology for reconstructions of urogenital organs. curr opin urol. 2003;13:483-8. 22. yarmohamadi a, asl zare m, ahmadnia h, mogharabian n. salvage repair of vesicovaginal fistula. urol j. 2011;8:209-13. 23. alagol b, gozen as, kaya e, inci o. the use of human dura mater as an interposition graft in the treatment of vesicovaginal fistula. int urol nephrol. 2004;36:35-40. 24. farahat ya, elbendary ma, elgamal om, et al. application of small intestinal submucosa graft for repair of complicated vesicovaginal fistula: a pilot study. j urol. 2012;188:861-4. 25. lee d, dillon be, zimmern pe. long-term morbidity of martius labial fat pad graft in vaginal reconstruction surgery. urology. 2013;82:1261-6. 26. vaidyanathan s, soni b, hughes p, singh g, oo t. preventable long-term complications of suprapubic cystostomy after spinal cord injury: root cause analysis in a representative case report. patient saf surg. 2011;5:27. 27. nardos r, browning a, member b. duration of bladder catheterization after surgery for obstetric fistula. int j gynaecol obstet. 2008;103:30-2. 28. nardos r, menber b, browning a. outcome of obstetric fistula repair after 10-day versus 14-day foley catheterization. int j gynaecol obstet. 2012;118:21-3. female urology 2427 reconstructive surgery 204 urology journal vol 6 no 3 summer 2009 supracrural rerouting as a technique for resolution of posterior urethral disruption defects seyed jalil hosseini,1 alireza rezaei,1 mojtaba mohammadhosseini,1 iraj rezaei,1 babak javanmard1 introduction: selection of an acceptable method for the treatment of posterior urethral disruption defects would be highly desirable. we determined the efficacy and success rate of some techniques including supracrural rerouting for removing of these defects among our patients. materials and methods: records of 200 consecutive men treated with anastomotic urethroplasty for traumatic posterior urethral strictures were reviewed at our teaching hospital. prior treatment, surgical approach, and ancillary techniques required during reconstruction were evaluated. results: success rate due to posterior urethral reconstruction was achieved in 78.0% of cases. supracrural urethral rerouting was performed in 11 patients (5.5%), of whom 7 sustained recurrent stricture requiring intervention. the highest success rate of defect resolving was reported by urethral mobilization (92.4%). conclusion: supracrural rerouting is not an acceptable technique and can result in postoperative complications such as recurrent stricture in most of the patients with posterior urethral disruption defects. urol j. 2009;6:204-7. www.uj.unrc.ir keywords: urethra, injuries, rupture, posterior urethral strictures, reconstructive surgical procedures department of reconstructive urology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran corresponding author: babak javanmard, md po box: tehran 13185-1678, iran tel: +98 21 2235 5280-1 fax: +98 21 2235 5281 e-mail: dr_javanmard@yahoo.com received december 2008 accepted july 2009 introduction management of posterior urethral disruption defects is quite challenging, and different techniques have been proposed with variable long-term results.(1) these techniques may be associated with several serious complications and often require the expertise of a specialist.(2) over the years, various management strategies have been employed in an attempt to minimize the morbidity associated with posterior urethral disruption defects and their resolution has dramatically improved. therefore, the selection of an acceptable method for the treatment of this defect would be essential in order to achieve desirable outcomes. however, the efficacy of supracrural rerouting has been remained unclear. using this method has been reported to result in recurrent stricture in most of the patients.(3) in the present study, we retrospectively evaluated the efficacy and success rate of this technique for removing of posterior urethral disruption defects among our patients. materials and methods in a retrospective study, 200 consecutive men treated with anastomotic urethroplasty for traumatic posterior urethral strictures were reviewed at our teaching hospital. supracrural rerouting for urethral injuries—hosseini et al urology journal vol 6 no 3 summer 2009 205 in the acute setting, early realignment with a urethral catheter was attempted when deemed clinically appropriate. furthermore, emergent treatment with open or percutaneous suprapubic drainage was more commonly done. realignment techniques varied but the predominant technique used was antegrade manual passage of an 18-f coudé catheter during transvesical exploration with retrograde retrieval of a 16or 18-f catheter into the bladder. once realignment was completed, the urethral catheter was removed after 4 to 6 weeks. suprapubic cystostomy was maintained subsequently if a voiding trial failed. open repair was performed 6 months after the injury. combined antegrade and retrograde cystourethrography was performed preoperatively under fluoroscopic guidance, in order to evaluate urethral distraction length and coronal displacement of the prostatic urethra. urethral reconstruction was performed using a technique previously described.(4) patients’ charts were reviewed for etiology, prior treatment, and ancillary techniques used during reconstruction. urethroplasty success was quantified by urethrography, direct interview with the patient, and cystoscopy with retrograde urethrography, when necessary (whenever the patient reported a problem). the routine follow-up included cystoscopy and retrograde urethrography, 3 and 12 months postoperatively. the need for clean intermittent catheterization or dilation was considered treatment failure. urethral stricture on retrograde urethrography and cystoscopy which needed ancillary treatment was also considered failure. results the mean age of the patients was 30.4 ± 8.2 years (range, 14 to 67 years). they had a mean followup period of 19.3 ± 7.7 months (range, 4 to 35 months), postoperatively. car and motor accident were the main causes in 147 (73.5%) and 36 (18.0%) patients, respectively. gunshot wounds of the posterior urethra accounted for 9 (4.5%) of the lesions and straddle injury was the underlying etiology in 8 (4.0%). successful posterior urethral reconstruction was achieved in 156 of the 200 patients (78.0%). thirty-six cases were considered as failed because of voiding dysfunction reported by the patient and 21, because of urethral stricture on retrograde urethrography. also, 28 patients had urethral stricture on follow-up cystoscopy, and 29 needed ancillary treatment, including urethrotomy and dilation (table). direct anastomosis with scar excision and urethral mobilization was performed in 79 of 200 patients (39.5%). corporal splitting was performed in 69 cases (34.5%) and inferior pubectomy was done in 22 (11.0%). supracrural urethral rerouting was performed only in 11 patients (5.5%). a combined abdominoperineal procedure was performed to reconstruct complex defects in 19 patients (9.5%), which was successful in 15 of them (78.9%). supracrural rerouting technique was performed when free-of-tension anastomosis was not successful and the urethra was rerouted around the left corpus cavernosum for achieving more length of the urethra for anastomosis. the underlying etiology of injury in 11 patients who underwent supracrural rerouting included car and motor accident in 9 (81.8%), gun shot in 1 (9%), and straddle injury in 1 (9%). six these patients (54.5%) had a history of failed pervious open surgery, and none of them had a history of primary realignment. these patients had a mean follow-up period of 24.4 ± 6.7 months primary state operative steps not realigned realigned successful treatment (%) urethral mobilization 77 2 73 (92.4) corporal splitting 67 2 50 (72.4) inferior pubectomy 22 0 16 (72.7) urethral rerouting 11 0 2 (18.2) abdominoperineal salvage 18 1 15 (78.9) total 195 5 156 (78.0) operative steps versus urethral realignment and outcome supracrural rerouting for urethral injuries—hosseini et al 206 urology journal vol 6 no 3 summer 2009 (range, 18 to 31 months) with cystoscopy and urethrography. during the follow-up period, 7 patients (63.6%) developed sustained recurrent stricture requiring intervention, all whom had voiding dysfunction, 3 had stricture on retrograde urethrography, and 4 had stricture on cystoscopy. after ancillary intervention, the stricture recurred in 6 patients during follow-up period. early urethral realignment during the acute treatment phase after pelvic fracture was associated with subsequent successful delayed reconstruction in all patients (all of the 5 cases). of the 5 patients with early realignment, 2 successfully underwent reconstruction with only urethral mobilization, 2 underwent corporal splitting, and 1 underwent abdominoperineal salvage alone (table). none of the patient required inferior pubectomy. discussion several studies investigated various maneuvers for reconstruction of posterior urethral disruption defects; however, some patients needed supracrural rerouting. in the present study, supracrural urethral rerouting was performed only in 5.5% of the patients and the success rate of this step was only 18.2%. other available studies have also obtained similar results in comparison with our study. in one study, supracrural rerouting was performed in 3% of the patients, of whom 75% experienced recurrent stricture.(3) also, in another study by pratap and colleagues, 6 of 25 patients required supracrural rerouting.(4) cooperberg and colleagues did not use this step among their patients with posterior urethral disruption.(1) comparable results were also obtained by jordan.(5) in a 2003 update of the experience of webster and ramon, flynn and coworkers(6) also noted a chronological progression in 2 decades towards more elaborate repairs with urethral mobilization (8%), only rarely completed without the addition of corporal splitting (34%), inferior pubectomy (12%), or supracrural urethral rerouting (38%). some reconstructive centers noted that urethral rerouting is almost always unnecessary,(7) and some investigators found that liberal urethral mobilization and corporal splitting alone are sufficient, when needed, to enable successful posterior urethral construction in most patients.(1) in the present study, we also confirmed that urethral mobilization and corporal splitting had high success rates in comparison with rerouting. it seems that supracrural urethral rerouting has a limited role only for measurement of last resorts, and because of its complications such as recurrent stricture, this technique should not be routinely used by urologists. in the present study, the success rate of urethral mobilization was considerably higher than other steps. this high success rate was also reported in other studies.(3,6) the most common approach to the treatment of posterior urethral distraction defect, consisting of urethral mobilization to bridge defects up to 3.0 cm, was described primarily in 1977 by turner-warwick.(8) it seems that most of the patients can be treated with urethral mobilization alone. conclusion similar to the previous studies, it can be concluded that the supracrural rerouting is not an acceptable technique in the patients who undergo urethral construction, and in most of the cases, this defect can be successfully removed only with other acceptable steps such as urethral mobilization. conflict of interest none declared. references 1. cooperberg mr, mcaninch jw, alsikafi nf, elliott sp. urethral reconstruction for traumatic posterior urethral disruption: outcomes of a 25-year experience. j urol. 2007;178:2006-10. 2. fishman ij, hirsch ih, toombs bd. endourological reconstruction of posterior urethral disruption. j urol. 1987;137:283-6. 3. kizer ws, armenakas na, brandes sb, cavalcanti ag, santucci ra, morey af. simplified reconstruction of posterior urethral disruption defects: limited role of supracrural rerouting. j urol. 2007;177:1378-81. 4. pratap a, agrawal cs, tiwari a, bhattarai bk, pandit rk, anchal n. complex posterior urethral disruptions: management by combined abdominal transpubic perineal urethroplasty. j urol. 2006;175:1751-4. 5. jordan gh. management of membranous urethral supracrural rerouting for urethral injuries—hosseini et al urology journal vol 6 no 3 summer 2009 207 distraction injuries via the perineal approach. in: mcaninch jw, carroll pr, jordan gh, editors. traumatic and reconstructive urology. philadelphia: wb saunders; 1996. p. 393-409. 6. flynn bj, delvecchio fc, webster gd. perineal repair of pelvic fracture urethral distraction defects: experience in 120 patients during the last 10 years. j urol. 2003;170:1877-80. 7. morey af, mcaninch jw. reconstruction of posterior urethral disruption injuries: outcome analysis in 82 patients. j urol. 1997;157:506-10. 8. turner-warwick r. complex traumatic posterior urethral strictures. j urol. 1977;118:564-74. new section in urology journal fillers fillers are materials, including text and image, to be published in the blank spaces of the journal. the subject is not restricted, but those related directly or indirectly to medicine and urology are preferred. quotations, interesting pictures, historical notes, and notice on events are some examples. please contact the editorial office via e-mail (urol_j@unrc.ir) to send fillers. vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2579 pictorial bladder agenesis associated with crossed fused renal ectopia and vertebral anomalies: a rare entity stephen lalfakzuala sailo,1* laltanpuii sailo2 a 9-month-old girl presented with dribbling urine and no normal voiding since birth. there was no history of urinary tract infection. on examination, the child appeared healthy. an abdominal examination was normal. on separation of the labia, a single opening with leaking urine was seen; no separate urethral opening was identified (figure 1). abdominal ultrasonography revealed a crossed left renal ectopic kidney. computed tomography also showed a normally excreting crossed fused ectopic kidney/lump kidney (figure 2a), ureters draining into a urogenital sinus, and butterfly and block lumbar vertebrae (figure 2b). the serum creatinine level was normal (0.3 mg/dl). endoscopy using a pediatric cystoscope inserted through the genital opening revealed a urogenital sinus in which both ureteric openings were located (figure 3); both ureters refluxed when the sinus was filled with contrast (figure 4). we plan to divert the ureters to a cutaneous stoma. agenesis of the urinary bladder is extremely rare; only 23 living cases have been reported. agenesis is attributable to injury to the urogenital sinus at weeks 5~7 of embryogenesis.(1) the condition is associated with renal and skeletal anomalies. young age is not a contra-indication for continent urinary diversion using a self-catheterizable pouch.(2) figure 1. genital opening filled with urine (arrow). figure 2. computed tomographic images of a) the crossed fused ectopic kidneys/lump kidney (arrow) and, b) the crossed fused ectopic kidneys, ureters draining into the urogenital sinus (triangle), block vertebra (arrow), and butterfly vertebra (star). department of urology,1 and anaesthesia,2 north eastern indira gandhi regional institute of health and medical sciences, shillong, meghalaya, india. *correspondence: department of urology, north eastern indira gandhi regional institute of health and medical sciences, shillong, meghalaya, india. tel: +91 364 2538006. fax: +91 364 2538010. e-mail: stephensailo@gmail.com. received: june 2016 & accepted: september 2016 references 1. pacheco-mendoza ba, gonzalez-ledón fj, diaz-pardo m, soto-blanquel jl, castelán-martínez od. bladder agenesis and incomplete kidney duplication: ileal reservoir with continent diversion as definitive treatment. can urol assoc j. 2015;9:e142-4. 2. pfister d, sahi d, heidenreich a, rohrmann d. a continent urinary diversion in a female with agenesis of the bladder: a 5-year follow-up. urology. 2012;80:437-9. figure 3. endoscopy using a pediatric cystoscope shows the urogenital sinus and left ureteric orifice (arrow). figure 4. both ureters and the pelvi-calyceal systems became opacified when the urogenital sinus was filled with contrast. bladder agenesis and vertebral anomalies-sailo and sailo. pictorial urology 2580 vol 16 no 03 may-june 2019 322 case report a case report of synchronous prostate cancer and rectal gastrointestinal stromal tumor and its management ryuta watanabe¹*, akira ozawa¹, tokuhiro iseda¹, hiroaki hatano² a 72-year-old japanese man presented to the hospital with complaints of gross hematuria. contrast enhanced computed tomography revealed a broad-based, approximately 3-cm bladder tumor near the right ureteral orifice and a 5-cm mass located between the prostate and rectum. the patient underwent transurethral resection of the bladder tumor and a transrectal biopsy of the lesion. histological examination of the specimens suggested that the patient had a muscle invasive adenocarcinoma from transurethral resection and a rectal gastrointestinal stromal tumor in trus biopsy. patient underwent total pelvic exenteration and ileal and colonic stomas to divert urine and faeces. final pathology report of the resected specimen revealed a rectal gastrointestinal stromal tumor and prostatic adenocarcinoma, which had invaded the urinary bladder and seminal vesicles. synchronous gastrointestinal stromal tumor in rectum and prostate cancer treated with total pelvic exenteration has not been reported before in literature. keywords: prostate cancer; gastrointestinal stromal tumor (gist); synchronous cancer; total pelvic exenteration (tpe) introduction gastrointestinal stromal tumors (gists) are common gastrointestinal mesenchymal tumors commonly found in the stomach and small intestine. however, gists of the rectum represent less than 2% of all gists in the adult population(1). furthermore, gists display a wide variety of histopathological features and are thus difficult to confirm with a definite diagnosis. here we report the diagnostic difficulties and treatment of a simultaneous case of advanced prostate cancer and gist of the rectum using total pelvic exenteration (tpe), along with some literature review. case report a 72-year-old japanese man presented to our hospital, matsuyama shimin hospital, with complaints of painless gross hematuria. he was a farmer and he had observed macrohematuria after crop work. he was 167 centimeters 1department of urology, matsuyama shimin hospital, ehime, japan. 2department of surgery, matsuyama shimin hospital, ehime, japan. *correspondence: department of urology, matsuyama shimin hospital outemachi 2-6-5, matsuyama city, ehime 790-0067, japan. phone: +81-89-943-1511; fax: +81-89-947-0026. e-mail: ryuta_w_pooh@yahoo.co.jp. received january 2017 & accepted october 2017 figure 1. cystoscopy demonstrated a non-papillary, broad-based, bladder tumor near the right ureteral orifice in height and weighed 57 kilograms. he had no particular physical and family history. primary scanning with ultrasonography (us) revealed a tumor lesion in the bladder, and cystoscopy demonstrated an approximately 3-cm, non-papillary, broad-based bladder tumor near the right ureteral orifice (figure 1). computed tomography (ct) showed a bladder tumor extended to the right ureteric orifice, causing hydronephrosis of the right kidney (figure 2a), whereas magnetic resonance imaging (mri) showed a mass of approximately 5 cm in diameter that was located between the prostate and rectum (figure 2b). bone scintigraphy, chest and abdominal ct scan demonstrated no sign of metastasis. the radiological diagnosis in conclusion was advanced bladder cancer (t3b) and gist of the rectum. urine cytology was negative for malignant cells and total prostate-specific antigen (psa) was 5.01 ng/ml. a few days later, transurethral resection of the bladder tumor (turbt) and transrectal prostatic biopsy was performed. histological examination of the bladder tumor tissue suggested an adenocarcinoma, whereas examination of the prostatic biopsy tissue revealed a gist with spindle cells, and prostatic tissue. because of the diagnosis of synchronous invasive bladder adenocarcinoma and gist at the recto-prostatic shelf, we performed open cysto-prostatectomy with ileal conduit and miles’ operation in a few weeks after the turbt. intraoperative analysis of ureteric margins was negative for cancer. we dissected lateral and internal iliac lymph nodes and obturator lymph node according to the protocol of total cystectomy. histopathological examination of the resected specimen revealed gist of the rectum (figures 3a, 3b) and prostatic adenocarcinoma, which had invaded the urinary bladder and seminal vesicles (pt4). the cystoprostatectomy specimen had a gleason score of 4+5, a positive extraprostatic extension (epe), and a positive resection margin (rm) (figures 4a, 4b, 4c). there was no connection between prostate cancer and gist. there was no sign of metastasis in the resected lymph nodes. because the postoperative course was uneventful besides slight fever due to pyelonephritis, the patient was discharged from our hospital on day 36 postoperatively. plain ct and the blood collection for psa level were taken every 3 months after operation. although the serum psa level dropped to 0.001 ng/ml, it rose to 0.304 ng/ml 6 months postoperatively. the ct revealed no sign of recurrence or metastasis even when the psa level elevated. the patient is currently undergoing maximal androgen blockade (mab), and a serum psa level of 0.001 ng/ml is being currently maintained. now the patient has no clinical condition such as macrohematuria, lower abdominal discomfort or fever. based on follow-up imaging examinations there is no sign of recurrence or metastasis, and is not any complications associated with urinary tract or bowel function 25 months after the operation. figure 2. a: computed tomography showed that the bladder tumor extended to the right orifice, causing hydronephrosis. b: magnetic resonance image revealed a mass of approximately 5 cm in diameter that was located between the prostate and rectum. figure 3. a: the gastrointestinal stromal tumor protruded to the inner side of the rectum, as concluded from macroscopic analysis. b: histopathological examination of the resected gastrointestinal stromal tumor of the rectum specimen showed a spindle cell tumor that originated from muscularis propria. prostate cancer and rectal gist-watanabe et al. case report 323 vol 16 no 03 may-june 2019 324 discussion the term gist was defined in 1983(2), and it includes tumors of the gastrointestinal tract that cannot be classified as either smooth muscle or neurogenic in origin. among gastrointestinal mesenchymal tumors, gists are the most common. by definition, gist is a mesenchymal neoplasm expressing the kit protein, and it is driven by mutations in kit or platelet-derived growth factor receptor-alpha (pdgfr-α). gists are derived from the interstitial cells of cajal (icc), which are kit-positive, pacemaker cells that regulate peristalsis and have varying immunophenotypic and ultrastructural features of both smooth muscle and neural differentiation. activation of kit by mutations leads to icc proliferation and gist(3). in the present case report, tumor cells demonstrated diffuse, cytoplasmic, c-kit-positive immunostaining. gist is a rare disease whose annual incidence is approximately 10 cases per million. the reported incidence rate of gist of the rectum is approximately 1 case per 1000 gists(4). primary prostate and rectal carcinoma are the leading malignancies, but the incidence of synchronous was 0.2%, between 2006 and 2011(5). thinking of the gist’s rarity, the synchronous prostate and gist is rarer. the improvement of diagnostic accuracy of mri have led to detect more synchronous prostate and rectal adenocarcinoma. pre-treatment mri for rectal disease plays a very important role for detecting synchronous diseases(6). large gists may result in altered intestinal function, rectal bleeding (in the case of ulceration), abdominal pain, and urinary symptoms attributed to bladder compression. surgery is the standard treatment for non-metastatic gists. the tumor should be removed en bloc with its pseudocapsule to yield an adequate resection margin. in some cases, preoperative treatment with imatinib may be considered(7), although there are currently no studies to support this practice. in the present case, we performed tpe, including open total cystectomy and prostatectomy with ileal conduit and miles’ operation, based on the preoperative diagnosis of invasive bladder tumor and gist of the rectum. as a matter of course, prostate cancer is sensitive for radiotherapy. and recently there are techniques which have both higher curability and less side effect such as brachytherapy, imrt or vmat (volumetric arc therapy)(8-12). but in the present case we did not reach the precise diagnosis preoperatively. furthermore, there is no evidence that gist is radio-sensitive. therefore, we did not select radiation therapy for the first-line therapy. however, histopathological examination of the resected specimen demonstrated gist of the rectum and prostatic adenocarcinoma, which had invaded the urinary bladder and seminal vesicles. rectal gists are rare tumors, whereas prostatic adenocarcinoma is the most common neoplasia in elderly men. because of weak evidence that the prostate cancer was invasive, a lack of continuity between the bladder tumor and prostate based on cystoscopy, and relatively low serum psa levels, a precise preoperative diagnosis was extremely difficult. in addition, there are only a few cases of invasive prostate carcinoma with low serum psa levels. a transperineal prostate biopsy might be effective; however, our transrectal prostatic biopsy included no prostatic tissue. therefore, we had made wrong diagnosis. we maybe should have undertaken transperineal prostatic biopsy and diagnosed properly before operation. if we could have fortunately diagnosed this case as advanced prostatic adenocarcinoma preoperatively, it might be possible that we could cure prostatic cancer with hormonal therapy or radiotherapy instead of total cystectomy with ileal conduit. similarly, in the case of synchronous prostate and rectal adenocarcinoma the diagnosis is also difficult due to the possibility that rectal and prostatic carcinomas can arise simultaneously(13). because the diagnosis may change the treatment selection, cooperation with pathologist is also necessary. on the other hand, when the psa elevated postoperatively, radiation therapy was the expected option. we strongly proposed the patient radiotherapy after biological psa progression, but the patient firmly refused it due to misleading fear for radiation exposure. fortunately, in the present time there has been no sign of recurrence since then, but the hormone resistance may appear in the near future. before and after the operation, we discussed the neoadjuvant and adjuvant imatinib therapy for the gist with digestive surgeons. the effectiveness of adjuvant imatinib is proven by rcts(14-15). joensuu(16) et. al reported that particularly with a high risk of gist recurrence, compared with 12 month of adjuvant imatinib, 36 months of imatinib improved overall survival of gist patients. in the present case, because the gist was totally resected with negative margin and the histopatholprostate cancer and rectal gist-watanabe et al. figure 4. a: histopathological examination of the resected specimen revealed prostatic adenocarcinoma, which invaded the urinary bladder and seminal vesicles (pt4). b: example of prostatic carcinoma cells, demonstrating the glandular cavity structure (gleason score of 5+4). c: example of tumor cells, demonstrating diffuse, cytoplasmic, prostate-specific antigen-positive immunostaining ogy examination revealed the moderate risk gist, we did not administrate adjuvant imatinib. we will consider imatinib use in case gist recurs. on the other hand, if we had preoperatively known the bladder tumor were prostate adenocarcinoma, we would be able to administrate imatinib first before operation in anticipation of the tumor size reduction and then might be able to undertake less minimally invasive anal preserving operation. thus, although the preoperative diagnosis is difficult, the synchronous case of prostate cancer and gist of the rectum is a rare occurrence. conclusions we report a case of simultaneous double cancer of advanced prostate cancer and gist of rectum with diagnostic difficulties which we treated by tpe as a report of rare occurrence. conflict of interest the authors report no conflicts of interest. references 1. macías-garcía l, de la hoz-herazo h, roblesfrías a, pareja-megía mj, lópez-garrido j, lópez ji. collision tumour involving a rectal gastrointestinal stromal tumour with invasion of the prostate and a prostatic adenocarcinoma. diagn pathol 2012; 7: 150 2. mazur mt, clark hb. gastric stromal tumors. reappraisal of histogenesis. am j surg pathol. 1983; 7: 507–19 3. jubk-sik huh, kyung kgi park, young joo kim, et al. diagnosis of a gastrointestinal stromal tumor presenting as a prostatic mass: a case report. world j mens health 2014; 32: 184-8 4. yaman e, coskun u, sozen s, yamac d, buyukberber s. coexistence of gastrointestinal stromal tumor (gist) of the rectum and adenocarcinoma of the prostate in a patient with familial gist. onkologie. 2008; 31: 697–9 5. kavanagh do, quinlan dm, armstrong jg, hyland jm, o'connell pr, winter dc. management of synchronous rectal and prostate cancer. int j colorectal dis. 2012; 27 :1501-8 6. sturludóttir m, martling a, carlsson s, blomqvist l. synchronous rectal and prostate cancer--the impact of mri on incidence and imaging findings. eur j radiol. 2015; 84: 5637 7. scaife cl, hunt kk, patel sr, benjamin rs, burgess ma, chen ll. is there a role for surgery in patients with “unresectable” c-kit + gastrointestinal stromal tumors treated with imatinib mesylate? am j surg. 2003; 186: 665–9 8. ng sp, tran t, moloney p, sale c, mathlum m, ong g, lynch r. synchronous prostate and rectal adenocarcinomas irradiation utilising volumetric modulated arc therapy. j med radiat sci. 2015; 62: 286-91 9. lavan na, kavanagh do, martin j, small c, joyce mr, faul cm, kelly pj, o'riordain m, gillham cm, armstrong jg, salib o, mcnamara da, mcvey g, o'neill bd. the curative management of synchronous rectal and prostate cancer. br j radiol. 2016; 89: 20150292 10. lahmar r, bahloul r, mokrani a, afrit m, labidi s, boussen h. synchronous primary rectal and prostate cancers. tunis med. 2014; 92: 648 11. colonias a, farinash l, miller l, jones s, medich ds, greenberg l, miller r, parda ds. multidisciplinary treatment of synchronous primary rectal and prostate cancers. nat clin pract oncol. 2005; 2: 271-4 12. siu w, kapp ds, wren sm, king c, terris mk. external beam radiotherapy for synchronous rectal and prostatic tumors. urology. 2001; 57: 800 13. ayhan s, ozdamar a, nese n, aydede h. the synchronous primary carcinomas of the rectum and prostate. indian j pathol microbiol. 2011; 54: 800-2 14. dematteo rp, ballman kv, antonescu cr, et al. adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebocontrolled trial. lancet. 2009; 373: 1097-104 15. casali p. imatinib failure-free survival in patients with localized gastrointestinal stromal tumors (gist) treated with adjuvant imatinib: the eortc /agitg /fsg /geis /isg randomized controlled phase iii trial. j clin oncol. 2013; 31: (suppl): 632s 16. joensuu h, eriksson m, sundby hall k, et al. one versus three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. jama. 2012; 307: 1265-72 prostate cancer and rectal gist-watanabe et al. case report 325 miscellaneous 980-nm diode laser vaporization versus transurethral resection of the prostate for benign prostatic hyperplasia: randomized controlled study mehmet cetinkaya,1* kadir onem,2 mehmet murat rifaioglu,3 veli yalcin4 purpose: we compared the effectiveness and complications of 980-nm diode laser vaporization and transurethral resection of the prostate (turp) in patients with benign prostatic hyperplasia (bph). materials and methods: in total, 72 consecutive patients with bph entered the study. all patients underwent general and urological evaluations. the primary outcome was improvement in the international prostate symptom score (ipss). the secondary outcomes were ipss quality of life (qol), maximum urinary flow rate (qmax), residual volume, and complications. patients were allocated randomly to the turp and laser groups. the ceralas hpd120, a diode laser system emitting at a wavelength of 980 nm, was used for photoselective vaporization of the prostate (pvp). turp was performed with a monopolar 26 french resectoscope. preoperative and operative parameters and surgical outcomes were compared. results: in total, 36 patients in each group underwent pvp and turp. the mean age ± standard deviation was 63.1 ± 9.1 years and 64.7 ± 10.2 years in the pvp and turp groups, respectively. there were no statistically significant differences in age, prostate size, prostate-specific antigen concentration, qmax, preoperative ipss, or preoperative qmax between the two groups. the operation duration was also similar between the groups (p = .36). the catheterization time was 1.45 ± 0.75 and 2.63 ± 0.49 days in the pvp and turp groups, respectively (p < .01). the pvp group had a shorter hospital stay than the turp group. the 3-month postoperative qmax increased to 9.90 ± 3.61 and 6.59 ± 6.06 ml/s from baseline in the turp and pvp groups, respectively; there was no difference in the increases between the groups (p = .08). the ipss and ipss-qol were significantly improved with the operation (p < .01), and this improvement was similar in both groups p = .3 and p = .8, respectively . the complication rate was also similar between the two groups. conclusions: pvp with a diode laser is as safe and effective as turp in the treatment of bph, and the techniques have similar complication rates and functional results. pvp has the advantage of shorter hospitalization and catheter indwelling times and no need for discontinuation of anticoagulant therapy. keywords: ablation techniques; lasers; semiconductor; therapeutic use; prostatic neoplasms; surgery; transurethral resection of prostate; urinary bladder neck obstruction; urinary catheterization. introduction the prevalence of benign prostatic hyperplasia (bph) increases with age in older men.(1,2) approximately 30% of patients with bph require treatment. (3) transurethral resection of the prostate (turp) is still considered the gold standard surgical treatment of bph.(4,5) despite the high success rate of turp, there are concerns regarding its perioperative morbidity and operative safety, especially related to bleeding.(6) dilutional hyponatremia secondary to irrigant absorption is another perioperative and postoperative complication of turp. although there have been technical improvements in turp, the blood transfusion rate and early revision rate are still 2.0% to 7.1% and 3.0% to 5.0%, respectively.(6) 1 department of urology, school of medicine, mugla sitki kocman university, mugla, turkey. 2 department of urology, ondokuz mayis medical faculty, ondokuz mayis university, samsun, turkey. 3 department of urology, medical faculty, mustafa kemal university, hatay, turkey. 4 department of urology, cerrahpasa medical faculty, istanbul university, istanbul, turkey. *correspondence: department of urology, school of medicine, mugla sitki kocman university, mugla, turkey. tel: +90 505 3117005. e-mail: drmemoly@yahoo.com. received december 2015 & accepted september 2015 several laser devices working at various wavelengths have been introduced in the last few decades.(7,8) early laser techniques included the neodymium-doped yttrium aluminium garnet (nd:yag) laser (wavelength: 1064 nm) and the holmium:yag (ho:yag) laser (wavelength: 2140 nm).(9) the potassium-titanyl-phosphate (ktp) laser (wavelength: 532 nm) has been used for efficient vaporization in photoselective vaporization of the prostate (pvp). it is highly absorbed by hemoglobin and thus provides excellent homeostasis.(10) however, its ablative properties are rather slow because the absorption in water is minimal, resulting in prolonged operation times.(11) the diode laser at 980 nm offers a high degree of simultaneous absorption in water and hemoglobin. the aim of this study was to compare the effectiveness and comvol 12 no 05 september-october 2015 2355 plication rates of 980-nm diode laser pvp and turp in patients who underwent surgery for treatment of bph. materials and methods study design the study was designed as a two-arm, prospective, randomized controlled study. primary outcome the primary outcome was the change in the international prostate symptom score (ipss). secondary outcomes the secondary outcomes were quality of life (qol), maximum urinary flow rate (qmax), hospital stay, operation time, the need for analgesics, and complications. patient selection and evaluation from june 2010 to july 2011, patients with bph and prior unsuccessful alpha-blocker treatment were enrolled. urinary tract images were evaluated and the prostate volume and post-void residual urine volume were measured with transabdominal ultrasonography. all patients underwent standard general and urological evaluations, including digital rectal examination (dre), urinalysis, uroflowmetry, and blood sample analysis with measurement of prostate-specific antigen (psa) levels. the international prostate symptom score (ipss) and ipss-qol questionnaires were filled out by all patients. prostate biopsies were performed to exclude prostate cancer in patients with abnormal dre findings or high serum psa levels (> 4 ng/ml). inclusion criteria the inclusion criteria were bph refractory to medical treatment, recurrent urinary retention, prostate volume of < 80 ml, qmax of ≤ 15 ml/s (under medical treatment), an ipss of ≥ 15, and an ipss-qol of ≥ 3. exclusion criteria patients with prostate or bladder cancer histories, neurogenic bladder dysfunction, bladder stones, urethral structures, or previous bladder, urethral, or prostate surgery were excluded. randomization patients were allocated randomly to the diode laser vaporization or turp group with a schedule balanced in blocks of three. the allocation was performed by a nurse and biostatistician. all patients underwent operations within 3 weeks after allocation (figure). patients were informed about the operation and were not blinded for ethical reasons. surgical techniques laser vaporization the evolve 980, ceralas hpd120 (biolitec-ag, jena, germany) is a 120-w diode laser system emitting at a wavelength of 980 nm. the light is transmitted via a flexible 600-mm side-fire fiber to vaporize the tissue in a non-contact mode. a 24 french (f) continuous flow laser cystoscope and 30° optics were used with saline irrigation. vaporization started at the bladder neck level with the bladder filled with saline. starting from the lateral lobes, the area between the 1and 11-o’clock positions was vaporized. reflected beams were usually sufficient to vaporize the upper fibromuscular stroma, table 1. demographic data, patient’s characteristics, preoperative, intraoperative variables, and functional outcomes of the patients in the two study groups. variables diode laser (n = 36) turp (n = 36) p value age (years) 63.1 ± 9.1 64.7 ± 10.2 .5 psa (ng/ml) 2.23 ± 2.32 2.37 ±2.58 .8 prostate volume (ml) 50.6 ± 16.0 54.8 ± 22.7 .4 preoperative ipss 22.6 ± 5.23 21.36 ± 4.81 .3 preoperative ipss-qol 4.44 ±1.21 4.84 ± 0.89 .7 preoperative qmax (ml/s) 9.63 ± 3.18 8.41 ± 4.50 .2 urinary retention before surgery 3 patients 5 patients .1 anticoagulant use 2 ---- .6 functional follow up results and intraoperative and postoperative characteristics operative duration (min) 82.6 ± 30.4 74.7 ± 25.6 .3 energy (kj) 201.49 ± 69.9 --- catheterization time (day) 1.45 ± 0.75 2.63 ± 0.49 < .01 hospital stay (day) 1.58 ± 0.64 2.81 ± 0.58 < .01 need for analgesic medication (injection per day) 1.5 ± 0.3 1.5 ± 0.4 .8 postoperative ipss 8.38 ± 2.89 8.31 ± 3.32 .9 postoperative ipss-qol 1.34 ± 0.61 1.43 ± 0.75 .7 postoperative qmax (ml/s) 16.34 ± 6.9 18.5 ± 3.99 .2 abbreviations: tur-p, transurethral resection of the prostate; ipss, international prostate symptom score; qmax, maximum urinary flow rate; qol, quality of life; psa, prostate specific antigen. diode laser vaporization vs turp for bph-cetinkaya et al. miscellaneous 2356 although further vaporization was performed when necessary, particularly in large glands. the fiber tip was kept ≥ 0.5 mm away from tissue for efficient vaporization. direct contact with tissue was avoided as much as possible. power was decreased to 80 w at the bladder neck level and around the sphincteric area, and the continuous mode was changed to the pulsed mode. turp turp was performed with the use of a standard monopolar 26 f resectoscope (karl storz, tuttlingen, germany). mannitol/sorbitol solution (purisole sm; fresenius, bad homburg, germany) was used for irrigation. all patients underwent operations by the same high-volume urologist who was familiar with both turp and diode laser vaporization (> 50 cases/year for both procedures). spinal or general anesthesia was used. after discharge from the hospital, a nonsteroidal anti-inflammatory (diclofenac 50 mg, as needed) drug and antibiotic (ciprofloxacin, 500 mg twice/daily) were prescribed in all patients. alpha-blockers and anti-cholinergic drugs were not prescribed for lower urinary symptoms to prevent masking any lower urinary tract symptoms related to the procedures. statistical analysis the sample size was calculated for the study with α = 0.05 (for one primary outcome), a power of 80%, and β = 0.2. the sample size was 34 patients for each group. the calculation assumed that a clinically significant difference in the ipss was 2 ± 3 (standard deviation) points. we compared age; psa level; prostate volume; operation duration; catheterization time; perioperative and postoperative ipss, qol, and qmax; complications; changes in ipss, qmax, and qol; and the need for postoperative analgesic medication between the pvp and turp groups. statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0 was used for the mann–whitney u test, χ2 test, table 2. preoperative and postoperative 3rd month ipss, ipss-qol, and qmax. variables baseline postoperative 3rd month p value tur-p (n = 36) ipss 21.36 ± 4.81 8.31 ± 3.32 < .001 ipss-qol 4.84 ± 0.89 1.43 ± 0.75 < .001 qmax (ml/s) 8.41 ± 4.50 18.5 ± 3.99 < .001 laser (n = 35) ipss 22.6 ± 5.23 8.38 ± 2.89 < .001 ipss-qol 4.44 ± 1.21 1.34 ± 0.61 < .001 qmax (ml/s) 9.63 ± 3.18 16.34 ± 6.9 < .001 abbreviations: tur-p, transurethral resection of the prostate; ipss, international prostate symptom score; qmax, maximum urinary flow rate; qol, quality of life. abbreviations: tur-p, transurethral resection of the prostate; ipss, international prostate symptom score; qmax, maximum urinary flow rate; qol, quality of life; ns, not significant. * complications were classified according to clavien-dindo classification of surgical complications. variables diode laser (n = 35) turp (n = 36) p value change in ipss -14.38 ± 4.65 -13.04 ± 4.48 .38 change in qol -3.1 ± 0.73 -3.4 ± 0.82 .83 change in qmax (ml/s) 6.59 ± 5.06 9.90 ± 4.21 .08 urinary retention and re-treatment 1 0 ns (clavien-dindo grade 3a) bleeding (clavien-dindo grade 2) 1 (conversion to tur-p) 1 (need blood transfusion) ns capsule perforation 0 1 ns (clavien-dindo grade 1) tur syndrome ---- 1 ----(clavien-dindo grade 1) total 2 3 ns table 3. comparison of complications and functional outcomes between two study groups.* diode laser vaporization vs turp for bph-cetinkaya et al. vol 12 no 05 september-october 2015 2357 and independent-samples t-test. p values of < .05 were considered to indicate statistical significance. follow-up three months after the surgical procedure, follow-up assessments were performed by research staff blinded to the patient’s procedure. patients were assessed with the ipss, ipss-qol, uroflowmetry, residual urine after uroflowmetry, and urinalysis. results in total, 36 patients underwent pvp with the diode laser and 36 patients underwent standard turp. one patient in the laser group was excluded from the study because of bleeding and conversion to turp. the mean age ± sd was 63.1 ± 9.1 years and 64.7 ± 10.2 years in the pvp and turp groups, respectively. demographic data and preoperative variables of the patients are shown in table 1. primary outcome both groups showed statistically significant improvements in the ipss (table 2). there was no statistically significant difference in the preoperative and postoperative ipss in the two groups (tables 1, 3). secondary outcomes there was no statistically significant difference in age, prostate size, psa level, qmax, or ipss-qol between the two groups (table 1). urinary retention was observed in three and five patients in the pvp and turp groups, respectively. in the pvp group, two patients used and continued to use an anticoagulant drug (clopidogrel bisulfate), although no patient used an anticoagulant drug in the turp group. the operation duration was similar between the groups (p = .36). the mean energy delivered is shown in table 1. the catheterization time was 1.45 ± 0.75 and 2.63 ± 0.49 days in the pvp and turp groups, respectively. the mean catheterization time was significantly longer in the turp than pvp group. the postoperative use of nonsteroidal anti-inflammatory drugs (diclofenac sodium 75 mg/3 ml) is summarized in table 1. the need for analgesic medication was not significantly different between the groups. the hospital stay was significantly shorter in the pvp than turp group (table 1). at 3 months postoperatively, the mean ipss, ipss-qol, and qmax were similar; there was no statistically significant difference between the pvp and turp groups (table 1). the 3-month postoperative qmax increased significantly from baseline in both groups (table 2). the increase was not significantly different between the groups (table 3). the ipss and ipss-qol also improved significantly with the operation, but the improvement was similar in both groups (table 3). complications intraoperative and postoperative complications are listed in table 3. urinary retention was observed after catheter removal in one patient in the laser group. this patient underwent reoperation with the diode laser. in the laser group, one operation was converted to turp because of bleeding and lack of visualization. this patient was excluded from the study. one patient in the turp group required a blood transfusion after the operation because of bleeding. intraoperative capsule perforation was observed in one patient in the turp group, while no perforation was observed in the laser group. bleeding was not observed in patients with continuing anticoagulant drug use in the laser group. turp syndrome was detected in one patient in the turp group and was treated with furosemide and hypertonic saline solution. no complication, such as urinary tract infection or urethral stricture, was reported at the 3-month visit. discussion the selection of an appropriate treatment modality for symptomatic bph can be challenging. these modalities now include medical treatment, minimally invasive procedures, turp, laser prostatectomy, vaporization, and open prostatectomy. important parameters in the treatment decision include effectiveness, durability, complication rates, hospitalization and catheterization times, and cost analysis. turp is the most commonly performed procedure in the surgical management of bph.(12) the unique properties of laser energy have led to its widespread use in urology, particularly in the treatment of bph. various lasers are now available for laser prostatectomy, with success initially reported using the ho:yag laser and more recently the ktp laser, the lithium triborate laser, and the semiconductor diode (scd) laser. a promising surgical procedure is pvp. pvp is easy to learn and has gained increasing acceptance among urologists worldwide. pvp is safe and effective and has tissue debulking properties that lead to prompt improvement over urinary tract obstruction due to bph.(13-16) the increasing risk of turp syndrome and intraoperative bleeding generally limits performance of the turp procedure. the most favorable aspect of pvp is that it offers the prospect of treating patients on ongoing anticoagulant and antiplatelet agents.(17-19) the light weight of the 980nm scd generator (30 kg) makes transportation easy. it uses regular electrical power (220/110 v and 50/60 hz) together with air cooling. success requires keeping the distance between the fiber and tissue at 0.5 mm for efficient vaporization. this requires continuous movement of the fiber tip using a sweeping or brushing technique in accordance with the tissue becoming more distant as it is vaporized. the scd laser uses a wavelength that has the highest absorption for hemoglobin and water, providing both hemostatic and ablative properties. wendt-nordalh and colleagues compared scd laser treatment, ktp laser treatment, and turp. they found that the scd laser had approximately double the tissue ablation rate (7.24 ± 1.48 g/10 min) compared with the ktp laser (3.99 ± 0.48 g/10 min). turp had the fastest tissue ablation rate (8.28 ± 0.38 g/10 min).(11) in the present study, the operation duration in the pvp and turp groups was 82.6 ± 30.4 and 74.7 ± 25.6 min, respectively, and the patients had similar prostate volumes. the operative duration in the pvp group was slightly longer than that in the turp group, but the difference was not statistically significant. the bleeding rate in both the scd (0.14 ± 0.07 g/min) and ktp (0.2 ± 0.07 g/min) laser groups were approximately 100-fold less than that in the turp group (20.14 ± 2.03 g/min). the depth of the coagulation zones was 290.1 ± 46.9 μm for the diode laser, 666.9 ± 64.0 μm for the ktp laser (p < .05), and 287.1 ± 27.5 μm for turp. (11) ali and colleagues performed pvp with a 120-w diode laser in 47 patients with bph. four patients used diode laser vaporization vs turp for bph-cetinkaya et al. miscellaneous 2358 anticoagulant drugs, and no bleeding was reported.(20) ruszat and colleagues also reported that no patient had bleeding issues during diode laser ablation of the prostate among 55 patients with bph despite 51% of the patients being on anticoagulant medication.(21) the 980nm diode laser has superior coagulation capacity for prostate vaporization. seitz and colleagues compared ktp, ho:yag, and diode lasers on ex vivo porcine kidney. the diode laser had a 10-fold better coagulation capacity than the other lasers. a large coagulation zone has been observed during high-intensity diode laser ablation of the prostate. this demonstrates the usefulness of this technique for establishing excellent homeostasis in the treatment of bph.(22) in the present study, three patients taking anticoagulant agents in the laser group continued their anticoagulant drugs, and blood transfusion was not required in any patient. pvp with the diode laser was safe for patients undergoing anticoagulant therapy. in our study, only one operation was converted to turp because of bleeding due to lack of visualization in a patient not taking an anticoagulant drug. in the present study, the functional results were similar between the two groups. the differences in the mean ipss, ipss-qol, and qmax were not statistically significant between the preoperative and postoperative periods in either group. published clinical trials have demonstrated that the mean qmax, ipss, and qol significantly improved with prostate vaporization with diode lasers.(20) ali and colleagues reported that the ipss declined from 21.93 ± 4.88 to 10.31 ± 3.79 and that the qol decreased from 4.19 ± 0.85 to 2.82 ± 1.16. moreover, the qmax increased from 8.87 ± 2.18 to 17.51 ± 4.09 ml/s at 3 months postoperatively. in another report, the mean qol (pre: 3.2 ± 1.7 vs. post: 0.9 ± 0.8), ipss (pre: 18.7 ± 7.9 vs. post: 6.0 ± 2.7), and qmax (pre: 10.7 ± 5.4 ml/s. vs. post: 17.8 ± 3.4 ml/s) significantly improved with 120-w diode laser vaporization. (21) in terms of functional outcomes in the present study, the qmax, ipss, and ipss-qol significantly improved with pvp. we can conclude that diode laser vaporization of the prostate is an efficacious method for the treatment of bph. several reports that compared laser prostatectomy/ vaporization and turp have been published. tugcu and colleagues demonstrated that similar significant improvements were observed in patients undergoing pvp with a ktp laser and in those undergoing turp. (23) tugcu also reported that pvp had the advantage of shorter hospitalization and catheter indwelling times and no need for discontinuation of anticoagulant therapy compared with turp.(23) horasanli and colleagues demonstrated that early functional results (ipss, qmax, and residual volume) with turp were superior to those with pvp using a ktp laser in patients with enlarged prostates (> 70 ml). additionally, volume reduction was significantly higher in the turp group and retreatment was needed in patients undergoing pvp, although no patient needed retreatment in the turp group.(24) however, the blood transfusion rate was reportedly 8.1% in patients treated with turp, whereas no patient needed transfusion in the pvp group. ruszat and colleagues compared turp and ktp laser vaporization. patients were stratified by age (< 70, 70–80, and > 80 years).(25) ruszat and colleagues reported that although bleeding complication rates were higher in the turp group, the postoperative qmax was higher in the turp group. improvements in ipss were similar in both groups. volume reduction was 63% in the turp group and 44% in the pvp group, and the reoperation rate was lower in the turp group (3.9% vs. 6.7%). a major limitation of the study was that prostate volumes were not similar between the turp and pvp groups.(25) to our knowledge, the present study is the first report to compare 980-nm diode laser and turp procedures. our study revealed that turp and pvp with a diode laser have similar functional outcomes (qmax, ipss, and ipss-qol) in patients with bph exhibiting similar characteristics, although the mean catheterization time in the pvp group was significantly lower than that in the turp group. in term of complications, ali and colleagues reported that dysuria was observed in 23% of patients who underwent ktp laser vaporization and that late bleeding was observed in one patient. urinary recatheterization was figure. flow diagram of patients through trial phase. diode laser vaporization vs turp for bph-cetinkaya et al. vol 12 no 05 september-october 2015 2359 needed for two patients because of temporary urinary retention. retrograde ejaculation developed in 31% of patients undergoing pvp, and temporary urinary incontinence was observed in two patients.(20) ruszat and colleagues also reported complication rates in patients who underwent ktp laser vaporization. in their study, conversion to turp (4%, 2 patients), dysuria (24%, 13 patients), urge incontinence (4%, 7 patients), urinary tract infection (6%, 11 patients), bladder neck strictures (8%, 15 patients), and retreatment (10%, 18 patients) were reported as complications.(21) in the present study, the total complication rates were 5.4% and 8.2% in the pvp and turp groups (2 vs. 3 patients), respectively. the total complication rate seemed to be higher in the turp group, but the difference was not statistically significant. in the laser group, one operation was converted to turp because of bleeding and lack of visualization and was excluded from the study (figure). one patient in the turp group required a blood transfusion after the operation because of bleeding. limitations of our study include the lack of long-term follow-up and late complication data, such as urethral strictures and retrograde ejaculation. another limitation of this study was the limited number of patients, but the number was sufficient according to the power analysis. a 2-point improvement in the ipss can reflect a clinical improvement. thus, the power analysis was calculated according to the ipss (primary outcome) with 80% power (alpha = 0.05). prospective randomized clinical trials with larger numbers of patients and longer follow-up periods are still needed. conclusions according to our study, which is the first to compare diode laser vaporization and turp procedures, prostate vaporization with a diode laser seems to be as effective as turp, safe, and a minimally invasive treatment option for bph. major advantages of pvp with a diode laser were shorter catheterization times and shorter hospital stays. conflict of interest none declared. references 1. garraway wm, collins gn, lee rj. high prevalence of benign prostatic hypertrophy in the community. lancet. 1991;338:469-71. 2. glynn rj, campion ew, bouchard gr, silbert je. the development of benign prostatic hyperplasia among volunteers in the normative aging study. am j epidemiol. 1985;121:78-90. 3. guess ha, arrighi hm, metter ej, fozard jl. cumulative prevalence of prostatism matches the autopsy prevalence of benign prostatic hyperplasia. prostate. 1990;17:241-6. 4. de la rosette jj, alivizatos g, madersbacher s, et al. eau guidelines on benign prostatic hyperplasia (bph). eur urol. 2001;40:256-63. 5. simforoosh n, abdi h, kashi ah, et al. open prostatectomy versus transurethral resection of the prostate, where are we standing in the new era? a randomized controlled trial. urol j. 2010;7:262-9. 6. rassweiler j, teber d, kuntz r, hofmann r. complications of transurethral resection of the prostate (turp)--incidence, management, and prevention. eur urol. 2006;50:969-79. 7. fried nm. new laser treatment approaches for benign prostatic hyperplasia. curr urol rep. 2007;8:47-52. 8. kuntz rm. laser treatment of benign prostatic hyperplasia. world j urol. 2007;25:241-7. 9. costello aj, bowsher wg, bolton dm, braslis kg, burt j. laser ablation of the prostate in patients with benign prostatic hypertrophy. br j urol. 1992;69:603-8. 10. reich o, bachmann a, schneede p, zaak d, sulser t, hofstetter a. experimental comparison of high power (80 w) potassium titanyl phosphate laser vaporization and transurethral resection of the prostate. j urol. 2004;171:2502-4. 11. wendt-nordahl g, huckele s, honeck p, et al. 980-nm diode laser: a novel laser technology for vaporization of the prostate. eur urol. 2007;52:1723-8. 12. dawkins gp, miller ra. sorbitol-mannitol solution for urological electrosurgical resection-a safer fluid than glycine 1.5%. eur urol. 1999;36:99-102. 13. bachmann a, ruszat r, wyler s, et al. photoselective vaporization of the prostate: the basel experience after 108 procedures. eur urol. 2005;47:798-804. 14. sarica k, alkan e, luleci h, tasci ai. photoselective vaporization of the enlarged prostate with ktp laser: long-term results in 240 patients. j endourol. 2005;19:1199-202. 15. te ae, malloy tr, stein bs, ulchaker jc, nseyo uo, hai ma. impact of prostatespecific antigen level and prostate volume as predictors of efficacy in photoselective vaporization prostatectomy: analysis and results of an ongoing prospective multicentre study at 3 years. bju int. 2006;97:1229-33. 16. javanmard b, hassanzadeh haddad a, yaghoobi m, lotfi b. diode laser ablation of prostate and channel transurethral resection of prostate in patients with prostate cancer and bladder outlet obstruction symptoms. urol j. 2014;11:1788-92. 17. reich o, bachmann a, siebels m, hofstetter a, stief cg, sulser t. high power (80 w) potassium-titanyl-phosphate laser vaporization of the prostate in 66 high risk patients. j urol. 2005;173:158-60. 18. ruszat r, wyler s, forster t, et al. safety and effectiveness of photoselective vaporization of the prostate (pvp) in patients on ongoing oral anticoagulation. eur urol. 2007;51:1031-8. 19. sandhu js, ng ck, gonzalez rr, kaplan sa, te ae. photoselective laser vaporization prostatectomy in men receiving anticoagulants. diode laser vaporization vs turp for bph-cetinkaya et al. miscellaneous 2360 j endourol. 2005;19:1196-8. 20. erol a, cam k, tekin a, memik o, coban s, ozer y. high power diode laser vaporization of the prostate: preliminary results for benign prostatic hyperplasia. j urol. 2009;182:107882. 21. ruszat r, seitz m, wyler sf, et al. prospective single-centre comparison of 120-w diodepumped solid-state high-intensity system laser vaporization of the prostate and 200-w highintensive diode-laser ablation of the prostate for treating benign prostatic hyperplasia. bju int. 2009;104:820-5. 22. seitz m, ackermann a, gratzke c, et al. [diode laser. ex vivo studies on vaporization and coagulation characteristics]. urologe a. 2007;46:1242-7. 23. tugcu v, tasci ai, sahin s, zorluoglu f. comparison of photoselective vaporization of the prostate and transurethral resection of the prostate: a prospective nonrandomized bicenter trial with 2-year follow-up. j endourol. 2008;22:1519-25. 24. horasanli k, silay ms, altay b, tanriverdi o, sarica k, miroglu c. photoselective potassium titanyl phosphate (ktp) laser vaporization versus transurethral resection of the prostate for prostates larger than 70 ml: a short-term prospective randomized trial. urology. 2008;71:247-51. 25. ruszat r, wyler sf, seitz m, et al. comparison of potassium-titanyl-phosphate laser vaporization of the prostate and transurethral resection of the prostate: update of a prospective non-randomized two-centre study. bju int. 2008;102:1432-8. diode laser vaporization vs turp for bph-cetinkaya et al. vol 12 no 05 september-october 2015 2361 213 urology journal unrc/iua vol. 1, no. 3, 213-214 summer 2004 printed in iran large adenocarcinoma of the right adrenal cortex: a case report khatami m, fanaie a, mehrvarz sh, kosari f department of surgery, baghiatallah university of medical sciences, tehran, iran key words: adrenal, cancer, metastasis, survival introduction adrenocortical carcinoma is a rare tumor with an estimated incidence between 0.5 and 2 per one million people yearly. tumors are classified as functioning when they are associated with endocrine manifestations or elevated hormone levels. non-functioning tumors are defined as tumors that do not secrete hormones above normal levels.(1) adrenocortical carcinoma is a rare entity and usually has poor prognosis. however, the natural history and response to therapy of patients with this malignancy have often been conflicting. complete tumor resection may be associated with improved survival.(2) meanwhile, the presence of intravascular tumor extension alone, should not be a contraindication to radical surgical therapy, as it is the best hope for prolonged survival.(3) case report a 36-year-old male with stage ii (t2, n0, m0) adrenocortical carcinoma of the adrenal gland was referred to our hospital in may 2000. the patient's chief complaint was swelling of both legs up to the knee. he had been admitted to the hospital with a diagnosis of deep vein thrombosis, which had been treated medically with heparin. he also had two episodes of transient ischemic attack, 7 and 3 years before his first admission for dvt, which had been treated and no cerebral sequelae suggesting of this condition was present. a thorough investigation was performed; all laboratory tests were normal except for a positive c reactive protein (crp) and a cardiolipin level of 36. ultrasound studies revealed a 13 × 6.8 cm mass in the right adrenal gland, which was later confirmed by ct scan. liver and abdominal viscera were otherwise normal and chest ct scan was unremarkable. considering all the examination performed, the tumor was classified as stage ii. the patient underwent an adrenalectomy. pathologic diagnosis was pheochromocytoma. in his follow-up 28 months after surgery, a mass of 53 × 54 mm was observed in the right lobe of the liver. other investigations were normal. the liver mass was excised with a sufficient margin of unaffected tissue. histopathological study suggested a diagnosis of metastatic adrenal adenocarcinoma. considering the inconsistency of two pathologic diagnoses, the samples from the adrenal mass were reviewed. immunohistochemical studies were strongly in favor of adrenal adenocarcinoma for the primary lesion (fig. 1,2). three years after the surgery, imaging studies have revealed further metastasis. discussion the prognosis of adrenocortical carcinoma in adults is generally poor. based on the recent studies, mean survival is approximately 18 months. the overall 5-year survival rate after diagnosis is 15% to 47%. most case series have shown statistically significant differences in survival based on patient's age, gender, or tumor functional status. however, the tumor stage is a significant prognostic factor. surgical resection seems to be the only effective therapy for adrenocortical carcinoma that significantly prolongs survival, particularly when disease is detected at stages i and ii. also based on previous studies, after complete resection median survival is 13 to 28 months.(1) invasive radical surgery for treatment of the primary lesion as well as early liver metastatectomy may explain why our patient outcome was better than expected. this supports the belief that invasive radical resection of the tumor and its metastases is the most effective method of treatment for this disease. moreover, this case is a good example of effectiveness of surgical management accepted for publication in april 2004 large adenocarcinoma of the right adrenal cortex: a case report in treating the recurrent or metastatic disease. the differential diagnosis of adrenocortical carcinoma (acc) includes adrenocortical adenoma, metastatic hepatocellular carcinoma (hcc), renal cell carcinoma (rcc), and pheochromocytoma.(3) distinction of adrenal cortical adenoma from carcinoma may be difficult in well-differentiated cases. high mitotic figures (>1 per 10 high power field), atypical mitoses, diffuse growth and tumors weighing more than 100 grams in adults are typically useful histological signs of carcinoma and so are high nuclear grade, vascular/capsular invasion, and clear cells <25% of tumor (fig. 1). necrosis >2 high power fields and broad fibrous bands are also good discriminates. more over, metastatic dissemination in the present case is the definite criterion for malignancy. careful morphologic correlation with other features such as clinical presentation, location, thorough investigation for the presence of other primary tumors or the results of special stains for intracellular glycogen or mucosubstance often provides definite information as to the correct diagnosis. in a few cases, however, there may be lingering uncertainty. most rccs and nearly all cases of hcc are positive for cytokeratin and other epithelial markers, such as epithelial membrane antigen (ema), that are negative in accs. a potentially important immunohistochemical finding for synaptophysin in a significant proportion of accs is as in the present case (fig. 2). clinical manifestation and demonstration of urinary excretion of free catecholamines and their metabolites such as vanilylmandelic acid (vma) and metanephrines are helpful diagnostic tools in pheochromocytoma. on the other hand, on mri, pheochromocytomas tend to show very high signal intensity on t2 weighted images. adrenal cortical carcinomas tend to have intermediate signal intensity. acc is often a bulky neoplasm, with the average weight in several series being 510 gr to 1210 gr. meanwhile, the average weight of pheochromocytomas in several large series has been 73 gr to 150 gr. in gross inspection, acc often has areas of necrosis, which is not a consistent feature in pheochromocytoma. microscopically, pheochromocytomas are composed of pleomorphic cells arranged in sheets or in clusters (zellballen nests), separated by delicate fibrous septa. however, the tumor cells in acc are much more pleomorphic and have more tendency to arrange in variable sized sheets and cords. immunohistochemically, the tumor cells in acc are positive for synaptophysin and characteristically negative for chromogranin, whereas, both markers are positive in pheochromocytoma. in addition, sustentacular cells are strongly positive for s100 protein in pheochromocytoma.(4) references 1. ng l, libertino jm. adrenocortical carconoma: diagnosis, evaluation and treatment. j urol 2003; 169: 5-11. 2. tritos na, cushing gw, heatley g, libertino ja. clinical features and prognostic factors associated with adrenocortical carcionma: lahey clinic medical center experience. am surg 2000; 66: 73-79. 3. hisham an, sarojah a, zanariah h. large aderenocortical carcinoma extending into the inferior vena cava and right atrium. asian j surg 2003; 26(1): 40-42. 4. lack ee. afip atlas of tumor pathology: tumors of the adrenal gland and extra adrenal paraganglia (atlas of tumor pathology). 3rd ed. american registry of pathology; 1997. 214 fig. 2. strong cytoplasmic positivity of the tumor cells for synaptothyfin (imunohistochemical staining-x400) fig. 1. high power view of the tumor cells with enlarged hyperchromatic pleomorphic nuclei and frequent prominent nucleoli with large amount of pink eosinophils (h and e staining-x400) vol 15 no 06 november-december 2018 306 endourology and stone disease the effect of local anesthetic agent infiltration around nephrostomy tract on postoperative pain control after percutaneous nephrolithotomy: a single-centre, randomised, double-blind, placebocontrolled clinical trial gokce dundar,1* kaan gokcen,2 gokhan gokce,2 emin yener gultekin2 purpose: insufficient alleviation of pain after percutaneous nephrolithotomy causes patient dissatisfaction and generates additional morbidity factors by preventing early mobilization. this study investigated the effects of bupivacaine infiltration with two different doses around the nephrostomy tract after percutaneous nephrolithotomy. materials and methods: patients who underwent subcostal single entrance percutaneous nephrolithotomy were randomly divided into 3 groups of 20 patients. while the first and second group were planned to receive bupivacaine at rates of 0.5% and 0.25% respectively, the third group was planned to receive a placebo agent to preserve the doubly blinded nature of the study. results: a statistically significant difference was found in the number of patients using tramadole. the frequency of analgesic administration was found lower in the two groups that received bupivacaine in comparison to the group that did not, while the time of the first analgesic administration in the group that received high dose bupivacaine was significantly later than the other groups. although there was no difference between the groups in terms of total amount of analgesic usage, patients who received higher concentrations of bupivacaine were likely to require a lower amount of narcotic agent. the frequency of analgesic administration decreased significantly in patients of both groups that received bupivacaine. moreover, by administering bupivacaine at a 0.5% rate, fewer patients (50%) required narcotic analgesia and the first time of analgesic administration was found to be significantly later. conclusion: administering bupivacaine at a 0.5% rate around the nephrostomy tract after surgery was demonstrated to be more effective. keywords: percutaneous nephrolithotomy; postoperative pain; bupivacaine. introduction urinary system stone diseases are the third most frequent reasons of urological complaints following urinary tract infections and prostate pathologies(1). nephrolithiasis is a highly prevalent disease worldwide with rates in the range of 7-13% in north america, 5-9% in europe, and 1-5% in asia(2). in terms of urinary system stones, turkey is considered endemic and the occurrence rate in the population of the ages 18 to 70 is 11.1%(3). pnl is an endoscopic method that is used frequently in kidney stone treatment, while its success rate is high, morbidity is low and duration of hospitalization is considerably short in comparison to open surgery(4). after rupel and brown removed the obstructive stone from the nephrostomy path they created surgically, fernström and johansson defined the new stone surgery method they named as percutaneous pyelolithotomy in 1976(5). the advancements in technique and the tools used in operations allowed urologists to remove stones percutaneously with increased success and reduced complications(6). the alleviation of the pain based on renal entrance dilatation or nephrostomy catheter after pnl may be achieved with various painkillers from simple nonsteroidal anti-inflammatory drugs to narcotic analgesics. prevalent usage of narcotics for pain control after surgery has brought about issues such as respira1urology department, cizre state hospital, şırnak, turkey. 2department of urology, faculty of medicine, cumhuriyet university, sivas, turkey. *correspondence: cizre state hospital, şırnak, turkey. postal code: 73200. mobile: +90 505 2464648. fax: +90 486 6170410. mail: dr@gokcedundar.com. received august 2017 & accepted december 2017 tory depression. however, in the case of inadequate pain management, in addition to the discomfort of the patients, there is a possibility of additional morbidity factors and increased treatment costs by obstruction of mobility in the short-term(7). balanced analgesia administration gained importance in terms of increasing the activity of postoperative pain treatment, and especially, minimizing the side effects of narcotic drugs(8,9). with this purpose, combined administration of narcotic drugs and nonsteroidal anti-inflammatory drugs or techniques used with local anesthesia, brought about reduction in side effects related to narcotic drugs and increase in quality of analgesia(10). as for all local anaesthetics, the mechanism of action of the bupivacain is based on their ability to reversibly inhibit voltage-gated sodium channels in nervous fibres. this inhibition occurs in a manner that is both time dependent and voltage dependent and results in an increased threshold for activating the action potential, reducing the propagation of the electric impulse along the nerve fibres with complete block of their function. the most rapid onset but the shortest duration of action occurs after intrathecal or subcutaneous administration of local anesthetics. these differences in the onset and duration of anesthesia and analgesia are due in part to the particular anatomy of the area of injection, which will influence the rate of diffusion and vascular absorption and, in turn, affect the amount of local anesthetic used for various types of regional anesthesia(11). this study aimed to investigate the postoperative pain management effects of two different dosages of bupivacaine, which is a long-acting local anesthetic agent, that we administered after the pnl operation we carried out for kidney stone treatment; the literature was reviewed, and the effectiveness of local anesthetics in similar studies were analyzed. patients and methods study population the study included 60 patients over the age of 18 between january 2015 and april 2016 who were given subcostal single percutaneous entry at the urology clinic of cumhuriyet university research and application hospital with body mass index of 35 kg/m2 or lower, with a stone burden of lower than 900 mm2, with an operation duration of shorter than 3 hours whose one-sided kidney interventions were planned. the study excluded patients with coagulation disorders, heart, respiration or kidney diseases, bupivacaine allergies, those with supracostal or multiple percutaneous entry, those given bilateral simultaneous pnl, and those who did not agree to participate. this study was conducted with the approval of cumhuriyet university clinical research ethics board (decision no: 2015-01/01) and by informing the patients in written and verbal form. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. study design this was a single-center, prospective, randomized-controlled, and double-blind study. the cases were randomly distributed into 3 groups of 20 people with the method of sealed envelopes. while the first and second group were planned to receive bupivacaine (marcaine; zentiva, kırklareli, turkey) at rates of 0.5% (100 mg/20 ml) and 0.25% (50 mg/20 ml) respectively, the third group was planned to receive a placebo agent (saline) to preserve the doubly blinded nature of the study. we named the groups as: group high dose bupivacaine (hb), group low dose bupivacaine (lb) and group placebo agent (pa). anesthesia anesthesia was induced (propofol 2–3 mg/kg, fentanyl 1 µg/kg, rocuronium 0.5 mg/kg iv) followed by endotracheal intubation. controlled ventilation was provided with oxygen, nitrous oxide (50:50), sevoflurane (2% dial setting), 1 l/minute fresh gas flow. surgical technique renal capsule – skin distances of all patients were measured in their preoperative unenhanced computer tomography. after the pnl operation was carried out under general anesthesia, 20 fr malecot-nephrostomy catheters were placed. in the first and second groups; before removing the nephrostomy sheath, infiltration was made using a 25-gauge spinal anesthesia needle in a homogenous way from the renal capsule to the skin for 5 ml in each of the 4 quadrants right near the nephrostomy tract. attention was paid for the needle to enter in parallel to the nephrostomy tract and perpendicular to the skin, as much as the renal capsule – skin distance. the third group was not given any local anesthetic agents (figure 1). table 1. preoperative signs of the individuals in the groups group hb n:20 group lb n:20 group pa n:20 p age mean ± sd (min max) 51.9 ± 10.5 (33 – 68) 50.7 ± 7.8 (40 – 64) 44.1 ± 13.4 (26 – 75) 0.059 gender (n) male 11 12 10 0.817 female 9 8 10 body mass index mean ± sd (min max) 29 ± 4.9 (19 – 39.5) 28.5 ± 5.8 (21.3 – 47.2) 28.8 ± 5.1 (21.3 – 40.8) 0.954 stone burden (mm2) mean ± sd (min max) 428 ± 224 (160 – 897) 399 ± 192 (134 – 899) 376 ± 244 (90 – 898) 0.531 stone hounsfield mean ± sd (min max) 1162 ± 366 (340 – 1730) 1115 ± 398 (288 – 1781) 1058 ± 375 (320 – 1532) 0.687 operation side right 8 12 11 0.420 left 12 8 9 stone opacity opaque 18 20 18 0.343 non-opaque 2 0 2 stone location upper calyx 0 1 0 0.316 middle calyx 0 3 1 lower calyx 7 5 9 renal pelvis 13 11 10 abbreviations: sd, standard deviation; min, minimum; max, maximum; n, number; hu,hounsfield unit. group hb group lb group pa p operation time mean ± sd (min max) 63.6 ± 24.6 (35 – 120) 61.4 ± 17.8 (30 – 90) 74.8 ± 35.4 (30 – 165) 0.251 fluoroscopy time (second) 253.1 ± 157.5 (89 – 792) 251.8 ± 127.2 (92 – 580) 290.0 ± 195.6 (45 – 900) 0.702 creatinine change (mg/dl) 0 ± 0.2 (-0.3 – 0.3) 0 ± 0.2 (-0.3 – 0.4) 0 ± 0.2 (-0.5 – 0.2) 0.291 hemoglobine change (g/dl) -1.1 ± 1.0 (-4.0 – 0) -1.4 ± 0.9 (-3.1 – 0.6) -1.4 ± 1.3 (-5.3 – 0.1) 0.487 nephrostomy removal time (day) 3.0 ± 0.5 (2.0 – 4.0) 3.3 ± 0.5 (3.0 – 4.0) 3.3 ± 0.6 (3.0 – 5.0) 0.126 hospitalization time (day) 3.6 ± 0.8 (3.0 – 6.0) 3.9 ± 0.9 (3.0 – 7.0) 4.2 ± 1.1 (3.0 – 6.0) 0.090 abbreviations: sd, standard deviation; min, minimum; max, maximum. table 2. perioperative signs of the individuals in the groups bupivacain effect on percutaneous nephrolithotomy – dundar et al. endourology and stone diseases 307 vol 15 no 06 november-december 2018 308 outcome assessment postoperative pain levels at rest were assessed using the visual analogue scale (vas), and dynamic vas (dvas) was used to assess the level of pain during coughing and deep breathing. the patients were asked to evaluate their pain with vas and dvas under the supervision of our clinical nurses who were blind to the study. on a need-basis, the suitable analgesic was given to the patient in the following way: if the greater of the vas or dvas scores is higher than 4 (≥ 5), 1mg/kg tramadol (contramal; abdi i̇brahim, istanbul, turkey), and if it is lower than 5, 50 mg diklofenac (dikloron; deva, tekirdağ, turkey) were given. the maximum dosage was determined as 400 mg/day for tramadol and 150 mg/day for diclofenac. in addition to the patients’ sociodemographic information, localization of their stones, stone load, operation time, fluoroscopy duration, preoperative hemoglobin and creatinine values, and vas and dvas scores in the 2nd, 4th, 6th, 8th, 12th and 24th hours were recorded. time of the first analgesic use, analgesic requirement, amount of analgesics administered, and concomitant analgesic doses were also recorded. postoperative complications were assessed according to the modified clavien classification. the data obtained in our study were coded into the spss 22.00 software, and in the analysis of the data; when normal distribution assumptions were satisfied (kolmogorov-smirnov), for difference analyses, f test was used in variables with more than two groups and independent samples t-test was used for variables with two groups; when normal distribution assumptions were not satisfied, kruskal-wallis test was used in variables with more than two groups and mann-whitney test was used in variables with two groups. in the difference analyses of categorical variables, the chi-squared test of association was used. the statistical analyses were interpreted in a 95% confidence interval. results no significant differences were found in terms of age, bmi, stone size and placement among the 3 groups consisting of sixty patients including thirty-three men and twenty-seven women. table 1 shows the distribution and demographic data of the groups. the mean durations of operation for the groups were 63.6, 61.4 and 74.8 minutes respectively, while the mean fluoroscopy durations were calculated respectively as 253.1, 251.8 and 290 seconds. no significant differences were found among the groups in terms of operation and fluoroscopy group hb group lb group pa p vas2 mean ± sd (min max) 3.3 ± 3.0 (0 – 9) 4.5 ± 2.9 (0 – 10) 6.5 ± 2.8 (0 – 10) 0.004* vas4 mean ± sd (min max) 3.1 ± 3.0 (0 – 9) 3.2 ± 2.7 (0 – 10) 3.9 ± 2.3 (0 – 7) 0.567 vas6 mean ± sd (min max) 2.6 ± 2.5 (0 – 7) 2.8 ± 2.2 (0 – 8) 3.8 ± 3.0 (0 – 10) 0.327 vas8 mean ± sd (min max) 2.0 ± 1.7 (0 – 6) 2.2 ± 2.3 (0 – 9) 2.7 ± 2.6 (0 – 9) 0.810 vas12 mean ± sd (min max) 1.1 ± 1.0 (0 – 3) 1.7 ± 2.0 (0 – 8) 1.3 ± 1.3 (0 – 4) 0.795 vas24 mean ± sd (min max) 0.7 ± 0.7 (0 – 2) 1.0 ± 1.2 (0 – 4) 0.8 ± 1.2 (0 – 3) 0.626 dvas2 mean ± sd (min max) 3.9 ± 3.1 (0 – 9) 5.0 ± 2.9 (0 – 10) 7.3 ± 2.8 (0 – 10) 0.002* dvas4 mean ± sd (min max) 3.8 ± 3.3 (0 – 10) 3.9 ± 2.8 (0 – 10) 5.0 ± 2.4 (0 – 9) 0.273 dvas6 mean ± sd (min max) 3.3 ± 2.8 (0 – 8) 3.9 ± 2.3 (0 – 9) 4.7 ± 3.0 (1 – 10) 0.261 dvas8 mean ± sd (min max) 2.7 ± 1.9 (0 – 7) 3.1 ± 2.5 (0 – 10) 3.7 ± 2.5 (0 – 10) 0.437 dvas12 mean ± sd (min max) 1.8 ± 1.0 (0 – 4) 2.4 ± 2.1 (0 – 9) 2.4 ± 1.3 (0 – 5) 0.430 dvas24 mean ± sd (min max) 1.2 ± 1.1 (0 – 3) 1.6 ± 1.4 (0 – 4) 1.3 ± 1.6 (0 – 4) 0.679 table 3. vas and dvas values of the groups abbreviations: vasx, visual analogue scale score at time “x”; dvasx, dynamic visual analogue scale score at time “x”; sd, standard deviation; min, minimum; max, maximum; *p < 0,05, significant. figure 1. bupivacaine infiltration near the nephrostomy tract, into 4 quadrants (a: marking 4 quadrants around the renal capsule; b, c, d, e: 5ml bupivacaine infiltration into the quadrants; f: fixation of nephroureterostomy to the skin with no. 1 silk suture) bupivacain effect on percutaneous nephrolithotomy – dundar et al. durations (p > .05). while no difference was observed among the groups in preoperative and postoperative hemoglobin and serum creatinine values, removal of nephrostomy catheters and hospital discharge times were found similar. the perioperative data of the patients are summarized in table 2. when the pain levels of the patients were analyzed using vas and dvas in the 2nd, 4th, 6th, 8th, 12th and 24th hours, significant differences were found only in the values measured in the 2nd hour, and no significant difference was found in values measured at other times (table 3). the mean usage of diclofenac in case the greater of the vas and dvas scores was < 5 was found as 42.1, 37.5 and 35.0 mg respectively in the groups hb, lb and pa. in case the greater of the vas or dvas scores was ≥ 5, the mean tramadol usage was found 52.4, 83.6 and 100.6 mg in the groups. no significant difference was found between the diclofenac and tramadol usage amounts in the groups (respectively p = .543, p = .066). however, a statistically significant difference was found in the numbers of patients using tramadol among the groups (p = .029). while 17 patients in group pa and 16 in group lb needed analgesics to require tramadol, only 10 patients were given tramadol in group hb. in terms of analgesic implementation frequency and the time of applying the first analgesics, there was a significant difference (respectively p = .002, p = .033). in the subgroup analysis in terms of analgesic implementation frequency while differences were found between the groups hb and pa (p1-3 = .002) and the groups lb and pa (p2-3 = .009), no difference was found between the groups hb and lb (p1-2 = .640). in terms of the first time of analgesic implementation, there were differences between the groups hb and pa (p1-3 = .009) and the groups hb and lb (p1-2 = .047), but not between the groups lb and pa (p2-3 = .557) (table 4). comparison of postoperative complications in terms of the modified clavien classification between the groups did not indicate any significant difference (p > 0.05). group hb group lb group pa p analgesic implementation frequency mean ± sd (min max) 1.40 ± 0.82 (0 – 3) 1.60 ± 1.05 (0 – 4) 2.35 ± 0.88 (1 – 5) 0.002* first analgesic implementation time (min) mean ± sd (min max) 86 ± 98 (25 – 360) 44 ± 21 (20 – 100) 40 ± 18 (15 – 100) 0.033* table 4. analgesic implementation frequency and first analgesic implementation time (min) of the groups author anesthetic vas / dvas groups: (n) analgesic agent outcomes effect result year dose times applications ugras r 2, 6, 24 1: 30 ml r 16 metamizole vas 6 / pef 2, 6 : (+) 2007 (13) 0.02 % 2: 30 ml s 18 fat :(+) (+) taa : (+) aaf : (+) haleblian b 2, 4, 24, 48 1: 1.5 mg/kg b 10 narkotic vas : (-) (+/-) 2007 (14) 0.25 % 2: 60 ml s 12 taa : (-) jonnavithula b 2009 (15) 0.25 % 2, 4, 6, 8, 10, 12, 14, 1: 20 ml b 20 tramadol vas : (+) (+) 16, 18, 20, 22, 24 / same 2: none 20 fat : (+) taa : (+) aaf : (+) parikh b 0, 0.5, 1, 1.5, 2, 4, 6, 1: 20 ml b 30 tramadol fat : (+) (+) 2011 (16) 0.25 % 8, 12, 16, 20, 24 / same 2: 20 ml s 30 taa : (+) aaf : (+) parikh r 0, 0.5, 1, 1.5, 2, 4, 6, 8, 1: 10 ml r 30 tramadol vas : (+) (+) 2013 (17) 0.25 % 12, 16, 20, 24 / same 2: 10 ml s 30 fat : (+) taa : (+) aaf : (+) tüzel l 2, 4, 6, 8, 12, 24 1: 75 mg/30 ml l 23 meperidine vas : (-) (-) 2014 (18) 0.25 % 2: 30 ml s 23 fat : (+) taa : (-) am : (-) gokten l 6, 24 1: (sp) 20 ml s+p 20 meperidine vas : lp (+) 2011 (20) 0.25 % 2: (lp) 20 ml l+p 20 aaf : lp (+) levobupivakin + parasetamol 3: (ls) 20 ml l+s 20 mob : lp (+) (+) taa lp (+) parikh r 0.5, 1, 1.5, 2, 4, 6, 8, 1: (r) 20 ml r + 30 vas/dvas : rm (+) 2013 (21) 0.25 % 12, 16, 20, 24 / same 0.5 ml distile water tramadol fat : rm (+) ropivakain + morphine 2: (rm) 20 ml r + 30 aaf : rm (+) (+) 0.5 ml (5 mg) m taa : rm (+) nirmala b 4, 8, 12, 16, 20, 24 1: (b) 20 ml b 20 tramadol vas/dvas : bb (+) 2015 (22) 0.25 % 2: (bb) 20 ml b 20 aaf : bb (+) bupivacaine + buprenorphine + 100 µg b taa :bb (-) (+) abbreviations: b, bupivacaine; r, ropivacaine; l, levobupivacaine; s, salin; p, parasetamol; m, morphine; b, buprenorphine; taa, total analgesic amount; aaf, analgesic administration frequency; fat, first analgesic administration time; mob, mobilization; am, ambulation time; pef, peak expiratory flow; (+), effective; (-), not effective; (+/-), partially effective table 5. studies on activity of a local anesthetic agent in similarity to our study bupivacain effect on percutaneous nephrolithotomy – dundar et al. endourology and stone diseases 309 vol 15 no 06 november-december 2018 310 discussion postoperative pain is an outcome of the inflammation that occurs as a result of tissue damage, and management of this pain is a critical component of the operation(12). while narcotic analgesics are one of the main options for postoperative pain management, their usage for analgesia is limited after major surgical interventions due to their adverse effects. thus, narcotic analgesics that are accepted as a standard option in treatment of acute postoperative pain are now being replaced by the method of multimodal analgesia. with the help of this approach, synergic effects are obtained by the usage of different drugs that influence the central and peripheral nervous systems. additionally, lower amounts of side effects may be achieved in comparison to analgesia using a single agent(13). since ugras et al.’s(14) first analgesic application with ropivacaine in the percutaneous tract to our time, similar studies have been conducted with different local anesthetics. most of these studies investigated the activity of a single molecule(14-19). parikh et al. compared the activities of bupivacaine and ropivacaine in 2014(20). in addition to these, there are also studies that measured the activities of local anesthetic substances in combination of added molecules (such as paracetamol, morphine, buprenorphine)(21-23). a large part of the studies that involved administration of local anesthetic agents into the nephrostomy tract used the local anesthetic with long-lasting effects bupivacaine and its 0.25% concentration. while this molecule’s positive effects by administration into the percutaneous entrance pathway are known in general, its 0.5% form was not administered into the nephrostomy tract, and there is a dearth of data on which concentration is effective or if so, which is more effective. the studies in the literature investigating the activity of a local anesthetic agent are summarized in table 5. in a study where 0.02% ropivacaine was applied to the nephrostomy tract and the skin and methimazole was used as a recovery analgesic on 34 patients, in the group given local anesthesia, the vas values and total analgesic amounts were lower in the 6th hour, the first time of analgesia was later, and analgesia application frequency was lower. it was also asserted that parenteral methimazole administration in combination with ropivacaine application to the surgical area decreased postoperative pain and the amount of analgesics used, and additionally, it improved respiration by increasing peak expiratory flow(14). in another study, in a series of 22 patients where bupivacaine was applied to the postoperative nephrostomy tract, the vas values and total analgesic amounts did not differ in comparison to the control group, but there was a tendency found in the patients in the local anesthetic group in terms of lowered usage of narcotic anesthetics(15). in similar studies where 0.25% bupivacaine was administered to the nephrostomy tract in which recovery analgesia was achieved with 1 mg/ kg intravenous tramadol; in patients with bupivacaine administration, vas scores were lower, first analgesia time was later, total analgesics amount and analgesia frequency were lower(16,17). similar results were reached with 0.25% ropivacaine applied to the nephrostomy tract in combination with ultrasound(18). in another study with 46 patients investigating the activity of levobupivacaine where recovery analgesia was achieved with meperidine; the time of first analgesia was found to be later in comparison to the control group, no significant difference was found between the group in terms of vas scores, total analgesic amounts and ambulation time(19). among the 6 studies where local anesthetic agents were applied singly and analyzed for activity, 3 used bupivacaine, 2 used ropivacaine and 1 used levobupivacaine, while bupivacaine was always used in a concentration of 0.25%. the 2nd hour vas and dvas scores of the first group with 0.5% bupivacaine concentration and the second group with 0.25% bupivacaine concentration in our study were found significantly lower than those in the third group with no intervention. on the other hand, no significant differences were found among the groups in terms of vas and dvas scores measured after the 2nd hour. in addition to studies that showed local anesthetic substance infiltration into the pnl tract did not affect vas scores(15,19), there are also those that reported significant decreases in vas scores (16,18). in ugras et al.’s study, only the vas in the 6th hour was found significantly lower(14). in this study, the vas and dvas scores were mostly lower in the groups given bupivacaine, but the difference was statistically significant only in the vas scores measured in the 2nd hour. in most studies where a single local anesthetic substance is infiltrated into the nephrostomy tract, data were presented towards lowered total analgesics requirement(14,16-18). in two similar studies, no significant change was found in the total analgesic amounts used in the postoperative period as a result of local anesthetic infiltration(15,17). the difference among the groups in our study was found insignificant in terms of the amounts of diclofenac and tramadol used. what is noteworthy here is that diclofenac usage decreased and tramadol usage increased along the way from group hb to group pa. the patients given 0.5% bupivacaine infiltration required almost half of the tramadol given to the patients to whom no infiltration was given. additionally, there was a tendency for lower tramadol requirement for patients given the higher concentration of bupivacaine. another interesting issue in our study was that the difference among the groups in terms of the patients who required tramadol was found to be statistically significant. by giving bupivacaine in a concentration of 0.5%, fewer patients (17 versus 10 patients) needed narcotic analgesics. there are data suggesting that the first analgesic agent is administered in a later postoperative period with local anesthetic substance infiltration into the percutaneous tract (14,16-19). in this study, when bupivacaine was given in the concentration of 0.5%, the first analgesic administration time was found to be significantly later. however, when bupivacaine was given in the dosage of 0.25%, while this time was later than the control group (as in the dosage of 0.5%), the difference was not statistically significant. in a study that compared the administration of 0.25% bupivacaine and 0.25% ropivacaine into the nephrostomy tract with the guidance of ultrasonography, it was found that the vas scores in the 6th and 8th hours were significantly lower and the times of first analgesia were significantly later in the group given ropivacaine. while the total amount of analgesics and analgesia frequency were lower in the group given ropivacaine, the difference between this group and the group given bupivacaine was not found statistically significant (20). in addition to the infiltration of a local anesthetic agent bupivacain effect on percutaneous nephrolithotomy – dundar et al. into the percutaneous tract, studies where these are combined with different molecules also reported in general that vas and dvas scores were lower, the first time of analgesia was later, and the total analgesics amount and analgesia frequency were lower(21-23). there are also studies demonstrating that intercostal or paravertebral blockage with bupivacaine and thoracic paravertebral blockage with levobupivacaine applied for pain management after pnl increased patient satisfaction, decreased usage of narcotic analgesics, and achieved good perioperative analgesia with minimal side effects(24-26). the limitation of our study was that we included patients with single punctures with a single nephrostomy tube, thus being unable to evaluate the efficacy of our study when more than one puncture was involved. moreover, other long-acting agents with different doses would be likely to provide further benefit and should be evaluated. conclusions our study reached the conclusion that bupivacaine, which is a local anesthetic agent with long-lasting effects, decreased the pain scores only in the second postoperative hour. while no significant difference was found among the groups in terms of the total amount of analgesics used, there was a tendency to need lower amounts of narcotic analgesia in patients provided with the higher concentration of bupivacaine. the analgesic administration frequency was reduced significantly in both dosages of bupivacaine. moreover, with the 0.5% concentration of bupivacaine, fewer patients (50%) needed narcotic analgesia, and their first time of analgesia was found to be significantly later. in conclusion, administrating bupivacaine at a 0.5% rate around the nephrostomy tract immediately after surgery was demonstrated to be more effective than lower dose bupivacaine. acknowledgments we appreciate our statistician selim cam for his great contribution in analysis of the statistics. the authors also would like to thank dr. esat korgali and appreciate his support for the percutaneous procedures. conflict of interest the authors report no conflict of interest. references 1. smith lh. the medical aspects of urolithiasis: an overview. j urol. 1989 mar;141(3 pt 2):707-10. 2. sorokin i, mamoulakis c, miyazawa k, rodgers a, talati j, lotan y. epidemiology of stone disease across the world. world j urol. 2017 feb 17. 3. muslumanoglu ay, binbay m, yuruk e, et al. updated epidemiologic study of urolithiasis in turkey. i: changing characteristics of urolithiasis. urol res, ;39:309-14, 2011. 4. wein aj, kavoussi lr, novick ac, et al. chapter 47: percutaneous approaches to the upper urinary tract collecting system, campbell-walsh urology. elsevier saunders, philadelphia, 10th edition, 1324-56, 2012. 5. fernström i ve johanson b. percutaneous pyelolithotomy: a new extraction technique. scand j urol nephrol, 1976; 10:257-259. 6. lingeman je, newmark jr, wong myc. classification and management of staghorn calculi, smith ad (ed.) contoversies in endourology. wb saunders, philadelphia, p:136-144, 1995. 7. white pf, rawal s, latham p, et al. use of a continuous local anesthetic infusion for pain management after median sternotomy. anesthesiology, 2003; 99: 918–23. 8. kehlet h ve dahl jb. the value of multimodal or balanced analgesia in postoperative pain treatment. anesthesia analgesia, 1993; 77:1048–56. 9. kehlet h. controlling acute pain–role of preemptive analgesia, peripheral treatment and balanced analgesia and effects on outcome. pain 1999–an updated review, m mitchell. iasp pres, seattle, 1999; 459–62. 10. pinzur m, gupta p, pluth t. continuous postoperative infusion of a regional anesthetic after amputation of the lower extremity: a randomized clinical trial. j bone joint surg am, 1996; 78:1501–5. 11. miller, r. d. (2015). local anesthetics. in miller's anesthesia (8th ed.). philadelphia, pa: churchill livingstone/elsevier. pp. 1028–54. 12. barden j, derry s, mcquay hj, moore ra. single dose oral ketoprofen and dexketoprofen for acute postoperative pain in adults. cochrane database syst rev, 2009; 7:cd007355. 13. buvanendran a ve kroin js. multimodal analgesia for controlling acute postoperative pain. curr opin anaesthesiol, 2009; 22:588– 93. 14. ugras my, toprak hi, gunen h, yucel a, gunes a. instillation of skin, nephrostomy tract, and renal puncture site with ropivacaine decreases pain and improves ventilatory function after percutaneous nephrolithotomy. j endourol, 2007; 21:499-503. 15. haleblian ge, sur rl, albala dm, preminger gm. subcutaneous bupivacaine infiltration and postoperative pain perception after percutaneous nephrolithotomy. j urol, 2007;178(3 pt 1):925-8. 16. jonnavithula n, pisapati mv, durga p, krishnamurthy v, chilumu r, reddy b. efficacy of peritubal local anesthetic infiltration in alleviating postoperative pain in percutaneous nephrolithotomy. j endourol, 2009;23:857-60. 17. parikh gp, shah vr, modi mp, chauhan nc. the analgesic efficacy of peritubal infiltration of 0.25% bupivacaine in percutaneous nephrolithotomy a prospective randomized study. j anaesthesiol clin pharmacol, 2011;27:481-4. bupivacain effect on percutaneous nephrolithotomy – dundar et al. endourology and stone diseases 311 vol 15 no 06 november-december 2018 312 18. parikh gp, shah vr, vora ks, parikh bk, modi mp, panchal a. ultrasound guided peritubal infiltration of 0.25% ropivacaine for postoperative pain relief in percutaneous nephrolithotomy. middle east j anaesthesiol, 2013;22:149-54. 19. tüzel e, kızıltepe g, akdoğan b. the effect of local anesthetic infiltration around nephrostomy tract on postoperative pain control after percutaneous nephrolithotomy. urolithiasis, 2014; 42:353-8. 20. parikh gp, shah vr, vora ks, parikh bk, modi mp, kumari p. ultrasound guided peritubal infiltration of 0.25% bupivacaine versus 0.25% ropivacaine for postoperative pain relief after percutaneous nephrolithotomy: a prospective double blind randomized study. indian j anaesth, 2014; 58:293-7. 21. gokten oe, kilicarslan h, dogan hs, turker g, kordan y. efficacy of levobupivacaine infiltration to nephrosthomy tract in combination with intravenous paracetamol on postoperative analgesia in percutaneous nephrolithotomy patients. j endourol, 2011; 25:35-9. 22. parikh gp, shah vr, vora ks, modi mp, mehta t, sonde s. analgesic efficacy of peritubal infiltration of ropivacaine versus ropivacaine and morphine in percutaneous nephrolithotomy under ultrasonic guidance. saudi j anaesth, 2013; 7:118-21. 23. nirmala j, kumar a, devraj r, vidyasagar s, ramachandraiah g, murthy pv. role of buprenorphine in prolonging the duration of postoperative analgesia in percutaneous nephrolithotomy: comparison between bupivacaine versus bupivacaine and buprenorphine combination. indian j urol, 2015 ;31:132-5. 24. honey rj, ghiculete d, ray aa, pace kt. a randomized, double-blinded, placebocontrolled trial of intercostal nerve block after percutaneous nephrolithotomy. j endourol, 2013; 27:415-9. 25. ak k, gursoy s, duger c, et al. thoracic paravertebral block for postoperative pain management in percutaneous nephrolithotomy patients: a randomized controlled clinical trial. med princ pract, 2013; 22:229-33. 26. borle ap, chhabra a, subramaniam r, et al. analgesic efficacy of paravertebral bupivacaine during percutaneous nephrolithotomy: an observer blinded, randomized controlled trial. j endourol, 2014; 28:1085-90. bupivacain effect on percutaneous nephrolithotomy – dundar et al. 1 department of radiology, primary health care center "novi sad", novi sad 21000, serbia. 2 center of radiology, clinical center of vojvodina, novi sad 21000, serbia. 3 center for radiology, institute for pulmonary diseases of vojvodina, sremska kamenica 21208, serbia. *correspondence: department of radiology, primary health care center "novi sad", novi sad 21000, serbia. tel: +38 163 523767. e-mail: grujicnada@yahoo.com. received july 2015 & accepted february 2016 pictorial unilateral blind ending ureter with vesicoureteral reflux and associated renal agenesis -multidetector computed tomography imaging findings nada g. vasić,1* olivera nikolić,2 tatjana bošković3 a 50-year old woman was admitted to emergency room due to an episode of recurrent renal colic. double-j ureteral stent has been placed several weeks earlier due to mild hydronephrosis of the left kidney. she had a history of urinary tract infections and poorly defined abdominal pain. abdominal computed tomography (ct) scan revealed normal left kidney and normal left urinary tract without calculi, presence of double-j ureteral stent and absent right kidney (figure 1 coronal multiplanar reformatted image). excretory phase of ct scan showed retrograde opacification of distal, blind-ending, nondilatated, nonobstructed right ureteral stump. visualized structures suggested remnant of the incompletely developed right ureteral bud, with normal position of the right ureteral orifice (figure 2a, coronal curved-planar reformatted and figure 1. abdominal computed tomography scan (coronal multiplanar reformatted image) shows normal left kidney and normal left urinary tract without calculi, presence of double-j ureteral stent and absent right kidney. figure 2. excretory phase of computed tomography scan demonstrates retrograde opacification of distal, blind-ending, nondilatated, nonobstructed right ureteral stump. visualized structures suggested remnant of the incompletely developed right ureteral bud, with normal position of the right ureteral orifice. a) coronal curved-planar reformatted; b) volume-rendered image. case report 2657 vol 13 no 02 march-april 2016 2658 figure 2b, volume-rendered image). most blind-ending ureters are detected incidentally and are clinically insignificant.(1) in some cases, though, they may induce recurrent urinary tract infections, renal colic or poorly defined abdominal pain due to presented vesicoureteral reflux.(2) presence of calculi in blind ending urethral bud has been described with the patient having overactive bladder syndrome and dyspareunia.(3) conflict of interest none declared. references 1. floyd ms jr, scally j, irwin pp. incidental detection of a unilateral dilated blind-ending ureter, renal agenesis, and a dilated seminal vesicle. urol j. 2012;9:639. 2. rathi v. a blind-ending ureter with infection due to vesicoureteric reflux with associated renal agenesis: a rare cause of pain abdomen. urol ann. 2011;3:100-2. 3. wiedemann a, kociszewski j, gumprich t, füsgen i. calculi in a blindly ending ureteric bud an unusual cause for an overactive bladder syndrome and dyspareunia. aktuel urol. 2011;42:193-6. unilateral blind ending ureter and renal agenesis-vasić et al. outcome of percutaneous nephrolithotomy in patients with spinal cord neuropathy heshmatollah sofimajidpour,1* pooya kolahghochi,2 fardin gharibi3 purpose: to investigate technical problems, complications and stone clearance rate in patients with spinal neuropathy who had undergone percutaneous nephrolithotomy. materials and methods: this cross-sectional study was done between 2004 and 2013 on 29 patients with both spinal cord neuropathy and kidney stones who were chosen for percutaneous nephrolithotomy in sanandaj city, iran. the data were obtained from patients’ medical records and were documented in a researcher-made checklist. absolute and relative frequency, mean and standard deviation were calculated. results: a total of 43 percutaneous nephrolithotomies were performed on 32 kidneys. in 51.7% the right kidney, in 37.9% the left kidney and in three patients (10.3%) both kidneys were involved. there were 24 patients (82.8%) with spinal cord injury. five patients (17.2%) had spina bifida. the mean of operation time was 129.7 minutes and the mean of hospital stay was 8.3 ± 3.1 days. the mean of kidney stone size was 35.7 ± 6.1 mm (25 to 45 mm). in 58.5% of the patients, surgery lasted more than two hours. stone clearance rates were 53.1% and 78.1% after the first and second percutaneous nephrolithotomy. conclusion: although patients with spinal cord injury have problems in terms of surgery and complications, percutaneous nephrolithotomy is an appropriate and safe treatment method for their kidney stones. pre-operative counseling with a radiologist and an anesthesiologist is recommended. keywords: kidney calculi/surgery; nephrostomy, percutaneous/adverse effects; postoperative complications/etiology; spinal cord injuries; spinal dysraphism; treatment outcome. introduction patients with spinal cord injury are at higher risk of obtaining kidney stones. studies have shown that the prevalence of urinary stones in this group of patients is about 7% and recurrence rate after treatment is about 77%. spinal cord injuries (traumatic or non-traumatic) because of urinary tract nervous system dysfunction result in numerous problems in this system. urinary stasis, infection, immobility, chronic catheterization, and vesicoureteral reflux are associated with stone formation. despite major improvements in stone treatment, urinary stones treatment in this group of patients has remained a challenge.(1-3) effective stone treatment is very important, because the presence of stones is associated with decreasing kidney function.(4) in the past decades extracorporeal shock wave lithotripsy (swl), with its low morbidity and improved stone clearance rates, has been a valid option for treating stones in patients with spinal cord injury.(3) however, the required positioning for swl and its initial insufficiency as a treatment means that there are a number of patients who need percutaneous nephrolithotomy (pcnl). furthermore, previous studies have shown that pcnl can be safely done in high risk patients.(5) pcnl was first done in 1973 in sweden as a less invasive alternative to open surgery on the kidneys.(6) then it replaced open surgery for the treatment of patients with large and complex kidney stones. because of the complexity of patients with spinal neuropathy, pcnl has more complications in these patients compared to the general population.(1) although there are limited reliable data on pcnl mortality and morbidity in patients with spinal neuropathy, it still has a higher risk in these patients. in a study by culkin and colleagues, 8.5% major complications were recorded after surgery for 23 men with spinal cord injury who had underwent pcnl.(7) pcnl is generally a safe treatment method and is associated with a low but specific complication rate.(8) many complications develop from the initial puncture including injury of the surrounding organs such as colon, spleen, liver, pleura, and lung. other specific complications include postoperative bleeding and fever.(9) fever is a common postoperative complication of pcnl 1 department of urology, school of medicine, kurdistan university of medical sciences, sanandaj, iran. 2 school of medicine, kurdistan university of medical sciences, sanandaj, iran. 3 tohid hospital, kurdistan university of medical sciences, sanandaj, iran. *correspondence: tohid hospital, basij sq., geryashan boulevard, sanandaj, iran. tel: +98 873 3282772. fax: +98 873 3282772. e-mail: hsmajidpour@gmail.com. endourology and stone diseases vol 13 no 03 may-june 2016 2672 nal deformity. percutaneous puncture and dilation of the tract was done by an urologist surgeon. contrast material was given through the ureter catheter and an 18-gauge needle was used to puncture the collecting system. a super stiff guide wire 0.038 inch was placed down the needle and the tract was dilated up to 30f by one shout amplatz dilators. the access sheet was then placed. a lithoclast® lithotripter was used to fragment the stones. at the end of the procedure, a 20f foley catheter was used as nephrostomy tube. all patients were evaluated on the first day after surgery with a kub and kidney ultrasound. we had defined success by complete absence of stones or presence of insignificant fragments less than 4 mm. if patients were stone free, the nephrostomy tube was taken out. if there were significant residual stones, nephrostomy tube was kept in place for the second pcnl. the second pcnl procedure was scheduled within two weeks after the first pcnl. all patients were evaluated in terms of stone clearance and intra-operative and post-operative complications. final treatment success was defined as being stone free on non-contrast computed tomography at the six months follow-up. nephrostomy tube was used for all patients and was only removed when a nephrostogram showed clear and free drainage of the operated system three days after surgery. urinary leakage was seen in five patients after removing the nephrostomy tube. this was stopped with conservative therapy after 7-10 days. in 11 patients nephrostomy tube was kept for two weeks due to residual stones and they were prepared for the second pcnl. statistical analysis data were analyzed by statistical package for social sciences (spss) software version 18 (chicago, il, usa) and described by descriptive statistics including absolute and relative frequency, mean and standard deviation. results among 29 patients with spinal cord injury who had underwent pcnl in this study, 12 (41.4%) were men and 17 (58.6%) were women. the mean age was 45.45 ± 13.7 years old (age range of 32 to 68 years old). the mean of operation time was 129.7 minutes (range of 45 to 190 minutes). in 51.7% the right kidney, in 37.9% the left kidney and in three patients (10.3%) both kidneys were involved. there were 24 patients (82.8%) with spinal cord injury, two of whom were paraplegic. in 58.5% of the patients, surgery lasted more than two hours. with 10.8% overall incidence. bleeding during pcnl is generally common but is rarely substantial to require transfusion.(10) given the importance of treatment and management of urolithiasis in patients with spinal neuropathy, the aim of this study was to investigate technical problems, complications and stone clearance rate in patients with spinal neuropathy who had underwent pcnl in a hospital in sanandaj city, iran, from 2004 until 2013. materials and methods this cross-sectional study was done on 29 patients with spinal cord neuropathy and kidney stones who were chosen for pcnl from 2004 until 2013 in tohid hospital of sanandaj city. patients with spinal cord neuropathy and kidney stone larger than 2 cm who had shown stone resistance to swl were included in this study. data including laboratory test results, counseling, treatment progress, physician’s order, imaging data relating to kidney lithiasis and surgery sheets were obtained from patients` medical records and documented in a researcher-made checklist. preoperative considerations urine cultures were obtained from patients before surgery. all of them had bacteriuria and were admitted one day before the surgery. an appropriate antibiotic was used before the procedure. voiding dysfunction due to neurogenic bladder in our patients was managed by clean intermittent catheterization for 16 patients, indwelling catheterization for six patients and diversion with conduit for seven patients. twelve patients had severe scoliosis. this anatomical deformity caused several problems in positioning. all patients underwent preoperative upper tract imaging (kidney ultrasound, intravenous urography, and non-contrast computed tomography). stone size was determined by measuring the greatest length of the stone on kidneys, ureters, and bladder (kub) and computed tomography. in case of multiple stones, stone burden was determined by adding the sizes of all the stones. surgical technique all pcnl procedures were done by a single surgeon in our department. under general anesthesia in lithotomy position, a rigid ureteroscope was inserted and a 5 french (f) ureteric catheter was advanced up to the renal pelvic. the ureteric catheter was fixed to a 16f foley catheter. the patient was then turned to the prone position. the choice of tract site was determined by biplanar fluoroscopic guidance at 0 and 30 degrees primarily by stone location, stone burden, and the presence of spipcnl in spinal cord neuropathy-sofimajidpour et al. endourology and stone diseases 2673 the mean of hospital stay was 8.3 ± 3.1 days (range of 3 to 14 days). from 32 kidneys which underwent pcnl, the hospital stay of eight cases was more than 10 days because of respiratory complications and severe infection. the mean of kidney stone size was 35.7 ± 6.1 mm (range of 25 to 45 mm). of the 32 kidneys, seven had only one stone, 17 had multiple stones, and eight had complete staghorn. the stone clearance rates were 53.1% after the first pcnl and 78.1% after the second pcnl. complications were urosepsis, significant hemorrhage that required blood transfusion, visceral injury (pneumothorax), intensive care unit stay, and fever. nephrostomy drainage lasted 7 to 10 days in five cases. mortality rate was zero. 34.37% of cases had post-operative fever with temperature higher than 38.5 degrees centigrade (table). discussion risk factors for urolithiasis in patients with spinal cord dysfunction are recurrent urinary tract infections secondary to urinary stasis or catheterization and hypercalciuria associated with prolonged immobility. in a study by hall and colleagues the association between the presence of chronic indwelling foley catheter and the development of bladder and kidney stones has been confirmed.(11) because of the mentioned problems, many patients with spinal cord dysfunction are at risk of stone formation. urinary stone occurs more often during the first two years after spinal cord injury, especially during the first six months.(12) in a cohort study there was a significantly greater risk of kidney stones in people older than 45 years old within the first year after spinal cord injury.(13) after the diagnosis of urinary stones, choosing an appropriate treatment method in patients with spinal cord dysfunction is challenging. kidney’s anatomic abnormalities, chronic urinary tract infections, decreased pulmonary capacity, and morbidity due to movement restrictions should be considered for selecting a treatment method. urinary tract infections in patients with spinal cord injury develop as a result of neurogenic bladder and the need for catheterization. pathogenetic factors include bladder over-distention, vesicoureteral reflux, high-pressure voiding, large post-voiding residual volume, stones in the urinary tract, and outlet obstruction. (14) open surgery was the only method for treating kidney stones in patients with spinal cord injury for a long time. when swl was introduced, it seemed that an effective and safe method for the treatment of these patients has become available. but the success of swl in patients with spinal cord dysfunction and multiple stones was not acceptable. difficulty in positioning, movement restrictions, as well as anatomical disorders in these patients affected the success rate of swl. although swl is well tolerated in these patients, the clearance of stones is poor and delayed.(15) with the development of pcnl a new hope flourished to cure these patients. pcnl is still the standard treatment for stones larger than 2 cm.(16) it can also be used in patients with body and musculoskeletal abnormalities. urolithiasis management is challenging in spinal cord injury patients due to anatomic variations and cardio-respiratory dysfunction.(17) we evaluated the effect of 32 pcnl procedures on 29 patients in our study. in our study mean of operation time was 129.7 minutes while in a study by hubsher and costa it was 150 minutes.(18) reasons such as the condition of patients with spinal cord injury and urologist’s skill during surgery can reduce the surgery length. additionally, because of anatomical disorders, positioning limitations, severe lower limbs spasm, presence of screws and plates of previous surgeries and severe scoliosis, the access time is long in these patients. in our study, duration of the first puncture with needle until onset of nephroscopy was almost 13 minutes. considering multiple and sporadic stones, accessing calyces with rigid nephroscope is difficult and time-consuming, prolonging the operation time. we used rigid nephroscope for our patients. stone clearance rates were 53.1% and 78.1% after the first and second pcnl. in case of bleeding and pulmonary problems, the operation was ended based on an anesthesiologist’s advice. in a study by nabbout and colleagues after the first pcnl, stone clearance rate was 53.8%. also kidney stone removal success rate for the treatment of upper urinary tract stones in patients with spinal cord injuries was 88.5% with an average two procedures per stone.(1) in symons and colleagues’ study this was 62%.(2) in a study by culkin and colleagues stone removal rate was 53.6% with one procedure and 90.4% with an average of 1.67 procedures per stone.(19) table. the frequency of complications in our studied patients. variables number % blood transfusion 7 21.8 visceral injury 2 6.25 icu stay 7 21.8 urosepsis 6 18.75 fever 11 34.37 abbreviation: icu, intensive care unit. pcnl in spinal cord neuropathy-sofimajidpour et al. vol 13 no 03 may-june 2016 2674 these authors in their next study have reported the low rate of stone removal for patients with spinal cord injuries.(7) donnellan and bolton have reported 84% stone removal rate with an average of 1.3 procedures for each stone.(20) stone removal success rate with pcnl was 81% in a study by lawrentschuk and colleagues(3) and 96% in a study by rubenstein and colleagues.(5) major complications in patients with spinal cord dysfunction are bleeding, urosepsis, urine leakage, pulmonary problems, and post-operative fever. in our study, six cases (18.75%) had urosepsis. they were hospitalized in the intensive care unit and broad spectrum antibiotics were administered for them. they also received pulmonary support and sufficient hydration. all patients had positive urine culture before the operation. they were hospitalized 1-3 days before the operation and broad spectrum antibiotics were administered for them. the operation was done under antibiotic therapy; hence their urine culture was positive after the operation too. then they stayed in the hospital for 5-14 days to remove infectious symptoms. perhaps this was the reason for the increase in hospital stay in our study (8.3 ± 3.1 days). in a study by nabbout and colleagues the rate of adverse events was 14.3% and three patients had urinary tract infection.(1) lawrentschuk and colleagues had reported 12% adverse effects in their study.(3) this has been 17% and 20% in other studies.(7,19) in a study by symons and colleagues, nine patients had experienced minor complications such as fever, hypotension and leakage from the nephrostomy site.(2) in our study, 21.8% of the patients needed blood transfusion. the frequency of blood transfusion in previous studies was 28.6%(1) and 21%(3,21) which are similar to our study. inflammation can lead to activation of the coagulation system. as a response to severe infection or trauma, acute inflammation results in a systemic activation of the coagulation system.(5) bleeding in these patients may be due to chronic infection of the urinary tract which causes chronic inflammation and eventually blood coagulation disorders. conclusions kidney stone surgery in patients with spinal cord injury is quite challenging. although pcnl has technical difficulties and major complications in these patients, it is an appropriate and safe method for their kidney stone treatment. pre-operative counseling with an anesthesiologist, a radiologist, and even an infectious disease specialist is recommended. acknowledgements the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. conflict of interest none declared. references 1. nabbout p, slobodov g, mellis a, culkin dj. percutaneous nephrolithotomy in spinal cord neuropathy patients: a single institution experience. j endourol. 2012;26:1610-3. 2. symons s, biyani cs, bhargava s, et al. challenge of percutaneous nephrolithotomy in patients with spinal neuropathy. int j urol. 2006;13:874-9. 3. lawrentschuk n, pan d, grills r, et al. outcome from percutaneous nephrolithotomy in patients with spinal cord injury, using a single-stage dilator for access. bju int. 2005;96:379-84. 4. sekar p, wallace dd, waites kb, et al. comparison of long-term renal function after spinal cord injury using different urinary management methods. arch phys med rehabil. 1997;78:992-7. 5. rubenstein jn, gonzalez cm, blunt lw, clemens jq, nadler rb. safety and efficacy of percutaneous nephrolithotomy in patients with neurogenic bladder dysfunction. urology. 2004;63:636-40. 6. fernström i, johansson b. percutaneous pyelolithotomy: a new extraction technique. scand j urol nephrol. 1976;10:257-9. 7. culkin dj, wheeler js, nemchausky ba, et al. percutaneous nephrolithotomy: spinal cord injury vs. ambulatory patients. j am paraplegia soc. 1990;13:4-6. 8. rudnick dm, stoller ml. complications of percutaneous nephrostolithotomy. can j urol. 1999;6:872-5. 9. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. european urol. 2007;51:899-906. 10. seitz c, desai m, häcker a, et al. incidence, prevention, and management of complications following percutaneous nephrolitholapaxy. eur urol. 2012;61:146-58. 11. hall mk, hackler rh, zampieri ta, zampieri jb. renal calculi in spinal cord injured patient: association with reflux, bladder stones and foley catheter drainage. urology. 1989;34:126-8. 12. ku jh, jung ty, lee jk, park wh, shim hb. risk factors for urinary stone formation in men with spinal cord injury: a 17-year follow-up study. bju int. 2006;97:790-3. 13. chen y, devivo mj, roseman jm. current pcnl in spinal cord neuropathy-sofimajidpour et al. endourology and stone diseases 2675 trend and risk factors for kidney stones in persons with spinal cord injury: a longitudinal study. spinal cord. 2000;38:346-53. 14. cardenas dd, hooton tm. urinary tract infection in persons with spinal cord injury. arch phys med rehab. 1995;76:272-80. 15. adams jr, wheeler js, culkin dj. extracorporeal shock wave lithotripsy in patients with spinal cord dysfunction. j endourol. 2009;4:217–21. 16. li jx, xiao b, hu wg, zhang x, chen s. semi-rigid nephroscope: the future of pcnl? european urol suppl. 2015;14:e592– e592a. 17. chan g and dormans jp. update on congenital spinal deformities: preoperative evaluation. spine. 2009;34:1766-74. 18. hubsher cp, costa j. percutaneous intervention of large bladder calculi in neuropathic voiding dysfunction. int braz j urol. 2011;37:636-41. 19. culkin dj, wheeler js jr, nemchausky ba, fruin rc, canning jr. percutaneous nephrolithotomy in the spinal cord injury population. j urol. 1986;136:1181–3. 20. donnellan sm, bolton dm. the impact of contemporary bladder management techniques on struvite calculi associated with spinal cord injury. bju int. 1999;84:280-5. 21. maheshwari pn, oswal at, bansal m. percutaneous cystolithotomy for vesical calculi: a better approach. tech urol. 1999;5:40-2. pcnl in spinal cord neuropathy-sofimajidpour et al. vol 13 no 03 may-june 2016 2676 female urology the efficacy and safety of intravesical bacillus-calmetteguerin in the treatment of female patients with interstitial cystitis: a double-blinded prospective placebo controlled study irani d, heidari m, khezri aa faghihi hospital, shiraz university of medical sciences, shiraz, iran abstract purpose: to evaluate the efficacy and safety of intravesical bacillus calmette-gurein injection in the treatment of female patients with interstitial cystitis. materials and methods: thirty women meeting the national institute of arthritis, diabetes, digestive and kidney diseases criteria for interstitial cystitis, were randomized in a double-blinded fashion in two groups each consisted of 15 patients to receive six, weekly instillation of 120 mg bcg vaccine of iranian institute of pastor or placebo. periodic questionnaires on symptoms of interstitial cystitis, voiding diaries, bladder capacity at first desire to void, and maximum bladder capacity were obtained. adverse events were closely monitored during the treatment and follow-up phases of the study. subjective and objective baseline values were compared with the follow-up data. results: with a mean follow-up of 24 (range 6 to 33) months 11 out of 15 (73%) in bcg group, and 3 out of 15 (20%) in placebo group responded to the treatment (p<0.002). responders were defined the patients with more than 40% improvement in the symptoms of interstitial cystitis. the global improvement in symptoms and signs of interstitial cystitis was 62%. adverse events were similar in both groups, mostly irritative in nature and no significant systemic event was noted. bcg did not worsen interstitial cystitis symptoms. conclusion: we concluded that intravesical bcg is safe, effective, available, and inexpensive with relatively durable results in the treatment of interstitial cystitis. key words: interstitial cystitis, bcg vaccine, immunotherapy 27 urology journal unrc/iua vol. 2, 27-30 spring 2004 printed in iran introduction interstitiad cystitis is a chronic disabling disease presenting with irritative symptoms, pain, and sterile urine. it was described for the first time by hunner in 1915.(1) although near a hundred years have been passed form then, the etiology and definite treatment is unknown. a series of various causes have been suggested including mast cell related inflammation, infection, and immunologic system alteration.(1) zeidman et al reported the experience of effective bacillus calmette-guerin (bcg) intravesical installation in 1994. they selected five patients with resistant interstitial cystitis as candidates for a 6-week therapy with intravesical installation of bcg and observed significant improvement in bladder capacity (p=0.027), daytime frequency (p=0.013), nocturnal frequency (p=0.019), and pain and bladder discomfort (p=0.031).(2) zeidman's interest was attracted accepted for publication in august 2003 the efficacy and safety of intravesical bacillus-calmette-guerin in the treatment of female patients with interstitial cystitis: a doubleblinded prospective placebo to bcg when he found that its installation into bladders with suspected tumors led to improvement of symptoms which were later defined to be due to interstitial cystitis.(2,3) bcg vaccine is fda approved and produced by pastor institute in iran with a low cost and acceptable availability; thus we decided to try the efficacy and safety of bcg vaccine on interstitial cystitis in the patients referred to educational medical centers of shiraz university of medical sciences. materials and methods this study was designed as a double-blinded randomized controlled trial at shiraz university of medical sciences' hospitals to be done from january 1999 to september 2002. thirty patients who met niddk diagnostic criteria were selected from among 150 females with irritative symptoms and bladder pain, after performing cystoscopy under anesthesia, bladder hydrodistention, and other preliminary evaluations. they were randomly assigned into the study and control groups, each containing 15 patients, based on the prediction of 15% response to the treatment vs. 20% response in the control group, the study power of 80%, and error of 5%.(2-5) the excluding criteria were immunocompromising conditions, steroids, warfarin, or immunosuppressant administration, pregnancy, vesicoureteral reflux, a history of interavesical installation in the last 3 months, positive hiv serology, positive cutaneous ppd, and males due to the risk of catheterization.(3,4) primary evaluations consisted of history and physical examination, complete blood count, biochemical hiv selorogic test, cutaneous ppd test, chest x-ray, cystography, cystoscopy, bladder hydrodistension, and bladder capacity measurement. bladder biopsy would be done if tumor was suspected or in some particular conditions. a general questionnaire was filled before and after (during the study) the intervention in which vaginal or urethral pain, pelvic pain, painful intercourse, urgency, dysuria, feeling of healthy, sleep status, life quality,(6) and validated questions of viscontin university about interstitial cystitis symptoms,(7) day time urination profile, the average volume of the bladder that induces fullness, and the average tolerable urine volume were included. also, patients with involuntary contraction of the bladder or the ones responded to anticolinergic medications were excluded in this study. routine cystometrography was not performed in all the patients in order to minimize the research costs and physicians' intervention. thirty patients who had positive hydrodistension and glomerulization in more than 75% of bladder mocusa under general anesthesia and met the niddk criteria for interstitial cystitis, were randomly assigned into two groups each contained 15 patients. they received intravesical installation of 120 mg of bcg vaccine or 50 cc of normal saline (as placebo) through foley catheter for six weeks. vials of placebo with similar appearance were produced. consecutive cases were selected to received either the placebo or bcg, vials nominated blindly as drugs a and b. the staff who were involved with the therapy were blind to the drugs type and nominating the drugs and listing the patients were done by a third person not enrolled in the study. in case of severe fever or a serious complication the patient would be excluded from the blind procedure to be treated for bcg complications. the patients were informed about the details of placebo controlled design of the study and their written consent was taken before the study. also charges were omitted. they were asked to maintain the solution in the bladder for two hours and change the position every 15 minutes. in case of inconvenience the bladder would be emptied temporarily and the contents would be installed again. an emergency telephone number was available to contact if any probable complications occurred over the first three days of treatment. follow-up after 1,2,3, and 6 months was done when the 6-week therapy period finished. the last follow-up was performed at least six months later. the study remained double-blinded until the end of the follow-up. the comparison of the symptoms and signs before and after the treatment was done preceding the revealing of the groups. according to parson, over 40% improvement of valid scores of wisconsin university for interstitial cystitis were considered as response to the treatment. this was selected as a criterion to evaluate other symptoms.(8) patients were asked to show the severity of the symptoms before and after the treatment on a graded 10 cm rulers. statistic analysis was done by mann-whitney u signed rank test using spss software. 28 the efficacy and safety of intravesical bacillus-calmette-guerin in the treatment of female patients with interstitial cystitis: a doubleblinded prospective placebo results demographic characteristics of the two group were similar with no significant statistic difference. these parameters are demonstrated in table 1. changes in primary symptoms and signs were evaluated during 1,2,3, and 6 months follow-ups. eleven out of 15 patients who received bcg vaccine (73%, p<0.002) responded to the treatment, compared to 3 out of 15 in the control group (20%, p<0.05). the mean two year follow-up showed that of 11 patients improved with bcg installation 7 (63.6%) did not required any excessive therapy in order to control the symptoms. the overall improvement was 62% (p<0.05). frequency and nocturia reduced by 33.5% and 40%, respectively, in the bcg group, while no considerable change was observed in the control group. some of the other symptoms and signs in bcg group vs. control group improved as follows: dysuria 75% vs. 42%, urgency 42% vs. 24.3%, painful coitus 61% vs. 13.4%, pelvic pain 65% vs. 22%, appropriate sleep 63% vs. 17%, and feeling healthy 51% vs. 18%. improvement of valid scores of wisconsin university for interstitial cystitis was achieved 56% vs. 16.5%. life quality (fs 36) increased by 63% vs. 16%. mean bladder capacity at the first feeling of fullness increased approximately by 27 cc (47%) vs. 7 cc (9.6%). maximum tolerable volume increased by a mean of 53 cc (70%) in bcg group compared to 13 cc (21%) in control group. differences between the two group and p values are presented in tables 2 and 3. analysis of the results in the control group did not reveal any statistically meaningful changes in symptoms and signs of interstitial cystitis neither before the study, nor during or after then (p>0.1). no complication interrupted the double-blinded design of the study and all patients were cooperative and with high compliance. discussion bcg vaccine has been used widespread in bladder cancer for 20 years. the first investigation was reported in 1970 showing its efficacy in the treatment of bladder tumors.(9,10) although bcg therapeutic mechanism is still unknown, mediating and adjusting the immune system has been suggested. as a whole its efficacy has been proved by peter and it is easy to administer.(3,4,11) 29 table 1. the comparison of symptoms and signs of the patients receive bcg and placebo variable bcg group placebo group p value patients 15 15 1 age (year) 40.8±13.96 36±12.84 0.529 disease (year) 9.4±5.98 6.8±5.5 0.315 urination per day (times) 14.6±4.35 12.7±5.25 0.218 urination per night (centimeter) 4.9±1.19 4.2±1.31 0.218 urgency (centimeter) 5.45±1.11 5.6±1.14 0.315 dysuria (centimeter) 5.56±1.1 5.51±1.16 0.971 painful intercourse (centimeter) 5.32±0.93 4.89±0.9 0.393 pelvic pain (centimeter) 4.88±1.2 4.76±0.95 0.853 valid scores of wisconsin university for interstitial cystitis (no.) 31.2±8.5 25.4±6.7 0.105 feeling well (centimeter) 4.66±8.5 4.98±0.95 0.393 sleep (centimeter) 4.7±1.3 4.5±1 0.393 bladder volume in the first feeling of urination (cc) 57±243.52 62.2±27.61 0.796 maximum tolerable bladder capacity (cc) 187±81.79 183±61.1 0.796 score of 36 graded questions of life quality (no.) 53±4.3 54±3.75 0.165 table 2. the comparison of symptoms and signs of the patients enrolled in bcg and placebo groups 24 months after the treatment variable bcg group placebo group p value interstitial cystitis validated score of the university of viscontine (no.) 16.6±11.45 21.2±7.69 0.143 urination per day (times) 9.7±4.39 12.2±3.55 0.123 urination per night (centimeter) 2.9±1.91 3.9±1.52 0.19 dysuria (centimeter) 2.59±2.31 5.16±1.22 0.015 urgency (centimeter) 3.39±2.23 4.74±1.3 0.165 painful intercourse (centimeter) 2.59±1.86 4.23±1.46 0.009 pelvic pain (centimeter) 2.32±2.15 4.61±0.99 0.015 sleep (centimeter) 2.3±1.4 4.2±0.7 0.016 feeling well (centimeter) 2.27±2 4.49±0.83 0.019 bladder volume in the first feeling of urination (cc) 85±35.35 68.5±27.6 0.529 maximum tolerable bladder capacity (cc) 240.5±93.7 196.5±61.8 0.165 score of 36 graded questions of life quality (no.) 31.2±8.05 57.6±8.15 0.001 table 3. mean differences in the symptoms between the two groups after 24 months variable mean±sd p value interstitial cystitis validated score of the university of viscontine (no.) 9.4±8.59 0.003 urination per day (times) 2.7±3.18 0.001 urination per night (centimeter) 1.15±1.59 0.023 dysuria (centimeter) 1.66±1.79 0.002 urgency (centimeter) 1.23±1.49 0.002 painful intercourse (centimeter) 1.94±1.76 0.001 pelvic pain (centimeter) 1.35±1.40 0.002 feeling well (centimeter) 1.39±1.40 0.015 bladder volume in the first feeling of urination (cc) 16.7±15.06 0.002 maximum tolerable bladder capacity (cc) -35.25±28.75 0.001 score of 36 graded questions of life quality (no.) -14.9±14.73 0.0001 the efficacy and safety of intravesical bacillus-calmette-guerin in the treatment of female patients with interstitial cystitis: a doubleblinded prospective placebo why bcg vaccine is effective in interstitial cystitis? bcg is a strong stimulator of the immune system and some evidence indicate that interstitial cystitis is an autoimmune disease.(11-19) presence of abnormal hla in bladder mucosa provides this fact. it seems that a type of immune reaction occurring in the bladder wall causes increased activity of type ii t helper cells compared to type is, leading to tissue injury. bcg vaccine induces the activity of type i t helper cells, so that it regulates the adjustment of type ii ones and protection of the tissues.(12,18) these patients have interleukin-6 in their urine, six times as much as normal individuals and the severity of the disease is directly related to the amount of il-6. bcg vaccine can reduce il-6.(17-19) interstitial cystitis is associated with low amounts of nitric oxide (no) in the urine and bcg is a strong stimulator of no secretion in the urine, so that it may have a role in the treatment.(20) eventually, bcg may lower the sensitivity of sensory neuron fibers and consequently reduce pain and increase urinary reservoir.(3,4) sixty two percent of our respective patients responded to bcg installation that is comparable with zeidman findings (75%) and peter's studies (60% and 70%).(2-4) in this study patients who had a bladder capacity of lower than 250 cc under general anesthesia and severe symptoms, did not respond to the treatment properly. however, bcg installation did not yield any case of aggravating symptoms. conclusion this study showed that intravesical injection of bcg vaccine is an effective, safe, and cost-effective treatment of interstitial cystitis which is easily available and durable. references 1. hunner gl. a rare type of bladder ulcer in women: report of cases. boston med surg j 1915; 172: 660-664. 2. zeidman ej, helfrick b, pollard c, et al. bacillus calmette-guerin immunotherapy for refractory interstitial cystitis. urology 1994; 43: 121-124. 3. peters k, diokno a, steninerd b, et al. the efficacy of intrvesical tice strain bcg in the treatment of interstitial cystitis: a double-blind, prospective, placebo controlled trial. j urol 1997; 157: 2090-2994. 4. peters km, diokno ac, steninerd b, et al. the efficacy of intrvesical tice strain bcg in the treatment of interstitial cystitis. long-term follow up. j urol 1997; 159: 1483-1487. 5. gillenwater jy, wein a j. summary of the national institute of arthritis, diabetes, digestive and kidney diseases workshop on interstitial cystitis. j urol 1988; 140: 203-206. 6. ware je, sherbourne cd. the mos 36 item short-from health survey (sf 36): i. conceptual framework and item selection. med care 1992; 30: 473-476. 7. keller ml, mccarthty do, neider rs. measurement of symptoms of interstitial cystitis. urol clin n amer 1994; 21: 67-70. 8. parsons cl, benson g, childs s, et al. a quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosan polysulfate. j urol 1993; 150: 845-848. 9. morales a, eidinger d, bruce aw. intracavitary bcg in the treatment of superficial bladder tumors. j urol 1976; 116: 180-190. 10. akaza h, hinotsu s. bcg in treatment of existing papillary bladder cancer and carcinoma in situ of the bladder. four year results. the bladder cancer bcg study group. cancer 1995; 75: 552-555. 11. liebert m, wedemeyer g, stein ja. evidence of urothelial cell activaton in interstitial cystitis. j urol 1993; 149: 470475. 12. christmas tj, bottazzo gf. abnormal urothelial hla-dr expression in interstitial cystitis. clin exp immunol 1992; 87: 450-454. 13. silk mr. bladder antibodies in interstitial cystitis. j urol 1970; 103: 307-309. 14. joustra b, karrenbeld a, mensink h. specific autoantibodies in interstitial cystitis patients suggest an autoimmune etiology. j urol 1996; (part 2) 155: 431 aabstract 483. 15. keay s, zhang co, trifillis al. urine autoantibodres in interstitial cystitis. j urol 1997; 157: 1083-1087. 16. ochs ri, muro y, chan ekl. autoantibadies to dfs70 in patients with interstitial cystitis or ectopic dermatitis (abstract). international research symposium on interstitial cystitis, washington dc; 1997. p. 80. 17. mosmann tr, moore kw. the role of il10 in the cross regulation of th1 and th2 responses. immunol today 1997; 12: a 49. 18. bohle a, nowc ch, ulmer aj, et al. elevation of cytokines il1, il2 and tnf in the urine of patient after bcg immunotherapy. j urol 1990; 144: 59-62. 19. erickson dr. urine marker of interstitial cystitis. urol 2001; 57: 15-21. 20. smith sd, wheeler ma, foster he, et al. improvement in interstitial cystitis symptom scores during treatment with oral 1argentine. j urol 1997; 158: 703-707. 30 bolus injection versus infusion of furosemide in kidney transplantation: a randomized clinical trial afshar zomorrodi1, hassan mohammadipoor anvari 2*, farzad kakaei3, farzin solymanzadeh1, esmaeil khanlari1, amin bagheri1 purpose: furosemide is commonly administered to increase the urinary output in patients with transplanted kidneys. this study compared the two administration routes of furosemide (bolus versus infusion) in kidney transplanted patients. materials and methods: fifty patients who had undergone kidney transplantation in 2015 in a hospital in tabriz, iran, were included in this clinical trial. they were divided into two groups: bolus (120 mg stat) and infusion (4 mg/ minute) groups. the primary outcome was urine onset time. secondary outcomes were urine output volume, vital signs (blood pressure, heart rate), and electrolyte level (creatinine, blood urea nitrogen, sodium and potassium). after arterial and venous anastomoses, arterial clamp removal time and diuresis onset were recorded. finally, the urinary output volumes of both groups were measured with regular urine bags for an hour after anastomosis. then it was repeated each three hours for 24 hours, and eventually two and three days thereafter. finally, all data were statistically analyzed. results: around 72% of the patients were men (mean age of 37.15 ± 14.67 years). urine output was higher in bolus group but it was not statistically significant. diuresis duration was measured after arterial declamping and its averages were 5.41 ± 3.7 minutes and 9.36 ± 7.65 minutes in bolus and infusion groups, respectively (p = .040). furosemide bolus injection and infusion had no significant effect on creatinine, blood urea nitrogen, sodium and potassium. conclusion: furosemide bolus injection can reduce diuresis onset time compared to furosemide infusion. keywords: clinical trial; furosemide; infusion; kidney transplantation; loop diuretic. introduction kidney transplantation is the last stage of kidney failure treatment with a more favorable lifestyle results and a reduction in mortality rate. the main drawback of kidney transplantation is its rejection. here, the acute transplantation rejection is the most important predictor. the transplanted kidney will have a good long-term prognosis if it has a proper function from the beginning.(1-3) an important and fundamental issue regarding this procedure is the diuresis initiation. currently, high dosages of diuretics are being used for speeding up the diuresis initiation. the longer it takes to initiate diuresis, further complications, such as fluid retention, pulmonary edema, and even acute kidney failure might occur.(3) administration of mannitol is a commonly used method to precipitate diuresis initiation. mannitol is a major protective osmotic agent in kidney preservation.(4) sufficient hydration during kidney transplantation is very important and the kidney requires sufficient perfusion for its maximum function. there is a relationship between kidney transplantation and acute tubular necrosis occurrence.(3) thus, the strategy for preventing acute tubular necrosis includes limiting the extent and duration of kidney ischemia and establishing and preserving the abundant intravascular volume to reduce the incidence of acute tubular necrosis.(5) overhydration and diuretics, such as furosemide, have positive effects on reducing kidney transplant rejection. diuresis initiation time is important for transplanted kidney’s survival. a transplanted kidney with a good function from the beginning has a good long-term prognosis. thus, this study has compared the effect of bolus injection versus infusion of furosemide on diuresis initiation time of patients who had received kidney transplantation. materials and methods written informed consent was obtained from them before their participation in the study. the inclusion criteria were: 1) having an end-stage kidney disease and being a kidney transplant candidate; 2) having blood pressure more than 100/60 mmhg at the start of surgery; and 3) not having a systematic disease (except for end-stage kidney disease). the exclusion criteria were: 1) being older than 65 years; 2) having metastatic tu1department of urology, emam reza hospital, tabriz university of medical sciences, tabriz, iran. 2department of anesthesiology, emam reza hospital, tabriz university of medical sciences, tabriz, iran. 3department of surgery, emam reza hospital, tabriz university of medical sciences, tabriz, iran. *correspondence: mahan building, twenty-meter third eastern, paradise alley, street elgoli, tabriz, iran. postal code: 5167935731. tel: +98 41 34 78 2216. fax: +98 41 33 35 2073. mobile: +98 918 811 2210. email: hmohammadipour@yahoo.com. received december 2016 & accepted january 2017 kidney transplantation vol 14 no 02 march-april 2017 3013 mors; 3) having sever homeostatic alterations during transplantation (blood pressure less than 80/50 mmhg for more than half an hour); 4) presence of chronic hepatic disease; 5) urinary tract infections; 6) urinary tract anomalies; and 7) aortoiliac diseases. study design the participants were divided into two groups, i.e. bolus and infusion groups, using the simple randomization, according to the codes assigned to each group by minitab software. then, the codes were categorized and the patients were divided accordingly. in the bolus group, 120 mg of bolus furosemide was administered within one minute immediately before arterial declamping. in the infusion group, the infusion dosage began with 4 mg/min thirty minutes before declamping and continued afterwards. all participants received dialysis 24 hours before surgery. biochemical tests for sodium, potassium, urea, and creatinine were performed. personal characteristics, including age, sex, and body weight, were recorded. all open nephrectomy procedures were done on living donors by the same expert surgeon and all transplant recipients were operated by the same surgery team. in all cases, kidney veins were anastomosed to external iliac veins and arteries were anastomosed to the internal iliac arteries. throughout the procedure, systolic blood pressure was preserved in the range of 120-140 mmhg. central venous pressures were maintained within 10-12 and 14-16 cmh2o before and after arterial clamping, respectively. blood transfusion was done as needed based on hemoglobin and hematocrit levels. following arterial and venous anastomoses, the arterial clamp removal time and diuresis onset were recorded. finally, urinary output volumes were measured for an hour after anastomosis. then it was repeated each three hours for 24 hours, and eventually two and three days thereafter. in addition, the levels of sodium, potassium, blood urea nitrogen, and creatinine were recorded preoperatively and then daily for four days after the surgery. outcome assessment the primary outcome was urine onset time. therefore, when the arterial blood declamping was established, the patient's urine was measured in minutes. secondary outcomes included volume of urine output, vital signs (blood pressure, heart rate), and electrolyte level (creatinine, blood urea nitrogen, sodium and potassium). statistical analysis statistical differences were presented as mean ± standard deviation. data analysis was done using statistical package for the social sciences (spss) software version 16.0 (chicago, il, usa). numerical variables were compared by independent samples t-test. categorical variables were compared by chi square or fisher’s exact tests as appropriate. results a number of 50 patients who received kidney transplantation participated in this clinical trial (25 participants in each group, figure 1). their mean ages were 32.96 ± 1.48 and 40.2 ± 10.68 years old in bolus and infusion groups, respectively (p = .084). the surgery duration was 4.16 hours in bolus group and 4.19 hours table 1. patients' demographic information. bolus group infusion group variables frequency % frequency % p value age (years old) < 20 8 32 1 4 .076 21-30 3 12 3 12 31-40 7 28 11 44 > 40 7 28 10 40 sex male 21 84 15 60 .052 female 4 16 10 40 past medical history htn yes 13 52 15 60 .0569 no 12 48 10 40 dm yes 6 24 4 16 .149 no 19 76 21 84 seizure yes 0 0 2 8 no 25 100 23 92 surgery duration (hours) 3-3.9 6 24 10 40 .322 4-4.9 13 52 8 32 5-5.9 6 24 7 7 abbreviations: htn, hypertension; dm, diabetes mellitus bolus injection versus infusion of furosemide in transplantation-zomorrodi et al. kidney transplantation 3014 in infusion group (p = .879, table 1). there was no significant difference between the two groups regarding heart rate and systolic and diastolic blood pressures before and 120 minutes after anesthesia induction (table 2). diuresis duration was measured after arterial declamping. its averages were 5.41 ± 3.7 minutes and 9.36 ± 7.65 minutes in bolus and infusion groups (p = .040). there was no significant difference between the two groups in terms of urinary output since the arterial anastomosis until four days after it, postoperatively table 2. heart rate, systolic and diastolic blood pressure of patients before induction and during surgery heart rate systolic blood pressure diastolic blood pressure time (minutes) study groups mean sd p value mean sd p value mean sd p value before induction bolus 84.25 15.81 .125 151 17.4 .117 91.7 13 0.76 infusion 80.69 23.34 140.6 26.5 85.47 18.3 0-15 bolus 83.08 17.75 .419 136.8 22.4 .59 85.7 15.8 .120 infusion 79.54 11.68 125 16.4 79.6 14.8 16-30 bolus 78.08 15.02 .497 138.2 19.2 .052 89.5 14 .102 infusion 80.83 12.7 128.7 13 84.8 12.2 31-45 bolus 79 16.77 .678 127.1 13.9 .875 75.8 13.1 .685 infusion 80.08 14.19 126.4 16.7 77.2 10.7 46-60 bolus 86.5 19.21 .395 130.3 14.9 .134 75.3 9.5 .770 infusion 82.16 15.54 123.4 16.4 77.2 11.9 61-75 bolus 90.39 17.55 .580 131.3 14.7 .300 75.3 9.8 .451 infusion 87.6 16.27 126.7 14.7 74.4 10.7 76-90 bolus 91.78 17.69 .727 131.9 10.1 .212 74.6 11.2 .959 infusion 93.7 16.15 127 14.2 74.8 8.6 91-105 bolus 88.5 17.38 .218 135 12.2 .818 76.8 11.2 .230 infusion 95.29 15.96 136.1 17.8 81.2 11.1 106-120 bolus 89.47 19.87 14.03 133.1 11.9 .433 75.8 13.7 .206 infusion 95 14.03 139 24.8 82.2 13.6 figure 1. patients' flow diagram bolus injection versus infusion of furosemide in transplantation-zomorrodi et al. vol 14 no 02 march-april 2017 3015 (table 3). furthermore, there was no significant difference in electrolyte levels before and four days after the surgery between both groups (table 4). discussion in human kidney transplantation, attaining good immediate homograft function is an important factor for its ultimate success. when this is achieved, there will be massive postoperative diuresis along with improvement in the patient’s general condition.(6) one way to trigger diuresis is using diuretics such as furosemide. most of the participants of our study were men in their fourth decades of lives. in similar studies the majority of patients have been men with the age range of 30-40 years old.(7,8) this is the range in which the person is actively present in the society and kidney transplantation can significantly impact his/her life quality. in this study, it was observed that the bolus injection of furosemide increased the urinary output in kidney transplanted patients, but it was not statistically significant. however, the diuresis initiation time reduced table 3: urine output of the patients since arterial anastomosis up to four days after the surgery time study groups mean sd p value anastomosis or one hour after surgery bolus 568 322.06 .811 infusion 542.8 412.31 2-3 hours after surgery bolus 1924 1131.1 .118 infusion 1472 818.13 4-6 hours after surgery bolus 3086 1127 .151 infusion 2682.25 776.1 7-9 hours after surgery bolus 3186 466.2 .100 infusion 2597.91 588.3 10-12 hours after surgery bolus 2558 831.6 .154 infusion 2264.58 553.9 2nd day after surgery bolus 11883.6 6522.7 .871 infusion 1211875 2794 3rd day after surgery bolus 7594 2986 .776 infusion 7816 2429.7 4th day after surgery bolus 5224 1821.4 .798 infusion 5335.83 1119 creatinine urea nitrogen sodium potassium time study groups mean p value mean p value mean p value mean p value preoperative bolus 6.93 .207 94.69 .210 137.18 .132 4.91 .154 infusion 7.86 115 139.72 4.43 surgery day bolus 4.95 .944 75.5 .577 136.6 .122 4.58 .217 infusion 4.99 82.7 139.37 4.2 1st day after surgery bolus 3.3 .337 65.88 .334 138.76 .769 4.13 .641 infusion 3.22 77.65 139.16 4 2nd day after surgery bolus 1.47 .146 62.64 .953 138.72 .721 3.96 .841 infusion 1.79 61.91 138.12 3.92 3rd day after surgery bolus 1.31 .061 62.6 .597 138.5 .971 4.14 .209 infusion 1.75 56.87 138.54 3.77 4th day after surgery bolus 1.55 .920 64.56 .396 139.52 .244 4.57 .244 infusion 1.6 55.04 132.65 3.99 table 4. patients’ electrolyte level before and four days after the surgery bolus injection versus infusion of furosemide in transplantation-zomorrodi et al. kidney transplantation 3016 significantly. in a study by lachance and colleagues the urinary output was 2.2 liters per day in patients who had received furosemide and 1 liter per day in their control group (who had not received furosemide) (p < 0.05). so, furosemide had increased the urinary output.(9) razzaghi and colleagues reported that urine outputs were significantly higher in one, four, and 24 hours after transplantation in lidocaine receiving group than furosemide receiving group (p < .001). in a meta-analysis, alqahtani and colleagues found that in eight examined cases, there was no significant difference in urinary output of patients who had received furosemide by bolus or infusion. but in eight other cases, the urinary output was significantly higher in patients who had received continuous furosemide than in those who had received furosemide frequently.(11) we did not find any other similar studies in the literature. so, most studies support the furosemide bolus administration. this method, in comparison with infusion method, was able to further precipitate the diuresis onset. in our study, no significant difference was observed in the levels of sodium, potassium, blood urea nitrogen, and creatinine between the two studied groups. lachance and colleagues reported that furosemide significantly reduced creatinine level in kidney transplanted patients compared to their control group (who had not received furosemide).(9) in razzaghi and colleagues’ study, which compared the continuous injection versus bolus administration of furosemide in patients with heart failure, it was observed that furosemide injection increased creatinine level in the bolus group by 0.8 mg/ dl and decreased it in the infusion group by 0.8 mg/dl (p < .001). in addition, the level of glomerular filtration rate decreased by 9 ml/min/1.73 m2 in their bolus group and was increased by 6 ml/min/1.73 m2 in their infusion group (p < .05).(10) in palazzuoli and colleagues’ study, it was observed that patients who had received continuous dosages of furosemide had higher serum creatinine level and lower glomerular filtration rate compared to those who received bolus dosages. furosemide can contribute considerably to electrolyte excretion and serum creatinine level reduction by increasing glomerular filtration rate. (12) in our study, furosemide administration method did not change electrolyte level. a limitation of our study was lack of a control group to measure the amount of urine output without receiving furosemide. conclusions bolus injection of furosemide can reduce diuresis onset time compared to furosemide infusion. acknowledgements this study is based on a thesis of tabriz university of medical sciences. the authors would like to thank hassan soleimanpour for the preparing this manuscript. also, they would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. conflict of interest none declared. references 1. tanabe k, takahashi k, toma h. causes of long-term graft failure in renal transplantation. world j urol. 1996; 14: 230-5. 2. humar a, johnson em, payne wd, wrenshall l, sutherland de, najarian js, et al. effect of initial slow graft function on renal allograft rejection and survival. clin transplant. 1997;11:623-7. 3. mojtahedzadeh m, salehifar e, vazin a, mahidiani h, najafi a, tavakoli m, et al. comparison of hemodynamic and biochemical effects of furosemide by continuous infusion and intermittent bolus in critically ill patients. j infus nurs. 2004;27:255-61. 4. andrews pm, cooper m, verbesey j, ghasemian s, rogalsky d, moody p, et al. mannitol infusion within 15 min of cross-clamp improves living donor kidney preservation. transplantation. 2014;98:893-7. 5. karlberg i, nyberg g. cost-effectiveness studies of renal transplantation. int j techno assess health care. 1995;11:611-22. 6. starzl te, marchioro tl, holmes jh, waddell wr. the incidence, cause, and significance of immediate and delayed oliguria or anuria after human renal transplantation. surg gynecol obstet. 1964;118:819-27. 7. hosseinzadeh h, golzari se, abravesh m, mahmoodpoor a, aghamohammadi d, zomorrodi a, et al. postnephrectomy changes in doppler indexes of remnant kidney in unrelated kidney donors. urol j. 2009;6:1948. 8. zomorrodi a, bohluli a, tarzamany mk. evaluation of blood flow in allograft renal arteries anastomosed with two different techniques. saudi j kidney dis transpl 2008;19:26-31. 9. lachance sl, barry jm. effect of furosemide on dialysis requirement following cadaveric kidney transplantation, j urol. 1985;133:9501. 10. razzaghi mr, heidari f. a comparative study on the effect of lidocaine and furosemide on urinary output and graft function after renal transplantation. urol j. 2004;1:256-8. 11. alqahtani f, koulouridis i, susantitaphong p, dahal k, jaber b. a meta-analysis of continuous vs intermittent infusion of loop diuretics in hospitalized patients. j crit care. 2014;29:10-7. 12. palazzuoli a, pellegrini m, ruocco g, martini g. continuous versus bolus intermittent loop diuretic infusion in acutely decompensated heart failure: a prospective randomized trial. crit care. 2014;18:134. vol 14 no 02 march-april 2017 3017 bolus injection versus infusion of furosemide in transplantation-zomorrodi et al. laparoscopic urology laparoscopic pyelolithotomy in children less than two years old with large renal stones: initial series mohammad hossein soltani,* nasser simforoosh, akbar nouralizadeh, mehdi sotoudeh, mohammad javad mollakoochakian, hamidreza shemshaki purpose: treatment of pediatric urolithiasis is still on debate. this study was designed to evaluate the safety and efficacy of laparoscopic pyelolithotomy in five children less than two years old. materials and methods: five children (less than two years old) with large kidney stones underwent laparoscopic pyelolithotomy. all patients underwent laparoscopic pyelolithotomy via a transperitoneal approach. after medial mobilization of colon and once renal pelvis and ureteropelvic junction were exposed, a longitudinal or circular incision was made on the renal pelvis, depending on the location and shape of the stone. stones were extracted using an endobag. demographic data, size of stones, operation time, duration of hospital stay and stone free rate were assessed. results: four boys and a one girl were included in this study. the mean age of patients was 17.6 (range: 13-22) months and the mean duration of operation was 130 (range: 115-145) minutes. the mean size of stone was 24.6 (range: 22-27) mm and the mean duration of hospital stay was 4.4 (range: 4-5) days. stone free rate was 100%. there was no major complication. conclusion: even with a small number of patients, our results seem to show that laparoscopic pyelolithotomy could be a treatment option for selected cases of young pediatric cases with large renal stones. we believe that transperitoneal laparoscopic pyelolithotomy is feasible and it introduces a novel approach for managing kidney stones in pediatric population. keywords: children; laparoscopic pyelolithotomy; urolithiasis. introduction pediatric urinary tract calculi, although relatively un-common in comparison to adult stone disease, pose a significant challenge in view of the smaller size of the urinary tract and a greater risk of stone recurrence, due to higher incidence of metabolic causes and longer risk period, especially in the presence of residual calculi. although, there is a paucity of epidemiologic data, but the review of different studies reveals increasing incidence(1). shock wave lithotripsy (swl) is currently the procedure of choice for treating most urinary stones in children. however, it is not so effective in stones greater than 1.5 cm and stones with cystine components(2). the safety and efficacy of percutaneous nephrolithotomy (pcnl) for large stone burdens have been well established in adults but regarding parenchymal damage and the associated effects on renal function, radiation exposure with fluoroscopy, and the risks of major complications including sepsis and bleeding, performing pcnl in children is on debate(3). ureteroscopy was not considered primary option for managing of upper tract stones in children due to concern for ureteral ischemia, perforation, stricture formation, and development of vesicoureteral reflux as a result of dilatation of small caliber ureteral orifices(4). so, treatment of large stone burdens in children is a major challenge among urologists. recently, laparoscopy and robotic-assisted laparoscopy were performed in children in small series and successful transperitoneal laparoscopic pyelolithotomy (lp) has been described in eight children who previously failed pcnl with no noted major complications(5). however, the children range of age in this study was 3 to 10 years and it is obvious the function, size and accessibility of kidney in children vary with their age. as our knowledge there is no study to evaluate laparoscopic pyelolithotomy in children less than two years old. therefore, this study was designed to evaluate the efficacy and safety of laparoscopic pyelolithotomy in five children less than two years old with large cystine renal stones. materials and methods this study reports on children less than two years old with large renal pelvic stone with extra-renal pelvis and no previous history of open stone surgery or pcnl. endourology department of shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences (sbmu), tehran, i.r. iran. *correspondence: endourology department of shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences (sbmu), tehran, i.r. iran. tel: 0098 21 22588016 mhsoltani60@gmail.com. received may 2016 & accepted july 2016 laparoscopic urology 2837 surgical method lp was performed under general anesthesia in modified lateral decubitus position. first, a 5 mm port was fixed at the umbilicus using open access approach. then three 5 mm ports were inserted at sub xiphoid, 2 cm medial of anterior superior iliac spine and para rectal region parallel to the umbilicus under direct vision. all patients underwent lp via a transperitoneal approach. after medial mobilization of colon and once renal pelvis and ureteropelvic junction were exposed, a longitudinal or circular incision was made on the renal pelvis, depending on the location and shape of renal stone. stones were extracted using an endobag. a double-j stent was passed through renal pelvis to the bladder. finally, pelvis was closed using a 4-0 absorbable polyglactine suture in an interrupted fashion. we removed foley catheter three days after operation on a regular basis. drain was removed when its daily output reached lower than 25 ml. double-j stent was also removed 4 weeks later and under general anesthesia. the study design was approved by the ethics committee of iranian urology and nephrology research center. results four boys and one girl were included in this study. the mean of age was 17.6 (range: 13-22) months and the mean duration of operation was 130 (range: 115-145) minutes. the mean size of renal stone was 24.6 (range: 22-27) mm and the mean duration of hospital stay was 4.4 (range: 4-5) days. stone free rate was 100%. all cases were free of stone after mean one year follow up period. the first case was a 20 month-old boy, a known case of tetralogy of falot. this case presented with gross hematuria and right flank pain. he had history of right open stone surgery 10 months ago at another center. ultrasonography revealed a 27 mm stone at right kidney with bilateral hydroureteronephrosis. time of surgery was 145 minutes. he had a fever < 38.5 c for two days that was managed with conservative treatments. hospitalization time was 5 days. the second case was a 22 month-old boy who underwent lp because of a 25 mm stone at right renal pelvis. he had a history of two episodes of unsuccessful eswl. ultrasonography showed normal appearance of both kidneys. time of surgery was 130 minutes and hospital stay was 4 days. the third patient was a 13 month-old girl presented with a 24 mm stone in left renal pelvis, 11 mm stone at middle part of the right ureter, a 6 mm stone at middle calyx of right kidney and grade one hydronephrosis at this side in computed tomography scan. she had no previous history of renal stone interventions. right transureteral lithotripsy was not successful for managing of the 11 mm stone at right ureter; so, right laparoscopic ureterolithotomy was done and one month later, left renal stone was extracted using left lp. operative time was 140 minutes and no postoperative adverse events were seen. hospitalization duration was 4 days. ureteral stents in both sides were removed at one session. patient number four was a 15 months old boy with previous history of neurogenic bladder and bilateral grade iii vesicoureteral reflux. ultrasonography and ct scan revealed moderate hydronephrosis and a 22*14 mm stone at ureteropelvic junction level at right side and two large stones with diameter of 20 and 23 mm in the bladder (figures 1 and 2). in past medical history the patient only had history of club foot. at first, the patient underwent percutaneous cystolitholapexy for removal of bladder stones and then underwent left laparoscopic pyelolithotomy two weeks later. duration of surgery was 115 minutes. after surgery, ileus and abdominal distention happened for two days that was managed with conservative treatment. hospital stay was 5 days. the last patient was an 18 month-old boy that was referred to our clinic from pediatrics nephrology clinic with chief compliant of bilateral kidney stones. he had no history of pcnl, eswl or other stone surgeries. in sonography he had 2.5 cm stone at left ureteropelvic junction and numerous stones at middle and lower calices of right kidney (figure 3). at first, the patient underwent left laparoscopic pyelolithotomy and stent insertion. duration of surgery was 120 minutes. no fever or other adverse effects happened after surgery. hospitalization time for him was 4 days. after three weeks, he underwent pcnl for contralateral side and the left side stent was removed. figure 4 reveals the cosmetic appearance of the abdomen one month after operation. laparoscopic pyelolithotomy in young children-soltani et al. figure 1: ct scan revealed moderate hydronephrosis and a 22*14 mm stone at ureteropelvic junction level at right side figure 2: two large stones with diameters of 20 and 23 mm in the bladder. vol 13 no 05 september-october 2016 2838 no major peri and postoperative complications occurred and no blood transfusion was done in all cases. discussion treatment of large stone burdens in children is technically challenging and often requiring multiple procedures. the universal principles of surgical treatment of stone disease entail: preservation of renal function, maximal stone clearance and minimal patient morbidity. with the current array of minimally invasive techniques available at the disposal of the urologist, the challenge lies in selecting the most appropriate treatment modality and using it judiciously, keeping in mind the small size of the urinary tract in children. the role of laparoscopic surgery in management of renal calculi is still in a state of evolution. although, laparoscopic pyelolithotomy takes a longer time to perform, requires considerable skill and has a steeper learning curve compared to pcnl but nonparenchymal damage, similar hospital stay and similar stone-free rates are the advantages(6-8). while, there is lack of data to compare pcnl versus laparoscopic pyelolithotomy in children, laparoscopy and robotic-assisted laparoscopy have been utilized successfully in adults for treatment of calculi. small series utilizing these techniques in children have only recently been described and showed safe and effective alternative to open stone surgery. in the first report of robotic-assisted laparoscopic pyelolithotomy, lee et al(9). described their experience in five patients; four with cystine staghorn calculi refractory to pcnl and swl and one with calcium oxalate calculi and concurrent ureteropelvic junction obstruction. of these cases, four were completed robotically, with one patient having a residual 6 mm lower pole stone and one patient required conversion to an open procedure. mean operative time in this series was 315 minutes and the mean estimated blood loss was 19.0 ml. these early experiences demonstrate that laparoscopic pyelolithotomy is feasible, safe, and efficacious as an alternative to open pyelolithotomy in children. our results confirmed their findings; however, more future studies should be designed, especially in lower age range. gaur et al(7). successfully performed retroperitoneal laparoscopic ureterolithotomy in five patients with calculi impacted in the upper and middle ureter. interestingly, all the patients were discharged after 24h. casale et al(5). evaluated transperitoneal laparoscopic pyelolithotomy in eight children (mean age: four years) with a mean stone burden of 2.9 cm and showed 100% success rate, a mean hospital stay of 2.15 days, and a mean operative time of 1.6 hours with no major complications. likewise, agrawa and their colleagues(10) revealed the feasibility and safety of laparoscopy for managing of pediatric renal and ureteric stones. they performed 22 procedures including 12 pyelolithotomies and 10 ureterolithotomies with 95% stone free rate and 13.5% complication rate [urinoma (4.54%), failure (4.54%) and omental prolapse (4.54%)]. our study showed acceptable efficacy and safety for laparoscopic pyelolithotomy in children less than two years old with large renal stones. the strongest advantage of our study is that all our cases were less than two years old. so we could better evaluate the efficacy and safety of this surgical approach in pediatric urolithiasis. however, more comparative studies with large sample size and longer follow-up are warranted to lighten the role of this treatment in managing of pediatric nephrolithiasis. conclusions even with a small number of patients, our results seem to show that laparoscopic pyelolithotomy should be a treatment option. we believe that transperitoneal laparoscopic pyelolithotomy is feasible and it introduces a novel approach complex stone pediatric population. conflict of interest the authors declare that they have no conflict of interest. references 1. van dervoort k, wiesen j, frank r, et al. laparoscopic pyelolithotomy in young children-soltani et al. figure 3. a 2.5 cm stone at left ureteropelvic junction and numerous stones at middle and lower calices of the right kidney. figure 4. one month after the operation. laparoscopic urology 2839 urolithiasis in pediatric patients: a single center study of incidence, clinical presentation and outcome. j urol. 2007; 177:2300–5. 2. slavkovic a, radovanovic m, siric z, vlajkovic m, stefanovic v. extracorporeal shock wave lithotripsy for cystine urolithiasis in children: outcome and complications. int urol nephrol 2002;34:457-61. 3. samad l, aquil s, zaidi z. paediatric percutaneous nephrolithotomy: setting new frontiers. bju int 2006;97:359-63. 4. smaldone mc, gayed ba, ost mc. the evolution of the endourologic management of pediatric stone disease. indian j urol 2009;25:302-11. 5. casale p, grady rw, joyner bd, zeltser is, kuo rl, mitchell me. transperitoneal laparoscopic pyelolithotomy after failed percutaneous access in the pediatric patient. j urol 2004;172:680-3. 6. goel a, hemal ak. evaluation of role of retroperitoneoscopic pyelolithotomy and its comparison with percutaneous nephrolithotripsy. int urol nephrol 2003;35:73-6. 7. gaur dd, agarwal dk, purohit kc, darshane as. retroperitoneal laparoscopic pyelolithotomy. j urol 1994;151:927-9. 8. gaur dd, trivedi s, prabhudesai mr, gopichand m. retroperitoneal laparoscopic pyelolithotomy for staghorn stones. j laparoendosc adv surg tech 2002;12:299303. 9. lee rs, passerotti cc, cendron m, estrada cr, borer jg, peters ca. early results of robot assisted laparoscopic lithotomy in adolescents. j urol 2007;177:2306-9. 10. agrawal v1, bajaj j, acharya h, chanchalani r, raina vk, sharma d.laparoscopic management of pediatric renal and ureteric stones. j pediatr urol. 2013; 9:230-3. laparoscopic pyelolithotomy in young children-soltani et al. vol 13 no 05 september-october 2016 2840 urological oncology predictors of urinary continence recovery after modified radical prostatectomy for clinically high-risk prostate cancer guo-liang hou*, yun luo*, jin-ming di, li lu, yi yang, jun pang, jie si-tu, xin gao** purpose: to retrospectively determine predictors of urinary continence (uc) recovery in clinically high-risk prostate cancer (pca) patients treated with modified radical prostatectomy (rp). materials and methods: a total of 184 patients with clinically high-risk pca who underwent modified rp in a single chinese center were retrospectively reviewed. pelvic floor muscle training with biofeedback was routinely performed after catheter removal. uc was defined as wearing 0 or 1 protective pad daily. univariate and multivariate cox regression analyses were performed to determine the predictors of uc recovery. results: the median age at surgery was 69.5 years (range 48-82), and the median follow-up duration was 40 months (range 12-111). only 40 patients (21.7%) received a nerve-sparing procedure. for patients with restored uc, the median time to continence was 1 month (range 1-24). uc recovery at 1 month, 6 months, 12 months and the most recent follow-up was observed in 99 (53.8%), 158 (85.9%), 171 (92.9%) and 174 (94.6%) patients, respectively. multivariate cox regression analysis showed that patient age < 70 years (hazard ratio 1.684, p = .003) and smaller prostate volume (hazard ratio 0.989, p = .036), but not the surgical approach or treatment with a nerve-sparing procedure, independently predicted uc recovery. conclusion: age < 70 years and smaller prostate volume were independent predictors of uc recovery in clinically high-risk pca patients. the adverse factors of high-risk disease were not significantly associated with uc recovery. these results may help surgeons preoperatively counsel patients regarding expected uc outcomes following rp. keywords: prostatectomy; methods; recovery of function; postoperative complications; treatment outcome; urinary incontinence. introduction prostate cancer (pca) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death among men in western countries. (1) traditionally, china has been considered as one of the lowest ranking nations with respect to pca occurrence. however, the incidence of pca in china has increased dramatically over the past two decades.(2) because prostatespecific antigen (psa) screening was not performed routinely, most patients have presented with advanced tumors with nodal involvement and/or metastases.(3) the optimal treatment for patients with clinically high-risk pca remains under debate. however, surgical treatment has become increasingly popular, and some recent studies demonstrated more favorable oncological and functional results for radical prostatectomy (rp) than for external beam radiotherapy and/or androgen deprivation therapy (adt) in clinically high-risk pca patients.(4-6) although effective cancer control is the most important goal for both patients and surgeons, incontinence following rp exerts the greatest negative effect on patients’ quality of life.(7) in the subgroup of clinically high-risk pca patients, a non-nerve-sparing technique and more aggressive local resection have typically been recommended for obtaining optimal oncological outcomes. presumably, the recovery of urinary continence (uc) is to some degree affected by wide surgical resection. both surgeons and patients have been concerned about the poor uc outcomes after rp. this concern regarding incontinence may occasionally affect therapy decision making and prevent the patients with clinically high-risk pca from receiving curative treatment. nevertheless, a paucity of studies is available regarding the factors that influence uc recovery after rp in patients with clinically high-risk pca. in this study, we aimed to investigate the predictive factors of uc recovery following rp among 184 patients with clinically high-risk pca who received follow-up for a minimum duration of 12 months at a single institution in china. materials and methods patient selection between december 2004 and december 2012, 756 patients diagnosed with pca underwent rp at the third affiliated hospital of sun yat-sen university. all clinical data, including demographic characteristics, clinicopathological characteristics and follow-up results, were prospectively recorded in a computerized database as approved by our institutional review board. the clinical data were retrospectively reviewed, and we identified 184 patients with clinically highrisk pca according to the d’amico risk stratification scheme(8) (clinical stage ≥ t2c or gleason score ≥ 8 or psa > 20 ng/ml) for uc recovery evaluation. all patients were continent before surgery. the preoperative data included age at surgery, body mass department of urology, the third affiliated hospital, sun yat-sen university, guangzhou, 510630, china. * guo-liang hou and yun luo contributed equally to this work. **correspondence: department of urology, the third affiliated hospital, sun yat-sen university, tianhe road 600, guangzhou, 510630, china. tel: +86 20 85252990. fax: +86 20 85252678. e-mail: urogx@hotmail.com. *received january 2015 & accepted february 2015. urological oncology 2021 characteristics number or mean percentage or range no. of patients 184 age (years) 69 48-82 bmi (kg/m2) 23.8 20.4-26.1 previous turp 15 8.2 psa level (ng/ml) 30.5 1.89-104.3 < 10 35 19.0 10-20 52 28.3 > 20 97 52.7 biopsy gleason score ≤ 6 67 36.4 7 46 25.0 ≥ 8 71 38.6 clinical stage t1 48 26.1 t2 124 67.4 t3 12 6.5 prostate volume (ml) 44.0 10.6-120.1 neoadjuvant adt 36 19.6 surgical approach lrp 134 72.8 rrp 50 27.2 surgery duration (min) 205.7 110-440 hospital stay (days) 18.7 9-39 estimated blood loss (ml) 238.4 30-3000 nerve sparing no 144 78.3 unilateral 7 3.8 bilateral 33 17.9 pathological gleason score ≤ 6 49 26.6 7 57 31 ≥ 8 78 42.4 pathological stage t2 113 61.4 t3-4 71 38.6 n1 28 15.2 anastomotic leakage 44 23.9 anastomotic stricture 17 9.2 follow-up duration (months) 43.2 12-111 table 1. the clinicopathological characteristics of 184 patients with clinically high-risk prostate cancer. abbreviations: bmi, body mass index; psa, prostate-specific antigen; turp, transurethral resection of the prostate; adt, androgen deprivation therapy; rrp, open retropubic radical prostatectomy; lrp, laparoscopic radical prostatectomy. predictors of urinary continence recovery-hou et al vol 12. no 01 jan-feb 2015 2022 index (bmi), serum psa level, history of transurethral resection of the prostate (turp), clinical stage, biopsy gleason score, prostate volume and neoadjuvant adt. the prostate volume was measured via transrectal ultrasonography.(9) all patients preoperatively underwent computed tomography or magnetic resonance imaging and a radionuclide bone scan to exclude distant metastases. the patients were fully informed with regard to the surgical approach (open retropubic vs. laparoscopic) and its possible complications. the choice of therapy was determined via consultation between the surgeons and the patients. surgical technique the surgery was performed using a transperitoneal approach. all patients underwent extended bilateral pelvic lymph node dissection before rp. laparoscopic radical prostatectomy (lrp) and open retropubic radical prostatectomy (rrp) were performed on 134 and 50 patients, respectively. the technique of rp with modified prostate apex dissection was applied as previously reported. (10) a nerve-sparing procedure was discreetly performed based on age, clinical stage, the psa level, sexual function and the patient’s request. all operations were performed by a single surgeon (x.g.). routine cystography was performed at 7-10 days after surgery. the urethral catheter was removed if no anastomotic leakage was detected based on cystography. all of the patients were instructed to carry out daily pelvic floor muscle training (pfmt) after catheter removal. biofeedback was simultaneously applied to assist the patients with contracting the pelvic floor muscles via electrical stimulation or verbal instruction. all patients received adjuvant adt for 9 months beginning 3 months after surgery. follow-up postoperative follow-up was performed quarterly for the first 2 years, semi-annually for the next 3 years, and annually thereafter and consisted of psa measurement, digital rectal examination and other clinical assessments (e.g., chest x-ray and bone scan) as indicated. biochemical recurrence was defined as psa levels greater than 0.2 ng/ml based on two consecutive measurements within 3 months. the uc state and pad use were assessed simultaneously at the follow-up visits or during telephone interviews by a special interviewer. uc was defined as wearing no pad or wearing a protective pad daily. patients who used two or more pads a day were considered incontinent. patients who did not achieve uc at 12 months after surgery underwent urodynamic measurements to determine the type of incontinence. the primary outcome measure was predictors of uc recovery after rp for clinically high-risk pca. the secondary outcome measure was the median time to uc, and the percentage of patients exhibiting uc recovery at different time point. statistical analysis kaplan-meier analysis and the log-rank test were used to compare time to uc and the percentage of continent variables univariate multivariate hr (95% ci) p value hr (95% ci) p value age group (< 70 years vs. ≥ 70 years) 1.858 (1.358-2.541) < .001 1.684 (1.191-2.382) .003* bmi (kg/m2) 1.062 (0.938-1.202) .344 1.068 (0.934-1.22) .337 previous turp (yes vs. no) 0.906 (0.524-1.567) .724 0.751 (0.385-1.461) .398 psa (ng/ml) 1.002 (0.996-1.008) .522 1.003 (0.997-1.009) .333 prostate volume (ml) 0.99 (0.981-0.999) .029 0.989 (0.978-0.999) .036* neoadjuvant adt (yes vs. no) 1.006 (0.692-1.464) .974 1.038 (0.696-1.549) .853 surgical approach (rrp vs. lrp) 0.896 (0.642-1.251) .52 0.851 (0.587-1.232) .392 surgery duration (min) 0.998 (0.995-1.001) .267 1.001 (0.997-1.005) .602 nerve sparing .704 .868 unilateral vs. no 1.379 (0.644-2.955) 1.242 (0.56-2.757) bilateral vs. no 0.988 (0.665-1.468) 1.023 (0.667-1.569) pathological gleason score .986 .915 7 vs. ≤ 6 1.023 (0.689-1.518) 1.092 (0.716-1.664) ≥ 8 vs. ≤ 6 0.993 (0.687-1.436) 1.039 (0.669-1.612) pt stage (pt3-4 vs. pt2) 0.793 (0.582-1.081) .142 0.771 (0.527-1.128) .18 lymph node involvement (positive vs. negative) 0.88 (0.575-1.345) .554 0.941 (0.577-1.534) .806 anastomotic leakage (yes vs. no) 0.72 (0.505-1.029) .071 0.742 (0.503-1.095) .133 anastomotic stricture (yes vs. no) 0.911 (0.544-1.524) .722 0.991 (0.558-1.759) .974 * variables displaying a significance difference based on multivariate cox regression analysis. significance was defined as p < .05. abbreviations: bmi, body mass index; psa, prostate-specific antigen; turp, transurethral resection of the prostate; adt, androgen deprivation therapy; rrp, open retropubic radical prostatectomy; lrp, laparoscopic radical prostatectomy; hr, hazard ratio; ci, confidence interval. table 2. cox regression analysis of factors predictive of urinary continenece recovery during follow-up. predictors of urinary continence recovery-hou et al urological oncology 2023 vol 12. no 01 jan-feb 2015 2024 patients at follow-up. univariate and multivariate cox regression analyses were performed to determine the predictors of uc recovery during the follow-up. all statistical tests were two-sided, and a p value of < .05 was considered statistically significant. the data were analyzed using ibm statistical package for the social science (spss inc, chicago, illinois, usa) version 19.0. results the clinicopathological characteristics of the 184 patients are summarized in table 1. the median age at surgery was 69.5 years (range 48-82), and the median follow-up duration was 40 months (range 12-111). fifteen patients had a history of turp. no patient received neoadjuvant chemotherapy. considering the unfavorable pathological characteristics of clinically high-risk pca, only 40 (21.7%) patients were cautiously selected to undergo a nerve-sparing procedure (7 for a unilateral nerve-sparing procedure and 33 for a bilateral nerve-sparing procedure). the mean operation time was 203 minutes (range 120-330) and 212 minutes (range 110-440) for lrp group and rrp group, respectively. forty-four (23.9%) patients exhibited anastomotic leakage and were treated by prolonged urethral catheterization. the catheter was not removed until the cystography showed an intact anastomosis. seventeen patients (9.2%) developed a symptomatic anastomotic stricture that required endoscopic treatment. for the patients who achieved uc, the median time to continence was 1 month (range 1-24). the median time to continence is 1 month in lrp group and 3 months in rrp group. the number of patients exhibiting uc recovery at 1 month, 6 months, 12 months and at the most recent follow-up was 99 (53.8%), 158 (85.9%), 171 (92.9%) and 174 (94.6%), respectively. for the 13 patients who did not achieve uc at 12 months after surgery, 3 patients need 3 pads per day, 7 patients need 4 pads per day, and 3 patients need 6 pads per day. only 3 (1.6%) patients with incontinence at 12 months recovered uc by the most recent follow-up, and no patient with incontinence at 24 months regained uc. all 13 patients with incontinence at 12 months were found to exhibit stress urinary incontinence (sui) based on urodynamic measurements. among these patients, 3 patients exhibited grade i sui and 10 patients exhibited grade ii sui according to burkhard’s criteria.(11) no patient exhibited grade iii sui, and no patients underwent male anti-incontinence surgery (e.g., artificial urinary sphincter implantation). table 2 shows the factors that were predictive of uc recovery during the follow-up. multivariate cox figure. the continence rate of the two age groups during follow-up; (a) kaplan–meier estimates of urinary continence recovery in all of the patients after radical prostatectomy (b) and in the subgroups stratified according to the median age (c) and prostate volume (d). level of statistical significance was defined as p < .05. predictors of urinary continence recovery-hou et al regression analysis showed that patient age < 70 years (hazard ratio 1.684, 95% confidence interval [ci]: 1.1912.382, p = .003) and smaller prostate volume (hazard ratio 0.989, 95% ci: 0.978-0.999, p = .036) were independent predictive factors of uc recovery during follow-up. patients with larger prostate and older than 70 years exhibited a delayed restoration of uc. no significant association was detected between uc recovery and bmi, the psa level, previous turp, neoadjuvant adt, the pathological gleason score, the pathological stage, the surgical approach, nerve-sparing procedure, anastomotic leakage and anastomotic stricture. figure shows the uc rate of the two age groups during the followup and the kaplan–meier estimates of uc recovery. discussion recent studies have demonstrated that rp produces excellent oncological outcomes for not only localized pca but also clinically high-risk pca.(4,5) accompanied with the surgery, the significant negative impact on quality of life is post-prostatectomy incontinence. it is likely that uc recovery is somewhat affected by wide resection during surgery in clinically high-risk pca patients. for these patients, determining whether rp results in a satisfactory uc outcome without compromising cancer control and identifying the predictive factors of uc recovery are matters of concern. however, the majority of studies have focused on uc recovery among the entire cohort of pca patients, and few studies have examined uc recovery in the subgroup of clinically high-risk pca patients. we retrospectively investigated the uc recovery outcomes of clinically high-risk pca patients who received modified rp and found that the uc outcomes were comparable to those of localized pca patients who received rp. in the subgroup of patients with clinically high-risk pca, the reported rate of incontinence has varied between 5.8% and 22%.(12-14) this wide variation in the reported data has been attributed to the definition of uc, the surgical technique, and the time point and methodology used for assessing uc. we have adopted the most commonly used definition of uc: the use of zero or one protective pad daily.(15) it has been generally accepted that uc improves over time and that most patients achieve uc within 12 months postoperatively.(16,17) in the present study, the uc rate improved from 53.8% at 1 month to 92.9% at 12 months. however, very few incontinent patients at 1 year postoperatively became continent thereafter.(18,19) our study showed a similar result, in which only 3 patients regained uc after 1 year, and no patients regained uc after 2 years. the proposed risk factors of uc recovery after rp include preoperative factors (e.g., age,(18) the prostate volume(20) and previous turp(21)), the surgical technique (e.g., a nerve-sparing technique,(11) the experience level of the surgeon,(22) the surgical approach,(16) bladder neck preservation(23) and the performance of apical dissection(24)) and postoperative factors (e.g., the performance of pelvic floor muscle training,(25) the use of biofeedback,(5) anastomotic leakage and anastomotic stricture(15)). age at surgery has consistently been considered as the most important factor associated with uc recovery after rp.(15,18) in this study, 92 patients (50%) were 70 years of age or older. we found that patient age < 70 years was an independent predictive factor of uc recovery. this finding is in accordance with the results reported by kundu and colleagues and kim and colleagues(18,20) the role of the prostate volume in uc recovery after rp remains controversial. kim and colleagues performed a retrospective analysis of 452 patients with clinically localized pca who underwent robot-assisted rp to investigate the factors that predicted early recovery of uc.(20) the results of their study demonstrated that factors including younger age (< 70 years) and smaller prostate volume (< 40 ml) independently predicted recovery of uc within 3 months after surgery. however, pettus and colleagues did not detect a correlation between prostate size and uc at one year following rp.(24) our results showed that smaller prostate volume is an independent predictor of uc recovery based on multivariate analysis. the patients with a larger prostate experienced a delayed restoration of uc. the reason for this effect may be that a larger prostate complicates the manipulation of the prostate apex and the urethra and the mobilization of the prostate during surgery; moreover, the surgery may even occasionally injure the external urethral sphincter. the nerve-sparing technique was once considered as the most important surgical technique for uc recovery. burkhard and colleagues evaluated the uc of 536 patients treated with attempted nerve-sparing rp who received follow-up for a minimum duration of 1 year.(11) they found that uc was highly associated with the use of a nervesparing technique. however, the predictive value of this factor has been extensively debated, as some studies have presented conflicting findings. marien and colleagues evaluated uc in 1100 patients who underwent nervesparing rp.(26) these patients exhibited similar cu rates at 24 months regardless of whether a bilateral or unilateral nerve-sparing technique was performed. in the present study, uc recovery was not significantly associated with the performance of a nerve-sparing procedure. the results regarding the effect of the nerve-sparing technique on uc recovery were disparate. we propose that the primary reason for this discrepancy is that attempted nerve sparing does not truly indicate that the nerves are adequately preserved. the neurovascular bundles are often unintentionally injured due to periprostatic adhesions or obscured dissection planes. therefore, the actual status of the so-called “spared nerves” is undetermined. the other surgical technique in this cohort that is related to uc may be the modification of prostate apex dissection. eastham and colleagues argued that meticulous dissection of the prostate apex resulted in both an improvement in time to continence and the overall rate of uc.(21) the purpose of this modification was to preserve the urethral musculature, the periurethral fascial attachments and the continence-associated nerves during surgery.(10) this technique may also preserve maximal functional urethral length, which might improve early uc.(27) our preliminary results indicated that this technique improved uc recovery.(10) regarding other surgical factors, no difference was observed in uc recovery according to the surgical approach or the history of turp. in addition, the experience level of the surgeon may affect the time to uc following rp.(22) in this cohort, all of the procedures were performed by a single surgeon. with regard to postoperative factors, pfmt and biofeedback are the most commonly used conservative treatments for hastening the restoration of uc. kampen and colleagues conducted a randomized controlled study to evaluate the effect of pfmt on incontinence after rp in clinically localized pca patients.(25) their study showed that the pfmt-treated group exhibited improvements in both the duration and the degree of incontinence compared predictors of urinary continence recovery-hou et al urological oncology 2025 vol 12. no 01 jan-feb 2015 2026 to the control group. in the pfmt-treated group, uc was restored in 88% of the patients after 3 months. in our study, pfmt with biofeedback was routinely performed after catheter removal. most patients exhibited uc within 1 year. however, the uc rate at 3 months (75.5%) was lower than that in kampen and colleagues there may be two reasons for this difference: (1) the present study included older patients, of which half of the patients were greater than 70 years of age; (2) all of the patients in the present study suffered from clinically high-risk pca, and these patients more frequently experience urinary incontinence compared to the clinically localized pca patients who were included in kampen’s study. there are several limitations to the present study. first, this study was a retrospective analysis of a relatively small number of patients with clinically high-risk pca. second, this study did not evaluate the uc status based on a validated questionnaire, and the acceptance of a safety pad may represent a confounding factor. third, because the entire cohort received either rrp or lrp, the findings of the present study may have limited external generalizability to uc recovery after robotic prostatectomy. finally, the focus of our study was to determine the predictor of uc recovery. only a small number of patients were performed nerve-sparing procedure and all patients received adjuvant adt, so we did not assessed sexual function. conclusion the present study demonstrated the value of age < 70 years and smaller prostate volume, but not the psa level, the cancer stage, the gleason score, previous turp, the surgical approach or the use of a nerve-sparing technique, for predicting uc recovery after rp in patients with clinically high-risk pca. the adverse factors of high-risk pca were not significantly associated with uc recovery. these results may help surgeons preoperatively counsel patients regarding expected uc outcomes following rp. acknowledgements the authors acknowledge the financial support from national natural science foundation of china (81201694), the program of 5010 of sun yat-sen university (2007028), reserve personnel plan of the third affiliated hospital of sun yat-sen university and specialized research fund for the doctoral program of higher education of china (20120171120059). conflicts of interest none declared. references 1. siegel r, ma j, zou z, jemal a. cancer statistics, 2014. ca: a cancer journal for clinicians. 2014;64:9-29. 2. cullen j, elsamanoudi s, brassell sa, et al. the burden of prostate cancer in asian nations. j carcinog. 2012;11:7. 3. peyromaure em, mao k, sun y, et al. a comparative study of prostate cancer detection and management in china and in france. can j urol. 2009;16:4472-7. 4. sooriakumaran p, nyberg t, akre o, et al. comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality outcomes. bmj. 2014;348:g1502. 5. sato yt, fukuhara h, suzuki m, et al. longterm results of radical prostatectomy with immediate adjuvant androgen deprivation therapy for pt3n0 prostate cancer. bmc urol. 2014;14:13. 6. petrelli f, vavassori i, coinu a, borgonovo k, sarti e, barni s. radical prostatectomy or radiotherapy in high-risk prostate cancer: a systematic review and metaanalysis. clin genitourin cancer. 2014;12:215-24. 7. augustin h, pummer k, daghofer f, habermann h, primus g, hubmer g. patient self-reporting questionnaire on urological morbidity and bother after radical retropubic prostatectomy. eur urol. 2002;42:112-7. 8. d'amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998;280:96974. 9. gancarczyk kj, wu h, mcleod dg, et al. using the percentage of biopsy cores positive for cancer, pretreatment psa, and highest biopsy gleason sum to predict pathologic stage after radical prostatectomy: the center for prostate disease research nomograms. urology. 2003;61:589-95. 10. gao x, wang kb, pu xy, zhou xf, qiu jg. modified apical dissection of the prostate improves early continence in laparoscopic radical prostatectomy: technique and initial results. j cancer res clin oncol. 2010;136:5116. 11. burkhard fc, kessler tm, fleischmann a, thalmann gn, schumacher m, studer ue. nerve sparing open radical retropubic prostatectomy-does it have an impact on urinary continence? j urol. 2006;176:189-95. 12. joniau sg, van baelen aa, hsu cy, van poppel hp. complications and functional results of surgery for locally advanced prostate cancer. adv urol. 2012;2012:706309. 13. lavery hj, nabizada-pace f, carlucci jr, brajtbord js, samadi db. nerve-sparing robotic prostatectomy in preoperatively highrisk patients is safe and efficacious. urol oncol. 2012;30:26-32. 14. ward jf, slezak jm, blute ml, bergstralh ej, zincke h. radical prostatectomy for clinically advanced (ct3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. bju int. 2005;95:751-6. 15. sacco e, prayer-galetti t, pinto f, et al. urinary incontinence after radical prostatectomy: incidence by definition, risk factors and temporal trend in a large series with a long-term followpredictors of urinary continence recovery-hou et al up. bju int. 2006;97:1234-41. 16. ficarra v, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012;62:40517. 17. simforoosh n, javaherforooshzadeh a, aminsharifi a, tabibi a. early continence after open and laparoscopic radical prostatectomy with sutureless vesicourethral alignment: an alternative technique, 8 years' experience. urol j. 2009;6:163-9. 18. kundu sd, roehl ka, eggener se, antenor ja, han m, catalona wj. potency, continence and complications in 3,477 consecutive radical retropubic prostatectomies. j urol. 2004;172:2227-31. 19. nandipati kc, raina r, agarwal a, zippe cd. nerve-sparing surgery significantly affects longterm continence after radical prostatectomy. urology. 2007;70:1127-30. 20. kim jj, ha ys, kim jh, et al. independent predictors of recovery of continence 3 months after robot-assisted laparoscopic radical prostatectomy. j endourol. 2012;26:1290-5. 21. eastham ja, kattan mw, rogers e, et al. risk factors for urinary incontinence after radical prostatectomy. j urol. 1996;156:1707-13. 22. samadi db, muntner p, nabizada-pace f, brajtbord js, carlucci j, lavery hj. improvements in robot-assisted prostatectomy: the effect of surgeon experience and technical changes on oncologic and functional outcomes. j endourol 2010;24:1105-10. 23. razi a, yahyazadeh sr, sedighi gilani ma, kazemeyni sm. bladder neck preservation during radical retropubic prostatectomy and postoperative urinary continence. urol j. 2009;6:23-6. 24. pettus ja, masterson t, sokol a, et al. prostate size is associated with surgical difficulty but not functional outcome at 1 year after radical prostatectomy. j urol. 2009;182:949-55. 25. van kampen m, de weerdt w, van poppel h, de ridder d, feys h, baert l. effect of pelvicfloor re-education on duration and degree of incontinence after radical prostatectomy: a randomised controlled trial. lancet. 2000;355:98-102. 26. marien tp, lepor h. does a nerve-sparing technique or potency affect continence after open radical retropubic prostatectomy? bju int. 2008;102:1581-4. 27. coakley fv, eberhardt s, kattan mw, wei dc, scardino pt, hricak h. urinary continence after radical retropubic prostatectomy: relationship with membranous urethral length on preoperative endorectal magnetic resonance imaging. j urol. 2002;168:1032-5. predictors of urinary continence recovery-hou et al urological oncology 2027 the effect of phosphodiesterase 5 inhibitor on biochemical recurrence following radical prostatectomy in patients with prostate cancer jae-wook chung, jin woo kim, yun-sok ha, seock hwan choi, jun nyung lee, bum soo kim, hyun tae kim, eun sang yoo, tae gyun kwon, tae-hwan kim* purpose: recently, controversy exists regarding the oncologic outcomes associated with the use of phosphodiesterase 5 inhibitor (pde5i). therefore, we attempted to verify the effect of pde5i on biochemical recurrence (bcr) following radical prostatectomy (rp) in patients with prostate cancer (pca). materials and methods: from january 2011 to may 2016, 351 patients who had undergone bilateral neurovascular bundle saving and who were confirmed as having pt2n0m0 disease were included in the present study. we divided these patients into three groups: no pde5i use, pde5i use on demand , and pde5i use for rehabilitation. we retrospectively analyzed the effect of pde5i on bcr of pca. mean follow-up period was 34.4 months and mesurement of outcome was whether the patients developed bcr during regular follow-up. results: 25 (7.1%) patients showed bcr and univariate analysis found no significant differences in bcr between the three groups (5 (6.9%) in no pde5i use, 8 (9.5%) in pde5i use on demand, 12 (6.2%) in pde5i use for rehabilitation). multivariable analyses showed that treatment type was not a significant factor for bcr between the groups with no pde5i use and pde5i use (hr = 1.34 [0.49–3.70]; p = .573) and between the groups with on demand and rehabilitation use (hr = 1.37 [0.35–5.37]; p = .646). kaplan-meier survival curves show that there were no significant differences in psa recurrence-free survival in three groups (p > .05). conclusion: use of pde5is was not associated with any adverse effects on bcr after rp in patients with pca. keywords: phosphodiesterase 5 inhibitor; prostate cancer; prostatectomy; recurrence introduction prostate cancer (pca) is the most common solid ma-lignancy and remains the second leading cause of death from cancer in men, with approximately 233,000 new diagnoses and 29,480 deaths from the disease in the united states in 2014.(1) there has been a rapid rise in the incidence of pca in several asian countries, with pca steadily becoming one of the leading cancers in asian men.(2) similarly, in korea, the incidence rate of pca has rapidly increased during the past decade.(3) radical prostatectomy (rp) is the gold standard for surgical treatment for patients with localized prostate cancer. erectile dysfunction (ed) following rp for pca is a common complication reported to urologists.(4-7) ed leads to severe economic and psychological problems that increase distress and decrease quality of life after rp for patients with pca. following the determination that the main mechanism of postoperative ed was the injury of neurovascular bundles, nerve-sparing rp has been widely performed.(8) since the introduction of phosphodiesterase 5 inhibitor (pde5i), these agents have been widely used for the treatment of ed following rp in patients with pca. numerous studies have demonstrated the safety and efficacy of pde5i.(9,10) however, controversy has recently arisen regarding oncologic outcomes associated with the use of pde5i. (11department of urology, school of medicine, kyungpook national university, daegu, korea. *correspondence: department of urology, school of medicine, kyungpook national university, daegu, korea tel: +82-53-200-2166. fax: +82-53-321-3207. e-mail: doctork@knu.ac.kr. received november 2017 & accepted april 2019 14) gallina et al. reported that the use of pde5i was not associated with an increased risk of biochemical recurrence (bcr).(11) on the other hand, michl et al. reported that postoperative use of pde5i may adversely impact bcr.(14) since these two studies have shown contrary outcomes with pde5i use following rp, additional evaluation of the potential effects of postoperative pde5i use is thought to be clinically important in the field of oncology. therefore, we attempted in the present study to verify the effect of pde5i on bcr after rp in patients with pca. patients and methods study population from january 2011 to may 2016, a total of 750 patients were diagnosed with pca and underwent rp. we included patients who underwent bilateral neurovascular bundle saving and who were confirmed as having pt2n0m0 disease so as to choose the patients who have the similar chance of bcr before the exposure of pde5i. on the other hand, we excluded patients who did not undergo regular follow-up, who underwent non or unilateral neurovascular bundle saving, who received neoadjuvant or adjuvant hormone/radiation therapy, whose pathologic reports showed pt3 or 4 or ptanyn1 disease, or who experienced distant metastasis. finally, urological oncology urological oncology 255 vol 16 no 03 may-june 2019 256 351 patients were included in the study. this study was approved by the ethics committee of the kyungpook national university school of medicine (irb number knuh 2016-08-017). study design this study was a retrospective single center trial. we divided these patients into three groups: no pde5i use, pde5i use on demand, and pde5i use for rehabilitation. the patients were allocated for each group according to the age, sexual activity and economic status. the rehabilitation group was defined on the basis of daily pde5i use for more than 3 months. we retrospectively analyzed the effect of pde5i on bcr of pca (defined as two consecutive prostate-specific antigen [psa] levels ≥ 0.2 ng/ml). mean follow-up period was 34.4 months and measurement of outcome was whether the patients developed bcr during regular follow-up. 176 patients (176/279, 63.1%) started pde5i intake within 4 weeks after surgery. statistical analysis patient characteristics were analyzed using the chisquare test (surgical technique, pathologic gleason score, surgical margin status, type of pde5i, bcr), student’s t-test (number of pills taken, period of pde5i use, time to first intake of pde5i after rp) and kruskal-wallis test for the method of post hoc analysis (age, body mass index (bmi), preoperative psa, follow-up period). in addition, multivariable cox regression was used for analysis of the impact of pde5i on bcr, and kaplan-meier curves via a log-rank test were used for analysis of bcr-free survival. statistical analysis was performed using spss 16.0 for windows (spss inc., chicago, il, usa), and p < 0.05 was considered statistically significant. effect of pde5i on bcr-chung et al. figure 1. probability estimates of biochemical recurrence-free survival in all patients stratified by use of phosphodiesterase type 5 inhibitors (no pde5i use versus pde5i use). probability estimates of biochemical recurrence-free survival in all patients stratified by use of phosphodiesterase type 5 inhibitors (on demand versus rehabilitation). variablesa overall no pde5i use pde5i use on demand pde5i use for rehabilitation p value patients, n (%) 351 (100.0) 72 (20.5) 84 (23.9) 195 (55.6) age, years 65.4 ± 6.6 67.8 ± 6.9 66.1 ± 5.7 64.2 ± 6.6 < .001 bmi, kg/m2 23.8 ± 2.8 24.0 ± 2.9 24.1 ± 3.0 23.7 ± 2.6 .326 preoperative psa, ng/ml 9.1 ± 9.1 11.2 ± 15.1 8.1 ± 4.1 8.9 ± 7.6 .094 surgical technique, n (%) .322 robotic 247 (70.4) 40 (11.4) 59 (16.8) 148 (42.2) open 104 (29.6) 32 (9.1) 25 (7.1) 47 (13.4) pathologic gleason score, n (%) .509 ≤ 6 66 (18.8) 19 (5.4) 13 (3.7) 34 (9.7) 7 239 (68.1) 44 (12.5) 61 (17.4) 134 (38.2) 8 34 (9.7) 7 (2.0) 9 (2.6) 18 (5.1) 9 12 (3.4) 2 (0.6) 1 (0.3) 9 (2.6) surgical margin status, n (%) .599 negative 210 (59.8) 44 (12.5) 48 (13.7) 118 (33.6) positive 141 (40.2) 28 (8.0) 36 (10.3) 77 (21.9) type of pde5i .121 udenafil 136 (48.7) 35 (12.5) 101 (36.2) non-udenafil 143 (51.3) 49 (17.6) 94 (33.7) number of pills taken, n 132.9 ± 138.9 47.4 ± 40.9 169.8 ± 149.7 < .001 (10-1680) period of pde5i use, months 11.8 ± 11.1 6.7 ± 8.4 13.9 ± 11.4 < .001 (3-56.8) time to first intake of pde5i after rp 2.7 ± 4.1(1-33) 4.9 ± 6.6 1.8 ± 1.7 < .001 follow-up period, months 34.4 ± 17.7(5.2-65.2) 41.1 ± 16.4 40.2 ± 15.8 29.4 ± 17.5 < .001 bcr, n (%) .317 no 326 (92.9) 67 (19.1) 76 (21.7) 183 (52.1) yes 25 (7.1) 5 (1.4) 8 (2.3) 12 (3.4) adata are presented as mean ± sd or number (percent) abbreviations: pde5i, phosphodiesterase 5 inhibitor; bmi, body mass index; psa, prostate specific antigen; bcr, biochemical recurrence; rp, radical prostatectomy. table 1. descriptive characteristics of 351 patients according to use of phosphodiesterase 5 inhibitors. results among the 351 patients enrolled in this study, the no pde5i use group included 72 patients (20.5%) and the pde5i use group included 279 (79.5%). the pde5i use group was divided into two groups: on demand (n = 84, 23.9%) and rehabilitation use (n = 195, 55.6%). descriptive characteristics of 351 patients according to use of phosphodiesterase 5 inhibitor are shown in table 1. the mean patient age was 65.4 ± 6.6 years. the pde5i use group was significantly younger than the no pde5i use group, and the rehabilitation group was significantly younger than the on demand group (p < .001). there was no significant differnce in bmi of each groups. the mean preoperative psa level was 9.1 ± 9.1 ng/ml, and there was no significant difference among the groups (p = 0.094). robot-assisted laparoscopic rp was performed in 247 (70.4%) patients. there were no significant differnces in surgical technique of each groups. pathologic gleason score and surgical margin status were not significantly different among the three groups. positive surgical margin was shown in 141 (40.2%) patients. among the pde5i use group, 136 patients (48.7%) took udenafil (zydena®, dong-a pharmaceutical co., ltd., seoul, korea). the rehabilitation group took a significantly greater amount of pde5i than the on demand group and also used pde5i significantly longer than the on demand group (p < .001). time to first intake of pde5i after rp was significantly shorter in the rehabilitation group (p < .001). the mean follow-up period was 34.4 ± 17.7 months and mean follow-up period of rehabilitation group was significantly shorter than the other groups (p < .001). twenty-five patients (7.1%) showed bcr, and univariate analysis revealed no significant differences among the three groups (p = 0.317). multivariable cox regression analyses (mva) are shown in table 2. pathologic gleason score and surgical margin status were significant factors for bcr between no pde5i use and pde5i use group (p < .05, respectively). only surgical margin status was a significant factor for bcr between pde5i use on demand and pde5i use for rehabilitation group (p < .05). mva showed that treatment type was not a significant factor for bcr (no pde5i use versus pde5i use, hazard ratio [hr] = 1.34 [0.49–3.70], p = .573; on demand versus rehabilitation, hr = 1.37 [0.35–5.37], p = .646, respectively). type of pde5i, number of pills taken, period of pde5i use, and time to first intake of pde5i were also not associated with an increased rate of bcr between the on demand and rehabilitation groups (hr = 0.54 [0.17–1.69], p = .291, hr = 1.00 [0.99– 1.01] p = .482, hr = 1.02 [0.96–1.08], p = .504, hr = 0.75 [0.53–1.05], p = .100, respectively). kaplan-meier survival curves showed that there were no significant differences in psa recurrence-free survival in the groups with no pde5i use versus pde5i use (p = .339) (figure 1) or in the groups with on demand versus rehabilitation use (p = .933) (figure 1). discussion all forms of pca treatment, especially rp, are associated with a significant risk of ed as a result of trauma sustained by the cavernosal nerves.(15) it is a wellknown fact that pde5i significantly improves erectile function following rp in patients with pca.(16-19) a relatively large volume of literature has shown that pde5is represent a significant advance in the treatment of ed in patients with pca. currently, sildenafil, tadalafil, and vardenafil are approved for the treatment of ed in the united states. sildenafil is the most widely used oral agent for penile rehabilitation in post-rp patients.(20-23) however, unlike the other centers, our center studied the effect of pde5i on penile rehabilitation after rp using udenafil 50 mg. (24) udenafil is a selective pde5i made available table 2. multivariable cox regression analyses (mva) predicting biochemical recurrence in patients. mva including use of no pde5i use versus pde5i use mva including use of on demand versus rehabilitation hr (95% ci) p value hr (95% ci) p value age 0.99 (0.93–1.06) .836 0.96 (0.88–1.04) .301 preoperative psa 1.01 (0.98–1.05) .482 1.02 (0.98–1.07) .342 surgical technique robotic 1.00 (ref) 1.00 (ref) open 0.95 (0.37–2.43) .921 0.97 (0.32–2.97) .954 pathologic gleason score ≤ 6 1.00 (ref) 1.00 (ref) 7 1.18 (0.26–5.44) .832 0.71 (0.14–3.50) .673 8 7.07 (1.55–32.36) .012 3.66 (0.74–18.06) .112 9 11.77 (1.93–71.91) .008 6.11 (0.83–45.18) .076 surgical margin status negative 1.00 (ref) 1.00 (ref) positive 3.29 (1.44–7.50) .005 2.89 (1.12–7.50) .029 type of pde5i udenafil 1.00 (ref) non-udenafil 0.54 (0.17–1.69) .291 treatment type no pde5i use 1.00 (ref) pde5i use 1.34 (0.49–3.70) .573 pde5i use, on demand 1.00 (ref) pde5i use, rehabilitation 1.37 (0.35–5.37) .646 number of pills taken 1.00 (0.99–1.01) .482 period of pde5i use 1.02 (0.96–1.08) .504 time to first intake of pde5i 0.75 (0.53–1.05) .100 abbreviations: pde5i, phosphodiesterase type 5 inhibitor; mva, multivariable cox regression analyses; hr, hazard ratio; ci, confidence interval; psa, prostate specific antigen. effect of pde5i on bcr-chung et al. urological oncology 257 vol 16 no 03 may-june 2019 258 in recent years for the treatment of ed.(24) the results of our 2016 study analyzing udenafil could provide urologists with useful information for counseling patients undergoing rp and for selecting optimal candidates for penile rehabilitation. following the identification of patients with pca treated with udenafil or other pde5is, this study was designed to assess whether pde5i is associated with bcr after rp in patients with pca. a review of the history of pde5is since their introduction, from the late 1990s to early 2000, revealed that numerous studies reported that these agents showed potential as anticancer drugs. in 1999, goluboff et al. demonstrated that the pde5i exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug sulindac, suppresses the growth of human pca in a nude mouse xenograft model by increasing apoptosis. (25) in 2001, these authors also analyzed the safety and efficacy of exisulind for the treatment of recurrent pca after rp.(26) moreover, narayanan et al. showed that a combination of celecoxib with exisulind prevented prostate carcinogenesis, enhancing apoptosis.(27) with regard to commercially available pde5is, qian et al. showed that sildenafil citrate was not associated with any significant alteration in primary pca tumor growth or in the development of regional or distant metastases in animal models.(28) in animal and in vitro studies on the effects of pde5is on anti-cancer immune responses, sildenafil treatment resulted in increased t-cell infiltration into tumor cells, enhancing tumoricidal activity.(29) according to more recent studies of the effect of pde5is on pca, gallina et al. showed in 2015 that among patients treated with rp, pde5i use was not associated with an increased risk of bcr, regardless of the therapeutic regimen used.(11) in 2016, jo et al. analyzed records of 1082 patients who underwent bilateral nerve-sparing rp for clinically localized pca between 2005 and 2014.(12) they concluded that pde5i treatment following rp was not found to have any significant impact on biochemical outcome regardless of therapeutic strategy, timing, duration, or drug type, findings that suggest that pde5i treatment following rp is oncologically safe. this study differs from ours in that jo et al. designed their study with sildenafil but our center used udenafil, and our study showed that surgical margin status was also a predictive factor for bcr after rp. on the other hand, in 2015, michl et al. demonstrated that the use of pde5i after rp may adversely impact bcr.(14) this study (median follow-up: 60.3 months) included 4,752 consecutive patients with localized pca treated with bilateral nerve-sparing rp between january 2000 and december 2010. of these patients, 1110 (23.4%) received pde5i postoperatively while 3642 (76.6%) did not. five-year bcr-free survival estimates in the pde5i versus non pde5i groups were 84.7% (95% confidence interval [ci]: 82.1–87.0) and 89.2% (95% ci: 88.1–90.3), respectively (p = .0006). the authors’ multivariate regression analysis showed that pde5i use was an independent risk factor for bcr (hr: 1.38, 95% ci: 1.11–1.70, p = .0035), and this was also true after propensity score matching. similarly, in 2016, kim et al. raised a question about the safety of pde5i use after rp.(13) they reviewed the results of preclinical studies showing that the nitric oxide (no) and cyclic guanosine monophosphate (cgmp) signaling pathway play a role in both suppression and development of pca. these conflicting results regarding the influence of the no and cgmp signaling pathway might be the findings that highlighted the necessity of assessing the safety of pde5i in pca. moreover, a longitudinal cohort study reported that pde5i increased the risk of the development of melanoma, a result also suggesting the adverse effect of pde5i on some kinds of cancers. with regard to our study, some limitations include the retrospective and single-center study design. the follow-up periods were relatively short compared to those in other studies. furthermore, in this retrospective study, high grade prostate cancer was included a lot when comparing with general study cohort and high proportion of high grade prostate cancer may be part of limitations. high ratio of positive surgical margin is as a result of these points. still, there are some controversies about adjuvant therapy in patients with positive surgical margin. according to policy of our urologic center, we do not perform adjuvant therapy routinely in patients with positive surgical margin who were confirmed as having pt2n0m0 disease. when bcr is developed, we perform hormonal therapy or radiation therapy. post-operative psa of most patients was observed at an undetectable level. and finally, the rehabilitation therapies were not uniform for all patients. conclusions in summary, our study demonstrated that pde5i use, either on demand or as a rehabilitation therapy, is not associated with an increased risk of bcr in patients treated with nerve-sparing rp for localized pca. we think that pde5i use for penile rehabilitation following bilateral nerve-sparing rp is oncologically safe. however, conflicting data have recently emerged regarding adverse effects of pde5is on bcr. therefore, prospective, randomized, multicenter trials should be performed in the future. acknowledgement this study was approved by the ethics committee of the kyungpook national university school of medicine (irb number knuh 2016-08-017). conflict of interest the authors report no conflict of interest. references 1. siegel r, ma jm, zou zh, jemal a. cancer statistics, 2014. ca-cancer j clin. 2014;64:929. 2. pu ys, chiang hs, lin cc, huang cy, huang kh, chen j. changing trends of prostate cancer in asia. aging male. 2004;7:120-32. 3. jung kw, won yj, kong hj, oh cm, seo hg, lee js. cancer statistics in korea: incidence, mortality, survival and prevalence in 2010. cancer res treat. 2013;45:1-14. 4. brock g, nehra a, lipshultz li, et al. safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radical retropubic prostatectomy. j urol. 2003;170:1278-83. 5. resnick mj, koyama t, fan kh, et al. longeffect of pde5i on bcr-chung et al. term functional outcomes after treatment for localized prostate cancer. n engl j med. 2013;368:436-45. 6. sanda mg, dunn rl, michalski j, et al. quality of life and satisfaction with outcome among prostate-cancer survivors. new engl j med. 2008;358:1250-61. 7. mulhall jp. defining and reporting erectile function outcomes after radical prostatectomy: challenges and misconceptions. j urol. 2009;181:462-71. 8. walsh pc, donker pj. impotence following radical prostatectomy: insight into etiology and prevention (reprinted from j urol, vol 128, pg 492-497, 1982). j urol. 2002;167:1005-10. 9. lowe g, costabile ra. 10-year analysis of adverse event reports to the food and drug administration for phosphodiesterase type-5 inhibitors. j sex med. 2012;9:265-70. 10. salonia a, burnett al, graefen m, et al. prevention and management of postprostatectomy sexual dysfunctions part 2: recovery and preservation of erectile function, sexual desire, and orgasmic function. eur urol. 2012;62:273-86. 11. gallina a, bianchi m, gandaglia g, et al. a detailed analysis of the association between postoperative phosphodiesterase type 5 inhibitor use and the risk of biochemical recurrence after radical prostatectomy. eur urol. 2015;68:750-3. 12. jo jk, kim k, lee se, lee jk, byun ss, hong sk. phosphodiesterase type 5 inhibitor use following radical prostatectomy is not associated with an increased risk of biochemical recurrence. ann surg oncol. 2016;23:1760-7. 13. kim sj, kim jh, chang hk, kim kh. let's rethinking about the safety of phosphodiesterase type 5 inhibitor in the patients with erectile dysfunction after radical prostatectomy. j exerc rehabil. 2016;12:1437. 14. michl u, molfenter f, graefen m, et al. use of phosphodiesterase type 5 inhibitors may adversely impact biochemical recurrence after radical prostatectomy. j urol. 2015;193:479-83. 15. rambhatla a, kovanecz i, ferrini m, gonzalez-cadavid nf, rajfer j. rationale for phosphodiesterase 5 inhibitor use post-radical prostatectomy: experimental and clinical review. int j impot res. 2008;20:30-4. 16. mydlo jh, viterbo r, crispen p. use of combined intracorporal injection and a phosphodiesterase-5 inhibitor therapy for men with a suboptimal response to sildenafil and/or vardenafil monotherapy after radical retropubic prostatectomy. bju int. 2005;95:843-6. 17. ohebshalom m, parker m, guhring p, mulhall jp. the efficacy of sildenafil citrate following radiation therapy for prostate cancer: temporal considerations. j urol. 2005;174:258-62. 18. schiff jd, bar-chama n, cesaretti j, stock r. early use of a phosphodiesterase inhibitor after brachytherapy restores and preserves erectile function. bju int. 2006;98:1255-8. 19. teloken pe, ohebshalom m, mohideen n, mulhall jp. analysis of the impact of androgen deprivation therapy on sildenafil citrate response following radiation therapy for prostate cancer. j urol. 2007;178:2521-5. 20. zippe cd, jhaveri fm, klein ea, et al. role of viagra after radical prostatectomy. urology. 2000;55:241-5. 21. zippe cd, kedia aw, kedia k, nelson dr, agarwal a. treatment of erectile dysfunction after radical prostatectomy with sildenafil citrate (viagra). urology. 1998;52:963-6. 22. raina r, lakin mm, agarwal a, et al. efficacy and factors associated with successful outcome of sildenafil citrate use for erectile dysfunction after radical prostatectomy. urology. 2004;63:960-6. 23. feng mi, huang s, kaptein j, kaswick j, aboseif s. effect of sildenafil citrate on postradical prostatectomy erectile dysfunction. j urol. 2000;164:1935-8. 24. kim th, ha ys, choi sh, et al. factors predicting outcomes of penile rehabilitation with udenafil 50 mg following radical prostatectomy (vol 28, pg 25, 2015). int j impot res. 2016;28:80-. 25. goluboff et, shabsigh a, saidi ja, et al. exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis. urology. 1999;53:440-5. 26. goluboff et, prager d, rukstalis d, et al. safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy. j urol. 2001;166:882-6. 27. narayanan ba, reddy bs, bosland mc, et al. exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin d1 against prostate carcinogenesis: in vivo evidence. clin cancer res. 2007;13:5965-73. 28. qian cn, takahashi m, kahnoski r, teh bt. effect of sildenafil citrate on an orthotopic prostate cancer growth and metastasis model. j urol. 2003;170:994-7. 29. serafini p, meckel k, kelso m, et al. phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. j exp med. 2006;203:2691-702. effect of pde5i on bcr-chung et al. urological oncology 259 vol 16 no 03 may-june 2019 endourology and stone disease comparison of retrograde intrarenal surgery and percutaneous nephrolithotomy methods for management of bigsized kidney stones(≥ 4 cm): single center retrospective study ahmet nihat karakoyunlu1, mehmet çaglar çakıcı1, sercan sarı2*, emre hepsen3, hakkı ugur özok4, azmi levent sagnak1, hikmet topaloglu1, aykut bugra sentürk5, hamit ersoy1 purpose: management of ≥ 4 cm sized kidney stone is a rarely seen problem in urology. few studies are present about this issue. percutaneous nephrolithotomy(pnl), retrograde intrarenal surgery(rirs) and open surgery are the methods used in stone management. in our study we aimed to compare rirs and pnl in the management of ≥ 4 cm sized kidney stones. materials and methods: among patients who had undergone rirs and pnl in dıskapı yıldırım beyazıt training and research hospital, 94 patients who had ≥ 4 cm sized kidney stones were included our study. the demographic, intraoperative and postoperative data of these patients and complications were evaluated retrospectively. results: 94 patients (67 pnl, 27 rirs) were in the study. stone laterality, urinary anomaly and gender were similar in two groups.(group pnl(p) and group rirs(r)) stone number were 2.55 ± 1.44 and 2.78 ± 1.42 in group p and r, respectively. stone size were 47.06 ± 7.02 and 46.41 ± 6.00 mm. in group p and r, respectively. the differences between two groups were not statistically significant.(p > .05) in group p scopy time, hospital stay and stone free rate were higher and operation time was lower than group r. and the difference was statistically significant(p < .05). conclusions: as a result, pnl is an effective method and operation time is lower than rirs. also a second operation for jj stent taking is lower in pnl . rirs is a safe method. rirs has less complications and hospitalization time. they are feasible in treatment of ≥ 4 cm sized kidney stones. keywords: nephrolithiasis; percutaneous nephrolithotomy; retrograde intrarenal surgery introduction big sized ( ≥ 4 cm) kidney stone management is a rare seen problem in urology. kidney stones are detected in the early period with developing technology and screening methods. however big sized stones can be seen. percutaneous nephrolithotomy(pnl) is the first choice in the management of these stones. but serious life threatening complications can be seen in pnl(1). pnl may not be suitable in patients with morbid obesity, bleeding disorders and anatomic anomalies complicating percutaneous access(2,3).there are several publications asserting the feasibility of pnl and even equal complications in patients with obesity.(4) retrograde intrarenal surgery(rirs) is recently seen method. it is used more and more due to new technology. rirs is a safe method. serious complications are rarely seen in rirs. rirs was used at first in the management of <2 cm sized stones.(5) rirs was used in the management of > 2 cm sized kidney stones with the advanced technology.(6) rirs is used in big sized stones too. in 1department of urology, university of health sciences , diskapi yildirim beyazit training and research hospital , ankara, turkey. 2department of urology, bozok university, yozgat, turkey. 3department of urology, çubuk state hospital, ankara, turkey. 4department of urology, karabük university, karabük, turkey. 5department of urology, hitit university, çorum, turkey. *correspondence: studio deluxe aparts yozgat türkiye 00905356608838. sercansari92@hotmail.com. received july 2017 & accepted april 2018 our study we aimed to compare the efficiency and safety of rirs and pnl methods for the management of big sized kidney stones. materials and methods we retrospectively analysed the data of patients undergoing operation for kidney stone between 2011-2015 years in ankara dıskapı yıldırım beyazıt training and research hospital. patients with ≥ 4 cm sized stones were evaluated. laboratory examinations and radiologic imagings were done preoperatively. urine cultures were sterile preoperatively. stone size was determined as the longest diameter in the kidney ureter bladder graphy(x-ray kub) for radiopaque stones and for nonopaque stones, the longest diameter in ultrasound were determined as the size of the stones. the longest diameter of each stone is measured in multiple stones. and the sum of all is defined as the size of stone. before the operation informed consent was taken from all patients. 1 hour before the operation parenteral antibiotic was administered to all patients. treatment method was devol 16 no 03 may-june 2019 232 fined according to the choice of the surgeon and patient. 94 patients were included in the study. rirs was performed under general anesthesia. 7.5 french (f.) flexible renoscope was used. (flex x2 karl storz, tutlingen, germany). routine rigid renoscopy was performed before flexible renoscopy for dilating ureter in modified supine lithotomy position. under fluoroscopic control 0.035/0.038 inch hydrophilic guidewire was placed. later ureteral access sheath was placed over the hydrophilic guidewire. in case of displacement of ureteral access sheath, flexible renoscope was placed over the guidewire. with 200 mm holmium: yttrium-aluminum-garnet laser probe (dornier medilas h20; med tech, munich, germany), stone fragmentation was performed. dusting and fragmentation were used by surgeons. jj stent was inserted according to intraoperative conditions. time between starting endoscopy and completion of jj stent insertion was calculated as operation time. pnl was performed under general anesthesia. in modified supine lithotomy position, open ended ureter catheter was inserted. patient was taken to prone position. percutaneous access was supplied by 18 gauge needle under fluoroscopic control. 0.035 inch j tipped guidewire was placed into collecting system over the needle under fluoroscopic control. dilatation was performed with amplatz dilatators (microinvasive, natick. ma) up to 30 f. later rigid nephroscope (26 f, karl storz®) was placed. stone was fragmented with pneumatic lithotripter (lithoclast; ems, nyon, switzerland). the stones fragments removed with forceps through a rigid nephroscope (26f, karl storz®). at the end of the procedure, percutaneous nephrostomy tube was inserted. time between starting endoscopy and end of nephrostomy fixation was calculated as operation time. after intraoperative fluoroscopic control and postoperative first day control with x-ray kub and ultrasound, patients who were stone-free or with clinically insignificant urolithiasis(< 4mm) one month after the last operation were considered to have been treated successfully. jj stent was taken 3 weeks later. in case of being unsuccessful, second operation was planned 3 weeks later. the patient and operation datas such as stone size, operation and fluoroscopy time, hospitalization time, success rates, jj stent placement, stone free rates and complication rates of two groups were compared. complications were evalutaed according to modified clavien grading system. the data was analysed with spss version 16. we used chi square test for qualitative variables and student-t test for continuous values. normality was checked before using t-test. p < .05 value was accepted as statistically significant. results 67 patients were in pnl group and 27 patients were in rirs group. the mean age and body mass index(bmi) were higher in group p. the difference was not statistically significant.(p=.278 and .848) stone laterality, urinary anomaly and gender were similar in two groups. in group p, 16(23.9%) patients have previous surgery history. in group r, five(18.5%) patients have previous surgery history. in group p, 13(19.4 %) patients had shock wave lithotripsy history(swl). in group r eight(30.8%) patients had swl history. in group p, 61(91%) patients have opaque stones. in group r, 24(89%) patients have opaque stones. stone number and stone size were similar between group p and r. (table 1) in the pnl group, (group p) the important part of the stones were multicaliceal. in the rirs group,(group r) important part of the stones were multicaliceal similarly. (table 1) operation time was statistically significantly shorter in group p. (p = .036) fluoroscopy time and hospitalization time were statistically significantly longer in group p.(p = .041/.047) jj stent placement rate was statistically significantly lower in group p.(table 2) success rate was statistically significantly higher in group p. in group r, two patients have unsuccessful operation due to narrow ureter. four patients have unccessful operation due to narrow infundibulopelvic angle and two patients have unsuccessful operation due to stone burden. in group p, ten patients have unsuccessful operation due to stone burden.(table 2) complications were seen in five patients of group p rirs vs. pcnl for stone> 4cm-karakoyunlu et al. group p (pnl) (n=67) group r(rirs) (n=27) p value age (sd± ) (years) 49.81 ± 12.80 46.56 ± 13.66 .278 gender male/female (n) 47/20 18/9 .741 bmi (sd±) (kg/m2) 24.91 ± 3.02 24.77 ± 3.01 .848 previous surgery history, n (%) 16 (23.9) 5 (18.5) .342 swl öyküsü, n (%) 13 (19.4) 8 (30.8) .273 opacity, n (%)61(91) 24(89) .72 urinary anomaly, n (%) 2 (3) 2 (7.4) .142 stone laterality right/left (n) 25/42 14/13 .542 stone number (sd ±) (n) 2.55 ± 1.44 2.78 ± 1.42 .494 stone size (sd ±) (mm) 47.06 ± 7.02 46.41 ± 6.00 .740 stone localization, n .386 renal pelvis 14/67 8/27 lower calyx 6/67 4/27 mid calyx 2/67 2/27 upper calyx 0 2/27 multicaliceal 45/67 11/27 diverticule 0 0 table 1. demographic data and stone characteristics. abbreviations: rirs, retrograde intrarenal surgery; pnl, percutaneous nephrolithotomy; bmi, body mass index; swl, shock wave lithotripsy; sd, standard deviation endourology and stones diseases 233 vol 16 no 03 may-june 2019 234 and one patient of group r. in group p blood transfusion was made for three patients. in group p one patient died due to cardiac arrest. fever was seen in one patient of each group.(table 2) in group p, four patients had rirs and three patients had swl in unsuccessful patients. in group r, eight patients had second rirs and one patient had swl in unsuccessful group. one patient in each group did not follow up. (table 3) discussion big sized kidney stone is a rare seen urological problem. the first choice is pnl in management but rirs is used in the management of big sized stones recently. aso et al. reported 50 % stone clearence rate and 50 % fever in a study they performed flexible ureteroscopic electrohydraulic lithotripsy for 34 staghorn kidney stones(7). mariani used combined electrohydraulic lithotripsy and holmium: yag laser ureteroscopic nephrolithotripsy methods for > 4 cm sized kidney stones in 17 renal units and reported 88 % stone free rate. fever was seen in three patients and pneumonia was seen in one patient three days later discharge(8). in our study stone free rate was 51.8 % and success rate was 62.9 % in group r. one patient had fever in group r. there are few studies comparing treatment methods in management of big sized kidney stones. haggag et al. compared laparoscopic nephrolithotomy(lnl) and pnl methods in big sized renal pelvic kidney stone management. 50 patients were included in the study.(40 pnl, 10 lnl) stone free rate was 78.6 % and complication rate was 35.7 % in pnl group(9). singh et al. compared retroperitonoscopic pyelolithotomy and pnl methods for management of > 3 cm sized solitary pelvic stones. stone free rate was 72.7 % for pnl group in 44 patients study(10). laparoscopic pyelolithotomy can be also used in treatment of big sized kidney stones(11). in our study stone free rate was 62.68 % in group p. in our study fluoroscopy and hospitalization time were higher in group p. fluoroscopy time was higher due to time for percutaneous access. hospitalization time was higher due to time taking percutaneous nephros group p (pnl) (n=67) group r (rirs) (n=27) p value operation time ( ± sd) (min.) 61.88 ± 20.93 83.29 ± 14.17 .036 fluoroscopy time( ± sd) (min) 5.55 ± 3.32 2.22 ± 0.42 .041 dilatation method, n (%) baloon amplatz 67/67(100) access number, n (%) 1 67/67(100) 2 access calyx, n (%) lower 65/67(97.01) mid 2/67(2.99) upper 0 diverticule 0 nephrostomy tube, n (%) tubeless present 67/67 stone-free (%) stone free 42/67(62.69) 14/27(51.85) cirf 17/67(25.37) 3/27(11.11) the rest 8/67(11.94) 10/27(37.04) .039 nephrostomy duration time (± sd) (day) 3 hospitalization time ( ± sd) (day) 3.06 ± 0.29 1.07 ± 0.38 .047 complications (n) (%) grade i fever 1(1.5) 1(3.7) .670 grade ii blood transfusion 3 (4.5) .347 urınary tract infection 1(1.5) 1(3.7) .670 grade iii grade iv exitus 1(1.5) table 2. intraoperative and postoperative data. abbreviations: rirs, retrograde intrarenal surgery; pnl, percutaneous nephrolithotomy; swl, shock wave lithotripsy; sd, standard deviation; cirf, clinically insignificant residuel fragment sd: standard deviation group p (pnl) (n=67) group r (rirs) (n=27) p value rirs 4/8 8/10 re pnl 0 0 swl 3/8 1/10 jj stent placement, n (%) 27(40.3) 22(81.5) .047 abbreviations: rirs, retrograde intrarenal surgery; pnl, percutaneous nephrolithotomy; swl, shock wave lithotripsy table 3. procedures performed to the unsuccessful patients. rirs vs. pcnl for stone> 4cm-karakoyunlu et al. tomy tube. tubeless pnl can decrease hospitalization time. the decision of tubeless pnl is given according to intraoperative conditions. in our study there was no patient tubeless pnl performed. in our study operation time was 61.88 ± 20.93 minutes in group p and 83.29 ± 14.17 minutes in group r. in a study in which ureteroscopic nephrolithotomy was performed for > 4 cm sized kidney stones in 17 renal units, average operation time was 49 minutes.(8) the mean operation time was 51.19 ± 24.39 min. in a study in which pnl was performed for big sized kidney stones. (9) in our study, operation time was higher in group r due to stone fragmentation time and high patient number in group r. complication number was higher in group p. according to modified clavien grading system, one grade 2 and one grade 1 complications were seen in group r. four grade 2 and one grade 4 complications were seen in group p.(12) bleeding is frequent in pnl. bleeding may occur at a level that requires embolization to a conservative approach. meria et al. reported three venous bleeding in 16 patient study.(13) in our study transfusion needed bleeding was seen in three patients in group p. one patient died due to cardiac arrest in group p. the limitations of the study are retrospective design and low patient number. large patient number and prospective designed studies are needed. conclusions as a result for the management of big sized kidney stones, pnl and rirs are effective and safe methods. pnl is an effective method and operation time is lower than rirs. also a second operation for jj stent taking is lower in pnl . rirs is a safe method. rirs has less complications and hospitalization time. conflict of interest there is no conflict of interest among the authors. references 1. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol 2007;51:899-906 2. symons s, biyani cs, bhargava s et al. challenge of percutaneous nephrolithotomy in patients with spinal neuropathy. int j urol 2006;13:874-9. 3. rizvi sa, naqvi sa, hussain z, et al. the management of stone disease. bju int 2002;89(s1):62-8. 4. ozgor f, ucpinar b, binbay m. effect of obesity on prone percutaneous nephrolithotomy outcomes: a systemic review. urol j. 2016 mar 5;13:2471-8. 5. javanmard b, kashi ah, mazloomfard mm, ansari jafari a, arefanian s. retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j. 2016;13:2823-8. 6. atis g, culpan m, pelit es et al. comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery in treating 2040 mm renal stones. urol j. 2017;14:2995-9. 7. aso y, ohta n, nakano m, et al. treatment of staghorn calculi by fiberoptic transurethral nephrolithotripsy. j urol 1990;144:17. 8. mariani aj. combined electrohydraulic and holmium: yag laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. urolithiasis; 177:168-173. 9. yasser m. haggag, gamal morsy, magdy m. badr, et al. comparative study of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in the management of large renal pelvic stones. can urol assoc j 2013; 7:e:171-175. 10. singh v., sinha r.j., gupta d.k. et al. prospective randomized comparison of retroperitoneoscopic pyelolithotomy versus percutaneous nephrolithotomy for solitary large pelvic kidney stones. urol int 2014;92:392-395. 11. nouralizadeh a, kashi ah, valipour r, nasiri kopaee mr, zeinali m, sarhangnejad r. bilateral laparoscopic stone surgery for renal stonesa case series. urol j. 2017;14(6):5043-6. 12. tefekli a, karadag ma, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard european urology 53 ( 2 0 0 8 ) 184–1 13. meria p, milcent s, desgrandchamps f et al. management of pelvic stones larger than 20 mm: laparoscopic transperitoneal pyelolithotomy or percutaneous nephrolithotomy? urol int 2005;75:322-6. rirs vs. pcnl for stone> 4cm-karakoyunlu et al. endourology and stones diseases 235 pictorial cystic retroperitoneal mass due to ureteral injury as an outcome of lumbar disc hernia operation süha akpinar,1 güliz yilmaz,1* emre çelebioğlu2 retroperitoneal organ injury, especially ureteral injury, is a rare complication associated with surgical repair of lumbar disc hernia (ldh).(1-3) a 44-year-old male patient was admitted to the urology department with a history of left flank pain, fever, and intermittent hematuria. he had a history of repeat surgical repair of an ldh at the same level 1 month previously. ultrasound examination revealed a multiloculated cystic mass anterior to the psoas muscle, and abdominal computed tomography scan showed grade 1 hydronephrosis with proximal ureteral dilatation and free fluid in the pelvis (figure 1a and b). a 10 french (f) pigtail ureteral drainage catheter was percutaneously inserted into the cystic mass under ultrasound guidance with a prediagnosis of abscess or urinoma (figure 2). owing to continuous urine drainage, antegrade pyelography was performed at the time of fluoroscopy and revealed ureteral discontinuity and extravasation of contrast material (figure 3). therefore, a 10 f nephrostofigure 1. axial computed tomography scan of the abdomen. (a) a retroperitoneal multiloculated cystic mass is indenting the left psoas muscle (thick arrow), and lateroconal fascial thickening is present (thin arrow). (b) grade 1 hydronephrosis (thick black arrow), posterior perirenal fluid (white arrow), and a cystic mass anterior to the left psoas muscle (thin black arrow) are evident. figure 2. axial computed tomography scan of the abdomen. a 10 french pigtail ureteral catheter is draining the giant urinoma (arrow). figure 3. antegrade pyelography. mid-ureteral discontinuity (thin arrow), contrast material extravasation distal to the ureteral avulsion (thick arrow), and insertion of the pigtail catheter into the retroperitoneal urinoma (arrowhead) are shown. 1 department of radiology, faculty of medicine, near east university, nicosia, north cyprus, turkey. 2 department of radiology, burhan nalbantoğlu state hospital, nicosia, north cyprus, turkey. *correspondence: department of radiology, faculty of medicine, near east university, nicosia, north cyprus, turkey. tel: +90 392 6751000. fax: +90 392 6751090. e-mail: glz.yilmaz@hotmail.com. received december 2014 & accepted june 2015 pictorial 2291 my catheter was placed in the collecting system of the left kidney to control the extravasation of urine. endto-end ureteroureterostomy was followed by double j ureteral catheter placement, and the catheter was left in place for 2 months. during the follow-up period, the extravasation of urine stopped and hydronephrosis resolved without any narrowing at the ureteral injury site. conflict of interest none declared. references 1. demirkesen o, tunç b, ozkan b. a rare complication of lumbar disk surgery: ureteral avulsion. int urol nephrol. 2006;38:459-61. 2. trinchieri a, montanari e, salvini p, berardinelli l, pisani e. renal autotransplantation for complete ureteral avulsion following lumbar disk surgery. j urol. 2001;165:1210-1. 3. turunç t, kuzgunbay b, gul u, ozkardes h. ureteral avulsion due to lumbar disc hernia repair. can j urol. 2010;17:5478-9. vol 12 no 04 july-august 2015 2292 ureteral injury as an outcome of lumbar disc hernia operation-akpinar et al. pediatric urology incidence of complications following thermocautery-assisted circumcisions ahmet ali tuncer1*, mutlu deger2 purpose: this study aimed to examine the shortand long-term complications of thermocautery-assisted circumcisions. materials and methods: a total of 1780 children who consecutively underwent thermocautery-assisted circumcisions from may 2014 to may 2016 in yuksekova state hospital in turkey were included in this study. these children were classified into perioperative, early postoperative, and long-term complication groups. in addition, the age groups were compared in terms of complications. results: the patient age and surgical duration means were 4.16 ± 3.805 years old and 6.14 ± 1.703 minutes, respectively. complications were observed in twelve patients, or 0.6% of the whole observation set. one patient exhibited bleeding and was included in the perioperative complications group. four patients were included in the early postoperative complications group; three of them had bleeding and one had an infection. finally, three patients had trapped penises, two patients had meatitis, one patient had a delayed wound healing issue, and one had a glans-skin bridge. these seven patients fell into the long-term complications group. the patients younger than 3 years old had significantly higher complication rates when compared to the older patients, and this comparison was statistically significant (p = 0.001). conclusion: the results showed that thermocautery-assisted circumcision is a safe and efficient surgical technique for use in children. keywords: circumcision; child; complication; surgical technique; thermocautery introduction male circumcision is a well-known surgical proce-dure performed worldwide(1). statistically, one out of every six men is circumcised globally. circumcisions can be performed using different approaches, including scalpels and scissors, clamps (ali’s clamp, mogen clamp, or shang ring), and electrical devices (thermocautery or bipolar cautery)(1,2). a circumcision reduces the risks of several serious illnesses, like urinary system infections, pyelonephritis, penile and prostate cancers, cervical cancer in female partners, human papillomavirus, herpes simplex virus 2, human immunodeficiency virus (hiv), and other sexually transmitted diseases(3,4). thermocautery has also been proven to be a cheap and practical circumcision method, and it has become more popular. however, there are not yet adequate academic studies of the shortand long-term complications of the thermocautery-assisted circumcision technique. this paper provides several statistical results and comparisons within a huge set of patients that underwent thermocautery-assisted circumcisions. the shortand long-term complications were examined, and the thermocautery-assisted circumcision technique was discussed in light of the current literature. patients and methods this research was carried out in accordance with the 1afyon kocatepe university, medical faculty, department of pediatric surgery, afyonkarahisar, turkey. 2yuksekova state hospital, clinic of urology, hakkari, turkey. *correspondence: afyon kocatepe university, medical faculty, department of pediatric surgery, ankara-izmir karayolu 8. km. 03200, afyonkarahisar, turkey. e-mail: drtaali@yahoo.com. received november 2017 & accepted january 2018 helsinki declaration rules, and with the approval of the local ethics committee (clinical ethics committee of afyon kocatepe university, date 02/03/2017, issue 2017/2-52). in addition, consent forms were obtained from the legal representatives of the patients for the use of the medical images. a total of 2700 children underwent circumcisions from may 2014 to may 2016 at the yuksekova state hospital in turkey. of those children, 737 were circumcised by a different surgeon. another circumcision method was used for 20 of the children. five patients were older than 18 years old, and 17 had systemic diseases. one hundred and fifteen patients had concurrent inguinal pathologies, 11 underwent recircumcisions due to complications, and 15 had megameatus intact preputium variants of hypospadias. therefore, in total, 920 of the 2700 enrolled patients were excluded from the statistical analysis. the remaining 1780 patients were classified into perioperative, early postoperative, and long-term complications groups. the perioperative complications group included bleeding during the circumcision or during the hospital stay. the early postoperative complications group included complications emerging during the first ten days after discharge from the hospital. the long-term complications group included those complications occurring ten or more days after discharge from the hospital. the surgical complications related to the circumcisions were evaluated according to the modified clavien-dindo classification system(5). pediatric urology 359 vol 15 no 06 november-december 2018 360 the following symptoms were not evaluated as complications: foreskin swelling, glans penis incrustation due to a phimosis opening, or a temporary color change after local anesthesia. circumcision technique the circumcisions were performed under local anesthesia using bupivacaine hcl (marcaine 0.5%; astrazeneca, istanbul, turkey) and prilocaine hcl (citanest 2%; astrazeneca, istanbul, turkey). while the guillotine technique was being applied, the cutting and bleeding control were performed using a thermocautery device (thermo-med tm 802-b; thermo medical, adana, turkey). while cutting, the appropriate heat level was chosen from among the six different device adjustments (degrees) according to the patient’s age and foreskin thickness. after the bleeding was controlled with the thermocautery device, the skin-mucosa connection was provided with 5/0 absorbable sutures, and the wound was dressed. two different surgeons (the authors of this paper) performed the circumcisions as described above. the patient was observed for one hour after the circumcision. after that, the patient and parents were advised to continue with their daily life routines. in those cases in which an excoriation due to phimosis opening, the patient or his parents were advised to apply epithelizing cream to the wound. after all the circumcised infants and children were controlled on the 10th postoperative day, only the patients with complications were followed for the long-term. the possible complications were explained to the patients and parents, and we asked them to visit the hospital if any symptoms developed, such as penile bleeding, color change, or shape change. in those cases, the patients were assessed, followed up, and treated by the first author of this paper. statistical analysis the observation set, which consisted of those patients circumcised using the thermocautery-assisted method, was evaluated with the statistical package for the social sciences software (spss inc., chicago, il, usa). the data distribution was examined using the kolmogorov-smirnov test. the continuous variables were expressed as the mean ± standard deviation (range: minimum–maximum), and the appropriate categorical variables were denoted as the numbers and percentages. the chi-squared and mann-whitney u tests were applied to evaluate the categorical data and the quantitative variables, respectively. two-tailed p values of less than 0.05 were accepted as statistically significant. results the mean age of the patients was 4.16 ± 3.805 years old (range: 14 days–18 years old). the average surgical duration was 6.14 ± 1.703 minutes (range: 4–15 minutes). complications were observed in twelve patients, or 0.6% of the whole dataset. the complications were evaluated according to the modified clavien-dindo classification method (table 1). one patient had bleeding from the suture line, which was classified as a perioperative complication. the bleeding was stopped immediately via cauterization. one infection and three bleeding cases were classified as early postoperative table 1. thermocautery circumcision complication rates. patient age clavien-dindo classification treatment complication perioperative bleeding (n=1) 1y 3a cauterization early postoperative (< 10 days) bleeding (n=3) 15y, 1y, 2y 3a, 3a, 3a cauterization, dorsal vein knotting, frenular artery knotting infection (n=1) 1 2 medical late postoperative (> 10 days) secondary phimosis/trapped 3m, 6m, 8m 3b, 3b, 3b redo surgery penis (n=3) meatitis (n=2) delay in wound healing (n=1) glans-skin bridge (n=1) 40d, 2y 2 medical 2y 1 medical 6m 3a surgical abbreviations: d, day; m, month; y, year; n, number figure 1. long-term complications of thermocautery-assisted circumcision: a. trapped penis, b. meatitis, c. glans-skin bridge. thermocautery circumcision complicationstuncer et al. complications. the infection was treated with antibiotics and a dressing. due to a ligated artery, a one-yearold patient had frenular artery bleeding on the first day after the circumcision. one two-year-old patient had dorsal vein bleeding that was treated via vein ligation. a fifteen-year-old patient had suture line bleeding due to a hard dressing, but the bleeding was stopped via thermocauterization. seven patients fell into the late complications group (figure 1). the penises of three patients were trapped, table 2. a sample of the circumcision techniques and complication rates in the current literature (2, 13, 15-24, 30). first author technique number of patients duration of surgery complication rate and major complications tuncer (present study) thermocautery 1780 6.14 ± 1.703 min 0.67% -bleeding (n=4, 0.22%) -trapped penis (n=3, 0.16%) -meatitis (n=2, 0.11%) -delay in wound healing (n=1, 0.05%) -infection (n=1, 0.05%) -glans-skin bridge (n=1, 0.05%) aslan (2) thermocautery 5781 -bleeding (0.05%) -scrotal abscess (0.01%) -tachycardia and syncope after injection (0.01%) saracoglu (15) thermocautery 55 5.15 min -hyperesthesia of the glans penis (n=6, 12%) conventional technique 55 13.55 min -hyperesthesia of the glans penis (n=5, 10%) -secondary phimosis (n=1, 1.8%) kazeem (13) plastibell device 3760 -bleeding (0.5%) frenular manual compression -urinary retention (0.32%) -delay in wound healing (0.15%) ophthalmological 3750 -bleeding (0.05%) thermal cautery -urinary retention (0.93%) -delay in wound healing (0.77%) méndez-gallart (16) bipolar diathermy 115 10.8 ± 1.2 min -edema (19%) scissors conventional scalpel 115 19.1 ± 2.6 min -edema + bleeding (11.3%) technique jimoh (17) plastibell 2276 1.1% -bleeding (n=12, 0.52%) -retained plastibell (n=11, 0.48%) -wound infection (n=1) young (18) mogen 1239 2.7% -bleeding (n=10, 0.80%) -too little foreskin removed (n=9, 0.72%) -infection (n=5, 0.40%) -meatal abrasion (n=3, 0.24%) -impetigo (n=3, 0.24%) -damage to the glans (n=1, 0.08%) senel (19) ali's clamp 7500 4.5 ± 1.5 min 2% -buried penis (n=78, 1.04%) -infection (n=45, 0.6%) -bleeding (n=30, 0.4%) conventional 5700 23 ± 4 min 10.4% -buried penis (n=68, 1.2%) -infection (n=238, 4.2%) -bleeding (n=285, 5%) huang (20) shang ring 2589 19.16 min 1.27% awori (21) no-flip shang ring 80 circumcision 5% 7.4 ± 3.2 min -wound disruption (n=2, 2.5%) ring removal -pain during removal (n=1, 1.25%) 4.4 ± 4.2 min -wound disruption with mild infection (n=1, 1.25%) amir (22) gomco 1000 1.9% -bleeding (n=6, 0.6%) -preputial adhesions (n=4, 0.4%) -superficial sepsis (n=4, 0.4%) -inadequate (n=3, 0.3%) -frenular ulcers (n=2, 0.2%) buwembo (23) -dorsal slit 2471 22.5 min 0.6% -bleeding (n=9, 0.36%) -infections (n=5, 0.20%) -other (n=1, 0.04%) -sleeve 2681 25.3 min 1.4% -bleeding (n=20, 0.75%) -infections (n=12, 0.45%) -wound dehiscence and infection (n=2, 0.08%) -other (n=2, 0.07%) mavhu (24) prepex device 1000 -prepex removal (n=10, 1%) -pain (n=12, 1.2%) shen (30) langhe disposable 89 8.1 ± 2.0 min -second operation for bleeding (n=2, 2.2%) circumcision suture device -infection (n=4, 4.7%) -blood loss (4.21 ± 1.31 ml) -cases requiring manual staple removal (7/85) daming disposable 94 7.6 ± 2.2 min -infection (n=13, 13.8%) circumcision suture device -blood loss (2.56 ± 1.45 ml) abbreviation: min, minute thermocautery circumcision complicationstuncer et al. pediatric urology 361 vol 15 no 06 november-december 2018 362 and they were surgically circumcised again. a 40-dayold patient developed meatitis three months after the circumcision, while a two-year-old patient had the same issue six months after the circumcision. both children were medically treated. one patient exhibited delayed wound healing 20 days after the circumcision, and ointment was applied daily to the penis. finally, one patient had a glans-skin bridge complication six months after the circumcision and was surgically treated. except for one patient, complications were only observed in children younger than 3 years old (n < 3 = 781, n3 ≤ –18 = 999). therefore, the patients younger than 3 years old had significantly higher complication rates when compared to the older patients (p = 0.001). a total of 1310 circumcisions were performed by the first author, and 9 (0.7%) of these patients developed complications. the second author performed 470 circumcisions, and complications developed in 3 of the patients (0.6%). according to the analysis, these two surgeons had statistically similar complication rates (p = 0.912). discussion male circumcisions are very popular worldwide, and they are considered to be simple surgical procedures. however, a circumcision can lead to serious complications(1). although there are different studies of the various circumcision methods in the literature, researchers are still debating the most convenient circumcision age and the safest circumcision method. the applied technique should be practical, cheap, and safe, and it should induce very few or no complications. for this purpose, we compared the thermocautery-assisted method with the other circumcision methods in terms of the early and long-term complications. the early complications included bleeding, pain, inadequate skin removal, infection, chordee, iatrogenic hypospadias, glanular necrosis, and glanular amputation. the long-term complications included epidermal inclusion cysts, suture sinus, penile adhesions, phimosis, urethrocutaneous fistula, trapped penis, meatitis, and meatal stenosis(3, 6,7). in addition, hydronephrosis and permanent renal damage can be caused by a meatal stenosis(8). the thermocautery-assisted technique exploits the heat energy used for cauterizing. when compared with the monopolar cautery technique, which uses an electrical current, the thermocautery-assisted method carries the heat locally. according to the skin features of the patient, the heat levels are adjustable on the most recently developed thermocautery devices. previous studies have shown that optimum hemostasis is achieved with a temperature ranging between 100°c and 400°c. although a range between 350°c and 900°c can be obtained within in vivo environments, the highest heat level is reduced by half in a bloody environment(9). thermocautery devices have been used successfully in local dermatological excisions with the implementation of cardiac devices(9). however, there have been few studies on the use of thermocauterization in circumcisions(2,10-12). it has been shown that the thermocautery technique results in similar wound healing when compared to the scalpel technique(11). aslan et al. performed mass circumcisions with thermocautery devices in sudan, and they reported a complication rate of 0.086% in the early postsurgical period (3 weeks). these complications included bleeding, scrotal abscess, tachycardia, and syncope after the local anesthesia injection(2). kazem et al. performed 3-minute manual frenular compressions for bleeding control in 3760 newborn patients undergoing plastibell circumcisions. they also used an ophthalmological thermocautery technique on a different study set including 3750 patients. while a 0.5% complication rate was observed in the first group, the thermocautery method exhibited a 0.05% complication rate(13). although urinary retention has been reported when using the plastibell technique, the ophthalmological thermocautery-assisted circumcisions took longer with regard to urinary retention and wound healing(13,14). according to our observations, the circumcision line usually heals within 7 days when using the thermocautery technique. we observed that the wound healing was extended to 20 days in only one patient in our data set. moreover, urinary retention was not observed in any of our thermocautery-assisted circumcisions. saraçoglu et al. compared the thermocautery technique with conventional circumcisions in their prospective study. hyperesthesia of the glans penis was observed in 12% of the patients with the thermocautery method and 10% of the patients with the surgical method. in the long-term follow-up, 0.9% of the patients who underwent the surgical circumcisions had secondary phimosis(15). although the short-term complications were examined in these studies, there have not been adequate observations of the long-term complications. this paper provides a complete evaluation of the thermocautery-assisted circumcision technique with respect to the shortand long-term complications. the patients in our dataset were followed up postoperatively for one to three years. since the cauterization is performed during the cutting process in the thermocautery technique, the bleeding risk is less when compared to the other methods. here, the long-term complications observed when using the thermocautery technique have been reported for the first time in the english literature. all of the complications, except for one patient, were observed in children under three years old, and a statistically significant difference was found among the age groups in terms of the complications. in recent years in turkey, circumcisions have been increasingly preferred for children at earlier ages, due to the belief that this leads to faster wound healing. however, our study results show that this may not be accurate. our observations show that children older than three years have less shortand long-term complications when undergoing circumcisions. there are many different circumcision techniques currently in use, and these have been summarized in the context of the current literature in table 2 (2,13,15-24, 30). for example, the plastibell circumcision technique can be applied safely in infants from newborns to one-yearolds(25). the operation takes between five and ten minutes, and the plastibell is abandoned in the penis for one or two weeks until it comes off by itself. complications related to this method have been reported in 3% of the patients(25), and jimoh et al. reported a complication rate of 1.1% in their plastibell study of 2276 patients(17). the mogen clamp is often used among the jewish population(26), and young et al. reported a complication rate of 2.7% in their mogen clamp study of 1239 patients(18). ali’s clamp is a tool widely used in turkey. it consists of a whistle-shaped tube on the glans and a ring that thermocautery circumcision complicationstuncer et al. compresses the foreskin through it. the average duration of this application is approximately five minutes. senel et al. reported a complication rate of 2% in their ali's clamp study of 7500 patients(19). they showed that ali’s clamp is easier to apply, and the operation time was less than in the other current methods, with fewer complications(19). another technique uses the shang ring, which was developed in china. it is an apparatus that compresses the foreskin between two rings; however, this method carries the risk of glans amputation(27). the ring is removed after 5–7 days(21). in one meta-analysis including 18 randomized clinical studies, huang et al. reported a complication rate of 1.27% in 2589 patients circumcised using shang rings(20). the gomco method uses a metal clamp with a bell-shaped tip, and amir et al. reported a complication rate of 1.9% in their study of 1000 patients(22). ozen et al. reported that 13 newborns who were circumcised using the gomco technique developed meatal stenoses. meatoplasties were used to treat these patients(7). the dorsal slit, guillotine, and sleeve methods are defined as open circumcision surgical techniques. for the dorsal slit method, a vertical incision is made in the forward direction; then, an appropriate amount of mucosa is selected with the foreskin and removed by cutting the tissue around the penis with scissors. following hemostasis, the remaining skin and mucosa are stitched together. in the sleeve technique, the incision on the foreskin is done circularly with a scalpel, and the mucosal boundaries are excised. the skin is cut in the form of a band and then removed. this process is followed by hemostasis and stitching. buwembo et al. reported a complication rate of 0.6% in their dorsal slit study of 2471 patients, and a complication rate of 1.4% in their sleeve study of 2681 patients(23). the application of monopolar diathermy runs the potential risk of coagulation due to the electrical current at the penile base(28). previous studies have revealed serious complications, such as penile ablation, necrosis, and gangrene(29). shen et al. compared two disposable circumcision suture devices (langhe and daming). complications such as bleeding, manual staple removal, and infections are frequently observed when using these devices(30). the relatively small cohort size, retrospective design, and lack of standardization among the surgical techniques of the operating surgeons are the limitations of this research study of the thermocautery-assisted circumcision method. conclusions the results of this study show that thermocautery-assisted method is a safe, practical, reliable, and efficient technique for performing male circumcisions. acknowledgements the authors wish to thank prof. dr. salih çetinkursun and mehmet ali çagrı tuncer for the critical review of this manuscript. the authors received no financial support for the research, authorship, and/or publication of this article. conflicting interests the authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. thermocautery circumcision complicationstuncer et al. references 1. dunsmuir wd, gordon em. the history of circumcision. bju internatıonal. 1999; 83:112. 2. arslan d, kalkan m, yazgan h, unuvar u, şahin c. collective circumcision performed in sudan: evaluation in terms of early complications and alternative practice. urology. 2013; 81:864-8. 3. krill aj, palmer ls, palmer js. complications of circumcision. scientific world journal. 2011; 11:2458-68. 4. cao d, liu l, hu y, et al. systematic review and meta-analysis of circumcision with shang ring vs conventional circumcision. urology. 2015; 85:799-804. 5. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009; 250:187-96. 6. eke n. major surgical complications from minor urological procedures. j natl med assoc. 2000; 92:196-9. 7. özen ma, gündoğdu g, taşdemir m, eroğlu e. complication of newborn circumcision: meatal stenosis or meatal web? j pediatr urol. doi: 10.1016/j.jpurol.2017.05.007 [epub ahead of print] 8. saeedi p, ahmadnia h, akhavan rezayat a. evaluation of the effect of meatal stenosis on the urinary tract by using ultrasonography. urol j. 2017; 14:3071-4. 9. lane je, o'brien em, kent de. optimization of thermocautery in excisional dermatologic surgery. dermatol surg. 2006; 32:669-75. 10. abdel hay s. the use of thermal cautery for male circumcision. jkau med sci. 2009; 16:89-93. 11. tuncer aa, bozkurt mf, bayraktaroğlu a, et al. examination of histopathological changes of scalpel, monopolar, bipolar, and thermocautery applications in rat experimental circumcision model. am j transl res. 2017; 9:2306-13. 12. karaman mi, zulfikar b, caskurlu t, ergenekon e. circumcision in hemophilia: a cost-effective method using a novel device. j pediatr surg. 2004; 39:1562-4. 13. kazeem mm, mehdi az, golrasteh kz, behzad fz. comparative evaluation of two techniques of hemostasis in neonatal circumcision using the plastibell® device. j pediatr urol. 2010; 6:258-60. 14. mihssin n, moorthy k, houghton wj. retention of urine: an unusual complication of the plastibell device. bju int. 1999; 84:747. 15. saracoglu m, ozturk h, zengin t, kerman hs. comparison of thermal cautery-assisted circumcision with the conventional technique. pediatric urology 363 vol 15 no 06 november-december 2018 364 human andrology. 2014; 4:34-7. 16. méndez-gallart r, estévez e, bautista a, et al. bipolar scissors circumcision is a safe, fast, and bloodless procedure in children. j pediatr surg. 2009; 44:2048-53. 17. jimoh bm, odunayo is, chinwe i, akinfolarin oo, oluwafemi a, olusanmi ej. plastibell circumcision of 2,276 male infants: a multicentre study. pan afr med j. 2016; 23:35. 18. young mr, bailey rc, odoyo-june e, et al. safety of over twelve hundred infant male circumcisions using the mogen clamp in kenya. plos one. 2012; 7:47395. 19. senel fm, demirelli m, oztek s. minimally invasive circumcision with a novel plastic clamp technique: a review of 7,500 cases. pediatr surg int. 2010; 26:739-45. 20. huang c, song p, xu c, wang r, wei l, zhao x. comparative efficacy and safety of different circumcisions for patients with redundant prepuce or phimosis: a network meta-analysis. int j surg. 2017; 43:17-25. 21. awori qd, lee rk, li ps, et al. use of the shang ring circumcision device in boys below 18 years old in kenya: results from a pilot study. j int aids soc. 2017; 20:1-8. 22. amir m, raja mh, niaz wa. neonatal circumcision with gomco clamp--a hospitalbased retrospective study of 1000 cases. j pak med assoc. 2000; 50:224-7. 23. buwembo dr, musoke r, kigozi g, et al. evaluation of the safety and efficiency of the dorsal slit and sleeve methods of male circumcision provided by physicians and clinical officers in rakai, uganda. bju int. 2012; 109:104-8. 24. mavhu w, hatzold k, ncube g, et al. safety and acceptability of the prepex device when used in routine male circumcision service delivery during active surveillance in zimbabwe. j acquir immune defic syndr. 2016; 72:63-8. 25. moosa fa, khan fw, rao mh. comparison of complications of circumcision by ‘plastibell device technique’ in male neonates and infants. j pak med assoc. 2010; 60:664-7. 26. reynolds rd. use of the mogen clamp for neonatal circumcision. am fam physician. 1996; 54:177-82. 27. abdulwahab-ahmed a, mungadi ia. techniques of male circumcision. j surg tech case rep. 2013; 5:1-7. 28. altokhais ti. electrosurgery use in circumcision in children: is it safe? urol ann. 2017; 9:1-3. 29. uzun g, ozdemir y, eroglu m, mutluoglu m. electrocautery-induced gangrene of the glans penis in a child following circumcision. bmj case rep. 2012. 30. shen j, shi j, gao j, et al. a comparative study on the clinical efficacy of two different disposable circumcision suture devices in adult males. urol j. 2017; 14:5013-7. thermocautery circumcision complicationstuncer et al. comparison of the effects of clofibrate and silafibrate on sperm parameters quality and sex hormones in male rats masoud delashoub1*, mojtaba ziaee2,3**, arash khorrami4,5, seyed mehdi banan-khojasteh6. purpose: fibrates are drugs widely used for the treatment of hyperlipidemic disorders. previous studies on a novel analogue of clofibrate, called silafibrate, have shown good lipid lowering effects. this study was designed to assess the role of silafibrate as a peroxisome proliferator-activated receptors (ppars) agonist on sperm health and spermatogenesis in adult male rats. material and methods: seventy male wistar rats were randomly allocated into 7 groups: cl-10, cl-20, and cl-40 mg/kg/day (clofibrate); si-10, si-20, and si-40 mg/kg/day (silafibrate); and c, control. after a 28-day treatment, all rats were euthanized. blood samples were taken for determination of testosterone, total antioxidant capacity, levels of malondialdehyde, and oxidized low-density lipoprotein. reproductive organs were dissected and spermatozoa collected from the epididymis for analysis. result: sperm parameters (count, motility, viability, and morphology) and total serum testosterone decreased significantly in clofibrate-treated (20 and 40 mg/kg) rats (p < 0.05) as compared with normal rats. conclusion: we conclude that ppars agonists have significant adverse effect on sperm viability, motility, and total serum testosterone, and could be harmful for sperm parameters and male reproductive function in rats. keywords: clofibrate; silafibrate; spermatogensis; rats. introduction infertility is a serious life problem. over the past dec-ades, an increasing body of evidence has indicated a steady and dramatic increase in prevalence of infertility: 10-15% of all couples of reproductive age in our times suffer from infertility(1,2). approximately 50% couples’ infertility is due to impaired semen parameters(3). multiple conditions may interfere with spermatogenesis process and cause decline in sperm quality and production(4). several factors—such as medicines, toxins, and diseases—lead to impaired spermatogenesis at different stages(5). fibrates, peroxisome proliferator-activated receptor-α (ppar-α) agonists are effective in treatment of hypertriglyceridaemia and hypercholesterolaemia(6). fibrates differ in their potency, and it seems a structure–activity relationship (sar) exists(7). the pharmacologic and toxicologic properties of silafibrate as a potent analogue of clofibrate have been studied in experimental animals(7) but it has not been clinically trialed in human yet. studies have been shown that silafibrate causes significant reduction in toxicity(7). sperm viability and motility are important for convince and are essential factors in evaluating the fertilizing ability of sperm. relation between the velocity of sperm motility and fertilization rates have been proved(8). the lipid and fatty acids which constitute spermatozoa can modulate their mobility and viability(9). several studies have been conducted to focus on the association of fibrates with male infertility. cook et al. showed clofibrate may cause suppression of spermatogenesis at dosages ranging from 160 to 240 mg/kg(10). however, results also show some variation, and the exact molecular mechanism(s) of action are still poorly known. it has not been clearly understood if the suppressive effect of clofibrate is cause by ppar-α receptors or by its chemical properties. similarly, the functional role of peroxisomes in spermatogenesis and fertility is not known exactly(11). the second interest in the present study is to evaluate the androgenic effects of different doses of silafibrate as a novel ppar-α agonist on sperm parameters by using hormone measurements. we assess the effects of silafibrate on sperm parameters and modulate malondialdehyde (mda) concentration, spermatogenesis, and oxidative stress. hence, our hypothesis is that chronic administration of clofibrate and silafibrate might lead to changes in sperm quality and hormonal situations of rats. 1department of basic science, tabriz branch, islamic azad university, tabriz, iran. 2medicinal plants research center, institute of medicinal plants, acecr, karaj, iran. 3cardiovascular research center, tabriz university of medical sciences, tabriz, iran. 4pharmacology and toxicology department, maragheh university of medical sciences, maragheh, iran 5phytopharmacology research center, maragheh university of medical sciences, maragheh, iran 6department of animal biology, university of tabriz, tabriz, iran. *correspondence: department of basic science, tabriz branch, islamic azad university, tabriz, iran. **correspondence: medicinal plants research center, institute of medicinal plants, acecr, karaj, iran. complex of iranian academic center for education, culture and research (acecr) p.o.box: 31375-1369 central office:+98 21 66561470. campus tel: +98 263 476 4019. mobile phone: +98 914 313 1830. e-mail: ziaee@imp.ac.ir. received april 2017 & acceptd november 2017 sexual dysfunction and andrology sexual dysfunction and andrology 38 materials and methods a total of 70 adult male wistar rats weighing between 280 and 300 g were used. they were obtained from the animal facility of the pasture institute of iran. the animals were housed in temperature controlled rooms (22 ºc) with constant humidity (40–70%) and 12-h light and 12-h dark conditions for one week before the commencement of the experiments. they had free access to standard laboratory chaw and tap water. experiments on animals were performed according to animal ethics guidelines of the tabriz university of medical sciences ethics committee. rats were randomly allocated into seven groups of ten animals per group. group 1 was control and received normal saline daily for 28 days(12); groups 2–4 gavaged silafibrate (10, 20, and 40 mg/kg/ day, oral) for 28 consecutive days; and groups 5–7 received clofibrate (10, 20, and 40 mg/kg/day, oral) for 28 consecutive days. at the end of these treatments, the animals were euthanized, blood samples were taken, and reproductive organs were dissected out for biochemical and histopathological examinations. surgical procedure on the twenty-eight day (at the end of the treatment period, i.e.), the rats were euthanized with diethyl ether, blood was collected into heparinized tubes, and serum was separated by centrifugation for further analysis. testes were dissected out and spermatozoa were collected from the epididymis(13). testis, epididymis, and seminal vesicle weight measurement the reproductive organs—testes, epididymis, and seminal vesicles—were dissected out from surrounding adipose and connective tissues by an expert anatomist and were weighed using analytical balance with 0.1 mg accuracy. epididymal sperm motility, viability, count, and sperm abnormality sperm from the cauda epididymis were released by cutting into 2 ml of medium (hams f10) containing 0.5% bovine serum albumin(14). after 5 min incubation at 37 ºc (with 5% co 2 ), cauda epididymis sperm reserves were determined using the standard haemocytometric method. sperm motility was then analyzed by microscope at 10 field and reported as the mean of motile sperm according to who methods(15). sperm abnormality was also evaluated according to the standard method of narayana(16). briefly, smears of sperm suspension were made on clean glass slides and stained with periodic acid-schiff’s reaction haematoxylin. the stained smears were observed under a light microscope with 40× magnification. the sperms were classified into normal and abnormal. the total sperm abnormality was expressed as percentage incidence. serum total testosterone, lh, and fsh hormone serum concentrations of fsh and lh were determined in duplicated samples using radioimmunoassay (ria) (isotope company ltd., budapest, hungary). rat fsh/ lh kits were obtained from isotope company ltd. and used according to the protocol provided with each kit. the sensitivities of hormone detected per assay tube were 0.2 ng/ml and 0.14 ng/ml for fsh and lh respectively. serum concentration of total testosterone was measured by using a double antibody ria kit from immunotech beckman coulter company, usa. the sensitivities of hormones detected per assay tube were 0.025 ng/ml. total antioxidant capacity and malondialdehyde concentration measurement in serum a total antioxidant capacity (tac) detecting kit was obtained from nanjing jiancheng bioengineering institute, china. according to this method, the antioxidant defense system, which consists of enzymatic and non-enzymatic antioxidants, is able to reduce fe3+ to fe2+(14). tac was measured by the reaction of phenanthroline and fe2+ using a spectrophotometer at 520 nm. at 37 °c, a tac unit is defined as the amount of antioxidants required to make absorbance increase 0.01 in 1 ml of serum. radical damage was determined by specifically measuring malondialdehyde (mda). mda was formed as an end product of lipid peroxidation treated with thiobarbituric acid to generate a colored product. concentration of mda was measured in seeffects of clofibrate and silafibratedelashoub et al. table1. the effect of clofibrate and silafibrate in comparison to control group on testis, epididymis and seminal vesicle weight. control clofibrate 10 mg/kg clofibrate 20 mg/kg clofibrate 40 mg/kg silafibrate 10 mg/kg silafibrate 20 mg/kg silafibrate 40 mg/kg testis (g) 1.74 ± 0.8 1.75 ± 0.7 1.73 ± 0.9 1.70 ± 0.5 1.72 ± 0.6 1.67 ± 0.8 epididymis (g) 0.08 ± 0.34 0.07 ± 0.37 0.09 ± 0.37 0.04 ± 0.39 0.06 ± 0.31 0.05 ± 0.32 seminal vesicle (g) 0.03 ± 0.52 0.04 ± 0.53 0.06 ± 0.49 0.07 ± 0.54 0.03 ± 0.52 0.04 ± 0.50 data are presented as mean ± sd; continuous variables were compared by independent samples t-test. control clofibrate 10 mg/kg clofibrate 20 mg/kg clofibrate 40 mg/kg silafibrate 10 mg/kg silafibrate 20 mg/kg silafibrate 40 mg/kg sperm 66.5 ± 3.8 61.4 ± 3.9 3.6* ± 55.7 3.2* ± 48.2 65.7 ± 3.4 63.6 ± 3.7 60.2 ± 3.3 concentration (total count) (no. of sperm/rat × 106) motility (%) 48.2 ± 1.7 45.7 ± 1.2 1.9* ± 36.3 1.5* ± 30.8 46.4 ± 1.6 43.5 ± 1.8 1.5* ± 40.9 viable sperm (%) 66.5 ± 3.8 64.9 ± 4.4 3.8* ± 54.7 3.9 ± 50.2 65.7 ± 3.9 62.9 ± 4.2 61.3 ± 3.9 data are presented as mean ± sd; continuous variables were compared by independent samples t-test *significant different at p < 0.05 level, (compared with the control group). table 2.the effect of clofibrate and silafibrate in comparison to control group on motility, viability and number of sperms. vol 15 no 02 march-april 2018 39 sexual dysfunction and andrology 40 rum and testis homogenates using a method prescribed previously(17). testicular tissue was removed and homogenized in a teflon-glass homogenizer with a buffer containing 1.5% potassium chloride to obtain 1:10 (w/v) whole homogenate. the lipid peroxide was measured spectrophotometrically at 532 nm and expressed as nano mole mda per ml of serum or gram of testis tissue. statistical analysis quantitative data is presented as mean ± sd. sperm counts, morphology, and motility of control and experimental groups are compared using one-way analysis of variance (anova); lsd test was used to find the statistical differences among their means. a value of p < .05 was considered to be statistically significant. results tissue weight the results of 28-day oral administration of clofibrate (10, 20, and 40m/kg/day) and silafibrate (10, 20, and 40m/kg/day) are summarized in table 1. no significant differences can be seen among testicle, epididymis plus vas deferens of any groups administered clofibrate or silafibrate as compared to the control group (p > 0.05). sperm count, motility and viability table 2 shows results of 28-day oral administration of clofibrate (10, 20, and 40m/kg/day) and silafibrate (10, 20, and 40m/kg/day) on sperm motility, viability, and count in rats. oral administration of clofibrate 20 and 40 mg/kg/day for 28 consecutive days causes considerable decline in sperm viability and motility in both experimental groups as compared to the control group (p < .05). furthermore, sperm count reduced significantly as compared to the control group (p < .05). oral administration of silafibrate 10, 20, and 40 mg/kg/day result in a reduction in sperm viability and concentration parameters—but these differences are not significant (p > .05). there is only a statistical difference in motility of sperms in group of silafibrate 40mg/kg/day (p < .05). serum total testosterone, lh, and fsh hormone measurement results of this study show that serum total testosterone levels are significantly low in rats receiving clofibrate 20 and 40 mg/kg/day for 28 consecutive days (p < .05). as shown in table 3, silafibrate did not considerably alter levels of serum total testosterone in any of the experimental groups (p > .05). administration of clofibrate 20 and 40 mg/kg/day for 28 consecutive days elevated the fsh hormone level, while 40 mg/kg/day of silafibrate increased fsh hormone level in the experimental group as compared to the control group—but this was not statistically remarkable. there was no significant difference in the level of lh hormone between the experimental and control groups (table 3). total antioxidant capacity and malondialdehyde concentration measurement in serum administration of silafibrate 20 and 40 mg/kg/day for 28 consecutive days significantly decreased the level of mda concentration in the experimental groups as compared to the control group (p < .05). administration of silafibrate 40 mg/kg/day for 28 consecutive days significantly increased the level of tac. there was no significant difference in the level of mda and tac between clofibrate and control groups (table 4). discussion dyslipidemia is emerging as an important and rising health issues in young people in the reproductive bracket. dyslipidemia includes raised levels of triglycerides (tgs) and low density lipoprotein cholesterol (ldl), and low levels of high density lipoprotein cholesterol (hdl-c)(18). cholesterol is one of the most important bio-molecules: it plays crucial functions in the area of male and female reproductive physiology. according to current guidelines(19), in patients with very high hypertriglyceridemia, lowering of tgs is necessary due to the increased risk of acute pancreatitis and cardiovascular diseases (20). fibrates such as ppars agonists have been prescribed to treat elevated serum triglycerides and cholesterol dyslipidemia for decades(21). silafibrate as a novel analogue of clofibrate has shown good lipid lowering effects in animal studies(7) but it has not been used in human yet. we estimated the safe and effective applicable dose in human (70 kg) based on naire et al(22) formula as follow: hed (mg / kg = animal noael mg/kg) × (weightanimal [kg]/weighthuman [kg])(1–0.67) control clofibrate 10 mg/kg clofibrate 20 mg/kg clofibrate 40 mg/kg silafibrate 10 mg/kg silafibrate 20 mg/kg silafibrate 40 mg/kg testosterone 0.18 ± 5.07 0.13 ± 5.00 0.12* ± 4.88 4.52 ± 0.12* 0.15 ± 5.09 0.13 ± 5.01 4.95 ± 0.11 fsh 0.04 ± 0.54 0.08 ± 0.60 0.07* ± 0.64 0.67 ± 0.09* 0.08 ± 0.52 0.09 ± 0.55 0.58 ± 0.07 lh 0.76 ± 0.12 0.78 ± 0.09 0.14 ± 0.77 0.72 ± 0.16 0.74 ± 0.09 0.11 ± 0.79 0.77 ± 0.13 table 3.the effect of clofibrate and silafibrate in comparison to control group on lh, fsh and testosterone. data are presented as mean ± sd; continuous variables were compared by independent samples t-test *significant different at p < 0.05 level, (compared with the control group). control clofibrate 10 mg/kg clofibrate 20 mg/kg clofibrate 40 mg/kg silafibrate 10 mg/kg silafibrate 20 mg/kg silafibrate 40 mg/kg mda 1.62 ± 0.09 1.72 ± 0.11 1.68 ± 0.17 1.75 ± 0.15 1.68 ± 0.08 0.11* ± 1.57 1.42 ± 0.07* tac 0.04 ± 0.27 0.03 ± 0.24 0.23 ± 0.05 0.24 ± 0.03 0.04 ± 0.26 0.05 ± 0.29 0.31 ± 0.03* data are presented as mean ± sd *significant different at p < 0.05 level, (compared with the control group). table 4.effects of clofibrate and silafibrate t on serum’s malondialdehyde (mda) and total anti oxidation concentration (tac). effects of clofibrate and silafibratedelashoub et al. (20 mg/kg)x (0.3[kg]/70[kg])0.33 =3.30 mg/kg x75 [kg](patient’s weight)=248 mg studies have also shown that ppars agonists such as clofibrate and fenofibrate may have miscellaneous side effects, such as suppression of spermatogenesis and erectile dysfunction(10,23). chronic use of these drugs may result in decrease in sperm quality and in infertility. our study on organ weights showed that no significant changes can be discerned in the morphology and weight of testis, epididymis, and seminal vesicle between treatment and control groups over the course of 28 consecutive days. while oral administration of clofibrate 20 mg/kg/day for 28 days leads to 16.2% reduction in sperm count, clofibrate 40 mg/kg/day for the same time period decreases sperm count by 27.5%: statistically, all of these results are considerable in comparison to normal rats (p < .05). additionally, along with sperm count, sperm viability and motility also decreased significantly by clofibrate as compared to the control group (p < .05). the decrease in sperm count, viability, and motility were not statistically significant in all doses of silafibrate in comparison to the normal control group (p > .05). testosterone is pivotal factor for spermatogenesis: it requires normal stimulation of luteinizing hormone (lh) and follicle-stimulating hormone (fsh). these are produced in the hypothalamus, where their secretion is controlled by the release of gonadotropin releasing hormone (gnrh)(13). results of this study reveal that levels of testosterone, lh, and fsh in groups treated with various doses of silafibrate do not change considerably (p > .05). conversely, in clofibrate 20 and 40 mg/kg groups, testosterone hormone was increased significantly and fsh was elevated remarkably (p < .05). meeker and colleagues demonstrated that fsh, lh, and testosterone are associated with human semen quality(24). they announced that fsh and lh are inversely associated with sperm quality, motility, and morphology. fsh is produced and secreted by the anterior pituitary and acts on sertoli cells in the seminiferous tubules to initiate spermatogenesis. spermatogenesis is regulated by testosterone and its deficiency leads to increased germ cell apoptosis. however, the mechanism by which testosterone controls spermatogenesis remains unclear(25). studies conducted on rats with a xenobiotic such as ethane 1,2-dimethanesulfonate (eds) —a leydig cell toxicant—have demonstrated a rise in germ cell apoptosis(26). clofibrate may inhibit testosterone secretion by dispersing rodent leydig cells. it may be caused by the blood testis barrier, which inhibits entry of clofibrate to the testis across the testicular barrier; however, clofibate can enter the hypothalamus more easily. we supposed that pituitary fsh and lh secreting cells, as well as sertoli and leydig cells, may show progressive deterioration due to the high dose of clofibrate in serum. fsh rise and testosterone fall in rats can cause the depletion of mature spermatids through phagocytosis by sertoli cells(27). generally, these findings explain the inhibitory effect of clofibrate on serum testosterone and fsh levels. our data shows that serum total testosterone decreases significantly in test groups (p < .05), and levels of fsh increase significantly only in the group that receives high doses of clofibrate (p < .05): nonetheless, there was no difference in the level of lh between the experimental and control groups. our results in this study confirm the subtractive effect of clofibrate, and that silafibrate as a novel siliconized analogue has no considerable side effects on sperm quality. sperm motility is essential for normal fertilization and one of the most important parameters in evaluating the fertilizing ability of ejaculated sperm. in this regard, correlations between the velocity of sperm movement or sperm motility and fertilization rates as proved by present results clearly indicate that clofibrate as a ppars agonist has a subtractive effect on spermatogenesis in rats. our results show that administration of clofibrate (20 and 40 mg/rat/day) for 28 consecutive days causes a significant decrease in sperm count, viability, and motility as compared to normal rats. oxidative stress was measured by malondialdehyde levels, reactive oxygen species (ros) generation, and alterations in antioxidant defenses(13). sperm concentration, motility, and function are susceptible to oxidative stress: these contribute to decreased fertility(28,29). results of this study reveal that mda decreases with silafibrate 20 and 40 mg/kg/day and tac increases with the 40 mg/kg/day of silafibrate. the exact mechanism of antioxidant action of fibrates is still to be examined: the following may be possible routes for further research. first, several metabolites (not fibrates themselves) have direct radical scavenging properties(30). second, some experiments have shown that treatment with fibrates decreases the susceptibility of plasma proteins, especially ldls, to oxidation(30,31). third, our previous studies (6,7,32,33) and several other studies have demonstrated that fibrates possess potent anti-inflammatory effects and antioxidant effects(34). it seems that the remarkable antioxidant and anti-inflammatory effects of silafibrate may prevent adverse effects on sperm parameters in comparison to the parent analogoue. these are in accordance with other investigations, which was reported a negative correlation with mda level and testosterone, fsh and lh(13,35). the limitations of this study was lack of histological analysis due to research budget restrictions. our work demonstrates that clofibrate therapy, at 10 mg per day, has no effect on total testosterone and gonadotropin serum level. however, this significantly affects sperm parameters in rats: silafibrate as a novel analogue may be considered as a safe lipid lowering drug on sperm quality. future research should aim towards a randomized placebo-controlled assay with a larger cohort and a longer study period to confirm silafibrate effects on human fertility. conclusions in conclusion, our study shows for the first time that the administration of silafibrate to healthy and normocholesterolaemic subjects does not affect their sperm parameters (vitality, number, and motility). while considering the long duration of clofibrate treatment with 20 and 40 mg/kg—whose clinical benefit with respect to cardiovascular diseases is beyond question—potential negative consequences on reproductive functions should be taken into account when deciding to initiate such a treatment, especially for human. acknowledgments we would like to thank the staff at the islamic azad university of tabriz for their help and financial support. effects of clofibrate and silafibratedelashoub et al. vol 15 no 02 march-april 2018 41 sexual dysfunction and andrology 42 references 1. sharlip id, jarow jp, belker am, et al. best practice policies for male infertility. fertil steril. 2002;77:873-82. 2. direkvand-moghadam a, delpisheh a, direkvand-moghadam a. effect of infertility on the quality of life, a crosssectional study. j clin diagn res. 2014;8:135. 3. ross c, morriss a, khairy m, et al. a systematic review of the effect of oral antioxidants on male infertility. reprod biomed online. 2010;20:711-23. 4. isidori am, pozza c, gianfrilli d, isidori a. medical treatment to improve sperm quality. reprod biomed online. 2006;12:704-14. 5. khojasteh smb, khameneh rj, houresfsnd m, yaldagard e. a review on medicinal plants used for improvement of spermatogenesis. biol med. 2016;8:1. 6. ziaee m, samini m, bolourtchian m, et al. synthesis of a novel siliconized analog of clofibrate (silafibrate) and comparison of their anti-inflammatory activities. iran j pharm res . 2011;11:91-5. 7. ziaee m, eghbal ma, rahmani j, ghaffarzadeh m, khorrami a, garjani a. biological evaluation of a siliconized analog of clofibrate (silafibrate) in rodents. iran j pharm res. 2013;12:471. 8. hirano y, shibahara h, obara h, et al. andrology: relationships between sperm motility characteristics assessed by the computer-aided sperm analysis (casa) and fertilization rates in vitro. j assist reprod genet. 2001;18:215-20. 9. kadivar a, khoei hh, hassanpour h, et al. peroxisome proliferator-activated receptors (pparα, pparγ and pparβ/δ) gene expression profile on ram spermatozoa and their relation to the sperm motility. paper presented at: vet res forum, 2016. 10. cook jc, klinefelter gr, hardisty jf, sharpe rm, foster pm. rodent leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans. crit rev toxicol. 1999;29:169-261. 11. huang j-c. the role of peroxisome proliferatoractivated receptors in the development and physiology of gametes and preimplantation embryos. ppar res. 2008;2008. 12. oakberg ef. duration of spermatogenesis in the mouse and timing of stages of the cycle of the seminiferous epithelium. am j anat. 1956;99:507-16. 13. khorrami a, ghanbarzadeh s, ziaee m, arami s, vajdi r, garjani a. dietary cholesterol and oxidised cholesterol: effects on sperm characteristics, antioxidant status and hormonal profile in rats. andrologia. 2015;47:310-7. 14. hamidi m, ziaee m, delashoub m, et al. the effects of essential oil of lavandula angustifolia on sperm parameters quality and reproductive hormones in rats exposed to cadmium. j rep pharm sci. 2015;4:121-8. 15. organisation wh. who laboratory manual for the examination of human semen and sperm-cervical mucus interaction: cambridge university press; 1999. 16. narayana k. an aminoglycoside antibiotic gentamycin induces oxidative stress, reduces antioxidant reserve and impairs spermatogenesis in rats. j toxicol sci. 2008;33:85-96. 17. alexandropoulou i, komaitis m, kapsokefalou m. effects of iron, ascorbate, meat and casein on the antioxidant capacity of green tea under conditions of in vitro digestion. food chem. 2006;94:359-65. 18. gotto am, moon je. management of cardiovascular risk: the importance of meeting lipid targets. am j cardiol. 2012;110:3a-14a. 19. perk j, de backer g, gohlke h, et al. european guidelines on cardiovascular disease prevention in clinical practice (version 2012). euro heart j. 2012;33:1635-701. 20. katsiki n, nikolic d, montalto g, banach m, mikhailidis dp, rizzo m. the role of fibrate treatment in dyslipidemia: an overview. curr pharm des. 2013;19:3124-31. 21. moutzouri e, kei a, elisaf ms, milionis hj. management of dyslipidemias with fibrates, alone and in combination with statins: role of delayed-release fenofibric acid. vasc health risk manag. 2010;6:525. 22. nair ab, jacob s. a simple practice guide for dose conversion between animals and human. j basic clin pharm. 2016;7:27. 23. bruckert e, giral p, heshmati h, turpin g. men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. j clin pharm ther. 1996;21:8994. 24. meeker jd, godfrey‐bailey l, hauser r. relationships between serum hormone levels and semen quality among men from an infertility clinic. j androl. 2007;28:397-406. 25. ilyas s, lestari sw, moeloek n, asmarinah a, siregar sc. induction of rat germ cell apoptosis by testosterone undecanoate and depot medroxyprogesterone acetate and correlation of apoptotic cells with sperm concentration. acta med indones. 2016;45. 26. khorsandi l, mirhoseini m, mohamadpour m, orazizadeh m, khaghani s. effect of curcumin on dexamethasone-induced testicular toxicity in mice. pharm biol. 2013;51:206-12. 27. saito h, saito t, kaneko t, sasagawa i, kuramoto t, hiroi m. relatively poor oocyte quality is an indication for intracytoplasmic sperm injection. fertil steril. 2000;73:465-9. effects of clofibrate and silafibratedelashoub et al. 28. rajender s, rahul p, mahdi aa. mitochondria, spermatogenesis and male infertility. mitochondrion. 2010;10:419-28. 29. azenabor a, ekun ao, akinloye o. impact of inflammation on male reproductive tract. journal of reproduction & infertility. 2015;16:123. 30. aviram m, rosenblat m, bisgaier cl, newton rs. atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation. atherosclerosis. 1998;138:271-80. 31. chaput e, maubrou-sanchez d, bellamy fd, edgar ad. fenofibrate protects lipoproteins from lipid peroxidation: synergistic interaction with α-tocopherol. lipids. 1999;34:497-502. 32. ziaee m, eghbal ma, ghaffarzadeh m, garjani a. comparison of hepatoprotective effects of clofibrate and its novel siliconized analogue in isolated rat hepatocyts. ann biol res. 2012;3:1895-903. 33. nafisi s, heidari r, ghaffarzadeh m, et al. cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen-induced toxicity in isolated rat hepatocytes. arh hig rada toksikol. 2014;65:169-77. 34. tziomalos k, athyros vg, karagiannis a, mikhailidis dp. anti-inflammatory effects of fibrates: an overview. curr med chem. 2009;16:676-84. 35. aktaran ş, akarsu e, meram i, kartal m, araz m. correlation of increased lipid peroxidation with serum gonadotropins and testosterone levels in type 2 diabetic men with erectile dysfunction. turk j endocrinol metabol. 2005;4:119-24. effects of clofibrate and silafibratedelashoub et al. vol 15 no 02 march-april 2018 43 pediatric urology the prevalence of redo-ureteroneocystostomy and associated risk factors in pediatric vesicoureteral reflux patients treated with ureteroneocystostomy dogus guney1*, tugrul tiryaki2 purpose: the aim of the study was to examine the prevalence of redo-ureteroneocystostomy (redo-unc) in pediatric vesicouretheral reflux (vur) patients following open unc and factors associated with redo-unc. material and methods: data on 122 patients who underwent open unc for vur were analyzed in this retrospective case–control study. the patients were divided into a successful initial unc group (unc group, control) and an unsuccessful initial unc group (redo-unc group, case). the following variables were analyzed: sex, age, dysfunctional voiding, laterality of vur (unilateral or bilateral), vur grade, etiology of vur (primary or secondary), relative renal function on renal scintigraphy, and surgical technique. the use of the following procedures in the initial unc was recorded: an endoscopic subureteric injection(esi) and ureteral tapering. results: in our clinic, 122 patients (177 ureters), with an average age of 55.7 ± 41.2 months (range, 1–18 years) underwent open unc for vur between november 2005 and june 2014. of these,67 (55%) had unilateral vur, and 55 (45%) had bilateral vur. there were 127 (71.8%) cases of grade 4–5 reflux. postoperatively, hydronephrosis was noted in 19 (15.6%) patents. ten (8.2%) patients underwent redo-unc. in eight cases (6.5%), redo-unc was performed because of ureterovesical (uv) junction obstruction.in the other two cases (1.7%), redo-unc was due to high-grade reflux. there were no statistically significant differences between the redo-unc and unc groups in any of the variables studied. conclusion: redo-unc was required in 10 (8.2%) of cases after unc. age, sex, laterality of vur, vur grade, existence of primary or secondary vur, relative renal function on renal scintigraphy, unc technique, esi procedure, and ureteral tapering were not risk factors for redo-unc in our series. keywords: re-ureteroneocystostomy; ureteroneocystostomy; vesicoureteral reflux introduction operative and nonoperative options are available for the treatment of vesicoureteral reflux (vur). endoscopic vur treatment has become popular during the last 20 years as an alternative to open procedures. endoscopic vur treatment is widely used due to its ease of use, ready availability, and absence of complications in outpatients(1-4). conversely, the use of ureteroneocystostomy (unc) for vur has shown a declining trend. although unc has a high success rate(5-7), redo-operations are required in some cases. according to the literature, vur persisted in 19.3% of cases with high-grade reflux who underwent unc, and 0.3–9.1% of these cases required reoperations(6). there is a paucity of studies on the risk factors for redo-ureteroneocystostomy (redo-unc). redo-unc after failed open correction of vur can be a challenging procedure because of scar formation at the anastomosis site and decreased vascularity of the ureter(5,7). the aim of this study was to 1university of health sciences, ankara child health and diseases hematology oncology training and research hospital, pediatric surgery clinic, ankara 06130,turkey. 2university of health sciences, ankara child health and diseases hematology oncology training and research hospital, pediatric urology clinic,ankara 06130,turkey. *correspondence: university of health sciences ankara child health and diseases hematology oncology training and research hospital pediatric surgery clinic address: sehit ömer halis demi̇r cad. kurtdereli sokak altındag/ ankara 06130 türkiye tel: +905307772285.fax: +903123472330. e-mail: dous_caliskan@hotmail.com. aeceived august 2017 & accepted april 2018 examine the prevalence of redo-unc in children treated by unc for vur and to identify factors that can predict the success or failure of unc. patients and methods study population data on 122 children with vur who underwent open surgery interventions in our clinic between november 2005 and june 2014 were analyzed retrospectively. the study was approved by the hospital’s local ethics committee (2013/203). vur was diagnosed in patients with various complaints, such as urinary tract infections (utis), a neurogenic bladder, voiding dysfunction, and antenatal hydronephrosis. it was also diagnosed by sibling screening. the classification system used by the international reflux study group was used for grading reflux on voiding cystourethrography(8). the study included all pediatric surgical patients with pediatric urology 72 vol 16 no 01 january-february 2019 73 primary or secondary reflux etiology. the exclusion criteria were as follows: treatment not completed in our clinic, treatment initiated in another clinic, absent data during file screening, medical treatment without surgical interventions, and endoscopic treatment without open procedures or other initial surgical interventions (e.g., ureteropelvic obstruction, urolithiasis, primary obstructive megaureter, and extrophia vesica). preoperative evaluation procedure in our series, an open surgical intervention was selected as the first choice in patients aged 1 year and older with bilateral/unilateral high-grade reflux or kidney function loss in follow-up detected on scintigraphy. open surgery was also performed in cases of failure of the endoscopic subureteric injection (esi) procedure and in patients with recurrent utis. before unc, urine culture, urinary system ultrasonography (usg), and renal scintigraphy technetium-99m mercaptoacetyltriglycine 3 (mag 3) were performed in all patients. differential kidney function was classified as follows: 40–50%, good; 20–39%, average; and 0–19%, poor(1). in all patients, lower urinary tract dysfunction were evaluated based on a voiding diary and symptom scoring systems(9). patients thought to have voiding dysfunctionunderwent urodynamic testing. bladder training, constipation treatment, anticholinergic treatment, and biofeedback were prescribed, as appropriate. the treatment was continued for at least 3 months before the surgical intervention. surgical technique in our clinic, the cohen, politano–leadbetter, or lich– gregoir techniques were applied as open surgical methods. in the selection of the surgical technique, reflux grade, ureter dilatation, and the surgeon’s preference were taken into consideration. for patients undergoing unc with the cohen and politano–leadbetter techniques, a 6 french ureteral catheter and perivesical penrose drain were inserted and then removed at the end of the 7th postoperative day. ureteral tapering was applied in cases of advanced ureteral dilatation, and ureteral catheters were left for 10 days in these patients. a ureteral catheter was not used for patients undergoing unc with the lich–gregoir method. in all cases, an age-appropriate bladder catheter was inserted at the beginning of the operation and removed 24 h later when the ureteral catheter was removed. circumcision was performed routinely in all boys with vur to decrease the risk of utis. redo-unc technique dissection of the bladder from the anterior abdominal wall requires careful attention. intravesical and extravesical dissection of the ureter and extensive mobilization are required to achieve an adequate submucosal tunnel. the ureter was carefully evaluated, and ischemic segments were excised. the politano–leadbetter type re-ureteroneocystostomy was performed in all redo-unc patients outcome assessment all the patients underwent renal usg in the first month following ureteral reimplantation to detect hydronephrosis and possible obstructions. mild dilation was expected due to transient edema. patients with moderate or worsening hydronephrosis underwent monthly usg for 3 months due to the suspicion of an obstruction. asymptomatic postoperative hydronephrosiswas assessed by comparing the degree of postoperative hydronephrosis to preoperative usg images. voiding cystouretrography (vcug) was performed in the 6th month postsurgery, and scintigraphy and renal function were evaluated again in the first year after the operation. during the postoperative follow-up, patients who reported reflux persistence and in whom hydroureteronephrosis had increased were re-evaluated by urodynamics. cystoscopy was applied in cases of obstruction for the evaluation of the ureterovesical (uv) junction, and the location of the obstruction was identitable 1. comparison results of the the two groups redo-unc group (n= 10) unc group (n=112) n % n % p sex female 6 60 63 56.2 1.000 male 4 40 49 43.8 diagnosis primary 6 60 77 68.8 0725 secondary 4 40 35 31.2 side unilateral 3 30 64 57.1 0.183 bilateral 7 70 48 42.9 initial intervention sting 5 50 49 43.8 0.749 unc 5 50 63 56.2 surgical technique cohen 6 60 51 45.5 0.651 politano leadbetter 4 40 47 42 lich–gregoir 0 0 14 12.5 tapering applied 2 20 4 3.6 0.076 not applied 8 80 108 96.4 vur grade 1–2 0 0 9 8 0.325 3 1 11 27 24 4-5 9 89 76 67 scintigraphy good 1 10 28 25 0.493 average 4 40 47 42 poor 5 50 37 voiding dysfunction yes 2 20 29 26 0.682 no 8 80 83 74 unc in pediatric vur patientstreated with unc-guney et al. fied by synchronic retrograde pyelography. a redo procedure was performed in the following cases: an increase in hydronephrosis as a result of an obstruction or renal parenchymal thinning with renal function loss and high-grade reflux on follow-up. study design in this retrospective case–control study, the patients were divided into a successful initial unc group (unc group, control) and an unsuccessful initial unc group (redo-unc group, case). these two groups were then compared in terms of sex, age of operation, laterality of vur (unilateral or bilateral), vur grade, vur etiology (primary or secondary), dysfunctional voiding, relative renal function on renal scintigraphy, and unc technique. in addition, the use of the following procedures in the initial unc was recorded: esi and ureteral tapering. the mann–whitney u test, fisher’s exact test, and χ2 test were used, as appropriate based on data characteristics and distribution. all analyses were performed using the statistical package for the social sciences, version 22.0 (ibm spss, inc., chicago, il, usa ). p-values of < 0.05 were considered signicant. results in total, 122 vur patients (girls, n = 69; boys, n = 53 boys; 177 ureters),with an average age of 55.7 ± 41.2 months (range, 1–18 years) underwent unc between november 2005 and june 2014. the patients’ demographic data are outlined in table 1. vur persisted in 22 (18%) patients after unc. vur resolved spontaneously on follow-up in 13 of 22 (10.6%) patients. the esi procedure was performed in seven patients with persistent vur. two (1.7%) patients with high-grade reflux underwent redo-unc. postoperatively,an increase in hydronephrosis was noted in 19 (15.6%) patients. a double j stent was inserted in four (3.3%) of these patients, and hydronephrosis was resolved in all these cases. severe voiding dysfunction was noted in another two (1.7%) patients with hydronephrosis. following bladder exercises and anticholinergic treatment, hydronephrosis was resolved in these patients. redo-unc was performed in eight patients (6.5%) because of uv junction obstruction. hydronephrosis resolved spontaneously in five (4.1%) patients. in total, 10 (8.2%) of the 122 patients underwent redo-unc. in this group, the average time to redo-unc was 16.4 ± 13.2 months (range, 4–48 months) after the initial procedure. two of these patients had persistent high-grade reflux after the initial unc. in one of these patients, grade 5 reflux persisted following the initial unc, and an esi attempt was made before the redo-unc was performed. the same patient experienced acute pyelonenephritis and developed new renal scarring after the initial unc. following redo-unc, this patient had no new pyelonephritis, renal scarring, or decreased renal function on follow-up. in addition, the vur resolved. the other patient was followed up due to recurring utis after the initial unc. the patient also had persistent grade 5 reflux, as seen on vcug. new scars were apparent on renal scintigraphy, and redo-unc was performed. high-grade reflux persisted after the redo-unc in this patient. however, at the 2-year follow-up, no pyelonephritis or new scarring was seen. on pathology, distal ureteral specimens from both patients showed mild lymphoplasmocytic inflammation. these two patients had initially undergone open surgery without any endoscopic procedure. the remaining eight patients had no vur on follow-up vcug 6 months after the initial unc but uv junction obstruction, with progressive hydroureteronephrosis was present. in all cases, the uv junction obstruction was diagnosed by retrograde pyelography and confirmed by a mag 3 renal scan. in four patients (3.3%), the distal ends of the ureters were strictured. tapering of the ureter was performed in two (1.7%) of these patients. the esi procedure was the initial approach in table 2. comparison of data in the two groups. redo-unc group (n= 10) unc group (n=112) n(%) n (%) p sex female 6 (60) 63 (56.2) 1.000 male 4 (40) 49 (43.8) diagnosis primary 6 (60) 77 (68.8) .725 secondary 4 (40) 35 (31.2) side unilateral 3 (30) 64 (57.1) .183 bilateral 7 (70) 48 (42.9) initial intervention esi 5 (50) 49 (43.8) .749 unc 5 (50) 63 (56.2) surgical technique cohen 6 (60) 51 (45.5) .651 politano–leadbetter 4 (40) 47 (42) lich–gregoir 0 (0) 14 (12.5) tapering applied 2 (20) 4 (3.6) .076 not applied 8 (80) 108 (96.4) vur grade 1–2 0 (0) 9 (8) .325 3 1 (11) 27 (24.1) 4–5 9 (89) 76 (67.9) scintigraphy good 1 (10) 28 (25) .493 average 4 (40) 47 (42) poor 5 (50) 37 (33) voiding dysfunction yes 2 (20) 29 (26) .682 no 8 (80) 83 (74) unc in pediatric vur patientstreated with unc-guney et al. pediatric urology 74 vol 16 no 01 january-february 2019 75 three of the four patients with stricture. during the initial unc, the ureter was passed through the intestine in one patient, and ureteral stricture was noted in this patient on follow up. redo-unc and small bowel serosal repair were performed in this patient. high-grade (grade 4) reflux was present on vcug 6 months after redo-unc in one of the patients with uv junction stricture. however, at the 4-year follow-up, neither pyelonephritis nor new scarring in the kidney was present. the other three patients (2.5%) had no complications following redo-unc. all four patients showed chronic inflammation, with eosinophil leukocytes highly represented in resected specimens from the distal ends of the ureters. angle-related uv junction obstructions were determined in four (3.8%) patients. tapering was not performed in any of these patients, and the patients had no further complications during the follow-up after reunc. as with the stricture group, all four patients had signs of chronic inflammation at the distal ends of the ureters. the comparison of the redo-unc and unc groups revealed no significant differences in the variables studied between the two groups. table 2 summarizes the results of the statistical comparison between the two groups. discussion due to the widespread use of endoscopic vur treatment during the last 20 years, the number of open surgical procedures for vur has declined. although unc has a high success rate(5-7), for various reasons, some cases require redo-unc. in our series, the redo-unc rate was 8.2%. previous research reported a redo-unc rate after unc of between 0.3 and 9.1%(6). there was no difference in the average age of the patients in the two groups (51.20 ± 51.97 months in redo-unc, n=10; 56.19 ± 40.41 months in unc, n=112; p = .431), with normal age distributions in both groups and similar medians (42 and 48 months, respectively). in the redo-unc group, 6 (60%) were girls, and 63 (56.2%) were girls in the unc group (p = 1.000). the age and sex distribution of the patients in the redo-unc and unc groups were similar. renal function and laterality in vur were the same in both groups. there were no between-group differences in the ratios of bilateral versus unilateral vur and vur grades (p = .325) or renal function (p = .493). the esi procedure was performed in 5 (50%) of the redo-unc patients before the initial unc, whereas it was performed in 49 (43.8%) of unc patients. the number of patients (unc and redo-unc) initially treated endoscopically was similar. initial endoscopic treatments did not increase the risk of redo-unc. undiagnosed or untreated bladder problems are the primary cause of many unsuccessful reimplantations in vur patients(10-12). in many patients, postoperative persistent reflux regresses following treatment of voiding dysfunction(13). voiding dysfunction was present in 29 (26%) of the unc group and 2 (20%) of the redo-unc group (p = .682). in our study, voiding dysfunction did not affect the development of complications requiring redo-unc, and voiding dysfunction did not differ between the groups. complications associated with antireflux surgical procedures may appear shortly after the surgery or some time post surgery. in our clinic, in all vur patients, urinary system ultrasound is performed in the first postoperative month, and vcug is performed after 6 months, regardless of symptoms. in many clinics, vcug is not routinely performed after unc, and some authors have argued that routine vcug is not necessary(14,15). although relatively rate, an obstruction following unc is a major complication(16-18). ureteral obstructions are the most serious types of surgical complications of reimplantation. such complications can be caused by kinking due to excessive angulation or devascularization of the distal ureter. the diagnosis is readily made on ultrasound, with severe hydroureteronephrosis confirmed by delayed function and excretion on renal scintigraphy. in severe cases, drainage of the system, either by retrograde insertion of a double j stent or a percutaneous nephrostomy tube may be necessary. following treatment (i.e., placement of a stent or percutaneous nephrostomy tube), many cases resolve and do not require additional surgery. in our series, percutaneous nephrostomy was not preferred. we followed up four patients in a double j stent was placed without reoperation. after unc ureteral dilatation and mild grade hydronephrosis is relatively common. most cases of mild-grade hydronephrosis resolve spontaneously. in this series,spontaneous resolution of hydronephrosis occurred in five (4.1%) patients. if dilatation persists for 3 months after unc or the grade increases overtime, redo-unc should be considered. if renal scar formation occurs, accompanied by utis, the patient should undergo comprehensive radiologic evaluations(19). a permanent ureteral obstruction may be a late complication after unc. this type of complication, which arises in 2–4.2% of vur cases, requires redo-unc(20-23). in the current study, the rate of permanent ureteral obstructions was about 6.5% of patients. half of these obstructions comprised a stricture of the uv junction, and the remaining were angle-related obstructions. as compared with reports in the literature(6), the uv obstruction rate in our series was rather high. performing unc is technically more difficult in cases of secondary vur, and a ureteral obstruction can develop post-unc(12,24,25). briefly, in the redo-unc group, 60% (6/10) had primary vur, whereas 68.8% (77/112) had primary vur in the unc group (p = .725). however, in the present study, we found no statistically significant differences in complications post unc that led to redo-unc in patients with primary versus secondary vur. failure of antireflux procedures in primary low-grade reflux is extremely rare. most failures are due to highgrade reflux or an inadequate ratio of tunnel length to ureteral diameter(5-7,21) . in our study, the rate of grade 4 and 5 reflux was 72% in the unc group and 89% in the redo-unc group, but this difference was not significant. persistent vur appeared to be the most common postoperative complication in all series, with an incidence of 4–5.6%(6,26,27). in our study, reflux after unc persisted in 22 patients, and redo-unc was performed in two of 22 patients because of renal function loss and frequent uti comorbidity. in seven patients, vur resolved following the esi procedure. on follow-up, spontaneous resolution of persistent vur after unc was noted in 13 patients. in our study, ureteral tapering was performed in 6 (4.9%) patients, and re-unc was required in only 2 unc in pediatric vur patientstreated with unc-guney et al. of these patients as a result of stricture growth, with no significant (p = .651) differences between the groups. in six (4.9%) of the reoperated patients, the initial unc technique used was cohen, and the politano–leadbetter technique was employed in the other four (3.2%) patients. previous studies that compared ureteral obstructions following the use of different unc methods reported that obstructions were rarer with the cohen method than with the politano–leadbetter technique(21,28). the present study find no association between the incidence of ureteral obstructions and type of technique used. neither the unc techniques applied nor rates of ureteral tapering differed between the groups. redo ureteral reimplantation in vur cases is technically more challenging than primary implantation and requires careful attention to detail and meticulous surgical techniques. dis-section of the ureter and extensive mobilization is required to achieve an adequate submucosal tunnel. careful dissection of the ureter is best accomplished by a combination of extra vesical and intravesical mobilization, as needed. the ureter should be carefully evaluated, and ischemic segments should be excised. free bleeding from the divided distal end should be observed, in addition to peristaltic activity, to check for normal musculature and blood supply. it is preferable to create a new hiatus and submucosal tunnel. in cases where the ureter is short, a psoas hitch can be used to facilitate the creation of the antireflux mechanism. in our series, all the patients were reoperated using the politano–leadbetter technique, and no other procedures were required in these patients. the politano–leadbetter procedure was performed extraperitoneally to reduce potential complications, such as small bowel injury. the main limitations of the present study were the small sample size, heterogeneity of the patients, and low power of the study. conclusions ten (8.2%) of the 122 vur cases required redo-unc: two (1.7%) patients with persistent vur and eight (6.5%) patients with an increase in hydronephrosis after the initial unc. age, sex, laterality of vur, vur grade, existence of primary or secondary vur, relative renal function on renal scintigraphy, unc technique, esi procedure, and ureteral tapering were not risk factors for redo-unc after open vur repair in our series. acknowledgments: none to declare conflict of interest: the authors state that there are no conflicts of interests. references 1. puri p, kutasy b, colhoun e, hunziker m. single center experience with endoscopic subureteral dextranomer / hyaluronic acid injection as first line treatment in 1,551 children with intermediate and high grade vesicoureteral reflux. j urol 2012;188:14851489. 2. peters ca, skoog sj, arant bs jr et al. summary of the aua guideline on management of primary vesicoureteral reflux in children. j urol. 2010; 184:1134-44 . 3. kirsch aj, perez-brayfield m, scherz hc. minimally invasive treatment of vesicoureteral reflux with endoscopic injection of dextranomer/hyaluronic acid copolymer: the children's hospitals of atlanta experience. j urol 2003;170: 211-215. 4. herz d, hafez a, bagli d, capolicchio g, mclorie g, khoury a. efficacy of endoscopic subureteral polydimethylsiloxane injection for treatment of vesicoureteral reflux in children. a north american clinical report. j urol 2001; 166: 1880-1886. 5. deitz hg, schmidt a, bader jb, markus a. the politano-leadbetter antireflux plasty. investigation of complications in 245 children. eur j pediatr surg 1996;6: 177-80. 6. elder js, peters ca, arant bs et al. pediatric vesicoureteral reflux guideline panel summary report on the management of primary vesicoureteral reflux in children. j urol 1997; 157: 1846-1851. 7. steffens j, langen ph, haben b, hiebl r, steffens l, polsky ma. politano-leadbetter ureteroneocystostomy. urol int 2000; 65: 9-14. 8. lebowitz rl, olbing h, parkkulainen kv, smellie jm, tamminen-mobius te. international system of radiographic grading of vesicoureteric reflux. international reflux study in children. pediatr radiol. 1985;15:105–9. 9. akbal c, genc y, burgu b, ozden e, tekgul s. dysfunctional voiding and incontinence scoring system: quantitative evaluation of incontinence symptoms in pediatric population.j urol. 2005; 173: 969-73. 10. suer e, ozcan c, mermerkaya m et al. can factors affecting complication rates for ureteric re-implantation be predicted? use of the modified clavian classification system in a paediatric population bju int. 2014; 114:595600. 11. brandström p, esbjorner e, herthelius m, et al. the swedish reflux trial in children. i. study design and study population characteristics. j urol 2010;184:274–9. 12. willemsen j, nijman r. vesicoureteral reflux and videourodynamics studies: results of prospective study. urology 2000; 55: 939-943 13. sparks s, decambre m, christman m, kaplan g. salvage ureteral reimplantation after failure of dextranomer/hyaluronic acid injection. j urol. 2011;186:257-60. 14. grossklaus dj, pope jc, adams mc, brock jw. is postoperative cystography necessary after ureteral reimplantation? urology 2001; 588:1041-1045. 15. lavine ma, siddiq fm, chan dj, caesar re, koyle ma, caldamone aa. vesicoureteral reflux after ureteroneocystostomy: indications for postoperative voiding cystography. tech urol 2001; 7: 50-54. unc in pediatric vur patientstreated with unc-guney et al. pediatric urology 76 vol 16 no 01 january-february 2019 77 16. aboutaleb h, bolduc s, bägli dj, khoury ae. correlation of vesicoureteral reflux with degree of hydronephrosis and the impact of antireflux surgery j urol. 2003; 170:1560-2. 17. lamesh aj. retrograde catheterization of the ureter after antirefluxplasty by the cohen technique of transverse advancement. j urol 1981; 125:73-74. 18. wallis mc, brown dh, jayanthi vr, koff sa. a novel technique for ureteral catheterisation and/or retrograde ureteroscopy after crosstrigonal ureteral reimplantation. jurol 2003; 170:1664-1666.299 . 19. bell le, mattoo tk.update on childhood urinary tract infection and vesicoureteral reflux.semin nephrol. 2009;29:349-59 20. heidenreich a, özgür e, becker t, haupt g. surgical management of vesicoureteral reflux in pediatric patients world j urol 2004; 22:96-106. 21. austin jc, cooper cs. vesicoureteral reflux: surgical approaches. urolclin north am 2004; 31:543-557. 22. carpentier pj, bettink pj, hop wcj, schroder fh. reflux-a retrospective study of 100 ureteric implantations by the politano leadbetter method and 100 by cohen method. br j urol 1982; 54:230 -233. 23. steffens j, stark e, haben b, treiyer a. politano-leadbetter ureteric reimplantation. bju int. 2006;98:695-712. 24. santos jd, lopes ri, koyle ma. bladder and bowel dysfunction in children: an update on the diagnosis and treatment of a common, but underdiagnosed pediatric problem.can urol assoc j. 2017;11:64-72 25. noe hn. the role of dysfunctional voiding in failure or complication of ureteral reimplantation for primary reflux. j urol 1985; 134: 1172-5 26. barrieras d, lapointe s, reddy pp, et al. are postoperative studies justified afterextravesical ureteral reimplantation? j urol 2000;164:1064–6. 27. lavine ma, siddiq fm, cahn dj, caesar re, koyle ma, caldamone aa. vesicoureteral reflux after ureteroneocystostomy: indications for postoperative voiding cystography.tech urol. 2001;7:50-4. 28. khoury a, bagli dj. reflux and megaureter. in wein aj, kavoussi lr, novick ac, partin aw, andpeters ca (eds): campbell-walsh urology, 9th ed. philadelphia: wb saunders, 2007. unc in pediatric vur patientstreated with unc-guney et al. female urology reproducibility of leak point pressure in female stress urinary incontinence eu chang hwang, sun-ouck kim,* dong deuk kwon purpose: to assess the reproducibility of the valsalva leak point pressure (vlpp) based on urodynamics in females with stress urinary incontinence (sui). materials and methods: from october 2008 to december 2009, 65 consecutive women with urodynamically confirmed sui underwent duplicate vlpp measurements. the intra-individual reproducibility of the vlpp recording obtained by one urologist was determined. the two observations were separated by a 10-min interval. results: the differences between the repeated measurements were not significant (initial vs. repeat vlpp, 84.8 ± 19.9 vs. 86.7 ± 20.3 cmh 2 o; p = .094). repeated vlpp measurements were reproducible. defining intrinsic sphincter deficiency (isd) as vlpp < 60 cmh 2 o, the diagnosis of isd changed between successive tests in three cases (from 55 to 89, 58 to 64, and 61 to 55 cmh 2 o). conclusion: in female sui, the vlpp is a reproducible method for evaluating urethral resistance. for vlpp < 90 cmh 2 o, the diagnosis of isd changed in repeated measurements in some patients; therefore, other clinical findings must be considered when deciding on a treatment method. keywords: urinary incontinence; stress; urodynamics; valsalva maneuver; physiology; female; pressure. introduction continence of urine is maintained so long as the urethral pressure exceeds the bladder pressure, if the anatomy is intact. traditionally, urologists have assessed the positive urethral pressure gradient at rest with the passive urethral pressure profile and under stress with the dynamic or cough urethral pressure profile. an alternative measurement of urethral resistance favored by urologists is the leak point pressure (lpp), which is the abdominal pressure at which the urethral resistance is overcome and fluid leakage is observed. coughor valsalva-induced lpp is an important objective tool that is used routinely in the diagnosis of stress urinary incontinence (sui) in urodynamics clinics. valsalva leak point pressure (vlpp) has been used for evaluating urethral sphincter resistance in women with urinary incontinence that has been shown to be reproducible and to correlate with other measures of urethral resistance and the clinical severity of urinary incontinence.(1-3) vlpp has been promoted as a relatively simple test that can differentiate among sui, bladder neck hypermobility, and intrinsic urethral sphincter deficiency (isd). however, urodynamic techniques still have several major shortcomings in terms of reproducibility for predicting isd or incontinence severity.(3) the reliability of a diagnostic test is dependent on the accuracy and reproducibility of the measurement tool, which can be determined by comparing the results of repeated examinations of the same subject. after assessing the reproducibility of the technique at maximum cystometric capacity with different catheter sizes, bump and colleagues(3) demonstrated the reproducibility of vlpp in approximately 80% of adult women with sui. because vlpp is gaining more widespread acceptance as a clinically useful test for evaluating women with sui, we studied the reproducibility of vlpp measured in females with sui by comparing the results of two repeated cystometries. materials and methods study population from october 2008 to december 2009, 65 consecutive women with urodynamically confirmed sui provoked by the valsalva maneuver underwent duplicate vlpp measurements. all patients underwent a comprehensive assessment, including a clinical history evaluation, physical examination, and a multichannel urodynamic evaluation according to the standards of the international continence society.(4) subjects were excluded, if they had a diagnosis of neurogenic disease possibly indepartment of urology, chonnam national university medical school, gwangju, korea. *correspondence: department of urology, chonnam national university hospital and medical school 8, hak-dong, dong-gu, gwangju #501-757, south korea. tel: +82 62 2206702. fax: +82 62 2271643. e-mail: seinsena@hanmail.net. received september 2015 & accepted january 2016 female urology 2697 ducing neurogenic bladder, severe urogenital prolapse (pelvic organ prolapse quantification stages 2–4),(5) a history of anti-incontinence surgery or other surgeries that influence the urine stream, evidence of detrusor overactivity on filling cystometry, or if any lpp data measured using the urethral channel or visualization methods were missing. urodynamic study vlpp was measured with the patient in the lithotomy position on an urodynamic table, using a compact urodynamic device (dantec dynamics, skovlunde, denmark). the pressure transducers, zeroed at atmospheric pressure, were leveled at the upper edge of the symphysis pubis and connected to the intravesical and rectal catheter. a three-channel, fluid-filled 8 french (f) urethral cystometry catheter was used for every vlpp measurement. residual urine was evacuated. rectal pressure was measured with a water filled 8f balloon catheter. the bladder was filled with body temperature saline at 50 ml/min. a diagnosis of sui was made, if the subject had symptoms of stress incontinence and there was direct visualization of urine leakage produced by stress without concurrently demonstrable detrusor activity during cystometry, after the bladder was filled to a volume of 250 ml. each measurement was repeated twice, and the lowest value was selected for analysis. statistical analysis the intra-individual reproducibility of the vlpp recording was determined for one urologist with tests performed 10 min apart. the determination of test–retest reliability was made using the paired t-test, kappa agreement with statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0. results were considered statistically significant when the p value was < .05. results patient characteristics the 65 subjects had a mean age of 51.5 ± 7.9 (range 31–72) years, mean parity of 2.4 ± 1.7 (range 0–7), and mean symptom duration of 7.2 ± 6.1 (range 1–31) years. three subjects (4.6%) had undergone hysterectomies. the subjects were divided into three groups according to the initial vlpp parameters (cmh 2 o): vlpp < 60, 60–90, and > 90 (table 1). difference and agreement between test–retest vlpp values the mean difference between the repeated measurements was –1.84 ± 8.76 and they did not differ significantly (figure, p = .094). the agreement of test-retest vlpp values were excellent (kappa agreement value; 0.801, p = .001), however, defining isd as vlpp < 60 cmh 2 o, the diagnosis of isd changed between successive tests in three cases as the measured vlpp changed from 55 to 89, 58 to 64, and 61 to 55 cmh 2 o (table 2). discussion this study demonstrates that repeated vlpp measuretable 1. baseline characteristics of the patients. characteristics values no. of patients 65 mean age (years) 51.5 ± 7.9 bmi (kg/m2) 25.6 ± 2.9 hysterectomy, no (%) 3 (4.6) menopause, no (%) 42 (64.6) parity, mean ± sd 2.4 ± 1.7 hormonal therapy, no (%) 8 (12.3) mean symptom duration, years (mean ± sd) 7.2 ± 6.1 stamey grade, no (%) i 39 (60) ii 22 (33.8) iii 4 (6.2) initial vlpp (cmh2o) ≤ 60 11 60 < vlpp ≤ 90 26 > 90 28 abbreviations: bmi, body mass index; vlpp, valsalva leak point pressure. variables initial vlpp (cmh 2 o) ≤ 60 60 < vlpp ≤ 90 > 90 repeat vlpp (cmh 2 o) ≤ 60 9 1 0 60 < vlpp ≤ 90 2 20 3 90 > 0 5 25 abbreviation: vlpp, valsalva leak point pressure. kappa agreement value: 0.801 (p = .001). table 2. distribution of the initial and repeat vlpp measurements. reproducibility of leak point pressure-hwang et al. vol 13 no 03 may-june 2016 2698 ments are reproducible in women with sui, with excellent intra-individual agreement between consecutive measurements. however, we also found some variation in the diagnosis of isd in a few cases. defining isd as vlpp < 60 cmh 2 o, the diagnosis of isd changed between the initial and repeat test. despite the high reproducibility of vlpp, we suggest that repeated and careful measurement of vlpp is needed for an accurate diagnosis, and that other clinical findings must be considered when deciding on a treatment method for the vlpp range of 60–90 cmh 2 o. lpp is a urodynamic measure of the abdominal pressure at which leakage starts during a sudden or sustained increase in abdominal pressure caused by a cough or valsalva maneuver.(6) this value is believed to provide information about the presence of isd and is used for predicting the surgical outcome in women with sui.(7–9) since the concept of isd as an etiologic class of sui was introduced, vlpp measurements have been used for the urodynamic determination of isd.(10) the clinical usefulness of this measurement is that, it distinguishes between the two etiologies of sui: anatomical causes and isd. despite the validity of the concept, the lack of a standardized methodology for measuring vlpp has created confusion among clinicians and has delayed the validation of the role of vlpp in outcome studies of the treatment of sui. urodynamic parameters need to be standardized for measuring vlpp include catheter size, calibrate the transducer to zero, patient position, bladder volume, type of stress, and timing of measurement.(11) our present study is one of only a few studies that have assessed the reproducibility of the technique. bump and colleagues(3) assessed the reproducibility of the technique to compare it to other measures of urethral resistance, and to assess the effects of methodological variation on measurement. they demonstrated that, vlpp was highly reproducible at the maximal cystometric capacity in approximately 80% of adult women with stress incontinence, so long as the catheter size was constant. differences between two positive measurements using the same catheter are clinically and statistically non-significant. regarding the issue of reproducibility of urodynamic parameters in asymptomatic women, sorensen(12) reported good to high reproducibility for urodynamic data measured on separate occasions within a 2-month period and found no significant change in variables with a small coefficient of variation. sand and colleagues(13) studied 100 neurologically normal women with urinary incontinence in three repeated sessions, 1~2 weeks apart, and found a non-significant trend toward greater cystometric volume with each successive measurement. they showed 84% reproducibility of cystometrograms from the test–retest analysis. selected cut-off values of vlpp have been used worldwide for the diagnosis and determination of treatment methods in sui based on results obtained by mcguire and colleagues(8) showing that a vlpp < 60 cmh 2 o indicates the presence of significant isd, a vlpp of 60 – 90 cmh 2 o suggests a combination of urethral hypermobility and some component of isd, and a vlpp > 90 cmh 2 o suggests urethral hypermobility and minimal isd. since mcguire and colleagues(8,14) introduced the concept of vlpp in women with sui in 1993, using videourodynamic studies as the urinary detection method, many authors have proposed several modifications of the method, including the use of a flowmeter, electronic detection with a microtip catheter, and visualization with or without stepwise increases in abdominal pressure.(3,15–18) however, there appears to be marked disparity in the values measured with these techniques for detecting the start of urinary leakage, even among values from a single patient. to understand the issues related to vlpp measurement, it is important to clarify some of the terminology used in the literature. vlpp is also referred to as abdominal leak point pressure (alpp) and stress leak point pressure (slpp), both of which are the intravesical pressure measured during stress maneuvers. in some cases, cough has also been used for measuring vlpp, slpp, and alpp. use of the valsalva maneuver generates a slow sustained strain, whereas a cough creates a quick, sudden rise in intravesical pressure. however, valsalva reproducibility of leak point pressure-hwang et al. figure. reproducibility of the valsalva leak point pressure (cmh 2 o, vlpp) showing a boxplot of each vlpp measurement (initial vs. repeat vlpp, 84.8 ± 19.9 vs. 86.7 ± 20.3 cmh 2 o; p = .094). female urology 2699 and cough have been used interchangeably in descriptions of vlpp measurement. bump and colleagues(3) reported a significantly higher cough lpp than vlpp. they attributed this to the finding, that reflex contraction of the external sphincter occurs during a cough and not while performing the valsalva maneuver.(19) another suggested issue is that the vlpp during a valsalva maneuver facilitates pinpointing of the pressure at which leakage occurs versus a cough. in this study, we measured vlpp at a bladder volume of 250 ml, as recommended by mcguire and colleagues(7) several authors have reported progressive lowering of the vlpp with increasing bladder volume during filling in the same patients.(20,21) they suggested that during urodynamic studies, the observed vlpp depends on the detrusor pressure, the fluid used for the study, and the state of the other abdominal viscera. however, petrou and kollmorgen found that bladder volume did not statistically change the vlpp value.(22) before using the vlpp in clinical practice, investigators should consider the effect of various variables on the value of vlpp. further validation and standardization of the vlpp methodology will provide valuable information for its use in addressing the treatment outcome of sui and in selecting the proper treatment for correcting sui. this study has some limitations. first, the number of patients included in the study were very few. second, inter-individual reproducibility was not assessed. third, we compared 2 measurements, made only 10 minutes apart, by a single urologist thus potentially allowing bias from memory of the first measurement to affect the second measurement. also, this study is without a control arm that should be investigated both in patients and healthy controls. ideally, reproducibility should be tested and controlled by a replication study, which must be completely independent and generate identical findings known as commensurate results to clearly verify the results of the first study. additionally, vlpp measuring device may have a design flaw and we have to consider the possibility of confounding bias conducting the reproducibility study. however, few studies have examined the reproducibility of lpp. therefore, despite these limitations, we believe that our study provides valuable information on the unnecessary use of repeated measurement of lpp, which is a time-consuming, uncomfortable, invasive procedure, in diagnosing incontinence severity in women. conclusions vlpp is a reproducible method for evaluating the urethral resistance of women with sui. although, there is excellent agreement of test-retest vlpp measurement, for a vlpp in the range of 60–90 cmh 2 o, the diagnosis of isd might change with repeated measurements in a few subjects; therefore, other clinical findings must be considered when deciding on a treatment method for correcting sui in these patients. conflict of interest none declared. references 1. theofrastous jp, bump rc, elser dm, wyman jf, mcclish dk. correlation of urodynamic measures of urethral resistance with clinical measures of incontinence severity in women with pure genuine stress incontinence. the continence program for women research group. am j obstet gynecol. 1995;173:407-12. 2. nitti vw, combs aj. correlation of valsalva leak point pressure with subjective degree of stress urinary incontinence in women. j urol. 1996;155:281-5. 3. bump rc, elser dm, theofrastous jp, mc.clish dk. valsalva leak point pressures in women with genuine stress incontinence: reproducibility, effect of catheter caliber, and correlations with other measures of urethral resistance. continence program for women research group. am j obstet gynecol. 1995;173:551–7. 4. abrams p, blaivas jg, stanton sl, andersen jt. the standardization of terminology of lower urinary tract function. the international continence 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2700 urodyn. 2006;25:685–8. 10. gary m, king cj. urodynamic evaluation of the intrinsically incompetent sphincter. urol nurs. 1993;12:67–9. 11. daneshgari f. valsalva leak point pressure: steps toward standardization. curr urol rep. 2001;2:388–91. 12. sørensen s. urodynamic investigations and their reproducibility in healthy postmenopausal females. scand j urol nephrol suppl. 1988;114:42–7. 13. sand pk, brubaker lt, novak t. simple standing incremental cystometry as a screening method for detrusor instability. obstet gynecol. 1991;77:453–7. 14. wan j, mcguire ej, bloom da, ritchey ml. stress leak point pressure: a diagnostic tool for incontinent children. j urol. 1993;150:700–2. 15. siltberg h, larsson g, hallen b, johansson c, ulmsten u. validation of cough-induced leak point pressure measurement in the evaluation of pharmacological treatment of stress incontinence. neurourol urodyn. 1999;18:591–602. 16. kocjancic e, tarrano e, panella m, et al. evaluation of minimally invasive analysis system for cough leak point pressure measurement. j urol. 2004;172:994–7. 17. siltberg h, larsson g, victor a. coughinduced leak-point pressure a valid measure for assessing treatment in women with stress incontinence. acta obstet gynecol scand. 1998;77:1000–7. 18. faerber gj, vashi ar. variations in valsalva leak point pressure with increasing vesical volume. j urol. 1998;159:1909–11. 19. shafik a. straining urethral reflex: description of a reflex and its clinical significance. preliminary report. acta anat (basel). 1991;140:104–7. 20. miklos jr, sze eh, karram mm. a critical appraisal of the methods of measuring leak-point pressures in women with stress incontinence. obstet gynecol. 1995;86:349– 52. 21. payne ck, stanford ca, raz s, et al. the valsalva leak point pressure in the evaluation of stress incontinence: technical aspects of measurement. j urol. 1994;151:478a. 22. petrou sp, kollmorgen ta. valsalva leak point pressure and bladder volume. neurourol urodyn. 1998;17:3–7. reproducibility of leak point pressure-hwang et al. female urology 2701 vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2509 endourology and stone diseases association of the bsmi, apai, taqi, tru9i and foki polymorphisms of the vitamin d receptor gene with nephrolithiasis in the turkish population omer onur cakir,1 akin yilmaz,2 emre demir,3 kutluhan incekara,4 mustafa omur kose,4 nagehan ersoy tunali4* purpose: to analyze the relationship between nephrolithiasis and vitamin d receptor (vdr) gene bsmi (rs1544410), apai (rs7975232), taqi (rs731236), tru9i (rs757343) and foki (rs2228570) polymorphisms in a study group from the turkish population. materials and methods: ninety-eight patients with calcium oxalate kidney stones and 70 controls were enrolled in this study. five polymorphisms of the vdr gene were studied using the polymerase chain reaction restriction fragment length polymorphism (pcr-rflp) method. results: for all polymorphisms, genotype frequencies were in line with hardy-weinberg equilibrium in the patients and controls. for the bsmi polymorphism, allele frequency distribution was found to differ significantly between the patients and the controls (p < .05). the “b” allele was found to increase the risk of nephrolithiasis by approximately 1.5-fold (odds ratio = 1.55, 95% confidence interval: 1.00-2.40; p = .048). however, we did not find any statistically significant differences in the allele and genotype frequencies for the apai, taqi, tru9i and foki polymorphisms. proportionally, the “bat” and “bat” haplotypes were more common than other haplotypes in the cases and controls, respectively. for the haplotypes of the bsmi and taqi polymorphisms, the “bt” haplotype frequency was found to be common in both the patients and the controls. however, we did not find statistically significant differences between the cases and the controls for either the bsmi / apai / taqi or the bsmi/taqi haplotypes. moreover, no relationship was identified between family history and development of stone disease. conclusion: the “b” allele of the bsmi polymorphism of the vdr gene may increase stone development risk. further investigations are needed to improve our knowledge regarding the genetic factors affecting urinary stone development. keywords: nephrolithiasis; genetics; mutation; humans; vitamin d3 24-hydroxylase/genetics; metabolism; hypercalcemia; hypercalciuria; nephrocalcinosis. introduction nephrolithiasis is a common multifactorial disease that is influenced by both environmental and genetic factors.(1) several studies have reported an increase in its morbidity rate in recent years.(2) moreover, it has a recurrence rate of approximately 50% within 10 years. most stones (up to 75%) are composed of calcium oxalate (caox) crystals, and their formation occurs in a complex manner.(3) with regard to understanding the genetic basis of the disease, several single nucleotide polymorphisms (snps) have been analyzed to determine the risk of stone formation in different populations. to date, snps found in osteopontin (spp1),(4) calcium sensing receptor (casr), matrix-gla protein (mgp), urokinase (plau) (recently reviewed by arcidiacono and colleagues),(5) e-cadherin (chd1),(6) calcitonin receptor (calcr),(7) transient receptor potential vanilloid member 5 (trpv5),(8) fetuin-a(9) and vitamin d receptor (vdr)(10-23) genes have been analyzed, and some of them are related to nephrolithiasis development. the vdr gene encodes a nuclear receptor for the active form of vitamin d, 1,25-dihydroxy vitamin d3 [1,25(oh) 2 d 3 ]. after it binds to its response element on dna, it regulates hundreds of genes with different functions, including calcium homeostasis.(24) the vdr gene has several polymorphisms, and some of them have been associated with urinary stone formation in some populations.(10-23) whereas the foki (rs2228570, c.2t > c, p.met1arg) polymorphism 1 department of urology, istanbul bagcilar research and training hospital, 34800, istanbul, turkey. 2 department of medical biology, faculty of medicine, hitit university, 19030, corum, turkey. 3 department of biostatistics, faculty of medicine, hitit university, 19030, corum, turkey. 4 halic university, department of molecular biology and genetics, istanbul halic university, 34060, istanbul, turkey. *correspondence: halic university, department of molecular biology and genetics, istanbul halic university, 34060, istanbul, turkey. tel:+90 532 6850526. fax:+90 212 3470042. e-mail: nagehanersoy@halic.edu.tr. received january 2016 & accepted february 2016 is located in the second exon of the vdr gene, the bsmi (rs1544410, 1024+283g > a), apai (rs7975232, c.1025-49g > t), taqi (rs731236, c.1056t > c, p.ile352ile) and tru9i (rs757343, c.1024+443g > a) polymorphisms are found at the 3′ end of the gene.(25) the foki (rs2228570, c.2t > c, p.met1arg) polymorphism changes the translation start codon and causes the production of two different vdr protein variants. the first one is a long variant and is coded by the t allele or the “f” allele. the second short variant is shortened by three amino acids and is coded by the c-allele or the “f” allele.(25) compared with the long vdr form, the short form has greater transcriptional activation capability.(26) the bsmi (rs1544410, 1024+283g > a), apai (rs7975232, c.1025-49g>t) and tru9i (rs757343, c.1024+443g > a) polymorphisms are located in the 8th intron of the gene,(25) whereas the taqi (rs731236, c.1056t > c, p.ile352ile) polymorphism is a synonymous variation at codon 352 in exon 9 of the gene, and this t > c alteration does not change the amino acid sequence (p.ile352ile).(27) the bsmi, apai, tru9i and taqi polymorphisms are located at the 3′ end of the gene and are near the regulatory 3’ untranslated region (3’-utr) of mrna. thus, when the bsmi, apai, and taqi polymorphisms are found in specific haplotypes, they have been shown to affect vdr mrna stability and the rate of transcription.(19) for example, in green monkey kidney cells, the "bat" haplotype of the bsm / apa / taq polymorphisms was shown to increase vdr expression compared with the "bat" haplotype.(27) a relationship between the bb genotype of the bsmi polymorphism and higher urinary calcium extraction and a link between the t allele of the taqi polymorphism and hypocitraturia were shown in the literature. however, there are conflicting data regarding the relationship between the foki and apai polymorphisms and urinary stone formation mechanisms.(28) there is a lack of knowledge in the literature regarding the association of the bsmi, apai, taqi, tru9i and foki polymorphisms of the vdr gene with nephrolithiasis in the turkish population. thus, in this study, we aimed to investigate the possible relationship between development of nephrolithiasis and five common polymorphisms [bsmi (rs1544410), apai (rs7975232), taqi (rs731236), tru9i (rs757343) and foki (rs2228570)] of the vdr gene in patients and control subjects from the turkish population. moreover, a haplotype analysis was also performed for the bsmi, apai and taqi polymorphisms. materials and methods study population between march 2006 and march 2008, patients with urinary calcium oxalate stones who were treated at the istanbul sisli etfal research and training hospital and erzurum numune hospital were enrolled in the study. the study population was composed of 98 patients with caox nephrolithiasis (65 male and 33 female) who were initially diagnosed by computerized tomography (ct) scan. fifty-two (53%) cases out of 98 had familial stone history (maternal and/or paternal urolithiasis history), and 33 of them were male. for the control group, seventy individuals (52 male and 18 female) without family history or clinical signs of urinary stone disease (assessed via urine testing, plain abdominal radiography, or ultrasonography) were included in the study. all cases and controls were matched according to age and gender. eleven of 98 patients had recurrent stone disease. after treatment with extracorporeal shock wave lithotripsy (swl) or surgery, stone samples were collected, and stone analysis was performed using an x-ray diffraction (xrd) machine. xrd analysis confirmed that they contained calcium oxalate crystals. patients with ca oxalate stones were included in the study. patients with abnormal levels of serum creatinine, calcium, phosphate, uric acid, liver enzymes, sodium, potassium, chloride and 1,25(oh) 2 d 3 , thyroid-stimulating hormone, free thyroxin, free triiodothyronine, and parathyroid hormone were excluded from the study. furthermore, patients diagnosed with hypercalcemia, renal tubular acidosis, hyperuricemia, gout, hyperparathyroidism, urinary tract infection, renal failure and hyperthyroidism were also excluded from the study. the last group of exclusion criteria included patients who take drugs that effect calcium and hormone metabolism, such as diuretics, calcium and vitamin d supplements, and anti-diabetic and anti-hypertensive agents. informed consent was obtained from all patients and healthy subjects in accordance with the helsinki declaration (revised 2001), and the study protocol was approved by the local ethics committee (approval number: irb 2007 / 88-685) analysis of vdr gene polymorphisms blood samples were collected in ethylenediaminetetraacetic acid (edta) containing tubes, and the genomic dna of the study subjects was isolated with a high pure polymerase chain reaction (pcr) template preparation kit (roche, mannheim, germany) according to the manufacturer’s protocol. the concentrations and purity of the samples were checked spectrophotometrically. the detection of the 5 polymorphisms [bsmi vdr gene polymorphisms in nephrolithiasis-cakir et al. endourology and stone diseases 2510 vol 13 no 01 january-february 2016 2511 (rs1544410), apai (rs7975232), taqi (rs731236), tru9i (rs757343) and foki (rs2228570)] of the vdr gene was carried out using the conventional polymerase chain reaction restriction fragment length polymorphism (pcr-rflp) method.(29-31) each amplification reaction was performed in a 25 µl final volume consisting of 1 u/µl unit taq dna polymerase, each primer at a concentration of 10 pmol/µl, a 100 ng dna sample, 100 µm dntp, and 2 mm mgcl2. primer sequences, annealing temperatures, restriction endonucleases and allele sizes are provided in table 1. the pcr and restriction enzyme products were electrophoresed in a 2.0% agarose gel and then stained with ethidium bromide. for all studied polymorphisms, agarose gel electrophoresis pictures demonstrating alleles and genotypes are provided in figure 1 a-e. dna sequencing for all polymorphisms, homozygote and heterozygote samples identified via pcr-rflp analysis were confirmed by dna sequencing in the laboratories of iontek (istanbul, turkey). the sequences obtained were analyzed using clustal w (version 1.83) alignment software and compared with the rflp results. all sequenced samples were in agreement with the rflp data. statistical analysis descriptive statistics with a normal distribution were presented as the mean ± standard deviation, and nominal variables were presented as numbers of cases and percentages (%). distributions of the groups were evaluated with the kolmogorov–smirnov and shapiro-wilk normality tests. the significances of the differences between the two groups were evaluated with student’s t-test for the means. categorical variables were evaluated using pearson’s chi-square or fisher’s exact test. the distributions of the genotype and allele frequencies between the groups and their relationship to caox nephrolithiasis were compared with a chi-square (χ2) test. hardy–weinberg equilibrium (hwe) was also tested using the χ2 test based on observed and expected vdr gene polymorphisms in nephrolithiasis-cakir et al. polymorphism chr 12: methodical primer annealing product restriction alleles position nomenclature sequences temperature (°c) size (bp) enzyme bsmi(29) 47846052 intronic f: 5′-caaccaagactacaagtaccgcgtcagtga-3′ 63 825 bsmi g (b): 650+175 (rs1544410) (forward strand) (1024+283 g>a) r: 5′-aaccagcgggaagaggtcaaggg-3′ a (b): 850 apai(29) 47871419 intronic f: 5′-cagagcatggacagggagcaa-3′ 60 722 apai t (a): 722 (rs7975232) (forward strand) (c.1025-49 g > t) r: 5′-gcaactcctcatggctgaggtctc-3′ 60 g (a): 509+213 taqi(29) 47844974 synonymous f: 5′-caaccaagactacaagtaccgcgtcagtga-3′ 63 2000 taqi t (t): 2000 (rs731236) (forward strand) (p.ile352ile) r: 5′-cacttcgagcacaaggggcgttagc-3′ c (t): 1800+200 c.1056 t > c tru9i(28) 47845892 intronic f: 5′-tgtattggtccagcttgctct-3′ 63 252 tru9i a (u): 193+59 (rs757343) (forward strand) c.1024+443g > a r: 5′-cagggtttctccatgttggt-3′ g (u): 252 foki(30) 47879112 start lost f: 5′-agctggccctggcactgactctgctct-3′ 63 265 foki t (f): 196+69 (rs2228570) (forward strand) c.2t > c r: 5′-atggaaacaccttgcttcttctccctc-3′ (p.met1arg) table 1. primers, annealing temperatures, product sizes, restriction enzymes, and allele sizes used for vitamin d receptor gene genotyping. variables patients (n = 98) controls (n = 70) p value age, years, mean ± sd 47.2 ± 16.3 42.6 ± 13.5 .536 gender, no (%) male 65 (66.3) 52 (74.3) .349 female 33 (33.7) 18 (25.7) .349 bmi, kg/m2, mean ± sd 24.9 ± 3.7 24.1 ± 3.1 .552 smoking, no (%) 40 (40.8) 33 (47.1) .511 family history, no (%) 52 (53) ---- ----abbreviations: bmi, body mass index; sd, standard deviation. table 2. characteristics of the study groups. genotype numbers with the ‘hardy weinberg’ package table 3. genotype and allele frequency of the five vitamin d receptor gene polymorphisms in the patients and controls and the results of the hardy-weinberg equilibrium tests.* variables patients (n = 98) hwe p value adjusted hwe**p value controls (n = 70) hwe p value adjusted hwe** p value bsmi .568 .673 .781 .911 bb 29 (29.6) 13 (18.6) bb 46 (46.9) 33 (47.1) bb 23 (23.5) 24 (34.3) bb+ bb 75 (76.5) 46 (65.7) allele frequency b 104 (53.1) 59 (42.1) b 92 (46.9) 81 (57.9) apai .271 .351 .834 .948 aa 43 (43.9) 26 (37.1) aa 40 (40.8) 34 (48.6) aa 15 (15.3) 10 (14.3) aa+aa 55 (56.1) 44 (62.9) allele frequency a 126 (64.3) 86 (61.4) a 70 (35.7) 54 (38.6) taqi .443 .541 .454 .582 tt 35 (35.7) 31 (44.3) tt 44 (44.9) 29 (41.4) tt 19 (19.4) 10 (14.3) tt+tt 63 (64.3) 39 (55.7) allele frequency t 114 (58.2) 91 (65.0) t 82 (41.8) 49 (35.0) tru9i .223 .290 .176 .249 uu 18 (18.4) 6 (8.6) uu 41 (41.8) 37 (52.9) uu 39 (39.8) 27 (38.6) uu+uu 80 (81.6) 64 (91.4) allele frequency u 77 (39.3) 49 (35.0) u 119 (60.7) 91 (65.0) foki .305 .399 .494 .658 ff 48 (49) 39 (55.7) ff 38 (38.8) 25 (35.7) ff 12 (12.2) 6 (8.6) ff+ff 50 (51.0) 31 (44.3) allele frequency f 134 (68.4) 103 (73.6) f 62 (31.6) 37 (26.4) vdr gene polymorphisms in nephrolithiasis-cakir et al. endourology and stone diseases 2512 abbreviation: hwe, hardy-weinberg equilibrium. * data are presented as no (%) ** chi-square p value with continuty correction. vol 13 no 01 january-february 2016 2513 table 4. genotype and allele frequency of the five vitamin d receptor gene polymorphisms in the patients and controls.* variables patients (n = 98) controls (n = 70) p value or (95% ci) p value bsmi bb 29 (29.6) 13 (18.6) .158 2.33 (0.98-5.55) .055 bb 46 (46.9) 33 (47.1) 1.45 (0.70-3.01) .311 bb 23 (23.5) 24 (34.3) 1.00** bb+ bb 75 (76.5) 46 (65.7) 1.70 (0.86-3.36) .124 allele frequency b 104 (53.1) 59 (42.1) .048 1.55 (1.00-2.40) .048 b 92 (46.9) 81 (57.9) 1.00** apai aa 43 (43.9) 26 (37.1) .595 1.00** aa 40 (40.8) 34 (48.6) 0.71 (0.36-1.39) .317 aa 15 (15.3) 10 (14.3) 0.91 (0.35-2.31) .838 aa+aa 55 (56.1) 44 (62.9) 0.77 (0.40-1.41) .382 allele frequency a 126 (64.3) 86 (61.4) 1.00** a 70 (35.7) 54 (38.6) 0.88 (0.56-1.39) .593 taqi tt 35 (35.7) 31 (44.3) .474 1.00** tt 44 (44.9) 29 (41.4) 1.34 (0.68-2.63) .389 tt 19 (19.4) 10 (14.3) 1.68 (0.68-4.16) .258 tt+tt 63 (64.3) 39 (55.7) 1.43 (0.76-2.68) .262 allele frequency t 114 (58.2) 91 (65.0) 1.00** t 82 (41.8) 49 (35.0) 1.34 (0.85-2.09) .205 tru9i uu 18 (18.4) 6 (8.6) .148 2.08 (0.73-5.91) .166 uu 41 (41.8) 37 (52.9) 0.77 (0.40-1.49) .432 uu 39 (39.8) 27 (38.6) 1.00** uu+uu 80 (81.6) 64 (91.4) allele frequency u 77 (39.3) 49 (35.0) 1.20 (0.77-1.88) .424 u 119 (60.7) 91 (65.0) 1.00** foki ff 48 (49) 39 (55.7) .614 1.00** ff 38 (38.8) 25 (35.7) 1.23 (0.64-2.38) .529 ff 12 (12.2) 6 (8.6) 1.62 (0.56-4.72) .370 ff+ff 50 (51.0) 31 (44.3) allele frequency f 134 (68.4) 103 (73.6) 1.00** f 62 (31.6) 37 (26.4) 1.29 (0.80-2.08) .302 abbreviations: or, odds ratio; ci, confidence interval. * data are presented as no (%). ** chi-square p value with continuity correction. vdr gene polymorphisms in nephrolithiasis-cakir et al. in r software. possible haplotypes for the bsmi / apai / taqi (rs1544410 / rs7975232 / rs731236) and bsmi/ taqi (rs1544410 / rs731236) polymorphisms were determined using the hapstat analysis tool, and their relationship to nephrolithiasis was analyzed using the χ2 test. odds ratios (ors) were presented with 95% confidence intervals (cis), and p values less than 0.05 were considered statistically significant. all statistical procedures were performed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 20.0. statistical power was calculated using quanto 1.2.4 software (website: http://biostats. usc.edu/software).(32) quanto is specifically written to calculate either the power or the required sample size for association studies of genes, environmental factors, gene-environment interactions, or gene-gene interactions. in our study, for the less frequent alleles (42.1% for bsmi, 38.6% for apai, 35% for taqi, 35% for tru9i and 26.4% for foki) with p = .05, the study had a power > 85% for the bsmi, apai, taqi, and tru9i polymorphisms and > 80% for the foki polymorphism (or = 2.0; mode of inheritance: log-additive, population risk: 14.8%). results the characteristics of the subjects are provided in table 2. the mean ages of the patients and normal controls were 47.2 ± 16.3 and 42.6 ± 13.5 years, respectively. the mean body mass index (bmi) (kg/m2) values of the patients and controls were 24.9 ± 3.7 and 24.1 ± 3.1, respectively. the genotype and allele distributions of the 5 vdr polymorphisms (bsmi, apai, taqi, tru9i and foki) in the nephrolithiasis patients and controls are provided in table 3. none of the genotype frequencies were found to deviate from hardy-weinberg equilibrium in either the patients or the controls for the analyzed polymorphisms (p > .05). for the bsmi polymorphism, allele frequency distribution was found to differ significantly between the patients and the controls (p < .05). the “b” allele was found to increase the risk of nephrolithiasis by approximately 1.5-fold (or = 1.55, 95% ci: 1.00-2.40; p = abbreviations: or, odds ratio; ci, confidence interval. * referent haplotype. haplotypes patients (2n = 196) (%) controls (2n = 140) (%) or (95% ci) p value bsmi / apai / taqi bat 64 (0.3253) 53 (0.3768) 1.00* bat 81 (0.412) 48 (0.3448) 1.40 (0.84-2.33) .198 bat 7 (0.03575) 2 (0.01199) 2.90 (0.58-14.54) .297 bat 17 (0.08861) 9 (0.06802) 1.56 (0.64-3.79) .320 bat 27 (0.1383) 28 (0.1984) 0.80 (0.42-1.51) .492 bsmi / taqi bt 91 (0.4639) 81 (0.5755) 1.00* bt 81 (0.4124) 48 (0.3453) 1.50 (0.94-2.39) .086 bt 24 (0.1237) 11 (0.07914) 1.94 (0.90-4.21) .089 table 5. bsmi / apai / taqi and bsmi / taqi haplotypes of the patients and controls. figure 1. gel electrophoresis images of the pcr products after digestion with restriction enzymes. a: bsmi polymorphism, b: apai polymorphism, c: taqi polymorphism, d: tru9i polymorphism, and e: foki polymorphism. sizes of the alleles specifying genotypes are given in table 1. vdr gene polymorphisms in nephrolithiasis-cakir et al. endourology and stone diseases 2514 vol 13 no 01 january-february 2016 2471vol 13 no 01 january-february 2016 2515 table 6. genotype and allele frequency of the five vitamin d receptor gene polymorphisms in patients with or without family history.* variables positive (n = 52) negative (n = 46) p value or (95 ci) p value bsmi bb 16 (30.8) 13 (28.3) .846 1.00** bb 23 (44.2) 23 (50.0) 0.81 (0.32-2.06) .662 bb 13 (25.0) 10 (21.7) 1.07 (0.35-3.18) .922 bb+bb 36 (69.2) 33 (71.7) 0.89 (0.37-2.12) .786 allele frequency b 55 (52.9) 49 (53.3) 1.00** b 49 (47.1) 43 (46.7) 1.01 (0.58-1.78) .958 apai aa 23 (44.2) 20 (43.5) .801 1.00** aa 20 (38.5) 20 (43.5) 0.87 (0.37-2.06) .751 aa 9 (17.3) 6 (13.0) 1.30 (0.39-4.31) .662 aa+aa 29 (55.8) 26 (56.5) 0.97 (0.44-2.16) .94 allele frequency a 66 (63.5) 60 (65.2) 1.00** a 38 (36.5) 32 (34.8) 1.08 (0.60-1.94) .798 taqi tt 21 (40.4.) 14 (30.4) .391 1.00** tt 20 (38.5) 24 (52.2) 0.56 (0.27-1.37) .199 tt 11 (21.1) 8 (17.4) 0.92 (0.29-2.85) .880 tt+tt 31 (59.6) 32 (69.6) 0.65 (0.28-1.49) .305 allele frequency t 62 (59.6) 52 (56.5) 1.00** t 42 (40.4) 40 (43.5) 0.88 (0.50-1.55) .661 tru9i uu 8 (15.4) 10 (21.7) .583 0.76 (0.25-2.33) .631 uu 24 (46.1) 17 (37.0) 1.34 (0.55-3.24) .514 uu 20 (38.5) 19 (41.3) 1.00** uu+uu 44 (84.6) 36 (78.3) 1.13 (0.50-2.53) .774 uu+uu 32 (61.5) 27 (58.7) 0.59 (0.24-1.48) .261 allele frequency u 40 (38.5) 37 (40.2) 0.93 (0.52-1.65) .802 u 64 (61.5) 55 (59.8) 1.00** foki ff 28 (53.8) 20 (43.5) .584 1.00** ff 18 (34.6) 20 (43.5) 0.64 (0.27-1.51) .311 ff 6 (11.6) 6 (13.0) 0.71 (0.20-2.54) .602 ff+ff 34 (46.2) 26 (56.5) 0.93 (0.43-2.01) .862 allele frequency f 74 (71.2) 60 (65.2) 1.00** f 30 (28.8) 32 (34.8) 0.76 (0.42-1.39) .372 abbreviations: or, odds ratio; ci, confidence interval. * data are presented as no (%). ** referent genotype/allele. vdr gene polymorphisms in nephrolithiasis-cakir et al. .048). likewise, the bb genotype was more frequently observed in the patients than in the controls. however, this difference was not statistically significant (p = .055). moreover, the frequency of individuals carrying bb+bb genotypes was more frequent in the patients than in the controls (76.5% vs. 65.7%) (table 4). the proportional frequencies of the “a” allele of the apai polymorphism, the “t” allele of the taqi polymorphism, the “u” allele of the tru9i polymorphism, and the “f” allele of the foki polymorphism were shown to be less than those of their second alleles in the patients and control subjects. however, we did not find any significant differences in the allele and genotype frequencies of the apai, taqi, tru9i and foki polymorphisms (table 4). we also analyzed the haplotypes of the bsmi / apai / taqi polymorphisms and bsmi / taqi haplotypes. haplotype analysis revealed that there were 5 common haplotype blocks for the bsmi, apai and taqi polymorphisms, as shown in table 5. proportionally, the “bat” and “bat” haplotypes were found to be more common than other haplotypes in the cases and controls, respectively. with regard to the haplotypes of the bsmi and taqi polymorphisms, the “bt” haplotype frequency was found to be common in both patients and controls. for the haplotype distribution, we did not show statistically significant differences between the cases and the controls for either the bsmi / apai / taqi or the bsmi/ taqi haplotypes. of the 98 patients, 52 of them (17 females and 35 males) had a positive family history of nephrolithiasis, and the remaining patients (15 females and 31 males) were negative. we did not find any differences between family history and vdr gene polymorphisms (table 6). discussion the involvement of the vdr gene locus and its polymorphisms in nephrolithiasis development has been shown in several studies. initially, a strong linkage was shown between calcium stone formation and the d12s339 marker, which is located near the vdr gene locus on chromosome 12, by scott and colleagues. using a candidate gene approach.(28) then, genetic association studies were performed to analyze the relationship between stone formation and vdr gene polymorphisms in different populations,(10-23) and as seen in the literature, contradictory results were obtained for commonly analyzed vdr snps. in one of the analyses performed by bid and colleagues,(10) a significant difference in genotype frequencies for the vdr foki polymorphism between subjects with calcium oxalate nephrolithiasis and control subjects in the indian population was shown. in another study, bid and coworkers analyzed vdr gene foki and calcitonin receptor (ctr) gene polymorphisms in pediatric stone patients. with regard to the foki variation, an apparent difference was demonstrated between the pediatric cases and the control group.(11) in a study performed in taiwan by liu and colleagues,(12) the foki variation of the vdr gene was demonstrated to be a meaningful parameter in the clinical appearance of calcium stone formers. the ff genotype of the foki polymorphism was found to be associated with recurrence of calcium stones and stone development age. however, no significant difference was shown between patients and healthy controls in terms of foki genotype frequency. similarly, we found no significant differences in the allele and genotype frequencies for the foki polymorphism in the study group from turkish population (table 4). in the chinese han population, wang and colleagues(13) studied five polymorphisms (foki, bsmi, ddei, apai and taqi) of the vdr gene, and they showed an association for only the apai polymorphism. the apai genotypes were found to differ between groups, and the “a” allele was shown to be related to an increased risk of stone recurrence. in japanese stone patients, the taqi “t” allele was shown to correlate with an approximately 5-fold increased risk of stone development and increased urinary calcium levels. however, they were not able to show differences between apai polymorphism distribution and severe and recurrent stones.(22) in korean stone patients, seo and colleagues did not show any relationship between the alwi, foki, apai, and taqi polymorphisms of the vdr gene and urinary stone development.(23) the bsmi, apai, and taqi genotypes were analyzed in hypercalciuric children from turkey, and the aa genotype of the apai snp was shown to be related to a 3.5-fold increased risk of idiopathic hypercalciuria.(14) moreover, in pediatric stone patients and matched controls, ozkaya and colleagues(15) analyzed vdr apai, bsmi and taqi snps and found that apai and taqi variations were related to nephrolithiasis and family history of the disease, respectively. in another study from turkey, gunes and colleagues(16) found a relationship between apai polymorphisms and family history of stone development. however, in our study, such an association was not found for the apai polymorphism for either stone development or family history. however, we found that the bb genotype was present less frequently in stone patients, as shown in table 3. gunes and colleagues(16) did not find any significant vdr gene polymorphisms in nephrolithiasis-cakir et al. endourology and stone diseases 2516 vol 13 no 01 january-february 2016 2517 differences between urolithiasis patients and controls in the black sea coastal region of turkey with respect to genotype frequencies of the bsmi, apai and taqi polymorphisms. with regard to this study, we found a more similar genotype and allele distribution in the healthy control group. likewise, similar frequencies were also observed in the patients, except for the bsmi polymorphism (b allele 43%; b allele 57%). an approximately 10% difference between the bsmi allele frequencies of the two studies may be attributed to various factors, such as stone type or patient characteristics. in another study, the bb genotype of the bsmi polymorphism was found to be significantly higher in hypercalciuric stone patients than in normacalciuric stone patients in the brazilian population.(16) in the taiwanese population, the bsmi polymorphism was not found to be associated with calcium oxalate stone disease.(20) heilberg and colleagues showed that the bsmi polymorphism was not related to bone loss in hypercalciuric calcium-stone-forming brazilian patients.(21) as seen in the literature, conflicting results have been noted regarding the relationship between vdr gene polymorphisms and nephrolithiasis development. these differences among studies may result from the complex etiology of stone formation, ethnicity, patient characteristics, sample size, environmental effects and other genetic factors. recently, a meta-analysis aiming to reveal a possible relationship between vdr gene polymorphisms and nephrolithiasis was performed by zhou and colleagues. (18) six studies were included in their analysis, and they showed no association between the vdr bsmi, foki, taqi or apai polymorphisms and stone formation in either the overall population or caucasians. however, foki, taqi and apai polymorphisms were related to the development of nephrolithiasis in the asian population. (18) some alleles of vdr gene polymorphisms also tend to show linkage disequilibrium with each other.(25) therefore, a haplotype analysis of bsmi, apai and taqi polymorphisms has been performed in some studies. mossetti and colleagues(19) analyzed the bsmi/taqi haplotypes and did not show any differences between stone patients and controls with respect to haplotype frequencies. however, they showed that the bt haplotype was associated with an earlier age of onset and elevated stone rate, as well as diminished urinary citrate excretion. in our study, the bat, bat and bat haplotypes of the bsmi / apai / taqi polymorphisms and bt and bt haplotypes of the bsmi/taqi polymorphisms were found to have higher frequencies in both patients and controls. however, we did not show statistically significant differences between the groups (table 5). the limitations of current study include a low number of patients (98), which seems to be insufficient to represent the entire turkish population. however, when looking at our results, the bsmi polymorphism of the vdr gene is related to nephrolithiasis, and this association may be stronger in a study including a higher number of cases and controls. however, this specific cohort consisted of patients with urinary caox stone and for all polymorphisms, the power was > 80%, which was acceptable. another limitation was the need for more detailed serum and 24 hour urine tests that could be performed for all patients. this would have resulted in a stronger discussion. conclusions more studies should be performed to reveal the possible association between vdr gene polymorphisms and the risk of nephrolithiasis in a larger cohort. understanding the genetic tendency toward kidney stone development and recurrence may provide an opportunity for early diagnosis and may also be helpful for the clinical follow-up of urinary stone sufferers. conflict of interest none declared. references 1. mittal rd, bid hk, manchanda pk, kapoor r. predisposition of genetic polymorphism with the risk of urolithiasis. indian j clin biochem. 2008;23:106–16. 2. shoag j, tasian ge, goldfarb ds, eisner bh. the new epidemiology of nephrolithiasis. adv chronic kidney dis. 2015;22:273–8. 3. aggarwal kp, narula s, kakkar m, tandon c. nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators. biomed res int. 2013;2013:292953. 4. tekin g, ertan p, horasan g, berdeli a. spp1 gene polymorphisms associated with nephrolithiasis in turkish pediatric patients. urol j. 2012l;9:640-7. 5. arcidiacono t, mingione a, macrina l, pivari f, soldati l, vezzoli g. idiopathic calcium nephrolithiasis: a review of pathogenic mechanisms in the light of genetic studies. am j nephrol. 2014;40:499–506. 6. yilmaz a, menevse s, onaran m, et al. e-cadherin gene 3′-utr c / t polymorphism in turkish patients with nephrolithiasis. mol biol rep. 2011;38:4931–4. vdr gene polymorphisms in nephrolithiasis-cakir et al. 7. shakhssalim n, basiri a, houshmand m, et al. genetic polymorphisms in calcitonin receptor gene and risk for recurrent kidney calcium stone disease. urol int. 2014;92:356–62. 8. khaleel a, wu m-s, wong hs-c, hsu y-w, chou y-h, chen h-y. a single nucleotide polymorphism (rs4236480) in trpv5 calcium channel gene is associated with stone multiplicity in calcium nephrolithiasis patients. mediators inflamm. 2015;2015:1–7. 9. aksoy h, aksoy y, ozturk n, aydin hr, yildirim ak, akçay f. fetuin-a gene polymorphism in patients with calcium oxalate stone disease. urology. 2010;75:928-32. 10. bid hk, kumar a, kapoor r, mittal rd. association of vitamin d receptor-gene (foki) polymorphism with calcium oxalate nephrolithiasis. j endourol. 2005;19:111–5. 11. bid hk, chaudhary h, mittal rd. association of vitamin-d and calcitonin receptor gene polymorphism in paediatric nephrolithiasis. pediatr nephrol. 2005;20:773–6. 12. liu cc, huang ch, wu wj, et al. association of vitamin d receptor (fok-i) polymorphism with the clinical presentation of calcium urolithiasis. bju int. 2007;99:1534–8. 13. wang s, wang x, wu j, et al. association of vitamin d receptor gene polymorphism and calcium urolithiasis in the chinese han population. urol res. 2012;40:277–84. 14. söylemezoğlu o, ozkaya o, gönen s, misirlioğlu m, kalman s, buyan n. vitamin d receptor gene polymorphism in hypercalciuric children. pediatr nephrol. 2004;19:724–7. 15. ozkaya o, söylemezoğlu o, misirlioğlu m, gönen s, buyan n, hasanoğlu e. polymorphisms in the vitamin d receptor gene and the risk of calcium nephrolithiasis in children. eur urol. 2003;44:150–4. 16. gunes s, bilen cy, kara n, asci r, bagci h, yilmaz af. vitamin d receptor gene polymorphisms in patients with urolithiasis. urol res. 2006;34:47–52. 17. ferreira lg, costa pereira a, pfeferman heilberg i. vitamin d receptor and calciumsensing receptor gene polymorphisms in hypercalciuric stone-forming patients. nephron clin pract. 2010;114:c135–44. 18. zhou t-b, jiang z-p, li a-h, ju l. association of vitamin d receptor bsmi (rs1544410), fok1 (rs2228570), taqi (rs731236) and apai (rs7975232) gene polymorphism with the nephrolithiasis susceptibility. j recept signal transduct. 2015;35:107–14. 19. mossetti g, rendina d, viceconti r, et al. the relationship of 3' vitamin d receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis. nephrol dial transplant. 2004;19:2259-65. 20. chen wc, chen hy, hsu cd, wu jy, tsai fj. no association of vitamin d receptor gene bsmi polymorphisms with calcium oxalate stone formation. mol urol. 2001;5:7-10. 21. heilberg ip, teixeira sh, martini la, boim ma. vitamin d receptor gene polymorphism and bone mineral density in hypercalciuric calcium-stone-forming patients. nephron. 2002;90:51-7. 22. nishijima s, sugaya k, naito a, morozumi m, hatano t, ogawa y. association of vitamin d receptor gene polymorphism with urolithiasis. j urol. 2002;167:2188-91. 23. seo iy, kang ih, chae sc, et al. vitamin d receptor gene alw i, fok i, apa i, and taq i polymorphisms in patients with urinary stone. urology. 2010;75:923-7. 24. haussler mr, jurutka pw, mizwicki m, norman aw. vitamin d receptor (vdr)mediated actions of 1α,25(oh)2 vitamin d3: genomic and non-genomic mechanisms. best pract res clin endocrinol metab. 2011;25:543–59. 25. uitterlinden ag, fang y, van meurs jbj, pols hap, van leeuwen jptm. genetics and biology of vitamin d receptor polymorphisms. gene. 2004;338:143–56. 26. arai h, miyamoto k, taketani y, et al. a vitamin d receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in japanese women. j bone miner res. 1997;12:915–21. 27. morrison na, qi jc, tokita a, et al. prediction of bone density from vitamin d receptor alleles. nature. 1994;367:284-7. 28. valdivielso jm, fernandez e. vitamin d receptor polymorphisms and diseases. clin chim acta. 2006;371:1-12. 29. scott p, ouimet d, valiquette l, et al. suggestive evidence for a susceptibility gene near the vitamin d receptor locus in idiopathic calcium stone formation. j am soc nephrol. 1999;10:1007-13. 30. pani ma, knapp m, donner h, et al. vitamin d receptor allele combinations influence genetic susceptibility to type 1 diabetes in germans. diabetes. 2000;49:504-7. 31. douroudis k, tarassi k, ioannidis g, et al. association of vitamin d receptor gene polymorphisms with bone mineral density in postmenopausal women of hellenic origin. maturitas. 2003;45:191-7. 32. gauderman wj, morrison jm. quanto 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies, http://hydra.usc.edu/gxe, 2006. vdr gene polymorphisms in nephrolithiasis-cakir et al. endourology and stone diseases 2518 an unusual foreign body in the bladder and percutaneous removal younesi m1, ahmadnia h2, asl zare m2 1department of uorology, mazandaran university of medical sciences, mazandaran, iran 2department of uorology, mashhad university of medical sciences, mashhad, iran key words: bladder, foreign body, endoscopy, percutaneous 53 urology journal unrc/iua vol. 2, 53-54 spring 2004 printed in iran introduction foreign bodies in the bladder have been commonly reported. however, we describe a rare foreign body which was a carpule containing lidocaine that was removed percutaneously. case report a 28-year male, married patient was referred to this center with irritative urinary symptoms (frequency, nocturia, and dysuria) initiated a week before. in his history, he mentioned the existence of an ampule in his body and masturbation for seven years. psychological disorder or drug abuse was not reported. physical examination was normal except for a mild tenderness in the suprapubic area. a foreign body was observed in pelvic anteroposterior radiography (fig. 1). cystoscopy under local anesthesia was performed and a lidocaine carpule was detected. removal throughout urethra was not viable as it was fragile. thus, we considered percutaneous extraction as the treatment of choice. open surgery could be an alternative approach.(1,2) laparoscopic technique has recently been reported as well.(3) the patient was secured in the supine position. under general anesthesia a 18 f foley catheter was inserted, the bladder was filled up to its normal capacity with normal saline, and the skin was incised 1 cm long in the suprapubic area, 1.5 cm over the symphysis pubis using scalpel. we entered the bladder with a puncture needle and placed a 0.035 inches j type guide wire as soon as we confirmed that the needle was within the bladder. tract dilatation up to 30 f was done by a telescopic dilatator and finally a 30 f amplatz sheet was placed. cystoscopy was performed using a wolf 25° nephroscope and a dentistry type lidocaine carpule was seen. it was successfully removed with a grasp (fig. 2,3). eventually, the skin was sutured with a 2.0 nylon and a 18 f foley catheter was placed for three days. tree-month follow-up showed complete improvement and no complication. accepted for publication in august 2003 fig. 1. anteroposterior radiography demonstrates lidocaine carpule fig. 2. the nephroscope, grasp, and amplatz sheet used in this case an unusual foreign body in the bladder and percutaneous removal discussion bladder is the most susceptible part of the genitourinary system for foreign bodies. usually foreign bodies are pushed to the urethra while trying to eliminate them or involuntary perineal muscle contraction that makes them enter the bladder. in men, they should be passed through a 20-25 cm pathway to reach the bladder. surprisingly, the urethral curve remains intact and there is no persuading explanation for this event.(4) almost everything surrounding the human has been reported as bladder foreign body such as nasal mucosa, hair, pieces of broom-straw, perfume bottle, pearl shaped bottoms, wires, beans, cables, sutures, clips, and toothbrush.(5) according to their main characteristics and origin, foreign bodies are classified as: 1. particles from animal bodies or insects: dog penis, ant, snake, tail vertebra, etc., 2. plants and vegetables: grass, wood stick, elm used for abortion, etc., 3. liquefiable materials: wax, chewing gum, glue, etc. however, some foreign bodies can't be included in this classification. in some cases they may enter to the bladder unintentionally such as hair while catheterization.(6) a common one is thermometer that slips into the bladder in females.(7) in exceptional cases, foreign bodies has been pushed into the bladder in sexual harassments.(8) trauma, particularly gunshot is another causal factor. in addition, iatrogenic entrance and migration of foreign bodies from adjacent organs have been described as the mechanism.(5,9) percutaneous approach to remove foreign bodies is a safe and effective method and is of great help in the cases in which removal is not possible through the urethra. we successfully used this method considering the limitations of our case. percutaneous approach is also an ideal alternative to open surgical operation. references 1. najafi e., maynard jf. foreign body in lower urinary tract. urology 1975; 5: 117. 2. osca jm, broseta e, server g, et al. unusual foreign bodies in the urethra and bladder. bju 1991; 68: 510. 3. ejstund p, roulsen j. laparoscopic removal of an electric wire from the bladder. bju 1997; 30: 338. 4. aliabadi h, cass as, gleich p, et al. self-inflicted foreign bodies involving lower urinary tract and male genitals. urology 1985; 26: 12. 5. abdulla mm. foreign body in the bladder. bju 1990; 65:420. 6. zeitlin ab, cottrell tl, lloyd fa. hair as a lower urinary tract foreign body. j urol 1957; 77: 840. 7. aspinall a. removal of clinical thermometer (half minute) from the bladder by manipulation. med j aust 1931; 2:454. 8. detarnowsky g. a unique foreign body in the urinary bladder. jama 1915; 64: 1495. 9. kyriakidis a, stokidis d, giannopoulos a. urological complications due to foreign bodies in the alimentary tract. aeta urol belg 1982; 50:331. 54 fig. 3. lidocaine carpule extracted from the bladder case report 127urology journal vol 6 no 2 spring 2009 aspergillus fungal balls causing ureteral obstruction ashish ahuja, baldev s aulakh, deepinder kaur cheena, ravi garg, sandeep singla, sushil budhiraja urol j. 2009;6:127-9. www.uj.unrc.ir keywords: aspergillus, urinary tract infections, ureteral obstruction dayanand medical college and hospital, ludhiana, punjab, india corresponding author: sandeep singla, md h no 265, sector-10, panchkula (haryana), india tel: +91 98 7277 7620 e-mail: drsandeepdmch@yahoo. co.in received january 2008 accepted may 2008 introduction fungal bezoar of the kidney is a rare clinical entity, usually seen in a diabetic, immunocompromised, or chronic alcoholic patient who has prolonged catheterization.(1) angio-invasive fungal infections such as aspergillosis are associated with severe renal lesions and kidney failure with high morbidity and mortality rates.(2) we describe a patient who developed complete obstruction of the left ureter as a result of aspergillus fungal balls which were successfully removed ureteroscopically. case report a 48-year-old diabetic woman presented with a dull pain in the left flank, recurrent urinary tract infections, and passage of small particles during urination for the past 2 years. urine microscopic examination showed a field full of pus cells. diagnosis of aspergillosis was confirmed by urine culture (figure 1). intravenous urography showed left hydroureteronephrosis. no invasion to the renal parenchyma was detected on abdominal computed tomography (figure 2). preoperative retrograde pyelography and ureteroscopy showed complete obstruction in the pelvic ureter (figure 3). the fungal balls were removed ureteroscopically from the left ureter and the renal pelvis and sent for microbiological examination. microscopic examination of the wet mount preparation revealed hyaline septate hyphae with branching at acute angles. the lactophenol cotton blue mount from the figure 1. lactophenol cotton blue mount of aspergillus culture shows septate hyphae and conidiophores ending in a vesicle (× 400). figure 2. contrast-enhanced abdominal computed tomography shows a bulky left kidney with normal enhancement of the renal parenchyma. fungal balls causing ureteral obstruction—ahuja et al 128 urology journal vol 6 no 2 spring 2009 fungal culture demonstrated septate hyphae with conidiophores terminating in a vesicle. the features were consistent with the diagnosis of aspergillus infection. the patient received oral itraconazole, 400 mg, for 1 month, and irrigation through ureteral catheter with amphotericin b was done for 7 days. retrograde urography on the 10th postoperative day showed good drainage of contrast medium from the left kidney (figure 4). the patient’s recovery period was uneventful. discussion opportunistic pathogens such as candida, aspergillus, mucor, cryptococcus, and histoplasma are known to infect the kidneys in patients with serious complications.(2) typically, fungal diseases involve the urinary drainage system.(3) the usual locations of involvement by aspergillus include the lungs, central nervous system, sinuses, and skin.(3-5) in immunocompromised patients, disseminated infections with involvement of kidney may occur. aspergillosis of the kidney may present as any of the following patterns: disseminated aspergillosis with renal involvement resulting from hematogenous spread of the fungi to the kidneys, leading to formation of multiple focal abscesses; aspergillus cast of the renal pelvis; and ascending panurothelial aspergillosis of the urethra, bladder, pelvis, and kidney.(2) a fungal bezoar causing ureteral obstruction is extremely rare. only about 50 cases of such fungal balls have been reported.(5) most fungal bezoars causing ureteral obstruction are due to candida species. only about 12 cases of ureteral obstruction by aspergillosis have been reported to date.(6) most of ureteral obstructions are unilateral. bilateral ureteral obstruction due to fungal bezoars is extremely rare.(6,7) fungal infections of the urinary tract must be diagnosed quickly and treated aggressively. if they remain untreated, they can cause urinary obstruction through formation of accretions called fungal balls resulting in hydronephrosis, oligu ria or anuria, destruction of the renal parenchyma, wide-spread figure 4. postoperative retrograde urography shows normal drainage of the left ureter. figure 3. retrograde urography shows complete obstruction of pelvic ureter. fungal balls causing ureteral obstruction—ahuja et al urology journal vol 6 no 2 spring 2009 129 dissemination of the organism, and death of the patient.(2,8) unfortunately, excretory urography, computed tomography, and even retrograde urography have been reported to be unreliable in diagnosis of this condition.(6-8) otherwise, endourological procedures including percutaneous nephrostomy, ureteroscopy, nephroscopy, and ureteral stents are valuable in the diagno sis and management of fungal infections in the urogenital system and offer better ways of han dling these patients to the urologist.(7) at the same time, percutaneous irrigation permits administration of highly toxic antifungal drugs to the patients with localized infection and as a result, minimizes systemic side effects.(8) endourological procedures along with oral and topical antifungals can be successfully used to manage patients with disseminated fungal infection. conflict of interest none declared. references 1. simsek u, akinci h, oktay b, kavrama i, ozyurt m. treatment of catheter-associated candiduria with fluconazole irrigation. br j urol. 1995;75:75-7. 2. gupta kl. fungal infections and the kidney. indian j nephrol. 2001;11:147-57. 3. mindell hj, pollack hm. fungal disease of the ureter. radiology. 1983;146:46. 4. guleria s, seth a, dinda ak, et al. ureteric aspergilloma as the cause of ureteric obstruction in a renal transplant recipient. nephrol dial transplant. 1998;13:792-3. 5. vuruskan h, ersoy a, girgin nk, et al. an unusual cause of ureteral obstruction in a renal transplant recipient: ureteric aspergilloma. transplant proc. 2005;37:2115-7. 6. kueter jc, macdiarmid sa, redman jf. anuria due to bilateral ureteral obstruction by aspergillus flavus in an adult male. urology. 2002;59:601. 7. visser d, monnens l, feitz w, semmekrot b. fungal bezoars as a cause of renal insufficiency in neonates and infants--recommended treatment strategy. clin nephrol. 1998;49:198-201. 8. smaldone mc, cannon gm, benoit rm. case report: bilateral ureteral obstruction secondary to aspergillus bezoar. j endourol. 2006;20:318-20. vol 13 no 05 september-october 2016 2744 the association of a number of anatomical factors with the success of retrograde intrarenal surgery in lower calyceal stones” sercan sarı,1* hakki ugur ozok,2 hikmet topaloglu,2 mehmet caglar cakıci,2 harun ozdemir,3 ahmet nihat karakoyunlu,2 aykut bugra senturk,4 hamit ersoy2 purpose: to determine anatomical factors affecting retrograde intrarenal surgery (rirs) success in the treatment of renal lower calyx stones. materials and methods: the results of patients were evaluated retrospectively. the patients who have preoperative intravenous urography (ivu) and computed tomography (ct) were divided into two groups as successful (s)(n=103) and unsuccessful(u) (n=29). the anatomic characteristics such as infundibulopelvic angle (ipa), infundibular length (il), infundibular width (iw) and pelvicaliceal height (pch) values were compared among two groups. results: mean patient age was 47±13.6 years in group s and 49.5 ±11.9 years in group u. the mean stone size was 10mm (6-54mm) in group s and 19mm (8-45mm) in group u (p < .001) mean ipa was 85.8 ±16.9 degree in group s versus 54.7 ± 11.5 degree in group u. the mean pch was 1.9cm (0.5-4cm) in group s versus 2.3cm (0.7-3.9cm) in group u. the mean il were 2.7 ± 0.8 cm and 3.2±0.7cm in group s and group u, respectively. the mean iws were 0.7 cm (0.2-2.3cm) and 0.7cm (0.3-2) in group s and group u, respectively. the differences were statistically significant for ipa, pch, il (p < .05) while was not statistically significant for iw (p > .05). after multivariate analyses, pch, ipa and stone size were statistically significant factors. conclusion: in our study we found that ipa, pch and stone size were significant anatomical factors affecting rirs success in the treatment of renal lower calyx stones. the patients whose ipa, pch and stone size valuables are unsuitable, may need multiple rirs sessions or additional treatment modalities. keywords: anatomy; lower calyx; retrograde intrarenal surgery; stone; success. introduction urinary stone disease affects human health to a great degree. today, retrograde intrarenal surgery (rirs) is used more and more due to its high success in kidney stone treatment and low complication rates. (1) the probability of failure is higher for the stones in lower renal calices.(2) predicting the failure especially in lower calyx stones can prevent unnecessary interventions. studies investigating the factors that predict this failure were carried out. the number of patients who have lower calyx stones is low in these studies. in this retrospective study, we aimed to determine the anatomical factors that predict this failure by comparing the data of the patients who underwent successful and unsuccessful rirs procedures , which were performed for the treatment of the stones in the lower renal calices. materials and methods in this study, 1035 patients who had undergone rirs due to kidney stone at our urology clinic were analysed retrospectively upon receiving the local ethics board approval between february 2012 and november 2014. 1deparment of urology, sarikamis state hospital,kars,turkey. 2dışkapı yıldırım beyazıt training and research hospital, department of urology, ankara, turkey. 3haseki training and research hospital, department of urology, istanbul, turkey. 4hitit university faculty of medicine, department of urology, corum, turkey. *correspondence: sarikamış snowlife otel kars türkiye. tel: 00905356608838. e mailsercansari92@hotmail.com. received august 2016 & accepted may 2017 among cases with isolated lower calyx stone, 132 patients who had intravenous uroghraphy (ivu) and computerized tomography(ct)and undergone successful (103 patients) or unsuccessful (29 patients) rirs procedure were included in the study. only patients whose stones were treated in lower calyx were included our study. patients with ureteropelvic junction obstruction, horseshoe kidney, ureteral stricture, preoperative hydronephrosis and multiple caliceal stones were excluded. among the cases that underwent unsuccessful rirs, failure due to ureteral perforation, urethra or ureteral stricture, ureteropelvic junction obstruction and parenchyma stone were excluded from the study. complete blood count, serum biochemical values, bleeding and coagulation profile, urine analysis, urine cultures of all patients were evaluated. for radiopaque stones, the longest diameter in x-ray of kidney ureter bladder (x-ray kub), and for non-opaque stones, the longest diameter in ultrasound were measured to calculate the size of the stones. in multiple stones, the longest diameter of each stone was measured and the sum of all measurements was defined as the size of stone. informed consent was taken from all patients before the endourology and stone disease vol 14 no 04 july-august 2017 4008 operation. parenteral antibiotic was administered to all patients 1 hour before the operation. following general anaesthesia in supine position, the position of the patient was changed to modified dorsal lithotomy. later, semirigid ureterorenoscopy was performed and guide wire was inserted into the ureter under fluoroscopic control. following the first guide wire, ureter was approached with semirigid ureterorenoscopy and diagnostic ureterorenoscopy was performed which also dilated the ureter. in the event that it was not possible to pass from ureteral orifice, the operation was performed two weeks after passive dilatation upon placing jj stent. later on, ureteral access sheath was inserted into upper ureter under fluoroscopic control over the guide wire. lithotripsy was performed with 200micron holmium laser probe (ho: yttrium aluminum garnet(yag) laser; dorniermedtech; munich, germany) after monitoring the stone with flexible ureterorenoscopy (flex-x2, karl storz, tutlingen, germany). the stone basketing was used by a manual pump or tipless nitinol baskets (zero tip™; boston scientific microvasive) . during the operation, the following settings were used for the laser energy: 8-10 hertz frequency and a power of 1200-1500 joule . fragmentation and dusting were used for stone management. intraoperative fluoroscopic control and monitoring all calyces with flexible ureterorenoscopy were performed to control the clearance of stones at the end of the operation when the stones were fragmented. after the procedure, jj stent was placed in the patients. 16fr foley urethral catheter was inserted following the procedure. success was evaluated with x-ray for opaque stones and ultrasound for non-opaque stones 24 hours after the operation in addition to intraoperative control. the procedure was interpreted as successful in patients in whom all the stones were removed. on the 1st postoperative day, urethral catheter was removed. in case when additional procedure was not planned, jj stent of the patient was removed 3 weeks later. patients were followed for six months. all patients have preoperative ivu and ct. but for determining anatomical factors we made the measurements in ivu . some variables such as infundibulopelvic angle(ipa), infundibular length(il), infundibular width(iw) and pelvicaliceal height (pch) were measured on ivu of the patients. (figure 1) ipa is the angle formed when the axis that passes through lower calyx and the axis that passes through ureteropelvic junction intersect, pch is the distance to the horizontal axis drawn from the middle point of pelvis and from the lowest point of lower calyx il is the axis that extends from lower calyx infundibulum to pelvis, iw is the narrowest infundibulum diameter in lower calyx. statistical analysis the data was analysed with spss 11.5 for windows statistical software package. for the significance of the intergroup mean values, student’s t test, and for the significance of the median value difference, mann whitney u test were used. categorical variables were examined with pearson chi-square, fisher’s exact or probability ratio test. in distinguishing whether or not clinical measurements such as ipa, il, iw, pch and stone size were determinant for procedure success we calculated the area below the roc curve and 95% reliability interval. the most important determining factor(s) in differentiating the group in which the procedure was performed successfully and unsuccessfully was (were) investigated with multivariate retrospective stepwise elimination logistic regression analysis. according to hosmer and lemeshow, variables with p < .25 in univariate statistical analyses that might be considering significant in multivariate analyses were included in multivariate regression model. according to this information, the variables with p < .25 in univariate analyses were included in logistic regression model as potential risk factors. in the next step using backward lr method, the most specific factors, were used to distinguish the groups from each other. all the variables found with p < .25 in univariate statistical analyses were included in the multivariate model as potential risk factors. the anatomical factors and rirs success-sari et al. endourology and stone diseases 4009 variables successful (n=103) unsuccessful (n=29) p-value age (year) (mean±sd) 47.0 ± 13.6 49.5 ± 11.9 0.381 gender n(%) 0.118 male 58 (56.3%) 21 (72,4%) female 45 (43.7%) 8 (27.6%) weight (kg) (mean±sd) 73.8 ± 8.5 75.0±7.9 0.479 height (cm) (mean±sd) 169.5 ± 64 171.4 ± 5.9 0.149 bmi (kg/m2) (mean±sd) 25.7 ± 2.8 25.5 ± 2.8 0.815 asa n(%) 0.814 i 16 (15.5%) 5 (17.2%) ii 76 (73.8%) 22 (75.9%) iii 11 (10.7%) 2 (6.9%) table 1. demographic and clinical features of groups s and u. abbreviations: bmi, body mass index; asa, american society of anesthesiologists odds rate of each variable, 95% confidence interval and wald statistics were calculated. results were accepted as statistically significant for p < .05. results the mean age were 47(±13.6) years in group s and 49.5(± 11.9) years in group u. comparing the patient ages, no statistically significant difference was found between group s and u (p = .35). when patient groups were compared with regard to demographic features, no statistical significant difference was observed in terms of gender, body weight, height, body mass index ( bmi) (kg/m2), american society of anesthesiologists (asa) scores (table 1). when the intergroup clinical findings were examined, no statistically significant difference was observed in terms of the side of the stone (right/left) access sheath usage, operation time, jj stent usage, hospital stay (table 2). when the other clinical findings were examined, while no statistically significant difference was observed in systolic blood pressure (sbp), diastolic blood prestable 2. other clinical features of groups s and u. variables successful (n=103) unsuccessful (n=29) p-value stone pole n(%) 0.182 left 48 (46.6%) 18 (62.1%) right 54 (52,4%) 10 (34,5%) bilateral 1 (1.0%) 1 (3,4%) number of the stones (min-max.) 1 (1-3) 2 (1-4) < 0.001 multiple stone n(%) 24 (23.3%) 17 (58.6%) < 0.001 stone size (mm.)(min.-max.) 10 (6-54) 19 (8-45) < 0.001 access sheath usage 83 (80.6%) 27 (93.1%) 0.159 operation time(min.)(min.-max.) 45 (15-80) 45 (30-80) 0.203 djs usage n(%) 78 (75.7%) 22 (75.9%) 0.988 hospital stay (min.-max.) 1 (1-1) 1 (1-1) residual stone size (min.-max.) 10 (5-24) sbp(mmhg) (mean±sd) 128.4 ± 7,5 127.9 ± 7,4 0,766 dbp(mmhg) (mean±sd) 81.3 ± 4,4 80,2 ± 5,1 0,239 spo2(mean±sd) 98.3 ± 1.1 98,5 ± 0,7 0,498 swl n(%) 23 (22.3%) 13 (44,8%) 0,016 secondary n(%) 15 (14.6%) 10 (34,5%) 0,016 opaque n(%) 68 (66.7%) 26 (89,7%) 0,015 result n(%) follow-up 103 (100,0%) 16 (55,2%) pcnl 7 (24,1%) rirs 6 (20,7%) abbreviations: djs, double j stent; min,minimum; max,maximum; sbp, systolic blood pressure; dbp, diastolic blood pressure; swl, shock wave lithotripsy; pcnl, percutaneous nephrolithotomy; rirs, retrograde intrarenal surgery. variables successful (n=103) unsuccessful (n=29) p-value ipa (deg.)( mean±sd) 85,8 ± 16,9 54,7 ± 11,5 < 0.001 il (cm.) (mean±sd) 2,7 ± 0,8 3,2 ± 0,7 0.004 iw (cm.) (min.-max.) 0,7 (0,2-2,3) 0,7 (0,3-2,0) 0.139 pch (cm.) (min.-max.) 1,9 (0,5-4,4) 2,3 (0,7-3,9) 0.007 abbreviations: ipa, infundibulopelvic angle; il, infundibular length; iw, infundibular width; pch, pelvicaliceal height; min, minimum; max, maximum table 3. anatomical features of inferior calyx in groups s and u. anatomical factors and rirs success-sari et al. vol 14 no 04 july-august 2017 4010 sure (dbp), oxygen saturation (spo 2 ) between the groups, statistical significant difference was found in shock wave lithotripsy (swl) history, being opaque/ non-opaque, being secondary (that is to say that patient underwent a surgery before). while 16 patients were followed in the group u, percutaneous nephrolithotomy (pnl) procedure was performed for 7 patients, and rirs was performed on 6 patients (table 2). the patients who had undergone second pnl and rirs were stone free after the second procedure. when the other variables were examined, while significant difference was observed in ipa, il, pch values, no statistical difference was observed in iw values (table 3). the evaluation performed calcutating the area below the roc curve and 95% confidence interval with the aim of determining whether or not clinical measurements such as ipa, il, iw, pch and stone size were determiming factors in differentiating the groups in which the procedure was performed successfully and unsuccesfully indicated that ipa was quite a significant determinant, whereas il, pch, stone size had lesser degree of significance (table 4). multivariate retrospective stepwise elimination logistic regression analysis in which all the variables found to be p < .25 as a result of the single-variable statistical analyses were included as potential risk factors. basal model was formed considering the significant variables in single-variable analysis. the variable with the highest p value was not included in the next evaluation. similarly, the variable with the highest p value was excluded from the evaluation each time. in the end, final model was created. stone size, ipa and pch were found as determining factors as a result of the multivariate retrospective stepwise elimination logistic regression analysis (table 5). endourology and stone diseases 4011 ipa il iw pch size abc 0.945 0.707 0,590 0.665 0.742 %95 ri 0.905-0.984 0.606-0.808 0.473-0.707 0.553-0.777 0.641-0.843 p-value < 0.001 < 0.001 0.139 0.007 < 0.001 cut-off value < 69.4 > 2.73 > 2.02 ≥ 17 number of the cases 132 132 132 132 sensitivity 27/29 (93.1%) 23/29 (79.3%) 22/29 (75.9%) 17/29 (58.6%) specificity 85/103 (82.5%) 58/103 (56.3%) 61/103 (59.2%) 82/103 (79.6%) pev 27/45 (60.0%) 23/68 (33.8%) 22/64 (34.4%) 17/38 (44.7%) nev 85/87 (97.7%) 58/64 (90.6%) 61/68 (89.7%) 82/94 (87.2%) abbreviations: abc, the area below the curve; ri, reliability interval; pev, positive estimated value; nev, negative estimated value; ipa, infundibulopelvic angle; il, infundibular length; iw, infundibular width; pch, pelvicaliceal height. table 4. 95 % reliability interval, the area below the roc curve, the best interception points and the diagnostic performance indicators in relation to ipa, il, iw, pch and stone size in differentiating group s from u. anatomical factors and rirs success-sari et al. figure 1. ipa, il, iw, pch measurement images ipa il iw pch discussion the aim of kidney stone management is to remove the stones in the least damaging way possible for the patient. to this end, various methods are used. rirs is being used more due to absence of incision, shorter hospital stays. a study by reşorlu et al., compared rirs and pnl methods in the treatment of kidney stones in children who did not respond to swl treatment. while no difference was found in terms of the effectiveness of these methods in the stones 2 cm in size or smaller than 2 cm, rirs was found to be superior to pnl with regard to undesired results such as complications, hospital stay and radiation exposure.(1) in our study one patient had a 54 mm size kidney stone. this patient had a previous stone surgery in the history. the patient had multiple stones in lower calyseal system. and the sum of all stones were measured and defined as the size of the stone. pnl is recommended in the treatment of larger stones. although several studies found this method quite successful, some limitations that adversely affect the success of this method are available. the studies carried out on rirs report lower success rate in lower calyx stones. in this study, we investigated the anatomical factors that affect rirs success in lower calyx stones. in our study, we showed that gender, age, bmi, asa scores did not affect rirs success in lower calyx stones. in consistent with the previous studies, cannon et al., found similar success rates in prepubertal and postpubertal patients with kidney stone.(3) dash et al., did not find any significant difference between the success in obese and non-obese patients and the rate of kidney stone absence.(4) the size and the number of the stones especially multiple stones, previous history of swl and secondary procedures affect rirs success in consistent with previous studies in literature. the study by hyun lim et al. indicated that stone size, swl history and secondary procedures affected rirs success.(2) stav et al. and jurg et al. , stated that rirs was a safe and effective method in swl resistant kidney stones, however, large stones and lower calyx kidney stones were negative predictor factors that decreased the success of rirs.(5,6) the studies related to the impact of pelvicalyceal anatotable 5. identifying the most important determining factors in differentiating group s from u according to multivariate retrospective stepwise elimination regression analysis. variables odds rate %95 reliability interval wald p-value upper limit lower limit basal model male factor 1.675 0.315 8.916 0.366 0.545 multiple stone 0.729 0.074 7.172 0.074 0.786 stone size ≥ 17 mm. 8.895 0.850 93,143 3.327 0.068 surgery time 1. 042 0.977 1,111 1.574 0.210 ipa < 69.4 deg. 50.261 8.395 300.920 18.405 < 0.001 il > 2.73 cm. 2.110 0.289 15,410 0.541 0.462 iw 0.979 0.173 5.523 0.001 0.980 pch > 2.02 cm. 7.210 1.032 50.357 3.968 0.046 swl 1.566 0.326 7.535 0.314 0.575 secondary 5.463 0.726 41.120 2.718 0.099 opaque 5.156 0.605 43.910 2.252 0.133 model 8 stone size ≥ 17 mm. 7.647 1.790 32.672 7.539 0.006 ipa < 69.4 deg. 66.569 12.128 365.408 23.352 < 0.001 pch > 2.02 cm. 5.947 1.516 23.332 6.536 0.011 secondary 3.190 0.597 17.045 1.841 0.175 final model stone size ≥ 17 mm. 6.476 1.659 25.285 7.225 0.007 ipa < 69.4 deg. 73.197 13.588 394.296 24.968 < 0.001 pch > 2.02 cm. 5.518 1.474 20.660 6.430 0.011 abbreviations: ipa, infundibulopelvic angle; il, infundibular length; iw, infundibular width; pch, pelvicaliceal height; swl, shock wave lithotripsy anatomical factors and rirs success-sari et al. vol 14 no 04 july-august 2017 4012 my in stone treatment are generally carried out on swl. sampaio et al. , indicated in their study that ipa< 90 degrees, and iw< 4mm decreased the stone free rate. (7) elbahnasy indicated that ipa was an important factor in stone removal.(8) fong et al. indicated that iw was an important determinant in stone removal following swl.(9) keeley et al. maintained that iw was not an important factor; however, ipa was an important one. (10) when we investigated the factors that affect rirs success, as a result of the multivariate analyses we found that stone size, ipa, pch factors determine the rirs success. when the analysis was repeated taking the cutoff value, we found 69.4 degree for ipa, 2.02 cm for pch and 17 mm for stone size. a study which investigated the impact of pelvicalyceal anatomy on rirs success performed on kidney lower calyx stones evaluated the data of 11 out of 67 patients who underwent unsuccessful rirs and 56 out of 67 patients who underwent successful rirs ipa and stone size were the factors that affect rirs success. while difference was observed between the successful and unsuccessful operation groups, this difference was not statistically significant .(11) another study about rirs treatment results and stone free rate examined 66 procedures performed on 63 patients. stone localization and stone size were found as predictive factors affecting rirs success. it was found that success rate was lower in lower calyx stones.(2) yet another study carried out on the effect of pelvicalyceal anatomy on the success of rirs examined 47 patients. patients were divided into 3 groups according to ipa values (< 30 degree, 30-90 degree, > 90 degree). the success of operation was found to be higher in those ipa > 90 degree .the success was above 90 % in this group. il effect was found statistically significant. (12) grasso and ficazzola evaluated 90 patients who underwent rirs on lower calyx stone.(13) this study showed that inferior calyx infundibulum larger than 3 cm is itself a determinant factor in rirs success (total success was found as 91 %.) sharp ipa and dilated collecting system were seen as the forcing factors. in 2 patients, infundibular width blocked the entry to calyx. a study performed with the aim of determining a scoring system for predicting post-rirs stone free rate examined 207 patients. patients were divided into groups according to demographic features, stone numbers, stone localizations, pelvicalyceal anatomic factors. the multivariate analysis showed that factors such as stone size, stone content, number of stones, ipa, renal malformation affected rirs success. 88 out of 207 patients had lower calyx stones and operations in 19 of these patients were unsuccessful.(14) in our study, since the operation success in lower calyx stones was lower than the stones in the other calyx, we examined patients with isolated lower calyx stones. since the patients with renal malfunction and multiple calyxes were excluded from the study, those factors could not be assessed. in parallel with the studies in the literature, we concluded that ipa and stone size were factors that affected rirs success in lower calyx stones. different from the studies in literature, we indicated that pch was a factor that affected rirs success. in a study performed with swl, stone free rate was 92 % in patients with pch<15 and 52 % in patients with pch≥15mm in a study carried out on swl.(15) no complication arose in either group in our study. when we look at the limitations of our study, the disadvantages include that it was performed retrospectively; unfortunately we did not have any information about the technical difficulties. patients were evaluated with ivu and the number of the patients. in a study carried out on swl, patients were evaluated using ivu and helical ct (hct). in lower calyceal anatomy evaluation, it was seen that 3d-hct was not superior to ivu. we chose ivu over 3d-hct because of lower costs of ivu compared to 3d-hct and the high radiation dose in 3d-hct.(16) in our study we intended to determine the anatomical factors affecting rirs success. therefore, we did not evaluate the hounsfield units. there is no study in literature performed with the same patient number like our study which investigated the anatomical factors that affected rirs success. european association of urology 2014 stone treatment guideline recommends rirs or pnl in case that swl is not suitable in lower calyx stones larger than 1.5 cm .(17) pnl is an effective method with high success rates. however, serious complications might be seen during and post pnl procedure. this makes the doctors prefer rirs method, which is a rapidly evolving method. rirs is used more and more due to its increasing success rates, short hospital stay and being less invasive. however, rirs is not a successful method in all patients. patient selection is important for rirs success. otherwise, kidney stones can be treated after multiple sessions. conclusions ipa is an important factor in predicting the success of lower kidney calyx stones. it affects the success of rirs to a great extent. additionally, stone size and pch, although not as important as ipa, are important in predicting the success of rirs. rirs should not be preferred for kidney stone management in patients with low ipa, high pch and stone size. the patients whose ipa, pch and stone size vales are unsuitable may need multiple rirs or additional treatment modalities. conflict of interest there is no conflict of interest among the authors. references 1. resorlu b, unsal a, tepeler a, et al. comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in children with moderate-size kidney stones: results of multi-institutional analysis. urology 2012; 80:519-23. 2. soo hyun lim, byong chang jeong, seong ii seo, seong soo jeon, deok hyun han. treatment outcomes of retrograde intrarenal surgery for renal stones and predictive factors of stone-free korean j urol 2010;51:777-82. 3. cannon gm, smaldone mc, wu hy, et al. ureteroscopic management of lower-pole stones in a pediatric population. j endourol anatomical factors and rirs success-sari et al. endourology and stone diseases 4013 2007;21:1179 -82. 4. dash a, schuster tg, hollenbeck bk, et al. ureteroscopic treatment of renal calculi in morbidly obese patients: a stone-matched comparison. urology. 2002;60:393-7. 5. stav k, cooper a, zisman a, leibovici d, lindner a, siegel yi. retrograde intrarenal lithotripsy outcome after failure of shock wave lithotripsy. j urol 2003;170:2198-201. 6. jung h, norby b, osther pj. retrograde intrarenal stone surgery for extracorporeal shock-wave lithotripsy-resistant kidney stones. scand j urol nephrol 2006;40:380-4. 7. sampaio fjb. renal collecting system anatomy: its possible role in the effectiveness of renal stone treatment. curr opinion urol 2001; 11:365-366. 8. elbahnasy am, shalhav al, hoenig dm, et al. lower caliceal stone clearance after shock wave lithotripsy or ureteroscopy: the impact of lower pole radiographic anatomy. j urol. 1998;159:676-82. 9. fong yk, peh so, ho sh. et al. lower pole ratio: a new and accurate predictor of lower pole stone clearance after shockwave lithotripsy? int j urol. 2004;11:700-703. 10. keeley fx jr, moussa sa, smith g, et al. clearance of lower-pole stones following shock wave lithotripsy: effect of the infundibulopelvic angle. eur urol. 1999;36:371-5. 11. resorlu b, oguz u, resorlu be, oztuna d, unsal a. the impact of pelvicaliceal anatomy on the success of retrograde intrarenal surgery in patients with lower pole renal stones j.urol 2012 79 61-6. 12. geavlete petrisor, multescu razvan, geavlete bogdan. influence of pyelocaliceal anatomy on the success of flexible ureteroscopic approach. journal of endourol.2008; 22: 2235-9. 13. grasso m, ficazzola m. retrograde ureteropyeloscopy for lower pole caliceal calculi. j urol. 1999; 162:1904-8. 14. resorlu b, unsal a, gulec h, oztuna d. a new scoring system for predicting stonefree rate after retrograde intrarenal surgery: the ‘’resorlu –unsal stone score’’. j urol, 80:517,2012. 15. tuckey j, devasia a, murphy l, et al. is there a simple method for predicting lower pole stone clearance after shock wave lithotripsy than measuring infundibulopelvic angle? j endourol. 2000; 14:475-8 16. rachid filho d, favorito la, costa ws, et al. kidney lower pole pelvicaliceal anatomy: comparative analysis between intraveous urogram and three-dimensional helical computed tomography. j endourol. 2009; 23:2035-40. 17. türk c, knoll t, petrik a, et al.the updated anatomical factors and rirs success-sari et al. eau guidelines on urolithiasis. eururol2014; 63:1169-71. vol 14 no 04 july-august 2017 4014 pictorial persistent grade 5 reflux into a transplanted kidney in a spinal patient despite sphincterotomy michael s floyd jr, vasileios sakalis, melissa c davies keywords: reflux; spinal injury; sphincterotomy; transplantation; videourodynamics. a 43 year-old spinal injury patient was found to have asymptomatic hydronephrosis of his transplant during annual surveillance (figure 1). prior to presentation, he had developed urinary tract infection and serum creatinine was measured at 159μmol/l. his past history was remarkable for type 1 diabetes since the age of 5, spinal artery thrombosis aged 19 culminating in a c6 incomplete tetraplegia and diabetic nephropathy for which he received a live donor transplant at the age of 37. bladder management involved convene drainage and he had undergone two previous sphincterotomies. videourodynamics revealed a stable bladder during filling but high pressure sustained contractions during voiding resulting in grade v reflux into the transplanted kidney (figures 2a & b). the bladder emptied completely with no evidence of dyssynergia. the patient was counselled regarding his treatment options and was listed for repeat videourodynamics in 6 months. there is limited data on renal transplant outcome in spinal injury patients. it is acknowledged that transplant reduces urolithiasis and has similar outcomes to non-spinal patients.(1) endoscopic management is recognised as first line treatment for transplant related reflux.(2) where concomitant graft reflux and acute retention occur due to prostatic hyperplasia hybrid techniques involving holmium enucleation and simultaneous nephrostomy have been described.(3) departments of urology & duke of cornwall spinal injury unit, salisbury nhs foundation trust, wiltshire, sp2 8bj, united kingdom. *correspondence: departments of urology & duke of cornwall spinal injury unit, salisbury nhs foundation trust, salisbury, wiltshire, sp2 8bj, united kingdom. email: nilbury@gmail.com. received january 2016 & accepted december 2016 pictorial 2989 figure 1. ultrasound revealing hydronephrosis of the transplanted kidney. figure 2. a: videourodynamic trace demonstrating reflux into the transplanted kidney with clubbing of the calyces; b: videourodynamic trace demonstrating grade 5 reflux into the transplanted kidney and neoureter with clubbing of the calyces. reflux grade v into transplnated kidney-floyd et al. references 1. basiri a, shakhssalim n, hosseinimoghddam sm, parvaneh mj, azadvari m. renal transplant in patients with spinal cord injuries. exp clin transplant. 2009; 7 :28-32. 2. akiki a, boissier r, delaporte v, maurin c, gaillet s, karsenty g. et al. endoscopic treatment of symptomatic vesicoureteral reflux after renal transplantation. j urol. 2015; 193: 225-9. 3. nohara t, matsuyama s, shima t, kawaguchi s, seto c. holmium laser enucleation of the prostate with percutaneous nephrostomy into the transplanted kidney in patient with severe benign prostatic hyperplasia with vesicoureteral reflux a case report. urol case rep. 2015; 4: 33-5. vol 14 no 01 january-february 2017 2990 endourology and stone disease the tolerability of potassium citrate tablet in patients with intolerance to potassium citrate powder abbas basiri1, fatemeh taheri2 , maryam taheri1* purpose: to assess the tolerability of potassium citrate (kcit) tablets in patients with kidney stones that were not able to use the powder form of this drug due to unfavorable salty taste and /or gastrointestinal complications. materials and methods: twenty-three stone formers, with intolerance to potassium citrate powder form, which had referred to labbafinejad stone preventive clinic in 2015, were included in this study. all of the patients took two potassium citrate tablets (10 meq), three times a day for two weeks. spot urine samples and the 24-hour urine collections were performed before and after kcit therapy. in addition, a visual analog taste scale was completed to gauge the taste and palatability of the kcit tablets in comparison with the powder form. results: all of the patients claimed that they consumed the tablets as prescribed. the urine ph (5.7 ± 0.6 to 6.1 ± 0.8, p = 0.006), 24-hour citrate (235.8 ± 190.2 to 482.5 ± 323.2, p = 0.0002) and potassium (45.25 ± 22.5 to 75.27 ± 37, p = 0.002) were significantly higher after the treatment. in addition, the mean visual analog scale score was significantly improved in kcit therapy with tablet form versus to powder form of the drug (good vs. terrible score). conclusion: oral tolerance of kcit therapy is improved with the use of potassium citrate tablet, with beneficial effects on 24-hour urine citrate, potassium, and ph. keywords: potassium citrate; tolerance; taste; gastrointestinal side-effects. introduction kidney stones remain a public health problem around the world and have a high rate of recurrence even with treatment(1). the urine profile is one of the deciding indicators of urine stone formation as well as recurrence(2). consequently, clinical efforts should be focused on correcting the underlying abnormalities. one of these correctable abnormalities is hypocitraturia that is described as an isolated abnormality in up to 10% of calcium stone formers. furthermore, it is also associated with additional abnormalities in 20% to 60% of stone formers(3-5). the alkali citrate treatment has two major effects. at first, it increases urinary citrate levels in patients with calcium nephrolithiasis. moreover, it provides an overall alkalization which is advantageous for patients with uric acid(6) and cystine stones(7). the numerous benefits of the alkali citrate treatment, promotes its usage in a wide range of urinary system stones treatments. in 1985, the food and drug administration (fda) approved potassium citrate (kcit) for the treatment of a wide variety of disorders that cause stone formation (8). kcit is available in three forms in global pharmaceutical market: extendedrelease tablets, powder for dilution, and oral solution. between these three forms, however the gastrointestinal (gi) side effects of the liquid preparations have been shown to be more than tablets (33% vs 9.3%)(9), but its effectiveness is better in patients with short intestinal transit such as chronic 1urology and nephrology research center, department of urology, shahid beheshti university of medical sciences, tehran, iran. 2school of nutritional sciences and dietetics, tehran university of medical sciences, tehran, iran. *correspondence: urology nephrology research center, no. 103, 9th boostan street, pasdaran avenue, tehran, iran. tel: 0098 21 22567222. fax: 0098 21 22567282. email: taheri233@yahoo.com. received december 2017 & accepted january 2018 diarrheal syndromes(10). despite its widespread use, compliance to long term treatment with kcit is low, mainly due to its inappropriate salty taste suspected side effects(11) and inconvenience of bid (two times a day) or tid (three times a day) dosing specially with powder form that is necessary to be prepared. considering the inconvenient use of the powder formulation and improvement of its tablet taste as declared by the manufacturer, we decided to evaluate the palatability and efficacy of simple form of kcit tablet (urocitra) in groups of kidney stone forming patients with intolerance to powder form of this drug due to the unfavorable taste and upper gi side effects. materials and methods this study was conducted as a quasi-controlled trial in stone formers referred to labbafinejad stone clinic in 2015. enrollment criteria included recurrent calcium stone formers whom only urinary metabolic risk factor was hypocitraturia (24-hour urinary citrate less than 320 mg/24 h) and were treated with potassium citrate powder, and were unable to tolerate this drug due to unfavorable salty taste and gastrointestinal complications. the patients were included only after at least one month of therapeutic interventions. participants were excluded if they had renal failure (creatinine clearance < 60 ml/min), were taking on treatment that altering potassium metabolism (angiotensin-converting enzyme inhibitors, beta-blockers, potassium-sparing diuretics), endourology and stone diseases 16 or consumed any kinds of citrate supplement within the last four weeks. women were also excluded if they were in pregnancy or lactation. the institutional review board of the urology and nephrology research center (unrc) approved the study protocols. twenty-three patients who met the mentioned criteria were enrolled in the study. informed consent was taken from patients before participating in the study. demographic information and initial questionnaires for all individuals were filled. serum sample, fast urine and 24-hour urine were collected at baseline. to assess the drug influence on kidney function, serum potassium and creatinine were checked. twenty-four hour urine was measured for volume, potassium, citrate and creatinine. urinary ph was immediately determined on post-voiding spot urine sample using a ph electrode. then, patients underwent treatment with potassium citrate tablets with the dosage of 6 tablets per day (2 tablets every 8 hours, each tablet contains 5 mili-equivalent citrate) for two weeks. at the end of the study, the analysis of serum metabolites, spot urine sample and 24-hour urine metabolites were repeated. the visual analog taste scale (vats) (figure 1) was used to assess patients' satisfaction. furthermore, the amount of remained kcit tablet and measurement of 24-h urinary potassium were used as another criteria to evaluate patients' compliance (12). it is noteworthy that all of our patients in this study have been advised to general dietary recommendation of preventive stone clinic protocol, at least three months before treatment with potassium citrate tablet. method of analyzing serum and urine parameters: serum creatinine were measured using a jaffe kinetic method with bs-480 chemistry fully automated analyzer. urine creatinine were measured using a jaffe kinetic method with bt-4000 full-automated chemistry analyzer. urinary citrate was determined by an enzymatic procedure using reagents from darman faraz kave using eppendorf biophotometer. serum and urine potassium were measured with the eppendorf flame photometer and easylyte electrolyte analyzer, respectively. urinary ph was measured with a ph electrode in urine samples immediately post-voiding using bante 220 portable ph meter. statistical analysis was performed by spss 19. the normal distribution of the data was investigated through the kolmogrov-smirnov test. as all variables were normally distributed, changes in patients’ urinary metabolic profile and serum parameters before and after treatment with kcit tablet were identified by the paired t test. significant changes were defined as p value < .05. results all the patients completed the study and their average age was 51.14 ± 9.89 (16 males and 7 females). the urinary metabolic profile and serum parameters of the studied population before and after kcit therapy were compared and the results are shown in table 1. the patients’ urinary ph increased significantly from 5.7 ± 0.6 to 6.1 ± 0.8 after treatment with kcit tablets (p = .006). urinary citrate also showed a significant increase from 235.8 ± 190.2 to 482.5 ± 323.2 (p = .0002). in addition, mean urinary potassium showed significant increase (p = .002) as expected which indicates patients’ compliance. no remarkable changes were observed in serum creatinine and potassium (table 2). all the individuals claimed that they consumed the tablets as prescribed. only two patients, who had the history of gastrointestinal problems following food intake and most medications, experienced a little heartburn after consumption of kcit tablets, though it was tolerable for them with meals and they finished the delivered tablets. the vats score at baseline to assess the patients’ satisfaction about kcit powder, was 8.35 ± 0.77 which represents “terrible” and after treatment changed to 2 ± 0.14, which accounts for “good” in this scale (p = .0001). as it is obvious from the results, patients’ satisfaction significantly increased after intake of kcit tablets. discussion kidney stone removal has been significantly facilitated by using the recently emerging non-invasive treatments(5). although these therapiesnamely percutaneous nephrolithotomy and extracorporal shockwave lithotripsyprovide satisfactory results with associated acceptable rate of complications, they do not alter the underlying metabolic abnormality. furthermore, stone recurrence is typically found post-treatment, even in figure 1. visual analogue taste scale for assessment the patient’s satisfaction(30). tolerability of potassium citrate tablets-basiri et al. mean ± sd1 number (percent)2 age (years) 51.14 ± 9.89 sex male 16 (70%) female 7 (30) duration of initiation of stone disease (years) 12.71 ± 9.74 history of stone intervention eswl (yes) 8 (42%) surgery (yes) 14 (74%) duration of kcit powder consumption before 3.77 ± 4.43 the study (months) causes of intolerance to kcit powder inappropriate salty taste 8 (35%) epigastric pain 7 (30%) nausea 6 (26%) heartburn 2 (9%) 1. sd: standard deviation. 2. number for quantitative variables and percent for qualitative variables. 3. the collection of the dispersed time of consuming the powder form of potassium citrate. table 1. demographic data of the patients and the prevalence of gastro-intestinal complications with powder form of potassium citrate (kcit). vol 15 no 01 january-february 2017 17 those with a stone-free post-therapy status. in addition, following those therapies, the retained stone particles may aggregate or constitute a nucleus for new stone formation, thereby causing an elevated rate of stone growth. based on the stone recursion frequency, the development of a medical prophylactic program to prevent recurrences is of utmost importance(5). in addition, patient’s compliance to medical recommendations of kidney stone clinic is another important factor, which affects the treatment outcomes. our study revealed that the compliance of our patients to the tablet form of potassium citrate was satisfactory. potassium citrate has been used as a medical therapy of urolithiasis for more than two decades. its effectiveness in treatment of urinary system stones has been reported in several studies(1,12). citrate is a known inhibitor of stone formation. in renal tubules citrate complexes with calcium, reduces the availability of ionic calcium to interact with oxalate or phosphate(13,14). moreover, citrate helps the inhibitory effects of macromolecular modulators of calcium oxalate crystallization processes, partly by interaction with tamm-horsfall protein(15). in addition, citrate prevents crystal agglomeration and growth through its ability to bind to the crystal’s surface, and it may prevent adhesion of calcium oxalate to renal epithelial cells(16). low urinary potassium is related to hypocitraturia(17), therefore one of the advantages of potassium preparations is either prevention or correction of hypokalemia. also simultaneous administration of citrate with thiazide agents can be more effective in lowering urinary calcium excretion(18). lastly, potassium citrate is a meaningful treatment for uric acid and cystine nephrolithiasis, as it provides an alkali load which increases urinary ph, one of the principal determinants of uric acid and cystine solubility(5). also with considering the effect of kcit in delaying of the urease-induced crystallization, it may be useful in urinary infection stones(19). several authors supported the benefit of alkaline citrates in patients with renal calculi. a meta-analysis conducted by phillip et al.(1), including seven randomized controlled trials with a total of 477 participants in preventing stone recurrence through the long-term administration of citrate preparations (at least six months), have been shown that kcit not only reduced the stone size, but also reduced new stone formation significantly, and increased citrate levels. in another review, mattle et al.(20) on a short-term therapy (between 1 to 12 weeks) with alkali citrate(21-28) showed that after taking potassium citrate, urine ph increased by 114% comparing to pretreatment values. the same was true for urinary citrate, which increased by between 27%94%. despite the significant therapeutic effects of alkali citrate, the main limitation of its widespread usage is the relatively low gi tolerability of available alkali citrate preparations. in one study, only 62% of patients consumed low doses of potassium citrate in long term (11). in a review by mattle et al., overall, 17% of subjects on placebo and 33% of treated patients with alkali citrate, in order to prevent stone recurrence, prematurely left the randomized trials due to drug side effects. adverse effects that reduce treatment compliance included upper gastrointestinal disturbances (epigastric pain, heartburn, and nausea), loose stools and rash(1). the problems with compliance are poorly reported in the literature, but some reasons cited are high cost, bad taste, and the inconvenience of bid or tid dosing (29,30). thus, the development of more tolerable alkali citrate preparations remains an important issue in the treatment of urinary stones. in this study, comparing the price of these two forms of potassium citrate shows that the cost of taking the tablet form is about 30% higher than powder (1.09 $ vs. 0.83 $); however, considering the better tolerability of tablet form and reported unused powder form of this drug, it is obvious that this amount of higher cost of tablet form is acceptable. whereas in middle europe there is a preference for potassium sodium citrate, in north america (us, canada) kcit is the favored preparation. the result of the criticism levelled against potassium sodium citrate by us authors, is that sodium moiety causes increased calciuria. more specifically, sodium may abolish the decrease in calciuria, one of the beneficial effects possibly exhibited by potassium citrate(29). in our country, currently the only available preparation of kcit is the powder form, which some patients cannot tolerate it, especially due to its unappealing salty taste. the results of this study showed that the transformation of powder formulation into kcit tablets, improves the taste of kcit, facilitates taking the drug, and reduces gastrointestinal complications. there is no other study for comparison, the results of this study illustrate that the compliance for kcit tablets was satisfactory with regard to the subjects who took the tablet forms, and completed the study(30). in some countries, there are also other forms of the medication such as the slow-release preparation, which is better tolerated. other researchers have added an artificial sweetener (splenda) to the powder form to enhance the taste property and compliance(30). our study confirms that changing the powder form to kcit tablet results in more tolerability, however, the question that whether this effect is truly durable in long term has remained unanswered, since if these changes sustain over time, there will be a significant reduction in kidney stone recurrence rate. the small sample size and short follow-up time could be considered as shortcomings and limitations of the study. therefore, a long-term study using higher doses of this easily tolerable medication is suggested to test and challenge our study results. acknowledgment the authors would like to thanks mr. ali aghaei for his good cooperation in preparation the drug. we thank saba jalali and navid mokhtari for their kind assistance in clarifying the patient’s data and writing the manuscript, respectively. in addition, we would like to thanks dr. seyedehleila tabatabaeefar for her very tolerability of potassium citrate tablets-basiri et al. endourology and stone diseases 18 before kcit after kcit p value total volume (ml) 1690 ± 473* 2050 ± 760 0.03 ph 5.7±0.6 6.1 ± 0.8 0.006 urine potassium (mg/day) 45.25 ± 22.5 75.27±37 0.002 citrate (mg/day) 235.8 ± 190.2 482.5±323.2 0.0002 creatinine (mg/day) 1.2 ± 0.5 1.1 ± 0.4 0.23 serum potassium (meq/l) 4.19 ± 0.4 4.15±0.4 0.81 creatinine (mg/dl) 1.18 ± 0.17 1.16±0.15 0.55 table 2. the results of serum and urine analysis. meq: milliequivalent. ml: mili-litre. mg: mili-gram. kcit: potassium citrate. careful correction of the last edition of this manuscript. conflict of interest the authors report no conflict of interest. references 1. phillips r, hanchanale vs, myatt a, somani b, nabi g, biyani cs. citrate salts for preventing and treating calcium containing kidney stones in adults. cochrane database syst rev. 2015cd010057. 2. rahman f, birowo p, widyahening is, rasyid n. effect of citrus-based products on urine profile: a systematic review and metaanalysis. f1000res. 2017;6:220. 3. pattaras jg, moore rg. citrate in the management of urolithiasis. j endourol. 1999;13:687-92. 4. pak cy, poindexter jr, adams-huet b, pearle ms. predictive value of kidney stone composition in the detection of metabolic abnormalities. am j med. 2003;115:26-32. 5. bultitude mf. campbell‐walsh urology tenth edition. bju international. 2012;109. 6. moe ow, abate n, sakhaee k. pathophysiology of uric acid nephrolithiasis. endocrinol metab clin north am. 2002;31:895-914. 7. joly d, rieu p, mejean a, gagnadoux mf, daudon m, jungers p. treatment of cystinuria. pediatr nephrol. 1999;13:945-50. 8. pak cy. citrate and renal calculi: new insights and future directions. am j kidney dis. 1991;17:420-5. 9. pak cy, fuller c, sakhaee k, preminger gm, britton f. long-term treatment of calcium nephrolithiasis with potassium citrate. j urol. 1985;134:11-9. 10. fegan j, khan r, poindexter j, pak cy. gastrointestinal citrate absorption in nephrolithiasis. j urol. 1992;147:1212-4. 11. jendle-bengten c, tiselius hg. long-term follow-up of stone formers treated with a low dose of sodium potassium citrate. scand j urol nephrol. 2000;34:36-41. 12. robinson mr, leitao va, haleblian ge, et al. impact of long-term potassium citrate therapy on urinary profiles and recurrent stone formation. j urol. 2009;181:1145-50. 13. meyer jl, smith lh. growth of calcium oxalate crystals. ii. inhibition by natural urinary crystal growth inhibitors. invest urol. 1975;13:36-9. 14. nicar mj, hill k, pak cy. inhibition by citrate of spontaneous precipitation of calcium oxalate in vitro. j bone miner res. 1987;2:215-20. 15. hess b, zipperle l, jaeger p. citrate and calcium effects on tamm-horsfall glycoprotein as a modifier of calcium oxalate crystal aggregation. am j physiol. 1993;265:f784-91. 16. sheng x, jung t, wesson ja, ward md. adhesion at calcium oxalate crystal surfaces and the effect of urinary constituents. proc natl acad sci u s a. 2005;102:267-72. 17. domrongkitchaiporn s, stitchantrakul w, kochakarn w. causes of hypocitraturia in recurrent calcium stone formers: focusing on urinary potassium excretion. am j kidney dis. 2006;48:546-54. 18. zuckerman jm, assimos dg. hypocitraturia: pathophysiology and medical management. reviews in urology. 2009;11:134-44. 19. wang yh, grenabo l, hedelin h, pettersson s. the effects of sodium citrate and oral potassium citrate on urease-induced crystallization. br j urol. 1994;74:409-15. 20. mattle d, hess b. preventive treatment of nephrolithiasis with alkali citrate--a critical review. urol res. 2005;33:73-9. 21. hesse a, bach d, may p. der harnsäurestein. in: vahlensieck w, ed. das harnsteinleiden: ursachen · diagnose · therapie. berlin, heidelberg: springer berlin heidelberg; 1987:481-518. 22. nicar mj, peterson r, pak cy. use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. j urol. 1984;131:430-3. 23. nicar mj, hsu mc, fetner c. urinary response to oral potassium citrate therapy for urolithiasis in a private practice setting. clin ther. 1986;8:219-25. 24. lindberg j, harvey j, pak cy. effect of magnesium citrate and magnesium oxide on the crystallization of calcium salts in urine: changes produced by food-magnesium interaction. j urol. 1990;143:248-51. 25. herrmann u, schwille po, schwarzlaender h, berger i, hoffmann g. citrate and recurrent idiopathic calcium urolithiasis. a longitudinal pilot study on the metabolic effects of oral potassium sodium citrate administered as short-, mediumand long-term to male stone patients. urol res. 1992;20:347-53. 26. ito h, suzuki f, yamaguchi k, nishikawa y, kotake t. reduction of urinary oxalate by combined calcium and citrate administration without increase in urinary calcium oxalate stone formers. clin nephrol. 1992;37:14-8. 27. khanniazi mk, khanam a, naqvi sa, sheikh ma. study of potassium citrate treatment of crystalluric nephrolithiasis. biomed pharmacother. 1993;47:25-8. 28. grases f, conte a, march jg, garcia-ferragut l. evolution of lithogenic urinary parameters with a low dose potassium citrate treatment. int urol nephrol. 1998;30:1-8. 29. schwille po, herrmann u, wolf c, berger i, meister r. citrate and recurrent idiopathic calcium urolithiasis. a longitudinal pilot study on the metabolic effects of oral potassium tolerability of potassium citrate tablets-basiri et al. vol 15 no 01 january-february 2017 19 citrate administered over the short-, medium and long-term medication of male stone patients. urol res. 1992;20:145-55. 30. mechlin c, kalorin c, asplin j, white m. splenda(r) improves tolerance of oral potassium citrate supplementation for prevention of stone formation: results of a randomized double-blind trial. j endourol. 2011;25:1541-5. tolerability of potassium citrate tablets-basiri et al. endourology and stone diseases 20 215 urology journal unrc/iua epithelioid type of paratesticular leiomyosarcoma: a case report and literature review mohammadi torbati p1*, zham h2 1department of pathology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran 2department of pathology, mahdieh medical center, shaheed beheshti university of medical sciences, tehran, iran key words: leiomyosarcoma, scrotal mass, testicular tunica vol. 1, no. 3, 215-217 summer 2004 printed in iran introduction paratesticular leiomyosarcoma is a rare neoplasia, which has been reported in less than 100 cases so far. according to its prevalence, this neoplasia is originated from testicular tunica (48%), spermatic cord (48%), epididymis (2%) and dartos muscle, as well as subcutaneous tissue of scrotum (2%).(1,2,3) this lesion is seen in all age groups. however, it is mostly diagnosed in the 6th decade and more than 80% of patients are over 40 years old.(4) leiomyosarcoma is the result of neoplastic transformation of smooth muscle cells or multipotential mesenchymal cells in various sites of the body.(1,5) the behavior of these lesions depends on the site of origination, but little is known for grading of such tumors in paratesticular region.(4,6) like other mesenchymal tumors of this region, leiomyosarcoma is manifested as a painless mass without hydrocele and the disease may be symptomatic in less than one year. size of tumor is usually between 2 and 9 cm with a mean of 5 cm. almost all cases are primary lesions rather than the extension of a retroperitoneal lesion.(2) case report an 18-year-old male was referred with a painless, firm, and gradually growing right scrotal mass. the history, physical examination, and ultrasonographic findings, which indicated a solid oval mass were compatible with testicular tumor, thus, radical orchidectomy was performed. macroscopically, a firm solid homogeneous gray-white mass with a dimension of 52 × 39 mm involving a relatively large area of tunica albuginea was observed. however, no sign of testis involvement was seen. the mass had a clear demarcation without degenerative changes (fig. 1). spindle cells with delicate eosinophilic cytoplasm within crossed or vertically decorated bands were noted in microscopic study. furthermore, a considerable part of lesion with a different microscopic feature consisted of irregular tubules, cellular masses, and trabeculae made by a range of cubic to flat epithelioid cells were seen as well as different amounts of eosinophilic cytoplasm, some of which were vacuolized (fig. 2). the above-mentioned findings suggested three differential diagnoses: adenomatoid tumor, epithelioid leiomyosarcoma, and malignant mesothelioma. immunohistochemical stain was used to differentiate the lesions from each other and the results were as follows: accepted for publication in august 2003 *corresponding author: department of pathology, shaheed labbafinejad medical center, boustan 9, pasdaran, tehran, iran. postal code: 16666. tel: +98 21 2549010-16, fax: +98 21 2549039. fig. 1. gross appearance of the tumor epithelioid type of paratesticular leiomyosarcoma: a case report and literature review 1. negative reaction with calretinin marker, thrombomodulin, and cytokeratin cocktail; 2. strong positive reaction with vimentin, smooth muscle actin, muscle specific actin, and desmin (fig. 3). the findings were compatible with the diagnosis of leiomyosarcoma. following the final diagnosis, abdominal and chest ct scan were performed to rule out any other neoplastic origin. discussion the low prevalence of this disease has limited the evaluation of its clinical course and the adaptation of a therapeutic regimen with high confidence.(7) however, there are two basic points which should be concerned; firstly, considering all differential diagnoses of spindle cell paratesticular tumors and to assure leiomyosarcoma diagnosis, and secondly, grading of leiomyosarcoma. differential diagnoses are as follows.(6) 1subcutaneous scrotal leiomyoma: this tumor could have polyomorphic nucleus, but two mitoses in every hpf indicates sarcomatous change.(8) 2malignant mesothelioma: it is usually manifested with the development of progressive hydrocele, and contrary to leiomyosarcoma, it has an infiltrative margin. sarcomatoid mesothelioma has an extremely collagenized background. differentiation is made by immunohistochemical staining.(9,10) 3fibrosing inflammatory pseudomotors: they are always associated with a significant inflammation. when inflammation severity is more than usual in leiomyosarcoma or inflammatory pseudomotor positively reacts with desmin, diagnosis would be difficult. cases of fibroblastic proliferation of pseudosarcoma such as nodular fasciitis are reported in this region. these tumors have mitosis but their nuclei are pale, regular, and spindle shape.(11) 4deep invasive fibromatosis: it has an infiltrative growth and it is completely firm. this lesion consists of wavy myofibroblastic or fibroblastic bands within an extremely collagenized background. immunohistochemical staining and electronic microscopy are used for differentiation.(12) the grading of paratesticular leiomyosarcoma is based on the evaluation of the number of mitoses (the mean number of mitoses in 5 hpf in a part of tumor with the highest mitosis rate and cellularity), the percentage of necrosis and the severity of nuclear pleomorphism. these are important in predicting biologic behavior: grade 1: tumors with no necrosis, less than 6 mitoses in 10 hpf, and mild disseminated pleomorphism. grade 2: tumors with focal necrosis (<15%), more than 6 mitoses in 10 hpf, or obvious nuclear pleomorphism. grade 3: tumors with vast necrosis (>15%), regardless of the number of mitoses or the severity of pleomorphism. significant regions with epithelioid change, like what has been seen in this case, was only reported in 4% of cases.(13,14) the considerable increase in the number of mitoses in this region which is associated with serious biologic behaviour, is a remarkable point. in brief, attention to the following points is recommended: 1. since the lesions are mostly low grade and have better biologic behavior, grading of paratesticular leiomyosarcoma would be of great importance. grade 3 lesions are extremely invasive.(7,15) 2. the results of long-term follow-up of patients 216 fig. 2. epithelioid cells arranged in solid sheets fig. 3. immunoreactivity with desmin, clone: d33 epithelioid type of paratesticular leiomyosarcoma: a case report and literature review indicate that the use of radiotherapy following radical orchidectomy decreases local recurrence and distant metastasis, particularly in grade 3 lesions.(15) 3. since the tendency to hematogenic metastasis is high, the effect of retroperitoneal lymphadenectomy is unclear and generally not suggested.(16) 4. immunohistochemical staining of more than 40% of nuclei with ki-67 marker indicates poor prognosis; therefore, this staining is suggested to be added to other criteria for tumor grading. 5. it seems that chemotherapy has only a palliative role.(17) references 1. banik s, guha pk. paratesticular leiomyosarcoma: a clinicopathologic review. j urol 1995; 121: 823-6. 2. tolley da, buckley pm. leiomyosarcoma of the spermatic cord. br j urol 1981; 53: 193. 3. davides kc, king lm. primary leiomyosarcoma of the epididymis. b j urol 1985; 114: 642-4. 4. donovan mg, fitzpatrick jm. paratesticular leiomyosarcoma. br j urol 1987; 60: 590. 5. bianchi g, tallarigo c, lotto a. about two cases of leiomyosarcoma of the spermatic cord. acta urol brit 1994; 52: 483-6. 6. folpe a, weiss s. paratesticular soft tissue neoplasms. semin diagn pathol 2000; 17: 307-18. 7. soosay gn, parkinson mc, paradinas j, et al. paratesticular sarcoma revisited: a review of cases in the british testicular tumor panel and registry. br j urol 1996; 77: 143-6. 8. slone s, connor d. scrotal leiomyomas with bizarre nuclei. mod pathol 1998; 11: 282-7. 9. hurlimann j. desmin and neural marker expression in mesothelial cells and mesotheliomas. hum pathol 1994; 25: 753-7. 10. miettinen m. immunoreactivity for cytokeratin and epithelial membrane antigen in leiomyosarcoma. arch pathol lab med 1998; 112: 637-40. 11. jones a, yong rh. benign fibromatous tumors of the paratesticular region. am j surg pathol 1997; 21: 296305. 12. lai fm, allen pw. aggressive fibromatosis of the spermatic cord. am j clin pathol 1995; 104: 403-7. 13. pianan s, roncaroli f. epithelioid leiomyosarcoma of retroperitoneum with granular cell change. histopathology 1994; 25: 90-3. 14. salm r, evans dj. myxoid leiomyosarcoma. histopathology 1985; 9: 159-69. 15. wile ag. evans hl. leiomyosarcoma of soft tissue: a clinicopathologic study. cancer 1991; 48: 1022-32. 16. weitzner s. leiomyosarcoama of spermatic cord and retroperitoneal lymph node dissection. am surg 1993; 39: 352-4. 17. fisher c, goldman j, epstein j. leiomyosarcoma of the paratesticular region. am j surg pathol 2001; 25: 114349. 217 pictorial pyelointerstitial, pyelovenous, and pyelosinus backflow during retrograde pyelography wojciech szewczyk1*, andrzej prajsner,1 michal szewczyk2 keywods: backflow; percutaneous nephrolithotomy; pyelovenous; pyelosinus. a 65-year-old male was admitted to the hospital for percutaneous nephrolithotripsy because of a stone in the pelvis of the right kidney. during the retrograde pyelography a very discreet pyeloiterstitial backflow, and a massive backflow to the main renal vein was seen (figure 1). about one minute after first injection of the contrast medium, pyelovenous backflow was no more observed, while pyelosinus backflow was clearly present (figure 2). repeated injection of small amount of contrast medium resulted in almost immediate pyelovenous backflow, and persistent pyelosinus backflow (figure 3). for fear of massive absorption of irrigation fluid during percutaneous procedure, a classic open pyelolithotomy was performed. the patient was discharged from hospital on the sixth day after surgery. pyelovenous backflow is rarely discussed in the literature. static radiographs rarely catch this quick mowing event.(1,2,3) 1 department of urology in sosnowiec of medical university of silesia in katowice, poland. 2 student of the medical university of silesia in katowice, poland. *correspondence: wojciech szewczyk, department of urology in sosnowiec of medical university of silesia in katowice, poland. tel.+48 602600813. e-mail: szewczykw@wp.pl. received june 2016 & accepted november 2016 figure1. pyelointerstitial backflow during retrograde pyelography, seen as wedge-shaped striated area of blush extending from a calyx (arrowhead). pyelovenous backflow showed massive flow of contrast agent into the main renal vein (thick arrow). figure 2. pyelosinus backflow (headarrow) after retrograde pyelography. contrast entered the renal sinus and obscured the renal collecting system. figure 3. pyelovenous backflow (arrow) and pyelosinus backflow (headarrow) during retrograde pyelography, could be seen at the same time. pictorial 2932 backflow in retrograde pyelographyszewczyk et al. references 1. geara a, kamal l, el-imad b, el-sayegh s. visualization of the renal vein during pyelograhpy after nephrostomy: a case report. j med case rep. 2010; 23; 493. doi: 10.1186/1752-1947-4-93. 2. tezval h, matuschek i, jonas u. pyelovenous backflow or veno-caliceal valve fistula? scand j urol nephrol. 2007; 41(4): 346-8. 3. nemeth aj, patel sk. pyelovenous backflow seen on ct urography. ajr. 2004; 182(2): 532-3. vol 13 no 06 november-december 2016 2933 miscellaneous risk factors and types of urinary incontinence among middle-aged and older male and female primary care patients in kaunas region of lithuania: cross sectional study rosita aniulienė,1 povilas aniulis,2 vesta steibliene3* purpose: the aims of the study were to evaluate the incidences, types of urinary incontinence (ui) and its risk factors among middle-aged and older (> 40 years) men and women visiting a general practitioner (gp). materials and methods. this is a descriptive and cross-sectional comparative study using a questionnaire-based survey included 172 male and female patients who consecutively visited a primary care center in kaunas region of lithuania. results: all 86 women (100%) and 65 men (75.58%) had symptoms of ui (p < .001). about 55% of women were classified as having stress urinary incontinence (sui) and 60% of men urge urinary incontinence (uui) (p < .001). the risk factors for women with sui were: age below 60 years (odds ratio [or] = 2.89, 95% confidence interval [ci]: 1.89-4.43; p < .001), being married (or = 6.31, 95% ci: 2.35-16.97; p < .001), sedentary-standing job (or = 1.492, 95% ci: 1.01-2.20; p = 0.041), arterial hypertension (or = 2.03, 95% ci: 1.39-2.96: p < .001), diabetes mellitus (or = 3.01, 95% ci: 1.02-8.86; p = .032), menopause (or = 1.48, 95% ci: 1.20-1.83; p < .001) and features of past pregnancies. the uui was associated with age over 60 years (or in men = 2.93, 95% ci: 1.15-7.51; p = .022, in women or = 8.76, 95% ci: 2.37-32.33; p < .001. low health-related quality of life was the most prevalent among men with uui (50.8%) and among women with sui (23.3%) (p = .023). conclusion: ui was common among patients aged > 40 years visiting gp and affected more women of the same age range. sui was more prevalent among women, while more men had uui. age below 60, being married, pregnancy and delivery history, concomitant illnesses were significant risk factors for women’ sui and older age and menopause for uui. the only risk factor for men’ uui was age over 60 years. keywords: prevalence; risk factors; urinary incontinence; epidemiology; etiology; female; male. introduction urinary incontinence (ui) is an involuntary loss of urine which is objectively demonstrable and resulting in psychosocial or hygienic impairment.(1,2) ui affects 20%-30% of people worldwide; 20%–50% of women and 11-34 % of men are affected over the course of their lives.(3) it is four times more common in women under 60 years than in men of the same age range.(4) the most common form of ui in women is stress urinary incontinence (sui), an involuntary loss of urine during physical activity (49%); followed by urge urinary incontinence (uui) or overactive bladder (21%), characterized by involuntary detrusor contractions during the filling phase, which may be spontaneous or provoked (and patient cannot completely suppress); and mixed urinary incontinence (mui) (29%), the complex of 1 department of obstetrics and gynecology, lithuanian university of health sciences, lithuania. 2 department of urology, lithuanian university of health sciences, lithuania. 3 department of psychiatry, lithuanian university of health sciences, lithuania. *correspondence: department of psychiatry, lithuanian university of health sciences, mickeviciaus str., 9, kaunas, lt44307, lithuania. tel: +370 687 39116. e-mail: vsteibliene@gmail.com. received june 2015 & accepted november 2015 symptoms of sui and uui.(1,5) uui is the prominent type of incontinence in men (40%-80%), followed by mui (10%-30%) and sui (less than 10%).(1) incidence of ui increases with age and it is more prevalent in an aging population. the aging changes in the bladder and pelvic structures could contribute to ui among women.(6) prevalence of men ui even more steadily increases with increasing age: due to bladder outlet obstruction which may cause detrusor instability.(7) but the presence of ui is not restricted by an elderly age group. ui in women is often assumed to be attributable to the effects of pregnancy and childbirth, vaginal delivery and parity. the atrophic changes in the urogenital tract during menopause increases susceptibility to urinary tract infections and could cause storage symptoms of ui.(1) obesity, chronic diseases and use of miscellaneous 2552 vol 13 no 01 january-february 2016 2553 medications have also been reported to be associated with ui.(8) a very important issue is the quality of life, because moisture-associated skin damage is cumbersome for a person with ui, especially at an older age. (1) these problems tend to limit patient’s social life and mental health, resulting in loneliness, lowered self-esteem, anxiety, and depression that can impair the quality of one’s professional and sexual life.(9-11) data concerning costs and treatment as well as registry of ui subjects is absents in lithuania, therefore the aid to people with ui is inconsequent. no sufficient attention is paid to preventive measures for people at risk of ui; no screening that would enable early diagnosis of ui, and no data about incontinence-related quality of life. the general practitioner (gp) or other physicians usually do not ask and patients do not report ui because of embarrassment or feeling that this disorder is an inevitable part of aging. therefore, these patients do not receive appropriate treatment. the aims of this study were to evaluate the incidence and types of ui, their risk factors and impact on health-related quality of life (hrqol) among middle-aged and older (> 40 years) men and women visiting gp. materials and methods study subjects the study and its consent procedure were approved by kaunas regional bioethics committee (approval no.bec-mf-550), lithuania. the research was carried out at three primary health care centers in kaunas region, lithuania: in 1 rural and 2 urban areas during a one year period starting at july 2013. this study was carried out as a descriptive and cross-sectional comparative study using a questionnaire-based survey. inclusion criteria for the study were: [1] middle-aged and older (> 40 years) men and women who consecutively visited the general practitioner and [2] giving informed consent. exclusion criteria consisted of cognitive dysfunction or disability to understand the study procedures and sign the inform consent. two hundred and eighty five patients were invited to participate in the study. the flowchart of study participants is presented in figure. data of 172 surveys (60.4%) was included into final analysis. questionnaires the tool of measurement in the study was a questionnaire developed according to previously validated questionnaires.(12-14) the first part of the questionnaire includes demographic characteristics such as age, gender, educational level, marital status, weight, height, character of job and medical history (9 questions). the second part of the questionnaire for women comprises questions about pregnancy and obstetric history, including last menstruation date, number of pregnanurinary incontinence among primary care patients-aniulienė et al. cies, vaginal/caesarean deliveries, episiotomy, the birth weight of newborns, previous gynecological and abdominal surgery (8 questions). the questionnaire for men includes an assessment of the international prostate symptom score (ipss), an instrument to grade urinary symptom severity, which is based on the answers of the 7 questions. points from 0 to 5 assigned to each answer indicate increasing severity of the particular symptom. total score ranges from 0 to 35. third part included an assessment for ui using overactive bladder questionnaire (oab-q). the oab-q is a validated condition-specific instrument that contains an 8-item symptom bother scale and a 25-item hrqol scale. scores on each scale are normalized on a scale of 0–100. higher scores on the symptom bother scale reflect greater bother, and higher scores on the hrqol scale and domains reflect a greater impact of ui on hrqol. the fourth part includes the hospital anxiety and depression scale (hads). the scale consists of 14 items comprising hads-a (anxiety, 7 questions) and hads-d (depression, 7 questions) subscales. all items urinary incontinence among primary care patients-aniulienė et al. miscellaneous 2554 characteristics men (n = 86) women (n = 89) p value age, mean ± sd, years 64.8 ± 13.52 63.5 ± 11.74 .552 age group, years no. % no. % .133 < 50 18 20.9 12 14.0 50-59 13 15.1 23 26.7 60-69 17 19.8 24 27.9 70-79 26 30.2 19 22.1 ≥ 80 12 14.0 8 9.3 height, mean ± sd, m 1.8 ± 0.06 1.7 ± 0.04 < .001 weight, mean ± sd, kg 85.6 ± 14.85 78.1 ± 10.67 < .001 bmi, mean ± sd, kg/m2 26.3 ± 4.25 27.9 ± 3.93 .012 bmi groups, kg/m2 .016 < 25 32 37.2 21 24.4 25-29.9 42 48.8 38 44.2 ≥ 30 12 14.0 27 31.4 education .136 incomplete secondary school 8 9.3 6 7.0 secondary school 31 36.1 32 37.2 higher education (college) 10 11.6 22 25.6 higher education (university) 37 43.0 26 30.2 marital status .248 single/divorced/widowed 23 26.8 30 34.9 married 63 73.3 56 65.1 job < .001 sedentary 20 23.3 19 22.1 sedentary and standing 22 25.6 20 23.3 moving 17 19.8 15 17.4 hard physical 27 31.4 15 17.4 housekeeper 0 0.0 17 19.8 hrqol < .001 low 68 79.1 40 46.5 high 18 20.9 46 53.5 table 1. socio-demographic characteristics of the study population (n = 172). abbreviations: bmi, body mass index; hrqol, health related quality of life; sd, standard deviation. vol 13 no 01 january-february 2016 2555 table 2. socio-demographic and clinical characteristics of the study population with symptoms of urine incontinence (n = 151). disorders characteristics men women p value participants, no. % 65 75.58 86 100.0 < .001 age, mean ± sd, years 70.62 ± 9.46 63.52 ± 11.74 < .001 age group, years no. % no. % .03 <50 1 1.5 12 14.0 50-59 9 13.8 23 26.7 60-69 17 26.2 24 27.9 70-79 26 40.0 19 22.1 >80 12 18.5 8 9.3 bmi, mean ± sd, kg/m2 26.9 ± 4.43 27.9 ± 3.93 .152 bmi groups no. % no. % .076 < 25 19 29.2 21 24.4 25-29.9 36 55.4 38 44.2 ≥ 30 10 15.4 27 31.4 job no. % no. % .001 sedentary 12 18.5 19 22.1 sedentary and standing 15 23.1 20 23.3 moving 15 23.1 15 17.4 hard physical 23 35.4 15 17.4 housekeeper 0 0.0 17 19.8 types of ui no. % no. % < .001 stress ui 6 9.2 47 54.7 urge ui 39 60.0 26 30.2 mixed ui 20 30.8 13 15.1 signs of ui no. % no. % frequent urination during the daytime hours 62 95.4 45 52.3 < .001 incontinence while sleeping 59 90.8 43 50.0 < .001 waking up at night because had to urinate 56 86.2 43 50.0 < .001 an uncomfortable urge to urinate 64 98.5 33 38.4 < .001 sudden urge to urinate with little or no warning 60 92.3 39 45.4 < .001 accidental loss of small amounts of urine 43 66.2 41 47.7 .024 an uncontrollable urge to urinate 57 87.7 39 45.4 < .001 urine loss associated with a strong desire to urinate 49 75.4 73 84.9 .142 incontinence while coughing or sneezing 24 36.9 60 69.8 < .001 concomitant diseases hypertension 49 75.4 51 59.3 .039 diabetes 19 29.2 14 16.3 .057 depressive disorder 8 12.3 8 9.3 .552 erection dysfunction (men) 43 66.2 .542† prostate cancer (men) 18 27.7 < .001† hrqol .001 low 48 73.8 40 46.5 high 17 26.2 46 53.5 abbreviations: bmi, body mass index; ui, urinary incontinence; hrqol, health related quality of life. †the z-test for 2 population proportion was made. urinary incontinence among primary care patients-aniulienė et al. are rated on a four-point scale, scored from 0 to 3, resulting in maximum subscale scores of 21 and an overall total score ranging from 0 to 42 with higher scores miscellaneous 2556 showing a greater self-reported severity of depression/ anxiety. statistical analysis table 3. the analysis of association between socio-demographic and clinical characteristics as risk factors and types of urine incontinence in study population (men n = 86, women n = 86). characteristics stress urine incontinence urge urine incontinence mixed urinary incontinence men (n = 6) women (n = 47) men (n = 39) women (n = 26) men (n = 20) women (n = 13) or 95% ci or 95% ci or 95% ci or 95% ci or 95% ci or 95% ci p value p value p value p value p value p value age groups < 60 years ns 2.89 [1.89-4.43] ns ns ns ns < .001 > 60 years ns ns 2.93 [1.158.76 [2.37 0.53 [0.420.52 [0.42 7.51] 32.33] 0.67] 0.65] .022 .001 < .001 .001 married yes ns 6.31 [2.35-16.97] ns ns ns ns < .001 no ns ns 0.11 [0.04-0.32] ns ns < .001 sedentarystanding job type ns 1.492 [1.01-2.20] ns ns ns ns .041 hypertension ns 2.03 [1.39-2.96] ns 5.88 [1.81-19.13] ns ns < .001 0.002 diabetes ns 3.01 [1.02-8.86] ns ns ns ns .032 erection disorders† ns _____ ns _____ 5.10 [1.54_____ 16.92] .005 prostate cancer† ns _____ ns _____ 63 [13.53_____ 293.32] < .001 menopause‡ _____ 1.48 [1.20-1.83] _____ 9.09 [1.14 _____ ns 72.7] < .001 .015 vaginal childbirth method‡ _____ 18.08 [2.90-130.83] ____ ns _____ ns < .001 _two and more childbirth‡ _____ 5.76 [1.48-22.49] ____ ns _____ ns .006 _weight of fetus > 3 kg‡ _____ 0.77 [0.65-0.91] _____ ns _____ ns .001 rupture of perineum‡ _____ 3.13 [1.13-8.69] _____ ns _____ ns .026 †men; ‡ women. urinary incontinence among primary care patients-aniulienė et al. vol 13 no 01 january-february 2016 2557 the statistical analysis was performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 21. for descriptive statistics, scale variables were described using mean and standard deviation (sd). categorical variables were described by distribution, in numbers (and percent. kolmogorov-smirnov test was used to assess normality of the data and p < .05 was considered to indicate a non-gaussian distribution. values of men’ age (n = 86) showed a non-gaussian distribution (p = .012), values of women’ age (n = 86) showed normal distribution (p = .2). in the later statistical analysis non-parametric tests were used. the frequency rates and relationship between ui and its risk factors were conducted using the pearson chi-square test, the fisher’s exact chi-square test, and the continuity correction test. significantly related variables were assessed using the spearman's correlation and model of logistic regression. statistical significance was set at the 5% level (p < .05). the sample size calculation was made according the assumption about 30% estimated prevalence of ui, based on the average prevalence in the studies.(1) the absolute precision was set at 7% (above and below the 30%) with a 95% ci level. accordingly, the estimated sample size was 164 subjects. results women aged from 41 to 88 years and men aged from 42 to 88 years participated in the study. there was no significant difference between men and women regarding mean age and prevalence of ui in age groups. the sociodemographic characteristics of study subjects by gender are given in table 1. calculation of bmi revealed that 48.8% of men and 44.2% of women were overweight, 14% of men and 31% of women were obese (p = .016). the significant differences in height, weight and bmi were observed between genders: mean height and weight were significantly higher in men group (p ≤ .001), but mean bmi was higher in women group (p = .012). a comparison of the patients’ education and marital status did not reveal significant differences between genders. job type differed significantly between genders (p < .001): contrary to men who all had paid jobs, one-fifth of women (19.8%) were housewives; one-third of men (31.4%) had a physically demanding job. significantly more men (79.1%) evaluated their hrqol as low in comparison to women (46.5%, p < .001). there were no differences in had-a and had-d subscales results among genders. the data of questionnaires revealed that all women enrolled in the study (n = 86, 100%) and 65 men (75.58%) had symptoms of the ui, with significantly higher prevalence of ui among women (p < .001). table 2 summarizes the sociodemographic and clinical characteristics of 151 participants with ui by gender. men with ui were older than women (70.62 ± 9.46 vs. 63.52 ± 11.74, respectively, p < .001). more than 62% of men with ui were in age range 60-79 years, and more than 54% of women with ui in age range 50-69 years (p = .03). participants who related ui to physical activity, sneezing, or coughing were classified as having sui; those who experienced urine loss immediately following a sense of urgency were classified as having uui; those who reported urinary leakage under both situations were classified as having mui. the types of ui significantly differ by gender (p < .001): 60% of men (n = 39) were classified as having pure uui, 55% of women (n = 47) as having pure sui. only two incontinence signs, such as loss of small amounts of urine associated with a strong desire to urinate and incontinence while coughing or sneezing were more prevalent in women, but only incontinence while coughing or sneezing was determined as significant (p < .001). all other signs presented in table 2 were significantly more common among men. the prevalence of hypertension as a risk factor was more prevalent among men with ui (p = .039), but no gender differences in incidence of diabetes or depressive disorder among subjects with ui were observed. the z-test was made to compare proportions of men with erection disorders and prostate cancer. percentage of men with ui and erection dysfunction did not significantly differ from men with ui without erection dysfunction. the prostate cancer was found in a smaller table 4. the analysis of association between health related quality of life and prevalence of types of urinary incontinence. gender hrqol stress urine incontinence urge urine incontinence mixed urinary incontinence total p value men, no. (%) low 6 (9.2) 33 (50.8) 9 (13.8) 48 (73.8) .001 high 0 (0) 6 (9.2) 11 (16.9) 17 (26.2) women, no. (%) low 27 (31.4) 11 (12.8) 2 (2.3) 40 (46.5) .023 high 20 (23.3) 15 (17.4) 11 (12.8) 46 (53.5) abbreviation: hrqol, health related quality of life. urinary incontinence among primary care patients-aniulienė et al. part of men with ui (p < .001), but all 18 patients with prostate cancer had symptoms of ui (without differences among surgically treated vs. not treated). in the whole study sample, significantly more men with ui evaluated their hrqol as low, in comparison to women with ui (73.8% vs. 46.5%, p = .001). self-reported severity of depression and anxiety did not differ between men and women with ui. we sought to discover the association between the patients age and symptom severity of ui. the older male patients reported more severe urinary symptoms on the ipss scale (r = .577; p < .001). both gender patients age positively correlated with the bother severity on symptom bother scale: male (r = 0.454; p < .001); and female (r = 0.655; p < .001) patients. positive associations between older age and lower hrqol was determined only for male (r = 0.623; p < .001), but not for female patients with ui. there was no correlation between severity of ui, bmi and mental symptoms. the analysis of association between sociodemographic and clinical characteristics as risk factors for all three types of ui in both genders is shown in table 3. no relations between sui for men and any of sociodemographic/ clinical factors were found. the risk factors proved to increase the odds for women sui were: age below 60 (or = 2.89, 95% ci: 1.89-4.43; p < .001), being married (or = 6.31, 95% ci: 2.35-16.97; p < .001), sedentary-standing type of job (or = 1.492, 95% ci: 1.01-2.20; p = .041), arterial hypertension (or = 2.03, 95% ci: 1.39-2.96; p < .001), diabetes mellitus (or = 3.01, 95% ci: 1.02-8.86; p = .032). the study revealed that gynecological factors, such as menopause (or = 1.48, 95% ci: 1.20-1.83; p < .001), vaginal childbirth (or = 18.08, 95% ci: 2.90-130.83; p < .001), two or more childbirths (or = 5.76, 95% ci: 1.48-22.49; p = .006), weight of fetus over 3 kg (or = 0.77, 95% ci: 0.65-0.91; p = .001) and perineum rupture (or = 3.13, 95% ci: 1.13-8.69; p = .026) were risk factors for women sui. the uui in both genders was associated with age over 60: in men it increased the or for the uui 2.93, 95% ci: 1.15-7.51; p = .022, in women, or = 8.76, 95% ci: 2.37-32.33; p < .001. single marital state for women (or = 0.11, 95% ci: 0.04-0.32; p < .001), arterial hypertension (or = 5.88, 95% ci: 1.81-19.13; p = .002) and menopause (or = 9.09, 95% ci: 1.14-72.7; p = .015) were determined as risk factors for women uui. the age over 60 was determined as a risk factor for mui in men (or = 0.53, 95% ci: 0.42-0.67; p < .001) and in women (or = 0.52, 0.42-0.65; p = .001). prostate cancer (or = 63, 95% ci: 13.53-293.32; p < .001) and erection disorders (or = 5.10, 95% ci: 1.54-16.92; p = .005) showed significant associations with mui in the male group. bmi, depressive disorder, episiotomy for women, pelvic organs surgery and other variables were not detected as risk factors for different types of ui. as shown in table 4, hrqol significantly differed between the types of ui in men (p = .001) and women (p = .023). low hrqol was most prevalent in men with uui (50.8%) and in women with sui (23.3%). discussion worldwide literature presents that aging increases the risk of developing ui. our study revealed that all middle-aged and older women (> 40 years) and three-fourth of men of the same age consecutively visiting their gp had the symptoms of ui. we have determined that ui is more prevalent and occurs at a younger age in women: approximately one-third of women with ui were between 60 and 69 years while in men, from 70 to 79 years. gender differences in our study were also found in the distribution of ui types, more than a half of women had sui, followed by one quarter having uui; two third of men had pure uui and one-fifth mui. these results are in accordance with other researchers, who determined a dominance of uui type in men and sui type in women.(1) sui, most prevalent type of ui among women in our study mostly related with pregnancy and delivery risk factors, two and more childbirth, vaginal childbirth method, rupture of perineum; it could be the explanation to why sui occurs at a younger age. similar findings about younger women with symptoms of sui were in ueda and colleagues’ study. they revealed that women with sui were mostly in the age group of 50 to 60 or over the age of 40.(15) rortveit and colleagues showed that childbearing was associated with increased risk of both sui and mui as well.(16) sui was associated with the type of delivery. it was more frequent after vaginal delivery than after caesarean section; but the risk of sui was higher among women who had caesarean sections than among nulliparous women.(17) birth giving the first child at an age less than 20 years, vaginal delivery of a large baby with an episiotomy and more than 3 pregnancies are sui risk factors.(18) according to our data, the state of being married was associated with sui. sexual activity of marital women associated with sui, even 92% sexually active women reported sui symptoms.(19) sedentary-standing job was detected as a risk factor for women sui. according the nygaard and colleagues’ study, about 30% of women reported urinary leakage during a physical job.(20) urinary incontinence among primary care patients-aniulienė et al. miscellaneous 2558 vol 13 no 01 january-february 2016 2559 in our study 16% of women with symptoms of ui had diabetes mellitus and this concomitant illness was determined as a risk factor for women’s sui. it is known that diabetes can disrupt the mechanism of continence: women with diabetes were more likely to experience severe ui.(21) each one unit increase in glycosylated hemoglobin (hba1c) was associated with 34% increase in women sui.(22) our data revealed that hypertension was more prevalent in men than in women with ui, however hypertension was determined as the significant risk factor for sui and uui in women. in the brazil population-based study among women 50 years and over total prevalence of ui was 52.3%. hypertension was one of factors significantly associated with higher prevalence of ui.(23) the hypertension group had a significantly higher risk of ui than the group without hypertension. (24) the results of our study revealed that older age and menopause status mostly associated with second most prevalent type of ui among women, uui. menopause, as a risk factor, increased the risk of having uui symptoms more than 8 times. this corresponds to the results of a norwegian study, a higher prevalence of uui in women of age 45-55 coincides with the menopause transition.(5) it could be explained that estrogens loss contributes to the problem of ui.(1) our findings about the unmarried status as risk factor for uui in women associated with the findings, that uui was the most prevalent among single women.(19) we did not determine hysterectomy or other pelvic surgery as a risk factor for women ui, however findings of other studies are controversial. hysterectomy for benign indications, irrespective of surgical technique, increased the risk for subsequent sui surgery.(25) a meta-analysis did not find any evidence of different risk for sui or uui after hysterectomy.(26) evaluation of risk factors for most prevalent types of ui in our study shows only one significant risk factor for men uui, age above 60. however, a japanese study found that ui among men was the most prevalent at a younger age60-69 years.(15) the incidence of men with ui in our study corresponds to the data of the population-based study, where 80% of men population reported lower urinary tract symptoms (luts), but just 18% of them reported uui.(27) the prevalence of erection dysfunction in our study did not differ among men with and without symptoms of ui. prostate cancer was found just in one-third of men with ui, but the evaluation of associations between types of ui and prostate cancer/ erection dysfunction showed them as significant risk factors for mui in men. age older than 60 was found to be significant for men mui. scientific literature determines sui as a symptom associated with prostate cancer treatment.(28) the evaluation of men following radical prostatectomy (rp) and transurethral resection of the prostate (turp) showed that 77% of men with ui following rp and 64% of men following turp after 6 weeks were wet,(29) but our results did not correspond to those findings. concomitant illnesses in our study did not show associations with men ui. but study of parsons and colleagues determined the elevated fasting plasma glucose and diabetes in men as risk factors for benign prostatic hyperplasia. (30) tikkenen and colleagues’ study shows overall prevalence of ui in 22% of men with diabetes mellitus in comparison to 14% of those without the disease.(31) despite the fact that more than a half of participants in our study were overweight or obese, the bmi was not associated with risk for ui in both genders. the opposite findings were in the study of chinese women, where the bmi > 28 kg/m2 was associated with a risk for ui.(21) the eltatawy and colleagues’ study found that the bladder neck descent was more marked in obese women compared with normal weight women.(32) in our study neither socioeconomic characteristics nor the level of education has been identified as a risk factor for ui. in other studies the prevalence of ui was higher among women with lower education,(17) or with a high educational level.(33) depression/anxiety symptoms in our study were not determined as risk factors for ui. a study performed in the us reported that the ui group was almost twice as likely to feel depressed as the non ui group, and that ui had a significant negative impact on all aspects of quality of life. ui women had large role limitations caused by emotional problems, body pain, general health, and vitality domains.(11) despite the fact that men in our study presented significantly lower hrqol in comparison to women, we already could state, that ui affecting hrqol in both genders: almost half of female with ui reported their hrqol as low and ui in male patients diminished their hrqol in 79%. significantly lower hrqol was reported by men with uui and by women with sui. we also found relations between lower hrqol of men and older age, when symptoms of ui among men were more prevalent. buckley and colleagues reported that any type of ui in men was significantly associated with reduced hrqol.(29) it is important to mention that management of modifiable risk factors as hypertension and glycaemia control is important in reducing the risk for ui. however the majority of evaluated risk factors are not modifiable urinary incontinence among primary care patients-aniulienė et al. and ui requires active treatment interventions. in many cases proper treatment of ui can improve hrqol and psychological well-being.(16) the main advantage of our study is that it was conducted in urban and rural areas and both gender subjects were enrolled, therefore, it represents a more informative patients’ situation in the lithuanian primary care. using a wide range of questionnaires helped to recognize signs of ui even without patients’ complaints and to evaluate the risk factors for ui. absence of ui registry in lithuania means that health care specialists provide help for patients individually, without team approach or general strategy. despite the small sample size, our study should draw the attention to ui prevalence in general population. the evaluation of all age groups should be used in future studies, which would help to analyze the prevalence of different types of ui and their risk factors, as well as contribute to the development of ui registry and determine prevention and treatment strategies. conclusions ui was common among middle-aged women and older men visiting gp. ui affected more women of the same age range. the frequency of ui was higher than previously assessed because this condition is neither recognized nor diagnosed. sui was more prevalent among women, but uui among men. age below 60 years, being married, pregnancy and delivery history and concomitant illnesses were risk factors for women with sui; older age and menopause for women with uui. the only risk factor for men with uui was age over 60 years. this study should encourage gps to become increasingly aware on the recognition of ui among primary care patients. acknowledgements we wish to thank the lithuanian society of urogynecology for consulting, lecturer at department of languages and education of lithuanian university of health sciences violeta use for english language revision and all the patients for participation in this study. conflict of interest none declared. references 1. milsom ia, cartwright r. epidemiology of urinary incontinence (ui) and other lower urinary tract symptoms (luts), pelvic organ prolapse (pop) and anal incontinence (ai). in: abrams pc, khoury, s., wein aj, editor. incontinence. 5 ed. ed. paris: international consultation on urological diseases and european association of urology; 2013. p. 17-107. 2. haylen bt, de ridder d, freeman rm, et al. an international urogynecological association (iuga)/international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. neurourol urodyn. 2010;29:4-20. 3. buckley bs, lapitan mc. prevalence of urinary incontinence in men, women, and children--current evidence: findings of the fourth international consultation on incontinence. urology. 2010;76:265-70. 4. nitti vw. the prevalence of urinary incontinence. rev urol. 2001;3 suppl 1:s2-6 5. hannestad ys, rortveit g, sandvik h, hunskaar s. a community-based epidemiological survey of female urinary incontinence: the norwegian epincont study. epidemiology of incontinence in the county of nord-trondelag. j clin eidemiol. 2000;53:1150-7. 6. davis k, kumar d. pelvic floor dysfunction: a conceptual framework for collaborative patient-centred care. j adv nurs. 2003;43:55568. 7. shah d, badlani g. treatment of overactive bladder and incontinence in the elderly. rev urol. 2002;4 suppl 4:s38-43. 8. tozun m, ayranci u, unsal a. prevalence of urinary incontinence among women and its impact on quality of life in a semirural area of western turkey. gynecol obstet invest. 2009;67:241-9. 9. coyne ks, wein aj, tubaro a, et al. the burden of lower urinary tract symptoms: evaluating the effect of luts on healthrelated quality of life, anxiety and depression: epiluts. bju int. 2009;103 suppl 3:4-11. 10. lobchuk m, rosenberg f. a comparison of affected individual and support person responses on the impact of urinary incontinence on quality of life. urol nurs. 2014;34:291-302. 11. horng ss, huang n, wu si, fang yt, chou yj, chou p. the epidemiology of urinary incontinence and it's influence on quality of life in taiwanese middle-aged women. neurourol urodyn. 2013;32:371-6. 12. lim ym, song j, oh h. translation and validation of the korean version of mudi and musiq with urinary incontinent older men. yonsei med j. 2009;50:122-31. 13. innerkofler pc, guenther v, rehder p, et al. improvement of quality of life, anxiety and depression after surgery in patients with stress urinary incontinence: results of a longitudinal short-term follow-up. health qual life outcomes. 2008;6:72. 14. matza ls, thompson cl, krasnow j, brewster-jordan j, zyczynski t, coyne ks. urinary incontinence among primary care patients-aniulienė et al. miscellaneous 2560 vol 13 no 01 january-february 2016 2561 test-retest reliability of four questionnaires for patients with overactive bladder: the overactive bladder questionnaire (oab-q), patient perception of bladder condition (ppbc), urgency questionnaire (uq), and the primary oab symptom questionnaire (posq). neurourol urodyn. 2005;24:215-25. 15. ueda t, tamaki m, kageyama s, yoshimura n, yoshida o. urinary incontinence among community-dwelling people aged 40 years or older in japan: prevalence, risk factors, knowledge and self-perception. int j urol. 2000;7:95-103. 16. rortveit g, daltveit ak, hannestad ys, hunskaar s. urinary incontinence after vaginal delivery or cesarean section. n engl j med. 2003;348:900-7. 17. wu jm, vaughan cp, goode ps, et al. prevalence and trends of symptomatic pelvic floor disorders in u.s. women. obstet gynecol.. 2014;123:141-8. 18. seshan v, muliira jk. self-reported urinary incontinence and factors associated with symptom severity in community dwelling adult women: implications for women's health promotion. bmc women's health. 2013;13:16. 19. su cc, sun by, jiann bp. association of urinary incontinence and sexual function in women. int j urol. 2015;22:109-13. 20. nygaard i, girts t, fultz nh, kinchen k, pohl g, sternfeld b. is urinary incontinence a barrier to exercise in women? obstet gynecol. 2005;106:307-14. 21. liu b, wang l, huang ss, wu q, wu dl. prevalence and risk factors of urinary incontinence among chinese women in shanghai. int j clin exp med. 2014;7:686-96. 22. wang r, lefevre r, hacker mr, golen th. diabetes, glycemic control, and urinary incontinence in women. female pelvic med reconstr surg. 2015;21:293-7. 23. reigota rb, pedro ao, de souza santos machado v, costa-paiva l, pinto-neto am. prevalence of urinary incontinence and its association with multimorbidity in women aged 50 years or older: a population-based study. neurourol urodyn. 2016;35:62-8. 24. chang km, hsieh ch, chiang hs, lee ts. risk factors for urinary incontinence among women aged 60 or over with hypertension in taiwan. taiwan j obstet gynecol. 2014;53:183-6. 25. altman d, granath f, cnattingius s, falconer c. hysterectomy and risk of stress-urinaryincontinence surgery: nationwide cohort study. lancet. 2007;370:1494-9. 26. robert m, soraisham a, sauve r. postoperative urinary incontinence after total abdominal hysterectomy or supracervical hysterectomy: a meta-analysis. am j obstet gynaecol. 2008;198:264 e1-5. 27. kogan mi, zachoval r, ozyurt c, schafer t, christensen n. epidemiology and impact of urinary incontinence, overactive bladder, and other lower urinary tract symptoms: results of the epic survey in russia, czech republic, and turkey. curr med res opin. 2014;30:2119-30. 28. kielb sj, clemens jq. comprehensive urodynamics evaluation of 146 men with incontinence after radical prostatectomy. urology. 2005;66:392-6. 29. buckley bs, lapitan mc, glazener cm. the effect of urinary incontinence on health utility and health-related quality of life in men following prostate surgery. neurourol urodyn. 2012;31:465-9. 30. parsons jk, carter hb, partin aw, et al. metabolic factors associated with benign prostatic hyperplasia. j clin endocrinol metab. 2006;91:2562-8. 31. tikkinen ka, agarwal a, griebling tl. epidemiology of male urinary incontinence. curr opin urol. 2013;23:502-8. 32. eltatawy hh, elhawary tm, soliman mg, taha mr.the link between female obesity and urinary stress incontinence. urotoday int j. 2011;4:63. 33. legendre g, ringa v, panjo h, zins m, fritel x. incidence and remission of urinary incontinence at midlife: a cohort study. bjog. 2015;122:816-24. urinary incontinence among primary care patients-aniulienė et al. special feature 157urology journal vol 6 no 3 summer 2009 prostate cancer screening in greece current facts konstantinos stamatiou, michael lardas, evagelos kostakos, vasilios koutsonasios, dimitrios lepidas introduction: the purpose of the current article is to summarize the existing literature focusing on the current status of prostate cancer screening behaviour in greece. materials and methods: we identified studies published from 2000 onwards by searching the medline database of the national library of medicine. initial search terms were prostate-specific antigen screening, prostate cancer screening, and greece. bibliographic information of the selected publications was checked for relevant publications not included in the medline search. results: currently in greece, there is no official recommendation for prostate cancer screening, and thus, its practice depends on the social and educational status of the patient and where the patient lives in greece. conclusion: we conclude that patients should be thoroughly informed of the limitations of prostate cancer screening by prostate-specific antigen test, and in consultation with urological specialists, make their personal decision of whether to receive it. therefore, a project to support shared decisionmaking and informed choice for men considering testing for prostate cancer should be undertaken. urol j. 2009;6:157-61. www.uj.unrc.ir keywords: prostatic neoplasms, early detection of cancer, mass screening, prostate-specific antigen department of urology, tzaneio general hospital of piraeus, piraeus, greece corresponding author: michael lardas, md 19 odemisiou st, 17122, nea smirni, greece e-mail: lardamk@otenet.gr received february 2009 accepted april 2009 introduction prostate cancer is the most frequent cancer among men in the western world and the second leading cause of cancer death in this population after lung cancer.(1) unless in cases of urinary tract obstruction, metastases, and related disorders which occur in advanced disease, prostate cancer is usually asymptomatic; therefore, efforts to reduce the mortality of the disease are based on earlier diagnosis and treatment. the primarily available tests to detect prostate cancer include digital rectal examination (dre) and the serum prostatespecific antigen (psa) test. at the moment, there is no single effective screening test for early diagnosis of prostate cancer in apparently healthy men; neither the psa test nor the dre is 100% accurate. comparisons of screening tests carried out on asymptomatic patients showed that an elevated serum psa level is much more sensitive than dre.(2) in general, the higher the psa level, the more likely there is a malignant tumor in the prostate, and also, the higher the psa level in one with prostate cancer, the more likely that the cancer has spread. however, psa levels alone do not prostate cancer screening in greece—stamatiou et al 158 urology journal vol 6 no 3 summer 2009 give enough information to distinguish between benign prostatic conditions and cancer. in fact, the level of psa may also be high in men who have an infection or inflammation of the prostate or benign prostatic hyperplasia. other factors that go into interpreting psa scores include age and size of the prostate. another drawback is that psa itself cannot tell how dangerous the cancer is that some prostate cancers, particularly those of an aggressive nature, may not produce much psa. herein, we reviewed the current knowledge and experiences in prostate cancer screening and its outcomes in greece. material and methods we identified studies published from 2000 onwards by searching the medline database of the national library of medicine. initial search terms were prostate-specific antigen screening, prostate cancer screening, and greece. bibliographic information in the selected publications was checked for relevant publications not included in the medline. all retrieved publications were reviewed in an attempt to scrutinize the current status of screening programs of prostate cancer in greece. results in greece, there is currently no official recommendation on prostate cancer screening, and it is being performed unofficially in patients visiting outpatient departments of most greek hospitals, as well as in men visiting consulting rooms.(3) actually, patient’s anxiety increases the likelihood of taking the screening test, by influencing the decisions of physicians, whose clinical judgment would otherwise make them least inclined to order the test.(4) it is also notable that a general practitioner, a family doctor, or an internist requests most of the psa tests.(5) the exact magnitude of this opportunistic screening is not known; however, according to the official reports of the ministry of public health, 31% of men between 45 and 54 years of age and more than 50% of men older than 65 years undergo serum psa test yearly.(3) due to the geographical peculiarity of our country, it is hard to conclude that psa screening implementation has had any effects in prostate cancer mortality.(3) in fact, more than half of the country’s population live in 2 large urban areas (athens in the southern and thessaloniki in the northern greece), while the remaining live in small towns and in rural or isolated areas, having different levels of access to the health services, and consequently, different screening behavior. the prevalence of unofficial prostate cancer screening with psa serum examination has been estimated to be extremely high in the abovementioned urban areas. in contrast, overall prostate cancer screening is rarely practiced in rural and isolated areas.(3) indeed, most hospitals are located in the 2 larger cities, while only primary healthcare settings exist in rural and/or isolated areas. moreover, wide fluctuations exist in the distribution and the availability of healthcare services between different—even neighbouring—regions of greece, and consequently, different intensity of the psa screening is conducting in various regions.(3) in rural and isolated areas where a patient would never visit a physician, unless being symptomatic, the overall number of psa measurements is low. this results in a dramatic increase of healthcare costs and/or a possible high rate of overtreated premalignant conditions and cancers in urban areas, while in rural areas, the diagnosis of prostate cancer is often attained at a stage when cure is not possible.(6) disparities in prostate cancer screening practices have also been noticed among men with different educational levels. a recent study demonstrated that prostate cancer screening was significantly more frequent among those with higher education. on the contrary, low-literacy populations showed low prostate cancer screening rates.(4) a relation between the socioeconomic level and prostate cancer screening has also been observed, with more than 80% of men of higher socioeconomic level and less than 65% of men of median and low socioeconomic levels seeking consultation with healthcare providers.(3) the relative percentages for psa testing and dre are 60.4% and 52.4% versus 19.7% and 8.2% for these two socioeconomic groups, respectively.(3) finally, the distribution of printed educational material on prostate cancer screening did not prostate cancer screening in greece—stamatiou et al urology journal vol 6 no 3 summer 2009 159 seem to change greek men’s attitude regarding prostate cancer screening in favor of dre acceptance behavior.(4) discussion from 1994 onwards, the use of the psa testing has been approved for the detection of prostate cancer, and in consequence, it has been used widely in prostate cancer screening. justifiable concern about overdiagnosis and overtreating has risen since then.(7) on the one hand, evidence supports the usefulness of serum psa evaluation for the screening of prostate cancer; several studies showed an eventual increase in the prostate cancer detection rate and a shift towards earlier pathological stage and less invasive forms.(8) on the other hand, there is no clear proof that the decrease in deaths of prostate cancer is due to early detection and treatment based on psa level or due to other factors.(9) moreover, there is evidence that screening may cause overdiagnosis of slow-growing indolent cancer and may lead to unnecessary or inappropriate invasive treatment, which can have serious risks and side effects, including urinary incontinence, erectile dysfunction, and bowel dysfunction. for these reasons, screening tests for prostate cancer is still under study, and clinical trials evaluating the usefulness of prostate cancer screening are ongoing in many countries. full results from these studies are expected in several years. currently, there is no standard recommendation for prostate cancer screening. screening is presently discouraged by the european commission’s advisory committee on cancer prevention for its negative effects are evident and its benefits still uncertain.(10) according to the us preventive services task force, evidence is insufficient to recommend in favor of or against routine prostate cancer screening in men younger than 75 years, and screening in men aged 75 years or older is not recommended.(11) meanwhile, there are no official recommendations for prostate cancer screening provided by european association of urology, a member of which is the hellenic urologic association.(12) even the american cancer society has modified its position on men eligible for prostate cancer screening from “should undergo digital rectal examination and psa testing annually” to “recommends that both the psa testing and digital examination be offered annually.(13)” similarly, the american academy of family physicians and the us preventive services task force do not recommend routine screening in low-risk patients.(13) the abovementioned professional organizations and health agencies as well as most of medical experts agree that it is important to take into account the benefits and risks of diagnostic procedures and treatment when considering whether to undertake prostate cancer screening. on the other hand, men particularly those aged older than 50 years have several reasons—the belief in the benefit of early diagnosis, the need to have trust, and a desire for reliable screening resembling those for women—to undergo routine testing for psa.(14) information and decision aids have been proved to increase the patient’s knowledge about prostate cancer screening, to support the physician’s judgment, and to promote shared decisionmaking as well. therefore, they should include the current mainstays of prostate cancer screening strategy. after all, every man can have balanced information on the pros and cons of prostate cancer screening to help him make an informed decision, while physicians who perform screening by the psa test can maintain strong clinical acumen and judgment when deciding whom to screen.(15) under the light of the current knowledge, prostate cancer screening in low-risk populations is a very controversial issue. prostate cancer risk appears to be associated with both genetic factors (ethnicity), dietary practices (fat consumption), and environmental factors (ambient sunlight exposure), and mortality rates differ between geographical regions. in several geographical regions such as the eastern asia, where both prostate cancer incidence and mortality rates are 50 times lower than in the northern europe and northern america,(15) screening for prostate cancer is worthless since the disease does not constitute a serious public health problem. despite the fact that greece stands in a geographical region where histological and prostate cancer screening in greece—stamatiou et al 160 urology journal vol 6 no 3 summer 2009 clinical prostate cancer is not very common,(16,17) there is considerable demand for the psa test amongst men worried about the disease. it is often that many men younger than 50 years and older than 70 years who are not informed about the risks and benefits of prostate cancer screening, are seeking for serum psa examination and many of psa examinations result from the perspective of patient’s knowledge on prostate cancer. greek men’s concerns about prostate cancer are in part justifiable; however, annual prostate cancer mortality rates in greece continued to increase despite the increased intensity of the psa screening since 1996, when psa examination was introduced.(18) although the government and medical and cancer councils have never recommended prostate cancer screening in greece, the ministry of public health is developing a national screening program targeting to decrease disparities in the screening behavior among greeks. under those circumstances, patient participation in prostate cancer screening decision-making will require a multidimentional approach that seeks to adequately prepare patients to participate in decision-making. yet, against a background of decreased enthusiasm and interest for prostate cancer screening, most of the public and private insurance companies have adopted psa serum examination on the standard annual checkup, and this opportunistic screening significantly increases the healthcare costs. to our knowledge, men who undergo prostate cancer screening by psa alone are exposed to the potential harms of diagnostic follow-up, which are a possible overdetection of clinically insignificant prostate cancers and, if actively treated, further increase of the overall healthcare costs. conclusion according to the perspective of the authors, patients should be thoroughly informed of the limitations of prostate cancer screening, and in consultation with urological specialists, make the personal decision of whether to receive it. therefore, a project to support shared decisionmaking and informed choice for men considering testing for prostate cancer should be undertaken. in an environment where so little is known about how such decisions are made, the above concept would be a step forward. conflict of interest none declared. references 1. american cancer society [homepage on the internet]. cancer facts and figures 2007 [cited may 2009]. available from: http://www.cancer.org/downloads/stt/ caff2007pwsecured.pdf 2. gosselaar c, kranse r, roobol mj, roemeling s, schroder fh. the interobserver variability of digital rectal examination in a large randomized trial for the screening of prostate cancer. prostate. 2008;68:98593. 3. toundas g. health status of the greek population. athens: odisseas-nea igia; 2008. 4. stamatiou k, skolarikos a, heretis i, et al. does educational printed material manage to change compliance with prostate cancer screening? world j urol. 2008;26:365-73. 5. schwartz k, deschere b, xu j. screening for prostate cancer: who and how often? j fam pract. 2005;54:586-96. 6. toundas g. society and health. athens: odisseas-nea igia; 2004. 7. auvinen a, calais da silva f, denis lj, hugosson j, schroeder f. the european randomised study for prostate cancer (erspc). international cooperation and preliminary data. new york: parthenon; 1996. p. 167-72. 8. [no author listed]. rationale for randomised trials of prostate cancer screening. the international prostate screening trial evaluation group. eur j cancer. 1999;35:262-71. 9. de koning hj, auvinen a, berenguer sanchez a, et al. large-scale randomized prostate cancer screening trials: program performances in the european randomized screening for prostate cancer trial and the prostate, lung, colorectal and ovary cancer trial. int j cancer. 2002;97:237-44. 10. [no author listed]. recommendations on cancer screening in the european union. advisory committee on cancer prevention. eur j cancer. 2000;36:1473-8. 11. u.s. preventive services task force. screening for prostate cancer: u.s. preventive services task force recommendation statement. ann intern med. 2008;149:185-91. 12. heidenreich a, aus g, bolla m, joniau s, matveev vb, schmid hp, zattoni f; european association of urology. eau guidelines on prostate cancer. eur urol. 2008;53:68-80. 13. zoorob r, anderson r, cefalu c, sidani m. cancer screening guidelines. am fam physician. 2001;63:1101-12. prostate cancer screening in greece—stamatiou et al urology journal vol 6 no 3 summer 2009 161 14. haggerty j, tudiver f, brown jb, herbert c, ciampi a, guibert r. patients’ anxiety and expectations: how they influence family physicians’ decisions to order cancer screening tests. can fam physician. 2005;51:1658-9. 15. globocan 2000 [database online]. international agency for research on cancer, lyon, france. cancer incidence, mortality and prevalence worldwide. database version 1.0 (built november 30, 2000). available from: http://www.iarc.fr 16. deliveliotis c, alivizatos g, karayiannis a, et al. the value of prostatic specific antigen in the early diagnosis of prostatic cancer: a greek view. br j urol. 1995;75:637-41. 17. stamatiou k, alevizos a, agapitos e, sofras f. incidence of impalpable carcinoma of the prostate and of non-malignant and precarcinomatous lesions in greek male population: an autopsy study. prostate. 2006;66:1319-28. 18. bouchardy c, fioretta g, rapiti e, et al. recent trends in prostate cancer mortality show a continuous decrease in several countries. int j cancer. 2008;123:421-9. the correlation between semen parameters in processed and unprocessed semen with pregnancy rate in intrauterine insemination in the treatment of male factor infertility dadkhah f*†, nahabidian a, ahmadi gh department of urology, shaheed modarress hospital, shaheed beheshti university of medical sciences, tehran, iran and royan institute, tehran, iran abstract purpose: our aims were to determine the relation of semen parameters in processed and unprocessed semen samples with pregnancy rate in intrauterine insemination (iui) in the treatment of male factor infertility. materials and methods: in a quasi experimental study, 412 couples with male factor infertility were studied. to treat male factor infertility, 561 iui cycles were done. results: total pregnancy rate was 7.84% (44 in 561) per cycle. there was an inverse relationship between pregnancy rate and duration of infertility.total sperm count after processing was higher in pregnant cycles than in non-pregnant ones (p <0.05). the mean total motile sperms after processing for pregnant and non-pregnant cycles was 72.2 ± 78.8 and 53.2 ± 54.3, respectively (p <0.05). conclusion: iui is a valuable method for the treatment of male factor infertility. the higher number of sperms, total motile sperms and iui sessions, and lower duration of infertility, all have a positive relationship with pregnancy rate. key words: male factor infertility, intrauterine insemination, pregnancy rate 273 urology journal unrc/iua vol. 1, no. 4, 273-275 autumn 2004 printed in iran introduction about 15% of couples are infertile, of which 40% are infertile because of male factor infertility and 40% are because of female factor infertility, and in the remainder, both factors are implicated.(1) there are several methods for treatment of infertility, one of which is intrauterine insemination (iui). iui, as a cost-effective and noninvasive method, is used in treatment of infertility with various etiologies. in this method, the number of motile sperms in distal segment of fallopian tubes increases.(2) for prevention of backward movement of sperm suspension, insemination is done with 0.3 to 0.5 ml volume. when the size of dominant follicle reaches 18 to 20 mm, ovulation induction with 1000 to 5000 iu of hcg is done. thereafter, insemination is done within 38 to 40 hours.(3) of the contributory factors in a successful iui are semen parameters in semen analysis. we studied the relationship between semen parameters in semen analysis and successful iui in male factor infertility. materials and methods all of the patients who underwent iui in royan institute, in 2000, were enrolled in this quasiexperimental study. physical exam and hormonal evaluation were done in all. the husbands were normal anatomically and had normal hormonal milieu. the wives had normal pelvic ultrasonogrophy and normal hysterosalpingography. normal laparoscopy was our inclusion criteria, but it was not mandatory. for iui accomplishment, ovulation induction was done using one of the three standard methods. as the ovulation was an inclusion criterion, the method used was a confounding factor. using vaginal ultrasonogropy, follicles received april 2004 accepted august 2004 *corresponding author: department of urology, shaheed modarress hospital, sa'adatabat, tehran, iran. tel: +98 912 148 4390 †financial interest and/or other relationship with royan institute semen parameters and pregnancy rate in intrauterine insemination were studied and when they reached 20 mm in size, 5000 iu of human chorionic gonadotropin (hcg) was injected intramuscularly. afterwards, within maximum 48 hours, we performed iui and used percoll concentration gradient method for processing all the semen samples. the method of insemination and the team work were the same for all. spss 10 was used for statistical analysis and for comparison of dichotomous and continuous variables, chi-square and t tests were used, respectively. results overall, 561 iui treatment cycles were eligible for this study. the overall results with regard to positive and negative pregnancy are shown in table 1. total sperm count after processing was higher in pregnant cycles than in non-pregnant ones (p <0.05). there was no significant difference in the mean percent of motile sperms after processing between pregnant and non-pregnant cycles. however, the mean total motile sperms after processing for pregnant and non-pregnant cycles was 72.2 ± 78.8 and 53.2 ± 54.3, respectively (p <0.05). in addition, the mean percent of normal sperms before processing and the mean percent of motile sperms were not different in the two groups. ovulation induction method was not regarded as a confounding factor; however, the rate of pregnancy was calculated for each method. the pregnancy rate in induction with clomiphene citrate, clomiphene citrate and human menopausal gonadotropin (hmg), and hmg alone was 8.75%, 7.2%, and 7.2%, respectively (p = ns). overall, 561 treatment cycles were done in 412 patients (1.3 cycles per patients). in 59.2% of cases, iui was done for the first time, and the remainder (40.8%) have had undergone at least one previous iui. the mean number of iuis was not different in pregnant and non-pregnant cycles. the two groups were not different, regarding the mean age of husbands and wives and duration of infertility. discussion pregnancy rate per cycle in male factor infertility in our study was 7.84%. this is between 8 and 16% in the literature(4) and it seems that our result is acceptable. this also agrees with two other studies in our center. in a study that was done on oligoasthenospermic patients, the pregnancy rate was 6% and 8% in suspension and percoll methods of sperm processing, respectively.(5) in another study, pregnancy rate in male factor infertility was 8.2%.(6) our sample size is significant, but in comparison with other studies, the number of iui cycles per patient was low. for example, in a study by hauser, the mean treatment cycles was 2.4 per patient.(7) this explains the lower pregnancy rate in our study. the difference in pregnancy rate with iui in various studies is somewhat due to the number of iuis. one of our aims in this study was to clarify the relationship between semen parameters in semen analysis and pregnancy rate. the sperm count and the total motile sperm count after processing, both had significant relationship with pregnancy rate. brasch(8) and campana(9) showed significant relationship between total motile sperms and pregnancy rate. also, the pregnancy rate with total motile sperms greater than 20×106 was higher than those with less than 20×106 total motile sperms. we recommend the semen processing methods with higher rate of sperm preservation and higher rate of motility improvement to be used. in this study, there was not any significant relationship between pregnancy rate and percent of normal sperms. this agrees with other studies. karabinus and gelety reported that there is not any relationship between sperm morphology and the result of iui.(10) burr reported that in samples with less than 10% normal morphology the 274 table 1. demographic characteristic and semen analysis, shown as mean ± sd *s = significant, p <0.05 **ns = non-significant p > 0.05 ��������� ���� � ������ ��������� ����� ��������� ������� ����� � ����� ��������� ��� ������� �������������� ����������� ������� � � �� � ������ ��� ������� ������������� � ��������� ��� ��� � �� ���������� �������� ������ � ������ �� ���������� ��������� �� �� �� ��� �� � ���� ����� ��� �� �������� ���������� ��������� �� !��� ����� ����� ���������� �"#���� $ ��%� ������ ���� ������������ ������ ���� � � � ���� ����� ���� ����� ���������� �"#����� ������������ ������������ ������ ���� �� &����� ���� ����� ���������� �'� � ������������ ��������� � ���������� �� !��� ����� ������ ���������� �"#���� $ �� ��� ���� ����� ���������� ������� ���� �� ���� ����� ���� ������ ���������� �"#����� ���� ��������� �� ������ ��� ���������� � �� &����� ���� ������ ���������� �'� ���� �������� � ������� � ��������� � �� !��� (��� ��� �� ��������� ������ ���������� �'� ������������� � ������� � ����������� �� dadkhah et al probability of pregnancy rate is low and in these cases ivf and icsti are recommended.(11) this is 14% in toner's study.(12) also, in our study, there was not a significant relationship between husbands' age and pregnancy rate. this agrees with the results of campana's study.(9) however, in patients older than 40 years, there was not any pregnancy. pregnancy rate in patients undergoing the fourth or fifth iui session was 17.6% and this was 4.9% in the first cycle of iui. therefore the patients must not be discouraged with the first failed iui. maximum number of iui cycles in our study was 6. therefore, we can not recommend the ideal number of iui cycles. but, berg et al reported that the pregnancy rate reach a plateau after 4 cycles of iui, and thereafter, it is constant till the tenth iui, and then it decreases to zero.(13) conclusion iui is a valuable treatment modality for male factor infertility. however, it does not lead to pregnancy in patients older than 40 years; therefore, alternative methods must be considered in these patients. the probability of pregnancy increases by the following factors: higher sperm count and total motile sperms in processed sample, repetitive treatment cycles, and lower duration of infertility. hence, improvement in sperm processing methods that yields to increased sperm count and total motile sperm count, cause higher pregnancy rate with iui. references 1. shamma fn, decherney ah. infertility: a historical perspective. in: keye wr jr, chang rj, rebar rw, soules mr, editors. infertility: evaluation and treatment. 1st ed. philadelphia, pa: wb saunders; 1995. p.3-7. 2. sigman m, howards ss. male infertility. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell's urology. 7th ed. philadelphia: wb saunders; 1998. p.1291-320. 3. prietl g, van der ven h, krebs d. homologous intrauterine insemination. in: rabe t, diedrich k and runnebaum b, editors. manual on assisted reproduction. berlin: springer-verlag; 1997. p.178-203. 4. turek pj. male infertility. in: tanagho ea, mcaninch jw, editors. smith's general urology. 15th ed. new york, ny: lang medical books/mcgraw-hill; 2000. p.759-63. 5. zonouzi f. evaluation of the methods and results of intrauterine insemination in patients with oligoasthenospermia [disserastion]. tehran: iran university of medical sciences. 1372. 6. nejad-shamsi e. controlled ovarian hyperstimulation (coh)-intrauterine insemination (iui) therapy and evaluation of 972 cycles in royan institute from 1372 to 1374 [disserastion]. tehran: iran university of medical sciences. 1374. 7. hauser r, yogev l, botchan a, lessing jb, paz g, yavetz h. intrauterine insemination in male factor subfertility: significance of sperm motility and morphology assessed by strict criteria. andrologia. 2001;33:13-7. 8. brasch jg, rawlins r, tarchala s, radwanska e. the relationship between total motile sperm count and the success of intrauterine insemination. fertil steril. 1994;62:150-4. 9. campana a, sakkas d, stalberg a, et al. intrauterine insemination: evaluation of the results according to the woman's age, sperm quality, total sperm count per insemination and life table analysis. hum reprod. 1996;11:732-6. 10. karabinus ds, gelety tj. the impact of sperm morphology evaluated by strict criteria on intrauterine insemination success. fertil steril. 1997;67:536-41. 11. burr rw, siegberg r, flaherty sp, wang xj, matthews cd. the influence of sperm morphology and the number of motile sperm inseminated on the outcome of intrauterine insemination combined with mild ovarian stimulation. fertil steril. 1996;65:127-32. 12. toner jp, mossad h, grow dr, morshedi m, swanson rj, oehninger s. value of sperm morphology assessed by strict criteria for prediction of the outcome of artificial (intrauterine) insemination. andrologia. 1995;27:143-8. 13. berg u, brucker c, berg fd. effect of motile sperm count after swim-up on outcome of intrauterine insemination. fertil steril. 1997;67:747-50. 275 case report bladder malakoplakia simulating neoplasm in a young girl: report of a case and review of literature seyed mohammad-reza rabani1*, seyed hossein rabani2 associate professor of urology and renal tx; beheshti teaching hospital; yasuj university of medical sciences; yusuj, iran. tel: +989177411389. e mail: smrrabani@yahoo.com. rabani.smr@yums.ac.ir. medical researcher, shahid beheshti university of medical sciences. +989123254037. rabani.md@gmail.com. *correspondence: associate professor of urology and renal tx; beheshti teaching hospital; yasuj university of medical sciences; yusuj, iran. tel: +989177411389. e mail: smrrabani@yahoo.com. rabani.smr@yums.ac.ir. received february 2018 & accepted august 2018 malakoplakia is a granulomatous disorder caused by infectious process. it was described by von hanseman in 1901 for the first time and then by michaelis and gutman in 1902. although the most frequent site of involvement is genitourinary tract, various organs have been reported to be affected. the peak age incidence is about 50 years and it is rare in childhood. in this paper we report a case of bladder malakoplakia which to our knowledge is the youngest with isolated bladder malakoplakia that has been reported. keywords: bladder; children; malakoplakia; neoplasm; pediatrics introduction malakoplakia is a rare granulomatous disease of infectious etiology that most commonly is found in genitouri-nary tract. it is commonly observed in immunocompromised patients. depending on the organ involvement, the patients may present in a myriad of ways and causing a huge diagnostic challenge. malakoplakia is microscopically characterized by a collection of large mononuclear cells with abundant cytoplasm(1). these cells are called hanseman macrophages and are full of calcium and iron-laden lysosomal material that are known as michaelis – gutman bodies. case report the patient was a 20-month-old girl that was brought for voiding dysfunction and repeated urinary tract infections and e. coli growth in urine culture. urinalysis revealed pyuria. blood profile, renal, and liver function tests were normal. abdominal and pelvic ultrasound and c.t. scan showed a mass in anterior part of the right lateral wall of the bladder, about 4 by 4 by 2.5 cm in size with suggestion for possibility of central necrosis (figure 1). cystoscopy showed a bladder mass, but biopsy was not informative and was suggestive for chronic cystitis. exploration was done from a low-midline, retroperitoneal incision as the clinical diagnosis was a malignant neoplasm and the mass was resected with enough free margins (partial cystectomy). histopathology report (figure 2) suggested malakoplakia. the patient received trimethoprim-sulfamethoxazole for 3 months after partial cystectomy and her figure 1. c.t.scan of the pelvis. figure 2. histopathology of the bladder mass suggestive for malakoplakia. 2(a): michaelis-gutmann body. 2(b): michaelis-gutmann body. 2(c): michaelis-gutmann body. 2(d): michaelis-gutmann body. 2(e): michaelis-gutmann body urology journal/vol 16 no. 6/ november-december2019/ pp. 614-615. [doi: 10.22037/uj.v0i0.4428] vol 16 no 06 november-december2019 500 9 years postoperative period was uneventful. discussion malakoplakia is usually seen in immunocompromized patients, but it can also be seen in immunocompetent individuals. although the most common site of involvement is genitourinary tract, other common sites are gastrointestinal tract and retroperitoneum, but it can be seen everywhere in the body(2). it is more common in males except for malakoplakia of genitourinary system that is more common in females. the peak age incidence is about 50 years and it is rare in childhood. the typical lesion of malakoplakia is grossly characterized by a soft yellow-brown mass or plaque with central ulceration and peripheral hyperemia. a patient with malakoplakia may present with a range of findings, but the standard criterion for diagnosis is pathologic evaluation. the pathologic findings are caused by defects in phagocytic degradative function of histiocytes in response to gram negative coliforms (e. coli or proteus) that results in a chronic inflammatory process, followed by intracellular deposition of calcium and iron, a pattern that is known as michaelis guttmann bodies. large macrophages or von hansemann cells with a variable inflammatory cells consisting mainly of lymphocytes, plasma cells and neutrophils are microscopic findings in malakoplakia. although there is not a definite cause and effect relationship between coliforms and malakoplakia, many studies have shown an incidence of 89% to 93% coliform infections in patients with malakoplakia(3,4). kajbafzadeh and baharnoori have reported a case of renal malakoplakia simulating neoplasm in a 10-year-old boy suffering from fever and headache for 20 days accompanied with poor condition and cachexia. an open biopsy of the mass was suggestive for malakoplakia and a trial treatment with bethanechol chloride, 12.5 mg three times daily, trimethoprim-sulfamethoxazole, one adult tablet per 12 hours, and ascorbic acid, 500 mg three times daily for 21 days managed the disease without surgical intervention(5). amar shah and harish chandran reported a case of malakoplakia presenting as multiple bladder polyps in an 11-year-old boy with no response to long-term antibiotic treatment, they performed surgical excision of the polyps and resolved his problem(6). also they proposed surgical excision as an alternative form of management of this rare lesion. surgical excision as an alternative treatment also has been suggested for very large lesions witch complete eradication of them may be impossible by medical therapy alone(7). kuldeep and coworkers reported spontaneous perforation of the bladder in a 9-year-old female with coexistence of xanthogranulomatous cystitis with malakoplakia(8). raghavaiah and coworkers have reported a case of nephrogenic adenoma of urinary bladder associated with malakoplakia in a 12-year-old female child, associated with recurrent escherichia coli urinary tract infection, but to our knowledge our patient is the youngest with isolated bladder malakoplakia that has been reported.(9) references 1. damjanov i, katz sm. malakoplakia. pathol annu. 1981;16:103-26. 2. curran ft. malakoplakia of the bladder. br j urol. 1987;59:559-63. 3. stanton mj, maxted w. malacoplakia: a study of the literature and current concepts of pathogenesis, diagnosis and treatment. j urol. 1981;125:139-46. 4. deridder pa, koff sa, gikas pw, heidelberger kp. renal malacoplakia. j urol. 1977;117:428-32. 5. kajbafzadeh a, baharnoori m. renal malakoplakia simulating neoplasm in a child: successful medical management. urol j. 2004;1:218-20. 6. shah a, chandran h. malakoplakia of bladder in childhood. pediatr surg int. 2005;21:113-5. 7. ammani a, ghadouane m, janane a, moufid k, ameur a, abbar mjajou. pseudotumoral malacoplakia of the bladder. 2009;15:107-10. 8. sharma k, singh v, gupta s, sankhwar s. xanthogranulomatous cystitis with malacoplakia, leading to spontaneous intraperitoneal perforation of the urinary bladder in a 9-year-old girl. bmj case rep. 2015;2015. 9. raghavaiah nv, noe hn, parham dm, murphy wm. nephrogenic adenoma of urinary bladder associated with malakoplakia. urology. 1980;15:190-3. bladder malakoplakia-rabani et al. vol 16 no 06 november-december2019 615 urinary incontinence of women in a nationwide study in sri lanka: prevalence and risk factors female urology ramya pathiraja1, shamini prathapan2*, sampatha goonawardena2 purpose: urinary incontinence, be stress incontinence or urge incontinence or a mixed type incontinence affects women of all ages. the aim of this study was to describe the prevalence and risk factors of urinary incontinence in sri lanka. materials and methods: a community based cross-sectional study was performed in sri lanka. the age group of the women in sri lanka was categorized into 3 age groups: less than or equal to 35 years, 36 to 50 years of age and more than or equal to 51 years of age. a sample size of 675 women was obtained from each age category obtaining a total sample of 2025 from sri lanka. an interviewer-administered questionnaire consisting of two parts; socio demographic factors, medical and obstetric history, and the king’s health questionnaire (khq), was used for data collection. stepwise logistic regression analysis was performed. results: the prevalence of women with only stress incontinence was 10%, with urge incontinence was 15.6% and with stress and urge incontinence was 29.9%. stepwise logistic regression analysis showed that the age groups of 36 – 50 years (or = 2.03; 95% ci = 1.56 2.63) and 51 years and above (or = 2.61; 95% ci= 1.95 – 3.48), living in one of the districts in sri lanka (or = 4.58; 95% ci = 3.35 – 6.27) and having given birth to multiple children (or = 1.1; 95% ci = 1.02 – 1.21), diabetes mellitus (or = 1.97; 95% ci = 1.19 3.23), and respiratory diseases (or = 2.17; 95% ci = 1.48 3.19 ) showed a significant risk in the regression analysis. conclusion: the risk factor, mostly modifiable, if prevented early, could help to reduce the symptoms of urinary incontinence. keywords: prevalence; sri lanka; urinary incontinence. introduction urinary incontinence (ui) is defined as the invol-untary loss of urine, which is a social or hygienic problem and is objectively demonstrable(1). ui could be stress urinary incontinence (sui), urge urinary incontinence (uui) or mixed urinary incontinence (mui). it is difficult to make the correct distinction between these three types of ui based on just questionnaires alone and urodynamic tests are often considered gold standard(2). ui affects people of all ages. the exact prevalence of ui is uncertain but it varies from 10 to 60% in europe and limited data are available for women in asian countries (3,4,5). these variations are due to lack of standardization of definitions, age of target population, and variable study designs(6,7) . the prevalence of ui increases with age, with 20.0–30.0% prevalence in young adults, a peak around middle age (prevalence 30.0–40.0%) and a steady increase in old age (prevalence 30.0–50.0%) (8). women are much more susceptible to ui than men. reproductive and hormonal changes associated with pregnancy and menopause explains the differences prevailing between male and female(9,10,11). it is highly probable that socio-economic and cultural factors play a crucial role in ui. however the extent of the influence of these factors on women's health remains relatively unknown. in sri lanka, inadequate epidemiological data on the 1department of obstetrics and gynecology, faculty of medical sciences, university of sri jayewardenepura. 2department of community medicine, faculty of medical sciences, university of sri jayewardenepura. *correspondence: department of community medicine, faculty of medical sciences, university of sri jayewardenepura. e-mail: shamini@sjp.ac.lk. received october 2016 & accepted april 2017 prevalence of female ui led us to conduct this study. the aims of this community-based cross-sectional study were to investigate the prevalence and associated risk factors of ui in women in three districts of sri lanka and also to increase the awareness of both health care providers and the community about this health issue. in addition, one of our aims was to refer women with incommodious symptoms to specialized health care centers for further management. materials and methods this study was a community based cross-sectional study conducted in the years 2015 2016. out of the 24 districts in sri lanka, three districts; colombo, ratnapura and trincomalee, were randomly selected for this study as the women in these three districts would represent the sri lankan female population. the initial hypothesis was that through this population we could access a very large part of the female population of our country. we believe that the distinctive characteristics of these three districts allow us to a very considerable extent, to extrapolate the results of our sample to the majority of the general female population. the inclusion criteria was women in the age group of 18 and above, living in one of the above three districts for more than three years. women with any surgeries that were related to female urology 3075 the research was conducted with the permission of deputy provincial director of health services of the three districts and from the relevant moh’s of the districts. chi square test and odds ratios were used to describe the risks and associated factors. test of proportions and the prevalence were calculated for each district and for the three age groups. those risk factors with a p value less than 0.05 in bivariate analysis were selected to enter into the multivariate model and the final model was constructed by backward stepwise method with the significance level set at 5%. analysis was performed with spss version 15. ethical clearance was obtained urinary incontinence in women in sri lankapathiraja et al. figure 1. flow chart for sampling technique. vol 14 no 03 may-june 2017 3076 defining the severity of ui. ui occurrence was considered mild if it occurred once or twice a week, moderate if it was once or twice a day and severe if it was 3 or more times a day. women who had ui less than once a week or a month or who did not have any complaints were considered continent. medical conditions were considered to be present if there was a diagnosis made by a consultant physician or a consultant endocrinologist and only if the patient had a diagnosis card. an interviewer-administered questionnaire (iaq) was used as the data collection instrument. this iaq consists of two parts; socio demographic factors, medical and obstetric history, and the king’s health questionnaire (khq), which consists of ui symptoms for the prevalence study. the khq is a validated questionnaire with high reliability(12) and has been translated into two languages sinhala and tamil. to ensure that the questionnaire was easily understandable, a few months before the onset of the study, pre testing was done in a small group of women (n=50) in borelesgamuwa moh area. after reviewing these preliminary results, some questions were revised resulting in an improved, final version. the khq's good reliability was evidenced by cronbach's alpha coefficients of > 0.60, indicating reasonable consistency in all domains. informed written consent was obtained from study participants prior to conducting the study. all subjects were told that participation in the investigation was strictly voluntary and that data collected would not be used for anything except the aims of the research. the public health midwives were trained to collect data and all subjects were told that participation in the investigation was strictly voluntary. the questionnaire was administered in a setting that provided privacy during the interview and the time taken to complete the questionnaire was between 15 and 20 minutes per subject. only the investigators handled the data and the confidentiality was maintained. all women who were identified to have more than moderate ui were referred to the respective /nearest tertiary hospitals. figure 2. prevalence of ui in the three districts of sri lanka. from the ethical review committee of the faculty of medical sciences, university of sri jayewardenepura. results the total of 2354 participated in the study 896 (38.1%) from colombo, 725 (30.8%) from rathnapura and 733 (31.1%) from trincomalee. the mean age of the women was 43.8 + 14.3 years (range 18 – 90 years). most women (92.4%) were married and 66.7% reported two or more children. nearly 78% had completed secondary education, but with only 13% being employed. majority in the study were sinhala buddhist (65.6%); the remaining participants, primarily estate workers, were tamil hindus. nearly 12% had co-morbidities such as diabetes and respiratory disease. among all women, 44.4% had no symptoms of ui, whereas 10% had symptoms of only stress incontinence, 15.6% had symptoms of only urge incontinence and 29.9% had symptoms of both stress and urge incontinence. our results indicated that 1308 women (55.5 %) had suffered from symptoms of ui within the last 3 months. there was a statistically significant difference in the prevalence of ui in all three districts (p < 0.001). compared to other two districts, ratnapura district had a higher prevalence of si (14.5%) and trincomalee district had a higher prevalence of ui (36.8%). (figure 2) it was observed that the prevalence of ui increased with age, being especially apparent in the age groups of 36– 50 years and 51 years and over (p = 0.001). in comparison of the severity of incontinence, for both sui and uui, there was a statistically significant association in the trend analysis between the age groups from young to old. incontinence was mostly observed in females who were 51 years and above. table 4 shows stepwise logistic regression analysis, formed with possible risk factors. those in the age group 36 – 50 years and 51 years and above had two times the risk of ui than those in the 18 – 35 age group. compared to employed women, unemployed women had a higher risk of ui. those with respiratory problems and with diabetes were also found to have higher risk of ui. those living in the trincomalee district were found to have higher risk of ui when compared to those living in colombo district (or = 4.58; 95% ci = 3.35 – 6.27). according to the results, no significant association was revealed between the frequency of ui and the women’s marital status and educational status. discussion ui is usually a hidden problem, either because the patient considers the problem as normal or they feel embarrassed to seek health care. significant ui can be simply defined as bothersome urinary leakage and it is important to find out the mean number of woman with significant ui rather than the crude prevalence rate to optimize the health care resources(6). in the literature worldwide, there is great diversity in the prevalence of ui reported among women, which is between 16.3 and 54.8%(2,6,13). in studies carried out in sri lanka, prevalence of 9.8% was reported by some researchers(14) and much higher prevalence rate of 23.3% was reported by others(15). we used a validated questionnaire rather than the questions prepared urinary incontinence in women in sri lankapathiraja et al. female urology 3077 table 1. the socio demographic and medical characteristics of the women studied. variable n % age group (years) < 35 787 33.4 36 – 50 781 33.2 > 51 780 33.1 total 2448* education level no schooling 110 4.7 primary education 396 16.8 studied up to grade 10 990 42.1 studied up to advanced level 798 33.9 post graduate education 46 2.0 total 2340* religion buddhist 1557 65.6 others 793 34.3 total 2350* employment status housewives 2270 83.1 workers 84 13.0 total 2354 marital status married/ living together 2174 92.4 single/ unmarried/ divorced 159 6.7 total 2333* number of births no births 74 3.1 1 615 26.1 2 795 33.8 ≥ 3 774 32.9 total 2258* co morbidities diabetes mellitus 179 7.6 bronchial asthma/respiratory diseases 102 4.3 continence status continent 1046 44.4 incontinent 1308 55.6 stress incontinence only 235 10.0 urge incontinence only 368 15.6 both stress and urge incontinence 705 29.9 on the basis of the literature, used by some researches and our prevalence rate is 55.5%. this is much higher than the similar studies carried out using validated questionnaire, which was reported to be around 29% 16. the reasons for this high discrepancy may include variations in definitions of the frequency and nature of incontinence, sampling methodologies, response rates and question formats(13). there are many conflicting results in the literature, regarding the type of ui reported. we haven’t used any urodynamic investigations and diagnosis is based mainly on symptoms. some suggested mui as the commonest type(17) in agreement with the present study. in all three districts mui is the commonest (29.9%), followed by uui (15.6%) and si (10%). uui was more common in women in trincomalee district, where as si was commoner in colombo and rathnapura district. only 30 % of women in rathnapura district reported symptoms of uui, which is much lower than the other two districts. the differences in the findings in the prevalence of different types of ui in three districts could be due to the standardization problems in the definition of ui and the differences in the ethnical and socio demographic characteristics of societies which also have been reported in previous researchers(18). the severity of incontinence in cases of sui and uui was mild in both situations (65.2% and 63.6% respectivley). a similar finding was reported in south wales, where 64% of women surveyed complained of only slight incontinence(19). a limitation in the study was that we assessed, how the patients perceive their problem and the severity was not objectively measured. however, as the severity of the disease is very important in decision making pertaining to treatment, and as severity affects quality of life, perceived severity of the problem could be equalized to the true status of the problem. in accordance with some other studies 20, as the education level of women decreased, the prevalence of ui increased and this could be due to the fact that women with lower education levels accept ui symptoms as normal rather than a disease process and also perceive it as shameful and avoid presenting to health centers. in consistent with previous studies (21,22,23,24), a significant association of ui with increase age, being pregnant, childbirth and increased parity was found in our study. similar to other studies(25), perineal trauma following vaginal delivery was significantly associated with ui. there was a significantly risk of incontinence among women with co morbidities such as diabetes and respiratory problems in agreement with some studies20. this may be due to increased urine volume and detrusor over activity associated with diabetes and increased abdominal pressure when coughing associated with respiratory diseases. interestingly, treatment-seeking behavior has been reported to be very poor(15) and only about 12%. we did not include investigation on the reasons in the current study. none of the patients were examined gynaecologically and the presence of ui was determined by verbal inquiry alone and this can reduce the precision of arriving at a diagnosis of ui. the prevalence of ui found in the women we studied was relatively high, with women displaying increasing severity and prevalence with increasing age. despite the bias of this study based purely on the household female population, the sample can be considered representative of the country's female population since the urinary incontinence in women in sri lankapathiraja et al. vol 14 no 03 may-june 2017 3078 age groups in years 18-35 years (%) 36 – 50 years (%) 51 years and above (%) p value stress incontinence no incontinence 583 (41.3) 426 (30.2) 403 (28.5) mild 145 (23.7) 247 (40.4) 220 (35.9) .001 to a certain extent 35 (19.8) 59 (33.3) 83 (46.9) frequently 24 (16.3) 49 (33.3) 74 (50.3) urge incontinence no incontinence 546 (42.7) 366 (28.6) 366 (28.6) mild 186 (27.3) 277 (40.7) 218 (32.0) .001 to a certain extent 37 (14.1) 91 (34.6) 135 (51.3) frequently 18 (14.3) 47 (37.3) 61 (48.4) table 3. severity of incontinence among different age groups table 2. distribution of the different types of ui in different age groups no ui stress ui urge ui stress and urge ui age groups in years 18-35 years 481 (46.1) 65 (27.8) 102 (27.7) 139 (19.8) 36 – 50 years 296 (28.4) 70 (29.9) 130 (35.3) 285 (40.6) 51 years and above 267 (25.6) 99 (42.3) 136 (37.0) 278 (39.6) table 4. significant independent variables for ui by regression analysis variable no ui ui or 95% ci age group (years) 18-35 years 481 (61.1) 306 (38.9) 36 – 50 years 296 (37.9) 485 (62.1) 2.03 1.56 2.63 51 years and above 267 (34.2) 513 (65.8) 2.61 1.95 – 3.48 district colombo 453 (50.6) 443 (49.4) ratnapura 450 (62.1) 275 (37.9) 0.61 0.48 – 0.77 trincomalee 143 (19.5) 590 (80.5) 4.58 3.35 – 6.27 number of children (mean ± sd) 2.19 (1.11) 2.63 (1.53) 1.11 1.02 – 1.21 mode of delivery normal vaginal delivery 627 (43.8) 806 (56.2) cesarean section 233 (59.6) 158 (40.4) 0.61 0.46 – 0.79 occupation occupied 158 (51.8) 147 (48.2) presently not occupied 848 (43.4) 1108 (56.6) 1.75 1.28 – 2.39 diseases no diseases 949 (45.8) 1124 (54.2) respiratory problems 40 (39.2) 62 (60.8) 2.17 1.48 3.19 diabetes mellitus 57 (31.8) 122 (68.2) 1.97 1.19 3.23 data are comprehensive in terms of the current census. although the prevalence and severity of ui was higher in older age groups, a significant proportion of women belonging to the younger age groups experienced ui as well. as ui was significantly associated with pregnancy and parity, lack of optimum perinatal and post-natal care may have contributed to the high prevalence rates in this age group. as many of the affected women were not aware of the preventive measures and available treatment options, it is important to provide education on lower urinary tract health both to the general public and healthcare providers. in sri lankan community, women have very close relationship with members of the primary health care team specially, with the public health midwife (phm) for maternal care, childcare and family planning. therefore, it would be beneficial to train phm on raising awareness of ui among women and also they should be taught how to make basic continence assessments and informed the women that the occurrence of ui is not a normal part of aging and the availability of effective treatment options. acknowledgements this study was funded by the research grant of the university of sri jayewardenepura. references 1. abrams p, blaivas jg, stanton sl, andersen jt. standardisation of terminology of lower urinary tract function. neurourology and urodynamics. 1988 jan 1;7:403-27. 2. schulman c, claes h, matthijs j. urinary incontinence in belgium: a population-based epidemiological survey. european urology. 1996 ; 32:315-20. 3. bhatia jc, cleland j. self-reported symptoms of gynecological morbidity and their treatment in south india. studies in family planning. 1995; 1:203-16. 4. bhatia jc, cleland j, bhagavan l, rao ns. levels and determinants of gynecological morbidity in a district of south india. studies in family planning. 1997; 1:95-103. 5. thomas tm, plymat kr, blannin j, meade tw. prevalence of urinary incontinence. br med j. 1980; 8;281:1243-5. 6. el‐azab as, mohamed em, sabra hi. the prevalence and risk factors of urinary incontinence and its influence on the quality of life among egyptian women. neurourology and urodynamics. 2007; 1;26:783-8. 7. yip sk, chung th. treatment-seeking behavior in hong kong chinese women with urinary symptoms. international urogynecology journal. 2003; 14:27-30. urinary incontinence in women in sri lankapathiraja et al. female urology 3079 8. thom d. variation in estimates of urinary incontinence prevalence in the community: effects of differences in definition, population characteristics, and study type. journal of the american geriatrics society. 1998;46:473-80. 9. bø ka, borgen js. prevalence of stress and urge urinary incontinence in elite athletes and controls. medicine and science in sports and exercise. 2001; 33:1797-802. 10. fitzgerald st, palmer mh, kirkland vl, robinson l. the impact of urinary incontinence in working women: a study in a production facility. women & health. 2002; 35:1-6. 11. schmidbauer jo, temml c, schatzl g, haidinger g, madersbacher s. risk factors for urinary incontinence in both sexes. european urology. 2001; 39:565-70. 12. kelleher cj, cardozo ld, khullar v, salvatore s. a new questionnaire to assess the quality of life of urinary incontinent women. bjog: an international journal of obstetrics & gynaecology. 1997;104:1374-9. 13. hunskaar s, burgio k, diokno a, herzog ar, hjälmås k, lapitan mc. epidemiology and natural history of urinary incontinence in women. urology. 2003;62:16-23. 14. hemachandra nn, rajapaksa lc, manderson l. a “usual occurrence:” stress incontinence among reproductive aged women in sri lanka. social science & medicine. 2009;69:1395401. 15. perera j, kirthinanda ds, wijeratne s, wickramarachchi tk. descriptive cross sectional study on prevalence, perceptions, predisposing factors and health seeking behaviour of women with stress urinary incontinence. bmc women's health. 2014;14:78. 16. özerdoğan n, beji nk, yalçın ö. urinary incontinence: its prevalence, risk factors and effects on the quality of life of women living in a region of turkey. gynecologic and obstetric investigation. 2004;58:145-50. 17. diokno ac, brock bm, brown mb, herzog ar. prevalence of urinary incontinence and other urological symptoms in the noninstitutionalized elderly. the journal of urology. 1986;136:1022-5. 18. ateskan u, mas mr, doruk h, kutlu m. urinary incontinence among the elderly people of turkey: prevalance, clinical types and health-care seeking. turk geriatri dergisi. 2000;3:45-50. 19. yarnell jw, voyle gj, richards cj, stephenson tp. the prevalence and severity of urinary incontinence in women. journal of epidemiology and community health. 1981;35:71-4. 20. tozun m, ayranci u, unsal a. prevalence of urinary incontinence among women and its impact on quality of life in a semirural area of western turkey. gynecologic and obstetric investigation. 2009;67:241-9. 21. kuh d, cardozo l, hardy r. urinary incontinence in middle aged women: childhood enuresis and other lifetime risk factors in a british prospective cohort. journal of epidemiology and community health. 1999;53:453-8. 22. viktrup l. the risk of lower urinary tract symptoms five years after the first delivery. neurourology and urodynamics. 2002;21:2-9. 23. bortolotti, a., bernardini, b., colli, e., di benedetto, p., giocoli nacci, g., landoni, m., et al. . prevalence and risk factors for urinary incontinence in italy. european urology; 37: 30–35. 24. thom dh, van den eeden sk, brown js. evaluation of parturition and other reproductive variables as risk factors for urinary incontinence in later life. obstetrics & gynecology. 1997;90:983-9. 25. thom dh, van den eeden sk, brown js. evaluation of parturition and other reproductive variables as risk factors for urinary incontinence in later life. obstetrics & gynecology. 1997;90:983-9. urinary incontinence in women in sri lankapathiraja et al. vol 14 no 03 may-june 2017 3080 endourology and stone disease limitations of spinal anesthesia for patient and surgeon during percutaneous nephrolithotomy abbas basiri1, amir h kashi1,2*, mahdi zeinali1, mahmoudreza nasiri1, reza valipour1, reza sarhangnejad1 purpose: to evaluate the intraoperative pain score of patients who undergo percutaneous nephrolithotomy under spinal anesthesia and to evaluate surgeons' and patients' convenience with this type of anesthesia. materials and methods: pcnl cases who were performed by two endourology fellows under spinal anesthesia during june to july 2014 were included. spinal anesthesia was performed using injection of 0.25mg/kg bupivacaine 0.5% in the intrathecal space. all procedures were performed with the patient in the prone position. stone access was made by using fluoroscopic guidance, and the tract was dilated using a single-stage technique. visual analogue pain score was used to assess patients' pain during operation, immediately after, and 2 hours later. results: 50 patients were enrolled during the study period. visual analogue pain score of 10 and 8 were observed in 5 and three patients respectively. in two patients the operation was terminated because of patient anxiety and pain. in another patient a second access was not obtained to remove a staghorn stone because of patient's agitation. gross agitation was observed in six patients. apart from flank pain, intraoperative pain was felt in the flank, scapula, abdomen and/or chest. conclusion: spinal anesthesia does not provide enough analgesia for the patient in a limited frequency of percutaneous nephrolithotomy operations. we could not find statistically significant predictors of insufficient analgesia based on patients' demographics, stone characteristics or access location. keywords: percutaneous nephrolithotomy; spinal anesthesia; pain perception; satisfaction. introduction in the decades after introduction of percutaneous nephrolithotomy (pcnl), urologists have proposed modifications to the procedure to improve its safety and efficacy. different positions (supine, prone, flank and flank-flexed), tubeless pcnl and regional anesthesia were introduced by several researchers.(1,2) regional anesthesia has been used for pcnl by spinal and combined spinal-epidural (csea) methods.(3-8) both spinal and csea were reported to be as effective as general anesthesia by some researchers including one previous publication from our center.(2,4,9-12) after this previous publication on the efficacy and safety of spinal anesthesia for pcnl, pcnl procedures were often performed under spinal anesthesia in our center. we encountered some cases in which the patient was restless during the procedure or in extraordinary pain. this study was designed to investigate patients' pain during pcnl under spinal anesthesia, surgeons' and patients' convenience during the procedure and to explore factors that can affect the above variables. materials and methods all patients who were scheduled for pcnl operation under spinal anesthesia by two endourology fellows during june to july 2014were included in this study. pcnl is typically scheduled in our center for renal stones larger than 2 cm, stones resistant to eswl, large 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2hasheminejad kidney center, iran university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center, no. 103, 9th boustan st., pasdaran ave., tehran, 16666, iran. tel & fax: +98 21 22588016, email address: ahkashi@gmail.com. received june 2017 & accepted september 2017 upper ureteral stones and large stones in horseshoe kidneys. preoperative evaluation included serum electrolytes and hemoglobin, ultrasonography of the kidney and urinary system and either intravenous pyelography or computed tomography of the kidney and urinary system. typically patients with any contraindication to spinal anesthesia (e.g. spinal deformity), renal anomaly, history of bleeding disorders, and anticoagulant or antithrombotic medication and addiction to opium and alcohol and those patients who were anticipated to have a long operation duration underwent general anesthesia and were excluded from the study. anesthesia specialists were unaware of the study objectives. patients were explained about visual analogue pain score (vas) before the operation in the waiting room by the operating surgeon. patients who were selected for general anesthesia were excluded from the study. the protocol for spinal anesthesia has been defined previously and is summarized below. spinal anesthesia the anesthesia protocol has been previously described and is summarized below.(2) patients were placed initially in the lateral position and then 0.25 mg/kg bupivacaine 0.5% (up to 40 mg) was injected in the intrathecal space (l3–l4). the induction of spinal anesthesia was achieved when at least the t6 dermatome was anesthetized; regression to t9 was considered as failure of endourology and stone diseases 164 anesthesia. then the patients were returned to the lithotomy position after 3 minutes. drug fixation time was 13 to 15minutes (3 to 5 minutes for drug administration in the lateral position and 10 minutes for repositioning to the supine position and then lithotomy). pcnl procedure all procedures were performed with the patient in the prone position. the details of pcnl is our center has been previously published(13,14) and is summarized below. stone access was made by using fluoroscopic guidance, and the tract was dilated using a single-stage technique until 28 f to 30 f. stones were extracted by grasper after breaking them by pneumatic lithotripter. a double-j stent was not inserted in patients routinely, and nephrostomy tube insertion was optional and depended on surgeon preference. after transfer of the patients to recovery room, they were asked about their vaps during the operation and vas on entry to recovery room. the surgeon was also asked about his convenience with anesthesia during the operation period and any reason for inconvenience was recorded. vas was also asked from the patient 2 hours after operation termination. patient satisfaction with anesthesia during the operation was asked according to a likert type 5 scale questions on the 1st postoperative morning. anesthesia duration was defined as from beginning of spinal anesthesia to nephrostomy fixation. operation duration was defined from the start of percutaneous access needle insertion to nephrostomy fixation. statistical analysis statistical package for social sciences ver. 16 (chicago, il) was used for data entry and analysis. vas and patient or surgeon satisfaction were compared by nonparamentric mann-whitney or kruskal-wallis tests. the association of vas and satisfaction scores with operation duration was analyzed by spearman r. the ethics of this study have been approved by the ethics committee of the urology and nephrology research center and are in accordance with the 1964 declaration of helsinki and its later amendments. patients were explained about the study objectives and informed consent was obtained. results 50 patients were enrolled during the study period. table 1 summarizes patients' demographic data and operation characteristics. there was one patient with malrotated kidney in the studied patients. figure 1 shows surgeons' and patients' satisfaction scores and intraoperative, immediately postoperative and 2 hours after operation vas scores. five patients experienced intraoperative vas of ten and in three of these five patients the following complications were observed. one patient experienced severe pain and agitation which caused leaving a residual fragment and no further try to remove it. another patient experienced gross nausea and vomiting. in the third patient, the operation was terminated upon request of the anesthesia specialist. in all these three cases pain was associated with patient agitation. three patients experienced intraoperative vas of 8 and in two patients pain was associated with patient's agitation. intraoperative vas scores of 5 to 6.5 were observed in seven patients and in one patient it was associated with patient's agitation. intraoperative vas scores of 1 to 4.5 were observed in eight patients and in one patient because of patient anxiety and agitation, the anesthesia specialist did not agree on obtaining a second access for complete removal of a staghorn stone. excessive talking was observed in one patient during the operation. intraoperative nausea and vomiting was observed in two patients (one patient with intraoperative vas of ten described before and another patient with intraoperative vas of zero). intraoperative and postoperative headache were observed in one and one patient respectively. intraoperative pain was felt in areas other than the flank and consisted of scapula, abdomen and chest. moderate inconvenience of the surgeon was observed in six cases because of patients' pain, agitation and/or obligatory termination of the operation. severe inconvenience of the surgeon was observed in three patients because of patients' pain and/or agitation during the operation. intraoperative and immediately postoperative vas scores were associated with duration of anesthesia (rsp= 0.300, p = .034 and rsp= 0.285, p = .045 respectively). two-hour postoperative vaps score was not associated with duration of anesthesia (rsp = 0.222, p = .12).operation duration was not associated with vas scores. surgeons' satisfaction scores were negatively table 1. patients' and operations' characteristics variable age (years), mean ± sd 48.1 ± 12.2 gender (male), n(%) 29(58) access, n upper, middle, and lower pole 11, 4, 35 anesthesia duration (minutes) , mean ± sd 83.4 ± 21.5 operation duration (minutes), mean ± sd 52.7 ± 23.0 preoperative hemoglobin (mg/dl), mean ± sd 13.9 ± 1.5 postoperative hemoglobin (mg/dl), mean ± sd 12.3 ± 1.4 figure 1. boxplots for likert satisfaction scores for surgeons and patients plus visual analogue pain scores during operation, immediately after operation and 2 hours after operation. limitations of spinal anesthesia for pcnl-basiri et al. vol 15 no 04 july-august 2018 165 associated with patient's intraoperative vas score (rsp = -0.73, p <.001). patients' satisfaction scores were negatively correlated with intraoperative vas (rsp = -0.597, p < .001), immediately postoperative vas (rsp = -0.538, p < .001), and 2 hour postoperative vas (rsp = -0.474, p = .001). vas scores and patient or surgeon satisfaction scores were not associated with access location (lower calyx, middle calyx or upper calyx; all p > .05). discussion pcnl was originally performed under general anesthesia. in general anesthesia there is risk of tube displacement during change of position from supine to prone. (8) general anesthesia is also less cost effective and is carried with a higher risk of pulmonary complications. (8) therefore, some researchers were motivated to evaluate the role of regional anesthesia in pcnl due to the regional nature of the procedure. use of spinal and csea were reported in some previous publications with satisfactory results. the use of analgesic medications and patient satisfaction were reported higher in csea relative to general anesthesia in the studies by kuzgunbay et al.,(5) saeid et al.(7) and karacalar et al.(4) spinal anesthesia has also been reported to be associated with less postoperative pain and favorable operative factors by mehrabi et al.(11,15) and nouralizadeh et al.(2) yet only one study has evaluated convenience of the surgeon with the anesthesia(4) and up to our knowledge no study has evaluated the intraoperative pain score of the patients in spinal anesthesia or csea. most studies focused on postoperative pain of the patients. intraoperative convenience of the patient is of outmost importance because it provides a safe and stable condition in awake patient for successful operation. furthermore, in some previous studies large exclusion criteria were applied. for example in a previous report from our center,(2) patients with history of pcnl or open stone surgery were excluded from the study compromising the generalization of the results of the study to the population of pcnl patients. the results of this study reveal that spinal anesthesia has been associated with intolerable pain or discomfort in some patients (5 patients, 10%). this has caused premature termination of the operation upon request of anesthesia specialist (1patients) or gross inconvenience of the operating surgeon due to movement and/or anxiety of the patient (4 patients). in our opinion this is of outmost concern because the primary objective of anesthesia is to provide enough intraoperative analgesia during the operation and continuation of anesthesia into the postoperative period (that has been the concern of most previous studies) is a second less important purpose. as general anesthesia usually provides pain free operation, it was expected that regional anesthesia provides little and tolerable pain during the operation relative to general anesthesia. however, unfortunately the pain scores were severe(8-10) in 5 patients (10%) and moderate in another 10 patients. in this study, the duration of anesthesia was associated with increasing intraoperative vas in patients. this observation has previously been reported by karacalar et al. they reported insufficiency of spinal anesthesia for pcnl operations longer than 160 minutes.(4) conclusions spinal anesthesia does not provide enough analgesia for the patient in a limited frequency of percutaneous nephrolithotomy operations. increasing anesthesia duration is associated with increasing pain during operation. we could not find other statistically significant predictors of insufficient analgesia based on patients' demographics, stone characteristics or access location. conflict of interest the authors report no conflict of interest. references 1. basiri a, mohammadi sichani m, hosseini sr, et al. x-ray-free percutaneous nephrolithotomy in supine position with ultrasound guidance. world j urol. 2010;28:239-44. 2. nouralizadeh a, ziaee sa, hosseini sharifi sh, et al. comparison of percutaneous nephrolithotomy under spinal versus general anesthesia: a randomized clinical trial. j endourol. 2013;27:974-8. 3. cicek t, gonulalan u, dogan r, et al. spinal anesthesia is an efficient and safe anesthetic method for percutaneous nephrolithotomy. urology. 2014;83:50-5. 4. karacalar s, bilen cy, sarihasan b, sarikaya s. spinal-epidural anesthesia versus general anesthesia in the management of percutaneous nephrolithotripsy. j endourol. 2009;23:15917. 5. kuzgunbay b, turunc t, akin s, ergenoglu p, aribogan a, ozkardes h. percutaneous nephrolithotomy under general versus combined spinal-epidural anesthesia. j endourol. 2009;23:1835-8. 6. movasseghi g, hassani v, mohaghegh mr, et al. comparison between spinal and general anesthesia in percutaneous nephrolithotomy. anesth pain med. 2014;4:e13871. 7. saied mm, sonbul zm, el-kenawy m, atallah mm. spinal and interpleural bupivacaine for percutaneous nephrolithotomy. middle east j anesthesiol. 1991;11:259-64. 8. singh v, sinha rj, sankhwar sn, malik a. a prospective randomized study comparing percutaneous nephrolithotomy under combined spinal-epidural anesthesia with percutaneous nephrolithotomy under general anesthesia. urol int. 2011;87:293-8. 9. andreoni c, olweny eo, portis aj, sundaram cp, monk t, clayman rv. effect of singledose subarachnoid spinal anesthesia on pain and recovery after unilateral percutaneous nephrolithotomy. j endourol. 2002;16:721-5. 10. gonen m, basaran b. tubeless percutaneous nephrolithotomy: spinal versus general anesthesia. urol j. 2014;11:1211-5. 11. mehrabi s, mousavi zadeh a, akbartabar toori m, mehrabi f. general versus spinal anesthesia in percutaneous nephrolithotomy. limitations of spinal anesthesia for pcnl-basiri et al. endourology and stone diseases 166 urol j. 2013;10:756-61. 12. singh i, kumar a, kumar p. "ambulatory pcnl" (tubeless pcnl under regional anesthesia) -a preliminary report of 10 cases. int urol nephrol. 2005;37:35-7. 13. radfar mh, basiri a, nouralizadeh a, et al. comparing the efficacy and safety of ultrasonic versus pneumatic lithotripsy in percutaneous nephrolithotomy: a randomized clinical trial. eur urol focus. 2017;3:82-8. 14. sichani mm, kashi ah, al-mousawi s, tabibi a. an assessment of serum sodium within 48 h after percutaneous nephrolithotomy with half-strength saline solution. urol res. 2010;38:413-6. 15. mehrabi s, karimzadeh shirazi k. results and complications of spinal anesthesia in percutaneous nephrolithotomy. urol j. 2010;7:22-5. limitations of spinal anesthesia for pcnl-basiri et al. vol 15 no 04 july-august 2018 167 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran introduction aberrant vessels are considered as the extrinsic cause of upj obstruction particularly in adults and it has an incidence of 15-52%. however, the exact role of aberrant vessels in ureteropelvic junction obstruction (upjo) is still controversial. to date the generally accepted idea is that cutting, relocating the crossing vessels is not sufficient, and pyeloplasty is needed, as the obstruction is a primary intrinsic type due to a original article laparoscopic ureteropelvic junction decompression for the management of obstruction simforoosh n*, tabibi a, nooralizadeh a, shayani nasab h urology and nephrology research center, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: we reported the outcome and complications of laparoscopic aberrant vessels transposition without performing pyeloplasty in patients with ureteropelvic stenosis. materials and methods: a total of 10 patients with ureteropelvic stenosis accompanying with aberrant vessels underwent laparoscopic transposition of vessels between june 2001 and march 2003. 4 of the cases were male and 6 were female, and 4 out of 10 had right side and 6 had left side involvement. the mean age was 31.9 (14 59). reaction of aberrant vessels was performed by cutting the vain and fixing the artery to the lipid layer around the kidney and renal pelvis. results: the procedure was successful in all the cases without any perioperative complications. the operative time was 2.20 hours (1.45 2.50) including cystoscopy, dj placement, and transposition. mean hospital stay was 2.9 (2-5) days, and patients were followed up an average of 9.1 (3-22) months. except one case of rehospitalization due to pain, no complication occurred. the rate of clinical and radiological improvement was 100% and ivp showed a decrease in the degree of hydronephrosis as well as the resolution of obstruction observed in renogram. conclusion: with regard to our findings, it seems, at least in a proportion of patients with upj stenosis accompanied with crossing vessels, that mechanical compression is the mere cause of obstruction and primary stenosis does not coexist. as a result, treatment is achieved by transposition of the crossing vessels without entering the renal unit. key words: transposition, aberrant vessel, upj obstruction, laparoscopy, pyeloplasty accepted for publication laparoscopic ureteropelvic junction decompression for the management of obstruction dysfunctional propagation of peristaltic waves. (1) von rokitansky was the first one who lighted on the association of hydronephrosis with aberrant vessels in 1842.(2) open surgical transposition of the vessels responsible for upjo was performed and reported by h. nixon(3), c. mccreadie(4), and t.l. chapman.(5) however, according to some references, the role of crossing vessels in obstruction is trivial.(6, 7) we describe our experience in laparoscopic surgery of 10 cases with upjo and lower pole aberrant vessel. materials and methods a total of 10 patients (4 males and 6 females, mean age 31.9, 14-59) underwent transperitoneal laparoscopic transposition of aberrant vessels. 4 had right sided and 6 had left sided involvement. one case was detected accidentally and others admitted with pain. three trocars were inserted intraoperatively. parietal peritoneum was dissected on linea alba, umbilical area (10 mm), midline, 5 cm above umbilicus (5 mm), and midclavicular line next to the umbilicus (10 mm). the colon was pushed aside and upper ureter and renal pelvis was set loose. the vain was cut and the artery was relocated and fixed to the pelvis. afterwards, if normal peristalsis and complete emptying of renal pelvis was seen, the artery would be fixed to the lipid layer around renal pelvis by means of a vicryl suture. classic pyeloplasty was done in case of incomplete drainage of the pelvis. no drain was placed and patients were followed up by renogram and ivp after 3 months, and clinical examination, urine analysis, urine culture, cbc, and cr. results the procedure was successfully done without any perioperative or postoperative complication. the vain was cut and the artery was fixed to the renal pelvis and the lipid layer around the kidney in all patients. open conversion did not occurred at all. the operation time was 2.20 hours (1.452.50) including cystoscopy, dj placement, and transposition and mean hospital stay was 2.9 (25) days. 3 patients received intra venous pethedine hcl (25 mg) but other patients did not require analgesics during hospital stay. perioperative or postoperative transfusion was not required in any case. patients were followed up for an average 9.1 (3-22) months. one case of pain and uti was observed during the follow-up in whom conservative therapy was efficient. radiological evaluation of all patients showed a reduction in hydronephrosis degree and patients recovered from pain and other clinical problems existing before operation. it can be inferred that radiological and clinical improvement was 100%. blood pressure and urine culture were normal in all cases. 7 patients underwent cystoscopy preceding the operation and dj catheter was placed in the ureter. in 3 cases dj catheter was not used. discussion lower renal pole aberrant vessels accompanying upjo are frequent and it is believed that the establishment of upj obstruction is due to abnormal propagation of peristaltic waves in this point and the extrinsic compression of crossing vessel does not play a primary role. consequently, cutting or transposition of vessels is not sufficient and pyeloplasty is necessary (1). however, there are a few reports of improvement without complementary pyeloplasty. (3-5) open surgery is the approach used in previous studies, but since laparoscopy is applicable and less invasive, we can use it to relocate these vessels without pyeloplasty. smith and coworkers used chapman's technique in open surgeries of 19 patients. they dispensed with pyeloplasty and performed transposition in cases in which normal peristalsis and emptying of renal pelvis were observed. they were successful in 80% of patients. durand(14) cut the vessels in 97 patients underwent open surgery and pyeloplasty was required in only 10%. kelly cut the vessels using laparoscope in 2 cases, both with clinical improvement.(15) johnston showed resolution of obstruction in 32 out of 36 transpositions by pelvic pressure studies.(13) cutting renal arteries results in ischemia and hypertension as they are end arteries, so it is not recommended. whereas, cutting aberrant veins, particularly right renal vein which is shorter is possible and brings out no complication. thus, we decided to cut the vein and relocate the artery and fix it to the lipid layer of pelvis and kidney. 2 laparoscopic ureteropelvic junction decompression for the management of obstruction patients were selected to undergo pyeloplasty or transposition intraoperatively, according to observation of emptying and decompression of renal pelvis, and normal peristalsis. in this approach we do not enter the renal system avoiding the risk of leakage, fistula, secondary stenosis, and uti seen in the classic pyeloplasty. also transposition of vessels is more feasible and faster than performing pyeloplasty and patients do not require dj catheter and drain as we did not insert dj catheter in the last 3 cases. patients can be discharged home on the first postoperative day (last 3 cases). symptoms were relieved or improved after the operation. ivp after the 3rd postoperative month demonstrated reduction in the degree of hydronephrosis, dilated urinary system, or patent upj in all of the cases, indicating a 100% success. these results are comparable to open and laparoscopic pyeloplasty outcomes.(9-12) it is note worthy to mention that preoperatively detection of the cases is not possible and we did not evaluate the existence of aberrant vessels in any patients either. it seems that in some patients with upjo and aberrant vessel, extrinsic compression and angulation of the ureter plays a primary role in the obstruction in the absence of any primary disorder. accordingly, treatment can be obtained merely by transposition of the vessels. further studies with larger sample size and longer followup are warranted in order to confirm our findings. conclusion based on the mentioned findings, it seems at least in a proportion of patients with upj stenosis accompanied with crossing vessels, that mechanical compression is the mere cause of obstruction and primary stenosis does not coexist. thus, the treatment is achieved by transposition of the crossing vessels without entering the renal unit. references 1. jenny sb, franke jj, smith ja. management of upper urinary tract obstruction. in: walsh, pc, retik ab, vaughan jr. ed, editors. campbell's urology. 8th ed. philadelphia: w. b. saunders; 2002. p. 464. 2. brosig w, kollwitz aa. transposition of lower polar vessels: an operative approach to hydronephrosis. j urol 1961; 85: 453-458. 3. nixon hh. hydronephrosis in children: a clinical study of seventy-eight cases with special reference to the role of aberrant renal vessels and the results of conservative operations. br j surg 1953; 40: 601-609. 4. mcreadie c. results of treating hydronephrosis by the chapman technique. proc r soc med 1968; 61:1142-1143. 5. addonizio cj, patel rc. innocent aberrant renal vessels producing ureteropelvic junction obstruction. urology 1980; 26: 176-180. 6. smith js, mcgeorge a, abel bj, et al. the results of lower polar renal vessel transposition (the chapman procedure) in the management of hydronephrosis. br j urol 1982; 54 (2): 95-7. 7. o'reilly ph, brooman pj, et al. the long term results of anderson hynes pyeloplasty. br j urol 2001; 57 (4): 287-9. 8. lowe fc, marshall ff. ureteropelvic junction obstruction in adults. urology 1984; 23 (4): 331-5. 9. jarrett tw, chan dy, charambura tc, et al. laparoscopic pyeloplasty: the first 100 cases. j urol 2002; 167 (3): 1253-6. 10. eden cg, cahill d, allen jd. laparoscopic dismembered pyeloplasty: 50 consecutive cases. br j urol 2002; 88(6): 526-31. 11. johnston jh. the pathogenesis of hydronephrosis in children. br j urol 1969; 41(6): 724-34. 12. durand l, mollard p, chamonton f, massoumi r. les hydronephroses dites par vaisseou anormal. resultats de 98 section vasculaires. j urol nephrol 1962; 68: 300-303. 13. keeley fxjr., bagley dh, et al. laparoscopic division of crossing vessels at the ureteropelvic junction. j endourol 1996; 10(2): 163-8. 3 endourology and stone disease epidemiologic and clinical characteristics of patients presenting with renal colic in korea dae young hong, jong won kim, kyeong ryong lee, sang o park, kwang je baek* purpose: to investigate the epidemiologic and clinical characteristics of renal colic in korea. materials and methods: forty-six participating emergency departments provide their essential information to the national emergency medical center. we extracted the national emergency department information system data from january to december 2010. we analyzed data on demographics, visit time, chief complaints, mode of arrival, outcome, and length of stay. a total of 23,653 patients with renal colic visited the 46 emergency departments, and this patient population comprised 1.8% of all emergency department visits. results: the median patient age was 45 years, and the male-to-female ratio was 2:1. the peak time of incidence for patients with renal colic occurred between 06:00 and 10:00 h. the peak incidence occurred in august, whereas the lowest incidence occurred in winter. the most common chief complaint was flank pain, followed by abdominal pain and hematuria. the median length of stay in the emergency department was 171 min, and female patients stayed longer in the emergency department relative to male patients. the median length of stay was shorter for weekend visits than for weekday visits. most patients were discharged from the emergency department; only 6% of patients were admitted. monday was the day with the highest admission rate. the length of stay did not correlate with age, whereas the admission rate increased with age. conclusion: the epidemiologic and clinical features derived from this study may facilitate further investigations aimed at understanding the etiology of renal colic. keywords: colic; epidemiology; emergency service; incidence; kidney calculi; prevalence; korea. introduction acute renal colic is the most frequent clinical pres-entation of urolithiasis and a common cause of patient visits to emergency departments (eds) worldwide. the lifetime risk of urolithiasis is estimated to range from 5–12% in europe and in the united states, affecting 13% of males and 7% of females in the population.(1,2) furthermore, the lifetime recurrence rate has been estimated to be as high as 50% within 10 years of the initial urolithiasis episode.(3) several prior studies have shown a worldwide trend toward an increasing prevalence and incidence of urolithiasis; this trend has also been observed in korea.(4-6) given the high prevalence of urolithiasis, the total annual health care expenditure for urolithiasis in the united states was estimated to be 5 billion us dollars in 2009.(7) acute renal colic may be characterized by a sudden severe flank or lower back pain that may radiate down to the genitalia. additional symptoms may include nausea, vomiting, and macroscopic or microscopic hematuria. the diagnosis of urolithiasis is generally based on the history, clinical symptoms, and physical examination. the need to evaluate the presence of a stone with radiologic imaging studies is controversial. either intravenous urography or intravenous pyelogram has traditionally been the preferred imaging study. recently, there has been pressure in the international literature to obtain a non-contrast helical computed tomography (ct) scan of all patients.(8) most patients with acute renal colic can be managed conservatively with pain medication, hydration, and expected stone passage.(9) although the ed plays an important role in the diagnosis and management because patients present to the ed with renal colic, the epidemiologic and clinical data from eds have been less well studied in korea. the objectives of this study were to investigate the demographic, epidemiologic, and clinical characteristics of renal colic in eds in korea. we also analyzed several factors associated with hospital admission. materials and methods study population and variables we conducted a retrospective observational study of patients with renal colic attack using the national emergency department information system (nedis) of korea, a nationwide electronic emergency medical care database. this system has operated since 2003, and information for the database is drawn annually from participating eds. information regarding all patients is automatically transferred from each hospidepartment of emergency medicine, konkuk university school of medicine, seoul, korea. *correspondence: department of emergency medicine, konkuk university medical center, 1-120 neungdong-ro (hwayang-dong), gwangjin-gu, seoul 729-143, korea. tel: +82 2 2030 5790. fax: +82 2 2030 5789. e-mail: kuhembkj@gmail.com received january 2015 & accepted april 2015 endourology and stone disease 2148 descriptors no. of patients proportion (%) all 23,653 100 age group (years) 18-44 11,750 49.7 45-64 9,871 41.7 ≥ 65 2,032 8.6 time of day (h) 00:00~06:00 5,844 24.7 06:00~12:00 7,974 33.7 12:00~18:00 4,525 19.1 18:00~24:00 5,310 22.4 season of year spring 5,637 23.8 summer 6,766 28.6 autumn 5,966 25.2 winter 5,284 22.3 chief complaint flank pain 14455 61.1 abdominal pain 5426 22.9 hematuria 374 1.6 back pain 264 1.1 other 3134 13.2 modes of arrival private ground transport 11,306 47.8 walk-in 8,456 35.8 ems ambulance 3,094 13.1 other 797 3.4 table 1. demographic and clinical characteristics of patients with renal colic. abbreviation: ems, emergency medical service. variables length of stay (min) p value gender < .001 male 166 (119-244) female 179 (130-265) age group (years) .808 18-44 171 (122-242) 45-64 168 (121-250) ≥ 65 174 (123-259) time of day (h) < .001 00:00~06:00 173 (120-271) 06:00~12:00 177 (129-258) 12:00~18:00 175 (123-246) 18:00~24:00 158 (114-226) day of week <.001 sunday 166 (121-235) monday 178 (125-267) tuesday 173 (122-252) wednesday 175 (124-259) thursday 169 (119-251) friday 174 (123-262) saturday 165 (120-240) table 2. length of stay in emergency departments of patients with renal colic. tal to a central server within 14 days of the patient’s discharge from an ed or hospital ward. we evaluated all patients whose data were available in the nedis and who visited participating eds from january 2010 to december 2010 (12-month period). a total of 46 eds were included in this study. renal colic attacks in patients visiting the ed were defined according to assignment of the following codes from the korea standard classification of disease, 6th revision (kcd-6 codes): n132, n200-n203, and n210-n211. because the incidence of renal colic attack was low among individuals younger than 18 years, we confined the data analysis to patients aged 18 years or older. we did not have data on the exact time of onset of the renal colic, but because in the participating regions it is considered good practice to present to the ed as soon as possible after flank or abdominal pain, we presumed that the patients visited the ed on the day of the renal colic attack. the analysis included the following variables: age, gender, chief complaints, mode of arrival, arrival and departure times, ed diagnosis, and outcome of ed management. all patients were divided into 3 groups according to their age: 18–44, 45–64, and ≥ 65 years old. additionally, patients were assigned to four 6-h time groups according to the ed visit time (00:00– 06:00 h, 06:00–12:00 h, 12:00–18:00 h, and 18:00– 24:00 h). the 12-month analysis period was divided into 4 seasons; spring (march to may), summer (june to august), autumn (september to november), and winter (december to february). length of stay (los) was defined as the interval in minutes between the arrival time at the ed and the departure time from the ed. we also compared the number and rate of admissions according to each gender, age group, day of the week, and season. statistical analysis all data were processed using microsoft office excel 2007 (microsoft corp., redmond, wa, usa), and all statistical analyses were performed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 17.0. continuous variables were expressed as medians (25–75% interquartile ranges [iqrs]), and the kruskal–wallis test was employed to compare nonparametric data. categorical variables were expressed as frequencies and percentages, and the chi-square test was used for comparisons. chisquare goodness-of-fit tests were performed to test the uniformity of patient distribution among the times of day and seasons. we performed a multivariate logistic regression analysis to find predictors associated with admission. all statistical tests were 2-sided, and a p epidemiologic and clinical characteristics of renal colic in korea-hong et al. vol 12 no 03 may-june 2015 2149 value of < .05 was considered statistically significant. ethics statement the study protocol was reviewed and approved by the konkuk university medical center institutional review board (irb no. kuh1260016). the requirement for informed consent from the participants was waived by the board. results during the study period, a total of 1,305,049 patients visited the 46 participating eds. of these patients, 23,653 (1.8%) patients with renal colic were included. the demographic and clinical features of the renal colic patients are summarized in table 1. renal colic episodes were significantly more common in men (66.6%) than in women (33.4%). the median patient age was 45 (35–54) years. the women were slightly but significantly older than the men (49 [37–58] vs. 43 [34–52] years, p < .001). the incidence of renal colic began to increase after the age of 20, peaked between the ages of 40 and the early 50s, and then began to decline (figure 1). there were 11,750 (49.7%), 9,871 (41.7%), and 2,032 (8.6%) presentations of renal colic attacks in the 18–44, 45–64, and ≥ 65-year age groups, respectively. the circadian pattern of renal colic attack is shown in figure 2. a highly significant circadian pattern was observed in the overall population, with a morning peak (06:00–10:00 h) and afternoon dip (15:00–19:00 h). the onset of renal colic occurred between 06:00 and 12:00 h in 7,974 patients (33.7%), between 00:00 and 06:00 h in 5,844 patients (24.7%), between 18:00 and 24:00 h in 5,310 patients (22.4%), and between 12:00 and 18:00 h in 4,525 patients (19.1%). the incidence of renal colic was significantly higher between 06:00 and 12:00 h than during the other three 6-hour periods (p < .001). the peak incidence of renal colic occurred in the months of july, august, and september (6,916/23, 653, 29.2%); august had the highest incidence of renal colic (10.6% of all renal colic episodes). the number of ed visits according to a monthly analysis showed a significant increase during the hottest months of the year. the incidences of renal colic for each gender group and age group were higher in the summer (p < .001). the most common chief complaint was flank pain (61.1%), followed by abdominal pain (22.9%) and hematuria (1.6%). the mode of arrival was mainly private ground transport (47.8%), followed by walk-in (35.8%) and emergency medical service ambulance (13.1%) (table 1). a total of 21,807 (92.2%) patients were managed and discharged from the eds, and only 1,416 (6.0%) patients were admitted; 175 (0.7%) of the admitted patients were transferred to other hospitals. the median los of all patients was 171 (122–255) min. factors associated with a short los in the eds were male gender, time of visit from 18:00–24:00 h, and a saturday visit (p < .001). in contrast, the los did not correlate significantly with age group (table 2). the number and rate of admitted patients with renal colic are summarized in table 3. women (8.3%) had a higher admission rate than men (6.0%). the older age group (≥ 65 years) had the highest admission rate (11.6%). the admission rate of patients who visited on monday (7.8%) was significantly higher than that of patients who visited on other days of week. however, the seasonal variation in the admission rate was not significant (p = .894). table 4 demonstrates the results of a multivariate logistic regression analysis to find predictors associated with hospital admission. women were 1.3 times more likely to be admitted than men. the older age group had a significantly higher likelihood of admission, compared with the other age groups (odds ratio [or] 2, 95% confidence interval [ci]: 1.70–2.33). the probability of admission in patients who visited eds from 00:00–06:00 h was significantly lower than that of patients who visited during other times of the day. visits on monday had a 1.55-fold higher or for admission (95% ci: 1.28–1.87) compared with visits on sunday. discussion the present study revealed demographic, epidemiologic, and clinical data from patients with renal colic in eds in korea. urolithiasis was more common in men than in women in our study, with a male-to-female ratio of 2:1, and the peak incidence of renal colic occurred in the fifth and early sixth decades of life. these results were consistent with the results of previous studies.(10-12) in a prior study, circadian variations in renal colic were observed and characterized by a morning peak independent of gender or the presence of demonstrable kidney stones.(13) another study showed that the highest and lowest rates of hospital visits due to renal colic were recorded in the morning and during the night, respectively.(14) in the present study, we also found that episodes of renal colic exhibited a significant circadian pattern with a morning peak and an afternoon dip. however, our results differed slightly from those of a previous study of the hourly distribution of visits to the ed. the peak morning time reported in a study by cupisti and colleagues was between 09:00 and 12:00 h,(12) whereas in our study we observed a morning peak from 06:00 to 10:00 h. the results of previous studies represented single-center data with relatively small sample sizes. therefore, it was not possible to generalize those results to the general population. in contrast, this study was the first large population-based study to examine circadian variations in the incidence of renal colic attack. the results of our investigation confirm that episodes of renal colic exhibit a circadian pattern characterized by a morning peak. urinary stone formation can be influenced by many factors such as stone-forming components, urinary ph, and inhibitors and promoters of crystallization. most, if not all, renal functions (e.g., glomerular filtration, urine production, and renal solute excretion) exhibit temporal changes leading to an increasing nighttime urine concentration, which could act as a predisposing factor for the morning occurrence of renal colic attacks. in addition, the rates of urine production and renal solute excretion reach minimum levels during the night.(15) as expected, our study showed that the greatest incidence of renal colic occurred during the summer, whereas the lowest incidence was observed during the winter. the seasonal variation in renal colic onset in korea exhibited a peak in july, august, and september, following the warmest months of the year (june, july, and august). furthermore, seasonal variations in renal colic did not differ significantly by patient gender or age. however, a study conducted in iraq found a correlation between renal colic onset and the autumn months, and a norwegian study associated a high incidence of renal colic with the autumn epidemiologic and clinical characteristics of renal colic in korea-hong et al. endourology and stone disease 2150 figure 1. age distribution of renal colic patients (n = 23,653). figure 2. circadian patterns of renal colic patients (n = 23,653). variables admission rate (%) p value gender < .001 male 938/15745 (6.0) female 654/7908 (8.3) age group (years) < .001 18-44 672/11750 (5.7) 45-64 684/9871 (6.9) ≥ 65 236/2032 (11.6) day of week .001 sunday 217/4034 (5.4) monday 263/3376 (7.8) tuesday 227/3368 (6.7) wednesday 241/3240 (7.4) thursday 211/3066 (6.9) friday 221/3165 (7.0) saturday 212/3404 (6.2) season of year .894 spring 376/5637 (6.7) summer 445/6766 (6.6) autumn 412/5966 (6.9) winter 359/5284 (6.8) total 1592/23653 (6.7) table 3. number and rate of patients admitted with renal colic. and winter months.(16,17) in other studies, a peak incidence of renal colic occurs during the summer, and the mean number of renal colic visits per day and the mean daily temperature shows a very high and significant correlation.(18,19) in contrast, a study conducted in sweden failed to observe any seasonal correlations.(20) the symptom of flank pain has been reported to be the most common chief complaint of patients with renal colic, followed by abdominal pain.(21) likewise, these complaints were the 2 most common symptoms in the present study (61.1% and 22.9%, respectively). the pain is often described as waxing and waning with a maximal intensity lasting 20–60 min. in our study, female patients had a longer los, compared with male patients. a longer los may reflect larger amounts of ed resources required for patient care. elderly patients generally require more ed resources, and thus a longer los should be expected in the ed. interestingly, increasing age did not correlate with a longer los in this study. the los of patients visiting from 18:00–24:00 h and on weekend days was shorter than that of patients visiting at any other time during the day and on weekdays. in contrast, downing and colleagues observed that nighttime visits were associated with a higher risk of a longer los in the ed.(22) the longest los in the ed was observed on mondays. although a clear explanation for these finding is unknown, it would appear that monday is the busiest day in hospital eds and outpatient clinics. however, patients are more likely to require admission to the hospital on a monday (admission rate 7.8%). the overall average rate of admission was 6%, a relatively low figure considering that in other studies, as many as 13–22% patients presenting with renal colic were admitted to the hospital.(23,24) the admission rate increased with age in both male and female patients. regarding older patients (≥ 65 years), the los in the ed did not differ from of the los of other age groups, but the admission rate was significantly higher (11.6%). however, seasonal variations did not have a significant effect on the admission rate. one potential reason for the low weekend admission rate is that it is more difficult to access additional supportive services at these times. this study had several limitations. first, the data were collected from relatively large metropolitan eds, and therefore the generalization of our findings to eds across the country may not be appropriate. second, a one-year study period does not clearly account for seasonal variations and climatic influences. additionally, the associations between events and climatic factors may be different in other geographical locations. the participating eds lie between 35° and 37° latitude and experience 4 distinct seasons. therefore, there seems to be little difference in climatic factors. a third limitation arises from the use of kcd-6 codes. these codes epidemiologic and clinical characteristics of renal colic in korea-hong et al. vol 12 no 03 may-june 2015 2151 variables adjusted or 95% ci gender male 1 female 1.32 1.18-1.46 age group (year) 18-44 1 45-64 1.18 1.06-1.32 ≥ 65 2.00 1.70-2.33 day of week sunday 1 monday 1.55 1.28-1.87 tuesday 1.34 1.11-1.63 wednesday 1.49 1.23-1.81 thursday 1.38 1.13-1.67 friday 1.38 1.13-1.67 saturday 1.19 0.98-1.45 time of day (h) 00:00~06:00 1 06:00~12:00 1.33 1.15-1.54 12:00~18:00 1.81 1.55-2.11 18:00~24:00 1.30 1.10-1.52 table 4. multivariate logistic regression analysis of hospital admission. abbreviations: or, odds ratio; ci, confidence intervals. are assigned based on the ed diagnoses made by ed physicians. there may be some variability concerning how physicians identify patients with renal colic. conclusion this large-scale study provides important epidemiologic and clinical information about patients with renal colic in a korean population. the epidemiologic and clinical features derived from this study may facilitate further investigations aimed at understanding the etiology of renal colic. acknowledgement this work was supported by konkuk university. conflict of interest none declared. references 1. preminger gm, tiselius hg, assimos dg, et al. 2007 guideline for the management of ureteral calculi. j urol. 2007;178:2418-34. 2. hollingsworth jm, rogers ma, kaufman sr, et al. medical therapy to facilitate urinary stone passage: a meta-analysis. lancet. 2006;368:1171-9. 3. wilkinson h. clinical investigation and management of patients with renal stones. ann clin biochem. 2001;38:180-7. 4. hesse a, brändle e, wilbert d, köhrmann ku, alken p. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2003;44:709-13. 5. stamatelou kk, francis me, jones ca, nyberg lm, curhan gc. time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003;63:1817-23. 6. lee hn, yoon hn. shim bs. the trend change of incidence and treatment of urolithiasis between the 1980s and 2000s. korean j urol. 2007;48:40-4. 7. ghani kr, roghmann f, sammon jd, et al. emergency department visits in the united states for upper urinary tract stones: trends in hospitalization and charges. j urol. 2014;191:90-6. 8. liu w, esler sj, kenny bj, goh rh, rainbow aj, stevenson gw. low-dose nonenhanced helical ct of renal colic: assessment of ureteric stone detection and measurement of effective dose equivalent. radiology. 2000;215:51-4. 9. graham a, luber s, wolfson ab. urolithiasis in the emergency department. emerg med clin north am. 2011;29:519-38. 10. hesse a, brändle e, wilbert d, köhrmann ku, alken p. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2003;44:709-13. 11. chen yk, lin hc, chen cs, yeh sd. seasonal variations in urinary calculi attacks and their association with climate: a population based study. j urol. 2008;179:564-9. 12. cupisti a, pasquali e, lusso s, carlino f, orsitto e, melandri r. renal colic in pisa emergency department: epidemiology, diagnostics and treatment patterns. intern emerg med. 2008;3:241-4. 13. manfredini r, gallerani m, cecilia ol, boari b, fersini c, portaluppi f. circadian pattern in occurrence of renal colic in an emergency department: analysis of patients› notes. bmj. 2002;324:767. 14. boari b, manfredini r. circadian rhythm and renal colic. recenti prog med. 2003;94:191-3. 15. robert m, roux jo, bourelly f, boularan am, guiter j, monnier l. circadian variations in the risk of urinary calcium oxalate stone formation. br j urol. 1994;74:294-7. 16. al-dabbagh tq, fahadi k. seasonal variations in the incidence of ureteric colic. br j urol. 1977;49:269-75. 17. laerum e. urolithiasis in general practice. an epidemiological study from a norwegian district. scand j urol nephrol. 1983;17:313-9. 18. cervellin g, comelli i, comelli d, et al. epidemiologic and clinical characteristics of renal colic in korea-hong et al. endourology and stone disease 2152 regional short-term climate variations influence on the number of visits for renal colic in a large urban emergency department: results of a 7-year survey. intern emerg med. 2011;6:141-7. 19. cervellin g, comelli i, comelli d, et al. mean temperature and humidity variations, along with patient age, predict the number of visits for renal colic in a large urban emergency department: results of a 9-year survey. j epidemiol glob health. 2012;2:31-8. 20. ahlstrand c, tiselius hg. renal stone disease in a swedish district during one year. scand j urol nephrol. 1981;15:143-6. 21. serinken m, karcioglu o, turkcuer i, ozkan hi, keysan mk, bukiran a. analysis of clinical and demographic characteristics of patients presenting with renal colic in the emergency department. bmc res notes. 2008;1:79. 22. downinh a, wilson rc, cooke mw. which patients spend more than 4 hours in the accident and emergency department. j public health. 2004;26:172-6. 23. trinchieri a, cappoli s, esposito n, acquati p. epidemiology of renal colic in a district general hospital. arch ital urol androl. 2008;80:1-4. 24. eaton sh, cashy j, pearl ja, stein dm, perry k, nadler rb. admission rates and costs associated with emergency presenting of urolithiasis: analysis of the nationwide emergency department sample 2006-2008. j endourol. 2013;27:1535-8. epidemiologic and clinical characteristics of renal colic in korea-hong et al. vol 12 no 03 may-june 2015 2153 erratums erratum: paraurethral cyst in adult women: experience with 85 cases. farzaneh shaririaghdas, azar daneshpajooh, mahboubeh mirzaei urology and nephrology research center, labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. abstract this corrects the article on pages 1896-9 volume 11 number 5, pmid: 25361711. 1. the last name of first author sharifiaghdas was misspelled as shaririaghdas. 2. the authors would like to acknowledge that the provided figures were wrong. therefore the figures of the article should be replaced by the right figures. the authors apologize for this mistake and its repercussions.the last name of the first author and the figures were corrected online. erratum 2293 figure 5. pathological characteristics of benign paraurethral cyst. reconstructive surgery effects of anastomotic posterior urethroplasty (simple or complex) on erectile function: a prospective study jalil hosseini1,2*, farzen soleimanzadeh2, behrouz fadavi2, hamidreza haghighatkhah3 purpose: although improvements in urological function have been less challenged, concern about andrological problems following urethral stricture surgeries has been growing in recent years. the aim of this study is to evaluate the role of the anastomotic urethroplasty itself on erectile function in patients with posterior urethral injuries. materials and methods: in this prospective cohort study, patients with urethral strictures referring to tajrish hospital during october 2013 to august 2016 for anastomotic urethroplasty, were included. all subjects underwent radiologic studies along with rigid and flexible cystoscopy before surgery. erectile function was evaluated before surgery (twice, addressing pre-traumatic and pre-operational conditions) and after surgery (3 and 6 months post-operatively) via iief-5 erectile function questionnaire and color doppler ultrasound assessment of penile vasculature. results: a total of 65 patients with an average age of 30.6 ± 6.1 years were included. a significant decline was observed in erectile function of patients after the injury based on iief-5 questionnaire filled twice separately addressing patient conditions before and after trauma (mean iief score 23.15 ± 0.93 to 13.45 ± 5.43, p = .001). there was also a significant difference in erectile function of subjects with pelvic fractures compared to those without pelvic fractures (10.43 ± 3.78 vs. 18.96 ± 3.18 p = .001). univariate and multivariate analyses showed that urethroplasty itself does not significantly affect erectile function in patients according to penile color doppler ultrasonography (peak cystolic velocity at cavernosal arteries before and after surgery: right 26.87 ± 6.93 vs26.16 ± 6.53 respectively and left 27.23 ± 5.21 vs 26.52 ± 4.38 respectively) and iief-5 erectile function questionnaire (13.12 ± 5.38 vs. 13.54 ± 5.44; p = .26). conclusion: the results of this study showed that urethroplasty does not significantly affect erectile function in patients with urethral strictures. the marginal results showing a negatively affected erectile function in patients with complex strictures may be attributed to a real impact of the surgery in this subgroup or lower number of these cases in our study. keywords: erectile dysfunction; reconstructive surgical procedures; urethral stricture; urethroplasty; urethral transection. introduction urethral stricture is among the complex urological problems that has always been a challenge for urologists. treatments for urethral strictures include various reconstruction techniques, the most suitable of which can be selected according to the length and site of stricture, extent of spongiofibrosis and the surgeon’s skills(1). it is undeniable that urethroplasty techniques are associated with high success rates, if performed properly. sufficient evidence exists on the results of anastomotic and substitutional techniques. by thorough assessment of objective factors such as flow rate, different authors have reported success rates of more than 8090% for bulbar(2), penile(3) and even posterior urethra(4). although urethral injuries are not prevalent, but their incidence has increased due to the rising number of motor-vehicle accidents in recent years. most urethral injuries are due to pelvic fractures associated with blunt abdominal traumas or straddle injuries(5). in injuries to the posterior urethra particularly in complicated cases, surgeon’s accessibility is limited due to the specific 1infertility and reproductive health research center, shahid beheshti university of medical sciences, tehran, iran. 2department of urology, tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 3department of radiology, tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: infertility and reproductive health research center, shahid beheshti university of medical sciences, tehran, iran. tel: +98 21 2271 8001. fax: +98 21 8852 6901. e-mail: jhosseinee@gmail.com. received october 2017 & accepted november 2017 anatomy of this region and so potential complications after surgery such as urinary incontinence and erectile dysfunction (ed) are more prevalent(6). main branches of common penile artery in posterior urethroplasty and its distal branches in anterior urethroplasty are prone to surgical injuries. moreover, the neurovascular bundles approximate to the posterior membranous urethra are susceptible to neurogenic injuries as well(7). the psychological stress caused by urethral stricture and its surgical interventions along with the inflammation and edema after surgery could also contribute to development of ed. as mentioned, ed is the result of a multifactorial process and its components can be affected by urethroplasty surgeries. although, increasing attention has been drawn to different andrological aspects of urethral stricture surgeries, but the relation between urethroplasty and erectile function is still a matter of discussion. lack of sufficient evidence, inclusion of heterogeneous sample populations and different methodologies and statistical analyses have led to incongruent results on this matter(8). accordingly, we aimed to assess the effects of urethroplasty vol 15 no 02 march-april 2018 33 reconstructive surgery 34 on erectile function of patients with traumatic posterior urethral strictures referring to tajrish hospital, which is the only specialized center for urological reconstruction interventions in iran. materials and methods study population in this prospective cohort study, 65 patients with urethral strictures referring to tajrish hospital during october 2013 to august 2016 were included. all subjects with different traumatic causes of urethral strictures had suprapubic catheters in place, more than 6 months had passed from their causative trauma and they were candidates for anastomotic urethroplasty. none of them had erectile dysfunction prior to the trauma, they were all married and capable of having intercourse. exclusion criteria subjects who were found to have a psychological erectile dysfunction according to nocturnal penile tumescence test (npt), any hormonal problems in their laboratory evaluations or any uncontrolled systemic diseases such as diabetes, hypertension, dyslipidemia, thyroid dysfunction and etc. and patients with a history of using any medicine that could affect erectile function such as anti-depressants or psychoactive drugs were excluded. evaluations patients underwent a thorough evaluation including a complete medical history taking, physical examination and laboratory assessments. all subjects also underwent retrograde urethrogram along with voiding cysto-urethrogram, and then simultaneous rigid and flexible cystoscopy via the anterior urethra and cystostomy tract, respectively. bladder neck, posterior urethra, anterior urethra, length and location of the stricture were assessed and patients eligible for anastomotic urethroplasty were selected. the anatomical site of defect was described as bulbar (proximal bulbar, adjacent to the membranous area), bulbo-membranous and membranous urethra. the stricture was calculated by a simple ruler considering the minimization percentage of the digitally printed graph. medical history included information on previous pelvic fractures, previous pelvic surgeries, previous endoscopic interventions and failed urethroplasties. complex cases were defined as the patients with history of previous urethral surgery and stricture length more than 6 centimeters. color doppler ultrasound assessment of the penile vasculature was performed by a radiologist before and 6 months after the surgery by injection of 30 mg papaverine. peak systolic velocity (psv) and end-diastolic velocity (edv) were calculated and psv < 25 cm/s and edv > 5 cm/s were considered as arterial obstruction and venous insufficiency, respectively. erectile function was evaluated via a translated and culturally adapted iranian version of the international index of erectile function (iief 5) questionnaire, validated by pakpour et al. in 2014(9). for each patient the questionnaire was filled twice on the day before surgery based on their sexual activity condition before and after trauma. the results were categorized into 5 groups based on the scores form this questionnaire: scores of 5 7 as severe dysfunction, 8 11 as moderate dysfunction, 12 16 as mild to moderate dysfunction, 17 21 as mild dysfunction and 22 25 as normal(10). the iief scores of all patients before trauma were 22 25 (normal). further assessments were performed 3 and 6 months after the surgery. anastomotic urethroplasty was done by a single surgeon in all subjects. procedures technically in our center, posterior urethral end to end anastomosis includes a perineal approach to the urethra through meticulous dissection of the urethra, proper exposure of the area, finding the distal end of the stricture site by a nelaton catheter and the proximal end of the stricture by flexible cystoscopy. then we transect the urethra on fibrotic stricture area and resect the abnormal tissue until access to the healthy urethral tissue containing no fibrotic scar tissue. then spatulation and anastomosis is performed using six 3-0 vicryl sutures. in longer strictures crural separation and partial (rarely total) pubectomy may be necessary to achieve a tension-free anastomosis. statistical analysis: spss version 20.0 software was ed classification before urethroplasty 6 months after n (%) urethroplasty n (%) no ed 10 (15.4) 11 (17.0) mild ed 12 (18.5) 7 (9.2) mild to moderate ed 9 (13.8) 14 (24.6) moderate ed 19 (29.2) 15 (21.5) severe ed 15 (23.1) 18 (27.7) total 65 (100.0) 65 (100.0) table 1. the frequency of pelvic fracture, previous pelvic surgery, previous endoscopic interventions and failed urethroplasty based on the location and length of the stricture. characteristics history of history of previous history of failed history of pelvic pelvic fracture n (%) endoscopic manipulation n(%) urethroplasty n (%) surgery n (%) bulbar urethra (14 patients) 5 (35.7) 8 (57.1) 3 (21.4) 2 (14.2) membranous urethra (3 patients) 1 (33.3) 2 (66.7) 0 (0.0) 0 (0.0) bulbo-mmembranous urethra (48 patients) 36 (75) 10 (20.8) 15 (31.2) 15 (31.5) stricture length ≤ 2 (6 patients) 2 (33.3) 3 (50.0) 0 (0.0) 2 (33.3) 2 < stricture length ≤ 4 (32 patients) 21 (65.6) 12 (37.5) 4 (12.5) 6 (18.7) 4 < stricture length ≤ 6 (19 patients) 14 (73.7) 5 (26.3) 9 (47.4) 7 (36.8) stricture length > 6 (8 patients) 5 (62.5) 0 (0.0) 5 (62.5) 2 (25.0) table 2. frequency of erectile dysfunction according to iief-5 questionnaire, before and 6 months after urethroplasty. table 3. results of linear regression analysis on the variables affecting erectile function after urethroplasty variable linear regression p value site of urethral stricture -1.38 ± 2.07 0.50 age -0.07 ± 0.05 0.15 length of urethral stricture 0.57 ± 1.75 0.74 history of pelvic fracture 0.41 ± 0.74 0.57 history of pelvic surgery -0.37 ± 0.81 0.64 history of endoscopic manipulation 0.22 ± 0.67 0.74 history of failed urethroplasty 0.02 ± 0.84 0.97 anastomotic urethroplasy and erectile function hosseini et al. used for statistical analysis (ibm corp., chicago, il, usa). data were presented as mean and standard deviation for quantitative variables and as frequency and percentage for qualitative variables. chi-square test and fisher’s exact test were used for comparison of qualitative variables while quantitative variables were analyzed by paired samples t test and independent samples t test. linear regression analysis was also used to assess simultaneous effects of variables. a p value of less than 0.05 was considered as statistically significant in all analyses. the methods of the study were assessed and confirmed by the institutional review board of tajrish hospital and the ethics committee of shahid beheshti univeristy of medical sciences. the aims and methods of the survey and its importance was thoroughly explained to the patients and an informed written consent was obtained from the subjects willing to participate. the study was conducted in accordance to the principles of helsinki’s declaration. gathered information was considered confidential and used anonymously throughout the survey. results a total of 65 patients with an average age of 30.6 ± 6.1 years were included. the most prevalent cause of urethral stricture was motor-vehicle accident reported in 48 (73.8%) patients followed by fall from heights observed in 9 subjects (14%). the remaining 8 patients (12.2%) had membranous urethral strictures due to occupational trauma (6 patients) or traumatic catheterization (2 patients). comprising the majority of patients for each variable, 32 subjects (49.2%) were aged between 20 to 30 years old, 48 (73.8%) had stricture at the bulbomembranous urethra and 32 patients (49.2%) had strictures measuring 2 4 cm in length. a total of 42 subjects (64.6%) had pelvic fractures, of which 20 (47.6%) were found to have displacement of pubis symphysis. table 1 presents the frequency of pelvic fracture, previous pelvic surgery, previous endoscopic interventions and failed urethroplasty in the sample population based on the location and length of their stricture. a significant decline was observed in erectile function of patients based on iief 5 questionnaire after the incident (23.15 ± 0.93 to 13.45 ± 5.43; p = .001). table 2 presents the correlation between erectile function and urethroplasty. based on the results of analyses a significant difference was observed in erectile function of subjects with pelvic fractures compared to those without pelvic fractures (10.43 ± 3.78 vs. 18.96 ± 3.18; p = .001). there was also a significant difference in erectile function of patients with pelvic fractures between subjects with and without displacement of pubis symphysis (9.25 ± 3.72 vs. 11.55 ± 3.55; p = .04). univariate and multivariate analyses showed that urethroplasty did not significantly affect erectile function in patients according to penile color doppler sonography and iief-5 erectile function questionnaire (13.12 ± 5.38 vs. 13.54 ± 5.44; p = .26). there was also no significant difference in erectile function of patients based on whether 3 or 6 months had passed from their urethroplasty (13.40 ± 5.53 vs. 13.12 ± 5.38 p = .61). in brief, the iief-5 score changed from 13.45 ± 5.43 before surgery to 13.12 ± 5.38 three months after surgery and finally 13.40 ± 5.53 six months after surgery. age, location and length of stricture had no significant effects on erectile function of patients before and after urethroplasty (p > .05), but stricture longer than 6 cm had a marginal p value of .06 in univariate analysis. table 3 shows that none of the evaluated variables were able to independently predict the effects of urethroplasty on erectile function of patients. table 4 presents the edv and psv of the right and left cavernosal arteries, before and after urethroplasty and table 5 shows the frequency of ultrasound findings, before and after urethroplasty. discussion ed is one of the important issues pointed out in the studies evaluating patients with urethral strictures after reconstruction surgeries. in the present survey we showed that urethroplasty does not significantly improve or aggravate erectile function in these patients according to findings of the iief 5 questionnaire and ultrasound assessments of the penile vasculature. injuries of the posterior urethra in most trauma cases are associated with pelvic ring fractures which can lead to development of ed directly through injuries to the adjacent neurovascular structures, or indirectly via local inflammation, edema and fibrosis. of the patients with pelvic fractures associated with urethral injuries, 42% develop ed while only 5% of subjects with pelvic fractures without urethral injuries develop this problem(11). the incidence of ed after trauma has been reported from 18 to 72% in different studies(12). although the relative effects of trauma and potential iatrogenic factors during urethroplasty reconstruction surgeries is still not clear(8). koraitim et al. showed that ed is typically due to the primary trauma and rarely (2%) could be attributed to the urethroplasty after injury(4). in another study, bergvariable before urethroplasty 6 months after urethroplasty p value right psv (mean ± standard deviation) 26.87 ± 6.93 26.16 ± 6.53 0.15 left psv (mean ± standard deviation) 27.23 ± 5.21 26.52 ± 4.38 0.16 right edv (mean ± standard deviation) 3.95 ± 2.23 4.14 ± 2.22 0.26 left edv (mean ± standard deviation) 4.53 ± 1.84 4.60 ± 1.81 0.72 table 4. edv and psv of the right and left cavernosal arteries, before and 6 months after urethroplasty. color doppler ultrasound classification before urethroplasty after urethroplasty normal n (%) 20 (30.7) 20 (30.7) one-sided arterial occlusion n (%) 8 (12.3) 4 (6.1) two-sided arterial occlusion n (%) 3 (4.6) 5 (7.7) one-sided venous insufficiency n (%) 10 (15.4) 9 (13.8) two-sided venous insufficiency n (%) 8 (12.3) 8 (12.3) mixed arterial & venous n (%) 16 (24.6) 19 (29.2) anastomotic urethroplasy and erectile function hosseini et al. table 5. frequency of ultrasound findings, before and 6 months after urethroplasty. vol 15 no 02 march-april 2018 35 reconstructive surgery 36 er et al. found no significant change in development of ed (17%) after reconstructive urethroplasty of the posterior urethra(13). santucci et al. also reported only a 1% increase in the prevalence of ed after bulbar anastomotic urethroplasty in 168 patients(14). kessler et al. followed patients for a longer period of time after anastomotic urethroplasty and found only 2 new cases of ed among 40 patients with urethral injuries, among which 33% were bulbar, 10% were bulbomembranous and 57% were membranous injuries(15). the results of these studies were congruent with the findings of the present study which showed urethroplasty to have no significant effects on erectile function of patients. in their study in 1995, mark et al. reported that older patients are more at risk for erectile dysfunction after pelvic fracture urethral distraction defects (p = .013) (16). although the present study found no significant difference in ed between different age groups, but this could be attributed to the fact that most patients included in our study were younger than 40 years old (92.3%). mundy et al. reported that 53% of their patients developed ed after anastomotic urethroplasy within 3 months of the surgery, while after a one year follow up only 5% were still suffering from this problem(17). in our study also, the mean score of erectile function at 6 months after urethroplasty (13.40 ± 5.53) was found to have improved compared to the figure calculated at 3 months (13.12 ± 5.38); however, the differences were not statistically significant. in spite of difficulty in doing end to end anastomosis in cases of stricture length more than 5 centimeters, there has been reports of success by this technique even in children(18). considering the length of stricture, gao et al. found a significant difference in incidence of ed between the two groups of patients with different stricture lengths after anastomotic urethroplasty: one comprised of 17 subjects with a mean stricture length of 2.3 ± 1.3 cm and the other including 35 patients with an average stricture length of 3.8 ± 1.1 cm(19). we also found a marginal p value of 0.06 for development of ed in patients with strictures longer than 6 cm. on the other hand, morey and mcaninch reported an improvement from 38% to 58% among patients with ed after urethroplasty and no new cases of ed were observed in their sample population(20). however, ed had improved in only 4 patients (6.1%) in the present study. anger et al. followed 25 patients who had underwent bulbar anastomotic urethroplasty for an average of 6.2 months and reported the mean score of iief to decrease from 62.2 to 59.6 from a total score of 75 and the mean score for erectile function to decrease from 26.9 to 24.6 from a total score of 30. however, these changes were found to be statistically insignificant(21) which is compatible with the findings of the present survey. in our study, based on iief 5 questionnaire, erectile function had improved in 4 subjects (6.1%) and declined in 9 (13.8%). according to the color doppler ultrasound assessment of penile vasculature, erectile function was found to have declined in 6 patients (9.2%) which could be attributed to neurogenic injuries that cannot be detected by ultrasonography. the higher risk of erectile dysfunction in complex urethroplasty could be attributed to the extra manipulations in these subjects such as opening the crura, releasing the proximal urethra or inferior pubectomy for creating a tension free anastomosis. despite improvements of erectile function in 4 patients according to iief-5 questionnaire, none of the patients were found to have improvement in their ultrasound findings, which can be the result of resecting fibrotic tissues (improvement in cavernosal nerve function) and psychological aspects of becoming catheter free, neither of which can be detected via ultrasound. these findings had not been assessed in previous studies. limitations: this study may be limited by different factors. although the total number of patients included in this study is considerable, the subgroup numbers are limited and this may affect our results negatively in subgroup analysis. additionally, we have not performed specific assessments for neurogenic causes of ed and this may alter some of the results. conclusions this is one of the few prospective studies evaluating erectile function after anastomotic urethroplasty simultaneously via color doppler ultrasound of penile vasculature. the results of this study showed that anastomotic urethroplasty does not significantly affect erectile function in patients with urethral strictures and no independent predictors were identified for the effects of urethroplasty on erectile function of patients. further investigations are required in which larger sample populations should be evaluated, subjects should be followed for a longer duration of time and specific neurogenic assessments for the etiology of ed should be performed. application of other standard questionnaires designed for assessment of erectile function such as brief male sexual function inventory (bmfsi) and sexual life quality questionnaire (slqq) is also recommended. acknowledgments we would like to thank the infertility and reproductive health research center that supported this project and all the staff of tajrish operating rooms who helped us in implementing this survey. we would also like to show our appreciation towards dr. mohammadreza yousefi, dr. arash ranjbar, dr. morteza fallah karkan and dr mohammad ali hosseini for their invaluable help throughout this study. conflict of interest the authors have nothing to declare. references 1. hosseini j, kaviani a, hosseini m, mazloomfard mm, razi a. dorsal versus ventral oral mucosal graft urethroplasty. urol j. 2011;8:48. 2. barbagli g, guazzoni g, lazzeri m. onestage bulbar urethroplasty: retrospective analysis of the results in 375 patients. eur urol. 2008;53:828-33. 3. dubey d, kumar a, mandhani a, srivastava a, kapoor r, bhandari m. buccal mucosal urethroplasty: a versatile technique for all urethral segments. bju int. 2005;95:625-9. 4. koraitim mm. on the art of anastomotic posterior urethroplasty: a 27-year experience. anastomotic urethroplasy and erectile function hosseini et al. j urol. 2005;173:135-9. 5. singh l, sharma p. managing urethral injuries in suburban india—general surgeon's perspective.. med j armed forces india. 2012;68:159-64. 6. hosseini j, tavakkoli tabassi k. surgical repair of posterior urethral defects: review of literature and presentation of experiences. urol j. 2008;5:215-22. 7. costello aj, brooks m, cole oj. anatomical studies of the neurovascular bundle and cavernosal nerves. bju int. 2004;94:1071-6. 8. xambre l. sexual (dys) function after urethroplasty. adv urol. 2016; mar 9;2016. 9. pakpour ah, zeidi im, yekaninejad ms, burri a. validation of a translated and culturally adapted iranian version of the international index of erectile function. j sex marital ther. 2014;40:541-51. 10. rhoden e, telöken c, sogari p, souto cv. the use of the simplified international index of erectile function (iief-5) as a diagnostic tool to study the prevalence of erectile dysfunction. int. j. impot. res. 2002;14:245. 11. king j. impotence after fractures of the pelvis. j bone joint surg am. 1975;57:1107-9. 12. koraitim mm. predictors of erectile dysfunction post pelvic fracture urethral injuries: a multivariate analysis. urology. 2013;81:1081-5. 13. berger ap, deibl m, bartsch g, steiner h, varkarakis j, gozzi c. a comparison of one‐ stage procedures for post‐traumatic urethral stricture repair. bju int. 2005;95(9):1299302. 14. santucci ra, mario la, mc aninch jw. anastomotic urethroplasty for bulbar urethral stricture: analysis of 168 patients. j urol. 2002;167:1715-9. 15. kessler tm, schreiter f, kralidis g, heitz m, olianas r, fisch m. long-term results of surgery for urethral stricture: a statistical analysis. j urol. 2003;170:840-4. 16. mark s, keane t, vandemark r, webster g. impotence following pelvic fracture urethral injury: incidence, aetiology and management. bju int. 1995;75:62-4. 17. mundy a. results and complications of urethroplasty and its future. bju int. 1993;71(3):322-5. 18. jianpo z, jianwei w, guizhong l, et al. successful perineal urethroplasty for long pelvic fracture urethral distraction defect (pfudd) in a 9 year-old boy. urol j. 2016 mar 5;13:2576-8. 19. gao w, xu c, xu y. the study of etiology about erectile dysfunction after pelvic fracture urethral injury. chin j urol. 2000;21:378-81. 20. morey af, mcaninch jw. reconstruction of posterior urethral disruption injuries: outcome analysis in 82 patients. j urol. 1997;157:50610. 21. anger jt, sherman nd, webster gd. the effect of bulbar urethroplasty on erectile function. the j urol. 2007;178:1009-11. anastomotic urethroplasy and erectile function hosseini et al. vol 15 no 02 march-april 2018 37 preoperative statin use associated with lower psa but similar prostate size and histopathologic outcomes: implications for active surveillance? kristian stensland1, russell b. mcbride1,2, michael leapman1, adele hobbs1, seyed behzad jazayeri 3, david b. samadi md3,* purpose: the potential effects of statins on clinical and histopathologic variables, prostate size, or psa density (psad) and resulting influences on active surveillance eligibility have not been adequately explored. this study examines the effect of statins on prostate specimens following prostatectomy. materials and methods: patients that received robotic-assisted laparoscopic prostatectomy (ralp) (n = 2,632) were dichotomized according to preoperative statin use. logistic regression was used to evaluate associations between statin use and patient clinical and pathological characteristics. results: men using statins at the time of prostatectomy were older (61.6 ± 6.4 versus 58.8 ± 7.2 years, p < .001), and had poorer health status (p < .001). biopsy gleason grade, clinical stage and prostate size were similar among the two groups, although statin users had lower diagnostic psa levels (5.5 ± 3.6 versus 6.3 ± 4.9 ng/ml, p < .001) and psad (.12 versus .13, p = .001). conclusion: men taking statins at the time of prostatectomy had similar histopathologic characteristics to non-users, despite having significantly lower serum psa, being older and having similar sized prostates. this supports prior studies suggesting a psa reduction effect of statins may warrant consideration of statin usage in decision algorithms for active surveillance. keywords: active surveillance; neoplasm; psa; robotic prostatectomy; prostate; statins. introduction statins (3-hydroxy-3-methyl-glutaryl-coa reductase inhibitors) are one of the most-prescribed classes of medications worldwide.(1) they have long been used in the management of cholesterol related conditions, but their potential role as a chemopreventive agent is the subject of recent debate. many investigations have focused specifically on their relationship to prostate cancer. though evidence are equivocal on the link between statin use and prostate cancer incidence(2,3). several studies have shown decreased rates of aggressive disease(4,5) and disease recurrence(6-8) with statin use, potentially due to either the anti-inflammatory properties or nascent anti-neoplastic effects of the statins themselves. statins were not related to recurrence rate in other studies.(9,10) in contradistinction, one recent report demonstrated increased rates of aggressive disease and higher risk of biochemical recurrence in patients on statins.(11) it is possible that the varied findings in aggressive and recurrent outcomes may be due to the lower serum psa concentrations found among patients taking statins confounding referral and biopsy/treatment patterns. (12-14) the use of statins have been clearly shown to reduce serum psa concentration but to our knowledge has not yet been fully evaluated in the context of active surveillance (as) for low-risk prostate cancer. as protocols are largely based on parameters that include biopsy gleason score and psa concentration, with some protocols also incorporating other factors such as psa density (psad: psa concentration divided by prostate volume).(15) other drugs, such as 5-alpha reductase inhibitors, have been shown to lower both psa and prostate size.(16) similarly, statins have been shown to lower psa to a greater degree than prostate size, potentially leading to an “artificially” lowered psad.(17) thus, it is possible that statin use may affect the qualification of certain patients for as protocols based on an “artificially low” psa and/or psad. in this context we sought to investigate the effects of statins on preoperative psa, prostate size, and the resulting implications for as eligibility. materials and methods under institutional review board approval at lenox hill hospital, 2,632 patients were considered for enrollment in this study who underwent robotic assisted laparoscopic prostatectomy (ralp) at our institution between may 2004 and july 2012. this is a retrospective analysis on a database of patients diagnosed with prostate cancer. patients’ diagnosis was based on pathology proven presence of prostate adenocarcinoma. no patient was considered for surgery based on an abnormal psa level per se. investigated variables included demographic information, american society of anesthesiology score, preoperative diagnosis of diabetes, preoperative 1department of urology, mount sinai school of medicine, new york, ny, usa. 2institute for translational epidemiology, mount sinai school of medicine, new york, ny, usa. 3department of urology, lenox hill hospital, new york, ny, usa. *correspondence: chairman, department of urology. chief of robotic surgery. lenox hill hospital. 485 madison avenue, floor 21. new york, ny 10022. phone: 212-241-8766. fax: 212-308-6107. email: robotmd@yahoo.com. received september 2016 & accepted april 2017 urological oncology vol 14 no 03 may-june 2017 3064 5-alpha reductase inhibitor usage, statin use, body mass index (bmi), and standard histopathologic outcomes (pathologic gleason score, prostate weight, pathologic stage, margin status, extracapsular extension, perineural invasion, seminal vesicle involvement, lymphovascular invasion). prostatectomy specimens were sectioned in quadrants and mounted in standard fashion. all radical prostatectomy specimens were examined by dedicated genitourinary pathologists. statin use was defined as any hmg-coa reductase inhibitor taken by the patient prior to surgery. this information was driven from the patient chart at the hospital and self-reported list of drugs at office visit. positive surgical margins on pathologic examination were categorized as either focal or extensive (< 3 or ≥ 3 mm, respectively).(18) biochemical recurrence was defined as a single serum psa measurement greater than .2 ng/ml beyond 6 weeks after surgery. pathologic weight was used as a surrogate for prostate volume, which has been validated as the preferred measurement of prostate size in ralp cohorts in previous studies.(19) psa density was then approximated by dividing preoperative psa by this surrogate volume. baseline characteristics and histopathologic outcomes were reported using means for continuous variables and proportions for categorical variables. a logistic regression was performed utilizing log-transformed values for psa. t-tests or anova were used to compare continuous variables and chi-square tests were used to compare categorical variables between statin users and non-users. a cox proportional hazards model was created to assess predictors of biochemical recurrence using enter method. age at diagnosis, race, asa scale, pathologic gleason score, pathologic stage, clinical stage, prostate weight, statin use and preoperative psa level were used in the analysis. significance was defined as a two-sided p value < .05. analyses were performed using spss version 20 (ibm inc., armonk, ny). results in total, 1,913 of 2,632 patients had complete clinical and medication records and were included in analysis. whites comprised 77% of the cohort, blacks comprised 11%, and all other races comprised 9%. of all patients, 630 (33%) were taking statins preoperatively. demographics of the two groups are presented in table 1. the group of statin users were older (61.6 ± 6.4 versus 58.8±7.2 years, p < .001), more likely to be diabetic (12% vs. 4%, p=.001), had fewer blacks (7% vs. 14%, p < .001), and had slightly higher, but not significantly different, bmi (27.8 vs 27.5, p = .09). the statin group also had more comorbidities as measured by the proportion with asa scores >2 (40% vs. 19%, p < .001). forty-nine patients (23 statin users, 26 non-users, p = .03) were taking 5-alpha reductase inhibitors preoperatively. patients taking 5-alpha reductase inhibitors were excluded from the analysis in psa level. preoperative disease characteristics of the two groups are presented in table 2, and histopathologic outcomes among the two groups are presented in table 3. preoperative clinical staging and d’amico risk were similar with the vast majority of both groups having a clinical stage of t1c or below, and low or intermediate risk prostate cancer. proportions of biopsy gleason sums were also similar between the groups. the mean preoperative psa was significantly lower among the statin group than among the non-statin group (5.6 vs. 6.4 ng/ml, p < .001). this finding persisted in multiple subanalyses that divided patients into groups of similar ages, prostate weights, tumor volumes and pathologic stages. statin users were also more likely to have presented with initial psa values less than 4 ng/ ml (32% vs. 24%, p < .001) and less likely to have presented with initial psa values ≥ 10 ng/ml (7% vs. 11%, p < .001). there were no differences in clinical stage between statin users and non-users who were above and below each respective psa threshold. additionally, the mean prostate weight was similar bestatins’ effect on psa level and as-stensland et al. table 1. demographic and clinical characteristic of patients in the study no statin use statin use p value n = 1283 (67%) n = 630 (33%) age, years; mean ± sd 58.8 ± 7.2 61.6 ± 6.4 < .001 race; n(%) white 990 (77%) 543 (86%) < .001 black 176 (14%) 42 (7%) other 117 (9%) 45 (7%) bmi categories; n(%) < 24.9 318 (25%) 129 (21%) .11 25.0-29.9 680 (53%) 349 (55%) > 30 285 (22%) 152 (24%) diabetes; n(%) no 1225 (96%) 554 (88%) < .001 yes 58 (4%) 76 (12%) asa; n(%) 1 71 (6%) 5 (1%) < .001 2 974 (75%) 375 (59%) 3 234 (18%) 243 (39%) 4 4 (1%) 7 (1%) urological oncology 3065 tween both groups (51.0 g vs. 51.6 g, p = .52). psa density, calculated using preoperative psa divided by pathologic weight, was significantly lower among statin users compared to non-statin users (.12 vs. .13, p = .001). further, the range of psad was much smaller among statin users (.02-.75) than non-statin users (0 1.31). there were no significant differences in pathologic staging, tumor volume or pathologic gleason scores between statin users and non-users. median and mean follow-up were similar between the two groups (median 16.4 and 14.4 months for statin users and non-users, respectively (p = .19), both with a mean of 20 months). biochemical disease-free survival (bdfs) rates 2 years post-operatively were also similar (94% vs. 92% for statin users and non-users, respectively, p = .23). in logistic regression models (table 4), preoperative statin usage was a significant predictor of psa concentration (95% confidence interval (ci) = -.069 -.023), p < .001), along with age (95% ci = .002 .005, p < .001), gleason score on biopsy (95% ci = .081 .113, p < .001), and prostate weight (ci 95% = .002 .003, p < .001). in cox regression analysis, pathologic gleason score (hazard ratio (hr) = 9.3, 95% ci = 2.2 38.8, p = .002), pathologic stage (hr = 3.2, 95% ci = 2.1 4.9, p < .001) and preoperative psa level (hr = 4.9, 95% ci = 2.5 9.5, p < .001) but not statin usage (hr = .77, 95% ci = .48 1.08, p = .11) were predictive of biochemical recurrence. discussion statins are the most commonly prescribed medications for hypercholesterolemia, and are currently used by over 24 million americans,(20) a number that continues to rise.(21) aside from their use in primary, secondary and tertiary prevention of cardiovascular morbidity and mortality, many studies have focused on possible antineoplastic effects as they relate to prostate cancer prognosis and psa screening.(22) despite early studies that demonstrated an inverse relationship between prostate cancer incidence and statin use, recent reviews and meta-analyses have not shown conclusive evidence to support such an association.(2,3) however, a recent meta-analyses on 13 paper with 100,536 patients conclude that statin use is associated with better overall and prostate cancer specific survival.(23) some studies have suggested that statins decrease the likelihood of advanced or aggressive disease, rather than preventing de novo prostate cancer incidence.(4,5) possible mechanisms proposed include statins’ effect on inflammation and angiogenesis.(24) it has also been postulated that statins’ reduction of cholesterol-based lipid rafts, which regulate certain apoptotic signaling pathways such as akt, may be an important mechanism behind these findings. (25) loss of low density lipoprotein receptor regulation with a possible role for statins has been proposed in prostate cancer cells as well.(26) in our study we could not find any difference in pathologic characteristics and pathologic stage of the prostate cancer between statin users and non-users. aside from a potential therapeutic benefit, statins’ effect on clinical parameters may have an impact on screening and treatment options for prostate cancer. statins have been consistently shown to reduce serum levels of psa.(12-14) in this higher psa population, in whom prostate cancer is heavily screened, the impact of lowered psa values in relation to delayed diagnosis remains to be defined. our study demonstrated that patients using statins had lower psa level at all stages of the disease. though the effects of statins on screening and surgically treated populations have been described, the influence on eligibility for as protocols, and the potable 1. preoperative characteristics of patients in the study no statin use statin use p value n = 1283 n = 630 psa density; mean ± sd ⃰ 0.13 ± 0.10 0.11 ± 0.08 .001 psa; mean ± sd ⃰ 6.3 ± 4.9 5.5 ± 3.6 < .001 psa categories; n(%) < 2.5 64 (5%) 51 (8%) < .001 2.5-4.0 246 (19%) 149 (24%) 4.1-9.9 828 (65%) 387 (61%) > 10 145 (11%) 43 (7%) biopsy gleason sum; n(%) < 6 696 (54%) 333 (53%) .84 7 476 (37%) 240 (38%) > 8 111 (9%) 57 (9%) clinical stage; n(%) t1c and below 1092 (85%) 530 (84%) .57 t2 and above 191 (15%) 100 (16%) d'amico risk; n(%) low 649 (51%) 313 (50%) .88 intermediate 498 (39%) 252 (40%) high 136 (11%) 65 (10%) ⃰ patients taking 5-alpha reductase are not included in the analysis statins’ effect on psa level and as-stensland et al. vol 14 no 03 may-june 2017 3066 tential treatment benefit for patients on such protocols, has not yet been explored. the ability to forego or defer treatment in active surveillance hinges on prognostication: the ability to identify parameters that will predict low-risk disease with an acceptable degree of certainty. these protocols tend to be based on biopsy gleason score, clinical stage, total psa, and often psa density in addition to other factors.(15) imaging studies including multiparametric magnetic resonance imaging (mpmri) are under investigation to provide sound information in patients undergoing as protocols. although primary investigations have provided promising results, the role table 3. surgical pathology characteristics of patients in the study non-statin users statin users p value n = 1283 n = 630 gleason sum; n(%) < 6 308 (24%) 152 (24%) .40 7 905 (71%) 434 (69%) > 8 70 (6%) 44 (7%) prostate weight (g): mean 51.6 (20.3) 50.9 (17.6) .52 pathological staging; n(%) < t2 993 (77%) 493 (78%) .67 > t3 290 (23%) 137 (22%) lymph node involvement; n(%) 9 (0.9%) 1 (0.2%) .12 margins; n(%) negative 1021 (80%) 516 (82%) .43 focal 182 (14%) 82 (13%) extensive 80 (6%) 32 (5%) extracapsular extensions; n(%) no 1000 (78%) 503 (80%) .34 yes 283 (22%) 127 (20%) tumor in seminal vesicles; n(%) no 1204 (94%) 592 (94%) .91 yes 79 (6%) 38 (6%) perineural invasion; n(%) no 277 (22%) 132 (21%) .75 yes 1006 (78%) 498 (79%) lymphovascular invasion; n(%) no 1230 (96%) 612 (97%) .17 yes 53 (4%) 18 (3%) figure 1. hypothetical influence of statin use in patient eligibility for active surveillance protocols statins’ effect on psa level and as-stensland et al. urological oncology 3067 of imaging in as is still to be determined.(27) as statins lower psa levels, patients may “inappropriately” qualify for active surveillance protocols that are driven by psa thresholds. this may shift some patients from a higher risk into a lower risk group based on the as protocol cut-offs. studies have shown that higher psa values are more affected by statin use than lower values. hamilton et al. reported that in men with a pre-statin psa above 4 ng/ml, median psa declined by 12.5%, but when analyzed in men with pre-statin psa above 2.5 ng/ml this decline was only 9.5%.(28) notably, they also reported that in men with baseline psa between 2.5 and 10 ng/ml, those receiving robust ldl responses with statin usage experienced median psa declines of 17%.(29) in our study population, statin users had an average 8.7% lower psa levels. while studies have not yet directly described the effect of statins on men with psa above 10 ng/ml, the trend at lower levels potentially makes it more likely that a patient with a psa value around the as protocol eligibility cutoffs (i.e. a psa of 10 or 15 ng/ml) may have their psa lowered below the cutoff. for example, a psa of 11 ng/ml would render a man ineligible for many as protocols, but a reduction as reported by hamilton et al. brings him to 9 ng/ml and would not exclude eligibility for any protocol based on psa alone. (figure 1) further, our study demonstrated that while psa was lower among statin users, prostate size was similar between the two groups. as a result, psa density was lower among statin users compared to non-statin users. the use of a psad cutoff as a common inclusion criterion in as protocols, combined with the increasing prevalence of statin use in this population, raises the concern that a common pharmacologic intervention may distort a standard prognostic biomarker. the extent to which statins mask the true psa level, without offering any actual reduction in risk, could result in a non-trivial number of statin users enrolled in as trials having a disproportionately higher risk profile at entry, as well as worse survival outcomes. the unclear nature of the relationship between statins and prostate cancer risk underscores the need for more careful monitoring of statin use in these study populations. while the effect of statins on psa is clear, the explanatory mechanism remains elusive. one possible explanation for our results involves the previously reported anti-inflammatory effects of statins.(12) prostatic inflammation is a known cause of elevated serum psa in men without prostate cancer.(30) decreased inflammation could thus theoretically lower psa while not affecting prostate size or tumor characteristics, a scenario that would be consistent with our findings. the observed demographic differences in asa, bmi, age and history of diabetes are expected, as hyperlipidemia shares a pathophysiologic relationship associated with other comorbid conditions such as diabetes and obesity. it has been postulated that statins’ lowering effect on psa may be influenced by hemodilution in obese, statin-using cohorts.(31) drugs such as 5-alpha reductase inhibitors can also directly decrease serum psa.(32) however, in our cohort, differences in bmi were minimal and not statistically significant, and after controlling for bmi and use of 5-alpha reductase inhibitors our results were unaffected. while some studies support our histopathologic findings,(2,17) others studies have reported a protective benefit of statins against prostate cancer, in contrast to our findings.(4,6,33) similarly, lower prostate cancer recurrence rates have been reported for statin users, and attributed variously to statins’ purported anti-neoplastic activity, protective effects against aggressive disease or a reduction in prostate cancer cells’ ability to produce psa.(6-8) these studies used clinical staging and biopsy characteristics to determine histopathologic risk, which is known to be suboptimal given the inaccuracies of clinical prostate cancer staging.(34) additionally, ritch and colleagues(11) observed a higher recurrence rate 5 years after surgery among statin users, and suggested this may be due the masking of aggressive disease by an artificially lowered psa, as is suggested by our results. while our follow-up may be too short (median 14.7 months) to reveal true differences in biochemical recurrence, no differences in early bcr were noted. similar findings were noted in the study of cattarino et al. with a medial follow up time of 42.3 months.(10) the similarity of histopathologic outcomes between groups despite disparate psa and psad values appears to imply the necessity for inclusion of psa and psa density modulation by statins in clinical decision making. as higher psa values are generally associated with both a higher gleason score and poorer prognosis,(33) an artificially lowered psa and/or psad as observed in our cohort of patients on statins may lead to an underestimation of risk of high-grade disease, recurrence or subsequently higher-grade disease on pathologic specimen. in this sense, it may be important to weigh other arms of protocols (e.g. gleason sum, number of positive cores) more highly in prognosticating patients on statins, or account for their lower psa concentration. our study does have additional notable findings. our patient cohort was 11% black, a higher proportion than most published studies of statins and psa or prostate cancer.(35) our cohort in this sense may better represent the american population than other published studies. additionally, our findings of a reduced psa density in the setting of prognosticating patients and selecting treatment plans underscore the current debate on prostate cancer treatment selection and suggest the table 4. clinical features predicting log transformed psa ⃰ beta 95% ci p value statin usage -.046 -.069, -.023 < .001 age .004 .002, .005 < .001 race .026 .009, 0.044 .004 year of surgery .002 -.005, 0.009 .57 biopsy gleason .097 .081, 0.113 < .001 clinical stage -.020 -.050, 0.011 .20 bmi -.001 -.017, 0.015 .87 asa .008 -.013, 0.029 .45 diabetes status .013 -.029, 0.056 .54 path weight .003 .002, 0.003 < .001 ⃰ patients taking 5-alpha reductase inhibitors are not included in the analysis statins’ effect on psa level and as-stensland et al. vol 14 no 03 may-june 2017 3068 importance of further studies into both the selection of patients for treatment options and the potential for chemoprevention of prostate cancer. we lacked specific data regarding the duration of preoperative statin treatment, which has previously been shown to impact statins’ overall effect on psa.(4,35) we recognize that our cohort was comprised entirely of patients who underwent surgical extirpation for prostate cancer following prostate biopsy. the inherent biases of such study design prevent screening-based epidemiologic conclusions from being drawn from such a cohort. further, there may be variations in some measures between a ralp cohort and actual active surveillance cohort, such as prostate size between the trus calculated values and pathologic weight, though previous studies have shown prostate weight to be the best measure of prostate size for use in psad corrections.(19) these measure must of course be taken under consideration and validated in a cohort considering active surveillance. however, given the large number of patients with standardized histopathologic analysis by dedicated genitourinary pathologists, our findings are interesting and hypothesis-generating. prospective studies involving larger cohorts are needed to confirm our findings with detailed information of the type, dosage and duration of statin usage. conclusions psa levels were lower in statin users than non-statin users among men presenting for robotic-assisted laparoscopic prostatectomy. despite this difference, prostate size, histopathologic outcomes and short term biochemical recurrence were similar between the two groups. further investigation is needed to test causal hypotheses for these findings, to establish whether differential active surveillance criteria are warranted for statin users, and to explore the potential therapeutic benefits of statins in the active surveillance population. conflict of interest the authors declare that there is no conflict of interest to state. references 1. thavendiranathan p, bagai a, brookhart ma, choudhry nk. primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. arch intern med. 2006;166:2307-13. 2. coogan pf, kelly jp, strom bl, rosenberg l. statin and nsaid use and prostate cancer risk. pharmacoepiderm dr s. 2010;19:752-5. 3. dale km, coleman ci, henyan nn, kluger j, white cm. statins and cancer risk: a metaanalysis. jama. 2006;295:74-80. 4. moyad ma, merrick gs, butler wm, et al. statins, especially atorvastatin, may favorably influence clinical presentation and biochemical progression-free survival after brachytherapy for clinically localized prostate cancer. urology. 2005;66:1150-4. 5. platz ea, leitzmann mf, visvanathan k, et al. statin drugs and risk of advanced prostate cancer. j natl cancer i. 2006;98:1819-25. 6. gutt r, tonlaar n, kunnavakkam r, karrison t, weichselbaum rr, liauw sl. statin use and risk of prostate cancer recurrence in men treated with radiation therapy. j clin oncol. 2010;28:2653-9. 7. hamilton rj, banez ll, aronson wj, et al. statin medication use and the risk of biochemical recurrence after radical prostatectomy. cancer. 2010;116:3389-98. 8. kollmeier ma, katz ms, mak k, et al. improved biochemical outcomes with statin use in patients with high-risk localized prostate cancer treated with radiotherapy. int j radiat oncol. 2011;79:713-8. 9. keskivali t, kujala p, visakorpi t, tammela tl, murtola tj. statin use and risk of disease recurrence and death after radical prostatectomy. prostate. 2016;76:469-78. 10. cattarino s, seisen t, drouin sj, et al. influence of statin use on clinicopathological characteristics of localized prostate cancer and outcomes obtained after radical prostatectomy: a single center study. can j urol. 2015;22:7703-8. 11. ritch cr, hruby g, badani kk, benson mc, mckiernan jm. effect of statin use on biochemical outcome following radical prostatectomy. brit j urol int. 2011;108:e211-e6. 12. chang sl, harshman lc, presti jc. impact of common medications on serum total prostatespecific antigen levels: analysis of the national health and nutrition examination survey. j clin oncol. 2010;28:3951-7. 13. cyrus-david ms, weinberg a, thompson t, kadmon d. the effect of statins on serum prostate specific antigen levels in a cohort of airline pilots: a preliminary report. j urol. 2005;173:1923-5. 14. krane ls, kaul sa, stricker hj, peabody jo, menon m, agarwal pk. men presenting for radical prostatectomy on preoperative statin therapy have reduced serum prostate specific antigen. j urol. 2010;183:118-25. 15. buethe dd, pow-sang j. enrollment criteria controversies for active surveillance and triggers for conversion to treatment in prostate cancer. j natl comp cancer netw. 2012;10:1101-10. 16. ross ae, feng z, pierorazio pm, et al. effect of treatment with 5‐⃰ reductase inhibitors on progression in monitored men with favourable‐risk prostate cancer. brit j urol int. 2012;110:651-7. 17. fowke jh, motley ss, barocas da, et al. the associations between statin use and prostate cancer screening, prostate size, high-grade prostatic intraepithelial neoplasia (pin), and prostate cancer. cancer cause control. 2011;22:417-26. 18. shikanov s, song j, royce c, et al. length statins’ effect on psa level and as-stensland et al. urological oncology 3069 of positive surgical margin after radical prostatectomy as a predictor of biochemical recurrence. j urol. 2009;182:139-44. 19. hong mk, yao hh, rzetelski‐west k, et al. prostate weight is the preferred measure of prostate size in radical prostatectomy cohorts. brit j urol int. 2012;109:57-63. 20. larosa jc, he j, vupputuri s. effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. jama. 1999;282:2340-6. 21. mann d, reynolds k, smith d, muntner p. trends in statin use and low-density lipoprotein cholesterol levels among us adults: impact of the 2001 national cholesterol 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statins. prostate int. 2016;4:56-60. 27. barrett t, haider ma. the emerging role of mri in prostate cancer active surveillance and ongoing challenges. american journal of roentgenology. 2017;208:131-9. 28. hamilton rj, goldberg kc, platz ea, freedland sj. the influence of statin medications on prostate-specific antigen levels. j natl cancer i. 2008;100:1511-8. 29. lucia ms, darke ak, goodman pj, et al. pathologic characteristics of cancers detected in the prostate cancer prevention trial: implications for prostate cancer detection and chemoprevention. cancer prev res. 2008;1:167-73. 30. greene kl, albertsen pc, babaian rj, et al. prostate specific antigen best practice statement: 2009 update. j urol. 2009;182:223241. 31. bañez ll, hamilton rj, partin aw, et al. obesity-related plasma hemodilution and psa concentration among men with prostate cancer. jama. 2007;298:2275-80. 32. thompson im, chi c, ankerst dp, et al. effect of finasteride on the sensitivity of psa for detecting prostate cancer. j natl cancer i. 2006;98:1128-33. 33. pierorazio p, desai m, mccann t, benson m, mckiernan j. the relationship between preoperative prostate‐specific antigen and biopsy gleason sum in men undergoing radical retropubic prostatectomy: a novel assessment of traditional predictors of outcome. brit j urol int. 2009;103:38-42. 34. cohen ms, hanley rs, kurteva t, et al. comparing the gleason prostate biopsy and gleason prostatectomy grading system: the lahey clinic medical center experience and an international meta-analysis. eur urol. 2008;54:371-81. 35. flick ed, habel la, chan ka, et al. statin use and risk of prostate cancer in the california men's health study cohort. cancer epidem biomar. 2007;16:2218-25. statins’ effect on psa level and as-stensland et al. vol 14 no 03 may-june 2017 3070 endourology and stone disease inter-observer agreement between urologists and radiologists in interpreting the computed tomography images of emergency patients with renal colic jun young hong1, dong hoon lee2*, in ho chang3, sung bin park4, chan woong kim5, byung hoon chi6 purpose: low-dose non-enhanced computed tomography (ldct) has been shown to provide low radiation exposure with proper diagnostic accuracy compared to standard dose non-enhanced computed tomography (sdct) in patients with renal colic. the goal of our study is to estimate the accuracy of ldct and sdct interpretation by emergency medicine residents who primarily treated patients with renal colic. materials and methods: thirty sample images of both ldct and sdct from renal colic patients were extracted from january 2013 to december 2015 in a tertiary teaching hospital. five emergency medicine residents interpreted 60 image samples over a time span of 3 weeks. the presence of a ureteric stone, the stone’s size and location, and signs of obstruction were recorded in the reports. a total of 300 reports were compared with formal readings by a radiologist. the inter-observer agreement and kappa value were calculated for comparative analysis. results: identification of ureteric stones showed almost perfect inter-observer agreement on sdct (kappa value: 0.93), and the percentage of agreement was 96.7%. however, on ldct, the inter-observer agreement was substantial (kappa value: 0.73), and the percentage of agreement was 88.0%. conclusion: using sdct, emergency medicine residents had almost perfect inter-observer agreement in interpreting the ct images of patients with renal colic compared to a radiologist. however, when using ldct, they had a lower inter-observer agreement. keywords: emergency department; non-enhanced computed tomography; radiation dose; renal colic; urolithiasis. introduction approximately 12 percent of males and 6 percent of females will experience urolithiasis during their lifetime, and up to 50 percent of these individuals will experience a recurrence of urolithiasis within 10 years (1-3). renal colic is a common symptom seen in the emergency department (ed). in the united states, more than a million patients are treated for urolithiasis in an emergency department over the span of a year(4). in the past, intravenous urography (ivu) was the imaging method of choice for diagnosing urolithiasis. however, unenhanced helical computed tomography (ct) has become the standard for diagnosing acute flank pain, and has replaced ivu as the best initial diagnostic imaging modality in patients with renal colic (5). furthermore, ct examination is often repeated to assess the progress of the condition. in 2007, broder et al. reported that approximately half of the patients who had been diagnosed with urolithiasis in the ed received two more ct scans over the course of their condition and that approximately 30 percent of these patients underwent more than three scans(6). the risk of cancer is increased at a rate greater than 1/1000 per abdominal ct 1department of emergency medicine, college of medicine, chung-ang university, seoul, republic of korea. 2department of emergency medicine, college of medicine, chung-ang university, seoul, republic of korea 3department of urology, college of medicine, chung-ang university, seoul, republic of korea. 4department of radiology, college of medicine, chung-ang university, seoul, republic of korea. 5department of emergency medicine, college of medicine, chung-ang university, seoul, republic of korea. 6department of urology, college of medicine, chung-ang university, seoul, republic of korea. *correspondence: department of emergency medicine, college of medicine, chung-ang university, seoul, republic of korea. tel: 82-2-6299-3109. e-mail: emdhlee@cau.ac.kr. received march 2017 & accepted november 2017 scan, and the risk is higher in young patients (7,8). therefore, a means to reduce radiation exposure is needed, and low-dose ct (ldct) was studied as a diagnostic modality. the correct interpretation of urolithiasis by an emergency physician via ct images could be advantageous for the early diagnosis and treatment of renal colic patients. sdct interpreted by emergency physicians has an appropriate percentage of inter-observer agreement compared with formal reporting by a radiologist(9). however, there has not been a study that evaluated the accuracy of the ldct interpretation of urolithiasis by emergency physicians. in this study, we compared the accuracy of ldct interpretation by emergency medicine residents with radiologists. methods this study was approved by the institutional review board of the chung-ang university hospital (irb no. c2016023). written informed consent was obtained from each participant. we have residency program in major of emergency medicine for 4 years. five emergency medicine (em) residents (two junior and three endourology and stone diseases 6 senior residents) of chung-ang university hospital were included to compare the accuracy of interpretation of ldct. study design this study retrospectively reviewed images of renal colic patient performed in emergency department. five emergency medicine residents interpreted 60 patient ct scans over a time span of 3 weeks and reported total 300 cases. a simple reporting method was provided to the em residents. each interpretation was recorded on the reporting form, which included brief clinical information. the case report form included the presence of ureteric stones, their size and location, and signs of obstruction. other clinical findings that were unrelated to ureteric stones were recorded to create a descriptive clinical picture. the participants’ reports were compared for inter-observer agreement with reports by a professional radiologist. sampling images 974 patient image samples were composed of unenhanced abdominal pelvic ct conducted in the emergency department from january 2013 to december 2015. during this period, another study was conducted to compare the diagnostic efficacy of ldct with sdct (title: diagnostic trial of low-dose ct for the detection of urolithiasis irb no. c2013234(1194)). all 30 ldct and sdct image samples were randomly extracted from 974 patient image samples and those were anonymized and randomized. total 60 patient ct images were used for the interpretation. ct protocol all of the unenhanced ct studies were performed using a 256-mdct scanner (brilliance ict, philips healthcare, cleveland, oh, usa). all patients underwent a scan using the standardor low-dose protocol from the proximal aspect of the t12 vertebra to the distal aspect of the symphysis pubis in the supine position. the standard-dose protocol and low-dose protocol was achieved at a manually set peak tube voltage of 120 kvp and 100kvp, with automated z-axis dose modulation by the scout image (doseright, philips healthcare, cleveland, oh, usa),and the tube current was limited to 150 mas and 100mas, respectively. the remaining scanning parameters were as follows: detector configuration, 128x0.625; pitch, 0.915; beam collimation, 80 mm; rotation time, 0.4 sec; and helical acquisition. image noise was reduced by iterative reconstruction in the acquired scan images and could reduce the radiation dose from 5.77 msv to 1.34 msv. sample size and statistical analysis to compare the accuracy of diagnostic performance utilizing ldct by em residents with a radiologist, the inter-observer agreement was used. the kappa coefficient was calculated using the r statistical computing program (r foundation for statistical computing, vienna, austria. http://www.r-project.org/). we considered a kappa value of ≤ 0.19 as poor, a kappa value of 0.200.39 as fair, a kappa value of 0.40-0.59 as moderate, a kappa value of 0.60-0.79 as substantial, and a kappa value of ≥ 0.80 as almost perfect(10). if the expected lower boundary for a kappa one-sided 95% confidence interval (ci) was 0.5 and the expected preliminary kappa value and prevalence were 0.73 and 0.5, respectively, based on a previous study, a minimum of 146 subjects were required for this study of inter-observer agreement by 2 raters. we estimated sample size using the kappasize library statistical program in r-project (r core team [2012]. r: a language and environment for statistical computing; r foundation for statistical computing, vienna, austria. http://www.r-project.org/) results this study included 44 men and 16 women. the mean age was 47.5 years (inter-quartile range: 34.25 to 59.75). overall, 55% (n = 33) of the ct images were positive for urolithiasis, and 45% (n = 27) were negative for urolithiasis. all five em residents who participated in this study had experience with more than 1000 scans for sdct and fewer than 100 scans for ldct. when identifying ureteric stones on sdct, the percentage of agreement between residents and radiologists was 96.7%, and the inter-observer agreement was near perfect (kappa value; 0.93). however, ureteric stones were identified at a percentage of agreement of 88.0%, and the inter-observer agreement was substantial (kappa value; 0.73) on ldct scans. the ldct interpretation by an em resident had a 75% negative predictive value compared with the interpretation conducted by a radiologist. this was significantly low compared with the 98% of agreement on sdct scans (table 1). the results of the interpretation of size and location of ureteric stones were perfect in terms of the inter-observer agreement (kappa value; 0.85, 0.95) on sdct and table 1. diagnostic performance of identifying urolithiasis agreement (95% ci) kappa sensitivity(%) specificity(%) ppv† (%) npv‡ (%) total ct 92.3(89.3-95.4) 0.85 90.9(86.5-95.3) 94.1(90.0-98.1) 94.9(91.5-98.4) 89.4(84.3-94.6) sdct 96.7(93.8-99.6) 0.93 96.7(92.0-100) 96.7(92.9-100) 95.1(89.5-100) 97.8(94.6-100) ldct 88.0(82.7-93.3) 0.73 87.6(81.2-94.0) 88.9(79.3-98.4) 94.8(90.4-99.3) 75.5(63.5-87.4) †ppv, positive predictive value; ‡npv, negative predictive value sign of urinary obstruction stone size(5 mm) stone location agreement (95% ci) kappa agreement (95% ci) kappa agreement (95% ci) kappa total ct 76.3 (71.5 81.2) 0.52 85.0 (80.9 89.1) 0.76 89.3 (85.8 92.8) 0.84 sdct 86.0 (80.4 91.6) 0.71 91.3 (86.8 95.9) 0.85 91.3 (86.8 95.9) 0.93 ldct 66.7 (59.0 74.3) 0.34 78.7 (72.0 85.3) 0.66 78.7 (72.0 85.3) 0.76 table 2. diagnostic performance of sign of obstruction, stone size and location interpretation of low-dose ct in ed-hong et al. vol 15 no 02 march-april 2018 7 were substantial for inter-observer agreement (kappa value; 0.66, 0.76) on ldct (table 2). sign of obstruction results had a kappa value of 0.71 on sdct and 0.34 on ldct (table 2). discussion rafi et al. compared the accuracy of interpretation of conventional ct scans by emergency physicians for patients with renal colic, and the results had a sensitivity of 92%, a specificity of 99%, and a kappa value of 0.89(9). these results indicate that emergency physicians could interpret the images of sdct almost perfectly for patients with renal colic in the ed. therefore, emergency physicians used non-enhanced ct to evaluate patients in many eds who presented with renal colic. recently low-dose, non-enhanced helical ct was studied in patients with renal colic to reduce the radiation threat of sdct. therefore, there have been several reports that ldct had high sensitivity and specificity for the diagnosis of urolithiasis when interpreted by radiologists and urologists(11,12). in our study, the kappa value was 0.93 (table 1), which was similar to that found in rafi’s previous study. kwon et al. reported that a recent survey, ldct in patients with renal colic demonstrated similar sensitivity and specificity compared with the conventional standard-dose ct (sdct)(13-15). however, there have not been studies on the accuracy of ldct interpretation performed by emergency physicians. in this study, we compared the agreement of interpretation on ldct the kappa value was 0.73, which is a lower value than that of sdct. thus, when ldct was used in the ed and the result was read by an emergency medicine resident, some patients could have been misdiagnosed, although the final confirmation of interpretation was made by a radiologist. yang et al. reported that the diagnostic performance of low-dose appendiceal ct was influenced by the amount of a physician’s experience with both lowand standard-dose ct interpretation(12). urologists with an appropriate amount of experience seem to frequently be in agreement with radiologists on ldct scans. however, our participants (emergency physician residents) had worked with more than 1000 scans of sdct for a year; therefore, they were familiar with images of sdct. according to this study, emergency medicine residents could find urolithiasis in the images of sdct as well as a radiologist could and could interpret the exact location and size. therefore, there was minimal difficulty in making a clinical decision with sdct. in contrast, the images from ldct were coarser than those of sdct because of the low radiation amount. emergency medicine residents had no experience with interpreting images from ldct prior to this study. each resident had worked with fewer than 100 scans of ldct, and they had not trained in the interpretation of ldct during the study period. therefore, they were not familiar with the coarse and low-quality ldct images. in this study, emergency medicine residents simply read the images of ldct based on previous knowledge and competence with sdct. to improve the accuracy of interpreting ldct images, emergency medicine residents may be required to have sufficient experience and training. in this study, sign of obstruction, size, and location of ureteric stones had substantial to almost excellent inter-observer agreement (kappa value; 0.71, 0.85, 0.93) compared with formal readings on sdct (table 2). in contrast, a fair to substantial inter-observer agreement (kappa value: 0.34, 0.66, 0.76) was observed on ldct scans. the signs of obstruction and the size and location of ureteric stones are important for determining the prognosis and first-line treatment for renal colic patients (16). therefore, emergency medicine residents should be trained in the interpretation of ldct. when emergency medicine residents could find stones in ldct or sdct, they had little difficulty with interpreting the characteristics of urolithiasis. when they had not been trained to interpret the low-quality images of ldct, it was difficult to deduce the presence of a stone. therefore, if they have more experience with ldct images and receive training on the interpretation of these images, ldct might be as useful in the assessment of urolithiasis as sdct. ldct has been reported to have adequate diagnostic performance while reducing the risk of cancer from radiation as compared with sdct in a variety of diseases(17-19). accordingly, ldct was used for the examination of several diseases in some eds. if emergency physicians can properly interpret ldct without waiting for a formal reading, they can potentially determine the appropriate treatment course and prognosis in the ed more expediently. as our study showed, the interpretation of ldct by emergency medicine residents had low inter-observer agreement compared with formal reading. for proper interpretation with ldct scans in renal colic patients, additional experience and education may be required. limitations the participants who enrolled in this study were in one tertiary medical center. therefore, the sample could not represent the accuracy of interpretation of ldct by an emergency physician. however, our participants had a similar accuracy of interpretation on sdct compared with a previous study that included emergency physicians. we used a lower greyscale monitor compared to radiologists, who use a higher greyscale monitor for formal reading. this could have affected the diagnostic accuracy of our participants due to the lower imaging quality. however, emergency physicians do not use a high-resolution monitor for readings in the ed setting. further, in a real ed setting, emergency physicians take detailed histories and conduct physical examinations of patients before reading the ct results. our study included only brief patient information prior to reading. conclusions when sdct was performed in the ed for patients with renal colic, emergency medicine residents had a high level of agreement of interpretation compared with radiologists. however, on low-dose unenhanced ct, emergency medicine residents had relatively lower levels of agreement of interpretation with the use of sdct compared with a radiologist. conflicts of interest the authors declare that they have no conflict of interest. references 1. bartoletti r, cai t, mondaini n, et al. epidemiology and risk factors in urolithiasis. interpretation of low-dose ct in ed-hong et al. endourology and stone diseases 8 urol int. 2007;79 suppl 1:3-7. 2. curhan gc. epidemiology of stone disease. urol clin north am. 2007;34:287-93. 3. sierakowski r, finlayson b, landes rr, finlayson cd, sierakowski n. the frequency of urolithiasis in hospital discharge diagnoses in the united states. invest urol. 1978;15:43841. 4. brown j. diagnostic and treatment patterns for renal colic in us emergency departments. int urol nephrol. 2006;38:87-92. 5. türk c, petřík a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. european urology. 2016;69:468-74. 6. broder j, bowen j, lohr j, babcock a, yoon j. cumulative ct exposures in emergency department patients evaluated for suspected renal colic. the journal of emergency medicine. 2007;33:161-8. 7. [no authorlisted]. radiation and your patient: a guide for medical practitioners. ann icrp. 2001;31:5-31. 8. brenner d, elliston c, hall e, berdon w. estimated risks of radiation-induced fatal cancer from pediatric ct. ajr am j roentgenol. 2001;176:289-96. 9. rafi m, shetty a, gunja n. accuracy of computed tomography of the kidneys, ureters and bladder interpretation by emergency physicians. emergency medicine australasia. 2013;25:422-6. 10. landis jr, koch gg. the measurement of observer agreement for categorical data. biometrics. 1977159-74. 11. kwon jk, chang ih, moon yt, lee jb, park hj, park sb. usefulness of low-dose nonenhanced computed tomography with iterative reconstruction for evaluation of urolithiasis: diagnostic performance and agreement between the urologist and the radiologist. urology. 2015;85:531-8. 12. yang hk, ko y, lee mh, et al. initial performance of radiologists and radiology residents in interpreting low-dose (2-msv) appendiceal ct. ajr am j roentgenol. 2015;205:w594-611. 13. poletti p-a, platon a, rutschmann ot, schmidlin fr, iselin ce, becker cd. lowdose versus standard-dose ct protocol in patients with clinically suspected renal colic. american journal of roentgenology. 2007;188:927-33. 14. niemann t, kollmann t, bongartz g. diagnostic performance of low-dose ct for the detection of urolithiasis: a meta-analysis. ajr am j roentgenol. 2008;191:396-401. 15. kulkarni nm, uppot rn, eisner bh, sahani dv. radiation dose reduction at multidetector ct with adaptive statistical iterative reconstruction for evaluation of urolithiasis: how low can we go? radiology. 2012;265:158-66. 16. glenn m. preminger m, co-chair; hansgoran tiselius, md, phd, co-chair; dean g. assimos, md, vice-chair; peter alken, md, phd; a. colin buck, md, phd; michele gallucci, md, phd; thoma knoll, md, phd; james e. lingeman, md; stephen y. nakada, md; margaret sue pearle, md, phd; kemal sarica, md, phd; christian turk, md, phd; j. stuart wolf, jr., md. 2007 guideline for the management of ureteral calculi. american urological association. 2007. 17. berrington de gonzález a, mahesh m, kim k-p, et al. projected cancer risks from computed tomographic scans performed in the united states in 2007. archives of internal medicine. 2009;169:2071-7. 18. keyzer c, tack d, de maertelaer v, bohy p, gevenois pa, van gansbeke d. acute appendicitis: comparison of low-dose and standard-dose unenhanced multi-detector row ct. radiology. 2004;232:164-72. 19. team nlstr. reduced lung-cancer mortality with low-dose computed tomographic screening. the new england journal of medicine. 2011;365:395. interpretation of low-dose ct in ed-hong et al. vol 15 no 02 march-april 2018 9 urology journal unrc/iua vol. 1, no. 4, 276-277 autumn 2004 printed in iran 276 case reports huge benign prostatic hyperplasia hosseini sy1, safarinejad mr2* 1department of urology, shaheed modarress hospital, shaheed beheshti university of medical sciences, tehran, iran 2department of urology, military university of medical sciences, tehran, iran key words: benign prostate hyperplasia, large prostate, diagnosis introduction when prostate gland grows massively in an intravesical direction, diagnosis, both radiographically and clinically may be difficult. although modern imaging techniques have increased the diagnostic yield, it may mimic other lower urinary tract and pelvic diseases. we report a huge filling defect in the bladder caused by intravesical enlargement of the prostate and discuss differential diagnosis. case report a 47-year-old male was admitted with lower urinary tract symptoms (luts). the patient complained of straining, nocturia, dysuria, hesitancy, and severe constipation. on rectal examination, a firm, small, and smooth prostate thought to weight approximately 20 gr with a large pelvic mass above the prostate were palpated. blood chemistry and urinalysis were normal, but serum prostatic specific antigen (psa) level was 69 ng/ml. ultrasound revealed a pelvic solid mass. additional transrectal ultrasound did not confirm intraprostatic location of a solid structure. ct scan and magnetic resonance imaging (mri) only depicted a solid pelvic mass measured 9 ×10 cm (fig. 1). on urethrocystoscopy, prostatic urethra was normal, but bladder outlet was completely obstructed. histopathological examination of needle biopsies from the mass, demonstrated benign prostatic hyperplasia. a suprapubic surgical approach to the bladder was performed. a pedunculated lesion arising from the bladder neck was noted. the mass was enucleated. it weighed 508 gr and consisted of stromal and glandular hyperplasia. the postoperative course was uneventful. serum psa level, three months after surgery, was 2.6 ng/ml. discussion median lobe enlargements tend to push intravesically and produce marked filling defects in the floor of the bladder. clinical diagnosis of solitary subcervical or median lobe hypertrophy can be quite difficult. rectal examination is not only unsatisfactory, but may even be misleading for, if the lobe grows intravesically, it cannot be felt through the rectum. symptomatology may not be proportional to the degree of hyperplasia. huge enlargement of the gland in an intravesical direction may give minimal symptoms. the radiographic differential diagnostic possibilities, considered for filling received november 2003 accepted april 2004 *corresponding author: p.o. box: 19395-1849, tel: +98 912 109 5200, e-mail: safarinejad@unrc.ir fig.1. ct scan demonstrated a huge intravesical mass, occupying most of the bladder. hosseini, safarinejad 277 defect within the bladder, include defects caused by blood clot, solitary vesical calculus, bladder tumor, or an extravesical mass arising posterior to the bladder. retrovesical masses include prostatic utricle cyst, prostatic abscess, seminal vesicle hydrops, seminal vesicle cyst, seminal vesicle empyema, large ectopic ureterocele, and connective tissue tumors such as myxoid liposarcoma and malignant fibrous histiocytoma.(1) occasionally, radiological differentiation of these conditions may be impossible. ultrasonography may be especially helpful in confirming the cystic nature of a mass, even if it contains high-density hemorrhagic fluid, and localization of large cysts close to the bladder. transrectal ultrasound has been increasingly popular as a diagnostic tool to evaluate the prostate and seminal vesicles. it is essential to minimize the possibility of missing important clues and achieve accurate diagnostic imaging studies, such as ct scan and/or mri.(2) ct scan accurately demonstrates the anatomical relationship of associated internal pelvic organs. in our patient ct scan and mri only disclosed a solid pelvic mass without localization of it into the prostate. others have stressed the usefulness of endorectal mri, which may provide further diagnostic information of the pelvic mass.(3) occasionally, preoperative or intraoperative biopsy and histopathological examination remains the key for diagnosis. references 1. dahms se, hohenfellner m, linn jf, eggersmann c, haupt g, thuroff jw. retrovesical mass in men: pitfalls of differential diagnosis. j urol. 1999;161:1244-1248. 2. genevois pa, van sinoy ml, sintzoff sa jr, et al. cysts of the prostate and seminal vesicle: mr imaging findings in 11 cases. ajr am j roentgenol. 1990;155:1021-1025. 3. parsons rb, fisher am, bar-chama n, mitty ha. mr imaging in male infertility. radiographics. 1997;17:627-631. endourology and stone diseases the outcome of percutaneous nephrolithotomy using intravenous catheter for obtaining percutaneous access as a treatment for renal stone disease in children: a pilot study purpose: using percutaneous nephrolithotomy (pnl), it is easy to reach stones in various parts of the kidney via a single access tract. in the current study, we set out to demonstrate that the intravenous catheter is a safe way to gain renal access, and that pnl is safe in children. materials and methods: we retrospectively reviewed the medical records of patients who underwent pnl as a treatment for renal stone disease at our center between september 2013 and december 2014. there were no specific exclusion criteria. we used 14 gauge intravenous catheter for renal access in all cases. results: eleven of the 32 patients (34.4%) were female and 21 (65.6%) were male. the mean ± sd patient age was 4.7 ± 3.71 years (9 months-16 years). six patients (18.7%) were infants less than 1 year of age. fifteen of the stones (46.8%) were located in the right kidney, and 17 of the stones (53.1%) were located in the left kidney. the average stone size was 13.9 ± 4.8 mm (range, 12-28). the average duration of operation was 69.7 ± 10.4 minutes (range, 50-110), and the average duration of fluoroscopy was 2.21 ± 1.06 minutes (range, 1-6). there were complications in 5 of the cases (15.6%). conclusion: the access and dilatation stages are quite important. we propose that the intravenous catheter is a safe and inexpensive tool for renal access in pnl in pediatric age group patients. keywords: kidney calculi; surgery; child; minimally invasive surgical procedures; methods; nephrostomy; percutaneous; treatment outcome. introduction urinary stone disease is common in turkey. a mul-ticenter study reported a prevalence of the disease of 14.8%,(1) and this percentage is even higher in the regions of turkey with warmer climates, such as eastern and southeastern anatolia. renal stones in children cause growth and developmental delays, urosepsis, and renal impairment. due to the high rate of relapse in this age group, minimally invasive methods to treat childhood urinary stone disease are crucial. studies from turkey show that the average rate of relapse for renal stone disease in children between the ages of 1 month and 6 years is 15%, and that 37.5% of these patients have a metabolic disorder.(2) in the past 6 decades, remarkable improvements have been achieved in the treatment of renal calculi. goodwin and colleagues first inserted a nephrostomy catheter into the kidney of a patient with hydronephrosis in 1955.(3) not long after, harris and colleagues reported the first removal of a renal stone percutaneously using a flexible bronchoscope.(4) in 1967, fernstrom and johansson performed and described percutaneous nephrolithotomy (pnl).(5) in 1980, their accomplishment was followed by the invention of extracorporeal shock wave lithotripsy (swl).(6) pnl is the preferred treatment method for swl resistant patients. swl is generally contraindicated for large stones and cystine stones and is not specific for lower calyceal stones. the success rate of pnl is high and its morbidity level is markedly low. the most important stage in pnl is achieving percutaneous access to the kidney. for renal puncture in this stage of the pnl procedure, the intravenous catheter (angiocath) has been described in the literature as highly maneuverable, able to fit comfortably in the palm of the hand, and quite inexpensive.(7) in particular, use of an angiocath decreases mehmet serif arslan,* hikmet zeytun, erol basuguy, serkan arslan, bahattin aydogdu, mehmet hanifi okur *correspondence: departments of pediatric urology and pediatric surgery, university of dicle, sur, diyarbakir 21210, turkey. tel: +90 505 6260047. fax: +90 2488001. e-mail: mserif.arslan@dicle.edu.tr received january 2016 & accepted february 2016 endourology and stone diseases 2502 vol 13 no 01 january-february 2016 2503 the risk of complications such as renal tissue damage and extravasation. in the current study, we aimed to demonstrate the outcome of pnl using an angiocath in the treatment of renal stone disease in children, with particular attention paid to the infant patient group, which has been rarely noted in the literature. materials and methods study population our study included 32 patients who underwent pnl treatment for renal stone disease at our clinic between september 2013 and december 2014. the medical records of these patients were retrospectively reviewed. the cases were analyzed in terms of gender, age, radiological signs such as stone location and stone area (according to stone protocol computerized tomography), size of sheath used, duration of operation, complications, and treatment results. this study included pediatric patients in whom pnl was indicated and other treatment methods such as swl were insufficient. there were no specific exclusion criteria. this retrospective study was issued an approval number of 48/2014 by our human ethics committee. evaluations all patients underwent pre-operative studies including percutaneous nephrolithotomy and children-arslan et al. urological oncology 2405 table 1. demographics and stone characteristics of patients. variables renal stones (n = 32) age, years (mean ± sd) 4.7 ± 3.71 (9 months–16 years) male/female, no (%) 21 (65.6) / 11 (34.4) stone load, mm2 (mean ± sd) 160 ± 89.7 (120–250) stone size, mm (mean ± sd) 13.9 ± 4.8 (12–28) stone number, mean ± sd (range) 3.31 ± 2.4 (1-13) left/right side stone, no (%) 17 (53.1) / 15 (46.8) patients with special situations, no (%) solitary kidney 1 (3.1) hydronephrosis 12 (32.4) residual stones after swl 3 (9) stone locations, no (%) pelvic stone 10 (31.2) middle calyceal stone 5 (15.6) lower calyceal stone 5 (15.6) upj stone 4 (12.5) multiple calyceal stones 8 (25) abbreviations: sd, standard deviation; upj, ureteropelvic junction. figure 1. a) guidewire inserted through the sheath of angiocath; b) fluoroscopic image of access. urinalysis, complete blood count, serum biochemistry, and routine coagulation and serological tests. additionally, all patients were examined with renal ultrasound (rus) and noncontrast spiral computerized tomography (nsct). scans of 3-mm coronal and reformatted 3-mm axial sections were evaluated on the dicle university (diyarbakır, turkey) picture archiving and communication system (pacs). maximal stone diameter was measured in two dimensions in the reformatted coronal and axial sections by one reviewer. preoperative nephrostomy was not used in any patient. procedures the pnl procedure was performed by three surgeons. pnl was classified for each procedure as described by tepeler and colleagues, using the size of the external sheath as a criterion.(8) pnl access was performed using a 14 gauge angiocath in the lithotomy position, as described by penbegul and colleagues (figure 1).(7) for this procedure, a 3 french (f) ureteral catheter was placed into the ureteropelvic region of the supine patient, after which the patient was placed in the prone position, and renal access was obtained using an angiocath and fluoroscopy. diluted (40%–50%) contrast medium was injected into the collecting system to confirm the puncture. then, after removing the needle, a 0.038 inch hydrophilic guide wire was passed through the outer sheath into the renal unit. the tract was mechanically dilated to 12 f over the guide wire. a 12 f working sheath was placed in the pelvicaliceal system. the stones were visualized using a rigid nephroscope (9.5 f nephroscope; karl storz, tuttlingen, germany) and fragmented with pneumatic lithotripsy. many reports in the literature describe pneumatic and laser lithotripsy. stone fragmentation with pneumatic lithotripsy is cheaper and faster than laser lithotripsy via pnl. therefore, we preferred pneumatic lithotripsy in all of our patients, which allowed the fragmented stones to be removed by forceps and the turbulence of fluid flow. during the procedure, if extravasation was noted, an 8 f nephrostomy catheter was passed through the working table 2. intraoperative and postoperative parameters. variables renal stones (n = 32) initial stone free rate, no (%) 28 (87.5) final stone free rate, no (%) 31 (96.9) hospital stay, days, mean ± sd (range) 4.34 ± 1.09 (2–8) operative time, min, mean ± sd (range) 69.7 ± 10.4 (50–110) fluoroscopy time, min, mean ± sd (range) 4.8 ± 1.06 (2-7) hemoglobin drop, g/dl, mean ± sd (range) 0.97 ± 1.9 (2–4.2) pnl size *, no (%) pnl+12 15 (46.8) pnl+14 10 (31.2) pnl+18 6 (18.7 ) pnl+24 1 (3.1) puncture locations, no (%) middle/lower pole calyces 12 (37.5 ) / 20 (62.5) infracostal/supracostal 25 (78.1) / 7 (218) significant complications, no (%) clavien grade 1 4 (12.5) clavien grade 2 1 (3.1) stone composition, no (%) calcium oxalate and/or phosphate 12 (37.5) / 20 (62.5) uric acid 5 (15.6) struvite 6 (18.7) cystine 5 (15.6) abbreviations: sfr, stone free rate; pnl, percutaneous nephrolithotomy; sd, standard deviation. * pnl classification as described by tepeler et al.(8) percutaneous nephrolithotomy and children-arslan et al. endourology and stone diseases 2504 vol 13 no 01 january-february 2016 2505 channel into the renal collecting system, and its placement was confirmed by administering contrast. twelve hours post-surgery, the ureteral and foley catheters were removed. the nephrostomy catheter was removed after rus confirmed the absence of a urinoma. patients with no complications were discharged from the hospital on the second post-operative day and were prescribed oral anti-inflammatories. the initial stone-free rate (sfr) is defined as a stone-free or asymptomatic state and a clinically insignificant residual stone of ≤ 4 mm on rus at 24–48 hours post-pnl. the final sfr is the same as the initial sfr at 1 month post operatively and after any repeat pnl or auxiliary procedures. collected stones were sent for analysis. statistical analysis data were reported as numbers and percentages or as means ± sd as appropriate (tables 1 and 2). analyses were conducted using pasw statistics software (statistical package for the social science (spss inc, chicago, illinois, usa, version 18.0). results the current study had a male-to-female ratio of 18 to 14 (table 1). the mean age of the patients was 4.7 ± 3.7 years (range, 9 months to 16 years). fifteen patients had a stone in the right kidney (46.8%) and 17 had a stone in the left kidney (53.1%). in terms of the location of stones, 10 cases exhibited stones in the renal pelvis (31.2%), 5 cases in the middle calyx (15.6%), 4 cases in the ureteropelvic junction (12.5%) and 5 cases in the lower calyx (15.6%); in 8 (25%) cases, stones were located in multiple calyces. the average size and area of the stones were 13.9 ± 4.8 mm and 160 ± 89.7 mm2, respectively. there was hydronephrosis in 12 patients, 3 patients had histories of failed swl procedures, and 1 patient had a solitary kidney. none of the patients had anatomical abnormalities. a single access tract was used to remove stones in all patients. supracostal access was utilized in 7 cases, while infracostal access was used in 25 cases. renal stones were accessed through the middle calyx in 12 cases and through the lower calyx in 20 cases. we operated on 15 of the patients (46.8%) using a 12 f access sheath, and 6 of these cases (40%) were infants (< 1 year). in 10 cases (31.2%), the stone’s area was greater than 180 mm2 and the pnl procedure was performed using a 14 f sheath to decrease the duration of the procedure. in six cases (18.7%), the stones were struvites greater than 220 mm2 and the pnl procedure was performed using an 18 f sheath. in one case, nsct identified multiple stones in the right kidney, and during the procedure we found 13 stones in multiple calyces. in this case, the procedure was started with a 12 f sheath; however, the stones moved continuously due to the turbulence of the liquid flow and the stone fragments were unusually large, which necessitated a 24 f sheath. the larger stones were removed using pneumatic lithotripsy and the remaining 11 stones were removed with forceps (figure 2). operation time is considered as the time between the first renal puncture to the completion of stone removal. the average duration of the operation was 69.7 ± 10.4 minutes (range, 50–110 minutes), and the average duration of fluoroscopy was 2.21 ± 1.0 minutes (range, 1–6 minutes). the average hemoglobin (hb) decrease in the post-operative follow-up was 0.97 ± 1.9 g/dl (range, 2–4.2 g/dl). according to the modified clavien classification,(9) complications were identified in only five cases (15.6%). in four of five cases, figure 2. a) preoperative computerized tomography scan view of a 5-year old patient with solitary kidney and 13 stones; b) cystine stones removed from the same case. percutaneous nephrolithotomy and children-arslan et al. grade 1 urinary extravasation, hematuria, and pain developed, and an 8 f nephrostomy catheter was placed. on the second post-operative day, in both patients the nephrostomy catheter was initially clamped and a rus check was performed, and when extravasation was excluded the nephrostomy catheter was removed. a grade 2 complication was observed in only 1 of 5 cases that developed complications. in this final case, pain and hematuria continued for more than 2 days postoperatively. the patient’s hb values decreased from 12.6 g/dl to 7.6 g/dl, and an erythrocyte suspension was administered. in the follow up of all 5 cases, no problems were identified (table 2). on the second postoperative day, standing direct abdominal radiography and rus were performed on all patients to measure the preliminary success rate. these demonstrated initial sfr kidneys in 28 patients (87.5%). anti-inflammatories were prescribed for all patients and all were fully hydrated. after the final sfr, the success rate for eliminating renal stones was 96.9% (31 out of 32 patients) (table 2). in only one case, a 6 mm stone was found in the lower calyx. the treatment regimen was continued without any change for 3 months. chemical analyses of the stones revealed calcium-oxalate and/or phosphate in 16 cases, uric acid in 5 cases, struvite in 6 cases, and cystine in 5 cases. discussion urinary stone disease is especially prevalent in certain regions of the world. in turkey, 5% of all patients seen in pediatric urology clinics suffer from urinary stone disease, and the overall prevalence of the disease in turkey is 14.8%. both the incidence and relapse rate of urinary stone disease are quite high in turkey, as is the case in much of the world. the incidence is higher in regions with warmer climates, such as eastern and southeastern anatolia.(1) according to the current protocol for treating urinary stone disease, various minimally invasive treatments can be used, including swl, ureterorenoscopy (urs), retrograde intrarenal surgery (rirs), micro-pnl, and pnl.(10) renal stones in children cause growth and developmental delays, urosepsis, and renal impairment. due to the high rate of relapse in this age group, minimally invasive methods to treat childhood urinary stone disease are crucial. pnl is the most common endourology treatment method. its many advantages include: shortened hospital stays, decreased complication rates, high stone-free success rates, and the capacity to reach almost any calyx when entered from the right access point.(11) pnl is known to be an appropriate treatment for pelvic stones larger than 1.5 cm, pole stones larger than 1 cm, and cystine stones larger than 1 cm in children.(2) the effectiveness and reliability of pnl in pediatric patients has been proven by various studies. etemadian and colleagues concluded that pnl using adult sized instruments was relatively safe in children, with a sfr of 67%.(12) in another study, the sfr was determined to be 87.5%, and following additional procedures such as swl, urs, and re-pnl, a final success rate of 98% was achieved.(13) one study reported that the risk of bleeding complications increases as the diameters of the renal access tract and the nephroscope increase.(14) this study demonstrates that the risk of complications is determined by the operative technique (e.g., the access method), the number of tracts, the tract dilatation method, and tract diameter.(14) bilen et al. showed that, when 20-26 f access sheaths were used, more blood transfusions were needed; however, use of 14 f access sheaths did not necessitate transfusions.(15) given that in pediatric cases the collecting tubules are shorter and the kidney is smaller, the smallest possible instruments and tracts should be used to prevent major complications such as bleeding and renal damage.(16) desai and colleagues emphasize that it is quite safe to operate using access sheaths smaller than 14 f in preschool-aged children, and that the rate of complications such as bleeding and parenchymal damage is low.(17) accessing the renal unit is the most important step in pnl. chiba-type aspiration needles are commonly used for this purpose. long, flexible needles may be problematic for the surgeon, which may result in higher rates of complications such as bleeding.(18) the use of an alken guide confers advantages including less radiation exposure and shorter access and operative times in adults, even in the supine position.(19) for patients of all ages, the most important step of pnl is to gain access; for this step, 11 to 15 cm long 18 gauge needles are usually used. for obese patients and adult patients, long needles are preferable due to their longer access tracts; otherwise, we prefer shorter needles because they can easily be orientated and manipulated. in addition, in pediatric cases, a smaller skin incision is occasionally required to overcome difficulties with inserting these needles. while investigating the cost of materials according to the purchase prices of our hospital, we noted that the angiocath, costing only 0.30 turkish lira (tl), was less than one hundredth of the price of the percutaneous access needle, which costs 32.20 tl.(18) as a percutaneous nephrolithotomy and children-arslan et al. endourology and stone diseases 2506 vol 13 no 01 january-february 2016 2507 comparison, bhullar and colleagues developed a highly reliable renal access tool, but the cost was estimated at around $700 (about 1,900 tl).(20) in contrast, in our clinic we used 14 gauge angiocath for renal access in all cases; we regard these tools, which require no preliminary preparation and that provide practical, efficient, inexpensive, and safe access, to be reliable and cost-effective. in our study, the success rate of removing stones with the pnl technique utilizing 12-24 f external sheaths was 96.9%, and the complication rate was 15.6%. in 15 of our 32 patients (46.8%) we were able to use a 12 f sheath, which was the smallest pnl sheath available; 6 of these 15 cases (40%) were infants (< 1 year), an age group which is rarely reported on in the literature. the size of the external sheath can be increased as necessary using the same tract and guide wire. in one of our patients, we started the procedure with a 12 f sheath, and during the operation were able to increase the size to a 24 f sheath to shorten the duration of the procedure and remove the stones successfully. our experience has shown that the angiocath can be safely used for renal access in pnl. using pnl, it is easy to reach stones in different parts of the kidney via a single access tract, making it a minimally invasive treatment. the most significant complications of this procedure are bleeding and extravasation. the indications for pnl are large, complex renal stones, hard stones which are resistant to swl, such as cystine stones and cases where other endourology treatment methods fail.(21) pnl is a more effective treatment method for children with renal stones compared to swl, urs, and rirs. in pnl, all of the steps following successful access to the renal unit and careful dilatation are easier than in urs or rirs. in the latter two endourologic methods, a stone can only be reached after passing through the urethra, bladder, and ureteropelvic regions; however, for the pnl technique in pediatric patients, the anatomic distance generally does not exceed 3–5 cm. pnl is the preferred minimally invasive treatment method for the treatment of renal stones in all pediatric patients, including infants. pnl can be used to treat stones of different sizes and locations. the access and dilatation stages are quite important, and it is crucial to perform pnl with the smallest access sheath possible to ensure a successful treatment outcome. conclusions we are of the opinion that pnl has increased our success in treating renal stones in pediatric patients, because using the angiocath for renal access allows us to reach the collecting duct system safely and efficiently. the current study had two limitations: its relatively small sample size and retrospective design. future prospective studies are required to further compare angiocath to other devices for gaining renal access. conflict of interest none declared. references 1. akinci m, esen t, tellaloglu s. urinary stone disease in turkey: an updated epidemiological study. eur urol. 1991;20:200-3. 2. oner a, demircin g, ipekcioglu h, bulbul m, ecin n. etiological and clinical patterns of urolithiasis in turkish children. eur urol. 1997;31:453-8. 3. goodwin we, casey wc, woolf w. percutaneous trocar (needle) nephrostomy in hydronephrosis. j am med assoc. 1955;157:891-4. 4. harris rd, mclaughlin ap, 3rd, harrell jh. percutaneous nephroscopy using fiberoptic bronchoscope: removal of renal calculus. urology. 1975;6:367-9. 5. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 6. lycklama a nijeholt aa, jonas u. [crushing of kidney stones: tomorrow's reality? (noninvasive lithotripsy by shock waves)]. ned tijdschr geneeskd. 1983;127:1093-4. 7. penbegul n, bodakci mn, hatipoglu nk, et al. microsheath for microperc: 14-gauge angiocath. j endourol. 2013;27:835-9. 8. tepeler a, sarica k. standard, mini, ultra-mini, and micro percutaneous nephrolithotomy: what is next? a novel labeling system for percutaneous nephrolithotomy according to the size of the access sheath used during procedure. urolithiasis. 2013;41:367 9. tefekli a, ali karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008;53:184-90. 10. scales cd, jr., smith ac, hanley jm, saigal cs, urologic diseases in america p. prevalence of kidney stones in the united states. eur urol. 2012;62:160-5. 11. okur mh, arslan. ms, aydoğdu. b, et al. our initial experience with percutaneous nephrolithotomy in children. dicle med j. 2014;41:151-2. 12. etemadian m, maghsoudi r, shadpour p, mokhtari mr, rezaeimehr b, shati m. pediatric percutaneous nephrolithotomy using adult sized instruments: our experience. urol j. 2012;9:465-71. 13. hatipoglu nk, bodakci mn, penbegul n, et al. monoplanar access technique for percutaneous nephrolithotomy and children-arslan et al. percutaneous nephrolithotomy. urolithiasis. 2013;41:257-63. 14. unsal a, resorlu b, kara c, bozkurt of, ozyuvali e. safety and efficacy of percutaneous nephrolithotomy in infants, preschool age, and older children with different sizes of instruments. urology. 2010;76:24752. 15. bilen cy, kocak b, kitirci g, ozkaya o, sarikaya s. percutaneous nephrolithotomy in children: lessons learned in 5 years at a single institution.j urol. 2007;177:1867-71. 16. guven s, istanbulluoglu o, ozturk a, et al. percutaneous nephrolithotomy is highly efficient and safe in infants and children under 3 years of age. urol int. 2010;85:455-60. 17. desai j, zeng g, zhao z, zhong w, chen w, wu w. a novel technique of ultra-minipercutaneous nephrolithotomy: introduction and an initial experience for treatment of upper urinary calculi less than 2 cm. biomed res int. 2013;2013:490793. 18. penbegul n, soylemez h, bozkurt y, et al. an alternative and inexpensive percutaneous access needle in pediatric patients. urology. 2012;80:938-40. 19. el harrech y, abakka n, el anzaoui j, goundale o, touiti d. one-shot dilation in modified supine position for percutaneous nephrolithotomy: experience from over 300 cases. urol j. 2014;11:1575-82. 20. singh bhullar j, scott r, patel m, mittal vk. kidney access device. jsls. 2014;18(4). 21. kim sc, kuo rl, lingeman je. percutaneous nephrolithotomy: an update. curr opin urol. 2003;13:235-41. percutaneous nephrolithotomy and children-arslan et al. endourology and stone diseases 2508 relationship between calcium stone disease and metabolic syndrome emre can polat,1* levent ozcan,2 suleyman sami cakir,3 murat dursun,3 alper otunctemur,3 emin ozbek3 purpose: we aimed to investigate relationship between metabolic syndrome and calcium-oxalate stone formation. materials and methods: between january 2008 and february 2015 we retrospectively investigated biochemical parameters and anthropometric characteristics (height, weight, and waist circumference) of 198 patients who had calcium-oxalate stones and we also randomly selected 200 participants who had no history of urolithiasis as the controls. results: the presence of obesity increased the risk of calcium stones in both men (p = .003, or = 2.92) and women (p = .03, or = 2.18). diabetes was significantly correlated to the risk of calcium stones (p = .04, or = 1.94). however, when calculated separately for men and women, diabetic men had a higher risk of calcium-oxalate stone disease (p = .04, or = 2.59), but diabetic women did not (p > .05). hypertension also significantly increased the risk of calcium stones when compared with normotensive individuals (p = .0001, or = 3.03). conclusion: the risk for the development of calcium-oxalate stone disease is most significantly associated with the patient’s body mass index and the presence of hypertension. keywords: metabolic syndrome; epidemiology; outcome assessment; prevalence; risk assessment; urolithiasis; etiology. introduction metabolic syndrome (ms), the simultaneous oc-currence of hyperglycemia, hyperlipidemia, hypertension, and visceral obesity, is a chronic disease associated with high mortality. in addition, this condition substantially increases the risk of developing cardiovascular diseases and type 2 diabetes.(1) in the united states, the prevalence of ms is 24% in men and 23.4% in women, increasing at ages 60-69 years to 43.5% in both sexes.(2) through out the years, numerous definitions of ms have been proposed by various organizations. the national cholesterol education program adult treatment panel iii (ncep/atp iii) definition is the one most used today because it incorporates the key concepts of ms, relies on commonly used laboratory studies available to most physicians, and is less restrictive than the other classifications.(3) the prevalence of urolithiasis ranges from 2 to 20% throughout the world based on the geographic and socioeconomic characteristics of the different populations. the worldwide prevalence of the disease appears to have increased in the last quarter of the twentieth century for both men and women. the identification of common, modifiable risk factors for kidney stones may result in new approaches to the treatment and prevention of urolithiasis.(4) much like ms and obesity, the prevalence of nephrolithiasis in the united states and other countries is increasing. there is evidence that these parallel changes might be linked.(5) studies have shown that ms and its components (obesity/increased waist circumference [wc], hypertension, and etc.) are associated with increased rates of nephrolithiasis.(6-8) although the exact pathophysiologic mechanisms underlying the association between ms and nephrolithiasis are unclear, ms has been associated with changes in urinary constituents, including lower urinary ph, decreased citrate excretion, and increased uric acid and calcium excretion, leading to increased risks of uric acid and calcium stone formation.(9-12) since 80% of kidney stones consist of calcium oxalate (caox),(13,14) studies exploring the relationship between urinary risk factors for calcium stone formation and features of the ms are critical. therefore in this study, we aimed to investigate the relationship between caox stone disease and ms components. 1 department of urology, istanbul medipol university, istanbul, turkey. 2 department of urology, derince training and research hospital, kocaeli, turkey. 3 department of urology, okmeydani training and research hospital, istanbul, turkey. *correspondence: department of urology, istanbul medipol university, istanbul, turkey. tel: +90 532 7149604. e-mail: ecpolat@medipol.edu.tr. received january 2015 & accepted november 2015 endourology and stone diseases endourology and stone diseases 2391 materials and methods we retrospectively investigated biochemical parameters and anthropometric characteristics (height, weight, and wc) of 198 patients who had caox stones and we also randomly selected 200 participants who had no history of urolithiasis as the controls between january 2008 and february 2015. patients who had a surgery for urolithiasis (open nephrolithotomy, percutaneous nephrolithotomy and ureterorenoscopy) and whose stones were stones with a caox content ˃ 70% and a calcium apatite content ˂ 5% with fourier transform infrared spectroscopy and high-resolution x-ray diffraction(15) were enrolled in the study. patients were excluded from the study if they had primary hyperparathyroidism, chronic diarrheal syndromes, intestinal malabsorption, complete distal renal tubular acidosis, primary hyperoxaluria, recurrent or active urinary tract infection, history of kidney transplantation, ongoing 5-α reductase inhibitor therapy, liver disease, primary gout, any debilitating chronic illness, or a calculated creatinine clearance of ≤ 50 ml/minute. weight, wc, and blood pressure were measured after an overnight fasting, and a blood sample was drawn. fasting blood glucose, serum total cholesterol, high-density lipoprotein (hdl) cholesterol, and triglycerides were measured using enzymatic methods with an autoanalyzer. ms was defined according to the criteria established in 2005 by the ncep/atp iii. for the criteria for ms, abdominal obesity was defined as wc ≥ 102 cm in men and ≥ 89 cm in women, according to the ncep/atp iii obesity criteria. ms was diagnosed in those who satisfied at least 3 of the following 5 criteria: wc ≥ 102 cm in men, ≥ 89 cm in women, triglyceride concentration >150 mg/dl or undergoing treatment for hypertriglyceridemia, hdl cholesterol concentration < 40 mg/dl in men and ˂ 50 mg/dl in women or undergoing treatment for low hdl-cholesterol level, blood pressure > 130/85 mmhg or undergoing treatment for hypertension, and fasting blood glucose level > 100 mg/dl or undergoing treatment for hyperglycemia.(3) statistical analysis analyses were performed using chi-square tests. odds ratios (or) were calculated. statistical determinations were within the 95% confidence interval (ci). all p values were two-tailed, and p < .05 was considered statistically significant. the data were analyzed with statistical package for the social science (spss inc, chicago, illinois, usa) version 16. results baseline demographic characteristics of the 398 participants are shown in table 1. in the study population, 198 were patients with caox stone disease, aged 36-58 years and 200 were patients without urolithiasis aged 31-64 years. body mass index (bmi) was significantly correlated with the risk of caox stone disease. overall, participants with a bmi > 30 kg/m2 increased their risk of calcium stones by 2.54-fold when compared with participants with a bmi < 30 kg/m2 (table 2). the presence of obesity increased the risk of calcium stones in both men (p = .003, or = 2.92) and women (p = .03, or = 2.18). increased wc also increased the risk of caox stone disease (p =.002, or = 1.91). when wc table 1. demographic characteristics of the participants. variables caox stone (+) stone (-) p value gender, male/female; n (%) 105/93 (53/47) 108/92 (54/46) ˃ .05 age (years) 43.3 ± 9.3 42.7 ± 9.7 ˃ .05 abbreviation: caox, calcium oxalate. abbreviations: bmi, body mass index; ci, confidence interval; caox, calcium oxalate. * data are presented as no (%). bmi subjects without stone subjects with caox stone p value odds ratio 95% ci overall ˂ 30 172 (86) 140 (70.7) .0003 2.54 1.53-4.21 ˃ 30 28 (14) 58 (29.3) for men ˂ 30 95 (88) 75 (71.4) .003 2.92 1.42-5.99 ˃ 30 13 (12) 30 (28.6) for women ˂ 30 77 (83.7) 65 (70) .03 2.18 1.07-4.43 ˃ 30 15 (16.3) 28 (30) table 2. correlation of body mass index (kg/m2) and presence of caox stone disease.* calcium stone disease with metabolic syndrome-polat et al. vol 12 no 06 november-december 2015 2392 calcium stone disease with metabolic syndrome-polat et al. was calculated separately for men and women, both abdominally obese men (wc ≥ 102 cm) and abdominally obese women (wc ≥ 89 cm) had higher risk of caox stone disease respectively (p = .02, or = 2; p = .02, or = 2.07) (table 3). of the participants, 50 (12.5%) had been diagnosed with diabetes mellitus and 99 (24.8%) with hypertension. diabetes was significantly related to the risk of calcium stones (p = .04, or = 1.94). however, when calculated separately for men and women, diabetic men had a higher risk of caox stone disease (p = .04, or = 2.59), but diabetic women did not (p > .05) (table 4). hypertension also significantly increased the risk of calcium stones when compared with normotensive individuals (p = .0001, or = 3.03) (table 5). multi-variant analysis revealed that only hypertension and obesity had significant impacts on the development of caox stone disease (p = .001 and p = .02, respectively). the calculated or was 2.32 (95% confidence interval [ci]: 1.32–3.51) for hypertension and 1.43 (ci: 1.21–2.42) for obesity. discussion our study was a retrospective analysis designed to explore the relationship between ms factors and the caox stone disease. we found that, both obesity and hypertension were independently and significantly associated with caox stone disease. insulin resistant individuals often have an abnormal distribution of fat that is predominantly characterized by upper body fat. (16) upper body obesity may result in insulin resistance in otherwise normal weight individuals, so we analyzed our data for bmi and wc as separate entities. our results showed that the number of individuals with a wc of over 100 cm (n = 106, 26.6%) was greater than the number of individuals with a bmi of over 30 kg/m2(n = 86, 21.6%). uric acid and infectious stones are both linked with increased body weight as well as insulin resistance.(17,18) although the association between body weight and calcium nephrolithiasis has not been clearly established, table 3. the association between waist circumference and caox stone disease.* wc subjects without stone subjects with caox stone p value odds ratio 95% ci overall abdominal obesity (+) 78 (39) 109 (55) .002 1.91 1.28-2.85 abdominal obesity (-) 122 (61) 89 (45) for men ˂102 cm 81 (75) 63 (60) .02 2 1.11-3.59 ≥102 cm 27 (25) 42 (40) for women ˂89 cm 41 (44.5) 26 (28) .02 2.07 1.12-3.82 ≥89 cm 51 (55.5) 67 (72) abbreviations: wc, waist circumference; ci, confidence interval; caox, calcium oxalate. * data are presented as no (%). abbreviations: dm, diabetes mellitus; ci, confidence interval; caox, calcium oxalate. * data are presented as no (%). dm subjects without stone subjects with caox stone p value odds ratio 95% ci overall dm (+) 18 (9) 32 (16.2) .04 1.94 1.05 3.6 dm (-) 182 (91) 166 (83.8) for men dm (+) 7 (6.5) 16 (15.2) .04 2.59 1.02 6.59 dm (-) 101 (93.5) 89 (84.8) for women dm (+) 11 (12) 16 (17.2) dm (-) 81 (88) 77 (82.8) table 4. relation of caox stone disease with diabetes mellitus.* endourology and stone diseases 2393 sarica and colleagues showed that an increased body size increased the excretion of urinary stone-forming risk factors such as oxalate, calcium, and citrate.(19) parvin and colleagues realized that oxalate play the most important role as a urinary stone risk factor in idiopathic calcium stone disease followed by calcium and uric acid and that the adjusted values for body weight is a stronger and more determinant factor in calcium stone formation than their concentration.(20) siener and colleagues(21) evaluated the relationship between bmi and 24 h urine parameters in a population of idiopathic caox stone formers and found that an increased bmi was strongly associated with an increase in the excretion of stone promoters but not inhibitors. in our study, the or was 2.92 for men and 2.18 for women with bmi ≥ 30 kg/m2 versus bmi ˂ 30 kg/m2. as with bmi, wc also showed a significant correlation with the risk of caox stone disease. the calculated or was 2 for men and 2.07 for women with wc of 102 and 89 cm, respectively. although our study showed a strong association between body weight (bmi and wc) and caox stone disease, one of the limitations of our research is the lack of the metabolic evaluation of the individuals. taylor and colleagues(22) showed a higher prevalence of a past history of kidney stones and a higher incidence of stone episodes among diabetic patients than among non-diabetic patients. this association was independent from age and bmi. the crosssectional study conducted by meydan and colleagues compared the prevalence of kidney stone disease between diabetic and age-matched non-diabetic subjects. diabetic individuals had a significantly higher prevalence of nephrolithiasis (21% among 321 vs. 8% among 115).(23) lieske and colleagues,(24) in a case–control community-based study, compared 3,561 stone formers with 3,561 age and gender-matched control subjects to show the relationship between urolithiasis and diabetes. their results showed that a higher proportion of stone formers were diabetic and that stone formers had a 22% increased risk of being diabetic. the frequency of diabetes was much higher in patients with uric acid nephrolithiasis. our results showed that diabetes was significantly related to the risk of calcium stones (p = .04, or = 1.94). however, when calculated separately for men and women, diabetic men had a higher risk of caox stone disease (p = .04, or = 2.59), but diabetic women did not (p > .05). differences in racial/ethnic variables, age distribution, and study populations may have affected the results of analyses. therefore, additional studies are needed to determine whether diabetes is an independent risk factor for the formation of calcium stones. to date, several epidemiologic studies have analyzed the association between hypertension and nephrolithiasis. in cross sectional studies, it has been reported that nephrolithiasis is more frequent in hypertensive patients than in those who are normotensive, but the pathologic link between hypertension and stone disease remains to be clarified.(21-24) in addition, some prospective studies reported the risk of stones in hypertensive patients.(22,25) animal studies have consistently shown hypercalciuria and metabolic acidosis in hypertensive rodent models. (26) the research of eisner and colleagues(27) has confirmed that there is an increased excretion of calcium in hypertensive patients. another possible mechanism may be the hypocitraturia, which occurs secondary to acidosis in hypertensive patients. in our study, we found a significant correlation between hypertension and caox stone disease with an or of 3. our study has several inherent limitations. due to the retrospective nature of the study, 24-hour urine data, urine ph and metabolic evaluation were either unavailable or unobtainable for an unacceptable number of patable 5. correlation of caox stone disease with hypertension.* ht subjects without stone subjects with caox stone p value odds ratio 95% ci overall ht (+) 30 (15) 69 (34.8) .0001 3.03 1.86-4.92 ht (-) 170 (85) 129 (65.2) for men ht (+) 13 (12) 32 (30.5) .002 3.2 1.57-6.53 ht (-) 95 (88) 73 (69.5) for women ht (+) 17 (18.5) 37 (39.8) .002 2.91 1.49-5.7 ht (-) 75 (81.5) 56 (60.2) abbreviations: ht, hypertension; ci, confidence interval; caox, calcium oxalate. * data are presented as no (%). calcium stone disease with metabolic syndrome-polat et al. vol 12 no 06 november-december 2015 2394 tients. also due to the lack of number of the patients, we could not make age related statistical analysis. we believe that since 80% of kidney stones consist of caox, studies exploring the relationship between urinary risk factors for calcium stone formation and features of the ms with metabolic evaluation will be more critical on this topic. conclusions patients who have ms components are at a higher risk for developing caox stone formation. among the components, the risk for the development of caox stone disease is most significantly associated with the patient’s bmi and the presence of hypertension with the lack of the patient’s metabolic evaluation. conflict of interest none declared. references 1. eckel rh, grundy sm, zimmet pz. the metabolic syndrome. lancet. 2005;365:141528. 2. ford es, giles wh, dietz wh. prevalence of the metabolic syndrome among us adults: findings from the third national health and nutrition examination survey. jama. 2002;287:356-9. 3. huang pl. a comprehensive definition for metabolic syndrome. dis model mech. 2009;2:231-7. 4. binbay m, yuruk e, akman t, et al. updated epidemiologic study of urolithiasis in turkey ii: role of metabolic syndrome components on urolithiasis. urol res. 2012;40:247-52. 5. stamatelou kk, francis me, jones ca, nyberg lm, curhan gc.time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003;63:1817-23. 6. taylor en, stampfer mj, curhan gc. obesity, weight gain, and the risk of kidney stones. jama. 2005;293:455-62. 7. taylor en, stampfer mj, curhan gc. diabetes mellitus and the risk of nephrolithiasis. kidney int. 2005;68:1230-5. 8. curhan gc, willett wc, rimm eb, speizer fe, stampfer mj. body size and risk of kidney stones. j am soc nephrol. 1998;9:1645-52. 9. jeong ig, hwang ss, kim hk, ahn h, kim cs. the association of metabolic syndrome and its components with serum prostatespecific antigen levels in a korean-screened population. cancer epidemiol biomarkers prev. 2010;19:371-80. 10. sakhaee k, maalouf nm. metabolic syndrome and uric acid nephrolithiasis. semin nephrol. 2008;28:174-80. 11. sakhaee k. recent advances in the pathophysiology of nephrolithiasis. kidney int. 2009;75:585-95. 12. iba a, kohjimoto y, mori t, et al. insulin resistance increases the risk of urinary stone formation in a rat model of metabolic syndrome. bju int. 2010;106:1550-4. 13. pak cy, sakhaee k, peterson rd, poindexter jr, frawley wh. biochemical profile of idiopathic uric acid nephrolithiasis. kidney int. 2001;60:757-61. 14. pak cy, sakhaee k, moe o, et al. biochemical profile of stone forming patients with diabetes mellitus. urology. 2003;61:523-7. 15. amato m, lusini ml, nelli f. epidemiology of nephrolithiasis today. urol int. 2004;72 suppl 1:1-5. 16. grundy sm, cleeman ji, daniels sr, et al. diagnosis and management of the metabolic syndrome: an american heart association/national heart, lung and blood institute scientific statement. circulation. 2005:112:2735-52. 17. curhan gc, willett wc, rimm eb, speizer fe, stampfer mj. body size and risk of kidney stones. j am soc nephrol.1998;9:1645-52. 18. taylor en, stampfer mj, curhan gc. obesity, weight gain and the risk of kidney stones. jama. 2005;293:455-62. 19. sarıca k, altay b, erturhan s. effect of being overweight on stone forming risk factors. urology. 2008;71:771-4. 20. parvin m, shakhssalim n, basiri a, et al. the most important metabolic risk factors in recurrent urinary stone formers. urol j. 2011;8:99-106. 21. siener r, glatz s, nicolay c, hesse a. the role of overweight and obesity in calcium oxalate stone formation. obes res. 2004;12:106-13. 22. taylor en, stampfer mj, curhan gc. diabetes mellitus and the risk of nephrolithiasis. kidney int. 2005;68:1230-5. 23. meydan n, barutca s, caliskan s, camsari t. urinary stone disease in diabetes mellitus. scand j urol nephrol. 2003;37:64-70. 24. lieske jc, de la vega ls, gettman mt, et al. diabetes mellitus and the risk of urinary tract stones: a population-based case-control study. am j kidney dis. 2006;48:897-904. 25. daudon m, traxer o, conort p, lacour b, jungers p. type 2 diabetes increases the risk for uric acid stones. j am soc nephrol. 2006;17:2026-33. 26. batlle dc1, sharma am, alsheikha mw, sobrero m, saleh a, gutterman c. renal acid excretion and intracellular ph in saltsensitive genetic hypertension. j clin invest. 1993;91:2178-84. 27. eisner bh, porten sp, bechis sk, stoller ml. hypertension is associated with increased urinary calcium excretion in patients with urol ithiasis j urol. 2010;183:576-9. calcium stone disease with metabolic syndrome-polat et al. endourology and stone diseases 2395 extra-renal transplanted kidney stone: case presentation and literature review abbas basiri, mohammad nadjafi semnani, hamed mohseni rad* keywords: transplantation; urolithiasis. urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. email: sirhamed@hotmail.com. received january 2017 & acceptd june 2017 soft tissue calcification is common in uremic patients. wound calcification or ossification is not so prevalent except in specific conditions like inflammation and ischemia or wound tension. we present a 40-year-old transplanted patient, not only perirenal ossification but also with multiple perirenal stones. the presentation was severe pain on the site of transplantation. pre-op ct scan revealed perirenal calcified mass. intraoperative finding was very thick tissue accompanied with a lot of stones around the transplanted kidney. the patient had history of ureteral fistula after renal transplantation that needed temporary percutaneous nephrostomy and then uretero-neocystomy. it seems that urinary leakage through nephrostomy site probably is the predisposing factor for stone formation around the kidney where as there is no stone inside the kidney. introduction postoperative calcifications are visible in up to 25.7% of postoperative abdominal computed tomography (ct) scans of midline incisions(1). soft tissue and vascular calcifications are commonly present in uremic patients due to disturbances in calcium and phosphate balance and also, hyperparathyroidism(2). however, visceral calcifications are serious and uncommon complications of end-stage renal disease(3). subcutaneous calcification has been well described in the medical literature as a complication of chronic venous insufficiency, inflammation and ischemia or wound tension(4). regardless of the etiology, the presence of calcium deposits in soft tissues may lead to chronic wounds that do not respond to conservative local wound care(5). while calcification and opacification is reported in literature, but to our best knowledge there is no report of stone formation around the kidney. case report a 40-year-old man received a first renal transplant in 2011 from living donor by right pararectal incision. the cause of end-stage renal disease was hypertension. percutaneous nephrostomy had been performed six months after transplantation due to hydronephrosis and fever with ureteral fistula and the patient had eventually undergone ureteral neocystostomy operation with same para-rectal incision and 4-0 vicryl suture and 4.8 fr double-j stenting which was extracted 4 weeks later. case report figure 1. pre-operative abdomen-pelvic ct scan. case report 58 vol 15 no 02 march-april 2018 59 extra renal transplanted kidney stone-basiri et al. five years later, he came with pain and discomfort at right lower quadrant around the graft. examination revealed subcutaneous tense and immobile mass. patient serum creatinine was 1.7 mg/dl without any urinary problem. we accomplished biopsy which reported inflammation and fibrosis with calcification. computed tomography (ct) marked large calcified mass ventral to graft but sparing the graft and spreading to pelvic cavity. (figure 1) we planned surgery by incision on previous surgery line. the graft was intact without any invasion. we excised the calcified mass and stones. the excised masses were just like numerous packed kidney stones (figure 2). histology demonstrates calcification and ossification and stone analysis reported calcium oxalate 20%, calcium hydrogen phosphate 20%, amonium mg phosphate 5% and remaining 55% as undetermined. 24 hour urine collection of patient was as follows : volume1440 cc, creatinine:1303mg, ph:6.6, calcium:323 mg, oxalate 27mg, citrate 299mg, and uric acid 389mg. serum investigations revealed calcium: 9.9 mg/dl, pth: 69 pg/ml, and uric acid 6.9 mg/dl. discussion a review of the literature suggests that dystrophic wound calcification is a topic that is currently not well understood. despite tight regulation of serum calcium, subcutaneous or cutaneous tissue calcification may occur(7). focal tissue damage (hematoma, infection, injection of heparin, wound tension) can yield to calcification or ossification(3). dystrophic calcifications have been seen in a variety of clinical settings, including chronic venous insufficiency, areas of trauma, osteomyelitis, panniculitis, hypervitaminosis d and areas of infarcts. metastatic tissue calcification is seen in cases where there is an underlying defect in calcium and/or phosphate metabolism. the most well published form of metastatic tissue calcification is seen in chronic renal failure(6). chronic renal failure may deposit calcium in tissues as benign nodular calcifications or in the form of calciphylaxis. calciphylaxis is characterized by progressive vascular calcification, soft tissue necrosis, and ischemic necrosis of the skin(8). cutaneous ossification involves membranous and enchondral bone formation in the skin. this condition may be seen in areas surrounding neoplasm, in calcified tissue, in inflammatory and metabolic diseases, and infrequently in normal tissue(9). differentiating subcutaneous calcification from subcutaneous ossification cannot be made by gross visualization of the wound or wound deposits. use of radiographs is only somewhat helpful in making the distinction. histopathologic evaluation of the deposits is the only way to differentiate the two types of wound deposits. calcified tissue may be seen with osseous deposits at the time of biopsy(7). it is believed that calcification is a precursor to ossification. it is a common occurrence to see calcium deposits in conjunction with osseous tissue(7) . the mechanism of formation of such material is not well understood but involves deposition of collagen type i matrix by osteoblasts. it is interesting to note that virtually any process that calcifies may secondarily ossify, but primary ossification is a rare occurrence(9). as for normal ossification, the exact mechanisms by which osseous metaplasia development is triggered remains unclear; however, heterotopia, dystrophic calcifications, ossification of damaged areas, metastatic calcification, and metaplasia in healing tissue may be considered predisposing factors. dense areas of scar tissue may become secondarily ossified(10). while fibroblasts potentially represent osteogenic precursor cells and orchestrate the whole process of neo-osteogenesis, ischemia and inflammation may act as inducing factors, altogether forming a suitable environment for ossification(11). increasing evidence suggests that pericytes, the smooth muscle cells enwrapping micro vascular endothelial cells, behave like mesenchymal stromal cells and can be the source of osteogenic cells in heterotopic ossification(12). in this case there was a lot of real stone beside histologic report of inflammation, calcification and ossification. probably urine leakage in the setting of percutaneous nephrostomy is the culprit. so we concluded to name it extra renal kidney stone which is rare complication in kidney transplantation post operational care based on our literature review. references 1. kim j, kim y, jeong wk, and et al. heterotopic ossification developing in surgical incisions of the abdomen: analysis of its incidence and possible factors associated with its development. j comput assist tomogr. 2008;32:872–6 2. alfrey ac, solomons cc, ciricillo j, miller nl. extraosseous calcification. evidence for abnormal pyrophosphate metabolism in uremia. j clin invest 1976;57:692-9 3. labidi j, ariba yb, gabsia ab, ajili f, figure 2. extra renal stones excised. battikh r, louzir b, et al. severe metastatic calcifications in a hemodialysis patient. saudi j kidney dis transpl 2016;27:1037-42 4. peled i, bar-lev a, wexler m. subcutaneous calcifications of the lower limbs. ann plastic surg 1982; 8:310-3 5. sunquist a, kurien a, duke m. subcutaneous calcification of the legs in chronic venous insufficiency. connecticut med 1966; 30:412. 6. walsh j, fairley j. calcifying disorders of the skin. [continuing medical education] j amer acad dermatol 1995; 33:1-28. 7. richard j. brietstein, e. david sonkin, charles jason hubbard. nonhyperparathyroid wound calcifications: two case presentations and literature review. wounds. 2002; 14:13641. 8. burkhart cg, burkhart cn, mian a. calciphylaxis: a case report and review of literature. wounds 1999; 11:58-61. 9. touart d, sau p. cutaneous deposition diseases, part ii. [continuing medical education] j amer acad dermatol 1998;39:134. 10. sanders bp, orlando g, peloso a, katari rs, iskandar ss, farney ac,et al.osseus metaplasia in kidney allografts as a paradigm of regenerative medicine principles. exp clin transplant. 2014 aug; 12:371-3. 11. asami g, dock w. experimental studies on heteroplastic bone formation. j exp med. 1920; 32:745-66. 12. doherty mj, ashton ba, walsh s, et al. vascular pericytes express osteogenic potential in vitro and in vivo. j bone miner res. 1998; 13:828–838. extra renal transplanted kidney stone-basiri et al. case report 60 urology journal unrc/iua vol. 2, 8-13 spring 2004 printed in iran 8 review article preparing live donor for kidney donation mahdavi r department of kidney transplantation, imam reza hospital, mashhad university of medical science, mashhad, iran abstract purpose: in order to select the most appropriate donor and minimize psychological and physical complications in the kidney donors, it is of high importance to prepare the donor meticulously. the essential respective items are reviewed in this study. materials and methods: the available published literature and papers presented in medline from 1983 to 2003 were reviewed. results: one the sources of sources of kidney donation is the live donor which is mostly used in iran. similarly, due to long waiting lists of kidney recipients, live donor kidney transplantation have been increasingly used in developed countries. consequently, several aspects of this issue have been considered and specific recommendations have been discussed; anatomy of the donor's kidney, age, abo blood group, viral infections, weight, hla type compatibility, psychological status, and diseases such as diabetes, adpkd, and alport syndrome should be evaluated in donation candidates. conclusion: live donor kidney donation has the advantage of elective and programmed transplantation over cadaveric transplantation. however, removal of an intact organ from the body of a normal individual may lead to complications, as it may so in any other major surgical operation. thus, it is strongly recommended to select the most appropriate donor patiently by a series of accurate evaluations. key words: kidney, transplantation, donation, alive introduction in 1954, the first successful kidney transplantation was performed in a 23-year-old male receiving kidney from his twin brother by dr. j.e. murray in boston. this procedure, without any use of immunosuppressive medication, provided a normal life until the recipient died of a non-renal cause.(1) between 1954 and 1980, desirable outcomes were achieved by using related donor, due to the tissue compatibility between the recipient and the donor, but transplantation from cadaver which was accompanied with serious complications was not popular; freeman reported that patients would still have preferred hemodialysis to transplantation in 1985s.(2) better understanding immunological aspects, particularly introducing cyclosporine and monoclonal and polyclonal antibodies, yielded an improvement of short-term graft survival, but it was not significant yet. even live related donor transplantation was disputed by starlz in 1987.(3) however, terrasaki and cecka demonstrated the advantage of related or unrelated live donor transplantation over cadaveric transplantation, despite of new medications usage. in 1998, they observed that transplantation from related or unrelated donor results in a 10-15% and 10-12% higher 1and 5-year graft survivals than from cadaver.(4,5,6,7) nowadays, kidney transplantation is more requested due to better hemodialysis status and higher esrd patients' survival. while cadaveric donation for transplantation is increasingly used preparing live donor for kidney donation in developed countries, the number of patients waiting for transplantation has risen in parallel. for instance, annual report of eurotransplant in 2000 revealed that only 3145 patients out of 12524 (25%) in the waiting list has received transplanted kidney of which 569 (18%) received from living donors.(8,9) also in the united states where they have a long-term established programme for cadaver transplantation, because of the increase in esrd patients waiting list, living donor transplantation has been increased and unrelated donors (spouse, friend, etc.), previously comprised 4.1% of the total living donors in 1988, have reached 14.2% in 1996.(5,8) at the moment, they serve as 20 to 27% of living donors for kidney transplantation in the united states.(9) moreover, since laparoscopic nephrectomy technique has been introduced with low postoperative complication rate, more people are encouraged to donate kidney.(4,10) discussion one of the most pivotal advantages of living donor transplantation, as well as providing programmed procedure in a desirable condition and at a proper time, is that long-term hemodialysis which is associated with the risk of rejection, particularly if frequent transfusion had been required, could be prevented.(11) consequently, some authorities prefer pre-emptive transplantation, specially in children and diabetic patients in whom dialysis leads to various medical problems.(5) does donation impact the donor's physical health condition? this is a frequently asked question by donation candidates. the answer is that short-term non-specific complications such as hemorrhage, infection, wound problems, and even death are inevitable as they are in any major surgical operation, but studies with long-term follow-ups have shown that 5year life expectancy of 35 year old donors is 99.1% which is not significantly different from that in general population (99.3%). also an eligible life quality has been reported in kidney donors.(12,13) does the removal of one kidney have unfavourable effects on the other kidney? studies on rats have revealed that eliminating one kidney causes hyperfilteration in the form of sclerosis progression and reduction of the spared kidney function.(14,15) whereas, 20-year follow-up of hundreds of donors and those who have lost one kidney due to urological problems, have shown that the solitary kidney has appropriate function till the end of life, besides a preliminary compensating hypertrophy,(12,13,16,17) so that the insurance companies consider kidney donors as normal individuals.(18) few studies have reported that in longterm after donation microalbuminuria and proteinuria increases the risk of hypertension to a little extent.(19) although living donation has a great advantage over cadaver donation, we should consider that the removal of a normal organ from a normal individual has its own risk of complications like any other major operation. hence, in order to reduce psychological and physical complications as far as possible, it is necessary to select and prepare the donors meticulously. here is a review of the stages of this process: psychological evaluation psychological assessments are necessary to confirm psychological stability of the donor, as the rate of depression, anxiety, and even suicide following the kidney donation is 1.5% or more.(20,21) these problems are often seen in the donors who were not completely contented with donation for any reason or in the cases of graft failure. consequently, it is recommended to continue psychological follow-up after the procedure. when the donor is a relative of the recipient, his/her consent should be confirmed to avoid obligatory donation. it is suggested that the donor's most intimate relatives such as parents and spouse be aware of the donation procedure. this is of utmost importance in countries such as iran in which most donors are not related to the recipient. donor's age a proper age is within the range of 18 to 60 years, but recent reports have shown that an exact age limit can't be defined, because biologic age plays a more decisive part than true age does. kanesmasu and coworkers presented the outcomes of transplantation from 518 over-60-year-old donors and they found that although graft survival in the first years was not meaningfully different from the control group (89% vs. 91%), serum creatinine level was higher even in the fist years and 4-year graft survival difference was more pro9 preparing live donor for kidney donation nounced (76% vs. 81%). they concluded that kidney donors older than 60 should be selected for older recipients.(22,23,24) abo blood group the donor's abo blood group should be matched with the recipient's. otherwise, irreversible graft rejection will occur in the presence of blood group incompatibility. rh factor does not impact the outcomes, so donor can be either rh positive or rh negative. in the countries in which they don't use unrelated donors, due to the limited number of donors, transplantation from the donors with a2 blood group (20% of people with a blood group) or b subgroups to the recipients with o blood group have been performed successfully. in such cases plasmapheresis precedes the procedure in order to eliminate anti-a and anti-b antibodies and to prevent acute rejection. in addition, by donor-specific skin grafting test they evaluate the preparation for transplant; any inflammatory reaction in the skin graft region predicts a poor prognosis for the kidney graft.(25,26) immunologic tests t-lymphocyte test is the first donor-recipient immunologic test to be done. in this test the reaction between the donor's lymphocytes and the recipient's serum is studied. when more than one properly matched donor is available, the one with completely negative t-lymphocyte test will be selected.(27) some centers consider mixed lymphocyte reaction test (mlr), but new immunosuppressive medications have disputed the value of this test and currently it is just useful to select the best donor from among the family members who all have hla compatibility with the recipient.(27) when there are a few serologic compatible donors in a family, hla tissue typing should be done to select the one who is hla identical. history taking and physical examination in the cases of chronic renal failure, due to autosomal polycystic kidney disease (adpkd), alport syndrome, hypertension, and diabetes, meticulous evaluation of the related donor is warranted. diagnostic criteria for adpkd have been identified; ravine (1994) suggested the number of cysts in each kidney of the patients with positive family history detected by ultrasonographic studies be used to classify the criteria: two cysts in one of the kidneys or both in patients under 30 years old, two cysts in each kidney of patients between 31 and 59, and four cysts in both kidneys of over-60s must be considered as adpdk.(27) it is also recommended to select related donors of over 30 to be able to identify the cysts by ct scan using rapid injection of contrast media and prevent transplantation of polycystic kidneys.(28,29) alport syndrome may present with microscopic hematuria and proteinuria in the family members and renal biopsy can provide the definite diagnosis if needed.(30) these patients should be excluded from the donors list. hypertension is often a hereditary transmitted disease and also, it is seen in 15 to 25% of the patients over 50 years old.(31) consequently, candidates for kidney donation should undergo blood pressure evaluation in three separate times and sometimes even 10 times.(17) a series of examinations have been recently recommended to be done in donors with borderline blood pressure including echocardiography, intima and media thickness measurement of carotid vessels, examination of retina, and urinary albumin concentration, all demonstrating the subsequent damage to the eye and kidneys.(17) furthermore, it has been proved that hypertension can be transmitted to the recipient by the transplanted kidney.(32) generally, patients with a blood pressure of 140/80 or more, with persistent diastolic pressure of over 90 mmhg, or who need medication to control the blood pressure are not appropriate candidates for donation and should be excluded.(32,33) diabetes mellitus type ii diabetes mellitus incidence is increasing nowadays; reports have shown that 6% of the people will have diabetes by the age of 50 and 20% by 70.(9,27) thus, evaluation of latent diabetes is very crucial. in addition, there are a few reports representing the development of latent diabetes to an apparent diabetes following nephrectomy that leads to diabetic nephropathy in the donor.(34) consequently, in some centers they evaluate related donors of a diabetic recipient by the measurement of hb a1c2 and anti-islet antibody as well as a 5-hour glucose tolerance test.(9) in some cases proteinuria should not be present in a 24-hour urine collection specimen and it is recommended the age of the donor to be at least 10 preparing live donor for kidney donation 10 years more than the age of the recipient at the time of diabetes onset. eventually, kidney donation must not be done in case of a positive glucose tolerance test.(9,34) obesity overweight more than 30% of the ideal body weight is a relative contraindication for donation and patients are recommended to lose weight before kidney transplantation science obesity may cause pulmonary emboli or cardiovascular complications as well as problematic nephrectomy.(8,27) a history of thromboembolism or thrombophlebitis increases the risk of pulmonary emboli in the donor, so that they had better be excluded.(15,27,33) paraclinical evaluations biochemical and serologic tests: complete blood count, coagulation tests, renal function tests (bun, creatinine, and creatinine clearance), liver function tests, serum cholesterol, calcium, and phosphorous, urine analysis and culture, 24-hour urine collection test, and serologic tests for viral infections should be requested for donors. the most common serologic tests are the ones for antiviral antibodies of cmv, hiv, hepatitis b, hepatitis c, htlv i, and htlv ii. hiv antibody: a positive hiv antibody is the absolute contraindication of transplantation. cmv antibody: cmv is one of the most prevalent post-transplant infections that can influence mortality, morbidity, and graft survival. it is also responsible for acute graft rejection. detecting igg antibody, using elisa, is necessary to indicate cmv infection. the risk of cmv disease must be assessed if cmv antibody is positive.(35) transplantation of a recipient with negative cmv igg from a cmv positive donor has a great risk of cmv disease in the recipient and may develop 4 to 5 weeks after the procedure. as a result, prophylactic ganciclovir is highly recommended.(9) hepatitis b and c: hepatitis is a frequent leading cause of chronic liver failure that may present with cirrhosis, liver failure, and liver cancer.(36,37) consequently, hbs-ag positive donors must be excluded from the transplant program, but donation from a hbs-ag negative but hbc-ab positive is possible since it has proved not to have any effect on the graft or morbidity and mortality at least in short-term, despite of its relative risk of hbv infection.(37) being anti-hcv positive is not an absolute contraindication for kidney donation, but interferon therapy is necessary before donation, because hepatitis b or c virus transmission is accompanied with difficulty to treatment as interferon rapidly increases rejection risk.(36) totally, kidney donation from a hepatitis c disease positive patient is not recommended if we presume a longterm survival.(36,37,38) htlv i: human lymphotrophic virus type i is the first known retrovirus in the human, spread worldwide. the most considerable epidemiologic characteristic of the infection is the existence of highly endemic areas such as iran, specially khorasan.(39) ten to 20% of individuals with htlv i infection will have htlv i associated diseases such as t cell leukemia of adults, myelopathy, uveitis, etc.(39,40) accordingly, anti htlv i test is a routine examination in kidney donors and in case of a positive result transplantation should be canceled if the recipient is anti-htlv i negative. radiological studies imaging studies are done when all the previously mentioned steps are passed without any problem. chest x-ray and renal ultrasonography are first to be performed. if ultrasonography showed no abnormality, a selective arteriography of the kidney with excretory phase could be requested. pyelocaliceal system is detectable in the excretory phase of the kidney, so that ivp is not necessary before angiography.(41) today, we can benefit from 3-dimensional or spiral ct scan in order to investigate detailed anatomy of the kidney. this method is more helpful in centers in which laparoscopic nephrectomy is performed.(9,42) catheter inserting into renal vessels is no more needed when using these new methods. however, it is note worthy that making final diagnosis of vascular lesions, particularly of small renal vessels such as unilateral fibromascular dysplasia is more attainable by angiography.(43) we can use digital subtraction angiography (dsa) rather than conventional angiography to avoid catheterization and its complications.(8,43) angiography can show the existence of one or more arteries for the kidney. it is obvious that a kidney with one artery is preferred. also, the left kidney is more desirable due to its longer vein. we can eliminate vascular lesion after nephrectomy if anomalies such as aneurism or fibromascular renal artery stricture, limited to the beginning of 11 preparing live donor for kidney donation the artery, is present. however, nephrectomy is just permitted only if the spared kidney of the donor is completely normal.(8,15,44) in our center, over a 12 year period, from among 715 donors, there were 26 cases with two renal arteries and 2 cases with 3 arteries. only 7 of 26 cases with two renal arteries were unrelated donors. in young female donors in whom pregnancy is anticipated in the future, right kidney should be selected for nephrectomy since obstructive uropathy due to pregnancy often occurs in the right kidney. as a rule in live donor nephrectomy, the more intact kidney is preserved for the donor. this rule must be considered in all cases. relative and absolute contraindications of kidney donation, extracted from european association of urologists' (eau) 2003 guidelines, are shown in tables 1 and 2. as kidney transplantation is a team work and a team consisting of nephrologist, urologist, anesthesiologist, paraclinics expert, nurses, and operation room group intervene in the procedure, according to our experience, it is suggested that the completed examinations and laboratory results of both donor and recipient may be evaluated in a session by all the team members and controversial items may reassessed to arrive at the operation decision. when all the criteria for donation to a definite recipient are achieved, the donor will be admitted a night before the operation and hydration with a saline or dextrose-saline serum can be initiated in order to preserve ample diuresis during the operation. the anesthesiologist is proposed to visit the donor before the procedure and skilled nurses should educate the patient to prevent post-operative atelectasis and thromboembolic complications. after the anesthesia is brought off and before the skin incision, an intravenous injection of a first or second generation of cephalosporines (1gr) is suggested. finally, it is strongly recommended that shaving to be done in the operation room.(27) references 1. kusse r, bourget p. an illustrated history of organ transplantation: the great adventure of the century. france: rueil-malmaison, sandoz, 1992. 2. freeman rb. treatment of chronic renal failure on update. n eng j med 1985; 312: 577. 3. brener bm, meyer tw, et al. dietary protein intake and the progressive nature of kidney disease the role of hemodynamically mediated glomerular injury in the pathogenesis of glomerular sclerosis in aging renal ablation and intrinsic renal disease. n eng j med 1989; 307: 652. 4. altani d, pretagostini r, rossi m, et al. living unrelated kidney transplantation. a 12 years single center experience. transplant proc 1997; 29(1-2): 191-194. 5. briggs jd. the recipient of a renal transplant in: kidney transplant principle and practice. 5th ed. w.b. saunders; 2001. p. 45-58. 6. cecku jm. the unos scientific renal transplantation registry. clinic transplant 1998; 1-16. 7. terasaki pi, cecka jm, et al. high survival rates of kidney transplant from spousal and living unrelated donors. n engl j med 1995; 333: 333. 8. cosimi ab, ko sd. the donor and donor nephrectomy. in: morris pj, editor. kidney transplantation. 5th ed. w.b. saunders; 2001. p. 89-105. 9. kalbe t, fulda g, benort m, et al. guidelines on renal transplantation. european urology 2003; 16: 7-9. 10. ranter le, montogery ra, kavossi lr. laparoscopic live donor nephrectomy: a review of the first live years. urologic clinic of na; 28 (4): 709-720. 11. nerurkar vr, achiron a, song kj, et al. human t-cell lymphotropic virus type i in iranian born mashhad jeus: genetic and phylogenetic evidence for common source of infection. j med virol 1995; 45: 361-6. 12. johnson em, remucal mj, et al. complications and risks of living donor nephrectomy. transplantation 1997; 64: 1124. 13. nagarian js, chaver sbm, mchugh l, matus aj. 20 years or more of follow up of living kidney donors. lancet 1992: 1354-1355. 12 table 1. contraindications for kidney donation (eau guideline, february 2003 renal transplantation) absolute contraindications age under 18 hypertension (more than 140/90, requiring medical therapy) diabetes (impaired gtt or hb a1c) proteinuria more than 300 mg/24h microscopic hematuria history of thrombosis or thromboembolism significant underlying disease (chronic pulmonary disease, malignant tumors, cardiovascular disease) history of renal calculus relative contraindications donated kidney anomaly (urologic or vascular) obesity ( 30% more than the ideal body weight) psychological disorders table 2. factors indicating that the donor is not a good candidate for kidney donation (eau guideline, february 2003 renal transplantation) decreased gfr which is abnormal for the donor’s age proteinuria more than 300 mg/24h microhematuria unless urologic and renal evaluations are normal multiple renal calculi polycystic kidney three or more renal arteries family history of adpkd except the cases over 30 years old in which ultrasonography or ct scan results are normal fibromascular dysplasia of both renal arteries preparing live donor for kidney donation 14. brener bm, meyer tw, et al. dietary protein intake and the progressive nature of kidney disease the role of hemodynamically mediated glomerular injury in the pathogenesis of glomerular sclerosis in aging renal ablation and intrinsic renal disease. n eng j med 1989; 307: 652. 15. durog f, tylen g, blow b. living-donor nephrectomy how safe is it: transplant pro 1995; 27: 803-804. 16. fehrman ei, duner f, brink b, et al. no evidence of accelerated loss of kidney function in living kidney donors, results from a cross-sectional follow up. transplantation 2001; 72: 444-449. 17. sommerer c, wiesel m, schweitzer j, et al. the living kidney donor: giving life. avoiding harm nephrology. dialysis transplantation 2003; 18: 23-26. 18. spital a. life insurance for kidney donors an update transplantation 1998; 45: 819. 19. horner d, fliser d, klimm hp, ritz e. albuminuria in normotensive and hypertensive individuals attending offices of general practitioners. j hepertens 1996; 14: 655. 20. fehrman ekholm i, brink b, ericsson c, elinder cg, et al. kidney donors don't regret transplantation. 2000; 69: 2067-2071. 21. taghavi r, mahdavi r. the psychological effects of kidney donation on living kidney donor. transplantation proc 2001; 33 (5): 2636-2637. 22. beckurts ut, strippel d, pollok m. single center experience with old to old program for renal transplantation. transplant proc 2001; 33: 3779-3780. 23. kanematsu a, tanabek, ischikawa n, et al. impact of donor age on long-term graft survival in living kidney transplantation. transplant proc 1998; 30: 3118-3119. 24. modlin cs, goldforb da, novick ac. the use of expanded criteria cadaver and living donor kidneys for transplantation. urologic clinics of north american 2001; 28(4). 25. karakayali h, moray g, demirag a, et al. long term follow up of abo-incompatible renal transplant recipients. transplant proc 1999; 31: 250-257. 26. toma, tanabe k, todumoto t. long term outcome of aboincompatible renal transplantation. urologic clinic of northamerican 2001; 28 (4). 27. scant leubury v. cadaveric and living donatation. in: ron s, editor. renal transplantation. 4th ed. appleton and lange; 2001. p. 73-94. 28. ravin d, gibson rn, walker rg, et al. evaluation of ultrasonographic for adpkd. lancet 1994; 343: 824. 29. dementrion k, tziakowic, anninouk, et al. autosomal dominant poly cystic kidney disease type 2. ultrasound, genetic and clinical correlations. nephrol dial transplant 2000; 15: 205-211. 30. pirson y. making the diagnosis of alport's syndrom. kidney int 1999; 56: 760-775. 31. cusse c, hense hw, stieberg doring a, liese ao, et al. assessing hypertension management in the community trend of prevalence, detection, treatment and control of hypertension in the monica project augsburg 1984-1995. j humhypertens 2001; 15: 27. 32. curtis jj, luke rg, dusten hp, et al. remission of essential hypertension after renal transplantation. n eng j med 1983; 309: 1009-1015. 33. bia mg, ramos fl, danovitch gm, et al. evaluation of living donors: the current practice of u.s. transplant centers. transplantation 1995; 60: 322-327. 34. timmors d, searle m. risk of diabetic nephropathy in potential living related living donors. bmj. 1998; 316: 846848. 35. lowance d, neumayer hh, legendre cm, et al. valocydovir for the prevention of cytomegalovirus disease after renal transplantation. international prophylaxis transplantation study group. n eng j med 1999; 340: 14621470. 36. otero j, rodrigues m, escudero o, et al. kidney transplants with positive antihepatitis c virus donors. transplantation 1990; 50: 1086-1087. 37. sutterth waite r, ozgu i, shidgan h, et al. risk of transplantation kidneys from hepatitis b surface antibody positive donor transplantation. 1997; 64: 432-435. 38. karpinski j, lajoie g, cattran d, fenton s, zatzman j, et al. outcome of kidney transplantation from high-risk donors is determined by both structure and function. transplantation 1999; 67: 1162-1167. 39. faridhosseini r, pishnamaz m. htlv1-infection and associated diseases. mums 2002; 45 (76). 40. safai b, huang jk, et al. prevalence of htlv-i infection in iran: serologic and genetic study. aid research and hur; 12: 1185-1190. 41. spring db, salvutierru oj, plaubinskas aj, et al. results and significance of angiography in potential kidney donors. radiology 1979; 133: 45-47. 42. lucan m, rotariu p, jacob g, cohervun l. technical aspects in retroperitoneoscopic harvesting. the kidney, abdominal organ transplantation from living donors: state of the art. hybern 2002; 85 [abstract volume]: 21-23. 43. davidson ra, wilcox cs. newer tests for the diagnosis of renovascular disease. jama 1992; 268: 3353-3358. 44. cragg ah, smith tp, thompson bh, et al. incidental fibromuscular dysplasia in potential renal donors: long-term clinical follow up. radiology 1989; 172: 145-147. 13 case report a nonspecific penile ulcer leading to the diagnosis of wegener’s granulomatosis hassan ahmadnia*, amin hasanzadeh haddad, mohammadreza darabimahboub, ali akhavan, alireza akhavan rezayat faculty of medicine, mashhad university of medical sciences, mashhad,iran. *correspondence: prof. of urology, faculty of medicine, mashhad university of medical sciences, mashhad,iran. e-mail:ahmadnia2001@yahoo.com. received april 2018 & accepted july 2018 the presented case describes a 53-year-old male who had been treated for non-specific cutaneous lesions for two months without any improvement. he was referred to our department after developing an erosive penile ulcer. investigation for sexually transmitted diseases and mycobacterium tuberculosis ended with negative results. penile ulcer biopsy suggested the diagnosis of wegener’s granulomatosis (wg). the patient presented with upper respiratory tract symptoms during this period. measuring antineutrophil cytoplasmic antibodies (c-anca), confirmed the diagnosis. immunosuppressive therapy was initiated and resulted in a favorable response. keywords: antineutrophil cytoplasmic antibodies; penile ulcer; wegener's granulomatosis introduction wegener’s granulomatosis is characterized by a necrotizing granulomatous vasculitis of the upper and low-er respiratory tracts accompanied by glomerulonephritis. presentation is usually with symptoms of upper respiratory tract involvement(1). dermatologic manifestations are common and a broad range of skin lesions have been described(2). urogenital involvement is a rare incidence. ulcerative lesions of the nonkeratinized epithelium of the glans of penis and corona are uncommon and a very few number of cases have been reported(3). the present case concerns a patient with a nonspecific erosive penile ulcer and cutaneous lesions in which penile biopsy and assessing c-anca level helped us to establish the correct diagnosis and administer the appropriate treatment. case report a 53-year-old man was referred to our department for a recent appearance of a penile ulcer. he had earlier noted pruritic cutaneous lesions on his body and extremities. topical and oral antibiotics had been administered to him by an outpatient clinic. the lesions were refractory to treatment. about a week before presentation the patient developed a penile ulcer. the patient had a history of coronary artery bypass surgery and nasal polyp removal five and ten years ago, respecfigure 1. erosive penile ulcer. urology journal/vol 17 no. 2/ march-april 2020/ pp. 210-212. [doi: 10.22037/uj.v0i0.4526] tively. he also mentioned a chronic rhinitis with relapsing episodes in cold months. he emphasized that the symptoms including nasal congestion and rhinorrhea had been worsening since the beginning of the cutaneous lesions. there was no complaint of general malaise nor weight loss. no respiratory or gastrointestinal was mentioned. on physical examination some well circumscribed pruritic, depressed lesions on the anterior wall of the chest and abdomen as well as on the back of his hands and on his ankles with a maximum size of 2 centimeters were noted. there was a tender, erosive ulcer on the dorsal aspect of the coronal sulcus, extending to the edge of glans (figure 1). inspection of nasal mucosa showed some degree of edema and erythema. complete physical examination was otherwise normal. history was negative for unsafe intercourse and serological and microbiological investigations did not show positive results for sexually transmitted infections. wound cultures for gram positive and gram negative and anaerobic microorganisms were negative either. a wound sample was sent for mycobacterium tuberculosis dna-pcr which did not yield positive results. acute phase inflammatory markers (esr and crp) were not elevated. renal and liver function test, blood cell count and serum albumin were all within the normal limits. urine analysis was negative for leukocyturia, hematuria and proteinuria. chest x-ray also showed normal results. biopsy from the penile ulcer was performed and while waiting for the results, patient’s condition turned worsen by the sudden onset of epistaxis, headache and anorexia. on examination crusted mucosal ulcer on both sides of nasal septum was detected. histopathological examination of penile ulcer biopsy indicated vasculitis with endothelial edema and infiltration of neutrophils. scatters of giant cells were also present in vascular wall. the findings were suggested to be compatible with wegener’s granulomatosis (wg). in order to confirm the pathology report, antineutrophilic cytoplasmic antibodies (c-anca) was checked which was positive to the level of 96.14 ru/ml (positive: > 20 ru/ml). the patient was treated with methotrexate and prednisone which resulted in the improvement of the cutaneous and penile ulcers after 2 months. prednisone was maintained for another six months, then it was gradually tapered to a minimum maintenance dose. six months after the biopsy, penile lesion was completely healed. discussion wg is a necrotizing vasculitis disease which in most cases affects upper and lower respiratory tract associated with renal involvement(4). the incidence ranges from 3 to 9.7 cases per million/year. the disease is more prevalent in the caucasian population and the average age of involvement is about 40 years(5). it is usually described in two subcategories: general or systemic form and localized or limited form(6,7). the current consensus is that limited disease, in contrast to systemic one, includes manifestations of wg that poses no immediate threat to either the patient’s life or the function of a vital organs(8). the usual onset of wg is associated with progressive necrosis in upper and lower respiratory tracts. subsequently the disease spreads through the body and targets different organs producing a variety of symptoms(9). although any organ can be affected, only a few reports about urogenital manifestation in organs such as prostate, seminal vesicles, testis, bladder, and penis have been reported(10). penile involvement is a very rare presentation in wg. cases in which an isolated unspecific erosive penile lesion is the only symptom of wg have been reported in only 5 patients so far(2). in the present case, penile ulcer appeared at a short interval after the cutaneous lesions. dermatologic manifestations have been described in 50% of cases of wg. mostly, palpable purpura is the reported lesion(4). when dermatological lesions are the only presentation, determining the correct diagnosis may become somehow difficult. that is because histologic examination does not always correlate with the pathognomonic findings of wg which include leukocytoclastic vasculitis of small and medium size vessels alongside necrotizing granuloma(11). al rajabi and colleagues(2) reported a patient with a penile lesion in glans of penis for four months before the breakthrough of upper respiratory tract symptoms which led to taking a biopsy from the lesion and diagnosis of wg. meanwhile, he had been treated with topical steroids and antibiotics without any improvement. a biopsy from the penile lesion led them to the diagnosis of wg. our case also follows the same course. the patient was treated with empiric treatment for the skin lesions till the appearance of the penile ulcer. the penile biopsy was the key factor for the right diagnosis. davenport and colleagues(12) reported 8 cases of wg involving urogenital tract. six of the cases were of the limited form. one of the patients with the diagnosis of limited wg in urethra and penis had been treated with repeated urethral dilations for a long time before developing a systemic illness after 7 years. many studies emphasize the value of autoimmune investigations for the diagnosis of wg. when c–ancas is present in the blood of a patient whose symptoms or signs suggest wg, the likelihood of the diagnosis increases considerably. in most cases, however, it is still very important to biopsy an involved organ to verify the diagnosis. monitoring of these antibodies can be helpful in both the diagnosis and assessment of disease activity(13). bories et al.(4) reported a 50-year-old man with a 3 month history of penile ulcer. penile lesion biopsy was performed and the results showed a perivascular and inflammatory dermal infiltrate containing a majority of polynuclear neutrophils with some multinucleated histiocytes. the findings were compatible with an infectious disease or a neutrophilic dermatosis. the diagnosis of pyoderma gangrenosum was established for him and treatment with topical tacrolimus had some favorable results. 15 months later the ulcer relapsed. this time autoimmune assessment revealed elevated c-anca, suggesting the diagnosis of wg. matsuda and colleagues(9) reported a 37 year old male with a sudden onset of penile swelling and progression to necrosis which led to complete penile loss. histopathologic examination and investigating c -anca levels confirmed the diagnosis of wg. they described it as a progressive disease, refractory to different kinds of immunosuppressive regimens. subsequent pulmonary and gastric bleedings resulted to patient’s death. treatment strategy depends on the severity of the disease(14). severe disease requires immediate adminiscase report 413 a nonspecific penile ulcer-ahmadnia et al. vol 17 no 02 march-april 2020 211 tration of an aggressive therapeutic regimen which includes cyclophosphamide and glucocorticoids. on the other hand the limited form usually responds to a less toxic treatment such as methotrexate or rituximab and glucocorticoids(8). mucocutaneous lesions may be an early sign and there are reports that active generalized disease can be delayed for a long period of time(14). our patient showed a short time gap of only two months between the appearance of cutaneous lesions and upper respiratory tract symptoms. penile biopsy and assessment of c-anca helped to determine a correct diagnosis. the limited form of the disease was suggested and treatment with methotrexate and prednisone resulted in remission of the disease. conclusions our patient seems to be a rare case of wg presenting with cutaneous lesions followed by an erosive penile ulcer. taking medical history and performing routine laboratory studies were not very helpful to find the main cause of manifestation. a histologic examination of the ulcer was the key factor to narrow the list of different diagnosis. the elevated level of c-anca confirmed wg. administration of immunosuppressive therapeutic regimens was successful and led to remission of the disease. conflict of interest the authors report no conflict of interest. references 1. vella ej, waller dg. granulomatous vasculitis of the penis with glomerulonephritis. postgrad med j. 1981;57:262-4. 2. al rajabi w, venturini m, sala r, calzavarapinton p. wegener's granulomatosis of the penis: genital presentation of systemic disease. dermatology. 2006;212:370-2. 3. stucker f, masouye i, toutous-trellu l. fever and penis ulcer in an 87-year-old man. dermatology. 2006;212:397-8. 4. bories n, becuwe c, marcilly mc, wolf f, balme b, thomas l. glans penis ulceration revealing wegener's granulomatosis. dermatology. 2007;214:187-9. 5. gomes gl, halpern as, souza fh, shinjo sk. association between saddle nose deformity and retro-orbital mass in wegener's granulomatosis. acta reumatol port. 2010;35:340-5. 6. jayne d. update on the european vasculitis study group trials. curr opin rheumatol. 2001;13:48-55. 7. stegeman ca, boomsma mm, tervaert jwc. trimethoprim-sulfamethoxazole monotherapy for active loco-regional or limited wegener's granulomatosis. anca associated vasculitis: occurrence, prediction, prevention, and outcome of relapses. 2001107. 8. stone jh. limited versus severe wegener's granulomatosis: baseline data on patients in the wegener's granulomatosis etanercept trial. arthritis rheum. 2003;48:2299-309. 9. matsuda s, mitsukawa s, ishii n, shirai m. a case of wegener's granulomatosis with necrosis of the penis. tohoku j exp med. 1976;118:145-51. 10. takeuchi h, kuroda i, takizawa i, aoyagi t, tachibana m. granulomatosis with polyangiitis (wagner’s granulomatosis) accompanied by dysuria. case rep urol. 2016;2016:3. 11. francès c, du l, piette j, et al. wagner’s granulomatosis: dermatological manifestations in 75 cases with clinicopathologic correlation. arch dermatol. 1994;130:861-7. 12. davenport a, downey se, goel s, maciver ag. wegener's granulomatosis involving the urogenital tract. br j urol. 1996;78:354-7. 13. geffriaud-ricouard c, noel lh, chauveau d, houhou s, grunfeld jp, lesavre p. clinical spectrum associated with anca of defined antigen specificities in 98 selected patients. clin nephrol. 1993;39:125-36. 14. lutalo pm, d'cruz dp. diagnosis and classification of granulomatosis with polyangiitis (aka wegener's granulomatosis). j autoimmun. 2014;48-49:94-8. a nonspecific penile ulcer-ahmadnia et al. case report 212 miscellaneous comparing monotherapy with tadalafil or tamsulosin and their combination therapy in men with benign prostatic hyperplasia: a randomized clinical trial hossein karami*, amin hassanzadeh-hadad, morteza fallah-karkan purpose: to compare monotherapy with tadalafil or tamsulosin and their combination therapy in men with benign prostatic hyperplasia and erectile dysfunction by comparing ipss score, prostate volume and qmax and some other outcomes. materials and methods: this randomized, single-blind, paralleled group clinical trial was done in 2013 on patients who had referred to our hospital in tehran. all patients with lower urinary tract symptoms, benign prostatic hyperplasia and any grade of erectile dysfunction were recruited. they were randomly divided into three groups (61 participants in each group): group a received 20 mg/daily tadalafil; group b received 0.4 mg/daily tamsulosin; group c receieved a combination of 0.4 mg/daily tamsulosin and 20 mg/daily tadalafil. primary outcomes were prostate volume, prostate specific antigen, post-void residual volume, ipss score, luts severity, qmax, iief and erectile dysfunction severity and secondary outcome was complications. results: the mean ± sd of ultrasonographic prostate volume was 61.4 ± 15.1 ml and prostate specific antigen level was 2.4 ± 1.9 ng/dl. post-void residual level was significantly different before and after the treatment, except for group a. also, this group had no meaningful difference compared to the other groups in this regard (p > 0.05). there were significant differences between preand post-treatment international prostate symptom scores in each group (p < 0.05). conclusion: combination of tamsulosin and tadalafil can improve international prostate symptom scores, international index of erectile function questionnaire scores and qmax in patients with lower urinary tract symptoms and benign prostatic hyperplasia to more degrees than their separate use. this combination is recommended because of its synergistic effects, well toleration and safety. keywords: benign prostate hyperplasia; erectile dysfunction; tadalafil; tamsulosin introduction a major difficulty in comparing the prevalence of lower urinary tract symptoms (luts) among different groups is lack of a common definition. luts because of benign prostate hyperplasia (bph-luts) often interferes with patients’ daily activities. many men with benign prostate hyperplasia luts seek treatment to improve their quality of life. research on luts in men has traditionally focused on the development and testing of treatments for progressive disease.(1) benign prostate hyperplasia is a histological diagnosis which is identified by nonmalignant hyperplasia of prostatic tissue due to smooth muscle and epithelial cell proliferation in the prostate transition zone.(2) the prevalence of histologically diagnosed prostatic hyperplasia increases from 8% in men aged 31 to 40 years old to 40-50% in men aged 51 to 60 years old. this increases to over 80% in men older than 80 years old.(3) benign prostate hyperplasia can result in prostate enlargement. this leads to the development of luts such as storage, voiding and post-micturition symptoms. an increased smooth muscle tone in the prostate or the vasculature supporting the lower urinary laser application in medical sciences research center, shohadaye tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: laser application in medical sciences research center, shohadaye tajrish hospital, tajrish sq, tehran, iran postal code: 1989934148 tel: +98 21 22736386. fax: +98 21 22736386. mobile: +98 912 1142080. email: karami_hosein@yahoo.com. received august 2016 & accepted november 2016 tract may play a contributing role.(4) luts has no common definition. a large population-based study found the prevalence of moderate or severe luts for men in the fifth, sixth, seventh, and eighth decades of life to be 26%, 33%, 41%, and 46%, respectively.(5) bph-luts are common in aging men worldwide.(6) given that bph-luts often interferes with daily activities,(7) many men with bph-luts seek treatment to improve their quality of life.(8) when pharmacological treatment is required, the most common drugs are a-blockers and 5-alpha reductase inhibitors (5aris). the five extensively available alpha-blockers are doxazosin, terazosin, tamsulosin, alfuzosin and silodosin, the last one being the only one that is a1a adrenoreceptor specific. as for 5aris, two drugs are available, finasteride and dutasteride. in addition, combining these two classes of drugs has been shown to be more effective in bph-luts than using each separately.(9) tadalafil's mechanism as a long-acting phosphodiesterase 5 (pde5) inhibitor in the treatment of men with bph-luts is associated with increased activity of the nitric oxide/cgmp (cyclic guanosine monophosphate)/ miscellaneous 2920 protein kinase g pathway via pde5 isoenzymes’ inhibition in different lower urinary tract tissues. these re sults can be detected in smooth muscle relaxation in the bladder, urethra, prostate, and supporting vasculature, increased blood perfusion to the pelvic area, and finally modulation of sensory stimuli from this area.(10-12) epidemiological and pathophysiological links have been found between bph-luts and erectile dysfunction.(7,10) although the current medical therapy for bphluts is effective, it has potential side-effects on sexual function.(13) moreover, pde5i increases the concentration and activity of intracellular cgmp, thus reducing smooth muscle tone of the detrusor, prostate and urethra.(14) it is believed that these mechanisms may help to treat bph-luts. this clinical trial has compared monotherapy with tadalafil or tamsulosin and their combination therapy by comparing ipss score, luts severity, iief score and some other measurements in men with benign prostatic hyperplasia and erectile dysfunction. materials and methods this randomised, single-blind, paralleled group clinical trial was done in 2013 on patients who had referred to the urology clinic of shohadaye tajrish hospital in tehran. all patients with luts, benign prostate hyperplasia and any grade of erectile dysfunction were recruited for this study. inclusion and exclusion criteria we assessed patients with these inclusion criteria: men older than 45 years old, international prostate symptom score (ipss) ≥ 12, and having a history of erectile dysfunction. patients with previous benign prostate hyperplasia or erectile dysfunction treatment, history of surgical procedure for their prostatic problem, contraindication for tadalafil (i.e. nitrate consumption) or tamsulosin (i.e. allergic reactions), bladder stone, history of urinary retention, active urinary tract infection, prostate cancer, post-void residual urine test > 200 ml, kidney failure, liver insuficiency, history of pelvic radiation, urethral stricture, ureteral stone in past six months before entering the study, overt hematuria, consumption of finastridie, anti-depressent drugs and beta-adrener table 1. demographics of the participants characteristics group a group b group c p value number of participants 60 59 58 age, years (mean ± sd) 68.2 ± 7.8 68.5±8.9 67.9 ± 8.8 .90 bmi, kg/m2 (mean± sd) 27.4 ± 1.2 26.7±2.4 27.1 ± 2.3 .17 tadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. vol 13 no 06 november-december 2016 2921 characteristics group a group b group c p value prostate volume, ml (mean ±sd) 59.6±14.1 61.1±16.1 63.2±12.1 0.46 psa, ng/ml (mean±sd) 2.5±1.8 2.3±1.9 2.1±1.6 0.51 pvr volume, ml (mean ±sd) 61.6±63.3 57.2±59.7 58.6±60.2 0.78 ipss (mean ±sd) total ipss 19.9±6.3 20.6±7.3 21.2±7.5 0.63 ipss voiding 14.6±4.0 14.2±4.5 14.9±4.1 0.42 ipss storage 5.8±2.1 6.5±2.7 6.6±3.2 0.19 ipss qol index 3.9±1.3 3.9±1.2 4.1±1.2 0.27 luts severity, n (%) 0.34 moderate 48 (80) 45 (76.2) 44 (75.8) sever 12 (20) 14 (23.8) 14 (24.2) qmax, ml/s (mean ±sd) 12.6±5.4 12.3±3.8 12.4±4.8 0.33 iief (mean±sd) 10.1±1.8 10.9±1.6 10.6±1.7 0.08 erectile dysfunction severity, n (%) mild 18 (30) 18 (30.5) 16 (27.6) 0.29 moderate 33 (55) 31 (52.5) 32 (55.1) severe 9 (15) 10 (17) 10 (17.3) table 2. distribution of clinical, laboratory and functional characteristics of the participants before treatment psa, ng/ml (mean ± sd) before 2.5±1.8 2.3±1.9 2.1±1.6 0.58 3 month follow-up 2.5±1.7 2.2 ± 2.0 2.1±1.5 0.37 p value ns ns ns change 0.0 ± 0.1 0.0 ± 0.3 0.0 ± 0.2 ns pvr, ml (mean ± sd) before 61.6 ± 63.3 57.2±59.7 58.6 ± 60.2 0.74 3 month follow-up 49.8 ± 25.9 38.9±21.6 35.4 ± 20.9 0.06 p value 0.06 0.0009 0.0001 change -11.9 ± 37.1 -19.1±36.2 -23.4 ± 40.1 0.32 ipss total (mean ± sd) before 19.9 ± 6.3 20.6±7.3 21.2 ± 7.5 0.52 3 month follow-up 11.4 ±3.6 10.6±3.5 10.1 ± 3.2 0.22 p value 0.0001 0.0001 0.0001 change -8.6 ± 2.8 -10.1 ± 3.9 -11.1 ± 4.4 0.01 ipss storage (mean ± sd) before 5.8 ± 2.1 6.5 ± 2.7 6.6 ± 3.2 0.36 3 month follow-up 3.7 ± 1.9 3.6 ± 1.8 3.4 ± 2.1 0.54 p value 0.0001 0.0001 0.0001 change -2.1±1.2 -2.9 ± 1.1 -3.3 ± 1.0 0.0004 ipss voiding (mean ± sd) before 14.6 ± 4.0 14.2 ± 4.5 14.9 ± 4.1 0.49 3 month follow-up 7.6 ± 2.5 7.1 ± 1.7 6.9±1.5 0.18 p value 0.0001 0.0001 0.0001 change -7.1 ± 1.3 -7.1± 2.7 8.0±2.5 0.03 qmax, ml/s (mean±sd) before 12.6 ± 5.4 12.3 ± 3.8 12.4 ± 4.8 0.78 3 month follow-up 13.9 ± 4.4 15.6 ± 3.1 15.9 ± 2.1 0.001 p value 0.06 0.0001 0.0001 change 1.5 ± 1.5 3.3 ± 2.1 3.5±2.7 0.0002 iief (mean ± sd) before 10.1 ± 1.8 10.9 ± 1.6 10.6 ± 1.7 0.09 3 month follow-up 17.7 ± 2.3 12.1± 5.1 17.2 ± 3.2 0.0001 p value 0.0001 0.06 0.0001 change 7.8 ± 1.7 4.6 ± 2.1 7.6 ± 1.9 0.0001 table 3. comparison of functional tests and their changes before treatment and in follow up sessions in the three studied groups tadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. miscellaneous 2922 gic blockers and history of substance addiction were excluded from the study. randomization a number of 200 patients with luts were candidates to particpate in this study. seventeen patients were excluded for not having the inclusion criteria and not consenting to participate. so, 183 participants were randomly divided into three groups with a sample randomization chart (61 participants in each group): group a received 20 mg/daily tadalafil; group b received 0.4 mg/daily tamsulosin; group c receieved a combination of 0.4 mg/daily tamsulosin and 20 mg/daily tadalafil. two patients of group b, one of group a and three of group c were lost in the follow-up process because of discontining their drugs. so, 59 participants in group b, 60 participants in group a and 58 participants in group c were evaluated until the end of follow-up. (figure 1) the participants’ medical history and drug use were taken at the fisrt visit. then complete systemic and rectal examination of prostate was done. laboratary blood samples were taken to measure blood urea nitrogen, creatinine and prostate specific antigen. urine analysis was done as well. ultrasound of kidneys and bladder including determining residual urine volume and uroflometric test were done for each patients. we also completed the ipss and international index of erectile function (iief) questionnaire for the participants. we repeated these assessments three months after the first visit and compared the three study groups’ ipss, qmax and post-void residual results. statistical analysis the data analysis was performed with the statistical package for social sciences (spss) software version 19 (chicago, il, usa). descriptive statistics (mean ± standard deviation) and student t-test were used show and analyze the quantitative outcomes. the qualitative data were presented with frequency and percentage and their analysis was done with chi-square test and fisher’s exact test. correlational analysis was done by pearson or spearman correlation coefficients. we used one-way anova test for comparison of indexes between groups. p-value less than 0.05 was considered significant. ethics all participants signed an informed consent and benefits and complications were explained to them before entering the study. the study protocol was approved by ethics committee of shahid beheshti university of medical sciences. results the participants’ mean age was 68.40 ± 8.80 years and the mean time of symptoms’ existence was 4.8 ± 12.6 months. the mean ± sd of body mass index mean was 27.1 ± 2.3 kg/m2. (table 1) the mean±sd of ultrasonographic prostate volume was 61.4 ± 15.1 ml and prostate specific antigen level was 2.4 ± 1.9 ng/dl. the mean of prostate functional scores were 59.4 ± 61.3 for post-void residual level based on trans-abdominal ultrasound, 12.5 ± 4.8 for qmax and 20.6 ± 7.8 for ipss in all patients. 137 participants had moderate and 40 participants had severe ipss scores. mild, moderate and severe erectile dysfunctions were seen in 52, 96 and 29 participants, respectively (table 2). there were no significant differences between prostate volume, prostate specific antigen, post-void residual volume, ipss score (also in its three components; voiding, storage, quality of life indexes), luts severity, qmax, iief and erectile dysfunction severity between the three groups (p > 0.05). there was no significant difference in prostate specific antigen before and after the treatment in all groups and figure 1: flow chart of study design; group a: patients received only tadalafil, group b: patients received only tamsulosin, group c: patients received both tadalafil and tamsulosin tadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. vol 13 no 06 november-december 2016 2923 complications group a group b group c total myalgia, n (%) 3 (5) 0 (0) 4 (6.7) 7 (3.9) headache, n (%) 3 (5) 1 (1.6) 3 (5) 7 (3.9) back pain, n (%) 4 (6.6) 1 (1.6) 3 (5) 8 (4.5) nasopharyngitis, n (%) 2 (3.3) 1 (1.6) 3 (5) 6 (3.3) dizziness, n (%) 1 (1.6) 2 (3.3) 2 (3.3) 5 (2.8) discontinuation because of an ae, n (%) 1 (1.6) 2 (3.3) 3 (5) 7 (3.9) total, n (%) 14 (23.3) 7 (11.8) 18 (31.03) 39 (22.03) table 4. drug complications in the three studied groups between them (p > 0.05). post-void residual level was significantly different before and after the treatment, except for group a. also, this group had no meaningful difference compared to the other groups in this regard (p > 0.05). there were significant differences between preand post-treatment ipss in each group (p < 0.05) (table 3). complications the most frequent complications in all of participants were back pain (4.5%) and myalgia, headache and discontinuation because of adverse side-effects (3.9% for each). despite of higher complication rate in group c, there was no significant difference between the three groups in this regard (table 4). discussion both erectile dysfunction and bph-luts are common in men and their prevalence increases with aging.(15-17) several studies have studied the efficacy of monotherapy with tadalafil(8,18-23) and tamsulosin.(24-26) also, there are studies on their combination with other drugs or comparing them with each other. (27-29) however, to our knowledge no study has evaluated the effect of each of these drugs with their combination. also, there was no study with these drugs in an iranian population. in our study we found out that increase of weight is a risk factor for benign prostate hyperplasia. the mean of body mass index was 27.1 ± 2.3 kg/m2 in our study. our analyses explored the relationships between total ipss and storage and voiding sub-scores of the ipss, before the treatment and at the end of follow up (after 3 months). these relationships have not been studied in detail before. it is now well recognized that storage luts are the most troublesome for symptomatic patients. however, algorithms for the management of patients with predominantly storage luts or predominantly voiding luts offer generic guidance to clinicians with respect to the relative proportions of storage to voiding luts and their severity. this reflects the lack of published information on this subject. we can emphasize the importance of our analysis, which offers reassurance that the ipss storage and voiding sub-scores maintain a tight, fixed ratio to each other similar to chapple and colleagues’ results.(12) however, we did new comparisons of our three groups unlike them. although this could be predicted from the ipss design and by bearing in mind that only three of the seven questions in the ipss consider storage symptoms, it is important to emphasize that separate analysis of ipss storage and voiding sub-scores is not validated. (30) in other monotherapy studies with these drugs, the ipss results are in line with our results. double-blind, randomized, placebo-controlled studies of 5 mg tadalafil once-daily in japanese men,(19) japanese, korean and taiwanese men,(8) and japanese and korean men(20) has demonstrated greater improvement in the change from baseline to endpoint in total ipss for monotherapy with 5 mg tadalafil compared to placebo. these improvements were significantly greater in two of these studies (p < 0.05),(8,20) whereas in the third study(19) the magnitude of symptom improvement (ipss) was only greater numerically (p = 0.062). although these results are consistent with our outcomes, ipss improvement in our study was greater and this is related to combination therapy of tadalafil/α-blocker treatment. still, there is no large, double-blind, placebo-controlled study on the efficacy of tadalafil/α-blocker combination therapy. there are just several small sampled clinical trials that have reported tadalafil/α-blocker combination therapy may have better effect on total ipss than α-blocker(28,29,31) or tadalafil monotherapies(29,32) in men with bph-luts. however, these studies either had a small number of participants, involved tadalafil dosages > 5 mg once-daily, or were not placebo controlled. in our clinical trial, we have corrected these issues. so, based on our findings combination therapy could better improve ipss score in patients with bph-luts and is recommended for them because of its synergistic effects. this can be concluded from the results of our single groups in comparison with combined therapy that showed improvement in ipss score in both single groups separately and more ipss score in combined therapy group rather than each of them. our results showed that although qmax was significantly improved in the three studied groups, its improvement was greater in the combination therapy group than the other groups. we also showed that postvoid residual level was significantly different before and after treatment in each group, but there was no meaningful difference between the three groups (p > 0.05). other studies have also demonstrated the same greater improvements in qmax index with 5 mg tadalafil compared with placebo in men with bph-luts. the improvements at 12 weeks were maintained for 42 weeks, demonstrating the long-term efficacy of 5 mg tadalafil.(2,8,12,19,21,23,32) singh and colleagues showed that a significant increase in qmax and decrease in postvoid residual level were observed in combination therapy (33.99%, p < 0.05; 29.78%, p < 0.05; and 37.04%, p < 0.05) and monotherapy with tadalafil (-60.90%, p < 0.05; -49.45%, p < 0.05; and -62.97%, p < 0.05, respectively).(32) the complications of combination therapy in our study were myalgia, headache, back pain, nasopharyngitis, dizziness and discontinuation because of adverse effects. although the complication rate was higher in combination therapy group compared to monotherapy groups, it was not significant. in singh and colleagues study the side effects of combination therapy were dyspepsia, heartburn, headache, flushing, myalgia, and backache and adverse effect dropout and no participant experienced any severe or serious adverse events.(32) other randomized, controlled studies such as bechara and colleagues, liguori and colleagues, goldfischer and colleagues and kim and colleagues(21,28,29,32,33) have investigated the safety and tolerability of 5 mg tadalafil once-daily in three months as a treatment for bphluts in men, and had a safety profile consistent with the known safety profile of tadalafil as per the current package insert for 5 mg to 20 mg tadalafil as needed for erectile dysfunction.(8) integrated analysis of safety data from these studies demonstrated that the most common treatment-emergent adverse events were nasopharyngitis, dyspepsia and headache and few participants experienced serious adverse events.(21,28,29,33) the safety of 5 mg tadalafil in combination with α-blockers (alfuzosin, silodosin, tamsulosin, doxazosin or terazosin) was investigated in a double-blind, randomized, placebo-controlled trial on men with bph-luts in the united states (tadalatadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. miscellaneous 2924 tadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. fil/α-blocker, n = 158; placebo, n = 160).(33) this study was not designed to assess efficacy. no new safety concerns were identified for tadalafil/α-blocker combination therapy in this study. furthermore, the proportion of participants reporting treatment-emergent dizziness or with a positive orthostatic test was similar between the tadalafil/α-blocker combination therapy group and the placebo/α-blocker combination therapy group.(33) so, it can be concluded that the safety of combination therapy is nearly good and its short-term outcomes should be considered for patients and told to them. however, these complications are not serious and threatening. we investigated the iief score and showed that there were significant improvements in each group and between the groups in this regard. these improvements were higher in tamsulosin and combination groups, respectively. similarly, singh and colleagues showed that iief score increases significantly in the same three groups (+39.28%, p < 0.05; +45.96%, p < 0.05; and +60.23%, p < 0.05, respectively).(32) in another study bechara and colleagues showed that the iief improved in tamsulosin plus tadalafil group (p < 0.001), but not in tamsulosin alone group (p > 0.05).(28) based on these results, combination therapy with tadalafil and tamsulosin is recommended because of its good outcomes in erectile dysfunction. the limitation of this study was that some patients lost the follow ups and excluded from study and study period prolonged. conclusion combination therapy can better improve the ipss score, iief score and qmax in patients with bph-luts than monotherapy with tamsulosin or tadalafil. it is recommended because of its synergistic effects, well toleration and its safety. although we designed this study to investigate the previous studies' problems, large-scale, multi-centered, randomized, placebo-controlled studies are needed to further assess the long-term safety and effectiveness of these agents in treating bph-luts and erectile dysfunction. acknowledgements this study was funded by laser application in medical sciences research center, shahid beheshti university of medical sciences. the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. conflict of interests none declared. references 1. platz ea, joshu ce, mondul am, peskoe sb, willett wc, giovannucci e. incidence and progression of lower urinary tract symptoms in a large prospective cohort of us men. j urol. 2012;188:496-501. 2. oelke m, bachmann a, descazeaud a, et al. eau guidelines on the treatment and followup of 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assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of luts/bph. pilot study. j sex med. 2008;5:2170-8. 29. liguori g, trombetta c, de giorgi g, et al. efficacy and safety of combined oral therapy with tadalafil and alfuzosin: an integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. preliminary report. j sex med. 2009;6:544-52. 30. giuliano f, uckert s, maggi m, birder l, kissel j, viktrup l. the mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. eur urol. 2013;63:506-16. 31. kara ö, yazici m. is the double dose alphablocker treatment superior than the single dose in the management of patients suffering from acute urinary retention caused by benign prostatic hyperplasia? urology journal. 2014;11:1673. 32. singh dv, mete uk, mandal ak, singh sk. a comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. j sex med. 2014;11:187-96. 33. goldfischer e, kowalczyk jj, clark wr, et al. hemodynamic effects of once-daily tadalafil in men with signs and symptoms of benign prostatic hyperplasia on concomitant alpha1-adrenergic antagonist therapy: results of a multicenter randomized, doubleblind, placebo-controlled trial. urology. 2012;79:875-82. miscellaneous intra-operative oxycodone reduced postoperative catheter-related bladder discomfort undergoing transurethral resection prostate: a prospective, double blind randomized study juncheng xiong 1, xiang chen 1, chengwei weng 1, shuqun liu 1, jian li2* purpose: to observe the efficacy of intravenously injected oxycodone intraoperative on postoperative urinary catheter-related bladder discomfort (crbd). materials and methods: patients with asa i-iii who received trans-urethral resection of prostate under general anesthesia were observed. patients who were randomized to the control group(c) (n = 45) received placebo and the group oxycodone(q) received oxycodone (n =46 ) 0.03mg/kg of oxycodone before the end of operative 10min. the incidence and severity (mild, moderate, severe) of crbd were assessed at 0, 1/2 h, 2 h and 6 h postoperatively. vas scores were used to assess pain intensity during the same period. postoperative pca analgesic sufentanil dose and the incidences of nausea, vomiting, dizziness, over sedation were recorded in these patients. result: compared with the control group, the incidence of crbd was significantly lower in the oxycodone group at 0 [22 (49 %) vs. 10 (22%); p = .007], 1/2h [18 (40%) vs. 9 (20%); p = .033], 2h [11 (24%) vs. 4 (9%); p = .001]. the severity of crbd at 0 [mild, 9 (38%) ; moderate 9 (20%), severe 4 (9%)] was lower in the group q than the controlled group [mild, 4 (38%) p = .023; moderate 5 (11%), p = .034, severe 1 (2%), p = .012]. 1/2 h [mild, 11 (24%) vs 5(11%), p = .020]. compared with the group c, vas scores were lower in group q at 0, 1/2h (p = .001) and significantly decreased sufentanil dosage within 6h ( p = .001). there were no significant differences in the incidence of postoperative adverse effects between two groups. conclusion: oxycodone can effectively prevent patients with crbd after turp without incurring serious adverse effects. keywords: oxycodone; catheter-related bladder discomfort; postoperative, complication; trans-urethral resection prostate; visual analgesic score introduction patients with urinary bladder catheterization fre-quently complain of catheter-related bladder discomfort (crbd) postoperatively.(1) crbd is a common and distressing complication that often occurs in post-anesthesia care unit(pacu). crbd causes irritability and delirium, aggravates pain, and reduces the quality of recovery.(2) many risk factors for crbd have been indentified in previous studies such as male sex, diameter of the foley catheter, and types of operations. (3,4) in our previous study, we have observed a high occurrences of crbd in female patients underwent laparoscopic hysterectomy.(5) unlike postoperative pain, crbd may be resistant to conventional analgesic therapy such as opioids, because a different underlying mechanism is involved. many agents, including the muscarinic receptor blockers such as oxybutynin, tolterodine, tramadol and butylscopolamine(6-9) and central nerves system inhibitors such as ketamine and gabapentin(10,11), have been investigated as approaches in the prevention or treatment of crbd. 1department of anesthesiology, wenzhou people’s hospital. no.57 canghou street, lucheng district of wenzhou city, zhejiang province, people republic of china, 325000. 2 department of anesthesiology, the first affiliated hospital of wenzhou medical university, nanbaixiang ouhai district of wenzhou, zhejiang, p. r. china, 325000. *correspondence: department of anesthesiology, the first affiliated hospital of wenzhou medical university, nanbaixiangouhai district of wenzhou, zhejiang,p.r.china, 325000. tel: +8613758431800. e-mail: 313591073@qq.com. received november 2017 & accepted february 2018 but various side-effects of these agents limited their use. oxybutynin, tolterodine, are oral agents with various anticholinergic side-effects.(6,7) tramadol and ketamine were effective for the prevention and treatment of crbd, but these agents can cause sedation after operation.(8,10,11) oxycodone is a semi-synthetic opioids prepared from opium alkaloidthebaine plant derivative.(12) its μ and κ dual-receptor agonism has a unique effect in the treatment of visceral pain.(13-15) we have reported that oxycodone was effective for the treatment of crbd after laparoscopic hysterectomy in our previous study.(5) but the effects for crbd during turp has no investigated. we conducted a prospective, double-blind randomized, single-center study to investigate whether oxycodone has preventive effects on early postoperative crbd after turp. materials and methods study population this prospective, randomized, double-blind and placebo controlled study was performed after approval from urology journal/vol 16 no. 4/ july-august 2019/ pp. 392-396. [doi: http://dx.doi.org/10.22037/uj.v0i0.4267] ethic committee of wenzhou people’s hospital, number: 2016003. the protocol for this clinical trial was registered at chictr.org.cn (chictr-ipr-16008814). during preoperative visit, all patients provided informed consents and were educated about the symptoms of crbd (characterized as a burning sensation with an urge to void or as discomfort in the suprapubic area). inclusion and exclusion criteria patients with an asa physical status i to iii, who were scheduled to transurethral resection prostate, were included. patients were excluded if they had a history of severity heart disease, lung disease, psychiatric disease, chronic pain or long-term administration of analgesics. procedures patients were randomly assigned to one of two groups (control(c) or oxycodone(q)) with the help of a computer generated random number table. the assignments were concealed in opaque envelopes and opened immediately before induction by a nurse who was blinded to this study and was responsible for preparing the study drugs. all medications were administered in identical 2 ml syringes. all patients had no premedication, standard monitoring consisted of ecg, non-invasive arterial pressure (nibp), and pulse oximetry (spo2). anesthesia was induced with 0.05 mgkg midazolam, 4μg/kg fentanyl, 1.5 mg/kg propofol and 0.6mgkg-1rocuronium. intraoperative maintenance anesthesia relied on intravenous anesthesia; remifentanil infusion were maintained 0.2 μg/kg/min; intraoperative propofol infusion rate was adjusted to maintain bis value within 40-60; rocuronium was intermittently injected. 10min before the end of operative, the group controlled received same volume normal saline, whereas the oxycodone group received intravenous inject oxycodone 0.03mgkg-1(product batch number: aw259, mundipharma, britain). 22/24 foley urinary catheter was inserted and 5 ml sterile normal saline was injected into the balloon at the end of operation. after the surgery, 0.5 mg atropine and 1 mg neostigmine were administered to antagonize residual muscle relaxation. these patients were transferred to pacu after the endotracheal catheter was removed. pcia analgesia was postoperatively applied. the analgesic was 100 μg sufentanil added to 100ml normal saline, the background infusion was 1 ml per hour, the predetermined time was 8 min and the volume of each press was 2 ml. oxycodone reduce crbd in turp-xiong et al. figure1. patient flow diagram table1. characteristics of patients, anesthesia and surgery. a con group oxy group p value age (yr) 71 ± 8 74 ± 9 .577 bmi (kg/m2) 24 ± 6 26 ± 5 .087 asa class (ⅰ~ⅱ/ⅲ) 32/14 34/11 .522 urinary catheter size (f22/f24) 26/20 28/17 .580 duration of anesthesia (min) 118 ± 25 123 ± 32 .409 duration of surgery (min) 101 ± 24 105 ± 18 .372 time to extubation (min) 7.1 ± 1.6 7.7 ± 2.2 .140 intraoperative remifentanil resumption (mg) 1.84 ± 0.25 1.79 ± 0.32 .409 intraoperative propofol resumption (mg) 697 ± 185 731 ± 223 .431 a data are presented as mean ± sd or number (percent) abbreviations: bmi, body mass index；asa, american society of anesthetists miscellaneus 393 evaluations the primary outcome was defined as the reduction in the severity of crbd.(7) occurrences and severity of bladder discomfort was recorded as: none, when patients did not complain of any crbd on questioning; mild discomfort, patients were reported crbd on questioning only; moderate, urge to pass urine reported by the patient without questioning; severe discomfort, urge to pass urine accompanied by behavioral responses, such as flailing limbs, strong vocal responses or attempts to pull the catheter out. secondary outcomes were time to extubation, sufentanil consumption, heart rates (hrs), mean arterial pressure (map) in pacu, and adverse effects included ponv, over sedation, dry mouth and facial flushing. all these outcomes were assessed at 0, 1/2 h, 2, and 6 h after administration of the study drug by blinded assessors. vas scores were used to assess pain in these patients: 0 point, no pain; 10 points, unbearable pain. the ramsay sedation scale was measured postoperatively at 0, 1/2 h, 2, 6 hand recorded as follows: 1 (anxious, agitated or restless); 2 (cooperative, oriented and tranquil); 3 (responds to commands, asleep); 4 (brisk response to light glabellar tap or loud noise); 5 (sluggish response to light glabellar taps or loud noise); or 6 (no response). patients with a sedation scale score of at least 4 were considered over sedation. the patients with severe vomiting received intravenous injection of 4 mg ondansetron. analgesic doses received by the two groups of patients within 6 hours after the operation were recorded. statistical analysis according to a previous study, 53% of patients complain of crbd postoperatively.(7) assuming that this incidence would decrease to 15% after intervention, we calculated that 36 patients would be needed in each group to achieve statistical significance (α = .05 and β = .20). considering a 20% dropout rate, 91 patients per group were included. all data were analyzed with spss16.0 software package(spss, inc., chicago, il,usa). the severity of crbd were analyzed by mann-whitney u test, hr and map over time between the groups were analyzed by repeated measures analysis of variance (anova) and then t-test was used to compare values at each time point. rescue analgesics was analysed by t-test. analyses of categorical variables (incidence of side effects) were performed by χ2 or fisher’s exact-tests. data were analyzed according to the intention-to-treat principle. p < 0.05 indicated statistically significant differences. results 110 patients from august 2016 to december 2016were screened for inclusion in the study. nineteen patients were excluded [not meeting inclusion criteria (n = 11), declined to participate (n = 6), cancelled operation (n = 2)]. the remaining 91 patients comprised the study group (figure 1). no differences in the demographic characteristics of the groups were observed (table 1). compared with the control group, the incidence of crbd was significantly lower in the group q at 0 [22(49%) vs. 10 (22%); p = .007], 1/2h [18 (40%) vs. 9(20%); p = .033], 2 h [11 (24%) vs. 4(9%); p = .001], respective. the severity of crbd at 0 [mild, 9 (38%) ; moderate 9 (20%), severe 4 (9%)] was lower in the group q than the controlled group [mild, 4 (38%) p = .023; moderate 5 (11%), p = .034, severe1 (2%), p = .012]. 1/2 h [mild, 11 (24%) vs 5(11%), p = .020]. (table 2) the difference in vas scores in 0 and 1/2h in group q was significance lower compared with group c (p = .001). sufentanil dosage within 6 hours after the operation was lower in observation group than in control group (p = .001). there were no statistical significant differences in map, hr and spo2 in any period betable 2. incidence and severity of postoperative crbd, vas scores and sufentanil consumptions 6 h after operation a group group oxycodone group control time (h) 0 1/2 2 6 0 1/2 2 6 crbd 10 9 9 5 22 18 16 12 crbd severity mild 4 5 3 2 9 11 7 4 moderate 5 3 1 1 9 5 3 1 severe 1 1 0 0 4 2 1 0 postoperative vas value 3.05 ± 0.14 2.61 ± 0.66 1.79 ± 0.67 1.75 ± 0.17 6.72 ± 0.21 4.89 ± 0.14 3.52 ± 0.33 3.06 ± 0.41 sufentanil consumption(ug) 8.2 ± 0.85 12.1 ± 1.16 a data are presented as mean ± sd or number (percent) abbreviation: crbd, catheter related bladder discomfort a group t0 t1 t2 t3 t4 map (mmhg) group c 88 ± 22 82 ± 19 85 ± 18 74 ± 16 72 ± 22 group q 92 ± 18 75 ± 7 76 ± 12 77 ± 18 74 ± 18 hr (bpm) group c 78 ± 12 65 ± 8 71 ± 7 73 ± 8 72 ± 8 group q 82 ± 10 63 ± 9 75 ± 7 68 ± 8 65 ± 8 spo2 (%) group c 97 ± 2 98 ± 1 98 ± 2 96 ± 2 99 ± 1 group q 98 ± 1 96 ± 2 97 ± 2 98 ± 2 98 ± 1 a data are presented as mean±sd table 3. patients' vital signs of preoperative and postoperative oxycodone reduce crbd in turp-xiong et al. vol 16 no 04 july-august 2019 394 tween two groups (table 3). during this study, 3 cases (7%) in trial group and 1 case (2%) in control group experienced over-sedation (p = .317); there were no significant differences nausea [3(7%) vs. 1 (2%); p = .317], and vomiting [2 (4%) vs. 1 (2%); p = .570] between group q and group c. the difference in dizziness between twogroups had no significance [5 (11%) vs. 3 (7%); p = .479] (table 4). discussion we have demonstrated that intraoperative oxycodone reduces the incidence and severity of postoperative crbd and postoperative opioid requirements in patients undergoing turp. crbd is one of the most important factors causing postoperative irritability. the incidence of crbd in previous studies was reported with various ranges of 64 to 90% after general anesthesia in varies operations. in this study, 28 (60%) of 46 patients in the control group complained of crbd at 6 h postoperatively undergoing turp, which is lower than the incidence of crbd after urological operations, and according to the previous study. the causes for crbd include urethral mucosa injury due to urethral catheterization, the central nervous system is in the inhibitory state and the patients psychologically reject catheter-related discomfort. gynecological endoscopic procedures and retraction the uterus through the vagina may irritate the neck of bladder, constituting one of the causes for occurrence of crbd. the peripheral nerves of lower urinary tract consist of sacral parasympathetic nerve, thoracolumbar sympathetic nerve and sacral-pudendal nerve.(16) previous studies had shown that application of muscarinic subtype 3 receptor inhibitors oxybutynin, tolterodine, can substantially reduce the risk or severity of crbd. but these drugs have many adverse effects, such as dry mouth, dizziness and facial flushing, that cannot be fully avoided.(6-8,10) cns acting drugs and opiods receptors agonists ketamine, pentazocine, tramadol, were effective for the prevention and treatment of crbd, but these agents can cause sedation and ponv after operation.(11) oxycodone is μ and κ opioid receptor dual agonist. it can be used intraoperatively and postoperatively to relieve pain, especially with unique analgesic effect on visceral pain.(17,18) the onset of iv. oxycodone is 2-3 min, with a peak effect at 5min, and a elimination halt effects ranged from 4-6 h. in our study, we administered oxycodone 0.03mg/kg, which is used to treatment of acute pain postoperative single injection, reduced the postoperative incidence of crbd at 0, 1, 2, and 6h respectively. the mechanism of oxycodone action in the treatment of crbd may include: firstly, oxycodone activates κ receptor to effectively relieve pain induced by spasms of vesical neck and urethra mucosal injury in patients. secondly, oxycodone acts on central nervous system to regulate and control the central excitability of vesical afferent reflex and sacral reflex, leading to reduced sensitivity to crbd in patients. thirdly, the inhibitory effect of oxycodone on m1 and m3 muscarinic receptors is not yet confirmed, but previous studies showed that tramadol, a drug similar to oxycodone, was able to inhibit m1 and m3 muscarinic receptors to effectively prevent the occurrence of crbd in addition to its opioid receptor agonism.(8) i.v. oxycodone was clinically effective for the treatment of crbd as an antimuscarinic agent, but an inhibitory action of oxycodone on the activity of the detrusor muscle has not been reported in animal or human studies. further experiments in these areas are warranted. this study showed that oxycodone could reduce vas scores and pca dosage in all postoperatively periods, suggesting that oxycodone was able to relieve postoperative pain and reduce postoperative analgesic dosage in addition to its efficacy on crbd. there was no significant difference of extubation time. 3 cases in the observed group and 1 case in the control group had finger pulse oxygen saturation less than 90%, the condition returned to normal after oxygen inhalation through the mask. compared with the controlled group, the incidence of nausea and vomiting was not higher in the oxycodone group. there were no significant differences in other adverse reactions such as dizziness and sedation between the two groups. several limitations of the current study should be considered. first, a single dose of 0.03 mg/kg oxycodone was used in this study. we did not evaluate the dose–response effect of oxycodone for the prevention of crbd. in our previous study, however, it was shown that increase dose of oxycodone could result in adverse effects of vomiting and dizziness.(19) secondly, various agents are routinely used to decrease crbd. in this study, however, a direct comparison between the effect of oxycodone and others agents on the incidence of crbd was not performed. conclusions intravenous injection of 0.03mg/kg oxycodone 10 minutes before the end of operation can effectively prevent the occurrence and severity of crbd, decrease pca dosage, and reduce vas scores without causing severe adverse reactions in these patients after the operation. acknowledgement we thank wu yq, li h, who is anesthetists in the department of anesthesiology, wenzhou people’s hospital for invaluable assistance in collecting the data in this study. conflict of interest no other competing interests declared. references 1. bai y, wang x, li x, et al. management of catheter-related bladder discomfort in patients who underwent elective surgery. j endourol. 2015; 29: 640-9. 2. tauzin-fin p, stecken l, sztark f. catheterrelated bladder discomfort in post-anaesthesia table 4. the incidence of adverse reactions postoperative a group c group q p value over-sedation 1(2%) 3(7%) .317 nausea 1(2%) 3(7%) .317 vomiting 1(2%) 2(4%) .570 dizziness 3(7%) 5(11%) .479 a data are presented as number (percent) oxycodone reduce crbd in turp-xiong et al. miscellaneus 395 care unit. ann fr anesth reanim. 2012; 31: 605-8. 3. sun jl, lu yp, huang b, et al. effect of a novel analgesic disposable urinary catheter in prevention of restlessness caused by catheter-related bladder discomfort in general anesthesia patients in recovery period. zhong hua yi xue za zhi. 2008; 88: 1750-2. 4. li c, liu z, yang f. predictors of catheterrelated bladder discomfort after urological surgery. j hua zhong univ sci technolog med sci. 2014; 34: 559-62. 5. li j, zhu cf, xiong jc, liu sq, wu yq. effects of oxycodone in treatment of catheter related bladder discomfort. zhong guo yi shi za zhi (chinese). 2016; 18: 594-6. 6. agarwal a, dhiraaj s, singhal v, kapoor r, tandon m. comparison of efficacy of oxybutynin and tolterodine for prevention of catheter related bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. br j anesth. 2006; 96: 377-81. 7. tauzin-fin p, sesay m, svartz l,krolhoudek mc, maurette p. sublingual oxybutynin reduces postoperative pain related to indwelling bladder catheter after radical retropubic prostatectomy. br j anaesth. 2007;99:572-75. 8. agarwal a, yadav g, gupta d, singh pk, singh u. evaluation of intra-operative tramadol for prevention ofcatheter-related bladder discomfort: a prospective, randomized, double-blind study. br j anesth. 2008; 101: 506-10. 9. ryu jh, hwang jw, lee jw, et al. efficacy of butylscopolamine for the treatment of catheterrelated bladder discomfort: a prospective, randomized, placebo-controlled, double-blind study. br j anaesth. 2013; 111: 932-37. 10. agarwal a, dhiraaj s, pawar s, kapoor r, gupta d, singh pk. an evaluation of the efficacy of gubapentin for prevention of catheter-related bladder discomfort；a prospective；randomized；placebo, controlled, double-blind study. anesthanalg. 2007; 105: 1454-57. 11. maghsoudi r, farhadi-niaki s, etemadian m, et al. comparing the efficacy of tolterodine and gabapentin versus placebo in catheter related bladder discomfort after percutaneous nephrolithotomy: a randomized clinical trial.j endourol. 2017 dec 26. doi: 10.1089/ end.2017.0563. [epub ahead of print] 12. mclaughlin jp, myers lc, zarek pe, et al. prolonged kappa opioid receptor phosphorylation mediated by g-protein receptor kinase underlies sustained analgesic tolerance. j biolchem.2004; 279: 1810-8. 13. lenz h, sandvik l, qvigstad e, bjerkelund ce, raeder j. a comparison of intravenous oxycodone and intravenous morphine in patient-controlled postoperative analgesia after laparoscopic hysterectomy. anesth analg. 2009; 109: 1279-83. 14. lenz h, sandvik l, qvigstad e, bjerkelund ce, raeder j. a comparison of intravenous oxycodone and intravenous morphine in patient-controlled postoperative analgesia after laparoscopic hysterectomy. anesthanalg.2009; 109；1279-83. 15. friedman bw, dym aa, davitt m, et al. naproxen withcyclobenzaprine, oxycodone/ acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. jama. 2015;314:1572-80. 16. yamanishi t. chapple cr, chess-williams r. which muscarinic receptor is important in the bladder? world j urol. 2001; 19:299. 17. staahl c, dimcevski g, andersen sd, et al. differential effect of opioids in patients with chronic pancreatitis: an experimental pain study. scand j gastroenterol. 2007; 42；38390. 18. nielsen ck, ross fb, lotfipour s, saini ks, edwards sr, smith mt. oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studiesin two rat models of neuropathic pain. pain. 2007; 132: 289-300. 19. xiong jc, zhu cf, li j, wu yq, liu sq. effect of hydroclic oxycodone with postoperative pain after hysterscope. lin chuang ma zui xue za zhi (chinese), 2015; 31: 607-8. oxycodone reduce crbd in turp-xiong et al. vol 16 no 04 july-august 2019 396 endourology and stone disease the agreement between current stone analysis techniques and sem-edax in urolithiasis maryam taheri1*, abbas basiri2, fatemeh taheri1, ali reza khoshdel3, mohammad ali fallah1, faranak pur nourbakhsh4 purpose: nowadays, there are many physical and chemical methods available for urinary stone analysis. according to the latest guidelines, infrared spectroscopy (ir) or x-ray diffraction (xrd) are the two preferred methods in this issue. therefore, we decided to do a practical comparison between the two above-mentioned techniques with a reference method in order to set up a proper analysis method in our clinical laboratories. materials and methods: a total of 60 kidney stones were obtained at labbafinejad hospital through open surgery or percutaneous nephrolithotomy. then stone analysis techniques included both a morphological examination by sem (scanning electron microscopy) and internal structure analysis by edax (elemental distribution analysis x-ray), xrd, ir and wet chemical analysis. sem together with edax (sem-edax) was considered as reference methods. results: the results of xrd had the highest agreement with sem-edax analysis (93%), while the total agreement of ftir and wet chemical analysis was 81% and 71% respectively. the agreement of ftir for calcium oxalate stones was acceptable (90%), but for uric acid and cystine stones was challenging (65% and 76% respectively). conclusion: our results revealed that xrd is more reliable than ftir; but considering cost issues, ftir is more suitable for routine clinical laboratory. moreover, wet chemical analysis, which is routinely used in our laboratories is insufficient for stone analysis and it is mandatory to be replaced by techniques that are more accurate. keywords: agreement; analysis methods; infrared spectroscopy; urolithiasis; x-ray diffraction introduction urolithiasis is a recurrent condition(1), with the re-currence rate as high as 10–23% per year and might reach 50% within the first five years after treatment, in case the patient does not have an appropriate work-up and proper follow-up.(2) therefore, in addition to focusing on suitable urological interventions for removing urinary stone, the institution of further prophylactic measurements to prevent recurrences including a thorough metabolic work-up and an accurate quantitative stone analysis is of great importance.(3) the first purpose of stone analysis is the extensive qualitative differentiation of all stone components, and identification of each component quantitatively is in the second order of importance.(4,5) the most common in vitro techniques for stone analysis are x-ray diffraction (xrd), infrared spectroscopy (ir), polarization microscopy or chemical analysis.(6,7) xrd identifies the crystalline components of stone material. in this technique non-refractive amorphous materials that are mixed with crystalline component cannot be detected, so can cause problems when amorphous calcium phos1urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 2urology and nephrology research center, shahid labbafinrjad medical center, shahid beheshti university of medical sciences, tehran, iran. 3department of epidemiology, aja university of medical sciences, tehran, iran. 4department of mineralogy, geological survey of iran, tehran, iran. *correspondence: urology nephrology research center, no. 103, 9th boostan street, pasdaran avenue, tehran, iran. tel: +98 21 22567222, fax: +98 21 22567282, email: taheri233@yahoo.com, taherim@sbmu.ac.ir. received َaugust 2017 & accepted may 2018 phate and non-mineralogical components (such as protein and matrix) are present in the stone composition. (8) ir is a rapid and specific method that is based on the interaction of the infrared light with the molecules in the stone components.(4) kasidas et al. revealed that unlike xrd, ir can also identify non-crystalline materials therefore, it is useful for the identification of organic stone components particularly purines and drug metabolites.(8) in the analysis by polarization microscopy, the stone is fractured to reveal its internal structure. then the illumination of each sample is investigated by optical microscopy using polarized light. therefore, the small amounts of crystalline material in mixed stone component cannot be identified which limits the use of this technique. wet chemical analytic techniques detect the individual ions of stone material. this technique is still widely applied in routine hospital laboratories in many countries(8,9), however it is obsolete by the majority of laboratories due to very high proportion of errors that has been occurred with wet chemical analysis method (6.5% to 94%).(10) since wet chemical analysis is the only method in endourology and stone diseases 6 vol 16 no 01 january-february 2019 7 our routine laboratories, we decided to do this study to make a practical comparison between xrd and ir analysis methods in order to set up a proper stone analysis method in our clinical laboratories. according to previous studies sem can produce very high-resolution images of a sample surface(11) and, edax shows the internal elemental structure of a sample with high precision(12), therefore we applied sem together with edax (semedax) as a reference method(12) for evaluating the agreement of xrd, ir and wet chemical analysis results in different groups of urinary calculi. materials and methods study population sixty kidney stones were obtained from patients who were treated at labbafinejad medical center, consecutively. all of the stone fragments that were removed from each patient, were stored in plastic bags without using any solution for analysis during 2-3 weeks later. the procedures were in accordance with the ethical standard of the responsible committee of urology nephrology research center (unrc) and informed consent was obtained from the participants. in this study, the stones considered as pure if only one composition was identified and, mixed stone if there were other stones components from different chemical groups.(13) procedures prior to the internal structural analysis, all of the stone samples were carefully washed in order to remove any remaining blood clots or tissue, dried and then were analyzed by the following techniques: scanning electron microscopy (sem). before the examination, the samples were made conductive by gold sputtering in order to be prepared for morphological analysis by sem (tescan, vega3 series, usa). by this technique the morphology of all crystalline component of the stone samples were recorded through taking photographs at different magnifications. then the stone samples were powdered, homogenized and divided into four aliquots. representative fragments of each stone were sent to the laboratories committed to the analysis method, separately (edax, xrd, ftir and wet chemical analysis methods). elemental distribution analysis x-ray (edax). elemental analysis was carried out by edax probe (tescan, vega3 series, usa), which was pointed to the different areas of the sample. then through the analysis of the produced wave, the components of the crystals were recognized. scanning electron microscopic with elemental distribution analysis x-ray (sem-edax). this is the combination of high-resolution images of crystal morphology by sem together with precise elemental analysis through edax probe that we used as a reference method in this study(12). sem-edaxa total the agreement between the agreement the agreement between analysis report agreement xrdb and sem between ftirc wet chemical analysis edax results and sem-edax results and sem-edax results all 60 84% 93% 81% 71% g1 11 88% 100% 90% 59% g2 4 82% 89% 65% 92% g3 2 82% 82% 76% 65% g4 18 92% 98% 78% 91% g5 13 81% 95% 44% 91% g6 7 86% 96% 70% 77% g7 3 93% 92% 71% 100% g8 2 67% 82% 0%* 89% table 1. the agreement between the results of xrd, ftir and wet chemical analysis techniques with sem-edax results as the reference method. g1 (group 1): calcium oxalate, g2 (group 2): uric acid, g3 (group 3): cystine, g4 (group 4): calcium oxalate + calcium phosphate, g5 (group 5): calcium stone + uric acid, g6 (group 6): calcium stone + cystine, g7 (group 7): calcium stone + mg-nh4-p stone, g8 (group 8): uric acid + cystine. a sem-edax: scanning electron microscopic with elemental distribution analysis x-ray. b xrd: x-ray diffraction c ftir: fourier transform infrared spectroscopy figure 1. scanning electron micrograph of two kidney stones. a. calcium oxalate stone. b. cysine stone. the agreement of xrd and ftir with sem-edaxtaheri et al. x-ray diffraction (xrd). in this technique through monochromatic x-ray penetration to the sample, the crystalline atoms of stone composition produce a beam of x-rays that diffract into many specific directions. a crystallographer by measuring these diffracted beams, can produce a threedimensional pictures of electron within the crystal that is characteristic for that crystal composition. then, according to the searched match analysis performed on d4 endeavor x-ray diffractometer (brucker, germany) using a database, all crystalline components of kidney stones were identified. fourier transform infrared spectroscopy (ftir). the stone powders were homogenized and mixed with potassium bromide and placed in the ir beam of the spectrometer (brucker, germany). the infrared radiation, stimulates atomic vibration in the stone sample and then energy absorption, which results in absorption bands in the infrared spectrum that is characteristic for their structure through comparison with a reference library. wet chemical analysis. this technique was performed with commercial kit (darmankav company, isfahan, iran). the samples were analyzed for the presence or absence of carbonate, oxalate, calcium, magnesium, urate, cystine, ammonium and phosphate. the results were interpreted according to the instruction of the kit manufacturer. statistical analysis the assessment of the frequency of pure and mixed stone components using each stone analysis techniques was done by kalpha spss macro software. the inter-coder agreement of the stone type was assessed by krippendorff’s alpha. the krippendorff’s alpha values range is between from 0 to 1 which, 0 is perfect disagreement and 1 is perfect agreement. krippendorff suggests: “it is conventional to require α ≥ .800, the lowest conceivable limit that tentative conclusions are still acceptable is where α ≥ .667. this method takes into account both observed and expected agreement as well as the frequency of each category of pure and mixed stone components. results among the 60 patients, 17 were women and 43 were men, the mean age of the patients was 47.16 (sd: 11.82, range: 18-79). eight stones were extracted by anatrophic nephrolithotomy and 52 remained samples were obtained by percutaneous nephrolithotomy. using sem with suitable magnification, the morphology of the surface crystals was evaluated, the images of two samples are indicated in figure 1 (a, b). according to edax analysis, the main elements identified were calcium, carbon, phosphorus, oxygen, nitrogen, magnesium and sulfur. the presence of calcium, phosphorus and oxygen showed that the sample was a mixed composition of both calcium oxalate and calcium phosphate. (11) a prominent peak for sulfur in edax analysis is pertaining to cystine composition,(14) which was found in 11 stones. in addition, we found a peak of nitrogen in 18 stones and magnesium in seven stones. the presence of nitrogen with sulfur is related to cystine component while co-existence of nitrogen with oxygen is referred to the uric acid composition. finally, magnesium is included in the composition of magnesium ammonium phosphate or magnesium hydrogen phosphate kidney stones. by considering the sem-edax as a reference method, the results of analysis by three other methods are illustrated in figure 2. based on xrd analysis, 21 (35%) stones had pure composition: calcium oxalate 11 (18.3%), uric acid6 (10%) and cystine4 (6.7%). the diagrams related to analysis of three samples is shown in figure 3 (a, b). according to the ftir analysis, the percentage of pure stones were lower than xrd technique (23.3%). as it is clear in figure 2, ftir was weak in the detection of pure uric acid stones and falsely reported more mixed stones of calcium oxalate and cystine composition comparing to xrd analysis. the wet chemical analysis identified only 11 pure samples; calcium oxalate6 (54.5%), uric acid3 (27.2%), cystine-2 (18.1%). in wet chemical analysis, false positive detection of calcium phosphate and mixed composition of uric acid and calcium stones are noticeable. according to the classification of pure and mixed figure 2. the results of x-ray diffraction, fourier transform infrared spectroscopy and wet chemical stone analysis techniques in this study. figure 3. analysis results of three kidney stones. a. mixed composition of calcium oxalate and calcium phosphate (elemental distribution analysis x-ray). b. uric acid stone (x-ray diffraction). c. mixed composition of calcium oxalate and uric acid (x-ray diffraction). the agreement of xrd and ftir with sem-edaxtaheri et al. endourology and stone diseases 8 vol 16 no 01 january-february 2019 9 stones, we had eight groups in our results that are summarized in table 1. the agreement between results of analysis by xrd, ftir and wet chemical techniques for detection of pure and mixed stone components versus sem-edax results (as the reference method) were indicated in table 1. discussion the urinary stones may have the mineral composition, organic or both. it is noteworthy that the same chemical components may crystallize in different forms. therefore, a proper stone analysis technique should be able to identify all chemical constituents in the calculus with their exact crystalline form.(11) the sem-edax ability in the detection of the surface and internal structure of stone samples is very high, but due to its high cost (the cost of sem together with edax analysis per sample is 102.3 $) , it is not recommended as a routine technique in clinical laboratories. the comparison between the total agreement of xrd and ftir analysis revealed that the highest agreement was between xrd and sem-edax results (93%). the total agreement of ftir with sem-edax results were lower (81%), the main reason for this decline is the problem of the differentiation of uric acid from cystine stones according to this study. determination of stone composition is very important for understanding its etiology since the composition of calculus not only specifies the lithogenic conditions involved in its formation, but also reflects long-term or transient urinary or metabolic disorders. thus, precise determination of stone composition can have an important role in choosing suitable medical treatment for prevention of stone recurrence.(2-4) in the nineties, there was a progressive increase in the use of physical techniques (ir and xrd) rather than chemical methods for analyzing the urinary stones, as far as chemical methods have decreased and are considered to be obsolete in some countries.(9) sem-edax indicates the stone structure on the surface and interior clearly with very low theoretical detection limits (according to reed(15) about 0.08 percent of stone weight) which makes it a good technique to be used as a reference method(12). giannossi et al.(16) showed that sem and petrographic thin section analysis of calcium oxalate kidney stones led to the identification of more cores in the same stones. also they reported that not only the central zone in some stones, but also the point of attachment to the kidney wall can be represented as a core. but this method is much more expensive to be utilized as a routine technique for stone analysis,(11) so that is now applied just in modern research laboratories. according to previous studies, xrd is a reliable and accurate method when is used for qualitative and quantitative analysis of the kidney stones.(17) hidas et al. revealed that x-ray diffraction is the most accurate technique among the three most common methods (xrd, ftir and polarization microscopy). therefore, they compared the in vivo dual-energy ct findings of their patient’s renal stone composition by xrd analysis as standard reference technique.(6) in the study by uvarof et al.(13), 278 kidney stones from the patients were analyzed by xrd, 64.1% were pure and, 35.9% of stones had mixed components. in another study in japan, on 1816 urinary tract calculi using infrared spectroscopy(18), 58.4% of kidney stones had pure composition and remained 41.6% were mixed stones consisted of calcium oxalate with other components. in our study according to xrd analysis, 35% and 65% of stones had pure and mixed components, respectively. previous studies showed that the infrared spectroscopy technique is able to characterize nearly all stone samples. in addition, in cases that the peak size will directly match with the computerized reference library, the quantity of stone composition can be identified.(3,11,19) however, singh et al. revealed that quantification of all components of mixed stones with various amount of oxalate, phosphate and urate is problematic, and only semi-quantitative results can be obtained.(3) in another study, charafi et al. revealed that the detection of minor components by ftir can be done when their amount were not less than one tenth of the magnitude of the major component.(20) in the present study, since the library of the ftir method was limited we could not have a proper qualitative and quantitative analysis of all components in kidney stone samples. the most important problem in our results was the inappropriate differentiation of uric acid from cystine. for example, we identified four pure uric acid stones by sem-edax, which only one of them reported as the same component by ftir technique. one samples reported a combination of uric acid with cystine and, the other two samples reported as pure cystine composition. in addition, among mixed stone results by semedax which composed of calcium oxalate together with uric acid, ftir results were reported the combination of calcium oxalate and cystine. fazil et al. stated that recognizing cystine in mixture stones by ftir method is problematic, due to the similarity of wavelengths of cystine composition with calcium oxalate and uric acid component.(14) our results showed that the correlation of ftir with sem-edax results in detection of cystine and uric acid components was 76% and 65%, respectively. while, the correlation of ftir with sem-edax results in detection of calcium oxalate was 90%. it is noteworthy that the differentiation of calcium oxalate dihydrate from calcium oxalate monohydrate was not easy by ftir technique and to achieve this purpose, use of another combination method such as xrd or polarizing microscopy (depending on the cost of the combined methods for routine practice in clinical laboratories) is recommended. it is noteworthy that the cost of each analysis by infrared spectroscopy and x-ray diffraction is about 18.1 and 31.4 $, respectively. in our study, the cumulative correlation of wet chemical analysis with sem-edax was 71%, with the most correlation in mixed calcium stones and pure uric acid composition. in addition, the lowest correlation was between the detection of pure calcium oxalate and cystine stones (59% and 65% respectively). the most components that were reported as false positive were calcium phosphate and magnesium phosphate in comparison with sem-edax results. another problem of wet chemical analysis technique in our study was false negative report of cystine in mixed stones. two external quality assurance scheme (eqa schemes) in 1998 and 1993(21) showed relatively poor performance for wet chemical analysis methods with high false positive and negative results. the study by kasidas et al.(8) demonstrated that among different used methods in studied laboratories, xrd and ftir techniques gave the agreement of xrd and ftir with sem-edaxtaheri et al. more acceptable results and should be used in routine laboratories for kidney stone analysis. as seen in table 1, the best agreement was between xrd results and sem-edax technique with 93% correlation fallowing by ftir analysis method (81%). the main limitation of the study is referred to non-familiarity of laboratory staff with infrared spectroscopy in order to analyzing the composition of kidney stones. in addition, due to the limited library of infrared spectroscopy device, the proper qualitative and quantitative analysis of all components of our samples were not possible. conclusions no single method is sufficient to provide all the clinically essential information for determination of kidney stone composition and structure.(11) in our study the results of xrd had more agreements with sem-edax than other used methods. although considering the economy, infrared spectroscopy is less costly if there is a proper reference library. to avoid missing detection of rare stone components with infrared spectroscopy, it is necessary for clinicians to be in communication with the laboratory staff that perform the analysis in order to alert them when needed.(22) acknowledgment the authors thank mrs. farah rahmani for her kind assistance in our introduction to mineralogy department of geological survey of iran. in addition, we thank from the colleagues of geological survey of iran (sem and infrared spectroscopy departments), razi metallurgical research center (edax and xrd departments) and pathobiology laboratory center (chemical analysis department) for their good cooperation and assistance in analyzing our stone samples. conflict of interest none. references 1. wein aj, kavoussi lr, partin aw, peters ca. campbell-walsh urology 11th edition elsevier health sciences; 2016. 2. krepinsky j, ingram aj, churchill dn. metabolic investigation of recurrent nephrolithiasis: compliance with recommendations. urology. 2000;56:915-20. 3. singh i. renal geology (quantitative renal stone analysis) by 'fourier transform infrared spectroscopy'. int urol nephrol. 2008;40:595602. 4. schubert g. stone analysis. urol res. 2006;34:146-50. 5. cloutier j, villa l, traxer o, daudon m. kidney stone analysis: "give me your stone, i will tell you who you are!". world j urol. 2015;33:157-69. 6. hidas g, eliahou r, duvdevani m, et al. determination of renal stone composition with dual-energy ct: in vivo analysis and comparison with x-ray diffraction. radiology. 2010;257:394-401. 7. siener r, buchholz n, daudon m, et al. quality assessment of urinary stone analysis: results of a multicenter study of laboratories in europe. plos one. 2016;11:e0156606. 8. kasidas gp, samuell ct, weir tb. renal stone analysis: why and how? ann clin biochem. 2004;41:91-7. 9. abdel-halim re, abdel-halim mr. a review of urinary stone analysis techniques. saudi med j. 2006;27:1462-7. 10. hesse a, kruse r, geilenkeuser wj, schmidt m. quality control in urinary stone analysis: results of 44 ring trials (1980-2001). clin chem lab med. 2005;43:298-303. 11. fazil marickar ym, lekshmi pr, varma l, koshy p. edax versus ftir in mixed stones. urol res. 2009;37:271-6. 12. fazil marickar ym, lekshmi pr, varma l, koshy p. elemental distribution analysis of urinary crystals. urol res. 2009;37:277-82. 13. uvarov v, popov i, shapur n, et al. x-ray diffraction and sem study of kidney stones in israel: quantitative analysis, crystallite size determination, and statistical characterization. environ geochem health. 2011;33:613-22. 14. fazil marickar ym, lekshmi pr, varma l, koshy p. problem in analyzing cystine stones using ftir spectroscopy. urol res. 2009;37:263-9. 15. reed sjb. electron microprobe analysis and scanning electron microscopy in geology: cambridge university press; 2005. 16. giannossi ml, mongelli g, tateo f, summa v. mineralogical and morphological investigation of kidney stones of a mediterranean region (basilicata, italy). j xray sci technol. 2012;20:175-86. 17. siritapetawee j, pattanasiriwisawa w. an attempt at kidney stone analysis with the application of synchrotron radiation. j synchrotron radiat. 2008;15:158-61. 18. hossain rz, ogawa y, hokama s, morozumi m, hatano t. urolithiasis in okinawa, japan: a relatively high prevalence of uric acid stones. int j urol. 2003;10:411-5. 19. lehmann ca, mcclure gl, smolens i. identification of renal calculi by computerized infrared spectroscopy. clin chim acta. 1988;173:107-16. 20. samira c, mohamed m, antoniacosta b, rafaelm p, abdelkhalek o, felix g. a comparative study of two renal stone analysis methods. nephrourol mon. 2010;2:469-75. 21. rebentisch g, muche j, reinauer h. external quality assessment of analysis of urinary calculi--a new scheme based mainly on natural concrement materials. scand j clin lab invest suppl. 1993;212:56-7. 22. krambeck ae, khan nf, jackson me, lingeman je, mcateer ja, williams jc, jr. inaccurate reporting of mineral composition by the agreement of xrd and ftir with sem-edaxtaheri et al. endourology and stone diseases 10 vol 16 no 01 january-february 2019 11 commercial stone analysis laboratories: implications for infection and metabolic stones. j urol. 2010;184:1543-9. the agreement of xrd and ftir with sem-edaxtaheri et al. case report 217urology journal vol 6 no 3 summer 2009 penile metastases from prostate cancer vinayak rohan, abhinandan hanji, jayesh patel, jignesh goswami, rajen tankshali urol j. 2009;6:217-9. www.uj.unrc.ir keywords: penis, prostatic neoplasms, neoplasm metastasis gujarat cancer and research institute, mp shah cancer hospital, ahmedabad, india corresponding author: vinayak s rohan, ms room-9, research hostel, gcri, ahmedabad 380016, india tel: +91 94 2675 3762 e-mail: rohanvinayak28@gmail.com received may 2008 accepted august 2008 introduction the penis is an uncommon site for metastasis originated from the prostate cancer despite their proximity (0.3%). if develops, it usually presents as painless nodules in the glans penis.(1,2) conservative management is generally advocated with emphasis on improving the quality of life.(3) here, we present a case of a penile lesion which was diagnosed as metastasis from a prostate cancer. case report an 80-year-old man presented to our surgical outpatient department in december 2007 with the complaint of bilateral palpable inguinal lymphadenopathy of 1 month duration. the patient had a history of circumcision 4 months earlier for a preputial growth. histopathological report was indicative of squamous cell carcinoma of the penis. tissue blocks were not available for review as the patient had come from a remote area. the patient had no urinary complaints. ultrasonography of the groin showed bilateral inguinal lymphadenopathy. fine needle aspiration from the nodes proved to be metastases, and the patient subsequently underwent a bilateral ilio-inguinal lymph node dissection. histopathological evaluation of the lymph nodes revealed metastatic adenocarcinoma with 13 of 23 nodes positive on the right and 3 of 10 positive on the left side. retrospectively, the patient was clinically re-evaluated in search of a primary lesion. digital rectal examination showed a moderately enlarged prostate, firm in consistency. transrectal ultrasonography showed diffuse heterogenous and mildly altered echopattern of the prostate (hypoechoic), measuring 39 × 29 × 40 mm, involving both lobes of the prostate (t2c lesion). a subsequent guided biopsy confirmed prostatic adenocarcinoma with a gleason score of 6. serum level of prostate-specific antigen (psa) was 8.29 ng/ml, and a whole-body isotope bone scan did not reveal any bony metastases. as further treatment was being planned, the patient developed a skin nodule on his glans penis and scrotal skin (figure 1). biopsy confirmed them to be prostatic metastases (figure 2). immunohistochemical examination of the lymph nodes and the penile nodule showed psa and cytokeratin to be positive. as the penile nodule was accompanied by severe pain and discharge, the patient underwent partial amputation with palliative intent in february 2008. bilateral subcapsular orchiectomy was also performed in the same setting as a means for androgen ablation. thereafter, the patient was asymptomatic on regular followups. penile metastases from prostate cancer—rohan et al 218 urology journal vol 6 no 3 summer 2009 discussion metastatic spread of prostate cancer to the penis occurs by several routes.(4-7) retrograde venous or direct lymphatic/vascular invasion and direct extension through the lumen of the vas deferens are the most common mechanisms. involvement of the prostatic urethra by prostatic adenocarcinoma increases the likelihood of penile metastases.(8-10) it may also spread from the prostatic urethra into the inguinal, pelvic, or retroperitoneal lymph nodes. penile metastases from prostate cancer present as single or multiple skin nodules over the prepuce, glans, or the coronal sulcus. these lesions are hard in consistency. pain may be an important clinical symptom. other modes of presentation are urethral ulceration, local obstruction, priapism, and severe penile pain.(3) diagnosis is made by open biopsy in a known case of prostate cancer. management of such cutaneous metastases without systemic spread has been challenging due to the rarity of the situation. over the past years, various treatment modalities have been evaluated; however, none of them provides satisfactory results. ninety-eight cases of penile metastases from carcinoma of the prostate were identified in the literature until 2003 with 4 more new cases till date.(11-14) however, all these patients were earlier diagnosed as cases of carcinoma of the prostate which later developed penile metastases. in our case, the patient never had any of the urinary symptoms suggestive of a prostatic disease and the penile lesions were the presenting feature which was very unusual and deceptive. tu and colleagues reported a study on 12 such patients who were retrospectively analyzed.(2) these patients responded to androgen ablative therapy with median survival of 66 months. ten of them received chemotherapy. the penile metastases appeared at a median of 50 months after the diagnosis. the psa levels did not correlate with the burden of the disease. even in our patient, the psa level was elevated, but not in the metastatic range. treatment options depend on the general condition of the patient, site and extent of the primary tumor, presence of metastases, and symptoms. the patient should be treated as those with metastatic prostate cancer. androgen ablation either by hormonal therapy (gonadotropin-releasing hormone analogues) or surgical orchiectomy is the initial treatment. chemotherapy has also been tried with varying success rates. amputation of the penis with urethrostomy formation is to be considered in the patients with ulceration, irritating secretion, and intractable penile pain.(15) in patients presenting with priapism, total penile amputation may be required. management of the patients with penile metastases from carcinoma of the prostate should be focused on improving the quality of life in view of the poor prognosis. hormonal therapy and chemotherapy should form the main line of management. role of surgery is limited to relieving severe intractable pain and ulceration. figure 1. microscopy shows adenocarcinoma in penis (hematoxylin-eosin, ×10). figure 2. scrotal nodule is shown as metastasis of the prostate. penile metastases from prostate cancer—rohan et al urology journal vol 6 no 3 summer 2009 219 conflict of interest none declared. references 1. mccrea lw, karafin l. carcinoma of the prostate: metastases, therapy and survival; a statistical analysis of five hundred cases. j int coll surg. 1958;29:723-8. 2. tu sm, reyes a, maa a, et al. prostate carcinoma with testicular or penile metastases. clinical, pathologic, and immunohistochemical features. cancer. 2002;94:2610-7. 3. philip j, mathew j. penile metastasis of prostatic adenocarcinoma: report of two cases and review of literature. world j surg oncol. 2003;1:16. 4. osther pj, løntoft e. metastasis to the penis. case reports and review of the literature. int urol nephrol. 1991;23:161-7. 5. savion m, livne pm, mor c, servadio c. mixed carcinoma of the prostate with penile metastases and priapism. eur urol. 1987;13:351-2. 6. patel np, ward jn. carcinoma of prostate metastatic to prepuce and glans penis. urology. 1978;11:269-70. 7. hamm fc, weinberg sr. secondary malignant infiltration of penis; report of four cases, two with surgical treatment for palliation. j urol. 1955;73:34954. 8. smehaug j. metastases to the penis from carcinoma of the prostate. a case report. scand j urol nephrol. 1979;13:205-6. 9. van den berg gm, menke he, stolz e. nodules on the glans penis, an unusual metastatic pattern of prostate carcinoma: case report. genitourin med. 1986;62:126-8. 10. taylor gb, mcneal je, cohen rj. intraductal carcinoma of the prostate metastatic to the penile urethra: a rare demonstration of two morphologic patterns of tumor growth. pathology. 1998;30:218-21. 11. cai t, salvadori a, nesi g, et al. penile metastasis from a t1b prostate carcinoma. onkologie. 2007;30:249-52. 12. cortés gonzález jr, garza r, martínez r, gómez l. [prostate adenocarcinoma metastatic to penis]. actas urol esp. 2006;30:832-4. spanish. 13. sawada a, segawa t, nakanishi s, et al. prostate cancer with penile metastasis: a case report. hinyokika kiyo. 2005;51:771-3. 14. sanz mayayo e, burgos revilla fj, gómez garcía i, garcía gonzález r, escudero barrilero a. [penile metastasis of a prostatic adenocarcinoma]. arch esp urol. 2004;57:841-4. spanish. 15. bar-moshe o, abdul-sater a, vandendris m. acute urinary retention secondary to cavernous metastases from a prostatic tumor. prog urol. 1991;1:1042-5. miscellaneous gender and workforce in urology: use of the bg index to assess female career promotion in academic urology jenny jaque1#, eileen m. wanke2#, ruth müller2, jan bauer2, daniela ohlendorf2, stefanie mache2, doris klingelhöfer2*, david quarcoo2 purpose: today, the majority of medical graduates in countries such as the uk, the us or germany are female. this poses a major problem for workforce planning especially in urology. we here use first the first time the previously established brüggmann groneberg (bg) index to assess if female academic career options advance in urology. methods: different operating parameters (student population, urology specialist population, urology chair female:male (f:m) ratio) were collected from the federal office of statistics, the federal chamber of physicians and the medical faculties of 36 german universities. four time points were monitored (2010 ,2005 ,2000 and 2015). from these data, female to male (f:m) ratios and the recently established career advancement (bg) index have been calculated. results: the german hospital urology specialists’ f:m ratios were 499) 0.257 female vs. 1944 male) for ,2015 0.195 for 0.133 ,2010 for 2005 and 0.12 for 2000. the career advancement (bg) index was 0.0007 for ,2000 0,0005 for 0.094 ,2005 for 2010 and 0.073 for 2015. the decrease from 2010 to 2015 was due to an increase in the f:m ratio of hospital urologists and female medical students. conclusion: the bg index clearly illustrated that there is an urgent need for special academic career funding programs to counteract gender problems in urology. the bg index has been shown to be an excellent tool to assess female academic career options and will be very helpful to assess and document positive or negative changes in the next decades. keywords: academic medicine; career promotion; gender difference; promotion index; bg-index introduction despite the influx of females into medicine it is very likely that female urologists will remain a minority for the foreseeable future(1). the challenge for urology was supposed to be how to recruit more female physicians to become specialists in an atmosphere where it has been reported that female physicians are discouraged from pursuing surgery by lifestyle factors, lack of interest and most disturbingly female discrimination(1,2). among the different factors that influence the selection of specialization, questions of career advancement gain more and more importance(3,4). the potential presence of obstacles to female career promotion may prevent female physicians to become urologists. especially in surgical fields this question is subject to debate amongst other influencing factors(5-10). it would be of great use to assess gender issues by the use of measurable indices. however, no precise indices have been used so far for urology hat describe the magnitude of gender imbalance concerning academic career progression. using the recently established bg-index for female career promotion(11), we here present the first 1 department of obstetrics and gynecology, keck school of medicine of usc, los angeles, california, usa. 2 department of social medicine, the institute of occupational medicine, social medicine and environmental medicine, goethe-university, frankfurt, germany. # equal contribution *corerspondence: department of social medicine, the institute of occupational medicine, social medicine and environmental medicine, goethe-university, frankfurt, germany. telephone: +49 (0) 69 6301 6650, fax +49 (0) 69 6301 7053. email: klingelhoefer@med.uni-frankfurt.de. received august 2017& accepted june 2018 data for the field of urology for the time points 1995, 2000, 2005, 2010 and 2010 for germany. methods this study is the first use of the bg index (equation 3) to obtain a first insight in to the field of urology concerning gender issues. the following databases were used to access student and physician data: destatis database and federal chamber of physicians data base. the destatis database is an online platform which is maintained by the federal statistical office, germany (12). the bg-(brüggmann-groneberg) index (equation 3) has recently been introduced by brüggmann and groneberg as an index to characterize female career promotion in academic medicine(11). they used a set of different female to male ratios (f:m) to construct this index which can be used to denominate the extend by which women can ascent in their academic career(11). in order to assess the field-specific academic promotion in the field of urology, presently the ratio of female to male (f:m) medical students was chosen as an entry parameter according to brüggmann and groneberg(11), urology journal/vol 17 no. 1/ january-february 2020/ pp. 86-90. [doi: 10.22037/uj.v0i0.4116] vol 17 no 01 january-february 2020 87 since the medical student numbers describe the total of candidates for top academic urology positions. we used the data on numbers of students on a 5 year basis of the years 1995, 2000, 2010 and 2015, as described by brueggmann and groneberg(11). the database of the federal chamber of physicians(13), an institution run by the regional chambers of physicians, is also published on a yearly basis and supplies relevant data on the physician demography in germany. as a third set of operating figures needed for the bg-index, we identified the numbers of female full professors/chairs in urology by internet searches and consultations of journals. as described by brueggmann and groneberg(11), the numbers of female chairs were exactly given between the period of 2000 – 2015 in 5 years steps. the exact number of male chairs was only obtainable for 2015. at the time points 2010, 2005 and 2000, there is an error of margin possible, due to difficulties to identify the exact date, when the chair appointment process was terminated and the possibility of more than one chair per university (i.e. charité berlin). as previously described, the number of 36 (common and realistic assumption that all faculties have a urology chair) was used with the numbers of female chairs being subtracted to get the male number for the ratio. results medical student numbers in the year 2015, a total of 89 998 medical students (54 638 female students and 35 360 male students) studied medicine with a f:m ratio of 1.545. this ratio was 1.142 in 2000 and 0.888 in 1995 (table 1). specialized urologists and urology chairs in 2015, a total of 5771 urology specialists worked in germany. the f:m ratio was 0.192 (931 female vs. 4840 male urologists). in comparison, the f:m ratios were 0.142 for 2010, 0.106 for 2005 and 0.081 for 2000, respectively (table 2). generally, the f:m ratio increased towards the present situation but there is still with a large majority of male urologists. the analysis of numbers of urologists who work at hospitals resulted in a slightly higher f:m ratio: in 2015, 499 female urologists worked at german hospitals (vs. 1944 male, f:m ratio of 0.257). in 2010, this f:m ratio was 0.195 (340 female and 1743 male urologists). in 2000, the f:m ratio was 0.120 (147 female and 1222 male urologists). the number of female chair positions was 0 for urology in 2000. it increased towards 1 for urology in 2010 and stayed at 1 in 2015 (table 2). bg-index in 2015, this f:m ratio for medical students in 2013 was 1.545. this parameter was then related to the f:m ratio of full urology professors/academic chairs. the resulting preliminary index is for the year 2015: (equation 1) this index describes the general urology-specific ascension by which in this case, female medical students reach chair positions in urology. ideally, this ratio could be 1 in a society that is fully gender-equal. these results using the preliminary index formulae demonstrate a dramatic difference to the ideal gender equity situation in both fields on first appearance. as next step, the bg-index integrates a factor that mirrors the appeal that a given medical field – here urology has on female physicians in medical training: the f:m ratio of registered urologists which can be found in the databases of the federal chamber of physicians. this ratio represents a corrector factor for urology as a field of medicine, which is per se less appealing for women and which therefore does not attract high numbers of female physicians to specify in this field. the resulting preliminary index is for the year 2015: (equation 2) as stated by brüggmann and groneberg, the integration of the general attractivity of a clinical field (f:m ratio of total registered specialists) may not completely reflect the attractivity towards a career in hospital medicine which ultimately reaches its climax in the position of a clinical chair. therefore, the f:m ratio of hospital-based urologists was used in the final bg-index (equation 3). for the year 2015, the final index was: (equation 3) for the year 2000, this bg-index was 0.0007, for 2005 it was 0.0005 and for 2010 it was 0.094 (for detailed calculations see appendix). it has to be noted that the first female chair for urology was appointed in 2008 and therefore, calculations of the bg-index in 2000 and 2005 were normalized with 0.0001 instead of 0 for n= 0 female chairs (figure 1). in order to visualize the influence of the variables, we new index to assess female career promotion-jaque et al. figure1. evolution of the urology bg index between 2000 and 2015. year total number medical students total male female f:m ratio 2015 89 998 35 360 54 638 1.545 2010 80 574 31 182 49 392 1.584 2005 79 847 32 025 47 822 1.493 2000 80 200 37 440 42 760 1.142 1995 84 958 44 992 39 966 0.888 table 1. f:m ratio of medial students in germany from 1995-2015. retrieved from (12) present in equations 4, 5 and 6 hypothetic variations in the variables f:m ratio chairs (equation 4 and 5) and f:m ratio medical students (equation 6). to show the influence of a small increase in the number of female chairs, we hypothesize a number of 2 female chairs and 34 male chairs. this would increase the index to 0.149. equation(4) to show the influence of a larger increasing number of female chairs, we hypothesize a number of 10 female chairs and 26 male chairs. this would increase the index to 0.969. (equation 5) to show the influence of an increasing number of male students, we hypothesize a ratio of 10000 female medical students to 79998 male students. this would increase the index to 0.903. that means that in a hypothetic world in which only a low number of women study medicine, the current situation of 1:35 female to male chairs would not lead to a very low index level. (equation 6) discussion the present study is the first use of the bg-index to characterize female academic promotion in urology. it used germany since data bases were available of the different variable used by the index. the urology-specific bg-index seems to be quite low with values of 0.073 for 2015 or 0.094 for 2010. in the years before, it is even lower since zero female chairs lead to an extremely low bg-index. what are the limitations of the study? the high weighting of zero female chairs in the bg-index is one limitation. changes in the variable "f : m. ratio of chairs" have a relatively strong influence on the index level. to show this purpose, we used hypothetic values of 10 female versus 26 male chairs. using this ratio, the index increases to 0.969, indicating, that women gain more influence in the field of urology. likewise, when the number of female students decrease hypothetical in equation 5 to a number of 10 000 female students the index also increases (0.903) since women also relatively gain importance due to the decreasing number of female students. a further limitation is the time period. the index needs to cover a longer time period to get a better picture of female promotion patterns. even so, the index represents an important step, as discussed by sugimoto(14). concerning this issue, we currently expanded the period to 1995 in contrast to the first establishment of the index. in the us, the supply of urology specialists relative to the us population growth decreased(15). this short come is expected to be exacerbated due to factors such as an aging and relatively older urology physician workforce, particularly in rural areas, and the migration of younger urologists towards group practice in urban areas(15). in contrast to countries such as the us with a decreasing urology workforce(15), the german urology workforce has seen slightly increasing numbers as illustrated in table 2 of the results section. as shown for the us with a slight increase in absolute numbers female urologists, there is also an increase in absolute numbers of female german urologists present. however, from a relative viewpoint, the f:m ratio is decreasing. a strength of the bg-index is the possibility to compare the gender dynamics in a field such as urology over a long-time period. given the assumption, that e.g. in the year 2020 there would be two appointed female chairs of urology, the index would increase to 0.149, indicating a relative improvement of female career promotion in academic urology. increases of this index can be used as an indicator of an increasing attractivity for young female physicians to specialize in this area of medicine. as a matter of fact, this increase of female urology chairs can be anticipated since there are currently a number of female associated professors who might receive an appointment to a full professorship/ chair position within the next years. it is also interesting to compare the present data to other fields of medicine year urology specialists at work specialists at hospital occupied university chairs 2015 total 5771 2443 36 female 931 499 1 male 4840 1944 35 f:m ratio 0.192 0.257 0.086 2010 total 5204 2083 36 female 648 340 1 male 4556 1743 35 f:m ratio 0.142 0.195 0.029 2005 total 4 804 1889 36 female 461 222 0 male 4343 1667 36 f:m ratio 0.106 0.133 0.029 2000 total 4384 1369 36 female 329 147 0 male 4055 1222 36 f:m ratio 0.081 0.120 0 table 2. specialized urologists and urology chairs 2000-2015. new index to assess female career promotion-jaque et al. miscellaneous 88 vol 17 no 01 january-february 2020 89 and surgery. in this respect, brüggmann and groneberg introduced first data of their new index in the fields of obstetrics and gynecology and ent(11). in these two fields, the bg-indices were in the year 2013 0.044 for obgyn with 4 female chairs and 38 male chair. for ent, the value of the bg-index was 0.113 (3 female vs 30 male chairs, 516 female vs 894 male hospital ent specialists and a f:m student ratio of 1.54). hence, the current urology bg index with 0.073 for the year 2015 is even better than the index for obgyn. this means that academic career promotion for a female urologist is probably easier than for a female obgyn specialist even if there is only one female urology chair but 4 female obgyn chairs. the reason for this slightly better female career promotion opportunity in urology compared to obgyn is based upon the difference in the ratios of hospital specialists for both medical specialities: the obgyn female:male hospital specialist ratio is 1.566 while the urology ratio is 0.257. for ent, the bg index is 0.113. this value is better than the urology bg index. the reason for this is that there are 3 female and 30 male chairs while the f:m hospital ent specialist ratio is 0.577. women are needed in urology. a very recent study by kim et al. has especially pointed to their importance with regard to female patients: more than half of female participants who were asked had a preference for female urologists. by contrast, the majority of male participants did not express a preference for the gender of their urologist(16). but why is the attractivity of urology so low for female physicians? an excellent summary is given by dr. gwen grimsby in a recent commentary entitled "the journey of women in urology: the perspective of a female urology resident"(17): "i chose urology for the patient variety and wonderful mix of clinic and surgery. i never considered my gender an issue, but i am continually surprised by the reaction of others in this regard. i am frequently asked by male patients why i chose urology. women in the clinic are excited to see me, and men call me “honey,” ask when the “real doctor” is coming in, label me as the nurse, or call me by my first name, even though i just introduced myself as dr. gwen grimsby."(17) similar problems have also been reported in a 2006 survey among urology residents by jackson et al (18): most common challenges of female urology residents were refusal to be seen by male patients (60%), the inappropriate treatment by male colleagues (36%) or male patients (29%). also, sexual harassment was a major issue (22%)(18). facing these unique struggles, g. grimsby concluded that there is a special need to continue to foster female success for the future in urology(17). in this respect, our present approach offers the opportunity to establish an urology-specific index that incorporates numbers of female medical students who are the basis for future urologists, female urology specialists – who are the basis for future chairwomen of urology and numbers of chairwomen. the index can be used on a yearly basis to dissect and illustrate positive and negative changes. we here used germany as an example since the system of academic urology is quite simple and follows a strict hierarchical system with the chair at the top position of urology. this index might be of use for other countries with a similar structure. this approach will now be used on a yearly basis in order to characterize the f:m ratio and female academic progression in urology in the future. conflict of interest the authors declare no conflict of interest. references 1. barrass bjr, armitage j, burgess n. the influence of gender on workforce planning in urology. bju international. 2013;111:101820. 2. fitzgerald je, tang sw, ravindra p, maxwellarmstrong ca. gender-related perceptions of careers in surgery among new medical graduates: results of a cross-sectional study. am j surg. 2013;206:112-9. 3. sigsbee b, bernat jl. physician burnout: a neurologic crisis. neurology. 2014;83:2302-6. 4. buckley lm, sanders k, shih m, kallar s, hampton c. obstacles to promotion? values of women faculty about career success and recognition. committee on the status of women and minorities, virginia commonwealth university, medical college of virginia campus. acad med. 2000;75:2838. 5. tesch bj, wood hm, helwig al, nattinger ab. promotion of women physicians in academic medicine. glass ceiling or sticky floor? jama. 1995;273:1022-5. 6. zhuge y, kaufman j, simeone dm, chen h, velazquez oc. is there still a glass ceiling for women in academic surgery? ann surg. 2011;253:637-43. 7. flannery am. success, women, and academic surgery. surgery. 2002;131:670-1. 8. brewer sl, mongero lb. women in perfusion: a survey of north american female perfusionists. j extra corpor technol. 2013;45:173-7. 9. jonasson o. leaders in american surgery: where are the women? surgery. 2002;131:6725. 10. sexton kw, hocking km, wise e, et al. women in academic surgery: the pipeline is busted. j surg educ. 2012;69:84-90. 11. bruggmann d, groneberg da. an index to characterize female career promotion in academic medicine. j occup med toxicol. 2017;12:18. 12. office fs. destatis. https://http://www. destatis.de/de/zahlenfakten/indikatoren/ langereihen/bildung/lrbil05.html. accessed 2015-02-02. 13. physicians fco. physician statistics. http:// w w w . b u n d e s a e r z t e k a m m e r . d e / p a g e . asp?his=0.3.12002. accessed 2015-01-02. 14. conroy g. gender proportions in medical schools are almost equal, but disparities persist further up the ranks, a new tracking new index to assess female career promotion-jaque et al. tool reveals. https://http://www.natureindex. com/news-blog/new-tool-tracks-genderimbalance-in-medicine. 2017. 15. pruthi rs, neuwahl s, nielsen me, fraher e. recent trends in the urology workforce in the united states. urology. 2013;82:987-93. 16. kim so, kang tw, kwon d. gender preferences for urologists: women prefer female urologists. urol j. 2017;14:3018-22. 17. grimsby gm, wolter ce. the journey of women in urology: the perspective of a female urology resident. urology. 2013;81:3-6. 18. jackson i, bobbin m, jordan m, baker s. a survey of women urology residents regarding career choice and practice challenges. j womens health (larchmt). 2009;18:1867-72. new index to assess female career promotion-jaque et al. miscellaneous 90 endourology and stone diseases treatment of moderate sized renal pelvis calculi: stone clearance time comparison of extracorporeal shock wave lithotripsy and retrograde intrarenal surgery hakan ercil,1* ergun alma,1 okan bas,2 nevzat can sener,1 ediz vuruskan,1 faruk kuyucu,1 umut unal,1 mehmet resit goren,3 yalcin evliyaoglu1 purpose: to compare the stone clearance times in patients undergoing extracorporeal shock wave lithotripsy (swl) or retrograde intrarenal surgery (rirs) for single radiopaque renal pelvis stones 10-20 mm in size. the results of this study may guide urologists and patients and aid in selecting the optimal preoperative treatment. materials and methods: between january 2013 and february 2015, we conducted a retrospective study and collected data from 333 patients treated with swl (n = 172) or rirs (n = 161). we included successfully treated patients with a single radiopaque renal pelvis stone 10-20 mm in size to calculate stone clearance times. results: the average stone size for the swl group was 14.62 ± 2.58 mm and 14.91 ± 2.92 mm for the rirs group. the mean hounsfield unit (hu) of the patients was 585.40 ± 158.39 hu in the swl group and 567.74 ± 186.85 hu in the rirs group. following full fragmentation, the mean stone clearance time was 26.55 ± 9.71 days in the swl group and 11.59 ± 7.01 days in the rirs group (p < .001). conclusion: one of the most overlooked parameters in urinary stone treatments is stone clearance. we believe this study will shed light for those who aim to conduct larger randomized prospective studies. keywords: lithotripsy; methods; kidney calculi; surgery; treatment outcome; retrospective studies; ureteroscopy. introduction with the advancements in endourologic technol-ogy, in the last 30 years, renal stone treatment has dramatically changed, and minimally invasive treatments options, such as extracorporeal shock wave lithotripsy (swl), percutaneous nephrolithotomy (pcnl), mini-pcnl, retrograde intrarenal surgery (rirs) or laparoscopy, have replaced open surgery.(1) the primary aim of all of these procedures is to maximize the removal of stones with minimal morbidity. although, minimally invasive treatment modalities have an excellent stone fragmentation rate, the clearance of stone fragments may not be immediate and can occur for any time after the intervention. additionally, clearance of stone fragments may not have an immediate clinical concern but are likely to affect the patient’s well-being in the long term.(2,3) if the spontaneous passage of the stone fragments is prolonged, additional procedures, labor loss and hospital admittance due to renal colic episodes, increase. thus, the total cost caused by the condition and treatment increases and treatment compliance dramatically decreases.(4) the european association of urology (eau) guidelines,(5) recommends pcnl for renal pelvic stones greater than 2 cm, and swl is suggested primarily for stones less than 1 cm in size. although swl, rirs and pcnl are all presented as treatment options for stones between 1 and 2 cm in size, which application is a matter of preference. the choice of treatment decision usually depends on many factors, such as patient/ doctor preference, success rate, patient’s comorbidities, complications of the treatment, treatment costs, existing surgical equipment, stone clearance time, and patient’s compliance. in the decision-making process, patients are informed about each procedure’s success rates, possible complications, invasiveness, the need for anesthetics, and hospital stay. however, there is no clear information for the patient regarding the amount of time taken to clear the stones from the urinary system after treatment. although stone clearance times for ureteral stones are widely studied,(6-8) few reports have studied the elimination of renal stones after swl,(9,10) 1 department of urology, ministry of health, numune teaching and research hospital, adana, turkey. 2 department of urology, ministry of health, abdurrahman yurtarslan onkoloji teaching and research hospital, ankara, turkey. 3 department of urology, baskent university adana medical and research center, adana, turkey. *correspondence: department of urology, ministry of health, numune teaching and research hospital, adana, turkey. tel: +90 505 4308550. e-mail: hakanercil@yahoo.com. received september 2015 & december 2015 endourology and stone diseases 2490 vol 13 no 01 january-february 2016 2491 and no study has evaluated or compared clearance after rirs. thus, we compared the stone clearance times in patients who had undergone swl or rirs for single radiopaque renal pelvic stones 10-20 mm in size. the results of this study can serve as a guide for urologists and patients trying to decide the best optimal treatment preoperatively. materials and methods study population between january 2013 and february 2015, we conducted a retrospective study on 333 patients treated with swl (n = 172) or rirs (n = 161). patients with a single radiopaque renal pelvis stone in size 10-20 mm were included the study. treatment method was chosen according to the patient’s preference. patients with pediatric age group, those with multiple stones, obstruction in the urinary system (ureteropelvic or ureterovesical junction obstruction etc.), taking alpha blocker or calcium channel blocker medication, a history of renal or ureter surgery, creatinine level > 2mg/dl, anatomic anomaly of the urinary system (duplicated collecting system, kidney rotation anomalies etc.), irregular followed patients and those with non-radiopaque stones were excluded to provide highest compliance among groups. patients with preoperative and/or peroperative double j (dj) stent placement in rirs group and preswl dj stent placement in swl group were also excluded. additionally, only successfully treated patients with completely stone free or clinically insignificant residual fragments (cirfs) (< 3 mm) at the end of the follow-up were included in the study. a total of 104 patients met these criteria and were divided into 2 groups according to the procedure performed; swl group (n = 58), and rirs group (n = 46). flow diagram of the study with exclusion criteria are summarized in figure 1. we did not consider patients with treatment failure. we accepted stone-free status or cirfs (< 3 mm), which we detected on kidney-ureter bladder (kub) radiography or ultrasonography (usg) or non-contrast computerized tomography (ncct) as a treatment success in both groups. we defined treatment failure as residual fragments (≥ 3 mm) or insufficient fragmentation of a stone after three sessions in the swl group. in the rirs group, we defined treatment failure as the need for additional interventions, residual fragments (≥ 3 mm) and technical failure (such as failure of the access sheath placement). we evaluated patients with kub radiography, usg or intravenous urography and ncct, preoperatively. we evaluated all patients with ncct preoperatively. we calculated stone sizes from the greatest diameter on the ncct obtained from picture archiving and communication system. we also measured the hounsfield unit (hu) on ncct. we calculated stone clearance time from the day of complete stone fragmentation after swl in swl group and the operation day in rirs group until the complete clearing of stones from the urinary system after treatment. we performed another calculation following the first swl session to achieve complete fragmentation time for informing patients. the primary aim of the present study was to compare the stone clearance times after rirs and swl. we also compared group differences in stone diameter, age, sex, body mass index, fluoroscopy time (second) and hu. procedures we treated all patients according to the outpatient treatment protocol for swl. before the procedure, we evaluated urine tests, urine culture, blood and clotting parameters. we used an electrohydraulic extracorporeal lithotripter (argemet a1000, ankara, turkey) for the swl. we performed the swl with a team comprised of an experienced urologist and a technician. we performed the swl treatment with 60-shocks/per minute and lasted to visible stone fragmentation. if stone fragmentation was not visible, we did not exceed 3000 shock waves per session. we applied the swl sessions at intervals of two weeks. we administered nonsteroistone clearance time comparison-ercil et al. figure 1. flow diagram of the study with exclusion criteria. abbreviations: swl, extracorporeal shock wave lithotripsy; rirs, retrograde intrarenal surgery; dj, double j. dal anti-inflammatory drugs (nsaids) to the patients for pain relief after the swl session. for rirs, we admitted patients to the hospital and conducted routine tests for general anesthesia. we applied the rirs to patients under general anesthesia in the lithotomy position. firstly, under semi-rigid ureteroscopy, we placed a hydrophilic guidewire in the renal pelvis. then, accompanying the guidewire, we advanced a ureteral access sheath (11/13 french [f]) as far as the proximal ureter. we reached the renal pelvis using the rirs flexible ureteroscope (flex-x2, karl storz, tuttlingen, germany) contained in the ureteral access sheath. for fragmentation of the stones, we used the holmium: yag laser (sphinx, lisa, katlenburg, germany) with 272-micron fiber, set at energy 0.5-1 j and frequency 5-20/sec. the stones were fragmented as small as possible to pass through the ureter spontaneously. we did not actively remove the stones. none of the patients had inserted dj stents after the procedure. we administered nsaids in the postoperative period and discharged patients with non-complicated operations on postoperative day 1. evaluations we followed-up with our patients as described below. in the swl intervention, we assessed stone clearance with kub radiography after 48-72 hours of the swl session. we repeated swl sessions if stones were un-fragmented or semi-fragmented. the intervals between swl sessions were two weeks. for the rirs procedure, we assessed stone clearance with postoperative 1st day kub radiography. in both procedures, we evaluated patients with complete disintegration of the stone, weekly with kub radiography and usg for stone clearance time. we evaluated stone-free status with kub radiography and usg. we followed-up with kub and usg. we utilized nccts if there was doubt regarding the stone-free status or in symptomatic patients with a normal kub radiography. this algorithm is in figure 2. statistical analysis we performed statistical analysis using statistical abbreviations: bmi, body mass index; swl, extracorporeal shock wave lithotripsy; rirs, retrograde intrarenal surgery. variables swl group (n = 58) rirs group (n = 46) p value age, year 38.93 ± 10.05 40.54 ± 13.02 .491 stone size, mm 14.62 ± 2.58 14.91 ± 2.92 .592 bmi, kg/m2 23.61 ± 3.05 23.55 ± 3.25 .924 fluoroscopy time, s 32.95 ± 13.99 11.48 ± 3.97 < .001 hounsfield units 585.40 ± 158.39 567.74 ± 186.85 .610 stone clearance time of swl starting first day of treatment, days 37.74 ± 12.35 11.59 ± 7.01 < .001 stone clearance time following the completion of swl treatment, days 26.55 ± 9.71 11.59 ± 7.01 < .001 table. comparison of patient demographic and clinical characteristics. stone clearance time comparison-ercil et al. figure 2. the algorithm of the follow-up. abbreviations: swl, extracorporeal shock wave lithotripsy; rirs, retrograde intrarenal surgery. endourology and stone diseases 2492 vol 13 no 01 january-february 2016 2493 package for the social science (spss inc, chicago, illinois, usa) version 20. we used the shapiro-wilk test to assess normality; all normally distributed data are presented as mean ± the standard deviation. we used the student’s t-test for parametric variables and the mann-whitney u test for nonparametric variables. for multivariate analysis, we used the linear regression analysis test. we performed a retrospective power analysis and considered p < .05 statistically significant. results we evaluated 161 patients in the rirs group. a total of 19 patients experienced treatment failure due to residual stone, technical problems, or steinstrasse. the success rate in the rirs group was 88.2%. however, only 46 of these patients met the inclusion criteria. we evaluated 172 patients in the swl group. a total of 35 patients experienced treatment failure due to a residual stone, an unfragmented stone, or steinstrasse, and etc. the success rate in the swl group was 79.7%. however, only 58 of these patients met the inclusion criteria. the mean age of the patients was 38.93 ± 10.05 years and 40.54 ± 13.02 years for the swl and rirs groups, respectively. the average stone size for the swl group was 14.62 ± 2.58 mm and 14.91 ± 2.92 mm in the rirs group. the mean hu of the patients was 585.40 ± 158.39 hu in the swl group and 567.74 ±186.85 hu in the rirs group. as delineated in table, there was no significant difference between the groups on demographic characteristics. the mean number of sessions for the swl group was 1.86 (range 1-3). we treated 19 patients in one session, 28 patients in two sessions, and 11 patients in three sessions. the mean fluoroscopy screening time was 32.95 ± 13.99 seconds in the swl group and 11.48 ± 3.97 seconds in the rirs group (p < .001). following full fragmentation, the mean stone clearance time was 26.55 ± 9.71 days in the swl group and 11.59 ±7.01 days in the rirs group (p < .001). when calculated from the beginning of swl treatment, 37.74 ± 12.35 days was found necessary for complete stone clearance. we performed multivariate linear regression analysis to evaluate risk factors of stone clearance time. the type of treatment (p < .001) and stone size (p = .04) were significant factors in stone clearance time. however, hu (p = .552), age (p = .173), and bmi (p = .858) did not have an effect on stone clearance time. the retrospective power analysis yielded 91% power. discussion the treatment modality selection of renal stones usually depends on stone-related factors (location, size, and composition), clinical factors (patient’s comorbidities, patient’s compliance, solitary kidney, and abnormal anatomy), and technical factors (equipment available for treatment, success rates, possible complications, invasiveness, the need for anesthetics, hospitalization times, and costs).(11) all of these factors may shift the balance towards a certain modality or away from other treatments. patients may desire immediate or nearly immediate stone-free status with a single procedure or a less invasive procedure. conversely, a patient may be reluctant to anesthetics, hospitalization or the possibility of a temporary ureteral stent.(12) therefore, patients must be informed of the available treatment options, and patient’s expectations should be considered, including the relative benefits and risks associated with each treatment. in the decision-making process, patients are informed about factors predicting poor treatment outcomes and can be advised about alternative therapeutic modalities. however, there is no clear information to the patients about the time taken for clearing stones from the urinary system after treatment. the exact time taken for all stone fragments to clear from the urinary system after treatment is difficult to predict precisely; it is estimated from weekly imaging techniques (mainly plain radiographs or ultrasonography). in a study conducted by goren and colleagues(6) 117 patients with ureteral stones, treated with swl were followed. in 20 days, 93.1% of patients remained stone-free after the first session. the authors claim a mean of 13.1 (range 7-42) days for the clearance of proximal ureteral stones in 27 patients with a mean stone size of 20.7 mm. currently, the swl technique has been applied successfully in an outpatient setting (without anesthesia), with a low morbidity rate, and high patient compliance for the treatment of kidney and ureter stones. although patients with renal pelvic stones between 10 and 20 mm have several treatment options (swl, rirs or pcnl), it is still challenging deciding which treatment is the first choice. pcnl can achieve better results but is more invasive, is associated with greater morbidity and complications, and may be reserved for selected circumstances.(13) with similar success rates and complication rates, it is very challenging to prefer one modality over another. there are a limited number of studies that have evaluated stone clearance times in renal stones after swl. in 2008, naja and colleagues(9) evaluated the role of tamsulosin in the clearance of stone fragments after swl for the treatment of single radiopaque renal stones (5-20 mm). the stone positions were mostly in the renal pelstone clearance time comparison-ercil et al. vis (renal pelvis in 90 patients, superior calyx in 16 patients, and middle calyx in 10 patients). the total days required for a successful treatment were 35.53 ± 9.47 in the tamsulosin group and 47.22 ± 23.64 in the control group (p = .006). the authors reported that tamsulosin facilitates earlier clearance of fragments after swl and reduces the pain intensity associated with the tendency of the spontaneous clearance of steinstrasse. in the control group, the mean values of the stone size, the number of swl sessions, success rate and stone clearance time were determined as 13.06 ± 3.49 mm, 2.16, 84.6% and 47.22 ± 23.64 days respectively. similar to the previously study, zaytoun and colleagues(10) compared stone clearance times of renal stones with and without alpha receptor blockers after swl. the study included patients with single radiopaque renal stones up to 20 mm in diameter located in the renal pelvis, middle or upper calices. the mean expulsion time was 7.3 ± 2.7 weeks in the control group, 5.3 ± 2.6 weeks in tamsulosin group and 6.8 ± 2.8 weeks in the doxazosin group. the tamsulosin group was significantly shorter than both the control group (p = .002) and the doxazosin group (p = .026). on the other hand, there were no significant differences between the groups regarding the overall stone expulsion rates. in our study, the mean values of stone size, the number of swl sessions and stone clearance time were 14.62 ± 2.58 mm, 1.86 ± 0.71 sessions, and 26.55 ± 9.71 days. the shorter stone clearance time in our study group is thought to be due to the patient’s selection criteria and strict follow-up. stone clearance following kidney stone treatment is not well defined. for lower pole stones, sener and colleagues compared rirs with swl and reported a stone-free rate of 52.3% with patients treated using rirs one week after treatment. however after three months, the stone-free rate improved to 100%.(14) however, this study did not calculate stone-free clearance time. there is no clear information in the literature related to stone clearance time following rirs treatment. in the current study, stone size and stone clearance time were found to be 14.91 ± 2.92 mm and 11.59 ± 7.01 days respectively. to our knowledge, this is the first study to address stone clearance following swl and rirs. even though the study may be a great influence, there are several limitations. the study is retrospective, with a relatively low number of patients and lacked randomization. also, the comparison of rirs and swl seems to cause bias, but a comparison is necessary for informing patients. conclusions with advancements in endourology, many treatment options are available for both patients and physicians. having similar morbidities and success rates, rirs has a shorter clearance time, thus, may be one step ahead of the ‘gold standard’ race. therefore, prospective randomized studies on larger cohorts are needed. conflict of interest none declared. references 1. matlaga br, assimos dg. changing indications of open stone surgery. urology. 2002;59:490-4. 2. sener nc, bas o, sener e, et al. asymptomatic lower pole small renal stones: shock wave lithotripsy, flexible ureteroscopy, or observation? a prospective randomized trial. urology. 2015;85:33-7. 3. inci k, sahin a, islamoglu e, eren mt, bakkaloglu m, ozen h. prospective long-term followup of patients with asymptomatic lower pole caliceal stones. j urol. 2007;177:218992. 4. dellabella m, milanese g, muzzonigro g. efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. j urol. 2003;170:2202-5. 5. turk c, knoll t, petrik a, sarica k. guidelines on urolithiasis. european association of urology 2015 http://www.uroweb.org/ publications/eau-guidelines/ 6. resit-goren m, dirim a, ilteris-tekin m, ozkardes h. time to stone clearance for ureteral stones treated with extracorporeal shock wave lithotripsy. urology. 2011;78:2630. 7. seitz c, liatsikos e, porpiglia f, tiselius h-g, zwergel u. medical therapy to facilitate the passage of stones: what is the evidence? eur urol. 2009;56:455-71. 8. zhu y, duijvesz d, rovers mm, lock tm. alpha-blockers to assist stone clearance after extracorporeal shock wave lithotripsy: a metaanalysis. bju int. 2010;106:256-61. 9. naja v, agarwal mm, mandal ak, et al. tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi: results from an open-label randomized study. urology. 2008;72:1006-11. 10. zaytoun om, yakoubi r, zahran arm, et al. tamsulosin and doxazosin as adjunctive therapy following shock-wave lithotripsy of renal calculi: randomized controlled trial. urol res. 2012;40:327-32. 11. lehtoranta k. cost and effectiveness of different treatment alternatives in urinary stone practice. scand j urol nephrol. 1995;29:437stone clearance time comparison-ercil et al. endourology and stone diseases 2494 vol 13 no 01 january-february 2016 2471 47. 12. resorlu b, oguz u, resorlu eb, oztuna d, unsal a. the impact of pelvicaliceal anatomy on the success of retrograde intrarenal surgery in patients with lower pole renal stones. urology. 2012;79:61-6. 13. bas o, bakirtas h, sener nc, et al. comparison of shock wave lithotripsy, flexible ureterorenoscopy and percutaneous nephrolithotripsy on moderate size renal pelvis stones. urolithiasis. 2014;42:115-20. 14. sener nc, imamoglu ma, bas o, et al. prospective randomized trial comparing shock wave lithotripsy and flexible ureterorenoscopy for lower pole stones smaller than 1 cm. urolithiasis. 2014;42:127-31. stone clearance time comparison-ercil et al. vol 13 no 01 january-february 2016 2495 pediatric urology 233urology journal vol 5 no 4 autumn 2008 lubrication of circumcision site for prevention of meatal stenosis in children younger than 2 years old hassan bazmamoun,1 manoochehr ghorbanpour,2 seyed habibollah mousavi-bahar3 introduction: circumcision is one of the most common surgical operations throughout the world, and meatal stenosis is one its late complications. we evaluated the topical use of a lubricant jelly after circumcision in boys in order to reduce the risk of meatal stenosis. materials and methods: a randomized control trial was performed, in which 2 groups of boys younger the 2 years old underwent circumcision according to the sleeve method. the parents in the study group were instructed to use petroleum jelly on the circumcision site after each diaper change for 6 months. in the control group, no topical medication was used. the children were followed up regularly and evaluated for meatal stenosis, bleeding, infection, and recovery time. results: a total of 197 boys in each group completed the study. none of the children in the study group but 13 (6.6%) in the control group developed meatal stenosis (p < .001). infection of the circumcision site was seen in 3 (1.5%) and 23 (11.7%) children of the lubricant and control groups, respectively (p < .001), and bleeding was seen in 6 (3.0%) and 37 (18.8%), respectively (p < .001). the mean time of recovery in the lubricant group was 3.8 ± 1.2 days, while it was 6.9 ± 4.2 days in the control group (p = .03) conclusion: based on the findings of this study, it seems logical to use a lubricant jelly for reducing postcircumcision meatal stenosis and other complications. urol j. 2008;5:233-6. www.uj.unrc.ir keywords: circumcision, urethral stenosis, lubrication, wound infection 1division of gastroenterology, department of pediatrics, school of medicine, hamedan university of medical sciences, hamedan, iran 2division of pediatric surgery, department of surgery, school of medicine, hamedan university of medical sciences, hamedan, iran 3department of urology, school of medicine, hamedan university of medical sciences, hamedan, iran corresponding author: hassan bazmamoun, md besat hospital, hamedan 6514845411, iran tel: +98 912 133 1917 e-mail: dbazmamoun@yahoo.com received april 2008 accepted october 2008 introduction male circumcision means removing the foreskin that naturally covers the head of penis.(1) this is a surgery that is widely carry out among muslims and the jewish.(2) circumcision is done by different people whether by practitioners in the medical field or by nonqualified regional people. neglecting hygienic considerations and correct methods in circumcision can lead to dangerous early and late complications. early complications include bleeding, infection, urinary retention, hematoma, ischemia, necrosis of the glans, and amputation of the penis, and late complications are meatal stenosis, excessive or not enough prepuce, torsion of the penis, granuloma at circumcision site, circumcised hypospadias, etc.(3-6) meatal stenosis is an abnormal narrowing of the urethral meatus in men and is most commonly associated with circumcision.(7) it is likely that the newly exposed tip of the penis (including the meatus) suffers mild injury as it rubs against a diaper or the child’s own skin. lubrication following circumcision—bazmamoun et al 234 urology journal vol 5 no 4 autumn 2008 over time, this chronic irritation can result in scarring and a narrowing of the meatus. it can also result from mild ischemia that occurs with circumcision.(8,9) injury to the tip of the penis, inflammatory skin conditions (including balanitis and balanitis xerotica obliterans), or prolonged use of urinary catheters can also increase the risk of meatal stenosis.(8,10) physical examination will reveal a small narrowed meatus. this should correlate with urinating symptoms of urinary obstruction. upon close inspection, the lower surface of the meatus is often adhered. measuring the meatus is often unnecessary and will expose the patient to further risk of injury. surgical intervention with a meatotomy is the most reliable treatment.(9) several studies have been carried out regarding the appropriate age of circumcision, early and late complications of circumcision, the effect of circumcision on reducing the urinary tract infection, and comparing different techniques for doing circumcision in iran.(11-14) nonetheless, published study lack enough suggestions on postcircumcision care such as the use of mineral oils for reducing complications. some authors have reported routine use of lubricants to the meatal area after circumcision.(15) given the good results of applying petroleum jelly to the meatal area for preventing the recurrence of stenosis after meatotomy,(8) and also its good effect in preventing soap-related chemical urethritis,(16) we decided to perform a randomized controlled trial to evaluate postoperative lubrication of the circumcision site for prevention of meatal stenosis. materials and methods this study was a randomized controlled trial carried out on 400 boys younger than 2 years old referred to ekbatan hospital in hamedan, iran, between january 2006 and december 2007. they were referred for circumcision and a written informed consent was obtained from their parents for participation of their children in the study. the study design was approved by the local ethics committee. the sample size, according to previous studies was calculated to be 200 subjects for each study arm based on the following: p1 = 20%, p2 = 10%, α = 5%, and β = 20%. the children were divided according to the simple random sampling method into 2 equal groups. children in the first group underwent circumcision and used commercially available petroleum lubricant jelly for 6 postoperative months (lubricant group), while those in the control group did not use any topical medication after circumcision. all circumcisions were done by one surgeon according to the sleeve method,(17) and a gentamicin-soaked gauze was applied to the circumcision area in all cases. children in both groups were evaluated for 6 months (every other day for the first 2 weeks, then once per week for 1 month, and then every fortnight and also whenever a specific problem appeared). the parents in both groups were instructed to consider hygienic principles. in addition, parents in the lubricant group were instructed to apply the lubricant jelly to the glans and meatal area after each diaper change. diagnosis of meatal stenosis was made according to the history given by parents and direct observation of urinary caliber and meatus (loss of elliptical shape to a circular shape), difficulty in urination, high flow of urinary stream, pain during urination, and the need to sit or stand back from the toilet bowl to urinate. also the recovery duration of the circumcision scar, infection, and bleeding of the circumcision site were assessed according to the history given by the parents and physical examination. the collected data were analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). comparisons between the two groups were done by the chi-square test, the fisher exact test, and the t test, where appropriate. a p value less than .05 was considered significant. results four hundred boys younger than 2 years old participated in the study, and 6 (3 in each group) were excluded from the analysis because of irregular follow-up visits. the mean age was 8.7 ± 5.7 months (range, 8 days to 23 months) for the children in the lubricant group and 9.2 ± 8.1 lubrication following circumcision—bazmamoun et al urology journal vol 5 no 4 autumn 2008 235 months (range, 10 days to 23.5 months) for those in the control group (p = .67). none of the children in the lubricant group developed meatal stenosis, while 13 (6.6%) in the control group developed postcircumcision meatal stenosis (p < .001). infection of the circumcision site was observed in 3 (1.5%) and 23 (11.7%) children of the lubricant and control groups, respectively (p < .001). six boys (3.0%) in the lubricant group and 37 (18.8%) in the control group had postcircumcision bleeding (p < .001). finally, the mean time of recovery in the lubricant group was 3.8 ± 1.2 days, while it was 6.9 ± 4.2 days in the control group (p = .03). discussion diagnosis of meatal stenosis has been reported in 0.9% to 11% of the boys undergoing circumcision. (7,14,18) however, higher rates may be seen in areas in which the procedure is done nonqualified regional people.(14) the present study showed that using petroleum jelly after circumcision was considerably effective for reducing the frequency of postcircumcision meatal stenosis. we did not observe any case of meatal stenosis in children whose circumcision site was lubricated for 6 months, while with the operation of the same surgeon, 6.6% of the children in the control group developed stenosis. to our knowledge, there is no similar study regarding the effect of lubricants for reducing postcircumcision meatal stenosis. we found less frequent cases of postcircumcision bleeding in boys with lubrication of the circumcision site when compared with the control group. bleeding has been reported as the most common early complication after circumcision and its prevalence was reported between 1% and 23 %, depending on the experience and talent of the practitioner and the technique used.(19,22) our main goal was to prevent meatal stenosis, but lubrication was also effective in reducing the early episodes of bleeding. we also achieved good results regarding the infection in the circumcision site. different statistical findings, ranging from 0.1% to3.9%, have been reported in other studies for the prevalence of infection at the circumcision site.(12,21,22) these figures depend on the practitioner’s skill and the technique used. there were no similar studies to show the effect of lubrication on this kind of infection. okeke reported application of bland petroleum jelly to the external urethral meatus in boys with chemical urethritis and yielded promising results.(16) lubrication might be effective in reducing inflammation of the procedure site, and consequently, in reducing the rate of infection. finally, as the patient’s needs concerns, shortening the recovery period is an aim of postoperative care. with lubrication of the circumcision site, we reduced it from and average of 6.9 days to less than 4 days. conclusion based on the findings in this randomized controlled study, we can conclude that using petroleum jelly after circumcision is considerably effective for reducing postcircumcision meatal stenosis and other complications. acknowledgement we would like to thank dr hossein mahjoub, professor of epidemiology and biostatistics in hamedan university of medical sciences. conflict of interest none declared. references 1. hirji h, charlton r, sarmah s. male circumcision: a review of the evidence. j mens health gend. 2005;2:21-30. 2. parigi gb. [destiny of prepuce between quran and drg]. pediatr med chir. 2003;25:96-100. italian. 3. muula as, prozesky hw, mataya rh, ikechebelu ji. prevalence of complications of male circumcision in anglophone africa: a systematic review. bmc urol. 2007;7:4. 4. okeke li, asinobi aa, ikuerowo os. epidemiology of complications of male circumcision in ibadan, nigeria. bmc urol. 2006;6:21. 5. demirseren me, gokrem s. circumcision in unqualified hands: a significant risk of complication. plast reconstr surg. 2004;113:1090-2. 6. elder js. anomalies of the penis and urethra. in: kliegman rm, behrman re, jenson hb, stanton bf, editors. nelson textbook of pediatrics. 18th ed. philadelphia: wb saunders; 2007. p. 2255-6. 7. van howe rs. incidence of meatal stenosis following neonatal circumcision in a primary care setting. clin lubrication following circumcision—bazmamoun et al 236 urology journal vol 5 no 4 autumn 2008 pediatr (phila). 2006;45:49-54. 8. angel ca. meatal stenosis [monograph on the internet]. emedicine [updated 2006 jun 12; cited 2008 nov 12]. available from: http://www.emedicine.com/ ped/topic2356.htm 9. persad r, sharma s, mctavish j, imber c, mouriquand pd. clinical presentation and pathophysiology of meatal stenosis following circumcision. br j urol. 1995;75:91-3. 10. frank jd, pocock rd, stower mj. urethral strictures in childhood. br j urol. 1988;62:590-2. 11. arbabi a. neonatal circumcision with plastibell, benefits and complications. iran j urol. 2000;24:17-22. 12. totonchi p, mahmoodzadeh h, nematollahzadeh k. evaluation of circumcision. j fac med. 1999;56:25-8. 13. simforoosh n, khalili-ardestani a, afjehi a. evaluation of neonatal circumcision effect on urinary tract infection in infancy. iran j urol. 2001;25: 7-14. 14. yegane ra, kheirollahi ar, salehi na, bashashati m, khoshdel ja, ahmadi m. late complications of circumcision in iran. pediatr surg int. 2006;22:442-5. 15. mayoclinic.com [homepage on the internet]. circumcision for baby boys: weighing the pros and cons [updated 2008 mar 1; cited 2008 nov 12]. available from: http://www.mayoclinic.com/health/ circumcision/pr00040 16. okeke li. soap induced urethral pain in boys. west afr j med. 2004;23:48-9. 17. jordon gh, schlossberg sm. surgery of the penis and urethra. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1045-6. 18. stenram a, malmfors g, okmian l. circumcision for phimosis--indications and results. acta paediatr scand. 1986;75:321-3. 19. fesharakinia a, ghafouri kh, foadaldini m, saadatjou sar. study of circumcision condition in birjand city. j birjand univ med sci. 2006;12:45-9. 20. vahedian m, zeinalinezhad h, sotoudeh-nejad a, pourseyedi b, aghaee-afshar m. evaluation of postoperative complication of plastibell circumcision in infants under 6 months of age. iran south med j. 2002;5:141-5. 21. dehghani v, moein m, mirshamsi mh. prevalence of circumcision complications in boys under 2 years old. j yazd shahid sadooghi univ med sci. 2001:8:41-5. 22. fanai s.a, musaviani s.m, mehrvarz s.h. plastibble and conventional circumcision in infants. a randomized clinical trial. j rafsanjan univ med sci. 2003;2:68-73. vol 13 no 05 september-october 2016 2864 sexual dysfunction and infertility comparison of polypropylene mesh and primary repair in the treatment of blunt testicular rupture ibrahim nuvit tahtali,1* fikret halis,2 turan yıldız,2 ahmet gokce,2 zekeriya i̇lçe,2 mevlana derya balabay3 purpose: this study aimed to show the applicability of polypropylene mesh (pm) grafting in blunt testicular ruptures. materials and methods: data of 16 patients treated for testicular rupture following blunt scrotal trauma between march 2007 and april 2015 were analyzed retrospectively. eight primary repairs and eight pm graftings were performed to repair the tunica albuginea (ta). postoperatively, patients underwent doppler ultrasonography at 3 weeks and then at 3, 6, and 12 months, followed by annual scans. the measurement of plasma testosterone levels was performed 12 months after the surgery. results: the average follow-up time was 24.8 (range 12–48) and 42.8 (range 14–75) months for patients treated with pm grafting and primary repair, respectively. differences in testicular size between treatment groups were only significant at 12 months postoperatively with the value of 26.5 ml (range 24–28) and 22.8 ml (range 13–27) in patients treated with a pm graft and primary repair, respectively (p = .045). there were no complications for those patients treated with the pm graft. two patients who underwent primary repair developed testicular atrophy within 1 year postoperatively. conclusion: pm grafting is a safe alternative to primary closure of a ta defect following blunt testicular trauma. keywords: etiology; rupture; testis injuries; urogenital surgical procedures. introduction testicular rupture is a tear in the tunica albuginea (ta), and for this reason it is a surgical emergency. scrotal trauma comprises less than 1% of all trauma-related injuries. the primary etiologies of scrotal trauma include blunt, penetrating, degloving, and electrical burn injuries to the scrotal contents(1,2). both penetrating and blunt traumas can cause testicular rupture(3,4). specifically, blunt trauma accounts for 75% of testicular injuries(5). individuals aged 10–30 years are the most vulnerable group to testicular trauma(6). there are serious repercussions if a testicular rupture is missed. although not life-threatening, loss of a testicle could impair future fertility, contribute to a hypogonadal state, and affect the psychosocial wellbeing of the patient(1). the surgeon should attempt to salvage/ preserve any viable tubules, as studies have revealed reduced endocrine abnormalities and improved semen quality when tubules are preserved, as compared to orchiectomy(6). the standard treatment of testicular rupture is early exploration and debridement. if testicular rupture intervention occurs within the first 72 hours, the chance of saving the testes is 90%, whereas it drops to 30% after 72 hours(7,8). in some cases, closure of the ta might not be possible if the seminiferous tubules are swollen or the tear in the tunica is large. in these cases, alternative closure methods are available. this study reports the results of treatment of testicular rupture with primary repair versus polypropylene mesh (pm) grafting. long-term results were also evaluated. materials and methods data of 16 patients treated for testicular rupture following blunt scrotal trauma between march 2007 and april 2015 were analyzed retrospectively. eight patients underwent pm grafting and eight underwent a primary repair. the study included 5 pediatric and 11 adult patients. the patients' age, cause of scrotal trauma, clinical findings, imaging results, time between trauma and hospital admission, operative findings, and postoperative outcomes were evaluated. patients with penetrating or gunshot testicular trauma and those with an avulsion of the scrotum were excluded from this study. surgery procedures all patients were evaluated with doppler ultrasound (us) and with preoperative and intraoperative physical examination. following scrotal trauma, sufficient exposure was obtained via the injury or through a midline vertical incision, and the scrotal hematoma was evacuated (figure 1). nonviable and extruded seminiferous tubules were debrided. the rupture in the ta was then revealed. if the ta could be re-approximated, a primary repair was performed with 3-0 polydioxanone. if the tunica could not be re-approximated, or if a change in color of the testicular tissue was observed, a 1 mm thick pm graft was positioned and attached with 3-0polydioxanone sutures (figure 2). a paratesticular penrose 1 department of urology, malatya state hospital, malatya, turkey. 2 department of urology, school of medicine, sakarya university, sakarya, turkey. 3 department of urology, memorial sisli hospital, i̇stanbul, turkey. *correspondence: department of urology, malatya state hospital, malatya, turkey. tel: +90 532 6112182. e-mail: nuvit_tahtali@hotmail.com. received may 2016 & accepted june 2016 drain was also placed, and removed within 24–48 hors. immediately after the operation, the scrotum was elevated, iced, and anti-inflammatory therapy was started. follow-up postoperatively, patients underwent doppler us once in 3 weeks and then once in 3, 6, and 12 months, followed by annual scans (figure 3). the average follow-up period was 24.75 months (range 12–48) for patients who underwent pm grafting, and 42.75 months (range 14–75) for patients who underwent primary repair. two of the patients, one from each group, moved to another city after one year. for this reason, one-year follow-up results of the patients were given in the study. testicle size and echogenicity, as well as the state of the pm grafts, were assessed during follow-up. a normal testis is 4–5 cm long, 3 cm wide, and 2.5 cm thick, with a volume of 30 ml(9). the postoperative testicular volume was calculated from us measurements using the empirical formula of lambert (length × width × height × 0.71)(10). the level of plasma testosterone was measured at 12 months postoperatively to evaluate hormonal status. total testosterone was measured by electro-chemiluminescence immunoassay (eclia). statistical analysis treatment technique patient age cause of injury side intervention time (hours) complications polypropylene mesh grafts 1 13 fight right 36 2 14 fight left 12 3 35 occupational accident right 6 4 34 fight right 18 5 23 sports left 12 6 26 sports right 6 7 16 sports left 12 8 49 fight left 4 primary repair 9 16 fight right 12 testicular atrophy 10 28 fall from height righ t 24 11 16 sports left 6 12 24 fight left 8 testicular atrophy 13 19 sports right 4 14 21 fight right 6 15 18 sports right 5 16 24 motorcycle accident right 8 table 1. characteristics of patients who underwent primary repair and/or polypropyl mesh grafts on blunt type testicular rupture. figure 1. the testicular tissue extruded in scrotal exploration after blunt trauma. figure 2. the polypropylene mesh graft in place. polypropylene mesh for blunt testicular rupture-tahtali et al. sexual dysfunction and infertility 2865 vol 13 no 05 september-october 2016 2866 statistical analyses were performed using the statistical package for the social science (spss inc, chicago, illinois, usa) version 13.0. the mann–whitney u-test, the nonparametric equivalent of student’s t-test, was used to compare differences between the independent groups. as the sample size was less than 10, the use of a non-parametric test was more suitable. a p value less than .05 was considered statistically significant. results overall, the mean interval between injury and surgery was 11.2 hours (range 4–36). when evaluating the group-specific time interval, it was 9.1 hours (range 4–24) for primary repair and 13.25 hours (4–36) for pm repair. this difference was not significant (p = .286). the cause of testicular rupture was a fight with blunt trauma in seven patients (43%) and sports injuries in six patients (37.5%), primarily being struck by a ball or a foot during a football match. of the remaining three patients, one was injured in an occupational accident (6%), one was injured in a fall (6%), and one was injured in a motorcycle accident (6%). none of the patients suffered additional organ trauma (table 1). patients who underwent pm grafting had an average age of 26.25 years (range 13–49) and were followed for an average of 24.75 months (range 12–48), postoperatively. four pm graft patients had a right testicular rupture and four had a left testicular rupture. the average hospital stay for a pm graft patient was 3.37 days (range 2–5). patients who underwent primary repair had an average age of 20.75 years (range 16–28) and were followed for an average of 42.5 months (range 14–75), postoperatively. six (75%) primary repair patients had a right testis rupture and two had a left rupture. the hospital stay for primary repair patients averaged 3.25 days (range 2–5). the average testis sizes on follow-up doppler us for patients who underwent pm grafting were 27.2 (range 25–30), 27 (range 24–29), 26.6 (range 24–28), and 26.5 (range 24–28) ml at 3 weeks and 3, 6, and 12 months after operation, respectively (table 2). for patients who underwent primary repair, the average sizes were 27.6 (range 25–30), 24.4 (range 17–28), 23.8 (range 16–26), and 22.8 (range 13–27) ml at 3 weeks and 3, 6, and 12 months after operation, respectively. differences in testicular size between treatment groups were only significant at 12 months postoperatively (p = .045). two of the patients who underwent primary repair developed testicular atrophy. the testicular volumes for these two patients 12 months after surgery were 13 and 15 ml. the interval between testicular trauma and hospital admission was 8–12 hours, and there was no relationship between the timing of surgical intervention and the development of atrophy. there were no significant differences in the time interval between admission and surgery for the two treatment groups (p = .238). plasma testosterone levels were measured after 12 months postoperatively to evaluate hormonal status. the mean testosterone level was 492.5 ng/dl (range 320– 750) in patients who underwent pm grafting and 478 ng/ dl (range 280–780) in patients who underwent primary repair. no significant difference was found in the testosterone levels of the two treatment groups (p = .527). discussion blunt scrotal trauma can result in a variety of injuries including testicular rupture, torsion, dislocation, hematoma, or contusion, as well as epididymal, scrotal, and urethral injuries. if not diagnosed aggressively and repaired surgically, testicular rupture can lead to testicular atrophy and loss(11). the maximum preservation of viable testicular tissue is essential, because subfertility is a late complication of testicular trauma(12). to avoid debriding viable testicular tissue, a graft can be used to cover the defect(13). the standard treatment of testicular rupture is early surgical exploration and an attempt to save the testis(1). the hematoma is evacuated intraoperatively, extruded seminiferous tubules are debrided, and the ta is closed pritime of us primary repair group polypropylene mesh group p value 3 weeks 27.6 (25–30) ml 27.2 (25–30) ml .667 3 months 24.4 (17–28) ml 27 (24–29) ml .179 6 months 23.8 (16–26) ml 26.6 (24–28) ml .060 1 year 22.8 (13–27) ml 26.5 (24–28) ml .045 table 2. testicular volume at follow-up. abbreviation: us, ultrasonography. figure 3. the doppler ultrasonography photograph, taken six months after treatment of a patient who was treated with polypropylene mesh for blunt testicular trauma. polypropylene mesh for blunt testicular rupture-tahtali et al. marily. if the completion of these steps is not possible, alternative methods include using a free graft of tunica vaginalis or a vascularized tunica vaginalis graft(8,14). for adolescent patients with testicular rupture due to blunt trauma, cubillos and colleagues found that rest, antibiotic treatment, and a conservative approach with serial us follow-ups is suitable if no atrophy develops(4). chandra and colleagues reported that patients with blunt scrotal trauma should undergo scrotal exploration, without us, if there is a hematocele, and that the maximum tissue is saved if exploration is performed within 72 hours(7). although successful, non-operative management has recently been reported. this approach is traditionally thought to be associated with a greater risk of infection, testicular atrophy, and resulting orchiectomy. the standard treatment for testicular rupture remains early exploration and debridement to attempt testicular salvage(4,5). polypropylene meshes are a type of non-absorbable mesh(15). the use of synthetic meshes as a means of strengthening the abdominal wall was popularized after the work by usher and gannon in a canine model. usher subsequently reported the clinical usefulness of synthetic mesh in the repair of abdominal and thoracic defects(16); however, the wide acceptance of pm took place in 80's following lichtenstein's report(17). the use of pm in hernia surgery has become increasingly popular. the use of synthetic mesh for achieving a tension free repair has resulted in a significant reduction in postoperative recurrences(18). polypropylene meshes have a mild reactivity upon implantation and in-growth, with low susceptibility to mesh infection. furthermore, they have a tensile strength that is retained for indefinite periods of time(19). however, these meshes can induce adhesion of viscera when placed intraperitoneally(20). polypropylene mesh has been widely used in the treatment of urinary incontinence in urological surgery since 1980s.suburethral slings have become the preferred technique for the treatment of stress urinary incontinence(21). studies confirm that the choice of a tension free pm allow high success rates and the transvaginal taps (tvt)® simplified the stress urinary incontinence therapy, becoming one of the most common options for the treatment of this disease(22,23). ferguson et al. initially used polytetrafluoroethylene grafts in two patients with testicular rupture as a result of gunshot trauma. however, orchiectomies were performed because of severe epididymo-orchitis, a common occurrence for ruptures caused by gunshot trauma. typically polytetrafluoroethylene graft infections are caused by a foreign body and are resistant to antibiotic treatment. ferguson and colleagues also used free tunica vaginalis grafts in seven patients with gunshot wounds, and the results proved satisfactory(14) .all of the patients in the present study had blunt scrotal trauma, and none developed epididymo-orchitis. grigoryuk and colleagues found that polytetrafluoroethylene stimulated the local production of pro-inflammatory cytokines when compared with polypropylene in their study. polytetrafluoroethylene is a more reactogenic material than polypropylene; it mainly stimulates the local production of pro-inflammatory cytokines. the local anti-inflammatory effect of polypropylene was less pronounced, but persisted for longer time(24). we performed scrotal exploration 12 hours after a sports-related accident, resulting in testicular rupture. despite the debridement of the testicular tissue that was extruded, we were not able to do primary repair of the ta. we did not use a free graft of tunica vaginalis or a vascularized tunica vaginalis graft as there was edema and fragmentation of the ta. instead of performing an orchiectomy, we repaired the rupture using pm. thus, as the results were encouraging, we used it as an alternative technique in traumas. to treat testicular rupture, jian et al. used vascularized tunica vaginalis grafts and suggested this method as an alternative treatment when the ta cannot be reapproximated(8). kuritov and colleagues used tunica vaginalis grafts after performing a testicular fasciotomy in three patients to prevent compartment syndrome(25). however, in blunt scrotal testicular ruptures, it is often difficult to obtain a vascularized graft due to the presence of a hematoma in the scrotal layers or edema in the tunica vaginalis. therefore, tunica vaginalis grafts were not used in the present study. to the best of our knowledge, this study is the first to demonstrate that a pm graft can be used to successfully close a ta defect during testicular rupture repair following blunt trauma. there were several limitations to this study, including the retrospective design and small cohort. in the present study, semen analyses were not carried out during the postoperative period, although one patient treated with pm became a father after the operation, and another is expecting his second child. in both groups, plasma testosterone levels 12 months postoperatively were normal, and no statistical difference was found between the treatment groups. measuring the testicular pressure with a handheld compartment monitor could have prevented the development of compartment syndrome after primary closure. lastly, one of the limitations of this study was not having measured the devitalized tissue amount that was debrided in patients with testicular rupture. conclusions in conclusion, following testicular rupture due to blunt trauma, there might be insufficient tissue with which to close the ta because of aggressive seminiferous tubule debridement. aggressive seminiferous tubule excision in an attempt to close the ta can lead to significant loss of testicular parenchyma, and the forced closure of the free ends of the ta with the application of tension can cause testicular atrophy via compartment syndrome. in such cases, pm is a safe synthetic material that should be used to close the defect and should serve as an alternative to primary repair of the ta with aggressive debridement or use of tension. conflict of interest none. references 1. buckley jc, mcaninch jw. diagnosis and management of testicular ruptures. urol clin north am. 2006;33:111-6. 2. deurduli c, mittelstaedt ca, chong wk. us of acute scrotal trauma: optimal technique, imaging findings, and management. radio graphics. 2007;27:357-69. 3. dogra vs, gottlieb rh, oka m, rubens polypropylene mesh for blunt testicular rupture-tahtali et al. sexual dysfunction and infertility 2867 vol 13 no 05 september-october 2016 2868 dj. sonography of the scrotum. radiology. 2003;227:18-36. 4. cubillos j, reda ef, gitlin j, zelkovic p, palmer ls. a conservative approach to testicular rupture in adolescent boys. j urol. 2010;184:1733-8. 5. cass as, luxenberg m. testicular injuries. urology. 1991;37:528-30. 6. chang aj, brandes sb. advances in diagnosis and management of genital injuries, urol clin north am. 2013;40:427-38. 7. chandra rv, dowling rj, ulubaşoşlu m. rational approach to diagnosis and management of blunt scrotal trauma. urology. 2007;70:230-4. 8. jian py, nelson ed, roth dr. use of a vascularized tunica vaginalis flap for repair of testicular rupture in the pediatric patient. urology. 2012;79:1363-4. 9. chung bi, sommer g, brooks jd. anatomy of the lower urinary tract and male genitalia, in alan jw (ed): campbell-walsh urology, 10th ed. philadelphia: saunders vol.1, 2012. p. 6768 10. sakamoto h, saito k, ooh m. testicular volume measurement: comparison of ultrasonography, orchidometry, and water displacement. urology. 2007;69:152-7. 11. munter dw, faleski ej. blunt scrotal trauma: emergency department evaluation and management. am j emerg med. 1989;7:22734. 12. kukadi an, ercole cj, gleich p, hensleigh h, pryor jl. testicular trauma: potential impact on reproductive function. j urol. 1996;156:1643-6. 13. molokw cn, doulla ri, townell nh a. novel technique for repair of testicular rupture after blunt trauma. urology. 2010;76:1002-3. 14. ferguson gg, brandes sb. gunshot wound injury of the testis: the use of tunica vaginalis and polytetrafluoroethylene grafts for reconstruction. j urol. 2007;178:2462-5. 15. morris-stiff gj, hughes le. the outcomes of nonabsorbable mesh placed within the abdominal cavity: literature review and clinical experience. j am coll surg. 1998;186:352-67. 16. usher fc, gannon jp. marlex mesh, a new plastic mesh for replacing tissue defects. i. experimental studies ama arch surg.1959;78:131-7. 17. lichtenstein il, shulman ag, amid pk, montllor mm. the tension-free hernioplasty. am j surg. 1989;157:188-93. 18. amid pk, lichtenstein il, shulman ag, hakakha m. biomaterials for "tensionfree" hernioplasties and principles of their applications. minerva chir. 1995;50:821-6. 19. morris-stiff gj, hughes le. the outcomes of nonabsorbable mesh placed within the abdominal cavity: literature review and clinical experience. j am coll surg. 1998;186:352-67. 20. voyles cr, richardson jd, bland ki, tobin gr, flint lm, polk hc jr. emergency abdominal wall reconstruction with polypropylene mesh: short-term benefits versus long-term complications. ann surg. 1981;194:219-23. 21. niknejad k, plzak ls 3rd, staskin dr, loughlin kr. autologous and synthetic urethral slings for female incontinence. urol clin north am. 2002;29:597-611. 22. leach ge, dmochowski rr, appell ra, et al. female stress urinary incontinence clinical guidelines panel summary report on surgical management of female stress urinary incontinence. j urol. 1997;158:875-80. 23. rodriguez lv, raz s. prospective analysis of patients treated with a distal urethral polypropylene sling for symptoms of stress urinary incontinence: surgical outcome and satisfaction determined by patient driven questionnaires. j urol. 2003;170:857-63. 24. grigoryuk a, turmova ep. effects of polypropylene and polytetrafluoroethylene prostheses for abdominal plasty on local and systemic cytokine production. bulletin of experimental biology and medicine.2014; 156:530-4. 25. kutikov a, casale p, white ma. testicular compartment syndrome: a new approach to conceptualizing and managing testicular torsion. urology. 2008;72:786-9. polypropylene mesh for blunt testicular rupture-tahtali et al. miscellaneous comparative results of transurethral incision with transurethral resection of the prostate in renal transplant recipients with benign prostate hyperplasia mehmet sarier1*, ibrahim duman1, suleyman kilic2, yucel yuksel3, meltem demir4, mesut aslan3, levent yucetin3, sabri tekin5, asuman havva yavuz6, mestan emek7 purpose: the aim of this study is to compare the results of transurethral incision of the prostate (tuip) and transurethral resection of the prostate (turp) for the surgical treatment of benign prostate hyperplasia (bph) in patients with renal transplantation. materials and methods: between april 2009 and may 2016, bph patients with renal transplants whose prostate volumes were less than 30 cm3 were treated surgically. forty-seven patients received turp and 32 received tuip. the patients' age, duration of dialysis, duration between transplant and turp/tuip, preoperative and postoperative serum creatinine (scr), international prostate symptom score (ipss), maximum flow rate (qmax) and postvoid residual volume (pvr) were recorded. at 1-,6and 12-month follow-up, early and long-term complications were assessed. results were evaluated retrospectively. results: in both groups, scr, pvr and ipss decreased significantly after the operation, while qmax increased significantly (p < .001). there was no difference between the two groups in terms of increase in qmax and decrease in ipss, scr and pvr (p = .89, p = .27, p = .08, and p = .27). among postoperative complications, urinary tract infection (utis) and retrograde ejaculation (re) rates were higher in the turp group than the tuip group (12.7% versus 6.2% and 68.1% versus 25%,respectively), whereas urethral strictures were more prevalent in the tuip group (12.5% versus 6.3%). conclusion: for the treatment of bph in renal transplant patients with a prostate volume less than 30 cm3, both tuip and turp are safe and effective. keywords: benign prostate hyperplasia; renal transplantation; transurethral resection of prostate; transurethral incision of prostate; tuip; turp. introduction benign prostatic hyperplasia (bph) is a chronic progressive disease affecting one-third of men older than 60 years of age. obstructive symptoms due to bph will eventually demand surgical intervention in approximately 25% of patients.(1) the mean age for renal transplantation has been increasing lately, and functional results of transplanted kidneys in the elderly are quite satisfying.(2) presumably, the incidence of bph in elderly male transplant patients is increasing.(3) bladder dysfunction, particularly due to bph, is common in elderly male patients.(4) however, bph incidence in renal transplant recipients is often miscalculated, as patients with chronic renal failure are oliguric or anuric. bph and related lower urinary tract symptoms (luts) emerge after the restoration of diuresis following transplantation and may compromise graft function and patient outcomes.(5) therefore, optimal bladder function is crucial for patients who undergo renal transplantation. transurethral resection of the prostate (turp) is cur1department of urology kemerburgaz university istanbul 34170 turkey. 2department of urology liv hospital istinye university istanbul 34120 turkey. 3department of transplantation unit medical park hospital antalya 07100 turkey. 4department of clinical biochemistry kemerburgaz university istanbul 34170 turkey. 5department of surgery kemerburgaz university istanbul 34170 turkey. 6department of nephrology medical park hospital antalya 07100 turkey. 7public health diroctorate, antalya 07140 turkey. *correspondence: medical park hospital department of urology muratpaşa, antalya, 07100 turkey. tel: +905333324960. fax: +902423143030. email: drsarier@gmail.com. received july 2017 & accepted december 2017 rently accepted as the gold standard treatment for luts caused by bph. although turp is associated with low mortality and morbidity, it is not completely complication-free. transurethral incision of the prostate (tuip) is a simpler and less invasive procedure than turp. for this reason, tuip is mostly recommended as an ideal treatment option for younger, sexually active males with prostate volumes less than 30 cm3.(6,7) there are numerous studies comparing the results of turp and tuip. however, there is no comparative study evaluating the effects of these two procedures in renal transplant patients. the aim of this study is to compare the results of tuip with turp in renal transplant recipients with small benign prostate adenomas less than 30 cm3 in volume. materials and methods between april 2009 and march 2016, a total of 3453 renal transplantation procedures were performed in the organ transplant unit of medical park hospital. patients who underwent renal transplantation and suffered from vol 15 no 04 july-august 2018 209 bph refractory to medical treatment received surgery for bph. of these, 89 received turp and 32 received tuip. in order to ensure standardization, patients with prostate volumes greater than 30 cm3 on transrectal ultrasound (trus) were excluded from the study. a total of 47 turp and 32 tuip patients who received surgery for bladder outlet obstruction (boo) caused by bph after renal transplantation were included in the study. this study compared these two different patient series retrospectively. the study was approved by the local ethics committee and written informed consent was obtained from all patients before the surgery. for each patient, digital rectal examination, urinary ultrasonography (usg), trus, prostate specific antigen (psa), uroflowmetry, voided volume, maximum flow rate (qmax), average flow rate (qave), postvoid residual urine volume (pvr), serum creatinine (scr), urine analysis and urine culture tests were carried out preoperatively. based on these results, flexible cystoscopy was performed if necessary. indications for surgery were moderate to severe luts ( international prostate symptom score ipss ≥ 10, if applicable, i.e. not with an indwelling urethral catheter for urinary retention), qmax<10 ml/s, previous medical therapy failure, pvr>100 ml in the presence of recurrent uti, urinary retention and bph-related upper tract dilatation in the transplanted kidney on usg along with an increase in scr. candidates for surgery were assessed for medical and surgical suitability before the procedure. turp or tuip was performed under spinal anesthesia or general anesthesia. all patients received antibiotic prophylaxis 30 minutes prior to surgery, and antibiotherapy was continued for 24 hours after surgery. turp was performed using 26 fr continuous-flow bipolar resectoscopes according to standard technique. tuip was performed using the orandi technique, by creating incisions with collin's knife at the 5 and 7 o'clock positions bilaterally on the bladder neck and prostate. after the tuip or turp procedures, an 18 or 20 fr 3-way foley catheter was inserted and the bladder was continuously irrigated until next morning. the volume of resected prostate tissue was measured after turp procedure. dufour catheter was removed when urine became clear. complete blood count, scr and urine culture tests were performed in the postoperative period. pvr measurement was repeated before discharge in all patients. urine analysis with cultures, scr, uroflowmetry and pvr were measured at 1-month follow-up; and retrograde ejaculation (re) presence was investigated at 6-month follow-up. the minimum follow-up duration was 12 months. on long-term follow-up, all patients were assessed for operation outcomes and long-term complications such as urethral stricture and bladder neck contractures. the results were evaluated retrospectively. all statistical analyses were performed using the spss statistical software (spss for windows, version 22.0; spss, inc., chicago, il, usa). the normality of data distribution was determined using shapiro-wilk tests. data with normal distribution were presented as mean and standard deviation. data showing non-normal distribution were presented as median (min-max). the comparison of the preand post operation data was made using t-test and wilcoxon signed rank test. comparison of the two independent operation groups was made using the t-test and mann whitney u test. qualitative variables were expressed as frequencies with percentages and comparisons between proportions were made with the chi-square test. a p-value < 0.05 was considered statically significant. results the mean age of the 47 patients in the turp group was 60.1±7.7. the median dialysis duration was 28 (0-180) months. the median duration between renal transplantation and turp was 14 (0-84) months. preoperatively, the mean scr level was 2.06 ± 0.8 mg/dl, the mean serum total psa was 1.31 ± 0.8 mg/ml, and the mean prostate volume was 24.1 ± 3.3 cm3 (table 1). the mean ipss was 18.8 ± 2.8. uroflowmetry parameters qmax and qave were 9.7 ± 3.6 ml/s and 6.2 ± 2.3 ml/s, respectively. the mean pvr was 90 (5-400) ml. none of the patients had preoperative complications. none of the patients needed blood transfusion postoperatively. the mean duration of catheter use was 2.65 ± 0.7 days. as short-term postoperative complications, one (2.1%) patient experienced acute urinary retention (aur) aftable 1. characteristics of patients in turp and tuip groups. characteristica turp tuip p age (years), mean (sd) 60.1 ± 7.7 44.2 ± 8.2 < .001 duration of dialysis before rt (months) 28 (0-180) 34 (0-204) .939 time between rt and turp/tuip (months) 14 (0-84) 19 (0-66) .231 mean psa (ng/ml), mean (sd) 1.31 ± 0.8 0.96 ± 0.6 .019 mean prostate volume (cm3), mean (sd) 24.1 ± 3.3 20.2 ± 4.2 < .001 duration of catheterization following turp/tuip 2.65 ± 0.7 1.46 ± 0.6 < .001 median follow-up after turp/tuip (months) 42 (12-94) 38 (12-46) .006 adata is presented as mean ± sd or medain(range) adata is presented as mean ± sd or medain(range) preoperative postoperative p value scr (mg/dl)a turp 2.06 ± 0.8 1.76 ± 0.7 < .001 tuip 2.01 + 0.8 1.65 ± 0.6 = .001 qmax (ml/s)a turp 9.7 ± 3.6 23.6 ± 10.8 < .001 tuip 9.4 ± 4.2 26.9 ± 9.5 < .001 qave (ml/s)a turp 6.2 ± 2.3 13 ± 6.1 < .001 tuip 5.8 ± 2.4 14.7 ± 6.2 < .001 pvr (ml)a turp 90 (5-400) 10 (0-200) < .001 tuip 80 (5-300) 5 (0-205) < .001 ipssa turp 18.8 ± 2.8 5.5 ± 2.4 < .001 tuip 18.6 ± 3 6.1 ± 2.2 < .001 table 2. urological and renal functional outcomes of turp and tuip. turp vs. tuip for bph in renal transplantation-sarier et al. miscellaneous 210 ter catheter removal. postoperative urinary tract infections (utis) were observed in 6 (12.7%) patients. none of the patients developed urinary incontinence. at 1 month follow-up, the mean scr value significantly decreased to 1.76 ± 0.73 mg/dl (p < .001). likewise, the mean ipss significantly decreased to 5.5 ± 2.4 and the mean pvr significantly dropped to 10 ml (0-200) (p < .001). both qmax and qave increased significantly (23.6 ± 10.8 ml/s and 13 ± 6.1 ml/s, respectively, p < .001) (table 2). the median long-term follow-up duration was 42 (12-94) months. the re rate was 68.1% for the turp group. during follow-up, re-operation was performed on 3 (6.3%) patients due to urethral stricture, and 2 patients (4.2%) were re-operated for bladder neck contracture (bnc) (table 3). the mean age of the 32 patients in the tuip group was 44.2 ± 8.2. the median duration of dialysis was 34 (0204) months. the median duration between renal transplantation and tuip procedure was 19 (0-66) months. preoperatively, the mean scr was 2 ± 0.8 mg/dl, the mean serum total psa was 0.96 ± 0.6 ng/ml and the mean prostate volume was 20.3±4.2 cm3 (table 1). the mean ipss was 18.6 ± 3. uroflowmetry parameters qmax and qave were 9.4 ± 4.2 ml/s and 5.81 ± 2.4 ml/s, respectively. the mean pvr was 80 (5-300) ml. none of the patients in the tuip group experienced peroperative complications. the mean urinary catheter use was 1.46 ± 0.6 days. one (3.1%) patient experienced urinary retention in the postoperative period. two (6.2%) patients developed uti in the postoperative period. none of the patients developed urinary incontinence. the mean serum creatinine levels decreased to 1.65 ± 0.6 mg/dl at 1 month follow-up (p = .001). the ipss and pvr values dropped significantly 6.1 ± 2.2 and 5 (0-205) ml, respectively, (p < .001). both qmax and qave increased significantly 26.9 ± 9.5 ml/s and 14.75 ± 6.2, respectively, (p < .001) (table 2). the median long-term follow-up duration was 38 (12-46) months. the re rate in the tuip group was 25%. during follow-up, re-operation was performed on 4 (12.5%) patients due to urethral stricture, and one patient (3.1%) was operated for bnc (table 3). there was no difference between the two groups by means of dialysis duration and the duration between transplantation and turp/tuip procedure (p = .939 and p = .231). the mean catheter duration was significantly longer in the turp group (p < .001). when the effectiveness of the two procedures on the voiding parameters and renal functions were compared, there was no difference between two groups in terms of improvement in qmax, qave, pvr ipss and scr values (p = .89, p = .11, p = .24, p = .27 and p = .08). postoperative utis were more frequent in the turp group. (turp: 12.7% versus tuip: 6.2). on long-term follow-up, re rate was significantly higher in the turp group (p < .001). urethral stricture rates were higher in the tuip group compared to the turp group. (tuip: 12.5%; turp: 6.3%). discussion being a well-standardized operation, renal transplantation is the most suitable method for kidney replacement for end-stage renal disease.(4) urological complications following renal transplantation may cause significant morbidity and mortality, frequently warranting a second surgical procedure.(8) urological complications arise in 2.5 to 30% of all graft recipients.(9) boo due to bph is a serious urological complication that may affect graft survival in the long term. bph is directly or indirectly associated with recurrent urinary tract infections, bladder stones, bladder diverticuli, vesicoureteral reflux, hydronephrosis, renal insufficiency, and urinary retention.(10) therefore delayed diagnosis and treatment of clinical bph constitutes an independent risk factor for transplant failure in renal transplant recipients. though turp is the gold standard surgical treatment in men with boo due to bph, it is also associated with some risks, such as sexual function problems and blood loss requiring transfusion. tuip is a simpler and less invasive procedure than turp. therefore, due to its low morbidity rate, tuip is recommended by the american urological association and the european association of urology guidelines as an alternative to turp for the surgical treatment of bph in appropriate patient groups. (11,12) despite these suggestions, tuip is not performed very frequently by urologists. for instance, in england, tuip is considered an under-utilized procedure. the annual number of tuip procedures in england is approximately 2500, whereas the annual number of turp procedures is 25000.(13) similarly, according to medicare program for 1999 data, the ratio of turp vs tuip is 36 to 1.(14) in the light of the findings obtained from the literature, it appears that turp is favored in renal transplant recipients with boo caused by bph. while there are few studies focusing on the results of turp and tuip in renal transplant recipients, studies evaluating tuip are even fewer. currently, there is no published study comparing the long term results of turp and tuip in renal transplant recipients. vedrine et al conducted a study analyzing the results of tuip and turp in the early period after transplantation and reported similar results for both procedures.(15) however, this study had limitations such as being based on a low number of cases and including only the patients who underwent tuip/turp shortly after renal transplantation. many studies in literature indicate that turp improves renal functions both in the short and long term in non-transplant chronic kidney disease patients.(16,17) similarly, there are studies reporting improved scr levels following turp in renal transplant recipients.(18) in our study, the fact that the improvement in scr after tuip is equivalent to turp suggests that tuip, when applied to appropriate renal transplant patients, may not only improve luts but also improve renal function. utis are principal causes of morbidity and hospitalizacomplication turp (n) tuip (n) postoperative utis 12.7% (6) 6.2% (2) postoperative aur 2.1% (2) 3.1% (1) retrograde ejaculation 68.1% (32) 25% (8) (p < .001) re-opr. due to urethral stricture 6.3% (3) 12.5% (4) re-opr. due to bph 3.1% (1) re-opr. due to bnc 4.2% (2) re-opr, re-operation; utis, urinary tract infections; aur, acute urinary retantion; bph, benign prostate hyperplasia; bnc, bladder neck contracture. *statistical analysis was made only for the group of retrograde ejaculation, since the number of cases in other groups were deemed too small for analysis. table 3. comparison of turp and tuip complications turp vs. tuip for bph in renal transplantation-sarier et al. vol 15 no 04 july-august 2018 211 tion following renal transplantation.(19) bph is known to be linked with utis, and utis are commonly present on bph diagnosis. therefore, recurrent utis caused by chronic urinary retention in men with bph form an independent risk factor affecting graft loss in renal transplant recipients.(20) utis in bph may cause not only a risk in the preoperative period but also serious morbidity and mortality in the postoperative period. reinberg et al. reported death due to urosepsis in the postoperative period after turp.(21) all utis are classified into four categories. asymptomatic bacteriuria, lower uti, acute pyelonephritis and urosepsis.(22) in our study, the uti presentations detected in both groups after turp and tuip were asymptomatic bacteriuria or lower uti. in the postoperative period, none of the patients had fever exceeding 38°c. according to the european urology guideline, the ideal perioperative prophylaxis for turp is a single preoperative dose.(23) because immunosuppressive therapy renders transplant recipients vulnerable to infections and thus poses great risks, we applied antibiotics for up to the first postoperative day. volpe et al. have adopted an antibiotic regimen similar to ours in their study and reported that postoperative uti rate after turp was 3.1%.(18) however, in our study, uti rates were 6.2% and 12.7% in the tuip and turp groups, respectively. renal transplantation not only improves renal function but also significantly improves quality of life and sexual functions. several studies have reported enhancement in libido and sexual function following transplantation.(24) it is especially important to take into account the sexual-life expectancies of young renal transplant patients. re is one of the most important causes of morbidity after turp and tuip procedures. re has a serious negative impact on quality of life because it impairs both orgasmic function and fertility. in literature, re rates have been reported as 52.5-65.4% and 18.2-22.5% for turp and tuip, respectively.(6,25) the incidence of re was not affected by the volume of removed prostate tissue by turp.(26) considering the concomitant comorbidities, patient age is an important factor influencing the choice of transurethral surgical option. along with the increased quality of life after renal transplantation, strategies aimed at securing ejaculatory function should also be taken into account in the elderly. in this study, re rates for turp and tuip were 68.1% and 25%, respectively. in light of these results, tuip should always be considered as the first option for sexually active renal transplant recipients with a prostate volume less than 30cm3. many studies conducted on non-transplant patients have shown that urethral stricture is one of the longterm complications of transurethral procedures. in these studies, urethral stricture incidence was found to be 2.2-9.8% for turp(27) patients and 4.1% for tuip(25) patients. urethral stricture may cause significant morbidity especially in renal transplant patients. however, literature regarding the incidence of urethral stricture following turp/tuip in renal transplant patients is scarce. volpe et al. reported that 2 (6.25%) of the 32 kidney transplant patients undergoing turp developed urethral stricture.(18) our study yielded similar results, with an urethral stricture incidence of 6.3%. in their study, dörsam et al. have not reported any data on urethral stricture incidence following tuip, since the follow-up period for their study was at most 6 months.(28) in our study, though the follow-up period of the tuip group was shorter than the turp group (tuip 38 months; turp 42 months), urethral stricture incidence in the tuip group was considerably high (12.5%). there are multiple suggestions explaining the etiopathogenesis of urethral stricture following transurethral procedures. an iatrogenic urethral mucosa rupture has been determined as a major risk factor for urethral stricture, by causing urine leakage underneath the epithelium, which in turn leads to inflammation and scar formation.(29) we believe that the determining factor here is age. the mean age of tuip and turp groups were 44.2 years and 60.1 respectively. young patients may be much more prone to scar formation. in their study, balbay et al. found that urethral stricture development after turp is inversely correlated with age, which is further strengthening our argument.(30) for this reason, we conclude that young renal transplant patients should be closely monitored for evidence of urethral stricture after transurethral procedures. this study has some limitations because of its design. the significant difference between tuip and turp groups with respect to age may be seeen as a drawback. the reason why tuip was performed more frequently, especially in young patients, is to avoid postoperative ejaculatory dysfunction which is a well-documented complication of turp operations in non-transplant patients in the literature. conclusions for the treatment of bph in renal transplant patients with a prostate volume less than 30 cm3, both tuip and turp are safe and equally effective in achieving symptomatic improvement. tuip stands out with low uti rates after surgery and low re rates, while turp stands out with the relative infrequency of long-term complications requiring reoperation such as urethral strictures. conflict of interest no potential conflict of interest was reported by the authors. references 1. yang q, peters tj, donovan jl, et al. transurethral incision compared with transurethral resection of the prostate for bladder outlet obstruction: a systematic review and meta-analysis of randomized controlled trials. j urol. 2001; 165:1526-32. 2. cameron js, compton f, koffman g, et al. transplantation in older people. lancet (london, england) 1994; 343:1169-70. 3. tsaur i, jones j, melamed rj, et al. postoperative voiding dysfunction in older male renal transplant recipients. transplant proc. 2009; 41:1615-18. 4. ergesi b, winkler y, kistler t, et al. prevalence and management of lower urinary tract symptoms related to benign prostatic obstruction in a contemporary series of renal transplant recipients. nephrourol mon. 2016; 8:e35497. 5. mitsui t, shimoda n, morita k, et al. lower turp vs. tuip for bph in renal transplantation-sarier et al. miscellaneous 212 urinary tract symptoms and their impact on quality of life after successful renal transplantation. int j urol. 2009; 16:388-92. 6. abd-el kader o, mohy el den k, el nashar a, et al. transurethral incision versus transurethral resection of the prostate in small prostatic adenoma: long-term follow-up. african j urol. 2012; 18:29-33. 7. tkocz m, prajsner a. comparison of long-term results of transurethral incision of the prostate with transurethral resection of the prostate, in patients with benign prostatic hypertrophy. neurourol urodyn. 2002; 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96:400-5. 20. abbott kc, swanson sj, richter er, et al. late urinary tract infection after renal transplantation in the united states. am j kidney dis. 2004; 44:353-62. 21. reinberg y, manivel jc, sidi aa, et al. transurethral resection of prostate immediately after renal transplantation. urology. 1992; 39:319-21. 22. golebiewska je, dębska-ślizień a, rutkowski b. urinary tract infections during the first year after renal transplantation: one center’s experience and a review of the literature. clin transplant. 2014; 28:1263-70. 23. grabe m, bartoletti r, bjerklund-johansen te, et al. guidelines on urological infections. eur assoc urol. 2015:50-58. 24. toorians aw, janssen e, laan e, et al. chronic renal failure and sexual functioning: clinical status versus objectively assessed sexual response. nephrol dial transplant. 1997; 12:2654-63. 25. taylor bl, jaffe wi. (2015) electrosurgical transurethral resection of the prostate and transurethral incision of the prostate (monopolar techniques). can j urol. 2015; 22 suppl 1:24-29. 26. møller-nielsen c, lundhus e, møller-madsen b, et al. sexual life following “minimal” and “total” transurethral prostatic resection. urol int. 1985; 40:3-4. 27. rassweiler j, teber d, kuntz r, et al. complications of transurethral resection of the prostate (turp)—incidence, management, and prevention. eur urol. 2006; 50:969-80. 28. dorsam j, wiesel m, mohring k, et al. transurethral incision of the prostate following renal transplantation. j urol. 1995; 153:1499-501. 29. jørgensen pe, weis n, bruun e. etiology of urethral stricture following transurethral prostatectomy. a retrospective study. scand j urol nephrol. 1986; 20:253-5. 30. balbay md, ergen a, sahin a, et al. development of urethral stricture after transurethral prostatectomy: a retrospective study. int urol nephrol. 1992; 24:49-53. turp vs. tuip for bph in renal transplantation-sarier et al. vol 15 no 04 july-august 2018 213 association between human papillomavirus and transitional cell carcinoma of the bladder pourya abdollahzadeh1, seyed hamid madani2*, sedigheh khazaei2, soraya sajadimajd2, babak izadi2, farid najafi1 purpose: bladder carcinoma is one of the most common malignancies in worldwide. among several risk factors, human papilloma virus (hpv) have been presumed to play a causative role in the etiology of bladder cell carcinoma. the aim of this study was to evaluate the involvement of hpv infection in biopsy specimens of patients with transitional cell carcinoma at the west of iran. materials and methods: in this study, 97 biopsy specimens including 67 patients with transitional cell carcinoma (tcc) of bladder and 30 cases of control group with the mean age of 63 years were studied using immunohistochemistry to identify hpv. results: 22.4% of patients with tcc of bladder and 3.3% of control group were positive for hpv with a meaningful relation (p=.019). the prevalence of hpv was 4.3 fold higher in men than women. most tcc patients belonged to grades ii and iii. conclusion: considering the higher incidence of hpv positivity in patients with tcc of bladder compared to control group, it seems to be a meaningful association between hpv infection and tcc of bladder, at least in the west of iran. keywords: biopsy; bladder carcinoma; immunohistochemistry; hpv; transitional cell carcinoma. 1kermanshah university of medical sciences, kermanshah, iran. 2molecular pathology research center, imam reza university hospital, kermanshah university of medical sciences, kermanshah, iran. *correspondence: molecular pathology research center, imam reza hospital, kermanshah university of medical sciences, kermanshah, iran. tel:(98)9181324029. fax:(98)831-7235149. e-mail: shmmadani@yahoo.com. received october 2016 & accepted september 2017 introduction bladder carcinoma as a leading cause of death in worldwide, arises from urothelial epithelium(1-3). transitional cell carcinoma (tcc) is the most common type of bladder carcinoma which represents 90% of bladder malignancies and is commonly associated with cancers of other parts of the urinary tracts such as kidney, ureters and urethra. bladder cancer is the fourth most common in men, but is less common in women(4,5). several risk factors have been considered to be important in development of bladder carcinoma including smoking, certain industrial exposure, arsenic in drinking water, chronic irritation as well as bacterial and viral infection (6,7). among them, the causative role of human papilloma virus (hpv) infection has been evluated in several studies(8-12). it has been suggested that hpv is the most important risk factor for development of carcinoma in urogenital system(13-15). the oncogenic types of hpv, hpv16 and hpv18, have been identified in invasive carcinoma of genital areas. since the proliferative cycle of hpv is dependent to sequential phases of differentiation of epithelial cells, hpv possesses a particular tendency for epithelial cells with the expression of its oncogenes and pathogenesis(16,17). in addition, neoplastic alterations in urothelium have several stages in which carcinogenic initiator agent via modification of dna leads to malignancy. in this line, several studies have suggested the involvement of hpv infection in the development of bladder carcinoma, especially transitional cell carcinoma(18-21). given that hpv is not able to grow in cellular cultures and also antibody tests are only available in research laboratories, several methods including pcr, in situ hybridization and appropriative immunohistochemical (ihc) staining have been developed to confirm hpv infection in bladder carcinoma tissues. in this study, we aimed to evaluate hpv infection in samples related to patients with tcc using immunohistochemical staining of paraffin embedded blocks to find the interplay between hpv and tcc. materials and methods clinical samples specimens were retrieved from paraffin embedded bladder carcinoma tissues stored in laboratory of imam reza hospital medical center, including 67 cases with tcc diagnosis and 30 cases from normal biopsies from 2008 to 2011. the slides prepared from paraffin embedded specimens were stained with the conventional hematoxylin and eosin method. all specimens were reviewed and original diagnoses were confirmed. immunohistochemistry immunohistochemical evaluation was performed on 5 μm formalin fixed paraffin embedded tissue sections. in brief, an anti-human hpv mouse monoclonal antibody (clone k1h8, dako) was used as the primary antibody at a dilution of 1/ 30000. then, secondary antibody conurological oncology urological oncology 5047 jugated with horseradish peroxidase and diaminobenziden chromogen were added to identify the presence of hpv in samples. candyloma specimen was used as a positive control. nuclear staining of tumoral cells in tcc specimens and urothelial cells in normal specimens were considered as positive samples. statistical analysis statistical analysis was performed by spss statistical software package version 16, using t-test and chisquare tests. results in this study, immunohistochemistry was performed on paraffin embedded bladder tcc tissues to distinguish the involvement of hpv infection in development of carcinogenicity of bladder (figure 1). from the population of 67 tcc specimens and 30 normal biopsy specimens, 15 and 1 cases, respectively, were positive for hpv infection. there was a meaningful relation between tcc carcinogenicity and hpv infection (p = .019) (figure 2). among tcc patients, 86.6% (58 cases) were male and 13.4% (9 cases) were female. in control group, 56.7% (17 cases) were male and 43.3% (13 cases) were female. as shown in figure 3, there was not meaningful relation between gender and hpv infection (p = .933). the histological grading of tumor specimens indicated that 1 case with grade 1, 24 cases with grade 2, 32 cases with grade 3 and 10 cases with grade 4 were found in 67 tcc specimens according to who/isop classification (figure 4a). among them, immunohitochemical analysis showed that 5 cases of grade 2, 4 cases of grade 3 and 6 cases of grade 4 were positive for hpv nuclear staining. according to figure 4b, there was no meaningful relation between the grade of tcc and hpv infection (p = .718). discussion the involvement of human papillomavirus in bladder carcinoma has been reported by several studies(18,22). in this line, the high prevalence of hpv infection in patients with tcc indicated the possible association of hpv and carcinogenesis of transitional cell carcinoma of bladder(23-26). in this study, we aimed to investigate the meaningful relationship between hpv and patients with transitional cell carcinoma. we studied the expression of hpv in 67 patients with tcc and 30 normal samples as control using immunohistochemistry. 15 cases (22.4%) of tcc patients’ group and 1 case (3.3%) of control group were found to be positive for hpv infection. the first report about the association of hpv and bladder carcinoma was reported by kitamura based on southern blot analysis in 1988(27). after that, several hpv in bladder carcinoma-abdollahzadeh et al. figure 1. immunohistochemical staining for human papilimavirus (hpv) in bladder cell carcinoma. candyloma section (positive-hpv) as control with magnifications of 20x and 40x (a; b), hpv negative in tcc with magnifications of 20x and 40x (c; d) and hpv positive in tcc with magnifications of 20x and 40x (e; f) indicated by nuclear and cytoplasmic staining of tumor tissues. figure 2. infection pattern of hpv in bladder biopsy specimens among patients and control groups. figure 3. the incidence of sex in bladder biopsy specimens among patients and control groups. vol 14 no 06 november-december 2017 5048 contradictory studies have been reported about the involvement of hpv in carcinoma of bladder. lopez-beltran et al. assessed the role of hpv in tcc using ihc and ish methods. they identified 25 cases with hpv infection using ihc and 12 cases with positive hpvdna positive using pcr in 76 patients with tcc(28). in another study, youshya and co-workers studied the involvement of hpv in 76 patients with tcc using pcr and ihc methods. interestingly, different results were acquired from two methods. 47 cases were positive for hpv according to ihc while none were positive for hpv–dna by pcr. therefore, they suggested that there were no possible association between hpv infection and carcinogenesis of tcc(9). shigehara et al. evaluated the etiologic role of hpv infection in bladder carcinoma. they studied the involvement of hpv in 244 cases of patients with bladder cancer during 1997 to 2007. they analyzed the expression of hpv-dna in frozen specimens of tur bladder tissue with pcr and hpv-l1 capsid protein of hpv using ihc. therefore, it seems that high risk types of hpv leads to carcinogenesis of low grade bladder cancer in juvenile patients (19). another controversial study about the involvement of hpv in urothelial cancer was performed by yavuzer et al. they studied 70 cases of urothelial carcinoma to find hpv using pcr with respect to 18 cases of patients with cervical carcinoma as control. they found that there was no association between hpv infection and bladder urothelial carcinoma(29). in another study by barghi et al., 58 cases of tcc specimens and 20 normal cases as control was evaluated using pcr to identify hpv-dna. they found that the possibility of hpv involvement in tcc is related to geographical regions(15). selma et al indicated the interplay of hpv and tcc in tunisia. they examined 119 patients with tcc, 5 cases with squamous cell carcinoma and one case with adenocarcinoma by pcr based method to distinguish different subtypes of hpv. their results showed that anogenital hpv infection seems not to play a significant role in pathogenesis of bladder carcinoma(30). eslami et al. considered 147 cases of tcc patients and 39 cases of normal specimens as control to study the relation between hpv infection and tcc. they used pcr to identify hpv-dna in patients. they found that there is no meaningful association between hpv infection and grade of bladder tumor; while it seems that genital hpv infection especially subtype 18 augmented the risk of bladder carcinoma in iranian population(31). conclusions taken together, our present study indicated that there was a meaningful association between hpv infection and transitional cell carcinoma. however, we could not found any meaningful relation between grade of tcc, age and sex of patients and the presence of hpv. acknowledgments the authors appreciate the financial support of this investigation by kermanshah university of medical sciences, and the archived file center of imam reza hospital and taleghani hospital. conflict of interest the authors declare that they have no conflict of interest. references 1. oosterlinck w, lobel b, jakse g, et al. guidelines on bladder cancer. eur urol. 2002;41:105-12. 2. silverberg e. statistical and epidemiologic data on urologic cancer. cancer. 1987;60:692717. 3. kaufman ds, shipley wu, feldman as. bladder cancer. lancet. 2009;374:239-49. 4. young r. usual variants of primary bladder lesions and secondary tumours of the bladder. pathology of bladder cancer. baltimore: williams and wilkins; 1996:326–37. 5. eble jl, sauter g, epstein ji. world health organization classification of tumours. pathology and genetics of tumours of the urinary system and male genital organs. lyon: iarc press; 2004: 221-49. 6. burger m, catto jw, dalbagni g, et al. epidemiology and risk factors of urothelial bladder cancer. eur urol. 2013;63:234-41. 7. freedman nd, silverman dt, hollenbeck ar, schatzkin a, abnet cc. association between smoking and risk of bladder cancer among men and women. jama. 2011;306:73745. 8. noel jc, thiry l, verhest a, et al. transitional cell carcinoma of the bladder: evaluation of figure 4. histological grading of urinary bladder carcinoma in bladder biopsy specimens among patients (a). relation between hpv positivity and histological grading of tcc patients(b). hpv in bladder carcinoma-abdollahzadeh et al. urological oncology 5049 the role of human papillomaviruses. urology. 1994;44:671-5. 9. youshya s, purdie k, breuer j, et al. does human papillomavirus play a role in the development of bladder transitional cell carcinoma? a comparison of pcr and immunohistochemical analysis. j clin pathol. 2005;58:207-10. 10. wiener js, walther pj. a high association of oncogenic human papillomaviruses with carcinomas of the female urethra: polymerase chain reaction-based analysis of multiple histological types. j urol. 1994;151:49-53. 11. zur hausen h. papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers. cancer res. 1989;49:4677-81. 12. gutierrez j, jimenez a, de dios luna j, soto mj, sorlozano a. meta-analysis of studies analyzing the relationship between bladder cancer and infection by human papillomavirus. j urol. 2006;176:2474-81; discussion 81. 13. griffiths tr, mellon jk. human papillomavirus and urological tumours: ii. role in bladder, prostate, renal and testicular cancer. bju int. 2000;85:211-7. 14. shigehara k, sasagawa t, kawaguchi s, et al. prevalence of human papillomavirus infection in the urinary tract of men with urethritis. int j urol. 2010;17:563-8. 15. barghi mr, hajimohammadmehdiarbab a, moghaddam sm, kazemi b. correlation between human papillomavirus infection and bladder transitional cell carcinoma. bmc infect dis. 2005;5:102. 16. alexander re, wang l, lopez-beltran a, et al. human papillomavirus (hpv)-induced neoplasia in the urinary bladder: a missing link? histol histopathol. 2016;31:595-600. 17. shigehara k, sasagawa t, namiki m. human papillomavirus infection and pathogenesis in urothelial cells: a mini-review. j infect chemother. 2014;20:741-7. 18. de gaetani c, ferrari g, righi e, et al. detection of human papillomavirus dna in urinary bladder carcinoma by in situ hybridisation. j clin pathol. 1999;52:103-6. 19. shigehara k, sasagawa t, kawaguchi s, et al. etiologic role of human papillomavirus infection in bladder carcinoma. cancer. 2011;117:2067-76. 20. anwar k, naiki h, nakakuki k, inuzuka m. high frequency of human papillomavirus infection in carcinoma of the urinary bladder. cancer. 1992;70:1967-73. 21. li n, yang l, zhang y, zhao p, zheng t, dai m. human papillomavirus infection and bladder cancer risk: a meta-analysis. j infect dis. 2011;204:217-23. 22. furihata m, inoue k, ohtsuki y, hashimoto h, terao n, fujita y. high-risk human papillomavirus infections and overexpression of p53 protein as prognostic indicators in transitional cell carcinoma of the urinary bladder. cancer res. 1993;53:4823-7. 23. agliano am, gradilone a, gazzaniga p, et al. high frequency of human papillomavirus detection in urinary bladder cancer. urol int. 1994;53:125-9. 24. larue h, simoneau m, fradet y. human papillomavirus in transitional cell carcinoma of the urinary bladder. clin cancer res. 1995;1:435-40. 25. chen t, kong q, cao h. [the study on relation of human papillomavirus and p53 expression with bladder transitional cell carcinoma]. zhonghua shi yan he lin chuang bing du xue za zhi. 2000;14:345-8. 26. wiwanitkit v. urinary bladder carcinoma and human papilloma virus infection, an appraisal of risk. asian pac j cancer prev. 2005;6:2178. 27. kitamura t, yogo y, ueki t, murakami s, aso y. presence of human papillomavirus type 16 genome in bladder carcinoma in situ of a patient with mild immunodeficiency. cancer res. 1988;48:7207-11. 28. lopez-beltran a, escudero al, carrasco-aznar jc, vicioso-recio l. human papillomavirus infection and transitional cell carcinoma of the bladder. immunohistochemistry and in situ hybridization. pathol res pract. 1996;192:1549. 29. yavuzer d, karadayi n, salepci t, baloglu h, bilici a, sakirahmet d. role of human papillomavirus in the development of urothelial carcinoma. med oncol. 2011;28:919-23. 30. ben selma w, ziadi s, ben gacem r, et al. investigation of human papillomavirus in bladder cancer in a series of tunisian patients. pathol res pract. 2010;206:740-3. 31. eslami g, golshani m, rakhshon m, fallah f, goudarzi h. the study on relation of human papillomavirus with bladder transitional cell carcinoma. cancer therapy. 2008;6:355-60. hpv in bladder carcinoma-abdollahzadeh et al. vol 14 no 06 november-december 2017 5050 reconstructive surgery 265urology journal vol 5 no 4 autumn 2008 clean intermittent catheterization with triamcinolone ointment following internal urethrotomy jalil hosseini, ali kaviani, ali reza golshan introduction: our aim was to evaluate clean intermittent catheterization (cic) results in combination with triamcinolone ointment for lubrication of the catheter after internal urethrotomy. materials and methods: seventy patients who underwent internal urethrotomy were assigned into 2 groups and performed cic with either triamcinolone 1% ointment or a water-based gel (control) for lubrication of the catheter. they continued cic regimen up to 6 month and were followed up for 12 months. retrograde urethrography and urethrocystoscopy were done 6 and 12 months postoperatively. in case of obstructive symptoms or any difficulty in passing the urethral catheter, internal urethrotomy would be performed, if needed, and the same follow-up protocol would be started again. the recurrence rates after the first and second urethrotomy attempts were compared between the two groups. results: thirty patients in the triamcinolone group and 34 in the control group completed the study. there were no significant differences in the baseline characteristics of the patients or the etiology of the stricture between the two groups. there was a 30.0% recurrence rate in the patients of the triamcinolone group versus 44.1% in those of the control group after the first internal urethrotomy (p = .24). following the second internal urethrotomy, the urethra was stabilized in 88.9% of the patients in the triamcinolone group and 60.0% those in the control group (p = .15). conclusion: administration of triamcinolone ointment in patients on cic regimen after internal urethrotomy only slightly decreased the stricture recurrence rate, and its possible effects should be more investigated. urol j. 2008;5:265-8. www.uj.unrc.ir keywords: urethral stricture, reconstructive surgery procedures, urinary catheterization, triamcinolone, urethra division of reconstructive urology, shohada-e-tajrish hospital and urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: jalil hosseini, md department of urology, shohada-etajrish hospital, tajrish sq, tehran, iran tel: +98 21 2271 8001 fax: +98 21 2271 9017 e-mail: sjhosseinee@yahoo.com introduction internal urethrotomy has been classically recommended for urethral strictures shorter than 1.5 cm, but has been associated with high recurrence rates.(1) a number of complementary procedures including clean intermittent catheterization (cic) have been proposed to overcome this problem. in 1972, transurethral use of triamcinolone was proposed by hebert.(2) clinical improvement of hypertrophic scars after treatment with intralesional steroids has been shown.(3) however, there are not enough clinical trials in the literature to support the use of these agents for internal urethrotomy cases. in an animal study, 5-fluorouracil/triamcinolone decreased scar tissue formation induced by acute subglottic trauma in rabbits.(4) we compared the effect of using a corticosteroid (triamcinolone) for lubrication of clean intermittent catheterization with triamcinolone —hosseini et al 266 urology journal vol 5 no 4 autumn 2008 the catheter with placebo (lubricant gel) on the development of scar tissue in the patients on cic following internal urethrotomy. materials and methods in this double-blind randomized placebocontrolled trial, patients with urethral stricture were approached at the urology clinic of shohada-e-tajrish hospital. we excluded those with complete urethral obstruction and/or strictures longer than 1.5 cm. informed consent was obtained from all the eligible patients. the figure shows the allocation and assignment of the patients. the patients were scheduled for internal urethrotomy and cic. seventy patients were assigned into 2 groups to perform cic with lubrication by either triamcinolone ointment (triamcinolone group) or a water-based lubricant gel (control group) after internal urethrotomy. randomization was performed using a random table. triamcinolone 1% ointments and lubricant gel were manufactured and packed in similar tubes by the laboratory of the department of pharmacology at shahid beheshti university (mc). all patients had some degrees of spongiofibrosis, defined as the presence of dense fibrosis in the urethral lumen during urethrocystoscopy. spongiofibrosis was determined by retrograde urethrography, ultrasonography, and urethrocystoscopy. internal urethrotomy was performed by incising the stricture site at 12, 3, 6 and 9 o’clock positions of the urethral lumen. our technique was the same in all patients. we used classical cold knife urethrotomy in all of the patients and incised only the scar tissue and avoided cutting too deep to cause bleeding. following internal urethrotomy, the patients were instructed to perform cic by an18-f nelaton catheter. one milliliter of triamcinolone or one peanut size of the ointment was recommended to be used for lubrication of the catheter. the regimen was tapered over a 6-month period (table 1). the patient and the physicians involved in the research project were blind to the type of the lubricants. the patients were visited regularly after the internal urethrotomy 1, 2, 3, 6, 9, and 12 months postoperatively, and all underwent retrograde urethrography and urethrocystoscopy at the 6th and 12th months of follow-up. if the patients had recurrence of the obstructive and irritative symptoms or any difficulty in passing the urethral catheter, urgent retrograde urethrography, urethrocystoscopy, and internal urethrotomy (if needed) would be performed. the consolidated standards of reporting trials flowchart of the randomized study.(5) postoperative time catheterization 1st week daily 2nd week every other day 3rd week twice a week 4th week once a week 2nd month every 2 weeks 3rd to 6th month once a month after 6 months cessation of regimen table 1. clean intermittent catheterization regimen following internal urethrotomy clean intermittent catheterization with triamcinolone —hosseini et al urology journal vol 5 no 4 autumn 2008 267 statistical analyses were done by the chi-square test and t test for comparisons of the dichotomous and continuous variables between the two groups, respectively, using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). a p value less than .05 was considered significant. results five patients in the triamcinolone group and 1 in the control group were lost to follow-up, and therefore, were excluded. analyses were done on the data collected from the records of 30 and 34 patients in the triamcinolone and control groups who fulfilled the12-month follow-up period after the last internal urethrotomy. there were no significant differences in the baseline characteristics of the patients or the etiology of the stricture between the two groups (table 2). recurrence was noted in 9 (30.0%) and 15 (44.1%) of the patients in the triamcinolone and control groups and needed a repeat procedure after the first attempted internal urethrotomy (p = .24). the urethra was stabilized in 8 of 9 patients (88.9%) in the triamcinolone group and 9 of 15 (60.0%) in the control group without any stricture recurrence during 12 months of followup after second internal urethrotomy (p = .15). there were no reported febrile urinary tract infection episodes or any other local or systemic complications specific to the use of triamcinolone ointment in our patients. discussion internal urethrotomy has been recommended for urethral strictures shorter than 1.5 cm; however, it has been associated with high recurrence rates.(1,6-9) hafez and colleagues believed that internal urethrotomy provided a safe therapeutic option for urethral strictures shorter than 1 cm in children.(10) it was also mentioned that this procedure had 20% to 40% success rate and could be repeated 2 or 3 times in maximum.(11) urethral stricture recurrence after the first, second, and third internal urethrotomies was reported to be about 50%, 60% to 100%, and 100%, respectively.(12) ishigooka and associates mentioned that factors with no influence on recurrent stricture formation included age, etiology, site of the stricture, and duration of indwelling catheterization. on the other hand, stricture length appeared to influence the outcome (p < .001). recurrence rate was only 4.4% in short strictures (1 cm and shorter), while it was 42.9% in longer strictures.(13) however, this was in contrast with the idea of some other researchers who believe that initial urethrotomy or urethral dilation followed by urethroplasty in those with recurrent stricture is the most costeffective strategy.(14) clean intermittent catheterization following internal urethrotomy is an acceptable procedure to reduce the failure rate of the treatment.(15) it was once recommended that cic regimen be tapered within 3 to 6 months in such patients.(6) mazdak and colleagues found that submucosal injection of mitomycin c significantly reduced recurrence of the stricture after internal urethrotomy.(16) transurethral injection of triamcinolone was addressed by hebert in 1972.(2) clinical improvement of hypertrophic scars after treatment with intralesional corticosteroid has been shown elsewhere.(3,4) sharpe and finney believed that intralesional steroid might be used in many types of strictures, but it was especially characteristics triamcinolone control p mean age 37.7 ± 17.1 (11 to 72) 34.5 ± 13.3 (10 to 80) .14 mean ureteral stricture length, cm 0.85 ± 0.40 (0.3 to 1.5) 0.90 ± 0.30 (0.4 to 1.5) .11 cause of urethral stricture urethral distraction disease 15 (50.0) 14 (41.2) .48 straddle injury 4 (13.3) 8 (23.5) .30 urethral catheterization 5 (16.7) 5 (14.7) .83 others 6 (20.0) 7 (20.6) .95 previous urethroplasty 18 (60.0) 17 (50.0) .42 table 2. baseline characteristics in triamcinolone and control groups* *values in parenthesis are ranges for age and stricture length, and percents for stricture cause and previous urethroplasty. clean intermittent catheterization with triamcinolone —hosseini et al 268 urology journal vol 5 no 4 autumn 2008 useful in cases with strictures in the distal urethra or the meatus, those occurring after radical prostatectomy, and in some cases with 1 or more urethroplasty procedures.(17) our study showed that adding triamcinolone ointment to cic regimen after internal urethrotomy slightly decreased the recurrence of stricture after the first and second internal urethrotomies; however, we failed to achieve a statistically significant difference between the use of triamcinolone and conventional lubricant gels. nonetheless, since the use of intralesional steroids is an easy method with low costs, it is worth to further study their effects in patients who undergo cic after urethrotomy. conclusion administration of triamcinolone ointment in patients on the cic regimen after internal urethrotomy slightly decreased the stricture recurrence rate. its efficacy should be further investigated to confirm any practical benefit of this minimal modification of the treatment protocol for the patients. conflict of interest none declared. references 1. naudé am, heyns cf. what is the place of internal urethrotomy in the treatment of urethral stricture disease? nat clin pract urol. 2005;2:538-45. 2. hebert pw. the treatment of urethral stricture: transurethral injection of triamcinolone. j urol. 1972;108:745-7. 3. manuskiatti w, fitzpatrick re. treatment response of keloidal and hypertrophic sternotomy scars: comparison among intralesional corticosteroid, 5-fluorouracil, and 585-nm flashlamp-pumped pulseddye laser treatments. arch dermatol. 2002;138:114955. 4. cincik h, gungor a, cakmak a, et al. the effects of mitomycin c and 5-fluorouracil/triamcinolone on fibrosis/scar tissue formation secondary to subglottic trauma (experimental study). am j otolaryngol. 2005;26:45-50. 5. moher d, schulz kf, altman dg. the consort statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. lancet. 2001;357:1191-4. 6. gerald hj, steven ms. surgery of the penis and urethra. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3886-954. 7. prajsner a, szkodny a, salamon m, bar k. long-term results of treatment of male urethral strictures using direct vision internal urethrotomy. int urol nephrol. 1992;24:171-6. 8. guirrassy s, simakan nf, sow kb, et al. endoscopic internal urethrotomy in the treatment of male urethral stenosis at the urology service of the chu ignace deen] ann urol (paris). 2001 may;35(3):167-71. french. 9. albers p, fichtner j, bruhl p, muller sc. longterm results of internal urethrotomy. j urol. 1996;156:1611-4. 10. hafez at, el-assmy a, dawaba ms, sarhan o, bazeed m. long-term outcome of visual internal urethrotomy for the management of pediatric urethral strictures. j urol. 2005;173:595-7. 11. fanciullacci f. [internal urethrotomy: procedure]. arch ital urol androl. 2002;74:109-10. italian. 12. heyns cf, steenkamp jw, de kock ml, whitaker p. treatment of male urethral strictures: is repeated dilation or internal urethrotomy useful? j urol. 1998;160:356-8. 13. ishigooka m, tomaru m, hashimoto t, sasagawa i, nakada t, mitobe k. recurrence of urethral stricture after single internal urethrotomy. int urol nephrol. 1995;27:101-6. 14. greenwell tj, castle c, andrich de, macdonald jt, nicol dl, mundy ar. repeat urethrotomy and dilation for the treatment of urethral stricture are neither clinically effective nor cost-effective. j urol. 2004;172:275-7. 15. lawrence wt, macdonagh rp. treatment of urethral stricture disease by internal urethrotomy followed by intermittent ‘low-friction’ self-catheterization: preliminary communication. j r soc med. 1988;81:136-9. 16. mazdak h, meshki i, ghassami f. effect of mitomycin c on anterior urethral stricture recurrence after internal urethrotomy. eur urol. 2007;51:1089-92; discussion 92. 17. sharpe jr, finney rp. urethral strictures: treatment with intralesional steroids. j urol. 1976;116:440-3. endourology and stone disease retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial babak javanmard1, amir hossein kashi2,3*, mohammad mohsen mazloomfard1,4, anahita ansari jafari2,4, saeed arefanian5 purpose: to compare outcomes of retrograde intrarenal surgery (rirs) with extracorporeal shock wave lithotripsy (swl) for stones ≤ 2 cm. materials and methods: patients who were diagnosed with kidney stones of ≤ 2 cm underwent rirs or swl in a parallel group randomized clinical trial with balanced randomization [1:1] from 2011 to 2014. the primary outcome of interest was stone free rate after a single session intervention. patients were evaluated by ultrasonography and kub at 1 and 3 months after the intervention for the presence of residual stone by a radiologist who was blinded to the study. results: the stone free rate one month after a single session intervention in the rirs group was higher than the swl group (90% versus 75%, p = .03). the success rates after two sessions of rirs versus swl were 96.7% versus 88.3% respectively. (p = .08) patients in the rirs group had significantly lower postoperative visual analogue pain score compared to the swl group (5.2 ± 2.8 versus 3.1 ± 2.7, p < .001). steinstrasse formation and renal hematoma were observed in 4 and one patient in the swl group versus no patient in the rirs group. postoperative hospital stay was significantly shorter in the swl group (6.7 ± 1.3 versus18.9 ± 4.3 hours, p < .001). conclusion: the rirs procedure is a safe treatment option for renal stones of ≤2cm with less pain and higher success rate at first session compared to swl. keywords: endoscopes; kidney; laser; lithotripsy; nephrolithiasis; retrograde intrarenal surgery; shockwave lithotripsy introduction the current preferred treatment for renal stones less than 2 cm is extracorporeal shock wave lithotripsy (swl) due to its minimal morbidity and simplicity.(1) however, the efficacy of swl drops significantly for large renal stones.(2) several factors such as stone composition and position, kidney malposition and obesity of the patient can decrease the success rate of swl.(3) alternative procedures to swl include laparoscopic nephrolithotomy and percutaneous nephrolithotripsy (pnl) which are more invasive and harbor a profile of complications.(1,4) vast development of endoscopic technology as well as introduction of holmium laser for treatment of urologic stones has made flexible ureterorenoscopy (f-urs) a good alternative procedure for the management of renal stones.(5,6) retrograde intrarenal surgery (rirs) seems a promising technique which is performed at many centers for patients who have previously undergone swl or pnl(7). few studies that have compared efficacy and safety of rirs with other procedures including swl reported that rirs can be considered as an option for treating medium sized renal stones.(6,8) some studies reported success rates approaching 90% when rirs is applied to single renal stones with maximal diameter of less than 3 cm.(5, 6,9) this randomized clinical trial was conducted to compare outcomes and complications of swl with rirs for the management of renal stones ≤ 2 cm. patients and methods study population study participants were patients who were diagnosed with medium sized renal stones (maximum diameter of 6 mm to 2 cm) from march 2011 to march 2014. patients were enrolled in the study after a routine preoperative evaluation. inclusion criteria were presence of renal stones ≤ 2 cm in diameter. exclusion criteria were kidney anomalies, uncontrolled coagulopathies, ureteral obstruction, history of previous renal surgery or swl, pregnancy and renal failure (serum creatinine ≥ 3mg/dl). the nature of the study was explained to each patient and informed consent was obtained. the protocol of this study was approved by the ethics committee of the laser application in medical sciences research center (lamsrc). patients’ enrollment algorithm has been illustrated in figure 1. 1 laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran. 2 urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 3 hasheminejad kidney center, iran university of medical sciences, tehran, iran. 4 urology department, tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 5 department of surgery, school of medicine, washington university in st. louis, saint louis, missouri, united states. *correspondence: hasheminejad kidney center, iran university of medical sciences, tehran, iran. tel: +98 21 88644486. fax: +98 21 88644497. e-mail: ahkashi@gmail.com. received april 2016 & accepted july 2016 endourology and stone diseases 2823 vol 13 no 05 september-october 2016 2824 rirs vs. swl for renal stone≤2cm-javanmard et al. one hundred and twenty patients underwent further evaluation consisting of urine analysis, urine culture and renal functional assays. a full course of antibiotics was administered before intervention in case of positive urine culture. in patients with negative urine culture, a single dose of prophylactic antibiotics was administered before swl or rirs. ct urography was the primary modality to determine the size, number and location of calculi, as well as the anatomy of the upper urinary tract. routine prophylactic intravenous antibiotics were administered before surgery. study design this study was a prospective single center, parallel-group randomized clinical trial with balanced randomization [1:1] which was performed in a referral hospital in tehran, iran. sample size was calculated considering a 30 percent expected difference between rirs and swl in the primary outcome of interest. considering type i error of 0.05 and type ii error of 0.1, 59 samples were needed for each arm. therefore 60 samples were decided to be enrolled in each arm of the study. patients were randomly assigned to one of the two treatment groups of swl or rirs (sixty patients in each group). randomization was carried out using computerized random numbers. the allocated treatment for each patient was recorded in concealed envelopes. after achieving eligibility criteria and patient’s agreement on participation, the concealed envelopes were opened by one of the researchers and the allocated treatment was performed as explained below. surgical technique the swl procedure was performed using the dornier hm3 lithotripter (dornier medtech, wessling, germany) on sedated patient in the supine position. all swl procedures were performed by a single urologist. the therapeutic power was started from 15 kv and increased stepwise up to 20 kv. the rate of delivered shocks was 60 to 90 per minute. the number of shock waves was limited to 3,000 per session. shocks were given based on stone dissolution while stones were fragmented under f1uoroscopic/ultrasonic guidance. the therapy head of the electromagnetic lithotripter was positioned below the treatment table and conductive gel was applied. in the rirs group, patients received spinal anesthesia and then were turned into the lithotomy position. after inserting an 11 fr semirigid ureteroscope (olympus) under endovision guidance thorough the bladder, a 0.035-inch hydrophilic coated guide-wire was introduced through the channel into the ureteral orifice and then ureteroscopy was performed with hydrodilation to dilate the ureter. thereafter, an 11 fr ureteral access sheath was placed and a 4fr/6fr feeding tube was placed trans-urethrally to maintain low pressure of the bladder. an 8.5/5.3 fr flexible ureteroscope (olympus) was introduced under fluoroscopic guidance to the renal pelvis to identify the stone. stone fragmentation was performed using holmium:yag laser with 200 µm fibers. lower and middle calyceal stones were relocated into renal pelvis or upper calyx by basketing before lithotripsy if it was not possible to fragment them in their primary position. final ureteronephroscopy was performed after fragmentation, followed by a control fluoroscopy to detect any probable residual stones. a double-j stent was placed in the ureter for two weeks in cases of difficult dilation, prolonged procedure or residual stone. in case of no ureteral injury, a ureteral stent was inserted and fixed to the foley catheter. the ureteral catheter was removed the day after surgery. rirs procedures were performed by a single experienced endourologist. outcome assessment the primary outcome of interest was stone free rate after one session of rirs or swl. residual stones were evaluated by plain abdominal radiographs and renal ultrasonography 1 and 3 months after treatment. the radiologists who performed ultrasonography or reported kub were totally blind to the study objectives and protocols. patients were considered stone free if residual stones were ≤ 3 mm. a second treatment session was planned for large and/or symptomatic stones detected at one month follow up. secondary outcomes included stone free rate after two treatment sessions, pain after procedures, hospital stay, and complications including table 1. patients' demographic data and clinical characteristics. characteristicsa swl rirs p value age (years) 31.3 ± 6.5 32.4 ± 7.8 0.4 male gender 39 (65) 37 (61.7) 0.7 body mass index (kg/m2) 27.1 ±4.3 26.7 ± 4.1 0.6 stone diameter (mm) 16.4 ± 3.3 16.8 ± 2.1 0.4 number of stones 1.3 ± 0.7 1.3 ± 0.6 0.9 stone location superior calyx 17 (28.4) 15 (25) middle calyx 11 (18.3) 12 (20) inferior calyx 5 (8.3) 6 (10) pelvis 22 (36.7) 21 (35) multiple 5 (8.3) 6 (10) left sided stone 30 (50) 27 (45) 0.6 adata is presented as mean ± sd or number (percent) figure 1. patients’ enrollment algorithm postoperative fever, renal hematoma, hematuria, pelvicaliceal system injury, and steinstrasse formation. postoperative pain was evaluated by visual analogue pain scale (vas) 24 hours after the procedure. duration of the operation was defined as the time between the first and last shock for swl and from ureteroscope insertion to foley insertion for rirs. data analysis was performed using spss software (statistical package for the social sciences, v. 16.0; spss inc, chicago, il, usa). numerical variables were compared by independent samples t-test. ordinal variables were compared by mann-whitney u test. categorical variables were compared by chi square or fisher exact tests as appropriate. all analyses were planned as intention to treat. results as explained in the methods section, sixty patients were enrolled in each arm of the study. ten patients were excluded from study due to exclusion criteria. patients’ demographic data in the two study groups has been outlines in table 1. there was no statistically significant difference between the groups regarding stone parameters including location, number and size. operative data and postoperative investigations have been illustrated in table 2. the mean ± sd of energy used with the holmium:yag laser for lithotripsy was 150.8 ± 11 kj. success rate of procedure at first session was 75% in swl group and 90% in rirs group which raised to 88.3% and 96.7% after the second session. there was a significant superiority of success rate for rirs over swl in resolving the inferior calyx stones (100% vs. 40%, p = .02). after excluding patients with inferior caliceal stones and patients with multiple stones which are known limitations of swl, the success rate of swl increases to 96% which is very close to the observed success rate of rirs (98%) for these patients. mean operation duration and hospital stay were significantly shorter in the swl group (48.2 ± 14.6 minutes versus 79.9 ± 14.1 minutes, p = .001; 6.7 ± 1.3 hours versus 18.9 ± 4.3 hours, p = .001). postoperative fever was observed in 4 patients in the swl group and one patient in the rirs group which was managed with broad spectrum antibiotics. perforation of the pelvicaliceal system was not observed in any patient. one patient in the swl group experienced anemia due to renal hematoma which was treated conservatively. one case of adrenal hematoma was observed in the same group that was managed uneventfully. steinstrasse formation was reported in four patients in the swl group which necessitated ureteroscopic management. patients in the rirs group reported lower vas for postoperative pain and required less analgesic medication postoperatively. in two patients in the rirs group, performing rirs was not possible in the first session due to difficult dilation. in these two patients, a dj catheter was inserted and rirs was successfully performed after two weeks. in another four patients in the rirs group dj stent was inserted after completion of lithotripsy because of lengthy operation duration as mentioned in the methods section. discussion swl has an excellent success rate in treating renal stones with diameters of less than 2 cm.(10) some factors including anatomical variations, obesity, kidney malpositioning and stone composition can preclude table 2. patients’ intraoperative and postoperative data characteristicsa swl rirs p value postoperative fever 4 (6.7) 1 (1.6) 0.1 renal hematoma 1 (1.6) 0(0) 0.3 gross hematuria 8 (13.3) 4 (6.7) 0.2 steinstrasse 4 (6.6) 0(0) 0.04 injury to adjacent organs 1 (1.6) 0(0) 0.3 pyelocaliceal system disruption 0(0) 0(0) pain vas 5.2 ± 2.8 3.1 ± 2.7 0.001 number of procedures 1.6 ± 0.3 1.2 ± 0.2 0.001 need for second session 15 (25) 6(10) 0.03 operation duration (minutes) 48.2 ± 14.6 79.9 ± 14.1 0.001 hospitalization duration (hours) 6.7 ± 1.3 18.9 ± 4.3 0.001 success rate at first session 45 (75) 52 (90) 0.03 success rate 53 (88.3) 58 (96.7) 0.08 superior calyx 16 (94) 15 (100) 0.3 middle calyx 11 (100) 11 (91.6) 0.3 inferior calyx 2 (40) 6 (100) 0.02 pelvis 21 (95.5) 21 (100) 0.3 multiple 3 (60) 5 (83) 0.4 adata is presented as mean ± sd or number (percent) rirs vs. swl for renal stone≤2cm-javanmard et al. endourology and stone diseases 2825 vol 13 no 05 september-october 2016 2826 successful swl(3). improvements in endoscopic technology have made retrograde stone removal a more popular approach as endourologic procedures dynamically expand their role for treatment of urinary calculi. (11-12)this comparative study was conducted to compare the efficacy and safety of rirs in the management of renal stone ≤ 2cm with swl as a procedure of choice in many centers. the success rate of rirs at first session was 90% which was higher than swl which supports the reported data from previous studies.(13) in their study, hussein et al. suggested the diameter of 2 cm as the upper limit of stone size which assures stone clearance in a single procedure regardless of its density or location (13); a finding that was confirmed in a review of the literature.(14) recently some authors have evaluated the role of rirs in the management of renal stones of >2cm diameter and suggested it as a favorable option for selected patients with renal stones of 2 to 4 cm. however, in these researches high success rate was achieved after two or three treatment sessions.(5,15) the higher success rate of rirs after one session in the present study suggests that this method is a promising alternative for swl. nevertheless, it is noteworthy that the main differences in the success rates of swl versus rirs were observed mainly in patients with lower pole stones and also in patients with multiple stones. the success rates of swl were essentially similar to rirs for stones in the superior calyx, pelvis or middle calyx (table 2). holmium:yag lithotripsy is mainly performed through photothermal mechanisms to fragment stones (12). therefore, its efficacy in stone fragmentation and clearance is not dependent on stone composition.(16) in contrast, multiple authors have reported that swl success varies between different stone compositions and even within stones of the same composition.(3) a principle in performing swl is the correlation between the higher distance from the skin surface to the stone and the lower chance of stone fragmentation.(3,14) as a consequence, some urologists prefer to manage obese patients with renal calculi by pnl.(17) increased respiratory compromise with positioning such patients in the prone position makes rirs a potentially viable treatment method.(14) according to a recent meta-analysis, the use of rirs in obese patients is efficient with low complications, and with an overall stone-free rate of 87.5%.(14) the residual calculi remaining within the kidney can lead to recurrent stone formation after the swl procedure.(18) in addition to this probable complication, expulsion of the produced stone fragments is usually followed by renal colic.(19) this fact can explain the higher reported pain scores from patients in the swl group. considering the probability of repeated treatment sessions for swl and the consequential induction of multiple episodes of pain in patients, a high first session success rate for rirs makes it a favorable modality for individual who are more susceptible to pain. steinstrasse formation is another complication that can affect 2% to 10% of the patients who have received the swl procedure.(20) this complication is directly correlated with increasing stone burden and was observed in four patients in the swl group in the current study. steinstrasse is one of the drawbacks of swl which increases the number of auxiliary treatment in these patients.(20) although some surgeons have suggested use of routine stenting before swl to decrease the chance of steinstrasse formation and increase the stone-free rates, stenting is clearly associated with increased morbidity. (21,22) on the other hand, the need for insertion of ureteral stent after ureteral access is also mentioned as a limitation for the rirs procedure.(23) despite the advantages of ureteral access sheaths by facilitating multiple passages of the flexible ureteroscope as well as providing lower intrarenal pressures and better flow through the ureteroscope, it might be associated with ureteral injuries with reported rates as high as 46.5%.(23-25) for this reason, routine ureteral stenting is often recommended if a ureteral access sheath is used. in order to avoid the extra admission for jj stent removal, we prefer not to introduce ureteral stent unless the case is complicated or failed. matani et al. recommended risk factor stratification for jj stenting and believed that its routine insertion is impractical and weakly supported.(26) also, another study has suggested that patients could be selected for no ureteral stent if ureteroscopy was uneventful.(23) hospital-stay duration and operation time were higher in the rirs arm of the current study. one drawback of rirs is long operation duration that is dependent on stone size, number, and location and experience of the surgeon. nevertheless, in spite of having a reported duration of 30 to 60 minutes per swl session, this procedure regularly requires repeated treatment sessions along with a high rate of extra admissions for renal colic management.(6) required equipment for rirs include flexible ureteroscope and holmium laser which are expensive and may be unavailable in many centers.(1) also, unfamiliarity of urologists with this technique make rirs a technique that is usually performed in limited referral centers. lack of double blind design was a limitation of our study. we did neither evaluate stones’ hounsfield units preoperatively to identify its effect on the success rate nor performed chemical analysis of the stones. therefore the influence of stone composition on the success of rirs could not be evaluated. cost effectiveness of each procedure was not included in the protocol of this study and is another limitation of this study. and at last we should mention that according to the protocol of our ward we limited the number of shockwaves to 3000. it is possible to use shockwave numbers of up to 4000. this could have made a difference in some cases. however, excluding patients with lower pole or multiple stones, swl success was parallel to rirs for patients with stones size of 6 mm to 2 cm. conclusions our data suggests that rirs is a safe, successful and less painful procedure for treatment for renal stone of ≤2cm. we suggest rirs as an option available for patients with small to medium sized renal stones especially in the lower pole in centers with available experience after consultation with the patient regarding alternative options available including swl. the optimum treatment modality should be chosen based on the patient and stone characteristics as well as the surgeon’s experience and availability of the equipment. acknowledgement this study was approved in laser application in medical sciences research center, shahid beheshti university of medical sciences, as a research project. the authors would like to thank dr. shahrzad azizaddini and appreciate her support for the preparing of this manuscript. rirs vs. swl for renal stone≤2cm-javanmard et al. conflict of interest the authors report no conflict on interests. references 1. karami h, mazloomfard mm, lotfi b, alizadeh a, javanmard b. ultrasonographyguided pnl in comparison with laparoscopic ureterolithotomy in the management of large proximal ureteral stone. int braz j urol. 2013; 39:22-8. 2. park h, park m, park t: two-year experience with ureteral stones: extracorporeal shockwave lithotripsy v ureteroscopic manipulation. j endourol. 1998; 12: 501-4. 3. paterson rf, lifshitz da, kuo rl, siqueira tm jr, lingeman je. shock wave lithotripsy monotherapy for renal calculi. int braz j urol. 2002; 28:291-301. 4. hemal ak, goel a, goel r: minimally invasive retroperitoneoscopic ureterolithotomy. j urol. 2003; 169: 480-2. 5. takazawa r, kitayama s, tsujii t. successful outcome of flexible ureteroscopy with holmium laser lithotripsy for renal stones 2 cm or greater. int j urol. 2012; 19:264-7. 6. mokhless ia, abdeldaeim hm, saad a, zahran ar. retrograde intrarenal surgery monotherapy versus shock wave lithotripsy for stones 10 to 20 mm in preschool children: a prospective, randomized study. j urol. 2014; 191(5 suppl):1496-9. 7. resorlu b, unsal a, tepeler a et al: comparison of retrograde intrarenal surgery and minipercutaneous nephrolithotomy in children with moderate-size kidney stones: results of multi institutional analysis. urology 2012; 80: 519. 8. knoll t, jessen jp, honeck p, wendtnordahl g. flexible ureterorenoscopy versus miniaturized pnl for solitary renal calculi of 10-30 mm size. world j urol. 2011; 29:755-9. 9. miernik a, wilhelm k, ardelt pu, adams f, kuehhas fe, schoenthaler m. standardized flexible ureteroscopic technique to improve stone-free rates. urology. 2012; 80:1198-202. 10. motola ja, smith ad: therapeutic options for the management of upper tract calculi. urol clin north am. 1990; 17: 191-206. 11. el-hout y, elnaeema a, farhat wa. current status of retrograde intrarenal surgery for management of nephrolithiasis in children. indian j urol. 2010; 26: 568–572. 12. razzaghi mr, razi a, mazloomfard mm, golmohammadi taklimi a, valipour r, razzaghi z. safety and efficacy of pneumatic lithotripters versus holmium laser in management of ureteral calculi: a randomized clinical trial. urol j. 2013; 10:762-6. 13. hussain m, acher p, penev b, cynk m. redefining the limits of flexible ureterorenoscopy. j endourol. 2011; 25:45-9. 14. aboumarzouk om, somani b, monga m. safety and efficacy of ureteroscopic lithotripsy for stone disease in obese patients: a systematic review of the literature. bju int. 2012; 110(8 pt b):e374-80. 15. aboumarzouk om, monga m, kata sg, traxer o, somani bk. flexible ureteroscopy and laser lithotripsy for stones >2 cm: a systematic review and meta-analysis. j endourol. 2012; 26:1257-63. 16. khoder wy, bader m, sroka r, stief c, waidelich r. efficacy and safety of ho:yag laser lithotripsy for ureteroscopic removal of proximal and distal ureteral calculi. bmc urol. 2014;14:62. 17. karami h, rezaei a, mohammadhosseini m, javanmard b, mazloomfard m, lotfi b. ultrasonography-guided percutaneous nephrolithotomy in the flank position versus fluoroscopy-guided percutaneous nephrolithotomy in the prone position: a comparative study. j endourol. 2010 ; 24:1357-61. 18. fine jk, pak cy, preminger gm. effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. j urol. 1995; 153:27-32. 19. gravina gl, costa am, ronchi p, galatioto gp, angelucci a, castellani d et al. tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones. urology. 2005; 66:24-8. 20. elkholy mm, ismail h, abdelkhalek ma, badr mm, elfeky mm. efficacy of extracorporeal shockwave lithotripsy using dornier sii in different levels of ureteral stones. urol ann. 2014; 6:346-51. 21. al-awadi ka, abdul halim h, kehinde eo, al-tawheed a. steinstrasse: a comparison of incidence with and without j stenting and the effect of j stenting on subsequent management bju int. 1999; 84:618-21. 22. karami h, javanmard b, hasanzadeh-hadah a, mazloomfard mm, lotfi b, mohamadi r et al. is it necessary to place a double j catheter after laparoscopic ureterolithotomy? a fouryear experience. j endourol. 2012; 26:1183-6. 23. torricelli fc, de s, hinck b, noble m, monga m. flexible ureteroscopy with a ureteral access sheath: when to stent? urology. 2014; 83:278-81. 24. stern jm, yiee j, park s. safety and efficacy of ureteral access sheaths. j endourol. 2007;21:119-123. 25. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013;189:580-584. 26. matani ys, al-ghazo ma, al-azab rs, banirirs vs. swl for renal stone≤2cm-javanmard et al. endourology and stone diseases 2827 vol 13 no 05 september-october 2016 2828 hani o, rabadi dk. emergency double-j stent insertion following uncomplicated ureteroscopy: risk-factor analysis and recommendations. int braz j urol. 2013; 39:203-8. rirs vs. swl for renal stone≤2cm-javanmard et al. pictorial brunn’s cyst: a rare cause of bladder outlet obstruction in a young man stephen lalfakzuala sailo,* laltanpuii sailo a 27-year-old man presented with obstructive voiding symptoms for eight years. his american urological as-sociation (aua) symptom score was 25 with bother score of 4. physical examination was unremarkable. he had normal urinalysis, and urine culture was sterile. he had a peak urine flow rate of 10 ml/s in a voided volume of 174 ml. bladder ultrasound showed a 1.4 × 1.2 cm cystic mass at the bladder neck (figure 1) and an intravenous urography revealed bilateral hydroureteronephrosis. cystoscopic examination showed a normal urethra, a bulge at the bladder neck and upon retro-flexion, a large cystic mass was noted at the bladder neck between 7 and 12 o’clock position (figure 2). transurethral de-roofing and resection of the cystic mass was done using resection loop. the pathological examination showed features of brunn’s cyst (figure 3). after the operation, the obstructive voiding symptoms subsided and he voided with a peak flow rate of 18 ml/s in a voided volume of 253 ml. cystoscopy done three weeks after the operation revealed no residual lesion. bladder outlet obstruction caused by brunn’s cyst has been reported previously.(1,2) de-roofing and resection is curative. brunn’s cyst should be considered as one of the rare causes of bladder outlet obstruction. references 1. franco i, eshghi m, schuttle h, srinivasan k, addonizio jc. bladder neck obstruction secondary to brunn’s cyst. j urol. 1988;139:126-7. 2. grimsby gm, tyson md, salevitz b, smith ml, castle ep. bladder outlet obstruction secondary to a brunn’s cyst. curr urol. 2012;6:50-2. figure 1. bladder ultrasound demonstrating a 1.4 × 1.2 cm cystic mass at the bladder neck. figure 2. cystoscopic examination demonstrating a large cystic mass at the bladder neck between 7 and 12 o’clock position. figure 3. histopathology demonstrates features of brunn’s cyst. department of urology, north eastern indira gandhi regional institute of health and medical sciences (neigrihms), shillong, meghalaya, india. *correspondence: department of urology, north eastern indira gandhi regional institute of health and medical sciences (neigrihms), shillong, meghalaya, india. tel: +91 364 2538006. fax: +91 364 2538010. e-mail: stephensailo@gmail.com. received april 2015 & accepted september 2015 vol 12 no 05 september-october 2015 2381 miscellaneous the effect of anticholinergics for prevention of storage symptoms after prostate photovaporization david alejandro martín way*, rocio barrabino martín, ignacio puche sanz, francisco javier vicente prados, jose manuel cozar olmo purpose: to evaluate the efficacy of oral anticholinergics as a preventive strategy of storage symptoms and urinary incontinence associated with the early postoperative period after greenlight laser photovaporization of the prostate (pvp). to analyze potential variables related to the onset of these symptoms. materials and methods: retrospective study of 105 patients who underwent pvp using a 180-w greenlight laser (xps). patients were divided into two groups, depending on whether they were or weren´t prescribed anticholinergics when discharged (oral solifenacin 5 mg for 1 month after surgery). differences between both groups were analyzed according to ipss, iciq-sf and oabq-sf scores at 1 and 6 months. the potentially predictive variables of the symptomatology after undergoing pvp that we analyzed included age, prostate volume, psa, ipss, iciqsf, oabq-sf, qmax, previous use of a permanent urinary catheter, energy used, and laser application time. results: 58 patients in the group with anticholinergics and 47 in the group without anticholinergics were compared. no significant differences were observed between both groups in ipss (p = .521), iciq-sf (p = .720) or oabq-sf (p = .851) at 1 and 6 months after surgery. regardless of the use of anticholinergics, there was a significant score improvement between the first and second checkup in all the questionnaires: there was a significant decrease in the mean ipss (p < .001) and the mean score of the eighth ipss question on patient’s quality of life (p = .026), iciqsf (p = .010) and oab-q related to symptoms (p = .001) as well as a significant increase in the mean oab-q score regarding quality of life (p = .005). none of the variables analyzed showed a significant relation to the storage-symptom rate, rate of incontinence, or iciq-sf and oabq-sf scores. conclusion: the use of solifenacin 5 mg after greenlight laser pvp is not an effective preventive treatment for storage and incontinence symptoms associated with this procedure, which seem to self-limit over time. keywords: anticholinergics; greenlight laser; oral anticholinergigs; prostate; storage symptoms introduction 180-w greenlight (xps) photoselective vaporization of the prostate is considered to be a safe and efficacious treatment option for lower urinary tract symptoms (luts) secondary to benign prostatic hyperplasia (bph)(1, 2), being particularly useful for anticoagulated patients, or in patients with other comorbidities (3). nevertheless, compared with turp, photovaporization of the prostate (pvp) using a greenlight laser (gl) has been associated with a higher rate of dysuria, storage symptoms, and urinary incontinence during the early months after surgery(4,5). these irritative symptoms, which are frequent after gl pvp, have not been studied enough and have not been completely understood(6,7). to date, no study has determined which treatment or strategy should be used to prevent the onset of these symptoms. oral anticholinergics are a possible therapeutic option for this symptomatology, as it has been previously demonstrated for other urological procedures(8,9); however no study on this matter has been carried out(10). the main objective of our research was to evaluate the urology department . hospital universitario virgen de las nieves. avenida de las fuerzas armadas, nº2 18014. granada (españa). *correspondence: urology deparment. hospital universitario virgen de las nieves. avenida de las fuerzas armadas, nº2 18014 granada (españa) tel: +34 626427161 email: dmartinway@gmail.com received november 2017 & accepted june 2018 efficacy of oral anticholinergics as a preventive strategy of storage symptoms and urinary incontinence associated with the early postoperative period of gl pvp. as secondary objective, variables possibly related to the onset of these irritative symptoms were analyzed. materials and methods the study is a retrospective and descriptive study with a cohort of 105 patients diagnosed with luts due to bph that underwent gl pvp at our department from october 2012 to march 2016. patients and variables measured were consecutively included in a prospective database. before surgery, the following measurements were collected: prostate volume by transrectal ultrasound, psa, flowmetry (qmax), international prostate symptom score (ipss), and scores of international consultation on incontinence questionnaire-short form (iciqsf) and overactive bladder questionnaire-short form (oabq-sf). during the procedure, the energy used and the exposure time were recorded. in the first and second checkups after surgery (at the first postoperative month urology journal/vol 16 no. 6/ november-december2019/ pp. 598-602. [doi: 10.22037/uj.v0i0.4297] and between the sixth and ninth months) flowmetric data and scores of the three previous questionnaires were recorded. also, it was qualitatively recorded whether patients showed storage symptoms or urinary incontinence. thus, the presence of dysuria, urgency, or pollakiuria, regardless of their amount, reported by the patient was considered storage symptoms. also, leakage, regardless of its amount, reported by the patient was considered urinary incontinence. at the second checkup, patient satisfaction with the procedure was assessed in a questionnaire. treatment prescribed to patients when discharged was retrospectively reviewed, dividing them into two groups according to whether they were prescribed oral anticholinergics (ac group), or not (nac group). some physicians prescribed them routinely to all patients to avoid irritative symptoms, and others didn´t, which allowed us to separate the patients into two groups, without there being any type of randomization. in all cases, the anticholinergic prescribed during the first postoperative month was solifenacin 5 mg, and the alternative was not receiving any treatment at all. the association of this event with urinary symptoms after surgery was statistically analyzed, checking whether there were differences among the mean scores of ipss, iciq-sf, and oabq-sf questionnaires in postoperative checkups. as potentially predictive preand intraoperative variables of storage symptoms and/or urinary incontinence after undergoing pvp, we analyzed age, prostate volume, psa, ipss, iciq-sf, oabq-sf, qmax, previous use of a permanent urinary catheter, energy used, and laser application time. continuous variables were expressed as mean and standard deviation, median and 25-75 percentiles in non-parametric cases. categorical variables were expressed through absolute and relative frequencies. the hypothesis of normality was confirmed using the shapiro-wilks test. differences between treatment groups were compared using the bivariate analysis: student’s t-test for independent samples, and the mann-whitney u test in cases of non-normality. to analyze the potential change of outcome variables at the different measured times, we used student’s t-test for related samples or repeated measures anova, and kruskal-wallis and friedman tests for non-parametric cases. a p-value under .05 was considered significant. data were analyzed using ibm spss statistics 19 software. results the study included 105 patients. patient characteristics are listed in table 1. none of them used to take anticholinergics before surgery. mean qmax and ipss significantly improved in the series as a whole due to the procedure. there were no significant changes in iciq-sf and oabq-sf scores before and after surgery. the percentage of patients with storage symptoms and incontinence in the first checkup was 46.8% and 50%, respectively. the percentage of patients with storage symptoms and incontinence interestingly decreased from the first to the second checkup, although this decrease was only statistically significant for storage symptoms (table 2). intraoperative complications were reported in only 6 patients (5.7%), which consisted of 5 cases of intraoperative bleeding and 2 perforations of the prostatic capsule. 32 patients (30.5%) reported postoperative complications: 12 patients had hematuria (11.4%), 1 (1%) required a red blood cell transfusion, 13 (13.3%) suffered from uti, 8 (7.6%) had acute urinary retention, 6 (5.7%) developed a posterior urethral stricture, prevention of irritative syndrome after pvp-way et al. table 1. preoperative characteristics of patients. mean ± sd median p25-p75 age (years) 68.75 ± 9.46 70 60-76.5 prostate volume (cc) 64.29 ± 27.52 62 45.6-80 psa (ng/ml) 3.33 ± 2.32 2.68 1.6-4.7 qmax (ml/seg) 8.74 ± 3.02 9 6.9-10.7 ipss 22.17 ± 5.55 22 19.752.25 qol ipss 4.48 ± 1.05 4 4-5 iciq-sf 4.11 ± 6.35 0 0-9 oabqsf-sym 37 ± 22.33 31.36 22.47-60.82 oabqsf-qol 70.85 ±15.41 70 61.55-83.87 n(%) permanent urinary catheter 33(31.4%) treatment prior to surgery alpha-blockers 24(22.9%) combined treatment (dutasteride + tamsulosin) 80(76.2%) current anticoagulant use up to surgery 17(16.2%) anesthetic risk (asa) asa i 9(8.7%) asa iii 37(35.6%) asa ii 53(51%) asa iv 5(4.8%) preoperative 1 mo 6-9 mo p mean qmax ± sd (ml/s) 8.4 ± 1.45 13.24 ± 2.36 15.27 ± 1.87 .048 mean ipss ± sd 22.89 ± 0.91 12.03 ± 0.98 9.78 ± 1.13 < .001 mean ipss qol ± sd 4.45 ± 0.22 2.41 ± 0.34 2.09 ± 0.37 < .001 mean iciq-sf ± sd 4.41 ± 1.61 8.23 ± 1.70 5.76 ± 1.66 .191 mean oabq-sf-sym ± sd 37.43 ± 5.56 31.73 ± 5.92 22.92 ± 5.86 .132 mean oabq-sf-qol ± sd 71.94 ± 15.15 76.82 ± 20.91 83.07 ± 19.38 .125 incontinence (% of total) (a) 50% 40.3% .109 storage symptoms (% of total) (a) 46.8% 25.8% .007 (a) non-collected variables during the preoperative period. table 2. changes in functional variables between the preoperative period and the postoperative checkups. vol 16 no 06 november-december2019 599 miscellaneous 600 and another 6 (5.7%) developed bladder neck stricture. 30 patients (28.6%) had to be attended in the er after being discharged from the hospital due to complications resulting from surgery. according to the clavien-dindo classification, 11 (34.4%) out of the 32 complications were grade i; 12 (37.5%), grade ii; 4 (12.5%), grade iiia; and 5 (15.6%), grade iiib. regarding patient satisfaction with the procedure, most patients were very satisfied or satisfied (17.7% and 51.9%, respectively), 21.5% stated that they were not so satisfied, and 8.9% stated they were dissatisfied. 71.8% of the patients would recommend the surgery to someone. to study homogeneity between both groups (ac vs nac), some preoperative (qmax, psa, prostate volume, prior treatment, anesthetic risk, ipss, iciq-sf, oabq-sf), intraoperative (energy used and laser application time) and postoperative (days of urinary catheter, hospital stay, complications) variables were compared. there were no statistically significant differences between both groups in any of these variables (table 3). after the surgery, there were no statistically significant differences between both groups in mean ipss, iciqsf and oabq-sf in the checkups that follow (table 4). regardless of anticholinergic treatment, there was a significant improvement in both groups between the first and second checkups in the mean scores of all the mentioned questionnaires. as shown in the results of the questionnaires listed in table 4, there was a significant decrease in the mean ipss (p < .001) and the mean score of the eighth ipss question on patient’s quality of life (p = .026), iciqsf (p = .010) and oab-q related to symptoms (p = .001) as well as a significant increase in the mean oab-q score regarding quality of life (p = .005). however, the percentage of patients that reported incontinence between the first and second checkup did not significantly change in ac group (p = .180) or nac group (p = 1). likewise, the number of patients who reported storage symptoms did not change significantly (p = .057 and p = .125, respectively). there were no significant differences between both groups regarding the grade of satisfaction (55% vs 54.3% of patients were satisfied in the ac and nac groups, respectively, p = .909), or in patient´s recommendation of the procedure (70.5% vs 73.5%, respectively, p = .805). none of the variables studied (age, prostate volume, psa, ipss, iciq-sf, oabq-sf, maximum flow rate, the use of a permanent urinary catheter, energy used, and laser application time) showed a statistically significant relation to storage symptom and incontinence rates and mean postoperative scores of iciq-sf and oabq-sf. discussion turp is still the gold standard technique for bph treatment(1). however, during recent years, new laser technologies are changing the surgical approach to this disease(11). among them, gl pvp has demonstrated a better perioperative profile than turp, with a shorter hospital stay and a shorter postoperative period of uritable 3. comparison of variables to determine the homogeneity of the groups. nac (n=47, 44.8%) ac (n=58, 55.2%) p preoperative ipss (mean ± sd) 22.87 ± 4.85 21.65 ± 6.04 0.428 preoperative qmax ml/s (mean ± sd) 8.52 ± 2.66 8.91 ± 3.28 0.661 preoperative psa ng/ml (mean ± sd) 3.51 ± 2.54 3.20 ± 2.15 0.527 preoperative prostate volume cc (mean ± sd) 62.57 ± 25.75 65.6 ± 28.96 0.577 preoperative iciq-sf (mean ± sd) 6.20 ± 7.68 1.78 ± 3.56 0.144 preoperative oabq-sf-sym (mean ± sd) 44.42 ± 21.84 29.61 ± 21.43 0.232 preoperative oabq-sf-qol (mean ± sd) 67.70 ± 16.17 74.01 ± 14.85 0.452 previous combined treatment (dutasteride + tamsulosin) 35(76.1%) 45(77.6%) 1 asa ii 23(50%) 30(51.7%) 0.139 energy applied joules (mean ± sd) 270935.48 ± 104564.79 315066 ± 123010.97 0.100 application time min (mean ± sd) 26.20 ± 8.95 32.12 ± 12.65 0.240 urinary catheter days (mean ± sd) 1.87 ± 0.92 1.79 ± 0.99 0.675 hospital stay days (mean ± sd) 2.28 ± 0.19 2.31 ± 0.19 0.901 intraoperative bleeding 2(4.3%) 3(5.2%) 1 postoperative hematuria 4(8.5%) 8(13.8%) 0.398 postoperative uti 6(12.8%) 8(13.8%) 0.878 postoperative aur 4(8.5%) 4(6.9%) 1 postoperative urethral stricture 3(6.4%) 3(5.2%) 1 postoperative cell sclerosis 4(4.3%) 4(6.9%) 0.689 1 month 6-9 months p ipss nac 11.89 ± 6.05 8.81 ± 6.81 .521 ac 12.65 ± 6.27 10.46 ± 8.27 ipss qol nac 2.39 ± 1.42 1.94 ± 1.70 .520 ac 2.43 ± 1.91 1.64 ± 1.95 iciq-sf nac 8.94 ± 5.98 6.19 ± 6.46 .720 ac 7,29 ± 7,63 3.71 ± 5.90 oabq-sf-sym nac 34.63 ± 23.47 21.98 ± 24.43 .851 ac 30.93 ± 23.27 16.87 ± 20.57 oabq-sf-qol nac 75.59 ± 22.14 84.52 ± 19.21 .894 ac 77.03 ± 21.14 86.81 ± 19.02 table 4. questionnaire comparison between groups at the two postoperative checkups. variables expressed in mean ± sd. prevention of irritative syndrome after pvp-way et al. nary catheterization(5). the most important study comparing bipolar turp with gl pvp is the goliath study, which showed that, after a two-year follow-up, gl pvp is a valid and long-lasting option for bph treatment, with similar results to tur in terms of efficacy and safety(12). however, gl pvp was associated with a higher rate of storage symptoms and urinary incontinence in the early months after surgery(5). to date, no study has determined which treatment or strategy should be used to prevent the onset of such symptomatology(10). since anticholinergics are a widely-used treatment for storage symptoms and for symptoms derived from an overactive bladder(1), our working group considered that they could be an adequate treatment for irritative and storage symptoms after gl pvp. during the study of our series, we observed that the percentage of patients with storage symptoms and incontinence decreased from the first to the second checkup. based on this, we thought it would be interesting to analyze the potential role of anticholinergics in the prevention of irritative symptomatology during the early months after surgery. the functional results of our series of patients are equivalent to those of the goliath study, although the improvement in the flowmetry and the ipss at 6 months after surgery is moderately smaller (qmax 15.25ml/s vs 23.3ml/s, ipss 9.78 vs 6.8, ipss qol 2.09 vs 1.5, respectively)(5). the number of patients with incontinence at 6 months (40.3%) was slightly higher than in other trials. only 11% of goliath patients reported incontinence at 6 months. these differences are probably due to the different baseline characteristics of our patients as well as the different criterion applied to define incontinence. thus, the mean prostate volume of our patients was 64.2cc while that of goliath patients was much lower (48.6cc)(5). the percentage of patients with irritative symptoms at 6 months was 25.8%, similar to the percentage of the goliath study and of other studies (13,14). only 6 patients (5.7%) suffered from intraoperative complications, fundamentally intraoperative bleeding, similar to other studies(14). regarding postoperative complications, patients principally reported uti (13.3%), hematuria (11.4%), acute urinary retention (7.6%), posterior urethral stricture (5.7%), and bladder neck stricture (5.7%), and 71.9% were grades i or ii on clavien-dinco. uti and hematuria rates at 6 months are below those in the goliath study, although in our series, the percentage of patients taking oral anticoagulants was 4 times higher(5). mean hospital stay and mean postoperative time using a urinary catheter were similar (5), thus confirming the excellent perioperative profile of this technique. it has not been established if there is an effective treatment for temporary storage symptoms after prostate surgery, and no predictors have been found either(10). in our series of patients, none of the preoperative variables influenced either the proportion of patients with postoperative storage symptoms and/or incontinence, or the iciq-sf and oabq-sf scores during follow-up. both groups characteristically improved in ipss, iciqsf, and oabq-sf scores between the first and second checkups, regardless of whether they took anticholinergics. this finding is in line with other studies which show that this irritative syndrome is temporary and significantly improves before the end of the first postoperative year(13,14,15). the main limitation of our research is that it is a retrospective study, which divided the patients into two different groups (ac and nac) according to clinical criteria. this fact could lead to prescribing anticholinergics more often to the more symptomatic patients. however, the main pre-, intraand postoperative objectifiable variables proved to be homogeneously distributed between both groups, allowing for their objective comparison. on the other hand, ipss is a questionnaire that has not been validated to quantify storage symptoms after endoscopic prostate surgery, since it requires symptoms to be stable for at least 3 weeks(10). therefore, new validated questionnaires capable of quantifying such symptomatology would be necessary to disseminate and compare results between studies. in addition, the definitions of incontinence and storage and dysuria symptoms are different in every study reviewed, which could explain the existing differences in the percentages of patients who have them. moreover, there is no accurate urodynamic diagnosis of each patient prior to surgery. since detrusor overactivity in patients with obstruction to bladder emptying due to bph may reach 45%(16), this may be a potential bias in determining the percentage of incontinence and emptying symptoms that are actually secondary to gl pvp. in our study, we tried to avoid this bias by excluding those patients who had taken oral anticholinergics at some time before surgery. finally, in our series, only solifenacin 5mg was used as a prophylactic treatment, avoiding the use of higher doses to reduce the risk of postoperative urinary retention. however, new studies with higher doses or with other anticholinergics may be considered to test its efficacy as a preventive treatment for this irritative syndrome. a stronger confirmation of our results would require prospective studies with a correct randomization of patients, probably comparing different therapeutic strategies. conclusions this is the first study to determine that the use of lowdose oral anticholinergic drugs after pvp with a 180-w greenlight laser (xps) is not an effective preventive strategy for storage symptoms and incontinence associated with this procedure, which seem to self-limit over time. neither prostate volume, nor total energy used, nor laser application time were predictors of the risk of suffering this postoperative irritative syndrome. conflict on interest the authors declare no conflict of interest. references 1. oelke m, bachmann a, descazeaud a et al. eau guidelines on the treatment and followup of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol 2013; 64:118-40. 2. mcvary kt, roehrborn cg, avins al et al. update on aua guideline on the management of benign prostatic hyperplasia. j urol 2011; prevention of irritative syndrome after pvp-way et al. vol 16 no 06 november-december2019 601 miscellaneous 602 185:1793-803. 3. amón sesmero jh. nuevas perspectivas de la laserterapia. arch esp urol 2008; 61:1163-9. 4. ahyai sa, gilling p, kaplan sa et al. meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. eur urol 2010; 58:384–97. 5. bachmann a, tubaro a, barber n et al. 180w xps greenlight laser vaporisation versus transurethral resection of the prostate for the treatment of benign prostatic obstruction: 6-month safety and efficacy results of a european multicentre randomised trial— the goliath study. eur urol 2014; 65:93142. 6. cornu jn, ahyai s, bachmann a et al. a systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. eur urol 2015; 67:1066–96. 7. audouin m, benbouzid s, terrasa jb et al. evaluation of postoperative symptoms after greenlighttm photovaporization of the prostate through a dedicated questionnaire [in french]. prog urol 2016; 26:108–14. 8. bai y1, wang x1, li x2 et al. management of catheter-related bladder discomfort in patients who underwent elective surgery. j endourol. 2015 jun; 29(6):640-9. 9. maghsoudi r, farhadi-niaki s, etemadian m et al. comparing the efficacy of tolterodine and gabapentin versus placebo in catheter related bladder discomfort after percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2018 feb; 32(2):168-174. 10. cornu jn, herrmann t, traxer o et al. prevention and management following complications from endourology procedures. eur urol focus 2 2016; 49-59. 11. yu x, elliott sp, wilt tj et al. practice patterns in benign prostatic hyperplasia surgical therapy: the dramatic increase in minimally invasive technologies. j urol 2008; 180:241–5, discussion 245. 12. thomas ja, tubaro a, barber n et al. a multicenter randomized noninferiority trial comparing greenlight-xps laser vaporization of the prostate and transurethral resection of the prostate for the treatment of benign prostatic obstruction: two-yr outcomes of the goliath study. eur urol 2016; 69:94–102. 13. capitán manjón c, de la gallega moreno jm, de la peña zarzuelo e et al. papel actual de la fotovaporización prostática con láser greenlight hps. aspectos técnicos y revisión de la literatura. actas urol esp 2009; 33(7):771-77. 14. ruszat r, seitz m, wyler sf et al. greenlight laser vaporisation of the prostate: single center experience and long-term results after 500 procedures. eur urol 2008; 54:893–901. 15. bachmann a, tubaro a, barber n et al. a european multicenter randomized noninferiority trial comparing 180 wgreenlight xps laser vaporization and transurethral resection of the prostate for the treatment of benign prostatic obstruction: 12-month results of the goliath study. j urol 2015; 193:570-78. 16. knutson t, edlund c, fall m et al. bph with coexisting overactive bladder dysfunction-an everyday urological dilemma. neurourol urodyn. 2001; 20:237-47. prevention of irritative syndrome after pvp-way et al. endourology and stone disease application of flexible ureteroscopy combined with holmium laser lithotripsy and their therapeutic efficacy in the treatment of upper urinary stones in children and infants junhua li**, huiqin yu**, peng zhou, huixian pan, ruipeng li, yanbin wang, chen song, yangfeng lou, jingyu zhu* purpose: to investigate the efficacy and safety of retrograde intrarenal surgery (rirs) for the treatment of pediatric patients. materials and methods: a total of 45 patients with upper urinary stones treated using flexible ureteroscopy combined with holmium laser lithotripsy at our department between june 2015 and january 2017 were examined in this study. results: the operative success rate of treatment using holmium laser lithotripsy via flexible ureteroscopy was 97.8% (44/45); one patient (1/45, 2.2%) was converted to laparoscopic pyelolithotomy, and the calculus was successfully removed. lithotripsy via flexible ureteroscopy was successful during the first phase in 38 patients (38/45, 84.4%), and second or third phase lithotripsy was needed for six patients (6/45, 13.3%). intraoperative ureteral fracture in the middle and lower sections occurred in one pediatric patient who was converted to laparoscopic pyelolithotomy and ureter bladder reimplantation. this patient was discharged after recovery at 2 weeks postoperative and showed no significant renal dysfunction over the 12-month follow-up period. severe postoperative gross hematuria occurred in one patient, who improved after hemostasis and other symptomatic treatments. high fever occurred in two patients (body temperature >39°c), who later improved. these pediatric patients were discharged after active anti-infection and other conservative treatments for 4 days. all of the included patients were followed up for 2-15 months, with an average follow-up period of 8 months. the total calculus clearance rate was 100% (45/45), with no recurrence of the calculus. conclusion: in this study, most upper urinary stones in children and infants were treated successfully with holmium laser lithotripsy applied via flexible ureteroscopy. keywords: infants and young children; upper ureteral calculi; flexible ureteroscopy; holmium laser introduction the treatment of upper urinary calculi in children and infants has always been a difficult problem for urologists. previously, treatment methods for upper urinary calculi in children and infants have generally consisted of those used in adults, including extracorporeal shock wave lithotripsy (eswl), percutaneous nephrolithotomy (pcnl), ureteroscopic lithotripsy, and laparoscopic pyelolithotomy. due to the physiological characteristics of children and infants, their renal volume is small, cardiopulmonary function is not fully developed, and their tolerance for surgery is low. the application of adult treatment methods for upper urinary stones may cause greater trauma in children. flexible ureteroscopic lithotripsy has recently been increasingly applied to treat upper urinary stones in infants and children because of its advantages, such as its natural access to the human body, limited trauma, satisfactory repeatability, quick recovery, low incidence of complications, and excellent safety and effectiveness(1). therefore, we applied flexible ureteroscopic lithotripsy to treat upper urinary stones in children and infants. a todepartment of urology, third hospital of hangzhou, no. 38 west lake road hangzhou, zhejiang, p. r. china. *correspondence: department of urology, third hospital of hangzhou, hangzhou, zhejiang, p. r. china; phone: 13819192063, e-mail: zhujingyu0309@126.com. ** junhua li and huiqin yu contributed equally to this work. received june 2018 & accepted november 2018 tal of 45 infants and children with upper urinary stones were treated with flexible ureteroscopy combined with holmium laser lithotripsy at our department between june 2015 and january 2017, and satisfactory results were achieved. these results are reported as follows. materials and methods study population after obtaining approval from the local ethics committee at our hospital. the calculi were diagnosed according to a reference(1), and diagnosis in all cases was confirmed by a color doppler ultrasound and computed tomography (ct) examination of the urinary system. a routine preoperative urine test and mid-urine culture examination were performed, and routine intravenous antibiotics were provided to control and treat infections. inclusion criteria: upper urinary stones, patients less than 14 years old. exclusion criteria: kidney anomalies, uncontrolled coagulopathies, ureteral obstruction, history of previous renal surgery or swl and renal failure (serum creatinine≥ 3 mg/dl)(2). urology journal/vol 16 no. 4/ july-august 2019/ pp. 343-346. [doi: http://dx.doi.org/10.22037/uj.v0i0.4640] vol 16 no 04 july-august 2019 344 procedures intravenous anesthesia was administered to all pediatric patients in the lithotomy position. after routine disinfection, an f4/5.6-f8/9.8 rigid ureteroscope was passed into the bladder via the urethra to locate the ureteral orifice, and a nickel holmium guide wire was placed in the ureter along the ureteroscope. if the ureteroscope successfully entered the upper section of the ureter (below the ureteral calculi or the ureteropelvic junction area), then the rigid ureteroscope was withdrawn, and a flexible ureteroscopy sheath (f10/12) was placed under the guidance of the pre-set guide wire. next, an f7.5 flexible ureteroscope was placed along the flexible ureteroscopy sheath via water injection using an artificial syringe to locate the calculi. the power of the holmium laser (18-32 w/30-40 hz) was adjusted for lithotripsy based on the size, color, and hardness of the calculus. high frequencies and low energy were used as much as possible to reduce mucosal damage and fully shatter the calculus or to remove the larger fragments of the calculus with a calculus basket. after the completion of lithotripsy, the flexible ureteroscope and its sheath were withdrawn, and an f6 dj tube was placed with the indwelling catheter. a postoperative routine examination of the kidney, ureter, and bladder (kub) was performed to determine the efficacy of the lithotripsy procedure and the position of the dj tube. if a "feeling of the scope being held" (the physician felt that the ureteroscope could not be pushed proximally forward) was noted during the placement of the f4/5.6-f8/9.8 rigid ureteroscope, then the operation was terminated with the indwelling f6 dj tube after withdrawing the scope. second or third phase lithotripsy was conducted via flexible ureteroscopy after 2 weeks. at 1-2 months after surgery, urinary system b ultrasound and ct results were reviewed to observe the stone clearance, and the presence of stone fragments <4 mm was defined as a successful operation. thus, the dj tube could be removed; otherwise, additional operations were performed until the stone was completely cleared. statistical analysis the statistical analysis was performed using spss 21.0 software. count data are presented as percentages (%). quantitative data are presented as medians and interquartile ranges. results the 45 pediatric patients in this study included 24 boys and 21 girls, ranging in age from 7-175 months (14 years and 7 months). the average patient age was 113.5 months (9.5 years), and four patients were < 3 years old. fifteen cases of calculi were observed in the unilateral upper ureter. moreover, 19 cases of unilateral renal calculi, including three cases of calculi in the ureteropelvic junction, four cases in the middle and upper calyx, six cases in the lower calyx, and six cases of multiple calculi; seven cases of unilateral renal calculi with ipsilateral ureteral calculi; and four cases of bilateral renal calculi were observed. the maximum diameter of the calculi was 0.8-3.3 cm, with an average of 1.7 cm. eleven calculi were >2.0 cm (table 1). in this study, lithotripsy via flexible ureteroscopy combined with holmium laser treatment was successful in 44 of the 45 cases; the remaining patient presented with ureter avulsion and was converted to laparoscopic pyelolithotomy to successfully remove the calculus. the single operation time ranged from 10-60 min, with an average of 30 min. if the stone was large (i.e., > 2.0 cm) and the surgery could not be completed within 60 min, then lithotripsy was conducted for the remaining stone during the second or third phase. in this study, one case (1/45, 2.2%) was converted to laparoscopic pyelolithotomy to remove the calculus. lithotripsy via flexible ureteroscopy was successful during the first phase in 38 cases (38/45, 84.4%), and second (4/45, 8.9%) or third (2/45, 4.4%) phase lithotripsy was needed in six cases (6/45, 13.3%). the major reasons for second or third phase lithotripsy were "ureteral stenosis" causing failure of scope placement in five cases (5/6, 83.3%), including three cases with the "feeling of the scope being held" (3/6, 50%). in 2 cases (2/6, 33.3%), the calculus was relatively large, and therefore, lithotripsy could not be completed in a single session (table 2). due to the limited proficiency of the surgical operation, one 7-year, 4-month-old girl presented with a severe intraoperative complication of ureteral avulsion during the early stage of the development of this technology. the calculus in this patient, which was approximately 1.5×2 cm, was located in the left ureteropelvic junction. a conventional f6/7.5 rigid ureteroscope was intraoperatively placed; the patient presented with ureteral stenosis and a "feeling of the scope being held". after ureteral dilatation, the ureteroscope was placed in the ureteropelvic junction. after the withdrawal of the scope, we found a rupture in the middle part of the ureter. after consultation with the parents and obtaining informed consent, the patient was converted to laparoscopic pyelolithotomy, and ureter bladder reimplantation was performed. this operation, resulting in postoperative f6-dj tube placement for 3 months, was successful. to date, the follow-up examinations table 1. preoperative data of the included cases. number of patients 45 average age (months) 113.5 (7-175) boys/girls 24/21 location of the calculi unilateral upper ureteral calculus 15 unilateral renal calculus 19 unilateral renal calculus with ipsilateral 7 upper ureteral calculus bilateral renal calculus 4 size of the calculi (cm) 1.7 (0.8-3.3) >2 cm 11 average operation time (min) 30 (10-60) length of hospital stay (d) 4.2 (3-5) calculus clearance rate after the first operation 38(84.4%) cases requiring phase ii surgical lithotripsy 4 (8.9%) cases requiring phase iii surgical lithotripsy 2 (4.4%) calculus clearance rate 45(100%) successful operation rate 44(97.8%) complication ureter avulsion 1 (2.2%) severe bleeding 1 (2.2%) urinary sepsis 2 (4.4%) follow-up time (month) 8 (2-15) calculus composition calcium oxalate calculus 13 (37.1%) urate calculus 4 (11.4%) phosphate calculus 3 (8.6%) calcium oxalate calculus with urate calculus 9 (25.7%) calcium oxalate calculus with phosphate calculus 6 (17.2%) table 2. intraoperative and postoperative status. flexible ureteroscopy for children stones-li et al. including urinary system b ultrasound scans and blood biochemistry measures have shown no obvious hydronephrosis or renal dysfunction (figure 1). therefore, the operation was terminated in subsequent cases when the surgeon noted a "feeling of the scope being held" while placing the rigid ureteroscope to avoid the occurrence of ureteral avulsion and other severe complications. in all other cases, no intraoperative ureteral perforation, avulsion, or other serious complications occurred; however, different degrees of postoperative gross hematuria were observed, including severe bleeding (bright red urine and decreased hemoglobin) in one 4-year, 3-month-old with a renal calculus in the lower calyx (1/45, 2.2%), indicated by 200 ml of bright red urine in the postoperative indwelling catheter drainage. the gross hematuria gradually disappeared after timely reporting of the condition to the physician, hemostasis, and other symptomatic treatments. the urinary catheter was withdrawn without obvious gross hematuria after 3 days, and a routine urine test on the fourth day revealed occult blood (+). the patient was discharged with an improved condition. urinary sepsis (the patient’s symptoms included a temperature >38.5℃, tachypnea, and a wbc count >11,000/μl) occurred in an 8-year, 6-month-old and a 13-year, 2-month-old (2/45, 4.4%). after hemostasis, active anti-infection therapy, rehydration, and other symptomatic treatments, the patients were discharged with an improved condition 4-5 days after the surgery. the remaining 41 pediatric patients did not show serious complications, and the catheter was removed 1-2 days after surgery, with a hospital stay of 3-5 days (average, 4.2 days). the postoperative follow-up period lasted 2-15 months, with an average of 8 months. the overall calculus clearance rate was 100% (45/45), and no recurrence was observed. in addition, the composition of the calculi from the 35 pediatric patients was postoperatively analyzed. the results showed that calculi containing calcium oxalate accounted for approximately 80% (28/35) of cases, which is similar to the composition of upper ureteral calculi found in adults (table 2). discussion due to upgrades of the flexible scope material and improvements in the technology of auxiliary equipment, the application of flexible ureteroscopy has become increasingly common in the diagnosis and treatment of calculi in the upper urinary tract. currently, some european and american medical centers use flexible ureteroscopy as the preferred treatment method for upper ureteral and renal calculi in children(3-8). cavildak et al. (9) showed that laparoscopic ureterolithotomy and flexible ureteroscopy are both effective and reliable for the treatment of proximal ureteral stones, and flexible ureteroscopy was recommended as the preferred method due to the shorter operation and hospitalization times and the ability to manage situations that require secondary interventions. however, the treatment of calculi in the upper urinary tract of children using flexible ureteroscopy has rarely been reported in china(1), which imposed a new challenge on our department regarding the implementation of this technology. first, pediatric patients in china often require flexible ureteroscopic lithotripsy after the placement of an indwelling dj tube, which differs from one-phase flexible ureteroscopic lithotripsy involving the pre-expansion of the ureter orifice, which is commonly applied by foreign surgeons. however, the success rate of first-stage lithotripsy is not different between the two methods(3-8). second, because flexible ureteroscopy achieves lithotripsy and calculus removal through a natural channel of the human body, surgical trauma, bleeding, renal damage, and other complications are significantly reduced compared to pcnl, laparoscopic surgery, and open surgery, and the technique has acceptable reproducibility. in a recent study, swl was shown to be less expensive, required a shorter hospitalization time and longer fluoroscopy time, have a similar stone-free rate, and have the same efficiency as flexible ureteroscopy for pediatric renal stones with a diameter between 10 and 20 mm(10). however, eswl can only be performed two times in one position because the infant’s kidney is too small to be manipulated repeatedly. flexible ureteroscopic lithotripsy surgery has specific requirements for the ureter anatomy, location of the calculus, and urinary tract infection, and serious complications might still occur. additionally, studies have shown that flexible cystoscopy does not require antibiotics to prevent infection before surgery(11). however, in the case of ureteroscopic lithotripsy, preoperative antibiotic use is necessary to prevent infection because the stones are associated with high levels of bacteria. for example, two patients had calculi with a large amount of adhered pus during the surgery. although increased preoperative and intraoperative anti-infection treatments were provided, the intraoperative renal pelvic perfusion pressure was reduced, and the operation time was shortened, postoperative urinary sepsis still ineviflexible ureteroscopy for children stones-li et al. figure 1. case of ureteral avulsion and reexamination at 6 months after ureter bladder reimplantation. endourology and stones diseases 345 vol 16 no 04 july-august 2019 346 tably occurred. in this study, flexible ureteroscopic lithotripsy had a good therapeutic effect, and the final stone-free rate reached 100%. however, this study also had some limitations. the sample size was relatively small, with only 45 cases, and it was a single center study. in addition, the composition of the stones was only analyzed in 35 cases. these results many not accurately reflect the current status of treatment for upper urinary stones in children and infants. conclusions in this study, most upper urinary stones in children and infants were treated successfully with holmium laser lithotripsy applied by flexible ureteroscopy. this method has the advantages of high efficiency, minimal invasiveness, and repeatability. the method allows successful surgical treatment for this type of calculi in clinical practice. acknowledgement the authors would like to thank dr. xiaoping qi (the 117th hospital of pla) for statistical support with this paper. this study was funded by the health science and technology program (key) project of hangzhou (grant number. 2016z03) and the medical and health technology project of zhejiang province (grant number. 2017ky531). conflict on interest the authors declare that they have no conflict of interest. references 1. li j, xiao j, han t, et al. flexible ureteroscopic lithotripsy for the treatment of upper urinary tract calculi in infants. exp biol med (maywood), 2017, 242:153-159. 2. javanmard b, kashi a h, mazloomfard m m, et al. retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j,2016,13:2823-28. 3. kim, s s, kolon, t f, canter, d, white, m, casale, p. pediatric flexible ureteroscopie lithotripsy: the children's hospital of philadelphia experience. j urol, 2008, 180:2616-19℃ 4. unsal a, resorlu b. retrograde intrarenal surgery in infants and preschool-age children. j pediatr surg, 2011, 46:2195-9℃ 5. erkurt b, caskurlu t, atis g, et a1. treatment of renal stones with flexible ureteroscopy in preschool age children. urolithiasis, 2014, 42:241-5. 6. ishii h, griffin s, somani bk. flexible ureteroscopy and lasertripsy (fursl) for paediatric renal calculi: results from a systematic review . j pediatr urol, 2014, 10:1020-5. 7. nason gj, headon r, burke mj, et a1. are adult ureteroscopes safe in the management of urolithiasis in a pediatric population. curr urol, 2015, 8:26-8. 8. nerli r b, patil s m, guntaka a k, hiremath, m b. flexible ureteroscopy for upper ureteral calculi in children . j endourol, 2011, 25:57982 9. cavildak i k, nalbant i, tuygun c, et al. comparison of flexible ureterorenoscopy and laparoscopic ureterolithotomy methods for proximal ureteric stones greater than 10 mm. urol j,2016,13:2484-9. 10. ergin g, kirac m, kopru b, et al. shock wave lithotripsy or retrograde intrarenal surgery: which one is more effective for 10-20-mm renal stones in children. ir j med sci,2018. 11. arrabal-polo, m a, cano-garcia, mdc, arrabal-martin, m, merino-salas, s. the effect of antibiotic prophylaxis on postoperative infection in patients undergone flexible cystos-copy. urol j,2017,14:3050-3. flexible ureteroscopy for children stones-li et al. ureterorenoscopy with stenting and its effect on female sexual function ekrem akdeniz*, mustafa suat bolat purpose: various etiological factors have been studied which negatively affect female sexual function, but the effects of ureteroscopic stone surgery on women's sexual dysfunction remain unknown. the aim of this study was to investigate the effect of ureteroscopic stone surgery with postoperative stenting on female sexual function. materials and methods: this study included 30 sexually active female patients who underwent ureteroscopic stone surgery with jj stenting (study group) and 26 age-matched female patients with ureteral stone surgery without jj stenting (control group). sexual function was assessed at preoperative and at the first and 3rd months postoperative using the female sexual function index. overall satisfaction in relation to the age, operation time, presence of stents, body mass index, educational status, previous operations, income status, and psychogenic status was evaluated. results: sexual function was adversely affected by ureteroscopic stone surgery with jj stenting; but psychogenic, educational and income status remained stable. mean individual female sexual function subscores were statistically significant between the study and control groups, but the differences in the mean beck scores minimally improved between the two groups at preoperative (p = 0.19) visit, whereas first month (p = 0.08) and third month (p = 0.31) of postoperative controls were deteriorated but the differences were not statistically significant, respectively. conclusion: ureterorenoscopy with jj stenting has considerably negative effects on female sexual function. jj stenting causes temporary sexual deterioration in women and it generally ceases at the end of the 3rd month after ureteroscopic surgery. therefore, jj stenting should be avoided or used for as short a time as possible. if jj stenting is inevitable, patients should be warned about a temporary decline in their sexual function during the first month of the operation that resolves at most in three months. keywords: female sexual function, ureterorenoscopy, jj catheterization. introduction sexuality plays an important role in an individual's quality of life. female sexuality is a complex function encompassing interactions between the nervous, endocrine, and vascular systems, as well as a variety of structures involved in sexual excitement, intercourse, and satisfaction(1). psychological, biological and social factors mostly affect women's sexuality,(2,3). this may, in turn, cause emotional stress and affect a woman's well-being and social interactions. urinary stone disease is a common problem. among the general population, there is a 10.2% lifetime risk of developing the urinary stone disease, with peak incidence occurring when individuals are 20–40 years old (4). the treatment strategy for the urinary stone disease should be based on stone size, localization and number of stones, anatomic properties of the patient and the surgeon's experience. ureteroscopy (urs) and percutaneous nephrolithotomy (pnl) are key components of surgical removal of stones in all parts of the kidneys and ureter(5). in addition to classical methods such as shock wave lithotripsy (swl) or open surgeries, in recent years, new surgical techniques have been developed to address this condition. these techniques include flexible ureteroscopy (furs), rigid ureteroscopy or laparoscopic procedures. and are used when other treatment methods fail. rigid ureteroscopy is the most preferred technique for ureteral stones among urologists. generally, it is difficult to conduct an assessment of a woman's sexual function, and there is a limited number of studies in the literature addressing the issue of sexual function among women(6). many studies have focused on various etiological factors which negatively affect female sexual function(7-10). however, there is currently no evidence-based data in the literature concerning how women's sexual function may be affected by ureteroscopic stone surgery. the present study uses the context of evidence-based medicine to assess whether urs with stenting was associated with postoperative female sexual dysfunction (fsd). materials and methods this clinical study was prospectively designed for consecutive patients referred for ureteroscopic stone surgery over a period of three months. the primary aim was to evaluate the effects of ureteroscopic stone surgery on female sexual function for three months postoperative. secondary aims were the assessment of effects urology department, samsun training and research hospital, health sciences university, samsun, turkey. *correspondence: urology department, samsun training and research hospital, health sciences university, samsun, turkey. phone:+090 362 311 1500. mobile phone:+90 5422358980. e-mail: msbolat@gmail.com. received december 2016 & accepted april 2017 endourology and stone disease endourology and stone diseases 3059 of body mass index (bmi), jj catheter time, psychogenic aspect, stone size, income status, and educational status of female sexual function. patient selection and evaluation inclusion criteria were being female older than 18 years, a presence of regular sexual activity, an absence of prior urs history, impaired renal function, radical pelvic surgery, prior pelvic radiotherapy before, and a presence of ureteral stones resistant to medical propulsive treatment despite 4–6 weeks waiting period or shock wave lithotripsy. from june to december 2015, 30 female patients with ureteral stones were enrolled in the study. these women comprised the study group and 26 age-matched female patients who underwent ureteral stone surgery without jj stenting were served as the control group. this sample size was determined based on a power analysis. after obtaining approval of the ethics committee from ondokuz mayis university (b.30.2.odm.0.20.08/1780), all of the patients were informed about the study and informed consent was obtained from all study participants. due to ethical concerns, patients were informed about the study and surgical procedure preoperatively. the female sexual function was evaluated using the turkish-version of the female sexual function index (fsfi), which consists of 19 questions validated by the turkish society of andrology(11). higher fsfi scores indicate better sexual functioning. within the individual domains, a domain score of zero indicates that the respondent reported having no sexual activity during the past month. "factors" have been created for all domains. the factors for desire, arousal, and lubrication and orgasm and satisfaction are 0.6, 0.3, and 0.4, respectively. individual scores of the domains were multiplied by the corresponding domain factor. the total scale score varied from 2 to 36 (table 1). the normal cut-off value was assumed to be equal to or greater than 25. if a respondent's total scale score was below this value, sexual dysfunction was assumed. satisfaction in relation to age, operation time, psychogenic status, stent durations, bmi, educational status, previous operations, income status, localization of the stone and stone-free rates was recorded. the beck depression scale, which consists of 21 items validated from 0 to 3, was used to assess psychological status.(12) the psychological state of each patient was classified as minimal depression (0–9 points), mild depression (10–16 points), moderate depression (17–29 points) and severe depression (30–63 points). surgical technique once sterile urine was proved, a plain kidney-ureter-bladder (kub) was obtained on the morning of the table 1. female sexual function index domain scores and full scale score. domain questions score range factor minimum score maximum score desire 1,2 1-5 0.6 1.2 6 arousal 3-6 0-5 0.3 0 6 lubrication 7-10 0-5 0.3 0 6 orgasm 11-13 0-5 0.4 0 6 satisfaction 14-16 0 (or 1)-5 0.4 0.8 6 pain 17-19 0-5 0.4 0 6 full scale score range 2 36 variable p-value no. of the patients 30 26 age (year), mean± sd (min-max) 41.9 ± 7.5 (22-51) 39.7 ± 9.3 (25-58) 0.25 body mass index (kg/m2) 29.1 ± 5.8 (21.3-44.9) 27.8 ± 4.0 (18.4-33.3) 0.19 stone burden (mm2) 66.7 ± 39.4 71.2 ± 21.6 0.09 the mean hospital stay (hours) 38.4 ± 10.8 (24-58) 31.2 ± 5.4 (24-48) 0.07 jj stay time (days) 15.7 ± 2.4 (14–21) monthly income (tl) 1083.3 ± 951.3 (0-3000) 1142.2 ± 526.1 (0-3000) 0.12 education (n/%) primary 23 (76.6) 21 (70.0) high school 2 (6.7) 4 (13.3) table 2. demographic characteristics of the patients. ureterorenoscopy and female sexual function-akdeniz et al. vol 14 no 03 may-june 2017 3060 surgery, and all the patients underwent cystoscopy. following the guide-wire catheter placement into the ureter under scopic vision, a 7.5 f rigid ureteroscope was introduced for stone fragmentation using laser lithotripter. the ureteral catheter was placed into the ureter at the end of the procedure. retrograde pyelogram was routinely performed to rule out any extravasation after the procedure. jj stenting was done for high volume stones, solitary kidney or proximally located stone diseases. all the patients were closely followed with kub and ultrasound for assessment of residual stones and obstruction. a urine culture was repeated in the first and third postoperative controls. at first and 3rd month controls, fsfi, and beck depression scales were repeated and recorded prospectively. statistical analysis was performed using spss software, version 15. data were presented as mean± standard deviation (sd) and frequency (%). the shapiro-wilk test was used to analyze normal distribution assumptions of the quantitative outcomes. to compare two independent groups, we used the mann-whitney u test for nonnormal data. results were evaluated using the nonparametric kruskal-wallis test for comparisons between groups. to compare two groups, we used the paired sample t test. pearson's chi-square and fisher's exact tests were used for comparisons of percentages. a p value of less than 0.05 was considered statistically significant. results the mean ages of the patients in the study and control groups were 41.9 ± 7.5 (22–51) and 39.7 ± 9.3 (25– 58) years (p = .25); the mean bmis were 29.1 ± 5.8 (21.3–44.9) and 27.8 ± 4.0 (18.4–33.3) kg/m2 (p = .19). the mean hospital stays were 38.4±10.8 and 31.2 ± 5.4 hours in the study and control groups, respectively (p = .07). the mean jj stay time was 15.7 ± 2.4 (14–21) days in the study group. the other demographic data and perioperative variables have been presented in table 2. the mean preoperative total fsfi scores were 14.5±9.6 and 13.2 ± 7.4, the mean 1st postoperative total fsfi scores were 12.8 ± 6.8 and 16.1 ± 5.1, and 3rd postoperative total fsfi scores were 17.7 ± 5.4 and 18.2 ± 5.8 in the study group and control group, respectively. the mean total fsfi scores were statistically significant between groups at 1st postoperative month (p < ureterorenoscopy and female sexual function-akdeniz et al. table 3. the mean fsfi subdomains and relationship between study and control groups fsfi subdomains preoperative postoperative 1st month postoprative 3rd month (mean±sd) desire study gr 3.4 ± 1.4 3.2 ± 1.6 3.8 ± 1.3 control gr 3.4 ± 1.6 3.3 ± 1.5 3.7 ± 1.4 arousal study gr 1.8 ± 1.1 2.1 ± 1.8* 2.8 ± 1.6 control gr 2.0 ± 0.9 2.6 ± 1.7 3.2 ± 1.4 lubrication study gr 1.9 ± 1.8 1.8 ± 2.2 2.8 ± 1.8 control gr 1.8 ± 2.2 2.7 ± 1.2 2.8 ± 1.4 orgasm study gr 1.6 ± 1.9 2.1 ± 1.6* 2.8 ± 1.2 control gr 1.8 ± 1.4 2.6 ± 1.4 2.8 ± 1.8 satisfaction study gr 1.8 ± 1.4 2.6 ± 1.3* 3.4 ± 1.8 control gr 2.0 ± 1.6 3.1 ± 1.2 3.4 ± 1.6 pain study gr 2.9 ± 1.8 2.8 ± 1.6* 2.1 ± 1.8 control gr 2.7 ± 1.6 2.1 ± 1.2 2.2 ± 0.8 total study gr 14.5 ± 9.6 12.8 ± 6.8* 17.7 ± 5.4 control gr 13.2 ± 7.4 16.1± 5.1 18.2 ± 5.8 sexual study gr 18.2 ± 5.8 53.3 56.8 dysfunction (%) control gr 70.9* 62.4 57.6 *p < 0.05 beck's depression score preoperative postoperative 1st month postoperative 3rd month study group 6.1±1.3 4.1±1.3 4.1±1.3 control group 4.9±1.8 5.6±1.7 5.2±0.8 p value 0.19 0.08 0.31 table 4. beck depression scale and sexual dysfunction rate variations in both groups. endourology and stone diseases 3061 .05), whereas preoperative and 3rd postoperative total fsfi scores were not (p > .05). the mean individual first postoperative arousal, orgasm, and satisfaction subdomains statistically decreased, and pain subdomain increased in the study group compared to control group (p < .05). all the subdomains were similar at preoperative and 3rd postoperative controls between two groups (p > .05) (table 3). sexual dysfunction rates were 53.3%, 70.9% and 56.2% in the study group and 56.8%, 62.4 and 57.6% in the control group at preoperative and at 1st and 3rd postop erative months (table 3). sexual dysfunction rate was significantly increased in the study group at postoperative 1st month (p = .02), whereas preoperative (p = .06) and postoperative 3rd month controls were not (p = .08). the mean beck depression scores at preoperative, 1st and 3rd month postoperative in controls were 6.1 ± 1.3, 4.1 ± 1.3, and 4.1 ± 1.3, and 4.9 ± 1.8, 5.6 ± 1.7, and 5.2 ± 0.8 in the study and control groups, respectively. there were no statistically significant differences between groups (p > .05). in the control group, the mean beck score was 4.2 ± 1.1. when the beck scores were compared, there was no statistically significant difference between the study and control group (p = .31) (table 4). discussion descriptive epidemiological data were shown in the literature indicate that 40–67.9% of adult women have at least one manifesting sexual dysfunction, and medical interventions may provoke this condition(13–15). surgical interventions may cause fsd, and sexual disturbance may have a negative effect on physical and mental health(16). in the current study, sexual dysfunction rates increased at postoperative 1st month and then normalized to the preoperative level at the 3rd month, compared to control group (53.3%) (table 3). deterioration of sexual health in women after ureteroscopy and an improvement at the 3rd month evaluation has been attributed to lower urinary access and ureteral stent use (17–19). our findings on fsd supported that the study group was much more affected due to jj catheterization. although we do not routinely prefer jj catheterization, it is mandatory to insert a catheter in certain circumstances, such as high volume stones, solitary kidney, urine leakage due to ureteral trauma or proximally located stone diseases. with this study, we are encouraged to use jj stenting for limited periods or not to insert jj catheter, if possible. patients often suffer from symptoms related to jj stents, such as intolerance to the stent, depression, severe stent-related pain, hematuria, or urgency due to the shape of the jj catheter, rather than the presence of urinary infection (20). although significant improvements have been achieved in regard to stent materials, a proportional comfort has not been observed to date. none of the patients were stentized due to urine extavasation. hematuria was observed in half of the patients, and urgency in one-third in the postoperative period. minimality or absence of these symptoms in the preoperative and third postoperative periods suggests that the catheter can cause itself urgency in patients by chronic irritation. urgency can be managed using anticholinergic agents, but sometimes it can be difficult to cope with this symptom during the early postoperative period (21). in such cases, early withdrawal of the jj catheter may aid in the early relief of urgency. moreover, using a one-day ureteral catheter instead of a jj catheter for uncomplicated and thoroughly disintegrated stones may help prevent urgency. the mean time of stent removal was 15.7 ± 2.4 (14–21) days, and it was kept as short as possible in order to avoid early complications. anxiety and depression typically become prominent with diseases provoked by painful crises and have a negative impact on an individual's psychological status (22). the relationship between urological stone management and anxiety or depression was shown to cause increased anxiety (23). rather than short-term treatment of the benign diseases, anxiety and depression are shown to be higher in chronic conditions such as malignant diseases(24). in this study, we found no significant difference using beck's depression score to evaluate the mental status of the patients (p = .31). this finding suggested that fsd is not affected by the psychological status of the patients (table 4). contrary to our results, joshi et al. stated that significant morbidity due to jj stents might provoke emotional and physical alterations in patients(19). it is reasonable that patients may experience a temporary decline in their sexual function in the postoperative period. this study showed once again that while urologists were focusing on protecting renal function from adverse effects of ureteral stones in daily practice, and exert utmost efforts should be taken for patients' social and sexual life in the postoperative period. for this reason, we think that sufficient preoperative information should be given and jj stenting should be minimalized as much as possible. the relationship between bmi and fsd remains controversial in the literature(16, 25). our results showed no relationship between fsd and bmi (p = .19). monthly income and educational status have been shown to be predictive factors for fsd in women, with a reported 2.54 fold increased the chance of fsd in low-income women(26–28). contrary to the literature, we found no correlation between sexual dysfunction and monthly income or educational status. this can be explained by the close proximity of monthly income levels between patients (p > .05). conclusions ureterorenoscopy with jj stenting has a considerable negative effect on fsd. although the deterioration of sexual function is temporary and generally ceases at the end of the 3rd month after ureteroscopic surgery, jj stents should be avoided whenever possible. if jj stenting is necessary, patients with stent should be informed that they may have some degrees of sexual dysfunction during the first month of the operation that resolves at most in three months. in addition, if jj catheterization proves necessary the indwelling should be kept as short as possible. conflicts of interest the authors report no conflict on interest. references 1. rao ts, nagaraj ak. female sexuality. indian j psychiatry. 2015; 57(suppl 2):s296-302. 2. hosseini l, iran-pour e, safarinejad mr. sexual function of primiparous women after ureterorenoscopy and female sexual function-akdeniz et al. vol 14 no 03 may-june 2017 3062 elective cesarean section and normal vaginal delivery. urol j.2012; 9:498-504. 3. mezzich je, hernandez-serrano r. in: psychiatry and sexual health – an integrative approach. lanham: jason aronson; 2006. epidemiology and public health considerations; pp. 33–43. 4. tseng ty, preminger gm. kidney stones. bmj clin evid. 2011; 2011. pii: 2003. 5. türk c, petřík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475-82. 6. eryildirim b, tuncer m, kuyumcuoglu u, faydaci g, tarhan f, ozgul a. do ureteral catheterisation procedures affect sexual functions? a controlled prospective study. andrologia. 2012; 44:419–23. 7. carrilho pjf, vivacqua ca , de godoy ep, et al. sexual dysfunction in obese women is more affected by psychological domains than that of non-obese. rev bras ginecol obstet. 2015; 37:552-8. 8. scheepe jr, alamyar m, pastoor h, hintzen rq, blok bf. female sexual dysfunction in multiple sclerosis: results of a survey among dutch urologists and patients. neurourol urodyn. 2017; 36:116-20. 9. frost dm, meyer ih, schwartz s. social support networks among diverse sexual minority populations. am j orthopsychiatry. 2016; 86:91-102. 10. oren a, megiddo e, banai s, justo d. sexual dysfunction, cardiovascular risk factors, and inflammatory biomarkers in women undergoing coronary angiography. j women aging. 2015; 22:1-8. 11. rosen r, brown c, heiman j, et al. the female sexual function index (fsfi) j sex marital ther. 2000; 26:191–208. 12. beck at, ward ch, mendelson m, mock j, erbaugh j. an inventory for measuring depression. arch gen psychiatry. 1961; 4:561-71. 13. lewis rw, fugl-meyer ks, corona g, et al. definitions/epidemiology/risk factors for sexual dysfunction. j sex med. 2010; 7:1598–607. 14. oksuz e, malhan s. prevalence and risk factors for female sexual dysfunction in turkish women. j urol. 2006; 175:654-8. 15. laumann eo, paik a, rosen rc. sexual dysfunction in the united states: prevalence and predictors. jama. 1999; 281:537-44. 16. smith am, patrick k, heywood w, et al. body mass index, sexual difficulties and sexual satisfaction among people in regular heterosexual relationships: a population-based study. intern med j. 2012; 42:641-51. 17. joshi hb, stainthorpe a, macdonagh rp, keeley fx, jr, timoney ag. indwelling ureteral stents: evaluation of symptoms, quality of life and utility. journal of urology. 2003; 169:1065–9. 18. haleblian g, kijvikai k, de la rosette j, preminger g. ureteral stenting, and urinary stone management: a systematic review. j urol. 2008; 179:424-30. 19. joshi hb, newns n, stainthorpe a, macdonagh rp, keeley fx jr, timoney ag. ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. j urol. 2003; 169:1060. 20. kogan mi, mojsjuk jg, shkodkin sv, sajdulaev da, idashkin jb. effectiveness of ureteral stents with nanostructured coating in renal transplantation (preliminary results). urologia. 2015; 1:58-61. 21. lee yj, huang kh, yang hj, chang hc, chen j, yang tk. solifenacin improves double-j stent-related symptoms in both genders following uncomplicated ureteroscopic lithotripsy. urolithiasis. 2013; 41:247-52. 22. diniz dh, blay sl, schor n. anxiety and depression symptoms in recurrent painful renal lithiasis braz j med biol res. 2007; 40:949-55. 23. brown sm. quantitative measurement of anxiety in patients undergoing surgery for renal calculus disease. j adv nurs. 1990; 15: 962-70. 24. alacacıoğlu , öztop i, yılmaz u. the effect of anxiety and depression on quality of life in turkish non small lung cancer patients. tur toraks der. 2012; 13: 50-5. 25. mozafari m, khajavikhan j, jaafarpour m, et al. association of body weight and female sexual dysfunction: a case-control study. iran red crescent med j. 2015; 17: e24685. 26. diehl a, silva rl, laranjeira r. female sexual dysfunction in patients with substancerelated disorders. clinics (sao paulo). 2013; 68:205-12. 27. worly b, gopal m, arya l sexual dysfunction among women of low-income status in an urban setting. int j gynaecol obstet. 2010; 111:241-4. 28. laumann eo, paik a, rosen rc sexual dysfunction in the united states: prevalence and predictors. jama. 1999; 81:537-44. ureterorenoscopy and female sexual function-akdeniz et al. endourology and stone diseases 3063 hypersensitive or detrusor overactivity: which is associated with filling symptoms in female bladder outlet obstructed patients? junlong zhang1, mingxin cao1, yu chen1, weijie liang1, yueyou liang1* purpose: to investigate and compare detrusor overactivity (do) and bladder filling sensation characteristics in female bladder outlet obstruction (fboo) patients with or without overactive bladder (oab) symptoms. materials and methods: one hundred fifty-seven fboo patients with urodynamic testing were recruited. patients who showed urinary urgency ( ≥ 6 episodes/3 d), with or without urinary frequency ( ≥8 voids/24 h), and urge incontinence ( ≥ 3 episodes/3 d) were considered to have oab. the detrusor overactivity (do) and bladder filling sensation measures including first sensation (fsf), first desire to void (fdv) and strong desire to void (sdv) during filling cystometry were recorded. the associations between urodynamic variables and oab symptoms were analysed. result: fboo patients had a high incidence (79%) of oab. fboo patients with oab symptoms had significantly younger age, higher incidence of do (19.4% versus 6.1%) (p = .051) and lower bladder volumes of fsf (180.32 ± 83.48 versus 226.18 ± 100.90 ml), fdv (269.00 ± 109.78 versus 330.45 ± 123.95 ml) and sdv (345.56 ± 135.43 versus 422.33 ± 148.40 ml) (p < .05) compared to patients without oab. in multivariate analyses, both do (or = 4.83, 95% ci: 1.02-22.85, p = .047) and lower bladder volumes at fdv(or = 2.47, 95% ci: 1.03-5.95, p = .044) and sdv (or = 3.07, 95% ci: 1.25-7.55, p < .014) were still independently associated with oab, after adjustment for age and other confounding factors. conclusion: fboo patients had a high incidence of oab. not only do but also bladder hypersensitivity were independently associated with oab symptoms in fboo patients. keywords: hypersensitivity;urinary bladder neck obstruction; urinary bladder, overactive; urodynamics; urinary incontinence, urge introduction female bladder outlet obstruction (fboo) is a rel-ative uncommon condition in clinical practice(1-4). overactive bladder (oab) symptoms, including urgency, frequency and nocturia, are quite common among female patients, especially in patients with bladder outlet obstruction, which severely affect women’s life quality(5-6). the reported incidence of oab among bladder outlet obstruction patients was around 50-75%(7). oab symptoms can be induced either by obstruction or the secondary effects of obstruction on the bladder(8). whereas, to date, the underlying mechanisms of oab symptoms in fboo patients remains the subject of debate and the anticholinergic drugs have many side effects(9). a more thorough investigation of its pathophysiological mechanisms will be helpful in further investigations of therapeutic drugs. detrusor overactivity (do), characterized by involuntary detrusor contractions during the filling phase in urodynamic test, is a known cause for oab symptoms(10). however, the antimuscarinic therapy based on this mechanism shows limited efficiency in clinical practice(11). urologist and clinical researchers have now placed a new focus on the effect of increasing bladder 1 department of urology, the first affiliated hospital of sun yat-sen university, guangzhou 510080, china. *correspondence: department of urology, the first affiliated hospital of sun yat-sen university, no. 58 zhongshan er road, guangzhou 510080, china. tel: +86-20-87333300. fax: +86-20-87333300. email: lyuey@mail.sysu.edu.cn. received january 2018 & accepted december 2018 sensation on oab symptoms. a few studies have found that oab patients had lower micturition and decreased bladder volumes, which suggested that bladder hypersensitivity contributes to the development of oab (12-13). however, the association between bladder filling sensation and oab symptoms was still not adequately investigated in fboo patients. the objective of this study was to examine the urodynamic parameters associated with oab symptoms in fboo patients. material and methods study design and participants this study was an observational study approved by the institutional review board of the first affiliated hospital of sun yat-sen university. the study was conducted according to the principles expressed in the declaration of helsinki. we screened female patients who referred for evaluation of lower urinary tract symptoms (luts) and underwent urodynamic testing in the first affiliated hospital of sun yat-sen university from 2008 to 2016. patients with clinical dysuria symptoms and having the maximum flow rate (qmax) ≤ 15 ml/s and detrusor pressure at the maximum flow (pdet. qmax) ≥ 20 cmh 2 o in urodynamic testing were eligible for female urology female urology 285 vol 16 no 03 may-june 2019 286 inclusion as fboo(1). exclusion criteria were the presence of diabetes mellitus, bladder stone, bladder tumor, urine infection, nervous diseases, pelvic prolapse, and urological surgery history. the severity of obstruction was assessed using the blaivas-groutz nomogram(3), and further categorized into severe obstruction (pdet. max ≥ 107 cmh 2 o), moderate obstruction (pdet.max between 57 to 107 cmh 2 o), and mild obstruction (pdet. max ≤ 57 cmh 2 o). according to the 3d-voiding diary, patients who showed urinary urgency (≥ 6 episodes/3 d) with or without urge incontinence (≥ 3 episodes/3 d) and urinary frequency (≥8 voids/24 h), were selected as oab patients.(14) urodynamic testing according to the suggested urodynamics practice standards of the international continence society(15), urodynamic testing was performed by a urotechnician using the delphis 94-r01-bt uds system (laborie medical technologies, canada). during the free-flow measurement, the maximum free-flow rate (free qmax) was recorded. subsequently, post-void residual urine (pvr) was measured. the bladder was filled with saline solution at a temperature of around 37℃ at a speed of 50 ml/min during the filling cystometry. bladder sensation variables were recorded when patients reported the first sensation of bladder filling (fsf), first desire to void (fdv), and strong desire to void (sdv) according to the international continence society definitions(15). lower bladder volumes at fsf, fdv, and sdv were considered as higher bladder sensitivity. do was considered positive when involuntary detrusor contractions appeared during the filling phase(15). meanwhile, voiding variables including qmax, pdet. qmax, maximum detrusor pressure (pdet. max) were also recorded during the voiding cystometry. statistical analysis data are presented as the mean ± standard deviation (sd) or number (percentage). for comparisons between oab-fboo and non-oab-fboo patients, a mann-whitney test was used for numerical variables and a chi square test for categorical variables. multivariate logistic regression models were used to analyse do and bladder volumes to predict the occurrence of oab in fboo patients separately, adjusting for age and other factors with p values < .1 in univariate analyses. all statistical analyses were pmerfored using spss for windows (version 13.0, ibm, usa). two-tail p values < .05 were considered to be statistically significant. results among 2600 female patients undergoing urodynamic studies, 157 patients were recruited as fboo, suggesting the prevalence of boo was approximately 6%. the mean age was 46 ± 14 years old. the incidence of do among fboo patients was around 16.6%. detailed urodynamic characteristics of fboo are listed in table 1. according to blaivas-groutz nomogram, 116 (73.9%) fboo patients were mild obstruction, and 36 (22.9%) were moderate obstruction and 5 (3.2%) were severe obstruction. the severe/moderate obstruction group showed a higher incidence of do (29.3%) compared with the mild obstruction group (12.1%). nevertheless, all bladder volume measures were not significantly different between groups with severe/moderate obstruction and mild obstruction. among the fboo patients, 124 (79.0%) had oab. as shown in table 2, patients with oab had a higher incidence of do than patients without oab (19.4% versus 6.1%, p = .051). fboo patients with oab had significantly lower fsf, fdv and sdv than those without oab (table 1). patients with oab seems to be younger than those without oab. after adjusting for age and pvr, do, fdv and sdv were still independently associated with the occurrence of oab, and fsf tended to independently associate with oab symptoms (table table 1. comparisons of clinical and urodynamic parameters in fboo patients with oab and non-oab symptoms. clincal&urodynamic parameters all fboo (n = 157) oab -fboo (n= 124) non-oab –fboo (n = 33) p value age, years 46.80 ± 14.45 45.44 ± 14.38 51.94 ± 13.71 .010 free qmax, ml/s 11.29 ± 4.91 11.11 ± 4.61 11.99 ± 5.91 .473 qmax, ml/s 7.88 ± 3.43 8.15 ± 3.41 6.86 ± 3.37 .103 pdet qmax , cmh 2 o 49.74 ± 80.32 51.46 ± 89.73 43.28 ± 21.15 .838 pdetmax, cmh 2 o 49.74 ± 23.02 49.50 ± 23.40 50.63 ± 21.86 .687 pvr, ml 87.04 ± 126.60 74.60 ± 109.19 133.42 ± 171.36 .064 do 26(16.6%) 24 (19.4%) 2 (6.1%) .051 fsf, ml 189.96 ± 89.07 180.32 ± 83.48 226.18 ± 100.90 .011 fdv, ml 281.92 ± 115.28 269.00 ± 109.78 330.45 ± 123.95 .009 sdv, ml 361.70 ± 141.29 345.56 ± 135.43 422.33 ± 148.40 .006 blaivas-groutz 1 (1-2) 1 (1-2) .875 abbreviations: fboo, female bladder outlet obstruction; oab, overactive bladder; free qmax, the maximum free-flow rate; qmax, the maximum flow rate; pdet qmax, detrusor pressure at maximum flow; pdetmax, maximum detrusor pressure; pvr, post-void residual urine; do, detrusor overactivity; fsf, first sensation of bladder filling; fdv, first desire to void; sdv, strong desire to void. data were showed as means ± sd, numbers (%) or medians (interquartile range). p value for comparison between oab-fboo patients and non-oab-fboo patients. urodynamic parameters occurrence of oab or (95 % ci) p value do 4.83 (1.02-22.85) .047 fsf < mean value 2.35 (0.99-5.59) .053 fdv < mean value 2.47 (1.03-5.95) .044 sdv < mean value 3.07 (1.25-7.55) .014 abbreviations: fboo, female bladder outlet obstruction; oab, overactive bladder; do, detrusor overactivity; fsf, first sensation of bladder filling; fdv, first desire to void; sdv, strong desire to void. hr, hazard ratio; ci, confidence interval. all urodynamic parameters were separately adjusted by age and pvr. table 2. results of logistic analyses on urodynamic factors to predict the occurrence of oab symptoms in fboo patients do and bladder hypersensitivity in female boo-junlong zhang et al. 2). one typical urodynamic report of fboo patients showing both do and bladder hypersensitivity was showed in figure 1. discussion in this cross-sectional study, we observe that both do and low bladder volumes were correlated with oab symptoms. such results may indicate that not only do but also increased bladder sensitivity could be the underlying pathophysiological mechanisms for oab symptoms in fboo patients. compared with male boo, fboo is a relative uncommon condition in clinical practice. the reported prevalence of boo in female population varies widely from 2.7% to 23% in different studies because of various diagnostic criteria(1-4,16). in our study, a combined criteria of qmax ≤ 15 ml/s and pdet qmax ≥ 20 cm h 2 o was used to define boo, which had a sensitivity of 74.3% and a specificity of 91.1% to predict obstruction(1). such criteria is thought to have good concordance with clinically diagnosed obstructions. the incidence of oab in fboo patients in our study was similar to the data in the male population (60-70%) (8). after adjusting for age and other confounding factors, the higher do rates was still independently associated with oab symptoms in fboo patients. the high incidence of oab symptoms with low incidence of do in fboo patients was consistent with a previous study, which also demonstrated that only 54% of women with oab had do on urodynamic test, and 27% of the women with a diagnosis of do on urodynamic test had oab symptoms(17). the inconsistence between oab and do rates suggests that other pathophysiological mechanisms might be responsible for oab symptoms in fboo patients. some researchers have placed focus on identifying the associations between bladder sensations and oab(1819). several studies reported that oab patients not only had a higher incidence of do but also revealed lower bladder volumes of fsf, fdv and sdv compared with non-oab patients, suggesting hypersensitive bladder in oab patients(12-13). in our study, we adopted urodynamic variables during filling cystometry as an objective method to record bladder sensations, which has been demonstrated to have good correlations with sensory questionnaire scores in a prior study(13). we found that the bladder volumes were lower in fboo patients with oab symptoms than those without oab symptoms. thus, this study suggested that fboo could induce lower bladder volumes which may be related to oab symptom in these patients. the mechanisms of oab symptoms in boo patients remain a matter of debate, with neurogenic mechanism classified as one of the leading causes(20). in the experimental studies, various neurochemical, such as nitric oxide synthase and nadph-diaphorase, have been shown to change in afferent pathways of the animal model of bladder outlet obstruction(21-22). additionally, short latency micturition reflex was found in urethral obstructed rats(23). these changes in reflex pathways were considered as neuronal plasticity, which indicated that the nerves were influenced by the pathological processes in target organs(24-25). recently, there are increasing interest in the investigation of afferent system (sensory) innervation as an important therapeutic target for lower urinary tract symptoms(26). our study might further support the neurogenic mechanisms and the importance of investigations on therapies directed at the afferent system in fboo patients with oab symptoms. this study had several limitations. first, there was no general agreement on the urodynamic parameters for defining fboo. we used the criteria of qmax ≤ 15 ml/s and pdet qmax ≥ 20 cmh 2 o in this study, which is thought to have high concordance with clinically diagnosed obstructions (27). second, this was a cross-sectional study, which could not support the cause and effect associations between do, bladder hypersensitivity and oab in fboo patients. further longitudinal, prospective, and large-scale studies are warranted to validate these findings. conclusions fboo patients had a high incidence of oab symptoms. both urodynamic do and bladder volumes in filling cystometry tests were independently associated with the occurrence of oab symptoms in fboo patients, suggesting that not only do but also increased bladder sensitivity may be pathophysiological mechanisms underlying this symptomatology. acknowledgement this study was supported by grants from science and technology planning project foundation of guangdong province, china (grant no. 2012b031800051). conflict of interest the authors declare that they have no competing interests. references 1. chassagne s, bernier pa, haab f, roehrborn cg, reisch js, zimmern pe: proposed cutoff values to define bladder outlet obstruction in women. urology 1998;51:408-411. 2. nitti vw, tu lm, gitlin j: diagnosing bladder outlet obstruction in women. j urol 1999;161:1535-40. do and bladder hypersensitivity in female boo-junlong zhang et al. figure 1. one typical urodynamic report of complicated fboo show high pdetmax and low qmax with do and hypersensitivity. female urology 287 vol 16 no 03 may-june 2019 288 3. blaivas jg, groutz a: bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. neurourol urodyn 2000;19:553-64. 4. choi ys, kim jc, lee ks, et al.: analysis of female voiding dysfunction: a prospective, multi-center study. int urol nephrol 2013;45:989-94. 5. bykoviene l, kubilius r, aniuliene r, bartuseviciene e, bartusevicius a: pelvic floor muscle training with or without tibial nerve stimulation and lifestyle changes have comparable effects on the overactive bladder. a randomized clinical trial. urol j 2018;15:186-92. 6. al-zahrani aa, gajewski j: urodynamic findings in women with refractory overactive bladder symptoms. int j urol 2016;23:75-9. 7. oelke m, baard j, wijkstra h, de la rosette jj, jonas u, hofner k: age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. eur urol 2008;54:41926. 8. abdel-aziz kf, lemack ge: overactive bladder in the male patient: bladder, outlet, or both? curr urol rep 2002;3:445-51. 9. lee kc, seong bm: does systemic disease aggravate the severity of dry mouth by anticholinergics in overactive bladder patients? urol j 2017;14:3035-9. 10. abrams p, cardozo l, fall m, et al.: the standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the international continence society. urology 2003;61:37-49. 11. herbison p, hay-smith j, ellis g, moore k: effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. bmj 2003;326:841-4. 12. lee sr, kim hj, kim a, kim jh: overactive bladder is not only overactive but also hypersensitive. urology 2010;75:1053-9. 13. rapp de, neil nj, govier fe, kobashi kc: bladder sensation measures and overactive bladder. j urol 2009;182:1050-4. 14. lee sr, kim hj, kim a, kim jh: overactive bladder is not only overactive but also hypersensitive. urology 2010;75:1053-9. 15. abrams p, cardozo l, fall m, et al.: the standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the international continence society. in, 2003:37-49. 16. lin cd, kuo hc, yang ss: diagnosis and management of bladder outlet obstruction in women. low urin tract symptoms 2016;8:30-7. 17. digesu ga, khullar v, cardozo l, salvatore s: overactive bladder symptoms: do we need urodynamics? neurourol urodyn 2003;22:105-8. 18. yamaguchi o, honda k, nomiya m, et al.: defining overactive bladder as hypersensitivity. neurourol urodyn 2007;26:904-7. 19. van brummen hj, heintz ap, van der vaart ch: the association between overactive bladder symptoms and objective parameters from bladder diary and filling cystometry. neurourol urodyn 2004;23:38-42. 20. roosen a, chapple cr, dmochowski rr, et al.: a refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature. eur urol 2009;56:810-9. 21. johansson rk, poljakovic m, andersson ke, persson k: expression of nitric oxide synthase in bladder smooth muscle cells: regulation by cytokines and l-arginine. j urol 2002;168:2280-5. 22. zhou y, ling ea: increased nadphdiaphorase reactivity in bladder afferent pathways following urethral obstruction in guinea pigs. j peripher nerv syst 1997;2:33342. 23. steers wd, de groat wc: effect of bladder outlet obstruction on micturition reflex pathways in the rat. j urol 1988;140:864-71. 24. heppenstall pa, lewin gr: neurotrophins, nociceptors and pain. in, 2000:573-6. 25. steers wd, kolbeck s, creedon d, tuttle jb: nerve growth factor in the urinary bladder of the adult regulates neuronal form and function. j clin invest 1991;88:1709-15. 26. chapple c: chapter 2: pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder". neurourol urodyn 2014;33 suppl 3:s6-s13. 27. akikwala tv, fleischman n, nitti vw: comparison of diagnostic criteria for female bladder outlet obstruction. j urol 2006;176:2093-7. do and bladder hypersensitivity in female boo-junlong zhang et al. case report ileo-cavernosal fistula after radiotherapy: a case report and review of the literature murat gul,1* necat islamoglu,2 mehmet kaynar,3 mustafa koplay,4 serdar goktas3 keywords: intestinal fistula; etiology; adverse effects; radiation ınjuries; carcinoma; radiotherapy; cystectomy; treatment outcome; urinary bladder neoplasms. introduction fistula is an abnormal connection between two hollow spaces that are lined with epithelial cells. fistulas are usually caused by injury or surgery, but radiation, infection or inflammation may also result in fistula formation. there are quite a few different types of fistula in human body. gastrointestinal tract fistulas (gif) may have various clinical presentation, etiology, and morbidity. because definitions can be various on the literature perry and colleagues recommends to categorize gif into two groups as congenital and acquired gif. acquired gif can be classified as external or cutaneous if they connect with the skin or internal if they involve other organ systems including genitourinary system.(1) here we present anextremely unusual case of an internal gastrointestinal fistula -ileopenilecorpus cavernosum fistula, developingafter external beam radiation therapy (ebrt). to the best of our knowledge, this is the first report in the literature demonstrating an ileo-corpus cavernosum fistula after ebrt. case report a 67-year-old man who had undergone radical cystectomy with ileal loop one year ago due to muscle invasive bladder carcinoma (mibc) was referred to our clinic with a complaint of common ache in his hips and suprapubic region. he did not report any trauma. he had a chronic kidney disease background preoperatively. his blood urea nitrogen and creatinine levels were113 md/dl and 2.5 mg/dl, respectively. other hematological examination and 1department of urology, van training and research hospital,van, turkey. 2department of radiology, van training and research hospital, van, turkey. 3 department of urology, school of medicine, selcuk university, konya, turkey. 4department of radiology, school of medicine, selcuk university, konya, turkey. *correspondence: department of urology, van training and research hospital, 65000 van, turkey. tel: +90 505 6316913. fax: +90 432 2157600. e-mail: drgulacademics@gmail.com. received january 2015 & accepted september 2015 figure. sagittal fat-sat t2 weighted (a, b) and sagittal t1 weighted images (c, d) show fistula (f) between ileum and penile corpus cavernosum. penile corpus cavernosumcontains stool and air (arrowheads). vol 12 no 05 september-october 2015 2377 biochemical profile was within normal limits. imaging studies showed no recurrence or soft tissue metastasis. bone scintigraphy revealed multiple metastatic lesions on pubic bone. radiotherapy (rt) was given to pelvic area to relief his pain. total dose of 3000 cgy (300cgy × 10 fractions) external beam radiotheraphy (ebrt) was administered. ebrt was well tolerated and patient’s pain started to regress. two months later patient applied to our clinic again with swelling and pain in his penis. magnetic resonance imaging (mri) detected a fistula between ileum and penile cavernosal body (figure). then patient hospitalized, oral intake was stopped and parenteral nutrition was started. infectious diseases treatment was began with vancomycin and meropenem administration. surgery decided but patient’s general condition didn’t permit us to take him to surgery. he eventually died because of sepsis. discussion rt proved itself at palliation of painful bone metastases with a 60%-80% likelihood of providing relief for localized pain.(2) but after administration of rtespecially to pelvic region, adjacent organs including gastrointestinal systemmay be injured. the most common complications of gastrointestinal system injuries are obstruction, hemorrhage, strictures, and fistulas. few reports of internal gif caused by rt were reported. levenback and colleagues described anenterovesical fistula following rt for gynecologic cancer.(3) lewinshtein and colleagues described recto-cavernosal fistula after radiation for rectal cancer.(4) recurrent disease and prior surgery are the most common reason of fistulization in these cases. our patient had both risks. besides, some other reports described urethro-carvernosal fistulas, mostly caused by blunt trauma, penile fracture and following shunt surgery for priapism.(57) but none of them are related to rt. no other corpus cavernosum related fistula has been reported. although fistulas can be demonstrated by conventional radiography or contrast-enhanced studies, today the advanced techniques and increased availability, has become cross sectional imaging modalities more popular. but it should be kept in mind that each fistula type has unique form and imaging studies may vary depending onfistula type.(1) in this case we showed the fistula tract by contrast enhanced mri (figure). in generally gif management includes localization and describing the fistula’s anatomy, nutritional support, detection and treatment of sepsis, and deciding to proper treatment. but the optimum management of a radiation induced fistula is unsettled yet. because “radiation induced fistula” term includes varying group of patientshaving different types of fistula anatomy, bowel properties, co-morbidity history and severity of radiation exposure. therefore whether radiation-induced fistula requires repair at fistula site or a more aggressive approach such as permanent urinary diversion is unknown, and each patient should be evaluated on a case by case basis.(8) because this is the first report of ileo-cavernosal fistula and penile corpus cavernosum is a highly vascularized tissue, we therefore assumed and treated our case as an intestino-arterial fistula. there are only three cases showing intestino-arterial fistula following urinary diversion. in these cases, sepsis was an inevitable result and represented the primary source of morbidity. patients didn’t survive at all.(9)as soon as the diagnosis of fistula made by mri we started to give total parenteral nutrition and proper antibiotics. surgery was decided but patient got worse and we couldn’t perform it. we think that either diversion or fistulectomy would be beneficial to the patient. conclusions ebrt is the mainstay for the treatment of painful bone metastases including pelvic malignancies. although the early and late complications of ebrt are acceptable, clinical follow-up must absolutely be performed to make early diagnosis and treatment of radiation therapy complications. even the slightest symptom that may indicate a fistula should be carefully examined and the initial principle of care should be controlling and eradicating underlying sepsis followed by surgery if needed. conflicts of interest none declared. references 1. pickhardt pj, bhalla s, balfe dm. acquired gastrointestinal fistulas: classification, etiologies, and imaging evaluation. radiology. 2002;224:9-23. 2. nieder c, pawinski a, dalhaug a. continuous controversy about radiation oncologists’ choice of treatment regimens for bone metastases: should we blame doctors, cancerrelated features, or design of previous clinical trials? radiat oncol. 2013;8:85. 3. levenback c, gershenson dm, mcgehee r, eifel pj, morris m, burke tw. enterovesical fistula following radiotherapy for gynecologic cancer. gynecol oncol. 1994;52:296-300. 4. lewinshtein d, mccormack m, péloquin f, poljicak m, karakiewicz p, saad f. rectocavernosal fistula after radiation for rectal cancer. can j urol. 2006;13:2988-9. 5. palaniswamy r, rao ms, bapna bc, chary ks. urethro-cavernous fistula from blunt penile trauma. j trauma. 1981,21:242-3. 6. juaneda castell b, montlleó gonzález m, ponce de león roca x, gausa gascón l, caparrós sariol j, villavicencio mavrich h. urethrocavernous fistula due to penile fracture. actas urol esp. 2008;32:1043-5. 7. manjunath as, mazur dj, han js, gonzalez cm. simultaneous urethrocutaneous and urethrocavernous fistula after proximal corporospongiosal shunt for priapism. urology. 2015;85:e13-4. 8. sharma a, kurtz mp, eswara jr. three distinct urethral fistulae 35 years after pelvic radiation. nephrourol mon. 2014;6:e14197. 9. ferrie bg. intestino-arterial fistula following urinary diversion. j r soc med. 1985;78:341. ileo-cavernosal fistula after radiotherapy-gul et al. case report 2378 the possible role of xrcc1 gene polymorphisms with idiopathic non-obstructive azoospermia in southeast turkey halit akbas1, mahmut balkan2*, mahir binici2, abdullah gedik3 purpose: x-ray repair cross-complementing group 1 (xrcc1) plays a role in repairing dna damage during spermatogenesis. we examined the effects the possible role of two single nucleotide polymorphisms of xrcc1 arg194trp and arg399gln in dna repair gene xrcc1 with risk of idiopathic non-obstructive azoospermia (inoa) in a south-east turkey population. materials and methods: the genotype and allele frequencies of two observed polymorphisms of xrcc1 arg194trp and arg399gln were examined by polymerase chain reaction-restriction fragment length polymorphism in 102 infertile men with inoa and 102 fertile controls. result: in our study, all the observed genotype frequencies were in agreement with hardy-weinberg equilibrium. the genotype frequencies of the xrcc arg194trp were 84% (cc), 16% (ct) and 2% (tt) among the men with inoa, while the frequencies of those genotypes in the controls were found to be 88% (cc), 12% (ct) and 2% (tt) (p < .05). similarly, the genotypes frequencies of gg, ga, and aa of the xrcc1 arg399gln were 44%, 39%, and 19% in the group of men with inoa, whereas these frequencies were 42%, 45%, and 15% in the control group, respectively. no significant difference between the control group and the men with inoa were found in the frequencies of genotypes and allele of xrcc1 arg194trp and arg399gln (p > 0.05). conclusion: neither arg194trp nor arg399gln polymorphisms in the xrcc1 gene influenced risk of inoa in our study. however, these findings may be helpful in improving the understanding of the etiology of male infertility. keywords: dna repair; idiopathic azoospermia; male infertility; single-nucleotide polymorphism; xrcc1. introduction male factor infertility is a multifactorial complex disorder that affects about 7% of male from the general population.(1,2) the most common cause of male infertility is impaired spermatogenesis, in which azoospermia is present in about 10%–15%.(3) azoospermia is characterized by no spermatozoa in semen and can be caused by either a physical blockage in the genital track, known as obstructive azoospermia, or spermatogenic failure, known as non-obstructive azoospermia. (4) in about 50% of non-obstructive azoospermia, the causes of infertility are unknown and categorized as idiopathic.(5–8) in approximately 15% of idiopathic non-obstructive azoospermia cases (inoa), the etiology is related to known genetic disorders including chromosomal aberrations and single gene mutations, such as y-chromosome microdeletions. however, approximately half of inoa has some unidentified genetic basis, and this suggests that polymorphism of genes in autosomal chromosomes may also play an important role in the spermatogenesis.(5–8) spermatogenesis is regulated by many infertility-relat1 department of medical biology and genetics, faculty of medicine, harran university, sanliurfa, turkey. 2 department of medical biology and genetics, faculty of medicine, dicle university, diyarbakır, turkey. 3 department of urology, faculty of medicine, dicle university, diyarbakır, turkey. *correspondence: department of medical biology and genetics, dicle university, faculty of medicine, diyarbakır 21280, turkey. tel: +90 0412 2488001-4638 fax: +90 0412 2488523. e-mail: balkanmah@gmail.com. received march 2018 & accepted november 2018 ed genes which is about 10% in the genome.(9) up to the present, approximately 150 dna repair genes have been identified, and most of them are known to have genetic variations in humans.(6) among them, x-ray repair cross-complementing group 1 (xrcc1) is a well-studied dna repair gene. it encodes a protein that interacts with several dna repair proteins and plays a critical role in base excision repair (ber) pathway. xrcc1 is located on chromosome 19q13.2 and contains 17 exons.(5, 8) many studies have been reported that the single-nucleotide polymorphisms (snps) in xrcc1 may be associated with the change of the dna damage-repair response, which may be risk factor for various complex diseases such as cancer.(10) xrcc1 knockout in mice has shown that xrcc1 is the most abundant gene in pachytene spermatocytes as well as in round spermatids, and it is suggested that this might maintain spermatogenesis by repairing dna damage during meiosis in germ cells. however, there have been only a few studies so far that examine the association between the xrcc1 polymorphisms and the risk of male infertility in human.(8) therefore, in the current study, we aimed to investigate the possible association between sexual dysfunction and andrology urology journal/vol 16 no. 4/ july-august 2019/ pp. 380-385. [doi: http://dx.doi.org/10.22037/uj.v0i0.4435] two known snps of arg194trp and arg399gln of the xrcc1 gene and inoa in a south-east turkey population. understanding the molecular mechanism of abnormal spermatogenesis and the genes involved are important in developing both diagnostic tools and treatment strategies for male infertility.(9) patients and methods study population the total 102 infertile men aged between 22 and 39 were included in this study. all infertile men are diagnosed with inoa, with at least one year of infertility. all men underwent at least two semen analyses. the semen analysis for sperm concentration, motility and morphology was performed according to the world health organization criteria.(11) inclusion criteria for the inoa group were primary infertility; absence of any known causes of infertility; clinical eugonadism; azoospermia and normal karyotype. individuals with known causes of infertility, including genetic factors (e.g. karyotyping, and y-chromosome microdeletion screening), lifestyle factors (e.g. alcoholism and occupation), clinical factors affecting the fertility (varicocele, cryptorchidism and infections, etc.) and men whose partner had factors involved in infertility were excluded from this study. the control group was consisted of 102 fertile controls with their ages ranging from 24 to 41 years. the controls were selected from fertile men who had at least one child without assisted reproductive technologies and had normal semen sperm parameters, and all the control cases had the normal karyotype. both the infertile men and the fertile controls were recruited within the same geographical region in the southeastern anatolia region of turkey. all studied men were referred from the urology department to the medical biology and genetics department at dicle university hospital. the study was approved by the ethics review board of dicle university’s faculty of medicine (reference number 87/26.02.2016). snps selection and genotyping of xrcc1 gene polymorphisms in the present study, for genotyping, we selected two known snps of the xrcc1 gene; arg194trp in exon 6 (rs1799782, ng_033799.1:g.27157c>t, nm_006297.2:c.580c>t ) and arg399gln in exon 10 (rs25487, ng_033799.1:g.29005a>g, nm_006297.2:c.1196a>g), which can alter dna repair capacity. snps were selected from the hapmap project and pubmed (http://www.ncbi.nlm.nih.gov/ pubmed). the snp id number and detailed sequence information are available in the public snp database(6). after informed consent from each subject, 2 ml heparinised peripheral venous blood was collected using a vacuum tube containing ethylenediaminetetra acetic (edta) to prevent coagulation. all samples were stored in tubes at -20°c until the dna extraction. genomic dna was extracted from whole blood using whole blood genomic dna purification kit (thermo scientific, st. leon-rot, germany) explained in our previous study,(12) then was stored at −80°c until using table 1. primer sequences, annealing temperature, restriction enzyme and allele sizes used for arg194trp and arg399gln polymorphisms of xrcc1 gene. ncbi primer sequences annealing temperature (°c) restriction enzyme allele size snp* rs 1799782; arg194trp (580c>t) f: 5´gccagggcccctccttcaa-3´ r: 5´taccctcagacccacgagt-3´ 57 pvuii c:485 t:396+89 rs25487; arg399gln (1196g>a) f: 5´-ttg tgc ttt ctc tgt gtc ca-3´ r: 5´-tcc tcc agc ctt ttc tga ta-3´ 68 mspi a: 615 g:374+221 *www.ncbi.nlm.nih.gov/gene figure 1. pcr-rflp products of xrcc1 gene arg194trp and arg399gln polymorphisms obtained by 3% agarose gel electrophoresis. (a) arg194trp polymorphism; lanes 1,2: homozygous cc alleles; lanes 3,4: heterozygous ct alleles; lanes 5,6: homozygous tt alleles. (b) arg399gln polymorphisms; lanes 1,2: homozygous aa alleles; lanes 3,4: heterozygous ga alleles; lanes 5,6: homozygous aa alleles. xrcc1 gene polymorphisms and azoospermia-akbas et al. sexual dysfunction and andrology 381 vol 16 no 04 july-august 2019 382 it for genotyping. polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) was used to genotype two snps of xrcc1, arg194trp and arg399gln, with the use of appropriate primer sets and restriction enzyme as previously described.(13,14) the primer sets and enzymes were used in this study are shown in table 1. the pcr reaction was performed in a 20 µl reaction volume containing 1xpcr buffer, 80 ng of dna, 2 mmol/l mgcl2,0.2 mmol/l of each dntp (fermentas, st. leon-rot, germany), 1 unit of taq dna polymerase (fermentas) and 0.2 mmol/l of primer for codon 194 or 0.8 µm primer for codon 399 (bio basic inc., markham, canada). a thermal cycler (senso-quest labcycler, sensoquest gmbh, göttingen,germany) was used with the following conditions: 4 min of initial denaturation at 94°c, followed by 30 amplification cycles. each cycle was consisted of denaturation at 94°c for 30s, annealing at 57°c and 68°c (for codon 194 and codon399, respectively) for 30 sand extension at 72°c for 30 s, with a final extension step of incubation at 72°c for 5 min. for genotyping of the arg194trp and arg399gln snps of xrcc1 gene, rflp analysis was carried out by using the restriction enzymes pvuii and mspi (new england biolabs, beverly, ma, usa). pcr products were digested by pvuii and mspi restriction enzymes, respectively, at 37°c overnight. the digested products were then separated on a 3% agarose gels (fmc bioproducts) along with a 100–1500 bp dna ladder (biobasic inc., markham, canada) and stained with ethidium bromide. ethidium bromidestained gels were analysed using the alphaimager imaging system (alphainnotech, san leandro, ca, usa). the 485 bp fragment of codon 194 yielded a 396 + 89 bp band, acting as an indicator of complete digestion. xrcc1 arg194trp genotypes cc (arg/arg), ct (arg/ trp), and tt (trp/trp) generated 485 bp, 485 + 396 bp and 396 bp dna bands, respectively (figure 1.a). xrcc1 codon 399 arg allele generated 2 dna bands (221 and 374 bp), whereas the variant gln allele has a single 615 bp uncut band, and the heterozygote (arg/ gln) displays all 3 bands (615, 374 and 221 bp) (figure 1.b). statistical analysis a goodness-of-fit chi-square test was used to determine the hardy-weinberg equilibrium of the observed genotype frequencies. statistical significance was defined as p < .05 and all statistical tests were two-tailed. the results were expressed as means with standard deviation (± sd) if the variables were continuous and as percentage if the variables were categorical. all statistical data were obtained using spss software (spss 11.5 for windows, spss inc., chicago, il, usa). results in this study, we analyzed the distribution of xrcc1 arg194trp and arg399gln polymorphisms in a sample of 102 men with inoa and 102 fertile controls in a turkish population and investigated their possible associations with inoa. the genotype and allele frequencies of the xrcc arg194trp and arg399gln polymorphisms for the cases and controls and their associations with the risk of inoa are shown in table 2. all observed snps were in agreement with hwe (χ2 test: p = .060 and .605, respectively). the genotype frequencies of the xrcc arg194trp were 84% (cc), 16% (ct) and 2% (tt) among the men with inoa, while the frequencies of those genotypes in the controls were found to be 88% (cc), 12% (ct) and 2% (tt) (χ2 test: p < .05). similarly, the genotypes frequencies of gg, ga, and aa of the xrcc1 arg399gln were 44%, 39%, and 19% in the group of men with inoa, whereas these frequencies were 42%, 45%, and 15% in the control group, respectively. however, these differences were not statistically significant among the cases and controls using the p < .05 threshold (p = .611 for arg194trp, and p = .064 for arg399gln). table 3 shows comparison of mean values (± sem) of semen analysis parameters, such as ejaculated volume, sperm count, total motility and normal morphology between fertile (control) and azoospermic group. semen volume was significantly lower in azoospermic group (p < .001). xrcc1 gene polymorphisms and azoospermia-akbas et al. table 2. genotype distributions and allele frequencies of xrcc1 arg194trp (c>t) and arg399gln (g>a) polymorphisms in infertile men with idiopathic nonobstructive azoospermia (inoa) and fertile controls. infertile men n = 102 (%) controls n = 102 (%) or 95% ci p-value xrcc1 580c>t (arg194trp) genotype cc 84 (82%) 88 (86%) reference ct 16 (16%) 12 (12%) 1.39 0.62-3.12 .41 tt 2 (2%) 2 (2%) 1.04 0.14-7.60 .96 allele c 184 (90%) 188 (92%) reference t 20 (10%) 16 (8%) 1.27 0.64-2.54 .48 xrcc1 1196g>a (arg399gln) genotype gg 44 (43%) 42 (41%) reference ga 39 (38%) 45 (44%) 0.82 0.45-1.51 .53 aa 19 (19%) 15 (15%) 1.20 0.54-2.68 .64 allele g 127 (62%) 129 (63%) reference a 77 (38%) 75 (37%) 1.04 0.69-1.55 .83 the distribution of the genotypes among the control subjects was in agreement with that predicted under the conditions of hardy-weinberg equilibrium (χ2 test: p = .060 for the arg194trp polymorphism and p = .605 for the arg399gln polymorphism). discussion several single nucleotide polymorphisms have previously been identified as responsible for male infertility. for example; in a case-control study, the possible association of snps in the follicle-stimulating hormone receptor (fshr) gene and male infertility have been investigated in south-east turkey, and the results showed that the fshr haplotype is not associated with different serum fsh levels. however, it has been showed a different distribution between fertile and infertile men.(15) in another study, the association of the methylenetetrahydrofolate reductase (mthfr), methionine synthase reductase (mtrr) and methylenetetrahydrofolate dehydrogenase (mthfd1) genes polymorphisms have been investigated in inoa among a population in south-east turkey. there has been found a synergistic interaction between some polymorphisms. therefore, this suggested that there has been no individual, but interactive association between four prominent folate metabolism pathway markers and male infertility.(2) furthermore, balkan et al.(16) have investigated the association of the snps of fas/faslg genes in male infertility. their results suggested that the aa-gg binary genotype for fas-670a/g snp might be a genetic predisposing factor of inoa among south-eastern anatolian men. in a recent study, the possible association of the microrna-related genes and male infertility have been investigated in a population of south-east turkey(17), and the results have showed a significant difference between patients and control groups for the individual aa genotype frequency of the gemin3 (rs197388) gene. it has indicated that the aa genotype may be considered as indicative of a high predisposition to inoa. recently, the potential role of the icam-1 gene polymorphism has been investigated in male infertility with inoa in a turkish population. it has been found that the e469k polymorphism of icam-1 is not posing a risk for inoa.(3) various studies have shown that the single nucleotide polymorphisms in dna repair genes affect dna repair capacity, and the absence or decrease of dna repair ability may increase the risk of several syndromes, such as renal disease, cancer, coronary artery disease and other diseases.(18,19) however, very few studies have reported the associations between these polymorphisms in male infertility. in our study, we investigate the associations of two well-characterized polymorphisms (arg194trp and arg399gln) of xrcc1 gene with risk of inoa in a south-east turkey population to reveal the possible role of genetic polymorphisms in xrcc1 gene during spermatogenesis. we did not identify any association between arg194trp and arg399gln polymorphisms and the risk of inoa. although the association of the xrcc1 arg194trp and arg399gln polymorphisms in male infertility has been shown previously,(5–8) as yet, there has been no final conclusion about the association of those polymorphisms in male infertility. for example, gu et al.(6) has explored the possible role of the xrcc1 arg399gln polymorphism in the susceptibility to risk of inoa in a chinese population and found that the aa genotype of arg399gln showed a significant association with a increased risk of inoa. these results are consistent with the study of zheng et al.(8), which indicated that arg399gln snp of xrcc1 gene could be a marker for genetic susceptibility to inoa and the a allele might be a risk gene of inoa in northern chinese han population. however, ghasemi et al.(20) has reported a conflicting result, which indicated that there has been no significant association between xrcc1 arg399gln polymorphism and risk of male infertility. in addition, another study investigated the associations of three polymorphisms (t-77c, arg194trp, and arg399gln) in xrcc1 gene with risk of inoa in a chinese population. they do not have any evidence of involvement of xrcc1 t-77c and arg194trp polymorphisms in inoa.(7) in another study, the effects of the xrcc1 polymorphisms (t-77c, arg194trp, arg280his, arg399gln) on male infertility have been explored in a chinese population. they do not have any evidence of involvement of xrcc1 t-77c, arg194trp, and arg280his polymorphisms in inoa.(5) in another report, xrcc1 polymorphisms (arg194trp, arg399gln) and xerodermapigmentosum group d (xpd) polymorphism (lys751gln) are investigated whether there was a risk of developing inoa in a chinese population. they founded that the xpd 751gln allele was seemed to be a risk allele for azoospermia. when combined the xpd 751 lys/ gln+gln/ gln genotype with the xrcc1 194 arg/arg or 399 arg/arg genotype, the risk of azoospermia increased. in conclusion, their study showed that the xpd and xrcc1 polymorphisms have contributed to the risk of parameters fertile (control) (n = 102) azoospermic (n = 102) volume (ml) 3.25 ± 1.37 2.15 ± 1.37 sperm count (million/ml) 80.35 ± 44.23 0 total motility (%) 71.16 ± 18.26 0 normal morphology (%) 63.25 ± 5.49 0 table 3. semen analysis parameters of fertile (control) and infertile men with idiopathic nonobstructive azoospermia (inoa). all values are expressed as mean ± sem. population arg194trp arg399gln references arg399 (%) 399gln (%) arg194 (%) 194trp (%) chinese 79 21 88 12 [10] korean 75 25 67 33 [19] thai 75 25 70 30 [26] indian 78 22 87 13 [27] german 68 32 93 7 [24] italian 72 28 92 8 [25] turkish 66 34 91 9 [21] turkish 69 31 89 11 [22] turkish 65 35 94 6 [23] turkish 63 37 92 8 this study table 4. the xrcc1 arg194trp and arg399gln allele frequencies among control groups of various populations. xrcc1 gene polymorphisms and azoospermia-akbas et al. sexual dysfunction and andrology 383 vol 16 no 04 july-august 2019 384 developing inoa.(6,7) it is speculated that the results of these studies might be attributed to differences in sample size, ethnic background and geographic variations. there is much evidence in the literature that the frequencies of genetic polymorphisms vary among different populations. in our study, 102 fertile controls were within the same geographical region in the southeastern anatolia region of turkey. the allele frequencies for the arg399gln and arg194trp variants of xrcc1 gene among various control populations are presented in table 4. in the present study, the frequencies of these variant alleles were similar to the frequencies reported for other turkish studies.(21–23) besides, allele frequencies for these variants that found in the present study for turkish population were quite similar to the frequencies reported for other caucasian population (german and italian).(24,25) conclusions our data suggests that the genotype of arg399gln and arg194trp polymorphisms are not associated with inoa in a turkish population. therefore, this does not appear to be responsible for spermatogenic failure in male infertility. since sample size is a significant factor affecting the result of case–control association studies, more works with large sample size and more various populations are needed to further explore the pathophysiology of these functional snps in inoa. in addition, it may be far better to investigate the role of xrcc1 arg194trp and arg399gln snps and their relationship to the sperm dna damage levels in the etiopathogenesis of inoa. conflict of interest the authors declare that they have no conflict of interest. references 1. yıldırım y, ouriachi t, woehlbier u, et al. linked homozygous bmpr1b and pdha2 variants in a consanguineous family with complex digit malformation and male infertility. eur j hum genet. 2018;26:876-85. 2. balkan m, atar m, erdal me, et al. the possible association of polymorphisms in mthfr, mtrr, and mthfd1 genes with male infertility. int med j. 2013;4:404–8. 3. balkan m, akbas h, penbegül n, rustemoğlu a, yücel i̇, yıldız i̇. a possible association between e469k polymorphism of icam1 gene and nonobstructive azoospermia in southern turkey. biotechnol biotechnol equip. 2017;31:143–7. 4. ayhan o, balkan m, guven a, et al. truncating mutations in taf4b and zmynd15 causing recessive azoospermia. j med genet. 2014;51:239-44. 5. ji g, gu a, zhu p, et al. joint effects of xrcc1 polymorphisms and polycyclic aromatic hydrocarbons exposure on sperm dna damage and male infertility. toxicol sci. 2010;116:92-8. 6. gu ah, liang j, lu nx, et al. association of xrcc1 gene polymorphisms with idiopathic azoospermia in a chinese population. asian j androl. 2007;9:781-6. 7. gu a, ji g, liang j, et al. dna repair gene xrcc1 and xpd polymorphisms and the risk of idiopathic azoospermia in a chinese population. int j mol med. 2007;20:743-7. 8. zheng lr, wang xf, zhou dx, zhang j, huo yw, tian h. association between xrcc1 single-nucleotide polymorphisms and infertility with idiopathic azoospermia in northern chinese han males. reprod biomed online. 2012;25:402-7. 9. ghalkhani e, sheidai m, gourabi h, noormohammadi z, bakhtari n, malekasgar am. study of single nucleotide polymorphism (rs28368082) in spo11 gene and its association with male infertility. j assist reprod genet. 2014;31:1205-10. 10. wang lj, wang ht, wang xx. association of xrcc1 gene polymorphisms and pancreatic cancer risk in a chinese population. genet mol res. 2016;15: 1-7. 11. world health organization. 1999 who laboratory manual for the examination of human semen and semen-cervical mucus interaction, 4th ed cambridge, uk, cambridge university press, 1999 12. akbas h, uyanikoglu a, aydogan t, et al. e-cadherin (cdh1) gene -160c>a promoter polymorphism and risk of gastric and esophageal cancers. actamedicamediterranea. 2013;29:671-6. 13. xing d, qi j, miao x, lu w, tan w, lin d. polymorphisms of dna repair genes xrcc1 and xpd and their associations with risk of esophageal squamous cell carcinoma in a chinese population. int j cancer. 2002;100:600-5. 14. ryu ra, tae k, min hj, et al. xrcc1 polymorphisms and risk of papillary thyroid carcinoma in a korean sample. j korean med sci. 2011;26:991-5. 15. balkan m, gedik a, akkoc h, et al. fshr single nucleotide polymorphism frequencies in proven fathers and infertile men in southeast turkey. biomed biotechnol. 2010;2010:640318 16. balkan m, atar m, erdal me, et al. possible association of fas and faslg polymorphisms with the risk of idiopathic azoospermia in southeast turkey. genet test mol biomarkers. 2014;18:383–8. 17. ay oi, balkan m, erdal me, et al. association of microrna-related gene polymorphisms and idiopathic azoospermia in a southeast turkey population. biotechnology & biotechnological equipment. 2017;31:35662. 18. trabulus s, guven gs, altiparmak mr, et al. dna repair xrcc1 arg399gln xrcc1 gene polymorphisms and azoospermia-akbas et al. polymorphism is associated with the risk of development of end-stage renal disease. molbiol rep. 2012;39:6995-7001. 19. lee sg, kim b, choi j, kim c, lee i, song k. genetic polymorphisms of xrcc1 and risk of gastric cancer. cancer lett. 2002;187:53–60. 20. ghasemi h, khodadadi i, fattahi a, moghimbeigi a, tavilani h. polymorphisms of dna repair genes xrcc1 and lig4 and idiopathic male infertility, syst biol reprod med. 2017;63:382-90. 21. vural p, degirmencioğlu s, doğruabbasoğlu s, saral ny, akgül c, uysal m. genetic polymorphisms in dna repair gene ape1, xrcc1 and xpd and the risk of preeclampsia. eur j obstet gynecol reprod biol. 2009;146:160-4. 22. tumer tb, yilmaz d, tanrikut c, sahinc g, ulusoya g, arinc e. dna repair xrcc1 arg399gln polymorphism alone, and in combination with cyp2e1 polymorphisms significantly contribute to the risk of development of childhood acute lymphoblastic leukemia¸ leukemia research. 2010;34:1275– 81. 23. erdal n, erdal me, savaşoğlu k,gökdoğan t. arg194trp and arg399gln polymorphisms of the dna repair gene x-ray repair crosscomplementing. turkiyeklinikleri j med sci. 2004;24:573-8. 24. harth v, schafer m, abel j, et al. head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair. j toxicol environ health a. 2008;71:887–97. 25. coppede f, migheli f, lo gerfo a, et al. association study between xrcc1 gene polymorphisms and sporadic amyotrophic lateral sclerosis. amyotroph lateral scler. 2009;25:1–3. 26. pakakasama s, sirirat t, kanchanachumpol s, et al. genetic polymorphisms and haplotypes of dna repair genes in childhood acute lymphoblastic leukemia. pediatr blood cancer 2007;48:16–20. 27. joseph t, kusumakumary p, chacko p, abraham a, pillai mr. dna repair gene xrcc1 polymorphisms in childhood acute lymphoblastic leukemia. cancer lett 2005;217:17–24. xrcc1 gene polymorphisms and azoospermia-akbas et al. sexual dysfunction and andrology 385 urological oncology association of akr1c3 polymorphisms with bladder cancer n. ozan tiryakioğlu, nagehan ersoy tunalı* purpose: polymorphisms in the genes coding for the carcinogen metabolizing enzymes may affect enzyme activities and alter the activation and detoxification rates of the carcinogens. akr1c3 is one of the very polymorphic xenobiotic metabolizing enzymes involved in the bioactivation process. here we aimed to investigate the association of two single nucleotide polymorphisms in akr1c3, rs12529 (c.15c > g) and rs1937920 (12259 bp 3’ of stp a > g) with urinary bladder cancer (ubc). materials and methods: two-hundred fifty ubc cases and 250 control subjects were genotyped using the polymerase chain reaction and restriction fragment length method. associations of the genotypes with ubc risk and tumor characteristics were assessed using logistic regression and fisher’s exact test. the results are corrected for multiple testing. results: we identified strong associations between the studied akr1c3 variants and ubc risk. the homozygous variant genotype of rs12529 was found to be inversely associated with ubc, and rs1937920 was shown to be associated with increased risk of ubc. none of the genotypes were found to be significantly associated with tumor characteristics. conclusion: we provided evidence that rs12529 and rs1937920 are significant in the molecular pathogenesis of ubc. however, the results presented here should be regarded as preliminary and might represent a first step of future larger studies aiming to better elucidate the role of akr1c3 polymorphisms in the susceptibility to bladder cancer. keywords: genetic association studies; humans; polymorphism; single nucleotide; urinary bladder neoplasms; genetics; 3-hydroxysteroid dehydrogenases; aryl hydrocarbon hydroxylases; aryl hydrocarbon receptor nuclear translocator. introduction urinary bladder cancer (ubc) is the ninth most common cancer worldwide, with approximately 400.000 new cases each year.(1) despite increased awareness against certain risk factors and recent promising developments in the diagnosis and treatment, worldwide incidence of ubc increases steadily. (2) bladder cancer is three to five times higher in men than women, and its incidence increases with age for both sexes, peaking at the seventh decade.(3). the main molecular pathways leading to ubc development are altered xenobiotic metabolism and mutations in genes involved in dna repair, tumor suppression and cell proliferation mechanisms.(4-8) the most common risk factor for ubc is cigarette smoking, followed by occupational exposure to aromatic amines used in the production of dyes, rubber and textiles and to polycyclic aromatic hydrocarbons (pahs) formed during combustion of fossil and carbon-containing fuels.(9,10) these well-studied and mutagenic carcinogens should undergo bioactivation in order to exert their carcinogenic potential. alterations in the activation and following detoxification mechanisms of these carcinogenic chemicals result in the formation of dna adducts, which eventually lead to dna damage. this process constitutes the basis for genetic susceptibility to ubc.(4) therefore, studies investigating genetic susceptibility to ubc focus on genes involved in xenobiotic metabolism and dna repair. the ultimate function of the xenobiotic metabolism is detoxification of carcinogens, where chemical modifications catalyzed by phase i enzymes result in the activation of carcinogens, and those catalyzed by phase ii enzymes facilitate the excretion of these compounds. polymorphisms in the genes coding for the xenobiotic enzymes may induce altered enzyme activities that confer susceptibility to various cancers, including ubc, due to altered activation/detoxification rates of carcinogens.(3) almost two thirds of all the ubc cases are shown to be associated with smoking. pahs, tobacco-specific n-nitrosamines and aromatic amines are the department of molecular biology and genetics, haliç university, istanbul, turkey. *correspondence: department of molecular biology and genetics, haliç university, istanbul, 34445 turkey. tel: +90 212 9242444. e-mail: nagehan.ersoy@gmail.com. received january 2016 & accepted march 2016 urological oncology 2615 vol 13 no 02 march-april 2016 2616 significant contributors to the carcinogenic effects of tobacco smoke via dna adducts or formation of reactive oxygen species (ros) leading to oxidative damage and ultimately dna mutations.(11-13) the balance between the activation and detoxification of these carcinogens by phase i and phase ii enzymes affect the amount of accumulating dna damage. aldoketoreductases (akrs) are phase i enzymes that belong to a superfamily of nad(p)h-linked oxidoreductases and catalyze the conversion of carbonyl group-containing xenobiotics to alcohols for conjugation reactions.(14) since they have been shown to activate polycyclic aromatic hydrocarbons (pahs) and nitrosamines in exhaust and cigarette smoke, akr family members are considered important for smoking-related cancers.(15) the human akr genes (akr 1, 6, 7) are highly polymorphic, where variant genotypes may cause alterations in respective protein functions, and act as modifiers of ubc risk. akr1c3 on chromosome 10p15-p14 is known to act on various subtrates including hormones and pahs.(12) in addition to that, in vitro studies have shown significant induction of akr1c3 upon exposure to cigarette smoke condensate, diesel exhaust and pahs.(13-16) on this background we hypothesized that genetic variations in the akr1c3 gene may contribute to ubc risk. akr polymorphisms have been previously investigated in a total of six studies for their possible involvement in various cancer susceptibilities,(17-22) however, there is only one study investigating the involvement of akr1c3 polymorphisms in bladder cancer.(17) in this work we aimed to investigate the association of two single nucleotide polymorphisms (snps), rs12529 (c.15c > g; p.his5gln) and rs1937920 (12259 bp 3’ of stp a > g), with the risk of developing ubc. rs12529 results in an amino acid substitution and has previously been shown to be inversely associated with bladder cancer risk.(17) there is no enough data to conclude on the physiological effects of this snp, however, according to current literature it is possible that homozygous variant genotype may induce akr1c3 expression to facilitate an efficient bioactivation process. rs1937920, residing in the 3’utr of the akr1c3 gene, has also been implicated previously in an association study(17) and has the potential to have regulatory roles in akr1c3 expression. materials and methods study population total of 500 caucasian subjects of turkish origin were included in the study. the clinical and demographic data of the patients and controls were provided in table 1. cases include 250 first-time diagnosed and histologically confirmed transitional cell carcinoma patients who had not received previous chemotherapy or radiotherapy. patient selection was not subjected to age, gender or tumor stage/grade restrictions. patients who had received previous radiotherapy, chemotherapy or radical cystectomy, patients with previous diagnosis of cancer, metastasized cancer, serum prostate-specific antigen (psa) > 2.5 ng/ml, and those with bladder tumors secondary to other malignancies were excluded from the study. clinical diagnosis of ubc was given by expert urologists based on urine cytology, urinary tract imaging and cystoscopic analysis. when abnormal tissue is recognized during cystoscopy, transurethral resection of the bladder tumor (turbt) was performed. tumors were classified according to the histologic tumor grading system of the world health organization (who) guidelines.(23) pathological staging of the tumors was performed according to the tnm classification of malignant tumors,(24) where pta and pt1 tumors were grouped as superficial and pt2-pt4 tumors were considered invasive. tumors were graded as low grade and high grade tumors. the control group includes ageand gender-matched healthy individuals admitted to the hospitals for routine check-up examination with no present or previous history of cancer. subjects with any degree of hematuria, urinary symptoms, benign prostate hyperplasia (bph), history of prostatitis and pre-cancerous lesions were excluded from the study. the study protocol was approved by haliç university human research ethics committee. all subjects have provided a written informed consent prior to their inclusion in the study in accordance with helsinki declaration, revised in 2000. data regarding age, gender, table 1. clinical and demographic data of the study population. variables controls patients p value age ± sd (years ) 64.2 ± 12.82 66.4 ± 13.21 .059 male, no (%) 200 (80) 198 (79.2) .92 female, no (%) 50 (20) 52 (20.8) bmi ± sd (kg/m2) 27.49 ± 4.22 28.3 ± 3.46 .019 non-smoker, no (%) 169 (67.6) 49 (19.6) < .001 smoker, no (%) 81 (32.4) 201 (80.4) tumor grade, (%) low 61.2 high 38.8 tumor stage, (%) superficial 62.8 invasive 37.2 abbreviations: bmi, body mass index; sd, standard deviations. akr1c3 polymorphisms in bladder cancer-tiryakioğlu et al. ethnicity, occupation, weight, height, family history of cancer, personal medical history and cigarette consumption were collected upon completion of standardized questionnaires. family history of bladder cancer was considered positive when first or second degree relatives of the subjects had given bladder cancer diagnosis. none of the subjects included in the study were under occupational exposure to hazardous carcinogens related to bladder cancer. subjects were classified as smokers (who had smoked more than 100 cigarettes in his lifetime) and non-smokers. ten ml blood samples were collected from patients in edta-containing tubes table 2. genotype and allele distributions for rs12529 and rs1937920. variables rs12529 cc cg gg c g no (%) no (%) no (%) no (%) no (%) patients 32 (12.8) 200 (80) 18 (7.2) 264 (52.8) 236 (47.2) controls 40 (16) 146 (58.4) 64 (25.6) 226 (45.2) 274 (54.8) p value for hwe .007152 rs1937920 aa ag gg a g no (%) no (%) no (%) no (%) no (%) patients 101 (40.4) 121 (48.4) 28 (11.2) 323 (64.6) 177 (35.4) controls 120 (48) 115 (46) 15 (6) 355 (71) 145 (29) p value for hwe .089977 r2 for ld .435795 abbreviations: hwe, hardy-weinberg equilibrium; ld, linkage disequilibrium. genotype/allele or 95% ci p value p* value rs12529 cc referent cg 1.712 1.027-2.856 .038 .076 gg 0.352 0.175-0.708 .003 .006 cc vs (cg+gg) 1.298 0.785-2.144 .308 .616 (cc+cg) vs gg 4.435 2.540-7.744 < .0001 < .0001 c ref. g 0.737 0.575-0.946 .016 .033 cat 0.606 .002 rs1937920 aa referent ag 1.250 0.865-1.806 .234 .468 gg 2.218 1.123-4.381 .020 .040 aa vs (ag+gg) 1.362 0.956-1.940 .087 .174 (aa+gg) vs gg 0.506 0.263-0.973 .038 .076 a referent g 1.342 1.028-1.751 .030 .061 cat 1.425 .024 abbreviations: cat, cochran -armitage trend test; or, odds ratio; ci, confidence interval. all p values were adjusted for age, gender, bmi and smoking status. p*: p values after bonferroni correction. table 3. associations of rs12529 and rs1937920 genotypes and alleles with bladder cancer risk. akr1c3 polymorphisms in bladder cancer-tiryakioğlu et al. urological oncology 2617 vol 13 no 02 march-april 2016 2618 and stored at 4oc until dna extraction. the control subjects have provided cheek epithelial cells on cotton swabs as the source of dna. genotyping dna was isolated from the whole blood samples of patients using high pure pcr template preparation kit (roche, germany) and from buccal swabs using gentra puregene buccal cell kit (qiagen, maryland, usa). isolated dna samples were quantified by spectrophotometry and loaded on 1% agarose gels to confirm their integrity. both single nucleotide polymorphisms (snps) were genotyped using polymerase chain reaction (pcr) and restriction fragment length polymorphism (rflp) methods. pcr-rflp assays were designed with biology workbench using primer3 and tcag modules.(25) rs12529 polymorphic region amplified using the forward and reverse primers, 5’-cctcctacatgccattggtt-3’ and 5’-caacccaatacgggtttcac-3’, respectively, and the samples were genotyped by bts-i digestion of the pcr products. rs1937920 polymorphism was genotyped by taqi restriction of the pcr products amplified using 5’-aggcaggcgaacagaaacta-3’ and 5’-gaaaaacacttgcattcgca-3’ primers. the specificity of the pcr products were analyzed by 2% agarose gel electrophoresis, and the digestion products were separated on 3% agarose gels. genotypes were table 4. associations of rs12529 and rs1937920 genotypes with tumor grade and stage genotype/ grade or 95 % ci p value p* value stage or 95 % ci p value p* value allele low high superficial invasive rs12529 cc 11 21 referent 18 14 referent cg 132 68 0.270 0.123-0.592 .00064 .00192 128 72 0.723 0.654-1.352 .399 1.0 gg 10 8 0.419 0.129-1.366 .145 .436 11 7 0.818 0.252-2.655 .738 1.0 c 154 110 referent 164 100 referent g 152 84 0.774 0.539-1.111 .164 .492 150 86 0.940 0.654-1.352 .740 1.0 rs1937920 aa 61 40 referent 65 39 referent ag 72 49 1.038 .605-1.780 .892 1.0 70 50 1.190 0.695-2.039 .525 1.0 gg 20 8 0.610 .245-1.518 .285 .855 22 8 0.606 0.246-1.493 .273 .819 a 194 129 referent 200 128 referent g 112 65 .873 .598-1.274 .48052 1.0 114 66 0.905 0.621-1.317 .60086 1.0 abbreviations: or, odds ratio; ci, confidence interval. all p values were calculated for allelic and additive model and adjusted for age, gender, bmi and smoking status. p*: p values after bonferroni correction. figure 1. bts-i (a) and taqi (b) digestion products run on 3% agarose gels for 15 minutes at 120 volts (50bp ladder, thermofisher, california-usa). akr1c3 polymorphisms in bladder cancer-tiryakioğlu et al. determined according to the rflp patterns on the gels (figure 1) and confirmed by sanger sequencing(26) of 50 randomly chosen samples (figure 2). statistical analysis the control samples were tested for hardy-weinberg equilibrium (hwe) with chi-square test. the associations between ubc risk and genotypes were examined with allelic, additive, dominant and recessive models using logistic regression. while cochran-armitage trend test was used to obtain a general odds ratio (or) for both snps, it was essentially used for rs12529, since genotype distribution was found to be departed from hwe. the demographic data have shown normal distribution among patients and controls according to the shapiro-wilk test results (p < .05). therefore, differences between the continuous variables were assessed using t test. fisher's exact test was used for the assessment of categorical variables. all the reported p values are two-tailed and adjusted for confounding factors including age, gender, body mass index (bmi) and smoking status. to account for multiple comparisons, bonferroni correction was applied. statistical package for the social science (spss inc, chicago, illinois, usa) version 21.0 was used for all statistical analyses and p < .05 was considered statistically significant. statistical power of 80% was considered as the lowest acceptable power score. power calculation was performed according to the method suggested by kelsey and colleagues. (27) previously reported genotype frequencies for the caucasian population were used as hypothetical exposure rates. the sample size for the minimally acceptable power was calculated for rs12529 and rs1937920 as 65 cases and 65 controls with 130 subjects, and 71 cases and 71 controls with 142 subjects, respectively. results the allelic and genotypic distributions for rs12529 and rs1937920 snps, together with hwe and linkage disequilibrium (ld) calculations are shown in table 2. according to the results, the two studied snps were not in ld (r2 = .44). both snps were shown to be significantly associated with ubc risk (table 3). our results point out rs12529 as a protective variant (or trend = 0.606; p trend = .002) and rs1937920 as a risk variant (or trend = 1.425; p trend = .024) for ubc. for the rs12529 snp, frequency of the g allele was found to be significantly different between patients and controls (p* = .016). the homozygous variant gg genotype is shown to decrease the risk of ubc (95% ci: .175-.708, or = 0.352, p* = .006). this effect is also apparent when homozygous wild type and heterozygous genotypes (cc+cg) were tested against the homozygous variant (95% ci: 2.540-7.744, or = 4.435, p* < .0001). the frequency of the rs1937920 variant allele was also significantly different between patients and controls (p* = .03). the variant genotype gg was identified to be a significant risk factor for ubc (95% ci: 1.123-4.381, or = 2.218, p* = .04), where the gg genotype raises the odds of developing ubc by 2.2 folds. the associations of the alleles and genotypes with tumor grades and stages are shown in table 4. the heterozygous genotype for rs12529 appears to be significantly associated with tumor grade (p* = .002). however, since the significance decreases in the dominant model, this seems to be an artificial effect due to high heterozygous genotype frequency and could be negated in a study with larger sample size. there was no other significant associations between the tumor grades/stages and the studied polymorphisms. discussion our results identified the 3’ utr snp, rs1937920, as a risk variant and the nonsynonymous rs12529 snp as a protective variant for ubc, thereby provided evidence that akr1c3 locus is important in the molecular pathogenesis of ubc. the number of studies investigating the association of akr1c3 polymorphisms with cancer is limited to a few. in three of the six studies prostate cancer samples were analyzed,(20-22) and the rest are three individual studies on non-hodgkin lymphoma, lung cancer and urinary bladder cancer.(17-19) rs1937920 polymorphism has been identified in a spanish bladder cancer study using golden gate assay(17) and minor allele frequency was reported to be 0.29 in the control population. to the best of our knowledge this is the first study investigating the rs1937920 snp figure 2. sanger sequencing results for rs12529. electropherogram for the wild type homozygous (a), heterozygous (b) and homozygous variant (c) genotypes. akr1c3 polymorphisms in bladder cancer-tiryakioğlu et al. urological oncology 2619 vol 13 no 02 march-april 2016 2620 in relation to bladder cancer. according to our results, homozygous variant genotype carriers of the turkish population are at 2.2 folds more risk of developing ubc. it can be speculated that this snp may result in decreased akr1c3 expression and/or activity, leading to inefficient bioactivation process. further association studies with large and different ethnic groups and tissue/in vitro expression studies are required in order to clarify the role of this polymorphism in ubc. we have identified the nonsynonymous rs12529 snp to be inversely associated with ubc risk. to the best of our knowledge, our results constitute the second contribution to the literature in terms of the involvement of rs12529 in ubc. here we report the association of the homozygous variant gg genotype with decreased risk for ubc (or gg = 0.352; 95% ci: 0.175 0.708; p* = .006). our results corroborated the findings of figuroea and colleagues(17) who previously reported an inverse association of ubc with this polymorphism in the spanish population (95 % ci : 0.52-1.18, or = 0.78, p = .04). these two consistent data in the literature support the idea that akr1c3 c.15 c > g polymorphism may contribute significantly to ubc pathogenesis via induction of akr1c3 expression to facilitate an efficient bioactivation process. however, this hypothesis should be confirmed with akr1c3 expression analyses in ubc patients. interestingly, the heterozygous genotype for rs12529 shows a trend towards significance (p* = .076) in terms of its association with increased ubc risk in our study. however, since the significance of this effect decreases in dominant model, this seems to be an artificial effect as a result of high heterozygous genotype frequency and could be negated in a study with larger sample size. regarding the associations of the alleles and genotypes with tumor characteristics, the only significant association was between the heterozygous genotype for rs12529 and tumor grade (p* = .00192). however, this is possibly due to high representation of the heterozygotes. we could not detect any other associations between the tumor characteristics and the studied genotypes. the association of rs12529 was investigated previously in chinese lung cancer patients by lan et al.(18) who reported two folds increased risk for the homozygous variant genotype (gg). in another study by lan and colleagues, no association between akr1c3 variants and non-hodgkin lymphoma was reported.(19) cunnigham and colleagues on the other hand, investigated akr1c3 variants in sporadic and familial prostate cancer, but could not find an association between rs12529 and prostate cancer risk.(20) two other studies on prostate cancer have revealed significant association of akr1c3 variants and prostate cancer risk when gene interactions were in taken into consideration.(21,22) while the discrepancy on the role of rs12529 snp can be attributed to differences in the pathogeneses of lung and urinary bladder cancers, a unique gene-gene or gene-environment effects specific to chinese population is more likely. this is also supported by the fact that rs12529 genotype distributions in asian populations are significantly different than that of caucasians such that asians have the frequency of 0.770 for the g allele, which was designated as the minor allele for other populations. conclusions in conclusion, our results suggest that akr1c3 rs12529 and rs1937920 variants have significant contributions to the risk of developing ubc. because of the case–control design of this study, population stratification and admixture effects may increase the type i error rate of association; therefore, the results presented here should be regarded as preliminary and might represent a first step of future larger studies aiming to better elucidate the role of akr1c3 polymorphisms in the susceptibility to bladder cancer. acknowledgements the authors thank haliç university for financial support. conflict of interest none declared. references 1. ferlay j, soerjomataram i, ervik m, dikshit r, eser s, mathers c, rebelo m, parkin dm, forman d, bray, f. globocan 2012 v1.1, cancer incidence and mortality worldwide: iarc cancerbase no. 11 [internet]. lyon, france: international agency for research on cancer; 2014. available from: http:// globocan.iarc.fr, accessed on 13/01/2016. 2. burger m, catto jw, dalbagni g, et al. epidemiology and risk factors of urothelial bladder cancer. eur urol. 2013;63:234-41. 3. franekova m, halasova e, bukovska e, luptak j, dobrota d. gene polymorphism in bladder cancer. urol oncol. 2008;26:1-8. 4. bartsch h, rojas m, nair u, nair j, alexandrov k. genetic cancer susceptibility and dna adducts: studies in smokers, tobacco chewers, and coke oven workers. cancer detect prev. 1999;23:445-53. 5. kalantari mr, ahmadnia h. p53 overexpression in bladder urothelial akr1c3 polymorphisms in bladder cancer-tiryakioğlu et al. neoplasms: new aspect of world health organization/international society of urological pathology classification. urol j. 2007;4:230-3. 6. jalali nadoushan mr, taheri t, jouian n, zaeri f. overexpression of her-2/neu oncogene and transitional cell carcinoma of bladder. urol j. 2007;4:151-4. 7. karimianpour n, mousavi-shafaei p, ziaee aa, et al. mutations of ras gene family in specimens of bladder cancer. urol j. 2008;5:237-42. 8. nanda ms, sameer as, syeed n, et al. genetic aberrations of the k-ras proto-oncogene in bladder cancer in kashmiri population. urol j. 2010;7:168-73. 9. zeegers mp, dorant e, goldblum ra, van den brandt pa. the impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. cancer. 2000;89:630-9. 10. rota m, bosetti c, boccia s, boffetta p, la vecchia c. occupational exposures to polycyclic aromatic hydrocarbons and respiratory and urinary tract cancers: an updated systematic review and a meta-analysis to 2014. arch toxicol. 2014;88:1479-90. 11. hecht ss. tobacco carcinogens, their biomarkers and tobacco-induced cancer. nat rev cancer. 2003;3:733–44. 12. palackal nt, lee sh, harvey rg, blair ia, penning tm. activation of polycyclic aromatic hydrocarbon trans-dihydrodiol proximate carcinogens by human aldo-keto reductase (akr1c) enzymes and their functional overexpression in human lung carcinoma (a549) cells. j biol chem. 2002;277:24799808. 13. nagaraj ns, beckers s, mensah jk, waigel s, vigneswaran n, zacharias w. cigarette smoke condensate induces cytochromes p450 and aldo-keto reductases in oral cancer cells. toxicol lett. 2006;165:182-94. 14. penning tm, jin y. aldo-keto reductases and bioactivation/detoxication. annu rev pharmacol toxicol. 2007;47:263-92. 15. penning tm, drury je. human aldo-keto reductases: function, gene regulation and single nucleotide polymorphisms. arch biochem biophys.. 2007;464:241-250. 16. courter la, pereira c, baird wm. diesel exhaust influences carcinogenic pah-induced genotoxicity and gene expression in human breast epithelial cells in culture. mutat res. 2007;625:72-82. 17. figuroea jd, malats n, garci-closas m, et al. bladder cancer risk and genetic variation in akr1c3 and other metabolizing genes. carcinogenesis. 2008;29:1955-62. 18. lan q, mumford jl, shen m, et al. oxidative damage-related genes akr1c3 and ogg1 modulate risks for lung cancer due to exposure to pah-rich coal combustion emissions. carcinogenesis. 2004;25:2177-81. 19. lan q, zheng t, shen m, et al. genetic polymorphisms in the oxidative stress pathway and susceptibility ton on-hodgkin lymphoma. hum genet. 2007;121:162-8. 20. cunningham jm, hebbring sj, mcdonnel sk, et al. evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer. cancer epidemiol biomarkers prev. 2007;16:969-78. 21. vaarala, mh, mattila h, ohtonen p, tammela tl, paavonen tk, schleutker j. the interaction of cyp3a5 polymorphisms along the androgen metabolism pathway in prostate cancer. int j cancer. 2008;122: 2511-6. 22. kwon em, holt sk, fu r, et al. androgen metabolism and jak/stat pathway genes and prostate cancer risk. cancer epidemiol. 2012;36:347-53. 23. miyamoto h, miller js, fajardo da, lee tk, netto gj, epstein ji. non-invasive papillary urothelial neoplasms: the 2004 who/isup classification system. pathol int. 2010;60:1-8. 24. hermanek p and sobin l (eds.) tnm classification of malignant tumors. berlin: springer-verlag. 1987;131-146. 25. subramaniam s. the biology workbench--a seamless database and analysis environment for the biologist. proteins. 1998;32:1-2. 26. database of single nucleotide polymorphisms (dbsnp). bethesda (md): national center for biotechnology information, national library of medicine. dbsnp accession:{rs12529}, (dbsnp build id: {144}). available from:http://www.ncbi.nlm.nih.gov/snp/ 27. kelsey jl, whittemore as, evans as, thompson wd. methods in observational epidemiology (2nd edition) 1996. tables 1215. oxford university press. akr1c3 polymorphisms in bladder cancer-tiryakioğlu et al. urological oncology 2621 miscellaneous 208 urology journal vol 6 no 3 summer 2009 analysis of suprapubic and transrectal measurements in assessment of prostate dimensions and volume is transrectal ultrasonography really necessary for prostate measurements? eriz özden,1 çağatay göğüş,1 özcan kılıç,2 önder yaman,1 erol özdiler1 introduction: the objective of this study was to evaluate the correlation of suprapubic ultrasonography and transrectal ultrasonography in measurements of prostate dimension and volume. materials and methods: one hundred consecutive patients with lower urinary tract symptoms were examined by suprapubic and transrectal ultrasonography modalities in a same session. measurements of the 3 dimensions of the prostate (anteroposterior, transverse, and craniocaudal) and its volume performed by suprapubic ultrasonography were compared with the corresponding measurements by transrectal ultrasonography in order to determine the correlation of the measurements. prostate volumes were calculated using the ellipsoid formula. data were further analyzed in subgroups according to prostate volumes smaller or larger than 50 ml, measured by suprapubic ultrasonography. results: the mean prostate volume of the 100 patients, measured by suprapubic and transrectal ultrasonography were 65.9 ± 35.8 ml and 62.5 ± 32.0 ml, respectively (r = 0.94; p < .001). the craniocaudal diameters had the strongest correlation among dimension measurements (r = 0.89; p < .001). suprapubic and transrectal ultrasonography measurements also showed significant correlations for both prostates smaller or larger than 50 ml. eighty-five percent of the patients had both volume measurements under or above this limit. conclusion: there was strong correlation between suprapubic and transrectal ultrasonography measurements of the prostate sizes, including both for volume or specific dimension measurements. keywords: ultrasonography, organ size, prostatic, prostatic hyperplasia 1department of urology, school of medicine, ankara university, ankara, turkey 2department of urology, school of medicine, selcuk university, konya, turkey corresponding author: ozcan kilic, md şeyhşamil m. eylül s.yenikent kardelen sitesi 15/36, selcuklu, konya,turkey. tel: +90 332 223 76 55 fax: +90 332 223 61 82 e-mail: drozcankilic@yahoo.com received september 2008 accepted april 2009 introduction dimensions of the prostate are used as a preoperative criterion for deciding on the operation method like transabdominal open prostatectomy, transurethral resection (tur), and laser ablation. therefore, it is quite important to accurately assess the dimensions of the prostate in patients with benign prostate hyperplasia.(1) digital rectal examination and intravenous pyelography are inadequate for determining the prostate dimensions.(2) transrectal ultrasonography (trus) is considered superior to digital rectal examination, cystourethrography, urol j. 2009;6:208-13. www.uj.unrc.ir suprapubic and transrectal measurements of prostate—ozden et al urology journal vol 6 no 3 summer 2009 209 and urethrocystoscopy in the evaluation of prostate volume.(1,3) according to the literature, there is a strong correlation between prostate weights measured by trus and the real prostate weight in specimens excised operatively or in cadavers.(1,4,5) although it is accepted that trus is superior to suprapubic ultrasonography (spus) in the evaluation of the prostate, spus is used more commonly in the measurement of prostate dimensions.(6) the aim of our study was to determine the correlation of spus and trus measurements of prostate dimensions and volume in patients with lower urinary tract symptoms. materials and methods in this study, 100 consecutive patients presented to our clinic with lower urinary tract symptoms were evaluated. they all had serum prostatic antigen (psa) levels equal or less than 4 ng/dl and their digital rectal examination showed no abnormal sign. informed consent was obtained from all patients, and they underwent both trus and spus at a same session. the study was planned and conducted in compliance with the helsinki declaration and good clinical practice rules. ultrasonographic examinations were performed using a toshiba ssa-250 ultrasonography system (tokyo, japan). a 3.5-mhz convex probe was used for spus and a biplane transrectal probe (6-mhz end fire sector, 7-mhz linear) for trus (figures 1 to 3). measurements were performed with a full bladder, which was determined as the patient having a desire to micturate, but not with a severe discomfort. measurements were performed in the supine position during spus and in left lateral decubitis position during trus examinations. the transverse (width), craniocaudal (length) and anteroposterior (height) dimensions of the prostates were measured using both methods. the craniocaudal and anteroposterior dimensions were measured in the sagittal plane, and the transverse dimensions were measured in the transverse plane. the longest dimension from the base of the prostate to the apex was measured for the craniocaudal dimension. the longest distance between the figure 1. suprapubic ultrasonographic measurement of prostate dimensions at the transverse and sagittal planes. figure 2. transrectal ultrasonographic measurement of prostate dimensions by biplane linear probe at the sagittal plane. figure 3. transrectal ultrasonographic measurement of prostate dimensions by biplane convex probe at the transverse plane. suprapubic and transrectal measurements of prostate—ozden et al 210 urology journal vol 6 no 3 summer 2009 anterior-posterior prostate margins that crosses the trace of carniocaudal measurement at an acute angle was measured for anteroposterior dimension. the longest dimension between the right and the left lateral margins where the prostate is observed widest was measured for transverse dimension. all measurements were performed at the same session. volume of the prostate was calculated by using the ellipsoid formula (multiplication of the three measured dimensions × 0.52).(7) the three dimension and volume measurements performed by spus were compared with corresponding measurements performed by trus in order to determine the correlation of the measurements. the patients’ data were further analyzed in subgroups according to prostate volumes measured by spus as smaller and larger than 50 ml. the paired-samples t test was used to compare differences of prostate volumes in groups, and correlations were assessed using the pearson correlation coefficient. results the mean age of the patients was 66.5 years (range, 45 to 77 years) and the mean level of serum psa was 2.8 ng/ml (range, 0.6 ng/ml to 4 ng/ml). the results of measurements performed by spus and trus and correlation coefficients are summarized in table 1. the pearson correlation coefficient test showed significant correlations between spus and trus in their measurements of the three dimensions and the volume of the prostate. the strongest correlation for dimension measurements was found in the craniocaudal dimension (r = 0.89; p < .001). according to the results, volume measurements performed by spus were 5.47 ± 1.53% greater than those measured by trus (range, 1.1% to 8.3%; p = .12). table 2 outlines the mean prostate volumes in groups of patients with a prostate volume of 50 ml or less and larger than 50 ml, based on the spus results. eighty-five percent of the patients had both trus and spus volume measurements under or above this limit, while 15% had one of the spus or trus measurements under this limit while the other was above. discussion ultrasonography has become an important part of urology in prostate examination as it is noninvasive and safe. developments in the technology in the recent 20 years enabled this imaging method to be used in the diagnosis, management, and follow-up of prostatic diseases, especially benign prostate hyperplasia.(8) determination of focal lesions in the prostate and imaging of paranchymal structure can be performed by trus.(1,4,9) this modality is also considered as the best in vivo method to calculate the volume of the prostate.(7) preoperative prostate volumes are used as a criterion for choosing the operation method like transabdominal open prostatectomy or tur.(1) reliable information about prostate volume prostate parameters spus trus r p volume, ml 65.9 ± 35.9 62.5 ± 32.1 0.94 < .001 craniocaudal dimension, mm 50.1 ± 11.0 51.9 ± 9.2 0.89 < .001 anteroposterior dimension, mm 43.9 ± 8.4 40.5 ± 8.9 0.86 < .001 transverse dimension, mm 50.5 ± 8.0 50.4 ± 6.2 0.79 < .001 *values are demonstrated as mean standard ± deviation. table 1. measurements of prostate size by suprapublic ultrasonography (spus) and transrectal ultrasonography (trus) and their correlation coefficients* prostate volume number of patients spus trus r p ≤ 50 ml 41 36.9 ± 9.9 38.1 ± 10.8 0.77 < .001 >50 ml 59 85.3 ± 32.8 78.9 ± 31.3 0.90 < .001 *dividing the patients according to their prostate volumes is based on the spus results. values are demonstrated as mean standard ± deviation. table 2. measurements of prostate volume by suprapublic ultrasonography (spus) and transrectal ultrasonography (trus) in small and large prostates* suprapubic and transrectal measurements of prostate—ozden et al urology journal vol 6 no 3 summer 2009 211 is also important, as when the time required to resect the adenoma increases, the risk of hemorrhage and tur of the prostate syndrome increases with larger gland volumes and operative morbidity increases in proportion to gland size during open prostatectomy.(10-12) a strong correlation has been reported between prostate weights measured by trus and the real prostate weight in specimens excised operatively or in cadavers.(5) however, trus is discomforting, especially in patients with anal diseases such as hemorrhoid, anal fissure, and anal fistula, as well as patients with a low pain threshold. moreover, it cannot be performed in patients with abdominoperineal resection.(7) on the other hand, although spus may have pitfalls in obese patients, in patients with very full bladders or in those, who cannot fill the bladder adequately, it is a nontraumatic method, and can be easily tolerated by the patients. it has been reported that in patients with benign prostate hyperplasia, there is a strong correlation between the measurements of prostate dimension and volume measured by spus and the real prostate weight in excised specimens.(13,14) in agreement with our findings, prassopoulos and colleagues reported a strong correlation between trus and spus in the measurement of prostate volume.(7) yuen and coworkers found that transabdominal measurement of prostate volume had a good correlation with the measurements performed by trus, and thus, there was no need for the discomforting trus.(8) we showed a very strong correlation between volume measurements performed by spus and trus. the correlation coefficient of the two methods was 0.94 for volume measurement (p < .001). however, spus may slightly overestimate the prostate volume. doebler found that prostate volumes were measured higher by spus with a mean value of 12.4% than trus.(15) prassopoulos and colleagues also reported that measurements with spus were higher with a rate of 5% than trus.(7) we reached the same results with a mean of 5.47% higher values by spus in comparison with trus. prostate volume is one of the helpful factors for deciding open prostatectomy or tur of the prostate. it has been reported that the volume limit for decision of open surgery differs between 50 ml and 100 ml for the prostate according to the experience of the surgeon.(11) gurdal and associates suggested that although open prostatectomy was suitable for large prostates, its operative morbidity also increased in direct proportion to the gland size.(12) in our study, the correlation of prostate measurements performed by each method was also evaluated by accepting 50 ml as cutoff value. according to our results, measurements performed by spus and trus shows a strong correlation both for prostates smaller than 50 ml, with a correlation coefficient of 0.77 (p < .001), and for prostates larger than 50 ml, with a correlation coefficient of 0.90 (p < .001). this shows that, correlation between trus and spus becomes stronger in higher prostate volumes. taking 50 ml as a threshold, 85% of patients had both trusand spus-based volumes under this limit or both above this limit. although previous studies reported that volume estimation by ultrasonography are volume dependent, our results showed that prostate volume did not affect the correlation significantly.(16,17) kim and kim reported that larger prostates might make the dimension measurements difficult, especially because of the difficulty in determination of the caudal end of the prostate. they concluded that experienced examiners can determine the caudal end more accurately.(16) we think that the high correlation of mesaurements for both small and large prostates in our study were due to the highly experienced radiologist who performed all the examinations. kim and kim also mentioned that an overdistended bladder may distort and displace the prostate, and as far as the prostate is within the field of view on taus, additional bladder filling is not helpful.(16) in our study group, there was a standardized moderate bladder fullness which enabled us to measure dimensions without distorting or displacing the prostate. another result of this study was the strong correlation found between dimension measurements. in addition to the importance of volume measurements, specific dimension measurements also have clinical importance. doebler stated that measurement of the transverse dimension of the prostate was suprapubic and transrectal measurements of prostate—ozden et al 212 urology journal vol 6 no 3 summer 2009 important before transurethral needle ablation, and added that this measurement could be performed by spus, because there was a strong correlation between spus and trus measurements.(15) chia and coworkers used craniocaudal measurements for determining the correlation of intravesical prostatic protrusion with bladder outlet obstruction.(18) watanabe and miyagawa used height and width of the prostate in calculating a parameter as the horizontal shape of the prostate and concluded that this parameter made a reliable assessment of the degree of prostatic obstruction.(6) these articles imply that, not only prostatic volume measurements, but also specific prostate dimension measurements are helpful parameters. according to our results, there is a strong correlation between dimension measurements performed by spus or trus. although strong correlations exists between transverse dimensions (r = 0.79; p < .001) and anteroposterior dimensions (r = 0.86; p < .001) measured by trus and spus, the strongest correlation of dimension measurements was determined for craniocaudal dimension in our study (r = 0.89; p < .001). some previous studies reported lowest correlations in the craniocaudal dimensions.(19) kim and kim has described that the problem in measuring craniocaudal dimensions were based on imaging the distal tip of the prostate, and this was because of very full or inadequate bladder distension and the inexperienced examiner, as the experiened examiner could determine the caudal part of the prostate more accurately in their study.(16) in our study, the correlation for craniocaudal dimension measurements were high, because all the examinations were performed by the same experienced radiologist and all the patients had full bladders up to a degree of having a desire to micturate, but not with a severe distension. therefore, we could image the distal tip of the prostate easily both with trus and spus. our results imply that in addition to the volume measurements, specific dimension measurements can also be performed by spus instead of trus. it should also be noted that a pitfall of this study was that all measurements were made by the same radiologist, and therefore, interexaminer variability could not be studied. conclusion we observed a strong correlation between the measurements of prostate volume or dimensions performed by spus and trus for both small and large glands. thus, we believe that spus can be a reliable alternative for trus, where it is discomforting, especially in patients with anal diseases and patients with a low pain threshold or a history of abdominoperineal resection. conflict of interest none declared. references 1. hendrikx aj, doesburg wh, reintjes ag, van helvoort-van dommelen ca, hofmans pa, debruyne fm. determination of prostatic volume by ultrasonography. a useful procedure in patients with prostatism? urology. 1989;33:336-9. 2. rathaus v, richter s, nissenkorn i, goldberg e. transperineal ultrasound examination in the evaluation of prostatic size. clin radiol. 1991;44:383-5. 3. vilmann p, hancke s, strange-vognsen hh, nielsen k, sorensen sm. the reliability of transabdominal ultrasound scanning in the determination of prostatic volume. an autopsy study. scand j urol nephrol. 1987;21:5-7. 4. greene dr, egawa s, hellerstein dk, scardino pt. sonographic measurements of transition zone of prostate in men with and without benign prostatic hyperplasia. urology. 1990;36:293-9. 5. jones dr, roberts ee, griffiths gj, parkinson mc, evans kt, peeling wb. assessment of volume measurement of the prostate using per-rectal ultrasonography. br j urol. 1989;64:493-5. 6. watanabe t, miyagawa i. new simple method of transabdominal ultrasound to assess the degree of benign prostatic obstruction: size and horizontal shape of the prostate. int j urol. 2002;9:204-9. 7. prassopoulos p, charoulakis n, anezinis p, daskalopoulos g, cranidis a, gourtsoyiannis n. suprapubic versus transrectal ultrasonography in assessing the volume of the prostate and the transition zone in patients with benign prostatic hyperplasia. abdom imaging. 1996;21:75-7. 8. yuen js, ngiap jt, cheng cw, foo kt. effects of bladder volume on transabdominal ultrasound measurements of intravesical prostatic protrusion and volume. int j urol. 2002;9:225-9. 9. lee f, torp-pedersen st, siders db, littrup pj, mcleary rd. transrectal ultrasound in the diagnosis and staging of prostatic carcinoma. radiology. 1989;170:609-15. 10. amen-palma ja, arteaga rb. hemostatic technique: extracapsular prostatic adenomectomy. j urol. 2001;166:1364-7. suprapubic and transrectal measurements of prostate—ozden et al urology journal vol 6 no 3 summer 2009 213 11. mebust wk. transurethral surgery. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell’s urology. 7th ed. philadelphia: wb saunders; 1998. p. 1511-28. 12. gurdal m, tekin a, yucebas e, sengor f. nd:yag laser ablation plus transurethral resection for large prostates in high-risk patients. urology. 2003;62:914-7. 13. abu-yousef mm, narayana as. transabdominal ultrasound in the evaluation of prostate size. j clin ultrasound. 1982;10:275-8. 14. walz ph, wenderoth u, jacobi gh. suprapubic transvesical sonography of the prostate: determination of prostate size. eur urol. 1983;9:148-52. 15. doebler rw. transverse prostate measurement obtained using transabdominal ultrasound: possible role in transurethral needle ablation of the prostate. urology. 2000;55:564-7. 16. kim sh, kim sh. correlations between the various methods of estimating prostate volume: transabdominal, transrectal, and three-dimensional us. korean j radiol. 2008;9:134-9. 17. loeb s, han m, roehl ka, antenor ja, catalona wj. accuracy of prostate weight estimation by digital rectal examination versus transrectal ultrasonography. j urol. 2005;173:63-5. 18. chia sj, heng ct, chan sp, foo kt. correlation of intravesical prostatic protrusion with bladder outlet obstruction. bju int. 2003;91:371-4. 19. blanc m, sacrini a, avogadro a, et al. [prostatic volume: suprapubic versus transrectal ultrasonography in the control of benign prostatic hyperplasia]. radiol med. 1998;95:182-7. italian. urology for people 234 urology journal vol 6 no 3 summer 2009 what’s up in urology journal, summer 2009? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. the persian translation of this article is available from www.uj.unrc.ir. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2009;6:234-5. www.uj.unrc.ir laparoscopic sugery for varicocele: a better choice? varicocele is an enlargement of veins that go through the groins to the testes in men. a painful mass called “bag of worms” appears in the groins. men with this problem are usually young and if do not seek treatment, they may face infertility in the future. dr shamsa and his colleagues in mashhad compared the advanced technique of laparoscopy with the conventional surgical methods for treatment of varicocele. in laparoscopy, small incisions are made and instruments, instead of the hands of the surgeon will go into the operation site. they found that using laparoscopy, the operation took around 30 minutes to perform, similar to the conventional surgeries. they also reported that complications with laparoscopy are somewhat more frequent. however, dr simforoosh a comment on the article by dr shamsa and colleagues, referring them to his similar article in which he found laparoscopy faster and with fewer complications. so, men with varicocele can consult with their doctors if they need surgical treatment to choose one of these options: laparoscopy, open surgery with general anesthesia, and open surgery with local anesthesia. each of these has their own advantages and risks, and each surgeon may prefer one of these based on their own unique experience. however, it is a minor and safe surgery with trivial risks, and the patients should not worry about choosing the surgical options. see page 170 for full-text article what happens to the othr kidney if you donate one? many people may ask whether loosing one kidney is a great danger to their life. today, scientists have proved that the answer is no, but they say it with care! a person with one kidney can have a normal life. that is why donating a kidney was ethically accepted among doctors. however, we cannot deny that one with only one kidney should be more careful about the remnant kidney that takes all the responsibility of the refinement of blood! dr bohlouli and his kidney transplant team followed kidney donors after transplantation to see what happens in the other kidney. they showed that within 3 months, the kidney enlarged and its blood circulation increased. this happens as a compensation for loosing the peer one the other side of the body. they also showed that function of the kidney was slightly impaired after 1 week, but it returned to its normal range after 3 months. therefore, a donor will have an almost normal kidney function. although the transplant teams believe that donation of a kidney is usually done safely, they always remind the potential donor that donation has its own risks of undergoing a major surgery, and that in the long-term, the donor may be a little more at risk of kidney problems. to date, research has shown that this risk is not considerable. but anyway, care should be taken to guarantee a normal life for the donor. see page 194 for full-text article urology for people urology journal vol 6 no 3 summer 2009 235 avicenna and his description of the prostate the canon of medicine of avicenna, the iranian scientist, is still a scientifically interesting book for dr madineh. he continued reviewing avicenna’s notes on the lower urinary tract diseases in the fourth part of his article series on history of medicine. avicenna explains the mechanism of a normal voiding and causes of an abnormal voiding. his description of the physiology and disease of the prostate is an interesting part of his book. avicenna also tries to explain what roles may be played by the secretions from the prostate in men, and points out an anti-infection concept which is still a matter of research in the contemporary medicine. for those who are interested in the golden era of science and medicine in the islamic world, the articles by dr madineh can be a reliable and valuable resource. see page 228 for full-text article vol 15 no 06 november-december 2018 400 case report spontaneous rupture of renal cell carcinoma in pregnancy, surgical management with fetal preservation:a case report abbas hassanpour1, faisal ahmed1*, babak shirazi yeganeh2, bahia namavar jahromi3, alireza makarem1 keywords: nephrectomy; pregnancy; renal cell carcinoma spontaneous retroperitoneal hemorrhage in pregnancy is a rare condition. renal angiomyolipoma (ra) is the most common cause of this hemorrhage. to the best of our knowledge, this is the first reported case of wunderlich syndrome (ws) due to renal cell carcinoma (rcc) diagnosed in the second trimester of pregnancy. introduction wunderlich syndrome with spontaneous non-traumatic retroperitoneal hemorrhage in pregnancy is a rare condition which is clinically characterized by lenk’s triadas, acute flank pain, flank mass, and hypovolemic shock.(1) the incidence of cancer during pregnancy is rare and occurs in approximately 1:1000 pregnancies.(2) the most common urological cancer during pregnancy is rcc.(3) spontaneous rupture of the kidney is very rare as the first presentation of rcc and to the best of our knowledge this is the first report.(4) we report a case of spontaneous rupture of the renal tumor in pregnancy with retroperitoneal hemorrhage and hypovolemic shock as the first manifestation of rcc that was treated by nephrectomy . case report a 20 year old woman in the 20th week of pregnancy (gravid 1, para1) referred to our center with severe generalized abdominal pain and flank pain. she described a history of 8 hours of severe, constant pain with sudden onset and radiation to the right flank that progressively aggravated. she did not have any predisposing factors or history 1department of urology, shiraz university of medical sciences, shiraz, iran. 2department of pathology, shiraz university of medical sciences, shiraz, iran. 3department of obstetrics and gynecology, shiraz university of medical sciences, shiraz, iran. *correspondence: department of urology, shiraz university of medical sciences, shiraz, iran. tel: 00987132326645. fax: 00987132326645. email: fmaaa2006@yahoo.com. received november 2017 & accepted february 2018 figure 1. ultrasound showed a 136*48 mm heterogeneous collection. figure 2. kidney with site of rupture at upper pole(arrow). of trauma, did not have previous medical disease, did not take any medication and was non-smoker. she was referred to our center in a shock state. bp: 80/55, pr: 110, rr: 18; also, she was febrile (oral temperature: 38.5c) blood investigation such as (complete blood cell, electrolyte profile, liver function test and coagulation screen) was done, showing only a drop in the serum hemoglobulin from 6.6 g/dl to 5.5 g/dl after just one hour with a decrease in the concentration of hematocrit level from 33.5% to 21.7%. urine sediment showed many rbc and 12-4 wbc with little bacteruria. resuscitation with intravenous fluid and 3 units of crossed match packed cell was done immediately. abdominal ultrasound showed a 136*48 mm heterogeneous collection in the anterior right pararenal space (figure 1). spontaneous rupture of the renal artery aneurysm and rupture of a renal mass were at the top of differential diagnoses. written informed consent was taken before the operation and the patient was transferred to or within 4 hours after admission. midline abdominal incision was done and after mobilization of the right colon and duodenum, a large hematoma was evacuated and the right kidney was exposed. a large renal mass between the mid to upper pole was seen; also, significant fresh bleeding was seen through the ruptured site of the mass, so due to hemodynamic instability, early clamping of the pedicle was done and simple nephrectomy performed. it should be considered that radical nephrectomy was not done due to the possibility of renal angiomyolipoma. the patient was admitted in the intensive care unit for close observation. the patient did well post-operatively and was discharged one week later. the pathology report revealed a 14x6x3.5 cm, which was slightly distorted with an area of rupture at the upper pole (figure 2 arrow). the cut section of the organ revealed a well-defined ovoid mass with variegated cut surface. microscopic examination of the tumor showed sheets of cells with moderate amounts of clear to eosinophilic cytoplasm and nuclei with nucleoli visible at 100x magnification, as well as areas in those tumor cells which became spindle shape (figures 3, 4). operative time was 1.5 hours and total transfusion was 5 crossed match red packed cell and 3 platelet. discussion wunderlich syndrome is a rare clinical disorder with spontaneous non-traumatic kidney rupture, significant retroperitoneal hemorrhage with sudden onset or flank pain, palpable flank mass, and hypovolemic shock with or without hematuria.(1,5) the first description of these symptoms was in 1856 by a german physician called carl reinhold august wunderlich.(1) the etiology of wunderlich syndrome may be neoplastic, as the most common cause (angiomyolipoma, rcc), or non-neoplastic, such as vascular causes (renal artery aneurysms, av malformations, renal vein thrombosis), cystic renal diseases, calculus diseases, nephritis, and coagulation disorders.(6) the current management options range from observation and minimally invasive measures, such as embolization, radiofrequency ablation, and cryoablation to partial or radical nephrectomy.(7) there is no a guideline in favor of either approach. the choice of the management method is influenced by the patient’s condition, availability, expertise, and surgeon judgment. maternal safety should always be a priority although management should be performed based on the patient’s wish regarding having a child. the management should be based on hemodynamic status, week of gestation, requirement of blood transfusion and association with tuberous sclerosis.(8) the patient in our study was hemodynamically unstable; huge hematoma and renal mass was observed during the operation, so nephrectomy was necessary to save her life. the safe radiological modality in pregnant women is ultrasonography with no teratogenicity or carcinogenesis.(9) ionizing radiation from the ct scan results in increased risk of cancer in the mother and fetus. it results in teratogenic effect as to the fetus at high up to 15 weeks post-conception.(10) however, in our case due to severe hemodynamic instability and unsuccessful aggressive intravenous hydration and progressive drop of hemoglobin, it was not possible to proceed for angioembolization, or even extend the diagnostics to mri or ct scan and the patient was indicated for urgent operative exploration. rcc in pregnancy-hassanpour et al. figure 3. clear cells and areas of sarcomatoid feature (h&e original magnification x40) figure 4. transitional areas between clear cells and spindle shape ones. (h&e original magnification x100) case report 401 vol 15 no 06 november-december 2018 402 acknowledgements the authors would like to thank shiraz university of medical sciences, shiraz, iran and also center for development of clinical research of nemazee hospital and dr. nasrin shokrpour for editorial assistance. conflict of interest the authors have no conflict of interest declare. references 1. katabathina vs, katre r, prasad sr, surabhi vr, shanbhogue ak, sunnapwar a. wunderlich syndrome: cross-sectional imaging review. j comput assist tomogr. 2011; 35: 425-33. 2. pavlidis n. cancer and pregnancy: what should we know about the management with systemic treatment of pregnant women with cancer? european j cancer. 2011; 47: s348-s52. 3. martin fm, rowland rg. urologic malignancies in pregnancy. urol clin north am. 2007; 34: 53-9. 4. kim jw, chae jy, yoon cy, oh mm, park hs, moon du g. wunderlich syndrome as the first manifestation of an extraskeletal ewing sarcoma. can urol assoc j. 2015; 9: e648-50. 5. phillips ck, lepor h. spontaneous retroperitoneal hemorrhage caused by segmental arterial mediolysis. rev urol. 2006; 8: 36-40. 6. zhang jq, fielding jr, zou kh. etiology of spontaneous perirenal hemorrhage: a metaanalysis. j urol. 2002; 167: 1593-6. 7. flum as, hamoui n, said ma et al. update on the diagnosis and management of renal angiomyolipoma. j urol. 2016; 195: 834-46. 8. zapardiel i, delafuente-valero j, bajo-arenas jm. renal angiomyolipoma during pregnancy: review of the literature. gynecol obstet invest. 2011; 72: 217-9. 9. boussios s, pavlidis n. renal cell carcinoma in pregnancy: a rare coexistence. clin transl oncol. 2014; 16: 122-7. 10. sadro ct, dubinsky tj. ct in pregnancy: risks and benefits. appl radiol. 2013; 42: 6-16. rcc in pregnancy-hassanpour et al. miscellaneous comparing monotherapy with tadalafil or tamsulosin and their combination therapy in men with benign prostatic hyperplasia: a randomized clinical trial hossein karami*, amin hassanzadeh-hadad, morteza fallah-karkan purpose: to compare monotherapy with tadalafil or tamsulosin and their combination therapy in men with benign prostatic hyperplasia and erectile dysfunction by comparing ipss score, prostate volume and qmax and some other outcomes. materials and methods: this randomized, single-blind, paralleled group clinical trial was done in 2013 on patients who had referred to our hospital in tehran. all patients with lower urinary tract symptoms, benign prostatic hyperplasia and any grade of erectile dysfunction were recruited. they were randomly divided into three groups (61 participants in each group): group a received 20 mg/daily tadalafil; group b received 0.4 mg/daily tamsulosin; group c receieved a combination of 0.4 mg/daily tamsulosin and 20 mg/daily tadalafil. primary outcomes were prostate volume, prostate specific antigen, post-void residual volume, ipss score, luts severity, qmax, iief and erectile dysfunction severity and secondary outcome was complications. results: the mean ± sd of ultrasonographic prostate volume was 61.4 ± 15.1 ml and prostate specific antigen level was 2.4 ± 1.9 ng/dl. post-void residual level was significantly different before and after the treatment, except for group a. also, this group had no meaningful difference compared to the other groups in this regard (p > 0.05). there were significant differences between preand post-treatment international prostate symptom scores in each group (p < 0.05). conclusion: combination of tamsulosin and tadalafil can improve international prostate symptom scores, international index of erectile function questionnaire scores and qmax in patients with lower urinary tract symptoms and benign prostatic hyperplasia to more degrees than their separate use. this combination is recommended because of its synergistic effects, well toleration and safety. keywords: benign prostate hyperplasia; erectile dysfunction; tadalafil; tamsulosin introduction a major difficulty in comparing the prevalence of lower urinary tract symptoms (luts) among different groups is lack of a common definition. luts because of benign prostate hyperplasia (bph-luts) often interferes with patients’ daily activities. many men with benign prostate hyperplasia luts seek treatment to improve their quality of life. research on luts in men has traditionally focused on the development and testing of treatments for progressive disease.(1) benign prostate hyperplasia is a histological diagnosis which is identified by nonmalignant hyperplasia of prostatic tissue due to smooth muscle and epithelial cell proliferation in the prostate transition zone.(2) the prevalence of histologically diagnosed prostatic hyperplasia increases from 8% in men aged 31 to 40 years old to 40-50% in men aged 51 to 60 years old. this increases to over 80% in men older than 80 years old.(3) benign prostate hyperplasia can result in prostate enlargement. this leads to the development of luts such as storage, voiding and post-micturition symptoms. an increased smooth muscle tone in the prostate or the vasculature supporting the lower urinary laser application in medical sciences research center, shohadaye tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: laser application in medical sciences research center, shohadaye tajrish hospital, tajrish sq, tehran, iran postal code: 1989934148 tel: +98 21 22736386. fax: +98 21 22736386. mobile: +98 912 1142080. email: karami_hosein@yahoo.com. received august 2016 & accepted november 2016 tract may play a contributing role.(4) luts has no common definition. a large population-based study found the prevalence of moderate or severe luts for men in the fifth, sixth, seventh, and eighth decades of life to be 26%, 33%, 41%, and 46%, respectively.(5) bph-luts are common in aging men worldwide.(6) given that bph-luts often interferes with daily activities,(7) many men with bph-luts seek treatment to improve their quality of life.(8) when pharmacological treatment is required, the most common drugs are a-blockers and 5-alpha reductase inhibitors (5aris). the five extensively available alpha-blockers are doxazosin, terazosin, tamsulosin, alfuzosin and silodosin, the last one being the only one that is a1a adrenoreceptor specific. as for 5aris, two drugs are available, finasteride and dutasteride. in addition, combining these two classes of drugs has been shown to be more effective in bph-luts than using each separately.(9) tadalafil's mechanism as a long-acting phosphodiesterase 5 (pde5) inhibitor in the treatment of men with bph-luts is associated with increased activity of the nitric oxide/cgmp (cyclic guanosine monophosphate)/ miscellaneous 2920 table 1. demographics of the participants characteristics group a group b group c p value number of participants 60 59 58 age, years (mean ± sd) 68.2 ± 7.8 68.5±8.9 67.9 ± 8.8 .90 bmi, kg/m2 (mean± sd) 27.4 ± 1.2 26.7±2.4 27.1 ± 2.3 .17 psa, ng/ml (mean ± sd) before 2.5±1.8 2.3±1.9 2.1±1.6 0.58 3 month follow-up 2.5±1.7 2.2 ± 2.0 2.1±1.5 0.37 p value ns ns ns change 0.0 ± 0.1 0.0 ± 0.3 0.0 ± 0.2 ns pvr, ml (mean ± sd) before 61.6 ± 63.3 57.2±59.7 58.6 ± 60.2 0.74 3 month follow-up 49.8 ± 25.9 38.9±21.6 35.4 ± 20.9 0.06 p value 0.06 0.0009 0.0001 change -11.9 ± 37.1 -19.1±36.2 -23.4 ± 40.1 0.32 ipss total (mean ± sd) before 19.9 ± 6.3 20.6±7.3 21.2 ± 7.5 0.52 3 month follow-up 11.4 ±3.6 10.6±3.5 10.1 ± 3.2 0.22 p value 0.0001 0.0001 0.0001 change -8.6 ± 2.8 -10.1 ± 3.9 -11.1 ± 4.4 0.01 ipss storage (mean ± sd) before 5.8 ± 2.1 6.5 ± 2.7 6.6 ± 3.2 0.36 3 month follow-up 3.7 ± 1.9 3.6 ± 1.8 3.4 ± 2.1 0.54 p value 0.0001 0.0001 0.0001 change -2.1±1.2 -2.9 ± 1.1 -3.3 ± 1.0 0.0004 ipss voiding (mean ± sd) before 14.6 ± 4.0 14.2 ± 4.5 14.9 ± 4.1 0.49 3 month follow-up 7.6 ± 2.5 7.1 ± 1.7 6.9±1.5 0.18 p value 0.0001 0.0001 0.0001 change -7.1 ± 1.3 -7.1± 2.7 8.0±2.5 0.03 qmax, ml/s (mean±sd) before 12.6 ± 5.4 12.3 ± 3.8 12.4 ± 4.8 0.78 3 month follow-up 13.9 ± 4.4 15.6 ± 3.1 15.9 ± 2.1 0.001 p value 0.06 0.0001 0.0001 change 1.5 ± 1.5 3.3 ± 2.1 3.5±2.7 0.0002 iief (mean ± sd) before 10.1 ± 1.8 10.9 ± 1.6 10.6 ± 1.7 0.09 3 month follow-up 17.7 ± 2.3 12.1± 5.1 17.2 ± 3.2 0.0001 p value 0.0001 0.06 0.0001 change 7.8 ± 1.7 4.6 ± 2.1 7.6 ± 1.9 0.0001 table 3. comparison of functional tests and their changes before treatment and in follow up sessions in the three studied groups tadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. vol 13 no 06 november-december 2016 2921 protein kinase g pathway via pde5 isoenzymes’ inhibition in different lower urinary tract tissues. these results can be detected in smooth muscle relaxation in the bladder, urethra, prostate, and supporting vasculature, increased blood perfusion to the pelvic area, and finally modulation of sensory stimuli from this area.(10-12) epidemiological and pathophysiological links have been found between bph-luts and erectile dysfunction.(7,10) although the current medical therapy for bphluts is effective, it has potential side-effects on sexual function.(13) moreover, pde5i increases the concentration and activity of intracellular cgmp, thus reducing smooth muscle tone of the detrusor, prostate and urethra.(14) it is believed that these mechanisms may help to treat bph-luts. this clinical trial has compared monotherapy with tadalafil or tamsulosin and their combination therapy by comparing ipss score, luts severity, iief score and some other measurements in men with benign prostatic hyperplasia and erectile dysfunction. materials and methods this randomised, single-blind, paralleled group clinical trial was done in 2013 on patients who had referred to the urology clinic of shohadaye tajrish hospital in tehran. all patients with luts, benign prostate hyperplasia and any grade of erectile dysfunction were recruited for this study. inclusion and exclusion criteria we assessed patients with these inclusion criteria: men older than 45 years old, international prostate symptom score (ipss) ≥ 12, and having a history of erectile dysfunction. patients with previous benign prostate hyperplasia or erectile dysfunction treatment, history of surgical procedure for their prostatic problem, contraindication for tadalafil (i.e. nitrate consumption) or tamsulosin (i.e. allergic reactions), bladder stone, history of urinary retention, active urinary tract infection, prostate cancer, post-void residual urine test > 200 ml, kidney failure, liver insuficiency, history of pelvic radiation, urethral stricture, ureteral stone in past six months before entering the study, overt hematuria, consumption of finastridie, anti-depressent drugs and beta-adrenergic blockers and history of substance addiction were excluded from the study. randomization a number of 200 patients with luts were candidates to particpate in this study. seventeen patients were excluded for not having the inclusion criteria and not consenting to participate. so, 183 participants were randomly divided into three groups with a sample randomization chart (61 participants in each group): group a received 20 mg/daily tadalafil; group b received 0.4 mg/daily tamsulosin; group c receieved a combination of 0.4 mg/daily tamsulosin and 20 mg/daily tadalafil. two patients of group b, one of group a and three of group c were lost in the follow-up process because of discontining their drugs. so, 59 participants in group b, 60 participants in group a and 58 participants in group c were evaluated until the end of follow-up. (figure 1) the participants’ medical history and drug use were taken at the fisrt visit. then complete systemic and rectal examination of prostate was done. laboratary blood samples were taken to measure blood urea nitrogen, creatinine and prostate specific antigen. urine analysis was done as well. ultrasound of kidneys and bladder including determining residual urine volume and uroflometric test were done for each patients. we also completed the ipss and international index of erectile function (iief) questionnaire for the participants. we repeated these assessments three months after the first visit and compared the three study groups’ ipss, qmax and post-void residual results. statistical analysis the data analysis was performed with the statistical package for social sciences (spss) software version 19 (chicago, il, usa). descriptive statistics (mean ± standard deviation) and student t-test were used show and analyze the quantitative outcomes. the qualitative data were presented with frequency and percentage and their analysis was done with chi-square test and fisher’s exact test. correlational analysis was done by pearson or spearman correlation coefficients. we used one-way anova test for comparison of indexes between groups. p-value less than 0.05 was considered significant. ethics all participants signed an informed consent and benefits and complications were explained to them before entering the study. the study protocol was approved by ethics committee of shahid beheshti university of medical sciences. results the participants’ mean age was 68.40 ± 8.80 years and the mean time of symptoms’ existence was 4.8 ± 12.6 months. the mean ± sd of body mass index mean was table 4. drug complications in the three studied groups complications group a group b group c total myalgia, n (%) 3 (5) 0 (0) 4 (6.7) 7 (3.9) headache, n (%) 3 (5) 1 (1.6) 3 (5) 7 (3.9) back pain, n (%) 4 (6.6) 1 (1.6) 3 (5) 8 (4.5) nasopharyngitis, n (%) 2 (3.3) 1 (1.6) 3 (5) 6 (3.3) dizziness, n (%) 1 (1.6) 2 (3.3) 2 (3.3) 5 (2.8) discontinuation because of an ae, n (%) 1 (1.6) 2 (3.3) 3 (5) 7 (3.9) total, n (%) 14 (23.3) 7 (11.8) 18 (31.03) 39 (22.03) tadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. miscellaneous 2922 27.1 ± 2.3 kg/m2. (table 1) the mean±sd of ultrasonographic prostate volume was 61.4 ± 15.1 ml and prostate specific antigen level was 2.4 ± 1.9 ng/dl. the mean of prostate functional scores were 59.4 ± 61.3 for post-void residual level based on trans-abdominal ultrasound, 12.5 ± 4.8 for qmax and 20.6 ± 7.8 for ipss in all patients. 137 participants had moderate and 40 participants had severe ipss scores. mild, moderate and severe erectile dysfunctions were seen in 52, 96 and 29 participants, respectively (table 2). there were no significant differences between prostate volume, prostate specific antigen, post-void residual volume, ipss score (also in its three components; voiding, storage, quality of life indexes), luts severity, qmax, iief and erectile dysfunction severity between the three groups (p > 0.05). there was no significant difference in prostate specific antigen before and after the treatment in all groups and between them (p > 0.05). post-void residual level was significantly different before and after the treatment, except for group a. also, this group had no meaningful difference compared to the other groups in this regard (p > 0.05). there were significant differences between preand post-treatment ipss in each group (p < 0.05) (table 3). complications the most frequent complications in all of participants were back pain (4.5%) and myalgia, headache and discontinuation because of adverse side-effects (3.9% for each). despite of higher complication rate in group c, there was no significant difference between the three groups in this regard (table 4). discussion both erectile dysfunction and bph-luts are common in men and their prevalence increases with aging.(15-17) several studies have studied the efficacy of monotherapy with tadalafil(8,18-23) and tamsulosin.(24-26) also, there are studies on their combination with other drugs or comparing them with each other. (27-29) however, to our knowledge no study has evaluated the effect of each of these drugs with their combination. also, there was no study with these drugs in an iranian population. in our study we found out that increase of weight is a risk factor for benign prostate hyperplasia. the mean of body mass index was 27.1 ± 2.3 kg/m2 in our study. our analyses explored the relationships between total ipss and storage and voiding sub-scores of the ipss, before the treatment and at the end of follow up (after 3 months). these relationships have not been studied in detail before. it is now well recognized that storage luts are the most troublesome for symptomatic patients. however, algorithms for the management of patients with predominantly storage luts or predominantly voiding luts offer generic guidance to clinicians with respect to the relative proportions of storage to voiding luts and their severity. this reflects the lack of published information on this subject. we can emphasize the importance of our analysis, which offers reassurance that the ipss storage and voiding sub-scores maintain a tight, fixed ratio to each other similar to chapple and colleagues’ results.(12) however, we did new comparisons of our three groups unlike them. although this could be predicted from the ipss design and by bearing in mind that only three of the seven questions in the ipss consider storage symptoms, it is important to emphasize that separate analysis of ipss storage and voiding sub-scores is not validated. (30) in other monotherapy studies with these drugs, the ipss results are in line with our results. double-blind, randomized, placebo-controlled studies of 5 mg tadalafil once-daily in japanese men,(19) japanese, korean and taiwanese men,(8) and japanese and korean men(20) has demonstrated greater improvement in the change from baseline to endpoint in total ipss for monotherapy with 5 mg tadalafil compared to placebo. these improvements were significantly greater in two of these studies (p < 0.05),(8,20) whereas in the third study(19) the magnitude of symptom improvement (ipss) was only greater numerically (p = 0.062). although these results are consistent with our outcomes, ipss improvement in our study was greater and this is related to combination therapy of tadalafil/α-blocker treatment. still, there is no large, double-blind, placebo-controlled study on the efficacy of tadalafil/α-blocker combination therapy. there are just several small sampled clinfigure 1: flow chart of study design; group a: patients received only tadalafil, group b: patients received only tamsulosin, group c: patients received both tadalafil and tamsulosin tadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. vol 13 no 06 november-december 2016 2923 ical trials that have reported tadalafil/α-blocker combination therapy may have better effect on total ipss than α-blocker(28,29,31) or tadalafil monotherapies(29,32) in men with bph-luts. however, these studies either had a small number of participants, involved tadalafil dosages > 5 mg once-daily, or were not placebo controlled. in our clinical trial, we have corrected these issues. so, based on our findings combination therapy could better improve ipss score in patients with bph-luts and is recommended for them because of its synergistic effects. this can be concluded from the results of our single groups in comparison with combined therapy that showed improvement in ipss score in both single groups separately and more ipss score in combined therapy group rather than each of them. our results showed that although qmax was significantly improved in the three studied groups, its improvement was greater in the combination therapy group than the other groups. we also showed that postvoid residual level was significantly different before and after treatment in each group, but there was no meaningful difference between the three groups (p > 0.05). other studies have also demonstrated the same greater improvements in qmax index with 5 mg tadalafil compared with placebo in men with bph-luts. the improvements at 12 weeks were maintained for 42 weeks, demonstrating the long-term efficacy of 5 mg tadalafil.(2,8,12,19,21,23,32) singh and colleagues showed that a significant increase in qmax and decrease in postvoid residual level were observed in combination therapy (33.99%, p < 0.05; 29.78%, p < 0.05; and 37.04%, p < 0.05) and monotherapy with tadalafil (-60.90%, p < 0.05; -49.45%, p < 0.05; and -62.97%, p < 0.05, respectively).(32) the complications of combination therapy in our study were myalgia, headache, back pain, nasopharyngitis, dizziness and discontinuation because of adverse effects. although the complication rate was higher in combination therapy group compared to monotherapy groups, it was not significant. in singh and colleagues study the side effects of combination therapy were dyspepsia, heartburn, headache, flushing, myalgia, and backache and adverse effect dropout and no participant experienced any severe or serious adverse events.(32) other randomized, controlled studies such as bechara and colleagues, liguori and colleagues, goldfischer and colleagues and kim and colleagues(21,28,29,32,33) have investigated the safety and tolerability of 5 mg tadalafil once-daily in three months as a treatment for bphluts in men, and had a safety profile consistent with the known safety profile of tadalafil as per the current package insert for 5 mg to 20 mg tadalafil as needed for erectile dysfunction.(8) integrated analysis of safety data from these studies demonstrated that the most common treatment-emergent adverse events were nasopharyngitis, dyspepsia and headache and few participants experienced serious adverse events.(21,28,29,33) the safety of 5 mg tadalafil in combination with α-blockers (alfuzosin, silodosin, tamsulosin, doxazosin or terazosin) was investigated in a double-blind, randomized, placebo-controlled trial on men with bph-luts in the united states (tadalafil/α-blocker, n = 158; placebo, n = 160).(33) this study was not designed to assess efficacy. no new safety concerns were identified for tadalafil/α-blocker combination therapy in this study. furthermore, the proportion of participants reporting treatment-emergent dizziness or with a positive orthostatic test was similar between the tadalafil/α-blocker combination therapy group and the placebo/α-blocker combination therapy group.(33) so, it can be concluded that the safety of combination therapy is nearly good and its short-term outcomes should be considered for patients and told to them. however, these complications are not serious and threatening. we investigated the iief score and showed that there were significant improvements in each group and between the groups in this regard. these improvements were higher in tamsulosin and combination groups, respectively. similarly, singh and colleagues showed that iief score increases significantly in the same three groups (+39.28%, p < 0.05; +45.96%, p < 0.05; and +60.23%, p < 0.05, respectively).(32) in another study bechara and colleagues showed that the iief improved in tamsulosin plus tadalafil group (p < 0.001), but not in tamsulosin alone group (p > 0.05).(28) based on these results, combination therapy with tadalafil and tamsulosin is recommended because of its good outcomes in erectile dysfunction. the limitation of this study was that some patients lost the follow ups and excluded from study and study period prolonged. conclusion combination therapy can better improve the ipss score, iief score and qmax in patients with bph-luts than monotherapy with tamsulosin or tadalafil. it is recommended because of its synergistic effects, well toleration and its safety. although we designed this study to investigate the previous studies' problems, large-scale, multi-centered, randomized, placebo-controlled studies are needed to further assess the long-term safety and effectiveness of these agents in treating bph-luts and erectile dysfunction. acknowledgements this study was funded by laser application in medical sciences research center, shahid beheshti university of medical sciences. the authors would like to thank seyed muhammed hussein mousavinasab for his sincere cooperation in editing this text. conflict of interests none declared. references 1. platz ea, joshu ce, mondul am, peskoe sb, willett wc, giovannucci e. incidence and progression of lower urinary tract symptoms in a large prospective cohort of us 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sexton cc, thompson cl, et al. the prevalence of lower urinary tract symptoms (luts) in the usa, the uk and sweden: results from the epidemiology of luts (epiluts) study. bju int. 2009;104:352-60. 16. coyne ks, sexton cc, bell ja, et al. the prevalence of lower urinary tract symptoms (luts) and overactive bladder (oab) by racial/ethnic group and age: results from oabpoll. neurourol urodyn. 2013;32:230-7. 17. platz ea, joshu ce, mondul am, peskoe sb, willett wc, giovannucci e. incidence and progression of lower urinary tract symptoms in a large prospective cohort of united states men. j urol. 2012;188:496-501. 18. oelke m, giuliano f, mirone v, xu l, cox d, viktrup l. monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. eur urol. 2012;61:917-25. 19. takeda m, nishizawa o, imaoka t, morisaki y, viktrup l. tadalafil for the treatment 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prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. j sex med. 2012;9:271-81. 23. donatucci cf, brock gb, goldfischer er, et al. tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. bju int. 2011;107:1110-6. 24. schulman cc, lock tm, buzelin jm, boeminghaus f, stephenson tp, talja m. long-term use of tamsulosin to treat lower urinary tract symptoms/benign prostatic hyperplasia. j urol. 2001;166:1358-63. 25. lyseng-williamson ka, jarvis b, wagstaff aj. vol 13 no 06 november-december 2016 2925 tamsulosin: an update of its role in the management of lower urinary tract symptoms. drugs. 2002;62:135-67. 26. nordling j. efficacy and safety of two doses (10 and 15 mg) of alfuzosin or tamsulosin (0.4 mg) once daily for treating symptomatic benign prostatic hyperplasia. bju int. 2005;95:100612. 27. gong m, dong w, huang g, et al. tamsulosin combined with solifenacin versus tamsulosin monotherapy for male lower urinary tract symptoms: a meta-analysis. curr med res opin. 2015;31:1781-92. 28. bechara a, romano s, casabe a, et al. comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of luts/bph. pilot study. j sex med. 2008;5:2170-8. 29. liguori g, trombetta c, de giorgi g, et al. efficacy and safety of combined oral therapy with tadalafil and alfuzosin: an integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. preliminary report. j sex med. 2009;6:544-52. 30. giuliano f, uckert s, maggi m, birder l, kissel j, viktrup l. the mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. eur urol. 2013;63:506-16. 31. kara ö, yazici m. is the double dose alphablocker treatment superior than the single dose in the management of patients suffering from acute urinary retention caused by benign prostatic hyperplasia? urology journal. 2014;11:1673. 32. singh dv, mete uk, mandal ak, singh sk. a comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. j sex med. 2014;11:187-96. 33. goldfischer e, kowalczyk jj, clark wr, et al. hemodynamic effects of once-daily tadalafil in men with signs and symptoms of benign prostatic hyperplasia on concomitant alpha1-adrenergic antagonist therapy: results of a multicenter randomized, doubleblind, placebo-controlled trial. urology. 2012;79:875-82. tadalafil, tamsulosin or both in prostatic hyperplasia-karami et al. miscellaneous 2926 vol 15 no 05 september-october 2018 231 endourology and stone disease assessment of cross-correlations between selected macromolecules in urine of children with idiopathic hypercalciuria. katarzyna jobs1, anna jung1, sławomir lewicki2*, piotr murawski3, leszek pączek4, robert zdanowski2 purpose: the aim of the study was assessment of four selected macromolecules level: osteopontin, calgranulin, uromodulin and bikunin in fresh morning urine sample in children with nephrolithiasis in the course of idiopathic hypercalciuria. materials and methods: the study included 90 subjects aged from 12 months to 18 years. the study group comprised 57 subjectschildren with urinary tract lithiasis in the course of idiopathic hypercalciuria and the control group 33 healthy children with no history of urolithiasis. determinations of osteopontin, calgranulin, uromodulin and bikunin levels in the first morning urine were performed. results: the study group had a significantly decreased osteopontin excretion and significantly increased bikunin excretion, and increased, however statistically nonsignificant, calgranulin excretion in comparison with the control group. uromodulin excretion did not differ between groups. in both groups a statistically significant positive correlation was observed between uromodulin and bikunin levels. conclusion: children with urinary tract lithiasis in the course of idiopathic hypercalciuria reveal a different distribution of the study proteins than a healthy population. keywords: idiopathic hypercalciuria; urolithiasis; inhibitor proteins; osteopontin; bikunin. introduction urinary tract lithiasis is one of the oldest and most common diseases(1, 2). its incidence in developed societies is increasing together with development of civilization, changes in lifestyle, diet rich in protein and perhaps global warming. it is estimated that for the life expectancy of 70 years, this pathology may in certain communities affect even 15% of the population(3). renal stones develop at every latitude independently of age, sex or ethnic group(2). in europe, about 2% of children are affected with urinary tract lithiasis(4,5). in recent years, we have observed an increase in the disease incidence in this group of patients. there are also reports of a growing incidence among infants(6). the disease is usually recurrent, which means that treatment and prevention concerns virtually the whole life of the affected subject. it is estimated that there is about 80% (between 50 and 100%, depending on the type of stone) chance of recurrence in untreated patients and 10-15% in patients undergoing treatment followed by further prevention(7). lithiasis, especially in the course of idiopathic hypercalciuria, may also be associated with reduced bone density(8). in more than 70% of cases, there are factors predisposing for development of this disease(9). in paediatric populations, metabolic 1military institute of medicine, clinic of paediatrics, nephrology and paediatric allergology, warsaw, poland. 2military institute of hygiene and epidemiology, department of regenerative medicine and cell biology, warsaw, poland. 3military institute of medicine, department of information and communications technologies, warsaw, poland. 4medical university of warsaw, transplantology institute, clinic of immunology, transplantology and internal diseases, warsaw, poland. *correspondence: department of regenerative medicine and cell biology, military institute of hygiene and epidemiology, warsaw, poland. tel: +48 261 816 108. fax: +48 261-816-141. e-mail: lewickis@gmail.com. received april 2017 & accepted december 2017 disturbances leading to development of stones and the risk of recurrence do not seem to be age-dependent(10). the most important and simplest imaging study in the diagnosis of kidney stone disease is ultrasonography. it is a highly sensitive test in the hands of a skilled ultrasonographer. it allows to visualize stones 2-3mm in diameter. a typical stone is seen as a hyperechogenic structure with posterior acoustic shadow and twinkle artefact in color doppler ultrasound. the most common type of lithiasis, equally in adults and children, is calcium oxalate lithiasis in the course of idiopathic hypercalciuria, which accounts for 7080% of renal stones(1). the term ‘idiopathic hypercalciuria’ is in use from 1953 when this definition was proposed by albright to describe the association of elevated urinary calcium excretion with a normal serum calcium level in patients with calcium containing renal stones(11). although the disease has existed for a long time and is widespread, its pathophysiology remains unknown. there are many factors that contribute to deposit formation. on one hand, there are environmental factors. on the other hand, there are genetic factors, metabolic disorders, infections, defects in renal and urinary structure, undernutrition and drugs administered for other concomitant diseases(12,13). it is also common knowledge that high body mass index in adults is related with a higher risk of lithiasis(14). stone formation is induced by an increased level of urine crystallisation promoters and reduced levels of its inhibitors. they are active at different stages of deposit formation – nucleation, aggregation and growth. the inhibitors include magnesium, citrates, zinc and organic compounds produced by renal tubular epithelial cells glycosaminoglycans, as well as various proteins, for instance uromodulin (tamm-horsfall protein), osteopontin (uropontin), osteocalcin (nephrocalcin), calgranulin and bikunin(15). according to some authors, crystal aggregation inhibitors reveal daily and annual patterns of activity (16). crystallization promoters are those substances that may constitute a nucleus on which stone is formed. these may include bacteria, foreign bodies or desquamated epithelial cells(9). healthy people regularly excrete calcium oxalate crystals in urine. however, stones are formed only in a small part of the population(1). affected subjects are those with disturbed processes of promotion and inhibition of crystal growth. what is the role of macromolecules? paradoxically, most of them may act as both promoters and inhibitors depending on circumstances (for example urine ph). we do not know the exact role of many proteins present in urine. there is a theory that normal level and structure of macromolecules may constitute protection against formation of large, intratubular precipitates of calcium salts. the purpose of treatment, apart from removal of stone(s), is to prevent formation of subsequent deposits(17,18). the aim of the study was assessment of four selected macromolecules level in fresh morning urine sample in children with nephrolithiasis in the course of idiopathic hypercalciuria. we examined the level of uromodulin, osteopontin, calgranulin and bikunin and compared their excretion in children with urolithiasis and in control group. patients and methods study population the study included 90 subjects aged from 12 months to 18 years hospitalised in the clinic of paediatrics, nephrology and paediatric allergology at the military institute of medicine, warsaw from june 2011 to june 2012. study group were children with urolithiasis in the course of idiopathic hyperclaciuria, who were in continuous care of the clinic and were diagnosed prior to the study. control group were healthy children with no urinary stones in ultrasound examination, no hypercalciuria and no history of urolithiasis study design in the study group, diagnosis of idiopathic hypercalciuria was based on tests performed in the clinic during previous hospitalisations. the basic criterion was increased calcium excretion in urine with normal serum calcium, normal gasometry and the presence of stones in urinary tract at any time since the onset of the disease (which was the appearance of the first concrement). for most patients, before qualification to the study, parathyroid hormone level was also determined, and for all patients creatinine, phosphorus, magnesium and uric acid in serum and in a 24-hour and 3-hour urine samples. the results of these tests showed no abnormalities, which was a decisive factor of qualifying the children to the study group of patients with idiopathic hypercalciuria. exclusion criteria comprised any acute febrile disease, urinary tract infection, renal disease other than lithiasis or defects in the urinary tract. in the control group, additional exclusion criteria were a positive medical history or a family history of urinary tract lithiasis. determination techniques determinations of serum creatinine, calcium, phosphorus and sodium and egfr calculations were performed for all the children (study group and control group). in patients with hypercalciuria blood tests were done to control again, that it is its idiopathic form and in case of control group they were done to ascertain that there are no abnormalities in tests results. the study molecules, i.e. osteopontin, calgranulin, uromodulin and bikunin were determined in the first morning fasting urine sample. all determinations were based on one sample of urine and blood. blood was collected in the morning on empty stomach. urine came from the first morning fasting sample collected in sterile conditions (as for urine culture). immediately after sampling, urine was centrifuged and placed in test tubes adapted to deep freezing, then frozen at -80°c. urine samples were collected after general urinalysis, which was performed to exclude urine infection. it was performed on a typical normocalcemic child diet without administration of medicines. schwartz equation (19) was used to calculate estimated glomerular filtration rate – egfr : gfr (ml/min/1.73m2) = k x growth (cm)/serum creatinine (mg/dl) where k = 0.413 (schwartz modification, common for all age groups). ultrasound scanning examinations were performed in our clinic, always by the same person, with the use of logiq 5 expert machine from medcorp. ultrasonography allowed to visualize stones up to 2 mm in diameter. serum calcium, phosphorus, magnesium, uric acid and creatinine were determined using a colorimetric method, while sodium levels were determined using the method of ion-selective potentiometry on cobes integra 800 autoanalyser from roche. protein levels in the first morning urine sample was determined with an immunoenzymatic method elisa with the use of commercial tests: ―bikunin level with human protein ambp elisa kit catalogue number e0965h from eiaab®, ―uromodulin level with human uromodulin elisa kit catalogue e2280h from eiaab®, ―calgranulin level with human protein s100-a9 elisa kit catalogue number e1793h from eiaab®, ―osteopontin level with quantikine human osteopontin immunoassay, catalogue number dost00 by r&d systems®. statistical analysis calculations and analysis were performed with the use of statistica 10.1 software with a medical pack (statsoft co). initially, distribution of collected variables was performed with the use of the following tests: kolmogorov-smirnov test with the lilliefors amendment and the shapiro-wilk test. for variables characterised with normal distribution, the student’s t-test of mean variables was used. for variables whose distribution did not meet normality criteria, mann-whitney-u non-parametric statistics was calculated. depending on the macromolecules in urine of children with idiopathic hypercalciuria-jobs et al. endourology and stone diseases 232 vol 15 no 05 september-october 2018 233 results of the previous analyses, the following calculations were performed: pearson's parametric correlation coefficient for variables with gaussian distribution, or its non-parametric equivalent spearman's correlation coefficient for non-gaussian variables. each time, statistical significance level of p ≤ .05 was used. results the study group comprised 57 subjects (27 girls and 30 boys), children with urinary tract lithiasis who were found to have idiopathic hypercalciuria. 32 of them (16 girls and 16 boys) were patients with renal stones at the moment of examination, shown in ultrasound and the remaining 25 (11 girls and 14 boys) were patients with no stones in urinary tract at the moment of examination. the control group comprised 33 children (19 girls and 14 boys) admitted to the clinic due to headaches, suspected allergy or episodes of fainting, who revealed no significant pathologies upon examination and who had no history of urolithiasis in patients and in their families, no hypercalciuria and no stones in performed ultrasound examination. the study and control groups did not reveal statistically significant differences with regard to age, sex and blood parameters – calcium, magnesium, phosphorus, sodium and glomerular filtration expressed as egfr. a significant difference with regard to serum creatinine is not of clinical importance, since both values are within standards for this age and there were no differences in calculated egfr between groups (table 1). next, excretion of osteopontin, calgranulin, uromodulin and bikunin was analysed. the study group revealed statistically significantly lower osteopontin excretion and statistically significantly higher bikunin excretion in comparison with the control group. moreover, increased, however statistically nonsignificant, calgranulin excretion was observed in the study group as compared to the control group. uromodulin excretion did not differ between groups (table 2). in order to find out if there is a cross-correlation between the levels of the studied proteins, they were examined separately in the study and control group with the use of the spearman test. in both groups, a statistically significant positive correlation was observed between uromodulin and bikunin levels (tables 3and 4). discussion crystals that change into stones develop in urine, which contains a mixture of ions, salts, macromolecules and metabolites(20). already in the 70's of the previous century, gill et al. showed an inhibitory effect of macromolecules from human urine on crystallisation of calcium oxalate(21). sheng et al. observed reduced calcium oxalate monohydrate (com) crystal adhesion to urinary epithelium depending on the presence of protein carboxyl groups(22). the findings showed that proteins that potentially protect against lithiasis may have a different composition in affected patients than in healthy subjects. therefore, macromolecules inducing stone formation should be examined both with regard to their quantity and quality. as for now, it is difficult to decide which proteins, in the rich urine proteome, should be examined with regard to their possible association with lithiasis. literature describes attempts of various correlations. the present study attempts to compare the level of four selected macromolecules (uromodulin, osteopontin, calgranulin and bikunin) in fresh morning urine sample in children with nephrolithiasis in the course of idiopathic hypercalciuria and in healthy control group. these four proteins were chosen for two reasonsthey were frequently described in literature and we had good experience with the tests in terms of obtaining reliable results. no statistically significant difference between groups was observed with regard to uromodulin excretion, which is in line with most literature data. uromodulin is the most important protein in urine of healthy people. table 1. distribution of age and parameters assessed in serum of the study and control group variablesa study group control group p-value mean ± sd mean ± sd min-max min-max median median age (years) 11.05 ± 4.99 9.21 ± 4.66 .09 1.0-18.0 1.0-17.0 11.0 9.0 creatinine serum mg/dl 0.539 ± 0.18 0.455 ± 0.13 .02 0.2-0.9 0.3-0.7 0.5 0.4 egfr: ml/min/1.73m2 118.87 ± 25.88 126.69 ± 20.70 .14 80.0-189.0 96.0-180.0 114.5 127.0 serum ca mg/dl 10.0 ± 0.37 9.96 ± 0.42 .64 9.1-10.9 9.1-10.7 10.0 9.9 serum p mg/dl 4.48 ± 0.75 4.73 ± 0.62 .09 3.0-6.2 4.7 4.45 3.3-5.7 serum na mmol/l 138.8 ± 2.09 138.7 ± 1.68 .70 135.0-144.0 135.0-142.0 139.0 139.0 serum mg mg/dl 2.07 ± 0.14 2.14 ± 0.15 .23 1.8-2.5 1.9-2.3 2.1 2.2 abbreviations: egfr, glomerular filtration; ca, calcium; p, phosphorus; na, sodium; mg, magnesium a continuous variables were compared by the student’s t-test or mann-whitney-u test (dependent of the results of kolmogorov-smirnov and shapiro-wilk tests). macromolecules in urine of children with idiopathic hypercalciuria-jobs et al. one of its numerous functions is affecting aggregation of calcium oxalate crystals. numerous researchers have proved, however, that uromodulin activity depends on the composition, instead of the amount of protein in urine, and that it is able to both prevent and promote stone formation(23,24). in a recently published paper, viswanathan et al. have shown that this protein contains less sialic acid in patients with lithiasis, which leads to reduction of its negative charge(25). this form of protein promotes aggregation of calcium oxalate monohydrate, whereas the same protein prevents aggregation in healthy subjects with normal content of sialic residues. wikiera-magott et al. also studied uromodulin level in urine of children with urinary tract lithiasis(26). they did not observe differences in concentration of the excreted protein between the group with symptomatic lithiasis, group endangered with lithiasis and the control group. in the study by baggio et al. children with lithiasis had increased uromodulin excretion(27). similarly, increased excretion of this protein, with its different composition at the same time, was observed by jaggi et al. in urine of affected adults with high intensity of stone formation(28). glauser et al. assessed 24-hour uromodulin excretion by means of elisa method and presented it in the form of uromodulin/creatinine ratio(29). they observed a significantly lower excretion of this protein in urine in subjects with calcium deposits as compared with the healthy control group. excretion was not correlated with age of the subjects, urine volume, dietary calcium supply or protein consumption. it was significantly correlated, however, with citrate excretion in both groups. so, those few publications presenting quantitative differences in uromodulin excretion did not have the same findings, which may indicate random nature of the differences. another examined protein was calgranulin. no statistically significant difference it its urine concentration was observed between the study and control group. the ability of calgranulin to inhibit crystallisation, aggregation and adhesion to urinary epithelium of calcium oxalate monohydrate crystals was revealed for instance by momohara et al.(30). the presence of calgranulin in caox deposits were also observed in the study by mushtaq et al.(31). this study, however, proved that the protein promoted crystal aggregation. bergsland et al. observed, similarly to this study, that the concentration and composition of calgranulin differed in subjects with a family history of urinary tract lithiasis in comparison with a healthy population(32). another examined protein was bikunin. a statistically significantly higher excretion of this protein in urine was observed in the affected children. atmani and khan described the ability of bikunin to inhibit nucleation and aggregation of calcium oxalate crystals(33). there are also data proving that bikunin of subjects with lithiasis does not prevent crystallisation so well as in healthy subjects(20,34). in a study by medetognon-benissan et al. strong inhibitory effect of bikunin on caox crystallisation was confirmed by in vitro studies(35). on the other hand, a comparison of this protein in urine of adults with calcium oxalate lithiasis with urine of healthy subjects by means of the elisa method, the authors confirmed that bikunin level was 50% lower in affected subjects. this observation is contrary to the findings of this paper, which may result from different sampling conditions or perhaps from a small count of the study group in the quoted paper (31 subjects vs 18 subjects in the control group). a higher bikunin level in urine, which we observed in the study subjects may reflect striving to prevent deposit formation, especially in relation with the findings concerning osteopontin and possible correlations between them. the last examined protein was osteopontin. its urine level was statistically significantly lower in patients with idiopathic hypercalciuria than in children of the control group. okada et al. conducted studies which showed an important role of osteopontin in transforming calcium oxalate crystals into stones(36). in their study on mice deprived of osteopontin, wesson et al. revealed that during experimental induction of hyperoxaluria the animals revealed numerous deposits of calcium oxalate crystals in renal tubules(37). such deposits were not found in wild mice on the same diet. osteopontin level in urine of patients with calcium oxalate lithiasis was table 2. data on excretion of the studied proteins in the study and control group variablesa mean – study group mean – control group p-value sd – study group sd – control group osteopontin ng/ml 2058.66 3590.20 .0005 1690.51 2305.48 calgranulin pg/ml 268.80 120.15 .07 451.71 84.15 uromodulin ng/ml 13.52 12.19 .39 7.74 5.37 bikunin ng/ml 23.11 16.48 .0128 14.79 2.98 a continuous variables were compared by the student’s t-test or mann-whitney-u test (dependent of the results of kolmogorov-smirnov and shapiro-wilk tests). variablesa r spearman p-value osteopontin & calgranulin -0.20 .13 osteopontin & uromodulin 0.12 .36 osteopontin & bikunin -0.08 .55 calgranulin & uromodulin -0.14 .29 calgranulin & bikunin 0.13 .33 uromodulin & bikunin 0.43 .00094 variablesa r spearman p-value osteopontin & calgranulin -0.15 .41 osteopontin & uromodulin -0.15 .42 osteopontin & bikunin -0.26 .15 calgranulin & uromodulin -0.26 .14 calgranulin & bikunin 0.04 .82 uromodulin & bikunin 0.46 .0074 a continuous variables correlations were compared by the pearson's or spearman's test (dependent of the results of kolmogorov-smirnov and shapiro-wilk tests). a continuous variables correlations were compared by the pearson's or spearman's test (dependent of the results of kolmogorov-smirnov and shapiro-wilk tests). table 3. assessment of correlations between the studied proteins in the study group. spearman's rank correlation. table 4. assessment of correlations between the studied proteins in the control group. spearman's rank correlation. macromolecules in urine of children with idiopathic hypercalciuria-jobs et al. endourology and stone diseases 234 vol 15 no 05 september-october 2018 235 found to be reduced by some researchers and to be normal by others(38,39). similar results to the present study were described by yasui et al. who observed a reduced osteopontin excretion in subjects with lithiasis(40). the latter authors associated a lower osteopontin level in the morning urine of patients with lithiasis with its embedding into the deposit matrix. studying the role of osteopontin in urinary deposit formation, mazzali et al. similarly to wesson et al. revealed that mice genetically deprived of this protein and with experimentally induced hyperoxaluria had intratubular deposits of calcium oxalate(37,38). mice of the same genetically modified type did not accumulate crystals inside tubules if there were no excess oxalates. the authors concluded that this proved existence of other crystallisation inhibitors that compensated for the lack of osteopontin. according to this theory, this role could be played in the children we studied by bikunin and calgranulin. de yoreo et al. observed in vitro that osteopontin from urine of healthy subjects had higher abilities to inhibit formation of calcium oxalate monohydrate crystals than in patients with lithiasis(34). the author found osteopontin to be the main component of organic matrix of stones. the role of osteopontin in formation of com crystal was also discussed by langdon et al.(41). they proved that the ability to inhibit crystallisation depends on osteopontin phosphorylation. summing up data on osteopontin it must be stated that its activity also seems to be dependent on differences in the molecule structure. this does not exclude, however, quantitative differences in its excretion between healthy and affected subjects. recently association between polymorphisms in osteopontin gene and urolithiasis was described (42, 43). finally, the comparison between the healthy and affected subjects presented in the present study revealed reduced osteopontin and increased bikunin levels in urine of the affected subjects. this may confirm the thesis about mutual correlations between these proteins. it may be assumed that the increased bikunin level was to compensate reduced osteopontin excretion. recently, a new publication by khan has appeared, which, based on huge amount of literature data, presents hypothesis about a participation of free oxygen species in stone formation(44). according to this hypothesis, macromolecules related to lithiasis are produced as a response to inflammation. the author presents mutual correlations between osteopontin, uromodulin, bikunin and calgranulin, and also prostaglandin e2, α-1 microglobulin and fibronectin. free radicals initially cause production of macromolecules inhibitors of crystallisation preventing stone formation. in the course of time, however, reduced antioxidative protection or permanent oversaturation of urine with crystallising substances may lead to increased production of free radicals and gradual formation of stones. similar theories are considered by hong(45). in our study a correlation between uromodulin and bikunin excretion was observed both in children with urolithiasis and in the control group. the higher was urine uromodulin, the higher was urine bikunin. limitations of the study unfortunately, in our patients with urinary tract lithiasis in the course of idiopathic hypercalciuria excretion of oxalates and citrates was not determined. it could be used for further group differentiation without changing diagnosis but possibly affecting interpretation of results, since it is common knowledge that citrates inhibit crystallisation and some patients with idiopathic hypercalciuria demonstrate concurrent excessive output of oxalates. both these parameters may affect stone formation. we studied relatively small group of children. in order to draw undisputed conclusions, all the findings of the present study should be confirmed on a much more extensive group of subjects. conclusions the children affected with urolithiasis in the course of idiopathic hypercalciuria reveal a different distribution of the studied proteins that the healthy population. it is only to speculate if our results can have practical clinical value, but they give us a possibility to look at one aspect of complicated pathogenesis of idiopathic hypercalciuria. we cannot have an impact on proteins level in urine of our patients, but if we knew their value, may be in the future we would be able to predict how active in terms of forming new stones is the disease. acknowledgement this study obtained a positive opinion of the bioethics committee of the military institute of medicine in warsaw (resolution no. 57/wim/2010 of 17 november 2010). the children's guardians and patients over 16 gave their written consent for the participation in the study. conflict of interest the authors report no conflict of interest. references 1. bihl g, meyers a. recurrent renal stone disease – advances in pathogenesis and clinical management. the lancet 2001; 358:651-56. 2. lopez m, hoppe b. history, epidemiology and regional diversities of urolithiasis. pediatr nephrol. 2010; 25:49-59. 3. evan ap. physiopathology and etiology of stone formation in the kidney and the urinary tract. pediatr nephrol. 2010; 25:831-41. 4. jobs k, jurkiewicz b, bochniewska v, straż-żebrowska e, jung a. kombinacja małoinwazyjnych metod w leczeniu kamicy układu moczowego – opis trzech przypadków. przegl pediatr. 2012; 42:1002. 5. hoppe b, 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osteopontin levels in urine and serum, and the risk of urolithiasisa metaanalysis. biomed res int .2015: 315043. doi:10.1155/2015/315043. 40. yasui t, fujita k, hayashi y, et al. quantification of osteopontin in the urine of healthy and stoneforming men. urol res. 1999; 27:225-30. 41. langdon a, wignall gr, rogers k, et al. kinetics of calcium oxalate crystal growth in the presence of osteopontin isoforms an analysis by scanning confocal interference microcopy. calcif tissue int. 2009; 84:240-8. 42. safarinejad mr, shafiei n, safarinejad s. associstion between polymorphisms in osteopontin gene (spp1) and first episode calcium oxalate urolithiasis. urolithiasis 2013; 41:303-13. 43. tugcu v, simsek a, tarhan t, et al. opn gene polymorphism (ala250) and lower serum opn levels are associated with urolithiasis. ren fail. 2013; 35: 825-9. 44. khan sr. reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation evidence from clinical and experimental investigations. j urol. 2013; 189:803-11. 45. hong sh, lee hj, sohn ej, et al. antinephrolithic potential of resveratrol via inhibition of ros, mcp-1, hyaluronan and osteopontin in vitro and in vivo. pharm reports. 2013;65:970-9. macromolecules in urine of children with idiopathic hypercalciuria-jobs et al. endourology and stone disease flexible ureterorenoscopy versus mini-percutaneous nephrolithotomy for the treatment of renal stones giray ergin1*, mustafa kirac1, burak kopru1, turgay ebiloglu2, hasan biri1 purpose: to compare the pain status and stone free rates of flexible ureterorenoscopy (f-urs) versus mini-percutaneous nephrolithotomy (mini-pnl) for the treatment of 1-to 2-cm renal stones. materials and methods: this study was retrospectively designed with match paired method. between january 2013 and december 2016, 387 patients underwent stone surgery for renal stones, 45 patients underwent furs and 45 patients underwent mini-pnl. 90 patients were divided into two groups according to the surgical procedures. group 1 patients underwent f-urs, and group 2 patients underwent mini-pnl. during the intraoperative and postoperative periods, pain management for all patients was standardized. pain scores were determined using a visual analogue scale (vas) completed at 2, 6, 12 and 24 hours postoperatively. the stone free status, hemoglobin levels, fluoroscopy time (ft), operation time (ot), hospitalization time (ht), return to work time (rwt), and complications were noted for each patient. results: of all patients, the mean age was 41.1 ± 12.1 years and the mean stone size was 13.9 ± 2.9 mm. the vas scores were significantly higher in the mini-pnl group at 2, 6, 12 and 24 hours (p < .05). the stone-free status and complication rates were similar between the two groups (p > .05); however, the hemoglobin decreases and the fluoroscopy, operation, hospitalization and return to work times were higher in the mini-pnl group than in the f-urs group (p < .05). conclusion: f-urs is less painful than mini-pnl for the treatment of 1to 2-cm renal stones. however, the stone free rate is similar between the two procedures while mini-pnl is superior in terms of fluoroscopy, operation, hospitalization and return to work duration. we think that f-urs is more comfortable and less painful than mini-pnl and achieves a similar stone free rate for the treatment of 1to 2-cm renal stones. keywords: flexible ureterorenoscopy; mini-percutaneous nephrolithotomy; stone treatment; urological surgery. introduction since the first placement of a percutaneous nephros-tomy tube for a hydronephrotic kidney in 1955(1), advancements in endourology have resulted in smaller devices for the percutaneous treatment of renal stones. in 1975, harris et al. used a bronchoscope to treat renal stones(2), and in the following year, fernstro ̈m and johansson defined the percutaneous pyelolithotomy technique by using a nephrostomy tract(3). in 1998, jackman et al. described the mini-percutaneous nephrolithtotomy (mini-pnl) technique using an 11-fr vascular sheath for infants and preschool-aged children(4). desai et al. then used the ultra-mini-pnl method in 2011, which had the least amount of access and utilized the 4.8-fr microperc tract(5). parallel to these advancements in percutaneous treatment methods, ureterorenoscopy technology provided new approaches to renal stone therapy. in 1990, fuchs et al. published the first report of a flexible ureterorenoscopy (f-urs) procedure(6), after which f-urs became an alternative treatment option for renal stones together with improvements in laser and fiber technologies. the current eau guidelines for urolithiasis recommend shock wave lithotripsy (swl) as the initial treatment for renal stones smaller than 2 cm, except for the lower 1koru ankara hospital, department of urology, ankara, turkey. 2gulhane training and research hospital, department of urology, ankara, turkey. *correspondence: koru ankara hospital, department of urology, ankara, turkey. tel: +90 532 306 3959. orchid number: 0000-0003-2893-166x. drgirayergin@gmail.com. received october 2017 & accepted january 2018 pole stones with unfavorable risk factors (7). for stones larger than 2 cm, percutaneous nephrolithotomy (pnl) is recommended as the gold standard while cysteine stones, swl refractory stones, or residual stones following open surgery could be also treated with pnl. miniperc (< 20 fr) and ultra-mini-pnl, which use a smaller tract size, expanded the use of the pnl technique for smaller stones in the area of swl and led to comparable stone-free rates and fewer complications (8,9). for stones smaller than 2 cm, f-urs has recently gained increasing attention for its significantly lower risk of complications and sufficient stone-free rates. stone-free rates > 80% have been reported for both the mini-pnl and f-urs techniques for renal stones larger than 10 mm(10). in this study, we investigated the effectiveness of the f-urs and mini-pnl techniques to determine which method is less invasive and painful while being more comfortable and suitable for renal stone treatment. materials and methods patients and grouping this study was retrospectively designed and approved by local ethic committee in our country. an informed consent was obtained from all individual participants endourology and stone diseases 313 vol 15 no 06 november-december 2018 314 included in our study. between january 2013 and december 2016, 387 patients underwent surgery for renal stones. of 387 patients, 90 were selected and matchpaired according to age, stone size (1 to 2 cm) and stone localization. all patients were divided in two groups according to surgical procedures. group 1 consisted of 45 patients who underwent furs while group 2 consisted of 45 patients who underwent mini-pnl. the exclusion criteria were age < 18 years or > 65 years, morbid obesity, non-opaque renal stones, or anatomic abnormality. in preoperative period, all patients were evaluated by urinalysis, urine culture, hemoglobin (hgb), serum urea and creatinine, coagulation tests and radiologic studies, including ultrasonography, radiography of the kidney, ureter, and bladder (kub) and computerized tomography (ct). the stone sizes were determined by the longest axis of the stones in radiologic test. all patients received a single-dose intravenous prophylactic antibiotic with a first-generation cephalosporin or quinolone during anesthesia induction. mini-pnl technique a retrograde 5-fr open-ended ureteral catheter was inserted into the patient under general anesthesia with 22-fr cystoscope in the lithotomy position. a 16-fr urethral catheter was inserted into the bladder for urine drainage. after ureteral catheter insertion, the patient was moved to a prone position with the appropriate padding placed under the pressure points. the gonads were also protected from x-rays with gonad shields. percutaneous access was achieved under c-arm fluoroscopic (siemens arcadis varic c-arm) guidance with an 18-gauge needle. a j-tipped curved guide wire (0.035 inch) was advanced to place the collecting system preferably in the upper calyx or ureter. the nephrostomy tract was dilated using teflon amplatz dilators (cook medical®) to establish an adequate tract size for the 14fr renal access sheath. a 10-fr rigid nephroscope (karl storz, berlin gmbh, germany) was used for stone fragmentation and removal. the irrigation fluids were warmed to avoid hypothermia. ultrasonic, pneumatic and laser lithotripsy were used for stone fragmentation. laser lithotripsy was performed using a holmium:yttrium-aluminum-garnet laser (dornier© medtech laser gmbh, medilas h, h20-1518, germany) through a reusable 420 micron flexifib fiber (lisa laser products ohg). if necessary, the stone fragments were extracted using either grasping forceps or a zero-tip nitinol stone basket. the operation was complete when no residual fragments could be detected by endoscopic and fluoroscopic imaging. at the end of the procedure, a 10-fr percutaneous nephrostomy (pcn) tube was inserted into the collection system. in some patients, the nephrostomy tube was not required. these patients had minimal or no bleeding, no collecting system or pelvic rupture, no stone fragmentation and no need for a secondary pnl procedure. a jj stent was routinely placed for all patients. the nephrostomy tube was removed when the drainage was clear in the absence of fever or urine leakage around the tube. the jj catheters were removed 2 weeks after the operation. f-urs technique before flexible ureteroscopy, a 7.5-fr rigid ureteroscopy (karl-storz, germany) was performed in all patients in the lithotomy position under general anesthesia to detect any previously unseen or nonopaque ureteral stones, place the safety guide-wire and dilate the ureter. all procedures were performed under visual (videoscopic) and fluoroscopic guidance. fluoroscopy was not routinely used. it was used when stent placement, access sheath insertion and necessary any reason. after the rigid ureteroscopy, a hydrophilic guide-wire was placed into the renal pelvis via rigid ureteroscope. a 9.5-11.5-fr access sheath (uas) (boston scientific®) was placed into the ureter, if possible. after ureteral access was obtained, a 7.5-fr flexible ureteroscope (karl storz flex x2, germany) was used for the stone treatment. the stones were fragmented with a holmium laser (dornier© medtech laser gmbh, medilas h, h201518, germany) using 170-200 µm laser fibers. the holmium laser was used at 0.6–1.2 j and 6–10 hz. first, we tried to crush the stones into several fragments and then relocate them to the middle or upper calyx by stone basket so the lithotripsy could be performed easily. the stone fragments were extracted using a nitinol basket, if possible (ngage® nitinol stone extractor). at the end of the procedure, a jj catheter was inserted if there was ureteral injury, ureteral or pelvic edema, an extended operation time or excessive passing of the ureteroscope for renal access. the jj catheters were removed under brief anesthesia 2 weeks after the operation. pain management the pain management for all patients was standardized. after the operation, all patients received a single dose of intravenous meperidine hydrochloride (pethidin) 1 mg/kg from the anesthesiologist in the operation room. during the postoperative period, 50 mg intramuscular dexketoprofen trometamol and 50 mg intramuscular meperidine hydrochloride were used for pain management. these drugs were used at request of the patients (dexketoprofen trometamol max 150 mg/day and meperidine hydrochloride max 100 mg/day). meperidine hydrochloride was used only on postoperative day 1. during the following postoperative days, pain was managed with 25 mg dexketoprofen hydrochloride taken orally twice per day. each analgesic request was noted. follow-up during the postoperative period, pain scoring was assessed using a visual analog scale (vas)(11). in our clinic, we routinely perform the vas measurements in post-operative period. the vas was used to classify pain severity among ten 1-cm horizontal segments, with no pain indicated at 0 cm and the worst pain at 10 cm. the vass were completed at 2, 6, 12 and 24 hours postoperatively. the fluoroscopy time (ft), operation time (ot), jj stent insertion rates, hospitalization time (ht) and return to work time (rwt) were also noted. complications were classified according to the clavien classification system(12). on the first postoperative day, patients’ general condition and pain status were evaluated, and kub was performed to verify the jj stent insertion and stone-free status. during the first postoperative month, low dose computed tomography was performed. stone-free status was defined as no residual fragments on ct evaluation during the first postoperative month. residual stones ≤4 mm in size were defined as clinically insignificant residual fragment (cirf)(13). after obtaining approval of the local ethics committee, we retrospectively assessed the patients’ files and documents in our clinics. an inform consent form including flexible urs versus mini-pcnl in terms of pain.-ergin et al. ethical and detailed surgical procedure was given to all patients before the surgery. statistical analysis statistical analysis was done using statistical package for social sciences 20.0 software (spss 20.0 for mac). descriptive statistics of nominal samples were expressed with numbers and percentiles. descriptive statistics of scale samples were expressed as mean ± standard deviation (minimum-maximum). shapiro-wilk, kurtosis, and skewness tests were used to assess the variables’ normalization. the independent sample t test was used to compare the pre and post procedure independent scale parameters with normally distribution. the mann-whitney u test was used to compare the pre and post procedure independent scale parameters without normally distribution. the paired sample t test was used to compare the pre and post procedure dependent scale parameters with normal distribution. the wilcoxon test was used to compare the pre and post procedure dependent scale parameters without normal distribution. mc nemar test was used to compare the pre and post procedure dependent nominal parameters. chi square test was used to compare the pre and post procedure independent nominal parameters. anova test was used to compare the repeated scale parameters with normal distribution. friedman test was used to compare the repeated scale parameters without normal distribution. probability of p < 0.05 was accepted as statistically significant. results the demographic data and preoperative parameters of all patients are shown in table 1. the demographic characteristics were similar between the groups (p < .05). the mean stone size was 13.7 ± 2.5 mm and 14.2 ± 3.3 mm in the group 1 and group 2, respectively (p = .251). after 1 month stone-free rates were similar between groups, but the hemoglobin decreases, ft, ot, ht and rwt were higher in the group 2 (p = .023, .002, .004, .001, and .001, respectively). the perioperative and postoperative parameters are reported in table 2. the mean vas scores were significantly higher in the group 2 at 2, 6, 12 and 24 hours (p < .05). the mean vas for all patients are shown in table 3. during the study period, there was no any major complication. clavien grade 1 complication were detected in two patients in group 1 and three patients in group 2. in group 2, 1 patient have a clavien 2 complication such as received transfusions. there was no statistically significant result in two groups in terms of complication rate (cr) (p = .054) in the post-operative period, total meperidine hydrochloride requirements were not different in two groups, however, amount of dexketoprofen trometamol needed were significantly less in group 1 (p = .001) (table 2). table 1. preoperative data of all patients demographic data f-urs mini-pnl p value the mean age ± sd mean ±s d 40.46 ± 12.4 41.93 ± 11.9 0.137 the mean stone size (mm) mean ± sd 13.7 ± 2.5 14.2 ± 3.3 0.251 gender (male/female) 31/14 29/16 0.421 side of surgery (left/right) 22/23 24/21 0.812 location of stone (%) 0.632 upper pole 10 (22.2) 11 (24.5) middle pole 19 (42.2) 16 (35.5) lower pole 16 (35.6) 18 (40.0) abbreviations: f-urs, flexible ureterorenoscopy; mini-pnl, mini-percutaneous nephrolithotomy; sd, standard deviation data f-urs mini-pnl p value fluoroscopy time (sec.) mean ± sd 3.1 ± 0.9 123 ± 14.3 0.002 operation time (min.) mean ± sd 37.5 ± 6.6 57.3 ± 7.5 0.004 hemoglobin drop (mg/dl) 0.44 2.15 0.023 complications rate (%) 0.054 clavien 1 2 (4.4) 3 (6.6) clavien 2 1 (2.2) clavien 3 clavien 4 jj stent insertion rate (%) 45 (100.0) 45 (100.0) nephrostomy tube insertion rate (%) 0 (0.0) 37 (82.2) mean hospitalization time (hour) mean ± sd 16.8 ± 3.2 43.9 ± 8.6 0.001 stone-free rate (1. month) 40/45 (88.8) 42 (93.3) 0.453 cirf rate (%) 2/45 (4.4) 1/45 (2.2) return to work time (day) mean ± sd 2.53 ±1.0 8.93 ± 2.2 0.001 the total mean analgesic requirement’s meperidine hydrochloride (mg) mean ± sd 76.5±14.3 78.7 ± 15.2 0.15 dexketoprofen trometamol (mg) mean ± sd 166.0±45.4 214 ± 39.5 0.001 abbreviations: f-urs, flexible ureterorenoscopy; mini-pnl, mini-percutaneous nephrolithotomy; cirf, clinical insignificant residual stone; sec, second; min, minute table 2. preoperative and postoperative parameters of all patients flexible urs versus mini-pcnl in terms of pain.-ergin et al. endourology and stone diseases 315 vol 15 no 06 november-december 2018 316 discussion managing renal stone disease with the highest possible success rate in a single setting is the aim of all endourologists worldwide. for this purpose, we reported our results in an effort to reach a consensus about the best method for a urinary system stone. however, what is the real measure of success after stone disease surgery: is it the stone-free rate, the cost, the resolution of pain, or the complication rate? following the invention of the mini-pnl method, many investigators reported less hemorrhage, less analgesia and reduced hospitalization time(12-14). in addition, use of the mini-pnl approach achieved a similar stonefree rate and no major complications compared with pnl(14,15). for the stones < 2 cm, another technique named f-urs was first described by fuchs et al(6). and was speculated to have even lower complication rates than mini-pnl. following the developments in laser and flexible endoscopic technologies, f-urs is also an acceptable treatment method for larger kidney stones (10-20 mm in size). according to the 2016 guidelines of the european association of urology, f-urs is third-line treatment option for 10-20 mm kidney stones (7) . moreover, some recent reports have suggested f-urs for stones >2 cm with lower complication rates than those observed for the gold standard treatment modality, pnl(16). in the terms of stone-free rates (sfr), kruck et al. encouraged the use of mini-pnl or f-urs rather than swl for stones > 1 cm. they reported that mini-pnl, f-urs and swl had 77.3%, 72.7%, and 14.8% sfrs for lower pole stones and 80.4%, 69.2%, and 39.3% for non-lower pole stones, respectively (17). a multicenter study reported 83.6%, 86.1%, and 77.2% sfrs in mini-pnl, f-urs, and swl, respectively(18). in another prospective study, mini-pnl and f-urs were reported to have 100% and 96.88% sfrs, respectively (19). akbulut et al. reported 85.7% and 90.3% sfrs for mini-pnl and f-urs, respectively(20). schoenthaler et al. used the 14-fr dilatation, as in our study, and reported 84% and 87% sfrs for the ultra-mini-pnl and f-urs groups, respectively(21). ozgur et al. compared the miniaturized pnl (with 20-f dilatation and a 17-f nephroscope) and f-urs in obese patients and reported 80.4% and 76.7% sfrs, respectively(22). according to these studies, although mini-pnl seems to be superior to f-urs, no studies have reported a statistically significant difference between the techniques. in a meta-analysis by gao xs and colleagues, it was reported that stone-free rates of mini-pnl were higher than rirs(23).they reported that in the meta-analysis mini-pnl provided a significantly higher stone free rate, especially for lover pole renal stones. in our study, we found 93.3 % and 88.8 % sfrs in the mini-pnl and f-urs groups on the first postoperative month. these results are not significantly different from each other, and our sfr results are similar to those obtained in most studies in the literature. at the 3-month follow up, there was only 1 patient in each group with significant residual stones (srs), and a second f-urs made these patients stone-free. in the study by lee et al., the mean vas scores at 1 hour and 1 day postoperatively in the mini-pnl and f-urs groups were reported to be 4.2 and 5.7 and 2.7 and 3.1, respectively. within the first postoperative hour, mini-pnl caused significantly lower pain than did f-urs, but at postoperative day 1, there was no difference(10). in the study by sabnis et al., f-urs reportedly caused less pain than mini-pnl did at 6, 24, and 48 hours postoperatively(19). in our research, f-urs caused less pain at 2, 6, 12, and 24 hours postoperatively. in our study, hgb decrease, ot and ft were reported to be less in the f-urs group than in the mini-pnl group. the complication rates were not different between the groups. according to gao xs and their colleagues’ meta-analysis, hgb decrease and hospitalization time were longer in mini-pnl group. they reported that ot and complication rates were no statistical differences between mini-pnl and f-urs(23). pan et al. reported the mean ot to be 73.07 ± 13.5 and 62.39 ± 10.6 min in the f-urs and mini-pnl groups, respectively(24). contrary to the results from the studies above, akbulut et al. reported a shorter ot but similar hgb decreases and ft for f-urs (20). in our study, we found significantly less hgb decreases and shorter ft and ot, thus favoring the use of f-urs. the diminished field visibility and the need for prolonged lithotripsy to obtain small fragments suitable for extraction through the small sheath were the major factors for the long operative time in the mini-pnl group. the crs were not significantly different between the groups, but 1 patients did require blood transfusions (clavien 2) in the mini-pnl group. hospitalization time (ht) and return to work time (rwt) are the other hints as to the usefulness of these techniques. kıraç and akbulut et al. reported a shorter ht for f-urs(20,25). schoenthaler et al. reported a ht of 2.3 and 2.0 days for ultra-mini-pnl and f-urs groups, respectively(21). ozgor et al. reported hts of 22.4 and 63.8 hours for miniaturized pnl and f-urs groups, respectively(22). our research supports the previous studies. in our study, we found significantly lower ht in f-urs group. however, we think that rwt is more important than ht for selecting a technique for 1-2 cm stones. with this in mind, we examined the rwt and determined that f-urs was a more useful technique than mini-pnl. our study has some limitations. patient size is the main limitation. additionally, the retrospective and multicenter nature of the study is another limitation. studies with more patients in a single center will reveal better results about this subject. conclusions f-urs and mini-pnl are effective treatment modalities for 1to 2-cm renal stones with a similar stone-free rate. f-urs is less painful compared with mini-pnl we concluded that f-urs results in shorter hospitalization and return to work times than mini-pnl. further studies are needed to confirm these results. table 3. the mean vas of patients during the postoperative period postoperative period f-urs mini-pnl p value 2. hours mean ± sd 1.8 ± 0.3 6.3 ± 1.1 0.001 6. hours mean ± sd 1.9 ± 0.3 5.0 ± 1.2 0.001 12. hours mean ± sd 1.1 ± 0.2 4.1 ± 0.6 0.002 24. hours mean ± sd 0.6 ± 0.1 2.5 ± 0.8 0.001 abbreviations: f-urs, flexible ureterorenoscopy; mini-pnl, mini-percutaneous nephrolithotomy flexible urs versus mini-pcnl in terms of pain.-ergin et al. conflict of interest the authors report no conflict of interest. references 1. goodwin we, casey wc, woolf w. percutaneous trocar (needle) nephrostomy in hydronephrosis. j am med assoc. 1955;157:891-4. 2. harris rd, mclaughlin ap, 3rd, harrell jh. percutaneous nephroscopy using fiberoptic bronchoscope: removal of renal calculus. urology. 1975;6:367-9. 3. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 4. jackman sv, hedican sp, peters ca, docimo sg. percutaneous nephrolithotomy in infants and preschool age children: experience with a new technique. urology. 1998;52:697-701. 5. desai j, solanki r. ultra-mini percutaneous nephrolithotomy (ump): one more armamentarium. bju int. 2013;112:1046-9. 6. fuchs gj, fuchs am. [flexible endoscopy of the upper urinary tract. a new minimally invasive method for diagnosis and treatment]. urologe a. 1990;29:313-20. 7. turk c, petrik a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016;69:468-74. 8. cheng f, yu w, zhang x, yang s, xia y, ruan y. minimally invasive tract in percutaneous nephrolithotomy for renal stones. j endourol. 2010;24:1579-82. 9. desai mr, sharma r, mishra s, sabnis rb, stief c, bader m. single-step percutaneous nephrolithotomy (microperc): the initial clinical report. j urol. 2011;186:140-5. 10. lee jw, park j, lee sb, son h, cho sy, jeong h. mini-percutaneous nephrolithotomy vs retrograde intrarenal surgery for renal stones larger than 10 mm: a prospective randomized controlled trial. urology. 2015;86:873-7. 11. bijur pe, silver w, gallagher ej. reliability of the visual analog scale for measurement of acute pain. acad emerg med. 2001;8:1153-7. 12. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 13. newman dm, lingeman je. management of upper urinary tract calculi with extracorporeal shock-wave lithotripsy. compr ther. 1989;15:35-40. 14. mishra s, sharma r, garg c, kurien a, sabnis r, desai m. prospective comparative study of miniperc and standard pnl for treatment of 1 to 2 cm size renal stone. bju flexible urs versus mini-pcnl in terms of pain.-ergin et al. int. 2011;108:896-9; discussion 9-900. 15. nagele u, schilling d, anastasiadis ag, et al. [minimally invasive percutaneous nephrolitholapaxy (mip)]. urologe a. 2008;47:1066, 8-73. 16. hyams es, munver r, bird vg, uberoi j, shah o. flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burdens that measure 2 to 3 cm: a multi-institutional experience. j endourol. 2010;24:1583-8. 17. kruck s, anastasiadis ag, herrmann tr, et al. minimally invasive percutaneous nephrolithotomy: an alternative to retrograde intrarenal surgery and shockwave lithotripsy. world j urol. 2013;31:1555-61. 18. kiremit mc, guven s, sarica k, et al. contemporary management of medium-sized (10-20 mm) renal stones: a retrospective multicenter observational study. j endourol. 2015;29:838-43. 19. sabnis rb, jagtap j, mishra s, desai m. treating renal calculi 1-2 cm in diameter with minipercutaneous or retrograde intrarenal surgery: a prospective comparative study. bju int. 2012;110:e346-9. 20. akbulut f, kucuktopcu o, kandemir e, et al. comparison of flexible ureterorenoscopy and mini-percutaneous nephrolithotomy in treatment of lower calyceal stones smaller than 2 cm. ren fail. 2016;38:163-7. 21. schoenthaler m, wilhelm k, hein s, et al. ultra-mini pcnl versus flexible ureteroscopy: a matched analysis of treatment costs (endoscopes and disposables) in patients with renal stones 10-20 mm. world j urol. 2015;33:1601-5. 22. ozgor f, tepeler a, elbir f, et al. comparison of miniaturized percutaneous nephrolithotomy and flexible ureterorenoscopy for the management of 10-20 mm renal stones in obese patients. world j urol. 2015. 23. gao xs, liao bh, chen yt, et al. different tract sizes of miniaturized percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and meta-analysis. j endourol. 2017;31:1101-10. 24. pan j, chen q, xue w, et al. rirs versus mpcnl for single renal stone of 2-3 cm: clinical outcome and cost-effective analysis in chinese medical setting. urolithiasis. 2013;41:73-8. 25. kirac m, bozkurt of, tunc l, guneri c, unsal a, biri h. comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in management of lowerpole renal stones with a diameter of smaller than 15 mm. urolithiasis. 2013;41:241-6. endourology and stone diseases 317 endourology and stone disease microperc versus miniperc for treatment of renal stones smaller than 2 cm in pediatric patients gokce dundar1*, gokhan gokce1, kaan gokcen1, esat korgali1, aydemir asdemir1, kenan kaygusuz2 purpose: pediatric stone disease is an important clinical problem in pediatric urology practice. we aimed to compare mini-percutaneous nephrolithotomy (miniperc) and micro-percutaneous nephrolithotomy (microperc) in pediatric patients who underwent unsuccesful swl procedure. materials and methods: a number of 43 pediatric patients, aged 17 years or younger, were treated with miniperc or microperc procedures due to renal calculi by a single surgeon. in group 1, there were 27 patients who underwent miniperc procedure. in group 2, 16 patients were treated by microperc. results: mean age of the patients were 9.5 (3-17) years in group 1 and 7.9 (2-16) years in group 2 (p = .25). stone burden was similar between the two groups. mean operation duration was 74.1 (40-110) minutes in miniperc group and 37.2 (20-55) minutes in microperc group (p < .01). patients who underwent microperc were discharged from clinic earlier. hyperthermia without bacteraemia was observed in 2 children in the miniperc group and was treated by using a single dose of paracetamol and also 2 children in the same group needed blood transfusion. there was a tendency for low haemoglobin decrease in microperc group compared to miniperc (p > .05). conclusion: the management of pediatric stone disease has evolved with improvements in techniques and minimalisation of surgical instruments and thus, it can be effectively and safely used in children by experienced surgeons. keywords: microperc; miniperc; nephrolithiasis; pediatric; percutaneous nephrolithotomy introduction pediatric stone disease is an important clinical disorder in pediatric urology practice. the incidence and characteristics of stones show a wide geographical variation in children. although urinary stone disease is generally considered to be a relatively rare disease, it is quite common in some regions of the world. pediatric stone disease is endemic in turkey, pakistan and some south asian, african and south american countries(1). according to a study, the annual incidence of primary urinary system stone disease is 1% in turkish school-aged children(2). stone evaluation, indications and treatment options are similar to adults however; small sized and specific instruments are needed for children(3). micro-percutaneous nephrolithotomy (pnl) is a recently introduced pnl technique that is performed using a 4.8 f micro-sheath all-seeing needle with no need for tract dilation or an additional access sheath.(4,5) it has a three-way 0.9 mm micro-optic connector, an irrigation system, and laser fragmentation capabilities. in this technique after lithotripsy procedure was performed for small stones, fragments passes spontaneously. it currently is the endpoint pnl technology used to treat kidney stones(6). shockwave lithotripsy (swl) provides convincing results especially in experienced centers. however, in large and complex stones, the presence of anatomic abnormalities, swl failure, hard stones like cystine and accompanying congenital anomalies there is a need for treatment by other minimal invasive techniques such as endourologic procedures(7). in this study; we aimed to compare mini-pnl (miniperc) and micro-pnl (microperc) treatments in pediatric patients who underwent unsuccesful swl procedure before. materials and methods in this retrospective study, patients who were treated with one of two endourological procedures (miniperc or microperc) in our department were included. we treated patients with miniperc between january 2010 and september 2013 and with microperc between october 2013 and march 2016. other inclusion criteria were age of 17 years or younger and swl failure. patients with anomalous kidneys, bleeding disorders or musculoskeletal deformities were not included. 43 pediatric patients were treated by a single surgeon due to renal calculi. in group one, there were 27 patients who underwent miniperc procedure and in group two, 16 patients were treated by microperc. demographic characteristics of the patients is illustrated in table 1. when we asked stone intervention history we learned that one child who underwent microperc had miniperc before. non of the children had co-morbidity. approval of the institutional ethics committee was taken for conducting the study and specific informed consent was obtained from patients' parents. while kidney urinary tract and bladder x-ray radiography (kub) and/or urinary ultrasonography (usg) were 1 department of urology, faculty of medicine, cumhuriyet university, sivas, turkey. 2 department of anesthesiology and reanimation, faculty of medicine, cumhuriyet university, sivas, turkey. *correspondence: cumhuriyet university faculty of medicine hospital, department of urology, tr-58140 sivas turkey phone: +90 505 246 46 48. e-mail: gokce@dundar.dr.tr. received april 2016 & accepted september 2016 endourology and stone diseases 2829 vol 13 no 05 september-october 2016 2830 performed for the evaluation of urolithiasis, abdominal computed tomography (ct) was performed for patients who were scheduled for surgery. prior to the surgery, the anesthesiology clinic was consulted about all study patients, and the patients' routine blood and urine tests were performed preoperatively. erythrocyte suspension was prepared for all pediatric patients before operation. stone size was calculated by measuring the largest diameter on radiological graphs or summing the measurements of multiple stones. operations were performed under general anaesthesia and prophylactic antibiotics were administered to the patients just before the operation. complete blood count and blood serum creatinine of patients were analysed at the end of surgeries. operation time was defined as the time between the first renal puncture to the completion of stone removal. we also suggested families to refer to our clinic again three weeks after discharge with stone analysis and 24 hour urine samples for metabolic analysis and thus possible medical treatments. the stone clearance was assessed using kub and urinary usg 24 or 48 hours after operation. stone clearance was defined as either stone free or with asymptomatic and clinically insignificant residual stone of ≤ 4 mm. it is well known that kub and usg are not as sensitive as computed tomography in the detection of residual stone fragments. in our study the stone-free status was assessed with kub and usg because of concerns about radiation exposure. miniperc technique all procedures were performed under general anaesthesia in prone position, after performing retrograde catheterisation with a 4 fr ureteral catheter in lithotomy position. the anatomy of the calyx was visualised by infusing contrast solution through the ureteral catheter. percutaneous access was achieved by a single surgeon under fluoroscopic guidance by using an 18-gauge needle. amplatz dilators of up to 12-20 fr were used for tract dilation through the hydrophylic guide. fragmentation and stone removal were accomplished in all patients using pneumatic or ultrasound energy. stone fragments were removed by retrieval graspers through a 12 f pediatric nephroscope. operation was completed when residual fragments were not detected on fluoroscopic imaging control. at the end of this procedure, a nephrostomy tube was placed after removing the ureteral catheter. microperc technique a 4 fr ureteral catheter was inserted in patients under general anaesthesia in lithotomy position. after catheterisation, the patient was turned to prone position. the anatomy of the calyx was visualised by infusing contrast media through the ureteral catheter. after detecting the suitable calyx, access was made under the guidance of fluoroscopy by the surgeon using an all-seeing needle. after removing the needle, a three-way connector was applied to the proximal part of the sheath to connect to the laser probe and irrigation system. the stone was fragmented by using holmium energy under direct vision. stone fragmentation was achieved with a 200 µm holmium laser fiber until stone fragments were deemed small enough to be passed spontaneously. the surgeon controlled a water pump which aided in vision and the clearance of stone fragments. drainage of the kidney was supplied through the open-ended ureteral catheter. stone fragmentation was confirmed by direct vision and fluoroscopy. the procedures were terminated with no need of any nephrostomy tube. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. statistical analysis statistical analysis was performed with ibm spss statistics for windows (version 22.0). data was given as mean±standard deviation (sd), minimum and maximum values for continuous variables. categorical variables were compared using chi-square test, while continuous variables were compared using independent sample t-test. statistical significance was considered at p ≤ .05 level. results mean age of the patients were 9.5 (range:3-17) years in the miniperc group and 7.9 (range: 2-16) years in the microperc group; the difference was not statistically significant (p = .25). there was no statistically significant difference in terms of stone burden and laterality. mean operation time was 74.1 (range: 40-110) minutes in the miniperc group and 33.6 (range: 25-45) minutes in the microperc group (p < .01). patients who underwent miniperc and microperc were discharged from clinic after an average 4.0 ± 1.7 (range: 2-11) days and 1.5±1.0 (range: 1-4) days from surgery, respectively (p < .01). residual fragments were detected in 2, and 1 patients respectively for miniperc and microperc groups and the stone clearance rates were found as 92.6% and 93.8% respectively (p = .48). postopermicroperc vs. miniperc for pediatric nephrolithiasis-dundar et al. table 1: characteristics of the patients miniperc microperc p-value patients: male-female n(%) total 13(48.1) – 14(51.9) 27 8 (50) – 8(50) 16 0.20 mean age ± sd (range); years 9.5 ±5.4 (3-17) 7.9 ± 3.6 (2-16) 0.25 operation side right-left n(%) 13(48.1) – 14(51.9) 8 (50) – 8 (50) 0.43 mean stone size ± sd (range); mm 13.4 ± 4.8 (7.8-18.7) 12.1 ± 4.3 (7.1-18.6) 0.22 stone localisation n (%) renal pelvis 18 (66.7) renal pelvis 7 (43.8) lower calyx + renal pelvis 6 (22.2) lower calyx 7 (43.8) other 3 (11.1) other 2 (12.4) ative findings of the patients is illustrated in table 2. residual fragments were between 5 and 7 mm in diameter. we did not perform any auxiliary procedures for those asymtomatic fragments. we decided non-interventional follow-up with 3 month intervals for those patients. we observed that resiual fragment of one patient in miniperc group was spontaneously cleared in follow-up. for other asymtomatic residual fragments of patients (one in miniperc and one in microperc group) we are continuing non-interventional follow-up. so final stone free rate sfr can be considered as 96.3% for the miniperc group and 93.8% for the microperc group. the mean decreases in haemoglobin values for miniperc and microperc groups were 1.14 ± 1.32 g/dl and 0.79 ± 0.49 g/dl (p > .05). erythrocyte transfusion was given for two patients in the miniperc group because of observing macroscopic hematuria and hemoglobin drop postoperatively (clavien grade ii). no transfusion was needed in the microperc group. there was a tendency for low haemoglobin decrease in microperc group compared to miniperc. the mean increase in creatinine values was 0.04 ± 0.13 mg/dl and 0.08±0.06 mg/dl for miniperc and microperc groups, respectively (p > .05). subfebrile hyperthermia was observed in 2 children in the miniperc group and was treated by using a single dose of paracetamol (clavien grade i). in the miniperc group, nephrostomy catheter was inserted for all patients. the average time of nephrostomy removal was on postoperative 3.3 (range: 2-4) days. urethral foley catheters of all patients were removed on the following day. in the microperc group, ureteral catheters were placed intraoperatively. in 7 patients, ureteral catheters were changed with double j catheters at the end of the operation due to intraoperative hematuria. urethral foley catheters of those patients were removed on the following day. in another 9 patients in group two, ureteral catheters were removed with the urethral foley drains on average postoperative 1.3 (range: 1-2) day. discussion there is a wide range in the incidence of pediatric urolithiasis; its incidence rates are 5 to 15% and 1 to 5% in developing countries and developed countries, respectively.(8) children with urinary stone disease represent a high risk group for stone recurrence.(9) since the recurrence rate is higher in children compared to adults, urologists are required to aim at leaving no residual stone fragments behind after any treatment made for urinary stones. a previous study showed that 69% of children with residual stone fragments of ≤ 5 mm following swl had an increase in stone size.(10) currently, most pediatric stones can be easily managed by swl. guidelines state that swl is the first choice for treating most renal pediatric stones and pnl can be preferred for larger and complex stones. the guidelines also mention that pnl can be used as monotherapy in most cases but is also used as an adjunctive procedure to other therapies.(1) in children, swl requires general anaesthesia with short hospital stay and stone free rates of almost 60-70% especially for lower calyx stones after repeated treatments, as well.(11) with the miniaturized access technique which is described in 1998, jackman et al. reported total success rate of 85% and listed the benefits of this new technique as increased maneuverability, decreased blood loss and shorter hospital stay, along with limitations including prolonged operative times and potential impairment of visualisation during the procedure, especially for larger stones(12) potential limitations for the use of pnl procedure in children include possible parenchymal damage and associated impairment in renal function, radiation exposure and the risk of major complications, including urinary sepsis and bleeding.(3) pnl has its invasiveness and related morbidity, mainly hemorhagic risk, as major limitation, especially in pediatric patients.(13) in our study, hyperthermia without bacteraemia was observed in 2 children in the miniperc group and was treated by using a single dose of paracetamol and also 2 children in the same group needed blood transfusion. the further miniaturisation of the urological instrumentation has very recently offered new possibilities for minimally invasive stone treatment. the “microperc” has been described as a new very minimally invasive pnl technique, which is performed by using a 4.85 f metallic needle.(14,15) microperc has been recently proposed in adult patients. caione et al. reported that the success rate of microperc was 100% in 5 children with a mean age of 5.8 years. in this study, except for one patient who needed conversion to retrograde intrarenal surgery due to stone migration and poor visibility, the mean hospital stay was 2.4 ± 0.6 days for four patients after the removal of ureteral catheter.(14) microperc is a new innovation whose potential and scope of indications have not yet been completely defined. a few authors demonstrated that microperc access in a limited number of pediatric patients can be considered as safe and effective and also in preschool children.(16-18) pediatric patients are more sensitive to hemoglobin decrease when compared with adults and the main advantage of microperc in pediatric patient is the low risk of bleeding. in the studies by desai and colleagues, the mean hemoglobin decrease was calculated as 1.4 g/dl.(16) in another study, the mean hemoglobin decrease was 0.1 ± 0.3 mg/dl (range: 0–1.1 mg/ dl) for moderate-size renal stones(19). in one study by dağgülli and colleagues, blood transfusion was not required for any of the pediatric patients, and the mean table 2: postoperative findings of the patients miniperc microperc p-value mean operation time ±sd (range); minutes 74.1±19.7 (40-110) 37.2 ± 9.8 (20-55) < 0.01 mean hospitalization time ±sd (range); days 4.0 ± 1.7 (2-11) 1.5 ±1.0 (1-4) < 0.01 mean haemoglobin change (range); g/dl –1.14 ± 1.32 (–3.9,1.1) –0.79 ± 0.49 (–1.4,0.1) 0.28 mean creatinine change ±sd (range); mg/dl 0.04 ± 0.13 (–0.13,0.3) 0.08 ± 0.06 (–0.01,0.17) 0.33 stone clearence % 92.6 93.8 0.48 microperc vs. miniperc for pediatric nephrolithiasis-dundar et al. endourology and stone diseases 2831 vol 13 no 05 september-october 2016 2832 hemoglobin decrease was 0.7 g/dl.(20) in our study, the hospital stay was shorter in the microperc group. one of the most important reasons behind this advantage might be the absence of nephrostomy tube. limitations of our study could be considered to be retrospective nature, the lack of long-term follow-up, and unavailability of data on stone composition. conclusions all of the endourological interventions are invasive treatments; therefore, they may sound offensive for pediatric patients and especially for their relatives. the management of pediatric stone disease has evolved with improvements in techniques and minimalisation of surgical instruments and thus, they can be effectively and safely used in children by experienced surgeons. both microperc and miniperc are minimal invasive treatment options for renal stones in children. according to our study, microperc procedure is more minimally invasive and has shorter hospitalisation duration, therefore, it may be preferred for pediatric patients in experienced centers. acknowledgment we appreciate ahmet altun and selim çam for their great helps in analysis of the statistics. conflict of interest the authors declare that they have no conflict of interest. references 1. tekgül s, dogan hs, erdem e, et al. european association of urology guidelines on paediatric urology limited update march 2015. 2. remzi d, cakmak f, erkan i. a study on the urolithiasis incidence in turkish school-age children. j urol. 1980 ;123:608. 3. unsal a, resorlu b, kara c, et al. safety and efficacy of percutaneous nephrolithotomy in infants, preschool age, and older children with different sizes of instruments. urology 2009; 76:247–52. 4. tepeler a, armagan a, sancaktutar aa, et al. the role of microperc in the treatment of symptomatic lower pole renal calculi. j endourol soc 2012; 27:13–8. 5. desai mr, sharma r, mishra s, et al. single-step percutaneous nephrolithotomy (microperc): the initial clinical report. j urol 2011; 186:140–145. 6. dede o, sancaktutar aa, baş o, et al. micropercutaneous nephrolithotomy in infants: a single-center experience.urolithiasis. 2016; 44:173-7. 7. oral i̇, nalbant i̇, öztürk u, et al. our experience with percutaneous nephrolithotomy in pediatric renal stone disease turkish journal of urology 2013; 39: 35-8. 8. mahmud m, zaidi z. percutaneous nephrolithotomy in children before school age: experience of a pakistani centre. bju int 2004; 94: 1352e4. 9. straub m, gschwend j, zorn c. pediatric urolithiasis: the current surgical management. pediatr nephrol 2010; 25: 1239-44. 10. afshar k, mclorie g, papanikolaou f, et al.outcome of small residual stone fragments following shock wave lithotripsy in children. j urol 2004; 172: 1600-3. 11. salerno a, nappo sg, matarazzo e, et al.treatment of pediatric renal stones in a western country: a changing pattern. j pediatr surg 2013;48:835–9. 12. jackman sv, hedican sp, peters ca, et al. percutaneous nephrolithotomy in infants and preschool age children: experience with a new technique. urology 1998; 52: 697-701. 13. desai m, mishra s. ’microperc’ micro percutaneous nephrolithotomy: evidence to practice. curr opin urol 2012;22:134–8. 14. caione p, de dominicis m, collura g, et al. microperc for pediatric nephrolithiasis: technique in valdivia-modified position. eur j pediatr surg. 2015; 25: 94-9. 15. sabnis rb, ganesamoni r, ganpule ap, et al. current role of microperc in the management of small renal calculi. indian j urol 2013; 29: 214–8. 16. desai mr, sharma r, mishra s, et al. single step percutaneous nephrolithotomy (microperc): the initial clinical report. j urol 2011; 186: 140–5. 17. silay ms, tepeler a, atis g, et al. initial report of microperc in the treatment of pediatric nephrolithiasis. j pediatr surg 2013; 48: 1578–83. 18. hatipoglu nk, sancaktutar aa, tepeler a, et al. comparison of shockwave lithotripsy and microperc for treatment of kidney stones in children. j endourol 2013;27: 1141–6. 19. armagan a, tepeler a, silay ms, et al. micropercutaneous nephrolithotomy in the treatment of moderate-size renal calculi. j endourol 2013; 27: 177–81. 20. dağgülli m, utanğaç mm, dede o, et al. micro-percutaneous nephrolithotomy in the treatment of pediatric nephrolithiasis: a single-center experience. j pediatr surg. 2015 . pii: s0022-3468(15)00595-3. microperc vs. miniperc for pediatric nephrolithiasis-dundar et al. case report 226 urology journal vol 6 no 3 summer 2009 stenturia a rare complication of indwelling ureteral stent vishwajeet singh, ankush gupta urol j. 2009;6:226-7. www.uj.unrc.ir keywords: stents, ureter, postoperative complications department of urology, chhatrapati shahuji maharaj medical university, lucknow, uttar pradesh, india corresponding author: ankush gupta, md department of urology, chhatrapati shahuji maharaj medical university, lucknow 226003, uttar pradesh, india tel: +91 52 2225 6543 fax: +91 52 2225 6543 e-mail:ankushuro@gmail.com received may 2008 accepted july 2008 introduction it is now more than 30 years that ureteral stents have been used for the management of urinary calculi. with its widespread use, the number of possible complications has increased, as well. over the years, ureteral stents have undergone a progressive improvisation, both in design and material. in the current era, the side effect profile of double-j stents has improved. common complications have been lower abdominal pain, dysuria, hematuria, fever, urinary frequency, and nocturia.(1,2) however, there is still no place for forgotten stents. long-term indwelling ureteral stents have led to stent migration, encrustation, calculus formation, and spontaneous fragmentation.(3) spontaneous fragmentation and excretion of fragments in urine is extremely rare. herein, we report a case of forgotten ureteral stent presented to our center. case report a 35-year-old man presented with right flank pain lasted for 6 months. there were no other associated symptoms. ultrasonography of the kidneys, ureters, and bladder showed multiple calculi with hydronephrosis in the right kidney and multiple left inferior caliceal calculi. the renal laboratory indicators were normal. intravenous urography revealed hydronephrosis in the right kidney with a calculus at the ureteropelvic junction and multiple left inferior caliceal calculi, with good dye excretion on both sides. initially, the patient was managed by insertion of a right double-j stent. he was advised to undergo right percutaneous nephrolithotomy. however, the patient was then lost to followup. after 1 year, he returned with a piece of approximately 5-cm tubular foreign body right after the initial part of the urethra (figure 1). this was a piece of previously inserted double-j stent. the patient was also complaining from hematuria. since the patient had been lost to follow-up, urinary tract infections could not be documented. although careful history was taken at the time of the second presentation to elucidate previous urinary tract infections, it was not suggestive of recurrent infections. plain abdominal radiography showed fragmented pieces of the stent in the urinary bladder and the right pyelocaliceal system (figure 2). the fragment in the bladder was retrieved by cystoscopy, and 1 week later, the proximal fragment in the pyelocaliceal system and the calculus were extracted by percutaneous nephrolithotomy. stenturia—singh and gupta urology journal vol 6 no 3 summer 2009 227 discussion late complications of ureteral stents occur in about one-third of the patients.(4) el-faqih and colleagues reported a spontaneous fragmentation rate of 0.3% in a review of complications associated with the presence of ureteral stents.(5) stent breakage is thought to be due to the hostility of the urine solution and prolonged indwelling time (more than 1 year). all ureteral stents may develop encrustation and lose tensile strength which results in stent fracture and even stenturia.(6) lithogenic factors need to be considered for the prevention of stent encrustation in these patients.(7) the clinical presentations may vary. three previous cases of this kind have been reported in the literature whose stent fragment was spontaneously excreted.(8,9) however, management of neglected or complicated forgotten ureteral stents usually needs endourological approaches.(10) this underscores the need for close follow-up of patients with in situ stents. conflict of interest none declared. references 1. pollard sg, macfarlane r. symptoms arising from double-j ureteral stents. j urol. 1988;139:37-8. 2. damiano r, oliva a, esposito c, de sio m, autorino r, d’armiento m. early and late complications of double pigtail ureteral stent. urol int. 2002;69:136-40. 3. monga m, klein e, castañeda-zúñiga wr, thomas r. the forgotten indwelling ureteral stent: a urological dilemma. j urol. 1995;153:1817-9. 4. ringel a, richter s, shalev m, nissenkorn i. late complications of ureteral stents. eur urol. 2000;38:41-4. 5. el-faqih sr, shamsuddin ab, chakrabarti a, et al. polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. j urol. 1991;146:1487-91. 6. singh i. indwelling jj ureteral stents-a current perspective and review of literature. indian j surg. 2003;65:405-12. 7. bouzidi h, traxer o, dore b, et al. [characteristics of encrustation of ureteric stents in patients with urinary stones]. prog urol. 2008;18:230-7. french. 8. kumar m, aron m, agarwal ak, gupta np. stenturia: an unusual manifestation of spontaneous ureteral stent fragmentation. urol int. 1999;62:114-6. 9. soyupek s, oksay t, koşar a. fragmentation of a forgotten double j stent and excreted with urine: case report. int urol nephrol. 2003;35:91-2. 10. singh v, srinivastava a, kapoor r, kumar a. can the complicated forgotten indwelling ureteric stents be lethal? int urol nephrol. 2005;37:541-6. figure 2. plain abdominal radiography of the patient showed fragmented pieces of the stent in the bladder and the right pyelocaliceal system. figure 1. an approximately 5-cm long piece of stent passed through the urethra. laparoscopic urology 170 urology journal vol 6 no 3 summer 2009 comparison of open and laparoscopic varicocelectomies in terms of operative time, sperm parameters, and complications ali shamsa, leila mohammadi, mehran abolbashari, mohammad-taghi shakeri, saeed shamsa introduction: varicocele is one of the most common causes of infertility. in this study, we evaluated and compared the operative time, sperm analysis results, and complications of three different methods of open and laparoscopic varicocelectomies. materials and methods: from among all bilateral varicocelectomies in our center, we randomly selected 30 of each following cases: laparoscopic varicocelectomy, open subinguinal varicocelectomy under general anesthesia, and open subinguinal varicocelectomy under local anesthesia. we compared the operative time, sperm analysis results, and complications between these three groups. results: the mean operative times were 30.0 ± 5.5 minutes for laparoscopies, 27.0 ± 3.5 minutes for open varicocelectomies under general anesthesia, and 38.0 ± 1.8 minutes for open varicocelectomies under local anesthesia (p = .02). intra-operative complications occurred only in the laparoscopic group, and postoperative complications were seen in 23.3%, 20.0%, and 4.2% of the patients with laparoscopy, open surgery under general anesthesia, and open surgery under local anesthesia, respectively. semen analysis did not show any significant changes after varicocelectomy except for a slight improvement of sperm morphology in patients who underwent open varicocelectomy under local anesthesia. conclusion: subinguinal varicocelectomy under local anesthesia is better than laparoscopic method in terms of recurrence, hydrocele formation, and operative time. subinguinal method under general anesthesia has intermediate efficacy regarding less complications than laparoscopic method and shorter operative time than the two other methods. urol j. 2009;6:170-5. www.uj.unrc.ir keywords: varicocele, laparoscopy, infertility department of urology, mashhad university of medical sciences, mashhad, iran corresponding author: ali shamsa department of urology, ghaem hospital, mashhad, iran tel: +98 511 801 2833 fax: +98 511 841 7404 e-mail: shamsaa@mums.ac.ir received may 2008 accepted april 2009 introduction varicocele is one of the most common causes of infertility. different approaches have been applied for treatment of varicocele, including open surgery, sclerotherapy, and recently, laparoscopy.(1-3) in 1991, aaberg and colleagues(4) introduced laparoscopy as the least-invasive surgical method in the treatment of varicocele. in this study, we evaluated and compared the operative time, sperm parameters, and complications in three different methods of open (subinguinal) and laparoscopic approaches through general anesthesia (ga) and open approach through local anesthesia (la). open and laparoscopic varicocelectomies—shamsa et al urology journal vol 6 no 3 summer 2009 171 materials and methods patients a total of 306 unilateral and bilateral varicoceles were operated on by one surgeon, from 2003 july till 2006 september at ghaem hospital in mashhad, iran. we approached cases of bilateral varicoceles from among this group and randomly selected 30 cases of open varicocelectomy under la, open varicocelectomy under ga, and laparoscopic varicocelectomy in 3 groups. group 1 consisted of 30 patients who underwent laparoscopic varicocelectomy; group 2, open subinguinal varicocelectomy through ga; and group 3, open subinguinal varicocelectomy through la. indications for varicocelectomy were the same in all groups and included infertility, scrotal pain, and documented abnormalities in sperm parameters. diagnostic protocol included physical examination, ultrasonography (especially in obese patients or in those with a thick scrotum), and color doppler ultrasonography (in patients with a thick scrotum, in obese patients, or for evaluation of the right-side varicocele and venous reflux). laparoscopic varicocelectomy after placement of urethral catheter and nasogastric tube, the patient was secured in the supine position. under ga, a 1-cm transverse midline incision was made immediately above the umbilicus. a 10-mm trocar was introduced into the peritoneal cavity after incision of the fascia. then, the abdomen was inflated with carbon dioxide gas (15 mm hg), and a 10-mm telescope was inserted through the 10-mm trocar. under direct vision, the 2nd and the 3rd trocars (both 5-mm) were bilaterally introduced through the incisions located in the two-third internal distance from the umbilicus to the anterior superior iliac spine. a grasper and a scissor were used to put 2 perpendicular incisions into the peritoneum overlying the internal spermatic veins. the vascular mass was lifted to separate the arterial and lymphatic components from the veins. then, the veins were ligated by clips (suturing or cauterizing veins was avoided to save time). in early cases, the veins were cut, but in the recent cases, we did not cut the veins after ligation. it must be noted that since only 10-mm clips applier were available, the 10-mm telescope was changed with a 5-mm telescope, and introduction of clips applier was through a 10-mm trocar. open surgery under local anesthesia twenty-five milliliters of lidocaine (1%) was infused around the spermatic cord and the illioinguinal nerve, 15 minutes before the operation. then, a standard subinguinal varicocelectomy was preformed. using this method, there was no need to incise the fascia. after controlling the spermatic cord, gentle pressure was applied onto the ipsilateral hemiscrotum in order to engorge the spermatic veins. the veins were separated and ligated, while preserving the arterial and lymphatic components. statistical analyses the collected data were analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa). comparisons of continuous variables were done with the paired t test and the 1-way analysis of variance test, where appropriate. a p value less than .05 was considered significant. results patients the mean ages of the patients were 27.4 ± 6.6 years (range, 17 to 43 years), 30.7 ± 5.3 years (range, 20 to 45 years), and 28.4 ± 4.4 years (range, 20 to 35 years) in groups 1 to 3, respectively. of the patients, 22, 28, 29 were married in groups 1 to 3, respectively. there were 22, 26, and 26 infertile patients, respectively (p = .33), of whom 2, 4, and 1 had secondary infertility. the follow–up duration was 3 to 36 months. follow-up visits were at the first and second postoperative weeks and every 3 months, afterwards operative time the operation time was calculated from trocar insertion to trocar extraction and skin closure open and laparoscopic varicocelectomies—shamsa et al 172 urology journal vol 6 no 3 summer 2009 for laparoscopic varicocelectomy, and from incision to skin closure in open varicocelectomy. the operative time was not considered from the beginning of anesthesia induction, because placement of the urethral catheter and nasogastric tube and preparation of laparoscopic equipment would add to the operative time of laparoscopy. the mean operative times were 30.0 ± 5.5 minutes (range, 17 to 60 minutes) for laparoscopies, 27.0 ± 3.5 minutes (range, 20 to 40 minutes) for open varicocelectomy under ga, and 38.0 ± 1.8 minutes (range, 32 to 43 minutes) for open varicocelectomy under la (1-way analysis of variance, p = .02). intra-operative complications in group 1 with laparoscopy, no vascular or intestinal complications occurred while introducing the first trocar. conversion from laparoscopic to open approach due to hemorrhage or other causes did not occur, either. in 1 patient, however, abdominal wall emphysema was encountered due to morbid obesity, but varicocelectomy was successful. no intraoperative complications were seen in groups 2 and 3. postoperative complications the patient with abdominal wall emphysema in group 1 complained of shoulder pain, which was alleviated by nonsteriod anti-inflammatory drugs. four patients in group 1 developed scrotal edema, which were treated by rest, nonsteriod antiinflammatory drugs, and scrotal supports. also, 1 patient in this group had mild hydrocele, which was managed by conservative treatment. two left varicocele recurrences developed in group 1, and the patients underwent open varicocelectomy under ga. no hernias occurred after laparoscopic varicocelectomy. in group 2, there were 3 patients with wound infection, 3 with scrotal edema, and 1 with left orchitis, all of which were managed by medical therapy. no recurrence was noted in this group. in the patients of group 3, the only complication was bilateral scrotal hematoma in 1 that was managed medically. overall, 22, 23, and 29 patients in groups 1, 2, and 3 had an uneventful operation, respectively. complications of these three methods are summarized in table 1. sperm parameters semen analysis results are summarized in table 2. the paired t test showed no significant changes complication laparoscopy open with general anesthesia open with local anesthesia hydrocele 1 (3.3) 0 0 scrotal edema 4 (13.3) 3 (10.0) 0 orchitis 1 (3.3) 1 (3.3) 0 wound infection 0 3 (10.0) 0 hematoma 0 0 1 (3.3) recurrence 2 (6.7) 0 0 table 1. varicocelectomy complications with different surgical methods* *values in parentheses are percents. varicocelectomy before treatment after treatment p laparoscopy sperm count, × 106/ml 58 ± 42 54 ± 33 .65 sperm motility, % 73 ± 49 92 ± 100 .26 sperm morphology, % 69 ± 52 74 ± 41 .31 open with general anesthesia sperm count, × 106/ml 40 ± 25 34 ± 20 .26 sperm motility, % 35 ± 20 35 ± 20 .91 sperm morphology, % 31 ± 16 38 ± 18 .07 open with local anesthesia sperm count, × 106/ml 51 ± 23 47 ± 25 .31 sperm motility, % 55 ± 19 58 ± 19 .18 sperm morphology, % 51 ± 27 57 ± 22 .045 table 2. semen analysis results with different varicocelectomy methods open and laparoscopic varicocelectomies—shamsa et al urology journal vol 6 no 3 summer 2009 173 in sperm count, motility, and morphology after the treatment, except for sperm morphology in group 3. the 1-way analysis of variance test demonstrated no significant differences in parameters’ changes between the three approaches. discussion there are different surgical methods for varicocele treatment. the first surgical method for varicocele was explained by celsus in the first century (ipsilateral orchidectomy which consisted of an atrophic testis).(5) currently, popular varicocelectomy methods include: the ivanissevich method (retroperitoneal), palomo method, subinguinal method (with or without testicular delivery), laparoscopic method, and sclerotherapy (internal spermatic vein embolization). the most effective and least invasive method is yet unknown. we compared open varicocelectomy under ga and la with laparoscopic approach. we found that although the three methods had comparable results, regarding the costs and complications, laparoscopic method was not superior. we found that the operation time in patients with open surgery under ga lasted shorted compared to those who underwent laparoscopy or open surgery under la. ghanem and colleagues(6) reported the operative time to be 45 minutes on average for unilateral subinguinal method and 25.6 minutes for the high retroperitoneal method. watanabe and coworkers(7) reported an operative time of 111.8 ± 21.1 minutes for unilateral high retroperitoneal varicocelectomy and 86.3 ± 28.4 minutes for unilateral subinguinal varicocelectomy under la. the operative time in our group of open surgery with la was 38 minutes on average. the operative time for laparoscopic varicocelectomy ranged from 17 to 60 minutes in our study. watanabe and colleagues reported a mean operative time of 109 ± 27 minutes, although their operations were unilateral.(7) kwon and associates reported a mean of 102 minutes for this parameter.(8) they did not mention whether this was for unilateral or bilateral varicocelectomy. ogura and colleagues performed bilateral laparoscopic varicocelectomy on 39 patients with an operative time of 96.6 minutes.(9) varicocele recurrence is a complication of varicocelectomy. misseri and coworkers reported 3% recurrence with the palomo method and 14% recurrence with the high retroperitoneal method.(3) al-kandari and colleagues(10) studied 120 patients with 147 varicocelectomies in three different methods. the recurrence rate was 2% (1 patient) with microscopic subinguinal varicocelectomy and 13% (7 patients) and 18% (9 patients) with open inguinal and laparoscopic methods, respectively. this report was statistically significant in favor of microscopic subinguinal varicocelectomy. al-said and coworkers(11) observed the same results (the recurrence rate was 2.6%, 11%, and 17% in microsurgical, open, and laparoscopic groups, respectively). hirsch and colleagues(12) concluded in their study on 41 patients with varicocele that laparoscopic varicocelectomy has no advantage over open subinguinal technique with respect to hospitalization, seeking analgesic, and going back to work. moreover, laparoscopic varicocelectomy was longer and had more complications than open subinguinal approach. watanabe and colleagues reported 6.1% recurrence in 33 patients with bilateral laparoscopic varicocelectomy. they mentioned a recurrence rate of 12% in 50 patients with unilateral varicocelectomy by high retroperitoneal method.(7) varicocele recurrence after laparoscopic method was reported to be 8.9%, but stood at 6.7% when the lymphatic vessels were preserved.(2) recurrence in our laparoscopic group was 6.6% (2 cases). hydrocele is another complication of varicocelectomy. incidence of this complication is 0.3% to 40.4% as reported by kocvara and coworkers.(2) etiology of postvaricocelectomy hydrocele is ligation of the lymphatic vessels that are colorless and sometimes are mistaken for veins.(10) schwentner and colleagues reported hydrocele in 16% of patients operated by conventional microscopic method.(13) in several studies, hydrocele after varicocelectomy has been reported in 3% of cases in expert hands.(13) kocvara and colleagues(2) reported hydrocele formation 17.9% with conventional laparoscopic varicocelectomy and 1.9% with their own open and laparoscopic varicocelectomies—shamsa et al 174 urology journal vol 6 no 3 summer 2009 method (preservation of lymphatic vessels). hassan and coworkers(1) observed hydrocele in 29.8% of 79 patients after 6 months of follow-up with unilateral laparoscopic varicocelectomy. they concluded that hydrocele formation rate is high in long-time and/or internal spermatic veins are ligated and cut (instead of ligated alone). in the study of al-kandari and associates, hydrocele formation was none, 13%, and 20% in microscopic, open, and laparoscopic groups, respectively,(10) according to al-said and colleagues, hydrocele formation was none, 2.8%, and 5.4% in those groups, respectively.(11) conclusion our study demonstrated that although sooner return to work is achieved by laparoscopic varicocelectomy, complications of this method are more frequent than the open method (under either ga or la). although sperm analysis results were the same for all the three methods, subinguinal method under la was better than laparoscopic method in terms of recurrence, hydrocele formation, and operative time. subinguinal method under ga has intermediate efficacy, ie, less complications than laparoscopic method and better results in operative time than the two other methods. conflict of interest none declared. references 1. hassan jm, adams mc, pope jct, demarco rt, brock jw, 3rd. hydrocele formation following laparoscopic varicocelectomy. j urol. 2006;175:1076-9. 2. kocvara r, dvoracek j, sedlacek j, dite z, novak k. lymphatic sparing laparoscopic varicocelectomy: a microsurgical repair. j urol. 2005;173:1751-4. 3. misseri r, gershbein ab, horowitz m, glassberg ki. the adolescent varicocele. ii: the incidence of hydrocele and delayed recurrent varicocele after varicocelectomy in a long-term follow-up. bju int. 2001;87:494-8. 4. aaberg ra, vancaillie tg, schuessler ww. laparoscopic varicocele ligation: a new technique. fertil steril. 1991;56:776-7. 5. spink ms, lewis gl. albucasis on surgery and instruments. berkeley: university of california press, 1973. p 438. 6. ghanem h, anis t, el-nashar a, shamloul r. subinguinal microvaricocelectomy versus retroperitoneal varicocelectomy: comparative study of complications and surgical outcome. urology. 2004;64:1005-9. 7. watanabe m, nagai a, kusumi n, tsuboi h, nasu y, kumon h. minimal invasiveness and effectivity of subinguinal microscopic varicocelectomy: a comparative study with retroperitoneal high and laparoscopic approaches. int j urol. 2005;12:892-8. 8. kwon ed, sandlow ji, donovan jf. varix ligation. in: smith ad, badlani gh, bagley dh, editors. smith’s textbook of endourology. 1st ed. st louis: quality medical publishing; 1996. p. 894-903. 9. ogura k, matsuda t, terachi t, horii y, takeuchi h, yoshida o. laparoscopic varicocelectomy: invasiveness and effectiveness compared with conventional open retroperitoneal high ligation. int j urol. 1994;1:62-6. 10. al-kandari am, shabaan h, ibrahim hm, elshebiny yh, shokeir aa. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology. 2007;69:417-20. 11. al-said s, al-naimi a, al-ansari a, et al. varicocelectomy for male infertility: a comparative study of open, laparoscopic and microsurgical approaches. j urol. 2008;180:266-70. 12. hirsch ih, abdel-meguid ta, gomella lg. postsurgical outcomes assessment following varicocele ligation: laparoscopic versus subinguinal approach. urology. 1998;51:810-5. 13. schwentner c, oswald j, lunacek a, deibl m, bartsch g, radmayr c. optimizing the outcome of microsurgical subinguinal varicocelectomy using isosulfan blue: a prospective randomized trial. j urol. 2006;175:1049-52. editorial comment i read with interest the article by shamsa and colleagues. the authors have tried to compare 3 different techniques of varicocelectomy by one surgeon, possibly with different levels of expertise in each technique. we have done a similar study previously comprising 50 laparoscopic varicocelectomies compared with 50 open varicocelectomies in a randomized controlled trial and found different results.(1) in our study using bipolar cautery instead of clips (which is a foreign body), operative time was significantly less with laparoscopy compared with open varicocelectomy (17.2 ± 9.8 minutes versus 31.02 ± 12.8 minutes). since there is an 8-time magnification during laparoscopic procedure, the lymphatic vessels as well as the open and laparoscopic varicocelectomies—shamsa et al urology journal vol 6 no 3 summer 2009 175 testicular artery are better preserved. that is why hydrocele formation was significantly less in our laparoscopy group. we also disagree with routine bilateral varicocelectomy since varicocele occurs 90% only in the left side.(2) nasser simforoosh department of urology, shahid labbafinejad medical center, shahid beheshti university (mc), tehran, iran. e-mail: simforoosh@iurtc.org.ir references 1. simforoosh n, ziaee sa, behjati s, beygi fm, arianpoor a, abdi h. laparoscopic management of varicocele using bipolar cautery versus open high ligation technique: a randomized, clinical trial. j laparoendosc adv surg tech a. 2007;17:743-7. 2. schneck fx, bellinger m.f. abnormalities of the testes and scrotum and their surgical management. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 3761. reply by author i appreciate the remarkable comments of professor simforoosh on our article. he pointed out to the following: first, laparoscopy provides a magnified vision of the operation site. we also agree this influential fact. second, he compared the operative times in their experience; the operative time was 17.2 ± 9.8 minutes for laparoscopic varicocelectomy and 31.0 ± 12.8 minutes for open varicocelectomy as reported by simforoosh and colleagues.(1) in our study, these were 30.0 ± 5.5 minutes and 27.0 ± 3.5 minutes, respectively. the difference between the two studies is that we had bilateral varicocelectomies, while simforoosh and colleagues reported their open surgery in unilateral varicocelectomy, for which an operative time of 31.0 minutes is too long, unless the patients had been obese or had had a previous surgical operation on the inguinal areas. third, hydrocele was quite more frequent in their study (14% for laparoscopy and 24% for open surgery).(1) we faced hydrocele in 3.3% of patients with laparoscopy and none of the patients in the open group. al-said and colleagues and also cayan and coworkers have compared the three options of laparoscopy, microsurgery, and open surgery.(2,3) al-said and colleagues had no cases of hydrocele in the microsurgery group, and cayan and coworkers reported a rate of 0.44% of hydrocele with this treatment method. fourth, professor simforoosh disagrees with routine bilateral varicocelectomy, as in 90% of the cases, only left-side varicocele is present. our response is that in bilateral cases, the treatment is simply bilateral varicocelectomy. consistent with the experiences of al-said and colleagues(2) and the report by glassberg and associates,(4) we believe that bilateral varicocelectomy results in superior outcomes. further, simforoosh and colleagues indicated an incidence of 15% to 57% for bilateral varicocele.(1) also, they reported bilateral varicocelectomy in 16 patients in their study. ali shamsa department of urology, mashhad university of medical sciences, mashhad, iran references 1. simforoosh n, ziaee sa, behjati s, beygi fm, arianpoor a, abdi h. laparoscopic management of varicocele using bipolar cautery versus open high ligation technique: a randomized, clinical trial. j laparoendosc adv surg tech a. 2007;17:743-7. 2. al-said s, al-naimi a, al-ansari a, et al. varicocelectomy for male infertility: a comparative study of open, laparoscopic and microsurgical approaches. j urol. 2008;180:266-70. 3. cayan s, shavakhabov s, kadioglu a. treatment of palpable varicocele in infertile men: a meta-analysis to define the best technique. j androl. 2009;30:33-40. 4. glassberg ki, poon sa, gjertson ck, decastro gj, misseri r. laparoscopic lymphatic sparing varicocelectomy in adolescents. j urol. 2008;180:32630. vol 16 no 01 january-february 2019 83 miscellaneous mean platelet volume and testicular torsion: new findings marta peretti1, nicola zampieri1*, mirko bertozzi2 , federica bianchi1, simone patanè1, valentina spigo1, francesco s. camoglio1 introduction: testicular torsion is an emergency at any age; the aim of this study is to evaluate the role of mean platelet volume to assess the viability of the testes before surgery materials and methods: we retrospectively analysed the medical records of consecutive patients who underwent surgical exploration for acute scrotal pathology between january 2014 and december 2016 in our institution. patients were divided into two groups (detorsion of testes and orchyectomy); a third group was created as control group. all patients underwent blood exam before surgery; inclusion and exclusion criteria were created. we also evaluated the association between mean platelets volume and the testicular recovery during surgery result: after reviewing medical charts following the inclusion and exclusion criteria, 8 patients were enrolled in group 1 and 11 patients in group 2. 33 healthy controls were enrolled in group 3. mpv value in group 1 resulted significantly different (p < 0.01) from the value in group 2 and 3. the duration of symptoms was shorter than 6 hours in 4/8 (50%) patients in group 1; this early referral to hospital allowed prompt detorsion and testicular recovery. in these “early-presenting” patients, mpv value was significantly lower than in patients with torsion of testicular appendage (p = 0.01) and in controls (p = 0.001). conclusion: mpv could be a useful adjunct in diagnosing tt, aiding its differential diagnosis with torsion of the testicular appendage. the lower mpv value in “early-presenting” patients with tt suggests a role in predicting the testis viability, and therefore the appropriate treatment. keywords: mean platelet volume; pediatric; testicular torsion. introduction testicular torsion (tt) occurs in 1 out of 4000 males younger than 25 years(1). the differential diagnosis with other conditions, such as epididymo-orchitis (eo) and torsion of the testicular appendage (tta), remains challenging. testis’ viability decreases after 6 hours after onset of symptoms, therefore a prompt diagnosis is necessary(2). the risk of testicular loss and unnecessary surgery improved the need for novel diagnostic techniques. recent studies focused on the role of hematologic parameters, such as mean platelet volume (mpv), in diagnosing tt(3). the present study aimed to evaluate this parameter in diagnosing tt and in its differential diagnosis with other acute scrotal pathologies. materials and methods we retrospectively analysed the medical records of consecutive patients who underwent surgical exploration for acute scrotal pathology between january 2014 and december 2016 in out institution, a tertiary referral centre. patients were divided into two groups: patients diagnosed with tt (group 1) and patients with other acute scrotal pathologies (group 2). patients with peri-natal (extravaginal) torsion and with history of scrotal trauma were excluded. controls were selected among healthy subjects referring to our hospital for 1women and child hospital, azienda ospedaliera universitaria integrata, university of verona, italy. 2department of pediatric surgery, azienda ospedaliera di perugia,university of perugia. *correspondence: woman and child hospital, azienda ospedaliera universitaria integrata, pediatric surgical unit, piazzale stefani 37134 verona, italy. e-mail: dr.zampieri@libero.it. received july 2017 & accepted november 2017 elective non-genitourinary surgery (group 3); a complete blood count was performed as common practice before the surgical procedure. patients from group 1 and 2 had a blood count performed at time of the admission at the emergency department (ed). clinical features, colour doppler ultrasound (cdus) and laboratory findings were compared. duration of symptoms in group 1 was classified as longer or shorter than 6 hours. statistical analysis was performed using the chisquare, student t-test and fisher exact tests with a p value less than .05 considered as significant. results during the study period 14 patients with testicular torsion, 19 with torsion of testicular appendage and 33 as controls were considered. after reviewing medical charts 8 patients were enrolled in group 1 and 11 patients in group 2 and all 33 healthy controls in group 3. those patients excluded were considered only for the mpv value but not for the timing of symptoms. patients’ characteristics are resumed in table 1. mpv value in group 1 resulted significantly different (p < 0.01) from the value in group 2 and 3 (table 2). the duration of symptoms was shorter than 6 hours in 4/8 (50%) patients in group 1; this early referral to hospital allowed prompt detorsion and testicular recovery. in these “early-presenting” patients, mpv value was significantly lower than in patients with tta (p = 0.01) and in controls (p = 0.001). all patients with tt underwent prompt scrotal exploration, with detorsion of the testis; viability was tested by testicluar puncture in three different zones. in cases of testicular necrosis, an orchiectomy was performed. no significant difference was evidenced in terms of mpv value between group 2 and group 3. no significant difference was found between group 1 and group 2 in terms of platelet (plt) count. discussion testicular torsion is an emergency condition which needs prompt recognition and treatment, in order to avoid gonadal necrosis and subsequent fertility impairment. the differential diagnosis with other acute scrotal pathologies, such as eo and tta, can be challenging. clinical and cdus findings aid the diagnosis, but in certain cases they can lead to unnecessary scrotal exploration. as previously reported, clinical findings show high sensitivity but low specificity (4); on the other hand, cdus shows specificity of 97-100%(5), but it is limited by high operator-dependence. in recent years, an effort has been made in order to find useful adjuncts in diagnosing tt. a study conducted by günes and colleagues(6) found a significant difference in terms of neutrophil to lymphocyte ratio (nlr), platelet to lymphocyte ratio (plr) and plt between patients with tt and controls, while no predictive role of mpv value was found. nlr and plr couldn’t be evaluated in our study, since these parameters aren’t routinary measured in our ed. a subsequent study conducted by bitkin and colleagues(3) found plt count and plr to be useful in differentiating between epididymitis and tt. mpv value didn’t show significant difference between the eo and the tt groups. moreover, recent studies(3,7) found mpv value significantly higher in the tt group than in the control group, in opposition to our findings. in the present study, 4 out of 8 (50%) patients with tt presented at the ed within 6 hours after onset of symptoms, while 9 out of 10 (90%) patients with tta referred to hospital later. this finding is consistent with previous reports(7-9). detorsion was possible in all these “early-presenting” patients, while orchiectomy was performed in the “late-presenting” ones; as reported in the literature, irreversible loss of the testicle begins after the first 6 hours(10). mpv value showed significant difference between “early-presenting” patients (< 6 hours) in group 1 and patients in group 2 and 3 with a significant cut-off of 6,5 fl. this finding suggests that mpv value could be an indicator of testis viability in selected patients. no significant difference was found between late-presenting patients in group 1 and the other groups. in conclusion, mpv could be a useful adjunct in diagnosing tt, aiding its differential diagnosis with tta. the lower mpv value in “early-presenting” patients with tt suggests a role in predicting the testis viability, and therefore the appropriate treatment. further large studies evaluating mpv role are needed. references 1. barada jh, weingarten jl, cromie wj. testicular salvage and age-related delay in the presentation of testicular torsion. j urol. 1989;142(3):746-8. 2. boettcher m, bergholz r, krebs tf, wenke k, aronson dc. clinical predictors of testicular torsion in children. urology. 2012;79(3):6704. 3. bitkin a, aydın m, özgür bc, irkilata l, akgunes e, keles m, sarıcı h, atilla mk. can haematologic parameters be used for differential diagnosis of testicular torsion and epididymitis? andrologia. 2017;00:e12819. 4. lemini r, guanà r, tommasoni n, mussa a, di rosa g, schleef j. predictivity of clinical findings and doppler ultrasound in pediatric acute scrotum. urol j. 2016;13(4):2779-83. 5. tekgul s, riedmiller h, gerharz e, et al. guidelines on paediatric urology. espu/ eau 2011. 6. güneş m, umul m, altok m, akyuz m, i̇şoğlu cs, uruc f, aras b, akbaş a, baş e. predictive role of hematologic parameters in testicular torsion. korean j urol. 2015; 56(4):324-9. 7. cicek t, togan t, akbaba k, narci h, aygun c. the value of serum mean platelet volume in testicular torsion. j int med res. 2015;43(3):452-9 8. yang c, song b, liu x, wei g, tan j, he d. acute scrotum in children. an 18-year retrospective study. pediatr emer care 2011;27: 270-274. 9. boettcher m1, krebs t, bergholz r, wenke table 1. general characteristics of study population group 1 (n=8) group 2 (n=11) mean age (years) 13 (12-15) 10 (8-13) side, left 4 (50) 7 (64) symptoms duration < 6 hours 4 (50) 1 (10) clinical findings swelling 8 (100) 3 (27) erythema 8 (100) 5 (45) fever 1(12) 0 vomit 2 (25) 0 cdus, blood flow absent 4 (57) 3 (43) decreased 1 (10) equal 5 (50) increased 4 (40) detorsion 4 (50) table 2. hematologic parameters of the study population group 1 group 2 group 3 mean age (years) 13 (12-15) 10 (8-13) 13 (10-17) laboratory results mpv (fl) < 6 h 6.5 (5.5-7.4) 8.1 (6-10.1) 8.25 (7-10.2) > 6 h 6.18 (5.9-6.4) 6.83 (5.5-7.4) plt (103/μl) 306.250 298.360 253.430 mean values are shown (range) mpv, mean platelet volume plt, platelet count testicular torsion and mean platelet volume-peretti et al. miscellaneous 84 vol 16 no 01 january-february 2019 85 testicular torsion and mean platelet volume-peretti et al. k, aronson d, reinshagen k. clinical and sonographic features predict testicular torsion in children: a prospective study. bju int. 2013 dec;112(8):1201-6. 10. güneş m, umul m, altok m, et al. is it possible to distinguish testicular torsion from other causes of acute scrotum in patients who underwent scrotal exploration? a multicenter clinical trial. cent european j urol. 2015;68(2):252-256. 11. cimador m1, dipace mr, castagnetti m, degrazia e. predictors of testicular viability in testicular torsion. j pediatr urol. 2007; 3(5):387-90. can urinary nerve growth factor and brain-derived neurotrophic factor be used in the diagnosis and follow-up of voiding dysfunction in children? purpose: we investigated the utility of urinary nerve growth factor (ngf) and brain-derived neurotrophic factor (bdnf) levels as non-invasive markers for diagnosis and evaluation of treatment efficacy in children with overactive bladder (oab). materials and methods: this prospective study included 24 children with oab and 30 healthy controls. at the time of diagnosis, micturition disorder symptom scores (mdss) were determined, blood and urine samples were collected, and anticholinergic therapy was initiated. clinical responses were evaluated, at the third and sixth month of treatment, by mdss and urinary ngf, bdnf, and creatinine levels. results: the patient group had significantly higher urine ngf/cr ratio (975 ± 827 and 159 ± 84, respectively, p < .001) and bdnf/cr ratio (5.98 ± 5.78 and 0.81 ± 0.70, respectively, p < .001) before treatment. significantly decreased bdnf/cr ratio was found at the sixth month (5.98 ± 5.78 and 2.24 ± 0.98, respectively, p = .004). ngf/cr > 360 was found to have 87.5% sensitivity and 100% specificity, and bdnf/cr > 1.288 was found to have 87.5% sensitivity and 83.3% specificity for oab diagnosis. conclusion: in conclusion, urine ngf/cr and bdnf/cr ratios may be useful markers for diagnosis of oab. the bdnf/cr ratio was found to be more significant in monitoring treatment response. keywords: biomarkers/urine; case-control studies; nerve growth factor; urinary bladder/physiopathology; urinary bladder, overactive/etiology. 1 department of pediatric nephrology, ege university school of medicine, i̇zmir 3500, turkey. 2 department of pediatric nephrology, pediatric hematology oncology training and research hospital, ankara 0600, turkey. 3 department of molecular biology, ege university school of medicine, i̇zmir 3500, turkey. *correspondence: department of pediatric nephrology, ege university school of medicine, i̇zmir 3500, turkey. tel: +90 232 4116281. fax: +90 232 390 10 84. e-mail: kcanturk1@hotmail.com. received november 2015 & accepted march 2016 pediatric urology kadriye ozdemir,1* nida dincel,2 afig berdeli,3 sevgi mir1 introduction bladder dysfunction (bd) is a common problem in childhood, presenting with lower urinary tract symptoms including weak urine stream, frequency, urgency, urge incontinence, and urinary tract infections (uti). potential causes of bd were hypothesized as delay in neurologic maturation and anatomical and neurological abnormalities. mistakes in potty training or disturbances during toilet training may cause bd symptoms in children.(1) more attention has been paid on cases of overactive bladder (oab). among bd cases, children with oab deserve more attention. oab is commonly seen between 5 and 7 years of age, and is one of the most common causes of functional urinary incontinence in children.(2) the diagnosis of oab is made based on urgency, with or without urge incontinence, usually with voiding frequency and nocturia, in the absence of an underlying metabolic or pathological condition.(3) use of non-invasive methods including clinical symptom scores, micturition diaries, micturition symptom scoring systems, and post-void residual urine measurements can be helpful in the diagnosis of oab. to confirm the diagnosis of oab, detrusor instability should be detected on urodynamic measurements. however, urodynamic study is an invasive method, and many external factors, including alterations in mental situation, hydration status, and the disease process itself may affect study results.(4) thus, in children it is difficult to perform urodynamic measurements. some studies have suggested a weak correlation between clinical symptoms and urodynamic findings in patients with oab. (4) therefore, readily applicable non invasive objective determinants are required for the diagnosis of oab in pediatric age group. urinary cytokines, c-reactive protein (crp), prostaglandins, and detrusor wall thickness have been suggested as markers for the diagnosis of oab. however, none of these measurements enter into routine clinical practice.(5,6) the role of neurotrophic factors was shown in bladder development and function and in the micturition pathway.(7) nerve growth factor (ngf) was the first memvol 13 no 03 may-june 2016 2690 ber of the neurotrophin (nt) family discovered; other neurotrophins include brain-derived neurotrophic factor (bdnf), nt-3, and nt-4/5.(8,9) ngf is the most frequently investigated neurotrophin in adults.(10) ngf is produced in the bladder epithelium and smooth muscle cells. increased ngf expression has been detected in situations such as detrusor over-activity, interstitial cystitis/painful bladder syndrome (ic/ pbs), and overactive bladder syndrome.(11) recent studies have shown increased urine ngf levels in adults with oab, and ngf may be a potential indicator of oab.(12) to our knowledge, up to date, only one study has been conducted in children related to this condition. (13) another neurotrophin, bdnf, is the most prevalent but least studied in the body. clinical studies on adults have documented significantly increased urine bdnf levels in patients with oab compared to healthy controls. (14) furthermore, enzyme-linked immunosorbent assay (elisa) yielded higher sensitivity and specificity in the detection of bdnf than that of ngf.(15) according to our english literature search, no study investigating bdnf levels in children with oab has been reported. we hypothesized that ngf and bdnf may be elevated in children with oab, which would be valuable to diagnose oab, and levels of ngf and bdnf may be correlated with symptoms. the aim of this study was to investigate the utility of urine ngf and bdnf levels as diagnostic markers and as biomarkers during follow-up in children with oab. materials and methods study population the study group consisted of 24 children aged 5-15 years who had been diagnosed with first-onset voiding dysfunction at the pediatric nephrology clinics of ege university. the control group included 30 healthy, agematched children with no symptoms of lower urinary system dysfunction, no history of a disease, symptom, or sign indicating uti, and no urgency or urge incontinence. they were chosen from children who applied to our hospital for routine check-up or elective surgery, such as hernia repair or circumcision, who had no nephro–urological or neurological dysfunction or lower urinary tract symptoms. ethical approval for the study was obtained from the clinical research ethics committee of ege university school of medicine. informed consent was obtained from children and/or their parents before initiation of the study. procedures urodynamic studies were done using an urodynamic instrument (aymed dyno urodynamics, istanbul, turkey). the same nurse, accompanied by a physician specialist in pediatric nephrology, performed urodynamic studies and the results were evaluated by the same specialist. after a diagnosis was made, anticholinergic therapy with oxybutynin at a total dose of 0.3-0.5 mg/ kg/day divided into three doses was started. no urodynamic study was performed in the control subjects. urine samples were collected before the initiation of the therapy and at the third and sixth months, and treatment response was evaluated by mdss. urine samples of 5 ml were obtained in the morning at room temperature, and stored at -80°c until measurements. another 3 ml urine was stored separately to measure creatinine levels.(12) urine samples were obtained as free-voided samples without catheterization in all children. quantitative urinary ngf measurements were done using a human beta-ngf elisa kit (ab99986 beta-ngf human elisa kit, abcam, cambridge, uk). assay sensitivity was < 14 pg/ml and the detection range was 6.86–5000 pg/ml. quantitative bdnf measurement in urine was performed using a human bdnf elisa kit (ab99978 bdnf human elisa kit, abcam). assay sensitivity was < 80 pg/ml and the detection range was 0.066–16 pg/ml. for the quantification of ngf and bdnf levels, the urine samples were diluted and tested as indicated in the manufacturer’s protocols. briefly, after the preparation of ngf and bdnf reactive ingredients, samples and standards, 100 µl of the standard or samples was added to the wells and incubated for 2.5 h at room temperature (rt). then, 100 µl of biotin antibody solution was added to the wells and incubated for 1 h. after incubation, 100 µl of streptavidin solution was added and incubated for about 45 min at rt. careful washing was carried out between steps. then, tetra methyl benzidine (tmb) reactive substrate was added to the wells and incubated for about 30 min until the color development was visualized. stop solution was then added and the wells were read at 450 nm with an elisa reader. each sample was tested twice using elisa and the mean value was obtained. measured urine ngf (pg/ ml) and bdnf (ng/ml) levels were divided by urine creatinine (cr, mg/dl) for standardization as ngf/cr and bdnf/cr ratios. evaluations in the urodynamic study, the diagnosis of bladder instability was made by taking into account the relaxed condition of the pelvic floor muscles during the micturition phase along with uncontrolled detrusor contractions. detrusor over activity was confirmed by the existence urinary ngf and bdnf in children with voiding dysfunction-ozdemir et al. pediatric urology 2691 of uncontrolled contractions of the detrusor muscle during the filling phase in the urodynamic study. all participants and their accompanying family members were asked to complete the micturition disorder symptom scoring (mdss) questionnaire developed by akbal and colleagues,(16) which consisted of 13 questions (scores of 0-35). a decrease in mdss score was considered a measure of clinical treatment response. inclusion and exclusion criteria inclusion criteria: patients with oab who exhibited one or more symptoms meeting the diagnostic criteria for voiding dysfunction, including the need to urinate at frequent intervals daily (urinating often but in lower volumes), feeling that the bladder is not completely empty were included. incontinence during the daytime, a feeling of sudden pressure, maneuvers such as crossing the legs to hold back urination until reaching the bathroom, dripping urine, dysuria (painful urination), straining during urination and intermittent flow during urination were considered other findings of voiding dysfunction and these patients also were included. exclusion criteria: patients with current or recent uti were excluded. children with functional or anatomical bladder outlet obstruction and those with findings of neurological dysfunction were also excluded. statistical analysis a power analysis was performed considering the results of a previous study.(17) we calculated a sample size of 24 patients in the study group and 30 subjects in the healthy control group for α = 0.05 and β = 0.20 with a power of 0.90 in a two-tailed test. the statistical package for the social science (spss inc, chicago, illinois, usa) version 18.0 was used for statistical analyses. the normality of the distribution of quantitative variables was tested using the kolmogorov-smirnov test. student’s t-test was used to compare two groups on variables satisfying a normal distribution, and the mann– whitney u test was used to compare data that was not normally distributed or that was derived from a few individuals. for repeated measures of the same group, a paired t-test or wilcoxon test was used. pearson’s or spearman’s correlation analyses were used to evaluate the relationships between quantitative variables. the χ2 test was used to compare categorical data. cut-off values, along with sensitivity, specificity, positive predictive value (ppv), and negative predictive value (npv), were determined for ngf/cr and bdnf/cr using a receiver operating characteristic (roc) curve analysis. a p value of less than .05 was considered statistically significant. results in total, 24 pediatric patients with urinary dysfunction (6 boys, 18 girls; age range 5-15 years, mean age 109.7 ± 31.8 months), and 30 genderand age-matched healthy control children (8 boys, 22 girls) with no overt urinary dysfunction were included in the study. patient symptoms at the first visit were frequency (n = 13), micturition with intermittent flow (n = 9), constipation (n = 8), urgency (n = 24), enuresis nocturnal (n = 21), urinary incontinence (n = 20), and recurrent uti (n = 10). an urodynamic study was performed, and detrusor over activity was detected in all patients. patients had significantly higher urine ngf/cr (975 ± 827 vs. 159 ± 84; p < .001) and bdnf/cr ratios (5.98 ± 5.78 vs. 0.81 ± 0.70; p < .001) at the first (before treatment) measurement compared with the healthy controls (table 1). in the patient group, mdss and urine ratios of ngf/ cr and bdnf/cr before (first measurement) and at 3 and 6 months after treatment were compared. mdss scores decreased gradually from the first measurement to the second and third measurements. the mean mdss scores were 24, 11.1, and 6.4 at the first, second, and third measurements, respectively. significant differences were found in mdss scores between the first measurement and that at 3 months, between the first measurement and that at 6 months, and between table 1. demographic characteristics of the patients and the controls and urinary ngf/cr and bdnf/cr levels.* variables patients (n = 24) controls (n = 30) p value boy/girl, no 6/18 8/22 .890 age, month 109.7 ± 31.8 110.7 ± 31.9 .915 weight, kg 30.8 ± 13.8 32.7 ± 15.7 .652 height, cm 132.4 ± 16.6 133.6 ± 17.1 .797 urine ngf/cr ratio 975 ± 827 159 ± 84 < .001 urine bdnf/cr ratio 5.98 ± 5.78 0.81 ± 0.70 < .001 abbreviations: ngf, nerve growth factor; bdnf, brain derived neurotrophic factor, cr: creatinine. * data are presented as mean ± sd. urinary ngf and bdnf in children with voiding dysfunction-ozdemir et al. vol 13 no 03 may-june 2016 2692 the thirdand sixth-month measurements (p < .001, p < .001, and p = .002, respectively; table 2). when ngf/cr ratios were compared among the three measurements, although there was a slight decrease at the third month and some increase at the sixth month, only a marginally significant difference was found between the first and third month measurements (p = .049). however, no significant difference was detected between the first measurement and that at month 6 or between the thirdand sixth-month measurements (p > .05; table 2). comparison of the urine bdnf/cr ratios among the first, second, and third measurements showed significant decreases between the first (before treatment) and second (third month) measurement (p = .005) and between the first and third (sixth month) measurement s (p = .004), but there was no significant difference between thirdand sixth-month measurements (p = .831; table 2). correlation analyses among mdss and ratios of ngf/ cr and bdnf/cr showed significant correlations. positive correlations were found between mdss and ngf/ cr at the first measurement (r = .650, p = .001), between mdss and bdnf/cr at the third month (r = .443, p = .049), and between ngf/cr and bdnf/cr at all three measurement points (r = .713, p < .001; r = .550, p = .010; and r = .443, p = .035, respectively). considering the pre-treatment (first measurement) levels of ngf/cr and bdnf/cr ratios, values of ngf/cr and bdnf/cr were calculated to determine the cut-off point for designating sensitivity, specificity, positive predictive value (ppv), and negative predictive value (npv). at a cut-off level of ngf/cr > 360, the sensitivity was 87.5%, specificity 100%, ppv 100%, and npv 90.9%. at a cut-off level of bdnf > 1.288, the sensitivity, specificity, ppv, and npv values were 87.5%, 83.3%, 80.8%, and 89.3%, respectively (table 3). the roc curve for the first measurements of ngf/cr and bdnf/cr is shown in figure. discussion it is difficult to make a diagnosis and detect disease severity by medical history or symptoms in children with voiding dysfunction. to evaluate treatment efficacy, it is important to be able to determine changes in the severity of clinical symptoms. to make clinical evaluations more objectively, symptom-scoring systems have been developed. in the current study, we used the mdss, developed by akbal and colleagues(16) that detected the mdss cut-off value of 8.5, and the test was shown to have sensitivity and specificity of 90%.(16) before treatment, we determined the scores of mdss to be > 9 in all of our 24 patients. we observed gradually decreasing mdss values during the treatment process, supporting the position that mdss may be used as a clinical measure in the monitoring of treatment responses in voiding dysfunction. in our study, urine ngf and bdnf levels were tested pre-treatment and twice after treatment during follow-up. these values were evaluated together with mdss scores in oab children by clinical and urodynamic examinations. it is known that, ngf is secreted from the bladder epithelium and smooth muscle cells in the urinary system, and is detected in high levels in some conditions, such as detrusor over activity, ic/pbs, and oab.(18) in two previous studies, significantly higher ngf and prostaglandin levels were found in adult male and female patients with oab versus healthy controls.(19) in the study pediatric urology 2693 table 2. comparison of the measurement in patient group pre-treatment, at 3rd month and 6th month time points.* variables before treatment a 3rd month b 6th month c p value mdss 24.0 ± 6.1 11.1 ± 6.7 6.4 ± 6.7 a-b < .001, a-c < .001, b-c .002 urine ngf/cr 975 ± 827 660 ± 353 723 ± 435 a-b .049, a-c .097, b-c .531 urine bdnf/cr 5.98 ± 5.78 2.17 ± 1.37 2.24 ± 0.98 a-b .005, a-c .004, b-c .831 abbreviations: mdss, micturition disorder symptom scoring; ngf, nerve growth factor; bdnf, brain derived neurotrophic factor; cr, creatinine. * data are presented as mean ± sd. abbreviations: ppv, positive predictive value; npv, negative predictive value; ngf, nerve growth factor; bdnf, brain derived neurotrophic factor; cr, creatinine. cut-off value sensitivity (%) specificity (%) ppv (%) npv (%) ngf/cr > 360 87.5 100 100 90.9 bdnf/cr > 1.288 87.5 83.3 80.8 89.3 table 3. urine ngf/cr and bdnf/cr cut-off values and their sensitivity, specificity, positive predictive value and negative predictive values. urinary ngf and bdnf in children with voiding dysfunction-ozdemir et al. by liu and colleagues,(20) significantly elevated levels of urinary ngf/cr were detected in patients, and ngf/ cr levels decreased markedly in 50 responsive patients at the third month after treatment, but there was no decrease in 20 unresponsive patients. in the same study, a decrease in urine ngf levels was reported, along with attenuation in urgency, and an increase in urine ngf levels was seen with emerging oab symptoms. although many studies evaluating ngf levels in adult patients with oab have been conducted,(19) there are few studies with children. in the study by oktar and colleagues, urine ngf and ngf/cr levels were measured in 40 pediatric patients with oab and 20 healthy controls.(13) they reported higher ngf levels and higher ngf/cr ratios in the patients before antimuscarinic therapy compared with the healthy controls, with a significant decrease at the sixth month after therapy.(13) in our study, significantly higher ngf/cr levels were detected in 24 pediatric patients with oab compared with the controls before treatment. at the third month, a distinct decrease was observed, but an elevation was seen again at the sixth month. although the sensitivity and specificity of urine ngf/ cr have been reported in adult studies in the literature, no data exist regarding children. in a recent study, the sensitivity and specificity of urine ngf/cr were reported as 61.9% and 68.4%, respectively, in the diagnosis of oab in women,(15) whereas another study on adult patients reported 54.4% sensitivity and 95.6% specificity for ngf/cr in oab diagnoses.(21) in our study, a urine level of ngf/cr > 360 was found to have 87.5% sensitivity for oab diagnosis and 100% ability to correctly distinguish healthy individuals. our results indicate that ngf/cr levels had considerably higher sensitivity and specificity in the diagnosis of oab in children than has been suggested by results in adults. when we evaluated the clinical importance of urine ngf/cr levels related to treatment response monitoring, we detected significant attenuation in response at the third month. only the difference in measurements between the first and third month was statistically significant; no statistically significant difference was detected between the remaining measurements. in addition, although significant gradual decreases in patients’ mdss scores were recorded at the thirdand sixth-month evaluations compared with the initial measurements, indicating a positive treatment response, the lack of parallel decreases in ngf/cr levels indicates that ngf/cr levels may not be a good marker for monitoring treatment responses. in the study by oktar and colleagues, markedly attenuated ngf levels were reported at the sixth month after treatment.(13) in our patient group, although a significant decrease in urine ngf/cr level was seen at the third month, the level at the sixth month was indistinguishable from that of before treatment. also, the correlation of mdss with the ngf/cr level alone before treatment combined with the disappearance of this correlation during treatment suggest that ngf/cr is not a reliable parameter for monitoring treatment response. bdnf is expressed in inflamed bladder tissue,(22) and its expression in the bladder increases dramatically during chronic cystitis and following spinal cord injury.(23) recent studies have shown that urinary bdnf levels are high in patients with interstitial cystitis/painful bladder syndrome u (ic/pbs) and diminish after botulinum toxin injection.(24) in those patients, pain attenuation accompanied the lowered results for bdnf. in comparison with healthy controls, patients with oab have increased levels of urinary bdnf, and a decrease was recorded in bdnf levels following behavior modification and antimuscarinic therapy.(14,25) pinto and colleagues stated that intravenous delivery of a recombinant protein that neutralizes bdnf activity, diminished bladder contractions in rats with chronic cystitis, suggesting bdnf activity has a pivotal role in bladder function.(26) similar to ngf, higher urinary bdnf concentrations were also found in patients with ic/pbs, and the level significantly decreased after botulinum injections.(24) in our study, urinary bdnf/cr levels were significantly higher in patients than in healthy controls and the urine cut-off level of bdnf/cr > 1.288 was determined to have high sensitivity and specificity for figure. roc curve for ngf/cr vs. bdnf/cr values. abbreviations: roc, receiver operating characteristic; ngf, nerve growth factor; bdnf, brain derived neurotrophic factor; cr, creatinine. urinary ngf and bdnf in children with voiding dysfunction-ozdemir et al. vol 13 no 03 may-june 2016 2694 oab diagnosis. thus, we thought that similar to ngf/ cr levels, the bdnf/cr levels also useful parameter for oab diagnosis. this study is the first to evaluate the sensitivity and specificity of ngf/cr and bdnf/cr in children with oab. in one study on adult patients with oab, bdnf/ cr was reported to have 71.4% sensitivity and 89.5% specificity;(15) in another study, the sensitivity and specificity were found as 88.9% and 93.3%, respectively. (21) with regard to the diagnosis of oab, although the sensitivity of ngf/cr and bdnf/cr was at the same level in the present study, the specificity of ngf/cr was higher. in clinical evaluations, a distinct decrease was observed in mdss from the first measurement to the third measurement at sixth month. there was also a decrease in bdnf/cr levels at the third and sixth months compared with the first measurement. the only correlation between mdss and bdnf/cr was seen at the third month. given this, bdnf/cr seems to be a better parameter than ngf/cr for monitoring the treatment response. in a study by antunes and colleagues, ngf/ cr and bdnf/cr levels in urine samples of 21 female patients with oab were shown to decrease significantly following treatment.(15) in our study, bdnf/cr levels were diminished at the third month, and the low levels were preserved at the sixth month, whereas ngf/cr levels were significantly lower only at the third month. in a clinical study conducted by wang and colleagues, a positive correlation was found between a decrease in symptom scores and ngf/cr and bdnf/cr levels.(21) in a study of the relationship between the indevus urgency severity scale (iuss), a scoring system that measures the severity of urgency and urinary dysfunction, and levels of ngf/cr and bdnf/cr, the only association was between bdnf/cr and iuss.(15,21) in the current study, we found positive correlations between ngf/ cr and mdss at the diagnosis and between bdnf/cr and mdss at the third month. we suggest that even though bdnf/cr levels decreased significantly and gradually, the absence of a correlation between bdnf/ cr and mdss, except at the third month, may be related to the small patient population in this study. the results of this study can only be applied to pediatric age group, because we included only children. another limitation of the study is the lack of follow-up for ngf and bdf measurements at the third and sixth months in healthy controls for comparison with the patients. conclusions in conclusion, we evaluated the clinical significance of ngf and bdnf in oab diagnosis and in monitoring treatment responses in children with oab. we showed that urinary ngf/cr could be a useful marker for oab diagnosis, and bdnf/cr may be a beneficial marker for evaluating treatment efficacy in children with oab. conflict of interest none declared. references 1. fotter r, riccabona m. functional disorders of the lower urinary tract in children. radiologie. 2005;45:1085-91. 2. hoebeke p, van laecke e, van camp c, raes a, van de walle j. one thousand video-urodynamic studies in children with non-neurogenic bladder sphincter dysfunction. bju int. 2001;87:575-80. 3. nevéus t, von gontard a, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents: report from the standardization committee of the international children's continence society. j urol. 2006;176:314-24. 4. bael a, lax h, de jong tp, et al. european bladder dysfunction study (european union bmh1-ct94-1006). the relevance of urodynamic studies for urge syndrome and dysfunctional voiding: a multicenter controlled trial in children. j urol. 2008;180:1486-93. 5. kuo hc, liu ht, chancellor mb. urinary nerve growth factor is a better biomarker than detrusor wall thickness for the assessment of overactive bladder with incontinence. neurourol urodyn. 2010;29:482-7. 6. bhide aa, cartwright r, khullar v, digesu ga. biomarkers in overactive bladder. int urogynecol j. 2013;24:1065-72. 7. steers wd, tuttle jb. mechanisms of disease: the role of nerve growth factor in the pathophysiology of bladder disorders. nat clin pract urol. 2006;3:101-10. 8. faydacı g, tarhan f, gül ae, erbay e, kuyumcuoğlu u. mesane çıkım obstrüksiyonunda nerve growth factor reseptörünün rolü. türk ürol derg. 2004;30:72-9 9. skaper sd. the biology of neurotrophins, signaling pathways, and functional peptide mimetics of neurotrophins and their receptors. cns neurol disord drug targets. 2008;7:46–62. 10. kuo hc, liu ht, guan z, tyagi p, chancellor mb. promise of urinary nerve growth factor for assessment of overactive bladder syndrome. luts. 2011;3:2-9. 11. steers wd, kolbeck s, creedon d. nerve growth factor in the urinary bladder of the adult regulates neuronal form and function. j clin invest. 1991;88:1709-15. 12. ochodnicky p, cruz cd, yoshimura n, pediatric urology 2695 urinary ngf and bdnf in children with voiding dysfunction-ozdemir et al. michel mc. nerve growth factor in bladder dysfunction: contributing factor, biomarker, and therapeutic target. neurourol urodyn. 2011;30:1227-41. 13. oktar t, kocak t, iyidoganyo, et al. urinary nerve growth factor in children with overactive bladder: a promising, noninvasive and objective biomarker. j pediatr urol. 2013;9:617-21 14. antunes-lopes t, carvalho-barros s, cruz cd, cruz f, martins-silva c. biomarkers in overactive bladder: a new objective and noninvasive tool? adv urol. 2011;2011:382431. 15. antunes-lopes t, pinto r, carvalho-barros s, et al. urinary levels of brain-derived neurotrophic factor (bdnf) in women with overactive bladder (oab) syndrome correlate with the severity of symptoms. eur urol suppl. 2011;10:277-81. 16. akbal c, genç y, burgu b, ozden e, tekgul s. dysfunctional voiding and ıncontinence scoring system: quantitative evaluation of ıncontinence symptoms ın pediatric population. j urol. 2005;173:969-73. 17. korzeniecka-kozerska a, porowski t, michaluk-skutnik j, wasilewska a, płoński g. urinary nerve growth factor level in children with neurogenic bladder due to myelomeningocele. scand j urol. 2013;47:411-17. 18. jacobs bl, smaldone mc, tyagi v, philips bj, jackman sv, leng ww. increased nerve growth factor in neurogenic overactive bladder and interstitial cystitis patients. can j urol. 2010;17:4989-94. 19. kim jc, park ey, seo si, park yh, hwang tk. nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. j urol. 2006;175:1773-6. 20. liu ht, chancellor mb, kuo hc. decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. bju int. 2009;103:166872. 21. wang lw, han xm, chen ch, ma y, hai b. urinary brain-derived neurotrophic factor: a potential biomarker for objective diagnosis of overactive bladder. int urol nephrol. 2013;46:341-7. 22. oddiah d, anand p, mcmahon sb, rattray m. rapid increase of ngf, bdnf and nt-3 mrnas in inflamed bladder. neuro report. 1998;9:1455-9. 23. qiao ly, vizzard ma. spinal cord injury-induced expression of trka, trkb, phosphorylated creb, and c-jun in rat lumbosacral dorsal root ganglia. j comp neurol. 2005;482:142-9. 24. pinto r, lopes t, frias b, et al. trigonal injection of botulinum toxin a in patients with refractory bladder pain syndrome / interstitial cystitis. eur urol. 2010; 58:360-5. 25. antunes-lopes t, pinto r, barros sc, et al. urinary neurotrophic factors in healthy individuals and patients with overactive bladder. j urol. 2013;189:359-65. 26. pinto r, frias b, allen s, et al. sequestration of brain derived nerve factor by intravenous delivery of trkb-ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis. neuroscience. 2010:166:907-14. urinary ngf and bdnf in children with voiding dysfunction-ozdemir et al. vol 13 no 03 may-june 2016 2696 endourology and stone disease short-term alteration of renal function and electrolytes after percutaneous nephrolithotomy subhabrata mukherjee1,4, rajan kumar sinha2,4*, tarun jindal3,4, pramod kumar sharma4, soumendra nath mandal4, dilip karmakar4 purpose: to analyse the changes in renal function and serum electrolytes in the early post-operative period of percutaneous nephrolithotomy (pcnl). materials and methods: a total of 110 patients with normal renal function, who underwent pcnl in our institute were evaluated prospectively. haemoglobin percentage, packed cell volume, blood urea nitrogen, serum creatinine and serum electrolytes, namely sodium, potassium, chloride and ionized calcium were measured on the day before surgery and after 72 hours of the procedure. renal function was assessed by cockcroft-gault formula and estimated glomerular filtration rate was calculated by modification of diet in renal disease formula. results: serum creatinine increased significantly from a mean value of 0.89 ± 0.199 mg/dl to 0.96 ± 0.252 mg/dl (p = 0.0002) and both creatinine clearance and estimated glomerular filtration rate experienced a significant fall from a median value (interquartile ranges) of 82.99 (72.37 to 96.88) ml/min to 75.38 (63.89 to 94.05) ml/min in case of creatinine clearance (p = 0.0004) and from a mean value of 95.18 ± 19.87 ml/min/1.73 m2 to 89.30 ± 23.14 ml/min/1.73 m2 in case of estimated glomerular filtration rate (p = 0.003). furthermore, there were significant drops in both haemoglobin percentage and packed cell volume. there were no significant alterations in serum electrolytes sodium and potassium (mmol/l) [median (iqr)] changed from a pre-operative figure of 137.5 (134.0 to 140.0) and 3.85 (3.60 to 4.10) to a post-operative value of 138 (135.0 to 140.0) and 3.85 (3.50 to 4.10) respectively. conclusion: even though there is no significant variation in serum electrolytes, pcnl causes significant reduction in renal function in the early post-operative period. keywords: creatinine clearance; estimated glomerular filtration rate; percutaneous nephrolithotomy; serum creatinine; serum electrolytes introduction urinary stones have troubled humans since the ear-liest records of civilization(1). among the various surgical options for management of renal stone, percutaneous nephrolithotomy (pcnl), a minimally invasive endoscopic treatment, has emerged significantly over the last few decades. it is often the preferred treatment option especially for patients with large or complex renal stones, stones that are refractory to shock wave lithotripsy (swl), residual stones after failed alternative modalities and so on(2-4). it is an efficient and safe procedure for removal of renal calculi with low incidence of serious complications(5,6). interestingly, people have different views about the impact of pcnl on renal function in the early post-operative period. on the one hand, stone removal can improve renal function by relieving obstruction and eradicating underlying infection(7). on the other hand, dilation and establishment of nephrostomy tract and associated stone removing procedure may negatively impact func1department of urology, northwick park hospital, london north west university healthcare nhs trust, harrow, uk. 2department of urology, kidney stone and urology clinic, bhagalpur, india. 3department of urology, tata medical centre, kolkata, india. 4department of urology, calcutta national medical college and hospital, kolkata, india. *correspondence: department of urology, kidney stone and urology clinic, bhagalpur, india. tel: +91-9007205371. e-mail: rajan_rims@yahoo.co.in. received april 2018 & accepted may 2019 tional integrity(8-12). to add on, some studies have also demonstrated that kidney function remains unchanged in the initial post-operative period(13-15). apart from that, usage of large amount of irrigation fluids during pcnl may also alter the serum electrolyte levels. in this study attempts have been made to evaluate the changes in renal function in the form of creatinine clearance (crcl) by cockcroft-gault formula (cgf) and estimated glomerular filtration rate (egfr) by modification of diet in renal disease (mdrd) formula in the early post-operative period of pcnl along with estimation of changes in serum electrolytes at the same point of time (16,17). knowledge in this field will help us managing post-operative cases of pcnl in a much better way, especially while making decisions regarding selection of drugs, or offering swl or repeat pcnl. materials and methods study population this prospective observational study was carried out at urology journal/vol 16 no. 6/ november-december2019/ pp. 530-535. [doi: 10.22037/uj.v0i0.4558] vol 16 no 06 november-december2019 531 calcutta national medical college and hospital, kolkata over a period of one and half year. ethical clearance was obtained from the institutional ethical committee when our first author requested for it as a part of his dissertation at the beginning of the study. inclusion and exclusion criteria patients with renal stone who were planned for pcnl (size >2 cm for non-lower pole stones, size > 1 cm for lower pole stones and stones of any size that were swl resistant or within a calyceal diverticulum) and gave consent for the study were included. whereas, patients with age < 18 years; radiolucent stones; preoperative impaired renal function (serum creatinine > 1.4 mg/dl or egfr by mdrd equation < 60 ml/min/1.73 m2); poorly functioning contralateral kidney on intravenous urography (ivu); solitary kidney; history of previous renal surgery; history of swl within 6 months; history of anticoagulant intake or uncontrolled coagulopathy; history of intraoperative or postoperative blood transfusion; patients who required repeat pcnl in same admission with nephrostomy tube in situ; and patients who did not give consent for the study were excluded. a total of 110 patients were ultimately selected following these criteria. procedures all patients underwent thorough clinical evaluation before the procedure. urinary infection, if present, was treated with the antibiotics as per culture and sensitivity report. all patients received injection ceftriaxone (1g) and infusion levofloxacin (500mg/100ml) intravenously just before the procedure(18). standard prone pcnl were performed by the same surgical team using 0.9% normal saline as irrigation solution. all patients received 0.9% normal saline intra-operatively followed by 0.9% normal saline and 5% dextrose solution in 2:1 ratio in first 24 h after operation. serial tract dilatation was done with amplatz fascial dilators up to 26 fr. nephroscopy was performed with 24 fr rigid nephroscope (richard wolf) and stone fragmentation was carried out using swiss pneumatic lithoclast. at the end of the procedure, stone clearance was checked on combined fluoroscopy and nephroscopy. antegrade double j stent (dj stent) was inserted in all the cases. 24 fr nephrostomy tube was placed in case of perforation of pelvicalyceal system, suspected residual fragments, incomplete stone clearance or bleeding from the tract. intraoperative data like number of access, type of access, total procedure time (from cystoscopy to postoperative retrograde dj stenting ± nephrostomy tube insertion), scope time (duration of nephroscopy) and amount of irrigation fluid (only during nephroscopy) were recorded in all the cases. nephrotoxic drugs like aminoglycosides and nonsteroidal anti-inflammatory drugs were avoided during this period(19,20). x-ray of kidney, ureter and bladder (x-ray kub) was performed after 48 hours and nephrostomy was removed before 72 hours unless there was no evidence of big residual fragments. pcnl procedure success was defined as no residual stone visible on x-ray kub. complications were also recorded. evaluations haemoglobin percentage (hb), packed cell volume (pcv), blood urea nitrogen (bun), serum creatinine (secr) and serum electrolytes, namely sodium (na+), potassium (k+), chloride (cl-) and ionized calcium (ica++) were measured on the day before surgery and repeated after 72 hours. crcl (by cgf) and egfr (by mdrd formula) were calculated both pre and post procedure. statistical analysis data were summarized by routine descriptive statistics namely mean and standard deviation (sd) for normally distributed numerical variables and count and percentage for categorical variables. median values with interquartile ranges (iqr) have been presented for numerical variables with skewed distribution. pre and post procedure values of numerical parameters have been table 1. demographic data of the study population along with operative details parameters data no. of patients 110 age (years) [mean ± sd] 40.27 ± 11.525 sex [no. (percentage)] male 70 (63.64%) female 40 (36.36%) body weight (kg) [mean ± sd] 57.09 ± 10.656 laterality of stones [no. (percentage)] left 53 (48.18%) right 57 (51.82%) no. of access [no. (percentage)] one 103 (93.64%) two 7 (6.36%) type of access [no. (percentage)] infracostal 100 (90.91%) supracostal 8 (7.27%) combined 2 (1.82%) total procedure time (min) [mean ± sd] 80.05 ± 20.782 scope time (min) [median (iqr)] 45 (30 to 55) irrigation fluids (l) [mean ± sd] 13.44 ± 6.147 stone clearance [no. (percentage)] complete 78 (70.91%) incomplete 32 (29.09%) effect of percutaneous nephrolithotomy on renal function and electrolytes-mukherjee et al. figure 1. scatter diagram and regression line showing significant positive correlation of preoperative serum creatinine with change in egfr by mdrd formula measured 72 hours after pcnl (r= 0.31 , p = 0.001) compared by paired t test or wilcoxon’s matched pairs signed rank test as appropriate. change in egfr was compared between subgroups by student’s unpaired t test. association between change in egfr and numerical variables were explored by calculating pearson's correlation coefficient r or spearman's rank correlation coefficient rho as appropriate. scatter plots were constructed wherever relevant. analysis has been two tailed and p < .05 has been considered as statistically significant. medcalc version 11.6 (maria kerke, belgium; medcalc software, 2011) was used for statistical analysis. results demographic data of the study population along with operative details are presented in table 1. the comparative preoperative and 72 hours postoperative data are illustrated in table 2. there were no statistically significant alterations in the values of serum electrolytes and bun. however, secr was increased significantly from a mean value of 0.89 ± 0.199 mg/dl to 0.96 ± 0.252 mg/dl (p = .0002). along with it, both crcl and egfr experienced a significant fall from a median value (iqr) of 82.99 (72.37 to 96.88) ml/min to 75.38 (63.89 to 94.05) ml/min in case of crcl (p = .0004) and from a mean value of 95.18 ± 19.87 ml/ min/1.73 m2 to 89.30 ± 23.14 ml/min/1.73 m2 in case of egfr (p = .003). furthermore, there were significant fall in both hb and pcv. preoperative mean values of hb and pcv were 13.78 ± 2.01 gm/dl and 40.59 ± 5.85 percent respectively, and these declined to 11.68 ± 1.74 gm/dl and 34.6 ± 5.21 percent respectively in the postoperative period (p < .0001 in both the cases). the relationship between the change in egfr and different preoperative variables were analysed in detail and are summarised in table 3. sex, post-operative residual stone, age, body weight, total procedure time, scope time and amount of irrigation fluid did not have any significant association with egfr change. although the fall in egfr was more in two-accesses group (a mean drop of 13.94 ± 16.35 ml/min/1.73 m2) compared to one-access group (a mean drop of 5.33 ± 20.94 ml/min/1.73 m2), it did not achieve statistical significance (p = .29). preoperative secr had a significant positive correlation (r = 0.31, p = .001) (figure 1) and preoperative crcl and egfr had a significant negative correlation (r = -0.21, p = .025 and r = -0.35, p = .0002 respectively) with the change in egfr. similarly, the relationship between the change in hb and different preoperative variables were analysed. interestingly, men had significant drop in hb (a mean decline of 2.46 ± 1.93 gm/dl) as compared to women (a mean decline of 1.48 ± 1.39 gm/dl). however, fall in hb was comparable between one access and two accesses both had an average decline of around 2 gm/ dl. only preoperative hb had a significant negative table 2. comparative preoperative and 72 hour postoperative data dataa preoperative 72 hours postoperative p-value na+ (mmol/l) [median (iqr)] 137.5 (134.0 to 140.0) 138 (135.0 to 140.0) .1870 k+ (mmol/l) [median (iqr)] 3.85 (3.60 to 4.10) 3.85 (3.50 to 4.10) .9407 cl(mmol/l) [mean ± sd] 100.94 ± 3.449 101.88 ± 3.534 .0704 ica++ (mmol/l) [median (iqr)] 1.12 (1.00 to 1.23) 1.15 (0.99 to 1.21) .6391 bun (mg/dl) [mean ± sd] 9.34 ± 3.223 9.81 ± 3.887 .2749 serum creatinine (mg/dl) [mean ± sd] 0.89 ± 0.199 0.96 ± 0.252 .0002 creatinine clearance (ml/min) [median (iqr)] 82.99 (72.37 to 96.88) 75.38 (63.89 to 94.05) .0004 mdrd egfr (ml/min/1.73 m2) [mean ± sd] 95.18 ± 19.868 89.30 ± 23.143 .0036 hb (gm/dl) [mean ± sd] 13.78 ± 2.006 11.68 ± 1.742 < .0001 pcv (%) [mean ± sd] 40.59 ± 5.847 34.6 ± 5.215 < .0001 a. categorical variables [no. (percentage)]a change in egfr(ml/min/1.73 m2) [mean ± sd] p-value sex male [70 (63.64%)] -4.67 ± 18.328 .4219 female [40 (36.36%)] -7.99 ± 24.481 no. of access one [103 (93.64%)] -5.33 ± 20.944 .2895 two [7 (6.36%)] -13.94 ± 16.349 post-operative residual stone no (complete clearance) [78 (70.91%)] -7.5397 ± 18.872 .1898 yes (incomplete clearance) [32 (29.09%)] -1.8172 ± 24.538 b. numerical variablesb r or rho value p-value age -0.1543 .1076 body weight -0.02319 .8100 total procedure time -0.005153 .9574 scope time 0.0416 .6661 amount of irrigation fluid -0.06213 .5190 preoperative serum creatinine 0.3056 .0012 preoperative creatinine clearance -0.2131 .0254 preoperative mdrd egfr -0.3506 .0002 a change in egfr was compared between subgroups by student’s unpaired t test. b association between change in egfr and numerical variables were explored by calculating pearson's correlation coefficient r or spearman's rank correlation coefficient rho as appropriate. effect of percutaneous nephrolithotomy on renal function and electrolytes-mukherjee et al. table 3. association between change in egfr and different variables endourology and stone diseases 532 vol 16 no 06 november-december2019 533 correlation with change in hb (r = -0.59, p = < .0001). rest of the parameters did not have any significant correlation with hb change. discussion pcnl is one of the most commonly performed surgical intervention for management of renal stone disease with minimum morbidity(2-6). most of the clinical studies have almost uniformly established that pcnl does not have any significant effect on long term renal function and even, at times, it may ameliorate renal performance (21-23). however, the literature is inadequate and even contradictory regarding the consequence of pcnl on early renal function (table 4). according to webb and fitzpatrick, who worked in a canine model, crcl were similar at baseline, 48 hours, or 6 weeks after the procedure(13). saxby measured urinary crcl and urinary prostaglandin f2α immediately before and at 24 hours and 2 weeks after pcnl.(14) there was no difference in crcl values. although urinary prostaglandin level was increased at 24 hours, it returned to preoperative levels at 2 weeks. additionally, in the study by hegarty and desai, crcl was unchanged in single tract pcnl in the early post-operative period (15). in contrast, there are some literatures suggesting a decline in renal function in the early period after pcnl. handa and colleagues demonstrated a statistically significant fall in gfr in their consecutive animal studies at 1h, 1.5 h and 4.5 h after operation which returned to baseline at 72 hours(8,10). this group also performed a retrospective analysis of 196 patients undergoing single-stage unilateral pcnl and detected an overall significant increase in secr concentration (0.14 ± 0.02 mg/ dl; p < .001) 24 hours after the procedure(8). nouralizadeh and co-workers prospectively evaluated 94 patients who underwent unilateral pcnl and crcl was estimated by cgf preoperatively and at 6, 24, 48 and 72 hours after operation(11). the mean ± sd of preoperative crcl was 87.5 ± 32.2 ml/min, which decreased to 85.5 ± 29.4 ml/min 6 hours after operation. continuous decrease in crcl was observed up to 48 hours after operation (75.9 ± 25.0 ml/min), and then, a slight increase in crcl level was noted at 72 h after operation (81.9 ± 26.4 ml/min) although it was quite low compared to the pre-operative value. the drops in crcl at 24 and 48 hours after pcnl were statistically significant relative to their preoperative values (p < .05). tabibi and associates retrospectively assessed 486 cases that underwent pcnl and crcl was measured by cgf preoperatively and at 6, 24, 48 and 72 hours after operation and on the day of discharge(12). their findings in the initial post-operative days were almost similar to the study by nouralizadeh and colleagues. crcl returned to baseline level at the time of discharge from hospital. interestingly, a study by bayrak and co-workers has table 4. previous studies showing the effect of pcnl on renal function in the early post-operative period study parameter measured time point(s) after preoperative measurement change (compared to preoperative value) a. animal model 1. webb and fitzpatrick (1985) (13) crcl 48 h nil 6 wk nil 2. handa et al (2006) (8) gfr by inulin clearance 1.5 h drop* 4.5 h drop* 3. handa et al (2009) (9) gfr by inulin clearance single tract 1.5 h drop* 4.5 h drop* multiple tract 1.5 h drop* 4.5 h drop* 4. handa et al (2010) (10) gfr by inulin clearance 1 h drop* 72 h nil b. human model 1. saxby (1997) (14) urinary crcl 24 h nil urinary prostaglandin f2α 2 wk nil 24 h rise 2 wk nil 2. handa et al (2006) (8) secr 24 h rise* 3. hegarty and desai (2006) (15) crcl (cgf) single tract post op nil multiple tract post op drop* 4. handa et al (2009) (9) crcl (cgf) single tract 24 h drop* 48 h drop* multiple tract 24 h drop* 48 h drop* 5. nouralizadeh et al (2011) (11) crcl (by cgf) 6 h drop 24 h drop* 48 h drop* 72 h drop 6. bayrak et al (2012) (7) crcl (by cgf) 72 96 h rise* 7. tabibi et al (2014) (12) crcl (by cgf) 6 h drop 24 h drop* 48 h drop* 72 h drop discharge nil * = statistically significant change effect of percutaneous nephrolithotomy on renal function and electrolytes-mukherjee et al. demonstrated an improvement in renal function in the early post-operative period(7). they prospectively evaluated 80 patients who underwent unilateral pcnl and measured crcl by cgf preoperatively and between 72 to 96 hours after operation. the result was a statistically significant increase (104.30 ± 37.30 ml/min preoperative and 112.38 ± 40.1 ml/min postoperative) in crcl. in our study, we prospectively evaluated 110 patients with normal secr and found a statistically significant reduction in both crcl and egfr at 72 hours after unilateral pcnl. the results are in accordance with the outcome of other previous studies that reported a fall in crcl in the early post-operative period(8,11,12). alike other studies sex, age, body weight, total procedure time, scope time and amount of irrigation fluid did not have any significant association with egfr change (7,11,12). in this study, we observed that even though the fall in egfr was more in two-accesses group compared to single-access group, it was not statistically significant (p = .29). handa and colleagues also compared single tract and multiple tracts pcnl in animal and human model and found significant decrease in renal function in both the groups, at 1.5 hours and 4.5 hours in animal study and at 24 and 48 hours in human study, without any significant difference between them(9). similarly, nouralizadeh and co-workers and bayrak and co-workers did not find any significant difference in fall of renal function between the patients with multiple accesses (usually two) and single access(7,11). on the contrary, in the study by hegarty and desai comparing 40 patients with single tract versus multiple tract pcnl (2 to 6 tracts), a significant decrease in crcl was observed in only multiple tract group, whereas there was no change in single tract cohort(15). limited study population and more than two accesses might be the cause of this single divergent result. although in the study by saxby, a fall in serum potassium, sodium and calcium were noted 24 hours after pcnl, majority of other studies including ours did not find any change in electrolytes in the early post-operative period(7,14,,24,25). in the study by sichani and groups serum sodium slightly decreased from preoperative value of 140.3 ± 2.8 meq/l to 140.1 ± 3.6, 139.1 ± 3.4 (p < 0.01) and 139.3 ± 2.7 (p < 0.05) at 6, 24 and 48 h after the operation, respectively(26). it was probably due to the use of hyponatremic solution in postoperative period. one of the limitations of this study is measurement of serum creatinine and electrolytes only 72 hours after operation. it would have been interesting to get some longer term data to determine long term effects. also, the implementation of these wide exclusion criteria may compromise the generalizability of results. in addition, the degree of statistically significant drop in renal function may arguably not be clinically significant in this group of normal creatinine level patients. finally, if the patients were compared with a controlled group that was given anaesthesia and did not perform kidney surgery other factors could have been excluded which may affect the results. conclusions the results of this study show that significant impairment of renal function persists even at 72 hours after pcnl. no alteration in serum electrolytes has been observed during this period. also, no significant difference has been noticed in drop in renal function between the patients with multiple accesses (usually two) and single access. one should keep these factors in mind when planning for pcnl and try to avoid factors which may further impair renal function in the early post-operative period like nephrotoxic drugs, contrast agents, eswl or redo-pcnl. conflict on interest no competing financial interest exist. references 1. stoller ml. urinary stone disease. in: tanagho ea, editor. smith's general urology, 17th ed. new york: the mcgraw-hill companies; 2008. p. 246-77. 2. wolf js jr, clayman rv. percutaneous nephrolithotomy: what is its role in 1997? urol clin north am. 1997;24:43-58. 3. preminger gm, assimos dg, lingeman je, et al. aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005;173:19912000. 4. probst ce, denstedt jd, razvi h. preoperative indications for percutaneous nephrolithotripsy in 2009. j endourol. 2009;23:1557-61. 5. rudnick dm, stoller ml. complications of percutaneous nephrolithotomy. can j urol. 1999;6:872-75. 6. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899-906. 7. bayrak o, seckiner i, erturhan sm, mizrak s, erbagci a. analysis of changes in the glomerular filtration rate as measured by the cockroft-gault formula in the early period after percutaneous nephrolithotomy. korean j urol. 2012; 53: 552–5 8. handa rk, matlaga br, connors ba, et al. acute effects of percutaneous tract dilation on renal function and structure. j endourol. 2006;20:1030-40. 9. handa rk, evan ap, willis lr, et al. renal functional effects of multiple tract percutaneous access. j endourol. 2009;23:1951-6. 10. handa rk, willis lr, connors ba, et al. timecourse for recovery of renal function after unilateral (single-tract) percutaneous access in the pig. j endourol. 2010;24:283-8. 11. nouralizadeh a, sichani mm, kashi ah. impacts of percutaneous nephrolithotomy on the estimated glomerular filtration rate during the first few days after surgery. urol res. 2011;39:129-33. 12. tabibi a, khazaeli m, modir a, abedi a, nabavizadeh p, soltani mh. early effects of percutaneous nephrolithotomy on glomerular filtration rate and determining the potential risk factors responsible for acute postoperative renal function impairment. novel biomed effect of percutaneous nephrolithotomy on renal function and electrolytes-mukherjee et al. endourology and stone diseases 534 vol 16 no 06 november-december2019 535 2014;2:95-101. 13. webb dr, fitzpatrick jm. percutaneous nephrolithotripsy: a functional and morphological study. j urol. 1985;134:58791. 14. saxby mf. effects of percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy on renal function and prostaglandin excretion. scand j urol nephrol. 1997;31:141-4. 15. hegarty nj, desai mm. percutaneous nephrolithotomy requiring multiple tracts: comparison of morbidity with single-tract procedures. j endourol. 2006;20:753-60. 16. cockcroft dw, gault mh: prediction of creatinine clearance from serum creatinine. nephron.1976;16:31-41. 17. levey as, bosch jp, lewis jb, greene t, rogers n, roth d: a more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. modification of diet in renal disease study group. ann intern med. 1999;130:461-70. 18. lai ws, assimos d. the role of antibiotic prophylaxis in percutaneous nephrolithotomy. reviews in urology 2016;18:10-14. 19. walker r. j., duggin g. g. drug nephrotoxicity. annu rev pharmacol toxicol. 2008;28:331-45. 20. stillman mt, schlesinger pa. nonsteroidal anti-inflammatory drug nephrotoxicity. should we be concerned? arch intern med. 1990;150:268-70. 21. al-kohlany km, shokeir aa, mosbah a, et al. treatment of complete staghorn stones: a prospective randomized comparison of open surgery versus percutaneous nephrolithotomy. j urol. 2005;173:469-73. 22. moskovitz b, halachmi s, sopov v, et al. effect of percutaneous nephrolithotripsy on renal function: assessment with quantitative spect of (99m)tc-dmsa renal scintigraphy. j endourol, 2006;20:102-6. 23. ünsal a, koca g, res¸orlu b, bayindir m, korkmaz m. effect of percutaneous nephrolithotomy and tract dilatation methods on renal function: assessment by quantitative single-photon emission computed tomography of technetium-99m-dimercaptosuccinic acid uptake by the kidneys. j endourol. 2010;24:1497-502. 24. khoshrang h, falahatkar s, ilat s, et al. comparative study of hemodynamics electrolyte and metabolic changes during prone and complete supine percutaneous nephrolithotomy. nephrourol mon. 2012;4:622-8. 25. xu s, shi h, zhu j, et al. a prospective comparative study of haemodynamic, electrolyte, and metabolic changes during percutaneous nephrolithotomy and minimally effect of percutaneous nephrolithotomy on renal function and electrolytes-mukherjee et al. invasive percutaneous nephrolithotomy. world j urol. 2014;32:1275-80. 26. sichani mm, kashi ah, al-mousawi s, tabibi a. an assessment of serum sodium within 48 h after percutaneous nephrolithotomy with half-strength saline solution. urol res. 2010;38:413-6. point of technique reconstruction of an incompletely amputated penis with the radical penile crural dissection and radial forearm free flap turgay turan1, bulent erol1*, ismail ulus1, erdem guven2, turhan caskurlu1 keywords: reconstruction; penis; amputation; flap. introduction penile amputation is a rare injury that occurs most frequently because of self-mutilation in patients suffering from psychotic problems, especially schizophrenia. less frequent reasons for penile amputation are non-self-mutilation, trauma due to an industrial or traffic accident, incidents during circumcision, hypospadias repair or surgery for bladder extrophy, surgical resection for malignancy, strangulation by hair coil, and penetrating injuries during war. surgical techniques for penile reconstruction continue to evolve. however, because of the complexity of the penis, repairing and reconstructing this organ remains a great challenge for surgeons, anatomically, functionally, and aesthetically. treatment and care vary depending on the severity of the lesions, the delay in seeking consultation, and the patient’s mental state. the goal of penile reconstruction is to restore urinary and sexual functions with cosmetically acceptable results. ideally, surgical repair should be immediate, to preserve as much viable tissue as possible. this is because no other tissue in the body has the characteristics, in terms of elasticity, texture, and color, to be considered an ideal candidate for genital reconstruction. for penile amputation, microvascular replantation can be preferred as one of the treatments(1). when primary repair with genital tissue is not feasible, skin grafts and various pedicle and free flaps can be used for reconstruction. we report a case of criminal penile amputation that was restored by radical penile crural dissection and use of a radial forearm free flap (rfff) to cover the corpus cavernosum. 1istanbul medeniyet university faculty of medicine, department of urology. 2istanbul university faculty of medicine, department of plastic and reconstructive surgery. *correspondence: istanbul medeniyet university faculty of medicine, department of urology istanbul -turkey. tel: 0090532 352 65 64 fax: 0090 216 5709417. erolbulent@yahoo.com. received july 2017 & accepted november 2017 figure 1. 1a: incomplete amputation of penis; 1b:the release of penile suspensor ligament and the apparence of pubic junction; 1c: flaccid (soft) cavernosal tissue; 1d: artificial erection and the apparence of long cavernosal tissue; 1e: forearm closed by a split thickness skin graft; 1f: a right thigh split thickness skin graft donor site; 1g: penile erection (postoperative 6th month); 1h: a good urinary flow with an orthotopic urethral opening. vol 15 no 02 march-april 2018 55 point of technique 56 case report a 30-year-old man suffered from incomplete criminal amputation of the penis, approximately 2 cm distal from the mons pubis (figure 1a). the victim stopped the bleeding by applying pressure on the penile root and was rescued 3 days after the incident occurred. the cut part of the penis was abolished by the offender. the victim was admitted to an external center and cystostomy was applied immediately. the planned penile reconstruction was delayed because of urethral and perineal edema, and ecchymosis. eight months later, the patient was referred to our clinic. a urological examination revealed a 2-cm penile stump with a closed distal tip and palpable, long, proximal crural tissue. the scrotum and testicles were intact. perineal edema and ecchymosis were resolved, allowing for reconstructive surgery. radical penile crural dissection and the use of a rfff to cover the corpus cavernosum were planned. the proximal part of the remaining penis was dissected. the crus of the penis was dissected and the penile suspensory ligament was released (figure 1b). after radical dissection, the flaccid (soft) length was increased and the artificial erection length was 12 cm (figure 1c, d). the rfff was taken from the left arm and transferred to the penile stump. the deep inferior epigastric artery and vein were mobilized and transferred from the inguinal channel to the penile stump. only one end-toend arterial anastomosis was performed between the radial artery and deep inferior epigastric artery. the radial vein was anastomosed with the deep inferior epigastric vein. neurorrhaphies were performed between the lateral antebrachial cutaneous nerve and the dorsal nerves of the penis. the free radial forearm flap dimension was 10x8 cm. microsurgeon (e.g) have done the microsurgical arterial anastomosis with 8/0 ethilon and venous anastomosis with 9/0 ethilon. neurorrhaphies have done with 9/0 ethilon as well. the flap area was covered with a split thickness skin graft from the right thigh (figure 1e, f). there was moderate blood loss and we did not need any blood transfusion for the patient. operation was finished in 6.5 hours. low-dose aspirin and antibiotics were administered postoperatively for 1 week. the urethral catheter was removed at 2 weeks and a trial of micturition was performed. a successful cosmetic result was accompanied by an acceptable speed of micturition while standing and spontaneous erections, resulting in successful sexual intercourse (figure 1g, h). we planned to perform the second stage of surgery for glans reconstruction, but the patient did not want to undergo a second surgery. penile sensation was intact on follow up. two discrimination tests showed good results at a 6-month follow-up. discussion management of penile amputation varies according to the case upon arrival of emergency services. if the amputated penis tissue is available for surgery, microsurgical replantation should be rapidly applied. phalloplasty is required if replantation cannot be performed. the purpose of reconstructive surgery is to achieve a satisfactory result involving aesthetics and functional use. phallic reconstruction was first described by bogoras in 1936(2). chang et al. performed the first successful rfff phalloplasty in 1984(3). subsequently, the rfff technique became the gold standard treatment for penile reconstruction. an rfff was planned in our case because replantation was not an option. during the operation, only an rfff was used because an adequate length of the penis was obtained by radical dissection. in this phalloplasty technique, several serious complications have been reported, including urethral anastomosis and circulatory system disorders(4). in addition, penile prosthesis implantation is required for correcting erection problems. after urethral anastomosis, the appearance of a urethral fistula frequently occurs and re-operation is required (22–68% of cases)(4). after the penile prosthesis implantation, the rate of re-operation is 25%(5). in the present case, a perfect erection and good continence were obtained after radical penile crural dissection and use of the rfff to cover the corpus cavernosum. this procedure is less challenging than performing a total penile reconstruction including the urethra. there are no similar cases in the literature. if a replantation procedure is not possible, a sufficient length of penis can be obtained via radical dissection within the reconstruction(6). with this technique, potential complications relating to urethral anastomosis and penile prosthesis implantation can be avoided. before the reconstruction process, we can determine whether the length of the penis is adequate with a good physical examination and inducement of an artificial erection. a similar reconstruction process should be considered in future cases to increase the success of surgical repair and decrease the rate of complications. conclusions we believe that radical penile crural dissection and an rfff are good options for an incompletely amputated penis when penile crural length is acceptable. this is an easy and safe procedure that provides acceptable cosmetic results. additionally, urinary flow is good with an orthotopic urethral opening and normal erectile function. innervation using an rfff provides improved sensation to the reconstructed penis. conflict of interest the authors declare that they have no conflict of interest. references 1. babaei ar, safarinejad mr. penile replantation, science or myth? a systematic review. urol j. 2009;4:62-5. 2. bogoras n. uber die volle plastische wiederherstellung eines zum koitus fahigen penis (peni plastica totalis). zentralbl. chir. 1936;22:1271-6. 3. chang t-s, hwang w-y. forearm flap in onestage reconstruction of the penis. plastic and reconstructive surgery. 1984;74:251-8. 4. rashid m, tamimy ms. phalloplasty: the dream and the reality. indian journal of plastic surgery: official publication of the association of plastic surgeons of india. 2013;46:283. 5. garaffa g, spilotros m, christopher na, ralph penis reconstruction by forearm flap-erol et al. dj. total phallic reconstruction using radial artery based forearm free flap phalloplasty in patients with epispadias-exstrophy complex. the journal of urology. 2014;192:814-20. 6. leclair m-d, villemagne t, faraj s, suply e. the radical soft-tissue mobilization (kelly repair) for bladder exstrophy. journal of pediatric urology. 2015;11:364-5. penis reconstruction by forearm flap-erol et al. vol 15 no 02 march-april 2018 57 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran kidney transplantation a comparison of augmentation cystoplasty before and after renal transplantation with the control group basiri a*, simforoosh n, khoddam r, hoseini moghaddam mm, shayani nasab h urology and nephrology research center, shahid labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran abstract purpose: we compared two surgical methods of augmentation cystoplasty (ac), before and after renal transplantation, and the outcomes of both methods with transplant patients with normal bladder function. materials and methods: 1520 kidney transplantations were performed at shahid labbafinejad center between march 1988 and february 2002 of which 36 cases was accompanied with ac. in 20 patients (group a) ac was performed before transplantation. this group consisted of 14 males and 6 females with a mean age of 26.1 (1339) at the time of transplantation. sixteen patients consisting of 11 males and 5 females (mean age 27.3, 12-44) underwent ac after transplantation. eventually 40 transplant patients with normal bladder function were assigned in the control group including 18 males and 22 females with a mean age of 31.2 (11-55) (group c). results: normal graft function was achieved in 16, 13, and 33 patients of groups a, b, and c respectively over the mean follow-up of 70, 59, and 76 months (p<0.7). mean serum creatinine during the follow-up was 1.48±0.4, 1.7±1, and 1.4±0.55 for groups a, b, and c respectively. 9, 12, and 17 patients (26, 64, and 34 cases) with uti requiring hospital admission were observed in the 3 groups respectively. the incident of uti and the resultant hospitalization in group b was more than the one in group c (p<0.03), but it did not differ significantly from group a to group c. conclusion: ac is a safe and effective method to improve the lower urinary system function and with the exception of increased risk of uti following ac after transplantation (group b), there is no considerable difference in the complication rates between ac before and after renal transplantation. as a result, we can perform ac before or after kidney transplantation in patients with dysfunctional lower urinary tract system up to their specific conditions. key words: augmentation cystoplasty, renal transplantation, dysfunctional bladder accepted for publication a comparison of augmentation cystoplasty before and after renal transplantation with the control group introduction the idea of kidney transplantation of patients with reconstructed bladder is fairly new. in 1966 kelly and colleagues introduced kidney transplantation in a patient with dysfunctional bladder who had undergone ileal conduit.(1) in 1982 marshall performed pyeloileocecocystoplasty successfully in a patient with transplanted kidney hydronephrosis due to dysfunctional bladder.(2) since then a number of studies has been published reporting successful ac in renal transplant patients(3, 4), but these few studies has been done with very small sample sizes and short term follow-ups. it is of controversy whether to perform ac before or after the transplant procedure and the appropriate time of ac in association with transplantation is not defined yet. materials and methods 1520 kidney transplant was performed at shahid labbafinejad center between march 1988 and february 2002. 20 patients with dysfunctional lower urinary tract system not responded to conservative therapies had undergone ac during these years and afterwards they received transplanted kidney due to esrd. the gi segments used in reconstruction were ileum in 15, sigmoid colon in 1, and gaster in 4 cases. these patients (group a) included 14 males and 6 females. mean age was 26.1 (13-39) at the time of transplantation. mean interval between transplantation and ac was 33.4 (6-52) months. group b consisted of 16 esrd patients (11males and 5 females, mean age 27.3, 12-44) suffering from dysfunctional bladder in whom transplantation was performed and ac served as the next step. the gi segments used were ileum in 13, sigmoid colon in 2, and gaster in 1 cases. mean interval between the two procedures was 27.2 (2-108) months. we assigned 40 transplant patients with normal lower urinary system in group c as the control group. in order to avoid bias, the next 2 patients who underwent transplant just after each case of group a by the same surgeon were assigned. the resultant group included 18 males and 22 females and their mean age was 31.2 (1155). graft function was evaluated by serum creatinine in this study and the three groups were assessed by measuring mean serum creatinine level, episodes of acute rejection, and episodes of fever due to uti contributed to hospitalization. in addition, graft loss and mortality in each group were compared with another. results were analyzed by chi-square test (fisher's exact test) and leven test. significant p value was identified as p<0.05. results mean follow-up was 70 (14-85) months in group a, 59 (22-70) months in group b, and 76 (20-84) months in group c. no significant difference was seen between the mean follow-ups of them (p>0.1). male to female ratio was 14/6 in group a, 11/5 in group b, and 18/22 in group c, indicating a difference between groups a and c (p<0.04). mean ages of the three groups were 26.1±9, 27.3±11, and 31.2±8 respectively, without any meaningful differences. frequency of acute rejection episodes was approximately similar in groups a, b, and c (1.3±1.1, 1.5±0.9, and 1.1±1 respectively). 2.7±2, 3.8±2.1, and 1.2±0.9 episodes of pyelonephritis occurred in the three groups respectively, showing a considerable difference between groups b and c (p<0.02), but the differences between groups a and c (p>0.1) and groups a and b (p>0.08) was not significant. graft loss was seen in 4(20%), 3(18%), and 7(17%) cases respectively, which was not meaningfully different from each group to another (p>0.7). mortality rate was 2 in group a, one during the dialysis and one due to liver disease and cirrhosis. one patient died in group b of urosepsis following cystoplasty and one death occurred in group c while transplant procedure was in process. no statistic difference was seen in the mortality rates of the groups (p>0.07). the mean duration of warm ischemia was 60±14.4 seconds in group a, 78±23 seconds in group b, and 91.9±63 seconds in group c. there was one living related donor transplant in group a while there was no related donor in group b. in group c, 6 patients received kidney from related donors. a significant difference was observed between this group and group b (p<0.03). discussion 2 a comparison of augmentation cystoplasty before and after renal transplantation with the control group appropriate function of lower urinary system is necessary in order to maintain kidneys intactness. bladder must have a proper volume and a high compliance providing proper reservation and emptying with low pressure. augmentation cystoplasty is a known method in the treatment of bladder dysfunction when it does not respond to conservative therapies. in 1997 alfery and coinvestigators reported the outcomes of performing ac prior to renal transplantation in 10 children with esrd. because of catastrophic complications they recommended performing urinary conduit before transplantation instead of ac.(5) however, our study findings suggest that ac in esrd patients before or after renal transplantation is safe and complications are tolerable. no definite recommendation about the order of ac and renal transplantation has been yielded up to the present time. in 2000 power and coworkers retrospectively studied the outcomes of renal transplantation in 10 patients who had previously undergone ac. over a 27 months follow-up no mortality was reported and one graft lost. they concluded that renal transplantation in patients who had undergone cystoplasty because of dysfunctional bladder is practicable.(6) thomolla and colleagues evaluated 8 transplant recipients in a retrospective study of whom 7 had augmented bladder prior to transplantation (group a) and 1 had undergone ac after transplantation (group b). in the latter case urinary leakage occurred contributing to additional surgery. they stated that in patients with low capacity and low compliance bladders not responded to conservative therapies, performing ac preceding renal transplantation in order to provide desirable bladder reservoir and high compliance is preferred.(7) while mcinerney and mundy described the results of renal transplantation coupled with ac in 8 cases and according to complications such as mucous impaction and pyocystitis (dry cystoplasty) in patients with augmented cystoplasty prior to transplantation (group a) and probable injury to the pedicle of intestinal segment in transplantation in this group, they suggested a 3 to 6 months interval transplantation and subsequent ac.(8) fontaine presented the outcomes of 10 group a and 4 group b recipients of cadaveric kidneys over an 8 month follow-up in his study. a complication such as dry cystoplasty was rare and he concluded that ac is safe to be done either prior or after renal transplantation.(9) our findings indicated that ac is viable in renal recipients and its complications are acceptable. as no dry cystoplasty was observed in group a, it seems to be a rare condition seen only in anuric and severe oliguric patients. complications were similar in groups a and b with the exception of more uti episodes in group b. no meaningful difference in graft function was observed. eventually, it seems that ac is safe in renal transplant patients and viable either prior or after transplantation. conclusion the decision of when to perform ac in esrd patients seems to be dependent on the patient condition. for instance, in anuric or severe oliguric patients it is better to delay ac 3 to 6 months after transplantation, when urinary output has improved and immunosuppressive agents has reached the maintenance dose, in order to avoid dry cystoplasty complication. also in patients with low capacity and low compliance bladder in which irreversible fibrosis has not occurred yet, increasing urinary output may raise the bladder volume and a few months follow-up is preferred after transplantation as in some cases the improvement of bladder function may dispute the necessity of ac. references 1. kelly wd, et al. ileal urinary diversion in conjugation with renal homotransplantations. lancet 1966; 1: 222. 2. marshall ff, smelev jk, spees ek, jeffs rd, burdick jf. the urologic evaluation and management of patients with congenital lower urinary tract anomalies prior to renal transplantation. j urol 1982; 127: 1078. 3. yamazaki y, tanabe k, ota t, ito k, toma h. renal transplantation into augmented dysfunction bladder. int j urol 1998 sep; 5 (5): 423-7. 4. burns mw, watkins sl, mitchell me, tapper d. treatment of bladder dysfunction in chil3 a comparison of augmentation cystoplasty before and after renal transplantation with the control group dren with end stage renal disease. j ped surg 1992; 27: 170. 5. zaragoza mr, ritchey ml, bloom da, mcguire ej. enterocystoplasty in renal transplantation candidates: urodynamic evaluation and outcome. j urol 1993; 150: 1463. 6. barnett mg, bruskewitz rc, belzer fo, sollinger hw, uehling dt. ileocystoplasty bladder augmentation and renal transplantation. j urol 1987; 138. 7. thomalla jv, mitchell me, leapman sb, filo rs. renal transplantation into the dysfunctional bladder. j urol 1989; 141: 265. 8. sheldon ca, gonzales r, burns mw, gilbert a, buson h, mitchell me. renal transplantation into the dysfunctional bladder: the role of adjunctive bladder reconstruction. j urol 1994; 152: 972. 9. mcinerney pd, picramenos d, koffman cg, mundy ar. is cystoplasty a safe alternative to urinary diversion in patients requiring renal transplantation? eur urol 1995; 27: 117. 10. nahas wc, mazzucchi e, antonopoulos a, david-neto e, ianhez le, sabbaga e, arap s. kidney transplantation in patients with bladder augmentation: surgical outcome and urodynamic follow-up. proc 1997; 29: 157. 11. fontaine e, et al. renal transplantation in children with aubmentation cystoplasty: longterm results. j urol 1998 jun; 159 (6): 2110-3. 12. power re, et al. renal transplantation in patients with augmentation cystoplasty. bju int 2000 jul; 86 (1): 28-31. 4 a comparison study between theophylline and placebo in passage of ureteral stones tadayyon f, yazdani m, ebadzadeh mr department of urology, noor hospital, isfahan university of medical sciences, isfahan, iran abstract purpose: considering the high prevalence of urinary system stones and that nonmedical treatments have more costs and side effects, we decided to evaluate the effect of theophylline in the passage of ureteral stones. materials and methods: one hundred and fifty patients with ureteral stones were assigned into groups a and b, whose age, sex, size of stone, and location of stone were matched together. patients' ages ranged from 17 to 67 years. in group a theophylline (200 mg bid) was administered and group b received placebo for six weeks. both groups were followed up by visits every fortnight and radiological assessment was performed at the end of the sixth week. the proportion of patients whose stones were passed was compared between the two groups. result: in group a with theophylline consumption 46 out of 75 (61.3%) passed their stones. the mean duration between the initiation of the treatment with theophylline and stone passage was18.3 days. in group b with placebo, the stone passage occurred in 31 out of 75 (41.3%) patients (p<0.032) and the mean duration was 24.8 days (p<0.05). conclusion: with regard to the findings of this study, it seems that theophylline can increase the rate of ureteral stone passage and as well, accelerate it. key words: theophylline, urolithiasis, stone passage urology journal unrc/iua vol. 1, no. 3, 204-207 summer 2004 printed in iran 204 introduction ureteral stones substantially originate from kidney and then are released into ureter. entrapment of the stone in the ureter and subsequently initiating the symptoms occurs when the stone is greater than 2 mm. factors associated with spontaneous passage of stones consist of size and shape of stone, anatomical narrowing in ureter, ureteral peristalsis, hydrostatic pressure of urine over the stone, edema, and inflammation and spasm of ureteral wall in the stone location. from the above, hydrostatic pressure of urine and relaxation of ureter in the stone location, have a great importance.(1) as concerns the great effect of ureteral relaxation in the stone location and considering that theophylline can relax the smooth muscles of ureteral wall by increasing camp, it comes into question whether theophylline have a positive effect on the passage of ureteral stones or not and if the answer is yes, how much the amount of this effect is. accordingly, we intended to design this study in order to evaluate the effect of theophylline on the ureteral stone passage. materials and methods in this prospective clinical trial, 150 patients with ureteral stone, who had been presented to the urology clinic of noor hospital and did not have the indication of surgical management, were selected. diagnosis of urolithiasis had been confirmed by kub and ultrasonography or ivp. the range of the patients' ages was 17 to 67 years and they were 105 males and 45 females. the stones size varied from 3 mm to 9 mm. the patients were assigned into two groups each contained 75 persons. in order to decrease the confounding factors, the two groups were matched according to gender, age, stone location, and accepted for publication in april 2003 a comparison study between theophylline and placebo in passage of ureteral stones 205 stone size (table 1). matching was done trying to provide identical distributions of gender and age, and minimizing the differences in the size and location of stones. stratified randomization was performed according to the location of the stone and gender. theophylline (200mg/bd) was prescribed for group a, including 23 female and 52 male and placebo (capsules containing sugar) for group b, including 22 female and 53 male. neither the patients nor the data collectors were aware of the kind of prescribed capsules. the analgesic used for pain was the same in both groups. the patients were recommended to control the passage of stone in their urine. the patients' informed consent had been taken by completely instructing the study. both groups were followed up by every fortnight visits and radiological assessment was performed at the end of the sixth week. the groups were compared with each other according to the passage of the stone and the duration of the passage from the beginning of the treatment. for statistical analysis proportional competence exam was used. results in group a, 46 out of 75 patients who received theophylline, passed their stones (61.3%); whereas, in group b (placebo), ureteral stone passage occurred in 31 cases (41.3%) (p<0.032). as figure 1 shows, greater proportions of smaller stones were passed in both groups. however, theophylline effect in increasing the percent of stones passed is recognizable in all stone size groups; with regard that the percent of stones 4 mm or smaller, which were passed, was 73% in group b and 94% in group a. in cases with stones between 4 mm and 6 mm, the percent of the passed stones was 58% in group b and 68% in group a. eventually 14% of the stones 6 to 8 mm in diameter were passed in group b, whereas this percent was 28% in group a (table 2). in this study, age and gender did not influenced theophylline effect on stone passage. mean duration from the beginning of treatment to stone passage was 24.8 (range 4 to 41) days in group b and 18.3 (range 2 to 33) days in group a (p<0.05). discussion several factors are associated with ureteral stone passage, of which the most important is stone diameter. in one study it has shown that the probability of spontaneously stone passage in stones smaller than 4 mm, 4 to 6 mm, and larger than 6 mm in diameter are 80%, 59%, and 21%, respectively.(2,3) furthermore, the rate of spontaneous passage largely depends on the stone location. this rate in upper, mid, and lower ureter was 22%, 46%, and 71%, respectively, attained in a study by morse and colleagues.(4) also, miller et al(5) demonstrated that being smaller and more distal in ureter was associated with higher probability of stone passage as well as being in the right ureter; however, age, sex, and intensity of pain had no effect. in this study table 1. characteristics of stone size and location in study (a) and control (b) groups. table 2. number of passed stones in study and control groups according to the size of stones. ureteral stones study (a) group no.(%) control (b) group no.(%) size of the stone =<4 mm 16 (21.3) 15 (20) >4 mm and =<6 mm 38 (50.6) 38 (50.6) >6 mm and =<8 mm 14 (18.6) 14 (18.6) >8 mm and =<9 mm 7 (9.3) 8 (10.6) location of stone upper 7 (9.3) 8 (10.6) middle 17 (22.6) 16 (21.3) lower 51 (68) 51 (68) total 75 (100) 75 (100) size of the stone study (a) group no.(%) control (b) group no.(%) =<4 mm 15 (94) 11 (73) >4 mm and =<6 mm 26(68) 18 (58) >6 mm and =<8 mm 4 (28) 2 (14) >8 mm and =<9 mm 1 (14) 0 (0) fig. 1. the rate of passed stones in each group according to the size of the stone � �� �� �� �� �� �� �� � � ��� ��� �� �� �� ��� ��� �� �� �� ��� �� �� ���������� � � �� � � �� � � � � � � � �� �� � � � ����� ������� a comparison study between theophylline and placebo in passage of ureteral stones 206 in1999, it was observed that ample treatment period for the stones, 2 mm or smaller in size, was 31 days, and for the stones 2 to 6 mm was 40 days. in our study, the average duration from the beginning to the end of passage was 18.3 days in group a and 24.8 days in group b. there are different methods in treatment of urinary stones. in a research on 180 patients with urinary stones, performed in the united states, they showed a tendency towards medical treatment, specially in the ones who had undergone interventional procedures such as surgery, eswl, etc.(6) concerning the effects of different medical agents on ureter, it has been observed that although ureteral smooth muscles relaxation may be independent on cyclic nucleotides, it is believed that cyclic adenosine monophosphate (camp) has a mediatory role in ureteral relaxation depending on β-adrenergic agonists in smooth muscles.(1) in a research in 2001, it was seen that isoproterenol sulfate, as a β-agonist adrenoreceptor, largely decreased the friction between artificial stone and ureteral wall in rabbits and it was strongly suggested that loosening of smooth muscles by means of β-adrenergics can decrease the ureteral wall tension as the mechanical inhibitory effect of stone movement.(7) in another study, it was demonstrated that the inhibitory effect of prostaglandin e1 on the function of ureter in hamsters is along with increasing the level of camp.(8) moreover, it was seen that the inhibitors of phosphodiesterase enzyme such as theophylline and papaverine can increase the level of intra-cellular camp and subsequently, relax ureteral smooth muscles.(1) theophylline is an agent that directly relaxes the smooth muscles in bronchi and vessels, and so does in ureter. this effect seems to be largely associated with increasing camp. the other suggested mechanisms for theophylline effect are: changing the concentration of calcium ion in smooth muscles, inhibiting the prostaglandin effects on smooth muscles, blocking adenosine receptors, and inhibiting of histamine and leukotrienes release from mastocytes. theophylline also has other effects such as dilation of coronary arteries, increasing the urine output, and stimulation of brain, heart and skeletal muscles. it is highly absorbed orally. it metabolizes in liver through which it is converted into caffeine. theophylline is removed by kidneys, almost 10% of which is detectable unchanged in urine.(9) in a study by becker et al, the effect of theophylline on ureteral peristalsis was investigated. they concluded that it can be used in renal colic and hence, it can ease the passage of ureteral stones.(10) in another study, it was shown that invitro relaxing of rabbit ureter by theophylline facilitates the stone passage.(11) referring to authentic databases, it is seen that the other researches are in process, such as the one by audsoo and asuanc in yale urology department. conclusion due to theophylline's effect on relaxing of ureteral smooth muscles, and the relaxation of the ureter in stone site, the administration of the drug in selected patients with ureteral stone will facilitate the ureteral stone passage. references 1. weiss rm. physiology and pharmacology of the renal pelvis and ureter. in: in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell's urology. 8th ed. philadelphia: wb saunders; 2002. p. 377-403. 2. stoller ml, bolton dm. urinary stone disease. in: tanagho ea, mcaninch jw, editors. smith's general urology. 15th ed. mcgraw hill; 2000. p. 291-320. 3. ueno a, kawamura t, ogawa a, et al. relation of spontaneous of ureteral calculi to size. urology 1997; 109: 544-546. 4. morse rm, resniak mi. ureteral calculi, natural history and treatment in an era of advanced technology. j urol 1991; 145: 263-265. 5. millen f, kane cj. time to stone passage for ureteral calculi; a guide for patient education. j urol 1999; 162: 688-691. 6. kuo rl, aslan p, abrahamse ph, et al. incorporation of patient preference in the treatment of upper urinary tract calculi. j urol 1999; 162: 1913-8. 7. miyatake r, tomiyama y, murakami m, et al. effects of isoproterenol and butylscopolamine on the friction between an artificial stone and the intraureteral wall in rabbit.j urol 2001; 166: 1083-1087. 8. vermue na, den hertog a. the action of prostaglandins on ureter smooth muscle of guinea pig. eur j pharmacology 1997; 142: 163-7. 9. bradley ju, lowrence l. drug used in the treatment of asthmian. in: hardman jg, limibird el, editors. goodman and gilmans' the pharmacologic basis of therapeutics. tenth ed. mcgraw hill; 2001. p. 733-751. a comparison study between theophylline and placebo in passage of ureteral stones 207 10. becker aj, stief cg, meyer m, et al. the effect of the specific phosphodiestrase-iv-inhibitor rolipram on the ureteral peristalsis of the rabbit and in vivo. j urol 1998; 160: 920-925. 11. aquino rd, prodigalidad am, reyes jac, et al. invitro relaxation of rabbit ureter using theophylline to facilitate passage of an artificial ureteral stone. philippine journal of urology 1993; 3: 3-8. endourology and stone disease serum antioxidant enzyme levels are decreased in patients with urinary calcium oxalate stones omer onur cakir,1* mehmet gokhan culha,2 serdar arisan3, elif damla arisan4, murat altin,5 sam ward,6 oguzhan zengi,7 erbil ergenekon3 purpose: to compare the serum antioxidant enzyme levels between patients with urinary stone disease and healthy volunteers to determine the effect of cellular oxidative stress on urinary calcium oxalate stones formation. materials & methods: a total of 51 patients with proven urinary calcium oxalate stones (female 35.3%, mean age: 49.3 years) and 37 healthy subjects (female 45.9%, mean age: 44.1 years) were included. the serum levels of antioxidant catalase, glutathione peroxidase, superoxide dismutase and lipid peroxidation were measured in serum samples taken from the peripheral venous circulation. results: mean serum catalase level of patient group was insignificantly higher than healthy subjects (7.54 mmolh 2 o 2 /mg/sec versus 6.16 mmolh2o2/mg/sec, respectively; p = .06) whereas mean superoxide dismutase level (1.56 u/ml versus 3.86 u/ml, p = .047), glutathione peroxidase level (6.70 u/ml versus 8.19 u/ml, p = .022) and lipid peroxidation level (2.35 nmol/ml versus 3.31 nmol/ml, p = .034) of patient group were significantly lower than healthy subjects. patients with family history of urinary stone disease had significantly lower mean serum levels of catalase (p = .037), superoxide dismutase (p = .047) and glutathione peroxidase (p = .01), compared with patients without family history. conclusion: the findings of this study provide evidence regarding the role of oxidative stress in the development of urinary calcium oxalate stones. future clinical trials are necessary to elucidate the actual mechanisms of the calcium oxalate stone formation in the environment with increased oxidative stress. keywords: antioxidants; calcium oxalate; oxidative stress; reactive oxygen species; urinary stone disease. introduction with its increasing prevalence and economic bur-den, urinary stone disease continues to be a major health problem(1). it is expected that a climate-related increase of 1.6-2.2 million lifetime cases of nephrolithiasis will happen by the year 2050, which will result in a cost increase of $0.9-1.3 billion annually (year-2000 dollars)(1). however, our understanding related to the stone formation pathophysiology remains limited in spite of the recent studies, which demonstrated the crystallization and plaque formation mechanisms(2). the urinary stone formation is considered as a complicated physicochemical disorder. the epithelial cells inside the renal tubules respond to alterations in the urinary environment(3). these most crucial changes in urinary complex in the case of calcium oxalate (caox) stone formation are dysregulated mineral metabolism, abnormal levels of calcium, oxalate, phosphate and citrate. moreover, the increased production of crystallization modulating macromolecules plays an important role in the formation caox stone(4). it is well known that, the reactive oxygen species (ros) are involved in the process of caox stone formation as signalling molecules as well as agents of inflammation and injury(5). the plaque formation in kidney is triggered by ros and the formation of oxidative stress (os). exposure of the renal epithelial cells to high levels of caox/calcium phosphate (cap) crystals and oxalate generates excess ros, causing injury and inflammation(6). several authors demonstrated that reactive oxygen species (ros) may be involved in urinary stone formation (5,7). some of these studies reported increased renal enzymes in the urine of patients with calcium oxalate 1department of urology, bagcilar training & research hospital, istanbul. 2department of urology, samatya training and research hospital, istanbul, turkey. 3department of urology, sisli etfal training & research hospital, istanbul. 4department of molecular biology & genetics, kultur university, istanbul. 5department of psychiatrics, medical park gazi osman pasha hospital, istanbul, turkey. 6department of urology, kliniek sint jan hospital, brussels, belgium. 7department of biochemistry, bagcilar training and research hospital, istanbul, turkey. *correspondence: merkez mah. mimar sinan cad. 6. sokak 34200 bagcilar, istanbul, turkey. phone: +90-532-685-05-26. fax: +90-212-440-40-40. e-mail: omeronurcakir@gmail.com. received august 2016 & accepted june 2017 endourology and stone diseases 4015 (caox) stone, indicating ros associated renal damage (8), whereas some others identified antioxidant enzymes in the inner core of caox stones, suggesting their role in the nucleation process leading to inner matrix formation (9). results of the recently conducted national health and nutrition examination survey iii (nhanes iii) which included 17,695 subjects confirmed that patients with a kidney stone history have significantly lower serum antioxidants levels(10). however, the type of the stones was not specified in nhanes iii. this case-control study aims to compare the serum antioxidant levels between patients with urinary caox stones and healthy volunteers to determine the effect of cellular os on the development of urinary stone disease. considering the findings of this study, urologists may initiate antioxidant treatment in patients with caox stone disease. patients and methods patient selection a total of 85 patients with the diagnosis of caox urinary stone disease who were treated at our institution were screened. patients (n = 34) with any comorbidities (e.g. malignancy, hypertension, congestive cardiac failure, diabetes mellitus), history of eswl treatment within the last 3 months, urinary tract infection and/or who were using antioxidant supplements were excluded. after obtaining written informed consent of the patients, their medical history was taken and physical examination was performed. the patients provided their urine sample for urine analysis and urine culture. midstream urine samples were collected and evaluated immediately for urinary tract infections. patients with positive urine culture were excluded from the study. the presence of the urinary stones was confirmed with imaging studies such as kidney-ureter-bladder (kub) radiography, urinary ultrasonography, intravenous pyelography (ivp) or non-contrast-enhanced abdominopelvic computed tomography. the patients underwent ureterorenoscopy, percutaneous nephrolithotomy and open kidney stone surgery according to the size and location of the stone. the removed stone fragments were analysed with quantitative x-ray diffraction phase analysis and the stone type was assigned. patients whose urinary stone was not purely comprised of caox were excluded from the patient group and 51 eligible patients with confirmed caox urinary stone were included. a total of 37 healthy volunteers without any urinary stones according to the urine test, kub radiography and medical history constructed the control group. participants with any comorbidities and smoking habit were excluded. the study protocol was approved by the institutional ethics committee of istanbul sisli etfal research and training hospital. patients provided their informed consent prior to their enrolment into the study. laboratory methods patients and healthy subjects provided their venous blood sample for the measurement of serum antioxidant levels, which indirectly reflect the os of the patients and controls. blood samples were taken from patients who underwent stone removal surgery in the morning of the surgery day before induction of anesthesia. morning blood samples were taken from controls as well. the 2.5 ml blood samples were drawn from brachial vein into edta containing tubes. the samples were centrifuged at 1500 rpm for 5 minutes and extracted serum was preserved at -20° c until the levels of antioxidant catalase, superoxide dismutase, glutathione peroxidase and the level of malondialdehyde (mda) as the product of lipid peroxidation were determined, respectively. the serum samples were defrosted for the assessment of antioxidant enzyme activities with spectrophotometry (shimadzu, japan). superoxide dismutase and glutathione peroxidase enzyme activities are analysed with specific kits in accordance with the instructions of the manufacturer (randox laboratories limited, uk). the performance characteristics of superoxide dismutase and glutathione peroxidase kits and the other lab assays were shown in table 2. catalase activity was evaluated in serum at 25° c. the reaction related to h2o2 substrate was spectrophotometrically measured at 240 nm for 30 seconds and the activity was measured in mu/l. one unit of catalase activity was equal to the 1 μmol h2o2 synthesized per minute. lipid peroxidation was assessed by the measurement of thiobarbituric acid reactive substances (tbars) level inside the serum. mda was measured spectrophotometrically in 532 nm wavelength after the reaction with thiobarbituric acid and the results were table 1. demographic characteristic of the patients and healthy subjects. patients (n=51) healthy subjects (n=37) p age (mean ± sd) 49.3 ± 16.20 44.13 ± 13.05 0 .008* male 50.3 ± 17.28 44.24 ± 13.17 < 0.001* female 47.44 ± 14.3 44 ± 13.3 0.02* urinary stone family history; n (%) 31 (60.8) 8 (21.6) < 0.001** smoking history; n (%) 26 (51) 20 (54.1) 0,68** alcohol history;n (%) 10 (19.6) 10 (27.2) 0.43** body mass index, mean ± sd (kg/m2) 26.09 ± 3.2 22.97 ± 2.66 < 0.001* *mann-whitney u test **chi-square test oxidative stress and urinary calcium oxalate stone disease-cakir et al. vol 14 no 04 july-august 2017 4016 recorded as nmol/ml. statistics methods kolmogorov-smirnov test was used to determine the distribution of the data. student’s t test was used for the comparison of the antioxidant enzyme levels in patients with urinary caox stones and healthy controls. chi-square test was used for comparison of alcohol and smoking status. the statistical analyses were performed on ibm spss statistics (ibm corp. released 2012. ibm spss statistics for windows, version 21.0. armonk, ny: ibm corp). results a total of 51 patients with caox stones (female 35.3%, mean age: 49.3 years) and 37 healthy subjects (female 45.9%, mean age: 44.1 years) were included in the study. the stone patient population was older, had a higher bmi and had a greater proportion of males that the control population (table 1). mean serum catalase level of patient group was insignificantly higher than healthy subjects whereas mean superoxide dismutase level, glutathione peroxidase level and mda level of patient group were significantly lower than healthy subjects (table 2). in addition, patients with family history of urinary stone disease compared to those without family history had significantly lower mean serum levels of catalase (6.77 mmol h2o2/mg/sec versus 8.23 mmol h2o2/mg/sec, respectively; p = .037), mean superoxide dismutase level (1.44 u/ml versus 1.67 u/ml, respectively; p = .047), mean glutathione peroxidase level (6.11 u/ml versus 7.11 u/ml, respectively; p = .01). although mean mda enzyme activities were also lower among patients with family history of urinary stone disease, this difference did not reach statistical significance (2.45 nmol/ml versus 2.78 nmol/ml, p = .064) (table 3). discussion the etiological factors of the urinary stone disease are one of the most popular research topics in the field of urology. recent reports confirmed the possible role of the ros in stone formation (5,7-9). although the exact mechanism, by which ros contributes to the stone formation, is not clear, it is well known that, the ros are involved in the process of caox stone formation as signalling molecules as well as agents of inflammation and injury (5). the inflammation and os markers have been detected in urine samples of stone patients and in the urine of rats with experimentally induced caox nephrolithiasis(6). moreover, studies using animal models and tissue cultures reported that; antioxidant treatments may reduce crystal and oxalate induced injury(4). several authors demonstrated that antioxidant containing fruit juices and diets are associated with reduced risk for kidney stones(11-15). exposure of the renal epithelial cells to high levels of caox/calcium phosphate (cap) crystals and oxalate generates excess ros, causing injury and inflammation(6). the plaque formation in kidney is triggered by ros and the formation of os(6). the major mechanism of action can be explained as follows: ros regulate crystal formation, growth and aggregation by affecting the modulators responsible for the crystallization process. it is known that, there is an overproduction of ros and a decrease in the antioxidant capacity resulting in os, renal injury and inflammation, which may stimulate the caox stone formation(16). the availability of ros is controlled by several scavenging systems such as superoxide dismutase, glutathione peroxidase and catalase. superoxide dismutase eliminates superoxide anion (o 2 –•). however, glutathione peroxidase and catalase detoxify hydrogen peroxide (h 2 o 2 )(5,6). the level of os was assessed by the lipid peroxidation oxidative stress and urinary calcium oxalate stone disease-cakir et al. table 2. antioxidant enzyme activities of the patients and healthy subjects. patients (n=51)* healthy subjects (n=37)* p plasma catalase(mmolh 2 o 2 /mg/sec) 7.54 ± 1.34 6.16 ± 0.72 0.062 glutathione peroxidase (u/ml) 6.7 ± 1.61 8.19 ± 0.13 0.022 superoxide dismutase (u/ml) 1.56 ± 0.46 3.86 ± 0.58 0.047 malondialdehyde (nmol/ml) 2.35 ± 0.45 3.31 ±0.4 0.034 *result are given as mean ±sd (standard deviation) patients w/ history (n=31)* patients w/o history (n=20)* p catalase (mmolh 2 o 2 /mg/sec) 6.77 8.23 0.037 glutathione peroxidase (u/ml) 6.11 7.11 0.010 superoxide dismutase (u/ml) 1.44 1.67 0.047 malondialdehyde (nmol/ml) 2.45 2.78 0.064 abbreviations: w/ history, with urinary stone family history; w/o history, without urinary stone family history *result are given as mean (min-max) table 3. antioxidant enzyme activities of the patients with or without urinary stone family history. endourology and stone diseases 4017 assay, by measuring the amount of malondialdehyde (mda) due to oxidative stress as an end product of the lipid peroxidation process(17). there are only few reports, which assessed the serum antioxidant levels in kidney stone patients. the nhanes iii previously reported that elevated levels of serum antioxidants were inversely related to the prevalence of kidney stones(10). the authors evaluated the data of the 17,695 adult subjects and revealed the overall prevalence of kidney stones as 5.25%. furthermore, the authors detected a significant association between lower levels of alpha-carotene, beta-carotene and beta-cryptoxanthin, and the prevalence of kidney stones. in a prospective study, tracy et al.(18) demonstrated that recurrent stone formers have increased oxidative stress as measured by serum lipid peroxidation and thiobarbituric acid reactive substances levels. the authors also recorded that the antioxidant characteristics of the pomegranate extract supplementation may confer some modest benefit in preventing crystal formation among patients with caox stones. to our knowledge, serum antioxidant levels have not been specifically studied in patients with urinary caox stone disease before. our results demonstrated lower serum catalase, superoxide dismutase, glutathione peroxidase and mda levels among caox stone disease patients compared with healthy controls. these differences were statistically significant in all antioxidants except catalase. moreover, these antioxidants (except mda) were significantly lower among patients who had a family history of urinary stone disease, compared to those without familial urolithiasis history. to our knowledge, this finding has not been reported before and it provides further evidence regarding the involvement of oxidative stress in the stone formation suggesting that hereditary disorders in the production of antioxidants may play role in the occurrence of caox stones. as mda is an end product of lipid peroxidation process, the severity of os can be indicated with higher mda levels(6). however in our study the mda levels were reported lower in patients with caox stones. the small patient group should be the possible reason of that result. our study is not without limitation. first of all, having a larger study group may also detect lower catalase levels in patients with caox stones. unfortunately, we did not calculate the sample size prior to the commencement of the study because of not having any estimation related to the antioxidant enzyme levels. moreover, the patients were not matched with the control subjects in terms of demographic data. therefore, future studies with matched-control group must be designed. secondly, we could not assess the impact of hypertension and diabetes, both of which are linked to increased oxidative stress (19-22), because of excluding all the stone patients with comorbidities. performing a logistic regression analysis that includes these comorbidities along with age and bmi as confounding factors would be more appropriate to clarify the actual role of os on the pathophysiology of caox stones. lack of data on the markers of os is another limitation of the study. lower mda levels detected in the patient group may also be considered as a limitation. future studies with larger patient groups using additional oxidative stress parameters are needed to confirm rational values. moreover, having the levels of urinary ros and/or antioxidant levels would increase the validity of our findings. finally, assessment of the correlation between the stone volume and antioxidant levels would confirm the validity of our findings. conclusions the outcomes of this study provide evidence regarding the role of os in the urinary caox stone disease. future clinical trials are necessary to elucidate the actual mechanisms of the caox stone formation in the environment with increased os. references 1. brikowski th, lotan y, pearle ms. climaterelated increase in the prevalence of urolithiasis in the united states. proc natl acad sci u s a. 2008;105:9841-6. 2. coe fl, evan ap, lingeman je, worcester em. plaque and deposits in nine human stone diseases. urol res. 2010;38:239-47. 3. khan sr. role of renal epithelial cells in the initiation of calcium oxalate stones. nephron exp nephrol. 2004;98:e55-60. 4. khan sr. crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies. clin exp nephrol. 2004;8:75-88. 5. khan sr. reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: evidence from clinical and experimental investigations. j urol. 2013;189:803-11. 6. khan sr. reactive oxygen species, inflammation and calcium oxalate nephrolithiasis. transl androl urol. 2014;3:256-76. 7. khan sr. hyperoxaluria-induced oxidative stress and antioxidants for renal protection. urol res. 2005;33:349-57. 8. boonla c, wunsuwan r, tungsanga k, tosukhowong p. urinary 8-hydroxydeoxyguanosine is elevated in patients with nephrolithiasis. urol res. 2007;35:185-91. 9. mushtaq s, siddiqui aa, naqvi za, et al. identification of myeloperoxidase, alphadefensin and calgranulin in calcium oxalate renal stones. clin chim acta. 2007;384:41-7. 10. holoch pa, tracy cr. antioxidants and selfreported history of kidney stones: the national health and nutrition examination survey. j endourol. 2011;25:1903-8. 11. wabner cl, pak cy. effect of orange juice consumption on urinary stone risk factors. j urol. 1993;149:1405-8. 12. tugcu v, kemahli e, ozbek e, et al. protective effect of a potent antioxidant, pomegranate juice, in the kidney of rats with nephrolithiasis induced by ethylene glycol. j endourol. 2008;22:2723-31. 13. ilbey yo, ozbek e, simsek a, cekmen m, somay a, tasci ai. effects of pomegranate oxidative stress and urinary calcium oxalate stone disease-cakir et al. vol 14 no 04 july-august 2017 4018 endourology and stone diseases 4019 juice on hyperoxaluria-induced oxidative stress in the rat kidneys. ren fail. 2009;31:522-31. 14. taylor en, fung tt, curhan gc. dash-style diet associates with reduced risk for kidney stones. j am soc nephrol. 2009;20:2253-9. 15. ebisuno s, morimoto s, yasukawa s, ohkawa t. results of long-term rice bran treatment on stone recurrence in hypercalciuric patients. br j urol. 1991;67:237-40. 16. khan sr. renal tubular damage/dysfunction: key to the formation of kidney stones. urol res. 2006;34:86-91. 17. dargel r. lipid peroxidation--a common pathogenetic mechanism? exp toxicol pathol. 1992;44:169-81. 18. tracy cr, henning jr, newton mr, aviram m, bridget zimmerman m. oxidative stress and nephrolithiasis: a comparative pilot study evaluating the effect of pomegranate extract on stone risk factors and elevated oxidative stress levels of recurrent stone formers and controls. urolithiasis. 2014;42:401-8. 19. obligado sh, goldfarb ds. the association of nephrolithiasis with hypertension and obesity: a review. am j hypertens. 2008;21:257-64. 20. lieske jc, de la vega ls, gettman mt, et al. diabetes mellitus and the risk of urinary tract stones: a population-based case-control study. am j kidney dis. 2006;48:897-904. 21. jeong ig, kang t, bang jk, et al. association between metabolic syndrome and the presence of kidney stones in a screened population. am j kidney dis. 2011;58:383-8. 22. khan sr. is oxidative stress, a link between nephrolithiasis and obesity, hypertension, diabetes, chronic kidney disease, metabolic syndrome? urol res. 2012;40:95-112. oxidative stress and urinary calcium oxalate stone disease-cakir et al. urological oncology factors that predict neutropenia in korean patients with advanced urothelial cancer after cisplatinbased systemic chemotherapy whi-an kwon, tae hoon oh, jea whan lee, ill young seo, and seung chol park* purpose: the aim of this study was to identify factors that can be used to predict severe neutropenia (grade 3 or higher) in patients with advanced urothelial cancer after cisplatin-based systemic chemotherapy. materials and methods: the study examined 79 korean patients with advanced urothelial cancer who were treated with several cycles of cisplatin-based systemic chemotherapy from may 2006 to may 2015. risk factors for neutropenia (grade 3 or higher) and for the occurrence of neutropenia (grade 3 or higher) during the first cycle of chemotherapy were examined. result: thirty-six out of the 79 patients (45.6%) developed neutropenia at grade 3 or higher during the first cycle of cisplatin-based systemic chemotherapy: 18 (22.7%) of these experienced grade 3 neutropenia and 18 (22.7%) experienced grade 4. multivariate analysis identified pretreatment neutrophil counts (p = .001) as the only significant factor predictive for severe neutropenia. conclusion: the pretreatment neutrophil count was found to be the factor that poses a significant and independent risk in development of severe neutropenia induced by applying cisplatin-based systemic chemotherapy to patients with advanced urothelial cancer. keywords: bladder cancer; cisplatin; metastasis; neutropenia; predictive factor. department of urology, wonkwang university school of medicine, institute of wonkwang medical science, iksan, republic of korea. *correspondence: department of urology, institute of wonkwang medical science, wonkwang university school of medicine and hospital, 895 muwang-ro, iksan 54538, south korea tel: +82 63 8591334. fax: +82 63 858 1181. e-mail: sc.park@wonkwang.ac.kr. received january 2017 & accepted july 2017 introduction there are several different types of urologic can-cer. patients with metastatic urologic cancer usually undergo some form of anticancer chemotherapy. (1) recently, several regimens for urologic anticancer chemotherapy have been reported, including combination anticancer chemotherapy using gemcitabine and cisplatin (gc); indeed, this has come to be the standard treatment option for locally advanced and metastatic urothelial carcinoma.(2) until studies of gc were reported, methotrexate, vinblastine, doxorubicin, plus cisplatin (mvac) was the most used regimen in metastatic urologic cancer.(3) several studies suggested gc as the standard treatment for locally advanced and metastatic urothelial carcinoma because of its similar efficacy and lower toxicity compared with mvac.(4) a phase iii trial was designed to compare gc and mvac. the initial goal of this study was to show the superiority of gc. however, the results showed similar overall survival (os) (mvac: 14.8 months vs. gc: 13.8 months) and objective response rates (mvac: 45.7% vs. gc: 49.4%).(2,5) importantly, the gc group experienced significantly fewer side effects such as neutropenic sepsis (mvac: 12% vs. gc: 1%) and grade 3–4 mucositis (mvac: 22% vs. gc: 1%) than the mvac group.(2, 5) thus, due to lower toxicity, gc was considered the standard treatment for locally advanced and metastatic urothelial carcinoma. platinum-based agents such as cisplatin and carboplatin are the first-line chemotherapy agents for advanced urothelial cancer.(6) in vivo, neutrophils serve as the first-line defense against infection, by playing a crucial role at early stages of an inflammatory response and by overseeing the innate immunity. as such, invading bacteria is allowed to multiply when neutropenia weakens inflammatory responses against an infection. and, because the signs and symptoms of an infection are suppressed by neutropenia, patients may display a fever as the only indicative.(7) neutropenia following the application of cytotoxic anticancer drugs is inevitable. several studies identified factors that predict the occurrence of febrile neutropenia (fn) in patients receiving systemic chemotherapy based on an assortment of anticancer drugs.(8,9) the risk factors for febrile neutropenia included old age, serum albumin, baseline neutrophil count, hepatic disease and non-use of granulocyte colony-stimulating factors. neutropenia is defined as an absolute neutrophil count of less than 0.5 × 109/l.(10) an occurrence of neutropenia induced by chemotherapy is the most common type of neutropenia, and such occurrence can be used to define a toxicity line limiting a dose of cytotoxic anticancer treatments.(11) a western study shows that the incidence of docetaxel-induced grade 3-4 neutropenia in patients with castration-resistant prostate cancer is about 25%,(12) whereas a korean study reports an incidence of 17%.(13) as standard treatment for locally advanced and meturological oncology 168 astatic urothelial carcinoma, gc has a certain degree of adverse effects such as fn, despite having lower toxicity than mvac. a study of gc reported that the most frequent grade 3–4 hematologic toxicity was neutropenia in 45.4% for gc.(14) therefore, clinicians must understand the infectious adverse events that may occur during and after chemotherapy for urologic cancer. however, to the best of our knowledge, few studies have identified factors that predict neutropenia in patients with advanced urothelial cancer after cisplatin-based systemic chemotherapy. thus, this study aims to identify factors that can be used to predict neutropenia in patients treated with cisplatin-based systemic chemotherapy and to determine an incidence rate of neutropenia in such patients. materials and methods ethics and informed consent this study was conducted at wonkwang university hospital. written informed consent was obtained from all subjects before enrollment in the study. study protocols and informed consent forms were approved by the institutional review board. study population patients whose medical records show a diagnosis of an advance urothelial cancer and who received one or more cycles of cisplatin-based systemic chemotherapy at wonkwang university hospital, located in iksan, south korea, from may 2006 to may 2015 were reviewed retrospectively. baseline demographic, clinical, and laboratory data including the hemoglobin level, white blood cell (wbc) count, neutrophil count, platelet count, lymphocyte count, neutrophil to lymphocyte ratio (nl ratio), and platelet to lymphocyte ratio (pl ratio) before chemotherapy were collected retrospectively for all patients. this retrospective study was approved by the institutional review board of wonkwang university hospital. treatment protocol the following common urological anticancer chemotherapy regimens were examined: gc and mvac (methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin). all subjects must have required at least one cycle of chemotherapy and none had received prophylactic granulocyte-colony stimulating factor (g-csf) until completion of the first cycle. however, if neutropenic events had occurred, the administration dose of chemotherapy was reduced to 75%. the common terminology criteria for adverse events version 3.0 recommends that neutropenia is defined as a neutrophil count < 1500/mm3. in the present study, the state of neutropenia was divided in four separate grades: grade 1, < 1500/mm3; grade 2, < 1500–1000 / mm3; grade 3, < 1000–500 /mm3; and grade 4, < 500 / mm3 (national cancer institute, 2006). then, incidences of neutropenia ( ≥ grade 3) and potential risk factors for incidences of neutropenia were examined and evaluated during the first cycle of chemotherapy. statistical analysis clinicopathological data obtained for two groups of patients were compared: 1) a group of patients who developed ≥ grade 3 neutropenia during the first cycle of chemotherapy; and 2) a group of patients who did not. in order to compare continuous and categorical parameters between two groups, the mann-whitney u test and fisher’s exact test were used respectively. potential risk factors for grade 3-4 neutropenia in patients with advanced urothelial carcinoma were identified in a unipredictive factors for cisplatin-induced neutropenia-kwon et al. table 1. patient characteristics and pharmacokinetic parameters of cisplatin in the groups with or without severe neutropenia variables without severe neutropenia (n = 43) with severe neutropenia (n = 36) total (n = 79) p value mean age (years) 68.7 ± 8.76 69.8 ± 7.84 69.2 ± 8.29 .474 body mass index (kg/m2) 23.2 ± 3.19 22.8 ± 3.16 22.9 ± 3.15 .599 mean serum hg level (g/dl) 9.6 ± 1.61 9.6 ± 1.28 9.6 ± 1.44 .600 pretreatment wbc count (/mm3) 8152.97 ± 2134.27 6431.67 ± 1618.40 7304.11 ± 2074.04 < .001 posttreatment wbc count (/mm3) 3959.7 ± 1811.86 1944.4 ± 783.52 6928.7 ± 1978.24 < .001 pretreatment neutrophil count (/mm3) 5250.81 ± 2218.56 4005.83 ± 1434.19 4636.85 ± 1963.08 < .001 posttreatment neutrophil count (/mm3) 2067.3 ± 1647.58 500.0 ± 258.67 1294.3 ± 1418.55 < .001 pretreatment serum albumin level (g/dl) 3.84 ± 0.71 4.02 ± 0.59 3.92 ± 0.65 .188 serum creatinine level 1.40 ± 0.64 1.43 ± 0.42 1.41 ± 0.53 .198 pretreatment serum platelet count (/mm3) 277.5 ± 84.66 255.6 ± 74.94 266.7 ± 80.22 .229 pretreatment serum alp level (g/dl) 252.9 ± 125.45 196.4 ± 77.28 225.9 ± 108.25 .030 pretreatment serum lymphocyte count (/mm3) 1933.5 ± 785.94 1611.2 ± 614.87 1774.5 ± 720.38 .101 nl ratio 1.3 ± 1.26 0.4 ± 0.63 0.85 ± 1.07 < .001 pl ratio 170.9 ± 99.30 198.4 ± 160.66 184.4 ± 132.92 .395 charlson comorbidity index 1.8 ± 2.08 1.7 ± 1.36 1.7 ± 1.75 .483 geriatric index 13.6 ± 2.10 13.9 ± 2.01 13.7 ± 2.04 .627 n stage .990 0 23 22 45 1 10 10 20 2 4 3 7 3 1 1 2 performance status (ecog) .378 0 35 35 70 1 2 0 2 2 1 1 2 hydronephrosis .486 no 21 23 44 yes 17 13 30 abbreviations: ecoc, eastern cooperative oncology group; psa, prostate-specific antigen; wbc, white blood cell.; n ratio, neutrophil to lymphocyte ratio; pl ratio, platelet to lymphocyte ratio. the mann-whitney u test and fisher’s exact test were used to compare continuous and categorical variables, respectively, between groups. vol 15 no 04 july-august 2018 169 variate analysis. variables with a p-value > 0.05 were eliminated from the model. significant associated variables from the univariate were entered in a multivariate logistic analysis using backward elimination process. accordingly, a p-value of < .05 was considered significant. spss software, version 15.0, was used in all statistical analyses (spss inc., chicago, il, usa). result seventy-nine patients met the inclusion criterion, i.e., all had histologically confirmed urothelial carcinoma of the urinary tract. the origin site of the tumor was the bladder in 31 patients (39.2%), the ureter in 17 patients (21.5%), and the renal pelvis in 26 patients (32.9%). they were all chemotherapy-naïve patients, but four patients had received radiotherapy previously. cancer had infiltrated the bone marrow in 14 patients before they received chemotherapy. fourteen patients achieved a complete response (17.7%) and nine patients achieved a partial response (11.3%). the mean age of the 79 patients was 69.2 years (range, 46–87 years). the most common chemotherapy regimen was gc (n = 76); only three cases received mvac. median overall survival was 21.7 months (range, 1–66 months). forty-three patients were classified into the “without ≥ grade 3 neutropenia” group (54.4%) and 36 into the “with ≥ grade 3 neutropenia” group (45.6%). the latter developed ≥ grade 3 or more neutropenia during the first cycle of cisplatin-based systemic chemotherapy. thirteen patients (16.5%) experienced grade 1 neutropenia, 20 (16.5%) experienced grade 2, 18 (22.8%) experienced grade 3, and 18 (22.8%) experienced grade 4. of 14 patients who had bone metastasis, 13 experienced neutropenia. six patients (42.9%) experienced grade 1 neutropenia, one (7.1%) experienced grade 2, four (28.6%) experienced grade 3, and two (14.3%) experienced grade 4. however, there was no significant difference between the without and with ≥ grade 3 neutropenia groups among patients who had bone marrow infiltration of cancer (p = .57). there were significant differences between the without and with ≥ grade 3 neutropenia groups in terms of the pretreatment wbc counts (8152.97 ± 2134.27/mm3 vs. 6431.67 ± 1618.40/mm3, p < .001), pretreatment neutrophil counts (5250.81 ± 2218.56/mm3 vs. 4005.83 ± 1434.19/mm3, p < .001), pretreatment serum alkaline phosphatase (alp) levels (252.9 ± 125.45 g/dl vs. 196.4 ± 77.28 g/dl, p = .030), and pretreatment neutrophil/lymphocyte (nl) ratio (1.3 ± 1.26 vs. 0.4 ± 0.63, p < .001). the complete set of results for the two groups is presented in table 1. multivariate logistic analysis identified pretreatment neutrophil counts (p = .012) as the only significant predictive factor for neutropenia (table 2). discussion here, we showed that 45.6% of patients that underwent urologic anticancer chemotherapy experienced neutropenia of grade 3 or higher. multivariate analysis identified pretreatment neutrophil counts as the sole independent predictor of grade 3 or higher neutropenia during the first cycle of chemotherapy. other studies identified factors that predict subsequent complications in patients diagnosed with fn(15-17), as well as independent predictive factors for bacteremia and sepsis.(18-20) in a previous study, we showed that pretreatment wbc counts, pretreatment neutrophil counts, pretreatment serum creatinine levels, and pretreatment serum albumin levels were significant predictive factors for neutropenia in patients with castration-resistant prostate cancer after docetaxel-based systemic chemotherapy.(21) to the best of our knowledge, the present study is the first to identify a factor that predicts the occurrence of neutropenia (grade 3 or higher) in patients with advanced urothelial cancer. matsumoto et al. observed infectious complications in 93 patients with urologic cancer during 207 courses of anticancer chemotherapy. thirty (14.5%) neutropenic events occurred. risk factors were urinary diversion, hydronephrosis, and the duration of severe neutropenia (< 500/mm3).(22) several factors increase the risk of neutropenia, including older age, advanced stage of disease, previous episodes of neutropenia, no treatment with g-csf, lack of antibiotic prophylaxis, a low pretreatment absolute neutrophil count, diabetes, and prior chemotherapy.(11,23,24) however, these risk factors were identified in studies of hematologic malignancies, although some are applicable to patients with solid cancers. no previous study has focused on urothelial cancer patients. here, we found that the pretreatment neutrophil count was the only significant independent risk factor for grade 3 or higher neutropenia induced by cisplatin-based systemic chemotherapy. further, several studies identified additional patient-related factors that, although not identified in this study, predisposed the afflicted individuals to either fn(25,26) or excessive myelosuppression.(27) these included age > 65 years, advanced disease, anemia, poor performance status, prior chemotherapy treatment, combined chemo-radiotherapy, bone marrow infiltration, and medical comorbidities (particularly renal disease). however, many of these pretreatment risk factors were identified in studies that included patients with hematological malignancies. thus, the cogency or relevance of those factors are still questionable as to the adjuvant treatment of prostate cancer. other studies demonstrate that the first cycle absolute neutrophil count nadir is a predictive factor for subsequent neutropenic events.(28-30) indeed, we found similar results in the present study. there may be several reasons as to why there are differences between the results of this study and those of many previous studtable 2. multivariate analysis to identify factors that predict severe neutropenia in patients with advanced urothelial cancer variables 95% confidence interval (ci) p value pretreatment wbc count 0.999–1.005 0.213 pretreatment neutrophil count 0.967–0.996 0.012 pretreatment alp 0.956–1.004 0.108 pretreatment nl ratio 0.166–681.026 0.265 abbreviations: wbc, white blood cell; alp, alkaline phosphatase. predictive factors for cisplatin-induced neutropenia-kwon et al. urological oncology 170 ies. first, we examined only histologically confirmed urothelial carcinoma, whereas previous studies examined a variety of tumor types (i.e., lymphomas and solid tumors). secondly, our cohort was relatively small (n = 79) compare to the population of patients examined in previous studies. the small sample number is a major limitation of the present study. in cancer treatment, therapeutic strategies for cancer management keep evolving, and chemotherapy regimens continue to serve important roles. our future work will focus on evaluating the incidence of, and factors that predispose to, fn during other types of urologic chemotherapy, and setting up further necessary guidelines for this purpose. due to several limitations this study had in addition to the small sample size, drawing definitive conclusions from this study would be difficult. for example, the study was performed retrospectively rather than being prospective in nature. further, a larger study may have led use to identify other factors that can be used to predict neutropenia induced by cisplatin-based systemic chemotherapy in patients with advanced urothelial cancer. nonetheless, in this study, the patients were treated in single, not separate, institution with a limited number of attending physicians, and follow-up periods were relatively long. conclusions in conclusion, the results of this study identified only the pretreatment neutrophil count as an independent risk factor for grade 3 or higher neutropenia induced by cisplatin-based systemic chemotherapy in korean advanced urothelial cancer patients. this predictive factor helps better to make the therapeutic strategy during chemotherapy. for patients who have low pretreatment neutrophil counts, it is suggested that the dose of chemotherapy is reduced or prophylactic g-csf is given to prevent severe neutropenia. to the best of our knowledge, this study first identified such a significant independent risk factor in this patient group. however, to confirm these results, a large cohort and prospective study would be required. acknowledgements this study was supported by wonkwang university in 2018. references 1. yasufuku t, shigemura k, tanaka k, arakawa s, miyake h, fujisawa m. risk factors for refractory febrile neutropenia in urological chemotherapy. j infect chemother. 2013;19:211-6. 2. von der maase h, hansen sw, roberts jt, et al. gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase iii study. j clin oncol. 2000;18:3068-77. 3. ismaili n, amzerin m, flechon a. chemotherapy in advanced bladder cancer: current status and future. j hematol oncol. 2011;4:35 4. sonpavde g, watson d, tourtellott m, et al. administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community. clin genitourin cancer. 2012;10:1-5. 5. von der maase h, sengelov l, roberts jt, et al. long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. j clin oncol. 2005;23:4602-8. 6. porter mp, kerrigan mc, donato bm, ramsey sd. patterns of use of systemic chemotherapy for medicare beneficiaries with urothelial bladder cancer. urol oncol. 2011;29:252-8. 7. bodey gp, buckley m, sathe ys, freireich ej. quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. ann intern med. 1966;64:328-40. 8. lyman gh, delgado dj. risk and timing of hospitalization for febrile neutropenia in patients receiving chop, chop-r, or cnop chemotherapy for intermediate-grade nonhodgkin lymphoma. cancer. 2003;98:2402-9. 9. timmer-bonte jn, de boo tm, smit hj, et al. prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: a dutch randomized phase iii study. j clin oncol. 2005;23:797484. 10. moores kg. safe and effective outpatient treatment of adults with chemotherapyinduced neutropenic fever. am j health syst pharm. 2007;64:717-22. 11. crawford j, dale dc, lyman gh. chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. cancer. 2004;100:228-37. 12. italiano a, ortholan c, oudard s, et al. docetaxel-based chemotherapy in elderly patients (age 75 and older) with castrationresistant prostate cancer. eur urol. 2009; 55: 1368-75. 13. lee jl, kim je, ahn jh, et al. efficacy and safety of docetaxel plus prednisolone chemotherapy for metastatic hormonerefractory prostate adenocarcinoma: single institutional study in korea. cancer res treat. 2010;42:12-7. 14. dogliotti l, carteni g, siena s, et al. gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. eur urol. 2007;52:134-41. 15. persson l, soderquist b, engervall p, vikerfors t, hansson lo, tidefelt u. assessment of systemic inflammation markers to differentiate a stable from a deteriorating clinical course in patients with febrile neutropenia. eur j haematol. 2005;74:297-303. predictive factors for cisplatin-induced neutropenia-kwon et al. vol 15 no 04 july-august 2018 171 16. engel a, knoll s, kern p, kern wv. interleukin-8 serum levels at fever onset in patients with neutropenia predict early medical complications. infection. 2005;33:380-2. 17. uys a, rapoport bl, fickl h, meyer pw, anderson r. prediction of outcome in cancer patients with febrile neutropenia: comparison of the multinational association of supportive care in cancer risk-index score with procalcitonin, c-reactive protein, serum amyloid a, and interleukins-1beta, -6, -8 and -10. eur j cancer care (engl). 2007;16:47583. 18. persson l, engervall p, magnuson a, et al. use of inflammatory markers for early detection of bacteraemia in patients with febrile neutropenia. scand j infect dis. 2004;36:365-71. 19. viscoli c, bruzzi p, castagnola e, et al. factors associated with bacteraemia in febrile, granulocytopenic cancer patients. the international antimicrobial therapy cooperative group (iatcg) of the european organization for research and treatment of cancer (eortc). eur j cancer. 1994;30a:430-7. 20. hubel k, hegener k, schnell r, et al. suppressed neutrophil function as a risk factor for severe infection after cytotoxic chemotherapy in patients with acute nonlymphocytic leukemia. ann hematol. 1999;78:73-7. 21. kwon wa, oh th, lee jw, park sc. predictive factors for neutropenia after docetaxel-based systemic chemotherapy in korean patients with castrationresistant prostate cancer. asian pac j cancer prev. 2014;15:3443-6. 22. matsumoto t, takahashi k, tanaka m, kumazawa j. infectious complications of combination anticancer chemotherapy for urogenital cancers. int urol nephrol. 1999;31:7-14. 23. aapro ms, bohlius j, cameron da, et al. 2010 update of eortc guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapyinduced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. eur j cancer. 2011;47:8-32. 24. srokowski tp, fang s, hortobagyi gn, giordano sh. impact of diabetes mellitus on complications and outcomes of adjuvant chemotherapy in older patients with breast cancer. j clin oncol. 2009;27:2170-6. 25. aapro ms, cameron da, pettengell r, et al. eortc guidelines for the use of granulocytecolony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. eur j cancer. 2006;42:2433-53. 26. smith tj, khatcheressian j, lyman gh, et al. predictive factors for cisplatin-induced neutropenia-kwon et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidencebased clinical practice guideline. j clin oncol. 2006;24:3187-205. 27. lyman gh, dale dc, crawford j. incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. j clin oncol. 2003;21:4524-31. 28. rivera e, haim erder m, fridman m, frye d, hortobagyi gn. first-cycle absolute neutrophil count can be used to improve chemotherapy-dose delivery and reduce the risk of febrile neutropenia in patients receiving adjuvant therapy: a validation study. breast cancer res. 2003;5:r114-20. 29. savvides p, terrin n, erban j, selker hp. development and validation of a patientspecific predictive instrument for the need for dose reduction in chemotherapy for breast cancer: a potential decision aid for the use of myeloid growth factors. support care cancer. 2003;11:313-20. 30. silber jh, fridman m, dipaola rs, erder mh, pauly mv, fox kr. first-cycle blood counts and subsequent neutropenia, dose reduction, or delay in early-stage breast cancer therapy. j clin oncol. 1998;16:2392-400. urological oncology 172 vol 16 no 04 july-august 2019 endourology and stone disease comparison of flexible ureterorenoscopy and mini percutaneous nephrolithotomy in the management of multiple renal calculi in 10-30 mm size fatih yanaral1*, faruk ozgor1, onur kucuktopcu1, omer sarilar1, ali ayrancı1, metin savun1, bahar yuksel2, murat binbay1 purpose: to evaluate the efficacy and safety of flexible ureterorenoscopy (f-urs) and mini percutaneous nephrolithotomy (mini-perc) in the management of 10-30 millimeter multiple renal stones. materials and methods: the charts of patients who underwent f-urs or mini-perc for multiple kidney stones between january 2011 and july 2015 were retrospectively analyzed. patients with multiple 10-30–mm-sized renal stones were enrolled in the study. a total of 374 patients underwent mini-perc and 85 patients met the study inclusion criteria. in the same period, f-urs was performed in 562 patients, and 163 had 10-30–mm multiple renal stones. we selected 85 patients to serve as the control group from this cohort using propensity score matching with respect to the patient’s age, asa score, number, size, and location of stones to avoid potential bias between groups. results: the mean operation time and fluoroscopy screening time (fst) was significantly longer in the mini-perc group (p = .001 and p = .001, respectively). the mean hospitalization time was 76.9±38.7 hours in the mini-perc group and 25.0±27.7 hours in the f-urs group (p = .001). post-operative complications, according to the clavien classification system, were significantly more frequent in the mini-perc group (p = .003). the stone-free rate was 87% in the f-urs group and 83.5% in the mini-perc group (p = .66). conclusion: our study demonstrated that f-urs and mini-perc were effective treatment options for multiple renal stones 10-30 mm in size. however, f-urs was associated with a significantly lower complication rate, shorter operation time, shorter fst, and shorter hospitalization time. keywords: kidney calculi; lithotripsy; nephrolithiasis; nephrolithotomy, percutaneous; ureteroscopy introduction shock wave lithotripsy (swl) has gained popularity because of its acceptable success rates, outpatient nature, minimal anesthesia requirement and superior patient compliance since its introduction in urology practice. today, swl is accepted as the first-line treatment for renal stones < 20 mm and as the second-line treatment option for renal stones > 20 mm according to urolithiasis guidelines.(1) however, the effectiveness of swl decreases with lower pole stones, hard stones, multiple stones, and stones of large sizes.(2) with improvements in technology, flexible ureterorenoscopy (f-urs) and mini percutaneous nephrolithotomy (mini-perc) have become important management options for renal stones.(3) modern flexible ureterorenoscopes can access the entire pelvicalyceal system and holmium laser provides effective stone fragmentation, regardless of stone type. with increased surgical experience, f-urs became the preferable option for larger renal stones.(4) on the other hand; mini-perc ensures less postoperative morbidity when compared with conventional percutaneous nephrolithotomy 1department of urology, haseki teaching and research hospital, istanbul, turkey. 2department of obstetrics and gynecology, istanbul medical faculty, istanbul, turkey. *correspondence: department of urology, haseki training and research hospital, millet street, no: 11, 34096, fatih, istanbul, turkey. tel: +90 212 529 44 00. fax: +90 212 589 62 29. e-mail: fyanaral@yahoo.com. received february 2017 & accepted september 2018 (pnl).(5) although many studies have shown the effectiveness of f-urs and mini-perc on solitary renal stones in the literature, no studies have compared the effectiveness of f-urs and mini-perc in patients with multiple stones. in this study, we aimed to evaluate the efficacy and safety of f-urs and mini-perc in the management of 10-30–millimeter multiple renal stones. materials and methods study population in a tertiary academic center, the charts of patients who underwent f-urs or mini-perc for multiple kidney stones between january 2011 and july 2015 were retrospectively analyzed. patients who had multiple renal stones in different renal locations with 10-30 mm stone sizes were enrolled in the study. stone sizes were calculated as the sum of maximal diameters of all stones. exclusion criteria were patients aged below 18 years, patients with renal abnormalities, patients with multiple stones in the same location, and patients with staghorn stone. urology journal/vol 16 no. 4/ july-august 2019/ pp. 326-330. [doi: http://dx.doi.org/10.22037/uj.v0i0.3310] the patients’ medical history was obtained and physical examination was performed for all patients. preoperatively, renal stone and kidney characteristics were evaluated using intravenous pyelography and/or non-contrast abdominal computed tomography (ct). the patients’ demographic parameters including sex, age, asa score, body mass index (bmi), stone size, stone number, and stone location were recorded. preoperative laboratory tests were hemoglobin measurements, serum creatinine level, platelet counts, and coagulation screening tests. all patients had sterile urine cultures prior to surgery and each had signed an informed consent form. study design this study was a comparative, retrospective, observational study, which was performed in a referral hospital in istanbul, turkey. a total of 374 patients underwent mini-perc, 85 of whom met the study inclusion criteria. in the same period, f-urs was performed in 562 patients, 163 of whom had 10-30 mm multiple renal stones. we selected 85 patients to serve as the control group from this cohort using propensity score matching respect to the patient’s age, american society of anesthesiologists (asa) score, number, size, and location of stone. propensity score matching was utilized to minimize the bias related to the lack of randomization in this observational study by balancing a range of covariate patient and stone-related parameters in the groups. the selection of procedural technique was primarily based on the patients’ choice. surgical techniques f-urs technique under general anesthesia, a safety guide-wire was placed into the renal pelvis and semi-rigid ureteroscopy was performed for visual assessment of the ureter to facilitate positioning of the ureteral access sheath (9.5/11.5fr or 11/13 fr). a 7.5 f fiber-optic flexible ureterorenoscope (storz flex-x 2, tuttlingen, germany) with a 200 or 273 μm laser fiber was used for treatment. stone fragmentation was performed with holmium laser at 0.8-1.5 j and a rate of 5-10 hz. stone fragments < 2 mm were left for spontaneous passage and basket retrieval was performed for stone fragments > 2 mm. a 4.8 f jj stent was routinely placed in each patient at the end of procedures. operation time (or) was calculated as the time that passed from anesthesia induction to the completion of the jj stent placement. the jj catheter was removed 2 weeks after the operation using a cystoscope. mini-perc technique in the lithotomy position, a 5-fr ureteral catheter was inserted up to the kidney under general anesthesia. in the prone position, the calyceal system configuration was demonstrated using contrast media and access was gained to the proper calyx using an 18 g needle under the c-arm microscopy unit. after a 0.035-inch hydrophilic guide-wire was placed into the pelvicaliceal system, dilatation was performed using amplatz dilatators, and an 18or 20-fr amplatz sheath was inserted. with a 17-f rigid nephroscope, stone fragmentation was performed using laser or an ultrasonic lithotripter, and stone removal was performed using stone extraction forceps. at the end of the procedure, a nephrostomy tube was placed under fluoroscopy in the case of pelvicalyceal perforation, the presence of residual fragments, or according to the surgeon's choice. the operation time was defined as the period starting from anesthesia to the placement of the nephrostomy tube. outcome assessment operation success was evaluated with a kidney-ureter-bladder radiography on the first postoperative day. afterward, stone-free status was reassessed in an outpatient setting with non-contrast ct between 1 and 3 months, postoperatively. the procedure was accepted as successful if the patient was stone free or if the patients' residual fragments were < 2 mm. the primary outcomes were stone free rate and postoperative complications of f-urs or mini-perc. secondary outcomes included; or, fluoroscopy screening time (fst), hospitalization time, haemoglobin drop, and additional procedures. complications were classified in accordance with the clavien system.(6) statistical analysis the statistical package of social sciences for windows version 20 was used for statistical analysis. during statistical analyses, values were evaluated as numbers, means, percentages and intervals. propensity score matching minimized any bias caused by the lack of randomization in this observational study. numbers and percentages were compared using the chi-square test. before the comparison of means, the values were evaluated for normality by shapiro-wilk test. homogeneously distributed values were compared using student’s t-test and heterogeneously distributed values were compared using the mann-whitney u test. f-urs and mini-perc for multiple renal calculi. yanarl et al. endourology and stones diseases 327 table 1. patients’ demographics and clinical characteristics after propensity score matching. f-urs mini-perc number 85 85 gender (male / female) 53 / 32 52 / 33 age (years) 42.9 ± 16.9 41.1 ± 15.3 bmi (kg/m2) 25.8 ± 5.8 27.4 ± 5.5 asa score 1.75 ± 1.44 1.66 ± 1.54 stone size (mm) 23.4 ± 3.8 24.4 ± 5.4 stone number 2.3 ± 1.4 2.2 ± 1.3 operation side (right / left) 38 / 47 38 / 47 degree of hydronephrosis mild (grade 1-2) / severe (grade 3-4) 41 / 5 37 / 7 stone opacity (opaq / nonopaq) 81 / 4 82 / 3 abbreviations: bmi, body mass index; asa, american society of anesthesiologists data is presented as mean ± sd or number results in accordance with the design of our study, renal stone characteristics including renal stone number (p = .63), the sum of total stone size (p = .20), stone locations (p = .32), and stone opacity (p = .56) were comparable between groups. also, age (p = .46), bmi (p = .07), and asa scores (p = .78) of patients were similar between the f-urs group and mini-perc group. preoperative parameters are listed in tables 1 and 2. the mean operation and fst was significantly longer in the mini-perc group (p = .001 and p = .001, respectively). a flexible nephroscope was used in 19 patients (22.4%) during mini-perc. additional access was required in 22 patients (two access was required in 20 patients and three access in two patients) and the mean access number per patient was 1.28. in the mini-perc group, the mean hemoglobin drop after the procedure was calculated as 1.0 g/dl. hemoglobin values were not routinely assessed postoperatively in the f-urs group unless any uneventful hemorrhagic complications occurred. tubeless mini-perc was performed in 36 patients (42.3%). the mean hospitalization time was 25.0 ± 27.7 hours in the f-urs group and 76.9 ± 38.7hours in the mini-perc group (p = .001). post-operative complications, according to the clavien classification system, were significantly more frequent in the mini-perc group (p = .003). renal colic was treated in two patients in both the f-urs and mini-perc groups, and transient hematuria was observed in two patients of the mini-perc group (clavien 1). post-operative fever that required antibiotic therapy was seen in three patients and one patient in f-urs and mini-perc groups, respectively (clavien 2). a hemoglobin drop that required blood transfusion occurred in three patients in the mini-perc group (clavien 2). angioembolization was performed in one patient following mini-perc (clavien 3b). a jj stent was inserted in two patients without anesthesia (clavien 3a) and in four patients under anesthesia (clavien 3b) following mini-perc because of pain and persistent leakage of urine after the removal of the nephrostomy tube. the stone-free rate was 78.8% for the f-urs group and 74.1% for the mini-perc group after a single session procedure (p = .58). after additional procedures including, swl, urs/f-urs, and mini-perc, the success rate increased to 87% in the f-urs group and 83.5% in the mini-perc group, respectively (p = .66) (table 3). discussion in urolithiasis guidelines, the treatment recommendation for kidney stones substantially depends on stone size and location of the stone. however, many authors stated that the number of stones affected procedure outcomes including swl, f-urs, and pnl. ackermann et al. found stone number was more related with procedure success than the stone burden.(7) during stone fragmentation in operations or swl, multiple small stones can easily move up and escape from laser or shock waves. kanao et al. emphasized that focusing on one large stone was easier than targeting multiple small stones with the same stone burden.(8) shock wave lithotripsy was recently recommended as the first-line treatment for 10-20 mm renal stones and a second-line treatment alternative for renal stones > 20 mm. however, the success of swl is clearly adversely affected by the presence of multiple renal stones. cass et al. achieved ≤ 50% stone-free rates in the management of multiple renal stones following swl.(9) similarly; mcadams et al. investigated the importance of stone number in swl. the mean stone number was 2.81 in patients in whom swl failed, and 1.87 in patients who were treated successfully using swl.(10) therefore, f-urs and mini-perc have become important treatment alternatives for multiple renal stones in a zone where swl is not preferred, and the selection of treatment modality and must be clarified. we obtained 78.8% sfr after f-urs and our success rate increased to 87% following additional procedures. f-urs mini-perc p value pelvis + lower calyx 45 39 0.324 pelvis + middle calyx 2 4 pelvis + upper calyx 16 10 pelvis + multiple calyx 7 9 lower pole + upper calyx 3 7 lower pole + middle calyx 8 11 middle pole + upper calyx 2 5 lower pole + middle calyx + 2 0 upper calyx table 2. stone locations in f-urs and mini-perc group. f-urs mini-perc p value operation time (minutes) 62.6 ± 2.3 117.8 ± 43.7 0.001 fluoroscopy screening time (minutes) 2.4 ± 1.2 5.6 ± 4.1 0.001 hospitalization time (hours) 25.0 ± 27.7 76.9 ± 38.7 0.001 haemoglobin drop (g/dl) na 1.0 ± 1.1 postoperative complications (clavien classification system) 0.003 grade 1 2 4 grade 2 3 4 grade 3a 0 2 grade 3b 0 5 success after single session 0.585 residual fragment 18 (21.2%) 22 (25.9%) stone free 67 (78.8%) 63 (74.1%) additional procedures 0.365 swl 2 4 urs/f-urs 6 7 mini-perc 4 1 stone free after additional procedures 74 (87%) 71 (83.5%) 0.660 data is presented as mean ± sd or number table 3. patients’ intraoperative and postoperative data. f-urs and mini-perc for multiple renal calculi. yanarl et al. vol 16 no 04 july-august 2019 328 similarly, huang et al. achieved 60.7% and 85.7% sfr following single and second session f-urs in the management of multiple renal stones larger than 20 mm.(11) in another study, breda et al. treated multiple renal stones with f-urs and reported 92.2% sfr after two sessions.(12) however, all patients in breda’s study had stones < 15 mm in size and the mean stone size was smaller than in the present study (6.6 vs. 23.4 mm). in the mini-perc group, stone-free status was achieved in 74.1% of patients and increased to 83.5% after additional procedures. knoll et al. reported 96% sfr after mini-perc; however, all their patients had a solitary kidney stone.(13) a different study by kırac et al. demonstrated 91.9% sfr, but the mean stone size in their study was smaller than that study (10.5 vs 24.4 mm) and only 32.4% of patients had multiple renal stones in kırac’s study.14 additionally, unlike our study, patients with 3 mm stone fragments were accepted as stone free in kırac’s study, which may explain the lower success rates in the present study. lastly, our study emphasized that sfr following f-urs and mini-perc in the management of multiple renal stones 10-30 mm size did not show a significant difference (p = .66). in the present study, the mean operation time was found significantly longer in the mini-perc group compared with the f-urs group. different from our study, both knoll et al. (106 min vs. 59 min) and kırac et al. (66.4 min vs. 53.7 min) reported significantly longer operation times in f-urs group.(13,14) however, in both studies, the definition of operation time was not well clarified for both f-urs and mini-perc procedures. we accepted or from the induction of anesthesia to the completion of jj stent placement in the f-urs group, and placement of the nephrostomy tube in the mini-perc group, which is why we had significantly longer or in the mini-perc group. it is clear that changing patients from lithotomy position to the prone position requires special attention and is a time-consuming process. also, obtaining multiple accesses and changing of instruments (rigid nephroscope to flexible nephroscope) may contribute to longer operation times during mini-perc. previous studies that investigated f-urs in the management of multiple renal calculi have not reported fst. (11,12) additionally, knoll et al. and kırac et al. did not discuss fst between f-urs and mini-perc.(13,14) our study demonstrated that fst was significantly longer in the mini-perc group when compared with the f-urs group. similarly, when we analyzed the studies separately, we noticed that fst was longer with mini-perc than f-urs, as in our study.(15,16) additionally, the mean access number was 1.28, which may have contributed to the longer fst in the mini-perc group. we believe further studies should investigate fst in f-urs and mini-perc to clarify this subject. complications following f-urs were not serious and were mostly treated without surgical intervention when compared with mini-perc.(17) fever requiring antibiotic therapy was more common in the f-urs group, which may be a consequence of working with high intrarenal pressure during f-urs. although transfusion rates decreased with miniaturized instruments in pnl, three (3.5%) patients and one (1.2%) patient required blood transfusion and angioembolization in the mini-perc group, respectively. cheng et al. reported a 1.4% blood transfusion rate following mini-perc, but they excluded patients with multiple accesses, which may explain their lower transfusion rates.(5) in contrast, flexible ureteroscopes pass from natural orifices while reaching kidney; therefore, renal parenchyma and vascular structures are protected against procedure-related damage. as such, we do not routinely evaluate hemoglobin levels after f-urs. urine leakage from the nephrostomy tract and ureteral obstruction due to stone fragments are major problems following pnl and treated with jj stent insertion.(18) the jj stent insertion was a routine part of our f-urs procedure and we experienced no stent migration. in the mini-perc group, we inserted a jj stent in six patients due to renal colic and urine leakage after nephrostomy withdrawal. in the mini-perc group, in our first cases, we left particles for spontaneous passage after fragmentation of the stones into 2 mm stone particles with a laser lithotripter. after we realized the high jj stent insertion rate in mini-perc cases, we started to retrieve all fragments using a basket to reduce our jj stent insertion rates, which may explain our higher jj stent insertion rate. fragmentation type in endoscopic procedures may be a subject of another study. there are some weaknesses to the present study. although the present study is the first to research this subject, we are aware of the retrospective nature of the study. however, the preoperative characteristics were similar between the groups and we believe that the study scheme prevented potential bias between the groups. in addition, different surgeons including specialists and residents performed operations in both the f-urs and mini-perc groups; however, all procedures conducted by residents were performed under the supervision of an experienced specialist. also, we did not evaluate analgesic requirement after procedures and the effects of f-urs and mini-perc on patients’ quality of life. finally, we did not compare the stone type between groups due to the insufficient data. conclusions our study demonstrated that both f-urs and mini-perc were effective treatment options in the management of multiple renal stones 10-30 mm in size. however, f-urs was associated with a significantly lower complication rate, shorter operation time, shorter fst, and shorter hospitalization time. however, our findings must be supported by further prospective, randomized studies with larger patient volumes. conflict of interest the authors report no conflict of interest. references 1. türk c, knoll t, petrik a, et al. guidelines on urolithiasis. european association of urology 2015. 2. el-nahas ar, el-assmy am, mansour o, sheir kz. a prospective multivariate analysis of factors predicting stone disintegration by extracorporeal shock wave lithotripsy: the value of high-resolution noncontrast computed tomography. eururol. 2007;51:1688–93. 3. ghani kr, andonian s, bultitude m, et al. endourology and stones diseases 329 f-urs and mini-perc for multiple renal calculi. yanarl et al. vol 16 no 04 july-august 2019 330 f-urs and mini-perc for multiple renal calculi. yanarl et al. percutaneous nephrolithotomy: update, trends, and future directions. eururol. 2016;70:382-96. 4. akman t, binbay m, ozgor f, et al. comparison of percutaneous nephrolithotomy and retrograde flexible nephrolithotripsy for the management of 2-4 cm stones: a matchedpairanalysis. bju int. 2012;109:1384-89. 5. cheng f, yu w, zhang x, yang s, xia y, ruan y. minimally invasive tract in percutaneous nephrolithotomy for renal stones. j endourol. 2010;24:1579-82. 6. dindo, d, demartines, n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205–13. 7. ackermann dk, fuhrimann r, pfluger d, studer ue, zingg ej. prognosis after extracorporeal shock wave lithotripsy of radiopaque renal calculi: a multivariate analysis. eur urol. 1994;25:105-9. 8. kanao k, nakashima j, nakagawa k, et al. preoperative nomograms for predicting stonefree rate after extracorporeal shock wave lithotripsy. j urol. 2006;176:1453-6. 9. cass as. comparison of first generation (dornier hm3) and second generation (medstone sts) lithotriptors: treatment results with 13,864 renal and ureteral calculi. j urol. 1995;153:588-92. 10. mcadams s, kim n, ravish ir, et al. stone size is only independent predictor of shock wave lithotripsy success in children: a community experience. j urol. 2010;184:659– 64. 11. huang z, fu f, zhong z, zhang l, xu r, zhao x. flexible ureteroscopy and laser lithotripsy for bilateral multiple intrarenal stones: is this a valuable choice?. urology. 2012;80:800-4. 12. breda a, ogunyemi o, leppert jt, schulam pg. flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. eururol. 2009;55:1190-6. 13. knoll t, jessen jp, honeck p, wendtnordahi g. flexible ureterorenoscopy versus miniaturized pnl for solitary renal calculi of 10-30 mm size. world j urol. 2011;29:755-9. 14. kirac m, bozkurt of, tunc l, guneri c, unsal a, biri h. comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in management of lowerpole renal stones with a diameter of smaller than 15 mm. urolithiasis. 2013;41:241-6. 15. abdelhafez mf, amend b, bedke j et al. minimally invasive percutaneous nephrolithotomy: a comparative study of the management of small and large renal stones. urology. 2013;81:241-5. 16. doizi s, letendre j, bonneau c, gil diez de medina s, traxer o. comparative study of the treatment of renal stones with flexible ureterorenoscopy in normal weight, obese, and morbidly obese patients. urology. 2015;85:38-44. 17. jacquemet b, martin l, pastori j, et al. comparison of the efficacy and morbidity of flexible ureterorenoscopy for lower pole stones compared with other renal locations. j endourol. 2014;28:1183-7. 18. ferakis n, stavropoulos m. mini percutaneous nephrolithotomy in the treatment of renal and upper ureteral stones: lessons learned from a review of the literature. urol ann. 2015;7:1418. letter mean values after treatment or mean difference? behnam amani1, arash akbarzadeh2, bahman amani,1* in a systematic review and meta-analysis published in the urology(1) entitled “low-intensity extracorporeal shock wave therapy for erectile dysfunction: a systematic review and meta-analysis” by libo and guizhong in 2017, the authors in methods section state that “weighted mean difference (md) was used for continuous variables in their meta-analysis”. while, the authors used the endpoint scores as the mean difference in each group regardless of the baseline scores and one study(2) that baseline used as mean difference based on statistical literature in meta-analysis, the “mean difference” is change average from baseline to endpoint. so, to calculate the mean difference, we should use endpoint minus baseline mean score(3). in our understanding, , it seems that the result of libo’s meta-analysis(1) should revise for the mean difference as mentioned above. references 1. libo m, guizhong l. low-intensity extracorporeal shock wave therapy for erectile dysfunction: a systematic review and meta-analysis. urology. 2017. 2. vardi y, appel b, kilchevsky a, gruenwald i. does low intensity extracorporeal shock wave therapy have a physiological effect on erectile function? short-term results of a randomized, double-blind, sham controlled study. the journal of urology. 2012 may;187(5):1769-75. pubmed pmid: 22425129. epub 2012/03/20. eng. 3. cooper h, hedges lv, valentine jc. the handbook of research synthesis and meta-analysis: russell sage foundation; 2009. 1department of health sciences education development, school of public health, tehran university of medical sciences, tehran, iran. 2department of epidemiology and biostatistics, school of public health, tehran university of medical sciences, tehran, iran. correspondence: department of health sciences education development, school of public health, tehran university of medical sciences, tehran, iran. email: b-amani@alumnus.tums.ac.ir urology journal/vol 17 no. 3/ may-june 2020/ pp. 324-324. [doi: 10.22037/uj.v0i0.4646] case reports elephantiasis of penis and scrotum nasehi a, azadi sh department of urology, aiatollah kashani hospital, tehran, iran key words: elephantiasis, penis, scrotum, lymphedema 55 urology journal unrc/iua vol. 2, 55-57 spring 2004 printed in iran introduction lymphedema of penis and scrotum is rarely seen in countries in which filariasis is not endemic. the abnormal accumulation of lymphatic fluid in subcutaneous tissue of penis and scrotum could lead to swelling, pain, dysuria, and sexual dysfunction (impotency and erectile dysfunction). lymphedema may be idiopathic or secondary to inflammation, surgery, malignancies, trauma, radiation, hypoproteinemia, and other medical disorders. lymphatic obstruction is limited to penis and scrotum and is not seen in adjacent organs such as lower extremities, abdomen, and buttock.(1) regardless of the cause of scrotal and penile elephantiasis, this disease can lead to physical and spiritual weakness and its treatment is difficult particularly in the aged.(2) case report a 16-year-old boy was referred to our hospital because of painless swelling of penis and scrotum (fig. 1). he reported a history of swelling since his childhood, which had been intensified during the past year. no history of irradiation, surgery, trauma, or infection was reported. penis and scrotum was swelling and non tender. testes in the scrotum were palpable with difficultly. mild lower extremities edema was present. other systems were normal. ultrasonography of testes and lower urinary tract were normal. abdominal and pelvic ct scan, as well as cbc, u/a, esr and blood biochemical tests were normal. serologic study was negative for filariasis. with the diagnosis of idiopathic elephantiasis of penis and scrotum, surgery was planned in which extensive debridement of the involved tissue, scrotoplasty by the use of skin flaps of 1/3 of the posterior scrotum, and z plasty by applying extra skin of penis region to repair its cover were to be performed (fig. 2, 3, 4). pathology report was diffuse dermal edema with chronic inflammation around vessels, compatible with arteriovenous malformation (fig. 5). our patient had primary or idiopathic penile or scrotal lymphedema. in one year follow-up after reconstructive surgery, recurrence was not seen accepted for publication in january 2003 fig. 1. lymphedema or elephantiasis of penis and scrotum elephantiasis of penis and scrotum and he had a normal sexual function. discussion genital elephantiasis is mostly developed in tropical regions. degreef believes that about 20% of males in tropical regions develop penile and scrotal elephantiasis.(3) lymphedema has two types: primary and secondary. primary lymphedema is subdivided into three categories: 1. congenital-inherited (milory syndrome), 2. praecox (with early onset), and 3. tarda (with late onset).(1) secondary lymphedema has four subtypes: 1. obstructive (secondary to neoplasm, radiation, surgical intervention, mechanical trauma, and chemical agents injection), 2. inflammatory (parasitic, bacterial, and fungal infections), 3. phlebitis, and 4. angioneurotics.(1) penile and scrotal lymphedema mostly occurs following an infection or as a reaction to trauma. idiopathic lymphedema is rarely seen and is caused by a primary obstruction of lymphatic vessels of scrotum.(1) no effective medical treatment has been introduced; instead, different surgical methods for the treatment of chronic genital lymphedema have been reported in the literature. two main methods are as follows: 1. physiologic methods or lymphangioplasty through which lymphatic discharge from involved regions to new lymphatic channels is obtained. 2. lymphangiectomy with reconstructive surgery.(2) lymphangioplasty is used in the cases of recurrent lymphedema; however, this method can not be successful in the cases of chronic fibrosis or lymphedema caused by radiation because of the lack 56 fig. 2. freeing of testes and spermatic cord from the surrounding involved tissue through a horizontal incision on posterior part of the scrotum fig. 3. testes, spermatic cord and penis have been separated from the surrounding involved tissue through two longitudinal and spiral incisions. fig. 4. scrotoplasty and z plasty in order to construct the cover of penis following extensive debridement of the involved tissue fig. 5. a microscopic image from the involved tissue that shows diffuse edema in dermis, interstitial tissue, and muscle fibers elephantiasis of penis and scrotum of appropriate lymphatic channels.(2) lymphangiectomy includes the removal of superficial lymphatic network, which is located above the buck's fascia which is derived from median raphae and prepuce lymphatics. these lymphatics drain to superficial posterior lymphatic channels. a deeper system is located beneath the buck's fascia and is drained into deep inguinal lymph nodes.(4) this method of drainage leads to the success of this surgical method. it is essential to remove involved skin and subcutaneous tissue completely (reduction scrotoplasty) to prevent lymphedema recurrence followed by reconstructive surgery of penis and scrotum.(5,6) different surgical techniques are used in lymphangiectomy and repair of penis and scrotum which include jourdan and meller,(1) dlepech,(2,5) larrey,(5) cadogan and anderson,(7) raghaviah,(8) vaught,(9) dandapat,(3,5) morey,(10) apesos,(2) and malloy.(1) surgical complications of elephantiasis or genital lymphedema include hemorrhage, hematoma, urethral injury, infection, painful erection, decrease of sensation, and scar in suture line. these complications could be reduced by using a proper incision, use of z plasty instead of longitudinal suture, separating of testes and cord by an external incision in scrotum before taking any measure, and removal of involved tissue.(2,3) references 1. malloy tr, wein aj, gross p. scrotal and penile lymphedema: surgical consideration and anagement. j urol 1983; 130: 263. 2. apesos j, anigian g. reconstruction of penile and scrotal lymphedema. ann plast surg 1991; 27: 570. 3. dandapat mc, mohaparto sk, patro sk. elephantiasis of the penis and scrotum (a review of 350 cases). am j surg 1985; 149: 686. 4. brown wl, woods je. lymphedema of the penis. plast reconstr surg 1977; 59: 68-71. 5. prpic i. severe elephantiasis of penis and scrotum. br j plast surg 1966; 19: 173-8. 6. ketterings c. lymphedema of penis and scrotum. br j plast surg 1968; 21: 381-6. 7. anderson bb, cadogan ca. scrotal lymphedema praecox: disease and treatment. j natl med ass 1982; 74: 387. 8. raghavaiah nv. reconstruction of scrotal and penile skin in elephantiasis. j urol 1977; 118: 128. 9. vaught sk, litvak as, mcroberts jw. the surgical management of scrotal and penile lymphedema. j urol 1975; 113: 204. 10. morey af, meng mv, mcaninch jw. skin graft reconstruction of chronic genital lymphedema. urology 1997; 50: 423. 57 275urology journal vol 5 no 4 autumn 2008 case report true hermaphrodism presenting as pelvic abscess sushant wadhera, nitesh patidar, sudershan odiya, arvind ghanghoria, rajkumar mathur, ashish kumar gupta urol j. 2008;5:275-6. www.uj.unrc.ir keywords: true hermaphroditism, genitalia, mosaicism, differential diagnosis department of surgery, mgm medical college and my hospital, indore, madhya pradesh, india corresponding author: sushant wadhera, mbbs, ms department of surgery, my hospital, indore, madhya, pradesh, india tel: +91 989 363 6012 fax: +91 731 270 2088 e-mail: sushantwadhera@gmail. com received october 2007 accepted january 2008 introduction true hermaphroditism is a rare form of ambiguous genitalia characterized by simultaneous presence of both normal male and female gonadal tissues in a same patient.(1,2) although uncommon, true hermaphroditism has been reported in more than 400 individuals, to date.(3) we report a hermaphrodite patient presenting with a pelvic abscess. case report a 29-year-old patient presented with fever, abdominal pain, and pyuria since 8 days earlier. there was no history of episodic hematuria. the patient was reared as a male and appeared to be a phenotypically male with short stature and male pattern of body hair. local examination showed suprapubic fullness with distal penile hypospadias and an empty left scrotal sac. routine investigations showed moderate anemia and a total leukocyte count of 9 × 109/l. urine examination revealed innumerable pus cells, and culture showed presence of escherichia coli. abdominal ultrasonography showed a 13 × 7-cm, thick-walled encysted lesion in the midline pelvic area, displacing posterior wall of the bladder anteriorly and extending to the left iliac fossa. computed tomography revealed a large loculated fluid collection with thick walls and septations in the retrovesical plane including left lateral pelvic wall, which was highly suggestive of a large abscess. the patient underwent exploratory laparotomy in order to drain the retrovesical pus, which revealed a unicornuate uterus ending in a blind vaginal pouch along with left fallopian tube and ovary. the vaginal pouch was filled with pus and had a fistulous connection with the bladder anteriorly. hysterectomy with left salpingo-oophorectomy was performed along with ligation and excision of the fistulous tract between the bladder and the vaginal pouch and excision of the vaginal pouch. postoperative hormonal assay was carried out which showed a raised serum estradiol (66.5 pg/ml) and luteinizing hormone (13.2 miu/ml) with a progesterone (0.9 ng/ml), testosterone (541.4 ng/dl), and follicle-stimulating hormone (15.49 miu/ml) within the reference range. chromosomal analysis using gtc banding revealed normal male karyotype of 46xy in all cells analyzed. the operative specimen was sent for histopathological examination and revealed uterous endometrium and ovarian and vaginal tissue with diffused inflammatory cell infiltration. true hermaphrodism as pelvic abscess—wadhera et al 276 urology journal vol 5 no 4 autumn 2008 discussion there are 4 major groups of ambiguous genitalia: female pseudohermaphroditism, male pseudohermaphroditism, mixed gonadal dysgenesis, and true pseudohermaphroditism. in true pseudohermaphroditism, 4 types of gonadal distribution are seen. the most common is the presence of bilateral ovotestes. other variants include ovary on one side and ovotestis on the other side, testis on one side and ovotestis on the opposite side, and presence of testis on one side and ovary on the other side, which is the rarest form.(2,4,5) the most common cytogenetic pattern of these patients is genotypic female (46xx). all forms of mosaicism are next in frequency and the rarest are genotypic males (46xy). gonadal tumors occur with an incidence of 4% among those with 46xx karyotype and up to 10% in those with 46xy and 46 xx/xy mosaicism.(6) combination of 46xy genotype with the presence of the right testis and the left ovary makes this case the rarest of rare cases of true hermaphroditism. to our best knowledge, this is the first case of 46xy true male hermaphroditism with a functioning testis on one side and a contralateral functioning ovary presenting as a pelvic abscess. conflict of interest none declared. references 1. coran ag, polley tz jr. surgical management of ambiguous genitalia in the infant and child. j pediatr surg. 1991;26:812-20. 2. hadjiathanasiou cg, brauner r, lortat-jacob s, et al. true hermaphroditism: genetic variants and clinical management. j pediatr. 1994;125:738-44. 3. malik v, gupta d, gill m, salvi al. seminoma in a male phenotype 46xx true hermaphrodite. asian j surg. 2007;30:85-7. 4. aaronson ia. true hermaphroditism. a review of 41 cases with observations on testicular histology and function. br j urol. 1985;57:775-9. 5. luks fi, hansbrough f, klotz dh jr, kottmeier pk, tolete-velcek f. early gender assignment in true hermaphroditism. j pediatr surg. 1988;23:1122-6. 6. verp ms, simpson jl. abnormal sexual differentiation and neoplasia. cancer genet cytogenet. 1987;25:191218. thermal bladder injury after inadvertent irrigation with overheated saline during a bipolar prostate resection pictorial ioannis efthimiou,* zacharias chousianitis, kostadinos skrepetis case report a 75-year-old man with a medical history of type 2 diabetes mellitus (t2dm) and hypertension underwent a transurethral prostatectomy with the olympus bipolar turis system. unfortunately, inadvertent bladder instillation with overheated saline at the onset of the procedure complicated the surgery. shortly after the onset of the operation, the bladder was contracted and could not be distended by the fluid. at the same time, the fluid contacted the surgeon’s hand, making him realize that it was overheated. irrigation was department of urology, general hospital of messinia, kalamata, greece. *correspondence: megalou alexandrou 130, tk 24132, kalamata, greece. tel: +302 721 046990. fax: +302 721 033666. e-mail: efthimiou_ioannis@hotmail.com. received november 2015 & accepted february 2016 keywords: urinary bladder/injuries; prostatectomy; benign prostatic hyperplasia/surgery; adverse effects. figure 1. inflammation of bladder with patchy areas of necrosis. figure 3. area of extensive necrosis covered by snow-like dead tissue. figure 4. resection of the lesion in figure 3 shows necrosis and fibrosis of the detrusor muscle. figure 2. worm-like necrotizing lesions arising from the bladder wall. pictorial 2733 immediately abandoned, and only after the fluid came to the right temperature (41°c) did the surgery continue to completion. although the contact time of the bladder mucosa with the overheated saline was short, it caused major injuries in the patient’s lower urinary tract. to alleviate the consequences of the injury, the patient was managed postoperatively with intravenous antibiotics and supportive treatment with high doses of intravenous and urethral corticosteroids and an indwelling urethral catheter. the patient underwent a cystoscopy under spinal anesthesia 3 weeks later, which revealed the extent of the thermal injury. a heavily inflamed reddish mucosa with alternate pale and white areas was noticed (figure 1). white worm-like necrotizing lesions (figures 2–4) arising from the posterior wall and the dome of the bladder due to the direct contact of these areas with the excessively hot saline were also noticed. fortunately, both orifices (figure 1) were spared major thermal injury. in the follow-up period, the patient experienced severe frequency voiding and nocturia; both were managed conservatively. discussion during transurethral operations, surgeons should be aware of rare complications that can be caused to the bladder by the use of various kinds of thermal energy.(1) bladder irrigation using fluids warmed to near boiling point is a rare complication caused by human error. it has been described in the literature and it can be fatal for some patients.(2) animal studies have shown that bladder irrigation using fluids at temperatures below 44°c was well tolerated but temperatures above this level caused decreased bladder capacity, azotemia, and death.(3) conflict of interest none declared. references 1. mohammadzadeh rezaee m. intravesical explosion during endoscopic transurethral resection of prostate. urol j. 2006;3:109-10. 2. kirby r, dasgupta p, beacock c. the case of the boiled bladder--or, how to avoid medical errors. bju int. 2010;106:299-300. 3. haveman j, smals oa, rodermond hm. effects of hyperthermia on the rat bladder: a pre-clinical study on thermometry and functional damage after treatment. int j hyperthermia. 2003;19:45-57. thermal bladder injury with overheated saline-efthimiou et al. vol 13 no 03 may-june 2016 2734 case report laparoscopic repair of a ureterosciatic hernia with urosepsis kyong tae moon, hee ju cho, jae duck choi, jung yoon kang, tag keun yoo, jeong man cho* hernias of pelvic floor are very rare, and herniations of ureter into sciatic foramen are extremely rare condition which is globally reported only by 32 cases. clinical aspects of ureterosciatic hernias appeared variously according to the degree of hydronephrosis, inflammation and infection of kidney due to ureter obstruction. herein, we report our experience of laparoscopic repair in a patient with ureterosciatic hernia combined urosepsis. keywords: laparoscopy; piriformis muscle; sciatic hernia; ureterosciatic hernia; urosepsis introduction sciatic hernias are the rarest entities among hernias of pelvic floor(1). moreover, ureterosciatic hernias are very unusual lesions globally reported only by 32 cases; only 4 cases were reportedly repaired with laparoscopy(2-5). here we repot a successful case of laparoscopic repair of ureterosciatic hernias with urosepsis. case report preoperative management and work up a 72-year-old female visited our hospital for right flank pain and fever lasting 2 days. she underwent contrast-enhanced ct at the another hospital and was referred to our hospital for further evaluation and treatment. according to the laboratory results, leukocytosis, elevated crp and pyuria were found. based on outside ct, right perinephric infiltration and hydronephrosis were observed and the distal ureter was herniated to sciatic foramen (figure 1a). thus, we diagnosed and hospitalized the patient with urosepsis caused by ureterosciatic hernia, and operated percutaneous nephrostomy, immediately. after resolution of urosepsis, we decided to attempt correction of herniated ureter by retrograde approach. retrograde pyelography showed the right ureter was leant toward the outside of right side, and observe ‘’curlicue sign’’, which was formed as the knuckle of herniated ureter (figure 1b). and then, we tried to insertion of flexible guide wire through the herniation site, but failed. thus, we planned laparoscopic approach. department of urology, eulji medical center, eulji university school of medicine, seoul, korea. *correspondence: department of urology, eulji general hospital, 68 hangeulbiseong-ro, nowon-gu, seoul 139-872, korea. tel: +82-2-970-8306 fax: +82-2-970-8517. e-mail: uro02@eulji.ac.kr. received march 2018 & accepted january 2019 figure 1. a. computed tomography showed herniation of rt. ureter into sciatic foramen (arrow). b. retrograde pyelography showed ‘’curlicue ureter’’ sign of ureterosciatic hernia (arrow). urology journal/vol 16 no. 6/ november-december2019/ pp. 616-618. [doi: 10.22037/uj.v0i0.4459] operation management the patient was placed head down rt. semi-lateral position and then 12mm trocar for a camera was inserted at the level of umbilicus. and then one 12mm port and one 5mm port were placed under direct vision. after finding the ureter, dissection was performed to downward and the ureter was found to be herniated to the right sciatic foramen. as the herniated ureter was dissected from the sciatic foramen, the herniated ureter was repaired and curlicue appearance was gradually reduced and disappeared (figure 2). then, the defect of right sciatic foramen was repaired with 3-0 prolene® by running sutures suturing the edges of the surrounding connective tissue, and the operation was completed without ureteral stent placement. postoperative follow-up the patient did not have any complications. at the 3rd day after the operation, we performed the agp and obstruction was not found at the site of herniated ureter (figure 3a). then, percutaneous nephrostomy was removed. at the 10th day after the operation, we performed the dip, and found the improvement of hydronephrosis and ureteral kinking (figure 3b). discussion as the piriformis muscle occupies most of the greater sciatic foramen, organ of this site within pelvis would be herniated due to weakness and atrophy of piriformis muscle(6). even though the sciatic hernias of various organs within pelvis were reported, ureterosciatic hernias are very unusual lesion globally reported only by 32 cases(2-5). the clinical aspects of ureterosciatic hernias appeared variously according to the degree of hydronephrosis, inflammation and infection of kidney(7). the ureterosciatic hernia can be diagnosed generally with excretory urography, the knuckle of herniated ureter was shown as typical ‘’curlicue sign’’(8). it can be also diagnosed through ct; the distal ureter was leant to the posterolateral ischial spine and it was herniated to the sciatic foramen(9). traditionally most of ureterosciatic hernias are repaired through open surgery. since laparoscopic hernia repair was reported by gee et al. in 1999, 4 cases of laparoscopic ureterosciatic hernia repair have been reported(4,6,7,10). laparoscopic repair of ureterosciatic hernia is relative simple procedure and it is a possible option for treatment. unfortunately, long-term follow up has not been performed in our case, however there has been no report of complications or recurrence like as other previously reported cases. references 1. losanoff je, basson md, gruber sa, weaver dw. sciatic hernia: a comprehensive review of the world literature (1900-2008). am j surg. 2010;199:52-9. 2. loffroy r, bry j, guiu b, et al. ureterosciatic hernia: a rare cause of ureteral obstruction visualized by multislice helical computed tomography. urology. 2007;69:385.e1-3. 3. rommel fm, boline gb, huffnagle hw. ureterosciatic hernia: an anatomical radiographic correlation. j urol. 1993;150:1232-4. 4. tsuzaka y, saisu k, tsuru n, homma y, ihara h. laparoscopic repair of a ureteric sciatic hernia: report of a case. case rep urol. 2014;2014:787528. 5. kato t, komiya a, ikeda r, nakamura t, akakura k. minimally invasive endourological techniques may provide a novel method for relieving urinary obstruction due to ureterosciatic herniation. case rep nephrol dial. 2015;5:13-9. 6. gee j, munson jl, smith jj, 3rd. laparoscopic repair of ureterosciatic hernia. urology. 1999;54:730-3. 7. witney-smith c, undre s, salter v, al-akraa m. an unusual case of a ureteric hernia into the sciatic foramen causing urinary sepsis: successfully treated laparoscopically. ann r coll surg engl. 2007;89:w10-2. 8. beck wc, baurys w, brochu j, morton repair of a ureterosciatic hernia -moon et al. figure 2. images from laparoscopic repair of an ureterosciatic hernia. a. the ureter herniated into sciatic foramen (arrow); b. after dissected from the sciatic foramen (arrow); c. immediately reduced the ‘’curlicue’’ appearance (arrow); d. a small defect, sciatic foramen was identified (arrow). figure 3. a. anterograde pyelography at postoperative day 3. there was no more obstruction on previous herniated site (arrow); b. drip infusion pyelography (dip) at postoperative day 10. improved hydronephrosis and ureteral kinking. vol 16 no 06 november-december2019 617 case report 618 wa. herniation of the ureter into the sciatic foramen ("curlicue ureter"). j am med assoc. 1952;149:441-2. 9. arat a, haliloglu m, cila a, demirkazik f, balkanci f. demonstration of ureterosciatic hernia with spiral ct. j comput assist tomogr. 1996;20:816-8. 10. whyburn jj, alizadeh a. acute renal failure caused by bilateral ureteral herniation through the sciatic foramen. urology. 2013;81:e38-9. repair of a ureterosciatic hernia -moon et al. urological oncology prognostic significance of blood type a in patients with renal cell carcinoma kyungtae ko,1 young hyun park,2 chang wook jeong,2 ja hyeon ku,2 hyeon hoe kim,2 cheol kwak2* purpose: in this study, we evaluated the prognostic significance of the abo blood type in patients with renal cell carcinoma (rcc) who had undergone partial or radical nephrectomy. materials and methods: information on the abo blood type was obtained from 1750 patients with rcc. a total of 1243 men and 507 women (mean age, 55.41 ± 12.43 years) with rcc who had undergone partial or radical nephrectomy were enrolled in this study. the median follow-up duration was 35.0 months (interquartile range [iqr], 16.0–67.0). during the follow-up period, 271 patients experienced rcc recurrence, and 137 patients died from rcc. results: type a was the most common blood type (568, 32.5%), followed by type o (525, 30.0%), type b (464, 26.5%), and type ab (193, 11.0%). generally, blood type was not associated with any clinicopathological factors. unlike blood type o, the multivariate analysis of progression-free survival (pfs) showed that blood type non-o (a, b, and ab) was an independent prognostic factor for a worse outcome (95% confidence interval [ci]: 1.24– 2.37, hazard ratio [hr] = 1.71, p = .001; 95% ci: 1.08–2.13, hr = 1.51, p = .016; 95% ci: 1.03–2.43, hr = 1.58, p = .037, respectively). cancer-specific survival (css) analysis showed that blood type a was an independent factor associated with a worse prognosis for css (95% ci: 1.05–2.64, hr 1.66, p = .031, respectively). conclusion: the abo blood type is significantly associated with pfs and css in patients with rcc following partial or radical nephrectomy. blood type non-o (a, b, and ab) is an independent prognostic factor for a worse pfs outcome, and blood type a is an independent factor associated with a worse css prognosis. key words: abo blood group; renal cell carcinoma; prognosis; prognostic factor; nephrectomy introduction renal cell carcinoma (rcc) is the most deadly ma-lignancy in urology. approximately 30–40% of patients die from this disease.(1,2) in 2012, 338,000 patients were newly diagnosed with rcc, and 143,000 patients died from rcc worldwide.(3) recently, the diagnosis of smaller-sized early-stage renal masses has increased because of the development of radiological diagnostic tools and regular medical examinations. however, the incidence of rcc and the mortality rate per unit population have risen steadily.(4,5) therefore, more attention is now being paid to rcc prognosis. the tnm classification of malignant tumors stage is a strong prognostic factor in rcc. however, the tnm stage is not completely accurate as a prognostic indicator, as the prognosis of rcc varies widely between patients with same-stage tumors. many clinicians have been attempting to identify new prognostic factors, such as tumor size and fuhrman nuclear grade. (6,7) recently, we reported that body mass index (bmi) and nutritional status also impact prognosis in rcc.(8,9) other factors, such as hematologic indices, inflammatory markers, and serum calcium level, have also been introduced as next-generation prognostic factors.(6) the abo blood type is a classic prognostic factor in several malignant conditions. a correlation between the abo blood type and gastric cancer was reported sixty years ago.(10) thereafter, the correlation between the abo blood type and other malignancies, such as breast cancer, pancreatic cancer, lung cancer, and obstetric cancers, has been continuously reported.(11-14) the abo gene encodes for glycosyl transferase, which catalyzes the transfer of donor sugar to the h antigen to form the abo antigen. abo antigens exist not only on erythrocytes but also in other body tissues, predominantly in the endodermal epithelial lining and in some types of parenchymal cell lines, including those in the kidney.(15,16) through membrane signaling, mediation of intercellular adhesion, or angiogenic effects, the abo blood type may affect the progression or survival of patients with rcc. previous reports have been inconsistent regarding the influence of the abo blood type on the prognosis of patients with rcc. because these studies included small sample sizes, direct comparison with the abo blood type was not evaluated. in this study, we evaluated the prognostic value of the abo blood type in a relatively large cohort of patients with rcc urological oncology 2765 1 department of urology, hallym university college of medicine, seoul, korea. 2 department of urology, seoul national university college of medicine, seoul, korea. *correspondence: department of urology, seoul national university hospital, 28, yongon-dong, jongno-gu, seoul, korea. tel: +82 2207 22428. fax: +82 2742 4665. e-mail: mdrafael@snu.ac.kr. received january 2016 & accepted march 2016 vol 13 no 04 july-august 2016 2766 who had undergone partial or radical nephrectomy. materials and methods study population we performed a cross-sectional retrospective study of 1763 consecutive patients who had undergone partial (n = 676) or radical nephrectomy (n = 1087) for rcc at a single institution from march 1999 to december 2011. among the 1763 patients, abo blood type information was obtained from 1750 patients with rcc. this retrospective analysis of this patient population was approved by an institutional review board. evaluations for the preoperative evaluation, the clinicopathological data of the patients were examined. clinical data included sex, age, underlying diseases, american society of anesthesiologists (asa) score, bmi, and laboratory tests, including the complete blood cell count, serum chemistry (albumin, creatinine, calcium, and cholesterol), erythrocyte sedimentation rate (esr), c-reactive protein (crp), and the abo blood type. a preoperative computed tomography exam was performed to evaluate tumor size, tumor location, and distant metastasis. procedures partial or radical nephrectomy was performed according to standard procedures. when preoperative imaging revealed metastasis, nephrectomy and metastatic tumor excision were performed simultaneously in selected patients. similarly, when an enlarged lymph node was revealed, lymph node dissection was performed. in patients with completely resected metastasis and staging greater than t3, immunochemotherapy or targeted therapy was administered after radical nephrectomy. however, those with inoperable multiple metastases were excluded from the study. assessments the surgical specimens were evaluated by uropathologists according to the 2010 american joint committee on cancer guidelines and the fuhrman nuclear grading system. histological subtyping was conducted according to the 2004 world health organization classification. postoperative evaluations consisted of a physical examination, laboratory tests, postero-anterior chest radiography, and computed tomography. according to abo blood type in rcc-ko et al. table 1. clinicopathological factors variables n = 1750 (100%) sex male/female 1243 (71.0%) / 507 (29.0%) age 56.0 [iqr 47.0 to 65.0] years bmi 24.20 [22.19 to 26.24] kg/m2 tumor diameter 3.65 [iqr, 2.2 to 6.0] cm pathology clear cell type 1419 (81.1%) chromophobe type 155 (8.9%) papillary type 113 (6.5%) other 63 (3.2%) operation radical/partial 1078 (61.6%)/ 672 (38.4%) median follow-up duration 35.0 months [iqr 16.0 to 67.0] recurrence of rcc 271 patients (15.5%) death of rcc 137 patients (7.8%) abbreviations: iqr, interquartile range. figure 1. kaplan-meier survival analysis. (a) patients with blood type o showed a significantly longer progression-free survival (pfs) than those with blood type a; however, statistical significance was not reached compared with the results of patients with blood types b and ab. (b) patients with blood type o showed a longer cancer-specific survival (css) than those with blood type a; however, the difference did not reach statistical significance. pathological stage, these examinations were performed trimonthly or semiannually for the first 2 years and annually thereafter. survival and disease progression data were collected by reviewing medical charts, contacting the family members of patients, or reviewing death certificates. the follow-up duration was from the date of surgery to the last follow-up visit or the date of death. statistical analysis spss version 19 (spss, inc., chicago, illinois, usa) was used for the statistical analysis. the chi-square and mann-whitney tests were used to assess the correlation between the abo blood type and clinicopathological variables. cancer-specific survival (css) and progression-free survival (pfs) among the abo blood groups were estimated by the kaplan-meier method and logrank test. the cox proportional hazards regression model was used to identify significant factors related to css or pfs. the hazard ratios are presented, along with the 95% confidence intervals. for all tests, alpha table 2. relationship between abo blood type and clinical factors abo blood type total = n (%) p value o (n = 525, 30.0%) a (n = 568, 32.5%) b (n = 464, 26.5%) ab (n = 193, 11.0%) all (n = 1750, 100%) age .573b ≤ 46 125 (23.8%) 139 (24.5%) 108 (23.3%) 42 (21.8%) 414 (23.7%) 47-55 145 (27.6%) 138 (24.3%) 113 (24.4%) 46 (23.8%) 442 (25.3%) 56-65 137 (26.1%) 153 (26.9%) 131 (28.2%) 53 (27.5%) 474 (27.1%) > 65 118 (22.5%) 138 (24.3%) 112 (24.1%) 56 (26.9%) 420 (24.0%) sex .526a male 375 (71.4%) 408 (71.8%) 318 (68.5%) 142 (73.6%) 1243 (71.0%) female 150 (28.6%) 160 (28.2%) 146 (31.5%) 51 (26.4%) 507(29.0%) asa score .531b 1 242 (46.2%) 250 (44.0%) 220 (47.4%) 97 (50.3%) 809 (46.3%) 2 253 (48.3%) 281 (49.5%) 211 (45.5%) 85 (44.0%) 830 (47.5%) 3/4 29 (5.5%) 37 (6.5%) 33 (7.1%) 11 (5.7%) 110 (6.3%) pt stage .971b 1 394 (75.0%) 422 (74.3%) 351 (75.6%) 146 (75.6%) 1313 (75.0%) 2 29 (5.5%) 37 (6.5%) 27 (5.8%) 9 (4.7%) 102 (5.8%) 3 72 (13.7%) 84 (14.8%) 66 (14.2%) 27 (15.0%) 251 (14.3%) 4 30 (5.7%) 25 (4.4%) 20 (4.3%) 9 (4.7%) 84 (4.8%) pn stage .341a nx/n0 503 (95.8%) 548 (96.5%) 437 (94.2%) 185 (95.9%) 1673 (95.6%) n1 22 (4.2%) 20 (3.5%) 27 (5.8%) 8 (4.2%) 77 (4.4%) pm stage .740a m0 489 (93.1%) 522 (91.9%) 424 (91.4%) 179 (92.7%) 1614 (92.2%) m1 36 (6.9%) 46 (8.1%) 40 (8.6%) 14 (7.3%) 136 (7.8%) nuclear grade .817a 1/2 285 (54.6%) 298 (52.6%) 249 (54.2%) 99 (51.3%) 931 (53.5%) 3/4 237 (45.4%) 269 (47.4%) 210 (45.8% ) 94 (48.7%) 810 (46.5%) histology .051a clear cell 417 (79.4%) 466 (82.0%) 367 (79.1%) 169 (87.6%) 1419 (81.1%) non clear cell 108 (20.6%) 102 (18.0%) 97 (20.9%) 24 (12.4%) 331 (18.9%) operation .739a radical 319 (60.8%) 353 (62.1%) 281 (60.6%) 125 (64.8%) 1078(61.6%) partial 206 (39.2%) 215 (37.9%) 183 (39.4%) 68 (35.2%) 672 (38.4%) abbreviations: asa, american society of anesthesiologists. a,chi-square test; b, kruskal-wallis test abo blood type in rcc-ko et al. laparoscopic urology 2767 vol 13 no 04 july-august 2016 2768 was 0.05, the power was 80%, and p-values were 2-sided, with p < .05 considered statistically significant. results clinicopathological data are shown in table 1. a total of 1243 men (71.0%) and 507 women (29.0%) with rcc who had undergone partial or radical nephrectomy were enrolled in this study. the median age was 56.0 (interquartile range (iqr) 47.0 to 65.0) years. the median bmi was 24.20 (iqr, 22.19 to 26.24) kg/ m2. the mean ± sd and median tumor diameter were 4.63 ± 3.28 cm and 3.65 (iqr, 2.2 to 6.0) cm, respectively. in all, 1313 (75.0%), 102 (5.8%), 251 (14.3%), and 84 (4.8%) patients had pathological tumor stages of pt1, pt2, pt3, and pt4, respectively. seventy-seven patients (4.4%) had pathologically confirmed local metastatic lymph nodes, and 136 patients (7.8%) had distant metastases. clear cell type rcc was the most common subtype (1419, 81.1%), followed by the chromophobe type (155, 8.9%). the median follow-up duration was 35.0 months (iqr, 16.0–67.0). during the follow-up period, 271 patients experienced rcc recurrence, and 137 patients died from rcc. among the 1750 patients (table 2), the most common blood type was a (568, 32.5%), followed by o (525, 30.0%), b (464, 26.5%), and ab (193, 11.0%). the a and ab blood types were more frequent in patients with clear cell type rcc. however, the histological subtype was not significantly related to the blood type (p = .051). in general, blood type was not associated with any of the clinicopathological factors. the results of the kaplan-meier survival analysis of pfs and css according to abo blood type are shown table 3. progression-free survival and cox regression analysis. univariate multivariate hr 95% ci p value hr 95% ci p value sex (m/f) 0.83 0.63 – 1.09 .181 age ≤ 46 reference .001 .258 47-55 1.21 0.83 – 1.77 .330 1.12 0.76 – 1.66 .575 56-65 1.78 1.25 – 2.53 .001 1.42 0.98 – 2.05 .062 > 65 1.85 1.29 – 2.67 .001 1.24 0.84 – 1.81 .281 asa score 1 reference < .001 .162 2 1.63 1.25 – 2.12 < .001 1.03 0.78 – 1.37 .813 3/4 3.28 2.20 – 4.89 < .001 1.48 0.97 – 2.26 .071 pt stage t1 reference < .001 < .001 t2 5.11 3.38 – 7.72 < .001 2.99 1.95 – 4.59 < .001 t3 11.67 8.75 – 15.56 < .001 4.67 3.36 – 6.50 < .001 t4 11.32 7.76 – 16.49 < .001 4.00 2.63 – 6.09 < .001 pn stage 9.69 7.05 – 13.33 < .001 1.14 0.78 – 1.67 .488 pm stage 23.50 18.12 – 30.48 < .001 8.29 6.00 – 11.47 < .001 nuclear gr. (i-ii/iii-iv) 4.51 3.39 – 6.01 < .001 1.94 1.42 – 2.64 < .001 histology (clear / non clear) 1.32 0.95 – 1.84 .102 operation (radical/partial) 6.51 4.21 – 10.08 < .001 2.34 1.47 – 3.72 < .001 blood type o reference .096 .009 a 1.46 1.07 – 2.00 .018 1.71 1.24 – 2.37 .001 b 1.32 0.95 – 1.85 .102 1.51 1.08 – 2.13 .016 ab 1.48 0.97 – 2.25 .069 1.58 1.03 – 2.43 .037 abbreviations: asa, american society of anesthesiologists; hr, hazard ratio. abo blood type in rcc-ko et al. in figure 1a and 1b, respectively. the 5-year pfs in patients with blood type o was 84.2% (95% ci: 80.3– 88.1, data not shown). patients with blood type o had a longer pfs than patients with blood type a (p = .017, log-rank test). however, compared with patients with blood types ab and b, the difference did not reach statistical significance (p = .066 and p =.101, respectively; log-rank test). the 5-year css in patients with blood type o was 91.7% (95% ci: 88.8 – 94.6, data not shown). css was longer in patients with blood type o than in those with blood types a, b, and ab, although the difference did not reach statistical significance (p = .062, p =.209, and p = .085, respectively; log-rank test). in the univariate analysis, abo blood type was a significant prognostic factor for pfs. compared with blood type o, blood type a was associated with pfs (95% ci: 1.07–2.00, hr = 1.46, p = .018, respectively; (table 3). blood types b and ab were not associated with pfs (95% ci: 0.95–1.85, hr = 1.32, p =.102; 95% ci: 0.97–2.25, hr = 1.48, p = .069, respectively; table 3). furthermore, abo blood type was not related to css (95% ci: 0.98–2.39, hr = 1.53, p = .064; 95% ci: 0.84 – 2.17, hr = 1.35, p = .213; 95% ci: 0.92–2.95, hr = 1.65, p = .091, respectively; table 4). in the multivariate analysis of pfs, a non-o blood type (a, b, ab) was a significantly stronger prognostic factor for pfs than blood type o (95% ci: 1.24–2.37, hr = 1.71, p = .001; 95% ci: 1.08–2.13, hr = 1.51, p = .016; 95% ci: 1.03–2.43, hr = 1.58, p = .037, respectively; table 3). in the multivariate analysis of css (table 4), blood type a was found to be an independent factor leading to a worse prognosis for css (95% ci: 1.05–2.64, hr = 1.66, p = .031, respectively). however, the results for blood types ab and b did not reach urological oncology 2769 table 4. cancer-specific survival and cox regression analysis univariate multivariate hr 95% ci p value hr 95% ci p value sex (m/f) 0.98 0.68 – 1.42 .916 age ≤ 46 reference .027 .702 47-55 1.23 0.72 – 2.11 .456 1.28 0.73 – 2.22 .386 56-65 1.95 1.20 – 3.18 .007 1.34 0.80 – 2.26 .267 > 65 1.74 1.04 – 2.93 .037 1.16 0.66 – 2.04 .598 asa score 1 reference < .001 .204 2 1.76 1.20 – 2.58 .004 1.15 0.77 – 1.72 .499 3/4 4.06 2.37 – 6.95 < .001 1.68 0.95 – 2.99 .076 pt stage t1 reference < .001 < .001 t2 7.58 4.00 – 14.35 < .001 3.84 2.00 – 7.35 < .001 t3 17.00 10.57 – 27.32 < .001 4.66 2.76 – 7.86 < .001 t4 24.64 14.42 – 42.12 < .001 6.23 3.46 – 11.20 < .001 pn stage 11.18 7.41 – 16.88 < .001 1.50 0.93 – 2.41 .095 pm stage 27.20 19.22 – 38.50 < .001 8.12 5.33 – 12.37 < .001 nuclear gr. (i-ii/iii-iv) 7.14 4.44 – 11.48 < .001 2.58 1.56 – 4.28 < .001 histology (clear / non clear) 1.07 0.69 – 1.67 .750 operation (radical/partial) 32.91 8.14 – 133.03 < .001 7.55 1.82 – 31.36 .005 blood type o reference .234 .120 a 1.53 0.98 – 2.39 .064 1.66 1.05 – 2.64 .031 b 1.35 0.84 – 2.17 .213 1.26 0.78 – 2.05 .348 ab 1.65 0.92 – 2.95 .091 1.72 0.95 – 3.14 .075 abbreviations: asa, american society of anesthesiologists; hr, hazard ratio.. abo blood type in rcc-ko et al. vol 13 no 04 july-august 2016 2770 significance (95% ci: 0.95–3.14, hr = 1.72, p = .075; 95% ci: 0.78–2.05, hr = 1.26, p = .348, respectively). discussion studies have demonstrated that pathological changes in the abo antigen are related to rcc. first, abo antigens exist not only on the surface of erythrocytes but also in other body tissues, including the kidney.(15,16) the normal abo antigen is lost in rcc, and new tumor antigens are acquired.(13,17,18) thus, a structural change in the abo antigen occurs in rcc. the altered abo antigens in rcc are important mediators of membrane signaling and intercellular adhesion.(15,19) it is therefore possible that a specific blood type may enhance disease progression or survival. second, the deletion of a or b antigens in non-o blood group patients leads to the up-regulation of precursor h and lewisy expression, both of which stimulate angiogenesis.(20) in addition, non-o blood group patients have higher levels of von willebrand factor and factor viii.(21) thus, non-o blood group patients have a greater tendency of hypervascularity and hypercoagulability than blood group o patients, which are typical characteristics of rcc. third, single nucleotide polymorphism studies evaluating the abo gene locus have uncovered a relationship between the abo gene and plasma inflammatory markers, such as tumor necrosis factor alpha. (22) finally, abo antigens may be related to systemic inflammation, and chronic inflammation is associated with rcc.(23) in this study, esr levels were not related to abo blood type (kruskal-wallis test, p = .352, data not shown), whereas crp levels were related to abo blood type (kruskal-wallis test, p = .044, data not shown). in particular, patients with blood type o had a lower crp level than those with a non-o blood type (mann-whitney test, p = .007, data not shown). according to the tumor registry of the european institute of oncology, the abo blood type is generally associated with other cancer types. for example, blood type o patients have a significantly lower incidence of pancreatic cancer.(13) similar results have been reported in other studies. the prospective nurses’ health and health professionals follow-up cohort study revealed that the incidence of rcc is higher in non-o blood type subjects than in blood type o women.(24) a retrospective study in 900 patients with locoregional rcc reported that blood type o is a significant prognostic factor for overall survival but not a prognostic factor for disease-specific survival, and it is not related to lymph node metastasis.(25) conversely, martino et al reported that blood type o is not a prognostic factor for survival. although blood group o was associated with fewer lymph node metastases, the risk of bilateral rcc was increased.(26) the authors suggested that different inclusion criteria, racial variability, and a low event number may have been responsible for the different results in the survival rates between the two reports. in our study, we included both locoregional and advanced cases of rcc. in addition, korea is a single-race nation. furthermore, the present study included a relatively larger number of cases and a higher event number than previous studies. recently, results were published from a large cohort study in korea that evaluated the prognosis of rcc patients according to abo blood type.(27) the clinical data from our study and a previous study by lee et al. are very similar. in particular, the distribution of abo blood type was the same, which could be explained by the single ethnicity of the korean population. however, lee et al. reported that there was no relationship between survival and abo blood type in patients with rcc. although both groups conducted large cohort studies, the analysis was retrospective. our subjects had a higher asa score and pathological t stage and a short median follow-up duration. pathological m staging also differed slightly between the two groups. these differences may have contributed to the different results reported in these two studies. in this study, differences according to histological subtype did not reach statistical significance (p = .051, table 2). blood types a and ab were more frequent in patients with clear cell type rcc. however, blood types b and o were more frequent in patients with non-clear cell type rcc, although, in a multivariate analysis, histological subtype, unlike blood type, was not related to pfs and css. to our knowledge, the relationship between histological subtype of rcc and blood type a has not been previously studied. first, the a antigen is located on chromosome 9, which contains seven exons that span more than 18 kb of genomic dna, and it may be related to a tumor suppressor gene or oncogene. second, the a antigen may be related to chronic inflammation or an alteration in the systemic inflammatory reaction.(13,23) for example, a recent study reported that blood type a was related to nasopharyngeal carcinoma and skin cancer.(28,29) nevertheless, further studies are warranted. the abo blood type distribution varies widely according to country, region, and ethnicity.(30) the present data are similar to those reported in korea (a, 32%; o, 28%; b, 31%; ab, 10%), which is in contrast to the observations that nearly all bororo and peruvian indians have blood type o, eighty-two percent of north american indians (blackfoot) have blood type a, and only 9% of andamanese people have blood type o. however, it is unknown whether css or pfs are influenced by the specific blood type. furthermore, the abo blood type is inherited and cannot be changed. regarding this point, our study may be meaningful. although frequent check-ups are helpful to determine disease progression, more studies on single nucleotide polymorphisms and intracellular signaling of the abo antigen may be helpful in explaining this genetic variability. selection bias is one limitation of this retrospective cohort study. however, efforts were made to minimize the missing values, and we were able to collect a nearly complete dataset. this study also had a prospective component because the abo blood type cannot be changed after birth. thus, the patients in this cohort were automatically randomized after birth. second, because the data were obtained from a single korean institution, our results cannot be generalized to other populations due to the geographic and ethnicity-related differences in the prevalence of abo blood types. our results are, however, similar to those reported in studies from western countries. to the best of our knowledge, this study is the first to analyze the association between abo blood type, clinicopathological data, and rcc prognosis in an asian population. thus, our study provides a clinical basis upon which further research can be expanded. conclusion the abo blood type is significantly associated with pfs and css in patients with rcc who have underabo blood type in rcc-ko et al. gone radical or partial nephrectomy. a non-o blood type (a, b, and ab) was an independent prognostic factor for a worse pfs, and blood type a was an independent factor associated with a worse prognosis for css. conflict of interest there is no conflict of interest references 1. pantuck aj, zisman a, belldegrun as. the changing natural history of renal cell carcinoma. j urol. 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value of body mass index in korean patients with renal cell carcinoma. j urol. 2010;183:448-54. 9. ko k, park yh, lee jw, ku jh, kwak c, kim hh. influence of nutritional deficiency on prognosis of renal cell carcinoma (rcc). bju int. 2013;112:775-80. 10. aird i, bentall hh, roberts ja. a relationship between cancer of stomach and the abo blood groups. br med j. 1953;1:799-801. 11. costantini m, fassio t, canobbio l, landucci m, resasco m, boccardo f. role of blood groups as prognostic factors in primary breast cancer. oncology. 1990;47:308-12. 12. miyake m, taki t, hitomi s, hakomori s. correlation of expression of h/le(y)/ le(b) antigens with survival in patients with carcinoma of the lung. n engl j med. 1992;327:14-8. 13. iodice s, maisonneuve p, botteri e, sandri mt, lowenfels ab. abo blood group and cancer. eur j cancer. 2010;46:3345-50. 14. yuzhalin ae, kutikhin ag. abo and rh blood groups in relation to ovarian, endometrial and cervical cancer risk among the population of south-east siberia. asian pac j cancer prev. 2012;13:5091-6. 15. hakomori s. antigen structure and genetic basis of histo-blood groups a, b and o: their changes associated with human cancer. biochim biophys acta. 1999;1473:247-66. 16. dabelsteen e, gao s. abo blood-group antigens in oral cancer. j dent res. 2005;84:21-8. 17. ghazizadeh m, kagawa s, kurokawa k. immunohistochemical studies of human renal cell carcinomas for abo(h) blood group antigens, t antigen-like substance and carcinoembryonic antigen. j urol. 1985;133:762-6. 18. cordon-cardo c, reuter ve, finstad cl, et al. blood group-related antigens in human kidney: modulation of lewis determinants in renal cell carcinoma. cancer res. 1989;49:212-8. 19. wolpin bm, chan at, hartge p, et al. abo blood group and the risk of pancreatic cancer. j natl cancer inst. 2009;101:424-31. 20. halloran mm, carley ww, polverini pj, et al. ley/h: an endothelial-selective, cytokineinducible, angiogenic mediator. j immunol. 2000;164:4868-77. 21. tirado i, mateo j, soria jm, et al. the abo blood group genotype and factor viii levels as independent risk factors for venous thromboembolism. thromb haemost. 2005;93:468-74. 22. harrison ml, obermueller e, maisey nr, et al. tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase ii trials of infliximab at standard and high dose. j clin oncol. 2007;25:4542-9. 23. soyupek s, tulunay o, armagan a, hoscan b, perk h. clinical importance of intratumoral and normal renal parenchymal inflammatory cell infiltration in renal cell carcinoma. scand j urol nephrol. 2007;41:387-91. 24. joh hk, cho e, choueiri tk. abo blood group and risk of renal cell cancer. cancer epidemiol. 2012;36:528-32. 25. kaffenberger sd, morgan tm, stratton kl, et al. abo blood group is a predictor of survival in patients undergoing surgery for renal cell carcinoma. bju int. 2012;110:e641-6. 26. de martino m, waldert m, haitel a, schatzl g, shariat sf, klatte t. evaluation of abo blood group as a prognostic marker in renal cell carcinoma (rcc). bju int. 2014;113:e62-6. 27. lee c, you d, sohn m, et al. prognostic value of abo blood group in patients with renal cell carcinoma: single-institution results from a large cohort. j cancer res clin oncol. 2015;141:1441-7 28. ouyang py, su z, mao yp, liu q, xie fy. prognostic value of abo blood group in southern chinese patients with established nasopharyngeal carcinoma. br j cancer. 2013;109:2462-6. abo blood type in rcc-ko et al. laparoscopic urology 2771 vol 13 no 04 july-august 2016 2772 29. cihan yb, baykan h, kavuncuoglu e, et al. relationships between skin cancers and blood groups--link between non-melanomas and abo/rh factors. asian pac j cancer prev. 2013;14:4199-203. 30. bloodbook web site http://www.bloodbook.com/ world-abo.html. abo blood type in rcc-ko et al. renal autotransplantation in metachronous solitary contralateral ureteral metastasis from renal cell carcinoma: a case report introduction after nephrectomy due to localized renal cell carcinoma (rcc), up to 40% of patients will develop metastatic or locally recurring disease(1). the metastatic spread to the urinary tract, especially to the ureter, is a rare event and about 50 cases were published in literature before. of these cases, only 14 patients showed a metachronous metastasis to the contralateral ureter(2-7). we herein report a seldom clinical finding of a metachronous solitary contralateral ureteral rcc metastasis and an alternative and so far unique approach of surgical management: re1department of urology, landesklinikum mistelbach. 2department of urology, paracelsus medical university of salzburg. 3department of pathology, landesklinikum mistelbach. *correspondence: abteilung für urologie, liechtensteinstrasse 67, a-2130 mistelbach. tel: +43 699 10 96 03 69. fax: +43 2572 9004 49251. e-mail: stefanheidler@ymail.com. received june 2017 & accepted july 2017 katharina bretterbauer1, martin drerup2, stefan heidler1*, georg lösch3, walter albrecht1 ureteral metastasis of renal cell carcinoma (rcc) is rare and usually confined to the ipsilateral ureter. in literature, about 50 cases have been reported so far. of these, only 14 metastasized metachronously to the contralateral ureter. a seventy-one-year-old man was hospitalized with recurrent painless severe haematuria. seven years previously, he had undergone radical nephrectomy of the right kidney due to a clearcell renal cell carcinoma (crcc), fuhrman grad 2. intravenous urography and a retrograde ureterogram revealed a filling defect (25 mm) in the left distal ureter, which we expected to be an urothelial carcinoma. biopsy was not possible, due to ureteral stricture. diagnostic workup revealed no other sites of metastasis. to preserve kidney function and quality of life we refrained from performing nephroureterectomy and opted for an autotransplantation of the solitary left kidney with ureteral reimplantation in the bladder. we resected the ureter and histopathologicial examination showed a metastasis of crcc, fuhrman grade 2. postoperatively, the patient developed an acute postrenal failure, hence a nephrostomy and a bladder catherization were performed. after this, the patient improved significantly and the drains could be removed. currently the patient is free of complaints. the residual and contralateral ureter is a potential metastatic site after rcc. autotransplantation is an option for surgical treatment. case report keywords: renal cell carcinoma; ureteral metastasis; kidney autotransplantation. figure 1. retrograde ureterography indicating the filling defect. case report 5073 nal autotransplantation to preserve kidney function and quality of life. case report a 71-year-old man was hospitalized at our urology ward in april 2015, with recurrent painless severe haematuria. seven years previously, he had undergone a radical nephrectomy of the right kidney due to an 11x8x6cm upper pole tumor. at that time, pathologic evaluation demonstrated a fuhrman grade 2 clear cell renal adenocarcinoma (crcc): pt2, v1, r0. at rehospitalisation, an intravenous urogramm revealed a 25mm filling defect in the left distal ureter with consecutive hydroureteronephrosis, which we expected to be an urothelial carcinoma. subsequently a cystoscopy and a retrograde ureterogram were performed (figure1), biopsy was not possible due to a distal ureteral stricture. diagnostic workup included chest and abdominal ct scan which were negative for other sites of metastatic growth. we performed an autotransplantation of the solitary left kidney with ureteral antirefluxive reimplantation into the bladder without ureteral stenting in the left fossa iliaca. histo-pathologic examination showed a metastasis of crcc, fuhrman grade 2. postoperatively, the patient developed an acute postrenal failure and abdominal pain on the sixth day after surgery. a stenosis of the ureter implantation site was suspected, hence percutaneous nephrostomy was performed. after that, serum creatinine and symptoms declined rapidly. consecutively, an ureteral stent was positioned antegrade via the nephrostomy catheter and the nephrostomy catheter was removed. a cystographic examination was performed 8 days post-surgery, where no extravasation was detected. the transurethral catheter was then removed. after 4 weeks the ureteral stent was removed. currently, more than 24 months of follow-up, ultrasound examinations show no hydronephrosis and creatinine is only moderately increased with serum levels up to 1.4 mg/dl. discussion surgical treatment of ureteral tumors depends on the type, size, stage and location of the lesion. overall, removal of the entire kidney and ureter is the most common and safest procedure. the rationale behind performing renal autotransplantation was: we suspected an urothelial carcinoma and in order to provide a sufficient oncologic outcome, we therefore decided to resect the whole ureter. we disregarded boari flap-and psoas hitch plastic procedure, in order to provide better cystoscopic, as well as ureterrenoscopic follow-up investigations. intestinal operations, like ileal interpositions, were ruled out due to their high rate of complications (5). the apparent limitation in our approach is that this procedure is technically demanding and might even be harmful(8). in many cases, a reduced perfusion of the distal ureteral section due to a harvest injury can occur, which leads to ureteral stenosis and urinary leakage. the incidences is reported to be 10%, and in seldom cases a loss of the ureter occurs, which is difficult to manage(9). the strength of our chosen procedure is that renal autotransplantation is an effective procedure to reconstruct the urinary tract, therefore the operation might be beneficial in patients with solitary kidneys to preserve kidney function and quality of life(10). acknowledgement we thank univ.prof. dr. med. univ. ferdinand mühlbacher, head emeritus of the depatment of vascular surgery, medical university of vienna, for performing the renal autotransplantation together with us and the fruitful discussions. references 1. tosco l, van poppel h, frea b, gregoraci g, joniau s. survival and impact of clinical prognostic factors in surgically treated metastatic renal cell carcinoma. eur urol.2013; 63:646–52. 2. leblanc ga. contralateral ureteral metastasis from renal adenocarcinoma. j urol. 1961; 86:316-8. 3. mulira ae. ureteric metastases from bilateral adenocarcinomas of the kidney. bjs. 1981; 68:440. 4. esrig d, kanellos aw, freeman ja, stein jp, kiyabu m, ahlering te. metastatic renal cell carcinoma to the contralateral ureter. urology. 1994; 44:278-81. 5. chinegwundoh fi, french m, warfield ar. metastatic ureteral tumour. urol int. 1996; 56:55-6. 6. zorn kc, orvieto ma, mikhail aa, et al. solitary ureteral metastases of renal cell carcinoma. urology. 2006; 68:428. 7. zhang hj, sheng l, zhang zw, sun zq, qian wq, song jd. contralateral ureteral metastasis 4 years after radical nephrectomy. international journal of surgery case reports. 2012; 3:37-8. 8. krajewski w, dembowski j, kołodziej a, małkiewicz b, tupikowski k, matuszewski m, et al. urological complications after renal transplantation – a single centre experience. cent european j urol. 2016; 69: 306–11. 9. toguri ag, emtage jb, jarzylo sv. management of total ureteral loss after kidney transplantation. can j surg. 1983; 26:498-9. 10. holmäng s, johansson sl. tumours of the ureter and renal pelvis treated with resection and renal autotransplantation: a study with up to 20 years of follow-up. bju int. 2005; 95:1201-5. renal autotransplantation in metastatic contralateral rcc-bretterbauer et al. vol 14 no 06 november-december 2017 5074 vol 13 no 04 july-august 2016 2800 case report intradiverticular sarcomatoid carcinoma of the bladder: an overview starting from a peculiar case. francesco lembo,1 enrica subba,1 antonio simone laganà,2 salvatore giovanni vitale, 2* gaetano valenti,3 carlo magno1 keywords: carcinosarcoma; urinary bladder; neoplasm invasiveness; fatal outcome; urologic surgical procedures, male. introduction sarcomatoid carcinoma (sc) of the bladder is a rare and highly aggressive tumour, defined accord-ing to the world health organization (who) as a biphasic neoplasm exhibiting morphologic and/or immunohistochemical evidence of epithelial and mesenchymal differentiation.(1) sc of the urinary bladder is an uncommon neoplasm, accounting for 0.1 to 0.3% of all bladder malignancies and is more frequent during the seventh decade.(2-4) as standard protocol of the university hospital in which the case was reported, the patient was informed at the admission and signed an informed consent allowing data collection for research purposes. this case report is in accordance with the helsinki declaration, conforms with the committee on publication ethics 1 unit of urology, department of human pathology, university of messina, messina 98125, italy. 2 unit of gynecology and obstetrics, department of human pathology in adulthood and childhood "g. barresi", university of messina, messina 98125, italy. 3 department of general surgery and medical surgical specialties, university of catania, catania 95123, italy. *correspondence: unit of gynecology and obstetrics, department of human pathology in adulthood and childhood "g. barresi", university of messina, messina 98125, italy. phone: +39 3479354575. fax: +39 0902937083. e-mail: vitalesalvatore@hotmail.com. received january 2016 & accepted june 2016 figure 1. suspicious lesion inside a large bladder diverticulum. figure 2. pathology of the specimen: a. hematoxylin-eosin (h-e), 63x; b. (h-e), 100x; c. (h-e), 100x; d. (h-e),160x; e. (h-e), 200x; f. (h-e), 200x; g. (h-e), 200x; h-i-l-m: immunoperoxidase for: smooth muscle actin (h), ck20 (i), p53 (l), mib-1 (m) nuclear counterstaining with mayer's hemalum. (cope) guidelines (http://publicationethics.org/) and was approved by the institutional review board (irb) of the university hospital in which it was reported. case report a 77-year-old man was referred to our hospital for macroscopic hematuria, dysuria, and pelvic pain. cystoscopy showed a suspicious papillary lesion inside a large bladder diverticulum. chest and abdomen computed tomography (ct) (figure 1) showed no evidence of distant visceral metastases. cystoscopy confirmed the presence of a polypoid area within a bladder diverticulum. a transurethral resection of the tumor (tur-t) was performed and sc was histopathologically suspected. since the patient refused cystectomy, we have opted for a less invasive surgery: bladder diverticulectomy. at gross examination, the specimen measured 13 x 10.5 x 7 cm. surgical samples were formalin fixed, paraffin embedded and cut into 4 micron thick sections for the histological examination with haematoxylin-eosin stain and immunohistochemical procedures against smooth muscle actin (sma), cytokeratins 20, p53 and ki-67 (dakocytomation, glostrup, denmark). at the microscopic examination, the tumour had a biphasic appearance with an epithelial component represented by areas of squamous carcinoma with corneous pearls and areas of urothelial high grade carcinomas and a mesenchymal component with spindle, pleomorphic cells (figure 2a2g). frequent mitoses and necrosis were evidenced. the tumour infiltrated the whole thickness of the diverticulum wall into the perivisceral fat. at immunohistochemistry, the spindle areas were positive for sma (figure 2h), while the epithelial (squamous and urothelial) ones displayed intense cytokeratin 20 staining (figure 2i). p53 immunopositivity was found throughout the tumour (figure 2l). high proliferation index (50%) was documented by immunohistochemistry against ki-67 (figure 2m). based on the histological and immunohistochemical findings, sc of the urinary bladder was diagnosed. no postoperative radiotherapy or chemotherapy was performed. 40 days after, the patient’s clinical status worsened with haematuria and abdominal pain and he died. abdomen ct showed that pelvic cavity was largely occupied by a mass of heterogeneous appearance of 15x15 cm (figure 3), with several satellite nodules in the context of intraperitoneal fat, anterior abdominal wall, left paramedian and left obturator sites, with various dimensions from 3 to 6 cm. the right ureter was encompassed by the sarcomatous mass. discussion sc of the urinary bladder is a rare neoplasm and histogenesis is a controversial issue.(5-8) macroscopically, these tumors are usually large, polypoid or nodular. most of the reported cases contain high-grade papillary/undifferentiated urothelial carcinoma. in addition, other subtypes with epithelial origins, such as small-cell carcinoma, squamous carcinoma and adenocarcinoma have been reported. the most common sarcomatous elements are chondrosarcoma, leiomyosarcoma, and malignant fibrous histiocytoma.(4) according to recent data, the most common location of sc is the lateral wall of the bladder.(2) in our case the sarcomatous element was a leiomyosarcoma and was located in a bladder diverticulum. our patient presented with hematuria and pelvic pain. the only curative management of this kind of neoplasm could be early detection and aggressive surgery. the other preferred modalities of treatment include cystectomy or transurethral resection of the bladder (turb) with or without radiation therapy and chemotherapy. furthermore, chemotherapy and radiotherapy do not provide apparent survival advantages. transurethral resection and partial cystectomy carry the risk of incomplete tumour resection. neoadjuvant radiochemotherapy with radical cystectomy can provide 20 months of recurrence-free survival.(9) in a recent large retrospective study which analyzed 221 cases, the overall 5-year cancer-specific survival rate after radical cystectomy was 20.3%. the 1-, 5-, and 10-year survival rates for sc of the urinary bladder were 53.9%, 28.4%, and 25.8%, respectively.(2) treatment of bladder sc should be aggressive and multimodal but optional treatment is not still encoded. as already reported,(10) sc has a poor prognosis despite of all treatment modalities and a median cancer-specific survival of approximately 14 months. in particular, cancer-specific survival was significantly better for those who underwent cystectomy instead of transurethral resection. on one hand, chemotherapy and radiotherapy do not provide apparent survival advantages;(11) on the other hand, neoadjuvant/adjuvant radiochemotherapy has been used in many cases, and there were complete responses after neoadjuvant treatment.(12) considering our experience and the most updated literature, we solicit future multicentric large cohort analyses which may clarify the best evidence-based treatment of the reported condition. conflict of interest none declared. references 1. lopez-beltran a, sauter g, gasser t, et al. infiltrating urothelial carcinoma. in: eble jn, sauter g, epstein ji, sesterhnn ia, editors. world health organization classification of tumours. pathology and genetics of tumours sarcomatoid carcinoma of the bladder-lembo et al. figure 3. abdomen ct showing a mass of heterogeneous appearance of 15x15 cm which occupies the pelvic cavity. case report 2801 vol 13 no 04 july-august 2016 2802 of the urinary system and male genital organs. lyon: iarc press; 2004. p. 93-109. 2. wang j, wang fw, lagrange ca, hemstreet iii gp, kessinger a. clinical features of sarcomatoid carcinoma (carcinosarcoma) of the urinary bladder: analysis of 221 cases. sarcoma. 2010;2010. pii: 454792. 3. ikegami h, iwasaki h, ohjimi y, takeuchi t, ariyoshi a, kikuchi m. sarcomatoid carcinoma of the urinary bladder: a clinicopathologic and immunohistochemical analysis of 14 patients. hum pathol. 2000;31:332-40. 4. wright jl, black pc, brown ga, et al. differences in survival among patients with sarcomatoid carcinoma, carcinosarcoma and urothelial carcinoma of the bladder. j urol. 2007;178:2302-6. 5. giannopoulos a, alivizatos g, kyriakou v, mitropoulos d, dimopoulos ma. carcinosarcoma of the bladder. br j urol. 1991;67:106-7. 6. völker hu, zettl a, schön g, et al. molecular genetic findings in two cases of sarcomatoid carcinoma of the ureter: evidence for evolution from a common pluripotent progenitor cell? virchows arch. 2008;452:457-63. 7. wick mr, brown ba, young rh, mills se. spindle-cell proliferations of the urinary tract. an immunohistochemical study. am j surg pathol. 1988;12:379-89. 8. gorstein f, anderson tl. malignant mixed mesodermal tumors: carcinoma, sarcoma, or both? hum pathol. 1991;22:207-9. 9. tazi fm, ahallal y, benlemlih a, khallouk a, elfassi mj, farih mh. urinary bladder carcinosarcoma: a complete pathological response after neoadjuvant chemotherapy. turkish journal of urology. 2012;38:114-6. 10. atılgan d, gençten y. carcinosarcoma of the bladder: a case report and review of the literature. case rep urol. 2013;2013:716704. 11. lopez-beltran a, pacelli a, rothenberg hj, et al. carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. j urol. 1998;159:1497–503. 12. hoshi s, sasaki m, muto a, et al. case of carcinosarcoma of urinary bladder obtained a pathologically complete response by neoadjuvant chemoradiotherapy. int j urol. 2007;14:79–81. sarcomatoid carcinoma of the bladder-lembo et al. miscellaneous effect of preoperative finasteride on the volume or length density of prostate vessels, intraoperative and postoperative blood loss during and after monopolar transurethral resection of prostate: a dose escalation randomized clinical trial using stereological methods alireza aminsharifi,1,2* alireza salehi,3 ali noorafshan,4 amirhossein aminsharifi,5 khalil alnajar1 purpose: to evaluate the effects of two preoperative treatment courses with finasteride on intraoperative and postoperative bleeding complications and prostate blood vessel characteristics in men who underwent transurethral resection of prostate (turp) using monopolar energy. materials and methods: men scheduled for turp were randomized into group 1 (control n = 25, no medication), group 2 and 3 (n = 20 in each, 5 mg finasteride daily for 2 and 4 weeks before turp; respectively). hematocrit level in the irrigation fluid, weight of the resected prostate chips, decreases in blood hemoglobin (hb) level 6 and 24 hours after the operation together with volume and length density of prostate vessels using stereological methods were compared. results: the three groups were matched regarding preoperative demographic data, resection time and weight of the resected tissue. men who received preoperative finasteride (groups 2 and 3) had significantly lower hematocrit levels in irrigation fluid than control group (control, 0.59 ± 0.85, group 2, 0.25 ± 0.4, group 3, 0.175 ± 0.16; p = .028; power = .80). however, no statistically significant difference was found in hematocrit level in irrigation fluid between groups 2 and 3 (0.25 ± 0.4 vs. 0.175 ± 0.16, 95% confidence interval (ci) = -0.28-0.42; p = .68). these values were independent of the weight of the resected tissue and resection time. there were no significant differences between the three groups in the decrease in hb 6 hours (p = .58) and 24 hours after turp (p = .65). the stereological and histological characteristics of blood vessels in suburethral prostate tissue were similar in all three groups. conclusion: a 2-week preoperative course of daily finasteride seems sufficient to significantly reduce intraoperative blood loss; this effect was independent of the weight of the resected tissue and resection time. neither the 2-week nor the 4-week presurgical finasteride regimen could significantly decrease postoperative blood loss, and neither regimen induced significant changes in characteristics of prostate tissue blood vessels. keywords: postoperative complications; prostatic hyperplasia; surgery; transurethral resection of prostate; methods; adverse effects; treatment outcome; hemorrhage. introduction transurethral resection of the prostate (turp) is the gold standard procedure for the surgical management of symptomatic benign prostatic hyperplasia (bph) intractable to medical therapy. intraoperative and postoperative bleeding, one of the most common complications of turp, may result in poor intraoperative visualization, hemodynamic instability, clot retention and the need for surgical reexploration.(1) during the previous 3 decades, several modalities such as instillation of coagulating or sclerosing agents (e.g. fibrin adhesives, premarin or phenol solution) as well as maneuvers such as catheter traction have been proposed to reduce the bleeding complications of turp. these strategies, although they may be effective, can also be difficult to use or may have critical consequences such as scar formation in the prostatic fossa.(2) thanks to the modulating effect of 5-alpha-reductase inhibitors on angiogenesis growth factors in the prostate, these agents have attracted attention for the treatment of bph-associated gross hematuria. it has been shown that exposure of the prostate to finasteride for as little as 2 weeks is associated with reduced expression of vascular endothelial growth factor (vegf) (a potent angiogendepartment of urology,1 stem cell and transgenic technology research center,2 department of epidemiology,3 and histomorphometry and stereology research center,4 shiraz university of medical sciences, shiraz, iran. 5 general internal medicine, toronto general hospital, toronto, canada. *correspondence: shaheed faghihi hospital, zand street, shiraz, iran. tel: +98 917 7000656. fax: +98 711 2331006. e-mail: aminsharifi_ar@yahoo.com. received june 2015 & accepted november 2015 miscellaneous 2562 vol 13 no 01 january-february 2016 2563 esis growth factor) and reduced microvascular density (mvd) in the prostate tissue.(3) a few recent studies have been designed to address the clinical effects of preoperative treatment with 5-alpha-reductase inhibitors on bleeding complications of turp, with variable outcomes. an optimum preoperative treatment course has yet to be proposed. in the present study we evaluated the potential effects of finasteride on bleeding complications of turp. we assessed two preoperative treatment courses to define an optimum dose, and analyzed intraoperative and postoperative variables to determine the amount of bleeding in both periods. at the same time, we used stereological and histological methods to evaluate the suburethral prostatic tissue with regard to blood vessel characteristics, and to gain insights into the physiopathological mechanisms of the effect of finasteride. materials and methods ethics before the study we obtained approval from our institutional review board. all patients were informed about the purpose of the study and provided their informed consent. patients between january 2012 and january 2014, all men with an enlarged prostate who had moderate to severe lower urinary tract symptoms with a poor response to medical therapy with α1a-blockers were considered for inclusion. these patients referred to the university clinics of shiraz university of medical sciences, shiraz, iran. the exclusion criteria were prior treatment with 5-alpha reductase inhibitors, active urinary tract infection, any coagulation disorder, and recent use of anticoagulant, antiplatelet, or nonsteroidal anti-inflammatory drugs. men who were diagnosed as having prostate cancer or who had a history of previous prostate surgery, or with a creatinine level of > 1.5 mg/dl, were also excluded (figure 1). study design and surgical procedure this clinical trial was designed in accordance with the consort statement and guidelines. the patients were randomized by block randomization using sequentially numbered containers (block size = 3) to three groups. the random allocation sequence and participant enrollment and assignment to surgery were managed by different individuals (as and mka, respectively). patients in group 1 (control) received no medication whereas those in group 2 and group 3 took 5 mg daily finasteride (soha pharmaceutical company, karj, iran), for 2 weeks and 4 weeks, respectively prior to turp. the surgeon, histopathologist and laboratory technicians were blinded to the group assignment (figure 1). before the operation the patients’ lower urinary tract symptoms were scored with the international prostate symptom score (ipss) questionnaire. all patients underwent cystoscopic evaluation of the lower urinary tract, and prostate volume was recorded by transrectal ultrasonography just before turp. the operation was done with the patient in the lithotomy position under general anesthesia in all cases. all surgeries were done by the same surgeon (aa) with a 24 french (f) resectoscope (richard wolf gmbh, knittlingen, germany) using monopolar energy. figure 1. patient allocation during study. effect of preoperative finasteride on intraoperative and postoperative blood loss during and after monopolar turp-aminsharifi et al. study outcomes demographic data as well as prostate-specific antigen (psa) level, ipss score, prostate volume and operative time were recorded. to evaluate intraoperative bleeding (primary outcome), the returned irrigation fluid was collected from the initiation until the termination of prostate resection and hematocrit level was measured in a 10-mm sample. the weight of the resected prostate chips was also recorded. to estimate overall postoperative blood loss, the decrease in blood hemoglobin (hb) level was calculated by comparing preoperative hb with 6-hour and 24-hour postoperative hb. stereological study the stereological methods were used to obtain length density and volume density of the vessels per mm3 of the prostate tissue. the method provides reliable, comparable quantitative data.(4,5) the estimation of microvessel volume density does not require isotropic uniform random (iur) sections, but iur sections are necessary to estimate length density of the vessels. these sections were obtained by the orientator method.(4,5) briefly, to generate iur sections, tissue samples of the prostate cylinder were located in the center of a circle with 10 equidistant divisions around the circumference. a random number between 0 and 10 was selected and the each piece of tissue was excised in the selected direction. the first cut edge of the tissue was placed parallel to the 0–0 direction of a second circle with 10 sine-weighted nonequidistant divisions around the circumference. a new random number between 0 and 10 was chosen and a specimen was cut in the new direction. this new cut surface was the isotropic face of the tissue. the tissue pieces were embedded in a paraffin block from the isotropic face, and sections (4 µm thickeffect of preoperative finasteride on intraoperative and postoperative blood loss during and after monopolar turp-aminsharifi et al. table 1. characteristics of 65 men in a trial of finasteride to reduce intraoperative blood loss during transurethral resection of the prostate in iran, january 2012 to january 2014. variables group 1 group 2 group 3 p value (control) (finasteride 2 weeks) (finasteride 4 weeks) mean age ± sd, years 68.8 ± 11.3 66.1 ± 10.9 67.1 ± 6.0 .65 mean psa ± sd, ng/ml 2.95 ± 3.91 1.40 ± 1.29 3.80 ± 4.9 .13 prostate volume, ml 43.8 ± 13.7 45.7 ± 16.04 49.2 ± 15.2 .49 mean preoperative hb, g/dl 13.8 ± 1.8 14.0 ± 1.75 14.6 ± 1.9 .31 mean ipss ± sd 22.6 ± 7.21 23.1 ± 7.22 21.6 ± 8.54 .35 abbreviations: ipss, international prostate symptom score; psa, prostate specific antigen; sd, standard deviation; hb, hemoglobin. variables group 1 group 2 group 3 p value (control) (finasteride 2 weeks) (finasteride 4 weeks) resection time, min 43.4 ± 20.7 39.3 ± 10.9 42.3 ± 15.4 .69 mean irrigating fluid hematocrit, % 0.59 ± 0.85 0.25 ± 0.4 0.175 ± 0.16 .028 (power = 0.80) mean resection weight, g 14.4 ± 3.9 14.9 ± 4.7 15.7 ± 6.1 .65 mean irrigating fluid hematocrit/g resection weight 0.044 ± 0.068 0.018 ± 0.017 0.012 ± 0.012 .04 (power = 0.89) mean irrigating fluid hematocrit/min resection time 0.016 ± 0.022 0.007 ± 0.006 0.004 ± 0.004 .02 (power = 0.93) mean postoperative hemoglobin decrease, g/dl preoperative-6 hour postoperative 0.88 ± 0.65 0.73 ± 0.74 0.98 ± 0.93 .58 preoperative-24 hour postoperative 1.38 ± 0.79 1.13 ± 0.96 1.24 ± 0.98 .65 stereological and histological vascular findings in the suburethral prostate tissue mean volume density of the vessels, mm3/mm3 0.04 ± 0.02 0.06 ± 0.02 0.03 ± 0.01 .41 mean length density, mm/mm3 vessels smaller than 10 µm in diameter 46.8 ± 26.6 51.0 ± 26.5 62.5 ± 29.8 .63 vessels larger than 10 µm in diameter 13.7 ± 7.6 11.1 ± 3.4 12.5 ± 7.3 .35 table 2. intraoperative, postoperative and stereohistomorphologic variables in 65 men in a trial of finasteride to reduce intraoperative blood loss during transurethral resection of the prostate in iran, january 2012 to january 2014. miscellaneous 2564 vol 13 no 01 january-february 2016 2565 ness) were cut and stained with heidenhain’s azan trichrome. volume density of the microvessels was estimated with the stereological software. the stereological probes consisted of points that were superimposed on the images of the tissue sections, and were viewed on a monitor at a final magnification of 1800 × (figure 2). volume density (vv) was obtained with the following formula:(4,5) vv (vessels) = p(vessels) / p(reference) where p(vessels) indicates the number of points hitting the vessels and p(reference) is the number of points hitting the prostatic tissue. to estimate the length density of the vessels. (lv (vessels)), an unbiased counting frame was superimposed on the images of the tissue sections viewed on a monitor and the following formula was used (figure 1): lv (vessels) = 2∑q/∑a where ∑q is the total number of vessel profiles counted that fell within the counting frame and did not touch the left and lower borders, and ∑a is the area of all counting frames. vessel diameters were measured on the vessels sampled in the unbiased counting frame used to estimate length. the diameter was measured perpendicular to the long axis of vessels where the vessel was widest. length density was categorized as less than or more than 10 µm to distinguish between capillaries and larger vessels. statistical analysis parametrical tests were used as long as their assumptions were verified. selected endpoints were compared among the three treatment groups with one-way anova. to search for possible differences in different variables within groups, one-way anova and paired t-tests were used. the stereological data were analyzed with the mann-whitney u test. all data analyses were done with statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0 software and study power was calculated with sas® v. 9.1 software. results during the study period, 69 patients were randomized to one of the three groups. four patients were excluded from the trial because of foci of prostate cancer in their resected tissue, and data for the remaining 65 patients (group 1 n = 25, groups 2 and 3, n = 20 each) were analyzed (figure 1). all three groups were similar with regard to preoperative demographic data including age, ipss, psa, prostate volume, and preoperative serum hb level (table 1). there were no differences between groups in resection time, weight of the resected tissue or hospital stay, and no patient required intraoperative or postoperative blood transfusion (table 2). in patients who received preoperative finasteride (groups 2 and 3), hematocrit in irrigation fluid was significantly lower than in control group (p = .028; power = 0.80). however, no statistically significant differences were found in hematocrit level in the irrigation fluid between groups 2 and 3 (0.25 ± 0.4 vs. 0.175 ± 0.16, 95% confidence interval [ci] = -028-0.42; p = 0.68) (table 2). the amount of intraoperative bleeding per gram of resected prostate (irrigation fluid hematocrit/ weight of the resected prostate) was significantly greater in the control group (p = .04; power = 0.89), and was similar in groups 2 and 3 (0.018 ± 0.017 vs. 0.012 ± 0.012, 95% ci = -0.02-0.033; p = .69) (table 2). to adjust for the effect of resection time on intraoperative bleeding, we divided the irrigation fluid hematocrit by resection time. again, intraopertive blood loss per minute of resection time was significantly higher in the control group (p = .02; power = 0.93) and was similar in men who receive finasteride for 2 weeks and 4 weeks (0.007 ± 0.006 versus 0.004 ± 0.004, 95% ci = -0.0066-0.011; p = .59) (table 2). the change in serum hb level was determined by comparing postoperative and preoperative values. serum hb decreased significantly 6 and 24 hours after turp in all three groups (p < .001); however, there were no significant differences between the three groups in the decrease in hb 6 hours (p = .58 ) and 24 hours after the operation (p = .65) (table 2, figure 3). there was no relationship between the postoperative decrease in hb and resection time or figure 2. stereological estimates of prostatic tissue stained with heidenhain’s azan trichrome stain. left) point-counting method; right) length density estimate of vessels using the counting frame. the arrows indicate accepted vessel profiles. effect of preoperative finasteride on intraoperative and postoperative blood loss during and after monopolar turp-aminsharifi et al. weight of the resected tissue. no major complications were observed in any of the patients during their hospital course. the stereological and histological characteristics of blood vessels in the suburethral prostate tissue were similar in all three groups (table 2, figure 2). discussion human fetal and animal studies have established that vascularity in the prostate is influenced by dihydrotestosterone (dht), which induces the expression of vasoactive mediators such as vegf by prostatic epithelial and stromal cells.(3,6,7) increased vegf expression and mvd in the suburethral prostatic tissue have been proposed as the main mechanisms of bph-related intractable hematuria, i.e. the primary indication for turp in 12% of patients.(7,8) this mechanism also explains why in these patients, hematuria recurs frequently (more than 60% in 1 year) if left untreated.(8) as a 5-alpha reductase inhibitor, finasteride reduces the level of intraprostatic dht. lekas and colleagues have shown that after 10 weeks of treatment with finasteride for prostate hyperplasia, mvd in the suburethral region as well as the level of vegf are significantly reduced.(6) this angiostatic effect was also observed by donohue and colleagues. after a 2-week treatment course before turp. (3) interestingly, häggström and colleagues also noted a reduction in vegf expression; however, consistent with sandfeldt and colleagues they found no change in mvd after 3 months of treatment with finasteride before turp.(9,10) using contrast-enhanced magnetic resonance imaging in an animal model, jia and colleagues noninvasively evaluated prostatic suburethral microcirculation. in their dynamic imaging method, they found reduced blood perfusion after a 3-month course of finasteride.(11) interest in presurgical medical interventions with 5-alpha-reductase inhibitors to reduce bleeding during or after turp has paralleled our increased understanding of prostatic microcirculation. perhaps hagerty and colleagues were the first who, as early as 2000, subjectively described the potential benefits of preoperative treatment with finasteride for 2 to 4 months for significant postoperative bleeding events, namely the need for blood transfusion, clot retention and persistent gross hematuria requiring treatment.(2) özdal and colleagues in a comprehensive randomized clinical trial, documented the promising effects of 4-week presurgical treatment with finasteride on both intraoperative and early postoperative bleeding in patients who underwent turp. by measuring hb concentration in the irrigation fluid and the postoperative decrease in hb as surrogate markers of intraoperative and postoperative bleeding, respectively, they found that this benefit was independent of the resected prostate volume.(12) using similar surrogate markers, donohue and colleagues demonstrated that a 2-week course of preoperative finasteride significantly reduced intraoperative blood loss. however, they discerned no significant difference in the early postoperative decrease in hb.(13) in contrast, sandfeldt and colleagues after a 3-month presurgical course of finasteride, found neither a decrease in average intraoperative blood loss nor any difference in mvd in the resected prostate tissue.(10) meanwhile, lund and colleagues reported no benefit with a 3-month presurgical course of finasteride in terms of a postoperative decrease in hb.(14) crea and colleagues reported a smaller postoperative decrease in hb after a preoperative course of 8-10 weeks.(15) on the other hand, pastore and colleagues found that a 6-week course of dutasteride prior to turp was beneficial with regards to postoperative decrease in hb.(16) recently, the effectiveness of an 8 week course of dutastride before bipolar tupr for reduction of preoperative blood loss was shown only in patients with large prostate (> 50 ml).(17) there is no consensus regarding the optimum duration of preoperative treatment. different trials have used courses ranging in duration between 2 weeks and 4 months. the discrepancies among studies were addressed in a recent cochrane systematic review by aboumarzouk and colleagues.(18) they found only 4 valid randomized clinical trials(3,10,12,13,18) and noted that the effect of finasteride in different studies varied with regard to intraoperative and postoperative bleeding, and also with regard to histopathologic features of the prosfigure 3. preoperative, 6-hour and 24-hour postoperative hemoglobin values in three groups. serum hemoglobin decreased significantly 6 and 24 hours after transurethral resection of prostate in all three groups; however, there were no significant differences between the three groups in the decrease in hemoglobin 6 hours and 24 hours after the operation. effect of preoperative finasteride on intraoperative and postoperative blood loss during and after monopolar turp-aminsharifi et al. miscellaneous 2566 vol 13 no 01 january-february 2016 2567 tate tissue. to address the potential effect of finasteride on bleeding complications of turp and to determine whether this effect is dose dependent, we designed a 3-arm randomized trial to compare a 2-week versus a 4-week treatment course with a control group. we also recorded intraoperative and postoperative variables and used stereological and histological methods to compare blood vessel characteristics. we found that both 2-week and 4-week courses of finasteride were able to significantly reduce intraoperative blood loss, and that the effect was independent of the weight of the resected tissue and resection time. however, the two regimens did not differ significantly in terms of reducing intraoperative blood loss. this finding is consistent with that of donohue and colleagues,(13) and suggests that a course longer than 2 weeks may add no additional benefits in terms of reducing intraoperative blood loss. in our trial, there were no statistically significant differences between the three groups in the decrease in hb after the operation. in other words, the potential positive effect of finasteride was evident only during the operation. this finding parallels the results of some of previous studies.(13,14) in contrast to donohue and colleagues who observed significantly reduced mvd in prostate specimens treated with finasteride for a period as short as of 2 weeks,(3) our findings with a computerized stereological and histological technique showed that both 2-week and 4-week courses of finasteride were too short to affect the characteristics of the suburethral blood vessels. previously, sandfeldt and colleagues and häggström and colleagues separately found no changes in mvd after treatment with finasteride for 3 months.(9,10) because a 2-4 week period is considered too brief to produce any significant involution of the prostatic tissue, we postulate that the finasteride-induced reduction in intraoperative blood loss may originate mainly from a decrease in blood flow perfusion in the suburethral microcirculation. further dynamic imaging studies with contrast-enhanced magnetic resonance imaging(11) will be necessary to elucidate the mechanism that underlies the angiostatic effect of short-course finasteride treatment. moreover, the impact of these preoperative protocols on the overall treatment costs seems worthy to be addressed. conclusions in the present 3-arm randomized clinical trial, a 2-week preoperative course of daily finasteride seemed sufficient to significantly reduce intraoperative blood loss; this effect was independent of the weight of resected tissue and resection time. neither the 2-week nor the 4-week presurgical finasteride regimen could significantly decrease postoperative blood loss, and neither regimen induced significant changes in the characteristics of prostate tissue blood vessels in stereological and histological studies. key messages 1. a 2-week preoperative course of daily finasteride seemed sufficient to significantly reduce intraoperative blood loss during transurethral resection of prostate. 2. this effect was independent of the weight of resected tissue and resection time. 3. neither the 2-week nor the 4-week presurgical finasteride regimen could significantly decrease postoperative blood loss, and neither regimen induced significant changes in the characteristics of prostate tissue blood vessels in stereological and histological studies. acknowledgments this study was supported by shiraz university of medical sciences. the protocol has been registered in www.clinicaltrials.gov (clinicaltrials.gov identifier: nct01627522). this report is based on research done in partial fulfillment of the requirements for the specialty degree in urology (dissertation no. 89-01-01-2395) awarded to dr. alnajar. we thank k. shashok (author aid in the eastern mediterranean) for improving the use of english in the manuscript. conflict of interest none declared. references 1. mebust wk, holtgrewe hl, cockett at, peters pc. transurethral prostatectomy immediate and postoperative complications. a cooperative study of 13 participating institutions evaluating 3,885 patients. j urol. 2002;167:999-1003. 2. hagerty ja, ginsberg pc, harmon jd, harkaway rc. pretreatment with finasteride decreases perioperative bleeding associated with transurethral resection of the prostate. urology. 2000;55:684-9. 3. donohue jf, hayne d, karnik u, thomas dr, foster mc. randomized, placebo-controlled trial showing that finasteride reduces prostatic vascularity rapidly within 2 weeks. bju int. 2005;96:1319-22. 4. tschanz s, schneider jp, knudsen l. designbased stereology: planning, volumetry and sampling are crucial steps for a successful study. ann anat. 2014;196:3-11. 5. karbalay-doust s1, noorafshan a. stereological study of the effects of nandrolone decanoate on the rat prostate. effect of preoperative finasteride on intraoperative and postoperative blood loss during and after monopolar turp-aminsharifi et al. micron. 2006;37:617-23. 6. lekas ag, lazaris ac, chrisofos m, et al. finasteride effects on hypoxia and angiogenetic markers in benign prostatic hyperplasia. urology. 2006 ;68:436-41. 7. pareek g, shevchuk m, armenakas na, et al. the effect of finasteride on the expression of vascular endothelial growth factor and microvessel density: a possible mechanism for decreased prostatic bleeding in treated patients. j urol. 2000;169:20-3. 8. foley sj, soloman lz, wedderburn aw, et al. a prospective study of the natural history of hematuria associated with benign prostatic hyperplasia and the effect of finasteride. j urol. 2000;163:496-8. 9. häggström s, tørring n, møller k, et al. effects of finasteride on vascular endothelial growth factor. scand j urol nephrol. 2002;36:182-7. 10. sandfeldt l, bailey dm, hahn rg. blood loss during transurethral resection of the prostate after 3 months of treatment with finasteride. urology. 2001;58:972-6. 11. jia g, heverhagen jt, polzer h, et al. dynamic contrast enhanced magnetic resonance imaging as a biological marker to noninvasively assess the effect of finasteride on prostatic suburethral microcirculation. j urol. 2006;176:2299-304. 12. ozdal ol, ozden c, benli k, gökkaya s, bulut s, memiş a. effect of shortterm finasteride therapy on peroperative bleeding in patients who were candidates for transurethral resection of the prostate (tur-p): a randomized controlled study. prostate cancer prostatic dis. 2005;8:215-8. 13. donohue jf, sharma h, abraham r, natalwala s, thomas dr and foster mc. transurethral prostate resection and bleeding: a randomized, placebo controlled trial of the role of finasteride for decreasing operative blood loss. j urol. 2002;168:2024-6. 14. lund l, møller ernst-jensen k, tørring n, erik nielsen j. impact of finasteride treatment on perioperative bleeding before transurethral resection of the prostate: a prospective randomized study. scand j urol nephrol. 2005;39:160-2. 15. crea g, sanfilippo g, anastasi g, magno c, vizzini c, inferrera a. pre-surgical finasteride therapy in patients treated endoscopically for benign prostatic hyperplasia. urol int. 2005;74:51-3. 16. pastore al, mariani s, barrese f, et al. transurethral resection of prostate and the role of pharmacological treatment with dutasteride in decreasing surgical blood loss. j endourol. 2013;27:68-70. 17. busetto gm, giovannone r, antonini g, et al. short-term pretreatment with a dual 5α-reductase inhibitor before bipolar transurethral resection of the prostate (b-turp): evaluation of prostate vascularity and decreased surgical blood loss in large prostates. bju int. 2015;116:117-23. 18. aboumarzouk om, aslam mz, wedderburn a, turner k, hughes o, kynaston hg. should finasteride be routinely given preoperatively for turp? isrn urol. 2013;2013:458353. effect of preoperative finasteride on intraoperative and postoperative blood loss during and after monopolar turp-aminsharifi et al. miscellaneous 2568 endourology and stone disease platelet-to-lymphocyte ratio: a new factor for predicting systemic inflammatory response syndrome after percutaneous nephrolithotomy mehmet cetinkaya1*, ibrahim buldu2, omer kurt3, ramazan inan4 purpose: the first purpose of this study was to reveal factors affecting the postoperative development of systemic inflammatory response syndrome (sirs) in patients undergoing standard percutaneous nephrolithotomy (pnl) for renal stones. the second purpose was to determine the role of the preoperative platelet-to-lymphocyte ratio (plr) and the neutrophil-to-lymphocyte ratio (nlr) in the prediction of sirs. matarials and methods: in total, 192 patients who had undergone conventional pnl for renal stones from 2013 to 2015 were included in the study. sirs developed postoperatively in 41 (21.3%) patients. the patients were divided into sirs and non-sirs groups, and the effects of the plr, nlr, and other demographic and operative data were investigated to predict the development of sirs. variables significant in the univariate analysis were evaluated using a multiple logistic regression model to determine the independent risk factors for developing sirs after pnl. results: univariate analysis revealed significant differences in the preoperative plr (p < .001), preoperative nlr (p = .018), number of access sites (p < .001), mean renal parenchymal thickness (p = .02), operative time (p < .001), decrease in hemoglobin (p = .016), length of hospital stay (p < .001), stone-free status (p = .023), and complication rate between the two groups of patients. however, multivariate analysis showed that only the plr and the number of access sites were independent factors affecting the development of sirs. when the plr cut-off value was 114.1, development of sirs was predicted with 80.4% sensitivity and 60.2% specificity. conclusion: the preoperative plr is an effective and inexpensive biomarker with which to predict sirs after pnl. in particular, we recommend close monitoring of patients with a plr of >114.1 because of the possible development of serious complications. keywords: inflammation; kidney; lymphocyte; nephrolithotomy; nephrolithiasis; platelet ratio; systemic inflammatory response syndrome introduction percutaneous nephrolithotomy (pnl) is a minimal-ly invasive technique recommended as first-line treatment for renal stones > 2 cm in diameter because it has a high success rate.(1) however, pnl is associated with some complications. among them, sepsis occurs in 0.3% to 3.1% of patients(2), and reported mortality rates range from 25% to 50%.(3,4) sepsis prolongs the hospitalization period and increases treatment costs. systemic inflammatory response syndrome (sirs) is closely associated with the development of sepsis and results in both infectious and noninfectious inflammation. the platelet-to-lymphocyte ratio (plr) and the neutrophil-to-lymphocyte ratio (nlr) are biomarkers that increase during inflammation. various studies have evaluated the role of the plr and nlr in many oncological diseases.(5-8) some studies have investigated factors affecting sirs and the febrile state after pnl.(9,10) in this study, we investigated for the first time whether the preoperative plr and nlr are effective inflammatory markers with which to predict the occurrence of sirs after pnl. materials and methods study population in total, 192 patients (61 female and 131 male) who had undergone conventional pnl in a single center to treat renal stones from 2013 to 2015 were included in the study. the patients’ medical records were evaluated retrospectively. the patients were divided into a non-sirs group (group 1) and sirs group (group 2) based on whether they developed sirs postoperatively. children aged < 18 years, patients with at least one sirs criterion during the preoperative evaluation, patients with an oncological disease or previously placed nephrostomy tube or urinary stent, patients who had undergone ipsilateral or contralateral ureteroscopic intervention and bilateral standard pnl in the same session, and patients 1department of urology, faculty of medicine, mugla sitki kocman university, mugla, turkey. 2 department of urology, medova hospital, konya, turkey. 3department of urology, faculty of medicine, namik kemal university, tekirdag, turkey. 4 department of urology, samsun education and research hospital, samsun, turkey. *correspondence: department of urology, faculty of medicine, mugla sitki kocman university, mugla, turkey. tel: +905053117005. fax: +9 0 252 2111345. e mail:drmemoly@yahoo.com. received october 2016 & accepted july 2017 vol 14 no 05 september-october 2017 4089 without preoperative abdominal computed tomography (ct) images were excluded from the study. a detailed medical history was obtained from all patients, and a physical examination, urinalysis, urine culture, blood count, and serum biochemical and coagulation tests were performed. patients whose urine cultures demonstrated bacterial growth were treated preoperatively. prophylactic antibiotic therapy (ciprofloxacin, 400 mg/200 ml twice daily) was maintained until the nephrostomy catheter was removed. demographic and clinical data, including age, sex, body mass index, american society of anesthesiologists score, stone size and location, width of the renal parenchyma, preoperative nlr and plr, fluoroscopy time, decrease in hemoglobin, stone-free status, and complication rate were analyzed in both groups. all patients were evaluated preoperatively with ct scan. stone size was calculated by multiplying the maximum length and width of each stone and expressed in mm2. complications were evaluated based on the clavien classification. vital signs were monitored closely, and blood counts were performed postoperatively. the presence of sirs was determined based on the 2001 international sepsis definition conference criteria.(11) patients were diagnosed with sirs when two or more of the following criteria were met: body temperature of < 36°c or > 38°c, heart rate of > 90 bpm, respiratory rate of > 20 breaths/min or paco2of < 32 mmhg and white blood cell count of > 12,000/mm3 or < 4,000/mm3. procedures an open-ended 6-fr ureteral catheter was inserted with the aid of a rigid cystoscope with the patient in the lithotomy position under spinal anesthesia. the patient was then laid in the prone position, and radio-opaque material was inserted through the ureteral catheter using a c-arm fluoroscope. intrarenal access was gained safely with an 18-g needle inserted through the appropriate calyx. after the guidewire had entered the collecting system, the access tract was dilated to 30-fr with an amplatz dilators. a 26-fr nephroscope was inserted into the kidney, and the stones were fragmented with a pneumatic lithotripter and extracted with stone forceps. the presence or absence of residual fragments was determined with a fluoroscope, and a tubeless nephrolithotomy was performed as indicated in: patients who have stone burden <3 cm, single tract access, no significant residual stones, no significant perforation, minimal bleeding, and no requirement for a secondary procedure. after the procedure, the nephrostomy catheter was removed on postoperative day 1 to 3. if no hematuria was present, the ureteral catheter was removed the next day, and the patient was discharged. otherwise, the implanted double-j stent was removed on postoperative day 15. the patients were evaluated on postoperative day 1 new factor for predicting sirs after pnlcetinkaya et al. table 1. demographic and operative data of the patients enrolled into the study. overall group 1 group 2 p-value patient number (n) 192 151 41 age (years); mean ± sd 47.3±15.1 47.4±30.1 47.2±32.9 .967 sex (male/female); n (%) .424 -male 131 (68.2%) 104 (68.9%) 27 (65.9%) -female 61 (31.8%) 47 (31.1%) 14 (34.1%) previous stone treatment; n (%) 56 (29.1%) 46 (30.4%) 10 (24.4%) .255 -swl 33 (17.2%) 26 (17.2%) 7 (17.1%) -pnl 19 (9.9%) 17 (11.2%) 2 (4.8%) -open surgery 4 (2.0%) 3 (2.0%) 1 (2.4%) diabetes mellitus; n (%) 25 (13%) 22 (14.6%) 3 (7.3%) .169 preop plr; mean ± sd 116.7 ± 39.9 109.3 ± 34.3 142.9 ± 47.3 < 0.001 preop nlr; mean ± sd 2.6±1.5 2.4±1.4 3.1±1.9 .018 hydronephrosis; n (%) .065 -absent 42 (21.9) 37 (24.5%) 5 (12.2%) -present 150 (78.1) 114 (75.5%) 36 (87.8%) stone location; n (%) .246 -pelvis 40 (20.8%) 31 (20.5%) 9 (22%) -calix 39 (20.3%) 34 (22.5%) 5 (12.2%) -pelvis + calix 63 (32.8%) 51 (33.8%) 12 (29.3%) -staghorn 50 (26%) 35 (23.2%) 15 (36.6%) parenchymal thickness (mm); mean ± sd 17.4 ± 4.4 17.8 ± 4.5 15.9 ± 4.1 .020 bmi (kg/m²); mean ± sd 28.5 ± 5.1 28.8 ± 5.2 27.4 ± 4.3 .124 asa score; mean ± sd 1.39 ± 0.55 1.40 ± 0.54 1.37 ± 0.58 .695 stone size (mm2); mean ± sd 675.9 ± 619.1 652.7 ± 632.6 765.7 ± 567.0 .311 access number; n (%) < 0.001 -single 175 (91.1%) 145 (96%) 30 (73.2%) -multiple 17 (8.9%) 6 (4%) 11 (26.8%) operative time (minutes); mean ± sd 52.0 ± 31.8 47.4 ± 30.1 68.6 ± 32.9 < 0.001 hemoglobin drop (mg/dl); mean ± sd 2.3 ± 1.3 2.2 ± 1.1 2.7 ± 1.7 .016 tubeles; n (%) .304 -yes 26 (13.5%) 22 (14.6%) 4 (9.8%) -no 166 (86.5%) 129 (85.4%) 37 (91.2%) complication; n (%) .019 -minor 19 (79.2%) 12 (100%) 7 (58.3%) -major 5 (20.8%) 0 5 (41.7%) hospital stay (day); mean ± sd 1.88 ± 1.0 1.58 ± 0.8 3.0 ± 1.1 < 0.001 stone free; n (%) 0.023 -yes 172 (90.1%) 140 (92.7%) 32 (80%) -no 19 (9.9%) 11 (7.3%) 8 (20%) abbreviations: asa, american society of anesthesia; bmi, body mass index; nlr, neutrophil to lymphocyte ratio; plr, platelet to lymphocyte ratio; pnl, percutaneous nephrolithotomy; swl, shock wave lithotripsy. endourology and stone diseases 4090 with a kidney, ureter, and bladder x-rays (kub) and biochemical tests. the final stone-free rate was evaluated using ultrasound, kub, or ct. statistical analysis spss ver. 21 software (ibm corp., armonk, ny, usa) was used for the statistical analysis. numerical data are expressed as mean ± standard deviation, and categorical data are indicated as numbers and percentages. the chi-square test was used to analyze categorical variables, and the independent sample t-test was used for numerical variables. a p-value of < .05 was considered statistically significant. variables significant in the univariate analysis were evaluated using a multiple logistic regression model to determine the independent risk factors for developing sirs after pnl. adjusted odd ratios and 95% confidence intervals were calculated. a receiver operating characteristic (roc) curve was constructed, and a cut-off value for the preoperative plr was determined. results a total of 192 patients (131 male, 61 female) were included in the study. sirs developed postoperatively in 41 (21.3%) patients. the mean age of the patients was 47.3 ± 15.1 years (range, 18 – 81 years), and the mean body mass index was 28.5 ± 5.1 kg/m2 (range, 18.0 – 47.9 kg/m2). the mean stone size was 675.9 ± 619.1 mm2 (range, 90 – 3800 mm2). the mean plr was 116.7 ± 39.9 (range, 55 – 350), and the mean nlr was 2.6 ± 1.5 (range, 1 – 16). a total of 56 (29.1%) patients had previously undergone shock wave lithotripsy, pnl, or open surgery for renal stones. the mean operative time was 52.0 ± 31.8 min (range, 15 – 180 min). a single access site (n = 175; 91.1%) or multiple access sites (n = 17; 8.9%) were used to extract the stones, and the mean hospital duration was 1.88 ± 1.0 days (range, 1 – 7 days). minor complications developed in 19 (11.7%) patients, and 5 patients (2.6%) developed major complications. blood transfusion was required in 5 patients in group 1 and 3 patients in group 2. as a consequence, 156 (81.2%) patients were stone-free. residual fragments measuring ≤ 4 and > 4 mm in diameter were detected in 16 (8.4%) and 20 (10.4%) cases, respectively. the patient demographic and operative data are shown in table 1. univariate analysis revealed significant intergroup differences between the preoperative plr and nlr, mean parenchymal thickness, number of access sites, operation duration, decrease in hemoglobin, presence of complications, and stone-free rate (p < 0.001, 0.018, .020, p < 0.001, p < 0.001, 0.016, 0.019, p < 0.001, and 0.023, respectively) (table 1). multivariate analysis showed that the preoperative plr and number of access sites were independent factors affecting the postoperative development of sirs (95% ci: 1.002-1.022, or= 1.01, p = .018 and 95% ci: 0.058-0.838, or = 0.221, p = .026, respectively) (table 1). preoperative nlr was revealed insignificant in multivariate analysis. the preoperative plr cut-off value from the roc analysis was 114.1, which had 80.4% sensitivity, 60.2% specificity, a 35.4% positive predictive value, and a 91.9% negative predictive value (table 2). the area under the roc curve was 73.1% (figure 1). discussion pnl is a safe and effective minimally invasive method for managing renal stones, with a reported complication rate of 3% to 83%.(2,12) sepsis is one of the more serious complications and is associated with higher mortality and morbidity rates. some studies have reported that sepsis is the most frequent cause of perioperative mortality.(3,13) sirs was first defined by dr. william r. nelson in 1983. ischemia, inflammation, trauma, infection, or their combinations cause sirs, which is closely related to sepsis. however, few studies have reported the development of sirs after pnl.(10,14) the plr and nlr are among the few hematological markers related to sirs that increase in patients with sirs. many studies have reported that the plr and nlr are closely associated with gastrointestinal and genitourinary system tumors.(5-8) a large-scale study of 27,000 patients by proctor et al. demonstrated the importance of the plr for predicting the outcomes of various cancers.(15) the reported incidence rate of post-pnl sirs ranges from 16.7% to 27.4%, which is similar to our result (21.3%).(10,14,16-18) however, no consensus has been reached on the risk factors that predict post-pnl development of sirs. chen et al. performed a univariate analysis showing that operative time, stone size, presence of pyelocaliectasis, staghorn stones, number of table 2. multivariate analysis for predicting systemic inflammatory response syndrome after percutaneous nephrolithotomy. p odds ratio b 95%ci* preoperativ plr ratio 0,018 1,01 0,012 1,002-1,022 access number 0,026 0,221 1,508 0,058-0,838 abbreviations: ci, confidence interval; plr, platelet-to-lymphocyte ratio figure 1. receiver operating characteristic (roc) curve analysis results of platelet to lymphocyte ratio. new factor for predicting sirs after pnlcetinkaya et al. vol 14 no 05 september-october 2017 4091 access tracts, and blood transfusion were risk factors for the development of sirs after pnl. however, their multivariate analysis demonstrated that blood transfusion, number of access tracts, stone size, and presence of pyelocaliectasis were independent predictive factors for the development of sirs. according to their results, patients with these risk factors have a > 20-fold increased risk for developing sirs.(14) in contrast, erdil et al. reported that the results of preand intraoperative urine and stone cultures predicted the development of sirs after pnl; no other factors were significant. the authors attributed this result to the strict criteria applied and stringent implementation of a preoperative antibiotic regimen.(10) our univariate analysis showed that the preoperative plr and nlr, mean parenchymal thickness, number of access sites, operative time, decrease in hemoglobin, presence of complications, and stone-free rate were related to the development of sirs. similar to our results, gutierrez et al. concluded that the presence of residual stone fragments is related to postoperative fever, whereas draga et al. and erdil et al. found no association among residual stones, postoperative fever, and sirs.(9,10,19) although no study has demonstrated an association between renal parenchymal thickness and sirs, tepeler et al. reported a correlation between increased renal parenchyma thickness and a postoperative drop in hemoglobin.(20) based on this conclusion, the injury caused by pnl performed in patients with a thicker renal parenchyma is more severe, increases the risk of sirs, and results in more bleeding than in patients with a thinner renal parenchyma. studies based on the clavien classification have reported that sirs is associated with complications. indeed, a frequently observed post-pnl complication is fever, which is also a sirs criterion. one of our patients who developed postoperative fever with subsequent sepsis recovered without sequelae. evaluations based on the number of access sites have revealed that sirs occurs more frequently in patients with multiple access sites than in patients with a single access site. in addition, multiple access sites are an independent risk factor for the development of sirs. this result may be due to the increased trauma caused by multiple access sites, which enhances the systemic inflammatory response to trauma and may be responsible for the development of sirs. in addition to the factors analyzed to date, we have herein reported for the first time that the plr and nlr are novel noninvasive biomarkers that predict postpnl development of sirs. however, only the plr was statistically significant in the multivariate analysis. the preoperative plr was higher in patients with than without sirs. the plr cut-off value of 114.1 resulted in 80.4% sensitivity, 60.2% specificity, a 35.4% positive predictive value, and a 91.9% negative predictive value. our study had some limitations. because this study was retrospective, inflammatory markers such as c-reactive protein, interleukin-6, tumor necrosis factor-alpha, the sedimentation rate, and endotoxins were not evaluated. all of the patients were operated by two different urologists. in addition, intraoperative urine and stone cultures were not performed. conclusions predicting sirs, which is associated with sepsis and other complications, is important for the physician and patient. based on our findings, extreme care should be exercised in patients with a plr of > 114.1 and multiple access sites because these patients have an increased probability of developing sirs and should be followed up more closely. a preoperative plr evaluation is a simple, cost-effective, and noninvasive test with which to predict the development of sirs. further prospective randomized studies are required compare plr, nlr, access number and other parameter. conflict of interest no conflicts of interest are declared by the authors. references 1. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2015. 2. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899-906; discussion 3. o'keeffe nk, mortimer aj, sambrook pa, rao pn. severe sepsis following percutaneous or endoscopic procedures for urinary tract stones. br j urol. 1993;72:277-83. 4. rao pn, dube da, weightman nc, oppenheim ba, morris j. prediction of septicemia following endourological manipulation for stones in the upper urinary tract. j urol. 1991;146:955-60. 5. hsu jt, liao ck, le ph, et al. prognostic value of the preoperative neutrophil to lymphocyte ratio in resectable gastric cancer. medicine (baltimore). 2015;94:e1589. 6. carruthers r, tho lm, brown j, kakumanu s, mccartney e, mcdonald ac. systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer. colorectal dis. 2012;14:e701-7. 7. sidaway p. prostate cancer: platelet-tolymphocyte ratio predicts prostate cancer prognosis. nat rev urol. 2015;12:238. 8. lucca i, de martino m, hofbauer sl, zamani n, shariat sf, klatte t. comparison of the prognostic value of pretreatment measurements of systemic inflammatory response in patients undergoing curative resection of clear cell renal cell carcinoma. world j urol. 2015. 9. gutierrez j, smith a, geavlete p, et al. urinary tract infections and post-operative fever in percutaneous nephrolithotomy. world j urol. 2013;31:1135-40. 10. erdil t, bostanci y, ozden e, et al. risk factors for systemic inflammatory response syndrome following percutaneous nephrolithotomy. urolithiasis. 2013;41:395-401. 11. levy mm, fink mp, marshall jc, et al. 2001 vol 14 no 04 july-august 2017 4018 new factor for predicting sirs after pnlcetinkaya et al. endourology and stone diseases 4092 sccm/esicm/accp/ats/sis international sepsis definitions conference. intensive care med. 2003;29:530-8. 12. skolarikos a, de la rosette j. prevention and treatment of complications following percutaneous nephrolithotomy. curr opin urol. 2008;18:229-34. 13. de la rosette j, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol. 2011;25:11-7. 14. chen l, xu qq, li jx, xiong ll, wang xf, huang xb. systemic inflammatory response syndrome after percutaneous nephrolithotomy: an assessment of risk factors. int j urol. 2008;15:1025-8. 15. proctor mj, morrison ds, talwar d, et al. a comparison of inflammation-based prognostic scores in patients with cancer. a glasgow inflammation outcome study. eur j cancer. 2011;47:2633-41. 16. mariappan p, smith g, moussa sa, tolley da. one week of ciprofloxacin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study. bju int. 2006;98:1075-9. 17. margel d, ehrlich y, brown n, lask d, livne pm, lifshitz da. clinical implication of routine stone culture in percutaneous nephrolithotomy--a prospective study. urology. 2006;67:26-9. 18. koras o, bozkurt ih, yonguc t, et al. risk factors for postoperative infectious complications following percutaneous nephrolithotomy: a prospective clinical study. urolithiasis. 2015;43:55-60. 19. draga ro, kok et, sorel mr, bosch rj, lock tm. percutaneous nephrolithotomy: factors associated with fever after the first postoperative day and systemic inflammatory response syndrome. j endourol. 2009;23:9217. 20. tepeler a, binbay m, akman t, et al. parenchymal thickness: does it have an impact on outcomes of percutaneous nephrolithotomy? urol int. 2013;90:405-10. new factor for predicting sirs after pnlcetinkaya et al. vol 14 no 05 september-october 2017 4093 vol 16 no 02 march-april 2019 145 urological oncology long-term changes in renal function, blood electrolyte levels, and nutritional indices after radical cystectomy and ileal conduit in patients with bladder cancer makito miyake1*, takuya owari1, mitsuru tomizawa1, masaru matsui2, naoko nishibayashi3, kota iida1, kenta onishi1, shunta hori1, yosuke morizawa1, daisuke gotoh1, yoshitaka itami1, yasushi nakai1, takeshi inoue1, satoshi anai1, kazumasa torimoto1, katsuya aoki1, nobumichi tanaka1, and kiyohide fujimoto1 purpose: to assess the long-term changes in renal function, blood electrolyte levels, and nutritional indices after radical cystectomy and ileal conduit in patients with bladder cancer. patients and methods: in 129 patients who underwent radical cystectomy and ileal conduit, we evaluated clinicopathologic features, complications, and the change in the estimated glomerular filtration rate (egfr) from baseline to 1, 2, 3, 4, 5, and 10 years postoperatively. two nutritional indices, the geriatric nutritional risk index (gnri) and prognostic nutrition index (pni), were calculated with laboratory tests. results: in the ileal conduit group, a parastromal hernia was observed in 10% of patients, whereas 13% had an ureteroenteric anastomotic stricture, which was associated with greater decline in the egfr postoperatively. the first 5 year-decline in the egfr was 1.74 ml/min/1.73 m2/year. the levels of only potassium showed a significant increase at 1 year postoperatively (mean: 4.34 meq/l) and remained high compared with the baseline (4.14 meq/l). evaluation of the nutritional indices demonstrated that the gnri, and not pni, showed a significant, transient increase from 1 to 4 years (range: 108−110) postoperatively compared with the baseline (105). conclusion: the first 5 year-decline was much higher than that among japanese individuals who participated in an annual health examination program. further research should be performed to identify an appropriate strategy for selecting the suitable type of urinary diversion and postoperative nutritional interventions to improve the clinical outcome of patients with bladder cancer. keywords: urinary bladder neoplasms; cystectomy; urinary diversion; kidney failure, chronic; electrolyte, nutritional status introduction radical cystectomy (rc), with or without peri-operative, systemic chemotherapy, is the standard treatment for selected patients with high-risk, non-muscle invasive bladder cancer (stage tis or ta/1) and muscle-invasive uroethelial cancer of the bladder (stage ≥t2)(1,2). rc requires reconstruction of the lower urinary tract, which is called urinary diversion (ud). although ureterosigmoidostomy was the first widely selected ud, decrease of renal function with time, metabolic acidosis, and the risk of secondary bowel adenocarcinoma were significant disadvantages of this type of surgery and limited its clinical usefulness(3). subsequent advances in technology have provided several reconstructive options and substantial improvements in terms of both functional outcomes and health-related quality of life. among the currently available options for ud after rc, ileal conduit is considered the “gold standard” for those with incontinent ud and has remained the major choice for patients with contraindications to continent ud. the latest version of european association of urology 1 department of urology, nara medical university, 840 shijo-cho, kashihara-shi, nara 634-8522, japan. 2 first department of internal medicine, nara medical university, 840 shijo-cho, kashihara-shi, nara 634-8522, japan. 3 department of wound ostomy continence nursing, nara medical university, 840 shijo-cho, kashihara-shi, nara 634-8522, japan. *correspondence: department of urology, nara medical university, 840 shijo-cho, nara 634-8522, japan. tel: +81-744-22-3051 (ext 2338). fax: +81-744-22-9282. e-mail: makitomiyake@yahoo.co.jp received april 2018 & accepted september 2018 guideline recommends offering an orthotopic bladder substitute or ileal conduit diversion to male and female patients lacking any contraindications and who have no tumour in the urethra or at the level of urethral dissection(4). ileal conduits are relatively easy and quick to construct, leading to a minimized rate of postoperative complications(5,6). however, rc and accompanying ud are associated with high risks of perioperative and longterm morbidity and mortality, including subsequent decline in renal function (7,8). for many years, one of the goals of ud was to protect renal function and restore anatomy, because a high proportion of bladder cancer patients present with impaired renal function(9). although several reports have described deterioration of renal function over time after ileal conduit(10-13), definite conclusions could not be made because of variations in surgical skill and patient backgrounds. there is only limited information regarding long-term complications and changes in blood electrolyte levels and nutritional indices after ileal conduit. in this study, we explored the incidence of complications and post-surgical, chronological changes in blood examination results urological oncology 146 in patients with ileal conduits and investigated the risk factors of the development of this condition. patients and methods data collection and follow-up the ethics committee of the nara medical university approved this study, and all participants provided informed consent (reference id: 1256). the study was conducted in compliance with the study’s protocol and in accordance with the provisions of the declaration of helsinki (2013). the medical charts of 182 patients who underwent curative rc between 2000 and 2017 were retrospectively reviewed. eight patients were excluded because they underwent hemodialysis and did not require any ud procedure, and 14 patients were excluded because they had insufficient follow-up data, leaving 160 (88%) patients for inclusion in this study. of these, 129 (81%), 23 (14%), and 8 (5%) patients underwent ileal conduit, cutaneous ureterostomy, and ileal orthotopic neobladder, respectively (figure 1). ud procedure was selected at a physician's discretion. follow-up was performed according to our institutional protocol(1). laboratory data, including the serum creatinine, albumin, blood lymphocyte, and blood electrolyte (sodium, potassium, chloride, and calcium) levels, were measured at baseline and follow-up visits at regular intervals after rc and were obtained from the patients’ medical charts. the estimated glomerular filtration rate (egfr) long-term changes after radical cystectomy and ileal conduit-miyake et al. variables total cases type of ud p value ic cu nb 3 group comparison† 2 group comparison‡ 2 group comparison‡ ic vs cu ic vs nb no. of cases 160 (100%) 129 (81%) 23 (14%) 8 (5%) sex male 127 (79%) 103 (80%) 18 (78%) 7 (88%) 0.84 0.78 0.99 female 33 (21%) 22 (20%) 5 (22%) 1 (12%) ecog-ps 0 134 (84%) 111 (86%) 20 (87%) 7 (88%) 0.97 0.99 0.99 1—3 26 (16%) 18 (14%) 3 (13%) 1 (12%) charlson 0 133 (83%) 108 (83%) 17 (74%) 8 (100%) 0.22 0.25 0.61 comorbidity index 1—3 27 (17%) 21 (17%) 6 (26%) 0 (0%) clinical t t1/tis 9 (6%) 7 (5%) 2 (9%) 0 (0%) 0.07 0.018 0.69 category t2 71 (44%) 55 (43%) 11 (48%) 5 (63%) t3 45 (28%) 41 (32%) 0 (0%) 2 (25%) t4 35 (22%) 26 (20%) 8 (35%) 1 (12%) clinical n n0 146 (91%) 116 (90%) 22 (96%) 8 (100%) 0.44 0.69 0.99 category n ≥1 14 (9%) 13 (10%) 1 (4%) 0 (0%) carcnoma neagative 99 (62%) 82 (64%) 11 (48%) 6 (75%) 0.26 0.17 0.71 in situ positive 61 (38%) 47 (36%) 12 (52%) 2 (25%) neoadjuvant no 97 (61%) 71 (55%) 20 (87%) 6 (75%) 0.011 0.005 0.46 chemotherapy yes 63 (39%) 58 (45%) 3 (13%) 2 (25%) adjuvant no 134 (84%) 107 (83%) 20 (87%) 7 (88%) 0.85 0.77 0.99 chemotherapy yes 26 (16%) 22 (17%) 3 (13%) 1 (12%) age at rc (mean ± sd) 70.0 ± 8.7 69.8 ± 8.3 73.9 ± 10.1 63.3 ± 5.3 0.0013 0.049 0.037 bmi (mean ± sd) 22.5 ± 3.9 22.4 ± 3.7 23.3 ± 5.3 23.2 ± 2.7 0.67 0.99 0.99 (kg/m2) serum (mean ± sd) 1.09 ± 0.95 1.02 ± 0.88 1.55 ± 1.30 0.95 ± 0.36 0.025 0.022 0.99 creatinine (mg/dl) estmated gfr (mean ± sd) 62.0 ± 22.4 64.6 ± 21.9 46.5 ± 20.6 65.7 ± 18.4 0.0022 0.02 0.99 (ml/min/1.73m2) pni (mean ± sd) 49.8 ± 5.4 49.8 ± 5.3 48.2 ± 5.4 54.8 ± 3.8 0.015 0.88 0.028 gnri (mean ± sd) 95.3 ± 19.3 95.3 ± 19.9 100.1 ± 11.2 99.7 ± 28.6 0.15 0.99 0.16 table 1. characteristics of 160 patients undergoing radical cystectomy and comparison between urinary diversion. ud, urinary diversion; ic, ileal conduit; cu, cutaneous ureterostomy; nb, ileal orthotopic neobladder; ecog-ps, the eastern cooperative oncology group performance status; rc, radical cystectomy; bmi, body mass index; egfr, estimated glomerular filtration rate; pni, prognostic nutritional index; gnri, geriatric nutritional risk index; sd, standard deviation; †, kruskal-wallis or chi-squared test; ‡, post hoc dunn's test or fisher’s exact test figure 1. flow chart for creating the patient dataset. vol 16 no 02 march-april 2019 147 was calculated using the modification of diet in renal disease study formula for japanese patients: egfr ml/min/1.73 m2 = 194 × serum creatinine −1.094 × age−0.287 (× 0.739 for women) (14). the chronic kidney disease (ckd) stages were defined according to the egfr (15). the charlson comorbidity index, which was updated in 2011, was applied for evaluating preoperative comorbidities (16). the stage was assigned according to the 2009 tnm classification of the union of international cancer control. calculation of nutrition-based markers the geriatric nutritional risk index (gnri) and prognostic nutrition index (pni) were calculated using laboratory data that were measured during the follow-up period (17). the gnri score was calculated using the serum albumin levels and ratios of the actual body weight to ideal body weight, which was 22 × the square of height in meters. thus, gnri = 14.89 × the serum albumin concentration (g/dl) + 41.7 × (body weight in kg/ideal body weight). the pni was calculated as 10 × the serum albumin level (g/dl) + 0.005 × the total lymphocyte count (per mm3). both indices were reported as continuous variables for the analyses. rc, lymphadenectomy and ud procedures of the 129 patients with ileal conduit, 103 (80%) underwent open rc and 26 (20%) underwent laparoscopic rc. lymphadenectomy procedures, including removal of the obturator, external iliac, common iliac, and parasacral lymph node chains, were performed basically according to the extended template(18). regarding the construction of ileal conduits, the terminal ileum was preserved to ensure that bile salts, vitamin b12, and fat-soluble vitamins were adequately maintained(5). a segment of the ileum of approximately 20 cm was isolated and used for ud. the ureters were split and anastomosed to the oral side separately in an open endto-side manner. the ileal segment of the anal side was anastomosed to the abdominal wall in a nipple-to-stoma manner. cutaneous ureterostomy was performed by two methods: one ureter was brought across the midline and the two ureters were placed side by side in a double-barrel fashion or the two distal ureteric ends were placed individually. the stoma for cutaneous ureterostomy was created according to the toyoda method (19). in orthotopic ileal neobladder, ileal construction was performed according to studer reservoir (20). evaluation of postoperative complications complications after rc were objectively evaluated according to the clavien-dindo classification system (21). early and late complications were defined as complications occurring within 90 days of rc and 90 days after rc, respectively. parastomal hernia is defined as any protrusion in the vicinity of the urostoma with the patient straining in a supine and an erect position(22). statistical analyses the clinicopathological characteristics of the patients in this study were compared using the kruskal-wallis test, following the post hoc test (dunn test), chi-squared test, and fisher’s exact test, as appropriate. continuous variables are expressed in means ± standard deviations and shown in line charts. the normality was checked by shapiro-wilk test. the student t-test, mann-whitney u test, paired t-test, or wilcoxon’s signed-rank test was used, as appropriate. the cumulative rate of complications was drawn using the kaplan-meier plot. the linear regression analysis was used to calcurate the annual egfr decrement. ibm spss version 21 (spss inc., chicago, il, usa) and prism software version 7.00 (graphpad software, inc., san diego, ca, usa) were used for statistical analyses and data plotting, respectively. statistical significance was set at p < 0.05, and all reported p-values were two-sided. in the paired t-test for long-term changes in continuous values, power analysis using g*power (version 3.1.9.2) was performed a priori, and showed that a sample of 34 patients was required to detect a between-group difference given an effect size of 0.50, a power of 0.80 and an alpha of 0.05. results patient characteristics the clinicopathological characteristics of the 160 patients undergoing rc and ud are listed in table 1. the median follow-up period after rc was 44.1 months. during the follow-up period, 49 patients died (31%), including 35 with recurrent disease (22%). other causes of death were acute myocardiac infarction in two patients, pneumonia in two, panperitonitis due to intestinal perforation in two, other malignancy in two, chronic kidney disease in one, urinary tract infection in one, heart failure in one, and unknown in three, respectively. sixty-nine patients (39%) received two to three cycles of platinum-based neoadjuvant chemotherapy and 26 patients (16%) received two to three cycles of platinum-based adjuvant chemotherapy. almost half of the patients undergoing ileal conduit received neoadjuvant chemotherapy, whereas only 13% of patients undergoing cutaneous ureterostomy received neoadjuvant chemotherapy (p = 0.005). forty-one (32%) of the 129 patients undergoing ileal conduit had stage t3 long-term changes after radical cystectomy and ileal conduit-miyake et al. table 2. the early and late complications in 129 patients undergoing ileal conduit. early or late complications total clavien-dindo calssification i / ii iiia iiib iv early (< 90 days) bowel obstruction 32 (25%) 22 (17%) 8 (6%) 2 (2%) surgical site infection 29 (22%) 13 (10%) 10 (8%) 5 (2%) 1 (1%) pelvic abscess 19 (15%) 1 (1%) 10 (8%) 8 (6%) ureteroenteric anastomotic stricture 9 (7%) 5 (4%) 4 (3%) intestinal anastomotic leakage 7 (5%) 7 (5%) ureteroenteric anastomotic leakage 3 (2%) 1 (1%) 2 (2%) late (> 90 days) parastomal hernia 13 (10%) 12 (9%) 1 (1%) ureteroenteric anastomotic stricture 8 (6%) 2 (2%) 6 (5%) abdominal incisional hernia 8 (6%) 5 (4%) 3 (2%) stomal stenosis 3 (2%) 1 (1%) 2 (2%) urological oncology 148 disease, whereas no patients with stage t3 disease underwent cutaneous ureterostomy (p = 0.018). patients undergoing ileal conduit were younger than those who underwent cutaneous ureterostomy, but older than those who underwent orthotopic neobladder. the egfr in patients with cutaneous ureterostomy was lower than that in those with ileal conduit (p = 0.02). however, sex, performance status, the charlson comorbidity index, clinical n category, presence of carcinoma in situ, and adjuvant chemotherapy were not associated with the selected type of ud. early and late complications both early and late complications were observed after rc and ileal conduit. the incidence of complications, expressed as numbers and percentages, is summarized in table 2. the most frequent complication was bowel obstruction (32 patients, 25%), which sometimes required an indwelling ileus tube or surgical intervention, such as synectenterotomy. ureteroenteric anastomotic stricture, ureteroenteric anastomotic leakage, parastomal hernia, and stomal stenosis were complications that were specific to ileal conduit. among 17 patients presenting with an ureteroenteric stricture, bilateral strictures were observed in 5, while the remaining 12 had a unilateral stricture. regarding stoma-related, late complications during the follow-up period, parastromal hernia was observed in 13 patients, one of whom underwent repair surgery using mesh. among the patients presenting with complications, the median time from ileal conduit to the diagnosis of ureteroenteric stricture and parastomal hernia was 29 and 11 months, respectively (figure 2). three patients (2%) had stomal stenosis; however, none had prolapse of the stoma. baseline and postoperative change in renal function the baseline egfr of the 129 patients undergoing ileal conduit was 64.6 ± 21.9 ml/min/1.73 m2. the ckd stage was g1 in 9 (7%), g2 in 54 (42%), g3a in 34 (26%), g3b in 14 (11%), and g4 in 5 (4%) patients. the detailed 5-year follow-up data of 45 (35%) of these 129 patients were available and subjected to the analyses of the change in renal function over time. in these 45 patients, the ckd stage was g1 in 4 (9%), g2 in 19 (42%), g3a in 15 (33%), g3b in 6 (13%), and g4 in 1 (2%) patient, and this distribution was not statistically different from that of the remaining 84 of patients (p=0.81). the change in the egfr after surgery was plotted on line graphs (figure 3a). the mean egfr was 72.6 at baseline, 71.9 at 1 year, 69.3 at 2 years, 66.7 at 3 years, 64.6 at 4 years, 63.9 at 5 years, and 62.1 at 10 years postoperatively. the first 5-year decrease in the egfr was 8.7, and the next 5-year decrease was 2.2. during the first 5 years postoperatively, the egfr decrease rate was 1.74 per year. from 5 to 10 years postoperatively, the egfr decrease rate was only 0.55 per year. during the first 5 years following ileal conduit, the egfr decline rate was 1.74 per year (figure 3a). along with the creatinine level and egfr, the blood urea nitrogen (bun) level was used to evaluate renal function and help diagnose renal disease. the bun level significantly increased until 1 year postoperatively and did not continue to rise, and was not concordant with our observation of the egfr (figure 3b). the postoperative decrease rate of the egfr was compared between patients with an ureteroenteric stricture and those without (figure 3c). patients with an ureteroenteric stricture had slightly higher decrease in the egfr than did those without, although there was no significant difference. a similar analysis showed that perioperative chemotherapy (neoadjuvant or adjuvant) did not affect the decrease rate of the egfr after ileal conduit (figure 3d). the ckd stage of the 45 selected patients at baseline, 3 years, and 5 years is shown in figure 3e. the number of patients with stage g1/g2 decreased, whereas that of patients with stage g3/g4 increased over time. hemodialysis was required for two patients (4%) (ckd stage 5d) during the follow-up period. one of these patients was 53-year-old woman with an egfr of 23.8 at the baseline examination and the second was 78-year-old man with an egfr of 42.4 at baseline. postoperative changes in blood electrolyte levels and nutritional indices the change in blood electrolyte levels and nutritional indices from baseline to 10 years after ileal conduit was plotted on line graphs (figures 4a-f). among the four blood electrolytes that were tested, only potassium showed a significant increase at 1 year postoperatively, and its level remained high compared to that at baseline (figure 4b). an evaluation of the nutritional indices demonstrated that the gnri showed a significant, transient increase from 1 to 4 years postoperatively (figures 4f, g). in contrast, the pni did not change postoperatively (figure 4h). discussion in this single-center study, we reported the postoperative complications and changes over time in various laboratory examination results after rc and ileal conlong-term changes after radical cystectomy and ileal conduit-miyake et al. figure 2. kaplan-meier plots for calculating the cumulative incidence of complications. (a) ureteroenteric stricture and (b) parastomal hernia. the numbers at risk are shown. vol 16 no 02 march-april 2019 149 duit. invasive bladder cancer has aggressive features and requires intensive interventions, such as rc and ud. to improve a patient’s quality of life, long-term management of complications and changes after surgery has become essential. substantial variability exists in the incidence of early and late complications after ud (3,7,8). the types and rates of complications depend on the selected ud, and these complications can be classified roughly into three types: bowel anastomosis-related, reservoir/conduit-related, and ureteroenteric anastomosis-related (23). in the present study, we focused on two postoperative complications: parastomal hernia and ureteroenteric stricture. a parastomal hernia occurs when the edges of the stoma come away from the muscle, allowing abdominal contents such as a section of the bowel or omentum to come out(22). shimko et al. performed a large study of 1,057 patients with a median follow-up of 9.2 years and observed parastomal hernias in 14% of the patients (8), which was similar to the result of our cohort (10%). a symptomatic parastomal hernia leads to poor quality of life. while the hernias of most patients can be managed conservatively with stomal support, including an abdominal support belt, surgical intervention is required if there is incarceration or strangulation of the hernia, or other complications. because many patients with muscle-invasive uroethelial cancer of the bladder have baseline renal impairment to some degree (partially owing to high age)(9,24), protecting renal function and the upper urinary tract after ud is one of the main clinical concerns. according to previous reports, more than half of the patients undergoing rc and ud experienced deterioration of renal function, regardless of the type of ud (13,25). several risk factors, such as hypertension, diabetes mellitus, high age, baseline egfr, postoperative acute pyelonephritis, and the type of ud, contribute to a decrease in the postoperative egfr(10-13). we demonstrated that a ureteroenteric stricture could be associated with a decrease in the postoperative egfr, although it did not reach statistical significance. eisenberg et al. revealed that there was an association between ureteroenteric strictures and a decrease of more than 10 ml/min/1.73 m2 in the egfr in a multivariate analysis of 1,241 patients undergoing ileal conduit. according to a survey of the decline in renal function over 10 years in 120,727 participants aged 40 years or older, the average rate of egfr decline was 0.36 per year (26). during the first 5 years following ileal conduit, the egfr decline rate was 1.74 per year (figure 3a), which was much higher than that of individuals who participated in an annual health examination program in japan (0.36 per year). long-term changes after radical cystectomy and ileal conduit-miyake et al. figure 3. change over time in the renal function after radical cystectomy and ileal conduit. a and b: the change over time in the egfr and bun was shown and plotted with means ± standard deviations. values at each postoperative time point (1, 2, 3, 4, 5, and 10 years) were compared with values at baseline using the paired t-test or wilcoxon’s signed-rank test as appropriate. n.s.: not significant; *: p < 0.05; **: p < 0.01; and ***: p < 0.001. the data from 21 patients are available for 10-year study. c and d: comparison of changes in the egfr postoperatively according to ureteroenteric strictures and perioperative platinum-based chemotherapy. the data of patients with an ureteroenteric stricture (red) and those without (blue) were compared at each time point using the mann-whitney u-test. n.s.: not significant (b). the data of patients who received perioperative platinum-based chemotherapy (red) and those who did not (blue) were compared as well (c). d: the distribution of patients according to the ckd stage is shown as a bar plot for the baseline, 3-year postoperative, and 5-year postoperative values. egfr: estimated glomerular filtration rate; bun: blood urea nitrogen; ckd: chronic kidney disease figure 4. time course of change in the blood electrolytes and nutrition index after radical and ileal conduit urological oncology 150 a previous study reports metabolic acidosis rates of 14.8% at 1 month and 10.0% at 1 year after ileal conduit(27). a significant association between renal function and the development of metabolic acidosis was observed, and it was especially strong in the early postoperative period. the majority of patients present with clinically insignificant acidosis, but in some cases, acidosis can provoke bone demineralization and other complications. bowel segment maintains its absorptive function and enables many substances such as urine, ammonia, hydrogen, and chloride to be reabsorbed into the blood flow. this results in metabolic, hyperchloremic acidosis and an increased load of nitrogen compounds, especially when the colonic part is used for ud. acid-base imbalance is usually treated with sodium citrate, sodium bicarbonate, nicotinic acid, or chloropromazine(28). electrolyte disorders are more common in patients undergoing continent ud than in those with incontinent ud. when the ileum is used for ud, hypokalemia with coexisting acidosis is typical and problematic(29). among our cohort, no patients experienced clinically symptomatic acidemia, hyperchloremic acidosis, hypokalemia, or hypocalcemia. we previously reported that the pni value showed transient deterioration at 1 and 3 months after rc, with a return to baseline values at 6 months(30). in the current study, we evaluated long-term postoperative changes in two nutritional indices. although the pni did not show any postoperative change, the gnri value showed a significant, transient increase from 1 to 4 years postoperatively. the pni was invented to predict the risk of complications after gastrointestinal surgery, and the gnri was established to predict the risk of morbidity and mortality in hospitalized elderly patients. few studies have addressed the nutritional status of patients undergoing rc and ud. the accuracy and utility of established nutritional indices such as the pni, gnri, and controlling nutritional status index should be confirmed using a larger cohort of patients. the present study has several limitations. the first is its retrospective nature, with a potential selection bias; for example, some patients were excluded because their data were insufficient. there were missing data regarding the comorbidities including diabetic mellitus and hypertension, which could be potential risk factors for the decline in renal function. third, this study includes only 45 patients in the subanalysis, which is considered to be a relatively low sample size. conclusions we explored the long-term complications and change in renal function, blood electrolyte levels, and nutritional indices after rc and ileal conduit. further studies should be performed to identify an appropriate strategy for selecting a suitable type of ud and postoperative nutritional interventions to improve the clinical outcome of surgery in these patients. references 1. miyake m, morizawa y, hori s, et al. integrative assessment of pretreatment inflammation-, nutrition-, and muscle-based prognostic markers in patients with muscleinvasive bladder cancer undergoing radical cystectomy. oncology 2017; 93: 259-69. long-term changes after radical cystectomy and ileal conduit-miyake et al. references 1. miyake m, morizawa y, hori s, et al. integrative assessment of pretreatment inflammation-, nutrition-, and muscle-based prognostic markers in patients with muscle-invasive bladder cancer undergoing radical cystectomy. oncology 2017; 93: 259-69. 2. üçer o, albaz ac, atag e, et al. the rate of neoadjuvant chemotherapy use in muscle invasive bladder cancer and the approach of urologists in turkey. urol j. 2016; 13: 28414. 3. bochner b, dalbagni g, daneshmand s, et al. urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes. bju int 2014; 113: 11-23. 4. alfred witjes j, lebret t, compérat em, et al. updated 2016 eau guidelines on muscleinvasive and metastatic bladder cancer. eur urol 2017; 71: 462-75. 5. bricker em. bladder substitution after pelvic evisceration. surg clin north am 1950; 30: 1511-21. 6. cordonnier jj, nicolai ch. an evaluation of the use of an isolated segment of ileum as a means of urinary diversion. j urol 1960; 83: 834-8. 7. shabsigh a, korets r, vora kc, et al. defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. eur urol 2009; 55: 164-74. 8. shimko ms, tollefson mk, umbreit ec, farmer sa, blute ml, frank i. long-term complications of conduit urinary diversion. j urol 2011; 185: 562-7. 9. canter d, viterbo r, kutikov a, et al. baseline renal function status limits patient eligibility to receive perioperative chemotherapy for invasive bladder cancer and is minimally affected by radical cystectomy. urology 2011; 77: 160–5. 10. nishikawa m, miyake h, yamashita m, inoue ta, fujisawa m. long-term changes in renal function outcomes following radical cystectomy and urinary diversion. int j clin oncol 2014; 19: 1105-11. 11. eisenberg ms, thompson rh, frank i, et al. long-term renal function outcomes after radical cystectomy. j urol 2014; 191: 619-25. 12. osawa t, shinohara n, maruyama s, et al. long-term renal function outcomes in bladder cancer after radical cystectomy. urol j 2013; 10:784-9. 13. hatakeyama s, koie t, narita t, et al. renal function outcomes and risk factors for stage 3b chronic kidney disease after urinary diversion in patients with muscle invasive bladder cancer. plos one 2016; 11: e0149544. vol 16 no 02 march-april 2019 151 2. üçer o, albaz ac, atag e, et al. the rate of neoadjuvant chemotherapy use in muscle invasive bladder cancer and the approach of urologists in turkey. urol j. 2016; 13: 28414. 3. bochner b, dalbagni g, daneshmand s, et al. urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes. bju int 2014; 113: 11-23. 4. alfred witjes j, lebret t, compérat em, et al. updated 2016 eau guidelines on muscleinvasive and metastatic bladder cancer. eur urol 2017; 71: 462-75. 5. bricker em. bladder substitution after pelvic evisceration. surg clin north am 1950; 30: 1511-21. 6. cordonnier jj, nicolai ch. an evaluation of the use of an isolated segment of ileum as a means of urinary diversion. j urol 1960; 83: 834-8. 7. shabsigh a, korets r, vora kc, et al. defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. eur urol 2009; 55: 164-74. 8. shimko ms, tollefson mk, umbreit ec, farmer sa, blute ml, frank i. long-term complications of conduit urinary diversion. j urol 2011; 185: 562-7. 9. canter d, viterbo r, kutikov a, et al. baseline renal function status limits patient eligibility to receive perioperative chemotherapy for invasive bladder cancer and is minimally affected by radical cystectomy. urology 2011; 77: 160–5. 10. nishikawa m, miyake h, yamashita m, inoue ta, fujisawa m. long-term changes in renal function outcomes following radical cystectomy and urinary diversion. int j clin oncol 2014; 19: 1105-11. 11. eisenberg ms, thompson rh, frank i, et al. long-term renal function outcomes after radical cystectomy. j urol 2014; 191: 619-25. 12. osawa t, shinohara n, maruyama s, et al. long-term renal function outcomes in bladder cancer after radical cystectomy. urol j 2013; 10:784-9. 13. hatakeyama s, koie t, narita t, et al. renal function outcomes and risk factors for stage 3b chronic kidney disease after 14. matsuo s, imai e, horio m, et al. revised equations for estimated gfr from serum creatinine in japan. am j kidney dis 2009; 53: 982–92. 15. levey as, de jong pe, coresh j, et al. the definition, classification, and prognosis of chronic kidney disease: a kdigo controversies conference report. kidney int 2011; 80: 17–28. 16. quan h, li b, couris cm, et al. updating and validating the charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. am j epidemiol 2011; 173: 676-82. 17. narumi t, arimoto t, funayama a, et al. prognostic importance of objective nutritional indexes in patients with chronic heart failure. j cardiol 2013; 62: 307-13. 18. sundi d, svatek rs, nielsen me, schoenberg mp, bivalacqua tj. extent of pelvic lymph node dissection during radical cystectomy: is bigger better? rev urol. 2014; 16: 159-66. 19. toyoda y. a new technique for catheterless cutaneous ureterostomy. j urology. 1977; 117:276–8. 20. studer ue, turner wh. the ileal orthotopic bladder. urology. 1995; 45:185-9. 21. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg 2004; 240: 205-13. 22. jänes a, weisby l, israelsson la. parastomal hernia: clinical and radiological definitions. hernia. 2011; 15: 189-92. 23. farnham sb, cookson ms. surgical complications of urinary diversion. world j urol 2004; 22: 157–67. 24. imai e, horio m, watanabe t, et al. prevalence of chronic kidney disease in the japanese general population. clinical and experimental nephrology 2009; 13: 621–30. 25. gershman b, eisenberg ms, thompson rh, et al. comparative impact of continent and incontinent urinary diversion on long-term renal function after radical cystectomy in patients with preoperative chronic kidney disease 2 and chronic kidney disease 3a. int j urol 2015; 22: 651–6. 26. imai e, horio m, yamagata k, et al. slower decline of glomerular filtration rate in the japanese general population: a longitudinal 10-year follow-up study. hypertens res 2008; 31: 433-41. 27. krajewski w, piszczek r, krajewska m, dembowski j, zdrojowy r. urinary diversion metabolic complications underestimated problem. adv clin exp med 2014; 23: 633-8. 28. van der aa f, joniau s, van den branden m, van poppel h. metabolic changes after urinary diversion. adv urol 2011; 2011: 764325. 29. tanrikut c, mcdougal ws. acid-base and electrolyte disorders after urinary diversion. world j urol 2004; 22: 168-71. 30. miyake m, morizawa y, hori s, et al. clinical impact of postoperative loss in psoas major muscle and nutrition index after radical cystectomy for patients with urothelial carcinoma of the bladder. bmc cancer 2017; 17: 237. long-term changes after radical cystectomy and ileal conduit-miyake et al. urological oncology the efficacy of transrectal ultrasound guided biopsy versus transperineal template biopsy of the prostate in diagnosing prostate cancer in men with previous negative transrectal ultrasound guided biopsy. shady nafie*, michael wanis, masood khan purpose: we have previously demonstrated that transperineal template prostate biopsy (tptpb) has a significantly higher cancer detection rate compared to transrectal ultrasound guided (trus) biopsy in biopsy naive men with a psa < 20 ng/ml. we, therefore, performed a prospective study to determine whether tptpb is still superior to trus biopsy in the detection of prostate cancer in men with persistently elevated psa after one previous negative set of trus biopsies. materials and methods: 42 patients with a background of one previous negative set of trus biopsy, persistently elevated psa (but < 20 ng/ml) and benign feeling digital rectal examination (dre) underwent simultaneous standard 12-core trus biopsy and 36-core tptpb under general anaesthesia. we determined the prostate cancer detection rate between the two diagnostic modalities. results: mean age was 65 years (range: 50-75), mean prostate volume was 59 cc (range: 21-152), mean psa is 8.3 ng/l (range: 4.4-19), mean time difference between the study and the previous trus biopsy was 33 months (range: 1-150) with mean psa velocity of 0.7 ng/ml/year (range: 0-8). out of the 42 patients, 22 (52%) had benign pathology. of the 20 patients (48%) diagnosed with prostate cancer, 4 (10%) had positive results in both trus biopsy and tptpb, 1 (2%) had positive result in trus biopsy with negative tptpb, while 15 (36%) had negative trus biopsy with positive tptpb. hence, trus biopsy detected cancer in 5/42 (12%) patients versus (19/42) 45% detected by tptpb (p < 0.01). 13/19 (68%) of cancers detected by tptpb had gleason score ≥7. a total of 82/141 (58%) of positive cores was found in the anterior zone. one patient (2%) experienced urosepsis, 2 (5%) temporary urinary retention, 14 (34%) mild haematuria and 13 (32%) haematospermia. conclusion: tptpb still shows a significantly higher prostate cancer detection rate compared to trus biopsy (12% versus 45%, p < 0.01) in men with a previous set of negative trus biopsy, persistently elevated psa (but < 20 ng/ml) and benign feeling prostate on dre. keywords: biopsy; cancer; prostate; transperineal; transrectal; ultrasonography. introduction in the absence of a highly specific biomarker, obtain-ing biopsies from the prostate gland remains the gold standard investigation for establishing a diagnosis of prostate cancer (cap). over the last three decades, transrectal ultrasound guided (trus) biopsy of the prostate has been regarded the technique of choice as it is a well tolerated quick procedure that can be carried out under local anaesthesia in the outpatient setting. however, it is associated with a relatively low specificity of around 30% and confers a 5% risk of urosepsis. on the other hand, transperineal template prostate biopsy (tptpb) has been previously shown to have a significantly higher cancer detection rate (cdr) compared with trus biopsy (60% versus 32%, respectively) in biopsy-naïve men with an abnormally elevated psa < 20 ng/ml and a benign feeling prostate on digital rectal examination (dre).(1) furthermore, tptpb was shown to have a cdr of 58% in men with a persistently elevated psa following 2 previous sets of negative trus biopsies.(2) in order to determine whether tptpb would still prove to be superior to trus biopsy in detecting cap in patients with a background of one negative set of trus biopsy but still at risk of cancer, we carried out a prospective study, directly comparing both biopsy modalities by performing simultaneous tptpb and trus biopsies in this group of patients. patients and methods study population: between august 2012 and august 2014, subjects were selected if they had a history of one previous negative trus biopsy with benign pathology result, benign feeling prostate on dre and a persistently elevated serum psa more than the age specific range but < 20 ng/ml. all of our participants were given a comprehensive information leaflet explaining the nature of the study and gave written consent. the research protocol was registered and approved by the national research ethics service (nres) committee of east midlands and by the research and development (r&d) department at the university hospitals of leicester department of urology, university hospitals of leicester nhs trust, le5 4pw, leicester, united kingdom. *correspondence: specialty doctor in urology, department of urology, university hospitals of leicester nhs trust, leicester general hospital, gwendolen road, leicester, le5 4pw. tel: +447772506239& fax: +44116 273 0639. email: shady.nafie@me.com. received september 2016 & accepted february 2017 urological oncology 3008 nhs trust. procedure: all the patients underwent both biopsies under general anaesthetic by the same surgeon (mak) as a day case under antibiotic cover. each patient was given a single dose of oral ciprofloxacin 500 mg at least 30 minutes before anaesthesia. at induction of anaesthesia, 120 mg of gentamicin and 1.2 g of augmentin were administered intravenously unless the patient was penicillin allergic, in which case 400 mg of teicoplanin was intravenously administered. after placing the patient in the left lateral position, an ultrasound probe (bk medical pro-focus 2202; bk medical, mileparken, denmark) was placed in the rectum to visualise the prostate and calculate the prostate volume. then, 12 trus guided core biopsies were taken from the right and left peripheral zones as previously described by presti et al.(3) the ultrasound probe was taken out of the rectum. the patient was subsequently placed in the extended lithotomy position. the perineal area was shaved, the scrotum was secured away from the biopsy area using mepore tape, then the perineum and the genital area were prepped and draped. thereafter, a 14-fr urethral catheter was inserted in order to mark the urethra and determine the degree of haematuria at the end of the procedure. tptpb were then performed as previously described.(4) in short, the ultrasound probe was reinserted in the rectum, a stepper (galil medical; crawley, sussex, uk) with an articulated arm and a stabilizer was used to fix the ultrasound probe, then a standard 0.5 cm brachytherapy template grid was attached to the stepper and positioned over the perineum. with the prostate at its widest in the transverse plane, the gland was divided on the ultrasound screen into six sectors (right anterior, left anterior, right mid, left mid, right posterior and left posterior). in each sector six 18-gauge biopsy needles (pro-mag™ biopsy needle, 18g x 20cm, mcxs1820ax) were placed into the prostate in the transverse plane view using the brachytherapy template grid. once all six needles were inserted, the probe was switched to the sagittal plane view and the needles were gently withdrawn, one at a time. in every case, the biopsies were performed in exactly the same systematic manner starting with the right anterior sector followed by left anterior and then right mid and so on ending with the left posterior. it was decided that trus biopsies would be performed before the tptpb in order not to alter the sensitivity of trus biopsies in picking up cancer cells. evaluations: histological analysis was undertaken by the same pathologist (jpd), using standard haemotoxylin and eosin stained, formalin fixed and paraffin embedded sections. standard 4µm sections were examined over three levels from each core. where necessary immunoperoxidase to p63, 34betae12 and amacr (p504s) antigens were also employed to render a diagnosis. statistical analysis: analysis was carried out using fisher's exact test to evaluate the association of nominal variables, and student t-test to evaluate the difference in categorical variables. all calculated values were 2-sided, considering p < 0.05 statistically significant. power analysis was conducted using a power model based on a one-proportion z, chi-squared test within statistica (statsoft, tulsa, ohio). this analysis indicated that to obtain a power of 0.9 (using alpha value of 0.05, a trus frequency of 0.32 and a tptpb frequency of 0.6) would require 30 cases. furthermore, power analysis was undertaken for a 2-way 2-proportion z-test, this analysis indicated that to obtain a power of 0.8 (using the same alpha value and the same frequencies) would require 50 cases. this was based on a null hypothesis that the proportions of positive cases detected were equal. after performing 42 cases, the data was analysed and a large significant difference was determined in cdr between both biopsy modalities. hence, continuing further with the study was felt unethical, as eight further cases would not have altered the overall trend in the study outcome. results a cohort of 42 men were enrolled in our study, they had a mean age of 65 years (range: 50-75), mean prostate volume of 59 ml (range: 21-152), mean psa of 8.3 ng/l (range: 4.4-19) and mean psa density (psad) of 0.2 ng/ml/cc (range: 0.07-0.47) at the time of performing the study. at the time of the initial trus biopsy, tptpb after one negative trus biopsy-nafie et al. table 1. difference in psa levels, prostate volumes and psad between initial and study biopsies mean (± sd) study biopsy initial biopsies p value psa 8.3 (± 3.0) 6.6 (± 2.5) 0.0003 prostate volume 59 (± 26.9) 56 (± 23.7) 0.71 psad 0.20 (± 0.1) 0.15 (± 0.1) 0.55 abbreviations: psa, prostate specific antigen; psad, prostate specific antigen density; sd, standard deviation. pathology initial trus biopsy study trus biopsy study tptpb gleason 6 0 (0%) 3 (7%) 6 (14%) gleason 7 0 (0%) 2 (5%) 13 (31%) benign 24 (57%) 10 (24%) 5 (12%) atypia 1 (2%) 8 (19%) 8 (19%) asap 7 (17%) 4 (10%) 2 (5%) high pin 10 (24%) 15 (35%) 8 (19%) abbreviations: asap, atypical small acinar proliferation; pin, prostatic intraepithelial neoplasia. table 2. pathological findings of initial/new trus biopsies and tptpb vol 14 no 02 march-april 2017 3009 they had a mean psa of 6.6 ng/ml (range: 3.1-15) with mean psa density of 0.14 ng/ml/cc (range: 0.06-0.42). the time interval between the initial trus biopsy and the study biopsies ranged from one month up to 150 months, with median of 19 months and mean of 33 months. mean psa velocity was 0.65 ng/ml/year (range: 0-3.5). there was a significant difference in psa levels (p < 0.05) between the time of the initial trus biopsy and the study biopsies, but not in psad or psa volumes as shown in table 1. in total, 22/42 (52%) patients had benign pathology by both trus biopsy and tptpb, while 20/42 (48%) patients had cancer pathology in their biopsies. of those 20 patients diagnosed with prostate cancer, 15 (36%) had negative trus biopsies but positive tptpb, 4 (10%) had positive biopsies with both trus and tptpb and 1 (2%) had positive trus biopsies but negative tptpb. therefore, the overall cdr of tptpb was 45% (19/42) versus 12% (5/42) for trus biopsies (p < .001). calculated cohen's kappa was 0.17 indicating poor concordance between tptpb and trus biopsy results, denoting the genuine difference in the ability of tptpb to detect prostate cancer compared to trus biopsy in this setting. the histopathological findings of the initial trus biopsy, the study trus biopsy and the tptpb are all listed in table 2 and table 3. out of the 19 patients who had cancer detected by tptpb, 13 (68%) had gleason score of 7. furthermore, 11/15 (73%) of cancers that were exclusively detected by tptpb and missed by trus biopsy had gleason score of 7. a total of 82/141 (58%) of the positive cores detected by tptpb were found in the anterior sector of the prostate as shown in figure 1. only one patient (2%) experienced urosepsis, 2 (5%) had temporary urinary retention, 14 (34%) had mild haematuria and 13 had (32%) haematospermia that resolved spontaneously within two to three days. discussion over the last decade, tptpb has been recognized as a more clinically efficient diagnostic modality than trus biopsy in the initial and repeated biopsy settings. however, few studies have compared the two methods directly in a head-to-head comparison as we performed in this study. performing both biopsy modalities in each patient provided us with the best control group, as the patients acted as their own controls. in our case, the trus biopsy (presenting the conventional practice) was compared to the tptpb (presenting the newly evaluated practice) in the same our study further reinforces the superior clinical efficiency of tptpb over trus biopsy. tptpb is particularly indicated when a patient has been subjected to one or more negative sets of trus biopsy and a suspicion of prostate cancer remains. furthermore, a large proportion of cancers detected in the repeat biopsy setting are located anteriorly. studies have shown that approximately 20% of all prostate cancers are anterior and these cancers are more likely to have extracapsular extension at the time of treatment, potentially resulting in a higher positive surgical margin rate(5). over the last decade, tptpb has been recognized as a more clinically efficient diagnostic modality than trus biopsy. in 2014, we(1) compared trus biopsy and tptpb in 50 biopsy-naïve men with suspicion of prostate cancer where trus and tptpb were performed at the same setting. overall, 60% were diagnosed with cap, with 25% detected by only tptpb but missed by trus biopsy. on the contrary, all cancers detected by trus biopsy were also detected by tptpb. in 2007 kawakami et al. published a study of 324 men who underwent 12-core trus biopsy followed by 24-core combined trus biopsy and tptpb. 12 men were diagnosed with cancer by the combined technique but missed by trus biopsy alone. subsequent mpmri showed that 92% of cancers were located anteriorly.(6) in 2015 ong et al. conducted a study in which tptpb was performed in 160 biopsy-naïve men with clinical suspicion of cap underwent 12-core trus biopsy and 12-core tptpb simultaneously. most cancers detected by tptpb and missed by trus biopsy were located anteriorly, and although most cancers missed by trus biopsy were low grade and low volume, some clinically significant cancers were also missed.(7) in 2014, our clinical group also performed tptpb in 122 men with two negative sets of trus biopsy and persistently elevated psa. cap was detected in 58% of these men and 46% of those diagnosed had clinically significant cancer based on criteria of gleason score of ≥ 7, or more than three positive cores of gleason 6.(1) a larger study in 2013 by bittner examined a cohort of 485 men who underwent tptpb following negative trus biopsy due to either persistently elevated psa, atypical small acinar proliferation (asap) or high grade prostattable 3. cancer detection in trus biopsy and tptpb tptpb (negative cancer) tptpb (positive cancer) trus (-ve cancer) 22 15 trus (+ve cancer) 1 4 abbreviations: trus, transrectal ultrasound; tptpb, transperineal template prostate biopsy. figure 1. site of cancer positive cores detected by tptpb (n=141) tptpb after one negative trus biopsy-nafie et al. urological oncology 3010 ic intraepithelial neoplasia (pin). cancer was detected in 226 men (46.6%), 196 of which were clinically significant according to the epstein criteria and most of them were anterior. (8) results of other published series support the aforementioned findings, demonstrating a higher cdr from tptpb in the repeat biopsy context (4,7,9–11) as well as superior antero-apical sampling with trus biopsy(5,8,10,12). tptpb is associated with a much lower risk of sepsis compared with trus biopsy. a study from melbourne of 245 patients undergoing tpb showed that there were no readmissions with sepsis post-operatively.(13) similarly, in our experience from over 500 patients who have undergone tptpb we have not had a single case of urospesis (unpublished data). further published series support this with an overall risk of sepsis following tptpb approaching zero in some studies. on the contrary, the risk of sepsis following trus is in the region of 5% including infection with multi-resistant organisms.(13) therefore, tptpb is particularly favourable when selecting a procedure for patients who are diabetic or immunocompromised or those with previous antibiotic resistance.(14) studies have also shown that tptpb offers the benefit of mapping of the prostate, thereby decreasing the risk of under-grading patients compared with trus biopsy. a study published in 2015 of 431 patients who underwent rp following either trus biopsy or tptpb compared the final gleason grade with the initial grade on diagnosis.(15) tptpb was found to be more accurate than trus biopsy in predicting final gleason score. furthermore, a prospective randomized study comparing 12-core tptpb with 12-core trus biopsy in 200 men demonstrated a significantly higher diagnostic efficiency with tptpb in men with psa values in the lower end of the pathological range (i.e. 4.1 10ng/ml). (16) finally, tptpb also has the ability to diagnose cap in patients who have previously undergone abdomino-perineal (ap) resection for rectal cancer.(10) it is well known that more time is required to perform tptpb, including general anaesthetic time, and that more training is needed for the surgeon. although its provision is increasing, it is still less widely available than trus biopsy.(14) it has also been shown to be more painful than trb and harbor an increased risk of acute urinary retention in those with larger prostates. moreover, despite the majority of studies showing a higher cdr overall with tptpb compared with trus biopsy, some studies, although few in number, have shown statistically similar cdrs between the two techniques both in the initial(17,18) and the repeat biopsy setting (19). this could reflect variance in levels of operator experience. finally, a potential drawback of a higher cdr might be an increased detection of clinically insignificant cancer, which could be cause for concern particularly if tptpb becomes the modality of choice in diagnosing prostate cancer.(20) this could potentially subject some patients to further unnecessary tests downstream as well as increase financial burden on the healthcare system. there is emerging evidence that multiparametric mri (mpmri) may increase the efficiency of tptpb, whilst reducing the number of biopsies required for a diagnosis. this could result in reduced pain levels following the procedure as well as a lower risk of urinary retention. however, early studies show that mpmri may have a false negative rate of up to 20% and may miss some gleason 3 cancers.(20,21) the significance of the latter is uncertain. the promis trial which is currently taking place consists of a rct of 714 men and could help answer some critical questions, namely: whether mpmri could exclude clinically insignificant cancer, thus reducing the number of unnecessary biopsies; and whether prebiopsy mri increases the detection rate of clinically significant cancer. finally, it will hopefully determine the sensitivity, specificity, negative predictive value and overall cost-effectiveness of mpmri versus tpb and trb.(22) in this study we compared trus biopsies versus tptpb without the advantage of mri to determine whether we should abandon trus biopsies and look specifically for tptpb. our results have clearly shown that tptpb outperformed trus biopsies in the diagnostic yield for cap in men who had previous negative trus biopsies and persistently elevated psa. conclusions tptpb has a significantly higher prostate cancer detection rate in comparison to trus biopsies in men with persistently abnormally elevated psa < 20 ng/ml, benign feeling prostate on dre and one previous set of negative trus biopsies. our findings are consistent with the contemporary literature, which also demonstrates additional advantages in selecting tptpb, particularly in patients with an inherently higher risk of sepsis as well as those who have undergone previous ap resection. performing mpmri may further enhance the cdr from tptpb by performing tb and sb simultaneously. however, it is still not widely available and results from the promis trial are awaited to elucidate its role. conflict of interest the authors report no conflict of interest. refrences 1. nafie s, mellon jk, dormer jp, khan ma. the role of transperineal template prostate biopsies in prostate cancer diagnosis in biopsy naïve men with psa less than 20 ng ml(-1.). prostate cancer and prostatic diseases. 2014; 17: 170–3. 2. nafie s, pal rp, dormer jp, khan ma. transperineal template prostate biopsies in men with raised psa despite two previous sets of negative trus-guided prostate biopsies. world j urol. 2013; 32: 1–5. 3. presti jc, chang jj, bhargava v, shinohara k. the optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. j urol. 2000; 163: 163-6. 4. pal rp, elmussareh m, chanawani m, khan ma. the role of a standardized 36 core template-assisted transperineal prostate biopsy technique in patients with previously negative transrectal ultrasonography-guided prostate biopsies. bju int. 2012; 109: 367–71. 5. hossack t, patel mi, huo a, et al. location and pathological characteristics of cancers in tptpb after one negative trus biopsy-nafie et al. vol 14 no 02 march-april 2017 3011 radical prostatectomy specimens identified by transperineal biopsy compared to transrectal biopsy. j urol. 2012; 188: 781–5. 6. optimal sampling sites for repeat prostate biopsy: a recursive partitioning analysis of three-dimensional 26-core systematic biopsy. eur urol. 2007; 51: 675-83. 7. ong wl, weerakoon m, huang s, et al. transperineal biopsy prostate cancer detection in first biopsy and repeat biopsy after negative transrectal ultrasound-guided biopsy: the victorian transperineal biopsy collaboration experience. bju int. 2015; 116: 568–76. 8. bittner n, merrick gs, butler wm, bennett a, galbreath rw. incidence and pathological features of prostate cancer detected on transperineal template guided mapping biopsy after negative transrectal ultrasound guided biopsy. j urol. 2013; 190: 509–14. 9. kawakami s, hyochi n, yonese j, et al. threedimensional combination of transrectal and transperineal biopsies for efficient detection of stage t1c prostate cancer. international journal of clinical oncology. 2006; 11: 127– 32. 10. dimmen m, vlatkovic l, hole kh, nesland jm, brennhovd b, axcrona k. transperineal prostate biopsy detects significant cancer in patients with elevated prostate-specific antigen (psa) levels and previous negative transrectal biopsies. bju int. 2012; 110: 69-75. 11. mabjeesh nj, lidawi g, chen j, german l, matzkin h. high detection rate of significant prostate tumours in anterior zones using transperineal ultrasound-guided template saturation biopsy. bju. int 2012; 110: 993–7. 12. kawakami s, yonese j, igari t, et al. optimal sampling sites for repeat prostate biopsy: a recursive partitioning analysis of threedimensional 26-core systematic biopsy. eur urol. 2007; 51: 675-82. 13. grummet jp, weerakoon m, huang s, et al. sepsis and ‘superbugs’: should we favour the transperineal over the transrectal approach for prostate biopsy? bju int. 2014; 114: 384–8. 14. chang dts, challacombe b, lawrentschuk n. transperineal biopsy of the prostate -is this the future? nat rev urol. 2013; 10: 690– 702. 15. shen p-f, zhu y-c, wei w-r, et al. the results of transperineal versus transrectal prostate biopsy: a systematic review and metaanalysis. asian journal of andrology. 2012; 14: 310-5. 16. takenaka a, hara r, ishimura t, et al. a prospective randomized comparison of diagnostic efficacy between transperineal and transrectal 12-core prostate biopsy. prostate cancer prostatic dis. 2008; 11: 134–8. 17. guo l-h, wu r, xu h-x, et al. comparison between ultrasound guided transperineal and transrectal prostate biopsy: a prospective, randomized, and controlled trial. sci rep. 2015; 5: 16089. 18. hara r, jo y, fujii t, et al. optimal approach for prostate cancer detection as initial biopsy: prospective randomized study comparing transperineal versus transrectal systematic 12-core biopsy. urology. 2008; 71: 191–5. 19. abdollah f, novara g, briganti a, et al. trans-rectal versus trans-perineal saturation rebiopsy of the prostate: is there a difference in cancer detection rate? urology. 2011; 77: 921–5. 20. zaytoun om, jones js. prostate cancer detection after a negative prostate biopsy: lessons learnt in the cleveland clinic experience. int j urol. 2011; 18: 557–68. 21. siddiqui mm, rais-bahrami s, turkbey b, et al. comparison of mr/ultrasound fusionguided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. jama. 2015; 313: 390–7. 22. ekwueme k, simpson h, zakhour h, parr nj. transperineal template-guided saturation biopsy using a modified technique: outcome of 270 cases requiring repeat prostate biopsy. bju int. 2013; 111: 365-73. tptpb after one negative trus biopsy-nafie et al. urological oncology 3012 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran introduction advancements in endourology, laparoscopic urology, and interventional radiology continue to influence the management of urological complications in rt subjects.(1) percutaneous access and antegrade intervention has been introduced as acceptable method for the management of renal and ureteral complications in the rt patients. since this modality carry significant morbidity, one may consider ureteroscopy as an alternative to percutaneous and antegrade modalities.(2) previous experiences showed ureteroscopy has been used successfully in treatment of kidney graft urinary lithiasis.(3) this technique can be the first choice in management of some urological complications occurring after rt. in this study we report our results regarding diagnostic as well as therapeutic allograft ureteroscopy in kidney transplant patients. the role of ureteroscopy in the treatment of renal transplantation complications basiri a*, simforoosh n, nikoobakht mr, hoseini moghaddam mm department of urology, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran , iran abstract purpose: to determine the feasibility, safety, and efficacy of diagnostic and therapeutic ureteroscopy in renal allograft ureters. materials and methods: we reviewed 1560 consecutive renal allografts have been preformed between june 1989 and february 2002.twenty-eight patients (1.8%) had indication for endoscopic procedure on allograft ureter. six patients had obstructive ureteral calculi with a history of failed eswl, 3 had suspected ureteral stricture, 9 had upward migrated ureteral stents and 10 had ureteral stricture at ureteroneocystostomy site. ureters were anastomosed to bladder using leadbetterpolitano and lich-gregoire methods in 6 and 22 cases, respectively. ureteroscopies were performed with semi rigid 9.8f wolf ureteroscope. results: identifying and introducing the ureteral orifice was successful in 19(68%) cases. if we exclude 10 patients with ureteral stricture, ureteroscopy was successful in 13 out of 18 (72%). four ureteral calculi (67%) were removed with ureteroscope.seven out of nine migrated stents (78%) were retrieved. four patients with ureteral stricture at ureteroneocystostomy site (40%) had successful ureteral dilatation and double j ureteral catheters were also inserted. diagnostic ureteroscopy was successful in all cases. two complications including one urinary leakage and one symptomatic urinary tract infection occurred that were managed conservatively. conclusion: ureteral endoscopy was safe and effective method for management of urological complications after rt (renal transplantation). this procedure can be considered as the first choice compared with percutaneous and antegrade modalities. key words: ureteroscopy, urological complications, renal transplantation accepted for publication the role of ureteroscopy in the treatment of renal transplantation complications materials and methods between june 1989 and february 2002, 1560 rts have been performed at our institution. twenty-eight cases (1.8%) needed endourological procedures. the median followup was 39 months (3 to 80 months). ureterovesical anastomoses were performed using leadbetter-politano in 6 and lich-gregoire in 22 cases. indications for ureteroscopy were upward migration of ureteral stent in 9, failed eswl for ureteral calculi in 6, ureteral stricture in 10, and diagnostic ureteroscopy in 3 patients. in this study, we collected information regarding routine demographic data, indication for ureteroscopy, size and location of calculi, and complications. for all patients with ureteral calculi and ureteral stricture, intervention was indicated owing to obstruction and deteriorating kidney function. we performed ureteroscopy in lithotomy position and under general anesthesia using a wolf semi rigid 9.8 f ureteroscope. at first; cystoscopy was performed using a 30o lens. pervious surgical reports were also used for finding the ureteral orifice. ureteral orifice was usually visible as an irregular region with stippled epithelium. a guide wire was regularly inserted into visible ureteral orifice of transplanted kidney. access to the ureter was usually accomplished with dilatation of the orifice over the guide wire. then ureteroscope was introduced into the ureter over the guide wire. in patients with upward migrated ureteral stent, the catheter was removed with 3f forceps. ureteral stones less than 5mm in diameter were removed with basket. only in one case the stone passed after fragmentation using swiss lithoclast ballistic lithotripter. after stone removal, a 5f ureteral catheter was regularly left in place for 48 hours. in patients with ureterovesical junction strictures, a guide wire was gently placed up to the renal pelvis, and dilatation of the stricture was done with a 16 f balloon dilatator under direct vision. dilatation was done while balloon was inflated for four minutes at place using 15 atmosphere pressures. a permanent ureteral catheter was introduced and left in place for 4-6 weeks. patients underwent ultrasonography and dtpa renal isotope scan two months after stent extraction. results ureteral access was successful in 19(68%) cases and if we exclude 10 patients with ureteral stricture, success rate will rise to 72% (13 out of 18 remaining subjects). access was successful in 59% and 100% of patients underwent lichgregoire and leadbetter-politano methods, respectively. ureteroscopic attempts for stone removal were successful in 4(67%) cases. open stone extraction and percutaneous antegrade stone removal were performed for two remaining cases. ureteroscopy was successful in seven (78%) patients with upward migrated ureteral stents. percutaneous antegrade extraction of the stent and open surgery were done for two remaining patients. complete stent removal in cases with upward migrated ureteral stents was possible by standard endourological techniques in 89%. ureteroscopy for ureteral stricture dilatation was successful in four (40%) patients with ureteral stricture. all of these 4 cases had incomplete obstruction so that we were able to pass a guide wire at first, and the length of stenosis was 5 to 8 mm. diagnostic ureteroscopy was successful in all cases. complications in this series occurred in two cases including urinary leakage in a patient with ureteral stone and urinary tract infection in another one with ureteral stricture and stone. these patients were managed using antibiotics and bladder free drainage for one week. discussion today, the incidence of urological complications following renal transplantation is ranged between 2% and 10 percent. most of these complications occur within the 1st year and affect the distal ureter.(21) urological complications seem to be associated with significant morbidity in the immunosuppressed cases. these complications may ultimately cause long-term allograft dysfunction and loss. endourological procedures are performed safely and established as standards in managing a wide spectrum of renal and ureteral diseases.(4) complications of these procedures in transplant kidneys have decreased dramatically over the past two decades. this advancement may be due 2 the role of ureteroscopy in the treatment of renal transplantation complications to increasing technical experience and effectiveness of immunosuppressive drugs in less toxic doses.(5) previous reports indicate that advances in minimally invasive procedures practiced in general urology can be applied to ureter of transplanted kidneys.(6,7) due to increasing experience, endourological procedures sound to become more effective in treatment of urological complications in kidney transplant recipients. traditionally, all cases with post transplant obstruction were managed with open surgery.(13) shoskes et al described 71 primary urological complications (7.1%) in 1,000 consecutive renal transplants with a minimum follow-up of 12 months. in that study most ureteral complications were treated by an open operation. they concluded from these results that urological complications after renal transplantation can be treated successfully using surgical correction. although they had no graft loss due to urological complications, two patients died because of sepsis and hemorrhage, and post-operative morbidity was not described clearly.(22) although surgical operation was an acceptable approach for management of urological complications in kidney transplant cases, technologic development and fantastic success of endourological methods drew the surgeons' attention to new approaches. with increasing endoscopic expertise, double-j stent insertion, balloon dilatation, and cold knife incision the need for open intervention was approximately obviated. benoit and colleagues(17) reported on eight kidney-allograft patients treated for delayed ureteral obstruction. in all cases, standard endourological dilatation was performed using a balloon catheter, and this was followed by insertion of a pigtail stent. all eight cases showed improvement 1 month after dilatation (decrease in serum creatinine level and caliceal dilatation). at 6 months, renal function had deteriorated in six patients but remained good in two. one of the six patients was redilated with apparently good results. the remaining five underwent open surgery. they concluded that while internal drainage helps in distinguishing between obstruction and other causes of creatinine increase, antegrade dilatation is the treatment of choice for delayed ureteral obstruction .reviewing the previous studies in this regard showed success rates using balloon dilatation from 38 to 100 percent.(10, 11, 12, 15) based on our results percutaneous and retrograde approach is comparable with antegrade ureteral dilatation. urological complications will be more common with increasing numbers of transplantations as well as increasing graft survival secondary to improvements in immunosuppression.(16) predisposing factors for urolithiasis in rt include obstructive uropathy, recurrent urinary tract infection, hyperoxaluria, decreased fluid intakes, and internal stents.(8) in a historical cohort study on 42096 rt recipients in the united states, nephrolithiasis was uncommon after rt (104 cases per 100000 person years),but was still more common than in the general population. the only risk factor identified for nephrolithiasis was renal failure due to stone disease. kidney stones were more common than ureteral stones, and percutaneous procedures were more common than ureteroscopy or extracorporeal shock wave lithotripsy (eswl).(19) this article did not clearly report the success rate of ureteroscopy for management of ureteral calculi. nowadays, with advancement in undourology and shock wave equipment and greater experience of urologists, eswl and ureteroscopic procedures play a great role as the first choice in management of kidney and ureteral stones, respectively. urolithiasis in transplant kidney is a serious clinical problem and management seems to be based on anecdotal experience, rather than analysis of larger series.. in a study by klingler and colleagues, 19 rt patients were treated for 19 renal and 3 ureteral stones. they tried to find the best modality for treatment of urolithiasis in rt cases regarding the size, location and analysis of stones. they recommended that eswl is the treatment of choice for caliceal stones sized 5 to 15 mm. however, for stones greater than 15 mm or for ureteral stones, antegrade endoscopic procedures was seemed to be more favorable.(9) due to paucity of ureteroscopy cases the obtained results are not reliable. percutaneous and antegrade approach to the renal allografts has been successful in managing several complications including ureteral stricture, foreign-body migration, ureteral calculi and obstruction, but this approach may carry significant morbidity.(4, 10, 11, 12, 14) according to our 3 the role of ureteroscopy in the treatment of renal transplantation complications experience, ureteroscopy is feasible with good result and low morbidity. our main difficulty was: a) finding the ureteral orifice and b) negotiating the ureteroscope through the intramural ureter. del pizzo et al reported 100% success rate for endoscopic removal of ureteral calculi in rt recipients .they reviewed 540 consecutive renal allografts to determine the feasibility and morbidity of diagnostic and therapeutic ureteroscopy in renal allograft ureters. of these, 14 patients (2.5%) had indications for endoscopic intervention of the allograft ureter. ureteropyeloscopy was successful in 93% of the patients. a diagnosis was made in all cases, including one unsuccessful ureteroscopy, as this patient had allograft ureteral necrosis preventing passage of the endoscope into the renal pelvis. all of the migrated stents could be seen, and all but one was retrieved. all of the ureteral calculi were removed endoscopically. the only complication was ureteral perforation, which occurred in the patient with ureteral necrosis. they concluded that transplant ureteral endoscopy is a technically challenging intervention, but both diagnostic and therapeutic ureteroscopy can be performed with acceptable outcomes and minimal morbidity.(2) the method of ureteroneocystostomy was not described in this report. in addition, flexible ureteroscope was used in all of the cases but urinary calculi. our study showed ureteroscopy was successful in seven (78%) out of 9 patients with upward migrated ureteral stents. percutaneous antegrade extraction of the stent and open surgery were done for two remaining patients, respectively. then complete stent removal was possible by standard endourological techniques in 89%. in the study of del pizzo et al three cases had migrated double-pigtail stents. in that study, all of the migrated stents could be seen, and all but one was retrieved.(2) ureteroscopy seems to be the first choice for removal of migrated stent. conclusion modern endourological procedures including ureteroscopy have replaced open reconstructive surgery in the majority of rt patients with ureteral obstruction. these modalities are usually accompanied by low complications. in our series, two complications of retrograde renal access including one urinary leakage and one symptomatic urinary tract infection occurred who were managed conservatively. further large scale prospective studies are needed for better declaration of the role of ureteroscopy. references 1. hobart mg, streem sb, gill is. renal transplant complication minimally invasive management. urol clin north am 2000: 27(4): 787-98. 2. del pizzo jj, jacobs sc, sklar gn. ureteroscopic evaluation in renal transplant recipients. j endourol 1998: 12(2): 135-8. 3. benoit g, blanchet p, eschwege p, jardin a, charpentier b. occurrence and treatment of kidney graft lithiasis in a series of 1500 patients. clin transplant 1996 : 10(2): 176-80. 4. benoit g, dergham r, blanchet p, bellamy j, jardin a, charpentier b. treatment of kidney graft lithiasis. transplant proc 1995: 27:1743. 5. sert s, gulay h, hamaloglu e, haberal m. urological complications in 350 consecutive renal transplants. br j urol 1990: 66:568. 6. erturk, e, burzon dt, waldman d. treatment of transplant ureteral stenosis with endoureterotomy. j.urol 1999: 161:412. 7. youssef nl, jinal r, babayan rj, et al. the acucise catheter: a new endourological method for correcting transplant ureteric stenosis. transplantation 1994:57: 1398. 8. lancina martin ja, garcia buitron jm, diaz bermudez j,et al. urinary lithiasis in transplanted kidney. arch esp urol 1997 : 50(2):141-50. 9. klingler hc, kramer g,lodde m, marberger m.urolithiasis in allograft kidneys. urology 2002: 59(3):344-8. 10. koutani a, lechevallier e, eghazarian c, et al. acucise endoureterotomy for distal ureteral stenosis in a renal transplant. prog urol 1997:7(4): 633-6. 11. bosma rj, van driel mf, van son mj, de ruiter aj, mensink hj. endourological man4 the role of ureteroscopy in the treatment of renal transplantation complications agement of ureteral obstruction after renal transplantation. j urol 1996:156:1099-100. 12. lojanapiwat b, mital d, fallon l, et al. management of ureteral stenosis after renal transplantation. j am coll surge 1994: 179:21-4. 13. kim j, banner mp, ramchandan p, grossman ra, pollack hm. balloon dilation of ureteral strictures after renal transplantation. radiology 1993: 186(3): 717. 14. jones jw, hunter dw, matas aj . percutaneous treatment of ureteral strictures after renal transplantation. transplantation 1993:55(5): 1193. 15. loughlin kr, tilney nl, richie jp . urologic complications in 718 renal transplant patients. surgry 1984: 95: 297. 16. rhee bk, bretan pn jr, stoller ml. urolithiasis in renal and combined pancreas/renal transplant recipients. j urol 1999: 161(5): 1458-62. 17. benoit g, icard p, bensadoun h,et al. value of antegrade ureteral dilation for late ureter obstruction in renal transplants. transpl int 1989: 2(1):33-5. 18. santiago-delpin ea, baquero a, gonzalez z.low incidence of urologic complications after renal transplantation. am j surg 1986:151(3):374-7. 19. abbott kc, schenkman n, swanson sj, agodoa ly. hospitalized nephrolithiasis after renal transplantation in the united states. am j transplant 2003 : 3(4): 465-70. 20. aboutaieb r, rabii r, joual a, el mrini m, benjelloun s. ureteral reimplantation. ann urol (paris) 1996:30(5):240-3. 21. maier u, madersbacher s, banyai-falger s, susani m, grunberger t. late ureteral obstruction after kidney transplantation. fibrotic answer to previous rejection?. transpl int 1997:10(1):65-8. 22.shoskes da, hanbury d, cranston d, morris pj. urological complications in 1,000 consecutive renal transplant recipients. j urol 1995:153(1):18-21. 5 impact of four week swimming exercise with alpha-tocopherol supplementation on fertility potential in healthy rats abolfazl kalantari, abbas saremi,* nader shavandi, ali foroutan nia purpose: the aim of this study was to evaluate the effect of 4 week intensive swimming exercise and alpha-tocopherol supplementation on testicular oxidative stress and spermatogenesis in rats. materials and methods: 40 male rats were randomly assigned to control (c), sham (s), exercise (e) and exercise + supplement (es) groups. exercise training performed for 4 weeks (1session/day, 6days/week). each session included 180 minutes of swimming. in es group, alpha-ocopherol was injected at a dose of 50 mg/kg/day. 48 hours after last training session, all rats were killed and gonads of them were removed from their body for histological and biochemical assays. all statistical analysis was performed by spss 16. p values less than 0.05 were considered as statistically significant. results: total testicular antioxidant capacity increased significantly in e (p = .003) and es groups (p = .001) whereas there was no significant difference between c and e group in testicle malondialdehyde (a lipid peroxidation marker) level (p = .999) and spermatogenesis quality (p = .381). testicle malondialdehyde level decreased (p = .009) and spermatogenesis quality was improved significantly in es group (p = .001). conclusion: alpha-tocopherol supplementation is effective in order to improve spermatogenesis process in athletes who exercise with high intensity. key words: alpha-tocopherol; fertility; free radical; spermatogenesis; swimming department of exercise physiology, faculty of sport science, arak university, arak, iran. *correspondence: department of exercise physiology, faculty of sport science, arak university, arak, iran. tel: +98 086 32777400. fax: +98 086 32760104. e-mail: a-saremi@araku.ac.ir. received april 2017 & accepted june 2017 introduction nowadays, male infertility is one of the most im-portant medical challenges. several factors are related to increased risk of infertility such as: reproductive diseases, cancers, genetic anomalies, long-term use of some medications, and oxidative stress.(1-3) oxidative stress is the result of reactive oxygen species (ros) or reactive nitrogen species (rns) overproduction or body antioxidant defense weakness. it has negative effects on sperm quality and motility and also causes sperm dna damage and lipid peroxidation of sperm membrane.(2) doing exercise training with high intensity is one of the conditions which can lead to oxidative stress occurrence. it has been reported that intensive exercise develops free radical production and, simultaneously, reduced spermatogenesis quality and male fertility.(4) since it is estimated that semen ros level is higher than normal range in approximately 25% of infertile men,(5) oxidative stress due to intensive exercise can be suggested as a main reason for reduced fertility in high trained men. some antioxidants like alpha-tocopherol (vitamin e) are strong ros and rns detergents and using them may have positive effects on male reproductive function.(6) so in current study, it was assumed that vitamin e intake during intensive training may prevent negative effects of exercise on spermatogenesis process via antioxidant defense improvement. materials and methods 40 sperague dawley rats were selected as subjects. general specifications of the rats are given in table 1. they were housed at temperature 22 ± 2°c and 12-hour light/dark cycle with full access to food and water, in animal lab of arak university of medical sciences. the subjects were randomly classified into four experimental groups: 1. control group (c): rats of this group did not perform any exercise and no substance was injected to them. 2. exercise group (e): during research, rats of this group were performing aerobic swimming exercise at 10 a.m 3. exercise + supplement group (es): during research, rats of this group were performing aerobic swimming exercise at 10 a.m, after intraperitoneal (i.p.) injection of 50mg/kg vitamin e. 4. sham group (s): in order to investigate stress of injection and floatation in water, rats of this group were put in water at 10 a.m (15min/day) after injection of normal saline solution. water depth was 10 cm, therefore they could not swim in it. health deputy approved codes for working with laboratory animals were respected at all stages of the experiment. sexual dysfunction and andrology vol 14 no 05 september-october 2017 5023 pieces was submersed in bohen liquid for 24 hours. after fixation, tissue preparation was done by the following method: fixed tissue samples were put in xylene and then in paraffin for transparency. so paraffin blocks including samples were produced. 12 sections with 5 micron thickness were prepared from each block. tissue slices were investigated by microscope after painting with hematoxyline and eosin (h & e) method and spermatogenesis was scored based on modified johnsen score.(12) in this classification system, spermatogenesis is rated from1 (only sertoli cell existence in seminiferous tubules) to10 (normal condition). then scores are classified into three groups: scores of 1–3: poor spermatogenesis scores of 4–7: moderate spermatogenesis scores of 8–10: good spermatogenesis. for each sample, all tissue sections were investigated by microscope and an overall score was calculated (table 3). statistical analysis data from histological and biochemical assessment was collected and kolmogorov smirnov test was applied to check the normality of data distribution. comparisons were carried out using one way analysis of variance (anova) followed by post hoc tukey test. all statistical analysis was performed by spss 16. p values less than 0.05 were considered as statistically significant. results there was no significant difference between c and s groups in frap level (p = .986), mda level (p = .990) and spermatogenesis quality (p = .882). also, there was no significant difference in mda level of tissue samples between e and c groups (p = .999) but frap level of e group was significantly more than c group (p = .003). in es group, frap level were significantly higher (p = .001) and mda level was significantly lower (p = .009) than c group. spermatogenesis quality of es group was significantly higher than c group (p = .001) but difference between e and c group was not significant (p = .381). discussion large numbers of athletes, especially professional athletes, have heavy exercise programs. these programs impose great stresses on their body and consequently, body homeostasis is disturbed. this condition may mistune some organs or systems, for example reproductive system. in some studies, defect in male sexual hormones, sperm parameters and reproductive system function have been reported following intensive exercises.(13,14) etiology of these disorders are not clear exactly but oxidative stress has been introduced as one aerobic exercise program exercise program was aerobic swimming (1 session/ day, 6 days/week) that was performed in two stages: stage1 (one week preparation): during this stage, rats of e and es groups swam in a pool (150*50*50 cm) containing water with 32°c temperature . swimming duration was 60 minutes in first session which was increased gradually (20min/session) until reached up to 160 minutes. stage 2 (main exercise): during this stage, the rats swam in the pool for 4 weeks. exercise duration was 180 minutes in each session. this program is a mode of intense aerobic training.(7) providing gonad tissue samples 48 hours after last training session, all rats were anesthetized with i.p. injection of ketamine (70mg/kg) combined with xylazine (4mg/kg). then gonads of each rat were removed from its body and one of them was put in bohen solution for histological assay and the other one was put in an ice container for biochemical analyzing. evaluation of testicular biochemical parameters lipid peroxidation of testicles one of the most important productions of lipid peroxidation is malondialdehyde (mda).(8) therefore, its level was determined in tissue samples with ohkawa method. results were expressed as nmol/gkw (table 2). details of this procedure have been explained completely in previous studies.(9) ferric reducing antioxidant power (frap) assay the frap test uses antioxidants as reductants. in samples, reductants reduce ferric tripyridyl-triazine complex (fe3+tptz) in stoichiometric excess to a blue ferrous form (fe2+) with an increase in absorbance at 593 nm.(10) the absorbance values were read at 593 nm immediately and 4 min later using a spectrophotometer uv-1018 (table 2). details of this procedure have been explained completely in previous studies.(11) histological assay left gonad of each rat was divided into two equal pieces with a longitudinal cutting. in order to fix, each of these swimming exercise and fertility-kalantari et al. table 1. general characteristics of rats. group quantity age (month) weightª (gr) c 10 3-4 250.7 (± 5) s 10 3-4 250.4 (± 5.4) e 10 3-4 250.6 (± 5.3) es 10 3-4 250.5 (± 5.1) abbreviations: c, control group; s, sham group; e, exercise group; es, supplement group. ª weight of rats is presented as mean (±sd) group frap (µm) p value a mda(nmol/gkw) p value b c .76 (± .02) _ .11 (± .01) _ s .76 (± .03) .986 .1 (± .01) .990 e .81 (± .03) .003 .11 (± .01) .999 es .87 (± .02) .001 .09 (± .01) .009 abbreviations: c, control group; s, sham group; e, exercise group; es, supplement group. ª p value for frap compared with control group b p value for mda compared with control group table 2. mean (±sd) of biochemical assessment data. group spermatogenesis score p value a c 8.6 (± .33) _ s 8.5 (± .33) .882 e 8.4 (± .35) .381 es 9.4 (± .15) .001 abbreviations: c, control group; s, sham group; e, exercise group; es, supplement group. ª p value for spermatogenesis score compared with control group table 3. mean (±sd) of spermatogenesis scores. sexual dysfunction and andrology 5024 of the possible mechanisms.(15) oxidative stress occurs due to overproduction of free radicals or body disability for decrease their destructive effects optimally.(2) it’s estimated that in normal metabolism state of the body, within oxygen consumption, 2-5 percent of electrons are used in free radical generation. since oxygen consumption increases up to 20 times during intense aerobic exercises, free radical production is developed vigorously in these practices too.(16) furthermore, exercise trainings can lead to overproduction of free radicals through some other pathways such as: energy charge deficit in skeletal muscles, elevated catecholamine secretion and oxidation, nitric-oxide production, visceral ischemia, released fe union from red blood cells, blood flow reduction and reflux in cells and etc.(17,18) our body confronts with these free radicals by its antioxidant enzymes like superoxide dismutase (sod), catalase and glutathione-s-transferase (gst). suitable recovery after exercise sessions increases generation of these enzymes and therefore elevates body antioxidant capacity in athletes. but following high intensity exercise sessions which are repeated over and over, free radical production may overcome body antioxidant power and oxidative stress may occur.(19) this condition can impose some destructive effects on spermatogenesis process because testicular and sperm cell membrane are very vulnerable to attack by free radicals since they are rich in polyunsaturated fatty acids. sperm motility can be affected by increased lipid peroxidation and altered membrane function. also, epididymis is the site of sperm capacitation and maturation and also has an essential role in sperm motility. oxidative stress results harmful effects in the epididymis. furthermore, high concentration of free radicals causes sperm dna damage and reduces spermatogenesis quality.(20) however, results of current study showed that 4 weeks of intense aerobic exercise had no destructive effect on spermatogenesis quality in male rats. our results do not match with some previous studies.(14,21-23) this contradiction is perhaps pertaining to duration of research and shows that body antioxidant system, at least in short term training programs, is probably able to frustrate harmful effects of free radical overproduction. if period of our study was longer, harmful effects might be created. existence of antioxidants like selenium, vitamin c and alpha-tocoferol (vitamin e) in diet, enhances body antioxidant capacity. vitamin e is a powerful antioxidant that because of its lipophilic characteristic can locate itself in the interior of cell membrane, react with fatty acid peroxyl radicals and terminate the chain reactions. therefore it is able to alleviate wrecking functions of free radicals on male reproductive performance.(24) in the current study it was observed that testicular antioxidant capacity was elevated, testicle mda level was decreased and simultaneously, spermatogenesis quality was improved significantly in es group. these findings confirm beneficial effect of vitamin e supplementation on spermatogenesis process in male athletes and are supported by some previous studies.(25-27) however, it must be noted that free radicals also have some beneficial effects on male reproductive system. they have important roles in several processes like sperm maturation, capacitation and the hyper activation. they also control acrosome reaction and sperm-oocyte fusion.(28) therefore dose of vitamin e or other antioxidants for supplementation should be selected accurately because over suppressing free radicals may weaken their advantageous efficacy. conclusions alpha-tocopherol supplementation is useful to attenuate destructive effects of free radicals on spermatogenesis process and improves male fertility potential in athletes who have intensive exercise programs. acknowledgements we thank to arak university of medical sciences for cooperating with us during laboratory stages of this research. conflict of interest the authors report no conflict of interest. references 1. auger j, eustache f, andersen a, et al. sperm morphological defects related to environment, lifestyle and medical history of 1001 male partners of pregnant women from four european cities. human reproduction. 2001;16:2710-7. 2. bansal ak, bilaspuri g. impacts of oxidative stress and antioxidants on semen functions. veterinary medicine international. 2010;2011. 3. jungwirth a, giwercman a, tournaye h, et al. european association of urology guidelines on male infertility: the 2012 update. european urology. 2012;62:324-32. 4. tartibian b, maleki bh. the effects of honey supplementation on seminal plasma cytokines, oxidative stress biomarkers, and antioxidants during 8 weeks of intensive cycling training. journal of andrology. 2012;33:449-61. 5. zini a, al-hathal n. antioxidant therapy in male infertility: fact or fiction? asian journal of andrology. 2011;13:374. 6. agarwal a, virk g, ong c, du plessis ss. effect of oxidative stress on male reproduction. the world journal of men's health. 2014;32:117. 7. manna i, jana k, samanta pk. effect of different intensities of swimming exercise on testicular oxidative stress and reproductive dysfunction in mature male albino wistar rats. indian journal of experimental biology. 2004;42:816-22. 8. ohkawa h, ohishi n, yagi k. assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. analytical biochemistry. 1979;95:351-8. 9. dillioglugil m, maral kir h, gulkac m, et al. protective effects of increasing vitamin e and a doses on cisplatin-induced oxidative damage to kidney tissue in rats. urologia internationalis. 2005;75:340-4. 10. benzie if, strain j. [2] ferric reducing/ antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous swimming exercise and fertility-kalantari et al. vol 14 no 05 september-october 2017 5025 measurement of total antioxidant power and ascorbic acid concentration. methods in enzymology. 1999;299:15-27. 11. li m, zhou l, yang d, li t, li w. biochemical composition and antioxidant capacity of extracts from podophyllum hexandrum rhizome. bmc complementary and alternative medicine. 2012;12:263. 12. dieckmann kp, linke j, pichlmeier u, kulejewski m, loy v. spermatogenesis in the contralateral testis of patients with testicular germ cell cancer: histological evaluation of testicular biopsies and a comparison with healthy males. bju international. 2007;99:1079-85. 13. janett f, burkhardt c, burger d, imboden i, hässig m, thun r. influence of repeated treadmill exercise on quality and freezability of stallion semen. theriogenology. 2006;65:1737-49. 14. safarinejad mr, azma k, kolahi aa. the effects of intensive, long-term treadmill running on reproductive hormones, hypothalamus–pituitary–testis axis, and semen quality: a randomized controlled study. journal of endocrinology. 2009;200:259-71. 15. maleki bh, tartibian b, vaamonde d. the effects of 16 weeks of intensive cycling training on seminal oxidants and antioxidants in male road cyclists. clinical journal of sport medicine. 2014;24:302-7. 16. jackson mj, pye d, palomero j. the production of reactive oxygen and nitrogen species by skeletal muscle. journal of applied physiology. 2007;102:1664-70. 17. radak z, zhao z, koltai e, ohno h, atalay m. oxygen consumption and usage during physical exercise: the balance between oxidative stress and ros-dependent adaptive signaling. antioxidants & redox signaling. 2013;18:1208-46. 18. vinña j, gomez‐cabrera mc, lloret a, et al. free radicals in exhaustive physical exercise: mechanism of production, and protection by antioxidants. iubmb life. 2000;50:271-7. 19. lambertucci rh, levada-pires ac, rossoni lv, curi r, pithon-curi tc. effects of aerobic exercise training on antioxidant enzyme activities and mrna levels in soleus muscle from young and aged rats. mechanisms of ageing and development. 2007;128:267-75. 20. ourique gm, saccol em, pês ts, et al. protective effect of vitamin e on sperm motility and oxidative stress in valproic acid treated rats. food and chemical toxicology. 2016;95:159-67. 21. chigurupati s, son tg, hyun d-h, et al. lifelong running reduces oxidative stress and degenerative changes in the testes of mice. journal of endocrinology. 2008;199:333-41. 22. kinnunen s, atalay m, hyyppä s, lehmuskero a, hänninen o, oksala n. effects of prolonged exercise on oxidative stress and antioxidant defense in endurance horse. j sports sci med. 2005;4:415-21. 23. vaamonde d, da silva-grigoletto me, garcía-manso jm, vaamonde-lemos r, swanson rj, oehninger sc. response of semen parameters to three training modalities. fertility and sterility. 2009;92:1941-6. 24. schneider c. chemistry and biology of vitamin e. molecular nutrition & food research. 2005;49:7-30. 25. momeni hr, eskandari n. effect of vitamin e on sperm parameters and dna integrity in sodium arsenite-treated rats. international journal of reproductive biomedicine. 2012;10. 26. moslemi mk, tavanbakhsh s. seleniumvitamin e supplementation in infertile men: effects on semen parameters and pregnancy rate. int j gen med. 2011;4:99-104. 27. rengaraj d, hong yh. effects of dietary vitamin e on fertility functions in poultry species. int j mol sci. 2015;16:9910-21. 28. kothari s, thompson a, agarwal a, du plessis ss. free radicals: their beneficial and detrimental effects on sperm function. indian journal of experimental biology. 2010;48:42535. swimming exercise and fertility-kalantari et al. sexual dysfunction and andrology 5026 andrology effectiveness of sexual skills training program on promoting sexual intimacy and satisfaction in women in tehran (iran): a randomized clinical trial fatemeh salehi moghaddam1, shahnaz torkzahrani2*, azam moslemi3, seyyed ali azin4, giti ozgoli5, narges joulaee rad6 purpose: the purpose of this study was to evaluate the effectiveness of sexual skills training on intimacy and sexual satisfaction in women. materials and methods: this is a randomized clinical trial study with parallel design. 70 participants (n=35 each) were divided into 2 groups as control and intervention groups. women were selected in multiple steps. some requirements for inclusion criteria were: obtaining a standard score of marital satisfaction, women with a record of 6-24 months of marital life, not having a record of abortion, stillborn birth and not being in pregnancy period, not having a child, not suffering from an acute or chronic and serious disease, not having a surgery on pelvic organs, minimum elementary education of the couples and being iranian. exclusion criteria were: women’s absence in more than 2 training classes, pregnancy during the study. data collection was conducted through four questionnaires: demographic characteristics, marital satisfaction, sexual satisfaction and sexual intimacy. validity and reliability of the questionnaires were measured through content validity and chronbach alpha, respectively. the data extracted from the questionnaires were analyzed using spss software, version 18.0. for data analysis, descriptive statistics, independent t-test, paired t-test, or non-parametric tests were applied. significance level of the test was considered p < 0.05. results: the results showed that sexual skills training leads to promotion of sexual satisfaction (p < 0.001) and sexual intimacy (p < 0.001) among the women in intervention group and the impact of training was stable two months after completion of intervention. conclusion: in total, the training lessons gave positive views to participants towards their sexual issues so that they formed realistic and positive sexual expectations, healthier sexual behaviors and self-expressions and consequently, gained more sexual knowledge that made them able to experience more intimacy and satisfaction in sexual relationships with their spouses. keywords: sex education; sexual satisfaction; intimate relationship; iran introduction intimacy in a satisfactory sexual relationship is con-nected to the quality of marital life. coordination and satisfying the couples’ needs, satisfying emotional needs of each other, having the skills related to mutual understanding and the knowledge on how to love and how to show passion can lead to satisfaction with and survival of marital life(1). intimacy has been defined as closeness, similarity and 1student research committee, department of midwifery and reproductive health, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. 2department of midwifery and reproductive health, midwifery and reproductive health research center, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. 3department of biostatistics, faculty of medical sciences, arak university of medical sciences ,arak, iran. 4md, mph, fecsm, avicenna research institute, academic center for education, culture and research (acecr), tehran, iran. 5 md, mph, fecsm, reproductive biotechnology research center, avicenna research institute, acecr, tehran, iran. 6student research committee, department of midwifery and reproductive health, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. *correspondence: nursing and midwifery college of shahid beheshti university of medical sciences, in front of shahid rajaee heart hospital, niayesh intersection, valiasr avenue, tehran, iran. telephone:0098-2188560717 or 09124875076 -09196072554. email: zahranishahnaz@yahoo.com. received july 2018 & accepted january 2020 passionate or emotional relationship with someone else that requires a deep understanding and knowledge of each other in order to express the thoughts and feelings that are considered as a source of similarity and closeness(2). for an intimate relationship, sexual relationship is very important. although sexual relationship without intimacy and love is possible, the most pleasant sexual relationship takes place with love and intimacy(3). in the existing literature, perceived sexual conversation urology journal/vol 17 no.3/ may-june 2020/ pp. 281-288. [doi: 10.22037/uj.v0i0.4690] has been mentioned as the most common factor related to sexual satisfaction(4). therefore, the couple’s skill in communicating about sexual needs and interests is significant in order to retain sexual and a general satisfaction with the relationship(3). intimate sexual conversation is an important way for attaining key information on sexual arousal and confidence, intimacy, emotional support and ultimately increasing sexual satisfaction for both sex(5). counselors realized that most sexual problems result from issues related to the couple’s sexual intimacy not physiological problems. such problems include differences in sexual preferences about number, place, time and manner of sexual activity, presence or duration of foreplay and afterplay, the degree of interest and type of communication style used by each of the partners(3). according to the results of reports presented in iran, many couples suffer from lack of sexual satisfaction so that 5060% of divorces and 40% of non-marital and secret relationships are due to this problem(6-8). abdoly and pourmosavi found out that about 70% of women in tehran who referred to the courts to get divorced complained about sexual dissatisfaction(9). it is remarkable that complaining about sexual dissatisfaction among women was more than among men. despite occurrence of such unwholesome problems, many couples felt shameful and sinful to outline and talk about their sexual problems. as a result, they reflected their problems in the form of anxiety, depression, sleeping disorders or genital diseases. moreover, many couples are negligent about the impacts of this sexual dissatisfaction on their marital dissatisfaction(6,10). one problem faced by today iranian society is lack of sufficient information regarding sexual issues and exandrology 282 table 1. some demographic characteristics of both control and intervention groups of women variable control group intervention group p-value women’s age* 25.97 ± 4.495 26.03 ± 4.712 0.95 men’s age* 29.06 ± 3.262 30.40 ± 4.685 0.16 monthly household income (tomans) ** 1512857.14 1528571.43 0.73 duration of marriage (months)* 17.77 ± 7.341 14.14 ± 7.769 0.11 average number of sexual relationships during one week* 2.57 ± 1.195 2.77 ± 1.140 0.29 women’s education*** elementary school 1 (2.9) 0 (0) 0.18 secondary-high school 5 (14.3) 1 (2.9) diploma 5 (14.3) 8 (22.9) higher education 24 (68.6) 26 (74.3) men’s education*** elementary school 1 (2.9) 0 (0) 0.19 secondary-high school 5 (14.3) 2 (5.7) diploma 13 (37.1) 9 (25.7) higher education 16 (45.7) 24 (68.6) how they met each other for marriage*** friendship before marriage 9 (25.7) 3 (8.6) 0.11 personal acquaintance 4 (11.4) 4 (11.4) being introduced by family or relatives 21 (60) 22 (62.9) being introduced by fellow workers 0 (0) 4 (11.4) other 1 (2.9) 2 (5.7) duration of menstruation (day)*** 3-6 days 21 (60) 23 (65.7) 0.62 longer than 6 days 14 (40) 12 (34.3) interval between two menstruations (day)*** shorter than 20 days 2 (5.7) 2 (5.7) 0.55 20-35 days 31 (88.6) 33 (94.3) longer than 35 days 2 (5.7) 0 (0) normal contraception*** ld pills 3 (8.6) 2 (5.7) 0.56 condoms 12 (34.3) 17 (48.6) intramuscular injections 0 (0) 0 (0) levonorgestrel (emergencies) 0 (0) 0 (0) natural contraception 20 (57.1) 16 (45.7) iud 0 (0) 0 (0) lack of contraception 0 (0) 0 (0) source for collecting information on sexual issues*** book 5 (14.3) 4 (11.4) 0.51 friend 3 (8.6) 0 (0) family/ spouse 4 (11.4) 2 (5.7) midwife/doctor 3 (8.6) 3 (8.6) internet 3 (8.6) 5 (14.3) satellite channels 0 (0) 0 (0) movies/cd 1 (2.9) 0 (0) other 0 (0) 1 (2.9) multiple ways (combined) 16 (45.7) 20 (57.1) *mean ± sd ** average *** (%) the results were obtained from independent t-test, mann-whitney, chi-square and fisher’s exact test. the effect of sexual skills training on intimacy and sexual satisfaction in womensalehi moghaddam et al. istence of improper attitudes and beliefs towards this subject. in other words, there is a misconception of sexual affairs(8). therefore, it seems that iranian women’s main challenge is their weakness or lack of skills in communicating with spouse and perhaps, sexual relationship begins while sufficient intimacy has not been established between the couple. that’s what young and schwartz call non-artistic dialogue and believe that it will lead to some problems for sexual relationships (11). therefore, true and right training of sexual skills in order to enhance those skills among couples, early prevention from sexual problems and promoting sexual health are proposed as critical strategies in this respect (12,13). such learning makes the couples more aware and sensitive in their interpersonal relationships which leads to more intimacy and pleasure in their marital life (14,15). so, with respect to the emphasis put by world health organization on sexual health, i.e. “equality and mutual respect in sexual relationship” and on “talking with the sexual partner to ensure that the sexual relationship occurs as the partner wishes”,(16) the training concepts included in this study which emphasize the effective factors on several aspects of sexual intimacy have been less considered and this study aims to examine the effectiveness of sexual skills training programs in enhancement of sexual satisfaction and intimacy in women living in tehran. materials and methods sampling this randomized clinical trial study with parallel design, was conducted in 2015-2016 in which the research community was composed of all volunteer women who referred to healthcare centers at shahid beheshti university of medical sciences in tehran metropolitan. by considering sample loss in follow-up, 35 subjects were included in each control and intervention groups and total 70 samples were selected for this study (figure 1). the healthcare centers were selected using a multi-step selection method from healthcare centers covered by shahid beheshti university of medical sciences which were geographically located on the north-eastern, eastern and south-eastern areas in tehran. we first prepared a list of healthcare centers covered by that university the effect of sexual skills training on intimacy and sexual satisfaction in womensalehi moghaddam et al. table 2. a comparison of means of marital satisfaction, sexual intimacy and sexual satisfaction variables before and after training lessons, in control and intervention groups in women variable control group intervention group p-value* marital satisfaction before training 162.06±21.327 158.80±23.725 0.44 sexual intimacy before training 102.80±11.737 102.77±11.687 1 sexual satisfaction before training 102.17±11.341 103.46±11.436 0.53 sexual intimacy after training 102.14±11.758 110.97±9.253 0.001 sexual satisfaction after training 101.23±12.455 108.40±11.755 0.003 *the results were obtained from mann-whitney and wilcoxon test. data presented as mean±sd. score range of marital satisfaction questionnaire: 47-235 score range of sexual intimacy questionnaire: 30-120 score range of sexual satisfaction questionnaire: 25-125 figure 1. flow diagram of the study vol 17 no 03 may-june 2020 283 and then 2 centers with the largest homogeneity in terms of type and size (number) of clients were selected from each geographical district (north-east, east and southeast) in tehran by two-stage cluster sampling method. finally, these 2 centers were randomly assigned to control and intervention groups through simple randomly assignment method (tossing up a coin), so that the subjects taught to the research units in the intervention group were not accessible for those in the control group. therefore, in total, 6 healthcare centers, 3 for the intervention group and 3 for the control group, were selected. convenience sampling from the volunteer women was performed after public notifications across the selected centers (figure 2). after preliminary interviews with the qualified candidate women and giving the necessary information on how the study was supposed to be conducted, they were asked to take counsel with their husbands if they wished to participate in the study and if their husbands agreed, they could participate. then the qualified volunteers were evaluated using enrich marital satisfaction scale in order to investigate their level of satisfaction with their marriage. the short form of this scale includes 47 items composed of 9 sub-scales (personality issues, marital relationship, conflict resolution, financial management, leisure time activities, marriage and children, relatives and friends, religious bias, sexual relationships). the sum of scores for all 9 sub-scales is indicative of marital satisfaction. responses to the items were given in likert-type five-item scale (strongly agree to strongly disagree). the items were scored in 1-5 range. a standard score (t) less than 30 indicated severe dissatisfaction, a standard score (t) from 30 to 40 denoted dissatisfaction, a standard score (t) from 40 to 60 denoted relative and moderate satisfaction, a standard score (t) from 60 to 70 denoted high satisfaction and a standard score (t) higher than 70 indicated extreme satisfaction with marital relationships. the validity of enrich marital satisfaction scale has already been evaluated in a study conducted by soleimanian and colleagues, under the title “investigation of irrational marital thoughts” and its reliability has been established in several studies(17-20). the reliability of enrich marital satisfaction scale in this study was obtained 0.91 using chronbach alpha. then, women with a standard score of marital satisfaction 30 and higher of enrich questionnaire, were eligible to be recruited for the study; it is worthy of mention that those women with a standard score (t) lower than 30 were referred to family consultation clinics. patient and public involvement this study was conducted in 2015-2016 in which the research community was composed of all volunteer women who referred to healthcare centers at shahid beheshti university of medical sciences in tehran metropolitan. convenience sampling from the volunteer women was performed after public notifications across the selected centers. after preliminary interviews with the qualified candidate women and giving the necessary information on how the study was supposed to be conducted, they were asked to take counsel with their husbands if they wished to participate in the study and if their husbands agreed, they could participate. written letters of satisfaction were taken from all interviewees and they were assured that their information would be kept confidentially and their participation is completely voluntary. inclusion/exclusion criteria the requirements for inclusion in this study were: obtaining a standard score of marital satisfaction 30-40 and higher based on enrich scale (enriching and nurturing relationship issue, communication and happiness), lack of participation in different sexual training courses by the couples, women with a record of 6-24 months of marital life who were still living with their husband, not having a record of abortion, stillborn birth and not being in pregnancy period, not having a child, not experiencing the death of a loved one over recent 6 months, not figure 2. random allocation of centers the effect of sexual skills training on intimacy and sexual satisfaction in womensalehi moghaddam et al. andrology 284 suffering from an acute or chronic and serious disease or physical disabilities diagnosed by the physician such as depression, diabetes, obsessive-stressful diseases, addiction, rheumatoid arthritis in the couples, lack of dependence or addiction to alcohol or ecstatic drugs in the couples, not taking psychiatric and neuropathic medicine prescribed by a doctor over 2 recent years, not having a surgery on pelvic organs (internal or external), minimum elementary education of the couples and being iranian. exclusion criteria were: women’s absence in more than 2 training classes or pre-test and post-test, pregnancy during the study, occurrence of mishap between pre-test and post-test steps for the research women. procedure after coordination with the women in the intervention group and with the authorities of the clinic, the dates for training courses were set and the women in this group were invited to participate in sexual skills training courses a week after completion of pre-test so that one week before intervention, demographic characteristics of the women were completed by the research units using a researcher-made questionnaire. similarly, evaluations were performed through shahsiah’s sexual intimacy scale and larson’s sexual satisfaction (in the form of pre-test). shahsiah’s scale included 30 items each with a 4 choice range (always, sometimes, seldom, never) with 1-4 scores. as such, “always” gets 1 score and “never” gets 4 scores. maximum and minimum scores are 120 and 40, respectively. higher score indicates more sexual intimacy of the couples. the validity of content of shahsiah’s questionnaire was confirmed in studies by botlani and colleagues, who were psychologists and consultants at educational sciences department at isfahan university and its reliability was investigated in a study conducted by botlani and colleagues, on 70 couples who had referred to family cultural center in isfahan in 2008 and chronbach’s alpha coefficient was obtained 0.81% (21). in this study, the internal consistency of shahsiah sexual intimacy questionnaire was obtained 0.93 using chronbach’s alpha. larson’s sexual satisfaction questionnaire (lss) contains 25 items and responses are given to 5 choices set according to 5-point likert’s scale with 1-5 scores. in terms of qualitative classification, scores of 25-50 suggest lack of sexual satisfaction, 51-75 indicate low sexual satisfaction, 76-100 conveys moderate sexual satisfaction and 101-125 denotes high sexual satisfaction. validation of larson’s sexual satisfaction questionnaire was measured and used in several studies(8,22). in the study conducted by shams-mofaraheh and colleagues, the validity of the questionnaire was measured through face validity and content validity. in current work, the reliability of larson’s sexual satisfaction questionnaire was obtained 0.88 using chronbach’s alpha. contents of the sexual skills training program teaching methods were in the form of self-administered (self-made) educational package including: speeches, presenting powerpoints, playing educational videos, group discussion and question and answer discussions. the content of self-administered educational package (confirmed by more than 10 respective experts and authorities) was presented in 90 min classes, one day a week, for a total of 5 sessions and in cognitive areas (sexual knowledge and information), emotional (feelings, values and views about sexual issues) and behavioral (sexual behavior) under titles: sexual behavior, factors affecting sexual response and genital anatomy and physiology by an experienced and trained researcher. meanwhile, the participants were asked to share and practice the skills offered in the educational classrooms with their spouses at home so that their spouses indirectly learn those skills and finally the couple can experience a more intimate sexual relationship. after final data analysis, training lessons, were held where the material taught in the intervention group classes were presented to the control group, too. it is worthy of mention that evaluation of content learning in each lesson was performed through question and answer procedure. finally women in both groups were again evaluated and followed up using sexual satisfaction and intimacy questionnaire 2 months after the last lesson. ethical consideration after obtaining permission and license from the ethics committee of shahid beheshti university of medical sciences for conducting this research (sbmu. rec.1393.456), the researcher, holding a written recommendation letter from the authorities of the aforesaid university, referred to the selected healthcare centers of shahid beheshti university in tehran city. informed consent were taken from all interviewees and they were assured that their information would be kept confidentially and their participation is completely voluntary. this study was registered with a doi: irct201412165667n4 at iranian registry of clinical trials (irct). statistical analysis the data extracted from the questionnaires were analyzed using spss software, (statistical package for the social sciences, version 18.0, spss inc, chicago, illinois, usa). for data analysis, descriptive statistics (frequency table, mean, standard deviation and percentage), independent t-test, paired t-test, or non-parametric tests including mann-whitney, wilcoxon or chi-square and fisher’s exact test were applied. significance level of the test was considered p < 0.05. table 3. a comparison of means of sexual intimacy and sexual satisfaction variables before and after training lessons, in control and intervention groups by together in women variable control group p-value* intervention group p-value before training after training before training after training sexual satisfaction 102.17 ± 11.341 101.23 ± 12.455 0.07 103.46 ± 11.436 108.40 ± 11.755 0.001 sexual intimacy 102.80 ± 11.737 102.14 ± 11.758 0.053 102.77 ± 11.687 110.97 ± 9.253 0.001 *the results were obtained from wilcoxon test. data presented as mean ± sd. the effect of sexual skills training on intimacy and sexual satisfaction in womensalehi moghaddam et al. vol 17 no 03 may-june 2020 285 results in this study, 70 women with 6-24 months of marriage were included in two groups of intervention (35 subjects) and intervention (35 subjects). personal, social and midwifery records and characteristics of both groups are provided in table 1. the two groups didn’t show significant difference with respect to these variables (table 1). there were no significant statistical differences between the intervention and control groups in terms of marital satisfaction score (enrich), sexual intimacy and sexual satisfaction before initiation of this study (p > 0.05). both groups were the same concerning marital satisfaction and sexual intimacy and satisfaction when they entered the study (table 2). our findings demonstrated that there was a significant statistical difference between the mean scores of sexual satisfaction after training within a score range of 25-125 in the control group (101.23 ± 12.455) compared to the intervention group (108.40 ± 11.755) and between those of sexual intimacy after training within a score range of 30-120 in the control group (102.14 ± 11.758) compared to the intervention group (110.97 ± 9.253). the results of this study suggest that sexual skills training leads to enhancement of sexual satisfaction (p < 0.001) and sexual intimacy (p < 0.001) among the women in the intervention group and the training influence has been stable and steady two months after completion of intervention (tables 2 and 3) . it should be noted that, measuring the score of marital satisfaction has only been one of the inclusion criteria and measuring the score of marital satisfaction after intervention in two groups, has not been evaluated in this study. discussion our findings indicated that there is a significant statistical difference between the average scores of sexual intimacy and sexual satisfaction among the women in the intervention group after the test. the results of current work suggested that sexual skills training enhanced sexual intimacy and satisfaction in women in the intervention group and the impact of training was steady two months after completion of intervention. the results obtained in current research are consistent with those of the researchers who confirmed the effectiveness of sexual education(14,21-30). in explaining the results, we may state that in the training lessons, when the participants were able to establish and continue their first non-sexual emotional relationships and then sexual and emotional contacts with their spouses, led to more intimate and close relationships among the spouses. another issue that enhanced the participants’ sexual intimacy with their husbands was teaching how they could have sexual conversation with their spouses. the subjects of study learned to explicit discuss about their sexual needs, interests and priorities with their spouses. when the participants could convey their emotional and sexual issues in an intimate marital context to their spouses and know about their spouses’ views on their sexual relationships, conversation about sexual issues caused them to have new views about their sexual relationships and show behaviors that lead to more sexual intimacy. as a result of training lessons, the participants concluded that they should plan for their sexual relationships to experience more intimate and pleasant sexual relationships with their spouses. finally, it should be noted that changes in the mean scores of sexual intimacy and satisfaction in the research groups is a result of training the midwifery team who are the front line of treatment of women at healthcare centers in iran. this suggests that by providing such women with this kind of education at healthcare centers, before they refer to psychologists and sexologists who are not accessible for all iranian women due to cultural and financial issues, one can significantly help to promote women’s sexual health. however, it is worth mentioning that promoting sexual health requires team working with psychologists and respective specialists. this study had some limitations including: 1the degree of precision among research units at the time of responding to the questions and their emotional and mental state could affect their manner of responding and in order to remove this limitation and to relatively control it, we attempted to let them complete the questionnaires in a quiet and suitable atmosphere and to provide similar conditions and environments for all the women under study to complete the questionnaires; 2it was not possible for the researcher to hold simultaneous training courses for both women and men or spouses. despite the significant difference between sexual intimacy and sexual satisfaction after training intervention, it was expected that changing capacity of these variables goes further through this intervention. we may increase effectiveness of this intervention through exercising changes in the intervention process such as engaging these women’s spouses, simultaneous presence of the couples in the training programs and implementing educational interventions in women with a longer duration of marriage. conclusions in total, the training lessons gave positive views to participants towards their sexual issues so that they formed realistic and positive sexual expectations, healthier sexual behaviors and self-expressions and consequently, gained more sexual knowledge that made them able to experience more intimacy and satisfaction in sexual relationships with their spouses. therefore, regarding the impact of sexual satisfaction and intimacy in marital life, sexual skills training is suggested as one of the main strategies for promotion of sexual satisfaction and intimacy and ultimately the couples’ marital satisfaction. funding this study was funded by vice chancellor for research of shahid beheshti university of medical sciences. acknowledgement hereby, we would like to appreciate all colleagues who helped us to conduct this study as well as the authorities at healthcare centers supervised by shahid beheshti university of medical sciences. the authors gratefully acknowledge the women who supported the trial by way of participation, and staff at the women's health clinics at torab, sheibani, nader, kadoos, shobeir and safare health centers who contributed in the study. conflict on interest the effect of sexual skills training on intimacy and sexual satisfaction in womensalehi moghaddam et al. andrology 286 the authors report no conflict on interest. references 1. danesh a. the relation between marital satisfaction and sexual satisfaction of couples. brief articles of first family pathology congress, tehran, iran; 2004. 2. bagarozzi d, brunner r, taylor & francis group. enhancing intimacy in marriage. usa: brunner: routledge; 2001. p. 93-113. 3. long ll, young me. counseling and therapy for couples. translated by: nazari am. 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[influence of sexy skills training of attitudes of sex in young couples]. j knowledge res appl psychol. 2007; 30: 21-38. the effect of sexual skills training on intimacy and sexual satisfaction in womensalehi moghaddam et al. andrology 288 endourology and stone disease ascorbic acid supplements and kidney stones incidence among men and women: a systematic review and meta-analysis kehua jiang1,2, kun tang1, haoran liu1, hua xu1, zhangqun ye1, zhiqiang chen1* purpose: the relationship of ascorbic acid (aa) supplements and risk of kidney stones among men and women is controversial. this systematic evaluation was performed to obtain comprehensive evidence about the relationship of aa supplements and risk of kidney stones among men and women. material and methods: a systematic search of pubmed, the cochrane library, web of science, embase was performed to identify studies that exhibited the relationship of aa supplements and risk of kidney stones among men and women and were published up to mar 2017. outcomes of interest included kidney stones incidence and risk factors. results: four studies estimating the association between aa supplements and risk of kidney stones were included for meta-analysis. the kidney stones incidence was significantly higher in men than women with aa supplements (or= 1.62; 95% ci: 1.09 to 2.42; p = 0.02). aa supplements (250-499mg/d, 1000-1499mg/d) was remarkably correlated with the risk of renal stones among men (or= 1.14, 95% ci: 1.00 to 1.28, p = 0.04; or= 1.12, 95% ci: 1.11 to 1.13, p < 0.00001; respectively). however, aa supplements (500-999 mg/d, >1500 mg/d) did not correlate with the risk of renal stones among men (or= 1.20, 95% ci: 0.99 to 1.46, p = 0.06; or= 1.28, 95% ci: 1.00 to 1.63, p = 0.05; respectively). in addition, aa supplements (250-499mg/d, 500-999mg/d, 1000-1499mg/d, >1500mg/d) did not remarkably correlate with the risk of renal stones among women (or= 1.00, 95% ci: 0.82 to 1.22, p = 0.98; or= 1.08, 95% ci: 0.99 to 1.18, p = 0.09; or= 0.99, 95% ci: 0.90 to 1.08, p = 0.77; or= 0.99, 95% ci: 0.99 to 1.09, p = 0.88; respectively). conclusion: aa supplements was remarkably correlated with higher risk for kidney stones incidence in men, but not in women. further multicenter, prospective and long-term follow-up rcts are required to verify these findings. key words: ascorbic acid; vitamin c; kidney stones; oxalate; meta-analysis introduction the incidence of renal calculus is expected to in-crease worldwide over the next decade. a prominent risk factor for renal calculus is hyperoxaluria. diet is thought to play a crucial role in the pathogenesis of calcium oxalate calculus, particularly intake of calcium(1,2), sodium(1,2), and ascorbic acid(aa)(3-5). many studies found that ascorbic acid(aa) supplements increase the risk of kidney stones(4-6). the main dietary sources of aa or vitamin c are fresh fruits and vegetables. ingested aa increased the risk of calcium oxalate calculus formation because aa is metabolized into oxalate and excreted in urine(7,8). however, the relationship between aa supplements and kidney stones formation remains unclear. many studies indicated that aa supplements might increase urinary oxalate excretion and risk for renal calculus formation among men(3-5,7), while some studies found 1department of urology, institute of urology, tongji hospital, tongji medical college, huazhong university of science and technology, wuhan, china. 2department of urology, guizhou provincial people's hospital, guiyang, china. *correspondence: department of urology, tongji hospital, tongji medical college, huazhong university of science and technology, wuhan 430030, china. phone: 86-27-836-65208. fax: 86-27-836-65208. email: zhqchen8366@163.com. received december 2017 & accepted june 2018 that ingestion of aa does not increase the risk of renal calculus formation(9-11). thus, it can be seen that the results of the studies concerning the association between aa intake, and risk of kidney stones are controversial. hence, we performed a meta-analysis of the available published literature to assess the association between aa supplements and risk of kidney stones among men and women. materials and methods literature search strategy according to the cochrane handbook recommendations, a systematic review of published literature was performed up to oct 1, 2017 which evaluated the relationship between aa supplements and kidney stones formation(12). no ethical issues got involved in this study. a systematic dissertation was conducted using medline, embase, pubmed, cnki, and all relevant endourology and stones diseases 122 vol 16 no 02 march-april 2019 123 studies have been identified by the cochrane library. the following keywords were used: "ascorbic acid", "vitamin c", "urolithiasis", "kidney stones", "renal stones", "ascorbate", and "oxalate calcium". inclusion criteria and exclusion criteria studies should satisfy the following requirements(1) human studies(2) reporting original research(3) reporting indexes of aa supplements such as dosage, duration time, follow up(4) reporting evaluation kidney stone incidence(5) published in the english language. studies were excluded if(1) the study did not satisfy inclusion criteria or(2) the outcomes of literature were not mentioned or the parameters were impossible to analysis for the relationship between aa supplements and risk of kidney stones or(3) studies published only as abstracts and reports from meetings. data extraction and outcomes of interest two of the authors (jkh and tk) extracted the required data from the included studies through using a designed tabulation based on the inclusion criteria and a third author verified the data. all disagreements about eligibility reached a consensus by a third reviewer (lhr) by discussion. based on the cochrane handbook, missing or vague information was imputed and was required from the authors of original articles or other relevant articles when necessary. the following outcomes were extracted to evaluate the relationship between aa supplementation and kidney stones formation. demographic and clinical baseline characteristics (age, male/female, aa daily supplementation). follow-up and recorded the incidence of kidney stones (the primary outcome), the relative risk of stone table 1. characteristics of included studies of ascorbic acid supplements and risk of kidney stones between men and women first author, year country study interval design intervention loe no.of patients men/women curhan, 1996 usa 1986-1992 prospective aa: < 250mg/d 3b 45251/0 250-499mg/d 500-999mg/d 1000-1499mg/d >1500mg/d curhan,1999 usa 1976-1994 prospective aa: < 250mg/d 3b 0/85557 250-499mg/d 500-999mg/d 1000-1499mg/d >1500mg/d ferraro,2016 usa 1976-1988 prospective aa: < 90mg/d 2b 40536/156735 90-249mg/d 250-499mg/d 500-999mg/d >1000mg/d taylor,2004 usa 1986-2000 prospective aa: 0mg/d 3a 45619/0 1-99mg/d 100-499mg/d 500-999mg/d > 1000mg/d a meta-analysis of ascorbic acid supplements and kidney stone-jiang et al. abbreviations: aa= ascorbic acid; loe= level of evidence. figure 1. prisma diagram. the search strategy and number of studies identified for inclusion in this meta-analysis. a meta-analysis of ascorbic acid supplements and kidney stone-jiang et al. endourology and stone diseases 124 formation was calculated for comparison. study quality assessment in accordance with the criteria of centre for evidence-based medicine in oxford, we evaluated the level of evidence (loe) of included four studies. the jadad score was applied to evaluate the methodological quality of rcts(13). the newcastle-ottawa scale (nos) was applied to assess the methodological quality of non-rcts observational studies(14). two authors (jkh and czq) evaluated the quality of the studies and discrepancies were rechecked by the third reviewer (czq), and the consensus was achieved by discussion. statistical analysis all meta-analyses were conducted by review manager 5.3 (cochrane collaboration, oxford, uk). continuous and dichotomous variables were compared by weighted mean differences (wmds) and odds ratios(ors), respectively. all analysis results were reported with 95% confidence intervals(cis). i2 test and chi-squarebased q test were applied to evaluate the quantity of heterogeneity, and when i2 > 50%, the evidence was considered to have substantial heterogeneity, the randomeffects(re) model would be applied. otherwise, the fixed effects (fe) model was applied. the presence of publication bias was evaluated by egger's test and funnel plot. sensitivity analysis was used to estimate the influence of studies with a high risk of bias on the overall effect. results characteristics of eligible studies according to the search strategy, 4 studies(4-6,11) were included assessing the association of aa supplements and risk of kidney stones conformed to the inclusion criteria and were applied to performed this meta-analysis (figure 1). curhan et al. conducted a prospective study of the relationship between the intake of vitamins c and b6 and the risk of symptomatic kidney stones in a cohort of 45,251 men 40 to 75 years old with no history of kidney calculi. during 6 years of follow up 751 incident cases of kidney stones were documented. but these data do not support an association between a high daily intake of vitamin c or vitamin b6 and the risk of stone formation, even when consumed in large doses. curhan et al. also conducted a prospectively study to examine the association between the intakes of vitamins b6 and c and risk of kidney stone formation in women. the study included 85,557 women with no history of kidney stones. a total of 1078 incident cases of kidney stones was documented during the 14-year follow-up period. the results also showed that vitamin c intake was not associated with risk for kidney stones formation in women. ferraro et al. performed prospective cohort analysis and enrolled 156,735 women and 40,536 men. during a median follow-up of 11.3 to 11.7 years, 6,245 incident kidney stones were identified. the results showed that total and supplemental vitamin c intake was significantly associated with higher risk for incident kidney stones in men, but not in women. taylor et al. conducted a prospective cohort study and enrolled 45,619 men without a history of nephrolithiasis. a total of 1473 incident symptomatic kidney stones were documented during 477,700 person-years of follow-up. the results indicated that the association between calcium intake and kidney stone formation varies with age. magnesium intake decreases and total vitamin c intake seems to increase the risk of symptomatic nephrolithiasis. because age and body size affect the relation between diet and kidney stones, dietary recommendations for stone prevention should be tailored to the individual patient. the demographic and clinical characteristics of the literatures were shown in table 1. quality of the studies and level of evidence(table 1) in this meta-analysis, the newcastle-ottawa scale quality assessment method of the observational studies, and the us preventive services task force grading system were applied to evaluate the quality of included studies. 3 studies scored seven stars and were evaluated as high quality studies. also, the demographic variables of aa supplements and risk of kidney stones were extracted table 2. sensitivity analysis of high quality studies about the risk of aa supplements and kidney stones formation among men aa supplements no. of studies or (95%ci) p-value study heterogeneity chi2 df i2 p-value 250-499 mg/d 2 1.17[1.01,1.37] 0.04 0.07 1 0% 0.79 500-999 mg/d 2 1.32[1.13,1.55] < 0.001 0.10 1 0% 0.75 1000-1499 mg/d 2 1.12[1.11,1.13] < 0.001 3.62 1 72% 0.06 > 1500 mg/d 2 1.43[1.21,1.68] < 0.001 0.00 1 0% 0.97 abbreviations:baa= ascorbic acid; or = odds ratio; ci = confidence interval figure 2. forest plot and meta-analysis of aa supplements and kidney stones incidence among men and women; aa= ascorbic acid. vol 16 no 02 march-april 2019 125 independently from included literature (table 1). outcomes of kidney stones incidence among men and women(figure 2) pooling data of two studies(4,5) reported on aa supplements and risk of kidney stones among men and women, the results showed that the kidney stones incidence of men was significantly higher than women with aa supplements (or= 1.62; 95% ci: 1.09 to 2.42; p = 0.02) (figure 2). outcomes of aa supplements and risk of renal calculus among men and women (figures 3, 4) pooling data of four studies(4-6,11) reported on aa supplements and risk for renal calculus among men and women by multivariate analysis. the results showed that aa supplements (250-499mg/d, 1000-1499mg/d) was remarkably correlated with the risk of renal stones among men (or= 1.14, 95% ci: 1.00 to 1.28, p = 0.04; or= 1.12, 95% ci: 1.11 to 1.13, p < 0.00001; respectively) (figure 3). however, aa supplements (500-999 mg/d, >1500 mg/d) did not correlate with the risk of renal stones among men (or = 1.20, 95% ci: 0.99 to 1.46, p = 0.06; or = 1.28, 95% ci: 1.00 to 1.63, p= 0.05; respectively) (figure 3). in addition, aa supplements(250-499mg/d, 500-999 mg/d, 1000-1499 mg/d, >1500mg/d) were not remarkably associated with risk of renal calculus among women (or= 1.00, 95% ci: 0.82 to 1.22, p = 0.98; or= 1.08, 95% ci: 0.99 to 1.18, p = 0.09; or= 0.99, 95% ci: 0.90 to 1.08, p = 0.77; or= 0.99, 95% ci: 0.99 to 1.09, p = 0.88; respectively) (figure 4). sensitivity analysis sensitivity analysis was performed for studies matched for general variables by the method of higher quality studies. there was no change in the significance of another outcome except that the risk of aa supplements (500-999 mg/d, >1500 mg/d) and renal stones formation among men was significantly different in sensitivity analysis (p = 0.06 vs p < 0.001; p = 0.05 vs p < 0.001; respectively) (table 2). the method of sensitivity analysis can reduce the heterogeneity of studies to a certain extent. discussion urolithiasis is a worldwide issue, and approximately 75% to 80% of kidney stones diagnosed consist predominantly of calcium oxalate(15-17). hyperoxaluria is the prominent risk factors for calcium oxalate calculus, and aa supplements are thought to be the prominent source of hyperoxaluria, where increasing dosages are associated with increases in urinary oxalate because aa may increase urinary oxalate excretion(7,18). the study of baxmann et al. found urinary oxalate was remarkably increased in patients who received 1g of aa, but no statistically significant difference in urinary ph(7). another study of 29 patients with a history of calcium oxalate calculus and 19 non-stone formers, the results showed that oxalate level of stone formers had significantly higher than non-stone formers with aa supplements(19). many studies have investigated the effect of aa on urinary oxalate excretion and risk of renal calculus. however, their results are not consistent. chai et al. found that aa supplementation increased urinary oxalate levels, and the results indicated that aa was a risk factor for individuals predisposed to renal calculus(19). the study of baxmann et al. also found that ascorbic acid supplementation may increase urinary oxalate excretion and the risk of kidney stones forming, but no statistically significant difference was observed in urinary creatinine, sodium, potassium, calcium and chloride between healthy subjects and stone formers(7). taylor et al. showed that aa intake increases the risk for renal calculus formation(6). however, curhan et al. showed that there is no association between aa intake and kidney stones formation in men and women, even when consumed in large doses(5,11). ferraro et al. showed that aa supplementation was remarkably associated with higher risk of renal calculus in men, but not in women(4). in our meta-analysis, the results showed that the kidney stones incidence of men was significantly higher than women with aa supplements (or= 1.62; 95% ci: 1.09 to 2.42; p = 0.02). pooling data of four studies reported on aa supplements and risk of kidney stones among men and women by multivariate analysis was performed. the results showed that aa supplements a meta-analysis of ascorbic acid supplements and kidney stone-jiang et al. figure 3. forest plot and meta-analysis of aa supplements and risk of kidney stones among men; a: aa supplements 499-250mg/d; b: aa supplements 999-500mg/d, c: aa supplements 1499-1000mg/d, d: aa supplements >1500mg/d; aa= ascorbic acid. figure 4. forest plot and meta-analysis of aa supplements and risk of kidney stones among women; a: aa supplements 499-250mg/d; b: aa supplements 999-500mg/d, c: aa supplements 1499-1000mg/d, d: aa supplements >1500mg/d; aa= ascorbic acid. a meta-analysis of ascorbic acid supplements and kidney stone-jiang et al. (250-499mg/d, 1000-1499mg/d) was remarkably correlated with risk of renal calculus among men(or= 1.14, 95% ci: 1.00 to 1.28, p = 0.04; or= 1.12, 95% ci: 1.11 to 1.13, p < 0.00001; respectively). however, aa supplements (250-499 mg/d, 500-999mg/d, 1000-1499mg/ d, >1500mg/d) did not remarkably correlate with risk of renal calculus among women (or= 1.00, 95% ci: 0.82 to 1.22, p = 0.98; or= 1.08, 95% ci: 0.99 to 1.18, p = 0.09; or= 0.99, 95% ci: 0.90 to 1.08, p = 0.77; or= 0.99, 95% ci: 0.99 to 1.09, p = 0.88; respectively). the reason for the disparate results between men and women is unclear. however, some studies previously reported differential associations by sex for several dietary risk factors for stones, including animal protein, sucrose, potassium and sodium(2,6). it is possible that the effect of aa on renal calculus risk is different in men and women, and the potential reason was sex differences in aa metabolism(20,21). however, there were several limitations when analyzing and interpreting results in our meta-analysis. firstly, we did not have stone composition analysis, nor plasma levels of aa or 24-hour urine data for participants in studies. secondly, included studies were predominantly white, and results of our meta-analysis might not be generalizable to different races. thirdly, the heterogeneity of the included studies is high and may be due to the differences in ethnicity, especially measurement methods and aa supplementations. conclusions aa supplements remarkably correlated with higher risk of renal calculus incidence in men, but not in women. we advise that male stone former of calcium oxalate calculus abstain from supplemental but not dietary aa intake. further studies are needed to examine associations between aa, oxalate metabolism, and urolithiasis formation and explore the possible mechanism of sex on the relationship between aa intake and risk for kidney stones. acknowledgement this study was funded by hubei province health and family planning scientific research project (number: wj2017m257), natural science foundation of hubei province of china (number: 2017cfb516) and science and technology project of enshi of china (20132014). and we are very grateful to male musa for his language modification as a native speaker. doctoral foundation of guizhou provincial people’s hospital (gzsybs[2018]02), thank you very much. conflict of interest the authors report no conflict on interests. references 1. borghi l st, meschi t, guerra a, allegri f, maggiore u, novarini a. comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. n engl j med. 2002;346:77-84. 2. curhan gc ww, speizer fe, spiegelman d, stampfer mj. comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. ann intern med. 1997;126:497504. 3. taylor en, curhan gc. oxalate intake and the risk for nephrolithiasis. j am soc nephrol. 2007;18:2198-204. 4. 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contribution of ascorbic acid to renal calcium oxalate stones. ann nutr metab. 1997;41:269-82. 11. curhan gc ww, speizer fe, stampfer mj. intake of vitamins b6 and c and the risk of kidney stones in women. j am soc nephrol. 1999;10:840-5. 12. liberati a, altman dg, tetzlaff j, et al. the prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. j clin epidemiol. 2009;62:e134. 13. clark hd, wells ga, huet c, et al. assessing the quality of randomized trials: reliability of the jadad scale. control clin trials. 1999;20:448-52. 14. stang a. critical evaluation of the newcastleottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. eur j epidemiol. 2010;25:603-5. 15. scales cd, jr., smith ac, hanley jm, saigal cs, urologic diseases in america p. prevalence of kidney stones in the united states. eur urol. 2012;62:160-5. 16. wang w, fan j, huang g, et al. prevalence of kidney stones in mainland china: a systematic review. sci rep. 2017;7:41630. 17. zeng g, mai z, xia s, et al. prevalence of kidney stones in china: an ultrasonography based cross-sectional study. bju int. 2017. 18. traxer o, huet b, poindexter j, pak endourology and stones diseases 126 vol 16 no 02 march-april 2019 127 cy, pearle ms. effect of ascorbic acid consumption on urinary stone risk factors. j urol. 2003;170:397-401. 19. chai w, liebman m, kynast-gales s, massey l. oxalate absorption and endogenous oxalate synthesis from ascorbate in calcium oxalate stone formers and non-stone formers. american journal of kidney diseases. 2004;44:1060-9. 20. levine m c-cc, wang y, welch rw, washko pw, dhariwal kr, park jb, lazarev a, graumlich jf, king j, cantilena lr. vitamin c pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. proc natl acad sci u s a. 1996;93:3704-9. 21. jiao y, chen h, yan j, et al. genome-wide gene expression profiles in antioxidant pathways and their potential sex differences and connections to vitamin c in mice. int j mol sci. 2013;14:10042-62. a meta-analysis of ascorbic acid supplements and kidney stone-jiang et al. case report primary retroperitoneal transitional cell carcinoma – a rare clinical entity pramod kumar sharma, rajan kumar sinha*, subhabrata mukherjee keywords: primary; retroperitoneum; urothelial neoplasm; transitional cell carcinoma introduction transitional cell carcinoma (tcc) most commonly arises from the urinary bladder and less frequently from the upper urinary tract. we report a case of primary retroperitoneal tcc in a male patient. the entire urinary tract did not have any evidence of tumour. as far as we are concerned, only four such cases have been reported in the literature previously(1) and all of them were female. case description a 30 year-old male patient belonging to asian-indian race presented with intermittent left flank pain for 2 months with normal abdominal examination findings. the patient was a farmer by occupation and did not have any history of radiation exposure or any known family history of malignancy. ultrasonography along with intravenous urography (ivu) (figure 1a) revealed hydronephrotic left kidney suggestive of pelvi-ureteric junction obstruction (pujo) and diuretic renogram showed obstructive drainage from the left kidney. however, on careful retrospective evaluation of ivu plates there was evidence of upper ureteric compression with mild lateral deviation of left ureter which we missed preoperatively. with preoperative diagnosis of left pujo, the patient was taken up for pyeloplasty and on table retrograde pyelogram (pyelogram) exhibited patent ureter with jet sign at pelvis which collabo1department of urology, calcutta national medical college, kolkata 700014 ,india. *correspondence: department of urology, calcutta national medical college, kolkata 700014 phone: +91-9007205371. email: rajan_rims@yahoo.co.in. received march 2016& accepted august 2016 figure 1. (a) intravenous urography revealing hydronephrotic left kidney suggestive of pelvi-ureteric junction obstruction. (b) intraoperative image showing a large retroperitoneal mass with lateral deviation of ureter. (c) hematoxylin & eosin stained picture of incisional biopsy of retroperitoneal mass showing transitional cell carcinoma under 400x magnification. (d) computed tomography scan of abdomen showing mass encasing the great vessels. case report 2869 vol 13 no 05 september-october 2016 2870 rated with our diagnosis. on exploration, a large mass was found in the retroperitoneum which was encasing the great vessels (figure 1b). the ureter was arching over the mass with no evidence of primary pujo. incisional biopsy from the mass was taken and double-j stent was inserted into left ureter via ureterotomy. histopathological examination showed multiple pieces of greyish tissue on gross examination, and microscopically it was suggestive of high grade urothelial carcinoma with area of necrosis and perineural invasion (figure 1c). considering that the mass could be a secondary from an unknown primary site within the urinary tract, computed tomography (ct) urogram, cystoscopy, urine for malignant cell cytology, bilateral ureteroscopy and retrograde pyelography were performed, but no evidence of urothelial carcinoma was found in the urinary tract. ct of abdomen showed a large mass encircling the aorta and compressing the inferior vena cava with areas of necrosis (figure 1d). with the final diagnosis of primary retroperitoneal tcc, chemotherapy with gemcitabine and cisplatin was started after consultation with medical oncologists. patient did not respond to the chemotherapy and his general condition deteriorated. moreover, a swelling was noticed in left side of neck after first cycle of chemotherapy. fine needle aspiration cytology of that mass was suggestive of metastatic deposits of malignant epithelial neoplasm. finally, 5 months after diagnosis he succumbed to death. discussion adult retroperitoneal tumours are rare and constitute only 0.2-0.5% of all malignant tumours (2). they may arise from fat, areolar connective tissue, fascia, muscle, vascular tissue, nervous tissue, lymphatic tissue and urogenital ridge remnants. the two most common malignant primary tumours of the retroperitoneum are lymphosarcoma and liposarcoma (3). amongst the retroperitoneal tumours, primary tccs are extremely rare and carry a worst prognosis. till date, only 4 cases have been reported and all of which were cystic pelvic mass occurring in female patients (1). like ours, three out of those four patients had unresectable mass. this is the first case reported in male as per our best knowledge. retroperitoneal tumours grow unrestricted because of loose surrounding tissue. they are generally asymptomatic until they grow to very large sizes. the symptoms are often due to obstruction or compression of the adjacent structures. as they grow to a very large size before being detected, only 25% of these tumours can be completely excised (4). primary retroperitoneal tcc is an extremely uncommon entity. they are thought to originate from the remnants of urogenital ridge(5). braasch et al.(6) reviewed 101 cases of retroperitoneal tumour of which only 3 cases were found to arise from urogenital ridge. however, handfied-jones et al.(7) were of the opinion that majority of retroperitoneal tumours arise from urogenital apparatus. hansmann et al.(8) also supported their view of similar origin. koyanagi et al.(9) were first to report primary tcc of retroperitoneum arising from cloacal cyst. later gupta et al.(4) and basu et al.(2) also reported primary retroperitoneal tcc. all these above 3 cases died within 2 years of diagnosis. radiotherapy alone was used in 2 cases, while surgery was the primary modality of treatment in one of them followed by adjuvant chemotherapy. recently, ichinobe et al. (1) reported a case of primary retroperitoneal tcc with complete remission of the disease achieved with radiotherapy and concurrent oral chemotherapy (tegafur-uracil). the explanation they gave for their success was that the chemotherapeutic agent acted as a radiosensitisor. in our case, the patient died after 5 months with development of a metastatic neck deposit. to conclude, primary retroperitoneal tcc is an exceptionally infrequent neoplasm. due to retroperitoneal location they grow to very large size before being detected. modality of therapy has not been yet defined due to their rarity. prognosis is poor as most of the patient die within months. references 1. k ichinohe, m ijima, t usami, s baba. complete remission of primary retroperitoneal transitional cell carcinoma after radiotherapy and oral chemotherapy: a case report. ann r coll surg engl. 2013; 95:e52–e54. 2. basu s, ansari m, gupta s, kumar a. primary retroperitoneal transitional cell carcinoma presenting as a dumb-bell tumour. singapore med j 2009; 50: e384–e87. 3. kransdorf mj. malignant soft-tissue tumors in a large referral population: distribution of diagnoses by age, sex and location. am j radiol 1995; 164:129-34. 4. gupta s, gupta s, sahni k. retroperitoneal urogenital ridge transitional cell carcinoma. j surg oncol1983; 22: 41–44. 5. donnelly ba. primary retroperitoneal tumors-a report of 95 cases and a review of literature. surg gynecol obstet 1946;83:70517. 6. braasch jw, mon ab. primary retroperitoneal tumors. surg clin north am 1967; 47:663-78. 7. handfield-jones rm. retroperitoneal cysts: their pathology, diagnosis and treatment. br j surg 1924; 12:119-34. 8. hansmann gm, budd jw. massive unattached retroperitoneal tumours. am j pathol 1931; 7:631-73. 9. koyanagi t, tsuji i, motomura k, sakashita s. unusual extraperitoneal lesion of the pelvis: cloacal cyst with transitional cell carcinoma. int urol nephrol 1977;9:41–6. primary retroperitoneal tcc-kumar sharma et al. miscellaneous combination of thulium laser incision and bipolar resection offers higher resection velocity than bipolar resection alone in large prostates kuan chun huang1, yung chiong chow1,2,4* , marcelo chen1,2,4 allen w. chiu1,2,3 purpose: we compared the efficacy and safety of a combined thulium laser incision and bipolar resection of prostate technique (web procedure) with traditional bipolar turp. materials and methods: we reviewed the medical records of 96 web procedure, 93 traditional bipolar turp patients between 2013 and 2016. the web procedure consisted of thulium laser incision of the prostate at 3, 5, 7, 9 and 12 o’clock positions up to the resection plane and subsequent bipolar resection of the created prostate blocks. resected tissue weight, operative time, resection velocity, complications, blood loss, and early operative outcome were compared. result: no significant differences were noted among the web procedure (web group) and traditional bipolar turp in preoperative psa ( 6.3 vs 8.7 ng/ml, p = 0.295), preoperative postvoid residual urine (55.1 vs 76.4, p = .056), modified hemoglobin decrease (defined as total hb decrease divided by the weight of the resected tissue: 0.060 vs 0.051, p = .380), complication rate (5.2% vs 5.3 %, p =.958), hospitalization (4.0 vs 4.2 days, p = .120) and catheterization (2.5 vs 3.4, p = .066). the resection velocity was higher in the web group (0.23 vs 0.17 g/ min, p = .001). in subgroup analysis, the significant difference of resection velocity between two group was showed in large prostates (> 40 g: 0.25 vs 0.20 g/min, p = 0.02 ) but not in the small prostate group. there was no difference in postoperative postvoid residual urine (21.9 vs 30.3 p =.231) and postvoid residual urine decrease (33.1 vs 45.5, p = .167) 2 months after surgery. conclusion: the combination thulium laser incision and bipolar turp technique had a higher resection efficiency and comparable efficacy and safety than traditional bipolar turp. keywords: thulium laser; endoscopic prostatectomy; bipolar transurethral resection introduction transurethral resection of the prostate (turp) has been the gold standard for benign prostatic obstruction (bpo) for decades. compared with traditional monopolar turp, bipolar turp has comparable efficacy in improving voiding parameters(1,2). bipolar turp allows for a longer operative time to resect a larger prostate due to the high quality of hemostasis and a low risk of turp syndrome (turps)(1-3). the thulium laser is one of the novel technologies used for endoscopic prostatectomy. first used in prostatic surgery in 2005 by xia et al., the features of continuous and visible release of energy allow for both excellent instant vaporization and precise resection(4). various thulium laser techniques have been documented, including thulium laser resection of the prostate (tmlrp) and thulium laser vaporesection of the prostate (tmvrp), referring to elimination of prostatic adenoma by resecting it into small chips. these techniques have been shown to have comparable clinical outcomes and similar improvements in 1department of urology, mackay memorial hospital, taipei, taiwan. 2mackay medical college, new taipei city , taiwan. 3school of medicine, national yang-ming university , taiwan. 4mackay junior college of medicine, nursing, and management, new taipei city. *correspondence: no. 92, section 2, zhongshan n rd, zhongshan district, taipei city, 10491 tel: 886 2 2543 3535. fax: 886 2 25232448. e-mail: edwardhuang322@gmail.com. received january 2018 & accepted july 2018 voiding parameters with a lower transfusion rate and shorter catheter and hospitalization time compared with monopolar turp(4-6). tm:yag vapoenucleation (tmvep) and tm:yag laser enucleation of the prostate (tmlep) have been shown to be more efficient for large prostates as they can resect the adenoma into large pieces which can then be evacuated with a morcellator(1,7). previous studies have compared the different laser technologies as well as turp, and shown that tmvep has better adenoma retrieval volume and efficiency than tmvrp and turp with similar urodynamic results after surgery(3-5). however, bladder injury due to morcellation can be a serious concern in tmvep(2). one meta-analysis study also showed that thulium laser technology involves a longer operative time compared with bipolar turp(5). different endoscopic resection technologies have their own advantages. a previous study combining thulium laser and bipolar resection had good outcomes, but the case number was small(8). therefore, to investigate the advantages of a thulium laser combined with bipolar turp (web procedure), urology journal/vol 16 no. 4/ july-august 2019/ pp. 397-402. [doi: http://dx.doi.org/10.22037/uj.v0i0.4363] vol 16 no 04 july-august 2019 398 we conducted this study to investigate its efficacy and perioperative outcomes in endoscopic prostatic surgery in our institution. patients and methods patients a total of 189 patients who underwent a first endoscopic prostatic surgery were enrolled from 2013 to 2016. patients who received surgery other than prostate resection at the same time such as transrectal ultrasound-guided biopsy or endoscopic cystolithotripsy were excluded. ninety-six patients underwent web procedures (web group), and 93 patients underwent traditional bipolar turp (turp group). patients who could afford to pay for the laser procedure out-of-pocket or had private insurance underwent the web procedure, and the rest of the patients underwent bipolar turp. all of the procedures in both groups were carried out by a single experienced surgeon. all of the patients were candidates for surgery due to bpo with no improvements after treatment with medications. the prostate volume, prostate-specific antigen (psa), and postvoid residual urine (pvr) were measured in all patients preoperatively. perioperative outcomes including total operative time, resected prostatic tissue weight, decrease in modified hemoglobin (hb) (defined as total hb decrease per resected tissue weight; total hb decrease was determined by the difference of postoperative hb and preoperative hb values ) after surgery and complications were recorded using clavien-dindo classification(9). the resection velocity (resected prostatic volume/operative time [g/min]) was calculated. the resected prostatic volume was defined as the retrieved prostate chip weight measured by electronic scales. the operative time was defined as the time from start of cystoscopy to foley insertion after complete resection. the postoperative pvr was also assessed 2 months after surgery as an early outcome to access the efficacy of the procedure. ethics this study was approved by the institutional review board (irb) of our institution. ( irb number: 17mmhis174e) surgical techniques web procedures were carried out using the combination of a thulium laser fiber for incision (mapping) (vela® xl, starmedtec, starnberg, germany) and a bipolar cutting loop (olympus turis system, olympus america, melville, ny) for resection (cutting) (figure 1). this technique involved two steps: mapping and cutting. the initial incision was made from the bladder neck to the front of the verumontanum with the laser fiber at 3 o’clock (figure 1a). another incision line was made at 5 o’clock to distally connect with the line at 3 o’clock in front of the verumontanum. the ade web group (n=96) turp group (n=93) p value mean age (range) 72.1 yrs (50-94 yrs) 71.8 yrs (41-92 yrs) 0.824 preoperative psa (ng/ml) 6.3 ± 7.3 8.7 ± 20.7 0.295 prostate size (g) 56.6 ± 27.6 42.1 ± 16.3 < 0.001 preoperative pvr (ml) 55.1 ± 40.5 76.4 ± 62.1 0.056 table 1. patients characteristics and preoperative parameters note. data presented as mean values ± standard deviation; turp= transurethral resection of the prostate; pvr= postvoid residual urine figure 1. web procedure. (a) initial incision line was made at the 3 o’clock position. (b) another incision line was made at the 5 o’clock position. (c) the 3 and 5 o’clock incisions were joined near the capsule and the block was vaporesected up to the bladder neck without breaking the connection between the adenoma and bladder neck (black arrowhead). (d) the same procedure was repeated on the other side in the 7 and 9 o’clock positions. (e) an incision was made at the 12 o’clock position, and the blocks created between 9 to 3 o’clock were also vaporesected up to the bladder neck. (f) the median lobe was vaporesected in a similar fashion by joining the 5 and 7 o’clock incisions. (g) bipolar resectoscope was used to resect the blocks into chips combined of thulium laser and bipolar in prostatectomy-huang et al. noma was detached from the resection plane near the prostatic capsule using vaporesection in a retrograde direction to the bladder neck without breaking the bladder neck connection (figure 1c). we used 80 w for the incision and 20 w for hemostasis. the same surgical mapping was made on the other side from 7 to 9 o’clock (figure 1d). a 12 o’clock incision line was made to separate bilateral lateral lobes (figure 1e). vaporesection of prostatic tissue at 6 o’clock in front of the verumontanum was then performed to the bladder neck in order to isolate the median lobe (figure 1f). at the end of the mapping, five radial surgical lines were made on the prostate similar to the pattern of a web. blocks of prostatic adenoma were then lifted between each of the incision lines with each prostate adenoma still attached to the bladder neck so that the circumferential resection plane proximal to the verumontanum could be clearly identified. (figure 1g). the remaining prostate adenoma was then resected with the bipolar cutting loop, and prostatic chips were evacuated using an ellik bladder evacuator. compared with the traditional 3 lobe resection technique which starts at 5 and 7 o'clock(10), we chose 3 and 9 o'clock to identify the resection plane rather than 6 o'clock, as this may prevent subtrigonal perforation, especially in prostates with a large median lobe(11). once the resection plane has been identified, resection of the remaining adenoma using the bipolar cutting loop can be performed without concerns of capsular perforation and thus may improve the efficiency of the resection. bipolar turp procedures were performed using the bipolar cutting loop (olympus turis system, olympus america, melville, ny). the cutting power setting was 180 w, and the coagulating setting was 80 w. the adenoma was resected piece by piece according to standard procedures. statistical analysis independent t-test was used to compare means between two samples, and chi-square test was used to compare proportions. data were analyzed using medcalc statistical software version 17.9.5 (medcalc software bvba, ostend, belgium). a two-sided p value of less than 0.05 was considered to be statistically significant. results the preoperative baseline parameters of the patients are summarized in table 1. the prostate size was significantly larger in the web group, however there were no significant differences in preoperative psa and preoperative pvr between the two groups. the perioperative and early postoperative outcomes are shown in table 2. there were no significant differences in the decrease in modified hemoglobin, overall complication rate, hospitalization, catheterization, postoperative pvr and decrease in pvr between the two groups. the operative time was shorter and the resection tissue weight was larger in the web group compared with the turp group. as data on postoperative prostate volume were lacking, the amount of vaporized tissue could not be calculated. we also ignored the trivial time of ellik evacuation. the resection velocity in the web group was significantly higher than in the turp group despite the lack of data on vaporized tissue volume. to adjust for the effect of prostate size on resection velocity, we used the 40 g of the prostate size as a cutoff for subgroup analysis. subgroup analysis showed that in smaller prostates (< 40g), resection velocity was 0.18 ± 0.08 g/min in the web group and 0.14 ± 0.06 g/min in the bipolar group (p = .053), and in larger prostates (> 40g), resection velocity was 0.25 ± 0.14 g/min in the web group and 0.20 ± 0.09 g/min in the bipolar group (p = .02). the significantly higher resection velocity was found in web group particularly in the prostate size larger than 40 g. we also analyzed the correlation between resection velocity and prostate volume (figure 2). there was a positive correlation between resection velocity and prostate volume in each group, however the web group had a higher correlation coefficient than the turp group. this indicated that the web group had a significantly higher efficiency with larger prostates than the turp group. table 3 shows the complications according to the clavien-dindo classification system. eight patients (five in the web group and three in the turp group) had blood clot retention and required urinary bladder irrigation without anesthesia. none of the patients required a blood transfusion after surgery. one patient had a postoperative urinary tract infection and one patient suffered from pneumonia in the turp group. none of the patients had clavien grade iiib, iv or v complications. there was no significant difference in complications between the two groups. discussion monopolar turp is still the gold standard for bpo, however it is associated with a high immediate morbidity rate of up to 11.1%(1,12), with the most common complications being bleeding, turps, and blood clot retention(12). bipolar turp is an alternative technique which can be performed using normal saline, enabling a longer operative time for resection of larger prostates, and decreasing the risk of turps(12). the latest tech web group (n = 96) turp group (n = 93) p value operative time (min) 67.3 ± 24.4 73.3 ± 25.1 0.094 resected tissue weight (g) 16.7 ± 14.5 13.2 ± 9.5 0.051 resection velocity (g/min) 0.23 ± 0.13 0.17 ± 0.08 0.001 total hb decrease (g/dl) 0.61 ± 0.59 0.45 ± 0.53 0.049 modified hb decrease 0.060 ± 0.078 0.051 ± 0.071 0.380 catheterization (days) 2.5 ± 2.0 3.4 ± 4.2 0.066 hospitalization (days) 4.0 ± 0.4 4.2 ± 1.5 0.120 complication rate 5.2% 5.3 % 0.958 postoperative pvr(ml) 21.9 ± 21.7 30.3 ± 30.6 0.231 pvr decrease (ml) 33.1 ± 38.2 45.5 ± 60.5 0.167 table 2. perioperative outcomes and early postoperative outcomes note. data presented as mean values ± standard deviation; hb=hemoglobin; modified hb decrease = total hb decrease / the resected tissue weight; resection velocity = resected tissue weight / operative time; pvr= postvoid residual urine; pvr decrease = preoperative pvr-postoperative pvr combined of thulium laser and bipolar in prostatectomy-huang et al. miscellaneus 399 vol 16 no 04 july-august 2019 400 niques involve laser technology. greenlight laser photoselective vaporization (pvp) has been shown to be feasible in small-sized prostates with comparable outcomes with regards to urodynamic improvement, with a higher quality of hemostasis but higher retreatment rate in patients with larger prostates compared with turp(13-16). holmium laser enucleation of the prostate (holep) was first described by gilling et al. in 1998 and was a breakthrough in laser technology(17). as it involves the use of a morcellator, it has high efficiency for large-volume prostates. a previous meta-analysis reported that holep had favorable outcomes with regards to improvements in urodynamic parameters, shorter catheterization time and hospital stay compared with turp(13,18). thulium lasers were first introduced in 2005 for bpo surgery(4). similar to holmium lasers, thulium lasers have comparable energy absorption in soft tissue and water, allowing for excellent tissue vaporization with minimal thermal injury to the surrounding tissue(5). the wavelength of a thulium laser is between 1.75 and 2.22 μm with a penetration depth of 0.25 mm, with the characteristics of continuous-wave output allowing for precise incision and resection of tissue(1,19). tmvrp has been used in the endoscopic treatment of bph, and shown similar clinical outcomes and improvements with regards to urodynamic parameters with reduced morbidity compared with monopolar turp(13,20). tmvep and tmlep have been increasingly used for bph endoscopic surgery due to the benefits of efficient tissue reduction and low morbidity rate, particularly with larger prostates(7,14). tmvrp is performed in a similar manner to turp, in which the adenoma is resected into strips. compared with tmvep, a previous non-randomized controlled trial reported that tmvrp had lower efficiency in reducing tissue(21). although tmvep has been reported to have a higher resection efficiency compared with tmvrp, the complications of morcellation and enucleation including bladder wall injury and capsular perforation have also been reported(11,22-25). to combine the advantages of turp and tmvep and to eliminate the drawbacks of both, we introduced this technique using a thulium laser for incision combined with a bipolar turp cutting loop for resection in bph endoscopic surgery. our data showed a higher resection velocity compared with bipolar turp with equivalent early postoperative outcomes. making an incision using the laser fiber to identify the resection plane was safe and efficient. intraoperative bleeding may interfere with the efficiency of endoscopic prostatectomy due to the poor visualization under endoscope. the preoperative use of 5 alpha reductase inhibitor may decrease the intraoperative bleeding of prostate and facilitate the operation(26). laser technology is another method with the potential advantage in decreasing intraoperative bleeding. concentrating energy on the prostate tissue surface not only allows for instant vaporization but also coagulation of the microvessels of the prostate leading to excellent hemostasis(19). laser mapping of the resection plane also has the potential benefit of blocking the main branches of blood supply to the prostate, namely the anterior lateral branches at 2 and 10 o'clock and posterior lateral branches at 5 and 7 o'clock(11). at the end of mapping, almost complete devascularization of the adenoma can be achieved for resection(11). due to the relatively small size of the prostate volume in the turp group, we used modified hb decrease to evaluate perioperative blood loss rather than absolute hb decrease to adjust for the effect of the prostate size. however, compared with the web group, the turp group showed no increased risk of bleeding based on no significant difference in modified hb decrease and postoperative bladder irrigation. none of our patients required a blood transfusion after surgery. this may be due to improvements in video equipment for endoscopic surgery which provides a clear visual field for instant hemostasis. however, coagulation for hemostasis increases the operative time which may decrease the resection velocity. we believe that the lower coagulation time in the web group compared with the turp group improved the efficiency of the resection. in this study, the mean of resection velocity in web group was 0.23 g/min, which was significantly higher than in the turp group. in subgroup analysis, the resection velocity in web group was even higher in large prostates (0.25 g/min). however, our method for calculating the tissue resection velocity is different from some previous studies. we used the resected tissue/total operative time to assess resection efficiency instead of (resected tissue + vaporized tissue)/laser time(21). therefore, our resection velocity was generally lower than that reported in previous studies. in subgroup analysis, the significant difference of resection velocity between two group was showed in large prostates (> 40 g) but not in the small prostate group. we also analyzed the correlation between resection velocity and prostate volume, and found that the web group had a higher correlation coefficient than the turp group (0.4978 vs. 0.2392). this results indicates the potential advantage of processing large prostates using the web procedure. shih et al. reported the oyster method using a diode laser to enucleate adenoma from the prostate capsule (as in detaching an oyster from a shell) and a bipolar cutting loop to resect the remaining adenoma in prostates with a volume larger than 80 ml, and showed the procedure to be effective and safe(11). xie et al. performed a similar technique with bipolar turp combined with a thulium laser for prostates with a volume larger than 80 ml, and showed better outcomes than turp alone in surgical duration, hemostasis, resection efficiency and recovery[8]. tmvep has been reported to have benefits with web procedure (n=96) turp group (n=93) p value overall complications 5 (5.2%) 5 (5.3%) 0.958 grade ii -uti 1 (1%) 0.308 -pneumonia 1 (1%) 0.308 grade iiia -delayed bleeding with blood clot retention 5 (5.2%) 3 (3.2%) 0.498 table 3. complication according to the clavien-dindo classification combined of thulium laser and bipolar in prostatectomy-huang et al. larger prostates due to the larger amount of resected tissue volume in a single operation compared with bipolar turp(13,14). tmvep has also been shown to increase the resection velocity in larger prostates(14). however, due to the steep learning curve of tmvep, some complications can be expected in at least the first 50 cases(27). instead of an enucleation technique, we used deep vaporesection to create a huge adenoma block. the skill of enucleation involves the use of the beak of a resectoscope to dissect the adenoma from the prostate capsule. the difficult parts of enucleation include identifying the surgical plane between the adenoma and prostate capsule and maintaining one plane without capsular perforation during the whole procedure(28). although this technique allows for maximum adenoma resection, it can result in a prolonged operative time with a single procedure and capsular perforation, particularly with large prostates(11,28). furthermore, due to the use of blunt dissection in enucleation, the advantage of instant coagulation of microvessels by a laser may be less effective. in the web procedure, we identified the resection plane near the prostate capsule using vaporesection rather than blunt dissection, which may allow for the preservation of minimal adenoma on the prostate capsule as a “safe margin” without a retrograde “pushing” movement by the beak of the resectoscope. none of our cases had prostate capsule perforation. superficial bladder wall injuries caused by a morcellator have been reported in 1.3-6.6% of cases(5,11,29). to avoid the use of a morcellator, we preserved the connection between the remaining adenoma and bladder neck at the end of mapping rather than resect it as a huge adenoma in order to resect the lifted adenoma using the bipolar cutting loop into tur-like prostate chips. tmvrp has also been performed to resect the prostate into chips small enough to be evacuated through a resectoscope sheath, which can also avoid the use of a morcellator(6). however, one previous study reported that tmvrp was significantly less efficient than tmvep(21), and a meta-analysis reported that its efficiency was even lower than bipolar turp(30). the web procedure seems to combine the two advantages of high efficiency and avoiding morcellation. although the web group appeared to have shorter duration of hospitalization and catheterization compared with turp group, it did not reach statistical significance. this may be because the national health insurance program in taiwan combines all prostate endoscopic surgery into the same package of payment (diagnosis related group), thus the clinical course of each group was similar. there are several limitations to this study. the non-randomized design may have resulted in selection bias. although it was not the absolute indications, the patients with larger prostates and those receiving anticoagulants tend to be candidates for laser surgery according to the european association of urology guidelines(13). second, this study is retrospective. third, urodynamic evaluations were less comprehensive because we only used post-void residual urine volume as an index of voiding improvement, and we did not evaluate the international prostate symptom score (ipss) or maximum flow rate (qmax) postoperatively. fourth, we only focused on perioperative and early postoperative outcomes due to the limited duration of follow-up. future studies should focus on comprehensive urodynamic parameters as well as long-term complications including urethral stricture, bladder neck contracture, incontinence and erectile dysfunction and retreatment rate. conclusions the combination of thulium laser incision and bipolar turp technique had a higher resection efficiency and comparable efficacy and safety than traditional bipolar turp especially in the patient with large prostate size (> 40 g). future studies should focus on the details of improving urodynamics and long-term outcomes. conflict of interest the authors report no conflict of interest. references 1. yang, z., t. liu, and x. wang, comparison of thulium laser enucleation and plasmakinetic resection of the prostate in a randomized prospective trial with 5-year follow-up. lasers med sci, 2016. 31: 1797-1802. 2. hirik, e., et al., safety and efficacy of bipolar versus monopolar transurethral resection of the prostate: a comparative study. urol j, 2015. 12: 2452-6. 3. da silva, r.d., et al., bipolar energy in the treatment of benign prostatic hyperplasia: a current systematic review of the literature. can j urol, 2015. 22 suppl 1: p. 30-44. 4. xia, s.j., et al., [thulium laser resection of prostate-tangerine technique in treatment of benign prostate hyperplasia]. zhonghua yi xue za zhi, 2005. 85: 3225-8. 5. nair, s.m., m.a. pimentel, and p.j. gilling, a review of laser treatment for symptomatic bph (benign prostatic hyperplasia). curr urol rep, 2016. 17: 45. 6. bach, t., et al., revolix vaporesection of the prostate: initial results of 54 patients with a 1-year follow-up. world j urol, 2007. 25: 257-62. 7. bach, t., et al., feasibility and efficacy of thulium:yag laser enucleation (vapoenucleation) of the prostate. world j urol, 2009. 27: 541-5. 8. xie, t., et al., the effectiveness and safety of transurethral (bipolar) plasmakinetic resection of prostate combined with thulium laser for large benign prostatic hyperplasia (>80ml). urol j, 2016. 13:2889-92. 9. dindo, d., n. demartines, and p.a. clavien, classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg, 2004. 240: 205-13. 10. gilling, p., holmium laser enucleation of the prostate (holep). bju int, 2008. 101: 13142. 11. shih, h.j., et al., laser-assisted bipolar transurethral resection of the prostate with the oyster procedure for patients with prostate glands larger than 80 ml. urology, 2013. 81: combined of thulium laser and bipolar in prostatectomy-huang et al. miscellaneus 401 combined of thulium laser and bipolar in prostatectomy-huang et al. 1315-9. 12. reich, o., et al., morbidity, mortality and early outcome of transurethral resection of the prostate: a prospective multicenter evaluation of 10,654 patients. j urol, 2008. 180: 246-9. 13. herrmann, t.r., et al., eau guidelines on laser technologies. eur urol, 2012. 61: 78395. 14. bach, t., et al., prospective assessment of perioperative course in 2648 patients after surgical treatment of benign prostatic obstruction. world j urol, 2017. 35: 285-92. 15. bouchier-hayes, d.m., et al., ktp laser versus transurethral resection: early results of a randomized trial. j endourol, 2006. 20: 5805. 16. al-ansari, a., et al., greenlight hps 120w laser vaporization versus transurethral resection of the prostate for treatment of benign prostatic hyperplasia: a randomized clinical trial with midterm follow-up. eur urol, 2010. 58: 349-55. 17. fraundorfer, m.r. and p.j. gilling, holmium:yag laser enucleation of the prostate combined with mechanical morcellation: preliminary results. eur urol, 1998. 33: 69-72. 18. lourenco, t., et al., alternative approaches to endoscopic ablation for benign enlargement of the prostate: systematic review of randomised controlled trials. bmj, 2008. 337: a449. 19. huang, x., et al., comparison of the microvessel diameter of hyperplastic prostate and the coagulation depth achieved with monoand bipolar transurethral resection of the prostate. a pilot study on hemostatic capability. scand j urol nephrol, 2008. 42: 265-8. 20. fu, w.j., et al., comparison of 2-microm continuous wave laser vaporesection of the prostate and transurethral resection of the prostate: a prospective nonrandomized trial with 1-year follow-up. urology, 2010. 75: 194-9. 21. chung, j.s., et al., thulium laser (revolix) vaporesection versus vapoenucleation with morcellator (piranha) for the treatment of benign prostatic obstruction: a propensitymatched multicenter analysis. int j urol, 2014. 21: 1156-61. 22. iacono, f., et al., efficacy and safety profile of a novel technique, thulep (thulium laser enucleation of the prostate) for the treatment of benign prostate hypertrophy. our experience on 148 patients. bmc surg, 2012. 12 suppl 1: s21. 23. barbalat, y., et al., evidence of the efficacy and safety of the thulium laser in the treatment of men with benign prostatic obstruction. ther adv urol, 2016. 8: 181-91. 24. kim, s.h., et al., severe postoperative dyspnea caused by neglected massive intraperitoneal fluid collection during laser enucleation and morcellation of the prostate: a case report. korean j anesthesiol, 2016. 69: 185-8. 25. netsch, c., et al., a prospective, randomized trial comparing thulium vapoenucleation with holmium laser enucleation of the prostate for the treatment of symptomatic benign prostatic obstruction: perioperative safety and efficacy. world j urol, 2017. 35: 1913-21. 26. aminsharifi, a., et al., effect of preoperative finasteride on the volume or length density of prostate vessels, intraoperative, postoperative blood loss during and after monopolar transurethral resection of prostate: a dose escalation randomized clinical trial using stereolog methods. urol j, 2016. 13: 2562-8. 27. seki, n., et al., holmium laser enucleation for prostatic adenoma: analysis of learning curve over the course of 70 consecutive cases. j urol, 2003. 170: 1847-50. 28. elshal, a.m., et al., prospective assessment of learning curve of holmium laser enucleation of the prostate for treatment of benign prostatic hyperplasia using a multidimensional approach. j urol, 2017. 197: 1099-1107. 29. kyriazis, i., et al., transurethral anatomical enucleation of the prostate with tm:yag support (thulep): review of the literature on a novel surgical approach in the management of benign prostatic enlargement. world j urol, 2015. 33: 525-30. 30. zhao, c., et al., thulium laser resection versus plasmakinetic resection of prostates in the treatment of benign prostate hyperplasia: a meta-analysis. j laparoendosc adv surg tech a, 2016. 26: 789-98. vol 16 no 04 july-august 2019 402 urology in history 284 urology journal vol 5 no 4 autumn 2008 avicenna’s canon of medicine and modern urology part i: bladder and its diseases seyed mohammad ali madineh studying the avicenna’s canon of medicine, provides noteworthy information on the subjects related to urology. some examples of these amazing items have been confirmed by the modern urology: explaining the 2-stage function of the bladder (filling and emptying stages); indirect pointing to a scientific law, named later as the laplace’s law, which is applicable to bladder physiology and explains intravesical pressure stability; describing the bladder layers and strength of the urothelial layer, which was later proved to be due to the tight junctions; describing the intramural ureter and its antireflux mechanism; scientific classifying the urethral and bladder diseases; and describing meticulously the semiology and epidemiology of bladder calculi. avicenna has also pointed to inversion therapy in the treatment of urinary calculi, grating sign in bladder calculi, manipulation methods for treatment of bladder calculi, and finally, the crede maneuver. his methodology is completely scientific, based on experiments and truly a basis of the modern medicine. this article is a review of avicenna’s views in medicine and their comparison with the modern urology. urol j. 2008;5:284-93. www.uj.unrc.ir key words: bladder stones, percutaneous cystolithotripsy, children urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: seyed mohammad ali madineh, md mostafa khomeini hospital, italia st, tehran, iran tel: +98 21 6643 8140 fax: +98 21 6690 7895 e-mail: madinehurologist@yahoo.com introduction the persian muslim scientist and physician, abu ali (ibn) sina, namely avicenna in europe is the most famous islamic scientist and medical scholar in the history. he was born in 980 ad in a village near bokhara (which was a city of old persia) and died in 1037 ad in hamadan, iran. george sarton describes avicenna as one of “the most famous scientist of islam and one of the most famous of all races, places, and times.(1)” he is known as “doctor of doctors,” “prince of the physicians,” and “galenus of islam,” because of his immense medical encyclopedia,(2) the canon of medicine which is the first text book of medicine on earth.(2) canon of medicine has widely been used in the west. william osler wrote: “canon was a medical bible for a longer period than any other work.(3)” avicenna was also a great philosopher with several books in the field of philosophy. however in the canon, similar to scientists in the modern era, he discusses on human body and its disorders based experimental methods and his practical experiences in his articles. the subjects of the canon, irrespective of being dated in some issues, are similar to subjects of modern medical text books such as harrison’s text book of internal medicine or the campbell’s urology. concerning the 30-page chapter of the canon about urinary examination, for instance, similar topics to those in the campbell-walsh’s urology(4) urology in history urology journal vol 5 no 4 autumn 2008 285 are reviewed; avicenna discusses collection of urinary specimens first, and then tells us about the methods of examination and several characteristics of urine such as color, turbidity, consistency, odor, sediments, volume, and finally, presence of foam. then, he describes urine color in healthy and sick individuals along with the respective etiologies (table).(5,6) comparison of the canon with the contemporary literature does not mean that its context can be revived. the 2002 edition of the campbell’s urology was abolished by the new edition in 2007, and more than half of its contents became out of date. thus, we cannot expect a place for the canon’s theories and contents in the modern medicine with its overwhelming fast pace. however, a comparative study of this treasure can shed light on the history of medicine to see that how foundation of the new medical science was made in the renaissance by the influence of the theories of avicenna and other scientists of the islamic renaissance age. a german scientist in the 16th century, heinrich cornelius agrippa von nettesheim believed that avicenna had the same authority in medicine as hyppocrates and galenus. he went even further by saying that medical practice without avicenna’s books endangers public health.(7) at that time, medicine and other sciences were at their zenith in the middle east and the oriental references were translated to european languages. this made the basis of new experimental science that had a more or less same methodology and dynamic thinking. on the other hand, in the way knowledge progresses, questions, tentative solutions, conjectures, and refutations play their own role. karl popper believes that “these conjectures are controlled by criticism, ie, by attempted refutations which include severely critical tests.(8)” he quotes from sir john eccles, the australian great neuroscientist (1903 to 1997) who was the owner of multiple theories in neuroscience wrote: “i can now rejoice even in the falsification of a cherished theory, because even this is a scientific success.(8)” in reality, science is the result of these theories and their refutations. a trace of these attempts in the history of medicine can be found by studying books such as the canon. this is table of the contents on urine general remarks about urine the examination of the urine the significance of the color of urine the degrees of yellowness the degrees of redness the degrees of greenness the degrees of blackness whiteness the compound colors of urine like raw meat washings (blood stained) oleaginous oily purple (black) ruddy color mixed with a tinge of blackness the sings afforded by the density, quality, clearness or turbidity of the urine transparent (limpid) urine opaque (thick) urine clearness and turbidity the states to note good signs the signs derived from the odor of the urine fetid odor sweetsh odor putrid odor the indications afforded by the foam on urine the indications derived from the diverse kinds of sediment structure natural sediments abnormal sediments flaky or squamous sediments fleshy sediment fatty sediment mutoid sediment ichorous sediment hair-like sediment sandy or gritty sediment (gravel) cinerital sediment hirudiniform the quantity of sediment the quality of sediment, color odor black color red color yellow color green color white color odor the constitution, coherence and consistency of particles position the occupied sedimentation the form the signs relative to the daily quantity of urine a description of normal healthy urine the variations according to age the urine of animals and differences from human urine fluids resembling urine and how to distinguish them table of contents of canon of medicine under the subject of urine(6) urology in history 286 urology journal vol 5 no 4 autumn 2008 interesting to see what they knew centuries ago, what they did not, and what were their approach to explain the dark side of the human body. such points are can also be investigated in our today text books by our successors. avicenna’s canon which belongs to 10 centuries ago has its value in history of medicine, so as the campbell’s and harrison’s text books would have in future centuries despite refutations of their multiple theories. materials and methods this study is the comparison of modern urology to the urological chapters of avicenna’s canon of medicine. i used the canon in its original language (arabic),(9) along with its persian and english translations (figure 1).(6,10) part 19 of the 3rd book and some parts of the 1st book contain subjects related to urine, urinary tract, and urological diseases. i compared these sections to the current urological findings. selected topics from the canon are presented and a brief discussion follows each subject. a translation from the arabic version and comparison with the persian translation was done to present an accurate text. i did not enter the domain of traditional and herbal medicine such as the four cardinal humours (blood, phlegm, choler, and melancholy), temperaments, and herbal therapy which have been extensively discussed in avicenna’s books and his contemporaries. these subjects were beyond the aim of this paper, and i was only engaged to the items that the current modern medicine obviously and clearly proceeds with them. although i tried not to deviate from mere scientific discussion, there is, undoubtedly, the probability of error and mistake due to the difficult nature of such historical studies. this article can be an opening to comprehensive studies on better exploring our ancestors’ works. it should be noted that this paper is a revised version of an article by the author in persian which was published in the iranian journal of urology in 1995.(11) discussion book iii, part 19, treatise 1, chapter 1 book iii of the canon of medicine is on “specialized pathology: disease inflicting the human organs from head to foot, the external and internal manifestations (medical and surgical).” part 19 of this book is on the bladder (urocyst) and urine (figure 2). this part has two treatises: treatise 1, on the status of the urinary bladder (urocyst) and treatise 2, on timing of urine. in treatise 1, chapter 1, avicenna describes the anatomy of the urinary bladder and its physiology and patophysiology(9,10): the god on high has created an organ similar to cyst in human body to remove the useless and removable liquids (or urine). this allows the urine to gradually pour into the bladder and at a necessary time, it can completely be expelled from figure 1. the canon of medicine in arabic which was published in rome in 1593. adapted from the web site of the saab medical library of the american university of beirut. urology in history urology journal vol 5 no 4 autumn 2008 287 the body. otherwise, the human would have to urinate every minute and every hour, so as in patients with urinary dribbling [tagtirol bol in arabic; chakmizak in persian]. this leather-like bottle is named the bladder (urocyst) in which the removable liquid (or urine) accumulates.(9,10) discussion 1. the 2-phase function of the bladder to which avicenna pointed, has lately been described by yoshimora and chancellor as a premise.(12) according to this premise, function of the bladder has 2 separate phases of bladder filling (storage phase) and bladder emptying (voiding, urination, or emptying phase). it is noticeable that avicenna described this premise 10 centuries ago. discussion 2. urinary dribbling had been scrutinized and described by avicenna as a symptom. the bladder has been made by interlaced tendons [asab-ol-robat in arabic] and there are 2 real hidden reasons for this composition. first, the bladder becomes more fortifiable and inseparable; second, it becomes elastic. when the bladder is filled with urine, it extends and remains fixed, and the human can expel urine voluntarily when the blabber is full.(9,10) discussion 1. the bladder is a muscular organ which has been made by smooth muscle layers. bladder is an elastic organ and it obeys the laplace’s law. according to this law in physics, when the bladder extends and dilates by urine, its diameter increases. thus, its intramural pressure does not increase. pierre simon marquis de laplace (1779 to 1827) has been called the “newton of france.” laplace made the statement that the tension in the wall of a container necessary to contain a given pressure is directly proportional to the radius of the curvature at any point.(13) laplace’s equation means that there is direct relationship between wall tension and interavesical pressure and bladder size. this equation is established between tension (t), intravesical pressure (p), bladder radius (r), and wall thickness (d). during bladder filling p is relatively constant. with a fully distended bladder, d is ignored because of its relative thinness unless a hypertrophied wall exists. thus the equation in the form of t = p × r/2 approximates tension in a normal bladder.(12) discussion 2. urination is done under the control of the brain voluntarily. discussion 3. tendons are made of collagen. excess collagen decreases elasticity of the bladder and increases intravesical pressure. at the time of avicenna, there was no microscope, and thus, differentiation of the connective tissue from smooth muscles was impossible. in the bladder neck, there is a fleshy and sensitive material which is adjacent to the muscles related to the bladder.(9,10) discussion 1. just following the bladder neck and around the prostatic urethra, there is the prostate gland that is mainly a glandular and figure 2. the third book of the canon of medicine in arabic on bladder. adapted from the web site of the saab medical library of the american university of beirut. urology in history 288 urology journal vol 5 no 4 autumn 2008 secretary tissue, and there are some connective and muscular tissue too. the prostate, prostatic urethra, and bladder neck are innervated by the autonomic nervous system. discussion 2. according to avicenna’s following description of the external urethral sphincter, we understand that the fleshy and sensitive material is the prostate gland which is adjacent to the bladder-related muscles. the bladder has 2 layers: the internal and external layers. the internal layer is undercoat of the bladder and its power and firmness is twice as much as the external layer, because the internal layer has to be in touch with the astringent urine.(9,10) discussion 1. the bladder has 3 layers: the first layer is the urothelium, which is in contact with the urine. this layer, because of tight junctions between its adjacent apical cells, is impermeable to water. the middle layer is muscular and the external layer is adventitia. discussion 2. the second and third layers of bladder have been discussed as one layer by avicenna in the canon. at that time, there was no progression in the facilities for histological examination methods. the god on high, because of his grace and wisdom, has decided that the removable liquid (urine) pours into the bladder and then be expelled out. for this purpose, 2 water-transporting tubes or ureters [halebain in arabic] descend from the kidneys to the bladder. when the ureters reach the bladder, the bladder opens its two layers and includes the ureters in it. first, these tubes pass the hiatus of the first layer, and then, they pass between the two layers at the necessary distance. then, they perforate the lining undercoat layer and reach the depth and the cavity of the bladder. removable and useless liquid (urine) pours into the bladder until the bladder become full. the internal layer adheres to the external layer and these two layers are in contact together as if they are united originally and there is no pore and passage between them. because of this unity and adherence, the retained urine in the bladder has no retrograde pathway to the ureters or antergrade pathway to the urethra.(9,10) discussion 1. two ureters laterally descend from the kidneys towards the bladder, and then, the urine produced in the kidneys pours into the bladder, being ready to be expelled during urination through the urethra. anatomically, the ureteral pathway in the bladder wall is very interesting. the ureters first pass through the ureteral hiatus, and then, the seromusculer layers of the bladder (external and middle layers). after reaching the suburothelium, they traverse about 1 cm in the submucosa. ureteral submucosal pathway and its opening to the bladder are important in prevention of urinary reflux from the bladder to the ureters and kidneys known as antireflux mechanism. when the bladder becomes full of urine intravesical pressure increases. this pressure increase shifts to the submucosal pathway of the ureters and causes closure of the submucosal ureters. any abnormalities in this mechanism cause vesicouretreal reflux. discussion 2. antireflux mechanism of ureterovesical junction that avicenna accurately discusses in the canon is one of the most important and interesting items in bladder physiology and pothophysiology, and a large chapter in urological textbooks is about its abnormalities. ten centuries ago, avicenna who was not armored with microscope or voiding cystourethrograply, pointed to the antireflux mechanism. astonishingly, he was the first to become familiar with this mechanism with anatomic details. the god on high his power, has made a gulletlike organ [angha in arabic] to eliminate the removable liquids (urine) through the penile urethra. thus, this organ that is similar to water pipe [tanbousheh in persian] is continuous from the bladder to the penile urethra toward out and it has multiple curvatures. the philosophy of creation of these curvatures is that the liquid material would not be expelled out suddenly and totally. these curvatures in the male’s urethra are more than those in the female’s. there are 3 curvatures in males and only 1 in females, because the female’s bladder is very near to the uterus.(9,10) discussion 1. male urethra has 5 parts: prostatic urethra, membranous urethra, bulbar urethra, urology in history urology journal vol 5 no 4 autumn 2008 289 penile urethra, and glandular urethra. there are 35-degree curvatures between the beginning and the end of the prostatic urethra and the anterior concavity between the membranous and bulbar parts of the urethra, and also the anterior concavity between the bulbar and penile urethra. male urethra is long and meandering, and its length is 25 cm. female urethra is only 4 cm and has only 1 angle in the bladder neck that is very important in competency against urinary incontinence during crying sneezing, coughing, and laughing. discussion 2. this should be taken into consideration that avicenna describes the urethral anatomy carefully and according to the modern urologic descriptions. there is a gullet-like organ which is encircled at its origin in the proximal part by a muscle, the function of which is to compress and obstruct the urethra, so that urine is not expelled out without the human being’s willing. when human being intends to urinate, this guarding and obstructing muscle becomes loose. this gate-keeping muscle is helped by abdominal muscles. this work is done very regularly unless this gate keeper and water distributor muscle [mirab in persian] or its helper muscles are traumatized.(9,10) discussion 1. around the proximal urethra (membranous urethra), 1.5 cm from its beginning, there is a striated muscle (voluntary sphincter) that is voluntarily, which is innervated by the pudendal nerves. in the filling phase of the bladder function, when the human being does not intend to urinate, there is a guarding reflex that causes compression of this sphincter against urinary incontinence. sphincteric compression increases when the bladder volume increases by urinary filling. vice versa, this sphincter relaxes under the human being’s control during voiding, so that urine is expelled out. this striated sphincter is supported by the pelvic floor muscles. an impaired striated sphincter or pelvic floor muscle can lead to urinary incontinence. discussion 2. avicenna’s accurately description of the voluntary striated sphincter of the urethra accords with modern urologic findings. book iii, part 19, treatise 1, chapter 2 the second chapter of part 19, book iii is on the diseases of the urinary bladder. in this chapter, classification of bladder disorders is stated as below(9,10): (1) diseases due to bladder inflammation; (2) diseases due to bladder outlet obstruction, which includes bladder calculi; (3) diseases due to bladder volume abnormalities, in which the bladder is smaller or larger than normal; (4) local diseases, such as lumpy lesions and descent of the bladder; (5) disorders due to ulceration or rupture of the bladder, bladder splitting, etc; (6) bladder disorders which are due to nervous system disorders; and (7) disorders due to temperamental changes. in avicenna’s opinion, bladder disorders usually happen in cold weather, in wind-blowing seasons, in northern areas, and in cold seasons of the year. for the 6th item of the above, he explains “occasionally there is headache and vertigo along with bladder disorders, and sometime delirium or liver disease develop in bladder diseases. often, dropsy or thirstiness [estesgha in arabic] is associated with some bladder disorders.(9,10)” discussion 1. current bladder disease classification is almost similar to the canon’s classification(4): (1) bladder inflammatory disorders (cystitis) that include specific infections (eg, tuberculosis), nonspecific cystitis (bacterial and viral), interstitial cystitis (including hunner’s ulcer), and acute urethral syndrome; (2) bladder neck and infravesical obstructions that affect the bladder (including bladder calculi); (3) congenital bladder disorders, including congenital megacystis, congenital bladder hypoplasia, and epispadias-extrophy complex; urology in history 290 urology journal vol 5 no 4 autumn 2008 (4) bladder tumors, bladder diverticulum, pelvic floor laxity (including cystocele); (5) bladder trauma; and (6) neurogenic bladder due to central and peripheral nervous system diseases, neurological symptoms such as delirium in urosepsis, metastases of bladder tumor to the brain (rare); and neurological impairment of the bladder due to systemic disorders such as diabetes mellitus. discussion 2. please pay attention to the similarities of these two classifications! avicenna has knowledge on most disorders of the bladder except that there is no place in modern medicine for the 7th item he mentions in his article (temperamental changes). even he points out to bladder tumors in item 4 as “lumpy lesions” and in item 5 as “bladder ulcers.” book iii, part 19, treatise 1, chapter 5 chapter 3 (on what “warms up” the bladder) and chapter 4 (on what “cools off” the bladder) are about bladder temperamental alterations which are beyond the scope of this comparative study. chapter 5 is on urinary bladder calculi. below are some extracts of this chapter: bladder calculi are larger and harder than kidney calculi. their color is yellow to black, and occasionally, grayish to whitish. sometimes there are multiple smaller pieces in the bladder. bladder calculi are usually diagnosed after passage through the urethra. these calculi usually occur in thin persons, while kidney calculi mostly develop in obese people. children, adolescents, and young people usually have bladder rather than kidney calculi.(9,10) discussion 1. the epidemiology of bladder calculi stated in the canon is approximately similar to recent findings in modern urology.(14) in summary, in underdeveloped and developing countries and in poor and malnourished patients, bladder calculi are more prevalent, and in developed countries and wealthy people, the prevalence of bladder calculi decreases, while the prevalence of kidney calculi increases. bladder calculi are more prevalent in children that sometimes can be attributed to childhood malnutrition. probably, phosphate deficiency in children’s diet is related to bladder calculus formation. the most common causes of bladder calculi in children are metabolic disorders. discussion 2. it should be noted that the epidemiology of bladder calculi avicenna describes accurately accords to the findings of modern urology. however, at the time of avicenna, there were no radiological or ultrasonographic sources; thus, as he has stated, they could diagnose bladder calculi after their passage. in addition, a large percentage of bladder calculi are radiolucent (uric acid) and even today, they do not expose themselves in plain radiography, and we need ultrasonography or cystoscopy for definite diagnosis.(15) discussion 3. we read in one of the urology text books that “a solitary bladder stone is the rule but there are numerous stones in 25% of patients” which accords to the canon.(15) the urine of the patient with bladder calculus is totally whitish or grayish.(9,10) discussion . sometimes phosphaturia is seen in patients with bladder calculi, especially in those with alkaline urine. in this situation, the appearance of urine is turbid, and small granules in urine and some crystals are seen in the urinary sediment. occasionally, bladder calculi are associated with severe urinary tract infection, especially in obstructive uropathy in which sometimes urine is completely purulent and white. a bladder calculus causes pain that is not more severe than the pain due to kidney calculi, because bladder calculi are located in a hollow organ. but, if a bladder calculus obstructs the outflow of urine, its discomfort will be greater and its pain will be more severe than the pain due to kidney calculi. also, if the bladder calculus passes through the urethra, its pain is severe. bladder calculi are more likely than kidney calculi to become coarse, because bladder calculi are formed in a hollow space and it is more possible that the coarsening substance contact it. a bladder calculus is usually larger than a kidney calculus because its space is larger. sometimes, there are 2 or more calculi urology in history urology journal vol 5 no 4 autumn 2008 291 in the bladder or the calculi can scratch each other and as a result, multiple small fragments appear in urine. sometimes there is bran-like dross associated with sandy substances. in this condition, bladder undercoat might be scratched and desquamated because of the calculus. discussion 1. very large bladder calculi have been described for example, a giant bladder calculus reported in a 37-year-old woman and 2 large calculi in a 26-year-old man were reported.(16,17) also, we removed a 7-cm calculus (about 700 g) from the bladder of a 56-year-old man with benign prostatic hyperplasia (figure 3; unpublished). the “bran-like dross” explained by avicenna can be the matrix calculi that must be differentiated macroscopically from purulent material due to secondary infection, and also must be differentiated from desquamated material in bladder cancers associated with chronic infection and bladder calculi due to irritation of bladder mucosa. cloudy sandy urine produced by children in endemic areas indicates the early stages of calculus formation. girls are able to pass most of the debris through their urethra, but boys may retain these potential nidi. you notice that the similarities between debris in modern text books and bran-like dross in the canon. pain and discomfort caused by bladder calculi are less severe than renal colic or severe pain due to kidney or urethral calculi. if the calculus obstructs the bladder neck or urethra, it causes urinary retention and its pain is more severe. bladder calculi in long-term can cause obstruction, urinary tract infection, bladder mucosal irritation, squamous metaplasia of the urothelium, and even bladder cancer, especially in association with chronic irritation and infection. discussion 2. direct or indirect indication of almost all complications of bladder calculi is an amazing point in the canon. in the presence of bladder calculi, there is pain in the penile urethra in sympathy with the pain in the vesical area (suprapubic), and also itching and pain is present in the penile urethra, penile base, and suprapubic area. the patient, especially the child, who has a bladder calculus, may play with his penis. itching and pain at the penile urethra due to bladder calculus is continuous and it diffuses repeatedly and refers to the anal area. the anus may protrude outside, urine may be obstructed, and difficult urination may be a symptom. the patient has straining in urination in which the urine can pass through the obstructed urethra. the patient may have urinary retention and may pass urine with difficulty. in most cases of bladder calculus, there is bloody urine because of scratching the vesical undercoat, especially if the calculus is large and coarse. discussion. because of common innervations of the bladder, scrotum, penis, and especially glans penis (s2-s3), bladder calculi causes suprapubic pain which is referred to the penile urethra, scrotum, and penile base. bladder calculi, especially in children, are one of the causes of priapism.(18) hematuria, overflow incontinence, and frequency are the symptoms of bladder calculi. anal diseases such as hemorrhoid and anal prolapse can induce lower urinary tract symptoms. also, benign prostatic hyperplasia that is sometimes associated with bladder calculus can induce or aggravate the symptoms of anal disorders because of straining in urination. it is notable how the avicenna’s description of the symptoms of bladder calculi is compatible with modern urology’s description. sometimes, urinary retention occurs. in this condition, if the patient lies down in supine figure 3. a 7-cm calculus (about 700 g) from the bladder of a 56-year-old man with benign prostatic hyperplasia (operated by the author; unpublished). urology in history 292 urology journal vol 5 no 4 autumn 2008 position with both buttocks elevated and shook, the calculus can move away from the obstructed pathway and urine finds its route out. in this position, if the pressure is applied to the suprapubic area, the patient can urinate and this is the true evidence of bladder calculus. in the treatment of urinary retention, there is a method other than elevation of the buttocks. in this method, the patient takes the knee-chest position and squeezes his or her whole body or by entering the finger into the rectum, the calculus can be moved away from the urinary pathway. you can test these methods and succeed. in difficult cases, there is no other method than inserting a catheter [gasathir in arabic] into the penile urethra. you must not insert it forcefully. you can move the calculus away from the urethral lumen by this method. if the calculus obstructs the urinary lumen, the catheter can reach it and you can feel the contact of the catheter to a solid thing. this contact is a reason itself for the presence of the calculus. the head of the catheter can move it away and can open the pathway for urinary flow. sometimes, the calculus substance can be extracted by the catheter and you can recognize the original composition of the calculus by its examination. small calculi obstruct the urinary system more than larger ones because small calculi can access the urethral lumen, but the larger ones only obstruct the bladder neck and can be easily deviated away from lumen. discussion 1. after extracorporeal shock wave lithotripsy of the lower caliceal calculi, there is a method named inversion therapy, in which the head of the patient is downward and buttocks elevated; thus, the fragmented calculi can pass through the ureter. this method is very similar to the abovementioned method in the canon for bladder calculi. of course, avicenna stated that this method is for the relief of urinary retention caused by bladder calculi. discussion 2. putting pressure on the suprapubic area as stated by avicenna is indeed the crede maneuver that can be used for the relief of urinary retention due to neurogenic bladder, which is frequently associated with bladder calculi and is a familiar method for every urologist. discussion 3. digital rectal examination with mild pressure together with insertion of metallic bougies or catheter with good urethral lubrication can be used for bypassing or retrograde pushup of urethral calculi to relieve urinary retention before the definite treatment. interestingly, avicenna has pointed to all of these methods. discussion 4. grating sign due to contact of the head of metallic bougies with the calculus is a famous sign in urology which has been described by avicenna centuries ago. discussion 5. we can diagnose the type of the calculus by urinary examination or examination of the stony substances passed through the urethra. discussion 6. avicenna’s direct pointing to inversion therapy, crede maneuver, manipulation of calculi by catheterization and retrograde pushing up, grating sign, and determination of the calculus composition by urinary examination 1000 years age is really amazing. conclusion scientific methodology of avicenna’s canon of medicine and its comparison with modern urologic articles indicate that avicenna’s method in diagnosis and treatment of patients is really experimental and away from superstitious beliefs of his time. there is no place for nonscientific, ignorant, or foolish methods in avicenna’s approach to the diseases. acknowledgement i would like to express my gratitude to the great professor nasser simforoosh and professor abbas basiri whose guides and helps opened the closed doors for me in this difficult way of exploring historical views of medicine. i also would like to thank dr hossein hamati and mr mohammad hossein safakhah for providing me with the references in this field. references 1. sarton g. introduction to the history of science. malabar: krieger pub co; 1975. p. 710. urology in history urology journal vol 5 no 4 autumn 2008 293 2. ronan ca. the cambridge illustrated history of world’s science. cambridge: cambridge university press; 1984. p. 427. 3. osler w. the evolution of modern medicine. connecticut: yale university press; 1921. p. 98. 4. wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. 5. ibn sina. al-qanun fi al-tibb. rome: typgraphia mediciea; 1593. p. 68-74. 6. avicenna. the canon of medicine [translated into english by bakhtiar l]. chicago: kazi publications; 1999. 7. hunk s. islamic culture in europe [translated into persian by rohbani m]. tehran: islamic culture publication office; 1982. p. 41. 8. popper kr. conjectures and refutations: the growth of scientific knowledge. 5th ed. london: routledge & kegan paul; 1989. 9. ibn sina. al-qanun fi al-tibb. rome: typgraphia mediciea; 1593. 10. abu ali sina. qanun [translated in persian by sharafkandi ar]. tehran: soroush; 2004. 11. madineh sma. avicenna’s canon of medicine and modern urology. part i: bladder and its diseases. iran j urol. 1995;2:3-13. 12. yoshimora n, chancellor mb. physiology and pharmacology of the bladder and urethra. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1922-70. 13. chancellor mb, rivas da, bourgeois im. laplace’s law and the risks and prevention of bladder rupture after enterocystoplasty and bladder autoaugmentation. neurourol urodyn. 1996;15:223-33. 14. khai-linh v ho, segura jw. lower urinary tract calculi. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2663. 15. stoller ml. urinary stone disease. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 16th ed. 2004. p. 284. 16. fisher m, venkatesan k, grigorian c, cher ml. giant bladder calculus. appl radiol. 2006;35:324. 17. daneshbod y. images in clinical medicine. asymptomatic bladder stones. n engl j med. 2007;357:e7. 18. pautler se, brock gb. priapism. from priapus to the present time. urol clin north am. 2001;28:391-403. urological oncology oncological and functional outcomes of laparoscopic radiofrequency ablation and partial nephrectomy for t1a renal masses: a retrospective single-center 60 month follow-up cohort study jong mok park1, seung woo yang1, ju hyun shin1, yong gil na1, ki hak song1, jae sung lim1* purpose: it remains unclear whether laparoscopic radiofrequency ablation (rfa) for primary treatment of small renal masses is similar to partial nephrectomy (pn) in terms of long-term oncological and renal function outcomes. we reviewed the long-term outcomes for patients with t1a renal masses treated with either laparoscopic rfa or pn. materials and methods: this retrospective single-center study on 115 patients who were treated by laparoscopic rfa or pn for small (<4 cm) renal masses between january 2005 and october 2014 at chungnam national university hospital. estimated glomerular filtration rate (egfr) was measured before and 1–2 weeks after surgery and at last follow-up. the laparoscopic rfa and pn groups were compared in terms of clinical characteristics data and change in egfr after surgery using the chi-squared test or student’s t-test. survival data were analyzed using the kaplan-meier method and the log-rank test. results: of the 115 patients, 62 and 53 underwent laparoscopic rfa and pn, respectively. their mean (range) follow-up duration was 60 (30–104) and 68 (30–149) months, respectively (p = 0.092). the rfa patients were older (p = 0.023) and had smaller tumors (p = 0.000). rfa associated with shorter operation and hospitalization times and less perioperative blood loss (all p<0.001). the groups did not differ in terms of change in egfr 1–2 weeks after surgery (p = 0.252) or at the last follow-up (p = 0.395) or 5 year survival rates (p = 0.360). conclusion: laparoscopic rfa for small renal masses was comparable to pn in terms of oncological and functional outcomes and associated with shorter operative and hospitalization times and less perioperative bleeding. keywords: kidney neoplasms; partial nephrectomy; radiofrequency ablation introduction in recent years, the widespread use of contrast-en-hanced computed tomography (ct) and magnetic resonance imaging (mri) has greatly increased the detection of small renal masses (srms)(1). this change has also associated with significant changes in the management of patients with srms in the past decade. in particular, srms are now routinely treated with partial nephrectomy (pn) rather than radical nephrectomy. this change arose after multiple studies showed that radical nephrectomy associates with higher risks of chronic renal failure, mortality, and hospitalization compared with pn(2–4). another recent change in srm treatment is the increasing use of radiofrequency ablation (rfa), which can be applied via the open, percutaneous, or laparoscopic approaches. this relatively new technique has a significant advantage over pn, namely, it is better at preserving renal function. as a result, the 2009 american urological association (aua) guidelines state that rfa is an optional treatment for srms, particularly for patients who have a high operative risk(5). however, there is some evidence, albeit limited, that suggests that rfa is safe and effective enough to serve as a standard treatment for srms. in particular, two retrospective studies show that, for ct1a renal masses, rfa is similar 1department of urology, school of medicine, chungnam national university hospital, daejeon, 35015, republic of korea. *correspondence: department of urology, school of medicine, chungnam national university hospital, daejeon, republic of korea. tel: +82 42 2807779. fax: +82 42 2807206. e-mail: uro1217@gmail.com. received september 2017 & accepted may 2018 to pn in terms of diseaseand cancer-specific survival rates and local control(6,7). further research comparing the long follow-up efficacy and safety of laparoscopic rfa and pn for srms is very few. to address this, we conducted a retrospective single-center long follow-up cohort study that directly compared the oncological and renal function outcomes of laparoscopic rfa and pn for ct1a renal masses. patients and methods patients after institutional review board approval, the cohort consisted of all consecutive patients with ct1a renal masses who underwent laparoscopic rfa or pn between january 2005 and october 2014. of the 128 patients, 13 (10%) patients with benign tumors were excluded. all surgeries were performed by a single surgeon. patients were included if they had undergone a renal mass biopsy, had histologically confirmed renal cell carcinoma, had a small (< 4 cm) solitary tumor, and were followed up for at least 2 years after surgery by contrast imaging studies. patients with bilateral renal tumors, metastasis at presentation, or hereditary renal tumor were excluded. all patients underwent pre-treatment abdominal ct or mri and chest radiography. urological oncology 44 vol 16 no 01 january-february 2019 45 surgical techniques rfa was performed with the laparoscopic approach only. pn was performed via open surgery only. the indication for operation was the presence of an enhancing renal mass on ct or mri. the choice of surgical method and the approach that was used were based on the location, size, and proximity of the tumor to adjacent organs and patient characteristics such as age and performance status. the surgical techniques that we used for laparoscopic rfa have been described previously(8). thus, a trans-peritoneal or retroperitoneal approach was employed. in particular, when the renal tumor was located in the posterior aspect of the kidney, the retroperitoneal approach was preferred. renal tumors were identified after removing the perirenal fat and exposing the kidney surface. laparoscopic ultrasound was performed to identify the endophytic mass and to guide the placement of the rfa needle tip. the maximal ablation time per cycle was 12 minutes. the number of cycles that were applied depended on the size of the tumor and ranged from one to four cycles. generally, tumors that were <2, 2–3, and >3 cm in diameter were treated with 1–2, 1–4, and 2–4 12 minute cycles, respectively. when more than one cycle was used, the different cycles directed the current at different portions of the tumor. a biopsy was obtained immediately before rfa in all cases. open pn was performed using a retroperitoneal approach via a flank or subcostal incision. after exposing the renal tumor and mobilizing the renal hilum, the hilum was cross-clamped and the masses were excised with a safety margin. the renal defect was then repaired. follow-up all patients were discharged when the drain tube was removed and home life was possible. the patients were followed up by periodic physical examinations, chest x-rays, measurement of serum creatinine levels, and ct or mri. ct/mri follow-up initially involved scans 1, 3, 6, 12, 18, and 24 months after surgery; thereafter, those were performed every 12 months. the follow-up scan that was performed 1 month after surgery was performed to determine whether residual tumor or enhancing lesions were present after surgery. recurrence was defined as the detection of a new enhancing lesion or enlargement of the ablation defect after the 1 month follow-up visit. residual tumors 1 month after surgery were included in the study, but no recurrences were detected in the 1 month follow-up scan. there was no patient lost to follow-up. statistical techniques the rfa and pn groups were compared in terms of clinical characteristics data using the chi-squared test or student’s t-test, as appropriate. the rfa and pn groups were compared in terms of survival using the kaplan-meier method and the log-rank test. a p value less than 0.05 was considered to indicate a statistically significant difference between the groups. all statistical analyses were performed using ibm spss statistics ver. 20.0 (ibm co., armonk, ny, usa). results preoperative characteristics of the patients during the ~9 year study period, 115 patients with t1a renal tumors underwent laparoscopic rfa (n = 62) or pn (n = 53). their clinical and functional features are summarized in table 1. the rfa patients were significantly older at treatment (58 years) than the pn patients (53 years, p = 0.023), but the two groups did not differ in terms of gender (p = 0.725), body mass index (p = 0.053), diabetes (p = 0.309), hypertension (p = 0.076), american society of anesthesiologists score (p = 0.081), preoperative estimated glomerular filtration rate (egfr) (p = 0.499), or chronic kidney disease (ckd) stage (p = 0.957). tumor characteristics the tumor characteristics of the rfa and pn patients are shown in table 2. the rfa patients had significantly smaller tumors (mean size, 2.14 cm) than the pn group (2.75 cm, p = 0.00). however, the two groups did not differ significantly in terms of frequency of the table 1. preoperative characteristics of the patients undergoing laparoscopic radiofrequency ablation or open partial nephrectomy variable rfa pn p valuea n=62 n=53 no. (%) male 45 (72.5) 40 (75.5) 0.725 no. (%) female 17 (26.5) 13 (24.5) mean age (range) 58 y (32–84) 53 y (17–77) 0.023 mean bmi (range), kg/m2 26 (19–32.6) 24.9 (17.9–31.6) 0.053 no. (%) with diabetes 14 (22.2) 8 (15.1) 0.309 no. (%) with hypertension 30 (48.4) 17 (32.1) 0.076 no. (%) with asa score: 0.081 1 20 (32.3) 26 (49.1) 2 32 (51.6) 24 (45.3) 3 10 (16.1) 3 (0.06) mean preoperative 94.2 (35.82–193) 97.5 (30.2–155) 0.499 egfr (range), ml/min no. patients with ckd stage: 0.957 1 (egfr > 90 ml/min) 35 31 2 (egfr 90–60 ml/min) 22 17 3 (egfr 60–30 ml/min) 5 5 4 (egfr 30–15 ml/min) 0 0 5 (egfr <15 ml/min) 0 0 a the rfa and pn groups were compared using student’s t-test or chi-squared test, as appropriate. asa=american society of anesthesiologists; bmi=body mass index; ckd=chronic kidney disease; egfr= estimated glomerular filtration rate; rfa=radiofrequency ablation; pn=partial nephrectomy; preop=preoperative. laparoscopic rfa versus partial nephrectomy for t1a renal masses-park et al. tumor on the right or left side (p = 0.360), tumor pole location (p = 0.153), tumor depth (p = 0.274), or histological subtype (p = 0.294). one month after surgery, remnant tumor or recurrence was not detected in any of the patients. perioperative and postoperative characteristics the perioperative and postoperative outcomes of rfa and pn are shown in table 3. the rfa and pn groups were followed up for similar average durations (60 vs. 68 months, p = 0.092). on average, laparoscopic rfa took only 110 minutes as compared with 173 minutes for pn (p < 0.001). rfa also associated with a significantly shorter hospital stay (8, range 5–19, days) than pn (13, range 9–28, days, p < 0.001). moreover, rfa associated with a lower mean preoperative to nadir change in hematocrit (4.5, range -0.2–12.8) than pn (8.9, -2–23.3, p < 0.001). of 115 patients undergoing rfa or pn, 3 (2.6%) patients had major complications. one patient who underwent pn was recovered after coil embolization due to pseudoaneurysm with bleeding of renal artery after surgery. two of the patients who underwent rfa had ckd aggravation and ureteral stricture, respectively. the case with ureteral stricture was the third laparoscopic rfa in our center and then nephrectomy was performed due to renal shrinkage at 3 months later. table 4 reports the number of ablation cycles used per patient in the laparoscopic rfa group. the number of ablation cycles that were applied depended on the size of the tumor, the laparoscopic ultra-sonographic findings, and the judgement of the surgeon. the 23 tumors that were less than 2 cm in diameter were treated with one cycle in 14 patients (61%) and two cycles in nine patients (39%). the 29 tumors that were 2–3 cm in diameter were treated with one cycle in three patients (10.4%), two cycles in 18 patients (62.1%), three cycles in seven patients (24.1%), and four cycles in one patient (3.4%). of the 10 patients with tumors that were 3–4 table 2. tumor characteristics variable rfa pn p valuea n=62 n=53 mean (range) tumor size, cm 2.14 (0.8–3.6) 2.75 (1.3–4) 0.00 no. (%) on the right side 38 (61.3) 28 (52.8) 0.360 no. (%) on the left side 24 (38.7) 23 (47.2) pole location 0.153 no. (%) on upper pole 10 (16.1) 16 (30.2) no. (%) on middle pole 23 (37.1) 17 (32.1) no. (%) on lower pole 29 (46.8) 20 (37.7) tumor depth 0.274 no. (%) exophytic 16 (25.8) 12 (22.7) no. (%) mesophytic 38 (61.3) 28 (52.8) no. (%) endophytic 8 (12.9) 13 (24.5) histological subtype 0.294 no. (%) clear cell 49 (78.9) 37 (69.8) no. (%) papillary 3 (4.8) 5 (9.4) no. (%) chromophobe 6 (9.7) 8 (15.1) no. (%) oncocytoma 2 (3.3) 0 (0) no. (%) cystic renal cell 0 (0) 2 (3.8) no. (%) unclassified 2 (3.3) 1 (1.9) no. surgical failures incomplete 0 0 recurrence 0 0 a the rfa and pn groups were compared using student’s t-test or chi-squared test, as appropriate. pn = partial nephrectomy; rfa = radiofrequency ablation. a all data are shown as mean (range). b the rfa and pn groups were compared using student’s t-test or chi-squared test, as appropriate. c mean change relative to the egfr before surgery. egfr = estimated glomerular filtration rate; fu, follow-up; hct = hematocrit; preop=preoperative; pn = partial nephrectomy; rfa=laparoscopic radiofrequency ablation. variablea rfa pn p valueb n=62 n=53 operation time, min 110 (40–240) 173 (80–300) 0.00 hospital stay, days 8 (5–19) 13 (9–28) 0.00 change in preop to nadir hct 4.5 (-0.2–12.8) 8.9 (-0.2–23.3) 0.00 follow-up, months 60 (30–104) 68 (30–149) 0.092 preop egfr, ml/min 94.2 (30.2–155) 97.5 (35.8–193) 0.499 egfr at 1–2 wks fu, ml/min 96 (23.8–142) 95.2 (48–208) 0.867 egfr at last fu, ml/min 84.3 (18.4–138) 91 (41.9–133.7) 0.092 change in egfrc, ml/min follow-up at 1–2 weeks -1.81 (-41.2–34.2) 2.3 (-45.09–63.7) 0.252 at last follow-up (range) 9.85 (-26.7–47.9) 6.53 (-62.8–90.3) 0.395 table 3. perioperative and postoperative characteristics laparoscopic rfa versus partial nephrectomy for t1a renal masses-park et al. urological oncology 46 vol 16 no 01 january-february 2019 47 cm in diameter, one (10%) underwent two cycles, four (40%) underwent three cycles, and five (50%) underwent four cycles. changes in renal function the renal function of the rfa and pn groups after surgery is summarized in table 3. the rfa and pn groups had similar mean preoperative egfr values (94.2 vs. 97.5 ml/min, p = 0.499). they also had similar mean egfr values 1–2 weeks after surgery (96.2 vs. 95.2 ml/min, p = 0.867) and at the last follow-up visit (84.3 vs. 91 ml/min, p = 0.092). moreover, the rfa and pn patients did not differ in terms of the change in mean egfr (relative to preoperative values) 1–2 weeks after surgery (-1.81 vs. 2.3, p = 0.252) or at the last follow-up (9.85 vs. 6.53, p = 0.395). oncological outcomes the oncological outcomes of the rfa and pn groups during follow-up (starting 1 month after surgery) are shown in table 5. none of the patients had residual disease (i.e., an enhancing lesion at the original site of the tumor) or developed local recurrence or new metachronous tumors. moreover, none died from the disease. thus, the 5 year recurrence-free, metastasis-free, cancer-specific, and disease-specific survival rates of the rfa and pn groups were all 100%. during follow-up, two of the 62 patients in the rfa group died. one developed ckd progression and pneumonia 44 months after the initial rfa. however, the egfr of the patient was 30.2 ml/min, representing a drop in renal function, the other patient died of hepatocellular carcinoma 73 months after the initial rfa. thus, the 5 year overall survival rates of the laparoscopic rfa and pn groups were 98.4% and 100%, respectively (p = 0.360). long-term outcomes of patient with a follow-up period of more than 5 years of the 115 patients, 61 (53%) patients were followed-up for more than 5 years. the number of rfa and pn patients was 30 and 31, respectively. the rfa and pn subgroups were followed up for similar average durations (77.5 vs. 86.6 months, p = 0.084). the long-term outcomes of rfa and pn subgroups after surgery are shown in table 6. the rfa and pn subgroups did not differ in term of the change in mean egfr 1-2 weeks after surgery (1.9 vs 2.9, p = 0.825) or at the last follow-up (12.0 vs. 4.1, p = 0.201). in addition, no local recurrence or new metachronous tumor were seen in patients who underwent rfa and pn during follow-up for more than 5 years. thus, the 5 year recurrence-free, metastasis-free, cancer-specific, disease-specific, and overall survival rates of the rfa and pn groups were all 100%. discussion pn is currently the treatment of choice for ct1 renal masses, and rfa is considered to be an optional treatment for patients with high operative risk(5,9). this preference for pn is likely to reflect the relative lack of data showing the long-term oncological outcomes of rfa. however, several recent studies showed that rfa and pn for ct1a renal masses have comparable oncological outcomes(6,10). rfa can be performed via the open, percutaneous, and laparoscopic approaches(11). there is little research on rfa with open approach as it is seldom performed. most studies on rfa are on ablation performed via the percutaneous approach(12–14). thus, hegarty et al. showed that percutaneous rfa on 82 renal masses associated with a recurrence-free survival rate of 88.9% after a median follow-up duration of 12 months(12). similarly, zagoria et al. reported that, when 125 patients underwent percutaneous rfa, the recurrence-free survival rate after a mean follow-up duration of 13.8 months was 87%(13). moreover, levinson et al. reported that the recurrence-free survival rate of 31 renal masses was 90.3% after a mean follow-up duration of 61.8 months(14). by contrast, very few studies have assessed the oncological efficacy of rfa via the laparoscopic approach. in 2003, jacomides et al. were the first to document table 4. number of ablation cycles used for different tumor sizes in radiofrequency ablation no. of ablation cyclesa tumor < 2 cm tumor 2–3 cm tumor 3–4 cm n = 23 n = 29 n = 10 one cycle 14 (61) 3 (10.4) 0 two cycles 9 (39) 18 (62.1) 1 (10) three cycles 0 7 (24.1) 4 (40) four cycles 0 1 (3.4) 5 (50) a the data are shown as number (%). pn=partial nephrectomy; rfa=laparoscopic radiofrequency ablation. variable rfa pn p value n=62 n=53 no. with residual disease 0 0 no. with local recurrence 0 0 no. with new metachronous tumor 0 0 no. disease-specific deaths 0 0 no. deaths (overall) 2 0 0.163 5 year recurrence-free survival, % 100 100 5 year metastasis-free survival, % 100 100 5 year cancer-specific survival, % 100 100 5 year disease-free survival, % 100 100 5 year overall survival, % 98.4 100 0.360 table 5. oncological outcomes laparoscopic rfa versus partial nephrectomy for t1a renal masses-park et al. their initial experiences with laparoscopic rfa in 13 patients(15). a few years later, park et al. presented the intermediate follow-up outcomes of laparoscopic rfa in 39 patients. the operative success rate (i.e., full ablation) and the recurrence-free survival rate were 96.4% and 94.5%, respectively(16). finally, ji et al. reported in 2011 that 106 patients who underwent laparoscopic rfa had a local tumor control rate of 98.1% after a maximal follow-up duration of 48 months(10). the laparoscopic approach to rfa has the advantage over the percutaneous approach in that it allows more mobilization of the kidney and the renal tumors and allows observation of the thermal changes in the tumor during rfa: these advantages prevent damage to the muscles and perirenal organs. in addition, the laparoscopic approach allows the surgeon to perform additional cycles of ablation or conduct laparoscopic ultrasonography to determine the condition of the tumor when the surgeon suspects that the ablation is incomplete. this study showed that laparoscopic rfa for renal masses was effective in terms of both oncological and renal function outcomes after a mean follow-up duration of 60 months. first, none of the 62 patients who were treated with laparoscopic rfa and then followed up for at least 30 months exhibited incomplete ablation or local recurrence. second, the cancer-specific and disease-free survival rates of the rfa patients were both 100%, while their 5 year overall survival rate was 98.4% (61/62). these observations matched those made in the pn group. third, laparoscopic rfa and pn did not differ significantly in terms of change in renal function after surgery relative to baseline regardless of whether egfr was tested shortly after surgery or at the last follow-up visit. finally, there was no difference between rfa and pn groups when subgroup analysis was performed on patients with a follow up period of 5 years or more. the current study has several limitations. first, it is a retrospective study and as such may be subject to selection and information bias. second, because rfa equipment can vary widely, the surgical outcomes of our hospital cannot be generalized to those of other centers that perform laparoscopic rfa. finally, the sample size of the study was relatively small, which may have affected our ability to detect significant differences between laparoscopic rna and open pn in terms of oncological and functional outcomes. nevertheless, despite these limitations, this study adds to the limited existing data regarding the long-term effects of laparoscopic rfa for srms. these data suggest that broader use of laparoscopic rfa for srms may be justified. further rct or studies are needed to verify this. conclusions this retrospective long-term single-center cohort study showed that laparoscopic rfa for t1a renal masses had comparable oncological and renal function outcomes to pn. in addition, laparoscopic rfa associated with less perioperative bleeding and shorter operative times and hospital stays than pn. prospective randomized multicenter trials with more patients and long-term follow-up durations that compare laparoscopic rfa and pn in terms of their safety and oncological efficacy in the treatment of t1 renal tumors are warranted. conflict of interest the authors report no conflict of interest. references 1. hock lm, lynch j, balaji kc. increasing incidence of all stages of kidney cancer in the last 2 decades in the united states: an analysis of surveillance, epidemiology and end results program data. j urol. 2002;167:57-60. 2. go as, chertow gm, fan d, mcculloch ce, hsu cy. chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. n engl j med. 2004;351:1296– 305. 3. huang wc, levey as, serio am, et al. chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. lancet oncol. 2006;7:735–40. 4. thompson rh, boorjian sa, lohse cm, et al. radical nephrectomy for pt1a renal masses may be associated with decreased overall survival compared with partial nephrectomy. j urol. 2008;179:468–73. 5. campbell sc, novick ac, belldegrun a, et al. practice guidelines committee of the table 6. long-term outcomes of patients with a follow-up period of more than 5 years variable rfa pn p value number of patient 30 31 follow-up, months 77.5 (62-104) 86.6 (60-149) 0.084 change in egfr, ml/min follow-up at 1–2 weeks 1.9 (-27.6-34.2) 2.9 (-45.1-63.7) 0.825 at last follow-up (range) 12.0 (-26.7-47.9) 4.1 (-62.8-41.9) 0.201 no. with residual disease no. with local recurrence 0 0 no. with new metachronous tumor 0 0 no. disease-specific deaths 0 0 no. deaths (overall) 0 0 5 year recurrence-free survival, % 1 0 0.290 5 year metastasis-free survival, % 100 100 5 year cancer-specific survival, % 100 100 5 year disease-free survival, % 100 100 5 year overall survival, % 100 100 pn=partial nephrectomy; rfa=laparoscopic radiofrequency ablation. laparoscopic rfa versus partial nephrectomy for t1a renal masses-park et al. urological oncology 48 vol 16 no 01 january-february 2019 49 american urological association. guideline for management of the clinical t1 renal mass. j urol. 2009;182:1271–79. 6. olweny eo, park sk, tan yk, best sl, trimmer c, cadeddu ja. radiofrequency ablation versus partial nephrectomy in patients with solitary clinical t1a renal cell carcinoma: comparable oncologic outcomes at a minimum of 5 years of follow-up. eur urol. 2012;61:1156–61. 7. stern jm, svatek r, park s, et al. intermediate comparison of partial nephrectomy and radiofrequency ablation for clinical t1a renal tumours. bju int. 2007;100:287–90. 8. youn cs, park jm, lee jy, et al. comparison of laparoscopic radiofrequency ablation and open partial nephrectomy in patients with a small renal mass. kju. 2013;54:603-8. 9. ljungberg b, cowan nc, hanbury dc, et al. eau guidelines on renal cell carcinoma: the 2010 update. eur urol. 2010;58:398–406. 10. ji c, li x, zhang s, et al. laparoscopic radiofrequency ablation of renal tumors:32month mean follow-up results of 106 patients. j urol. 2011;77:798-802. 11. carraway wa, raman jd, cadeddu ja. current status of renal radiofrequency ablation. curr opin urol. 2009;19:143-7. 12. hegarty nj, gill is, desai mm, remer em, o’malley cm, kaouk jh. probe-ablative nephron-sparing surgery: cryoablation versus radiofrequency ablation. urology. 2006;68(suppl 1):7-13. 13. zagoria rj, traver ma, werle dm, perini m, hayaskka s, clark pe. oncologic efficacy of ct guided percutaneous radiofrequency ablation of renal cell carcinomas. ajr am j roentgenol. 2007;189:429-36. 14. levinson aw, su lm, agarwal d, sroka m, jarrett tw, kavoussi lr. long-term oncological and overall outcomes of percutaneous radio frequency ablation in high risk surgical patients with a solitary small renal mass. j urol. 2008;180:499-504. 15. jacomides l, ogan k, watumall l, cadeddu ja. laparoscopic application of radio frequency energy enables in situ renal tumor ablation and partial nephrectomy. j urol. 2003;169:49-53. 16. park s, anderson jk, matsumoto ed, lotan y, josephs s, cadeddu ja. radiofrequency ablation of renal tumors: intermediate-term results. j endourol. 2006;20:569-73. laparoscopic rfa versus partial nephrectomy for t1a renal masses-park et al. vol 15 no 06 november-december 2018 318 endourology and stone disease comparision of percutaneous nephrolithotomy and retrograde intrarenal surgery for the treatment of multicalyceal and multiple renal stones arif demirbas1*, veli mert yazar1, erim ersoy1, demirhan orsan demir1, serkan ozcan1, tolga karakan1, omer gokhan doluoglu1, berkan resorlu1, ahmet metin hascicek1, kadir omur gunseren2 purpose: comparison of efficiency and reliability of percutaneous nephrolithotomy (pnl) and retrograde intrarenal surgery (rirs) in treatment of multicalyceal and multiple renal stones in the same renal unit. materials and methods: between 2011 and 2015, records of patients who underwent surgery for renal stone were retrospectively reviewed. patients who had multiple stones located in different calices in the same renal unit were included. the patients that underwent pnl and rirs were defined as group i and group ii, respectively. patient criteria (age,sex); the stone characteristics; time of procedure, fluoroscopy and hospitalization; stone-free and complication rates of groups were evaluated between the treatment groups. result: there were no significant differences in terms of age, gender, bmi, laterality, number of stones, number of stone localization, hounsfield units and surface area characteristics of the stone between the pnl (n = 47) and rirs (n = 35) groups (p = .558, p = .278, p = .375, p = 0.051, p = .053, p = .064, p = .642, p = .080, respectively). stone free rate was 59.6% (n=28) in pnl, and 88.6% (n=31) in rirs (p=.004). 1st or 2nd degree complications according to modified clavien classification developed in 10 patients (21.3%) in group i and 1 patient (2.9%) in group ii (p = .015). the 3a or 3b complications were similar in groups (p = .077). time of procedure, fluoroscopy and hospitalization were significantly lower in group ii (p < .001, p < .001 and p < .001, respectively). conclusion: rirs is more effective and more reliable procedure than pnl with higher stone-free and lower complication rates in treatment of multicalyceal and multiple stone in the same renal unit. keywords: multiple renal stones; multicalyceal stones; percutaneous nephrolithotomy; retrograde intrarenal surgery. introduction the technological development of surgical instru-mentation used in treatment of renal stones and research into less invasive and safer techniques are major topics in endourology today(1-3). percutaneous nephrolithotomy (pnl) and retrograde intrarenal surgery (rirs) are the primary technical choices in treatment of moderateto large-sized renal stones that are not compatible with shock wave lithotripsy (swl), and these procedures have been compared in many studies of various conditions(1,4-7). meta-analyses have shown that pnl and rirs methods are effective with high stone-free rate, are safe for medium and large size stones and are alternative procedures to each other(8,9). it has been reported that localization of stones affects the success of the treatment option as much as stone sizes and therefore efficacy and reliability could be changed(10-13). it is known that in cases with multiple stones there is a decrease in stone-free rates after procedures and that treatment of solitary stones is more effective than treatment of multiple stones with similar stone burden in rirs(14,15). although pnl and rirs have been compared with each other in terms of size and localization of stones, 1department of urology, ankara training and research hospital, ankara, turkey. 2department of urology, i̇negöl state hospital, bursa, turkey. *correspondence: ankara training and research hospital, ankara, turkey. phone: +905322500072. e mail: demirbas-arif@hotmail.com. received october 2017 & accepted april 2018 the knowledge relating to multiple stones in the same renal unit is limited. in this study, we aimed to compare efficiency and reliability of rirs and pnl in treatment of multicalyceal and multiple renal stones in the same renal unit. in the current literature, no previous study has examined rirs and pnl for these specific conditions. materials & methods between 2011 and 2015, records of patients who underwent surgery for renal stone were retrospectively reviewed after approval by the local ethics committee. the renal stones were classified by localization as lower pole, middle pole, upper pole and pelvic. patients who had multicalyceal stones (>1 localization) and multiple stones (>1 number of stone) in the same renal unit were included in the present study. patients with congenital renal anomaly, coagulopathy, obesity (bmi > 30 kg/m2), skeletal deformity, previous renal surgery and untreated urinary tract infection were excluded from the present study. patients who were included in the study and underwent pnl were referred to as group i, and underwent rirs were referred to as group ii. for pnl, patients were placed in the prone position. using multidirectional c-arm fluoroscopic guidance (ziehm vision r c-arm, orlando, usa), a calyxial puncture at the appropriate calyx was performed with a 18-gauge skinny needle (cook medical, bloomington, in, usa). a flexible 0.035-inch terumo guidewire (boston scientific corp., miami, fl, usa) was inserted into the ureter or an upper-pole calyx through the renal pelvis. the skin and fascia were incised and a 24 to 30-fr amplatz renal dilatator set (boston scientific corp. usa) was used. a 22-fr nephroscope (olympus, hamburg, germany) and flexible nephroscope (richard wolf, chicago, usa) were inserted inside the sheath and the renal stones were fragmented by pneumatic/ultrasonic lithotripter or holmium:yag laser with a 365µm fiber (lisa laser usa, sphinx family). stone fragments were retrieved using an alligator or 5-fr grasping forceps. after the stone fragments were removed, a percutaneous nephrostomy tube was inserted if necessary. all pnl operations were performed with single access. for rirs, patients were positioned in the dorsal lithotomy position. before rirs, diagnostic rigid ureterorenoscopy (urs) (6.5/8.5 fr) (richard wolf, knittlingen, germany) was done with the same procedure routinely used for passive dilatation. after that a 9.5 or 11.5-fr ureteral access sheath (cook medical) was placed in position. a 7.5-fr flex-x2 flexible ureteroscope (karl storz) was inserted through the access sheath. a 272-µm laser fiber was used for treatment of the stones. holmium laser power was set to 10 w. fragmented stones were not removed with any stone basket. following completion of fragmentation, ureter was visualized all along its length to see any ureteral injury. jj stent was not routinely placed after the procedure, and it was placed if there was mucosal edema, injury or the duration of the procedure was long. the ureteral jj stent was usually removed within 2 to 4 weeks postoperatively. both operation techniques were performed from two different surgeons who had sufficient experience in this regard. the patients’ criteria (age, sex, bmi), the stone characteristics (side and number of stones, number of localizations, hounsfield units, stone surface area), and procedure time, fluoroscopy time, and hospitalization time were evaluated between the treatment groups. stone-free status and complications in the groups were also compared to determine efficiency and reliability of rirs and pnl. low-dose non-contrast computed tomography (ct) and intravenous urography (ivu) were performed before the operation to determine the number, localizations, hounsfield units (hu) and surface area of stones. “stone surface area = length x width x 0.25 x ≤” formula was used to calculate the surface area of stones from ct(1,16). the stone-free status was evaluated one month after pnl or rirs by non-contrast ct. the absence of a stone at any size was considered as the stone-free status. complications were defined and graded according to the modified clavien classification(17). statistical analysis the data analysis was performed by using spss for windows, version 11.5 (spss inc., chicago, il, united states). the normality of the distribution was tested with shapiro-wilk and kolmogorov-smirnov tests. descriptive statistics for variables with a non-normal variables, normal variables and nominal variables were shown as median (min max), mean ± standard deviation and number of cases and (%), respectively. the differences between independent groups regarding continuous variables were evaluated using the mann-whitney u test and student t-test. for categorical comparisons, chi-square or fisher’s exact test were used whenever convenient. p < 0.05 was regarded as statistically significant. results the characteristics of the patients including age, gender, bmi, and the laterality of the stones were similar in group i (n=47), and in group ii (n=35) (p = .558, p = .278, p = .375 p = .051, respectively) (table 1). there were also no differences in number of stone localizations, number of stones and mean hu of stones (p=.064, p=.053, 0.642, respectively) (table 1). mean stone surface area was 345.11 ± 184.85 mm2 in group i and 281.25 ± 141.72 mm2 in group ii. these outcomes were also similar (p = .080) (table 1). of 47 patients who underwent pnl 28 were stone-free and of 35 patients who underwent rirs 31 were stonefree. rirs effectuated higher stone-free rates than pnl (88.6%, 59.6%, respectively) and this difference was table 1. demograhic data and stone characteristics. group i group ii p value patients (n) 47 35 age (years) 47.46 ± 16.4 49.4 ± 13.28 0.558t bmi (kg/m2) 24.4 ± 4.1 23.8 ± 5.0 0.375t male/female 36/11 23/12 0.278t stone laterality right/left 22/25 9/26 0.051t number of stone 3 (2-8) 2 (2-7) 0.053m number of stone localisation 2 (2-4) 2 (2-3) 0.064m stone location pelvis 51 37 upper pole 23 14 middle pole 19 15 lower pole 20 16 mean stone size (mm2) 345.11 ± 184.85 281.25 ± 141.72 0.080t hounsfield units 658.40 ± 184.39 701.76 ± 192.81 0.642t p < 0.05, statistically significant difference. t: t test (mean ± std deviation) m: mann-whitney u test (median, min-max) pnlor rirs for multicalyceal stones-demirbas et al. endourology and stone diseases 319 vol 15 no 06 november-december 2018 320 statistically significant (p = .004). the mean residual stone sizes were also statistically different (p = .012) (table 2). the reason were unaccessible calyx in all patients who had residual stone. when the complications were compared, it was seen that 1st or 2nd degree complications according to modified clavien classification developed in 10 patients (21.3%) in group i and 1 patient (2.9%) in group ii. this was also statistically significant (p = .015) (table 2). complications of 3a or 3b degree developed in 9 patients (19.1%) in group i and 2 patients (5.7%) in group ii (table 2). the difference was similar between groups (p = .077). no 4th and 5th degree complications were seen in any patient (table 2). when the operation data were evaluated, procedure time and fluoroscopy time in group ii were significantly lower (p < .001 and p < .001) (table 2). the median hospitalization time for rirs was 1 (1-7) day, while it was 4 (2-15) days for pnl. this value was statistically significant (p < .001) (table 2). discussion recently minimal invasive techniques have replaced open surgical methods in renal stone treatment; however there is an ongoing discussion in endourology about choice of optimal technique. pnl and rirs are the most important techniques in this field and their success rates have been frequently compared in the literature(1-9). after definition of percutaneous stone extraction(18), the pnl procedure has replaced open surgery in treatment of moderateto large-sized stones and its efficacy has been researched in many studies(19,20). since it was first performed by huffmann et al.(21), rirs has become an important treatment modality for urinary stone disease using flexible devices and holmium laser(22). though pnl technique results in high stone-free rates for moderateto large-sized renal stones, there has been a search for alternative treatment methods due to its morbidity and mortality rates(23,24). increased experience with the rirs technique revealed that it has high stone-free rates even for large-sized stones and lower morbidity rates when compared with pnl(8,9). when two meta-analysis studies comparing pnl and rirs are taken into account, shuba de et al. found that pnl has higher stone-free rates, complication rates and blood loss(9). another meta-analysis published in 2014 proposed rirs as an alternative to pnl since rirs has similar stone-free rates when compared to pnl even for stones larger than 2 cm along with lower complication rates and shorter hospital stay periods(8). when localization of stones is taken into account, lower pole stones result in different stone-free rates and the pnl procedure was found to be more successful than rirs(25,26). a meta-analysis study, published in 2015, reviewed 6 randomized and 8 non-randomized studies comparing pnl, rirs and swl techniques for lower pole stones and found that pnl results in higher stonefree rates when compared to rirs and swl(27). it is known that presence of more than one stone decreases the success rates of treatment in kidney stone disease. cass et al.(28) reviewed 13,864 swl cases and found that the stone-free rate was 69.5-72.1% in single stone cases, whereas it was lower than 50% in multiple stone cases for same renal unit. a study of pediatric cases and swl showed that average stone number of cases was 1.87 for patients with stone-free treatment, whereas it was 2.81 for cases where treatment could not provide stone-free state in the same renal unit and they concluded that stone number influences success of swl(29). meanwhile, ozgor et al.(15) reported that rirs technique resulted in lower stone-free rates in patients with multiple renal stones when compared to patients with solitary renal stone even though both groups have similar stone burden (83.8% and 89.2%, respectively). when pnl is performed for multiple renal stones located in more than one calyx, more than one access may be required and it is known that multiple access may cause serious bleeding complications and loss of kidney function from previous studies(15,30). with regard to previous studies in the literature, we aimed to compare efficiency and reliability of rirs and pnl for treatment of moderateto large-sized multicalyceal and multiple renal stones in the same renal unit. to the best of our knowledge this is the first such study in the literature. postoperative stone-free rate, which is considered as the most important parameter for evaluating efficacy, was 88.6% for rirs and 59.6% for pnl and this difference was statistically significant (p = .004). complications were defined and graded according to the modified clavien classification. we found that grade 1 or 2 complications were encountered more frequently with the pnl technique and this finding was statistically significant; however there was no statistically significant difference between the two techniques with regard to major complications such as grade 3a or 3b (p = .015 and p = .077, respectively). higher complication rates for the pnl technique is compatible with previous studies(8,9). it was noteworthy that stonefree rates for this special patient group, performed pnl, were lower than previous literature data. however, stone-free rate for staghorn and partial staghorn table 2. comparison of operative and postoperative data. group i group ii p value stone free rate (%) 28 (59.6%) 31 (88.6%) 0.004c mean residual stone size (mm2) 120.14 ± 80.34 49.25 ± 40.18 0.012 t complication, clavien i-2 (%) 10 (%21.3) 1 (%2.9) 0.015c complication, clavien 3a-3b (%) 9 (%19.1) 2 (%5.7) 0.077c median fluoroscopy time (s) 150 (55-650) 12 (4-245) < 0.001m mean procedure time (min) 89.76 ± 29.07 62.8 ± 17.57 < 0.001t median hospitalization time (day) 4 (2-15) 1 (1-7) < 0.001m p < 0.05, statistically significant difference. t: t test (mean ± std deviation) m: mann-whitney u test (median, min-max) c: chi square test pnlor rirs for multicalyceal stones-demirbas et al. (located in minimum two calyces) was reported to be 53.9% in a recent study(31). a united kingdom-based prospective study of 1000 renal units reported that stone-free rate was seen to be 68% for pnl(32). despite there seems to be a contradiction between recruitment of flexible devices in our pnl operations and resultant low stone-free rates, we think that was due to degree of flexion of flexible devices moving to another calyx as calyceal access via flexible equipment is more difficult than reaching a calyx with pelvic access. moreover, it is known that a flexible nephroscope has limitations with respect to field of view due to bleeding complications in pnl(33). from this point of view, we think that rirs is more advantageous than pnl. when each group is examined according to data of during operation; rirs was found to be superior to pnl with respect to procedure time, fluoroscopy time and hospitalization time (p < .001, p < .001, p < .001, respectively). these findings were also compatible with the previous literature(9,26). when limitations of our study are considered, first of all it is retrospectively designed. another limitation is that although multicalyceal stones were operated in our study, only one access was used for pnl. however, based on previously reported high complication rates in pnl operations performed with multiple access(15,30), we prefer single access in our department. to the best of our knowledge our study is the first to compare efficacy and reliability of pnl and rirs techniques in this specific patient group that poses difficulties for treatment. conclusions in conclusion, rirs is superior to pnl with respect to both efficacy and reliability for multicalyceal and multiple renal stones in the same renal unit. moreover rirs is advantageous when fluoroscopy time and hospitalization time periods are taken into account. therefore we think that rirs should be the first choice of treatment in this specific patient group when their stone burden is considered. however, in order to support our conclusion, randomized controlled trials and meta-analyses are needed, as the principles of evidence-based medicine necessitate. conflict of interest the authors declare that they have no competing interests. references 1. türk c, knoll t, petrik a, et al. guidelines on urolithiasis. european assocociation of urology, 2015. http://uroweb.org/guideline/ urolithiasis/ 2. matlaga br, lingeman je. surgical management of urinary lithiasis. campbell’s urology. 2012: 1358-1410. 3. wilhelm k, hein s, adams f, et al. ultramini pcnl versus flexible ureteroscopy: a matched analysis of analgesic consumption and treatment-related patient satisfaction in patients with renal stone 10-35 mm. world j urol. 2015 ;33:2131-6. 4. bryniarski p, paradysz a, zyczkowski m, et al. a randomized controlled study to analyze the safety and efficacy of percutaneous nephrolithotripsy and retrograde intrarenal surgery in the management of renal stones more than 2 cm in diameter. j endourol. 2012; 26: 52-7. 5. zengin k, tanik s, karakoyunlu n, et al. retrograde intrarenal surgery versus percutaneous lithotripsy to treat renal stones 2-3 cm in diameter. biomed res int. 2015;2015:914231. 6. atis g, culpan m, pelit es, et al. comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery in treating 2040 mm renal stones. urol j. 2017.16;14:29959. 7. sari s, ozok hu, cakici mc, et al. a comparison of retrograde intrarenal surgery and percutaneous nephrolithotomy for management of renal stones ?2 cm. urol j. 2017 ;14:2949-54. 8. zheng c, xiong b, wang h, et al. retrograde intrarenal surgery versus percutaneous nephrolithotomy for treatment of renal stones >2 cm: a meta-analysis. urol int. 2014;93:41724. 9. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015;67:125-37. 10. bozkurt of, resorlu b, yildiz y, et al. retrograde intrarenal surgery versus percutaneous nephrolithotomy in the management of lower-pole renal stones with a diameter of 15 to 20 mm. j endourol. 2011;25:1131-5. 11. cecen k, karadag ma, demir a, et al. flexible ureterorenoscopy versus extracorporeal shock wave lithotripsy for the treatment of upper/middle calyx kidney stones of 10-20 mm: a retrospective analysis of 174 patients. springerplus. 2014; 3: 557. 12. resorlu b, issi y, onem k, et al. management of lower pole renal stones: the devil is in the details. ann transl med. 2016;4:98. 13. jung gh, jung jh, ahn ts, et al. comparison of retrograde intrarenal surgery versus a single-session percutaneous nephrolithotomy for lower-pole stones with a diameter of 15 to 30 mm: a propensity score-matching study. korean j urol. 2015;56:525-32. 14. grasso m, beaghler m, loisides p. the case for primary endoscopic management of upper urinary tract calculi: ii. cost and outcome assessment of 112 primary ureteral calculi. urology. 1995;45:372-6. 15. ozgor f, kucuktopcu o, ucpinar b, et al. is there a difference between presence of single stone and multiple stones in flexible ureterorenoscopy and laser lithotripsy for renal stone burden <300 mm2? int braz j urol. 2016; 42:xx-xx pnlor rirs for multicalyceal stones-demirbas et al. endourology and stone diseases 321 vol 15 no 06 november-december 2018 322 16. tiselius hg,anderson a. stone burden in an avarage swedish population of stone formers requirng active stone removal:how can the stone size be estimated in the clinical routine? eur urol 2003;3:275-81. 17. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. annsurg 2004; 240: 205-13. 18. fernstrom i, johansson b. percutaneus pyelolithotomy: a new extraction technique. scand j urol nephrol 1976;10:257. 19. quaresima l, conti a, vici a, et al. safety and efficacy of percutaneous nephrolithotomy in the galdakao modified supine valdivia position: a prospective analysis. arch ital urol androl. 2016;88:93-6. 20. pu c, wang j, tang y, et al. the efficacy and safety of percutaneous nephrolithotomy under general versus regional anesthesia: a systematic review and meta-analysis. urolithiasis. 2015;43:455-66. 21. huffman jl, bagley dh, lyon es. extending cystoscopic techniques into the ureter and renal pelvis. experience with ureteroscopy and pyeloscopy. jama 1983;250:2002-5. 22. fuchs gj, fuchs am. flexible endoscopy of the upper urinary tract. a new minimally invasive method for diagnosis and treatment. urologe a 1990;29:313-20. 23. michel ms, trojan l, and rassweiler jj. complications in percutaneous nephrolithotomy. european urology; 51: 899– 906. 24. karakan t, kilinc mf, doluoglu og, yildiz y, yuceturk cn, bagcioglu m, karagöz ma, bas o, resorlu b. the modified ultra-mini percutaneous nephrolithotomy technique and comparison with standard nephrolithotomy: a randomized prospective study. urolithiasis. 2016 may 12. [epub ahead of print] 25. unsal a, resorlu b, kara c, bayindir m. the role of percutaneous nephrolithotomy in the management of medium-sized (1-2 cm) lower-pole renal calculi. acta chir belg. 2011;111:308-11. 26. demirbas a, resorlu b, sunay mm, et al. which should be preferred for moderatesize kidney stones? ultramini percutaneous nephrolithotomy or retrograde intrarenal surgery? j endourol.2016;30:1285-9. 27. zhang w, zhou t, wu t, et al. retrograde intrarenal surgery versus percutaneous nephrolithotomy versus extracorporeal shockwave lithotripsy for treatment of lower pole renal stones: a meta-analysis and systematic review. j endourol. 2015 ;29:745-59. 28. cass as. comparison of first generation (dornier hm3) and second generation (medstone sts) lithotriptors: treatment results with 13,864 renal and ureteral calculi. j urol. 1995;153:588-92. 29. mcadams s, kim n, ravish ir, monga m, ugarte r, nerli r, et al. stone size is only independent predictor of shock wave lithotripsy success in children: a community experience. j urol. 2010;184:659-64. 30. gorbachinsky i, wood k, colaco m, et al. evaluation of renal function after percutaneous nephrolithotomy-does the number of percutaneousaccess tracts matter? j urol. 2016;196:131-6. 31. choi sw, bae wj, ha us, et al. prognostic impact of stone-scoring systems after percutaneous nephrolithotomy for staghorn calculi: a single center's experience over 10 years. j endourol. 2016;30:975-81. 32. armitage jn, irving so, burgess na. british association of urological surgeons section of endourology. percutaneous nephrolithotomy in the united kingdom: results of a prospective data registry. eur urol 2012;61:1188–93. 33. ganpule ap, mishra s, desai mr. multiperc versus single perc with flexible instrumentation for staghorn calculi. j endourol. 2009;23:16758. pnlor rirs for multicalyceal stones-demirbas et al. vol 15 no 03 may-june 2018 9 endourology and stone disease quantitative mineralogical composition of calculi and urine abnormalities for calcium oxalate stone formers: a single-center results andrey v. kustov,1-3 * alexander i. strelnikov,1 purpose: the paper focuses on the relationship of risk factors and metabolic disorders with mineralogical composition of calculi, age and gender of calcium oxalate stone formers. materials and methods: stone mineralogical composition, 24 hour biochemistry and ph-profile of urine were examined for sixty four stone formers using powder x-ray diffraction, spectrophotometric and potentiometric techniques. results: the analysis indicated that 44 % of calculi were composed of pure calcium oxalate monohydrate, whereas other 56 % contained both monohydrate and dihydrate or usually their mixtures with hydroxyl apatite. hypocitraturia, hypercalciuria and hyperuricosuria were identified as the most frequent disorders. patients with pure calcium oxalate stones and calcium oxalate mixed with apatite revealed different patterns including age, acid-base balance of urine, calcium, citrate excretion etc. conclusions: our results demonstrate that most patients simultaneously reveal several risk factors. the special attention should be paid to normalize the daily citrate, calcium and urate excretion. high risk patients, such as postmenopausal females or stone formers with a high apatite content require a specific metabolic evaluation towards in highlighting abnormalities associated with stone formation. keywords: calcium oxalate calculi; quantitative mineralogical analysis; urine components; metabolic disorders; risk factors introduction renal stone formers constitute a major part of every-day patients of urological clinics. urolithiasis is a highly prevalent and increasingly common disease affecting up to 15 % of population, between 60 up to 90 % of calculi being formed of calcium oxalate hydrates (caox) or their mixtures with minor components such as apatities or urates(1-4). caox stones are composed of two major constituents – calcium oxalate monohydrate (com) and calcium oxalate dihydrate (cod) or frequently their mixtures. the analysis of ten thousand patients with caox calculi indicates that com occurs about twice as frequently as cod, most stones being formed by both mineralogical phases. stones containing cod as the major component are correlated with permanent hypercalciuria for about 88 % of patients(5). if the cod content in a mixed com+cod stone becomes more than 15 mass %, it indicates that the stone is originated by both hypercalciuria and hyperoxaluria(5). another important metabolic disorder influencing calcium oxalate stone formation is hypocitraturia affecting up to 60 % of stone formers (6-8). since removal of existing caox stones does not prevent their further appearance(8) and a recurrence rate reaches up to 30-50 % within 5-year period(9,10), it is essential to find metabolic abnormalities which caused formation 1ivanovo state medical academy, 153012 ivanovo, russian federation. 2krestov institute of solution chemistry of ras, 153045 ivanovo, russian federation. 3ivanovo state university of chemistry and technology, 153012 ivanovo, russian federation. *correspondence: doctor of chemistry, the leading scientific researcher, united physical-chemical center of solutions, g.a. krestov institute of solution chemistry of russian academy of sciences & ivanovo state university of chemistry and technology, akademicheskaya str., 1, 153045, ivanovo, russian federation. phone, fax: +7(4932)336256. e-mail: kustov@isuct.ru. received march 2017 & accepted november 2017 of an initial calculus to provide a sound basis to prevent the recurrence. unfortunately, usual measures mainly devoted to a stone removal are not effective to highlight metabolic abnormalities. although the 24 hour urine analysis and the quantitative mineralogical study of renal calculi with ir-fourier spectroscopy or x-ray diffraction became routine procedures for many european centers, these are rarely performed in domestic clinics. the lack of this information significantly contributes to the high recurrence observed. with this information in mind, we have analyzed the mineralogical composition of calculi and the mean daily excretion of urine components for sixty four patients with calcium oxalate urolithiasis from central russia. the main goal of this study is to compare the clinical and biochemical patterns with the stone mineralogical composition, gender and age of caox stone formers in the hope that this information may provide a deeper insight into etiology of urolithiasis and allow to improve its diagnosis and treatment. patients and methods the calculi or their fragments removed with retrograde intrarenal surgery or usually extracorporeal shock-wave lithotripsy for sixty four caox stone formers were accurately examined with x-ray powder diffraction at the institute of solution chemistry using the d8 advance bruker diffractometer. the stones examined were classified according to their main component (com or cod) if the mass faction of the mineralogical phase was ≥ 55 mass %. seven caox ap stones contained from 10 to 44 mass % of hydroxyl apatite were also identified. all patients were routinely asked about possible stone formers in their family, past medical history concerning the last stone episode, physical activity and a normal diet. height and weight were also recorded to compute a body mass index. a 24 h urine collection was carried out for each patient supported on a random diet. the urine volume and concentration of urine components were determined. calcium, magnesium, phosphate and urate were measured spectrophotometrically in a clinical laboratory with standard kits. oxalate and citrate ions were determined with the enzymatic hydrolysis method. the daily ph-profile of urine for each patient was studied independently using the pocket ph-meters рн-009(i) (rohs) pre-calibrated with standard buffer solutions. the index of urinary supersaturation with respect to calcium oxalate was computed according to the tiselius equation(11). results given in tables 1, 2 are presented as means ± se. statistical analysis was performed using the origin 7.0 package. group differences were studied by the one-way anova test with comparisons according to bonferroni. for all cases we have used pairwise comparisons which provide for our results a deeper insight into the etiology of stone formation. these comparisons were considered to be significantly different if p < 0.05. the ethics board approval number for this study is isma ec 2013.12.08. results we have studied sixty four caox stone formers (mean age of 48.5 ± 2 years) consisting of 39 females (mean age of 49.8 ± 2 years) and 25 males (mean age of 46.2±3 years). the x-ray diffraction study has indicated that about 44 % of stones contained one com component, whereas other 56 % of calculi were composed of two (com+cod) or three (com+cod+hydroxyl apatite) mineralogical phases. we have found only ten calculi where the cod content was larger than the com one, none of them contained pure cod. the relevant parameters associated with stone formation are listed in table 1 for com (com > cod), cod (cod>com) and caox ap (apatite ≥ 10 %) stone formers. the risk factors and reference values for urine components were taken from straub et al. study (12). patients with cod stones were found to be significantly younger than those with com (p =.006) but not with caox ap (p =.11) calculi. the body mass index was not significantly persistent between all three groups. the mean daily oxalate excretion and the daily ph-profile for com and cod groups were identical. in contrast, the daily ph-profile for caox ap stone formers is shifted to more alkaline urine in comparison with cod and, especially, com (p =.04) patients. the mean daily excretion of ca and citrate as well as urinary saturation with respect to calcium oxalate differed between com and cod stone formers. the difference, however, was not yet statistically significant. we have found, however, that patients with caox ap stones reveal significantly increased phosphate (p =.006) and simultaneously decreased calcium excretion (p =.02) that cod stone formers. the ap [caox] index is also decreased (p =.03). despite the lower ap [caox] index, the shift of the ph-profile to more alkaline urine and elevated phosphate excretion significantly increase the risk of heterogeneous nucleation for such patients. in order to obviate to possible bias related to sex and age, we have computed the means ± se values of the biochemical parameters mentioned above for stone formers divided by sex and age (table 2). the excretion of calcium was elevated for old females in comparison with males of the same age (p = .03). the oxalate excretion was surprisingly normal for all groups. the lower level of oxalate in urine for young females in comparison with older ones was statistically insignificant. the daily excretion of citrate was reduced for all caox stone formers. postmenopausal females indicated a lower citrate excretion with urine than premenopausal stone forming women (p = .05) and simultaneously the higher ca/citrate ratio in comparison with old males (p = .04) and young females (p = .05). the mean daily urate excretion was surprisingly elevated both for males and, especially, females. the difference between these table 1. the 24 h urine chemistry (in mmol/day), mean age and ap[caox] indexes m ± se for three mineralogical groups of calcium oxalate stone formers. parameter cod a com caox ap patients patients patients ca b (<5 mmol/day) 6.97 ± 0.8 5.43 ± 0.5 3.39 ± 1.1 oxalate, (<0.5 mmol/day) 0.37 ± 0.08 0.38 ± 0.05 0.22 ± 0.03 citrate, (>2.5 mmol/day) 1.28 ± 0.18 1.65 ± 0.19 1.32 ± 0.26 phosphate, (<35 mmol/day) 15 ± 2 27 ± 3 37 ± 6 phmean 5.58 ± 0.15 5.55 ± 0.07 5.94 ± 0.16 ap[caox] 1.67 ± 0.47 1.11 ± 0.16 0.39 ± 0.11 mean age 33.6 ± 5 51.2 ± 2 43.1 ± 8 n 7 50 7 abbreviations: acom, calcium oxalate monohydrate (whewellite); cod, calcium oxalate dihydrate (weddellite); caox ap , calcium oxalate with apatite breference values for medical attention are given in brackets [12] patient group parameters of urine females n = 39 males n = 25 females > 50 n =21 females < 50 n =18 males > 50 n =12 males < 50 n =13 volume 2.04 ± 0.08 1.78 ± 0.09 1.99 ± 0.07 2.12 ± 0.09 1.74 ± 0.07 1.82 ± 0.17 ca 5.97 ± 0.49 4.44 ± 0.57 6.36 ± 0.88 5.52 ± 0.51 3.45 ± 0.67 5.34 ± 0.79 citrate 1.62 ± 0.22 1.49 ± 0.20 1.23 ± 0.27 2.1 ± 0.34 1.56 ± 0.29 1.43 ± 0.28 ca/citrate 7.4 ± 1.3 5.3 ± 0.1 9.8 ± 2.1 4.7 ± 1.1 3.4 ± 0.8 6.5 ± 1.7 oxalate 0.34 ± 0.06 0.39 ± 0.04 0.29 ± 0.04 0.40 ± 0.10 0.42 ± 0.07 0.33 ± 0.05 phosphate 27 ± 4 25 ± 2 31±7 23 ± 3 24 ± 2 26 ± 4 urate 6.49 ± 0.67 5.08 ± 0.41 6.32 ± 0.68 6.65 ± 1.28 4.60 ± 0.64 5.53 ± 0.52 table 2. parameters of the 24 h urine m±se for caox stone formers by gender and age (in mmol/day). stone mineralogy and urine abnormalities-kustov et al. endourology and stone diseases 10 groups was not yet significant (p = .09). table 3 compares the frequency of risk factors and possible metabolic abnormalities associated with calcium oxalate stone formation for the selected group of patients. the most frequent disorders are hypocitraturia, hyperuricosuria and hypercalciuria afflicting 75, 59 and 50 per cent of stone formers, respectively. discussion introduction of new options such as distant or contact shockwave lithotripsy, retrograde or antegrade endoscopic pyelolithotomy has allowed to achieve a rapid stone removal from the urinary tract. this low invasive treatment appears to be more attractive for many patients than routine metaphylaxis. however, the high recurrence of urolithiasis arising from non-treated metabolic disorders often leads to serious organic lesions both of kidneys and the urinary tract as a whole. another important point is the high cost of treating such life-threatening complications. this is in times higher than the expenditures for though tedious but really necessary diagnostic and metaphylactic measures. these, however, need further investigations to provide the sound basis to prevent the stone recurrence. we see from table 1 that cod stone formers are significantly younger than com patients. they also reveal a reduced citrate excretion and a simultaneously elevated calcium level in urine. this result was in a good agreement with the trinchieri et al. findings(8). the excess of the promoter of caox crystallization and growth with deficiency of citrate ions as inhibitors of stone formation induces urine supersaturation and rapid crystallization of cod. we have mentioned above that stones containing cod as the main component are correlated with permanent hypercalciuria for the majority of cases. in contrast, com stones are often associated with hyperoxaluria (5). this finding is not, however, confirmed by trinchieri et al.(8) and our results suggesting about a normal oxalate excretion for both groups. as for the mean daily calcium excretion, it is larger for cod stone formers (table 1). although the difference between com and cod groups for our patients is not yet statistically significant, this value suggests about mild hypercalciuria for cod patients that is in consistent with the daudon et al.(5) and trinchiery et al.(8) findings. it is worthy of note that com as a component of a renal stone can be formed directly due to the reaction between calcium and oxalate ions in urine or indirectly from thermodynamically unstable cod(13). hence, for some mixed cod+com calculi the com amount may be overestimated due to the cod to com transformation(13). this may artificially increase the percentage of com stone formers and shift the mean daily calcium excretion for this group to greater values. the recent study(13) supports this idea pointing out the importance of the analysis of stone texture to differentiate stone formers between com and cod groups. table 2 compares the mean daily excretion of urine components for males and females. we see that a calcium excretion is elevated both for young and, especially, old females. this is not the case for males, where the risk arises exceptionally for a younger group. hence, females over fifty are in a high risk group in comparison with males of the same age. the mean daily oxalate excretion is surprisingly normal for all groups. although the oxalate level for selected patients reaches 1 mmol/day and more, it is of 0.2-0.3 mmol/day in most cases. the similar findings have been reported elsewhere(3,8) for asian and european stone formers. the mean daily excretion of citrate is reduced for all groups. we have mentioned above that for younger females the citrate level in urine is higher than that for menopausal and post menopausal women (table 2). this is in a fair agreement with the observation that premenopausal stone forming females show greater values of a citrate excretion than males or postmenopausal females(7). it is important that ca/citrate ratio for the menopausal and post menopausal females is significantly elevated that strongly increases the risk of stone recurrence. taking into account the fact that the estrogen loss leads to the increase of calcium in urine and the simultaneous decrease of citrate(7), this result is of particular importance for the diagnosis and treatment of urolithiasis. as for the frequency of metabolic disorders and risk factable 3. frequency of risk factors and metabolic disorders (%) for calcium oxalate stone formers disorder or risk factora females males total females > 50 years males > 50 years total > 50 years hypercalciuria (ca excretion >8 mmol/day) 20 6 26 15 2 17 mild hypercalciuria (ca > 5 mmol/day) 19 5 24 8 2 10 hyperoxaluria (oxalate > 0.5mmol/day) 11 13 24 5 8 13 hypocitraturia (citrate < 2.5 mmol/day) 48 30 78 28 18 46 hypomagnesiuria (mg < 3 mmol/day) 12 8 20 7 5 12 hyperuricosuria (urate > 4 mmol/day) 34 25 59 20 13 33 hyperphosphaturia (phosphate >35 mmol/day) 15 3 18 7 2 9 constantly ph ≤ 5.8 (possibly acidic arrest of urine) 20 15 35 13 5 18 constantly ph > 5.8 (possibly renal tubular acidosis) 11 7 18 3 5 8 obesity (body mass index > 25 kg/m2) 33 18 51 28 13 41 low fluid intake (diuresis < 1.5 l) 15 20 35 7 7 14 a reference values for medical attention [12] stone mineralogy and urine abnormalities-kustov et al. tors shown in table 3, our results indicate that the most frequent disorder is hypocitraturia. it afflicts more than 75 % of patients, the significant part of stone formers excreting less than 1 mmol of citrate per day. this observation is in a fair agreement with recently reported results for chinese stone formers(3). if we use the reference value of 1.7 mmol/day proposed by pak(14), the frequency of hypocitraturia reduces to 55 %, which is in consistent with usually reported quantities(7). in many cases hypocitraturia is accompanied by an elevated calcium and urate excretion that significantly influences the recurrence rate. hypercalciuria is detected in 26 % of patients and yet 24 % of stone formers with mild hypercalciuria are in a high risk group. the high incidence of hypercalciuria for caox stone formers is in a good agreement with the findings given elsewhere(8-12). table 3 clearly shows that this disorder afflicts mainly females in the period of menopause and post menopause. another important abnormality is hyperuricosuria. this surprisingly frequent disorder for our patients is seen to observe both for males and females independently of age. being structurally similar to com crystals, uric acid crystallites may induce heterogeneous nucleation and initial aggregation of com species(15). other abnormalities such as hyperoxaluria, hypomagnesuria and hyperphosphaturia are less frequent. we have also identified several risk factors associated with stone formation. the first and most frequent factor is obesity which is found for many patients (table 3). the patient survey has indicated that an excessive caloric intake with a meal and low physical activity are the major reasons of this pathological condition. moreover, for many stone formers dietary habits include an excessive intake of sodium chloride, poultry protein and smoked food. it is clear that such a diet significantly contributes to the high incidence of hypocitraturia and hyperuricosuria. the second risk factor is the abnormal acid-base balance of urine. “acidic arrest” during the day is observed twice as frequently as urine excessive alkalization (table 3). acidic urine may also affect the tubular production of citrate that additionally supports the idea that the high frequency of hypercitraturia arises from a diet. the third and very important factor is low fluid intake resulting in significant supersaturation of urine with respect to calcium oxalate. it is clear that modern life style, obesity and dietary habits seem to be real promoters in the development of urolithiasis for caox stone formers. hence, all patients should follow at least the basic metaphylactic measures to normalize dietary habits, physical activity and exclude risk factors of stone formation(12,16,17). conclusions our results indicate that cod stone formers are younger than patients with com calculi and reveal higher calcium level in urine. caox ap patients demonstrate the lower mean daily calcium and oxalate excretion, the more alkaline ph-profile of urine and the significantly lower ap [caox] index. these observations lead to different strategies for diagnosing cod/com and caox ap patients(16). in particular, we are able to draw a tentative conclusion that for any cod stone former, the first step of a metabolic evaluation should contain the determination of the calcium and citrate excretion with urine. for caox ap stone formers the initial step should include the analysis of ph-profile, phosphate, calcium and citrate. menopausal and postmenopausal females are a high risk group due to the elevated ca/citrate ratio and need a compulsory metabolic evaluation. acknowledgments the partial financial support of this work by the russian foundation for basic researches is gratefully acknowledged (grant n 15-44-03016-reg). conflict of interest the authors report no conflict of interest. references 1. daudon m, bazin d, andre g, et al. examination of whewellite kidney stones by scanning electron microscopy and powder neutron diffraction techniques. j appl cryst. 2009; 42: 109-15. 2. schubert g. urinary stone analysis. in: rao pn, preminger gn and kavanagh jp, editors. urinary tract stone disease. london: springer-verlag; 2011. p. 341-53. 3. wu w, yang d, tiselius h.-g, et al. the characteristics of the stone and urine composition in chinese stone formers: primary report of a single-center results. urology 2014; 83: 732-7. 4. ansari ms, gupta np, hemal ah, et al. spectrum of stone composition: structural analysis of 1050 upper urinary tract calculi from northern india. int j urol. 2005; 12: 12– 6. 5. laurence me, levillain p, lacour b, daudon m. advantage of zero-crossing-point first-derivative spectrophotometry for the quantification of calcium oxalate crystalline phases by infrared spectrophotometry. clin chim acta 2000; 298: 1-11. 6. hess b. urinary citrate and citrate metabolism. in: rao pn, preminger gn and kavanagh jp, editors. urinary tract stone disease. london: springer-verlag; 2011. p. 181-4. 7. caudarella r, vescini f, buffa a, stefoni s. citrate and mineral metabolism: kidney stones and bone disease. front bioscience 2003; 8: 1084-106. 8. trinchieri a, castelnuovo ch, lizzano r, zanetti g. calcium stone disease: a multiform reality. urol res. 2005; 33:194-8. 9. bichler kh, lahme c, mattauch w, strohmaier wl. metabolische evaluation und metaphylaxe von harnsteinpatienten. aktuel urol. 2000; 31: 283-93. 10. preminger gm, tan yh: pharmacologic prophylaxis of calcium stones. in: stoller ml and meng mv, editors. urinary stone disease: the practical guide to medical and surgical management. new jersey: humana press; 2007. p. 269-84. 11. tiselius h.-g. risk formulas in calcium stone mineralogy and urine abnormalities-kustov et al. endourology and stone diseases 12 vol 15 no 03 may-june 2018 13 oxalate urolithiasis. w j urol. 1997; 15:17685. 12. straub m., strohmaier wl, berg w, et al. diagnosis and metaphylaxis of stone disease. consensus concept of the national working committee on stone disease for the upcoming german urolithiasis guideline. w j urol. 2005; 23:309-23. 13. bazin d, leroy c, tielens f, et al. hyperoxaluria is related to whewellite and hypercalciuria to weddellite: what happens when crystalline conversion occurs? c r chimie 2016; 19:1492-503. 14. pak cyc. citrate and renal calculi: an update. miner elect metab. 1994; 20: 371-377. 15. grases f., sanchis p., perello j., costa-bauzá a. role of uric acid in different types of calcium oxalate renal calculi. int j urol. 2006; 13:252–6. 16. kustov av, strelnikov ai, airapetyan ao, kheiderov shm. new step-by-step algorithms for diagnosis of calcium oxalate urolithiasis based on a qualitative mineralogical composition of calculi. clin neph & urol sci 2015; 2:3. 17. odvina cv, pak cyc. medical evaluation of stone disease. in: stoller ml and meng mv, editors. urinary stone disease: the practical guide to medical and surgical management. new jersey: humana press; 2007. p. 258-68. stone mineralogy and urine abnormalities-kustov et al. endourology and stone diseases efficacy of silodosin in expulsive therapy for distal ureteral stones: a randomized double-blinded controlled trial chung-jing wang, po-chao tsai, chien-hsing chang purpose: to evaluate the efficacy of silodosin in the medical expulsive therapy for symptomatic distal ureteral stones. materials and methods: this prospectively randomized controlled trial was carried out from may 2011 to december 2014. in all, 198 patients with radiopaque distal ureteral stones <10 mm in size were eligible: 61 patients in the control group and 62 patients in the silodosin group. the silodosin group received silodosin 8 mg daily, and the control group received lactose tablets. the primary outcome was the expulsion rate. the secondary outcomes the expulsion time, analgesic consumption, lower urinary tract symptoms, colic episodes, and adverse effects. statistical analyses were performed using a mann-whitney u-test and chi-square test. results: the final analysis was conducted with 61 control and 62 silodosin patients as the denominator in each randomization arm. the average expulsion times were 6.31 ± 2.13 days for the silodosin group and 9.73 ± 2.76 days for the control group (p < .001). conclusion: treatment with silodosin proved to be safe and effective, as demonstrated by the increased stone expulsion rate, the reduced expulsion time, and the reduced analgesics consumption. keywords: adrenergic alpha-1 receptor antagonists; dose-response relationship, drug; follow-up studies; prospective studies; treatment outcome; ureteral calculi/drug therapy. introduction urolithiasis is a significant and worldwide health problem.(1) ureteral stones play an important role in daily urological practice, and clinicians are frequently asked to prescribe adequate treatment.(2,3) the efficacy of minimally invasive therapies, such as extracorporeal shock wave lithotripsy (swl) and ureteroscopy, has been proven in several studies.(4,5) nevertheless, spontaneous passage of a stone prevents potential pain, related complications, and costs of a surgical intervention. recently, the duration of the watchful waiting approach has been extended by using pharmacological therapy that can reduce symptoms and facilitate stone expulsion.(6-9) in the stone migration process, the sympathetic nervous system modulates ureteral activity, as demonstrated by the presence of adrenergic receptors in the ureter.(10) several studies have shown that the density of α-1a adrenergic receptors in the ureteral smooth muscle cells is greater than that in other adrenergic receptors.(10-12) in addition, α-adrenergic antagonists inhibit basal tone and peristaltic frequency, dilating the ureteral lumen and facilitating stone passage.(13) in general, the main obstacle to the transport of lower ureteral stones is the intramural detrusor tunnel;(7,8) thus, blocking these receptors could allow stone passage. investigators have reported the effectiveness of pharmacological therapies in increasing ureteral stone expulsion and reducing total analgesic use.(2,6,8,9,14,15) furthermore, using real-time reverse transcription polymerase chain reactions and immunohistochemical staining, itoh and colleagues reported that human ureter α-1a and 1d adrenergic receptors are the most commonly expressed subtypes. (16) they also reported that α-1a adrenergic receptors are the main component in phenylephrine-induced ureteral contractions in the isolated human ureters.(17) they found that the selective α-1a adrenergic receptors’ antagonist, silodosin, was more effective than the selective α-1d adrenergic receptors’ antagonist, bmy7378, for noradrenaline-induced contractions in the human ureter.(18) blockage of α-1a adrenergic receptors could accelerate the passage of distal ureteral stones. therefore, the study was designed to evaluate the clinical role of silodosin in the medical expulsive therapy of symptomatic distal ureteral stones. department of surgery, division of urology, saint martin de porres hospital, chiayi, taiwan, r.o.c. *correspondence: department of surgery, division of urology, saint martin de porres hospital, chiayi, taiwan, r.o.c. tel: +88 65 2756000 ext. 1013. fax: +88 65 2788535. e-mail: jing@stm.org.tw. received november 2015 & accepted december 2015 vol 13 no 03 may-june 2016 2666 endourology and stone diseases 2667 materials and methods study design the study was approved #10b-015 by the institutional review board of st. martin de porres hospital, chiayi city, where the work was undertaken. all procedures involving human participants were performed in accordance with the ethical standards of the institutional and national research committee and in compliance with the 1964 helsinki declaration and its later amendments or comparable ethical standards. this prospectively randomized controlled trial was carried out from may 2011 to december 2014. the trial was registered at new zealand clinical trials registry and allocated the actrn: actrn12611000555954. study population we assessed the eligibility of 198 patients with radiopaque distal ureteral stones < 10 mm. the presence of stones and characteristics were diagnosed using non-enhanced computed tomography (ct). the stones were classified according to their diameter along the ureteral axis. no patients who had undergone previous ureteral surgery were included in this study. all patients signed an informed consent form before participating. exclusion criteria included: urinary tract infections, high-grade hydronephrosis, diabetes, peptic ulcers, history of hypersensitivity to α-1 blockers, pregnancy, or nursing. patients with a history of spontaneous stone expulsion, hypotension, or those with systolic blood pressure < 110 mmhg were also excluded. study interventions the patients were randomly divided into two groups: patients who received silodosin 8 mg daily and patients who received lactose tablets as the control. all patients were prescribed 10 mg of ketorolac three times per day as an analgesic and were allowed to use 0.2 mg of sublingual buprenorphine on demand; they were encouraged to drink a minimum of 2 l of water per day. to highlight any possible fragment or stone expulsion, all patients were asked to filter their urine. all patients were evaluated within two weeks because most studies in the literature have shown positive results within the first 10 days of medical therapy,(14) as determined from an outpatient visit, plain kidney-ureter-bladder radiography, abdominal ultrasonography, and non-enhanced ct, when necessary. randomization in all, 198 patients were eligible, and 164 were prospectively randomized into two groups (using a random numbers table) before they were enrolled in the study. in all, 164 patients were available for consideration in each group. among them, 12 patients, who were unwilling to be randomized in the control group, and 11 patients, who were unwilling to be randomized in the silodosin group, were excluded from the trial. of the remaining patients, 70 were allocated to the control group, and they received lactose tablets. among them, five missed the primary outcome and four withdrew their informed consent; thus, they were eliminated from silodosin in medical expulsive therapy-wang et al. table 1. baseline patients’ characteristics.* characteristics control group (n = 61) silodosin group (n = 62) p value age, years a .744 mean ± sd 51.51 ± 10.03 51.42 ± 8.68 range 28-72 36-71 gender, no (%) b .741 male 43 (70.49) 40 (67.74) female 18 (29.51) 22 (32.26) bmi, kg/m2 a 25.09 ± 2.79 25.51 ± 2.62 .389 male a 24.77 ± 2.91 25.12 ± 2.82 .661 female a 25.78 ± 2.39 26.23 ± 2.10 .309 no. r/l ureter b 33/28 26/36 .177 stone size, mm a mean ± sd 6.46 ± 1.31 6.47 ± 1.39 .860 range 5-10 4-9 abbreviations: bmi, body mass index; r, right; l, left. a mann-whitney u test b chi-square test * data are presented as mean ± sd. the analysis. another 71 patients were allocated to the silodosin group. among them, five missed the primary outcome and four withdrew their informed consent; thus, they were eliminated from the analysis. the final analysis was conducted with 61 patients in the control group and 62 in the silodosin group patients, as the denominator in each randomization arm (figure). study outcomes the primary outcome was the stone expulsion rate. the secondary outcomes were expulsion time, analgesics consumption, lower urinary tract symptoms, colic episodes, and adverse effects. the stone expulsion rate was defined by determining the number of stones passed and dividing by the total number of patients in each group. only patients without any residual fragments were considered to have successful outcomes. the expulsion time was defined as the date of stone passage, as reported by patients. the number of colic episodes, lower urinary tract symptoms (frequency, residual sensation, difficulty, urine retention, and tenesmus), the amount of analgesic consumption, and adverse effects of medical therapy were recorded in a diary and evaluated. sample size and statistical analysis we detected a 30% difference in the stone expulsion rate in the treatment groups at a significance level of 0.05 and a power of 80% via creative research sysendourology and stone diseases 2601 table 2. randomization results. variables control group silodosin group p value expulsion time, days a < .0001 mean 9.73 ± 2.76 6.31 ± 2.13 range 6-14 3-11 expulsion rate, no (%) b 33/61 (54.10) 48/62 (77.42) .006 lower urinary tract symptoms, no (%) b 26/61 (42.62) 22/62 (35.48) .417 ketorolac consumption, mg a < .0001 mean 343.77 ± 109.90 255.97 ± 112.48 range 90-480 90-420 buprenorphine consumption, mg a .771 mean 0.49 ± 0.29 0.47 ± 0.27 range 0.2-1.2 0.2-1.0 colic episodes a .160 mean 2.75 ± 1.38 2.39 ± 1.30 range 1-6 1-5 adverse effects, no (%) b 2/61 (3.28) 10/62 (16.13) .016 adjuvant therapy, no (%) b 28/61 (45.90) 14/62 (22.58) .006 swl/ursl, no 14/14 4/10 ----stone location b .177 right 33/61 (54.10) 26/62 (41.94) left 28/61 (45.90) 36/62 (58.06) abbreviations: swl, extracorporeal shock wave lithotripsy; ursl, ureterorenoscopic stone lithotripsy a mann-whitney u test. b chi-square test. figure. study flowchart vol 13 no 03 may-june 2016 2668 silodosin in medical expulsive therapy-wang et al. tems survey software; a sample size of 55 patients per group was needed. all analyses were conducted using statistical package for the social science (spss inc, chicago, illinois, usa) version 14.0.1. age, body mass index, stone size, expulsion time, ketorolac consumption, buprenorphine consumption, and colic episodes were evaluated using the mann-whitney u-test. the gender, stone laterality, stone expulsion rate, lower urinary tract symptoms, and adverse effects were evaluated using the chi-square test. results in all, 123 patients completed the study protocol: 61 patients in the control group and 62 patients in the silodosin group. no significant statistical difference was observed in patients’ ages, gender distribution, or laterality. the mann-whitney u-test did not reveal any significant statistical difference in the average stone size among the groups (p = .860) (table 1). a significant statistical difference in the stone expulsion rate was noted between the two groups (p = .006). the average time to expulsion was significantly different (p < .001). no significant differences were observed in the mean sublingual buprenorphine dosages or the number of colic episodes between male and female patients or between the right and left sides. the mean ketorolac consumption was significantly difference (p < .0001). no significant statistical difference was observed in the incidence of lower urinary tract symptoms between the two groups (p = .417). no patients were hospitalized for recurrent colic, and no urosepsis was recorded. only two patients in the control group experienced adverse effects associated with the medical expulsive therapy, whereas 10 patients in the silodosin group reported adverse effects (transient hypotension, asthenia, syncope, and palpitations), and a significant statistical difference in the incidence rate of complications was noted between the groups (p = .016) (table 2). no patients discontinued medical therapy, and the adverse effects disappeared. patients (28 in the control group and 14 in the silodosin group) who were not stone-free after the two-week follow-up were successfully treated with ureteroscopy(17) or swl(9). all ureteroscopic findings revealed moderate-to-severe inflammatory reactions of stone-impacted mucosa with edematous bullous changes. discussion during the last two decades, minimally invasive therapies, such as swl and ureteroscopy, have been widely used for the treatment of ureteral stones. the efficacy of these treatments has been proven by several studies. although such procedures are rather effective, they are predisposed to the risk of related complications or cause inconveniences and are quite expensive.(2,5,15) in the european association of urology guidelines on urolithiasis, several trials have demonstrated the α-blocker class effect on stone expulsion rates.(19) tamsulosin is one of the most commonly used α-blockers. however, one small study suggested that tamsulosin, terazosin, and doxazosin are equally effective, indicating a possible class effect.(20) this has also been indicated in several trials that demonstrated increased stone expulsion rates using doxazosin, terazosin, alfuzosin, naftopidil, and silodosin. according to our study, the medical therapy based on silodosin demonstrated positive results in 77.42% patients, with a significant statistical difference in the control group (54.10%). these results confirm that medical therapy with α-1 blockers can improve stone expulsion, as reported previously.(20) moreover, α-1 blockers limit analgesic usage by decreasing the frequency of phasic peristaltic contractions in the obstructed ureteral tract, thus decreasing the frequency of ureteral colic.(8) meanwhile, silodosin was effective for pain reduction and decreased the amount of analgesics administered in our study. in addition, no relationship between stone size and expulsion time was evident. gender and stone size did not influence the stone expulsion rate. as previously reported, these data suggest that stone size is not the only factor that influences expulsion times; other factors stone shape and edema around the stone also influence expulsion times.(7) patients who were not stone-free after the twoweek follow-up were successfully treated with ureteroscopy. this demonstrates that neither watchful waiting nor medical therapy seems to have a negative effect on the success rates of stone removal. from our ureteroscopic manipulation of the failed cases, all ureteroscopic findings revealed moderate-to-severe inflammatory reactions of stone-impacted mucosa with edematous bullous changes. therefore, medical therapy is not effective for impacted lower ureteral stones if they can be judged in advance. in other words, if the stone did not impact the ureter due to marked inflammatory changes of the surrounding tissue, perhaps medical therapy could be effective. we encountered three cases of serious adverse effects of medical expulsive therapy (postural hypotension in the silodosin group) that did not require its discontinuation. minor therapy-related side effects (dizziness, asthenia, postural hypotension) were observed in 10 pasilodosin in medical expulsive therapy-wang et al. endourology and stone diseases 2669 tients (in the silodosin group), but those patients completed the study. these results are similar to those of benign prostatic hyperplasia patients treated with α-1 blockers. regarding safety, α-1 blockers were well tolerated by the patients. lower urinary tract symptoms (frequency, residual sensation, difficulty, urine retention, and tenesmus) are other troublesome issues for distal ureteral stone patients. although our study did not demonstrate how α-1 blockers can alleviate lower urinary tract symptoms effectively, and did not show a significant statistical difference, it implies that silodosin is an α-1a specific blocker and more potent α-1 blocker for the relaxation of the lower ureter than other α-1 blockers. our study had one important limitation; namely, a highly homogenous population was included. all included patients had their first episode of distal ureteral stone, which is unachievable for most researchers and hence, may limit the scope of this study. conclusions the results of this study indicate that distal ureteral stones can be treated with expulsive medical therapy in patients when the watchful waiting approach is possible. in our study, medical treatments with silodosin proved to be safe and effective, as demonstrated by the low incidence of side effects, the increased stone expulsion rate, and the reduced expulsion times. moreover, medical therapy, particularly in regard to the α-1a-1d specific blocker-silodosin seems to decrease the incidence of adverse effects. acknowledgements we would like to thank jui-fang huang, from the department of research and education, st martin de porres hospital, chia-yi, taiwan, for his support with statistical methods. e-mail:h102_2@stm.org.tw contributions: research idea and study design: cjw and pct; data acquisition: cjw, pct, chc; data analysis/interpretation: cjw, pct, and chc; statistical analysis: cjw; and supervision or mentorship: cjw. each author contributed important intellectual content during this manuscript’s drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. cjw, pct, and chc take responsibility for ensuring that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study, as planned and registered, have been explained. there are no financial or commercial interests that should be acknowledged. the work has not already been published and has not been submitted simultaneously to any other journal. the corresponding author takes on the above responsibilities. conflict of interest none declared. references 1. pak cy. kidney stones. lancet. 1998;351:1797-801. 2. wang cj, huang sw, chang ch. efficacy of an α-1 blocker in expulsive therapy of lower ureteral stones. j endourol. 2008;22:41-5. 3. carstensen he, hansen ts. stones in the ureter. acta chir scand. 1973;433:66-71. 4. miller of, kane cj. time to stone passage for observed ureteral calculi: a guide for patient education. j urol. 1999;162:688-91. 5. segura jw, preminger gm, assimos dg, dretler sp, kahn ri, lingeman je, jr.. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. j urol. 1997;158:1915-21. 6. borghi l, meschi t, amato f, novarini a. nifedipine and methylprednisolone in facilitating ureteral stone passage: a randomized, double blind, placebo controlled study. j urol. 1994;152:1095-8. 7. porpiglia f, destefanis p, fiori c, fontana d, scarpa rm. effectiveness of nifedipine and deflazacort in the management of distal ureteralstones. urology. 2000;56:579-83. 8. cervenakov i, fillo j, mardiak j. speedy elimination of ureterolithiasis in lower part of ureters with the alpha 1 blockers— tamsulosin. int j urol nephrol. 2002;34:25-9. 9. ukhal m, malomuzh o, strashny v. administration of doxazosine for speedy elimination of stones from lower part of ureter. presented at xiv congress of the eau, stockholm, sweden, 1999. 10. latifpour j, morita t, o’hollaren b, kondo s, weiss rm. characterization of autonomic receptors in neonatal urinary tract smooth muscle. dev pharm ther. 1989;13:1–10. 11. sigala s, dellabella m, milanese g, et al. alpha1 adrenoceptor subtypes in men juxtavesical ureters: molecular and pharmacological characterization. eur urol. suppl 2004;3:119. 12. obara k, takeda m, shimura h, et al. alpha-1 adrenoreceptor subtypes in the human ureter: characterization by rt-pcr and in situ hybridisation. j urol. 1996;155(suppl 5):472a. silodosin in medical expulsive therapy-wang et al. vol 13 no 03 may-june 2016 2670 13. richarson cd, donatucci cf, page so, et al. pharmacology of tamsulosin: saturation binding isotherms and competition analysis using cloned alpha 1-adrenergic receptors subtypes. prostate. 1997;33:55–9. 14. porpiglia f, destefanis p, fiori c, fontana d, scarpa rm. role of adjunctive medical therapy with nifedipine and deflazacort after extracorporeal shock wave lithotripsy of ureteral stones. urology. 2002;59:835–8. 15. dellabella m, milanese g, muzzonigro g. efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. j urol. 2003;170:2202–5. 16. itoh y, kojima y, yasui t, okada a, tozawa k, kohri k. examination of alpha 1 adrenoceptor subtypes in thehuman ureter. int j urol. 2007;14:749–53. 17. sasaki s, tomiyama y, kobayashi s, kojima y, kubota y, kohri k. characterization of a (1)-adrenoceptor subtypes mediating contraction in human isolated ureters. urology. 2011;77:762 e13–7. 18. kobayashi s, tomiyama y, itoh y, et al. gene expressions and mechanical functions of alpha 1 adrenoceptor subtypes in mouse ureter. world j urol. 2009;27:775–80. 19. türk c, knoll t, petrik a, sarica k, skolarikos a, straub m, seitz c. eua guidelines on urolithiasis p26, 2015. 20. yilmaz e, batislam e, basar mm, tuglu d, ferhat m, basarr h. the comparison and efficacy of 3 different α1-adrenergic blockers for distal ureteral stones j urol. 2005;173:2010-2. silodosin in medical expulsive therapy-wang et al. endourology and stone diseases 2671 supine ultrasound-guided percutaneous nephrolithotomy with retrograde semi-rigid ureteroscopic guidwire retrieval: description of an evolved technique mahziar khazaali, dinyar khazaeli*, hayat moombeini, jamal jafari-samim purpose: ultrasound-guided pcnl in galdakao-modified supine valdivia (gmsv) position has taken into consideration during the last decade; however, guidewire slippage during tract dilatation is still a big concern in this approach. here we presented our results of combination of this modification with ureteroscopic guidewire retrieval to ensure a safe and confident renal access. materials and methods: from june 2015 to march 2016, 30 consecutive patients with renal stone of ≥ 2.5 cm were enrolled. after general anesthesia, all patients were positioned in gmsv position. semi-rigid ureteroscopy up to the renal pelvis was performed by an assistant urologist. ultrasound (us)-guided renal access and passage of guidewire was performed by another urologist after which the first urologist grasped and retrieved the guidewire from the renal pelvis to the ureter and then out of urethra. stone manipulation was performed as standard pcnl. all patients were evaluated regarding age, stone burden, anthropometrics measurements, major and minor surgical complications, and stone free rate. result: guidewire retrieval was successful in 26 patients (86.7%) and tract dilatation was achieved in all (100%) of this group. in other 4 patients (13.3%) retrograde endoscopic guide wire retrieval failed; in one patient, (3.33%) ureteroscope did not reach the renal pelvis because of tall stature; one patient (3.33%) had narrow calyceal infundibulum which prevented the guidwire passage along the stone to reach to the renal pelvis, and for two patients (6.67%) ureteroscope did not pass the ureteropelvic junction because of narrow ureteropelvic angle. conclusion: guidewire retrieval seems to improve the results of us-guided gmsv position pcnl by eliminating the possibility of guidewire slippage during tract dilatation. keywords: percutaneous nephrolithotomy; nephrostomy access; supine position; valdivia position; ultrasound-guided. introduction pyelocalyceal system (pcs) access is the outmost important part of a successful percutaneous nephrolithotomy (pcnl) and is generally performed under fluoroscopic guidance in prone position. protective barriers used by patients and physicians during this procedure are heavy and tiresome, and radiation exposure can still has its own hazard effect on the surgical team(1,2). this led to some new innovative techniques that substitute fluoroscopy with sonography. ultrasonographic pcs access has some definite advantages. it is cheaper, provides three dimensional pictures during puncture while fluoroscopy provides only two dimensional pictures and accurate imaging of all tissues/ viscera like intestines and lungs along an intended nephrostomy tract is possible only under ultrasound guidance. similarly imaging in numerous planes is possible simply by shifting, tilting and rotating the scanning head(3). on the other hand, prone position has its own anesthetic concerns regarding patient positioning (especially in morbidly obese patients, cardiopulmonary high-risk patients or patients with skeletal deformities) and the difficulty of obtaining a retrograde access to the kidney when needed(4,5). to overcome this issue some positional innovative techniques have been introduced including flank position, full supine position, valdivia position, and galdakao-modified supine valdivia (gmsv) position(6,7). totally sonographic percutaneous access however has some limitations including kinking of guidwire, guidwire slippage out of the collecting system during tract dilatation which results in losing the percutaneous access. it is also difficult to follow guidwire placement, tract dilatation and final position of amplatz sheath when we are using sonography to perform pcs access. to surmount these concerns in this study we introduced a new technique which consists of ureteroscopic guidwire retrieval from the renal pelvis to the ureter and then out of the urethra before safely dilating the renal access without concerns of guide wire slippage in gmsv position. patients and methods study population thirty patients who were referred to imam khomeini grand hospital, ahvaz, iran from june 2015 to march 2016 were enrolled. the inclusion criteria were age bedepartment of urology, ahvaz jundishapur university of medical sciences. *correspondence: imam khomeini hospital, azadegan ave., ahvaz, iran. tel: +98 613 222 7221: fax: +98 613 292 3541. e-mail adress: khazaeli_dinyar@yahoo.com. received october 2016 & accepted july 2017 endourology and stone disease vol 14 no 06 november-december 2017 5038 tween 20 and 70 years, and pelvic or calyceal stones that were larger than 2.5 cm in diameter. patients with gross kidney anomalies like horseshoe kidney or ectopic kidney, and those with uncontrolled coagulopathies and/ or orthopedic problems that restrict the galdakao-modified supine valdivia position were excluded from the study. study was performed under terms of ethical committee of ahvaz jundishapur university of medical sciences (irajums.rec.1395.741). all patients were informed regarding the nature of the study, benefits and possible complications and then an informed consent was obtained from each patient. study design this prospective observational study was performed to report our surgical technique, outcomes and complication of a new technique in 30 consecutive patients who were candidate for pcnl for renal stone disease in imam khomeini tertiary urology department. information regarding patients' age, height, weight, bmi, and stone burden (size and location, based on spiral ct scan) were obtained and reported. (table 1) surgical technique all patients were admitted in the morning of the surgery day. abdomino-pelvic spiral ct scan was performed for all patients to measure stone burden and to rule out retro-renal colon. the antithrombotic prophylaxis was administered based on american urological association best practice statement for the prevention of deep vein thrombosis(8). patient positioning and setting up after induction of general anesthesia patients were positioned in galdakao-modified supine valdivia position. to obtain this two jelly pillows were placed below the hip and thorax and the ipsilateral foot is placed in extension, while the contralateral foot is placed in full lithotomy position and then the upper torso was tilted at approximately 20 degrees and the ipsilateral hand was placed and secured on the chest using a long band while a pillow was placed between the arm and the chest. (figure 1). then preparation and draping was performed . ultrasonography machine (samsung medison sonoace x8 ultrasound system, south korea) was placed ipsilateral and cephalad. c-arm and fluoroscopic instrument were available in the operating room as well. video monitoring was placed contralaterally in front of the surgeon (figure 2). performing ureterorenoscopy and artificial hydronephrosis after introducing a safety wire and with the using of a guidwire, ureteroscopy was performed by a urologist colleague (6/ 7.5 french semi-rigid ureterorenoscope, richard wolf, knittlingen, germany). intra-renal pressure was set to 60 cm h2o to make hydronephrosis. after passing the uretero-pelvic junction the next step was performed by another urologist. performing us-guided renal assessment, guidwire retrieval and through and through renal access to the best of our experience, performing ureterorenoscopy just before the sonographic evaluation of the kidney made a good hydronephrosis which makes percutaneous access to the kidney easier (figure 3). after decision making regarding the best pcs location for percutaneous access to the kidney and posterior to the posterior axillary line, an 18g chiba needle was introduced to the targeted calyx under sonographic guidance. dropping of liquid out of chiba re-ensured the correct placement of the needle. then a single j 0.038-in guidewire passed through the chiba needle to the kidney pc system, which was then grasped with ureteroscopic forceps under clear direct vision of ureteroscope and retrieved from renal pelvis to the bladder and then to the urethral meatus to make a good through and through access to the kidney (figure 4). single-step renal access and stone manipulation then after dilatation of the tract with an 8 french dilator sheath, an alken guide was introduced to the calyx. a 26 french amplatz dilator was then placed over the alken guide and amplatz sheath was introduced to the pcs. during these maneuvers our surgical technician pushes the kidney from anterior side to fix the kidney in place. subsequently a 24 f rigid nephroscope (richard wolf knittlingen, germany) was inserted to inspect the collecting system. under direct vision stone fragmentation was performed using swiss lithoclast pneumatic guidewire retrieval in gmsv positionkhazaali et al. figure 1. galdakao-modified supine valdivia position. figure 2. operating room setting up. endourology and stone diseases 5039 lithotripter. after stones fragmentation using ballistic energy, stone fragments removed with graspers and gravity. after double j stent placement (if indicated), a 20 french nephrostomy tube placed in pcs at the end of operation and remained for 24 hours after which it removed. all patients were discharged the day after surgery. outcome assessment blood transfusion and any post-operative complication were recorded. a sonography and kidney-ureter-bladder (kub) x-ray was performed two weeks after operation to evaluate the stone free status and patients were considered stone free if the residual stone size were ≤ 3 mm. statistical analysis categorical data are reported as number (percentage). continuous variables were presented as mean ± sd. the shapiro-wilk’s test was used to examine the normality assumption of quantitative variables. the statistical software spss 18.0.0 (spss inc. chicago, il, usa) was used for all data analyses. results patients' demographic data are listed in table 1. of 30 patients, 22 (73%) were symptomatic for flank pain 18 (60%), hematuria 7 (23%) recurrent urinary tract infection 4 (13%), and renal colic 3 (10%). percutaneous renal access was gained in galdakao-modified supine valdivia position under sonographic guidance in all 30 patients. guidewire retrieval was successfully performed in 26 (86.7 %), however, we were not able to do so in 4 (13.3 %) patients: ureteroscope did not reach the renal pelvis because of tall stature (188 cm long) in one patient (3.33 %), narrow calyceal infundibulum which prevented the guidwire passage along the stone to reach to the renal pelvis in one patient (3.33 %), ureteroscope did not pass the ureteropelvic junction because of steep and narrow ureteropelvic junction in two patients (6.67%). figure 3. sonography of the kidney: (a) depicts a 3 cm right renal pelvis stone with posterior shadow. (b) the same patient after retrograde semi-rigid ureteroscopic access to the renal pelvis. figure 4. guidewire retrieval: (a) ureteroscope reached the renal pelvis over the safety wire. (b) j 0.038-in guidewire passed through the chiba needle to the renal pelvis. (c) guidwire grasped with ureteroscopic forceps under clear direct vision of ureteroscope. (d) guidwire retrieved from renal pelvis to the bladder and then to the urethral meatus. guidewire retrieval in gmsv positionkhazaali et al. vol 14 no 06 november-december 2017 5040 table 1. patients' demographic data. male female total number of patients (%) 20 (66.7%) 10 (33.3%) 30 (100%) age, year, mean ± sd(range) 43.5 ± 14.9 (22-72) 51.4 ± 13 (32-70) 46.1 ± 14.6 (22-70) height, cm, mean ± sd (range) 173.7 ± 5 (165-188) 161.6 ± 5.7 (150-170) 169.7 ± 7.8 (150-188) weight, kg, mean ± sd(range) 80.4 ± 15.8 (42-127) 72.1 ± 6.3 (56-78) 77.6 ± 13.8 (42-127) bmi, kg/m2, mean ± sd(range) 26.5 ± 4 (15.2-35.9) 27.6 ± 1.6 (24.9-29.3) 26.8 ± 3.4 (15.2-35.9) stone burden, mm, mean ± sd total 31.1 27.25 29.82 upper calyx n/a n/a n/a middle calyx 25.7 ± 15.2 (11-57) 22 ± 4.2 (19-25) 24.9 ± 13.3 (11-57) lowe calyx 16.7 ± 6.2 (10-25) 18.6 ± 8.5 (1030) 17.3 ± 6.7 (10-30) pelvis 26.5 ± 8.7 (17-42) 30.8 ± 9.4 (20-46) 27.9 ± 8.9 (17-46) stone number total 1.35 1.1 1.27 upper calyx n/a n/a n/a middle calyx 7 2 9 lowe calyx 9 4 13 pelvis 11 5 16 abbreviations: sd, standard deviation; bmi, body mass index; n/a, not applicable. tract dilatation was easily performed in all (26 out of 26) cases in whom guidewire retrieval was successful. in the group of patients whom guide-wire retrieval failed, tract dilatation performed correctly in three cases; however in one case (25%, one of 4) of patients in this group the guide wire slippage happened during tract dilatation and another access under fluoroscopic guidance in the same position was obtained. in one patient simultaneous trans-ureteral lithotripsy of a 1cm proximal ureteral stone was performed. antegrade ureteral stenting failed in two patients; however retrograde double j stenting was easily performed by ureteroscope for them. stone free rate in this study was 96.7% (29 out of 30). mean operation time was 68 minutes (5495 minutes) and mean access time was 8.4 minutes (514 minutes). post-operative fever happened in one patient (3.33%). no major surgical complication or blood transfusion (target hemoglobin of 10 g/dl) was seen in our study population. discussion in this study we reported our technique of performing us-guided pcnl with simultaneous semirigid ureteroscopy for creating through and through guidwire retrieval in gmsv position. the endeavor of this modification is to warrant a safe access to the pcs while maintaining all merits of supine and us-guided pcnl. chiba insertion under direct vision of ureteroscope not only has the advantage of making an artificial hydronephrosis which makes us-guided access simpler but also retrograde guide wire retrieval raise the confidence of access dilatation over a non-removable guidewire. other advantages of this combination technique include: the ability to perform simultaneous transurethral lithotripsy (tul) in cases of stone migration into the ureter; the ability to push back the proximal ureteral stones to pcs, and the possibility of retrograde double-j catheter insertion in cases of antegrade failure. since the first report of first percutaneous renal access in 1955 by goodwin(9) and performing the first pcnl in 1976(10) many different modifications has been invented. sono-guided pcnl to reduce radiation exposure has been taken into consideration in the last decade and its safety and feasibility has been proven by different authors(11-18). also some authors reported different supine and modified supine position whether fluoroscopic or sono-guided pcnl with encouraging results (3,11,15-21). falahatkar and colleagues showed the safety and feasibility of totally sono-guided supine pcnl with similar outcomes compared with fluoroscopic supine position pcnl. they enumerate the major advantages of their technique as elimination of radiation exposure to the surgeon and the operating room staff, avoidance of contrast material administration, identification of all the tissue between the skin and kidney, and decreasing energy expenditure of the surgeon as it was not necessary to wear a lead shield(12). disadvantages of the supine position include kidney movement anteromedially during tract dilatation as described by zhou and coworkers(22). solo sonographically guided pcnl has been reported with excellent results(23,24). we reduced kidney movement by simultaneous push back of the kidney by assistant's hand during tract dilatation. we also placed all patients in gmsv position and conducted all the procedures under sonography guidance and performed retrograde semirigid urs for all the patients to retrieve the guidwire into the bladder and out of urethra. it gave us the open hand to do simultaneous procedures such as tul and proximal ureteral stone push back into the renal pelvis and we agree with their conclusion that this technique simplifies the surgical steps and it is more favorable for the anesthesiologists, surgeons, operating room staff and above all for the patients. we also found that the bmi, weight, stone size and stone location has no relationship with the success rate of our method and supine sonographic assisted retrograde semirigid ureteroscopic guidwire retrieval for nephrostomy access in pcnl is safe and feasible for the majority of patients. in our study we found the gmsv position a suitable position for sonographic assisted pcnl and the anesthetists and operating room technicians were satisfied with the position and its benefits which mentioned previously. the present study has some limitations. first, this study is performed during surgeon's learning curve; however, the results and complications are acceptable and comparable to other studies. second, this is an observational study with limited sample size and prospective randomized controlled trials with larger sample size are needed to evaluate this new technique. conclusions supine sonographic assisted retrograde semirigid ureteroscopic guidwire retrieval for nephrostomy access in pcnl is a safe and feasible technique and reduces the risk of access failure during totally us-guided pcnl. however, this may be technically unobtainable in tall patients, steep and narrow upj, and patients with narrow calyceal infundibulum. galdakao-modified supine valdivia position gives the urologist an open hand to perform multiple procedures simultaneously with reducing the anesthesiology risks of prone position. totally sonographic pcnl reduces the risk of x-ray radiation for all of the operating room attendants. acknowledgment this paper is part of a master's thesis (project code: u-95135). all financial support for this study was provided by ahvaz jundishapur university of medical sciences. we sincerely thank ahvaz jundishapur university staff who collaborated genuinely with our research team. references 1. safak m, olgar t, bor d, et al. radiation doses of patients and urologists during percutaneous nephrolithotomy. j radiol prot. 2009;29:40915. 2. majidpour hs. risk of radiation exposure during pcnl. urol j. 2010;7:87-9. 3. basiri a, mohammadi sichani m, hosseini sr, et al. x-ray-free percutaneous nephrolithotomy in supine position with ultrasound guidance. world j urol. 2010;28:239-44. 4. scoffone cm, cracco cm, cossu m, et al. endoscopic combined intrarenal surgery in galdakao-modified supine valdivia guidewire retrieval in gmsv positionkhazaali et al. endourology and stone diseases 5041 position: a new standard for percutaneous nephrolithotomy? eur urol. 2008;54:1393403. 5. scoffone c, cracco c. percutaneous nephrolithotomy: opinionsupine position. clinical management of urolithiasis. heidelberg: springer; 2013:11721. 6. miano r, scoffone c, de nunzio c, et al. position: prone or supine is the issue of percutaneous nephrolithotomy. j endourol. 2010;24:931-8. 7. ibarluzea g, scoffone cm, cracco cm, et al. supine valdivia and modified lithotomy position for simultaneous anterograde and retrograde endourological access. bju int. 2007;100:233-6. 8. forrest jb, clemens jq, finamore p, et al. aua best practice statement for the prevention of deep vein thrombosis in patients undergoing urologic surgery. j urol. 2009;181:1170-7. 9. goodwin we, casey wc, woolf w. percutaneous trocar (needle) nephrostomy in hydronephrosis. j am med assoc. 1955;157:891-4. 10. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 11. falahatkar s, moghaddam aa, salehi m, nikpour s, esmaili f, khaki n. complete supine percutaneous nephrolithotripsy comparison with the prone standard technique. j endourol. 2008;22:2513-7. 12. falahatkar s, neiroomand h, enshaei a, et al. totally ultrasound versus fluoroscopically guided complete supine percutaneous nephrolithotripsy: a first report. j endourol. 2010;24:1421-6. 13. basiri a, mohammadi sichani m. supine percutaneous nephrolithotomy, is it really effective? a systematic review of literature. urol j. 2009;6:73-7. 14. basiri a, ziaee am, kianian hr, et al. ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2008;22:281-4. 15. manohar t, jain p, desai m. supine percutaneous nephrolithotomy: effective approach to high-risk and morbidly obese patients. j endourol. 2007;21:44-9. 16. hoznek a, rode j, ouzaid i, et al. modified supine percutaneous nephrolithotomy for large kidney and ureteral stones: technique and results. eur urol. 2012;61:164-70. 17. ng mt, sun wh, cheng cw, et al. supine position is safe and effective for percutaneous nephrolithotomy. j endourol. 2004;18:46974. 18. yan s, xiang f, yongsheng s. percutaneous nephrolithotomy guided solely by ultrasonography: a 5-year study of >700 cases. bju int. 2013;112:965-71. 19. steele d, marshall v. percutaneous nephrolithotomy in the supine position: a neglected approach? j endourol. 2007;21:1433-7. 20. bach c, goyal a, kumar p, et al. the barts 'flank-free' modified supine position for percutaneous nephrolithotomy. urol int. 2012;89:365-8. 21. kumar p, bach c, kachrilas s, et al. supine percutaneous nephrolithotomy (pcnl): 'in vogue' but in which position? bju int. 2012;110:e1018-21. 22. zhou x, gao x, wen j, et al. clinical value of minimally invasive percutaneous nephrolithotomy in the supine position under the guidance of real-time ultrasound: report of 92 cases. urol res. 2008;36:111-4. 23. hosseini mm, yousefi a, rastegari m. pure ultrasonography-guided radiation-free percutaneous nephrolithotomy: report of 357 cases. springerplus. 2015 jul 3;4:313. 24. nouralizadeh a, pakmanesh h, basiri a, et al. solo sonographically guided pcnl under spinal anesthesia: defining predictors of success. scientifica (cairo). 2016;2016:5938514. guidewire retrieval in gmsv positionkhazaali et al. vol 14 no 06 november-december 2017 5042 miscellaneous the role of ciprofloxacin resistance and extended-spectrum beta-lactamase (esbl) positivity in infective complications following prostate biopsy nesibe korkmaz1*, yunus gürbüz2, fatih sandıkçı3, gülnur kul4, emin ediz tütüncü2, i̇rfan şencan2 purpose: to evaluate ciprofloxacin resistance (cr) and extended-spectrum beta-lactamase (esbl) positivity in the rectal flora, antibiotic prophylaxis received, and post-biopsy infectious complications in patients undergoing prostate biopsy. material & methods: rectal swab samples collected from 99 patients suspected of prostate cancer two days before prostate biopsy were tested for microbial susceptibility and esbl production. all patients were given standard ciprofloxacin and ornidazole prophylaxis. ten days post-biopsy, the patients were contacted by phone and asked about the presence of fever and/or symptoms of urinary tract infection. results: escherichia coli (e.coli) was the most common isolate detected in 82 (75%) of the rectal swab samples. ciprofloxacin resistance was detected in 33% and esbl positivity in 22% of the isolated e.coli strains. no microorganisms other than e.coli were detected in blood, urine, and rectal swab cultures of patients who developed post-biopsy complications. cr e.coli strains also showed resistance to other antimicrobial agents. the lowest resistance rates were to amikacin (n = 2, 7.4%) and nitrofurantoin (n = 1, 3.7%). seven patients (7.6%) developed infectious complications. there was no significant difference in probability of hospitalization between patients with cr strains (14.3%) and those with ciprofloxacin-susceptible strains (14.3% vs. 4.7%; p = 0.194). however, strains that were both cr and esbl-positive were associated with significantly higher probability of hospitalization compared to ciprofloxacin-susceptible strains (28.6% vs. 3.8%; p = 0.009). conclusion: the higher rate of infectious complications with cr and esbl-positive strains suggests that the agents used for antibiotic prophylaxis should be reevaluated. it is important to consider local resistance data when using extended-spectrum agents to treat patients presenting with post-biopsy infectious complications. keywords: ciprofloxacin resistance; esbl; infective complications; prostate biopsy introduction transrectal ultrasound-guided biopsy (trus-bx) is the standard diagnostic method for prostate cancer (pca).(1) although trus-bx is a safe procedure, the incidence of infective complications has risen in recent years.(2) in multicenter studies, reported rates of infectious complications vary between 0.1% and 7% depending on the antibiotic prophylaxis administered.(2) the pathogenesis of post-biopsy infectious complications is complicated. risk factors such as diabetes mellitus (dm), prostatitis, immunosuppression, and repeated prostate biopsies have been identified; however, increasing quinolone resistance (qr) and the presence of extended-spectrum beta-lactamase (esbl)-producing enterobacteriaceae have been mostly emphasized. (3,4,5,6) rising prevalence of fecal carriage of esbl-positive 1department of infectious diseases and clinical microbiology, kahramankazan state hospital, ankara 06080, turkey. 2department of infectious diseases and clinical microbiology, diskapi yildirim beyazit education and research hospital, ankara 06080, turkey. 3department of urology, diskapi yildirim beyazit education and research hospital, ankara 06080, turkey. 4department of infectious diseases and clinical microbiology, kırıkhan state hospital, hatay 31440, turkey. *correspondence: department of infectious diseases and clinical microbiology, kahramankazan state hospital, ankara 06080, turkey. tel: 0505 6951975. e-mail: nesibeaydogan@hotmail.com. received august 2018 & accepted february 2019 pathogens in healthy populations is accompanied by a rapid increase in the rate of infections caused by esbl-producing gram-negative bacteria.(7) esbl-positive bacterial colonization may also cause urosepsis after trus-bx.(8) e.coli and k.pneumonia are the two most prevalent bacteria that synthesize esbl and cause morbidity. gram-negative bacteria that produce one of the esbl enzymes are generally resistant to all extended-spectrum cephalosporins and aztreonam.(9) the frequency of qr together with esbl positivity in e.coli ranges from 50% to 100%.(10) co-resistance to extended-spectrum beta-lactams and quinolone may be attributed to the wide use of quinolones like beta-lactam agents, as well as to multi-resistant gene transfer between patients via plasmids carrying esbl-encoding genes.(11) it is believed that there is a strong correlation between esbl-positive and ciprofloxacin-resistant bacteria and infectious complications after prostate biurology journal/vol 17 no. 2/ march-april 2020/ pp. 192-197. [doi: 10.22037/uj.v0i0.4755] vol 17 no 02 march-april 2020 193 opsy.(12) due to increasing rates of complications after prostate biopsy in our hospital, we conducted this study to determine antibiotic resistance profiles of the rectal flora and the frequency of esbl production among patients undergoing prostate biopsy, and evaluate the relationship between post-biopsy infectious complications and floral resistance profiles, comorbidities, and other factors. materials and methods study population this prospective study was conducted at ankara dışkapı training and research hospital, which has a patient capacity of 850. ninety-nine patients were scheduled for trus-bx between october 2015 and october 2016 for suspected prostate cancer (suspicious digital rectal examination and/or prostate specific antigen [psa] over 2.5 ng/ml). patients and their relatives were questioned about antibiotic use on the day the rectal swab culture was taken. patients taking antibiotics were not included in the study. presence / absence of post-biopsy infective complications were the main analyzed outcome (primary outcome) of this study. study design ethics committee approval was obtained from ankara dışkapı training and research hospital (decision number 36/10) and informed consent was obtained from all patients included in the study. rectal swab samples were obtained two days before prostate biopsy. the patients were questioned regarding risk factors, including age, smoking, use of ciprofloxacin in the last six months, catheterization history, urogenital infection, previous biopsy history, and comorbidities such as dm, chronic obstructive pulmonary disease (copd), cancer, hypertension (ht), hemorrhoids, immunosuppression, history of heart valve replacement, benign prostatic hyperplasia (bph). after culture incubation, isolates found to be gram-negative and oxidase negative were identified using citrate agar, triple sugar iron (tsi) agar, and motility-indole-lysine(mil) agar broths. api 20e kit was used for bacteria that could not be identified by those methods. antibiotic susceptibility tests were done using kirby-bauer disc diffusion method as per the recommendations of the european committee on antimicrobial susceptibility testing. esbl production was detected using modified disc (combined disc) diffusion test (eucast v. 6.0, 2018). antibiotic susceptibility was determined using ciprofloxacin (cip, 5µg), levofloxacin (lev, 5µg), ampicillin (amp, 10µg), amoxicillin/ clavulanic acid (amc, 20/10µg), cefepime (fep, 30µg), cefuroxime (cxm, 30µg), gentamicin (gm, 10µg), amikacin (ak, 30µg), tmp-sxt (1.25/23.75µg), cefoxitin (fox, 30µg), cefotaxime (ctx, 5µg), ceftriaxone (cro, 30µg), and ceftazidime (caz, 10µg) discs. biopsy technique and patient follow-up patients were prescribed 500 mg ciprofloxacin and 500 mg ornidazole every 12 hours for 5 days (taken the day before the procedure, in the morning of the procedure, and for 3 days post-biopsy)(1,13,14). all patients underwent bowel cleansing about 2-4 hours prior to biopsy. transrectal ultrasound-guided 12-core systematic biopsy using an 18-gauge biopsy needle was done as an outpatient procedure in an examination room in the urology ward. the patients were contacted by phone 10 days after biopsy and questioned about symptoms of fever, urinary incontinence, rectal blinding, bloody voiding, frequent urination, and flank pain. symptoprostate biopsy infection complications and antibiotic resistancekorkmaz et al. table 1. patients characteristics. number of patients 92 age, year; mean ± sd 63.6 ± 7.2 variables n (%) smoking status 22 (23.9) antibiotic use in the last 6 months 59 (64.8) ciprofloxacin use in the 6 months 43 (46.7) clinical history urogenital infection 9 (9.8) catheterization history 8 (8.7) previous biopsy history 32 (34.8) number of prior biopsies 1 26 (81.3) 2 5 (15.6) 3 1 (3.1) comorbidities copd 7 (7.6) dm 20(21.7) ht 32 (34.8) hemorrhoids 13 (14.1) bph 41 (44.6) biopsy results a (n=86) bph 4 (4.7) adenocarcinoma 19 (22.1) benign prostate tissue 39 (45.3) chronic active inflammation 26 (28.3) stool culture pathogen b(n=102) e. coli 76 (74.5) klebsiella 10 (9.8) enterobacter 6 (5.9) proteus 4 (3.9) pantoea 3 (2.9) citrobacter 2 (2.0) hafnia 1 (1.0) post-biopsy complications hospital admission 7 (7.6) abbreviations: copd, chronic obstructive pulmonary disease; dm, diabetes mellitus; ht, hypertension; bph, benign prostatic hyperplasia; a biopsy results were available for 86 patients. b numbers and percentages are based on total agents isolated. figure 1. ciprofloxacin resistance and esbl positivity detected in 99 patients. matic patients were advised to seek medical attention immediately. patients who presented to the emergency department with fever ≥38°c and/or urinary symptoms, and met the systematic inflammatory response syndrome (sirs) criteria for sepsis were admitted. hospitalized patients had blood and urine cultures and were evaluated for infection-related complications based on three criteria: symptomatic urinary system infection, acute prostatitis, and sepsis. statistical analysis descriptive and advanced analyses were performed using spss, open epi, and excel programs. potential risk factors were evaluated using estimated odds ratio (or), 95% confidence interval (ci), and 5% margin of error. p value < 0.05 was considered statistically significant. chi square test and fischer’s exact test swere used to test relationships between categorical variables. resistance levels to other antibiotics tested in the study were evaluated in ciprofloxacin-resistant isolates. a logistic regression model was used to predict the risk factors for ciprofloxacin resistance. the model included the following variables: history of catheter use, history of repeat biopsy, history of urogenital infections, and ciprofloxacin use in the last 6 months. the wald test (enter method) was used in the model. results the rectal swab samples of 99 patients were analyzed for esbl positivity, ciprofloxacin resistance, and related risk factors. on the day of biopsy, seven patients objected to the procedure for various reasons. therefore, post-biopsy complications were assessed in 92 patients. evaluation of the study group is presented in table 1. e.coli was the predominant agent isolated from rectal swab samples. e.coli was also the only agent isolated in blood and urine cultures and rectal swab samples of patients who had complications; no other microorganisms were detected. the prevalence of ciprofloxacin resistance was 27.5% and rate of esbl positivity was 19.3% in the fecal flora of the 109 agents isolated from 99 patients (figure 1). most of the ciprofloxacin-resistant e.coli strains also exhibited resistance to other antimicrobial agents. resistance was lowest to amikacin (n = 2, 7.4%) and nitrofurantoin (n = 1, 3.7%). ciprofloxacin-resistant e.coli strains were significantly resistant to all antibiotics tested (table 2). ciprofloxacin use in the previous six months was identified as a significant risk factor for ciprofloxacin resistance (p = .008). cr was not associated with the presence of dm, ht, bph, history of repeated biopsies, or the use of antibiotics other than quinolone. after controlling for other factors, the logistic regression model indicated that catheter use increased the risk of developing ciprofloxacin resistance by 7.4 fold, urogenital infection history by 5.4 fold, and ciprofloxacin use in the last 6 months by 2.9 fold (table 3). post-biopsy infectious complications were evaluated in 92 patients. the infectious complications and features of the bacteria isolated in 7 (7.6%) patients who were hospitalized are summarized in figure 2. two of the 7 patients were treated in the intensive care unit. there were no mortalities. in terms of comorbidities, when compared as inpatients and outpatients, the estimated relative risk of dm was 1.5 times higher among inpatients than outpatients, but the difference was not statistically significant (95% ci: 0.3-8.3) (p = .643). there was no significant difference in probability of hospitalization between patients with ciprofloxacin-resistant strains and those with ciprofloxacin-susceptible strains (p = .194). however, the probability of hospitalization was significantly greater in patients showing rectal flora colonization with ciprofloxacin-resistant table 2. resistance rates to other antimicrobial agents in ciprofloxacin-susceptible and resistant e. coli isolates antibiotic resistance ciprofloxacin-resistant ciprofloxacin-sensitive p or (95% ci) levels and esbl positivity e. coli n=27 e. coli n=55 n % n % ampicillin 21 77.8 23 41.8 .002 4.8 (1.7-14.8) amc 18 66.7 15 27.3 .001 5.2 (1.9-14.7) cefuroxime 11 40.7 6 10.9 .002 5.5 (1.7-18.4) cefoxitin 8 29.6 2 3.6 .001 10.8 (2.3-80.0) ceftriaxone 10 37.0 6 10.9 .005 4.7 (1.5-15.9) cefotaxime 12 44.4 6 10.9 .001 6.4 (2.1-21.3) ceftazidime 11 40.7 6 10.9 .002 5.5 (1.8-18.4) cefepime 9 33.3 4 7.3 .002 6.2 (1.7-25.8) amikacin 2 7.4 .187 6.8 (0.4-261.0) gentamicin 8 29.6 1 1.8 < .001 21.8 (3.2-516.5) nitrofurantoin 1 3.7 .220 4.1 (0.3-124.3) sxt 17 63.0 14 25.5 .001 4.9 (1.8-13.6) esbl 12 44.4 6 10.9 .001 6.4 (2.1-21.3) abbreviations: amc, amoxicillin-clavulanate; sxt, trimethoprim-sulfamethoxazole; esbl, extended-spectrum beta-lactamases risk factors p or adj 95% ci catheter history (yes/no) 0.030 7.4 1.2-45.6 repeated biopsy (yes/no) 0.249 1.9 0.6-5.5 urogenital infection history (yes/no) 0.057 5.4 1.0-30.9 ciprofloxacin use in the last 6 months (yes/no) 0.037 2.9 1.1-8.2 constant 0.244 table 3. logistic regression analysis of ciprofloxacin resistance and related risk factors. prostate biopsy infection complications and antibiotic resistancekorkmaz et al. miscellaneous 194 vol 17 no 02 march-april 2020 195 and esbl-positive strains compared to those with susceptible strains (p = .009). discussion increasing rates of quinolone resistance and esbl-producing bacteria pose the greatest concern regarding post-biopsy infectious complications.(4,6) the prevalence of fluoroquinolone resistance in rectal flora was reported as 10.6% by batura et al. in 2010, compared to 25% in a study by liss et al. in 2015.(15,16) in our study, quinolone resistance was calculated as 27% overall and 33% in the predominant agent, e. coli. in another study conducted in our region in 2014, fluoroquinolone resistance was reported at a similar rate (32.7%).(17) tigen et al., who also analyzed patient data in our region, reported the prevalence of esbl in rectal samples as 18%.(18) in our study, the prevalence of esbl positivity in the rectal swab samples of 99 patients was 19.3% for all agents and 22% for e. coli. although it is known that the use of quinolone antibiotics increases the prevalence of resistant bacteria in fecal flora, yağcı et al. pointed out that there is a paucity of data regarding how long the flora maintains such resistance after antibiotics are discontinued.(19) in line with previous studies, our analysis of cr and related risk factors showed that the use of ciprofloxacin in the previous six months was a statistically significant risk factor. e.coli may also develop resistance to other antibiotics by means of efflux pumps, enzymatic target modification and reduced membrane permeability.(20) minamida et al. compared quinolone-resistant and susceptible e.coli isolates with regard to their resistance to other antimicrobials and reported that resistant strains developed stronger resistance to other antibiotics compared to the quinolone-susceptible strains.(21) in this study, amikacin and phosphomycin resistance were not detected in quinolone-resistant isolates. similarly, hasanzadeh et al. showed that antibiotics with the least resistance in quinolone-resistant strains were amikacin (10.6%), phosphomycin (5.3%), and nitrofurantoin. when we performed a similar comparison between the two groups in our study, we observed higher resistance to antibiotics other than amikacin and nitrofurantoin.(22) although resistance to nitrofurantoin was low, this antibiotic does not have good tissue penetration and hence is not suitable for the treatment of infectious complications of the kidney parenchyma or prostate tissue.(23) phosphomycin resistance was not detected. the findings suggest that multidrug-resistant bacteria are becoming a major concern and are restricting the already limited treatment options. in multicenter studies, rates of post-biopsy infectious complications vary between 0.1% and 7% and sepsis rates between 0% and 3.6% depending on the antibiotic prophylaxis used.(2) in our study, 7 of the 92 patients (7.6%) were hospitalized and urosepsis was diagnosed in 5 patients (5.4%). our high rate of infectious complications may be related to the higher resistance rates. in hospitalized patients, the predicted relative risk of ciprofloxacin resistance and esbl positivity in the case of rectal swabs is 10.0 fold (95% ci: 2.0-51.3). among the 5 patients diagnosed with urosepsis, 4 had strains that were both esbl-positive and ciprofloxacin-resistant. previous studies have demonstrated that agents with both esbl positivity and ciprofloxacin resistance are strongly associated with post-biopsy infections.(12) of the 7 patients who were hospitalized in this study, 2 patients who had negative rectal swabs for ciprofloxacin-resistant, esbl-positive bacteria had a history of uncontrolled dm. dm has been shown to be an important risk factor for the development of infectious complications.(24,25) post-biopsy infectious complications developed in 10% of our diabetic patients. diabetes was also associated with a 1.5-fold higher risk of hospitalization, but this relationship was not statistically significant. due to increasing rates of esbl and quinolone resistance, a combination of quinolones with aminoglycosides is suggested in studies.(26,27) lorber et al. reported figure 2. outcome of the patients hospitalized post-biopsy due to infectious complications. prostate biopsy infection complications and antibiotic resistancekorkmaz et al. an 83% reduction in urosepsis cases with the administration of intramuscular gentamicin and ciprofloxacin prophylaxis.(27) on the other hand, miyazaki et al. compared patients given only levofloxacin prophylaxis and patients given combined amikacin and levofloxacin, and found no significant difference between the groups in terms of post-biopsy pyretic urinary tract infection. the authors attributed this to the effectiveness of the route of administration on the prostatic tissue and underlined the need for further investigation.(28) the present study has some limitations. although information regarding antibiotic use was obtained verbally from patients and confirmed using the hospital records system, there remains the possibility that some drugs were taken without a prescription or the patient did not recall taking them. resistance rates can also vary depending on the culture methods. moreover, if esbl-producing strains carry an additional enzyme not inhibiting byclavulanic acid (e.g. metallo-beta-lactamase or ampc enzyme), the sensitivity of the test decreases significantly. this can be avoided by using chromogenic agar, using agar containing cloxacillin, supplementing with edta to inactivate metallo-beta-lactamases, and using cefepime, which is a weak substrate for most ampc enzymes. despite the fact that most automated systems have these capabilities, the diagnostic sensitivity of these methods is lower than that of classical methods.(29) conclusions quinolone-resistant strains can develop co-resistance to multiple agents. in particular, there appears to be a steady rise in esbl production among quinolone-resistant strains. this suggests that esbl data should be considered as well as quinolone resistance when planning antibiotic prophylaxis. another important finding of this study is the higher rate of post-biopsy infection associated with strains that are both ciprofloxacin-resistant and esbl-positive. therefore, broad-spectrum antibiotics must be considered in the selection of empirical antibiotics. conflict of interest the authors report no conflict of interest. references 1. heidenreich, a., et al., eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent— update 2013.eur urol, 2014,65: 124-137 2. loeb, s., et al., systematic review of complications of prostate biopsy.eur urol, 2013.64: 876-92. 3. liss, m.a., et al., the preventıon and treatment of the more common complıcatıons related to prostate bıopsy update. 2016. 4. taylor, s., et al., ciprofloxacin resistance in the faecal carriage of patients undergoing transrectal ultrasound guided prostate biopsy. bju int, 2013.111: 946-53. 5. zowawi, h.m., et al., the emerging threat of multidrug-resistant gram-negative bacteria in urology. nat rev urol, 2015.12: 570-84. 6. song, w., et al., incidence and management of extended-spectrum beta-lactamase and quinolone-resistant escherichia coli infections after prostate biopsy.urology, 2014.84: 10017. 7. woerther, paul-louis, et al. "trends in human fecal carriage of extended-spectrum β-lactamases in the community: toward the globalization of ctx-m." clinical microbiology reviews 26.4 (2013): 744-758. 8. hadway, p., et al., urosepsis and bacteraemia caused by antibiotic‐resistant organisms after transrectal ultrasonography‐guided prostate biopsy.bju int, 2009.104: 1556-8. 9. bennett, j.e., r. dolin, and m.j. blaser, mandell, douglas, and bennett's principles and practice of infectious diseases. 2014: elsevier health sciences. 10. pitout, j.d., infections with extended-spectrum β-lactamase-producing enterobacteriaceae. drugs, 2010.70: 313-3. 11. lautenbach, e., et al., risk factors for fluoroquinolone resistance in nosocomial escherichia coli and klebsiella pneumoniae infections.archives of internal medicine, 2002.162:2469-77. 12. williamson, d.a., et al., infectious complications following transrectal ultrasound–guided prostate biopsy: new challenges in the era of multidrug-resistant escherichia coli. clinical infectious diseases, 2013. 57: 267-74. 13. american urological association. best practice policy statement on urologic surgery antimicrobial prophylaxis. available at:http:// w w w . a u a n e t . o r g / e d u c a t i o n / g u i d e l i n e s / antimicrobialprophylaxis.cfm 14. brewster, s., et al., fatal anaerobic infection following transrectal biopsy of a rare prostatic tumour.b j urol, 1993.72: 977-8. 15. steensels, d., et al., fluoroquinolone‐resistant e. coli in intestinal flora of patients undergoing transrectal ultrasound‐guided prostate biopsy—should we reassess our practices for antibiotic prophylaxis? clin microbiol inf, 2012;18: 575-81. 16. liss, m.a., et al., comparative effectiveness of targeted vs empirical antibiotic prophylaxis to prevent sepsis from transrectal prostate biopsy: a retrospective analysis.j urol, 2015.194: 397-402 17. tigen, e.t., et al., outcomes of fecal carriage of extended-spectrum β-lactamase after transrectal ultrasound–guided biopsy of the prostate.urology, 2014.84: 1008-15 18. kisa, erdem, et al. "fosfomycin: a good alternative drug for prostate biopsy prophylaxis the results of a prospective, randomized trial with respect to risk factors." intl braz j urol 2017; 43: 1068-74. 19. yagci, d., et al., prevalence and risk factors for selection of quinolone-resistant escherichia prostate biopsy infection complications and antibiotic resistancekorkmaz et al. miscellaneous 196 vol 17 no 02 march-april 2020 197 coli strains in fecal flora of patients receiving quinolone therapy.antimicrobial agents and chemotherapy, 2009.53: 1287-9 20. sieczkowski, m., et al., fluoroquinolonebased antimicrobial prophylaxis in patients undergoing transrectal ultrasound-guided prostate biopsy.european j clin microbiol & inf dis, 2015.34: 1815-21 21. minamida, s., et al., prevalence of fluoroquinolone-resistant escherichia coli before and incidence of acute bacterial prostatitis after prostate biopsy.urology, 2011.78: 1235-9. 22. hasanzadeh, amir, et al. "prevalence and significance of fluoroquinolone-resistant bacteria carriage in patients undergoing transrectal ultrasound prostate biopsy." urol j 2017; 14: 3085-90. 23. lipsky, b.a., i. byren, and c.t. hoey, treatment of bacterial prostatitis.clinical infectious diseases, 2010;50: 1641-52. 24. tsu, j.h.-l., et al., prevalence and predictive factors of harboring fluoroquinoloneresistant and extended-spectrum β-lactamase–producing rectal flora in hong kong chinese men undergoing transrectal ultrasound-guided prostate biopsy.urology, 2015;85: 15-22. 25. kehinde, e.o., et al., combined ciprofloxacin and amikacin prophylaxis in the prevention of septicemia after transrectal ultrasound guided biopsy of the prostate.j urol, 2013;189: 911-5. 26. womble, p.r., et al., a statewide intervention to reduce hospitalizations after prostate biopsy.the j urol, 2015;194: 403-9. 27. lorber, g., et al., a single dose of 240 mg gentamicin during transrectal prostate biopsy significantly reduces septic complications. urology, 2013;82: 998-1003. 28. miyazaki, yu, et al. "a prospective randomized trial comparing a combined regimen of amikacin and levofloxacin to levofloxacin alone as prophylaxis in transrectal prostate needle biopsy." urol j 2016; 13: 2533-40. 29. akova m., genişlemişspektrumlu betalaktamazlarveklinikönemi in: gramnegatifbakterii̇nfeksiyonları ed: s. ulusoy, h. leblebici, d. arman, bilimsel tıp yayınevi, 2012 :79-90 prostate biopsy infection complications and antibiotic resistancekorkmaz et al. endourology and stone disease flexible ureterorenoscopy management of calyceal diverticular calculi houmeng yang, xuping yao, chunbo tang, yuxi shan, guobin weng* objective: to introduce flexible ureterorenoscopy with holmium laser lithotripsy in the management of symptomatic caliceal diverticular calculi. materials and methods: the records of 26 patients who underwent flexible ureterorenoscopy and lithotripsy with holmium laser to manage symptomatic caliceal diverticular calculi from january 2012 to june 2016 were retrospectively reviewed. result: flexible ureterorenoscopy lithotripsy was successfully placed in all 26 patients. twenty-two cases accepted lithotripsy at the same time, and the success rate was 84.6%. the stone-free rate was 76.9%.the mean operative time was 48 ± 16 minutes. the mean hospital stay was 4.8 ± 1.6 days. there was no evidence of stone regrowth or recurrence at a mean follow-up of 11.5 months. conclusion: flexible ureterorenoscopy with holmium laser lithotripsy is safe and effective, and it can be offered as a first line therapy for symptomatic caliceal diverticular calculi. keywords: flexible ureterorenoscopy; stone disease; caliceal diverticula; ultrasound; puncture introduction calyceal diverticula are rare renal anomalies in the renal parenchyma that result in nonsecreto-ry, urothelial-lined cavities that are filled with urine refluxing from an adjacent collecting system(1,2). the connection between diverticula and the collecting system may be often very small and has limited drainage, resulting in infection and stone formation. diverticula are more commonly associated with the upper and mid-calyceal systems. although mostly asymptomatic, the indications for treatment of the calyceal diverticular calculi are related to flank pain, hematuria, and recurrent infection(3). current treatment options for the stone-bearing diverticula include extracorporeal shock wave lithotripsy (swl)(4,5),percutaneous nephrolithotomy (pnl)(6,7), flexible ureterorenoscopy lithotripsy (f-ursl)(7,8), and laparoscopic approaches(9). in recent years, f-ursl has been most commonly accepted by urologists for treating the stone-bearing diverticula because it iss less invasive and more efficient. materials and methods the records of 26 patients who underwent flexible ureterorenoscopy (7.5f storz) with holmium laser lithotripsy to manage symptomatic calyceal diverticular calculi from january 2012 to june 2016 were retrospectively reviewed. the demographic data and medical information were obtained from their medical records and charts (table 1). all patients were evaluated by medical history, physical examination, complete blood count, plasma urea and creatinine values, coagulation profiles, urinaldepartment of urology, ningbo urologic and nephrotic hospital, ningbo 315000, china. *correspondence: department of urology, ningbo urologic and nephrotic hospital, qianhe road 1, ningbo 315000, china. tel: +86 0574 55662999. fax: +86 13732112880. e-mail: 511538235@qq.com. received june 2017 & accepted august 2017 ysis and urine cultures. urinary infection was treated with appropriate antibiotics before the operations. six patients received a jj stent through cystoscopy outpatient two weeks before f-ursl, but the other patients refused the procedure. for 5 patients, prior treatment with swl was unsuccessful. all patients underwent ct urography before the operation (figure 1). f-ursl procedures were best performed under general anesthesia with the patient placed in the lithotomy position. rigid ureteroscopy (8/9.8f wolf) was routinely performed before flexible ureterorenoscopy in all patients to dilate the ureter and place a hydrophilic guidewire into the renal pelvis. thereafter, a ureteral access sheath (12-14f cook) was passed over the hydrophilic guidewire as far as the ureteropelvic junction. when the access sheath could not be advanced easily, the stent was remained for 2 weeks before repeating the procedure. the flexible ureterorenoscopy was inserted through the ureteral access sheath to identify the diverticular neck. if necessary, it was guided by ultrasound (figure 2)or used the blue spritz technique. the diverticular neck was gradually incised with a 200μm holmium laser probe and the stones were fragmented until they were deemed small enough to be passed spontaneously (figure 3). the small fragments were flushed out of the diverticulum or extracted using nitinol stone baskets (1.7 f cook). a jj stent was placed at the end of the procedure, if possible, it was placed with the upper segment within the diverticulum or the calyces, which was removed approximately 2-4 weeks postoperatively. a kub was obtained to observe the position of the jj stent．renal ultrasound was conducted to observe per endourology and stone diseases 12 vol 16 no 01 january-february 2019 13 inephric effusion or hematoma two days after surgery. a spiral ct was performed 1 month postoperatively to evaluate the status of the stones. symptom-free status was assessed at 2 months postoperatively. evaluation and scoring of complications were based on the modified clavien-dindo classification(10). results the 26 patients included 11 males and 15 females, the average patients’ age was 35.2 ± 13.6 years (range, 2562). all patients had unilateral calyceal diverticulum calculi, with 12, 9,and 5 cases having calyceal diverticular calculi in the upper pole, middle pole and lower pole of the kidney respectively. sand-like stones were observed in some calyceal diverticula. the average diameter of the stone was 12.3 ± 4.8mm. the presenting symptoms were flank pain (80.8%), recurrent infection(34.6%) ,and hematuria(19.2%) f-ursl was successfully placed in all 26 patients. twenty-two cases accepted lithotripsy at the same time, and the success rate was 84.6%. the stone-free rate was 76.9%. twenty-two patients were symptom free after the operation. the mean operative time was 48 ± 16 minutes. the mean hospital stay was 4.8 ± 1.6 days. caliceal diverticula were not found in 4 cases under flexible ureterorenoscopy. two cases accepted mini-pnl while 2 cases refused further treatment. there was no evidence of stone regrowth or recurrence at a mean follow-up of 11.5 months. four patients suffered from complications (clavien i-ii). three patients had postoperative fever, which was treated medically. one patient suffered from urine leak for the jj stent bend, the perirenal effusion was absorbed 2 weeks later after repositioning of the jj stent. discussion the pathogenesis of calculi within calyceal diverticula remains controversial and appears to be multifactorial. although the most common hypotheses include urinary stasis and metabolic derangements, the exact mechanisms of stone development in diverticula are unknown(11,12). most asymptomatic calyceal diverticular calculi do not require treatment. the indications for treatment of the calyceal diverticular calculi are related to flank pain, hematuria, and recurrent infection. current treatment options of the stone-bearing diverticula include swl,pnl,f-ursl and laparoscopic approaches. although technically simpler and potentially safer, stone-free rates with swl have not been comparable with pnl and f-ursl methods(13). batter and dretler utilized f-ursl in 26 patients with symptomatic calyceal diverticula, and, 18(70%) of the cases were treated successfully(1). in recent years, more and more urologists have chosen to use f-ursl because it is less invasive and more efficient. before performing f-ursl, urinary infection must be treated with appropriate antibiotics. perioperatively, broad-spectrum antibiotic prophylaxis should be instituted. imaging information (ivp or ctu) should be available to provide a road map table 1. demographic characteristics and surgical statistics variable value gender(n) male 11 female 15 age (years) 35.2 ± 13.6 (25-62) stone burden(mm) 12.3 ± 4.8 (0.8-18.6) location of diverticula (n) upper pole 12 middle pole 9 lower pole 5 surgery time (min) 48 ± 16 ± (37~84) success rate 84.6% symptomatic success 84.6% stone-free rate 76.9% hospitalization time (day) 4.8 ± 1.6 (4~9) complications(clavien i-ii) (n) 4 fever 3 urine leak 1 figure 1. left upper pole diverticulum . figure 2. look for the diverticular neck guided by ultrasound. management of calyceal diverticular calculi-yang et al. inephric effusion or hematoma two days after surgery. a spiral ct was performed 1 month postoperatively to evaluate the status of the stones. symptom-free status was assessed at 2 months postoperatively. evaluation and scoring of complications were based on the modified clavien-dindo classification(10). results the 26 patients included 11 males and 15 females, the average patients’ age was 35.2 ± 13.6 years (range, 2562). all patients had unilateral calyceal diverticulum calculi, with 12, 9,and 5 cases having calyceal diverticular calculi in the upper pole, middle pole and lower pole of the kidney respectively. sand-like stones were observed in some calyceal diverticula. the average diameter of the stone was 12.3 ± 4.8mm. the presenting symptoms were flank pain (80.8%), recurrent infection(34.6%) ,and hematuria(19.2%) f-ursl was successfully placed in all 26 patients. twenty-two cases accepted lithotripsy at the same time, and the success rate was 84.6%. the stone-free rate was 76.9%. twenty-two patients were symptom free after the operation. the mean operative time was 48 ± 16 minutes. the mean hospital stay was 4.8 ± 1.6 days. caliceal diverticula were not found in 4 cases under flexible ureterorenoscopy. two cases accepted mini-pnl while 2 cases refused further treatment. there was no evidence of stone regrowth or recurrence at a mean follow-up of 11.5 months. four patients suffered from complications (clavien i-ii). three patients had postoperative fever, which was treated medically. one patient suffered from urine leak for the jj stent bend, the perirenal effusion was absorbed 2 weeks later after repositioning of the jj stent. discussion the pathogenesis of calculi within calyceal diverticula remains controversial and appears to be multifactorial. although the most common hypotheses include urinary stasis and metabolic derangements, the exact mechanisms of stone development in diverticula are unknown(11,12). most asymptomatic calyceal diverticular calculi do not require treatment. the indications for treatment of the calyceal diverticular calculi are related to flank pain, hematuria, and recurrent infection. current treatment options of the stone-bearing diverticula include swl,pnl,f-ursl and laparoscopic approaches. although technically simpler and potentially safer, stone-free rates with swl have not been comparable with pnl and f-ursl methods(13). batter and dretler utilized f-ursl in 26 patients with symptomatic calyceal diverticula, and, 18(70%) of the cases were treated successfully(1). in recent years, more and more urologists have chosen to use f-ursl because it is less invasive and more efficient. before performing f-ursl, urinary infection must be treated with appropriate antibiotics. perioperatively, broad-spectrum antibiotic prophylaxis should be instituted. imaging information (ivp or ctu) should be available to provide a road map table 1. demographic characteristics and surgical statistics variable value gender(n) male 11 female 15 age (years) 35.2 ± 13.6 (25-62) stone burden(mm) 12.3 ± 4.8 (0.8-18.6) location of diverticula (n) upper pole 12 middle pole 9 lower pole 5 surgery time (min) 48 ± 16 ± (37~84) success rate 84.6% symptomatic success 84.6% stone-free rate 76.9% hospitalization time (day) 4.8 ± 1.6 (4~9) complications(clavien i-ii) (n) 4 fever 3 urine leak 1 figure 1. left upper pole diverticulum . figure 2. look for the diverticular neck guided by ultrasound. management of calyceal diverticular calculi-yang et al. endourology and stone diseases 14 vol 16 no 01 january-february 2019 15 management of calyceal diverticular calculi-yang et al. 1. batter sj, dretler sp: ureteroscopic approach to the symptomatic caliceal diverticulum. j urol .1997;158:709-713, 2. gross aj, fisher m. management of stones in patients with anomalously sited kidneys. curr opin urol. 2006; 16:100-105. 3. jr m a, pfister r c. stone-containing pyelocaliceal diverticulum: embryogenic, anatomic, radiologic and clinical characteristics.j urol, 1974;111:2-6. 4. hayashi m, kobayashi k, tanaka g, et al. treatment of caliceal diverticular calculi with extracorporeal shock wave lithotripsy. nishinihon journal of urology, 2002;64:141 5. 5. psihramis ke, dretler sp.extracorporeal shock wave lithotripsy of caliceal diverticula calculi. j urol .1987;138:707-711. 6. elshal a m, shoma a m, shokeir a a. percutaneous nephrolithotomy (pcnl) for calyceal diverticulum: an egyptian experience[m]// difficult cases in endourology. springer london, 2013:161 168. 7. bas o, ozyuvali e, aydogmus y, et al. management of calyceal diverticular calculi: a comparison of percutaneous nephrolithotomy and flexible ureterorenoscopy[j]. urolithiasis, 2015, 43(2):155-61. 8. sejiny m, alqahtani s, elhaous a, molimard b, traxer o . efficacy of flexible ureterorenoscopy with holmium laser in the management of stone-bearing caliceal diverticula.[j]. j endourol, 2010, 24:961-7. 9. miller sd, ng cs, streem sb, gill is. laparoscopic management of caliceal diverticular calculi. j urol.2002;167:1248 1252. 10. dindo d. demartines n. clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg 2004; 240:205-213. 11. auge bk, maloney me, mathias bj ,pietrow pk．preminger gm. metabolic abnormalities associated with calyceal diverticular stones. bju int,2006;97:10531056. 12. matlaga br, miller nl, terry c et al. the pathogenesis of calyceal diverticular calculi. urol res.2007; 35:35-40. 13. jones j a, lingeman j e, steidle c p. the roles of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy in the management of pyelocaliceal diverticula. j urol, 1991, 146:724-7. 14. long c j, weiss d a, kolon t f, srinivasan ak, shukla. pediatric calyceal diverticulum treatment: an experience with endoscopic and laparoscopic approaches. journal of ped urol, 2015,11:172.e1-172.e6. 15. gross a j, herrmann t r. management of stones in calyceal diverticulum. curr opin urol, 2007, 17:136-40. pediatric urology evaluation of the effect of meatal stenosis on the urinary tract by using ultrasonography parisa saeedi1, hassan ahmadnia 2, alireza akhavan rezayat 3* purpose: circumcision is one of the oldest surgical procedures that originated for religious purposes. circumcision in infancy is a common procedure in our country and secondary meatal stenosis due to circumcision is a common complication. the aim of our study is to determine the effect of meatal stenosis on the lower and upper urinary tract of circumcised boys by using ultrasonography. materials and methods: in this cross-sectional study, we enrolled 87 circumcised boys between 4 to 8 years old with severe meatal stenosis. clinical findings of our subjects were gathered by a checklist that included: thin stream of urine, upward urine stream deviation, infrequent voiding, urinary tract infections, voiding dysfunction, and urge incontinency. in lab data analysis, complete blood cell count (cbc), urine analysis, urine culture, blood urea nitrogen (bun), and plasma creatinine level were evaluated. ultrasonography detected hydronephrosis, hydroureter, bladder wall thickening in a full and empty bladder, bladder volume, and residual urine volume. result: narrowing of urine stream is commonly seen (about 54%) among patients with severe meatal stenosis, and similarly in sonographic evaluations the most common symptoms among patients was thickening of the bladder wall that increased in an empty and a full bladder (about 82%). conclusion: the author of this study recommends performing long-term follow up after circumcision and ultrasonography to detect meatal stenosis before permanent renal damage occurs. keywords: bladder; circumcision; meatoplasty; meatal stenosis; ultrasonography. introduction circumcision in one of the oldest surgical proce-dures that was originally used for religious purposes and religious circumcision is still done by muslims and jews worldwide(1). this surgery is also common in christian americans and is performed for cultural, medical, or aesthetic reasons among africans and native australians(2,3). hence, about one in three males worldwide are circumcised(3). in iran, most boys are circumcised between infancy and the age of 4-5 years(4). in north america, circumcisions are routinely performed in newborns(5).the aim of circumcision is to excise sufficient foreskin (both penile shaft and inner preputial epithelium) to leave the glans uncovered(1). there are four well-known scientific techniques (dorsal slit, shield, clamp, and excision) for performing circumcision(1). circumcision is also a protective procedure against urinary tract infection, acquired immunodeficiency syndrome (aids), other sexually transmitted diseases, and penile malignancy(3,6). similar to other surgical procedures, circumcision has operative and postoperative complications(5). early and intraoperative complications such as pain, bleeding, swelling, wound infection, meatitis, and inadequate skin removal are mostly slight and treatable(3). early complications such as bleeding are reported in 0.1-35% of patients(5), wound infection in 0.2-0.4%, and meatitis in 8-31%(2). the possible explanation for this low complication rate is probably under-reporting or late diagnosis (2). late complications include errors of emission and commission, concealed penis, meatal stenosis, inclusion cyst, secondary cordee, urethrocutaneous fistula, phimosis, lymphedema, wound infection, skin bridge formation between the penile shaft and the glans, urinary retention, meatal ulcer, loss of penile sensitivity, sexual dysfunction, and death from excess bleeding (3). when circumcision is performed in the neonatal period meatal stenosis is one of the late-onset complications(7). meatal stenosis can be congenital primarily in neonates with hypospadias or acquired mainly after circumcision. during circumcision, removal of the foreskin may induce significant meatal inflammation and cicatrix formation. frenular devascularization and chronic meatitis from diaper irritation of the exposed unprotected meatus and chemical dermatitis caused by urine after circumcision may be another cause of meatal stenosis(8). the normal urethral meatus is 10 french before 4 years of age, 12 french from 4 to 10 years of age, and 14 french after 10 years of age. meatal stenosis remains asymptomatic until urinary control is achieved (8). meatal stenosis should be considered in cases of reported urinary stream deviation in an upward direction resulting from a meatal baffle, narrow high velocity-stream, penile pain at the initiation of micturition, and the need to sit or stand back from the toilet bowel. in rare cases, severe symptoms are voiding dysfunction, urinary retention, urinary tract infection, decompensation of the bladder, vesicoureteral reflux, hydro1assistant professor of urology, mashhad university of medical science, mashhad, iran. 2professor of urology, mashhad university of medical science, mashhad, iran. 3assistant professor of urology, mashhad university of medical science, mashhad, iran. *correspondence: ghaem hospital. ahmad abad ave. mashhad. iran. mobile number: +989153148223. fax: 00985138012857.alirezaakhavan30@yahoo.com. received february 2017 & accepted april 2017 pediatric urology 3071 nephrosis, and renal failure(4,6,9). obstructive uropathy is reported as a rare complication of post-circumcision meatal stenosis(8). meatal stenosis is divided into mild, moderate to severe, and severe. mild types of meatal stenosis do not require any treatment, while in moderate to severe types treatment can be done using topical ointment or urethral dilation. in severe types, surgery such as meatotomy should be performed(1,7) as a curative procedure(1). urinary tract images, such as upper and lower urinary tract ultrasonography may not be necessary in every patient, but it may be useful for cases with associated urinary tract infection, voiding dysfunctions, urinary retention, and in cases of persistent symptoms(8,9). the aim of our study is to evaluate the effect of meatal stenosis on the upper and lower urinary tract by using ultrasonography in long-term follow up. materials and methods this is a cross-sectional study that was conducted in the pediatric urologic surgery department of doctor sheikh academic hospital in the mashhad university of medical sciences. we enrolled all meatal stenosis boys, aged 4-8 years old, who referred to the pediatric urologic surgery department between 2011-2015. chief complaints of our subjects were thin stream of urine, upward urine stream deviation, infrequent voiding, urinary tract infections, voiding dysfunction, and urge incontinency. all of our patients were circumcised in infancy (under the first six months) and were diagnosed with secondary meatal stenosis. other cases with a history of hypospadias repair or preputioplasty were excluded from this study. genitourinary examinations of all patients were done by a pediatric urologist. the diagnosis of meatal stenosis was confirmed by the inability to inserting an age matched nelaton catheter into the urethral meatus and the distortion of the meatus from an ellipsoid to a pinpoint shape. in laboratory data analysis complete blood cell count (cbc), urine analysis, urine culture, blood urea nitrogen (bun), and plasma creatinine level were evaluated. all patients were referred for urogenital upper and lower urinary tract ultrasonography before meatoplasty. hydronephrosis, hydroureter, bladder wall thickening in full and empty bladder, bladder volume, and residual urine volume were evaluated by ultrasonography. in 27 subjects, flowmetry was used before and after the meatoplasty was performed with the consent of their parents. during the study, voiding time, maximum flow rate, bladder volume, and flowmetry pattern were determined. the ethics committee of the mashhad university of medical science approved the initial study and all of the parents gave their parental consent before enrollment into the study. data was collected and analyzed by spss (version 11.5). comparison of flowmetry results after the operation with basic data was performed by the paired t test. data were expressed as mean or prevalence. mcnemar test was used to compare qualitative data. results data were collected on 87 circumcised boys with severe meatal stenosis between the ages 4 to 8 years old (mean ± sd age: 6.18 ± 1.38 years). the age of circumcision for all of these boys were less than six months and the mean age of the patients was 5.5 years old. the most common symptoms were urine stream narrowing and infrequent voiding that were detected in 47 (54%) subjects. thirty-five subjects (40.2%) complained of pain during the initiation of urination (painful urination) and urine stream deviation, and five patients (5.7%) suffered from urge incontinency and retention. forty subjects (45.9%) were symptomatic for more than two years. (table 1) laboratory findings in 33 cases (37.9%) showed microscopic hematuria in urine analysis. the cbc, bun, plasma creatinine level, and other lab data were within normal ranges in all of our patients. all patients underwent urogenital upper and lower ultrasonography. in this study, 84 subjects (96.5%) had a normal upper urinary tract. three cases (about 3.5%) aged 4, 5.5, and 6 years old showed bilateral mild hydronephrosis and bladder wall thickness. in 72 cases (82%), bladder wall thickness increased in an empty and full bladder, most of them were more than 6 years old (23 cases with an age range of 4.5-5.5 years old, 9 cases with an age range of 5.5-6 years old, and 40 cases with an age range of 6-8 years old). table 1. frequency of symptoms in meatal stenosis due to circumcision number frequency painful urination and urine stream deviation 35 40% stream narrowing and infrequent voiding 47 54% urge incontinency and retention 5 5.7% mild hydronephrosis and bladder wall thickness 3 3.5 before meatoplasty after meatoplasty paired t test p flow time (s) 26.38 ± 10.11 22.71 ± 6 2.21 0.03 voided volume (cc) 290 ± 132 292 ± 93 0.19 0.8 maximum flow rate (cc/s) 15 ± 8.2 20.15 ± 4.39 2.8 0.008 table 2. results of the flowmetry study in 27 subjects before and after meatoplasty effect of meatal stenosis on urinary tractsaeedi et al. vol 14 no 03 may-june 2017 3072 in 30 subjects (about 34.4%) residual urine was more than 20% of bladder volume after voiding (12 cases with an age range of 4-5 years old, 10 cases with an age range of 5-6 years old, and 8 cases were older than 6 years). the flowmetry study showed significant improvement in flow time and maximum flow rate after meatoplasty (table 2) and the obstructive pattern significantly decreased after meatoplasty (mcnemar= 19.66, p = .001). table 1. frequency of symptoms in meatal stenosis due to circumcision discussion circumcision is one of the most common surgical procedures in our country that is performed for religious reasons and can be done at all ages of a male's life; however, this surgery is often performed in infancy(4). about one in three males worldwide are circumcised (3) and this rate in iran is far more because all muslim boys are ritually circumcised(4). in our study, narrowing of the urine stream was the most common symptom among patients with severe meatal stenosis, and in ultrasonographic evaluation, the most common symptom was thickening of the bladder wall that increased in an empty and full bladder. urinary tract infections are ten to twenty times more common in uncircumcised boys than circumcised ones (6). urinary tract infection can result in renal scarring in about 10 to 15% of infants and it can lead to renal insufficiency in about 2 to 3% of these patients(6). like any surgical procedure, circumcision has operative and post-operative complications(5), but few epidemiological studies have reported the frequency of adverse events(3). our literature reviews show that serious adverse events due to circumcision are rare. however, mild to moderate surgical complications are frequent and include: pain, bleeding, swelling, wound infection, meatitis, inadequate skin removal, secondary epispadias or hypospadias, fibrous bridge formation, urethrocutaneous fistula, cysts of glans, fibrotic phimosis, preputial cysts, lymphedema or elephantiasis of the penile skin, laceration of penile or scrotal skin, penile denudation, asymmetric removal of the foreskin, and surgical loss of the penis. however, most of these complications are minor and easily treatable(4). meatal stenosis is one of the late complications of circumcision(4), which is difficult to detect by clinicians because of its little clinical findings(3), no adequate follow up after circumcision, and perhaps because of its similar symptoms to urinary tract infections(4,8). on general examination, the length of the meatus should be 25 to 30% of the diameter of the glans and a physiologic eversion of the distal part of the urethral lip. in some cases, secondary meatal narrowing due to circumcision leads to deflection of the urinary stream upward(9). in meatal stenosis, the lower moiety of the meatal slit is partially closed by a filmy membrane(10). recurrent pyelonephritis and obstructive uropathy is an under-recognized complication of meatal stenosis following circumcision(4,8). this condition may be a strong risk factor for renal damage and renal failure(8). radiologic studies like ultrasonography may not be necessary in every patient, but it is recommended to be performed in cases with associated urinary tract infection, voiding dysfunctions, urinary retention, and in cases of persistent symptoms(10). the definite incidence rate of meatal stenosis and its clinical manifestation following circumcision is unclear, but some studies have evaluated this condition. in a cross-sectional study, which was conducted by yeganeh et al. in 2006 to detect the prevalence of late complications of circumcision, late complications' rate was reported in about 7.39% of cases and the incidence rate of meatal stenosis was reported in about 0.9%(4). in a study by weiss et al. in nigeria on 141 circumcised boys, they reported meatal stenosis in 3.5% of patients during 6-week post operation follow up(3). in most studies, there is a difference in the reported prevalence of meatal stenosis and this may be due to inadequate post-surgical follow-up. in the present study, we recommend long term follow-up by using ultrasonography for early diagnosis of meatal stenosis before permanent renal damage occurs. in a study that was performed over a period of three years by persad et al. from 1991 to 1993, 8% of circumcised patients presented with meatal stenosis with symptoms that included pain at initiation of micturition and narrow high velocity urine stream(10). these are the most common symptoms and it is similar to the manifestations of our patients. in another study by joudi et al. in 2010, careful physical examination and laboratory tests were performed to determine the incidence of meatal stenosis after neonatal circumcision during one-year period. in this study, 20.4% of patients had severe meatal stenosis with a penis diameter of below 5 french, thickening of the bladder wall, and bilateral hydronephrosis in 11.1% of patients, and renal scarring in 0.75% of patients(7). the incidence of hydronephrosis in this study is more than our study and this can be due to their follow up and early diagnosis of meatal stenosis before its clinical presentation. in the university of kansas medical center, lishaw et. al. reported two infants with obstructive renal disease due to post circumcision meatal stenosis. one of them presented with severe dysuria and intermittent urinary stream and palpable large left kidney, and the other presented with hematuria, which are similar to manifestations of our patients. in both cases, bilateral hydronephrosis and hydroureters were detected using ultrasonography(12). obstructive uropathy is one of the few renal diseases that are treatable and reversible at the beginning. due to the ability of meatal stenosis to make an obstruction in the urinary tract, in cases of proven meatal stenosis, we recommend postoperative follow up to screen patients for obstructive uropathy and treat them before permanent renal damage occurs. the limitations of our study were: 1) post treatment ultrasonography was our plan, but for optimal evaluation, we needed more time after meatoplasty. therefore, we decided to plan another study to evaluate long-term results. 2) we planned to do flowmetry for all subjects before and after the surgery, but western pattern voiding is not routine for our children and so we could not obtain the proper co-operation for this test. hence, we could not perform this evaluation for all subjects. 3) differentiation between primary and secondary meatal stenosis due to circumcision was impossible. according to the rare prevalence of primary meatal stenosis in non-hypospadias subjects, we considered all subjects as having secondary meatal stenosis. effect of meatal stenosis on urinary tractsaeedi et al. pediatric urology 3073 conclusions as we described, long-term meatal stenosis can induce voiding dysfunction, bladder wall thickening, increased residual volume, and renal scarring. early diagnosis and correction of meatal stenosis may prevent these complications and voiding dysfunctions in the future. we recommend performing long-term follow up after circumcision to detect meatal stenosis before permanent symptoms and voiding dysfunctions occur, and using ultrasonography as a useful modality in this regard. conflict of interest none declared. references 1. williams n, kapila l. complications of circumcision. british journal of surgery. 1993;80:1231-6. 2. chaim jb, livne pm, binyamini j, hardak b, ben-meir d, mor y. complications of circumcision in israel: a one year multicenter survey. isr med assoc j. 2005;7:368-70. 3. weiss ha, larke n, halperin d, schenker i. complications of circumcision in male neonates, infants and children: a systematic review. bmc urology. 2010;10:1. 4. yegane r-a, kheirollahi a-r, salehi n-a, bashashati m, khoshdel j-a, ahmadi m. late complications of circumcision in iran. pediatric surgery international. 2006;22:4425. 5. pieretti rv, goldstein am, pierettivanmarcke r. late complications of newborn circumcision: a common and avoidable problem. pediatric surgery international. 2010;26:515-8. 6. wiswell te, geschke dw. risks from circumcision during the first month of life compared with those for uncircumcised boys. pediatrics. 1989;83:1011-5. 7. joudi m, fathi m, hiradfar m. incidence of asymptomatic meatal stenosis in children following neonatal circumcision. journal of pediatric urology. 2011;7:526-8. 8. mahmoudi h. evaluation of meatal stenosis following neonatal circumcision. urology journal. 2009;2:86-8. 9. linshaw ma. circumcision and obstructive renal disease. pediatrics. 1977;59:790-. effect of meatal stenosis on urinary tractsaeedi et al. vol 14 no 03 may-june 2017 3074 female urology long-term outcome of synthetic mesh use in iranian women with genital prolapse parvin bastani1,2, sakineh haj-ebrahimi1,2, fatima mallah1,2, parastoo chaichi3*, fatemeh sadeghi ghiasi1,2 purpose: to evaluate the long-term outcome of synthetic mesh use in the treatment of women with pelvic organ prolapse (pop). materials and methods: we evaluated the outcome of synthetic mesh implantation by vaginal surgery method in 153 women (mean age of 9.31±53.66 years) with pop grade >2 in the anterior compartment. demographic findings, baseline symptoms as well as subjective and objective outcome were recorded during the follow-up period of 11.33±36.89 months. results: pop relapse occurred in %3.3 indicative of %96.7 anatomical success rate. patients’ common baseline findings were frequency (%72.5), stress and urge incontinence (%59.5 and %47.7). subjective outcome were vaginal pain (%13.7), dyspareunia (%9.2) and tension feeling (%8.5), while objective outcomes were mesh exposure (%3.9), urge incontinence (%11.1) and vaginal infection (%1.3). stress incontinence was completely treated following surgery. there was significant improvement in dyspareunia, vaginal pain, urge and stress incontinence (all p < 0.001) and fecal incontinence (p = 0.02). after surgery, %88.42 were satisfied of the surgery outcome. conclusion: pop surgery with synthetic mesh has acceptable results, considerable improvement in symptoms and high rate of satisfaction during follow-up; however, side effects are not uncommon but tolerable. keywords: prolapse; synthetic mesh; outcome; complications introduction pelvic organ prolapse (pop) including genital pro-lapse is common with incidence rate of 40 % of women aged 45-85 years in general population, but only 12% of them are symptomatic (1,2). conservative and different surgical methods have been proposed for vaginal prolapse repair(3). however, there is an increased risk of recurrence regarding the surgery method and the type of materials used(4,5). transvaginal meshes have been introduced to increase the surgery efficacy and reduce the recurrence rate(6). after using synthetic meshes, studies have reported increased success rate with lower morbidity in genital prolapse surgeries(7). although previous studies have indicated that prolapse repair surgery with synthetic meshes are very effective with low prolapse and high patient’s satisfaction, there are several complications reported regarding mesh use including mesh exposure, pelvic pain, infection, bleeding, dyspareunia and with lower incidence, organ perforation(8). studies evaluating the long-term outcome of synthetic mesh use in vaginal prolapse surgery are few. in this study, we aim to evaluate the outcome and rate of complications following vaginal prolapse surgery using 1research center for evidence based medicine (rcebm), health management and safety promotion research instituted, tabriz university of medical sciences, tabriz, iran. 2iranian ebm center: a joanna briggs instituted affiliated group. 3gynecology and obstetrics department, ardabil university of medical sciences, tabriz, iran. *correspondence: women's reproductive health research center, alzahra hospital, south artesh ave., tabriz, iran. tel: +984135541221. fax: +984135541221.e-mail: pt.chaichi@gmail.com. received october 2018 & accepted may 2019 synthetic mesh among iranian women. patients and methods in this cross-sectional study, 300 women with pop undergone vaginal surgery with synthetic meshes between 2011 and 2016 in alzahra, taleghani and imam reza tertiary hospitals, tabriz, iran were evaluated and among them 153 patients meeting inclusion criteria and not having exclusion criteria were included. inclusion criteria were women between 40-80 years old, with pop stage 2-4 according to simplified pop-q scoring scale undergone surgery with synthetic mesh implantation (figure 1). patients with genital malignancies, body mass index > 40 kg/m2, infection, history of previous mesh implantation, collagen vascular disease and those with psychologic disease and no cooperation for maintaining mesh were excluded. also, those patients not returning for follow-up visits were excluded. the surgeries were performed by two experienced urogynecologists (pb and sh). this study was approved by ethics committee of tabriz university of medical sciences. mesh implantation was indicated when there was severe anterior prolapse stage >2 or accompanied with uterine or posterior prolapse. if there was concomitant urology journal/vol 17 no. 1/ january-february 2020/ pp. 73-77. [doi: 10.22037/uj.v0i0.4866] apical prolapse, sacrospinous fixation was used. after surgery, patients were followed with routine visits every six months for at least one year. in each visit, full physical examination was performed. before implanting the mesh, a vertical incision at the anterior vaginal wall was made from the point below the bladder neck to the lowermost part of the prolapse. diluted vasopressin solution was applied subcutaneous to reduce bleeding. with the allis forceps securing incision margins, full-thickness blunt dissection was done for the pubo-cervical fascia laterally until reaching the sacrospinous ligaments. dissection with 1–2 finger breadths further down from the ischial spines towards sacrum was done. all used meshes were from neomedic international company (madrid, spain). for anterior prolapse, the mesh is placed by a single incision procedure through one single vaginal incision. in its anterior part, the mesh is fixed to the internal obturator muscles by its two pocket system arms, with no needles and no skin perforations. for posterior prolapse, the surgeon cut the middle and anterior arms, fixating the mesh posteriorly to the sacrospinous ligament and anteriorly to the elevator anus muscles. for sacrospinous ligament fixation, the ischial spine was palpated and taken as the reference to pinpoint the sacrospinous ligament, which extends from the ischial spine medially to the coccyx and the lower portion of the sacrum. the pararectal fascia was penetrated, and the space was enlarged using blunt dissection; the rectum was retracted to the left using two breisky-navratil retractors, thereby exposing the sacrospinous ligament. no 1 non-absorbable suture (prolene) was placed 2-2.5 cm medially to the ischial spine, and one end of the suture was passed through the vaginal vault; surplus tissue located in the posterior vaginal wall was excised, and the upper 1/3 of the vaginal mucosa was repaired. following the vaginal vault repair, the vaginal vault was suspended from the right sacrospinous ligament by tying together the sacrospinous sutures located proximal to the apex of the vaginal vault. lastly, posterior repair and perineoplasty were performed, which marked the end of the procedure. demographic findings, patients’ symptoms and pop grade before surgery, improvement in symptoms and complications following mesh use were all recorded. subjective outcome was considered as pain, dyspareunia and mass extrusion and objective outcomes were mesh exposure, tenderness and urinary incontinence. patients’ satisfaction of the surgery was assessed using likert scale of four (excellent, well, moderate, poor). statistical analysis all data were analyzed using spss statistics, version 20 (ibm corporation, new york). results are expressed as mean ± sd or percentage. mcnemar test was used to evaluate the improvement in symptoms before and after surgery. p values of less than 0.05 were considered statistically significant. results patients’ baseline findings are demonstrated in table 1. the most common symptoms were frequency, urge and stress incontinence, and dyspareunia. posterior and uterine prolapse were mainly stage ii, while anterior prolapse was mainly stage iii. patients were followed for 36.89±11.33 months (range 12-60 months). all patients with fecal incontinence had posterior compartment prolapse and treated accordingly. during follow-up, prolapse recurrence occurred in 5 cases (3.3%), one treated with sacrocolpopexy, one with vaginal surgery and another mesh implantation and one with pessary. two other patients were treated conservatively. in the case treated with pessary, in first surgery just small piece of mesh was used for anterior compartment repair but the relapse was related to comtable 1. the grade of genitalia prolapse before mesh implantation in the study population variables age (years) 53.66 ± 9.61 gravida 4.56 ± 1.94 parity 4.18 ± 1.80 hypertension 8 (5.2%) diabetes mellitus 31 (20.3%) symptoms urge incontinence 73 (47.7%) stress incontinence 91 (59.5%) urgency 73 (47.7%) frequency 111 (72.5%) urination problems 37 (24.2%) dyspareunia 68 (44.4%) vaginal pain 56 (36.4%) fecal incontinence 5 (3.3%) prolapse typea stage i stage ii stage iii stage iv uterine 13 (8.5%) 88 (57.5%) 38 (25.18%) 14 (9.2%) anterior 11 (7.2%) 51 (33.3%) 91 (59.5%) ------posterior 29 (19%) 108 (70.6%) 16 (10.5%) ------a data are presented as mean ± sd or number (percent) before surgery after surgery p value dyspareunia 68 (44.4%) 14 (9.2%) < 0.001b vaginal pain 56 (36.6%) 21 (13.7%) < 0.001 urge incontinence 73 (47.7%) 17 (11.1%) < 0.001 stress incontinence 91 (59.5%) 0 < 0.001 fecal incontinence 5 (3.3%) 0 0.02 a data are presented as number (percent). b mcnemar test was used. table 2. comparing the symptoms before and after mesh implantation a figure 1. flowdiagram of the study population. synthetic mesh for genital prolapse. bastani et al. female urology 74 vol 17 no 01 january-february 2020 75 bined anterior and apical compartment, so we used capio system with mesh and we removed the previous one as much as possible and very gently subjective outcomes were vaginal pain in 21 (13.7%), dyspareunia in 14 (9.2%) and tension feeling in 13 (8.5%). mass extrusion was not reported in any of the cases. this tension was present in patients with higher prolapse grade and in the recent weeks after surgery which was later improved with no treatment in the following visits. of 14 dyspareunia cases after surgery, 4 persisted after surgery and 9 cases was de novo after surgery. ten cases of vaginal pain, were persistent after surgery and the other 11 cases were de novo. objective outcomes were mesh exposure in 6 cases (3.9%), urge incontinency in 17 cases (11.1%) and infection in 2 cases (1.3%). urge incontinency persisted in 9 cases and not improved following surgery, while 8 new de novo cases occurred after surgery. all stress incontinency cases were improved after surgery. of 6 patients with mesh exposure, symptoms occurred between 13-27 months after surgery, four cases were mild exposure and treated with vaginal estrogen. two cases returned with delay with complete mesh exposure, the extruded mesh part was removed and repaired. one of the cases with complete exposure had purulent vaginal discharges and treated with proper antibiotics. at the final follow-up, all 6 patients were symptom free. using a likert scale, the patients reported their satisfaction of the surgery as excellent in 54 cases (35.2%), well in 81 cases (52.9%), moderate in 14 cases (9.2%) and poor in 4 cases (2.6%). most patients had well to excellent satisfaction of surgery. following surgery, there was significant improvement in dyspareunia, vaginal pain, urge and stress incontinence and fecal incontinence (table 2). discussion in this study, we evaluated the long term outcome of using synthetic mesh in the vaginal surgery of genitalia prolapse in 153 women between 40-80 years old. there was significant improvement in prolapse stage after surgery with only 3.3% of recurrence indicative of 96.7% anatomical success rate. prolapse severity, urinary symptoms and fecal incontinence was significantly improved after surgery. in many studies, successful treatment was considered as pop grade ≤ 1 after surgery. the reported success rate are > 80% and in the recent studies are more than 9095% (9-14). similar to our findings, hong and colleagues reported total anatomical success rate of 96.5% after 18 months follow-up (10). it is even noted that regardless of recurrence of pop in some patients, they are mostly satisfied of the treatment due to the considerable improvement in symptoms (11-14). although some studies report that two years after mesh treatment, many women still report symptoms that negatively impact their quality of life (15). using synthetic meshes would accompany with some side effects which would limit its use. recent guidelines has recommended mesh in patients after full risk evaluation and to be performed by an expert surgeon (16). reported side effects of mesh use are mesh erosion, dyspareunia, hematoma, urinary incontinence, etc(17). mesh exposure is a complication related to procedure, mesh type and atrophy after mesh implantation. mesh exposure occurred in 3.9% of our patients. four cases had mild exposure and treated with vaginal estrogen. two cases with complete mesh exposure had the extruded part removed and repaired. the reported rate of mesh exposure in short and long term follow-up are variable. meyer and colleagues reported mesh exposure in 6% of patients in long term follow-up(18), which was higher than 2% in midterm follow-up(19). other studies have reported mesh exposure rate of 1-24% and mostly below 15% (9,18-23). fan and colleagues reported mesh exposure in 6 patients (13%) of which three meshes were removed(20). meyer and colleagues also reported that mesh exposure usually occurred in women with vaginal atrophy who stopped using vaginal estrogen(18). transvaginal mesh implantation had conflicting effects on sexual function in previous studies. meyer and colleagues observed that this surgery has no adverse effects on sexual function in long term(18). dyspareunia occurred in 36% of their study patients. alperin and colleagues also have reported dyspareunia in 28.9% of patients after surgery(9), while the reported rate in most studies are 2-20% (21-25). in our study, dyspareunia persisted in 2.7% and de novo dyspareunia occurred in 6.5%. the rate of dyspareunia after mesh implantation is not completely determined. the rate of new dyspareunia after surgery is reported to be between 4.4 to 20% (25-29). de novo dyspareunia could be due to mesh exposure or mesh shrinkage. milani et al. evaluated 127 patients after mesh implantation with 61 of them sexually active and observed new dyspareunia in 2% of cases (26). the main cause for this difference in the rate of dyspareunia could be due to the unwillingness of women to talk about their sexual relation in different areas, especially in religious countries such as ours. as in our study, older women did not like to talk about their sexual relations and it is possible that the real rate of new dyspareunia be higher. however, this low rate of dyspareunia is considerable and indicative of efficacy of treatment with mesh. in our study, stress incontinence was completely improved after surgery. vaginal pain persisted in 6.5% and newly occurred in 7.2% and urge incontinence was persistent regardless of surgery in 5.9% and de novo in 5.2%. patients considered their symptoms not severe and tolerable. alperin and colleagues reported pelvic pain in 4% (9). fan and colleagues reported stress incontinence in 11% of patients that were mostly mild and treated conservatively(20). we observed that 88.2% of patients were well to excellent satisfied of the treatment outcome. fan and colleagues reported overall satisfaction of 91% (20). the satisfaction rate in song et al. study was 84.7% (30). this study had also some limitations; one weakness of our study is that our data were collected partly retrospectively and so some data were not available. however, this study has the power of rather good sample size and long term follow-up. conclusions genitalia prolapse surgery with synthetic mesh has acceptable results, considerable improvement in symptoms and high rate of satisfaction during follow-up; however, side effects are not uncommon but tolerable. synthetic mesh for genital prolapse. bastani et al. conflicts of interest the authors declare that they have no conflict of interest. references 1. vergeldt tf, weemhoff m, inthout j, kluivers kb. risk factors for pelvic organ prolapse and its recurrence: a systematic review. int urogynecol j. 2015;26:1559-73. 2. ozcan l, polat ec, onen e, otunctemur a, ozbek e, somay a, et al. neuronal nitric oxide synthase expression in the anterior vaginal wall of patients with stress urinary incontinence. urol j. 2018;15:280-4. 3. oraekwe oi, udensi ma, nwachukwu kc, okali uk. genital prolapse: a 5-year review at federal medical centre umuahia, southeastern nigeria. niger med j. 2016;57:286-9. 4. jakus sm, shapiro a, hall cd. biologic and synthetic graft use in pelvic surgery: a review. obstet gynecol surv. 2008;63:253–66. 5. dällenbach p. to mesh or not to mesh: a review of pelvic organ reconstructive surgery. int j womens health. 2015;7:331-43. 6. meyer i, mcgwin g, swain ta, alvarez md, ellington dr, richter he. synthetic graft augmentation in vaginal prolapse surgery: long-term objective and subjective outcomes. j minim invasive gynecol. 2016;23:614-21. 7. abdel-fattah m, ramsay i. west of scotland study group. retro-spective multicentre study of the new minimally invasive mesh repair devices for pelvic organ prolapse. bjog 2008;115:22–30. 8. walter je, urogynaecology committee, lovatsis d, walter je, easton w, epp a, et al. transvaginal mesh procedures for pelvic organ prolapse. j obstet gynaecol can. 2011;33:168-74. 9. alperin m, ellison r, meyn l, frankman e, zyczynski hm. two-year outcomes after vaginal prolapse reconstruction with mesh pelvic floor repair system. female pelvic med reconstr surg. 2013;19:72-8. 10. hong mk, chu ty, wei yc, ding dc. high success rate and considerable adverse events of pelvic prolapse surgery with prolift: a single center experience. taiwan j obstet gynecol. 2013;52:389-94. 11. de tayrac r, gervaise a, chauveaud a, fernandez h. tension free polypropylene mesh for vaginal repair of anterior vaginal wall prolapse. j reprod med. 2005;50:75-80. 12. gauruder-burmester a, koutouzidou p, rohne j, gronewold m, tunn r. follow-up after polypropylene mesh repair of anterior and posterior compartments in patients with recurrent prolapse. int urogynecol j pelvic floor dysfunct. 2007;18:1059-64. 13. rane a, kannan k, barry c, balakrishnan s, lim y, corstiaans a. prospective study of the perigee system for the management of cystocoeles—medium-term follow up. aust n z j obstet gynaecol. 2008;48:427-32. 14. altman d, vayrynen t, ellstom engh m, axelsen s, falconer c; nordic transvaginal mesh group. anterior colporrhaphy versus transvaginal mesh for pelvic-organ prolapse. n engl j med. 2011;364:1826-36. 15. hansen bl, dunn ge, norton p, hsu y, nygaard i. long-term follow-up of treatment for synthetic mesh complications. female pelvic med reconstr surg. 2014;20:126-30. 16. moon jw, chae hd. vaginal approaches using synthetic mesh to treat pelvic organ prolapse. ann coloproctol. 2016;32:7-11. 17. committee opinion no. 513. vaginal placement of synthetic mesh for pelvic organ prolapse. obstet gynecol. 2011;118:1459-64. 18. nguyen jn, jakus-waldman sm, walter aj, white t, menefee sa. perioperative complications and reoperations after incontinence and prolapse surgeries using prosthetic implants. obstet gynecol. 2012;119:539-46. 19. wetta la, gerten ka, wheeler tl 2nd, holley rl, varner re, richter he. synthetic graft use in vaginal prolapse surgery: objective and subjective outcomes. int urogynecol j pelvic floor dysfunct. 2009;20:1307-12. 20. fan hl, chan ss, cheung ry, chung tk. tension-free vaginal mesh for the treatment of pelvic organ prolapse in chinese women. hong kong med j. 2013;19:511-7. 21. benbouzid s, cornu jn, benchikh a, chanu t, haab f, delmas v. pelvic organ prolapse transvaginal repair by the prolift system: evaluation of efficacy and complications after a 4.5 years follow up. int j urol. 2012;19:10106. 22. abed h, rahn dd, lowenstein l, balk em, clemons jl, rogers rg. systematic review group of the society of gynecologic surgeons. incidence and management of graft erosion, wound granulation, and dyspareunia following vaginal prolapse repair with graft materials: a systematic review. int urogynecol j. 2011;22:789-98. 23. de tayrac r, deffieux x, gervaise a, chauveaud-lambling a, fernandez h. longterm anatomical and functional assessment of trans-vaginal cystocele repair using a tensionfree polypropylene mesh. int urogynecol j pelvic floor dysfunct. 2006;17:483-8. 24. milani al, withagen mi, the hs, nedelcuvan der wijk i, vierhout me. sexual function following trocar-guided mesh or vaginal native tissue repair in recurrent prolapse: a randomized controlled trial. j sex med. 2011;8:2944-53. synthetic mesh for genital prolapse. bastani et al. female urology 76 vol 17 no 01 january-february 2020 77 25. lowman jk, jones la, woodman pj, hale ds. does the prolift system cause dyspareunia? am j obstet gynecol. 2008;199:707.e1-6. 26. milani al, hinoul p, gauld jm, et al. trocarguided mesh repair of vaginal prolapse using partially absorbable mesh: 1 year outcomes. am j obstet gynecol. 2011;204:74.e1-8. 27. kaufman y, singh ss, alturki h, lam a. age and sexual activity are risk factors for mesh exposure following transvaginal mesh repair. int urogynecol j. 2011;22:307-13. 28. milani r, salvatore s, soligo m, pifarotti p, meschia m, cortese m. functional and anatomical outcome of anterior and posterior vaginal prolapse repair with prolene mesh. bjog. 2005;112:107-11. 29. dwyer pl, o’reilly ba. transvaginal repair of anterior and posterior compartment prolapse with atrium polypropylene mesh. bjog. 2004;111:831-6. 29. song w, kim th, chung jw, cho wj, lee hn, lee ys, et al. anatomical and functional outcomes of prolift transvaginal mesh for treatment of pelvic organ prolapse. low urin tract symptoms. 2016;8:159-64. synthetic mesh for genital prolapse. bastani et al. pediatric urology determine the relationship between abdominal muscle strength, trunk control and urinary incontinence in children with diplegic cerebral palsy burcu talu purpose: the aim of this study is to determine the relationship between abdominal muscle strength, trunk control and urinary incontinence in children with diplegic cerebral palsy. materials and methods: the current study had a cross-sectional design using analytical study as well as an observational research model. fifty children between the ages of 5 and 18 years who were diagnosed with diplegic clinical type of cerebral palsy were included in this study using improbable-random sampling method. after patients' demographic information were obtained, dysfunctional voiding and incontinence symptoms score questionnaire (dviss), dysfunctional voiding symptom score (dvss), the manual muscle test of the muscles, trunk control test (tct) and trunk control measurement scale (tcms) were completed in order to evaluate trunk control. also, gross motor function classification system (gmfcs) was performed in order to define the functional level. results: in this study, a highly correlated negative relationship was found between dviss and dvss scores with muscle abdominal strength, tcms and tct. in addition, a highly correlated positive relationship was found between both gmfcs and dviss and gmfcs and dvss. conclusion: this is the first study that describes the effect of trunk control and muscle strength on urinary incontinence in children with diplegic cerebral palsy. this study showed that there is a correlation between trunk control, muscle strength and urinary incontinence. keywords: cerebral palsy; core stabilization; muscle strength; pelvic floor; trunk control; urinary incontinence. introduction voiding dysfunction is a very common problem during childhood. it is seen in almost 1 in every 5 children who visit pediatric urology clinics. urinary incontinence in children occurs because of either neurological problems or functional causes(1). more than half of the children with cerebral palsy visit hospitals with a voiding complaint. in order to understand the source of this issue and determine the effect of this dysfunction on voiding, a thorough clinical and functional examination needs to be done, in addition to a proper urinary system examination(2). trunk control insufficiency is the main cause of functional dysfunctions in cerebral palsy. the pelvic floor muscles are part of trunk stability mechanism, and this unit has passive, neural and active subsystem controls(3). the active sub-systems play an important role in protecting against urinary incontinence. they are not only necessary for urinary function, but these mechanisms also support organs against gravity in case of slow, rapid or unpredictable repletion. they are also necessary in order to increase intra-abdominal pressure(4,5). even though main functions are independent from other muscles in this system, other trunk muscles also contribute to the function of the pfm complex(6). for example, a department of physiotherapy and rehabilitation, faculty of health sciences, inonu university, malatya 44000, turkey. *correspondence: inonu university faculty of health sciences, physiotherapy and rehabilitation department, campus 44280, malatya, turkey. phone: +90 (422) 341 02 20 / 1141. fax: +90 (422) 341 02 19. mobile phone:+90 0531 791 0984. e-mail: fzt.burcu@hotmail.com, burcu.talu@inonu.edu.tr. received july 2017 & accepted october 2017 study which was conducted to understand the synergy between abdominal muscles and pfm, including all the muscle groups in the abdominal capsule, indicated that lumbar vertebrates, deep layers of the multifidus muscle, diaphragm, transversus abdominus and pelvic floor muscles are found in this capsule (core) structure(7). in the light of current studies, the pfm is thought to have two main functions of contributing to continence and elimination of both bladder and bowel and providing trunk stability(7) it has been reported that the pelvic floor muscle can be strengthened with the training of transversus abdominus muscle. this report is based on the belief that the pelvic floor muscles are a part of the abdominal capsule which surrounds abdominal and pelvic organs(6). the aim of this study is to determine the relationship between abdominal muscle strength, trunk control and urinary incontinence in children with diplegic cerebral palsy. materials and methods participants this study has a cross-sectional design using an analytical study of the observational research model. the subjects were selected from the children with cerebral palsy pediatric urology 180 who had been treated in three special education and rehabilitation centers in malatya city center. these three centers were also selected by lot from among the nine special education and rehabilitation centers in malatya city center. the patients who agreed to participate, and to provide the participation criteria were selected using the improbable random sampling method. in the power analysis, the sampling size was calculated as at least 43 patients in the 5% level of insignificance and 95% confidence interval, assuming that the incidence of diplegic cerebral palsy in the population is 3/1000. in order to conduct this study, the required permission and consent was obtained from the scientific research and publication ethics committee of inonu university health sciences (2015/5-5). an informative consent form was provided to parents of each patient before the study . the study protocol was approved based on the ethical standards of the declaration of helsinki. procedures fifty children between the ages of 5 and 18 years who were diagnosed with diplegic clinical type of cerebral palsy were included in this study, using improbable-random sampling method. after the patient demographic information was obtained, the dysfunctional voiding and incontinence symptoms score questionnaire (dviss), the dysfunctional voiding symptom score (dvss), the manual muscle test for the muscles, the trunk control test (tct) and the trunk control measurement scale (tcms) for the evaluation of trunk control were completed. also, gross motor function classification system (gmfcs) was performed in order to define the functional level and spasticity was assessed by modified ashworth scale. dviss consists of a total of 15 items in which one item evaluates quality of life and 14 items measure whether there is night and day voiding disorder in children if at all, questioning how it affects violence and activities of daily living(8,9). the results were evaluated using the dviss mean value in this study; values below 10 were good, values above 10 were considered bad. in addition, the percentage of responses to each item was recorded. the dysfunctional voiding symptom score (dvss) is a test which examines the urinary dysfunction with 10 items by evaluating its sensitivity and specificities (10,11). the manual muscle test was used to evaluate the upper and lower muscle weakness. the trunk control test (tct) is a scale which consists of 6 items. the scoring was performed by grading the movements, such as 0: cannot start, 1: can start a movement partially, 2: can perform more than half of the movement, 3: can complete the movement. the total score range was between 0 and 18. the values generally that are below average were accepted as bad, and the values above the average are accepted as good in the interpretation of the test(12,13). to evaluate the quality of trunk movement, the posturtable 1. muscle strength, trunk control and voiding test results of the individuals n:50 x±sd min-max muscle strength upper abdominal 2.50 ± 0.73 1-5 lower abdominal 2.14 ± 0.80 0-4 trunk control measurement scale (tcms) static sitting 6.78 ± 5.25 0-20 dynamic sitting 9.36 ± 7.82 0-28 dynamic lying 4.00 ± 2.73 0-10 total score 19.54 ± 14.40 0-56 trunk control test (tct) 11.16 ± 5.36 0-18 dysfunctional voiding and incontinence symptoms score (dviss) questionnaire 10.26 ± 8.09 0-29 dysfunctional voiding symptom score (dvss) 8.86 ± 5.15 1-20 1 does your child wet during the day? no sometimes 1–2 times/day always % 26% 38% 18% 18% 2 how wet is your child during the day? damp underwear damp pants only pants soaking wet % 44% 32% 24% 3 does your child wet during the night? no 1–2 nights/week 3–5 nights/week 6–7 nights/week % 44% 34% 12% 10% 4 how wet is your child during the night? damp underwear damp bed sheet only bed sheets soaking wet % 42% 38% 20% 5 how many times does your child void? 1–7/day more than7/day % 92% 8% 6 my child is too quick to finish his/her pee. no yes % 92% 8% 7 my child strains during voiding. no yes % 92% 8% 8 my child feels pain during voiding. no yes % 86% 14% 9 my child voids intermittently. no yes % 94% 6% 10 my child needs to go back voiding soon after finishes his/her pee. no yes % 94% 6% 11 my child has a sudden feeling of having to urinate immediately. no yes % 88% 12% 12 my child holds by crossing his/her legs. no yes % 68% 32% 13 my child wets on the way to the toilet. no yes % 80% 20% 14 my child misses his/her bowel movement every day! no yes % 38% 62% quality of life if your child experiences symptoms mentioned above, does it affect his/her family, social or school life? no sometimes yes affects seriously affects % 18% 44% 24% 14% table 2. percentage of each question and answer of dysfunctional voiding and incontinence symptoms score (dviss) questionnaire urinary incontinence in cerebral palsy-talu. vol 15 no 04 july-august 2018 181 al control and the functional strength of the trunk, the trunk control measurement scale (tcms) was used. tcms is formed from two main parts in terms of static sitting balance and dynamic sitting balance. the static sitting balance examines the static trunk control during movements of upper and lower extremity. the dynamic sitting control is classified as selective motor control and dynamic lying. the selective movement control of the dynamic sitting balance is a scale which evaluates the specific movements of the source of the support (trunk) in three dimensions. in the lower parts of the scale, there are 15 items which consist of 5, 7 and 3 different sub-items. the total score of the tcms ranges from 0 to 58(14,15). the gross motor function classification system (gmfcs) is a scale which evaluates the functional levels of individuals. in this scale, evaluation is measured between level 1 and level 5. in level 1, mobilization is provided independently and the mobilization is limited in level 5(16). data analysis spss version 16 package program was used in the statistical evaluation of this study. the mean ± standard deviation value was used for the definitive results, and variables which have non-normal distribution were assigned by using the median and interquartile range (frequency tables for the ordinal variables). the suitability of the normal distribution was investigated by using visual (histogram and probability graphs) and analytical (kolmogrow-smirnov/shapiro-wilk) tests. the relationship between dviss and dvss values and ordinal gmfcs levels were compared through use of the kruskal-wallis test. pairwise comparisons were done using the mann-whitney u test. the correlation coefficient which is defined with the measured variables and statistical significances were calculated using the pearson test. the correlation coefficients and statistical significance for the relationship between ordinal variables were calculated using the spearman test. for the statistical significance, a 5% type-1 error level was used. results were determined through the use of graphs and tables. using the power analysis with the ncss pass 13 program, the sampling size was determined to have a %5 error level, and at a 95% confidence interval, a sample size of at least 43 had 80% power. results 50 children with diplegic cerebral palsy were included in this study. 48% of the participating children(24) were male and 52% of them(26) were female. the average age of the children was 8.90 ± 3.75 years, the average height was 124.75 ± 25.42 cm, and the average body mass was 30.2 ± 14.81 kg. in evaluating the modified ashwort scale, children's gastrocinemius spasticity values were 1.71±1.01, hamstring spasticity value was 1.21 ± 0.82. the manual muscle test values for the abdominal muscles of the children, tct, tcms, dviss and dvss scores are presented in table 1. the average of the dysfunctional voiding and incontinence symptoms score (dviss) questionnaire was found as 10.26 ± 8.09. in the context of the scale, some questions were asked to patients and their relatives. their responses are given in table 2. according to correlation analysis of our study, significantly negative correlation was found between dviss and dvss scores and abdominal muscle strength, tcms low parameter and total score, and tct (table 3). in addition, significantly positive correlation was found between both gmfcs and dviss and gmfcs and dvss (table 4). as gmfcs levels were evaluated according to voiding values, dviss and dvss values also increased with the rising gmfcs levels (table 4). it was found that the difference between paired comparisons sourced from the gmfcs iv level. discussion this is the first study that describes the effect of trunk control and muscle strength on the urinary incontinence in children with cerebral palsy. this study showed that there is a moderate correlation between trunk control, table 3. the relationships between muscle strength, trunk control and voiding dysfunction of the individuals n:50 muscle strength tcms tct upper abdominal lower abdominal static sitting dynamic sitting dynamic lying total score r -0.533 -0.573 -.0.711 -0.592 -0.574 -0.636 -0.717 dviss p 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* dvss r -0.407 -0.461 -0.586 -0.393 -0.415 -0.466 -0.585 p 0.003* 0.001* 0.000* 0.005* 0.003* 0.001* 0.000* *p < 0.01 n:50 x±sd min-max dysfunctıonal voıdıng and incontınence symptoms score (dviss) questıonnaıre r 0.618 gmfcs i 3 0.00 ± 0.000 0-0 p 0.000* gmfcs ii 18 6.38 ± 4.28 1-13 gmfcs iii 16 10.37 ± 7.06 1-23 gmfcs iv 13 17.84 ± 8.25 2-29 dysfunctional voiding symptom score (dvss) r 0.663 gmfcs i 3 3.00 ± 1.73 1-4 p 0.000* gmfcs ii 18 6.16 ± 3.12 1-13 gmfcs iii 16 8.12 ± 3.55 3-17 gmfcs iv 13 14.84 ± 4.37 5-20 *p < 0.01 table 4. the relationships between voiding dysfunction and scores gmfcs of the individuals and voiding dysfunction value according to level urinary incontinence in cerebral palsy-talu. pediatric urology 182 muscle strength and urinary incontinence. dysfunctional urination is an issue which occurs either because of abnormal activity of pelvic floor muscles or insufficient relaxation. it occurs through developing the wrong urination habits during childhood. the pelvic floor muscles are striated muscles which are under voluntary control. these muscles especially play an important role in the development of detrusor instability. in children, the dysfunction of destructor sphincter muscle has been shown as a urinary incontinence issue(17,18). the neurological mechanisms behind urinary incontinence has not been very well understood, yet. however, recent functional mri studies indicated that there is a complex neurological mechanism behind this system(19). the neurological dysfunction in children with cerebral palsy occurs in the early developmental stage of the central nervous system(20). several studies showed that there is a strong correlation between iq and bladder control in children during developmental progression(21,22). a study which was performed with 346 children with bilateral cerebral palsy showed that gross motor functional classification score (gmfcs) and intellectual ability are strongly associated, which is independent from the sex factor(20). a study which was performed on 105 children with mental retardation indicated that severe motor disability might be the reason which prevents a child with cp to be toilet trained(23). in our study, a significant relationship was found between gmfcs and incontinence. it was looked at as the relationship between functional level and incontinence, and the children with better functional level had lower incontinence. it may be thought that incontinence decreases with increasing muscle strength, muscle coordination and functionality. as a newborn urinates approximately 20 times in a day with involuntarily muscle contractions, the urine volume increases in infancy with the development of muscle strength and coordination. the frequency of urination starts to decrease between the first and second years of age, and bladder repletion begins. in children aged 2 through 4, the ability to inhibit urination begins with sufficient sphincter control. therefore, a child should gain a normal urination function after 4 years of age. it has been shown that muscle strength and coordination is necessary for normal urination(24). the basic reason of the functional disorders in children with cerebral palsy is insufficient trunk control. trunk control was shown to affect functional mobility and balance in children with cp(13). in children with cerebral palsy, weak postural control, insufficient postural and balance reactions cause a delay in developing motor control(9,10). restriction in balance and preservative reactions can result in restrictions in postural control, and in the performance of voluntarily abilities(11,12). in one study, the trunk control measurement scale (tcms) was used to evaluate the static and dynamic functional ability of individuals. since tcms evaluates trunk abilities in a way that reflects real life, it is a clinically important tool(16,19). studies showed that trunk control plays an active role(15,20). roncesvalles et al. stated that the trunk is a key element in control of the postural stabilization and orientation. the measurements of trunk control and the relationships between trunk control, balance, walking and functional abilities indicate the important role of trunk control in daily activities(25). in every step of the developmental stages (turning, sitting, standing, etc.), the strength of the abdominal, back and pelvis muscles and the trunk control increased in functional activities(13). a number of studies in healthy volunteers indicated that pelvic floor co-contraction occurs during varied abdominal muscle contractions (13,18,25,26). thus, we believe that an increase in abdominal muscle strength and trunk control may result in an increase in pelvic floor muscle strength, and in continence ability. in our study, there was a high level of negative correlation between abdominal muscle strength and trunk control and urinary incontinence. the study by reid et al. which was conducted with 27 children with cerebral palsy showed that the most common symptom (74%) was urinary incontinence in daytime. they also reported that there were abnormal urodynamic examination results in 85% of the patients(27). in our study, we also observed urinary incontinence during daytime in 74% of the patients, which is compatible with the literature. several studies noted that various abdominal muscle contractions can occur during a pelvic floor contraction(18,26). it has been found that co-contraction of the pelvic floor muscles was observed during the r. abdominis muscle contractions in continent women, by using a bø&stien concentric needle(17). in a study that was conducted with six healthy women, sapsford & hodges found that pelvic floor muscle surface electromyography increases with transversus abdominus contractions(28). this result was also supported by another study which was performed with four continent women(17). sapsford et al. found that the isometric abdominal contraction which transverses the abdominus and internal oblique contraction, called ‘hollowing,’ increases urethral pressure to the extent that a pelvic floor muscle contraction increases. by taking these results into consideration, sapsford et al. suggested that training to prevent incontinence should start with the trunk stability-increasing core muscle trainings such as tra training, rather than pelvic floor muscles(6). the main limitation of our study was that we have not received clinical symptoms, especially the presence of urinary tract infections. neither we have evaluated of urodynamic findings and kidney function. in future studies, the decrease in the rate of inconsistency after strength and trunk control training can be investigated in children with cerebral palsy. in addition, the pelvic floor contraction during the abdominal muscle contraction can be evaluated through the use of an emg in children with cerebral palsy. even though some studies with healthy adults have been completed, neurological differences between children with cerebral palsy and healthy adults may be studied again. there are many factors which are responsible for urinary incontinence and the effect of functional disability is one of these factors. besides urodynamic findings, a thorough clinical and functional examination is also required in children with diplegic cerebral palsy. the urinary incontinence might be reduced by increasing muscle strength/coordination, enhancing functional levels and increasing trunk control levels. conflict of interest none declared. urinary incontinence in cerebral palsy-talu. vol 15 no 04 july-august 2018 183 references 1. butler rj, heron j. the prevalence of infrequent bedwetting and nocturnal enuresis in childhood. a large british cohort. scand j urol nephrol. 2008;42:257-64. 2. gannotti me, fuchs rk, roberts de, hobbs n, cannon im. health benefits of seated speed, resistance, and power training for an individual with spastic quadriplegic cerebral palsy: a case report. j pediatr rehabil med. 2015;8:251-7. 3. panjabi mm. the stabilizing system of the spine. part i. function, dysfunction, adaptation, and enhancement. j spinal disord. 1992;5:383-9. 4. burti js, hacad cr, zambon jp, polessi ea, almeida fg. is there any difference in pelvic floor muscles performance between continent and incontinent women? neurourol urodyn. 2015;34:544-8. 5. park h, han d. the effect of the correlation between the contraction of the pelvic floor muscles and diaphragmatic motion during breathing. j phys ther sci. 2015;27:2113-5. 6. sapsford r. rehabilitation of pelvic floor muscles utilizing trunk stabilization. man ther. 2004;9:3-12. 7. hides ja, stanton wr, mcmahon s, sims k, richardson ca. effect of stabilization training on multifidus muscle cross-sectional area among young elite cricketers with low back pain. j orthop sports phys ther. 2008;38:1018. 8. ors ao, irkilata hc, kibar y, zor m, korgalı e, dayanc m. noninvasive evaluation of the children with lower urinary tract dysfunction. turkish journal of urology. 2008;34:203-8. 9. dirim a, aygun yc, bilgilisoy ut, durukan e. prevalence and associated factors of daytime lower urinary tract dysfunction in students of two primary schools of turkey with different socioeconomic status. turkiye klinikleri journal of urology. 2011;2:1-6. 10. akbal c, genc y, burgu b, ozden e, tekgul s. dysfunctional voiding and incontinence scoring system: quantitative evaluation of incontinence symptoms in pediatric population. j urol. 2005;173:969-73. 11. yuksel s, yurdakul ac, zencir m, corduk n. evaluation of lower urinary tract dysfunction in turkish primary schoolchildren: an epidemiological study. j pediatr urol. 2014;10:1181-6. 12. parlak demir y, yıldırım sa. reliability and validity of trunk control test in patients with neuromuscular diseases. physiotherapy theory and practice. 2015;31:39-44. 13. ozal c, günel mk. spastik serebral palsili çocuklarda gövde kontrolü ile fonksiyonel mobilite ve denge arasındaki ilişkinin urinary incontinence in cerebral palsy-talu. incelenmesi. journal of exercise therapy and rehabilitation. 2014;1:01-8. 14. gonca a, günel mk. serebral palsili çocuklarda nörogelişimsel tedaviye dayalı gövde eğitiminin gövde kontrolüne etkisi. journal of exercise therapy and rehabilitation. 2015;2:79-85. 15. mitteregger e, marsico p, balzer j, van hedel hj. translation and construct validity of the trunk control measurement scale in children and youths with brain lesions. res dev disabil. 2015;45-46:343-52. 16. gunel mk, mutlu a, tarsuslu t, livanelioglu a. relationship among the manual ability 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exercises. neurourol urodyn. 2001;20:31-42. 27. reid cj, borzyskowski m. lower urinary tract dysfunction in cerebral palsy. arch dis child. 1993;68:739-42. 28. sapsford rr, hodges pw. contraction of the pelvic floor muscles during abdominal maneuvers. arch phys med rehabil. 2001;82:1081-8. vol 15 no 04 july-august 2018 185 purpose: urolithiasis during pregnancy poses risks for mother and the fetus with specific challenges in diagnosis and management. we report our experience with urgent percutaneous nephrolithotomy (pcnl) in seven pregnant patients with symptomatic renal stone in early pregnancy. materials and methods: seven pregnant patients with symptomatic renal stones were reviewed. the technique comprised pcnl with complete access under guide of ultrasonography in prone position under general anesthesia using pneumatic lithoclast for stone fragmentation. results: there was no significant residual fragment of stone in the operated kidneys. the patients discharged without complications and delivered their babies healthy. conclusion: pcnl should not be considered as the first therapeutic method in the first trimester of pregnancy, unless in urgent situations such as symptomatic renal pelvic stone with moderate to severe hydronephrosis in patients who do not tolerate or are complicated by nephrostomy or internal stent. however, this procedure could be technically demanding and should be done in centers with enough experience and equipment in percutaneous nephrolithotomy. key words: pregnancy; percutaneous nephrolithotomy; urolithiasis; ultrasonography. introduction nephrolithiasis affects 10% of the whole population and the incidence seems to be increasing especially in women(1). the incidence of urinary calculi in pregnancy and women in childbearing age are similar and about 1 in 1240 pregnancies(2), but urolithiasis during pregnancy poses risks for both the mother and the fetus (3) including: preterm delivery, miscarriage, premature rupture of membrane, and preeclampsia(4) with specific challenges in diagnosis and dilemmas in management(1). the treatment is challenging because of our limitation in using x-rays and extra corporeal shock wave lithotripsy (eswl)(5). the recommended procedures in symptomatic renal stones during pregnancy are nephrostomy insertion or ureteral stent insertion but sometimes a definite management seems necessary(6,7). in this paper, we report 7 pregnant women with refractory pain and symptomatic obstructive renal stone in which totally ultrasound guided percutaneous nephrolithotomy (pcnl) was performed. materials and methods all of our patients were referred by their perinatalogist because of recurrent renal colic. they were admitted in emergency department and received analgesic and antiemetic. three patients underwent cystoscopy and jj insertion at first but they later complained of severe luts which was unresponsive to medical therapy and they did not accept nephrostomy insertion. the other four patients were educated medical staff and refused shiraz nephro urology research center, shiraz university of medical sciences, shiraz, iran. *correspondence: assistant professor of urology, shiraz nephro-urology research center, shiraz university of medical sciences, shiraz, iran. tel & fax: +987132326645. email: alieslahi@yahoo.com. received july 2016 & accepted october 2017 any temporary diversion such as nephrostomy or jj stent despite of discussion about possible hazards of anesthesia and operation, and accepted and signed the informed consent. then, they were transferred to our department as urgent cases. after checking urine analysis and urine culture, intravenous cefriaxone 1 gram every 12 hours was started. moreover, we used ultrasonography for making the diagnosis and evaluating the extent of hydronephrosis. under general anesthesia, a 6f ureteral catheter was inserted in lithotomy position by cystoscopy. the catheter was advanced as far as it passed into renal pelvic stone and gush of urine was observed from the catheter. then, it was fixed to foley catheter and then patient’s position was turned to prone position. with the help of ultrasonography we located the stone inside the kidney and the existing hydronephrosis was also evaluated (figure 1) .we chose lower pole for access in all cases. (figure 2) after passing the chiba needle and confirming its correct position by instilling normal saline from the ureteral catheter for better visualization of system, guide wire (0.038) was advanced in a secure place .we removed needle sheath with accurate measurement of the inside depth of the sheath that was an estimate of the skin to renal access point distance. according to the measured scale and ultrasonography guidance tract dilation was done by elastic semirigid dilators to 12f and advanced to 27 f by metallic dilators. during dilation we injected normal saline retrogradely in each step to observe the outflow of urine from dilator lumen to make sure that they are in correct place. after insertionvol 14 no 06 november-december 2017 5034 endourology and stone disease percutaneous nephrolithotomy during early pregnancy in urgent situations: is it feasible and safe? mohammad mehdi hosseini, abbas hassanpour, ali eslahi*, leila malekmakan of 2bf amplatz sheath, we performed nephroscopy to locate the stone. pneumatic lithoclast was used to fragment the stone into small particles which were extracted by forceps. when meticulous nephroscopy showed no residual stones we inserted an 18f nephrostomy tube in order to maintain the patency and good drainage of the kidney. patients’ ureteral and foley catheters were removed on the first postoperative day and the nephrostomy tube was removed after 48 hours. all patients were discharged from hospital with good condition and very close outpatient follow up was scheduled. patients were followed by ultrasonography 1 week after the operation. results the demographic and clinical data of patients are summarized in table 1. the mean age of the patients was 28.8 years old and all the patients were in their first trimester of pregnancy between 8 to 13 weeks of gestation. the stones in all patients were located in the renal pelvic and also lower pole in three cases; causing moderate to severe hydronephrosis with a mean stone size of 22.2 mm (range, 14-40mm). we did not identify any abnormal creatinine during preoperative evaluation with a mean level of 0.78mg/dl. the mean estimated hemoglobin loss was 1.12gr/dl (range, 0.9-1.5) and none of the patients required blood transfusion. the preoperative data are summarized in table 2. mean operation time was 85 minutes (range, 65-115 minutes). as we evaluated our patients after the operation with follow up ultrasonography, there was no significant residual fragment of stone (> 4mm) in the operated kidneys. the patients passed their hospital course uneventful with a mean hospital stay of 57.6 hours (range, 48-72 hours). we did lower pole access in all cases with no intraoperative or postoperative complications. all patients were discharged from hospital in a good condition with clear urine and asymptomatic condition. we followed up the patients till their delivery time. all babies were born full-term, completely healthy and without any complications. discussion physiological alteration creates an optimal environment for stone formation during pregnancy. although the incidence of stone formation does not increase during pregnancy but due to its unique imposed risks, it merits a special attention for diagnosis and management(1). nowadays the modality of choice for evaluation of stone is non-contrast computed tomography (ct) in general population but ct emits radiation that is potentially teratogenic that limits its usage during pregnancy notably in the first trimester. ultrasonography is the safest method and is our mostly used diagnostic tool in pregnancy(1). about 70-80% of stones presenting during pregnancy will pass spontaneously therefore a trial of conservative management could be given to most of the patients(8). renal colic is a urological emergency because of associated complications for both the mother and the fetus and could also be life threatening by creating sepsis(9). maternal kidney stones can induce several complications, including recurrent abortions, hypertensive disorders, gestational diabetes, and cesarean deliveries(9). due to conservative management failure, sometimes an intervention seems necessary(10). retrograde ureteral double j stent insertion or percutaneous nephrostomy are two less invasive techniques for relieving the obstruction or better urinary drainage when kidney obstruction occurs(11). however, stent encrustation because of hypercalciuria are often observed in cases of long standing ureteral catheter usage and lower urinary tract symptoms are also attributable to indwelling stents (12). as an alternative method for urinary drainage, placement of the percutaneous nephrostomy was performed in 6 pregnant patients in first series by kavoussi et al. (13), however, nehphrostomy tubes harbor some disadvantages such as bacterial colonization and infection with risk of accidental dislodgment and the inconvenience of dealing with an external collection device(10). moreover, strict contraindication exists against using extracorporeal shockwave lithotripsy in pregnancy because of its deleterious effects on the fetus(10,11). pcnl is a safe treatment option with low complication pcnl in early pregnancy-hosseini et al. table 1. demographic and clinical data in 7 cases of percutaneous nephrolithotomy in pregnancy. characteristics case 1 case 2 case 3 case 4 case 5 case 6 case 7 age (year) 32 30 23 28 31 26 28 gestational age (week + day) 10+3 10 + 4 8 + 0 9 + 0 8 + 5 12 + 3 10 + 5 stone size(mm) 40+8 19 20 22 + 9 18 20 + 11 15 + 11 + 8 stone location renal pelvis renal pelvis renal pelvis renal pelvis renal pelvis renal pelvis renal pelvis and lower pole and lower pole and lower pole side of involvement right right right left left right left preoperative creatinine(mg/dl) 0.7 0.8 0.8 0.9 0.7 0.9 1.1 preoperative hemoglobin (g/dl) 15.3 13 12.7 11 12 12.6 13.3 characteristics case 1 case 2 case 3 case 4 case 5 case 6 case 7 operating time(minutes) 115 80 95 100 65 60 75 hydronephrosis moderate severe moderate moderate moderate severe moderate percutaneous access lower pole lower pole lower pole lower pole lower pole lower pole lower pole complications none none none none none none none hospital stay(hours) 48 60 48 60 72 60 72 postoperative hemoglobin (g/dl) 14 12.1 11.8 10 10.5 12.1 12.7 hemoglobin drop (mmol/l) 1.3 0.9 0.9 1.0 1.5 0.5 0.6 table 2.results of 7 percutaneous nephrolithotomies in pregnancy. endourology and stone diseases 5035 rates in renal calculi but its use has been limited in pregnancy because of radiation exposure of the fetus (10) and also the risk of general anesthesia and prone position of patient during operation(14). in spite of these threats there has been reports of performing pcnl under fluoroscopy with limited radiation exposure in first trimester of pregnancy by shah et al.(15). the feasibility and safety of complete ultrasonography guided pcnl has been previously described in 357 cases by hosseini and colleagues(16). there are also many reports of performing totally ultrasound guided pcnl in lateral flank(6,17) and supine positions(7). access under guide of ultrasonography can be safe because it allows to identify the kidney and calyceal system clearly and to obtain an optimum access by an expert surgical team(12). there are a few reports of pcnl under guide of ultrasonography in pregnancy period; toth et al. reported their experience in doing pcnl on a 31 year old pregnant woman at 11 weeks of gestation under guide of ultrasonography in prone position with a good result(18). there is also a successful report of ultrasonography guided supine pcnl in a 24 year old female in her 22 weeks of gestation by fregonesi et al.(10). basiri and colleagues recently published their expertise in supine and lateral flank position pcnl in pregnant patients in their second and third trimester with good results(19). some of the inhalational anaesthetic agents such as nitrous oxide and hallothane can be transfered to the fetus. in animal studies teratogenic effects of these agents were reported. therefore general anesthesia with these agent is not recommended in first trimester, and may be replaced with regional techniques.(20) in this study we report our experience with promising results in accomplishing pcnl under guide of ultrasonography in prone position in 7 pregnant patients with urinary stones. all the patients passed their pregnancy without any further complication and gave birth to healthy babies. however, this operation is not without risk during pregnancy so it is noteworthy to say that it should be done only in selected cases with caution. conclusions pcnl is not recommended as the first option in pregnancy, however it can help the patients with symptomatic obstructive renal stones who are complicated with longstanding indwelling ureteral catheters or nephrostomy tubes. in these urgent situations, we recommend that this procedure can be done in centers with enough experience and equipment in pcnl and special figure 1. ultrasonography shows large right renal pelvic stone figure 2. pecutaneous nephrolithotomy under guide of ultrasonography pcnl in early pregnancy-hosseini et al. vol 14 no 06 november-december 2017 5036 care by perinatalogist. . acknowledgement the authors would like to thank the anesthesiology team (dr. frootan, dr. mostafavi, dr. saem,and dr. hosseini) and also the obstetricians who cooperated in perioperative cares of our patients. conflict of interest the authors declare that they have no conflict of interest. references 1. semins mj, matlaga br (2014) kidney stones during pregnancy. nat rev urol 11:163-8. 2. butler el, cox sm, eberts eg, cunningham fg. symptomatic nephrolithiasis complicating pregnancy. obstet gynecol 2000; 96:753-6. 3. srirangam sj, hickerton b, van cleynenbreugel b. management of urinary calculi in pregnancy: a review. j endourol 2008; 22:867-75. 4. celik o, turk h, cakmak o, ekin rg, keskin mz, yildiz g, ilbey yo (2016) current approach for urinary system stone disease in pregnant women. arch ital urol androl 87:280-5. 5. buchholz np, biyabani r, sulaiman mn, talati j. urolithiasis in pregnancya clinical challenge. eur j obstet gynecol reprod biol 1998; 80: 25-9. 6. basiri a, ziaee sa, nasseh h, kamranmanesh m, masoudy p, heidary f, kianian h, abedinzadeh m. totally ultrasonographyguided percutaneous nephrolithotomy in the flank position. j endourol 2008; 22:1453-7. 7. basiri a, mohammadi sichani m, hosseini sr, moradi vadjargah a, shakhssalim n, kashi ah, kamranmanesh m, nasseh h. x-ray-free percutaneous nephrolithotomy in supine position with ultrasound guidance. world j urol 2010; 28:239-44. 8. mcaleer sj, loughlin kr. nephrolithiasis and pregnancy. curr opin urol 2004; 14:1237. 9. zhang s, liu g, duo y, wang j, li j, li c. application of ureteroscope in emergency treatment with persistent renal colic patients during pregnancy. plos one 2016; 11: e0146597. 10. fregonesi a, dias fg, saade rd, dechaalani v, reis lo. challenges on percutaneous nephrolithotomy in pregnancy: supine position approach through ultrasound guidance. urol ann 2013; 5:197-9. 11. juan ys, wu wj, chuang sm, wang cj, shen jt, long cy, huang ch. management of symptomatic urolithiasis during pregnancy. kaohsiung j med sci 2007; 23:241-6. 12. osman m, wendt-nordahl g, heger k, michel ms, alken p, knoll t. percutaneous nephrolithotomy with ultrasonography-guided renal access: experience from over 300 cases. bju int 2005; 96:875-8. 13. kavoussi lr, albala dm, basler jw, apte s, clayman rv. percutaneous management of urolithiasis during pregnancy. j urol 1992; 148:1069-71. 14. swanson sk, heilman rl, eversman wg. urinary tract stones in pregnancy. surg clin north am 1995; 75:123-42. 15. shah a, chandak p, tiptaft r, glass j, dasgupta p. percutaneous nephrolithotomy in early pregnancy. int j clin pract 2004; 58:80910. 16. hosseini mm, yousefi a, rastegari m. pure ultrasonography-guided radiation-free percutaneous nephrolithotomy: report of 357 cases. springerplus 2015; 4:313. 17. alan c, kocoglu h, ates f, ersay ar. ultrasound-guided x-ray free percutaneous nephrolithotomy for treatment of simple stones in the flank position. urol res 2011; 39:205-12. 18. toth c, toth g, varga a, flasko t, salah ma. percutaneous nephrolithotomy in early pregnancy. int urol nephrol 2005; 37:1-3. 19. basiri a, nouralizadeh a, kashi ah, radfar mh, nasiri mr, zeinali m, sarhangnejad r, hosseini-sharifi sh. x-ray free minimally invasive surgery for urolithiasis in pregnancy. urol j 2016; 13:2496-501. 20. pedersen h, finster m. anaesthetic risk in the pregnant surgical patient. anaesthesiology 1979; 51: 439–51 pcnl in early pregnancy-hosseini et al. endourology and stone diseases 5037 endourology and stone disease efficacy of medical expulsive therapy in renal calculi less than or equal to 5 millimetres in size sudarshan daga, vinayak wagaskar*, harshawardhan tanwar, umesh shelke, bhushan patil, sujata patwardhan purpose: natural history and modality of treatment for asymptomatic renal calculi less than or equal to 5 millimetres in size is still unknown. many options are available ranging from medical expulsive therapy to minimally invasive surgery. till date no study has focussed on this very common but asymptomatic issue. hence, this study is undertaken to evaluate efficacy of medical expulsive therapy in renal calculi less than or equal to 5mm in size. materials and methods: a prospective, parallel group, randomized study was carried out from 1st june 2014 to 31st may 2015, with total of 100 patients, 50 patients in each group. patients with renal stones less than or equal to 5mm were included in the study. group a patients were administered medical expulsive therapy which included tamsulosin 0.4 mg daily at night time, furosemide 20mg, spironolactone 50mg in a single morning dose, and syrup potassium magnesium citrate 20meq per dose three times a day for 12 weeks while group b patients were given placebo. the primary outcome variable was number of patients achieving clearance of stone during 12-week treatment period in both groups. results: no statistically significant differences in age, gender, stone size, and calyceal stone location was found between the two treatment arms. a spontaneous stone expulsion rate of 50% (at 6 weeks) and 86 %( at 12 weeks) was noted in group a versus 28% (at 6 weeks) and 38 % (at 12 weeks) in group b. less number of pain episodes and less analgesic medication was required in group a as compared to group b. conclusion: medical expulsive therapy for 12 weeks significantly improves stone free rates in renal calyceal calculi less than or equal to 5mm. key words: diclofenac sodium; furosemide; spironolactone; tamsulosin; urolithiasis. introduction urolithiasis affects almost varied population all over world (1,2). estimated world risk is 10%-25%(1, 3). natural history, progression and best modality of treatment for asymptomatic renal calculi less than 5mm is still not known. occupations like air force, navy, army and bus drivers, requires stone free status to join duty. available treatment options are observation, medical expulsive therapy (met), shockwave lithotripsy (swl), retrograde intra-renal surgery (rirs), micro-percutaneous nephrolithotomy (pcnl), ultra mini-pcnl. cost of operative treatment is higher than non operative modalities like observation and met(4). several medications have being evaluated over the last 10 years for medical management of renal stones(5). meta-analysis have demonstrated effectiveness of met in post swl procedure with added analgesic effect(6,7,8). medline searches did not yield any published study relating to use of medical expulsive therapy for asymptomatic renal calyceal calculi less than 5mm in size. karabacak et al. demonstrated presence of α1 receptors and their subtype in renal pelvis and calyces(9). they suggested that use of α1 blockers (tamsulosin) for treatment of renal cayceal stones may be implicated(9). after search of medline data base, we did not find any study performed with respect to met for particularly asymptomatic renal calyceal calculi and hence this is among the first prospective, randomized single institutional studies to evaluate efficacy of medical expulsive therapy for asymptomatic renal calyceal calculi ≤5mm in size. the purpose of this study was to evaluate efficacy of medical expulsive therapy for asymptomatic renal calyceal calculi ≤5mm in size. materials and methods a prospective, parallel group, randomized study was carried out from 1st june 2014 to 31st may 2015. with a total of 100 patients, 50 patients in each group. institutional ethical committee approval (ec-oa-105/2013) was taken. patients who fulfilled our inclusion/exclusion criteria during study period were included and assigned into two groups by simple random method. each patient was chosen entirely by a chance and had equal chance of being included in either group. a written informed consent was taken from all the patients. inclusion criteria: all patients with asymptomatic or history of a single episode of renal colic with well controlled pain by analgesics, age >18 years, and stone size ≤5 mm in renal calyces were included in the study. these asymptomatic patients came to us with ultrasonography kidney-ureter-bladder (usg kub) performed outside for other reasons department of urology, king’s edward memorial hospital, mumbai, india*correspondence: king’s edward memorial hospital, mumbai, india. *correspondence: king’s edward memorial hospital, mumbai india. tel: +91-9890906273 email: vinayakwagaskar@kem.edu. received may 2016 & accepted october 2016 vol 13 no 06 november-december 2016 2893 and were incidentally detected to have renal calculi. exclusion criteria: patients with stone greater than 5mm, solitary kidney, ureteric stone, distal ureteric stricture or subtle ureteric stricture like those with history of prior ureteroscopy or history of bilharziasis, bladder stone, pregnant female, recurrent stone formers, chronic renal failure, aberrant ureteral anatomy (e.g., ureteral ectopia, ureterocele and mega ureter), sensitivity to the drugs used in met, presence of renal stones more than 3 in number and patients with urinary tract infection were excluded from the study. we also excluded patients with recurrent stone formers as these patients usually have underlying metabolic abnormality and their treatment would have an influence on the results of our study. we did not include patients with clinical insignificant residual fragments (cirf). each patient was evaluated with history, physical examination, and laboratory investigations like haemoglobin, complete blood count, blood urea nitrogen level, serum creatinine, serum electrolyte, urine c/s, x-ray kidney-ureter-bladder (kub) and ultrasonography (usg) kub. literature supports that there is no significant difference in evaluation of urolithiasis by usg and computed tomography kub10. usg kub was done by the same physician in all patients. ct kub plain was done only when stone was visualized on ultrasound and was not seen on x-ray kub. group a patients were given medical expulsive therapy which included capsule tamsulosin 0.4 mg daily at night time, tablet furosemide 20mg, spironolactone 50mg single morning dose, and syrup potassium magnesium citrate 20meq per dose three times a day for 12 weeks while group b patients were given placebo. both groups were given dietary advice including water intake >3litre/day and tablet diclofenac sodium 50mg as per severity of pain. the primary outcome variable was number of patients achieving clearance of stone during the 12-week treatment period in both groups. secondary variables included expulsion rate for different calyceal location, and incidence of pain in both groups. expulsion rate was measured objectively by performing usg kub after 6 weeks and after 12 weeks. side effects were evaluated from start of study till completion. side effects such as dizziness, nausea, headaches and retrograde ejaculation (in male patients) in patients taking tamsulosin; muscle weakness and lethargy in patients taking furosemide and altered bowel habits, nausea and vomiting in patients taking potassium magnesium citrate syrup were explained to them. all patients were asked to follow up at 6 and 12 weeks. these patients were also informed to refer if they experienced any of above side effects. primary and secondary variable were evaluated at each visit. primary physician evaluated the patients during study time. he was concealed about the group of the patients. outcome variables such as pain or stone free-rate was measured separately each time and measured again in the next follow-up visits. imaging techniques included usg kub, x-ray kidney-ureter-bladder (kub) at 6 and 12-week follow up visit. imaging data were recorded for noting variables like stone size and location. statistical analysis since no data was available for sample size calculation, a universal sampling method was used. accordingly, 50 patients in each group were selected. the null hypothesis assumed there was no difference between met and placebo group on the effect of stone passage. data was recorded on microsoft excel 2010. chi-square test with two tail distribution was used to compare two groups, p-value < .05 was considered as significant. results no statistically significant differences in age, gender, stone size, and calyceal stone location were found between the two treatment arms (table 1). median stone size in entire study group was 4.7 mm (inter-quartile range [iqr]: 2.0-5mm). table 1. distribution of patients in the groups with respect to age, sex, side affected and size of stone. group a(met) group b (placebo) p value age, years; mean±sd(range) 35.14 ± 11.43 (17-68) 32.66 ± 10.24 (16-70) 0.443 sex male 31 32 0.8 female 19 18 0.8 side right 38 36 0.25 left 24 34 0.25 stone size, mm; mean ± sd 4.274 ± 1.06 4.49 ± 0.99 0.634 table 2. percentage of stone clearance achieved in the two groups at 6 weeks and at 12 weeks no. of patients achieved complete group a(met) group b(placebo) p value clearance at 6 weeks 25(50%) 14(28%) 0.04 12 weeks 43(86%) 19(38%) <0.01 met in renal stone < 5 mmdaga et al. endourology and stone diseases 2894 a spontaneous stone expulsion rate (table 2) of 50% (at 6 weeks ) and 86 %( at 12 weeks) was noted in group a and 28% (at 6 weeks) and 38 % (at 12 weeks) in group b. expulsion rate noted for different calyceal location at 6 weeks and 12 weeks are shown in table 3. with significant less number of pain episodes in group a as compared to group b, only 8 patients(16%) in group a required analgesic as compared to 19(38%)in group b which was statistically significant (p < .05). patients were asked to bring back empty strips of medication to evaluate compliance with medication at each visit. expulsion rates in respect to number of patients achieving stone free status achieved statistical significance at 6 weeks (p = .04) and 12 weeks (p < .01) (table 2). however, clearance rate in respect to number of stone from each calyx achieved statistical significance at 12 weeks only for superior and middle calyces (table 3). discussion many patients with renal calculi ≤5mm remain asymptomatic. evaluation of ureteral smooth muscle physiology and obstruction caused by urinary stones signifies that α-blockers can facilitate stone expulsion(11-13). distribution of α1 receptors and their subtypes has been confirmed by karabacak et al. in human pelvis and calyces(9). meta-analysis has confirmed use of α-blockers (tamsulosin) to achieve clearance of residual stone in post surgical cases(14-16). use of diuretics like furosemide has been shown to be effective in expulsion of the calcium fragments and also diuresis would further fasten expulsion of small stones(17). expectant management is followed for renal calculi less than 5 mm in size which are likely to pass spontaneously by follow up every 6 month(8). however, there is level iib/b evidence that for small ≤5mm calculi after swl when followed expectantly, a significant number would require intervention or have symptomatic episodes during follow-up. burgher and co-workers has described that stone > 4mm were 26 % more likely to fail observation than patients with smaller solitary calculi(18). hubner et al. reported that 83% of 62 patients with asymptomatic calyceal stone required intervention within 5 years of diagnosis. only 10% remained symptom free after 10 years(19). karabacak et al.(9) had described density expression of α-1 receptor subtypes for renal pelvis and calyces which were α-1d>α1a>α-1b. no difference was observed in the receptor expressions in pelvis with calyces. however, receptor met in renal stone < 5 mmdaga et al. stone free rate at calyceal location group a(met) group b(placebo) p value 6 weeks superior calyx 66.66%(10/15) 45.46%(10/22) 0.3 medial calyx 63.41%(26/41) 47.83%(22/46) 0.2 inferior calyx 50%(9/18) 50%(9/18) 0.7 12 weeks superior calyx 93%(14/15) 45.46%(10/22) <0.01 medial calyx 90.25%(37/41) 60.87%(28/46) <0.01 inferior calyx 78%(13/18) 55.56%(10/18) 0.4 table 3. calyceal-wise stone clearance rates in the two groups. figure 1. patients' flow diagram. vol 13 no 06 november-december 2016 2895 density for each calyx was not mentioned in study, which would have helped in predicting whether inferior calyx had less density of receptors which might be the reason for lower expulsion rate in our study. soygur et al. have concluded that use of potassium citrate in post swl lower pole calculi aided in spontaneous passage of stone and increasing clearance rates(20). gravina and colleagues studied the efficacy of tamsulosin as an adjunctive therapy after swl for renal stones(21). at 12 weeks, clinical success was achieved in 78.5% of patients receiving tamsulosin and 60% of patients not receiving tamsulosin (p =.037). the stones ranged in size from 4 mm to 20 mm(19). however lower pole calculi were not included in the study group. mean stone size in our study was 4.7 mm and the most commonly reported stone location was middle calyx (65.9%) followed by superior calyx (31.66%) and inferior calyx (27.27%). on subgroup analysis, expulsion rate of above 90% was achieved after 12 weeks for superior and middle calyceal calculi and 78 % for inferior calyceal calculi. overall number of patients achieving complete clearance of stone at 12 weeks was 43 out of 50(86%) which was statistically significant. stone expulsion was significantly (p < .05) better with met than with placebo (86% vs. 38%); with an absolute benefit (ab) of 48%; number needed to treat (nnt) was 4 in our study. four studies showed a beneficial effect for a-blockade for renal stones treated with swl(21-24). han et al. demonstrated a significant expulsion rate and decreased analgesic requirement with use of tamsulosin for upper ureteral stones after swl(25). in a prospective study of 70 patients performed by arrabal-martin m et al.(26), it was found that tamsulosin significantly increases stone expulsion rate (85.7%) as compared to hydration therapy (54.3%) in patients with distal ureteric calculi less than 10 mm. three double-blinded rcts did not demonstrated significant differences in expulsion rate for met using alfuzosin or tamsulosin for lower ureteral stone versus placebo(27-29). however average stone size in these 3 study group were 3.8 mm in pedro et.al.(27), (2.9mm -3.2mm) in vincendeau et al.(27) and (3.8mm -4.1 mm) in hermanns et al.(29). with stone size less than 4mm there is higher chances of stone passing spontaneously(8), therefore decreased efficacy of met is expected. in these studies, a-blockers still reduced time to stone passage, pain scores, and need for analgesia(28). similarly, ferre et al.(30) failed to demonstrate a significant higher expulsion rate in the tamsulosin group. again, mean stone size was 3.6 mm. meta-analysis of 33 trials (3105 patients) examined a-blockers (most often tamsulosin) or calcium channel blockers (nifedipine) in patients with renal stones (primarily < 10 mm; frequently distal ureter)(31). stone expulsion was significantly (p < .001) better with met than with placebo (80% vs. 54%); absolute benefit (ab) of 26%; number needed to treat (nnt) of four31.the more distal the stone, the lesser time required for expulsion. skolarikos a et al.(32) performed meta-analysis and demonstrated efficacy of a-blockers in stone clearance. they have also concluded that a-blockers significantly reduce the time to stone elimination, the intensity of pain, the formation of steinstrasse, and the need for auxiliary procedures. similarly, efficacy of α-1d receptor blockers in clearance of distal ureteric stones has been proven by other studies(33). european(34) and us(35) guidelines for urolithiasis recommend met as an option when the following criteria are met: newly diagnosed ureteral stone < 10 mm in patients without need for urgent urologic intervention; and well-controlled pain, no sepsis, good renal function, and following with periodic imaging to monitor stone position and assess hydronephrosis. the secondary variable of number of events of pain was significantly lower in met group versus placebo. patients in met arm required less analgesia than patients in the placebo arm. no serious complications were recorded in both groups. the common side effects of tamsulosin are dizziness, nausea, diarrhoea, headache and retrograde ejaculation. in our study the only adverse effect noted was dizziness in 4 patients and nausea in 3 patients in met group over a period of 12 weeks which was well tolerated. patients with residual calculi in both groups after 12 weeks were managed with other modalities like swl, or rirs. with recent understanding of distribution of alpha adrenoreceptors in renal calyces and pelvis, the present study is one of the first to compare the efficacy between met and placebo on renal calyceal calculi ≤5mm in size. the results suggest that treatment with use of met in patients with ≤5mm renal calculi when taken for 12 weeks is effective in achieving stone clearance, implying a higher number of patients achieving complete clearance and better pain management. being an initial step to address small renal calculi and use of medical therapy which is better than observation and less morbid than invasive procedure certain limitations of this study are: single institutional study and small population size; a multicenter placebo controlled double blind study will be able to validate results observed in our study. other limitations include the use of x-ray kub and usg kub to detect residual calculi when ct scans should be the imaging of choice to detect the calculus. met as a combine treatment of alpha blocker with diuretics and potassium citrate therapy was given to treatment group which has a confounding effect, however met achieved a significant expulsion rate and better patient tolerability of all drugs with minimal side effects. stone composition and metabolic evaluation was not addressed which would have been helpful to evaluate patients completely and starting specific medical therapy according to stone composition and addressing and minimizing future recurrences. our study fails to address difference between spontaneous passage and met for small stones. conclusions medical expulsive therapy for 12 weeks significantly improves stone free rates in renal calyceal calculi less than or equal to 5mm. however, further randomized studies are required to document these findings. conflicts of interest none declared. references 1. moe ow. kidney stones: pathophysiology and medical management. lancet 2006; 367:333–44. 2. romero v, akpinar h, assimos dg. kidney stones: a global picture of prevalence, incidence, and associated risk factors. rev urol 2010; 12:e86–96. met in renal stone < 5 mmdaga et al. endourology and stone diseases 2896 3. lee yh, huang wc, tsai jy, lu cm, chen wc, lee mh, et al. epidemiological studies on the prevalence of upper urinary calculi in taiwan. urol int 2002; 68:172–7. 4. saigal cs, joyce g, timilsina ar. direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? kidney int 2005; 68:1808–14. 5. moe ow, pearle ms, sakhaee k. pharmacotherapy of urolithiasis: evidence from clinical trials. kidney int 2011; 79:385– 92. 6. gravina gl, costa am, ronchi p, et al. tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones. urology 2005; 66:24-8. 7. naja v, agarwal mm, mandal ak, et al. tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi; results from an open-label randomized study. urology 2008; 72:1006-11. 8. zheng s, liu lr, yuan hc, et al. tamsulosin as adjunctive treatment after shockwave lithotripsy in patients with upper urinary tract stones: a systematic review and meta-analysis. scand j urol nephrol 2010;44:425-32. 9. karabacak or, yilmazer d, ozturk u, sener nc, saltas h, karabacak y, et al. the presence and distribution of alpha adrenergic receptors in human renal pelvis and calyces. urolithiasis. 2013; 41: 385–8. 10. carlo passerotti, chow js, silva a, schoettler cl, rosoklija i perez-rossello j et al. ultrasound versus computerized tomography for evaluating urolithiasis. the j urol 182: 1829–1834. 11. sigala s, dellabella m, milanese g, fornari s, faccoli s, palazzolo f, et al. evidence for the presence of alpha1 adrenoceptor subtypes in the human ureter. neurourol urodyn 2005; 24:142–8. 12. tomiyama y, kobayashi k, tadachi m, kobayashi s, inada y, kobayashi m, et al. expressions and mechanical functions of alpha1-adrenoceptor subtypes in hamster ureter. eur j pharmacol 2007; 573:201–5. 13. morita t, wada i, suzuki t, tsuchida s. characterization of alpha-adrenoceptor subtypes involved in regulation of ureteral fluid transport. tohoku j exp med 1987; 152:111–8. 14. vicentini fc, mazzucchi e, brito ah, chedid neto ea, danilovic a, srougi m. adjuvant tamsulosin or nifedipine after extracorporeal shock wave lithotripsy for renal stones: a double blind, randomized, placebo-controlled trial. urology 2011; 78:1016–21. 15. hussein mm. does tamsulosin increase stone clearance after shockwave lithotripsy of renal stones? a prospective, randomized controlled study. scand j urol nephrol 2010; 44:27–31. 16. john tt, razdan s. adjunctive tamsulosin improves stone free rate after ureteroscopic lithotripsy of large renal and ureteric calculi: a prospective randomized study. urology 2010; 75:1040–2. 17. suki wn, yium jj, von minden m, sallerhebert c,eknoyan g and martinez-maldonado m. acute treatment of hypercalcemia with furosemide.n engl j med 1970; 283:836-840. 18. bugher a, beman m, holtzman jl, monga m. progression of nephrolithiasis: long-term outcomes with observation asymptomatic calculi. j endourol. 2004;18:534–539. 19. hübner w, porpaczy p. treatment of caliceal calculi. british journal of urology. 1990 1;66:9-11. 20. soygur t, akbay a, kupeli s. effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower calyceal calcium oxalate urolithiasis: a randomized controlled trial. j endourol. 2002;16:149–52. 21. gravina gl, costa am, ronchi p, et al. tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones. urology. 2005;66:24-28. 22. bhagat sk, chacko nk, kekre ns, gopalakrishnan g, antonisamy b, devasia a. is there a role for tamsulosin in shock wave lithotripsy for renal and ureteral calculi? j urol 2007;177:2185–8. 23. naja v, agarwal mm, mandal ak, et al. tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi: results from an open-label randomized study. urology 2008;72:1006–11. 24. hussein mm. does tamsulosin increase stone clearance after shockwave lithotripsy of renal stones? a prospective, randomized controlled study. scand j urol nephrol 2010;44:27–31. 25. han mc, jeong ws, shim bs. additive expulsion effect of tamsulosin after shock wave lithotripsy for upper ureteral stones. korean j urol 2006;47:813–7. 26. arrabal-martin m, valle-diaz de la guardia f, arrabal-polo ma, palao-yago f, mijan-ortiz jl, zuluaga-gomez a. treatment of ureteral lithiasis with tamsulosin: literature review and meta-analysis. urol int. 2010;84:254-9. 27. pedro rn, hinck b, hendlin k, feia k, canales bk, monga m. alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study. j urol 2008;179:2244–7, discussion 2247. met in renal stone < 5 mmdaga et al. vol 13 no 06 november-december 2016 2897 28. vincendeau s, bellissant e, bansalah k, et al. lack of efficacy of tamsulosin in the treatment of distal ureteral stones. eur urol suppl 2008;7:149. 29. hermanns t, sauermann p, rufibach k, frauenfelder t, sulser t, strebel rt. is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? results of a randomised, doubleblind, placebo-controlled trial. eur urol 2009;56:407–12. 30. ferre rm, wasielewski jn, strout td, perron ad. tamsulosin for ureteral stones in the emergency department: a randomized controlled trial. ann emerg med 2009;54:432– 9. 31. seitz c, liatsikos e, porpiglia f, tiselius hg, zwergel u. medical therapy to facilitate the passage of stones: what is the evidence? eur urol 2009;56:455-71. 32. skolarikos a, grivas n, kallidonis p, mourmouris p, rountos t, fiamegos a, stavrou s, venetis c; members of rista study group. the efficacy of medical expulsive therapy (met) in improving stone-free rate and stone expulsion time, after extracorporeal shock wave lithotripsy (swl) for upper urinary stones: a systematic review and meta-analysis. urology. 2015 ;86:1057-64. 33. wang cj, tsai pc, chang ch. efficacy of silodosin in expulsive therapy for distal ureteral stones: a randomized doubleblinded controlled trial. urol j. 2016 28;13:2666-71. 34. tiselius hg, alken p, buck c, gallucci m, knoll t, sarica k, et al. guidelines on urolithiasis. arnhem, the netherlands: european association of urology; 2009. 35. american urologic association. 2007 guideline for the management of ureteral calculi. rockville, md: agency for healthcare research and quality; 2007. met in renal stone < 5 mmdaga et al. endourology and stone diseases 2898 vol 15 no 06 november-december 2018 348 urological oncology preoperative low lymphocyte-to-monocyte ratio predicts poor clinical outcomes for patients with urothelial carcinoma of the upper urinary tract xin-ke zhang#1,2, ping yang1,2, zhi-ling zhang1,3, wan-ming hu1,2, yun cao1,2* purpose: urothelial carcinoma of the upper urinary tract (uutuc) is a rare genitourinary tumor. pre-operative lymphocyte-to-monocyte ratio (lmr) is associated with worse outcome in several malignancies. the aim of this study was to determine the prognostic value of pre-operative lmr in uutuc. materials and methods: a historical cohort of 100 uutuc patients was recruited from january 1990 to june 2011. the counts of peripheral lymphocyte and monocyte were retrieved, and the lmr was calculated by dividing lymphocyte count by monocyte count. receiver operating characteristic curve (roc) analysis, log-rank test and cox proportional hazards regression models were used for univariate and multivariate analyses to evaluate the associations of lmr with overall survival (os) and disease-free survival (dfs). result: univariate analysis revealed that low level of lmr (≤ 3.0) was significantly associated with worse os (p = .024) but not dfs (p = .993). multivariate cox proportional hazard analysis showed that low level of lmr was a significantly independent predictor for worse os (hazard ratio = 0.366, 95% confident interval: 0.180-0.744). based on the results of multivariate analysis, the rates of os at 5 years developed by the prognostic model were as follows: low risk, 88.0%, intermediate risk, 44.0%, and high risk, 13.0%, respectively. conclusion: the pre-operative lmr serves an independent prognostic biomarker in uutuc. the prognostic model based on the lmr and pathologic factors can be available in selection of high risk patients for further aggressive therapy. keywords: urothelial carcinoma; lymphocyte-to-monocyte ratio; prognostic; biomarker; overall survival; disease-free survival introduction upper urinary tract urothelial carcinoma (uutuc) is a rare urological disease, and easily appears to a propensity for local relapse, multifocality and distant metastasis(1). it represents approximately 10% of renal tumors and 5% of urothelial neoplasms(2,3). because of the high rate of recurrence ranging from 30% to 75%, radical nephroureterectomy (rnu) with an excision of bladder cuff remains to be the golden standard for uutuc treatment(3-5). several studies have shown that pathological parameters, including pathological t stage, tumor grade, tumor necrosis, lymph node invasion, existence of lymphovascular invasion (lvi) and dna ploidy are of prognostic value in uutuc(6,7). these factors are useful for selection of patients for adjuvant chemotherapy. meanwhile, prognostic value of pre-operative markers consisting of lactate dehydrogenase (ldh) and alkaline phosphatase (alp) for uutuc were also clinical significance(8,9). these factors are associated with metabolism and the corresponding inhibitors of ldh and alp could be applied in clinical practice in the future(10,11). 1collaborative innovation center for cancer medicine; state key laboratory of oncology in south china; sun yat-sen university cancer center. 2department of pathology, sun yat-sen university cancer center; guangzhou, china. 3department of urology, sun yat-sen university cancer center; guangzhou, china. *correspondence: department of pathology, sun yat-sen university cancer center, no. 651, dongfeng road east, guangzhou, 510060 china. tel: 86-20-87343203, fax: 86-20-87343268, email: caoyun@sysucc.org.cn. received august 2017 & accepted march 2018 recent researches indicate that systemic inflammatory response plays a critical role in tumor aggressiveness and migration(12). tumor-associated lymphoid cells consisted of neutrophils, monocytes and macrophages facilitate tumor development by changing the extracellular matrix and stimulating tumor cell invasion and metastasis(13). on the other hand, the cytokines and their mediators secreted by inflammatory cells can further facilitate angiogenesis and cells migration(14,15). although peripheral blood draws taken can reflect inflammatory status within the tumor tissues when the tumor was diagnosed and treated, very few blood-based biomarkers were identified in uutuc. prior literatures have reported that elevating c-reactive protein (crp) level, high alkaline phosphatase (alp) level, white blood cell count and elevated lactate dehydrogenase (ldh) have been reported to be of adverse prognostic significances in patients with uutuc(8,9,16). the circulating blood lymphocyte-to-monocyte ratio (lmr) is an easily examined, economic and reproducible indicator to reflect systemic inflammation. recent researches showed that the absolute count of lymphocyte was independently correlated with the survival of patients with several malignancies, including gastric cancer, oropharyngeal cancer and acute lymphoblastic leukemia(17-19). other studies demonstrated that patients with low lmr had a worse overall survival in bladder cancer and pancreatic cancer(20,21). a recent study showed that the european patients with preoperative elevated lmr had the longer os in uutuc, and suggested the prognostic model including lmr would be better to predict clinical outcome(22). another study found that low lmr with uutuc patients had a worse dfs and progression-free survival (pfs) in chinese, but not mentioned os(23). in this study, we aimed to evaluate the prognostic implication of the preoperative lmr in chinese uutuc, also we tried to provide the prognostic model including lmr to predict the clinical outcome for future clinical management of the uutuc patients. patients and methods patients a total of 100 patients with upper urinary tract urothelial carcinoma (uutuc) underwent radical nephroureterectomy with bladder cuff excision were recruited from sun yat-sen university cancer center (sysucc) from january 1990 to june 2011. the use of tissues for this study has been approved by the institute research medical ethics committee of sysucc. the patient demographics and follow-up data were obtained from the medical record with approval of the institutional review board. the pathological finding, including tumor necrosis, vascular invasion, tumor grade, tumor location and tnm classification, were noted from the pathology reports. additional clinical information, such as preoperative laboratory data, was recorded from patients’ charts. the counts of lymphocyte and monocyte were achieved in two weeks before surgical resection. lymphocyte-to-monocyte ratio (lmr) was served as the ratio of the absolute count of lymphocyte and the monocyte count. patients without blood draw data and patients with pre-operative infection, fever and blood diseases, or received neoadjuvant chemotherapy were excluded(24). no informed consent (written or verbal) was obtained for the use of retrospective tissue samples from the patients, part of whom were deceased, because this was deemed unnecessary by the ethics committee. all samples were anonymous. the recruited patients were observed by physical examination consisted of computerized tomography (ct), magnetic resonance imaging (mri), cystoscopy and ureteroscopy. the patients were observed every 3 months for the first 3 years after surgery, every 3-6 months in the next year and every 6-12 mouths from the 5thyear, and annually thereafter (starting from the 6th year). overall survival (os) as the date of surgery to the date of death from any cause, or to the last follow-up date if the patient was alive and disease-free survival (dfs) as the length of time from the date of surgery on the primary tumor to local, regional, or distant recurrence or death from low lymphocyte-to-monocyte in uutuc-zhang et al. table1. correlation between the lmr and clinicopathological features in 100 patients with uutuc. lmr all cases ≤ 3.0 > 3.0 p value gender .949 female 21 10 (47.6%) 11 (52.4%) male 79 37 (46.8%) 42 (53.2%) age at diagnosis (years) .106 < 60 49 19 (38.8%) 30 (61.2%) ≥60 51 28 (54.9%) 23 (45.1%) pathological stage .305 pta-pt1 48 20 (41.7%) 28 (58.3%) pt2-pt4 52 27 (51.9%) 25 (48.1%) lymph node status .423 pnx/pn0 80 36 (45.0%) 44 (55.0%) pn1-pn3 20 11 (55.0%) 9 (45.0%) subsequent bladder tumor .723 no 62 30 (48.4%) 32 (51.6%) yes 38 17 (44.7%) 21 (55.3%) tumor diameter, cm .542 ≤ 3 35 15 (42.9%) 20 (57.1%) >3 65 32 (49.2%) 33 (50.8%) tumor grade .358 low 21 8 (38.1%) 13 (61.9%) high 79 39 (49.4%) 40 (50.6%) tumor site .371 pelvic 57 29 (50.9%) 28 (49.1%) ureteric 43 18 (41.9%) 25 (58.1%) multifocality .609 no 58 26 (44.8%) 32 (55.2%) yes 42 21 (50.0%) 21 (50.0%) vascular invasive .292 no 69 30 (43.5%) 39 (56.5%) yes 31 17 (54.8%) 14 (45.2%) tumor necrosis .168 no 52 21(40.4%) 31 (59.6%) yes 48 26 (54.2%) 22 (45.8%) achitecture .259 papillary 57 24 (42.1%) 33 (57.9%) non-papillary 43 23 (53.5%) 20 (46.5%) abbreviations: lmr:lymphocyte-to-monocyte ratio; uutuc: urothelial carcinoma of the upper urinary tract urological oncology 349 vol 15 no 06 november-december 2018 350 any cause. selection of cut-off value sensitivity and specificity for lmr cut-off were calculated with receiver operating characteristic (roc) curve. roc analysis was plotted to investigate optimal cut-off values that maximized sensitivity and specificity(25). the cut-off value of lmr was corresponding with the largest sensitivity and specificity on the roc curve. the valueless lower than or equal to cut-off value was considered as low level of lmr, and more than the cutoff value was determined as high level of lmr. risk factor classification for os and dfs a prior study has described the method of risk factor classification(24). overall survival distributions for groups classified according to the number of independent clinical risk factors are shown in the result section. statistical analysis statistical analysis was performed with spss software, version 16.0 (spss, chicago, usa). the suitable cutoff value of the diverse lmr was analyzed with roc curve. the association of lmr with other clinicopathological factors was analyzed by chi-square test. survival curve were plotted for both high and low level of lmr with the kaplan–meier method. univariate analysis was performed to identify the impact of clinicopathological factors on survival. multivariate analysis was used to explore the independent prognostic factors for survival. the evaluation of hazard ratios (hrs) was served as relative risks with corresponding 95% confidence intervals (cis). all data tests were 2-sided, with statistical significant set as p < .050. results the clinical and pathological characteristics of 100 patients with uutuc are detailed in table 1. the average age was 60.3 years (range from 30 to 85 years). seventy-nine (79%) patients were male and 21 (21%) were female (male to female ratio 3.8:1). the average follow-up interval was 45.83 months (range from 1 to 151 months). the median overall survival (os) was 37.0 months. the rates of os at 2nd and 5thyears after surgery were 83% and 70%, respectively. the median dfs was 32.0 months. the rates of dfs at 2ndand 5th years after surgery were 80% and 66%, respectively. to select an optimal cut-off value for lmr, the roc low lymphocyte-to-monocyte in uutuc-zhang et al. table 2. univariate and multivariate analyses of overall survival in uutuc univariate analysis multivariate analysis variable all cases hr (95% ci) p value hr (95% ci) p value gender .790 female 21 reference male 79 0.894 (0.391-2.042) age at diagnosis (years) .112 < 60 49 reference ≥ 60 51 1.705 (0.883-3.292) pathological stage <.001 4.854 (1.806-13.044) .002 pta-pt1 48 reference pt2-pt4 52 6.342 (2.636-15.259) lymph node status .004 1.291 (0.750-2.220) .357 pn0 46 reference pnx 34 0.903 (0.391-2.087) pn1-pn3 20 1.852 (1.267-2.708) subsequent bladder tumor .005 2.966 (1.428-6.163) .004 no 62 reference yes 38 2.537 (1.322-4.871) tumor diameter, cm .835 ≤ 3 35 reference > 3 65 0.930 (0.471-1.837) tumor grade .010 2.933 (0.252-34.119) .390 low 21 reference high 79 15.204 (1.937-119.344) tumor site .063 pelvic 57 reference ureteric 43 1.852 (0.968-3.541) multifocality .022 2.070 (1.039-4.123) .039 no 58 reference yes 42 2.143 (1.116-4.114) vascular invasion <.001 0.857 (0.319-2.302) .760 no 69 reference yes 31 3.273 (1.693-6.327) tumor necrosis <.001 3.773 (1.460-9.751) .006 no 52 reference yes 48 7.445 (3.090-17.936) architecture .001 2.217 (1.067-4.607) .033 papillary 57 reference non-papillary 43 3.096 (1.5816.064) lmr .028 0.366 (0.180-0.744) .005 ≤ 3.0 46 reference >3.0 54 0.478 (0.248-0.924) abbreviations: lmr, lymphocyte-to-monocyte ratio; uutuc, upper urinary tract urothelial carcinoma; hr, hazard ratio; ci, confident interval. curves were used. results showed that the area under the curve (auc) for age at diagnosis variable had the biggest area (auc = 0.382, p = .041, 95% confident interval: 0.272-0.491). lmr value of 3.0 had the largest sensitivity and specificity on the roc curve (figure 1). as a result, the value of 3.0 was chosen as the cutoff value of lmr for survival analysis. patients were divided into two groups: low level of lmr (≤ 3.0) and high level of lmr (> 3.0). no significant correlation was found between lmr and pathological variables, including gender, age, vascular invasion, pathological stage, lymph node status, subsequent bladder tumor, tumor site, tumor diameter, tumor grade, multifocality, tumor necrosis and architecture (table 1). in univariate analysis, lmr, along with a series of well-known clinicopathological prognostic factors (pathological stage, lymph node status, subsequent bladder tumor, tumor grade, vascular invasion, multifocality, tumor necrosis, architecture), was significantly associated with os in patients with uutuc (table 2). furthermore, in multivariate analysis, lmr retained independent significance in patients with uutuc for os (p = .005, table 2). kaplan-meier analysis revealed that patients with low lmr level had a significantly poorer survival (5-year os, 48.0%), compared with patients with high lmr level (5-year os, 68.0%) (p = .024, figure 2) but not dfs (p = .993, figure 2). risk factor classification for os multivariate analysis revealed that pathological stage, subsequent bladder tumor, multifocality, tumor necrosis, architecture and lmr (a total of 6 risk factors) were of independent significance in patients with uutuc for os (table 2). accordingly, the 100 patients were divided into seven groups through 0 to 6 risk factors. survival analysis showed that there were no significant differences for os among the groups simultaneously harboring the 0, 1 or 2 risk factors. however, there were inversely statistical differences for os between above mentioned three groups (simultaneously harboring the 0, 1 or 2 risk factors) and other groups including simultaneously harboring 3, 4, 5 or 6 risk factors (p < .001). therefore, these groups simultaneously harboring the 0, 1 or 2 risk factors was categorized into low risk groups. similarly, univarite analysis showed that there were no significant differences for os between the groups simultaneously harboring 3 and 4 risk factors, but os of both of groups as one variable had closely statistical differences comparing with that of simultaneously harboring 5 or 6 risk factors (p = .008, data no shown). thus, the groups simultaneously harboring 3 or 4 risk factors was served as intermediate risk group, and correspondingly the groups simultaneously harboring 5 or 6 risk factors was considered as high risk group. the median os and the 5-year os rate was 151.0 months and 88.0% in low risk group (50 patients), while the low lymphocyte-to-monocyte in uutuc-zhang et al. figure 1. roc curve analysis was conducted to determine the cutoff value for lmr. the sensitivity and specificity of each outcome were plotted for lmr: age at diagnosis, sensitivity = 0.627, specificity = 0.305, likelihood ration positive and negative = 90.3% and 81.8%, 95% confidence intervals = 0.272-0.491 (a), survival status, sensitivity = 0.297, specificity = 0.714, likelihood ration positive and negative = 103.8% and 101.6%, 95% confidence intervals = 0.290-0.526 (b), pathological stage, sensitivity = 0.923, specificity = 0.125, likelihood ration positive and negative = 105.5% and 162.3%, 95% confidence intervals = 0.346-0.575 (c), tumor grade, sensitivity = 0.316, specificity = 0.762, likelihood ration positive and negative = 132.8% and 111.4%, 95% confidence intervals = 0.329-0.602 (d), lymph node status, sensitivity = 0.618, specificity = 0.561, likelihood ration positive and negative = 140.8% and 146.9%, 95% confidence intervals = 0.426-0.677 (e), subsequent bladder tumor, sensitivity = 0.421, specificity = 0.710, likelihood ration positive and negative = 145.2% and 122.6%, 95% confidence intervals = 0.395-0.637 (f) figure 2.the association of lmr with uutuc patients’ survival (log-rank test).kaplan-meier survival analysis of lmr for overall survival (a) and disease-free survival (b) urological oncology 351 vol 15 no 06 november-december 2018 352 corresponding values were 47.5 and 44.0% in intermediate risk group (35 patients), and 20.3 and 13.0% in high risk group (15 patients). kaplan-meier analysis showed a distinct prognostic pattern among the three groups (figure 3). discussions the inflammatory cells response stimulated by tumors could lead to the increase of various cytokines and inflammatory mediators, further resulting in the upregulation of capability for invasion and migration(12,14). inflammatory responses are very important with respect to the tumor and outcome of patients by chronic cellular injury and oxidative stress, which will facilitate tumor initiation and progression(26), more importantly, the procession of tumor-recruited lymphocytes interacting with tumor cells might induce tumor progression by secreting diverse cytokines. herein, we have made an investigation on uutuc to evaluate the critically prognostic significances of circulating lymphocyte-to-monocyte ratio (lmr) and other clinical parameters. recent much advancement for the molecular and genetic alterations has been demonstrated in uutuc(27), however, the conventional clinicopathological parameters are still applied to assess the prognosis of patients with uutuc. at the same time, blood-based markers, including the count of lymphocyte, neutrophil and the variable of lmr, maybe used to estimate the relative risks in the patients with uutuc. recently, an elevated pre-treatment neutrophil-to-lymphocyte ratio (nlr) was demonstrated as an adverse prognostic biomarker for different human neoplasms, including soft tissue sarcoma(28), nasopharyngeal carcinoma(29), renal cell carcinoma(30), lung cancer(31), and uutuc(24). regarding the lmr, so far, the prognostic value has been investigated only in nasopharyngeal carcinoma (32), diffuse large b-cell lymphoma(33) and soft tissue sarcoma(34). recently, two publications reported that low lmr was closely associated with the poor prognosis of uutuc(22,23). hutterer gc et al.(22) reported that uutuc patients with preoperative low lmr had a worse overall survival in european, and song x et al.(23) showed that uutuc patients with preoperative low lmr had a worse dfs and pfs but without os information in chinese population. in our study, we found a statistically significant association of low lmr with poor os in uutuc patients in univariate as well as multivariate analysis. together with the kaplan-meier analysis result, we demonstrated for the first time that a decreased lmr represents a novel independent poor prognostic marker in uutuc patient in chinese, and we timely provided the prognostic models, which including lmr (pathological stage, subsequent bladder tumor, multifocality, tumor necrosis and lmr). we demonstrated that uutuc patients with high risk factor, intermediate risk factor and low risk factor had significantly statistical differences for the prediction of os. monocytes constitute about 5% of the circulating leukocytes and play an important role in innate immunity. derive from circulating monocytes, tumor-associated macrophages (tams) selectively recruited to the tumor microenvironment by locally secreted cytokines and chemokines, such as monocyte chemoattractant protein-1 (mcp-1), tnf-α and others. the interaction between tams and tumor cells is believed to have substantial effects in tumor initiation and progression. paik ky et al. have found that absolute monocyte count was associated with clinical outcomes in colorectal cancers patients(35) and lenz g et al. have demonstrated that the infiltrated monocytes in tumor tissue had abilities to promote tumor invasion and cell growth in large b-cell lymphoma(36). the predictive value of preoperative monocytes count in other solid tumor was also reported(37). the exact role of monocytes in tumor development has not yet been well identified. one possibility is the soluble factors released by infiltrative monocytes, including interleukin (il)-1, il-6, il-10 and tgf-α, which have been well studied to enhance neo-angiogenesis, invasion and migration, and are associated with worse prognosis in various malignances (38). furthermore, monocytes can inhibit mitogen and antigen-induced lymphocytes proliferative response, impair the host defense anti-tumor role by lymphocytes, resulting in suppression of anti-cancer immunity in cancers(39). this was demonstrated by our study from another aspect. in other words, when the circumstances of high monocytes in combination with low lymphocytes or low lmr were appeared, these patients had a worse os. therefore, inhibition of this pathway of decreased lymphocytes inducing by monocytes could be the newly therapeutic target. to the best of our knowledge, this is the first study indicating that preoperative lmr is an independent prognostic factor in chinese uutuc patients for os. this finding was partial in agreement with that of two other studies(22,23). our study and two other studies had a certain degree of similarities. firstly, hutterer gc et al.(22) reported that uutuc patients with preoperative low lmr had a worse os in european, which was consistent with that of our study, and in our study, we firstly revealed the same conclusion in chinese uutuc patients. meanwhile, they also believed that this parameter should be considered in future prognostic models. however, they did not accomplish this work, and we timely provided the prognostic models, which including lmr (pathological stage, subsequent bladder tumor, multifocality, tumor necrosis and lmr). we further demonstrated that uutuc patients with high, intermediate and low risk factor had significantly statistical differences for the prediction of overall survival. therefore, our results verified their speculalow lymphocyte-to-monocyte in uutuc-zhang et al. figure 3. kaplan-meier analysis for overall survival each risk factor group. tion and the model based on the lmr and pathologic factors can be available in clinical practice, especially in selection of high risk patients for further aggressive therapy. the limitation of our study was that small patients were recruited. therefore, large-scale prospective studies in multicenter are necessary to validate these conclusions. taken together, we firstly demonstrated that pretreatment peripheral lmr is an independent biomarker for predicting os of chinese uutuc patients. additionally, we firstly provided the prognostic model, which including lmr (pathological stage, subsequent bladder tumor, multifocality, tumor necrosis and lmr). in this prognostic model, we demonstrated that uutuc patients with high risk factor, intermediate risk factor and low risk factor had significantly statistical differences for the prediction of os. technically, our study is directly derived from routine blood test and easily applied in clinical practice. large-scale prospective studies in multicenter are warranted to advanced validate our findings. conculusions our analysis has showed the pre-operative lmr serves as an independent prognostic biomarker in uutuc. the prognostic model based on the lmr and pathologic factors can be available in selection of high risk patients for further aggressive therapy. acknowledgements we thank dr. chris zhi-yi zhang (department of pathology, sun yat-sen university cancer center) for critical reading of this manuscript. conflict of interest the authors have no conflict of interest to declare. references 1. genega em, porter cr. urothelial neoplasms of the kidney and ureter. an epidemiologic, pathologic, and clinical review. am j clin pathol. 2002;117 suppl:s36-48. 2. munoz jj, ellison lm. upper tract urothelial neoplasms: incidence and survival during the last 2 decades. j urol. 2000;164:1523-5. 3. oosterlinck w, solsona e, van der meijden ap, et al. eau guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma. eur urol. 2004;46:147-54. 4. zigeuner r, pummer k. urothelial carcinoma of the upper urinary tract: surgical approach 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jw, liu pp, liu dy, xiao jj, chen xq. elevated neutrophil-to-lymphocyte ratio predicts poor outcome in patients with advanced non-small-cell lung cancer receiving first-line gefitinib or erlotinib treatment. asia pac j clin oncol. 2014. 32. li j, jiang r, liu ws, et al. a large cohort study reveals the association of elevated peripheral blood lymphocyte-to-monocyte ratio with favorable prognosis in nasopharyngeal carcinoma. plos one. 2013;8:e83069. 33. watanabe r, tomita n, itabashi m, et al. peripheral blood absolute lymphocyte/ monocyte ratio as a useful prognostic factor in diffuse large b-cell lymphoma in the rituximab era. eur j haematol. 2014;92:204-10. 34. szkandera j, gerger a, liegl-atzwanger b, et al. the lymphocyte/monocyte ratio predicts poor clinical outcome and improves the predictive accuracy in patients with soft tissue sarcomas. int j cancer. 2014;135:362-70. 35. paik ky, lee ik, lee ys, sung ny, kwon ts. clinical implications of systemic inflammatory response markers as independent prognostic factors in colorectal cancer patients. cancer res treat. 2014;46:65-73. 36. lenz g, wright g, dave ss, et al. stromal gene signatures in large-b-cell lymphomas. n engl j med. 2008;359:2313-23. 37. hase s, weinitschke k, fischer k, et al. monitoring peri-operative immune suppression in renal cancer patients. oncol rep. 2011;25:1455-64. 38. pollard jw. tumour-educated macrophages promote tumour progression and metastasis. nat rev cancer. 2004;4:71-8. 39. laughter ah, twomey jj. suppression of lymphoproliferation by high concentrations of normal human mononuclear leukocytes. j immunol. 1977;119:173-9. low lymphocyte-to-monocyte in uutuc-zhang et al. urological oncology the association of mir-let 7b and mir-548 with pten in prostate cancer mojtaba saffari1, 2, sayyed mohammad hossein ghaderian3*, mir davood omrani4, mandana afsharpad5, kimia shankaie6, niusha samadaian7 purpose: this study aims to investigate the expression level of mir-let7b-3p and mir-548, which are involved in pten expression in tissue samples of prostate cancer patients versus benign prostate hyperplasia (bph) and normal adjacent tissue. materials and methods: prostate cancer tissues were obtained from patients after receiving informed consent. total rna extraction and cdna synthesis were performed for determining gene expression. results: ten patients were determined to have high gleason scores (> 7), 36 and seven samples had intermediate gleason scores (7≥) and bph, respectively, and 40 samples were derived from normal adjacent tissue. downregulation of mir-let7b and upregulation of mir-548 expression significantly correlated with high-risk gleason scores. conclusion: the present study showed that mir-let7b and/or mir-548 can be considered as potential targets in prostate cancer therapy. keywords: prostate cancer; mir-let7b; mir-548; pten introduction one of the most frequently diagnosed malignancies in men is prostate. various factors including environmental elements such as lifestyle, race and genetics alterations and epigenetic mechanisms influence prostate cancer and its progression toward advanced malignancy1,2. the discovery of genetic or epigenetic associations with prostate cancer in the post-genome era has improved diagnosis and management of therapy 3. pten tumor suppressor gene plays a key role in pi3k/ akt pathway regulation, which is the most prominent signaling pathway that regulates some cellular processes such as cell cycle, survival, metabolism, motility, genomic instability and angiogenesis, and frequent changes in prostate cancer. it was shown that the pten expression level decreased in 4% of primary prostate cancer and more than 40% in metastatic prostate cancer 4 . for this reason, the inhibition of pten suppressor can be used as a potential target therapy for metastatic prostate cancer. the early determination of prostate cancer is necessary for an effective treatment and to increase survival time. at present, the most common tools for the diagnosis of prostate cancer is serum prostate specific antigen (psa) level 5. sensitivity and specificity of a psa cutoff of 4 ng/ml are about 50% and 90%, respectively. this limitation leads to low detection rate 1department of medical genetics, school of medicine, shahid beheshti university of medical sciences, tehran, iran. 2cancer biology research center, cancer institute of iran, tehran university of medical sciences, tehran, iran. 3chronic kidney disease research center, shahid beheshti university of medical sciences, tehran, iran. 4urogenital stem cell research center, shahid beheshti university of medical sciences, tehran, iran. 5cancer control research center, cancer control fundation, iran, iran university of medical sciences, tehran, iran. 6department of biology, science and research branch, islamic azad university, tehran, iran. 7department of medical genetics, school of medicine, tehran university of medical sciences, tehran, iran. *correspondence: urology & nephrology research center, shahid beheshti university of medical sciences, tehran, iran pasdaran, 9th boostan ave. tehran, iran. tel: +982122770954 fax: +982122567282.e-mail: sghaderian@sbmu.ac.ir. received may 2018 & accepted september 2018 of prostate cancer in range of 4–10 ng/ml psa level (called gray zone), and therefore, it is a disadvantage of psa screening as a biomarker. although psa has decreased the mortality rate of prostate cancer, it can lead to over-diagnosis or overtreatment 6,7. micrornas (mirnas), on average 22 nucleotides long, are a class of small noncoding rnas and play key roles in the gene regulatory processes 8. first, they are transcribed in the nucleus by rna polymerase ii called pri-mirna, and then they are processed into pre-mirna by drosha and transported to the cytoplasm to be converted to 19-25 nucleotides double strand microrna by dicer. micrornas are transported into the rna-induced silencing complex (risc) that bind to 3útr of the target genes and negatively regulate translation 9. the alteration of mirna expression leads to changes in many fundamental cellular and biological processes such as differentiation, proliferation, migration, cell cycle and apoptosis that cause disease and cancer. chromosomal rearrangement such as deletion, amplification, mutation, and methylation of promoter alter mirna expression levels 10. increasing mirna expression profiling improves diagnosis, staging, progression, prognosis, and response to treatment in human cancers. therefore, mirnas can be used as a new oncomir or tumor suppressor mir, and new biomarkers for the diagnosis, prognosis and prediction of treatment urological oncology 267 vol 16 no 03 may-june 2019 268 response. it has been demonstrated that mirnas are very stable against heat, ph alteration, freeze-thaw and ribonuclease5. for this reason, mirna levels are studied in different types of patient samples. based on information from databases/literature, which show the potential mirnas that influence the pten target gene, we selected mir-let7b-3p and mir-548 for quantification by real-time polymerase chain reactions (rt-pcrs) and determined the pten expression levels between tumor tissues and normal tissues. in the present study, we showed dysregulation of mir-let7b and mir-548 expression levels in prostate cancer tissues. materials & methods target prediction for microrna two online computational algorithms, targetscan (www.targetscan.org) and diana tools (diana.imis. athena-innovation.gr), were used for the bioinformatics prediction of mirna binding sites. ethics statement all tests were carried out in conformity with relevant guidelines. written informed consent was obtained from each contributor prior to tumor sample collection. all the clinical samples were obtained from imam khomeini hospital of tehran university of medical sciences. this study was approved by the ethical review committee of shahid beheshti university of medical sciences. sample collection in this study, all the samples of newly diagnosed prostate cancer cases were collected from imam khomeini hospital between 2015and 2016. after informed consent, the patients for the study were selected as per the inclusion criteria: age above 40 years, high psa, histopathological findings of the needle biopsy specimens confirmed prostate cancer or bph, and no chemotherapy treatments were given before surgery. the exclusion criteria were: age 40 years or below, normal psa, and frequent urination without prostate cancer symptom. then a pathologist distinguished tumor tissue from adjacent healthy tissue as normal sample according to the pathology results of previous needle biopsy. rna extraction and cdna synthesis total rna extraction from the tissue samples was done with trizol (invitrogen carlsbad, ca) in line with the manufacturer’s protocol. the quantity of rna samples was assessed spectrophotometrically by using nanodrop nd-2000 (thermo fisher scientific). the mir-q method as described by sharbati-tehrani11 was used for mir-let7b and mir-548 cdna synthesis according to sequence-specific primers (table 1). reference gene validation analysis to validate housekeeping genes (hkgs) and to choose the most stable and reliable ones, nine of the most frequently used hkgs as internal control in rt-qpcr including sdha, tbp, rps13, ubc, actb, hsp90ab1, pgm1, hprt1, gapdh named as 1, 2, 3, 4, 5, 6, 7, 8, and 9 respectively, were studied by considering their functional characteristics as well. a total number of six prostate tissue samples—three prostate carcinomas and three bph—were included in this study. the qpcr of all the samples was carried out in triplicates, in a total volume of 20 µl containing 1x sybr®premix ex taq™ii(tlirnaseh plus) (takara), 5рm of each sense and anti-sense primer (table 2), plus 1µl of cdna template. pcr reaction was performed on the rotor-gene q 5plex hrm system (qiagene) under 30 sec enzyme activation at 95ºc, followed by 40 cycles of the association of mir-let 7b and mir-548 with pten in prostate cancer-saffari et al. table 1. oligonucleotide sequences were used to cdna synthesis and amplification of mirnas. oligonucleotide name sequence rt6-mirlet-7b tgtcaggcaaccgtattcaccgtgagtggtaaccac rt6-mir-548 tgtcaggcaaccgtattcaccgtgagtggtgcaaaa shortmirlet-7b-rev cgtcagatgtccgagtagagggggaacggcgtgaggtagtaggttgt shortmir-548-rev cgtcagatgtccgagtagagggggaacggcgtcaaaactggcaattac mp-fw tgtcaggcaaccgtattcacc mp-rev cgtcagatgtccgagtagagg gene symbol primer sequence (5´→3´) amplicon length (bp) sdha f:gcaaacaggaacccgagg 202 r: cagcttggtaacacatgc tbp f:tgaatagtgagacgagttcc 140 r: tagggattccgggagtcat ubc f: gcggtgaacgccgatgattat 125 r: gatctgcattgtcaagtgacg hprt1 f: cctggcgtcgtgattagtgat 131 r: agacgttcagtcctgtccatta rps13 f: aagtacgttttgtgacaggca 187 r: cggtgaatccggctctctattag hsp90ab1 f: tctgggtatcggaaagcaagcc 80 r: gtgcacttcctcaggcatcttg pgm1 f: agcattccgtatttccagcag 120 r: gccagttggggtctcatacaaa actb f: agcctcgcctttgcgga 174 r: ctggtgcctgggacg gapdh f: gaaggtgaaggtcggagtca 109 r: attgaaggggtcattgatgg pten f: gatgatgtttgaaactattccaatg 73 r: ctttagctggcagaccacaa table 2. gene symbol, primer sequence and amplicon length of selected candidate references genes 95ºc for 5 sec, 58ºc for 15 sec, and 72ºc for 20 sec. we used genorm (vandesompele et al., 2002), normfinder (andersen et al., 2004), and bestkeeper (pfaffl et al., 2004) statistical algorithms to evaluate the stability of each candidate hkg. the cycle threshold (ct) average values of each sample’s triplicates were inputted directly into bestkeeper software. for normfinder, the average ct of each sample was transformed to the relative quantities linear row data, using the q = 2-ct equation (livak and schmittgen, 2001), while the normalized ct values calculated via the q = e (minct-samplect) equation (q = normalized ct value for a given gene in the current specimen, e = pcr amplification efficiency (ranging from 1 to 2 with 100% = 2), minct = minimum ct value for the gene among all specimens and samplect = the ct value of the gene for the current specimen) were used as the input data for the genorm program. quantitative real-time pcr the quantitative assay of mature mirnas was performed by sybr premix ex taq ii (tli rnaseh plus) (takara, japan) by using the mir-q method and done in the rotor-gene q 5plex hrm system (qiagene). additionally, the expression level of pten was determined by using specific primers, as shown in table 3. the reaction mixtures were incubated at 95°c for 30 sec, followed by 40 cycles at 95°c for 5 sec, and at 60°c for 30 sec. the expression of mirna from each sample was normalized by using the 2−δδct method relative to 5s rrna. δδct was then computed by subtracting the δct of normal tissue from the δct of prostate cancer. the change in gene expression was calculated by using equation 2−δδct 12. statistical analysis data were presented as means ± sem and evaluated by the t-test, one way or two way analysis of variance (anova) followed by the tukey test (spss 24 and graphpad prism 7.0 software inc., la jolla, ca, usa). a p-value <0.05 was considered to be statistically significant. each point or column represents the mean ± sem (n = 4–5) (p < 0.05). results sample collection all the samples were divided into four groups: gleason score >7 (10 samples), gleason score ≤ 7 (36 samples), bph (7 samples) and non-cancerous (40 samples). the characteristics of the patients are listed in table 3. mir-let7b and mir-548 have predictive potential binding sites in the 3’utr of human pten according to bioinformatics tools (such as diana tools and targetscan) and analysis, we found that two putative binding sites of mir-let7b and mir-548 are exited in the 3’utr of human pten target gene (figure 1). cdna synthesis for mir-548 and let-7b the mir-q method as described by sharbati-tehrani table 3. clinical characteristics of patients group 1 group 2 group 3 group 4 gleason score g > 7 g ≤ 7 bph non-cancer sample 10 36 7 40 age(min-max) 56-70 52-81 47-83 62-85 median 64.6 65.4 65.8 71 mean 63 66.5 65 73.5 sd 5.37 6.7 14.8 8.7 figure 1. pten has two predictive banding sites for mir-548 and mir-let7b. a) sequences of mir-548 and its putative binding sites in 3’útr of pten. b) sequences of mir-let7b and its putative binding sites in 3’útr of pten. figure 2. schematic picture of mir-q design. first, cdna is synthesized by a mirna-specific oligonucleotide that has 5' overhang (rt6-mir-x) and six complementary bases (red). then, a single strand cdna is converted to a double strand by a specific oligonucleotide with 5' overhang (short-mir-x-rev). finally, amplification is performed by using two terminal universal primers (mp-fw &mp-rev) (13). the association of mir-let 7b and mir-548 with pten in prostate cancer-saffari et al. urological oncology 269 vol 16 no 03 may-june 2019 270 was used for mir-let7b and mir-548 cdna synthesis according to the sequence-specific adaptor and primers (table 1 and figure 2). this method is based on the sybr green assay. expression stability of candidate hkgs based on the m-value calculated by genorm, all the studied hkgs revealed values lower than the cutoff value of 1.5, suggesting that all of them could be reliably used as the reference gene in the qpcr analysis of prostate tissues (figure 3). the stability ranking of the nine studied hkgs from the most stable to the least stable based on genorm m-value were 5, 6, 8, 1, 2, 9, 4, 3, and 7, respectively (figure 3). the normalization factor calculated via pairwise variation values between two sequential normalization (v (n/n+1)) by taking 0.15 as a cut-off value, we suggested using two genes data for more reliable qpcr normalization (figure 4). according to normfinder stability values, the hkgs’ ranking of stability from the most stable expressed to the least stable were 5, 8 4, 3, and 7, respectively (figure 3). 4 and 9 also exhibited the best combination of two genes across all the samples, with a stability value of 0.003, suggesting more stability. considering pearson correlations, reported as the bestkeeper correlation coefficient by bestkeeper algorithm, stability ranking order of studied genes were quite in concordance with those resulted, using genorm and normfinder, by 5 as the most stable followed by 8, 6, 1, 2, 9, 3, 4, and 7 respectively (figure 3). finally, the expression of actb was used to normalize the qpcr reactions, as it was indicated to be the most stable hkg among the studied candidate hkgs by bestkeeper, genorm, and normfinder. down-regulation of let-7b expression correlated with increasing gleason scores following qrt-pcr analyses, it was revealed that mir-let7b was significantly decreased in the gleason>7 group versus the non-cancerous group. although the expression of mir-let7b reduced in gleason ≤7 patients, the data was not statistically significant. (*p < 0.05) (figure 5). over-expression of mir-548 in prostate cancer tissues correlated with increasing gleason scores the expression levels of mir-548c in all the four groups were performed quantitatively by qrt-pcr. as shown in figure 6, the amount of mir-548 expression level in the cancerous sample increased in high grade of prostate cancer in comparison with bph and normal tissues as non-cancerous tissues (*p < 0.05). discussion the dysregulation of various mirnas expressions are seen in prostate cancer patients, and therefore, determining the most important mirnas and their associated pathways is very important. in this study, we decided to evaluate the expression level of mir-548c-3p in canfigure 3. candidate housekeeping genes’ stability results. a) the genorm stability results. the calculated m-value (y-axis) is plotted on the y-axis, with lower m-values corresponding to a more stably expressed gene. b) the normfinder stability results. the calculated normfinder stability values are plotted on the y-axis, with lower stability values corresponding to more stably expressed genes. c) the bestkeeper stability results. the calculated bestkeeper correlation coefficient is plotted on the y-axis, with higher correlation coefficient corresponding to a more stably expressed gene. figure 4. determination of the optimal number of control genes required for normalization based on the pairwise variation value (vn/n+1), which is calculated between two sequential normalization factors. the optimal number of reference genes was calculated as 2. figure 5. the qrt-pcr analysis of mir-let7b expression in prostate cancer tissues and their matched adjacent non-cancerous tissues. data reveal that it is down regulated in both cancerous samples (gleason scores >7 and 7≤) about more than 45% (> 45% reductions, *p < 0.05). the association of mir-let 7b and mir-548 with pten in prostate cancer-saffari et al. cer tissue samples. previous studies have demonstrated that mirnas play several key roles in a number of cellular pathways and biological processes such as differentiation, apoptosis, cell cycle regulation, migration and metastasis13,14. pi3k/akt signaling pathway has a lipid kinase family and according to their substrate and sequence homology, divided into three classes. class-1 pertains to heterodimers and includes two subunits: catalytic and regulatory. pip2 is a substrate of class i pi3k and converts to pip3 as a second messenger. then it activates downstream cascades that lead to cell growth and proliferation15. pten is an antagonist of the pi3k signaling function that leads to pip3 accumulation in cells and inhibits the activation of its downstream signals. furthermore, pten is a tumor suppressor that dephosphorylates pip3and reverses the activity of pi3k/akt signaling pathway. therefore, pten inhibits cell growth and proliferation. pten mutation frequencies that affect both alleles and mono allelic loss of pten function have been shown in different cancers such as endometrial, glioblastoma, leukemia, prostate, and breast cancers. epigenetics phenomena including dna methylation and microrna decrease pten expression 16-18. transcriptional silencing can describe the role of pten haploinsufficiency, although the loss of heterozygosity of pten is more seen in sporadic tumors and the severity is negatively correlated to the tumor phenotype 19. in addition, the alteration of pten expression can influence prognosis and response to treatment; pten negative tumors have shown poor response to chemotherapy drugs such as trastuzumab or cetoximab20. inositol polyphosphate 4-phosphatase type ii (inpp4b) is another gene that acts either as a tumor suppressor or an oncogene. the negative regulation of pi3k/akt signaling pathway by inpp4b as a tumor suppressor has been seen in various cancers, although it has been demonstrated that inpp4b expression increases in colon cancer and stimulates cell growth by the down regulation of pten21. in addition, overexpression of inpp4b causes the activation of pi3k/akt pathway by the upregulation of gsk322. as a tumor suppressor, inpp4b, similar to pten, converts pip2 to pip3, which needs activation of the pi3k/akt signaling pathway23. in breast or prostate cancer, the loss of inpp4b function is associated with poor prognosis. accordingly, the overexpression of inpp4b may diminish cell proliferation24. angiogenesis, migration and invasion are inhibited by the overexpression of inpp4b in du-145 and pc-3 prostate cancer cell lines25,26. cellular homeostasis needs to be balanced between protein phosphorylation and dephosphorylation. phlpp, as a tumor suppressor, is a protein phosphatase that leads to loss of function of phlpp, and it has been shown to be same as that of pten in various cancers. hydrophobic motifs of pkc and akt are phlpp targets and are dephosphorylated by it. evidence suggests that co-deletion of phlpp and pten may cause metastatic progression27-29. therefore, according to previous studies, pten plays a key role in the regulation of pi3k/akt signaling pathway and the loss of pten function leads to malignancies. our study used two databases, targetscan and diana tools, for determining the mirnas that have putative binding sites in 3’utr of pten gene, which frequently alter in various cancers such as prostate cancer. according to this intent, mir-let7b and mir-548 were found to have two different potential binding sites in the 3’utr of pten. as mentioned earlier, previous studies have shown that pten, as an important tumor suppressor gene, is a phosphatase family member that regulates pi3k and akt. rna-induced transcriptional silencing by microrna is one the mechanisms for the down-regulation of pten expression. previous studies have shown that mir-let-7b acts as a tumor suppressor mir and the expression level of mir-let-7b is downregulated in many human cancers such as prostate cancer30,31. of course, our data showed that the mir-let7b expression level, as a tumor suppressor mirna, is downregulated in prostate cancer, and therefore, it seems that there is no correlation between the expression levels of pten and mir-let7b. additionally, we investigated the over expression of mir-548 expression level in prostate tumor tissues as compared to normal tissues adjacent. conclusions this study showed that there is a difference in the expression of mir-548 in tumor and normal tissues and over expression of mir-548 is seen in prostate tumor tissues. we suggest that when mir-548c-3p increases in prostate cancer, it may repress the level of pten expression. additionally, previous studies have reported that the expression levels of pten, inpp4b and phlpp decrease in prostate cancer and this is why they can be used as potential targets for cancer treatment. acknowledgments we acknowledge the support of the urogenital stem cell research center (ugscrc), shahid beheshti university of medical sciences. assistance by dr. hamid ghaedi is gratefully acknowledged. figure 6. the expression levels of mir-548 in prostate cancer tissues and non-cancerous tissues. the qrt-pcr analysis of mir548c expression in prostate cancer tissues (gleason scores < 7 and gleason scores ≥7) and their matched adjacent non-cancerous tissues. data reveal up to more than 2-fold change in high grade prostate cancer samples compare to bph and non-cancerous samples. the values represent the means and the error bars represent the sem (*p < 0.05). the association of mir-let 7b and mir-548 with pten in prostate cancer-saffari et al. urological oncology 271 vol 16 no 03 may-june 2019 272 conflict of interest the authors declare no conflict of interest. references 1. alegria-torres ja, baccarelli a, bollati v. epigenetics and lifestyle. epigenomics. 2011;3:267-77. 2. attard g, clark j, ambroisine l, et al. duplication of the fusion of tmprss2 to erg sequences identifies fatal human prostate cancer. oncogene. 2008;27:253-63. 3. koochekpour s. genetic and epigenetic changes in human prostate cancer. iran red crescent med j. 2011;13:80-98. 4. taylor bs, schultz n, hieronymus h, et al. integrative genomic profiling of human prostate cancer. cancer cell. 2010;18:11-22. 5. kim wt, kim wj. micrornas in prostate cancer. prostate int. 2013;1:3-9. 6. adhyam m, gupta ak. a review on the clinical utility of psa in cancer prostate. indian j surg oncol. 2012;3:120-9. 7. pelzer ae, volgger h, bektic j, et al. the effect of percentage free prostate-specific antigen (psa) level on the prostate cancer detection rate in a screening population with low psa levels. bju int. 2005;96:995-8. 8. he l, hannon gj. micrornas: small rnas with a big role in gene regulation. nat rev genet. 2004;5:522-31. 9. valinezhad orang a, safaralizadeh r, kazemzadeh-bavili m. mechanisms of mirna-mediated gene regulation from common downregulation to mrnaspecific upregulation. int j genomics. 2014;2014:970607. 10. rauhala he js, isotalo j, et al. mir‐193b is an epigenetically regulated putative tumor suppressor in prostate cancer. int j cancer. 2010;127:1363-72. 11. sharbati-tehrani s k-lb, bergbauer r, scholven j, einspanier r. mir-q: a novel quantitative rt-pcr approach for the expression profiling of small rna molecules such as mirnas in a complex sample. bmc mol biol. 2008;9:34. 12. schmittgen td, livak kj. analyzing realtime pcr data by the comparative c(t) method. nat protoc. 2008;3:1101-8. 13. peng y, croce cm. the role of micrornas in human cancer. signal transduct target ther. 2016;1:15004. 14. catto jw, alcaraz a, bjartell as, et al. microrna in prostate, bladder, and kidney cancer: a systematic review. eur urol. 2011;59:671-81. 15. samuels y, ericson k. oncogenic pi3k and its role in cancer. curr opin oncol. 2006;18:7782. 16. samuels y, waldman t. oncogenic mutations of pik3ca in human cancers. curr top microbiol immunol. 2010;347:21-41. 17. dubrovska a, kim s, salamone rj, et al. the role of pten/akt/pi3k signaling in the maintenance and viability of prostate cancer stem-like cell populations. proc natl acad sci u s a. 2009;106:268-73. 18. lim hj, crowe p, yang jl. current clinical regulation of pi3k/pten/akt/mtor signalling in treatment of human cancer. j cancer res clin oncol. 2015;141:671-89. 19. trotman lc, niki m, dotan za, et al. pten dose dictates cancer progression in the prostate. plos biol. 2003;1:e59. 20. berns k hh, hennessy bt, et al. a functional genetic approach identifies the pi3k pathway as a major determinant of trastuzumab resistance in breast cancer. cancer cell. 2007;12:395-402. 21. guo s cm, yang r, et al. inpp4b is an oncogenic regulator in human colon cancer. oncogene. 2016;35:3049. 22. gasser ja, inuzuka h, lau aw, wei w, beroukhim r, toker a. sgk3 mediates inpp4b-dependent pi3k signaling in breast cancer. mol cell. 2014;56:595-607. 23. westbrook tf, martin es, schlabach mr, et al. a genetic screen for candidate tumor suppressors identifies rest. cell. 2005;121:837-48. 24. woolley jf, dzneladze i, salmena 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2014;2014:376326. 31. boyerinas b, park sm, hau a, murmann ae, peter me. the role of let-7 in cell the association of mir-let 7b and mir-548 with pten in prostate cancer-saffari et al. differentiation and cancer. endocr relat cancer. 2010;17:f19-36 new biological markers in prostate cancer wiśniewski et al. urological oncology 273 in-vitro application of pentoxifylline preserved ultrastructure of spermatozoa after vitrification in asthenozoospermic patients purpose: to evaluate the effect of in vitro application of pentoxifylline (px) on sperm parameters and ultrastructure after vitrification in asthenozoospermic patients. materials and methods: a total of 30 asthenozoospermic semen samples (aged 25-45 years) were divided into four groups before vitrification, after vitrification, control (without px) and experimental (with px). in experimental group, each sample was exposed for 30 min to 3.6mmol/l px and the control group without any treatment apposing in 370c for 30 min. after incubation, the samples were washed and analyzed again. vitrification was done according to straw method. eosin–nigrosin and papanicolaou staining were applied for assessment of sperm viability and morphology, respectively. the samples without px and post treatment with px were assessed by transmission electron microscopy (tem). results: a significant decrease in sperm motility (p ≤ .001), morphology (11.47 ± 2.9 versus 6.73 ± 2.01) and viability (73.37 ± 6.26 versus 54.67 ± 6.73) was observed post vitrification, but sperm motility (19.85 ± 4.75 versus 32.07 ± 5.58, p ≤ .001) was increased significantly following application of px. this drug had no significant (p >.05) detrimental neither negative effect on ultrastructure acrosome, plasma membrane and coiled tail statues of spermatozoa. conclusion: vitrification had detrimental effects on sperm parameters, but px reversed detrimental effects on sperm motility. however, px had no alteration on ultrastructure morphology of human spermatozoa after vitrification. keywords: asthenozoospermia; pentoxifylline; vitrification; ultrastructure. introduction cryopreservation of human spermatozoa is widely used in many assisted conception units to preserve male fertility, for example before cytotoxic chemotherapy, radiotherapy or certain surgical treatments that may lead to testicular failure or ejaculatory dysfunction(1). vitrification is a method that can be useful to achieve the same purpose and does not use the special extenders. it is based on the ultrarapid freezing of the cell by quick immersion in liquid nitrogen. moreover, it is a simple procedure that requires less time and probably will become safer and more cost-effective than conventional freezing(2,3). a normal motility pattern in ejaculated spermatozoa is a basic condition for male fertility. because adenosine triphosphate (atp) supports the chemical–mechanical coupling catalyzed by dyneins (specific atpases of the flagellum), it is usually accepted that both glycolysis and oxidative phosphorylation are required for optimal sperm function(4). thus, it is supposed that impaired motility might follow a bioenergetic shortage, although other mechanisms are still possible(5). mohamed et al. showed the significant affection of the progressive motility, viability and mitochondrial membrane potential of human spermatozoa by cryopreservation. although, both con1research and clinical center for infertility, shahid sadoughi university of medical sciences, yazd, iran. 2department of anatomy, histology, forensic medicine and orthopaedics, la sapienza university of rome, rome, italy. *correspondence: research and clinical center for infertility, safayeh, bou-ali ave., box: 89195-999, yazd, iran. tel.: +983518247085. fax: +983518247087. e-mail: khalili59@hotmail.com. received august 2016 & accepted june 2017 ventional slow and the vitrification techniques had similar results, vitrification is faster, easier with less toxicity and costs(6). kuznyetsov showed that vitrification was an alternative method for freezing human spermatozoa without toxic permeable cryoprotectants (cpas). it can be used to optimize the vitrification and post thaw recovery of a small number of spermatozoa in normozoospermic and severe oligozoospermic samples(7). pentoxifylline (px) is a non-specific phosphodiesterase (pde) inhibitor of the methylxantine group, inhibiting the breakdown of cyclic adenosine monophosphate (camp). it is known that intracellular camp concentration plays a central role in sperm motility. it is considered to be a sperm movement enhancer, hyperactivation agent, inhibitor of reactive oxygen species formation and acrosome reaction-improving agent(8). electron microscope has been used for examining the ultrastructure of spermatozoa. studies by means of tem showed that cryopreservation has deleterious effects on spermatozoa, especially on plasmalemma, acrosomes and tails(9,10). after thawing, the rate of spermatozoa that were considered normal by means of tem evaluations decline. among defined abnormalities, the defects of acrosomal change and subacrosomal swelling increase. sexual dysfunction and infertility ali nabi1, mohammad ali khalili1*, ali reza talebi., esmat mangoli1, nahid yari1, stefania annarita nottola2, selenia miglietta2, fatemeh taheri1 vol 14 no 04 july-august 2017 4038 acrosomal change defect, which is described by natural equatorial acrosomal content but an altered apical acrosomal region. apical head alterations in acrosomal change defect are lack of stability, loss of acrosomal content and appearance of vesiculations. another abnormality was subacrosomal swelling, which is characterised by detachment of the inner acrosomal membrane from the nuclear envelope and filamentous widening of the subacrosomal space(10,11). so far, some studies evaluated the effects of px on cryopreserved spermatozoa and were focused mainly on post thaw sperm motility and characteristics like velocity, head movements, and linearity(1,8,12) rather than ultrastructure of it. in this study, we attempt to evaluate the effect of in-vitro application of px on sperm parameters and ultrastructure after vitrification in asthenozoospermic patients. material and methods study population a total of 30 asthenozoospermic semen samples were selected according to who criteria for sperm total motility of <32%. sperm specimens were obtained by masturbation into sterile cups. all subjects were asked to abstain from ejaculation from 2 to 3 days before collection. after liquefaction at 37ºc, a small aliquot was removed from each specimen and the sperm parameters were determined(1). inclusion and exclusion criteria in this study, smokers, patient with varicocele and patients with history of varicocelectomy were excluded. the patients agreed to participate in this project via filling out the consent forms. the ethics committee of the institution approved this study. evaluation of sperm parameters the seminal samples were prepared using the density gradient technique. sperm parameters of motility, viability and normal morphology (%) were evaluated for 100 spermatozoa in each sample. sperm motility was assessed using makler chamber and light microscopy (olympus, tokyo, japan). motility was expressed as % of progressive and non-progressive. sperm viability and morphology were evaluated by eosin and papanicolaou staining tests, respectively(13). assessments of sperm parameters were carried out before vitrification (group i), after warming (group ii), after the warming and without ptx treatment (group iii), and ptx treatment (group iv). final analysis of sperm parameters and ultrastructure were undertaken (figure 1). vitrification and warming vitrification was done by straw to straw method according to isachenko et al(14). in this process, the suspension was mixed with ham’s f10 medium supplemented with 5% hsa/0.5 mol/l sucrose (1:1) at room temperature, 100 μl of the sperm suspension was transferred into a 0.25 ml plastic straw maintained horizontal. then, it was placed into 0.5ml straws and sealed at the end, and were immersed directly into liquid nitrogen. at least after one week for warming, after cutting one end side of the straw, the samples were vacated in pre-warmed ham’s f10 with 5% hsa. the simple-wash method was applied and sperm parameters were evaluated according to who criteria(14). incubation with pentoxifylline a stock solution of px (sigma, usa) in distilled water was prepared each week and kept at 4°c until used. the samples were divided into two groups of control and vol 14 no 02 march-april 2017 3029 px and ultrastructure of human spermatozoa-nabi et al. variables* before vitrification (group iii) mean ± sd after warming (group iv) mean ± sd p value progressive motility (%) 40.57 ± 6.49 21.03 ± 4.57 <.001 non progressive motility (%) 14.57 ± 3.23 15.63 ± 3.22 .097 immotile (%) 43.47 ± 9.33 63 ± 5.32 <.001 normal morphology (%) 11.47 ± 2.9 6.73 ± 2.01 <.001 viability (%) 73.37 ± 6.26 54.67 ± 6.73 <.001 table 1. the results of sperm analysis between before vitrification and after warming abbreviations: px, pentoxifylline; sd, standard deviation. *values are mean ± sem. variables* without px treatment (group iii) mean ± sd px treatment (group iv) mean ± sd p value progressive motility (%) 19.87 ± 4.75 32.07 ± 5.58 <.001 non progressive motility (%) 15.63 ± 3.76 14.97 ± 3.7 .219 immotile (%) 64.3 ± 5.37 53.23 ± 6.16 <.001 normal morphology (%) 6.63 ± 1.97 6.53 ± 1.97 .083 viability (%) 53.07 ± 5.71 53.2 ± 5.85 .161 abbreviations: px, pentoxifylline; sd, standard deviation. *values are mean ± sem. table 2. the results of sperm analysis between without px treatment and px treatment sexual dysfunction and infertility 4039 experimental. in experimental group, each sample was exposed for 20 minutes to 3.6mmol/l px at 370c and the control group in 370c for 30 minutes. after incubation, the samples were washed and analyzed again(1). transmission electron microscopy (tem) the samples without px (group iii) and post treatment with px (group iv) were assessed by tem. for this goal, spermatozoa were fixed in 2.5% glutaraldehyde in phosphate buffered saline (pbs) for 2 h at 4°c. the sperm samples were washed three times in pbs by centrifugation suspension at 1000×g for 10 minutes and post fixed in 1% osmium tetroxide for 1 h. the samples were then centrifuged at 1000×g for 10 minutes and the pellets were dehydrated in graded acetone. finally, the pellets were embedded in epon. ultra-thin sections (5070 nm) were obtained with leica em uc7 ultra-microtome and stained with uranyl acetate and lead citrate. the samples were observed with the tem (zeiss, em 10) to evaluate intact (with acrosome), reacting (with ruptured and irregular outer acrosomal membrane), reacted sperm (without acrosome), nucleus , vacuole and coil tail(10,15). evaluations were according to visual atlas(16). different parts of hundred sperm samples were studied and illustrated as the percentage of healthy sperm in table 2. statistical analysis data were analyzed using spss version 20 software (spss, inc., chicago, il, usa).the data were shown as mean ± sd. paired-samples t test was used for comparison of sperm parameters between before vitrification and after warming, also this test was used for evaluated of sperm ultrastructure between without ptx treatment and ptx treatment. the term ‘statistically significant’ was used to signify a two-sided p value < .05 for sperm parameters and ultrastructure. results table 1 shows sperm parameters between before vitrification and after warming samples. this table reveals that sperm motility, morphology and viability revealed significant differences (p < .001) between before vitrification and after warming. table 2 shows the sperm parameters between without px treatment and px treatment. this table reveals that sperm motility had significant differences (19.85 ± 4.75 vs. 32.07 ± 5.58, p ≤ .001) between without px treatment and px treatment. the data showed that vitrification impaired sperm parameters and px can reverse detrimental effects of vitrification on sperm parameters. figure 2 shows the results of sperm analysis between after warming and px treatment. the results of sperm ultrastructure evaluation between groups iii and groups vi are presented in table 3. there were insignificant differences (p >.05) between the groups with regards to acrosome, plasma membrane, vacuole, nucleus and coiled tail statues (figure 3). discussion the findings of present study showed that almost all sperm parameters revealed significant decrease following vitrification. the decline in sperm parameters, especially motility after cryopreservation, is a matter of current study, since this is a vital factor affecting post freezing–thawing success rate. px indirectly increases intracellular camp concentration and plays a critical role in sperm motility improvement(17). the technique of vitrification is based on the ultra-rapid freezing of the cell by quick immersion in liquid nitrogen. thereby, formation of intracellular ice crystals is avoided withfigure 1. schematic diagram for study design. variables* without px treatment (group iii) mean ± sd px treatment (group iv) mean ± sd p value acrosome (%) 38 ± 5.71 37.5 ± 5.56 .914 plasma membrane(%) 32.5 ± 3.31 31 ± 3.46 .620 nucleus (%) 46.75 ± 7.89 43.5 ± 8.06 .655 vacuole (%) 48.5 ± 13.8 47.5 ± 15.1 .929 coiled tail(%) 64.5 ± 9.39 67.25 ± 9.17 .621 abbreviations: px, pentoxifylline; sd, standard deviation *values are mean ± sem. table 3. the results of sperm ultrastructure evaluation between without px and with px groups. px and ultrastructure of human spermatozoa-nabi et al. vol 14 no 04 july-august 2017 4040 in sperm cells(2). morris discussed that the intracellular compartment of the cell will vitrify during cooling and will not devitrify until approx-30ºc during warming. this caused the outer surface of the plasmalemma being exposed to the stresses of osmotic shock, therefore kills the sperm cell. ultrastructure analysis of rapidly cooled samples during warming showed wide ice recrystallization occurred around the cell during the warming phase. at 40 ºc, the solution around the cell would be fluid, but the intracellular compartment would still be a glass, this occasion cause extensive membrane impairment. it is described that rapid rates of cooling has frequently been elated to the formation of intra cellular ice and cellular damage(18). iasachenko et al. reported function of mitochondria decreased after vitrification(19). assuming that oxidative phosphorylation and proton transport are membrane-bound phenomena, it is possible that atp profigure 2. the results of sperm analysis between after warming and px treatment abbreviations: px, pentoxifylline figure 3. ultra micrograph of human spermatozoa (a) without px, shows acrosome discharged completely and vesiculating, the remnant of plasma membrane was seen. the midpiece disrupted. thin arrow shows the arrangement of tubulin in was section of tail disrupted and two sections of tail adherent together that means rolled tail. thick arrow shows two sections of tail adherent together that means rolled tail. the sperm was seen morbid. (b) without pentoxifylline (px), nucleolus show with large vacuoles, acrosome intact. thick arrow shows several sections of tail adherent together that means rolled tail. thin arrow shows the arrangement of tubulin in was section of tail disrupted and several sections of tail adherent together that means rolled tail. (c) addition with px, acrosome shows partly intact. disrupted midpiece and tail and shows several sections of different area of tail meaning rolling tail. (d) treatment with px, acrosome discharged completely, the remnant of plasma membrane was seen. the plasma membrane midpiece was swollen. one vacuoles is seen in chromatin. thick arrow shows a vesiculated acrosome. px and ultrastructure of human spermatozoa-nabi et al. sexual dysfunction and infertility 4041 duction would be reduced. also it is probable that change of the energy availability or damage to the axonemal components could contribute to the cause of motility failure after cryopreservation(20). in this study we observed some nuclear defect that were not statistically significant. after cryopreservation, the structure of chromatin is less condenses. the number of nuclear vacuole was increased and chromatin may have granular view. in some spermatozoa, a vacuole may expand and cause chromatin to marginalize. there are two factors may cause these expansions: ice crystal formation and osmotic shock. ice crystal in nuclear was not formed, because this structure is highly viscose and intracellular ice was not occurred. but, osmotic shock is more probable. the marginalized chromatin is the sign of apoptosis according to baccettişs study(21). no significant differences in the dna integrity of prepared spermatozoa was reported related to the freezing method or presence of a cryoprotectant(19). recently, reported vitrification did not show any adverse effect on dna integrity of human spermatozoa with tunel test(2). simultaneously, more study should be done to confirm that the shape of chromatin causes dna damage or not. our results confirm the findings of moein et al.(22) that patients with poor sperm motility can benefit from px added straight to the washed semen specimens. johanson and colleagues studied the role of px-treated cryopreservation ejaculates on pregnancy rate. the higher pregnancy rate in the px group proved that stimulated sperm motility is good predictor of fertility potential in an infertility treatment program(23). there are some studies that are in line with our results. esteves et al. showed that the use of px improves the capability of thawed spermatozoa to undergo the acrosome reaction in reaction to calcium ionophore. also, the treatment of poor quality human sperm with px may enhance postthaw sperm fertilizing ability(1). also, rashidi et al. observed an increase of motile spermatozoa and fertilization rate after addition of 3 mmol/l px to mouse sperm cells(24). px has been used as a useful compound prior to oocytes injection for improving icsi outcome in asthenozoospermic patients(17). since, the motility of sperm cells is reduced after freezing, adding px as a stimulant factor can improve it. to the best of our knowledge, this is the first investigation on the relationship between sperm ultrastructure and administration of the px after vitrification in asthenozoospermic patients. our results showed that treatment of spermatozoa with px after thawing did not have significant detrimental effect on sperm ultrastructure (acrosome, plasma membrane and coiled tail statues). conclusions px had no alteration on ultrastructure morphology (acrosome, plasma membrane and coiled tail statues) of spermatozoa post vitrification of asthenospermia samples. however, vitrification has detrimental effects on human sperm parameters of motility, morphology and viability, but px reversed detrimental effects on sperm motility. acknowledgements this study was supported by a grant from the research and clinical center for infertility, shahid sadougi university of medical sciences, yazd, iran. the authors specially thank dr. iman halvaei and dr. azam agharahimi for their skillful assistance during the course of study. conflict of interest none declared references 1. esteves sc, spaine dm, cedenho ap. effects of pentoxifylline treatment before freezing on motility, viability and acrosome status of poor quality human spermatozoa cryopreserved by the liquid nitrogen vapor method. brazilian journal of medical and biological research = revista brasileira de pesquisas medicas e biologicas / sociedade brasileira de biofisica ... [et al.]. 2007;40:985-92. 2. agha-rahimi a, khalili ma, nabi a, ashourzadeh s. vitrification is not superior to rapid freezing of normozoospermic spermatozoa: effects on sperm parameters, dna fragmentation and hyaluronan binding. reproductive biomedicine online. 2014;28:352-8. 3. sanchez r, risopatron j, schulz m, et al. canine sperm vitrification with sucrose: effect on sperm function. andrologia. 2011;43:23341. 4. yeung ch, majumder gc, rolf c, behre hm, cooper tg. the role of phosphocreatine kinase in the motility of human spermatozoa supported by different metabolic substrates. molecular human reproduction. 1996;2:591-6. 5. garolla a, maiorino m, roverato a, roveri a, ursini f, foresta c. oral carnitine supplementation increases sperm motility in asthenozoospermic men with normal sperm phospholipid hydroperoxide glutathione peroxidase levels. fertility and sterility. 2005;83:355-61. 6. ali mohamed ms. slow cryopreservation is not superior to vitrification in human spermatozoa; an experimental controlled study. iranian journal of reproductive medicine. 2015;13:633-44. 7. kuznyetsov v, moskovtsev si, crowe m, lulat ag, librach cl. vitrification of a small number of spermatozoa in normozoospermic and severely oligozoospermic samples. systems biology in reproductive medicine. 2015;61:13-7. 8. stanic p, sonicki z, suchanek e. effect of pentoxifylline on motility and membrane integrity of cryopreserved human spermatozoa. international journal of andrology. 2002;25:186-90. 9. woolley dm, richardson dw. ultrastructural injury to human spermatozoa after freezing and thawing. journal of reproduction and fertility. 1978;53:389-94. 10. ozkavukcu s, erdemli e, isik a, oztuna d, karahuseyinoglu s. effects of cryopreservation on sperm parameters px and ultrastructure of human spermatozoa-nabi et al. vol 14 no 04 july-august 2017 4042 and ultrastructural morphology of human spermatozoa. journal of assisted reproduction and genetics. 2008;25:403-11. 11. piomboni p, bruni e, capitani s, et al. ultrastructural and dna fragmentation analyses in swim-up selected human sperm. archives of andrology. 2006;52:51-9. 12. brennan ap, holden ca. pentoxifyllinesupplemented cryoprotectant improves human sperm motility after cryopreservation. human reproduction. 1995;10:2308-12. 13. talebi ar, mangoli e, nahangi h, anvari m, pourentezari m, halvaei i. vitamin c attenuates detrimental effects of diabetes mellitus on sperm parameters, chromatin quality and rate of apoptosis in mice. european journal of obstetrics, gynecology, and reproductive biology. 2014;181:32-6. 14. isachenko v, maettner r, petrunkina am, et al. cryoprotectant-free vitrification of human spermatozoa in large (up to 0.5 ml) volume: a novel technology. clinical laboratory. 2011;57:643-50. 15. soares at, silva sv, batista am, et al. ultrastructure evaluation of goat spermatozoa after freezing in a skim milk-based extender with trolox supplementation. andrologia. 2015;47:470-6. 16. sathananthan a. visual atlas of human sperm structure and function for assisted reproductive technology. national university hospital and serono, singapore. 1996279. 17. amer m, metawae b, hosny h, raef a. beneficial effect of adding pentoxifylline to processed semen samples on icsi outcome in infertile males with mild and moderate asthenozoospermia: a randomized controlled prospective crossover study. iranian journal of reproductive medicine. 2013;11:939-44. 18. john morris g, acton e, murray bj, fonseca f. freezing injury: the special case of the sperm cell. cryobiology. 2012;64:71-80. 19. isachenko v, isachenko e, katkov, ii, et al. cryoprotectant-free cryopreservation of human spermatozoa by vitrification and freezing in vapor: effect on motility, dna integrity, and fertilization ability. biology of reproduction. 2004;71:1167-73. 20. watson pf. recent developments and concepts in the cryopreservation of spermatozoa and the assessment of their post-thawing function. reproduction, fertility, and development. 1995;7:871-91. 21. baccetti b, strehler e, capitani s, et al. the effect of follicle stimulating hormone therapy on human sperm structure (notulae seminologicae 11). human reproduction. 1997;12:1955-68. 22. mohammad reza moein md, mohammad ali khalili, ph.d., arash davoudi,m.d. . the effect of oral administration of pentoxifylline on sperm motility of asthenozoospermic ejaculates from men with or without testicular varicoceles iranian journal of reproductive medicine 2005;3:25-9. 23. johnston rc, mbizvo mt, summerbell d, kovacs gt, baker hw. relationship between stimulated hyperactivated motility of human spermatozoa and pregnancy rate in donor insemination: a preliminary report. human reproduction. 1994;9:1684-7. 24. iraj rashidi mm, and taki tiraihi. the effects of pentoxifylline on mouse epididymal sperm parameters, fertilization and cleavage rates after short time preservation. iranian journal of reproductive medicine. 2004;2:51-7. px and ultrastructure of human spermatozoa-nabi et al. sexual dysfunction and infertility 4043 detection of polymorphisms in mthfd1 g1958a and its possible association with idiopathic male infertility amir afshin khaki1, asghar tanoomand2, abolfazl hajibemani3,4, beheshteh abouhamzeh3* purpose: the role of male infertility is important in human infertility pathology. spermatogenesis is a complex developmental process which is regulated by a number of genes. methylenetetrahydrofolate dehydrogenase1 (mthfd1) is involved in the synthesis of purine, pyrimidine, and methionine. the aim of this study was to identify the mthfd1, g1958a polymorphism and its association with idiopathic male infertility in iranian population. materials and methods: this case-control study was conducted on 200 iranian men, 100 cases with idiopathic infertility (experimental group) and 100 normal men (control group). the subjects were assessed for the mthfd1 g1958a polymorphism, using the polymerase chain reaction-restriction fragment length polymorphism technique (pcr-rflp). the chi-square test was used to determine the association between mthfd1 g1958a polymorphism and male infertility, using spss software. p ≤ 0.05 was considered significant. results: totally, the frequency of a allele and aa homozygous genotype was found 51% and 47.3% respectively, with 52.5% and 30% in the experimental group versus 42% and 21% in control group. there was a statistically significant correlation between the frequencies of a allele (95 % ci = 1.0282.265, or = 1.526, p = 0.035) and aa homozygous (% ci = 0.9954.494, or = 2.114, 95 p = 0.05) genotype with the mthfd1 g1958a polymorphism (p ≤ 0.05). conclusion: these results suggest that the polymorphism in mthfd1 g1598a gene could be considered as an important genetic disorder associated with the etiology of male infertility. keywords: idiopathic; infertility; male; mthfd1; polymorphism introduction infertility is a worldwide problem and has a major im-pact on the quality of life. male infertility has an important role in this condition. infertility of unknown reason is referred to as idiopathic male infertility. idiopathic male infertility may be caused by several factors, such as chronic stress and endocrine disruption due to environmental pollution, reactive oxygen species and genetic abnormalities(1,2). genetic risk factors of male infertility reported in some studies are as follows, klinefelter’s syndrome, deoxyribonucleic acid (dna) damage by reactive oxygen species and total antioxidant capacity, aberrant expression of c-kit , poly(adp-ribose) polymerase-1 (parp-1), proliferative cell nuclear antigen (pcna) expression in testicular tissues (3) and y chromosome microdeletions (4). it has been found that folates and homocysteine are important factors in spermatogenesis (figure 1)(5,6). the disturbance of folate metabolism may lead to spermatozoa dna damage which reduces semen quality, sperm concentration and motility as well as affecting sperm morphology(7,8). several enzymes are involved in the one-carbon metabolism pathways, including 5,10-methylenetetrahydrofolate dehydrogenase (mthfd); 5,10-methenyltetrahydro1department of anatomical sciences, faculty of medicine, tabriz university of medical sciences, tabriz, iran 2 department of basic sciences, faculty of medicine, maragheh university of medical sciences, maragheh, iran. 3 department of anatomical sciences, faculty of medicine , aja university of medical sciences,tehran, iran. 4 department of clinical sciences, faculty of veterinary medicine, university of tabriz, tabriz, iran. *correspondence: department of anatomical sciences, faculty of medicine , aja university of medical sciences,tehran, iran. e mail: b.abouhamzeh.ba@gmail.com. received june 2018 & accepted february 2019 folate cyclohydrolase (ch);10-formyltetrahydrofolate synthetase (fs); 5,10-methylenetetrahydrofolate reductase (mthfr); methionine synthase (ms); serine hydroxymethyltransferase (shmt)(9). mthfd1 is a trifunctional cytoplasmic enzyme, which catalyzes the conversion of tetrahydrofolate to the corresponding 10-formyl, 5,10-methenyl, and 5,10-methylene derivatives (figure 1). genetic disorders like polymorphism within the coding region of mthfd1 could affect the activity, stability, or level of the enzyme followed by impairment of dna synthesis and folate metabolism (9). many polymorphic variants have been found for the genes encoding mthfd1. to our knowledge, a few studies with controversial findings has been done on the association of the mthfd1g1958a polymorphism as a genetic risk factor with male infertility (9). no study has been performed to identify the mthfd1 g1958a polymorphism and its correlation with idiopathic male infertility in iranian population. the aim of this study was to identify the mthfd1 g1958a polymorphism and its relationship with idiopathic male infertility in iranian population. andrology urology journal/vol 16 no. 6/ november-december2019/ pp. 586-591. [doi: 10.22037/uj.v0i0.4647] materials and methods the study was approved by the ethics committee of the aja university of medical sciences (ir.ajaums. rec.1396.113). study population the study was conducted on a group of men between the ages 20 and 48 years (mean ± sd: 35.0 ± 4.8 years) in iranian population. a total of 200 men who referred to qafqaz fertility center (fertility clinic in ardabil, iran) were selected for this case-control study, 100 diagnosed with idiopathic infertility and 100 normal subjects. clinical examination and laboratory tests, including medical history analysis, physical examination and semen analysis were done for those with idiopathic male infertility. the experiment group consisted of men with infertility history of at least one year with their spouses with confirmed normal gynecological assessment (normal transvaginal ultrasound examination, no history of the pelvic inflammatory disease or abdominal operations), after at least one year of regular unprotected sexual intercourse (2-3 times weekly). the exclusion criteria for this study were: the history of prostatitis, urethritis, chromosome abnormality, obstructive lesions, cryptorchidism, varicocele, diabetes mellitus and parotiditis as well as occupational hazards. analyses of sperm count and motility, vitality, and morphology were performed according to the world health organization (who) guidelines (17). the control group was men who had fathered at least one healthy child. sample collection blood samples (2 ml) taken from each individual were collected in sample tubes containing the anticoagulant, potassium ethylenediaminetetraacetic acid (edta k3e 15%, 0.12 ml; bd vacutainer, bd vacutainer systems, plymouth, uk). the samples were sent to the laboratory of maragheh university of medical sciences and stored at -20°c for subsequent dna extraction. genomic dna extraction frozen samples were melted and vortexed for 10 seconds. dna was extracted from whole blood using a dna extraction kit (genet bio, south korea) according to the manufacturer’s instructions. the dna was quantified spectrophotometrically, and the integrity assessed via agarose gel electrophoresis (0. 8%). extracted genomic dna samples were stored at -20°c in a freezer compartment for subsequent analyses. primers polymerase chain reaction (pcr) was designed to amplify mthfd1 dna fragments, containing g1958a snps. two primers set used for pcr (18) were synthesized by cinnagen company, iran. the mthfd1 g1958a polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) analysis using a forward primer 5'-ccc actttg aag cag gat tg-3'and a reverse 5'-cat ccc aat tcc cct gat g-3'. expected length of the produced fragment by primer pair was 232 bp. genotyping and pcr-rflp we performed pcr in 25 μl reaction volumes containing 10 mm tris–hcl, ph = 8.4, 50 mm kcl, 1.5 mm mgcl2, 250 μm of each dntp, 10 pmol of each primer (cinnagen inc., tehran, iran), and 2.5 u taq dna polymerase (fermentas; glen burnie, maryland) using 4 μl of extracted dna as template. the pcr thermal cycling conditions were as follows: denaturation for 4 minutes at 94 °c, followed by 35 cycles of 45 seconds at 94 °c, 1 minutes at 58 °c, and 1 minutes at 72 °c with a final extension step of 10 minutes at 72 °c. amplification was performed using a bio-rad thermocycler (bio-rad laboratories inc., hercules, ca, usa). the pcr products were analyzed by agarose gel electrophoresis 1.5% following dna staining with safe dna gel stain and visualized under ultraviolet transillumination. pcr products were digested with 2 μl mspi for 18 hours at 37°c. the digested products were analyzed by agarose gel electrophoresis of 1.5%. restriction products of 125 bp and 107 bp identified the gg genotype; products of 232 bp, 125 bp, and 107 bp represented the ga genotype; and the 232-bp product represented the aa genotype. statistical analysis obtained data were analyzed using the spss statistical software (version 22.0, spss inc, chicago, illinois) at the significant level of p ≤ 0.05. genotypes distribution and allele frequencies in both groups were determined by direct counting and the correlation of the polymorphism within 1958 position of mthfd1 gen with idiopathic male infertility was evaluated using chi-square test. eventually, odds ratios (or) and 95% confidence intervals (cis) were calculated for the effects of high risk alleles. table 1. allele and genotype frequencies for mthfd1g1958a in infertile and control groups. alleles frequencies, n (%) mutation type n (%) g allele a allele gg ga aa infertility (n=100) 95 (47.5) 105 (52.5) 25 (25) 45 (45) 30 (30) controls (n=100) 116 (58) 84 (42) 37 (37) 42 (42) 21 (21) total (200) 211 (52.7) 189 (47.3) 62 (62) 87 (87) 51 (51) mthfd1 g1958a (infertility cases –controls) odds ratio p-value (95% ci) a vs g 1.526 0.035 1.0282.265 aa vs gg 2.114 0.05 0.9954.494 ga vs gg 1.586 0.169 0.8203.065 ga vs aa 1.333 0.480 0.6332.681 ga/aa vs gg 1.762 0.067 0.9593.236 aa vs. gg/ga 1.612 0.144 0.8473.069 table 2. genotypes distribution analysis in infertile and control groups. male infertility and polymorphisms in mthfd1 g1958a-khaki et al. vol 16 no 06 november-december2019 587 results we analyzed the snps in mthfd1 g1598a gene in 100 infertile and 100 fertile men by rflp-pcr system. pcr amplification of samples of mthfd1 g1598a is shown in figure 2 and genotyping mthfd1 g1958a polymorphism by pcr-rflp is shown in figure 3. gg, ga and aa genotypes represent no polymorphism in mthfd1 g1958a gene, polymorphism in one allele and in both alleles, respectively. genotype and allelic distribution of the g1958a polymorphism have been shown in table 1. the polymorphism within mthfd1 g1958a was found in both groups of experiment and control. the results of genotypes distribution analysis within mthfd1 g1598a gene in infertile and control groups are listed in table 2. the genotype frequency of the aa compared to gg for the mthfd1 g1958a polymorphism was significantly higher in experimental group than control group (95 % ci = 0.9954.494, or = 2.114, p = 0.05). there was no significant difference between two groups for the ga genotype frequency compared to gg and aa for the mthfd1 g1958a polymorphism (p >0.05). no significant difference was found between experimental and control groups for ga+aa genotype frequencies compared to that of gg genotype, as well as, for aa compared to gg+ga (p = 0.067), and ga compared to aa (p > 0.05). there was a statistically significant difference between the a allele frequency of infertile patients and control group for the mthfd1 g1958a polymorphism (p ≤ 0.05). taken together, a significant correlation was found in two genetic models of a vs g and aa vs gg and no significant association was found for the other genetic models and when all the eligible studies were pooled together (ga vs gg, ga vs aa, ga+aa vs gg and aa vs. gg+ga) (table 2). discussion in the present study, we evaluated the association of single nucleotide polymorphisms in mthfd1 g1598a gene as a risk factor of idiopathic male infertility in iranian population. to our best knowledge, no study has been conducted to date, on the association of polymorphism snps in mthfd1 g1598a gene and the risk of idiopathic male infertility in iranian population. mthfd1 is an important gene in folate metabolism pathway. the polymorphism snps of this gene has been extensively studied in other diseases. no significant association was found between mthfd g1258a snp and spontaneous recurrent abortions (10,11), in some studies. the same result was found for down syndrome, hypertension and neural tube defects in other studies (12-14) conversely, a male infertility and polymorphisms in mthfd1 g1958a-khaki et al. figure 1. folate-mediated one-carbon metabolism. mthfd, 5,10-methylenetetrahydrofolate dehydrogenase; ch, 5,10-methenyltetrahydrofolate cyclohydrolase; fs, 10-formyltetrahydrofolate synthetase; mthfr, 5,10-methylenetetrahydrofolate reductase; ms, methionine synthase; shmt, serine hydroxymethyltransferas figure 2. agarose gel electerophoresis after pcr amplification of samples of mthfd1 g1598a. “m” represents marker 100bp. the pcr product size was 232bp. figure 3. genotyping mthfd1 g1958a polymorphism by pcrrflp. m: marker 100bp. lane 1, 5: shows a 232 bp band indicating the homomutant type allele (aa genotype); lane 2, 3 and 8: show 125 and 107bp bands denoting wild type allele (gg genotype); lane 4, 6 and 7: show 232, 125 and 107bp bands denoting heteromutant type allele (ga genotype). andrology 588 significant relationship was found between polymorphism of snp in mthfd1 gene and neural tube defects in some population (14,15). another study showed that mthfd1 g1958a polymorphism might have a marginally significant association with a decreased risk of cancers (16). many studies have been examined the association of folate metabolism genes polymorphisms and male infertility (2,17-22). some previous studies have identified mthfd1 g1958a polymorphism in iranian population (23,24). they investigated the association of mthfd1 g1958a polymorphism with congenital heart defects and breast cancer in iranian patients (23,24). the frequency of gg and aa homozygote and ga heterozygote in patients group was (55.9, 30%,) (12.7 and 22.5%) and (31.4 and 48%), respectively, versus (74.5 and 24%), (4.1 and 22%) and (21.4 and 55%) in control group (23,24). in the present study, the frequency of g and a alleles in infertile men was 47.5% and 52.5% compared to 58% and 42% for corresponding alleles in healthy individuals. the frequency of gg, aa and ga genotypes in infertile group was found 25%, 30% and 45% versus corresponding genotype of control group of 37%, 21% and 42%. in the present study, results showed that the genotype frequency of aa compared to gg for the mthfd1 g1958a polymorphism in idiopathic infertile patients was significantly different from those in control group. however, the occurrence of polymorphism homozygotes (aa genotype) was significantly higher in the infertile patients compared to control. in addition, there was a significantly higher frequency of a allele in infertile patients than control group for the mthfd1 g1958a polymorphism. the results of this study indicate that the presence of aa genotype could be considered as a risk factor for idiopathic male infertility in iranian population. and also, our findings revealed that genotype frequencies of gg and ga were not significantly different between infertile and control groups, and no association between polymorphism snp in mthfd1 g1598a gene with male infertility was found for these genotypes. different results have been reported by different studies regarding the association of snp in mthfd1 g1598a gene with male infertility in different populations(9,25). in a study conducted on the romanian population, the reported frequency of g and a alleles in infertile group was 47.72% and 52.27% compared to 54.47% and 45.52% in control group and the frequency of gg and aa and ga in infertile subjects was 27.27%, 31.81% and 40.90% versus 26.86%, 17.91% and 55.22% in control group (26). in consistent with our finding, they realized that there is an association between mthfd1 1958aa homozygous genotype and male infertility and a higher rate of polymorphism snp in mthfd1 g1598agene was found in infertile men compared to control group. in another study in the russian population,(9) the frequency of gg, aa and ga in infertile group was 33.33%, 20.74% and 45.92% in compared to corresponding values of 25.29%, 50.58% and 24.12% in control group. in the same study, genotype ga, genotype aa and allele a showed a reverse association with the risk of azoospermia, indicating the role of polymorphisms in mthfd1 g1598a in male infertility(9). conversely, in a study in the turkish population, no significant differences were found in the genotype frequencies or the allelic frequencies as well as no relationship between polymorphism snp in mthfd1 g1598agene with male infertility in two groups of infertile and healthy men under the study. they reported the frequency of 58.80% and 41.20% for g and a alleles in infertile men versus 59.60% and 40.40% in control, and the frequency of 32.40%, 14.80% and 52.80 for % gg, aa and ga in infertility group compared to 35.20%, 16.00% and 48.80% in control(25) findings of their study demonstrated that genotype frequencies or the allelic frequencies were not significantly different between infertility cases and controls and were not any association between polymorphism snp in mthfd1 g1598agene with male infertility(25). various results have been obtained regarding the associations of the polymorphism snp in mthfd1 (g1598a) gene with male infertility in different populations and studies. the role of polymorphism of other genes of folate pathway in male infertility has been investigated in many studies. methylenetetrahydrofolate reductase (mthfr), methionine synthase (ms) and ms reductase (mtrr) have been found to be critical in dna synthesis and remethylation(2,27), and there are controversial data on the association of polymorphisms of these genes with male infertility(2,28,29). nevertheless, these differences may be arisen from genetic determinants and geographic factors effective in the distribution of the polymorphisms in folate metabolism-related enzyme genes. other factors including gene-nutrient/environmental and gene racial/ethnic interactions have also been shown to impact on these genetic variants(30). conclusions in summary, our data provide evidence that the polymorphism snp in mthfd1 g1598a gene could be an important genetic factor predisposing to idiopathic infertility in iranian men. so, folate supplement therapy could be an option for men with idiopathic infertility. however, further studies in different population are needed to confirm the association of different polymorphisms and idiopathic male infertility risk. acknowledgements we are grateful to mr. mostaphazade for his technical assistance. this work was supported by a grant from aja university of medical sciences of iran. the authors thank the maragheh university of medical sciences and qafqaz fertility center (fertility clinic in ardabil, iran) for their cooperation. conflict on interest the authors report no conflict of interest. references 1. dohle g, colpi g, hargreave t, et al. eau guidelines on male infertility. eur urol. 2005;48:703-11. 2. lee h-c, jeong y-m, lee sh, et al. association study of four polymorphisms in three folate-related enzyme genes with nonobstructive male infertility. hum reprod. 2006;21:3162-70. 3. akarsu s, büke b, gürgen sg, et al. differences in poly (adp-ribose) polymerase1-(parp1-) and proliferative cell nuclear antigen (pcna) immunoreactivity in patients who male infertility and polymorphisms in mthfd1 g1958-akhaki et al. vol 16 no 06 november-december2019 589 andrology 590 experienced successful and unsuccessful microdissection testicular sperm extraction procedures. urology journal. 2017;14:501822. 4. nuti f, krausz c. gene polymorphisms/ mutations relevant to abnormal spermatogenesis. reprod biomed online. 2008;16:504-13. 5. boxmeer jc, smit m, weber rf, et al. seminal plasma cobalamin significantly correlates with sperm concentration in men undergoing ivf or icsi procedures. j androl. 2007;28:521-7. 6. crha i, kralikova m, melounova j, et al. seminal plasma homocysteine, folate and cobalamin in men with obstructive and nonobstructive azoospermia. j assist reprod genet. 2010;27:533-8. 7. lewis s, aitken r. dna damage to spermatozoa has impacts on fertilization and pregnancy. cell tissue res. 2005;322:33-41. 8. saleh ra, agarwal a, nada ea, et al. negative effects of increased sperm dna damage in relation to seminal oxidative stress in men with idiopathic and male factor infertility. fertil steril. 2003;79:1597-605. 9. weiner as, boyarskikh ua, voronina en, et al. polymorphisms in folate-metabolizing genes and risk of idiopathic male infertility: a study on a russian population and a metaanalysis. fertil steril. 2014;101:87-94. e3. 10. crişan to, trifa a, farcaş m, et al. the mthfd1 c. 1958 g> a polymorphism and recurrent spontaneous abortions. j matern fetal neonatal med. 2011;24:189-92. 11. kim jh, jeon yj, lee be, et al. association of methionine synthase and thymidylate synthase genetic polymorphisms with idiopathic recurrent pregnancy loss. fertil steril. 2013;99:1674-80. e3. 12. fowdar jy, lason mv, szvetko al, lea ra, griffiths lr. investigation of homocysteinepathway-related variants in essential hypertension. int j hypertens. 2012;2012. 13. neagos d, cretu r, tutulan–cunita a, stoian v, bohiltea lc. methylenetetrahydrofolate dehydrogenase (mthfd) enzyme polymorphism as a maternal risk factor for trisomy 21: a clinical study. j med life.. 2010;3:454. 14. zheng j, lu x, liu h, zhao p, li k, li l. mthfd1 polymorphism as maternal risk for neural tube defects: a meta-analysis. neuro sc. 2015;36:607-16. 15. hol fa, put nm, geurds m, et al. molecular genetic analysis of the gene encoding the trifunctional enzyme mthfd (methylenetetrahydrofolate‐dehydrogenase, methenyltetrahydrofolate‐cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects. clin genet. 1998;53:119-25. 16. zhang h, ma h, li l, zhang z, xu y. association of methylenetetrahydrofolate dehydrogenase 1 polymorphisms with cancer: a meta-analysis. plos one. 2013;8:e69366. 17. aston ki, krausz c, laface i, ruiz-castane e, carrell dt. evaluation of 172 candidate polymorphisms for association with oligozoospermia or azoospermia in a large cohort of men of european descent. hum reprod. 2010;25:1383-97. 18. park jh, lee hc, jeong y-m, et al. mthfr c677t polymorphism associates with unexplained infertile male factors. j assist reprod genet. 2005;22:361-8. 19. stuppia l, gatta v, scarciolla o, et al. the methylenetethrahydrofolate reductase (mthfr) c677t polymorphism and male infertility in italy. j endocrinol invest. 2003;26:620-2. 20. ebisch im, van heerde wl, thomas cm, van der put n, wong wy, steegers-theunissen rp. c677t methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. fertil steril. 2003;80:1190-4. 21. murphy le, mills jl, molloy am, et al. folate and vitamin b12 in idiopathic male infertility. asian j. androl. 2011;13:856. 22. dohle g, halley d, van hemel j, et al. genetic risk factors in infertile men with severe oligozoospermia and azoospermia. hum reprod. 2002;17:13-6. 23. khatami m, ratki fm, tajfar s, akrami f. relationship of the mthfd1 (rs2236225), enos (rs1799983), cbs (rs2850144) and ace (rs4343) gene polymorphisms in a population of iranian pediatric patients with congenital heart defects. kaohsiung j med scis. 2017;33:442-8. 24. rasti m, tavasoli p, monabati a, entezam m. association between hic1 and rassf1a promoter hypermethylation with mthfd1 g1958a polymorphism and clinicopathological features of breast cancer in iranian patients. iran biomed j. 2009;13:199. 25. balkan m, atar m, erdal me, et al. the possible association of polymorphisms in mthfr, mtrr, and mthfd1 genes with male infertility. int med j. 2013;20:404-8. 26. popp ra, farcas mf, trifa ap, militaru ms, crisan to, pop iv. the methylenetetrahydrofolate dehydrogenase (mthfd 1) gene g1958a polymorphism and idiopathic male infertility in a romanian population group. clujul medical. 2012;85:548. 27. kurzawski m, wajda a, malinowski d, kazienko a, kurzawa r, drozdzik m. association study of folate-related enzymes (mthfr, mtr, mtrr) genetic variants with non-obstructive male infertility in a polish population. genet mol biol. 2015;38:42-7. male infertility and polymorphisms in mthfd1 g1958a-khaki et al. vol 16 no 06 november-december2019 591 28. bezold g, lange m, peter ru. homozygous methylenetetrahydrofolate reductase c677t mutation and male infertility. n engl j med. 2001;344:1172-3. 29. shen o, liu r, wu w, yu l, wang x. association of the methylenetetrahydrofolate reductase gene a1298c polymorphism with male infertility: a meta‐analysis. ann hum genet. 2012;76:25-32. 30. toffoli g, de mattia e. pharmacogenetic relevance of mthfr polymorphisms. 2008. male infertility and polymorphisms in mthfd1 g1958a-khaki et al. miscellaneous urinary and fecal diversion following pelvic exenteration: comparison of double-barrelled and plain wet colostomy sertac yazici1*, senol tonyali1, ali cansu bozaci1, hakan bahadir haberal1, erhan hamaloglu2, haluk ozen1 purpose: to assess early and late-term outcomes of patients who had undergone pelvic exenteration and simultaneous fecal and urinary diversion with plain wet colostomy (pwc) or double-barrelled wet colostomy (dbwc). materials and methods: the medical records of all patients who had undergone pelvic exenteration and urinary diversion between 2006 and 2017 at our hospital were reviewed retrospectively. results: in total, 15 patients with a mean age of 56 ± 13 years were included in the study. simultaneous urinary and fecal diversions were carried out as pwc (n = 8), or dbwc (n = 7). no significant differences were found between pwc and dbwc groups in terms of operation time (373.7 ± 66.5 versus 394.2 ± 133.2 min, p = .955), estimated blood loss (862.8 ± 462.4 versus 726.2 ± 489.4 ml, p = .613), length of hospital stay (13.2 ± 9.1 versus 14.1 ± 6.9 days), early complications (25% versus 28.6%, p = 1.0) and late term complications (37.5% versus 42.9%, p = 1.0). the rate of recurrent pyelonephritis in pwc group was higher than dbwc group but not statistically significant (37.5% versus 14.3%, p = .569). overall survival (os) of the patients was 385 ± 91 days. there was no difference between os of patients with pwc and dbwc (414 ± 165 versus 352 ± 70 days, p = .618). conclusion: pwc and dbwc are valid options for creating simultaneous urinary and fecal diversion after extensive pelvic surgery in patients with short life expectancy. dbwc might be superior to pwc in terms of decreased risk of recurrent pyelonephritis. keywords: pelvic exenteration; wet colostomy; double-barreled; urinary diversion introduction due to recent advancements in anesthesiology, sur-gical techniques and surgical tools, surgeons are able to perform more complicated, risky and long-lasting operations. “pelvic exenteration” is one of these complex procedures that is commonly used in the treatment of locally advanced pelvic tumors, organ injury secondary to radiotherapy, and benign but locally destructive pathologies. pelvic exenteration was first described by alexander brunschwig in 1948(1) in the treatment of pelvic tumors. besides rectosigmoid colon, pelvic peritoneum, draining lymph nodes, reproductive organs, urinary bladder and distal ureters are also excised necessitating reconstructions for urinary and intestinal diversions in these procedures. to date many researchers developed different techniques to store urine in pressures safe for upper urinary tract without causing an electrolyte imbalance(1-4). however, in addition to aforementioned principles, operation time, postoperative course/complications and patient quality of life (qol) must be considered. in this study, we aimed to report the outcomes of patients who had undergone simultaneous fecal and urinary diversion after pelvic exenteration, comparing plain wet colostomy (pwc) with double-barrelled wet colostomy (dbwc) technique. to our knowledge, this 1departments of urology hacettepe university school of medicine, ankara, turkey . 2departments of general surgery hacettepe university school of medicine, ankara, turkey. *correspondence: hacettepe university school of medicine, department of urology, sihhiye, ankara 06100, turkey. tel: +90-312-305 1885. fax: +90-312-311 2262. e-mail: msertacyazici@yahoo.com. received march 2018 & accepted april 2018 is the first retrospective study that compares pwc with dbwc. patients and methods study population the medical records of all patients who had undergone pelvic exenteration and urinary diversion for primary or recurrent pelvic malignancies at the hacettepe university hospital between 2006 and 2017 were reviewed retrospectively. the surgeries were performed under the collaboration of general surgery and urology departments. surgical technique all patients had undergone abdominoperineal resection (apr), which included resection of rectum, anus, urinary bladder, and pelvic lymph nodes accompanied by total prostatectomy in male patients and total abdominal hysterectomy, bilateral salpingo-oopherectomy, and total vaginectomy in female patients. in 8 patients, fecal and urinary diversions were carried out with plain wet colostomy (pwc), while 7 patients had undergone double-barrelled wet colostomy (dbwc). the choice of urinary diversion was based on perioperative decision of general surgeon and urologist, depending on the length of the mesocolon. if the mesocolon was long enough dbwc was preferred. dbwc was constructed as described previously by miscellaneous 290 vol 15 no 05 september-october 2018 291 carter et al(5). rectosigmoid or descending colon was used for loop colostomy depending on the level of colectomy. splenic flexure was mobilized to ensure a tension free position for the loop colostomy and the loop was constructed before the anastomosis of ureters to prevent twisting. the ureters were mobilized as much length as possible while taking care to preserve the periureteral vascular supply. the opposite sided ureter was then transposed to the loop colostomy side through a tunnel at mesocolon. each ureter was implanted individually into the distal, blind-ended limb of the loop colostomy. for prevention of reflux, ureters were anastomosed at the antimesenteric region with 3-4 cm long submucosal tunnels(5, 6). a mammary implant was placed in the pelvic cavity in 9 cases to prevent prolapsus of intestines. to preserve the anastomosis, ureteral stents were placed bilaterally, fixed to colonic mucosa with absorbable sutures and removed after 3 weeks. the loop was exteriorized and fixed to the abdominal wall as double-barreled following the implantation of the ureters. the distal blind-ended part of the loop acts as a reservoir for urine to minimize contact of urine and feces in patients with dbwc (5,7-9). in case of plain wet colostomy, ureters were anastomosed to colostomy forming an ureterocolostomy. outcome assessment the examined parameters consisted of patient demographics, primary pathology, type of surgery, operation characteristics, and post-operative follow-up including blood chemistry and imaging results. complications such as pyelonephritis, urinary leak and fistulas, hydronephrosis and metabolic disturbances were also compared between the two groups. renal functions of the patients were followed by plasma creatinine (cr), blood urea nitrogen (bun) and electrolytes. if the patient’s clinical findings indicated urinary tract infection, urine analysis and culture were performed. the primary disease, surgical outcome and urinary system were examined by abdominopelvic imaging [ultrasonography (usg), computed tomography (ct), or magnetic resonance imaging (mri)] at necessary periods. all procedures performed in studies involving human participants were in accordance with the 1964 helsinki declaration and its later amendments or comparable ethical standards. statistical analysis was performed using statistical package for social sciences (spss, version 21.0, ibm, chicago, il, usa). mean ± sd and range were used to express quantitative values, and number and percentage were given for qualitative values. chi-square test, fisher’s exact test, mann-whitney u test and student’s t test were applied to compare the two groups. kaplan-meier analysis was used for survival analysis. p values <0.05 were considered as statistically significant. table 1. patients demographics, characteristics, intraoperative/postoperative features and follow-up no sex age primary prior prior operation type of early late term electrolyte overall exitus pathology surgery radiotherapy diversion complication complication imbalance survival alive (days) 1. f 48 cervix ca tah+ bso yes apr+ pwc intraabdominal no no 7 ex cystectomy abscess 2. f 42 cervix ca none yes apr+ pwc ureterocolonic no no 87 ex cystectomy+ leakage tah + bso 3. f 70 colon ca none no apr+ pwc no no no 859 ex cystectomy+ tah + bso 4. m 51 rectum ca anterior yes apr + cp+ pwc no pyelonephritis no 418 ex resection sacrectomy 5. m 59 rectum ca anterior yes apr + cp pwc no pyelonephritis no 503 ex resection 6. m 55 prostate ca none yes apr + cp pwc no no no 43 ex 7. m 65 rectum ca anterior yes apr + cp pwc no no no 89 ex resection 8. m 45 rectum ca anterior yes apr + cp pwc* no pyelonephritis no 1313 ex resection 9. m 68 rectum ca anterior yes apr + cp dbwc no pyelonephritis no 628 ex resection 10. m 49 colon ca right hemi no apr + cp dbwc no no no 454 ex colectomy 11. m 79 rectum ca+ none yes apr + cp dbwc right no no 260 ex prostate ca pneumothorax 12. m 55 colon+ none no apr + cp dbwc no hydronephrosis no 496 ex rectum ca 13. m 57 colon ca colostomy no apr + cp + dbwc no sacral abscess no 329 ex sacrectomy 14. m 70 prostate ca none yes apr + cp dbwc ileus no no 222 ex 15. f 28 rectum ca anterior yes apr + dbwc no no no 78 ex resection cystectomy + tah + bso abbreviations: apr, abdominoperineal resection; tah, total abdominal hysterectomy; bso, bilateral salphingo-oopherectomy; il, ileal loop; cp, cystoprostatectomy; pwc, plain wet colostomy; dbwc, double-barrelled wet colostomy; f, female; m, male; ca, cancer; ex, exitus *converted to colostomy plus ileal loop urinary and fecal diversion following pelvic exenteration-yazici et al. results in total, 15 patients whom all data was available were included in the study. characteristics of patients are summarized in table 1. mean age of the patients was 56 ± 13 years, ranging from 28 to 79. in all patients, urinary system was affected by the primary pathology. eleven patients had previously received pelvic radiotherapy and 9 patients had undergone previous surgical procedures. mean operation time was 383 minutes (range 240 570). mean hospitalization time after surgery was 13.6 ± 7.8 days. preoperative and postoperative mean cr level were 1,02 ± 0.32 mg/dl and 1,18 ± 0.52 mg/dl, respectively. only one patient’s cr level was above the normal, whose level was also abnormal preoperatively. no metabolic disturbances were encountered related with colonic/urinary conduit. mean postoperative serum na and k+ levels were 136.1 ± 4.7 mg/dl and 4.1 ± 0.43 mg/dl, respectively. at early postoperative period (within one month after the surgery), one ureterocolonic anastomosis leakage and one intraabdominal abscess in the pwc group; one unilateral pneumothorax and one ileus in the dbwc group were observed. nephrostomy catheter was inserted to the kidney of the patient due to anastomosis leakage and the catheter was removed after demonstration of no leakage at 2nd month on anterograde pyelography with minimal hydronephrosis in usg. late-term (30 days or more after the surgery) complications were observed in 6 patients including 3 pyelonephritis and 1 sacral abscess, which were managed by antibiotic treatment. in one patient with recurrent pyelonephritis, pwc was converted to ileal conduit for urinary diversion. in one patient with dbwc, unilateral grade 2-3 hydronephrosis caused by ureterocolonic stenosis was managed with percutaneous nephrostomy initially, which was replaced by indwelling stent subsequently. pyelonephritis was observed only in one patient in the dbwc that was managed conservatively with antibiotics. one of the patients in the pwc group died 7 days after the surgery in the early postoperative period. she had multiple metastases due to cervix cancer and postoperatively experienced pulmonary thromboembolism which was treated with low molecular weight heparin. comparison of patient outcomes of dbwc and pwc are summarized in table 2. no significant differences were found between the two groups in terms of age, operation time, estimated blood loss, length of hospital stay, earlyand late-term complications (all p-values > .05). the rate of recurrent pyelonephritis in pwc group was higher than dbwc group but not statistically significant (37.5% versus 14.3%, p = .569). overall survival (os) of the patients was 385 ± 91 days. there was no difference between os of patients with pwc and dbwc (414 ± 165 versus 352 ± 70 days, p = .618). discussion pelvic exenteration is the standard choice of treatment for advanced or recurrent pelvic malignancies, which involves removal of all pelvic viscera. besides being an extensive surgery, it also requires reconstruction for urinary and fecal diversions(10). in the first series of pelvic exenteration, urinary diversion was carried out by anastomosing each ureter to ipsilateral colon segment and opening a terminal colostomy after the reconstruction stage, which was called as “proximal wet colostomy” (1,2). however, high volume watery diarrhea, severe electrolyte imbalance and pyelonephritis resulting in poor life quality led the surgeons to investigate new diversion types. besides, mixing up of urine and feces on intestinal surfaces was accused for the intestinal dysplasia and neoplasia diagnosed in long term follow up(2, 3,11). due to the lack of an optimum type of diversion, bricker et al. in 1949(4) described ileal segment to discard urine via a different way from feces, decreasing diarrhea and dysplasia. however, as majority of these patients had received radiotherapy, leakage from anastomosis was a major concern. also, the presence of two stomas not only resulted in prolonged operation time but also negatively influenced patient’s quality of life. in 1989, carter et al. first defined ‘double-barrelled wet colostomy’ (dbwc) which is the lateral loop colostomy that contains both urinary and intestinal diversions in the same segment and drains from a single stoma(5). it is a simple, safe and effective procedure to reconstruct urinary and fecal drainage after pelvic exenterations where orthotopic urinary or intestinal reconstructions are not possible(7-9,12-15). besides, using the distal colon for loop colostomy enables formation of feces proximally and prevents loss of excess fluid. in our patient cohort, we preferred pwc or dbwc for urinary and fecal diversion following pelvic exenteration depending on the length of mesocolon. to our knowledge, this is the first retrospective study that compares pwc with dbwc. previously published articles usually focused on comparison of dbwc with ileal conduit plus colostomy. dbwc enables single stoma and shorter operation time compared to two stomas technique and also preserves intestinal integrity that prevents intestine related complications i.e. pouch leak and enteric fistulas(5,7-10,12-15). in some studies, dbwc has also been found to be superior to two stomas technique in terms of hospital stay, pyelonephritis, sepsis, electrolyte imbalance, urinary leak and need of percugroups pwc (n=8) dbwc (n=7) p value age (year) 54.3 ± 9.7 58 ± 16.7 0.463 operation time (minutes) 373.7 ± 66.5 394.2 ± 133.2 0.955 estimated blood loss (ml) 862.8 ± 462.4 726.2 ± 489.4 0.613 length of stay (days) 13.2 ± 9.1 14.1 ± 6.9 0.613 pyelonephritis 37.5% 14.3% 0.569 early-term complication (%) 25% 28.6% 1.000 late-term complication (%) 37.5% 42.9% 1.000 overall survival (days) 414 ± 165 352 ± 70 0.618 table 2. comparison of patients’ characteristics and outcomes of dbwc and pwc procedures. urinary and fecal diversion following pelvic exenteration-yazici et al. miscellaneous 292 vol 15 no 05 september-october 2018 153 taneous nephrostomy. however, none of these studies showed the superiority of ileal conduit with colostomy in any evaluated parameters(10). complications related to wet colostomy following the first series of pelvic exenteration were usually associated with ascending urinary tract infections from reflux of intestinal contents, severe electrolyte imbalance, obstruction at the uretero-intestinal anastomosis resulting in progressive hydronephrosis and impaired renal function and development of fistulas from the anastomosis site(16). in a study focusing on urological complications after cystectomy, the urological complication rates was significantly higher after cystectomy as a part of pelvic exenteration (59%) compared to cystectomy alone (33%). urinary leak was observed in 6% and 14% of the patients who underwent pelvic exenteration for primary malignancies and recurrent malignancies, respectively. major blood loss and previous pelvic radiotherapy was found to be an independent predictor of conduit-associated complications(17). in our series most of the patients (9/14) underwent pelvic exenteration for recurrence. in another study comparing ileal versus colonic conduit after pelvic exenteration, colonic conduit was found to be associated with fewer complications (including sepsis, leak and pelvic collection) compared to ileal conduit (19% versus 40%, p < 0.01)(18). in our patient cohort, two complications (13.3%) (one leak and one intraabdominal abcess) were observed in concordance with aforementioned study. despite these severe complications reported previously, we have not encountered any severe electrolyte disturbance in our pwc serial. in the present study, three patients (37.5%) with pwc experienced recurrent pyelonephritis. two patients were treated with antibiotic therapy and in the other patient urinary diversion was converted to ileal loop. among patients with dbwc, only one patient (14.3%) experienced pyelonephritis. although, it was not statistically significant (p = .569), we found dbwc superior to pwc in terms of upper urinary tract infection. furthermore, none of the patients required re-operation during the early postoperative period. as described in previous studies(1,19), preserving periureteral vascular supply while mobilizing and preparing the ureter is of critical importance to avoid necrosis leading strictures and anastomotic leaks. at our institution, we are firmly committed to this principle and in our patient cohort, only one patient (6.6%) developed ureterocolonic leakage. in our series, not only patients with dbwc but also patients with pwc did not develop any secondary neoplasia due to mixing of urine and feces. we think this might be related to short survival period of our patients. the filling of pelvic cavity with intestinal loops following pelvic exenteration can result in increased risk of complications such as intestinal obstruction, enteric fistulas and radiation enteritis especially in patients undergoing postoperative radiotherapy. to avoid this complication, we placed mammary implants in the pelvic cavity of 9 patients, as described previously(20). no complications were observed related to the prosthetic implants in our series. this study has also some limitations. first of all, our sample size was relatively small and it was not possible to compare the quality of life between patients with different type of diversions because of the retrospective nature of the study. and the exact operation time of creating a diversion was not available in this study. so, it is difficult to determine the effect of type or urinary diversion on operation time. conclusions plain wet colostomy (pwc) and double barrelled-wet colostomy (dbwc) are valid options for creating urinary diversion after extensive pelvic surgery. dbwc might be superior to wet colostomy in terms of decreased risk of recurrent pyelonephritis. pwc could be the choice of urinary diversion especially in patients with short life expectancy to avoid intestinal neoplasia and dysplasia. conflict of interest the authors declare that they have no conflict of interest. references 1. brunschwig a. complete excision of pelvic viscera for advanced carcinoma; a onestage abdominoperineal operation with end colostomy and bilateral ureteral implantation into the colon above the colostomy. cancer. 1948;1:177-83. 2. brunschwig a, daniel w. pelvic exenteration operations: with summary of sixty-six cases surviving more than five years. ann surg. 1960;151:571-6. 3. wear jb, jr., barquin op. ureterosigmoidostomy. long-term results. urology. 1973;1:192-200. 4. bricker em. bladder substitution after pelvic evisceration. surg clin north am. 1950;30:1511-21. 5. carter mf, dalton dp, garnett je. simultaneous diversion of the urinary and fecal streams utilizing a single abdominal stoma: the double-barreled wet colostomy. j urol. 1989;141:1189-91. 6. kristjansson a, mansson w. refluxing or nonrefluxing ureteric anastomosis. bju int. 1999;84:905-10. 7. carter mf, dalton dp, garnett je. the double-barreled wet colostomy: long-term experience with the first 11 patients. j urol. 1994;152(6 pt 2):2312-5. 8. guimaraes gc, ferreira fo, rossi bm, et al. double-barreled wet colostomy is a safe option for simultaneous urinary and fecal diversion. analysis of 56 procedures from a single institution. j surg oncol. 2006;93:20611. 9. kecmanovic dm, pavlov mj, ceranic ms, masulovic dm, popov ip, micev mt. doublebarreled wet colostomy: urinary and fecal diversion. j urol. 2008;180:201-4; discussion 4-5. 10. gan j, hamid r. literature review: doublebarrelled wet colostomy (one stoma) versus urinary and fecal diversion following pelvic exenteration-yazici et al. vol 15 no 05 september-october 2018 293 urinary and fecal diversion following pelvic exenteration-yazici et al. ileal conduit with colostomy (two stomas). urol int. 2017;98:249-54. 11. urdaneta lf, duffell d, creevy cd, aust jb. late development of primary carcinoma of the colon following ureterosigmoidostomy: report of three cases and literature review. ann surg. 1966;164:503-13. 12. osorio gullon a, de oca j, lopez costea ma, et al. double-barreled wet colostomy: a safe and simple method after pelvic exenteration. int j colorectal dis. 1997;12:37-41. 13. blanco diez a, fernandez rosado e, alvarez castelo l, et al. [double-barreled wet colostomy: analysis of a urinary diversion]. actas urol esp. 2003;27:611-7. 14. takada h, yoshioka k, boku t, et al. doublebarreled wet colostomy. a simple method of urinary diversion for patients undergoing pelvic exenteration. dis colon rectum. 1995;38:1325-6. 15. lopes de queiroz f, barbosa-silva t, pyramo costa lm, et al. double-barrelled wet colostomy with simultaneous urinary and faecal diversion: results in 9 patients and review of the literature. colorectal dis. 2006;8:353-9. 16. teicher i, karlitz lm, shaftan gw. complications of a wet colostomy after pelvic evisceration corrected by separation of urinary and fecal streams; report of a case. ann surg. 1953;137:129-34. 17. brown kg, solomon mj, latif er, et al. urological complications after cystectomy as part of pelvic exenteration are higher than that after cystectomy for primary bladder malignancy. j surg oncol. 2017;115:307-11. 18. teixeira sc, ferenschild ft, solomon mj, et al. urological leaks after pelvic exenterations comparing formation of colonic and ileal conduits. eur j surg oncol. 2012;38:361-6. 19. chokshi rj, kuhrt mp, schmidt c, et al. single institution experience comparing double-barreled wet colostomy to ileal conduit for urinary and fecal diversion. urology. 2011;78:856-62. 20. valle m, federici o, ialongo p, graziano f, garofalo a. prevention of complications following pelvic exenteration with the use of mammary implants in the pelvic cavity: technique and results of 28 cases. j surg oncol. 2011;103:34-8. miscellaneous 294 endourology and stone disease the feasibility, safety, and efficacy of the preemptive indwelling of double-j stents in percutaneous nephrolithotomy surgery: a randomized controlled trial fuding bai, huifeng wu, nan zhang, jimin chen, jiaming wen* purpose: the goal of this study is to compare the feasibility, safety, and efficacy of the preemptive indwelling of double-j stents (pi-djs) versus the conventional preemptive indwelling of ureteral catheters (pi-uc) in percutaneous nephrolithotomy (pcnl) via a randomized, controlled clinical study. materials and methods: a total of 75 patients with complex renal calculi underwent pcnl surgery and were randomized, using random number table, to receive either a pi-djs (37 cases) or a pi-uc (38 cases). all operations were performed by the same experienced surgeon. several outcomes were measured, including duration of operation, time to establish passage, level of hemoglobin decline, rate of stone clearance and incidence of complications. results: guided by b-ultrasound, percutaneous passages were successfully established in all patients who then underwent one-stage pcnl. the time required to establish a passage using a pi-djs was 7.5min, whereas that of the group who received a pi-uc was 11.5min (p < 0.01). there was no significant difference between the two groups in terms of operation duration, postoperative hb decline rate, stone clearance rate, and perioperative complication incidences (all p > 0.05). conclusion: pi-djs during pcnl allowed for a reliable and stable reflux from the bladder into the renal pelvis to produce an artificial hydronephrosis without the formation of microbubbles, unlike conventional ureteral catheters. keywords: percutaneous nephrolithotomies; randomized controlled study; indwelling of double-j stents; indwelling of ureteral catheters introduction ever since it was described by fernstorm et al in 1976(1), percutaneous nephrolithotomy (pcnl) has become an important therapeutic strategy for the treatment of complex renal calculi(2), even in complicated situations like pregnancy(3,4). pcnl was demonstrated as an effective therapy to achieve stone-free rates in about 80% of patients with staghorn stones(5), one of the most challenging forms of urolithiasis. however, there are always challenges in the management of complex renal calculi during the pcnl process(6) and many improvements have been described that significantly enhance the safety and surgical outcome of pcnl(3,7-9). in order to have a successful pcnl, it is very essential to have an accurate puncture through the papilla into the target calyx, thereby creating the percutaneous access for stone disintegration and removal. in recent years, b-ultrasound localization for percutaneous renal puncture has seen higher adoption due to its enhanced accuracy, reliability, and safety, which was routinely used for pcnl surgery(2). importantly, percutaneous puncture often requires artificial hydronephrosis, which was traditionally achieved through perfusion of saline via a ureteral catheter. this method, however, might generate bubbles in the renal pelvis, leading to interference of b-ultrasound-guided percutaneous punctures(10). addidepartment of urology, second affiliated hospital, school of medicine, zhejiang university, hangzhou , china. *correspondence: department of urology, second affiliated hospital, school of medicine, zhejiang university , no. 88, jiefang road, hangzhou, zhejiang, china, 310009. tel: +86-571-87783550, e-mail: wenjiaming@zju.edu.cn. received november 2018 & accepted may 2019 tionally, sometimes indwelling of the double j stents at the end of the surgery presents difficulties and the positioning of the stent might be inaccurate. in this study, a randomized, controlled clinical trial was conducted to investigate the feasibility, safety, and efficacy of the preemptive indwelling of double-j stents (pi-djs) before pcnl, hoping to simplify the procedure in order to optimize surgical outcomes. materials and methods targeted patients and methods the present clinical trial is registered in the chinese clinical trial register (chictr, 1900021443). from august 2014 to december 2016, 75 cases of patients with complex renal calculi were randomly assigned to two different groups to undergo pcnl operations. 37 out of 75 cases underwent the procedure entailing the pi-djs, while the remaining 38 cases underwent the procedure involving the conventional preemptive indwelling of the ureteral catheter (pi-uc). all operations were performed by the same experienced surgeon. all patients underwent one-stage pcnl in which percutaneous renal punctures were successfully established via b-ultrasound guidance. the general information of the two groups of patients is shown in table 1. urology journal/vol 17 no. 3/ may-june 2020/ pp. 232-236. [doi: 10.22037/uj.v0i0.4957] vol 17 no 03 may-june 2020 233 inclusion and exclusion criteria renal stones were diagnosed by either ct or kidney, ureter, and bladder (kub) examinations. patients (1880 years old) with stone sizes larger than 2cm that required pcnl treatment were included in this study. the exclusion criteria include coagulation disorders, anatomic anomalies, urinary tuberculosis, previous pcnl history, and severe cardiac and pulmonary dysfunctions. total 92 patients were assessed for eligibility (figure 1). among them, 17 patients were excluded from the study due to not meeting inclusion criteria (n=9), declined to participate (n=6) and other reason (n=2). preemptive indwelling of double-j stent group (pi-djs) under general anesthesia, patients were placed in the lithotomy position. the retrograde insertion of an fr6 double-j stent via the ureter to the kidney was performed under transurethral ureteroscopy. subsequently, a three-way foley catheter was placed, and the urine drainage port was closed. physiological saline (bag of 3000ml, height about 60 ~ 80cm) was connected to the irrigating cavity. with the patient in prone position, the cavity was infused with normal saline to produce artificial hydronephrosis depending on reflux from the bladder to the renal pelvis. the posterior renal calyx was punctured under the guidance of b-ultrasound. guided by zebra guidewire, the percutaneous passage was expanded from f8 to f20 and a renal sheath was used for the entrance of kidney calices. subsequently, ureteroscopic lithotripsy was performed with a holmium laser under 8/9.8f ureteroscope. an f18 nephrostomy tube was retained subsequent to surgery. plain film of kidneys, ureters and bladder (kub) or b-ultrasound examination was performed 3-5 days after the operation to evaluate the presence of any residual stones. stones larger than 5mm would be considered incomplete removals. conventional pre-emptive indwelling of ureteral catheter (pi-uc) group under general anesthesia, the patient was placed in the lithotomy position. retrograde ureteral catheterization was performed under transurethral ureteroscopy and an f6 ureteral catheter was inserted into the kidney. after the patient was placed in the prone position, physiological saline was infused through the ureteral catheter to generate artificial hydronephrosis. the posterior renal calyx was punctured under the guidance of b-ultrasound technology. after the stone fragments were removed, the ureteral catheter was removed and an fr6 double-j stent was placed under the nephroscope. the rest of the procedure was identical to the description above for the pi-djs group. study outcomes the primary outcome measure is time to establish passage for pcnl, whereas a secondary outcome measure is incidence of complications, including pneumothorax, postoperative fever, significant hemorrhage and need for blood transfusion. statistical analysis all data were analyzed using spss 20.0 statistical software. analyses and comparisons of the following characteristics were conducted between the two methods: duration to establish the passage, duration of the operation, level of hemoglobin decline, rate of stone clearance, and perioperative complications. all data were expressed as the mean ± standard deviation (x ± s). t-tests were used for comparisons between the two groups. chi-square (x2) tests were used to compare the rates or proportions among different subgroups. a figure 1. the consort flow diagram. pi-djs: preemptive indwelling of double-j stent group; pi-uc: conventional pre-emptive indwelling of ureteral catheter group. rct of preemptive dj in pcnl-bai et al. p-value < 0.05 was considered to be statistically significant. results characteristics of the patient population the characteristics of patients included in the trial are summarized in table 1. no significant difference was found between patients allocated to pi-djs and pi-uc groups, in terms of age (pi-djs vs pi-uc: 48 ± 12.2 vs 47.7 ± 13.4), sex (27 male/10 female vs 28 male/10 female), affected side of kidney (20 left, 17 right vs 21 left, 17 right), size of stone (29.7 ± 4.4 vs 28.5 ± 4.7), percentage of staghorn stones (21.6% vs 23.7%) and stone locations (upper calyx 18 vs 13; middle calyx 19 vs 15; lower calyx 26 vs 29). study outcomes all patients underwent successful pcnl. the pi-djs group (7.5 ± 2.0 min) showed significantly shorter duration to establish the pcnl passage when compared with pi-uc group (11.5 ± 2.5 min). however, there were no significant differences in other parameters, namely, the duration of operation, level of hemoglobin decline, incidence of complications and rate of stone clearance. a summary of the clinical outcomes for the two groups is shown in table 2. in the pi-djs group, pneumothorax occurred in one patient after the removal of the nephrostomy tube and the patient was successfully treated via chest drainage. fever was observed in two patients, without occurrence of septic shock, who were then successfully treated with antibiotics. in the pi-uc group, surgery was aborted in one patient due to surgical vision field impairment as a result of bleeding. in another case, bleeding was found 4 days after the surgery, which was administrated with treatments including absolute bed rest, transfusion and hemostatic therapies. postoperative infection was observed in two cases, but the conditions improved upon administration of sensitive antibiotic therapies. in the pi-uc group, there were 2 cases where the placement of a double-j stent into the bladder was unsuccessful. the stents were finally removed under ureteroscope with intravenous anesthesia. when appropriate, patients who had residual stones after one-stage nephrolithotomy were administrated with second-stage treatments. such procedures include extracorporeal shock wave lithotripsy, flexible ureteroscopic lithotripsy and twostage pcnl. discussion pcnl was first reported by fernstom and johansson in 1976(1). the establishment of the percutaneous passage enabled larger stones to be disintegrated prior to their removal. this revolutionized the conventional concept that larger kidney stones could only be removed by open surgery(11). after more than 40 years of development, the procedures of pcnl have gradually been table 1. comparison of preoperative data between the two groups of patients pi-djs (n=37) pi-uc (n=38) p value age (year); mean±sd 48.3±12.2 47.7±13.4 p = 0.762 gender; n p = 0.944 male 27 28 female 10 10 affected side; n x2 = 0.011, p = 0.916 left kidney 20 21 right kidney 17 17 stone diameter (mm); ; mean±sd 29.7 ± 4.4 28.5 ± 4.7 t =1.141; p = 0.258 percentage of staghorn stones 21.6% 23.7% x2 = 0.045, p = 0.831 stone location; n x2 = 1.144, p = 0.565 upper calyx 18 13 middle calyx 19 15 lower calyx 26 29 all measurement data are expressed as the mean ± standard deviation or numbers unless otherwise specified. t-tests were used for comparisons between the two groups. chi-square (x2) tests were used to compare the rates or proportions among different subgroups pi-djs (n=37) pi-uc (n=38) p value duration to establish passage (min) 7.5 ± 2.0 11.5 ± 2.5 p < 0.001 duration of operation (min) 75 ± 45 79 ± 46 p = 0.704 rate of hemoglobin decline (g/l) 15.6 ± 3.4 16.2 ± 5.3 p = 0.562 incidence of complications (%) 13.5 13.2 p = 0.781 • pneumothorax 1 0 clavien ii • postoperative fever (>38.5° c) 2 2 clavien ii • significant hemorrhage 2 3 clavien ii • blood transfusion 0 1 clavien ii rate of stone clearance(%) 81.1 78.9 p = 0.817 all measurement data are expressed as the mean ± standard deviation (x ± s). t-tests were used for comparisons between the two groups. chi-square (x2) tests were used to compare the rates or proportions among different subgroups table 2. comparison of postoperative data between the two groups of patients rct of preemptive dj in pcnl-bai et al. endourology and stones diseases 234 vol 17 no 03 may-june 2020 235 standardized(11). initially, the patient was placed in the lithotomy position. retrograde insertion of the ureteral catheter through the affected kidney via the urinary tract should be completed before the patient was placed in the prone position(12). conventional pcnls were usually guided by x ray technology to determine localization. in recent years, b-ultrasound localization has seen higher adoption due to its enhanced accuracy, reliability, and safety(13). a ureteral catheter was infused with physiological saline to create an artificial hydronephrosis. the puncture of the renal calyx was performed under the guidance of ultrasound, whereas expansion of the punctured passage by renal sheath or balloon dilatation was carried out under the guidance of zebra urological guidewire. a lithotripsy was conducted after the establishment of the percutaneous renal puncture passage. in conventional pcnl, several uncertainties were frequently encountered. in the process of establishing the operation passage for pcnl, saline was infused via a pre-set ureteral catheter to create an artificial hydronephrosis, but microbubbles were consequently generated. these bubbles then interfered with the ultrasound imaging which, in turn, may have affected the success of the calyceal puncture. sometimes, problems such as inaccurate or difficult positioning of the double-j stent may occur toward the end of the surgery during the antegrade insertion of the stent as a result of a poor visual field or an inadequate angle between the ureter and the percutaneous puncture. the current study unveiled that the major advantage of the preemptive indwelling of double-j tubes over the conventional preemptive indwelling of ureteral catheters was that the establishment of the percutaneous passage was significantly shortened. when saline perfusion reached a height of 60 ~ 80cm, the reflux properties of the double-j tube caused the renal collecting system to produce a stable artificial hydronephrosis with no appearance of microbubbles. this condition enhanced a stable b-ultrasound imaging, making it conducive for calyceal puncture with close to a 100% success rate. hence, there was reduced interference under b-ultrasound and a shortened time spent for the percutaneous renal puncture and the establishment of a working passage. due to persistent perfusion, the indwelling double-j procedure was less likely to form blood clots, which provided a clearer surgical vision field and a reduction in the number of accidental injuries to the renal system during laser lithotripsy. additionally, pidjs prevented blindness during antegrade indwelling and ensured more reliable and accurate positioning. the present study concluded that pi-djs was a safe and feasible method during pcnl. in some scenarios of pyelolithiasis where the ureteropelvic junction was obstructed, the upper end of the double-j stent failed to coil in the renal pelvis; in such cases, the safety guide wire was first inserted under ureteroscopy to guide the subsequent indwelling of the double-j stent. when using the double-j stent, continuous perfusion, calyceal puncture, expansion of the punctured passage, and even the lithotripsy were much easier to achieve. in contrast to conventional pcnl, the newer method was less prone to clot formation and had a clearer visual field. this enhanced surgical safety and reduced the occurrence of accidental mucosal injuries to the renal collecting system. in addition, pi-djs also significantly shortened the operative time, a risk factor for surgical site infection. pi-djs prevented antegrade indwelling when used in the conventional way. in one conventional case, the patient’s fragmented stones blocked the ureter and prevented placement of the guide wire into the bladder. the double-j stent could only be placed after the patient was in the lithotomy position. in a different case, the placement of the guide wire into the ureter failed as a result of an inadequate angle between the ureter and the inferior renal calyceal puncture. similarly, the double-j stent was successfully placed after the patient assumed the lithotomy position. it is noteworthy that sheaths should be used during pcnl to prevent laser damage to the wall of the double-j stent, so as not to affect the effect of drainage and formation of mural stones after operation(14). conclusions to summarize, our study shows that the pi-djs is more advantageous than the conventional pcnl due to shortened time to establish passage (7.5 mins in pi-djs vs 11.5 mins in pi-uc) for pcnl and no increase in the incidence of complications. given that the current study has a limited sample size, a multi-center, large-scale, prospective, randomized, and controlled trial is warranted to further confirm observations from the present study. acknowledgements this work was supported by grants from zhejiang provincial natural science foundation of china (no. ly18h040007 to jiaming wen) and national natural science foundation of china (no. 81871153 to jiaming wen) and zhejiang provincial science and technology department (no. 2017c33063 to fuding bai). conflict of interest the authors declare no conflict of interest. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. ganpule ap, vijayakumar m, malpani a, desai mr. percutaneous nephrolithotomy (pcnl) a critical review. int j surg. 2016;36:660-4. 3. hosseini mm, hassanpour a, eslahi a, malekmakan l. percutaneous nephrolithotomy during early pregnancy in urgent situations: is it feasible and safe? urol j. 2017;14:5034-7. 4. basiri a, nouralizadeh a, kashi ah, et al. x-ray free minimally invasive surgery for urolithiasis in pregnancy. urol j. 2016;13:2496-501. 5. preminger gm, assimos dg, lingeman je, et al. chapter 1: aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005;173:19912000. 6. verma a, tomar v, yadav s. complex rct of preemptive dj in pcnl-bai et al. multiple renal calculi: stone distribution, pelvicalyceal anatomy and site of puncture as predictors of pcnl outcome. springerplus. 2016;5:1356. 7. khazaali m, khazaeli d, moombeini h, jafari-samim j. supine ultrasoundguided percutaneous nephrolithotomy with retrograde semi-rigid ureteroscopic guidwire retrieval: description of an evolved technique. urol j. 2017;14:5038-42. 8. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016;13:2899-902. 9. basiri a, kashi ah, zeinali m, nasiri m, sarhangnejad r, valipour r. ultrasound guided access during percutaneous nephrolithotomy: entering desired calyx with appropriate entry site and angle. int braz j urol. 2016;42:1160-7. 10. gu sp, zeng gh, you zy, et al. types of renal calculi and management regimen for chinese minimally invasive percutaneous nephrolithotomy. indian j surg. 2015;77:8726. 11. kim bs. recent advancement or less invasive treatment of percutaneous nephrolithotomy. korean j urol. 2015;56:614-23. 12. mak dk, smith y, buchholz n, elhusseiny t. what is better in percutaneous nephrolithotomy prone or supine? a systematic review. arab j urol. 2016;14:1017. 13. wang k, zhang p, xu x, fan m. ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a metaanalysis. urol int. 2015;95:15-25. 14. skolarikos a, papatsoris ag. diagnosis and management of postpercutaneous nephrolithotomy residual stone fragments. j endourol. 2009;23:1751-5. rct of preemptive dj in pcnl-bai et al. endourology and stones diseases 236 miscellaneous the adrenal gland: an organ neglected in pediatric trauma cases bahattin aydogdu1*, mehmet hanifi okur1, serkan arslan1, mehmet serif arslan1,hikmet zeytun1, erol basuguy1, mustafa icer2, cemil goya3, ibrahim uygun1, murat kemal cigdem1, abdurrahman onen1, selcuk otcu1 purpose: adrenal gland injury (agi) caused by trauma may cause bleeding and life-threatening problems in children. the objective of this study was to analyze the prevalence of agi in final diagnoses of trauma. materials and methods: the records of 458 patients with abdominal trauma (out of a total 8,200 pediatric patients with trauma of any sort), who were referred to our clinic between january 2009 and july 2014, were reviewed retrospectively. the numbers of patients with agi and their ages, gender, trauma patterns, affected organs, pediatric trauma scores (ptss), and injury severity scores (isss) were recorded, as well as the associated ultrasound (us) and tomographic scan data, treatments, and complications. computed tomography (ct) scans obtained after trauma were subjected to both primary and secondary evaluation. results: in total, 28 patients with agi were detected; their average age was 8.54 ± 4.09 (3–17) years. twenty (71%) patients were male and 8 (29%) were female. nineteen (68%) patients had fallen from heights; the most commonly injured organs were the kidneys, spleen, and lungs. injuries were right-sided in 26 (92.9%) patients. the mean iss was 13.2 (range 5–50) and the mean pts 8.6 (range 0–11). seven patients had iss > 16 and nine had pts < 8. agi was diagnosed by ct in 14 (50%) patients and in 3 (9%) by us at primary evaluation. upon secondary scan inspection focusing on the possibility of adrenal gland injury, such injury was ultimately detected in 28 patients. all patients underwent conservative follow-up, and one died. conclusion: we recommend calculation of the pts, as well as other trauma scores, when pediatric patients suffering multiple or blunt abdominal trauma(s) present to the emergency . in addition, we believe that in children with trauma involving the liver, spleen or kidneys, careful evaluation using a ct scan would increase the diagnosis of agi and reveal a realistic rate of agi in trauma cases. keywords: adrenal gland injury; blunt abdominal trauma; diagnosis; pediatric; prevalence. introduction post-traumatic adrenal gland injury (agi) was first identified by canton in 1863.(1) the rate of adrenal injury following abdominal and thoracoabdominal trauma in children is 1–4.95%.(2,3) computed tomography (ct), ultrasound (us), and magnetic resonance imaging (mri) have been used to diagnose agi.(4,5) ct is the preferred modality.(6) severe adrenal gland bleeding may develop because the gland has a complex vascular structure.(7) adrenal failure has been reported in some cases after bilateral adrenal injury.(8) complications of agi are often quickly followed by death and are accelerated by any severe trauma to other organs.(9,10) injuries to the major organs (liver, spleen, and kidney) are (naturally) prioritized during initial examination of patients with abdominal trauma, and adrenal trauma may be missed, therefore we aimed to study the real prevalence of traumatic adrenal injuries. 1 department of pediatric surgery and urology, medical faculty of dicle university, 21280 diyarbakir, turkey. 2 department of trauma and emergency, medical faculty of dicle university, 21280 diyarbakir, turkey. 3 department of radiology, medical faculty of dicle university, 21280 diyarbakir, turkey. *correspondence: department of pediatric surgery and pediatric urology, medical faculty of dicle university, 21280 diyarbakir, turkey. tel.: +90 412 248 8001; gsm: +90 505 234 4010. fax: +90 412 248 8523. e-mail address: bahattinaydogdu@hotmail.com. received september 2016 & accepted december 2016 materials and methods in total, 8,200 pediatric trauma patients (<18 years) were admitted to the emergency clinic of dicle university hospital between january 2009 and july 2014. we retrospectively examined the records of 458 patients with blunt abdominal trauma, of whom 28 were ultimately diagnosed with agi. we excluded patients with non-blunt abdominal trauma. patient's age, gender, trauma pattern, the extent of agi, the organs affected by trauma, location of the agi, and the pediatric trauma score (pts) and injury severity score (iss) were recorded (tables 1 and 2). initial us and ct scans taken in the emergency room (er) were examined; the grade of injury, the amount of blood transfused (if any), the duration of stay in the intensive care unit (icu) and clinic, and any complications were noted. during primary evaluation, we retrospectively analyzed ct images obtained during the first referral. all available radiological diagnostic data were analyzed retromiscellaneous 2916 spectively during the secondary evaluation. from our analysis, patients with adrenal hemorrhage were identified. all primary evaluations were performed by er on-call radiologists. secondary evaluations focusing on agi were performed by different experienced radiologists who were randomly selected and were blind to each others reports. agi was scored as recommended by the american association for the surgery of trauma (table 2). all data were analyzed using spss ver. 15.0 software (spss inc., chicago, il, usa). continuous variables are shown as means ± standard deviations (sds) and categorical variables as numbers with percentages (%). fisher's exact test was used to compare isss and ptss. a p-value < 0.05 was considered statistically significant. our ethics committee approved the study. results adrenal hemorrhage was evident in the primary ct scans of 14 (3.1%) of the 458 patients with abdominal trauma. during our secondary evaluation, we re-evaluated all primary scans with particular reference to the possibility of agi and detected a total of 28 cases. the average patient age was 8.54 ± 4.09 (3–17) years; 20 (71%) patients were male and 8 (29%) were female. the injury patterns were a fall from a height in 19 (68%) patients, motor vehicle traffic accident in 8 (28.5%), and falling of an iron mass in 1. agi was evident on the left side in 2 (7.1%) (figure 1a) patients and on the right side in 26 (92.9%) (figure 1b). the mean iss was 13.2 (range, 5–50); the mean pts was 8.6 (range, 0–11). seven patients had a iss > 16 and 9 patients had a pts < 8; these are the scores that prompted clinical observation. agi was detected in 3 (0.7%) patients by us and in 14 (3%) by ct during the first examinations of the 28 patients who were ultimately shown to have table 1. baseline characteristics of all patients with adrenal gland injuries n=28 age, years; mean±sd(range) 8.54 ± 4.09 (3–17) sex, (male/female ) 20 (71)/8(29) pediatric trauma score; mean±sd(range) 8.6±2.9(0-11) injury severity score; mean±sd(range) 13,2±10.6( 5–50) intensive care unit, day; mean±sd(range) 4.33±5,1(1-23) hospital stay, day; mean±sd(range) 2.54±1.28 (1-5) trauma mechanisms, n(%) falls from flat roofed 19 (68) motor vehicle injury 8 (28,5) falling of an iron mass 1 (3,5) associated organ injuries, n(%) kidney 28 (100) liver 12(43) head trauma 4( 14 ) spleen 3(11) lung i̇njury 3(11) femur fracture 3(11) pelvis fracture 1(3) classification of adrenal gland injuries, n(%) grade 4 13(46) grade 3 8(29) grade 2 6(21) grade 1 1(4) table 2. adrenal organ injury scale (the american association for the surgery of trauma)(19) grade description of injury i contusion ii laceration involving only cortex (<2 cm) iii laceration extending into medulla (> 2 cm) iv >50% parenchymal destruction figure 1. 1a: 10-year-old male patient, after a traffic accident, axial ct images (a. left adrenal injury "horizontal arrow", b. left kidney injury "star" , c. spleen injury "vertical arrow") respectively. 1b: 7 -year-old male patient after a traffic accident, coronal ct image ( a.liver injury "horizontal arrow" b. right kidney injury "star" c.right adrenal "head arrow") respectively. 1c. 10-year-old male patient after falling from height, coronal ct image (a.right adrenal injury "white arrow" b. right kidneyinjury "head arrow c.liver "black arrow") respectively. adrenal gland in pediatric traumaaydogdu et al. vol 13 no 06 november-december 2016 2917 suffered adrenal hemorrhage after trauma. fourteen new agi patients were diagnosed via secondary examination focusing on the adrenal gland (figure 1c). the most common additional organs injured were the kidneys, spleen, and lungs (table 1). five units of blood were required by four patients; one unit was infused into a patient with grade 4 agi and grade 3 liver injury; one into a patient with a grade 3 agi and a grade 5 kidney injury; one into a patient with a grade 1 injury to the left kidney and a grade 4 agi; and two units into a patient with a grade 3 spleen injury and a grade 2 agi. one patient with a pts score of 0 died from multiple trauma. the mean hospitalization durations were 2.54 ± 1.28 (1–5) days in the icu and 4.33 ± 5.14 (1–23) days in the clinic. two patients developed renal atrophy and required laparoscopic nephrectomy (without adrenal gland removal) during the follow-up period. discussion agi may be difficult to diagnose in pediatric cases with multiple organ injuries due to the anatomical location of the gland and the density of surrounding organs. agi may be diagnosed radiologically, surgically, or at autopsy.(9) in pediatric trauma series, the rates of agi were 0.22– 1%; we detected agi in 0.34% of our pediatric trauma patients. ct scans revealed agi in 3–5% of patients who suffered blunt abdominal trauma.(1) sevitt et al. reported that adrenal gland hemorrhage was evident in 28% of autopsies on patients who died of trauma.(10) the difference between the live and autopsy rates suggest that agi may be often missed in life. we therefore re-evaluated the ct scans of patients who suffered abdominal trauma and found that agi was more common than initially suspected. injuries to the major organs (liver, spleen, and kidney) are (naturally) prioritized during initial examination of patients with abdominal trauma, and adrenal trauma may thus be missed. if such trauma is carefully considered when evaluating ct scans, the reported rates of agi may be expected to rise. earlier studies found that agi was most prevalent after blunt (i.e., not penetrating) trauma.(1,11) our agi cases had indeed experienced blunt trauma. earlier studies found that 86–100% of agis were on the right side.(2, 3) this may be attributable to the fact that the right adrenal gland vein is shorter than the left and opens more posteriorly into the inferior vena cava, thus rendering the vein more susceptible to high-pressure trauma.(1) agi was present on the right side of 92.3% of patients in the present study. although some studies suggested that females suffered more agis than did males,(3,8) other studies found the reverse to be true.(2,12) agi was more common in males than in females in the present study. one-sided (but not bilateral) agi is rarely associated with clinical symptoms. even bilateral agi is seldom associated with acute adrenal failure.(1) schmidt et al. found that hypertension developed after agi.(13) none of our patients had bilateral agi and hypertension was not evident in any case during clinical follow-up. although experienced us radiologists may be able to detect a hyperechogenic mass in the adrenal area after trauma, agi is best diagnosed by abdominal ct, as suggested by an earlier study.(14) mri is rarely used to detect agi.(15) when we reviewed the scans of patients with abdominal trauma who had been referred to our er, agi was evident in 0.7% of the first us scans and 3% of the first ct scans. another radiologist evaluated the ct scans of all 458 patients admitted due to abdominal trauma, with particular attention being paid to agi; agi was ultimately detected in 28 patients. we attributed the lower rate recorded upon first examination to the fact that clinicians focused more on injuries to the major organs. none of our patients underwent mri. the iss is an anatomical score that reliably predicts trauma severity and mortality, which rises in patients with scores > 16,(16) the frequency of which attained 23.8% in a previous study.(3) in the present study, the rate was 25%, thus consistent with that of the literature. pts scores that considered adrenal trauma have not been reported in the literature; nevertheless, we calculated ptss in our present study. a pts < 8 was associated with higher risks of severe trauma and mortality; the risks were similar to those of patients with a iss > 16.(16) in total, 32.1% of agi patients in the present study had a pts < 8. the difference between the number of patients with a iss > 16 and pts < 8 was significant; more patients had a pts < 8 (p = .02). therefore, we believe that calculation of the pts is important. agi patients have been treated via adrenal gland repair, or partial or total adrenalectomy.(11) today, neither surgical nor endovascular procedures are commonly used to treat either adult or pediatric patients. however, surgery has been used in a limited number of unstable patients.(10,17) agi patients, especially those with bilateral agi, should be monitored for adrenal failure.(3,18) in line with recent practice, all patients were monitored in the icu for an average of 2.5 days and discharged without surgery after follow-up in the clinic. conclusions we believe that in children with trauma involving the liver, spleen or kidneys, careful evaluation using a ct scan would increase the diagnosis of agi and reveal a realistic rate of agi in trauma cases. physiological trauma score may be used with other trauma scores, when pediatric patients suffering multiple or blunt abdominal trauma(s) present to the emergency. conflict of interest the authors report no conflicts of interest. references 1. roupakias s, papoutsakis m, mitsakou p. blunt adrenal gland trauma in the pediatric population. asian j surg. 2011;34:103-10. 2. schwarz m, horev g, freud e, et al.traumatic adrenal injury in children. isr med assoc j. 2000;2:132-4. 3. figler bd, webman r, ramey c, et al. pediatric adrenal trauma in the 21st century: children's hospital of atlanta experience. j urol. 2011;186:248-51. 4. wilms g, marchal g, baert a, adisoejoso b, mangkuwerdojo s. ct and ultrasound features of post-traumatic adrenal hemorrhage. j comput assist tomogr. 1987;11: 112-5. 5. iuchtman m, breitgand a. traumatic adrenal hemorrhage in children: an indicator of visceral injury. pediatr surg int. 2000;16: 5868. adrenal gland in pediatric traumaaydogdu et al. miscellaneous 2918 6. sivit cj, ingram jd, taylor ga, bulas di, kushner dc, eichelberger mr. posttraumatic adrenal hemorrhage in children: ct findings in 34 patients. ajr am j roentgenol. 1992;158:1299-302. 7. rammelt s, mucha d, amlang m, zwipp h. bilateral adrenal hemorrhage in blunt abdominal trauma. j trauma. 2000; 48: 332-5. 8. asensio ja, rojo e, roldán g, petrone p. isolated adrenal gland injury from penetrating trauma. j trauma. 2003;54: 364-5. 9. stawicki sp, hoey ba, grossman md, anderson hl 3rd, reed jf 3rd. adrenal gland trauma is associated with high injury severity and mortality. curr surg. 2003;60:431-6. 10. sevitt s. post-traumatic adrenal apoplexy. j clin pathol. 1955;8:185-94. 11. gómez rg, mcaninch jw, carroll pr. adrenal gland trauma: diagnosis and management. j trauma. 1993;35:870-4. 12. lee ys, jeong jj, nam kh, chung wy, chang hs, park cs. adrenal injury following blunt abdominal trauma. world j surg. 2010;34:1971-4. 13. schmidt j, mohr vd, metzger p, zirngibl h. posttraumatic hypertension secondary to adrenal hemorrhage mimicking pheochromocytoma: case report. j trauma.1999;46:973-5. 14. pinto a, scaglione m, guidi g, farina r, acampora c, romano l. role of multidetector row computed tomography in the assessment of adrenal gland injuries. eur j radiol. 2006;59:355-8. 15. mcgehee m, kier r, cohn sm, mccarthy sm. comparison of mri with postcontrast ct for the evaluation of acute abdominal trauma. j comput assist tomogr. 1993;17:410-3. 16. senkowski ck, mckenney mg. trauma scoring systems: a review. j am coll surg.1999;189:491-503. 17. igwilo oc, sulkowski rj, shah mr, messink wf, kinnas nc. embolization of traumatic adrenal hemorrhage. j trauma. 1999 ;47:11535. 18. mehrazin r, derweesh ih, kincade mc, thomas ac, gold r, wake rw. adrenal trauma: elvis presley memorial trauma center experience. urology. 2007;70:851-5. 19. w w w . a a s t . o r g / l i b r a r y / t r a u m a t o o l s / injuryscoringscales.aspx adrenal gland in pediatric traumaaydogdu et al. vol 13 no 06 november-december 2016 2919 the ideal use of catheters in hypospadias repair: an experimental study pediatric urology haci polat1* umut gulacti2 purpose: to find answers to some catheter-related questions in hypospadias repair such as which type of catheter should be used, with which catheter balloon inflation volume, and when should the catheter be removed from the urethra? as catheter use and post-op retention time varies among surgeons in hypospadias repair. material and methods: fifty-four 10 french all-siliconeand 54 latex foley catheters were prepared and assigned to groups as senary. the catheter’s balloons were inflated with 2, 3 and 5 ml of sterile water. the catheters were submerged in artificial human urine and then removed from the solution at 24, 72, and 168 h after submersion. the catheter balloon volume losses, increases in the transverse diameter of the catheters, and angulation of the catheter tips were measured to determine catheter degradation. results: the minimum balloon volume loss was 0.4 ml in the group of all-silicone catheters that were inflated with 2ml and deflated after 24h (2ml 24h). according to balloon volume and deflation time, there were no increases in transverse diameter of the four groups of all-silicone catheters; 2ml 24h, 3ml 24h, 5ml 24h, and 2ml 72h. with 1 mm expansion, the lowest increase on transverse diameter of the latex catheters occurred in five groups; 2ml 24h, 3ml 24h, 5ml 24h, 2ml 72h, and 2ml 168h. conclusion: an all-silicone catheter inflated with 2ml and removed from the urethra within 24-72 hours may be the ideal catheter use in hypospadias repair. keywords: children; hypospadias; urinary catheters introduction in hypospadias repair, the type of catheter used and post-op retention time varies among surgeons. generally, all-silicone foley catheters are used during hypospadias repair and they are retained in the urethra between 0 to 7 days. several problems associated with catheters such as infection, encrustation, bladder spasm, catheter blockage, and trauma related to catheter insertion may occur in hypospadias repair (1). however, there are very few data about mechanical problems with catheter retention time, catheter removal, and use. additionally, most of the existing studies relate to suprapubic catheters and were associated with 4-6 week long-term catheters (2, 3). there are few studies on pediatric-sized catheters in the literature. one of the most influential reports is the study of hardwick et al. on hypospadias model (4). however, there were some important shortcomings of that study such as the sole inclusion of all-silicone catheters and that these were only examined after seven days of degradation, with no additional time points. we were inspired by this study and set out to investigate the degradation of latex (rubber) foley catheters and all-silicone catheters with different balloon inflation volumes and different deflation periods in this study. in our current practice of hypospadias repair, we use latex foley catheters with 2 ml balloon inflation volume and 24-48 hours urethral retention(5). we tried to find answers to some catheter-related questions in hypospadias repair such as which 1adıyaman university medical faculty, department of urology, adiyaman, turkey. 2adıyaman university medical faculty, department of emergency, adiyaman, turkey. *correspondence: adiyaman university, faculty of medicine, department of urology, adiyaman, turkey. tel: +90 416 216 10 15-3317. e-mail: dr.polat@hotmail.com. received april 2016 & accepted july 2016 type of catheter should be used, with which catheter balloon inflation volume, and when should the catheter be removed from the urethra? materials and methods fifty-four 10 french all-siliconeand 54 latex foley catheters (rüsch, laboratoires pharmaceutiques, betschdorf, france) were prepared. all catheters were numbered. all-silicone catheters were assigned to 9 groups as senary. groups were formed as follows; catheter balloons were inflated with 2, 3 and 5 ml of sterile water. latex catheters were grouped in the same way. the maximum transverse and longitudinal dimensions of the catheter balloon were measured with vernier calipers and catheters were inflated. urea (17.1 g) was added to a 1l compound sodium lactate solution to simulate human urine. all catheters were submerged in this solution and incubated in the dark at 37°c. catheters were removed from the solution at the specified times (24, 72, and 168h) after submersion. the catheter balloons were inspected for failure, deflation, and measured with vernier calipers (maximum longitudinal and transverse dimensions). balloon aspiration volume was recorded. all catheters were digitally photographed using a canon eos 650d camera on a standardized scaled background. the photographs were analyzed using imagej software (imagej1.40v; http://rsb.info.nih. gov/ij/). angulation of the catheter tip and maximum transverse external axis of the catheters was recorded. vol 13 no 05 september-october 2016 2856 statistical analysis data analysis was performed using spss for windows, version 11.5 (spss inc., chicago, il, united states). kolmogorov-smirnov test was used to determine whether the continuous variables were normally distributed. the levene test was used for the evaluation of homogeneity of variances. data were shown as median (iqr). the kruskal-wallis test was used for comparisons between more than two independent groups. when the p-value from the kruskal-wallis test was statistically significant, the bonferroni-adjusted mann-whitney u test was used to identify which group differed from the others. a p-value less than 0.05 was considered statistically significant. bonferroni correction was used to check latex silicon 24 h 72 h 168 h p-value d 24 h 72 h 168 h p-value d inflation volume losses (ml) 2 ml 0.75 (0.23) 0.80 (0.20) 0.60 (0.13) 0.052 0.40 (0.05)b,c 0.50 (0.10)b 0.60 (0.10)c < 0.001 3 ml 0.85 (0.13) 0.85 (0.13) 0.75 (0.25) 0.391 0.60 (0.03)c 0.65 (0.10)a 0.80 (0.10)a,c < 0.001 5 ml 1.00 (0.25) 0.80 (0.13) 0.80 (0.00) 0.042 0.70 (0.10)c 0.80 (0.03)a 1.05 (0.20)a,c < 0.001 inflation volume losses (%) 2 ml 37.5 (11.25) 40.0 (10.00) 30.0 (6.25) 0.052 20.0 (2.50)b,c 25 (5.00)b 30 (5.00)c < 0.001 3 ml 28.3 (4.17) 28.3 (4.17) 25.0 (8.33) 0.391 20.0 (0.83)c 21.7 (3.33)a 26.7 (3.33)a,c < 0.001 5 ml 20.0 (5.00) 16.0 (2.50) 16.0 (0.00) 0.042 14.0 (2.00)c 16.0 (0.50)a 21.0 (4.00)a,c < 0.001 transverse diameter increase (mm) 2 ml 1.0 (1.00) 1.0 (0.50) 1.0 (0.50) 0.904 0.0 (0.25)c 0.0 (0.25)a 1.0 (0.00)a,c 0.005 3 ml 1.0 (0.25) 1.5 (0.50) 2.0 (0.25) 0.032 0.0 (0.25)c 1.0 (0.25) 1.2 (0.13)c 0.007 5 ml 1.0 (1.00) 2.0 (0.50) 2.0 (0.00) 0.031 0.0 (1.00)b,c 1.7 (0.63)b 2.0 (0.63)c 0.004 angulation of the catheter tips (°) 2 ml 7.8 (4.33) 2.6 (11.05) 7.5 (7.29) 0.484 0.8 (2.22) 1.0 (0.49) 1.0 (0.43) 0.802 3 ml 3.1 (2.11) 4.7 (6.76) 5.6 (7.39) 0.484 1.3 (1.40) 1.1 (1.15) 1.0 (0.50) 0.751 5 ml 2.9 (1.04) 8.1 (8.49) 5.5 (6.24) 0.139 1.7 (0.56) 1.5 (0.64) 1.4 (0.19) 0.342 table1. the comparisons in terms of catheter balloon inflation volume losses, changes in the transverse diameter of the catheters, and angulation of the catheter tips in both catheter type. a: 72 h vs 168 h (p < 0.0028), b: 24 h vs 72 h (p < 0.0028), c: 24 h vs 168 h (p < 0.0028). d: the comparisons among durations of discharge, kruskal wallis test, according to the bonferroni correction p < 0.0083 was considered as statistically significant figure1. losses occurred in the balloon volumes at different deflation times. losses in the balloon volume of silicone catheters increased statistically significantly (p < 0.001) in all inflation volumes in parallel with deflation times. figure2. the increase in transverse diameter of catheters at different inflation volumes and deflation times. ideal catheter in hypospadiasis-polat et al. pediatric urology 2857 for type i errors in all possible multiple comparisons. results the catheter balloon volume losses, transverse diameter increases, and catheter tip angulations of the different balloon inflation volumes at different deflation times are shown in table 1. statistically significant volume losses occurred in parallel to increasing deflation times in all three balloon-inflation volumes of all-silicone catheters (p < .001). the lowest volume loss was 0.4 ml in the 2ml inflated all-silicone catheter group with deflation after 24h (2 ml 24 h). also greatest volume loss was 1.05 ml, which occurred in the 5ml-inflated all-silicone catheters with deflation after 168 h (5ml 168h). balloon volume loss was present in all latex catheter groups ranging between 0.6-1 ml. however, there was no statistically significant correlation between volume loss, catheter balloon inflation volumes, and deflation times (p > 0.05) (figure 1). there was a statistically significant increase in the transverse diameter of the catheter balloon in each all-silicone catheter group of the three inflation volumes, in parallel to the increased balloon deflation time (p < .005). there was no change in the transverse diameter of the four groups of all-silicone catheters that were deflated after 24h (2ml 24h, 3ml 24h, and 5ml 24h) and those inflated with 2ml and deflated after 72h (2ml 72h). the largest increase of 2 mm occurred in 5ml-inflated all-silicone catheters that were deflated after 168h (5ml 168h) (p < .005). in latex catheters, the transverse diameter of the catheter balloon increased from 1 to 2 mm in all inflation volumes and deflation times, but there were no statistically significant correlation between inflation volumes and deflation times. with 1mm expansion, the smallest increase in transverse diameter of the latex catheters occurred in five groups; 2ml 24h, 3ml 24h, 5ml 24h, 2ml 72h, and 2ml 168h. the largest increase in transverse diameter of latex catheters occurred in the following catheters; 3ml 168h and 5ml 168h (figure 2). there was a non-statistically significant minimal angulation between 0.8 and 1.7 degrees at the tip of the all-silicone catheters after balloon deflation (p > .05). similarly there was a non-statistically significant angulation between 2.9 and 8.1 degrees at the tip of the latex catheters (p > .05). however, these angulations were also present in the catheters before catheter balloon inflation (figure 3 and figure 4). discussion to be relevant for clinical practice, we worked with 2, 3, and 5 ml catheter balloon inflation volumes and 24, 72, and 168 h deflation times. we think that inflation of catheter balloons with 1 ml would not be adequate in clinical practice to prevent catheters from spontaneously falling through the urethra; therefore, we worked with 2 ml catheter balloon inflation as the lowest volume. we routinely inflate catheter balloons with 2 ml in hypospadias repair practice (5) and to date we have not encountered any spontaneously falling catheters. the balloon mechanisms of catheters are 1-2 mm wider than the actual catheter gauge prior to inflation (4). after deflation, the catheter balloon “cuffing” effect has been shown to increase the transverse diameter between 1 and 5 mm, and creases and ridges are formed (6-8). this “cuffing” effect causes problems during catheter removal. as we predicted before the study, cuffing increased in both catheter groups when the balloon inflation volume increased and deflation time was extended. however, although this degradation increased in parallel to the catheter balloon inflation volume and deflation time in all-silicon catheters, this increases was variable in latex catheters. several studies have reported the occurrence of cuffing is lower in latex catheters than in all-silicone catheters (2, 3). however, our experimental results show that this perception may not be correct, at least in low balloon inflation volumes and with short deflation times. although measurable cuffing did not occur at lower catheter balloon inflation volumes and short deflation times (2ml 24h, 3ml 24h, 5ml 24h, and 2ml 72h) in all-silicon catheters, it did occur in all groups of latex catheters. ideal catheter in hypospadiasis-polat et al. figure3. angulations at the tip of catheters. there was a non-statistically significant angulation between 2.9 and 8.1 degrees in the latex catheters (p > 0.05). figure 4. the images of the some catheters which were inflated with 2 ml and were deflated after 72 hours (2ml 72 h). "cuffing effect" seems to be evident in latex catheters. vol 13 no 05 september-october 2016 2858 conclusions we investigated the ideal use of catheters in pediatric hypospadias repair. in hypospadias repair, retention time of urethral catheters varies between physicians for various reasons from 0 to 7 days. when we considered our clinical practice together with these experimental results, we suggest that if a catheter is to be used, all-silicone catheters should be used, and that inflation with 2 ml and removal from urethra within 24-72 hours is the ideal form of catheter use. as a result of this study, we plan to change our practice and use all-silicone catheters in hypospadias repair. conflict of interest there is no conflict of interest. acknowledgments we thank salih erguder for statistical support. references 1. ramakrishnan k, mold jw. urinary catheters: a review. int j fam pract 2005:2. 2. parkin j, scanlan j, woolley m et al. urinary catheter‘deflation cuff’ formation: clinical audit and quantitative in vitro analysis. bju int 2002; 90:666-71. 3. jannings w, kelly m. difficulty in removing suprapubic urinary catheters in home based patients: a comparative descriptive study. aust j adv nurs 2001;19:20-5. 4. hardwicke j, jones e, wilson-jones n. optimization of silicone urinary catheters for hypospadias repair. journal of pediatric urology 2010;6:385-8. 5. polat h, yucel mo, cift a et al. the use of latex foley catheter in repair of hypospadias the most common seen congenital penile anomaly. int j clin exp med 2015;8:13421-3. 6. robinson j. clinical skills: how to remove and change a suprapubic catheter. br j nurs 2005;14:30-5. 7. robinson j. deflation of a foley catheter balloon. nurs stand 2003;17:33-8. 8. robinson j. suprapubic catheter removal: the cuffing effect of deflated catheter balloons. br j community nurs 2003;8:205-8. ideal catheter in hypospadiasis-polat et al. pediatric urology 2859 kidney transplantation 248 urology journal vol 5 no 4 autumn 2008 outcome of kidney transplantation in type 1 and type 2 diabetic patients and recipients with posttransplant diabetes mellitus behzad einollahi,1 mojgan jalalzadeh,1,2 saeed taheri,1 mohsen nafar,3 naser simforoosh3 introduction: we aimed to assess the effects of different types of diabetes mellitus (dm) on patients receiving living donor kidney allografts. materials and methods: a total of 111 kidney transplant patients with dm and 111 randomly selected kidney transplant recipients without dm were enrolled in the study. the characteristics of the kidney allograft recipients and the allograft and patient outcomes were assessed and compared between 4 groups of kidney recipients without dm and patients with type 1 dm, type 2 dm, and posttransplant dm. results: of the 111 patients with dm, 36 (32.4%), 20 (18.0%), and 55 (49.6%) had been diagnosed with type 1 dm, type 2 dm, and posttransplant dm, respectively. diabetic patients had significantly higher rates of rejection episodes (p = .049) and suffered more frequently from delayed graft function (p = .03) compared to the kidney recipients in the control group. patient and allograft survival rates were significantly lower in the patients with dm (regardless of their dm type) compared to the nondiabetic patients (p = .03 and p = .04, respectively). prominently, type 1 dm had significantly adverse effects on patient and allograft survival. patients with posttransplant dm had a relatively better patient survival compared to those with type 1 dm and type 2 dm. conclusion: we found that kidney recipients with dm, especially preexisting dm, had worse patient and graft survival rates compared to the nondiabetics. these findings suggest that kidney transplant patients presenting with any type of dm should be more closely followed. urol j. 2008;5:248-54. www.uj.unrc.ir keywords: kidney transplantation, risk factors, diabetes mellitus, survival analysis 1nephrology research center, baqiyatallah university of medical sciences, tehran, iran 2zanjan university of medical sciences, zanjan, iran 3department of kidney transplantation, shahid labbafinejad medical center, shahid beheshti university (mc), tehran, iran corresponding author: behzad einollahi, md nephrology and urology research center, baqiyatallah hospital, mollasadra st, vanak sq, tehran, iran tel: +98 21 8126 4154 fax: +98 21 8126 4157 e-mail: behzad.einollahi@gmail.com received august 2007 accepted august 2008 introduction over the past 2 decades, introduction of new effective immunosuppressive agents has altered the premise underlying the kidney transplantation practice. the new medications have considerably improved shortterm and long-term outcomes after transplantation; however, posttransplant morbidity remains high. overwhelming evidence suggest that in many cases, these morbidities are related to posttransplant diabetes mellitus (ptdm), and immunosuppression plays a major role in the development of ptdm. generally, diabetes mellitus (dm) is considered as one of the most important causes of end-stage renal disease (esrd) throughout the world.(1-3) the agediabetes mellitus and kidney transplantation outcome—einollahi et al urology journal vol 5 no 4 autumn 2008 249 adjusted incidence of kidney failure in diabetic patients is about 15 times more than that in their nondiabetic counterparts.(4) impairment in insulin and glucose metabolism are responsible for the kidney damage in diabetic patients; the issue is of extreme relevance both in the healthy population and in the kidney transplant patients.(5,6) posttransplant dm occurs mostly in the early period after transplantation and is thought to result from insulin resistance related to the use of corticosteroids and calcineurin inhibitors. in addition, ptdm is more common in some specific racial and ethnic populations.(7,8) african americans as well as recipients from hispanic and indian origins have a higher risk of developing ptdm in comparison with the caucasians and asians.(7,9) other reported risk factors of ptdm include obesity, age over 45 years, family history of dm, acute rejection episodes, and the donor source.(8-15) although it is generally speculated that diabetes mellitus, as the cause of both esrd and ptdm, is a risk factor of lower patient and graft survival rates, a number of surveys have reported no differences in patient and allograft outcomes between the diabetic and nondiabetic kidney allograft recipients.(16) moreover, there is scarce data on whether there is any difference between various types of dm, especially in recipients from living donors. this study aims to evaluate differences in the outcome of living donor kidney recipients with and without diabetes mellitus and its different types, consisting of ptdm, type 1 dm, and type 2 dm. materials and methods a total of 222 adult kidney transplant patients (age > 20 years) who were on regular follow-up at our outpatient clinic in baqiyatollah hospital were selected to be included in this retrospective cohort. they consisted of 111 patients who had been diagnosed with dm and the remaining were randomly selected nondiabetic kidney recipients. all of the patients were recipients of kidney allografts from living donors at our transplantation department between 1986 and 2001. according to the world health organization’s criteria,(17) diabetic patients were divided into 3 subgroups with respect to the type of diabetes mellitus: type 1 dm, type 2 dm, and ptdm. type 1 dm had been diagnosed if the patient had been insulin-dependent or had no measurable level of c-peptide before transplantation. type 2 dm had been diagnosed if the patient had not required insulin for survival, but experienced fasting hyperglycemia or abnormal glucose tolerance tests. posttransplant dm was clinically defined by the corresponding physician of each patient; the criterion for diagnosis of ptdm was developing repeated serum glucose levels of 11.0 mmol/l or higher. age, sex, year of transplantation, duration of dialysis, allograft source, age and sex of the donors, delayed graft function, early and late allograft rejection episodes, graft loss, and death were recorded for all of the patients. posttransplant information was obtained from standard transplantation follow-up protocols and all inpatient and outpatient records. early rejection episode was defined as rejection in less than 3 posttransplant months, and any rejection episode occurred after this period was considered as a late rejection episode. graft failure was defined by either creatinine level of 6 mg/dl for more than 3 consecutive months or a clinical diagnosis of rejection necessitating renal replacement therapy. in 30% of the cases, diagnosis of the allograft rejection was confirmed by allograft biopsy and in the remainder, it was determined clinically. statistical analyses were performed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). all numeric data were presented as mean ± standard deviation. differences between the categorical variables were compared using the chisquare test or the fisher exact test. the student t test was used for evaluating continuous variables. the 1-way analysis of variances test was used to compare continuous variables between the three diabetic groups. the tukey-kramer multiplecomparison tests were used to assess differences between the individual means. analyses of survival were performed using the kaplan-meier method and the log rank test. proportional hazards analysis using the cox regression analysis diabetes mellitus and kidney transplantation outcome—einollahi et al 250 urology journal vol 5 no 4 autumn 2008 was performed for evaluation of the independent impact of different factors on the outcome after adjustment for other contributing factors. a p value level of less than .05 was considered statistically significant. results of the total studied kidney allograft recipients, 111 were diabetic, of whom, 36 (32.4%), 20 (18.0%), and 55 (49.6%) were confirmed cases of type 1 dm, type 2 dm, and ptdm. of the study population, 161 (72.5%) were men and 61 (27.5%) were women. men also constituted 184 (82.8%) of the donors population. the mean age of the patients was 43.7 ± 10.7 years (range, 22 to 75 years) and for the donors, it was 28.5 ± 5.8 years (range, 19 to 48 years). a total of 205 (92.3%) and 17 (7.7%) allografts were harvested from living unrelated and living related donors, respectively. mean duration of dialysis before transplantation was 22.0 ± 29.6 months (range, zero to 192 months). panel reactive antibodies were positive in 25 patients (11.2%). also, 14 (6.3%) patients had a history of delayed graft function. four patients (1.8%) had a history of graft loss and 218 (98.2%) were first-allograft recipients. the diabetic patients were similar to the control group in terms of age, sex, duration of dialysis, follow-up duration, allograft source, number of transplants, and donors’ age and sex (table 1). diabetic patients had significantly higher rates of rejection episodes, death, and delayed graft function compared to the nondiabetic group (table 1). on the other hand, although diabetic patients showed more than 2-fold graft loss rates, the difference was not significant. patient and allograft survival rates were significantly lower in diabetic patients (p = .03 and p = .04, respectively). multivariate proportional analysis confirmed this finding (figure 1 and table 2). as presented in table 1, among the subgroups of dm, type 2 diabetic patients had a significantly higher age, but patients with ptdm had a significantly longer follow-up duration and lower rate of positive panel reactive antibodies. the dm subgroups were similar in their recipients’ sex distribution, donors’ characteristics, number of transplants, history of delayed graft function, early and late rejection episodes, and overall kidney recipients diabetes subgroups parameters dm no dm p type 1 dm type 2 dm ptdm p recipient’s age, y 44.6 ± 11.2 42.9 ± 10.2 .24 38.5 ± 8.4 53.6 ± 6.6 45.3 ± 11.7 < .001 donor’s age, y 28.3 ± 4.9 28.6 ± 6.1 .60 28.2 ± 4.8 27.7 ± 4.6 28.5 ± 5.3 .84 dialysis duration, mo 22.2 ± 30.0 21.8 ± 29.3 .92 22.6 ± 38.5 12.6 ± 11.8 25.9 ± 26.6 .31 follow-up duration, mo 34.3 ± 41.5 42.3 ± 41.9 .16 18.2 ± 24.6 15.0 ± 15.9 25.9 ± 26.6 < .001 recipient’s sex male 82 (73.9) 79 (71.2) 29 (80.5) 16 (80.0) 37 (67.3) female 29 (26.1) 32 (28.8) .65 7 (19.5) 4 (20.0) 18 (32.7) .29 donor’s sex male 92 (84.4) 90 (81.1) 31 (86.1) 19 (95.0) 42 (79.2) female 17 (15.6) 21(18.9) .59 5 (13.9) 1 (5.0) 11 (20.8) .24 donor source living related 8 (7.2) 9 (8.1) 4 (11.1) 0 4 (7.3) living unrelated 103 (92.8) 102 (91.9) .80 32 (88.9) 20 (100) 51 (92.7) .30 positive panel reactive antibodies 13 (11.7) 12 (10.8) .83 7 (19.4) 4 (20.0) 2 (3.6) .03 second transplants 3 (2.7) 1 (0.9) .31 0 0 1 (1.9) .60 delayed graft function 11 (9.9) 3 (2.7) .03 4 (11.1) 1 (5.0) 6 (10.9) .72 rejection episodes no 60 (54.1) 60 (54.1) 17 (47.2) 12 (60.0) 31 (56.3) early 41 (36.9) 49 (44.1) 19 (52.8) 8 (40.0) 22 (40.0) late 10 (9) 2 (1.8) .049 0 0 2 (3.6) .49 allograft loss 17 (15.3) 8 (7.2) .06 5 (13.9) 3 (15.0) 9 (16.3) .95 death 10 (9.3) 3 (2.8) .049 5 (15.9) 2 (10.0) 3 (5.5) .38 table 1. characteristics and outcomes of kidney allograft recipients with and without diabetes mellitus* *values in parentheses are percents. dm indicates diabetes mellitus and ptdm, posttransplant diabetes mellitus. diabetes mellitus and kidney transplantation outcome—einollahi et al urology journal vol 5 no 4 autumn 2008 251 allograft and patients’ outcomes. multivariate proportional hazard analysis also showed similar results; however, type 1 dm was associated with the risks of patient and graft loss (figure 2 and table 3). we also evaluated patient and allograft survival differences between the two groups of patients with type 1 dm and the controls. we found that patients with type 1 dm were significantly more likely to lose lives and allografts than the recipients without dm (p = .004 and p = .03, respectively), which was confirmed by multivariate hazard analysis (figure 3 and table 4). although type 2 dm group had relatively worse patient and graft outcome compared to the controls, the difference was not significant (p = .07 and p = .07, respectively). on the other hand, ptdm had comparable patient 95% confidence interval variables p exp(b) lower upper patient recipients’ sex .53 1.99 0.23 17.07 recipients’ age .06 1.07 0.99 1.16 donors’ sex .53 0.58 0.11 3.13 donors’ age .43 1.05 0.92 1.20 panel reactive antibodies .73 0.68 0.07 6.20 delayed graft function .79 1.35 0.15 12.33 diabetes mellitus posttransplant .07 1 … … type 1 .02 10.99 1.45 83.30 type 2 .23 3.63 0.43 30.42 graft recipients’ sex .07 0.35 0.11 1.08 recipients’ age .03 1.07 1.01 1.13 donors’ sex .02 0.25 0.08 0.79 donors’ age .73 1.02 0.92 1.12 panel reactive antibodies .98 0 0 … delayed graft function .11 3.21 0.75 13.72 diabetes mellitus posttransplant .05 1.00 … … type 1 .02 5.36 1.24 23.18 type 2 .08 4.27 0.84 21.58 table 3. proportional hazard analysis for evaluating independent impact of different types of diabetes mellitus on patient and graft outcomes 6050403020100 follow-up, mo 100 80 60 40 20 0 p at ie nt s ur vi va l no dm dm kidney recipients 140120100806040200 follow-up, mo 100 80 60 40 20 0 g ra ft s ur vi va l no dm dm kidney recipients figure1. patient and graft survival rates for the patients with and without diabetes mellitus (dm). 95% confidence interval variables p exp(b) lower upper patient diabetes mellitus .05 3.71 0.99 13.89 recipients’ sex .12 5.13 0.65 40.25 recipients’ age .41 1.02 0.97 1.07 donors’ sex .84 0.86 0.18 4.01 donors’ age .49 1.04 0.94 1.14 panel reactive antibodies .78 0.74 0.09 5.96 delayed graft function .95 0.93 0.12 7.59 graft diabetes mellitus .03 2.94 1.09 7.94 recipients’ sex .45 0.69 0.26 1.82 recipients’ age .04 1.04 1.00 1.09 donors’ sex .17 0.48 0.17 1.36 panel reactive antibodies .97 0 0 … dialysis duration .42 0.99 0.97 1.01 delayed graft function .05 3.42 0.99 11.75 table 2. proportional hazard analysis for evaluating independent impact of diabetes mellitus on patient and graft outcomes diabetes mellitus and kidney transplantation outcome—einollahi et al 252 urology journal vol 5 no 4 autumn 2008 and allograft outcomes with the controls. discussion the proportion of patients with diabetes mellitus requiring renal replacement therapy as well as the number of kidney transplant recipients developing ptdm has drastically increased over the recent decade.(9,18-21) the lower graft and patient survival rates of the diabetic patients has made the issue of kidney transplantation a matter of dispute. the proponents of the practice account the excellent patient and graft survival rates in diabetic patients with esrd compared to the patients undergoing dialysis.(22-24) on the other hand, opponents of performing kidney transplantation in diabetic patients argue that in the presence of allograft shortage, we should reserve kidney transplantation to those who have the best outcome. in this study, we found that diabetic recipients of living kidney transplants have worse graft and patient survival rates than their nondiabetic counterparts. moreover, among patients with different types of dm, only type 1 dm had significant adverse effects on patient and allograft survival compared to nondiabetic patients. we also found that ptdm patients had relatively better patient survival compared to the 100806040200 follow-up, mo 100 80 60 40 20 0 p at ie nt s ur vi va l ptdm type 2 dm type 1 dm diabetic kidney recipients 140120100806040200 follow-up, mo 100 80 60 40 20 0 g ra ft s ur vi va l ptdm type 2 dm type 1 dm diabetic kidney recipients figure 2. patient and graft survival rates for the patients with different types of diabetes mellitus (dm). 302520151050 follow-up, mo 100 80 60 40 20 0 p at ie nt s ur vi va l no dm type 1 dm kidney recipients 140120100806040200 follow-up, mo 100 80 60 40 20 0 g ra ft s ur vi va l no dm type 1 dm kidney recipients figure 3. patient and graft survival rates for the patients with type 1 diabetes mellitus (dm) versus kidney allograft recipients without dm. diabetes mellitus and kidney transplantation outcome—einollahi et al urology journal vol 5 no 4 autumn 2008 253 patients with the other types of dm. our findings are in accordance with some previous studies assessing the outcome differences in diabetic and nondiabetic kidney transplant recipients.(25,26) some of the associations between dm and graft failure can be explained by the higher risk of death. since dm is associated with an increased risk of infection, cardiovascular events, and other complications, it is plausible that dm can increase mortality. revanur and colleagues reported a lower patient survival, but not graft survival in both patients with preexisting dm and ptdm.(27) kronson and associates compared the outcomes of kidney transplant recipients with type 1 dm and type 2 dm and nondiabetic patients. they found that patients with type 2 dm represented lower patient and graft outcome compared to those with type 1 dm, but when death with the functioning graft was censored, they found that graft survival for these two diabetic groups and nondiabetic patients were the same.(22) results of this study showed a significant better patient survival but not graft survival rate for ptdm in comparison with that in other diabetic patients. the better patient survival in ptdm compared to types 1 and 2 dm can be well explained by this fact that patients with ptdm usually experience hyperglycemia in a shorter time duration than patients with the other two types of dm. however, in contrast to the abovementioned studies, we did not find any differences between types 1 dm and 2 dm in terms of patient and graft survival rates. to the best of our knowledge, this is the first study assessing and comparing survival outcomes of diabetic kidney recipients which simultaneously evaluates allograft and patient survival in 4 different subgroups (nondiabetic, type 1 dm, type 2 dm, and ptdm groups) receiving living kidney allograft. as a limitation, we did not mention how well our studied recipients had controlled their blood glucose levels; hence, we cannot have a conclusion whether hyperglycemia or some other factors are responsible for the poor outcome (eg, insulin metabolism). conclusion we found that diabetic kidney recipients had worse patient and graft survival compared to nondiabetics. among diabetic patients, ptdm has relatively the best patient survival. these findings suggest that kidney transplant patients representing any types of dm should be more closely followed, and development of ptdm does not necessarily worsen the outcomes in shortterm. conflict of interest none declared. references 1. go as, chertow gm, fan d, mcculloch ce, hsu cy. chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. n engl j med. 2004;351:1296-305. 2. weiner de, tighiouart h, amin mg, et al. chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. j am soc nephrol. 2004;15:1307-15. 3. anavekar ns, mcmurray jj, velazquez ej, et al. relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. n engl j med. 2004;351:1285-95. 4. brancati fl, whelton pk, randall bl, neaton jd, stamler j, klag mj. risk of end-stage renal disease in 95% confidence interval variables p exp(b) lower upper patient recipients’ sex .30 3.11 0.36 26.69 recipients’ age .47 1.03 0.95 1.12 donors’ sex .64 1.66 0.19 13.95 donors’ age .23 1.08 0.95 1.23 panel reactive antibodies .98 0 0 … delayed graft function .99 0 0 … type 1 diabetes mellitus .01 8.44 1.73 41.09 graft recipients’ sex .96 1.04 0.19 5.64 recipients’ age .04 1.07 1.00 1.15 donors’ sex .64 1.02 0.93 1.12 donors’ age .82 1.18 0.27 5.09 panel reactive antibodies .98 0 0 … delayed graft function .002 11.26 2.46 51.59 type 1 diabetes mellitus .049 4.52 1.01 20.29 table 4. proportional hazard analysis for evaluating independent impact of type 1 diabetes mellitus versus no diabetes mellitus on patient and graft outcomes diabetes mellitus and kidney transplantation outcome—einollahi et al 254 urology journal vol 5 no 4 autumn 2008 diabetes mellitus: a prospective cohort study of men screened for mrfit. multiple risk factor intervention trial. jama. 1997;278:2069-74. 5. sechi la, catena c, zingaro l, melis a, de marchi s. abnormalities of glucose metabolism in patients with early renal failure. diabetes. 2002;51:1226-32. 6. chen j, muntner p, hamm ll, et al. insulin resistance and risk of chronic kidney disease in nondiabetic us adults. j am soc nephrol. 2003;14:469-77. 7. sumrani nb, delaney v, ding zk, et al. diabetes mellitus after renal transplantation in the cyclosporine era--an analysis of risk factors. transplantation. 1991;51:343-7. 8. sumrani n, delaney v, ding z, et al. posttransplant diabetes mellitus in cyclosporine-treated renal transplant recipients. transplant proc. 1991;23:124950. 9. neylan jf. racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. fk506 kidney transplant study group. transplantation. 1998;65:515-23. 10. cosio fg, pesavento te, osei k, henry ml, ferguson rm. post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. kidney int. 2001;59:732-7. 11. boudreaux jp, mchugh l, canafax dm, et al. the impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients. transplantation. 1987;44:376-81. 12. hathaway dk, tolley ea, blakely ml, winsett rp, gaber ao. development of an index to predict posttransplant diabetes mellitus. clin transplant. 1993;7:330-8. 13. vesco l, busson m, bedrossian j, bitker mo, hiesse c, lang p. diabetes mellitus after renal transplantation: characteristics, outcome, and risk factors. transplantation. 1996;61:1475-8. 14. rao m, jacob ck, shastry jc. post-renal transplant diabetes mellitus--a retrospective study. nephrol dial transplant. 1992;7:1039-42. 15. von kiparski a, frei d, uhlschmid g, largiader f, binswanger u. post-transplant diabetes mellitus in renal allograft recipients: a matched-pair control study. nephrol dial transplant. 1990;5:220-5. 16. kasiske bl, snyder jj, gilbertson d, matas aj. diabetes mellitus after kidney transplantation in the united states. am j transplant. 2003;3:178-85. 17. alberti kg, zimmet pz. definition, diagnosis and classification of diabetes mellitus and its complications. part 1: diagnosis and classification of diabetes mellitus provisional report of a who consultation. diabet med. 1998;15:539-53. 18. locatelli f, canaud b, eckardt ku, stenvinkel p, wanner c, zoccali c. the importance of diabetic nephropathy in current nephrological practice. nephrol dial transplant. 2003;18:1716-25. 19. frei u, schober-halstenberg hj. annual report of the german renal registry 1998. quasi-niere task group for quality assurance in renal replacement therapy. nephrol dial transplant. 1999;14:1085-90. 20. collins aj, kasiske b, herzog c, et al. excerpts from the united states renal data system 2003 annual data report: atlas of end-stage renal disease in the united states. am j kidney dis. 2003;42:a5-7, s1230. 21. walczak da, calvert d, jarzembowski tm, et al. increased risk of post-transplant diabetes mellitus despite early steroid discontinuation in hispanic kidney transplant recipients. clin transplant. 2005;19:527-31. 22. kronson jw, gillingham kj, sutherland de, matas aj. renal transplantation for type ii diabetic patients compared with type i diabetic patients and patients over 50 years old: a single-center experience. clin transplant. 2000;14:226-34. 23. [no authors listed]. excerpts from united states renal data system 1991 annual data report. am j kidney dis. 1991;18:1-127. 24. brunkhorst r, lufft v, dannenberg b, kliem v, tusch g, pichlmayr r. improved survival in patients with type 1 diabetes mellitus after renal transplantation compared with hemodialysis: a case-control study. transplantation. 2003;76:115-9. 25. schiel r, heinrich s, steiner t, ott u, stein g. longterm prognosis of patients after kidney transplantation: a comparison of those with or without diabetes mellitus. nephrol dial transplant. 2005;20:611-7. 26. nyberg g, hartso m, mjornstedt l, norden g. type 2 diabetic patients with nephropathy in a scandinavian kidney-transplant population. scand j urol nephrol. 1996;30:317-22. 27. revanur vk, jardine ag, kingsmore db, jaques bc, hamilton dh, jindal rm. influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation. clin transplant. 2001;15:89-94. appendixes 297urology journal vol 5 no 4 autumn 2008 acknowledgement reviewers in volume 5 the editorial team of the urology journal would like to acknowledge a depth of gratitude to colleagues who have done us the great favor of peer reviewing of the submitted manuscripts over the past year: abdullah aa, uae aliasgari m, iran ameri aa, iran aminsharifi ar, iran aravantinos e, greece argani h, iran arshadi h, iran asgari sa, iran barghi mr, iran carnero lópez b, spain collodel g, italy dadkhah f, iran darabi-mahboub mr, iran djaladat h, iran einollahi b, iran farshi a, iran ghenaati h, iran ghohestani sm, iran gholamrezaei hr, iran hajebrahimi s, iran hayashi y, japan hosseini sy, iran kajbafzadeh am, iran karami h, iran kasouf w, canada kavoussi lr, usa kazemeini sm, iran kazemi b, iran kazemi rashed f, iran khorrami h, iran kim sh, south korea madaen sk, iran maghsoudi r, iran mahbobi, iran mahdavi r, iran mehraban d, iran mehrsaei ak, iran micali s, italy mohamadi sichani m, iran mohanna ma, yemen moradi mr, iran mousapour e, iran mousavi-bahar h, iran nahas wc, brazil naseh hr, iran nikolic o, serbia nikoobakht mr, iran nouralizadeh a, iran palma p, spain parvin m, iran perheentupa a, finland pourmand g, iran rabbani mr, iran rajaei esfahani m razi a, iran rekhi b, india rezazadeh, iran saeidi p, iran sayed ma, egypt schalamon j, austria sedighi gilani ma, iran shadpour p, iran shahrazad a, iran shakeri s, iran shakhssalim n, iran shamsa a, iran sharifi-aghdas f, iran sharifian m, iran sina ar, iran soleimani m, iran soufi majidpour h, iran suzuki m, japan tabibi a, iran taghizadeh a, iran tremblay rr, canada vutyavanich t, thailand yarmohammadi a, iran yüksel h, turkey zand s, iran zare s, iran zargar shoshtari ma, iran ziaee sam, iran urology journal unrc/iua 218 renal malakoplakia simulating neoplasm in a child: successful medical management kajbafzadeh am*, baharnoori m department of pediatric urology and renal transplantation, children medical center, tehran university of medical sciences, tehran, iran key words: renal malakoplakia, wilm's, bethanechol chloride, macrophage, diagnosis vol. 1, no. 3, 218-220 summer 2004 printed in iran introduction renal malakoplakia (rm) is a rare granulomatous disorder of adults, with less than 8 cases reported in pediatric age group in the literature. published cases of rm were collected form the archival literature by searching the medline database and by reviewing bibliographic references contained in articles on renal malakoplakia. ninety-six cases of rm have been published over the past 37 years. renal malakoplakia presents with fever, flank pain, and a palpable mass, which may be confused with a renal tumor or other infectious processes. the clinical diagnosis of renal malakoplakia is difficult and usually only proved by pathologic findings of michaelis-gutmann bodies after nephrectomy. we report a child with renal parenchymal malakoplakia presenting with a renal neoplasm and successfully treated medically with no recurrence in a five year follow-up period. case report a 10-year-old boy suffering form fever and headache for 20 days before admission in the pediatric infectious disease ward had been evaluated as a fever of unknown origin (fuo) at a local hospital. he was initially diagnosed as salmonellosis. antibiotic regimen was not effective (a 7 day course of chloramphenicol). the patient was transferred to our urology department with the initial diagnosis of huge renal mass, most probably a wilm's tumor. on physical examination the child was severely ill, with day and night fever, tachycardia, and right flank tenderness. a huge soft tissue mass was noted on the right upper quadrant, fixed to the surrounding muscles. his erythrocyte sedimentation rate (esr) was 110 mm/h in the first hour (normal 5 to 10 mm/h). all admission laboratory data were normal except for mild anemia and moderate leukocytosis. renal ultrasound showed a right kidney huge solid mass with some cystic formation with mixed echo pattern. abdominal ct scan confirmed the right renal solid mass measuring 111 × 69 × 61 mm with some necrosis and cyst formation (fig. 1). on physical examination, the child was cachectic with a large right flank mass. renal cortical scan by 99m tc dimercaptosuccinic acid (dmsa) showed normal left kidney with a large photopenic area at the right lateral renal border (fig. 2). a true cut needle biopsy failed and an open biopsy was taken from the right flank mass. the histopathological reports showed sever inflammation with infiltration of foamy histiocytes, compatible with malakoplakia (fig. 3). following confirmation of initial diagnosis, a trial treatment with bethanechol chloride, 12.5 mg three times daily, trimethoprim-sulfamethoxazole, one adult tablet per 12 hours, and ascorbic acid, 500 mg three times daily for 21 days, was initiated. he was afebrile three days after starting the new regimen. the general condition, as well as his appetite, improved. a repeat renal ultrasound and a ct scan confirmed dramatic renal mass shrinkage and decrease in the size and appearance of the mass (fig. 4) three weeks following the treatment. subsequently, the patient was followed for 46 months and renal ultrasound showed normal renal size with no detectable tumor. discussion the most common presenting signs and symptoms of renal malakoplakia are fever, flank pain, or a palpable flank mass. two basic patterns of accepted for publication in april 2004 *corresponding author: 2nd floor, no. 36, 7th street, saadat-abad, tehran 19987, iran. email: kajbafzd@sina.tums.ac.ir renal malakoplakia simulating neoplasm in a child: successful medical management 219 malakoplakia have been described: multifocal and unifocal.(1,2) multifocal type accounts for 75% of the reported cases and is bilateral in about half of the cases. unifocal disease usually appears as a large yellow-gray mass measuring 2.5 cm to 9 cm in diameter.(1) the mass is usually smooth and well marginated and central necrosis or cyst formation may be present. histological examination reveals aggregates of large histiocytic cells (von hansemann cells) admixed with an infiltrate fig. 2. intravenous urogram showed a soft tissue mass on the lateral border of right kidney causing caliceal elongation and distortion. fig. 3. the renal cortical scan by tc-99m dmsa showed normal left kidney with a photopenic area at the right lateral renal border. fig. 4. ct scan three weeks following medical management noted dramatic mass shrinkage. fig. 1. abdominal ct scan before medical management showed right renal solid mass with some necrosis and cyst formation. renal malakoplakia simulating neoplasm in a child: successful medical management 220 of lymphocytes, plasma cells, and interspersed well-defined bundles of fibroblasts and collagen. von hansemann histiocytes contain michaelisgutmann bodies, concentrically laminate and calcific inclusions pathognomonic of malakoplakia. patients with solitary kidney or bilateral upper tract involvement may present with azotemia or uremia. dramatic improvement has also been reported in patients treated with cholinergic agents and ascorbic acid.(2) both agents have corrected cellular abnormalities as well as enhancing phagocytosis by improving microtubule and vacuole formation. cholinergic actions may also include improving bactericidal function through enhancing super oxide production and release. it is known that the cholinergic agonists raise intracellular cyclic guanine monophosphate (cgmp)/cyclic adenosine monophosphate (camp) ratio and stimulate the production of tumor necrosis factor that enhances the microbiocidal function of macrophages.(3) references 1. hartman ds, davis cj jr, lichtenstein je, goldman sm. renal parenchymal malakoplakia. radiology 1980; 136: 33-42. 2. abdou ni, napombejara c, sagawa a, et al. malakoplakia: evidence for monocyte lysosomal abnormality correctable by cholinergic agonist in vitro and in vivo. n engl j med 1977; 297: 1413-19. 3. kajbafzadeh am. malakoplakia of the testis [correspondence]. br j urol 1995; 76: 276. prevalence and significance of fluoroquinolone-resistant bacteria carriage in patients undergoing transrectal ultrasound prostate biopsy amir hasanzadeh1, mohammad reza pourmand1*, ahad alizadeh2, gholamreza pourmand3 purpose: to determine the prevalence of fluoroquinolone-resistant (fqr) bacteria carriage in patients undergoing transrectal ultrasound prostate biopsy (trus-bx), and the relationship between the risk factors and fqr carriers as well as infections after prostate biopsy. materials and methods: rectal swabs were obtained from 158 patients undergoing trus-bx. the fqr organisms were isolated using selective media, and the antibiotic susceptibility pattern was determined. moreover, after prostate biopsy, blood and urine samples were collected from patients with post-biopsy infection (pbi) during 30 days of follow up. results: in total, 73 (46.2%) patients were positive for ciprofloxacin-resistant bacteria in rectal cultures. the most dominant isolates were escherichia coli (95.9%). the antibiotic susceptibility patterns for the fqr rectal and clinical isolates showed high levels of resistance to ampicillin (94%) and trimethoprim-sulfamethoxazole (89.5%), while the resistance to amikacin, fosfomycin and imipenem remained very low. the multivariate analysis showed that previous use of fqs (or, 2.54; 95% ci, 1.17-5.49; p = .019) and history of hospitalization (or, 7.85; 95% ci, 2.075-29.744; p = .002) were significantly risk factors for the fqr carriage. on the other hand, the risk of pbi was higher among intestinal carriers of fluoroquinolone resistant bacteria compared with noncarriers, that this difference was statistically significant (24% versus 3.5%, p < .001).the rates of pbi and hospitalization after trus-bx were 12.5%, and 4.43%, respectively. conclusion: an increase in the rectal fqr bacteria carriage is associated with elevated pbi, which strongly recommends the need for an appropriate prophylaxis to reduce infections in patients undergoing trus-bx. keywords: biopsy; drug resistance; prostate; risk factors. 1 department of pathobiology, school of public health, tehran university of medical sciences, tehran, iran. 2 department of epidemiology and reproductive health, reproductive epidemiology research center, royan institute for reproductive biomedicine, acecr, tehran, iran. 3 urology research center, tehran university of medical sciences, tehran, iran. *correspondence: department of pathobiology, school of public health and biotechnology research center, tehran university of medical sciences, tehran, iran tel: +98 21 88954910, fax: +98 21 66472267, e-mail address: mpourmand@tums.ac.ir. received december 2016 & accepted april 2017 introduction prostate cancer is one of the most commonly diag-nosed cancers among men and represents a significant health problem. worldwide, more than 1.1 million men are diagnosed with prostate cancer every year with the estimated number of deaths being 313,000 in 2013(1). transrectal ultrasound prostate biopsy (trus-bx) is considered the essential and gold standard procedure for the histological diagnosis of prostate adenocarcinoma. the risks and complications of trus-bx have been reported in the literature; some of these complications are minor, such as pain, bleeding, and hemospermia, but some complications are clinically important, including fever, chills, orchiepididymitis, acute bacterial prostatitis, urinary tract infection (uti), and sepsis(2,3). the frequency of infection varies across studies, with most studies reported the rates of infection and hospitalization to be 1.7–11.3% and 0–6.3%, respectively(4,5). most often, the organism diagnosed in infectious complications after trus-bx are escherichia coli (e. coli), with miscellaneous these strains most likely originating from the patient’s rectum at the time of prostate biopsy(6,7). according to the american urological association and european association of urology (eau) guidelines, the use of fluoroquinolone (fq) prophylaxis is generally considered before trus-bx because it has shown to decrease the rates of infection-related complications (8,9). in recent studies, the rate of fluoroquinolone-resistant (fqr) e. coli isolated from utis have shown to increase by 4.4 folds(10). moreover, a recent case series mentioning post-biopsy infections (pbis) suggests that in this setting, fqr e. coli in rectal flora is a risk factor for infectious complications after trus-bx(11-13). to the best of our knowledge, there are no reports that demonstrate the prevalence of antimicrobial resistance in intestinal flora of patients undergoing trus-bx in iran. our first aim of the current study was to determine the prevalence of antibiotic resistance in bacteria isolated from rectal swabs in iranian patients undergoing trus-bx. second, we evaluated potential predisposing risk factors and their correlation with the incidence of miscellaneous 3085 (1 year ago), history of infectious diseases (uti and prostatitis in the last 4 months), underlying diseases (diabetes mellitus and hypertension), history of prostate biopsy, frequent urination, and smoking was asked and recorded. the level of prostate-specific antigen (psa) and prostate volume were extracted from patients' medical records. an enema (fleet®) was administered in some patients for bowel preparation the night before and two hours before biopsy. oral fq was administered as the prophylactic antibiotic (500 mg, 2 hours before the biopsy up to 4 days after biopsy twice daily). the rectal swabs were collected from the patients immediately before prostate biopsy and were sent to microbiology laboratory for processing as described below. exclusion criteria were failure to complete the form, antibiotic resistance in related patients. third, we determined the incidence of infection complications after trus-bx. based on our findings, some recommendations were provided in the context of prophylaxis and treatment of these patients. material and methods patients and study design in total, 185 patients suspicious for prostate cancer were referred to the urology research center of tehran university of medical sciences, iran, for biopsy using trus-bx between march 2015 and february 2016. demographic informations, history of using fqs (6 months prior to biopsy), history of hospitalization table 1. patients’ demographic and clinical characteristics total ciprofloxacin -susceptible ciprofloxacin resistant p value total (%) mean ± sd no. (%) mean±sd no. (%) mean±sd age 158 64.37 ± 8.71 85 62.47 ± 8.23 73 66.60 ± 8.78 .006* bmi 158 25.92 ± 12.6 85 25.67 ± 13.28 73 26.21 ± 11.8 .252* psa 158 9.5 ± 12.7 85 9.1 ± 6.81 73 10.2 ± 8.21 .167* prostate volume 158 49.46 ± 22.02 85 46.46 ± 16.43 73 52.94 ± 26.8 .357* hospitalization in past 1 months 24 (15.2) 3 (3.5) 21 (28.8) <.001† ciprofloxacin use in past 6 months 55 (34.8) 19 (22.4) 36 (49.3) <.001† diabetes mellitus 25 (15.8) 11 (12.9) 14 (19.2) .284† prostatitis in past 4 months 28 (17.7) 8 (9.4) 20 (27.4) .003† uti in past 4 months 46 (29.1) 19 (22.4) 27 (37) .044† previous biopsy 30 (19) 9 (10.6) 21 (28.8) .003† hypertension 41 (25.9) 22 (25.9) 19 (26) .983† presence of a catheter 21 (13.3) 9 (10.6) 12 (16.4) .280† enema 51 (32.3) 27 (31.8) 24 (32.9) .834† frequent urination 95 (60.1) 50 (58.8) 45 (61.6) .718† smoking 28 (17.7) 15 (17.6) 13 (17.8) .979† *mannwhitney test † pearson chi-square risk factors adjusted odds ratio 95% ci p value age 1.043 .998-1.090 .062 hospitalization in past 1 year 7.856 2.075-29.744 .002 ciprofloxacin use in past 6 months 2.533 1.169-5.490 .019 prostatitis in past 4 months 1.515 .519-4.423 .448 uti in past 4 months 1.351 .583-3.129 .483 previous biopsy 1.644 .607-4.449 .328 ci, confidence interval table 2. multivariate logistic regression analysis examining independent patient risk factors for harboring ciprofloxacin-resistant rectal carriage. fluroquinolone resistance in trus bx of prostate-hasanzadeh et al. vol 14 no 03 may-june 2017 3086 failure to follow-up after trus-bx and the use of other antibiotics alongside fq. post prostate biopsy, all the patients were followed for 30 days via telephone interview to record the probable presence of infection. the patients were asked a number of questions, including fever over 38ºc, chills, dizziness, pain in the bladder and dysuria, and then were guided to visit the urology center for sampling. the bacteria isolated from blood and urine samples were evaluated for identification and antibiotic susceptibility. detection fq-r e. coli and antimicrobial susceptibility testing the samples collected using rectal swabs (cotton-tipped) before the trus-bx were transferred into 5 ml of brain heart infusion broth (merck, germany) containing 10 µg/ml ciprofloxacin. after incubating at 35°c, 0.1 ml of the broth was cultured in macconkey agar (merck, germany) with 10 µg/ml of ciprofloxacin, then plates were incubated overnight at 35°c. the plates with positive cultures were investigated to identify the isolates. an ciprofloxacin minimum inhibitory concentration (mic) was performed on the strains resistant to ciprofloxacin using the etest method (biomérieux) according to the manufacturer’s directions and antimicrobial susceptibility of fluoroquinolone-resistant e. coli clinical and rectal isoletes was determined with reference to the minimal inhibitory concentration breakpoint recommended by the clinical and laboratory standards institute(14). statistical analysis normal distribution of the data was evaluated using lilliefors and shapiro-wilk test. demographic characteristics and risk factors in patients of the two groups who are susceptible and resistant to fqs before and after prostate biopsy were descripted using mean and 95% confidence interval for quantitative variables and frequency, and percent for count data in table 1. ibm spss statistics 21.0 software and r version 3.0.1 were used to analyze the obtained results. the differences of the nonparametric variables were analyzed by mann– whitney u test. chi-square test was used to evaluate the association between categorical variables. simple and multivariate logistic regression was used to estimate the effects of risk factors on fluoroquinolone resistance. the type of statistical modeling was confirmatory so the enter method was used as a model selection method. the criterion for statistical significance was p < .05. results patient characteristics out of the 185 patients referred for biopsy, 27 patients were excluded from the study based on the aforementioned criteria. the remaining 158 patients in this study had an average age of 64.37 years (ranging between 44 and 83). the mean psa was 10.2 ng/ml, and the mean prostate volume was 49.46 ml (table 1). microbiological characteristics out of 158 patients, 73 patients (46.2%) had positive culture. gram-negative isolates resistant to ciprofloxacin were e. coli (95.9%, n = 70), citrobacter spp. (2.7%, n = 2) and pseudomonas spp. (1.6%, n = 1). the antibiotic resistance patterns for e. coli and citrobacter strains resistant to ciprofloxacin is shown in figure 1. very high levels of resistance to the current antibiotics ampicillin (94%) and trimethoprim-sulfamethoxazole fluroquinolone resistance in trus bx of prostate-hasanzadeh et al. antibiotic susceptible (%) ampicillin 0 levofloxacin 5.9 cotrimoxazolea 17.64 amoxicillin-clavulanate 23.52 cefazolin 41.17 ceftazidime 52.94 cefepime 64.70 gentamicin 64.70 piperacillin-tazobactam 82.35 nitrofurantoin 88.23 amikacin 100 fosfomycin 100 imipenem 100 table 3. sensitivities of e. coli and citrobacter spp. to antibiotics in 17 samples (14 urine, 3 blood) atrimethoprim/sulfamethoxazole. figure 1. resistance pattern for fluoroquinolone resistant bacteria miscellaneous 3087 (89.5%) were observed. high resistance to cephalosporin generations (36.8% to 52.6%) was significantly different. however, resistance to fosfomycin and imipenem had remained very low (5.3% and 0%, respectively). on the other hand, despite the high-level resistance to gentamicin and amoxicillin/clavulanic acid (63.2% and 36.8%, respectively), piperacillin–tazobactam and amikacin resistance remained low (10.5%). risk factors for fq-resistant rectal carriage table 1 shows the relationship between potential independent risk factors and fqr rectal carriage bacteria according to the univariate analysis. patient characteristics that conferred an increased risk of fqr rectal carriage on univariate regression included: (i) a history of hospitalization in the last year (or, 11.03; 95% ci, 3.13-38.86; p < .001), (ii) the use of fq in the last 6 months (or, 3.38; 95% ci, 1.7-6.71; p < .001), (iii) a history of uti (or, 2.03; 95% ci, 1.01-4.09; p = .044) and prostatitis (or, 11.03; 95% ci, 1.49-8.85; p =.003) in the last 4 months, (2) previous biopsy (or, 3.47; 95% ci, 1.47-8.19; p = .003), and (v) aging (or, 1.052; 95% ci, 1.002-1.102; p = .014). the multivariate analysis using logistic regression (the enter method) was used to confirm and predict the independent effects of these variables on carrying of bacteria resistant to fq (table 2). in this analysis, the use of fqs in the last 6 months (or, 2.54; 95% ci, 1.17-5.49; p = .019), and a history of hospitalization in the last year (or, 7.85; 95% ci, 2.075-29.744; p = .002) could predict the fqr carriage aging, as a potential independent factor in the univariate analysis, increased the fqr carriage, but it was not statistically significant according to the multivariate analysis (or, 1.043; 95% ci, .998-1.090; p = .062). on the other hand, in the univariate analysis, no association was found among the other risk factors such as psa, prostate volume, blood pressure, diabetes mellitus, enema, frequent urination, and smoking with increased fqr carriage. outcome of patients with post-biopsy infection (pbi): post-biopsy infection (pbi) was observed in 12.5% (n = 20) of our study population. of these 20 patients, 14 (70%) had a positive culture (14 urine and 3 blood samples), that e.coli was identified in 13 (93%) patients and citrobacter in 1 (7%). almost all the patients had been infected with fq-r bacteria. however, a patient was coinfected with both a fluoroquinolone-resistant and an fq-sensitive e. coli isolates. of 20 patients with pbi, 17 (85%) had pre-biopsy rectal cultures and the remaining 3 (15%) did not. so, the risk of pbi was higher among intestinal carriers of fluoroquinolone resistant bacteria compared with noncarriers; the difference was statistically significant (17/73 [24%] versus 3/85 [3.5%]; p < .001). at the end, seven patients (4.43%) of the study population were admitted to hospital with severe pbi. the antibiotic susceptibility patterns of bacteria isolated from patients with pbi are presented in table 3. according to the obtained results, despite the high resistance of clinical isolates to ampicillin, levofloxacin, and trimethoprim-sulfamethoxazole, resistance to imipenem, amikacin, and fosfomycin was not found. according to the univariate and multivariate analyses, the risk of infection was high in patients with positive cultures resistant to fqs before biopsy (or, 4.73; 95% ci, 1.115-20.061; p = .03). discussion prostate biopsy is considered as a standard method in the diagnosis of prostate cancer. thus, millions of people around the world are evaluated annually by this method(3). the aua and eau recommend the use of a fq as an antimicrobial prophylaxis before the trusbx procedure(8,9). however, some risks such as infections after the procedure threaten the health of relevant patients. initially, pbi was reported less than 1%, but several studies in recent years have confirmed increased pbi frequency after the trus-bx procedure(10,15). carigan et al. reported that the rate of pbi has increased from 0.52% between 2002 and 2009 to 2.15% between 2010 and 2011(16). previous studies have shown that fq resistance in the rectal carriage and the presence of risk factors in the patients are the main reasons for the increased rate of pbi(17,18). the present study that was conducted for the first time in iran investigated the prevalence of fqr bacteria carriage in the patients undergoing trus-bx and the rates of pbi along with the assessment of the presence of risk factors. numerous studies have been reported an increasing rate of fqr bacteria in the rectal carriage, ranging from 10% to 32.6% (12,19-21). in our study, the rate of fqr rectal gram-negative bacteria was 46.2%, which was higher than those in previous studies. nevertheless, other similar studies from east asia confirmed our findings (22). it seems that the asian race, taking antibiotics without prescription, particularly the middle east countries, as well as other risk factors in patients undergoing biopsy are the main reasons for the presence of fqr bacteria in the rectum. several studies have been conducted to investigate the relationship between the risk factors and the fqr bacteria in rectum (23,24). in the studies of sternest et al. and liss et al., the previous use of the fq has been identified as an important risk factor (12,19). using multivariate statistical analysis, taylor et al., showed that there is independent correlation between the previous use of the fq and occurrence of uti in the last 3 months and the fqr bacteria carriage (21). however, in our results, in addition to the previous use of the fq, it was found that the histories of patients’ hospitalization also played an important role in this independent relationship, which can predict the fqr bacteria carriage in the rectum. on the other hand, duplesis et al. showed aging as a predictor of the fqr bacteria carriage in intestinal normal flora(25), whereas our findings have shown this correlation as a trend close to significance (p = .062). it seems that aging and hospitalization raise the chance of encountering of the patients with antibiotics and the fqr bacteria carriage. the use of selective media containing ciprofloxacin to isolate fqr bacteria was the highlight of this study, which has also been mentioned in the study of liss et al.(12). we propose to use the enrichment media containing ciprofloxacin to isolate the fqr bacteria for saving the time and costs of testing with regard to the role of the fqr bacteria in pbi development. in general, the fq resistance in bacteria isolated from patients with pbi was 52% to 100% in previous studies that confirm our findings with 94.1% resistance to the fq after pbi (10,16,26). several studies have reported rates of pbi to range from 1% to 4% and even 9.3% in a study conducted by ashraf et al.(11,15), whereas the overall rate of pbi was 12.5% in our study, indicating a high rate of fluroquinolone resistance in trus bx of prostate-hasanzadeh et al. vol 14 no 03 may-june 2017 3088 infection. previous studies have shown that the rates of infectious complications in patients with fqr positive rectal cultures, who had used the fq as prophylaxis, were between 3.3% and 14.9%; whereas in the present study, the rate was 27.4%, which similar to the result obtained by minimida et al.(11). in a large-scale study involving canadian patients, nam et al. showed that the rate of postoperative hospitalization following trus-bx procedure increased from 1% in 1996 to 4.4% in 2005, which is consistent with our results (4.43%)(27). considering previous reports and our findings, increased fqr bacteria carriage and resulting infections in patients undergoing prostate biopsy is an undeniable fact; therefore, major measures should be considered to improve antibiotic prophylaxis. in our research, the fqr bacteria isolated from the rectum showed high-level resistance to ampicillin, cotrimoxazole, and amoxicillin/clavulanic acid, and this finding is in line with those of previous studies(12). however, the resistance to amikacin, nitrofurantoin, imipenem, and phosphomycin was at very low level, whereas the e. coli isolated from urine and blood samples were quite susceptible to imipenem, amikacin, and phosphomycin. in a study by volkan et al., phosphomycin was used as antibiotic prophylaxis before the trus-bx. according to their results, the rate of pbi had fallen sharply(28). this work confirms our findings with regard to the high sensitivity of fqr e. coli to phosphomycin. given the increasing rate of resistant e. coli isolates carried in the rectum and increased rate of pbi, we suggest that the empirical usage of fqs is associated with an inappropriate antibiotic prophylaxis. based on the present findings, we suggest to reduce the pbi as follows: the use of prophylactic strengthening in which another antibiotic such as amikacin should be used in addition to fq; phosphomycin usage as monotherapy and also the use of targeted prophylaxis in which resistant bacteria carried by the rectal swab culture of patients should be achieved one or more weeks prior to prostate biopsy, and appropriate prophylaxis could be selected for this purpose according to the antibiotic sensitivity pattern. this suggestions have other advantages, including saving medical expenses, reducing side effects of antibiotics used experimentally with the possibility of treatment failure, particularly in patients with prostate cancer. there were limitations in our study, such as the relatively small sample size as well as the unavailability of patient records in private clinics. therefore, a study with a larger sample size needs to be conducted in iran and the establishment of a shared information bank is required in the country. conclusions owing to the increased prevalence of the rectal fluoroquinolone-resistant bacteria carriage in patients undergoing trus-bx and increasing rates of pbi, an appropriate prophylaxis is necessary to reduce the infections in patients undergoing the biopsy. evaluation of risk factors can predict the presence of antibiotic-resistant bacteria carried. identification of antibiotic-resistant bacteria in the rectum along with their antibiotic susceptibility patterns is one of the strategies that could be useful factors in the determination of appropriate antibiotic therapy and targeted prophylaxis. acknowledgement this research was supported by the tehran university of medical sciences, tehran, iran (grant number: 28848). conflict of interest the authors report no conflict on interest. references 1. ferlay j, soerjomataram i, dikshit r, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer. 2015;136:e359-e86. 2. tal r, livne pm, lask dm, baniel j. empirical management of urinary tract infections complicating transrectal ultrasound guided prostate biopsy. j urology. 2003;169:1762-5. 3. loeb s, carter hb, berndt si, ricker w, schaeffer em. complications after prostate biopsy: data from seer-medicare. j urology. 2011;186:1830-4. 4. otrock zk, oghlakian go, salamoun mm, haddad m, bizri ar. incidence of urinary tract infection following transrectal ultrasound guided prostate biopsy at a tertiary-care medical center in lebanon. infect control hosp epidemiol. 2004;25:873-7. 5. djavan b, waldert m, zlotta a, et al. safety and morbidity of first and repeat transrectal ultrasound guided prostate needle biopsies: results of a prospective european prostate cancer detection study. j urology. 2001;166:856-60. 6. young jl, liss ma, szabo rj. sepsis due to fluoroquinolone-resistant escherichia coli after transrectal ultrasound-guided prostate needle biopsy. urology. 2009;74:332-8. 7. lange d, zappavigna c, hamidizadeh r, goldenberg sl, paterson rf, chew bh. bacterial sepsis after prostate biopsy—a new perspective. urology. 2009;74:1200-5. 8. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent—update 2013. european urology. 2014;65:124-37. 9. wolf a, wender rc, etzioni rb, et al. american cancer society guideline for the early detection of prostate cancer: update 2010. ca: a cancer journal for clinicians. 2010;60:70-98. 10. zaytoun om, vargo eh, rajan r, berglund r, gordon s, jones js. emergence of fluoroquinolone-resistant escherichia coli as cause of postprostate biopsy infection: implications for prophylaxis and treatment. urology. 2011;77:1035-41. 11. minamida s, satoh t, tabata k, et al. prevalence of fluoroquinolone-resistant escherichia coli before and incidence of acute fluroquinolone resistance in trus bx of prostate-hasanzadeh et al. miscellaneous 3089 bacterial prostatitis after prostate biopsy. urology. 2011;78:1235-9. 12. liss ma, chang a, santos r, et al. prevalence and significance of fluoroquinolone resistant escherichia coli in patients undergoing transrectal ultrasound guided prostate needle biopsy. j urology. 2011;185:1283-8. 13. liss ma, peterson em, johnston b, osann k, johnson jr. prevalence of st131 among fluoroquinolone-resistant escherichia coli obtained from rectal swabs before transrectal prostate biopsy. urology. 2013;81:548-56. 14. [no authorlisted]. clinical and laboratory standards institute (clsi). performance standards for antimicrobial susceptibility testing; twenty-fifth informational supplement m100-s26. clsi, wayne, pa;2016. 15. mosharafa aa, torky mh, el said wm, meshref a. rising incidence of acute prostatitis following prostate biopsy: fluoroquinolone resistance and exposure is a significant risk factor. urology. 2011;78:511-4. 16. carignan a, roussy jf, lapointe v, valiquette l, sabbagh r, pépin j. increasing risk of infectious complications after transrectal ultrasound–guided prostate biopsies: time to reassess antimicrobial prophylaxis? eur urol. 2012;62:453-9. 17. liss ma, taylor sa, batura d, et al. fluoroquinolone resistant rectal colonization predicts risk of infectious complications after transrectal prostate biopsy. j urology. 2014;192:1673-8. 18. williamson da, barrett lk, rogers ba, freeman jt, hadway p, paterson dl. infectious complications following transrectal ultrasound–guided prostate biopsy: new challenges in the era of multidrug-resistant escherichia coli. clin infect dis. 2013;57:26774. 19. steensels d, slabbaert k, de wever l, vermeersch p, van poppel h, verhaegen j. fluoroquinolone‐resistant e. coli in intestinal flora of patients undergoing transrectal ultrasound‐guided prostate biopsy—should we reassess our practices for antibiotic prophylaxis? clin microbiol infect. 2012;18:575-81. 20. batura d, rao gg, nielsen pb. prevalence of antimicrobial resistance in intestinal flora of patients undergoing prostatic biopsy: implications for prophylaxis and treatment of infections after biopsy. bju int. 2010;106:1017-20. 21. taylor s, margolick j, abughosh z, et al. ciprofloxacin resistance in the faecal carriage of patients undergoing transrectal ultrasound guided prostate biopsy. bju int. 2013;111:946-53. 22. tsu jh-l, ma w-k, chan wk-w, et al. prevalence and predictive factors of harboring fluoroquinolone-resistant and extended-spectrum ⃰-lactamase–producing rectal flora in hong kong chinese men undergoing transrectal ultrasound-guided prostate biopsy. urology. 2015;85:15-22. 23. kim sh, ha u-s, yoon bi, et al. microbiological and clinical characteristics in acute bacterial prostatitis according to lower urinary tract manipulation procedure. j infect chemother. 2014;20:38-42. 24. dai j, leone a, mermel l, et al. rectal swab culture–directed antimicrobial prophylaxis for prostate biopsy and risk of postprocedure infection: a cohort study. urology. 2015;85:814. 25. duplessis ca, bavaro m, simons mp, et al. rectal cultures before transrectal ultrasoundguided prostate biopsy reduce post-prostatic biopsy infection rates. urology. 2012;79:55663. 26. shigehara k, miyagi t, nakashima t, shimamura m. acute bacterial prostatitis after transrectal prostate needle biopsy: clinical analysis. j infect chemother. 2008;14:40-3. 27. nam rk, saskin r, lee y, et al. increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. j urology. 2010;183:963-9. 28. sen v, aydogdu o, bozkurt ih, et al. the use of prophylactic single-dose fosfomycin in patients who undergo transrectal ultrasoundguided prostate biopsy: a prospective, randomized, and controlled clinical study. can urol assoc j. 2015;9:e863. fluroquinolone resistance in trus bx of prostate-hasanzadeh et al. vol 14 no 03 may-june 2017 3090 urological oncology 189urology journal vol 6 no 3 summer 2009 predicting recurrence and progression in non-muscleinvasive bladder cancer using european organization of research and treatment of cancer risk tables m hammad ather, masooma zaidi introduction: we determined the recurrence and progression at 1 year in patients with non-muscle-invasive urothelial carcinoma who underwent transurethral resection of bladder tumor (turbt) and compared those with the calculated risk according to the european organization of research and treatment of cancer (eortc). materials and methods: follow-up data of 92 patients with non-muscleinvasive bladder cancer who underwent turbt were reviewed, and their 1st year recurrence and progression were recorded. the risk of recurrence and progression were calculated for 1 year according to the eortc scoring system, using tumors’ stage, grade, size, and multiplicity, and the presence of carcinoma in situ and previous recurrence episodes. the outcomes were compared with the eortc’s predictive scores. results: the patients were 75 men and 17 women with an age range of 31 to 91 years. sixteen patients (17.4%) had a recurrent disease, 41 (44.6%) had a tumor larger than 3 cm in diameter, 35 (38.0%) had multiple lesions, 2 (2.2%) had carcinoma in situ, 73 (79.3%) had stage t1 lesions, and 8 (8.7%) had a high-grade disease. recurrence was found in 34 patients (37.0%). the recurrence rates were 20.0%, 28.2%, 40.5%, and 83.3% in groups with the predicted eortc risks of 15%, 24%, 38%, and 61%, respectively. there were 2 patients (2.2%) with progression of the diseases. conclusion: a significant concordance was noted between the eortc’s predicted risk and the actuarial recurrence rate of stage ta t1 bladder cancer at 1 year. progression was less than that predicted, probably due to our small sample size. urol j. 2009;6:189-93. www.uj.unrc.ir keywords: urinary bladder neoplasms, disease progression, neoplasm recurrence, risk department of surgery, aga khan university, karachi, pakistan corresponding author: m hammad ather, fcps (urol), febu dept of surgery, po box 3500, stadium road, karachi 74800, pakistan tel: +92 21 486 4778 fax: +92 21 493 4294 e-mail: hammad.ather@aku.edu received january 2009 accepted may 2009 introduction bladder carcinoma is the most common malignancy of the urinary tract.(1) data from tumor registry data analysis of the armed forces institute of pathology, in rawalpindi, pakistan, showed that bladder cancer was the 5th most common cancer in men during a period between 1992 and 2001.(2) in a minimal cancer incidence data for karachi, the largest city of pakistan, for the years 1998 and 1999 indicate that tobacco-associated cancers in karachi were responsible for 38.3% of the tumors diagnosed amongst the men.(3) approximately 75% to 85% of patients with bladder cancer present with the disease confined to the mucosa (stage ta and carcinoma in situ) or submucosa (stage t1) with various grades of recurrence and progression in bladder cancer—ather and zaidi 190 urology journal vol 6 no 3 summer 2009 differentiation.(4) non-muscle-invasive urothelial cell carcinoma of the bladder (ucc) accounts for about 80% of all the newly diagnosed cancers. (1) transurethral resection of the bladder tumor (turbt) is the gold standard for diagnosis and treatment. reported recurrence after turbt is about 30% to 70%.(1) the classic way to categorize patients with stage ta and stage t1 tumors is to divide them into risk groups based on prognostic factors derived from multivariate analyses. using such a technique, it was proposed to divide patients into low-risk, intermediate-risk, and high-risk groups.(5) when using these risk groups, however, no difference is usually made between the risk of recurrence and progression. although prognostic factors may indicate a high risk of recurrence, the risk of progression may still be low and other tumors may have a high risk of both recurrence and progression. in order to separately predict the short-term and long-term risks of both recurrence and progression in individual patients, the european organization for research and treatment of cancer (eortc) developed a scoring system and risk tables.(6) the scores can be calculated for each patient according to the eortc recurrence and progression predictor table and percentage risk calculated. we undertook this study to validate the scoring system on our patients with non-muscle-invasive ucc. our aim was to compare the predicted (eortc model) versus actual recurrence rate, without taking into consideration the maintenance therapy. materials and methods patients this retrospective study was conducted on the records at a university hospital between march 1998 and december 2007, and 178 patients with non-muscle-invasive bladder cancer were evaluated. they were treated with turbt and diagnosed with stage ta or stage t1 transitional cell carcinoma (tcc) of the bladder based on the 2002 american joint committee on cancer tnm staging system.(7) the grades were determined using the 1973 world health organization system. patients with a history of muscle-invasive bladder cancer treated with a bladder-sparing protocol, non-tcc histology, primary carcinoma in situ, or a follow-up duration of less than 12 months were excluded. after exclusions, 92 patients were enrolled in this study. follow-up follow-up cystoscopies were done every 3 months for the first 2 years in all of the patients, followed by a protocol dictated by the risk stratification. after 2 years, the follow-up cystoscopies were done yearly for 5 years in low-risk patients. in high-risk patients, cystoscopies were done every 4 months during the 3rd year, and every 6 months during the 4th and 5th years. prior to each followup cystoscopy, 2 free voided urine cytology tests were performed in order to determine the need for random biopsy. we collected the clinical and pathological data, including sex, age, tumor size (< 3 cm or ≥ 3 cm), multiplicity (single or multiple), t category (ta or t1), tumor grade, presence of concomitant carcinoma in situ or squamous differentiation, and intra vesical therapy (single instillation following turbt and maintenance). follow-up data were also obtained, including pathologically proven recurrence and time to the first recurrence, which was defined as the time period between the date of initial diagnosis and the date of recurrence. all pathological specimens were routinely assessed in the pathology department. pathologists were not blinded to the results of initial pathology report or patients’ clinical findings. patients who were still alive or who had died before a recurrence were considered as censored at the date of the last available follow-up cystoscopy. european organization for research and treatment of cancer scoring scores of progression and recurrence risks at 1 year were calculated for each patient according to the eortc (available from: http://www. eortc.be/tools/bladdercalculator/).(8) we assessed the impact of various clinical and pathological features on the outcome of the 1st year. intravesical single instillation of chemotherapy (mitomycin c, 40 mg) was given to all patients recurrence and progression in bladder cancer—ather and zaidi urology journal vol 6 no 3 summer 2009 191 following initial transurethral resection. maintenance intravesical treatment (either with mitomycin c or bacillus calmette-guerin) was given to the patients with intermediate or high risk of progression. in accordance with the eortc model, the impact of either single instillation of chemotherapeutic agents following turbt, maintenance intravesical chemotherapy, and immunotherapy were not specifically assessed. the provided software implements the eortc scoring system and risk tables for stage ta t1 bladder cancer based on the data published by sylvester and colleagues.(6) they allow the user to estimate the probability of recurrence and progression in patients with stages ta and t1 bladder cancer based on 6 different factors: number of tumors , tumor size, prior recurrence rate, t category, concomitant carcinoma in situ, and grade. the endpoint was comparison of predicted versus actual recurrence, irrespective of the intravesical maintenance therapy. results the median age of the patients was 56 years (range, 31 to 91 years), and their median follow-up duration was 38 months (range, 12 to 101 months). they were 75 men (81.5%) and 17 women (18.5%). seventy-one patients presented with hematuria (77.2%), 15 with lower urinary tract symptoms (16.3%), and 6 with a combination of these symptoms (6.5%). tumor characteristics, including primary or recurrent, size, number, and pathological characteristics are summarized in table 1. after 1 year, there were 34 patients (37.0%) with recurrence of the tumor. the recurrence rates after 1 year are listed and compared with the predicted eortc risks in table 2. progression of the cancer was seen in 2 patients (2.2%) during the first postoperative year. the predicted risks of progression by the eortc in comparison with the progression cases are summarized in table 3. discussion the clinical management of non-muscle-invasive ucc is challenging, as it has a marked tendency to recur and to progress. these recurrences are most frequent in the first 3 years, but sometimes are seen even after long periods of dormancy.(9) regular urological follow-up assessments should be continued until at least 15 years of tumorfree status, especially in patients treated with intravesical chemotherapy or in those initially having multiple tumors. prediction of progression is made by various tumor characteristics such as tumor size, number of tumors, prior recurrence, and grade and stage of the disease. these factors are incorporated in the eortc’s developed a risk scoring system.(6) scores were calculated for each patient according to the eortc recurrence characteristics value (%) bladder tumor primary 76 (82.6) recurrent 16 (17.4) tumor size, cm < 3 51 (55.4) ≥ 3 41 (44.6) number of tumors 1 57 (62.0) 2 to 7 28 (30.4) ≥ 8 7 (7.6) concomitant carcinoma in situ 2 (2.2) tumor stage ta 19 (20.6) t1 73 (79.3) tumor grade 1 46 (50.0) 2 38 (41.3) 3 8 (8.7) table1. bladder tumor characteristics eortc’s recurrence prediction (score) patients recurrence after 1 year (%) 15% risk (0) 5 1 (20.0) 24% risk (1 to 4) 39 11 (28.2) 38% risk (5 to 9) 42 17 (40.5) 61% risk (10 to 17) 6 5 (83.3) table 2. predicted versus actual 1-year recurrence rate* *prediction scores were calculated according to the european organization for research and treatment of cancer (eortc). eortc’s progression prediction (score) patients progression after 1 year (%) 0.2% risk (0) 5 0 1% risk (1 to 6) 33 1 (3.0) 5% risk (7 to 13) 51 1 (1.9) 17% risk (14 to 23) 3 0 table 3. predicted versus actual 1-year progression rate* *prediction scores were calculated according to the european organization for research and treatment of cancer (eortc). recurrence and progression in bladder cancer—ather and zaidi 192 urology journal vol 6 no 3 summer 2009 and progression predictor table and percentage risk. however, sometimes patients with nonmuscle-invasive ucc are often observed without progression in the long-term follow-up period, although many of them experience recurrence of the disease. it is difficult to accurately predict the disease outcome of each patient with conventional prognostic criteria. in such situation, fujikawa and colleagues(10) proposed that the use of the artificial neural network has a potential to improve the prediction. they noted that long-term progressionfree survival of patients with noninvasive tcc of the urinary bladder can be precisely predicted using the artificial neural network, which would be one of the criteria for making decision about immediate or future total cystectomy. the use of molecular markers and gene expression profiling provides a promising approach for improving the predictive accuracy of current prognostic indexes for predicting progression. in order to establish prognostic factors of recurrence and progression in stage t1 tcc, paying special attention to prognostic value of p53 and ki67 is suggested by some authors. a group from spain(11) noted that solid microscopic pattern and p53 expression are the variables which best predict progression. a positive relationship was observed between p53 and progression: the greater the expression of p53, the greater the progression. tumor multifocality and ki67 expression of greater than 27% are the main prognostic factors for recurrence.(11) galectin-3 is a glycoprotein involved in various physiological cellular processes. altered expression or loss of function of galectin-3 is suggested to be involved in the pathogenesis and further progression of various human cancer entities. kramer and colleagues(12) studied the role of galectin-3 in the development and/or progression of nonmuscle-invasive (pta, pt1) tcc of the bladder. they noted that loss of galectin-3 appeared to be involved in the carcinogenesis of tcc and to serve as a valuable biological variable to identify a subgroup of patients with stage ta bladder cancer at a high risk of the development of recurrent disease. baak and colleagues(13) studied the predictive value for recurrence and stage progression of dna ploidy and s-phase fraction by flow cytometry and highly automated ultrafast image cytometry in biopsies of stages ta and t1 uccs of the bladder. they observed that dna image cytometric features predicted recurrence and stage progression more accurately than classic prognostic factors, independent of treatment modality. the clinical significance of various molecular markers in predicting prognosis is still being debated. current recommendations of the european association of urology guidelines(14) are to use eortc risk calculator incorporating. conclusion the current work showed that the recurrence rates were found to be similar as compared to the eortc model. progression rates were found to be less than that predicted by the scoring system, most likely because of the limitations in this study, including the small sample size. we propose validation of eortc table in a larger cohort for its global applicability. conflict of interest none declared. references 1. ferlay j, bray f, pisani p, parkin dm. globcan 2002, cancer incidence, mortality and prevalence worldwide, iarc cancerbase no 5, version 2.0. lyon: iarcc press; 2004. 2. jamal s, moghal s, mamoon n, mushtaq s, luqman m, anwar m. the pattern of malignant tumours: tumour registry data analysis, afip, rawalpindi, pakistan (1992-2001). j pak med assoc. 2006;56:359-62. 3. bhurgri y, bhurgri a, hasan sh, et al. cancer patterns in karachi division (1998-1999). j pak med assoc. 2002;52:244-6. 4. heney nm, ahmed s, flanagan mj, et al. superficial bladder cancer: progression and recurrence. j urol. 1983;130:1083-6. 5. millan-rodriguez f, chechile-toniolo g, salvadorbayarri j, palou j, algaba f, vicente-rodriguez j. primary superficial bladder cancer risk groups according to progression, mortality and recurrence. j urol. 2000;164:680-4. 6. sylvester rj, van der meijden ap, oosterlinck w, et al. predicting recurrence and progression in individual patients with stage ta t1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials. eur urol. 2006;49:466-5. 7. greene fl, page dl, fleming id, et al. ajcc cancer staging manual. 6th ed. new york: springer verlag; 2002. recurrence and progression in bladder cancer—ather and zaidi urology journal vol 6 no 3 summer 2009 193 8. european organization for research and treatment of cancer [homepage on the internet]. eortc risk tables for predicting recurrence and progression in individual patients with stage ta t1 bladder cancer [cited 2009 aug 1]. available form: http://www.eortc.be/ tools/bladdercalculator/ 9. fujii y, fukui i, kihara k, tsujii t, kageyama y, oshima h. late recurrence and progression after a long tumorfree period in primary ta and t1 bladder cancer. eur urol. 1999;36:309-13. 10. fujikawa k, matsui y, kobayashi t, et al. predicting disease outcome of non-invasive transitional cell carcinoma of the urinary bladder using an artificial neural network model: results of patient follow-up for 15 years or longer. int j urol. 2003;10:149-52. 11. rodriguez alonso a, pita fernandez s, gonzalezcarrero j, nogueira march jl. [multivariate analysis of recurrence and progression in stage t1 transitionalcell carcinoma of the bladder. prognostic value of p53 and ki67]. actas urol esp. 2003;27:132-41. spanish. 12. kramer mw, kuczyk ma, hennenlotter j, et al. decreased expression of galectin-3 predicts tumour recurrence in pta bladder cancer. oncol rep. 2008;20:1403-8. 13. baak jp, bol mg, van diermen b, janssen ea, buhrwildhagen sb, mestad o, øgreid p, kjellevold kh. dna cytometric features in biopsies of tat1 urothelial cell cancer predict recurrence and stage progression more accurately than stage, grade, or treatment modality. urology. 2003;61:1266-72. 14. babjuk m, oosterlinck w, sylvester r, kaasinen e, bohle a, palou j. guidelines on tat1 (non-muscle invasive) bladder cancer. arnhem (the netherlands): european association of urology (eau); 2008. pediatric urology predictivity of clinical findings and doppler ultrasound in pediatric acute scrotum. riccardo lemini1, riccardo guanà1*, nicola tommasoni1, alessandro mussa2, gianpaolo di rosa3, jurgen schleef1 purpose: to evaluate the role of doppler ultrasonography (dus) in diagnosing pediatric testicular torsion (tt), and its diagnostic accuracy, and helping clinicians increase specificity and decrease negative exploration rates. materials and methods: we performed a retrospective study of all consecutive patients with acute testicular symptoms referring to our pediatric emergency department (ed) from january 2010 to december 2013. results: we analyzed 1091 patients, with a mean age of 9 years. dus was performed in 498 patients (40.8%); 107 patients (8.8%) underwent surgery and 41 patients (3.3%) had a tt. the following clinical findings were collected: presence of scrotal pain, erythema and swelling, spermatic cord pain and abnormal cremasteric reflex. the clinical findings significantly associated with tt were spermatic cord pain (or = 37, 95% ci: 11.9-111.1, p < .001) and abnormal cremasteric reflex (or = 47.6, 95% ci: 13.5-166.6, p < .001); the presence of swelling was not associated with tt (or = 2.3, 95% ci: 0.7-8.4, p < .001). scrotal pain was not significantly associated with tt (p = .9), while erythema made tt unlikely (or = 0.22, 95% ci: 0.07-0.7, p = .0445). in all cases the dus significantly increased the predictivity. conclusion: tt was present in 3.3% of patients presenting with testicular symptoms. the predictivity based on clinical findings resulted high and the negative exploration rate for tt was 62%. dus increased the predictivity in all patients. keywords: acute scrotum; children; testicular torsion; ultrasonography; pediatric surgery introduction acute scrotum in the pediatric population is defined by the sudden onset of scrotal pain, erythema and swelling. acute scrotum may become a surgical emergency, since it can lead to the loss of the affected testicle, especially when a failure in diagnosing and an erroneous management occur. despite the presence of recent guidelines(1), the management of acute scrotum is not uniform world-wide. in many institutions an immediate surgical exploration is performed in all males presenting with acute scrotum, in order to save the highest number of testicles; however other institutions use a more conservative approach, unless testicular torsion is evident(2-4). the main causes of acute scrotum in pediatric age are testicular torsion (tt), torsion of the appendage of the testis (tat) and epididymo-orchitis (eo). the annual incidence of tt is 1:4000 in males aged under 18 which accounts for 5-25% of acute scrotum in children. furthermore, the bimodal distribution of tt, with peaks in the perinatal period and in adolescence, reflects the distinction between the extravaginal and the intravaginal torsion, which are respectively typical of newborns and older children. anamnestic data and clinical findings are the corner1 department of pediatric general, thoracic and minimally invasive surgery, regina margherita children's hospital, torino, italy. 2 department of public health and pediatric sciences, university of torino, torino, italy. 3 division of pediatric radiology, regina margherita children’s hospital, torino, italy. *correspondence: department of pediatric general, thoracic and minimally invasive surgery, regina margherita children's hospital – turin, italy. tel: +39 0113135276. fax: + 39 0113135660.e-mail: riccardoguan@gmail.com. received january 2016 & accepted june 2016 stones to diagnose acute scrotum. thus many studies have been performed in order to achieve clinical scores that could help surgeons in diagnosis and treatment(5-7). typically, tt presents with a sudden onset of severe pain followed by scrotal and inguinal swelling. often, a high riding testis, which can also lie transversely, is found. the absence of cremasteric reflex is one of the most consistent findings that supports the diagnosis of tt(2,8,9). an increased incidence of tt has been also associated with seasonal variations and lower temperatures(10,11). in addition to clinical examination, doppler ultrasonography (dus) has been progressively used in tt diagnostic management. it can provide very good and useful information about anatomy and perfusion, with a reported sensitivity of 64-91% and specificity of 97-100%(1,12). dus has become the standard imaging method in acute scrotum management, because of its wide availability, easy performance, non-invasiveness and low costs. however, it is limited by high operator dependency and non-negligible number of false-negative results that may lead to loss of the testicle. the aim of the present study was to identify reliable clinical findings associated with tt and to evaluate the role of testicular dus in diagnosing pediatric testicular torsion, under the aspect of diagnostic accuracy pediatric urology 2779 vol 13 no 04 july-august 2016 2780 and improvement, with an aim to achieve specificity increase and decrease in negative exploration rates. patients and methods study population and inclusion criteria we performed a retrospective analysis of all consecutive patients with acute testicular symptoms presenting to the emergency department (ed) of our hospital from january 2010 to december 2013. patients were selected from the hospital database using icd 9th edition codes: eo (6040, 60490, 60499), tat (60823), tt (60820), testicular pain (6089). 1091 patients were included in the analysis, for a total of 1219 ed admissions. patients with a diagnosis of intrauterine testicular torsion, varicocele, hydrocele, and cryptorchidism were excluded from the study. procedures and evaluations data were collected using patient charts and operating room records. regarding medical history, data included the age of the patient, time of arrival at the ed, first evaluation (ed, another hospital, general practitioner), duration of symptoms, and history of possible trauma. all patients were physically examined by a pediatric surgeon, who evaluated erythema, swelling, spermatic cord pain and consistency, cremasteric reflex, and fever (t > 38°c). a reduced or absent cremasteric reflex was considered an abnormal finding. dus was performed by a pediatric radiologist using philips iu22 ultrasound machine (philips corporation, andover, ma, usa) adjusted and optimized for testicular structures; ultrasonography was performed with a 12.5 hz linear transducer. the scanning method consisted of the visualization of the scrotum and its contents with longitudinal and transverse axes. both testicles were scanned in order to provide a comparison of anatomy and blood flow. the entire testicle was evaluated from one extreme to another, then the scan was repeated after rotating the probe 90° to obtain a transverse image of the testicle. once the gray-scale imaging was complete, the power doppler examination was performed. power doppler and pulsed doppler parameters were optimized to adequately evaluate the blood flow in testicles and their adjacent structures. the color gain was calibrated carefully to avoid any artifactual appearance of flow. a diagnosis of tt was made in cases of uncertainty or absent central perfusion. all patients presenting with scrotal symptoms and a clinical or a dus suspicion for tt underwent surgical exploration. in tt cases, the testis was detorqued and placed in warm sponges for 15-20 minutes; if no sign of perfusion was observed, an orchiectomy was performed, then the surgeons proceeded with a contralateral orchiopexy using the three-stitch triangular technique with a reabsorbable suture. in case of a viable testis, it was fixed in with 3-4 stitches. statistical analysis statistical analysis was performed using the spss software version 15.0 (spss, inc, chicago, il). the difference between groups was calculated using the fisher's test and a binary logistic multivariate backward stepwise analysis with variable inclusion threshold p < .1, expressed as odds ratios (or) and 95% confidence intervals (ci). finally we calculated the r2 nagelkerke index in order to evaluate the predictivity of the model. results the data from 1091 patients were analyzed, but since 128 patients were visited twice, 1219 ed visits were included in the final analysis. the mean age of the study population was 9.1 years (range 6 months – 16 years). the reported symptoms and clinical findings of the study population are summarized in table 1. the mean time of presentation to the ed from the onset of symptoms was 21.49 hours (range 45 minutes – 72 hours). for patients who underwent surgery, the mean duration was 19.89 hours (range diagnostic management in pediatric acute scrotum-lemini et al. table 1. reported symptoms and clinical findings characteristic value percentage mean age (year) 9.11 side right 592 48.56% left 558 45.77% bilateral 69 5.67% trauma yes 74 6.07% no 1145 93.93% pain yes 1144 93.92% no 75 6.08% pain location diffuse 475 41.52% upper pole 31 2.71% lower pole 638 55.77% swelling yes 528 43.31% no 691 56.69% erythema yes 430 35.27% no 789 64.73% painful 50 4.10% spermatic cord thickened 4 0.33% thickened and painful 20 1.64% normal 1145 93.93% cremasteric reflex normal 1108 90.89% reduced 62 5.08% absent 49 4.03% fever (t > 38°c) yes 13 1.06% no 1206 98.94% abbreviations: t = temperature 45 minutes – 48 hours). however, once there was a suspicion of a tt, the mean time between the physical examination and the operation was 1.07 hours (range 30 minutes 2 hours and 15 minutes). diagnostic results were: tt in 41 patients (all by surgical exploration), tat in 323 (288 by clinical and dus examination, 35 by surgical exploration), eo in 506 (479 by clinical and dus examination, 27 by surgical exploration), and other pathological diagnosis in 349 patients (including trauma, not-otherwise-specified testicle pain, idiopathic scrotal edema, inguinoscrotal hernia; 345 by clinical and dus examination, 4 by surgical exploration). dus was performed in 498 patients (40.85%), whose reports were compatible with the following diagnoses: eo 279 (56.02%), tt 27 (5.42%), tat 41 (8.24%), normal 144 (28.92%), uncertain 5 (1%), hematoma 1 (0.20%), inguinoscrotal hernia 1 (0.20%). all 27 patients with a dus report compatible with tt underwent surgical exploration, however in 5 patients the diagnosis changed to a non-tt category (3 eo, 1 tat, 1 hematoma). of the 471 cases with dus reports compatible with nontt, 7 underwent surgical exploration due to a strong tt suspicion and the tt diagnosis was confirmed. surgical exploration was performed in 107 cases (8.77%) and the diagnosis of tt was confirmed in 41 patients (3.36%). orchiectomy rate was 14.02%. none of patients discharged from the ed returned with tt. the negative exploration rate was 62%. the overall sensitivity, specificity, positive predictive value (ppv), and diagnostic accuracy of both clinical and dus findings have been presented in table 3. then we analyzed the association between the presence of scrotal pain, erythema, swelling, spermatic cord pain and/or thickness, and abnormal cremasteric reflex. (table 3) a prior selection was made using fisher's test, then a multivariate analysis model was produced. the clinical findings associated with tt were spermatic cord pain and/or thickness (95% ci: 11.9-111.1, or = 37, p < .001), and abnormal cremasteric reflex (95% ci: 13.5-166.6, or = 47.6, p < .001). the presence of erythema resulted associated with non-tt (95% ci: 0.07-0.7, or = 0.22, p = .0445) while the presence of swelling was not associated with tt (95% ci: 0.7-8.4, or = 2.3, p < .001). the presence of pain was excluded from the analysis model because of its low statistical specific relevance (p = .9). furthermore, the presence of spermatic cord pain and/ or thickness (95% ci: 17.2-76.9, or = 37, p < .001), abnormal cremasteric reflex (95% ci: 5.3-18.2, or = 9.9, p < .001), and swelling (95% ci: 2.4-9.3, or = 4.6, p < .001) were associated with surgical indication. in the second analysis we added the “dus findings compatible with tt” to the model, in order to verify contingent differences in predictivity. the dus variable was strongly associated with tt (95% ci: 11.9250, or = 55.55, p < .001). finally we calculated the r2 nagelkerke index to evaluate the predictivity of the model. first only considering clinical findings, the r2 index was 0.649, then adding dus variable, it increased to 0.784. this means that the dus significantly increases the predictivity of acute scrotum diagnostic process. discussion children presenting at the ed with acute testicular symptoms require an immediate examination. the most frequent causes of acute scrotum are tt, eo, and tat. in this study, the incidence of tt cases was lower (3.36%) than in previous reports(6,13-16). this can be explained by the fact that the current study included all patients with acute testicular symptoms, even those without abnormalities on physical examination. the optimal diagnostic management of acute scrotum should identify patients who require an immediate surgical exploration, in order to recognize all tts and save the highest number of twisted testicles. in our study we focused on spermatic cord pain and/ or thickness, and abnormal cremasteric reflex. the presence of pain and/or thickness of the spermatic cord showed to be highly predictive of tt, but we could not find reports in literature that consider this finding in their analysis. the abnormality of the cremasteric reflex was also strongly associated with an increased likelihood of tt. this result is supported by other studies(13,16,17,19-21), even if some of them(13,22) found an abnormal cremasteric reflex in all patients with tt. in the present study, 4 of the 41 patients with tt had a preserved cremasteric reflex. this difference can be explained by the large study population (1091 patients), in fact the previous series involved a smaller number of patients. moreover, a similar result can be found in recent reports(17,18). the presence of at least one of these findings should induce the suspicion of tt in children presenting at ed with acute testicular symptoms, in fact all patients with tt showed at least one of them. furthermore, no tt was found in patients without either finding. our negative exploration rate was of 62%, lower than in the known literature(17,18). the implementation of this approach would have further decreased it by 28%. the presence of erythema makes tt unlikely, as it is reported in several studies(17,18,23). the presence of swelling resulted slightly, but not significantly, associated with tt(19,23). the presence of pain was not statistically significant, because it is a common symptom of all causes of acute scrotum. however many studies demonstrated the association of a pain dutable 2: sensitivity, specificity, positive predictive value and diagnostic accuracy of clinical data and doppler ultrasonography in diagnosis of testicular torsion. clinical dus sensitivity 94.11% 75.86% specificity 95.37% 98.93% positive predictive value 47.05% 81.48% diagnostic accuracy 95.32% 97.59% abbreviations: dus, doppler ultrasonography table 3: analyzed clinical and dus findings or 95% ci erythema 0.22 0.07-0.7 swelling 2.3 0.7-8.4 spermatic cord pain/thickness 37 11.9-111.1 abnormal cremasteric reflex 47.6 13.5-166.6 abbreviations: dus = doppler ultrasonography, or = odd ratio, ci = confidence interval diagnostic management in pediatric acute scrotum-lemini et al. pediatric urology 2781 vol 13 no 04 july-august 2016 2782 ration lower than 24 hours, with tt(2,17,18,20,22,24). in the last few years, dus became an important part of the diagnostic process of acute scrotum, since it can evaluate the reduction/absence of central perfusion, it is a fast non-invasive procedure, and its costs are limited. however dus is highly operator dependent and in many institutions is not available during night hours. in the current study, we recorded a 75.86% sensitivity and a 98.93 specificity, similarly to what is written in international literature(25,26). from the statistical analysis, we found a strong association between dus findings and tt. nevertheless, dus cannot substitute the clinical examination, in fact 7 patients with tt had a preserved central perfusion. this circumstance occurred in other reports(2,17) as well and confirms our results. a limitation of the current study was that dus has been performed on 40.85% of patients, even if groups were statistically comparable. these results allow us to claim that clinical and dus findings must be enrolled together in order to increase the specificity, lowering the negative exploration rate and improving the model predictivity (r2 nagelkerke index: 0.649 → 0.784). thus we suggest to perform a dus before surgical exploration, unless either the suspicion of tt or the risk of a testicle loss are high. this approach is also consistent with other reports(17,27,28), even if there are studies that suggest an immediate surgical exploration in all patients with acute scrotum(4). conclusion acute scrotal symptoms are a common causes of presentation to a pediatric ed. tt incidence is low (3.36%). clinical findings show high sensitivity, but low specificity; thus there are no missed tt, but a high number of negative exploration. the spermatic cord pain and/or thickness and an abnormal cremasteric reflex are two essential findings to search for when diagnosing tt. the dus cannot replace the physical examination, but it is an actual aid for all cases of uncertain clinical suspicion. the ensemble of clinical and dus findings allow clinicians to improve diagnostic accuracy and specificity, and lower negative exploration rate. conflict of interest none declared. references 1. tekgul s, riedmiller h, gerharz e, et al. guidelines on paediatric urology. espu/ eau 2011. 2. yang c, song b, liu x, wei g, tan j, he d. acute scrotum in children. an 18-year retrospective study. pediatr emer care 2011; 27: 270-274. 3. cass as, cass bp, veeraraghavan k. immediate surgical esploration of the unilateral acute scrotum in young male subjects. j urol 1980; 124: 829-832. 4. murphy fl, fletcher l, please p. early scrotal exploration in all cases is the investigation and intervention of choice in the acute pediatric scrotum. pediatr surg int 2006; 22: 413-416. 5. gunther p, rubben i. the acute scrotum in childhood and adolescence. dtsch artebl int 2012; 109 (25): 449-58. doi: 10.3238/ arztebl.2012.0449. 6. mcandrew hf, pemperton r, kikiros cs, gollow i. the incidence and investigation of acute scrotal problems in children. pediatr surg int 2002;18: 435-437. 7. gunter p, schenk jp. testicular torsion: diagnosis, differential diagnosis and treatment in children. radiologe 2006; 46: 590-595 8. sharp vj, kieran k, arlen am. testicular torsion: diagnosis, evaluation and management. american family physician 2013; 88 (12): 835-840 9. caesar re, kaplan gw. the incidence of the cremasteric reflex in normal boys. j urol 1994; 152: 779-780. 10. srinivasan ak, freyle j, gitlin js, palmer ls. climatic conditions and the risk of testicular torsion in adolescent males. j urol 2007; 178: 2585-2588. 11. korkes f, cabral pr, alves cd, savioli ml, pompeo ac. testicular torsion and weather conditions: analysis of 21.289 cases in brazil. int braz j urol 2012; 38: 222-228. 12. gearhart jg. pediatric urology. sauders 2010; 42: 555-567. 13. kadish ha, bolte rg. a retrospective review of pediatric patients with epididymitis, testicular torsion, and torsion of testicular appendages. pediatrics 1998; 102, 73-76. 14. erikci vs, hosgor m, aksoy n, et al. treatment of acute scrotum in children: 5-years experience. turkish journal of trauma and emergency surgery 2013; 19: 333-336. 15. liang t, metcalfe p, sevcik w, noga m. retrospective review of diagnosis and treatment in children presenting to the pediatric department with acute scrotum. ajr am j rentgenol 2013; 200: 444-449. 16. van glabeke e, kairouni a, larroquet m, audry g, gruner m. acute scrotal pain in children: results of 543 surgical explorations. pediatr surg int 1999; 15: 353-357. 17. boettcher m, krebs t, bergholz r, wenke k, aronson d, reinshagen k. clinical and sonographic features predict testicular torsion in children: a prospective study. bju int 2013; 112: 1201-1206. 18. boettcher m, berghol r, krebs tf, wenke k, aronson dc. clinical predictors of testicular torsion in children. pediatric urology 2012; 79: 670-674. 19. beni-israel t, goldman m, bar chaim s, kozer e. clinical predictors for testicular torsion as seen in the pediatric ed. am j emerg med 2010; 28: 786-789. 20. ciftci ao, senocak me, tanyel fc, buyukpamukcu n. clinical predictors for differential diagnosis of acute scrotum. eur j pedriatr surg 2004; 14: 333-338. diagnostic management in pediatric acute scrotum-lemini et al. 21. kass ej, lundak b. the acute scrotum. pedriatr clin north am 1997; 44: 1251-1266. 22. rabinowitz r. the importance of the cremasteric reflex in acute scrotal swelling in children. j urol 1984; 132: 89-90. 23. karmazyn b, steinberg r, kornreich l, et al. clinical and sonographic criteria of acute scrotal problems in children: a retrospective study of 172 boys. pediatr radiol 2005; 35: 302-310. 24. jefferson rh, perez lm, joseph db. critical analysis of the clinical presentation of acute scrotum: a 9-year experience at a single institution. j urol 1997; 158: 1198-1200. 25. kalfa n, veyrac c, baud c, couture a, averous m, galifer rb. ultrasonography of the spermatic cord in children with testicular torsion: impact on the surgical strategy. j urol 2004; 172: 1692-1695. 26. baker la, singman d, mathews ri, benson j, docimo sg. an analysis of clinical outcomes using color doppler testicular ultrasound for testicular torsion. pediatrics 2000; 105: 604607. 27. jequier s, patriquin h, filiatrault d, et al. duplex doppler sonographic examinations of the tests in prepubertal boys. j ultrasound med 1993; 12: 317-322. 28. lam ww, yap tl, jacobsen as, teo hj. colour doppler ultrasonography replacing surgical exploration for acute scrotum: myth or reality? pediatr radiol 2005; 35: 597-600. diagnostic management in pediatric acute scrotum-lemini et al. pediatric urology 2783 case report robot assisted radical prostatectomy in a patient with previous abdominoperineal resection and pelvic external beam radiation therapy cem basatac*, haluk akpinar keywords: challenging conditions; prostate cancer; minimally invasive surgery; robot. though previous major abdominal surgery and pelvic irradiation may be a significant drawback of subsequent laparoscopic procedure, technological advances such as better visualization and more controlled finer movements of robotic arms allowing better dissection in robotic-assisted laparoscopic surgery may reduce some of these challenges. however, limited data are available on the effect and safety of robotic surgery in these patients. the aim of this case report is to present efficacy and safety of robot assisted radical prostatectomy in a patient who has rectal and concurrent prostate cancer with the history of abdominoperineal resection, pelvic irradiation and adjuvant chemotherapy. department of urology, istanbul bilim university, school of medicine, istanbul, turkey. *correspondence: istanbul bilim university, department of urology, istanbul/turkey phone: +90 (212) 213 64 86. facsimile number: +90 (212) 272 34 61. email: cembasatac@gmail.com. received march & accepted december 2017 introduction robotic assisted radical prostatectomy (rarp) has been recently introduced for the treatment of localized prostate cancer and rapidly gained acceptance in worldwide. many reports have been established that robotic surgery is not inferior when compared with other conventional approaches in terms of surgical, functional and oncologic outcomes(1-2). as with open radical prostatectomy, there are no anatomic contraindications for rarp. however, there are preoperatively identified factors considered as potentially challenging that have been described in the literature(3-5). the most important factors among these are previous pelvic external beam radiation therapy [ebrt] and major abdominal surgery. these factors can significantly affect operative outcomes because of severe adhesions and obliterated tissue plans. the aim of this case report is to present the advantages of rarp in patient with rectal and concurrent prostate cancer with the history of abdominoperineal resection (apr), ebrt and adjuvant chemotherapy. figure 1. ct-guided suprapubic biopsy was done due to closed anal verge secondary to previous surgery. case report 56 vol 15 no 03 may-june 2018 57 case report a 74-year-old male patient admitted to our hospital with elevated psa at 4.85ng/ml. in his past history, the patient had received apr, ebrt and adjuvant chemotherapy for rectal cancer at 2013. there were no findings suggestive of local recurrence and distance metastases of rectal cancer according to 18 fdg pet/ct imaging at the last follow up. a multiparametric magnetic resonance imaging showed multiple pi-rads 4 lesions involving both lobes of prostate but digital rectal examination and trus guided biopsy were not possible due to closed anal verge secondary to prior surgical resection. computerized tomography guided suprapubic biopsy revealed prostate adenocarcinoma with a gleason score of 4+4 (figure 1). definitive surgical treatment with robotic assistance was desired by the patient. therefore, we obtained informed consent in order to perform rarp. bowel preparation was done day before surgery and colostomy site was covered with lobantm film (3m, st, paul, mn) to prevent contamination. a 2 mm transvers skin incision was made 3 cm below from the left costal margin on the midclavicular line as the primary puncture site, known as palmer’s point. through this incision, a veress needle was inserted to create pneumoperitoneum. since high probability of the bowel injury due to intraperitoneal adhesions, first 5 mm trocar was inserted at the 3 cm below from the right costal margin on the midclavicular line. extensive intraperitoneal adhesions were completely removed from the surgical field and colostomy site by using with 4 mm laparoscopic scissor. afterwards, one 12 mm and three 8 mm trocars were inserted under direct vision. left 8 mm trocar was placed on 3 cm below and medial from the normal location due to end-colostomy and only one 12 mm assistant port was used since there was not enough space for other trocar (figure 2). total operation time and console time including bilateral lymph node dissection were measured as 181 and 135 minutes, respectively. blood loss was 150 ml. and no intraoperative complication was noted. however, length of stay was 8 days due to postoperative subileusthat resolved spontaneously. total urinary control was achieved at postoperative 3rd months. severe erectile dysfunction was observed since neurovascular bundles were not spared. psa values were measured at 3 and 6th months as < 0, 01 ng/ml and surgical margins were emphasized as negative. discussion previous major abdominal surgery and radiation therapy are not an absolute contraindication for rarp. however, these factors cause severe intestinal adhesions which may complicate port placement and require extensive surgical adhesiolysis. furthermore, radiation induced tissue adhesion can make the identification of the plans challenging especially during seminal vesicle and endopelvic fascia dissection. first radical retropubic prostatectomy series in the setting of previous pelvic radiation therapy for non-prostate malignancies was reported by materson et al. they were successful in doing rp in their 9 patients but higher rates of incontinence, voiding difficulty, bladder neck contracture and erectile dysfunction were reported(6). in addition to this, yang et al. compared surgical, oncologic and functional outcomes of laparoscopic radical prostatectomy (lrp) in patients with and without transurethral resection of prostate (tur-p). the authors concluded that lrp is feasible but challenging after tur-p with greater blood loss, longer operation times, higher complication rates and worst short term continence outcomes(7). robotic systems have several advantages over conventional laparoscopy in order to overcome some of these challenges. the advantages of robotic surgery like three-dimensional visualization, seven degree of freedom in movement and avoiding physiologic tremor can facilitate urethrovesical anastomosis and provide conveniences especially in the posterior dissection in the narrow small pelvis(8). during rarp in patients with previous major abdominal surgery, it is crucial to carried out a wide laparoscopic adhesiolysis before docking the robot since the position of the trocar sites cannot be changed without undocking the robot. boylu et al. reported a novel technique to lyse adhesions by using a teaching laparoscope with an offset eye piece and working channel to allow visualization of the operative field with concomitant passage of laparoscopic scissor(9). on the other hand, rajih et al. described a mini-laparotomy technique in order to lyse extensive peritoneal adhesions which facilitates subsequent minimally invasive surgery where laparoscopic adhesiolysis is difficult and unsafe. in this technique, a midline infraumblical incision was performed through a 7-10 cm and then, adhesions were divided sharply under direct vision(10). in the present case, we encountered severe and dense peritoneal adhesions due to previous apr with supra and infraumblical incision and ebrt. primarily, we chose palmer’s point in order to provide pneumoperitoneum because an abdominopelvic ct demonstrated no evidence of suspicious bowel adhesions on the left upper quadrant(11). classic closed technique with veress needle was used in order to create pneumoperitoneum. afterwards, meticulous adhesiolysis was performed by using laparoscopic scissor via a 5 mm additional trocar inserted on the right figure 2. postoperative aspect of port placements. robotic radical prostatectomy under challenging conditions-cem et al. upper quadrant to subsequently allow safe placement of additional robotic trocars. the main challenge for rarp in patient with prior apr is the port site limitations due to the end-colostomy. robotic left working arm had to be placed 3 cm caudally and medially from the colostomy in order to keep enough distance between camera port and 12 mm assistant port. care should be taken not to injure bowel segments at this stage. therefore, peritoneal adhesions should be completely removed around the colostomy site so as to provide safe change of the robotic instruments, if needed. to the best of our knowledge, this is the second case report related to rarp in patient with the history of apr, ebrt and adjuvant chemotherapy. first case was reported at 2009 by ham et al.(12) yet, the authors distinctly used hasson technique to create pnömoperitoneum and fourth robotic arm was not placed due to inadequate surgical space. they also did not perform lnd because of severe adhesions secondary to prior surgery. on the final pathology of their case, surgical margin was negative and total urinary control was achieved at the first postoperative month. finally, the authors concluded that history of apr and ebrt are not contraindication for rarp although there is a technical difficulty. conclusions although it is seen as a challenging procedure due to severe adhesions, prior apr and ebrt should not be considered as a contraindication for rarp since robotic surgery provides many advantages to the surgeon such as tremor reduction and magnified three-dimensional visualization that affect directly to surgical outcomes. conflict of interest the authors report no conflict of interest. references 1. seo hj, lee nr, son sk, kim dk, rha kh, lee sh. comparison of robot-assisted radical prostatectomy and open radical prostatectomy outcomes: a systematic review and metaanalysis. yonsei med j. 2016; 57:1165-77. 2. allan c, ilic d. laparoscopic versus roboticassisted radical prostatectomy for the treatment of localised prostate cancer: a systematic review. urol int. 2016; 96:373-78. 3. parsons jk, jarrett tj, chow gk, kavoussi lr. the effect of previous abdominal surgery on urological laparoscopy. j urol. 2002; 168:2387-90. 4. vallancien g, gupta r, cathelineau x, baumert h, rozet f. initial results of salvage laparoscopic radical prostatectomy after radiation failure. j urol 2003; 170:1838-40. 5. hou gl, luo y, di jm, et al. predictors of urinary continence recovery after modified radical prostatectomy for clinically high-risk prostate cancer. urol j. 2015;12:2021-27. 6. masterson ta, wedmid a, sandhu js, eastham ja. outcomes after radical prostatectomy in men receiving previous pelvic radiation for non-prostate malignancies. bju int. 2009; 104:482-85. 7. yang y, luo y, hou gl, et al. laparoscopic radical prostatectomy after previous transurethral resection of the prostate in clinical t1a and t1b prostate cancer: a matched-pair analysis. urol j. 2015;12:215459. 8. khatlani k, sharma s, mendoza pj, lee di. the current state of robot assisted radical prostatectomy. minerva urol nefrol. 2010; 62:193-01. 9. boylu u, oommen m, raynor m, lee br, thomas r. robot-assisted laparoscopic radical prostatectomy in patients with previous abdominal surgery: a novel laparoscopic adhesiolysis technique. j endourol. 2010; 24:229-32. 10. rajih e, alhathal n, alenizi am, el-hakim a. feasibility of planned mini-laparotomy and adhesiolysis at the time of robotic-assisted radical prostatectomy in patients with prior major abdominal surgery. can urol assoc j. 2016; 10:125-29. 11. tüfek i, akpınar h, sevinç c, kural ar. primary left upper quadrant (palmer's point) access for laparoscopic radical prostatectomy. urol j. 2010; 7:152-56. 12. ham ws, kim sw, kim wt, park sy, choi yd. robotic prostatectomy in patient with an abdominoperineal resection. j laparoendosc adv surg tech a. 2009; 19:383-87. robotic radical prostatectomy under challenging conditions-cem et al. case report 58 laparoscopic urology minilaparoscopy versus standard laparoscopic donor nephrectomy: comparison of safety, efficacy and cosmetic outcomes in a randomized clinical trial. nasser simforoosh, seyed hossein hosseini sharifi, reza valipour, behzad narouie, mohammad reza kamranmanesh, mohammad hossein soltani* purpose: this study was conducted to compare safety, efficacy and cosmetic outcome between standard laparoscopic live donor nephrectomy (sldn) and minilaparoscopic donor nephrectomy (mldn) in a randomized clinical trial. materials and methods: from march 2012 to june 2013, 100 consecutive kidney donors were randomly assigned to two equal groups for laparoscopic donor nephrectomy. mldn: six to eight centimeters pfannenstiel incision was made slightly above pubis symphysis and 11 millimeters trocar was fixed through exposed fascia using open technique. five mm port was placed under direct vision at the umbilicus for camera insertion and two 3.5 mm ports were placed in subxiphoid and paraumbilical area. sldn: ten mm port was placed at umbilicus using open access technique for camera insertion. five mm trocar for grasping and 11 mm trocar for vascular clipping were placed at subxiphoid and paraumbilical areas under direct vision, respectively. the second 5 mm trocar was placed in suprapubic area. cosmetic appearance was assessed three months after surgery by using the patient scar assessment questionnaire (psaq). results: demographic data of the patients was not significantly different between two groups. total operative time and ischemic time was nearly similar in both groups (104 ± 21 vs. 114 ± 24 min; p = .327 and 4.03 vs. 4.07 min; p = .592). there were no cases of conversion to open surgery. mean hospital stay was similar between the two groups [2.1 (2-5) vs. 2.4 (2-5) days; p = .346]. kidney graft function assessed by serum creatinine values (mg/dl) of recipients, was equivalent in both groups (1.58 vs. 1.86: p = .206). mean appearance score (34 vs. 29) and consciousness score (22 vs. 18) in psaq showed significantly better results in the mldn group. conclusion: our experience in this study revealed that periand post-operative findings were comparable between sldn and mldn, but mldn has significant better cosmetic appearance than standard laparoscopic approach. keywords: nephrectomy; methods; adverse effects; laparoscopy; tissue and organ harvesting. introduction with increasing need and desire for kidney trans-plantation, waiting lists for cadaveric kidney donors continue to grow and live organ donation has gained much more attention. postoperative pain and morbidity and cosmetic issues maybe some of major disappointing factors for potential kidney donors, thus, every effort should be encouraged for reducing disinclination of living donors. laparoscopic donor nephrectomy (ldn) has grown to be the preferred surgical technique in most transplant centers after the first report by ratner and colleagues. (1,2) several studies showed that ldn is associated with less hospital stay, better cosmetic results and similar complications and long term graft survival compared to open donor nephrectomy.(3,4) laparoendoscopic single-site (less) donor nephrectomy is an evolving technique for retrieval of the kidney but with confounding effects on cosmetic results.(5) natural orifice transluminal endoscopic surgery (notes) has shown encouraging results but is applicable in minority of cases.(6) minilaparoscopic surgery is an attempt to perform a less invasive surgery and enhance cosmetic result of laparoscopic surgery. recently, we reported initial series of minilaparoscopic live donor nephrectomy (mldn)(7) and results of the aforementioned study encouraged us to compare results of minilaparoscopy with conventional ldn in a randomized trial study. materials and methods from march 2012 to june 2013, 100 consecutive kidney donors were randomly assigned to two equal groups for laparoscopic donor nephrectomy: standard ldn (sldn) and mldn. simple randomization method was used. all patients signed written informed consent before the study and the ethical committee of iranian urology and nephrology research center approved the study design. regarding the power factor of 80% for the study and 95% confidence level, a sample size of 100 cases was shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. tel: +98 21 2256 7282 & fax: +98 21 2256 7282. e-mail: mhsoltani60@gmail.com. received june 2015 & accepted august 2015. laparoscopic urology 2223 calculated. computed tomography (ct) angiography was performed in all donors preoperatively. donors with multiple renal arteries and right side donor nephrectomy were excluded from this study. high body mass index (bmi greater than 29) was not an exclusion criterion in our study. all operations were performed under general anesthesia and in modified left flank position. technique of trocars insertion for mldn six to eight centimeters pfannenstiel incision was made slightly above pubis symphysis and 11 millimeters trocar for suctioning, cauterizing, and vascular clipping was fixed through exposed fascia using open technique. after peritoneal insufflations, 5 mm port was placed under direct vision at the umbilicus and used for insertion of the camera and two 3.5 mm ports that were placed in subxyphoid and paraumbilical area for grasping and scissoring, respectively. all trocars at visible areas of abdomen were 3.5 millimeters (figure 1). technique of trocars insertion for sldn ten mm port was placed at umbilicus using open access technique for camera insertion. after peritoneal insufflations, 5mm trocar for grasping and 11 mm trocar for vascular clipping were placed at subxyphoid and paraumbilical areas under direct vision, respectively. the second 5 mm trocar was placed in suprapubic area (figure 2). technique of ldn the white line of toldt was incised and descending colon mobilized medially and splenorenal and renocolic ligaments were dissected. the left ureter and the gonadal vein were dissected from surrounding tissues while preserving peri-ureteral tissues. the renal vein was dissected distal to the gonadal vein. bipolar cautery was used for coagulating of adrenal and lumbar veins. left renal artery was dissected and exposed from its origin. after renal hilar dissection, the kidney attachments to the abdominal wall were released. the renal artery was clipped using one hem-o-lock (10 mm) and one titanium clip and the renal vein was clipped using two hemo-lock clips (10 and 12 mm) and finally one hem-olock clip (12 mm) was used for ligation of ureter.(8) the kidney was hand extracted from the previously opened pfannenstiel incision and then incision closed anatomically.(9) a penrose drain was inserted and mini-port sites remained unsutured and only steri-strips were applied. cosmetic appearance, operating time, hospital stay, complications and graft survival were assessed in all patients in both groups. cosmetic results were assessed in all patients, three months after surgery by using the patient scar assessment questionnaire (psaq), a reliable and valid measure of the patient's perception of scarring and developed for plastic and reconstructive surgery (table 1).(10) statistical analysis was performed using statistical package for the social science (spss) version 19 (spss statistics for windows, version 19.0. armonk, ny: ibm corp., released 2010) using the independent t-test for quantitative data and the chi-square test for qualitative variables. a p value of < .05 was considered as statistically significant. results mean age of patients in mldn and sldn was 27.4 (2038) years and 28.2 (21-43) years, respectively (p = .98). mean body mass index (bmi) in mldn and sldn was 26.1 (19.1-29.2) and 24.7 (20.4-27.9), respectively (p = .703). operative time was divided into three parts (minute): 1) total time of surgery: (104 ± 21 vs. 114 ± 24; p = .327); 2) from induction of anesthesia to preparation of renal pedicle for clipping including renal artery and renal vein: (83 ± 24 vs. 89 ± 23; p = .406); 3) ischemic time (from ligation of renal artery to kidney immersion in ice slush) (4.03 vs. 4.07; p = .592). surgical blood figure 1. trocar configuration in minilaparoscopic donor nephrectomy. figure 2. trocar configuration in standard laparoscopic donor nephrectomy. table 1. patient scar assessment questionnaire consists of five subscales and range of score in each items. variables number of scored items minimum score maximum score appearance 9 9 36 consciousness 6 6 24 symptom 7 7 28 satisfaction with 8 8 32 appearance satisfaction with 5 5 20 symptoms vol 12 no 04 july-august 2015 2224 standard vs. minilaparoscopic donor nephrectomy-simforoosh et al. loss was negligible in both groups. mean hospital stay was similar between the two groups [2.1 (2-5) vs. 2.4 (2-5) days: p = .346]. mean follow up time of recipient was 9 months (6-19 months). kidney graft function; assessed by serum creatinine values (mg/dl) of recipients one month after transplantation and then every three months, was equivalent in both groups (1.58 vs. 1.86; p = .206). two grafts were lost in recipients of sldn donors, while only one was lost from mldn donors. rejection was the main reason of graft loss in all three aforementioned cases. there were no fatalities resulting from either procedure in donors. there were no cases of conversion to open surgery, vascular injury or graft extraction complication in both groups. no major perior post-operative complications occurred in both groups. two patients in sldn group and three patients in mldn group had complication with clavien dindo grading type ii (fever greater than 38.5°c longer than 48 hours that were managed by antibiotic therapy) (p = .527) (table 2). pasq is a validated questionnaire for the measurement of scar outcome and consists of five subscales. mean appearance score and consciousness score a showed significantly better results in the mldn group (table 3) (figure 3). discussion the only definitive therapy for end stage renal disease (esrd) is renal transplantation. even in developing countries, the availability of cadaveric organ is reaching a plateau while the burden of renal failure is escalating. even after expanding criteria for cadaveric renal donors, the supply of kidneys is outpaced by the growing demand, so; modern techniques of kidney delivery should consider the cosmetic effect of live donor nephrectomy, in order to increase the willingness and concerns of potential donors. various techniques have been described for graft retrieval. laparoscopic donor nephrectomy results in faster recovery, less hospital stay, better cosmetic results, and better quality of life of the donor and equal safety and graft function for recipients compared with open donor nephrectomy. laparoscopic retrieval has become the gold standard over the last decade for harvesting the kidney from a living donors.(11,12) the hand-assisted laparoscopic donor nephrectomy (haldn) for left side and hybrid technique using satinsky clamp haldn for right-sided has been used as a minimally invasive technique for organ donation.(13) less (laparoendoscopic single-site surgery) has been introduced to minimize the morbidity associated with laparoscopic surgery even more. it is hypothesized that reduced entry points will ultimately decrease morbidity, convalescence, and improve cosmetic outcome. although there are increasing numbers of reports about the use of less all over the world, the potential benefit of less remains to be defined due to controversial data on postoperative pain control and its minimal effect on cosmesis.(14,15) less has some drawbacks that limit its routine use including the requirement of the flexible lens, clashing of instruments, and requirement of a steep learning curve and likewise, it seems that less is not an ergonomic approach for live donor nephrectomy.(16) tisdale and colleagues(17) compared the operative and perioperative parameters after laparoscopic nephrectomy with intact specimen extraction through a pfannenstiel or expanded port site incision. they reported reduced morbidity with intact specimen extraction through a pfannenstiel incision such as shorter hospital stay, less analgesic requirement and reduced number of incisional hernia. less has also been associated with increased risk of complication, increased surgical cost, takes longer operative times, and carries a higher chance of conversion. autorino and colleagues(18) in a systematic review and meta-analysis compared the less living-donor nephrectomy (lldn) vs. standard laparoscopic donor nephrectomy. they reported similar visual analogue pain score, hospital stay, warm ischemia time and renal function of the recipient in two groups. the estimated blood loss and analgesic requirement were lower for less groups but less was more technically challengfigure 3. scar appearance of trocars in minilaparoscopic donor nephrectomy after three months. variables minilaparoscopic donor nephrectomy standard laparoscopicdonor nephrectomy p value mean age (years) 27.4 (20-38) 28.2 (21-43) .98 body mass index 26.1 (19.1-29.2) 24.7 (20.4-27.9) .703 total operative time (min) 104 ± 21 114 ± 24 .327 warm ischemic time (min) 4.03 4.07 .592 hospital stay (day) 2.1 (2-5) 2.4 (2-5) .346 complication (clavien grade) 3 grade ii 2 grade ii .527 graft loss in recipient (no.) 1 2 .32 serum creatinine in recipient (mg/dl) 1.58 1.86 .206 table 2. demographic data of 100 cases randomly assigned to two groups. laparoscopic urology 2225 standard vs. minilaparoscopic donor nephrectomy-simforoosh et al. ing than lldn, as shown by a greater likelihood of conversion and longer operative time. notes offers a potential of surgical intervention with the elimination of abdominal wall incisions. vaginal extraction of the specimen following laparoscopic nephrectomy has been described a decade ago.(19) currently, notes still represents an experimental surgical technique. there are few studies regarding using notes for laparoscopic nephrectomy in living donors. (6,20) notes in living donor nephrectomy and transvaginal kidney extraction is only applicable in selected female donors and this is a major drawback while at least fifty percent of donors are male. it also requires randomized controlled studies to further elucidate the potentials of this technique. the development of miniaturized instruments has created a new dimension to conventional laparoscopy. minilaparoscopy has been shown to be safe in almost all urologic indication and has been proposed for reduced postoperative pain and improved cosmetic results.(21) minilaparoscopy has been applied broadly in general surgery studies under separate names, such as miniport, needlescopy, and microlaparoscopy. li and colleagues(22) in a network meta-analysis of 43 randomized controlled trials, compared different kinds of laparoscopic cholecystectomy (single port, two ports, three ports, and four ports laparoscopic cholecystectomy and four ports minilaparoscopic cholecystectomy). they concluded that the best technique might be minilaparoscopy because of the highest level of cosmetic score, least postoperative complications, and minimal blood loss during operation. graft outcome (either short term or long term) is one of the major concerns in donor nephrectomy. minilaparoscopic donor nephrectomy applies the quite same principles of sldn and no additional step is required, so not surprisingly, its effect on graft outcome is similar. no significant differences were seen between the two groups regarding operative time, postoperative complication, conversion to open surgery, hospital stay and graft survival. like sldn, donor’s body mass index was not a limiting factor for mldn. there are some validated questionnaires such as cosmesis and body image score (cbis),(23) psaq and etc. pasq is a validated questionnaire for the measurement of scar outcome and consists of five subscales that were presented for plastic and reconstructive surgery in 2009.(10) thus, we used this validated questionnaire for cosmetic appearance evaluation. assessment of psaq data revealed significantly better cosmetic results in mldn. likewise, mldn has other benefits: mldn is quite similar to the standard technique and requires no specific additional training course for laparoscopic surgeons. using the suprapubic trocar for vascular clipping in mldn takes advantage of vascular clipping in a nearly perpendicular direction and as a result, it provided longer artery and vein for anastomosis. in contrast to less, no special and expensive instruments are needed for mldn and we did not use disposable instruments (ports, endo-gia, endocatch bag). these modifications have positive impact on financial burden. we accept that cosmetic and satisfaction assessment has some limitations. the cosmetic satisfaction of patients are dependent for many confounding factors such as age, sex, education, bmi, previous surgeries, believes, culture, and etc. that may be affect the final results. likewise, psychosocial status of participants, thoughts and behaviors, physical functioning, physical and emotional impediments to role functioning, vitality and social functioning were not assessed and matched preoperatively. cost-effectiveness is an important item that was not assessed and it is other drawback of our study. conclusions our experience in this randomized trial study revealed that periand post-operative findings were nearly similar between standard and minilaparoscopic live donor nephrectomy but minilaparoscopic has significant better cosmetic appearance than standard laparoscopic approach. conflict of interest none declared. references 1. ratner le, ciseck lj, moore rg, cigarroa fg, kaufman hs, kavoussi lr. laparoscopic live donor nephrectomy. transplantation. 1995;60:1047-9. 2. duchene da1, winfield hn. laparoscopic donor nephrectomy. urol clin north am. 2008;35:415-24. 3. lucas sm1, liaw a, mhapsekar r, et al. comparison of donor, and early and late recipient outcomes following hand assisted and laparoscopic donor nephrectomy. j urol. 2013;189:618-22. 4. simforoosh n1, basiri a, tabibi a, shakhssalim n, hosseini moghaddam sm. comparison of laparoscopic and open donor table 3. detailed information about subscales of psaqd in mldn and sldn group. variables mldn sldn p value appearance (mean score) 34 29 .001 consciousness (mean score) 22 18 .03 symptom (mean score) 25 24 .741 satisfaction with appearance (mean score) 31 28 .07 satisfaction with symptoms (mean score) 18 18 .42 abbreviations: mldn, minilaparoscopic donor nephrectomy; sldn, standard laparoscopic live donor nephrectomy. vol 12 no 04 july-august 2015 2226 standard vs. minilaparoscopic donor nephrectomy-simforoosh et al. nephrectomy: a randomized controlled trial. bju int. 2005;95:851-5. 5. lewandowski pm1, leslie s, gill i, desai mm. laparo-endoscopic single-site donor nephrectomy: techniques and outcomes. arch esp urol. 2012;65:318-28. 6. allaf me, singer a, shen w, et al. laparoscopic live donor nephrectomy with vaginal extraction: initial report. am j transplant. 2010;10:1473-7. 7. simforoosh n, soltani mh, hosseini sharifi sh, et al. minilaparoscopic live donor nephrectomy: initial series. urol j. 2014;10:1054-8. 8. simforoosh n, sarhangnejad r, basiri a, et l. vascular clips are safe and a great costeffective technique for arterial and venous control in laparoscopic nephrectomy: singlecenter experience with 1834 laparoscopic nephrectomies. j endourol. 2012;26:1009-12. 9. simforoosh n, soltani mh, basiri a, et al. evolution of laparoscopic live donor nephrectomy: a single-center experience with 1510 cases over 14 years. j endourol. 2014;28:34-9. 10. durani p, mcgrouther da, ferguson mw. the patient scar assessment questionnaire: a reliable and valid patient-reported outcomes measure for linear scars. plast reconstr surg. 2009;123:1481-9. 11. ratner le, montgomery ra, maley wr, et al. laparoscopic live donor nephrectomy: the recipient. transplantation. 2000;69:2319-23. 12. kok nf, lind my, hansson bm, et al. comparison of laparoscopic and mini incision open donor nephrectomy: single blind, randomised controlled clinical trial. bmj. 2006;333:221. 13. kim bs, kim kh, yoo es, kwon tg. hybrid technique using a satinsky clamp for right-sided transperitoneal handassisted laparoscopic donor nephrectomy: comparison with left-sided standard handassisted laparoscopic technique. urology. 2014;84:1529-34. 14. kaouk jh, autorino r, kim fj, et al. laparoendoscopic single-site surgery in urology: worldwide multi-institutional analysis of 1076 cases. eur urol. 2011;60:9981005. 15. pini g1, rassweiler j. minilaparoscopy and laparoendoscopic single-site surgery: mini and single-scar in urology. minim invasive ther allied technol. 2012;21:8-25. 16. oh th. current status of laparoendoscopic single-site surgery in urologic surgery. korean j urol. 2012;53:443-50. 17. tisdale be1, kapoor a, hussain a, piercey k, whelan jp. intact specimen extraction in laparoscopic nephrectomy procedures: pfannenstiel versus expanded port site incisions. urology. 2007;69:241-4. 18. autorino r, brandao lf, sankari b, et al. laparoendoscopic single-site (less) vs laparoscopic living-donor nephrectomy: a systematic review and meta-analysis. bju int. 2015;115:206-15. 19. gill is, cherullo ee, meraney am, borsuk f, murphy dp, falcone t. vaginal extraction of the intact specimen following laparoscopic radical nephrectomy. j urol. 2002;167:23841. 20. alcaraz a1, musquera m, peri l, et al. feasibility of transvaginal natural orifice transluminal endoscopic surgery-assisted living donor nephrectomy: is kidney vaginal delivery the approach of the future? eur urol. 2011;59:1019-25. 21. pini g, porpiglia f, micali s, rassweiler j. minilaparoscopy, needlescopy and microlaparoscopy: decreasing invasiveness, maintaining the standard laparoscopic approach. arch esp urol. 2012;65:366-83. 22. li l, tian j, tian h, sun r, wang q, yang k. the efficacy and safety of different kinds of laparoscopic cholecystectomy: a network meta analysis of 43 randomized controlled trials. plos one. 2014;9:e90313. 23. lind my, hop wc, weimar w, jn ij. body image after laparoscopic or open donor nephrectomy. surg endosc. 2004;18:1276-9. laparoscopic urology 2227 standard vs. minilaparoscopic donor nephrectomy-simforoosh et al. laparoscopic urology 163urology journal vol 6 no 3 summer 2009 early continence after open and laparoscopic radical prostatectomy with sutureless vesicourethral alignment an alternative technique, 8 years’ experience nasser simforoosh, ahmad javaherforooshzadeh, alireza aminsharifi, ali tabibi introduction: we reviewed urinary outcomes after sutureless vesicourethral alignment in open radical prostatectomy (orp) and laparoscopic radical prostatectomy (lrp). materials and methods: charts of 324 patients who underwent sutureless orp (n = 188) and lrp (n = 136) were reviewed. after prostatectomy, a 22 to 24-f silicon foley catheter was passed into the bladder via the preserved bladder neck. the foley balloon was filled, and mild traction was applied to appose the bladder neck to the urethral stump. the foley catheter was fixed to the patient’s leg. no cystostomy was placed. results: the follow-up period ranged from 12 to 60 months. the mean operative time was 65 minutes in orp and 260 minutes in lrp. blood transfusion was significantly less frequent with lrp (9.6% versus 19.7%, p = .02). the mean postoperative catheterization durations were 12 days in orp and 13 days in lrp. complete continence was achieve in 293 patients (90.4%) after 3 months of follow-up (88.9% in lrp and 91.5% in orp, p = .78). the continence rate improved to 96.3% in lrp and 95.2% in orp at 1 year (p = .52). bladder neck stricture rate was 13.6% (12.8% in orp versus 14.7% in lrp, p = .87). conclusion: sutureless vesicourethral alignment during orp and lrp is a promising approach with minimum urinary extravasation, a high rate of continence, and an acceptable rate of stricture. this technique could be considered as an alternative in anatomically demanding situations. urol j. 2009;6:163-9. www.uj.unrc.ir keywords: radical prostatectomy, continence, laparoscopy, prostatic neoplasms urology and nephrology research center and shahid labbafinejad hospital, shahid beheshti university (mc), tehran, iran corresponding author: nasser simforoosh, md department of urology, shahid labbafinejad hospital, 9th bousan st, pasdaran, tehran, iran tel: +98 21 2258 8016 fax: +98 21 2258 8016 e-mail: simforoosh@iurtc.org.ir received july 2009 accepted august 2009 introduction radical prostatectomy is now considered a gold standard for the management of selected patients with localized prostate cancer. both open radical prostatectomy (orp) and laparoscopic radical prostatectomy (lrp) are considered expeditious procedures in terms of oncologic control.(1,2) however, concerns about functional outcomes of are growing after both orp and lrp. this is because an increasing number of patients are being diagnosed at earlier ages and stages, and they require a better functional outcome. in particular, urinary continence is of the highest concern for patients undergoing radical prostatectomy. vesicourethral anastomosis (vua) during prostatectomy is a “jigsaw sutureless vesicourethral alignment in prostatectomy—simforoosh et al 164 urology journal vol 6 no 3 summer 2009 puzzle” many urologists have been facing since the introduction of the technique.(3,4) the impact of vua on continence depends on a well-healed stricture-free wide anastomosis that preserves the intrinsic sphincter mechanism of the bladder neck as much as possible. recently, it has been well established that such anastomoses should be performed in a way that provides a urethra long enough to ensure adequate functioning.(5,6) the longer the preoperative and postoperative anatomic or functional length of the urethra, the higher the rate of postoperative early continence.(7-9) although direct vua is still the standard method of reconstruction in both orp and lrp (with or without robotic assistance), direct suturing can be quite demanding in certain situations such as in obese patients and those with a narrow deep pelvis. furthermore, urethral suture bites might compromise functional urethral length to some degrees in difficult situations. here we present our 8 years’ experience with sutureless vesicourethral alignment during orp and lrp, with a main focus on functional urinary outcome with this technique. materials and methods patient selection after obtaining approval from our local ethics committee, the charts of 324 patients who underwent sutureless orp and lrp between 2001 and 2008 were reviewed. surgical procedure the prostate was removed through an open or transperitoneal laparoscopic antegrade approach. care was taken to preserve the bladder neck as much as possible. unilateral or bilateral nervesparing procedures were used based on the intraoperative findings and clinical stage. careful apical dissection was used to preserve the external sphincter mechanism and the puboprostatic ligament. during apical and seminal vesicular dissection, no electrocautery was applied, and hemostasis was accomplished with hemoclips in procedures involving nerve-sparing techniques or with bipolar electrocautery in other situations. vesicourethral alignment after open or laparoscopic prostate removal and adequate hemostasis, a 22to 24-f silicon foley catheter was inserted transurethrally and passed into the bladder via the preserved bladder neck. the foley balloon was filled with 40 ml to 50 ml of sterile water, and mild traction was applied to appose the bladder neck to the urethral stump. the bladder was filled and drained 2 or 3 times with 200 ml to 300 ml of hypertonic saline solution, in order to ensure a well-sealed alignment (figure 1). then, the foley catheter was fixed to the patient’s leg and an external drainage was placed in the retropubic space. no cystostomy was placed. patients with an external drainage greater than 75 ml/d after the 2nd postoperative day were considered to have prolonged urine leakage. figure 1. left, sutureless vesicourethral alignment during transperitoneal laparoscopic radical prostatectomy. right, a sealed vesicourethral junction after filling the bladder. sutureless vesicourethral alignment in prostatectomy—simforoosh et al urology journal vol 6 no 3 summer 2009 165 postoperative care and outcome the patients received intravenous antibiotics throughout their hospital course, and left complete bed rest after the 2nd postoperative day. the foley catheter was removed 10 to 14 days postoperatively. the patients’ age, pathological stage, and length of hospital stay were recorded. all patients were followed regularly every month for the first 3 months, every 3 months thereafter during the 1st year after the surgery, and then, every 6 months. serum level of prostate-specific antigen (psa) was determined at each follow-up visit. early continence status was determined 3 months after prostatectomy by asking the patients if they were totally continent (no pad or only a few drops on heavy exercises). on follow-up visits, the presence of any obstructive symptoms was queried. routine yearly follow-up cystoscopy was considered in our first 30 patients to evaluate the site of vua (figure 2). however, the remaining 294 patients underwent endoscopic evaluation only when obstructive urinary symptoms were encountered. stricture was defined as any vesicourethral scarring that required dilation with metallic sounds. results the mean age of the patients was 62.1 years (range, 45 to 74 years). of the 324 patients, 136 (42.0%) underwent lrp. characteristics of the patients, and the operative parameters and outcomes are shown in the table. the mean clinical parameter all laparoscopy open surgery pathologic stage ≤ t2 223 134 (71.3) 89 (65.4) > t2 101 54 (28.7) 47 (34.6) mean preoperative psa, ng/ml 13.1 12.7 13.6 mean operative time, min 146.9 65.0 260.0 blood transfusion 50 (15.4) 13 (9.6) 37 (19.7) mean postoperative catheterization, d 12.6 13.0 12.0 postoperative outcome continence at 3 months† 293 (90.4) 121 (89.0) 172 (91.5) continence at 1 year† 310 (95.7) 131 (96.30 179 (95.20 bladder neck stricture 44 (13.6) 20 (14.7) 24 (12.8) positive surgical margin 80 (24.7) 38 (27.9) 42 (22.3) *values in parentheses are percents. †continence was defined as no leak and no need for pad. clinical characteristics and surgical outcome of patients who underwent sutureless open and laparoscopic racial prostatectomy* figure 2. left, follow-up cystoscopic view of the site of vesicourethral junction after radical prostatectomy with sutureless vesicourethral alignment. a well-healed, stricture-free, wide vesicourethral junction is shown. left, cystoscopy 4 years after open surgery. right, cystoscopy 5 years after laparoscopy. sutureless vesicourethral alignment in prostatectomy—simforoosh et al 166 urology journal vol 6 no 3 summer 2009 follow-up period was 33.5 months (range, 12 to 60 months). one of our early patients (the 12th case) who had undergone lrp developed postoperative excessive urinary extravasation with prolonged ileus, nausea, and vomiting. on exploration, we found complete separation of the bladder neck from the urethral stump with the foley catheter tip in the pelvic cavity. he was managed by reconstructing the bladder neck and using sutureless vesicourethral realignment with a 22-f internal foley catheter. another 2 cases of lrp were complicated by inadvertent rectal injury which was diagnosed intra-operatively and repaired laparoscopically in 2 layers. both surgeries were successful and neither patient required colostomy. the blood transfusion rate was significantly lower in the patients with lrp than those with orp (9.6% versus 19.7%, p = .02; table). sutureless radical prostatectomy resulted in complete continent in 293 patients (90.4%) after 3 months of follow-up. there were no significant differences regarding early continence rate between the lrp and the orp groups (89.0% versus 91.5%, p = .78). at 1-year follow-up, the continence rate improved to 95.7% (310 patients). this improvement was seen in both the lrp and the orp groups, with no significant difference between them (96.3% versus 95.2%, p = .52; table). bladder neck stricture was found in 44 patients (13.6%). in the last 150 cases, the rate of stricture reduced to 8.7%. the approach technique did not influence the rate of stricture (14.7% in lrp versus 12.8% in orp, p = .88). there was no significant differences in the rate of stricture formation was seen in 30 patients (13.5%) with pathologic stages t1 and t2 and in 13 (13.8%) of those with stages t3 and t4 of the disease (p = .87). all of the patients with bladder neck stricture suffered from obstructive urinary symptoms or acute urinary retention. the time to the occurrence of stricture was 3 to 4 months. all of these patients were managed by outpatient dilation of the anastomosis site with metallic sounds, and this therapy was successful in all cases. twenty-eight of these patients (63.6%) were managed with a single session of urethral dilation, while the remaining patients required a second session. all strictures became self-limited with this approach, and none needed further interventions or redilation during subsequent follow-up (mean, 33 months). of the 44 patients with bladder neck stricture, 8 (18.2%) had a previous history of adjuvant radiotherapy. the overall rate of positive surgical margin was 24.7% (80 patients), and there was no significant difference between the lrp and orp groups regarding the rate of positive surgical margin (27.9% versus 22.3%, respectively; table). all of the patients with a positive surgical margin were managed by adjuvant radiotherapy. a preoperative serum psa level higher than 20 ng/ml was a significant risk factor of positive surgical margin, as about one-third (34.7%) of those with a psa higher than 20 ng/ml versus 21.1% of the patients with a psa less than or equal to 20 ng/ml had a positive surgical margin (p = .03). furthermore, the rate of positive surgical margin was directly related to pathologic stage: 13% of patients with stage t2 or lower versus 50.5% of those with higher stages of prostate cancer had a positive surgical margin (p < .001). discussion in the era of psa and screening for prostate cancer, radical prostatectomy has become a routine surgical procedure in many centers. however, vua, which directly influences postsurgical continence and the patients’ quality of life, has always been a challenge during this procedure.(10,11) given that functional urethral length has a direct effect on continence, the anastomotic sutures should be applied as precisely as possible to incorporate as little of the urethra as is feasible.(5-8) coakley and coworkers have shown that a membranous urethra longer than 12 mm on preoperative endorectal magnetic resonance imaging was associated with a higher rate of early continence.(7) similarly, paparel and colleagues have demonstrated that longer postoperative membranous urethras result in a higher rate of continence with a hazard ratio of 1.18 per millimeter.(8) although direct suture anastomosis is a standard practice, it can be laborious and timesutureless vesicourethral alignment in prostatectomy—simforoosh et al urology journal vol 6 no 3 summer 2009 167 consuming, especially in obese patients and those with a deep bony pelvis, anatomical constraints, or an ill-defined membranous urethral stump.(11) all of these barriers may compromise millimeters of functional urethral length. to overcome these difficulties, many investigators have tried modifications of the standard procedure. historically, pubectomy has been proposed to expand the surgical field during anastomosis.(12) in 1997, igel and wehle introduced their alternative vua technique based on the vest technique.(11) their alternative procedure incorporated 6 separate transperineal intra-urethral sutures which were tied over a bolster on the perineum. this maneuver took only about 12 minutes and showed its merits in 91 consecutive patients, with a continence rate of 87.9%, a stricture rate of 7.7%, and few instances of urinary extravasation. later, thiel and associates reviewed the 10-year long-term outcomes of this modification and found this technique efficient in the long-term.(13) novicki and coworkers compared direct vua with a modified vest technique and reported a slightly better 1-year urine continence rate in the vest group, but a higher rate of mild anastomotic stenosis.(4) the absence of urethral sutures and minimal urethral manipulation—both of which lead to a longer functional urethral length— may explain the higher rate of early and late continence with the vest technique. gallo and colleagues conducted the first randomized controlled trial to evaluate the effect of suture numbers (6 versus 4 versus 2) on functional outcome after radical prostatectomy.(14) interestingly, they showed that there was no significant difference in urinary functional outcomes (stricture and continence) and postoperative urinary leakage, and that the duration of anastomosis and degree of urethral trauma could be reduced considerably by decreasing the number of sutures. undoubtedly, vua during lrp even with robotic assistance can be much more technically demanding and time-consuming with a steep learning curve. these difficulties may have a negative impact on continence status by decreasing the length of the urethra during suture placement.(15,16) many authors have tried to minimize urethral trauma during this challenging procedure. hruby and coworkers developed a novel device that incorporated 6 pairs of retractable bladder and urethral tines over a standard foley catheter.(17) the tines acted as sutures to appose the bladder neck and urethra until healing occurred. they tested the efficacy of their novel device during lrp by comparing it to standard direct anastomosis in 30 pigs. there were no differences regarding urinary outcomes (continence, stricture, and urine extravasation), and histopathologic evaluation of the site of vua showed less fibrotic reaction with the use of bladder tines compared to absorbable suture material. with this innovation the duration of lrp and vua was markedly reduced.(17) parallel with these investigations we hypothesized that by eliminating urethral suturing, a longer functional membranous urethral length could be achieved. we showed the safety and efficacy of sutureless radical prostatectomy in both open and laparoscopic approaches with an excellent rate of early continence—the highest concern for these patients—and acceptable rate of stricture. we think that a 3-month early continence rate of 90.4% with this procedure is excellent, compared with postradical prostatectomy incontinence rates in the contemporary literature.(13) this high rate of early continence may originate mainly from leaving as maximum length as feasible membranous urethra during the procedure of “alignment” instead of “anastomosis.(5-8)” we assume that the part of urethra incorporating in the anastomotic stitches may not participate in continence mechanism and may lead to the shortening of maximum functional urethral length. continence following sutureless vesicourethral alignment may also come back to the minimum manipulation of external sphincter mechanism, together with the preserved bladder neck and puboprostatic ligaments. also with the use of minimum (if any) heat around the membranous urethra and suture-free alignment, the blood supply at the critical area of the membranous urethra and the striated sphincter can be saved sutureless vesicourethral alignment in prostatectomy—simforoosh et al 168 urology journal vol 6 no 3 summer 2009 adequately. in other words, by application of this technique, many of the incontinence contributing factors such as impaired visualization, imprecise suture placement, and aggressive hemostasis could be obviated.(19) therefore, distal apical continence mechanism (puboprostatic ligament, external sphincter, and urethral stump) is manipulated as little as possible. recently, libertino and colleagues have presented their initial experience with sutureless vesicourethral alignment.(20) they have used a novel device, named “continuum,” in order to “appose” (not suture) the bladder neck and the urethral stump during open and robotic radical prostatectomy in 19 patients. they achieved a 6-week continence rate of 88% using this technique. the incidence rate of bladder neck stricture after radical prostatectomy ranged between 0.5% to 32% in the most contemporary series.(19) this rate was 13.6% in our patients. consistent with the literature, all of these patients had “thin” stenotic rings that were managed outpatiently with only bladder neck dilation in no more that 2 sessions (63.6% needed only one session of dilation). the rate of stricture was comparable between laparoscopic and open approaches (14.7% and 12.8%, respectively), and these patients were completely continent after bladder neck dilation. we do agree with mccarthy and catalona that the caliber of the bladder neck is an important factor to control the rate of stricture and continence. as mccarthy and catalona have shown, the incidence of bladder neck contracture could be decreased significantly if the bladder neck caliber increased from 18 f up to 22 f to 24 f.(21) we also used this technique and found such a bladder neck diameter optimal regarding both stricture and continence issues. interestingly, it seems that the rate of stricture formation may decrease with experience. the rate of stricture in our last 150 cases was 8.7%; significantly lower than early 174 cases (17.8%). we think that our technique, by providing adequate urethral stump, has promising urinary outcome. however, this open-label study should be further investigated and confirmed by cohort studies and using both imaging and functional modalities to measure the anatomic and functional urethral length during this technique. conclusion sutureless vesicourethral alignment during orp and lrp is a feasible and promising approach with a minimal rate of urinary extravasation, high rates of early and late continence, and an acceptable rate of stricture. this technique could be considered as an alternative in anatomically demanding situations. acknowledgment we thank the center for development of clinical research of nemazi hospital in shiraz for editorial assistance and karen shashok (authoraid in the eastern mediterranean) for improving the use of english in the manuscript. conflcit of interest none declared. references 1. rassweiler j, seemann o, schulze m, teber d, hatzinger m, frede t. laparoscopic versus open radical prostatectomy: a comparative study at a single institution. j urol. 2003;169:1689-93. 2. galli s, simonato a, bozzola a, et al. oncologic outcome and continence recovery after laparoscopic radical prostatectomy: 3 years’ follow-up in a “second generation center”. eur urol. 2006;49:859-65. 3. steiner ms, morton ra, walsh pc. impact of anatomical radical prostatectomy on urinary continence. j urol. 1991;145:512-4; discussion 4-5. 4. novicki de, larson tr, andrews pe, swanson sk, ferrigni rg. comparison of the modified vest and the direct anastomosis for radical retropubic prostatectomy. urology. 1997;49:732-6. 5. rocco f, carmignani l, acquati p, et al. early continence recovery after open radical prostatectomy with restoration of the posterior aspect of the rhabdosphincter. eur urol. 2007;52:376-83. 6. majoros a, bach d, keszthelyi a, et al. analysis of risk factors for urinary incontinence after radical prostatectomy. urol int. 2007;78:202-7. 7. coakley fv, eberhardt s, kattan mw, wei dc, scardino pt, hricak h. urinary continence after radical retropubic prostatectomy: relationship with membranous urethral length on preoperative endorectal magnetic resonance imaging. j urol. 2002;168:1032-5. 8. paparel p, akin o, sandhu js, et al. recovery of urinary continence after radical prostatectomy: association with urethral length and urethral fibrosis sutureless vesicourethral alignment in prostatectomy—simforoosh et al urology journal vol 6 no 3 summer 2009 169 measured by preoperative and postoperative endorectal magnetic resonance imaging. eur urol. 2009;55:629-37. 9. curto f, benijts j, pansadoro a, et al. nerve sparing laparoscopic radical prostatectomy: our technique. eur urol. 2006;49:344-52. 10. teber d, erdogru t, cresswell j, gozen as, frede t, rassweiler jj. analysis of three different vesicourethral anastomotic techniques in laparoscopic radical prostatectomy. world j urol. 2008;26:617-22. 11. igel tc, wehle mj. vesicourethral reconstruction in radical retropubic prostatectomy: an alternative technique. j urol. 1999;161:844-6. 12. lange ph, reddy pk. technical nuances and surgical results of radical retropubic prostatectomy in 150 patients. j urol. 1987;138:348-52. 13. thiel dd, igel tc, brisson te, heckman mg. outcomes with an alternative anastomotic technique after radical retropubic prostatectomy: 10-year experience. urology. 2006;68:132-6. 14. gallo l, perdona s, autorino r, et al. vesicourethral anastomosis during radical retropubic prostatectomy: does the number of sutures matter? urology. 2007;69:547-51. 15. menon m, hemal ak, tewari a, shrivastava a, bhandari a. the technique of apical dissection of the prostate and urethrovesical anastomosis in robotic radical prostatectomy. bju int. 2004;93:715-9. 16. teber d, dekel y, frede t, klein j, rassweiler j. the heilbronn laparoscopic training program for laparoscopic suturing: concept and validation. j endourol. 2005;19:230-8. 17. hruby g, weld kj, marruffo f, et al. comparison of novel tissue apposing device and standard anastomotic technique for vesicourethral anastomoses. urology. 2007;70:190-5. 18. steiner ms. continence-preserving anatomic radical retropubic prostatectomy: the “no-touch” technique. curr urol rep. 2000;1:20-7. 19. park r, martin s, goldberg jd, lepor h. anastomotic strictures following radical prostatectomy: insights into incidence, effectiveness of intervention, effect on continence, and factors predisposing to occurrence. urology. 2001;57:742-6. 20. libertino j, tuerk i, landman j, kella n. sutureless vesico-ureteral anastomosis after radical prostatectomy: initial clinical feasibility data from the continuum study. eur urol suppl. 2008;7:249. 21. mccarthy j, catalona w. nerve-sparing radical retropubic prostatectomy. in: marshall ff, editor. textbook of operative urology. 1st ed. philadelphia: wb saunders; 1996. p. 537-44. vol 15 no 02 march-april 2018 61 penile glans necrosis developing after internal pudendal arterial embolization: a case report tae nam kim1,2, chan ho lee1,2, seung ryong baek1,2, kyung min lee1,2, sangmin choe2,3, nam cheol park1,2, hyun jun park1,2* penile glans ischemia or necrosis developing after internal pudendal arterial embolization is very rare; no relevant report has yet appeared. a 53-year-old male who visited our emergency room because of massive urethral bleeding was diagnosed with an internal pudendal artery-urethral fistula; he underwent selective embolization of the internal pudendal artery. however, unexpected penile glans ischemic necrosis developed after embolization. we successfully treated the patients with intravenous infusion of alprostadil, oral pentoxifylline and tadalafil. 1department of urology, pusan national university school of medicine, busan, south korea. 2medical research institute of pusan national university hospital, busan, south korea. 3departmeent of clinical pharmacology and therapeutics, pusan national university hospital, busan, south korea. *corresponence: department of urology and medical research institute of pusan national university hospital, pusan national university school of medicine, 179 gudeok-ro, seo-gu, busan 49241, south korea. tel: +82 51 2407347. fax: +82 51 2475443. e-mail: joon501@naver.com. received february 2017 & accepted september 2017 introduction ischemic or necrotic complications of the glans penis are very rare. the use of vasoconstricting agents, circum-cision, hematoma, excessive cauterization, placement of a tight compressive bandage, and arterial vasospasm caused by needling trauma may induce the condition(1). to the best of our knowledge, no report has yet described penile glans necrosis developing after internal pudendal arterial embolization. selective embolization of the pudendal artery has been used to treat post-traumatic high flow priapism; internal pudendal artery-urethral fistulae; pseudoaneurysms; and arteriovenous fistulae(2-4). however, as a side effect of this procedure, only few instances of transient erectile dysfunction (ed) have been reported(2). here we report a case of penile glans necrosis after internal pudendal arterial embolization successfully treated with intravenous infusion of alprostadil, oral pentoxifylline and tadalafil. case report keywords: glans; penis; necrosis; embolization; phosphodiesterase 5 inhibitor. figure 1. retrograde urethrography showed a contrast media leakage at the bulbous urethra (arrow) figure 2. left internal iliac artery angiography demonstrate active contrast leakage from left internal pudendal artery branch (arrow) discussion ischemic necrosis of the glans penis is very rare; no optimal treatment has yet been established. however, several reports employed various treatment options(1,5). the necrosis of the glans penis can be diagnosed easily by the black color or necrotic appearance of the glans penis, but it is helpful to perform color doppler sonography to detect the blood flow state of the intracavernosal arteries(1,6). the principle objective of treatment is to increase blood flow, allowing adequate oxygen delivery to, and revascularization of, ischemic tissues. reported treatments include topical 10% testosterone undecanoate, intracavernous glycerol trinitrate and bupivacaine, intravenous infusion of iloprost (a pgi2 analog), low-dose heparin infusion, and intravenous or oral pentoxifylline with hyperbaric oxygen(5). we prescribed intravenous infusion of alprostadil 5 µcg, oral pentoxifylline 400 mg bid for 4 weeks, and daily tadalafil 5 mg for 3 months. pentoxifyllin is a peripheral vasodilator that stimulates prostaglandin production and inhibits phosphodiesterase (pde) activity, thus increasing camp synthesis(1). to date, pde5 inhibitors have not been used to treat penile necrosis. however, it is useful to consider the utility of such treatment. pde5 inhibitors can be used to treat heart ischemic/reperfusion injuries; the effects are thought to reflect activation of protein kinase c/ extracellular signal-regulated kinase signaling, opening of mitochondrial adenosine triphosphate-sensitive potassium channels, and attenuation of cell death caused by necrosis and apoptosis(7). furthermore, an earlier report treated penile fibrosis developing after priapism with pentoxifylline and sildenafil(8). we thus prescribed combination pentoxifylline and tadalafil (the latter drug has the longest half-life among all pde5 inhibitors) and obtained satisfactory results. however, in order for tadalafil to be selected as a treatment for penile necrosis, more case studies and clinical trials should be supported. the patient reported that his erectile function was reduced immediately after injury, and also shortly after the onset of penile glans necrosis, but that partial recovery was evident after 3 months of treatment, which continued over time. takao et al. reported that erectile case report a 53-year-old male who had no history of illness such as diabetes or cardiovascular disease visited our emergency room because of massive urethral bleeding and perineal laceration. initial evaluation and management were conducted by a traumatologist. according to the patient, he was taking a shower while sitting in a plastic chair; the chair broke and a piece of plastic became embedded in his perianal buttocks. a pelvic x-ray revealed no abnormality of the pelvic bone, but computed tomography revealed active bleeding, with a hematoma, around the site of injury in the bulbous urethral region, and air in the perianal soft tissue. retrograde urethrography revealed leakage of the contrast medium in the region of the bulbous urethra (figure 1). a 16-f foley catheter was inserted. emergency angiography was performed via a right femoral arterial approach. selective arteriography combined with left internal iliac artery angiography revealed active contrast leakage from the left branch of the internal pudendal artery (figure 2). right internal iliac artery angiography revealed an intact penile artery arising from the right internal pudendal artery, without any focus of bleeding. selective embolization of the left branch of the internal pudendal artery branch was performed using n-butyl cyanoacrylate (nbca) mixed with iodized oil (lipiodol) at a ratio of 1:3. the extravasation disappeared on subsequent angiography. urethral bleeding ceased after embolization. however, after 10 days, the patient was transferred to the urological department because he complained of painful glans ischemia. physical examination revealed an ischemic, poorly perfused black glans (figure 3). the urgent color doppler sonography revealed good blood flow in both intracavernosal arteries. we commenced intravenous infusion of alprostadil 5 µcg, maintained the hospital stay (a further 10 days), and commenced oral pentoxifylline 400 mg bid for 4 weeks and tadalafil 5 mg daily for 3 months. the treatment outcome was excellent, with significant recovery of the ischemic necrotic glans (figure 4). erectile function was not fully normal immediately after embolization; however, the patient reported that his erectile function is improving as the tadalafil treatment continues. penile glans necrosis after pudendal embolization -kim et al. figure 3. ischemic, poorly perfused, black colored glans figure 4. recovery of the ischemic necrotic glans case report 62 function gradually recovered after embolization of a patient with post-traumatic high-flow priapism; recovery was complete 1 year after embolization(2). selective embolization of the penile artery was first described by wear et al. in 1997, and has been used to treat post-traumatic high flow priapism; internal pudendal artery-urethral fistulae; pseudoaneurysms; and arteriovenous fistulae(3,4). no report has yet described penile necrosis developing after embolization, but ed has been recorded. it remains unclear whether embolization actually causes ed, but transient ed develops soon after embolization in 15–20% of patients. however, the ed then gradually improves from 7 days to 1 year thereafter(2,9). chen et al.(10) reported a similar case with a bilateral fistula, who was treated via bilateral internal pudendal artery-urethral embolization. however, no side-effects, such as ed or necrosis, were noted. savoca et al.(8) suggested that if a lesion is bilateral, embolization of one side could be deferred to prevent development of an erectile problem. in this report, the patient received only one side of the procedure, but penile necrosis eventually occurred. therefore, we investigated whether or not penile necrosis was caused by other causes, but no other reason was found. conclusions unexpected penile glans ischemic necrosis developed after internal pudendal arterial embolization of a post-traumatic internal pudendal artery-urethral fistula. to date, no report of penile glans necrosis or ischemia developing after embolization has appeared. this case report underscores that penile glans necrosis can occur as a side effect of internal pudendal arterial embolization. it is necessary to closely observe whether abnormal signs such as color change occur on the glans penis after the procedure. acknowledgement none conflict of interest the authors report no conflict of interest. references 1. aslan a, karaguzel g, melikoglu m. severe ischemia of the glans penis following circumcision: a successful treatment via pentoxifylline. int j urol. 2005;12:705-7. 2. takao t, osuga k, tsujimura a, matsumiya k, nonomura n, okuyama a. successful superselective arterial embolization for posttraumatic high-flow priapism. int j urol. 2007;14:254-6. 3. mitropoulos d, pappas p, banias c, leonardou p, alamanis c, giannopoulos a. delayed presentation of posttraumatic internal pudendal artery-urethral fistula treated by selective embolization. j trauma. 2007;63:1388-90. 4. celtikci p, ergun o, tatar ig, conkbayir i, hekimoglu b. superselective arterial embolization of pseudoaneurysm and arteriovenous fistula caused by transurethral resection of the prostate. pol j radiol 2014;79:352-5. 5. garrido-abad p, suarez-fonseca c. glans ischemia after circumcision and dorsal penile nerve block: case report and review of the literature. urol ann. 2015;7:541-3. 6. aminsharifi a, afsar f, tourchi a. delayed glans necrosis after circumcision: role of testosterone in salvaging glans. indian j pediatr. 2013;80:791-3. 7. burnett al. molecular pharmacotherapeutic targeting of pde5 for preservation of penile health. j androl. 2008;29:3-14. 8. rajfer j, gore jl, kaufman j, gonzalezcadavid n. case report: avoidance of palpable corporal fibrosis due to priapism with upregulators of nitric oxide. j sex med. 2006;3:173-6. 9. savoca g, pietropaolo f, scieri f, bertolotto m, mucelli fp, belgrano e. sexual function after highly selective embolization of cavernous artery in patients with high flow priapism: long-term followup. j urol. 2004 ;172:644-7. 10. chen j, wang s, wu d, wu j. bilateral internal pudendal artery-urethral fistula formation by pseudoaneurysm. acta orthop traumatol turc. 2015;49:456-8. penile glans necrosis after pudendal embolization -kim et al. vol 15 no 02 march-april 2018 63 miscellaneous the association of postvoiding residual volume, uroflowmetry parameters and bladder sensation hakkı uzun1*, maksude esra kadıoglu2, nurgül orhan metin2, görkem akça1 purpose: to investigate whether postvoiding residual bladder volume (pvr) and uroflowmetry parameters associate with bladder sensation in male patients with bladder outlet obstruction (boo) and to find out the reliable time of these examinations. materials and methods: sixty men with bladder outlet obstruction underwent transabdominal ultrasound in order to measure postvoiding residual volume and uroflowmetry. at the first day, pvr was measured while the patients had mild bladder sensation. patients emptied their bladder during uroflowmetry. the next day, same patients underwent a second uroflowmetry and pvr measurement while the patients had severe bladder sensation. the first and next day pvr and uroflowmetry parameters were compared and their correlation with lower urinary tract symptoms (luts) were analysed. results: the mean age of the subjects was 69.7 ± 8.6 years. pvr measured at the first day while patients had mild bladder sensation was significantly lower than the next day pvr (mean ± sd: 80.79 ± 72.18 vs 158 ± 115.82, p < 0.001) and correlated with luts (rs =0.38, p = 0.012). in contrary, uroflowmetry parameters at severe sensation of bladder (mean ± sd: qmax:13.53 ± 6.32; qave:5.32 ± 2.31) showed correlation with luts (rs = -0.492, p = 0.001). conclusion: pvr measurement at mild bladder sensation correlates with luts and should be performed in the evaluation of male patients with boo. however, uroflowmetry is advised to be performed when the patient has severe bladder sensation. keywords: bladder sensation; postvoiding residual volume; bladder outlet obstruction; uroflowmetry introduction men with lower urinary tract symptoms (luts) related to bladder outlet obstruction (boo) including bening prostatic hyperplasia is a very prevalent disease constituting a great amount of patients evaluated in urology practice.(1) uroflowmetry and postvoiding residual urine volume (pvr) measurement are recommended for both the initial evaluation and follow-up after medical or surgical treatment of male patients with luts.(2) these examinations are simple, non-invasive, widespread and have a prominent role in the management of the patients.(2-4) ultrasound is commonly used for the estimation of pvr and easy to perform and highly accurate.(5) in most radiology departments, patients are advised to drink a significant amount of fluid to measure pvr and also to image the urinary tract reliably.(6-8) in guidelines, uroflowmetry is recommended to be carried out with a voided volume of over 150 ml.(2) consequently, pvr and urine flow rate are usually measured under severe sensation of bladder and this is quite incompatible with real life and does not represent the patient’s daily voiding practice. it is reported that a residual volume over 100 ml after an increased oral fluid intake may acutely and temporarily decompensate the bladder and might lead to the selection of an inappropriate treatment mo1department of urology, recep tayyip erdogan university medical school, rize, turkey. 2department of radiology, recep tayyip erdogan university medical school, rize, turkey. *correspondence: department of urology, recep tayyip erdoğan university school of medicine, rize, turkey. tel: +90 464 212 30 09. fax: +90 464 212 30 15. e mail: hakuzun@yahoo.com. received january 2018 & accepted august 2018 dality.(8) therefore, the accurate measurement of pvr and uroflowmetry in accordance to daily voiding practice is of clinical importance. in our clinical practice, some male patients with boo reported that they voided more troublesome prior to pvr measurement than their daily routine voiding activity. to the best our knowledge we noticed that in male patients with boo association of pvr and uroflowmetry parameters with bladder sensation has not been thoroughly investigated. therefore, we intended to investigate whether pvr and uroflowmetry parameters change according to bladder sensation at the first desire or strong desire to void and to find out the reliable time of these examinations. material and methods male patients complaining of luts related to boo were included in the study. boo was assigned according to the evaluation of urinary symptoms, radiologic and laboratory examinations with the exclusion of other pelvic pathologies. all patients were subjected to a diagnostic work-up including medical history, and examined for urinary symptoms with international prostate symptom score (ipss). physical examination including digital rectal examination was done and serum levels of urea and creatinine were measured. ultrasonography urology journal/vol 16 no. 4/ july-august 2019/ pp. 403-406. [doi: http://dx.doi.org/10.22037/uj.v0i0.4368] vol 16 no 04 july-august 2019 404 and urinalysis were also obtained to exclude other pelvic disorders. patients with a diagnosis of prostate or urothelial cancer, urinary tract infection, distal ureteral or bladder stones, urethral stricture, chronic pelvic pain syndrome, neurological disorder and unstable diabetes were not included into the study. in addition, patients on any medication for luts or with a history of urinary tract surgery or instrumental intervention were excluded. the study was performed at the urology and radiology departments of our university hospital between march and september 2017 and was approved by the ethical committee of our university and written informed consent was obtained from all patients. all patients underwent uroflowmetry and transabdominal ultrasound (logic e9 with xd clear ultrasonographic scanner, general healthcare, united states, equipped with a 4.5 to 6 -mhz convex probe) for the examination of the urinary tract and measurement of prevoiding bladder volume, prostate volume and pvr in the radiology department. both of the examinations were again carried out at the next day by the same radiologist and nurse. all ultrasonographic measurements including prevoiding bladder volume and pvr measurements were performed by the same radiologist (m.e.k). patients were advised to take an increased amount of water orally prior to examinations without limiting the time and hydration rate. the examinations were performed while the patients had first or strong desire to void. we intended to pretend daily routine practice, therefore urinary catheterisation was not applied for artificial bladder filling. at the first day, the ultrasound was carried out while the patients had first desire to void (mild bladder sensation). prevoiding bladder volume was measured and the patients were asked to empty their bladders during uroflowmetry. then, the first pvr (pvr1) was measured by the radiologist under ultrasound by using the prolate ellipsoid method based on the formula: volume = length x width x height x 0.52 on two dimensions.(9) the next day the same patients underwent a second prevoiding and postvoiding residual volume (pvr2) measurement while the patients had strong desire to void (severe bladder sensation). uroflowmetry was again performed prior to pvr2 measurement. maximum urine flow rate (qmax), average flow rate (qave) and voided volume were recorded. wilcoxon signed rank test was used to compare the first and next day pvr values and uroflowmetry parameters. spearman’s correlation rank test was used to determine whether the first and next day pvr was correlated with ipss total score, prostate volume, prostate specific antigen (psa), age, prevoiding bladder volume and serum creatinine levels. in addition, correlation between uroflowmetry parameters and ipss total score was analysed by the same statistical method. spps 23 was used for statistical analyses and p < 0.05 was considered as statistically significant. results sixty men with bladder outlet obstruction and a mean age of 69.7 ± 8.6 years were evaluated. descriptive characteristics of the patients are shown in table 1. most of the patients had moderate (15/60) or severe symptoms (41/60). only 4 patients presented with mild symptoms (ipps <7). the mean prostate volume and table 1. descriptive statistics minimum maximum mean sd age 53 86 69.7 8.6 ipss total score 4 35 21.04 8.1 psa (ng/dl) 0.21 15.95 4.12 3.83 prostate volume (ml) 14 190 67.8 37.9 serum creatinine (mg/dl) 0.71 2.23 1.0 0.3 testosterone 249.65 1078.08 554.08 192.89 abbreviations: ipss, international prostate symptom score; psa, prostate specific antigen abbreviations: pvr1, postvoiding residual volume measured at first desire to void; pvr2, postvoiding residual volume measured at strong desire to void; prev1, prevoiding bladder volume measured at first desire to void; prev2, prevoiding bladder volume measured at strong desire to void; qmax1, q maximum measured at first desire to void; qmax2, q maximum measured at strong desire to void; qave1, q average measured at first desire to void; qave2, q average measured at strong desire to void; vv1, voided volume at uroflowmetry at first desire to void; vv2, voided volume at uroflowmetry at strong desire to void mean sd significance (p) pvr1 80.79 72.18 pvr2 158.35 115.82 pvr2 – pvr1 < 0.001 prev1 203.16 108.18 prev2 422.33 203.22 prev2 – prev1 < 0.001 qmax1 10.74 5.77 qmax2 13.53 6.32 qmax2 – qmax1 0.021 qave1 4.03 1.90 qave2 5.32 2.31 qave2 – qave1 0.018 vv1 162.05 103.28 vv2 270.40 128.62 vv2 –vv1 < 0.001 table 2. wilcoxon signed rank test showed statistical significance between measurements at the first desire and strong desire to void. sensation, residual volume and uroflowmetry-uzun et al. mean serum psa was measured 67.8 mg and 4.12 ng/ dl, respectively. prevoiding bladder volume and postvoiding residual volume at the first desire to void (pvr1, measured at the first day) were significantly found lower than the strong desire to void (pvr2, measured at the next day) (p < 0.001) (table 2). furthermore, qmax and qave values and voided volume were also significantly lower at the first desire to void in comparison to the strong desire to void (table 2). while spearman’s rank correlation coefficient showed correlation between prv1 and ipss total score (rs =0.38, p = 0.012), pvr2 was not found correlated (table 3). in addition, prevoiding bladder volume at first desire and strong desire to void correlated with residual volume measured at the first and next day, respectively (table 3). prostate volume, total psa, age, and serum creatinine levels were not correlated with residual volume measured either at the first desire or strong desire to void. in contrary, qmax and qave values at the first desire to void did not show correlation with total ipss, but showed significant correlation at the strong desire to void (rs = -0.335, p = 0.28 and rs = -0.492, p = 0.001, respectively) (table 4). discussion although pvr measurement and uroflowmetry are one of the most frequently performed urologic examinations worldwide for male patients with luts, the optimal time of these examinations in terms of bladder sensation has not been adequately investigated. to the best of our knowledge this is the first study that compared the pvr and uroflowmetry parameters according to bladder sensation in male patients with boo. in our study, we found that patients at the strong desire to void showed higher prevoiding bladder volume and pvr. while pvr2 did not show correlation with luts, pvr1 was significantly correlated with luts. pvr measurement at mild bladder sensation of voiding (first desire to void) could be more reliable for the accurate diagnosis of boo. on the other hand, in contrast to pvr findings, qmax and qave values did not correlate with luts at the first desire to void, but a significant correlation was found with symptoms at the strong desire to void. severe bladder sensation for uroflowmetry could be more acceptable. male patients with luts related to boo are treated with medications (alpha blockers, antimuscarinics, 5 alpha reductase inhibitors) or surgery.(2) the choice of the treatment is mainly based on symptom severity and voiding examinations. although there is no consensus for the pvr threshold, many urologists suggest that high values are an indication for invasive therapy. (10) furthermore, large pvr volume has been reported to be associated with hydronephrosis, bladder calculi, nocturia, acute urinary retention and urinary tract infections.(11) all these relations show the importance of the accurate values of pvr. in a study by mochtar et al. only over 300 ml of pvr has been found correlated with a need for an invasive therapy.(12) in our study, prevoiding bladder volume at first and strong desire to void significantly correlated with pvr1 and pvr2, respectively. an increase in prevoiding bladder volume caused an increase in pvr which was not correlated with the symptom severity of the patients. we believe that patients should have mild bladder sensation prior to pvr measurement for the accurate treatment modality. previous studies that investigated the relationship of pvr with boo might have included patients which pvr was measured under severe bladder sensation. according to our results these studies could be better performed with patients at mild bladder sensation. further studies are needed for the re-evaluation of the relation between pvr and boo. uroflowmetry is a non-invasive, easily practiced and non-expensive test for the evaluation of patients with boo.(12) qmax is found an independent predictor of urodynamic boo(4) and 10 ml/sec is widely accepted as a threshold. however, similar to pvr, there is also a discrepancy and debate between the uroflowmetry parameters and diagnosis of boo.(13) it is generally accepted that the voided volume should be over 150 ml for the accuracy of the test.(2) in our study the mean voided volume at the first desire to void was 162.05 ml. however, no correlation was found between ipss total score and qmax and qave values when the patable 3. correlations between postvoiding residual volume at the first desire and strong desire to void and examined parameters. pvr1 pvr2 rs p rs p ipss total score 0.380 0.012 0.113 0.396 serum creatinine -0.003 0.987 -0.008 0.961 prev1 0.639 0.000 n/a n/a prev2 n/a n/a 0.709 0.000 psa 0.114 0.472 -0.088 0.580 prostate volume 0.221 0.154 0.179 0.250 age 0.058 0.714 -0.188 0.227 abbreviations: pvr1, postvoiding residual volume measured at first desire to void; pvr2, postvoiding residual volume measured at strong desire to void; prev1, prevoiding bladder volume measured at first desire to void; prev2, prevoiding bladder volume measured at first desire to void; ipss, international prostate symptom score; psa, prostate specific antigen; rs, spearman’s correlation coefficient. ipss total score rs p qmax1 -0.021 0.913 qave1 -0.265 0.086 qmax2 -0.335 0.028 qave2 -0.492 0.001 qmax1, q maximum measured at first desire to void; qmax2, q maximum measured at strong desire to void; qave1, q average measured at first desire to void; qave2, q average measured at strong desire to void; rs, spearman’s correlation coefficient table 4. correlations between q maximum and q average at the first and strong desire to void and ipss. sensation, residual volume and uroflowmetry-uzun et al. miscellaneus 405 vol 16 no 04 july-august 2019 406 tients voided at the first desire to void. on the other hand, mean voided volume at the strong desire to void was found increased and qmax and qave values were correlated with ipss total score. however, whether the mean voided volume at the first desire to void is over 150 ml and mean qmax is 10.7 ml/sec, uroflowmetry parameters might not be useful for the evaluation of the patients at mild bladder sensation. in contrast to pvr measurement, we claim that patients should undergo uroflowmetry at strong desire to void for the evaluation of relation between qmax and qave and urinary symptoms. alivizatos et al. studied the relation between pvr and increased oral intake of fluids.(8) they included the patients into their study with a pvr over 100 ml measured in the first examination after taking an amount of oral fluid. on a separate day, the same patients were let to drink as their usual days. pvr values significantly found higher at the first measurement but no correlation was found between neither first nor second pvr and ipss. they claimed that increased oral intake of fluids may suddenly decompensate the bladder and result in high residual volume which do not represent the daily voiding practice. however the authors did not include the patients with pvr less than 100 ml after the first measurement which constitutes a significant amount of patients applied to outpatient clinics. in our study, we did not restrict the patients to take oral fluids prior to ultrasound examination which is also needed for a better visualisation of the urinary tract. while alivizatos et al. concluded the negative effect of significant oral intake of fluids prior to pvr measurement, we advise the clinicians to measure pvr at the first desire to void which was correlated with luts. additionally, in a group of young men without luts 60% of men with a pvr less than 50 ml after mild or moderate bladder sensation had a pvr over 50 ml when they voided after a distended bladder.(11) although their study was performed on young healthy men which pvr was not needed to be measured in daily urology practice, it emphasized that bladder could fail to empty at very high capacities. the limitations of the study it is performed at only one center and lack of follow up of the patients in order to find out if there is any relation between the findings of our study and response to therapy. conclusions in conclusion, pvr measurement at the first desire to void with mild bladder sensation correlates with luts and should be performed in the evaluation of the male patients with boo. however, uroflowmetry is advised to be performed when the patient has strong desire to void. conflicts of interest no potential conflict of interest relevant to this article was reported. references 1. martin sa, haren mt, marshall vr, lange k, wittert ga, members of the florey adelaide male ageing s. prevalence and factors associated with uncomplicated storage and voiding lower urinary tract symptoms in community-dwelling australian men. world j sensation, residual volume and uroflowmetry-uzun et al. urol. 2011;29:179-84. 2. gratzke c, bachmann a, descazeaud a, et al. eau guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2015;67:1099-109. 3. sundaram d, sankaran pk, raghunath g, et al. correlation of prostate gland size and uroflowmetry in patients with lower urinary tract symptoms. j clin diagn res. 2017;11:ac01-ac4. 4. kim m, cheeti a, yoo c, choo m, paick js, oh sj. non-invasive clinical parameters for the prediction of urodynamic bladder outlet obstruction: analysis using causal bayesian networks. plos one. 2014;9:e113131. 5. griffiths cj, murray a, ramsden pd. accuracy and repeatability of bladder volume measurement using ultrasonic imaging. j urol. 1986;136:808-12. 6. dunsmuir wd, feneley m, corry da, bryan j, kirby rs. the day-to-day variation (test-retest reliability) of residual urine measurement. br j urol. 1996;77:192-3. 7. kolman c, girman cj, jacobsen sj, lieber mm. distribution of post-void residual urine volume in randomly selected men. j urol. 1999;161:122-7. 8. alivizatos g, skolarikos a, albanis s, ferakis n, mitropoulos d. unreliable residual volume measurement after increased water load diuresis. int j urol. 2004;11:1078-81. 9. dicuio m, pomara g, menchini fabris f, ales v, dahlstrand c, morelli g. measurements of urinary bladder volume: comparison of five ultrasound calculation methods in volunteers. arch ital urol androl. 2005;77:60-2. 10. hansen mv, wold t. a survey concerning the attitudes of urologists toward prostatism patients. scand j urol nephrol. 1994;28:25764. 11. ozden e, turgut at, gogus c, kosar u, baltaci s. effect of premicturitional bladder volume on the accuracy of postvoid residual urine volume measurement by transabdominal ultrasonography: rate of bladder fullness is of great importance for preventing falsepositive residue diagnosis. j ultrasound med. 2006;25:831-4; quiz 5-6. 12. reynard jm, yang q, donovan jl, et al. the ics-'bph' study: uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. br j urol. 1998;82:619-23. 13. oelke m, hofner k, jonas u, de la rosette jj, ubbink dt, wijkstra h. diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in men: detrusor wall thickness, uroflowmetry, postvoid residual urine, and prostate volume. eur urol. 2007;52:827-34. case report virtual three-dimensional magnetic resonance fetal cystoscopy: a novel modality for precise in utero evaluation of urinary tract abdol-mohammad kajbafzadeh1*, behnam nabavizadeh1, reza seyed hossein beigi1, pariya alinia1, seyed ali mirshahvalad1 1pediatric urology and regenerative medicine research center, children's medical center, tehran university of medical sciences, tehran, iran. *correspondence: pediatric urology and regenerative medicine research center, children's medical center, tehran university of medical sciences, no. 62, dr. gharib's street, keshavarz boulevard, tehran, iran p.o. box: 1419733151. tel: + 98-21-66565400. fax: + 98-21-66565500. email: kajbafzd@sina.tums.ac.ir. received may 2018 & accepted october 2018 urogenital anomalies are the most prevalent anomalies detected in the fetus during pregnancy. timely detection of these conditions could facilitate proper post-natal management and improve outcomes. in some cases, precise delineation of fetal urinary tract utilizing ultrasonography is not feasible. moreover, sometimes the ultrasound study is technically limited. magnetic resonance imaging could clarify the diagnosis in these situations. prenatal ultrasonography indicated hydronephrosis and a 14 mm cystic lesion at the right ureterovesical junction in a -25 week fetus. however, fetal magnetic resonance urography was not able to precisely clarify the condition and extension of ureterocele into the urethra. fetal magnetic resonance virtual cystoscopy clearly demonstrated anatomy and extension of ureterocele. this modality provides three-dimensional cystoscopic-like view of the urinary bladder and facilitates postnatal management. keywords: fetal mri ; ureterocele; three-dimensional; virtual cystoscopy introduction urogenital anomalies are considered as the most common abnormalities detected during prenatal period(1). most of these anomalies may result in the development of unilateral or bilateral antenatal hydronephrosis (anh). as the underlying causes of anh are highly diverse, the accurate diagnosis, management, and prognosis of this condition are still a matter of debate. initially, the presence of urogenital anomaly and anh is suggested during prenatal ultrasonography (us) as the first line imaging modality. this technique can facilitate determination of anh severity, diagnosis and postnatal outcome(1). additionally, detecting presence of other organ abnormalities and evaluation of adjacent structures are feasible with this technique. despite the fact that us is considered as the modality of choice for fetal screening, it is limited in several conditions such as oligohydramnios, maternal obesity, and undesirable fetal position(2). in such circumstances with inconclusive us findings, magnetic resonance imaging (mri) will play a major role for further evaluation of fetal figure 1. fetal mru obtained at 27 weeks of gestation which reveals a ureterocele at right ureterovesical junction (arrow). urology journal/vol 17 no. 1/ january-february 2020/ pp. 102-104. [doi: 10.22037/uj.v0i0.4569] vol 17 no 01 january-february 2020 03 urogenital abnormalities(3) facilitating postnatal counseling and early treatment. fetal magnetic resonance urography (mru) as a non-ionizing complementary to sonographic imaging, helps to clarify uncertain diagnoses and precisely detect vast majority of urogenital malformations(4). however, visualization of the lower urinary tract surface and sometimes exact anatomy of malformations is not attainable with this modality. three-dimensional (3d) virtual navigation is a cutting-edge technology created from overlapping image layers obtained from us or mri scan data(5). this technology is capable of providing information for the evaluation of different hollow fetal structures which is comparable to performing conventional invasive diagnostic procedures such as bronchoscopy(6). in the present case, we processed mri data to produce 3d views of the urinary tract in a case of anh with fetal ureterocele. case report a 31-year-old pregnant woman (p1 ; first parity) at 25 weeks of gestation was referred to our pediatric urology clinic for further evaluation following detection of severe right fetal hydronephrosis and a 14 mm cystic lesion at the right ureterovesical junction in prenatal us. anteroposterior diameter of right renal pelvis was equal to 15.3 mm. other sonographic findings were unremarkable. amniotic fluid and biophysical profile were reported normal during pregnancy. for further assessment, a fetal mru was obtained at 27 weeks of gestational age with different sequences and cuts using 1.5 tesla magnetom avanto siemens machine with advanced shimming gradient (figure 1). no contrast media was used in this regard. heavily t2-weighted pulse sequence was applied to acquire urine signal in fetal bladder. in order to render 3d images with viewpoint inside the fetal urinary bladder, we used advantage workstation for diagnostic imaging 4.2.2, general electric healthcare. 3d virtual cystoscopy provides detailed multislice images of inner surface of fetal bladder (figure 2.a). intravesical ureterocele was precisely depicted at right ureterovesical junction which was not obstructing without extension to the urethra (figure 2.b). the pregnancy was uneventful and labor was induced at 38 weeks with vaginal delivery of a female newborn. the apgar score was calculated 8 at 1 minute and 10 at 5 minutes. the baby weighed 2.850 kg (15th25th centile) and measured 47 cm (5th-15th centile) in length. the initial physical examination was completely normal. the newborn was immediately admitted in order to monitor renal function. laboratory data for renal function were within normal ranges. neonatal renal us at 3rd day revealed right duplicated collecting system with severe hydronephrosis (grade 3) in right upper moiety and a dilated tortuous ureter. right lower renal pelvis was relatively dilated with a diameter of 3.5 mm. left renal unit appeared normal in us. moreover, a non-obstructing ureterocele was detected at right ureterovesical junction. intravenous antibiotic was administered during hospitalization. she was discharged after one week under antibiotic prophylaxis and referred to the pediatric urology clinic. she underwent ureterocele endoscopic double puncture surgery at 3 months of age. she remains symptom-free after 10 months of follow up without any episodes of urinary tract infection (uti). discussion ureteroceles account for up to 3% cases of anh. historically, ureteroceles were mostly diagnosed in early life, when the symptoms (such as frequent utis, urinary retention, failure to thrive and etc.) became unmasked. currently, with the advent of routine prenatal us, most cases are detected in utero which allows early management of the condition before devastating complications occur. it is highly important to detect ureteroceles during prenatal period to improve postnatal outcomes. in essence, determining distal extension of ureterocele and possibility of bladder outlet obstruction is crucial for optimal postnatal management. in a study by upadhyay et al., patients with prenatally diagnosed ureteroceles encountered less uti and decreased risk of reoperation comparing to those with postnatally diagnosed ureteroceles(7). fetal ureterocele is visualized as a cyst inside the bladder on us and may be associated with duplicated collecting system. ectopic subtypes of ureterocele may develop lower urinary tract obstruction and generally require immediate intervention in order to prevent catastrophic complications. in fetal cases of ureterocele, this condition is more prominent. despite providing additional information comparing to prenatal us, mru is unable to show true extension of ureterocele into the urethra which is of utmost importance to define the timing of delivery and plan postnatal management and counseling. also visualization of bladder surface is not feasible by mru. if distal extension of ureterocele to the urethra and urinary obstruction is evident in a fetus, free urinary drainage should be maintained immediately after the delivery to preserve the newborn’s renal function. in our present case, virtual fetal cystoscopy using mri, three-dimensional fetal cystoscopy-kajbafzadeh et al. case report 413 figure 2. virtual fetal cystoscopy visualization acquired with magnetic resonance. (a): three-dimensional view of bladder surface and left ureteral orifice. (b): ureterocele with distal extension to the bladder neck (arrow). vol 17 no 01 january-february 2020 103 provides a novel perspective and it was capable of showing 3d cystoscopic-like view of urethra and bladder, clear distal extension of ureterocele, and possibility of bladder outlet obstruction (figure 2). in fact, these findings are crucial for assessing the need for prenatal intervention and planning endoscopic treatment of ureterocele using double puncture technique(8). moreover, detection of other etiologies of lower urinary tract obstruction (such as posterior urethral valves (5)) and evaluation of lower urinary tract surface are attainable in this technique. on the other hand, manipulation during conventional cystoscopy and ureteral peristalsis may preclude the diagnosis. virtual cystoscopy can overcome this issue and present untouched images of ureterocele. in a recent study, 3d virtual navigation using mri scan data showed clear visualization of urethral lumen, distended bladder, and hydroureter in a fetus with posterior urethral valve. the rendered images were very close to reality in their case(5). in conclusion, virtual fetal cystoscopy presents a novel intraluminal view of the fetal lower urinary tract, which could help to elucidate the etiology of anh. consequently, proper immediate postnatal counseling and interventions would be facilitated. however, further prospective investigations with larger study population are mandatory to standardize this non-invasive technology as an alternative for precise fetal urinary tract assessment and evaluate its additive value. conflicts of interests none references 1. yamacake kg, nguyen ht. current management of antenatal hydronephrosis. pediatr nephrol. 2013;28:237-43. 2. sozubir s, lorenzo aj, twickler dm, baker la, ewalt dh. prenatal diagnosis of a prolapsed ureterocele with magnetic resonance imaging. urology. 2003;62:144. 3. chapman t. fetal genitourinary imaging. pediatr radiol. 2012;42 suppl 1:s115-23. 4. kajbafzadeh am, payabvash s, sadeghi z, et al. comparison of magnetic resonance urography with ultrasound studies in detection of fetal urogenital anomalies. j pediatr urol. 2008;4:32-9. 5. werner h, lopes j, ribeiro g, et al. threedimensional virtual cystoscopy: noninvasive approach for the assessment of urinary tract in fetuses with lower urinary tract obstruction. prenat diagn. 2017;37:1350-2. 6. werner h, lopes dos santos jr, fontes r, et al. virtual bronchoscopy for evaluating cervical tumors of the fetus. ultrasound obstet gynecol. 2013;41:90-4. 7. upadhyay j, bolduc s, braga l, et al. impact of prenatal diagnosis on the morbidity associated with ureterocele management. j urol. 2002;167:2560-5. 8. kajbafzadeh a, salmasi ah, payabvash s, arshadi h, akbari hr, moosavi s. evolution of endoscopic management of ectopic ureterocele: a new approach. j urol. 2007;177:1118-23; discussion 23. three-dimensional fetal cystoscopy-kajbafzadeh et al. case report 104 case report laparoscopic pyelolithotomy for management of complete staghorn stone of an ectopic pelvic kidney mohammad hossein soltani1*, sepehr hamedanchi1,2, behnam shakiba1, hassan hoshyar1 a 40-year-old man was referred to our urology clinic due to vague abdominal pain and hematuria. computed tomography (ct) without contrast material visualized an ectopic kidney in the left iliac fossa with a complete staghorn stone. under general anesthesia, operation was done in supine position with a gentle lateral elevation on the right side. the surgeon stands on the right side of the patient. first, a 12 mm port was inserted at the umbilicus using the hasson technique. after creation of pneumoperitoneum, operation was done by three 5 mm trocars were arranges as paraumbilical, the point between umbilicus and inguinal canal at left and right side. a vertical pyelotomy incision was made over the anterior pelvic wall and then extended to a cross figure. the stone extracted intact with a laparoscopic stone grasper and placed in endobag. a short double j stent was placed via the pyelotomy incision and renal pelvis was closed using continuous 4.0 vicryl sutures. he was discharged from hospital after 3 days without any complication. introduction pelvic kidney is a rare congenital renal locational anomaly with an incidence between 1/2200 and 1/3000(1). the ectopic pelvic kidney is more susceptible to develop nephrolithiasis. this may be a result of the anteriorly placed pelvis, abnormal position of the uretero-pelvic junction and malrotation of the kidney(2). despite the availability of many treatment modalities for the stones in pelvic kidneys, like shockwave lithotripsy (swl), percutaneous nephrolithotomy (pnl), retrograde intrarenal surgery (rirs), laparoscopy and open surgery; choosing the best treatment modality is still confusing(3). we present a patient diagnosed as ectopic pelvic kidney with complete staghorn, which was managed with laparoscopic pyelolithotomy (lpl). 1endourology department of shahid labbafinejad hospital, urology and nephrology research center, shahid beheshti university of medical sciences (sbmu), tehran, iran. 2urology department of imam khomeini hospital, urmia university of medical sciences, urmia, iran. *correspondence: endourology department of shahid labbafinejad hospital, urology and nephrology research center, shahid beheshti university of medical sciences (sbmu), tehran, iran. e mail: mhsoltani60@gmail.com. received august 2017 & accepted november 2017 keywords: ectopic; laparoscopy; pyelolithotomy; renal stone; staghorn. figure1. ct scan shows a large renal calculi in an ectopic pelvic kidney. case report 214 case report a 40-year-old man was referred to our urology clinic due to vague abdominal pain and hematuria. in his past medical history, he had no previous history of urinary tract infection, renal stones, vesicoureteral reflux, or other renal diseases. on physical examination, no abnormalities were noted. laboratory tests showed hematuria and sterile pyuria in urine analysis. a urine culture excluded urinary tract infection. ultrasonography showed the ectopic left renal kidney with a large renal stone. computed tomography (ct) without contrast material visualized an ectopic kidney in the left iliac fossa with a complete staghorn with hounsfield unit of 1100 (figure 1). the right kidney was in normal position. after obtaining adequate informed consent, he was hospitalized in our department and planned for laparoscopic pyelolithotomy. the stone was larger than 2 cm so we decided not to perform swl or rirs for this patient. also because the pelvis was extrarenal and anteriorly positioned, we preferred to choose pure laparoscopy instead of lap assisted pnl. one gram of cephalotin was given to the patient preoperatively. under general anesthesia, operation was done in supine position with a gentle lateral elevation on the left side. the surgeon stood on the right side of the patient. first, a 12 mm port was inserted at the umbilicus using the hasson technique. after creation of pneumoperitoneum, operation was done through three 5 mm trocars arranged paraumbilical and the points between umbilicus and inguinal canal at left and right side. cecum and ascending colon were reflected medially by incising the white line of toldt, and retroperitoneal space was entered. renal pelvis was released and exposed. a vertical pyelotomy incision was made over the anterior pelvic wall and after several failed trials for stone extraction, extended to a cross figure. the stone extracted intact with a laparoscopic stone grasper (figure 2) and placed in an endobag. a short double j stent was placed via the pyelotomy incision and renal pelvis was closed using continuous 4.0 vicryl sutures. twelve mm port site was dilated and the endobag containing the stone was extracted (figure 3) . a drain was placed into the operation area through one port site, and the procedure was terminated. the patient started oral intake after 24 hours. drain was removed 48 hours after the operation when its output was < 30 ml. he was discharged from hospital after 3 days without any complication. double j stent was removed under local anesthesia after 4 weeks. discussion the ectopic pelvic kidney is more susceptible to hydronephrosis and nephrolithiasis than normally positioned kidneys. the position of renal pelvis, ureteral insertion, kidney malrotation and renal vasculature can cause urine stasis and renal stone (4). choosing the best modality for treatment of nephrolithiasis is still a debate due to risk of injury to the aberrant vessels, adjacent organs and nerves. there are several management modalities to deal with stones of ectopic pelvic kidney like swl, rirs, percutaneous nephrolithotomy (pnl), laparoscopy and open surgery. although some studies show that swl is a suitable option for treatment of renal stones in pelvic kidneys with stone free rate about 57% (2) there are some limitations and technical challenges for using this modality in a pelvic kidney. pelvic kidney is surrounded by bony structures and pelvic bone interferes with shock wave transmission and results in less effectiveness of swl. some studies reported that swl can be used as an effective modality in stone fragmentation, but abnormal drainage of pelvic kidney reduces stone free rate and increases residual fragments(5). some reports presented swl as a first line treatment in pelvic kidney stones less than 2 cm(6). rirs is another option for treatment of renal stones in pelvic kidneys, but tortuous ureter is often associates with difficulty in access to renal pelvis. the best results of swl or rirs are achieved in stones smaller than 2 cm in pelvic kidneys(4,7). we did not use these modalities for our case, because the stone was a staghorn. laparoscopic assisted pnl for the treatment of stones in a pelvic kidney was described by eshghi initially(8). figure 2. twelve mm port site was dilated and the endobag containing the stone was extracted by using an endobag. figure 3. the extracted stone intact with a laparoscopic stone grasper. laparoscopic pyelolithotomy in pelvic kidney-soltani et al. vol 15 no 04 july-august 2018 215 the advantages of this modality include suitable exposure of the kidney, enhancing safe puncture and correct tract placement(4). the majority of urologists choose this modality as preferred treatment for large stones in pelvic kidneys. in these years, successful laparoscopic pyelolithotomy for management of renal stones has advanced rapidly and some urologists prefer this modality. in comparison between pnl and lpl, risk of bleeding and nephron injury are higher in pnl related to transgression and dilation of renal parenchyma. in lpl, stones are extracted intact and stone free rate is very high in contrast to pnl in which fragmentation of stone may increase the residual fragments and decrease stone free rate(9). it should be mentioned that lpl is appropriate approach for kidneys with anterior or laterally positioned extrarenal pelvis(10). also we experienced in our case that extending the pyelotomy incision will help to extract stones with complex shapes and suturing those incisions is possible through laparoscopy. laparoscopic pyelolithotomy can be performed intraperitoneally or retroperitoneally. although the retroperitoneal access provides more appropriate access to the posterior aspect of the renal pelvis, avoids extensive dissection and eliminates peritoneal contamination with urine and blood, albeit it is not a suitable option in pelvic kidneys and we preferred the intraperitoneal route. intraperitoneal approach is more familiar to urologists and provide better anatomical landmarks and large working space. recently combination of laparoscopy and retrograde endoscopy has been used successfully for management of ureteral and pelvic stones(11,12). simultaneous endoscopy can help to locate the stone site and displace the stone to more accessible location for laparoscopic manipulation. in conclusion, laparoscopic pyelolithotomy is a safe and effective treatment modality and can be proposed as the first line treatment for staghorn stones in ectopic pelvic kidneys with anteriorly positioned large extrarenal pelvis with minimal bleeding and renal parenchymal injury. references 1. zafar fs, lingeman js. value of laparoscopy in the management of calculi complicating renal malformations. j endourol 1996;10:379 –83. 2. tunc l, tokgoz h, tan mo, kupeli b, karaglan u, bozkirli i. stones in anomalous kidneys: resuts of treatment by shock wave lithotripsy in 150 patients. int j urol. 2004;11:831– 6. 3. ergin g, kirac m, unsal a, kopru b, yordam m, biri h. surgical management of urinary stones with abnormal kidney anatomy. kaohsiung j med sci. 2017 apr;33:207-11. 4. cinman nm, okeke z, smith ad. pelvic kidney: associated diseases and treatment. j endourol. 2007 aug;21:836-42 5. theiss m, wirth mp, frohmuller hg. extracorporeal shock wave lithotripsy in patients with renal malformations. br j urol 1993;72:534–38. 6. ahangar s, durrani am, qadri sj, patloo am, ganaie rg, khan m. laparoscopic laparoscopic pyelolithotomy in pelvic kidney-soltani et al. trans-peritoneal pyelolithotomy in a pelvic kidney. saudi j kidney dis transpl. 2012 nov;23:1254-7. 7. ölçücüoğlu e, çamtosun a, biçer s, bayraktar am. laparoscopic pyelolithotomy in a horseshoe kidney. turk j urol. 2014 dec;40:240-4. 8. eshghi am, roth js, smith ad. percutaneous transperitoneal approach to a pelvic kidney for endourological removal of staghorn calculus. j urol 1985;134:525–27. 9. haggag ym, morsy g, badr mm, al emam ab, farid m, etafy m. comparative study of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in the management of large renal pelvic stones. can urol assoc j. 2013 mar-apr;7:e171-5. 10. sahin s, resorlu b, atar fa, eksi m, sener nc, tugcu v. laparoscopic ureterolithotomy with concomitant pyelolithotomy using flexible cystoscope.urol j. 2016 10;13:28336. 11. jurkiewicz b, zabkowski t, jobs k, samotyjek j, jung a. combined use of pyelolithotomy and endoscopy: an alternative surgical treatment for staghorn urolithiasis in children. urol j. 2016 ;13:2599-604 12. soltani mh, simforoosh n, nouralizadeh a, sotoudeh m, mollakoochakian mj, shemshaki hr. laparoscopic pyelolithotomy in children less than two years old with large renal stones: initial series. urol j. 2016 ;13:2837-40. case report 216 urological oncology evaluation of diagnostic accuracy of percutaneous biopsy for small renal masses and first report of post-biopsy adhesions: a prospective study tunkut doganca*, can obek purpose: in the present study, we evaluate the biopsy results, complications due to biopsy, and the correlation with the final pathology specimen of 19 patients who had surgery for their small renal masses. materials and methods: a total of 19 patients (11 male, 8 female) underwent percutaneous biopsy of their renal mass under ultrasound guidance. all patients subsequently underwent extirpative surgery. preoperative biopsy results were compared with postoperative specimens in terms of tru-cut and fine needle aspiration biopsies’ histopathological accuracy and the complications noted. results: average age was 56±10.5 years and tumor size was 37±10.6 mm. six patients had only fine needle, 4 patients had only tru-cut, and 9 patients had both fine needle and tru-cut biopsies. malignancy was reported in 14, and benign results in 5 patients. sensitivity, specificity, ppv and npv’s were 64%, 100%, 100%, 33% respectively for fnab. sensitivity, specificity, ppv and npv’s were all 100% for tru-cut core biopsy. two perirenal hematoma was detected which resolved spontaneously under conservative therapy. in 11 patients there were adhesions due to biopsy, which caused difficulty of dissection during the operation. conclusion: in this relatively small series, percutaneous ultrasound guided biopsy to determine the histology of small renal masses achieved a high diagnostic accuracy. fnab alone has a low diagnostic accuracy with false negative results when compared. however, tru-cut core biopsy has a diagnostic accuracy of %100. therefore we recommend tru-cut biopsy when histopathological diagnosis is required for small renal masses. adhesions due to biopsy may cause difficulties during dissection. keywords: biopsy adhesions; biopsy complications; renal biopsy; renal cancer; small renal masses introduction incidence of small renal masses (< 4cm) (srm) is in-creasing due to widely use of cross-sectional imaging techniques and management of these clinical issue is getting more important and complicated depending on which patients will need therapy and which therapy option is feasible and effective. biopsy of a renal mass is not the standard of care and is suggested in specific circumstances only. there has been a stage shift within the recent years with renal masses presenting at lower stages and smaller sizes at diagnosis. srm show heterogeneous histological properties with both malign and benign characteristics. smaller lesions tend to be more benign.(1,2) these patients may potentially be offered a variety of management options changing from observation only to radical surgery. the information which gained by the tissue sampling with accurate biopsies, can be decisive at choosing treatment method. in addition to the change in clinical presentation and management, advances in biopsy and immunohistochemical analysis techniques, along with successful outcomes of renal biopsies have caused an increased interest in the potential role of biopsy in renal masses.(3,4) in the present study, we evaluate diagnostic accuracy department of urology, acibadem taksim hospital, istanbul 34300, turkey. *correspondence: acibadem taksim hospital, department of urology, istanbul, turkey. mailing adress: inonu mah., nizamiye cad. no:1, 34373 sisli/istanbul/turkey. gsm: +905327042325 fax: +902122190987. tunkutdoganca@gmail.com. received october 2017 & accepted july 2018 of two different biopsy techniques (tru-cut and fnab) and the correlation with the final pathology specimen of 19 patients who had surgery for their small renal masses. also biopsy related complications such as post biopsy adhesions were noted and discussed. materials and methods study population a total of 20 patients with a renal mass (<5 cm.) who are candidates for extirpative surgery has been offered biopsy. size of the tumors measured with coaxial imaging techniques such as ct and mri. nineteen patients accepted the procedure and after consultation with radiology department, biopsies were performed. study design cysts with heterogeneity and masses suspected for collecting system malignancies were excluded. all patients underwent surgery after the biopsy and final pathological results were compared with the biopsy results. inefficient tissue samples, normal renal parenchyma, extrarenal tissue, blood cells and necrosis were accepted as inadequate biopsy result. biopsy related early and late complications were also noted and a post-op questionnaire for the surgeons was used to determine if the biopsy procedure affected and challenged the surgiurology journal/vol 16 no. 4/ july-august 2019/ pp. 357-360. [doi: http://dx.doi.org/10.22037/uj.v0i0.4215] cal procedure. sensitivity, specificity, positive and negative predictive values were also calculated. informed consent was obtained from all patients which had been approved by the local ethics committee (istanbul university ethics committee, file no: 01.09.20/s11) biopsy technique all biopsies were performed under local anesthesia with the guidance of ultrasonography (usg). patients were evaluated for hemorrhagic diathesis and routine biochemical tests were performed before the procedure. fine needle biopsy (fnb) in 6, tru-cut biopsy in 4, and fnb+tru-cut biopsies were performed in 9 patients. main concern about performing tru-cut biopsy was excessive vascularity of the tumor or nearness to the renal hilum. a cytopathologist evaluted fnab samples in the procedure room simultaneously and fna biopsies were repeated up to 3 times according to the information from the cytopathologist. tru-cut biopsies were performed by 18gauge needle. both center and peripheral zones of the tumors were tried to be sampled. separate tru-cut sampling technique were chosen instead of co-axial technique. necessity of using a trocar needle thicker than 18 gauge was the main concern in terms of higher possibility of bleeding. patients were observed for two hours with ultrasonography in case of hematoma formation. results there were 11 male and 8 female patients with average age of 56 (± 10.5) years. average tumor size was 36 mm (20-50) (± 10.6). mean time between biopsy and operation was 26.4 (± 7.2) days. nine of the tumors were right and 10 of them were left sided. final pathological results were 16 renal cell carcinoma (rcc), 2 oncocytoma and 1 glomus tumor. immunohistochemical techniques used in 4 specimens (%21. 2 of them were oncocytomas and 2 rccs). (table 1) fnb results were inefficient in 2, benign in 6 and malign in 7 patients. only 2 of 6 benign results were correlated with final pathology (4/6 false negative results). tru-cut samples were always adequate for histological evaluation. two benign and 11 malignant results were reported. all of these results show consistency with the final pathology. (fnab and tru-cut needle biopsy results are presented in table 2) sensitivity, specificity, positive and negative predictive values were %64, %100, %100 and %33 for fnab respectively. there were no false negative or false positive results in tru-cut, so all of the above values were %100. (table 2) complications two patients with post-biopsy hematomas (3 and 4 cm) managed conservatively and required no intervention. no clinical infection, pleural injury or pneumo/heamothorax were observed. there were adhesions in 11 patients (%61) which made the surgical procedure difficult according the post-op surgeon questionnaires. these adhesions also compromised tumor margins to be properly determined during surgery. in absence of validated or generally accepted adhesion scores for retroperitoneal surgery, effect of adhesions were evaluated with a simple questionnaire after the operation by the operating surgeon who defined the effects of biopsy on increased difficulty of dissection as minimal, moderate or severe. in 11 procedures, surgeons’ statements were as 2 moderate and 9 percutaneous biopsy for renal masses-doganca et al. table 1. demographic data of patients and histological diagnosis for each biopsy type and final pathology. patient no. gender age fnab tru-cut final pathology 1 m 55 rcc rcc 2 f 46 benign rcc 3 f 50 inadequate benign benign 4 f 68 benign rcc 5 f 52 benign rcc rcc 6 f 33 rcc rcc rcc 7 f 62 rcc rcc 8 f 56 benign rcc rcc 9 m 64 rcc rcc rcc 10 m 44 rcc rcc 11 f 63 rcc rcc rcc 12 m 60 rcc rcc 13 m 68 benign benign 14 m 65 rcc rcc 15 m 50 benign benign benign 16 m 66 rcc rcc 17 m 40 inadequate rcc rcc 18 m 52 rcc rcc rcc 19 f 69 rcc rcc abbreviations: fnab, fine needle aspiration biopsy; f, female; m, male; rcc, renal cell carcinoma final pathology, malignant final pathology, benign total fnab, malignant pathology 7 0 7 fnab, benign pathology 4 2 6 total (fnab) 11 2 13 tru-cut, malignant pathology 11 0 11 tru-cut, benign pathology 0 2 2 total (tru-cut) 11 2 13 abbreviations: fnab, fine needle aspiration biopsy table 2. pathological diagnosis for fnab and tru-cut biopsy. vol 16 no 04 july-august 2019 358 severe adhesions. frozen section evaluation of tumors showed two positive surgical margin status and resulted in re-excision which also caused prolonged ischemia time. adhesions were mainly detected in biopsy tracts but in some patients minor hemorrhagies and possible desmoplastic reactions caused severe adhesions also in perirenal fat tissues. during the early follow up after biopsies, there were no significant hypotension. pain scores were mild (all < 6 via visual analog – numeric pain scale) and didn’t required any painkillers except paracetamol and nonsteroids. one patient developed high fever in first 24th hours. ultrasonographic evaluation of biopsy site didn’t show any abnormalities such as hematoma, collection or abscess formation. during follow-up, fever was responsive to oral hydration and paracetamol therapies and there was no need for prolonged antibiotic therapy. macroscopic hematuria were observed in two patients with endophytic renal masses but there were no need for urethral catheterization due to excessive bleeding or urinary clots. none of the patients required blood transfusion. postoperative period of 9 patients who had severe post-biopsy adhesions were not eventful. prolonged ischemia time because of positive surgical margins at initial excision were not influential on postoperative creatinine levels. two patients had high fever in first 48 hours with no positive bacterial growth in urine and blood cultures and were evaluated as possible atelectasis related fever which solved in first 48 hours of antibiotic therapy. complications are presented in table 3 with clavien classification. discussion renal biopsy has not been routinely performed because of historical fear about hemorrhagic complications and tumor seeding. low diagnostic results due to poor techniques and inefficient instruments also caused drawbacks about performing biopsy for srms.(1) biopsy can be performed with fine-needle or tru-cut biopsy needle under ultrasonography, computerize tomography or magnetic resonance imaging. size, nature (necrotic areas or satellite lesions) and location of the lesion is important to determine sampling areas and numbers.(5) according to eau guidelines, biopsy is not recommended routinely for renal masses. role of biopsy is currently limited to masses which are candidate for active surveillance or ablative therapies.(6) publications before 2001 on renal biopsy reported 88.9% accuracy and 0-25% false negative results.(7-9) however these discouraging results are primarily because of inadequate sampling.(10) technical failure is also as high as 8.9%. in series published after 2001, accuracy was increased to 96% with better imaging techniques and better sampling with developments of biopsy needles.(1,5,11) immunohistochemistry is also used around 50% for evaluation of biopsy samples.(3,4) immunohistochemical techniques were also used in 4 patients in our study to determine histology. latest retrospective cohort study including 529 patients’ data represented a diagnostic yield at 90%, reaching 94% when a repeat biopsy was performed after a failed one. benign lesions were 20% likewise in other publications.(12) there are limited studies in the literature that compares the biopsy results with the surgical specimens. srm biopsy may not identify the whole mass because of partial sampling and heterogeneous nature of renal masses. (13,14) appropriate biopsy technique is another important issue besides mass’ characteristics. in recent studies, usg and ct imaging modalities were mostly used.(1517) we preferred usg for guidance because of its accessibility and cost effectiveness. also, biopsy needle types are important factors to achieve right diagnosis. there are some studies who stop using fnab and continue with only with tru-cut needles because of high percentage of inadequate sampling and low specificity results with fnab.(3) fnab achieved the right diagnosis in only 9 of 15 patients in our study with a accuracy rate of 69%. however, final pathology correlation was 100% for tru-cut samples. pathologist were not blind for the preoperative biopsy results when evaluating final specimens. correct subtyping of rcc’s are up to 94% in literature with a 91% for clear cell, 91% for papillary type and 100% for chromophobe rcc.(1) fuhrman grading is adequate only in 70% and 83%, with the reason of tumor heterogeneity.(1,7) in our study pathologists could report 9 biopsy samples’ fuhrman grades with a 100% correlation with final specimen. surgical challenge caused by post biopsy adhesions were never reported in literature. there were 11 moderate to severe adhesions in our study. two of these patients had hematoma, which were detected after biopsy and it’s uncertain that if these adhesions were related to hematoma formation or traumatic effect of biopsy needle at the tract. in one case, severe adhesion of perirenal fat tissue to the tumor, make difficult to determine safe surgical margins between tumor and parenchyma and resulted with conversion to open surgery from laparoscopy. retroperitoneal adhesions are mainly considered about retroperitoneal laparoscopic surgical procedures and are often related with previous percutaneous stone pt. no. biopsy complication (clavien grade) management surgery complication (clavien grade) management 1 fever (i) antipyretics none 2 none none 3 hematoma formation (i) conservative prolonged ischemia time (i) conservative 4 none prolonged ischemia time (i) conservative 5 hematoma formation (i) conservative none 6 hematuria (i) conservative none 7 hematuria (i) conservative none 8 none fever (i) antibiotics 9 none none table 3. classification of biopsy and surgery complications based on modified clavien classification for patients who had developed severe adhesions after biopsy. percutaneous biopsy for renal masses-doganca et al. urological oncology 359 surgery or nephrostomy tube placement in case of hydronephrosis. these adhesions are generally firm and allow blunt dissection during laparoscopic intervention. patients with srm are candidates for nephron sparing surgery and determining safe surgical margin between tumor and renal tissue is essential during partial nephrectomy. post-biopsy adhesions in case of hardening the clear surgical dissection and obtaining a clear cleavage may cause a rational drawback to perform biopsy. small sample size is a major limitation for our study. biopsy related complications such as hematoma formation was low, but within this small patient group, it’s not suitable to discuss on percentages. however, there was a significant adhesion rate which needs to be mentioned. retroperitoneal adhesions wre not studied and classified as intraperitoneal adhesions so far in the literature. adhesions may be grouped as filmy/strong, needs blunt/sharp dissection, or vascularized. in our study, adhesion levels were examined by surgeons’ feedback which is a highly subjective method. biopsy technique may effect the development of post-biopsy adhesions. we chose separate tru-cut sampling from tumors, which means more than one access was needed. using a trocar needle, which is thicker than 18 gauge as a co-axial technique may reduce access numbers but also increase bleeding possibility. histopathological nature of adhesions were not determinable in our study, with lack of histologic sampling from adhesions. fibrotic processes after biopsy related to tissue trauma or post bleeding formation are the main possible causes for these. but small size of groups did not allow us to compare these two techniques in terms of adhesion formation rate. however, high incidence of adhesions encouraged us on reporting. in the present study sensitivity, specificity results were accordant with the literature. there were no major complications. this may be related to limited number of patients. biopsy related adhesions which causes difficulties during surgical dissection is an issue which was not reported before and need to be evaluated with large series. conflict of interest the authors report no conflict of interest. references 1. dechet cb, zincke h, sebo tj, et al. prospective analysis of computerized tomography and needle biopsy with permanent sectioning to determine the nature of solid renal masses in adults. j urol. 2003;169:71-4. 2. campbell sc, novick ac, herts b, et al. prospective evaluation of fine needle aspiration of small, solid renal masses: accuracy and morbidity. urology. 1997;50:25-9. 3. schmidbauer j, remzi m, memarsadeghi m, et al. diagnostic accuracy of computed tomography-guided percutaneous biopsy of renal masses. eur urol. 2008;53:1003-11. 4. volpe a, mattar k, finelli a, et al. contemporary results of percutaneous biopsy of 100 small renal masses: a single center experience. j urol. 2008;180:2333-7. 5. marcelin c, ambrosetti d, bernhard jc, roy c, grenier n, cornelis fh. percutaneous image-guided biopsies of small renal tumors: current practice and perspectives. diagn interv imaging. 2017;98:589-99. 6. ljungberg b, bensalah k, canfield s, et al. eau guidelines on renal cell carcinoma: 2014 update. eur urol. 2015;67:913-24. 7. murphy wm, zambroni br, emerson ld, moinuddin s, lee lh. aspiration biopsy of the kidney. simultaneous collection of cytologic and histologic specimens. cancer. 1985;56:200-5. 8. truong ld, todd td, dhurandhar b, ramzy i. fine-needle aspiration of renal masses in adults: analysis of results and diagnostic problems in 108 cases. diagn cytopathol. 1999;20:339-49. 9. wood bj, khan ma, mcgovern f, harisinghani m, hahn pf, mueller pr. imaging guided biopsy of renal masses: indications, accuracy and impact on clinical management. j urol. 1999;161:1470-4. 10. laguna mp, kummerlin i, rioja j, de la rosette jj. biopsy of a renal mass: where are we now? curr opin urol. 2009;19:447-53. 11. lane br, samplaski mk, herts br, zhou m, novick ac, campbell sc. renal mass biopsy-a renaissance? j urol. 2008;179:20-7. 12. richard po, jewett ma, bhatt jr, et al. renal tumor biopsy for small renal masses: a single-center 13-year experience. eur urol. 2015;68:1007-13. 13. ball mw, bezerra sm, gorin ma, et al. grade heterogeneity in small renal masses: potential implications for renal mass biopsy. j urol. 2015;193:36-40. 14. blute ml, jr., drewry a, abel ej. percutaneous biopsy for risk stratification of renal masses. ther adv urol. 2015;7:265-74. 15. marconi l, dabestani s, lam tb, et al. systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. eur urol. 2016;69:660-73. 16. dave cn, seifman b, chennamsetty a, et al. office-based ultrasound-guided renal core biopsy is safe and efficacious in the management of small renal masses. urology. 2017;102:26-30. 17. jeon hg, seo si, jeong bc, et al. percutaneous kidney biopsy for a small renal mass: a critical appraisal of results. j urol. 2016;195:568-73. percutaneous biopsy for renal masses-doganca et al. vol 16 no 04 july-august 2019 360 sexual dysfunction and andrology comparison of the histopathological findings of testis tissues of non-obstructive azoospermia with the findings after microscopic testicular sperm extraction serdar toksöz1*, yalçın kizilkan2 purpose: to investigate the relationship between the histopathological findings of testis tissue samples and sperm retrieval success of micro-tese in non-obstructive azoospermia (noa) patients. method: histopathological examination results of the testis tissue samples of 795 noa patients who underwent micro-tese operation in our clinic between 2003 and 2014 were included. histopathological findings were grouped as hypospermatogenesis, incomplete spermatocytic arrest, complete spermatocytic arrest, sertoli cell only syndrome (scos), and fibrosis/atrophy. chi-square analysis was used to compare the histopathological findings with the sperm retrieval rates of micro-tese. result: sperm was found in 341 (42,9%) patients following micro-tese compared to 454(57,1%) patients where sperm were not detected (p < 0.001). sperm retrieval rates of micro tese were significantly higher in hypospermatogenesis and incomplete maturation arrest groups (93.2% (p < 0.001) and 72.5% (p < 0.001), respectively). complete maturation arrest, scos and fibrosis/atrophy were determined at significantly higher rates in patients (220.2%) with no sperm found compared to patients with sperm (p < 0.001). conclusion: the findings of this study are consistent with those of previous studies in the literature. testicular histopathological findings can provide additional data when informing noa patients about the expected success of further micro-tese operations. keywords: non-obstructive azoospermia; micro-tese; testicular sperm extraction; pathology introduction infertility is defined as the inability to become pregnant of a sexually active couple despite one year of unprotected intercourse(1). azoospermia is defined as the absence of sperm in ejaculate, and is seen in 10%-15% of patients with complaints of infertility. the absence of spermatozoa in the ejaculate due to failure of spermatogenesis or a very low number of mature sperm in the testes is known as non-obstructive azoospermia (noa) (2). the causes of noa are anorchia, acquired testis trauma, testis torsion, undescended testis, klinefelter syndrome, germ cell aplasia, focal hypospermatogenesis, maturation arrest, orchitis, radiation, testicular temperature increase, gonadotoxic agents, systemic diseases such as cirrhosis and kidney failure, testis tumors, varicocele, surgical interventions, and idiopathic reasons(3,4). in some noa cases, rare foci of spermatogenesis may be present and mature sperm cells can be obtained from these foci with a microsurgery method, known as microscopic testicular sperm extraction (micro-tese)(5). knowing the effect of testicular histopathological findings on micro-tese outcomes can provide additional data when informing noa patients about the expected success of further micro-tese operations. the aim of this study was to investigate the relation1hatay state hospital, departments of urology. 2ankara numune training and research hospital, departments of urology. *correspondence: hatay state hospital, department of urology, zirve caddesi, zirve sitesi d32 ekinci/hatay/ turkey phone: +90 3262194000, 0505 914 21 75. e mail: serdartoksoz@gmail.com. received september 2018 & accepted february 2019 ship between histopathological findings of testis tissue samples and sperm retrieval success of micro-tese in noa patients. materials and methods approval for this retrospective cohort study was granted by the ankara baskent university ethics committee (14/05/2014, ka14/162). obstructive azoospermic patients were excluded from the study. the study included 795 noa patients who underwent micro-tese operation and whose testis tissue samples were examined histopathologically at the urology clinic of baskent university hospital between 2003 and 2014. the histopathological findings were recorded as hypospermatogenesis, incomplete spermatocytic arrest, complete spermatocytic arrest, sertoli cell only syndrome (scos), and fibrosis/atrophy. the presence or absence of sperm were also recorded. in the micro-tese operation, a single longitudinal incision was made passing the scrotal raphe. by opening the layers of the scrotum with blunt and sharp dissections, the testis was exposed on the side where the procedure was to be applied. the avascular area was identified under the microscope and the tunica albuginea was opened with a transverse or longitudinal incision with a no. 15 scalpel. enlarged seminiferous tubules that were sexual disfunction & andrology 212 vol 16 no 02 march-april 2019 213 thought to have active spermatogenesis at x20 or x40 magnification were extracted. (figure 1). if sufficient mature spermatozoa were found, a testicular tissue sample for histopathological examination was obtained and the procedure was terminated. when sperm could not be found, the other testis was examined. after obtaining the testicular tissue samples with appropriate microdissection techniques, the incision in the tunica albuginea was sutured with an absorbable 5-0 or 4-0 suture and the scrotal layers were sutured appropriately. (figure 2) chi-square analysis was used to compare the histopathological findings with the sperm retrieval rates (srr) of micro-tese. statistical analyses of the date were performed using statistical package for social sciences (spss inc. chicago, il) v.22. statistical significance was determined as p < 0.05 for all analyses. results of 795 patients with noa, sperm was found in 341 (42.9%) cases who underwent micro-tese operation. the overall srr was calculated as 42.9% in this study. according to the histopathological diagnoses, srr was 93.2% in hypospermatogenesis, 72.5% in incomplete maturation arrest, 32.3% in complete maturation arrest, 27.5% in scos, and 20% in the fibrosis/atrophy group. the histopathological findings of the testis tissue samples and the srr are presented in table 1. of 201 patients who had previously undergone testis biopsy, sperm was found in 58 (28%). the mean age of the patients was 34.7(± 6.30) years. mean serum fsh, lh and testosterone levels were 17.70( ± 13.45) miu/ml, 8.88( ± 7.89) miu/ml, and 4.33( ± 1.90) ng/ ml, respectively. according to chi-square analysis, the srr of micro tese was significantly higher in the hypospermatogenesis and incomplete maturation arrest groups (93.2% (p < 0.001) and 72.5% (p < 0.001), respectively). complete maturation arrest, scos and fibrosis/atrophy were found to have a significant negative effect on the sperm retrieval success of micro-tese (32.3% (p < 0.001), 27.5% (p < 0.001) and 20%(p < 0.001), respectively). discussion noa is determined in 80%-85% of azoospermic patients(6-8). micro-tese is considered to be the gold standard surgical method for sperm retrieval in noa patients(9,10). the aim of the present study was to examine the testicular histopathological findings after micro-tese in noa patients and to investigate the relationship between histopathological findings and srr micro-tese operation. table 1. the histopathological results of the testis tissues examined after the micro-tese operation and the srr results micro-tese result histopathological findings sperm (+) sperm (-) total hypospermatogenesis* 41 (93.2%) 3(6.8%) 44(100%) incomplete spermatocytic arrest* 147 (72.5%) 56 (27.5%) 203 (100%) complete spermatocytic arrest* 80 (32.3%) 168 (67.7%) 248 (100%) sertoli cell only* 51 (27.5%) 135 (72.5%) 186 (100%) fibrosis/atrophy* 22 (20%) 92 (80%) 114 (100%) total 341 (42.9%) 434 (57.1%) 795(100%) *p-value < 0.001 figure 1. the identification and collection of tubules potentially with sperm, determined dilated and yellow-coloured during the micro-tese operation (image reproduced with the permission of baskent university, adana training and research hospital urology clinic). figure 2. schematic drawing of the incision in the micro-tese operation, showing access to the deep parenchymal tissue histopathology of non-obstructive azoospermia and micro-tese results-toksoz et al. sexual disfunction & andrology 214 testis biopsy is no longer used for diagnostic purposes. however testicular tissue sampling can be a part of the micro-tese procedure. testicular biopsy can be used to differentiate between obstructive and non-obstructive azoospermia. in conditions that lead to obstruction (such as vasectomy, vas agenesis), testis biopsy is not required. normal spermatogenesis, maturation arrest, scos and fibrosis/atrophy can be determined after the histopathological examination of testis biopsy samples. in hypospermatogenesis, all germ cell counts are reduced but all stages of spermatogenesis are present. patients with hypospermatogenesis may be azoospermic or oligozoospermic. in maturation arrest, primary spermatocytes or late spermatids are seen. in germinal aplasia, small testicular volumes and high fsh levels are present. several studies have reported that testis biopsy applied before micro-tese is the most important predictive parameter of srr(6). diagnostic testicular biopsy performed prior to micro-tese increases the risk of complications such as infection, bleeding, hematoma, tubular sclerosis and permanent devascularisation in the testis. it also requires patients to undergo 2 surgical interventions(11). in a study by salehi et al., srr of tese procedure was determined to be 48.8% in 170 noa patients. according to the histopathological examination, patients were grouped as hypospermatogenesis, maturation arrest and scos, and srr was determined as 94%, 43.5% and 21.6% respectively(12). in the current study, a similar srr of 93.2% was determined in the hypospermatogenesis group. in a study by kuai et al., the histopathological findings of testis tissue samples obtained from noa patients were compared with the results of intracytoplasmic sperm injection (icsi). there was no statistically significant difference between histopathological groups in respect of fertilisation, transferable embryos, high quality embryos and the number of transferred embryos. although several studies have reported scos histopathology to be associated with low srr in micro-tese, icsi success and normal birth rates after sperm retrieval are the same as for other groups(13,14). eken et al. investigated the effects of age, testicular volume, serum fsh, lh, testosterone levels and histopathological findings on srr in 145 noa patients. among these factors, only histopathological findings were shown to significantly affect srr. similar to that study, srr was also significantly higher in the hypospermatogenesis group in the present study(15). in another study, in addition to the effect of histopathology on srr, fertilization, pregnancy and live birth rates were also investigated in 271 patients. it was demonstrated that while srr and fertilization were significantly affected, pregnancy and live birth rates were not affected by the histopathological groups(16). the association between infertility and psychological state of both men and women is well known. when viewed from this aspect, the predictability of micro-tese outcomes carries additional importance(17). there are some limitations to this study. the retrospective design of the study is one of the limitations. although surgical procedures and histopathological examination techniques did not change during the 11 year period of this study, the fact that the micro-tese operation was performed by different surgeons and the histopathological findings were examined by different pathologists might have affected the results. conclusions to the best of our knowledge, the present study of 795 patients is the largest patient series in the literature. testis biopsy is still the most valuable predictive parameter for sperm retrieval success in micro-tese, although it is not currently a part of common practice. in this context, it can be considered that the histopathological findings are the most applicable and reliable parameter when informing noa patients about the expected success of further micro-tese operations. conflict of interest the authors declare no conflict of interests. references 1. world health organization. who manual for the standardized investigation and diagnosis of the infertile couple. cambridge: cambridge university press, 2000. http://www. who.int/reproductivehealth/publications/ infertility/0521774748/en/ 2. willott gm. frequency of azoospermia. forensic sci int 1982;20: 9-10. 3. jarow jp, espeland ma, lipshultz li. evaluation of the azoospermic patient. j urol 1989;142:62-5. 4. palermo g, joris h, devroey p, van steirteghem ac. pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. lancet 1992 ; 340: 17-8. 5. hopps cv, goldstein m, schlegel pn. the diagnosis and treatment of the azoospermic patient in the age of intracytoplasmic sperm injection. urol clin north am 2002; 29: 895911. 6. sabanegh e aa. male infertility. in: wein aj kl, novick ac, partin aw, peters ca, editor. campbell-walsh urology. 10th ed. philadelphia: saunders, elsevier inc.; 2012. p. 616-47. 7. jungwirth a1, giwercman a, tournaye h, diemer t, et all; european association of urology guidelines on male infertility. eur urol. 2012 ;62:324-32. 8. akarsu s, büke b, gürgen sg, akdemir s, gode f, biçer m, tekindal ma et al. differences in poly(adp-ribose) polymerase1(parp1 and proliferative cell nuclearantigen(pcna) immunoreactivity in patients who experienced successful and unsuccessful microdissection testicular sperm extraction proceduresurol j. 2017;14:5018-22.. 9. akinsal ec, demirtas a, ekmekcioglu o. comparison of the ratio of the lenght of the second and fourth digits in subgroups of fertileand infertile cases. urol j. 2017 ;14:3081-4. 10. dabaja aa, schlegel pn. microdissection testicular sperm extraction: an update. asian j histopathology of non-obstructive azoospermia and micro-tese results-toksoz et al. vol 16 no 02 march-april 2019 215 histopathology of non-obstructive azoospermia and micro-tese results-toksoz et al. androl 2013; 15: 35-9. 11. schlegel pn, su lm physiological consequences of testicular sperm extraction. hum reprod. 1997;12:1688-92. 12. salehi p, derakhshan-horeh m, nadeali z, hosseinzadeh m, sadeghi e, izadpanahi mh, salehi m. factors influencing sperm retrieval following testicular sperm extraction in nonobstructive azoospermia patients. clin exp reprod med. 2017 ;44:22-27 13. kuai yr, he zj, wang s, zhang k, zeng c, chen l, xue q, shang j, yang hx, xu y. testicular histology does not affect the clinical outcomes of icsi in men with non-obstructive azoospermia. zhonghua nan ke xue. 2017 ;23:889-893. 14. gul u, turunc t, haydardedeoglu b, yaycioglu o, kuzgunbay b, ozkardes h. sperm retrieval and live birth rates in presumed sertoli-cell-only syndrome in testis biopsy: a single centre experience. andrology. 2013;1:47-51. 15. eken a, gulec f. microdissection testicular sperm extraction (micro-tese): predictive value of preoperative hormonal levels and pathology in non-obstructive azoospermia. kaohsiung j med sci. 2018 ;34:103-108. 16. guler i, erdem m, erdem a, demirdağ e, tunc l, bozkurt n, mutlu mf, oktem m. impact of testicular histopathology as a predictor of sperm retrieval and pregnancy outcome in patients with nonobstructive azoospermia: correlation with clinical and hormonal factors. andrologia. 2016 ;48:765-73. 17. gumus k, gulum m, yeni e, ciftci h, akin y, huri e, et al. effects of psychological status onthe oxidation parameters of semen and blood in azoospermic men. urol j. 2018 sep 22. doi: 10.22037/uj.v0i0.4540. endourology and stone disease the efficacy of early extracorporeal shockwave lithotripsy for the treatment of ureteral stones chang hee kim1, dongseong shin2,3, tae beom kim1*, han jung1* purpose: to determine the efficacy of early extracorporeal shockwave lithotripsy (e-eswl) in colic patients with ureteral stones and the patient criteria for the most effective e-eswl. materials and methods: 335 patients who received eswl due to ureteral stone, were divide in two groups: e-eswl and d-eswl by the critical cut-off point. we performed the sensitivity and specificity cut-off analyses to identified the critical cut off point. to assess the difference in the factors affecting eswl success, univariate and multivariate logistic analyses were implemented with using variables: eswl success; age; gender; bmi; comorbidity; serum creatinine; stone size; stone location; stone laterality; hounsfield unit (hu); presence of hydronephrosis; and presence of tissue rim. the subgroup analysis for the screened variables was conducted. result: optimal e-eswl was defined to occur within a 24-hour critical cut-off time. multivariate regression analysis concluded with screened variables: age, stone size, stone location, and hu, that eswl success was 1.85-fold higher in the e-eswl patient group. the subgroup analyses the following conditions: ≤ 65 years old by 1.784fold; ≤10 mm stone size by 1.866-fold; mid to distal stone location by 2.234-fold; and ≤ 815 hu by 2.130-fold. when all the conditions were met, the e-eswl success was 3.22-fold higher. conclusion: in case of colic due to ureteral stones, the patient is recommended to receive a lithotripsy within the first 24 hours. e-eswl is recommended especially in patients who are ≤ 65 years, or with a ureteral stone hu ≤ 815, sized ≤ 10 mm, or in a mid to distal location. keywords: extracorporeal shock wave lithotripsy; ureteral stones; colic introduction ureteral obstruction from ureteral stones often re-sults in colic-like pain and is one of the most common conditions in the field of urology(1). for the treatment of acute colic caused by ureteral stones, methods such as extracorporeal shockwave lithotripsy (eswl), ureteroscopic (urs) lithotripsy, and conservative drug therapy are used. the treatment method is determined through consideration of factors such as the ureteral stone status; size, location, degree of obstruction, technical facilities, possible complications, surgeon and patient preference, and comorbidities. conservative drug therapy often leads to complications like recurrent pain, and urs lithotripsy shares the advantages of a more rapid stone clearance but requires a longer hospital stay with an increased rate of complications (2,3). recently, eswl is the treatment method of choice for ureteral stone patients because it is noninvasive compared to the surgical method, meaning there are fewer risks associ1department of urology, gachon university gil medical center, gachon university college of medicine, republic of korea. 2clinical trials center, gachon university gil medical center, gachon university school of medicine, republic of korea. 3department of pharmacology, gachon university college of medicine, republic of korea. *correspondence: department of urology, gachon university gil medical center, gachon university college of medicine, republic of korea. tel: +82-32-460-3330. fax: +82-32-460-8340. e-mail: tbkim@gilhospital.com, urohana@gilhospital.com. received may 2018 & accepted august 2018 ated with general anesthesia and a lower morbidity due to the advancements in equipment(4,5). performing eswl before a mucosal edema develops around the ureteral stones is expected to help with reducing the stone free time; many studies have since proceeded with eswl and have found that early treatment after the development of colic-like pain leads to fast stone break up and effective relief of the pain from obstruction(2,6-9). however, studies regarding the use of eswl in an emergency setting to conduct the most effective early eswl (e-eswl) are still insufficient(10). there is a requirement for e-eswl in order to effectively treat ureteral stones; therefore, the purpose of this study was to determine the efficacy of e-eswl and the patient criteria for the most effective e-eswl. materials and methods study design and eswl procedure this retrospective study conducted a single center, the urology journal/vol 16 no. 4/ july-august 2019/ pp. 331-336. [doi: http://dx.doi.org/10.22037/uj.v0i0.4537] vol 16 no 04 july-august 2019 332 gachon university gil medical center. this study included 378 patients who were admitted to the gachon university gil medical center emergency room, or to the urology department as an outpatient, due to colic-like pain caused by a solitary radio opaque ureteral stone resulting in treatment with eswl from january 2016 to december 2016. among the patients included in this study, the 43 patients were dropped out and the 335 patients completed follow up. the study patients did not have conditions which were contraindicative to esw: acute urinary tract infection or urosepsis; uncorrected bleeding disorders or coagulopathies; pregnancy; uncorrected obstruction distal to the stone, and did not receive any other procedures except until the end of treatment for the ureteral stone. before patients received eswl, their medical history was collected, and the patients underwent a physical examination, routine blood or urine tests, plain radiography of the kidney-ureter-bladder (kub), and non-contrast enhanced computed tomography (ncct). based on the radiological findings, stone factors including size, location, presence or absence of hydronephrosis, tissue rim sign, and mean hounsfield units (hu) were investigated. hu, a parameter generated from standard ct, are related to the density of the stone or structure of interest. prior to eswl, patients received an analgesic (dichlofenac, 30 mg, intra-muscular injection or pethidine, 50 mg, intravenous injection), after eswl, all patients were given pain medication. patients did not receive pain medication during the eswl procedure. eswl was conducted using a modulith slx-f2 urological workstation (storz medical, switzerland). in all cases, eswl procedures were conducted at 3000 shocks were performed per session, at a frequency of 90 shocks per minute (1.5hz) and the same power per shock wave. one week after the eswl session, plain radiography of the kub was used to check for the presence of residual ureteral stones. if residual stones could not be determined with plain radiography of the kub, ncct was used. when a residual stone was identified, the next eswl session was carried out. stone frees status was defined as no identification of any residual stones upon imaging. the time to eswl (from the start of the pain to the first eswl session), total number of eswl sessions, time to stone free status, and stone free status within 1 month of the first eswl session was defined as eswl success; the eswl success rate and complications after eswl were investigated. variables that affect eswl success rate in early eswl and statistics to determine the time to eswl in order to perform the most effective eswl (the critical point of the most effective eswl), the sensitivity and specificity depending on the cut-off time to eswl were analyzed. in a receiver operating characteristic (roc) curve, the true positive rate (sensitivity) is plotted in function of the false positive rate (100-specificity) for different cut-off time points to eswl. each point on the roc curve represents a sensitivity/ specificity pair corresponding to eswl success (stone-free within a month). we set the closest point to the upper left corner of the roc curve as a critical cut-off time point. based on this critical cut-off point, patients were categorized as into the e-eswl patient group or the deferred eswl (d-eswl) patient group to compare the patient characteristics and eswl success. univariate logistic regression was conducted on the eswl success with variables such as age, gender, bmi, comorbidity, serum creatinine, stone size, stone location, stone laterality, hu, presence of hydronephrosis, and presence of a tissue rim. those variables with a p-value < 0.1 were screened further with multivariate logistic regression analysis. in addition, to determine the patient criteria for the most effective e-eswl, further subgroup analysis was performed for those screened variables through univariate logistic analysis. ethical approval was obtained by the institutional retable 1. comparison of characteristics between the early eswl and the deferred eswl groups. variables early eswl a (n=215) deferred eswl a (n=120) p-value demographics age (yr) 46.71 ± 12.97 49.12 ± 15.35 0.1481b gender (male) 131 (60.93%) 79 (65.83%) 0.3736c bmi (kg/m2) 24.59 ± 3.13 24.11 ± 3.94 0.4918b hypertension 23 (10.70%) 29 (24.17%) 0.0011c serum creatinine (mg/dl) 0.8 (0-1.5) 0.8 (0-2.2) 0.6713d radiologic parameters stone size (mm) 6.93 ± 2.40 7.91 ± 2.99 0.5653d stone location (mid-to-distal) 127 (59.07%) 54 (45.00%) 0.0132c stone laterality (left) 102 (47.44%) 63 (52.50%) 0.3746c hounsfield unit 612.22 ± 360.05 647.00 ± 316.08 0.3769b hydronephrosis 171 (79.53%) 92 (76.67%) 0.5400c tissue rim sign 46 (22.12%) 44 (39.29%) 0.0011c eswl treatment time to eswl (hr) 15.64 ± 7.74 120 ± 167.08 <.0001d number of eswl 1.75 ± 1.63 2.31 ± 1.74 0.0149d post eswl treatment (urs lithotripsy) 7 (3.93%) 4 (4.49%) 1.0000e time to stone free (day) 14.0 ± 26.82 18.5 ± 51.30 0.0303d stone free within 1 month 171 (79.53%) 78 (66.00%) 0.0035c adverse events asymptomatic steinstrasse 0 (0.00%) 1 (0.83%) pain 5 (2.31%) 2 (1.67%) other 2 (0.93%) 1 (0.83%) abbreviations: eswl, extracorporeal shockwave lithotripsy; bmi, body mass index; urs lithotripsy, ureteroscopic lithotripsy amean ± sd or median (range) for continuous variables, n (%) for categorical variables; bt-test; cchi-square test; d. mann-whitney u test; e. fisher’s exact test. e-eswl for colic patients with ureteral stones-kim et al. view board (irb no. gcirb 2017-234). results the mean age of the 355 patients (210 men, 115 women) was 47.57 ± 13.9 years, the mean body mass index (bmi) was 24.36 ± 3.53 kg/m2, the mean serum creatinine was 0.72 ± 0.38 mg/dl, and comorbidities included 52 patients with hypertension (15.52%) and 32 patients with diabetes (9.55%). the mean ureteral stone size was 7.42 ± 2.92 mm; a left ureteral stone was found in 165 patients (49.25%), a right ureteral stone in 170 patients (50.75%), an upper ureteral stone in 154 patients (45.97%), and a middle and lower ureteral stone in 181 patients (54.03%). the mean hu of the stone was 624.68 ± 344.9, a tissue rim sign was identified in 90 patients (26.87%). patients received a mean of 1.95 ± 1.2 sessions of eswl, and eswl success was confirmed in 249 patients (74.33%). figure 1 showed the results of sensitivity and specificity cut-off analysis. the left diagram was a sensitivity/specificity plot versus time to ewsl and the right diagram was the roc curve. this roc curve with area under the curve (auc) = 0.6434 was significant in contrast to the reference line with auc = 0.5 (p < 0.0001). the critical point for time to eswl was determined to be 24 hours (area under the curve = 0.6434) (figure 1). based on this 24-hour time to eswl, patients were classified into the e-eswl patient group (n = 215) and d-eswl patient group (n = 120)(table 1). the significantly different variables between the patient groups were as follows: in the e-eswl patient group, the number of patients with signs of a tissue rim were significantly less (46 patients, 22.12% vs 44 patients, 39.23%), as was the number of patients with proximal ureter stones (88 patients, 40.93% vs 66 patients, 55.00%), the mean number of eswl sessions (1.75 vs 2.31), and the time to stone free status (14 days vs 18.5 days). the eswl success rate was higher in the e-eswl patient group when compared to the d-eswl patient group (171 patients, 79.53% vs 78 patients, 66.00%) (table 1). the univariate logistic regression analysis showed that age (p = .0098), stone size (p = .0066), stone location (p = .002), and hu (p = .0001) were variables with p-value < 0.1. results from the multivariate logistic regression analysis indicated that eswl success was 1.85 times greater in the e-eswl patient group compared with the d-eswl patient group (table 2). in order to determine the most effective e-eswl patient criteria, subgroup analysis was performed for screened variables, which showed that patients aged 65 or younger (n = 297), with stone size 10 mm or smaller (n = 320), a stone location of mid to distal (n = 181), and a hu of 815 or less (n = 243) showed greater eswl success in e-eswl than d-eswl by 1.784 fold, 1.866 fold, 2.234 fold, and 2.130 fold, respectively. when all these variables were met (n = 128), the eswl success was 3.22 times greater in the e-eswl group than in the d-eswl group (table 2). e-eswl for colic patients with ureteral stones-kim et al. table 2. variables that affect early eswl success using univariate and multivariate logistic regression analyses. variables unit odds ratio (95% c.i.) a p-value all patients (n=335)b age 10 0.789 (0.659-0.944) 0.0213 hypertension 0.487 (0.261-0.907) 0.0234 stone size 1 0.874 (0.793-0.963) 0.0066 hounsfield unit 100 0.888 (0.824-0.957) 0.0207 stone location 'mid to distal' vs 'proximal' 1.873 (1.101-3.186) 0.0018 early eswl 1.850 (1.093-3.130) 0.0219 all patients (n=335)c age 10 0.804 (0.667-0.968) 0.0213 hounsfield unit 100 0.888 (0.824-0.957) 0.0207 stone location 'mid to distal' vs 'proximal' 1.873 (1.101-3.186) 0.0018 early eswl 1.850 (1.093-3.130) 0.0219 patients aged < 65 years (n=297)c hounsfield unit 100 0.864 (0.796-0.938) 0.0005 stone location 'mid to distal' vs 'proximal' 1.912 (1.074-3.402) 0.0276 early eswl 1.784 (1.006-3.166) 0.0478 patients with stone size < 10 mm (n=320)c age 10 0.763 (0.627-0.928) 0.0068 hounsfield unit 100 0.896 (0.827-0.972) 0.0083 stone location 'mid to distal' vs 'proximal' 1.943 (1.117-3.378) 0.0187 early eswl 1.866 (1.080-3.223) 0.0254 patients with mid-to-distal ureter (n= 181)c hounsfield unit 100 0.860 (0.769-0.962) 0.0082 early eswl 2.234 (1.029-4.853) 0.0422 patients with hounsfield unit < 815 (n=243)c hypertension 0.284 (0.131-0.615) 0.0014 stone location 'mid to distal' vs 'proximal' 2.363 (1.198-4.660) 0.0131 early eswl 2.130 (1.084-4.187) 0.0283 patients favorably treated with early eswl d (n=128)c early eswl 3.222 (1.038-10.007) 0.0430 abbreviations: eswl, extracorporeal shockwave lithotripsy; ci, confidence interval aodds ratio for univariate logistic regression and adjusted odds ratio for multivariate logistic regression. bunivariate logistic regression analysis. cmultivariate logistic regression analysis. dpatients with age < 65 years, stone size < 10 mm, stone location = ’mid-to-distal’ ureter and hounsfield unit < 815. endourology and stones diseases 333 vol 16 no 04 july-august 2019 334 discussion in this study, we define optimal e-eswl to occur within a 24-hour critical cut-off time (area under the curve = 0.6434); e-eswl had a 1.85 times greater eswl success rate than d-eswl (adjusted odds ratio; 1.850). this was especially true in patients aged 65 or younger, with a stone size of 10 mm or smaller, with a stone location of mid to distal, and with a hu of 815 or less, who showed a 3.22-fold greater eswl success rate with e-eswl than d-eswl (adjusted odds ratio; 3.222) (table 2). once pain develops due to the ureteral stone, edema of the ureter mucosa occurs within 24-48 hours and inhibits the expansion chamber formation of the ureter; the fluid layer between the stone fragments and tissue disappears, disturbing the removal of stone fragments by eswl(10-14). in a study using an artificial neural network, it was suggested that the longer the delay in treatment after the development of pain from a ureteral stone, the longer it takes to remove the stones(12). as a result, many studies have recommended conducting eswl at an earlier stage, as soon as the colic-like pain develops; however, the definition of e-eswl varies between studies (6-72 hours)(15,16). in this study, sensitivity and specificity cut-off analysis depending on the time to eswl was conducted to determine the most effective e-eswl time point; our results suggest that the critical cut-off time to perform eswl is 24 hours (figure 1). since there are many factors that affect the eswl outcome, the patients were classified into e-eswl or d-eswl patient groups based on the critical 24-hour cut-off time to eswl to accurately determine the effectiveness of early lithotripsy. the variables identified in the univariate logistic analysis underwent multivariate logistic analysis to determine eswl success; it was confirmed that the e-eswl patient group had a 1.85 times greater success rate than the d-eswl patient group (adjusted odds ratio 1.850)(table 2). many studies to determine the patient criteria for the most effective e-eswl are also ongoing(16-20). in this study, we conducted subgroup analysis to identify the patient criteria for the most effective e-eswl. the results showed that e-eswl is most effective in patients aged 65 or younger (table 2)(18). increasing age is known to decrease the eswl success rate and increase the chance of side effects(21-23). many hypotheses are present for the decreasing success rate with the older age, including that the ureteric motility change with age affects the success rate(21). in this study, the patient group with a ureteral stone hu of 815 or less (n = 243) showed a higher success rate in e-eswl. previous studies have demonstrated that the stone’s density evaluation can be accessed via hu value measurement through computed tomography (ct) (24). therefore, as the mean hu value of the stone is considered the strongest predictive factor for the removal of a ureteral stone, it plays a critical role in determining the treatment method(17). in lithotripsy, a higher mean hu value of a stone leads to a lower success rate with a higher probability of residual stones, and thus, it is considered a critical predictive indicator for successful treatment(25). many studies have presented various cutoff values of hu for successful eswl treatment (785900)(24-28). a recent study showed that the success rate of lithotripsy was exceptionally higher with stones <815 hu compared to stones > 815 hu, regardless of the stone composition, which is similar to the findings of this study; stones < 815 hu had a 2.213 higher chance of success rate for e-eswl than d-eswl(17). stone size is also known as an important predictive factor for eswl success; increasing size of a ureteral stone negatively correlates with the eswl success rate, which is also associated with e-eswl(11). a study by tligui et al. reported that the success rate of an early lithotripsy is best with 6-10 mm sized stones, while 1020 mm sized stones had the worst results(8). in addition, choi et al. reported that stones sized 10 mm or smaller had the best eswl success rate(16). the subgroup analysis of this study also confirmed that the patient group with stones sized 10 mm or smaller had a 1.866 times greater probability (adjusted odds ratio 1.866) of success in e-eswl than in d-eswl. the location of the ureteral stone is another important factor for effective e-eswl. uguz et al. reported that figure 1. sensitivity and specificity at different ‘time to extracorporeal shock wave lithotripsy (eswl)’ (left); receiver operating characteristic (roc) curve of ‘time to eswl’ (right). e-eswl for colic patients with ureteral stones-kim et al. e-eswl of an upper ureteral stone resulted in a higher stone free rate(20). in addition, choi et al. reported that during e-eswl of proximal ureteral stones, the eswl success rate was high and eswl sessions were few(16). on the other hand, picozzi et al. reported that the location of the stone had no effect on the stone free rate after an early lithotripsy. a study by choi et al. suggested that although the success rate of e-eswl for mid to distal ureteral stones is high, it is not statistically significant due to the limitation of a small sample size(16). in this study, the effectiveness of e-eswl on mid ureteral stone location was analyzed (adjusted odds ratio 2.234) (table 2). considering the results of previous studies in our observations, we report that e-eswl is not only effective in treating proximal ureteral stones, but is also sufficiently effective in treating mid ureteral stones. formation of ureteral stone is a common condition that can lead to the development of various side effects, increasing the frequency of the hospital visits, leading to an economic burden on society. therefore, it is essential that the treatment of ureteral stones is safe and effective. according to the results of this study, conducting eswl as soon as the stone-associated pain develops can increase the treatment effectiveness. if possible, it is recommended that eswl is conducted within 24 hours. moreover, if a ureteral stone patient aged 65 or younger, with a hu of 815 or less than, stone size 10 mm or smaller, and stone location of mid to distal comes in for treatment, then early lithotripsy should be especially considered as priority. in addition, sufficient physical activity, balanced nutrition without excess of any component and sufficient circadian fluid intake of neutral beverages, and ipsilateral position are recommended to augment stone particles passage after eswl(29). there a couple of limitations to this study. the presence of residual stones was determined by imaging one week after the eswl session; thus, the exact time of stone removal cannot be determined if the stone was removed before the imaging. also, several patients were excluded from the study because they did not attend the follow-up because of reduced pain after eswl. in addition, stone composition was not included in the variables that affect the success of eswl. at the medical center where this study was carried out, eswl was conducted in out-patients; thus, recovering stone fragments was difficult. in this study, the efficacy of e-eswl is high on stone size 10 mm or smaller or stone location of mid to distal, but the smaller stones located in the distal ureter have a higher likelihood to pass spontaneously, also. and the previous studies have suggested that urs lithotripsy in the emergent setting is recommended for distally located stones(30). additional studies should be carried out to supplement these limitations and to accurately identify the criteria by which ureteral stone patients can receive more effective and safe treatment. conclusions e-eswl is an effective and safe treatment method for colic caused by a ureteral stone. we recommend conducting eswl within 24 hours of pain development. in addition, if the patient is 65 or younger, with a hu of 815 or less than, has a stone size 10 mm or smaller, and has a mid to distal stone location then e-eswl is especially recommended as a more effective lithotripsy result is expected. conflict of interest the authors report no conflict of interest. references 1. teichman jm. acute renal colic from ureteral calculus. n engl j med. 2004;350:684-93. 2. ghalayini if, al-ghazo ma, khader ys. evaluation of emergency extracorporeal shock wave lithotripsy for obstructing ureteral stones. international braz j urol. 2008;34:43342. 3. türk c, petřík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 4. dasgupta r, hegarty n, thomas k. emergency shock wave lithotripsy for ureteric stones. current opinion in urology. 2009;19:196-9. 5. cui x, ji f, yan h, et al. comparison between extracorporeal shock wave lithotripsy and ureteroscopic lithotripsy for treating large proximal ureteral stones: a meta-analysis. urology. 2015;85:748-56. 6. seitz c, fajković h, remzi m, et al. rapid extracorporeal shock wave lithotripsy treatment after a first colic episode correlates with accelerated ureteral stone clearance. eur urol. 2006;49:1099-106. 7. tombal b, mawlawi h, feyaerts a, wese fx, opsomer r, van cangh pj. prospective randomized evaluation of emergency extracorporeal shock wave lithotripsy (eswl) on the short-time outcome of symptomatic ureteral stones. eur urol. 2005;47:855-9. 8. tligui m, el khadime m, tchala k, et al. emergency extracorporeal shock wave lithotripsy (eswl) for obstructing ureteral stones. eur urol. 2003;43:552-5. 9. lucarelli g, ditonno p, bettocchi c, et al. delayed relief of ureteral obstruction is implicated in the long-term development of renal damage and arterial hypertension in patients with unilateral ureteral injury. the journal of urology. 2013;189:960-5. 10. picozzi sc, ricci c, gaeta m, et al. urgent shock wave lithotripsy as first-line treatment for ureteral stones: a meta-analysis of 570 patients. urol res. 2012;40:725-31. 11. mueller sc, wilbert d, thueroff jw, alken p. extracorporeal shock wave lithotripsy of ureteral stones: clinical experience and experimental findings. the journal of urology. 1986;135:831-4. 12. cummings jm, boullier ja, izenberg sd, kitchens dm, kothandapani rv. prediction of spontaneous ureteral calculous passage by an artificial neural network. the journal of urology. 2000;164:326-8. 13. deliveliotis c, chrisofos m, albanis s, serafetinides e, varkarakis j, protogerou v. management and follow-up of impacted e-eswl for colic patients with ureteral stones-kim et al. endourology and stones diseases 335 vol 16 no 04 july-august 2019 336 ureteral stones. urol int. 2003;70:269-72. 14. parr n, pye s, ritchie a, tolley d. mechanisms responsible for diminished fragmentation of ureteral calculi: an experimental and clinical study. the journal of urology. 1992;148:107983. 15. arcaniolo d, de sio m, rassweiler j, et al. emergent versus delayed lithotripsy for obstructing ureteral stones: a cumulative analysis of comparative studies. urolithiasis. 20171-10. 16. choi hj, jung j-h, bae j, cho mc, lee hw, lee ks. usefulness of early extracorporeal shock wave lithotripsy in colic patients with ureteral stones. korean journal of urology. 2012;53:853-9. 17. nakasato t, morita j, ogawa y. evaluation of hounsfield units as a predictive factor for the outcome of extracorporeal shock wave lithotripsy and stone composition. urolithiasis. 2015;43:69-75. 18. gökce mi, esen b, gülpınar b, süer e, gülpınar ö. external validation of triple d score in an elderly (≥ 65 years) population for prediction of success following shockwave lithotripsy. j endourol. 2016;30:1009-16. 19. kumar a, mohanty nk, jain m, prakash s, arora rp. a prospective randomized comparison between early (< 48 hours of onset of colicky pain) versus delayed shockwave lithotripsy for symptomatic upper ureteral calculi: a single center experience. j endourol. 2010;24:2059-66. 20. uguz s, senkul t, soydan h, et al. immediate or delayed swl in ureteric stones: a prospective and randomized study. urol res. 2012;40:739-44. 21. ng cf, wong a, tolley d. is extracorporeal shock wave lithotripsy the preferred treatment option for elderly patients with urinary stone? a multivariate analysis of the effect of patient age on treatment outcome. bju int. 2007;100:392-5. 22. abdel‐khalek m, sheir kz, mokhtar aa, eraky i, kenawy m, bazeed m. prediction of success rate after extracorporeal shock‐wave lithotripsy of renal stones a multivariate analysis model. scand j urol nephrol. 2004;38:161-7. 23. dhar nb, thornton j, karafa mt, streem sb. a multivariate analysis of risk factors associated with subcapsular hematoma formation following electromagnetic shock wave lithotripsy. the journal of urology. 2004;172:2271-4. 24. ouzaid i, al‐qahtani s, dominique s, et al. a 970 hounsfield units (hu) threshold of kidney stone density on non‐contrast computed tomography (ncct) improves patients' selection for extracorporeal shockwave lithotripsy (eswl): evidence from a prospective study. bju int. 2012;110. 25. pareek g, armenakas na, panagopoulos g, bruno jj, fracchia ja. extracorporeal shock wave lithotripsy success based on body mass index and hounsfield units. urology. 2005;65:33-6. 26. wiesenthal jd, ghiculete d, honey rjda, pace kt. evaluating the importance of mean stone density and skin-to-stone distance in predicting successful shock wave lithotripsy of renal and ureteric calculi. urol res. 2010;38:307-13. 27. wang l-j, wong y-c, chuang c-k, et al. predictions of outcomes of renal stones after extracorporeal shock wave lithotripsy from stone characteristics determined by unenhanced helical computed tomography: a multivariate analysis. eur radiol. 2005;15:2238-43. 28. pareek g, armenakas na, fracchia ja. hounsfield units on computerized tomography predict stone-free rates after extracorporeal shock wave lithotripsy. the journal of urology. 2003;169:1679-81. 29. ziaee sa, hosseini sr, kashi ah, samzadeh m. impact of sleep position on stone clearance after shock wave lithotripsy in renal calculi. urol int. 2011;87:70-4. 30. arcaniolo d, de sio m, rassweiler j, et al. emergent versus delayed lithotripsy for obstructing ureteral stones: a cumulative analysis of comparative studies. 2017;45:56372. e-eswl for colic patients with ureteral stones-kim et al. pictorial iatrogenic ureterocolic fistula following laparoscopic oophorectomy michael s floyd jr,* luke hanna, melissa c davies. keywords: fistula; laparoscopy; iatrogenic; ureter; oophorectomy. a 56 year old lady presented with gradual onset left flank pain, rigours and diarrhoea. her past history was re-markable for an uneventful, elective bilateral laparoscopic oophorectomy one month earlier under the gynaecology service. she had previously had breast cancer and was brca2 positive. on examination she was pyrexial and tender in her left flank. computerised tomography revealed moderate left sided hydronephrosis, extensive air within her left renal pelvis and a distal left ureterocolic fistula (figures 1-3). she was initially managed with antimicrobial therapy and stenting but eventually required a ureteric reimplantation. ureterocolic fistulae are rare and may occur as a result of iatrogenic injury(1). diverticular disease causing spontaneous ureterocolic fistulae has been reported(1,2) but the majority of cases occur due to impacted ureteric calculi. department of urology, salisbury nhs foundation trust, wiltshire, sp2 8bj, united kingdom. *correspondence: clinical fellow in neurourology, department of urology, salisbury nhs foundation trust, wiltshire,sp2 8bj, united kingdom. e mail: nilbury@gmail.com received january 2016 & accepted october 2017 figure 1. computerised tomography of the abdomen demonstrating gas in the left renal pelvis with a simple renal cyst and a normal contralateral kidney. figure 2. computerised tomography of the abdomen demonstrating air in the mid and distal left ureter consistent with a ureterocolic fistula. figure 3. plain x ray of abdomen demonstrating faecal loading and air in the left ureter extending up into the collecting system. pictorial 220 ureterocolic fistula after lap. oophorectomy-floyd et al. predisposing factors include inflammation, radiation, surgical trauma and neoplastic processes. diagnosis is made via abdominal imaging(3) or intraoperative retrograde studies(1). management is usually surgical with either nephroureterectomy in cases of a poorly functioning kidney or segmental resection, ileostomy and stenting in selected cases. conservative management has been described(3). as the incidence of elective oophorectomy for cancer prevention increases it is likely that this form of ureteric injury will become more prevalent. references 1. dowling cm, floyd jr ms, power re, jm hyland, dm quinlan. ureterocolic fistula in the presence of a solitary kidney. bmj case rep. 2009;2009. pii: bcr06.2008.0301. doi: 10.1136/bcr.06.2008.0301. epub 2009 feb 2. 2. cirocco w, priolo sr, golub rw. spontaneous ureterocolic fistula: a rare complication of colonic diverticular disease. am surg 1994; 60: 832–5 3. iwamoto y, kato m. a case with fistula formation between a perinephric retroperitoneal abscess, a ureter and a descending colon: successful outcome after conservative management. can urol assoc j. 2014 sep;8:e644-6. vol 15 no 04 july-august 2018 221 laparoscopic and robotic urology mini-laparoscopic pyeloplasty in adults: functional and cosmetic results eyyup sabri pelit1*, halil ciftci1, bülent kati1, ismail yagmur1, eser ordek1, erkan arslan1, ercan yeni1 purpose: the study objective was to evaluate the safety and efficacy of mini-laparoscopic pyeloplasty (mlp) in an adult population and to demonstrate the functional and cosmetic results. methods: data for 29 patients (19 men and 10 women) undergoing mlp for ureteropelvic junction obstruction (upjo) from may 2014 to december 2016 in turkey were collected in this prospective study. inclusion criteria were age ≥ 18 years, body mass index (bmi) ≤ 30 kg/m2 and primary upjo, and no previous surgery on the affected kidney or previous abdominal surgery. postoperative visual analogue scale scores and the patient scar assessment questionnaire (psaq) were used. demographic data, perioperative parameters, complications, and postoperative functional and cosmetic results were recorded. result: twenty-nine adults with a mean age of 29.4 ± 10.2 years (19–38 years) were included. the patients’ mean bmi was 22.4 ± 4.3 kg/m2 (a range of 16–29 kg/m2). mean operative time was 119 ± 28.5 minutes (85–144 minutes). major complications were not observed, as per the clavien-dindo classification of surgical complications (grades iv–v). the mean vas score was 1.2 ± 0.2 points. functional obstruction was reported in one patient on renal scintigraphy at 12 months postoperatively. the success rate of mlp was 97%. the minimum and maximum psaq scores at month 3 postoperatively were 24 and 86, respectively. all the patients were satisfied with the intervention and with their cosmetic results. conclusion: mlp is a safe, effective and feasible treatment method for upjo in adult patients. this treatment modality offers excellent cosmetic and functional results following treatment for upjo. keywords: laparoscopy; pyeloplasty; ureteropelvic junction obstruction introduction ureteropevic junction obstruction (upjo) is the most common congenital abnormality of the kidney and is responsible for flank pain, recurrent urinary infections, hydronephrosis and the loss of renal function.(1) until recently, open pyeloplasty (op) was the standard surgical treatment modality for upjo.(2) however, with the development of laparoscopic devices and surgical technology, laparoscopic pyelolasty (lp) has become the standard surgical treatment method globally. lp is a safe and effective, minimally invasive method for the treatment of upjo2. parallel to the improvement in surgical techniques, minimally invasive methods have evolved to reduce surgical trauma and obtain better cosmetic results. schuessler and kavoussi described the first case of laparoscopic dismembered pyelo¬plasty in 1993.(3,4) mini laparoscopy procedures are defined as the use of instruments with a diameter of ≤ 3 mm. mini-laparoscopic pyeloplasty (mlp) is used in numerous surgical procedures in urology and other surgical branches.(5-7) the objective of the current study was to demonstrate the safety and efficacy of mlp in an adult population and to report on the functional and cosmetic outcomes. to the best of our knowledge, this study is one of the largest series of mlp performed in overweight adult population. 1harran university faculty of medicine, department of urology. *correspondence: haran üniversitesi tıp fakültesi üroloji anabilim dalı,osmanbey kampüsü şanlıurfa/türkiye tel:+90 506 388 3186. e-mail: dreyyupsabri@hotmail.com. received december 2017 & accepted september 2018 methods a prospective study was conducted of 29 adult patients (19 mean and 10 women) undergoing mlp for upjo at a referral tertiary institution between may 2014 and december 2016 in turkey. this study was approved by the ethic committees of harran university, and written informed consent was obtained from all the participants. inclusion criteria were age ≥ 18 years, body mass index (bmi) ≤ 30 kg/m2 and primary upjo (no prior surgical interventions for obstruction), and no previous surgery on the affected kidney or previous abdominal surgery. a complete blood count, serum biochemistry, and urine analysis and culture was performed for the patients prior to surgery, in whom a sterile urine culture was determined preoperatively. urinary tract infections were treated according to the biosensitivity of the urine culture. the patients were evaluated with renal ultrasound, non-contrast computed tomography or intravenous pyelogram (ivp), and diethylenetriaminepentaacetic acid scintigraphy with a diuretic preoperatively. all patients had the t1/2 >20 min (obstructive pattern) in renal scintigraphy. the patients received intravenous antibiotic prophylaxis an hour before undergoing surgery. the patient demographic data, perioperative parameters such as operation and anastomosis time, crossing vessel and transmesocolic approach percentage and complications, as well as functional and cosmetic relaparoscopic and robotic urology 339 vol 15 no 06 november-december 2018 340 sults postoperatively, were recorded. the study participants routinely received intravenous paracetamol (1 g) postoperatively. any additional analgesic requirements were recorded. the visual analo gue scale (vas) was employed to measure the amount of pain experienced by the patients postoperatively, where a score of 1 was representative of the absence of pain and a score of 10 was indicative of the most unbearable pain imaginable. the vas scores were determined at 4, 12 and 24 hours postoperatively, and then daily from day 1 postoperatively until discharge. anderson-hynes transperitoneal lp (three port) was performed by the same surgeon. the patient was placed in a 45–60 ° lateral decubitus position under endotracheal anaesthesia. a veress® needle was used to obtain pneumoperitoneum using 12–14 mmhg of intra-abdominal pressure. the first 5 mm camera port (karl storz, tuttlingen, germany) was set 2 cm lateral to the umbilicus, depending on the patient anatomy. two 3 mm ports (karl storz) were placed under direct vision along the midclavicular line (figure 1). toldt’s fascia was incised and the standard colon retracting approach was used. however, when possible, in the case of a left upjo, a transmesocolic approach was used. the ureteropelvic junction (upj) was identified and the dilated renal pelvis was carefully dissected down to the proximal ureter. the pelvis was cut with “cold” scissors through the lowermost trocar. if anterior crossing vessels are present, in all of the cases the ureter and the renal pelvis was transposed ventrally to the vessels for completion of the anastomosis. the upj was left attached to the ureter for manipulation during spatialisation, suturing and double j stent insertion. a guidewire was sent from the proximal ureter to the bladder from the uppermost trocar, under the guidance of a 6 f amplatz dilatator. a 4.7 f 24/26 cm dj stent was then advanced over the guidewire in an antegrade manner. the redundant pelvis was extracted. sutures were inserted into the abdomen from 5 mm camera port. the dependent portion of renal pelvis was anastomosed to the apex of the spatulated ureter using the interrupted suturing technique (4-0 or 5-0 vicryl® sutures) (ethicon, somerville, usa). subsequently, anastomosis was completed using a continuous suture technique. excised segment of ureter was removed from 3 mm port. a 10 f drain was inserted on completion of the surgery. one separate suture closure was required at the camera port sites and a small, single adhesive strip was used at the other port sites. the patients were re-evaluated as outpatients on day 15 postoperatively. the dj stents were removed one month postoperatively. a standard scoring system used by plastic and reconstructive surgeons, the patient scar assessment questionnaire (psaq), was administered to the patients at three months postoperatively.(8) it is considered to be a reliable and valid measure of patient perceptions of scarring and consists of four subscales. the score for each question ranges from a minimum of 5 to a maximum of 36 points. ivp and renal scintigraphy (rs) were performed postoperatively at six and 12 months, respectively. the procedures were deemed to be successful following the resolution of symptoms and radiographic evidence of t 1/2 on renal scintigraphy (≤ 20 minutes) at the one year follow-up appointment. all statistical analyses were conducted by using spss statistical software (version 15.0; spss, inc., chicago, il, usa). a probability value (p value) of < 05 was considered statistically significant. results twenty-nine adult patients (19 men and 10 women) with a mean age of 29.4 ± 10.2 years (a range of 19–38 years) were included in this study. the mean bmi of the patients was 22.4 ± 4.3 kg/m2 (a range of 16–29 kg/ m2). the procedures were performed with the use of three ports. the mean operative time was 119 ± 28.5 minutes (85–144 minutes). the mean time to perform pelviureteral anastomosis was 21.7 ± 3.6 minutes (3.1– 8.6 minutes). a transmesocolic approach was used for the left mlp in 7 patients (41%). the mean vas score for the period from on day 1 postoperatively to discharge was 1.2 ± table 1. demografic data and preperative parameters of the patients. mean age (years), sd 29.4 (10.2) male/female 19/10 mean bmi, sd 22.4 (4.3) mean asa score, sd 1.4 (0.4) laterality l/r, n/% 17/12 (58.6%/41.4%) hydronephrosis on ct or ivp grade 3 n/% 24 (82.7%) grade 4 n/% 5 (17.3) flank pain n/% 21 (72.4%) recurrent uti n/% 4 (13.6%) mean operative time (min), sd 96 (18.5) mean time to complete anastomosis (min), sd 18.9 (5.6) mean blood loss (ml), sd crossing vessels n/% 9 (31.04%) transmesocolic approach on the left side 7 (41.1%) conversion to hybrid procedure conversion to open procedure peroperative complications table 2. perioperative parametres of the patients. table 3. postoperative and functional results of the patients. mean vas score 4 h after the surgery,sd 1.6 (0.1) mean vas score 12 h after the surgery, sd 0.7 (0.2) mean vas score 24 h after the surgery, sd 0.4 (0.1) mean vas score pod 1 to discharge, sd 1.2 (0.2) extra analgesic requirement, n/% 4 (13.7%) mean cathetater removal time, days,sd 2.8 (0.8) mean drain removal time, days, sd 2.3 (0.4) mean hospitalisation time, days, sd 3.3 (0.7) mean dj stent removal time, days, sd 30 (4.5) hydronephrosis on ivp at postoperative 6. month grade 1 n/% 12 (41.3%) grade 2 n/% 4 (13.7%) grade 3 n/% grade 4 n/% t 1/2 < 20 ′ at renal scintigraphy, n/% 28 (96.5%) symptom(pain/uti) relief after surgery, n/% 25 (100%) minor (clavien i-iii) complications, n/% 3 (10.3%) major (clavien iv-v) complications, n/% cosmetic results, mean (sd) total psaq 27.6 (1.7) appearance 9.8 (0.6) consciousness 5.1 (0.8) satisfaction with appearance 6.7 (0.5) satisfaction with symptoms 6 (0.2) table 4. cosmetic results of the patients. mini-laparoscopic pyeloplasty in adults-pelit et al. 0.2 points. the mean time taken to remove the catheter was 2.8 ± 0.8 days (a range of 2–6 days). the mean hospitalisation duration was 3.3 ± 0.7 days (2–6 days). the success rate of mlp that is defined as radiographic evidence of t 1/2 on renal scintigraphy (≤ 20 minutes) during the follow-up was 97% (in 28 of the 29 patients) and clinical resolution of the symptoms was observed in the same number of patients. significant hydronephrosis (≥ grade ii) was not observed on ivp at six months.(9) the minimum and maximum psaq scores at month 3 postoperatively were 24 and 86, respectively. major complications were not observed, as per the clavien-dindo classification of surgical complications (grades iv–v). (10) none of the patients required a blood transfusion. urine leakage from drainage catheter was observed in two patients. spontaneous resolution was seen to have occurred at the follow-up on day 5 in one patient, while the urine leakage ceased after the replacement of the 4.7 f 24/26 cm dj stent with a 6 f 26 cm dj stent in another study subject. one patient developed a urinary infection and was treated according to antibiogram test result for the urinary culture. another study subject underwent laser endopyelotomy with flexible ureteroscopy due to secondary upjo at the follow-up in the 12th month. the demographic and clinical characteristics of the patients, including the preoperative, intraoperative and postoperative findings, and the psaq scores, are summarized in tables 1–4. discussion globally, lp dramatically overtook op as the standard treatment option for upjo following the first lp that was carried out in 1993 by schuessler et al.(3) parallel to technological developments and the miniaturisation of medical devices, pyeloplasty techniques continue to evolve with a view to ensuring reduced surgical trauma and better functional and cosmetic results. the national surgical quality improvement program® database of prospectively collected data from 2.3 million surgical procedures, performed in 374 participating american institutions, shows that since 2008, 80% of pyeloplasty procedures have been performed using laparoscopic and robotic techniques. robotic-assisted pyeloplasty (rap), laparoendoscopic single-site (less) pyeloplasty, retroperitoscopic pyeloplasty, endopyelotomy, standard laparoscopic pyeleoplasty (slp) and mlp are minimally invasive methods that have recently been used to treat upjo.(11, 12) the advantage of retroperitoneoscopic pyeloplasty is that theoretically, there is no risk of bowel injury and contamination of the intra-abdominal organs with urine. it was shown in a recent meta-analysis that retroperitoneoscopic pyeloplasty was more advantageous in terms of reduced postoperative pain and duration of hospital stay when compared with the transperitoneal approach. however, the operating time was shorter using the transperitoneal approach.(13) in 2011, pini et al. described a novel retroperitoneal mini-laparoscopic approach; referred to as the small-incision access retroperitoneoscopic technique (smart), and compared this technique with slp. they reported statistically significant advantages with the use of smart over that of slp in terms of cosmetic outcome.(14) another minimally invasive treatment method, less, has attracted attention as it has the benefit of a single skin incision. a difference in hospitalization duration and postoperative pain was not established between slp and less. however, greater blood loss was demonstrated with the use of less pyeloplasty.(15) differences between slp and less have not yet been determined in terms of cosmetic outcome in any study to date. since the post-operative cosmetic appearance is one of the main anxieties that considerably have an impact on the patients satisfaction, many surgeon have tried performed less-invasive laparoendoscopic surgery. hong mei et al. compared transumbilical multiport (tump) and standard laparoscopic pyeloplasty in children and they found that tmlp had the better cosmesis and greater patient satisfaction rate evaluated by client satisfaction questionnaire-8 and 2 procedures had similar functional results.(16) initially, slp did not gain acceptance because the operating time was lengthy and advanced laparoscopic skills were needed to perform it. however, with the increase in surgical experience gained, the operating times were reduced and it is now widely performed worldwide. various approaches can be used in slp. turk et al. reported on the use of 49 lp procedures. they noted that the long-term success rate of this procedure was 98%, which was comparable with that achieved using op.(17) inakagi et al. reviewed 147 laparoscopic transperitoneal pyeloplasties performed using various techniques such as anderson-hynes dismembered (106), y-v(28) and fenger pyeloplasty(11), based on the intraoperative findings. they stated that slp had a comparable rate of success with op.(18) it was also found in comparative studies that slp pyeloplasty was associated with less morbidity, a shorter hospitalisation duration and almost the same surgical success rate, compared with open surgical repair.(19,20 ) although many minimally invasive treatment methods for upjo have been described, the role of mlp in the adult population has not been adequately discussed. porpiglia et al. reported the one-year results of 10 adult patients who underwent mlp. they evaluated the patients using vas scores for postoperative pain and using psaq scores for the cosmetic results, and did not observe a functional obstruction on renal scintigfigure 1. port placement for a right transperitoneal pyeloplasty. mini-laparoscopic pyeloplasty in adults-pelit et al. laparoscopic and robotic urology 341 vol 15 no 06 november-december 2018 342 raphy at the one-year follow-up. the patients in their series were reported to be satisfied with the surgery and cosmetic outcomes(21). in 2012, fiori et al. published a study in which the use of mlp and slp were compared in adult patients. a statistically significant difference between the two groups was not found in terms of the analgesic requirements, vas scores, operating time and blood loss. however, the hospitalisation duration for the slp group was significantly longer than that for the mlp group. the psaq results demonstrated that the cosmetic results of mlp were superior to those of slp (22). although simforoosh et al. compared slp and mlp in children younger than 1 year of age in terms of functional and cosmetic outcomes, the surgical principle was same as the adult population. they found that mean appearance score in the mlp and slp groups was 10.2 and 16.6, respectively (p = 0.0001). the mean consciousness score in the mlp and slp groups was 7.8 and 14.2, respectively (p = 0.0001). according to these results they concluded that mlp is more cosmetically pleasing and less invasive than slp, and has similar functional outcomes.(23) in our cohort, postoperative vas scores, psaq scores in relation to the cosmetic results and the success rate were similar to those reported in these studies. however, a difference was that overweight patients (bmi of 25–30 kg/m2) were included in our study. we experience difficulties with port placement in overweight patients, especially in cases of central obesity, owing to the short length of the ports (3 mm). thus, we concluded that mlp could be performed in select overweight patients with a relatively low waist circumference. besides, generally, we do not experience any further challenges during the procedure after the port has been placed. in addition, extra tools for pyeloplasty, such as bariatric-length laparoscopic instruments, are not required. not performing a comparison between mlp and standard laparoscopic techniques was a major limitation of this study, as was the relatively small sample size and the limited clinical information obtained. further randomized prospective comparative studies, with a high number of patients, are warranted before generalization of the study findings can be applied to the general population. conclusions mlp in adult population is feasible and seems to be safe and effective to manage upjo. it has a high success rate, with reports of high satisfaction with the cosmetic results by adult patients. this method of treatment can be performed without major complications, even in overweight patients, by skilled surgeons at technologically advanced health centers. a relatively short duration time and low postoperative analgesic requirements are key advantages of this procedure. conflict of interest the authors report no conflict of interest references 1. williams b, tareen b, resnick mi. pathophysiology and treatment of ureteropelvic junction obstruction. curr urol rep. 2007;8:111–7 2. kapoor a, allard cb. laparoscopic pyeloplasty: the standard of care for ureteropelvic junction obstruction. can urol assoc j. 2011;5:136-8. 3. schuessler ww, grune mt, tecuanhuey lv, preminger gm. laparoscopic dismembered pyeloplasty. j urol. 1993;150:1795–9. 4. kavoussi lr, peters ca. laparoscopic pyeloplasty. j urol.1993;150(6):1891–4. 5. david g, boni l, rausei s, et al. use of 3 mm percutaneous instruments with 5 mm end effectors during different laparoscopic procedures. int j surg. 2013;11 suppl 1:61–3. 6. liao ch, lai mk, li hy, chen cs, chueh sc. laparoscopic adrenalectomy using needlescopic instruments for adrenal tumors less than 5 cm in 112 cases. eur urol. 2008;54(3):640–6. 7. tan hl. laparoscopic anderson-hynes dismembered pyeloplasty in children using needlescopic instrumentation. urol clin north am. 2001;28:43–51. 8. durani p, mcgrouther da, ferguson mw. the patient scar assessment questionnaire: a reliable and valid patient-reported outcomes measure for linear scars. plast reconstr surg. 2009;123:1481–9. 9. fernbach sk, maizels m , conway jj . ultrasound grading of hydronephrosis: introduction to the system used by the society for fetal urology. pediatr radiol. 1993;23:478–80. 10. d. dindo, n. demartines, p.a. clavien classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg.2004;240:205-13. 11. hanske j, sanchez a, schmid m, et al. comparison of 30-day perioperative outcomes in adults undergoing open versus minimally invasive pyeloplasty for ureteropelvic junction obstruction: analysis of 593 patients in a prospective national database. world j urol. 2015;33:2107–13. 12. oberlin dt, mcguire bb, pilecki m, et al. contemporary national surgical outcomes in the treatment of ureteropelvic junction obstruction. urology. 2015;85:363–7. 13. wu y, dong q, han p, et al. meta-analysis of transperitoneal versus retroperitoneal approaches of laparoscopic pyeloplasty for ureteropelvic junction obstruction. j laparoendosc adv surg tech a. 2012;22:658– 62. 14. pino g, goezen as, shulze m, et al. small incision access retroperitoneoscopic technique (smart) pyelolasty in adult patients: comparison of cosmetic and poet-operative pain outcomes in a matched pair analysis with standard retroperitoneoscopy: preliminary report. world j urol. 2012;30:605–11. 15. brandao lf, laydner h, zargar h, et al. mini-laparoscopic pyeloplasty in adults-pelit et al. mini-laparoscopic pyeloplasty in adults-pelit et al. laparoendoscopic single site surgery versus conventional laparoscopy for transperitoneal pyeloplasty: a systematic review and metaanalysis. urol ann. 2015;7:289–96. 16. mei h, zhao x, li d et al. comparison of transumbilical multiport and standard laparoscopic pyeloplasty in children: midterm results at a single center. j pediatr surg. 2017 mar;52:473-7. 17. türk ia, davis jw, winkelmann b, et al. laparoscopic dismembered pyeloplasty – the method of choice in the presence of an enlarged renal pelvis and crossing vessels. eur urol. 2002;42:268–75. 18. inagaki t, rha kh, ong am, kavoussi lr, jarrett tw. laparoscopic pyeloplasty: current status. bju int. 2005;95 suppl 2:102– 5. 19. boylu u, basatac c, turan t, onol ff, gumus e. comparison of surgical and functional outcomes of minimally invasive and open pyeloplasty. j laparoendosc adv surg tech a. 2012;22:968–71. 20. simforoosh n, basiri a, tabibi a, et al. a comparison between laparoscopic and open pyeloplasty in patients with ureteropelvic junction obstruction. urol j. 2004;1:165–9. 21. porpiglia f, morra i, bertolo r et al. pure minilaparoscopic transperitoneal pyeloplasty in an adult population: feasibility, safety, and functional results after one year of follow-up. urology. 2012 mar;79:728-32. 22. fiori c, morra i, bertolo r et al. standard vs minilaparoscopic pyeloplasty: perioperative outcomes and cosmetic results. bju int. 2013 mar;111(3 pt b):e121-6. 23. simforoosh n, abedi a, hosseini sharifi s et al. comparison of surgical outcomes and cosmetic results between standard and mini laparoscopic pyeloplasty in children younger than 1 year of age. j pediatr urol 2014 10:819– 23. laparoscopic and robotic urology 343 a randomized control trial comparing combined glandular lidocaine injection and intraurethral lidocaine gel with intraurethral lidocaine gel alone in cystoscopy and urethral dilatation shahram gooran,1 pejman pourfakhr,2 shirin bahrami,1 alimohammad fakhr yasseri,1* amir javid,1 negar behtash,1 gholamreza pourmand1 purpose: cystoscopy is one of the most common urologic procedures. the aim of this study is to investigate the combined effect of intraurethral lidocaine gel and intraglandular injection of lidocaine 2% on pain during and after cystoscopy. materials & methods: in this double-blind, parallel group randomized clinical trial, 156 patients referred for double j removal, urethral dilatation, or cystoscopy were enrolled. the patients were divided into two groups, a and b. all patients received 20 cc of intraurethral lidocaine gel 2%. in group a (n = 75), lidocaine 2% was also injected into the glans penis. the patients in group b (n = 81) only received the intraurethral lidocaine gel. cystoscopy was performed 10 minutes later. the primary outcome of interest was measured in terms of pain score (visual analogue scale) during and 5 minutes after cystoscopy. results: immediate pain score after the procedure was 3.4 ± 3 and 4.6 ± 3 in groups a and b, respectively (p = .011). conclusion: based on the findings of the present study, lidocaine injection into the glans penis significantly reduced pain perception. keywords: pain perception; cystoscopy; local anaesthesia. 1urology research center, sina hospital, tehran university of medical sciences, hassan-abad sq., tehran, iran 2department of anesthesiology, school of medicine, tehran university of medical sciences, tehran, iran *correspondence: sina hospital, tehran, iran. tel:0098 9122451541. e-mail:yasseri_2006@yahoo.com. received may 2016 & accepted may 2017 introduction cystoscopy is one of the most common urologic pro-cedures(1). cystourethroscopy is a urological procedure to view the urethra and bladder(2). when lidocaine is injected into the glans penis, it spreads easily around the urethra and paralyses the sensory nerves around the urethra and anaesthetizes the urethra. outpatient cystoscopy under intracorporal anaesthesia has several advantages over the same procedure under general or spinal anaesthesia in the operating room: the risks of general or spinal anaesthesia, headache, and nausea, are avoided; the urologist can perform this surgical procedure in his office and the total cost is reduced markedly(3). in 2005, chen and his colleagues performed a randomized, double-blind trial in taiwan on the analgesic effect of lidocaine gel during cystoscopy. they showed that intraurethral lidocaine gel injection is a cost-effective analgesic method, which dramatically reduces the need for analgesic use after cystoscopy(4). chang et al. performed a study in china in the same year on the effect of intracorpus spongiosum lidocaine injection before certain urological procedures, including the endoscopic removal of stone and internal urethrotomy. they concluded that this anaesthetic could significantly decrease pain in 90% of the patients(3). several clinical trials have been conducted to find the most suitable way of making this procedure more tolmiscellaneous erable. using local anaesthesia before cystoscopy has many benefits over the use of general or spinal anaesthesia(3-6). although intracorpus spongiosum lidocaine injection has been used in a few studies around the world for certain endoscopic procedures, it has not been used in cystoscopy(3). by applying this method of anaesthesia, cystoscopy can be done in the urologist's office and is less expensive than conducting one in an operating room. this randomized trial compared the combined effect of intracorpus spongiosum lidocaine injection plus intraurethral lidocaine gel with the effect of intraurethral gel injection alone on pain perception during cystoscopy and urethral dilatation. materials and methods study population male patients referred for double j stent removal, urethral dilatation or cystoscopy between march 2014 and march 2015 entered the study. the exclusion criteria were the presence of meatal ulcers, acute prostatitis, and prolonged cystoscopy for more than 20 minutes. each patient provided written informed consent and the study was performed in accordance with rules of the 1989 declaration of helsinki. the patients’ enrolment algorithm has been illustrated in figure 1. a course of antibiotics was used before the intervention vol 14 no 04 july-august 2017 4044 and they were compared by the kolmogorov-smirnov test. the values of p < .05 were considered statistically significant. results in this interventional study, 156 patients undergoing cystoscopy or urethral dilatation were evaluated. overall, 75 patients (48.1%) received a combination of lidocaine injection 2% and intraurethral lidocaine gel (group a) and 81 patients (51.9%) received intraurethral lidocaine gel alone (group b). the procedure type was cystoscopy in 120 (76.9%) and urethral dilatation in 36 (23.1%) patients. the cause of cystoscopy was diagnostic in 45 (28.8%), double j stent removal in 97 (62.2%), double j stent removal of transplanted kidney in 10 (6.4%) and was associated with urethral dilatation in 2 (1.3%) patients. the mean age of the patients was 49.9 ± 17.5 years. the average age was 49.7 ± 17.3 in group a and in 50.3±17.9 in group b (p = .83). the mean cystoscopy duration was 5.4±4.1 minutes. the cystoscopy duration did not differ significantly in the two groups (5.12 ± 4.12 minutes in group a versus 5.6±4.1 minutes in group b, p = .52). the mean pain score (vas) was 4.1±3.1 and 1.4±1.7 immediately and 5 minutes after the procedure, respectively. the pain scores (number scale) during the procedure were 3.4 ± 3 in group a and 4.6 ± 3 in group b (p = .011). the pain scores (face scale) during the procedure were 2.3 ± 1.7 in group a and 3.1 ± 2.0 in group b (p =. 008). on the other hand, five minutes after the procedure no significant difference was found between the two groups in terms of the pain score. also, no significant differences were observed in preand post-procedural blood pressure and heart rate or in blood pressure between the two methods (table 1). then, this comparison was done for cystoscopy and the urethral dilatation procedure separately. the pain scores during the procedure (number scale) were 3.9 ± 3.2 and 4.8 ± 3.1 in groups a and b, respectively (p = .061). although the pain was more in group b, this in the case of a positive urine culture. in patients with negative urine culture, a single dose of 80 mg gentamycin was administered intramuscularly, 15 minutes before the procedure. the patients were observed for an hour after the procedure and they were warned about major complications. study design this study was a double-blind, randomized clinical trial performed in sina hospital, tehran, iran. one hundred and fifty-six patients were randomly categorized in two groups, a and b. we explained the visual analogue scale (vas) (a ten numbers scale and 6 faces scale) before the procedure to the patients. the other variables included age, demographic data, blood pressure, and pulse rate before and after the procedure. the patients were divided into groups a (lidocaine 2% injection+intraurethral lidocaine gel group) and b (intraurethral lidocaine gel alone group). surgical technique each cystoscopy was performed with a rigid cystoscope with 22 fr sheet and 30 degree lens and urethral dilatation was done with metal dilatators. all procedures were performed by a single urologist. after the patients' preparation and draping, all the patients received 20 cc of intraurethral lidocaine gel 2%. in group a, lidocaine 2% was also injected into the glans penis with a 5 ml syringe and 31 gauge needle. the injection was pushed in 2 or 10 o' clock of glans. the injection site was two millimetres from the meatus and two millimetres from the glans edge. the cystoscopy was performed ten minutes later. the pain experienced was assessed using the visual analogue scale immediately after the procedure (termed during the procedure for the purpose of this study) and five minutes later. outcome assessment the primary outcome was the pain score (vas) during and after five minutes. the secondary outcomes included blood pressure and pulse rate changes. after the collection of data, they were analysed with the software spss version 21, using descriptive and analytical analyses. the qualitative data were presented by mean ± sd lidocaine injection with gel in cystoscopy-gooran et al. figure 1. patients’ enrollment algorithm miscellaneous 4045 difference in pain between the two groups was not statistically significant (table 2). discussion this study shows that compared to intraurethral lidocaine gel alone, local anaesthesia with direct injection of lidocaine into the glans penis significantly reduces pain perception immediately after cystoscopy or urethral dilation (figure 1). however, no significant difference in pain perception was found between the two groups five minutes after the injection. also, no significant differences were observed in preand post-procedural blood pressure and heart rate. in 1997, a double-blind study was conducted by fisher et al. comparing the effects of lidocaine gel and lubricant gel on pain during rigid cystoscopy. they injected 300 ml of gel in the tract and cystoscopy began 20 minutes later. they showed that the injection of lidocaine gel was ineffective for reducing pain in women, but it significantly reduced the pain in men(1). in france, thompson and colleagues conducted a study 1999 on the temperature of the gel, showing that cold lidocaine gel leads to more effective analgesia in patients during cystoscopy(2). in 2001, derry hurst suggested the use of 600 ml intravesical lidocaine gel for reducing the pain during cystoscopy(3). in 2005, chen and his colleagues performed a randomized, double-blind trial in taiwan on the analgesic effect of lidocaine gel during cystoscopy. they showed that lidocaine gel is a cost-effective analgesic method that dramatically reduces the need for analgesic use and hospitalization after cystoscopy(4). shan et al., in china, performed a study in the same year on the effect of intracorpus spongiosum lidocaine injection before certain urological procedures including the endoscopic removal of stone and internal urethrotomy. they concluded that this anaesthetic could significantly decrease pain in 90% of the patients(5). in 2006, shide and turfan evaluated the effect of lidocaine gel on analgesia during endoscopic procedures in a retrospective study. he concluded that the best result is obtained when 20 to 30 ml of gel is injected into the urethra. it is better to inject slowly (at least 10 seconds) to cause less pain(6). a meta-analysis in 2009 showed the effect of lidocaine gel on reducing moderate to severe pain during flexible cystoscopy(7). table 1. comparison of pain, blood pressure and pulse rate between groups a and b. variables groupa (mean ± sd) groupb (mean ± sd) p value pain during procedure(number scale) 3.47 ± 3.03 4.64 ± 3.06 0.011 pain during procedure (face scale) 2.26 ± 1.73 3.15 ± 1.97 0.008 pain 5 minutes after procedure (number scale) 1.23 ± 1.51 1.65 ± 1.91 0.230 pain 5 minutes after procedure ( face scale) 1.01 ± 1.17 1.36 ± 1.70 0.518 bp change, mmhg 0.4 ± 1.40 0.65 ± 1.49 0.271 bp before procedure, mmhg 13.96 ± 2.02 14.52 ± 2.30 0.324 bp after procedure, mmhg 14.38 ± 2.05 15.09 ± 2.23 0.094 pr before procedure 79.60 ± 12.430 78.29 ± 13.55 0.439 pr after procedure 79.54 ± 9.99 83.52 ± 15.07 0.402 abbrebviations: group a,lidocaine 2% injection plus intraurethral lidocaine gel group; group b,intraurethral lidocaine gel alone group; sd,standard deviation; bp,blood pressure; pr,pulse rate subgroups groupa (mean±sd) groupb (mean±sd) p value cystoscopy pain during procedure(number scale) 3.85 ± 3.20 4.85 ± 3.151 0.061 pain during procedure (face scale) 2.49 ± 1.82 3.27 ± 2.09 0.060 pain 5 minutes after procedure (number scale) 1.43 ± 1.61 1.86 ± 1.968 0.314 pain 5 minutes after procedure ( face scale) 1.20 ± 1.23 1.52 ± 1.75 0.689 urethral dilatation pain during procedure(number scale) 2.28 ± 2.10 3.94 ± 2.73 0.074 pain during procedure (face scale) 1.53 ± 1.17 2.78 ± 1.51 0.022 pain 5 minutes after procedure (number scale) 0.61 ± 0.979 1.00 ± 1.60 0.606 pain 5 minutes after procedure ( face scale) 0.41± 0.71 0.89 ± 1.49 0.568 abbrebviations: group a,lidocaine 2% injection plus intraurethral lidocaine gel group; group b,intraurethral lidocaine gel alone group; sd,standard deviation table 2. comparison of pain between groups a and b in cystoscopy and urethral dilatation subgroups. lidocaine injection with gel in cystoscopy-gooran et al. vol 14 no 04 july-august 2017 4046 ather et al. performed a nonrandomized study in 2009. they used intracorpus spongiosum lidocaine and sedation before optical urethrotomy and compared it with general or spinal anaesthesia. sixteen out of 32 patients received 2 to 3 ml of 1% lidocaine into the glans penis. in this group, 15 patients (94%) had no discomfort or pain. the anaesthetic effect lasted for an hour and it was satisfactory, without any complications. the visual analogue pain score was not different in the two groups. they concluded that urethrotomy using an intracorpus spongiosum lidocaine with sedation is as effective and safe as regional or general anaesthesia. this method is also cost-effective due to a shorter operative time(5). this study has some limitations. first, this is a single-centre study without a large sample size. second, the patients in this study were observed for one hour and no one showed a major complication except some injection-related effects on the other hand, based on the literature review, this study is the first clinical double-blind study to evaluate the role of intracorpus spongiosum anaesthesia in urologic procedures. another advantage of this study is the randomization and integration of the other factors related to pain. intracorpus spongiosum anaesthesia can be used easily in the office without any reported complication. it is recommended that future studies are carried out with larger sample sizes. higher doses of lidocaine are also recommended. this method can also be used in other endoscopic procedures such as urethral stone removal and internal urethrotomy. conclusions based on the findings of the present study, the injection of lidocaine 2% into the glans penis significantly reduces pain perception immediately after cystoscopy or urethral dilatation compared to the use of intraurethral lidocaine gel alone. so, this method could be used as an effective way of pain control during cystoscopy reducing the need of anaesthesia. acknowledgement this study was approved in urology research center of sina hospital. the authors would like to thank dr. ayat ahmadi for statistical analysis, mr akbari and miss pajoohan for their helps in procedures. conflict of interest the authors report no conflict of interest. references 1. goldfischer er, cromie wj, karrison tg, naszkiewicz l, gerber gs. randomized, prospective, double-blind study of the effects on pain perception of lidocaine jelly versus plain lubricant during outpatient rigid cystoscopy. j urol. 1997;157:90-4. 2. thompson tj, thompson n, o'brien a, young mr, mccleane g. to determine whether the temperature of 2% lignocaine gel affects the initial discomfort which may be associated with its instillation into the male urethra. bju int. 1999;84:1035-7. 3. dryhurst dj, fowler cg. flexible cystodiathermy can be rendered painless by using 2% lignocaine solution to provide intravesical anaesthesia. bju int. 2001;88:4378. 4. chen yt, hsiao pj, wong wy, wang cc, yang ss, hsieh ch. randomized doubleblind comparison of lidocaine gel and plain lubricating gel in relieving pain during flexible cystoscopy. j endourol. 2005;19:163-6. 5. ather mh, zehri aa, soomro k, nazir i. the safety and efficacy of optical urethrotomy using a spongiosum block with sedation: a comparative nonrandomized study. j urol. 2009;181:2134-8. 6. schede j, thuroff jw. effects of intraurethral injection of anaesthetic gel for transurethral instrumentation. bju int. 2006;97:1165-7. 7. aaronson ds, walsh tj, smith jf, davies bj, hsieh mh, konety br. meta-analysis: does lidocaine gel before flexible cystoscopy provide pain relief? bju int. 2009;104:506-9; discussion 9-10. lidocaine injection with gel in cystoscopy-gooran et al. miscellaneous 4047 vol 16 no 01 january-february 2019 67 pediatric urology management of congenital urethral strictures in infants. case series dalia gobbi 1*, francesco fascetti leon 2, michele gnech 3, marina andreetta 2, paola midrio 1, piergiorgio gamba 2, marco castagnetti 3 purpose: infra-vesical obstruction is uncommon in infants and generally due to urethral valves. congenital urethral strictures (cus), instead, defined as a concentric narrowing of the urethral lumen, are exceedingly rare in infants. materials and methods: we reviewed our experience with 7 patients treated at our institution for cus 1cm). success of treatment was defined as absence of urinary symptoms at follow-up, and radiological or endoscopic documentation of resolution of the stricture. statistical analysis only descriptive statistic was used. results seven patients met the inclusion criteria for study (table1). in a single patient, the urethral stricture was an isolated condition, 3 had a prune belly syndrome (pbs) and the remaining 3 had ano-rectal malformation (arm). in no patient the stricture was diagnosed prenatally but 4 had upper tract dilatation detected on prenatal ultrasound. four patients (2 pbs and 2 arm) presented with urinary retention and poor stream. one patient with pbs was urinating only via a patent urachus, whereas in the last patient with arm the stricture was detected for the impossibility to pass a catheter during surgery for creation of a colostomy at 24 hours of life. the single patient with an isolated stricture presented at 1 month of life with an urosepsis while he was followed conservatively for bilateral hidroureteronephrosis (hun) elsewhere. on ultrasound, 5 patients had evidence of bilateral hun. the patient with the isolated stricture had also ultrasound evidence of penile cysts. five patients had impaired renal function at diagnosis and 3, all pbs, have required renal transplantation so far. table 1. patients’ characteristics and management of the stricture treatment of stricture pt associated presentation upper tract renal urinary tract stricture stricture age at 1st 2nd additional surgery condition status at presentation function diversion at location length (mos) treatment treatment presentation padua 1 (mz) pbs prenatal bilateral hun renal vesicostomy penile > 1 cm 10 up to 12 fr detection of (no vur) failure at birth bil hun, (rtx) poor stream at birth 2(gf) pbs prenatal bilateral hun renal vesicostomy h bulbar < 1 cm 1 eu detection of (no vur) failure at birt (cold knife) bil hun, (rtx) poor stream at birth 3 (dc) none prenatal bilateral hun mild epicistostomy penile >1 cm 1 urethroplasty (prenatally detection (vur rt) chronic tube then detected bil of bil hun renal failure scrotal hun) urosepsis at (estimated urethrostomy 3 weeks of age gfr 70 ml/min/1,73m2) 4 (eb) arm impossibility bilateral normal epicistostomy bulbar <1 cm 5 eu eu urethroplasty (fistula to pass a hun renal tube (cold knife) (laser) with catheter at (vur bil) function bladder colostomy -neck) (2 days of life) 5 (fz) pbs voiding bilateral renal none penile >1 cm 2 padua via a hun failure up to 12 fr patent (vur rt) (rtx) urachus 6 (jt) arm poor normal epicistostomy bulbar <1 cm 6 padua eu urinary renal tube up to 10 fr (cold knife) stream function and impossibility to pass a catheter 7 (al) arm poor urinary normal vesicostomy penile >1 cm 1 urethroplasty stream and renal impossibility function to pass a catheter abbreviations: padua,progressive augmentation by dilating the urethra anterior; pbs, prune-belly syndrome; arm, anorectal malformation; vur, vesicoureteral reflux; hun, hydro-ureteronephrosis; rtx,renal transplantation; eu, endoscopic urethrotomy congenital urethral strictures – gobbi et al. pediatric urology 68 vol 16 no 01 january-february 2019 69 in all cases, but the one urinating via the patent urachus, initial management included percutaneous supra-pubic diversion of the bladder. a combination of retrograde urethrography and micturition cystourethrography (mcug) was used to confirm the diagnosis and determine the extension of the stricture in 7 out of 8 cases. all strictures were located in the anterior urethra (figure 1). on mcug, a dilated proximal urethra was present in all patients, and 4 cases had associated vesicoureteral reflux. all patients underwent endoscopic assessment. in 3 cases (2 pbs, 1 arm), a 3 fr urethral catheter could be passed into the bladder and an attempt to a padua was elected. the percutaneous drainage was converted in a formal vesicostomy in 2 such cases. the padua was successful in the 2 pbs patients whereas the patients with arm went on with a cold knife eu that was successful. eu was performed as primary procedure in two patients (1 pbs, 1 arm). a cold knife incision was successful in the patient with pbs whereas eu failed in the other patient despite two attempts, one with cold knife and the other with holmium laser. in the remaining two patients (1 isolated stricture and 1 arm), the stricture was considered unsuitable to attempt an endoscopic management. therefore, a scrotal urethrostomy and a formal vesicostomy were performed, respectively, in the prospect to perform a primary urethroplasty on an elective basis. formal urethroplasty was successful in both these patients as well as in the one with arm where two eu failed. overall, none of the 3 patients with pbs required a formal urethroplasty vs. 3 of the 4 remaining patients. discussion in children, urethral strictures, defined as a concentric narrowing of the urethral lumen, generally follow perineal traumas or urethral surgery, such as hypospadias repair or surgery for anorectal malformation(2,3,4), and occur after the first year of life. in infants, instead, infra-vesical obstruction is most commonly due to urethral valves whereas congenital urethral strictures are exceedingly rare. we identified 7 patients undergoing treatment for congenital urethral strictures at our centre over a 10-year period. these patients are peculiar in many respects. to begin with, 6 out of 7 had associated conditions including pbs and arm, 3 each. the associated underlying condition seems to have important implications both to explain the development of the stricture and for its management. it is indeed of note that the stricture could be fixed by progressive urethral dilatation or by eu, irrespective of its length, in all the 3 patients with pbs whereas 3 of the other 4 patients required a formal urethroplasty. stumme was the first suggesting that all the features of the pbs might be due to an in utero bladder outlet obstruction distal to the prostatic urethra. this obstruction would be typical transient and should disappear before birth(9). we assume, therefore, that our pbs patients had some degrees of developmental delay of the urethral lumen, but not an abnormal urethral wall, which can explain the good response to dilatation or eu in contrast to the stricture in the other patients(9). the other major group of patients included children with high arm. also in these patients, the presence of urethral stricture is not surprising as it might be part of the developmental defect leading to the formation of a rectal-urinary fistula. in keeping with previous reports, we noticed that under these circumstances, dilation with or without urethrotomy is fraught with a high failure rate(10,11). this would be consistent with a more significant abnormality of the urethra. an additional problem peculiar to this group is that the presence of a recto-urethral fistula can complicate the diagnostic workup. radiographic appearance of the urethra can be altered by inadequate passage of contrast in the urethra distally to the fistula opening. moreover, in one patient, the anomaly was discovered due to the impossibility to pass a catheter at the time of colostomy opening during the neonatal period before the urinary stream could be properly assessed and any radiological study of the urethra planned. still, this is a sign difficult to interpret since urethral catheterization in arm patients may be demanding per se due to the presence of a recto-urethra fistula. anyway, our series shows that this can be the first sign of a primary disorder of the urethra. regardless of the nature of the stricture and the associated condition, unless the patient has developed a pop off mechanism such as our patient with a persistent urachus, the first step in the management of these patients should be, in our opinion, the achievement of urinary diversion to preserve renal function. placement of a percutaneous epicystostomy tube is the option of choice at the outset, particularly considering that most of these patients present without a suspicion of a urethral stricture and can be symptomatic with acute urinary tract infection or also urosepsis. this diversion also allows checking safely bladder emptying after treatment of the stricture by intermittent closure of the tube. the drawback is that tube blockage or dislodgment is common in infants, therefore in a few cases conversion to a formal vesicostomy can be advantageous if the stricture tends to recur or to temporize final surgery. in patients with penile stricture a urethrostomy allows to bypass the figure 1. mcug performed via a suprapubic catheter. the white arrow shows a long stenosis involving the anterior urethra, with a proximal (posterior) rosary-like dilation. the white star points to a radiopaque marker located on the basis of the penis. congenital urethral strictures – gobbi et al. stricture while preserving bladder cycling. if this kind of diversion is elected the final repair can be easily postponed to an older age. however, diversion of the urinary flow proximally to the stricture may lower the success of dilatation and endoscopic incision of the stricture, as the urethra is no longer distended by the urinary flow during healing process and this might cause stricture recurrence. we selected this diversion in one patient and he was indeed scheduled for subsequent urethroplasty. it is noteworthy, anyway, that despite an early diversion 4 of our 7 cases in present series presented with renal failure, and 3 required renal transplantation eventually. this clearly depends from the degree of renal damage developed prenatally already. after urinary diversion, treatment options for anterior urethral strictures include wire-guided dilation, direct vision internal urethrotomy, and open surgery. the latter includes stricture excision and direct anastomosis, or augmentation urethroplasty with interposition of a graft as an onlay or inlay in the narrowed urethral segment (3-5). reportedly, urethral dilatation has the lowest success rate, ranging from 20% to 55%. it is considered suitable only for short and mild strictures. moreover, repeated attempts are discouraged and change to other strategies is recommended after the first or the second failure. as mentioned above, in our experience urethral dilatation worked in pbs patients, perhaps due to the peculiar nature of the stricture in these patients. it should be noted that we performed the dilatation using the padua technique (8). this procedure was first described in the late 80s specifically for anterior urethral hypoplasia. the principle is to avoid rapid dilation. urethral dilatation should occur passively. stent size is progressively increased at one-week intervals until an adequate caliber, of at least 8 fr, is achieved. in a few cases, we managed to change the catheter over a guide in an outpatient setting. the final caliber was steadily achieved after a median of 4 weeks. we consider this approach easier than balloon dilation, which requires the child to undergo repeated sections under fluoroscopy. furthermore, the success rate of balloon dilatation appears unsatisfactory(8-9). in contrast, formal urethroplasty, with a success rate ranging from 80% to 95 %, is reportedly the most effective treatment option for urethral strictures in children(2,3,8,9). urethroplasty, however, is also the most invasive option and carries a specific morbidity. in our opinion, it remains the option if less invasive manoeuvres fail or if the strictures cannot be negotiated at all during initial endoscopy. direct vision internal urethrotomy stays somewhere in between urethral dilatation and formal urethroplasty and this is generally recommended as primary treatment for short (less than 1 cm) urethral strictures. nevertheless, a notable technical problem related to the endoscopic treatment of urethral stricture in infants is that urethral instrumentation can be difficult with the small endoscopic instruments required in this age group and not as effective as with the instruments used in older children and adults. for instance, our subjective impression was that the small cold knifes available for the 8 fr and 9.5 fr cystoscopes are generally ineffective in obtaining a satisfactory incision of a stricture. of course, this is likely to improve with the development of new technologies. the holmium laser seems to allow for a more effective incision, and the smaller fibres easily congenital urethral strictures – gobbi et al. fit in endoscopes as small as 7.5 fr. though, we used the holmium laser in one case and despite the incision looked deep and net, the stricture recurred and required a formal urethroplasty eventually. given the lack of solid evidence, we generally individualized the treatment based on patient characteristics. moreover, the treatment of the stricture has to be put in the contest of the other surgeries required, such as in arm patients. in general, once an adequate urinary diversion is ensured, unless in cases of very long and severe strictures that we scheduled for urethropalsty from the outset, we think that a stepwise approach moving from dilatation, to endoscopic incision to formal urethroplasty might be the most reasonable strategy. this, however, can be quite a long process requiring months to be accomplished. conclusions diagnosis and treatment of cus in infants and children remains difficult to standardize. the paucity of cases in the literature does not allow an agreed flowchart and treatment has to be tailored to each single patient. urinary diversion should be achieved at presentation to avoid progressive renal damage in infants that can already have an impaired renal function. following management should be tailored based on the location and length of the stricture, and the associated condition. in our opinion a stepwise approach should be favoured. anterior strictures in patients with pbs are likely to be fixed with progressive dilatation irrespective of their length, whereas this treatment modality is unlikely to be effective in other patients. in the latter, an endoscopic urethrotomy can be attempted, but if it fails urethroplasty should be considered. placement of a formal vesicostomy or, if possible, a urethrostomy depending on the location of the stricture, allows temporizing this surgery until after one year of age. conflict of interest there are no conflicts of interest to be disclosed. references 1. dewan pa, keenan rj, morris ll et al. congenital urethral obstruction: cobb’s collar or prolapsed congenital obstructive posterior urethral membrane (copum). br j urol. 1994;73:91-5. 2. banks fc, griffin sj, steinbrecher ha, malone ps. aetiology and treatment of symptomatic idiopathic urethral strictures in children. j paediatr urol. 2009;5:215-8. 3. kaplan gw, brock jw, fisch m, koraitim mm, snyder hm. siu/icud consultation on urethra strictures: urethra strictures in children. urology. 2014;83(3 suppl):s71-3. 4. dewan pa. congenital posterior urethral obstruction: the historical perspective. pediatr surg int. 1997;12:86-94. 5. adorisio o, bassani f, silveri m. cobb’s collar: a rare cause of urinary retention. bmj case rep. 2013. 22;2013. 6. shoukry ai, abouela wn, elsheemy ms. use of holmium laser for urethral strictures pediatric urology 70 vol 16 no 01 january-february 2019 71 congenital urethral strictures – gobbi et al. in paediatrics: a prospective study. j paediatr urol. 2016;12:42e1-42.e6g. 7. belloli g, pesce c, musi l, campobasso p, citarella e, cappellari f. management of urethral strictures in children. pediatr surg int. 1996;11:344-347. 8. passerini-glazel g, araguna f, chiozza l, artibani w, rabinowitz r, firlit cf. the p.a.d.u.a. (progressive augmentation by dilating the uretra anterior) procedure for the treatment of severe uretral hypoplasia. j urol. 1988; 140:1247-9. 9. smith ea, woodard jr. prune-belly syndrome. gearhart, rink, moriquand edts, pediatric urology p. 577-92. 10. boemers tm, rohrmann d. iatrogenic urethra strictures following pull-through procedures: buccal mucosa inlay repair. j paediatr urol. 2005;1:389-93. 11. chatterjee sk, banerjee s, basu ak, das s. rectourinary fistula with a narrow urethra. pediatr surg int. 2001; 17:410-3. 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran definition laparoscopy is to study peritoneum cavity via a camera entered abdominal cavity through abdominal wall following induced pneumoperitoneum. ordinary surgery processes are performed during laparoscopic surgery but with less lesions and faster improvement comparing toaccepted for publication laparoscopic era modern status of laparoscopic surgery in the urology of iran and world simforoosh n*, basiri a, maghsoodi r, shafi h urology and nephrology research center, shaheed labbafinejad hospital, shaheed beheshti university of medical sciences, tehran, iran first, we would like to introduce laparoscopic procedures conducted at labbafinjad medical center, some of which were performed for the first time in iran and some others were conducted for the first time worldwide, by which iran has been known as a leading country among mediterranean countries in laparoscopic urology. 1. laparoscopic ileocystoplasty (to extend bladder by ileum with intestinal anastomosis) simultaneously with laparoscopic malon to control stool incontinence (first case in the world) (9 cases) 2. laparoscopic urethrocystoplasty (first case in the world) (2 cases) 3. radical laparoscopic prostatectomy by an innovative technique with no suture (20 cases) 4. laparoscopic antireflux in children by lich method (40 cases) 5. laparoscopic retroperitoneal and pelvic lymphadenectomy (6 cases) 6. laparoscopic pyeloplasty (to repair pelvic obstruction) (50 cases) 7. laparoscopic donor nephrectomy (170 cases) 8. laparoscopic nephrectomy (65 cases) 9. laparoscopic adrenalectomy (11 cases) 10. laparoscopic adrenalectomy (15 cases) 11. laparoscopic surgery of retrocaval ureter (1 cases) 12. laparoscopic removal of ureteral and pelvic stones (140 cases) 13. nephropexy (1 cases) 14. varicocelectomy (102 cases) 15. laparoscopic repair of hydrocele and hernia (28 cases) 16. laparoscopic therapy of renal cyst (25 cases) 17. the detection and treatment of ectopic testis (247 cases) 18. partial adernalectomy (1 case) 19. histrosalpingoanorectomy (1 case) modern status of laparoscopic surgery in the urology of iran and world open surgery. the variety of mentioned procedures indicated that approximately all open abdominal urological surgeries could be conducted by laparoscopy, provided that there is due practice. laparoscopic urologic procedures have some advantages including: 1. they prevent large incisions in abdominal urologic surgeries, which are cosmetically important and prevent hernia and infection at the place of incision. 2. they reduce immediate and chronic postoperative incision pain (especially at flank position). in contrast to open surgeries, no pain or a very little pain is felt in laparoscopic procedures. 3. faster return to the normal life and work due to less pain and immobility is possible, which leads to better economical outcome for families and society. in general, modern surgery tends to decrease pain and invasion and laparoscopy has found its place among minimally invasive procedures as an approach, which replaces urological open surgeries in lots of cases. introduction and history the idea of minimal stress and invasion has been come in mind since a long time ago. the use of tube and speculum in medical sciences refers to ancient greek civilizations. new endoscopy was innovated in 1805 by bozzini who tried to observe urethra and vagina by the light of candle through a tube.(1) by the invention of cystoscope by nitze in 1875, edoscopic surgery (to observe urethra and bladder and perform surgery by endoscope) was started and developed parallel to open surgery.(2) in 1901 von ott reported first examination of abdominal cavity by light concentration provided by a mirror connected to speculum. one year later killing reported a laparoscopic surgery performed on an alive dog by a cystoscope after blowing filtered air.(3) the first human laparoscopy was conducted by jacobeus in 1910 via a cystoscope4. in 1929, passing through two separate trocars was viable and in 1933, co2 was applied to produce pneumoperitoneum. consistent control of co2 pressure during laparoscopy was reported in 1944 by palmer.(5) although modern laparoscopy was developed in europe by gastroenterologists, obstetricians were the most beneficiaries of laparoscopy and were the pioneers. though the first laparoscopy was performed via a cystoscope, its first practical urological application was reported in 1976 to detect cryptorchidism.(6) wickham extracted ureteral stone by laparoscopy in 1979.(7) eshghi used laparoscope to remove staghorn stone through skin in 1985.(8) animal urologic laparoscopies were conducted by winfield in 1990 and schuesster reported the first retroperitoneal lymphadenecetomy to treat prostate cancer in 1991.(9, 10) performing laparoscopic varicocelectomy by donvan, winfield, and haywood and nephrectomy by clayman were reported at the same year.(11,12,13) later on, several procedures (bladder diverculitis, retroperitoneal lymphadenectomy, urethrolease, bladder neck suspension, renal cyst, pyeloplasty, radical nephrectomy, ileocystoplasty, radical cystectomy, radical prostatectomy, and antireflux) were preformed and reported by urologists and researchers. although there are many reports on laparoscopic urological surgeries, this method has not totally adapted in most centers, so it needs further developments to achieve its real position. undoubtedfully, lots of laparoscopic technological aspects and instruments would be developed in future, so that applying this technique would be much easier and would be expanded to other procedures too. furthermore, less dependency on instruments could lead to less expensive laparoscopy. for example, consistent metal instruments and trocars are used in our center instead of disposable ones. principals of laparoscopic surgical procedures proper selection of patients, knowledge of related complications, familiarity with laparoscopic techniques and availability of laparoscopic equipments and their directions are essential in laparoscopic procedures. in this article, we would like to review how to prepare a patient and select him for laparoscopic surgery. 2 modern status of laparoscopic surgery in the urology of iran and world patient's selection and preparation precise physical examination and history taking are considered as important steps at the beginning of the work. a history of sever cardiac or respiratory disease is a limited factor for the procedure. sever adhesion by previous abdominal or pelvic surgeries is relatively considered as a contraindication in laparoscopic surgeries, though not always (especially for skilled surgeons). a history of generalized peritonitis, sever obesity, large hiatal hernia and incarcerated hernia are contraindications as well. congenital and acquisitioneal umbilical disorders (hernia, urachal cyst, purulent discharge) should be studied, so that in case of presence, trocars should not be inserted around umbilicus. in the cases of aortic aneurism, it is better not to insert the needle and trocar in the midline. they should be inserted with direct vision. mainly it is preferable to insert the first trocar with direct vision in order to prevent entrance complications. in a report a comparison was made in more than 12000 laparoscopic surgeries between the method of blind insertion of veress trocar needle and the method of inserting the first trocar openly, it was found that the complications were much less (50%) in the second method.(22) definite contraindications for laparoscopy are as follows: 1. generalized peritonitis 2. infection of abdominal wall 3. intestinal obstruction 4. uncorrected coagulation disorders patient should be aware of this procedure and should be asked for permission for any open surgery if needed. intestinal preparation is needed and it is preferred to use liquid diet 48 hours postoperatively in addition to 300gr mgoh in order to repair primarily any intestinal complication. in the cases of intestinal segment surgeries neomicine 2gr and oral metromidazole 2gr should be administered in 2 doses a night before surgery with an interval of 4 hours (a survey is being conducted in this center on the necessity of preoperative intestinal preparation if ileum is going to be involved). any drug that disturbs blood coagulation (like aspirin and anti inflammatory drugs) should be stopped provided that coagulation time becomes normal. routine tests are available and depending on the type of procedure and its extension, transfusion may be requested. iv antibiotic is administered 30 minutes before surgery and continued for 2 days or more depending on the type of procedure. open surgery instruments should be always prepared to be used for a laparoscopic patient who may need open surgery during the procedure. preparation for procedure foly catheter and ng tube should be applied to empty bladder and gastric cavities during laparoscopy. patient's legs should be tied by elastic bandage or pneumatic socks should be used to prevent postoperative emboli. penis and scrotum should be bandaged separately to prevent any pneumomoscrotum and pneumofalus. liquid should be received through the vessels of neck as much as possible to let the hands be free, for the use of arm boards impedes the movement of surgeon and his assistants. like other abdominal surgeries, abdominal and genital parts are prepped with iodine. some researchers believe that in case of long procedures 5000 units sc heparin should be injected 6 hours preoperatively and 12 hours postoperatively till the patient resumes his movement. usually, the surgeon and scrub nurse are positioned near the patient in contrast to pathology and assistant surgeon positioned next to the patient at pathology side. laparoscopic instruments (tv and co2 blower) are positioned near the patient's feet and above his both sides, it is better to use 2 tvs, so that the surgeon and his assistant could easily observe the surgery field and the level of abdominal co2 pressure. before beginning the procedure, all needed instruments should be controlled to assure their accurate working, it is essential to control the following instruments: 1. co2 blower 2. indicator system (camera, endoscope, tv, light source) 3. suction and washing unit 4. cuter 3 modern status of laparoscopic surgery in the urology of iran and world important points in anesthesia and laparoscopy analgesia, amnesia and muscle relaxation are important factors in laparoscopy. though epidural anesthesia is preferred by some surgeons and patients for some short-term surgeries such as tubal ligation general anesthesia is considered as the preferable method for laparoscopy. since there is a risk of vomiting and aspiration due to increased abdominal pressure and trendelenburg position, intubation of the trachea is recommended. important anesthetic complications are not so common in laparoscopy. however, less important complications such as headache, vomiting, muscles pain, shoulder pain and dizziness may be occurred which is due to the used drugs. n2o is not preferred by surgeons, because it causes intestinal expansion and consequently difficulty during the procedure (applying n2o for 2 hours leads to 100% increase in intestinal gas volume in 70% of cases). n2o also causes postoperative vomiting and pneumothorax if pleura is opened. patient should be totally relaxed because the smallest improper movements could lead to insertion of trocar in intestines or large vessels. the administration of anti-h2-receptor (cimetidine) and metoclopramide in patients who are at high risk of aspiration (those with excess body fat, hiatal hernia and diabetes) could prevent this complication and minimize aspiration of gastric acidic contents. the neck veins are preferred for water, electrolytes, and blood transfusion. it is essential to monitor blood o2 saturation to prevent hypoxia... the insertion of especial laparoscopic needle (veress needle) veress needle is inserted to fill peritoneum cavity with co2 in order to insert the first trocar. the needle could be disposable or durable. needle no.14 has a diameter of 1.2 mm and a length of 70 to 120 mm. the needle has an outer cover with a sharp tip and an axis with a blunt tip. the central or inner margin of the needle is pushed on the handle of scalpel to assure that by pushing central and blunt part, the needle would be retracted and by omitting the pressure, it would be quickly returned to its place. patient is positioned at 10 to 20 degrees in a way that the head would be at a lower level than the pelvis. the place of inserting needle should be exactly above or under umbilicus which is bilaterally retracted upwards by 2 grasping pencets in a way that the abdominal wall would be kept away from inner organs, then a small curved incision is incised on the skin by a scalpel, through which, the needle is inserted vertically toward peritoneum. the insertion of needle through fascia and peritoneum is sensible and to assure it, a syringe of 5 mm n.s is connected to the needle. then the syringe is aspirated to assure the lack of blood or intestinal contents (yellowish liquid) outflow. next, n.s is injected and aspirated. if the fluid was injected in peritoneum cavity, it could not be aspirated. when syringe is disconnected from the needle particularly if abdominal wall is retracted upward, needle's remaining drops would rapidly enter the peritoneum. afterwards, the blower of co2 is connected to the needle and the gas is blown by an amount of 1 lit/min. abdominal pressure should be lower than 10 mmhg before the flow of co2. if the pressure is higher and no co2 flow is seen (flow=0) or if the pressure rapidly reaches 15 mmhg (with an amount of one lit/min), the surgeon should retract the needle back a little. if the pressure is high again, needle should be pulled out before gas blow reaches 200 mm and the surgeon should try the needle once again. it should be confirmed that the needle is inserted in peritoneum and the gas is flowed, even if the needle was inserted for several times. one sign of inserting veress in abdominal cavity is that natural dullness of liver would be omitted in percussion during gas flow and the abdomen is gradually extended. the abdomen is filled with gas till the pressure reaches 15 mmhg and then the trocar is inserted. the insertion of the first trocar regarding the fact that inserting the first trocar, which is performed blindly like veress, is of great importance, a small incision (1 cm) is made above or bellow umbilicus and then an incision is cautiously made in fascia. the surgeon holds a 10 mm trocar in his right hand and his assistant bilaterally retracts the umbilicus upwards and 4 modern status of laparoscopic surgery in the urology of iran and world lifts abdominal wall so that when the surgeon pushes the trocar inside the peritoneum, umbilical wall is kept away from inner organs by two grasping pencets . the insertion of the trocar is associated with a special sound. to insert the trocar more inside the abdomen, it should be pushed toward an imaginary line started from umbilicus toward a point between promontorium and bladder. before the insertion, co2 pressure could be temporary increased to 20 mmhg and maximally to 25 mmhg, so that a maximum distance between abdominal wall and inner organs is obtained. following the first trocar insertion, other trocars are inserted in a proper place according to the type of procedure and by observing the system. the insertion of the first trocar by direct observation and without the use of veress a 1 cm incision is usually made above umbilicus. fascia is incised a little by a scalpel. peritoneum is opened 1 cm or less while abdominal wall is kept away from the inner organs. then 1 mm trocar is inserted by direct observation (without scalpel). to prevent co2 leakage from the place of the first trocar entrance, fascia incision should be a little smaller than trocar diameter and a spiral pluge should be seen at the surface of trocar (new trocars are mostly grooved). then the lense and other trocars are inserted by a direct observation. this method excluds the blindly performed processes and their complications in laparoscopy and facilitates teaching urology to assistants and fellowships. the following method is used in case of veress insertion. considering practical laparoscopic experiments performed at unrc, the use of veress has been omitted and the first trocar is always inserted in abdomen with a direct observation, which leads to 2 important advantages: 1. it prevents blindly insertion of veress to omentum, intestines and great vessels particularly in children, besides it precludes the detachment of peritoneum form fascia and gas leakage in peritoneum. 2. the abdomen is filled with gas by trocar much faster than veress; thus, applying trocar is time-saving. trocar extraction by the end of laparoscopy and before the extraction of trocars, the field of procedure is examined with low pressure (5 mmhg) for any hemorrhage, and then it is washed by 200 to 500 ml n.s and 500mg cephazoline. the drain of any brown-yellowish material or blood (a sign of intestinal injury) should be noticed very carefully. if none of them were observed, the liquid would be sucked. some surgeons do not extract this liquid to decrease adhesion of intestines to the passage of trocars and to decline infection. the small trocar is extracted first, the place of which is observed by laparoscope to detect any hemorrhage. the largest torcar is extracted finally and its place is covered by the finger till the gas is emptied, then the margins of fascia are joined together by an 8 like suture, remember that before fastening the suture the gas should be completely emptied. skin passage of trocars should be sutured by 4.0 chromic or 5.0 vicryl subcutaneously and then the incision is covered by a light piece of gauze. postoperative cares postoperative cares are dependent on the type of procedures as in small procedures like varicocele or laparoscopic diagnosis of udt performed at outpatient departments, liquid diet is administered in the afternoon and normal diet is given a day after. the patient could start walking 6 hours later. in the case of large procedures and suspected hemorrhage the repetition of hb, na, and k tests seems to be essential. if the patient suffers form sever pain, a narcotic drug would be administered every 6 hours; however, acetaminophen could be helpful on next day. if abdominal pain lasted or increased after 24 hours, intestinal perforation should be carefully suspected and studied. if shoulder pain which is particularly felt after large procedures (due to remaining abdominal gas and diaphragm stimulation), is continued specially in adults, patient should be examined by ecg and chest scan for any cardiac complication or pulmonary emboli. antibiotics are usually administered for 5 modern status of laparoscopic surgery in the urology of iran and world 2 days or occasionally more, depending on the type of procedure. if the patient suffers from delayed abdominal pain, hernia or infection of the region of surgery should be doubted. echymosis of abdominal wall particularly in lower parts after vast pelvic operations are common and improved spontaneously. in case of increased echymosis and decreased blood hb, abdominal ct scan should be ordered for the detection of any hematoma. hydrocele is observed after long procedures due to the gathering of washing liquid. this would be improved spontaneously and by tight fastening of testis bandage and resting for one to two weeks. laparoscopic complications performing laparoscopy by skilled surgeons is not associated with considerable complications, though at learning stage more complications may occur, which are gradually decreased. complications are reported to be about 4% and mortality rate to be 0.03%. laparoscopic complications have several major parts: those which have occurred during inserting veress and inserting trocar and in pneumoperitoneum stage, as well as vascular complications which are developed by applying some surgical instruments, and those complications occurred at the stage of trocar extraction which include vascular complications (the most common), gaseous emboli, hypotension, cardiac rhythmic disorders, hypoxia, hypercapnia, acidosis, aspiration, pneumothorax, pneumomediastinum, pneumopericardium, subcutaneous emphysema, visceral injuries, peripheral nerve injuries, intestinal complications, and the rise of creatinine. the familiarity with the technique and accurate consideration to preventive measures are the best ways of preventing complications and decreasing them in laparoscopic procedures (as in open surgeries). even though if any complication occurs, timely diagnosis and treatment would be of great importance. the elimination of veress, blind insertion of first trocar and the insertion of first trocar with direct vision could omit most essential complications especially for surgeons use laparoscopy newly. laparoscopy applications in urology by traditional use of cystoscope for diagnosis and treatment and through endoscope, surgical urology entered the new world of surgical endoscopy. moreover, by performing bladder tumor and prostate tur, the attitude of urologists toward treating diseases was changed and finally by the progress of technology, urethral entrance and ultimately renal entrance became practical via precise instruments, through which renal and urethral tumors and stones were treated. in 1976 a new gate was opened toward modern world of treating urologic diseases, that was by performing laparoscopy to detect udt. gradually, the practice of different laparoscopic techniques was confirmed as a surgical fact. in 1991, schuessler reported the first surgical laparoscopy through which pelvic lymphadenectomy was conducted in a patient with prostate cancer. radical nephrectomy for renal cancer was carried out by clayman, who broke off the kidney by merciliter and extracted it./ consequently performing large procedures through some small openings became a reality.(10, 13) this procedure was appreciated by many urologists; however, some others opposed it because it lasted for 9 hours. yet, the time of radical nephrectomy was gradually reduced to reach the time of open surgery or a little more. it was indicated that laparoscopy could be an actual rival and an appropriate replacement for open surgery. in accordance with different reports on laparoscopic nephrectomy outcomes, this procedure has been introduced as a substitution for open surgery, for it prevents large and painful flank incision which leads to hernia and postoperative sever pain. to date, nephrectomy is routinely conducted in lots of centers and it has replaced large procedures in big centers as a standard of care. one thousand cases of laparoscopic radical prostatectomy have been recently reported in europe. schuessler was the first in the usa to perform this procedure; however, he concluded that it was incomparable to open surgery. one year later, following a report of 300 cases of laparoscopic radical prostatectomy by vacnsine from france, the procedure was once again carried out by gill from the usa, which was lasted for 3-4 hours and urethral catheter was removed 6 modern status of laparoscopic surgery in the urology of iran and world after 2-5 days.(14) twenty cases of laparoscopic radical prostatectomy were conducted in iran at labbafinejad medical center during the last year. postoperative urine control and stenosis of anastomosis were the same as open surgery, but with lower hemorrhage and sooner return to normal life. laparoscopic repairing procedures are also common. first laparoscopic surgery and pyeloplasty was performed in 1993. it outran endopyelotomy in a way that its outcomes were similar to those of open surgery. fifty cases of pyeloplasty have been already conducted in this center (fig. 1) with satisfied outcomes. the first case of laparoscopic cystoplasty was reported by gill in 2000.(16) the first laparoscopic cystoplasty was carried out in this center in 2002. nine cases of ileocystoplasty and one ureterocystoplasty have been already conducted. the most complicated procedures were performed by gill et al at cliolind clinic which included radical cystectomy and ileal conduit, 11 cases of which were conducted in 2001, followed by 5 cases of radical cystectomy and orthotopic patch. gill et al were introduced as a unique group in laparoscopic surgery field and were awarded best prize in laparoscopy at the urology congress.(17) nephrectomy due to benign lesions was carried out for the first time by clayman in 1991. in 1993 laparoscopy was performed in iran at labbafinejad medical center to diagnose and 7 fig. 1. aberrant vessels in a patient with upj fig. 3. postoperative photo of a patient who underwent rplnd laparoscopic retroperitoneal lymphadenetomy with 3 trocars. the scar of previous open orchidectomy is observed underneath. fig. 4. renal cyst in a 2-year child who underwent laparoscopy fig. 2. laparoscopic lymphadenectomy for testicular tumor; lymph nodes between aorta and vena cava has been totally removed. modern status of laparoscopic surgery in the urology of iran and world treat udt and varicoclectomy.(18) although, learning how to conduct laparoscopy is more difficult and time-consuming, it is practical by obtaining more skill. this center is an obvious example which initiated its laparoscopic activities by a limited experience with diagnostic laparoscopy. larger procedures such as adernalectomy, rplnd (fig. 2, 3), urethral stone and renal cyst (fig. 4) were conducted by gradual obtaining of experience at the first 4 years. laparoscopic progresses were such fast that lots of mentioned surgeries were performed routinely during the last 2 years and some others such as ureteroplasty and ileocystoplasty with intraabdominal anastomosis and appendix diversion toward abdominal wall were also carried out for the first time worldwide which were accepted at usa urologic congress for the first time from iran and were represented in april 2003.(20,19) to date, all international journals of urology are filled with successful reports of laparoscopic procedures, which indicates the increasing progress in urology. it could be claimed that laparoscopy is now the first surgical alternative. it is believed that all those who are familiar with surgical principals are able to practice laparoscopy as well. references 1. bozzini p. lichtleiter, eine erfindung zur anschauuny innerer teile und karankheiten, nebst der abbildung. j praktischen arzneykunde wundarzney kunst (berlin) 1806; 24: 107-124. 2. nitze m. eine neue beobachtungs-und untersuchungsmethode fur harnrohre, harnblase und rectum. wien med wochenschr 1879; 24: 649-652. 3. kelling g. die tumponnade der bauchhohle mit luft zur stillung lebensgefahrlicher intestinal buthngen. munch med wochenschr 1901; 48: 1535-1538. 4. jacobaeus hc: uberdie moglichkeit die zystoskopic bei untersuchung seroser hohlen anzuwenden. munch med wochenschr 1910; 57: 2090-2022. 5. palmer r. instrumentation et technique de la coelioscopie gynecologique. gynecol dostet (paris) 1947; 46: 450-431. 6. cortesi n, ferrari p, zambarda e, et al. diagnosis of bilateral abdominal cryptorchidism by laparoscopy. endoscopy 1976; 8:33-34. 7. wickham jea. the surgical treatment of renal lithiasis in urinary calculous disease. new york: churchill livingstone; 1979.p. 145-198. 8. eshghi am, roth js, smith ad. percutaneous transperitoneal approach to a pelvic kidney for endourological removal of staghorne calculus. j urol 1985; 134: 525-527. 9. winfield hn, donovan jf, godet as, clayman rv. human laparoscopic partial nephrectomy case report. j endourol 1992; 6: 59. 10. schuessler w, vancaillie tg, reich h, griffith dp. transperitoneal endosurgical lymphadenectomy in patient with localized prostate cancer. j urol 1992; 147: 77-78. 11. donovan jf, winfield hn. laparoscopic varix ligation. j urol 1992; 147: 77-81. 12. hagood pg, mehan dj, worischek jh, et al. laparoscopic varicocelectomy: preliminary report of a new technique. j urol 1992; 144: 73-76. 13. clayman rv, kavoussi lr, soper nj, et al. laparoscopic nephrectomy: initial case report. j urol 1991 (b); 146: 278-282. 14. guillonneau b, cathelineau x, doublet jd, vallancien g. laparoscopic radical prostatectomy. j endourol 2001 may; 15 (4): 441-5. 15. schuessler w, grune mt, tecuanluey lv, preminger gm. laparoscopic dismembered pyeloplasty. j urol 1993; 150: 1795-1799. 16. gill is, rankley rr, meraney am. llparocopic entrocystoplasty. urology 2000 (b); 55: 178-181. 17. fergany af, gill is, kauck jh, et al. laparocopic intracorporeally constructed ileal conduit after porcine cystoprostatectomy. j urol 2001; 166: 285. 18. simforoosh n. laparoscopic surgery of pediatric hydroceles without narrowing or suturing ring. 19th world congress on endourology and swl, 17th basic research symposium. 8 modern status of laparoscopic surgery in the urology of iran and world bangkok (thailand): 2001. 19. simforoosh n, bassiri a, ziaee sam, tabibi a, et al. laparoscopic versus open live donor nephrectomy, the first prospective clinical trial. the viii international mesot congress. oman: 2002. 20. simforoosh n, shadpour p, maghsudi r, shafi h. laparoscopic combined ileocystoplasty and malone procedures: totally intracorporeal freehand suturing. aua 2003 chicago (usa). 21. simforoosh n, shadpour p. laparoscopic detrusororrhaphy in children with vesicoureteral reflux. aua 2003 chicago (usa). 22. catarci m, carlini p, gentileschi p, santoro e, the lap group roma. major and minor injuries during the creation of pneumoperitoneium. a multicenter study on 12919 cases. surg endosc 2001; 15: 566-569. 9 female urology association of severity of lower extremity arterial disease and overactive bladder syndrome: a cross sectional study bahar yuksel1*, faruk ozgor2, mazlum sahin3, metin savun2,murat sahan2 ,ufuk caglar2,omer sarilar2 introduction according to the international continence society, overactive bladder syndrome (oab) is a clinical entity including urgency with or without urgency incontinence, frequency and nocturia in the absence of pathological and/or metabolic disorder that may clarify these signs (1). according to literature, the prevalence of oab has been reported in a wide range up to 53% causing significant deterioration in patients sexual function, mental health, and overall life quality. although, previous reports have reported several factors including aging, central and peripheral sensory, somatic and peripheral neuropathy, and atherosclerosis , the underlying mechanism has not been understood clearly yet (2) . atherosclerosis (at) is a course that progressive hardening and thickening of arteries wall forms as a result of fat deposit plaques on their inner lining. also, at is a systemic disorder and small-medium size arteries such as iliac artery branches are more vulnerable to atherosclerotic lesions(3). capple et al. stated that pelvic ischemia due to at is trigger point for development of lower urinary system symptoms such as urgency, frequency and nocturia(4). on the other hand, at in the iliac artery and distal branches of iliac artery is associated purpose: the aim of this study aim is to clarify the relationship between overactive bladder syndrome (oab) and severity of lower extremity ischemia by using fontaine classification system. materials and methods: patients who were diagnosed with lower extremity arterial disease were enrolled into the study. the fontaine score of each patient was taken and all patients completed the validated turkish version of oab-v8 questionnaire. body mass index, serum creatinine, blood urea nitrogen, cholesterol and fasting plasma glucose levels were measured. the patients were divided into two groups. patients with oab-v8 score above 8 were enrolled into group 1 and patients with oab-v8 score under 8 were enrolled into group 2. results: at the end of study period, 181 patients who met the inclusion criteria were enrolled into the study. patients with oab ≥ 8 score (n= 79) were compared with patients with oab < 8 score (n= 102). the mean age and the mean bmi were significantly higher in patients with oab ≥ 8 (p = .001 and p = .001, respectively). also, hdlcholesterol level was found significantly lower in group 1 patients (p= .001). multivariate regression analysis showed that presence of fontaine score ≥ class 2b, age ≥ 60 years, bmi ≥ 30 kg/m2 , and hdl-cholesterol levels < 60 mg/dl were predictive factors for oab. conclusion: the present study demonstrated that incidence of oab is higher in patients with severe lower extremity ischemic symptoms, older age, high bmi, and lower hdl-cholesterol level. keywords: atherosclerosis, fontaine classification, oab-v8 form, overactive bladder, urgency 1department of obstetrics and gynecology, esenler maternity and children’s hospital, istanbul, turkey 2department of urology, haseki teaching and research hospital, istanbul, turkey 3department of cardiovascular surgery, haseki teaching and research hospital, istanbul, turkey *correspondence: department of obstetrics and gynecology, esenler maternity and children’s hospital, istanbul, turkey tel: +90 [0212] 440 39 00. fax: +90 [0212] 440 39 00. e-mail: baharyl86 @gmail.com. received october 2018 & accepted december 2019 with lower limb ischemia and lead symptoms including sense of fatigue, numbness, muscle pain, and muscle cramp. to determine severity of peripheral artery ischemia, fontaine at al. described a classification system including four stages: asymptomatic patients, patients with intermittent claudication, patients with rest pain and patients with ischemic ulcers or gangrene(5). previous reports have demonstrated the relationship between pelvic ischemia and oab, however none of these studies has evaluated the presence of oab in patients with peripheral lower extremity artery ischemia. the aim of this study was to clarify the relationship between oab and severity of lower extremity ischemia using fontaine classification system. materials and methods after obtaining local ethics committee approval, patients diagnosed with lower extremity at between january 2017 to january 2018 in the cardiovascular unit of a tertiary academic center were enrolled into the study. the research was managed in accordance with helsinki declaration and informed consent was obtained from all patients. to achieve indiscrete study population, patients younger than 18 years old, patients with benign prostate hyperplasia, uncontrolled diabetes melliurology journal/vol 17 no. 2/ march-april 2020/ pp. 180-184. [doi: 10.22037/uj.v0i0.4886] vol 17 no 02 march-april 2020 181 tus, uncontrolled hypertension, neurological disorders, urinary system cancers, and history of pelvic radiation were excluded from the study. moreover, patients with residual volume > 100 ml and maximum flow rate < 15 ml/s were also excluded. history of incontinence surgery and pelvic organ prolapse surgery, and presence of pelvic organ prolapse at the time of enrollment were other exclusion criteria. asymptomatic patients with lower extremity at and patients with ischemic symptoms (fatigue, numbness, muscle pain, muscle cramp, skin ulcers and tissue loss) due to lower extremity at were evaluated by a single cardiovascular surgeon in an outpatient setting. detailed medical history was obtained and physical examination was performed in all patients. the fontaine score of each patient was evaluated and all patients completed the validated turkish version of 8item validated overactive bladder (oab) questionnaire (oab-v8) . smoking history and body mass index (bmi) were noted. also, serum creatinine, blood urea nitrogen, cholesterol, hdlcholesterol, ldlcholesterol, triglyceride and fasting plasma glucose levels were measured. moreover, urine culture, urinalysis, sonography of the urinary tract, uroflowmetry, and bladder diary were performed routinely. the patients were divided into two groups based on severity of oab symptoms evaluated by oab-v8 questionnaire. patients with oab-v8 score above 8 were enrolled into group 1 and patients with oab-v8 score under 8 were enrolled into group 2, respectively. the groups were compared according to patients’ medical history, severity of lower extremity ischemic symptoms, oab-v8 scores, serum blood test results, sonography of the urinary tract and uroflowmetry findings. 8item validated overactive bladder (oab) questionnaire the form oab-v8 is a self-reported questionnaire, including 8 queries that evaluate severity of irritative symptoms including urgency, frequency, nocturia and urgency urinary incontinence. a score of 8 and above of the oab shows significant association with oab and a score under 8 indicates that diagnosis of oab is questionable or absent. in this questionnaire, urgency and frequency are accepted as a sudden urge to pass urine and eight or more micturition per day. the nocturia is defined as waking at night to void ≥ 2 times and involuntary leakage with urgency is described urgency urinary incontinence(6). fontaine classification the fontaine classification is a clinical classification method to evaluate the severity of peripheral artery disease which includes four stages. patients with subclinical peripheral artery disease without any symptoms are enrolled in class 1. patients with intermittent claudication after walking are considered class 2 (2a: intermittent claudication after more than 200 meters of pain free walking and 2b: intermittent claudication after less than 200 meters of walking). patients with rest pain and patients with ischemic ulcers or gangrene are grouped in stage iii and stage iv, respectively. statistical analysis the statistical package of social sciences for windows (spss) version 20 was used for statistical analysis. we divided patients into 2 groups based on their oab-v8 score. categorical variables were presented as numbers and percentages and compared with chi square test. continuous variables were presented as means and standard deviations and compared with independent sample t-test. logistic regression analysis was used to examine the possible association between age, bmi, hdl and fontaine score. statistical significance was considered as a two-tailed p value < 0.05. lower extremity arterial disease and veractive bladder-yuksel et al. table 1. comparison of patients’ characteristics groups oab non-oab p value [group 1] [group 2] number 79 102 gender [male/female] 66/13 81/21 .483 age [years]* 64.2 ± 8.1 56.0 ± 7.9 .001 bmi [kg/m2]* 32.3 ± 3.9 27.5 ± 3.9 .001 oab-v8* 18.7 ± 5.8 3.8 ± 2.1 .001 oab wet/oab dry 28/ 51 na na total water intake (ml) 1750 ± 680 1320 ± 430 .001 total caffeine intake (ml) 440 ± 280 280 ± 120 .001 total alcohol intake (ml) 50 ± 15 35 ± 10 .127 fontaine score .001 class 1 1 [1.3%] 47 [46.1%] class 2a 32 [40.5%] 55 [53.9%] class 2b 29 [36.7%] 0 class 3 15 [19.0%] 0 class 4 2 [2.5%] 0 ht 26 [32.9%] 32 [31.4%] .827 smoking 29 [36.7%] 32 [31.4%] .454 ldl, mg/ml* 130.4 ± 35.8 127.1 ± 36.2 .546 hdl, mg/dl* 45.1 ± 5.8 76.6 ± 32.2 .001 cholesterol, mg/dl* 265.7 ± 89.1 243.2 ± 87.8 .091 trigliseride, mg/dl* 163.6 ± 44.2 172.0 ± 49.2 .238 glucose, mg/dl* 136.8 ± 28.7 137.8 ± 30.0 .819 creatinine, mg/dl* 1.2 ± 0.7 1.4 ± 0.9 .195 * mean ± standard deviation abbreviations: na : not available; p < 0.05 : statistically significant difference; oab: over active bladder; oab v8: 8item validated over active bladder syndrome questionnaire score; bmi: body mass index; mg/dl: milligram per deciliter; ht: hypertension; ldl: low density lipoprotein; hdl: high density lipoprotein female urology 182 results at the end of one-year study period, 322 patients were enrolled into the study out of which 181 patients met the study inclusion criteria and where included in the final analysis. due to benign prostate hyperplasia, uncontrolled diabetes mellitus, neurological disease, history of pelvic radiation, history of pelvic organ surgery and usage of medication for oab, 71, 12, 15, 9, 6 and 19 patients were excluded from the study, respectively. also, 9 patients were excluded due to other reasons in accordance with study exclusion criteria. the patients with oab ≥ 8 score (n = 79) and the patients with oab < 8 score (n = 102) were compared. the mean age and the mean bmi were significantly higher in patients with oab≥ 8 (p = 0.001 and p = .001, respectively). the mean age of patients with wet oab was higher although the difference was not statistically significant (66.2 vs 62.7, p = .114). on the other hand, gender, presence of hypertension and smoking history were comparable between two groups (p = .483, p = .827 and p = .454, respectively). moreover, levels of serum creatinine, fasting plasma glucose, ldlcholesterol and triglyceride did not show statistical difference between patients with oab ≥ 8 and patients with oab < 8 score. however, hdlcholesterol levels were found significantly lower in patients in group 1 (45.1 mg/dl vs 76.6 mg/dl, p = .001). when groups were compared according to fontaine classification system, the patients with oab ≥ 8 score had higher scores (p = .001). the mean post voiding volume was 42.5 ml in group 1 and 41.9 ml in group 2 (p =.887). also, the mean maximum flow rate and the mean average flow rate were similar between two groups (p = .660 and p = .784, respectively). the patient number according to fontaine classification is listed in table 1. multivariate regression analysis showed that presence of fontaine score ≥ class 2b is an independent risk factor for oab and increases the risk of oab upto 4 fold . additionally, age ≥60 years, bmi ≥ 30 kg/m2 and lower hdl-cholestrol level (60 mg/dl) were predictive factors for oab (table 3). discussion atherosclerosis is a multifocal, smoldering and immune inflammatory disorder that leads to endothelial dysfunction affecting all arteries of the body. it’s well known that small and medium sized arteries like penile and vesical arteries are more vulnerable to at due to their relatively small lumen diameter compared to wider sized arteries. in accordance with this hypothesis, authors showed that the significant relationship between coronary artery disease and erectile dysfunction indicates the possible role of oab(7,8). the severity of lower extremity ischemia has been reported in a wide range according the literature due to the subjective examination finding and different interpretation of imaging modalities. thus, classification systems have been created for more objective evaluation of ischemia, better surgical planning and comprehensive patient counseling. additionally, using classification system has led to further scientific reporting(9). the fontaine classification system is the first determined tool to clarify severity of lower extremity ischemia by european society of cardiovascular surgery. the system is solely based on physical examination and severity of ischemic symptoms classified into stage 1 to 4 (5). according to artery size hypothesis, patients categorized within a higher fontaine class, are expected to face bladder ischemia, including oab syndrome more often. in accordance with that hypothesis, we found significantly higher oab-v8 score in patients categorized within higher fontaine class and multivariate analysis table 2. comparison of patients according to oab symptoms and uroflow parameters between groups groups oab [group 1] non-oab [group 2] p value number 79 102 urgency 70 [88.6%] 22 [21.6%] .001 frequency 41 [51.9%] 20 [19.6%] .001 nocturia 43 [54.4%] 29 [28.4%] .001 urgency urinary incontinence 42 [53.2%] 7 [6.9%] .001 postvoiding urinary residue, ml* 42.5 ± 18.4 41.9±18.7 .887 max flow rate, ml/s* 20.4 ± 3.4 20.7±3.9 .660 average flow rate, ml/s* 13.6 ± 2.4 13.5±2.4 .784 voided volume, ml* 200.1 ± 43.8 213.1±67.1 .135 * mean ± standart deviation p < 0.05 : statistically significant difference abbreviation: oab: over active bladder odds ratio* p* odds ratio** p** agea 1.9 (1.4-2.6) 0.001 2.5 (1.1-5.6) .027 bmib 2.6 (1.9-3.7) 0.001 4.2 (1.8-9.5) .001 hdlc 17.5 (4.5-68.3) 0.001 30.9 (6.7-142.3) .001 fontain scored 1.3 (0.9-1.9) 0.002 4.0 (1.2-13.5) .023 * univariate analysis **multivariate analysis a: < 60 years vs ≥ 60 years b: < 30 kg/m2 vs ≥ 30 kg/m2 c: < 60 mg/dl vs ≥ 60 m/dl d: < grade 2b vs ≥ grade 2b table 3. univariate and multivariant analysis lower extremity arterial disease and veractive bladder-yuksel et al. vol 17 no 02 march-april 2020 183 revealed classification as fontaine 2b or higher is an independent risk factor for oab development. the incidence of atherosclerosis increases with age, it reduces blood flow and corrupts oxygenation of tissues. pinggera et al. compared bladder perfusion of 32 elderly patients which have lower urinary tract symptoms and 20 young healthy volunteers with transrectal colour doppler ultrasonography. they found significantly lower bladder perfusion rate in symptomatic elderly patients than in the younger healthy volunteers(10). in a more recent study by kilinc et al. age was identified as independent risk factor for oab development in multivariate regression analysis(11). in accordance with studies mentioned above, we also determined a statistically significant relation with age and oab in the present study. several authors had stated that prevalence of oab syndrome has a positive correlation with obesity due to increased intraabdominal and intravesical pressure that leads overactivity of detrusor muscle. richter et al. claimed high abdominal pressure may deteriorate innervations of pelvic floor(12). in another possible hypothesis, ghrelin-a peptide hormone that regulates metabolic activity and reach higher levels in obese patients may be the other trigger causing an increase on contractile activity of the bladder through its receptors on preganglionic neurons(13). moreover, relationship between obesity and at risk factors such as dyslipidemia, hypertension, insulin resistance is well known. in this present study, we found significantly higher bmi in patients who were diagnosed oab syndrome and bmi ≥ 30 kg/ m2 increased oab syndrome risk 4.2 fold times. however, we did not find any association between other at risk factors and oab syndrome. our study sample may justify these results since only patients whose diabetes mellitus and hypertension were under control were included into study. we found higher ldlcholesterol levels in patients with oab. however, univariate analysis did not predict ldl-cholesterol as risk factor for oab development. however, we did not evaluate the possible effect of dyslipidemia duration and central obesity in the oab development. these may be a subject of another study. plasma lipids have crucial role in at development. the one of cholesterol subtype called as hdl cholesterol facilitates promotion of reverse cholesterol transport, accelerates plaque regression, and leads to endothelial function improvement. moreover, hdl has anti-inflammatory and anti-thrombotic characteristics. thus, some authors hypothesize that increase in hdl levels may be associated with reduction of at events(14). in accordance with that knowledge, we found significant higher hdlcholesterol levels in patients without oab (76.6 mg/dl vs 45.1 mg/dl, p = 0001, respectively). moreover, multivariate regression analysis revealed higher hdlcholesterol level as a predictive factor to prevent oab. however, some studies emphasized the hdlcholesterol functionality is more important to prevent at event beyond plasma hdl-cholesterol concentration. correlation between oab and hdlcholesterol functionality may be a subject of another study. the present study has some limitations. first, our study was a cross sectional study with a relatively small patient number. additionally, this study included patients from only a single center and represented only single center experience. however, all patients were evaluated by a single cardiovascular surgeon and urologist that improve internal validity of the study. also, we could not evaluate the interval time between the beginning of ischemic symptoms and oab symptoms. lastly, we did not analyze the treatment response and treatment cost of patients who referred to outpatient urology clinic from the cardiovascular unit. the present study demonstrated that incidence of oab was higher in patients with severe lower extremity ischemic symptoms. additionally, patients with older age, high bmi and lower hdl-cholesterol level face oab symptoms more frequently. our study supported that investigating bladder function is advisable in patients with severe leg ischemia. our findings must be supported by further prospective studies with a larger patient volume. conflict of interest none declared by the authors. references 1. azurı j, kafri r, ziv-baran t, stav k. outcomes of different protocols of pelvic floor physical therapy and anti‐cholinergics in women with wet over‐active bladder: a 4‐year follow‐up. neurourol urodyn , 2017; 36.3: 755-8. 2. bykoviene l, kubilius r, aniuliene r,bartuseviciene e, bartusevicius a. effects on the overactive bladder. a randomized clinical trial. urol j. 2018;15: 186-192. 3. herrington w, lacey b, sherliker p. epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. circ res 2016; 118:535–46 4. chapple c (2014) chapter 2: pathophysiology of neurogenic detrusor overactivity and the symptom complex of “overactive bladder”. neurourol urodyn 33(suppl 3): s6–s13. 5. novo s., coppola g. milio g. critical limb ischemia: definition and natural history. current drug targets-cardiovascular & hematological disorders, 2004; 4.3: 219-25. 6. tarcan t, mangir n, ozgur mo et al. oab-v8 overactive bladder questionnaire validation study. üroloji bülteni 2012; 21:113–6 7. montorsi p, ravagnani pm, galli s. association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient. eur urol, 2006; 50:721–31 8. acquadro c, kopp z, coyne ks, corcos j, tubaro a, choo ms. translating overactive bladder questionnaires in 14 languages. urology, 2006; 67: 536-40. 9. ozgor f, yanaral f, savun m, ozdemir h, sarilar o, binbay m. comparison of stone, croes and guy’s nephrolithometry scoring systems for predicting stone-free status and complication rates after percutaneous nephrolithotomy in obese patients. lower extremity arterial disease and veractive bladder-yuksel et al. urolithiasis, 2017; 1-7. 10. pinggera g, mitterberger m, steiner e et al association of lower urinary tract symptoms and chronic ischaemia of the lower urinary tract in elderly women and men: assessment using colour doppler ultrasonography. bju int 2008; 102:470–4 11. kilinc mf, yasar e, aydin hi, yildiz y, doluoglu og. association between coronary artery disease severity and overactive bladder in geriatric patients. world j urol, 2018; 36:35-40. 12. richter he, creasman jm, myers dl, wheeler tl, burgio kl, subak ll. urodynamic characterization of obese women with urinary incontinence undergoing a weight loss program: the program to reduce incontinence by diet and exercise (pride) trial. international urogynecology journal, 2008; 19:1653-8. 13. ferens, d. m., yin, l., ohashi‐doi, k., habgood, m., bron, r., brock, j. a.,furness, j. b. . evidence for functional ghrelin receptors on parasympathetic preganglionic neurons of micturition control pathways in the rat. clinical and experimental pharmacology and physiology, 2010;37 :926-932. 14. zhou p, li b, liu b, chen t, xiao j. prognostic role of serum total cholesterol and high-density lipoprotein cholesterol in cancer survivors: a systematic review and metaanalysis. 2018; 477:94-104. lower extremity arterial disease and veractive bladder-yuksel et al. female urology 184 pediatric urology a comparison between dextranomer/ hyaluronic acid and polyacrylate polyalcohol copolymer as bulking agents for treating primary vesicoureteral reflux farshid alizadeh1, iman omidi1, saeid haghdani2*, mohammad hatef khorrami1, mohammad hossein izadpanahi1, mehrdad mohammadi sichani1 purpose: in recent years, endoscopic subureteral injection has gained popularity as a therapeutic alternative to open surgery because of its high success rates and low morbidity. we compared the success and complication rates of polyacrylate polyalcohol copolymer (ppc) and dextranomer/hyaluronic acid (dx/ha) in the endoscopic treatment of vur. materials & methods: we retrospectively reviewed the patients who underwent endoscopic correction of their vur by subureteric injection of ppc or dx/ha from jan 2010 to april 2016. the injection technique was sting (subureteric), distal hit (intraureteric), and double hit according the hydrodistention (hd) grade. the success rate, injection technique, injection volume, vur grade, and obstruction rate were evaluated and compared between two groups. results: 107 renal refluxing units (rru) with a mean age 55.23 ± 36.58 months and 64 rru with a mean age 52.13 ± 31.66 months were treated in dx/ha and ppc groups, respectively. the ppc group showed a more successful outcome in comparison to the dx/ha group (92.2% versus 75.7% of the rru with p < .001) at 3 months follow up. the injection technique was not significantly different between two groups. in ppc group the success rate was decreased significantly with increasing reflux grade but this reduction was not statistically significant in dx/ha group. the injected volume was significantly more in ppc group; in addition, there was statistically significant correlation between injected volume of the bulking agent and obstruction rate. however, the obstruction rate did not establish significant difference between the two groups (p = .83), however it was earlier in vantris (4 months versus 22 months). conclusion: our investigation approved ppc as a more effective material, regardless of other confounding variables such as reflux grade, learning cure, and technique of injection, in endoscopic treatment of vur. in addition, the other remarkable point is this effectiveness is not accompanied by more post-operation obstruction. keywords: vesicoureteral reflux; dextranomer/ hyaluronic acid; polyacrylate polyalcohol copolymer; endoscopic treatment introduction vesicoureteral reflux (vur), the abnormal flow of urine from the bladder into the ureters or kidneys, is the most common urological anomaly in children(1). the primary goal of therapy in vur is to prevent pyelonephritis which can lead to long-term sequelaes such as renal scarring, hypertension, reduced somatic growth, renal insufficiency and end-stage renal disease (2,3). treatment routes for vur include observation, antibiotic prophylaxis, and surgical intervention(4,5). ureteroneocystostomy is the gold standard of surgical therapy with the success rate of greater than 95%(6). in recent years, endoscopic subureteral injection has been introduced as a therapeutic alternative to open surgery because of its high success rates about 80-95%, low incidence of complications, its minimally invasive nature and short hospital stay (7-9). this technique was initially described by matouschek in 1981(10) and the first case series was reported by o’donnell and puri in 1984 (11). 1department of urology, isfahan university of medical sciences (iums), isfahan, iran. 2department of urology, hasheminejad kidney research center (hkrc), iran university of medical science, tehran, iran. *correspondence: hasheminejad kidney research center (hkrc), iran university of medical science, tehran, iran. postal address: hasheminejad kidney center, north valiasr street, vanak square, tehran, iran. tel: +989133154014. fax: +983136284154. email: saeed_haghdani@yahoo.com. received september 2017 & acceted may 2018 since then, different materials have been used in subureteral injection which include: collagen, polytetrafluoroethylene (teflon®)(12), polydimethylsiloxane (macroplastique®) (13), calcium hydroxyapatite (coaptite®) (14), dextranomer/hyaluronic acid copolymer (dx/ha, deflux)(8) and recently, polyacrylate polyalcohol copolymer(15). in 2001, the food and drug administration approved dextranomer/hyaluronic acid copolymer (deflux; q-med scandinavia, uppsala, sweden) for subureteral injection and thereafter, the endoscopic management of vur has emerged as a first line treatment of vur worldwide(8). dx/ha is a viscous biocompatible gel consisting of dextranomer microspheres of 80 to 120 µm in diameter and non-animal hyaluronic acid. the overall success rate, depending on the vur grade, stated in the literature ranges between 68 and 92% (9,16). in these conclusions, the long term recurrence rate of 10% to pediatric urology 174 vol 16 no 02 march-april 2019 175 26% with dx/ha propel researchers into another tissue-augmenting substance in order to reach better longterm efficacy in the endoscopic treatment of vur(16-19). some have recommended that the biodegradable nature of dx/ha is responsible for the concluding vur recurrence (17). therefore, polyacrylate polyalcohol copolymer (ppc, vantris, promedon, cordoba, argentina) as a new non-biodegradable tissue-augmenting substance was developed. polyacrylate polyalcohol copolymer is a biocompatible agent with an average diameter of 300µm made of microparticles of ppc in glycerol and physiological solution (20). the overall success rate of ppc in the literature was reported to be between 83.6% and 94.9% in the short-term follow-up(15,20,21). in addition, one study with over three years follow up showed no vur recurrence with ppc(21). the comparative studies between these two agents in literature are rare(22-24). there are controversial results in short term observations. while some studies presented ppc as the more successful substance, pogorelic et al.(25) study showed no significant difference in cure rates between the vurdex and ppc. in this study, we compared the success rate of ppc and dx/ha in the endoscopic treatment of vur with considering other suggested variables such as the injection technique and volume. materials and methods we retrospectively reviewed the records of patients under the age of 15 years who fulfilled inclusion criteria of the study and underwent endoscopic correction of their vur by a single pediatric urologist (fa) from jan 2010 to april 2016. before the april 2013, patients were treated by subureteric injection of ppc (43 patients, 64 rru) and after that time, by dx/ha injection (65 patients, 107 rru). inclusion criteria included patients with diagnosis of unilateral or bilateral primary vur grades ii–v with breakthrough utis despite prophylactic antibiotics, persistent vur after a period of observation, poor compliance with prophylactic antibiotics, and evidence of new renal scarring on a 99-m technetium dimercapto-succinic acid (dmsa) renal scan. grade i vur were treated only if accompanied by a contralateral higher grade reflux. the first evaluation of patients after uti or finding of hydronephrosis on ultrasound study was with voiding cystourethrography (vcug) and reflux grading was performed according to the international classification system (international reflux study committee). the preoperative work-up included a detailed history and physical examination, a vcug, a urinalysis and culture. before surgery, all patients were evaluated for the presence of neurologic deficits, dysfunctional voiding and/or constipation. if any symptoms of enuresis, nocturia, urgency, frequency (documented by a voiding diary), postponement, holding maneuvers, urinary and/or fecal incontinence or constipation existed, a flowmetry/ pelvic floor electromyography (emg) was performed to check for the presence of dysfunctional voiding (dv). this test was also performed if increased bladder wall thickness (>3 mm with full bladder) or increased post-void residual urine were observed on ultrasound in the absence of active uti or bladder outflow obstruction. a formal pressure-flow study was performed in patients with significant bladder wall trabeculation on vcug or documented neurological abnormalities. all patients with proven dv were first treated by biofeedback-assisted pelvic floor muscle training. we considered the vur to be secondary if it was accompanied by a known neurologic deficit, severe form of dv (hinman syndrome) or documented urethral obstruction (e.g. posterior urethral valve). exclusion criteria were isolated grade i vur, active uti at the time of surgery, past history of open ureteroneocystostomy or subtrigonal injection of bulking agents, anatomical anomalies of the urinary tract (concomitant ureteropelvic junction obstruction, double urinary collecting system, ectopic ureter, posterior urethral valve) and alterations in bladder dynamics (untreated dv and neuropathic bladder). the committee of ethics approved the protocol, and parents signed a written informed consent before operation. technique in the operation room, cystoscopy was performed by a 8-9.8 fr offset lens, wolf cystourethroscope and if the ureteral orifice was in the extravesical position (not diagnosed on vcug), the patient was considered ineligible for endoscopic surgery. the injection technique was sting (subureteric) in the absence of hydrodistention (hd) of the ureteral orifice, distal hit (intraureteric) when the hd was grade 1 or 2, and double hit in the presence hd grade 3. a combination of hit and sting was used whenever a slitlike orifice and disappearance of hd was not achieved by hit alone. the material was injected until complete coaptation of the ureter was achieved and the type and volume of injected agent was recorded. the patient was discharged the evening of the day of surgery if no fever or significant hematuria was observed. after discharge from hospital, prophylactic oral cephalexin 15mg/kg at bed time was prescribed until post-operative imaging showed reflux resolution or down-grading to grade a on rnc. follow up study follow-up radionuclide cystography (rnc) was performed 3 months after the operation or after any episode of febrile uti in patients who had been cured of their reflux. according to the protocol, repeat rnc in cured patients was performed only in the presence of febrile uti or new-onset hydroureteronephrosis (hun). renal and bladder ultrasound was performed at the post-operative month one, every 3 months during the first year, every 6 months during the next 2 years and then, yearly. if a new-onset hun or exacerbation of the previous one was observed, a repeat rnc and a lasix renogram was requested. we devided post-operative ureteral obstruction into early and late. early-onset obstruction presents with renal colic in the early post-operative period and resolves spontaneously, while late-onset obstruction presents with urinary tract infection, creatinine rise (in bilateral cases) or as an incidental finding on post-operative imaging. success was defined as complete vur resolution. in patients with bilateral reflux, if resolution occurred in one side, the operation was considered to be failed. data were entered into the spss software (ibm corporation, new york, united states), version 22. fisher’s exact test, mann-whitney u test, t-test and one-way anova were used for analyzing the data. bulking agents for treating primary vesicoureteral reflux-alizadeh et al. pediatric urology 176 results one hundred and seven rru and 64 rru were treated in dx/ha and ppc groups, respectively. the demographic data and patients’ characteristic are presented in table 1. the success was achieved in 92.2% (59) rru in ppc group and 75.7% (81) rru in dx/ha group (p < .001). by mann-whitney test, in reflux grade in ppc group the success rate was decreased significantly with increasing reflux grade (p = .04) but this reduction was not statistically significant in dx/ha group (p = .30). in post-operative period, early-onset obstruction was observed in 3 (4.7%) and 4 (3.7%) rru in ppc and dx/ha groups, respectively while late-onset ureteral obstruction occurred in 2 (3.1%) and 2 (1.9%) of rru in ppc and dx/ha groups, respectively. the obstruction rate did not establish significant difference between the two groups (p = .83). however, in patients with late-onset obstruction, the mean time from injection to obstruction was longer in dx/ha group (22 moths vs. 4 months). the spearman analysis showed statistically significant correlation between injected volume of the bulking agent and obstruction rate in ppc group (r=0.24, p = .04); however, the dx/ha group failed to confirm this relationship (p = .52). during the follow-up, 4 patients (10.2%) in the ppc group and 7 patients (18.4%) in the dx/ha group who had been cured of their vur, developed febrile uti that underwent repeat rnc. one patient (25%) in the former group showed recurrence of vur while this figure was 4 (57%) in the latter group. discussion in our study the ppc group showed a more successful outcome (92.2% of the rru and 90.6% of the patients) in comparison to the dx/ha group (75.7% of the rru and 58.4% of the patients). these results were in accordance with previous investigations. karakus et al.(22) compared these two agents which revealed ppc promises higher resolution rate than dx/ha (88.6% vs 70.3%), although the former group had markedly higher ureterovesical junction obstruction. in another comparative study, reflux resolved after the first deflux injection in 63% of rru and vantris injection in 92.7% of rru(24). however, in turk et al. study(23) the overall treatment success rate was 79% in dx/ha group and 81% in ppc group which was not significantly different. the overall success rate reported with use of dx/ha ranged between 68–92% based on the vur grade (8,16,24,26). one study that examined dx/ha, demonstrated a success rate of 78.5% for grades i and ii, 72% for grade iii, 63% for grade iv and 51% for grade v reflux which revealed this hypothesis that increasing the grade of reflux decrease the success rate of treatment with this material(27). although our result did not demonstrate any significant decrease in success rate in grade iv and v vur in the dx/ha group. ppc comes from the family of acrylics, particles of polyacrylate polyalcohol copolymer immersed in a glycerol and physiological solution carrier. when injected in soft tissues, it causes a bulkiness that remains stable(28). a multicentric study comprising 88 renal units treated with ppc showed the overall success rate about 83.6%(20). in sencan study(29), the accumulative success rate after the injection of ppc at the end of the first year was 98.1%. chertin et al. reported the success rate of ppc after a single injection as 94.9% (15). they bulking agents for treating primary vesicoureteral reflux-alizadeh et al. table 1. demographic data and patients’ characteristic in both groups. characteristics ppc group dx/ha group p value mean age (months) 52.13 ± 31.66 55.23 ± 36.58 0.57 sex male 10(15.6%) 22(20.6%) 0.54 female 54(84.4%) 85(79.4%) laterality of vur left 35(54.7%) 53(49.5%) 0.53 right 29(45.3%) 54(50.5%) hx of uti 60(93.8%) 81(75.7%) 0.003 pre-operative renal cortical scar 47(74.6%) 45(48.9%) 0.001 variables ppc group dx/ha group p value injection technique 0.36 hit 16 (25%) 40 (37.4%) double hit 6 (9.4%) 11 (10.3%) sting 20 (31.2%) 25 (23.4%) hit+sting 22 (34.4%) 31 (29%) injected volume(ml) 0.78 ± 0.39 0.58 ± 0.30 0.001 vur grade (rru) i 2 (3.1%) 6 (5.6%) 0.93 ii 11 (17.2%) 13 (12.1%) iii 21 (32.8%) 42 (39.3%) iv 20 (31.2%) 27 (25.2%) v 10 (15.6%) 19 (17.8%) follow up (months) 17.17 ± 12.81 18.81 ± 11.92 0.4 table 2. procedural detail in both groups. vol 16 no 02 march-april 2019 177 also demonstrate cure of reflux with a single injection in 92.1% of all patients in one year follow up. in warchol study, reflux resolved in 93% of all treated rrus after first procedure, and in 100% after the second procedure. for high grade vur, that is iv and v, success was achieved in almost 90% after the first injection and 100% after the second injection(24). chertin et al. evaluated prospectively the long term efficacy of ppc in children with vur which showed no vur recurrence in 3 years of follow-up, while recurrence rate with dx/ ha ranges from 10% to 26% in long term follow up (21,30). radiographic investigation in the sedberry-ross et al. and swedish reflux study also demonstrated high radiographic recurrence (27%-38%) that was attributed to biodegradable nature of dx/ha(31,32). the use of ppc to correct grades iv and v is also very efficient with an overall success rate achieved of over 80% (33,34). but in our study the success rate decreased in ppc (but not the dx/ha) group significantly with increasing reflux grade. technique of injection is suggested as another variable for success rate of materials in recent literature. single subureteral transurethral injection (sting) technique was used first time in 1984 for the endoscopic treatment of pediatric vur(35). the suggested injection site is 2 to 3 mm below the affected ureteric orifice, at the 6 o’clock position. hydrodistention implantation technique (hit), which entails inserting the needle into the submucosal tunnel of the ureter via hydrodistention has been introduced in 2004 (16). kirsh et al. by using hydrodistention implantation technique injection (hit), showed the short-term results with the endoscopic correction close to those results after open surgery. a success rate of 92% using the hit procedure compared with the 79% using the sting procedure was reported(16). yucel et al.(36) and watters et al.(37) found no differences on vur resolution rate between the two techniques. double hydrodistention implantation technique was also described by these researchers (38). double hit, included two intraluminal ureteric tunnel injections which involves both proximal and distal intraureteral injections. kalisvaart et al. revealed 96% clinical success with double hit after 1 year of follow-up(38). akin et al.(39) observed a higher success rate with double hit treatment compared to hit. however, our data did not show significant difference between hit and double hit technique in either study groups. another important factor, predicting the success rate of the procedure, is learning curve. in our study groups this variable was omitted because the same surgeon did the procedure in both groups after passing the learning curve during the fellowship training program. in fact, although dx/ha injection was done after ppc injection, this group had lower success rate. therefore, the effect of surgeon’s experience as the cause of difference in success rate is precluded. complications following endoscopic injection are rare and including mainly obstruction of the vesicoureteric junction and development of a new contralateral vur. in our dx/ha group and ppc group 5.6% and 7.8% of patients developed obstruction respectively, with no statistically significant difference between them. although several variables involve in the likelihood of obstruction, the amount of injection material was not related to obstruction frequency in our data. there is not unanimous result in this field and controversial observations have been presented up to now(40). one difference was the mean time to obstruction that was longer in the dx/ha group (22 vs. 4 months). this finding suggest that long-term follow-up should be rigorous, especially in patients who receive dx/ha. this study has some limitations such as small sample size of groups, lack of follow-up rnc after reflux resolution in all patients, non-randomized nature of the study and different inclusion criteria which contained more uti history and scar formation in ppc group. these problems demand more studies with detailed date and longer follow up. conclusions our investigation approved ppc as a more effective material, regardless of other confounding variables such as reflux grade, learning cure, and technique of injection, in endoscopic treatment of vur. in addition, the other remarkable point is this effectiveness is not accompanied by more post-operation obstruction. conflict of interest none declared. references 1. savage dc, wilson mi, mchardy m, dewar da, fee wm. covert bacteriuria of childhood. a clinical and epidemiological study. arch dis child. 1973;48:8-20. 2. jacobson sh, hansson s, jakobsson b. vesico-ureteric reflux: occurrence and longterm risks. acta paediatr suppl. 1999;88:2230. 3. shaikh n, ewing al, bhatnagar s, hoberman a. risk of 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[preliminary results of endoscopic treatment of vesicoureteric reflux in children. prospective comparative study of deflux vs. coaptite]. prog urol. 2005;15:1114-9. 15. chertin b, arafeh wa, zeldin a, kocherov s. preliminary data on endoscopic treatment of vesicoureteric reflux with polyacrylate polyalcohol copolymer (vantris(r)): surgical outcome following single injection. j pediatr urol. 2011;7:654-7. 16. kirsch aj, perez-brayfield m, smith ea, scherz hc. the modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. j urol. 2004;171:2413-6. 17. lee ek, gatti jm, demarco rt, murphy jp. long-term followup of dextranomer/ hyaluronic acid injection for vesicoureteral reflux: late failure warrants continued followup. j urol. 2009;181:1869-74; discussion 74-5. 18. lackgren g, wahlin n, skoldenberg e, stenberg a. long-term followup of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. j urol. 2001;166:1887-92. 19. chertin b, kocherov s. long-term results of endoscopic treatment of vesicoureteric reflux with different tissue-augmenting substances. j pediatr urol. 2010;6:251-6. 20. ormaechea m, ruiz e, denes e, et al. new tissue bulking agent (polyacrylate polyalcohol) for treating vesicoureteral reflux: preliminary results in children. j urol. 2010;183:714-7. 21. chertin b, arafeh wa, zeldin a, ostrovsky ia, kocherov s. endoscopic correction of vur using vantris as a new non-biodegradable tissue augmenting substance: three years of prospective follow-up. urology. 2013;82:2014. 22. karakus sc, user ir, kilic bd, akcaer v, ceylan h, ozokutan bh. the comparison of dextranomer/hyaluronic acid and polyacrylatepolyalcohol copolymers in endoscopic treatment of vesicoureteral reflux. j pediatr surg. 2016;51:1496-500. 23. turk a, selimoglu a, demir k, celik o, saglam e, tarhan f. endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer and dextranomer/ hyaluronic acid in adults. int braz j urol. 2014;40:379-83. 24. warchol s, krzemien g, szmigielska a, bombinski p, brzewski m, dudek-warchol t. comparison of results of endoscopic correction of vesicoureteral reflux in children using two bulking substances: dextranomer/hyaluronic acid copolymer (deflux) versus polyacrylatepolyalcohol copolymer (vantris). j pediatr urol. 2016;12:256 e1-4. 25. pogorelic z, gudelj k, budimir d, et al. comparison of dextranomer/hyaluronic acid based bulking agents in the treatment of vesicoureteral reflux in children: deflux versus vurdex. can j urol. 2016;23:8312-7. 26. chertin b, colhoun e, velayudham m, puri p. endoscopic treatment of vesicoureteral reflux: 11 to 17 years of followup. j urol. 2002;167:1443-5; discussion 5-6. 27. elder js, shah mb, batiste lr, eaddy m. part 3: endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infections in patients with vesicoureteral reflux. curr med res opin. 2007;23 suppl 4:s15-20. 28. ormaechea m, paladini m, pisano r, et al. vantris, a biocompatible, synthetic, non-biodegradable, easy-to-inject bulking substance. evaluation of local tissular reaction, localized migration and long-distance migration. arch esp urol. 2008;61:263-8. 29. sencan a, ucan b, evciler h, serdaroglu e, hosgor m. early results of endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer. urol int. 2014;92:219-22. 30. chertin b, abu arafeh w, kocherov s. endoscopic correction of complex cases of vesicoureteral reflux utilizing vantris as a new non-biodegradable tissue-augmenting substance. pediatr surg int. 2014;30:445-8. 31. sedberry-ross s, rice dc, pohl hg, belman ab, majd m, rushton hg. febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/ hyaluronic acid. j urol. 2008;180:1605-9; discussion 10. 32. holmdahl g, brandstrom p, lackgren g, et al. the swedish reflux trial in children: ii. vesicoureteral reflux outcome. j urol. 2010;184:280-5. 33. de badiola fi, soria r, vagni rl, ormaechea mn, moldes jm, benmaor c. results of treatment of grades iv and v vesicoureteral reflux with endoscopic injection of polyacrylate polyalcohol copolymer. front bulking agents for treating primary vesicoureteral reflux-alizadeh et al. vol 16 no 02 march-april 2019 179 bulking agents for treating primary vesicoureteral reflux-alizadeh et al. pediatr. 2013;1:32. 34. kocherov s, ulman i, nikolaev s, et al. multicenter survey of endoscopic treatment of vesicoureteral reflux using polyacrylatepolyalcohol bulking copolymer (vantris). urology. 2014;84:689-93. 35. puri p, ninan gk, surana r. subureteric teflon injection (sting). results of a european survey. eur urol. 1995;27:71-5. 36. yucel s, gupta a, snodgrass w. multivariate analysis of factors predicting success with dextranomer/hyaluronic acid injection for vesicoureteral reflux. j urol. 2007;177:15059. 37. watters st, sung j, skoog sj. endoscopic treatment for vesicoureteral reflux: how important is technique? j pediatr urol. 2013;9:1192-7. 38. kalisvaart jf, scherz hc, cuda s, kaye jd, kirsch aj. intermediate to long-term follow-up indicates low risk of recurrence after double hit endoscopic treatment for primary vesico-ureteral reflux. j pediatr urol. 2012;8:359-65. 39. akin m, erginel b, karadag ca, et al. a comparison of the double hydrodistention implantation technique (hit) and the hit with a polyacrylate/polyalcohol copolymer (ppc) for the endoscopic treatment of primary vesicoureteral reflux. int urol nephrol. 2014;46:2057-61. 40. alizadeh f, mazdak h, khorrami mh, khalighinejad p, shoureshi p. postoperative ureteral obstruction after endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer (vantris(r)). j pediatr urol. 2013;9:488-92. pediatric urology testicular ischemia caused by incarcerated inguinal hernia in infants: incidence, conservative treatment procedure, and follow-up mustafa yasar ozdamar,1* osman zeki karakus2 purpose: testicular ischemia and necrosis, especially in the infant age, may result from incarcerated inguinal hernia. duration of ischemia is a significant factor for the affected testicle. we aimed to present a case series on the conservative management in the testicular ischemia caused by incarcerated inguinal hernia. materials and methods: inguinal hernia repairs performed in between march 2009 and december 2014 were investigated retrospectively. patients’ characteristics, hernia side, incarceration, testicular ischemia and complications were recorded. color doppler ultrasonography was performed in the incarcerated inguinal hernia patients preoperatively and was repeated on 3 and 7 days and then at 1, 3 and 6 months postoperatively. the testicle sizes, volumes, and arterial flow patterns of them were recorded at the same time. results: total 785 inguinal hernias were treated in 738 male patients, ranging from 18 days to 16 years. from all male patients, 44 (5.9%) had the iih. there were 16 (36.3%) irreducible hernias in 44 incarcerated hernia patients. of these 16, testicular ischemia was determined in 9 (56.2%) infants with the irreducible incarcerated hernia. orchidopexy procedure was performed in these patients. testicular atrophy was occurred in two patients (22.2%). in the others, testicular volumes and perfusions were normal during follow-up (mean 8.3 ± 2.2 months). conclusion: testicular ischemia resulting from incarcerated inguinal hernia may be treated conservatively without orchiectomy for the ischemic testicle and testicular ischemia may be followed with color doppler ultrasound for at least 6 months. the inguinal hernia repair in infants should be subject to urgent surgery rather than elective surgery. so, the testicular ischemia in infants with the inguinal hernia will be an avoidable complication. keywords: incarcerated inguinal hernia; testicular ischemia; testicular necrosis; testicular atrophy; infant. introduction the incidence of incarcerated inguinal hernia (iih) ranges from 6% to 31% in children(1,2). iih may give rise to intestinal obstruction, ovarian or testicular ischemia. testicular ischemia being encountered intraoperatively intraoperative in the iih cases may require orchiectomy. while testicular atrophy incidence secondary to the ischemic injury is 0.3% after the non-incarcerated inguinal hernia repairs, it varies from 2.3% to 50% in the iih(2-5). an impairment of the testicular blood supply can be investigated by using noninvasive imaging techniques, preoperatively. gray-scale ultrasonography combined with color doppler ultrasound (cdu) imaging has been a clearly accepted technique for assessing testicular lesions and testicular blood perfusion. the insufficient testicular blood supply in cdu examination should alert the physician in terms of the testicular ischemia occurring secondary to iih(6). nevertheless, the most important question to be answered is whether orchiectomy procedure for an ischemic testis should be performed or not. in the current study, we aimed to present a conservative treatment method and follow-up results of the patients who developed testicular ischemia and necrosis due to iih, and also to discuss whether this condition is avoidable or not. patients and methods study population and design this retrospective study was approved by institutional ethics review board for clinical research (2014/158/604-197) and was conducted in two referral hospital of yozgat and tokat in turkey. we reviewed institutional-based data of 738 male patients who underwent inguinal hernia repair between march 2009 and december 2014, retrospectively. demographic characteristics of the patients, side of hernia, presence of incarceration and testicular ischemia, follow-up time and complications were recorded. the patients who developed testicular ischemia due to iih were investigated in terms of surgical approach, postoperative follow-up procedures and results. duration of incarceration was evaluated according to the history of the symptoms obtained from the parents or caregivers of the patients and calculated. iih patients scheduled for delayed surgery for reasons such as undescended testis, congenital heart disease, and bleeding diathesis were not included in the study. surgical technique conventional open inguinal hernia repair with high ligation of patent processus vaginalis at the level of the 1department of pediatric surgery, erzıncan university, medical school, erzıncan 24000, turkey. 2department of pediatric surgery, dokuz eylul university, medical school, izmir 35000, turkey. *correspondence: department of pediatric surgery, erzincan university, medical school, 24100, başbağlar, erzincan, turkey. tel: +0446 226 18 18. fax: +0446 226 18 18 (pbx). e-mail: mustafayasarozdamar@gmail.com. received august 2016 & accepted may 2017 vol 14 no 04 july-august 2017 4030 pediatric urology 4031 internal inguinal ring was performed in all patients under general anesthesia. preoperative prophylactic cefazolin sodium (50 mg/kg) intravenously as a single dose was used. when an ischemic testis whose hemorrhagic or necrotic looking was determined macroscopically (figure 1), it was covered with warm physiologic saline-soaked gauze for 10 minutes, and then fixed in the scrotal dartos pouch as performed in orchidopexy procedure. outcome assessment color doppler ultrasonography (cdu) examination evaluating arterial blood flow of the testes was performed preoperatively in all the patients diagnosed with iih in the emergency clinic. in the early period, patients with testicular ischemia were followed up by performing cdu postoperatively on 3rd and 7th days in order to evaluate whether there are testicular blood flow and intra-scrotal abscess formation or not. cdu examination was repeated at 1, 3 and 6 months after discharge. testes sizes of the patients were measured by ultrasonography without the inclusion of the epididymis. testicular volume was calculated by using the empirical formula of lambert: volume = length (l) × width (w) × height (h) × 0.71. although it has the limited efficacy for infants, it was used for at least predicting the testicle volume measurement(6,7). the interval between the groin swelling (incarceration onset) and the surgical repair time was accepted as the duration of incarceration. data analysis was performed using spss software (statistical package for the social sciences, 18.0; spss inc, chicago, il, usa). the data were expressed as mean ± 1sd. in statistical analysis, the wilcoxon signed-rank test was used to evaluate the volume of the affected testes. the mann-whitney u test was used to compare the volumes between ischemic and contralateral testes in the follow-up. the relationship between the ages of patients with iih and the duration of incarceration were assessed with the spearman's rank correlation. the statistical significance was set at p < .05. results a total 785 inguinal hernias were treated in 738 male patients whose mean ages were 2.3 ± 2.5 years (range, 18 days to 16 years). seven iih patients were excluded from the study because they meet the exclusion criteria. from all male patients, 44 (5.9%) had iih. out of 44 iih patients, the study group, manual hernia reduction was successfully performed in 28 (63.6%) patients in the pediatric emergency service. sixteen (36.6%) patients underwent emergency surgery due to inguinal hernia and testicular ischemia in infants-özdamar et al. duration of incarceration (hours) (mean±sd) testicular ischemia (n) ages (n) 0 – 12 months (11) 11.4 ± 2.3 9 1 – 5 years (3) 8.0 ± 1.4 0 6 – 10 years (2) 5.0 ± 1.4 0 table 1. characteristics of the male patients with incarcerated inguinal hernia at the time of hernia repair. patients no age (months) pre-op atv post-op atv (3th month) post-op atv (6th month) ctv 1 4 0.93 0.56 0.58 0.52 2 4 1.14 0.48 0.48 0.54 3 6 1.23 0.64 0.61 0.57 4 3 0.89 0.45 0.42 0.39 5 2 1.48 0.38 † 0.12 * 0.63 6 4 1,27 0.68 0.72 0.63 7 3 0.96 0.49 0.45 0.47 8 4 1.19 0.53 0.54 0.56 9 4 1.62 0.41 † 0.13 * 0.69 pre-op atv: affected testis volume preoperatively (milliliter) post-op atv: affected testis volume postoperatively (milliliter) ctv: postoperative contalateral testis volume(mililitter) when the affected testis volume compared with the contralateral testis volume; *: p < 0.001, at the end of 6 months follow-up †: p>0.05, at the end of 3 months follow-up table 2. testicle volumes of the patients with testicular ischemia at the time of the preoperative evaluation and during 6-month follow-up the irreducible iih. minimal hydrocele composed of serous and hemorrhagic fluid was observed in all the irreducible iih, but not in patients with reducible iih. when the hydrocele sac was opened intraoperatively, there was the purple looking testicle in these patients. despite application of warm fluid to the testicle, its ischemic-purple appearance did not change (figure 1). there were testicular ischemia and hemorrhagic necrosis in 9 (56.2%) of the irreducible iih patients whose mean ages were 3.7 ± 1.3 months (range, 2 to 6 months). additionally, the testicular ischemia rate was 20.4% for all 44 ihh patients. hernia site of these 9 patients were right in 7 and left in 2. the mean duration of incarceration was 11.4 ± 2.3 hours in the symptomatic interval. incarceration time was found less in older children (table 1). there was a significant negative correlation between the mean ages of the iih patients and mean duration of the incarceration (r = -0.90, p = .03). no patient underwent orchiectomy during hernia repair. ibuprofen (10 mg/kg/day) was used as an analgesic and anti-inflammatory drug in all iih patients for one week postoperatively. while the testicular arterial blood flow (tabf) of the nine irreducible iih patients in the cdu examination revealed decreasing pattern preoperatively compared to the contralateral testis, tabf of these affected testicles was normal on 3rd and 7th postoperative days. there was no abscess formation in these testicles in the early postoperative period. testicular atrophy took place only in two (22.2%) patients with the irreducible iih during the 6-month follow-up. on the other hand, the testicular atrophy incidence was 4.5% in all patients with iih. the testicular size of two patients with the irreducible iih approximately decreased up to 10% of their volumes within 6-months, postoperatively (table 2). on the other hand, the testicular atrophy incidence was 4.5% in all patients with iih. in the irreducible iih patients without atrophy, the postoperative testicle volumes were not decreased when compared with the preoperative volumes in the 6-month follow-up (p = .10) (table 2). in the hernia sac of the patients with irreducible iih, small bowel segments was observed in 7 cases, and small bowel together with omentum in 9 cases. no need for intestinal resection occurred. in the current series, we did not encounter any complications except two patients with the testicular atrophy during follow-up. the mean follow-up period of the patients with iih were 8.3 ± 2.2 months (range, 6 to 12 months). discussion incidence of inguinal hernia in children is between 0.8 4.4% in term and 30% in premature babies(3). the incarceration risk of an inguinal hernia varies between 6% and 31% (2,3,8). intestinal necrosis or testicular ischemia secondary to compression of vascular structures in the inguinal canal is an undesirable consequence of the iih(3,7). although intestinal damage resulted from iih may be seen as low as 0.1%, testicular ischemia may occur at higher rates ranging from 0.3% to 15% (2-4,8). the infants aged under 6-month are more vulnerable to testicular ischemia resulting from incarceration than older children(5,8). moreover, it has been reported that the tendency for testicular ischemia in the infants is mostly due to vascular structures where there is no rich collateral vessel network of the testicle (2,4,8,9). in contrast to the infants, adults have several collateral blood flows in both arterial supply and venous drainage protecting the testes from ischemic damages following impairment of blood flow through inguinal canal (10-12). in children with the iih, however, an increased pressure result from the hernia contents in relatively narrow and inflexible superficial inguinal ring may lead to congestive testicular infarction with venous obstruction, especially in infants. as the incarceration continues, venous thrombosis, hemorrhage, and arterial insufficiency inevitably result in the infarction(10,13). in the current study, the rate of testicular ischemia in the iih patients was 20.4%. this rate seems to be high, but the ischemia rate was 1.2% for all male boys with an inguinal hernia. diagnosis of the testicular ischemia in the patients with iih may be confirmed on the cdu examination, preoperatively(8). however, there is no data on the reversible time interval of the ischemia of the compressed testicle and the vasculature in the iih. complexities in the evaluation of testicular ischemia secondary to iih derive from a paucity of long-term follow-up. it has also been reported that lack of long-term imaging follow-up makes it impossible to know whether there is a longterm effect of an inguinal hernia on testicular volume (8). we have observed that the duration of incarceration was 2.3 times longer in infants compared with older children. we have also determined a significant negative correlation between the patients’ ages and the average duration of incarceration (r = -0.90, p = .03). the impact of late diagnosis on the treatment in infants is a handicapping factor in addition to challenges related to anatomical variations and restrictions. if a practitioner detects an ischemic and necrotic testicle at surgery in iih, he or she must sensibly decide to what surgical procedure (orchiectomy or orchidopexy ) is required. some authors have supported that visualization of the testicle is not routine during hernia repair(8,14,15). as defined in our study, however, the testicle can be evaluated by opening its tunica vaginalis during surgery, especially in the ihh cases. it has been reported that orchiectomy can be performed in the infants after a certain waiting period if the testicular bleeding via the incision of the tunica albuginea does not occur(16,17). in the current study, we preferred orchidopexy procedure figure 1. testicular ischemia caused by the incarcerated inguinal hernia in a 4-month-old infant. inguinal hernia and testicular ischemia in infants-özdamar et al. vol 14 no 04 july-august 2017 4032 in these iih patients. we have thought that the incision of the tunica albuginea in the ischemic testicles may not contribute to the follow-up results. it is impossible to know macroscopically whether the degree of testicular ischemia is low or high or is there a segmental infarction or not. tabf may be followed with cdu in the early postoperative period in terms of flow pattern and abscess formation. testicular abscess did not occur in any cases in the postoperative period of the current study. the incidence of testicular atrophy after inguinal hernia repair varies from 0.3% to 50% in the several series(2-5). although the testicular size may be of normal volume up to 6 weeks in the postoperative period, the ischemic orchitis leading to the testicular atrophy might occur up to 12 months(5). in our study, testicular atrophy occurred in two patients (56.2%) with irreducible iih at the end of the postoperative period of 6 months. we determined that the testicular size of two patients with the irreducible iih began to decrease in the postoperative on month 3 and approximately decreased up to 10% of their volumes within 6 months after operation. this decrease in the volume was statistically significant (p < .001). an increased pressure originated from hernia content in the iih, especially in infants, results in gradual vascular failure leading to congestive testicular infarction. incision of the tunica albuginea to figure out the testicular vitality may not be necessary. however, a standard orchidopexy procedure should be performed in the male infants with the iih with testicular ischemia. the patients should be closely followed up by cdu examination at least 6 months. the most common elective surgical procedure in children is inguinal hernia repair (18). because of risk described above, we cannot ignore the necessity that the inguinal hernia repair in infants especially under six months should be urgent surgery rather than semi-urgent or elective, thus probably preventing testicular ischemia occurred secondary to iih. conflict of interest authors declared that they have no conflict of interest. references 1. goldman rd, balasubramanian s, wales p, mace se. pediatric surgeons and pediatric emergency physicians’ attitudes towards analgesia and sedation for incarcerated inguinal hernia reduction. j pain 2005; 6:6505. 2. puri p, guiney ej, o’donnell b. inguinal hernia in infants: the fate of the testis following incarceration. j pediatr surg 1984; 19:44-6. 3. ein sh, njere i, ein a. six thousand three hundred sixty-one pediatric inguinal hernias: a 35-year review. j pediatr surg 2006; 41:980-6. 4. niedzielski j, krol r, gawlowska a. could incarceration of inguinal hernia in children be prevented? med sci monit 2003; 9:16-8. 5. walc l, bass j, rubin s, ottawa mw. testicular fate after incarcerated hernia repair and/or orchidopexy performed in patients under 6 months of age. j pediatr surg 1995; 30:1195-7. 6. aso c, enriquez g, fite m, toran n, piro c, piqueras j, et al. gray-scale and color doppler sonography of scrotal disorders in children: an update. radiographics 2005; 25:1197–214. 7. sakamoto h, saito k, oohta m, inoue k, ogawa y, yoshida h. testicular volume measurement: comparison of ultrasonography, orchidometry, and water displacement. urology 2007; 69:152-7. 8. orth rc, towbin aj. acute testicular ischemia caused by incarcerated inguinal hernia. pediatr radiol 2012; 42:196-200. 9. beddy p, ridgway pf, geoghegan t, pierce c, govender p, keane fb, et al. inguinal hernia repair protects testicular function: a prospective study of open and laparoscopic herniorrhaphy. j am coll surg 2006; 203:17– 23. 10. hill mr jr, pollock wf, sprong dh, jr. testicular infarction and incarcerated inguinal herniae. arch surg 1962; 85:351–4. 11. murdoch rw. testicular strangulation from incarcerated inguinal hernia in infants. jr coll surg edinb 1979; 24:97–101. 12. turgut at, olcucuoglu e, turan c, kiliçoğlu b, koşar p, geyik po, et al. preoperative ultrasonographic evaluation of testicular volume and blood flow in patients with inguinal hernias. j ultrasound med 2006; 26:1657-66. 13. ameh ea. incarcerated and strangulated inguinal hernias in children in zaria, nigeria. east afr med j 1999; 76:499–501. 14. le coultre c, cuendet a, richon j. frequency of testicular atrophy following incarcerated hernia. z kinderchir 1983; 38:39–41. 15. gamble wg, keller ga. testicular infarction associated with incarcerated inguinal hernia. minn med 1987; 70:529–32. 16. alyami f, whelan t. incarcerated inguinal hernia in infancy associated with testicular infarction: case report and review of the literature. can urol assoc j 2013; 7:367-9. 17. waseem m, pinkert h, devas g. testicular infarction becoming apparent after hernia reduction. the journal of emergency medicine 2013; 38:460–2. 18. kapur p, caty mg, glick pl. pediatric hernias and hydroceles. pediatr clin north am 2008; 45:773-85. inguinal hernia and testicular ischemia in infants-özdamar et al. pediatric urology 4033 huge renal hydatid cystan unusual presentation: a case report introduction hydatid cyst disease, also known as echinococcosis, is a zoonotic infection caused by the genus echinococcus.(1) it is a public health problem around the world. humans are an accidental intermediate host.(2) the most commonly affected organ is liver (75%), followed by lung (15%) and other organs (10%) such as kidney.(3) although hydatid cyst disease can be present in all parts of the body, isolated renal involvement is a rare condition, comprising only 2-4% of all cases.(4) renal hydatid cysts usually remain symptomless for years.(5) we hereby report a rare case of huge renal hydatid cyst disease. to our knowledge, this case is the largest renal hydatid cyst reported to date. 1 department of surgery, shahid sadoughi university of medical sciences, yazd, iran. 2 department of urology, shahid sadoughi university of medical sciences, yazd, iran. 3 resident of surgery, shahid sadoughi hospital, shahid sadoughi university of medical sciences, yazd, iran. 4 student research committee, shahid sadoughi university of medical sciences, yazd, iran. 5 school of paramedicine, shahid sadoughi university of medical sciences, yazd, iran. 6 general surgeon, yazd, iran. *correspondence: department of urology, shahid rahnemoon hospital, shahid sadoughi university of medical sciences, yazd, iran. tel: +98 3538224000. fax: +98 3538224100. e-mail: drzaree@yahoo.com. received october 2016 & accepted january 2017 jamal jafari nodoushan 1, samad zare 2*, seyed mostafa tabatabaei 3, mojtaba babaei zarch 4, fatemeh imani 5, fatemeh ehsani 6 isolated renal hydatid cyst is a rare entity accounting for only 2-4% of cases. a 60-year-old male presented to our clinic complaining of pain in right flank. he had a history of eating raw sheep liver. imaging revealed an expansive cystic mass measuring approximately 300×180 mm in the right side of abdomen. the patient was treated by open surgery in combination with perioperative chemotherapy with albendazol. in this case, we reported an unusual presentation of hydatid cyst disease. physicians should be aware of its clinical presentations and complications. case report keywords: abdomen; case reports; hydatid cyst; kidney; mass; nephrectomy. figure 1. ct scan shows an expansive cystic mass measuring approximately 300*180 mm with thick septations in the right side of abdomen with peripheral enhancement. there was not invasion to the adjacent organs. case report 3040 case report a 60-year-old male, living in an urban area in south of iran, presented to our clinic complaining of dull pain and palpable mass in his right flank for the last one year. the pain was worse than a month ago. the patient noted nocturia, incontinency and 4 kg weight loss over the past two months. he had no history of urinary tract infection, hematuria, fever, nausea and vomiting. his medical and drug history was unremarkable, however he had a history of eating raw sheep liver. physical examination revealed guarding, tenderness and a mobile mass in the right upper quadrant of abdomen. his vital signs were normal. laboratory tests revealed a mild leukocytosis (12400/µl) but, there was no eosinophilia. in addition, serum level of creatinine was normal and urine analysis had sterile pyuria. liver function tests, were within normal limits. immunological examination revealed elevated hydatid antibody titers (antibody level = 2.5—negative up to 1). chest x ray showed increased heart size and homogeneous opacity in the lower zone of right lung. ultrasonography of the abdomen revealed increased size of right and left liver lobes with cysts in various sizes. in addition, right kidney was not assessable. it was suggestive of liver hydatid cyst and abdominal ct scan was indicated. ct scan of abdomen and pelvis revealed an expansive cystic mass measuring approximately 300×180 mm with thick septations in the right side of abdomen with peripheral enhancement. there was not invasion to the adjacent organs (figure 1). although liver cyst was reported in primary abdominal ultrasonography, but in chest and abdominal ct scan as well as after surgical exploration, only an isolated hydatid cyst of right kidney was established. no cystic or solid lesions were found in spleen, and left kidney. oral treatment with albendazole was started. finally, he was candidate for surgery. after preperation and drape, under general anesthesia in supine position, the abdomen was opened by right kocher's incision. there was a cystic mass measuring 30×18 cm in size which spread from diaphragm to pelvis and pushed abdominal organs to left side of body. initially, the hypertonic saline (20% sodium chloride solution) was injected into the cyst and surrounding tissues were protected using gauze soaked in hypertonic saline. there was adhesion between the cyst and liver, aorta, ivc, ascending colon and diaphragm. adhesions were removed gently. the right kidney parenchyma was completely destroyed, which ultimately nephrectomy and cyst removal was performed. drain was placed. the abdominal wall was repaired. we continued albendazole for 4 months. after 6-month follow-up period, the patient was asymptomatic and doing well. recurrence did not occurr. discussion hydatid cyst disease, also known as hydatosis or echinococcosis, is a zoonotic and parasitic disease caused by the larval stage of echinococcus granulosus.(6,7) this infection may involve liver, lung and other organs.(7) renal involvement is a rare condition.(8) the endemic areas include parts of the middle east, australia, south america, new zealand, and alaska.(9) our case was a presentation of isolated renal hydatid cysta rare condition. isolated renal hydatid cyst disease may reside symptomless for a long time. clinical presentations include fever, malaise, flank pain, palpable mass, hematuria and hydatiduria.(10) although hydaturia (passing grape skin like structures in urine) is a pathognomonic sign, it has been seen only in 5%-25% of renal hydatid cyst disease. (10,11) in our case, the patient had dull pain and palpable mass in right flank with loss of weight and urinary symptoms such as nocturia and incontinency. however, there was no evidence of hydaturia. ultrasonography, magnetic resonance image (mri) and computed tomography (ct) scan are important means of diagnosis. contrast enhanced ct has an accuracy of 98% to reveal the daughter cysts. ct scan usually demonstrates a tumor with a well-defined wall as well as daughter cysts within the mother cyst.(12) imaging studies are helpful but usually inadequate for separation of a hydatid cyst from a renal tumor or complicated cyst.(13) there is no specific laboratory test for renal hydatid cyst disease. however, eosinophilia is present in 20% to 50% of cases(9) and may occur in othhuge renal hydatid cyst: case report-jafari nodoushan et al. figure 2. surgical specimen revealed multiple daughter cysts. vol 14 no 02 march-april 2017 3041 huge renal hydatid cyst: case report-jafari nodoushan et al. er parasitic diseases.(6) in general, surgery is the treatment of choice for renal hydatid cyst(14) and it should be based on the size of cyst, location, number, renal function and surgical methods.(15) kidney sparing is possible in 75% of cases. however, nephrectomy is performed only if the kidney is damaged by the cyst or non-functioning kidneys.(9,16) both open and laparoscopic methods have been described in the literature. the cyst may rupture during laparoscopy. extreme care should be taken to prevent leakage during the surgery. pre and postoperative administration of albendazole is recommended to sterilize the cyst, decrease the chance of anaphylaxis occurrence.(14) to the best of our knowledge, this case is the largest renal hydatid cyst disease reported to date. previously, open surgery, laparoscopy technique and combination of these methods have been used for treatment of renal hydatid cyst disease. in our case, the size of lesion was large, thus the surgeon decided to perform open surgery. in the present case, the huge cyst had destroyed the renal parenchyma, and because of its size, open nephrectomy was indicated and performed (figure 2). no complications occurred. the patient was discharged with good condition. on macroscopic examination, received specimen in formalin consisted of an opened cyst. the cyst wall was gray-brown & firm, measuring 0.2-0.5 cm in thickness. there were also multiple separated cysts, measuring 1-3 cm in dimensions. the cysts walls were white with gelatinous consistency, measuring 0.1 cm in thickness and they contained clear watery fluid. conclusions in this case, we reported an unusual presentation of hydatid cyst disease. our patient was a case of isolated huge renal hydatid cysta rare condition. this case report emphasizes that the diagnosis of renal hydatid cyst disease needs high degree of suspicion and physicians must be aware of its clinical presentations and complications. acknowledgement the authors also thank shahid rahnemoun hospital staffs. conflict on interest the authors report no conflict on interest. references 1. da silva a. cystic echinococcosis in the liver: nomenclature and surgical procedures. j surg surgical res 1 (3): 059-065. doi: 10.17352/2454. 2015;2968:60-70. 2. nadeem m, biyabani sr, pervez s. renal failure: unusual clinical presentation of an isolated intrarenal hydatid cyst. bmj case reports. 2013;2013:bcr2013200616. 3. angulo jc, sanchez-chapado m, diego a, escribano j, tamayo jc, martin l. renal echinococcosis: clinical study of 34 cases. the journal of urology. 1997;157:787-94. 4. prabhudessai sc, patankar rv, bradoo a. laparoscopic treatment of renal hydatid cyst. journal of minimal access surgery. 2009;5:20. 5. madani ah, enshaei a, pourreza f, esmaeili s, madani mh. macroscopic hydatiduria: an uncommon pathognomonic presentation of renal hydatid disease. iranian journal of public health. 2015;44:1283. 6. mokhtar aa, sayyah aa, al-hindi h, seyam rm, khudair wa. isolated renal hydatid disease in a non-endemic country: a single centre experience. can urol assoc j. 2012;6:e224-9. 7. paramythiotis d, bangeas p, kofina k, papadopoulos v, michalopoulos a. presence of an isolated hydatid cyst in the left kidney: report of a case of this rare condition managed surgically. case rep urol. 2016;2016:6902082. 8. soares at, couto c, cabral mj, carmona l, vieira i. renal hydatid cyst: medical treatment. j bras nefrol. 2016;38:123-6. 9. razzaghi mr, mazloomfard mm, bahramimotlagh h, javanmard b. isolated renal hydatid cyst: diagnosis and management. urol j. 2012;9:718-20. 10. hota d, pujari s, choudhuri s, panda s. isolated renal hydatidosis presenting as renal mass: a diagnostic dilemma. urol case rep. 2015;3:103-5. 11. bhat gs, burude va, hegde sd, tembadamani vs. isolated renal hydatid cyst masquerading as cystic renal cell carcinoma: a case report. j clin diagn res. 2015;9:pd07-8. 12. priyadarshi v, mishra s, bera mk, pal dk. isolated hydatid cyst in a single moiety of an incomplete duplex kidney. apsp j case rep. 2015;6:2. 13. ucar m, karagozlu akgul a, celik f, kilic n. excisional treatment of renal hydatid cyst mimicking renal tumor with diode laser technique: a case report. j pediatr urol. 2016;12:264 e1-5. 14. garg r, nahar u, mandal ak. a rare case of primary renal hydatid cyst. ann parasitol. 2015;61:129-31. 15. rexiati m, mutalifu a, azhati b, et al. diagnosis and surgical treatment of renal hydatid disease: a retrospective analysis of 30 cases. plos one. 2014;9:e96602. 16. zmerli s, ayed m, horchani a, chami i, el ouakdi m, ben slama mr. hydatid cyst of the kidney: diagnosis and treatment. world j surg. 2001;25:68-74. case report 3042 urinary beta-2microglobulin: an indicator of renal tubular damage after extracorporeal shock wave lithotripsy hamidreza nasseh,* sepideh abdi, ali roshani, ehsan kazemnezhad purpose: this study aims to determine extracorporeal shock wave lithotripsy (eswl)-induced renal tubular damage and the affecting factors by measuring urinary beta2microglobulin (β2m) excretion. materials and methods: this is a cross-sectional study conducted on 91 patients with renal stones who underwent eswl during 2012. urinary beta2microglobulin was measured immediately before and after the procedure for each patient and analyzed based on different variables to evaluate factors affecting eswl-induced renal tubular injury. results: mean ± sd urinary beta2-microglobulin values, before and after eswl were 0.08 ± 0.07 and 0.22 ± 0.71 mg/dl respectively, the average difference between which was equal to 0.14 ± 0.07 mg/dl. these figures exhibited a 166.66% rise in the urinary β2m concentration after eswl which was statistically significant (p < .001). multivariate analysis showed that hypertension (p = .05) and the history of eswl (p = .02) were predictive factors of higher post-eswl urinary beta2-microglobulin excretion. conclusion: urinary excretion of beta2-microglobulin increased significantly immediately after eswl. these changes could indicate that eswl is a contributing factor to renal tubular damage. it also seems that in patients with hypertension and a previous history of eswl the likelihood of this injury is higher than others. keywords: acute kidney injury; beta2-microglobulin; extracorporeal shock wave lithotripsy; urinary stone introduction extracorporeal shock wave lithotripsy (eswl) is one of the most effective methods available for the treatment of urinary stones. it is a non-invasive procedure that does not require general anesthesia and can be used for outpatients. the mechanism of eswl is to use the shock wave energy to break the stones into small particles that can easily pass into the urinary tract(1). the effectiveness of this mechanism depends on various factors and all the treatments are not successful(2). on the other hand, studies have shown that treatment with eswl could have adverse effects and be followed by tissue damage in the kidneys.(3) urinary beta2-microglubulin is a sensitive marker of renal tubular injury,(4-6) the increased excretion of which after eswl represents the proximal tubule cell damage and dysfunction following the treatment.(7,8) it is a low molecular weight protein easily filtrated by the glomerulus and reabsorbed by about 99.9% in the proximal tubules of the kidney. beta2-microglobulin reuptake process is so effective that its urinary excretion is less than 400 ng per day.(9) for this reason, any disturbance in reabsorption of this protein in kidneys leads to higher excretion of urinary beta2-microglobulin and can represent subtle changes in renal tubular function. on the other hand, glomerular filtration rate (gfr) is the most important factor affecting serum beta2-microglobulin level. therefore, serum beta2-microglobulin level urology research center, school of medicine, guilan university of medical sciences, rasht, guilan, iran. *correspondence: urology research center, school of medicine, guilan university of medical sciences, sardar jangal st., razi hospital, 41448-95655, rasht, guilan, iran. tel & fax: +98 13 3352 5259. e-mail: nasseh_hamid@yahoo.com. received july 2016 & accepted october 2016 can be useful in detecting slight decline in gfr levels(6). urinary beta2-microglobulin will not increases in glomerular diseases. due to lack of studies about post-eswl urinary beta2-microglobulin changes and the affecting factors, we designed the current study in our country to determine extracorporeal shock wave lithotripsy induced renal tubular damage and the affecting factors by measuring the urinary beta2-microglobulin. materials and methods this is a cross-sectional study performed on 91 patients with urinary stones who underwent extracorporeal shock-wave lithotripsy at our center on an outpatient basis during 2012. all patients underwent lithotripsy procedure once with the power level of 3 and frequency of 2500 shock waves. patients having any of the following conditions were excluded from the study: age under 14, using of nephrotoxic drugs, autoimmune diseases, polycystic kidney disease and congenital renal malformations. besides, none of our patients had obstruction below the stone level in the urinary tract, complete obstruction at the stone level or uremia status. the study design was approved by ethics committee of the guilan university of medical sciences. after obtaining informed consent for participation in the study, the following variables were recorded for each patient: age, gender, co-administration of drugs, body mass index (bmi), gfr, serum creatinine level, miscellaneous vol 13 no 06 november-december 2016 2911 the history of hypertension, diabetes mellitus, previous eswl or kidney surgery and the number, size and location of the stones. the gfr level was measured based on cockroft gault formula as follows: clcr = (140 – age) x wt / 72 x pcr (x 0.85 for female patients)(10) urinary beta2-microglobulin level was measured in two discharged urine samples (the first and second samples were collected just before and right after the procedure respectively). to check urinary beta2-microglobulin level, an immunoassay kit,which measures the amount of this protein in urine by an elisa based methodwas used (mininephtm human beta2-microglobulin kit; the binding site ltd, birmingham, uk). the collected data was analyzed using spss software (the statistical package for the social sciences, version 17.0, spss inc., il). urinary beta2-microglobulin concentrations after eswl were compared to baseline values. to assess the changes in urinary beta2-microglobulin values before and after eswl, first, one-sample kolmogorov-smirnov test was utilized to determine the variables distribution. the results indicated that urinary concentrations of beta2-microglobulin did not follow a normal distribution. therefore, to assess its changes in urine after eswl according to different variables, nonparametric mann-whitney u test, wilcoxon signed ranks test and the kruskal-wallis test with spearman's correlation coefficients were used. to obtain odds ratios for significant variables, a logistic regression was used. all parameters with p-values less than 0.05 were considered statistically significant. results a total of 91 patients with the mean ± sd age of 48.93±14.03 years were studied. 53 patients (58.2%) were male and 38 (41.8%) were female. some data regarding patients' demographic variables have been summarized in table 1. the number of stones was 1 in 56 patients (66.7%) and more than one in the others, with the highest number of 16. stone location was the ureter in 8 patients (8.8%), the upper calyx in 18 (19.8%), the middle calyx in 21 (23.1%), the lower calyx in 28 (30.8%) and the pelvis in 10 (11%). seven patients (7.7%) had a history of previous kidney surgery and 50 (54.9%) patients mentioned a history of previous eswl. ten patients (11%) were hypertensive, eleven (12.1%) had diabetes mellitus and 5 (5.5%) had ureteral stent. mean urinary beta2-microglobulin values before and after eswl were 0.08 ± 0.07 and 0.22 ± 0.71 mg/dl respectively. the average changes in urinary β2m level were 0.14 ±0. 07, showing a 166.66% rise in its concentration after eswl (more than 1.5 times) which was significant in the wilcoxon signed ranks test (p < .001). in univariate analysis, history of hypertension, history of eswl, lower gfr level and having a ureteral stent caused a significant difference in the post-eswl urinary beta2-microglobulin level. the average difference in urinary beta2-microglobulin concentrations before and after eswl was higher in patients with hypertension (p = .003) and in patients with the history of previous eswl (p = .01) than those without. patients with lower gfr levels, manifested a greater increase in post-eswl urinary beta2-microglobulin value (p = .007) while having ureteral stent, was associated with lower post-eswl urinary beta2-microglobulin excretion (p = .03). table 2 shows some of the results of beta2-microglobulin after eswl-nasseh et al. variable age, year; mean ± sd 48.93±14.03 male/female 53/38 serum creatinine, mg/dl; mean ± sd 0.90±0.12 gfr, ml/minute/1.73m2; mean ± sd 99.53±23.07 history of previous eswl, n(%) 50(54.9) history of previous kidney surgery, n(%) 7(7.7) stone size, mm; mean ± sd 10.33±4.40 table 1. patients’ characteristics and demographic data table 2. urinary beta2-microglobulin concentrations percentiles according to different levels of studied variables in univariate analysis variable percentile 25 median percentile 75 p value gender male 0.01 0.02 0.07 0.26 female 0.02 0.04 0.07 hypertention yes 0.03 0.08 0.17 0.003 no 0.01 0.03 0.06 diabetes mellitus yes 0.01 0.02 0.07 0.76 no 0.01 0.03 0.07 ureteral stent yes 0.06 0.08 0.15 0.03 no 0.01 0.03 0.06 history of previous yes 0.00 0.03 0.17 0.99 kidney surgery no 0.01 0.03 0.07 history of eswl yes 0.01 0.03 0.09 0.01 no 0.01 0.03 0.05 miscellaneous 2912 univariate analysis. multivariate analysis using logistic regression showed that hypertension and history of eswl were predictive factors for higher excretion of urinary beta2-microglobulin after eswl. patients with hypertension, were at increased risk of higher urinary β2m excretion after eswl (odds ratio=5.53, 95% ci=0.95-31.99, p = .05). also, the history of previous eswl, increased the risk of higher post-eswl urinary beta2-microglobulin (odds ratio=2.48, 95% ci=1.09-5.63, p = .02). table 3 shows the results of logistic regression analysis. discussion although eswl is considered a safe course of treatment for urinary stones, various studies have shown that it can be accompanied by some degree of kidney damage and lead to a range of complications.(3,11-13) to determine eswl-induced renal tubular injury, we measured the beta2-microglobulin concentration in the urine before and after the procedure. urinary beta2-microglobulin is a low molecular weight protein known as a sensitive marker of renal tubular damage in various studies.(4,5,7) the results showed that urinary beta2-microglobulin concentration is significantly increased after eswl. these findings suggest the occurrence of renal tubular damage and dysfunction after this treatment. (7,8) sheng and colleagues study on patients with urinary stones treated with eswl revealed that the urinary beta2-microglobulin level is increased significantly as a result of eswl and peaked by 24 hours and immediately after the treatment.(13) another study by villany et al. showed a significant increase in post-eswl urinary excretion of beta2-microglobulin as well.(8) in addition, there are several other studies confirming that the level of urinary beta2-microglobulin increases significantly after eswl.(7,14-16) the exact mechanism of renal damage after eswl is still not fully understood. but the effects of temporary reduction in renal blood flow, formation of free radicals caused by ischemic damages and thermal and cavitation effects have been discussed.(17) according to previous studies, the primary effect of shock waves is to cause a traumatic vascular injury that leads to the rupture of blood vessels and pooling of blood in renal parenchyma.(18) on the other hand, renal vasoconstriction ensuing eswl results in tissue hypoxia. hence, both blood pooling and tissue hypoxia are observed simultaneously in the damaged kidneys after eswl.(19) this causes an ischemic-reperfusion injury affecting the urinary excretion of beta2-microglobulin in 2 ways: first, through tubular cell damage due to ischemic-reperfusion injury and the resulting oxidative stress that reduces reabsorption capacity and leads to increased excretion of these low molecular weight proteins(19,20); and second, through a possible transient impairment in glomerular filtration barrier leading to an increase in the concentration of urinary filtrated proteins after eswl-induced reperfusion injury.(21) however, studies in this area are limited and the role of glomerular damage in reperfusion injury-induced proteinuria is not completely known yet. the results of this study suggest that hypertension is an independent prognostic factor for higher post-eswl urinary beta2-microglobulin excretion. christensen et al. reported that the increased secretion of urinary beta2-microglobulin level in patients with hypertension is due to increased filtration of plasma proteins in these patients saturating their renal tubular reabsorption capacity.(22) in another study, musialik and colleagues suggested that increased secretion of urinary beta2-microglobulin in patients with hypertension is due to an increase in glomerular filtration rate and decreased reabsorption capacity of proximal tubule.(16) on these grounds, there is a possibility that in patients with hypertension, a further tubular injury might follow eswl. according to palm et al. study, hypertension can cause renal arteriolar dysfunction and impair renal auto-regulation. the endothelium becomes dysfunctional and vasodilatation response is gradually impaired.(23) it was also shown that shock waves induce vasoconstriction in the kidneys.(24) as a result, it can be concluded that b s.e. wald sig. exp(b) 95.0% c.i.for exp(b) lower upper step 1a age .000 .030 .000 .985 .999 .942 1.060 height -.045 .038 1.382 .240 .956 .888 1.030 weight -.029 .041 .501 .479 .972 .897 1.052 htn(1) 1.768 1.398 1.600 .206 5.860 .379 90.722 ureteral stent(1) 1.430 1.267 1.273 .259 4.180 .349 50.119 gfr -.009 .020 .217 .641 .991 .953 1.030 history of previous eswl 1.754 1.173 2.233 .135 5.775 .579 57.592 constant 9.486 5.618 2.851 .091 1.317e4 step 8a htn(1) 1.711 .895 3.650 .056 5.533 .957 31.999 history of previous eswl .910 .417 4.758 .029 2.485 1.097 5.633 constant 10.359 5.159 4.032 .045 3.153e4 table 3. variables included in the logistic regression analysi a. variable(s) entered on step 1: age, height, weight, htn, ureteral stent, gfr, history of previous eswl. beta2-microglobulin after eswl-nasseh et al. vol 13 no 06 november-december 2016 2913 patients with hypertension have lower ability to compensate eswl induced damages and the treatment can exacerbate underlying pathological conditions associated with hypertension in these patients. the history of previous eswl was another factor associated with a significantly higher post-eswl excretion of urinary beta2-microglobulin. the study by york and coworkers pointed out that the influence of the remaining stone particles and the tissue effects of eswl can contribute to a more difficult percutaneous nephrolithotomy in patients with urinary stones.(25) this could be a possible explanation of why patients with previous history of eswl had an increased urinary excretion of beta2-microglobulin in this study. variables such as stone size, number and location were not significantly associated with changes in post-eswl urinary beta2-microglobulin concentration in this study. lee and colleagues demonstrated that the stone size is a risk factor for renal hematoma formation after eswl, while no such association was seen for stone location.(26) kardakos et al. reported no relationship between the characteristics of the stone and the change in markers of kidney damage after eswl.(27) also dhar and coworkers found no association between stone location and the risk of renal hematoma after eswl.(28) it can be concluded from the literature that the complications of eswl do not bear a significant relationship with stone features and the results of our study provide further evidence for it. nonetheless, in some studies it has been shown that characteristics such as size, location and number of stones have a statistically significant relationship with eswl success rate.(2) drach et al. observed that by increasing the size and number of stones, the risk of obstruction and entrapment of stone particles after eswl increases.(29) madbouly et al. also disclosed that the size of the stone significantly increases the risk of steinstrasse after eswl.(30) these studies did not evaluate post-eswl kidney damage and none of them used the markers of renal tubular damage, so it can be assumed that the different results of our study in this regard can be attributed to its different method. but on the other hand it is likely that lack of significant correlation between these variables and urinary beta2-microglobulin changes after eswl, is the result of the rather small population sample size of our study. therefore, further studies with larger population sample sizes can be useful in this regard. studies about the factors which affect eswl-induced kidney damage are limited. however, our study shows that there is a possibility that certain groups of patients (hypertensive patients and patients with previous history of eswl) may be susceptible to further kidney damage after eswl according to their underlying conditions and identification of these risk groups can have a significant impact on choosing the best treatment for these patients. we did not repeat measurement of urinary beta2-microglobulin after the 1st postoperative day to document the length of its increase after eswl to differentiate between transient shortlasting increase in urinary beta2-microglobulin versus long-lasting elevation. this was the main limitation of current study and was due to financial considerations. conclusions the findings of this study demonstrate the occurrence of renal tubular injury after eswl and it appears that the damage is more severe in patients with hypertension and patients with a previous history of eswl. eswl should be used only when it is best indicated . conflict of interest none declared. references 1. chongruksut w, lojanapiwat b, ayudhya vcn, tawichasri c, patumanond j, paichitvichean s. prognostic factors for success in treating kidney stones by extracorporeal shock wave lithotripsy. j med assoc thai 2011;94:331-6. 2. al-ansari a, as-sadiq k, al-said s, younis n, jaleel oa, shokeir aa. prognostic factors of success of extracorporeal shock wave lithotripsy (eswl) in the treatment of renal stones. int urol nephrol 2006;38:63-7. 3. al-awadi ka, kehinde eo, loutfi i, et al. treatment of renal calculi by lithotripsy: minimizing short-term shock wave induced renal damage by using antioxidants. urol res 2008;36:51-60. 4. gatanaga h, tachikawa n, kikuchi y, et al. urinary α2-microglobulin as a possible sensitive marker for renal injury caused by tenofovir disoproxil fumarate. aids res hum retroviruses 2006;22:744-8. 5. sharifiaghdas f, kashi ah, eshratkhah r. evaluating percutaneous nephrolithotomyinduced kidney damage by measuring urinary concentrations of β-2microglobulin. urol j 2011;8:277-82. 6. wibell l. the serum level and urinary excretion of beta2-microglobulin in health and renal disease. pathol biol 1978;26:295-301. 7. karlsen s, berg k. acute changes in kidney function following extracorporeal shock wave lithotripsy for renal stones. br j urol 1991;67:241-5. 8. villányi kk, székely jg, farkas lm, jávor é, pusztai c. short-term changes in renal function after extracorporeal shock wave lithotripsy in children. j urol 2001;166:222-4. 9. miyata t, jadoul m, kurokawa k, van ypersele de strihou c. beta-2microglobulin in renal disease. j am soc nephrol 1998;9:172335. 10. serpa neto a, rossi fmb, amarante rdm, rossi m. predictive performance of 12 equations for estimating glomerular filtration rate in severely obese patients. einstein 2011;9:294-301. 11. li b, zhou x, zhang y. the relationship between the energy levels of shock waves and the degree of renal damage after eswl: a prospective clinical matching trail. j tongji med univ 1994;14:114-8. 12. rutz-danielczak a, pupek-musialik d, raszeja-wanic b. effects of extracorporeal beta2-microglobulin after eswl-nasseh et al. miscellaneous 2914 shock wave lithotripsy on renal function in patients with kidney stone disease. nephron 1998;79:162-6. 13. sheng b, he d, zhao j, chen x, nan x. the protective effects of the traditional chinese herbs against renal damage induced by extracorporeal shock wave lithotripsy: a clinical study. urol res 2011;39:89-97. 14. park h, lee h, lee k, choi j, jeong b, kim h. preventive effects of cox-2 inhibitor, celecoxib on renal tubular injury induced by shock wave lithotriptor. urol res 2010;38:2238. 15. kishimoto t, senju m, sugimoto t, et al. effects of high energy shock wave exposure on renal function during extracorporeal shock wave lithotripsy for kidney stones. eur urol 1990;18:290-8. 16. musialik d, raszeja-wanic b, głuszek j, pieczyαska a. excretion of beta-2microglobulin in hypertension. pol tyg lek 1993;49:239-41. 17. aksoy h, aksoy y, turhan h, keleα s, ziypak t, özbey i. the effect of shock wave lithotripsy on nitric oxide and malondialdehyde levels in plasma and urine samples. cell biochem funct 2007;25:533-6. 18. handa rk, mcateer ja, connors ba, liu z, lingeman je, evan ap. optimising an escalating shockwave amplitude treatment strategy to protect the kidney from injury during shockwave lithotripsy. bju int 2012;110:1041-7. 19. clark dl, connors ba, evan ap, willis lr, handa rk, gao s. localization of renal oxidative stress and inflammatory response after lithotripsy. bju int 2009;103:1562-8. 20. trinchieri a, mandressi a, zanetti g, ruoppolo m, tombolini p, pisani e. renal tubular damage after renal stone treatment. urol res 1988;16:101-4. 21. rippe c, rippe a, larsson a, asgeirsson d, rippe b. nature of glomerular capillary permeability changes following acute renal ischemia-reperfusion injury in rats. am j physiol 2006;291:1362-8. 22. christensen ck. rapidly reversible albumin and [beta]2-microglobulin hyperexcretion in recent severe essential hypertension. j hypertens 1983;1:45-52. 23. palm f, nordquist l. renal oxidative stress, oxygenation, and hypertension. am j physiol 2011;301:1229-41. 24. evan ap, mcateer ja, connors ba, blomgren pm, lingeman je. renal injury during shock wave lithotripsy is significantly reduced by slowing the rate of shock wave delivery. bju int 2007;100:624-8. 25. yuruk e, tefekli a, sari e, et al. does previous extracorporeal shock wave lithotripsy affect the performance and outcome of percutaneous nephrolithotomy? j urol 2009;181:663-7. 26. lee h-y, yang y-h, shen j-t, et al. risk factors survey for extracorporeal shockwave lithotripsy-induced renal hematoma. j endourol 2013;27:763-7. 27. kardakos is, volanis di, kalikaki a, et al. evaluation of neutrophil gelatinase–associated lipocalin, interleukin-18, and cystatin c as molecular markers before and after unilateral shock wave lithotripsy. urology 2014;84:7838. 28. dhar nb, thornton j, karafa mt, streem sb. a multivariate analysis of risk factors associated with subcapsular hematoma formation following electromagnetic shock wave lithotripsy. j urol 2004;172:2271-4. 29. drach g, dretler s, fair w, et al. report of the united states cooperative study of extracorporeal shock wave lithotripsy. j urol 1986;135:1127-33. 30. madbouly k, sheir kz, elsobky e, eraky i, kenawy m. risk factors for the formation of a steinstrasse after extracorporeal shock wave lithotripsy: a statistical model. j urol 2002;167:1239-42. beta2-microglobulin after eswl-nasseh et al. vol 13 no 06 november-december 2016 2915 vol 16 no 01 january-february 2019 27 two-stage lparoscopic repair of two-level ureteral strictures: our experience of 8 patients rui-zhi xue1, zheng-yan tang1,2, ming-qang zeng1, liang-huang1, jun-jie chen1, zhi chen1* purpose: to evaluate the feasibility and effectiveness of two-stage laparoscopic repair for two-level ureteral strictures. materials and methods: from october 2010 to january 2017, 8 patients with two-level ureteral strictures, which were located in upper and lower ureter, received two-stage laparoscopic repair in our institution. laparoscopic ureteroureterostomy was conducted for the upper ureteral strictures in first stage and 8 weeks later laparoscopic ureterovesical reimplantation was performed for lower stricture after the patency of upper lesion was confirmed by antegrade ureteropyelography. the kidney was drained by a nephrostomy tube during the interval period of two operations. result: all the operations were performed successfully without intraoperative complications except one patient converted to open surgery during second-stage operation. for first-stage surgery, mean operating time was 120.88 ± 16.88 min, mean blood loss was 89.38 ± 13.74 ml, and mean duration of postoperative hospitalization was 3.63 ± 0.74 days. while in second-stage surgery, mean operating time took 125.25 ± 17.00 min, mean blood loss was 65.63 ± 10.16 ml, and mean duration of postoperative hospitalization was 3.62 ± 1.41 days.. on ureteropyelography 10 weeks after second-stage surgery, the contrast medium flowed from kidney down into bladder unrestrictedly and the patency of entire ureter was restored in all patients. during the follow-up, one female was observed kidney atrophy with ureteral calculus formed on the lesion side, and was successfully treated by ureteroscopic lithotripsy. no sign of stricture recurrence was found on other patients. conclusion: two-stage laparoscopic repair is a feasible and effective treatment for two-level ureteral strictures. but its indication is relatively narrow and confined to ureteral strictures located in two sites with sufficient interval distance and minor stricture length. keywords: laparoscopy; reconstruction; ureteral stricture; ureteroureterostomy; ureterovesical reimplantation introduction during recent years, the widespread diffusion of minimally invasive procedure in ureteral treatments has led to an increasing incidence of ureteral strictures.(1) among them, the two-level ureteral stricture, which is defined as two sites of strictures in unilateral ureter, is a relatively rare but definitely challenging issue for urology surgeons to deal with. although numerous clinicians have tried various efforts to restore patency, few of them achieved the satisfied outcome, recurrence of strictures is the most common final results for these therapeutic attempts.(1,2) in our report, by describing operational and follow-up data of 8 patients with two-level ureteral strictures, we aim to evaluate the feasibility of our two-stage laparoscopic repair for this complicated disease, and explore the optimal indication of this procedure. 1department of urology, xiangya hospital, central south university, changsha, hunan, p.r. china, 410008. 2hunan engineering laboratory for diagnosis and treatment technology of urogenital diseases, changsha, hunan, p.r. china, 410008. statement: dr.rui-zhi xue and dr.zheng-yan tang contributed equally to this study and should be considered as co-first author *correspondence: department of urology, , xiangya hospital, central south university, changsha, hunan, p.r. china, 410008.tel: +86 15243676149, fax: +86 0731 89753012, e-mail: docfrankhsueh@126.com. received august 2017 & accepted april 2018 material and methods patients from october 2010 to january 2017, 8 patients with two-level ureteral strictures were referred to our institutes and received the two-stage laparoscopic surgery. all of the patients signed the informed consent agreements and this study had been approved by ethic committee of the xiangya hospital of central south university. ranging from 28 to 63 years old, these 8 patients share the same chief complains of flank pain and discomfort. among them, 5 patients’ etiology were considered as holmium laser injuries, their historical operational records offered by the local hospital showed that the laser was mainly operated in the upper and lower parts of ureter, and the patients developed hydronephrosis rapidly after surgery. 3 patients were diagnosed as two-level ureteral strictures which were caused by impacted calculus. according to their description, they had multiple times of hematuria followed by experience of urinating stones a few months before, and none of laparoscopic and robotic urology them had received ureteral surgeries in the past. there is only one patient who had no operation in the past and denied any symptoms of urolithiasis, we concluded his etiology as idiopathic. because of the fast development of hydronephrosis, all patients had received percutaneous nephrostomy and kept a nephrostomy tube for temporary drainage in local hospital prior to admission to our institution. operative technique facing this challenging disease, instead of repairing the two lesions in one single surgery, we adopted two-stage laparoscopic operation. in first stage we repaired the upper stricture of ureter by transperitoneal laparoscopic end-to-end anastomosis, while lower ureteral strictures were dealt with ureteral reimplantation in second-stage surgery. before operation, upper ureteral stricture was confirmed by antegrade ureteropyelography in all patients (figure 1a). when the first-stage surgery began, under general endotracheal anesthesia, patients were placed in a supine position with lesion side elevated, then the three-port laparoscopic approach was established with a 12-mm port positioned infraumbilically and two 12-mm ports in the lateral border of rectus muscles. the ureter was mobilized in the first step, ureteral part above the stricture site is often dilated, thus the joint site of dilated ureter and non-dilated ureter indicates the position of lesion and stricture site of upper ureter could be located accordingly (figure 2a). the ureteral stricture lesion was excised and its lumen turned out to be completely occluded, no urine flowed out from proximal end (figure 2b). after trimming the lesion site until normal lumen was seen, an interrupted anastomosis with 4–0 monocryl was performed accordingly. when the upper ureteral anastomosis was finished, since the lower stricture still existed, we kept the nephrostomy tube in place to divert urine and had not placed the double j stent. patients were discharged with nephrostomy tube and readmitted 8 weeks later to receive second-stage surgery. before second surgery, all patients’ upper ureter had been confirmed unobstructed by antegrade ureteropyelography, the contrast medium passed through original upper stricture lesion fluently (figure 1b) but obstructed in lower stricture area, and no contrast medium table 1. preoperative data of patient case age gender side etiology presentation distance between distance between interval (years) us & upj(cm) ls & uvj(cm) distance (cm) 1 44 m l holmium laser left flank pain 9 2 15 2 38 f l impacted calculus left flank pain 3 1 22 3 56 m r holmium laser right flank pain 12 4 8 4 55 f r holmium laser right flank pain 7 3 14 5 63 f l impacted calculus left flank pain 10 1 12 6 33 f r holmium laser right flank pain 7 2 15 7 28 m r idiopathic causes right flank pain 9 3 14 8 40 m l holmium laser left flank pain & fever 7 1 18 abbreviations: us, upper stricture; upj, ureteropelvic junction; ls, lower stricture; uvj, ureterovesical junction fig.1 a. preoperative antegrade ureteropyelography of patient showed the contrast medium was obstructed at stricture site of left upper ureter (arrow). b. before the second surgery, an antegrade ureteropyelography was arranged, the contrast medium passed the anastomotic site of upper ureter smoothly without any sign of stricture or leakage (arrow). c. although the patency of upper ureter was restored, the contrast medium was obstructed in lower strictured area, and no contrast medium had reached bladder. d. 10 weeks after second-stage surgery, an antegrade ureteropyelography via nephrostomy tube (arrow) was arranged, it showed patency of the entire length of ureter and contrast medium flowed from renal pelvis down into bladder unrestrictedly. repair of two-level ureteral strictures-xue et al. laparoscopic and robotic urology 28 vol 16 no 01 january-february 2019 29 had reached bladder (figure 1c). in such situation, the second surgery of laparoscopic ureteral reimplantation was performed accordingly. the patient was put in supine position with pads under their hips, then three-port laparoscopic approach was established with one 12-mm trocar in the umbilicus, one 12-mm trocar above the symphysis pubis and one 12-mm trocar in the mcburney point or its symmetry point. after the isolation of the stricture lesion of lower ureter (figure 2c), a cystotomy was made for the reimplantation of the ureter. prior to complete the ureteroneocystostomy with 4-0 interrupted stitches (figure 2d), a double j stent was placed. prevention of vesicoureteric reflux is routinely performed in our institution. anastomotic part of ureter obliquely passed through the bladder muscular layer and was regularly wrapped by vesical membrane to form an artificial tunnel for ureter. the double j stent was kept for 8 weeks, and for safety reasons the nephrostomy tube was still kept in place when second-stage surgery was finished. before removal of the nephrostomy tube, which was regularly arranged 10 weeks after the second-stage operation, antegrade ureteropyelography via nephrostomy tube was scheduled for all patients, and images showed patency of the entire length of ureter and contrast medium flowed from renal pelvis down into bladder unrestrictedly (figure 1d). results for all the 8 patients, the diagnosis of two-level ureteral stricture was confirmed by antegrade ureteropyelography and retrograde pyelography, which respectively demonstrated upper and lower stricture lesion. according to imaging data, the measured distance from the upper ureteral stricture to ureteropelvic junction ranged from 3 cm to 12 cm, and distance between lower ureteral stricture and ureterovesical junction was no longer than 4 cm. correspondingly, the approximated interval distance between upper and lower strictures was measured varying from 8 cm to 22 cm. specific preoperative details of the patients are listed in table 1. all patients received the surgical treatments on schedule and no intraoperative complication was occurred except one patient was converted to open surgery during his second-stage operation, due to the extreme adhesion and difficulty of dissection under laparoscopy. for first-stage surgery, mean operating time was 120.88 ± 16.88 min, mean blood loss was 89.38 ± 13.74 ml, and mean duration of postoperative hospitalization was 3.63 ± 0.74 days. while in second-stage surgery, mean operating time took 125.25 ± 17.00 min, mean blood loss table 2. operative and follow-up data of patients case operation data follow-up dataa operating time operating time blood loss blood loss lhs after lhs after complications duration of radiography of fss (min) of sss (min) of fss (ml) of sss (ml) fss (days) sss (days) follow-up (months) recheck 1 115 136 90 75 3 3 none 79 no recurrence of stricture 2 131 112 100 55 4 3 none 33 no recurrence of stricture 3 120 153 90 80 3 7 converted to open 30 no recurrence surgery during sss of stricture 4 105 130 80 70 3 3 kidney atrophy & 25 kidney atrophy & ureteral calculus ureteral calculus formed formed 5 139 95 100 65 3 3 none 22 no recurrence of stricture 6 90 122 60 70 4 3 none 15 no recurrence of stricture 7 132 125 100 50 5 4 none 11 no recurrence of stricture 8 135 129 95 60 4 3 moderate stenosis 3 moderate stenosis of upper of upper anastomotic site anastomotic site abbreviations: fss, first-stage surgery; sss, second-stage surgery; lhs, length of hospital stay. athe data was documented since second-stage surgery, there was no complication or unexpected event occurred during and after the first operation. fig.2 a.the first stage surgery was performed through transperitoneal approach, after the ureter was mobilized, we located the strictured site of upper ureter (arrow). b. when the ureteral stricture lesion was excised, the lumen turned out to be completely occluded and no urine flowing out from proximal end of incision (arrow). c. the second surgery was laparoscopic ureteral reimplantation. the stricture lesion was located at lower end of ureter (arrow). d. the anastomotic site of ureteroneocystostomy was sutured with 4/0 interrupted stitches repair of two-level ureteral strictures-xue et al. was 65.63 ± 10.16 ml, and mean duration of postoperative hospitalization was 3.62 ± 1.41 days. foley catheter was removed in the first day after first-stage surgery, while for second-stage surgery the catheter was normally kept for 7 days before removal to prevent early vesicoureteric reflux. in both stages of surgeries, all patients’ abdominal cavity drainage tube was removed when the daily drained volume was less than 10 ml. these 8 patients were under persistent follow-up. one female was observed kidney atrophy and ureteral calculus formed on the lesion side. the ureteral calculus was treated successfully by ureteroscopic lithotripsy the day we found it, by far her serum creatinine and estimated glomerular filtration rate (gfr) are still normal and under regular recheck. no recurrence of strictures or aggravation of hydronephrosis was showed of all other patients. the feedback of telephone follow-up indicated all the patients are asymptomatic by far. specific perioperative and follow-up data is provided in table 2. discussion as a by-product of fast development of endoscopic therapy in urology, ureteral strictures occur much more frequently than the past, and patients with multiple sites of ureteral strictures are not rare to see in nowadays. for decades, urologists have been groping for solutions continuously, but except traditional open ureteral reconstruction surgery, which had been proved attached with severe complications and surgical trauma, current minimal invasive treatments for this disease have been fruitless and rarely reported.(2-5) the surgical procedure adopted in our report is the twostage laparoscopic ureteroplasty, which includes ureteroureterostomy and ureterovesical reimplantation. the main reason of conducting this surgery in two stages instead of in one is to simplify complexity of the operation and guarantee good healing of the anastomotic site. by dividing treating procedure into two stages, we focused on only one site of lesions in each surgery, and performing the second-stage treatment only after the success of first surgery was confirmed. through this step-by-step operation, the curative effect is actually enhanced with minor surgical difficulty. both of the two stages of laparoscopic surgeries were conducted through transperitoneal approach. although there are some surgeons preferring to perform upper ureteral anastomosis by retroperitoneal laparoscopy, we think a larger surgical space and greater clarity of vision offered by transperitoneal approach could much facilitate the operation. the laparoscopic ports placement in the first surgery was arranged by reference to the relevant surgical instructions(6). to be noticed, the two ports on lateral border of rectus muscles should not be placed too far from midline of body, otherwise much difficult will be met during the process of turning the colon downward to expose retroperitoneal structures. the placement of ports in the second surgery, which aimed to facilitate the dissection of lower ureter and bladder, was regularly adopted in ureteral reimplantation. however, intense carefulness should be paid when inserting the first trocar in umbilicus, because firststage surgery may have caused intestinal adhesion with visceral abdominal wall, and intestinal puncture injury could occur due to blinded actions. thus fully pulling up of abdominal skin before puncture and a progressive piercing manoeuvre are necessary to prevent such complication. another advantage of two-stage operation is that it can protect the blood supply of ureter and guarantee good healing of anastomotic site. ureteral blood supply mainly comes from vascular network that embedded in the periureteral sheath (sheath of waldeyer).(7,8) performing resection and anastomosis of both sites in onestage surgery will inevitably involve large-scale dissection of periureteral sheath, which will lead to damage of main blood supply of ureters.(9,10) according to the study of 64 patients who recieved ureteral anastomosis from wang,(11) overmuch dissection of periureteral sheath can easily cause ischemia necrosis of anastomosis site, while preserving periureteral sheath or covering pedicled omentum on it remarkably reduced this complication. in our report, during each stage we only operated on one site of ureter, leaving periureteral sheath and blood supply of rest part conserved. by alternately repairing the upper and lower ureteral strictures, maximum protection of ureteral blood supply was achieved. the interval time between two surgeries was set as 8 weeks, which can guarantee scare tissue of anastomotic site stabilized and sufficient neovascularization formed. (12-14) we do not recommend longer interval time due to risks of renal function deterioration and nephrostomy tube falling out. as for the repairing sequence, although all the patients in our report received upper stricture repair firstly due to preference of the surgeon, we presume the reversed repairing sequence is also practicable and further relevant control study should continue in future. there are also some limitations of our surgical procedures. first of all, the two-stage laparoscopic repair is mainly suitable for two-level ureteral strictures with short lesion length (usually the stricture length should be no longer than 3 cm), otherwise the anastomosis may fail due to overwhelming anastomotic tension. secondly, for strictures that are located too closely to each other (usually < 10cm), the second stage laparoscopic repair may not be achieved. among our patients, the only one that converted to open surgery in second-stage operation is also the one that has the narrowest interval distance (8cm). because when the two stricture lesions are too close, the second operation may share the same operational area with the first one. as is well-known, the severe tissue adhesion of surgical region caused by the first surgery will bring extreme inconvenience to second laparoscopic operation. lastly, due to the relatively long period of the whole treating procedures, patients with unfavorable general conditions or residual renal function less than 25%, should be under careful evaluation before being selected for two-stage laparoscopic surgery. one female patient in our study developed kidney atrophy after surgery and renogram showed remained function of the diseased kidney was under 10% by now. we consider this outcome is largely related to the severe hydronephrosis of this patient and long duration of the whole treating process. although nephrostomy tube can temperately alleviate hydronephrosis, longtime indwelling drainage device can also damage renal function.(15) conclusions two-stage laparoscopic repair is a feasible and effective treatment for two-level ureteral strictures. but its indication is relatively narrow and confined to ureteral strictures located in two sites with sufficient interval repair of two-level ureteral strictures-xue et al. laparoscopic and robotic urology 30 vol 16 no 01 january-february 2019 31 repair of two-level ureteral strictures-xue et al. distance and minor stricture length. acknowledgement we thank for the support from national natural science foundation of china (no. 81570627) and natural science fund for youth in hunan province (no. 2015jj3162). conflict of interest no competing interests exist. references 1. patel rc, newman rc. ureteroscopic management of ureteral and ureteroenteral strictures. urol clin north am. 2004;31:10713. 2. komyakov bk, novikov ai, ochelenko va, guliev bg, al-attar tk, onoshko mv. [technical features of intestinal ureteroplasty. art 6: simultaneous ureteral and bladder substitution]. urologiia. 201712-5. 3. kamat n, khandelwal p. laparoscopyassisted ileal ureter creation for multiple tuberculous strictures: report of two cases. j endourol. 2006;20:388-93. 4. shokeir aa, ghoneim ma. further experience with the modified ileal ureter. j urol. 1995;154:45-8. 5. goldfischer er, gerber gs. endoscopic management of ureteral strictures. j urol. 1997;157:770-5. 6. rv k. difficulties in laparoscopic ureteral and bladder reconstruction. in: al-kandari am gi, ed. difficult conditions in laparoscopic urologic surgery. vol 2. new york: springer; 2011:321. 7. elkoushy ma as. surgical, radiologic, and endoscopic anatomy of the kidney and ureter. in: wein aj kl, novick ac, partin aw, peters ca, ed. campbell-walsh urology. vol 2. 11th ed. philadelphia: elsevier; 2016:976. 8. sukumar cd jr, mahalakshmamma v. an anatomical study on blood supply of ureter. int j anat res. 2015;3:970-5. 9. javali t, kasaraneni d, banale k, babu ps, nagaraj hk. vesicouterine fistula and concomitant ureteric necrosis following uterine artery embolization for fibroid uterus. int urogynecol j. 2015;26:1877-8. 10. sutherland rs, pfister rr, koyle ma. endopyelotomy associated ureteral necrosis: complete ureteral replacement using the boari flap. j urol. 1992;148:1490-2. 11. wang g, han g, ren y, et al. [clinical effects of pedicled omentum covering and wrapping the ureteral anastomosis to prevent ureteral anastomotic leakage after surgery of abdominal and pelvic tumors]. zhonghua zhong liu za zhi. 2014;36:232-5. 12. andreoni cr, lin hk, olweny e, et al. comprehensive evaluation of ureteral healing after electrosurgical endopyelotomy in a porcine model: original report and review of the literature. j urol. 2004;171:859-69. 13. sherratt ja, dallon jc. theoretical models of wound healing: past successes and future challenges. c r biol. 2002;325:557-64. 14. sahin s, resorlu b, atar fa, eksi m, sener nc, tugcu v. laparoscopic ureterolithotomy with concomitant pyelolithotomy using flexible cystoscope. urol j. 2016;13:2833-6. 15. nissenkorn i, gdor y. nephrovesical subcutaneous stent: an alternative to permanent nephrostomy. j urol. 2000;163:528-30. point of technique 269urology journal vol 5 no 4 autumn 2008 conservative management of early bladder rupture after postoperative radiotherapy for prostate cancer abbas basiri, mohammad hadi radfar urol j. 2008;5:269-71. www.uj.unrc.ir keywords: prostate cancer, radiotherapy, bladder rupture, therapy department of urology, shahid labbafinejad hospital and urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: abbas basiri, md urology and nephrology research center, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 77282 e-mail: basiri@unrc.ir received june 2008 accepted august 2008 introduction pelvic irradiation is known to cause several complications involving urinary bladder such as radiation cystitis, ulceration, and incontinence.(1,2) spontaneous intraperitoneal rupture of the urinary bladder is a rare complication following pelvic irradiation.(3-5) to the best of our knowledge, there is only one report of radiation-induced bladder rupture following irradiation for prostate cancer which was managed surgically.(6) here, we present a case of spontaneous intraperitoneal bladder rupture occurred 8 months after adjuvant radiotherapy for prostate cancer that was successfully managed conservatively. case report a 65-year-old man was admitted with the chief complaint of gross hematuria. he had generalized abdominal pain particularly over the lower abdomen. he reported normal bowel function and denied any abdominal trauma. he had undergone radical prostatectomy for prostate adenocarcinoma (clinical stage, t2b), 2 years earlier. due to an increase in serum prostate-specific antigen level, he had also received postoperative external pelvic irradiation 8 months earlier, consisted of 1.2 gy per day, 5 days a week, to a total of 72 gy. then, he had developed a massive fibrotic tissue over the suprapubic region and suffered from mild obstructive symptoms and frequency. on admission, the patient was afebrile. his abdomen was mildly distended without generalized tenderness. bowel sounds were diminished. there was marked tenderness without rebound tenderness and guarding over the lower abdomen. the bladder was catheterized and about 70 ml of bloody urine was obtained. daily urinary volume was normal. serum prostate-specific antigen, serum creatinine and blood urea nitrogen remained within the normal range. ultrasonography examination revealed a small amount of intra-abdominal fluid. since abdominal pain improved gradually after catheterization, cystoscopy and cystography were performed to examine the bladder. since the bladder neck was severely elevated on cystoscopy, entering the bladder was very difficult. cystoscopic examination showed a low-volume bladder with edematous inflamed mucosa, but no point of perforation was diagnosed. cystography showed extravasation of the contrast medium into the peritoneal cavity (figure 1). hence, spontaneous intraperitoneal rupture of the urinary bladder was diagnosed. management of bladder rupture after radiotherapy—basiri and radfar 270 urology journal vol 5 no 4 autumn 2008 technique regarding the high complication rate of surgery on irradiated tissues and improvement of the patient’s situation, we decided to treat the patient conservatively with remaining the indwelling catheter for a longer period. results abdominal pain and hematuria disappeared on hospital days 2 and 7, respectively, after urethral catheter insertion. cystography was obtained 5 weeks later which showed a bladder capacity of 100 ml and no extravasation (figure 2). thereafter, the foley catheter was removed and the patient continued intermittent selfcatheterization. ultrasonography revealed postvoid residue of less than 10 ml. the patient’s recovery was uneventful with no further bladder rupture or elevation of serum prostate-specific antigen after 5 months. discussion the most common cause of rupture of the urinary bladder is trauma.(2) nontraumatic rupture is known as spontaneous rupture.(7,8) causes of spontaneous rupture include bladder wall lesions (malignant tumor, inflammatory lesions, and irradiation) or distention of the bladder wall (neurogenic bladder, outlet obstruction, and alcohol intoxication).(7,8) bastable and colleagues reported 66 cases of spontaneous bladder rupture, of whom 28 (42.4%) had a diseased bladder, while 23 (34.8%) had urinary retention.(8) late effects of pelvic irradiation can be observed in the bladder with hematuria, radiation cystitis, fibrosis, and ulceration.(9) the spontaneous intraperitoneal rupture of the urinary bladder subsequent to pelvic radiotherapy is an extremely rare event.(3-5) the majority of reported cases of radiation-induced bladder rupture are in women figure 1. cystography on admission. figure 2. cystography after 5 weeks of catheter insertion. management of bladder rupture after radiotherapy—basiri and radfar urology journal vol 5 no 4 autumn 2008 271 with a history of carcinoma of the uterine cervix who had undergone surgical treatment prior to radiotherapy and had a latency of at least 1.5 years.(2) only one case of bladder rupture after radiation therapy for prostate cancer has been reported in which the rupture occurred 17 years after radiation, which was managed surgically.(2) intrapelvic surgery and radiotherapy are both known to induce neurogenic bladder.(9,10) histologic changes caused by irradiation would weaken the bladder wall.(11) it is also supposed that postoperative changes in the bladder induce an expansion of the impaired bladder wall.(12) these changes together with some unknown factors would finally result in rupture of the bladder. most of the reported cases had a generalized peritonitis necessitating surgical intervention.(2) however, in some reports conservative management using indwelling catheter has been applied.(13) it should be noted that surgery on irradiated tissue has a higher complication rate.(14) repeat rupture is a complication which may occur after either surgical or conservative treatment. however, it could be managed conservatively in a patient the first rupture has been managed conservatively.(13) in the present report, conservative management protected the patient from surgical complications. although our patient had intraperitoneal rupture of the urinary bladder, he did not show signs of generalized peritonitis and improved with foley catheter insertion. hence, we decided not to practice surgery. after 5 weeks of remaining the indwelling catheter, cystography revealed no extravasation. the patient did not have any repeat rupture during the 5-month follow-up. surgical operation on the patient could be risky because of huge fibrotic tissue observed over the lower abdomen. spontaneous bladder rupture following pelvic irradiation could complicate the disease not only in women with cancer of the uterine cervix, but also in men with prostate cancer. to our best knowledge, this is the first case of spontaneous intraperitoneal rupture of the urinary bladder due to prostate cancer which was managed conservatively. conflict of interest none declared. references 1. marks lb, carroll pr, dugan tc, anscher ms. the response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. int j radiat oncol biol phys. 1995;31:1257-80. 2. nishimura t, suzuki k, iijima m, et al. spontaneous rupture of bladder diverticulum after postoperative radiotherapy for carcinoma of the uterine cervix: a case report. radiat med. 2000;18:261-5. 3. fujikawa k, miyamoto t, ihara y, matsui y, takeuchi h. high incidence of severe urologic complications following radiotherapy for cervical cancer in japanese women. gynecol oncol. 2001;80:21-3. 4. addar mh, stuart gc, nation jg, shumsky ag. spontaneous rupture of the urinary bladder: a late complication of radiotherapy--case report and review of the literature. gynecol oncol. 1996;62:314-6. 5. kato a, yoshida k, tsuru n, et al. spontaneous rupture of the urinary bladder presenting as oliguric acute renal failure. intern med. 2006;45:815-8. 6. ketata s, boulaire jl, al-ahdab n, bargain a, damamme a. spontaneous intraperitoneal perforation of the bladder: a late complication of radiation therapy for prostate cancer. clin genitourin cancer. 2007;5:287-90. 7. stone e. spontaneous rupture of the urinary bladder: report of two cases. arch surg. 1933;23:129-44. 8. bastable jr, de jode lr, warren rp. spontaneous rupture of the bladder. br j urol. 1959;31:78-86. 9. fujikawa k, yamamichi f, nonomura m, soeda a, takeuchi h. spontaneous rupture of the urinary bladder is not a rare complication of radiotherapy for cervical cancer: report of six cases. gynecol oncol. 1999;73:439-42. 10. seski jc, diokno ac. bladder dysfunction after radical abdominal hysterectomy. am j obstet gynecol. 1977;128:643-51. 11. meyer k, welsch h. [spontaneous rupture of the urinary bladder after radiotherapy]. zentralbl chir. 1993;118:230-1. german. 12. tabaru a, endou m, miura y, otsuki m. generalized peritonitis caused by spontaneous intraperitoneal rupture of the urinary bladder. intern med. 1996;35:880-2. 13. kaneko t, nozawa t, owari y, et al. [recurrent spontaneous rupture of the urinary bladder: a case report]. hinyokika kiyo. 2000;46:137-9. japanese. 14. maier u, ehrenbock pm, hofbauer j. late urological complications and malignancies after curative radiotherapy for gynecological carcinomas: a retrospective analysis of 10,709 patients. j urol. 1997;158:814-7. sexual dysfunction and andrology sexual dysfunction in married women with urinary incontinence handan zincir1, gokce demir2, yurdagül günaydın3, betül ozen4* purpose: this study was conducted in descriptive and cross-sectional design in order to determine prevalence of urinary incontinence severity in women with urinary incontinence (ui), correlation between ui and sexual dysfunction materials and methods: the study had descriptive and cross-sectional design. in sample selection, four family health centers areas were determined by lot and totally 384 women with ui were reached by making home visits in these regions. as data collection tool, severity index in female urinary incontinence determining ui condition and female sexual function index determining sexual functioning were used. results: average age of the women participating in the study was 37.3 ± 1.02. mean body mass index of the women was 26.3 ± 5.41. it was determined that 22.1% of the women participating in the study had ui for 3-5 years and 15.1% had ui for six years and a longer time. it was determined that 53.9% of the women participating in study had mild incontinence, 40.6% had moderate incontinence, 3.6% had severe incontinence, and 1.8% had very severe incontinence. a significant correlation was found between severity index in female urinary incontinence (isi) score and female sexual function index (fsfi) score (p < 0.05). there was a positive and weak correlation between isi scores and age, duration of marriage, and number of pregnancy of the women who participating in the study; and a positive and very weak correlation between isi scores and body mass index and spontaneous abortion (p < 0.05). conclusion: almost half of women with ui were determined to have moderate and more severe urinary incontinence. a significant correlation was found between isi and fsfi score. keywords: sexual dysfunction; urinary incontinence; woman. introduction urinary incontinence (ui) is a multidisciplinary problem that affects woman from all ages and may negatively influence life quality with social aspects. its prevalence in female population is estimated to be at the rate of 17% and 58.4%. prevalence of ui, an important problem, varies between 10 and 30% in women aged between 15-64 years, and between 17 and 55% in elderly people(1,2). as studies conducted on women with urinary incontinence were examined; they were found to experience problems such as having low body images, high sense of shame, not feeling themselves feminine in terms of physical and sexual aspects, being concerned because of smell, always using pad/diaper, and phobia of urinary incontinence(3). urinary incontinence experienced during coitus, negative reactions of spouse, and thinking reduction of attraction cause different types of sexual dysfunctions influencing sexual life of women negatively. it was determined in previous studies that social and occupational lives of individuals with ui were affected and their sexual lives and marriage relationships were damaged(4). because women with ui are not capable of controlling their urinary functions, they may experience problems such as urinary incontinence during 1department of community health nursing, erciyes university faculty of health sciences, 38039, kayseri-turkey. 2department of community health nursing, ahi evran university college of health department of nursing, 40100, kırsehir-turkey. 3department of community health nursing, erciyes university faculty of health sciences, 38039, kayseri-turkey. 4department of community health nursing, erciyes university faculty of health sciences, 38039, kayseri-turkey. *correspondenc: department of community health nursing, erciyes university faculty of health sciences, kayseri 38039, turkey. tel: +90-352-207 66 66-28561. fax: +90-352-437 92 81. e-mail: betulozen@erciyes.edu.tr. received june 2017 & accepted october 2017 coitus, negative reactions of husband/partner, thinking about reduction in attraction, and decreased self-confidence. depression experienced based on these problems may cause sexual dysfunctions (sd) negatively influencing sexual lives of women(5). in a study conducted on 216 women aged between 19-66 years with ui complaint, 34% of women were determined to have reduced sexual drive, 23% had dysfunction of sexual arousal, and 11% had insufficiency of orgasm(6). because of this important problem influencing women, preventing ui to develop, encouraging women suffering from ui to answer questions specific to sexuality, and enabling them to express their concerns about sexual issues are found among fundamental responsibilities of nurses. according to these information, the study was conducted in descriptive and cross-sectional design in order to determine prevalence of urinary incontinence severity in women with ui, correlation between ui and sexual dysfunction, and the effective factors. materials and methods study population the study was planned as a cross-sectional type between march-july 2016. the population of the study consisted of nine family health centers (fhc) with vol 15 no 04 july-august 2018 193 different socio-economic characteristics in the city center of kırşehir. the sample group was formed by simple random sampling technique. the frequency of urinary incontinence was unknown in the population of the study. for this reason, sample size of study was calculated as 384 by examining means of other studies conducted on urinary incontinence(1,2) and using formula of unknown number of individuals in the population (d = 0.05, p = 0.50, t = 1.96 were taken at confidence interval of 95%)(7). inclusion and exclusion criteria the women who were diagnosed with urinary incontinence at least for 6 months, were older than 15, had no psychological disability, and were married, were included in the study. the women who did not agree to participate in the study and were in pregnancy and lactation periods were not included in the study. procedures the study was conducted in accordance with the principles of helsinki declaration in 2008 [world medical associations declaration of helsinki.2008]. approval was received from ethics committee (2016-03/14). verbal and written consents were received from the women who agreed to participate in the study. in sample selection, four fhc areas were determined totally 384 women with ui were reached by making home visits in these regions. the data were collected by using face-to-face interview method. evaluations this questionnaire was prepared by the researchers upon the literature review(3,4,7-9).as data collection tool, the questionnaire including socio-demographic characteristics and some obstetric characteristics of the women, severity index in female urinary incontinence determining ui condition and female sexual function index determining sexual functioning were used. severity index in female urinary incontinence (isi): isi is a scale consisting of two items and measuring severity of female urinary incontinence. isi was developed by sandvik et al., in 1993(10). turkish validity and reliability analysis of the scale was conducted by uyar-hazar and sirin in 2008 and cronbach’s alpha coefficient was found as 0.67(11). the index consists of two multiple-choice questions. one of the questions measures frequency of incontinence and the other one measures its amount. the first question has four choices and the second question has three choices and these choices are scored between 1-4 and 1-3, respectively. in calculation of index score; scores received from both questions are multiplied. accordingly, scores are as follows, 1-2 points are mild incontinence, 3-6 points are moderate, 8-9 points are severe, and 12 points are very severe(10,11). cronbach’s alpha coefficient of this scale was found as 0.61 in the present study. female sexual function index (fsfi): fsfi is a likert-type scale consisting 19 items and evaluating female sexual dysfunction. fsfi was developed by rosen et al., in 2000 and cronbach’s alpha coefficient was found as 0.82(12). turkish validity and reliability analysis of the scale was conducted by öksüz and malhan in 2005 and cronbach’s alpha coefficient was found as 0.95(13). the index consists of six individual titles as desire, arousal, lubrication, orgasm, satisfaction, and pain. each title is scored between 0/1-6 points. the lowest score is two and the highest score is thirty six. high score refers to a better function(12,13). in the study conducted by rosen et al., (2000) and taş et al., (2006), functional condition was classified as good if fsfi score is > 30, as moderate if between 23-29, as poor if < 23(12,14). existence of sexual dysfunction is accepted in women who received 23 points and less in this study in which cronbach’s alpha coefficient was 0.93. data assessment the data were analyzed by using spss statistics version 22.0 (ibm corp., armonk, new york,usa). the data were evaluated by using number, percentage, mean, median, and spearman’s correlation analysis. multiple linear regression analyses backward method were used to test the relation between the determined dependent and independent variables. the extraction value was taken as 0.10. the results for other statistical analyzes were evaluated at 95% reliability level, and the significance was set to p < 0.05. in the study, independent variables, which were thought to be effective on dependent variables, were evaluated by using multiple regression analysis. results average age of the women participating in the study was 37.3 ± 1.02. mean body mass index of the women was 26.3 ± 5.41. average marriage age of the women was 20.3 ± 3.43 and average duration of marriage was 16.9 ± 1.14 years. mean pregnancy number of the women was 2.5 ± 1.75 and 18.5% of the women stated to have intentionally an abortion at least once, and 36.2% had spontaneous abortion at least once. it was determined that 22.1% of the women participating in the study had ui for 3-5 years and 15.1% had ui for six years and a longer time. 45.6% of women suffering from ui were affected by sexual life, and 68.2% did not consult a physician because of ui (table 1). it was determined that 53.9% of the women participating in study had mild incontinence, 40.6% had moderate table 1. distribution of women’s fsfi scores in terms of severity of urinary incontinence duration of ui diagnosis n (n=384) % less than 1 year 126 32.8 1-2 years 115 29.9 3 -5 years 85 22.1 6 years and more 58 15.1 affected sexual life after ui yes 176 45,6 no 208 54.2 consulting a physician due to affected sexual life (n=176) yes 56 31.8 no 120 68.2 severity of incontinence n (n=384) % fsfi score distribution test mild (1-2 points) 207 53.9 16.6 ± 6.02 moderate (3-6 points) 156 40.6 16.9 ± 6.64 χ² = 7.942 severe (8-9 points) 14 3.6 16.4 ± 8.51 p = .039 very severe (12 points and higher) 7 1.8 12.6 ± 1.14 table 2. distribution of women’s fsfi scores in terms of severity of incontinence sexual dysfunctıon in urınary incontınence -zincir et al. sexual dysfunction and andrology 194 incontinence, 3.6% had severe incontinence, and 1.8% had very severe incontinence. a significant correlation was found between isi score and fsfi score (p < .05) accordingly, fsfi mean score of the women with very severe ui was lower and sexual 1function was worse (table 2). categorical variables were defined as dummy variable. in table 3, it was found that there was a significant correlation between variables model 1fsfi (r2 = 0.082 f value= 7.860, p < 0.001), model 2-desire (r2 = 0.200 f value=24.987, p < 0.001), model 3arousal (r2 = 0.029 f value=6.762, p < 0.001), model 4 –lubrication (r2 = 0.126 f value = 12.016, p = 0.001), model 5 -orgasm (r2 = 0.082 f value = 9.606, p < 0.001), model 6 -satisfaction (r2 = 0.038 f value = 5.984 , p < 0.001), and model 7-pain (r2 = 0.122 f value = 14.309, p < 0.001) (table 3). there was a positive and weak correlation between isi scores and age, duration of marriage, and number of pregnancy of the women who participating in the study; and a positive and very weak correlation between isi scores and body mass index and spontaneous abortion (p < .05). according to this, severity of incontinence increased as age increased, body mass index, number of pregnancy, and number of spontaneous abortion increased, and duration of marriage increased. in addition, there was no correlation between intentionally having an abortion and isi score (p > .05). a positive and weak correlation was found between fsfi score and age of the women participating in the study; and a positive and very weak correlation between fsfi score and body mass index, duration of marriage, and number of pregnancy (p < .05). accordingly, sexual function decreased as age increased, duration of marriage increased, body mass index and number of pregnancy increased (table 4). discussion ui is a medical problem which affects women from all ages and is seen widely, and a condition that affects women in terms of physical, hygienic, psychosocial, economic, and sexual aspects. ui is also one of health problems that may influence all subscales within the scope of life quality and is experienced for a long time. koçak et al., determined that 79.8% of women who were 18 and older had mild urinary incontinence, 15.7% had moderate urinary incontinence, and 4.5% had severe urinary incontinence(15). in this study, 53.9% of the women were found to have mild urinary incontinence, 40.6% moderate urinary incontinence, 3.6% severe urinary incontinence, and 1.8% very severe urinary incontinence (table 2). 22.1% of the women who participated in the study were also determined to have ui for 3-5 years and 15.1% had for six years and more (table 1). the reason behind why results of moderate level in this study were found to be higher compared to the other study was thought to be age factor and that they experienced ui for a long time. as severity of ui increases, sd increases. according to statement of önem et al., ui and pelvic organ prolapse are found to be primary among risk factors causing sd in women(16). it was reported that ui had negative impacts on female sexual functions and prevalence of sexual dysfunction in this patient group ranged between 26% and 43% (6,17). prevalence of sd in the study conducted by özerdoğan et al., was determined to be 4.290 times more frequent in those with ui compared to those without ui(18). in the study conducted by coyne et al., on ui and sexual dysfunction, they reported that the women without incontinence problem had sexual intercourse more frequent than those with incontinence problem (91% 50%), their sexual desires decreased depending on incontinence, and they felt embarrassment because of incontinence and this caused a decrease in their body images(19). while van balken et al., reported that even independent variables dependent variables model 1-total fsfi model 2-desire model 3-arousal β* se t p β* se t p β* se t p age 0.658 0.106 3.947 .001 -0.532 0.034 -3.426 .001 0.172 0.025 3.226 .001 bmi 0.109 0.063 2.060 .040 _ _ _ _ _ _ _ _ number of live birth 0.123 0.353 1.777 .076 _ _ _ _ _ _ _ _ spontaneous abortion -0.186 0.425 -3.529 .001 0.210 0.137 4.289 .001 0.145 0.323 -2.723 .007 type of marriage -0.592 0.102 -3.303 .001 0.688 0.031 4.351 .001 _ _ _ _ model, adjusted r2 = 0.082 model, adjusted r2 = 0.200 model, adjusted r2 = 0.029 f value = 7.860, p < 0.001 f value = 24.987, p < 0.001 f value = 6.762, p < 0.001 model 4lubrication model 5 –orgasm model 6-satisfaction β* se t p β* se t p β* se t p age 0.968 0.083 5.948 .001 0.699 0.066 4.203 .001 _ _ _ bmi 0.094 0.050 1.836 .067 0.106 0.039 2.022 .044 0.113 0.040 2.134 033 number of live birth 0.137 0.277 2.032 .043 _ _ _ _ 0.122 0.176 2.249 .025 spontaneous abortion -0.209 0.333 -4.080 .001 -0.207 0.265 -3.940 .001 -0.161 0.269 -3.084 .002 type of marriage -0.993 0.080 -5.676 .001 -0.616 0.060 -3.627 .001 _ _ _ _ model, adjusted r2 = 0.126 model, adjusted r2 = 0.082 model, adjusted r2 = 0.038 f value = 12.016, p < 0.001 f value=9.606, p < 0.001 f value = 5.984 , p < 0.001 model 7pain β* se t p age 0.776 0.076 4.768 .001 bmi _ _ _ _ number of live birth _ _ _ _ spontaneous abortion -0.227 0.306 -4.419 .001 -0.661 0.069 3.988 .001 model, adjusted r2 = 0.122 f value = 14.309, p < 0.001 table 3. the effect of variables of age, bmi, number of live birth, spontaneous abortion and type of marriage on fsfi total and subgroup score sexual dysfunctıon in urınary incontınence -zincir et al. vol 15 no 04 july-august 2018 195 women experiencing less problems concerning urinary system had high levels of sexual dysfunction(20), handa et al., reported that sexual anorexia, vaginal dryness, and sexual pain disorders were more prevalent in women with severe ui(21). pathiraja et al., reported that the prevalence of women with incontinence was 10%, with stress and urge incontinence was 29.9%.(22). it was found in this study that 45.6% of women with ui were affected by sexual life (table 1) and there was a significant correlation between isi score and fsfi score (p < .05) (table 2). accordingly, it can be asserted that fsfi mean score of the women with very severe urinary incontinence was lower and their sexual functions were poor. a significant correlation was found between model 1-7 fsfi and independent variables in women with ui (table 3) (p < .05). there was a significant correlation between isi and subscale desire of fsfi (p < .001). almost half of the women stated their sexual lives were affected and therefore they did not consult a physician (table 1). this might be associated with decrease of sexual desire and the fact that the women did not consider it as a problem. as a result of their study, beji et al., determined that sexual lives of 43.7% of the women were affected by ui, the women tried different ways for having their husbands not to recognize this problem, and endeavored to postpone sexual intercourse(23). as development level of countries increases, status of woman rises and as status of woman increases, prevalence of sd may vary because woman makes healthy decision about her own body. in above-mentioned numerous studies, in studies conducted in both turkey and in several countries of the world, prevalence sd confronts us as an important health problem having a prevalence seen in more than half of women and waiting for solution. however, the reason behind why women did not consult a physician and seek for solution might be that sexual issues in turkish society are considered as a taboo due to both religious and cultural reasons. sd are affected by several independent factors such as age, chronic diseases, bmi, parity, type or time of marriage. age among these independent factors is defined as the most important factor having an effect on female sexual dysfunction(6). as well as decrease in functional capacity of tissues and organs with increased age, increasing number of birth and hormonal changes may cause sexual dysfunction in advanced ages compared to young age(6,24). prevalence of female sd increases with age and chronic diseases(25,26). in compliance with the literature, it was determined that there was a positive correlation between fsfi and isi score and age (table 4) and sexual lives of almost half of women were affected (table 1). frequent urinary incontinence in elderly population is associated with age-dependent changes such as decreased estrogen, decreased capacity of bladder, and impairment in ability to urinate. a significant correlation was found between bmi, number of live birth, spontaneous abortion, and type of marriage, which were thought to be effective on dependent variables in the study, and independent variables (model 1fsfi, r2 = 0.082 f value = 7.860, p < 0.001). in the study conducted by gunhilde et al., on 140 women, they determined that mean bmi was 27.2 (kg/m2), was 29 (kg/m2) in women with incontinence, and 25.4 (kg/ m2 ) in continent women(27). in the study conducted by koçak et al., on 1012 women aged between 18-92 years, bmi of 31.3% of women with incontinence was reported to be over 25 (kg/m2) and bmi was lower than 25 (kg/m2) in 14.5%(28). fertility process causes some permanent and temporary changes in reproductive organs. these experienced changes; some special cases such as frequent, many, early and advanced age pregnancies, difficult delivery, interventional birth may influence sexual life because of risk for damaging on reproductive organs(29). different results are remarkable in studies conducted in order to determine correlation between fertility and sd. while superfecundity was determined as a risk factor in terms of sd in most of studies supporting our results(30), there was no correlation between fertility and sd in certain studies(31). the reason behind why these results are different might be the effect of socio-cultural characteristics of sample in the study. in addition, higher prevalence of sd in women married via prearranged marriage can be explained by these women’s possibility to have low educational level and low social status in general. almost half of women with ui were determined to have moderate and more severe urinary incontinence. a significant correlation was found between isi score and fsfi score. age, bmi, parity, and type of marriage were determined to influence total fsfi score of the women with ui. in accordance with these results; -women with ui having the risk factors of sexual dysfunction should be early diagnosed and multidisciplinary approach should be considered for those women to prevent severe sexual problems. -it will be beneficial to conduct studies to be planned about sexual consultancy and sexual education on groups showing different ethnic and socioeconomic structure, and different settlement (rural, urban) characteristics. -training programs and psychological counseling services increasing sexual self-confidence, sexual self-efficacy, and marital satisfaction levels of married individuals can be developed. -it is recommended for healthcare personnel to know the effect of culture on treatment of diseases and accordingly to give care individuals. table 4. correlation analysis of women’s some characteristics, isi and fsfi scores characteristics correlation level of isi score* p value correlation level of fsfi score* p value age .280 .201 .001 .001 body mass index .160 .168 .002 .001 duration of marriage .304 .001 .168 .001 number of pregnancy .290 .001 .115 .025 number of spontaneous abortion .148 .029 .004 .571 *spearman’s correlation analysis. sexual dysfunctıon in urınary incontınence -zincir et al. sexual dysfunction and andrology 196 limitations of the study domestic life and sexual life are regarded as a taboo in culture of turkish society and what are experienced in this aspect are kept in family. for this reason, results of the study cannot be generalized to all women with ui. however, it is important because the number of similar studies conducted in turkey is limited and also understanding problems in domestic life and sexual lives of these families will facilitate helping these families. acknowledgement this research was presented orally at international conference on nursing (icon 2017). conflicts of interest the authors have no conflict of interest to declare. references 1. biri a, durukan e, maral i et al. incidence of stress urinary incontinence among women in turkey. int urogynecol j pelvic floor dysfunct. 2006;17: 604–10. 2. van der vaart ch, lamers bhc, heintz apm. feasibility and patient satisfaction with pelvic organ prolapse and urinary 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dysfunction among turkish women attending a maternity and gynecology outpatient clinic. sex disabil. 2011; 29:37786. 31. güvel s, yaycıoğlu ö, bağış t, savaş n, bulgan e, özkardeş h. evli kadınlarda cinsel fonksiyonlara etkin faktörler. türk üroloji dergisi. 2003; 29: 43-8. sexual dysfunction and andrology 198 validity of neutrophil gelatinase associated lipocaline as a biomarker for diagnosis of children with acute pyelonephritis azar nickavar1, baranak safaeian2*, ehsan valavi3**, farhad moradpour4 purpose: novel biomarkers have been investigated for various renal disorders, including urinary tract infection (uti). the aim of this study was to assess whether urine neutrophil gelatinase associated lipocaline (ngal), could represent a reliable biomarker for diagnosis and treatment of children with acute pyelonephritis (apn). materials and methods: a total of 37 children (32 females, 5 males) with apn were included in this prospective study. urine ngal was measured before and 5-7 days after antibiotic treatment in the uti group, using elisa kit and compared with 26 (8 females, 18 males) control group children admitted for other bacterial infections. results: mean age of the uti group was 39 ± 28 months, compared to 43.6 ± 31.5 months for the control group with no statistically significant difference. median urine ngal level was significantly higher in patients with apn than the other subjects [0.48 (interquartile range (iqr): 0.15-0.72) vs. 0.065 (0.01-0.24), p = .001], and decreased significantly after antibiotic treatment (p = .002). using a cutoff of 0.20 ng/ml, sensitivity and specificity of urine ngal were 76% and 77% for prediction of apn, respectively. the area under the roc curve (auc) for urine ngal was 0.75 (ci= 0.61-0.88), suggesting urine ngal as a relatively good predictive biomarker of apn. conclusion: urine ngal is a good biomarker for diagnosis and treatment monitoring of apn in children. keywords: ngal; acute pyelonephritis; children; diagnosis; treatment introduction urinary tract infection (uti) is one of the most common serious bacterial infections in early life. early diagnosis and treatment of acute pyelonephritis (apn) is important to prevent its long-term complications, including renal scars, hypertension, and chronic renal failure(1) . however, more severe forms of uti may cause dehydration and subsequent prerenal azotemia(2). although urine culture has been considered the gold standard test for diagnosis of uti, positive culture requires 2–3 days for identification of the responsible organism with false positive and negative results(3). in addition, sensitivity and specificity of urinary tract symptoms, pyuria, nitrite test, leukocyte esterase (le), wbc, esr, and crp are low and do not accurately localize upper and lower uti(4-7). dmsa scan have been considered as the gold standard test for diagnosis of apn in recent years. however, based on new guidelines for the evaluation of apn, dmsa scan has been recommended for screening of renal damage 3-6 months following the acute phase of infection(8). therefore, it is necessary to develop a sensitive, rap1associate professor, pediatric nephrology department, aliasghar children's hospital, iran university medical sciences, tehran, iran. 2 assitant professor, division of pediatric nephrology, neonatal and children's health research center, golestan university medical sciences, golestan, iran. 3 associate professor, abuzar children's hospital, chronic renal failure research center, ahvaz jundishapur university of medical sciences, ahvaz, iran. 4 social determinants of health research center, kurdistan university of medical sciences, sanandaj, iran. * correspondence: neonatal and children's research health center, golestan university of medical sciences, golestan, iran. email: baranak 54 @yahoo.com or. **correspondence: abuzar children's hospital, chronic renal failure research center, ahvaz jundishapur university of medical sciences, ahvaz, iran. email: dr_ehsan_valavi@yahoo.com. received april 2016 & accepted september 2016 id and noninvasive test with therapeutic implications for early diagnosis of apn, especially in suspicious patients(9). neutrophil gelatinase associated lipocalin (ngal) is a recently investigated biomarker for diagnosis of acute kidney injury. it is a component of the innate immune system(6), which reduces bacterial growth in the early phase of inflammation(5), and has been identified in different human tissues, including renal proximal tubules and neutrophil granules(9,10,11). increased urine ngal concentration facilitated rapid diagnosis of apn in the absence of acute kidney injury and chronic kidney disease in the recent investigations (6,9,10). the aim of this study was to determine the value of urine ngal for early prediction of children with apn, compared to the other bacterial infections. materials and methods this is a hospital based case-control study, conducted over a 1-year period between 2014 and 2015. it was approved by the institutional ethics committee and informed consent was obtained from parents. inclusion criteria consisted of 37 consecutive children less than 12 years admitted for apn with no other infectious pediatric urology vol 13 no 05 september-october 2016 2860 or inflammatory conditions (case group). a total of 26 age matched children admitted for other bacterial infections such as meningitis, pneumonia, septicemia or septic arthritis with no history of urological complaints were considered as control group. apn was defined as positive urine culture (any growth in suprapubic aspiration, > 105 cfu/ml of a single pathogen in urine bag collection, or > 104 cfu/ml by uretheral catheterization) associated with fever >38.5°c, leukocyte count more than the normal value according to age, positive crp, increased esr, and pyuria (urine wbc > 5/hpf). patients with known urologic or anorectal malformations, decreased renal function, recent antibiotic treatment, recent history of urological intervention, single kidney, associated infections and inflammatory disorders, neurologic disorders, and immunodeficiency were excluded from the study. based on new guidelines, dmsa scan was performed in patients with abnormal ultrasound, atypical uti, or confirmation of suspicious apn, which showed pyelonephritic changes as focal or diffuse areas of decreased cortical uptake, with the preservation of renal contour in 60% of patients(8). urine sample was obtained in both groups before antibiotic treatment and 5-7 days after treatment in the uti group, and frozen at –80°c. urine ngal was measured using a commercially available elisa kit (bioporto diagnostics, gentofte denmark), according to the manufacturer's instructions, and expressed as ng/ml. statistical analysis sample size was calculated based on the previous study(9) with sensitivity and specificity of 90 and 92%, respectively. it was determined by 0.8 estimated power and 95% confidence level. statistical analysis was performed using spss software version 22 (chicago, il, usa). normality of continuous variables was assessed by kolmogorov-smirnov test. normally distributed continuous variables were assessed by independent sample t-test, whereas mann-whitney u test was used for group comparison of nonnormal continuous variables. chi-square test was used to evaluate qualitative binary data. predictive factors of apn were assessed by univariate and multivariate analysis on variables with p-value ≥ 0.2. crude and adjusted or were obtained by stepwise backward logistic regression. removal probability ˂ 0.1 was considered for stepwise analysis. receiver operating curve (roc) analysis was used to determine optimal cot-off point of sensitivity and specificity. comparison of roc curve has also been performed by stata se software version 11. case control p-value subject (%) 37(59) 26(41) ngal ± sd .47 ± .34 .22 ± .34 0.001a age ± sd 39.0 ± 28 43.6 ± 31.5 0.55a fever ± sd 38.3 ± .81 38.6 ± 0.36 0.029a wbc ± sd 13827 ± 5170 12538 ± 4623 0.3b esr ± sd 43 ± 22 37 ± 19 0.27 b male/female (%) 5/32(13.5/86.5) 18/8(69/31) <0.001c antibiotic administration (%) 23 (62) 19 (73) 0.366c table 1. demographic and clinical characteristics of the study groups a mann-whitney u test, b independent t test, c chi-square test univariable analysis multivariable analysis or(ci) p adjusted or(ci) p ngal 8.9(1.67-47.2) 0.01 5.2(0.74-35) 0.09 age 0.99(.9761.01) 0.54 fever 0.49(0.21-1.1) 0.085 0.36(0.13-1.006) 0.05 wbc 1 0.3 esr 1.01(0.98-1.04) 0.27 asex 0.069(0.02-0.24) <0.001 0.079(0.02-0.31) < 0.001 antibiotic administration 1.6(0.55-4.9) 0.37 afemale is reference table 2. univariate and multivariable analysis of characteristics associated with the presence of acute pyelonephritis urine ngal in acute pyelonephritis-nickavar et al. pediatric urology 2861 results totally, 37 patients in the apn group and 26 in the control group were enrolled in this study. mean age of cases was 39 ± 28 months compared to 43.6 ± 31.5 months in the control group, with no significant difference (p = 0.55). female gender was higher in apn compared to the control group (86.5% vs. 31%). median urine ngal level was significantly higher in patient with apn than the control group [(0.48 (interquartile range (iqr): 0.15-0.72) vs. 0.065 (0.01-0.24), p = .001]. table 1 demonstrates demographic and laboratory variables in the cases and controls. mean initial urine ngal was 0.46 ± 0.35 and decreased significantly to 0.25 ± 0.27 after antibiotic treatment (p = .002). urine ngal and gender were associated in univariate analysis. however, fever and gender were significant independent variables in multivariate analysis (table 2). the best cutoff level of urine ngal for predicting apn was 0.2 ng/ml. using these cutoff points, the sensitivity and specificity of urine ngal were 74% and 67%, respectively (table 3). the area under the roc curve (auc) for urine ngal was 0.75 (ci= 0.61-0.88), suggesting urine ngal as a relatively good predictive biomarker of apn (figure 1). there was no significant difference in the auc between reference final model, fever (p = .08) and urine ngal (p = .12) (table 3). urine ngal in acute pyelonephritis-nickavar et al. discussion this study was performed to evaluate the potential value of urine ngal for prediction of children with apn. we confirmed significant increase of urine ngal during the acute phase of apn, which wasndowngraded with the appropriate treatment. the value of serum and urine ngal for diagnosis and therapeutic monitoring of febrile uti have been recently reported. in a similar study, arambasic et al. showed higher level of urine ngal in children with apn compared to acute cystitis and other febrile infections. it was considered a useful biomarker for diagnosis of apn in children(12). in an experimental model of apn, urine ngal increased in the early phase of acute inflammation following cortical injection of ecoli, suggesting urine ngal as a new biomarker of apn(13). urine ngal was a specific test for evaluation of apn in ghasemi et al. study, compatible with dmsa scan grading and crp level. they recommended measurement of other common biomarkers such as esr, leukocyte count, and crp combined with urine ngal for the prediction of renal parenchymal involvement(14). in lee et al. study, urine ngal was in accordance to the acute photon defects of dmsa renal scan, obviating imaging studies in children with low urine ngal level(9). dmsa scan was performed in half of our patients, and nonsignificant correlations may not reflect the true incidence. however, urine ngal increased in both upper and lower uti, with no differentiation between these two groups in the other reports(3). similar to our study, urine ngal significantly decreased 3–4 days after antibiotic treatment(7,9) and have been considered as predictive biomarker for therapeutic monitoring of apn(6). persistently elevated urine ngal may be associated with treatment unresponsiveness in children with acute febrile utis(7). we found urine ngal as a relatively sensitive (74%), specific (67%) and accurate test (auc = 0.75) for diagnosis of children with apn, which was similar to yim et al. study with 75% sensitivity and 73.7% specificity(6). however, it was a more valid biomarker for diagnosis of uti with 97% sensitivity and 76% specificity in yilmaz et al. report(5). urine ngal had lower or equal sensitivity and specificity for diagnosis of apn, compared to leukocyte esterase; 99% versus 70%, bacteriuria; 81% versus 83%(8), urine nitrite; 53% versus 98%, and pyuria; 73% versus 81% in our study, respectively. increased serum ngal concentration have been also detected as an early biomarker of apn in patients with acute bacterial infections(6). serum ngal was a rapid table 3. sensitivity, specificity and area under the curve (auc) for optimal cut-off values of ngal, fever and sex compared with full model for diagnosis of acute pyelonephritis sensitivity specificity auc cut off p-value full model 97.3 69.23 84(0.72-0.95) reference ngal 75.68 76.92 75(0.61-0.88) > = 0.2 0.12 fever 54.05 88.46 66(0.52-0.79) 0.08 sex 86.5 69.2 figure 1. diagnostic characteristics of ngal, fever in comparison with the full model (ngal, fever, and sex) vol 13 no 05 september-october 2016 2862 and sensitive test for prediction of apn with a significant correlation with dmsa renal cortical defect in the acute phase of febrile uti in seo et al. study(7), and excluded radiologic evaluation in lower level. other studies showed a correlation between plasma ngal level with duration of fever, wbc, crp, and creatinine level(15). in conclusion, urine ngal was a relatively sensitive and accurate biomarker for differentiation of apn from other infectious disorders. however, compared to the other parameters, we recommended screening of apn with simple inexpensive traditional urinalysis, and urine ngal is suggested to identify highly suspicious patients with false negative results, differentiate contamination from urinary tract infection, in addition to serve as a therapeutic biomarker. this study provides a small piece of evidence that urine ngal excretion could be considered in further and larger populations to confirm the potential application of this biomarker. conclusions: urine ngal is a good biomarker for diagnosis and treatment monitoring of apn in children. acknowledgement this study was supported by neonatal and children's research health center, golestan university of medical sciences, golestan, iran. conflict of interest the authors have declared that no conflict of interest exists. references 1. nickavar a, sotoudeh k. treatment and prophylaxis in pediatric urinary tract infection. int j prev med. 2011; 2:4-9. 2. petrovic s, bogavac-stanojevic n, pecoantic a, ivanisevic i, kotur-stevuljevic j, paripovic d, sopic m, jelic-ivanovic z. clinical application neutrophil gelatinaseassociated lipocalin and kidney injury molecule-1 as indicators of inflammation persistence and acute kidney injury in children with urinary tract infection. biomed res int. 2013;2013:947157. 3. urbsc’hat a, obermüller n, paulus p, reissig m, hadji p, hofmann r, geiger h, gauer s.upper and lower urinary tract infections can be detected early but not be discriminated by urinary ngal in adults. int urol nephrol. 2014;46:2243-9. 4. kim bh, yu n, kim hr, yun kw, lim is, kim th, lee mk. evaluation of the optimal neutrophil gelatinase-associated lipocalin value as a screening biomarker for urinary tract infections in children. ann lab med. 2014;34:354-9. 5. yilmaz a, sevketoglu e, gedikbasi a, karyagar s, kiyak a, mulazimoglu m, aydogan g, ozpacaci t, hatipoglu s. early prediction of urinary tract infection with urinary neutrophil gelatinase associated lipocalin. pediatr nephrol. 2009;24:2387-92. 6. yim he, yim h, bae es, woo su, yoo kh. predictive value of urinary and serum biomarkers in young children with febrile urinary tract infections. pediatr nephrol. 2014;29:2181-9. 7. seo wh, nam sw, lee eh, je bk, yim he, choi bm. a rapid plasma neutrophil gelatinaseassociated lipocalin assay for diagnosis of acute pyelonephritis in infants with acute febrile urinary tract infections: a preliminary study. eur j pediatr. 2014;173:229-32. 8. elder js. urinary tract infection. in: kliegman rm, stanton bf, st geme jw, schor nf. nelson textbook of pediatrics. philadelphia, elsevier publication. 2016. 2559-61. 9. lee he, kim do k, kang hk, park k.the diagnosis of febrile urinary tract infection in children may be facilitated by urinary biomarkers. pediatr nephrol. 2015;30:123-30. 10. lee he, lee sh, baek m, choi h, park k.urinary measurement of neutrophil gelatinase associated lipocalin and kidney injury molecule-1 helps diagnose acute pyelonephritis in a preclinical model. j biomark. 2013; 2013:413853. 11. nickavar a, safaeian b, sadeghi-bojd s, lahouti harah dashti a. urine neutrophil gelatinase associated lipocalin to creatinine ratio: a novel index for steroid response in idiopathic nephrotic syndrome. indian j pediatr. 2016; 83: 18-21. 12. arambašić j, mandić s, debeljak ž, mandić d, horvat v, šerić v. differentiation of acute pyelonephritis from other febrile states in children using urinary neutrophil gelatinaseassociated lipocalin (ungal). clin chem lab med. 2016; 54:55-61. 13. kuroyanagi y, kusaka m, mori t, ishikawa k, shiroki r, kurahashi h, hoshinaga k. increased urinary neutrophil gelatinase associated lipocalin levels in a rat model of upper urinary tract infection. j urol. 2009;181:2326-31. 14. ghasemi k, esteghamati m, borzoo s, parvaneh e, borzoo s. predictive accuracy of urinary neutrophil gelatinase associated lipocalin (ngal) for renal parenchymal involvement in children with acute pyelonephritis. electron physician. 2016; 25:1911-7. 15. sim jh, yim he1, choi bm, lee jh, yoo kh. plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections. pediatr res. 2015;78:48-55. 16. hatipoglu s, sevketoglu e, gedikbasi a, yilmaz a, kiyak a, mulazimoglu m, aydogan g, ozpacaci t. urinary mmp-9/ ngal complex in children with acute cystitis. pediatr nephrol. 2011; 26:1263-8. urine ngal in acute pyelonephritis-nickavar et al. pediatric urology 2863 miscellaneous a comparative study on the efficacy of four types of circumcision for elderly males with redundant prepuce jiagui mu1#, li fan1#, duo liu1**, dongsheng zhu2*, purpose: circumcision is a common human urologic surgery performed in males with redundant prepuce to prevent the transmission and reduce the risk of urologic diseases. however, the optimal circumcision method for elderly men remains to be determined. herein, the current study was conducted to characterize the efficacy of four different kinds of circumcision for elderly males with redundant prepuce. methods: this retrospective study included 132 elderly males diagnosed with redundant prepuce who underwent circumcision at the outpatient department. among them, 38 cases were subjected to traditional surgery (group a), 23 cases to sleeve circumcision (group b), and 42 cases to shang ring circumcision (group c) and 29 cases to suturing device circumcision (group d). subsequently, the operation time, loss of blood, postoperative pain, complications, wound healing, and the satisfaction were respectively compared and analyzed. results: the operation time of these 4 groups was calculated to be 27.3 ± 2.39 min, 30.4 ± 2.23 min, 6.3 ± 1.33 min, 7.6 ± 1.29 min, in group a, group b, group c, group d, respectively (p < 0.05). besides, the loss of blood was 15.6 ± 2.84 ml, 11.8 ± 1.73 ml, 1.3 ± 0.44 ml, 3.7 ± 1.41 ml, respectively (p < 0.05). the elderly males who underwent shang ring circumcision exhibited the highest postoperative pain score, the longest pain duration, the longest healing time, the lowest recovery satisfaction rate and the highest operation experience satisfaction rate (p < 0.05). conclusion: taken together, all four types of male circumcision present with advantages and drawbacks. the traditional male circumcision and sleeve circumcision led to longer operation time and more bleeding, but no additional medical equipment was needed. meanwhile, the shang ring circumcision caused the shortest operation time and the least bleeding, accompanied by the longest pain duration and recovery time. therefore, the application of sleeve circumcision or a suturing device was recommended for elderly males suffering from redundant prepuce. keywords: redundant prepuce; male circumcision; elderly; pain; complication. introduction redundant prepuce is one of the most common clinical disease in urology which affects normal penile development. patients suffering from redundant prepuce often elect for operative treatment, and male circumcision is the most widely applied method globally.(1) male circumcision also serves as risk-reduction for several diseases, such as urinary tract infections, pyelonephritis, penile cancer, cervical cancer in female partners, and some sexually transmitted diseases. recent advancements have given rise to a plethora of male circumcision methods, such as the traditional male circumcision, sleeve circumcision, shang ring (sr) circumcision and suturing device circumcision. a significant proportion of males undergo circumcision, with prevalence reaching up to 30% worldwide. how1 department of urology, the second people’s hospital of lianyungang, no.161, xingfu road, haizhou district, lianyungang, 222000, p.r.china. 2 tianjin medical university, no. 22, qixiangtai road, tianjin, 300211, p.r. china *correspondence: tianjin medical university, no. 22, qixiangtai road, tianjin, 300211, p.r. china tel: +86 23702280668; e-mail: zhudongsheng@tum.edu.cn. **department of urology, the second people’s hospital of lianyungang, no.161, xingfu road, haizhou district, lianyungang, 222000, p.r.china. tel: +86 88575042; e-mail: jsslygld@163.com. # these authors are co-first authors. received november 2018 & accepted july 2019 ever, only 5% of the male populace in china have been circumcised, which is much lower compared to the rest of the world.(2) these remarkably low male circumcision rates indirectly explain the extremely large number of elderly males suffering from redundant prepuce in china. the glans cannot be exposed naturally after urination in redundant prepuce, and the residual urine is caught between the prepuce and the glans, which results in the accumulation of smegma. if elderly males do not clean cautiously, smegma buildup may cause balanitis and retrograde urinary tract infections, sometimes leading to penile malignant tumors.(3) with the gradual aging of society and improvements in health awareness, progressively increasing number of elderly males are undergoing circumcision in clinical scenarios. however, until recently, no study has compared the efficacy of male circumcision modalities in the elderly. herein, the urology journal/vol 17 no. 3/ may-june 2020/ pp. 301-305. [doi: 10.22037/uj.v0i0.4973] current study aims to examine the operation time, intraoperative blood loss, duration of postoperative pain, postoperative complications, complete healing time of the incision, and surgical satisfaction in order to evaluate the surgical outcomes of four different types of male circumcision, hoping to provide new insights for clinical urologists when offering circumcision to elderly males. materials and methods ethics statement the current study was conducted under the approval of the ethics committee of the second hospital of lianyungang. signed consents were obtained from all participants. patients a total of 132 elderly males with redundant prepuce undergoing circumcision at the outpatient department of the second hospital of lianyungang l between december 2014 and december 2017 were recruited for the current study. all included subjects were older than 65 years, aged 65-82 years. in accordance with the different surgical methods, patients were divided into the following groups: group a (traditional male circumcision, n = 38), group b (sleeve circumcision, n = 23), group c (sr circumcision, n = 42), and group d (suturing device circumcision, n = 29). all included patients were diagnosed with redundant prepuce, accompanied by various degrees of foreskin balanitis. among them, 13 patients suffered from diabetes and 6 patients presented with sexually transmitted diseases. the patients were recruited for the current study if they were at least 65 years old with a history of redundant prepuce, and were willing to participate in this study and sign the written informed consent. the exclusion criteria were as follows: 1) abnormal blood coagulation; 2) severe mental illness, cardiovascular diseases or other systemic intolerance surgery; 3) other congenital abnormalities of the penis, such as hypospadias or concealed penis; 4) local acute penile infection; or 5) poor blood sugar control. surgical procedures shang ring, thereafter referred to as sr (wuhu shengda medical treatment appliance technology co., ltd., wuhu city, anhui province, china), as a disposable, single-use device, was employed for circumcision of elderly males in group c. whereas, a one-time penile circumcision and suturing device (jiangxi yuanshenglang medical equipment technology co., ltd., yongfeng city, jiangxi province, china) was applied for the individuals in the group d. after skin preparation and draping, dorsal penile nerve block anesthesia was administered with 1% lidocaine. the operative methods of the 4 groups were in accordance with previous literature respectively, group a,(4) group b,(5) group c,(6) group d.(7) oral antibiotics were administered to all the patients 3 days prior to the operation. ibuprofen was administered, if post-surgery pain was significant. in addition, it was ensured that there was no bleeding or insufficient blood supply of the glans. the dressing was renewed every 24 hours after the surgery. evaluation of outcomes in order to evaluate clinical outcomes, we measured and recorded various intraoperative and postoperative parameters, including operative time, blood loss during operation, postoperative pain scores, wound healing time, complications and degree of satisfaction in all 4 aforementioned groups. the operation time was recorded from the initiation of the surgery to the end of surgery. intraoperative blood loss was measured using a piece of completely soaked gauze (5 cm × 5 cm), which represented an average carrying capacity of 5 ml blood.(8) the pain scores were calculated using the internationally recognized wong-banker face pain rating scale.(9) identification of sample size based on our pilot data, the sample size was estimated at a study power of 80% and a significance level of 5%. it was suggested that at least 22 patients were required per group. statistical analysis statistical analyses was performed using spss 17.0 statistical software (spss inc., chicago, il, usa). measurement data were presented as means ± standard devifour types of circumcision in the elderly males-mu et al. variables a group a (n = 38) group b (n = 23) group c (n = 42) group d (n = 29) p-value operation time (minute) 27.32 ± 2.39 30.39 ± 2.23 6.26 ± 1.33 7.62 ± 1.29 .000 mean ± sd (range) b (20 32) (26 36) (4 10) (6 12) loss of blood; ml 15.58 ± 2.84 11.78 ± 1.73 1.26 ± 0.44 3.72 ± 1.41 .000 mean ± sd (range) c (12 26) (9 15) (1 2) (2 8) 24h pain; score 2.76 ± 0.54 2.70 ± 0.55 4.05 ± 0.38 2.66 ± 0.55 .000 mean ± sd (range) d (1 4) (2 4) (3 5) (1 3) 7d pain; score 0.08 ± 0.27 0.17 ± 0.38 3.67±0.65 0.14 ± 0.35 .000 mean ± sd (range) e (0 1) (0 1) (1-4) (0 1) pain duration; day 2.95 ± 0.65 3.17 ± 0.78 6.83 ± 1.31 2.97 ± 0.73 .000 mean ± sd (range) f (2 5) (2 5) (3 8) (2 5) healing time; day 12.42 ± 1.69 11.61 ± 1.44 21.90 ± 4.26 12.24 ± 2.31 .000 mean ± sd (range) g (10 16) (9 16) (14 33) (9 20) table 1. comparison and quantitation of four types of circumcision in elderly males. a one-way analysis of variance (anova) followed by lsd test as post hoc test b lsd post hoc test: pa-b = .000, pa-c = .000, pa-d = .000, pb-c = .000, pb-d = .000, pc-d = .003; c lsd post hoc test: pa-b = .000, pa-c = .000, pa-d = .000, pb-c = .000, pb-d = .000, pc-d = .000; d lsd post hoc test: pa-b = .611, pa-c = .000, pa-d = .384, pb-c = .000, pb-d = .773, pc-d = .000; e lsd post hoc test: pa-b = .434, pa-c = .000, pa-d = .602, pb-c = .000, pb-d = .779, pc-d = .000; f lsd post hoc test: pa-b = .365, pa-c = .000, pa-d = .938, pb-c = .000, pb-d = .430, pc-d = .000; g lsd post hoc test: pa-b = .284, pa-c = .000, pa-d = .429, pb-c = .000, pb-d = .799, pc-d = .000. miscellaneous 302 ation (range: minimum maximum). one-way analysis of variance (anova) was adopted to compare the differences in the mean among the 4 groups, followed by an lsd post hoc test. meanwhile, the categorical data were expressed as numbers, which were analyzed by pearson's chi-square and bonferroni correction among 4 groups. the difference was statistically significant at p < 0.05. results after successful completion of all surgeries, the patients were followed up until the incision was completely healed. however, 5 patients were lost to follow-up, among whom 4 individuals belonged to group a and 1 to group c. the operation time was calculated to be 27.3 ± 2.39 min, 30.4 ± 2.23 min, 6.3 ± 1.33 min, 7.6 ± 1.29 min (p < .001), while the blood loss was 15.6 ± 2.84 ml, 11.8 ± 1.73 ml, 1.3 ± 0.44 ml, 3.7 ± 1.41 ml, (p < .001) in group a (traditional male circumcision), group b (sleeve circumcision), group c (sr circumcision), group d (suturing device circumcision), respectively. in addition, the 24-h and 7-day pain scores were determined to be 2.8 ± 0.54, 2.7 ± 0.55, 4.0 ± 0.38, 2.7 ± 0.55 (p < .001), and 0.08 ± 0.27, 0.17 ± 0.38, 3.67 ± 0.65, 0.14 ± 0.35 (p < .001), in group a, group b, group c, group d, respectively. the duration of pain was further analyzed to be 2.9 ± 0.65 d, 3.2 ± 0.78 d, 6.8 ± 1.31 d, 3.0 ± 0.73 d (p < .001) in group a, group b, group c, group d, respectively. healing time was additionally noted and revealed to be 12.4 ± 1.69 d, 11.6 ± 1.44 d, 21.9 ± 4.26 d, 12.2 ± 2.31 d in group a, group b, group c, group d, respectively (p < .001) (table 1). furthermore, the surgical complications in patients from the 4 groups were observed and analyzed. merely 1 case was found to be infected in group c, which did not occur in the patients of the remaining groups (p = .54). postoperative bleeding was observed in a total of 5 cases, among which 2 cases were in group a and 3 cases in group d (p = .10). it is noteworthy that edema was the most commonly diagnosed complication after male circumcision. totally, 8 cases were noted, with 2 cases in group a, 2 cases in group b, and 4 cases in group c (p = .38). besides, only 1 individual experienced incision dehiscence, who was in group c (p = .54) (table 2). additionally, we assessed the degree of satisfaction about the male circumcision after surgery in all groups. in total, 5 patients were lost to follow-up, with 4 cases in group a and 1 in group c. elderly males in group c were the most satisfied with the surgical procedures (p = .02), while being the least satisfied with the recovery process (p = .03). in term of the appearance, the patients in group a displayed the lowest satisfaction rate, but no statistical differences were identified among the 4 groups (p = .31) (table 3). discussion male circumcision is the operative-treatment of choice for redundant prepuce in the elderly. in addition to its use in redundant prepuce, male circumcision also has additional benefits of augmenting local hygiene, relieving discomfort, as well as reducing the risk of foreskin balanitis and urinary tract infections. furthermore, male circumcision can enhance the prevention of sexually transmitted diseases and even the incidence of spouse cervical malignancies.(10) circumcision is also applied for the treatment of premature ejaculation, a common sexual dysfunction in elderly males. the process of male circumcision possesses the ability to diminish the sensitivity of the glans, thereby effectively relieving the symptoms of premature ejaculation.(11,13) a recent survey established that 84.5% of elderly males between 60 69 years of age are sexually active, and so are the 31.1% of elderly males above the age of 80 years.(13) thus, it is of critical significance to explore the clinical values and efficacy of male circumcision in the elderly males. firstly, the key findings of the current study revealed that elderly males in the 4 different groups presented with significant differences in terms of operative time and blood loss. notably, group c (sr circumcision) exhibited the shortest operation time and the least blood loss, which was consistent with the results reported in previous studies.(5-7,14) in addition, patients in group c presented with the longest healing time, the most table 2. complications of four types of circumcision in elderly males. variables a group a (n = 38) group b (n = 23) group c (n = 42) group d (n = 29) p-value infection 0 0 1 0 .54 bleeding 2 0 0 3 .10 edema 2 2 4 0 .38 incision dehiscence 0 0 1 0 .54 a kruskal-wallis one-way anova variables a group a (n = 34) group b (n = 23) group c (n = 41) group d (n = 29) p-value operation experience; satisfaction/dissatisfaction; n 27/7 20/3 41/0 27/2 .02 recovery; satisfaction/dissatisfaction; n 29/5 20/3 25/16 23/6 .03 appearance; satisfaction/dissatisfaction; n 27/7 21/2 37/4 27/2 .31 a pearson's chi-square test and anova with bonferroni correction table 3. satisfaction evaluation of four types of circumcision in elderly males. four types of circumcision in the elderly males-mu et al. vol 17 no 03 may-june 2020 303 complications, and the most immense pain, which was different with some studies performed among adult patients.(18) in the clinical scenarios, the elderly are found with inherent characteristics: 1) they have a long history of male circumcision, and some patients suffer from severe local adhesion; 2) they experience years of repeated friction, and hyperplasia and hypertrophy occur in foreskin; 3) they have plenty of smegma and urine impregnation, rhagades, redness, and even skin ulceration; 4) the immune function is degraded due to old age, and some are diagnosed with diabetes. in regard to sr circumcision, some patients were still inflicted by incrustation and edema even after the sr was removed, due to the thicker foreskin in elderly males. however, group c also exhibited the longest healing time and pain duration, which may be attributed to the slow metabolism and weak healing ability. additionally, we evaluated the degree of satisfaction by comparing and analyzing the surgical experience, postoperative recovery, and appearance after healing. intraoperative anxiety in elderly males is usually dependent on operation time and the occurrence of bleeding, thus, the satisfaction in operation experience of patients in group c was the highest among the 4 groups owing to shorter operation times and less bleeding. however, longer recovery times and pain duration documented in the subjects also resulted in the most unfavorable recovery satisfaction in group c. a recent study conducted by lv et al. consistently reported that suturing device circumcision was associated with a pronounced decline in intraoperative and postoperative pain compared to sr circumcision using a satisfaction-evaluation study encompassing 942 patients.(16) the findings of the current study suggest that more emphasis should be laid on the preoperative examinations for prepuce with hyperplasia and hypertrophy, when determining the surgical modality for elderly males with redundant prepuce, in which case sr circumcision should be avoided. our discoveries also indicate that sleeve circumcision has an obvious superiority in elderly males with local prepuce with enlarged and increased veins. collectively, the patient demographics of elderly males should be clearly inspected, in order to opt for surgical methods with short operation and recovery times, due to heart burden, myocardial ischemia, severe angina pectoris, and even myocardial infarction caused by pain stimulation. nonetheless, the limited sample size and data collection from a single-center population may lead to deficiencies of the current study. despite these limitations, our findings shed light and provide clinical values on circumcision for elderly males with redundant prepuce, enlightening the urologists treating redundant prepuce. conclusions in summary, our observations and discoveries suggest that all 4 types of surgical methods have their own advantages and drawbacks. strikingly, the application of a suturing device or sleeve circumcision is recommended for the treatment of elderly patients with redundant prepuce. thereby, the sr circumcision associated with long healing time and short operation time should be carefully evaluated prior to the surgery. conflict of interest the authors declare no conflict of interest references 1. dunsmuir wd, gordon em. the history of circumcision. bju int. 1999;83 suppl 1:1-12. 5. ben kl, xu jc, lu l, et al. [male circumcision is an effective "surgical vaccine" for hiv prevention and reproductive health]. zhonghua nan ke xue. 2009;15:395-402. 6. kelly r, kiwanuka n, wawer mj, et al. age of male circumcision and risk of prevalent hiv infection in rural uganda. aids. 1999;13:399405. 7. tobian aa, adamu t, reed jb, kiggundu v, yazdi y, njeuhmeli e. voluntary medical male circumcision in resource-constrained settings. nat rev urol. 2015;12:661-70. 8. abdulwahab-ahmed a, umar a. dorsal slitsleeve technique for male circumcision. j surg tech case rep. 2014;6:46. 9. ma q, fang l, yin wq, et al. chinese shang ring male circumcision: a review. urol int. 2018;100:127-33. 10. han h, xie dw, zhou xg, zhang xd. novel penile circumcision suturing devices versus the shang ring for adult male circumcision: a prospective study. int braz j urol. 2017;43:736-45. 11. shen j, shi j, gao j, et al. a comparative study on the clinical efficacy of two different disposable circumcision suture devices in adult males. urol j. 2017;14:5013-7. 12. ye jj, lee kt, chou yy, sie hh, huang rn, chuang cc. assessing pain intensity using photoplethysmography signals in chronic myofascial pain syndrome. pain pract. 2018;18:296-304. 13. tobian aa, gray rh, quinn tc. male circumcision for the prevention of acquisition and transmission of sexually transmitted infections: the case for neonatal circumcision. arch pediatr adolesc med. 2010;164:78-84. 14. tian y, wazir r, wang k. male circumcision decreases penile sensitivity as measured in a large cohort. bju int. 2013;112:e2-3. 15. senel fm, demirelli m, misirlioglu f, sezgin t. adult male circumcision performed with plastic clamp technique in turkey: results and long-term effects on sexual function. urol j. 2012;9:700-5. 16. lee dm, nazroo j, o'connor db, blake m, pendleton n. sexual health and well-being among older men and women in england: findings from the english longitudinal study of ageing. arch sex behav. 2016;45:133-44. 17. wu x, wang y, zheng j, et al. a report of 918 cases of circumcision with the shang ring: comparison between children and adults. urology. 2013;81:1058-63. 18. peng yf, yang bh, jia c, jiang j. [standardized male circumcision with shang four types of circumcision in the elderly males-mu et al. miscellaneous 304 ring reduces postoperative complications: a report of 351 cases]. zhonghua nan ke xue. 2010;16:963-6. 19. lv bd, zhang sg, zhu xw, et al. disposable circumcision suture device: clinical effect and patient satisfaction. asian j androl. 2014;16:453-6. four types of circumcision in the elderly males-mu et al. vol 17 no 03 may-june 2020 305 case report a rare case report of undescended testis: both on one side davoud tasa1, ahmad fotoohi2*, farhang safarnejad3 , anvar elyasi4 undescended testis (udt) is a medical term that is used for any testis which is not in its normal place (bottom of the scrotum). udt can be classified as unilateral and bilateral. unilateral udt is more common than bilateral udt. there is a very rare condition in which both testicles are on the same side and have not descended. we report in this article a 3 years old boy presenting with a chief complaint of bilateral testicular mass absence. diagnostic evaluation revealed absent testes in the scrota. exploring laparoscopy was performed and a rare case of udt was diagnosed, in which both testicles were on the left side of the pelvis with two separate spermatic cord. the shorter spermatic cord was fixed on the left scrotum and the longer one was fixed on the right side. the testes were normal in follow up examinations. keywords: undescended testis; crossed testicular ectopia; cryptorchidism introduction the normal location of the testis is in the bottom of the scrotum.(1) undescended testis (udt), cryptorchidism, retention testis and male descending testis are medical terms that are used for any testis which is not in its normal place.(2) udt is a common male genitalia anomaly(3) by an incidence of 1-3% in term neonates and 30% in preterm neonate.(3,4) udt pathophysiology is not understood completely but variable genetic and hormonal factors have been suggested.(2,5) an important complication of udt is testicular malfunction especially in spermatogenesis and testicular cancer.(2) udt is categorized based on congenital or acquired, palpability, and unilateral or bilateral state. (1) udt can be classified as unilateral and bilateral. unilateral udt is more common than bilateral udt by a rate of 4:1. (6) there is a very rare condition in which both testicles are on the same side and have not descended. (7) we report in this article one of these rare cases, in which both testicles were on one side of the pelvis and not descended. based on our searches on medline, and pubmed and googlescholar only one similar case was reported by ebrahimi in 2010. case rport a three-year-old boy presented to our surgery clinic by a chief complaint of testicular absence. he was admitted for more diagnostic evaluation and therapeutic management. patient’s mother had no history of drug usage or x-ray radiation during pregnancy. she had another son without any medical problems. parents were not 1assistant professor , faculty of medicine, department of surgery, kurdistan university of medical sciences, sanandaj, iran. 2medical student, student research committee, kurdistan university of medical sciences, sanandaj, iran. 3assistant professor, faculty of medicine, department of surgery, kurdistan university of medical sciences, sanandaj, iran. 4assistant professor, faculty of medicine, department of surgery, kurdistan university of medical sciences, sanandaj, iran. *correspondence: medical student, student research committee, kurdistan university of medical sciences, sanandaj, iran tel: +989189792369. fax: 08733788930. e-mail: ahmadfotoohi@gmail.com. received may 2018 & accepted november 2018 figure 1. no testis in the right side of pelvic in laparoscopic view. arrow shows right inferior epigastric artery figure 2. both spermatic cord on the left side of the pelvis. both vas deferens inters into the left inguinal canal (red arrows). and left testis head is visibl in the proximal of canal (green arrow) urology journal/vol 17 no. 1/ january-february 2020/ pp. 105-106. [doi: 10.22037/uj.v0i0.4573] relatives. allergic and drug history were negative. on physical examination, he had no papable testes in either scrotum. other parts of the physical examination were normal. ultrasonographic evaluation of the abdomen, pelvic and scrota was performed. the radiologist reported bilateral empty scrota and no specific mass in the pelvis. multiplanar and multisequentional magnetic resonance imaging (mri) of the abdominopelvic area was performed to get more diagnostic data (figure 1). the report of the mri revealed an open left inguinal canal with the left testis adjacent to its superficial ring and an undetectable right testis. no other specific findings were noted. biochemical evaluation including complete blood count (cbc) and coagulative tests were normal. after medical consultations were obtained, the patient underwent laparoscopic surgery to check for the possible existence of the testes. entrance site was from the left inguinal. no testis was found on the right side (figure 2). after more probing, two separate spermatic cords were found on the left side (figure 3) and both testes were seen after applying different maneuvers. the left testis was observed in proximal part of the left inguinal canal and the right was seen in the abdomen. the right duct deferens was attached to the right testis and was free intra-abdominally and the left one was attached to the left testis and continued to the proximal of the left inguinal canal. both had separate arteries and veins. the testes were released from the abdominal wall . unlike the case reported by ebrahimi in 2010, our case had two separate spermatic cords (figure 4). after release, both testiss were descended into the scrotum via the left inguinal canal due to right spermatic cord shortness. the left testis was fixed in the left scrotum and the right testis was fixed in the right scrotum after passing the median raphe. . the longer spermatic cord belonged to the right scrotum and the shorter one was fixed on the left side. in the follow-up visits and doppler ultrasonography evaluation, testis size and the position was normal and testis remained viable at weeks 1, 4, and 8 and 16 after the operation. discussion udt is the most common disease in the field of children urology. it is often congenital but not always.(8) although udt is a common condition,; crossed testicular ectopia (cte) is a rare condition.(7) cte is defined as migration of one testis towards the opposite inguinal canal. in cte, both testes descend through a single inguinal canal resulting in an ipsilateral inguinal hernia and contralateral cryptorchidism. definite diagnosis is always made after operation.(9) three different types of cte are defined in the literature including: i. associated with an inguinal hernia alone; ii. associated with persistent mullerian remnants; iii. associated with other anomalies without mullerian remnants(7, 9) . here, we reported a very rare case of udt with cte, with two separate spermatic cords. both testes were fixed into the scrota and were kept alive successfully. rferences 1. niedzielski jk, oszukowska e, słowikowskahilczer j. undescended testis–current trends and guidelines: a review of the literature. arch med sci. 2016;12:667. 2. virtanen he, bjerknes r, cortes d, jørgensen n, meyts rd, thorsson av, et al. cryptorchidism: classification, prevalence, and long‐term consequences. acta paediatr. 2007;96:611-6. 3. spinelli c, liloia c, paolini s, tognetti f, pica f, pisano g, et al. management of undescended testis: italian experience of a single center of pediatric surgery. ann reprod med treat. 2017;2:1006. 4. penson df, krishnaswami s, jules a, seroogy jc, mcpheeters ml. evaluation and treatment of cryptorchidism. 2012. volume,page 5. bergh a, söder o. studies of cryptorchidism in experimental animal models. acta paediatrica. 2007;96:617-21. 6. ritzén em. undescended testis: a consensus on management. eur j endocrinol. 2008;159(suppl 1):s87-s90. 7. ebrahimi a. ectopic testis: a rare case. acta med iran. 2010;48:75-6. 8. mouriquand pd. undescended testis in children: the paediatric urologist's point of view. eur j endocrinol. 2008;159(suppl 1):s83-s6. 9. esteves e, pinus j, maranhão rfda, abib sdcv, pinus j. crossed testicular ectopia. sao paulo med j. 1995;113:935-40. undescended testis: both on one side-tasa et al. figure 3. two separate spermatic cord of each undescended testis. the green arrow shows the right vas deferens and the red one shows the left vas deferens. case report 106 sexual dysfunction and infertility 267urology journal vol 6 no 4 autumn 2009 sildenafil or vardenafil nonresponders’ erectile response to tadalafil berat cem ozgur,1 faruk gonenc,2 ahmet h yazicioglu2 introduction: erectile dysfunction has usually been treated by a phosphodiesterase 5 inhibitor in men, especially in the past decade. although sildenafil and vardenafil are widely used, there is a high percentage of people who do not respond to these drugs. this study was performed in order to evaluate the efficacy of the lastly presented phosphodiesterase 5 inhibitor, tadalafil, in nonresponder group of patients to sildenafil and vardenafil. materials and methods: forty married men with erectile dysfunction who had taken sildenafil or vardenafil at the maximum recommended doses and had not responded to the treatment were included. they were treated with tadalafil, 20 mg, at least 4 doses on different days. the effectiveness of the treatment was reviewed by different questionnaires, including the international index of erectile function-5 (iief-5), sexual encounter profile (sep) questions 2 and 3, and the global assessment question (gaq), at the end of the 12th week. results: the iief-5 scores were 11.90 ± 4.78 and 12.67±6.70, before and after at least 4 doses of tadalafil, respectively (p = .30). the rate of positive responses to sep2, sep3, and gaq questions were also insignificantly different after the treatment. during this period, flushing was seen in 10 and headache was seen in 5 patients. conclusion: the recommended maximum dose for tadalafil insignificantly improved the iief5, sep2, sep3, and gaq scores in patients with erectile dysfunction who had not responded to sildenafil and vardenafil. the other treatment alternatives should be in mind after getting no response to the optimum doses and enough trials of sildenafil or vardenafil before trying a tadalafil regimen. urol j. 2009;6:267-71. www.uj.unrc.ir keywords: tadalafil, erectile dysfunction, sildenafil, vardenafil, treatment failure 1department of urology, ankara gazi hospital, ankara, turkey 2department of urology, ankara yuksek ihtisas education and training hospital, ankara, turkey corresponding author: b cem ozgur, md libya st 62\17 06650, kocatepe, ankara, turkey tel: +90 312 417 8421 fax: +90 312 212 6675 e-mail: bcemozgur@hotmail.com received may 2009 accepted july 2009 introduction erectile dysfunction (ed) is defined as the inability to achieve or maintain a satisfactory erection for sexual activity.(1) for an erection, relaxation of the corpora cavernosa of the penis through noncholinergic nonadrenergic receptors is mediated by nitric oxide and cyclic guanosine monophosphate. inhibition of phosphodiesterase type 5 (pde5) isoenzyme results in increased corporal levels of cyclic guanosine monophosphate and an augmented penile erection.(2) the development of the pde5 inhibitors, sildenafil, vardenafil, and lastly tadalafil, potentiated nitrergic cavernosal relaxation, and they are all effective in the treatment of male ed. the introduction of these compounds, as orally active drugs for the treatment of ed, have demonstrated improvement in erectile response to tadalafil—ozgur et al 268 urology journal vol 6 no 4 autumn 2009 erectile function and shown to be well tolerated in many populations all over the world.(3) compared with sildenafil and vardenafil, the last agent, tadalafil, is characterized by a practical dosing, good efficacy, long elimination half life, that allows for more flexibility of timing for patients. the duration of action of tadalafil is much longer than that of sildenafil or vardenafil (nearly 36 hours), and because of such reasons, it has quickly become one of the favorite choices of patients with ed and their partners.(4) although for patients who are proven nonresponders to pde5 inhibitors, some alternatives exist; such as vacuum constriction devices, intracavernosal injections of vasoactive agents (such as prostaglandin e1), transurethral delivery of alprostadil, implantation of penile prostheses, and venous or arterial surgery; failure to achieve successful intercourse after the use of maximum recommended dose of sildenafil or vardenafil is always a problem if the patient is not desirous to such treatments. the aim of this study was to evaluate the efficacy of high-dose lastly presented pde5 inhibitor, tadalafil, as an alternative therapy for patients refractory to the maximum recommended dose of sildenafil or vardenafil in order to maintain an alternative before suggesting more invasive therapies. materials and methods this study was carried out in 2 different centers in ankara during the period from june 2005 to january 2008. patients with ed who had not responded to sildenafil or vardenafil were approached to participate in the study. all other options such as intracavernosal injection, vacuum constriction device, or penile prostheses were introduced to the patients before starting tadalafil. men who preferred more invasive therapies or who did not consent to participate in the study were also excluded. we included only men who were married with an available partner. patients were excluded if they had a history of radical prostatectomy, penile anatomical defects, a primary diagnosis of premature ejaculation, spinal cord injury, uncontrolled diabetes mellitus, low testosterone levels, major hematologic, renal or hepatic abnormalities, or a recent myocardial infarction and also if they were receiving nitrates, anti-androgens, and α-blockers. forty consecutively selected patients with ed who had taken sildenafil or vardenafil properly, at least 4 maximum recommended dose of 100 mg/d for sildenafil and 20 mg/d for vardenafil and maximum 1 dose per day before sexual activity, and did not respond to the treatment during an average period of 4 months were included. the diagnosis of ed and response to either of the pde5 inhibitors was evaluated by the international index of erectile function-5 (iief-5) questionnaire. scores of 20 or lower indicates an abnormal degree of erectile functioning. all patients received 12 weeks of treatment with tadalafil, 20 mg, for at least 4 and a maximum of 10 doses on different days that they intended sexual attempts. the 20 mg tadalafil (cialis, eli lilly, indianapolis, in, usa) dose was selected according to the recommended maximum dose for the majority of patients.(5) the patients were advised to dispense 1 tablet per instance of intended sexual intercourse, at least 30 minutes before sexual intercourse, with a maximum of 1 dose daily. all of the patients were asked to supply the drugs on their own as the manufacturer of tadalafil had no relation with this study. during the treatment phase all patients were seen in the clinic at the end of 1st, 2nd, and 3rd months of treatment. at the interviews, a selfadministered questionnaire form that consisted questions about drug taking time, number of drugs taken, days a sexual attempt was tried, any adverse effects were given to patients. control of the complete administration of the drugs by the patients was established by these visits. response to the treatment was interrogated by the iief-5, the percentage of positive responses to sexual encounter profile (sep) questions 2 and 3 (sep2 and sep3), and the global assessment question (gaq) at the end of the 12th week. the international index of erectile function-5 questionnaire is one of the most frequently used forms for the patients applying with sexual dysfunction that consist of 5 selected easy erectile response to tadalafil—ozgur et al urology journal vol 6 no 4 autumn 2009 269 questions about sexual activity. patients choose the appropriate column for each question about their sexual abilities over the past 4 weeks.(6) the sep2 (“were you able to insert your penis into your partner’s vagina?”) and sep3 (“did your erection last long enough for you to have sexual intercourse?”) were two different forms which were also asked from our patients. the baseline and endpoint score for each sep question was the patient’s mean percentage of “yes” responses to that question before the treatment period and the posttreatment period.(7) we analyzed iief erectile function domain scores using a last-observation carried forward convention. statistical analysis of the gaq was performed with logistic regression analysis. for each sep question, pretreatment and posttreatment scores were considered the percentage of “yes” responses relative to the number of sexual encounters during the run-in period and the treatment period, respectively. posttreatment sep questions included percentage of positive responses relative to the number of sexual attempts in the treatment period. for diary questions, mean success rates over the baseline and treatment periods were averaged for all patients, and were reported as the overall mean. a p value less than .05 was considered significant. results the mean age of the 40 enrolled patients was 60 ± 8.2 years (range, 50 to 74 years). thirty-two patients (80.0%) had a history of ed of 1 year or longer. in the remaining 8 patients, ed history was at least 6 months. many of the participants had concomitant diseases as hypertension (30.0%), controlled diabetes mellitus (25.0%), or hyperlipidemia (22.5%). the number of sexual attempts by the couple was only 1, at least 30 minutes after taking recommended dose of tadalafil. overall, the mean iief-5 scores before and after the treatment were 11.90 ± 4.78 and 12.67 ± 6.70, respectively. tadalafil did not improve the mean iief-5 intercourse satisfaction (p = .30). the percentage of positive answers to the sep-2 and sep-3 questions were both 10.0% before the treatment and 12.5% after the treatment, and only 1 patient mentioned positive response to the maximum dose of tadalafil on the questionnaire forms. the gaq used to assess the overall effect of the treatment indicated that tadalafil was not superior to prior therapies (p = .47) in improving erections (tadalafil, 22.5%; prior therapies, 20.0%). the most common treatment adverse events seen frequently (≥ 5%) with tadalafil were headache (12.5%), dyspepsia (10.0%), flushing (25.0%), back pain (5.0%), and myalgia (5.0%). these adverse events were mostly mild to moderate that did not affect the patient’s daily life, lead to take any drugs, or require hospitalization. discussion the food and drug administration has approved the three drugs of the pde5 inhibitors for clinical use in the treatment of ed. sildenafil was the first drug in this class, followed by vardenafiland tadalafil. these drugs are potent and selective inhibitors of pde5, acting by potentiating the action of intracavernosal nitric oxide, thereby leading to a more sustained erection.(8) sildenafil was the first pde5 inhibitor to undergo evaluation and has been studied extensively in many trials.(9-12) more recently, other agents, vardenafil and lastly tadalafil, have been introduced. all the drugs have been shown to be effective across a wide range of etiologies of ed. the drugs have been shown to improve erectile function domain scores and penetration and maintenance of erection, resulting in more successful intercourse. their effects are greater at higher doses. sildenafil and vardenafil are shorteracting agents, while tadalafil has a longer halflife allowing the user more flexibility in sexual activity. the drugs are generally well tolerated and withdrawals from the clinical studies as a result of drug-related adverse effects were rare. common adverse effects include headache, nasal congestion, flushing, myalgia, and dyspepsia, all actions related to inhibition of pde5.(13) all the three pde5 drugs have similar efficacy and toxicity profiles. sildenafil and vardenafil have similar molecular structures, but tadalafil is different in structure, which is reflected in its pharmacokinetic profile. with regard to the onset of action, achievement of an erection that leads erectile response to tadalafil—ozgur et al 270 urology journal vol 6 no 4 autumn 2009 to successful intercourse, sildenafil and vardenafil both have half lives of approximately 4 hours, but the half life of tadalafil is approximately 18 hours. another difference between the pde5 inhibitors is that fatty food especially affects the pharmacokinetic profiles of sildenafil and vardenafil, but not that of tadalafil, giving comfort about the meals to the patients.(14) in our cohort, the improvement in the erectile function domain score on the iief-5 and the percentage of sexual intercourse attempts marked by successful vaginal penetration and completion was insignificantly greater with tadalafil, 20 mg, than prior therapies in trials of 12 weeks duration. improvement in scores on other domains of the iief and the percentage of positive responses to a gaq measuring erection improvement were also insignificantly greater with on demand tadalafil than other pde5 inhibitors. the adverse events associated with tadalafil were generally mild to moderate and decreased in frequency with continued administration. the most commonly reported adverse events were flushing and headache. the incidence of cardiovascular adverse events was not significantly different in tadalafil.(15) it seems that if the patient has not responded to sildenafil or vardenafil, the maximum recommended dose of tadalafil also seems ineffective. satisfaction with the sexual experience is considered important when evaluating the impact of treatments for ed, yet enhanced satisfaction has been infrequently assessed in the sexual trials. we evaluated the efficacy of sildenafil and vardenafil versus tadalafil in turkish men with ed and determined the self-based rating of medicinal preference. sildenafil and vardenafil are the potent inhibitors of the pde5, in the corpus cavernosa, and therefore, they increase the penile response to sexual stimulation. tadalafil is also a pde5 inhibitor that increases the level of cyclic guanosine monophosphate in cavernous smooth muscle cells, which is a second messenger for the vasodilator effects of nitric oxide causing smooth muscle relaxation. in this study, sildenafil and vardenafil nonresponders treated with 20 mg of tadalafil were found to be associated with insignificant higher mean scores for the questions of the iief-5. also frequency of penetration and maintenance of erection after sexual penetration were not found to be enhanced significantly with tadalafil in nonresponder patients to sildenafil and vardenafil. similarly, overall erectile satisfaction also did not show a significantly positive improvement in the treated group, as shown by the gaq scores. this study further concludes that there is not a major point of difference between the short-acting agents sildenafil and vardenafil and the longer-acting tadalafil.(16) several factors can contribute to the failure of ed treatments using pde-5 inhibitors. the reasons for acute or delayed failure include severe ed at presentation, worsening of endothelial dysfunction, and progression of penile atherosclerosis because of some factors such as diabetes mellitus, anxiety of performance, erectile dysfunction after radical surgeries, unidentified hypogonadism, inadequate patient education, incorrect usage of the prescribed drugs, development of tachyphylaxis, and some psychosocial factors.(17) conclusion in practice, pde5 inhibitors are often used once or twice a week, so a patient would have to spend at least 3 months trying the various compounds and dosages to achieve adequate exposure to all the three pde5 inhibitors; this would seem an unrealistic strategy in current clinical practice. compared with the other two pde5 inhibitors, sildenafil and vardenafil, tadalafil is characterized by rapid onset, independence of meals before taking the drug, convenient dosing (especially the 36-hour duration of effectiveness deriving from long elimination half-life), and allowing for more flexibility to scheduled medication. higher satisfaction of patients and their partners with tadalafil is mainly due to such psychosocial benefits as decreased time concerns. the duration of action of tadalafil is longer than that of sildenafil or vardenafil. tadalafil is well-tolerated, consistent with the principle of safely, effectiveness, and convenient dosing and is becoming the favorite choice of patients with ed and their partners. however, in our study, although it was not a placebo-controlled erectile response to tadalafil—ozgur et al urology journal vol 6 no 4 autumn 2009 271 randomized trial, it was demonstrated that tadalafil is not an effective agent for sildenafil and tadalafil nonresponders’ group. it might be an option that the urologist should talk about the other treatment alternatives such as intracavernosal injection, vacuum constriction device, or penile prostheses with the patient after getting no response to the maximal recommended doses and enough trials of sildenafil or vardenafil without trying a new tadalafil regimen protocol or try it at first if the patient wishes a more flexible and meal-independent drug with a longer period for taking the drug before sexual activity. conflict of interest none declared. references 1. lue tf. erectile dysfunction. n engl j med. 2000;342:1802-13. 2. mcmahon cg. high dose sildenafil citrate as a salvage therapy for severe erectile dysfunction. int j impot res. 2002;14:533-8. 3. becker aj, uckert s, stief cg. the basics of phosphodiesterase type 5 (pde5) inhibition in urology. urologe a. 2008;47:1582-7 4. deng sm. tadalafil for erectile dysfunction: outstanding efficacy for 36 hours. zhonghua nan ke xue.2008;14:857-60. 5. kuan j, brock g. selective phosphodiesterase type 5 inhibition using tadalafil for the treatment of erectile dysfunction. expert opin investig drugs. 2002;11:1605-13. 6. rosen r, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997;49:822-30. 7. curran m, keating g. tadalafil. drugs. 2003;63:220312. 8. savas m, yeni e, ciftci h, topal u, utangac m, verit a. is penile length a factor in treatment of erectile dysfunction with pde-5 inhibitor? j androl. 2009;30:515-9 9. rendell ms, raifer j, wicker pa, et al. sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. sildenafil diabetes study group. jama. 1999;3;281:421-6. 10. aubin s, heiman jr, berger re, murallo av, yungwen l. comparing sildenafil alone vs. sildenafil plus brief couple sex therapy on erectile dysfunction and couples’ sexual and marital quality of life: a pilot study. j sex marital ther. 2009;35:122-43. 11. montorsi f, padma nathan h, glina s. erectile function and assessments of erection hardness correlate positively with measures of emotional wellbeing, sexual satisfaction, and treatment satisfaction in men with erectile dysfunction treated with sildenafil citrate. urology. 2006;68:26-37. 12. hellstrom wjg, elhilali m, homering m, et al. vardenafil in patients with erectile dysfunction: achieving treatment optimization. j androl. 2005;26:604-9. 13. basu a, ryder re. new treatment options for erectile dysfunction in patients with diabetes mellitus. drugs. 2004;64:2667-88. 14. comparison of phosphodiesterase type 5 (pde5) inhibitors. int j clin pract. 2006;60:967-75. 15. yip wc, chiang hs, mendoza jb, tan hm, li mk, wang wc, kopernicky v. efficacy and safety of on demand tadalafil in the treatment of east and southeast asian men with erectile dysfunction: a randomized double-blind, parallel, placebo-controlled clinical study. asian j androl. 2006;8:685-92. 16. syed t. effectiveness of sildenafil citrate and tadalafil on sexual responses in saudi men with erectile dysfunction in routine clinical practice. pak j pharm sci. 2008;21:275-81. 17. chelsea n, mcmahon, christopher j smith, ridwan shabsigh. treating erectile dysfunction when pde-5 inhibitors fail. bmj. 2006;332:589-92. urological oncology does presence of a median lobe affect perioperative complications, oncological outcomes and urinary continence following robotic-assisted radical prostatectomy? nurullah hamidi1*, ali fuat atmaca2, abdullah erdem canda3, murat keske1, bahri gok2, erdem koc1, erem asil1, arslan ardicoglu2 purpose: to evaluate of the presence of a median lobe(ml) affect perioperative complications, positive surgical margins(psm), biochemical recurrence(bcr) and urinary continence(uc) following robotic-assisted radical prostatectomy(rarp). materials and methods: data of 924 consecutive patients who underwent rarp for prostate cancer (pca) and who have at least 1-year follow-up were evaluated retrospectively. all patients were divided into two groups: group 1(n=252) included patients with ml and group 2 (n=672) included patients without ml. the primary endpoint of this study was to compare complication rates between two groups. the secondary endpoints were to compare psm, bcr and uc rates. result: both groups were statistically similar in terms of demographics and variables about pca. mean prostate volume was higher in group 1 vs. group 2 (69 ± 31 vs. 56 ± 23 ml, p < .001). total operative time was longer in group 1 vs. group 2 (144 ± 38 vs. 136 ± 44 min, p = .01). biochemical recurrence, psm, perioperative and postoperative complication rates of our population were 13.6%, 14.9%, 1.7% and 8.7%, respectively. there were no statistical differences in terms of perioperative complication, psm and bcr rates between the groups(p > 0.05). at the first month after rarp, total continence rate was statistically significant lower in group 1 vs. group 2 (49.2% and 56.5%, p = .03), respectively. however, there were no significant differences in terms of continence rates at 3rd month, 6th month and 1st-year follow-up. conclusion: due to our experience, the presence of ml does not seem to affect perioperative complication, intraoperative blood loss, psm and bcr following rarp. however, the presence of ml seems to be a disadvantage in gaining early uc following rarp. keywords: clavien-dindo; complication; median lobe; robotic; radical prostatectomy; urinary incontinence introduction prostate cancer surgery is trending toward robotic-as-sisted radical prostatectomy (rarp) by developing technology. the main advantages of rarp compared to open radical prostatectomy are better magnification, filtering the tremors of the surgeon's hand and better ability of surgical instruments movement in narrow pelvic area. however, contrary to open surgery, there are some technical difficulties such as tactile sense absent and limited exposure angle in rarp procedures. the presence of a ml is one of the most common challenge that frequently encountered during rarp. sarle et al. firstly reported the difficulty of dissection in a patient who has large ml.(1) in patients with ml, the technical difficulty arises by poor exposure (due to laparoscopic camera view angle) during posterior vesico-prostatic junction incision and posterior prostate base dissection stages, especially from base to apex approaches. this difficulty can cause longer total operat1department of urology, ankara atatürk training and research hospital, cankaya, ankara 06430, turkey 2department of urology, ankara yildirim beyazit university faculty of medicine, cankaya, ankara 06430, turkey 3department of urology, koc university school of medicine, maltepe, istanbul 34010, turkey *correspondence: department of urology, ankara atatürk training and research hospital, cankaya, ankara 06430, turkey. tel: +90 553 205 0307, fax: +90 312 508 2147, e-mail: dr.nhamidi86@gmail.com. received december 2017 & accepted july 2018 ing time(2), higher blood loss(3), increased potential complication (like ureteral orifice injury)(4) and increased psm rates(5) especially in base or posterior surgical margins of prostate. in addition, a wide excision of the bladder neck is needed during enlarged ml removing and it can lead to wide defect in bladder neck. to date, the effect of the presence of ml during rarp on perioperative complication was discussed in a few articles and it was reported that the ml does not affect the complication rates.(2,3,6-8) however, the complications were compared without a standardized classification system in these previous studies. the modified clavien classification system (mccs) has been widely used for standardization of complications in surgical procedures after gaining popularity.(9) this is important, because, it may help us to evaluate the safety of surgery, to analyze learning curves of surgical techniques, to compare different approaches and different patient population based on standardized classification, thereurological oncology 248 vol 15 no 05 september-october 2018 249 by improving management and prevention.(10) in this study, we aimed to compare perioperative complications between rarp patients with and without ml based on mccs. to the best of our knowledge, the present study is the first to evaluate the applicability of the mccs to compare complications between rarp patients with and without ml. furthermore, we compared positive surgical margin (psm), biochemical recurrence (bcr) and urinary continence (uc) rates. materials and methods ethical approval for this retrospective study was obtained from the institutional review board (irb decision no: 95 decision date: 14.04.2017). study population, inclusion and exclusion criteria: we evaluated the data of consecutive patients who underwent rarp at our institution between feb 2009-jan 2016 and who had at least 12 months follow up. patients who had neoadjuvant androgen deprivation therapy and 5-alpha reductase inhibitor treatment history during the last 6 months were excluded. in all patients, data regarding age, body mass index (bmi), asa(american society of anesthesiologists) score, total pre-operative prostate-specific antigen (psa), prior prostate surgery history, gleason score (gs) at biopsy, tumor involvement per core and number of positive cores at biopsy, clinical and pathological disease stage, total operation time (from last port insertion to prostatectomy specimen removal, min), estimated blood loss (ebl) volume (ml) during rarp, intra-operative and post-operative blood transfusion (unite), bladder neck and nerve sparing during rarp, hospital stay (day), drainage and urethral catheter removal time (day), gs at surgical specimen, prostate volume at surgical specimen, psm, localization of psm, biochemical recurrence (bcr) and total continence rate were collected prospectively. all data were recorded prospectively during rarp. complications within 30 days after surgery were classified based on mccs. surgical technique: all rarp procedures were performed by two experienced surgeons (afa, aec). a transperitoneal approach was used in the steep (30) trendelenburg position. totally, 5 ports were placed, a 12-mm port for the camera, three 8-mm ports for the robotic arms, and a 12-mm port for bedside assistance. the procedure was started by making an incision on the anterior peritoneal covering of the douglas pouch, approximately 1 cm proximal to its reflection on the rectum. denonvilliers fascia was opened after vas deferentia and seminal vesicles dissection. then, we incised the anterior peritoneum wall. anterior attachments between the bladder and abdominal wall were taken down by monopolar scissors and the retzius space was entered. after defatting, the endopelvic fascia was opened and levator ani muscle fibers were dissected off all the way along the lateral prostatic fascia. the dorsal venous complex was identified and suture tied distal to the apex of the prostate. then, the detrusor apron overlying the prostate anteriorly was identified and dissected superiorly until the entrance of the urethra into the prostate at the bladder base was observed where its anterior bladder neck was incised. the posterior neck area was table 1. all demographics and comparison between groups. parameters overall (n=924) without ml (n=672) with ml (n=252) p value age, year; mean ± sd 62.2± 6.8 62± 6.8 62.7 ± 6.7 .18 bmi, kg/m2; mean ± sd 27.1 ± 2.7 27± 2.7 27.2±2.8 .37 total psa, ng/ml; mean ± sd 9.6 ± 9.5 9.3 ± 9.6 10.3 ± 9.1 .17 prostate volume at surgical specimen, gr; mean ± sd 60 ± 26 56 ± 23 69 ± 31 < .001 prior prostate surgery history, n (%) .61 none 869 (94) 629 (93.6) 240 (95.2) transurethral resection 49 (5.3) 38 (5.7) 11 (4.4) transvesical prostatectomy 6 (0.7) 5 (0.7) 1 (0.4) number of positive biopsy cores; mean ± sd 3.5 ± 2.7 3.6 ± 2.6 3.3 ± 2.6 .12 percent positive biopsy core; mean ± sd 39.4 ± 24.7 39.7 ± 24.3 38.4 ± 25.6 .49 gs at biopsy, n (%) .7 gs 3+2 4 (0.4) 3 (0.4) 1 (0.4) gs 3+3 584 (63.2) 422 (62.8) 162 (64.3) gs 3+4 149 (16.1) 107 (15.9) 42 (16.7) gs 4+3 80 (8.7) 63 (9.4) 17 (6.7) gs 3+5 12 (1.3) 11 (1.6) 1 (0.4) gs 4+4 64 (6.9) 46 (6.8) 18 (7.1) gs 4+5 17 (1.8) 11 (1.6) 6 (2.4) gs 5+4 10 (1.1) 7 (1) 3 (1.2) gs 5+5 4 (0.4) 2 (0.3) 2 (0.8) clinical t stage .69 t1a 6 (0.6) 5 (0.7) 1 (0.4) t1b 10 (1.1) 8 (1.2) 2 (0.8) t1c 640 (69.3) 471 (70.1) 169 (67.1) t2a 177 (19.2) 128 (19) 49 (19.4) t2b 14 (1.5) 9 (1.3) 5 (2) t2c 77 (8.3) 51 (7.6) 26 (10.3) asa score, n (%) <.001 asa 1 310 (33.5) 194 (28.9) 116 (46) asa 2 595 (64.4) 462 (68.8) 133 (52.8) asa 3 19 (2.1) 16 (2.3) 3 (1.2) asa 4 asa 5 abbreviations: asa, american society of anesthesiologists; bmi, body mass index; gs, gleason score; ml, median lobe; psa, prostate specific antigen the association between median lobe and perioperative outcomeshamidi et al. checked for the presence of the ml and the presence of a ml (yes or no) was confirmed by the operating surgeon. the ml is grasped and elevated out of the bladder by using the fourth robotic arm which was described by patel et al.(11) subsequently, high anterior release and neurovascular bundle (nvb) dissections were carried out. the procedure was completed after division of dorsal venous complex and vesicourethral anastomosis with the use of the van velthoven technique with or without posterior rocco construction. the prostate was extracted from the abdomen after the enlargement of the supra-umbilical port site following inclusion into the endobag. an abdominal drain was left in place. patients underwent follow-up visits at first month after urethral catheter removal, then every 3 months in the first year after rarp, then every 6 months in years 2 to 5 and annually thereafter. total psa values were recorded at every patient visit. bcr was defined by two consecutive psa measurements of ≤ 0.2 ng/ml after rarp.(12) total urinary continence was defined as the use of “0-1 pad”. total continence rates were recorded during 1st, 3rd, 6th and 12th months visits. statistical analysis: spss 16.0 (chicago, illinois, usa) was used for all statistical analysis. data were presented as mean ± sd. comparisons between groups were performed with chi-square and t tests. univariate and multivariate logistic regression analyses were conducted to identify variables predictive of gs upgrading. for statistical significance p value of < .05 was accepted. results overall 924 patients included to this study. the mean age, bmi, total psa and prostate volume of our population were 62.2 ± 6.8 year, 27.1 ± 2.7 kg/m2, 9.6 ± 9.5 ng/ml and 60 ± 26 gr, respectively. the mean total operative time, ebl, drainage catheter removal, hospitable 2. comparison of pathological, perioperative and postoperative characteristics between patients with and without median lobe parameters overall (n=924) without ml (n=672) with ml (n=252) p value total operative time, minute; mean ± sd 138 ± 43 136 ± 44 144 ± 38 .01 estimated blood loss, ml; mean ± sd 144 ± 138 142 ± 138 149 ± 136 .44 intraoperative blood transfusion, n(%) .43 no, 910 (98.5) 661 (98.4) 249 (98.8) 1 unit 8 (0.9) 5 (0.7) 3 (0.2) 2 unit 4 (0.4) 4 (0.6) 3 unit 2 (0.2) 2 (0.3) postoperative blood transfusion, n (%) .72 no, 891 (96.5) 650 (96.7) 241 (95.6) 1 unit 30 (3.2) 20 (3) 10 (4) 2 unit 3 (0.3) 2 (0.3) 1 (0.4) drainage catheter removal time, day; mean ± sd 2.6 ± 1.5 2.6 ± 1.6 2.5 ± 1.4 .84 hospital stay, day; mean ± sd 4.8 ± 2.5 4.7 ± 2.5 4.9 ± 2.4 .16 urethral catheter removal time, day; mean ± sd 8.6 ± 3.9 8.7 ± 4.1 8.5 ± 3.4 .58 gs at surgical specimen, n (%) .06 not detected 17 (1.8) 15 (2.2) 2 (0.8) gs 3+3 417 (45.1) 289 (43) 128 (50.8) gs 3+4 239 (25.9) 181 (26.9) 58 (23) gs 4+3 126 (13.6) 92 (13.7) 34 (13.5) gs 3+5 22 (2.4) 15 (2.2) 7 (2.8) gs 4+4 38 (4.2) 34 (5.1) 4 (1.6) gs 4+5 32 (3.5) 25 (3.7) 7 (2.8) gs 5+4 28 (3) 19 (2.7) 9 (3.5) gs 5+5 5 (0.5) 2 (0.3) 3 (1.2) pathological t stage, n (%) .09 t0 17 (1.8) 15 (2.3) 2 (0.8) t2a 135 (14.6) 91 (13.5) 44 (17.5) t2b 64 (7) 49 (7.3) 15 (6) t2c 389 (42.1) 289 (43) 100 (39.7) t3a 217 (23.5) 162 (24.1) 55 (21.8) t3b 100 (10.8) 64 (9.5) 36 (14.2) t4a 2 (0.2) 2 (0.3) lymphadenectomy during rarp, n (%) 682 (73.8) 498 (74.1) 184 (73) .73 presence of positive lymph node, n (%) 219 (23.7) 154 (22.9) 65 (25.7) .36 bladder neck sparing, n (%) 683 (73.9) 528 (78.6) 155 (61.5) <.001 nerve sparing approach, n (%) .07 non-nerve sparing 79 (8.5) 51 (7.6) 28 (11.1) unilateral nerve sparing 81 (8.8) 43 (6.4) 38 (15.1) bilateral nerve sparing 764 (82.7) 578 (86) 186 (73.8) psm, n (%) 138 (14.9) 100 (14.9) 38 (15.1) .9 localization of psm, n (%) apex 81 (8.7) 58 (8.6) 23 (9.1) .81 base 66 (7.1) 50 (7.4) 16 (6.3) .56 lateral 25 (2.7) 21 (3.1) 4 (1.5) .2 posterior 58 (6.2) 37 (5.5) 21 (8.3) .12 anterior 25 (2.7) 21 (3.1) 4 (1.5) .2 bcr, n (%) 126 (13.6) 94 (14) 32 (12.7) .6 receiving adjuvant radiotherapy, n (%) 248 (26.6) 184 (27.3) 64 (25.4) .54 receiving androgen deprivation therapy, n (%) 238 (25.7) 170 (25.2) 68 (26.9) .8 abbreviations: bcr, biochemical recurrence; gs, gleason score; ml, median lobe; psm, positive surgical margin; rarp, robot-assisted radical prostatectomy the association between median lobe and perioperative outcomeshamidi et al. urological oncology 250 vol 15 no 05 september-october 2018 251 talization and urethral catheter removal time were 138 ± 43 min, 144 ± 138 ml, 2.6 ± 1.5 day, 4.8 ± 2.5 day and 8.6 ± 3.9 day, respectively. bladder neck was sparred in 683 (73.9%) of all patients. psm was detected in 138 (14.9 %) patients. psm was detected in 81 (8.7 %) patients at apex side, in 66 (7.1 %) patients at base, in 25 (2.7 %) patients at lateral side, in 58 patients (6.2 %) at posterior side and in 25 (2.7 %) patients at anterior side of prostate. during the follow-up (median 51 months), bcr was observed in 126 (13.6 %) patients. intraoperative and postoperative complications were observed in 16 (1.7 %) and 81 (8.7 %) of all patients, respectively. the continence rates at 1st, 3rd, 6th, and 12th months after rarp in all patients were 54.5%, 69.9%, 82.4% and 91.3%, respectively. all patients were divided into two groups according to presence of ml during rarp. group 1 (patients with ml) consist of 252 patients and group 2 (patients without ml) consist of 672 patients. the mean prostate volume was statistically higher in patients with ml than patients without ml (69 ± 31 vs. 56 ± 23, p < .001). patients with ml has lower asa score than patients without ml. other patient demographics and preoperative characteristics were comparable between two groups and all details were given in table 1. there were no statistically significant differences in term of mean ebl, mean intraoperative and postoperative blood transfusion rates, mean drainage and urethral catheter removal time, mean hospitalization time, gs at surgical specimen, pathological t stage and psm rates between two groups. however, the mean total operative time (144 ± 38 min vs. 136 ± 44 min, p=.01) was statistically longer in patients with ml than without ml. bladder neck sparing (61.5% vs 78.6%, p < .001) rate was statistically higher in patients without ml than with ml. all perioperative and postoperative comparisons were detailed in table 2. logistic regression analyzes includes age, total psa, bmi, prostate volume, prior prostate surgery history, presence of a ml, gleason grade, pathological stage, table 3. univariate analysis for urinary incontinence. univariate analysis variables or 95% ci p value age (advanced) 1.3 0.648-2.802 .61 total psa (higher) 1.1 0.256-1.392 .7 bmi (higher) 1.4 0.564-3.21 .33 prostate volume (higher) 1.2 0.43-5.148 .09 gleason grade (≥ 8) 1.4 0.184-1.436 .07 pathological stage (≥ t3a) 1.1 0.532-1.498 .3 prior prostate surgery history (yes) 2.2 1.028-3.13 .001 presence of a median lobe(yes) 3.9 2.134-4.918 .001 total operative time (longer) 1.5 0.768-1.898 . 42 urethral catheter removal time (longer) 2.4 0.672-3.09 .85 bladder neck preserving (no) 2.8 1.238-4.026 .001 nerve sparing (no) 1.6 0.412-2.392 .5 receiving adjuvant radiotherapy (yes) 3 1.165-4.784 .01 receiving androgen deprivation therapy (yes) 1.1 0.754-1.856 .57 abbreviations: bmi; body mass index; or, odds ratio; ci, confidence interval; psa, prostate-specific antigen the association between median lobe and perioperative outcomeshamidi et al. figure 1. continence rates in patients with and without median lobe total operative time, urethral catheter removal time, bladder neck sparing, nerve sparing, adjuvant radiotherapy and androgen deprivation therapy variables were performed to determine factors associated with urinary incontinence. presence of prior prostate surgery history, presence of a ml, bladder neck preserving and receiving adjuvant radiotherapy were found to be associated with increased risk of gs upgrading in univariate analysis. outcomes of univariate analysis are summarized in table 3. multivariate analysis was performed to determine the independent predictors of urinary incontinence. presence of a ml (or: 4.1, 95% ci: 2.804-5.14, p < .001), non-preserving of bladder neck (or: 2.2, 95% ci: 1.014-4.138, p = .001) and receiving adjuvant radiotherapy (or:3, 95% ci: 1.413-5.458, p < .001) were found to be significant predictors of urinary incontinence. intraoperative and postoperative complications were developed in 14 (1.5 %) and 81 (8.7 %) of all patients. as intraoperative complication; rectal injury, bladder perforation, ileum injury and ureteral orifice injury were developed in 3 (0.3 %), 9 (% 1), 1 (0.1 %) and 3 (0.3 %) of all patients, respectively. postoperative complications were classified based on mccs and grade i, grade ii, grade iiia, grade iiib and grade iva complication were developed in 28 (3 %), 32 (3.5 %), 7 (0.7 %), 9 (1 %) and 5 (0.5 %) patients, respectively. there were no statistically significant differences in terms of intraoperative and postoperative complication rates between two groups. all complications and comparisons of complications were shown in table 4. the continence rates at 1, 3, 6, and 12 months after rarp in patients with ml were 49.2%, 67.8%, 81.3% and 89.2 respectively. at the same postoperative intervals, the continence rates in the group without ml were 56.5%, 70.6%, 82.8% and 92.1%, respectively. at first visit (1 month after rarp), continence rate was statistically significant higher in patients without ml than with ml (56.5% vs. 49.2%, p = .03). at subsequent patient visits, there were no statistically significant differences on continence rates between two groups. all continence rates and comparisons were detailed in figure 1. discussion the first comparison between patients with and without ml was reported by jenkins et al(7). they emphasized in their small sample (totally 58 patients) sized study that there was no significant difference in term of total operative time in patients with and without ml.(7) in jenkins et al.’s(7) study, the mean total operative times were 289 min and 274 min in patients with and without ml, respectively. although approximately 15 min difference was observed between the two groups, this difference was not statistically significant (p = .61). these outcomes may depend on small number of patient. contrary to jenkins et al.’s study, it was observed that total surgery time is longer in patients with ml than patients table 4. comparison of intraoperative and postoperative complications between patients with and without median lobe overall (n=924) without ml (n=672) with ml (n=252) p value intraoperative complications, n(%) 16 (1.7) 12 (1.7) 4 (1.6) .27 rectal injury 3 2 1 bladder perforation 9 7 2 ileum injury 1 1 ureteral orifice injury 3 2 1 postoperative complications, n(%) 81 (8.7) 54 (8) 27 (10.7) .2 mccs grade i 28 (3) 17 (25) 11 (4.4) .14 postoperative pain (managed by nonopioid analgesics) 3 2 1 postoperative fever (>38.0 °c) (managed by observation without antibiotics) 9 6 3 urine leakage (managed by watchful waiting) 4 1 3 ileus (spontaneously resolved) 6 3 3 wound infection (managed by observation without antibiotics) 4 3 1 intraabdominal fluid collection (managed by observation) 2 2 mccs grade ii 32 (3.5) 21 (3.1) 11 (4.3) .78 symptomatic uti (managed with antibiotics) 7 5 2 postoperative fever (>38.0 c) managed with antibiotics 2 2 arrhythmia 1 1 bleeding requiring blood transfusion 150 10 5 epileptic seizure (managed by anticonvulsant) 1 1 positional vertigo attack (managed by medical drug) 1 1 ileus (managed by nasogastric decompression) 2 1 1 wound infection (managed by antibiotics) 3 1 2 mccs grade iiia 7 (0.7) 5 (0.7) 2 (0.8) .93 intraabdominal abscess or urine collection (requiring percutaneous drainage) 3 2 1 intraabdominal fluid/ lymphocele collection (requiring percutaneous drainage) 4 3 1 mccs grade iiib 9 (1) 7 (1.1) 2 (0.8) .73 wound evisceration (requiring primary closure under ga) 3 ileus (requiring laparotomy) 1 1 bleeding (requiring laparotomy) 1 1 necrosis of glans penis (requiring grafting) 1 1 urethro-vesical anastomosis leakage (repeat urethral catheterization under ga) 3 2 1 mccs grade iva 5 (0.5) 4 (0.6) 1 (0.4) .7 acute renal failure (requiring icu management) 1 1 acute myocardial infarction (requiring icu management) 1 1 cerebrovascular accident 1 1 pulmonary thromboembolism 1 1 hyposaturation requiring icu management abbreviations: ga, general anesthesia; icu, intensive care unit; mccs, modified clavien classification system; ml, median lobe; uti, urinary tract infection the association between median lobe and perioperative outcomeshamidi et al. urological oncology 252 vol 15 no 05 september-october 2018 253 without ml in many studies with high number of patients.(2,3,6). meeks et al.(2) reported that approximately 70 min additional time required in patients with ml compared to patients without ml. they emphasized that this additional time required for posterior bladder neck and seminal vesicle dissection and as well as for bladder neck reconstruction.(2) our outcomes supported these previous studies(2,3,6) in term of total operation time and we observed statistically significant longer total operation time (approximately 8 min) in patients with ml. our additional required time in patients with ml is shorter than that of meeks et al.’s (8 vs. 70 min). meeks et al.(2) performed rarp in this order: incision and dissection of the anterior bladder neck, identifying of the ml (if presence), incision and dissection of the posterior bladder neck, dissection of the seminal vesicles and posterior surface of the prostate dissection. we think, the seminal vesicles dissection can be difficult and time consuming at meeks at al.’s dissection directions in patients with ml. differently from meeks et al.’s rarp technique, the seminal vesicles dissection is performed at the beginning of the rarp procedure. after dissection of the seminal vesicles and posterior surface or the prostate, we dissected and incised the anterior bladder neck. jenkins et al.(7) compared ebl volume between patients with and without ml and they reported that there was no statistically significant difference (296 ml in patients without ml and 304 ml in patients with ml, p = .46). coelho et al.(6) also reported similar outcomes in term of ebl (100 vs. 100 ml, p = .15). we observed statistically similar mean ebl volumes, intraoperative and postoperative blood transfusion rates for our both groups. conversely, it has been reported that statistically significant lower ebl volume was observed in patients without ml compared to patients with ml by meeks et al.(2)(380 vs. 464 ml, p = .05), huang et al.(3) (236 vs. 193 ml, p = .002) and jung et al.(8) (the rate of >300 ml bleeding, 8.4% vs. 4.2%, p = .004). the main point of interest of these studies(2,3,8) is that the definition and dissection of plane between the posterior bladder neck and prostate basis can be difficult in patients with large ml and this condition can lead excessive bleeding during dissection. in our population, psm rates (14.9% vs. 15.1% p = .9) were comparable between two groups. similarly, it has been reported that psm rates were comparable between patients with and without ml in the majority of previous studies.(2,3,6,7) in a small sample sized study, jenkins et al. reported psm rates as 10% and 21% in patients with and without ml.(7) although psm rate is twice as high in the patients without ml compared the patients with ml, there was no statistically significant difference (p = .47). similarly, statistically similar psm rates were reported by coelho et al.(6) (9.7% vs. 10.2%, p = .884), huang et al.(3) (9.5% vs. 13.6%, p = .45) and meeks et al.(2) (11% vs. 10%, p = .89). meeks et al.(2) emphasized that the presence of the ml appears to affect psm around seminal vesicle and posterior bladder neck localization, however, positive surgical margins occur at the apex of prostate in the majority of pca patients, as known. strangely, jung et al.(8) observed statistically significant lower psm rates (16% vs. 24%, p=.044) in patients with ml compared to patients without ml. when they compared the psm rates at different localization of the prostate, they observed that the patients with ml were less likely to have positive margins at posterior side of prostate (21% vs. 47%, p = .034).(8) they explained this finding that the surgeon provided more exposure during posterior prostate dissection when the surgeon retracts the ml to more anteriorly which described by patel and coworkers(11). previous studies(3,6-8) demonstrated that the presence of a ml does not affect complication rates. huang et al.(3) reported statistically similar anastomosis stricture (p = .78), rectal injury (p = .12), inadvertent cystotomy (p = .27), urine leakage (p = .64), ureteral injury (p = .95) and urinary tract infection (p = .72) rates for patients with and without ml. the similar overall complication rates were also reported by jenkins et al.(7) (10.3% vs. 13.7%, p > .05) and coelho et al.(6) (5.3% vs. 4.6%, p = .719). differently, jung et al.(8) grouped complications as intraoperative and postoperative and they observed statistically similar intraoperative (2.5% vs. 3.3%, p = .66) and postoperative complication (11.6% vs. 7.5%, p = .36) rates between patients with and without ml. similarly to previous studies(3,6-8), the overall complication rates were comparable between patients with and without ml in our patients. the main difference of our study from previous studies is that we compared the complications objectively based on mccs. in previous studies, the complications were compared according to number and percentage of complicated patients without standardized classification system. recently, european association of urology (eau) guidelines panel emphasized the importance of standardized, systematic and objective classification system like mccs using to evaluate of complications.(13) because, it allows more accurate definition of complication of various surgical approach, earlier recognition of the complication’s pattern, for comparing the surgical outcomes between institutions or individual surgeons, and for comparing techniques in case randomized trials are either lacking or difficult to perform. in our population, intraoperative and postoperative complications rates were 1.7% and 8.7%. recently, the pasadena consensus panel considered patients with a large ml as one of the challenging cases and it was emphasized that rarp procedures in patients with ml should be performed by experienced surgeons which are doing at least 40 cases per year.(14) also, it was supported by some authors that experience of the surgeon can significantly affect functional, oncologic outcomes, complication rates and the incidence of urethro-vesical junction anastomosis leakage after rp, especially in patients with a challenging anatomy, such as the presence of a ml.(6,15) our institution is one of the referral centers in our region and our surgeons perform about 100 cases per year and we think that low complication rates depend on the surgeon’ experience. in previous studies(3,6,7), there was no difference in term of uc rates between patients with and without ml. huang et al.(3) reported their mid and long term (up to 24th months) uc rates. they reported that there were no statistically significant differences in term of mid and long term uc rates between patients with and without ml (at 5th month p = .48, at 12th month p=.58 and at 24th month p = .12). similarly, jenkins et al.(7) compared uc between patients with and without ml. they recorded the mean interval to recovery of full continence to evaluate uc. their mean interval to recovery of full continence 183 and 128 days in patients with the association between median lobe and perioperative outcomeshamidi et al. and without ml, respectively.(7) although there was 55 days of difference between two groups, this difference was not statistically significant (p = .36).(7) moreover, their bladder neck reconstruction rate was statistically significant higher in patients with ml compared to patients without ml (55% vs. 3%, p < .001). in coelho et al.’s(6) study, early and late uc rates were comparable between patients with and without ml (at 4 week 42.3% vs. 48%, at 24 week 91.5% vs. 94.1%, for all comparisons p > .05). similarly to jenkins et al.’s study, in coelho et al.’s(6) study, the bladder neck reconstruction rate was statistically higher in patients with ml than without ml (93% vs. 65%, p < .001). in our series, total urinary continence was defined as the use of 0-1 pad. the continence rate of our population at early term after rarp (at first month visit) was statistically significant lower in patients with ml compared to patients without ml (49.2%, vs. 56.5%, p = .03) while no statistically significant difference was found at subsequent follow-up periods. we also observed patients with ml had lower bladder neck sparing rate (61% vs. 78%, p < .001). we think that the difference of early uc rates between our groups may depend on lower bladder neck preservation rate during rarp in patients with ml. the impact of bladder neck sparing and reconstruction on recovery of urinary continence after rp is still unclear. srougi and coworkers concluded that preservation of the bladder neck does not significantly affect recovery of urinary continence after rrp.(16) however, many authors considered that the patients who bladder neck preserved regained uc earlier compare to patients who bladder neck unpreserved despite similar long term uc rates.(17,18) our study has several limitations. first, our study is retrospective. second, the presence of ml during rarp was evaluate subjectively and it considered based on surgeon perspective. we could use radiological imaging technique (like preoperative magnetic resonance imaging or ultrasound of prostate) for objective evaluation of presence of ml. third, time to urinary continence was not assessed in this study and we did not use objective asking forms for evaluation of uc. finally, we do not have data about patient symptoms before rarp such as voiding or obstructive lower urinary tract symptoms. we could exclude symptomatic patients. this may affect our urinary continence rates. conclusions the presence of a ml does not seem to affect perioperative complication, intraoperative blood loss, psm and bcr following rarp especially in experienced hands. however, the presence of a ml seems to be a disadvantage in gaining early uc following rarp. acknowledgement none declared. conflict of interest no conflict of interest was declared by the authors. references 1. sarle r, tewari a, hemal ak, menon m. robotic-assisted anatomic radical prostatectomy: technical difficulties due to a large median lobe. urol int. 2005; 74: 92-4. 2. meeks jj, zhao l, greco ka, macejko a, nadler rb. impact of prostate median lobe anatomy on robotic-assisted laparoscopic prostatectomy.urology. 2009; 73: 323-7. 3. huang ac, kowalczyk kj, hevelone nd, et al. the impact of prostate size, median lobe, and prior benign prostatic hyperplasia intervention on robot-assisted laparoscopic prostatectomy: technique and outcomes. eur urol. 2011; 59: 595-603. 4. molinari a, simonelli g, de concilio b, et al. is ureteral stent placement by the transurethral approach during robot-assisted radical prostatectomy an effective option to preoperative technique? j endourol. 2014; 28: 896-8. 5. jeong cw, lee s, oh jj, et al. quantification of median lobe protrusion and its impact on the base surgical margin status during robotassisted laparoscopic prostatectomy. world j urol. 2014; 32: 419-23. 6. coelho rf, chauhan s, guglielmetti gb, et al. does the presence of median lobe affect outcomes of robot-assisted laparoscopic radical prostatectomy? j endourol. 2012; 26: 264-70. 7. jenkins lc, nogueira m, wilding ge, et al. median lobe in robot-assisted radical prostatectomy: evaluation and management. urology. 2008; 71: 810-3. 8. jung h, ngor e, slezak jm, chang a, chien gw. impact of median lobe anatomy: does its presence affect surgical margin rates during robot-assisted laparoscopic prostatectomy? j endourol. 2012; 26: 457-60. 9. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240: 205-13. 10. rassweiler jj, rassweiler mc, michel ms. classification of complications: is the claviendindo classification the gold standard? eur urol. 2012; 62: 256-8. 11. patel sr, kaplon dm, jarrard d. a technique for the management of a large median lobe in robot-assisted laparoscopic radical prostatectomy. j endourol. 2010; 24: 18991901. 12. cookson ms, aus g, burnett al, et al. variation in the defination of biochemical recurrence in patients treated for localized prostate cancer: the american urological association prostate guidelines for localized prostate cancer update panel report and recommendations for a standard in the reporting of surgicl outcomes. j urol. 2007; 177: 540-5. 13. mitropoulos d, artibarni w, graefen m, remzi m, roupret m, truss m. reporting and grading of complications after urologic surgical procedures: an ad hoc eau guidelines the association between median lobe and perioperative outcomeshamidi et al. urological oncology 254 vol 15 no 05 september-october 2018 255 panel assessment and recommendations. eur urol. 2012; 61: 341-9. 14. montorsi f, wilson tg, rosen rc, et al. best practices in robot-assisted radical prostatectomy: recommendations of the pasadena consensus panel. eur urol. 2012; 62: 368-81. 15. vickers aj, savage cj, hruza m, et al. the surgical learning curve for laparoscopic radical prostatectomy: a retrospective cohort study. lancet oncol. 2009; 10: 475-80. 16. srougi m, nesrallah lj, kauffman jr, nesrallah a, leite kr. urinary continence and pathological outcome after bladder neck preservation during radical retropubic prostatectomy: a randomized prospective trial. j urol. 2001; 165: 815-23. 17. selli c, de antoni p, moro u, macchiarella a, giannarini g, crisci a. role of bladder neck preservation in urinary continence following radical retropubic prostatectomy. scand j urol nephrol. 2004; 38: 32-7. 18. deliveliotis c, protogerou v, alargof e, varkarakis j. radical prostatectomy: bladder neck preservation and puboprostatic ligament sparing effects on continence and positive margins. urology. 2002; 60: 855-8. the association between median lobe and perioperative outcomeshamidi et al. reconstructive surgery a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran hosseini j, soltanzadeh k department of urology, shohada-e-tajrish hospital, shaheed beheshti university of medical sciences, tehran, iran abstract purpose: to compare buccal mucosa graft with penile skin flap techniques in the management of anterior urethral diffuse strictures longer than 3 cm. materials and methods: thirty seven patients with a mean age of 28.5 (range 5 to 50) years had been treated by these two techniques using the ventral onlay patch from february 1997 to march 2002. patients' follow-up included physical examination, history taking, retrograde urethrography, cystoscopy and uroflowmetry at the month six, at the end of the first and the second years, and then yearly if required. results: these techniques were applied for anterior urethral strictures (bulbar and penile) longer than 3 cm. buccal mucosal graft (bmg) was used in 18 patients and penile skin flap (psf) in 19. mean follow-up was 27.5 (range 6 to 50) months. mean age was 30.8±11.8 years for bmg group and 27.8±15.6 years for psf group. urethral stricture etiology, surgery history, and previous endoscopic surgery history were similar in both groups. the stricture site in bmg group was penile in 2 patients (11.1%), bulbar in 8 patients (44.4%), and penobulbar in 8 patients (44.4%). in psf group the stricture site was penile in 11 patients (57.9%), bulbar in 5 patients (26.3%) and penobulbar in 3 patients (15.8%). success rate in 6-month follow-up was 93.9% for bug group and 83% for psf. by performing dilatation and internal rethrotomy for mild strictures, the success rate with mean follow-up of 27.5 months was 13.8% for bmg group and 78.9% for psf. only one patient from bmg developed temporary impotence for about 12 months. conclusion: bmg and psf are considered as simple and proper techniques with good long term outcomes in the management of diffuse anterior urethral strictures. these 2 techniques could be applied in patients with history of several surgeries. the results of bmg were better than psf, still, this difference was not statistically significant. key words: urethral strictures, treatment, graft, flap 31 urology journal unrc/iua vol. 2, 31-35 spring 2004 printed in iran introduction if a patient with urethral stricture needs urethrocystoplasty, while the excision of stricture and the anastomosis of the ends of urethra are impossible or improper, suggesting substitutions would be essential. using grafts and flaps for augmentation or complete urethral substitution in the form of patch or tube may be applied. different studies reported that the success rate of flap or graft was generally 85% with no consideration to follow-up duration.(1) in this study the less frequent bmg accepted for publication in july 2003 a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran technique was compared to the more familiar technique of psf. materials and methods from february 1997 to march 2002, 37 patients with diffuse anterior urethral (bulbar, penile) stricture longer than 3 cm enrolled in this historical cohort study and underwent bmg or psf. those patients with associated posterior urethral strictures were excluded from the study. stricture length was determined by urethral retrograde urethrography or retrograde urethrography simultaneously with cystogram. patients were examined by 14 f rigid or 12 f flexible cystoscopes to determine the length of stricture and to observe urethral mucosa. before urethroplasty, a minimum 6 mounths elapsed from the last urethral surgery. all procedures were performed by one surgeon and by using reconstructive surgical principals. patients were secured at lithotomy position after general anaesthesia. corpus spongiosum was freed at the stricture site in ventrum and was vertically opened by ventral incision in a way that normal mucosa at both sides of stricture became visible to a distance of about 5 mm. cystoscopy was carried out again during the procedure to assure the normality of proximal urethra. according to the length of urethra, one or two grafts of buccal mucosa from the internal surface of cheek or pedicled island penile skin were used. davis ecartor was applied to open the mouth and remove mucosa for grafting. this was done by intranasal or oral intubation. the width of graft or flap was about 1.5 cm and its length was based on the length of urethral stricture. during the removal of buccal mucosa, we were careful not to hurt parotid gland duct. then the graft was fairly thinned and the site of its removal left unsutured. the graft or flap was interruptedly sutured over a 18f silicourethral catheter in the adult or appropriately in children with a distance of 2 mm in the form of ventral onlay with 4.0 vicryl. if stricture site was bulbar, spongioplasty would have been performed as well, but if the site of stricture was penile a vascular flap from dartus or tunica vaginalis was applied as a flap or graft. cystostomy was carried out in all patients. patients were at complete bed rest for 5 days and received iv antibiotics for one week and oral antibiotics for another one week after the removal of catheter. retrograde urethrography along foley catheter was conducted at the end of the third week. if extravasation of contrast media was not seen, foley catheter would be removed, otherwise, it would be remained for another week. if the patient urinated properly 48 hours after the removal of foley catheter, cystostomy would have been also removed. patients were followed up at the end of the week 4, months 3, 6, 12, 18, and 24, and then annually for examination and history taking. retrograde urethrography, uroflowmetry and cystoscopy were conducted at the months 6, 12, and 24. any urethral stricture in cystoscopy was considered as a failure. spss software was used for statistical analysis. descriptive statistical indicators included mean standard deviation and median and analytic statistical indicators consisted of independent t test, mann-whitney u test, x2 test, fisher's exact test, and gehan's test. a p value of lower than 0.05 was regarded as significant difference or correlation. minimum follow-up of patients was 6 months and patients were followed up for a mean of 27.5 (range 6 to 50) months. eighteen out of 37 patients underwent bmg and 19 underwent psf. their mean age was 28.5 (range 5 to 50) years. mean age for bmg was 30.8±11.8 years and for psf was 27.8±15.6. (t=0.64, df = 35, p=0.52) the length of strictures was between 3 and 12 cm. the site of stricture in the cases of bmg was penile in 2 patients (11.1%), bulbar in 8(44.4%), and penobulbar in 8 (44.4%). while in the cases of psf, it was penile in 11 patients (57.9%), bulbar in 5(26.3%), and penobulbar in 3 (15.8%) (table 1). the etiology of stricture was catheterization in 6 patients, turp in 1, trauma in 10, extrophy in 1, hypospadiasis in 8 , urethritis in 4, and unknown in 7 (table 2). in bmg, 9 patients (50%) had a history of surgical urethroplasty and in psf 10 patients (52.6%) had the same history. (x2=0.02, df =1, p=0.87). the episodes of endoscopic surgeries (dilatation and internal urethrotomy) in bmg were 1.3±1.9 and in psf were 0.8±1.1 (mwu=157, p=0.64). 32 table 1. frequency distribution of sites of urethral strictures bmg = buccal mucosal graft psf = penile skin flap site of stricture technique of surgery penile bulbar penobulbar total bmg 2(11.1%) 8(44.4%) 8(44.4%) 18(100%) psf 11(57.9%) 5(26.3%) 3(15.8%) 19(100%) total 13(35.1%) 13(35.1%) 11(29.7%) 37(100%) a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran results the mean length of bmg was 2.3±7 cm and of psf was 6.4±2.7 cm (t=0.62, df =35, p = 0 . 5 3 ) . patients who underwent urethroplasty with buccal mucosa of mouth did not develop any problem during hospitalization. besides, they were able to urinate after the removal of foley catheter. in 6month follow-0up, urethral stricture was observed through cystoscopy in one out of 18 patients (6month success rate was 93.6%). in 12-month follow-up of 14 patients, 86% developed no stricture. in 18-month follow-up of 11 patients, the same success rate was seen. in psf, 2 patients developed wound infection and fistula and one developed dehiscence of suture during hospitalization. primary surgical success rate was 83.3%. in 6month follow-up of 19 patients no urethral stricture was reported and the success rate was 83.3%. no stricture was seen in 12-month follow-up of 13 patients (77.3%) (table 3). these results statistically had no significant difference (overall comparison statistics=0.7, df =1, p=0.37). in general, 4 patients in bmg developed urethral stricture and consequently underwent internal urethrotomy or dilatation, of which one patient had no stricture in follow-up cystoscopy; however, no judgment could have been done for the 3 other patients because of insufficient followup duration. thus, they were considered finally as failed cases. psf was failed in 7 patients due to fistula or tissue dehiscence, therefore, repeated surgery was decided. internal urethrotomy was carried out for the other 4 patients with recurrent stricture reported by cystoscopy, in 3 of whom the stricture improved without any procedure, while surgery was required for the other one. regarding the results of internal urethrotomies due to postoperative strictures with a mean followup of 27.5 months in bmg, 15 out of 18 patients (83.8%) improved, while in psf 15 out of 19 (78.9%) improved with no need of repeated surgery. the difference was statistically significant. (table 4) (fisher's exact test p=0.53). potency was studied in 29 patients; temporary impotency occurred for 12 months in just one patient of bmg who had bulbar stricture. discussion in this study the success rate of bmg was compared to psf. total success rate of flaps and grafts was 85%.(1) six months success rate of the two groups of bmg and psf was respectively 93.9% and 83.3%, which were comparable to the success rate of other studies. in 2002, a study was performed by andrich and mundy(2) in which 14 patients underwent patch urethroplasty with buccal mucosa and 4 patients underwent psf. recurrence of disease occurred in one patient (success rate was 93%). our results were comparable to those of this study. in a study conducted by meneghini and cucuola,(3) published in 2001, 20 patients with a mean stricture length of 3.6 cm underwent bmg; their mean follow-up was 13 months with a success rate of 80% which was comparable to our bmg study with 12-month 33 table 2. frequency distribution of preoperative etiology of urethral stricture bmg = buccal mucosal graft psf = penile skin flap technique of surgery etiology bmg psf total catheterization 5(27.8%) 1(5.3%) 6(16.4%) turp 0(0%) 1(5.3%) 1(2.7%) trauma 5(27.8%) 5(26.3%) 10(27%) bladder extrophy 0(0%) 1(5.3%) 1(2.7%) hypospadiasis 4(22.2%) 4(21.1%) 8(21.6%) urethritis 1(5.6%) 3(15.8%) 4(10.8%) unknown 3(16.7%) 4(21.1%) 7(18.9%) total 18(100%) 19(100%) 37(100%) table 3. the rate of success in different follow up time bmg = buccal mucosal graft psf = penile skin flap success survival of treatment based on surgical technique postoperative time bmg psf o 100% 83.3% 6-month 93.9% 83.3% 12-month 86.7% 77.3% 18-month 86.7% 77.3% table 4. frequency distribution of final success of treatment excluding follow-up period in bmg and psf groups final success technique of surgery yes no total bmg 15 83.3% 3 16.7% 18 100% psf 15 78.9% 4 21.1% 19 100% total 30 81.8% 7 18.9% 37 100% a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran follow-up and success rate of 86.7%, considering that the stricture length was longer in our study. in 2001 a study was published by andrich and mundy(4) in which 129 patients underwent bmg in the form of onlay or tube graft. success rate of onlay graft was 89% and the results were similar to our study. the manifestation of clinical symptoms was described as the recurrence of disease in their study. another survey was carried out by webster and islelin(5) in 1999, in which, 29 patients were studied. the skin of penile shaft was used in 20 patients, prepuce in 7 and the buccal mucosa in 2. the success rate was 97% in 19month follow-up. these results were better than ours, however, success rate in the mentioned study was reported according to patients' symptoms and those strictures which were observed in rug or cystoscopy and the patients had not any symptom, were regarded as the success of treatment. barbagli et al(6) studies 37 patients; in whom the scrotum was used in 31 patients and the buccal mucosa in 6. mean follow-up was 21 months and success rate was 92% which was better than our study. however, in this study the mean length of flaps was 4.7 cm and the mean length of graft was 4 cm which indicated shorter strictures and less complicated patients. in a review article, mcaninch and wessells1 studied diffuse anterior urethral strictures in which end to end anastomosis could not be done. they found out that the success rate of free graft was 84% and flap was 85%. this was also similar to the results of our study. the same authors(7) performed another study in which 40 patients were treated by penile skin, prepuce and the buccal mucosa. thirty (86%) out of 33 patients with proper follow-up had successful results. these success rates had no relation to the site of used graft, previous intervention and the cause of stricture and generally agree to that of ours. in this study 37 patients with diffuse anterior urethral stricture were studied, of whom18 were treated by the buccal mucosa and 19 by the penile skin. mean patients' follow-up was 27.5 months. all patients were followed up for at least 6 months and both groups were similar in age, etiology of stricture; length of stricture, episodes of previous urethrotomies and history of previous surgery, however, no complete similarity was seen in the site of stricture which was due to the higher number of cases with penile stricture in psf. the psf of 3 patients ended in failure during hospitalization, 2 of whom developed urethral fistula to skin due to wound infection and one with bladder extrophy and multiple pervious urethroplasties, developed dehiscence. in this study, contrary to some of the above mentioned studies, strictures which were observed in follow-up cystoscopy without patients' symptom were also considered in final results. in 6-month follow-up, success rates of bmg and psf were respectively 93.9% and 83.8% which were decreased with time, as they became 86.7% and 77.3% in 18-month follow-up, respectively. the results of urethrotomy and dilatation of postoperative strictures were not taken into account. regarding the outcome of secondary treatment, 15 out of 14 patients (78.9%) in psf and 15 out of 18 patients (83.8%) in bmg with a mean follow up of 27.5 months improved. although bmg's primary outcome of treatment and its follow-up were better than psf, this difference was not statistically significant (p=0.53). in comparison with failed treatment group with successful treatment group, no significant difference was seen in the length of stricture and previous urethroplasty (stricture length of 6.7±2.1 cm vs 6.6±3.2 cm and history of urethroplasty in 36.4% vs 57.7%) (p=0.88, df=35, t=-0.14 for length of stricture and p=0.23, df=1, x2=1.4 for history of surgery). subjective potency was studied in 29 out of 37 patients. this analysis was not carried out in 8 patients due to lower age or mental retardation. all of the patients were potent preoperatively. only a 40-year-old patient in bmg with bulbar stricture developed postoperative temporary impotency which lasted for about one year. in most studies, potency was not considered in the outcome of treatment. in a survey published by webster and islein5 in 1999, 5 out of 29 patients (14%) developed temporary impotency which lasted for about 3-6 months. patients' mean age in this study was ≥41 years. mean age of impotent patients was 50 years. conclusion both bmg and psf are simple and proper techniques with approximately similar and good long term results in the management of diffuse anterior urethral strictures. regarding cosmetic aspect and the scar of genital site bmg is better than psf; however, no difference is seen in the cure rate. the results of treatment have no clear relationship with surgical history and the length of stric34 a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran ture. the mentioned techniques have no effect on patients' potency. references 1. wessells h, mcaninch jw. current controversies in anterior urethral stricture repair: free graft versus pedicled skin flap reconstruction. world j urol 1998; 16(3): 175-180. 2. joseph jv, andrich de, mundy ar. urethroplasty for refractory anterior urethral stricture. j urol 2002 jan; 167(1): 127-129. 3. meneghini a, cacciola a, cavarretta l, et al. bulbar urethral stricture repair with buccal mucosa graft urethroplasty. eur urol 2001 mar; 39(3): 264-267. 4. andrich de, mundy ar. substitution urethroplasty with buccal mucosa free grafts. j urol 2001 apr; 165(4): 11311133. 5. iselin ce, webster gd. dorsal onlay graft urethroplasty for bulbar urethral stricture. j urol 1999 mar; 161(3): 815-818. 6. barbagl., g., palminteri, e., rizzo, m., dorsal onlay graft urethroplasty susing penile skin or buccal mucosa in adult bulbo-urethral strictures, j.urol., (1998) oct, 160(4), 13071309. 7. wessells h, mcanrich jw. use of free grafts in urethral stricture reconstruction.. j urol 1996 jun; 155(6): 19121915. 35 pediatric urology results of a two-stage technique for treatment of proximal hypospadias with severe curvature: creation of a urethral plate using a vascularized preputial island flap rahşan özcan,1* senol emre,1 pınar kendigelen,2 mehmet eliçevik,1 haluk emir,1 yunus söylet,1 sn cenk büyükünal1 purpose: to present the results of a two-stage technique used for the treatment of proximal hypospadias with severe curvature. materials and methods: the medical records of children with proximal hypospadias and severe curvature were retrospectively analyzed. a 2-stage procedure was performed in 30 children. in the first stage, the release of chordee was performed, and a well-vascularized preputial island flap was created. the vascularized island flap was brought anteriorly and sutured over the ventral surface of the glans and degloved penile shaft. the second stage was performed 6-8 months later. a neourethra was reconstructed by the tubularization of the preputial-urethral plate utilizing the principles of duplay technique. all surgical procedures were performed between 2005 and 2011. results: the mean age of the patients was 4.4 years (1–17 years). the mean duration of urethral catheterization was 6 days after the first stage and 10 days following the second stage. the flaps were viable in all of the children. there was no residual chordee. following the second stage (n = 30), complications developed in 11 children (36%), namely, a fistula in 7, a pinpoint fistula in 3, and a diverticulum formation in 1. the cosmetic outcome was satisfactory. uroflowmetry measurements were evaluated, and only one patient had a diverticulum formation at the late follow-up. conclusion: vascularized preputial island flap is an alternative to free grafts for the reconstruction of the urethra. the main advantage of this flap technique is the creation of a thick, healthy and well-vascularized urethral plate. the advantages of this technique include better aesthetic appearance, an acceptable complication rate, and a very low rate of diverticula formation. keywords: hypospadias; surgery; postoperative complications; urologic surgical procedures; reconstructive surgical procedures; surgical flaps; urethra. introduction division of the urethral plate is inevitable in cases of severe proximal hypospadias with a curvature of more than 35-40 degrees. during the last decade, “twostage procedures” have increased in popularity for this group of patients.(1) in two-stage techniques for the creation of a new urethral plate, the use of free preputial or buccal mucosal grafts is widely practice. after release of the curvature by excision of fibrotic tissues in the ventral part and midline dorsal plication, we prepared a rectangular island flap from the inner part of the dorsal preputium with its own vascular supply and transferred it to the ventral part to create a new urethral plate. the main advantage of this technique was the creation of a thick, healthy neourethral plate due to sufficient blood flow from the dorsal penile vessels. materials and methods the medical records of patients with proximal hypospadias (penoscrotal, perineal) and severe curvature were retrospectively analyzed. the inclusion criteria for this two-stage technique were penoscrotal or perineal hypospadias with a severe curvature of more than 35-40 degrees. the degree of hypospadias was determined before the release of the penile curvature. those patients with a history of circumcision or loss of foreskin due to previous surgery to correct hypospadias were excluded. in spite of every effort to release the penile curvature and protect the urethral plate, division of the urethral plate was inevitable in this series. first stage (figures 1-3): after complete degloving and the chordee test, fibrotic tissues in the ventral part were excised, and a midline dorsal plication was performed. 1 department of pediatric surgery, division of pediatric urology, istanbul university, cerrahpaşa medical faculty, istanbul, 34098, turkey. 2 department of pediatric anesthesiology, istanbul university, cerrahpaşa medical faculty, istanbul, 34098, turkey. *correspondence: department of pediatric surgery, division of pediatric urology, istanbul university, cerrahpaşa medical faculty, istanbul, 34098, turkey. tel: +90 212 5870310. fax: +90 212 4143320. e-mail: rozcan1@gmail.com. received february 2016 & accepted april 2016 pediatric urology 2629 vol 13 no 02 march-april 2016 2630 a completely straight penis was created. then, the distance between the ectopic meatus and the glanular tip was measured. a transverse rectangular vascularized island flap (same length with the measured distance) was fashioned according to the principles of standoli and duckett (figures 1 and 2).(2-5) this flap was rotated ventrally and laid between the ectopic orifice and inner part of the glanular wings. the proximally located orifice was surrounded with 2 short wings from the preputial flap to position non-hair-bearing tissue around it (figure 3). to prevent serum accumulation under the vascularized flap, 4-5 tiny incisions were made on the plate, and 5-6 fixation sutures were placed to ease the adhesion between the flap and tunica albuginea (figure 3). the edges of the flap and the glanular wings and penile skin were stitched with 7/0 vicryl sutures. a foley catheter was used for drainage for 6 days. the dressing consisted of a combination of bactigras and sponge. second stage (figures 4 and 5): six to eight months after the initial operation, a two-layer urethroplasty using duplay’s principle was performed. a ventrally transposed thick and healthy dartos tissue near the plate were used to cover the neourethra. in cases of insufficient or thin dartos tissue, a healthy, thick tunica vaginalis flap was used as a second layer coverage. glanular wings were re-approximated by glanuloplasty, using 6/0 vicryl sutures (figures 4-7). a silicon catheter was inserted for 7-10 days, and a silicon foam dressing (smith-nephew co. cavi-care, hull, uk) was applied for 5 days. the follow-up studies included a physical examination, direct observation of the urinary stream, and review of mobile-phone videos of urination in the home environment. postoperative cosmetic evaluation was performed using the hypospadias objective scoring evaluation (hose) scoring system. the uroflowmetry parameters of patients who had a uroflowmetre over 5 years were summarized. the maximum flow rate (q) max values were compared to the uroflowmetry normogram in healthy boys between 5 and 15 years of age.(6) in 4 of these 30 cases, there were minor (2 cases) and prominent (2 cases) forms of penoscrotal transposition. minor ones were corrected during the 2nd operation, while prominent ones were corrected with an additional 3rd operation. under general anesthesia, a caudal or pudendal block (using ultrasound microprobe) was administered during each stage by the pediatric anesthesiology team. results this 2-stage technique was used in 30 patients with the above-mentioned inclusion criteria. the mean age was table 1. clinical and demographic characteristics of study patients. variables values age, years (mean) 4.4 (1-17) type of hypospadias, no. penoscrotal 25 perineal 5 penoscrotal transposition, no. 4 follow-up, years (mean) 6.5 (4-10.5) reoperations, no. (%) final location of neomeatus, no. pinpoint fistula 3 glanular region 22 urethral fistula 7 subcoronal region 8 diverticulum formation 1 _____ total reoperations 11 (36) _____ table 2. reoperations due to various complications and final location of the neomeatus in 30 patients. figure 1. penoscrotal hypospadias with severe chordee. figure 2. following the correction of the ventral curvature, a rectangular vascularized flap is prepared from the dorsal preputial mucosa. two-stage technique for treatment of proximal hypospadias-ozcan et al. 4.4 years (range, 1-17 years). the mean follow-up time was 6.5 years (range, 4-10.5 years) (table 1). early postoperative controls were performed on the 7th day and at 1 and 3 months. late controls were performed at the end of the 1st year and the 5th to the 10th postoperative year (figures 4-7). a healthy, thick and elastic urethral plate was created in all patients. small tiny incisions and fixation sutures between the flap and corpora appeared to be responsible for the existence of a thick and healthy neourethral plate. due to the nice, elastic and well-vascularized texture of the neourethral plate, it was easy to perform a duplay urethroplasty in each case. the number of additional operations due to various types of complications and the position of the neomeatus is presented in table 2. from the surgeons' perspective, end aesthetic results appeared to be much better than our previous experience with patients treated with single-stage procedures. the satisfaction rate was similar for parents and surgeons as well. the hose scoring system was used to conduct the postoperative cosmetic evaluation, and the mean hose score was 15 (range, 12-16). the results are presented in table 3. a group of patients who had undergone the operation 5-10 years ago were investigated for urethral dilatation and /or diverticulum formation. we detected only one case of diverticulum formation (table 2). uroflowmetry findings are summarized in table 4. we excluded five patients less than 5 years of age and compared the uroflowmetry parameters of 10 patients between 5-15 years of age based on nomograms for healthy boys. the qmax value was between the 25th-50th percentile in 5 patients (mean age 6.2, range, 5-7 years) and was greater than the 50th percentile in 5 patients (mean age 10.8, range, 9-15 years). due to the formation of the neourethra using a well-vascularized thick urethral plate and the reinforcement of neourethra with dartos and/or a tunica vaginalis flap, neither diverticula formation nor urethral dilatation was observed in this series. we did not detect any urination problem with visual examination of the patients during urination and a review of short voiding videos created by the parents. because the follow-up did not exceed 10 years, we have no information with regard to problems with ejaculation. discussion the choice of singleor double-stage operations for the variables of hose hose score number of patients (n = 30) meatal location, no. distal glanular 4 15 proximal glanular 3 7 coronal 2 8 penile shaft 1 _____ meatal shape vertical slit 2 22 circular 1 8 urinary stream single stream 2 30 spray 1 _____ erection straight 4 25 mild curvature (< 10) 3 5 moderate curvature 2 _____ severe curvature 1 _____ fistula formation none 4 20 single-subcoronal or more distal 3 7 single-proximal 2 3 multiple or complex 1 _____ table 3. postoperative cosmetic evaluation with the hose scoring system. abbreviation: hose, hypospadias objective scoring evaluation. ufm parameters range mean qmax, ml/s 6-22 13.1 time to maximum flow, s 7-37 17.4 duration of flow, s 17-55 31.5 mean flow, ml/s 4-17 13.2 urine volume, ml 109-760 253 abbreviation: ufm, uroflowmetry. table 4. results of late uroflowmetric analysis in 10 patients. figure 3. this non-tubularized flap is laid between the original urethra and the tip of the glans. two-stage technique for treatment of proximal hypospadias-ozcan et al. pediatric urology 2631 vol 13 no 02 march-april 2016 2632 treatment of severe hypospadias with a severe curvature problem is under debate. duckett drew our attention to single-stage techniques in the early 80s.(3,4) according to and colleagues, there was only a 10% complication rate with the single-stage transverse island flap technique.(7) however, over the past 10-15 years, two-stage techniques have been re-popularized, especially with the efforts of braca who used free buccal mucosal grafts. (8,9) this was a type of revolution in the treatment of severe proximal cases of hypospadias with prominent curvature and that of patients with crippled hypospadias who had insufficient healthy penile skin. today, the 2-stage techniques using free grafts from the oral cavity or inner prepuce appear to be the most popular methods for treating such cases. based on clinical practice, the use of 2-stage techniques to treat patients with penoscrotal or perineal hypospadias with severe curvature, in whom division of urethral plate is inevitable, may provide better surgical and aesthetic results. zheng and colleagues compared the results of single and two-stage techniques and reported similar complication rates in 66 cases of proximal hypospadias treated by single or 2-stage procedures.(10) however, in 2 reports, castagnetti and colleagues claimed that a lower complication rate and less favorable cosmetic results were associated with 2-stage techniques.(1,11) we used a well-vascularized preputial island flap with an attached healthy and thick dartos pedicle. this healthy and thick figure 4. urethroplasty is performed by tabularizing the neourethral plate. a urethral catheter is placed. figure 6. postoperative slit like meatus (first post-operative year). figure 5. silicone foam dressing (smith-nephew cavi-care) intact for 5 days. figure 7. postoperative coronal meatus (first post-operative year). two-stage technique for treatment of proximal hypospadias-ozcan et al. dartos tissue served as a safe, 2nd layer for the reinforcement of the urethral tube in the 2nd stage. according to snodgrass, better results can be obtained if free preputial grafts are used instead of vascularized flaps.(12) conversely, powell and colleagues. did not find any significant difference in complications rates when using free grafts or vascularized flaps.(13) some have criticized the use of vascularized flaps because of reports of a higher rate of diverticula formation.(14) however, a tight adhesion can be created by inserting tiny incisions on the flap and placing several stitches between the flap and corporal body. in case of insufficient or inadequate dartos tissue, we always used tunica vaginalis flaps as a 3rd reinforcement layer. these additional techniques appeared to be effective in preventing diverticula formation, at least as of the 5-10 year follow-up. in this group, our aim was always to create a slit-like, wide meatus in the tip of the glans. however, if the meatus was located in the coronal area and if there was no problem with the calibration and direction of urination, we did not attempt to advance the meatus to the tip of the glans penis. a wide neomeatus, located in the coronary sulcus, may occasionally be helpful in preventing possible complications such as diverticula formation, meatal stenosis or fistula formation. mcnamara and colleagues reported a reoperation rate of 49% in 134 cases treated for proximal hypospadias.(15) haxhirexha identified a 40% incidence of voiding and ejaculation problems at long-term follow-up in those cases treated with 2 stage techniques.(16) our reoperation rate of 36% therefore appears to be reasonable for a very select group of patients with proximal hypospadias and remarkable curvature problems. uroflowmetry findings are not trustworthy in patients less than 5 years of age because of difficulties in evaluation. we compared qmax values from 10 patients with the nomograms of healthy boys.(6) the qmax value was < 5th percentile in 2 patients (mean age, 6 years), between the 5-10th percentile in 4 patients (mean age, 6.5 years), between the 25-50th percentile in 2 patients (mean age, 8 years), and between the 50-75th percentile in 2 patients (mean age, 15.5 years). though age-dependent improvements in uroflowmetry patterns and values after hypospadias repair have been reported,(17) we did not have sufficient data from consecutive uroflowmetry studies to investigate this outcome. there are some limitations to this technique. for instance, previous circumcision or operations for hypospadias with a loss of foreskin make patients ineligible for this procedure. moreover, we were not able to obtain sufficient information regarding the incidence of sexual and ejaculation problems in this series. conclusions creation of a healthy urethral plate using a well-vascularized transverse rectangular island flap from the inner part of the foreskin is a nice alternative in cases of proximal hypospadias with severe curvature when division of the urethral plate is inevitable. effective strategies to prevent diverticula formation at long-term follow-up include a) the development of dense adhesions created by tiny incisions and small fixation sutures between the tunica albuginea and the flap and b) the reinforcement of the neourethra using a thick and well-vascularized dartos patch and/or the tunica vaginalis. prolonged follow-up is necessary for the evaluation of sexual and ejaculatory problems. conflict of interest none declared. references: 1. castagnetti ma, el-ghoneimi a. surgical management of primary severe hypospadias in children: systematic 20-year review. j urol. 2010;184:1469-74. 2. standoli l. one-stage repair of hypospadias: preputial island flap technique. ann plast surg. 1982;9:81-8. 3. standoli l. vascularized urethroplasty flaps. the use of vascularized flaps of preputial and penopreputial skin for urethral reconstruction in hypospadias. clin plast surg. 1988;15:35570. 4. duckett jw jr. transverse preputial island flap technique for repair of severe hypospadias. urol clin north am. 1980;7:423-30. 5. duckett jw. the island flap technique for hypospadias repair. urol clin north am. 1981;8:503-11. 6. gupta dk, sankhwar sn, goel a. uroflowmetry nomograms for healthy children 5 to 15 years old. j urol. 2013;190:1008-13 7. singal ak, dubey m, jain v. transverse preputial onlay island flap urethroplasty for single-stage correction of proximal hypospadias. world j urol. 2015 sep 22 [epub ahead of print]. 8. bracka a. hypospadias repair: the two-stage alternative. br j urol. 1995;76 suppl 3:31-41. 9. bracka a. a versatile two-stage hypospadias repair. br j plast surg. 1995;48:345-52. 10. zheng dc, yao hj, cai zk, et al. two-stage urethroplasty is a better choice for proximal hypospadias with severe chordee after urethral plate transection: a single-center experience. two-stage technique for treatment of proximal hypospadias-ozcan et al. pediatric urology 2633 vol 13 no 02 march-april 2016 2590vol 13 no 02 march-april 2016 2634 asian j androl. 2015;17:94-7. 11. castagnetti m, zhapa e, rigamonti w. primary severe hypospadias: comparison of reoperation rates and parental perception of urinary symptoms and cosmetic outcomes among 4 repairs. j urol. 2013;189:1508-13. 12. snodgrass w, bush n. surgery for primary proximal hypospadias with ventral curvature > 30 degrees. curr urol rep.2015;16:69. 13. powell cr, mcaleer i, alagiri m, kaplan gw. comparison of flaps versus grafts in proximal hypospadias surgery. j urol. 2000;163:12868. 14. divarci e, dökümcü z, ergün r, elekberova v, ulman i ̇, avanoglu a. comparison of bracka and tipu techniques for proximal hypospadias repair. forth world congress of pediatric surgery, 2013; abstract book. 12/4. 15. mcnamara er, schaeffer aj, logvinenko t, et al. management of proximal hypospadias with 2-stage repair: 20-year experience. j urol. 2015;194:1080-5. 16. haxhirexha kn, castagnetti m, rigamonti w, manzoni ga. two-stage repair in hypospadias. indian j urol. 2008;24:226-32. 17. andersson m, doroszkiewicz m, arfwidsson c, abrahamsson k, sillen u, holmdahl g. normalized urinary flow at puberty after tubularized incised plate urethroplasty for hypospadias in childhood. j urol. 2015;194:1407-13. two-stage technique for treatment of proximal hypospadias-ozcan et al. vol 15 no 05 september-october 2018 295 case report kimura’s disease presenting as scrotal mass: a difficult diagnosis deng piao xie1, yan fang xu2, ming quan li1* keywords: kimura’s disease; scrotal mass. herein we report a case of kimura’s disease with unusual manifestations. a 46-yearold chinese man presented with mass in scrotum which gradually increased in size for approximately 7 years. a computerized tomographic scan of abdomen revealed a soft-tissue density shadow in scrotum and enlargement of lymph nodes in groin and retroperitoneum. the scrotal mass was excised and the biopsy specimen revealed angiolymphoid hyperplasia with infiltration of eosinophils. in conclusion, clinical doctors should pay attention that the patient with eosinophilia and scrotal mass could be indicative for kimura’s disease. introduction kimura’s disease(kd) is a rare, chronic inflamma-tory disease of unknown etiology firstly described by chinese in 1937. kd usually manifests as single or multiple subcutaneous masses, chiefly in the head and neck. lymph nodes and salivary glands could also be involved. significant elevation of serum ige and eosinophils often occurs in kd. the characteristic of biopsy lesions in kd are follicular hyperplasia and reactive germinal centers infiltrated by significant eosinophils. the diagnosis of kd largely depends on the biopsy and manifestations. 1chengdu university of traditional chinese medicine, sichuan province, china. 2department of nephrology, first affiliated hospital of fujian medical university, fujian province, china. *correspondence: chengdu university of traditional chinese medicine, sichuan province, china. e-mail: 3511725549@qq.com. received september 2017 & accepted january 2018 case report a 46-yearold chinese man presented with the mass in scrotum which gradually increased in size for approximately 7 years. two months ago, the patient was admitted to nephrology department because of recurrent episodes of edema in legs and complained of scrotal mass enlargement. on physical examination, there was a soft-tissue mass in scrotum about 3x3cm in size. laboratory results were: white blood cells, 13.6x109/l; eosinophils, 5.58x109/l,(41%); serum ige,4330iu/ ml;serum creatinine,3.6mg/dl. 24-hour urinary protein quantitation was 0.8g. the patient underwent renal biopsy due to kidney failure as well as proteinuria. refigure 1. a large of esinophil and some lymphocytes deposit in renal interstitium. figure 2. red arrow points scrotal mass about 5x3.5cm in size. nal biopsy specimen revealed that lots of eosinophils were deposited in renal interstitium (figure 1). a computerized tomographic scan of abdomen revealed a soft-tissue density shadow in scrotum and enlargement of lymph nodes in groin and retroperitoneum (figure 2). ten days later, the patient was admitted to urology department, because the patient complained that scrotal mass was larger. besides, cardiovascular, respiratory and abdominal physical examinations were unremarkable. laboratory data changed to: white blood cells, 16.3x109/l; eosinophils, 11.78x109/l; (66.1%); serum creatinine, 1.57mg/dl. the scrotal mass was excised and was about 5x3.5x2cm in size. the biopsy specimen revealed angiolymphoid hyperplasia with infiltration of eosinophils (figure 3). kd was diagnosed based on the histological features combined with laboratory results. discussion kd is often misdiagnosed because its rarity and this patient was even harder to be correctly diagnosed because the patient was lacking the characteristic symptoms. a retrospective study conducted by kawada showed that 163 patients had facial involvement in total of 194 cases. other involved sites included 43 cases in neck,40 cases in popliteal region, 35 cases in groin, 23 cases in axilla and 2 cases in forearm and male to female ratio was 7:1(1).the patient we reported only had involved scrotum rather than head or neck. therefore, we speculate that kd might involve any subcutaneous tissues. the patient with kd need to be differentiated from some diseases. the most common disease is angiolymphoid hyperplasia with eosinophilia(alhe), because there are some similar features between these two diseases, including predisposition for involvement of the head and neck, some histopathological features and easy recurrence(2). however, there are some characteristics to distinguish kd from alhe. kd has the following features: male predominance, usually elevated serum ige and peripheral blood eosinophils > 10% of total white cell count. on the other hand, alhe has the following features: female predominance, usually normal serum ige and peripheral blood eosinophils < 10% of total white cell count(3). hodgkin’s lymphoma and myeloid leukemia that both can present as eosinophilia should also be differentiated from kd. hodgkin’s lymphoma figure 3. the specimen shows angiolymphoid hyperplasia with significant infiltration of eosinophils. and myeloid leukemia can be diagnosed based on the lymph node biopsy and bone marrow biopsy. in this patient, the differential diagnosis should have included common diseases that cause the scrotal mass, including scrotal tumor, tuberculosis of scrotum and inguinal hernia. both scrotal tumor and tuberculosis of scrotum can be diagnosed based on biopsy . a ct scan of abdomen could diagnose inguinal hernia. there is no consensus diagnostic criteria for kd. we recommend clinical doctors to consider kd, if patients present with the following characteristics: 1. young male asian, 2.chronic history, 3. swelling of subcutaneous tissues in head or neck, 4. lymphadenopathy, 5. significantly elevated serum eosinophils and ig e, 6. histopathological features: the involvement of tissue shows follicular hyperplasia and reactive germinal centers with significant infiltration of eosinophils(4,5). however, there are some patients who have unusual manifestations. therefore, if the patient presents with eosinophilia and subcutaneous masses, kd needs to be considered and biopsy should be performed to further confirm the diagnosis. conclusions clinical doctors should bear in mind that eosinophilia and scrotal mass could be indicative for kd. conflict of interest the authors have no conflicts of interest to disclose. references 1. kawada a. kimura's disease: manifestation of the disease and its differential diagnosis. hautarzt,1976;27:309-17. 2. seregard s. angiolymphoid hyperplasia with eosinophilia should not be confused with kimura’s disease. acta ophthalmol scand 2001; 79: 91–93. 3. kung i t m, gibson j b, bannatyne p m. kimura's disease: a clinico-pathological study of 21 cases and its distinction from angiolymphoid hyperplasia with eosinophils. pathology, 1984, 16:39. 4. motoi m, wahid s, horie y,akagi t. kimura's disease:clinical, histologic and immunohistochemicalstudies. acta medokayama 1992;46:449-55. 5. r p s punia, r aulakh, s garg. kimura’s disease: clinicopathological study of eight cases. the journal of laryngology & otology, 2013, 127, 170–4. kimura’s disease: a difficult diagnosis-xie et al. case report 296 urological oncology robot-assisted partial nephrectomy with segmental renal artery clamping: a single center experience cem basatac*, haluk akpinar purpose: the aim of our study is to evaluate the feasibility and effectiveness of robotic partial nephrectomy performed with segmental clamping of tumor-feeding arteries. materials and methods: thirty-six patients with renal tumor who underwent robotic partial nephrectomy with segmental renal artery clamping were included in this study. prospectively recorded patient demographics, mean operation time, estimated blood loss, warm ischemia time, length of hospital stay, preand postoperative renal functions and oncological outcomes were analyzed retrospectively. all complications were graded based on the modified clavien-dindo classification system. surgical success was defined as no conversion from segmental artery clamping to the main renal artery clamping. results: mean tumor size was 40 mm and, r.e.n.a.l nephrometry score was 6.74. mean operation time, estimated blood loss and warm ischemia time were 162 min, 236 ml, and 16 min, respectively. five postoperative complications were observed. there were no significant differences in terms of renal functional outcomes before and after surgery (p = .18). of 36 patients, 34 were completed successfully; however, main renal artery clamping was required in two patients due to excessive bleeding from the tumor bed. the success rate of the segmental renal artery clamping technique was determined as % 94.4 (34/36) in our study. conclusion: segmental renal artery clamping may be considered as a reliable and effective surgical method for vascular control during robotic partial nephrectomy. for this technique, tumor characteristics and intrarenal vascular anatomy should be precisely evaluated by the preoperative contrast-enhanced computerized tomography with 3-d reconstruction. keywords: partial nephrectomy; robotic surgery; renal functions; segmental renal artery; warm ischemia time introduction majority of renal masses are now diagnosed at early clinical stage due to the widespread use of cross-sectional imaging systems. although open radical nephrectomy has historically been considered the treatment of choice, partial nephrectomy (pn) is now accepted as a standard of care especially for treating t1a and t1b renal tumors amenable to nephron-sparing surgery.(1) when compared with radical nephrectomy, pn can achieve preserved renal function, improved overall patient survival, and reduced cardiovascular events.(2) minimally invasive nephron-sparing options such as laparoscopic and robotic partial nephrectomy (rapn) have gained acceptance during the past two decades. however, laparoscopic partial nephrectomy is a technically challenging procedure due to the steep learning curve and necessity of the intracorporeal suturing that limits its use to highly experienced laparoscopic surgeons.(3-5) more recently, the robotic surgery gives surgeons several advantages over traditional laparoscopy to overcome these drawbacks. these advantages include tremor filtering, motion scaling, and magnified three-dimensional vision with a fully articulating endowrist making tumor excision easy even in posterior department’s name: istanbul bilim university, department of urology, istanbul, turkey. *correspondence: istanbul bilim university, department of urology, istanbul/turkey telephone: +90 (212) 288 34 00, fax: +90 (212) 272 34 61, email: cembasatac@gmail.com received july 2018 & accepted december 2018 tumor location. the most important step of pn is clamping of the main hilar vessels to minimize blood loss and improve intraoperative visualization. by this way, renal tumors can be resected more easily and then; secure renorraphy can be performed. however, renal hilar control causes warm ischemia and prolonged warm ischemia time (wit) is associated with renal functional impairment induced by renal ischemia-reperfusion injury.(6) because of this reason, wit should be minimized as much as possible to prevent chronic kidney disease and cardiovascular events.(7-8) several techniques have been described to reduce this injury such as zero ischemia, zero ischemia with microdissection technique and segmental renal artery clamping (sac).(9-12) however, no consensus related to the impact of the type of renal ischemia on the postoperative renal function has been assigned, yet. therefore, the present study aims to evaluate the safety and efficacy of sac during rapn focusing on operative, post-operative and functional outcomes in the 36 consecutive patients. patient and methods study population and design urology journal/vol 16 no. 5/ september-october 2019/ pp. 469-474. [doi: 10.22037/uj.v0i0.4713] between february 2013 and august 2018, 42 consecutive patients underwent rapn. thirty-six of these operations (86 %) with clinical t1-2 renal tumors were perform with segmental renal artery clamping technique and included in this study. all procedures were carried out by the single surgeon who performed several hundred robotic surgeries since 2005 before attempting sac rapn. segmental renal artery clamping technique was attempted for vascular control in almost all patients during the study period when it was feasible. tumors that were excised under main renal artery clamping, patients with a solitary kidney, multifocal tumors, patients with radiological evidence of locally advanced disease, patients with incomplete records or follow-up < 6 months were excluded. patients’ characteristics and follow up data were enrolled in our database prospectively. preoperative preparation preoperative evaluation included medical history, physical examination, routine laboratory studies, including serum creatinine, urinalysis and chest x-ray. all patients underwent a preoperative radiologic evaluation with contrast-enhanced computed tomography (ct) with 3-dimensional reconstruction to delineate precise segmental branches of the renal artery. target arteries were defined as the feeding segmental arterial branches of the main renal artery entering directly into the tumor which were preoperatively determined by 3-d models of ct (figure 1). outcome assessment tumor size was reported as the largest single dimension of the lesion as measured on the ct. pathological staging was performed according to the 2009 iucc/ american joint committee on cancer tumor-node-metastasis staging system.(13) all tumors were scored according to r.e.n.a.l. nephrometry score.(14) prospectively recorded patient demographics, mean operation time, estimated blood loss (ebl), wit, length of hospital stay, preand postoperative renal functions and oncological outcomes were analyzed retrospectively. preoperative creatinine levels and estimated glomerular filtration rates (egfr) calculated with the modification of diet and renal disease(15) formula were compared with the postoperative creatinine and egfr levels at the 1st month follow up. all complications within 30 days of the procedure were recorded prospectively and graded based on the modified clavien-dindo classification system.(16) surgical success was defined as no conversion from segmental artery clamping to the main renal artery clamping. surgical technique and follow-up all operations were performed by using da vinci si robotic surgical system (intuitive surgical, inc., sunnyvale, ca). written informed consent was obtained from all the patients in this study which was approved by the institutional review board. a five-port transperitoneal approach was used for left-sided tumors. an additional 5 mm port was used for liver retraction for right-sided tumors (figure 2). following the endotracheal intubation under general anesthesia, a ureteral catheter was placed in patients whose tumor was too close to the collecting system. then, the patient was placed in a 60° modified flank position, and the pneumoperitoneum was achieved with a veress needle at palmer’s point(17) for left renal tumors and 2 cm cranial from the midpoint between the umbilicus and anterior superior iliac spine for right renal tumors. the colon was reflected medialtable 1. preoperative characteristics and perioperative outcomes in patients with renal tumor underwent sac rapn. no, of patients. 36 age (years, mean [sd]) 57 (± 12) gender, n (%) male 29 (% 81) female 7 (% 19) tumor side, n (%) right 18 (50) left 18 (50) body mass index (±sd) 31 (± 4) tumor size, mm (±sd) 40 (± 14) r.e.n.a.l score (±sd) 6.74 (± 1,8) mean operation time (min) (±sd) 162 (± 44) mean warm ischemia time (min) (±sd) 16 (± 7) estimated blood loss (ml) (±sd) 236 (± 149) mean hematocrit decline (%), (±sd)a 3.98 (± 2.08) mean decrease in postoperative egfr b4.88(± 17.1) (mil/min/1.73 m2), (±sd) drain removal time (days), (±sd) 2,5 (± 1) length of hospital stay (days), (±sd) 3,2 (± 1,3) intraoperative complication, n, (%) 1 (3) postoperative complications, n, (%) 5 (14) ap <.01, ci%95: 3,06 4.90. bp .18, ci%95: -2.57 12.20. figure 1. vascular segmentation of renal artery a(left). preoperative assessment of renal vascular anatomy. b(right). segmental branches of renal artery feeding the tumor on 3-d ct imaging. c) peroperative appearance of renal vasculature. (ra=renal artery, ps=presegmental artery, s=segmental artery, rv= renal vein, ta= targeted artery) robotic partial nephrectomy with partial ischemia-basatac et al. urological oncology 470 vol 16 no 04 september-october 2019 471 ly. main renal vein, renal artery, and targeted segmental arteries were separately dissected and encircled by vascular loops in all cases. the renal capsule was scored using monopolar shears. two 15-cm long 3-0 polyglyconate barbed sutures on a 26 mm ½ circle needle were placed in the abdominal cavity for renal parenchymal repair. metal and plastic bulldog clamps of different size (scanlan international, st. paul, mn) depending the size of the renal arterial branch were used in order to control segmental branches of the main renal artery supplying the tumor. cold excision of the tumor was performed with robotic hot shears. it was also necessary to clamp additional segmental arteries when there was arterial bleeding from tumor bed. if the pelvicaliceal system was opened up, it was repaired by uninterrupted 4-0 polyglactin suture. afterward, tumor bed was sutured continuously with two preplaced barbed sutures. subsequently, bulldog clamps were released (early unclamping). in case of pulsatile arterial bleeding, vessels were controlled in a figure of eight fashion by using 4-0 polyglactin suture. renal parenchyma was further approximated using 0-0 polyglactin sutures on ct-1 needle with sliding-clip renorrhaphy technique.(18) a jackson-pratt drain was placed in all patients. in follow-up, all patients received comprehensive metabolic panel every 3 months for two years and then yearly. an abdominal ultrasound and chest radiography were done at 3rd months. abdominal and thorax ct were performed at 6th months and yearly thereafter, if necessary. statistical analysis all statistical analyses were performed using spss statistics version 24 (ibm, armonk, ny, usa) software. the sample mean was used to determine the average of the quantitative variables met the normal distribution according to the kolmogorov-smirnov test. paired sample t-test was used to compare descriptive statistics for the before and after the intervention. the confidence interval was taken 95%, and a p < 0.05 was considered as statistically significant. results table 1 summarizes patient demographics and early postoperative characteristics. the mean age was 57 (± 12) years. the mean body mass index, r.e.n.a.l. nephrometry scores, and tumor size were 31 (± 4), 6.74 (± 1.8) and 40 mm (± 14), respectively. the mean operation time was 162 min (± 44) and the mean warm ischemia time was 16 min (± 7). the mean targeted arteries dissection time was measured as 17 (± 10) min. estimated blood loss was 236 ml (± 149). the mean decline in hematocrit was %3.98 (± 2,08), and this was statistically significant (p < .01). mean preand post-operative egfr values (ml/min/1.73 m2) were 89.88 and 85. the mean reduction in egfr at 1 month after surgery was not statistically significant (p = .18). drain removal time and length of stay were 2.5 and 3.2 days, respectively. of 36 patients in whom sac was performed, 34 were completed successfully, while in 2 patients the main renal artery clamping was required due to excessive bleeding from the tumor bed. therefore, the success rate of the sac technique was determined as % 94.4 (34/36) in our study. a renal vein injury occurred during dissection of the renal hilum and was successfully sutured by the 4-0 polyglactin sutures. five postoperative complications were observed and recorded as clavien grade 1-2 and 3-b. these complications were one sub-ileus that eventually resolved spontaneously, two postoperative bleeding necessitating blood transfusions, one pneumothorax requiring chest tube, and one urinoma requiring percutaneous drainage. pathological characteristics of patients are listed in table 2. final pathological examination of 36 resected tumors revealed 30 malignant tumors (% 83) and 6 benign tumors (% 17). pathology results showed 15 cases of clear cell carcinoma, 7 papillary carcinoma, 8 chromophobe rcc, 3 angiomyolipomas, 2 oncocytomas, and 1 renal cyst. pathologic classifications of malignant tumors showed 19 cases of t1a, 9 t1b, 1 t2a and 1 t3a. the positive surgical margin was reported in one patient on the final pathology. however, no tumor recurrence occurred in the mean follow-up of 36 (± 22) months. discussion partial nephrectomy is now considered as the gold standard surgical technique in the treatment of t1a, and when technically feasible in t1b renal tumors.(19) renal function after pn can be impaired as a result of either ischemic injury induced by vascular clamping and loss of vascularized renal parenchyma. in order to achieve negative surgical margin, resection of some normal robotic partial nephrectomy with partial ischemia-basatac et al. table 2. pathological features and oncological outcomes tumor location, n (%) upper 9 (24) middle 10 (27) lower 17 (49) tumor growth pattern, n (%) endophytic 19 (53) exophytic 17 (47) malign histology (rcc), n (%) 30 (83) subtypes of malign tumors, n (%) clear cell type 15 (42) papillary type 7 (19) chromophobe type 8 (22) pathologic stage of pt1a 19 malignant tumors, n pt1b 9 pt2a 1 pt3a 1 benign histology, n (%) 6 (17) subtypes of benign tumors, n (%) angiomyolipoma 3 (8) oncocytoma 2 (6) benign cyst 1 (3) positive surgical margin, n (%) 1 (3) local recurrence, n 0 mean follow up (months), (±sd) 36 (22) figure 2. port placement for right robotic partial nephrectomy. functional renal parenchyma during rapn is inevitable; however, total or partial warm ischemia remains as the major modifiable factor for preservation of postoperative renal reserve. in our opinion, the main goal should be minimizing warm ischemia during rapn. though total hilar control provides optimal intraoperative visualization with the bloodless surgical field, prolonged warm ischemia time causes renal functional impairment by renal ischemia-reperfusion injury. for this reason, selective artery clamping of tumor-feeding branches of the renal artery has gained popularity as an interesting strategy to limit ischemia to the targeted tumor area. in this manner, general warm ischemia can be avoided, and renal functions can be effectively protected. a single center series, from frukawa et al., compared postoperative renal functional outcomes of sac with the main artery clamping. they showed that sac had significantly less renal functional decrease at 1 week after surgery. however, in that study, changes in renal functional results were similar at first month in both techniques.(20) similarly, shao et al. have also demonstrated that patients who underwent rapn with sac technique have a better early renal functional recovery when compared with main renal artery clamping.(21) at the present study, local warm ischemia time was 16 minutes and mean decline in postoperative renal functions were not statistically significant at the 1st month of follow up. even though patients included in this study had relatively higher r.e.n.a.l nephrometry scores and endophytic tumor growth pattern, our findings were similar when compared to those reported in the literature.(22) although some studies have shown promising perioperative results for sac, the real benefit of this technique remains debatable. the possibility of the more significant blood loss should be taken into account because of excessive hilar dissection and uninterrupted main renal artery. thus, the main renal artery and vein should be wholly mobilized and encircled with a vessel loop in case severe bleeding. in 2015, zhou et al. published a systematic review of 7 retrospectively designed studies conducted to compare sac versus main renal artery clamping. there were no differences among groups in terms of mean operation time, surgical complications and length of stay. although estimated blood loss was significantly higher with sac technique, no significant difference was noted in blood transfusion rate among groups according to this meta-analysis.(23) in our study, only one renal vein injury occurred during hilar dissection which was successfully repaired by suturing. though the mean decline in postoperative hematocrit was statistically significant within the cohort, only two patients received blood transfusions at postoperatively. clavien grade 3 or higher complications were observed in two patients (% 5.5). postoperative complications of our study are similar to those reported series for sac during rapn in the literature ranging from % 7-16.(22-25) it’s not clearly demonstrated in the current literature whether the increase in intraoperative blood loss has any negative impact on oncological outcomes of sac. the largest rapn series have reported psm rates from % 0 to % 10.(26-29) in our study, one patient who had an utterly endophytic tumor with high r.e.n.a.l. nephrometry score had positive surgical margin but, no local recurrence has occurred during follow up. finally, we think that increase in intraoperative blood loss during rapn performed with sac technique has no negative impact on the oncologic outcomes according to our results. in our study, sac was successfully performed in all but two patients. these two had to be converted to main renal artery clamping due to uncontrolled bleeding during dissection. renal tumors of these patients had completely endophytic growth pattern and renal nephrometry scores of these tumors were 8 and 10. in endophytic and laterally located tumors as in these cases, multiple segmental arteries may supply the tumor which is difficult to control. total clamping of the main renal artery might be more suitable for these patients. therefore, we strongly recommend to study on intrarenal vascular anatomy before sac attempt during rapn. a contrast-enhanced ct with 3-d modification is the best tool to visualize arterial branches of the main renal artery before surgery. this imaging modality provides a preoperative mapping of renal vascular anatomy which is facilitating dissection plans from the main renal artery to target segmental branches feeding the tumor. intraoperative ultrasonography using a drop-in probe can also be beneficial to visualize accurate surgical margin. it can be used to assess for specific segmental or interlobar arteries supplying the tumor. however, it was not used since not available in the current cohort. at the present study, the success rate of the sac technique was % 94.4 (34/36). this success rate is similar to those previously reported retrospective studies of robotic and laparoscopic partial nephrectomy series using sac technique ranging from % 77-100.(20,21,30) our study has some limitations that need to be considered. first, this study is a single center, single surgeon experience. the cohort has insufficient power to detect definitive conclusion on the surgical outcomes. second, no control group was included in this study to compare outcomes of the sac with the other techniques such as off clamp and total ischemia. the last limitation of this study is the interpretation of the renal functions. all patients included in this study have a normal contralateral kidney that limits the ability to interpret egfr changes. though almost all studies choose comparison of the egfr values to analyse the pre and post-operative renal functional changes, renal scans might be a more accurate way to evaluate functional changes. nevertheless, this single-center study suggests that sac of tumor-feeding arteries is a reliable surgical method of vascular control during rapn. conclusions segmental artery clamping seems safe and effective surgical technique in order to minimize warm ischemia time during rapn. it may be an alternative surgical method of vascular control. however, higher renal nephrometry scores and tumor growth pattern might have negative impact on surgical success rates. therefore, preoperative mapping of renal vascular 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robotic partial nephrectomy with partial ischemia-basatac et al. urological oncology 474 urological oncology comparison of partial and radical laparascopic nephrectomy: long-term outcomes for clinical t1b renal cell carcinoma yi cai, han-zhong li, yu-shi zhang* purpose: to compare the long-term clinical and oncologic outcomes in patients treated with laparoscopic partial nephrectomy (lpn) and laparoscopic radial nephrectomy (lrn) for clinical t1b renal cell carcinoma. materials and methods: we retrospectively reviewed the records of all patients who underwent lpn or lrn for a single clinical t1b tumor between january 2005 and january 2012, an actual follow-up of 2-year or greater was available in 39 and 160 after lpn and lrn, respectively. survival was calculated using the kaplan-meier method. multivariable cox regression analysis was done to assess predictors of survival. results: the two cohorts of patients were similar in age, sex, body-mass index and preoperative egfr. there were no differences in tumors size (4.97 vs 5.29cm, p = .08), and pathological stage distribution between the two cohorts. the median follow-up after lpn and lrn were 67 (range: 18-118) and 70 (19-120) months, respectively. for lpn versus lrn, 5-years overall and cancer specific survival rates were 93.33% vs 85.69% and 96.00% vs 91.35%, respectively. for lpn versus lrn, 10-years overall and cancer specific survival rates were 85.56% vs 73.41% and 88.00% vs 82.85%, respectively. on multivariate analysis, patients’ age, asa score and pathological stage were the major factors affecting overall survival, and patients’ age and pathological stage were associated with cancer specific survival. the percent decrease in glomerular filtration rate was significantly lower in the lrn group at early and last followup. conclusion: lpn is an effective treatment option in appropriately selected patients with ct1b rcc. it provides 5-year, 10-year overall survival and cancer specific survival comparable to those of lrn as well as better preservation of renal function than lrn. overall survival and cancer specific survival are associated with nonmodifiable factors but not by the choice of operative technique. keywords: renal cell carcinoma; t1b; laparoscopy; partial nephrectomy. introduction partial nephrectomy (pn) is the current standard of care for localized rcc, especially in patients with tumors < 4cm(1,2). the oncological equivalence and better functional outcomes of pn compared to radical nephrectomy (rn) for t1a renal cell carcinoma have been widely reported. further, pn is associated with improved quality of life, preservation of renal function and potentially improved overall survival. however, up to 25% of rccs are still detected at a size of 4 ~7cm (t1b), for which rn was the gold standard of treatment in the last decades(3). recent data suggest that pn should be performed if feasible for t1b renal tumors(4,5). with advances in laparoscopic suturing techniques and the availability of hemosealant substances, laparoscopic partial nephrectomy (lpn) has also become a well-defined method(6,7). in fact, lpn for t1b renal tumor has been demonstrated to be feasible in expert hands(8,9). there are some studies about the short-term oncological and renal function outcome of lrn or lpn on t1b renal tumors(7). however, the long-term clinical and oncologic outcomes of lrn and lpn remain to be defined. department of urology, peking union medical college hospital, chinese academy of medical sciences and peking union medical college. 1 shuaifuyuan road, beijing, china, 100730. *correspondence: department of urology, peking union medical college hospital, chinese academy of medical sciences and peking union medical college, beijing 100730, china. tel: +86 138 1003 3903. fax: +86 010-8915 2510. e-mail: zhangyushi2014@126.com. received march 2017 & accepted in the current study, we reviewed a single-institution database of patients treated with lpn and lrn for clinical t1b renal cell carcinoma to assess long-term clinical and oncologic outcomes. materials and methods study design institutional review board approval was obtained for this retrospective study. we reviewed the records of all patients who underwent lpn or lrn between january 2005 and january 2012 at peking union medical college hospital. all patients were preoperatively evaluated with computed tomography or magnetic resonance imaging. only those with histologically confirmed rcc, a solitary tumor with a maximum diameter of 4.0 to 7.0 cm (clinical stage t1b) and a minimum 2-year post treatment radiographic follow up were included in analysis. patients with synchronous bilateral, clinic stage tumor (ct) ≥ 2, benign tumors in pathology specimens and those who underwent open surgery (laparoscopic switch open surgery also was excluded) were excluded from study. in addition, patients with solitary kidneys or end-stage renal disease (esrd) (stage 5, estimated glourological oncology 16 merular filtration rate (egfr) <15ml/minute/1.73m2) were excluded from the study as well. estimated gfr was calculated using the modification of diet in renal disease equation, egfr in ml/minute/1.73m2 =186.3×(serum creatinine)-1.154×(age)-0.203 × (0.742 if female)(10). statistical analysis the spss software package (version 17.0) was used for all statistical analysis. between-group comparisons were assessed using student’s t-test, chi-square test, mann-whitney test or fisher exact test. the kaplan-meier method was applied to generate survival curves, which were compared using the log rank test. multivariable cox regression analysis performed to determine predictors of survival. p value < 0.05 was defined as statistically significant. results patient clinical characteristics between january 2005 and january 2012, a total of the 633 patients underwent lpn or lrn, including 39 and 160 patients treated with lpn and lrn, respectively (figure 1). table 1 lists patient demographics and tumor characteristics. the mean age in the lpn cohort was 54 (range: 20-79) years and in the lrn cohort was 53 (range: 38-74) years (p = .63). there were no differences in tumors size (4.97 vs 5.29cm, p = .08), and pathological stage distribution between the two cohorts. the mean follow-up was 67 (range: 18-118) months in the lpn cohort and 70(19-120) months in the lrn cohort (p = .29). no significant differences were observed between the two groups for patients’ sex, body mass index, diabetes mellitus, coronary artery disease, hypertension and preoperative egfr. there was no significant difference in tumor characteristics between the two cohorts, including the laterality of the affected kidney, histology subtype, fuhrman nuclear grade, pathologic stage and histology feature (table 1). only one patient in the lpn cohort was diagnosed with positive surgical margin, because the tumor was located completely within the renal parenchyma. the patient died from cardiovascular disease 36 months after lpn for a 5.2cm clear renal cell carcinoma, however, the patient did not experience local recurrence or metastasis. renal function analysis table 1 displays renal functional outcomes. preoperative gfr was 78.94 ± 18.74 and 85.27 ± 19.87ml/ minute/1.73m2 in the lpn and lrn cohorts (p = .09), and the early gfr (lowest measured value 7 to 180 days postoperatively) was 66.43 ± 23.08 and 59.59 ± 15.42 ml/minute/1.73m2, respectively (p = .04). the latest gfr (value at last followup) was 67.14 ± 17.07 and 52.36 ± 13.21ml/minute/1.73m2, respectively (p < .001). the median percent decrease in gfr was 15.04% and 38.59% after lpn and lrn, respectively (p < .001). renal functional outcomes of lpn were superior to those of lrn both in early and long term follow-up period. table 1. baseline demographics and patient characteristics. characteristics lpn(n=39) lrn(n=160) p-value age, median(range) 53 (38-74) 54 (20-79) 0.632 gender (%) male(%) 26 (67%) 97(61%) 0.486 female(%) 13 (33%) 63(39%) bmi(kg/m2), mean±sd 23.55 ± 3.82 23.25 ± 4.19 0.654 asa score, mean±sd 1.96 ± 0.44 1.95 ± 0.49 0.461 follow-up(months), median(range) 67 (18-118) 70 (19-120) 0.293 laterality right(%) 21 (54%) 68 (43%) 0.201 left(%) 18 (46%) 92 (57%) no. hypertension (%) 13 (33%) 55 (34%) 0.902 no. diabetes mellitus (%) 4 (10%) 24 (15%) 0.445 no. coronary artery disease (%) 1 (3%) 6 (4%) 0.718 mean tumor size (cm), mean±sd 4.97 ± 0.75 5.29 ± 0.74 0.082 no. histology (%): clear cell rcc 28 (72%) 129 (81%) 0.226 other rcc subtype 11 (28%) 31 (19%) papillary rcc 8 15 chromophobe rcc 3 12 translocation rcc xp11.2 2 carcinoma of the collecting ducts of bellini 2 histology feature sarcomatoid-change (%) 1 (3%) 5 (3%) 0.854 tumor necrosis (%) 3 (8%) 15 (9%) 0.743 no. fuhrman nuclear grade (%) 1 or 2 30 (77%) 115 (72%) 0.525 3 or 4 9 (23%) 45 (28%) psm 1(3%) pt stage, (%) pt1 37 (95%) 145 (91%) 0.394 ≥ pt2 2 (5%) 15 (9%) gfr ml/min/1.73m2 pretreatment 78.94 ± 18.74 85.27 ± 19.87 0.091 early 66.43 ± 23.08 59.59 ± 15.42 0.042 latest 67.14 ± 17.07 52.36 ± 13.21 < 0.001 median % renal functional decrease 15.04% 38.59% < 0.001 abbreviations: bmi,body-mass index; lpn,laparoscopic partial nephrectomy; lrn,laparoscopic radical nephrectomy; asa, american society of anesthesiologists; psm, positive surgical margins; pt stage, pathological tumor stage. comparison of lpn and lrn long-term outcomes for ct1b rcc-cai et al. vol 15 no 02 march-april 2018 17 overall and cancer specific survival analysis the 5-year and 10-year overall survival (os) in patients who underwent lpn was 93.33% and 85.56%, respectively, and in the lrn cohort, 85.69% and 73.41%, respectively (log-rank test p = .15) (figure. 2a). the 5-year and 10-year os seems to be better in the lpn cohort compared with lrn, however, this difference showed marginally significant. in the lpn cohort, the 5-year cancer specific survival (css) was 96.00% and 10-year css was 88.00%. in the lrn cohort, the 5-year css was 91.35% and 10-year css was 82.85%. the difference was not significant between the two groups for 5 or 10 year css (log-rank test p = .39) (figure 2b). the factors that significantly affected os were the patients’ age, pt stage and preoperative asa score. each year of age increased the risk of death by 1.02-fold. the increase of the asa class one point increased 1.65-fold the risk of death. the increase of the pt stage (pt1 vs. pt2 vs. ≥ pt3) by one unit increased the risk of death by 1.36-fold. os was not affected by the surgical technique or fuhrman grade (table 2). css was significantly affected by the patients’ age and pt stage. however, css was not affected by the surgical technique, preoperative asa score or fuhrman grade (table 2). discussion the optimal treatment for clinical t1b rcc is controversial at present, partial nephrectomy is becoming an alternate standard to radical nephrectomy in the management of t1b tumors. milonas d et al(11) in their study reported that open partial nephrectomy showed better 12-year os (55.2% vs 53.7%) and css (80.6% vs 69.6%) compared with open radical nephrectomy, although no significant differences were observed between the two groups. emerging data demonstrate feasibility of lpn for increasing the proportion of ct1b tumors; however, recent trends analyses demonstrate that the majority of t1b pn are still carried out by open surgery, and concerns continue about prolonged ischemic times and risk of bleeding(12). lpn appears to have comparable short-term functional and oncologic outcomes relative to lrn. in one of the most recent studies with about 20 months follow-up conducted by deklaj t.(8), lpn was an approach to nss that was feasible and associated with preservation of intermediate-term renal function compared with lrn. a prospective, randomized eortc intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy showed that nss seems to be significantly less effective than rn in terms of os, however, the major parts of patients were low-stage renal cell carcinoma (≤ 5 cm)(13). long-term results of oncologic and functional outcomes comparison of lpn and lrn for clinical t1b renal cell carcinoma remain to be defined. our study is specific because it reported 10-year oncologic and renal functional outcomes of lpn and lrn for ct1b rcc. in our study, the 5-year os in the lrn group was 93.33% compared with 85.69% in the lrn group; and the 10-year os was 85.56% and 73.41%, respectively. css at 5 years was 91.35% and 96.00% in the lrn and lpn groups, respectively; and at 10 years, 82.85% and 88.00%. better 10-year os and css in lpn cohort were also observed in the current study, although the difference was not significant. on multivariate analysis, patients’ age, asa score and pathological stage were the major factors affecting overall survival, and patients’ age and pathological stage was the associated with cancer specific survival. no significant differences in os or css were observed according to surgical approach. there were no local recurrences in lrn group. one patient in the lpn group demonstrated local recurrence and received radical surgery three years after lpn. then, he got sorafenib treatment and was alive in a recent follow-up. another one lpn patient was table 2. predictors of overall survival and cancer specific survival for patients. os css variables univariable multivariable univariable multivariable hr(95% ci) p-value hr(95% ci) p-value hr(95% ci) p-value hr(95% ci) p-value age 1.45 (1.36-1.54) < 0.001 1.17 (1.10-1.24) < 0.001 1.07 (1.01-1.12) 0.012 1.16 (1.08-1.23) 0.022 asa score 1.58 (1.39-1.78) < 0.001 1.64 (1.21-2.14) 0.008 1.79 (1.12-2.58) 0.043 1.56 (0.97-2.23) 0.094 pt stage (pt1 vs ≥ pt2) 1.98(1.83-2.17) <0.001 1.39(1.13-1.45) < 0.001 2.13(1.83-2.79) < 0.001 1.62(1.23-2.08) < 0.001 fuhrman grade (1/2 vs 3/4) 0.47(0.38-0.62) 0.022 0.65(0.19-2.15) 0.482 0.39 (0.22-0.58) 0.031 0.63(0.19-2.12) 0.462 lpn vs lrn 1.45（0.78-3.26（ 0.461 1.37(0.41-4.55) 0.603 1.21(0.56-3.78) 0.553 1.13(0.36-3.47) 0.833 abbreviations: os, overall survival; css, cancer specific survival; pt stage, pathological tumor stage; asa, american society of anesthesiologists; lpn, laparoscopic partial nephrectomy; lrn, laparoscopic radical nephrectomy. figure 1. study population included in analysis. comparison of lpn and lrn long-term outcomes for ct1b rcc-cai et al. urological oncology 18 found psm because the tumor was located completely within the renal parenchyma, although we used scissors to remove the tumor with a margin of 0.5cm. the patient died for cardiovascular disease 3 years after lpn, however, the patient did not experience local recurrence or metastasis. interesting, several studies demonstrated that psm were not associated with tumor recurrence, which may be explained by ischemic damage to residual tumor from hemostatic sutures, or intraoperative fulguration of the tumor bed(14,15). the most important aims of pn is to preserve renal function. in this study, renal functional outcomes of lpn were superior to those of lrn both in early and long term follow-up period. chronic renal insufficiency is a well-established risk factor for the development of anemia, hypertension, malnutrition, and neuropathy (16,17). it is associated with poorer quality of life, increased risk of hospitalization, cardiovascular events, and death(18,19). better health-related quality of life also represents an advantage of lpn relative to lrn and may cancel out some of the short-term disadvantages of lpn, relative to lrn. our study has several limitations(1). this was a retrospective design with obvious selection bias. however, the baseline patients’ characteristics were comparable in the two groups (table 1)(2). given the significant number of patients who were lost to followup, survival outcomes in our study may be underestimated or overestimated(3). our sample sizes were relatively small. despite these limitations our results support the clinical usefulness of lpn in approximately selected patients with ct1b rcc. a randomized, controlled trial in larger samples could be ideal and may be done in the future to validate our preliminary results. conclusions lpn is an effective treatment option in appropriately selected patients with ct1b rcc. it provides 5-year, and 10-year overall survival and cancer specific survival comparable to those of lrn as well as better preservation of renal function than lrn. overall survival and cancer specific survival are associated with nonmodifiable factors but not by the choice of operative technique. acknowledgments this research was supported by the national natural science foundation of china (81670611) and pumch youth scientific research fund (ih1028800). figure 2. overall survival (a) and cancer-specific survival (b) according the surgical type (lpn vs lrn). conflict of interest the other authors declare that they have no competing interests. references 1. ljungberg b, bensalah k, canfield s, et al. eau guidelines on renal cell carcinoma: 2014 update. eur urol. 2015;67:913-24. 2. liss ma, wang s, palazzi k, et al. evaluation of national trends in the utilization of partial nephrectomy in relation to the publication of the american urologic association guidelines for the management of clinical t1 renal masses. bmc urol. 2014;14:101. 3. karakiewicz pi, lewinshtein dj, chun fk, et al. tumor size improves the accuracy of tnm predictions in patients with renal cancer. eur urol. 2006;50:521-8; discussion 9. 4. volpe a, amparore d, mottrie a. treatment outcomes of partial nephrectomy for t1b tumours. curr opin urol. 2013;23:403-10. 5. m crépel cj, p perrotte , u capitanio , h isbarn , sf shariat , d liberman , m sun , g lughezzani , p arjane , h widmer , m graefen , f montorsi , j patard , pi karakiewicz nephron-sparing surgery is equally effective to radical nephrectomy for t1bn0m0 renal cell carcinoma: a population-based assessment. urology. 2010;75:271-5. 6. simmons mn, chung bi, gill is. perioperative efficacy of laparoscopic partial nephrectomy for tumors larger than 4 cm. eur urol. 2009;55:199-207. 7. aron m, gill is. minimally invasive nephronsparing surgery (minss) for renal tumours part i: laparoscopic partial nephrectomy. eur urol. 2007;51:337-46; discussion 46-7. 8. deklaj t, lifshitz da, shikanov sa, katz mh, zorn kc, shalhav al. laparoscopic radical versus laparoscopic partial nephrectomy for clinical t1bn0m0 renal tumors: comparison of perioperative, pathological, and functional outcomes. j endourol. 2010;24:1603-7. 9. alyami fa, rendon ra. laparoscopic partial nephrectomy for >4 cm renal masses. can urol assoc j. 2013;7:e281-6. comparison of lpn and lrn long-term outcomes for ct1b rcc-cai et al. vol 15 no 02 march-april 2018 19 10. levey as, bosch jp, lewis jb, greene t, rogers n, roth d. a more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. modification of diet in renal disease study group. ann intern med. 1999;130:461-70. 11. milonas d, skulcius g, baltrimavicius r, et al. comparison of long-term results after nephron-sparing surgery and radical nephrectomy in treating 4to 7-cm renal cell carcinoma. medicina (kaunas). 2013;49:2238. 12. lee hj, liss ma, derweesh ih. outcomes of partial nephrectomy for clinical t1b and t2 renal tumors. curr opin urol. 2014;24:44852. 13. van poppel h, da pozzo l, albrecht w, et al. a prospective, randomised eortc intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. eur urol. 2011;59:543-52. 14. ani i, finelli a, alibhai sm, timilshina n, fleshner n, abouassaly r. prevalence and impact on survival of positive surgical margins in partial nephrectomy for renal cell carcinoma: a population-based study. bju int. 2013;111:e300-5. 15. favaretto rl, sanchez-salas r, benoist n, et al. oncologic outcomes after laparoscopic partial nephrectomy: mid-term results. j endourol. 2013;27:52-7. 16. go as, chertow gm, fan d, mcculloch ce, hsu cy. chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. n engl j med. 2004;351:1296305. 17. huang wc, levey as, serio am, et al. chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. lancet oncol. 2006;7:735-40. 18. mukkamala a, he c, weizer az, et al. longterm renal functional outcomes of minimally invasive partial nephrectomy for renal cell carcinoma. urol oncol. 2014;32:1247-51. 19. rh thompson sb, cm lohse , bc leibovich , ed kwon , jc cheville , ml blute radical nephrectomy for pt1a renal masses may be associated with decreased overall survival compared with partial nephrectomy. the j urol. 2008;179:468-73. comparison of lpn and lrn long-term outcomes for ct1b rcc-cai et al. urological oncology 20 anterior urethral advancement as a single-stage technique for repair of anterior hypospadias: our experience reconstructive surgery venkat a. gite, jayant v. nikose,* sachin m. bote, saurabh r. patil purpose: many techniques have been described to correct anterior hypospadias with variable results. anterior urethral advancement as one stage technique was first described by ti chang shing in 1984. it was also used for the repair of strictures and urethrocutaneous fistulae involving distal urethra. we report our experience of using this technique with some modification for the repair of anterior hypospadias. materials and methods: in the period between 2013-2015, 20 cases with anterior hypospadias including 2 cases of glanular, 3 cases of coronal, 12 cases of subcoronal and 3 cases of distal penile hypospadias were treated with anterior urethral advancement technique. patients’ age groups ranged from 18 months to 10 years. postoperatively, patients were passing urine from tip of neomeatus with satisfactory stream during follow up period of 6 months to 2 years. results: there were no major complications in any of our patients except in one patient who developed meatal stenosis which was treated by periodic dilatation. three fold urethral mobilization was sufficient in all cases. conclusion: anterior urethral advancement technique is a single-stage procedure with good cosmetic results and least complications for anterior hypospadias repair in properly selected cases. keywords: advancement; anterior urethra; hypospadias; urethral mobilization; urethrocutaneous fistula. introduction most (65-70%) hypospadias cases occur in anteri-or while 30% are in posterior urethra.(1) urethral reconstruction represents a great challenge in urologic surgeries.(2) many techniques have been demonstrated to treat anterior hypospadias. one of these is anterior urethral advancement, first described by ti chang shing in 1984.(3) later on various experiences have been reported for urethral advancement as a treatment of hypospadias with some drawbacks.(1) the aim of this study was to modify this technique and assess the results with our modification. materials and methods study population a total of 20 patients of anterior hypospadias were treated during the period between june 2013 to december 2015 by anterior urethral advancement technique. inclusion criteria: cases who presented with varying degrees of anterior hypospadias. exclusion criteria: patients with hypoplastic distal urethra, severe chordee, mid penile and proximal penile hypospadias were excluded from this study. the preoperative meatal sites were glanular in 2 cases, coronal in 3 cases , subcoronal in 12 cases and distal penile in 3 cases. commonest age group was 2-5 years in 10 cases (50%). sixteen cases were non-circumcised and 4 were circumcised. all patients were subjected to history, general and local examination of genitalia and coagulation profile. department of urology, grant govt. medical college and sir j.j. group of hospitals, mumbai, maharashtra, india. *correspondence: saikrupa, h-21, tirupati supreme enclave, jalan nagar, aurangabad. 431005. phone90116546446. email: balajigite@yahoo.com. received may 2016 & accepted january 2017 surgical technique all patients were operated under general anesthesia. a 6/0 traction suture was placed at the tip of glans penis. feeding tube was introduced into urethra (figure 1). distance between hypospadiatic meatus and tip of glans was measured and recorded (figure 2).circumcising incision, 5mm proximal to coronal sulcus with ‘u’ shaped extension proximal to hypospadiatic meatus on ventral aspect was made. degloving of skin down to penoscrotal junction was done to release cutaneous chordee. dissection of urethra stared in proximal area in avascular plane and was maintained above the tunica albuginea covering each corpus cavernosum medially till reaching beneath the corpus spongiosum upto the hypospadiatic meatus (figure 3). after 2/3rd mobilization of urethra inspite of deep vertical or transverse glanular slit, we excised 1-2mm rim of ventral glanular mucosa in full depth along with strip of urethral plate (our modification) so that there was adequate space to accommodate the urethra. trimming of distal urethra in oblique fashion about 2mm more on ventral aspect was done. two glanular wings were satisfactorily mobilized laterally. tension free anastamosis was accomplished from urethra to glans with interrupted sutures. two glans wings were closed in two layers over the urethra (figure 4). intermittent fixation sutures were taken between tunica albuginea of corpus cavernosa and corpus spongiosum. bayer’s flap and closure of skin was done. urethral feeding tube was secured with glanular retention sutures (figure 5). dressing was applied. all vol 14 no 04 july-august 2017 4034 table 1. demographic and operative data. variables no. of patients distance between hypospadiatic < 0.5 cm 2 meatus to tip of glans 0.5-1 cm 15 1.1-2 cm 3 site of hypospadiac meatus glanular 2 coronal 3 subcoronal 12 distal penile 3 age groups 1-1.9 years 8 2-4.9 years 10 5-10 years 2 complications meatal stenosis 1 patients received broad spectrum antibiotics and anti-inflammatory drugs for seven days. proximal urinary diversion was not used in any of our cases. feeding tube was removed on 10th postoperative day . results all patients passed urine from the tip of the penis with good stream after removal of per uretehral feeding tube. three fold urethral mobilization (the distance between hypospadiatic meatus to tip of the glans penis ) was sufficient to achieve tension free anastamosis in all cases (table 1). the extent of advancement of urethra ranged from 0.5 to 2 cm. none of the patients had major complications like stricture, dehiscence or fistula, except one case which had meatal stenosis which occurred during our early experience (table 1). the long term outcome was satisfactory with regards to functional and cosmetic aspect (adequate sized meatus at tip of glans and good urinary stream). discussion for anterior hypospadias, the improvement in the cosmetic appearance of penis is the most important indication for surgery.(4) many techniques have been described to correct anterior hypospadias.(5) the goal of hypospadias repair is to have functionally and cosmetically normal penis.(1) the preoperative meatal sites were glanular in 2 cases, coronal in 3 cases, subcoronal in 12 cases and distal penile in 3 cases (table 1). common age group was 2-5 years in 10 cases (table 1). sixteen cases were non-circumcised and 4 were circumcised. various techniques used to treat anterior hypospadias have their own drawbacks like breakdown of repair due figure 1. (a): pre op image with feeding tube; (b): measurement of urethral plate. figure 2. (a): dissection of urethra in proximal area; (b): excision of ventral glanular mucosa with urethral plate; (c): intermittent fixation sutures between tunica and corpus cavernosa and spongiosa; (d): glans wings closed in layers. anterior urethral advancement technique for anterior hypospadias repair-gite et al. reconstructive surgery 4035 to precarious blood supply in mathieu, meatal regression and stenosis in meatal advancement and glanuloplasty (magpi). results of tubularised incised plate urethroplasty (tips) repair depend on various factors like characters of urethral plate, together with an incidence of disruption, fistula and meatal stenosis.(1) urethral advancement is considered as a good single-stage technique for distal hypospadias repair,(2) but the main drawback for this technique was meatal stenosis and need for high degree of expertise of the surgeon to dissect the urethra without causing any injury. (3) various methods used to decrease meatal stenosis are vertical and horizontal slitting of the glans, tunneling of the glans using hair transplant apparatus, and trimming of urethra in an oblique fashion about 1 to 2 mm more on vertical aspect.(3) in all our cases, the entire urethral plate was made free from corpora in glanular area by cutting 1 to 2 mm rim of ventral glanular mucosa in full depth with satisfactory lateral mobilization of glanular wings which is not described in other series, along with oblique spatulation of urethra. by this technique, in our series only one patient developed meatal stenosis which happened during early phase of our experience. this was resolved by twice weekly dilatation with feeding tube under local anesthesia for two weeks. urethral mobilization should be started proximally where urethra is surrounded by spongiosa all around and not distally where spongiosa tissue splayed laterally.(1) threefold urethral mobilization can provide tension free urethral anastomosis in patients with anterior hypospadiasis as observed in our series,(5) however atala et al. described 4 to 5 fold urethral mobilization to provide tension free urethral anastomosis. this difference may be due to inclusion of mid shaft hypospadias cases in their series.(6) the extent of urethral advancement in our series ranged from 0.5 to 2 cm, matching with other series where maximum urethral advancement was 1.5 cm,(7) 2.1 cm,(1) and 2.5 cm.(8) average operative time to dissect urethra in our series was 40 minutes matching with 30 to 60 minutes described by awad et al.(3) we did not employ proximal diversion except per urethral feeding tube which was kept for 10 days. stenting or urinary diversion is unnecessary after distal hypospadias surgery.(6) urethral advancement for distal hypospadias repair has variable incidence of fistula ranging from less than 1% to 16.7%.(2) in our series postoperative fistula was not recorded as we had fixed the healthy distal end of urethra to the tip of glans penis after excision of unhealthy distal 2 mm of urethra, with meticulous dissection of urethra without injuring it. absence anastomosis between urethra and the neo-urethra may also be the reason for absence of fistula. in our series patients were followed up from 6 months to 2 years with respect to site and size of the meatus, caliber of urinary stream, presence of fistula and chordee. all patients had cosmetically and functionally normal penis with 100 % success rate in our series by this technique with our modification except one case who developed meatal stenosis which was resolved by meatal dilatation. in a series of aawad et al., 3.9 % patients developed meatal stenosis which was resolved by dilatation.(3) anterior urethtral advancement with our modification is easy to learn, rapid procedure and gives excellent results. however, limitation of our study is small number of cases and technique applied to a selected group of patients. conclusions anterior urethral advancement technique is a single-stage procedure with best cosmetic results with least complications for anterior hypospadias in properly selected cases. conflict of intrest none of the contributing authors have any conflict of intrest, including specific financial interests or relationships and affiliations relevant to the subject matter or figure 3. postoperative image. figure 4. voiding photo with satisfactory stream at 6 months follow up. anterior urethral advancement technique for anterior hypospadias repair-gite et al. vol 14 no 04 july-august 2017 4036 materials discussed in the manuscript. references 1. alaa el-din a.m. elmoghazy, h.m. hammouda, y.s. hassan, a.m. abdelateef, m.a. elgammal. further experience with urethral advancement for anterior hypospadias repair. egypt j. plast. reconstr. surg. 2009; 33: 119-22. 2. m.m.el-saadi, adel m. tolba, abdeirahman sarhan. anterior urethral advancement in repair of hypospadias: a modification of the technique. annals of paediatric surgery. 2010; 6: 18-21. 3. mohamed m. s. awad. urethral advancement technique for repair of distal penile hypospadias: a revisit. indian j plast surg. 2006; 39: 34-8. 4. yves heloury, earl y. cheng. distal hypospadias: circumcision vs preputial reconstruction. j urol. 2014; 191: 17-9. 5. youssef saleh hassen, atef mohamed abdelateef. new concept in urethral advancement for anterior hypospadias. egypt j plast reconstr surg. 2008; 32: 223-7. 6. atala a. urethral mobilization and advancement for mid shaft to distal hypospadias. j urol. 2002; 168: 1738. 7. haberlik a., schmidt b., uray e., mayr j. hypospadias repair using a modification of beck’s operation: follow-up. j urol. 1997; 157: 2308. 8. koff s.a. mobilization of the urethra in the surgical treatment of hypospadias. j urol. 1981; 125: 394. anterior urethral advancement technique for anterior hypospadias repair-gite et al. reconstructive surgery 4037 pediatric urology dextranomer-hyaluronic acid and polyacrylate-polyalcohol copolymer are equally efficient for endoscopic treatment of vesicoureteral reflux in children uros bele1*, dejan bratus1 purpose: to compare the efficacy of two bulking agents, dextranomer-hyaluronic acid (dxha) and polyacrylate-polyalcohol copolymer (ppc) used for endoscopic treatment of vesicoureteral reflux (vur). materials and methods: we endoscopically treated 125 patients (89 girls and 36 boys) diagnosed with vur grades i-v, comprising a total of 174 refluxing ureters (rus). patients were categorized into two groups, 99 (56,9%) rus were treated with dxha (group 1) and 75 (43,1%) rus with ppc (group 2). rus treated with both bulking agents were excluded. the success of treatment was evaluated with postoperative vcug at 3and 12-months after the endoscopic procedure, only complete resolution of vur was considered as treatment success. data was collected and analyzed retrospectively. statistical calculations were performed using the chi-square test. results: after a single injection 80,0% (60/75) and 68,7% (68/99 rus) of rus resolved completely when treated with ppc and dxha, respectively (p = .094). a second injection of ppc healed another 10 rus (total 93,3%), whereas dxha resolved additional 16 rus (total 84,8%) (p = .097). a third injection was needed for 1 ru, treated with ppc and another 3 rus with dxha. twelve months post-operatively, we achieved a total resolution rate of 94,7% (71/75 rus) with ppc, while dxha successfully treated 87,9% (87/99) of rus (p = .125). conclusion: dxha and ppc showed no statistically significant differences neither in the number of injections needed nor in the total success rate after 12 months of follow-up. keywords: deflux; dextranomer hyaluronic acid; endoscopic injection; polyacrylate polyalcohol copolymer; vantris, vesicoureteral reflux introduction vesicoureteral reflux (vur) is a common urological condition in children, which can in the presence of urinary tract infections (uti) lead to renal scarring, hypertension and renal failure(1). endoscopic treatment of vur with injecting a bulking agent beneath the ureteral orifice and the distal ureter has become widely accepted and performed in several urological centers worldwide. although no strict recommendations have been made regarding the indication for open surgical procedures versus endoscopic treatment(1), some authors believe that endoscopic interventions should be first line treatment, regardless of vur grade(2). although several reports on effectiveness of different bulking agents for treating vur have been published, no clear consensus has been made, which bulking agent showed best results. it is not only vur resolution rate, but also other aspects, such as protection against uti, effective long-term results, treatment complications and others, that must be considered as an important factor of an effective bulking agent(3). the aim of our study was to compare the efficacy of two different bulking agents: a) dextranomer-hyaluronic acid (dxha) (deflux®, q-med scandinavia, uppsala, sweden) and b) polyacrylate-polyalcohol copolymer department of urology, university medical centre maribor, ljubljanska ulica 5, si-2000 maribor, slovenia. *correspondence: department of urology, university medical centre maribor, ljubljanska ulica 5, si-2000 maribor, slovenia. tel.: +386 40 731 510, fax: +386 2 332 48 30, e-mail: uros.bele@gmail.com. received march 2018 & accepted august 2018 (ppc) (vantris®, promedon, córdoba, argentina) used for endoscopic vur treatment. this is, to our knowledge, the biggest study, that directly compared these two substances. materials and methods study population between january 2005 and july 2014, we endoscopically treated 125 patients (89 girls and 36 boys). vur was unilateral in 76 patients (60,8%) and bilateral in 49 patients (39,2%), comprising a total of 174 refluxing ureters (rus) (table 1). inclusion criteria were pediatric patients, with unilateral or bilateral vur grade i – v (based on the international classification of vur), with breakthrough febrile uti, despite antibiotic prophylaxis with trimethoprim/sulfametoxasol. exclusion criteria were anatomical abnormalities of the urinary tract (including posterior urethral valves, double urinary collecting system or ectopic ureter), presence of hydronephrosis, functional bladder anomalies or treatment with both bulking agents (dxha and ppc). the study has been reviewed and approved by the committee for medical ethics of the university medical centre maribor. urology journal/vol 16 no. 4/ july-august 2019/ pp. 361-365. [doi: http://dx.doi.org/10.22037/uj.v0i0.4462] study design patients that met the inclusion criteria were enrolled in our study. we performed renovesical ultrasound and voiding cystourethrography (vcug) on all patients preoperatively and 3-months and 12-months after the endoscopic procedure. patient were categorized into two groups, based on the bulking agent which they were treated with. data was collected and analyzed retrospectively. we treated 99 (56,9%) rus with dxha (group 1) and 75 (43,1%) rus were treated with ppc (group 2). patients received different bulking agents, based on the availability of each bulking agent in our medical centre. rus treated with both bulking agents were excluded from our study. surgical technique endoscopic treatment was performed by two experienced urologists. patients received general anesthesia and were placed in the lithotomy position. we performed the sting procedure, using a rigid, ch 9 cystoscope with 0°optics to perform a subureteral injection of the selected bulking agent just below the ureteral orifice at 6 o’clock position. the method of administration of the bulking agent was the same for both treatment groups. outcome assessment the success of treatment was evaluated using the postoperative vcug at 3and 12-months after the endoscopic procedure. to exclude potential vcug evaluator influences on the postoperative vcug assessments, the bulking agent used was only known to the surgeon. the treatment was considered as successful if 12-months postinjection vcug showed complete vur resolution. if during follow-up vur persisted or was only downgraded, it was considered as a therapeutic failure. statistical calculations were performed using the chi-square test, with ibm spss statistics software (ibm, armonk, usa). values p < .05 were considered as significant. results altogether we treated 174 rus. demographic data, together with the distribution of rus among treatment groups and different vur grades is shown in table 1. after a single injection 80,0% (60/75) of rus resolved completely when treated with ppc, in contrast to a success rate of 68,7% (68/99 rus) with dxha (p = .094) (table 2). a second injection of ppc healed another 10 rus (total 93,3%), whereas dxha resolved additional 16 rus (total 84,8%) (p = .097). a third injection was needed for 1 ru, treated with ppc and another 3 rus with dxha. twelve months post-operatively, we achieved a total resolution rate of 94,7% (71/75 rus) with ppc, while dxha successfully treated 87,9% (87/99) of rus (p = .125). the treatment success within each vur grade for both treatment groups are presented in table 3 and table 4. endoscopic treatment was unsuccessful in 5,3% (4/75 rus) with ppc, of which 2 rus (2,7%) were treated with open surgical procedures and 2 children (2 rus) discontinued treatment. the failure rate of dxha was 12,1% (12/99 rus), of which 9 rus (9,1%) were treated with open surgical procedures and 3 children (3 rus) discontinued treatment. we observed 2 complications after endoscopic treatment, one in each study group. in study group 1 dxha versus ppc treatment of vur in children bele et al. table 1. demographic data and patient characteristics. primary vur cases (rus) 174 unilateral 76 (43,7%) bilateral 98 (56,3%) patients dxha ppc total male 22 (31%) 14 (26%) 36 (28,8%) female 49 (69%) 40 (74%) 89 (71,2%) total 71 54 125 mean age 3,98 yrs 2,64 yrs vur grade (rus) i 2 (2,0%) 1 (1,3%) 3 (1,7%) ii 36 (36,3%) 26 (34,7%) 62 (35,6%) iii 48 (48,5%) 38 (50,7%) 86 (49,5%) iv 11 (11,1%) 9 (12,0%) 20 (11,5%) v 2 (2,0%) 1 (1,3%) 3 (1,7%) total rus 99 75 174 abbreviations: dxha, dextranomer-hyaluronic acid; ppc, polyacrylate-polyalcohol copolymer; rus, refluxing ureters; vur, vesicoureteral reflux; yrs, years. table 2. treatment results. dxha ppc p-value* n° rus treated 99 75 correction after 1st injection 68 (68,7%) 60 (80,0%) 0,094 2nd injection 16 (16,1%) 10 (13,3%) 0,097 3rd injection 3 (3,1%) 1 (1,3%) / total success 87 (87,9%) 71 (94,6%) 0,125 failure 12 (12,1%) 4 (5,3%) *chi-square test abbreviations: dxha, dextranomer-hyaluronic acid; n°, number of; ppc, polyacrylate-polyalcohol copolymer; rus, refluxing ureters. vur grade i ii iii iv v n° rus treated 2 36 48 11 2 correction after 1st injection 2 (100,0%) 32 (88,9%) 30 (62,5%) 4 (36,3%) 0 2nd injection 0 4 (11,1%) 10 (20,8%) 2 (18,2%) 0 3rd injection 0 0 1 (2,1%) 1 (9,1%) 1 (50,0%) total success 2 (100,0%) 3 (100,0%) 41 (85,4%) 7 (63,6%) 1 (50,0%) failure 0 0 7 (14,6%) 4 (36,4%) 1 (50,0%) abbreviations: n°, number of; rus, refluxing ureters; vur, vesicoureteral reflux. table 3. treatment results per vur grade for dextranomer-hyaluronic acid (dxha). vol 16 no 04 july-august 2019 362 (dxha) one patient (1 ru, 1% rus), who was successfully treated, with no signs of hydronephrosis or residual vur, gradually worsened in kidney function, finally resulting in a non-functional kidney, thus we performed a nephrectomy. in study group 2 (ppc) we noticed a hydronephrosis in one patient (1 ru, 1,3% rus) on the site, where the bulking agent was injected. an endoscopic revision was performed with a partial removal of the bulking agent. during follow-up hydronephrosis gradually resolved, with no signs of vur. in the study we observed the development of a new, contralateral vur in 4 patients (4% rus) that were treated with dxha. discusion the first description of endoscopic vur treatment with subureteral injection of teflon was described in 1981 by matouschek(4). since then several different bulking agents were described and the endoscopic technique nowadays represents an attractive, minimally invasive alternative to open surgical procedures. although the success of endoscopic treatment versus open surgical techniques has always been questioned, recent studies confirmed that endoscopic treatment of vur grades ii to iv are as effective as ureteral reimplantation, during shortand long-term follow up(5). several factors that affect the vur resolution rate after endoscopic and surgical interventions have been identified. during the first 3 years of follow up, vur resolution rates decrease with patients’ history of voiding dysfunction, breakthrough infections and “golf-hole” or “stadium” ureteral orifice appearance and increase with increased ureteral orifice distance(6). with longer follow-up (up to 11 years), high vur grade, but also ureteral orifice appearance and a history of pyelonephritis, have been identified as factors, contributing to a higher failure rate, with up to 67% failure rate for vur grade v(7). despite several published studies using different bulking agents, no clear consensus has been made, which bulking agent showed best results. the success rates of endoscopic vur treatment with dxha differ from one study group to another. the overall success rates described range from 68%-92% and the quite large success range interval is probably vur grade dependent(8). longer follow-up studies with promising short-term success rates of 84% show more recurrences during longer follow-up, with a decreased success rates to 74% during their mean follow-up time of 5 years, although the vur grade in this study was grade 3 or greater(9). our results with dxha show a complete vur resolution rate of 87,9% after 12 months of follow-up. similar conclusions could be drawn from the study of stradele et al., who also treated 99 ru (grades ii-iv) with dxha. they report an initial 81,5% success rate with dxha at 3-month post injection. nevertheless 42 of 62 successfully treated children underwent another vcug after 3 years, which showed that only 78,5% remained free of vur.(10) one of the possible explanations for this late recurrence onset could be the biodegradable dxha properties.(11) on the other hand, ppc has a very high molecular mass and is classified as a non-biodegradable bulking agent. (12) that is why it is suspected to have better long-term results. some authors even report no vur recurrence of complex cases after a prospective, 3 years follow-up(13), although the number of patients that completed the follow up is rather small. in another study, 81% of the initial 86 rus were vur free 3 months after endoscopic treatment with ppc, although the number slightly decreased to 77% after 12 months and stayed the same after 24 months of follow-up.(14) our results with ppc do correlate with other published studies, where treatment success with a resolution rate of more than 90% was described.(3,13,15) in our study we successfully treated 94,6% of the initial 75 rus with ppc. kocherov et al. report similar or even better total success rates of 97,5%, of which 93,7% resolved after the first injection and 3,8% required a total of up to 3 injections until complete resolution.(15) also, chertin et al. report a high success rate of 89,4% after single injection of ppc and another 5,4% after a second injection with a complete success rate of 94,8%.(15) the study of corbetta et al. had a similar study design to our research and the results are comparable as well. they report an overall 92,3% success rate with ppc during their median follow-up time of 14 months.(3) as presented in table 1, 85,1% of our patients had vur grades ii-iii, which could explain the high success rates of endoscopic treatment with both substances in our study. it was shown in a meta-analysis that patient selection depending on vur grade is an important factor that influences endoscopic treatment outcomes. the primary success rates of endoscopic treatment for vur grades i and ii was 78,5% and 72% for grade iii, with furthermore decline rates of 63% and 51% for grade iv and v respectively.(16) also our results, shown in table 3 and 4, demonstrate that with higher vur grade more repeated injections and higher treatment failure rates are observed for both treatment groups. another important factor of our study is that only two experienced endoscopic urologists performed the treatment, with both bulking agents. in that way the successfulness of treatment in both study groups was not compromised. this seems a rather important factor, since it has already been shown that not only the injected table 4. treatment results per vur grade for polyacrylate-polyalcohol copolymer (ppc). vur grade i ii iii iv v n° rus treated 1 26 38 9 1 correction after 1st injection 1 (100,0%) 24 (92,3%) 31 (81,6%) 4 (44,4%) 0 2nd injection 0 2 (7,7%) 5 (13,1%) 3 (33,3%) 0 3rd injection 0 0 0 0 1 (100,0%) total success 1 (100,0%) 26 (100,0%) 36 (94,7%) 7 (77,8%) 1 (100,0%) failure 0 0 2 (5,3%) 2 (22,2%) 0 abbreviations: n°, number of; rus, refluxing ureters; vur, vesicoureteral reflux. dxha versus ppc treatment of vur in children bele et al. pediatric urology 363 material and injection location, but also sufficient experience with the injection technique seems to correlate with the treatment outcome.(17) although the complications after endoscopic vur treatment are rare, they should not be overseen. most frequently ureteral obstruction and development of a new, contralateral vur are described, but also dysuria, hematuria, fever, lumbar pain and utis without vur.(3,14,18,19,20) the reported ureteral obstruction rates for dxha vary from 0,7% to 5,7% rus (19,21) and for ppc from 1,2% to 4,6% .(3,15,22) we have observed 1 (1,3%) ureteral obstruction after ppc treatment, that was endoscopically cured with removing a part of the bulking agent. another complication occurred in the study group 1 (dxha), where we observed a gradually progressing kidney dysfunction without any signs of vur or obstruction. as described in the literature, development of a new, contralateral vur after a successful endoscopic treatment occurs in up to 10% of treated patients.(23) in our study, we detected 4 patients (4 rus, 4%) who developed a new, contralateral vur after treatment and all of them were treated with dxha. we strongly believe that the choice of a bulking agent does not affect the incidence of developing a new contralateral vur and that it was only a coincidence that all these children were treated with dxha. our results showed no statistically significant differences in success rates using dxha versus ppc. although it seems that ppc shows slightly better results, there is no statistically significant difference neither in the number of injections needed nor in the total success rate after 12 months follow-up, which does correlate to the results published by blais et al.(24) on the contrary, some studies did show a statistical significant difference in the success rates in favor of ppc(25,26), although the number of patients and rus included in our study was bigger. both substances have shown good success rates with low rates of complications. nevertheless, there is a 15% price difference per ampule of the bulking agents in favor of ppc, at least in our country. given the similar success results it does raise the question of cost effectiveness. despite efforts, our study has its limitations, one being the follow-up of 1 year. to objectify the treatment results we have performed two vcugs after the procedure on each patient, the first at 3 and the second at 12 months post-operatively, with the investing radiologist being blinded for the bulking agent used. even though pediatric nephrologists have followed-up all patients further on, no objective conclusions could be made for the follow-up past 1 year. another limitation of our study is the fact that the data was collected retrospectively. although patients were not randomized in a standard manner, they received the bulking agent based on the availability of each bulking agent in our medical center. the availability was not influenced by the researchers, which makes us certain, that this kind of patient allocation did not influence the results of our study. conclusions endoscopic treatment of vur offers an attractive, minimally invasive alternative to open surgery. the treatment success rates are high and the complication rates are relatively low. based on our result dxha and ppc have shown no statistically significant differences neither in the number of injections needed nor in the total success rate after 12 months follow-up time. nevertheless, there is a tendency of better success rates with ppc and considering the costs, we prefer using ppc in our center. conflict of interest the authors have no conflict of interest to declare. references 1. tekgül s, riedmiller h, hoebeke p, kočvara r, nijman rjm, radmayr c, et al. eau guidelines on vesicoureteral reflux in children. eur urol 2012;62:534–42. 2. lendvay ts, sorensen m, cowan ca, joyner bd, mitchell mm, grady rw. the evolution of vesicoureteral reflux management in the era of dextranomer/hyaluronic acid copolymer: a pediatric health information system database study. j urol 2006;176:1864–7. 3. corbetta jp, bortagaray ji, weller s, ruiz j, burek c, sager c, et al. the use of polyacrylate-polyalcohol copolymer hydrogel in the endoscopic treatment of primary vesicoureteral reflux in children. j pediatr surg 2015;50:485–8. 4. matouschek e. 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children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. j urol 2001;166:1887–92. 10. stredele rjf, dietz h-g, stehr m. longterm results of endoscopic treatment of vesicoureteral reflux in children: comparison of different bulking agents. j pediatr urol 2013;9:71–6. 11. lee ek, gatti jm, demarco rt, murphy dxha versus ppc treatment of vur in children bele et al. vol 16 no 04 july-august 2019 364 jp. long-term followup of dextranomer/ hyaluronic acid injection for vesicoureteral reflux: late failure warrants continued followup. j urol 2009;181:1869–74; discussion 1874–5. 12. ormaechea m, paladini m, pisano r, scagliotti m, sambuelli r, lopez s, et al. vantris, a biocompatible, synthetic, non-biodegradable, easy-to-inject bulking substance. evaluation of local tissular reaction, localized migration and long-distance migration. arch esp urol 2008;61:263–8. 13. chertin b, abu arafeh w, kocherov s. endoscopic correction of complex cases of vesicoureteral reflux utilizing vantris as a new non-biodegradable tissue-augmenting substance. pediatr surg int 2014;30:445–8. 14. sharifiaghdas f, tajalli f, otukesh h, shamsabadi rh. endoscopic correction of primary vur by using polyacrylate polyalcohol copolymer (vantris) in young girls: 2-year follow-up. j pediatr urol 2014;10:1032–6. 15. kocherov s, ulman i, nikolaev s, corbetta jp, rudin y, slavkovic a, et al. multicenter survey of endoscopic treatment of vesicoureteral reflux using polyacrylate-polyalcohol bulking copolymer (vantris). urology 2014;84:689– 93. 16. elder js, shah mb, batiste lr, eaddy m. part 3: endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infections in patients with vesicoureteral reflux. curr med res opin 2007;23 suppl 4:s15–20. 17. kirsch aj, perez-brayfield mr, scherz hc. minimally invasive treatment of vesicoureteral reflux with endoscopic injection of dextranomer/hyaluronic acid copolymer: the children’s hospitals of atlanta experience. j urol 2003;170:211–5. 18. rubenwolf pc, ebert a-k, ruemmele p, rösch wh. delayed-onset ureteral obstruction after endoscopic dextranomer/hyaluronic acid copolymer (deflux) injection for treatment of vesicoureteral reflux in children: a case series. urology 2013;81:659–62. 19. mazzone l, gobet r, gonzález r, zweifel n, weber dm. ureteral obstruction following injection of dextranomer/hyaluronic acid copolymer: an infrequent but relevant complication. j pediatr urol 2012;8:514–9. 20. ormaechea m, ruiz e, denes e, gimenez f, dénes ft, moldes j, et al. new tissue bulking agent (polyacrylate polyalcohol) for treating vesicoureteral reflux: preliminary results in children. j urol 2010;183:714–8. 21. vandersteen dr, routh jc, kirsch aj, scherz hc, ritchey ml, shapiro e, et al. postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic acid copolymer. j urol 2006;176:1593–5. 22. alizadeh f, mazdak h, khorrami mh, khalighinejad p, shoureshi p. postoperative ureteral obstruction after endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer (vantris®). j pediatr urol 2013;9:488–92. 23. menezes m, mohanan n, haroun j, colhoun e, puri p. new contralateral vesicoureteral reflux after endoscopic correction of unilateral reflux--is routine contralateral injection indicated at initial treatment? j urol 2007;178:1711–3. 24. blais a-s, morin f, cloutier j, moore k, bolduc s. efficacy of dextranomer hyaluronic acid and polyacrylamide hydrogel in endoscopic treatment of vesicoureteral reflux: a comparative study. can urol assoc j j assoc urol can 2015;9:202–6. 25. taşkinlar h, avlan d, bahadir gb, delibaş a, nayci a. the outcomes of two different bulking agents (dextranomer hyaluronic acid copolymer and polyacrylate-polyalcohol copolymer) in the treatment of primary vesicoureteral reflux. int braz j urol off j braz soc urol 2016;42:514–20. 26. karakus sc, user şr, kılıc bd, akçaer v, ceylan h, ozokutan bh. the comparison of dextranomer/hyaluronic acid and polyacrylatepolyalcohol copolymers in endoscopic treatment of vesicoureteral reflux. j pediatr surg 2016;51:1496–500. dxha versus ppc treatment of vur in children bele et al. pediatric urology 365 endourology and stone disease calculi in the prostatic surgical bed as a complication after holmium laser enucleation of the prostate young ju lee1, seung-june oh2* purpose: to report de novo calculi in the prostatic surgical bed as a complication of holmium laser enucleation of the prostate (holep). materials and methods: patients who underwent holep and were enrolled in our benign prostatic hyperplasia (bph) database registry from july 2008 to december 2015 were reviewed. cases of calculi removal in the prostatic surgical bed were identified. clinical data, including preoperative evaluation, postoperative symptoms with a detailed history, urinalysis, pathology, cystourethroscopy, and stone analysis were collected and described. results: eight patients were identified including one patient who underwent holep at another hospital. among the 877 patients in our bph database, 7 (0.8%) underwent calculi removal in the prostatic surgical bed. median age was 67.0 years. median prostatic volume was 75.5ml. the most common symptom was severe stabbing urethral pain (n = 4), with a median of 13 months after holep. calculi were pedunculated in the prostatic surgical bed or in the bladder neck with a small mucosal connection. pathology of the resected tissue showed granulation tissue formation and dystrophic calcification. conclusion: calculi in the prostatic surgical bed or the bladder neck after holep have never been reported previously. although it is very rare, recurrent urethral pain, persistent pyuria, and recurrent gross haematuria are signs for further investigation. cystourethroscopy should be performed to rule out the presence of stones. careful history taking and having an index of suspicion are important for the diagnosis. keywords: prostatic hyperplasia; urinary calculi; transurethral resection of prostate; complication. introduction open prostatectomy or transurethral resection of the prostate (turp) has been the standard of care in the treatment of benign prostatic hyperplasia (bph). laser prostatectomy was initially described in 1986 and became popular in 1990s(1). the use of this method has increased in the last decade in the treatment of bph(2). holmium laser enucleation of the prostate (holep) is an effective and less invasive alternative to open prostatectomy for the surgical treatment of bph. this method is associated with more favourable outcomes than monopolar turp(3). the coagulative property of holmium laser provides a relatively bloodless field with no risk of systemic fluid absorption resulting in transurethral resection syndrome. overall, the complications after holep are fewer than those after turp(4). however, we discovered patients with de novo calculi in the prostatic surgical bed or bladder neck after holep, which has never been reported previously. the purpose of this study is to report this as a complication and the characteristics of its clinical presentation. 1department of urology, seoul national university bundang hospital, seongnam-si, republic of korea. 2department of urology, seoul national university hospital, seoul national university school of medicine, seoul, republic of korea. *correspondence: department of urology, seoul national university hospital, seoul national university school of medicine, 101 daehak-ro, jongno-gu, seoul, 03080, korea. phone: +82-2-2072-2406. fax: +82-2-742-4665. e-mail: sjo@snu.ac.kr. received may 2017 & accepted december 2017 patients and methods patients we reviewed a patient cohort who had undergone holep at our institution by a single surgeon (sjo) from july 2008 to december 2015. after the approval of institutional review board, we identified patients who also underwent urethral stone removal after holep and reviewed their clinical presentation. in the course of research, additional 1 patient was identified who underwent holep at another hospital and included for the analysis. patients who underwent transurethral surgery due to de novo calculi were included. patients who had previous urinary calculi were excluded. holep was performed as we have previously described (5). for the enucleation, the three-lobe or four-lobe technique was used with 26fr resectoscope. after careful haemostasis by using holmium laser, morcellation was performed with a tissue morcellator (versacut; lumenis ltd.) through the guidance of a 26-fr nephroscope. after the operation, the patients were discharged on postoperative day 1 after a voiding trial. when considerable haematuria existed, the discharge was deferred for 1 or 2 days. follow-up was done at postoperative 2 weeks, 3 months, 6 months, and 12 months. careful endourology and stone diseases 238 vol 15 no 05 september-october 2018 239 history taking, physical examination, and workups including urinalysis and uroflowmetry were performed at every follow-up visit. cystoscopic examination was performed when the patient complained of severe urethral pain, gross haematuria or persistent microscopic haematuria. computed tomography was performed for gross haematuria and persistent pyuria. data analysis data on preoperative evaluation, holep procedures, the date of calculi removal in the prostatic surgical bed, the main presenting symptom, symptom onset after holep, the interval from symptom onset to the diagnosis, cystoscopic findings, pathology if present, and the result of stone analysis were obtained. the pathological images were examined by a pathologist. physical stone analysis was performed using infrared absorption spectrometry. the results were expressed as a true value or median, which was calculated by using microsoft excel software. result a total of 8 patients who underwent calculi removal in the prostatic surgical after holep were identified, including one patient who underwent holep at another hospital. in our prospective bph database, 7 (0.8%) patients were identified among 877 patients who underwent holep between july 2008 and december 2015. the characteristics of the patients are presented in table 1. their median age was 67 years. all patients underwent holep without immediate complications and were discharged at postoperative day 1 after a successful voiding trial. severe urethral stabbing pain (n = 4) was the most common presenting symptom followed by gross haematuria (n = 2), pyuria (n = 2), and microscopic haematuria (n=1). the urethral pain was typically very unpleasant, burning sensation after voiding or during voiding. the median duration from holep to symptom onset was 13 months (range, 3–44 months). the median interval from the initial onset of symptoms to the diagnosis was 2 month (range, 0.7–12 months). after the diagnosis of calculi in the prostatic surgical bed, calculi removal was performed. all patients had calculi at the bladder neck and/or the prostatic surgical bed. the cystoscopic images of five patients are presented in figure 1. the largest one was 1.7 cm sized (case 3). most calculi were less than 1 cm and spiculate in shape. the stones were hanging and/or impacted in the prostatic surgical bed in a scattered pattern. calculi in the bladder neck dangled from the bladder neck, connected to the mucosa. transurethral resection of the surgical bed was performed in one patient, and the pathological examination revealed urothelial denudation, granulation tissue formation, and dystrophic calcification (figure 2). the symptoms were resolved after the surgery. however, 1 patient (case 5) had a turbid urine and microscopic haematuria after 8 months and underwent the same surgery again for recurred table 1. characteristics of the patients. clinical characteristics at the time of holep case 1 case 2 case 3 case 4b case 5c case 6 case 7 case 8 age (years) 61 61 67 62 71 77 73 67 total prostate volume (ml)a 121 39 68 n.a. 85 56 83 n.a. prostatic calcificationa no no no n.a. no no no n.a. main presenting symptom new onset severe gross severe severe gross urethral pain new onset persistent urethral haematuria, urethral urethral haematuria, at the end of microscopic pyuria pain after postvoid stabbing pain during uui voiding, haematuria voiding urethral pain, and after new onset discomfort urgency voiding, persistent uui pyuria symptom onset after holep (months) 3 13 19 13 11 6 44 26 symptom onset to diagnosis (months) 3 1 0.7 1 6 12 3 1 stone analysis 90% ca, 65% 80% 60% 60% 65% 80% 95% 10% caoxd, brushite, caoxm, caoxm, caoxd, caoxm, caoxd, caoxd 35% ca 20% 30% 30% 35% ca 20% 5% caoxm caoxd, caoxd, struvite caoxm 10% ca 10% ca abbreviations: ca, carbonate apatite; caoxm, calcium oxalate monohydrate; caoxd, calcium oxalate dihydrate; n.a., not available; psa, prostate-specific antigen; pvr, postvoid residual volume; qmax, maximal flow rate; uui, urge urinary incontinence. a) measured with transrectal ultrasonography. b) referred from another hospital. c) had a recurrence after 8 months. figure 1. cystoscopic images. (a) small stellated stones are impacted in the mucosa of the prostatic surgical bed (case 1). (b) numerous stones were identified in the prostatic surgical bed and the bladder neck (case 4). (c) transurethral resection of the prostatic surgical bed in case 4 after clearing the stones from the surgical bed. (d) stones dangled from the bladder neck (case 5). (e) recurred stone hanging in the bladder neck (case 5). (f) stone dangled from the bladder neck connected to the bladder mucosa (case 6). calculi in the prostatic surgical bed after holep-lee et al. bladder neck stone. stone analysis for the 2nd operation revealed 95% calcium oxalate dihydrate and 5% calcium oxalate monohydrate. there were no evidence of urinary tract infection before the diagnosis, except 1 patient (case 1) who complained of left testicular discomfort. discussion long-term complications of holep include retreatment, urethral stricture, bladder neck contracture, and meatal stenosis. to our knowledge, this is the first case series on calculi in the prostatic surgical bed after holep. the occurrence of calculi in the surgical bed after laser prostatectomy is rare but possible. previous reports include a case of urethral stone formation after potassium-titanyl-phosphate (ktp) laser ablation of the prostate(6). these stones can form even 5 years postoperatively(7). many etiologic factors have been postulated to explain calculi formation after photoselective vaporization of the prostate with a ktp laser. first, stasis of urine at the prostatic fossa can form urethral calculi, provided that no concurrent urethral strictures exist(6). second, the presence of debris or foreign bodies after the surgery can serve as a nidus for stone formation, which can grow with time(7). finally, the coagulative necrosis caused by the laser energy itself can induce dystrophic calcification as a reaction to tissue damage, leading to calculi formation. a holmium laser operates at a wavelength of 2,140 nm in a pulsed mode(8). this high-power energy can be used for incision, ablation, resection, and enucleation of prostatic tissues. diffusion of thermal energy into the surrounding tissue is minimal when using a holmium laser. the thermal energy is absorbed by water, and the safety of the tissue is not compromised, unless direct contact occurs(9). a holmium laser can be used for superficial tissue ablation and adequate haemostasis for vessels with a < 1 mm diameter. substantial tissue coagulation can be accomplished at a depth of 3–4 mm(10). although the holmium-yag laser can penetrate tissues to a depth of only 0.4 mm, a 1–2-mm rim of surrounding tissue coagulation was observed after holmium ablation of the prostate in a canine model(11). because we use cutting, ablation, and coagulation freely during surgery, coagulative necrosis may occur, which can induce dystrophic calcification as a postoperative reactive change. in addition, threads of mucosa can serve as a nidus for stone formation during the wound-healing process, as fluttering mucosal flags are observed immediately after surgery. unlike in radical prostatectomy, mucosa-to-mucosa anastomosis is not possible during an endoscopic procedure. the wound-healing process is essential for the recovery process. during the recovery, chronic inflammatory infiltrates and granulation tissues replace the necrotic coagulum from the base at 7 weeks after thermal laser injury(12). until 12 weeks after the laser surgery, a few fragments of necrotic tissues or eschars adhere to the prostatic urethra. during the restoration of mucosal injury, mucosal flags can serve as a nidus for calculi formation. during the healing process, crystal deposition can occur on the de-epithelialized surface, resulting in subsequent stone growth. the presence of pyuria and microscopic haematuria after prostatic surgery is not always a pathological finding(13). persistent pyuria is one of the most common complications after transurethral prostatectomy(14). previous reports have noted that pyuria persisted longer than microscopic haematuria regardless of the type of the surgery (monopolar turp vs. bipolar turp vs. open prostatectomy). persistent pyuria lasted a median of 274 days, which was significantly longer than the duration of persistent microscopic haematuria (176 days). therefore, postoperative pyuria can be underestimated, and even ignored, if the patient does not have the compatible symptoms. however, as one patient in this study showed persistent pyuria after treatment with antibiotics, further evaluation is necessary. as noted in our cases, a high degree of suspicion for urethral stones should be adopted in patients with recurrent gross haematuria and unexplained severe urethral pain at any time after holep. early and careful history taking and cystourethroscopy can be helpful in such cases. a large intake of water might prevent urine stasis and urethral calculi formation, especially during the early postoperative recovery period. our study has a few limitations. this study was retrospective in nature, involving a cohort of patients operated by a single surgeon. however, the data were prospectively collected. although this is a very rare complication, the surgeon’s preference for the use of figure 2. pathology of the specimen from the transurethral resection described in fig. 1c (case 4). (a) haematoxylin and eosin staining of the resected tissue showing granulation tissue formation (× 40) and dystrophic calcification. (b) a magnified view of the rectangled area of fig. 2a showing dystrophic calcification (× 100). the urethral luminal side is marked with an arrow. calculi in the prostatic surgical bed after holep-lee et al. endourology and stone diseases 240 vol 15 no 05 september-october 2018 241 laser power and the haemostatic pattern can be factors affecting the incidence of urethral stones after holep. conclusions in conclusions, urinary calculi formation in the prostatic fossa or the bladder neck after holep is a rare but possible complication. unexplained urethral pain or discomfort, persistent pyuria, and recurrent gross haematuria require further investigation. cystourethroscopy should be performed to rule out the presence of stones. a focused history taking and having an index of suspicion are essential to the diagnosis. acknowledgement ye-young rhee provided photos of pathology. conflict of interest the authors report no conflict of interest. references 1. floratos dl, de la rosette jj. lasers in urology. bju int. 1999;84:204-11. 2. schroeck fr, hollingsworth jm, kaufman sr, hollenbeck bk, wei jt. population based trends in the surgical treatment of benign prostatic hyperplasia. j urol. 2012;188:183741. 3. cornu jn, ahyai s, bachmann a, et al. a systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. eur urol. 2015;67:1066-96. 4. vincent mw, gilling pj. holep has come of age. world j urol. 2015;33:487-93. 5. kim m, lee he, oh sj. technical aspects of holmium laser enucleation of the prostate for benign prostatic hyperplasia. korean j urol. 2013;54:570-9. 6. tasci ai, tugcu v, ozbay b, mutlu b, cicekler o. stone formation in prostatic urethra after potassium-titanyl-phosphate laser ablation of the prostate for benign prostatic hyperplasia. j endourol. 2009;23:1879-81. 7. malde s, rajagopalan a, koslowski m, simoes ad, choi wh, shrotri nc. potassium-titanylphosphate laser vaporization of the prostate: a case series of an unusual complication. j endourol. 2012;26:682-5. 8. le duc a, gilling pj. holmium laser resection of the prostate. eur urol. 1999;35:155-60. 9. van rij s, gilling pj. in 2013, holmium laser enucleation of the prostate (holep) may be the new 'gold standard'. curr urol rep. 2012;13:427-32. 10. tooher r, sutherland p, costello a, gilling p, rees g, maddern g. a systematic review of holmium laser prostatectomy for benign prostatic hyperplasia. j urol. 2004;171:177381. 11. kabalin jn. holmium: yag laser prostatectomy canine feasibility study. lasers surg med. 1996;18:221-4. 12. orihuela e, pow-sang m, motamedi m, cowan df, warren mm. mechanism of healing of the human prostatic urethra following thermal injury. urology. 1996;48:600-8. 13. olvera-posada d, villeda-sandoval c, ramirez-bonilla m, et al. natural history of pyuria and microhematuria after prostate surgery. actas urol esp. 2013;37:625-9. 14. cho kh, song kh, chang ys. study of the duration of pyuria after transurethral prostatectomy. korean j urol. 2007;48:199205. calculi in the prostatic surgical bed after holep-lee et al. july-august 2017 reviewer of the issue hans-göran tiselius hans-göran tiselius august 2017 dr. hans-göran tiselius was born in stockholm on 11th april, 1945. he got his medical degree in 1972 and then passed a phd course in clinical chemistry in 1974. he got a certificate of specialty in general surgery in 1977 and specialty in urology 1979. he startged as an associate professor of urologic surgeries from 1980 and became a professor of urology in the university of linköping at 1992. he moved to the karolinska institutet, stockholm) at 1999 and since 2011 is professor emeritus at the karolinska institutet. dr. tiselius has been the secretary of the scandinavian association of urology subgroup for renal stones from 1982 to 1984 and the chairman of the group mentioned above during 1985 to 1987. he has been the managing editor of scandinavian journal of urology and nephrology from 1989 to 1992; member of the advisory board of european symposium on urolithiasis during 1993 – 1997; president of the 6th european symposium on urolithiasis in stockholm in 1995; chairman of the eau health care office workning party on urolithiasis from 1997 to 2009; and president of the advisory board of european urolithiasis research from 1997 to 2009. he has spent more than 40 years of his academic life on urolithiasis and has been involved in educational/ training courses and conferences on urolithiasis including: co-organizer of a stone course, linköping, 1977; co-organizer of a minisymposium on urolithiasis, linköping, 1979; co-organizer of the swedish urologic association meeting in linköping, 1986; and co-organizer of an international eswl conference in linköping, 1986. he has been member of the steering committee of the international society of urolithiasis 1996 – 2008; chairman of the eau guideline group on urolithiasis ( 2009); co-chairman of the aua/eau collaboration on guidelines on ureteral stone treatment (2003-2008). he has been an honorary member of european association of urology since 2011; honorary member of eulis; and honorary member of the swedish association of urology since 2012. he has received awards for his activities on urolithiasis including: he received the fernström award to young scientists in 1984; curt engelhorn award, the european foundation for the advancement of medicne , 1998; honorary award, group of urinary calculi of chinese assocociation of urology, 2012; and life-time achievement award, international urolithiasis society, 2016. dr. tiselius has more than 200 original publications mostly in the field of urolithiasis. the urology journal has benefited many times the sincere cooperation of dr. tiselius as a reviewer in the section of endourology and stone diseases. dr. tiselius was elected as the reviewer of the issue in the july-august 2017 issue of the urology journal by the journal editors for his valuable and timely review of manuscript. below we have provided his own feeling regarding contribution to the urology journal: “for every journal it is of utmost importance to have reviewers that carefully can read and scrutinize the submitted manuscripts. it is accordingly both a pleasure and honour to have contributed in this regard to the urology journal. the review process always has been a way to guarantee the quality of publications and has become even more important in the steadily increasing flow of submitted manuscripts. personally i have a clinical and scientific experience in urology since approximately 40 year and have spent most of my professional life with different aspects of stone disease and its treatment. in this regard my background in medical and clinical chemistry has been a great advantage. hans-göran tiselius md, phd professor emeritus of urology, karolinska institutet stockholm.” vol 16 no 02 march-april 2019 141 urological oncology association study of retinoic acid related orphan receptor a (rora) gene and risk of prostate disorders mohammad taheri1, rezvan noroozi2, arash dehghan3, golnaz atri roozbahani4, mehrnoosh musavi5, mir davood omrani1*, soudeh ghafouri-fard6* purpose: prostate cancer (pca) and benign prostate hyperplasia (bph) are two prevalent disorders among men with considerable mortality and morbidity. several association studies have been conducted in different populations to find genetic loci linked with these disorders. retinoic acid-receptor-related orphan receptor alpha (rora) codes for a transcription factor which regulates expression of several cancer-related genes. besides, rora has been shown to be down-regulated in pca tissues and cell lines. materials and methods: in the present study we evaluated genotype and allele frequencies of rs11639084 and rs4774388 variants within rora gene in pca and bph patients compared with healthy subjects. result: the rs11639084 and rs4774388 alleles were not different between pca and normal groups 95% ci: 0.521.24, or = 1.04, p = .34; 95% ci: 0.48-1.33, or = .79, p = .39 respectively. moreover, we did not detect any significant difference in allele, genotype or haplotype frequencies of these snps between the other study groups. conclusion: the mentioned rora variants are possibly not involved in the pathogenesis of pca and bph. future studies are needed to assess the associations between other variant within this gene and pca risk to suggest a putative mechanism for involvement of rora in pca. keywords: benign prostatic hyperplasia; prostate cancer; retinoid-related orphan receptor alpha; rora; single nucleotide polymorphism introduction prostate cancer (pca) and benign prostate hyperpla-sia (bph) are two prevalent disorders among men with considerable mortality and morbidity(1). several researches have focused on evaluation of risk factors of these disorders at genomic (2,3) and transcriptomic levels (4). among candidate genes whose involvement in pca pathogenesis has been demonstrated is retinoic acid-receptor-related orphan receptor alpha (rora). this gene encodes a transcription factor which is categorized as one of the orphan nuclear receptors. the existence of response elements for rora in the promoter region of cell cycle-related genes implies its involvement in the regulation of cell cycle. moreover, expression of rora in androgen-independent pca cells has suppressed cell growth as demonstrated by in vitro and in vivo studies (5). more evidences for tumor suppressor role of rora have been provided by observation of its down-regulation in various cancer tissues (6). certain single nucleotide polymorphisms (snps) within this gene have been associated with risk of breast cancer in different ethnic groups (7,8). despite the prominent role of rora in pca pathogenesis, there is no study for assessment of the association between rora variants and risk of pca or bph. consequently, in the present 1 urogenital stem cell research center, shahid beheshti university of medical sciences, tehran, iran. 2 phytochemistry research center, shahid beheshti university of medical sciences, tehran, iran. 3 department of pathology, hamadan university of medical sciences, hamadan, iran. 4 faculty of life science and technology, shahid beheshti university, tehran, iran. 5 student research committee, hamadan university of medical sciences, hamadan, iran. 6 department of medical genetics, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urogenital stem cell research center, shahid beheshti university of medical sciences, tehran, iran. tel & fax: +982123872572, e-mails: davood_omrani@yahoo.co.uk. received january 2018 &accepted april 2018 study we evaluated genotype and allele frequencies of rs11639084 and rs4774388 variants in pca and bph patients compared with healthy subjects to find if these variants are involved in the pathogenesis of these disorders or can be used as genetic risk factors for pca or bph. materials and methods study participants subjects in the present case-control study a total of 144 pca cases, 177 bph cases and 112 normal males participated. pca and bph patients were selected from newly diagnosed patients in whom the histological examination of samples obtained from transrectal needle biopsy or transurethral resection of the prostate confirmed the diagnosis of disorder. control subjects were normal agematched males selected from a routine hospital-based health survey during 2016. the thee study groups have also been matched in age and body mass index (bmi). the study protocol has been approved by ethical committee of shahid beheshti university of medical sciences. all study participants were selected from hospitals affiliated with shahid beheshti university of medical sciences after assessment of their compliurological oncology 142 ance with the study inclusion criteria and signing the informed consent. control subjects had no history of lower urinary tract symptoms, prostate enlargement or family history of prostate cancer. pca or bph was diagnosed through examination of clinical prostate biopsies by an expert pathologist especially in bph patients with high psa levels (4.0 ng/ml or more) in whom transrectal biopsies ruled out the presence of pca. those with insufficient pathologic sample for evaluation, patients with the history of previous malignancies in other organs and any former chemo-radiotherapy were excluded from the study. blood samples were collected from patients before initiation of any treatments such as surgery, radiotherapy, and chemotherapy. we also collected clinicopathologic characteristics of study participants including prostate weight, psa levels and gleason score through filling questionnaires and evaluation of patients' clinical reports. genotyping of rs11639084 and rs4774388 we genotyped the rs11639084 (c/t) and rs4774388 (c/t) variants lcated in the intronic regions of the rora gene by tetra primer-amplification refractory mutation system-pcr (4p-arms-pcr) method using primers designed by primer1 online tool as reported in our previuos study(9). briefly, for each reaction we used 100 ng of genomic dna, 5 pmol/l of outer primers, 10 pmol/l of inner primers and 12.5 μl taq dna polymerase 2 × master mix red (ampliqon, denmark). all reactions were performed in a flexcycler (analytik jena, germany) with a pcr program consisted of an initial denaturation at 95 °c for 5 min and subsequent 35 cycles of 95 °c for 45 seconds, 55 °c for 45 seconds and 72 °c for 45 seconds. the results obtained by 4p-arms-pcr method were verified by sanger sequencing of 10% of total samples in abi 3730xl dna analyzer (macrogen, korea). statistical analysis snpstats was used for assessment of allele, genotype and haplotype frequencies in distinct study groups and their accordance with hardy-weinberg equilibrium using chi-square test (two-sided)(10). the association of rs11639084 and rs4774388 polymorphisms with pca and bph risk was evaluated in all assumed inheritance models and described using odds ratios (ors) and 95% confidence intervals (cis). haplotype frequencies for rora were computed using the snpanalyzer program (istech ltd, goyang-si, korea) based on the expectation-maximization algorithm. the pairwise linkage disequilibrium (ld) between mentioned snps was assessed through measurement of d' and r2 values. d' was described as the ratio of the unstandardized coefficient to its maximal/minimal value. p value less than 0.05 were considered statistically significant. results general data of study participants clinical and demographic data of study participants including the 144 pca cases, 177 bph cases and 112 normal males which were obtained through questionnaires and assessment of clinical reports are summarized in table 1. results of snps genotyping the assessed snps in the current study are located in intronic regions of rora gene. detailed information of these two snps is demonstrated in table 2. we assessed the compliance of these snps with hardy-weinberg equilibrium. as demonstrated in table 3, genotype frequencies of these snps in all three study groups are in hardy-weinberg equilibrium. no significant difference has been found in allele and genotype frequencies of rs11639084 and rs4774388 snps between three study groups (pca, bph and normal controls). table 4 shows the allele and genotypes frequencies of these snps in distinct study groups. we further assessed the frequencies of four supposed haplotypes of these two snps in distinct study groups but did not detect any difference between pca, bph and healthy subjects (table 5). rora and prostate disorders-taheri et al. table 1. demographic and clinical data of study participants. variables prostate cancer group bph group controls age (mean ± sd) 68.94 ± 9.89 66.96 ± 10.97 64 ± 9.1 bmi (mean ± sd) 25.07 ± 3.67 24.97 ± 3.47 24.17 ± 4.25 prostate weight (gr) (mean ± sd) 52.01 ±25.32 62.17 ± 23.63 psa (ng/ml) (mean ± sd) 9.26 ± 9.53 8.54 ± 6.1 <4 < 4 27 (18.75%) 32 (18%) 112 (100%) 4 -10 75 (52.0%) 89 (50.2%) 0 > =10 42 (28.25%) 56 (31.8%) 0 smoking never smoker (%) 74 (51.3%) 118 (66.6%) 75 (67%) current or former smoker (%) 70 (48.7%) 59 (33.4%) 37 (33%) gleason score < =6 74 (51.3%) > 6 7 0 (49.7%) abbreviations: bmi, body mass index, bph, benign prosttae hyperplasia, psa, prostate specific antigen, sd, standard deviation. snp position minor allele maf mac type rs11639084 chr15:60774317 t .24 1197 intron rs4774388 chr15:61174799 c .30 1507 intron abbreviations: maf, minor allele frequency, mac, minor allele content (the average amount of minor alleles per subject). table 2. descriptive information of rs11639084 and rs4774388 of rora gene. vol 16 no 02 march-april 2019 143 discussion in the present study we assessed allele, genotype and haplotype frequencies of two snps within rora gene in iranian patients with pca and bph compared with healthy subjects and demonstrated no significant difference between three study groups. rora has been shown to participate in the pathogenesis of a wide range of human disorders including attention-deficit hyperactivity disorder (11), bipolar disorder(12), major depression (13), autism(9), multiple sclerosis(14) and breast cancer (7). previous studies have provided evidences for rora contribution in suppression of pca cell growth. rora has been shown to down-regulate the expression of 5-lipoxygenase and restrict the mitogenic function of fatty acids on pca cells. consequently, rora has been suggested as a therapeutic target in pca (15). in addition, down-regulation of rora in cancerous tissues might change the expression of its downstream target genes such as cdk inhibitor p21 and n-myc which participate in carcinogenesis process(16). we have recently demonstrated the association of the rs4774388 within this gene with autism spectrum disorder (9) as well as breast cancer risk(7). the rs4774388 is supposed to change the affinity of the encoded protein to bind with pou5f1 as predicted by haploreg v4.1 (17). the retrogene pou5f1b encodes a homolog of the principal embryonic stem cell transcription factor oct4. breyer et al. have demonstrated the correlation between 8q24 risk alleles and decreased expression of pou5f1b gene in prostate tissues. in addition, they suggested the association between harmful pou5f1b missense variants and pca. their experiments showed the involvement of pou5f1 in self-renewal capability of embryonic stem cells as well as the pathogenesis of cancer(18). besides, participation of rora in regulation of circadian rhythm(19) and dysregulation of circadian rhythm and melatonin pathways in pca(20) increase the possibility of contribution of rora variants in pca risk. taken together, we hypothesized that rora variants might be regarded as risk factor for pca. the absence of associations between these variants and pca or bph risk in iranian population does not exclude the participation of rora in the pathogenesis of these disorders. our study has some limitations. first, due to the relative small sample size we could not analyze genotype and allele frequencies in subgroups of pca patients including those with small tumor size, low gleason grade or low stage separately. in addition, we could not assess the associations between mentioned snps and patients' survival or response to treatments. finally, we did not assess associations between other functional rora variants and risk of pca or bph. conclusions although we could not find any association between two variants within rora gene and prostate disorders, based on the proposed function of this gene, other variants within this gene might alter risk of pca or bph. so, future studies are needed to assess the associations between other variant within this gene and pca risk to suggest a putative mechanism for involvement of rora in pca. table 3. exact test for hardy-weinberg equilibrium. snp rs11639084 p-value rs12826786 p-value all cc ct tt tt ct cc cancer 144 85 (59%) 54 (37.5%) 5 (3.4%) .47 84 (58.3%) 49 (34%) 11 (7.6%) .37 bph 177 119 (67.2%) 52 (29.3%) 6 (3.3%) 1 96 (54.2%) 63 (35.6%) 18 (10.1%) .13 control 112 76 (67.8%) 30 (26.7%) 6 (5.3%) .21 58 (51.7%) 44 (39.2%) 10 (8.9%) .65 snp model sample size (%) cancer vs. control bph vs. control cancer vs. bph cancer(%) bph(%) control(%) or p-value or p-value or p-value allele t vs. 64 (22) 64 (18) 42 (19) 1.04 (.52-1.24) .34 1.04 (.68-1.61) .84 .77 (.52-1.14) .19 224 (78) 290 (82) 182 (81) co-dominant tt vs. cc 5 (3.5) 6 (3.4) 6 (5.4) 1.34 (.39-4.58) .64 1.56 (.49-5.03) .45 .86 (.25-2.90) .80 ct vs. cc 54 (37.5) 52 (29.4) 30 (26.8) .62 (.36-1.07) .08 .90 (.53-1.54) .71 .69 (.43-1.10) .12 dominant tt+ct vs. 59 (41) 58 (32.8) 36 (32.1) .68 (.41-1.14) .15 .97 (.59-1.61) .91 .70 (.44-1.12) .13 cc 85 (59) 119 (67.2) 76 (67.9) rs recessive tt vs. 5 (3.5) 6 (3.4) 6 (5.4) 1.57 (.47-5.30) .46 1.61 (.51-5.13) .42 .97 (.29-3.26) .97 1163 ct+cc 139 (96.5) 171 (96.6) 106 (94.6) 9084 over tt+cc vs. 90 (62.5) 125 (70.6) 82 (73.2) 1.64 (.96-2.81) .07 1.14 (.67-1.92) .63 1.44 (.90-2.30) .12 dominant ct 54 (37.5) 52 (29.4) 30 (26.8) allele c vs. 71 (25) 99 (28) 64 (29) 1.22 (.82-1.81) .32 .91 (.62-1.32) .62 1.34 (.94-1.92) 0.10 t 217 (75) 255 (72) 160 (71) co-dominant cc vs. tt 11 (7.6) 18 (10.2) 10 (8.9) 1.32 (.52-3.30) .56 .92 (.39-2.13) .84 1.43 (.64-3.20) .38 ct vs. tt 49 (34) 63 (35.6) 44 (39.3) 1.30 (.77-2.20) .33 1.16 (.69-1.91) .57 1.12 (.70-1.80) .62 dominant cc+ct vs. 60 (41.7) 81 (45.8) 54 (48.2) 1.30 (.79-2.14) .3 1.10 (.69-1.77) .68 1.18 (.76-1.84) .64 tt 84 (58.3) 96 (54.2) 58 (51.8) recessive cc vs. 11 (7.6) 18 (10.2) 10 (8.9) 1.18 (.48-2.90) .71 .87 (.38-1.95) .73 1.37 (.62-2.99) .43 rs tt+ct 133 (92.4) 159 (89.8) 102 (91.1) 477 over tt+cc vs. 95 (66) 114 (64.4) 68 (60.7) .79 (.48-1.33) .39 .85 (.52-1.39) .53 .93 (.59-1.48) .77 4388 dominant ct 49 (34) 63 (35.6) 44 (39.3) abbreviations: bph, benign prostate hyperplasia, or, odd ratio table 4. allele and genotype frequencies of rs11639084 and rs4774388 snps in three study groups (pca, bph and normal controls). rora and prostate disorders-taheri et al. urological oncology 144 acknowledgement the current study was supported by a grant from shahid beheshti university of medical sciences. conflict on interest the authors declare no conflicts of interest. references 1. ghafouri-fard s, ousati ashtiani z, sabah golian b, hasheminasab sm, modarressi mh. expression of two testis-specific genes, spata19 and lemd1, in prostate cancer. arch med res. 2010;41:195-200. 2. taheri m, pouresmaeili f, omrani md, et al. association of anril gene polymorphisms with prostate cancer and benign prostatic hyperplasia in an iranian population. biomark med. 2017;11:413-22. 3. taheri m, habibi m, noroozi r, et al. hotair genetic variants are associated with prostate cancer and benign prostate hyperplasia in an iranian population. gene. 2017;613:20-4. 4. faramarzi s, ghafouri-fard s. expression analysis of cancer-testis genes in prostate cancer reveals candidates for immunotherapy. immunotherapy. 2017;9:1019-34. 5. moretti rm, marelli mm, motta m, et al. activation of the orphan nuclear receptor roralpha induces growth arrest in androgenindependent du 145 prostate cancer cells. prostate. 2001;46:327-35. 6. roshan-moniri m, hsing m, butler ms, cherkasov a, rennie ps. orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers. cancer treatment reviews. 2014;40:1137-52. 7. taheri m, omrani md, noroozi r, ghafourifard s, sayad a. retinoic acid-related orphan receptor alpha (rora) variants and risk of breast cancer. breast disease. 2017;37:21-5. 8. truong t, liquet b, menegaux f, et al. breast cancer risk, nightwork, and circadian clock gene polymorphisms. endocr relat cancer. 2014;21:629-38. 9. sayad a, noroozi r, omrani md, taheri m, ghafouri-fard s. retinoic acid-related orphan receptor alpha (rora) variants are associated with autism spectrum disorder. metab brain dis. 2017;32:1595-601. 10. solé x, guinó e, valls j, iniesta r, moreno v. snpstats: a web tool for the analysis of association studies. bioinformatics. 2006;22:1928-9. 11. neale bm, lasky-su j, anney r, et al. genomewide association scan of attention deficit hyperactivity disorder. american journal of medical genetics part b-neuropsychiatric genetics. 2008;147b:1337-44. 12. le-niculescu h, patel sd, bhat m, et al. convergent functional genomics of genome-wide association data for bipolar disorder: comprehensive identification of candidate genes, pathways and mechanisms. american journal of medical genetics part b-neuropsychiatric genetics. 2009;150b:15581. 13. garriock ha, kraft jb, shyn si, et al. a genomewide association study of citalopram response in major depressive disorder. biol psychiatry. 2010;67:133-8. 14. eftekharian mm, noroozi r, sayad a, et al. rar-related orphan receptor a (rora): a new susceptibility gene for multiple sclerosis. j neurol sci. 2016;369:259-62. 15. moretti rm, montagnani marelli m, sala a, motta m, limonta p. activation of the orphan nuclear receptor roralpha counteracts the proliferative effect of fatty acids on prostate cancer cells: crucial role of 5-lipoxygenase. int j cancer. 2004;112:87-93. 16. zhu y, mcavoy s, kuhn r, smith di. rora, a large common fragile site gene, is involved in cellular stress response. oncogene. 2006;25:2901-8. 17. ward ld, kellis m. haploreg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. nucleic acids research. 2012;40:d930-d4. 18. breyer jp, dorset dc, clark ta, et al. an expressed retrogene of the master embryonic stem cell gene pou5f1 is associated with prostate cancer susceptibility. am j hum genet. 2014;94:395-404. 19. solt la, kojetin dj, burris tp. the reverbs and rors: molecular links between circadian rhythms and lipid homeostasis. future medicinal chemistry. 2011;3:623-38. 20. gu f, zhang h, hyland pl, et al. inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia. int j cancer. 2017;141:1794-802. table 5. haplotype frequencies in pca, bph and healthy subjects. rs11639084 rs4774388 pca bph control pca vs. control bph vs. control pca vs. bph or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value c t .58 .60 .57 1.00 --1.00 --1.00 --c c .20 .22 .24 1.20 (.76 1.90) .44 1.12 (.73 1.72) .61 1.04 (.68 1.59) .85 t t .17 .12 .14 .81 (.46 1.43) .47 1.21 (.67 2.20) .53 .64 (.38 1.10) .11 t c .05 .06 .05 .98 (.32 3.04) .98 .82 (.30 2.22) .69 1.21 (.52 2.83) .66 abbreviations: bph, bph, benign prostate hyperplasia, or, odd ratio, pca, prostate cancer rora and prostate disorders-taheri et al. therapeutic effects of aqueous extracts of cerasus avium stem on ethylene glycolinduced kidney calculi in rats ehsaneh azaryan1*, mohammad malekaneh2, maryam shemshadi nejad3, fatemeh haghighi4 purpose: to investigate the therapeutic effects of the aqueous extract of cerasus avium stem on kidney calculi. materials and methods: in this experimental study, forty-eight (48) male wistar rats were randomly allocated into six (6) groups and were studied during a 30 day period. group a served as normal control and group b received 1% ethylene glycol in drinking water (eg group). c, d, e, and f groups, received 1% ethylene glycol from day 1 and were used as prevention and treatment subjects. rats in prevention groups of low dose (c) and high dose (d) extract, were gavaged with 200 and 400 mg/kg extract respectively from first day of the experiment and treatment groups of low dose (e) and high dose (f) extract, were gavaged with 200 and 400 mg/kg extract respectively from the 15th day of the experiment. results: on the 30th days of the experiment, serum level of magnesium and potassium decreased significantly in eg group compared with a,c,d,e and f groups (p < .05), while serum level of calcium, creatinine, uric acid, sodium and urine level of calcium, creatinine, uric acid, increased significantly in eg group compared with a,c,d,e and f groups (p < .05). in the prevention and treatment groups, the number of deposits decreased significantly compared with eg group on the 30th day (p < .05). conclusion: cerasus avium stem has a therapeutic effect on calcium oxalate stones in rats with nephrolithiasis and reduces the number of calcium oxalate deposits. keywords: cerasus avium stem; ethylene glycol; kidney calculi; calcium oxalate introduction urinary tract stones are the third important cause of urinary tract diseases(1). the spread of urinary tract stones is increasing due to changes in peoples’ diet and life style(2). the annual incidence of urolithiasis in iran in 2005 was 147.2 for men and 129.6 for women per 100,000 population. in the same year in iran, the average cumulative recurrence rate was 16% after 1 year, 32% after 5 years, and 53% after 10 years(3). kidney stone formation is a complex process that results from a succession of several physicochemical events including supersaturation, nucleation, growth aggregation and retention within renal tubules(4). oxalate, struvite, urate, brushite, cystine were the most commonly reported urolithiases in man and animal species. however, epidemiological studies have shown that majority (70%) of stones commonly contain calcium oxalate(5,6). in the present study, we successfully induced caox formation in the rat’s kidney by adding eg to drinking water, which is in line with other studies(7-9). calcium oxalate stone formation is a multi-factorial process involving various etiological factors. hyperoxaluric rat model is the most potent experimental model for preclinical evaluation of antiurolithiatic efficacy of medicinal herbs because the physiological process mimics the etiology of kidney stone formation in human and animal(10). the hepatic enzymes metabolize eg to oxalic acid by glyoxalate mechanism, which is combined with calcium ion in the renal tubular epithelium to form calcium oxalate crystals(11). extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy techniques mainly include the surgical removal of stones. but, these techniques cause undesirable side effects such as tubular necrosis, hypertension, hemorrhage and subsequent fibrosis of the kidney leading to cell injury and recurrence of renal stone formation(12) nowadays, most contemporary researchers are using and focusing on homemade and natural remedies as well as their effects on the treatment of kidney stone(13). in addition, other parts of some plants such as the stem and root are frequently used in alternative medicine(14). cerasus avium is a tree from the family of the genus prunus rosacea and one of rare and valuable species in northern forests of iran(15). in recent years, cerasus avium stems have been widely used in folk medicine. after having been dried and boiled cerasus avium stem is used for treatment(14). its fruit stalks are sold by herbal druggists in iran and are used as decoction to relief renal stones, edema and hypertension.(16) however, there is no evidence for the therapeutic usage of this traditional medicine. therefore, we aimed to evaluate the effects of aqueous extract of cerasus avium stem on the treatment of caox calculi in a rat model. 1department of biochemistry, payamenoor university of mashhad, mashhad,iran. 2department of clinical biochemistry, birjand university of medical sciences, birjand, iran. 3department of biology, faculty of science, university of sistan and baluchestan, zahedan,iran. 4department of pathology, birjand uniniversity of medical sciences, birjand, iran. *correspondence: department of biochemistry, payamenoor university of mashhad, mashhad,iran. email :ehsaneh.azaryan@gmail.com. received november 2016 & accepted may 2017 endourology and stone disease vol 14 no 04 july-august 2017 4024 materials and methods preparation of aqueous extract of cerasus. avium stem the cerasus avium stems were purchased from a local herb store in birjand, iran. they were powdered and dried. then, 500 g of powdered herb was mixed, through the soaking method, with distilled water. after 24 hours, the extract solution was separated by filter paper. then, the resulting solution was incubated at 40°c, until it completely dried, then the residues were weighed (30g) and kept. before prescribing to the animal, the desired concentration of the extract was prepared in distilled water. treatment of animals the experiment was conducted in accordance with the guide for the care and use of laboratory animals and the study was approved by the ethics committee of birjand university of medical science. forty-eight wistar rats with an average weight of 200 ± 20 g were procured from pasteur institute of iran. the animals were acclimatized to standard laboratory effect of cerasus avium on nephrolithiasis-azaryan et al. table 1. effect of cerasus avium stem extracts on urinary and serum parameters in control and experimental animals. all values are expressed as mean ± sem for 8 animals in each group. parametres days agroup b group c group d group e group f group serum (mg/dl) calcium 15 8.8 ± 0.17 10.25 ± 0.33 a,* 10.5 ± 0.4 a,* 10.18 ± 0.25 a,* 10.28 ± 0.25 a,* 11.03 ± 0.41a,* 30 8.92 ± 0.49 11.22 ± 0.31a,* 9.28 ± 0.18 b,* 9.32±0.25 b,* 9.41± 0.17b,* 9.63±0.42 b,* creatinine 15 0.62 ± 0.06 0.7 ± 0.07 a 0.59 ± 0.09 b 0.7 ± 0.07 a 0.68 ± 0.03 ab 0.75 ± 0.03 a 30 0.55 ± 0.02 0.78 ± 0.05 a,* 0.5 ± 0.05 b,* 0.58 ± 0.03 b,* 0.65 ± 0.02 ab,* 0.64 ± 0.04 ab,* potassium 15 5.22 ± 0.5 4.96 ± 0.24 a 5.18 ± 0.25 a 5.63 ± 0.29 a 5.13 ± 0.26 a 5.55 ± 0.35 a 30 5.71 ± 0.3 4.4 ± 0.36 b,** 5.65 ± 0.16a,** 5.08 ± 0.43a,** 5.51 ± 0.19 a,** 5.58 ± 0.37 a,** sodium 15 162.3 ± 6.27 174.2 ±10.01ab 177 ± 2.98 ab 174 ± 3.3 ab 182 ± 4.04 a 185 ± 5 a 30 164 ± 6.89 189.8 ±1.15 a,* 163.1 ± 3.6 b,* 171.57 ± 4.21b,* 170.33 ± 1.76 b,* 165.66 ± 6.31 b,* magnesium 15 1.92 ± 0.19 1.78 ± 0.17 c,** 2.32 ± 0.12 ab,** 2.26 ± 0.18abc,** 2.11 ± 0.16abc,** 2.5 ± 0.06a,** 30 2.07 ± 0.12 1.68 ± 0.18 c,* 2.83 ± 0.36 b,* 2.23 ± 0.18 bc,* 4.58 ± 0.21 a,* 4.61 ± 0.23 a,* acid uric 15 2.05 ± 0.13 3.4 ± 0.19 a,* 3.25 ± 0.17 a,* 3.10 ± 0.22 a,* 3.63 ± 0.29 a,* 3.53 ± 0.34 a,* 30 2.37 ± 0.30 4.14 ± 0.35 a,* 2.92 ± 0.16 bc,* 2.58 ± 0.28 bc,* 3.32 ± 0.17 b,* 3.01 ± 0.27 bc,* urin(mg/dl) calcium 15 1.72 ± 0.21 2.33 ± 0.66 a 2 ± 0.33 a 1.98 ± 0.20 a 2.12 ± 0.31 a 2.06 ± 0.31 a 30 1.18 ± 0.03 1.58 ± 0.09 a,** 1.21 ± 0.15 b,** 1.24 ± 0.07b,** 1.15 ± 0.07 b,** 1.39 ± 0.14 ab,** creatinine 15 37.37 ± 10.44 66.54 ± 25.70 a 50.52 ± 10.80 a 54.48 ± 8.74 a 60.51 ± 8.60 a 66.13 ± 13.73 a 30 34.42 ± 7.40 81.36 ± 23.64 a** 45.88 ± 9.52 a** 45.18 ± 20.24 a** 50 ± 15.01 a** 55.20 ± 15.05 a** acid uric 15 3.15 ± 0.37 6.10 ± 1.50 a 3.84 ± 0.72 a 3.93 ± 1.37 a 5.88 ± 1.70 a 5.92 ± 1.73 a 30 3.41 ±0.55 7.32 ± 2.45 b,** 2.95 ± 0.52 a,** 2.56 ± 0.38 a,** 3.16 ± 0.91 a,** 2.20 ± 0.10 a,** all values are expressed as mean±sem for 8 animals in each group. *statistically significant at*p < .01 **statistically significant at **p < .05 a comparisons are made with group a. b comparisons are made with group b. c comparisons are made with group c. endourology and stone diseases 4025 conditions (temperature: 25 ± 2 ◦c) and maintained on 12-hour light:12-hour dark cycle and they were given standard diet and had free accesses to food and water ad libitum throughout the study. they were randomly divided into six groups of 8 and treated according to the experimental protocol for 30 days. the control group (a) only received normal water. the other five groups received 1 % ethylene glycol (merk,germany) during the study period. eg group (b) did not receive any other treatment during the study period. ethylene glycol was added from the first day for thirty(30) days to the water of prevention groups of low-dose (c) and high-dose (d). from the first day of adding ethylene glycol to the water, aqueous extract of cerasus. avium stem was added with 200 and 400 mg per kg of body weight. ethylene glycol was added from the first day for 30 days to the treatment groups of low-dose (e) and high-dose (f). from the fifteenth day of adding ethylene glycol to the water, aqueous extract was added with 200 and 400 mg per kg of body weight. in duration of experiment two rat of a and b groups died. blood samples the blood samples were collected on days 15 and 30. (in the 15th day using orbital sinus and in the 30th day using cardiac puncture). blood was collected in non-heparinized tubes and centrifuged at 3500 rpm for 15 min to obtain serum. serum level of calcium, creatinine, uric acid, magnesium, potassium, sodium, were measured with an auto analyzer.(prestige) and colorimetric method. urine samples twenty-four hour (24 h) urine collection of rats in each group was performed on the 15th and 30th days, individually in metabolic cages. food and water was available during experimentation in the cages. for analysis, 1 ml of urine was taken in centrifugal tube and centrifuged at 2500 rpm for 5 min, urine level of calcium, creatinine and uric acid were measured by prestige auto analyzer. histological examination for histological examination at the end of the experiment (the 30st day), all the rats were anesthetized and the kidneys removed and fixed in 10% formaline, dehydrated in a gradient of ethanol, embedded in paraffin, and then cut in to 5μ serial sections. then, slides containing five actions from each kidney were deparaffinized, stained with hematoxyline and eosine, and then examined by olympus light microscope, in each slide 10 microscopic field with a magnification of 10*40 were selected randomly and the aggregation of caox deposits were counted in the aforementioned fields. mean of oxalate crystals, number was reported. figure1. figure representative microscopic images of kidney sections from, (a) control group shows absence of crystals deposition, (b) the large number and size of calcium oxalate crystals (arrow) in a renal tubule in ethylene glycol group (c,d) the the reduction of calculi number and size of calcium oxalate crystals in (arrow) in a renal tubule preventation and treatment groups. figure 2. the number of calcium oxalate crystal deposits in the kidneys of the rats at the end of the experiment. data are expressed as mean ± standard error. vol 14 no 04 july-august 2017 4026 effect of cerasus avium on nephrolithiasis-azaryan et al. data analysis data were analyzed with spss software (version 20.0) using one-way anova followed by duncan’s test for multiple comparisons among all groups. p values less than .05 were considered statistically significant. data were presented as mean ± standard error. results serum parameters the mean level of calcium, creatinine, uric acid and serum sodium of the prevention and treatment groups in the 30th day decreased significantly as compared to the eg group.(p < .05). (for details see table 1).the mean concentration of magnesium and serum potassium of the prevention and treatment group in the 30th day increased significantly, as compared to eg control group (p < .05). (for details see table 1) urine parameter the calcium, creatinine and uric acid level of urine in prevention and treatment groups in the 30th day, decreased significantly compared to the eg group (p < .05). (for details see table 1) pathology results the examination of kidney sections in control group showed no calcium oxalate deposits or other abnormalities in different segments of the nephrons (figures 1 and 2). but in eg group, calcium oxalate deposits, were found in different segments of the nephron (figures 1 and 2). in prevention and treatment groups, the number of deposits decreased significantly compared with eg group in both doses of aqueous extract of cerasus. avium stem on the 30th day crystals in different parts of nephrons in the kidney specimens of these groups were also thin, small, and fewer compared with those in group b. (figures 1 and 2) discussion although, in recent years various chemical drugs have become available in the market that may be effective in prevention and treatment, and there is no effective drug therapy without surgery that can lead to complete treatment or prevention of urinary tract stones(2). several studies reported calcium oxalate crystals are injurious to renal epithelial cells by providing substrates for nucleation of crystals aggregation, and exposing sites for the attachment and retention of crystals leading to its adhesion to the epithelial cells, and consequently, the cells may produce some products as well as free radicals, inducing heterogeneous crystal nucleation and cause aggregation of crystals.(17,18) due to the presence of substances such as caffeic acid, ferulic acid, syringic acid, ellagic acid, quercetin, α-tocopherol, pyrogallol, phydroxybenzoic acid, vanillin, p-coumaric acid, gallic acid and ascorbic acid, the cerasus avium stems have antioxidant and antiradical properties(19). therefore, it is speculated that cerasus avium stem, could prevent the formation of caox calculi and their disaggregation through its anti-inflammatory and antioxidant mechanisms. in the present study, quercetin and tocopherol reduced the morality of tubular and level of free radicals, thereby reducing the formation of calcium oxalate crystals(20,21). in addition, quercetin, α-tocopherol and frolic acid lower cholesterol in serum(19,22,23). according to the study, the increase of fat is one of the causes of kidney stones(24). in this context, oxalate has been reported to induce lipid peroxidation and cause renal tissue damage by reacting with polyunsaturated fatty acids in cell membrane(25). it is possible that one of the reasons for the effect of cerasus avium stem on reducing calcium oxalate stones is the anti-fat roles of quercetin , α-tocopherol and frolic acid. some studies suggest that calcium stones may have an infectious origin. nano bacterium, an intracellular bacterium, is found in the kidney stones. these bacteria cause an increase in calcium stones(26,27). pyrogallol is a substance found in the stem of cerasus avium having anti-bacterial and anti-microbial properties(5). hence, it might be that the anti-bacterial property of cerasus avium stem is effective in the treatment of kidney stones in addition to afore-mentioned mechanisms in the formation of caox crystals. the present study showed that the major cause of kidney stone is potassium and magnesium reduction and promising results in preventing recurrence have been shown in patients treated with potassium magnesium citrate. magnesium complexes with oxalate, reduce the supersaturation of calcium oxalate and as a consequence reduce the nucleation rate and growth of crystals(28,29,30). the cerasus avium stem treatment increased the magnesium and potassium level of serum and thus reduced the growth of calcium oxalate crystals in drug treated animals. in urolithiasis, the glomerular filtration rate (gfr) decreases due to the obstruction to the outflow of urine by stones in urinary system. due to this, the waste products, particularly nitrogenous substances such as urea, creatinine and uric acid get accumulated in blood(31). the results of this study show that aqueous extract of cerasus avium stem reduced serum and urine creatinine and uric acid in prevention and treatment groups. it is not clear which mechanisms in the plants have effects on kidney stones. this may be as a result of its anti-inflammatory, antioxidant, anti-bacterial, and anti-fat properties. however, there is need to do more research so as to certain the effects of this plant. conclusions the aqueous extracts of cerasus avium stem significantly reduced the elevated level of calcium oxalate ions. the histopathological findings also show sign of improvement after treatment with extract. all these observation provided the basis for the conclusion that cerasus avium stem extract inhibit the 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supplementation on disease risk factors in community-dwelling adults. j am diet assoc. 2011;111:542-9 23. packer l, weber su, rimbach g. molecular aspects of α-tocotrienol antioxidant action and cell signalling. nutrition j. 2001;131:369s-73s. 24. schmiedl a, schwille po, bonucci e, erben rg, grayczyk a, sharma v. nephrocalcinosis and hyperlipidemia in rats fed a cholesterol-and fat-rich diet: association with hyperoxaluria, altered kidney and bone minerals, and renal tissue phospholipid–calcium interaction. urol res. 2000;28:404-15. 25. ernster l, nordenbrand k. oxidation and phosphorylation. in:ronald, w.e., maynard, e.p. (eds.), methods in enzymology. academic press, new york.1967; 10: 574– 580,. 26. ma k, xu qq, huang xb, wang xf, li jx, xiong ll, yang b, ye xj, chen l, na yq. analysis and clinical implication of upper urinary tract stone's bacterial spectrum. zhonghua wai ke za zhi. 2010;48:293-5. 27. kramer g, klingler hc, steiner ge. role of bacteria in the development of kidney stones. curr opin urol. 2000;10:35-8. 28. reungjui s, prasongwatana v, premgamone a, tosukhowong p, jirakulsomchok s, sriboonlue p. magnesium status of patients with renal stones and its effect on urinary citrate excretion. bju. int. 2002;90:635-9.. 29. selvam r, kalaiselvi p, govindaraj a, murugan vb, kumar as. effect of a. lanata leaf extract and vediuppu chunnam on the urinary risk factors of calcium oxalate urolithiasis during experimental hyperoxaluria. pharmacol res. 2001;43:89-93. 30. soundararajan p, mahesh r, ramesh vol 14 no 04 july-august 2017 4028 effect of cerasus avium on nephrolithiasis-azaryan et al. t, begum vh. effect of aerva lanata on calcium oxalate urolithiasis in rats. indian j exp biol. 2006;44: 981-6 31. ghodkar pb. chemical tests in kidney disease. textbook of medical laboratory technology. 1994:118-32. endourology and stone diseases 4029 effect of cerasus avium on nephrolithiasis-azaryan et al. miscellaneous treatment satisfaction with flexible-dose fesoterodine in patients with overactive bladder who were dissatisfied with previous anticholinergic therapy: a multicenter single-arm clinical study jin bong choi1, kang jun cho1, won hee park2, dong hwan lee3, young-ho kim4, in rae cho5, hana yoon6, young sik kim7, joon chul kim1* purpose: we investigated treatment satisfaction with flexible-dose fesoterodine in patients with overactive bladder (oab) who were dissatisfied with previous anticholinergic therapy. materials and methods: the subjects were prescribed fesoterodine 4 mg for 4 weeks and fesoterodine 4 mg or 8 mg for another 8 weeks. the primary end point of this study was patients’ satisfaction after 12 weeks of fesoterodine treatment on a five-point likert scale. secondary end points included a change in the number of daytime micturition, urgency incontinence episodes, urgency episodes, and nocturnal micturition in a -24hour period from baseline to final assessment. results: overall, 84 patients were assigned to the treatment group in this study and 63 patients completed the -12week treatment course. a final fesoterodine dose of 4 mg and 8 mg was used by %71.4) 45) and %28.6) 18) patients, respectively. the satisfaction and dissatisfaction rates at 12 weeks were %69.9 and %14.2, respectively. mean changes in the daytime micturitions (4.72 ± 9.73 vs. 2.86 ± 7.76), urgency episodes (5.68 ± 7.73 vs. ± 3.71 4.09), and nocturnal micturitions (1.36 ± 2.13 vs. 1.12 ± 1.68) in 24 hours improved significantly with flexibledose fesoterodine treatment (p < .05). most adverse events were mild and none were severe. conclusion: the flexible dose fesoterodine represents an alternative treatment modality in patients with oab who are dissatisfied with previous anticholinergic therapy in korea. keywords: fesoterodine; overactive bladder; patient satisfaction introduction overactive bladder (oab) is defined as a syndrome that causes urgency (with or without urge incontinence), frequency, and nocturia.(1) the overall prevalence of oab is approximately 16% in the usa and six european countries (sweden, france, spain, italy, germany, and the united kingdom). the prevalence of the syndrome does not differ by sex even though the severity and expressed symptoms do.(2,3) the overall prevalence of oab in korea has been reported to be approximately 12% and increases with age.(4) although anticholinergics are considered the mainstay of treatment for oab(5), their variable efficacy and poor compliance due to adverse effects such as dry mouth, constipation, and even cognitive impairment lead to low patient satisfaction.(6,7) as a result, physicians switch 1department of urology, bucheon st. mary’s hospital, college of medicine, the catholic university of korea, bucheon, republic of korea. 2department of urology, inha university college of medicine, incheon, republic of korea. 3department of urology, incheon st. mary's hospital, college of medicine, the catholic university of korea, incheon, republic of korea. 4department of urology, soonchunhyang university bucheon hospital, soonchunhyang university college of medicine, bucheon, republic of korea. 5department of urology, ilsanpaik hospital, inje university college of medicine, goyang, republic of korea. 6department of urology, school of medicine, ewha womans university, seoul, republic of korea. 7department of urology, national health insurance service, ilsan hospital, goyang, republic of korea. *correspondence: department of urology, bucheon st. mary’s hospital, college of medicine, catholic university of korea, 327 sosa-ro, bucheon-si, gyeonggi-do 14647, republic of korea. tel: +82-32-340-7071, fax: +82-32-340-2124, e-mail: kjc@catholic.ac.kr. received june 2018& accepted february 2019 drugs or modify the dose when patients are dissatisfied with previous anticholinergic therapy. previous studies have demonstrated that fesoterodine at dosages of 4 mg or 8 mg once daily significantly improved oab symptoms.(8,9) furthermore, the availability of the flexible doses of fesoterodine provides an opportunity to maintain an optimal balance between benefits and risks in patients.(10) recent data has shown that flexible-dose fesoterodine is associated with a high rate of patient treatment satisfaction, produced significant improvements in voiding diary variables and negative symptoms, and resulted in a greater health-related quality of life.(11) several studies also reported the efficacy of switching anticholinergic therapy, including to fesoterodine, when patients were dissatisfied with previous anticholinergics.(11-13) however, there have been urology journal/vol 17 no. 1/ january-february2020/ pp. 97-101. [doi: 10.22037/uj.v0i0.4650] only a few study of flexible-dose fesoterodine in the asian patients. therefore, in this study, we examined treatment satisfaction with flexible-dose fesoterodine in adult subjects with oab who were dissatisfied with previous anticholinergic treatment in the korean population. materials and methods study design this prospective, multi-center, open-label, single-arm clinical study was conducted at seven different medical centers in korea for 1 year. all seven centers are superior general hospitals under the college of medicine. written informed consent was obtained from all subjects. the study was performed in accordance with the good clinical practice guidelines of the international conference on harmonization and the ethical principles of the declaration of helsinki. the duration of the study was 12 weeks except for a washout period of 2 weeks and a 2 weeks baseline period for screening. we recruited patients currently undergoing treatment for oab or through an irb-approved subject recruitment announcement. after 4 weeks with fesoterodine 4 mg daily, the dosage was either maintained at fesoterodine 4 mg daily or increased to 8 mg daily for the remaining 8 weeks of the study. dose escalation was based on the subjects and physician assessments of efficacy and tolerability. if the symptom improvement was weak, the dose of fesoterodine was increased to 8mg, or if the side effects such as dry mouth were severe, 4mg of fesoterodine was maintained. adherence was measured by pill counts. ethics this study was approved by the institutional review board of the catholic university of korea (hc10mimi0094). subjects the study included men or women aged ≥ 18 years with oab (mean micturition frequency of > 8 per 24 hours and mean number of urgency episodes > 3 per 24 hours in a 3-day voiding diary) for > 3 months who were “somewhat dissatisfied” or “very dissatisfied” in the five-point likert scale with other anticholinergic treatments (propiverine, oxybutynin, trospium, and solifenacin) for at least 1 month. subjects with the following conditions were excluded from the study: history of acute urinary retention requiring catheterization, neurogenic bladder, lower urinary tract surgery within 6 months, predominant stress urinary incontinence, significant pelvic organ prolapse, significant hepatic or renal function impairment, and any contraindications to fesoterodine usage. a sample size of 100 subjects was calculated to provide 10% level of margin for error and the 95% confidence interval for the percentage of treatment satisfaction rate at week 12. however, because the study was open label, the response to fesoterodine could be observed throughout the study. therefore, the principal investigator decided to stop recruitment when obvious changes in subjects reporting treatment satisfaction were observed. outcome measurements the primary end point of this study was patients’ satisfaction after 12 weeks of fesoterodine treatment on a five-point likert scale as follows: very satisfied, somewhat satisfied, neither satisfied nor dissatisfied, somewhat dissatisfied, and very dissatisfied. secondary end points included changes from baseline to week 12 in the number of daytime micturitions, urgency incontinence episodes, urgency episodes with urgency scale (fivepoint urinary sensation scale as follows: no urgency, mild urgency, moderate urgency, severe urgency, and urge incontinence), and nocturnal micturitions in 24 hours from the baseline to the final assessment through a 3-day voiding diary. safety assessments included adverse events. statistical methods sas software version 9.4 (sas institute, cary, nc, usa) was used for statistical analysis. the data is presented as the mean ± standard deviation (sd). comparative analysis of change of variables in the voiding diaries was performed with a two-sided paired t-test. a p-value of < .05 was considered statistically significant. safety analysis included all subjects who received at least one dose of the study drug. results subjects ninety-seven patients had been screened in 7 centers and 84 patients were enrolled and assigned to the treatment arm. the reasons for screening failure were that the inclusion criteria were not met or consent was withdrawn. sixty-three patients completed the 12-week treatment period, while 21 did not. the reasons for discontinuation were adverse events, protocol violation, loss to follow-up, and consent withdrawal (ure 1). treatment satisfaction with flexible-dose fesoterodine-choi et al. table 1. demographic and baseline parameters parameters patients (n = 63) age, years 59.1 ± 13.3 range 26-82 mean duration for suffering from oab, months 42.6 ± 37.8 12 months or less 15 (23.8) 12 to 36 months 25 (39.7) over 36 months 23 (36.5) somewhat dissatisfied with prior anticholinergics 47 (74.6%) very dissatisfied with prior anticholinergics 16 (25.4%) data are presented in the format of mean ± standard deviation or n (%). abbreviations: oab, overactive bladder miscellaneous 98 vol 17 no 01 january-february 2020 99 the average age of the patients was 59.1 ± 13.3 years (range: 26 to 82 years) with the average age of female patients being 58.3 ± 13.2 years (range: 26 to 82 years) and the average age of male patients being 64.4 ± 10.3 years (range: 45 to 76 years). the mean duration for suffering from oab was 42.6 ± 37.8 months with 12 months or less in 15 patients (23.8%), 12 to 36 months in 25 patients (39.7%), and over 36 months in 23 patients (36.5%). the number of subjects that were “somewhat dissatisfied” with prior anticholinergics were 47 (74.6%) with 16 (25.4%) being “very dissatisfied” with prior anticholinergics (table 1). compliance on treatment after 12 weeks was 100% in 27 patients, 80-99% in 34 patients, and 60-79% in 2 patients. primary outcome variable sixty-three patients who conducted the evaluation of satisfaction and voiding diary on treatment for 12 weeks were available for efficacy evaluation. a final fesoterodine dose of 4 mg and 8 mg/day was used by 45 patients (71.4%) and 18 patients (28.6%), respectively. the satisfaction rate at 12 weeks of fesoterodine treatment was 69.9% (very satisfied at 19.1% and somewhat satisfied at 50.8%) and the dissatisfaction rate was at 14.2% (somewhat dissatisfied at 6.3% and very dissatisfied at 7.9%). secondary outcome variable mean changes in the number of daytime micturitions (9.73 ± 4.72 vs. 7.76 ± 2.86, p = .001), urgency episodes (7.73 ± 5.68 vs. 3.71 ± 4.09, p = 0.005), and nocturnal micturitions (2.13 ± 1.36 vs. 1.68 ± 1.12, p < .001) in 24 hours improved significantly with the flexible dose fesoterodine treatments. there was no statistically significant improvement in the number of instances of urgency urinary incontinence (table 2). safety and tolerability eighty-four patients who participated in this clinical study who took fesoterodine at least 1 time and underwent safety evaluations were available for tolerability evaluation. adverse events occurred in 22 patients (26.2%) at 12 weeks. dry mouth was the most commonly reported adverse event and more commonly reported at 12 weeks compared to 4 weeks. there were no serious adverse events (table 3). discussion the main findings of this multicenter, open-label, single-arm clinical study were: (1) the satisfaction rate after 12 weeks of flexible-dose of fesoterodine treatment was approximately 70% with the dissatisfaction rate being around 14%. (2) mean changes in the number of daytime micturitions, urgency episodes, and nocturnal micturitions in 24 hours improved significantly with flexible dose fesoterodine treatment. (3) most of the adverse events that occurred were mild and none were severe. these findings are consistent with the results of other previously published studies. the efficacy, safety, and tolerability of fixed dose fesoterodine (4 mg and 8 mg) for oab were proven in two randomized clinical trials where the dose response effect of fesoterodine was defined.(14,15) in superiority trial, fesoterodine 8 mg showed statistically significantly superior efficacy than fesoterodine 4 mg or placebo.(8) flexible-dose fesoterodine also significantly improved oab symptoms and treatment satisfaction in several randomized, double-blind, placebo-controlled trials(16-19) and open-label trials.(10,11,20) recent systematic review of data from these clinical trials showed that flexible-dose fesoterodine provided clinical benefit to patients with oab because of its dose-response effects. (21) these studies were designed to reflect clinical practice better in that the patients decided the dose escalation according to their clinical response rather than to a defined study protocol. in previous open label, flexible-dose trials of fesoterodine, 50 to 59% of subjects who received fesoterodine 4 mg requested dose escalation to 8 mg.(10,11,20) however, a final fesoterodine dose of 8 mg/day was used by only 18 patients (28.6%) in our study, while approximately 70% of subjects who requested fesoterodine 4 mg continuously or increase to 8 mg exhibited improvements in efficacy and tolerability as seen in other studies. subjects who wanted to escalate their dose from fesoterodine 4 mg to 8 mg generally reported more severe baseline symptoms than subjects who wanted to continue the 4 mg dosage. the patients also exhibited lower improvements in efficacy and a higher incidence rate in adverse events during treatment with fesoterodine 4 mg. the patients’ baseline symptoms in our study were better than other studies and the rate of adverse events was low during treatment. as a result, patients who wanted to increase their dose of fesoterodine were fewer in number. there was no statistically significant improvement in table 2. change of parameters of the voiding diary per 24 hours from baseline to fesoterodine treatment at 4 weeks and 12 weeks baseline 4 weeks p-value 12 weeks p-value mean ± sd mean ± sd (baseline vs. 4 weeks ) mean ± sd (baseline vs. 12 weeks ) no. of daytime micturitions 9.73 ± 4.72 7.98 ± 2.66 <0.001 7.76 ± 2.86 0.001 no. of nocturnal micturitions 2.13 ± 1.36 1.69 ± 1.19 0.008 1.68 ± 1.12 0.005 no. of urgency episodes 7.73 ± 5.68 4.16 ± 4.40 <0.001 3.71 ± 4.09 < 0.001 no. of urgency urinary 0.25 ± 0..66 0.15 ± 0.58 0.132 0.26 ± 0.83 0.656 incontinence episodes data are presented as the mean ± sd. abbreviations: sd, standard deviation adverse events 4 weeks no. (%) 12 weeks no. (%) dry mouth 5 (5.9) 9 (10.7) dry eye 0 (0) 1 (1.2) constipation 1 (1.2) 1 (1.2) gastrointestinal discomfort 0 (0) 1 (1.2) voiding difficulty 2 (2.4) 2 (2.4) others (headache, leg edema, 6 (7.1) 8 (9.5) cystitis, gum bleeding, sore throat, diabetes, cervicalgia, cholangitis) table 3. adverse events in response to fesoterodine treatment treatment satisfaction with flexible-dose fesoterodine-choi et al. the number of instances of urgency urinary incontinence among the secondary outcome variables. while urgency urinary incontinence is considered a more notable symptom of oab, continent oab also has negative effects and decreases health-related quality of life. coyne et al. reported that urinary urgency had a significant negative effect on health-related quality of life compared to incontinence urgency urinary incontinence in a national community survey using the national overactive bladder evaluation program.(22) although urinary urgency can be quantifiable through counting urgency episodes in a voiding diary, this is insufficient to understand the patients’ overall symptoms. therefore, patient-reported outcome data should be investigated to measure the overall impact of treatment including adverse effects and tolerability. the current study has several limitations. the main limitation of the study was the relatively small sample size compared to other similar studies. therefore, these findings cannot be generalized to the entire korean population. there was also a lack of male patients with most of subjects being women (87.3%). as a result, a study involving a larger sample including more men should be performed in the future. second, this study was an open label study and did not include a placebo group. however, fesoterodine (4 mg and 8 mg) has been reported to be more efficacious for oab symptoms than placebos in previous randomized placebo-controlled clinical trials.(14,15) in addition, open-label studies are advantageous in that they reflect actual clinical practice and can determine an optimal balance between efficacy and tolerability. third, we could not compare outcomes in subjects who received fesoterodine 4 mg for 12 weeks with subjects who escalated to the 8 mg dosage after 4 weeks. this is the limitation of an open-label, flexible dosing design because the baseline symptoms may vary between the two groups at the time of determination of dose escalation. fourth, the satisfaction measurement was only dependent on the five-point likert scale survey, not on the objective measurements. so the reliability of the responses of the patients about their satisfaction of the medication was considered low. this should be supplemented in future studies. conclusions patients with oab who were dissatisfied with previous anticholinergic therapy had a high satisfaction rate and tolerated the flexible dose fesoterodine well. therefore, this treatment represents an alternative treatment modality in patients with oab who are dissatisfied with previous anticholinergic therapy in korea. a study using a larger sample size including a number of male subjects should be performed in the future. acknowledgement the study was funded by pfizer pharmaceutical korea ltd. conflict of interest the authors have no conflicts of interest to declare. references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the international continence society. urology. 2003;61:37-49. 2. stewart wf, van rooyen jb, cundiff gw, et al. prevalence and burden of overactive bladder in the united states. world j urol. 2003;20:327-36. 3. milsom i, abrams p, cardozo l, roberts rg, thuroff j, wein aj. how widespread are the symptoms of an overactive bladder and how are they managed? a population-based prevalence study. bju int. 2001;87:760-6. 4. lee ys, lee ks, jung jh, et al. prevalence of overactive bladder, urinary incontinence, and lower urinary tract symptoms: 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endourology and stone disease percutaneous nephrolithotomy versus laparoscopy in the management of large proximal ureteral stones: the experience of two different settings seyed habibollah mousavi bahar1, shahriar amirhassani1*, akbar nouralizadeh2, nikan zerafatjou1, jaber rasiuli1 purpose: this study was conducted to compare the success rate and complications of percutaneous nephrolithotomy (pcnl) and laparoscopic ureterolithotomy for the treatment of large proximal ureteral stones. materials and methods: in this prospective cohort study, the success rate and complications in 52 patients undergoing pcnl in hamadan's shahid beheshti hospital and 55 patients undergoing laparoscopic ureterolithotomy in tehran's shahid labbafinejad hospital were compared. all patients had large proximal ureteral stones. results: in the pcnl group, the mean age was 47.78 ±16.72 years, 75% were male, and 50% of calculi were on the upper right side and the rest on upper left side. the mean duration of surgery was 32 ± 9.4 minutes and success rate 100%. the mean stone size was 18.33 ± 2.63 mm in pcnl group and 21.29 ± 2.18 mm in laparoscopy group which was significantly different (p <.001). in the laparoscopy group, the mean age of patients was 42.92 ± 16.10 years and 83.6% were male. in this group, 46.6% of calculi were on the right side and the rest were on the left side. the mean duration of surgery was 107.43 ± 22.86 minutes and success rate was 100%. there was not a statistically significant association between surgical technique and age, gender, stone location, mean hospital stay length after surgery, degree of hydronephrosis and success rate (p >.05). however, surgery duration was significantly shorter in the pcnl group compared to the laparoscopy group (p <.001) and the decrease in hemoglobin, hematocrit and serum urea level was more pronounced in the pcnl group than in the laparoscopy group. conclusion: pcnl and laparoscopic ureterolithotomy met with the same success rate in the treatment of upper large ureteral stones. however, the two methods should be utilized depending on the hospital facilities and equipment, surgical team qualifications, and patient conditions. keywords: percutaneous nephrolithotomy: laparoscopy: ureteral stone: surgery: hydronephrosis. introduction ureteral calculi are the third leading urological disease after urinary tract infection and prostate disorder (1). the likelihood of spontaneous passage of a ureteral stone is associated with the location and size of the stone(1,2). the majority of stones less than 4 mm in diameter pass spontaneously(3,4). stone diameter over 5 mm is associated with a progressive decrease in the spontaneous passage, which is unlikely with stones over 10 mm in diameter(5-10). in the recent years, the endourology techniques and the technology associated with the ureteroscopic treatment of stones have advanced significantly(11-23). among various techniques for treatment of upper ureteral stones such as extracorporeal shock wave lithotripsy (eswl), transurethral lithotripsy (tul), percutaneous nephrolithotomy (pcnl), laparoscopy and open surgery, the best choice depends on patient’s condition, surgeon experience, and equipment(24-42). in order to verify the best technique, comparative studies are also useful. approaching upper ureteral ureter is one of the biggest challenges. in almost all cases, pcnl is performed to treat proximal ureteral stones larger than 1.5 cm. although some studies have compared pcnl, tul, 1urology & nephrology research center, hamadan university of medical sciences, hamadan, iran. *correspondence: hamadan university of medical sciences, hamadan, iran. email: shmbahar@yahoo.com. received april 2018 & accepted december 2018 eswl, and open surgery with each other, no study has yet been conducted to compare pcnl and laparoscopy. because the selection of the correct approach to treat large ureteral stones has always been challenging, we compared the success rate and complications of the two surgical techniques of pcnl and laparoscopic ureterolithotomy for the treatment of large proximal ureteral stones. materials and methods in this prospective, cohort study, the success rate and complications in 52 patients undergoing pcnl in shahid beheshti hospital (hamadan, iran) and 55 patients undergoing laparoscopic ureterolithotomy in shahid labbafinejad hospital (tehran, iran) were compared. all patients had large (>1.5 cm) proximal ureteral stones. data was collected from july 2016 to january 2018. first, all patients provided informed consent to participate in the study and were given explanations regarding the potential complications of the two techniques. kub, ivp, and ultrasonography were performed and patients with stones larger than 1.5 cm were enrolled after providing signed informed consent. the study protocol was approved by the ethics committee of hamadan university of medical sciences (ir.umurology journal/vol 16 no. 5/ september-october 2019/ pp. 448-452. [doi: 10.22037/uj.v0i0.4538] sha.rec.1394.124). general laboratory tests including cbc, bun, creatinine, urine analysis, and urine culture were performed in both groups before and after surgery. the severity of hydronephrosis was also determined in the two groups. patients with active urinary tract infection were excluded. kub was performed on the morning of the operation day to determine the definite location of the stone. prophylactic antibiotic was administered one hour before surgery. then, standard spinal or general anesthetic procedures were used to conduct anesthesia. inclusion criteria was patients with upper ureteral stone of at least 1.5 cm in diameter and the exclusion criteria was having contraindications for percutaneous surgery such as coagulation disorders and active urinary tract infection. the difference in the size of the stones between the two groups can reduce the accuracy of the study. data analysis was performed by the spss (version 24.0, chicago, illinois, usa) using chi-squared test, fisher's exact test, wilcoxon test, paired-sample t-test and man-whitney test. p < 0.05 was considered statistically significant. results out of 107 patients, 52 underwent pcnl and the rest underwent laparoscopy. in the pcnl group, 75% and in the laparoscopy group, 83.6% of patients were male (p= .270). the mean age of patients was 47.78 ± 16.72 years in the pcnl group and 42.92 ± 16.10 years in the laparoscopy group, with no statistically significant difference (p = .128). the stone was right-sided in 50% of the pcnl group and 43.6% of the laparoscopy group (p > 0.05). the mean stone size was 18.33 ± 2.63 mm in the pcnl group and 21.29 ± 2.18 mm in the laparoscopy group, with a statistically significant difference (p <.001). as shown in table 1, the rate and severity of hydronephrosis in the two groups were similar. the success rate was 100% in the two groups with no significant difference (p = 1.000). mean surgery duration was 32.02 ± 9.40 minutes in the pcnl group and 107.43 ± 22.86 minutes in laparoscopy group, with a statistically significant difference (p < .001). as shown in table 2, serum hemoglobin, hematocrit, urea, and creatinine levels in both groups significantly decreased (p < 0.001); but the decrease in all variables, except for creatinine, was more pronounced in the pcnl group (p <.001). the mean hospital stay length was 2.15 ± 0.5 days in the pcnl group and 2.14 ± 0.4 days in the laparoscopy group, with no statistically significant difference (p = 0.92). table 3 shows the comparison of the mean preoperative and postoperative serum hemoglobin, hematocrit, urea, and creatinine levels between the two groups. according to the results, there were no significant differences in mean preoperative hemoglobin and creatinine levels between the pcnl and laparoscopy groups (p > .05). however, there were significant differences in mean preoperative hematocrit and urea levels between two groups (p <.05). regarding postoperative measurements, only the mean urea level was significantly different between the two groups (p <.001). as shown in table 4, there were no differences in terms of adverse effects between the two groups except for fever (p = 0.04),and also none of the patients had iatrogenic organ injury. discussion urinary stones are a common urological disease with an incidence rate of 10 to 15% and a recurrence rate of 50 percent(42). during recent decades, surgical techniques including pcnl and laparoscopy have advanced significantly(43). nowadays, use of open lithotomy is restricted to few cases such as large stones with high rigidity, abnormal shapes, and post-surgical complications(44). for large upper ureter stones, the pcnl is the first treatment of choice and laparoscopy is the alternative technique(45). we matched the two groups for age, gender, and side of the stone. however, in the study of mousavi bahar et al., age, gender, weight, and hydronephrosis had no effect on the success rate(38). a meta-analysis by zhao et al. reported no differences in age, body mass index, urinary tract infection, and gender between patients undergoing pcnl and laparoscopy(41). aminsharifi et al. also reported similar results among patients undergoing open surgery, laparoscopy, pcnl vs laparoscopy in large proximal ureteral stones-mousavi bahar et al. table 1. frequency distribution of hydronephrosis across the two groups method hydronephrosis total p value negative mild moderate severe pcnl frequency 0 14 26 12 52 0.20 percentage 0 26.9 50 23.1 100 laparoscopic frequency 1 7 29 18 55 percentage 1.8 12.7 52.7 32.7 100 method indices mean ± standard deviation mean difference p value preoperative postoperative pcnl hemoglobin (mg/dl) 14.34 ± 1.69 13.36 ± 1.56 0.98 < 0.001 hematocrit (mg/dl) 43.80 ± 4.50 40.34 ± 40.51 3.37 < 0.001 urea (mg/dl) 40.70 ± 18.32 29.51 ± 8.43 11.19 < 0.001 creatinine (mg/dl) 1.313 ± 0.71 1.06 ± 0.26 0.256 < 0.001 laparoscopic hemoglobin (mg/dl) 13.18 ± 1.44 12.88 ± 1.42 0.3 < 0.001 hematocrit (mg/dl) 39.67 ± 4.55 38.61 ± 4.84 1.06 < 0.001 urea (mg/dl) 18.40 ± 5.44 15.51 ± 5.75 2.89 < 0.001 creatinine (mg/dl) 1.15 ± 0.32 1.04 ± 0.33 0.109 < 0.001 table 2. distribution frequency of laboratory indices across the two groups vol 16 no 04 september-october 2019 449 and pcnl for stag-horn stones(44) which was partly consistent with our results as we did not investigate body mass index and urinary tract infection. the mean hospital stay length was reported 2.33 days for pcnl by majidpour et al(42) and 3.8 days for laparoscopy by noorbala et al(41). zhao et al.(43) and aminsharifi et al.(44) reported hospital stay length was not significantly different between the two groups which is consistent with our study. the stone removal rate in both groups was 100% in our study. simforoosh et al. reported the success rate of laparoscopy to be 96.7% (33). skolarikos et al. reported success rate of pcnl as 100%(34). basiri et al. reported 86% and 90% of patients undergoing pcnl and laparoscopy, respectively, were stone free(37) and zhao et al.(43) reported better outcomes for laparoscopy compared with pcnl but aminsharifi et al. reported better results for laparoscopy(44). a study reported the success rate of pcnl as 87.1% (36) and majidpour et al. reported it to be 91% (40). noorbala et al. reported no conversion to open surgery in laparoscopic procedures(39). the success rate of pcnl was reported 90.7% by mousavi bahar et al(39). a success rate of 92.3% has also been reported for pcnl in children(40). zhao et al.(43) and aminsharifi et al.(42) had reported that laparoscopy led to better results. other studies reported various success rates(38-42). inconsistency in the available evidence can be attributed to surgeon experience, the applied instruments and the differences in size, location, and type of stones. in this study, the mean surgery duration was shorter and hemoglobin, hematocrit, and urea levels decreased more pronouncedly in pcnl group, which is in agreement with the study of zhao et al(43). shorter surgery duration with significant decrease in hematocrit has been reported for both laparoscopy and pcnl(44). noorbala et al. reported a mean duration of 98 minutes for laparoscopic procedure and a mean hospital stay length of 3.8 days with none of the patients requiring blood transfusion and conversion to open surgery(41). the results of our study are consistent with the studies of zhao et al. (43) and aminsharifi et al.(44) in the current study, the mean decrease in hemoglobin and hematocrit, and fever were higher in pcnl group. two cases of blood transfusion and drain leak were reported in pcnl group, but no organ injury was observed. consistently, zhao et al. (43) and aminsharifi et al.(44) reported more hemoglobin and hematocrit drop and higher need for blood transfusion. the main limitation of our study was small sample size and the conduction of procedures in two separate settings, influencing the generalizability of the results obtained. conclusions pcnl and laparoscopy achieved the same success rate for the treatment of upper ureteral large stones. the two methods, however, should be utilized depending on the hospital facilities, equipment and the surgical team's qualifications. both methods have certain benefits and suffer from some limitations. shorter duration of surgery is the benefit of pcnl and less hemoglobin and hematocrit drop is the benefit of laparoscopic ureterolithotomy. it is also essential to take into consideration available equipment and facilities and also the surgeon's experience in selecting the surgical technique. conflict of interest the authors declare no conflict of interest. references 1. stoller m. urinary stone disease in; 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45:603-8. 19. liang t, zhao c, wu g, tang b, luo x, lu s, et al. multi-tract percutaneous nephrolithotomy combined with ems lithotripsy for bilateral complex renal stones: our experience. bmc urol, 2017; 17:15. 20. tao j, sheng l, zhang hj, chen r, sun zq, qian wq. acute abdominal compartment syndrome as a complication of percutaneous nephrolithotomy: two cases reports and literature review. urol case rep, 2016; 8:12-4. 21. jo jk, autorino r, chung jh, kim ks, lee jw, baek ej, et al. randomized controlled trials in endourology: a quality assessment. j endourol, 2013;27:1055-60. 22. aslzare m, darabi m.r, shakiba b, et al. colonic perforation during percutaneous nephrolithotomy: an -18year experience. j urol, 2014; 8:323. 23. said sh, al kadum hassan ma, ali rh, aghaways i, kakamad fh, mohammad kq. percutaneous nephrolithotomy; alarming variables for postoperative bleeding. arab j urol, 2017; 15:24-9. 24. cicekbilek i, resorlu b, oguz u, kara c, unsal a. effect of percutaneous nephrolithotomy on renal functions in children: assessment by quantitative spect of (99m)tc-dmsa uptake by the kidneys. ren fail, 2015; 37:1118-21. 25. simforoosh n, aminshararifi a, nouralizadeh a. difficulties in laparoscopic surgery for urinary stones. in: kandari, gill is, editors. difficult conditions in laparoscopic urology.1 st ed, london: springer-verlag. 2011; pp. 305-319. pcnl vs laparoscopy in large proximal ureteral stones-mousavi bahar et al. vol 16 no 04 september-october 2019 451 26. wang y, zhong b, yang x, wang g, hou p, meng j. comparison of the efficacy and safety of ursl, rplu, and mpcnl for treatment of large upper impacted ureteral stones: a randomized controlled trial. bmc urol, 2017; 17:50. 27. simforoosh n, aminsharifi a. laparoscopic management in stone disease. cure opin urol, 2013; 23: 169-174. 28. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j, 2016; 13:2899-902. 29. kim jy, kang sh, cheon j, lee jg, kim jj, kang sg. the usefulness of flexible cystoscopy for preventing double-j stent malposition after laparoscopic ureterolithotomy. bmc urol, 2017; 15;17:44. 30. nouira y, kallel y, bionous my, dahmoul h, horchani a. laparoscopic retroperitoneal ureterolithotomy :initial experience and review of literature. j endourol, 2014; 18:55761. 31. ergin g, kirac m, unsal a, kopru b, yordam m, biri h. surgical management of urinary stones with abnormal kidney anatomy. kaohsiung j med sci, 2017; 33:207-11. 32. desai jd. prospective outcomes of 11-13ch. ultra-mini percutaneous nephrolithotomy (ump): a consecutive cohort study. arch esp urol, 2017; 70:202-10. 33. simforoosh n, basiri a, danesh ak, et al. laparoscopioc management of ureteral calculi: a report of 123 cases. urol j, 2007; 4:138-41. 34. skolarikos a, papatsoris ag, albanis s, assimos d. laparoscopic urinary stone surgery: an update evidence – based review. urol res, 2010; 38: 44-337. 35. skrepetis k, doumas k, siafakas i, et al. laparoscopic versus open ureterolithotomy. a comparative study. eur urol, 2001; 40; 32-36. 36. goel a, hemal ak. evaluation of role of retroperitoneoscopic pyelolithotomy and its comparison with percutaneous nephrolithotripsy. int urol nephrol, 2003; 7635:73. 37. basiri a, simforoosh n, ziaee a, et al. retrograde, antegrade, and laparoscopic approaches for the management of large proximal ureteral stones: a randomized clinical trial. j endourol, 2008; 22:2677-80. 38. mousavi-bahar sh, minaei ma. results of pcnl for renal and upper ureteral stones without fluoroscopy. sci j hamadan univ med sci, 2003; 10:35-8. 39. mousavi bahar sh, babolhavaeji h, mani kahsani kh, zand-vakili h. percutaneous nephrolithotomy in the management of pediatric renal calculi. j med counc iran, 2006; 24:271-8. 40. mousavi bahar sh, babolhavaeji h, mani kahsani kh. study of response rate to pcnl therapy for renal and upper ureteral stones. j tabriz univ med sci, 2007; 29: 103-9. 41. noorbala h. laparoscopic ureterolithotomy: results and report of transperitoneal tul (laparoscopic assisted). jaums, 2006; 4:939-42. 42. soufi majidpour h, yousefinejad v. percutaneous management of urinary calculi in horseshoe kidneys. urol j, 2008; 5:188-91. 43. zhao c, yang h, tang h, xia d, xu h, chen z, et al. comparison of laparoscopic stone surgery and percutaneous nephrolithotomy in the management of large upper urinary stones: a meta-analysis. urolithiasis, 2016; 44:47990. 44. aminsharifi a, irani d, masoumi m , goshtasbi b, aminsharifi a, mohamadian r. the management of large staghorn renal stones by percutaneous versus laparoscopic versus open nephrolithotomy: a comparative analysis of clinical efficacy and functional outcome. urolithiasis, 2016; 44:551-7. 45. lopez m, hoppe b. history, epidemiology and regional diversities of urolithiasis. pediatr nephrol, 2010; 25:49–59. 46. yong c, knudsen be. ureteroscopy: accessory devices. minerva urol nefrol, 2016; 68:527-46. endourology and stones diseases 452 pcnl vs laparoscopy in large proximal ureteral stones-mousavi bahar et al. case report laser treatment for urethral hemangiomas: report of three cases mohammad javad soleimani, pejman shadpour*, kaveh mehravaran, amir h kashi keywords: hemangioma; laser; blood coagulation; urethra; recurrence to present our experience with coagulation/laser treatment of urethral hemangiomas. three cases with small to medium sized urethral hemangiomas in penile and posterior urethra presented with hematuria or urethral bloody discharge. all patients were male. they were treated with thermal or holmium-yag laser coagulation in the first session. recurrence of hematuria/bloody discharge happened in two patients within one month from the first treatment that was managed with a second session of laser coagulation. no third session of intervention for hematuria/ bloody discharge was required in any patient during 10-39 months of follow up. in cases of relapse after thermal or laser coagulation of small to medium sized urethral hemangiomas, after appropriate consultation with the patient, a second session of laser coagulation can be successful before contemplating more invasive measures like open surgery. introduction genitourinary hemangiomas are among the less common causes of hematuria or hematospermia(1). urethral hemangiomas are very rare and most cases have been described in male patients(2). by the end of 2008, the total number of reported cases was less than 30(3). most patients have presented in the second or third decade of life(4,5). until a decade ago, the advocated treatments for urethral hemangiomas were thermal or laser coagulation in case of small lesions and open surgery in case of large lesions or recurrence after initial endoscopic intervention(1,5). recently, transurethral resection and laser ablation of larger male urethral hemangiomas have been reported(2). we report on our 3 patients with moderate sized urethral hemangioma who were endoscopically managed with coagulation and/or laser treatment. hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. vanaksq, tehran 19697, iran. *correspondence: hasheminejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. vanaksq, tehran 19697, iran . tel: 98 21 88644444. fax: 98 21 88644447. pshadpour@gmail.com and shadpour.p@iums.ac.ir. received september 2016 & accepted may 2017 figure 1. hemangiomatous lesion in distal penile urethra. figure 2. hemangioma at 12 o’clock position (indented black arrow indicates 12 o’clock position) case report 3097 case 1 a 41 year-old man presented with a 10 day history of hematuria and painless urethral bleeding. his physical examination was unremarkable, and prostate was less than 20 g in digital rectal examination. laboratory examinations were normal except for isolated hematuria. ultrasonographic evaluation of the urinary tract was normal. he was scheduled for cystoscopy during which, a 5 mm hemangioma was observed in the proximal penile urethra. (figure 1) the lesion was coagulated using pin-point low-power monopolar electrocautery and the patient was discharged the day after surgery. he presented one month later with recurrent urethral bleeding. he underwent a second cystoscopy, blood clots were evacuated from urethra and the same hemangioma lesion was coagulated again with holmium-yag laser at 3 watts of energy. the patient was discharged on the first postoperative day and bleeding episodes have not recurred during 39 months of follow up. case 2 a 22 year-old man presented with intermittent post-erection hematuria since 1 year before admission which had increased in severity within the preceding 1 month. physical examination was unremarkable. normal hemoglobin was observed in laboratory examinations. other laboratory examinations were normal except for periodic hematuria. ultrasonographic examination of the urinary tract was unremarkable. he underwent cystoscopy at which, a 10 mm hemangioma was observed in penile urethra at the 12 o’clock position. (figure 2) the lesion was coagulated with holmium-yag laser at 2 watts. an 18 f urethral catheter was inserted to assist for temporary tamponade which was removed 2 days later. after 2 month, the patient was scheduled for cystoscopy because of recurrence in our previous case. during cystoscopy, no lesion was observed and the patient has not experienced hematuria during 19 months of follow up. case 3 a 14 year-old male adolescent presented with chief complaint of painless bloody discharge from urethra lasting 5 days. bloody discharge was occasionally massive leading to serum hemoglobin level below 7. the patient had unremarkable medical history including absence of lower urinary tract symptoms, urolithiasis, or flank pain. physical examination was also unremarkable. laboratory examinations were normal. transrectal ultrasonography had been performed elsewhere which revealed normal prostate and seminal vesicles. he underwent cystoscopy which revealed a 1 cm hemangioma in the distal third of penile urethra from 3 to 5 o’clock positions and a 1.5 cm hamartomatous lesion 2-3 cm distal to the hemangioma. both lesions were coagulated with laser at 3 watts energy. two weeks later, the patient presented with hematuria recurrence. he was scheduled for cystoscopy and two small hemangiomatous lesions were observed obviously distal to the previously treated ones were coagulated at the second session with laser coagulation at 2 watts. a 16 f urethral catheter was inserted after coagulation which was removed on the 1st postoperative day. the patient has not experienced recurrent bleeding during 10 month follow up. discussion the most common presentation for of urethral hemangioma is intermittent hematuria which is typically painless and sometimes massive(1). bloody urethral discharge and hematospermia has been rarely reported. the classical diagnostic method for urethral hemangioma is cystoscopy, however this modality may underestimate the presence or extent of disease and pelvic mri has been suggested to better delineate the extent of disease(4,6,7). cattolica et al. suggested that cystoscopy during penis flaccidity may miss these lesions which enlarge and become more visible during erection(8). saito and colleagues proposed that endoscopy immediately after ejaculation with reduced irrigation flow will increase the probability of diagnosing these lesions(9). currently, thermal or laser ablation has been reported for urethral hemangiomas which can be associated with incomplete ablation and relapse in some cases.(2) open surgery with urethral reconstruction has been advocated cases that have relapsed(1,5). we presented a series of 3 patients managed by laser ablation of urethral hemangiomas. the laser device used in these patients was a pulsed low power holmium-yag laser device. the interesting point is that the majority of patients (2 out of 3) presented with recurrent bleeding after a first session of coagulation or laser treatment. therefore, it seems wise to consult patients about the possibility of relapse as indicated by previous reports when laser or thermal coagulation is planned for urethral hemangiomas. nevertheless, all patients in this series responded to a second session of laser coagulation with no subsequent substantial bleeding observed during follow up. no patient needed any further intervention after the second session of laser coagulation during a medium term follow-up (10 to 39 months). we performed follow up cystoscopy in cases of gross or microscopic hematuria or bloody discharge form the urethra. there is the possibility of urethral stricture after any sort of urethral interventions. patients should be consulted about this possibility and follow up be scheduled accordingly. we think that as previously reported by saito et al., the real prevalence of urethral hemangiomas can be higher than previously thought(9). careful examination of urethra during cystourethroscopy can reveal small easily overlooked lesions. this point will be of utmost importance when confronting a relapse of hematuria or urethral bloody discharge in a patient previously treated for urethral hemangiomas. thorough investigation of the urethra is advised to identify any previously missed or newly surfaced hemangiomatous lesions. conclusions in cases of relapse after thermal or laser coagulation of urethral hemangiomas there can be a choice of trying a second session of laser coagulation before resorting to open surgery after appropriate consultation with the patient. conflict of interests none declared. references laser for urethral hemangioma-soleimani et al. vol 14 no 03 may-june 2017 3098 laser for urethral hemangioma-soleimani et al. 1. parshad s, yadav sp, arora b. urethral hemangioma. an unusual cause of hematuria. urol int. 2001;66:43-5. 2. ongun s, celik s, aslan g, yorukoglu k, esen a. cavernous hemangioma of the female urethra: a rare case report. urol j. 2014;11:1521-3. 3. han h, zhou xg, fan dd, tian l, zhang xd. an unusual etiology for hematospermia and treatments that were successful. urology. 2015;86:740-3. 4. manuel es, seery wh, cole at. capillary hemangioma of the male urethra: case report with literature review. j urol. 1977;117:804. 5. roberts jw, devine cj, jr. urethral hemangioma: treatment by total excision and grafting. j urol. 1983;129:1053-4. 6. hayashi t, igarashi k, sekine h. urethral hemangioma: case report. j urol. 1997;158:539-40. 7. stewart sb, leder ra, inman ba. imaging tumors of the penis and urethra. urol clin north am. 2010;37:353-67. 8. cattolica ev. massive hemospermia: a new etiology and simplified treatment. j urol. 1982;128:151-2. 9. saito s. posterior urethral hemangioma: one of the unknown causes of hematuria and/or hematospermia. urology. 2008;71:168.e11-4. case report 3099 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran introduction the method of treating submucosal ureteral stones is always a matter of discussion in urology. the surgery of submucosal ureteral stone is difficult and occasionally leads to the dissection of ureter from behind the bladder and ultimately to open surgery. the classic use of endourologic devices, particularly in impact submucosal ureteral stones, is not always possible, since factors such as submucosal ureteral edema, the change of ureteral orifice posteriorly, and bolus edema formation around the ureteral orifice may cause unsuccessful classic uretroscopy. thus, sometimes it is necessary to apply other methods of treatment such as submucosal ureteral incision (ureteral meatotomy) in order to remove submucosal ureteral stones. thus, the detection of these stones is of great importance and it leads the urologist to use subthe application of kub for detecting of submucosal ureteral stones aghamir smk*, mohseni mg, ardastani a department of urology, sina hospital, tehran university of medical sciences, tehran, iran abstract purpose: the accurate diagnosis of submucosal ureteral stones in order to choose a proper and less complicative method of treatment is of significant importance. the use of kub to detect submucosal ureteral stones has been studied in this research. materials and methods: this prospective study has been carried out on 33 patients (23 males and 10 females) with lower ureteral stone (17 cases in the right ureter and 16 in the left) located under iscial spine as was indicated in their kub. the distance from the lower end of stone to the midline of sacrum was measured per millimeter using kub. all patients underwent ureteroscopy, and accordingly those with submucosal ureteral stones were distinguished. the correlation between the distance of the lower end of stone from the middle line of sacrum and the existence of submucosal ureteral stone was analyzed. results: nineteen out of 33 studied patients had submucosal ureteral stones. the average distance between the peak of stone and the middle line of sacrum in patients with submucosal ureteral stone was 9.7 mm with an accuracy of 1.4 mm, a confidence interval 95% and standard deviation of 3.1 mm. accordingly, if the distance of stone from the middle line of sacrum is lower than 13.7 mm, in 90% of cases the stone will be submucosal. conclusion: in patients with lower ureteral stone, the kub of whom indicates a stone under iscial spine, if the distance of the peak of stone from the midline of sacrum was lower than 15 mm, the stone could most likely be submucousal, a point, which should be considered during treatment. in such cases the intravesical approach should be considered intraoperatively and preparation for submucosal ureteral incision must be provided. this method would be useful in stone removal, if the classic ureteroscopy was not successful. key words: submucosal ureteral incision, ureteral meatotomy, kub, submucosal ureteral stone accepted for publication the application of kub for detecting of submucosal ureteral stones stitutional methods. definite diagnosis of submucosal ureteral stones is obtained by cystoscopy. in the following situations, the submucosal ureteral stone is suspected: observation of stone in ureteral orifice, bulging of stone in submucosal ureter, and bolus edema around the ureteral orifice. a noninvasive method that could detect submucosal ureteral stone accurately has not been reported yet. it is just mentioned that if a stone in kub is located in the lower ureter horizontally, it could likely be a submucosal ureteral stone.(1) in this study the distance of stone from the midline of sacrum (which is measured by the use of kub) is evaluated as a quantitative criterion in submucosal ureteral stone diagnosis. meterials and methods from dec. 1999 to sep. 2000, 87 patients were referred for lower ureteral stone, of whom the kub of 33 patients indicated a stone parallel to or lower than iscial spine. of these, 17 and 16 had right and left side ureteral stone respectively. twenty three patients were male and 10 were female. the mean age was 43 years (range 2466). the ureteral orifice and submucosal ureter were seen by an 8.5 fr ureteroscope. if the stone was seen at the ureteral orifice or there was a stone bulging in submucosal ureter, the diagnosis of submucosal ureteral stone would be made. ureteroscopy was carried out at lithotomy position and under general or spinal anesthesia. when classic ureteroscopy was possible, the stone was fragmented by lithoclast, otherwise it was removed by mucosal ureteral incision, and then the whole ureter up to the kidney was observed. in order to reduce edema and prevent postoperative pains, ureteral stent was placed in all patients for 48 hours. using kub, the horizontal distance of stone from the midline of sacrum was measured per millimeter and the correlation between this distance and the existence of submucosal ureteral stone was studied (fig.1). results nineteen out of 33 studied patients had submucosal ureteral stone (table 1). the mean distance between the peak of stone and the midline of sacrum in patients with submucosal ureteral stone was 9.7±3.1 mm. regarding the sample size formula of descriptive studies, if we assume ?=0.05, ?=3.1, and n=19 ( the number of patients with submucosal ureteral stone), the standard deviation with 95% confidence interval would be 1.4 mm. considering the obtained results, if the distance of stone from the middle line of sacrum is lower than 13.7, the stone is likely to be submucosal ureteral by a chance of 90%. discussion the definite diagnosis of submucosal ureteral stone before any treatment could lead the urologist to choose a proper and less complicative method of treatment. nowadays, the use of ureteroscopy is regarded as a preferable treatment of submucosal ureteral stones.(2) however, the occasional failure of classic ureteroscopy leads to the application of substituional methods such as ureteral meatotomy. now, ureteral meatotomy is considered as the most common approach in the treatment of submucosal ureteral impact stones.(3, 4) thus, the failure in detecting submucosal ureteral stone, while using alternative methods is impossible for the urologist can yield to unsuccessful treatment. a few studies of detecting submucosal ureteral stones have been conducted and available data indicates that there is not any definite noninvasive method of detecting such stones to be reported. in this study the distance of the peak of stone from the midline of sacrum has been studied as a quantitative criterion in the diagnosis of submucosal ureteral stones. ninety percent of these stones were located at lower than 13.7 mm. form the middle line of sacrum. accordingly, there is a correlation between the distance of the peak of 2 table 1. the frequency of patients with submucosal ureteral stone according to the distance between the peak of stone and the midline of sacrum number of patients with submucosal ureteral stone (%) total number of patients the distance from midline of sacrum (mm) 13(100%) 13 x< 10 mm 3(43%) 7 10 15 mm the application of kub for detecting of submucosal ureteral stones stone from the midline of sacrum and the existence of submucosal ureteral stone. hence, if this distance is lower than 15 mm, the stone will most likely be in submucosal ureter. in such cases, it may be simple to access the stone intravesically during surgery. however, ureteral meatotomy devices should be available while using endourologic methods. ureteral meatotomy could be used to remove the stone whenever classic ureteroscopy is impossible. conclusion in patients with lower ureteral stone, the kub of whom indicates a stone under iscial spine, if the distance of the peak of stone from the midline of sacrum was lower than 15 mm, the stone could most likely be submucousal, a point, which should be considered during treatmentin such cases the intravesical approach should be considered intraoperatively and preparation for submucosal ureteral incision must be provided. this method would be useful in stone removal, if the classic ureteroscopy was not successful. references 1. el-sheriff ae. endoscopic management of impaired stones in intramural or meatal part of ureter without performing meatotomy. british j urol 1995; 76: 394-396. 2. kapoor da, leech je, yap wt, et al. cost and efficacy of extracorporeal shock wave lithotripsy versus ureteroscopy in treatment of lower ureteral calculi. j urol 1992; 148: 1095-1096. 3. hussain i. topical urology and renal disease. edinburgh: churchill livingstone; 1984. p. 165-199. 4. clarck p. operations in urology. edinburgh: churchill livingstone; 1984. p. 256-272. 3 fig. 1. a 23 year female with left submucosal ureteral stone. the distance between the tip of the stone and midline is 9 mm. quantitative analysis of ultrasound tissue diffusion elastography in the diagnosis of benign and malignant prostate lesions jun guo1,2, lei liang2, nan zhou2, de-yu li1* purpose: this study aims to evaluate the value of quantitative analysis of ultrasound real-time tissue diffusion elastography in the diagnosis of benign and malignant prostate lesions. materials and methods: from march 2010 to june 2013, 52 patients suspected with prostate cancer based on laboratory or clinical test results and underwent prostate biopsy in our hospital were enrolled into this study. the age of these patients ranged between 45-82 years, with an average age of 67.2 ± 6.8 years. all patients underwent transrectal real-time ultrasound elastography (trte) before biopsy. a total of 63 prostate nodules were detected, and the 11 elastic characteristic quantities of these nodules were quantitatively analyzed via tissue diffusion quantitative analysis. the results of ultrasonography were compared with the results of operation and pathology. result: among these 11 characteristic quantities, which include the mean (mean) and standard deviation (sd), blue area ratio (area%), complexity (comp), kurtosis (kurt), skewness (skew), contrast (cont), equality (ent), entropy (idm), consistency (asm) and correlation (corr), except for comp and corr, the differences in other nine characteristic quantities between benign and malignant prostatic nodules were statistically significant (p<0.05). among these, the area% and mean had the highest correlation, which were 0.791 and -0.791, respectively. the youden’s index (sensitivity and specificity) of area% in the roc curves was the highest, the cutoff value was 80.65% for the diagnosis of prostate cancer, sensitivity was 87.9%, and specificity was 96.6%. conclusion: quantitative analysis of ultrasound real-time tissue diffusion elastography is helpful in the diagnosis of benign and malignant prostate lesions, provides a relatively accurate evaluation method in clinical practice, and has broad application prospects. keywords: ultrasound; elastography; prostate cancer; tissue dispersion quantitative analysis; biopsy introduction prostate cancer has become one of the major diseases that threatens the health of elderly men. in recent years, its incidence has increased annually in china. furthermore, the missed diagnosis rate of digital rectal examination in the diagnosis of cancers is as high as 80%, hence, its value is very limited.(1) prostate-specific antigen (psa) detection and transrectal ultrasonography (trus) greatly improves the early diagnosis of prostate cancer, and are significantly better than digital rectal examination.(2) however, 25-45% of prostate cancer patients present with normal psa levels.(3) at present, the conventional diagnosis of prostate nodules by trus is mainly according to the location, shape, envelope, internal echo and blood flow at the sites of the lesions; which has low sensitivity and specificity.(4) in addition, cell density in prostate cancer is higher than in normal tissues, and this increase in cell density would lead to changes in tissue elasticity.(5) 1school of biological science and medical engineering, beihang university, beijing, 100191, china. 2department of ultrasound, aero space central hospital, beijing, 100049, china. *correspondence: school of biological science and medical engineering, beihang university, no.37 xueyuan road, haidian district, beijing,100191, china. tel: + 86-10-82339093, fax: + 86-10-82339093, e-mail: lideyu_dn@sina.com. received november 2017 & accepted december 2018 clinical pathology studies have shown that there are significant differences in the elastic coefficients of fat, breast, fibrotic tissue, non-invasive carcinogenesis and invasive cancerous tissue. therefore, the degree of deformation of different tissues under different external forces will be different. the tissue elastography technique is based on this theory and receives the information of the tissue displacement after compression by echo, and displays it by color signal encoding after computer super-high speed processing. real-time tissue elastography (rte) is by means of exert internal pressure or external pressure on tissues with the probe. under the conditions of elastic mechanics and biomechanics, these tissues generate a response such as the distribution of displacement, strain and velocity. according to differences in the elastic coefficient of tissues, the strains vary. furthermore, the echo signals before and after compression were collected and analyzed. according to the displacement of different positions in the tissues, the deformation degree is calculated and displayed as images using grayscale or color coding. urological oncology urology journal/vol 16 no. 4/ july-august 2019/ pp. 347-351. [doi: http://dx.doi.org/10.22037/uj.v0i0.4224] vol 16 no 04 july-august 2019 348 in the present study, with postoperative puncture and pathological results as the gold standard, rte and the quantitative analysis of tissue diffusion were applied in the differential diagnosis of benign and malignant prostate lesions to evaluate its diagnostic value. materials and methods research data this study was approved by the ethical committee. from march 2010 to june 2013, 52 patients suspected with prostate cancer based on laboratory or clinical test results and underwent prostate biopsy in our hospital were enrolled into this study. the age of these patients ranged between 45-82 years, with an average age of 67.2 ± 6.8 years. exclusion criteria were: patients who received treatment for prostate disease before admission including transurethral resection of the prostate, particle implantation for prostate cancer, and prostate hormone therapy, patients with a prostate size exceeding the transrectal real-time ultrasound elastography (trte) range, and patients who underwent prostate puncture within one year. all patients underwent ultrasound-guided biopsy or surgery to obtain pathological results. there are two pathologists who both had experience over ten years and they were unaware of the clinical conditions and ultrasound performance of the patients. all patients agreed to participate in this study and provided a signed informed consent. instruments and methods the hivision 900 color doppler ultrasound diagnostic apparatus (tokyo, japan) was used for this study, with the eup-v53w probe. the frequency ranged between 4-9 mhz. the patient was positioned in the left lateral position and underwent routine trus to detect the nodules and observe the morphology, envelope, internal echo and blood flow, and measure systolic velocity (vs) and diastolic velocity (vd) of the blood flow and resistance index (ri) within the lesions. the mode was switched to elastic imaging, and the gray-scale map and elastic graph were simultaneously observed using the dual display function. the probe was adjusted to show the nodule at the center of the screen, pressure was manually exerted on the prostate using a transrectal probe, and elastic imaging was performed by steady small jitter until a stable and repeatable dynamic elastic graph was obtained. if nodules were not found by two-dimensional ultrasound, the mode was switched to elastic imaging after conventional trus; and the whole prostate was first observed. then, the probe was laterally adjusted, and the bilateral internal prostate gland, transitional zone and the outer gland region were observed. the pressure value was displayed as a number within 1-5 in real-time. it was only when the elastic images were continuously displayed and the pressure values were within 4-5 that the test results could be evaluated with valid results. quantitative measurement of tissue diffusion the image was analyzed using the random elastic tissue diffusion quantitative analysis software. the position of the sampling frame did not exceed the largest rectangular area of the scope of the lesion. measurement was conducted three times, and the mean was calculated. hence, 11 quantitative parameters of tissue diffusion were obtained, including the mean (mean) and standard deviation (sd), blue area ratio (area%), complexity (comp), kurtosis (kurt), skewness (skew), contrast (cont), equality (ent), entropy (idm), consistency (asm) and correlation (corr). statistical analysis data were analyzed using statistical software spss 12.0. the 11 characteristic quantities of the elastic imaging of benign and malignant lesions of the prostate were tested for normal distribution. data in normal distribution were compared using t-test, and data in non-normal distribution were compared using nonparametric u-test. p < 0.05 was considered statistically significant. the correlation between elastic characteristic quantities and pathological grades was analyzed using spearman correlation analysis. the receiver operating characteristic curve (roc) was drawn using significant characteristic quantities. then, the sensitivity and specificity of each characteristic quantity in the diagnosis of prostate cancer was calculated. results among the 52 patients in study group, a total of 63 prostate lesions were detected by trte. it was confirmed by biopsy that 20 lesions were malignant. among these lesions, 12 nodules had a gleason score of 2-6 points, two nodules had a gleason score of 7 points, and six nodules had a gleason score of 8-10 points. furthermore, 43 nodules were benign lesions. among these lesions, nine cases were combined with chronic inflammation of the prostate and one case was combined with grade ii of prostatic intraepithelial neoplasm (pin, figures 1-3). furthermore, the psa levels of these included patients ranged between 0.38-100 ng/ml, with an average value of 39.9 ng/ml and a median value of 18.7 ng/ml. among these patients, seven patients had a psa level of < 4 ng/ml, 13 patients had a psa level of > 4 ng/ml and <10 ng/ml, and 32 patients had a psa level of ≥ 10 ng/ml. the 11 characteristic quantities of prostate lesions were determined to be not in the normal distribution. nonparametric u-test analysis revealed that, except for comp and corr, differences in other nine characteristic quantities between benign and malignant prostatic nodules were statistically significant (p < 0.05). correlation analysis revealed that area%, idm, skew, kurt and asm were positively correlated with the malignant ultrasonic elastography in prostatic diseases-guo et al. table 1. analysis of elastic characteristic quantity of benign and malignant lesions of prostate. group number of lesions mean sd area% comp kurt skew cont ent idm asm optimum 29 86.75 ± 30.49 38.56 ± 12.77 36.24 ± 27.52 25.83 ± 8.97 3.15 ± 1.11 0.65 ± 0.47 29.97 ± 5.57 3.18 ± 0.35 0.26 ± 0.08 0.00 ± 0.00 malignant 33 18.18 ± 3.16 19.76 ± 12.67 91.09 ± 14.29 25.14 ± 17.64 6.60 ± 4.16 1.57 ± 0.77 24.87 ± 4.33 2.22 ± 0.62 0.57 ± 0.18 0.09 ± 0.14 f value 11.49 6.01 21.401 4.502 18.828 7.397 1.565 4.751 17.514 34.816 p valuea 0.000 0.016 0.000 0.038 0.000 0.009 0.216 0.033 0.000 0.000 a p < 0.05 was considered statistically significant. urological oncology 349 degree of lesions; and the correlation coefficients were 0.791, 0.754, 0.581, 0.488 and 0.398, respectively. furthermore, the correlation with area% was the highest. mean, ent, sd and cont were negatively correlated with the malignant degree of lesions, and the correlation coefficients were -0.791, -0.721, -0.600 and -0.466, respectively. furthermore, correlation with mean was the highest (table 1). the roc for the diagnosis of prostate cancer was drawn using the 11 characteristic quantities of elastic imaging. the youden’s index (sensitivity and specificity) of area% was the highest, the area under the curve (auc) was 0.961, the diagnostic cutoff value was 80.65%, sensitivity was 87.9%, and specificity was 96.6%. based on the youden's index (from high to low), the diagnostic efficiencies of the other eight characterfigure 1. different types of prostate pathological changes of color doppler ultrasound and ultrasound elasticity imaging. 1a right low echo between inner and outer gland nodules,inside, and high resistance arterial spectrum, trus malignant likely prompt. 1b the right between the inner and outer gland nodules,trte showed lesions subject for the green,with a little blue, score, level, a diagnosis of benign hyperplastic nodule. confirmed by biopsy for prostate hyperplasia, interstitial small amounts of acute or chronic inflammatory cells infiltration. figure 2 . different types of prostate pathological changes of color doppler ultrasound and ultrasound elasticity imaging. 2a the left outer gland low echo nodules, inside, and high resistance arterial spectrum，trus malignant likely prompt. 2b the left outer gland nodules is almost covered by blue, blue and lesion area roughly the same，score ， level，a diagnosis of malignant. confirmed by biopsy for moderately differentiated adenocarcinoma of prostate, gleason score 3 + 3 = 6 points. figure 4 . positive correlation characteristics of benign and malignant lesions of the prostate diagnostic value of roc curve. figure 3. different types of prostate pathological changes of color doppler ultrasound and ultrasound elasticity imaging. 3a the left side is no clear boundary between internal and external gland，diffuse to reduce，on the right side of the outer gland low echo nodules，trus prompt malignant. 3b lesions completely covered by blue, and the blue range is greater than the trus detected lesions area, involvement of bilateral internal and external gland, trte score ， level, a diagnosis of malignant, confirmed by biopsy in poorly differentiated adenocarcinoma of prostate, gleasonscore 5 + 4 = 9 points, both inner and outer gland needle puncture eight right carcinoma tissue. ultrasonic elastography in prostatic diseases-guo et al. vol 16 no 04 july-august 2019 350 istic quantities were mean, asm, idm, ent, cont, sd, skew and kurt, respectively; and the cutoff values were 45.15, 0.005, 0.315, 2.695, 16.65, 23.25, 0.93 and 3.75, respectively. furthermore, the sensitivities were 87.9%, 93.1%, 84.8%, 93.9%, 96.6%, 93.1%, 89.7% and 78.8%, respectively; and the specificities were 96.6%, 90.9%, 93.1%, 82.8%, 78.8%, 81.8%, 69.7% and 79.3%, respectively (figures 4 and 5). discussion since 1991, real-time tissue diffusion elastography was proposed, and was gradually developed and applied. at present, it has gradually become mature in the diagnosis of breast and thyroid diseases. in the past, the diagnosis method of prostate elasticity was kamoi 5-grade scoring.(6) its principle is to exert internal pressure such as heart beat and respiration or external pressure on tissues with the probe. under the conditions of elastic mechanics and biomechanics, these tissues generate a response such as the distribution of displacement, strain and velocity. according to differences in the elastic coefficient which is stress/strain of tissues, the strains vary. furthermore, the echo signals before and after compression were collected and analyzed. according to the displacement of different positions in the tissues, the deformation degree is calculated and displayed as images using grayscale or color coding. in recent years, trte transforms the migration amplitude of echo signals before and after compression into real-time color images, and describes the soft, medium hard and hard textures as red, green and blue colors, respectively. the large change in the displacement of tissues after compression is shown as red, the small change in the displacement of tissues after the compression is shown as blue, and the medium change in the displacement of tissues after the compression is shown as green. the elasticity of different tissues is encoded using color, which reflects its relative hardness.(7-9) kamoi k et al. confirmed that the above methods were helpful in improving the diagnostic rate of prostate lesions.(7) on this basis, hitachi has developed the tissue diffusion quantitative analysis software, which obtains 11 elastic characteristic quantities through the measurement of the strain histogram, for the quantitative evaluation of tissue flexibility. the core of this method is the characteristic quantity extraction, grading and analysis of the degree of tissue diffusion in real-time tissue elastography.(10) in this study, this technique was used for the quantitative evaluation of prostate gland lesions. results revealed that among the 11 elastic characteristic quantities, except for comp and corr, differences in other nine characteristic quantities between benign and malignant prostatic nodules were statistically significant (p < 0.05). among these, area% and mean had the highest correlation, the youden’s index of area% was the highest, and the cutoff value in the diagnosis of prostate cancer was 80.65%. in this study, the area% was lower than this cut-off value in two cases of malignant lesions, and the clinical stages of these two cases were highly differentiated adenocarcinoma. from the pathological perspective, due to the retention of the lumen, highly differentiated adenocarcinoma is very similar to normal prostate glands.(11-13) therefore, in further studies, the relationship between the degree of differentiation of prostate cancer and the hardness of cancer tissues should be examined, in order to provide a more accurate preoperative assessment in clinical practice. however, this study had some limitations. first, sample size needs to be enlarged in the future study. second, the external pressure on tissues with the probe have subjectivity. acknowledgement this study was supported by the foundation of aero space central hospital. (201124). conflict on interest the authors have no conflicts of interest to declare. references 1. nygård y, haukaas sa, halvorsen oj, et al. a positive real-time elastography (rte) combined with a prostate cancer gene 3 (pca3) score above 35 convey a high probability of intermediateor high-risk prostate cancer in patient admitted for primary prostate biopsy. bmc urol. 2016;16;1:1-8. 2. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent—update 2013. euro urol. 2014; 65;1: 124-37. 3. catalona wj, smith ds, ratliff tl, et al. measurement of prostate-specific antigen in serum as a screening test for prostate cancer. n engl j med 1991; 324;17: 1156-61. 4. walz j, loch t, salomon g, wijkstra h. [imaging of the prostate][j]. der urologe. ausg. a 2013; 52;4: 490-6. 5. zhang q,yao j,cai y, zhang l, wu y, xiong j, shi j, wang y, wang y.elevated hardness of peripheral gland on real-time elastography is an independent marker for high-risk prostate cancers.la radiologia medica,2017,122:944-51. 6. brock m, eggert t, palisaar rj, et al. multiparametric ultrasound of the prostate: figure 5. negative correlation characteristics of benign and malignant lesions of the prostate diagnostic value of roc curve. ultrasonic elastography in prostatic diseases-guo et al. adding contrast enhanced ultrasound to realtime elastography to detect histopathologically confirmed cancer. j urol 2013; 189;1: 93-8. 7. kamoi k, okihara k, ochiai a, et al. the utility of transrectal real-time elastography in the diagnosis of prostate cancer. ultrasound med biol 2008; 34;7: 1025-32. 8. porsch m, wendler jj, liehr ub, lux a, schostak m and pech m. new aspects in shear-wave elastography of prostate cancer. j radiol 2015; 15;60: 5. 9. brock m, eggert t, palisaar rj, et al. multiparametric ultrasound of the prostate: adding contrast enhanced ultrasound to realtime elastography to detect histopathologically confirmed cancer. j urol 2013; 189: 93-8. 10. tatsumi c, kudo m, ueshima k, et al. noninvasive evaluation of hepatic fibrosis for type c chronic hepatitis. intervirology 2010; 53;1: 76-1. 11. brock m, sommerer f, löppenberg b, et al. comparison of real-time elastography with grey-scale ultrasonography for detection of organ-confined prostate cancer and extra capsular extension: a prospective analysis using whole mount sections after radical prostatectomy. bju int 2011; 108;8: e217-e222. 12. walz j, marcy m, maubon t, et al. real time elastography in the diagnosis of prostate cancer: comparison of preoperative imaging and histology after radical prostatectomy. ultrasound med biol 2011; 21;13: 925-31. 13. salomon g, köllerman j, thederan i, et al. evaluation of prostate cancer detection with ultrasound real-time elastography: a comparison with step section pathological analysis after radical prostatectomy. euro urol 2008; 54;6: 1354-62. ultrasonic elastography in prostatic diseases-guo et al. urological oncology 351 laparoscopic urology laparoscopic -2port varicocelectomy with scarless periumblical mini-incision: initial experience in approach and outcomes won ik seo1, jong kyou kwon2, pil moon kang3, wansuk kim1, jang ho yoon1, taek sang kim3, jae seung chung4, cheol kyu oh4* purpose: as with other areas, there have been many efforts for minimally invasive surgery in varicocelectomy. we present our initial experience with laparoscopic varicocelectomy with a two-port scarless periumbilical mini-incision. materials and methods: the study enrolled 18 patients who underwent laparoscopic varicocelectomy with a twoport scarless periumbilical mini-incision from february 2012 to april 2013. the laparoscopic varicocelectomy was performed using two 5-mm ports at periumbilical sites in skin creases. here, the surgical procedure is introduced and the outcomes of the case series are summarized. we reviewed other laparoscopic techniques and compared them with our technique. results: the mean patient age was 34.8 years. of the 18 patients, 15 had grade 3 varicoceles. the mean operating time was 62.5 minutes. postoperatively, the scrotal pain level decreased immediately from a mean vas score of 6.3 to 4.4 and then to 1.7 by 24 hours postoperatively. the mean hospital stay was 2.8 days. complications included one hydrocele and two recurrent varicoceles. the operating time decreased as the surgeon’s experience increased. conclusion: laparoscopic varicocelectomy with a two-port scarless periumbilical mini-incision is a feasible technique that can be mastered relatively easily. prospective and comparative studies are required to validate this new technique. keywords: laparoscopy; minimal invasive surgery; scar; umbilicus; varicocele. introduction surgical approaches for varicocele treatment include open, microscopic, laparoscopic varicocelectomy, and sclerotherapy techniques. recent reports suggest that microscopic varicocelectomy has superior outcomes.(1,2) however, advanced techniques and instruments have enabled laparoscopic varicocelectomy, which has many advantages over other approaches, including a more rapid recovery than open varicocelectomy and shorter operating times. laparoscopic varicocelectomy is easy to learn and costs less than microscopic varicocelectomy.(3–7) consequently, laparoscopic varicocelectomy has become a reasonable approach for varicocele treatment. many ways to decrease the postoperative pain and visible scars in laparoscopic surgery have been proposed. these include reducing the diameter and number of trocars.(8,9) for varicocele treatment, the introduction of natural orifice transluminal endoscopic surgery and laparoendoscopic single-site surgery have helped to achieve minimal invasiveness with surgical results comparable to those of other approaches.(10,11) although a small incision can be used in open or microscopic varicocelectomy, there is a trend to minimize the invasiveness of surgical varicocele treatment using laparo1department of urology, inje university busan paik hospital, busan, korea. 2department of urology, yonsei university severance check-up, seoul, korea. 3department of urology, gosin university gospel hospital, busan, korea. 4department of urology, inje university haeundae paik hospital, busan, korea. *correspondence: department of urology, inje university haeundae paik hopspital, 1435 jwandong, haeundaegu, busan, korea. postal no. 612-896. tel: +82-51-890-6384. fax: +82-52-892-2728. e-mail: ckohuro@gmail.com. received february 2017 & accepted november 2017 scopic approaches.(12,13) link et al. reported their initial experience with two-port laparoscopic varicocelectomy in a small number of patients and obtained outcomes comparable with traditional open surgical approaches. (13) they used only two 5-mm trocars to minimize the size and number of ports and reported good convalescence and cosmetic results. however, the placement of the second 5-mm port in the abdominal wall results in a small scar. here, we review our initial experience with laparoscopic two-port varicocelectomy with a scarless periumbilical mini-incision procedure for clinically significant varicoceles. materials and methods this study enrolled 18 consecutive patients who underwent laparoscopic varicocelectomy with a two-port scarless periumbilical mini-incision from february 2012 to april 2013. patients older than 18 years of age with clinically palpable varicoceles (grade 2 or 3) were eligible to enroll in this study. those with a secondary varicocele due to non-scrotal causes were excluded. the major indication for surgery was scrotal pain with a diagnosis of varicocele based on a physical examination and scrotal ultrasound. a concomitant hydrocelectomy and epididymal cyst excision was performed in four and laparoscopic urology 10 two patients, respectively. one patient also underwent circumcision. all surgeries were performed by a single surgeon (c.k.o.) who had experience with conventional twoport laparoscopic varicocelectomy. for the surgical procedure, the patient was placed in a supine position. surgery was performed via a transperitoneal approach and two 5-mm-long incisions were made in peri-umbilical skin creases at between 12 and 1 o’clock for the 0-degree laparoscope and 6 and 7 o’clock for the working port (figure 1). pneumoperitoneum was established using a veress needle and a non-threaded 5-mm trocar was inserted. the co2 pressure was maintained at 20 mmhg and was decreased to 12 to 15 mmhg after inserting the second trocar. after identifying the course of the spermatic vessel bundle, a longitudinal peritoneal incision was made along the lateral border of the spermatic vessels (figure 2, a). the peritoneal incision was widened using a dissector, and then a vertical t-shaped peritoneal incision was made beginning from the spermatic vessels. the testicular artery was dissected carefully and separated from the spermatic veins in all patients (figure 2,b and c). further dissection was performed to identify additional branches of the spermatic veins around the spermatic artery. all spermatic veins were clamped using hem-o-lok® non-absorbable polymer locking clips of medium size(5mm applied) and divided (figure 2, d). the peritoneum incision site was packed with surgicel® and left unsutured. the prospectively collected data on the enrolled patients included patient age, height, weight, body mass index, bilaterality and grade of varicocele, number of ligated veins, operating time, estimated blood loss, visual analog scale (vas) score for perioperative pain, length of hospital stay, concomitant procedures, and postoperative complications, including recurrence. when there was a concomitant operation such as hydrocelectomy, circumcision, or epididymal cyst excision, we defined the operating time as the actual surgery time for the varicocelectomy. the patients underwent postoperative evaluations at 1 week to check the wound site and at 4 weeks and 3 months to check the resolution of pain and postoperative complications. to measure perioperative scrotal pain, a vas scoring system was used that ranged from 0 (no pain) to 10 (worst pain imaginable). variables for baseline characteristics of patients were analyzed by descriptive analysis using mean value and standard deviation. to analyze the learning curve of the operation, the distributions of variables were evaluated using the kolmogorov-smirnov test and logarithmic transformation was used to normalize the distribution using the real values of the operating time as reference values for the logarithmic values. a statistical analysis was performed using spss 20.0.0.2 (ibm corp., armonk, ny, usa). this study was performed in accordance with applicatable 1. baseline characteristics of patients who underwent laparoscopic two-port varicocelectomy with scarless periumbilical mini-incision age (years, mean ± sd) 34.8 ± 17.9 height (cm, mean ± sd) 174.6 ±8.3 weight (kg, mean ± sd) 72.3 ± 15.2 body mass index (kg/m2, mean ± sd) 23.6 ± 4.2 varicocele grade 2 3 3 15 number of ligated veins ≤ 2 13 ≥ 3 5 operation time (minute, mean ± sd) 62.5 ± 15.6 estimated blood loss (cc, mean ± sd) 20.3 ± 10.2 preoperative pain by visual analogue scale (score, mean ± sd) 6.3 ± 1.2 postoperative pain by visual analogue scale (score, mean ± sd) immediate postoperative 4.4 ± 1.5 6-h after operation 3.1 ± 1.4 24-h after operation 1.7 ± 1.1 hospital stay (days, mean±sd) 2.8 ± 1.9 concomittent procedure(number of cases) hydrocelectomy 4 circumcision 1 epididymal cyst excision 2 complications(number of cases) recurrence 2 hydrocele 1 testicular atrophy 0 figure 1. ports site of laparoscopic 2-port varicocelectomy with scarless periumblical mini-incision. figure 2. procedures of laparoscopic 2-port varicocelectomy with scarless periumblical mini-incision. scarless laparoscopic 2-port varicocelectomy-seo et al. vol 15 no 02 march-april 2018 11 ble laws and regulations, good clinical practices, and ethical principles as described in the declaration of helsinki. the institutional review board of haeundae paik hospital approved the study protocol and all patients provided informed consent before participating in this study. results table 1 summarizes the basic characteristics of the enrolled patients. the mean age was 34.8 years. in total, 3 patients had grade 2 and 15 patients had grade 3 varicoceles. the mean operating time was 62.5 minutes and the mean estimated blood loss was 20.3 ml. patients gave the scrotal pain a mean vas score of 6.3 preoperatively. postoperatively, the pain decreased to a mean vas score of 4.4 immediately and the mean pain vas score was 1.7 by 24 hours postoperatively. the mean hospital stay was 2.8 days. table 2 summarizes the cases that underwent laparoscopic varicocelectomy with a two-port scarless periumbilical mini-incision. all patients experienced pain relief after surgery. one patient had a scrotal hydrocele after the operation, but it was small and did not require excision. two patients had recurrent varicoceles postoperatively, but both recurrences were subclinical and did not cause pain or significant symptoms. although not listed in the table, there were no such problems as omphalitis due to stress on umbilical tissue during procedure. the kolmogorov-smirnov test and logarithmic transformation showed that the operating time decreased as the surgeon’s experience increased (figure 3). discussion varicoceles are diagnosed clinically in 8–16% of adolescents. similar prevalence rates are reported in adults, likely because varicoceles do not resolve spontaneously.(14–16) a varicocele can cause male infertility; 21–39% of infertile men have varicoceles.(17,18) the other chief complaints of varicoceles are scrotal pain or discomfort and a palpable mass in the scrotum.(19,20) in our case series, all of the patients were adults and they presented mainly with scrotal pain and not fertility problems. the patients had grade 2 or 3 varicoceles as confirmed by a physical examination. sperm analysis was not performed when not desired by the patient. this paper focuses on the technical aspects of the surgical procedure, degree of pain relief, and short-term complications. the results of ultrasonography or testicle size are not reported here. with the success of modern laparoscopic surgery, there have been many technical improvements.(21) in varicocelectomy, laparoscopic surgery also has advantages over open surgery. several comparative studies have shown that the advantages of laparoscopic varicocelectomy include a shorter operating time, less required training, and lower costs.(22,23) some studies indicate that microscopic varicocelectomy has favorable results compared with a laparoscopic approach in terms of the low incidence of recurrence and hydrocele formation. (1,2) some authors criticize laparoscopic varicocelectomy because of the longer operating times and no difference in long-term complications compared with open surgery.(24) consequently, there is no standard surgical figure 3. operation time for laparoscopic 2-port varicocelectomy with scarless periumblical mini-incision as surgeon experience. visual analogue scale case age (yr) bmi varicocele operation time (min) immediate 6-h 24-h hospital resolution complications number (kg/m2) grade postoperative stay of pain 1 46 28.9 3 80 3 3 1 2 yes no 2 20 20.99 3 80 8 6 3 3 yes no 3 26 25.15 3 60 4 3 2 2 yes recurrence 4 82 22.64 2 55 4 3 2 4 yes no 5 23 16.86 3 60 4 3 2 5 yes recurrence 6 24 18.4 3 85 7 3 4 9 yes no 7 24 23.23 3 60 4 2 1 3 yes no 8 24 23.5 3 70 4 3 0 2 yes no 9 22 21.71 2 65 4 3 3 2 yes no 10 32 32.57 3 85 4 2 2 2 yes no 11 41 25.89 3 70 4 4 1 2 yes no 12 24 18.83 3 35 6 3 1 1 yes no 13 57 31.08 3 80 4 3 3 3 yes hydrocele 14 21 19.88 3 60 3 7 1 1 yes no 15 68 23.95 2 40 4 1 1 2 yes no 16 34 21.22 3 45 3 2 1 1 yes no 17 37 25.71 3 45 3 2 1 1 yes no 18 22 24.88 3 50 7 3 2 5 yes no table 2. operation results of laparoscopic two-port varicocelectomy with a scarless periumbilical mini-incision scarless laparoscopic 2-port varicocelectomy-seo et al. laparoscopic urology 12 treatment for varicocele. surgical techniques that maximize the advantages of laparoscopic varicocelectomy, especially its minimal invasiveness with comparable effectiveness, have been studied. a conventional laparoscopic varicocelectomy uses three ports. so, some patients prefer open surgery because there are only one or two scars and the scars were nearly covered by pubic hair or fainted with skin crease. in an attempt to decrease the number of port sites and improve the cosmetic outcome, a single-site laparoscopic approach was developed.(25) several studies have reported the effectiveness, feasibility, and improved cosmetic outcome of single-incision laparoscopic varicocelectomy.(11,12,26) a recent randomized study compared single-incision transumbilical laparoscopic varicocelectomy (sil-v) with the conventional laparoscopic technique in 80 patients. the authors reported the advantages of sil-v in terms of postoperative pain, rapid return to normal activity, and high patient satisfaction with the cosmetic outcome.(25) two other randomized studies reported similar outcomes in terms of cosmetic results, pain relief, and return to normal activity.(12,27) in a systematic review and meta-analysis that compared single-site laparoscopic varicocelectomy with the conventional laparoscopic technique, zhang et al. reported that single-site laparoscopic varicocelectomy had advantages in terms of recovery time and pain.(28) while the clinical effects and incidence of hydrocele and varicocele recurrence did not differ significantly between the two groups. although we cannot evaluate the degree of patient satisfaction and our patients had different characteristics from previous series, the results are similar in terms of perioperative pain. for the vein ligation method, some authors mentioned using bipolar energy device is superior to open ligation method(29). although the use of bipolar energies is expected to shorten the operation time, the authors thought that the number of laparoscopic instruments used was not very different and there would not be a huge cost benefit. other studies will be needed to determine whether there is a difference in the results between ligation methods in laparoscopic varicocelectomy. for single-site laparoscopic varicocelectomy, a transverse 2-cm skin incision is used and one 10-mm and two 5-mm cannulas are introduced through a single-incision laparoscopic surgery port or surgical glove.(25) in this background, two-port mini-incision techniques have been attempted for fewer ports. we made two 5-mm periumbilical incisions along skin creases, which achieved good cosmetic results 1 week postoperatively. figure 1 shows a healed scarless wound. our method is not a single-port technique, but it has promising outcomes in terms of pain and the cosmetic results (table 1). in our series, one 57-year-old patient developed a hydrocele and the varicoceles recurred in two other patients. the scrotal pain resolved in all 18 patients. the varicocele recurrences required no additional treatment because both were subclinical varicoceles (table 2). the primary concern with a laparoscopic approach to varicocelectomy has been the high associated costs and expertise required.(28) the operating time is a basic indicator of the surgeon’s skill level. we found that the operating times were comparable despite an initial lack of experience, ranging from 35 to 80 (mean 62.5 ± 15.6) minutes. analyzing the learning curve, with each subsequent case the operating time decreased (figure 3). we expect that the operating time will decrease further as the surgeon’s experience increases. a two-port system may help to reduce the operating time over a three-port system because there is one less port to place and close. the reduced number of trocars also decreases equipment costs. in our series, we did not find it necessary to place a third port for additional hands to obtain hemostasis, but we were prepared to do so if needed. in summary, our technique and sil-v have similar advantages. compared with sil-v, we expect better cosmetic outcomes and cost-effectiveness than sil-v. for surgeons with experience in laparoscopic surgery, our technique should be feasible, safe, and easy to learn. nevertheless, our study has several limitations. first, it enrolled only adult patients who were not concerned about infertility, so the results of sperm analysis and ultrasonographic testis size were not reported. therefore, we did not fully evaluate the effectiveness of varicocele treatment. however, we expect similar effectiveness based on the reported outcomes of laparoscopic techniques because the procedures are the same, other than the ports. second, the degree of patient satisfaction was not evaluated. more objective evidence is needed regarding the improved cosmetic results (e.g., a questionnaire). third, this study was not a comparative study; a comparison with other laparoscopic techniques and open varicocelectomy is required to obtain additional evidence regarding the effectiveness, safety, patient satisfaction, and cost advantages of our method. fourth, hospital days of present study were relatively long compared to other studies. this part was difficult to compare with other studies. this may be due to differences of admission system for surgery in our institutions. basically, it is based on 2 nights and 3 days. in addition, patients with long hospital stays were more likely to tolerate patients' personal circumstances. conclusions this study introduced another laparoscopic varicocelectomy technique to minimize invasiveness and maximize cosmetic outcomes. two-port laparoscopic varicocelectomy with a scarless periumbilical mini-incision appears to be comparable with traditional open surgical approaches in terms of recurrence and complication rates. it may also have similar advantages to single-incision laparoscopic varicocelectomy. it is easily mastered if the surgeon has experience with laparoscopic surgery without a requirement for microsurgical skills. nevertheless, prospective and comparative studies are required before there is popular acceptance of our laparoscopic technique. we hope it will become an acceptable alternative for varicocele treatment. acknowledgments this work was supported by grant from inje university, 2011 references 1. baazeem a, belzile e, ciampi a, et al. varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. eur urol. 2011;60:796-808. 2. diegidio p, jhaveri jk, ghannam s, scarless laparoscopic 2-port varicocelectomy-seo et al. vol 15 no 02 march-april 2018 13 pinkhasov r, shabsigh r, fisch h. review of current varicocelectomy techniques and their outcomes. bju int. 2011;108:1157-72. 3. wang j, xia sj, liu zh, et al. inguinal and subinguinal micro-varicocelectomy, the optimal surgical management of varicocele: a meta-analysis. asian j androl. 2015;17:7480. 4. ding h, tian j, du w, zhang l, wang h, wang z. open non-microsurgical, laparoscopic or open microsurgical varicocelectomy for male infertility: a meta-analysis of randomized controlled trials. bju int. 2012;110:1536-42. 5. al-kandari am, shabaan h, ibrahim hm, elshebiny yh, shokeir aa. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology. 2007;69:417-20. 6. riccabona m, oswald j, koen m, lusuardi l, radmayr c, bartsch g. optimizing the operative treatment of boys with varicocele: sequential comparison of 4 techniques. j urol. 2003;169:666-8. 7. mcmanus mc, barqawi a, meacham rb, furness pd,3rd, koyle ma. laparoscopic varicocele ligation: are there advantages compared with the microscopic subinguinal approach? urology. 2004;64:357-60; discussion 360-1. 8. lee kw, poon cm, leung kf, lee dw, ko cw. two-port needlescopic cholecystectomy: prospective study of 100 cases. hong kong med j. 2005;11:30-5. 9. tagaya n, rokkaku k, kubota k. needlescopic cholecystectomy versus needlescope-assisted laparoscopic cholecystectomy. surg laparosc endosc percutan tech. 2007;17:375-9. 10. clayman rv, box gn, abraham jb, et al. rapid communication: transvaginal singleport notes nephrectomy: initial laboratory experience. j endourol. 2007;21:640-4. 11. kaouk jh, haber gp, goel rk, et al. singleport laparoscopic surgery in urology: initial experience. urology. 2008;71:3-6. 12. lee sw, lee jy, kim kh, ha us. laparoendoscopic single-site surgery versus conventional laparoscopic varicocele ligation in men with palpable varicocele: a randomized, clinical study. surg endosc. 2012;26(4):1056-62. 13. link ba, kruska jd, wong c, kropp bp. two trocar laparoscopic varicocelectomy: approach and outcomes. jsls. 2006;10:1514. 14. zampieri n, cervellione rm. varicocele in adolescents: a 6-year longitudinal and followup observational study. j urol. 2008;180(4 suppl):1653-6; discussion 1656. 15. kumanov p, robeva rn, tomova a. adolescent varicocele: who is at risk? pediatrics. 2008;121:e53-7. 16. stavropoulos ne, mihailidis i, hastazeris k, et al. varicocele in schoolboys. arch androl. 2002;48:187-192. 17. cho ks, seo jt. effect of varicocelectomy on male infertility. korean j urol. 2014;55:7039. 18. greenberg sh. varicocele and male fertility. fertil steril. 1977;28:699-706. 19. lomboy jr, coward rm. the varicocele: clinical presentation, evaluation, and surgical management. semin intervent radiol. 2016;33:163-9. 20. mohammed a, chinegwundoh f. testicular varicocele: an overview. urol int. 2009;82:373-9. 21. mouret p. celioscopic surgery. evolution or revolution? chirurgie. 1990;116:829-32; discussion 832-3. 22. mendez-gallart r, bautista-casasnovas a, estevez-martinez e, varela-cives r. laparoscopic palomo varicocele surgery: lessons learned after 10 years' follow up of 156 consecutive pediatric patients. j pediatr urol. 2009;5:126-31. 23. borruto fa, impellizzeri p, antonuccio p, et al. laparoscopic vs open varicocelectomy in children and adolescents: review of the recent literature and meta-analysis. j pediatr surg. 2010;45:2464-9. 24. vanderbrink ba, palmer ls, gitlin j, levitt sb, franco i. lymphatic-sparing laparoscopic varicocelectomy versus microscopic varicocelectomy: is there a difference? urology. 2007;70:1207-10. 25. youssef t, abdalla e. single incision transumbilical laparoscopic varicocelectomy versus the conventional laparoscopic technique: a randomized clinical study. int j surg. 2015;18:178-83. 26. friedersdorff f, aghdassi sj, werthemann p, et al. laparoendoscopic single-site (less) varicocelectomy with reusable components: comparison with the conventional laparoscopic technique. surg endosc. 2013;27:3646-52. 27. wang j, xue b, shan yx, et al. laparoendoscopic single-site surgery with a single channel versus conventional laparoscopic varicocele ligation: a prospective randomized study. j endourol. 2014;28:15964. 28. zhang z, zheng sj, yu w, et al. comparison of surgical effect and postoperative patient experience between laparoendoscopic single-site and conventional laparoscopic varicocelectomy: a systematic review and meta-analysis. asian j androl. 2017;19:248255.. 29. simforoosh n, ziaee sa, behjati s, beygi scarless laparoscopic 2-port varicocelectomy-seo et al. laparoscopic urology 14 fm, arianpoor a, abdi h. .laparoscopic management of varicocele using bipolar cautery versus open high ligation technique: a randomized, clinical trial. j laparoendosc adv surg tech a. 2007;17:743-747. scarless laparoscopic 2-port varicocelectomy-seo et al. vol 15 no 02 march-april 2018 15 vol 16 no 03 may-june 2019 242 endourology and stone disease evaluation and comparison of metabolic disorders between patients with unilateral and bilateral staghorn renal stones mehrdad mohammadi sichani1, amir jafarpisheh2, alireza ghoreifi2,3* purpose: metabolic disorders are common in patients with staghorn renal stones. aim of this study was to evaluate and compare the metabolic disorders in patients with unilateral and bilateral staghorn stones. materials and methods: in this cross sectional study, 78 patients who underwent percutaneous nephrolithotomy (pcnl) for staghorn renal stones were included. the urine volume, the level of calcium, oxalate, uric acid, phosphate, sodium, citrate, creatinine, and cystine from 24 hour urine collection as well as the serum levels of calcium, phosphorus, magnesium, creatinine, blood urea nitrogen (bun), parathyroid hormone (pth) and uric acid were recorded and compared among the two groups with unilateral and bilateral renal stones. results: 56 patients (71.8%) had unilateral and 22 (28.2%) had bilateral renal stones. at least one abnormal metabolic factor was found in 32 (57.1%) and 15 (68.2%) patients with unilateral and bilateral renal stones, respectively (p = .044). cystine urine levels and serum levels of bun were higher in cases with bilateral compared to unilateral renal stones (36.4% vs. 12.5%, p = .025 and 27.3% vs. 1.8%, p = .002, respectively). conclusion: metabolic factors are strongly correlated with the formation of staghorn renal stones specially bilateral ones. in our study among different metabolic factors, cystine urine levels and serum levels of bun were significantly higher in patients with bilateral renal stones. proper metabolic assessments are recommended in patients with staghorn urolithiasis. keywords: metabolic diseases; risk factors; staghorn calculi; urinary calculi chemistry inrtroduction staghorn stones represent 10 to 20% of all nephro-lithiasis cases. however, currently, in developed countries, this incidence has decreased con¬siderably due to early prevention and treatment of urinary tract infections (utis).(1) these stones are mainly composed of struvite followed by calcium or cysteine based materials. despite several published papers focusing on the significant role of utis as the most important etiology of such conditions, it is also believed that other factors like metabolic diseases could finally lead to such morbidities.(2,3) furthermore, the existence of metabolic disorders is highly expected to be accompanied by bilateral staghorn stones.(4) the treatment of staghorn stones still remains controversial as the patients with sustained staghorns in their kidneys could end up in renal failure. mostly, the therapeutic pathways consist of 3 steps as follows: complete extraction of the stone, looking for the underlying metabolic etiologies and final treatment with the maximum basic anatomy preservation for optimal renal functions. (4,5) thus, it is assumed that proper treatment of patients with such renal stones must also include metabolic as1isfahan kidney transplantation research center, department of urology, al-zahra research institute, isfahan university of medical sciences, isfahan, iran. 2department of urology, faculty of medicine, mashhad university of medical sciences, mashhad, iran. 3kidney transplantation complications research center, mashhad university of medical sciences, mashhad, iran. *correspondence: department of urology, imam reza hospital, ebne sina st, mashhad university of medical sciences, mashhad, iran, tel: +985138583885, fax: +985138591057, e-mail: aghoreifi@yahoo.com, ghoreifina@mums.ac.ir received december 2017 & accepted june 20, 2018 sessments in different aspects covering the possible recurrence.(6) considering the fact that metabolic disorders can play an important role in occurrence of staghorn stones and the critical role of diagnosis of these conditions in prevention of nephrolithiasis, we conducted this study to evaluate the metabolic disorders in patients with unilateral and bilateral renal stones. materials and methods in this analytic cross-sectional study, 78 patients with staghorn stones who referred to our urology department from 2014 to 2016 were enrolled. all patients were candidates for unilateral or bilateral percutaneous nephrolithotomy (pcnl). the study protocol was approved by the ethical and scientific review committee of isfahan university of medical sciences (ethics committee reference number: ir.iums.fm.rec.101947). written consents were obtained and the patients were assured that all the data will remain completely confidential by the authors and results will be reported as overall statistics and not addressing to any specific individual. the inclusion criteria were as follows: patients with unilateral or bilateral staghorn renal stone (defined as any branched stone occupying more than one portion of the collecting system), availability of the necessary information in patients' admission files and the consent of the patient to enter the study. furthermore, patients with spinal cord injury and urinary diversion were excluded from the study. in order to collect the data and facilitate the statistical analysis, a compact questionnaire was designed, including all the variables in details. a 24 hour urine volume and the levels of calcium, oxalate, uric acid, phosphate, sodium, citrate, creatinine, and cystine from a 24 hour urine collection and also the serum levels of calcium, phosphorus, magnesium, creatinine, blood urea nitrogen (bun), parathyroid hormone (pth) and uric acid were recorded from the patients' files. according to the references of our laboratory, cystine > 250 mg, citrate < 450 mg in males and < 550 mg in females, sodium > 220 meq, oxalate > 40 mg, uric acid > 800 mg and calcium > 200 mg from 24 hour urine collections and also serum levels of calcium > 10.2 mg/dl, phosphorus > 4.5mg/dl, magnesium > 2.2mg/dl, creatinine > 1.2 mg/dl in males and > 1.1 mg/dl in females, bun > 20mg/dl, pth > 65 pg/ml and uric acid > 7 mg/ dl in males and > 6 mg/dl in females were considered abnormal. finally all the data were analyzed by the spss (ibm corp. released 2011. ibm spss statistics for windows, version 20.0. armonk, ny: ibm corp). the variables were initially evaluated for normality statistical tests and t-tests or non-parametric statistical tests (e.g. man-whitney or chi-square tests) were applied whenever needed. the significance cut-off range was considered as p value < .05. results of 78 patients, 56 (71.8%) and 22 (28.2%) cases had unilateral and bilateral renal stones, respectively. the mean age of patients with unilateral and bilateral stones were 48.4 ± 16.8 and 45.6 ± 12.3 years old, respectively revealing no significant difference (p = .49). also, 51.8% of patients in the unilateral group and 40.9 % of bilateral group were under 50 years old (p = 0.26). 33 (58.9%) patients from unilateral and 16 (72.7%) from bilateral group were men (p > .05). the mean size of stones in unilateral and bilateral stones was 3.53 ± 1.51 mm and 4.95 ± 0.21 millimeters, respectively which showed a significant difference between the two groups (p < 0.001). only one patient suffered from hyperparathyroidism (1.3%) and other co-morbidities relevant to staghorn stones formation like renal tubular acidosis (rta) or gout were not reported by the patients. high cystine, citrate, sodium, oxalate, uric acid and calcium levels from 24 hour urine collections were seen in 19.2%, 18%, 16.7%, 12.8% and 6.4% of patients, respectively. these metabolites were the most frequent urine components in our patients. applying chi-square and fisher exact tests, only cystine levels from 24 hour urine collections were significantly higher in bilateral stones (p = .025). (table 1) the p values refer to the comparison between the high levels of both groups. high serum levels of creatinine, pth, bun, uric acid and phosphorus were seen in 14.1%, 14.1%, 9%, 1%, 3.8% and 3.8% of all patients, respectively. the serum level of bun was also significantly higher in bilateral stones (p = .002). (table 1) according to the results, 24 (42.9 %) patients from unilateral and 7 (31.8%) from bilateral renal stone groups metabolic disorders in staghorn renal stones-mohammadi sichani et al. table 1. frequencies of metabolites in the urine and serum samples of subjects with staghorn urolithiasis. source variables unilateral stone number (%) bilateral stone number (%) p-value 24 hour urine calcium normal 52 (92.9) 21 (95/5) 0.99 high 4 (7.1) 1 (4/5) oxalate normal 47 (83.9) 18 (81/8) 0.99 high 9 (16.1) 4 (18/2) uric acid normal 50 (89.3) 18 (81/8) 0.46 high 6 (10/7) 4 (18/2) phosphate normal 56 (100) 22 (100) 1 high 0 (0) 0 (0) sodium normal 43 (76/8) 21 (95/5) 0.12 high 12 (21/4) 1 (4/5) low 1 (1/8) 0 (0) citrate normal 42 (76/4) 20 (90/9) 0.072 higher than normal 3 (5/5) 2 (9/1) lower than normal 10 (18/2) 0 (0) creatinine normal 56 (100) 22 (100) 1 abnormal 0 (0) 0 (0) cystine normal 49 (87/5) 14 (63/6) 0.025 high 7 (12/5) 8 (36/4) serum calcium normal 55 (98/2) 20 (90/9) 0.19 high 1 (1/8) 2 (9/1) phosphorus normal 54 (96/4) 21 (95/5) 0.99 high 2 (3/6) 1 (4/5) magnesium normal 56 (100) 22 (100) 1 high 0 (0) 0 (0) creatinine normal 51 (91/1) 16 (72/7) 0.07 high 5 (8/9) 6 (27/3) bun normal 55 (98/2) 16 (72/7) 0.002 high 1 (1/8) 6 (27/3) phosphorus normal 54 (96/4) 20 (90/9) 0.32 higher than normal 2 (3/6) 2 (9/1) pth normal 50 (89/3) 17 (77/3) 0.28 abnormal 6 (10/7) 5 (22/7) endourology and stones diseases 243 vol 16 no 03 may-june 2019 244 had no metabolic disorders. 32 (57.1%) patients with unilateral and 15 (68.2%) patients with bilateral renal stones reported at least one abnormal metabolic factor (p = .044). calcium oxalate and uric acid were the most components in unilateral stones and calcium oxalate and struvite were the most in bilateral subjects. applying mann-whitney test, we found that the proportion of calcium phosphate and cystine materials were statistically higher in patients with bilateral staghorn stones (table 2). discussion to the best of our knowledge, there is no study that compares the metabolic state in unilateral and bilateral staghorn renal stones. our finding showed the importance of metabolic evaluations in staghorn stones, particularly in bilateral ones. the state of metabolic disorder in urolithiasis may be variable according to the ethnical and geographic differences. some previously published papers reported metabolic alternations in 52.9% of men and 40.7% of women with staghorn calculus in western countries. (7) in a recent study done in us patients on 52 kidneys with complete staghorn calculi, 56% were metabolic and 44% were infection stones. multiple urinary metabolic abnormalities were noted in all patients with metabolic stones who completed evaluation which the most common findings were increased urinary sodium, low urine volume, hypocitraturia and hypercalciuria while no patient had a corresponding serum abnormality.(8) some studies showed greater correlation. in two brazilian studies, metabolic disorders were present in nearly 70% and 95.5% of patients with staghorn calculi, respectively. in both studies hypercalciuria and hypocitraturia were the most common disorders.(4,5) also in a swedish study among 33 patients with staghorn stones, 24-hour urine composition was normal in only 3 patients. furthermore, in 59 percent an increased calcium oxalate risk index was observed suggesting that calcium oxalate risk factors might contribute to the development of staghorn stones.(9) on the other hand some eastern studies revealed different results. in a study on japanese patients with staghorn renal stones, it was shown that hypercalciuria and cystinuria was present in 37.8 % and 2.4% of the patients, respectively.(10) another japanese study on 58 patients showed that of 13 patients with infectious staghorn stones containing calcium oxalate in the nuclei, only 2 had metabolic disorders.(11) in a thai study on 5445 urolithiasis patients complete staghorn stones were seen in 1.6% of cases and hyperuricemia was the most common metabolic disorder which was seen in 61.8% of patients with this calculus.(12) in our study the levels of metabolic factors had higher figures than normal ranges and were also found more in bilateral stone group significantly. the most common disorder was hyperuricemia which was seen in 13.1% followed by hypercalciuria (6.4%) but none of them had cystinuria. also the levels of urine cystine and serum bun were significantly higher in bilateral ones, while other factors were not statistically different. in our study calcium oxalate was the main component followed by uric acid and struvite in unilateral and bilateral renal stones, respectively. this could be attributed to the increase of metabolic syndrome even among iranian people,(13,14) which leads to the increase of urolithiasis specially calcium and uric acid stones.(15) some previous studies and guidelines have shown that staghorn calculi are most frequently composed of struvite and/or calcium carbonate apatite.(16) also they suggest that metabolic stones are uncommon in the composition of such stones. this is mainly because of the association between urolithiasis and urinary tract infection, although this relationship is complex and difficult to analyze.(17) recently some other studies showed the changing composition of renal stones.(18,19) in one cohort study metabolic stones comprised a large proportion of complete staghorn calculi and calcium phosphate was the most common stone composition.(11) one of the limitations of our study was that we did not evaluate the urinary cultures. also the small sample size and the retrospective character of the study are considered major limitations of our study which was mainly based on the number of patients with staghorn renal stone referred to the pointed study center. for future studies we recommend considering multi-centric similar studies, evaluating other variables in even longer periods. conclusions metabolic factors are strongly involved in the formation of staghorn renal stones which is more significant in bilateral ones. in our study the most common disorder was hyperuricemia followed by hypercalciuria. furthermore, among different metabolic factors, cystine urine levels and serum levels of bun were significantly higher in patients with bilateral stones. proper assessments are recommended regarding these conditions in patients with staghorn urolithiasis. acknowledgement we appreciate all our colleagues, co-operating and participating in our study, especially the staff of urology research center at al-zahra medical center of isfahan. table 2. frequencies of consisting materials of the stones in subjects with unilateral and bilateral staghorn urolithiasis. material unilateral bilateral p-value count percent count percent calcium phosphate no 44 78/6 9 40/9 0.001 yes 12 21/4 13 59/1 struvite no 32 57/1 7 31/8 0.044 yes 24 42/9 15 68/2 cystine no 50 89/3 16 72/7 0.09 yes 6 10/7 6 27/3 uric acid no 27 48/2 13 59/1 0.39 yes 29 51/8 9 40/9 calcium oxalate no 5 8/9 3 13/6 0.54 yes 51 91/1 19 86/4 metabolic disorders in staghorn renal stones-mohammadi sichani et al. conflict on interest the authors report no conflict of interest. references 1. rieu p. infective lithiasis. ann urol (paris). 2005; 39: 16-29. 2. segura jw. staghorn calculi. urologic clinics. 1997 ;24:71-80. 3. gettman mt, segura jw. struvite stones: diagnosis and current treatment concepts. journal of endourology. 1999 ;13:653-8. 4. amaro cr, goldberg j, agostinho ad, damasio p, kawano pr, fugita oe, et al. metabolic investigation of patients with staghorn calculus: is it necessary? int braz j urol. 2009 ;35:658-61. 5. amaro cr, goldberg j, amaro jl, padovani cr. metabolic assessment in patients with urinary lithiasis. int braz j urol. 2005; 31: 2933. 6. skolarikos a, straub m, knoll t, sarica k, seitz c, petřík a, et al. metabolic evaluation and recurrence prevention for urinary stone patients: eau guidelines. eur urol. 2015 ;67:750-63. 7. resnick mi, boyce wh. bilateral staghorn calculi-patient evaluation and management. j urol. 1980;123:338-41. 8. viprakasit dp, sawyer md, herrell sd, miller nl. changing composition of staghorn calculi. j urol. 2011 186:2285-90. 9. wall i, hellgren e, larsson l, tiselius hg. biochemical risk factors in patients with renal staghorn stone disease. urology. 1986 ;28:377-80. 10. akagashi k, tanda h, kato s, ohnishi s, nakajima h, nanbu a, et al. characteristics of patients with staghorn calculi in our experience. int j urol. 2004; 11: 276-81. 11. takeuchi h, tomoyoshi t. [formation of the staghorn calculi]. hinyokika kiyo. 1985 ;31:1381-5 12. tanthanuch m. staghorn calculi in southern thailand. j med assoc thai. 2006 ;89:208690. 13. mohebbi i, saadat s, aghassi m, shekari m, matinkhah m, sehat s. prevalence of metabolic syndrome in iranian professional drivers: results from a population based study of 12,138 men. plos one. 2012;7:e31790. 14. polat ec, ozcan l, cakir ss, dursun m, otunctemur a, ozbek e. relationship between calcium stone disease and metabolic syndrome. urology journal. 2015 ;12:2391-5. 15. wong yv, cook p, somani bk. the association of metabolic syndrome and urolithiasis. int j endocrinol. 2015;2015. 16. preminger gm, assimos dg, lingeman je, nakada sy, pearle ms, wolf js jr; aua nephrolithiasis guideline panel). chapter 1: aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005 ;173:19912000. 17. borghi l, nouvenne a, meschi t. nephrolithiasis and urinary tract infections: 'the chicken or the egg' dilemma? nephrol dial transplant. 2012 ;27:3982-4. 18. mandel n, mandel i, fryjoff k, rejniak t, mandel g. conversion of calcium oxalate to calcium phosphate with recurrent stone episodes. j urol. 2003 jun;169:2026-9. 19. kustov av, strelnikov ai. quantitative mineralogical composition of calculi and urine abnormalities for calcium oxalate stone formers: a single-center results. j urol. 2017 dec 26. metabolic disorders in staghorn renal stones-mohammadi sichani et al. endourology and stones diseases 245 bilateral laparoscopic stone surgery for renal stonesa case series akbar nouralizadeh1, amir h kashi1,2*, reza valipour1, mahmoodreza nasiri kopaee1, mahdi zeinali1, reza sarhangnejad1 purpose: to present our experience with synchronous or metachronous laparoscopic pyelolithotomy and ureterolithotomy for patients with bilateral urolithiasis. materials and methods: the data of all patients who underwent laparoscopic pyelolithotomy (± ureterolithotomy) for bilateral renal and/or ureteral stones from november 2009 to july 2014 were included. laparoscopic operations were performed through a transperitoneal approach. results: 10 patients underwent laparoscopic operations for renal stones (19 kidney stones) and ureteral stones (1 ureteral stone). 4 patients underwent synchronous operations and 6 patients underwent metachronous operations. the mean ± sd of operation duration were 212 ± 51 minutes for synchronous operations and 166 ± 41 minutes for metachronous operations. residual stone was observed 5 patients. no patient developed urinary leakage. conclusion: laparoscopic pyelolithotomy and/or ureterolithotomy for bilateral stones is a feasible option in centers with experience in laparoscopy. keywords: laparoscopy; pyelolithotomy; ureterolithotomy; ureterolithiasis; nephrolithiasis; synchronous; metachronous introduction laparoscopic pyelolithotomy (lpl) was introduced more than 2 decades ago by gaur et al.(1) in the following years after its introduction several series of comparative and non-comparative studies were published assessing the outcome of lpl and/or comparing it with percutaneous nephrolithotomy (pcnl).(2-10) currently, lpl is accepted as an alternative second choice modality for treatment of renal stones especially single pelvis stones in centers with enough laparoscopy experience. simultaneous treatment of bilateral renal stones through pcnl has been reported by a few researchers.(11-13) we could find only limited cases in reports of laparoscopic treatment of bilateral renal and/or ureteral stones.(3,14) materials and methods this study is an observational descriptive and retrospective study (case series). laparoscopic management of renal stones has been accomplished in our center (labbafinejad hsopital) since may 2002. laparoscopic pyelolithotomy had been performed on a total of 188 patients from may 2002 to dec 2013 which included 10 cases of bilateral operations in same or different sessions. we collected data only on all bilateral laparoscopic procedures for renal stones with or without ureteral stones. preoperative evaluation included taking the clinical history, physical examination, urine analysis and culture, serum creatinine and hemoglobin, intravenous pyelography or computerized tomography (ct) scan, and renal ultrasonography. the choice of surgery by laparoscopy, percutaneous or transureteral approach was made by the discretion of the operating surgeon. percutaneous and transureteral procedures are routinely performed in our center with high volumes each year (more than 2000 operations by pcnl or transurethral lithotripsy each year) therefore, the above laparascopic procedures include a small percent of the endourologic procedures for stones in our center. the choice of other methods including percutaneous approach and transureteral approach was explained for the patient and his/her informed consent was obtained. laparoscopic pyelolithotomy and ureterolithotomy were performed through transperitoneal route as described before(9) and are summarized below. after general anesthesia, the patient was positioned in the modified lateral decubitus with minimal flexion. a 10-mm camera port was inserted in the umbilicus by open access. three 5-mm working ports were inserted under direct vision in the midline, 10 cm above the umbilicus, in the midclavicular line parallel to the umbilicus, and 5 cm below the umbilicus lateral to the rectus muscle. the white line of toldt was incised, and the colon was medially reflected. the pelvis and ureter were identified, the renal pedicle was exposed, and then the renal pelvis was freed from surrounding peripelvic fat. the pyelotomy incision was made by electrocautery on 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2hasheminejad kidney center, iran university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center, 9th boostan street, pasdaran avenue, tehran, iran. tel & fax: +98 21 22541185, email address: ahkashi@gmail.com. received november 2016 & accpted july 2017 laparoscopic urology 5043 laparoscopic urology the renal pelvis and extended from the superior to inferior calyx with scissors, cautiously to prevent excessive pelvis tearing. the tip of the pelvic stone was freed from the ureteropelvic junction, and then the stone was extracted with curve grasper and/or babcock grasper. additional stones were removed, and the pyelocalyceal system was washed out with normal saline. a ureteral stent was inserted, and the edge of the incision line on the renal pelvis was re-approximated using 4-0 vicryl (ethicon, inc., johnson & johnson, somerville, nj) sutures. the stones were extracted from the abdominal cavity using surgical glove. in one case of ureteral stone, after medializing colon, ureter was identified and dissected free of surrounding tissues with care not to push the ureteral stone backward. proximal ureter above the stone was hold with locking babcock and the ureter was incised in the proximal part of the stone. the stone was freed from ureteral mucosa and removed by graspers and extracted from abdominal cavity using surgical glove. the drain was fixed in the peritoneal cavity near the operative field and was subsequently removed 3–5 days after the operation. the foley catheter was retained for 5–7 days. the ureteral stent was removed 1 month after the surgery. the assessment of residual stones was performed by using plain abdominal radiography 1 day after the operation. all patients were followed up by non-contrast ct scan and/or ivp in the next 2-4 weeks after the operation. operative and postoperative data was extracted from patients' records. results laparoscopic pyelolithotomy has been performed on a total of 188 patients from may 2002 to dec 2013 which included 10 cases of bilateral operations in same or different sessions. bilateral procedures had been performed from november 2009 to july 2014. they included synchronous bilateral procedures in 4 patients and metachronous bilateral procedures in 6 patients. the mean ± sd of patients' age was 45.5 ± 17.2 years. all patients were male. one patient had previous history of swl (table 1). another patient had history of both swl and pcnl who underwent metachronous operations. operations' characteristics have been summarized in tables 1 and 2 separately for synchronous and metachronous operations. synchronous operations in patients with synchronous bilateral stone operations, one patient developed postoperative fever on the 4th postoperative day that resolved on the 5th day by intravenous antibiotics. no patient developed postoperative urinary leak. no patient received packed cells(pc) either during the operation or during postoperative hospitalization. intraoperative ureteral stent was inserted for all patients. in one patient with bilateral pelvic stones, ureteral stent was not inserted on the right side with a single pelvic stone but was inserted on the left side with several pelvic stones. in one 11-year-old adolescent male, right pelvis stone and left upper ureteral stone were simultaneously operated. metachronous operations in patients with metachronous bilateral stones (6 patients, 12 operations), postoperative fever was observed in 3 patients. fever in all these operations lasted for 24-48 hours and resolved by intravenous antibiotics. packed cells were infused in 4 patients during 6 operations: in 3 operations, the patients received 1 unit pc; in one operation, the patient received 3 units of pc; and in two operations, the patients were given 4 units of pc. residual stones were observed in 4 patients. in two patients, pcnl was performed to clear residual stones. these two patients originally had staghorn stones before their lpl operations. the latency time between metachrounous operations ranged from 7 days to 3 years. discussion laparoscopic pyelolithotomy has long been used for treatment of renal stones. currently, lpl is indicated in the treatment of renal stones as an alternative procedure to pcnl in cases of large, hard, or impacted stones, failed sessions of pcnl or endourology, associated anatomical abnormalities, and before embarking to open surgery.(5,9,15) however, there are reports on the performance of laparoscopic pyelolithotomy as the initial procedure for renal stones(15,16) and recent randomized clinical trials and meta-analyses highlighting the safety of laparoscopy for renal stones have been published. (6,7,17) additionally the combination of laparoscopy with endourologic lithotripsy through the laparoscopic ports has been reported with success rates similar to open surgery.(18) bilateral pcnl operations have been reported by some researchers.(11-13) as in pcnl renal parenchyma is invaded and is associated with bleeding from injured patable 1. patients' and operations' characteristics for synchronous operations variable data patients n = 4 operation duration (minutes), mean ± sd 212 ± 51 creatinine before operation (mg/dl), , mean ± sd 2.6 ± 1.1 creatinine 1st postop day (mg/dl), mean ± sd 2.2 ± 1.2 hemoglobin before operation (mg/dl), mean ± sd 12.1 ± 3.1 hemoglobin 1st postop day (mg/dl), mean ± sd 11.4 ± 1.5 hospitalization days, mean ± sd 7.7 ± 2.2 history of failed swl, n 1 operations n = 8 stone location, n pelvis, multiple, ureter 3,4,1 stone size (mm) , mean(range) 25.2(10-56) residual stone, n(%) 1(12.5) table 2. patients' and operations' characteristics for metachronous operations (n = 12) variable data stone location, n pelvis, multiple, staghorn 6,3,3 stone size (mm), mean ± sd 29.1 ± 6.7 operation duration (minutes) , mean ± sd 166 ± 41 creatinine before operation (mg/dl), , mean(range) 4.2(1-16) creatinine 1st postop day (mg/dl), mean(range) 3.5(1.2-10) hemoglobin before operation (mg/dl), mean ± sd 11.4 ± 1.5 hemoglobin 1st postop day (mg/dl), mean ± sd 10.6 ± 1.7 ureteral stent insertion, n(%) 12(100) hospitalization days, mean(range) 6.7(3-20) bilateral laparoscopy for urolithiasis-nouralizadeh et al. vol 14 no 06 november-december 2017 5044 renchymal tissue; there is concern regarding contralateral simultaneous operation which increases risk of bleeding. in laparoscopic operations, renal parenchyma is not invaded and risk of bleeding is less in comparison with pcnl as reported previously by several comparative trials(5-7,10) and one recent meta-analysis.(19) therefore, bilateral simultaneous laparoscopic operations can be feasible if the first side operation can be accomplished in a reasonable duration with no complications. the patient will then be turned on the contralateral side, contralateral colon will be mobilized and operation will continue on the contralateral side. in patients with multiple renal stones in whom the sole use of laparoscopy for stone removal may result in impaired stone clearance rates several suggestions including the use of endoscopic lithotripsy through laparoscopic ports have been suggested.(18) a unique scenario will be simultaneous operation of renal and ureteral stones on the same or contralateral side(s) which is not always possible in pcnl especially if upper ureter is not dilated or the ureteral stone in not in the vicinity of the uretero-pelvic junction. despite reports of bilateral synchronous pcnl operations, there are few reports on bilateral synchromous or metachromous laparoscopic pyelolithotomy operations. nambirajan et al. reported bilateral matrix stones in a horseshoe kidney which was operated by laparoscopic pyelolithotomy in separate sessions.(14) gaur et al. also reported bilateral retroperitoneal laparoscopic pyelolithotomy in one patient.(3) we could not find details of laparoscopic bilateral stone operations in the other series reported. in the current series, we performed lpl on 2 patients with high preoperative serum creatinine. after the first operation, serum creatinine decreased substantially and the second side was then operated. in brief; it seems that bilateral laparoscopic operations on patients with bilateral renal and/or ureteral stones seems feasible and can be performed in centers with extensive laparoscopic experience. conclusions bilateral laparoscopic operations for renal and/or ureteral stones seem feasible for centers with laparoscopic expertise. conflict of interest the authors report no conflict of interest. references 1. gaur dd, agarwal dk, purohit kc, darshane as. retroperitoneal laparoscopic pyelolithotomy. j urol. 1994;151:927-9. 2. aminsharifi a, hosseini mm, khakbaz a. laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for a solitary renal pelvis stone larger than 3 cm: a prospective cohort study. urolithiasis. 2013;41:493-7. 3. gaur ddp, h.m.; madhusudhana, h.r.; rathi, s.s. retroperitoneal laparoscopic pyelolithotomy: how does it compare with percutaneous nephrolithotomy for larger stones? minim invasive ther allied technol. 2001;10:105-9. 4. goel a, hemal ak. evaluation of role of retroperitoneoscopic pyelolithotomy and its comparison with percutaneous nephrolithotripsy. int urol nephrol. 2003;35:73-6. 5. haggag ym, morsy g, badr mm, al emam ab, farid m, etafy m. comparative study of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in the management of large renal pelvic stones. can urol assoc j. 2013;7:e171-5. 6. lee jw, cho sy, jeong cw, et al. comparison of surgical outcomes between laparoscopic pyelolithotomy and percutaneous nephrolithotomy in patients with multiple renal stones in various parts of the pelvocalyceal system. j laparoendosc adv surg tech a. 2014;24:634-9. 7. li s, liu tz, wang xh, et al. randomized controlled trial comparing retroperitoneal laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for the treatment of large renal pelvic calculi: a pilot study. j endourol. 2014;28:946-50. 8. meria p, milcent s, desgrandchamps f, mongiat-artus p, duclos jm, teillac p. management of pelvic stones larger than 20 mm: laparoscopic transperitoneal pyelolithotomy or percutaneous nephrolithotomy? urol int. 2005;75:322-6. 9. nouralizadeh a, simforoosh n, soltani mh, et al. laparoscopic transperitoneal pyelolithotomy for management of staghorn renal calculi. j laparoendosc adv surg tech a. 2012;22:61-5. 10. tefekli a, tepeler a, akman t, et al. the comparison of laparoscopic pyelolithotomy and percutaneous nephrolithotomy in the treatment of solitary large renal pelvic stones. urol res. 2012;40:549-55. 11. gigli f, cerruto ma, zattoni f. [synchronous bilateral percutaneous nephrolithotomy (pcnl).]. urologia. 2008;75:108-12. 12. maheshwari pn, andankar m, hegde s, bansal m. bilateral single-session percutaneous nephrolithotomy: a feasible and safe treatment. j endourol. 2000;14:285-7. 13. rao rk, ranganath ms, prasad tk. synchronized bilateral percutaneous nephrolithotripsy in a horseshoe kidney. indian j urol. 2008;24:120-2. 14. nambirajan t, jeschke s, albqami n, abukora f, leeb k, janetschek g. role of laparoscopy in management of renal stones: singlecenter experience and review of literature. j endourol. 2005;19:353-9. 15. simforoosh n, aminsharifi a. laparoscopic management in stone disease. curr opin urol. 2013;23:169-74. 16. basiri a, tabibi a, nouralizadeh a, et al. comparison of safety and efficacy of laparoscopic pyelolithotomy versus bilateral laparoscopy for urolithiasis-nouralizadeh et al. laparoscopic urology 5045 percutaneous nephrolithotomy in patients with renal pelvic stones: a randomized clinical trial. urol j. 2014;11:1932-7. 17. wang j, yang y, chen m, et al. laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for treatment of large renal pelvic calculi (diameter >2 cm): a metaanalysis. acta chir belg. 2016;116:346-56. 18. pastore al, palleschi g, silvestri l, et al. combined laparoscopic pyelolithotomy and endoscopic pyelolithotripsy for staghorn calculi: long-term follow-up results from a case series. ther adv urol. 2016;8:3-8. 19. wang x, li s, liu t, guo y, yang z. laparoscopic pyelolithotomy compared to percutaneous nephrolithotomy as surgical management for large renal pelvic calculi: a meta-analysis. j urol. 2013;190:888-93. bilateral laparoscopy for urolithiasis-nouralizadeh et al. vol 14 no 06 november-december 2017 5046 vol 16 no 03 may-june 2019 224 efficacy and safety of tamsulosin in the medical expulsion therapy for distal ureteral calculi: a systematic review and meta-analysis of placebo-controlled trials rong-zhen tao1, zhi-qiang qin2, fa-de liu1, jian-lin lv1* purpose: tamsulosin, a medical expulsive therapy (met), was always recommended for patients with distal ureteral calculi less than 10 mm. the aim of the systematic review was to assess the efficacy and safety of tamsulosin in met compared with placebo. materials and methods: a comprehensive search was conducted in the databases pubmed, embase and web of science for relevant articles, covering all the literatures published until april 2018. all placebo controlled trails were identified in which patients were randomized to receive either tamsulosin or placebo for distal ureteral calculi. results: a total of seven placebo controlled studies including 4135 patients met the inclusion criteria and were involved in the review. we found that tamsulosin was associated with a significantly higher expulsion rate (esr) [odds ratio (or) = 1.10, 95% confidence interval (ci) = 1.00-1.21] than placebo in patients with distal ureteral stones less than 7 mm. the esr ranged from 67.0%-90.7%. but the significant difference was better seen in patients with distal ureteral stones less than 10 mm (or = 1.11, 95% ci = 1.01-1.21). even though tamsulosin has a higher incidence of retrograde ejaculation than placebo, no significant difference was observed in the incidence of other adverse events. conclusion: the results of the current meta-analysis indicated that tamsulosin was superior to placebo in its efficacy for distal ureteral stones though retrograde ejaculation was worse with tamsulosin use. it should be a safe and effective medical expulsive therapy choice for distal ureteral stones when stone sizes are less than 10 mm. keywords: tamsulosin; distal ureteral calculi; medical expulsion therapy; urolithiasis; meta-analysis introduction urolithiasis, ranks as the third most common afflic-tion in the urinary system, is a well-known disease affecting public health problem(1). it is reported that 1 of 11 persons in the united states suffers from stone disease, and the lifetime recurrence rate is approximately 50% (2,3). meanwhile, the increasing incidence of ureteric stones, which has close associations with the improved quality of life, has been paid greater attentions in this era(4). preminger et al. revealed that most ureteral stones are sited in the distal ureter, and it is estimated that 68% of ureteral stones have the size of 5 mm and 47% of stones that between 5-10 mm are expelled spontaneously(5). when it comes to the patients getting a diagnosis of distal ureteral stones less than 10 mm, the most common treatment approaches include shock wave lithotripsy (swl), medical expulsive therapy (met), as well as ureteroscopy (urs). due to the high healthcare expenditures and invasive procedures associated with swl and urs, the α-blockers and calcium channel antagonists, the two types of met, is preferred by patients for the promotion of the spontaneous expulsion 1 from the department of urology, the affiliated jiangning hospital with nanjing medical university, nanjing, jiangsu, china. 2 from the department of urology, nanjing first hospital, nanjing, jiangsu, china. *correspondence: department of urology, the affiliated jiangning hospital with nanjing medical university, nanjing 211100, china. tel: +86-25-52178496, fax: +86-25-52178496, e-mail: ljlxx01@163.com. received august 2018 & accepted december 2018 of distal ureteral stones. both the european association of urology (eau) and the american urologic association (aua) have recommended that the patients with ureteral stones less than 10 mm should receive α-adrenoceptor blockers therapy for stone passage in accordance with the proposals of numerous placebo-controlled trials and meta-analyses(5,6). tamsulosin, an α1a/1d-adrenoceptor blockers, is the most frequently used drug to facilitate the ureteral stones expulsion, prominently in distal ureteral stones(7,8). a recent double-blind and placebo-controlled study regarding 3296 patients suggested that the stone expulsion rate of tamsulosin (86%) is higher than the placebo (79%; p < 0.001) for distal ureteral stones(9). although several meta-analysis studies have laid stress on the curative effect of tamsulosin, the majority of trails were not placebo controlled and blinded(10,11). therefore, a systematic review and meta-analyses from placebo-controlled trials were urgently needed to conduct in order to assess the functions of tamsulosin in the treatment of distal ureteral calculi. review methods search strategy and study selection the systematic review was performed in accordance with the cochrane reviews guidelines as well as the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines(12). the databases, such as pubmed, embase and web of science, have been comprehensively searched for relevant eligible articles, which cover all the studies published until april 2018. there were no language restrictions for these studies. the literature retrieval was carried out with the combinations of free words and keywords: “tamsulosin”, “ureteral calculi” or “urolithiasis” or “stone”, “medical expulsion therapy” and “placebo controlled trials”. except for searching the original papers from electronic databases, other relevant review articles were searched by hand from reference lists of original articles or reviews so as to further seek additional eligible studies. in addition, abstract booklets and presentations were also consulted from the annual academic conferences. besides, if more data was needed, we contacted the corresponding author for obtaining desired information by sending emails. except that, we would also ask the person involved in the trial to see if the study was not retrieved in the trial. last but not least, if multiple articles were published using the same study series, only those with the latest or complete data were selected. the estimation of the level of evidence (le) for each included study was performed in accordance with the criteria provided by the oxford centre for evidence-based medicine(13). the inclusion criteria for eligible articles were as follows:(1) studies should be placebo controlled trials;(2) the patients in this study were limited to patients with the stone size of 10 mm or smaller of ureteral calculi.;(3) all patients underwent preliminary diagnosis of kidney, ureter, and bladder (kub) by abdominal ultrasound and plain abdominal x-ray. an unenhanced ct scan was implemented if it was necessary. the maximum diameter that measured on a plain abdominal film was recorded as the stone size;(4) the included studies should have sufficient data. the exclusion criteria were presented as follows:(1) the studies without available information or complete data;(2) patients in the studies suffered from urinary tract infections, renal insufficiency, high grade hydronephrosis, ureteric strictures, previous therapies for the stone, or solitary kidney;(3) patients in the studies had a history of ureteral surgery or endoscopic surgery; (4) duplicates of previous publication. the most important outcome for this present study was the stone expulsion rate. the secondary outcomes were the stone expulsion time (hours) and complications. complications were defined as one of the following symptoms: self-reported dizziness, headache, fatigue and retrograde ejaculation. if one of these aforementioned outcomes was reported, the trials were deemed to be eligible. the reviewers appraised the qualifications of the remaining studies by gradually reviewing the titles, abstracts, as well as full texts. data extraction and quality assessment two co-authors (rong-zhen tao and zhi-qiang qin) independently and carefully reviewed all the identified studies in order to determine the compliance of individual studies with inclusion criteria. all data was extracted from the qualified publications and any disagreement appearing in this process was resolved by consulting a third reviewer. all the data selected from the included articles, were recorded in a standardized form, and the extracted information included study characteristics (title, publication year and the number of patients), patient characteristics (age, the location and size of the stone, control (placebo), intervention, method (blinding, randomization and loss to follow-up) as well as outcomes (expulsion rate, expulsion time, and some relevant complications). furthermore, the cochrane collaboration’s table 1. characteristics of individual studies included in the meta-analysis. study country therapy in experimental group therapy in control group sample size (e/c) inclusion population follow-up ye et al. 2017 [9] china tamsulosin 0.4 mg placebo 1642/1654 adults, 18-60 years; 4 weeks with renal colic; presence of a single distal ureteral stone (range 4-7 mm in size). jeremy et al. 2015 [16] australia tamsulosin 0.4 mg placebo 161/155 with symptoms suggestive 4 weeks of ureteric colic and a distal ureteral stone of less than 10 mm in diameter. sebastien et al. 2015 [17] france tamsulosin 0.4 mg placebo 61/61 patients older than 18 years, 6 weeks with acute renal colic and distal ureteral stone (range 2-7 mm in size). taha et al. 2010 [18] arabia tamsulosin 0.4 mg placebo 75/75 patients older than 18 years, 4 weeks distal ureteral stone (range 4-10 mm in size). abdulla et al. 2009 [19] arabia tamsulosin 0.4 mg placebo 50/46 patients presented with 4 weeks acute flank pain and none received swl. lower ureteral stone less than 10 mm in diameter. thomas et al. 2009 [20] switzerland tamsulosin 0.4 mg placebo 45/45 patients older than 18 years 3 weeks presenting with acute renal colic. distal ureteral stone≤7 mm. raul et al. 2011[21] mexico tamsulosin 0.4 mg placebo 32/33 patients older than 18 4 weeks years and presented with reno-ureteral stones less than 7 mm in diameter. e/c: experimental group/control group. the treatment of tamsulosin for distal ureteral calculi-tao et al. review 225 vol 16 no 03 may-june 2019 226 tool was utilized for the evaluation of the risk of selection, performance, detection, attrition, and reporting biases among the included studies(14). if high risk of bias was found among studies, meta-analyses stratified by study quality could be performed. data synthesis and analysis the pooled odds ratios (ors) with its corresponding 95% confidence intervals (cis) were implemented for the assessment of the strength of differences between the experimental and the control groups (tamsulosin vs. placebo). the verification of the heterogeneity assumption was accomplished by the calculation of the chisquare test and i-square test. the random-effects model (dersimonian-laird method) was conducted with the presence of heterogeneity. otherwise, the fixed-effects model (mantel-haenszel method) was used. between-study heterogeneity was assessed by the χ² test, p values and i2 statistics. i2 values of 0, 25, 50, and 75% represent no, low, moderate, and high heterogeneity, respectively. besides, if significant heterogeneity was detected among studies, the sources of heterogeneity were discussed. based on which, subgroup analysis was further conducted by different complications between the experimental and the control groups. in addition, sensitivity analysis was performed by omitting an individual study each time, with the purpose of appraising the stability of results. moreover, begg’s funnel plot and egger’s linear regression test were applied for the examination of publication bias among all the enrolled studies. p values were all two-sided, and the values less than 0.05 were considered statistically significant(15). all statistical data in this present meta-analysis were conducted by using stata software (version 12.0; statacorp lp, college station, tx). results the baseline characteristics for the included studies in total, seven placebo controlled studies with total figure 1. flow diagram of the study selection process. figure 2. (a). forest plots of the efficacy of tamsulosin in the medical expulsion therapy for distal ureteral calculi; (b). forest plots of the efficacy of tamsulosin in the medical expulsion therapy for distal ureteral calculi when distal ureteral stones < 7 mm. the treatment of tamsulosin for distal ureteral calculi-tao et al. 4,135 patients who had met the inclusion criteria were enrolled in the present meta-analysis(9,16-21), which had accrued between september 2009 and april 2018 (figure 1). the baseline characteristics of all the included studies are comprehensively displayed in table 1. in this current meta-analysis, these articles consisted of two groups: the experimental group (tamsulosin 0.4 mg) and the control group (placebo). five trials provided tamsulosin for 4 weeks, one provided the drug for 3 weeks, and the remaining one provided for 6 weeks. expulsion rate in all cases in these included studies, tamsulosin presented an obviously higher expulsion rate (or = 1.11, 95% ci = 1.011.21) than placebo in treating the patients with distal ureteral stones less than 10 mm, and there was no heterogeneity among these studies (p = 0.935; i2 = 0.0%). additionally, the expulsion rate for those patients with distal ureteral stones that received tamsulosin ranged from 69.0%-87.0% (figure 2a). moreover, a total of five studies including 3,678 participants (1,833 in the experimental group and 1,845 in the control group) made it possible for analyzing the expulsion rate of patients with distal ureteral stones less than 7 mm. within contrast to placebo, tamsulosin showed a remarkedly higher expulsion rate (or = 1.10, 95% ci = 1.00-1.21) , and no heterogeneity was detected among these studies (p = 0.964; i2 = 0.0%). the expulsion rate for those patients with distal ureteral stones less than 7 mm that treated with tamsulosin was ranged from 67.0%-90.7% (figure 2b). expulsion time (hours) of distal ureteral stones a total of four studies concerning 3,579 participants figure 3. forest plots of the expulsion time (hours) of distal ureteral stones in the medical expulsion therapy. figure 4. forest plots of all complications of tamsulosin in the medical expulsion therapy for distal ureteral calculi. (a). dizziness; (b). headache; (c). retrograde ejaculation; (b). fatigue. the treatment of tamsulosin for distal ureteral calculi-tao et al. review 227 vol 16 no 03 may-june 2019 228 (1,785 in the experimental group and 1,794 in the control group) made it possible for analyzing the expulsion time (hours) of distal ureteral stones less than 10 mm. according to the obtained results, no significant differences were found in terms of the expulsion time of the experimental group versus the control group [standardized mean difference (smd) = -0.77, 95% ci = -1.970.42], and significant heterogeneity was discovered amog these studies(p < 0.001; i2 = 98.4%)[figure 3]. complications dizziness a total of four studies including 3,557 participants (1,769 in the experimental group and 1,788 in the control group) helped to bring about the analysis of the dizziness. no significant results were detected between the experimental group and the control group (or = 1.00, 95% ci = 0.69-1.47), and no heterogeneity was detected among these studies (p = 0.814; i2 = 0.0%) (figure 4a). headache a total of three studies regarding 3,514 participants (1,753 in the experimental group and 1,761 in the control group) helped to bring about the analysis of the headache. the results still showed no significant differences (or = 0.91, 95% ci = 0.62-1.35), and no heterogeneity was found among these studies (p = 0.984; i2 = 0.0%) (figure 4b). retrograde ejaculation a total of five studies concerning 3,669 participants (1,830 in the experimental group and 1,839 in the control group) was conductive to the analysis of the retrograde ejaculation. the meta-analysis indicated that tamsulosin was related to a significantly higher rate of retrograde ejaculation than placebo (or = 1.57, 95% ci = 1.09-2.25), and no heterogeneity was discovered among these studies (p = 0.571; i2 = 0.0%) (figure 4c). fatigue a total of three studies including 3,514 participants (1,753 in the experimental group and 1,761 in the control group) was conductive to the analysis of the fatigue. there were no significant differences detected between the experimental group and the control group (or = 1.21, 95% ci = 0.74-1.97), and no heterogeneity was detected among these studies (p = 0.940; i2 = 0.0%) (figure 4d). test of heterogeneity under the fixed-effects model, a galbraith radial plot was utilized for the heterogeneity of all the included studies (figure 5). the obtained results elucidated that no significant heterogeneity was observed between studies. publication bias sensitivity analysis was implemented to evaluate whether the deletion of each individual study functions on the pooled ors. figure 6 showed the sensitivity analysis with respect to the efficacy of tamsulosin in the treatment of distal ureteral calculi under the fixed-effects model, which implied the reliability of our results. the begg’s funnel plot along with the egger’s test was applied for the evaluation of the potential publication bias for the data in all the enrolled eligible studies. based on the funnel plot analysis, we found that the shape of the funnel plot was symmetrical (figure 7). the results demonstrated that no publication bias was found in the begg’s test and egger’s test under the fixed-effects model (p = 0.881; p = 0.630). discussion in 2001, the latest print versions of the eau guidelines regarding the treatment of urolithiasis were published (22). in the next year, the tamsulosin was firstly reported for the promotion of the spontaneous passage of distal ureteral stones(23). from then on, the publications of several meta-analyses were mainly used to discuss the curative effect of tamsulosin in treating those patients with distal ureteral stones less than 10 mm(11, 24-25). however, our systematic review and meta-analysis involving in 7 randomized, double-blind, and placebo-controlled trials was directly used for the evaluation of the efficacy between tamsulosin and placebo. the obtained results figure 5. galbraith plot of the efficacy of tamsulosin in the medical expulsion therapy for distal ureteral calculi in the fixed-effects model. figure 6. sensitivity analysis in the fixed-effects model. the treatment of tamsulosin for distal ureteral calculi-tao et al. in our study fully showed that tamsulosin could significantly improve the stone expulsion rate (ser), shorten the expulsion time and reduce the complications except for retrograde ejaculation. additionally, the results of our meta-analysis also presented that tamsulosin was superior to placebo for the treatment of distal ureteral stones, especially a strong trend towards the stone size less than 10 mm, which was inconsistent with the findings in previous meta-analyses(11, 24-25). tamsulosin, acting as an α-blocker, consists of α1a and α1d-selective adrenergic antagonist, while α1a and α1d-adrenoceptors were mainly expressed in smooth-muscle cells of the human ureter(26). the produce of the related reactions were realized for the distal end of the ureter could be relaxed by reducing the ureteric smooth muscle tone. a systematic review with a combined of 1384 participants showed that tamsulosin significantly improved stone passage in patients with ureteral stones 5-10 mm (risk difference = 22%; 95% confidence interval 12% to 33%; number needed to treat = 5)(11). seitz et al. also performed a meta-analysis, and the findings revealed that there were higher and faster stone expulsion rate in patients after receiving α-blocker therapy (rr = 1.45 vs. 1.49)(27). meanwhile, a recent multicenter, randomized, double-blind and placebo-controlled trial demonstrated that subgroup analysis identified a specific benefit of tamsulosin when patients with large distal ureteral stones (6-7 mm) had been treated, but no effect for stones ≤ 5 mm(9). therefore, it could be concluded that stone size was an important parameter for the prediction of met-success in patients with distal ureteral stones. besides, several studies have suggested that approximately 68%-98% of stones less than 5 mm are expected to pass spontaneously for patients with distal ureteral stones(5,28). however, the esr was unfortunately decreased to 60.3% with stone size increasing (ranging from 5 to 10 mm). in this meta-analysis, a significantly higher esr was found in tamsulosin (or = 1.10, 95% ci = 1.00-1.21) in contrast to placebo in distal ureteral stones patients with the stone size less than 7 mm. the esr ranged from 67.0%-90.7%. except that, this kind of significantly difference was better presented in distal ureteral stones patients with the stone size less than 10 mm (or = 1.11, 95% ci = 1.01-1.21). these findings confirmed the results of previous reviews, and the meaningful functions of tamsulosin on stone expulsion in distal ureteral stone would be also observed when the stone size was 8-10 mm. it was reported that different α1-adrenoceptor blockers commonly presented with various side effects, including dizziness, headache, rhinitis, syncope, retrograde ejaculation as well as fatigue(29-31). except for a higher incidence of retrograde ejaculation in tamsulosin in comparison to placebo, no other significant difference was detected in the incidence of other side effects. besides, tamsulosin was well-tolerated and just mild adverse effects in most patients. in these trials, retrograde ejaculation was the most commonly reported adverse effects for tamsulosin. since the standard daily dose of tamsulosin was 0.4 mg, the 0.4 mg daily was selected as an effective and well tolerated treatment dose for tamsulosin for distal ureteral stones. moreover, met should be an economical and effective treatment for those patients with ureteral calculi who had a stone size of 10 mm or smaller, and these patients are willing to a waiting management. some limitations in our meta-analysis should be acknowledged to a certain extent when interpreting the data. firstly, the results were more or less based on unadjusted estimates due to the small numbers of published studies and small sample size of patients. as a consequence, the inclusion criteria for each patient in previous articles vary greatly, which can reduce heterogeneity through subgroup analysis. secondly, many factors could affect esr, such as compliance of met, exercise volume and different follow-up periods, but these factors were not taken into consideration in our subgroup analysis. in addition, the patients with high grade hydronephrosis were excluded from our meta-analysis, which may introduce a bias to patient selection. last but not least, most of the studies were conducted in australian and asian populations, suggesting that there may be some merit in the analysis. hence, more researches should attach great importance on the influence of different factors in subsequent articles to guaranty reliability of our meta-analysis. silodosin, as a kind of selective α-1a adrenergic receptor’ antagonist, has also been proved to be safe and effective in the medical expulsive therapy for symptomatic distal ureteral stones in multiple studies(32,33). further studies could be conducted to compare the efficacy and safety between tamsulosin and silodosin in met of ureteral stones. conclusions in summary, the results of the current meta-analysis provided evidence that tamsulosin was still superior to placebo in terms of its efficacy for the treatment of distal ureteral stones even if retrograde ejaculation was worse with the application of tamsulosin. tamsulosin should be a safe and effective choice in treating distal ureteral stones when stone sizes are less than 10 mm. in the future, high-quality multicenter randomized controlled trial (rcts) and placebo-controlled trials are necessary to thoroughly evaluate the outcome. figure 7. begg’s funnel plot of publication bias test in the fixed-effects model. the treatment of tamsulosin for distal ureteral calculi-tao et al. review 229 vol 16 no 03 may-june 2019 230 references 1. stefanos pj, michael c: trussa: treatment strategies of ureteral stones. eau-ebu update series 2006; 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z, ding h, et al. tamsulosin for ureteral stones: a systematic review and metaanalysis of a randomized controlled trial. urol int. 2012; 89:107-15. 26. wang rc, smith-bindman r, whitaker e, et al. effect of tamsulosin on stone passage for ureteral stones: a systematic review and meta-analysis. ann emerg med. 2017; 69:353-61. 27. tzortzis v, mamoulakis c, rioja j, et al. medical expulsive therapy for distal ureteral stones. drugs 2009; 69: 677-92. the treatment of tamsulosin for distal ureteral calculi-tao et al. 28. seitz c, liatsikos e, porpiglia f, et al. medical therapy to facilitate the passage of stones: what is the evidence? eur urol. 2009;56:45571. 29. phipps s, tolley da, young jg, et al. the management of ureteric stones. ann r coll surg engl. 2010;92:368-72. 30. chapple cr. a comparison of varying alphablockers and other pharmacotherapy options for lower urinary tract symptoms. rev urol. 2005; 7 (suppl 4): s22-30. 31. daga s, wagaskar vg, tanwar h, et al. efficacy of medical expulsive therapy in renal calculi less than or equal to 5 millimetres in size. urol j. 2016;13:2893-8. 32. yuceturk cn, dadali m, bagbanci ms, et al. efficacy of silodosin dose in medical expulsive therapy for distal ureteral stones: a retrospective study. urol j. 2017;14:29448. 33. wang cj, tsai pc, chang ch. efficacy of silodosin in expulsive therapy for distal ureteral stones: a randomized doubleblinded controlled trial. urol j. 2016 ;13:2666-71. the treatment of tamsulosin for distal ureteral calculi-tao et al. review 231 sexual dysfunction and andrology impact of spirulina supplementation on semen parameters in patients with idiopathic male infertility: a pilot randomized trial roya modarresi,1 alireza aminsharifi,2 farzaneh foroughinia,3, 4* purpose: to evaluate the efficacy of therapy with spirulina supplement on semen parameters in patients with idiopathic male infertility. materials and methods: a total of 40 men with idiopathic infertility were randomly assigned into two groups. group a received 2 g spirulina supplement as well as conventional regimen for the treatment of infertility selected by their physician (220 mg/day zinc sulfate, 500mg/day l-carnitine, and 50 mg/day clomiphene) during 12 weeks of the study, while group b received placebo plus conventional therapy during the study period. semen parameters were analyzed at baseline and at the end of the study as a primary endpoint. the secondary endpoint was the rate of pregnancy occurring in the patients. wives. result: no significant differences in semen parameters were observed between the spirulina and control groups [count (16.43 vs. 46.00, p = .164), motility (51.00 vs. 48.7, p = .008), and morphology (47.50 vs. 15.00, p = na)]. our results showed a pregnancy rate of 5% in the spirulina group versus 0% in the control group. conclusion: this pilot randomized trial provides initial evidence on the possible beneficial effects of spirulina mainly in patients with impaired sperm motility or morphology. due to the limited sample size, further larger randomized trials not only at the level of semen parameters but at the scope of paternity are required to confirm these potential benefits. keywords: idiopathic male infertility; pregnancy; semen parameters; spirulina supplement. introduction idiopathic infertility is one of the most common re-productive disorders in men worldwide. approximately one out of ten couple is infertile and infertility in about half of them is the result of male factors. the pathogenesis and etiology of infertility are not completely understood in most cases; therefore, it is named idiopathic infertility. this disorder results from interaction between genetic and environmental factors and can be easily manipulated.(1,2) because of the society’s shift toward industrialism during the last decades, concerns have arisen about the effect of higher exposure to chemicals and radiations in everyday life and workplace that could also lead to infertility.(3,4) although some progression has been reported in the treatment of infertility in the literature, there is still no standard treatment with acceptable efficacy for this problem. vitamins and minerals as efficient anti-oxidants help to protect the body from oxidative damage. therefore, these supplements have been studied for the management of fertility problems in both men (oligospermia) and women (anovulation).(5,6) spirulina is a cyanobacterium blue-green micro-alga. it 1student research committee, shiraz university of medical sciences, shiraz, iran. 2department of urology, shiraz university of medical sciences, shiraz, iran. 3clinical neurology research center, shiraz university of medical sciences, shiraz, iran. 4clinical pharmacy department, shiraz university of medical sciences, shiraz, iran. *correspondence: clinical neurology research center, department of clinical pharmacy, shiraz university of medical sciences, shiraz, iran. tel: +989177136095, e-mail: farzanehforoughinia@yahoo.com. received august 2017 & accepted february 2018 has protein content of 50-70% of total dry weight and also it is full of vitamins such as a, e, d, k, b1, b2, b3, b6, b12, panthotenic acid, folate and minerals such as mg, zn, fe, cu, and selenium.(7,8) it has been mentioned as a safe edible alga. various studies on mice have shown no adverse effects on non-pregnant and pregnant mice that were given spirulina in their daily routines.(9,10) to our best of knowledge, no clinical trial has been done to address the effect of spirulina on idiopathic male fertility. therefore, in this pilot trial, we investigated the effect of sprirulina as a rich supplement for the management of male patients with infertility for the first time. materials and methods study design this is a pilot randomized clinical trial with double-blind study design that was conducted in two infertility clinic, shahid motahari and shahid faghihi, affiliated to shiraz university of medical sciences (sums), shiraz, iran. the study was approved by the ethical committee of sums. the identifier code of sexual dysfunction and andrology 78 vol 16 no 01 january-february 2019 79 (irct) is irct2016081320441n5. as to the ethics, all participants were counseled about the possible efficacy and side effects of spirulina and their consents were obtained. study population this trial was performed from june 2015 to june 2016. all patients with male factor-infertility and poor semen parameters were considered. male infertility was diagnosed if one or more standard semen parameters were below the cutoff levels accepted by who (1999) (sperm density less than 20 *106/ml, sperm motility less than 50%, and normal morphology less than 30%)(11). to eliminate possible adverse effects of various factors on spermatogenesis, all the participants had at least two semen analysis performed 3 months apart. inclusion and exclusion criteria inclusion criteria were the ages between 20-40 years old of participants and their wives, abnormal semen parameters, and documentation of fertile female partner. exclusion criteria were as follows: known medical (varicocele or cryptorchidism) or surgical condition which can result in infertility, a history of cancer chemotherapy, body mass index 30kg/m2 or greater, a history of alcohol, drug, or other substance abuse, administration of androgens, anti-androgens, and immunosuppressant, severe kidney (serum creatinine greater than 2.0 mg/ dl) and liver insufficiency (serum bilirubin greater than 2.0 mg/dl), azoospermia, and endocrinopathy. procedures a total of 40 patients with idiopathic male infertility were enrolled in the study. patients were randomized into group a (spirulina group, n=20) and group b (control group, n=20) by simple randomization. all participants were asked to complete occupational and lifestyle questionnaire face to face. presence of varicocele was determined by doppler ultra-sonography of the scrotum with the valsalva maneuver. patients in group a received 2 g spirulina supplement (far east microalgae ind. co., ltd, taiwan) as well as conventional regimen for the treatment of infertility selected by their physician (220mg/day zinc sulfate,(12) 500mg/day l-carnitine,(13) and 50mg/day clomiphene(14) during 12 weeks of the study, while group b received placebo plus conventional therapy during the study period. patient’s compliance was assessed by comparing the number of pills ingested and the number of days between dispensing visits. the follow up visits were in weeks 4, 8, and 12 after treatment administration, during which the patient’s compliance were evaluated. the investigator, responsible to provide drugs for patients and follow-up them, was blinded. evaluations two standardized semen samples were collected from all patients at baseline and after 12 weeks of treatment. the samples were obtained at home by masturbation into polypropylene containers after 3 to 5 days of abstinence and delivered to laboratory within 1 hour after production. semen parameters were analyzed blinded by two laboratory technicians at baseline and at the end of the study as a primary endpoint. the secondary endpoint was the rate of pregnancy occurring in the patientsˈ wives confirmed by a positive blood pregnancy spirulina supplementation on semen parameters-modarresi et al. table 1. semen parameters analysis at baseline and after 12 weeks of treatment in two study groups. baseline 12 weeks p value groups control (n = 20) spirulina (n = 20) control (n = 20) spirulina (n = 20) mean ± sd n (%) mean ± sd n (%) mean ± sd n (%) mean ± sd n (%) baseline baseline 12 weeks baseline controlcontrol-12 controlspirulina-12 baseline weeks 12 weeks weeks spirulina control spirulina spirulina oligospermia 16.23 ± 3.69 3 5.42 ± 2.25 3 46.00 ± 29.13 3 16.43 ± 7.72 3 .0123 .153 .164 .076 (sperm count) (15) (15) (15) (15) (106/ml) asthenosperima 33.04 ± 9.72 10 37.3 ± 10.97 8 48.7 ± 13.82 10 51.00 ± 7.12 8 .39 .008 .675 .01 (sperm motility) (50) (40) (50) (40) (% motile) teratospermia 19.0 ± 0.00 1 5.5 ± 0.5 2 15 ± 0.00 1 47.5 ± 10.5 2 na na na .02 (sperm morphology) (5) (10) (5) (10) (% normal) oligospermia 10.3 ± 4.59 4 14.90 ± 3.1 2 17.75 ± 13.2 4 6.88 ± 1.28 2 .28 .327 .334 .077 + + (20) + (10) + (20) + (10) asthenospermia 21.42 ± 15.94 31.34 ± 3.66 38.25 ± 8.31 35.50 ± 6.50 .46 .110 .703 .512 asthenospermia 40 ± 0.00 1 30.00 ± 0.00 1 55 ± 0.00 1 40.00 ± 0.00 1 na na na na + + (5) + (5) + (5) + (5) teratospermia 15 ± 0.00 15.00 ± 0.00 65 ± 0.00 65.00 ± 0.00q na na na na oligospermia 17 ± 0.00 1 8.03 ± 5.30 4 28 ± 0.00 1 10.9 ± 7.85 4 na na na .566 + + (5) + (20) + (5) + (20) asthenospermia 29 ± 0.00 18.00 ± 11.8 20 ± 0.00 21.75 ± 14.21 na na na .698 + + + + + teratospermia 5 ± 0.00 13.00 ± 3.31 25 ± 0.00 35.00 ± 15.00 na na na .028 abbreviations: na, not assigned test. statistical analysis statistical analysis was performed using statistical package for social sciences software, version 22 (spss inc, chicago, usa). variables were tested for normality by kolmogorov-smirnov test. categorical variables were described with absolute and relative (percentage) frequencies. continuous variables were expressed as mean ± standard deviation (sd). student t-test and paired t-test were applied for statistical analysis of continuous variables. differences in proportions were tested by pearson chi-square when assumptions were met; if not, the fisher’s exact test was used. p-value< 0.05 was considered as the significance level. results the consort diagram of the clinical trial is reported in figure 1. during the follow up period, 5 patients in each group were excluded from the analysis due to the loss of follow up and withdrawal of consent. evaluation of patients before/after treatment in the control group revealed that the average sperm motility in patients with one disordered factor was the only measure that was significantly increased after the treatment with conventional regimen (33.04 ± 9.72 vs. 48.70 ± 13.82, p = .008) (table 1). assessment of participants before/after treatment in the experimental arm showed that both the average sperm motility in isolated motility disorder (37.30 ± 10.97 vs 51.00 ± 7.12, p = .01) and the average sperm morphology in isolated morphology problem (5.5 ± 0.50 vs 47.50 ± 10.5, p = .02) were recovered completely after treatment and these differences were statistically significant. however, in participants with all three disordered factors of the sperm count, sperm morphology, and sperm motility, the only factor that was statistically improved after the treatment was sperm morphology (p = .02) (table 1). in groups in which there was only a single outlier participant with a specific disorder, their given statistics were not calculated. according to our results, the average sperm count, morphology, and motility were not significantly different between the study groups at the end of the study period (table 1). our results showed a pregnancy rate of 5% in the partner of patients in the spirulina group versus 0% in the control group. discussion we found no significant differences with regards to semen parameters between the study groups. on the other hand, significant improvement in the sperm morphology and motility was reported after the treatment with spirulina (compared to pre-treatment specimen); while motility was the only variable that was improved in the control group (compared to pre-treatment specimen). although the exact etiology of male infertility is unknown, it is attributed to several environmental factors such as exposure to certain chemicals, heavy metals, pesticides, electromagnetic radiation, smoking, alcohol abuse, chronic stress, and inflammation in the male reproductive system.(15-18) most of these factors ultimately cause oxidative stress. the resulting excessive free radicals cause a pathological response that can lead to reduced sperm count, decreased sperm motility, and development of abnormal sperm morphology.(19) the semen protective antioxidant system consists of enzymetic and non-enzymatic factors. vitamin a, e, c, and b complex, glutathione, pantothenic acid, carotenoids, coenzyme q10, carnitine, and minerals such as zinc, selenium, and copper are efficient anti-oxidants that help to protect the body from oxidative damage. (19) as a result, various clinical trials have been perfigure1. flow diagram of the trial spirulina supplementation on semen parameters-modarresi et al. sexual dysfunction and andrology 80 vol 16 no 01 january-february 2019 81 formed to evaluate the possible beneficial effects of these agents on improvement of the sperm parameters in males as well as pregnancy rates in their partners in patients with idiopathic male infertility.(20-21) in a study, the effects of selenium supplementation in males with infertility were considered. results showed that a low dosage of selenium could improve the sperm motility and increase the chance of successful conception. however, not all participants responded to treatment in this study and only 56% of them showed a positive response to this treatment.(5) our results also showed that treatment with spirulina could significantly increase the sperm motility based to baseline-12 weeks of treatment sub-analysis in spirulina-treated patients. in another study, the efficacy of folic acid and zinc sulfate on semen parameters was evaluated in infertile and subfertile men. results revealed that treatment with these supplements could significantly increase the total sperm count (74%) and also lead to minor increase in abnormal spermatozoa (4%) in both subfertile and fertile men. however, pre-intervention concentrations of folate and zinc in the blood and seminal fluid did not significantly differ between fertile and subfertile men. (12) the improving effects of zinc sulfate on the semen parameters have been studied in another trial in infertile men. this study reported strong linear associations between the sperm count and normal sperm morphology with seminal zinc concentrations.(20) in our study, there was a trend toward an increase in the level of sperm count after 12-week treatment period in spirulina-treated patients (5.42 vs. 16.43, p = .076). though, this improvement was not statistically significant which may be due to a significant lower baseline sperm count in this group compared to controls and a limited sample size in both groups, therefore; it deserves further evaluation in the clinical setting. a trial analyzing the efficacy of coenzyme q10 supplementation on semen parameters showed a significant improvement in the semen morphology, density, and motility in infertile men. this study mentioned a positive correlation between treatment duration with coenzyme q10 and improvement in semen parameters. coenzyme q10 also significantly decreased the serum follicle stimulating hormone and luteinizing hormone at the 26-week treatment phase.(21) another trial was performed on 228 men randomly distributed in two groups of placebo and coenzyme q10 treatment (200mg/day for 26 weeks). at the end of the trial, the sperm density, motility, and morphology increased significantly in the men treated with coenzyme q10.(22) with regard to the protective effects of vitamins and minerals in the improvement of spermatogenesis in men with idiopathic infertility and the fact that spirulina is full of minerals, vitamins and caretinoids, in this study, we evaluated the hypothesis that this supplement may have beneficial effect on the semen parameters in infertile men.(7) the efficacy of spirulina on animal fertility has been extensively studied. its beneficial effects on improving the reproductive performance and reducing teratogenicity in albino mice were addressed previously. an increase in fertility rate from 77.5% to 82.5% and a 33.7% decrease in stillbirth rate were shown. this agent also improved the survival rate of off-springs in diabetic mice from 83.61% to 88.9%.(23) in another study, spirulina was shown to be safe as a supplement used in laying hens’ diets with a significant improvement on reproductive and productive performances. (24) in a pilot study carried out on 6 boars, it was revealed that the addition of spirulina to the main diet for 40 days could increase the volume of ejaculation (30 ml) as well as the spermatozoa concentration (27mln/ ml). the sperm motility also had a 30% increase in this study.(25) despite these promising experimental studies, we did not find any clinical study in the literature to assess the efficacy of spirulina on human reproductive function. therefore, we designed this pilot study with randomized trial design to analyze the value of this natural product on the semen parameters in comparison with conventional treatment in men with infertility and abnormal semen analysis. according to the who definition, abnormality in any of the sperm count or motility or morphology can lead to infertility. this study showed that the addition of 2 g spirulina per day to the conventional treatment did not significantly improve the semen parameters and sperm function in all subgroups. in addition to routine analysis mentioned in previous studies, to better assess the results, we evaluated the efficacy of treatments in different subgroups (i.e. patients with isolated versus multiple abnormalities in their semen analysis). in the spirulina-treated group there were significant differences between baseline and post-treatment sperm motility and morphology in patients with isolated motility or morphology disorders. interestingly, the positive effect of spirulina on improvement of the sperm morphology was also observed in patients with combined oligospermia, asthenospermia, and teratospermia disorders. therefore, with attention to one case of confirmed pregnancy in the spirulina arm, it sounds that it exerts its benefit on fertility mainly by improving the morphology of sperm. study limitations we admit that the small sample size of this pilot study in the subgroups can be a limitation for a thorough statistical analysis. improved semen quality and quantity does not certainly translate into an improved pregnancy rate. although we followed all the patients for assessing pregnancy occurrence during the study period, there were 7 single males in the control group and 4 in the spirulina group that made this assessment impossible for all participants. conclusions this pilot randomized trial provides initial evidence on the possible beneficial effects of spirulina mainly in patients with impaired sperm motility or morphology. due to the limited sample size, further larger randomized trials not only at the level of semen parameters but at the scope of paternity are required to confirm these potential benefits. acknowledgments this research, extracted from a thesis written by roya modarresi, was financially supported by pharmaceutical sciences research center, shiraz university of medical sciences, shiraz, iran (grant number: 8346). the authors would like to express their gratitude to center for development of clinical research of nemazee hospital for statistical analysis, dr shokrpour for editorial assistance, and the assistance of the staff of spirulina supplementation on semen parameters-modarresi et al. shahid motahari and shahid faghihi clinics. conflict of interest the authors declare that there is no conflict of interest. references 1. de kretser dm, baker hw. infertility in men: recent advances and continuing controversies. j clin endocrinol metab. 1999;84:3443-50. 2. safarinejad mr. infertility among couples in a population-based study in iran: prevalence and associated risk factors. int j androl. 2008;31:303-14. 3. carlsen e, giwercman a, keiding n, skakkebaek ne. evidence for decreasing quality of semen during the past 50 years. bmj. 1992;305:609-13. 4. vayena e, rowe pj, peterson hb. assisted reproductive technology in developing countries: why should we care? fertil steril. 2002;78:13-5. 5. scott r, macpherson a, yates rw, hussain b, dixon j. the effect of oral selenium supplementation on human sperm motility. br j urol. 1998;82:76-80. 6. salas-huetos a, bulló m, salas-salvadó j. dietary patterns, foods and nutrients in male fertility parameters and fecundability: a systematic review of observational studies. hum reprod update. 2017;23:371-389. 7. www.naturalways.com/spirulina-analysis. htm. 8. nutritiondata.self.com/facts/vegetables-andvegetable-products/2765/2. 9. chamorro g, salazar s, favila-castillo l, steele c, salazar m. reproductive and periand postnatal evaluation of spirulina maxima in mice. j appl phycol. 1997; 9:107-12. 10. kapoor r, mehta u. effect of supplementation of blue green alga (spirulina) on outcome of pregnancy in rats. plant foods hum nutr. 1993;43:29-35. 11. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. hum reprod update. 2010;16:231-45. 12. wong wy, merkus hm, thomas cm, menkveld r, zielhuis ga, steegerstheunissen rp. effects of folic acid and zinc sulfate on male factor subfertility: a doubleblind, randomized, placebo-controlled trial. fertil steril. 2002;77:491-8 13. wang yx, yang sw, qu cb, et al. l-carnitine: safe and effective for asthenozoospermia. zhonghua nan ke xue. 2010;16:420-2. 14. ghanem h, shaeer o, el-segini a. combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. fertil steril. 2010;93:2232-5. 15. gyllenborg j, skakkebaek ne, nielsen nc, keiding n, giwercman a. secular and seasonal changes in semen quality among young danish men: a statistical analysis of semen samples from 1927 donor candidates during 1977–1995. int j androl. 1999;22:2836. 16. thonneau p, bujan l, multigner l, mieusset r. occupational heat exposure and male fertility: a review. hum reprod. 1998;13:2122-5. 17. de celis r, pedron–nuevo n, feria–velasco a. toxicology of male reproduction in animals and humans. arch androl. 1996;37:201–218. 18. agarwal a, sharma rk, desai nr, prabakaran s, tavares a, sabanegh e. role of oxidative stress in pathogenesis of varicocele and infertility. urology. 2009;73: 461–469. 19. walczak–jedrzejowska r, karol wolski j, slowikowska–hilczer j. the role of oxidative stress and antioxidants in male fertility. cent european j urol. 2013;66: 60–67. 20. colagar ah, marzony et, chaichi mj. zinc levels in seminal plasma are associated with sperm quality in fertile and infertile men. nutr res. 2009;29:82-8. 21. safarinejad mr. efficacy of coenzyme q10 on semen parameters, sperm function and reproductive hormones in infertile men. j urol. 2009;182:237-48. 22. safarinejad mr, safarinejad s, shafiei n, safarinejad s. effects of the reduced form of coenzyme q10 (ubiquinol) on semen parameters in men with idiopathic infertility: a double-blind, placebo controlled, randomized study. j urol. 2012;188:526-31. 23. pankaj pp. efficacy of spirulina platensis in improvement of the reproductive performance and easing teratogenicity in hyperglycemic albino mice. indian j pharmacol. 2015;47:430– 435. 24. mariey, y.a., samak h.r. ibrahem m.a. effect of using spirulina platensis algae as a feed additive for poultry diets: 1-productive and reproductive performances of local laying hens. egypt poult sci. 2012;32:201-215. 25. kistanova e, marchev y, nedeva r, et al. effect of the spirulina platensis included in the main diet on the boar sperm quality. biotech anim husbandry. 2009;25:547-557. spirulina supplementation on semen parameters-modarresi et al. sexual dysfunction and andrology 82 endourology and stone disease 249urology journal vol 6 no 4 autumn 2009 sterile water versus isotonic saline solution as irrigation fluid in percutaneous nephrolithotomy seyed mohammad kazem aghamir,1 farshid alizadeh,2 alipasha meysamie,3 shadi assefi rad,4 ladan edrisi4 introduction: we evaluated the safety of sterile water as an irrigation solution for percutaneous nephrolithotomy (pcnl). materials and methods: forty-four patients with kidney calculi were enrolled in this study and randomly divided into two groups for pcnl. approaches to the calculi were through a single subcostal access with an amplatz sheath, and either sterile water or isotonic saline solution was used as the irrigation fluid. serum hemoglobin, haptoglobin, sodium, potassium, and creatinine were measured before and 12 hours after the procedure. the patients were evaluated for signs of transurethral resection of the prostate syndrome during the operation for 24 hours afterwards. results: the mean calculus size, irrigation volume, irrigation time, and age were not significantly different between the two groups. hemolysis occurred in 10 and 9 patients in sterile water and saline groups, respectively. the mean change in haptoglobin level was -1.7 ± 59 mg/dl in the sterile water and 11 ± 55 mg/dl in the saline group. also, the mean change in plasma sodium level was -2.2 ± 4.7 and -0.4 ± 3.8 in sterile water and saline groups, respectively. none of these values were significantly different between the two groups, nor were other laboratory values. none of the patients developed transurethral resection of the prostate syndrome or needed transfusion. conclusion: sterile water is an inexpensive alternative to isotonic saline for irrigation during pcnl. we did not find any difference between the two irrigation solutions regarding the safety; however, this should be confirmed further, especially for larger calculi. urol j. 2009;6:249-53. www.uj.unrc.ir keywords: lithotripsy, kidney calculi, irrigation, water 1department of urology, tehran university of medical sciences, tehran, iran 2department of urology, isfahan university of medical sciences, isfahan, iran 3department of community and preventive medicine, tehran university of medical sciences, tehran, iran 4tehran university of medical sciences, tehran, iran corresponding author: farshid alizadeh, md no 8, farhad alley, daneshgah ave, isfahan, iran tel: +98 913 317 9509 fax: +98 21 8855 5320 e-mail: f_alizadeh_md@yahoo.com received may 2009 accepted july 2009 introduction percutaneous nephrolithotomy (pcnl) is the standard treatment for most kidney calculi that are not good candidates for extracorporeal shock wave lithotripsy (swl) or not responding to it. its advantages over open surgery include the lower cost, less postoperative pain, shorter hospital stay, and minimal scarring.(1,2) however, this endoscopic procedure is associated with a number of potentially serious postoperative complications. one of them is rapid absorption of irrigating solution, which is due to direct intravascular absorption through the opened veins or peritoneal resorption after opening the peritoneal space.(3) postnephrolithotomy syndrome, which is more or less similar to the transurethral resection of the prostate (turp) syndrome, has been described when glycine 1.5% has been used as the irrigation solution. (4) under general sterile water in percutaneous nephrolithotomy—aghamir et al 250 urology journal vol 6 no 4 autumn 2009 anesthesia, the diagnosis of this syndrome is difficult and often delayed. the usual signs are unexplained rise and then fall in blood pressure and refractory bradycardia. changes in electrocardiography, including nodal rhythm, st-segment changes, u waves, and widening of the qrs complexes, may be observed. recovery from general anesthesia and muscle relaxants may be delayed.(5) it is well known that using water for irrigation during turp carries a risk of hemolysis. however, water has advantages over the other irrigation solutions; the visibility is slightly better as blood in the operating field is hemolyzed (although not significant with modern optics) and, if absorbed, water molecules are rapidly distributed in the total body water, resulting in less hypervolemia and less hyponatremia than glycine and mannitol solutions. furthermore, plain water has no potentially harmful substances usually added to avoid hemolysis. last but not least, water is an inexpensive available irrigation solution. in most developing countries, addition of glycine, mannitol, or sorbitol cannot be afforded.(6) the use of water as the irrigation solution in turp has been investigated in several studies.(69) however, its use in pcnl has not been widely studied. the aim of this study was to evaluate the effect of sterile water as the irrigation solution in pcnl and its effect on hemolysis and electrolyte changes. materials and methods between june 2006 and july 2007, a total of 107 patients with kidney calculi were referred to our clinic. the diagnosis of calculus was made by ultrasonography and plain abdominal radiography. when pcnl was planned, an intravenous urography was also performed to delineate the pyelocaliceal anatomy. the calculus size was determined by measuring the largest diameter of its shadow (opaque calculi) or filling defect (radiolucent calculi). in rare cases in which the overlapping bowel gas made accurate measurement impossible, the size measured by ultrasonography was relied on to avoid performing spiral computed tomography scan. among the patients, 44 were selected and randomized into 2 equal groups of 22. adult patients between 18 and 60 years, with an american society of anesthesiologists class i or ii, and with pelvis or caliceal calculi larger than 2 cm that could be approached through a single subcostal access or smaller than 2 cm not responsive to swl were included. the local ethics committee approved this study for calculi that could be treated through a single subcostal access to reduce the possibility of complications that could occur due to absorption of large amounts of water into the circulation. the exclusion criteria were the presence of hepatic, renal, pulmonary or cardiovascular failure, active urinary tract infection, history of hemolytic or hemorrhagic disorders, syndromes causing electrolyte changes such as syndrome of inappropriate antidiuretic hormone secretion (siadh) and diabetes insipidus, any electrolyte disturbances, hypertension, and any medication affecting serum electrolytes. laboratory studies including complete blood count, blood urea nitrogen (bun), plasma creatinine, sodium, potassium, haptoglobin, urinalysis and urine culture were performed the day before and 12 hours after the operation. induction of general anesthesia was achieved with the same method for all of the patients with thiopental, atracurium, and fentanyl and continued with isoflurane. a 5-f ureteral catheter was placed and anchored to a foley catheter, and then, the patient turned to the prone position with appropriate padding. percutaneous access to the renal collecting system was established under the guidance of monoplane fluoroscopy by the use of a 19-gauge percutaneous needle. then, the tract was dilated with telescopic metal dilators and a 30-f amplatz sheath was placed in the tract. calculus fragmentation was performed with pneumatic lithotripsy (swiss lithoclast) using a rigid nephroscope. irrigation was performed by either sterile water or isotonic saline solution with the reservoir being kept at a height of 80 cm from the patient. the statistician provided us with closed numbered pockets, each of which containing a piece of paper with either “saline” or “water” being written on it. for each patient, the related pocket was opened and the type of irrigation fluid was chosen accordingly. sterile water in percutaneous nephrolithotomy—aghamir et al urology journal vol 6 no 4 autumn 2009 251 the procedure was done in a totally tubeless manner unless pelvis perforation or severe bleeding occurred, in which cases, a 24-f nephrostomy tube was placed for tamponade. the ureteral catheter was removed upon the completion of the procedure. intravenous isotonic saline was infused during and after the operation. the dose was calculated by the anesthesiologist according to the ongoing and insensible water loss, as well as blood pressure; hence, it was individualized for each patient and included 100 ml/kg for the first 10 kg of the weight, 50 ml/kg for the second 10 kg, and 20 ml/kg for the remainder of weight, plus 15 ml/kg/d as the insensible water loss. however, when hypotension was encountered during the operation, additional booster doses of isotonic saline were administered to keep the systolic blood pressure above 100 mm hg. the patient was kept nil per os until the next morning, when the intravenous fluid was discontinued and oral intake started. pulse oxymetry and noninvasive monitoring of the cardiac function and blood pressure were established during the operation and in the recovery room. the patients were continuously checked for signs of turp syndrome during the operation, in the recovery room, and at 3-hour intervals in the ward by checking blood pressure and level of consciousness for the next 24 hours, afterwards. statistical analyses were performed by the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). comparisons between groups were done using the chi-square test, fisher exact test, t test, or mann-whitney u test, where appropriate. comparison of values measured before and after the procedures were done using the paired t test. a p value less than .05 was considered significant. results the patients’ demographic and surgical characteristics are presented in table 1. hemolysis, as detected by a fall in serum haptoglobin, was observed in 10 (45.5%) and 9 (40.9%) patients in the sterile water and normal saline groups, respectively (p = .81). there was no difference between plasma mean haptoglobin before the operation in the two groups (table 2). the mean difference between haptoglobin before and after the operation in the saline and sterile water groups were 10.7 ± 55 mg/dl and -1.7 ± 58.7 mg/dl, respectively (p = .47). none of the patients developed signs of turp syndrome during or after the operation. also, there was no difference between sodium values before and after the procedure or the mean changes in these values after the operation in the two groups (tables 2 and 3). irrigation fluid characteristic 0.9% saline sterile water p age, y 36.8 ± 9.8 35.6 ± 11.2 .69 male/female 15/ 7 17/ 5 .50 calculus size, mm 31.0 ± 9.9 25.9 ± 10.9 .13 irrigation time, min 35.0 ± 13.1 29.27 ± 10.7 .12 irrigation volume, l 6.70 ± 3.37 6.90 ± 2.77 .85 asa class i/ ii 18/ 4 15/ 7 .11 table 1. demographic and surgical characteristics of patients who underwent percutaneous nephrolithotomy using sterile water or isotonic saline* *asa indicates american society of anesthesiologists. parameter before after p 0.9% saline sodium, meq/dl 140.80 ± 3.30 140.40 ± 1.90 .87 potassium, meq/dl 4.16 ± 0.30 4.00 ± 0.56 .65 creatinine, mg/dl 1.10 ± 0.22 1.20 ± 0.31 .51 hemoglobin, g/dl 14.50 ± 1.15 13.68 ± 1.17 .61 haptoglobin, mg/dl 84.10 ± 1.15 94.80 ± 43.10 .37 sterile water sodium, meq/dl 140.50 ± 3.75 138.30 ± 3.31 .76 potassium, meq/dl 4.18 ± 0.31 3.90 ± 0.32 .39 creatinine, mg/dl 1.17 ± 0.27 1.32 ± 0.15 .51 hemoglobin, g/dl 14.87 ± 1.21 13.97 ± 1.00 .77 haptoglobin, mg/dl 90.30 ± 45.70 88.60 ± 43.30 .62 table 2. blood laboratory values before and after percutaneous nephrolithotomy using sterile water or isotonic saline sterile water in percutaneous nephrolithotomy—aghamir et al 252 urology journal vol 6 no 4 autumn 2009 by dividing the mean irrigation volume into mean irrigation time, the mean irrigation velocity was calculated to be 0.19 l/min and 0.23l/min for saline and sterile water groups, respectively (p = .47). serum creatinine rise (> 1.5 mg/dl) occurred in 1 patient in the saline group that returned to normal after 24 hours. laboratory values before and after the operation and their mean changes are presented in tables 2 and 3. renal pelvis perforation occurred in 2 and 1 patients in the sterile water and saline groups, respectively. when perforation was diagnosed, the procedure was terminated, a nephrostomy tube was placed, and the operation deferred to a later date. only 1 patient in the sterile water group showed a fall in haptoglobin, but hyponatremia occurred in none. none of the patients needed transfusion after the operation. the rate of becoming calculus-free, defined as complete calculus clearance or residuals smaller than 4 mm, was 95% (21/22) and 91% (20/22) in the sterile water and saline groups, respectively. it was evaluated by plain abdominal radiography for opaque and spiral computed tomography for nonopaque calculi. a sample of tehran tap water was analyzed chemically, in order to determine its electrolyte composition and osmolality. the results are presented in table 4. discussion irrigation solutions are widely used in endourological procedures for better vision. ideally, they should be isotonic, nonhemolytic, nontoxic, transparent, easy to sterilize, and inexpensive.(10) however, such a solution is not yet available. solutions such as isotonic saline or ringer lactate are least harmful when absorbed into the circulation. although sterile water has many qualities of an ideal irrigating fluid, its disadvantages are extreme hypotonicity, shock, and kidney failure.(5) using distilled water as the irrigation solution in turp has been evaluated in a number of studies. mommsen and colleagues showed that the concentration of serum sodium decreased and plasma free hemoglobin increased significantly, but without significant change in haptoglobin level, after turp using distilled water.(11) however, in a study by chen and associates, haptoglobin decreased immediately and 24 hours after the operation, while all other parameters (plasma hemoglobin, lactate dehydrogenase, sodium, and creatinine levels) returned to their preoperative levels 24 hours after surgery in patients with hemolysis. they found hemolysis in 43.6% of their patients after turp using distilled water.(7) haptoglobin is an α2-glycoprotein which is mainly produced in the liver. since it is an acutephase protein, its concentration may increase by inflammation or tissue trauma during surgery or decrease as a result of hemolysis. although its halflife is about 5 days, when bound to hemoglobin, it will be cleared from plasma within minutes.(12) warkentin and coworkers showed that decrease in serum haptoglobin levels due to hemolysis occured much faster than its increase due to acute-phase response.(13) others have shown that mean changes parameter 0.9% saline sterile water p sodium, meq/dl -0.40 ± 3.76 -2.18 ± 4.75 .18 potassium, meq/dl -0.15 ± 0.60 -0.22 ± 0.37 .63 creatinine, mg/dl 0.10 ± 0.13 0.15 ± 0.12 .22 hemoglobin, g/dl -0.81 ± 0.91 -0.89 ± 0.77 .75 haptoglobin, mg/dl 10.72 ± 55.03 -1.72 ± 58.77 .47 table 3. mean differences of laboratory values before and after percutaneous nephrolithotomy using sterile water or isotonic saline parameter tap water 0.9% saline sodium, meq/dl 30.0 2542.0 potassium, meq/dl 2.0 … chloride, meq/dl 22.0 5390.0 magnesium, meq/dl 17.3 … calcium, meq/dl 35.2 … sulphate, meq/dl 50.0 … nitrate, meq/dl 3.2 … osmolality 23.0 308.0 table 4. electrolyte composition of tehran tap water and isotonic saline sterile water in percutaneous nephrolithotomy—aghamir et al urology journal vol 6 no 4 autumn 2009 253 in an acute-phase reaction, hemolysis is associated with plasma depletion of haptoglobin. (12) we checked haptoglobin 12 hours after the operation to minimize the effect of acute-phase increase in its plasma levels, which could probably counterbalance its decline as a result of hemolysis. malhorta and colleagues showed that a mean volume of 696.7 ml of irrigation solution is absorbed during pcnl.(14) thus, development of hemolysis or turp syndrome is a potential risk when water is used as an irrigation solution. using distilled water for pcnl, feizzadeh and associates found no case of symptomatic or asymptomatic hyponatremia among their patients.(15) we did not find any case of hyponatremia either. moreover, the mean plasma haptoglobin, potassium, creatinine, and hemoglobin before and after the operation and the mean changes in these values were not significantly different between the two groups. in these both studies, the calculi were approached through a single tract and amplatz sheath was also used. it seems that these two factors were important in decreasing the amount of water absorbed and the possibility of hyponatremia and hemolysis. to our knowledge, our study was the first to evaluate the effect of water as an irrigation fluid for pcnl on both hemolysis and electrolyte changes. we found sterile water to be a safe and inexpensive alternative to isotonic saline for irrigation during pcnl, but considering the small mean calculus size in this study (28.45 ± 10.67 mm), the safety of sterile water for large calculi or when multiple tracts are required has to be further evaluated. conclusion sterile water is an inexpensive alternative to isotonic saline for irrigation during pcnl. although we did not find any difference between the two irrigation fluids with regard to the safety for smaller calculi, its safety has to be confirmed with larger studies, especially for large calculi. aknowledgement we thank mehrnaz hadidi, soghra rahimi, simin hajinia, and mehdi soori for their contribution in conducting this study. conflict of interest none declared. references 1. o’keeffe nk, mortimer aj, sambrook pa, rao pn. severe sepsis following percutaneous or endoscopic procedures for urinary tract stones. br j urol. 1993;72:277-83. 2. lang ek. percutaneous nephrostolithotomy and lithotripsy: a multi-institutional survey of complications. radiology. 1987;162:25-30. 3. gehring h, nahm w, zimmermann k, fornara p, ocklitz e, schmucker p. irrigating fluid absorption during percutaneous nephrolithotripsy. acta anaesthesiol scand. 1999;43:316-21. 4. fellahi jl, richard jp, bellezza m, antonini a, thouvenot jp, cathala b.the intravascular transfer of glycine during percutaneous kidney surgery. cah anesthesiol. 1992;40:343-7. 5. moorthy hk, philip s. turp syndrome current concepts in the pathophysiology and management. indian j urol. 2001;17:97-102. 6. hultén jo, tran vt, pettersson g. the control of haemolysis during transurethral resection of the prostate when water is used for irrigation: monitoring absorption by the ethanol method. bju int. 2000;86:989-92. 7. chen ss, lin at, chen kk, chang ls. hemolysis in transurethral resection of the prostate using distilled water as the irrigant. j chin med assoc. 2006;69:270-5. 8. memon a, buchholz np, salahuddin s. water as an irrigant in transurethral resection of the prostate: a cost-effective alternative. arch ital urol androl. 1999;71:131-4. 9. creevy cd, reiser mp. the importance of hemolysis in transurethral prostatic resection: severe and fatal reactions associated with the use of distilled water. j urol. 1963;89:900-5; 10. madsen po, madsen re. clinical and experimental evaluation of different irrigating fluids for transurethral surgery. invest urol. 1965;3:122-9. 11. mommsen s, genster hg, moller j. changes in the serum concentrations of sodium, potassium, and free haemoglobin during transurethral resection of the prostate--parts of the tur-syndrome? urol res. 1977;5:201-5. 12. kormoczi gf, saemann md, buchta c, et al. influence of clinical factors on the haemolysis marker haptoglobin. eur j clin invest. 2006;36:202-9. 13. warkentin dl, marchand a, van lente f. serum haptoglobin concentrations in concurrent hemolysis and acute-phase reaction. clin chem. 1987;33:1265-6. 14. malhotra sk, khaitan a, goswami ak, gill kd, dutta a. monitoring of irrigation fluid absorption during percutaneous nephrolithotripsy: the use of 1% ethanol as a marker. anaesthesia. 2001;56:1103-6. 15. feizzadeh b, doosti h, movarrekh m. distilled water as an irrigation fluid in percutaneous nephrolithotomy. urol j. 2006;3:208-11. case report wilms' tumor and benign renal tumor combined with hypospadias and incomplete orchiocatabasis appearing simultaneously in a 10 months old baby chun li1, wei-song li1* we herein report a case of left renal wilms’ tumor and right renal hamartoma combined with hypospadias and incomplete testis descent in a 10-month-old boy. in the literature to date, no case has been reported. the preoperative abdominal computerized tomography (ct) scan was suggestive of bilateral nephroblastomas, and clinical diagnosis was bilateral renal tumors with external genitals malformation. finally, we used b-ultrasonic guided percutaneous biopsy to help determine the nature of bilateral renal tumors. afterwards, the boy underwent preoperative chemotherapy, surgery (left radical nephrectomy and right wedge excision of the renal tumor) and postoperative chemotherapy. after 3 years of follow-up, there was no evidence of tumor recurrence, the renal function was normal, and the boy’s height, weight and intelligence were also within normal range. keywords: wilms’ tumor ; benign renal tumor ; bilateral renal tumors ; hypospadias; boy introduction wilms’ tumor is the most primary malignant renal tumor in children. renal hamartoma is a benign neoplasia and is extremely rare in children. we report a case of wilms’ tumor and renal hamartoma combined with hypospadias and cryptorchidism appearing simultaneously in a 10-month-old boy. in the literature to date, no identical cases have been reported. owing to no case as a reference, preoperative imaging diagnosis, final etiological diagnosis and appropriate treatment are very important. department of pediatric surgery, department of general surgery, the first affiliated hospital of anhui medical university, 218 jixi avenue, hefei 230022, anhui, pr china. *correspondence: department of pediatric surgery, department of general surgery, the first affiliated hospital of anhui medical university, 218 jixi avenue, hefei 230022, anhui, pr china. tel: +86 551 62923764. fax: +86 551 62923770. e-mail: leiforget1970@hotmail.com. received july 2018 & accepted april 2019 urology journal/vol 17 no. 3/ may-june 2020/ pp. 321-323. [doi: 10.22037/uj.v0i0.4714] figure 1. a) preoperation: shows a giant heterogeneous mass was arising from upper and middle pole of left kidney and crossing the midline to the right side of the abdomen on ct scan, the right lesion shows a heterogeneous and hypodense lesion, and its boundary was not clear on contrast enhancement. b) postoperation: 3 years follow up, tumor recurrence was not seen in the primary site. c) tissue specimens: the left ( renal hamartoma ) lesion specimen was harder than the right ( wilm’s tumor ) tumor specimen, and the cut surface showed a solid and off white appearance. d,e) wilms’ tumor ( stage ii, favorable histology ) primitive epithelial and rhabdoid differentiation, primitive embryo h＆e ×100. hamartoma which contained mature mesenchymal tissues and mature tubular-like structures, cartilages. h&e×100. case report a 10-month-old boy was presented to a palpable abdominal mass with hypospadias and cryptorchidism. laboratory studies showed the blood cell counts, hemoglobin level, blood urea nitrogen, serum creatinine , sex and cortisol hormones were within the reference range. urinalysis was also normal. abdominal ultrasound study showed a large solid inhomogeneous retroperitoneal tumor and the urinary system was normal. computerized tomography (ct) of the abdomen showed a giant heterogeneous mass 11 cm × 10 cm in size, arising from the upper and middle pole of left kidney and crossing the midline of the abdomen. the lesion 2.5 cm×1.5cm in size located into the lower pole of right kidney exhibited a heterogeneous and hypodense mass on the contrast-enhanced ct scan (figure 1a). the ct scan was suggestive of bilateral nephroblastomas. we used b-ultrasonic guided percutaneous biopsy to help determine the nature of bilateral renal tumors. pathology result showed that: the left tumor was a nephroblastoma and the right tumor tended to be a hamartoma. afterwards, the boy received 6 courses of actinomycin-d and vincristine chemotherapy treatment, there was no significant change in bilateral renal tumors. after chemotherapy treatment, the child was prepared for surgery; a left radical nephrectomy and right tumor wedge excision was performed, and topical cooling of the kidney and vascular control techniques were applied in the right tumor excision (figure 1c). postoperative pathology and immunohistochemistry showed that the left tumor was a wilms’ tumor (favorable histology, stage ii) and right lesion was a hamartoma (figure 1d,e). subsequently, the boy received actinomycin-d, vincristine and adriamycin for approximately 38 weeks in postoperation. the boy underwent orchidopexy and urethroplasty at the age of 1.5 and 3 years. at 3 year follow-up, there was no evidence of tumor recurrence (figure 1b), the renal function was normal, and the boy’s height, weight and intelligence was also normal. discussion wilms tumor is the most common pediatric renal tumor, benign renal tumors had been reported infrequently in children, in our case, this boy had two different natures of bilateral renal tumors and congenital ectogenital deformity. syndromic approach could also be thought of like wagr(1) (wilms' tumor, aniridia, ambiguous genitalia, mental retardation), wiedemann-beckwith syndrome(2) (aniridia, hemihypertrophy, urogenital malformation, wilms' tumor), perlman syndrome(3) (fetal gigantism, nephroblastomatosis, hypertrophy of the endocrine pancreas). for this purpose, we examined the boy and his parents’ chromosomes and genes in post-operation, the results were normal. from birth to now，the boy’s height, weight and intelligence are within normal range. according to the related examination results, we think that the boy’s various disease performances may not be related, but we do not rule out the possibility of a kind of syndrome, we need further follow-up and discover similar cases. as a rare disease, the radiological appearance of renal hamartoma had been reported infrequently in human, especially in children. and the right lesion was once considered a nephroblastoma before biopsy. common hamartoma exhibited well-circumscribed, round or lobulated nodules 1-3cm in diameter with sharp margin, classical morphologic features such as “popcorn” or fat, a heterogeneous appearance, and identification of calcification within the nodule or fat allows for a confident diagnosis of hamartomas on ct images in lung and reflected the gross patterns ranging from a predominantly cystic mass to a complex solid mass in liver (4-7). and nephroblastoma had a characteristic inhomogeneity with a predominance of hypodense areas and increased inhomogeneity after contrast administration (8). by contrast, we can understand the similarities and differences between these two types of tumors in ct. therefore, based on the lack of related literature, we can use this case combined with related literatures as summary of renal hamartoma characteristics in ct: it is generally less than 3cm in size and ct showing a heterogeneous, hypodense appearance and a little irregular margin of solid mass which confined within the renal capsule, this tumor could be considered as a renal hamartoma or benign lesion. in our case, considering the growing tumor on the right side, and risk of rupture and malignant transformation (3), we decided to perform a right wedge excision simultaneously. due to the unconspicuous effect of preoperative chemotherapy，we added the adriamycin into postoperative chemotherapy. in addition, the boy had subcoronal hypospadias with mild curvature. we performed tubularized incised-plate (tip) urethroplasty and the function and cosmetic result was good. recently some modified techniques are good options for treatment of anterior hypospadias, like anterior urethral advancement technique (9) modified firlit’s technique (10) they have the characteristics of one-stage，easy to learn, good appearance and low complications, especially in properly selected case; moreover, ”two-stage procedure” has seen increased in popularity for patients of proximal hypospaidas and severe curvature, like vascularized preputial island flap technique has been successfully for management of this patients (11). in conclusion, we may have provided some experiences with this disease, and long-term follow-up with a sufficient number of cases may be needed to define optimal diagnosis and treatment options. references 1. huynh mt, boudry-labis e, duban b, et al. wagr syndrome and congenital hypothyroidism in a child with a mosaic 11p13 deletion. am j med genet a. 2017; 173:1690-1693. 2. elbracht m, prawitt d, nemetschek r, et al. beckwith-wiedemann syndrome (bws) current status of diagnosis and clinical management: summary of the first international consensus statement. klin padiatr 2018; 230:151-159. 3. neri g, martini-neri me, katz be, et al. the perlman syndrome: familial renal dysplasia with wilms tumor, fetal gigantism and multiple congenital anomalies. 1984. am j med genet a 2013; 161a: 2691-2696. 4. de cicco c, bellomi m, bartolomei m, et al. imaging of lung hamartomas by multidetector computed tomography and positron emission tomography. ann thorac surg. 2008;86:1769– 72. wilm’s tumor and hamartoma with ectogenital deformity-li et al. case report 322 vol 17 no 03 may-june 2020 112 5. yamashita k, matsunobe s, tsuda t, et al. solitary pulmonary nodule: preliminary study of evaluation with incremental dynamic ct. radiology. 1995;194:399-405. 6. hochhegger b, nin cs, alves gr, et al. multidetector computed tomography findings in pulmonary hamartomas: a new fat detection threshold. j thorac imaging 2016;31:11-4. 7. cetin m, demirpolat g, elmas n, et al. stromal predominant type mesenchymal hamartoma of liver: ct and mr features. comput med imaging graph . 2002;26:167-169. 8. rohrschneider wk, weirich a, rieden k, et al. us, ct and mr imaging characteristics of nephroblastomatosis. pediatr radiol. 1998;28:435-443. 9. gite va, nikose jv, bote sm, patil sr. anterior urethral advancement as a singlestage technique for repair of anterior hypospadias: our experience. urol j.2017 jul 2;14:4034-4037. 10. alizadeh f, shirani s. mild chordee t treated by modified firlit’s technique. urol j.2016 dec 8;13:2908-2910. 11. ozcan r, emre s, kendigelen p, et al. results of a two-stage technique for treatment of proximal hypospadias with severe curvature: creation of a urethral plate using a vascularized preputial island flap. urol j. 2016 apr 16;13:2629-2634. wilm’s tumor and hamartoma with ectogenital deformity-li et al. vol 17 no 03 may-june 2020 323 the use of transperineal sector biopsy as a first-line biopsy strategy: a multi-institutional analysis of clinical outcomes and complications david eldred-evans1,2*, veeru kasivisvanathan3,4, fahd khan1, mieke van hemelrijck1, alexander polson1, peter acher5, richard popert1 purpose: systematic transrectal ultrasound biopsies have been the first-line biopsy strategy in men with suspected prostate cancer for over 30 years. transperineal biopsy is an alternative approach but has been predominately reserved as a repeat biopsy strategy and not widely used as a first-line approach. this study evaluates the diagnostic and clinical outcomes of transperineal sector biopsy (tpsb) as a first-line biopsy strategy in the diagnosis and management of prostate cancer. materials and methods: a multi-institutional review of 402 consecutive patients who underwent primary transperineal sector biopsy. all patients had no prior history of prostate biopsy. tpsb was carried out as a day-case procedure under general or regional anaesthesia. the cancer detection rate, location and complications for all cases were evaluated. results: prostate cancer was identified in 249 patients (61.9%) and was comparably sited across anterior, middle and posterior sectors. the disease was clinically significant (gleason 3+4 or > 4mm maximum cancer length) in 187 patients (47%). post biopsy urinary retention occurred in 6 patients (1.5%). hematuria requiring overnight hospital admission occurred in 4 patients (1.0%). there were no cases of urosepsis. conclusions: as a primary diagnostic strategy, tpsb is a safe and effective technique with high cancer detection rates. it also offers an attractive compromise to more extensive transperineal protocols, which can be more time-consuming and associated with higher morbidity. keywords: biopsy; disease management; prostate cancer; transperineal; needle biopsy introduction systematic transrectal ultrasound biopsies have been the gold standard first-line biopsy strategy in men with suspected prostate cancer for over 30 years. the original sextant technique was described by hodge et al(1). and was extended to include 10 to 12 core biopsy schemes directed towards the lateral peripheral zones(2). these extended biopsy schemes improved cancer detection rates but a significant proportion of tumours are missed(3,4) and disease is mischaracterised(5,6). approximately a third of patients with low risk disease on transrectal biopsies are found to have intermediate or high risk disease on subsequent transperineal biopsy(7-9). this leads to diagnostic uncertainty and as a consequence risks both over and under treatment. there are further concerns regarding increasing rates of transrectal biopsy sepsis with the emergence of fluroquinolone resistant bowel flora(10,11). transperineal template biopsy developed as a more comprehensive biopsy to improve the sampling of the anterior and apical regions which are not easily biopsied transrectally, particularly in the larger gland(12). initially thought to be rare, these anterior tumours when large (pt3) increase the likelihood substantially of a positive surgical margin(13) and a recent study demonstrated anterior tumours accounted for 80% of cancer on saturation biopsy(14). drawbacks are associated with cost of equipment, general anesthesia and extended pathological processing. to offset these, benefits are a painless procedure, reduced risk of sepsis13 and improved pathological information, which would improve the stratification of disease and selection of patients for active surveillance or radical treatment options. previous studies on transperineal biopsy have focused on its use as a repeat biopsy strategy. there have been limited reports on its use as an initial primary diagnostic procedure. with the increasing use of pre-biopsy mri, targeted biopsies may become the norm(15). for the time being, however, it is necessary to systematically sample the normal appearing peripheral zone to avoid missing disease not visible on mri(16). this paper evaluates our transperineal sector biopsy (tpsb) approach in the primary biopsy setting between 2007 and 2013. the biopsies were a systematic sampling 1 department of urology, guy’s and st. thomas’ nhs foundation trust, london, uk. 2 mrc centre for transplantation, nihr biomedical research centre, king’s college london, guy’s hospital, uk. 3 division of surgery and interventional sciences, university college london, uk. 4 department of urology, university college london hospitals trust, london, uk. 5 department of urology, southend university hospital, essex, uk. *correspondence: the urology centre, guy's hospital, guy's and st thomas' nhs foundation trust, london, uk. se1 9rt e-mail : eldredevans@doctors.org.uk received april 2016 & accepted june 2016 urological oncology urological oncology 2849 vol 13 no 05 september-october 2016 2850 of the peripheral zone and were not directly informed by pre biopsy mri findings. we report the cancer detection rate, clinical outcomes and morbidity of tpsb in patients undergoing their first set of prostate biopsies. patients and methods databases at three institutions were interrogated for information on patients who underwent primary transperineal sector biopsy (tpsb) between january 2007 and august 2013. the inclusion criteria were all patients referred with an elevated age-adjusted psa and/ or abnormal dre. men who had a previous biopsy were excluded. all patients were provided with information on standard transrectal biopsy under local anaesthetic and tpsb under general anaesthetic. at two institutions, tpsb was offered as the optimal approach for patients fulfilling the criteria in table 1. in the third institution within the private sector, tpsb was as the first-line approach for the majority of patients. four hundred and one patients underwent the procedure as a day-case under regional or general anaesthesia. pre-operative administration of alpha-blockers or catheterisation was not carried out. at induction an intravenous aminoglycoside (usually gentamicin) was administered as prophylaxis. all patients were positioned in the extended dorsal lithotomy position and a rectal examination was done. the technical setup was similar to that for brachytherapy. a biplanar transrectal ultrasound probe machine attached to a stepping unit with a standard 5mm brachytherapy template grid was positioned over the perineum. volumetric ultrasonographic evaluation of the prostate was performed to determine prostate size by ellipsoid approximation. an 18-gauge biopsy needle with a 22mm sampling depth was directed through the brachytherapy template grid traversing the perineum to the apical prostate in the sagittal plane. real time transrectal ultrasonography aided differentiation of transition-peripheral zone interface to facilitate preferential sampling of the peripheral zone according to our standardised sector biopsy protocol(17). the procedure time is approximately 15 minutes per patient. patients were discharged after successful voiding, usually within four hours, and patients were discharged with 3 to 5 days of an oral fluoroquinolone (usually ciprocloxacin). all patients were reviewed 7 to 14 days post biopsy and any complications recorded. our tpsb protocol is standardised biopsy scheme in which the prostate is divided into sectors (figure 1). biopsies were taken from anterior, middle and posterior sectors with additional basal sectors in prostates larger than 30cc. the exact number of biopsies was determined by the volume of the prostate and ranged from a minimum of 24 to a maximum of 38 cores (figure 1). cores were placed into separate pots by sector distribution (i.e. one pot per sector). all cores were analysed by dedicated uro-pathologists. the primary outcome measures were the detection rate of any prostate cancer as well as detection rate of clinically significant cancer. clinically significant disease was defined as maximum cancer core length transperineal prostate biopsy–eldred-evans et al. table 1: criteria for primary tpsb immunocompromise inferring increased risk of sepsis e.g. diabetes, immunosuppressant drugs increased risk of fluoroqinolone resistant bowel flora e.g. recent treatment with fluoroquinolone antibiotics or travel to south-east asia. anterior/ apical anomaly on mri enlarged prostate (> 40cm3) patient preference for general anaesthetic characteristic all patients prostate cancer no prostate cancer p value no of patients (%) 402 249 (61.9) 153 (38.1) mean (sd, median) age at biopsy, years 61.1 (8.73, 61) 62.0 (8.6, 62) 59.0 (8.4, 60) 0.02a prebiopsy psa, ng/ml 12.8 (31.2, 6.9) 15.9 (29.0, 7.5) 7.7 (6.1, 6.3) <0.01a free/total psa ratio 15.3 (9.38, 14.0) 16.0 (0.1, 14.0) 14.0 (0.05, 12.0) 0.77b prostate volume, ml 47.0 (25.2, 40.0) 41.3 (19.2, 39.5) 56.4 (30.5, 50.0) <0.01a psa density, ng/ml/ml 0.27 (5.4, 0.15) 0.38 (6.4, 0.19) 0.14 (3.1, 0.12) <0.01a no. biopsy cores 28.6 (6.2, 29) 27.7 (6.2, 27.5) 29.9 (5.9, 31) 0.35b dre (%) 0.02c normal prostate 281 (70) 95 (38) 26 (83) abnormal finding 121 (30) 154 (62) 127 (17) astudent’s t-test, bmann-whitney u-test,c pearson’s chi-square test table 2: baseline patient characteristics, stratified by tpsb biopsy diagnosis figure 1. transperineal sector biopsy core number protocol (mccl) greater than 4mm and/or gleason score 3+4 or greater(18). secondary outcome measures included tumour location and adverse events. statistical analysis was performed using the statistical package for social sciences software (version 20.0; spss inc., chicago. il). the mann-whitney u-test, student’s t-test and pearson’s chi square test were used to compare continuous and categorical variables as appropriate. all p-values were two sided and statistical significance was set at p < .05. this study was approved by the local ethics and governance boards as a prospective audit. results prostate cancer was diagnosed in 249 patients giving a cancer detection rate of 61.9%. high grade pin was found in 31 patients (7.7%), and asap in 7 patients (1.7%). entirely benign pathology was found in 115 patients (29%). the baseline characteristics of the study population are summarised in table 2. the mean age at tpsb was 61.1 years and the median pre-biopsy psa was 6.9 ng/ml. a mean of 28.6 biopsy cores was obtained per patient. table 3 summarises the pathological features of the patients diagnosed with prostate cancer. clinically significant disease was identified in 75.1% of those with cancer (187/249). cancer was located in the anterior sectors in a similar frequency to the mid and posterior sectors. there were 43 patients (17.3%) where the cancer was located exclusively in the anterior sector and this was clinically significant in 27 (10.8%). the cancer detection rate stratified by psa level, prostate volume and age is shown in table 4. in the 209 patients with psa level 4-10.0 ng/ml, the cancer detection rate was 56%. in patients with psa >10.1 ng/ml, this increased to over 70%. low prostate volume, high psa density and increasing age were predictors of cancer detection. the free/total psa ratio was available for 130 patients and was not found to be predictive of prostate cancer in this series. there were few complications reported following tpsb (table 5). six patients (1.4%) developed acute urinary retention requiring short-term catheterisation. the mean prostate volume in these patients was 85.6 cc. all these patients were able to void following a successful trial without catheter. two were subsequently treated with holep. four patients (1.0%) required overnight hospitalisation for haematuria and were successfully managed by bladder irrigation. table 6 shows the management outcomes of the patients diagnosed with prostate cancer. prostatectomy specimens were available for 55 patients and all had cancer volumes greater than 0.5ml and/or gleason score 3+4 or above. there was exact concordance between gleason score at prostatectomy and the diagnostic tpsb in 47 patients (85.3%). there were no episodes of gleason downgrading following pathological examination of the specimen. 8 patients (14.6%) were upgraded from gleason 3+3 to 3+4. table 3: pathological features n (%) clinically significant cancer(18) significant 187 (75.1) insignificant 62 (24.9) gleason score 3 + 3 120 (48.2) 3 + 4 73 (29.3) 4 + 3 23 (9.2) ≥ 8 33 (13.3) positive cores 1 – 4 106 (42.6) 5 – 12 110 (44.2) > 12 33 (13.3) sector location anterior only 43 (17.3) mid only 13 (5.2) posterior only 26 (10.4) anterior & mid 27 (10.8) mid & posterior 22 (8.8) posterior & anterior 12 (4.8) anterior, mid & posterior 106 (42.6) variable prostate no prostate detection cancer cancer rate psa, ng/ml 0 – 4.0 36 30 55% 4.1 – 10.0 117 92 56% 10.1 – 20.0 58 25 70% 20.1 – 50.0 31 5 86% > 50.0 7 1 87% volume, ml 0 – 40 151 64 70% 40 – 60 65 39 63% > 60.0 33 50 40% age, year < 50 21 25 46% 50 – 60 86 62 58% 60 – 70 94 56 63% > 70 48 10 83% table 4: detection rates by age, psa & volume variable n (%) acute urinary retention 6 (1.5) haematuria requiring irrigation 4 (1.0) sepsis 0 (0) transfusion 0 (0) transperineal prostate biopsy–eldred-evans et al. table 5: complications after biopsy urological oncology 2851 vol 13 no 05 september-october 2016 2852 discussion we report the results of tpsb protocol developed at our institution in the primary biopsy setting. to our knowledge this is currently the largest reported primary transperineal biopsy series. the overall cancer detection rate was 61.9%. of those with cancer, clinically significant disease was identified in 75.1% and 17.3% had disease exclusively in the anterior sector. at present there is no standardised transperineal biopsy protocol and approaches have varied widely in the anatomical distributions sampled and number of biopsies obtained(19). table 7 summarises cancer detection rates across primary series using different approaches. transrectal biopsy has detection rates of approximately 40% to 44% in cohorts of men with similar risk to our study. the higher detection rate achieved by tpsb might be interpreted as a consequence of the higher number of cores taken. however, attempts to improve diagnostic yields of transrectal biopsy by increasing prostatic sampling density have not been successful in the primary biopsy setting(20). lane et al.(21) reported a cohort of 257 men who underwent transrectal saturation biopsy with a median of 24 cores and achieved a cancer detection rate of 43% comparable to the yield from non-saturation transrectal biopsies. the difference in detection rates is most likely due to better sampling of the peripheral zones, which are preferentially targeted by tpsb. there are two factors, firstly transperineal biopsies are taken along the length of the peripheral zone (pz) in the sagittal plane whereas transrectal biopsies tend to be fired across the pz towards the transition zone (apart from the most laterally directed cores, as in the presti protocol). as a consequence three areas are consistently undersampled by transrectal biopsies. the anterior apical to middle gland peripheral zone, the posterior basal region in the midline which corresponds to mcneal’s central zone surrounding the ejaculatory ducts and the midline apical region of the peripheral zone, which is avoided in transrectal biopsy because of the urethra and patient discomfort. transperineal midline biopsies pass below the urethra. in our cohort, 17% were identified as having isolated anterior tumours that may have been missed by transrectal biopsy. this is consistent with studies of prostatectomy specimens where anterior tumours are found to account for 21% of prostate cancers(22). transperineal template-guided mapping biopsy (ttmb), as reported by taira et al.(23), involves taking biopsies at a higher sampling density with the prostate sampled every 5 mm on a brachytherapy grid(24). using ttmb, a median of 55 cores were taken from 79 patients with a high cancer detection rate of 76% but associated with significant procedure-related morbidity. the rate of acute urinary retention rate was reported as 29% despite the routine use of alpha blockers prior and for two weeks post ttmb. this retention rate is consistent with other ttmb series(3,25) and probably reflects the additional trauma from multiple biopsy needles sampling the transition zone leading to intra-prostatic oedema. the key difference between our sector biopsy approach and other transperineal template guided approaches is that it preferentially targets the peripheral zones and avoids unnecessary sampling of the transition zone. the transition zone has a low incidence of isolated cantable 6: treatment decisions variable n (%) active surveillance 67 (26.9) dynamic prostate brachytherapy 53 (21.3) radical prostatectomy 67 (26.9) hormones and/or ebrt 62 (24.9) biopsy no. of patients psa (ng/ml) cores (median) detection rate transperineal template-guided current study 402 6.9a 29 62% furuno et al (28) 86 6.2b 18 49% taira et al (23) 79 4.8a 55 76% transperineal freehand hara et al (32) 126 8.3b 12 42% ficarra et al (35) 480 7.6b 14 44% kawakami et al (36) 289 10.7b 14 36% kojima et al (37) 541 5.3a 12 24% transrectal presti et al (2) 2229 6.1a 12 44% gore et al (38) 264 5.9a 12 42% presti et al (39) 483 10 42% eskew et al (40) 119 8.9b 13 40% lane et al(21) 257 5.5a 24 43% amedian, bmean table 7: primary biopsy literature review transperineal prostate biopsy–eldred-evans et al. cer as shown on both tp mapping biopsy studies(26) and on radical prostatectomy series where 83% of tumours were located predominately in the peripheral zone(27). other techniques distribute their cores evenly through the prostate without differentiating transition zone and peripheral zone. this may explain the higher detection rates of our series compared to furuno et al.(28) this tpsb protocol limits the maximum number of cores taken even in larger prostates. the preferential targeting of the peripheral zone results means it achieves comparable cancer detection rates with reduced morbidity to other ttmb series. our retention rate was 1.3% and alpha blockers were not routinely prescribed. given the high detection rates with minimal morbidity, tpsb may be a practical compromise to the drawbacks associated with more extensive biopsy schemes. mri-targeted biopsy may further improve detection rates(16) though this was not investigated in this series. however, if the mri does not identify a targetable lesion a systematic biopsy is still required and tpsb would provide a means of doing this. following the introduction of multi-parametric mri, our centre has reported that despite having no targetable lesion on mri, 36.6% of patients had intermediate risk prostate cancer with tpsb(29). even in the event of an mri lesion, there is significant debate whether systematic biopsy can be omitted and it has been argued that the remaining prostate should still be systematically biopsied to avoid missing significant disease(30). the randomised controlled trial frequently cited in national guidelines(31) to justify the use of transrectal biopsy as a primary biopsy strategy found no significant difference in detection rates between transrectal and transperineal biopsy(32). however, it was based on a freehand transperineal approach, which is a vastly different approach to the template-guided techniques described above. fewer cores are taken and no template is used to guide the biopsy needle through the relatively long transperineal needle path. this freehand needle placement increases the probability of inaccurate biopsy and several studies have shown it achieves cancer detection rate ranging from 24% to 44% (table 7). transrectal biopsy has the advantage of requiring fewer cores and can be performed in an outpatient setting. however, it is known to underestimate the presence of cancer and is estimated to miss approximately a third of clinically significant disease(7-9). bittner et al. reported a series of 485 patients with a previous negative transrectal biopsy. following transperineal biopsy, 40% were identified as having clinically significant prostate cancer(25). resources allocated to prostate cancer diagnostics have been built around delivering transrectal biopsy as the default technique. this paper provides some evidence that there are a number of advantages to be gained from transperineal biopsies in terms of safety and detection of significant disease. whilst there is a place for transrectal biopsy (e.g. the patient with obvious palpable abnormality who simply needs histological confirmation prior to treatment), it is likely that transperineal biopsy will become more popular in conjunction with mri, particularly in an era of increasing infection rates. tpsb may reduce the need for repeat biopsy and facilitate the confident discharge of those with negative biopsies. it allows accurate risk stratification of patients at low risk and suitable for active surveillance. in addition, in our tpsb cohort there were no instances of post-biopsy sepsis requiring hospitalisation. hospital admissions for transrectal biopsy complications have risen from 0.6% to 3.6% over the last decade(33). this reflects a higher rate of post-biopsy sepsis due to the growth of fluroquinolone resistant escherichia coli(11,34). in tpsb, biopsy needles pass through prepared skin rather than bowel reducing infection risk. however, our results may also be influenced by an extensive antibiotic prophylaxis protocol. these benefits need to be weighed against the costs of introducing tpsb as a primary biopsy strategy. tpsb is well tolerated as a day case but may not be feasible for some centres due to financial constraints and pressures on operative time. we acknowledge that there are resource implications due to the requirements of general anaesthesia, operative time and increased pathology analysis. further studies providing detail on cost effectiveness are required. a further limitation of this case series is that it is not possible to make a direct comparison with alternative biopsy techniques. conclusions tp sector biopsy is a safe technique, which offers a high cancer detection rate in the primary setting. as a primary biopsy technique it has advantages over transrectal biopsy in reducing sepsis and better characterisation of cancer thus allowing accurate treatment decisions to be made. it also offers an attractive compromise to more extensive transperineal protocols, which can be more time-consuming and associated with higher morbidity. acknowledgements the authors acknowledge financial support from the department of health via the national institute for health research (nihr) comprehensive biomedical research centre at guy's & st thomas' nhs foundation trust in partnership with king's college london and king's college hospital nhs foundation trust. the authors also acknowledge the support of the mrc centre for transplantation. the views expressed are those of the authors and not necessarily those of the nhs, the nihr or the department of health. conflicts of interest veeru kasivisvanathan is funded by a doctoral research fellowship from the national institute for health research. the views expressed in this publication are those of the author(s) and not necessarily those of the nhs, the national institute for health 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urol. 2005;48:932-7. 36. kawakami s, yamamoto s, numao n, ishikawa y, kihara k, fukui i. direct comparison between transrectal and transperineal extended prostate biopsy for the detection of cancer. int j urol. 2007;14:71924. 37. kojima m, hayakawa t, saito t, mitsuya h, hayase y. transperineal 12-core systematic biopsy in the detection of prostate cancer. int j urol. 2001;8:301-7. 38. gore jl, shariat sf, miles bj, et al. optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. j urol. 2001;165:1554-9. 39. presti jc, jr., chang jj, bhargava v, shinohara k. the optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. j urol. 2000;163:163-6; discussion 6-7. 40. eskew la, bare rl, mccullough dl. systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. j urol. 1997;157:199-202; discussion -3. transperineal prostate biopsy–eldred-evans et al. urological oncology 2855 urological oncology the association of mynn and terc gene polymorphisms and bladder cancer in a turkish population fikriye polat 1, meral yilmaz 2*, songul budak diler3 purpose: researchers reported that, mynn rs10936599 polymorphism is in strong or moderate linkage disequilibrium with snps within the 3q26.2 chromosomal regions that also include the terc gene. in addition, it has been reported that mynn rs10936599 had a strong cumulative association with bladder cancer risk, and terc gene suppresses cell growth in bladder cancer cell lines. therefore, we aimed to determine whether polymorphisms of mynn rs10936599 and terc rs2293607 play any roles for bladder cancer in the turkish population in this study. materials and methods: in this case-control study, 70 patients and 150 controls were investigated. genotyping analysis was performed by polymerase chain reaction, restriction fragment length polymorphism and dna sequencing techniques. results: genotype distribution between study groups for mynn rs10936599 snp was significantly different (p = .001); although there was no difference in genotype distribution for terc rs2293607 snp. in addition, patients with ct genotype and ct+tt genotype combination of mynn snp have a decreased risk for bladder cancer. two times increased risk ratio on development of bladder cancer was obtained for cc genotype of the snp (p = .001). besides, it was found that genotype combination of gg+ag/cc versus aa/cc genotypes (terc/mynn) showed stronger correlation. we observed that statistically significant relationship between the c-g haplotypes of two polymorphisms and bladder cancer risk (p = .0001). conclusion: at the end of the study, we suggested that there may exist an association between a combination of mynn rs10936599 and terc rs2293607 polymorphisms and development of bladder cancer in turkish population. keywords: bladder cancer; mynn gene; polymorphism; terc gen introduction bladder cancer (bc) is a major problem and, 11th most common cancer in the world(1). bc is higher in men than women, and its incidence increases with age for both gender, peaking at the seventh decade(2). genetic and potential environmental factors play role in the etiology of the disease and, familial cancer history increasing risk of bc. in addition, there is important heterogeneity in terms of its clinical and genetic backgrounds of urothelial carcinomas and, the heterogeneity partly originates from different changes in different genes that affect various mechanisms associated with cell proliferation and cancer(3, 4). a genome-wide association studies (gwas) have informed that new locus on chromosome (chr) 3q may be correlated with bc risk. in addition, it has been reported that the locus on chromosome 3q is included in mynn gene and terc gene and, these genes are strong candidates for the association with bladder cancer(4). myoneurin (mynn) gene locates on 3q26.2 and encodes a member of the btb/poz and zinc finger (zf) domain-containing protein family that is involved in 1department of mathematics and science education, faculty of education, kocaeli university, kocaeli 41380, turkey. 2department of research centre, faculty of medicine, cumhuriyet university, sivas 58140, turkey. 3department of biotechnology, faculty of science and letters, nigde ömer halisdemir university, nigde 51240, turkey. *correspondence: department of research centre, faculty of medicine, cumhuriyet university, 58140-sivas, turkey. phone: +90 346 2191156, fax: +90 346 2191155, e-mail: meralylmz@cumhuriyet.edu.tr. received august 2017 & accepted may 2018 the control of gene expression(5). certain polymorphic regions were discovered on the mynn gene. the rs10936599 polymorphism is one of these regions. the function of rs10936599 polymorphism on the mynn gene is not known. some research concludes that this synonymous variation is associated with both longer telomeres and the colorectal cancer or patients with adenomas(6-8). additionally, it has been suggested that the mynn polymorphism may be associated with ovary and bladder cancers(5,9). furthermore, the variation which is close to telomerase rna component (terc) gene participates at least partly in tumorigenesis at early stages(7,10). telomerase is a specialized ribonucleoprotein polymerase that adds ttaggg repeats to telomere ends in soma human cells, including stem cells. the holoenzyme consists of a protein component with reverse transcriptase (tert) activity, and a rna component (terc). the tert utilizes the terc as a template to add repeats to the existing telomeres (7, 11). the terc is a 451 base pairs (bp) long gene, located on chromosome 3q26.2. terc is a template for telomeric dna urological oncology 50 vol 16 no 01 january-february 2019 51 synthesis. besides, it has the same important roles including catalysis, accumulation, localization and holoenzyme assembly (12). telomerase is up-regulated in the majority of human cancers. the increased telomerase activity is thought to be required to allow tumor cells to divide after genetic rearrangements enabled by telomere dysfunction(13). consistent the data, soder et al. (1997) reported that the level of terc expression increases with tumor progression. it has been known that gene polymorphisms may cause significant changes in enzyme activity(14). according to remarkable data in the study of figueroa and co-workers (2014), it has been reported that the rs10936599 snp is in complete linkage disequilibrium with snp rs2293607. terc has been appeared to affect telomere length and mrna folding in several functional studies. based on the literature, no study has investigated the association of terc rs2293607 polymorphism and bc risk. until now, there has been no study investigating the effects of mynn rs10936599 and terc rs2293607 polymorphisms on bc risk. therefore, we aimed to determine whether mynn gene rs10936599 and terc rs2293607 polymorphisms that were closely located on 3q26.2 play any roles in the bladder cancer in a turkish population. materials and methods study population: the patients and controls were selected among the ones from urology clinic of luleburgaz and niğde state hospital, turkey. we investigated the mynn rs10936599 and terc rs2293607 snps (single nucleotide polymorphisms) in 70 bladder cancer patients and 150 healthy controls. protocol of the present study was reviewed and approved by the institutional review board of the local human ethics committee (decision number: kaek 2014/144). informed consent was submitted by all subjects when they were enrolled. inclusion and exclusion criteria: patient group was generated with individuals who have been diagnosed bladder cancer by histopathological examination. bladder cancer type of all patients is transitional cell carcinoma. patients, who have received any chemotherapy or radiotherapy, were not accepted in the study. the control group matched with age and gender distributions of patients was selected from healthy volunteers without bladder cancer history. dna isolation and genotyping: genomic dna was extracted from the whole blood treated with edta using the qiaamp dna blood mini kit (maryland, usa), according to the manufacturer’s guidelines. pcr amplifications of both the polymorphic regions in mynn and terc genes were using specific primer sets (for mynn rs10936599 polymorphism f:5’tcaagggtaaaattccattctg-3’ and r:5’tcacagagaaaacctgcttcc-3’; for terc rs2293607 polymorphism f:5’-agttcgctttcctgttgg-3’ and r:5’attcattttggccgactt-3’). the pcr was performed in a final reaction volume of 20 µl containing 10 ng of genomic dna, 10 pmol of each primer, 5x firepol master mix (solis biodyne). pcr reaction was made on these conditions: after initial denaturation at 95°c for 5 minutes, then followed by 38 cycles including of denaturation at 95°c for 40 seconds for denaturation, 58°c in the rs10936599 polymorphism, 59°c in the rs2293607 polymorphism for 30 seconds for annealing, and 72°c for 30 seconds for extension. the reaction was completed by a final extension of 5 min at 72°c. evaluations: snp rs10936599 is a point mutation occurring with c → t substitution at nucleotide 18 in mynn gene and, this mutation causes coding of a synonymous variant (his6his). snp rs2293607 is a point mutation occurring with a → g substitution at nucleotide 514 in terc gene (15). pcr products of mynn and terc polymorphic regions were digested with hpych4iii at 37°c for over-night and bsrdi at 65°c for 30 min, respectively. pcr products were separated by electrophoresis on 2% agarose gels, and visualized under ultraviolet (uv) illumination after nucleic acid staining solution (eco safe). the pcr product size for mynn rs10936599 snp was 104 base pair (bp) and the wild-type allele (c) contains two fragments of 58 and 46 bp. the polymorphic variant (t) was seen a fragment of 104 bp. pcr product size for terc rs2293607 snp, was 159 bp. after enzymatic digestion of these products, the fragment sizes were 94 bp and 65 bp for the wild type (a). a fragment of 159 bp was seen for the variant allele (g). statistical analysis: the genotype and allele frequencies of two snps were tested for hardy-weinberg equilibrium using a chi-square (χ2) test. deviations from hardy-weinberg equilibrium (hwe) were analyzed by using michael h. court’s (2005-2008) online calculator. on the result of power analysis which was performed for detecting an association between bc and the studied polymorphisms, sample sizes were found to table 1. demographic characteristics of bladder cancer patients and controls parameters patients controls p value or (95% ci) n = 70 (%) n = 150 (%) aage year ± sd 61.95 ± 10.63 59.41 ± 12.92 .15 (age range) (25-81) (22-94) bsex .09 male 61 (87.1) 118 (78.7) female 9 (12.9) 32 (21.3) bsmoking status .002* 2.55 (1.42-4.58) smoker 36 (51.4) 44 (29.3) non-smoker 34 (48.6) 106 (70.7) abbreviation: ±sd, standard derivation; *p < .05; significantly different from control group; acontinuous variables were compared by independent samples t-test; bcategorical variables including sex and smoking status were compared by chi square test. mynn and terc gene polymorphisms in bladder cancer-polat et al. be sufficient for case and control groups consisting of 70 and 150 individuals (α: 0.05, β: 0.20 and test power; 0.80). statistically analysis of demographic feature was performed via student’s t-test and chi-square tests by using spss version 18. the frequencies of genotype and allele for these two snps in patients and controls were compared using cochrans’s and mantel-haenszel statistics test. for each polymorphism, unconditional logistic regression was used to calculate adjusted (with smoking habit and gender) odds ratios (or) in 95% confidence intervals (95% ci) for bc. p < .05 value was considered as statistically significant. eh program was used for analysis of haplotype frequencies. results the demographic characteristics of patients and controls were demonstrated on table 1. when frequencies of mean age and gender were compared in both groups, the control group was found to be compatible with patients (for mean age p = .051, for gender p = .09). smoker count in patient group (51.4%) compared with those in controls was found significantly higher (p = .002). frequencies of genotype and allele for two polymorphisms in patient and control groups were shown in table 2. genotype distribution of mynn rs10936599 snp among both groups was different and, the value was statistically significant (p = .001). in addition, patients with ct genotype and ct+tt genotype combination versus cc genotype and t allele versus c allele of the mynn polymorphism compared those with controls have a decreased odds ratio for bc. similar odds ratio was also obtained when the heterozygous genotype together with other risk factors such as gender and smoking habit were evaluated. all these data are illustrated in table 2. interestingly, the frequency of cc genotype (wild type for rs10936599) in patients was higher than one in controls. when cc genotype was compared to other genotypes of the mynn polymorphism among case-control groups, approximately 2 times increased odds ratio between bc development and this genotype was found [p = .001, or = 2.64 (1.46-4.77)]. frequencies of genotypes (aa, ag, gg) and alleles (a and g) for terc rs2293607 polymorphism were observed as 38.6, 55.7, 5.7% and 66.4, 33.6% in patients, respectively and 45.3, 51.3, 3.3% and 71, 29% in controls, respectively. for the terc snp, we detected that gg genotype versus aa genotype resulted in odds ratio of two fold, but the ratio was not statistically significant (p = .44). in addition, gene-gene interaction and haplotype analysis among cases and controls were made in the study. it was observed in gene-gene interaction analysis that genotype combination of gg+ag/cc (terc gene/ mynn gene) versus wild type genotypes of two polymorphisms (aa/cc) revealed stronger correlation (table 3). besides, four possible haplotypes of mynn (rs10936599) and terc (rs2293607) snps were identified in our study. c-a haplotype was accepted as a reference haplotype because it was more common in two groups. for the two variants, a linkage was found in both patients and controls (χ2 = 24.09, p = .0001 for patients; χ2 = 178.77, p = .0001 for controls). we obtained statistically significant relationship between patients and controls for the c-g haplotypes (p = .0001) (table 3). there is no data about histological types and stage of patients with bladder cancer, so these parameters were not evaluated in the study. discussion mynn rs10936599 and terc rs2293607 snps in 70 bladder cancer patients and 150 healthy controls were analyzed in this current study. in our study, genotype distributions in controls for two polymorphisms were not compatible with the principle of hwe. the cause of the drift from hwe is selection from hospital-based individuals of control group in this study. in addition, we evaluated as reference allele, so c allele for the mynn gene polymorphism is wild type in the current study. table 2. the genotypes and allele frequencies of mynn (rs10936599) c/t and terc (rs2293607) a/g genes snps in bladder cancer patients and control individuals in turkish population dcrude values eadjusted values gene patients controls p or p or cgenotypes n = 70 (%) n = 150(%) value ci (95%) value ci (95%) mynn (rs10936599) cc 46 (66) 63 (42) 1 ct 19 (27) 78 (52) .001* 0.33 (0.17-0.62) .15 2.45 (0.71-8.41) tt 5 (7) 9 (6) .77 0.76 (0.23-2.42) .78 0.84 (0.25-2.77) ct+tt 24 (34) 87 (58) .001* 0.37 (0.20-0.68) .003* 2.53 (1.38-4.63) alleles c 111 (79) 204 (68) 1 t 29 (21) 96 (32) .01* 0.55 (0.34-0.89) terc (rs2293607) aa 27 (39) 68 (45) 1 ag 39 (55) 77 (51) .45 1.27 (0.70-2.29) gg 4 (6) 5 (4) .44 2.01 (0.50-8.07) .27 0.71 (0.38-1.30) ag+gg 43 (60) 82 (55) .38 1.32 (0.74-2.35) .35 0.50 (0.12-2.11) alleles a 93 (66) 213 (71) 1 g 47 (34) 87 (29) .37 1.23 (0.80-1.90) cdistributions of genotypes in groups were compared by chi square test; dcrude values of odds ratios were calculated by fisher exact test; eindependent variables were compared by logistic regression. adjusted with smoking habit and gender adjusted values of odds ratios were calculated by using the statistic method. *p < .05 indicates statistically significant. mynn and terc gene polymorphisms in bladder cancer-polat et al. urological oncology 52 vol 16 no 01 january-february 2019 53 however, for rs10936599 snp, more of the individuals with c allele were obtained in patients compared to controls in our study. therefore, all genotypes without pointing out a reference allele were analyzed again. we obtained significant odds ratio for cc genotype for bladder cancer among patients (these data were not shown on table). we suggest that t allele may have a protective effect in spite of c allele for bladder cancer. as consisted with our data, in a genome wide association studies (gwas), wang et al., (2014) reported that c allele of mynn rs10936599 polymorphism may entail a risk for bladder cancer and the snp together with other polymorphic side may be used, collectively, to effectively measure inherited risk for bladder cancer (16). besides, it has been reported that t allele for rs10936599 polymorphism at 3q26.2 shows a protective effect on bladder cancer in another gwas by figueroa et al., (2013) (oradj per t allele = 0.85, 95% ci 0.81-0.90 and p = 4.53x10-9)(4). when the effect of the polymorphism in other cancer species has been investigated, similar results were detected. carvajal-carmona et al. (2013) examined some snps in colorectal cancers. they found that rs10936599 snp of the mynn gene was associated with adenoma risk(8). at the same time, in a gwas studies conducted by huolston et al., (2010), lubbe et al., (2012), and real et al., (2014), rs10936599 polymorphism was found risky in colorectal cancers(9,17,18). furthermore, speedy et al., (2014) identified new susceptibility loci mapping to 3q26.2 (rs10936599) for chronic lymphocytic leukemia (cll) in a genome-wide association study(19). it has been reported in some studies by houlston et al., (2010), lubbe et al., (2012), and kantor et al., (2014) that, c allele for rs10936599 snp was major and risk allele in colorectal cancer(9,17, 20). furthermore, as similar to our finding, t allele was shown as effective allele when the association of rs10936599 snp and telomere length for coronary heart disease (chd) was investigated in han chinese population(21). in addition, it has been found that the t allele may have a protective effect in the study or = .907 (0.825–0.995). telomere length was not analyzed in current study but we thought that bladder cancer risk of the polymorphism may be affected by alteration of telomere length. however, broberg et al., (2005) reported that telomere length was significantly shorter in buccal cells from patients with bladder cancer than in control subjects. telomere shortening increases the cancer risk rather than preventing it. it has been identified as the reason of the discrepancy in the study that short telomeres may increase the risk of developing cancer, particularly epithelial cancers via non-reciprocal translocations(22). the reason of this discrepancy may be the effects of other genes and risk factors. wang et al., 2014 found that seven significant variants including mynn rs10936599 had a strong cumulative association with bladder cancer risk. these loci showed the potential to predict the risk of bladder cancer in combination with the smoking risk factor in the chinese population(16). in another study, it has been reported that this susceptibility locus rs10936599 at 3q26.2 is in linkage disequilibrium with snps in terc. in addition, it has been suggested that terc gene suppresses cell growth in bladder cancer cell lines(23). on the other hand, it has been indicated that rs10936599 could change the regulatory elements of mynn or nearby genes to discuss the bladder cancer risk(16). moreover, with regard to the results from a study by jones et al. on mynn and terc, rs10936599 alleles were associated with both longer telomeres and colorectal cancer risk. they reported that this variation close to terc probably acts at an early stage in tumorigenesis. terc rs2293607 is estimated by rna fold to change the transcript’s secondary mrna structure. furthermore, jones et al. stated that data from the encode project had indicated h3k4me1 and h3k4me3 histones in the immediate vicinity of rs2293607. additionally, the same region is considerably sensitive to dnasei and estimated binding site of multiple transcription factors as like nfkb, pu.1, pou3f2 and myc(7). figueroa et al. (2014) found significantly higher terc mrna expression in muscle-invasive bladder tumors than adjacent normal bladder tissues(4). according to their report, terc gene may have functional relevance for predisposition to bladder cancer but the possible functional effect of the mynn gene in the associated ld block cannot be excluded as a molecular cause of this association. from some gwas studies, some researchers found that rs10936599 snp is in strong or moderate ld with snp within the region 3q26.2 that includes the terc gene(10). in our study, we also investigated whether there is an association between terc rs2293607 (a/g) polymorphism and bladder cancer risk. no significant association was found for the polytable 3. analysis of genegene interaction and haplotype for mynn (rs10936599) and terc(rs2293607) polymorphisms gene patients controls p or genotypes n (%) n (%) value ci (95%) mynn gene (rs10936599)/terc gene (rs2293607) cc-aa 24 (52.2) 62 (98,4) 1 ct/aa 3 (15.8) 6 (7.7) .71 1.29 (0.29-5.58) ct/ag 16 (84.2) 72 (92.3) .15 0.57 (0.28-1.17) tt/ag 1 (20) 4 (44.4) 1 0.64 (0.06-6.07) tt/gg 4 (80) 5 (55.6) .44 2.06 (0.51-8.35) ct+tt/aa 3 (11.1) 6 (8.8) .71 1.29 (0.29-5.58) gg+ag/cc 22 (47.8) 1 (1.6) .0001* 56.8 (7.25-445.3) ct+tt/gg+ag 21 (46.7) 81 (56.6) .30 0.67 (0.34-1.31) mynn gene (c/t)/terc gene (a/g) haplotypes c a 45 100 1 c g 11 20 .0001* 12.22 (2.60-57.42) t a 2 6 1 0.74 (0.14-3.81) t g 12 42 .29 0.63 (0.30-1.32) *p < .05 indicates statistically significant. mynn and terc gene polymorphisms in bladder cancer-polat et al. morphism. we did not find any data related to the terc polymorphisms and bladder cancer risk in literature. so, our findings associated with terc (rs2293607) snp were not compared. when the data related to localization of mynn rs10936599 which is close to terc genes(7) was considered, together with these mynn and terc snps were analyzed for bladder cancer risk in the present study. after gene-gene interaction analysis, a stronger correlation was obtained between gg+ag genotype combination for terc (rs2293607) and cc genotype for mynn (rs10936599) polymorphisms. it has been predicted that gg+ag combination of the terc gene may cause telomere shortening. the remarkable finding was found consistent with those from broberg et al. (2005)(22). in addition, it has been shown in our study that c and g haplotypes (for mynn and terc snps, respectively) had odds ratio value of approximately 12 fold in development of bladder cancer. conclusions we think that mynn and terc genes together may be associated with development of bladder cancer in the current study. in addition, establishing larger numbers of study groups, increasing the number of snps in the studied genes, and measuring the telomere lengths and evaluating them together will conclude more effective results. acknowledgement the authors confirm that all data underlying the findings are fully available without restriction. all relevant data are contained within the paper. the laboratory facilities of medicine faculty both kocaeli and sivas were used. a part of the manuscript has been presented in 5th international molecular biology and biotechnology congress in tetova, macedonia (orally-) at 25-29 august 2016. we would like to thank to scientific research project unit of kocaeli university (project no: 2014045) conflict of interest statement all authors have no potential conflicts of interest to disclose. references 1. altunkol a, savaş m, dilmeç f, utanğaç mm, abat d, gümüş k, karlıdağ i, and yeni e.detection of cyp1a1 and gstp1 gene polymorphisms in bladder cancer patients in a turkish population using a polymerase chain reaction-restriction fragment length polymorphism method. turk j urol. 2018 mar; 44: 125–31. 2. tiryakioglu no, tunali ne. association of akr1c3 polymorphisms with bladder cancer. urol j. 2016 16;13:2615-21. 3. ousati ashtiani z, mehrsai ar, pourmand mr, pourmand gr. high resolution melting analysis for rapid detection of pik3ca gene mutations in bladder cancer: a mutated target for cancer therapy. urol j. 2018 23;15:26-31. mynn and terc gene polymorphisms in bladder cancer-polat et al. 4. figueroa jd, ye y, siddiq a, et al. genomewide association study identifies multiple loci associated with bladder cancer risk. hum 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cancer. 2014;135:2653–60. 17. lubbe sj, whiffin n, chandler i, broderick p, houlston rs. relationship between 16 susceptibility loci and colorectal cancer phenotype in 3146 patients. carcinogenesis. 2012;33:108–112. urological oncology 54 vol 16 no 01 january-february 2019 55 18. real lm, ruiz a, gayán j, et al. a colorectal cancer susceptibility new variant at 4q26 in the spanish population identified by genomewide association analysis. plos one. 2014;9:e101178. 19. speedy he, di bernardo mc, sava gp, .et al. a genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. nature genetics. 2014;46:56-60. 20. kantor ed, hutter cm, minnier j, et al. gene– environment interaction involving recently identified colorectal cancer susceptibility loci. cancer epidemiology biomarkers prev. 2014;23:1824–33. 21. ding h, yan f, zhou ll, et al. association between previously identified loci affecting telomere length and coronary heart disease (chd) in han chinese population. clinical interventions in aging. 2014;9:857–61. 22. broberg k, björk j, paulsson k, höglund m, albin m. constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. carcinogenesis. 2005;26:126371. 23. blasco ma. telomere length, stem cells and aging. nat chem biol. 2007;3:640–9. mynn and terc gene polymorphisms in bladder cancer-polat et al. miscellaneous concurrent repair of inguinal hernias with mesh application during transperitoneal robotic-assisted radical prostatectomy: is it safe? ali fuat atmaca1#, nurullah hamidi2*#, abdullah erdem canda3, murat keske2, arslan ardicoglu1 purpose: to assessment the safety of concurrent repair of inguinal hernia (ih) with mesh application during transperitoneal robotic-assisted radical prostatectomy(rarp). materials and methods: data of 20 patients (totally 25 procedures) who performed concurrent ih repair with mesh application during rarp were retrospectively enrolled in this study. preoperative patient characteristics, intra and postoperative parameters (pathological gleason grade, prostate volume at surgical specimen, operative time, herniorrhaphy time, estimated blood loss, complications, time of hospitalization, catheterization, and drainage) were evaluated. standard psa control and postoperative complications of mesh application such as hernia recurrence, mesh infection, seroma formation and groin pain were evaluated at every follow-up visits (every three in the first year, then every 6 months in years 2 to 5 and annually thereafter. result: the mean age was 66 ± 8 years in our population. fifteen (60 %) patients had a unilateral hernia and 5 (40 %) patients had bilateral hernias. the mean operative time was 139 ± 21minutes and estimated mean blood loss was 108 ± 76 ml. the mean duration of ih repair in patients which was 27 ± 5 (range: 1740) minutes. the mean time of drainage, hospitalization, and catheterization were 2.5 ± 0.8 days (range: 2-6), 4 ± 0.9 days (range: 2-7) and 8.2 ± 1.9 days (range: 7-14), respectively. we did not observe any intra-operative complication due to rarp or ih repair. wound evisceration at camera port site developed in only a patient on postoperative day 20. our median follow-up time was 13 months and we did not observe mesh infection or hernia recurrence during follow-up. conclusion: concurrent ih repair with rarp procedure seem to be easy to perform, effective and safe procedure. keywords: robotic surgery; inguinal hernia; mesh application; radical prostatectomy introduction prostate cancer (pca) and inguinal hernia (ih) are usually diagnosed at advanced age and these diseases can be detected concomitantly. inguinal hernia is detected approximately in one-third of the patients undergoing radical prostatectomy (rp) with preoperative imaging studies or incidentally.(1,2) the incidence rate of asymptomatic ih approached up to 33 %.(2) on the other hand, ih is considered a manifest of rp by many authors and the incidence of ihs is higher in men undergoing rp when compared with non-operated men.(3-4) concurrent ih repair at the time of prostatectomy was first described by mcdonald and huggins in 1949. (5) they performed concurrent ih repair during open prostatectomy through two incisions. then, several studies reported the safety and feasibility of concurrent ih repair with laparoscopic radical prostatectomy.(2,6) nowadays, concurrent ih repair is increasingly being performed safely with robotic-assisted radical prostatectomy (rarp).(7-10) the main rationale of concurrent ih repair is that subsequent ih repair might be more difficult and there might be potential complications such as vascular or 1department of urology, ankara yildirim beyazit university faculty of medicine, ankara atatürk training and research hospital, cankaya, ankara 06430, turkey. 2department of urology, ankara atatürk training and research hospital, cankaya, ankara 06430, turkey. 3department of urology, koc university school of medicine, maltepe, istanbul 34010, turkey *correpondence: department of urology, ankara atatürk training and research hospital, cankaya, ankara 06430, turkey. tel: +90 553 205 0307, fax: +90 312 508 2147, e-mail: dr.nhamidi86@gmail.com. # these authors contributed equally to this work received september 2017 & accepted february 2018 bladder injury because of adhesions in surgical area following previous rp surgery. moreover, concurrent ih repair at the time of rp has also advantage on surgery time. repair at the time of minimal invasive rp adds an additional 10 to 30 minutes of operative time whereas subsequent ih repair, either laparoscopic or open, may take 45 to 111 minutes.(7-11) however, there are some concerns in terms of concurrent ih repair due to risk of mesh infection, postoperative groin pain and postoperative adhesions of intraperitoneal structures.(12) another, controversial concern is the risk of bowel adhesions when prosthetic mesh is used during ih repair. to reduce these risks, surgeons recommend reperitonealization after mesh stabilization and/or using coated mesh which is resistant to adhesion formation.(7,12) the theoretical risk of infection arises from the possibility that the mesh may contact with urine in the presence of a vesico-urethral anastomotic leakage. contrary, recent previous studies have showed that concomitant ih repair with mesh during rp is safe and there were no instances of mesh infection or groin pain reported.(7-10) there are mainly two tension-free minimal invasive ih repair techniques: totally extraperitoneal (tep) and transabdominal preperitoneal (tapp). otherwise, hermiscellaneous 381 vol 15 no 06 november-december 2018 382 nias can be repaired with suture alone. concurrent ih repair during rarp is novel technique and it is increasingly being performed for recent years. our department is one of the referral robotic surgery center in our country and herein, we aimed to present our initial experiences with concurrent ih repair during rarp with tapp technique. materials and methods this retrospective study was approved by the institutional review board (irb decision no: 76, decision date: 14/04/2017). patients were informed and written informed consent was obtained from all patients. study population, inclusion and exclusion criteria: we retrospectively evaluated the data of 414 consecutive rarps between june 2015-may 2017. we included the patients who underwent ih repair with mesh during rarp to this study. we excluded the patients who have previous ih repair surgery history, bleeding diastasis and untreated urinary tract infection. a total of 25 concurrent herniorrhaphies were performed in 20 patients. nine (45 %) patients had incidentally detected ihs during rarp whereas 11 (55 %) patients had ihs detected before rarp during physitable 1. demographic and pathological data of all patients. parameter 25 procedures in 20 patients age, year; mean ± std (range) 66 ± 8 (49-79) psa, ng/ml; mean ± sd (range) 8.2 ± 3.2 (3.9-17.2) prostate volume, ml; mean ± sd (range) 64 ± 17 (20-140) pathological gleason grade, number of patients (%) 3+3 9 (45) 3+4 7 (35) 4+3 3 (15) 4+4 1 (5) hernia laterality unilateral (left/right) 15 (9/6) bilateral 5 hernia type, number of procedure (%) direct 15 (60) indirect 10 (40) mesh types, number of procedures (%) ventralighttm st mesh 10 (40) seprameshtm ip mesh 13 (52) 3dmaxtm (polypropylene) mesh 2 (8) total operative time, min; mean ± sd (range) 139 ± 21 (100-195) estimated blood loss, ml; mean ± sd (range) 108 ± 76 (10-300) drainage time, day; mean ± sd (range) 2.5 ± 0.8 (2-6) hospitalization time, day; mean ± sd (range) 4 ± 0.9 (2-7) catheterization time, day; mean ± sd (range) 8.2 ± 1.9 (7-14) abbreviations: psa, prostate specific antigen figure 1. bilateral direct inguinal hernia repair during robotic-assisted radical prostatectomy. before applying the mesh over the hernia defect, the hernia sac is dissected (a). the hernia wall is retracted and it is fixed to the pubic bone (b). a proper size of the mesh was chosen according to the defect size (c). a laparoscopic tacker was used an applied to fix the mesh material around the hernia defect (d). hernia repair during robotic prostatectomy-atmaca et al. cal examination. all patients had sterile urinalysis and urine culture. preoperative patient characteristics (age, body mass index) prostate specific antigen(psa), intra and postoperative parameters (pathological gleason grade, prostate volume at rp specimen, operative time, estimated blood loss, complications, lymph node dissection, time of hospitalization, catheterization and drainage) were entered into prospective database. inguinal hernia repairing technique: we have started ih repair with mesh application since (june 2015) after our two robotic urologic surgeons (afa and aec) attending a hands-on training course organized by general surgeons who are experienced on laparoscopic ih repair. all rarp procedures were performed by two experienced surgeons (afa, aec) by applying the surgical technique as previously described in the literature. (13) all hernias were repaired robotically after completing pelvic lymph node dissection when indicated, and ensuring a watertight vesico-urethral anastomosis and good hemostasis. before applying the mesh over the hernia defect, the hernia sac was dissected and fixed to the pubic bone (fig 1a and fig 1b). ventralighttm st (bard, davol inc., warwick, ri, uk), seprameshtm ip (bard, davol inc., warwick, ri, uk), and 3dmaxtm (bard, davol inc., warwick, ri, uk) meshes were used for 10, 13 and 2 procedures, respectively. before opening sterile mesh, the bedside assistant and nurse change gloves in order to decrease the risk of contamination. a proper size of the mesh was chosen according to the defect size (fig 1c). a laparoscopic tacker was used an applied to fix the mesh material around the hernia defect (abdominal wall and upper side of the pubic bone) (figure 1d). addition to tacker, we fixed the mesh with table 2. previous articles in literature on concurrent inguinal hernia repair during robotic assisted radical prostatectomy author year number of herniorrhaphy mesh type reperitonealization total hernior follow-up mesh mean hernia complication patient technique rhaphy duration infection estimated recurrence (number of duration rate blood loss rate total procedure) finley et al.7 2008 80 (104) modified marlex, in initial 15 min mean none %1.3 none stoppa polypropylene, cases (36/80) 12 months technique ultrapro, proceed coated, 3d-max, combination of both umbrella and xat mesh, suture alone joshi et al.8 2010 4 (6) tapp polypropylene yes 24 min median none none mesh, 33 months polyester mesh, parietex mesh do et al.9 2011 93 (109) tep primalene no none 240 ml none lymphocele mesh (required drainage) in three patients qazi et al.17 2015 2 tep primalene no 12 min mean none 250ml none none mesh 12 months ludwig 2016 11 (11) tep max, no 30 min mean 33 none 210 ml none seroma in a et al.10 parietex months patient, anatomic lymphocele mesh, (required multifilament drainage) polyester mesh in a patient mourmouris 2016 29/37 darning suture alone 6 min mean 32 175ml none none et al.16 suture months technique our series 20/25 tapp ventralight only in 27 min median none 108 ml none wound mesh, one patient 13 months evisceration sepramesh which at in a patient mesh and polypropylene 3dmax mesh (polypropylene) applicated mesh hernia repair during robotic prostatectomy-atmaca et al. miscellaneous 383 vol 15 no 06 november-december 2018 384 running absorbable sutures. after the procedure drain was inserted. reperitonealization was performed only in one patient (bilateral procedure) which was 3dmaxtm mesh (polypropylene) applicated. all mesh application procedures were performed by two same experienced surgeons (afa, aec). postoperative cystogram was performed on postoperative day 7 in all patients who underwent rarp. if no extravasation is observed, the catheter is removed. evaluations: standard psa control and postoperative complications of mesh application such as hernia recurrence, mesh infection, seroma formation and groin pain were evaluated at every follow-up visits (every 3 months in the first year, then every 6 months in years 2 to 5 and annually thereafter. hernia recurrence was evaluated according to surgeon physical examination. presence of symptoms including fever, hyperemia, swelling and pain on the groin localization considered as mesh infection. the presence of groin pain was evaluated according to patient’s statement. results in 20 patients, totally 25 concurrent ih repair procedures were performed at the time of rarp. the mean age and mean psa value of the patients were 66 ± 8 years (range: 49-79 years) and 8.2 ± 3.2 ng/ml (range: 3.9-17.2), respectively. fifteen (60 %) patients had unilateral hernia and 5 (40 %) patients had bilateral hernias. four (20 %) patients had previous abdominal surgery (appendectomy in 3 patients, laparoscopic cholecystectomy in 1 patients) history. the mean total operative time was 139 ± 21 minutes (range: 100-195 minutes) and estimated mean blood loss was 108 ± 76ml (range: 10-300). perioperative blood transfusion was never deemed necessary. the mean duration of ih repair in patients which was 27 ± 5 (range: 1740) min. no conversion to open surgery was necessary. eleven (55 %) patients underwent bilateral extended pelvic lymph node dissection during rarp. the mean time of drainage, hospitalization and catheterization were 2.5 ± 0.8 days (range: 2-6), 4 ± 0.9 days (range: 2-7) and 8.2± 1.9 days (range: 7-14), respectively. the demographic and pathological data were detailed in table 1. we did not observe any intra-operative complication due to rarp or ih repair. at post-operative period, wound evisceration at camera port place which was lengthened and used and for specimen extraction over the umbilicus requiring primary closure under general anesthesia developed in a patient on postoperative day 20. groin pain, wound infection or seroma were not developed in our population. our median follow-up duration was 13 months and we did not observe mesh infection or hernia recurrence during the follow-up. discussion the ih is seen in 25% of the general male population during lifetime.(14) the ih can occur at any age, however, the peak incidence is during early childhood (0-5 age) and over 75 ages.(14) the pca is also seen in older age. thus, pca and ih are can be detected concomitantly. the incidence rate of asymptomatic ih which is detect during prostatectomy approached up to 33%.2 in a retrospective study, asymptomatic ih was detected in 20.4% of the patients who underwent rp by preoperative computed tomography.(1) on the other hand, ih is considered a manifest of rp by many authors and the incidence of ihs is higher in men undergoing rp when compared with non-operated men.(3-4) first, regan et al. reported that significantly higher incidence of ih is developed after rp (12%) when compared with the general population (5%).(3) more recently, national prostate cancer register of sweden reported that the incidence of ih repair were 14% and 10% in men who were treated with retropubic rp and with minimal invasive rp, respectively whereas 4% in control population.(4) therefore, pca surgery either minimal invasive or open seem to be a risk factor postoperative ih development. in the light of technological developments, the trend of rp gradually shifted towards rarp since reporting similar oncological and functional outcomes.(15) nowadays, especially in developed countries, majority of rps are performed with robotic assistance. concordantly, a few articles have been published on concurrent ih repair with rarp with different hernia repairing technique.(7-10,16,17) these publications are summarized in table 2. our outcomes were consistent with previous studies. concurrent repair of ih during rarp has several advantages. first, operation time for concurrent repair is shorter when compared both surgeries are performed separately.(7,12,16) additionally, this would be an additional morbidity due to second surgical procedure on the patient with additional anesthesia exposure. second, if the ih is not repaired concurrently during rarp procedure, it might be more difficult to repair it via laparoscopic or robotic surgery due to scarring in the preperitoneal space in the following months after the previous rarp procedure.(12,16) concerns might be present related with concurrent ih repair with mesh during rp due to the possible risk of mesh infection, postoperative inguinal pain, postoperative bowel adhesions, seroma formation and other complications. the theoretical risk of infection arises from the possibility that the mesh may contact with urine in the presence of vesico-urethral anastomosis. however, there is no evidence about that concurrent ih repair during rp increases risk of mesh infection based on previous studies.(7-10) mesh is a foreign body and there is a risk for adhesions to intraperitoneal structures. reducing this risk can be achieved with two methods. first, reperitonealization may be safely achieved after the completion of prostatectomy to avoid contact of mesh with intraperitoneal structures. second, using adhesion-resistant, coated mesh is another solution that reduces risk of adhesion formation while avoiding related postoperative complications. finley et al. did not experience mesh-related complications in patients undergoing simultaneous rarp and ih repair.(7) we used adhesion-resistant coated mesh (dual meshes) in 19 patients. polypropylene mesh was used only in a patient. in this case, we closed the anterior peritoneum for reducing bowel adhesion risk. seroma formation is a frequent complication after hernia repair especially in incisional hernia patients.(18,19) however, the incidence of seroma development ranged between 1.9 to 22.9% after laparoscopic ih repair.(19,20) bansal et al. evaluated the rate of seroma formation after laparoscopic tapp and tep procedures.(21) they reported their seroma formation rates as 32.5% and 16.2% after postoperative day 7 for tep and tapp groups, respectively, while these rates were 3.7% and 1.9% after hernia repair during robotic prostatectomy-atmaca et al. 1 month.(21) this rate is very low in series of concurrent ih repair with rarp. seroma formation was reported in one patients only by ludwig et al.(10) there were no seroma formation in other concurrent ih repair with rarp series.(7-9,16,17) the etiology of seroma formation remains unknown, but it seems to be due to a local inflammatory response to a mechanical injury by tissue aggression during surgery and the presence of foreign bodies such as mesh.(19) most seromas are asymptomatic and resolve spontaneously without any intervention. however, seroma persistence over 6 weeks can become a major problem for patients, impairing their quality of life due to discomfort sense, pain, and cosmetic reasons. (18,19) infected seromas can also lead mesh removal or hernia recurrence.(22) preventing of seroma formation can be achieved with good hemostasis, drainage of subcutaneous tissue, compression to surgery side, and fixing the mesh with running absorbable sutures to prevent the formation of dead space.(22) we did not observe seroma formation in our patients. this outcome may depend on that our patients have non-complex ihs and our patients have no previous unsuccessful hernia surgery. moreover, we fixed the mesh to aponeurosis with tacks and running absorbable sutures combination in majority of our patients. another concern related with rarp and concurrent ih repair might be prolonged lymphatic drainage in patients with extended pelvic lymph node dissection. in our series 11 patients had extended pelvic lymph node dissection. the main drainage catheter removal time was 2.4 ± 0.8 days in these patients and we did not have any patient with prolonged lymphatic drainage. stolzenburg et al.(6) observed prolonged lymphatic drainage in 5 of 10 patients who underwent laparoscopic radical prostatectomy and concurrent ih repair, however no lymphocele or additional problems were observed. in current literature, the rate of symptomatic lymphocele (which required drainage) development during minimal invasive rp and concurrent ih repair is up to 5 %.(9,10) lymphocele which was asymptomatic and did not require intervention was developed in one of our patients. the main concern in lymphocele development is probability of mesh infection. in order to prevent prolonged lymphatic drainage, it might be important to apply endoclips during performing extended pelvic lymph node dissection rather than applying only cautery that could be expected to prevent postoperative prolonged lymphatic drainage particularly in patients who underwent robotic tapp repair with rarp procedure. our surgeons (afa, aec) are experienced (each performing more than one hundred cases per a year) in rarp surgery. they participated in hands on training course on laparoscopic ih repair which was organized by general surgeons before starting to tapp operations. our surgeons performed the initial tapp procedures under supervision of a general surgeon which experienced in laparoscopic hernia repair surgery. our study has several limitations. first, the nature of the study is retrospective despite all data were recorded prospectively. second, this study is limited by the small numbers of patients which may affect the reliability of the statistical analysis. third, although same rarp technique was used, ih repairs were performed by two surgeons performed which may add variability to our results. fourth, none of the patients had previous hernia repairs, so we cannot draw conclusions for cases with previous herniorraphy. finally, our follow up time is short and we cannot present definitive conclusions such as long term hernia recurrence rate. conclusions due to our experience, concurrent ih repair with mesh during rarp procedure seem to be easy to perform, effective and safe following taking specific precaution such as having a proper initial training, obtaining a preoperative sterile urine culture, intraoperative good hemostasis, a watertight vesico-urethral anastomosis and sufficient endoclip application for extended pelvic lymph node dissection. conflict of interest none declared. references 1. fukuta f, hisasue s, yanase m, et al. preoperative computed tomography finding predicts for postoperative inguinal hernia: new perspective for radical prostatectomyrelated inguinal hernia. urology. 2006; 68: 267-71. 2. nielsen me and walsh pc. systematic detection and repair of subclinical inguinal hernias at radical retropubic prostatectomy. urology. 2005; 66: 1034-7. 3. regan tc, mordkin rm, constantinople nl, spence ij, dejter sw jr. incidence of inguinal hernias following radical retropubic prostatectomy. urology. 1996; 47: 536-7. 4. nilsson h, stranne j, stattin p, nordin p. incidence of groin hernia repair after radical prostatectomy a population-based nationwide study. ann surg. 2014; 259: 1223-7. 5. mcdonald df and higgins c. simultaneous prostatectomy and inguinal herniorrhaphy. surg gynecol obstet. 1949; 89: 621-3. 6. stolzenburg ju, rabenalt r, dietel a, et al. hernia repair during endoscopic (laparoscopic) radical prostatectomy. j laparoendosc adv surg tech. 2003; 13:27. 7. finley ds, savatta d, rodriguez e, kopelan a, ahlering te. transperitoneal roboticassisted laparoscopic radical prostatectomy and inguinal herniorrhaphy. j robot surg. 2008; 1: 269-72. 8. joshi ar, spivak j, rubach e, goldberg g, denoto g. concurrent robotic trans-abdominal pre-peritoneal (tap) herniorrhaphy during robotic-assisted radical prostatectomy. int j med robot. 2010; 6: 311-4. 9. do m, liatsikos en, kallidonis p, et al. hernia repair during endoscopic extraperitoneal radical prostatectomy: outcome after 93 cases. j endourol. 2011; 25: 625-9. 10. ludwig ww, sopko na, azoury sc, et al. inguinal hernia repair during extraperitoneal robot-assisted laparoscopic radical prostatectomy. j endourol. 2016; 30: 208-11. hernia repair during robotic prostatectomy-atmaca et al. miscellaneous 385 vol 15 no 06 november-december 2018 386 11. forbes ss, eskicioglu c, mcleod rs, okrainec a. metaanalysis of randomized controlled trials comparing open and laparoscopic ventral and incisional hernia repair with mesh. br j surg. 2009; 96: 851-8. 12. kaler k, vernez sl, dolich m. minimally invasive hernia repair in robot-assisted radical prostatectomy. j endourol. 2016; 30: 1036-40. 13. canda ae, atmaca af, akbulut z, et al. results of robotic radical prostatectomy in the hands of surgeons without previous laparoscopic radical prostatectomy experience. turk j med sci. 2012; 42: 1338-46. 14. jenkins jt and o’dwyer pj. inguinal hernias. bmj. 2008; 336: 269-72. 15. mustafa m, davis jw, gorgel sn, pisters l. robotic or open radical prostatectomy in men with previous transurethral resection of prostate. urol j. 2017; 14: 2955-60. 16. mourmouris p, argun ob, tufek i, et al. nonprosthetic direct inguinal hernia repair during robotic radical prostatectomy. j endourol. 2016; 30: 218-22. 17. qazi ha, rai bp, do m, et al. robot-assisted laparoscopic total extraperitoneal hernia repair during prostatectomy: technique and initial experience. cent european j urol. 2015; 68: 240-4. 18. morales-conde s. a new classification for seroma after laparoscopic ventral hernia repair. hernia. 2012; 16: 261-7. 19. cihan a, ozdemir h, ucan bh, et al. fade or fate. seroma in laparoscopic inguinal hernia repair. surg endosc. 2006 20: 325-8. 20. lau h and lee f. seroma following endoscopic extraperitoneal inguinal hernioplasty. surg endosc. 2003; 17: 1773-7. 21. bansal vk, misra mc, babu d, et al. a prospective, randomized comparison of longterm outcomes: chronic groin pain and quality of life following totally extraperitoneal (tep) and transabdominal preperitoneal (tapp) laparoscopic inguinal hernia repair. surg endosc. 2013; 27: 2373-82. 22. birolini c, de miranda js, utiyama em, rasslan s. a retrospective review and observations over a 16-year clinical experience on the surgical treatment of chronic mesh infection. what about replacing a synthetic mesh on the infected surgical field? hernia. 2015; 19: 239-46. hernia repair during robotic prostatectomy-atmaca et al. 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran introduction bladder cavernous hemangioma (bch) is a rare cause of hematuria. it may appear in every part of the urinary tract and presents mostly in childhood. bladder hemangioma (bh) is suspected by cystoscopy and radiologic findings and confirmed by pathologic examinations. the treatment of bh differs from partial cystectomy and endoscopic removal or laser therapy. since bch is a rare case and because of its big size and specific cystoscopic findings, we report a treated case of it in this article. case report a 19-year old boy from zabol, southeast of iran, was referred to this center with frequent hematuria, blood clot in urine, and anemia (hematocrit=21%) from which he has suffered for 6 years. renal function tests were normal. the upper urinary tract was normal in ivp; however, there was a filling defect in the right side of bladder in the cystogram phase (fig. 1). an echogen mass was detected by sonography in the right wall and dome of the bladder. the same mass without external invasion was indicated at the same side in ct scan (fig. 2). the patient underwent cystoscopy and biopsy to confirm the diagnosis. diffuse port red wine colored bleeding mucosal lesions were seen. biopsies and bimanual examination were performed. there case report cavernous hemangioma of the bladder mahdavi r*, rahmani m department of urology, imam reza hospital, mashad university of medical sciences, mashad, iran key words: cavernous hemangioma, bladder, diagnosis accepted for publication fig. 1. cystography of the patient with bladder cavernous hemangioma fig. 2. ct scan of the patient with bladder cavernous cavernous hemangioma of the bladder was no adhesion to the pelvic wall. pathologic examination revealed bch. no other sources of hemangioma were detected in the patient's body. the patient's frequent hematuria, progressive anemia, and several blood transfusions led to surgical tumor removal. by a midline incision under the umbilicus, abdomen was opened. the bladder was defined by extraperitoneal approach. the tumor was palpated. it was like a bag of worm in the right upper side. a part of bladder containing tumoral vascular tissues with a safe margin was removed. pathologic study of samples confirmed bch (fig. 3). cystoscopy was done to assure the lack of any urine leakage one week later and then the patient was discharged (fig. 4). discussion bladder hemangioma is a rare cause of hematuria. although cavernous hemangioma is mostly developed in derma and epidermis, it is rarely reported in the mucosal parts. generally, there is a congenital cause for it. cavernous hemangioma occurs most often in children and youth. it may be single or multiple. hematuria is considered as its clinical sign; however, it is usually diagnosed by cystoscopy. in 30% of patients with bladder cavernous hemangioma, we may find hemangioma in other organs. in some cases of cavernous hemangioma, klippel-trenaunay or sturge-weber syndrome was reported too. head, neck, and upper limbs are the most common parts in which cavernous hemangioma is diagnosed. the disease may occur in deeper organs too; in this case, it does not regress. the pressure of cavernous hemangioma may cause a destructive effect on its close tissues. thus, in most cases surgical removal is needed. it rarely becomes malignant. histologically, cavernous hemangioma has the same characteristics of usual hemangioma except for its dilated, big, and full blood vessels covered by flat endothelium. thrombocytopenic purpura, in addition to hemorrhage, is one of the major complications of cavernous hemangioma, which occurs most often in infancy and secondary to the rapid enlargement of the hemangioma. different methods such as partial cystectomy or laser photocoagulation can be used in the treatment of bladder hemangioma. radiotherapy is not sufficient and endoscopic resection may result in hemorrhage or incomplete resection. in some rare cases selective arterial embolization of tumor may be done. references 1. chang e, boyd a. successful treatment of infantile hemangioma. j pediatric hematol oncol 1997 may-jun ; 19 (3). 2. duke bj, levy as. cavernous angioma of cauda equina: case report and review of literature. surgery-neurology 1998 nov; 52 (5). 3. engel jd, kuzel tm. angiosarcoma of bladder a review. urology 1998 nov; 52 (5). 4. hendry wf, vinnieombe j. hemangioma of bladder in children and young adults. br j urol 1971;43: 309-16. 5. lavilledieu s, et al. bladder hemangioma a rare cause of hematuria. prog urol 1998 feb; 8 (1). 2 fig. 3. pathology result after partial cystectomy fig. 4. cystography after partial cystectomy cavernous hemangioma of the bladder 6. lee kw, rodo j. cavernous hemangioma of the bladder. br j urol 1995 june: 799-801. 7. mor y, hitchcock rj. bladder hemangioma in a child. scand j urol nephr 1997 jun; 31 (3). 8. shoji n, nakada t. acute onset of coagulopathy in a patient with kasabach-merritt syndrome following tur-bt. urol int 1998; 61 (7). 9. smith ja. laser treatment of bladder hemangioma. j urol 1990; 143: 282-4. 3 laparoscopic urology laparoscopic ureterolithotomy with concomitant pyelolithotomy using flexible cystoscope selcuk sahin1*, berkan resorlu2, feyzi arda atar1, mithat eksi1, nevzat can sener1, volkan tugcu1 purpose: to report and discuss the treatment of ipsilateral upper ureteral and renal stones by laparoscopic ureterolithotomy with concomitant pyelolithotomy using flexible cystoscope. materials and methods: a total of 19 patients (14 men and 5 women) underwent laparoscopic retroperitoneal ureterolithotomy with concomitant pyelolithotomy using flexible cystoscope through the ureterotomy site. the mean age of the patients was 37.9 (22-61) years. stones were on the right side in 12, on the left side in 7, and multiple in 6 patients. all ureteral stones were located in the upper ureter. most renal stones were in the pelvis or in the calices. results: all procedures were completed laparoscopically without conversion to open surgery. mean operation duration was 86.5 (range: 80-93) minutes, thus operation duration was prolonged by a mean of 24.4 minutes in patients with concomitant stone extraction. fifteen cases were treated using flexible cystoscope and a nitinol basket; in the remaining four cases holmium laser lithotripsy was performed. complete stone clearance was confirmed by postoperative imaging in all patients. conclusions: laparoscopic ureterolithotomy with concomitant pyelolithotomy is a feasible and effective technique for patients with large ureteral stone and low renal stone burden. keywords: flexible ureteroscopy, laparoscopic ureterolithotomy; pyelolithotomy introduction during the last 3 decades with improvement and miniaturization of instruments, the treatment of urinary stone disease has dramatically changed. minimally invasive surgical techniques like extracorporeal shock wave lithotripsy (swl), ureteroscopy (urs), and percutaneous nephrolithotomy (pnl) have played an important role in the treatment of urinary stones. (1,2) for patients who were failed on these treatments, open surgery is needed.(1) however several drawbacks are associated with this approach. since the introduction of the laparoscopy in urologic surgery, most urologic surgeries, including ureterolithotomy, can now be performed laparoscopically. compared to the open ureterolithotomy, the laparoscopic approach enables lower postoperative morbidity, less blood loss, less postoperative pain, reduced hospitalization, a short convalescence period, and better cosmetic results.(3,4) patients with ipsilateral renal and ureteral stones, pose a challenge for treatment. they often require multiple interventions or open surgery in order to have their stones retrieved. recently, laparoscopic pyeloplasty or ureterolithotomy with concomitant flexible ureteroscopic renal stone extraction through a laparoscopic port has been reported.(5-8) the aim of our study is to evaluate the effectiveness of laparoscopic retroperitoneal ureterolithotomy with concomitant pyelolithotomy using flexible cystoscope for the treatment of ipsilateral ureteral and renal calculi. materials and methods study population we retrospectively reviewed the charts of 161 patients (163 renal units) who had undergone laparoscopic ureterolithotomy in our institution from april 2006 to august 2014. of these patients, 19 had concomitant ipsilateral renal stones at the time of diagnosis which included 14 men and 5 women with a mean age of 37.9 (range: 22-61) years. stones were on the right side in 12, on the left side in 7, and multiple in 6 patients. all ureteral stones were located in the upper ureter. most renal stones were in the pelvis or in the calices (table 1, figure 1). procedures patients underwent laparoscopic retroperitoneal ureterolithotomy with concomitant pyelolithotomy using flexible cystoscope through the ureterotomy site. evaluations all patients underwent radiologic imaging including ultrasonography, intravenous urography (ivu), and computed tomography (ct). stone size was defined as the greatest diameter of the stone. in cases of multiple kidney stones, the greatest diameter of the largest stone was used. preoperatively, we performed physical examination, renal function test, urine analysis and culture, complete blood count and coagulation profile tests. in patients with active urinary tract infection, appropriate treatments were performed. a stone free status at 2 weeks or having clinically insignificant residual stones (<4 mm) were considered as treatment success. 1bakirköy dr. sadi konuk training and research hospital, department of urology, istanbul, turkey 2department of urology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey *correspondence: department of urology, istanbul bakirköy dr. sadi konuk training and research hospital, bakirkoy, istanbul 34000, turkey. tel: +90 506 82 83; +90 212 414 64 94. e-mail: urosahin@gmail.com. received february 2016 & accepted june 2016 laparoscopic urology 2833 operation technique under general anesthesia a retroperitoneal approach was employed in all patients. we have previously described our laparoscopic retroperitoneal ureterolithotomy technique in detail with its modifications(9). after ureteral stone removal, a 16 fr storz flexible cystoscope (karl storz endoscopy-america, inc., culver city, ca) was introduced through an available working port under direct laparoscopic guidance into the collecting system (figure 2). usually a port that is well aligned with the pelvis or ureter should be chosen for passing the instrument. pyeloscopy is performed under direct vision. continuous irrigation via the cystoscope allowed for superb visualization. renal stones were removed with a nitinol basket. if the stone was large, holmium laser lithotripsy was performed. the laparoscopic suction device was placed below the renal pelvis to aspirate irrigation fluid from the operative field. an indwelling double-j ureteral stent was placed at the end of the procedure based on surgeon preference. the ureterotomy was closed with interrupted 4-0 absorbable sutures. the stone was removed in a homemade bag and was extracted through the first port. a closed suction drain was placed through one of the trocar sites. the fascia and skin were closed in the standard fashion. ureteral stents were removed 4 to 6 weeks after surgery. this was followed by ivu examination 3 months after the operation. analgesics were not routinely administered. diclofenac sodium (75 mg intramuscularly) and paracetamol (500 mg oral) were given to achieve analgesia whenever needed. analgesic usage and visual analog pain scores pyelolithotomy by cystoscope-şahin et al. (vas) were measured on the day of operation and on the first postoperative day. vas score was clearly explained to each patient before the examination. the vas score, in which 0 represents minimum (no) pain and 10 represents maximum (the worst possible) pain, was used to evaluate pain as perceived by each patient. results all the procedures were completed laparoscopically with no conversion to open surgery. the mean size of ureteral stones was 21.2 (range: 16-32) mm. renal calculi size ranged from 3 to 14 mm and a mean of 1.5 stones per patient was removed (range, 1 to 4 stones). mean operative time was 86.5 (range: 80-93) minutes, thus the operation duration was prolonged by a mean of 24.4 minutes in patients with concomitant stone extraction. fifteen cases were treated using a flexible cystoscope and a nitinol basket; in the remaining four cases holmium laser lithotripsy was performed. double-j stent was inserted in 9 patients. the detailed perioperative data of patients are listed in table 2. complete stone clearance confirmed by postoperative imaging was achieved in all patients. no intraoperative complications were noted. no patient received blood transfusion. one patient who was not stented during the operation, was treated conservatively for high drain output which lasted for 6 day postoperatively . one patient developed fever and required antipyretic treatment. in one patient subcutaneous emphysema developed and ileus was seen in another patient which required conservative treatment. stones analysis was available in 14 patients which revealed calcium oxalate, calcium phosphate, struvite and uric acid composition in 9, 2, 2 and 1 patients respectively. discussion current standard treatment of urinary stones includes extracorporeal swl, urs and percutaneous antegrade removal as important role players(1). the frequently known limitations are high stone density, large and impacted stones(10). the presence of concomitant ipsilateral ureteral and renal stone disease presents a challenging situation for the urologist. multiple stones are found in 20% to 25% of patients with urolithiasis. in cases with multiple stones, 29% to 36% of patients have ureteral stones with renal stones simultaneously(11-14). on the basis of a 40% to 50% stone-free rate (sfr) for table 1. patient demographics and stone characteristics variables values number of patients 19 male:female 14:5 age, years; mean (range) 37.9 (22-61) right:left 12:7 ureteral stone size, mm; mean (range) 21.2 (16-32) multiple renal stones; number (range) 6 (2-4) renal stone size, mm; (range) 3-14 variables values mean operative time, minutes; mean (range) 86.5 (80-93) additional time for pyelolithotomym, minutes 24.4 intraoperative dj insertion, (n) 9 analgesia requirement, days; mean ± sd 4.3 ± 0.82 average vas score on the day of operation; mean ± sd 5.93 ± 1.1 average vas score 1st postoperative day; mean ± sd 3.94 ± 0.88 mean hospital stay, day; mean ± sd 2.97 ± 0.86 mean return to normal activity, day; mean ± sd 8.91 ± 2.21 auxilary procedures, n 0 stone-free rate (%) 100 table 2. operative and postoperative data figure 1. preoperative ct imaging vol 13 no 05 september-october 2016 2834 swl in patients with multiple stones, questions are being raised about the effectiveness of swl for these patients(15). improvements in flexible ureteroscopes, instruments, and laser technology have made retrograde stone removal more attractive. in case of large and multiple stones, complete stone clearance rate decreases and auxillary procedures may be required(14,16) .due to these factors some patients require open surgery. open ureterolithotomy has several drawbacks. compared to open ureterolithotomy, the laparoscopic approach enables lower postoperative morbidity, less blood loss, less postoperative pain, reduced hospitalization, a short convalescence period, and better cosmetic results(3,4). the success rate of laparoscopic ureterolithotomy for large ureteric stones is more than 95% as described by various researchers(17,18). currently, laparoscopic ureterolithotomy is performed either transperitoneally or retroperitoneally(19). the retroperitoneal approach is advantageous in that the ureter can be accessed more directly and intraperitoneal contamination or infection due to urine leakage is less likely. another advantage of this approach is the absence of peritoneal irritation(20,21) .in laparoscopic ureterolithotomy, dealing with concomitant kidney stones is a very difficult situation. laparoscopic pyeloplasty with concomitant pyelolithotomy has been previously reported, and has been typically performed using a flexible nephroscope introduced through a laparoscopic port(5-7). ball et al. have reported complete stone clearance in 6 out of 7 patients undergoing simultaneous laparoscopic pyeloplasty and pyelolithotomy using a flexible endoscope and stone basket through the laparoscopic port without the use of intraoperative fluoroscopy(5). atug et al. reported the use of robotic graspers in one patient and flexible nephroscopy in seven patients for pyelolithotomy during robot-assisted laparoscopic pyeloplasty. their stonefree rate was 100%, but operative time was 61.7 minutes longer for patients undergoing pyelolithotomy(6). you and collegues, have recently described the methods for treating ipsilateral renal and ureteral calculi by combining retroperitoneal laparoscopic ureterolithotomy(8). they performed laparoscopic ureterolithotomy with renal stone extraction using a stone basket under flexible ureteroscopy in 11 patients. mean ureteral stone size was 19.9 mm. in addition 25 renal stones ( mean size 7.48 mm, range 2-12) were removed. mean laparoscopic urology 2835 operation duration was 78.5 minutes. previously we have demonstrated this concomitant surgical technique. the removal of stones through the ureterotomy site was succesfully completed in three patients(9). laparoscopic retroperitoneal ureterolithotomy is the method of choice in large and impacted ureteral stones due to the low percentage of auxillary procedures in comparison to swl or urs. if there is a concomitant renal stone present, then we prefer flexible cystoscopy and laser lithotripsy during laparoscopy in renal stones lower than 15 mm diameter irrespective of its multiplicity. in patients having a concomitant renal stones larger than 15 mm diameter, percutaneous stone extraction during retroperitoneal laparoscopy could be an option. sun and collegues presented their study of treating ipsilateral renal and ureteral calculi by combining retroperitoneal laparoscopic surgery with tubeless mini-percutaneous nephrolithotomy. the mean number of stones in their study was 3.3 (range 2–7), and the mean stone size was 2.5 cm (range 0.9–3.8 cm) in 11 patients(22). our opinion is that concomitant percutaneous nephrolithotomy for patients having small renal stone is an invasive method and flexible cytoscopy is morenadvantegeous. conclusions laparoscopic ureterolithotomy with concomitant pyelolithotomy using flexible cystoscope was a safe and effective procedure and required relatively little extra operative time. we obtained complete stone clearance in all patients, without the need for additional procedure and morbidity. this combined technique requires expertise in laparoscopy and endourology. in addition, the diameter of the concomitant renal stone determines the best treatment option . references 1. türk c, knoll t, petric a, et al. guidelines on urolithiasis. european association of urology 2011; 1-104. 2. preminger gm, tiselius hg, assimos dg, et al. 2007 guideline for the management of ureteral calculi. j urol. 2007; 178: 2418-34. 3. falahatkar s, khosropanah i, allahkhah a, jafari a. open surgery, laparoscopic surgery, or transureteral lithotripsy—which method? comparison of ureteral stone management outcomes. j endourol. 2011; 25: 31-4. 4. skrepetis k, doumas k, siafakas i, lykourinas m. laparoscopic versus open ureterolithotomy. a comparative study. eur urol. 2001; 40: 32-36. 5. ball aj, leveillee rj, patel vr, wong c. laparoscopic pyeloplasty and flexible nephroscopy: simultaneous treatment of ureteropelvic junction obstruction and nephrolithiasis. jsls 2004; 8: 223–8. 6. atug f, castle ep, burgess sv, thomas r. concomitant management of renal calculi and pelvi-ureteric junction obstruction with robotic laparoscopic surgery. bju int 2005; 96: 1365–8. 7. aneesh srivastava, pratipal singh, manu gupta, et al. laparoscopic pyeloplasty with figure 2. flexible cystoscope introduced through an available working port pyelolithotomy by cystoscope-şahin et al. concomitant pyelolithotomy – is it an effective mode of treatment? urol int. 2008; 80: 306-9. 8. you jh, kim yg, kim mk. flexible ureteroscopic renal stone extraction during laparoscopic ureterolithotomy in patients with large upper ureteral stone and small renal stones. can urol assoc j. 2014; 8: 9-10. 9. tugcu v, simsek a, kargi t, polat h, aras b, tasci ai. retroperitoneal laparoendoscopic single-site ureterolithotomy versus conventional laparoscopic ureterolithotomy. urology. 2013; 81: 567-72. 10. gaur dd, trivedi s, prabhudesai mr, madhusudhana hr, gopichand m. laparoscopic ureterolithotomy technical considerations and longterm follow-up. bju int 2002; 89: 339-43. 11. kanao k, nakashima j, nakagawa k et al. preoperative nomograms for predicting stonefree rate after extracorporeal shock wave lithotripsy. j urol. 2006; 176: 1453-6. 12. abe t, akakura k, kawaguchi m, et al. outcomes of shockwave lithotripsy for upper urinary-tract stones: a large-scale study at a single institution. j endourol 2005; 19: 76873. 13. abdel-khalek m, sheir kz, mokhtar aa, eraky i, kenawy m, bazeed m. prediction of success rate after extracorporeal shockwave lithotripsy of renal stones: a multivariate analysis model. scand j urol nephrol 2004; 38: 161-7. 14. lim sh, jeong bc, seo si, jeon ss, han dh. treatment outcomes of retrograde intrarenal surgery for renal stones and predictive factors of stone-free. korean j urol 2010; 51: 777-82. 15. abe t, akakura k, kawaguchi m, et al. outcomes of shockwave lithotripsy for upper urinary-tract stones: a large-scale study at a single institution. j endourol 2005; 19: 76873. 16. resorlu b, unsal a, gulec h, oztuna d. a new scoring system for predicting stone-free rate after retrograde intrarenal surgery: the "resorlu-unsal stone score". urology 2012; 80: 512-8. 17. ko yh, kang sg, park jy, et al. laparoscopic ureterolithotomy as a primary modality for large proximal ureteral calculi: comparison to rigid ureteroscopic pneumatic lithotripsy. j laparoendosc adv surg tech a. 2011; 21: 7-13. 18. hruza m, schulze m, teber d, gözen as, rassweiler jj. laparoscopic techniques for removal of renal and ureteral calculi. j endourol. 2009; 23: 1713-8. 19. skolarikos a, papatsoris ag, albanis s, assimos d. laparoscopic urinary stone surgery: an updated evidence-based review. urol res. 2010; 38: 337-44. 20. kijvikai k, patcharatrakul s. laparoscopic ureterolithotomy: its role and some controversial technical considerations. int j urol 2006; 13: 206-10. 21. farooq qadri sj, khan n, khan m. retroperitoneal laparoscopic ureterolithotomy–a single centre 10 year experience. int j surg. 2011; 9: 160-4. 22. sun l, peng fl. treatment of ipsilateral renal ureteral calculi by combining retroperitoneal laparoscopic surgery with tubeless minipercutaneous nephrolithotomy. urol int 2013; 90: 139-43. pyelolithotomy by cystoscope-şahin et al. vol 13 no 05 september-october 2016 2836 pediatric urology ischemia modified albumin and d-dimer in the diagnosis of testicular torsion: an experimental model fatma sarac1*, selman yeniocak2, akif erbin3, esma yucetas4, kamile altundal5, burak ucpinar3, ayse saygili6, macit koldas4 purpose: we aimed to investigate the potential early diagnostic value of ischemia modified albumin (ima) and d-dimer in testicular torsion. material and methods: a total of 42 prepubertal wistar-hannover rats (26-30 days old, weighing 75-125 grams) were used in the study. they were randomly divided into 2 groups as torsion (21 rats) and control (21 rats). both torsion and control groups were subdivided into three subgroups as 30th, 120th and 240th minutes. intraperitoneal injection of 70 mg/kg ketamine (ketalar, pfizer, istanbul, turkey) plus 10 mg/kg of xylazine (rompun, bayer, istanbul, turkey) were used for general anesthesia. in the control group, scrotal incision was made and the left testis gently extracted. then, intracardiac blood and testicular tissue were obtained at 30th, 120th and 240th minutes. in torsion group, testicular ischemia was achieved by rotating left testis 720° clockwise and maintained by fixing the testis. blood and testicular samples were obtained at 30th, 120th and 240th minutes. all animals were sacrificed after completion of the study. results: there was a statistically significant difference between the ima and d-dimer levels at 30th, 120th and 240th minutes of torsion group when compared with the control group (p = .001). when compared in terms of pathological changes at 30th, 120th and 240th minutes, significant difference was found for all 3 periods (p = 0.039, p = 0.014, p = 0.03, respectively). the d-dimer and ima estimated torsion with reasonable accuracy [area under the curve (auc)= 0.771 (p = 0.003, 95% confidental interval: 0.620-0.922) and auc = 0.706 (95% confidental interval: 0.549-0.863, p = 0.022), respectively. conclusion: the elevated d-dimer and ima serum levels observed in the experimental testicular torsion model seem to have a potential role as a serum marker in the early diagnosis of testicular torsion. keywords: d-dimer; ischemia modified albumin; testicular torsion introduction testicular torsion (tt) occurs due to the loss of blood flow to the testis and surrounding tissues as a result of spermatic cord rotation.(1) testicular recovery is likely if intervention is performed within the first 6 hours after the onset of symptoms.(2-4) testicular torsion causes ischemic injury; detorsion causes reperfusion damage and they both cause structural and biochemical changes in the testis.(5-7) in case of ischemia, cellular stress factors such as hypoxia, acidosis, free radical damage and deterioration of membrane integrity change the structure of the albumin molecule. at the n-terminal end of the albumin, some changes that reduce the binding capacity of transitional metals such as copper, cobalt and nickel occur. this newly-formed damaged albumin is called “ischemia modified albumin” (ima).(8-10) d-dimer is a degradation product of 1department of pediatric surgery, haseki traning and research hospital, istanbul, turkey. 2department of emergency medicine, haseki traning and research hospital, istanbul, turkey. 3department of urology, haseki traning and research hospital, istanbul, turkey. 4department of biochemistry, haseki traning and research hospital, istanbul, turkey. 5department of pathology, haseki traning and research hospital, istanbul, turkey. 6department of pediatrics, arnavutkoy state hospital, istanbul, turkey. *correspondence: department of pediatric surgery, haseki traning and research hospital, istanbul, turkey. phone: +90 533 460 69 06. fax: +90 212 529 4400. e-mail: fsarac75@gmail.com. received november 2018 & accepted april 2019 fibrin. local fibrin formation and lysis are part of the inflammatory response and fibrin degradation products such as d-dimer, regulate the acute phase response and the production of systemic inflammatory mediators. both markers are mainly elevated in ischemic-hypoxic and thromboembolic conditions(11-16). examination of testicular blood flow by color doppler ultrasonography (usg) or scintigraphy are the main diagnostic methods in the diagnosis of tt. however, these methods may not be easily accessible in every case . so, there is a need for fast laboratory tests which are practical, easily accessible and have a high diagnostic value. some limited animal studies have shown that ima and d-dimer can have a significant value in the diagnosis of tt. in this experimental study, we aimed to investigate the role of serum levels of ima and d-dimer in the early diagnosis of tt in prepubertal rats. since tt is mostly urology journal/vol 16 no. 6/ november-december2019/ pp. 567-571. [doi: 10.22037/uj.v0i0.4974] seen in pediatric age group and young adults, we preferred to use prepubertal rats. material and methods study design the present animal stud y was approved by bezmialem vakif university (bvu) local ethics committee of the animal experiments (irb number: 2018/18) and was carried out in the bvu experimental animal research laboratory. animals used in the experiment were kept in steel cages at a room temperature of 22°c and were fed with normal water and standard food until the day of the study. water-only diet was provided for the last 12 hours before the induction of the study. a total of 42 experimentally naïve and drug-naïve male prepubertal wistar-hannover rats were used in the study. they were randomly divided into 2 groups as torsion (21 rats) and control (21 rats) group. both torsion and control groups were subdivided into three groups as 30th, 120th and 240th minutes. intraperitoneal injection of 70 mg/ kg ketamine (ketalar, pfizer, istanbul, turkey) plus 10 mg/kg of xylazine (rompun, bayer, istanbul, turkey) were used for general anesthesia. in control group, scrotal incision was made and the left testis gently extracted. then intracardiac blood and testicular tissue were obtained at 30th, 120th and 240th minutes. in torsion group, testicular ischemia was achieved by rotating left testis 720° clockwise and maintained by fixing the testis. blood and testicular samples were obtained at 30th, 120th and 240th minutes. all animals were sacrificed after completion of the study. biochemical investigations to measure serum ima and d-dimer levels, rat ima elisa kit (catalog no. ck-e91024, eastbiopharm., hangzhou eastbiopharm co. ltd.) and rat d-dimer (d2d) elisa kit (catalog no. ck-e91432, eastbiopharm., hangzhou eastbiopharm co. ltd.) were used, respectively. specimen absorbances were determined on a biotek elx800 (biotek, winooski, vt, usa) microplate reader at a wavelength of 450 nm. the ima results were expressed in iu/ml and the minimum detectable level was 1 iu/l. the d-dimer results were expressed in ng/ml and the minimum detectable level was 5 ng/l. histopathological examinations testicular tissues were fixed in 10% formaldehyde solution and they were embedded into paraffin for follow-up procedures. standard sections of four microns were prepared and they were stained with hematoxylin and eosin (h&e). the slides were evaluated by using a light microscope and classified according to the classification system which was designed by cosentino et al.17: stage 1: normal testicular tissue (figure 1.a) stage 2: less regular germ cells, irregular convergent seminiferous tubules (figure 1.b) stage 3: irregular germ cells, diminished pycnotic nuclei and destructed bounded seminiferous tubules (figure1.c) stage 4: seminiferous tubules filled with irregular germ table1. summary of population characteristics of the rats torsion group control group n 21 21 mean age days, (range) 27.9 (26-30) 28.1 (27-29) mean weight days, (range) 101.2 (75-125) 103,4 (75-125) d-dimer ima control group median torsion group median pa control group median torsion groupc median pa (iqr) (min-max) (iqr) (min-max) (iqr) (min-max) (iqr) (min-max) 30 min 118.2 (34.1) 127.7 (23.7) .001 32.0 (17.5) 36.3 (6.0) .001 (105.5-171.6) (113.1-160.6) (24.7-48.0) (32.1-41.6)d, e 120 min 110.1 (14.4) 142.6 (25.7) .001 35.6 (12.3) 37.2 (10.3) .001 (94.0-234.3) (126.4-208.4) (25.5-46.4) 9(30.3-54.5)f 240 min 116.0 (18.3) 149.3 (54.7) .001 35.5 (16.4) 61.9 (22.4) .001 (86.5-187.9) (119.6-258.5) (22.5-47.3) (43.4-82.9) pb .428 .967 .174 .02 abbreviations: ima: ischemia modified albümin; iqr: interquartile range; min-max: minimum-maximum a wilcoxon test b kruskal-wallis test cmann-whitney u test was performed to test the significance of pairwise differences using bonferroni correction (p = .05/3=.017) to adjust for multible comparisons; dp = .565 (comparison of 30 min and 120 min); e p = .002 (comparison of 30 min and 240 min); fp = .006 (comparison of 120 min and 240 min). table 2. comparison of serum ima and d-dimer levels at 30, 120 and 240 minutes between torsion and control groups figure 1. histopathological findings of each stage a. normal testicular tissue (stage 1) b. less regular germ cells, irregular convergent seminiferous tubules (stage 2) c. irregular germ cells, diminished pycnotic nuclei and destructed bounded seminiferous tubules (stage 3) d. seminiferous tubules filled with irregular germ cells which have coagulation necrosis (stage 4) early diagnosis of testicular torsion-sarac et al. pediatric urology 568 cells which have coagulation necrosis (figure 1.d) statistical analysis data were analyzed by using statistical package for the social sciences software package version 16 (spss inc., chicago, il, usa). descriptive analyses were presented using median, interquartile range (iqr), minimum and maximum for non-normally distributed variables. the wilcoxon test was used to compare torsion group with it’s control group. more than two group comparisons were made by kruskal wallis test; if there was a significiant difference, mann-whitney u test was performed to test the significance of pairwise differences using bonferroni correction (p = .05/30 = .017) to adjust for multiple comparisons. the comparison of torsion group with its control group in terms of pathological staging was performed with the chi-square test. cut-off point value was determined by roc analysis. statistical significance was accepted as p <.05. results the characteristic of the rats is shown in table1. also, serum ima and d-dimer levels of torsion and control groups are summarized in table 2. there was a statistically significant difference between the ima and d-dimer levels at 30th, 120th and 240th minutesin the torsion group when compared tothe control group (p = .001). there was a significant difference in terms of ima levels between subgroups of the torsion group (30th vs 240th minutes and 120th vs 240th minutes, p = .002 and p = .006, respectively). however, no significant difference was detected in terms of d-dimer values (p = .174). when torsion and control groups were compared in terms of pathological changes at 30, 120 and 240 minute according to the cosentino classification, significant difference was found for all 3 periods (p = .039, p = .014, p = .03, respectively). in the torsion group, the mean cosentino stage was 2.6, 3.3 and 3.4 at 30, 120 and 240 minute, respectively. however, these values were between 1.1 and 2.1 in the control group. the receiver operating characteristics (roc) curves of both markers are shown in figure 2. the d-dimer and ima estimated torsion with reasonable accuracy [area under the curve (auc) = .771 (p = .003, 95% confidental interval: 0.620-0.922) and auc = 0.706 (p = .022, 95% confidental interval: 0.549-0.863), respectively. sensitivity, specificity and predictive values of d-dimer and ima are shown in detail in table 3 and table 4. at a cut-off point of 118.9 mg/dl, the d-dimer has a sensitivity of 90.5%, specificity of 61.9%, ppv of 70.4% and npv of 86.7%. the ima was 81% sensitive and 52.4% specific in the diagnosis of tt at a cut-off point of 35.5 mg/dl. discussion viability and preservation of testis in tt is dependent on the degree and the duration oftorsion. it has been shown that 360 degrees of tt does not have an effect on fertiliy, whereas, 720 degrees and above has negative impacts on fertiliy. it has been stated that chances of testicular preservation in 6, 12 and 24 hours of tt is 90%, 50% and 10%, respectively.(6) therefore, immediate diagnosis and treatment of tt is required in order to preserve testis and fertility. sensitive and specific laboratory parameters which may aid in the early diagnosis of tt are limited. suspicion of tt generally ends up with surgical exploration of the testis. sensitive, fast and practical biochemical markers are of importance as they would serve as adjunct to diagnosis and increase efficiency of tt management. the d-dimer and ima assays are fast and practical laboratory tests that are routinely available in an outpatient setting via quantitative assays. therefore, in the present animal model, we studied the d-dimer and ima markers. both markers are mainly elevated in ischemic-hypoxic and thromboembolic conditions. because of fact that torsion is an ischemic condition and it creates thrombotic formations in arterial and venous vasculature, it is expected that the d-dimer and ima levels increase in ovarian and testicular torsion. ima measurement has recently been proposed as a sensitive marker for the diagnosis of myocardial ischaemia. clinical usage of ima in pathological conditions has grown in number, with additional application in deep venous thrombosis, pulmonary thromboembolism, lower limb ischemia, cerebrovascular events and pediatric urology 569 early diagnosis of testicular torsion-sarac et al. table 3. the predictive characteristics of d-dimer at different cut-off values d-dimer (mg/dl) sensitivity specifity ppv npv 118.9 90.5% 61.9% 70.4% 86.7% 123.3 81% 66.7% 70.8% 77.8% 131.4 66.7% 81% 77.8% 70.8% abbreviations: ppv: positive predictive value; npv: negative predictive value table 4. the predictive characteristics of ima at different cut-off values ima (mg/dl) sensitivity specifity ppv npv 35.5 81% 52.4% 63% 73.3% 35.63 76.2% 57.1% 64% 70.6% 36.84 66.7% 66.7% 66.75% 66.7% figure 2. the receiver operating characteristics (roc) curves of d-dimer and ima disseminated intravascular coagulation. also, ima is regarded as a marker of oxidative stress related to ischaemia reperfusion in any organ, because it is found elevated in various clinical entities associated with oxidative stress such as systemic sclerosis, type-2 diabetes and polycystic ovary syndrome.(17) in an animal torsion model study by mentese et al., detorsion was performed 4 hours later and testicular tissues were histopathologically examined 2 hours and 2 weeks after. ima values were found to be elevated in early and late stages. the authors stated that ima values were valuable in evaluation of acute and long-term testicular injury and evaluation of fertility capacity. (11) in contrary to our study, the samples were obtained after tt, thus, the effect of reperfusion on histopathological results wasinevitable. in our study, we have investigated markers which can aid in early diagnosis of tt. ischemia was performed but detorsion was not applied and effects of reperfusion was not investigated. in an experimental ovarian ischemia/reperfusion (i/r) model, ima values were found to be higher when compared with the control group and also, positive correlation between ima values and histopathologic results were detected in the i/r group.(12) in an experimental testicular torsion, it was shown that an increase of d-dimer level could be detected in the blood of rats within 4 hours.(13) other experimental studies showed that d-dimer started to increase in minutes after the onset of ischemia and reached its highest value in 6-12 hours.(14-15) all these results suggest that d-dimer can be a potential valuable marker in the early diagnosis of tt. in the present study, the predictive characteristics of the both markers (d-dimer and ima) were satisfactory (auc = 0.771 and auc = 0.706, respectively; these results can be interpreted as reasonable accuracy). in the patients who had ovarian torsion, d-dimer sensitivity was detected to be 71.4% and specifity was detected to be 85% in roc curve analysis. (14) other than ima and d-dimer, some new biomarkers have been proposed in early diagnosis of tt. in a randomized, controlled, experimental study, turedi et al studied plasma scube1 (a novel marker of platelet activation) protein and they proposed that its measurement may have diagnostic, therapeutic or prognostic value in tt. (7) in a clinical study, gunes et al investigated some hematological parameters (neutrophil / lymphocyte ratio; nlr, platelet/lymphocyte ratio (plr), mean platelet volume (mpv), and platelet) and they claimed that nlr may be used as a predictive factor for testicular viability following tt. (3) peretti et al. proposed that lower mpv value in "early-presenting" patients with tt playsa role in predicting testis viability.(18) gul et al. reported that caspase-3 immunoreactivity increases in the torsion group and that melatonin and melatonin plus pulsed magnetic field (pmf) treatment reduces the rate of immuno-reactivity.(19) despite these promising results, there is a need for further studies to routinely use these markers in clinical practice. conducted studies have generally focused on the ischemia/reperfusion injury and approaches to treatment. (20) postpubertal rats were used in almost all of them. we investigated the ischemia markers on pre-pubertal rats. however, our study hadsome limitations. the major limitation was the relatively small sample size; thus, large-scale randomized experimental and clinical trials are encouraged to be designed, so that the above conclusions can be verified with an increased statistical power. other biochemical markers were not studied in our study and this can be cited as another limitation. conclusions on the basis of the findings ofthis experimental study, serum d-dimer and ima levels are significantly higher in rats with tt compared to the control group. the elevated serum d-dimer and ima levels seem to have a potential role as a serum marker in the early diagnosis of tt. future investigations about biomarkers for the early diagnosis of tt should be the focus of further clinical studies. acknowledgement we are thankful to the academic studies commitee of haseki training and research hospital for providing financial support for the expenses (including ima elisa kit and d-dimer elisa kit) associated with this study. conflicts of interest the authors report no conflict of interest. references 1. da justa dg, granberg cf, villanueva c, baker la. contemporary review of testicular torsion: new concepts, emerging technologies and potential therapeutics. j pediatr urol 2013;9:723-30. 2. matthews pn. spermatic cord torsion. arch. dis. child 1986;62:426-7. 3. günes m, umul m, altok m, akyuz m, isoglu cs, uruc f, et al. predictive role of hematologic parameters in testicular torsion. korean j urol 2015;56:324-9. 4. reyes jg, farias jg, henriquez –olavarrieta s, madrid e, parraga m, zepeda ab, et al. the hypoxic testicle: physiology and pathophysiology. oxid med cell longev 2012; 2012:929285 . 5. cvetkovic t, stankovic j, najman s, pavlovic d, stokanovic d, vlajkovic s, et al. oxidant and antioxidant status in experimental rat testis after testicular torsion/detorsion. in j fertil steril 2015;9:121-8. 6. rashed fk, ghasemi b, deldade mogaddam h, mesgari m. the effect of erithropoietin on ischemia/reperfusion injury after testicular torsion/detorsion: a randomized experimental study. isrn urol 2013. 31;2013:351309. 7. turedi s, tatli o, alver a, karaguzel e, karaca y, turkmen s, et al. the diagnostic value of plasma scube 1, a novel biomarker of platelet activation, in testicular torsion: a randomized, controlled, experimental study. urology 2015;86:516-20. 8. d bar-or, g curtis, n rao, bampos n, lau e. characterization of the co2+ and ni2+ binding amino-acid residues of the n-terminus of human albumin: an insight into early diagnosis of testicular torsion-sarac et al. pediatric urology 570 vol 16 no 06 november-december2019 571 the mechanism of a new assay for myocardial ischemia. eur j of biochem 2001;268:42-7. 9. talwalkar ss, bon homme m, miller jj, elin rj. ischemia modified albumin, a marker of acute ischemic events: a pilot study. ann clin lab sci 2008;38:132-7. 10. sinha mk, roy d, gaze dc, collinson po, kaski jc. role of “ischemia modified albumin’’, a new biochemical marker of myocardial ischaemia, in the early diagnosis of acute coronary syndromes. emerg med j jany 2004;21:29-34. 11. mentese a, turkmen s, karaguzel e, karaca y, tatli o, sumer au, et al. the predictive value of ischemia-modified albümin in longterm results of ischemia-reperfusion injury in an experimental testicular torsion model. urology 2012;80:689-94. 12. yildirim a, yildirim s, topaloglu n, tekin m, kucuk a, erdem h, et al. correlation of ischemia-modified albümin levels and histopathologic findings in experimental ovarian torsion . turk j emerg med 2016;16:811. 13. yilmaz e, hizli f, afsarlar ce, demirtas c, apaydin s, karaman i, et al. early diagnosis of testicular torsion in rats by measuring plasma d-dimer levels: comparative study with epididymitis. j pediatr surg 2015;50:651-4. 14. incebiyik a, camuzcuoglu a, hilali ng, vural m, camuzcuoglu h. plasma d-dimer level in the diagnosis of adnexal torsion. j matern fetal neonatal med 2015;28:1073-6. 15. kart c, aran t, guven s, karahan sc, yulug e. acute increase in plasma d-dimer level in ovarian torsion: an experimental study. hum reprod 2011;26:564-8. 16. guven s, karahan sc, bayram c, ucar u, ozeren m. elevated concentrations of serum ischaemia-modified albumin in pcos, a novel ischaemia marker of coronary artery disease. reprod biomed online 2009;19:493-500. 17. cosentino mj, nishida m, rabinowitz r, cockett at. histopathology of prepubertal rat testes subjected to various durations of spermatic cord torsion. j androl 1986;7:2331. 18. peretti m, zampieri n, bertozzi m, bianchi f, patanè s, spigo v. et al. mean platelet volume and testicular torsion: new findings. urol j 2019;16:83-85. 19. gul ss, gurgul s, uysal m, erdemir f. the protective effects of pulsed magnetic field and melatonin on testis torsion and detorsion induced rats indicated by scintigraphy, positron emission tomography/computed tomography and histopathological methods. urol j 2018;15:387-396. 20. gultekin a, tanriverdi hi, inan s, yilmaz o, gunsar c, sencan a. the effect of tunica albuginea incision on testicular tissue after early diagnosis of testicular torsion-sarac et al. detorsion in the experimental model of testicular torsion. urol j. 2018;15:32-39 endourology and stone disease a comparison of retrograde intrarenal surgery and percutaneous nephrolithotomy for management of renal stones ≥ 2 cm sercan sari*1,hakki ugur ozok2, mehmet caglar cakici2, harun ozdemir3, okan bas2, nihat karakoyunlu2, levent sagnak2, aykut bugra senturk4, hamit ersoy4 purpose: in this retrospective study, we aimed to compare the outcomes in patients who have been treated with percutaneous nephrolithotomy (pnl) and retrograde intrarenal surgery (rirs) on renal stones ≥ 2 cm size. materials and methods: we evaluated patients who underwent pnl or rirs for renal stones ≥ 2 cm size between november 2011 and november 2014. stone size, operation, fluoroscopy and hospitalization time, success rates, stone-free rates and complication rates were compared in both groups. patients were followed for three months. results: 254 patients were in the pnl group. 185 patients were in the rirs group. the mean age was 46.88 and 48.04 years in pnl and rirs groups, respectively. the patient and stone characteristics (age, gender, body mass index, kidney anomaly, swl history and stone radioopacity) were similar between two groups. the mean stone size preoperatively was significantly larger in patients who were treated with pnl (26.33mm.vs 24.04 mm.; p = .006). in the rirs group, the mean stone number was significantly higher than pnl group (p < .001). the mean operative, fluoroscopy and hospitalization time were significantly higher in pnl group (p < .001). the stone-free rate was 93.3% for the pnl group and 73.5% for the rirs group after first procedure (p < .001). no major complication (clavien iii–v) occurred in the rirs group. conclusion: although the primary treatment method for renal stones ≥ 2cm size is pnl, serious complications can be seen. therefore, rirs can be an alternative treatment option in the management of renal stones ≥ 2 cm size. keywords: percutaneous nephrolithotomy; retrograde intrarenal surgery; urolithiasis introduction currently, shock wave lithotripsy(swl), retrograde intrarenal surgery(rirs) and percutaneous nephrolithotomy(pnl) are the three main modalities for renal stone treatment. the european association of urology and american urological association guidelines for the treatment of renal stones >20mm recommend percutaneous nephrolithotomy as the first-line therapy, independent of stone location within the kidney(1,2). pnl has an excellent success rate in clearing stone burden at reported rate up to 96,1%(3). despite its effectiveness, serious complications, such as blood loss, sepsis, adjacent organ injury and life-threatening medical complications are rare but still a source of concern(4). therefore, there have been efforts to modify the procedure to decrease potential complications (such as mini-pnl, ultra mini-pnl)(5-7). the aim of all these efforts is to apply more effective treatment choices and less invasive methods to patients, to reduce complications and to return to ensure a normal life as soon as possible. rirs has recently been a very impressive treatment option for the majority of renal stones, as a result of the technological advances and developments in flexible ureteroscope, it can minimize the risks associated with pnl as an outpatient procedure(1). rirs is approved as effective and minimally invasive procedure with achieving higher stone-free rates than swl and lower morbidity than pnl(8). however, rirs may be a first-line option for larger stones (even ≥ 2 cm size) in patients where pnl is not an option or contraindicated(1). moreover, several groups have demonstrated excellent success rates with rirs for large renal stones and it has already replaced pnl as a first choice treatment for renal stones requiring active treatment at some centers(9-11). in this retrospective study, we aimed to compare the outcomes of patients who have been treated with standard pnl and rirs on renal calculi ≥2 cm size. recently, several authors have reported similar studies in a limited number of patients(3,12). to the best of our knowledge, this study is the largest cohort that compares these methods directly in the management of large renal calculi (> 2cm size). we aimed to compare the effectiveness and safety of pnl and rirs in the 1department of urology,sarikamis state hospital, kars, turkey. 2department of urology, diskapi yildirim beyazit training and research hospital, ankara, turkey. 3department of urology, haseki training and research hospital, istanbul,turkey. 4department of urology, hitit university, faculty of medicine, çorum, turkey. *correspondence: department of urology,sarikamis state hospital, kars, turkey. phone: +905356608838. e-mail: sercansari92@hotmail.com. received august 2016 & accepted december 2016 endourology and stone diseases 2949 treatment of renal stones sized ≥ 2 cm. materials and methods in this study, we retrospectively reviewed patients data who underwent standard pnl or rirs for renal calculi sized ≥2 cm by the same surgical team at a single institution between november 2011 and november 2014. treatment method was chosen according to the urologist and patients preference after assessing both potential risks and benefits (complication rates, stone-free rates, the passage of residual fragments, possible operative times and re-treatment rates, postoperative double-j stent placement, etc.) of each surgical option. patients with an ureteropelvic junction obstruction, anomalous kidneys (except horseshoe kidney), a history of open or percutaneous interventions to the ipsilateral kidney, <18 years of age, or those having a solitary kidney were excluded. a total of 439 patients met these criteria and were divided into two groups according to the procedure performed; pnl group n = 254, and rirs group n=185. the demographics of the patients and operative outcomes were compared. preoperative patient assessment included medical history, physical examination, complete blood count, serum biochemistry, urinalysis and urine cultures, coagulation profiles, and by the use of different imaging methods (kidney ureter bladder (kub) graphy, ultrasonography (usg), intravenous urography and/or computed tomography). a preoperative negative urine culture was required before surgery, so any positive urine cultures were treated according to the antibiogram results. stone size was defined as the maximum diameter of the stone on computed tomography. in cases of multiple stones, stone size was defined as the sum of the longest axis of each stone. informed consent was taken from all patients preoperatively. pnl technique all pnl procedures were performed under general anesthesia.patients were placed in the lithotomy position.cystourethroscopy was made for open ended uretheral catheter insertion. after uretheral catheter insertion , percutaneous access was achieved by c-arm fluoroscopic guidance using an 18-gauge needle with the patient in a prone position. a 0.035-inch j-tipped guidewire was passed through the needle and into the collecting system under fluoroscopic guidance, and the nephrostomy tract was dilated up to 30 f with polyurethane serial amplatz dilators(microinvazive,natick,ma) or metal alken dilators. a 30f amplatz sheath was then placed over the dilators. all steps of tract dilation and sheath placement were done under fluoroscopic imaging. stone fragmentation was accomplished with pneumatic lithotripter (lithoclast; ems, nyon, switzerland) and the stones fragments removed with forceps through a rigid nephroscope (26f, karl storz®). a nephrostomy tube was placed in all the patients at the end of the procedure(13). time between entering the cystoscope and nephrostomy tube placement was defined as operation time. rirs technique all rirs procedures were applied under general anesthesia with the patient placed in the lithotomy position and semi-rigid ureteroscopy was routinely performed before flexible ureteroscopy to facilitate the ureter dilatation for insertion of access sheath.. a 0.035/0.038inch hydrophilic safety guidewire was inserted into the renal pelvis under fluoroscopic guidance. thereafter, a ureteral access sheath (9.5/11.5 f or 11/13 f) (elit flex, ankara, turkey) was placed over the hydrophilic guidewire in all patients. if the access sheath could not be placed easily, the stent was left approximately 1-2 weeks before repeating the procedure . the flexible ureterorenoscope (karl storz, flex x2, gmbh, tuttlingen, germany) was inserted through the ureteral access. stone fragmentation was achieved with a 200 μm holmium laser fibers (dornier med-tech gmbh, medilas h20, wessling, germany) until they were deemed small enough to be passed spontaneously. the small fragments were finally evacuated using a manual pump or tipless nitinol baskets (zero tip™; boston scientific microvasive). in the majority of patients, a jj stent was put into place at the end of the procedure and removed approximately 14-21 days postoperatively as an outpatient procedure(11). the repeated session was achieved at intervals of 1–3 weeks in patients with incomplete fragmentation or residual stones which were checked on postoperative day 1 with kub graphy and usg (if necessary). time between starting endoscopy and jj stent placement was defined as operation time. stone size, operation and fluoroscopy time, hospitalization time, postoperative jj stent placement, success rates, stone-free rates and complication rates (using the modified clavien grading system) were compared in both groups. data was reported as the number and percent or median (range) as appropriate. stone clearance was assessed in the operation with fluoroscopic control and the day after surgery by kub graphy or usg . all patients were evaluated with kub graphy and usg after one month postoperatively in an outpatient clinic setting. asymptomatic stones smaller than 3 mm were considered as clinically insignificant urolithiasis. patients who were stone-free or with clinically insignificant urolithiasis one month after the last operation were considered to have been treated successfully. patients were followed for three months. statistical analysis analyse of data was made with statistical package for the social sciences for windows packet programme (spss, chicago). distribution of numerical measurement values was tested with one-sample kolmogorov-smirnov test. if p value was < 0.05, distribution was not normal. differences in terms of gender, renal abnormality, stone side and localization, bleeding, dj usage, residual stone presence, opacity, success after the first session, complication, hydronephrosis, preoperative surgery and swl history between two groups were searched with pearson chi-square test. differences in terms of age, weight, preoperative hemoglobin value between two groups were evaluated with student’s t test. differences in terms of height, american society of anesthesiologists (asa) scores, stone number, stone size, operation time, hospital stay, preoperative urea and creatinine and body mass index (bmi) between two groups were evaluated with mann-whitney u test. in pnl and rirs groups, whether changes in preoperative and postoperative hemoglobin, urea and creatinine were significant, were measured with wilcoxon signed ranks test. p < 0.05 was considered statistically significant. rirs and pnl for stones ≥2 cm-sari et al. vol 14 no 01 january-february 2017 2950 results in our study 254 patients were in the pnl group. 185 patients were in the rirs group. the mean age was 46.88 and 48.04 years in pnl and rirs groups respectively. the patient and stone characteristics(age, gender, body mass index(bmi), kidney anomaly, swl history and stone radioopacity) were similar between two groups. the mean stone size preoperatively was significantly larger in patients who were treated with pnl, with the average size for rirs being 24.04 mm. and that for pnl being 26.33 mm. (p = 0.006). in the rirs group, the mean stone number was significantly higher than pnl group (p < 0.001). the demographic data and stone characteristics are summarized in table 1. eleven patients in the rirs group and eight patients in the pnl group had horseshoe kidney. in the rirs group, 57 patients and 70 patients in pnl group had previously undergone unsuccessful swl applications. the mean operative time, fluoroscopy screening time and hospitalization time were significantly higher in pnl group (p < 0.001, for all of them). in one patient access sheath was not placed and jj stent was placed 2 weeks before the second procedure. however, postoperative jj stent placement was also significantly higher in the rirs group (p < 0.001). the stone-free rate was 93.3% for the pnl group and 73.5% for the rirs group after a single procedure (p < 0.001). in the rirs group, 23 patients had asymptomatic residual fragments < 10 mm in the lower pole of the kidney and were followed without any intervention; 22 required additional procedure (swl in 1, second rirs in 16, pnl in 5) and all of them were completely stone free, resulting in an overall success rate of 85.4%. four patients were also lost the follow-up in rirs group. in the pnl group, the success rate increased to 94.8% after a rirs intervention (in 4 patients). thirteen patients were followed without any intervention due to the asymptomatic residual fragments. when we look at the complication (major and minor) rates, the difference was not statistically significant (p = .058). five patients in the pnl group received blood transfusions, whereas none of the patients in rirs group were transfused. no major complication (clavien iii–v) occurred in the rirs group. however, there were four major complications (1.5%) in the pnl group. three patients suffered from prolonged urine leakage (clavien iii) which was treated with a jj stent. one patient died (clavien v) due to cardiac arrest. operative and postoperative data are summarized in table 2. discussion pnl is recommended as a first line treatment option in the management of renal stones sized ≥ 2 cm(1,2). however, life-threatening complications can be seen. another treatment method is rirs. arising in 1990’s, use of rirs has increased by developing technology and extending experience(14). development in new flexible renoscopes and laser technology led to increase in area of use of this method(15-17). in the literature, there are studies about the usage of rirs for the treatment of renal stones sized ≥ 2 cm. breda et al. reported a success rate of 93.3% for 15 parirs and pnl for stones ≥2 cm-sari et al. pnl group (n=254) rirs group (n=185) p value age (mean ± sd) (years) 46.88 ± 14.35 48.04 ± 14.09 ns. gender; male/female (n) 155/99 111/74 ns. mean bmi (kg/m2) 27 ± 3.78 25.71 ± 3.02 ns. anomalous kidney, n (%) 8 (3.1) 11 (5.9) ns. history of swl, n (%) 70 (27.6) 57 (30.8) ns. radioopacity of stone, n (%) non-opaque 26 (10.2) 20 (10.2) ns. opaque 228 (89.8) 165 (89.8) stone laterality; right/left (n) 120/134 89/94 ns. stone number (mean ± sd) 1.5 ± 0.1 2.0 ± 0.1 < 0.001 stone size (mean ± sd) (mm) 26.33 ± 0.44 24.04 ± 0.39 0.006 stone location, n (%) renal pelvis 102 (40.2) 62 (33.5) lower calyx 66 (24.4) 52 (28.2) middle calyx 12 (4.7) 25 (13.5) < 0.001 upper calyx 8 (3.1) 13 (7) multicaliceal 70 (27.6) 33 (17.8) table 1: demographic data and stone characteristics abbreviations: sd, standard deviation; bmi,body mass index; swl, shock wave lithotripsy; rirs, retrograde intrarenal surgery; pnl, percutaneous nephrolithotomy; ns, non significant endourology and stone diseases 2951 tients with renal stones of 20-25 mm(10). mariani et al. reported a success rate of 92% in 15 patients with renal stones of 2-4 cm size(18). grasso et al. reported a success rate of 91% for 51 patients with renal stones sized ≥ 2 cm(19). palmero et al. applied rirs to 106 patients with renal stones sized ≥ 2 cm(20). hyams et al. stated a success rate of 85% for 120 patients with renal stones of 2-3 cm size for the study in which rirs method was applied(21). there are few studies comparing rirs and pnl methods for treatment of renal stones 2-4 cm in size. in their research in which 68 patients were included and rirs and pnl methods were compared, akman et al. found the success rates of 91.2% and 73.5% for pnl and rirs groups, respectively(22). in the follow-up conducted three months later, success rates of 97% and 94.1% were found for pnl and rirs groups, respectively. bryniarski et al. compared rirs and pnl methods in 64 patients with pelvis stones of 2-4 cm size in a prospective study(23). success rates of 81.25% and 50% were detected for pnl and rirs groups, respectively and the success rates of 93.75% and 75% were reported after a follow-up study of 3 weeks. de et al. compared the rirs and pnl methods in their review(24). the stone size was between 24 cm in only two of ten studies taken into consideration. in our study, rirs and pnl methods were compared in 439 patients with renal stones sized ≥ 2 cm. the following success rates were found: 93.3% and 73.5 for pnl and rirs groups, respectively and 94.9% and 85.4% for the same groups in terms of total success rate. the results were similar to those found in studies in the literature. in our study, the operation duration was found to be 79.2 table 2: per-operative and postoperative data pnl group (n=254) rirs group (n=185) p value operation time (min) 79.25 ± 35 54.29 ± 14.09 < 0.001 fluoroscopy screening time (min) 6.5 ± 4.97 1.04 ± 1.32 < 0.001 preferred access, n (%) lower calyx 244 (97) middle calyx 10 (3) hospitalization time (day) (mean ± sd) 3.94 ± 1.22 1.02 ± 0.23 < 0.001 double-j placement, n (%) 76 (30) 155 (83.8) < 0.001 stone-free status, n (%) stone free 229 (89.8) 151 (72.6)a /167 (80.3)b /168 (80.7)c cirf d 9 (3.5) 5(2.4)a /0 (0)b /0 (0)c rest 17 (6.7) 52 (25)a/ 41 (19.7)b /40 (19.3)c success rates e, n (%) 237 (93.3) 136 (73.5) < 0.001 complication rates, n (%) 21 (8.3) 7 (3.8) ns. minor (clavien i-ii) complications fever 12 (4.72) 7 (3.8) blood transfusion 5 (1.96) urinary tract infection 7 (2.75) 7 (3.8) major (clavien iii-v) complications jj placement for urine leakage 3 (1.18) death 1 (0.39) auxiliary procedure, n (%) swl 1 (0.005) rirs 4 (1.57) 16 (8.67) pnl 5 (2.7) observation 13 (5.11) 23 (12.7) abbreviations: sd, standard deviation; bmi, body mass index; swl, shock wave lithotripsy; rirs, retrograde intrarenal surgery; pnl, percutaneous nephrolithotomy; ns, non significant a: 1st rirs sessions, b: 2nd rirs sessions, c: 3rd rirs sessions d: clinically insignificant residual fragments e: success is defined as stone free + cirf rirs and pnl for stones ≥2 cm-sari et al. vol 14 no 01 january-february 2017 2952 ± 34.9 and 54.29 ± 14.09 minutes for pnl and rirs groups, respectively. the efforts for stone clearence are one reason for this result. akman et al. indicated the operation durations of 38.7 ± 11.6 and 58.2 ± 13.4 minutes for pnl and rirs groups, respectively(22). in another study, bryniarski et al. reported 100.1 and 85 minutes for the pnl and rirs groups, respectively(23). in our study, the scopy time was determined to be 6.5 ± 4.97 and 1.04 ± 1.32 minutes for pnl and rirs groups, respectively. the results were similar to those found in studies in the literature. the difference was explained on the basis of taking scopy for entry to kidney via percutaneous access. in terms of hospitalisation period, we determined the periods of 3.94 ± 1.22 and 1.02 ± 0.23 days for pnl and rirs groups, respectively. the period passing for taking percutaneous nephrostomy led to increase in hospitalisation time in the pnl group. applying tubeless pnl may shorten this period. the decision for tubeless pnl is made on the basis of existence or nonexistence of intraoperative bleeding, residual stones or perforation. tubeless pnl was not applied to any patient in our research. in terms of bleeding status, it was significantly higher in pnl group compared to rirs group. it was associated with longer operation duration. in their research, akman et al. concluded that the need for blood transfusion increases by 2.82 times in pnl operations longer than 58 minutes(25). when complication rates are taken into consideration, although more complication was seen in pnl group, the difference was not statistically significant. no major complication was seen in rirs group. in pnl group major complications were seen. in pnl group one patient died due to cardiac arrest. the number of minor complications were higher in pnl group but the difference was not statistically siginificant. when the literature is assessed, life-threatening complications may be seen in pnl operation. these are transfusion-requiring bleeding, septicaemia, colon injury, hemothorax, fever and urinary system infection. in our study, one of our patients died. transfusion-requiring bleeding was detected at the rates of 0.8% to 45% in pnl operation in literatüre(26-28). significant complications are not observed in rirs operation due to developing technology. mini and ultra mini pnl can be applied to prevent the complications due to the sheath size. in our study jj stent usage was higher in the rirs group. the major reason is access sheath usage .another reason is residuel stones. the stone free rates were lower in the rirs group . if we look at limitations of our study, its being retrospective is a disadvantage. due to retrospective nature, stone size was different between the groups. another limitation is short patient follow up. therefore an important complication related to access sheath usage in rirs was not seen in our study. when previous studies are taken into consideration, it is the largest study in the literature in terms of number of patients. for treatment of renal stones sized < 2 cm rirs can be used as first line treatment(29). rirs can be used for patients not requesting invasive treatment for stones of sized ≥2cm. total cost level is a disadvantage to rirs. its shorter duration of hospital stay and operation as well as lower complication levels can compensate this disadvantage. another disadvantage is that it may require multiple sessions. pnl can be taken into consideration for patients requesting treatment in single session. as a conclusion, ≥ 2sized stone treatment is one of the controversial issues in urology. pnl is more effective than rirs in treatment of these stones. and primary treatment method. although the primary treatment method is pnl, significant complications can be seen. rirs can be taken into consideration in cases not requiring invasive treatment. comprehensive and prospective studies are needed. conflict of interest no competing financial interests existed. references 1. turk c, knoll t, petrik a, et al: guidelines office (2012). guidelines on urolithiasis. in: eau guidelines, edition presented at the 27th eau annual congress, paris. 2012. 2. preminger gm, tiselius h-g, assimos dg, et al: 2007 guideline for the management of ureteral calculi. eur. urol. 2007; 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160: 346–51. 20. palmero jl, castelló a, miralles j, et al: results of retrograde intrarenal surgery in the treatment of renal stones greater than 2 cm. actas urol. esp. 2014; 38: 257–62. 21. hyams es, munver r, bird vg, et al: flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burdens that measure 2 to 3 cm: a multi-institutional experience. j. endourol. endourol. soc. 2010; 24: 1583–8. 22. akman t, binbay m, ozgor f, et al: comparison of percutaneous nephrolithotomy and retrograde flexible nephrolithotripsy for the management of 2-4 cm stones: a matchedpair analysis. bju int. 2012; 109: 1384–9. 23. bryniarski p, paradysz a, zyczkowski m, et al: a randomized controlled study to analyze the safety and efficacy of percutaneous nephrolithotripsy and retrograde intrarenal surgery in the management of renal stones more than 2 cm in diameter. j. endourol. vol 14 no 01 january-february 2017 2954 rirs and pnl for stones ≥2 cm-sari et al. clinical implications of peripheral cd+3cd+69 t-cell and cd+8cd+28 t-cell proportions in patients prior to radical prostatectomy yu zhang1, ziye zhang1, lina zhang2, sheng zhao1, jing zhao1, qing ye1, yingli gao1, chenyi jiang1, di cui1, shujie xia1, bangmin han1*, yifeng jing1* purpose: to investigate the clinical implications of cd+3cd+69 t-cells and cd+8cd+28 t-cells in the peripheral blood of patients prior to radical prostatectomy. materials and methods: a total of 91 prostate cancer (pca) patients and 50 benign prostatic hyperplasia (bph) patients were enrolled from january 2016 to december 2017. the proportions of cd+3cd+69 t-cells and cd+8cd+28 t-cells in the peripheral blood of pca and bph patients were detected by flow cytometry, and the association of these t-cell populations with pathological grade group and pathological tnm classification was evaluated. data analysis was performed with sas version 9.4 software. results: the proportions of cd+3cd+69 and cd+8cd+28 t-cells in peripheral blood were higher in pca patients than those in bph patients. multivariate analysis identified a higher cd+3cd+69 t-cell proportion as a risk factor for pca (odds ratio (or) = 4.783, p = 0.0013), but the diagnostic efficacy of the cd+3cd+69 t-cell proportion (area under the curve (auc)=0.6833, p = 0.0003) for pca was still inferior to that of the tpsa level (auc=0.7531, p < 0.0001). the aucs for cd+3cd+69 t-cell and cd+8cd+28 t-cell proportions for pca were 0.6959 (p = 0.0372) and 0.6935 (p = 0.0395), respectively, among men with tpsa levels of 10.0-4.0 ng/ml. a lower cd+3cd+69 t-cell proportion was associated with higher pathological grade group (p=0.0074). conclusion: the proportions of cd+3cd+69 t-cells and cd+8cd+28 t-cells in peripheral blood are potential diagnostic indicators for pca. the preoperative proportion of cd+3cd+69 t-cells in peripheral blood may have prognostic value in terms of the pathological grade group in pca. keywords: cd+3cd+69 t-cell; cd+8cd+28 t-cell; immune function; prostate cancer; radical prostatectomy introduction prostate cancer (pca) is the most commonly diag-nosed malignancy and the second leading cause of cancer-related mortality in american males, with an estimated 164,690 new cases and 29,430 deaths expected in 2018 (1).the occurrence, development, recurrence and metastasis of tumors are processes representative of tumor escape from immune surveillance, which is strongly related to host immune function(2). detecting subsets of t lymphocytes in peripheral blood may be a beneficial way to understand immune function, and assist in the clinical diagnosis of disease(2,3). cd28 is expressed on approximately 50% of cd8+ t-cells(4). cd28 is known to be the primary t-cell costimulatory molecule that interacts with its natural ligands, cd80 and cd86, located on antigen-presenting cells (apcs). the signal leads to the activation and proliferation of t-cells and cytokine secretion(5). previous studies have found that cd69+ t lymphocytes downregulate the inflammatory process and could be a negative regulator of the differentiation of t lymphocytes toward the th17 lineage through tgf-β or jak3/stat5 signaling(6-8). therefore, understanding the mechanisms 1department of urology, shanghai general hospital, shanghai jiao tong university school of medicine, shanghai, china 2department of biostatistics, shanghai jiao tong university school of medicine, shanghai, china *correspondence: department of urology, shanghai general hospital, shanghai jiao tong university school of medicine, 100 haining road, shanghai, china. tel: +8613918839913; fax: +86021-63240825; e-mail: jyf_123@163.com (yfj); tel: +8618939757031; fax: +86-21-63240825; e-mail: hanbm@163.com (bmh) received january 2019 & accepted july 2019 of cd69+ t-cells that modulate the immune response could enable them to be targeted by cancer immunotherapies. in the present study, we examined the differences in cd3+cd69+ and cd8+cd28+ t-cell populations in preoperative peripheral blood between pca and bph patients to find potential diagnostic targets for pca and investigated the relationships between cd3+cd69+ and cd8+cd28+ t-cell proportions and clinicopathological characteristics to determine their roles as biomarkers for pca. materials and methods patients and sample size our study was approved and carried out according to the instructions of the ethics committee of shanghai general hospital. all peripheral blood samples were taken from patients after obtaining written informed consent. from january 2016 to december 2017, 91 patients with pca underwent laparoscopic radical prostatectomy (lrp) performed by one single experienced surgeon, and they formed the experimental group. patients in the following situations were excluded: (1) the patients had urological oncology urology journal/vol 17 no. 3/ may-june 2020/ pp. 257-261. [doi: 10.22037/uj.v0i0.5103] accepted any type of neoadjuvant hormonal therapy prior to the operation; (2) the patients had suffered from incurable endocrine diseases; (3) the patients had acute prostatitis, urinary tract infection and previous surgical intervention on the prostate; (4) the patients had systematic tumors or chronic diseases, such as hepatitis; and(5) the patients had other diseases of the immune system(10). in addition, 50 bph patients who underwent transurethral thulium laser resection of the prostate were selected to form the control group over the same timeframe; the same exclusion criteria used for patients with pca was also used for controls; their postoperative pathological results showed bph. tissue samples, histological classification and tnm stage paraffin-embedded tissue samples from 91 patients surgically treated for pca were utilized. histological classifications were assessed by pathological grade group according to the criteria of the international society of urological pathology (isup) 2014 grade groups(10). the pathological tumor node metastasis (tnm) stage was evaluated according to the tnm classification of pca in european association of urology (eau) 2016 guidelines(10). blood sample preparation and flow cytometer venous blood was obtained from each patient in the morning, prior to surgery. blood samples were divided into two separate anticoagulated tubes per subject and were sent to the clinical laboratory for the immediate analysis of t-cell subsets. for immunostaining, the following conjugated antibodies were all obtained from bd pharmingen, usa. anti-cd3-percp and anticd69-fitc mabs were added to one tube, while anti-cd8-pe and anti-cd28-apc mabs were added to the other tube. the tubes were then mixed gently and incubated for 30 min. after lysing red blood cells, the tubes were centrifuged at 1000 rpm for 5 min, and the precipitate was obtained. the precipitate was washed with phosphate-buffered saline (pbs), after which the tubes were centrifuged again at 1000 rpm for 5 min, and the precipitate was obtained. the precipitate was resuspended in pbs. the detection of cd3+cd69+ and cd8+cd28+ t-cells was performed by flow cytometry (bd pharmingen, usa). in addition, the prostate-specific antigen (psa) level was tested before the operation. statistical analysis an independent t test was used to compare the age, total prostate-specific antigen (tpsa) level and proportions of t-cells in peripheral blood between the two groups. in addition, a wilcoxon rank-sum test was used to compare the proportions of t-cells in peripheral blood between the two groups when the tpsa threshold was set to 4-10 ng/ml. data are expressed as the mean and standard deviation (sd). multivariate logistic regression analyses were performed to evaluate the associations between t-cell proportions and disease outcomes. to determine the optimal cutoff value, youden’s index was calculated using receiver operating characteristic (roc) curve analysis. spearman rank correlation analysis was used to explore the association between the t-cell proportions and clinical conditions, including pathological grade group, and ptnm classification. all statistical analyses were performed using sas version 9.4 software. results the patients’ clinicopathological and demographic characteristics are summarized in table 1. the 91 pca patients and 50 bph patients involved in this study showed no significant difference in age (p = 0.535). peripheral cd3+cd69+ and cd8+cd28+ t-cells in pca-zhang et al. table 1. clinical characteristics of 91 pca patients and 50 bph patients (mean ± sd) variables pca (n=91) bph (n=50) p value age (years) 67.62 ± 5.66 68.40 ± 7.71 0.535 tpsa (ng*ml-1) 15.16 ± 13.90 3.50 ± 2.62 0.000** cd8+cd28+ t-cells (%) 8.50 ± 3.91 6.55 ± 3.77 0.005** cd3+cd69+ t-cells (%) 1.33 ± 0.12 0.66 ± 0.05 0.000** pathologic tnm classification, n (%) / / t2 43(47.3%) t3 48(52.7%) grade group, n (%) / / 1 25(27.5%) 2 21(23.1%) 3 26(28.6%) 4 8(8.8%) 5 11(12.0%) abbreviations: pca prostate cancer, bph benign prostate hyperplasia, tpsa total prostate-specific antigen. **: p < 0.01. variable or 95% ci of or p value cd3+cd69+ t-cells (%) 4.783 1.840 12.432 0.0013** abbreviations: or odds ratio, ci confidence interval. **: p < 0.01. table 2. multivariate logistic regression analysis of proportion of cd3+cd69+ t-cells in peripheral blood in predicting pca urological oncology 258 vol 17 no 03 may-june 2020 259 however, the preoperative tpsa level was higher in the pca group than in the bph group (p < 0.001). the comparison of the proportions of cd3+cd69+ and cd8+cd28+ t-cells in the peripheral blood of pca and bph patients is shown in table 1. the proportions of cd8+cd28+ and cd3+cd69+ t-cells were higher in the pca group than in the bph group. multivariate logistic regression analysis was performed to evaluate the associations between the proportions of cd8+cd28+ or cd3+cd69+ t-cells and disease outcomes. table 2 shows that a high proportion of cd3+cd69+ t-cells in peripheral blood was associated with a higher risk of pca when adjusted for age and tpsa. roc curve analysis was performed to determine the optimal cutoff value of the cd3+cd69+ t-cell population for pca (area under the curve (auc)=0.6833, p = 0.0003, figure 1). because a cd3+cd69+ value of 0.9 showed the maximal youden’s index on this curve, the cutoff value of cd3+cd69+ for pca was set at 0.9. the auc for cd8+cd28+ was 0.6645 (p = 0.0013), and the auc for tpsa was 0.7531 (p < 0.0001). there was no significant difference in the auc between the two biomarkers, but the auc for tpsa was the highest. when we set the threshold of the tpsa level (4-10 ng/ ml), there were 31 patients in the pca group and 14 patients in the bph group. a nonparametric test was performed to determine the differences in the two t-cell proportions between the two groups. table 3 shows that the proportions of cd8+cd28+ and cd3+cd69+ t-cells in the pca group were higher than those in the bph group. the roc curves of cd3+cd69+ and cd8+cd28+ for pca were analyzed to determine the optimal cutoff values (auc=0.6959 for cd3+cd69+; auc=0.6935 for cd8+cd28+, figure 2). the cutoff values of cd3+cd69+ and cd8+cd28+ for pca were set at 1.6 and 8.2, respectively. in addition, figure 2 shows that the auc for the ratio of free to total psa (f/tpsa) was 0.9055 (p<0.0001). these data suggest that a higher proportion of cd3+cd69+ or cd8+cd28+ t-cells is a predictor of pca in men with tpsa levels of 4.0-10.0 ng/ml. we compared the distribution of clinicopathological characteristics between the two groups, along with the two t-cell proportions. table 4 shows that the proportion of cd3+cd69+ t-cells in peripheral blood was weakly negatively correlated with the pathological grade group in pca patients. figure 3 shows that the auc for cd3+cd69+ t-cells for the pathological grade group (gs≥3) was 0.6429 (p = 0.0189). youden’s index was still 0.9. in addition, the proportion of cd8+cd28+ t-cells in circulating blood was not significantly associated with any of the analyzed clinicopathological parameters. discussion pca is one of the most common cancers in men, and the global burden of this disease is rising(11). early diagnosis is vital for the treatment of pca. the current gold standard, prostate biopsy, is an invasive testing method for the diagnosis of pca, but pca does not present with obvious clinical manifestations, therefore, the decision to perform a prostate biopsy depends on serum psa, digital rectal examination (dre) and multiparametric magnetic resonance imaging results(12). however, there are drawbacks of psa as an early detection biomarker of pca. the gray area of psa (4.0-10.0 ng/ml) leads to a high rate of negative biopsies and overtreatment. dre is a subjective procedure that can lead to false-positive results and unnecessary biopsies. as a consequence, there is still an urgent need for novel biomarkers that could further improve diagnostic capability(13,14). jamali et al. found that the combined contribution of spop, daxx, rarres1, and lamp2 could be a putative regulatory element acting as a prognostic signature and therapeutic target in pca. guo j et al. demonstrated that quantitative analysis of ultrasound real-time tissue diffusion elastography is helpful in the diagnosis of benign and malignant prostate lesions and provides a relatively accurate evaluation method in clinical practice, with broad application prospects. taheri et al. assessed the associations between two genomic variants (rs1800795 and rs2069845) of the il-6 gene and risk of pca. saffari et al. showed that mir-let7b and/or mir548 can be considered as potential targets in prostate table 3. comparison of proportions of cd3+cd69+ and cd8+cd28+ t-cells in peripheral blood between pca and bph patients with tpsa levels ranging from 4.0-10.0 ng/ml (mean ± sd) variables pca (n=31) bph (n=14) p value cd8+cd28+ t-cells (%) 9.57±0.78 7.13±0.71 0.0389* cd3+cd69+ t-cells (%) 1.50±0.22 0.76±0.11 0.0362* abbreviations: pca prostate cancer, bph benign prostate hyperplasia, tpsa total prostate-specific antigen. *: p < 0.05. variables r s p value pathological tnm classification (t2, t3a, ≥ t3b) -0.17455 0.098 pathological grade group (2016 who new classification, 1-5) -0.22729 0.0303* abbreviations: pca prostate cancer, bph benign prostate hyperplasia, rs spearman rank correlation coefficient, tnm tumor, node and metastasis. *: p < 0.05; **: p < 0.01. table 4. clinicopathological characteristics of the pca patient cohort in relation to cd3+cd69+ t-cells (spearman correlation analysis) peripheral cd3+cd69+ and cd8+cd28+ t-cells in pca-zhang et al. cancer therapy. pca patients always present with immunological dysfunction. in the present study, we assessed the immune function variation by measuring cd3+cd69+ and cd8+cd28+ t-cell subsets in the peripheral blood of pca patients prior to any form of treatment, including hormonal therapy, surgery, chemotherapy, and radiotherapy. we found that the proportions of cd3+cd69+ and cd8+cd28+ t-cells were higher in the circulating blood of pca patients than bph patients. previous research has shown that the mean proportion of cd8+cd28+ t-cells is significantly lower in patients with b-cell chronic lymphocytic leukemia than in healthy controls(4). in 2011, katarzyna starska et al. found that the expression of cd69+ antigen on cd3+cd4+ t-cells was higher for pt3 and pt4 tumors than for pt2 squamous cell laryngeal carcinomas(15). our results suggest that the proportions of cd3+cd69+ and cd8+cd28+ t-cells in peripheral blood could be associated with the occurrence of pca. in addition, we identified cd3+cd69+ t-cells as an independent risk factor for pca. our data suggest that cd3+cd69+ and cd8+cd28+ t-cell proportions are effective for the diagnosis of pca, especially in patients with tpsa levels of 4.0-10.0 ng/ml. thus, these data indicate that the proportions of cd3+cd69+ and cd8+cd28+ t-cells in the peripheral blood of patients may be potential diagnostic biomarkers for pca and that high proportions of cd3+cd69+ and cd8+cd28+ t-cells in the peripheral blood of patients could reflect an increased risk of pca. the prognosis of pca can be evaluated by the gleason grading system based on its microscopic appearance because the histological differentiation of pca is closely related to the prognosis, treatment and patient outcome (16). our results show a correlation between the proportion of cd3+cd69+ t-cells in peripheral blood and the pathological grade group. pca patients with a lower cd3+cd69+ t-cell proportion in peripheral blood had a higher pathological grade group, indicating earlier recurrence (17). nonetheless, fundamental research and further studies with more cases are needed. although there are still some limitations in our study, on the one hand, t-cells in pca should be analyzed carefully, as blood cell proportions may be affected by inflammation. on the other hand, it is likely that some participants in the present study were taking drugs, such as steroids or nonsteroidal anti-inflammatory drugs, which could have affected the circulating t-cell populations. to the best of our knowledge, this study is the first to investigate the value of subtypes of circulating t-cells in the diagnosis of pca. the fact that complete blood count tests are performed during routine workups makes t-cell proportions in peripheral blood accessible, inexpensive clinical parameters(18). conclusions we conclude that the proportion of cd3+cd69+ t-cells in circulating blood may be an effective predictor of pca diagnosis combined with the psa level, especially in those with tpsa levels ranging from 4.0 figure 1. receiver operating characteristic (roc) curve of cd3+cd69+ t-cells, cd8+cd28+ t-cells and tpsa for pca diagnosis figure 3. receiver operating characteristic (roc) curve of cd3+cd69+ t-cells for pathological grade group figure 2. receiver operating characteristic (roc) curve of cd3+cd69+ t-cells, cd8+cd28+ t-cells and f/tpsa for pca diagnosis in men with psa level 4.0 ng/ml-10.0 ng/ml peripheral cd3+cd69+ and cd8+cd28+ t-cells in pca-zhang et al. urological oncology 260 vol 17 no 03 may-june 2020 261 ng/ml to 10.0 ng/ml, and it also may be a useful prognostic tool in prostate cancer; however, further study is required. acknowledgment this work was partly supported by national nature science foundation of china (no. 81402091). conflict of interest the authors declare that they have no conflicts of interest. references 1. siegel rl, miller kd and jemal a. cancer statistics, 2018. ca cancer j clin 2018; 68: 7-30. 2. wang zk, yang b, liu h, et al. regulatory t cells increase in breast cancer and in stage iv breast cancer. cancer immunol immunother 2012; 61: 911-916. 3. krupnick as, kreisel d, szeto wy, et al. multiparameter flow cytometric approach for simultaneous evaluation of t lymphocyteendothelial cell interactions. cytometry 2001; 46: 271-280. 4. frydecka i, kosmaczewska a, bocko d, et al. alterations of the expression of t-cell-related costimulatory cd28 and downregulatory cd152 (ctla-4) molecules in patients with b-cell chronic lymphocytic leukaemia. br j cancer 2004; 90: 2042-2048. 5. bocko d, kosmaczewska a, ciszak l, teodorowska r and frydecka i. cd28 costimulatory molecule--expression, structure and function. arch immunol ther exp (warsz) 2002; 50: 169-177. 6. martin p, gomez m, lamana a, et al. cd69 association with jak3/stat5 proteins regulates th17 cell differentiation. mol cell biol 2010; 30: 4877-4889. 7. martin p and sanchez-madrid f. cd69: an unexpected regulator of th17 cell-driven inflammatory responses. sci signal 2011; 4: pe14. 8. esplugues e, sancho d, vega-ramos j, et al. enhanced antitumor immunity in mice deficient in cd69. j exp med 2003; 197: 1093-1106. 9. yang w, jia x, su y and li q. immunophenotypic characterization of cd45ro+ and cd45ra+ t cell subsets in peripheral blood of peripheral t cell lymphoma patients. cell biochem biophys 2014; 70: 993-997. 10. mottet n, bellmunt j, bolla m, et al. eauestro-siog guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent. eur urol 2017; 71: 618-629. 11. cuzick j, thorat ma, andriole g, et al. prevention and early detection of prostate cancer. lancet oncol 2014; 15: e484-e492. 12. lee dj, ahmed hu, moore cm, emberton m and ehdaie b. multiparametric magnetic resonance imaging in the management and diagnosis of prostate cancer: current applications and strategies. curr urol rep 2014; 15: 390. 13. yang z, yu l and wang z. pca3 and tmprss2-erg gene fusions as diagnostic biomarkers for prostate cancer. chin j cancer res 2016; 28: 65-71. 14. katafigiotis i, tyritzis si, stravodimos kg, et al. zinc alpha2-glycoprotein as a potential novel urine biomarker for the early diagnosis of prostate cancer. bju int 2012; 110: e688693. 15. starska k, glowacka e, kulig a, lewy-trenda i, brys m and lewkowicz p. prognostic value of the immunological phenomena and relationship with clinicopathological characteristics of the tumor--the expression of the early cd69+, cd71+ and the late cd25+, cd26+, hla/dr+ activation markers on t cd4+ and cd8+ lymphocytes in squamous cell laryngeal carcinoma. part ii. folia histochem cytobiol 2011; 49: 593-603. 16. epstein ji, pound cr, partin aw and walsh pc. disease progression following radical prostatectomy in men with gleason score 7 tumor. j urol 1998; 160: 97-100; discussion 101. 17. pins mr, fiadjoe je, korley f, et al. clusterin as a possible predictor for biochemical recurrence of prostate cancer following radical prostatectomy with intermediate gleason scores: a preliminary report. prostate cancer prostatic dis 2004; 7: 243-248. 18. lee h, jeong sj, hong sk, byun ss, lee se and oh jj. high preoperative neutrophillymphocyte ratio predicts biochemical recurrence in patients with localized prostate cancer after radical prostatectomy. world j urol 2016; 34: 821-827. peripheral cd3+cd69+ and cd8+cd28+ t-cells in pca-zhang et al. endourology and stone disease comparison of success rate in complete supine versus semi supine percutaneous nephrolithotomy: (the first pilot study in randomized clinical trial) siavash falahatkar, ali ghasemi, keivan gholamjani moghaddam, samaneh esmaeili*, ehsan kazemnezhad, seyednaser seyed esmaeili, reza motiee purpose: to compare outcomes and complications of percutaneous nephrolithotomy (pcnl) in the complete supine versus semi supine position in order to select the best position. materials and methods: in this clinical trial, between july 2011 and may 2014, a total of 44 patients who presented for pcnl were prospectively enrolled and randomly divided into 2 groups [complete supine (n=22), and semi supine (n = 22)]. the results in both positions were compared regarding the complexity and outcomes. stone free rate was considered as a main target of the study. however, it was the first study to focus on overlapping the vertebral density during the access. results: the two groups were comparable in age, gender, body mass index, and preoperative glomerular filtration rate, hemoglobin and creatinine. the mean operative time was significantly shorter for complete supine versus semi supine (36.68 ± 14.12 min versus 47.50 ± 16.45 min, p = .024). at the angle of 0˚, overlapping with the spine occurred in 7 patients (31.8%) in semi supine group and just in 1 patient (4.5%) in complete supine group. also, overlapping with the edge of bed occurred in 10 cases (45.5%) of complete supine and 1 (4.5%) of semi supine; the differences were statistically significant (p = .023, p = .002, respectively). no significant difference was found between the two groups in terms of stone free rate and complications. conclusion: although, we had to convert two cases from semi supine into the complete supine position but we have demonstrated that pcnl in both positions is safe, effective and suitable for the patients. the stone free rate was similar in both groups. but the complete supine position is associated with a significantly shorter postoperative hospital stay and operative time, which may improve ease and safety of pcnl for patients. key words: complexity; fluoroscopy; operative time; percutaneous nephrolithotomy; supine; stone free rate. introduction percutaneous nephrolithotomy (pcnl) is considered the treatment of choice for most renal stones, especially for large, complex and staghorn calculi. this technique has long been performed in the prone position. but recently, there have been many reports about pcnl in the supine position and complete supine position.(1-4) supine position in pcnl is a strong alternative to prone position and is commonly performed in various modification, including the valdivia, galdakao-modified valdivia, modified supine, semi supine and complete supine pcnl (cspcnl).(1,5) the supine position as compared to the prone position has numerous advantages such as convenience for patient and surgeon during surgery, low pressure in pyelocalyceal system thus decreasing the migration of residual stones, evacuation of stone fragments, not exposing the surgeon hands to x-ray(6), rapid access to air way that is important in morbidly obese patients(5), possibility to perform coincidental the pcnl and ureteroscopy for treatment complex stones(1,5,7-13), and less bleeding (5,14-15), however this method is not familiar to most of the endourologists yet and is neglected by most urologists.(2,16-17) some controversial reasons for less trends of urologist to use supine position despite its benefits include: unfamiliar and insufficient training for pcnl in supine position in most educational institutions, reducing the pressure in the collecting system and collapsing the pyelocalyceal system and therefore decreasing operating field(11), anteromedial kidney displacement during accessing(18), and overlapping the stone with vertebra in semi supine position.(18) because of many advantages of supine pcnl, we believe the conflict between supine and prone will terminate in the coming years but the next question will remain as to which kind of supine is appropriate? in the present clinical trial we compared outcomes and complications of pcnl in the complete supine position versus the semi supine position to choose a better position for patients. materials and methods in this clinical trial, 44 patients were enrolled. in all patients informed consent was taken and then patients were randomly allocated to two groups using random block method (ratio 2:2) from july 2012 to may 2014. urology research center, school of medicine, guilan university of medical sciences. *correspondence: urology research center, school of medicine, guilan university of medical sciences e mail: samaneh_815@yahoo.com. received july 2017 & accepted endourology and stone diseases 3000 all patients underwent semi and complete supine pcnl by an expert surgeon. group a (22 patients) underwent complete supine position and group b (22 patients) underwent semi supine position (figure 1). included patients were at least 12 years of age, had single or multiple stones in the upper urinary tract (calyx, the pelvis, upper ureter) with stone burden ≥ 2 cm, lower calyx stones with stone burden ≥ 1.5 cm, swl-resistant stones ≥ 1 cm. excluded patients were those with uncontrolled coagulopathy, pregnancy, history of immunosuppression, renal anomalies and untreated uti (urinary tract infection), upper urinary tract stones with the stone burden ≤ 2 cm, lower calyx stones with stone burden ≤1.5 cm and complete staghorn stones. all pcnls were performed under fluoroscopic guidance in subcostal access method by a single surgeon who had previous experience of pcnl in the complete supine and semi supine position and general anesthesia was used for all the patients. in complete supine position, patients were located near the edge of the bed, but elevation on the flank and changes in lower limb did not occur. lower limbs were in full extension and upper limbs were in abduction and extension, as the same technique that the authors described in 2008.(1) in semi supine position, by a 3-liter saline bag, 20-30 degrees elevating on the ipsilateral flank was created, but the position of upper and lower limbs was similar to comtable 1. demographics of the patients characteristics complete supine group (n=22) semi supine group (n=22) p-value gender (%) male 8 (36.4) 10 (45.5) 0.380 female 14 (63.6) 12 (54.5) mean age ± sd (year) 52.59 ± 11.77 47.55 ± 12.92 0.183 mean bmi ± sd 27.41 ± 4.11 27.07 ± 5.18 0.812 previous intervention eswl yes 7 (31.8) 6 (27.3) 0.500 no 15 (68.2) 16 (72.7) open/pcnl yes 9 (40.9) 5 (22.7) 0.166 no 13 (59.1) 17 (77.3) stone number (%) single 8 (36.4) 9 (40.9) 0.500 multiple 14 (63.6) 13 (59.1) stone location (%) only one calyx 6 (27.3) 2 (9.1) only pelvis 4 (18.2) 3 (13.6) 4 (18.2) only upper ureter 0 (0.0) 1 (4.5) multiple locations 11 (50.0) 12 (54.5) staghorn 1 (4.5) 4 (18.2) complex stone (%) yes 12 (54.5) 16 (72.7) 0.147 no 10 (45.5) 6 (27.3) opacity (%) radiopaque 21 (99.5) 22 (100.0) 0.500 radiolucent 1 (4.5) 0 (0.0) hydronephrosis (%) yes 16 (72.7) 19 (86.4) 0.228 no 6 (27.3) 3 (13.6) stone burden ±sd 35.41 ± 10.89 34.23 ± 9.93 0.709 cspcnl vs. semi supine pcnl-falahatkar et al. vol 14 no 02 march-april 2017 3001 plete supine position. (figure 2) in all pcnls, the puncture was done between middle and posterior axillary line with an 18 gauge needle in subcostal position. on the base of our previous experiences and other studies this area is safe to enter the kidney.(2,7,13,19) fluoroscopy was used for intraoperative monitoring as well as pneumatic method for lithotripsy. one shot dilation was done to dilate (first by 9 fr dilator and then 28 fr amplatz dilator) and 30 fr amplatz sheath was used. nephrostography was applied before finishing the surgery to diagnose residual stones and extravasation. in the end, all patients in both groups were tubeless. gfr was estimated by the mdrd formula. hemoglobin and creatinine were assessed the day before surgery and 6 and 24 hours after surgery, respectively. blood transfusion was administered when hemoglobin dropped to less than 10. stone free status was considered as residual stone less than 4 mm. the stone free rate was main target of study to compare the feasibility of semi supine and cspcnl. other outcomes and complications were measured as a second endpoint of the study. the assessment of outcomes and complications was done by a blind analyzer. independent t-test and in case of non-normality the mann-whitney test were used to cspcnl vs. semi supine pcnl-falahatkar et al. table 2. intraoperative and postoperative parameters in 2 groups. characteristics complete supine group (n=22) semi supine group (n=22) p-value access calyx (%) upper 4 (18.2) 0 (0.0) middle 6 (27.3) 6 (27.3) 0.102 lower 12 (54.5) 16 (72.7) kidney displacement with 18 gauge needle (mm) 9.55 ± 4.36 10.50 ± 4.51 0.480 kidney displacement with 9fr amplatz dilator (mm) 15.14 ± 4.88 17.27 ± 5.40 0.176 kidney displacement with 28fr amplatz dilator (mm) 20.05 ± 4.86 22.59 ± 7.51 0.191 fst (fluoroscopic screening time) (second) 86.76 ± 47.42 110.23 ± 49.67 0.121 access time (second) 133.55 ± 129.37 133.41 ± 175.18 0.707 operation time (minutes) 36.68 ± 14.12 47.50 ± 16.45 0.024 post cr ±sd (mg/dl)* 1.13 ± 0.49 0.979 ± 0.19 0.179 post gfr ±sd (%)* 73.61 ± 23.07 80.52 ± 19.94 0.294 post hb ±sd (mg/dl)* 12.62 ± .94 12.97 ± 1.59 0.512 postoperative hospital stay (days) 1.91 ± 1.23 2.27 ± 0.703 0.057 stone free rate yes / no 19 (86.4) / 3 (13.6) 18 (81.8) / 4 (18.2) 0.500 changing the position 0(0.0) 2(10.0%) 0.221 tubeless ** 22 22 feasibility to get the access 22 22 * post: post-operative ** without nephrostomy tube characteristics complete supine group (n=22) semi supine group (n=22) p-value complication (%) yes 4 (18.2) 2 (9.1) 0.332 no 18 (81.8) 20 (90.9) clavien classification grade 0 18 (81.8) 20 (90.9) grade 1 1 (4.5) 1 (4.5) 0.697 grade 2 2 (9.1) 1 (4.5) grade 3 1 (4.5) 0 (0.0) table 3: complications in 2 groups endourology and stone diseases 3002 compare quantitative variables between the two groups, and for qualitative variables, chi-square test or fisher exact test was used. data were analyzed using spss software version 19. the criterion for statistical significance was set to p < 0.05 for all comparisons. the institutional review board and ethical committee of guilan university of medical sciences approved the protocol of this study. the trial was registered at www.irct. ir with registration number irct201405041853n10. result twenty two patients underwent complete supine and another twenty two patients underwent semi supine pcnl. the preoperative parameters of the patients were comparable in both groups, with no statistically significant difference (p > .05). (table 1) no differences in the history of previous intervention such as eswl (extra shock wave lithotripsy), open surgery and pcnl were found between groups. the demographic data of patients and characteristics of the stones are presented in table 1. we were able to obtain access in all patients of the two groups. the mean operative time in complete supine group was 36.68 ± 14.12 minutes that in comparison to semi supine group 47.50 ± 16.45 was significantly lower (p = .024). also, hospitalization after operation in complete supine group was lower than semi supine group (1.91±1.23, 2.27 ± 0.703 days, respectively). although there was an obvious difference between semi and cspcnl, it was not statistically significant (p = .057). although, shorter time was found toward fluoroscopic screening time in the complete supine group (86.76 ± 47.42 seconds for the complete supine versus 110.23 ± 49.67 seconds for the semi supine), the difference was not statistically significant (p = .121). stone free status was achieved in 19 patients (86.4%) in complete supine group and in 18 (81.8%) patients in semi supine group, that was nor statistically significant (p = .500). during the last minutes of the operation in two semi supine cases we had to convert the position into the complete supine to achieve the better stone free rate because of wider space for nephroscop maneuver and lack of vertebral density interfering in cspcnl. the main intraoperative and postoperative parameters are summarized in table 2. four patients in complete supine group and 2 patients in semi supine group had complications. four patients experienced complications in complete supine group: gross hematuria in 1 patient, hemoglobin drop requiring transfusion in 1 patient, gross hematuria and hemoglobin drop requiring transfusion in 1 patient had been reported and 1 patient had all of these complications plus urinary retention with clots. in semi supine group, fever was observed in 1 patient and another patient experienced hemoglobin drop requiring transfusion. in complete supine group, 3 patients (13.6%) received blood transfusions and 1 patient (4.5%) underwent fluids treatment. in semi supine group, 1 patient (4.5%) was treated conservatively and 1 patient (4.5%) was treated with blood transfusions. no significant differences between patients in the two groups were observed for complications (p = .332). the complications on the base of clavien categories (grades 1, 2 and 3) in both groups are shown in table 3. overlapping with the spine at the angle of 0˚ occurred in 7 patients (31.8%) in semi supine group and just in 1 patient (4.5%) in complete supine group, which was statistically significant (p = .023). two patients in both groups had overlapping with the spine at the angle of 30˚. there was significant difference in the overlapping with the edge of the bed at the angle of 0˚ in two groups (10 patients (45.5%) in group a versus 1 patient (4.5%) in group b; p=.002). no patient in both groups had overlapping with the edge of the bed at the angle of 30˚. (table 4) discussion for many years, pcnl was performed in the prone position. studies have shown that the supine position is as effective and safe as prone position in pcnl. (6,13,14,20) although, the stone free rates, and rates of complications and transfusion of both methods are equivalent to each other(19,21) but supine position does not harbor table 4: overlapping with the spine and the edge of the bed at the angle of 0 and 30 degrees in 2 groups characteristics complete supine group (n=22) semi supine group (n=22) p-value overlapping with the spine at the angle of 0˚ (%) yes 1 (4.5) 7 (31.8) 0.023 no 21 (95.5) 15 (68.2) overlapping with the spine at the angle of 30˚ (%) yes 2 (9.1) 2 (9.1) 0.697 no 20 (90.1) 20 (90.1) overlapping with the edge of the bed at the angle of 0˚ (%) yes 10 (45.5) 1 (4.5) 0.002 no 12 (54.5) 21 (95.5) overlapping with the edge of the bed at the angle of 30˚ (%) yes 0 0 no cspcnl vs. semi supine pcnl-falahatkar et al. vol 14 no 02 march-april 2017 3003 some disadvantages of prone position such as necessity to reposition the patient after ureteral catheter insertion, increased risk of pulmonary and anesthetic complications, risk of colonic, central and and peripheral nervous system injuries.(6,7,13,14,18,20,22,23) the supine position offers several technical advantages for the surgeon such as evacuation of stone fragments, shorter operation time, feasibility to do cystoscopy or ureteroscopy coincidentally, less patient handling, siting position for the surgeon, easier access to the airway, feasibility to get the access to the upper calyces, and etc. today, supine position is being performed in various safe and effective types such as: valdivia, galdakao-modified valdivia, and modified supine, semi supine and complete supine.(1,5-6) our results showed that there were no significantly difference between the two study groups in terms of sex, age, body mass index, diabetes and preoperative glomerular filtration rate, creatinine and hemoglobin. tubeless pcnl was found a safe and effective procedure with reduced postoperative hospital stay and pain even for staghorn stone and more ease and comfort to the patient.(24-26) tubeless pcnl had similar results in cspcnl compared to the prone position(10,24) so, this method was performed for all patients in this study. we were able to get access in all patients of two groups in this study, this confirms that pcnl in complete and semi supine position is feasible as other studies mentioned.(1,2,6) in our study, history of swl and history of open nephrolithotomy or pcnl were evaluated but no significant differences was found between the two studied groups (p = .500, p = .166). therefore, these factors could have little influence on the outcomes. in another study figure 2: a: semi supine position, b: cspcnl position cspcnl vs. semi supine pcnl-falahatkar et al. figure 1: flow diagram of the study. endourology and stone diseases 3004 in 2011 by falahatkar et al., previous open surgery had no effect on kidney stone free rate and complications after the complete supine pcnl.(27) yuruk et al. found that pcnl after failed eswl is safe and successful but it makes the procedure more difficult with prolonged operative time and fluoroscopic screening time.(28) also, in 2014 khorrami et al. reported that pcnl can be performed in patients with one or more open stone surgery history successfully without further complications.(29) we believe the history of open nephrolithotomy can make the access more difficult. the reasons of this difficulty is the existence of fibrosis and previous sutures along the access pathway. mean access time and operative time were 133.55 ± 129.37 seconds and 36.68 ± 14.12 minutes in complete supine group, and 133.41±175.18 seconds and 47.50±16.45 minutes in semi supine group. there was no significant difference in the access time (p=.707) but the duration of operative time was significantly higher in semi supine group (p = .024). the longer operative time in semi supine position could be related to some factors such as less number of patients, the duration that needed to prepare the position and because of the less experience of the surgeon in this position. mean operative time was reported 11.52 ± 44.5 minutes(2) in the studies of xu et al., 123.5 ± 51.2min by honzek et al.(30) 162.1 minutes by neto et al.(17) and 65 minutes by rana et al.(26). in two previous studies by falahatkar et al. the mean operative time of complete supine group were reported 74.7 ± 25.1 minutes and 95.14 ± 26.57 minutes.(1,10) although, two meta-analysis have shown the superiority of supine pcnl regarding operative time(19,21) but we should mentioned the operative time can be affected by several factors including the position of the patient, stone characteristic, surgeon’s experience, migration of stone toward upper calyx and etc. stone free rate is one of the most important outcomes of pcnl that is measured by researchers in all studies of this field to evaluates the success rate. stone free rate has been reported in different studies ranges from 70.2% to 89% for supine position.(2,5,7,13,26) we believe that the stone free rate like other outcomes can be affected by several factors such as: stone characteristic, and also the experience of the surgeon. in two meta-analysis stone free rate in supine position was found the same as prone position [(82.4% in the supine position versus 82.1% in the prone position) (19), (83.5% in the supine position versus 81.6% in the prone position) (21)] but a meta-analysis in 2014 found significantly lower stone-free rate in the supine position (72.9%) compared to prone position (77.3%).(4) in this study the stone free rate was 86.4% (19/22) in cspcnl versus 81.8% (18/22) in semi supine group but this difference was not statistically significant (p = .500). the cushion under the patient in some cases of semi supine precluded to have a complete look to calices, as we mentioned it was a difficulty of semi supine position that would need to remove the cushion and consequently to change the position to cspcnl. hospital stay after surgery was 1.91±1.23 day in complete supine, and 2.27 ± 0.703 days in semi supine. no statistically significant difference was observed between the two groups (p = .057). in comparison with other studies such as honzek et al. (3.4 ± 1.9 days)(30), steele et al.(3 days)(22), neto et al. (4.5 days)(17), falahatkar et al. (3.7 days)(6), rana et al. (2 days)(12) and pan et al. (7.63 ± 2.39 days)(8) duration of hospitalization after surgery in our study was shorter in both groups. although, hospital stay of patients depends on some factors such as bleeding, fever, infection, pain and discomfort, trauma to others organs and etc, but we believe the policy of the surgeon has an important role in this matter, because nowadays surgeons trend to discharge the patients sooner. according to an article previously published by the authors, the kidney displacement was measured with transparent graph paper (covered in 5 × 5 mm squares) during accessing to target calyx with 18 gauge needle, and dilation by 9 and 28 fr amplatz dilators.(18) the mean kidney displacements were respectively 9.55 ± 4.36, 15.14 ± 4.88 and 20.05 ± 4.86 mm in the complete supine group and 10.50 ± 4.51 , 17.27 ± 5.40 and 22.59 ± 7.51 mm semi supine group that was not statistically significant (p = .191 , .176 and 480 respectively). in shoma et al. study, anteromedial kidney displacement in the supine pcnl was more than prone pcnl (11% versus 0%).(7) in 2011, falahatkar et al. showed that the mean kidney displacement in the complete supine pcnl in stage 1 and 2 (when the 18 gauge needle and 9fr dilator had moved the kidney) was significantly lower than prone group. this amount for stage 3 (when the 28fr amplatz dilator had moved the kidney) was lower in complete supine group too, however it was not statistically significant.(18) there was a little study to show kidney displacement during the pcnl. however, it seems that the kidney displacement is so different in case by case and the position of the patients is one of the factors that can influence on kidney movement. nevertheless, the concrete declaration in these field requisites further studies. our results showed that there was no significant difference between two groups for overlapping at the angle of 30˚ with the spine. our study has shown that in semi supine position overlapping of kidney with spine might be an important problem and one of the important difficulties in cspcnl was interfering of the edge of the bed during the access that these difficulties were solved with the increasing of the angle of fluoroscopy. so, this simple but useful maneuver should be in the surgeon’s mind during the surgery. this study was performed in a center which has extensive prior experience in cspcnl. therefore, the results cannot be simply generalized to other centers. another limitation of this survey was the small sample size of our study. conclusions there were some differences between cspcnl and semi supine pcnl in our study. the advantages of cspcnl were: not using cushion, more simple position, little interference with overlapping with spin density, perhaps shorter operative time and hospital stay, evacuation of stone fragments, proper stone free rate, and no need to convert the position. but there were some disadvantages for cspcnl such as: interfering of bed edge during the access, less familarity to many urologists. although, in two cases we had to convert the position cspcnl vs. semi supine pcnl-falahatkar et al. vol 14 no 02 march-april 2017 3005 from the semi supine procedure to complete supine position but our results have clearly shown that complete supine and semi supine pcnl were safe, feasible and also there were a little difference between them. we believe in the future the battle is among modification of supine position for pcnl. so, further prospective studies should be conducted in the future to detect the complexity and benefits of these methods. acknowledgments this study was supported by urology research center, guilan university of medical sciences. and also, it is adapted from the specialty thesis of ali ghasemi. conflict of interest the authors declare that they have no competing financial interests in relation to the work described. references: 1. falahatkar s, moghaddam aa, salehi m, nikpour s, esmaili f, khaki n. complete supine percutaneous nephrolithotripsy comparison with the prone standard technique. j endourol. 2008; 22: 2513-8. 2. xu kw, huang j, guo zh, lin tx, zhang cx, liu h, et al. percutaneous nephrolithotomy in semisupine position: a modified approach for renal calculus. urol res. 2011; 39:467-75. 3. ibarluzea g, scoffone cm, cracco cm, poggio m, porpiglia f, terrone c, et al. supine valdivia and modified lithotomy position for simultaneous anterograde and retrograde endourological access. bju int. 2007;100:233-6. 4. zhang x, xia l, xu t,wang x, zhong s, shen z. is the supine position superior to the prone position for percutaneous nephrolithotomy (pcnl)? urolithiasis 2014; 42:87-93. 5. valdivia jg, scarpa rm, duvdevani m, gross aj, nadler rb, nutahara k, et al. supine versus prone position during percutaneous nephrolithotomy: a report from the clinical research office of the endourological society percutaneous nephrolithotomy global study. j endourol. 2011; 25:1619-25. 6. falahatkar s, farzan a, allahkhah a. is complete supine percutaneous nephrolithotripsy feasible in all patients? urol res. 2011; 39:99-104. 7. shoma am, eraky i, el-kenawy mr, elkappany ha. percutaneous nephrolithotomy in the supine position: technical aspects and functional outcome compared with the prone technique. urology. 2002;60:388-92. 8. pan tj, li gc, ye zq, wen hd, shen gq, zhang jq. flank suspended supine position for percutaneous nephrolithotomy. urologia. 2012;79:58-61. 9. romero v, akpinar h, assimos dg. kidney stones: a global picture of prevalence, incidence and associated risk factors. rev urol. 2010; 12(2-3):e86-96. 10. falahatkar s, khosropanah i, atrkar roshan z, golshahi m, emadi sa. decreasing the complications of pnl with alternative techniques including complete supine pnl and subcostal approach. pak j med sci. 2009; 25:353-58. 11. de la rosette jjmch, tsakiris p, ferrandino mn, elsakka am, rioja j, preminger gm. beyond prone position in percutaneous nephrolithotomy: a comprehensive review. eur urol. 2008; 54:1262-1269. 12. rana am, mithani s. tubeless percutaneous nephrolithotomy: call of the day. j endourol. 2007; 21:169-72. 13. de sio m, autorino r, quarto g, calabrò f, damiano r, giugliano f, et al. modified supine versus prone position in percutaneous nephrolithotomy for renal stones treatable with a single percutaneous access: a prospective randomized trial. eur urol. 2008; 54:196-202. 14. ng mt, sun wh, cheng cw, chan es. supine position is safe and effective for percutaneous nephrolithotomy. j endourol. 2004; 18:469-474. 15. soucy f, ko r, duvdevani m, nott l, denstedt jd, razvi h. percutaneous nephrolithotomy for staghorn calculi: a single center’s experience over 15 years. j endourol. 2009; 23:1669-73. 16. falahatkar s, allahkhah a, soltanipour s. supine percutaneous nephrolithotomy: pro. urol j. 2011;8:257-64. 17. neto eac, mitre ai, gomes cm, arap ma, srougi m. percutaneous nephrolithotripsy with the patient in a modified supine position. j urol. 2007; 178:165-8. 18. falahatkar s, asgari sa, nasseh h, allahkhah a, farshami fj, shakiba m, esmaeili s. kidney displacement in complete supine pcnl is lower than prone pcnl. urol res. 2011;39:159-64. 19. wu p, wang l, wang k. supine versus prone position in percutaneous nephrolithotomy for kidney calculi: a meta-analysis. int urol nephrol. 2011;43:67-77. 20. llanes l, sáenz j, gamarra m, pérez da, juárez a, garcía c, arroyo jm, ibarluzea g. reproducibility of percutaneous nephrolithotomy in the galdakao-modified supine valdivia position. urolithiasis. 2013;41:333-40. 21. liu l, zheng s, xu y, wei q. systematic review and meta-analysis of percutaneous nephrolithotomy for patients in the supine versus prone position. j endourol. 2010;24:1941-6. 22. steele d, marshal v. percutaneous nephrolithotomy in the supine position:a neglected approach? j endourol. 2007; 21:1433-37. cspcnl vs. semi supine pcnl-falahatkar et al. endourology and stone diseases 3006 23. zhou x, gao x, wen j, xiao c. clinical value of minimally invasive percutaneous nephrolithotomy in the supine position under the guidance of real-time ultrasound: report of 92 cases. urol res. 2008;36:111-4. 24. falahatkar s, khosropanah i, roshani a, neiroomand h, nikpour s, nadjafi-semnani m, akbarpour m. tubeless percutaneous nephrolithotomy for staghorn stones. j endourol. 2008;22:1447-51. 25. jou yc, cheng mc, lin ct, chen pc, shen jh. nephrostomy tube-free percutaneous nephrolithotomy for patients with large stones and staghorn stones. urology. 2006;67:304. 26. rana am, bhojwani jp, junejo nn, das bhagia s. tubeless pnl with patient in supine position: procedure for all seasons?-with comprehensive technique. urology. 2008; 71:581-5. 27. falahatkar s, asli mm, emadi sa, enshaei a, pourhadi h, allahkhah a. complete supine percutaneous nephrolithotomy (cspcnl) in patients with and without a history of stone surgery: safety and effectiveness of cspcnl. urol res. 2011;39:295-301. 28. yuruk e, tefekli a, sari e, karadag ma, tepeler a, binbay m, muslumanoglu ay. does previous extracorporeal shock wave lithotripsy affect the performance and outcome of percutaneous nephrolithotomy? j urol. 2009;181:663-7. 29. khorrami m, hadi m, sichani mm, nourimahdavi k, yazdani m, alizadeh f, izadpanahi mh, tadayyon f. percutaneous nephrolithotomy success rate and complications in patients with previous open stone surgery. urol j. 2014;11:1557-62. 30. hoznek a, rode j, ouzaid i, faraj b, kimuli m, de la taille a, et al. modified supine percutaneous nephrolithotomy for large kidney and ureteral stones: technique and results. eur urol. 2012;61:164-70. vol 14 no 02 march-april 2017 3007 cspcnl vs. semi supine pcnl-falahatkar et al. staged bilateral laparoscopic adrenalectomy for infantile acth-independent cushing’s syndrome (bilateral micronodular non-pigmented adrenal hyperplasia): a case report introduction cushing’s syndrome is a potentially life-threatening disorder which usually occurs in adults. approximately 10% of cushing’s syndrome are observed in children (up to 18 years old), and it is a very rare disorder in the infancy period. endogenous cushing’s syndrome is typically categorized to acth-dependent and acth-independent variants. more than 80 percent of cushing’s syndrome are due to pituitary adenomas and are acth-dependent (so called cushing disease). acth-independent cushing’s syndrome is far uncommon and may be due to adrenal adenoma, hyperplasia or cortisol producing carcinoma(1). 1 professor, department of urology, shahid labbafi nejad hospital, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 2 h. aliasghar children's hospital, iran university of medical sciences, tehran, iran. 3 metabolic disorders research center, endocrinology and metabolism molecular-cellular sciences institute, tehran university of medical sciences, tehran, iran. 4 associated professor, department of urology, shahid labbafi nejad hospital, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 5department of urology, shahid labbafi nejad hospital, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: professor nasser simforoosh, department of urology, shahid labbafi nejad hospital, urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. tele: +98-21-22588018. fax: +98-21-22588016. email: simforoosh@iurtc.org.ir. received june 2017 & accepted july 2017 nasser simforoosh1*, maryam razzaghy azar2,3, mohammad hossein soltani4, mona nourbakhsh2, hamidreza shemshaki5 acth-independent cushing’s syndrome is an uncommon disorder in children. while laparoscopic adrenalectomy is well-established in adults, it is rarely used in infants and is associated with some concerns. a seven-month infant was referred to our hospital due to progressive signs and symptoms of cushing’s syndrome. laboratory data confirmed acth-independent hypercortisolism. no history of exogenous corticosteroid contact was observed. the patient underwent left transperitoneal laparoscopic adrenalectomy when she was 7 months old, nevertheless, complete response was not seen. the patient underwent right laparoscopic adrenalectomy (contra-lateral adrenal gland) when she was 20 months old. the signs and symptoms of cushing’s syndrome began to resolve and serum and urine cortisol levels became normal 3 months after the second surgery. laparoscopic adrenalectomy is safe and feasible in infants, and in this case, relieved patient of the symptoms and saved her life. case report key words: cushing’s syndrome; laparoscopic adrenalectomy; infant. figure 1. patient appearance before the first surgery. figure 2. first laparoscopic adrenalectomy on the left side (image taken after completion of the operation). case report 5030 acth-independent bilateral adrenal lesions are very rare in children and have occasionally been reported. some of these cases have been related to familial syndromes. primary pigmented nodular adrenal disorder (in relationship with carney complex disease) and bilateral macronodular adrenal hyperplasia (as part of mc-cune-albright syndrome) are some instances(2, 3). laparoscopic adrenalectomy is seldom done in younger children with cushing’s syndrome owing to extreme obesity, abundant perinephric fat and a high incidence of preand postoperative complications. here, we present our experience with a case of non-pigmented non-familial bilateral adrenal hyperplasia in an infant which resulted in acth-independent cushing’s syndrome; and was successfully treated with staged bilateral laparoscopic adrenalectomy. case presentation a 7-month-old infant was referred due to the symptoms and signs of cushing’s syndrome (figure 1). the patient was the first daughter of a non-consanguineous marriage and was born after an uncomplicated gestation and vaginal delivery. her birth weight was 3.170 kg and she did not have any problems up to three months of age. the early manifestations were moon face, facial plethora, progressive central obesity, hypertrichosis which were noted by her parents. no history of exogenous contact with corticosteroid containing products was reported. table 1 indicates the level of 8 am serum cortisol, urine free cortisol and acth, before and after low dose dexamethasone suppression test. very high levels of cortisol in serum and urine, plus suppressed serum levels of acth (<1 pg/ml) confirmed a case of acth-independent hypercortisolism. further assessment of adrenal region was performed using abdomino-pelvic computed tomography (ct) without and with contrast medium. the only abnormal finding was mild enlargement of left adrenal gland (11*8 mm vs. 8*5 mm for right adrenal gland) without any clear tumor. the patient underwent left laparoscopic adrenalectomy bilateral laparoscopic adrenalectomy in an infant-simforoosh et al. figure 3. patient appearance before the second surgery and after bilateral adrenalectomies. hormonal tests patient’s values reference range basal cortisol 08:00 a.m µg/dl 68 4.5 22 24h urine free cortisol µg/24h 110 up to 75.2 acth pg/ml < 1 7.2 64 after single dose overnight dexamethasone suppression test cortisol 08:00 a.m (µg/dl) > 50.7 4.5 22 post high dose dexamethasone suppression test cortisol 08:00 a.mr (µg/dl) 85 < 2 24h urine free cortisol (µg/24h) 239 < 5 acth pg/ml < 1 dhea-s (µg/dl) 564 5-85* testosterone (ng/ml) 1.26 0.01 – 0.05** androstenedione (ng/ml) 3.0 0.08 – 2.5*** pth (pg/ml) < 4 4.5 58 pth related peptide (pmol/l < 0.1 < 0.4 biochemical tests at 6 months before operation blood sugar (mg/dl) 128 < 126 blood urea nitrogen (mg/dl) 10 6 23 serum creatinine (cr) (mg/dl) 0.6 0.6 – 1.2 serum sodium (meq/l) 136 135 145 serum potassium ( mmol/l) 3.2 3.8 – 5.0 serum calcium (ca) (mg/dl) 12.4 8.9 – 10.5 serum phosphorus (p) 4.0 4.5 – 6.5 24 hr urine ca (mg/kg) 7.6 < 4 urine ca/cr ratio 1 0.8 fraction excretion of p 17% < 15% 25 (oh) d (ng/ml) 48 30 100 1,25(oh)2 d (ng/l) ` 50 20 135 after operation serum ca~ (mg/dl) 9.6 8.9 – 10.4 serum p~ (mg/dl0 5 4.5 – 6.5 abbreviations: p, phosphorus; ca, calcium; dl, deciliter; dhea-s, dehydroepiandrosterone sulphate; *, normal range (nr) < 9 years; **, nr for sex and age; ***, nr for child table 1. laboratory investigations of the patient. vol 14 no 05 september-october 2017 5031 when she was 7 months old (figure 2). the specimen reported to be micronodular adrenal hyperplasia. she was followed for resolution of clinical and laboratory abnormalities. although there was a mild reduction in symptoms and signs of cushing’s syndrome, complete response was not observed. laboratory data 10 months after surgery (when the child was 17 months old) indicated that the patient had hypercortisolism state. urine free cortisol was 95 µg/dl (normal range up to 75) and serum cortisol was 26.5 µg/dl (normal range up to 22). plasma acth level was again suppressed (1.2 pg/ml), indicating acth-independent hypercortisolism. the patient underwent right laparoscopic adrenalectomy roughly one year after the first surgery (contra-lateral adrenal gland), when she was 20 months old. the pathology report was micronodular adrenal hyperplasia, as well. the patient was given hormonal replacement therapy and soon, the signs and symptoms of cushing’s syndrome began to resolve and serum and urine cortisol levels became normal 3 months after surgery. figure 3 shows patient’s appearance before the second stage of adrenalectomy and 1 year after, respectively. after two years follow up, no recurrence was occurred. technique of surgery after general anesthesia and in lateral decubitus position, a 5 mm port was inserted at the umbilicus using open access approach. then three other 5 mm trocars (sub xiphoid, para rectal region parallel to umbilicus and medial of anterior superior iliac spine) were inserted under direct vision. laparoscopic surgery was done via a transperitoneal approach by developing pneumoperitoneum via four ports. after medicalization of colon, adrenal gland was identified and released from its bindings. in the left adrenal approach at first we determined the left renal vein and then ligated the adrenal vein by cautery and released the adrenal gland. in the right side, at first we released the adrenal from the surrounded tissues and ivc by cautery. adrenal gland was delivered using an endobag (figure 2). a penrose drain was inserted and left at place at the end of the surgery. the operation times were 135 and 95 minutes in the first and second surgeries, respectively. urinary catheter was removed one day after the surgery, and enteral diet was introduced whenever bowel movements were assured. in each of the operations, patient was discharged after four days with no peri-operative complications. penrose drain was removed at the time of discharge. long-term follow up showed minimal surgical scar, which is a benefit of laparoscopic surgery. discussion most cases of pediatric cushing’s syndrome are due to pituitary adenomas, which are acth-dependent and primarily treated with trans-sphenoidal surgery. acth-independent variant comprises a minority of patients with cushing’s syndrome (approximately 10%). autonomous and non-controlled secretion of cortisol from adrenal cortex is the main event that leads to subsequent symptoms and signs. the primary lesion in adrenal gland may be unilateral or bilateral, macro-adenoma or hyperplasia and sporadic or familial (such as part of mc-cune albright syndrome or carney complex disease)(1). medical therapy with steroidogenesis inhibitors (such as metyrapone and ketoconazole) can reduce plasma cortisol levels; however surgical resection of the diseased adrenal is highly and rapidly effective in eliminating the source and thus it has been globally accepted as the standard treatment of acth-independent cushing’s syndrome. laparoscopic adrenalectomy is considered as the standard treatment for benign adrenal masses in adults. nevertheless, pediatric laparoscopic adrenalectomy is less well defined due to the infrequency of pediatric adrenal masses(4). pampaloni and their colleagues in 2004 reviewed the initial case series of laparoscopic adrenalectomy in children. 83 cases were reported till that time, of which the majorities were due to pheochromocytoma and neuroblastoma. the age range was from 1 month to 16 years old. they concluded that laparoscopic adrenalectomy in the pediatric group is safe and feasible(5). laje and mattei in 2009 reported their experience with 8 cases of laparoscopic adrenalectomy in children aged 2 to 18 years old. the majority of cases were adrenal cortical adenomas(6). due to the very rare incidence of acth-independent cushing’s syndrome in children, its treatment is generally based upon data from adult type disease. the cases of pediatric acth-independent in children are infrequent, especially in infants. care must be given to differentiate between endogenous and exogenous cushing’s syndrome in infants (which may be due to topical corticosteroids occasionally used for diaper rash)(7). the case we reported herein was associated with special features. first, infantile acth-independent cushing’s syndrome is very rare and usually reported as part of mc-cune albright or carney complex disease in the literature. mc-cune albright syndrome is usually associated with large adrenal glands resulting from macro-nodular hyperplasia. carney complex disease leads to pigmented nodular hyperplasia of adrenal glands. our case was a sporadic form of bilateral non-pigmented micronodular hyperplasia. second, although laparoscopic adrenalectomy is widely accepted in adults and young adolescents, there may be still some concern in infants due to less experience and special features of infants. in contrast to open surgery, laparoscopic adrenalectomy may be associated with clearly less surgical scar, shorter convalescent period and minimal peri-operative complications (8). third, in this case of bilateral hyperplasia, resection of the greater adrenal gland (i.e. left adrenal) did not result in complete response, and the patient needed to undergo sequential contra-lateral adrenalectomy. this suggests that in cases of bilateral hyperplasia, pre-operative imaging findings like adrenal enlargement may not predict the response to unilateral adrenalectomy. however, the second laparoscopic operation was also feasible and performed without any side effects one year later. in conclusion, we reported a rare case of sporadic infantile bilateral micro-nodular adrenal hyperplasia, which resulted in sever signs and symptoms of acth-independent cushing’s syndrome. the patient was successfully treated with sequential bilateral laparoscopic adrenalectomy, showing dramatic response without any important side effects. references 1. storr hl, savage mo. management of endocrine disease: paediatric cushing's disease. eur j endocrinol. 2015; bilateral laparoscopic adrenalectomy in an infant-simforoosh et al. case report 5032 173:35-45. 2. gonçalves ft, feibelmann tc, mendes cm, fernandes ml, miranda gh, gouvêa ap, jorge pt. primary pigmented nodular adrenocortical disease associated with carney complex: case report and literature review. sao paulo med j. 2006; 124:336-9. 3. hamajima t, maruwaka k, homma k, matsuo k, fujieda k, hasegawa t. unilateral adrenalectomy can be an alternative therapy for infantile onset cushing’s syndrome caused by acth-independent macronodular adrenal hyperplasia with mccune-albright syndrome. endocr j. 2010; 57:819-24. 4. magiakou ma, chrousos gp. cushing's syndrome in children and adolescents: current diagnostic and therapeutic strategies. j endocrinol invest. 2002; 25:181-94. 5. pampaloni e, valeri a, mattei r, presenti l, centonze n, neri as, salti r, noccioli b, messineo a. initial experience with laparoscopic adrenal surgery in children: is endoscopic surgery recommended and safe for the treatment of adrenocortical neoplasms? pediatr med chir. 2004; 26:450-9. 6. laje p, mattei pa. laparoscopic adrenalectomy for adrenal tumors in children: a case series. j laparoendosc adv surg tech a. 2009; 19 suppl 1:s27-9. 7. buluş ad, andıran n, koçak m. cushing's syndrome: hidden risk in usage of topical corticosteroids. j pediatr endocrinol metab. 2014; 27:977-81. 8. conzo g, tartaglia e, gambardella c, esposito d, sciascia v, mauriello c, nunziata a, siciliano g, izzo g, cavallo f, thomas g, musella m, santini l. minimally invasive approach for adrenal lesions: systematic review of laparoscopic versus retroperitoneoscopic adrenalectomy and assessment of risk factors for complications. int j surg. 2015. pii: s1743-9191(15)01427-2. bilateral laparoscopic adrenalectomy in an infant-simforoosh et al. vol 14 no 05 september-october 2017 5033 worldwide cadaveric organ donation systems (transplant organ procurement) kazemeyni sm1, bagheri chime ar2, heidary ar3* 1department of urology, dr. shariati hospital, tehran university of medical sciences, tehran, iran 2department of neurology, tesocoba university, japan 3management center for transplantation and special diseases, ministry of health and medical education, tehran, iran 157 urology journal unrc/iua vol. 1, no. 3, 157-164 summer 2004 printed in iran introduction organ transplantation, thanks to scientific and technical advancements, is considered as a successful daily procedure. over one million people worldwide have received allograft organs and some of them have already survived more than 25 years.(1) five-year survival rates for most organ transplant programs are around 70%.(1) ever-increasing need to transplant organs has led to different approaches and methods in different countries in view point of transplant organ procurement. each system in organ procurement for transplantation has peculiar advantages and differences in their functions and donation rate are due to structural and cultural differences. the survey of all different systems in the world shows even the most successful ones can not provide all the needs to transplant organs; how ever, living donation in some organs like liver, kidney, and lung has grown by following scientific and ethical issues. there are currently nearly 40000 patients waiting for a kidney in western europe.(1) mortality rates for patients waiting for a heart, liver, or lung range from 15% to 30%.(1) the main purpose of this article is to briefly introduce different units/organizations in the world concerning transplant organ/tissue procurement. considering a three-year activity in cadaveric organ procurement in iran by the establishment of iranian network for organ procurement, comparing results and following useful experiences gained by leading countries in organ procurement can promote cadaveric organ donation to higher the current rate, 1 pmp (one per million population). transplant organ procurement unit/organization/system common aspects of different organ procurement units in different countries are presence of a center for national coordination and centralized organ allocation, presence of independent organ procurement unit in each hospital with transplantation department, and management of making connection with nation wide hospitals without transplant programs. there are also differences in multiple phases of organ procurement, which will be mentioned later. these differences are emerged from different approved protocols in different countries. one of the discriminative issues is family approach and getting consent. even though we can consider two ways of family approach and getting consent as presumed (opting out) and informed (opting in), there is another way that we call it theoritically presumed consent, but practically informed. in countries without legal limitation with presumed consent system, merely for ethical issues, coordinators approach the family to get consent for organ donation. different types of required consent in different countries listed in table 1.(1) studies have shown that organ donation in countries with presumed consent is almost 15% easier. nevertheless, even with same legislations and same national organizations, there are still differences in countries (such as france, italy, spain) in refusal rate for donation.(2) despite this supposition that donation rate is higher in countries with presumed consent, this rate is higher in spain and the united states (table 1). hence, it seems that the type of consent is less important than the function of the system, general awareness, and presence of trained personnel *corresponding author: management center for transplantation and special diseases, vanak, tehran, iran. email: omid1350ir@yahoo.com worldwide cadaveric organ donation systems (transplant organ procurement) in such systems. in 1998, cadaveric donation rates were 15 pmp in europe, 22 pmp in the united states and 31.5 pmp in spain as the leading one.(1) data related to donation and transplantation activities is shown in table 2. procurement organizations well-established organ procurement systems in the world have organ exchange organizations with a specific name in each country. ont (organization national de transplant) in spain, unos (united network for organ sharing) in the united states, scout (saudi center for organ transplantation) in saudi arabia, and jotnw (japan organ transplant network) are some examples of these kinds of organizations.(3,4,5) centralized management and organ sharing are common tasks of these organizations. continuous coordination between organ procurement units and transplant departments, equitable organ allocation based on approved protocols, and making connection with organ procurement networks in other countries are necessities to established such organizations. now, these international connections lead to donate organs to completely matched patients and in most cases to the ones with life-threatening conditions. iranian system in iran, centralized management and organ allocation are conducted in iranian network for organ procurement that is set up in management center for transplantation and special diseases, affiliated to ministry of health and medical education. patients' waiting list is continually updated in this center and in case of donation, organ sharing is done here following a general allocation policy: in priority order, locally, regionally, and nationally in non-urgent (elective) situations. approved phases for donor detection and identification, brain death determination, and organ/tissue retrieval are shown in figure1.(6) moreover, table 3 indicates briefly different phases of organ procurement. designed systems for iran is based on independent procurement units in each university of medical sciences. some of these universities are working in this regard now and the others are going to establish such units. each unit has a chief transplant coordinator who is in charge of making connection with iranian network for organ procurement. specialists who are in charge of brain death determination, based on legislation and decree, should be appointed by the minister of health and medical education and none of them are members of any transplant teams. in this system, two groups of coordinators have the major roles: transplant procurement coordinator (tpc) and recipient (clinical) coordinator. organ allocation is managed in iranian network for organ procurement as a centralized conduction. each university has its own waiting list and procured organs are implanted first locally, then regionally, and finally, nationally. the united states' model on transplant organ procurement in the united states, there is an organization that works independently from transplant centers or wards and consists of two sections: recipient section and host organ procurement organization, which practices under the supervi158 ����������������� �� � � � ������������� �� �������� � ������������ � � � � � � � � � � � � � � � � � ����������� � � � � � � � � ������ ���������������������������� � � �������������� �� ���� �� � ������ ������ � �����!��� ������������� �� "�����#� ���������$��������%�� �#� ������ &������������������ �������� ������ �� ����'����� �!�������� �����!��� �!���������� �� ! � ��%�� ���� ������&���������� � ���� �� ��"������ ��� ������ (������� ����� ������ ������ ��$��� ���������� "����� (������� � �������������� �� ������ � ������ ������ ��$���� fig. 1. algorithmic approach for brain death detection, identification, referral, determination, and transplant organs retrieval in iran table 1. types of consents required in different countries(1) presumed consent finland, portugal, austria, sweden, czech republic, slovakia, hungary, poland informed consent united states, latin america, united kingdom, ireland, denmark, netherlands, germany theoritically presumed consent, but practically informed consent spain, italy, greece, belgium, 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������ ,� ���� ��� ��� ��� �� *#�*�� ������� � ������ ,� ���� ��� �� ����� ;� *#�*�� ��!����� ��f������ %+� �������� ���� ��&������ ��!�� ����������"����� ������� ������� ��� ��&���� �,��� ��� ���� �%�� �+��&�������� ��!�� ��&�������� �+��&���f�����@� table 3. stages of organ transplant procurement w o r l d w id e c a d a v e r ic o r g a n d o n a t io n s y s t e m s (t r a n s p l a n t o r g a n p r o c u r e m e n t ) 1 6 1 ���������� �� ��� � �� ���� ������� ��� � �������� �� �� ����� �� ���� ��� ������ � ��� ��� ���� �� ��� �� �� �� ����� �� ����� �� ��� � �� ��� � �� ����� ����� ��� ��� �� ���!� "�� � �������������� �� ����������� ����� �� ������+����������� �������� ��� ���� �������,���� ������ �� ������,��+�;�������� ��������� ���������,��+�;������� � � � ����������%�������� ���� � � ����� ����� �&� �� ������ �&� ����� ��� ���� �����&���-;���79���0�� � � ���������� ,���� ������ ��� ��� �� ��� ��-���gd�ggh� ���33�i9� ��-�� �� ������ ��<�-��j��88h�� ���33��j9b�8���� ���1:�� �� 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����� � � ���� ������� ����������������� � ��< ���� ����� +�� ������ ���'� � ���'� % ���� ���� ����������& ����"������� ��1����� � � ����� ����%���� ��� �� ��)� ������*g?�� � � � ��!�� ���� ,��� ������� ��� �1�=g8� ��0�� ��!������+�� � ��� +��������������c'���'� ���'� �+� ����� �� %�� ���� ���� �&� ��&������� � � ��0+ ��� + ������� ��� %�� �������� "���� ���� ��� �������������%����������%+�������� �� ��$��%��������� ������!��%����������%+� ������������ �� ������ +�� ������ ��� ��+ �����& ����� ������+ � ������� ���������� &��������� ��� �����,� +� � ��!����� �������� ��� ��!�� ���� ������� �� �&� ������� � ����� �88����� ��!�� ���� �� ����� >98� (*c�� ��� %+� ���� ��� ��%����������� �������� ��;@9������?��*�������&������ � � ��4�� ����������� �� �������� ���:3������� �� ����)����� ���� ����� ������� �� ������������ 98������988 �� ����%+��:� � � �������� ������� ���������� ���������������������� �� �&���� ����-�(� !��� &��� +� ��� �"���� �&� ��������� ���� �������� ����������� ������ ��!���,� ���������������� ��!�� ����+� ���� ��f������ �������� &��� ���������� ��( ��������� ������ ��������� 3���� ���%�� ��� ����� +�k���������% �� ��&� ����� ��-������ �������� &�� ����� ���� �� %�� #� �� � � �� ��� ������� �� �,����� &��� ����� ��������� table 3. continued worldwide cadaveric organ donation systems (transplant organ procurement) sion of organ procurement and transplant network (optn) and united network for organ sharing (unos). every transplant center cooperates with one of opo's organizations.(7,8) the main duties of host opo are as fallows: 1to identify, evaluate, and manage brain death cases, 2to obtain consent from donor's family and to authorize legal processes, 3to retrieve organ, 4to supervise, guarantee, and confirm all conservative, package and organ transfer measures and carry out whole tests and tissue typing and compatibility, 5to share transplant organs. fifteen patients die each day, while waiting for an organ to become available in the united states. more than 75 thousands males, females, and children are enrolled in transplant waiting list. every 16 minutes one patient joins the list. only 25% to 35% of those who need bone marrow transplantation will find a match among their family members.(3) organ system practices in four major sections under the supervision of division of transplantation (dot) in the ministry of health. the main duty of dot is supervising of these practices. these four sections are as follows: 1organ procurement and transplantation network (optn), 2unos (a non-profit organization, its center is in richmond, virginia state) that was established in 1977 under the state laws. transplant centers, opos, laboratories of tissue compatibility, charity centers, religious, legal, ethical, specific advisory committees, etc. are its members. unos covers whole the united states in the yield of procurement and transplantation.), 3scientific registry of transplant recipient (srtr) that follows up and analyses transplant results and survival studies, as well), 4national marrow donor program (nmdp) that consists of 94 centers of bone marrow donation and 118 transplant wards, 5increasing organ and tissue donation (iotd) that attempts to increase social awareness and public education and professional training, as well as to promote the culture of donation. spanish model in procuring transplant organs(9,10) the first spanish transplant coordinator team was established in 1985 in clinic hospital in barcelona. this model was gradually extended to other centers, other areas and the whole country; consequently, an independent department by the name of transplant coordinator department was established in each hospital. this department consists of transplant procurement manager (tpm), transplant coordinators and other staff, who play an important role in increasing organ donation and transplant activities. medical care, training, research, and management and the quantity control are the main functions that is managed under the supervision of tpm. 1. medical care: clinical tasks are: 1to detect potential or possible donors: to find out donation potential in the subordinated area according to the number of icu beds and brain deaths, 2to facilitate brain death detection, 3to supervise donor and to perform organ and tissue compatibility, 4to interview the family. to observe legal aspects, 5to coordinate organ and tissue extraction and their distribution. 2. training and education: training is of great concern to tpm. ideally, training teenagers for donation and transplantation, as well as coordination with all groups and branches, which improve knowledge in the society, have great importance. training professional groups (physicians, nurses, social workers, …) for transplantation is one of basic principles. 3. research and development: the aims of tpm in the field of research and development are to increase the number of donors and to promote transplant organ and tissue quality, as well as to improve donor detection methods. also, introducing new subjects such as nhbd (non-heart-beating donor) and the use of marginal donor organs is another aim. 4. management: the management of resources and different activities in organ donation and transplantation process is one of tpm responsibilities. it includes the detection of required sources (human, equipment, financial and creditable), obtaining such sources and planning for them. the most appropriate place for the activity of organ transplant procurement unit in spain model are intra-hospital departments, which act separately from transplantation wards. 162 worldwide cadaveric organ donation systems (transplant organ procurement) in this model, the needed number of tpms varies from one to five, based on potential donation capacity (30 to 60 brain death pmp) and practical donation (1 tpm per 12 practical donor). effectiveness in a transplantation system is identified by donation rate, number of transplantations, and patient and graft survivals, which are dependent on the role of tpm. other models in spain in addition to the above mentioned general models of transplant organ procurement organization/unit, another structure also exists.(9) in this method, organ procurement is performed by a group of staff practiced at transplantation ward. this model was limited to some transplantation wards and is not popularized in different countries. transplant organ procurement system in japan although the debate on organ transplant was started in japan at public level and specialized scientific circles after performing first heart transplantation in 1968 in saporo university three decades ago, systematic activity in transplant organ procurement began in 1995 by the establishment of japan kidney transplant network. this network developed into japan organ transplant network following the approval of organ transplant law in 1997.(11) patients were obligated to travel to other countries such as china to receive transplant organ before the approval of the above mentioned law and because of limited organ transplant from living donors and legal impediments in using organs of patients with brain death and cadavers.(12) characteristics of organ transplant law in japan this law, which was approved in 1997, is only applied for cadaver organ transplant and cases with brain death and does not include living donor.(13) living donor transplant currently follows the obligations of japan organ transplant society. other characteristics of this law 1decision card for organ donation: patient's definition of death (respiratory arrest or complete heart and brain arrest), agreement or disagreement for organ donation and the kind of organ, are included in this card. there is a place for donor signature and family signature, as well. 2consent: according to the above-mentioned law, patient consent, in addition to his family consent, should be included too. thus, if organ donation card is only signed by organ donor with no signature of donor family, this card would not be legally valid. in addition, a separate consent form is obtained from patients' family. 3age limitation for organ donation: organ retrieval from children under 15 years is forbidden according to japan organ transplant law; therefore, children's organ donation card would be invalid. japan constitutional law declares that children under 15 years can not make such decisions. thus, children in need of receiving transplant organ could not find appropriate organ in many cases. parents have no right too in this regard, while it seems that decision making in organ donation from children with brain death could solve the problem of organ transplant in kids.(14) 4forbidding any organ trafficking as well as necessary prediction for any violation has been regarded in this low too. the role of organ transplant network according to the law, duties of organ network, which is a non-governmental and nonprofitable organization, are as follows: 1to provide general training in organ transplant and donation in the society, 2to distribute decision card for organ donation, 3to collect data about organ donation, 4to inform the family of patients and to perform legal process of consent taking, 5to carry out laboratory tests for donors, 6to allocate organ, 7to coordinate between organ donor and recipient hospitals, 8to transfer transplant organ, 9to provide special advice to donor families, following donation, this network currently consists of 7 main centers and one minor center at japan and its activities are supervised by direct supervision of ministry of health and it is mainly an executive body for organ transplant.(15) however, six years after the approval of organ transplant law in japan, this has not been welcomed in japanese society due to social and cultural believes. thus, despite high technical and scientific potentials in performing organ transplant, only 22 organ transplants has been conducted from brain death donors, while 13000 patients has been recorded in waiting list. 163 worldwide cadaveric organ donation systems (transplant organ procurement) references 1. meeting the organ shortage, current status and strategies for improvement of organ donation/ international figures on organ donation and transplantation in 1998. newsletter transplant 1999; 4(1). 2. transplant coordination manual, manyalich m. tpm educational project. barcelona (spain): university of barcelona; 2001. p. 50-51. 3. united network for organ sharing. available from: url: http://www.unos.org. 4. organ procurement and transplantation network. available from: url: http://www.optn.org. 5. organization national de transplant. available from: url: http://www.msc.es/ont/esp/estadisticas. 6. management center for transplantation and special diseases. cadaveric organ transplantation (protocols and stipulations) (1). tehran: ministry of health and medical education; 2003. p. 10. 7. phillips mg. organ procurement, preservation and distribution in transplantation. 2nd ed. unos; 1996. 8. firouzan a, shojaie s. organ transplant systems in europe and usa. cadaveric transplantation congress abstract book. tehran: 2000. p. 23-28. 9. transplant coordination manual, manyalich m. tpm educational project. barcelona (spain): university of barcelona; 2001. p. 11-23. 10. transplant procurement management, manyalich m. organization of organ donation and role of coordinators. saudi journal of kidney disease and transplantation 1999: 175-182. 11. japan organ transplant network (jotnw). available from: url: http://www.jotnw.or.jp/news.html. 12. awaya t. testimony at the u.s. congress on the transplantation of organs from executed prisoner in china. the review of tokuyama university 1998 dec; 50: 177189. 13. ministry of health, labor and welfare. manual for legal diagnosis of braindeath. tokyo: nippon ijishinposha; 1999. 14. bagheri a. children competency and donors prior declaration. eubio journal of asian and international bioethics.2001 nov; 11(6):195-196. 15. hiraga s, mori t, asaura t. current arrangement and activity of organ transplantation after new transplant legislation in japan. transplant proc 2000; 32: 86-89. 164 vol 16 no 01 january-february 2019 89 case report female urethral cavernous hemangioma, a rare entity: two case reports and review of the literature farzaneh sharifiaghdas1, nastaran mahmoudnejad2* ,niloofar rostaminezhad3, mahmoud parvin4 genitourinary hemangiomas are very rare. to our knowledge few cases of female urethral hemangiomas have been reported and presenting cases are the first reports in iran. they should be considered as differential diagnosis of any female patient with microscopic or gross hematuria or bloody urethral discharge, especially when other parts of urinary system are radiologically intact. thorough physical examination of genital area is highly recommended in order not to miss any urethral lesions. herein we report two cases of female urethral cavernous hemangioma, their management and a review of literature. keywords: urethral hemangioma; hematuria; urethral mass; cavernous hemangioma; female urethral mass introduction hemangioma of the urinary tract is an unusual entity and a few cases have been reported (table 1). they may occur in all parts of the urinary tract but kidneys seem to be the most frequently affected followed by 1professor of urology, shahid labbafinejad medical center, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. 2fellowship of female urology, shahid labbafinejad medical center, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. 3resident of urology, shahid labbafinejad medical center, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. 4associate professor of pathology, , shahid labbafinejad medical center, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. *correspondence: shahid labbafinejad medical center, 9th boustan st., pasdaran ave. tehran, postal code: 16666 iran tel/fax: +98-21-22588016. email: nastaran.mahmoudnejad@gmail.com. received february 2017 & accepted june 2018 figure 1. a: 1x1 cm reddish urethral mass. b&c: section show polypoid fragments of urothelial lined mucosa with presence of dilated cavernous vessels filled with blood and thrombus in lamina propria. lymphocytic infiltration around vessels is prominent. the bladder. they are generally seen as isolated lesions but they may be multiple and associated with congenital disorders such as klippletrenaunay syndrome , sturge-weber and systemic angiomatosis(1). herein we report two cases of cavernous hemangioma of the urethra in female patients for the first time in iran. to our best knowledge, there are less than ten documented case reports of female urethral cavernous hemangioma in the literature(2-7). case report case one: a 38 year old woman presented with painless urethral mass since 6 months ago. there was no complaint of gross hematuria or any other urinary symptoms. she mentioned episodes of mild bleeding from the mass in last few days. in physical examination a 1x1 cm round, reddish mass was seen in urethral meatus (figure 1, a). the gross appearance was similar to a urethral caruncle. urine analysis revealed microscopic hematuria. ultrasound of genitourinary system and urine cytology were normal. in cysto-urethroscopic evaluation, the origin of the mass seemed to be in distal urethra. other parts of the urethra and urinary bladder were normal. written informed consent was obtained from the patient and excisional biopsy of the mass was done at the same session. the mass had a broad base and was bigger than its initial view. the base of the mass was repaired with separate absorbable sutures. the pathology report revealed a cavernous hemangioma (figure1, b&c). case two: a 65 year old female presented with a relatively large urethral mass since 20 days ago following constipation and straining. there was no dysuria, hematuria or other irritative urinary symptoms however she mentioned difficulty in voiding in last few days. in physical examination, a large peri-urethral mass with diffuse areas of thrombosis in its surface was noticed (figure 2, a). in order to ameliorate obstructive urinary symptoms, a 16 french foley catheter was inserted in urethra and conservative management was initiated. meanwhile, further evaluations including ultrasonography of genitourinary tract, urine analysis and urine cytology were performed. after 10 days of medical and conservative treatment including topical estrogen and oral antibiotic, the mass seemed to be smaller in size however it was case first author journal year age of patient 1 uchida k. j urol. 2001 59 2 tabibian l. j urol. 2003 81 3 rao.a.r. urology 2005 26 4 rohan vs. saudi j kidney dis transpl. 2006 60 5 de silvagutierrez a. rev mex urol. 2013 84 6 ongun s. urol j. 2014 68 7 bolat ms. pan afr med j. 2015 51 8 regragui s. pan afr med j. 2016 61 9 chiao-ching li. medicine 2017 8 10 (present case1) sharifiaghdas f urol j. 2018 38 11 (present case2) sharifiaghdas f urol j. 2018 65 table 1. reports of female urethral hemangioma in the literature. figure 2. a: a large peri-urethral mass with diffuse areas of thrombosis in its surface. b: the same mass after conservative treatment. female urethral cavernous hemangioma-sharifiaghdas et al. case report 90 vol 16 no 01 january-february 2019 91 not completely resolved (figure 2, b). all para-clinical tests found to be normal except for microscopic hematuria. cysto-urethroscopic evaluation under spinal anesthesia showed normal blabber but a mass originating from distal urethra. excisional biopsy of the mass was performed at the same session using electro-cautery. in order to prevent subsequent meatal stenosis, eversion of urethral mucosa with simple 4-0 absorbable sutures was done properly. foley catheter remained for another 7 days. the pathology report revealed a cavernous hemangioma with multiple focies of thrombosis. in one year follow up of two cases, neither of them had any complications or recurrence of the mass. discussion the origin of hemangiomas is controversial but may arise from embryonic nests of unipotent angioblastic cells, which fail to develop into normal blood vessels (8). the lesions are composed of a mixture of endothelium lined spaces containing erythrocytes and organized thrombi. they grow slowly and do not communicate with the surrounding vessels therefore are not truly invasive(1). mean age of presentation is 22 years, while age ranges from 3 to 68 years(3). urethral hemangiomas are the least common genitourinary hemangiomas(9). female urethral hemangiomas are very rare and ninety percent of urethral hemangiomas are seen in men. the most common symptom of urethral hemangiomas is hematuria either microscopic or gross(3). sometimes the bleeding can be very intense and cause anemia(6). other clinical presentations are: intermittent urethral bleeding and discharge, meatal mass, urinary retention, and lower urinary tract symptoms(3,9,10). differential diagnosis for female urethral mass includes: urethral caruncle, urethral prolapse, peri-urethral abscess, warts, urethral polyp, granuloma gravidarum, leiomyoma, malignancies like squamous cell carcinoma, transitional cell carcinoma, sarcoma, and melanoma(6). urethroscopy is the diagnostic method of choice and will define the site and extent of the lesions(3). mri is another useful diagnostic modality(2,4). accurate diagnosis requires pathologic confirmation. treatment options depend on location and size of the mass and management should be individualized. asymptomatic lesions do not require any treatment(1). hemangiomas are often underestimated. even small lesions may extend further than is immediately obvious(1). small isolated lesions are treated endoscopically by electrocoagulation, fulguration or nd:yag, argon or ktp laser ablation(8,9). electro fulguration carries the risk of urethral scarring(1). other treatment options include: local resection, topical as well as oral steroids, sclerotherapy, and cryoablation(5,8,10). in case of local recurrence after endoscopic ablation, open exploration and wide excision is recommended(1). although urethral hemangiomas are very rare, they should be considered as differential diagnosis of any female patient with microscopic or gross hematuria or bloody urethral discharge. we believe that in "large masses" surgery is the treatment of choice and local medical treatment will change the gross appearance of the mass in a way that diagnosis would be very difficult with no benefit for the patient . acknowledgement the authors gratefully acknowledge dr. niloufar mahmoudnejad for her exemplary guidance and editing assistance. references 1. jahn h, nissen hm. haemangioma of the urinary tract: review of the literature. br j urol. 1991;68:113-7. 2. uchida k, fukuta f, ando m, miyake m. female urethral hemangioma. j urol. 2001;166:1008. 3. tabibian l, ginsberg da. thrombosed urethral hemangioma. j urol. 2003;170:1942. 4. rohan vs, hanji am, patel jj, tankshali ra. female urethral hemangioma. saudi j kidney dis transpl. 2008;19:647-8. 5. ongun s, celik s, aslan g, yorukoglu k, esen a. cavernous hemangioma of the female urethra: a rare case report. urol j. 2014;11:1521-3. 6. regragui s, slaoui a, karmouni t, el khader k, koutani a, attya ai. urethral hemangioma: case report and review of the literature. pan afr med j. 2016;23:96. 7. ahuja a, sen ak, bhardwaj m. cavernous hemangioma of anterior urethra: an unusual cause of vaginal bleeding. indian j pathol microbiol. 2016;59:245-6. 8. khaitan a, hemal ak. urethral hemangioma: laser treatment. int urol nephrol. 2000;32:2856. 9. parshad s, yadav sp, arora b. urethral hemangioma. an unusual cause of hematuria. urol int. 2001;66:43-5. 10. hayashi t, igarashi k, sekine h. urethral hemangioma: case report. j urol. 1997;158:539-40. female urethral cavernous hemangioma-sharifiaghdas et al. our results of laparoscopic partial nephrectomies without pedicle dissection: possible advantages and disadvantages ayhan verit1, ahmet urkmez2*, ozgur haki yuksel1, fatih uruc1 purpose: this study aimed to document the surgical and oncologic results of nephron sparing of non-ischemic laparoscopic partial nephrectomy without the step of hilus controlling and even without dissecting to expose the main renal vascularity and directly focusing on mass removal. materials & methods: the records of the patients who underwent our modified laparoscopic partial nephrectomy technique were evaluated retrospectively. the patients’ medical records, including tumor complexity calculated via r.e.n.a.l nephrometry scores, operation time, estimated blood loss, blood transfusions, hospital stay, preand postoperative serum creatinine levels, complications via the clavien classification system, pathological status of surgical margin, and follow-up times, were documented. result: the data of 55 patients with 58 renal units were evaluated. almost all tumors were in the low complex group (91%), with a mean size of 31.74 ± 7.38 mm (range: 12-46 mm). mean operation time, estimated blood loss, and transfusion rates were 138.62 ± 38.45 minutes (range: 90-240 min), 242.24 ± 107.12 ml (range: 100-500 ml), and 19%, respectively. the hemoglobin level decreased by a mean of 2.05 ± 0.87 g/dl. whereas the perioperative complications were clavien grades i, ii, and iii (74%, 23%, and 3%, respectively), mean hospital stay and follow-up time were 4.05 ± 1.97 and 19.67 ± 13.57 (ranges: 2-10 days and 1-44 months), respectively. conclusion: present un-controlled results pointed that tumor-focusing nephron-sparing non-ischemic partial laparoscopic nephrectomy may be preferable for small-sized, low-complex renal masses. keywords: laparoscopic partial nephrectomy; renal hilus dissection; tumor-focusing laparoscopy; zero ischemia introduction the term “renal incidentaloma” was generally used to define small renal masses that were reported incidentally due to the widespread use of high technologic diagnostic instruments for nonspecific abdominal symptoms.(1) since the advances in urological surgical techniques, laparoscopic partial nephrectomy (lpn) and robotic-assisted lpn are now the common procedures, instead of open surgery, for the treatment of small renal masses, meaning the clinical t1a (< 4 cm) tumors.(2-5) in the classical surgical description, after the standard steps of renal laparoscopic approaches and dissections, hilar control was maintained and the main vessels that carrying one-fifth of the cardiac output were prepared for possible ischemic occlusion or subsequent nephrectomy.(5) intraoperative ultrasonography can be used to confirm the location, width, and depth of the tumor after this step.(6) the main goals of lpn are to complete tumor excision without positive margins, obtain hemostasis, and decrease or even eliminate the warm ischemia time. since every minute of ischemia is regarded as precious time to save renal function, the term of “zero ischemia” became popular for endoscopic 1university of health sciences, fatih sultan mehmet hospital, dept. of urology, istanbul, turkey. 2university of health sciences, haydarpasa numune hospital, dept. of urology, istanbul, turkey. *correspondence: istanbul haydarpasa numune hospital saum, dept. of urology, uskudar tr34668 istanbul, turkey. e mail: ahmet urkmez 0.05). the patients’ medical data related to the operation, such as tumor size, operation time (ot), estimatedf blood loss (ebl), hospital stay, and follow-up times are noted in table 1. any perioperative complications resulting from laparoscopic surgery were reported. the hemoglobin (hb) level decreased by a mean of 2.05 ± 0.87 g/dl (range: 1-4.5 g/dl). moreover, the postoperative period was uneventful without major complications. however, due to continued postoperative bloody effusion through the surgical region drainage system and decrease of hb level to below 10 g/dl, 11 patients required one to three units of blood via transfusion. enucleation of the mass was possible in eighteen (31%) of all sessions. all laparoscopic partial nephrectomies without pedicle dissectionverit et al. table 1: demographic and perioperative data of the patients who underwent laparoscopic partial nephrectomy. minimum maximum median (mean ± sd) age (years) 28 79 48.32 ± 13.82 body mass index (kg/m2) 21.6 45.87 29.1 size (mm) 12 46 32 operation time (min.) 90 240 120 hospital stay (day) 2 10 3 estimated blood loss (ml) 100 500 200 decrease in hg (gr/dl) 1 4,5 2 follow up (month) 1 50 15 pathologic reports showed renal cell carcinoma (rcc) with subtypes as; clear cell (n: 50) and papillary (n: 8) and tumor-negative at the surgical margin, except for two (3.4%). no recurrence was noted at the surgical site during the control radiologic imagings during a mean follow-up of 19.67 ± 13.57 months (range: 1-50 months). neither urine leakage nor need of perior postoperative double j catheter was reported. preand postoperative renal functions did not alter depending on the serum creatinine levels. clavien scores were noted to be grade i (n = 43, 74%), ii (n = 13, 23%), and iii (n = 2, 3%) and were treated conservatively with antibiotics or blood transfusions, r.e.n.a.l nephrometry scores demonstrated mostly (91.4%) low tumor complexity, and the remaining ones were moderate (8.6%), with no high complexity. these data are summarized in table 2. there was a statistically significant relationship between the r.e.n.a.l score and the duration of hospitalization, the estimated blood loss and the clavien score in the positive correlation of 32.6%, 70.4% and 61.9%, respectively (p = .012; p = .001; p = .001)(table 3). discussion lpn as a minimally invasive procedure has strict advantages such as short hospital stay, quick recuperation and less postoperative discomfort, less blood loss, and no surgical scar compared with an open surgical technique.(2) in this study, we aimed to represent the results of our patients who underwent lpn without hilar clamping and dissecting and just targeting the renal mass directly and discussed its possible advantages and disadvantages. hilar clamping has the advantage of lower blood loss, shorter ot, and better surgical performance despite its disadvantage of possible irreversible renal function loss compared with the unclamped method.(6) however, the classic unclamping method also requires a hilar dissection step for patient and oncologic safety reasons. skipping this time-consuming surgical step, which is the dissection of the renal hilus to isolate the renal artery and vein and also the kidney dissection from the surrounding tissues according to the standard lpn, may provide a decreased ot. present ots (mean: 139 min) seemed to be a bit short in comparison with some non-ischemic lpn series in the literature (160210 min).(14,15) in our opinion, this relatively simplified surgical technique confirms our previous hypothesis that cases of cancer of the upper urinary system should not be excluded, even in the initial laparoscopic learning curve, based on the results of our early laparoscopic surgical series.(16) nevertheless, one of the limitations of this modified surgical procedure is that the surgical team should be experienced in both open and laparoscopic surgery because an urgent open procedure may be required in cases of severe bleeding to control the renal pedicle. thus, instead of a retroperitoneal approach, a transperitoneal-approach lpn was suggested for immediate control of the renal pedicle. however, any need of changing the planned surgical procedure was reported in our pioneer series. parallelly, in a robotic assist nephron sparing surgical series with clamping and off-clamping groups, acar o et al. concluded that non-ischemic option could be applied even in initial learning curve but with an expert surgeon in open surgery, however, unlikely to our study, authors preferred hilus dissection to enable rapid hilar control even in off-clamped group.(17) due to the fact that the present study is a non-ischemic form of lpn, the blood loss is considered to be more than in the ischemic type. (6) our mean ebl, which was approximately 240 ml, was similar to those of a recent systematic review and meta-analytic study involving mixed lpn studies that included clamped–unclamped and undefined methodologies (100–400 ml).(18) furthermore, aron et al. reported ebl as 300 ml in their small series (n = 12) with unclamped or early unclamped lpn.(19) however, there were some discordance between present ebl and hb values. most of the present blood lost was represent the measurement of the liquid at the aspiration tube after the subtract of the irrigation water. thus calculation discordance should bear in mind. on the other hand, some bleeding might spread over the abdomen and also the coagulated ones that skiped from the aspiration and the postoperative suction drainage. all in all, we think that the drop in serum hb levels (mean approximately 2 g/dl) were more predictive to monitor the blood loss in our study. a small, but significant, number (19%) of our patients needed blood transfusions due to a decrease in serum hemoglobin level below 10 g/dl. our blood transfusion rate (btr: 19) was slightly higher than that in the high-volume study (btr: 11) that involved the combined cases who underwent either clamped or unclamped lpn and robotic-assist lpn.(20) on the other hand, although it was not clearly reported in the literature, it should be considered that hilar dissection can expose the main renal vascularity to some very serious complications such as renal vascular perforations and thrombosis (e.g., main or segmental renal artery or laparoscopic partial nephrectomies without pedicle dissectionverit et al. table 2: tumor location, pathologic report, clavien and r.e.n.a.l (radius of the tumor size / exophytic / nearness to collecting system / anterior / location) nephrometry scores of the patients. n % tumor side right 29 50 left 29 50 tumor location lower pole 24 41 middle pole 14 24 higher pole 20 35 pathology of surgical margin (sm) eneculation 18 31 sm (-) 38 66 sm (+) 2 3 renal nephrometry (r.e.n.a.l) score low complexity (4-6) 53 91 moderate complexity (7-9) 5 9 clavien-dindo grading system (n) clavien 1 43 74 clavien 2 13 23 clavien 3 2 3 r.e.n.a.l score r p hospital stay (day) 0,326 ,012* estimated blood loss (ml) 0,704 ,001* clavien score 0,619 ,001* r: spearman’s rho correlation coefficient * p < 0.05 table 3: the correlation of r.e.n.a.l score with duration of hospitalization, estimated blood loss and clavien score laparoscopic & robotic urology 130 vol 16 no 02 march-april 2019 131 vein, gonadal artery, lumbar vein), which may increase the morbidity rates of the standard lpn and possibly lead to urgent nephrectomies, carrying a perioperative mortality risk. for example, in a large series with over 150 cases for planned lpn, some of them (3.3%) were switched to laparoscopic nephrectomies (ln) for undefined reasons during the operation.(14) in a meta-analysis, this conversion rate from lpn to ln is defined as 0% to 12%.(18) nevertheless, we think that the surgical site hemorrhage in the present study cannot have resulted in unnecessary nephrectomies even if the surgical strategy changed to the open procedure perioperatively due to the involvement of a few segmental arteries. besides, the rate of switching from lpn to open surgery noted in the literature is 0% to 14%. surprisingly, the reports that were close to the high point of the range were relatively recent reports instead of reports from the beginning of the laparoscopic revolution period. (18,21,22) it should be expected that these aforementioned rates lpn to ln or open surgery decrease to zero during the laparoscopic learning curve of the urology clinics. however, conversely, in the assessment of these data, it can be noted that lpn always has the risk of converting to ln and open procedure as partial/total nephrectomies in any clinic and with any surgeon. furthermore, postoperative lymphatic leakage (0.5%) is another possible special morbidity for conventional lpn, but not the present one, due to the destroying of the small vascularities, including the lymphatics of the renal hilum. (18,22) urinary leakage claimed to be more often in lpn series in comparison with the open pn(23), however we had any this kind of complication, probably, due to the reason that our series involved mostly uncomplicated small exophitic masses. the resection site hemorrhage during the procedure can be regarded as a frustrating factor for a safe surgical margin, and thus it might be claimed that there may be an increased risk for residue tumor at the resection region. as supporting this determination, enucleation of the renal masses occurred in 1/3 of our cases and could be regarded as oncologically unsafe procedure. nevertheless, zhang k reported that even 1mm inside the normal tissue was enough for a safe surgical margin. (24) however, all of our patients’ (except for two, 3.4%) pathology reports showed a negative surgical margin. this positive surgical margin rate was reported in a wide range as 0–11 in an lpn series.(18) moreover, there was no reported recurrence in the original operation region in our series with a mean of 20 months follow-up. on the other hand, in connection with one of the aims of this study, enucleation can be regarded as another nephron-sparing surgery (nss) option that theoretically involves any functional cancer-free nephron inside the pathologic specimen. renal hilus dissection for controlling renal pedicle either for the requirement of warm ischemia or switching to ln in the case of uncontrolled perioperative severe renal bleeding is regarded as a sine qua non of standard lpn. moreover, the literature point to the popularity of non-ischemic lpn for nephron-sparing concerns.(25) the present surgical approach for low complex small masses cannot be expected to result in renal functional abnormalities per-operatively and can be regarded as almost purely nephron sparing. nonetheless, non-ischemic lpn also drives through the renal pedicle exposition after a careful dissection. on the other hand, we think that severe life-threatening renal hemorrhage is not possible in small (≤ 4 cm) exophitic lesions of the kidney based on our results; thus, hilar controlling and the dissection for exposing the main renal vascularity are not mandatory. these masses in the present group were mostly (91%) low complexity according to r.e.n.a.l nephrometry scores, which is a classification for predicting blood loss and the type of surgery required (either open or lpn).(26) r.e.n.a.l nephrometry scores were created to standardize anatomical tumor definition. in our opinion, the r.e.n.a.l score may also help in selecting patients for our modified lpn technique. furthermore, in a study evaluating standard lpn (with hilus control) in two groups with renal mass below and above 4 cm, authors interestingly found that there was no differences in the peroperative complications in selected cases.(27) another disadvantage of renal hilus dissection for renal pedicle control is the possible difficult exposition in the ipsilateral secondary operations in cases of recurrence due to residual cancer or micro-multifocalities.(28) however, the primary tumor-focusing surgery provides a safer operation site via virgin renal hilus for the secondary procedures such as lpn or ln. finally, defined tumor-focusinglpn without renal pedicle exposition is convenient for robotic-assist lpn and also the principles of laparoendoscopic single-site surgery (less). kawai et al. described less lpn without hilar clamping in seven patients with similar tumor size (≤ 4 cm). no patient required blood transfusion, but one of them was converted to conventional lpn due to massive bleeding. however, it was unclear whether they prepared the renal pedicle initially and, in addition, whether they preferred a special cutting instrument such as a microwave tissue coagulator.(29) we did not use special instruments; all procedures were conducted via the available standard surgical instruments. in regard to the reducing the invasiveness of the procedure, we should mention that all of our procedures were conducted using three to four ports, but not a fifth one. the fifth trocar for hilar clamping was standard in the conventional lpn procedure.(5) with respect to present technique involving zero ischemia with zero hilar dissection, some authors introduce the method as selective renal parenchyma compression with special clamps (simon's clamp) that provide a relatively safe alternative to local ischemia, far from the renal pedicle inn the resection region, especially in polar renal tumors.(30) however, an advantage in the present procedure is that there is no need for a special instrument through a new port site and, moreover, local ischemia caused by simon’s clamp may be harmful to the local nephrons distal to the clamp. furthermore, the clamp itself can cause massive bleeding and nephron destruction. segmental artery clamping is another way to increase the effect of nss, but it cannot be considered less invasive.(31) another recent effort for nss during lpn is “controlled hypotension anesthesia,” which reduces the renal circulation during the procedure. this method is performed without renal hilar clamping, but with hilar control.(32) the other challenging minimally invasive procedures for nephron sparing, such as cryoablation and radiofrequency ablation, microwave thermotherapy, and laser interstitial thermal therapy, can be regarded as ongoing discussion topics, but have not been included in this article.(6) laparoscopic partial nephrectomies without pedicle dissectionverit et al. the main limitation of this study was its uncontrolled retrospective design with limited subjects. thus some data seemed to have discordance such as the ebl and decreased hb levels, although the possible explanations have been discussed. furthermore, as another restriction, all cases were not conducted by single surgeon. to conclude, we found that tumor-focusing lpn is preferred for small-sized exophitic renal masses, and that this procedure is in accord with nephron-sparing principles. the results of this pioneer study should be confirmed by large-volume prospective controlled studies with groups of conventional lpn and tumor-focusing lpn with the same tumor sizes and locations. conclusions despite the relatively high transfusion rate, this simplified lpn technique can be an alternative option and seemed to be without disrupting either patient or oncologic safety, especially for uncomplicated renal masses. references 1. kamachi k, kojima k, nishijima a, takeshita m, ando t, kimura s. small lymphocytic lymphoma presenting as bulky renal incidentaloma. int j hematol 2014; 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63:1072-81. 32. papalia r, simone g, ferriero m, et al. laparoscopic and robotic partial nephrectomy with controlled hypotensive anesthesia to avoid hilar clamping: feasibility, safety and perioperative functional outcomes. j urol 2012; 187;1190-4. miscellaneous an interesting relationship between maternal adipose tissue thickness and maternal pelvicalyceal system dilatation sezen bozkurt koseoglu1*, funda dinc elibol2 purpose: to evaluate whether maternal body mass index (bmi), visceral adipose tissue (vat) thickness, and subcutaneous adipose tissue (sat) thickness have effects on maternal pelvicalyceal system dilatation, which develops during pregnancy. materials and methods: between april 2018 and november 2018, a total of 120 pregnant women aged between 18-35 years in their third trimester were included in this prospective observational study. for each pregnant woman, sat and vat thicknesses were measured and renal sonography was performed by the same radiologist and obstetric ultrasound was performed by the same obstetrician. nine patients were excluded from the study because their maximal caliceal diameters were less than 5 mm. ultimately, 111 patients were divided into three groups according to the maximal calyceal diameter (mcd). results: asymptomatic hydronephrosis was diagnosed in 108/111 (97.3%) of the patients. there were 53 patients in group 1 (mcd of 5-10 mm), 39 patients in group 2 (mcd of 10-15 mm), and 19 patients in group 3 (mcd of >15 mm). there were statistically significant differences in terms of maternal sat and vat thickness between the groups (p = .001). there were also statistically significant differences between the groups for the estimated fetal weight and birth weight (p = .024, p = .003, respectively). in the correlation analysis, there was a negative correlation between maternal sat thickness, vat thicknesses, bmi, and maximal calyceal diameter (p = .001). conclusion: in this study, relationships between maternal bmi, vas thickness, sat thickness, the estimated fetal weight, birth weight, and renal pelvicalyceal dilatation have been shown. increasing maternal adipose tissue may have a protective effect of mechanical pressure of growing uterus on the ureters. keywords: adipose; body mass index; hydronephrosis; pelvicalyceal system; preganancy introduction during pregnancy, many anatomic and physiologic changes occur in the urinary system. the occurrence of asymptomatic hydronephrosis has been termed physiological and it is seen in more than 90% of pregnancies (1). however, hydronephrosis manifested by acute pain, refractory sepsis or even renal failure has been reported (2-6). it usually occurs after mid-pregnancy(7). acceptable explanations for pregnancy-induced dilatation are a mechanical compression of the gravid uterus on the ureters and smooth muscles relaxing the influence of progesterone(1,7,8). it is frequently more pronounced on the right than on the left kidney and rarely occurs bilaterally(7,9). the predisposition for the right side may be explained by the dextrorotation of the uterus and the protection of the left ureter provided by the sigmoid colon(10). it is notified that pelvicalyceal dilatation during pregnancy correlates with polyhydramnios and the estimated fetal weight at that moment (10). these findings suggest that pelvicalyceal dilatation may result from gravid uterus mechanical compression. pregnancy-induced pelvicalyceal dilatation also occurs in the second half of gestation, which supports this hypothe1mugla sitki kocman university training and research hospital, department of obstetric and gynecology, mugla, turkey. 2mugla sitki kocman university training and research hospital, department of radiology, mugla, turkey. *correspondence: mugla sitki kocman university training and research hospital, department of obstetric and gynecology, mugla, turkey. postal code: 48000 tel: +905052596606. e-mail: drsezenkoseoglu@gmail.com. received december 2018 & accepted july 2019 sis. growing uterus causes stasis in the urinary tract and stasis occurs as symptomatic or asymptomatic hydronephrosis in clinical terms. although it is known that estimated fetal weight is an etiologic factor for maternal pelvicalyceal dilatation, there are no data in the literature about maternal weight, body mass index (bmi) and maternal adipose tissue thicknesses. accordingly, the aim of this study was to evaluate whether maternal bmi, visceral adipose tissue (vat) thickness and subcutaneous adipose tissue (sat) thickness have effects on pelvicaliectasis, which develops during pregnancy in the maternal pelvicalyceal system. methods this observational study was conducted at mugla sitki kocman university, department of obstetrics and radiology, from april 2018 to november 2018. during this period, 120 singleton pregnancies were prospectively analyzed in the third trimester of their pregnancies. the exclusion criteria were as follows: multiple pregnancies, oligohydramnios, polyhydramnios, congenital urinary anomalies of pregnant women, a history urology journal/vol 16 no. 5/ september-october 2019/ pp. 506-510. [doi: 10.22037/uj.v0i0.5039] of maternal urological surgery, and any history of renal or ureteral stones, pregnancies involving girls below the age of 18 years and women over the age of 40 years. age at admission, gestational week, gravity, parity, side and degree of dilatation, and maternal weight and height were recorded by the obstetrician. bmi was calculated as weight divided by height squared. obstetric sonography and biometry were also performed by the same obstetrician (sbk), using a ge voluson pro 730 (general electric healthcare, little chalfont, uk), with a 2-9 mhz probe. estimated fetal weight was recorded according to obstetric sonography. after delivery, the weight of the newborns was evaluated and recorded. for each pregnant woman, sat and vat thicknesses were measured and renal sonography was performed by a single researcher, who had 10 years’ experience (fde), on the same day as the obstetric ultrasound using a toshiba aplio 500 (toshiba medical system corporation, tokyo, japan). renal ultrasound was performed to evaluate the status of the calyxes and renal pelvis, bilaterally. the side of the greater dilatation was taken into account. hydronephrosis was graded according to the maximal calyceal diameter (mcd), as detailed by zwergel et al.(11) patients were divided into three groups: -group 1 (grade 1); patients with mcd of 5-10 mm -group 2 (grade 2); patients with mcd of 10-15 mm -group 3 (grade 3); patients with mcd of >15 mm after the renal ultrasound, maternal vat thickness was quantified using ultrasound twice with the pregnant woman lying in the supine position. a convex transducer (3-8 mhz) was placed on the right side of the umbilicus at the same level of the umbilicus and from a distance of 3 cm to the umbilicus. the vat was measured at the median line extending from the linea alba to the lumbar vertebra corpus. maternal sat thickness was measured at the same point as vat thickness using a linear probe operated at 7-12 mhz. the measurements of sat thickness were made at a vertical distance from the skin to the linea alba in the transverse position. sat thickness was assessed twice and an image was captured during the expiratory phase of quiet respiration without any pressure applied to fat tissue. for both vat and sat thicknesses, the average of the two measurements was calculated. the primary outcome was the relationship between maternal vat thickness and the maternal pelvicalyceal diameter. the secondary outcomes were the relationships between maternal sat thickness, bmi, estimated fetal weight, fetal birth weight, and the maternal pelvicalyceal diameter. the study was designed and conducted in accordance with the helsinki declaration. the aims of the study were explained to the patients. written informed consent was obtained from all participants. ethical approval was granted by the local ethics committee. the spss 17.0 for windows package program was used (spss inc., il, usa) for statistical analyses. the mean and standard deviation (sd) values of the parameters were used to describe scale variables. one-way analysis of variance (anova) was used to compare the groups. pearson’s correlation test was used for determining correlations between the variables. multiple regression analysis was also used. in the multiple regression model, there were one dependent and more than one independent variables. the mathematical relationship of the dependent and independent variables were investigated. a p value <.05 was considered statistically significant. results a total of 120 patients were included in the study. after measurement of the maximal calyceal diameter, nine patients were excluded from the study because the maximal caliceal diameters were less than 5 mm. ultimately, a total of 111 pregnant women who were diagnosed as having hydronephrosis were included in maternal adipose tissue and pelvicalyceal dilatationkoseoglu et al. table 1. baseline characteristics of patients in groups. group 1 (n=53) group 2 (n=39) group 3 (n=19) p-value age (year)* 29.64 ± 4.8 27.71 ± 4.7 27.00 ± 4.66 .055 gestational age (week)* 34.66 ± 3.3 34.44 ± 3.2 34.32 ± 3.00 .282 gravida** 1-4 1-4 1-4 .651 parity** 0-2 0-2 0-2 .360 *: values are given by mean ± standard deviation **: values are given by minimum-maximum p < 0.05 was considered as statistically significant. one way anova test was used to compare groups. group 1(n = 53) group 2 (n = 39) group 3 (n = 19) p-value maternal weight (kg)* 75.66 ± 12.11 73.84 ± 14.23 65.79 ± 9.7 .001 maternal bmi (kg/m2)* 29.61 ± 3.9 27.67 ± 4.0 25.01 ± 3.5 .001 maternal subcutaneous adipose tissue thickness (mm)* 14.22 ± 4.4 10.24 ± 3.0 9.00 ± 2.7 .001 maternal visceral adipose tissue thickness (mm)* 12.92 ± 4.2 9.11 ± 3.0 7.76 ± 2.6 .001 estimated fetal weight (gr)* 2390.84 ± 686.2 2616 ± 693.3 2934.36 ± 773.94 .024 birth weight (gr)* 3022.82 ± 409.2 3189.30 ± 429.0 3442.36 ± 498.9 .003 *:values are given by mean ± standard deviation abbreviations: kg: kilogram; gr: gram; mm: millimeter; m: meter; bmi: body mass index p < 0.05 was considered as statistically significant. one way anova test was used to compare groups. table 2. comparison of study outcomes between groups vol 16 no 04 september-october 2019 507 the study. asymptomatic hydronephrosis of pregnancy was diagnosed in 108/111 (97.3%) of the pregnant women in our institution during this period. hydronephrosis was symptomatic in a total of 3 patients, and was treated with conservative management; each had severe right-side pain, which was treated with analgesia (hiyosin-n-butilbromur 20 mg/ml, buscopan®, zentiva, istanbul) and intravenous fluids (3 liters/day). all patients included in the study had greater hydronephrosis on the right side than on the left side. the remaining 111 patients were divided into three groups due to hydronephrosis type. there were 53 patients (47.7%) in group 1, 39 patients (35.1%) in group 2, and 19 patients (17.2%) in group 3. the mean demographic and clinical data for the patients are summarized in table 1. age, gravida, gestational age, and parity were not statistically different between the groups (table 1). it was found that there was a statistically significant positive correlation between maternal sat thickness and bmi (r: 0.463, p = .001). there was also a statistically significant positive correlation between maternal vat thickness and bmi (r: 0.453, p = .001). maternal weight, bmi, and the maternal sat and vat thickness results of the groups are presented in table 2. the bmi values were statistically significantly different between the groups (p = .001). the results of maternal sat and vat thicknesses are also shown in table 2. the maximal maternal sat thickness was found as 14.22 ± 4.4 mm in group 1. there were statistically significant differences in terms of maternal sat and vat thickness between the groups (p = 0.001). statistically significant differences were found between the study groups for the estimated fetal weight and birth weight. table 3 depicts the correlation between maternal sat and vat thicknesses, bmi, and maximal calyceal diameter. there was a negative correlation between maternal sat and vat thicknesses, bmi, and maximal calyceal diameter (p = .001). there was also a statistically significant positive correlation between vat and sat (table 4). multiple regression model was performed between pelvicalyceal dilatation and other independent variables without vat and sat (estimated fetal weight, birth weight, maternal weight, and bmi). this regression model was statistically significant (p = 0.005, r = 0.359). according to this model, bmi was found to be a predictor for maternal pelvicalyceal dilatation. then, a new multiple regression analysis was performed by adding vat and sat thicknesses. this new regression model was also statistically significant (p < 0.001, r = 0.533). according to this new model, only the sat was found as a predictor for maternal pelvicalyceal dilatation. ten patients were treated with antibiotics because of urinary tract infection. of these, five patients had grade 2 hydronephrosis and five had grade 3 hydronephrosis. the urine cultures of these patients all revealed escherichia coli infection. these 10 patients were re-evaluated after antibiotic treatment and no changes were found in calyceal diameter after the treatment. in our study, one patient (0.9%) delivered before the 37th week of the pregnancy period (35th week and 2 days). intrauterine growth restriction was not observed in any of the patients. ninety-eight patients were re-evaluated one month after delivery and pelvicalyceal system dilatation had disappeared in this second examination. thirteen patients did not attend the follow-up examination; therefore, we could not re-evaluate the post-pregnancy recovery of calyceal dilatation in these patients. discussion with this study, it is shown for the first time in the literature that increasing bmi and sat and vat thicknesses may have a protective effect against developing the pelvicalyceal system dilatation in pregnant women. also, a relationship between maternal weight, estimated fetal weight, birth weight, and renal pelvicalyceal dilatation has been shown. it is also initially shown in our study with regression models that bmi and sat were the predictor factors of maternal pelvicalyceal dilatation occurrence. in recent years, there have been a very limited number of publications on maternal pelvicalyceal system dilatation, which is a very common physiologic change of pregnancy. asymptomatic hydronephrosis is seen at 90% in pregnancies, whereas symptomatic hydronephrosis is seen at a rate of 0.2-3% (7,12). in line with the literature, in our study, 3 patients were symptomatic (2.7%) and 97.3% of the patients were asymptomatic. in our practice, it was determined that slim pregnant women were more prone to hydronephrosis. the pathogenesis of maternal hydronephrosis is still not exactly miscellaneus 508 table 3. correlation between maximal calyceal diameter and maternal subcutaneous adipose tissue thickness, visceral adipose tissue thickness, bmi maximal calyceal diameter r p-value maternal subcutaneous -.462 .001 adipose tissue thickness maternal visceral adipose -.466 .001 tissue thickness bmi -.264 .005 abbreviations: bmi: body mass index p < 0.05 was considered as statistically significant. pearson correlation analysis was used. figure 1. image of the measurement of calyceal system with ultrasound. maternal adipose tissue and pelvicalyceal dilatationkoseoglu et al. known. therefore, we aimed to establish one of the etiologic factors for maternal pelvicalyceal dilatation. the most frequently used explanatory mechanisms are the pressure of the growing uterus and the relaxing effect of progesterone. it has been observed that in cases in which the uterus grows more, such as polyhydramnios and multiple pregnancies, hydronephrosis can occur more frequently(10). in 2004, çoban et al. evaluated the relationship between estimated fetal weight, birth weight, and maternal hydronephrosis(13). similar to our study, they divided patients into 3 groups according to the maximal calyceal dilatation as defined by zwergel et al.(11). eighty-eight pregnant women with symptomatic hydronephrosis were included in their study and the estimated fetal weight at the time of the diagnosis and maximal calyceal dilatation were found to be related to pelvicalyceal dilatation grade. similar to our study, patients with polyhydramnios, oligohydramnios, and multiple pregnancies were excluded from their study because these conditions can change the degree of calyceal dilatation. however, in çoban’s study, maternal bmi, vat, and sat thicknesses, which can affect maternal calyceal dilatation, were not taken into account (13). hydronephrosis usually occurs in the second half of the pregnancy and mostly regresses a few weeks after delivery(7,9). in a study performed in 2014, it was found that symptomatic hydronephrosis was diagnosed on average in the 26th week of pregnancy(13). therefore, we evaluated maternal calyceal system dilatation in the third trimester of our pregnancies. four weeks after birth, follow-up renal ultrasound was performed on the available patients and we found that the maternal calyceal dilatation had regressed. in pregnancy, percutaneous interventions in nephrolithiasis, except for hydronephrosis, should not be preferred as a first-line treatment, especially in the first half of pregnancy(14). however, nephrolithiasis can be treated using ultrasonography-guided, percutaneous minimally invasive procedures after the second trimester. symptomatic hydronephrosis in pregnancy can be treated conservatively, especially mild hydronephrosis(7,12,15,16). a double-pigtail stent insertion can be performed if the patient’s condition is refractory to conservative management and severe hydronephrosis. the first choice should be conservative management due to surgery-related discomfort and the risk of complications(12,17). we also treat our patients with symptomatic hydronephrosis conservatively. in a recently published study, it was reported that there was no association between the grade of maternal hydronephrosis and the duration of pregnancy and perinatal mortality(13). similar to this study, we had only one patient who delivered before the 37th week and no perinatal complications occurred in any patients. ultrasound is a non-invasive, reliable, reproducible and valid method for the assessment of vat and sat thicknesses(18). ultrasound is also more feasible in evaluating vat and sat thicknesses than computed tomography or magnetic resonance imaging, because it is a non-ionizing low-cost imaging method that is widely accessible, especially for pregnant women(19). we used ultrasound to evaluate sat and vat thicknesses. in our study, a correlation was found between maternal bmi, sat thickness, vat thickness, and maternal pelvicalyceal dilatation. we think that the main protective factor against the mechanical pressure of the uterus on the kidneys can be related to maternal visceral adipose tissue. sat and vat measurements are correlated and it is clear that sat measurements with ultrasound are easier to perform than vat measurements and do not require as much experience as vat measurements. also, sat measurements can be easily evaluated by obstetricians during obstetric ultrasonography for pelvicalyceal dilatation estimation. furthermore, the sat was found to be a predictor factor in maternal hydronephrosis occurrence. with measuring sat besides obstetric ultrasound helps clinicians to estimate maternal pelvicalyceal status. bmi of the patients which can be calculated without special device requirements such as ultrasound was also helpful in maternal hydronephrosis occurrence. our results are important in the selection of suitable patients to be referred to radiologists for renal ultrasonography. the main limitation of our study is that the patient numbers of the groups are not homogeneous. secondly, we did not separate the patients according to their bmi. however, to the best our knowledge, our study is the first in which a relationship between bmi, and vat and sat thicknesses, and maternal pelvicalyceal dilatation development has been shown. asymptomatic hydronephrosis is a very frequent condition in pregnancy; however, it can rarely proceed to acute renal failure. conclusions with this study, it has been shown that bmi, and sat and vat thicknesses can be associated with maternal pelvicalyceal system dilatation, which is frequently seen among the physiologic changes of pregnancy. we think that increasing maternal adipose tissue may have a protective effect against the mechanical pressure of the growing uterus on the ureters. in clinical practice, it should be kept in mind that the pelvicalyceal system dilatation can be seen more frequently in slim pregnant women with unexplainable pelvic disorders. conflict of interest the authors report no conflict of interest. references 1. rasmussen pe, nielsen fr. hydronephrosis table 4. correlation between maternal visceral adipose tissue thickness and subcutaneous adipose tissue thickness the maternal visceral adipose tissue thickness the maternal subcutaneous adipose tissue thickness r p-value .993 .001 p < 0.05 was considered as statistically significant. pearson correlation analysis was used. maternal adipose tissue and pelvicalyceal dilatationkoseoglu et al. vol 16 no 04 september-october 2019 509 during pregnancy: a literature survey. eur j obstet gynecol reprod biol. 1988;7:249-59. 2. d'elia fl, brennan re, brownstein pk. acute renal failure secondary to ureteral obstruction by a gravid uterus. j urol. 1982;128:803-4. 3. eika b, skajaa k. acute renal failure due to bilateral ureteral obstruction by the pregnant uterus. urol int. 1988;43:315-7. 4. ferguson t, bechtel w. hydronephrosis of pregnancy. am fam physician. 1991;43:21357. 5. farr a, ott j, kueronya v, et al. the association between maternal hydronephrosis and acute flank pain during pregnancy: a prospective pilot-study. j matern fetal neonatal med. 2017;30:2417-21. 6. vansonnenberg e, casola g, talner lb, wittich gr, varney rr, d'agostino hb. symptomatic renal obstruction or urosepsis during pregnancy: treatment by sonographically guided percutaneous nephrostomy. ajr am j roentgenol. 1992;158:91-4. 7. puskar d, balagovic i, filipovic a, et al. symptomatic physiologic hydronephrosis in pregnancy: incidence, complications and treatment. eur urol. 2001;39:260-3. 8. clayton jd, roberts ja. the effect of progesterone on ureteral physiology in a primate model. j urol. 1972;107:945-8. 9. faundes a, bricola-filho m, pinto e silva jl. dilatation of the urinary tract during pregnancy: proposal of a curve of maximal caliceal diameter by gestational age. am j obstet gynecol. 1998;178:1082-6. 10. eckford sd, gingell jc. ureteric obstruction in pregnancy--diagnosis and management. br j obstet gynaecol. 1991;98:1137-40. 11. zwergel t, lindenmeir t, wullich b. management of acute hydronephrosis in pregnancy by ureteral stenting. eur urol. 1996;29:292-7. 12. fainaru o, almog b, gamzu r, lessing jb, kupferminc m. the management of symptomatic hydronephrosis in pregnancy. bjog. 2002;109:1385-7. 13. coban s, biyik i, ustunyurt e, keles i, guzelsoy m, demirci h. is there a relationship between the grade of maternal hydronephrosis and birth weight of the babies? j matern fetal neonatal med. 2015;28:1053-6. 14. basiri a, nouralizadeh a, kashi ah, et al. x-ray free minimally invasive surgery for urolithiasis in pregnancy. urol j. 2016;13(1):2496-501. 15. seidman ds, soriano d, dulitzki m, heyman z, mashiach s, barkai g. role of renal ultrasonography in the management of pyelonephritis in pregnant women. j perinatol. 1998;18:98-101. maternal adipose tissue and pelvicalyceal dilatationkoseoglu et al. 16. cecen k, ulker k. the comparison of double j stent insertion and conservative treatment alone in severe pure gestational hydronephrosis: a case controlled clinical study. scientificworldjournal. 2014;989173. 17. tsai yl, seow km, yieh ch, et al. comparative study of conservative and surgical management for symptomatic moderate and severe hydronephrosis in pregnancy: a prospective randomized study. acta obstet gynecol scand. 2007;86:104750. 18. stolk rp, wink o, zelissen pm, meijer r, van gils ap, grobbee de. validity and reproducibility of ultrasonography for the measurement of intra-abdominal adipose tissue. int j obes relat metab disord. 2001;25:1346-51. 19. schlecht i, wiggermann p, behrens g, et al. reproducibility and validity of ultrasound for the measurement of visceral and subcutaneous adipose tissues. metabolism. 2014;63:151219. miscellaneus 510 vol 15 no 06 november-december 2018 376 miscellaneous does tadalafil increase the uptake of finasteride into prostate tissue? a biochemical and histological evaluation in rats alper gök1*, can tuygun1, tugba taskin türkmenoglu2, gamze gök3, gamze avcıoglu3, cemil nural3, ibrahim güven kartal1, azmi levent sagnak1, osman raif karabacak1, hikmet topaloglu1, muhammed abdurrahim imamoglu1, hamit ersoy1 purpose: to histopathologically and biochemically evaluate the hypothesis that tadalafil increases the uptake of a second medication into the prostate tissue by increasing the blood supply in the prostate. methods: forty 12-week-old sprague dawley male rats were equally divided into 5 groups and were administered drugs orally as follows: group 1 – no drugs, group 2 – 10 days of finasteride, group 3 – 10 days of finasteride + tadalafil, group 4 – 30 days of finasteride, and group 5 – 30 days of finasteride + tadalafil. at the end of 10 days of drug administration in group1, 2, and 3, and at the end of 30 days of drug administration in group 4 and 5, blood samples were collected from rats and analyzed for serum androgen levels. in addition, prostate tissues were removed for histological examination. results: the mean dht level as well as the minimum and maximum epithelial thicknesses in group 3 were lower than those in group 2. however, there was no statistical significant difference (p = 0.989, p = 0.176, and p = 0.070, respectively). the mean dht level as well as the minimum and maximum epithelial thicknesses in group 5 were lower than those in group 4. however, there was no statistical significant difference (p = 0.984, p = 0.147, and p = 0.478, respectively). the mean minimum and maximum epithelial thicknesses in group 3 and group 4 were not statistically different (p = 0.488 and p = 0.996, respectively). conclusion: the similarity of the mean minimum and maximum epithelial thickness in group 3 and group 4 may be indicate that the combination therapy provides an early histological effect. however, the fact that there was no statistical significant difference between group 2 and group 3, and between group 4 and group 5, in terms of the mean dht level and minimum-maximum epithelial thicknesses suggests that longer term studies with more rats are necessary to test the validity of our hypothesis. keywords: pde5 inhibition; tadalafil; finasteride; prostate; benign prostatic hyperplasia; rats introduction androgen stimulation of androgen receptors (ar) causes a proliferative effect in prostate tissue(1). the 5≤-reductase enzyme (5-ar) is a nuclear-bound steroid enzyme that converts testosterone (t) to dihydrotestosterone (dht), a potent androgen that has a higher affinity to ar than testosterone. there are two isoforms of 5-ar encoded by the srd5a1 and srd5a2 genes. while the type i 5-ar isoform is found in extraprostatic tissues (e.g., skin and liver), the type ii 5-ar isoform is predominantly found in prostate tissue and other genitourinary tissues(2). finasteride (fin) is a type ii 5α-reductase enzyme inhibitor (5-ari) that is used in the treatment of benign prostatic hyperplasia (bph). fin reduces serum and intraprostatic dht lev1department of urology, university of health sciences, diskapi yildirim beyazit training and research hospital, ankara, 06110, turkey. 2department of pathology, university of health sciences, diskapii yildirim beyazit training and research hospital, ankara, 06110, turkey. 3department of biochemistry, yildirim beyazit university, ankara, 06800, turkey. *correspondence: diskapi yildirim beyazit egitim ve arastirma hastanesi, ziraat mahallesi, ömer halisdemir caddesi, 06110, diskapi/altindag/ankara phone: +90 532 603 11 81. fax number: +90 312 318 66 90. email: alper_gok@hotmail.com. received march 2018 & accepted april 2018 els, causing epithelial atrophy in the prostate tissue(3-6). clinically, fin decreases both the prostate weight and the international prostate symptom score (ipss), while increasing qmax(4,7-11). it has also been reported that fin reduces acute urinary retention (aur) and the need for surgery in bph patients(12-14). however, these positive clinical effects of fin occur only after 6-12 months of treatment. in october 2011, the us food and drug administration (fda) approved tadalafil (tad), a phosphodiesterase type 5 inhibitor (pde5i), for the treatment of bph. inhibition of the intracellular enzyme phosphodiesterase type 5 (pde5) reduces cgmp degradation. increased intracellular cgmp levels cause a decrease in intracellular calcium levels and lead to the relaxation of the prostate’s smooth muscle and vessels(15,16). in a study by morelli et al., lower genitourinary tract tissues were collected during urologic surgeries(17). these tissues were compared in terms of pde5 mrna expression(17). this study showed that pde5 mrna expression was higher in the prostatic arteries and corpus cavernosum tissues than other parts of male urogenital tract tissues(17). this study also compared the prostate tissues of spontaneous hypertensive rats (shr, characterized by reduced pelvic blood flow to the genitourinary tract) with healthy wistar kyoto rats, and found that shr rats had dilated hypoxic glandular alveolas and decreased interstitial and stromal spaces in prostate tissue(17). when the shrs were treated with tad starting at day 1, the blood supply and oxygenation of the prostate tissue began to improve; this was demonstrated by a significant decrease in hypoxyprobe immunopositivity, which was completely lost between the 7th and 28th day(17). in addition, other studies have shown that pde5i increases human and rat prostatic blood flow(15,17-19). to our knowledge, our current study is the first to evaluate whether pde5i, which has been shown to increase prostate blood flow, enhances the diffusion of a second medication into prostate tissue. since the histological changes in the prostate caused by 5-ari as well as its biochemical effects on serum are well known, we aimed to histologically and biochemically assess whether tad increases the diffusion of fin into prostate tissue in rats. materials and methods this study was approved by the local ethics committee of kobay deney hayvanları laboratuarı (22120.01.2017) and by scientific research board of yıldırım beyazıt training and research hospital as a scientific research project (62 / 02-09.02.2017). this study included forty 12-week-old male sprague-dawley rats (kobay deney hayvanlar laboratuarı, ankara, turkey) weighing between 300-350 grams. throughout the study, the rats were kept in a room with a temperature of 22 ± 2°c that was illuminated from 7 am to 7 pm. the rats were allowed to access water and food ad libitum. the rats were equally distributed into groups given ± fin ± tad for 10 or 30 days to evaluate the hypothesis that the biochemical and histological changes caused by a combination of fin+tad are more pronounced than those caused by fin alone. the distribution of the groups is shown in table 1. the rats were sacrificed by cervical dislocation after 10 days of drug administration in group1, 2, and 3, and at 30 days of drug administration in group 4 and 5. blood samples were taken from the rats via cardiac puncture. all of the rats underwent laparotomy, and their prostate, bladder, kidney, testes, and liver tissues were removed and stored for further studies. biochemical evaluation all blood samples were drawn into edta tubes and incubated for 20 minutes at room temperature, followed by centrifugation at 3000 rpm for 20 minutes. the supernatant (plasma) was stored in eppendorf tubes at -20°c until further use. immediately before use, the samples were thawed at room temperature, and then they were analyzed for dihydrotestosterone and testosterone via elisa (eastbiopharm rat dht and t elisa kit). biochemical evaluation was conducted by 3 experienced biochemists and the researchers were blinded to the study groups. histological evaluation specimens were fixed with 10% neutral buffered formalin and embedded in paraffin. slides were stained with hematoxylin and eosin and examined with a nikon eclipse ni microscope (nikon corp, japan). images were captured digitally with the nikon ds-fi1c camera (nikon instruments, japan). measurements of minimum and maximum epithelial thickness were performed at a magnification of 400x from the ten most central acini (figure 1). histological evaluation was conducted by a pathologist experienced in prostate histology and the researcher was blinded to the study groups. statistical analysis all statistical analyses were performed using ibm spss statistics version 17.0 software (ibm corporation, armonk, ny, usa). descriptive statistics were expressed mean ± sd, and one-way anova was used to determine the mean differences among groups. the post-hoc tukey hsd test was used to determine which group differed from others. values of p less than 0.05 were considered significant. results dht levels were significantly different between the groups (p = 0.007). specifically, the dht levels of the control group (group 1) were higher than those of group 3 (10 days fin+tad), group 4 (30 days of fin), and group 5 (30 days of fin+tad) (p = 0.041, p = 0.010, and p < 0.001, respectively). although group 2 (10 days of fin) had lower mean dht levels than group 1 (control), this difference was not significant (p = 0.118). in addition, the mean dht levels of group 3 (10 days fin+tad) were lower than those of group 2 (10 days of fin), and the mean dht levels of group 5 (30 days fin + tad) were lower than those of group 4 (30 days table 1. the distribution of the groups group 1 (n:8) control group (not given any drugs) group 2 (n:8) 10 days of 1 mg/kg/day fin by gavage group 3 (n:8) 10 days of 1 mg/kg/day fin + 2 mg/kg/day tad by gavage group 4 (n:8) 30 days of 1 mg/kg/day fin by gavage group 5 (n:8) 30 days of 1 mg/kg/day fin + 2 mg/kg/day tad by gavage figure 1. measures from epithelial thickness does tadalafil increase the uptake of finasteride into prostate tissue?-gok et al. miscellaneous 377 vol 15 no 06 november-december 2018 378 fin), but these differences were not significant (p = 0.989 and p = 0.984, respectively) (table 2). the mean testosterone levels were also significantly different between the groups (p < 0.001). the mean testosterone levels of all of the groups receiving drugs were higher than those of the control group (all p <0.001). however, the mean testosterone levels of groups 2 and 3 (10 days fin and fin+tad) and groups 4 and 5 (30 days fin and fin+tad) were similar (p = 1.000 and p = 1.000) (table 2). the mean maximum epithelial thickness levels in all of the groups receiving drugs were lower than those of the control group (p = 0.002 control vs group 2 (10 days fin), p < 0.001 control vs all other groups). although the mean maximum epithelial thickness levels were lower in the groups receiving a combination of fin+tad, these differences were not significant (p = 0.070 10 days fin vs fin+tad and p = 0.478 30 days fin vs fin+tad) (table 2). further, there was no difference in the mean maximum epithelial thickness between group 3 (10 days fin+tad) and group 4 (30 days fin) (p = 0.996) . the mean minimum epithelial thickness levels of all of the groups receiving drugs were lower than those of the control group (p < 0.001 for all). although the mean minimum epithelial thicknesses of the groups receiving a combination of fin+tad were lower than those receiving fin alone, these differences were not significant (p = 0.176 10 days fin vs fin+tad and p = 0.147 30 days fin vs fin+tad) (table 2). in addition, there was no significant difference between group 3 (10 days fin+tad) and group 4 (30 days fin) in terms of minimum epithelial thickness (p = 0.488). next, we compared mean prostate weights between the groups. the mean prostate weights of all of the groups receiving drugs were lower than those of the control group (p = 0.038 control vs 10 days fin, p = 0.046 control vs 10 days fin+tad, p = 0.031 control vs 30 days fin, and p = 0.020 30 days fin+tad). the mean prostate weights groups 2 and 3 (10 days fin vs fin+tad) and between groups 4 and 5 (30 days fin vs fin+tad) were similar (p = 1.000 and p = 1.000) (table 2). there were no differences between the groups in terms of mean body weights (p = 0.186) (table 2). discussion in the prostate, androgen receptors (ars) are predominantly located on the epithelial cells that lie on the inner surface of the glandular tissue, and therefore, the epithelial component of the prostate tissue is more sensitive to androgens than are its other components. fin initiates prostate epithelial atrophy by reducing serum dht levels by 62-82% and by reducing intraprostatic dht levels by 92%(3-6). clinically, fin provides a 1521% reduction in prostate weight and a 13-38% reduction in ipss, while increasing qmax by 1.6-2.2 ml/s (4,7-11). in addition to these effects, fin also reduces risk of acute urinary retention (aur) and the need for surgery in patients with bph(12-14). however, these positive clinical effects of fin occur only after at least 6-12 months of treatment. the expression of pde5 in human prostate arteries is localized to endothelial and smooth muscle cells(18). the expression of pde5 in the prostate arteries is comparable to that in the corpus cavernosum, while several studies have shown the pde5 expression in the prostate arteries is greater than its expression in other genitourinary tissues(17). to assess possible hemodynamic changes in the prostate tissue caused by tad, bertolotto et al. evaluated 12 patients with bph by transrectal contrast-enhanced ultrasound before and 90 minutes after tad administration, and found that tad led to increased blood flow in the prostate(15). in rats, morelli et al.(17) showed that inhibition of pde5 increases prostate blood supply and oxygenation. in light of these studies, we hypothesized that since tad increases prostate blood flow, a second drug given in combination with tad may access the prostate more easily. therefore, in the current study, we evaluated whether the combination of tad and fin, which is a 5-ari, could increase biochemical and histological changes in the prostate. the rats were administered fin at a dose of 1mg/kg/ day based on previous studies showing that this dose caused significant changes in rat prostate tissue and serum dht levels(1,20). the rats were given tad at a dose of 2 mg/kg/day based on the study of morelli et al. (17), which showed that this dose increased the oxygenation of rat prostate tissue from day 1. our hypothesis was supported by the findings that rats treated with a combination of fin+tad for 10 and 30 days had lower dht levels and lower minimum-maximum epithelial thicknesses compared to rats that were treated with fin alone. however, these differences were not significant (p > 0.05). in addition, the mean minimum and maximal epithelial thicknesses of group 3 (10 days fin+tad) were lower than those of group 4 (30 days fin), but these differences were not significant (p = 0.488 and p = 0.996, respectively). this finding is important, and supports our hypothesis, as it suggests that the histologic effects achieved by fin alone in 30 days was achieved group 1 group 2 group 3 group 4 group 5 p-value (control) (10 days fin) (10 days fin+tad) (30 days fin) (30 days fin+tad) dht (pg/ml) 814.7 ± 533.6a,b,c 484.1 ± 190.1 420.3 ± 122.9a 391.2 ± 123.5b 321.6 ± 57.8c 0.030† testosterone (ng/ml) 2.17 ± 0.43a,b,c,d 4.56 ± 0.83d 4.50 ± 0.64a 5.19 ± 0.91b 5.22 ± 0.90c < 0.001‡ maximum epithelial thickness (µm) 47.3 ± 9.8a,b,c,d 37.1 ± 4.1d 30.3 ± 1.9a 31.2 ± 2.0b 27.0 ± 2.0c < 0.001† minimum epithelial thickness (µm) 15.2 ± 2.3a,b,c,d 11.0 ± 2.3d 9.1 ± 1.0a 10.5 ± 0.7b 8.5 ± 1.3c < 0.001† prostate weight (g) 0.72 ± 0.13b,c 0.56 ± 0.11d 0.57 ± 0.10a 0.54 ± 0.12b 0.53 ± 0.10c 0.016‡ body weight (g) 325.4 ± 21.82 338.2 ± 11.47 334.9 ± 13.41 341.4 ± 10.93 339.1 ± 7.41 0.186‡ data are expressed as mean ± sd, † kruskal wallis test, ‡ one-way anova, a: group 1 vs group 3 (p < 0.05), b: group 1 vs group 4 (p < 0.05), c: group 1 vs group 5 (p < 0.05), d: group 1 vs group 2 (p < 0.001). table 2. biochemical and histological measurements of the study groups does tadalafil increase the uptake of finasteride into prostate tissue?-gok et al. by the combination of fin+tad in only 10 days. the mean prostate weights of groups 2 and 3 (10 days fin vs fin+tad) and groups 4 and 5 (30 days fin vs fin+tad) were similar. that is, the combination of fin+tad did not improve prostate weight compared to fin alone. however, this result might have been impacted in that we used young rats with no bph; if we had used older rats with bph (e.g., having rich prostate epithelial tissues), we may have obtained a different result. the fact that there was no statistical significant difference between group 2 and group 3, and between group 4 and group 5, in terms of the mean dht level and minimum-maximum epithelial thicknesses suggests may be a consequence of the small sample size. this could be considered a limitation to our study. unfortunately, there are limited studies in the literature examining the effects of fin+tad combination therapy in bph patients(21-24). one of these studies is an international, randomized, double-blind study conducted by casabe et al.(21). that study included a total of 695 patients over the age of 45 years with ipss ≥13 and prostate volume ≥ 30 ml who were divided into two groups. the first group consisted of 350 patients treated with fin+placebo and the second group consisted of 345 patients treated with fin+tad; both groups underwent treatment for 26 weeks(21). the fin+tad group had an ipss change of -4.0, -5.2, and -5.5 points with respect to baseline ipss after 4, 12, and 26 weeks of treatment, while the fin+placebo group had ipss changes of -2.3, -3.8, and -4.5 points over the same weeks, respectively. the ipss changes between the treatment groups were significantly different in each of the 3 periods (p ≤ 0.022) (21), demonstrating that the combination of fin+tad resulted in earlier symptomatic improvement compared to fin+placebo(21). this earlier symptomatic healing may be due to the tad-induced increase in blood flow, allowing more fin to reach the prostate tissue, as outlined in our hypothesis. however, it is not possible to make a definite judgment, since the study by casabe et al. did not measure the biochemical changes in the serum androgens, histological changes in prostate tissue or radiological changes in the prostate weight. conclusions although the results of the current study provide some evidence to support our hypothesis, we believe that more clinical, histological, biochemical, and radiological evaluations should be performed. if our hypothesis is validated by further studies, it can be said that an earlier and more effective treatment for bph can be achieved with a combination of fin+tad. in addition, other prostate tissue diseases (e.g., chronic prostatitis, prostate cancer) may be treated more effectively by combining pde5i with other suitable medications. acknowledgements this study was approved by the dı≤kapı yıldırım beyazıt education and research hospital board of scientific research support. conflict of interest the authors report no conflict of interest. references 1. ma z, hung nguyen t, hoa huynh t, tien do p, huynh h. reduction of rat prostate weight by combined quercetin-finasteride treatment is associated with cell cycle deregulation. j endocrinol. 2004;181:493-507. 2. audet-walsh e, yee t, tam is, giguere v. inverse regulation of dht synthesis enzymes 5alpha-reductase types 1 and 2 by the androgen receptor in prostate cancer. endocrinology. 2017;158:1015-21. 3. fornari a, rhoden el, zettler cg, ribeiro ep, rhoden cr. effects of the chronic use of finasteride and doxazosin mesylate on the histomorphometric characteristics of the prostate: experimental study in rats. int urol nephrol. 2011;43:39-45. 4. fullhase c, schneider mp. 5-alpha-reductase inhibitors and combination therapy. urol clin north am. 2016;43:325-36. 5. marks ls, partin aw, gormley gj, et al. prostate tissue composition and response to finasteride in men with symptomatic benign prostatic hyperplasia. j urol. 1997;157:21718. 6. wang k, jin s, fan d, wang m, xing n, niu y. anti-proliferative activities of finasteride in benign prostate epithelial cells require stromal fibroblasts and c-jun gene. plos one. 2017;12:e0172233. 7. andersen jt, ekman p, wolf h, et al. can finasteride reverse the progress of benign prostatic hyperplasia? a two-year placebocontrolled study. the scandinavian bph study group. urology. 1995;46:631-7. 8. kirby rs, roehrborn c, boyle p, et al. efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the prospective european doxazosin and combination therapy (predict) trial. urology. 2003;61:119-26. 9. lepor h, williford wo, barry mj, et al. the efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. veterans affairs cooperative studies benign prostatic hyperplasia study group. n engl j med. 1996;335:533-9. 10. marberger mj. long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. prowess study group. urology. 1998;51:677-86. 11. nickel jc, fradet y, boake rc, et al. efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the prospect study). proscar safety plus efficacy canadian two year study. cmaj. 1996;155:1251-9. 12. mcconnell jd, bruskewitz r, walsh p, et al. the effect of finasteride on the risk of acute does tadalafil increase the uptake of finasteride into prostate tissue?-gok et al. miscellaneous 379 vol 15 no 06 november-december 2018 380 urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. finasteride long-term efficacy and safety study group. n engl j med. 1998;338:557-63. 13. mcconnell jd, roehrborn cg, bautista om, et al. the long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. n engl j med. 2003;349:238798. 14. roehrborn cg. bph progression: concept and key learning from mtops, altess, combat, and alf-one. bju int. 2008;101 suppl 3:17-21. 15. bertolotto m, trincia e, zappetti r, bernich r, savoca g, cova ma. effect of tadalafil on prostate haemodynamics: preliminary evaluation with contrast-enhanced us. radiol med. 2009;114:1106-14. 16. lucas ka, pitari gm, kazerounian s, et al. guanylyl cyclases and signaling by cyclic gmp. pharmacol rev. 2000;52:375-414. 17. morelli a, sarchielli e, comeglio p, et al. phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats. j sex med. 2011;8:2746-60. 18. fibbi b, morelli a, vignozzi l, et al. characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract. j sex med. 2010;7:59-69. 19. giuliano f, uckert s, maggi m, birder l, kissel j, viktrup l. the mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. eur urol. 2013;63:506-16. 20. huynh h, seyam rm, brock gb. reduction of ventral prostate weight by finasteride is associated with suppression of insulin-like growth factor i (igf-i) and igf-i receptor genes and with an increase in igf binding protein 3. cancer res. 1998;58:215-8. 21. casabe a, roehrborn cg, da pozzo lf, et al. efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia. j urol. 2014;191:727-33. 22. elkelany oo, owen rc, kim ed. combination of tadalafil and finasteride for improving the symptoms of benign prostatic hyperplasia: critical appraisal and patient focus. ther clin risk manag. 2015 mar 30;11:507-13. 23. olesovsky c, kapoor a. evidence for the efficacy and safety of tadalafil and finasteride in combination for the treatment of lower urinary tract symptoms and erectile does tadalafil increase the uptake of finasteride into prostate tissue?-gok et al. dysfunction in men with benign prostatic hyperplasia. ther adv urol. 2016 ;8:257-71. 24. roehrborn cg, casabé a, glina s, sorsaburu s, henneges c, viktrup l. treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo. int j urol. 2015 ; 22:582-7. sexual dysfunction and andrology evaluation of pawp and plcζ expression in infertile men with previous icsi fertilization failure nahid azad1, hamid nazarian1, leila nazari2, marefat ghaffari novin3*, abbas piryaei1,4, mohammad hassan heidari1, reza masteri farahani1, seyedeh susan sadjadpour5 purpose: the aim of this study was to evaluate postacrosomal sheet ww domain binding protein (pawp) and phospholipase c ζ (plcζ) protein expression in patients with fertilization failure. materials and methods: semen samples were collected from 15 fertile men (control group) and 15 patients with previous fertilization failure following icsi (ff group) and were analyzed according to world health organization (who) criteria. the mean percentages of pawp and plcζ positive sperm and the total level of pawp and plcζ proteins were assessed using immunofluorescence staining. results: a significantly lower level and lower percentage of pawp positive sperm in patients with fertilization failure was found compared to the control group (p = 0.01 and p = 0.03, respectively). the mean percentage of plcζ positive sperm and level of plcζ protein were significantly lower in ff group compared to the control group (p = 0.0003 and p = 0.04, respectively). significant positive correlations was observed between pawp and plcζ positive sperms (r = 0.4, p = 0.008) and also total level of expression of plcζ and pawp proteins (r = 0.4, p = 0.02) in all participants in the study. conclusion: this is the first study that evaluates two main candidates for sperm-borne oocyte activating factors (soafs) simultaneously in patients with fertilization failure. considering lower expression of pawp and plcζ proteins in such patients, it seems like both factors might have the potential to be considered as soafs and diagnostic markers for the oocyte activation ability. keywords: fertilization failure; infertility; intra-cytoplasmic sperm injection (icsi); phospholipase c ζ (plcζ); postacrosomal sheet wwi domain binding protein (pawp). introduction infertility is a common clinical problem which affects men and women in the world(1). approximately, 60% of infertile couples directly or indirectly suffer from male infertility(2). intra-cytoplasmic sperm injection (icsi) is mainly used for male factor infertility such as suboptimal semen parameters(3) which is considered to be the most successful treatment for male infertility(4). although the rate of fertilization as a result of icsi is high (70–75%)(5), it is reported that 1–3% of icsi cycles still fail(4,6). the main cause of fertilization failure following icsi is suggested to be oocyte activation failure(6,7). oocyte activation is a series of programmed events following fertilization that gets ready an oocyte to undergo cell division(4). the activation impetus normally arises after the entrance of sperm borne oocyte activating factor (soaf) into the oocyte(8). several candidates have been proposed as the soaf for several years. phospholipase c ζ (plcζ) and postacrosomal sheet ww domain binding protein (pawp) are two main candidates under challenge(9). plcζ is the most critical candidate responsible for oocyte activation in several biochemical 1department of biology and anatomical sciences, school of medicine, shahid beheshti university of medical sciences, tehran, iran. 2department of obstetrics and gynecology, preventative gynecology research center, shahid beheshti university of medical sciences, tehran, iran. 3cellular and molecular biology research center, shahid beheshti university of medical sciences, tehran, iran. 4urogenital stem cell research center, shahid beheshti university of medical sciences, tehran, iran. 5department of cell and molecular biology, school of biology, college of science, university of tehran. *correspondence: cellular and molecular biology research center, shahid beheshti university of medical sciences, tehran, iran. phone numbers: 0098-2123872555. fax: 0098-2122413043. e-mail address: mghaffarin@yahoo.com. received may 2017 & accepted october 2017 and clinical evidence.(10) however, pawp also appears to have the appropriate conditions to be considered as a strong candidate for soaf(11,12). microinjection of plcζ (mrna or recombinant protein) into oocyte can elicit calcium oscillations in failed oocyte activation(13, 14). although injection of pawp (crna or recombinant protein) caused calcium oscillations and pronuclear formation in human and mouse oocytes(15); other studies showed that mouse and human pawp recombinant protein and crna were unable to stimulate calcium release in mouse oocytes(16,17). however, several studies have reported that patients with fertilization failure may represent plcζ deficiency, abnormal localization patterns and low expression of plcζ protein(13,18-20), there is a scarcity of studies regarding pawp as another soaf candidate among those patients. thus, we evaluate both plcζ and pawp proteins in patients with previous failed fertilization following icsi compared to fertile men. materials and methods materials a plcζ rabbit polyclonal antibody (ls-c144827) and sexual dysfunction and andrology 38 vol 15 no 03 may-june 2018 39 pawp rabbit polyclonal antibody were obtained from lifespan biosciences (usa) and proteintech (uk), respectively. ham's f-10, normal goat serum, dpbs and para-formaldehyde were purchased from sigma-aldrich (germany). anti-rabbit igg h&l (alexa fluor ®555) (ab150082) was from abcam company (uk). study population this study was performed on 30 men undergoing icsi cycles in the ivf center, taleghani hospital (rif clinic), during march 2015 to april 2017. the study was permitted by ethics committee of shahid beheshti university of medical sciences, tehran, iran and written informed consent was obtained from all participants prior to the study. inclusion and exclusion criteria low fertilization (≤ 25 %) to complete fertilization failure after at least one cycle of icsi was the inclusion criteria for the patients, independent to sperm parameters (group ff, n = 15). fertile control men with no history of infertility who had fathered children without the use of assisted reproductive techniques (art) and referred to the clinic for sex selection via preimplantation genetic diagnosis (pgd) were considered as control group (group control, n = 15). any history of female factor infertility, age > 35 years in females, and any history of trauma or surgery in testis were exclusion criteria for the participants. semen analysis the semen samples were gathered by masturbation following 2-5 days of abstinence. after complete liquefaction, sperm concentration, motility, and morphology were assessed under light microscopy according to world health organization criteria (who)(21). after washing the semen using swim up technique, sperms were used for immunofluorescence staining and plcζ, and pawp protein expression were assessed in sperm from control and ff groups. swim-up technique after centrifuging the semen, a pellet was prepared via removal of seminal plasma. the pellet was suspended in ham’s f10 (1 ml) supplemented with 10% human serum albumin. after centrifugation, the pellet was over layered with ham’s f10 supplemented with 10% human serum albumin and incubated in incubator at 37°c for 1 hour. finally, the supernatant was taken and washed sperms used for further evaluations. plcζ and pawp immunofluorescence staining plcζ and pawp immunofluorescence staining was performed as previously described,(16,18,22) with some modifications. briefly, after smear preparation on microscopic slide, sperms were fixed with freshly-made paraformaldehyde 4% in pbs for 10 minutes, and permeabilized with 0.2% triton x-100 in pbs for 10 minutes on ice. after washing, unspecific antigen bindings were blocked with 5% normal goat serum in pbs for 1 hour at 37°c, and incubated in primary antibodies; the plcζ rabbit anti-human polyclonal antibody and pawp rabbit polyclonal antibody overnight at 4°c. after washing, sperms were incubated with secondary antibody goat anti-rabbit igg h&l (alexa fluor ®555) at room temperature for 1 hour (light protected), and then washed three times for 5 minutes with washing buffer. after staining of sperm nuclei with dapi (10µg/ml), the slides were rinsed and mounted. immediate after mounting, slides were visualized under a nikon fluorescence microscope at x20 magnification at an exposure time of 1second and images were captured using nikon camera. afterwards, plcζ and pawp protein expression were assessed via analysis of the percentages of sperm exhibiting plcζ and pawp immunofluorescence (the percentages of plcζ and pawp positive sperm), and also quantitative analysis of total plcζ and pawp immunofluorescence in the sperm head. two hundred sperms were analyzed in each subject and results were recorded. figures 1 and 2 represent samples of sperms were stained with plcζ and pawp immunofluorescence procedure and counterstained with dapi. statistical analysis prism 6/graph-pad software (san diego, ca, usa) was used to perform all the statistical analyses. the normality of distribution of variables was tested first and then independent sample t-test and non-parametric tests were used for comparison of plcζ and pawp expression between groups. in addition, the correlation between pawp and plcζ expression was calculated using the pearson or spearman correlation tests according to normality of data. the level of significance was p < 0.05 . table 1. descriptive analysis of semen parameters in two groups variables control group (n=15) ff group (n=15) sperm concentration (×106) mean±sd [range] 60 ± 23.2 [25-95] 28.7 ± 22.4 [5-80] sperm motility (%) mean ± sd [range] 56.3 ± 14.6 [40-90] 40 ± 27.2 [0-90] normal morphology (%) (mean ± sd [range] 4.4 ± 1.7 [2-8] 2.3 ± 2 [0-8.5] abbreviation: ff; fertilization failure. figure 1. immunofluorescence staining of pawp protein and dapi in sperm cells from control group (a-c) and ff group (d-f) (a, d= pawp; b, e= merged image of dapi and pawp; c, f = bright field). error bar = 10µm. pawp and plcζ in fertilization failure-azad et al. results semen samples were collected from fifteen fertile control men aged 27 to 39 years (32.8 ± 1) (mean ± sem), and fifteen patients aged 25 to 38 years (31.7 ± 0.9) (mean ± sem) after at least one cycle with low fertilization or complete fertilization failure. routine semen analysis was performed according to who criteria. table 1 shows the basic sperm characteristics of participant samples. the mean of sperm concentration (×106/ml) (28.7 ± 22.4 vs 60 ± 23.2) (mean ± sd), the percentage of total motility (40 ± 27.2 vs 56.3 ± 14.6) (mean ± sd), and the percentage of normal sperm morphology (2.3 ± 2 vs 4.4 ± 1.7) (mean ± sd) were significantly lower in ff group compared to control group. plcζ and pawp were detected by immunofluorescence staining and plcζ, and pawp protein expression were assessed in sperm from control and ff groups. as shown in figure 3a, the mean percentage of pawp positive sperm was significantly lower in ff group (62.7 ± 20.1) (mean ± sd) compared to control group (80.3 ± 21.3) (mean ± sd) (p = 0.03). likewise, we found a significantly lower percentage of plcζ positive sperm in ff group (58.4 ± 25) (mean ± sd) compared to control group (87.6 ± 9.8) (p = 0.0003) (mean ± sd) (figure 3c). quantitative immunofluorescence analysis revealed that total levels of pawp was significantly lower in group ff compared to group control (p = .01) (figure 3b). as displayed in figure 3d, total levels of plcζ in ff group was significantly lower when compared to control group (p = .04). the correlation between percentages of plcζ and pawp positive sperm, and total plcζ and pawp levels was calculated. spearman correlation analysis demonstrated a significant positive correlation between the percentages of plcζ positive sperm and pawp positive sperm in all individuals (r = 0.4, p = .008) (figure 4a). moreover, a significant positive correlation was found between total level of expression of plcζ and pawp proteins in all participants in the study (r = 0.4, p = .02) (figure 4b). discussion in the present study, we assessed the expression level of plcζ and pawp proteins simultaneously in infertile men with previous fertilization failure for the first time and found lower expression of both pawp and plcζ proteins in such patients. in addition, we showed positive significant correlations between plcζ and pawp expression (both percentage of positive sperm and total level) in all individuals. the main cause of fertilization failure following icsi is considered to be the failure of oocyte activation(6). figure 2. immunofluorescence staining of plcζ protein and dapi in sperm cells. panels a-c show sperm from control group and panels d-f represent sperm from ff group (a, d= plcζ; b, e= merged image of dapi and plcζ; c, f = bright field). error bar = 10µm. figure 3. comparison of the mean percentages of pawp and plcζ positive sperm and the total level of pawp and plcζ proteins expression between ff and control groups (a-d). *p < 0.05, and ***p < 0.001 significant differences. pawp and plcζ in fertilization failure-azad et al. sexual dysfunction and andrology 40 vol 15 no 03 may-june 2018 41 oocyte activation occurs when spermatozoa releases an oocyte-activating protein into the oocyte, triggering calcium oscillations via phosphoinositide signaling pathway(23). currently, there are conflicting reports about which soaf (s) is (are) responsible for calcium oscillations. indeed, identifying the real soaf (s) has been an important goal for researchers in recent years (12,15-17). plcζ and pawp have been identified as two major soaf candidates under study(9); indeed, identifying the real soaf as a potential predictor of successful fertilization has been a key aim for researchers especially in the field of clinical research (24). although plcζ deficiency in fertilization failure is demonstrated in several clinical studies,(13,18-20), there is scarcity of data on the expression of pawp in patients with fertilization failure. the pawp protein is a component in the postacrosomal sheath of perinuclear theca (pas-pt) of sperm head which is accumulated during spermatogenesis and diffused into the oocyte cytoplasm after fertilization. blocking of calcium oscillations after injection of pawp competitive peptides indicates pawp role in oocyte activation(11, 24). in the current study, assessment of pawp expression level using immunofluorescence staining demonstrated that the percentage of pawp positive sperm as well as the total levels of pawp in ff group were significantly lower than the control group (figure 3, a-b). in line with our study, aarabi et al. reported significant positive correlations between expression of pawp with fertilization outcomes in patients undergoing icsi and suggested pawp levels in sperm as a predictive value for oocyte activation capability(25). recently, a study published by freour et al. reported no correlation between mrna and pawp protein with fertilization rate in patients without previous icsi cycles(26) which is in contrast to our results. the reason might be the differences in baseline characteristic of people studied in their report compared to the present study. in this study, we displayed lower percentage of plcζ positive sperm and lower expression of this protein in patients with previous fertilization failure compared to control group (figure 3 c-d) which was consistent with prior studies(13,18-20). accordingly, yoon et al. showed that sperm from the patients with repeated icsi failure was deficient in plcζ protein compared to fertile men(13). in the other study that was conducted by kashir et al., lower plcζ protein, lower proportion of plcζ positive sperm and abnormal localization patterns were verified in patients suffering from oocyte activation deficiency (oad). however, due to the significant variance in total levels of plcζ, some patients with failed fertilization showed similar amount of the protein compared to fertile men which may limit the predictive value of quantitative immunofluorescent analysis for oocyte activation capability(20). in addition, patients with history of failed fertilization and normal semen parameters may show plcζ deficiency.(18,19) in accordance to our results, yelumalai et al. found that the rate of fertilization is correlated with plcζ expression at the level of protein, localization patterns, and the percentage of plcζ positive sperm(27). however, in a study was performed by ferrer-vaquer et al., no significant difference of plcζ localization pattern and level of expression was observed between patients with previous fertilization failure and fertile men. the authors explained that normal plcζ expression is an essential but not a guarantee and sufficient factor for the correct oocyte activation necessarily(28). therefore, the assessment of other soaf candidates in patients with fertilization failure can help us for better understanding of the problem. in the present study, we assessed both pawp and plcζ proteins in patients with fertilization failure and found lower expression of both pawp and plcζ proteins in those patients. overall, our results are in agreement with a recent study investigating the correlation between expression of three potential factors including plcζ, pawp, and tr-kit with fertilization rate and found significant positive correlation between them in patients subjected to icsi. the authors also reported significant positive correlations between the percentage of pawp positive sperm with plcζ and trkit(29). in another study, positive correlation between plcζ and pawp at protein levels is demonstrated in globozoospermic men(30). similar to these studies, we also showed that total level and percentage of pawp positive sperm are correlated with plcζ significantly. in agreement with previous studies indicating similar level of plcζ expression in some control and patients with fertilization failure(20,28), in this study we observed surprisingly equal pawp protein expression in some individuals in the control and ff groups (figure 3 a-b). taken together, to the best of our knowledge, this is the first report evaluating two major soaf candidates simultaneously in patients with fertilization failure. we showed lower expression of both plcζ and pawp profigure 4. correlations between the mean percentages of pawp and plcζ positive sperm (r = 0.4, p = 0.008) (a), and the total level of pawp and plcζ proteins expression (r = 0.4, p = 0.02) (b). pawp and plcζ in fertilization failure-azad et al. teins and significant correlation between these factors in the patients. it seems both factors might hold the potential to be considered as soafs and diagnostic markers for oocyte activation ability. acknowledgement we thank ms. maryam karimi for providing samples. this study financially was supported by cellular and molecular biology research center, shahid beheshti university of medical sciences, tehran, iran. conflict of interest the authors report no conflict of interest. references 1. http://www.who.int/reproductivehealth/ topics/infertility/definitions/en/index.html. 2. esteves sc, miyaoka r, agarwal a. an update on the clinical assessment of the infertile male. [corrected]. clinics (sao paulo). 2011;66:691700. 3. terada y, schatten g, hasegawa h, yaegashi n. essential roles of the sperm centrosome in human fertilization: developing the therapy for fertilization failure due to sperm centrosomal dysfunction. tohoku j exp med. 2010;220:247-58. 4. vanden meerschaut dn, heindryckx b, de sutter p. assisted oocyte activation following icsi fertilization failure. reprod biomed online. 2014;28:560-71. 5. palermo gd, neri qv, takeuchi t, rosenwaks z. icsi: where we have been and where we are going. semin reprod med. 2009;27:191201. 6. flaherty sp, payne d, matthews cd. fertilization failures and abnormal fertilization after intracytoplasmic sperm injection. hum reprod. 1998;13 suppl 1:155-64. 7. rawe vy, olmedo sb, nodar fn, doncel gd, acosta aa, vitullo ad. cytoskeletal organization defects and abortive activation in human oocytes after ivf and icsi failure. mol hum reprod. 2000;6:510-6. 8. swann k. a cytosolic sperm factor stimulates repetitive calcium increases and mimics fertilization in hamster eggs. development. 1990;110:1295-302. 9. vadnais ml and gerton gl. from pawp to "pop": opening up new pathways to fatherhood. asian j androl. 2015;17:443-4. 10. amdani sn, yeste m, jones c, coward k. sperm factors and oocyte activation: current controversies and considerations. biol reprod. 2015;93:50. 11. aarabi m, qin z, xu w, mewburn j, oko r. sperm-borne protein, pawp, initiates zygotic development in xenopus laevis by eliciting intracellular calcium release. mol reprod dev. 2010;77:249-56. 12. aarabi m, sutovsky p, oko r. re: is pawp pawp and plcζ in fertilization failure-azad et al. the 'real' sperm factor? asian j androl. 2015;17:446-9. 13. yoon sy, jellerette t, salicioni am, et al. human sperm devoid of plc, zeta 1 fail to induce ca(2+) release and are unable to initiate the first step of embryo development. j clin invest. 2008;118:3671-81. 14. nomikos m, yu y, elgmati k, et al. phospholipase czeta rescues failed oocyte activation in a prototype of male factor infertility. fertil steril. 2013;99:76-85. 15. aarabi m, balakier h, bashar s, et al. sperm-derived ww domain-binding protein, pawp, elicits calcium oscillations and oocyte activation in humans and mice. faseb j. 2014;28:4434-40. 16. nomikos m, sanders jr, kashir j, et al. functional disparity between human pawp and plczeta in the generation of ca2+ oscillations for oocyte activation. mol hum reprod. 2015;21:702-10. 17. nomikos m, sanders jr, theodoridou m, et al. sperm-specific post-acrosomal wwdomain binding protein (pawp) does not cause ca2+ release in mouse oocytes. mol hum reprod. 2014;20:938-47. 18. lee hc, arny m, grow d, dumesic d, fissore ra, jellerette-nolan t. protein phospholipase c zeta1 expression in patients with failed icsi but with normal sperm parameters. j assist reprod genet. 2014;31:749-56. 19. chithiwala zh, lee hc, hill dl, et al. phospholipase c-zeta deficiency as a cause for repetitive oocyte fertilization failure during ovarian stimulation for in vitro fertilization with icsi: a case report. j assist reprod genet. 2015;32:1415-9. 20. kashir j, jones c, mounce g, et al. variance in total levels of phospholipase c zeta (plc-zeta) in human sperm may limit the applicability of quantitative immunofluorescent analysis as a diagnostic indicator of oocyte activation capability. fertil steril. 2013;99:107-17. 21. who. who laboratory manual for the examination and processing of human semen. 5th ed. geneva, switzerland: who press; 2010. 22. grasa p, coward k, young c, parrington j. the pattern of localization of the putative oocyte activation factor, phospholipase czeta, in uncapacitated, capacitated, and ionophoretreated human spermatozoa. hum reprod. 2008;23:2513-22. 23. whitaker m. calcium at fertilization and in early development. physiol rev. 2006;86:2588. 24. wu at, sutovsky p, xu w, van der spoel ac, platt fm, oko r. the postacrosomal assembly of sperm head protein, pawp, is independent of acrosome formation and dependent on microtubular manchette transport. dev biol. sexual dysfunction and andrology 42 vol 15 no 03 may-june 2018 43 2007;312:471–83. 25. aarabi m, balakier h, bashar s, et al. sperm content of postacrosomal ww binding protein is related to fertilization outcomes in patients undergoing assisted reproductive technology. fertil steril. 2014;102:440-7. 26. freour t, barragan m, ferrer-vaquer a, rodriguez a, vassena r. wbp2nl/pawp mrna and protein expression in sperm cells are not related to semen parameters, fertilization rate, or reproductive outcome. j assist reprod genet. 2017;34(6):803-10. 27. yelumalai s, yeste m, jones c, et al. total levels, localization patterns, and proportions of sperm exhibiting phospholipase c zeta are significantly correlated with fertilization rates after intracytoplasmic sperm injection. fertil steril. 2015;104:561-8 e4. 28. ferrer-vaquer a, barragan m, freour t, vernaeve v, vassena r. plcζ sequence, protein levels, and distribution in human sperm do not correlate with semen characteristics and fertilization rates after icsi. j assist reprod genet. 2016;33:747-56. 29. tavalaee m and nasr-esfahani mh. expression profile of plczeta, pawp, and tr-kit in association with fertilization potential, embryo development, and pregnancy outcomes in globozoospermic candidates for intra-cytoplasmic sperm injection and artificial oocyte activation. andrology. 2016;4:850-6. 30. kamali-dolat abadi m., tavalaee m, shahverdi a, nasr-esfahani mh. evaluation of plcζ and pawp expression in globozoospermic individuals. cell j. 2016;18:438-45. pawp and plcζ in fertilization failure-azad et al. vol 13 no 04 july-august 2016 2784 female urology is there a role for urodynamic study in women with urinary incontinence? elnaz ayati,1 zinat ghanbari,2** mohsen ayati,3* erfan amini3, maryam deldar pesikhani2 purpose: to compare clinical and urodynamic study (uds) findings in iranian women with mixed or stress ui (urinary incontinence). materials and methods: a total of 132 patients with either stress or mixed type of ui were enrolled. after accurate examination, data regarding age, parity, mode of delivery and menopausal state were recorded. furthermore the presence and severity of ui was evaluated with empty bladder supine stress test (esst) and cough test in supine and standing positions in all patients. eligible cases underwent uds evaluation by an expert urologist using a standardized protocol. results: stress and mixed ui were found in 33 (25%) and 99 (75%) patients respectively. by considering clinical evaluation as gold standard, sensitivity, specificity, positive and negative predictive value of urodynamic study were 83.4%, 30.4%, 43.4% and 80% for detecting stress ui and 96.1%, 35.6%, 34.7%, 96.2% for detecting mixed ui respectively. no correlation was noted between esst or cough test results and valsalva leak point pressure (vlpp) values in patients with stress ui, however esst was correlated with vlpp values in patients with mixed ui. conclusion: despite a relatively high sensitivity, the specificity was low and urodynamic evaluation seems to be of limited value in the assessment of ui in female patients. key words: female; urinary incontinence; urodynamics introduction urinary incontinence (ui) is defined as the involuntary loss of urine and is associated with discomfort, low self-esteem, and impaired quality of life(1). one third of women of all ages report ui and the prevalence of ui varies in different countries from 17 to 45%(2,3). differences in definitions, study characteristics and target populations are the causes of this wide range(4). ui is classified into three subtypes: stress, urgency, and mixed ui. stress ui (loss of urine on exertion such as coughing, sneezing, lifting or laughing) is common in premenopausal women(5), while urgency ui (loss of urine with a strong desire to urinate) and mixed ui (co-existing stress and urgency ui symptoms) become prevalent in older women(5). it is important to determine the type and severity of ui to consider the best treatment. both clinical signs and urodynamic findings are used for ui diagnosis. some investigators believe that urodynamic evaluation is not needed at first evaluation as it is costly and associated with discomfort(6,7) while others believe that it provides necessary information which helps accurate diagnosis(8). as there are controversies regarding application of urodynamic study (uds) in patients with ui and its correlation with subjective or objective measures of voiding function, we designed this study to compare clinical and uds findings in iranian women with mixed or stress ui. materials and methods we conducted this cross-sectional study at our institution between august 2014 and august 2015. all women with at least 3 month duration of stress or mixed ui who were referred to our clinic were considered for enrollment. questionnaire for urinary incontinence diagnosis (quid), was applied to distinguish between stress and urgency ui(9). in patients with mixed ui, those who had quid urgency ui score greater than stress ui score, were excluded from enrollment. additional exclusion criteria were patient age 18 years or younger, positive urine culture, apical, posterior or anterior pelvic organ prolapse 1 cm or greater (> stage 2), prior history of ui surgery, pelvic surgery or radiation therapy and neurogenic bladder. all participants were asked to fill informed consent forms and institutional review board approved the study. after accurate examination, data regarding age, par1 department of obstetrics and gynecology, tehran university of medical sciences, tehran iran. 2 department of pelvic floor, imam khomeini hospital complex, tehran university of medical sciences, tehran, iran. 3 uro-oncology research center, tehran university of medical sciences, tehran, iran. **correspondence: department of pelvic floor, imam khomeini hospital complex, tehran university of medical sciences, tehran, iran. tel:+982161192365. mobile:+989121305814. e-mail: drz_ghanbari@yahoo.com. *correspondence: uro-oncology research center, tehran university of medical sciences, tehran, iran. tel:+982161192794. mobile:+989121191522. received may 2016 accepted august 2016 ity, mode of delivery and menopausal state were recorded. furthermore the presence and severity of ui was evaluated with both cough and empty bladder supine stress test (esst) in all patients. included cases underwent uds evaluation by an expert urologist using a standardized protocol. patients were examined in supine position. prior to the examination, patients were asked to void and post-void residual urine was measured. urodynamic evaluation was performed with a 6f dual-lumen vesical catheter and a 9f rectal balloon catheter. normal saline was infused at a rate of 30ml/min. valsalva leak point pressure (vlpp) and cough leak point pressure were measured in cmh2o and recorded. all measurements were performed in both supine and standing positions. this study aimed to compare urodynamic variables with clinical findings to assess the correlation between uds findings and objective/subjective measures of voiding function. all data were analyzed using spss software version 20 (spss inc., chicago, il, usa). student’s t test and chi square test were used to compare continuous and categorical variables respectively. p value of less than .05 was considered statistically significant. results a total of 132 patients with mean age of 51.8 ± 10.7 years ranging from 31 to 81 met inclusion criteria and were considered for analysis. stress and mixed ui were found in 33 (25%) and 99 (75%) patients respectively. women with stress and mixed ui were comparable in terms of age, body mass index and parity. mean parity was 3.6 ± 1.6 and 4.3 ± 2.3 in women with stress and mixed ui respectively (p = .136). among patients who presented with sui, data on delivery mode was available in 30 patients. twenty one patients had history of vaginal delivery, one patient had history of cesarean section and 8 patients had history of both vaginal delivery and cesarean section. frequency of vaginal delivery was similar in both groups and we noted that the mode of delivery was not associated with incontinence type. moreover rate of menopause was 48.4% and 47.4% in the two study groups. among 33 patients with pure sui, the diagnosis was confirmed in 19 patients (57.6%) during uds. moreover uds confirmed ui in 41 of 99 (41.4%) patients who presented with mixed ui and predominant sui. by considering clinical evaluation as gold standard, sensitivity, specificity, positive and negative predictive values of urodynamic study were 83.4%, 30.4%, 43.4% and 80% for detecting stress ui and 96.1%, 35.6%, 34.7%, 96.2% for detecting mixed ui respectively. in a separate analysis we sub-classified study participants into three groups based on vlpp values (vlpp of 60 cmh2o or less, between 60 and 90 and > 90 cmh20). tables 1 and 2 show the frequency of patients with positive esst or cough test in each group. no correlation was noted between esst or cough test results and vlpp values in patients with stress ui, however esst was correlated with vlpp values in patients with mixed ui. to assess the effect of age on urodynamic parameters, we subclassified the study population into three groups. group 1 consisted of women younger than 45 years. in group 2 patients were between 45 and 60 and group 3 comprised women older than 60. mean vlpp value was 133.8 ± 27.0, 144.2 ± 102.5 and 125.1±29.8 in groups 1, 2 and 3, respectively. applying kruskal wallis test, no statistically significant difference was noted in vlpp values between different age groups (p=0.606). cystometric capacity was normal in study participants and did not differ between patients with stress and mixed ui. table 3 compares bladder volume at first sensation, normal desire and strong desire between the 2 groups. as shown in table 3 normal desire occurred at higher bladder volumes in patients with stress ui compared to those with mixed ui. furthermore maxrole of uds in incontinence-ayati et al. female urology 2785 table 1. correlation between vlpp in the urodynamic study and esst results in patients with stress or mixed urinary incontinence vlpp positive esst negative esst p-value stress ui < 60 60 90 0 2 .5 > 90 3 14 mixed ui < 60 1 0 60 90 0 4 .02 > 90 6 32 abbreviations: vlpp, valsalva leak point pressure; esst, empty bladder leak point pressure; ui, urinary incontinence abbreviations: vlpp, valsalva leak point pressure; ui, urinary incontinence vlpp positive cough test negative cough test p-value stress ui < 60 0 0 .6 60 90 1 1 > 90 6 11 mixed ui < 60 0 1 .7 60 90 1 3 > 90 12 24 table 2. correlation between vlpp in the urodynamic study and cough test results in patients with stress or mixed urinary incontinence vol 13 no 04 july-august 2016 2786 imal urine flow was comparable between the study groups and not correlated with the results of esst or cough test. urethral hypermobility was noted in 24 and 63 women with stress and mixed ui respectively. no correlation was also noted between the occurrence of urinary leakage during urodynamic evaluation and presence of urethral hypermobility in physical examination. discussion in this prospective study a large homogeneous group of female patients with stress or mixed ui were included and we noted that mixed ui is more prevalent compared to stress ui. our results are compatible with the results of digesu et al. in their study, 59% of women who were referred to a referral center in italy had mixed ui(10). mixed ui, comprises 29 to 61% of all types of incontinence in the literature(11-13). similarly in a study by pandey et al. among 202 women with ui, the most common type was found to be mixed ui (33.1%) followed by stress ui (31.6%) and urgency ui (13.3%)(14). in our study, mean bladder volumes at first sensation and strong desire were not significantly different between the two groups while mean normal desire was significantly higher in patients with stress incontinence. zaren et al. evaluated 99 women who had undergone urodynamic evaluation. mixed, urgency and stress ui were reported in 35%, 33.3% and 31.1% of their patients respectively. they showed that mean bladder volumes at first sensation, normal desire and strong desire were significantly different between the three groups(15). they also noted that mean maximal flow (q max) was not significantly different between study groups. in the present study we also noted that q max was comparable between patients with mixed ui and stress ui. our results showed that urodynamic findings are poorly correlated with clinical findings. vlpp was not correlated with the results obtained during clinical evaluation including esst results in patients with stress ui, however vlpp was correlated with esst findings in women with mixed ui. in 1993, mcguire et al. introduced vlpp as a diagnostic test for stress ui(16). it should be considered that vlpp measurement is not reliable in women who are not able to produce enough intra-abdominal pressure by valsalva maneuver. cough leak point pressure (clpp) measurement may be an alternative in these patients. as proposed by mcguire et al., clpp could be measured as an adjunct to vlpp and when the patient is not capable of producing valsalva maneuver. clpp was also not correlated with clinical findings (data not shown). frequency of hypermobility did not differ between patients with mixed and stress ui. furthermore hypermobility, detected during physical examination, was not correlated with vlpp values. we showed that uds has a low specificity and is of limited value in confirming the diagnosis of either mixed or stress ui. incontinence is a serious problem in women that affects all aspects of life including physical, psychological and social(17). along with efforts to treat these patients, physicians attempt to standardize the evaluation of such cases(15). history, physical examination, urinalysis and cystourethroscopy are usually applied in evaluation of patients with urinary incontinence. applying uds in the assessment of women with ui is controversial. uds is costly and might be associated with patient discomfort and serious adverse effects including urosepsis. since the etiology of ui can be determined through clinical evaluation and considering the poor correlation between urodynamic variables and clinical findings, this modality seems to be of limited value in evaluation of patients with ui especially in the absence of a specific neurologic disorder. uds has been considered as a useful modality in detecting occult stress ui, nevertheless, in a recent study occult stress ui was shown to be a poor urodynamic marker in predicting the development of post-hysterectomy stress ui. conclusion in this prospective study we showed that uds variables are poorly correlated with patients’ symptoms and clinical findings. despite a relatively high sensitivity, the specificity of urodynamic evaluation was low and it seems to be of limited value in the assessment of ui in female patients with no clear history of neurologic disorders and might not change therapeutic approaches. further multi-center studies with larger sample size are necessary for evaluation of the clinical usefulness of uds. conflict of interest none declared. references 1. borges jbr, guarisi t, camargo acmd, borges pcdg. correlation between urodynamic tests, history and clinical findings in treatment of women with urinary incontinence. einstein (são paulo). 2010;8:437-43. 2. wallner lp, porten s, meenan rt, et al. prevalence and severity of undiagnosed urinary incontinence in women. the american journal of medicine. 2009;122:1037-42. 3. zhu l, lang j, liu c, han s, huang j, li x. the epidemiological study of women with urinary incontinence and risk factors for stress urinary incontinence in china. menopause. 2009;16:831-6. 4. son y-j, kwon b. predictive risk 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[the diagnostic value of combined urodynamic study in different forms of urinary incontinence in women]. urologiia i nefrologiia. 199521-5. 7. teba dpf, vírseda cm, salinas cj, arredondo mf, fernandez la, fernández lc. [female urinary incontinence: clinical-urodynamic correlation]. archivos espanoles de urologia. 1999;52:237-42. 8. van leijsen sa, kluivers kb, mol bw, et al. protocol for the value of urodynamics prior to stress incontinence surgery (vusis) study: a multicenter randomized controlled trial to assess the cost effectiveness of urodynamics in women with symptoms of stress urinary incontinence in whom surgical treatment is considered. bmc women's health. 2009;9:22. 9. bradley cs, rovner es, morgan ma, et al. a new questionnaire for urinary incontinence diagnosis in women: development and testing. am j obstet gynecol. 2005;192:66-73. 10. digesu ga, hendricken c, fernando r, khullar v. do women with pure stress urinary incontinence need urodynamics? urology. 2009;74:278-81. 11. thom d. variation in estimates of urinary incontinence prevalence in the community: effects of differences in definition, population characteristics, and study type. journal of the american geriatrics society. 1998;46:473-80. 12. brown js, grady d, ouslander jg, herzog ar, varner re, posner sf. prevalence of urinary incontinence and associated risk factors in postmenopausal women. obstetrics & gynecology. 1999;94:66-70. 13. sandvik h, hunskaar s, vanvik a, bratt h, seim a, hermstad r. diagnostic classification of female urinary incontinence: an epidemiological survey corrected for validity. journal of clinical epidemiology. 1995;48:339-43. 14. pandey d, anna g, hana o, christian f. correlation between clinical presentation and urodynamic findings in women attending urogynecology clinic. journal of mid-life health. 2013;4:153. 15. zeren mf, yüksel mb, temeltas g. the comparison of urodynamic findings? n women with various types of urinary? ncontinence. international braz j urol. 2014;40:232-9. 16. mcguire e, fitzpatrick c, wan j, et al. clinical assessment of urethral sphincter function. the journal of urology. 1993;150:1452-4. 17. hunskaar s, lose g, sykes d, voss s. the prevalence of urinary incontinence in women in four european countries. bju international. 2004;93:324-30. female urology 2787 role of uds in incontinence-ayati et al. pediatric urology modified hinderer’s technique for serious proximal hypospadias with ventral curvature: outcomes and our experience ilhan ciftci1, metin gunduz1*, tamer sekmenli1 purpose: hypospadias is a congenital anomaly that includes defi¬cient ventral structure of the penis. proximal hypospadias cases make up 20% of all hypospadias cases. the choice of operative technique for hypospadias repair depends on the severity, and it is influenced by the surgeon’s experience and perception of where priorities should lie. several other factors interact to determine the type of repair, such as meatal site, presence of chordee, availability of the prepuce, and quality of the urethral plate and in addition surgeon’s experience affects the type of repair. materials and methods: the treatment records of 42 penoscrotal and perineal hypospadias cases that were treated in our clinic from 1998 to 2017 were reviewed retrospectively. cases with penoscrotal and perineal meatus were included in the study at the beginning of the urethroplasty. all cases had surgical intervention via hinderer’s technique. results: acceptable cosmetic results were obtained in 37 (85%) patients with an objective scoring system (hose) for evaluating the results of hypospadias surgery score. the mean score after surgery was 14.8. fistula and wound breakdown occurred in 7 out of the 42 cases. conclusion: in conclusion, the modified hinderer's technique is a safe and reliable technique for both proximal and perineal hypospadias. low complication rates and application in a single surgical session increase the comfort of both the patient and the surgeon. keywords: hypospadias; hinderer's technique, urethral surgery introduction hypospadias is a congenital anomaly that includes defi¬cient ventral structure of the penis. its prevalence is 1 in 300 live births, and proximal hypospadias cases make up 20% of all hypospadias cases(1). the choice of operative technique for hypospadias repair depends on the severity and it is influenced by the surgeon’s experience and perception of where priorities should lie(2). several other factors interact to determine the type of repair, such as meatal site, presence of chordee, availability of the prepuce, and quality of the urethral plate in addition to surgeon’s experience(3). the prepuce is an important source of tissue that can be used in different ways in the repair of hypospadias for neo-urethral reconstruction, to either provide a barrier layer to cover the repair or to provide skin cover to the ventral shaft. differently in our technique, flap was prepared from prepisium and not from mucosa. the aim of the present article is to show that hinderer’s method for penoscrotal and perineal hypospadias could be preferred because it is conducted in a single session and has both better aesthetic outcomes and lower complication rates. 1department of pediatric surgery, selcuk university medical faculty, konya,turkey. *correspondence: department of pediatric surgery, selcuk university medical faculty, konya,turkey. e mail: drmetingunduz@yahoo.com. received january 2018 & accepted october 2018 materials and methods the treatment records of 42 penoscrotal and perineal hypospadias cases that were treated in our clinic from 1998 to 2017 were reviewed retrospectively. cases with penoscrotal, and perineal meatus operated by a surgeon were included in the study at the beginning of the urethroplasty. all patients had severe ventral curvature (defined as greater than 45 degrees on artificial erection). all cases had surgical intervention via hinderer’s technique. exclusion criteria included either interventions with other techniques or the presence of either proximal penile or mid-shaft defects. either systemic or topical testosterone was administered, per the surgeon’s preference. subsequent to penile cleaning and cleaning of the region and in line with hinderer’s technique, the ventral skin of the penis was dissected and the chordee was corrected. during dissection a flap was prepared from meatus to dorsal prepisium for tubularization with protecting ventral plate. meatus and urethra continues with proximal flap and this is the main difference from island flap. a preputial flap was formed for the new urethra. in the modification that we conducted, the skin used for the new urethra was formed not of the inner skin of the preputium but rather from the inverted outer skin. the urology journal/vol 16 no. 5/ september-october 2019/ pp. 478-481. [doi: 10.22037/uj.v0i0.4376] flap was tubularized with a catheter (figure 1). the tubular penis was extended ventricularly and anostomised; it was accompanied by a glanular canal. after the urethra was supported with surrounding tissue, the penile skin was rewrapped around the penis. patients were administered parenteral ampicillin and oral ampicillin until the seventh postoperative day. during the operation, to form the tube and neourethra, 6/0 or 7/0 polydioxanone suture materials were used and the skin was closed with the same suture material. for the urethral stent, a 10 fr. silicon foley tube was preferred. in all cases, an elastic pressure bandage was applied to the penis to prevent the development of hematoma and edema. the bandage was removed on either the third or fourth postoperative day. the mean catheterization period was 10 days. hose hypospadias score was used in evaluation. the study was approved by selcuk university ethical committee (2018/33). descriptive statistical analyses was performed in the study. results the mean patient age at the time of surgical intervention using the modified hinderer’s technique was 20 months (range: 9 to 91months). preoperative testosterone was administered in 10 patients. the mean follow-up was at 36 months (range;5 to 80 months). three patients had early complications, such as bleeding, hematoma, and wound infection. all patients voided spontaneously after catheter removal. fistula and wound breakdown occurred in 7 out of the 42 cases (fistula 4:9.5%; breakdown or dehiscence 3:7.1%). a proximal fistula developed in one patient; the remaining were distal fistulas. all fistulas were repaired with a single intervention. no urethral strictures or meatal stenosis emerged after the operation. in three cases, minimal residual curvatures developed due to injuries that occurred during early catheter removal. the patients with recurrent ventral curvatures subsequent to wound breakdown were treated by degloving the skin and the surrounding tissue flaps. acceptable cosmetic results were obtained in 37 (85%) patients with an objective scoring system for evaluating the results of hypospadias surgery (hose) score(4) (table 1). the mean hose score after surgery was 14.8 (range:13–16) (figure 2). discussion hypospadias is a congenital abnormality occurring in 1 in 300 live births, with proximal hypospadias being identified in 20% of cases(1). there are various interventional techniques available for the treatment of hipospadias. despite the presence of multiple techniques and decades of research, the repair of either proximal or distal hypospadias remains one the most challenging complications in pediatric urology. outcomes are variable and difficult to interpret due to important inconsistencies in pre-operative patient characteristics, operative techniques, follow-up duration, and the surgeon’s outcome realization(5,6). moreover, few reports consider the patient’s quality of life and realization of the repair (7). in addition, there are differences in the repair of proximal and distal hypospadias. surgical interventions on the urethral plate are especially important. with recognition of the urethral plate as an anatomical object, pediatric urologists were able to present new techniques for repair based on either plate tubularization or augmentation: tubularized incised plate (tip) urethroplasty(8) or dorsal inlay graft (dig)(9). both techniques were initially used for distal hypospadias repair without chordee, but their application was prolonged due to proximal hypospadias(10). therefore, when transaction of the modified hinderer’s technique in proximal hypospadias-ciftci et al. table 1. the hose assessment form. variable score 1. meatal location distal glanüler 4 proksimal glanüler 3 coronal 2 penile shaft 1 2. meatal shape vertical slit 2 circular 1 3. urinary stream single stream 2 spray 1 4. erection (chordee) straight 4 mild angulation (<10) 3 modarate angulation (<45) 2 severe angulation (>10) 1 5. fistula none 4 single distal 3 single proximal 2 multipl or complex 1 figure 1. flapping and tubularization in technic, the urethral plate was preserved and the ventral curvature was corrected. vol 16 no 04 september-october 2019 479 urethral plate is required, repair can be realized with either tubularization of a pedicle flap or a free graft via either a singleor multi-stage procedure. whereas some authors prefer a single-stage repair(11), others support a two-stage repair to achieve better functional and cosmetic results(2,12). rapid improvements have occurred in proximal hypospadias repair techniques, and materials used for hypospadias surgery have undergone serious modifications. particularly, complete clarification of the preputium’s bloodstream has increased the success rate of preputial flap techniques. in contemporary hypospadias repair, normal anatomy and the aesthetic appearance of the penis have become as important as functional outcomes. these outcomes can be achieved via single-session surgical interventions. in addition, adjustments in microsurgical procedures and improvements in anesthesia have also paved the way for the surgeon to perform hypospadias repair on patients of increasingly younger ages(13). the main objectives of hypospadias surgery are improvement in both sexual and urinary functions as well as an acceptable appearance of the genitalia. relevant literature shows that, although tip urethroplasty achieves sufficient cosmetic improvement(14), it leads to more penile curvature and urethrocutaneous fistula(15). penile curvature requires either dorsal penile plication or much more aggressive treatment modalities. likewise, for fistula repair, at least one surgical intervention session must be considered. this condition makes tip urethroplasty an inadequate technique for both penoscrotal and perineal hypospadias. however, it remains an important technique for distal hypospadias(8,16,17). recently, use of the dig urethroplasty technique, especially in proximal hypospadias, has increased. in this technique, after the curvature is fixed, the urethral bed is formed with the loose flap. in another session, as with tip, urethroplasty is again applied. hence, this technique includes two surgical interventions. relevant studies have shown that the onlay flap method, when compared to tip urethroplasty, has had cosmetically less acceptable outcomes(15). when comparing fistula emergence and other complications, the results are comparable(15). notably, because it requires two surgical sessions, the patient acceptance rate is low(15). different studies have had different outcomes; however, the complication rates of both techniques are higher than those of the present technique. although the authors reported single-session anomaly correction using the dig technique, in terms of fistula, wound formation, and ventral curvature, complications were alike. fistula rates were reported as 25%, ventral curvatureas 15%, and total injury formation as 12% (15,16,17). however, relevant literature research has shown that urethral stenosis cases are compared to other techniques more frequently(18,19,20). this technique is advantageous because the plate is protected according to the island flap and the anastomosis line is more regular and shorter. in addition, urethral dilatation and stone formation are less common. despite being a single session in the dig procedure, the incidence of fistulae and ventral curvatures is higher. the reason that the braca procedure is two sessions is less preferable than our procedure. in the present study, fistula rates were determined as 9.5%, wound formation as 7.1%, and penile curvature as 7.1%. cosmetically, per the hose scale, 14.8 is an acceptable appearance. therefore, the modified hinderer technique, when applied in a single session, emerges as the more advantageous technique in terms of patient satisfaction and acceptance. conclusions in conclusion, the modified hinderer technique is a safe and reliable technique for both penoscrotal and perineal hypospadias. low complication rates and application in a single surgical session increase the comfort of both the patient and the surgeon. conflict of interest the authors declare that they had no conflict of interest. references 1. baskin ls. hypospadias and urethral development. j urol.2000;163:951e6 2. bracka a. hypospadias repair: the two-stage pediatric urology 480 figure 2. patient's appearance before surgery and after 3 months. modified hinderer’s technique in proximal hypospadias-ciftci et al. alternative. br j urol. 1995;76:31-41. review. 3. erol d, germiyanoglu c. the factors affecting successful repair of hypospadias. urol bull. 1995;6:138 4. holland aj, smith gh, ross fi, cass dt. hose: an objective scoring system for evaluating the results of hypospadias surgery. bju int. 2001;88:255-8. 5. prasad mm, marks a, vasquez e, yerkes eb, cheng ey. published surgical success rates in pediatric urology e fact or fiction? j urol. 2012;188:1643e8. 6. kiss a, sulya b, sza´sz am, romics i, kelemen z, to´th j, et al. long-term psychological and sexual outcomes of severe penile hypospadias repair. j sex med. 2011;8:1529e39. 7. mureau ma, slijper fm, slob ak, verhulst fc, nijman rj. satisfaction with penile appearance after hypospadias surgery: the patient and surgeon view. j urol 1996;155:703e6. 8. snodgrass w: tubularized, incised plate urethroplasty for distal hypospadias. j urol. 1994; 151: 464. 9. elder js, duckett jw, snyder hm. onlay island flap in the repair of mid and distal penile hypospadias without chordee. j urol.1987;138:376e9. 10. chen sc, yang ss, hsieh ch, chen yt. tubularized incised plate urethroplasty for proximal hypospadias. bju int. 2000;86:1050e3. 11. duckett jr jw. transverse preputial island flap technique for repair of severe hypospadias. urol clin north am 1980;7:423. 12. johal ns, nitkunan t, o’malley k, cuckow pm. the two-stage repair for severe primary hypospadias. eur urol. 2006;50:366e71. 13. ferro f, vallasciani s, borsellino a, atzori p, martini l. snodgrass urethroplasty: grafting the incised plate e10 years later. j urol. 2009;182:1730e5. 14. braga lh, pippi salle jl, lorenzo aj, skeldon s, dave s, farhat wa, khoury ae, bagli dj. comparative analysis of tubularized incised plate versus onlay island flap urethroplasty for penoscrotal hypospadias. j urol. 2007;178:1451-6;1456-7. 15. snodgrass wt and lorenzo a: tubularized incised-plate urethroplasty for proximal hypospadias. bju int. 2002; 89: 90. 16. gite va, nikose jv, bote sm, patil sr.anterior urethral advancement as a single-stage technique for repair of anterior hypospadias: our experience. urol j. 2017;14:4034-37. 17. alizadeh f, shirani s.outcomes of patients with glanular hypospadias or dorsal hood deformity withmild chordee ttreated by modified firlit's technique. urol j. 2016;13:2908-10. 18. castagnetti m, zhapa e, rigamonti w. primary severe hypospadias: comparison of reoperation rates and parental perception of urinary symptoms and cosmetic outcomes among 4 repairs. j urol. 2013;189:1508e13. 19. nuhoğlu b, ayyildiz a, balci u, ersoy e, gürdal m, germiyanoglu c, erol d. surgical treatment options in proximal hypospadias: retrospective analysis of 171 cases at a single institution. int urol nephrol. 2006;38:593-8. 20. thiry s, saussez t, dormeus s, tombal b, wese fx, feyaerts a. long-term functional, cosmetic and sexual outcomes of hypospadias correction performed in childhood. urol int. 2015;95:137-41. modified hinderer’s technique in proximal hypospadias-ciftci et al. vol 16 no 04 september-october 2019 481 differences in poly(adp-ribose) polymerase1(parp1-) and proliferative cell nuclear antigen (pcna) immunoreactivity in patients who experienced successful and unsuccessful microdissection testicular sperm extraction procedures purpose: the aim of this study is to evaluate expression of deoxyribonucleic acid (dna) synthesis and repair markers in testicular tissues of azoospermic men in whom sperm retrieval could and could not be achieved as a result of microdissection testicular sperm extraction (micro-tese) procedure. materials and methods: in this prospective cohort study, testicular tissues were retrieved from 60 non-obstructive azoospermia (noa) patients who underwent micro-tese procedure. these patients were divided into two groups: micro-tese positive group, which included 30 noa patients from whom sperm could be extracted via micro-tese procedure; and micro-tese negative group, which included 30 noa patients from whom sperm retrieval could not be achieved via micro-tese procedure. expression and distribution patterns of poly(adp-ribose) polymerase-1 (parp-1) and proliferative cell nuclear antigen (pcna) in extracted tissues were assessed by immunohistochemical staining to reveal any differences in dna synthesis and repair between the two groups. results: micro-tese positive group exhibited significantly stronger immunoreactivity for both pcna and parp1 (p = .001 and p = .001 respectively). the results of this study reveal that both dna synthesis and repair markers were expressed strongly in patients who experienced successful micro-tese procedure. conclusion: although further studies are needed to support these findings, parp-1 and pcna expression in testicular tissues of noa patients could be promising predictive factors for micro-tese procedure success. key words: azoospermia, micro-tese, pcna, parp-1 introduction male factor is an important cause of infertility, contributing to 40-50% of all cases. varicocele, cryptorchidism, infections, obstructive lesions, cystic fibrosis, erectile dysfunction, trauma, and tumors are very well known etiologies of male infertility as well as defective spermatozoa.(1) non-obstructive azoospermia (noa), which is defined as the absence of spermatozoa in semen due to impaired spermatogenesis, is the contributing factor for approximately 10% of cases of male factor infertility. (2) sexual chromosomal abnormalities, y chromosome translocations and microdeletions, trauma, oxidative stress, cryptorchidism, and radiation are possible etiologies for noa.(3) retrieval of spermatozoa is achieved by testicular sperm extraction (tese) in 50% of noa cases, which was described for the first time in 1994.(4,5) over time, micro-tese, which allows direct visualization of tubules containing more germ cells with active spermatogenesis via an operating microscope, became the method of choice for spermatozoa retrieval (sr).(6) poly adp-ribosylation is a post-translational modification of proteins that plays a key role in the maintenance 1 izmir medical park hospital ivf unit, izmir, turkey. 2 irenbe ivf center, izmir, turkey. 3 manisa celal bayar university, school of vocational health service, manisa, turkey. 4 izmir medical park hospital urology department, izmir,turkey. 5 izmir medical park hospital obstetric and gynecology department, izmir,turkey 6 izmir medical park hospital, biostatistics department, izmir,turkey. *correspondence: irenbe ivf center, talatpasa avenue, no:6, 35220 konak/izmir/turkey. e mail: barisbuke@hotmail.com received march 2017 & accepted june 2017 of genomic integrity and dna repair.(7) poly (adp-ribose) polymerase-1 (parp-1) is involved in many molecular and cellular processes such as dna damage detection and repair, cell differentiation, apoptosis, and chromatin structure modulation.(8) sufficient spermatogenesis depends on the proliferative activity of spermatogonia and the loss of germ cells during meiosis and spermiogenesis.(9) proliferative cell nuclear antigen (pcna) is a nuclear matrix protein involved in dna synthesis and repair. pcna is also a useful tool in the diagnosis of germinal arrest, which is a result of dna synthesis deterioration.(10) this study aimed to explore the differences in dna synthesis and repair in testicular tissues of noa patients from whom sperm retrieval could and could not be achieved, by way of evaluating the expression and distribution patterns of parp-1 and pcna immunohistochemically. patients and methods study population the study population included 60 primary infertile azoospermic men with no endocrinopathy, known chromosexual dysfunction and andrology süleyman akarsu1, baris büke2*, seren gülsen gürgen3, serkan akdemir4, funda gode1, merve biçer5, mustafa agah tekindal6 , ahmet zeki isik1 sexual dysfunction and andrology 5018 some disorder, retrograde ejaculation, history of urogenital surgery or erectile dysfunction, aged between 31-39 years, who applied to izmir university ivf clinic, between september 2015 and april 2016. patients with numerical, structural chromosome abnormalities and with partial translocation were not included in the study. the participants were subjected to micro-tese procedure by the same urologist and divided into two matched groups, those with sperm in tissue specimens, and those without in 30 men, sr could not be achieved (micro-tese negative group), while in the remaining 30 men, sr could be achieved (micro-tese positive group). the local ethics committee approved the study protocol. after obtaining informed written consent from each of the participants, general health data were collected. procedure for each individual, chromosome number and structures were studied by examining 20 metaphase numbers using lymphocyte cell culture from peripheral blood and gtg banding. all of the participants had normal karyotypes and hormonal status including fsh. azoospermia was confirmed in at least two different semen analyses of 60 primary infertile men, according to world health organization guidelines.(11) to evaluate testicular size and texture, all participants underwent testicular ultrasound and doppler sonographic examination. testicular tissue samples were extracted via microdissection-tese method as defined by schlegel.(12) the extracted tissues were fixed in neutral formalin for 24 hours. after washing the tissues in tap water for a night long, they were dehydrated through ascending grades of alcohol and cleared in xylene. 5 micron thick sections were taken to poly-lysine coated glass slides and parted for immunohistochemistry. evaluation immunohistochemistry the sections were incubated at 60 °c for overnight, deparaffinized in xylene, and dehydrated through descending grades of alcohol. for antigen retrieval, the sections were boiled in citrate buffer (10 mm, ph 6.0) for 15 minutes in a microwave processor (thermo, ca, usa). to prevent endogenous peroxidase activity, the sections were treated with 3% hydrogen peroxide (thermo, ca, usa) for 15 minutes. the sections were then blocked with blocking serum (ultra v block, thermo, ca, usa) for 10 minutes. subsequently, the sections were incubated with primary antibodies parp-1 (scbt, ca, usa) and pcna (thermo, ca, usa) for 60 minutes at room temperature and humid air. then, antigen-antibody complex was fixed with biotinylated secondary antibody and streptavidin-peroxidase complex (20 minutes). aec (thermo, ca, usa) was used for labeling. the sections were then counterstained with mayer’s hematoxylin and mounted for microscopic evaluation. the images were recorded via an olympus microscope with an attached camera (cx31 germany). ten fields on each slide were chosen randomly under x400 magnification, and the h score was established according to density and percentage of involvement. the density of involvement was scored as 0 (no involvement), 1(+, weak immunoreactivity), 2(++, moderate immunoreactivity), or 3(+++, strong immunoreactivity). the percentage of involvement/immunoreactivity was calculated by division of the number of immunoreactive cells to total cells and scored as 1 (0-10%, focal), 2 (11-50%, regional), and 3 (51-100%, diffuse). for each field, density and amount scores were calculated with the formula: “ hscore= σpi.(i+1)”. the sum of 10 fields’ scores in each slide made up the individual slide score.(13) image analysis software (leica q win v3 plus image, leica, germany) was used for each field’s score calculation. statistical analysis statistical analyses were performed using statistical package for social sciences version 20.0 (spss statistics for windows, version 20.0. armonk, ny: ibm corp.). for discrete and continuous variables, descriptive statistics (mean, standard deviation, median, minimum value, maximum value, and percentile) are given. in addition, the homogeneity of the variances, which is one of the prerequisites of parametric tests, was checked through levene’s test. the assumption of normality was tested via the shapiro–wilk test. a total of 60 individuals participated in the study. all the individuals were independent of each other. for this reason, two independent group comparisons were used for the study. to compare the differences between the two groups, the student’s t-test was used when the parametric test prerequisites were fulfilled, and the mann–whitney u test was used when such prerequisites were not fulfilled. results table 1 summarizes the statistical differences between groups. in the micro-tese negative group, fewer spermatogenic cells showed parp-1 expression, and immunoreactivity was weaker as well. in the micro-tese positive group, spermatogenic cells that showed parp-1 expression were more frequent, and immunoreactivity, especially in primary spermatocytes, was stronger (figure 1). regarding pcna staining, the micro-tese negative group included few immunoreactive cells, while in the micro-tese positive group, the number of immunoreactive cells was greater (figure 2). discussion the main purpose of this study was to determine whether there is a difference in parp-1 and pcna immunoreactivity in two groups of infertile men suffering from sexual dysfunction and infertility 4039 table 1. comparisons of parp-1 and pcna immunoreactivity in tese negative and positive groups. groupa n mean ±sd min-max p parp_1 tese-negative 30 73,30 ± 20,31 45-117 ,001 tese-positive 30 203,97 ± 18,23 176-240 pcna tese-negative 30 28,23 ± 4,71 19-37 ,001 tese-positive 30 61,90 ± 7,71 50-75 adata is presented as mean ± sd or number (percent) parp-1 and pcna immunoreactivity in tese tissues-akarsu et al. vol 14 no 05 september-october 2017 5019 non-obstructive azoospermia. the first group of patients consisted of men in whom sr could be achieved as a result of micro-tese procedure, while the other group included azoospermic men in whom sr could not be achieved. our data revealed that the micro-tese positive group showed stronger parp-1 and pcna immunoreactivity, which indicates better dna synthesis and repair. apart from genetic disorders, the etiologic factors for noa, such as alkylating agents, radiation, and toxins, are suggested to contribute noa by accumulating reactive oxygen species (ros). accumulation of ros causes dna damage and impairs dna integrity.(14) as a result of dna damage and loss of integrity, spermatogenesis and sperm-oocyte interaction is destructed.(15) furthermore, dna damage in sperm cells is related to fertilization failure, lower ivf success, poor placentation, and pregnancy complications.(16) ros-related dna damage causes a substantial amount of single and double strand dna breaks that lead to activation of parp enzymes.(17) parp enzymes act in many cellular processes including dna repair, cellular proliferation, differentiation, apoptosis, and necrosis. parp-1 is the enzyme responsible for more than 90% of parp activity in human testes.(18) parp-1 achieves dna repair by dna base excision, homologous recombination, and non-homologous end-joining processes. there is a large amount of evidence in the literature that poly adp-ribosylation plays an important role in safeguarding dna integrity in spermatogenesis.(19) however, there is evidence regarding a possible role of parp overactivation due to excessive amount of ros that can lead to male reproductive disorders via necroptotic cell death. it is considered to be related with the type and amplitude of the factor that brings out ros.(20,21) most of the studies regarding parp expression in testicular tissue have been implemented in rats. moreover, in the context of male fertility disorders, only a few studies exist. two different studies investigated parp expression in testicular tissue of varicocele patients and reported stronger immunoreactivity in the varicocele group, indicating increased dna repair.(22,23) two other studies investigated the effect of aging on parp expression in testicular tissues, and both studies reported stronger immunoreactivity in elder patients, similar to varicocele patients, indicating more dna repair due to increased amount of dna strand breaks.(24,25) the present study is the first to investigate parp expression in testicular tissues of noa patients undergoing micro-tese procedure. the results of this study revealed stronger immunoreactivity in micro-tese positive group regarding parp-1 staining, possibly indicating a better response to stress stimulus via increased dna repair. proliferative cell nuclear antigen (pcna) is a wellknown marker of dna synthesis that has a key role in dna replication. it also has a role in cell cycle regulation and dna repair.(10) the pcna index, which was developed to assess aggressiveness of tumors, has also been shown to be a useful marker to assess germ cell kinetics.(26,27) our data revealed stronger immunoreactivity for pcna in the micro-tese positive group, indicating increased dna synthesis and proliferation activity in this group. the testicular cell number in the seminiferous tubules is maintained by a dynamic balance between cell proliferation and apoptotic cell death(28) fragmentation of dna in the nucleus is one of the morphological changes in the apoptotic process and can be detected in histological sections using the tunel (in situ terminal deoxynucleotidlytransferase-mediated deoxy-utp nick end labeling) method.(29) this assay identifies single and double-stranded dna breaks, labeling free 3αoh termini with modified nucleotides in a template-independent manner(30) in this experimental study, we did not perform the apoptosis pathway. however, we are planning to investigate apoptotic signal relations in testicular tissue using the micro-tese procedure as a continuation of the present study. conclusions in summary, the results of the present study revealed inparp-1 and pcna immunoreactivity in tese tissues-akarsu et al. figure 1. immunohistochemical expression of parp-1 in testicular tissues of noa patients. a1 and a2 belong to tese negative group; b1 and b2 belong to tese positive group. α: immun positive spermotogenic cells. a1 and b1 x100 = 50 µm, x400 bar = 10 µm. mayer’s hematoxylin background staining. figure 2. immunohistochemical expression of pcna in testicular tissues of noa patients. a1 and a2 belong to tese negative group; b1 and b2 belong to tese positive group. : immun positive spermotogenic cells. a1 and b1 x100 = 50 µm, x400 bar = 10 µm. mayer’s hematoxylin background staining. sexual dysfunction and andrology 5020 creased parp-1 and pcna immunoreactivity reflecting greater dna repair and synthesis activity in testicular tissues of noa patients in whom sr could be achieved by micro-tese procedure. in other words, increased parp-1 and pcna immunoreactivity was evident in successful tese procedures. based on these findings, it is possible to suggest that stronger parp-1 and pcna immunoreactivity in testicular tissue of noa patients can be a promising predictor of successful sr following tese procedures. however, we should emphasize that it would be inappropriate to make such a decision solely on the basis of the immunohistochemical findings of a single study. further studies with additional dna repair, synthesis, and apoptosis markers will be useful to enlighten the issue. acknowledgement this study was approved in ivf center, izmir medical park hospital, as a research project. the authors would like to thank dr. mustafa agah tekindal and appreciate her support for the preparing of this manuscript. conflict of interest the authors report no conflict of interest. references 1. kumar n, sıngh a k. trends of male factor infertility, an mportant cause of infertility: a review of literature. j hum reprod sci. 2015; 8: 191. 2. palermo gd, schlegel pn, harıprashad jj, et al. fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. hum reprod. 1999;14:741-8. 3. ezeh ui. beyond the clinical classification of azoospermia: opinion. hum reprod. 2000;15:2356-9. 4. devroey p, lıu j, nagy z, et al. pregnancies after testicular sperm extraction and intracytoplasmic sperm njection in nonobstructive azoospermia. hum reprod. 1995;10:1457-60. 5. donoso p, tournaye h, devroey p. which is the best sperm retrieval technique for non-obstructive azoospermia? a systematic review. hum reprod update. 2007;13:539549. 6. bernıe am, mata da, ramasamy r, schlegel pn. comparison of microdissection testicular sperm extraction, conventional testicular sperm extraction, and testicular sperm aspiration for nonobstructive azoospermia: a systematic review and meta-analysis. fertil steril. 2015;104:1099-1103. 7. d'amours d, desnoyers s, d'sılva i, poırıer gg. poly (adp-ribosyl) ation reactions in the regulation of nuclear functions. biochem j. 1999;342:249-68. 8. olıver fj, menıssıer-de murcıa j, de murcıa g. poly (adp-ribose) polymerase in the cellular response to dna damage, apoptosis, and disease. am j hum genet. 1999. 64, 1282-8. 9. steger k, aleıthe i, behre h, bergmann m. the proliferation of spermatogonia in normal and pathological human seminiferous epithelium: an immunohistochemical study using monoclonal antibodies against ki67 protein and proliferating cell nuclear antigen. mol hum reprod. 1998;4:227-33. 10. altay b, çetinkalp , doanavargıl b, hekimgil m, semerci b. streptozotocinnduced diabetic effects on spermatogenesis with proliferative cell nuclear antigen immunostaining of adult rat testis. fertil steril. 2003;80:828-31. 11. cooper tg, noonan e, eckardstein s, auger j. world health organization reference values for human semen characteristics. hum reprod update. 2010;16:231-45. 12. schlegel, p. n. 1999. testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. hum reprod, 14, 131-5. 13. gürgen sg, sayın o, cetin f, yücel at. transcutaneous electrical nerve stimulation (tens) accelerates cutaneous wound healing and inhibits pro-inflammatory cytokines. inflammation. 2014;37:775-84. 14. aıtken rj, clarkson js, fıshel s. generation of reactive oxygen species, lipid peroxidation, and human sperm function. biol reprod. 1989;41:183-197. 15. saleh ra, hcld aa. oxidative stress and male infertility: from research bench to clinical practice. j androl. 2002; 23:737-52. 16. aıtken rj, krausz c. oxidative stress, dna damage and the y chromosome. reproduction. 2001; 122: 497-506. 17. maymon bbs, cohen-armon m, yavetz h et al. role of poly (adp-ribosyl) ation during human spermatogenesis. fertil steril, 2006;86:1402-7. 18. meyer-fıcca ml, meyer rg, jacobson el, jacobson mk. poly (adp-ribose) polymerases: managing genome stability. int j biochem cell biol, 2005;37:920-6. 19. celık-ozencı c, tasatargıl a. 2013. role of poly (adp-ribose) polymerases in male reproduction. spermatogenesis, 3, e24194. 20. du l, zhang x, han yy, et al. intramitochondrial poly (adp-ribosylation) contributes to nad+ depletion and cell death i̇nduced by oxidative stress. j biol chem, 2003; 278:18426-33. 21. vırág l, robaszkıewıcz a, rodrıguez-vargas jm, olıver fj. poly (adp-ribose) signaling in cell death. mol aspects med. 2013;34:115367. 22. el-domyatı mm, al-dın abm, barakat mt, et al. the expression and distribution of deoxyribonucleic acid repair and apoptosis parp-1 and pcna immunoreactivity in tese tissues-akarsu et al. vol 14 no 05 september-october 2017 5021 markers in testicular germ cells of nfertile varicocele patients resembles that of old fertile men. fertil steril. 2010; 93: 795-801. 23. chang fw, sun gh, cheng yy, chen ic, chıen hh, wu gj. effects of varicocele upon the expression of apoptosis related proteins. andrologia. 2010;42:225-230. 24. wyrobek aj, eskenazı b, young s, et al. advancing age has differential effects on dna damage, chromatin integrity, gene mutations, and aneuploidies in sperm. proc natl acad sci u.s.a.. 2006;103:9601-06. 25. el-domyatı mm., al-dın abm, barakat mt, el-fakahany hm, xu j, sakkas d. deoxyribonucleic acid repair and apoptosis in testicular germ cells of aging fertile men: the role of the poly (adenosine diphosphate-ribosyl) ation pathway. fertil steril. 2009;91: 2221-9. 26. delahunt b, bethwaıte pb, nacey jn, rıbas jl. proliferating cell nuclear antigen (pcna) expression as a prognostic indicator for renal cell carcinoma: comparison with tumour grade, mitotic index, and silver staining nucleolar organizer region numbers. j pathol, 1993;170:471-7. 27. zeng l, kong xt, su jw, xıa tl, na yq, guo yl. evaluation of germ-cell kinetics i̇n i̇nfertile patients with proliferating cell nuclear antigen proliferating ndex. asian j androl. 2001;1:63-66 28. russell ld, chiarini-garcia h, korsmeyer sj, knudson c. mbax-dependent spermatogonia apoptosis is required for testicular development and spermatogenesis. biol. reprod. 2002;66:950-958. 29. gavrieli y, sherman y, ben-sasson sa. identification of programmed cell death in situ via specific labeling of nuclear dna fragmentation. j cell biol 1992;119:493–501. 30. sun jg, jurisicova a, casper rf. detection of deoxyribonucleic acid fragmentation in human sperm (correlation with fertilization in vitro) . biol reprod. 1997; 56: 602–607 parp-1 and pcna immunoreactivity in tese tissues-akarsu et al. sexual dysfunction and andrology 5022 endourology and stone disease different approaches to detect “nanobacteria” in patients with kidney stones: an infectious cause or a subset of life? hani ansari, m.sc.1, abbas akhavan sepahi, ph.d.2*, mohsen akhavan sepahi, m.d.3 purpose: this research focused on the detection of nanobacteria in kidney stones of 30 iranian patients without adding fetal bovine serum (fbs) to the culture media. materials and methods: nanobacteria were isolated from a nephro-ureterolithiasis extract of the urinary tract and kidney of patients and were cultured in the laboratory. the growth of nanobacteria was monitored using a spectrophotometer, and with inverted microscopy technique, their crystallization was analyzed after two days. the images from atomic force microscopy (afm), transmission electron microscopy (tem) and scanning electron microscopy (sem) indicated the morphology and demonstrated the size of the cultured nanobacteria which is between 60 and 160 nm. fourier transform infrared spectroscopy (ftir) and x-ray diffraction (xrd) were used to study the chemical composition, surface functional groups and crystal structure of the igloo-like nanobacteria shell. ftir spectra in the region of 1000 to 1200 cm-1 and the xrd peaks provided evidence that the main components of the nanobacteria shell were apatite-based compounds. results: nanobacteria infected all the 27 patients with apatite kidney stone, and none of the three patients who had uric acid kidney stone were infected as confirmed by the cultivation of the stones samples. the results showed that nanobacteria might play a fundamental role in the formation of apatite-based kidney stones. conclusion: the biomineralization ability of nanobacteria may lead to calcification of the soft tissues, which in turn may result in other diseases. it is also suggested that nanobacteria may be a factor in calcification-related diseases and disorders with poorly characterized etiologies. this research with its different approaches, clarified significant doubts that nanobacteria act as contaminant, warranting continued investigation of its role in other diseases. key words: nanobacterium; biomineralization; calcium apatite; kidney stone; calcification; lithiasis. 1department of microbiology, islamic azad university of pharmaceutical sciences branch, tehran, iran 2department of microbiology, college of basic sciences, islamic azad university, tehran north branch, tehran, iran 3department of pediatric medicine research center, qom university of medical sciences, qom, iran *correspondence: department of microbiology, college of basic sciences, islamic azad university, tehran north branch, tehran, iran. tel: +98-2122949793. fax: +98-21-88329119. email: akhavansepahy@gmail.com. received july 2017 & accepted َaugust 2017 introduction nephrolithiasis is a condition with prevalence vary-ing geographically, presenting with multiple etiologies, and showing increasing annual incidents, though it is still recognized as a relatively rare medical problem in the world. there are several known factors that can cause the disease, these include metabolic disorders, anatomical malformations, and environmental and dietary factors. based on several studies, it has also been found that bacterial infections and metabolic factors can play a fundamental role in some urinary tract disorders such as biofilm formation on catheters(1), cancer(2-4) and lithiasis(5-9). the term “nanoform” was described previously in both geology and biology(10), and the terms related to this novel category are classified into two. the first class comprised of living nanoforms and is referred to as nanobacteria(11-13), while the second class is composed of non-living particles, specifically, mineralo fetuin complexes(14) or the calcifying nanoparticles referred to this discovery. nanobacteria are the smallest cell-walled bacteria that have been discovered in human and cow blood, as well as in commercial cell culture serum. they can be grown under mammalian cell culture conditions for characterization and study. one of the most controversial issues about nanobacteria relates to its resistance to physical and chemical agents as well as its strong heat resistance. nanobacteria produce mineralized shells made of carbonate apatite, and it is assumed that this apatite shell may be what protects the nanobacteria from various stresses(15). kajander(11) first reported nanobacteria as infectious agents in 1993. although, based on the current criteria of living organisms, nanobacteria do not have living organism’s features(16), but new evidence based on recent researches(17) and the findings of the current study support the idea that nanobacteria are living organisms. vol 14 no 05 september-october 2017 5001 being living or non-living, the fact or fiction of nanobacteria has been postponed for future research to show the final decision on this controversial scientific issue. similar to other infectious agents, nanobacteria have the ability to spread to other organs and tissues through the bloodstream, and therefore can be found in the blood, urine and saliva of infected persons. the ability of nanobacteria to produce mineralized shells and their existence in the urinary tract of humans led to the hypothesis that they play a role in the production and progression of lithiasis. in some studies, it was shown that nanobacteria could induce cell apoptosis and calcification of soft tissues, and that the formation of kidney stones could be induced after intrarenal injection or infection with nanobacteria(18-20). in this study, kidney stones from 30 iranian patients were collected and analyzed for the presence of nanobacteria in nephro-ureteroliths. this study aimed to detect nanobacteria in the cultures of specimens taken after surgery for kidney stone disease and investigate the presence of these bacteria using inverted microscopy, sem, tem, afm, xrd and ftir. materials and methods cultivation of the nanobacteria the samples used were obtained from thirty patients selected random, with kidney and upper urinary tract stones following nephrolithotomy surgery. the authors partnered with multiple hospital centers in iran to secure patient's documented permission and provided the commitment to anonymity without any consideration of eligibility to participate in the research. the chemical composition of the isolated stones based on the initial urinary calculi analysis was calcium oxalate in more than 85% of the samples. after the collecting phase, a crucible grinder was placed in an autoclave (121°c, 20 min) before being used to powder the individual kidney stone completely. the powdered stones were demineralized by treatment with a 1 n solution of hcl for 3 min before neutralization by tris buffer. the suspension was then centrifuged (14,000 ×g, 60 min) in a high-speed centrifuge from sigma. the supernatant was discarded, and the precipitate was collected and filtered with dmem prepared in the pasteur institute of tehran through a syringe-type ultrafilter (0.1 µm) into flasks. each flask contains 5 ml dmem without fetal bovine serum (fbs) to avoid any possible contamination from fbs even if it was irradiated with gamma and in the presence of antibiotic (100 u/ml of penicillin and 100 µg/ml of streptomycin). the flasks were incubated under aseptic conditions in a cell incubator (co 2 : 5%, air: 88%, 37°c). medium containing 5 ml dmem in the presence of antibiotics lacking any powdered stone was used as a negative control. all the processes mentioned above were carried out under strict sterile conditions in a laminar flow hood. nanobacteria (nb) growth was monitored table 1: patients demographic and characteristic table variables patient statics age group (years).(mean ± sd) 18-48. (34.77 ± 10.22) male to female ratio 20/10 bmi(kg/m2). range (mean ± sd) 22.8-34.3. (28.05 ± 3.24) height 158-180. (168.97 ± 5.23) weight 31.2-97. (77.91 ± 12.86) history of previos stone sugeries 17 history of calcification diseases 20 gender ratio out of 20 11 (male)/20 9 (female)/20 positive samples out of 30 27 (18 male and 9 female) negative samples out of 30 3(2 male and 1 female) abbreviations: sd: standard deviation, bmi: body mass index. figure 1: crystal formation by nanobacteria in culture media using inverted microscopy (a) first day after cultivation and (b) two days after the culture (magnification: 1000×). nanobacteria and kidney stone-ansari et al. endourology and stone diseases 5002 for up to five days by inverted microscopy. crystallization was initiation by nucleation of the nb, and turbidity of the culture media was considered as the nb growth index. tem examination morphological characteristics of the cultured nb were examined by high-resolution transmission electron microscopy (tem). the cultivated nb were incubated in a solution of 2.5% glutaraldehyde in 0.1 molar cacodylate buffer at 4°c for 1 h, then washed twice with sodium cacodylate buffer and incubated in a solution of 1% osmium tetroxide at room temperature for 1 h. afterward, all the samples were rinsed with buffer and dehydrated with different concentrations of ethanol (25, 50, 70, 90 and 100%). the samples were then soaked in propylene oxide (15 min) and then molded by resin before being placed in an oven (60°c ) for two days. the blocks were then cut into 70 – 120 nm thicknesses by ultra-microtome. uranyl acetate 3% (30 min) and lead citrate 2% (7 min) were used to stain the ultra-thin cut blocks which were then viewed under a carl zeiss em10c transmission electron microscope (carl zeiss, jena, germany) operating at 80 kv. sem examination the morphology of the cultured nb was analyzed using scanning electron microscopy (sem). one drop of the freshly prepared solution of the ultra-centrifuged culfigure 2. a) sem images of nanobacteria isolated from cell cultures of kidney stone specimens showing nanobacteria as a cluster with spherical coccoid shape, and similar morphology and a size distribution ranging from 60 to 160 nm. b & c) tem images of the cultured samples revealed that nanobacteria had hairy or needle-like structures within variable sizes of 68 x 64 to 158 x 129 nm. d) afm 2d and 3d images illustrate the structure of the nanobacteria and their spherical shape. the scale bar represents 78 nm and also corresponds to the maximum size range of the analyzed nanobacterial specimens. figure 3. ftir of the cultivated nanobacteria from positive samples (blue line) and the apatite kidney stone (black line). the peaks in 1000 to 1200 cm-1 range belong to phosphate absorption and the stretching bond of phosphate in the structure of the mineralized shell. ftir spectra of the negative sample are shown with the red line. the peaks in 1000 to 1200 cm-1 range are absent (highlighted zone). nanobacteria and kidney stone-ansari et al. vol 14 no 05 september-october 2017 5003 ture media was placed on carbon stickers, dried under air and coated with gold. a low voltage (10 kv) was set to observe nb particles with a hitachi s-4160 scanning electron microscope (japan). afm examination for atomic force microscopy (afm) examination, one drop of the ultra-centrifuged culture media was placed on sterile mica, then air dried under sterile conditions. the prepared mica was examined in an ara-afm device at the pharmaceutical research complex, azad university pharmaceutical science branch, tehran, iran. ftir examination the ir spectrum of the cultured nb was recorded on an ftir-430 spectrometer at room temperature. the instrument was operated at a frequency range of 500 – 4000 cm-1. for this spectroscopic analysis, 2 mg of the cultured nb was mixed with 100 mg of kbr and made into a pellet. finally, the ftir spectra were obtained using an 8400s (shimadzu co., japan). xrd examination a small volume of the powdered kidney stones was reserved in the preparation stages for xrd. it was moved into sterile autoclaved microtubes and transferred to the xrd laboratories of azad university of tehran, north branch. the technicians in the xrd laboratory shaped the samples into tablets and performed the x-ray diffraction analysis according to their standard protocols. results inverted microscopy images three days after the cultivation of the kidney stones, nanobacteria growth was monitored by a turbidity assay of the culture media using a spectrophotometer set at 650 nm. the results from the inverted microscope (fig 1) showed different stages of crystallization in the shell of the nanobacteria. electron and atomic force microscopy images sem, tem and afm images show that the size of the nanobacteria ranged from 60 to 160 nm. the morphology of the nanobacteria was spherical, and all the imaged nanobacteria had similar appearance. the sem micrograph (figure 2) showed spherical igloo-like structures with variable sizes mostly less than 100 nm, and in some scaled cases, the size was less than 50 nm or even 20 nm, as observed in different samples. the tem observations also indicate various sizes of nanobacteria. these images were taken by gold labeling of the samples with a hairy appearance, which is a discriminating feature of the nanobacteria. it is a controversial issue for researchers, as some of them believe that the edges are curled because of the dehydration of the samples during preparation while others, including the authors of this paper, think that this hairy appearance is due to the coat of the bacteria. in fact, the tem images revealed that the nanobacteria are surrounded by needle-like deposits that coat the bacteria in needle-like apatite crystals, causing the hairy appearance. afm analyses of the nanobacteria, including both 2d and 3d images, provided details of the morphological features and sizes of the nanobacteria, and also accentuate that the spherical bacteria are less than 100 nm in size, to be more exact, about 60 nm. (figure 2:a) sem images of nanobacteria isolated from cell cultures of kidney stone specimens showing nanobacteria as a cluster with spherical coccoid shape, and similar morphology and a size distribution ranging from 60 to 160 nm. b & c) tem images of the cultured samples revealed that nanobacteria had hairy or needle-like structures within variable sizes of 68 x 64 to 158 x 129 nm. d) afm 2d and 3d images illustrate the structure of the nanobacteria and their spherical shape. the scale bar represents 78 nm and also corresponds to the maximum size range of the analyzed nanobacterial specimens. ftir ftir spectrum analysis showed an abnormal peak of between 1000 and 1200 cm-1 which belonged to phosphate absorption, and a peak less than 900 cm-1 belonging to the stretching bond of phosphate in the hydroxyapatite structure of the nanobacteria’s mineralized shell. xrd the x-ray diffraction results showed that hydroxyapatite, ca 5 (po4) 3 (oh), and calcium hydrate, cac2o4(h 2 o) were the main components of the mineralized shell of the nanobacteria in positive samples, while in the negative samples, uric acid was the main crystal. discussion in the present study, the kidney stones of 30 iranian patients were examined for infection by nanobacteria through culturing of the samples. because nanobacteria produce a mineralized shell, it was possible to follow the growth of their cultures by measuring the turbidity of the media by a spectrophotometer. the combined figure 4. the xrd results showing that the main components of the shell of the cultivated nanobacteria are hydroxyapatite and calcium oxalate hydrate. a) an apatite kidney stone used for cultivation, b) hydroxyapatite and calcium oxalate hydrate, and c) the negative sample consisting of mostly uric acid. nanobacteria and kidney stone-ansari et al. endourology and stone diseases 5004 results from the turbidity assay, sem, tem, afm, ftir and xrd showed that 27 of these samples were infected by nanobacteria, while only three patients were free of the infection. the morphology and size of the cultivated nanobacteria were characterized using sem, tem and afm. the average size of the nanobacteria was measured to be between 60 and 160 nm as estimated by the sem and tem images. ftir and xrd techniques were used to analyze the composition of the mineralized shell. these results revealed that the main components of the shell were hydroxyapatite and calcium apatite. these apatite complexes did not exist in the kidney stones of the patients that were not infected with the nanobacteria. based on the results of this study, it seems that the presence of nanobacteria in the kidney is one of the main factors contributing to kidney stone formation. since first identified, the tentatively named nanobacteria were considered to be novel biofilm-producing or autonomously replicating bacteria that had been characterized by scanning electron microscopy to determine their morphology(11), which is one of the first steps required to start screening for their association with other diseases. labelling nanobacteria as controversial or incomprehensible would be correct since recent papers widely varied in its classification. for example, the author of one paper claims that nanobacteria are nonliving microorganisms that only mimic living organisms(20), while other authors argue that this ultra-small bacteria is an example of a subset of the microbial life on earth that we know almost nothing about(17). the distribution of these bacteria to different tissues in the body, evaluated by their injection into rabbits, facilitated the measurement of their in vivo effects and activities in the blood, plasma, liver, bone, kidney and spleen(18). there are different hypotheses on the possible pathogenicity of these bacteria, which include malacoplakia, a rare inflammatory disease with an unknown cause that is characterized by the presence of histocytes containing both intra and extracellular calcospherules called michaelis-gutmann bodies. researchers believe and propose that nanobacteria may cause this disease due to the structural resemblance of these spherules with nanobacteria(21). other researchers proposed a more astounding potential connection between hiv and nanobacteria, reporting in the first clinical study on this issue that 85% of hiv positive mothers had antibodies signifying exposure to nanobacteria(22). the presence of unique nanobacteria correlate with other serious health disorders such as prostate cancer(23), chronic prostatitis (24), alzheimer’s disease(25), gall stone inflammation (26), aortic valve and vascular calcification(27,28), dental pulp stones(29) and kidney stones(13,19,30,31). since nanobacteria produce a mineralized shell, it was possible to follow the growth of their cultures by measuring the turbidity of the media with a spectrophotometer. the combined results from the turbidity assay, sem, tem, afm, ftir and xrd showed that 27 of these samples were infected by nanobacteria, while only three were free of the infection. the morphology and size of the cultivated nanobacteria were characterized via sem, tem, and afm. the average size of the nanobacteria was measured to be between 60 –160 nm as estimated by the sem and tem images. ftir and xrd techniques were used to analyze the composition of the mineralized shell. these results revealed that the main components of the shell were hydroxyapatite and calcium apatite. these apatite complexes did not exist in the kidney stones of the patients that were not infected by the nanobacteria. the following interpretation is definable by the nanobacteria major function which it is biomineralization; nanobacteria by biomineralization activity, involves apatite minerals to form crystal. for this reason, nanobacteria have thick hard apatite shell covers which are impenetrable to many inhibitory materials and may be the main reason why they grow in exposure to broad-spectrum antibiotics such as penicillin and streptomycin. based on the results of this study, it seems that the presence of nanobacteria in the kidney is one of the main factors contributing to kidney stone formation. with regards to treatment of nanobacteria, a recent interesting paper claims that according to the surveys on patients suffering from prostatitis caused by nanobacteria, antibiotic therapy showed improvement in some patients, while other therapies were also suggested(32). all the new nanobacterial treatments need blind studies because much is not known about nanobacteria, and many aspects of its growth and development have not been investigated yet. additional studies are needed to explore the molecular mechanisms that lead to nanobacterial biofilm formation(33), as well as to discern the role of nanobacteria in infections, cancers, lithiasis, and in the current case, biomineralization mechanisms. the clinical reality of microbial infections as a major menace to health care is an obvious fact, and the selection of a suitable antibiotic therapy will be crucial to the treatment of urinary tract infections, and also the treatment of nanobacteria as pointed out by the authors. conclusions it is proposed that after detecting nanobacteria in the soft tissues of the body, they can act as nidi for nucleation, initiating biomineralization and stone formation. they might also play a role in tumor-inducing processes in the soft tissues. according to the current findings, stone formation is a complex process with different influences, and nanobacteria play the role of an initiator by favoring nucleation and crystal formation. in fact, because of the nanometer scale of these organisms and the fact that they can translocate via the bloodstream to any organ of the body, it is evident that there is no barrier for nanobacteria. the most important issue now is to find out more about the functions of these nanobacteria, from adherence, internalization and cytotoxicity to other biomineralization functions. this full characterization will occur only by sequencing nanobacteria dna and performing genetic scans to characterize its possible related roles and mechanisms, which is an ongoing study that is being conducted by the authors. funding information this work did not receive any specific grant from any funding agency. acknowledgements the authors appreciate prof. setareh haghighat and miss bita karimi-rad, ph.d. candidate of microbiology, for their valuable technical support. nanobacteria and kidney stone-ansari et al. vol 14 no 05 september-october 2017 5005 conflict of interest the authors declare that there is no conflict of interest. references 1. broomfield rj, morgan sd, khan a, stickler dj. crystalline bacterial biofilm formation on urinary catheters by urease-producing urinary tract pathogens: a simple method of control. j med microbiol. 2009;58:1367-75. 2. anderson-otunu o, akhtar s. chronic infections of the urinary tract and bladder cancer risk: a systematic review. asian pac j 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saudi j kidney dis transpl. 2010;21:181. 9. sharifian m, hatamian b, dalirani r, aghasi p, akhavan sm. evaluation of response to treatment with polycitra-k in urolithiasis of children. jqums. 2011. 10. benzerara k, menguy n, guyot f, dominici c, gillet p. nanobacteria-like calcite single crystals at the surface of the tataouine meteorite. proc natl acad sci u s a. 2003;100:7438-42. 11. akerman k, kuronen i, kajander e. scanning electron microscopy of nanobacteria-novel biofilm producing organisms in blood. scanning. 1993;15:90-1. 12. ciftcioglu n, bjorklund m, kuorikoski k, bergstrom k, kajander eo. nanobacteria: an infectious cause for kidney stone formation. kidney int. 1999;56:1893-8. 13. kajander eo, ciftcioglu n, miller-hjelle ma, hjelle jt. nanobacteria: controversial pathogens in nephrolithiasis and polycystic kidney disease. curr opin nephrol hypertens. 2001;10:445-52. 14. raoult d, drancourt m, azza s, et al. nanobacteria are mineralo fetuin complexes. plos pathog. 2008;4:e41. 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björklund m, çiftçioglu n. nanobacteria and man. enigmatic microorganisms and life in extreme environments: springer; 1999:195-204. 22. pretorius am, sommer a, aho k, kajander e. hiv and nanobacteria. hiv med. 2004;5:3913. 23. zhou z, hong l, shen x, et al. detection of nanobacteria infection in type iii prostatitis. urology. 2008;71:1091-5. 24. kim th, kim hr, myung sc. detection of nanobacteria in patients with chronic prostatitis and vaginitis by reverse transcriptase polymerase chain reaction. korean j urol. 2011;52:194-9. 25. kajander e, liesi p, ciftcioglu n. do autonomously replicating sterile-filterable particles have an association with amyloid accumulation. paper presented at: viruses and virus-like agents in disease: 2nd karger symposium, basel, 1993. 26. wen y, li yg, yang zl, et al. detection of nanobacteria in serum, bile and gallbladder mucosa of patients with cholecystolithiasis. chin med j (engl). 2005;118:421-4. 27. hu yr, zhao y, sun yw, et al. detection of nanobacteria-like material from calcified cardiac valves with rheumatic heart disease. cardiovasc pathol. 2010;19:286-92. 28. jelic tm, chang hh, roque r, malas am, warren sg, sommer ap. nanobacteriaassociated calcific aortic valve stenosis. j heart valve dis. 2007;16:101-5. nanobacteria and kidney stone-ansari et al. endourology and stone diseases 5006 29. zeng jf, zhang w, jiang hw, ling jq. [isolation, cultivation and initial identification of nanobacteria from dental pulp stone]. zhonghua kou qiang yi xue za zhi. 2006;41:498-501. 30. hjelle jt, miller-hjelle ma, poxton ir, et al. endotoxin and nanobacteria in polycystic kidney disease. kidney int. 2000;57:2360-74. 31. abo-el-sooud k, hashem m, ramadan a, el-aty aa, awadallaha ky, gab-allaha a. research strategies for treatment of nanobacteria. insight nanotechnology. 2011;1. 32. verze p, venturino l. treatment of nonbacterial prostatitis: what’s new? prostatitis and its management: springer; 2016:49-59. 33. alves mj, barreira jc, carvalho i, et al. propensity for biofilm formation by clinical isolates from urinary tract infections: developing a multifactorial predictive model to improve antibiotherapy. j med microbiol. 2014;63:471-7. nanobacteria and kidney stone-ansari et al. vol 14 no 05 september-october 2017 5007 vol 16 no 02 march-april 2019 157 urological oncology effect of hormonal therapy for volume reduction, lower urinary tract symptom relief and voiding symptoms in prostate cancer: leuprolide vs goserelin taha numan yıkılmaz1*, erdem öztürk1, fatih hızlı1, nurullah hamidi2, halil basar1 purpose: the complaints of lower urinary tract symptoms in cases with prostate carcinoma (pca) are associated with coexisting benign prostate hyperplasia or aging bladder. the aim of this study was to investigate and compare the effect of goserelin acetate with leuprolide acetate on total prostate volume (tpv), post voiding residue (pvr), international prostate symptom score (ipss) and maximum flow rate (qmax) reduction in cases of advanced pca. materials and methods: the study initially enrolled 71 patients who presented at our clinic for hormonotherapy because of advanced prostate carcinoma between may 2015 and august 2016. a total of 51 patients were found suitable for the study and were divided into two groups as group 1 who received goserelin acetate (10.8 mg /3 months) and group 2 who received leuprolide acetate (22.5 mg /3 months). age, gleason score, t stage, pre and post treatment prostate specific antigen (psa) and testesterone level, tpv, ipss, pvr, and qmax values were recorded retrospectively. changes in parameters were assessed every 3 months. results: analysis was made on 51 patients in this study. no statistically significant difference was determined between the two groups in respect of the mean percentage decrease in psa (98.7% and 98.4%, respectively; p = .9) and testosterone (92.9 % and 96.4 %, respectively; p = .15) from baseline to 6 months but tpv reduced by -20.2 % ± 4.8 and -15.6 % ± 1.04, the median total ipss score decreased by -34.77 % ± 8.8 and -19.77 % ± 6.1, median qmax increased by 45.34 % ± 10.16 and 23.21 % ± 6.93, and median pvr decreased by -31.54 % ± 8.4 and -19.23 % ± 5.5, respectively for the two groups (all parameters p < .05) conclusion: in this study, the improvement observed in voiding parameters with the use of goserelin acetate was better than with leuprolide acetate. the superiority of the goserelin acetate group was determined in particular on the reduction of tpv, pvr and ipss. although the psa follow-up time was short, no significant difference was determined between the groups in the early oncological outcomes. keywords: androgen deprivation therapy; total prostate volume; post voiding residue; voiding symptoms; prostate carcinoma introduction prostate carcinoma (pca) is one of the most common malignant cancers and the second greatest malignancy-related cause of death in males(1). in 2014, the prostate cancer incidence rate was reported as 35 cases per 100,000 in turkey(2). androgen deprivation therapy (adt) is a main stage in the treatment of metastatic or advanced prostate cancer and has been shown to improve overall survival(3). gonadotropin releasing hormone (gnrh) agonists remain the most widely used form of adt. as 70% of prostate carcinomas originate from the peripheral zone, they are frequently asymptomatic until growth is of a size that compresses the prostatic urethra, bladder neck or there is metastasis(4). therefore, complaints of lower urinary tract symptoms (luts) in cases with pca are associated with the coexistence of benign prostate hyperplasia (bph) or aging bladder(5). in these cases, total prostate volume (tpv), post voiding resi1 department of urology, ankara dr. abdurrahman yurtaslan oncology training and research hospital, ankara 06200, turkey. 2 atatürk training and research hospital, ankara 06200, department of urology. *correspondence: department of urology, dr. abdurrahman yurtaslan oncology training and research hospital, yenimahalle, ankara 06200, turkey. phone: +90 312 3360909. fax: +90 312 3340352. e-mail: numanyikilmaz@gmail.com. received november 2017 & accepted march 2018 due (pvr), the international prostate symptom score (ipss) and maximum flow rate (qmax) are important in the planning of the treatment. published data show that adt can reduce tpv ranges by 30 % to 55 %(6,7). hormonal therapy reduces tpv as well as the tumor volume and this downsizing of the prostate gland has an effect on pvr, ipss and qmax values(8). however, to the best our knowledge, there are no published studies that have investigated the effect of different gnrh agonists on luts. to adress this knowledge gap, the effect of goserelin and leuprolide acetate on luts of prostate cancer were investigated in this study. the aim of the study was to show that there may be regression of symptoms only with hormonotherapy in cases of prostate cancer with luts complaints. urological oncology 158 materials and methods study population and design a retrospective review was made of the data of 71 patients who received adt only for advanced prostate cancer between may 2015 and august 2016. patients with an indwelling urinary catheter, treatment with 5 alpha reductase inhibitors or alpha adrenoceptor blocker, had evident nervous system disorder or had undergone pelvic or urinary tract surgery were excluded from the study. after exclusion of these patients, the data of the remaining 51 patients were analyzed. written informed consent was obtained from patients who participated in this study. all study procedures were applied in compliance with the helsinki declaration and the good clinical practice guidelines. age, gleason score, t stage, pre and post treatment prostate specific antigen (psa) and testesterone level, tpv, ipss, pvr, and qmax values were recorded for each patient. in this study, patients with advanced prostate cancer received leuprolide or goserelin acetate for at least 6 months at the discretion of the attending physician (t.n.y. & e.ö.). three-month doses were applied to all cases. the cases were divided into 2 groups, as group 1 patients who received goserelin acetate (10.8 mg/3 months) and group 2 patients who received leuprolide acetate (22.5 mg/3 months). in all cases bicalutamide (50 mg once daily) was given for the first 10 days for flare protection and on the 10th day gnrh agents were inserted subcutaneously into the abdominal wall. blood samples were collected to analyse testosterone and psa levels with a validated chemiluminescence method at the beginning of the adt and the analyses were repeated at the 3rd and 6th month. ultrasonography and uroflowmetry were also performed before administration of the drug and at each 3-monthly visit by the same urologist using the same equipment. total prostate volume and pvr were calculated by an elliptical approximation (width x height x length x 0.5) with transrectal ultrasound (using a sono scape ssi5500bw ultrasound scanner, shenzhen, china). ultrasound was performed on day 0 and repeated 3 and 6 months later to assess evaluate the change in volume due to adt with the same equipment by the same urologist. ultrasound was also performed to measure pvr pre and post adt. the changes were recorded. the ipss questionnaire was completed by all the cases enrolled in the study. this score system is used to assess luts(9). it includes 7 symptoms of urinary tract: incomplete emptying, frequency, intermittency, urgency, weak stream, straining and nocturia(8). mild luts was defined as ipss of 1-7, moderate luts as ipss of 8-19 and severe as ipss of 20-35(10). a clinically significant response was defined as a change of at least 3 points in ipss(10). the ipss form was administered to the patients at the beginning of the treatment and was repeated at the 3rd and 6th months. statistical analysis spss version 19.0 software (spss inc., chicago, il, usa) was used for statistically analysis. all values are presented as mean ± standard deviation. values of the clinical factors were analyzed using the mann whitney u-test to determine the significance of differences between groups, and spearman rank correlation analysis was applied to evaluate the relationship between adt and the ipss score, qmax, tpv and pvr. a value of p < .05 was considered to be statistically significant. results the mean age of the patients was 63.9 ± 4.2 years (range, 46-83 years). group 1 (goserelin acetate) comprised 24 patients and group 2 (leuprolide acetate), 27 patients. patient characteristics (age, stage, gleason score, psa variables, total testosterone, tpv, ipss, q max and pvr) are shown in table 1. a statistically significant difference was found in mean age between the treatment groups (p = .035). serum psa, total testosterone, tpv, ipss, q max and pvr values were not statistically significant between the two groups (p = .09, p = .11, p = .06, p = .06, p = .11, p = .27, respectively) no statistically significant difference was determined between the groups in respect of mean percentage decrease in psa from baseline to month 6 (98.7 % and 98.4 %, respectively; p = .9). no significant difference was determined between the two groups in the changes of testosterone values in the 6th month of treatment compared with baseline values (92.9 % and 96.4 %, respectively; p = .15). leuprolide vs goserelin on luts-yikilmaz et al. table 1. demographic characteristics baseline characteristics goserelin acetate (10.8 mg) n=24 leuprolide acetate (22.5 mg) n=27 p age, years 67.4 (48-80) 64.25 (46-83) 0.035* time from diagnosis to initial treatment 61 57 t stage t1 8 11 t2 12 10 t3/4 4 6 gleason score ≤7 7 9 ≥8 17 18 tpv (ml) day of 0 64.12 (28-136) 81.18 (24-110) 0.06 ipss day of 0 13.45 (4-29) 12.39 (6-26) 0.06 qmax day of 0 12.4 (5-23) 12.19 (4-21) 0.11 pvr day of 0 73.02 (29-156) 75.9 (20-98) 0.27 psa levels, ng/ml (mean) 25.6 (4-100) 30.45 (4-81) 0.09 testosterone, ng/ml (mean) 2.77 (1.1-6.6) 2.98 (1.53-6.2) 0.11 abbreviations: tpv: total prostate volume, ipss: international prostate symptom score, qmax: maximum flow rate, pvr: post voiding residue, psa: prostate specific antigen vol 16 no 02 march-april 2019 159 total prostate volume (tpv) was reduced significantly from baseline to month 6 in both groups with mean ±standard error percentage decreases of -20.2 % ± 4.8 and -15.6 % ± 1.04 for goserelin acetate and leuprolide acetate, respectively. statistical evaluation showed that goserelin acetate was superior to leuprolide acetate (p = .02). from baseline to 6th month, the median total ipss score decreased by -34.77 % ± 8.8 and -19.77 % ± 6.1, median qmax increased by 45.34 % ± 10.16 and 23.21 % ± 6.93, median pvr decreased by -31.54 % ± 8.4 and -19.23 % ± 5.5, respectively in the two groups. statistically significant goserelin acetate was observed to be statistically significantly superior in all of these parameters (p < .05) (table 2 and figure 1). discussion hormone therapy is the main treatment for locally advanced and metastatic prostate carcinoma patients who are not eligible for radical treatment options. gonadotropin-releasing hormone (gnrh) receptor agonists are successful in obtaining the required therapeutic levels (serum testesterone < 0.5 ng/ml) in 90 % of patients(11). the first administration may create a sudden increase in serum t levels. therefore, because of this effect, the patient is given antiandrogen treatment for 10 days before the first injection to prevent clinical symptoms such as flare phenomenon, spinal cord compresion, bone pain and urethral obstruction(1). low urinary tract symptoms are one of the main concerns of prostate cancer patients. although studies have indicated that endocrine treatments have a diminishing effect on luts complaints, there are no studies that have measured the efficacy of goserelin acetate and leuprolide acetate on the improvement on ipss, tpv, pvr and qmax(8,12,13). the results of the current study show that hormonal therapy has a positive effect on luts symptoms and prostate volume within 6 months. prostate cancer frequently coexists with bph, which can cause luts. lehrer et al. reported that 55.6 % of pca patients have mild luts, 37.1 % have moderate symptoms, and 7.3 % have severe symptoms(14). hamilton et al. reported a significant improvement in luts complaints and reductions in pvr and tpv values after 12 months of hormonal therapy in patients with prostate cancer(4). in 2012, klarskov et al. showed 50 % reduction in ipss levels, 38 % increase of qmax, 26 % decrease in pvr value and 37 % decrease in tpv levels within 12 months of hormone therapy(13). as a result of that study, the best improvement in these parameters was observed to be in the first month of the adt. a few studies have detected the reduction in tpv to be in the range of 21 % to 48 % within 3.7 months as a result of adt(15,16). in the current study, tpv reduction secondary to hormone therapy was 20.2 % in the goserelin group, and 15.6 % in the leuprolide group in 6 months, which was similar to the findings of previous studies. the effects of testosterone suppression on bladder outlet obstruction have been determined in vitro and in vivo animal studies. blockage of gnrh receptors in the prostate smooth muscle and epithelial cells allows the down-regulation of pro-inflammatory cytokines, growth factors and α1-adrenoreceptors involved in these cells. an improvement in luts and a decrease in tpv were accepted in this patient group with the provided smooth muscle relaxation(10,17). it is believed that hormone therapy in the elderly bladder contributes to ipss scores through the effect on prostate carcinoma. in a study that compared degarelix and goserelin acetate, it was observed that the improvement was better in castable 2. changes parameter from baseline to 6th month in patients treated with goserelin acetate and leuprolide acetate goserelin acetate leuprolide acetate p psa (initial to 6th month) -98.7 % ±0.9 -98.4 % ±0.4 0.9 tt (initial to 6th month) -92.9 % ±5.8 -96.4 % ±6.9 0.15 tpv (initial to 6th month) -20.2 % ±4.8 -15.6 % ± 1.04 0.02* ipss (initial to 6th month) -34.77 % ±8.8 -19.77 % ±6.1 0.001* qmax (initial to 6th month) 45.34 % ± 10.16 23.21 % ± 6.93 0.001* pvr (initial to 6th month) -31.54 % ±8.4 -19.23 % ±5.5 0.01* abbreviations: tpv: total prostate volume, ipss: international prostate symptom score, qmax: maximum flow rate, pvr: post voiding residue, psa: prostate specific antigen, tt: total testesterone figure 1. voiding parameters and prostat size from initial to 6th month. comparison chart of the effects of goserelin acetate and leuprolide acetate on parameter (*p < 0.001, **p < 0.01, ***p < 0.02) leuprolide vs goserelin on luts-yikilmaz et al. urological oncology 160 es with low ipss scores in the 3rd month and degarelix was superior to goserelin acetate(10). in the current study, although ipss scores were not divided into voiding and storage scores, goserelin acetate was found to be statistically more significant in total score improvement (-34.77 % ±8.8 vs -19.77 % ± 6.1, respectively). the storage score of ipss is associated with pvr while qmax value is related to voiding scores. improvement in ipss has been similarly observed at q max and pvr levels(13). in the results of the current study, the increase in maximum flow rate (45.34 % ± 10.16) and decrease in postvoid residual volume (-31.54 % ± 8.4) were significanty higher in the goserelin acetate group than in the leuprolide acetate group in the 6th month (p < .01). there are different opinions that assume the upper level of testosterone as 0.2 ng/ml or 0.5 ng/ml as the ideal castration level. it is often accepted as adequate at 0.5 ng/ml as there has been seen to be no difference regarding the decrease in psa and progression in the follow-up of patients(3). in terms of comparing gnrh agonists, some studies have shown no statistically significant difference between goserelin acetate and leuprolid acetate(3). goserelin groups have shown some superiority over leuprolide(18). in the current study, for castration level < 0.5 ng/ml of testesterone, there was no significant difference between the groups (p = .15). similar results were observed in the changes in psa level, with no statistically significant difference observed between the groups in respect of the psa decrease (p = .9). there were some limitations to this study. although the number of patients was sufficient, the study was conducted at a single center. to the best of our knowledge, this is the first study to have compared the effect of goserelin acetate and leuprolide acetate on voiding parameters and reduction of prostate volume and postvoiding residue. conclusions the main goal of hormonal therapy is to treat patients with locally advanced and metastatic prostate carcinoma who are not eligible for radical treatment options, and in the current study, the effect of adt was observed on voiding symptoms and prostate volume. the improvement in voiding parameters of goserelin acetate was determined to be better than leuprolide acetate. in particular, the superiority of goserelin acetate was observed in the reduction of tpv, pvr and ipss. conflict of interest the authors report no conflict of interest. references 1. pourmand g, safavi m, ahmadi a et al. epca2.22: a silver lining for early diagnosis of prostate cancer. urol j. 2016;13:2845-8. 2. zorlu f, zorlu r, divrik rt, eser s, yorukoglu k. prostate cancer incidence in turkey: an epidemiological study. asian pac j cancer prev. 2014;15:9125-30. 3. nguyen pl, alibhai sm, basaria s, et al. adverse effects of androgen deprivation therapy and strategies to mitigate them. eur urol. 2015;67:825-36. doi: 10.1016/j. eururo.2014.07.010. epub 2014 aug 2. 4. hamilton w, sharp d. symptomatic diagnosis of prostate cancer in primary care: a structured review. br j gen pract. 2004;54:617-21. 5. andersson so, rashidkhani b, karlberg l, wolk a, johansson je. prevalence of lower urinary tract symptoms in men aged 45-79 years: a population-based study of 40 000 swedish men. bju int. 2004;94:327-31. 6. soloway ms, hachiya t, civantos f, murphy wm, gomez cc, ruiz he. androgen deprivation prior to radical prostatectomy for t2b and t3 prostate cancer. urology. 1994;43:52-6. 7. washino s, hirai m, saito k, kobayashi y, arai y, miyagawa t. impact of androgen deprivation therapy on volume reduction and lower urinary tract symptoms in patients with prostate cancer. low urin tract symptoms. 2016 dec 12. doi: 10.1111/ luts.12142. [epub ahead of print] 8. sun s, bai y, yang h, yang hw. investigation on lower urinary tract symptoms (luts) in elderly patients with prostate cancer (pc) received endocrine therapy. arch gerontol geriatr. 2015;60:535-7. doi: 10.1016/j. archger.2014.10.014. 9. stone nn, marshall dt, stone jj, cesaretti ja, stock rg. does neoadjuvant hormonal therapy improve urinary function when given to men with large prostates undergoing prostate brachytherapy? j urol. 2010;183:6349. doi: 10.1016/j.juro.2009.09.084. 10. axcrona k, aaltomaa s, da silva cm et al. androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: degarelix vs goserelin plus bicalutamide. bju int. 2012;110:1721-8. doi: 10.1111/j.1464-410x.2012.11107.x. 11. lepor h. comparison of single-agent androgen suppression for advanced prostate cancer. rev urol. 2005;7 suppl 5:s3-s12. 12. kucway r, vicini f, huang r, stromberg j, gonzalez j, martinez a. prostate volume reduction with androgen deprivation therapy before interstitial brachytherapy. j urol. 2002;167:2443-7. 13. klarskov ll, klarskov p, mommsen s, svolgaard n. effect of endocrine treatment on voiding and prostate size in men with prostate cancer: a long-term prospective study. scand j urol nephrol. 2012;46:37-43. doi: 10.3109/00365599.2011.637953. 14. lehrer s, stone nn, droller mj, stock rg. association between american urologic association (aua) urinary symptom score and disease stage in men with localized prostate cancer. urol oncol. 2002;7:73-6. 15. pinault s, têtu b, gagnon j, monfette g, dupont a, labrie f. transrectal ultrasound leuprolide vs goserelin on luts-yikilmaz et al. vol 16 no 02 march-april 2019 161 evaluation of local prostate cancer in patients treated with lhrh agonist and in combination with flutamide. urology. 1992;39:254-61. 16. whittington r, broderick ga, arger p et al. the effect of androgen deprivation on the early changes in prostate volume following transperineal ultrasound guided interstitial therapy for localized carcinoma of the prostate. int j radiat oncol biol phys. 1999;44:110710. 17. gallo cb, miranda af, felix-patricio b et al. effects of castration and hormone replacement in the urinary bladder of rats: structural, ultrastructural, and biochemical analysis. j androl. 2012;33:684-90. doi: 10.2164/ jandrol.111.014159. 18. sarosdy mf, schellhammer pf, sharifi r et al. comparison of goserelin and leuprolide in combined androgen blockade therapy. urology. 1998;52:82-8. leuprolide vs goserelin on luts-yikilmaz et al. female urology is a combination of antibiotics and non-steroidal anti-inflammatory drugs more beneficial than antibiotic monotherapy for the treatment of female acute uncomplicated cystitis? a randomized controlled pilot study kyungtae ko1, won ki lee4, cheol young oh3, seong ho lee5, sung tae cho2, woo jin bang3, tae young shin4, min soo choo5, jin seon cho3, young goo lee2, dae yul yang1* purpose: to compare the efficacy of non-steroidal anti-inflammatory drugs (nsaids) combination therapy to single-agent antibiotic therapy for the resolution of symptoms during two restricted activity days in patients with acute uncomplicated cystitis (auc) materials and methods: we performed a prospective, randomized control pilot study. a total of 55 patients were enrolled. group i (n=28) was treated with cepodoxime (100 mg twice per day), and group ii (n=27) was treated with cepodoxime (100 mg) and aceclofenac (100 mg) twice per day; both groups were treated for three days. upon dysuria after each administration, the participants entered a value on a numerical pain scale. the primary outcome was whether there were any differences in the decrease rate in pain scale between the two groups. result: the average age of the 55 patients was 49.9 ± 13.5 years, and prior to the clinical visit, the patients experienced an average of 2.4 ± 2.2 days of dysuria symptoms. the average numerical pain scale score for dysuria was 4.98 ± 2.18. thirty-four patients (61.8%) showed positive culture results, and e. coli was the most commonly found bacteria, cultured in 32 patients. fifty-one patients visited the clinic on day 7, and 42 (76.4%) reported symptom improvement, while nine patients (16.3%) had persistent symptoms. the follow-up numerical pain score was 0.39 ± 1.02 points. the pain score was dramatically decreased after medication. no difference was observed in the magnitude of the pain scale reduction between the two groups (p = 0.134). however, group ii showed faster symptom resolution (p = 0.035) at the third administration (day 1.5). conclusion: combination therapy with nsaids and antibiotics for auc patients can improve symptoms faster during two restricted activity days when patients have difficulty performing daily living activities. keywords: acute uncomplicated cystitis; antibiotic resistance; symptoms; antibiotics; nsaids introduction acute uncomplicated cystitis (auc) is a simple dis-ease that is treatable with three days of empirical antibiotic treatment in 90% of patients(1). however, several symptoms bother patients during the treatment period. dysuria is the most common symptom of cystitis and is accompanied by frequency, urgency, and gross hematuria. lower abdominal pain is also present in some cases(2). due to these symptoms, 54% of women report difficulty in work-related or other daily activities and a decline in their quality of life(3). it has been known that cystitis causes six symptomatic days and two restricted activity days on average(4). therefore, it must be worthwhile to control dysuria for cystitis management. in this sense, non-steroidal anti-inflammatory drugs (nsaids) are expected to reduce the dysuria, which may enhance the quality of life 1department of urology, hallym university kangdong sacred heart hospital, seoul, korea. 2department of urology, hallym university kangnam sacred heart hospital, seoul, korea. 3department of urology, hallym university hallym sacred heart hospital, gyeonggi, korea. 4department of urology, hallym university chuncheon sacred heart hospital, chuncheon, korea. 5department of urology, hallym university dongtan sacred heart hospital, hwaseong, korea. *correspondence: department of urology, hallym university kangdong sacred heart hospital, 150, seongan-ro, seoul 134-701, korea. tel: +82-2-2224-2290. fax:+82-2-2224-2338. e-mail: yang1408@hallym.or.kr. received october 2016 & accepted october 2017 during the treatment period. however, the vast majority of clinical researches about acute bacterial cystitis have focused on bacterial isolation, antimicrobial sensitivities, their risk factors, the emergence of extended spectrum beta-lactamase (esbl), and the management of resistant strains(5-7). because cystitis exhibits a fast response to antibiotic treatment, researchers have not examined the pain and decline in the quality of life that patients face during the acute phase of the disease(8-10). futhermore, most studies treating cystitis with nsaids have been conducted to evaluate the possibility of using nsaids as a substitute for antibiotic treatment to prevent development of antibiotic resistance(11,12). hence, we aimed to compare the efficacy of nsaid combination therapy (antibiotics + nsaids) to antibiotic single therapy for the resolution of symptoms during two restricted activity days in which the patients experienced the most discomfort. female urology 365 vol 15 no 06 november-december 2018 366 materials and methods participants this study was a prospective, open-labeled, and randomized control pilot study and was conducted at five academic medical centers between august 2014 and july 2015.women who were 18 years or older with pyuria that was confirmed by a urinalysis that showed more than five white blood cells per high-power field were included in this study. the patients complained of more than two symptoms, including urination frequency, dysuria, urgency, and lower abdominal discomfort. patients with interstitial cystitis, a history of cystitis within two weeks, suspected febrile urinary tract infection, and bladder outlet obstruction (residual urine more than 100 ml) were excluded. patients taking antibiotics or analgesics due to other medical conditions were also excluded from the study. a flow diagram of the selection process is reported in figure 1. all participants voluntarily provided written informed consent. a total of 55 patients were finally enrolled in this study. the study was ethically approved by the institutional review board committee of our hospital (irb no.14-1-32) and was registered by clinical research information service (kct0001876) study design and outcome until now, there hasn’t been any research on the effects of antibiotics and nsiads combination therapy on auc during the acute phase. therefore, a pilot study was planned to estimate the effect size before planning a large study. it’s rare to see auc patients in resident training hospitals, so participating patients collected over a year were used as the sample size. to reduce the selection bias, patient were allocated to group i (cefpodoxime 100 mg twice per day) or group ii (cefpodoxime 100 mg and aceclofenac 100 mg twice per day) by each hospital via randomization in blocks of six. block randomization was performed by computer program, with created randomized assignments being concealed from the doctors who were examining the patients. if the doctor includes the patient into the study after examination, research nurses perform treatment assignment according to the randomized order. the primary outcome of this study was whether there were any differences in the decrease rate in pain scale between the two groups when six medications were administered in three days. in addition, the improvement rate of the symptom on the seventh day and the prevalence of antibiotic resistance were the point of focus. intervention a thorough patient history, questionnaire, physical examination, urinalysis, and urine culture were performed as an initial assessment. after randomization, the participants were assigned to either group i or group ii. both groups were medicated twice per day for three days. upon each dysuria symptoms after medication administration, the participants rated their symptoms on a numerical pain scale by themselves. seven days after their initial assessment, the participants revisited the clinic to check their symptoms and the results of cultures. the patients were then evaluated for the resolution of their symptoms and subjected to a follow-up urinalysis. the symptom improvement was defined that pain scale decreased to below one point. positive urine culture was defined that bacteriuria (≥ 104 cfu/ml) in the mid stream urine. statistical analysis all clinicopathological and clinical follow-up data were analyzed on an intention to treat basis. descriptive statistics were used to summarize each patient’s symptoms and resistance rate to antibiotics. baseline clinicopathological data were analyzed using independent t-tests, mann-whitney u tests, and chi-square tests. changes in the pain scale score were analyzed by generalized linear mixed model. the statistical analysis was performed with spss 19.0 (spss inc. chicago, il, usa). all p-values were two-sided and were considered to be statistically significant when p < .05. results the average age of the 55 patients was 49.9 ± 13.5 table 1. demographics group i (n = 27) group ii (n = 28) p-value age, years; mean ± sd 50.26 ± 14.8 49.61 ± 12.3 .860 bmi, kg; mean ± sd 22.62 ± 3.04 21.70 ± 2.67 .237 coitus hx. within 2 weeks 11 (40.7%) 15 (53.6%) .422 culture positive 19 (70.4%) 17 (60.7%) .537 onset, day; mean ± sd 1.93 ± 1.54 2.89 ± 2.06 .055 oabss total, points; mean ± sd 7.81 ± 2.99 8.07 ± 3.41 .507 initial pain scale, points; mean ± sd 4.52 ±2.13 5.45 ± 2.18 .154 symptom improvement 18 (66.7%) 24 (85.7%) .075 abbreviations: bmi; body mass index, sd; standard deviation, oabss; overactive bladder symptom scores figure 1. flow chart combination treatment for acute cystitis-ko et al. years, and the average bmi was 22.2 ± 2.87 (table 1). before the clinical visit, the patients experienced an average of 2.4 ± 2.2 days of dysuria symptoms. the average initial oabss score was 7.95 ± 3.18 points and the numerical pain score for dysuria was 4.98 ± 2.18 points. twenty-six (47.3%) of the patients had a history of coitus within two weeks, and 21 (38.2%) patients experienced gross hematuria. dysuria was the most irritating symptom (29 patients, 52.7%), which was followed by frequency (12 patients, 21.8%), lower abdominal discomfort (eight patients, 14.5%), and residual sensation (five patients, 9.1%). in the previous five years, 68% of patients had cystitis more than once, 34% more than twice, and 6% more than five times. of the 55 patients, 34 (61.8%) showed positive culture results, and escherichia coli was the most common bacterium that was cultured (32 patients). aside from e. coli, enterococcus faecalis and streptococcus were also cultured in one patient. the resistance rates of e. coli were 64% to ampicillin, 22% to ampicillin/clavulanic acid, 46.4% to trimethoprim/sulfamethoxazole, 14.8% to third generation cephalosporin, and 25.9% to ciprofloxacin. all strains were susceptible to ertapenem (table 2). fifty-one patients visited the clinic on day 7, and 42 (76.4%) reported symptom improvement, while nine patients (16.3%) had persistent symptoms. no correlation was found between a positive urine culture and symptom improvement (p = .607, data not shown). the follow-up oabss score was 5.0 ± 2.85 points, and the numerical pain score was 0.39 ± 1.02 points (group i: 0.68 ± 1.38 vs. group ii: 0.115 ± 0.33, p = .105). pyuria with 1~4 wbc/hpf was observed in 45 patients in follow-up urinalysis, but pyuria with more than 5 wbc/ hpf was still observed in six patients. among these six patients, only two patients whose initial urine culture revealed e. coli resistant to cepodoxime had symptoms. no patient reported adverse drug effects in group i, but four patients had adverse effects in group ii (epigastric pain in three patients, epigastric pain and face edema in one patient). the pain scale score was dramatically decreased after medication. after the sixth administration, the pain score was decreased to 0.98 ± 1.00 in group i and to 0.5 ± 0.74 in group ii. no difference was observed in the magnitude of the pain score decrease between the two groups at the time of the sixth administration when the therapy was completed (p = .134, figure 2). however, analysis of the third administration cycle, which occurred on day 1.5, revealed faster symptom resolution in the group ii patients treated with nsaid combination therapy than in group i patients who were treated with antibiotic single therapy (p = .035). discussion in general, cystitis that occurs in healthy, premenopausal, non-pregnant women with no anatomical abnormality in the urinary tract is defined as auc. when such healthy patients have only one voiding symptom, the probability of auc is 50%. when patients have two symptoms (i.e., dysuria and frequency) without vaginal discharge, the probability is 90%(13). although symptoms are very important in the diagnosis and treatment of auc, little interest has been focused on the pain and quality of life that hyper-acute patients experience(8-10). cystitis symptoms improve after a single dose of antibiotics. symptom improvement was observed after 500 mg of ciprofloxacin was taken once daily in 50% of patients at six hours, 87% of patients at 24 hours, and 91% of patients at 48 hours after the first dose. the average duration for symptom improvement was 2.4 days. according to a previous study, twenty-two percent of patients reported complete resolution of symptoms within 24 hours, and 63% of patients reported resolution after the third dose of antibiotics(4). thus, cystitis causes an average of two restrictive activity days when daily work is limited and six symptomatic days when basic daily living activities are possible. therefore, 78% of patients on day 1 and 37% of patients on day 3 still have symptoms that restrict their daily life, and their symptoms could be relieved if nsaids are added during this early phase. in fact, other researchers have reported that the empirical use of phenazopyridine, which is an over-thecounter urinary analgesic, in combination with antibiotics until the voiding symptoms are resolved helped to improve the symptoms(14) many studies of the role of nsaids in auc have fofigure 2. combination therapy (group ii) produced faster symptom resolution than antibiotic monotherapy (group i). e. coli resistance (%) culture (+) 34 (61.8%) e. coli 32 (94.1%) ampicillin 64% e. faecalis 1 (2.9%) amp/clua 22.2% streptococcus 1 (2.9%) trim/sul 46.4% ciprofloxacin 25.9% third cepha 14.8% ertapenem 0% table 2. urine culture results. resistance rates of e. coli were 14.8% to third generation cephalosporin combination treatment for acute cystitis-ko et al. female urology 367 vol 15 no 06 november-december 2018 368 cused on treatment efficacy rather than symptom improvement. bleidorn et al. reported that single treatment ibuprofen showed similar symptom improvement to antibiotic treatment(11). in this study, the ibuprofen group had significantly more culture-positive samples in the follow-up urine cultures after 7 days of treatment, but no difference in symptom improvement was observed between the two groups. however, that did not indicate a difference in symptom improvement during the first three days because symptom assessment was performed after the fourth day of treatment. to assess the efficacy of nsaids combination therapy during the acute phase of auc, patients were told to record their symptoms on a numerical pain scale twice per day for three days to collect six numerical pain measurements, which was not performed in previous studies. we observed faster symptom improvement in the combination therapy group during the hyper-acute phase. various antibiotic therapies have been used as standard treatments for auc for many years(1). however, due to increasing resistance to antibiotics and the benign nature of auc, physicians have evaluated several alternative treatments that avoid the use of antibiotics, including increased fluid intake, wait-and-see prescriptions, intravesical instillation and nsaids as single agent therapies(11-13,15-19). these alternative treatments are supported for the following reasons. first, a placebo group that was not treated for auc exhibited early resolution in 25 to 50% of patients. second, nsaids have bactericidal effects in animal experiments and stabilize detrusor instability, which leads to the effective treatment of overactive bladders(20,21). third, no benefit was observed in the occurrence of pyelonephritis and the emergence of resistant strains in the antibiotic group, although the antibiotic group had a higher clinical cure rate and microbiological success rate than the placebo group. finally, the number of adverse events was higher in the antibiotic group(9). in summary, the primary objective of auc treatment is to relieve symptoms during two activity restricted days because auc does not typically progress to a serious condition(14). in actual practice, patients use many alternative treatments for auc care aside from antibiotic therapy due to high medical costs and limited access to health care. one of the most common treatments is the use of uroanalgesics such as methenamine hippurate and phenazopyridine hydrochloride. these over-the-counter drugs are effective for symptom improvement compared to placebos, but no report has clearly demonstrated their efficacy(16-18). according to a report of community-acquired urinary tract infections that was published in korea in 2011, the most common strain in auc is e. coli (72.7%), followed by e. faecalis (10.7%) and klebsiella pneumoniae (3.5%)(12). in our study, e. coli was isolated most frequently, and the resistance rate was similar to previous studies. one noteworthy point was that the resistance rate to third generation cephalosporin had more than doubled from 6.4% to 14.8%. this may be due to a recent increase in the use of cephalosporins to avoid quinolones. in general, antibiotics with a resistance rate greater than 20% are not appropriate as empirical antibiotics(1). therefore, the proper management of cephalosporin is necessary to prevent further increases in the rate of resistance. our study was a prospective, randomized study with several limitations. first, because it was a pilot study with a small number of participants, the sample size was not sufficient to prove statistical significance. second, our study measured the numerical pain score with dysuria only to represent the overall symptom status of patients. because patients differ in which symptoms they report most, a survey that is simple but measures more symptoms should be used in subsequent studies. third, it would have been helpful to have an nsaid monotherapy group that could clearly demonstrate the role of nsaids, although this group could not be included due to ethical issues in korea. conclusions nsaids and antibiotic combination therapy for auc cystitis can improve patient symptoms faster than antibiotic monotherapy and is useful when patients have difficulties performing daily living activities. conflict on interest there is no conflict of interest. references 1. gupta k, hooton tm, naber kg, et al. international clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the infectious diseases society of america and the european society for microbiology and infectious diseases. clin infect dis. 2011;52:e103-20. 2. yang hj, kim yh, kim me. a preliminary study of troublesome symptoms in women with acute uncomplicated cystitis korean j urol. 2007;48:1082-7. 3. klimberg i, shockey g, ellison h, et al. time to symptom relief for uncomplicated urinary tract infection treated with extended-release ciprofloxacin: a prospective, open-label, uncontrolled primary care study. curr med res opin. 2005;21:1241-50. 4. foxman b, frerichs rr. epidemiology of urinary tract infection: i. diaphragm use and sexual intercourse. am j public health. 1985;75:1308-13. 5. se jun park jhr, sang ho park, jung won choe, sang hyup lee, jung hoon kim, kyung do kim, tae hyoung kim, mi-kyung lee. selection of antibiotics according to the costs and efficacy of empirical antibiotics therapy for extended spectrum beta-lactamase producing uropathogens from urine culture test in patients with acute uncomplicated cystitis. korean j utii. 2012;7:29-35. 6. lee g, cho yh, shim bs, lee sd. risk factors for antimicrobial resistance among the escherichia coli strains isolated from korean patients with acute uncomplicated cystitis: a prospective and nationwide study. j korean med sci. 2010;25:1205-9. 7. alkhayal sw, rizvi fa. clinical features and management of methicillin-resistant staphylococcus aureus cystitis. urol j. combination treatment for acute cystitis-ko et al. 2012;9:617-9. 8. christiaens tc, de meyere m, verschraegen g, peersman w, heytens s, de maeseneer jm. randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. br j gen pract. 2002;52:729-34. 9. falagas me, kotsantis ik, vouloumanou ek, rafailidis pi. antibiotics versus placebo in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled trials. j infect. 2009;58:91-102. 10. ferry sa, holm se, stenlund h, lundholm r, monsen tj. the natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. scand j infect dis. 2004;36:296-301. 11. bleidorn j, gagyor i, kochen mm, wegscheider k, hummers-pradier e. symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?--results of a randomized controlled pilot trial. bmc med. 2010;8:30. 12. lee sj, lee ds, choe hs, et al. antimicrobial resistance in community-acquired urinary tract infections: results from the korean antimicrobial resistance monitoring system. j infect chemother. 2011;17:440-6. 13. bent s, nallamothu bk, simel dl, fihn sd, saint s. does this woman have an acute uncomplicated urinary tract infection? jama. 2002;287:2701-10. 14. hooton tm. clinical practice. uncomplicated urinary tract infection. n engl j med. 2012;366:1028-37. 15. baerheim a. empirical treatment of uncomplicated cystitis. scand j prim health care. 2012;30:1-2. 16. lee bs, bhuta t, simpson jm, craig jc. methenamine hippurate for preventing urinary tract infections. cochrane database syst rev. 2012;10:cd003265. 17. marcelin-jimenez g, angeles ap, martinezrossier l, fernandez sa. ciprofloxacin bioavailability is enhanced by oral coadministration with phenazopyridine: a pharmacokinetic study in a mexican population. clin drug investig. 2006;26:3238. 18. pergialiotis v, arnos p, mavros mn, pitsouni e, athanasiou s, falagas me. urinary tract analgesics for the treatment of patients with acute cystitis: where is the clinical evidence? expert rev anti infect ther. 2012;10:875-9. 19. zabkowski t, jurkiewicz b, saracyn m. treatment of recurrent bacterial cystitis by intravesical instillations of hyaluronic acid. urol j. 2015;12:2192-5. 20. mazumdar k, dutta nk, dastidar sg, motohashi n, shirataki y. diclofenac in the management of e. coli urinary tract infections. in vivo. 2006;20:613-9. 21. takagi-matsumoto h, ng b, tsukimi y, tajimi m. effects of nsaids on bladder function in normal and cystitis rats: a comparison study of aspirin, indomethacin, and ketoprofen. j pharmacol sci. 2004;95:458-65. combination treatment for acute cystitis-ko et al. female urology 369 effects of psychological status on the oxidation parameters of semen and blood in azoospermic men kemal gumus1*, mehmet gulum2, ercan yeni3, halil ciftci3, yigit akin4, emre huri2, hakim çelik5, özcan erel6 purpose: in limited number of studies performed concerning the psychological moods of female, and male with the diagnosis of infertility, data related to increased incidence of depression, and anxiety have been reported. the objective of this study is to determine whether azoospermia has any psychological effects on men, and investigate the potential effects of psychological mood on seminal, and plasma oxidative parametres. materials and methods: twenty-seven patients whose two consecutive semen analyses were reported as pellet –negative azoospermia constituted the azoospermic group, and 30 healthy individuals who applied to the infertility polyclinic with normal seminal parametres comprised the normozoospermic group. results: beck anxiety scores were significantly higher in the azoospermic group (p = 0.009). when compared with the normozoospermic group, higher levels of oxidative parametres, but lower levels of the antioxidative parametre were detected in the azoospermic group (p < 0.05). in the azoospermic group, a positive correlation was detected between beck anxiety and total oxidant status. anxiety may increase oxidative parametres in both plasma, and seminal fluid (r = 473, p = 0.026). conclusion: anxiety may increase oxidative parametres in both plasma, and seminal fluid. oxidative milieu may impair sperm quality, and affect the success rates of assisted reproductive treatments. the determination of oxidative potential in infertile men, thiol, and prolidase may be used as biomarkers. keywords: psychological status; oxidative parametres; azoospermia; infertility introduction infertility, defined as the inability to conceive after 1 year of regular unprotected sexual intercourse, affects around 15% of all couples of reproductive age, with about 50% being associated with abnormalities in the male, called male factor infertility(1,2). one of the causes of male factor infertility is azoospermia. azoospermia refers to absence of sperm in the ejaculate after centrifugation and microscopic analysis of two semen samples obtained at different time points. this condition affects approximately 1 % of the general male population and 15 % of subfertile men(3). the term “oxidative stress” (os) is defined as an imbalance between the production and the elimination of reactive oxygen species that results in an accumulation of oxidative damage(1). within the last decades, the knowledge concerning the link between os and psychiatric disorders has been surging(4). in limited number of studies performed concerning the psychological moods of female, and male with the diagnosis of infertility, data related to increased incidence of depression, and anxiety have been reported(5-7). it has been also reported that psychological conditions trigger the production of reactive free oxygen radicals 1balikligol hospital, department of urology, sanliurfa, turkey, kemalag27@hotmail.com. 2hacettepe university, faculty of medicine, department of urology, ankara, turkey, mehmetgulum@hotmail.com. 3harran university, faculty of medicine, department of urology, sanliurfa,turkey,ercanyeni@hotmail.com. 4izmir katip celebi university, faculty of medicine, department of urology, izmir, turkey; yigitakin@yahoo.com. 5harran university, faculty of medicine, department of physiology, sanliurfa, turkey. hakim celik, hakimcell@yahoo.com. 6yildirim beyazit university, faculty of medicine, department of clinical biochemistry, ankara, turkey. *correspondence: balikligol hospital, department of urology, sanliurfa, turkey, tr-63100, ankara, turkey. tel: +90-5076159971.e mail: kemalag27@hotmail.com. received april 2018 & accepted august 2018 leading to disruption of balance between free radicals, and antioxidants with resultant induction of oxidative stress(8,9). some biomarkers are used in the detection of oxidative stress including prolidase, and thiol/disulfide homeostasis(10-12). prolidase (pro) is an intracellular enzyme necessary to release proline and hydroxyl-proline from the carboxyl terminus of imidodipeptides which take part in collagen degradation, recycle proline for protein synthesis, matrix remodeling and cell growth (8). exposure of proline decreases antioxidant potential, suggesting its role in os. exposure of proline decreases antioxidant potential, suggesting that proline induces os. statistically significantly higher oxidative status and prolidase activities have been demonstrated in generalized anxiety disorder(8). dynamic thiol/disulphide homeostasis was defined as a novel oxidative stress marker by erel and neselioglu (13). dynamic thiol disulphide homeostasis status has critical roles in antioxidant protection, detoxification, signal transduction, apoptosis, regulation of enzymatic activity and transcription factors and cellular signalling mechanisms(14). moreover, dynamic thiol disulphide homeostasis is being increasingly implicated in many disorders. there is also a growing body of evidence sexual dysfunction and andrology sexual dysfunction and andrology 295 vol 16 no 03 may-june 2019 296 demonstrating that an abnormal thiol disulphide homeostasis state is involved in the pathogenesis of a variety of diseases, including diabetes, cardiovascular diseases, cancer, rheumatoid arthritis, chronic kidney disease, parkinson's disease, alzheimer's disease, friedreich's ataxia, multiple sclerosis(13). the objective of this study is to determine whether azoospermia which is a serious etiological factor of male infertility has any psychological effects on men, and investigate the potential effects of psychological mood on seminal, and plasma oxidative parametres. as far as we may know, this is the first study which investigated the effects of psychological mood on seminal, and plasma oxidative parametres of azoopermic men, and used both prolidase, and thiol/disulfide homeostasis as oxidative markers. materials and methods fifty seven patients who applied to infertility polyclinic of our hospital between january 2017 and june 2017 because of infertility and voluntarily participated in the trial were included in the study. twenty-seven patients whose two consecutive semen analyses were reported as pellet –negative azoospermia constituted the azoospermic group, and 30 healthy individuals who applied to the infertility polyclinic with normal seminal parametres comprised the normozoospermic group. approval of the local ethics commitee was obtained for the study (date of the approval: 05.01.2017 and registration #:01-18). the patients were informed about the study in detail, and then their undersigned consent forms were obtained. exclusion criteria of the study were as follows: presence of significant leucospermia, age > 45 years, bmi > 30 kg/m2, presence of varicocele, epididymo-orchitis, testicular torsion, testicular trauma, and tumour, smokers, and use of pentoxyfilline, vitamin preparations and antidepressants. in addition, participants were asked to fill in turkish version of the beck depression inventory (bdi) and beck anxiety inventory (bai). the bdi is composed of 21 questions that are scored on a four-point likert scale (0-3 points). the bai was used to assess the severity of clinical anxiety during the past week. it is a self-reported inventory containing 21 items on a fourpoint scale. beck anxiety inventory, and beck depression inventory classify the severity of depression, and anxiety as follows: 0-13 pts, absence of depression or anxiety; 14-19 pts, mild; 20-28 pts, moderate, and 2963 pts, severe depression, and anxiety(15). for the investigation of infertility after 3 days of sexual abstinence, the patient ejaculated into a sterile a contained by masturbation without using lubricating gel. one drop from collected semen samples was dropped on macler camera and examined under microscope at 20× magnification, and sperm counts, motility and leucocyte counts were determined. besides, semen sample was spread on a slide, properly stained and dried before examining sperm morphologies under microscope at 100 ×magnification. based on the results of spermiogram according to who 2010 criteria, the patients were categorised in azoospermic and normozoospermic groups. the remaining semen samples were centrifuged at 3 000 × g for 15 min and stored at −80°c till oxidative parameters were analysed. besides, venous blood samples were drawn from the participants after 12 hr of fasting and centrifuged at 4 000 × g for 10 min, and the separated serum portions were stored at −80°c ‘de till oxidative parameters (tas, tos ) were analysed. measurement of total oxidant status seminal plasma tos levels were analysed using commercial rel assay kits developed by erel. for the measurement of tos levels, as described in the operating principles of the test, colorimetric method based on oxidation of ferrous ion to ferric ion by oxidant molecules contained in the samples was used. the results were expressed in μmol h 2 o 2 /l(16). measurement of total antioxidant status seminal plasma tas was analysed using commercial rel assay kits developed by erel. this method developed by erel is fully automated system and measures total antioxidant capacity (tac) of the body against potent free radicals. measurement of tos levels is based on decolourisation of coloured abts cationic radical as a result of reduction by all antioxidant molecules contained in the sample in proportion with total concentration of antioxidant molecules(17). as a calibrator, trolox which is a water-soluble analogue of vitamin e is used. the results were expressed as mmol trolox equvalent/l. measurement of oxidative stress index oxidative stress index of the samples is calculated as the ratio of total oxidant levels of samples to total antioxidant levels of the samples and expressed as percentages(17). before calculation mmol unit of tas is converted to the unit of micromole as performed for tos test. blood sampling and measurement of dynamic thiol/disulphide homeostasis venous blood samples were drawn in tubes containing ethylenediaminetetraacetic acid and serum samples were immediately separated by centrifugation at 1500 g for 10 min. samples were coded and stored at −80°c. serum dynamic thiol/disulphide homeostasis was determined with a recently developed spectrophotometric method described by erel and neselioglu using an automated clinical chemistry analyser (roche, cobas 501, mannheim, germany)(13). sodium borohydride is the essential agent in this method that is used to reduce dynamic bonds to functional thiol groups. to prevent extra reduction of 5,5′-dithiobis-2nitrobenzoic acid (dtnb), unused sodium borohydride is removed by formaldehyde addition. the total thiol content of the sample is measured using a modified ellman reagent. substracting native thiol contentf rom total thiol gives twice the disulphide amount. having found the disulphide amount, the disulphide/total thiol ratio, disulphide/native thiol ratio and native thiol/total thiol ratio can be calculated. determination of prolidase activity serum was diluted 40-fold with 2.5 mmol/l mn 2+,40 mmol/l trizma hcl buffer (ph 8.0) and pre incubated at 37°c for 2 hr. the reaction mixture containing 30 mmol/l gly-pro, 40 mmol/l trizma hcl buffer (ph:8.0), and 100 μl of preincubation serum in 1 ml was incubated at 37°c for 30 min. adding 0.5 ml of 20 % trichloroacetic acid solution then stopped the incubation reaction. the supernatant was used for measurement of proline by the method proposed by myara et al.(18), which is a modification of chinard’s method. (19) intra-assay coefficient of variation of the assay was 3.8%. psychological status in azoospermic men -gumus et al. statistical analysis statistical analyses were performed using spss version 15 (spss inc. chicago usa) software program. distribution of numerous variables was evaluated using shapiro-wilk test. parametric tests were used for data with normal distribution. for intergroup comparisons parametric student ‘s t-test, and nonparametric mann-whitney u test were used. for correlation spearman’s correlation analysis was employed. the results were expressed as mean ± standard deviation, median (interquartile range); and p < .05 was accepted as the level of significance. results demographic and bdi, and bai data are shown in table 1. the groups were similar in mean age, education, body mass index (bmi), duration of marriage and infertility, and volume of semen. a significant intergroup difference was not found concerning beck d scores (p = 1.000). beck a scores were statistically significant higher in the azoospermic group (p = 0.009). in both azoospermic, and normozoospermic groups, any statistically significant correlation did not exist between beck a (r = 366, p = 0.079; r = 366, p = 0.079 and d scores (r=103,p = 0.631;r = 180, p = 0.400), with duration of marriage, and the infertility duration. semen analyses when compared with the normozoospermic group, higher levels of oxidative parametres namely prolidase, tos, and osi, but lower levels of the antioxidative parametre (ie. tas) were detected in the azoospermic group (p < 0.05)(table 2). in the normozoospermic group, the correlation between semen parameters (volume, sperm counts in one millilitre, sperm motility, and morphology), and tas, tos, osi, prolidase, beck a and d values was examined. statistically significantly negative correlations were detected between prolidase, and sperm counts (r = -566, p = 0.009), motility (r= -526, p = 0.017) , and morphology (r= -545, p = 0.013) , and also between osi, and sperm counts (r = -650, p = 0.002). a significant correlation was not detected between other parametres. serum analyses levels of serum prolidase, tos, osi were higher in the azoospermic group relative to normozoospermic group (p < 0.05), but antioxidant parametres (tas, native thiol, total thiol and disulphide) were lower than those of the normozoospermic group (p < 0.05) (table 3). in the azoospermic group, a positive correlation was detected between beck a and tos (r = 473, p = 0.026). a negative correlation was detected between beck a and plasma prolidase levels (r = 493, p = 0.017). discussion as a generally accepted corollary, major sources of seminal oxidative stress are leucocytes, and defective sperm cells. in our previous study(1), contrary to our prediction during planning of the study, we found higher oxidative stress, but lower antioxidative parametres in seminal plasma of azoospermic men devoid of leukocytes, and spermazoa in comparison with normozoospermic men. as a possible cause of this condition, we reported that azoospermia which is a serious etiological factor of infertility exerts psychological effects on men, and subsequently higher levels of plasma oxidative parametres increasing with stress pass through seminal vesicles, and prostate into seminal fluid leading to enhanced oxidative stress, but lower antioxidative parametres in seminal plasma of azoospermic men. however we did not analyze the psychological mood of azoospermic men in our previous study. therefore in the table 1. study subgroup participants’ demographic, anxiety depression scores and semen parameters variables azoospermic group, n = 27 normozoospermic group, n = 30 p value (mean ± sd) (mean ± sd) mean age (years) 29,4 ± 5,7 30.4 ± 6.4 0.535 education (years) 9.1 ± 4.45 10.5 ± 5.10 0.546 body mass index (bmi) 25.4 ± 5.8 26.5 ± 4.6 0.469 duration of marriage (years)* 4 (8) 3.5 (3.7) 0.887 duration of infertility (years)* 4.2 (1,9) -- na volume*, ml 1,4 (1) 1,6 (1) 0.605 concentration**(x106/ml) 0 34.6 ± 37,9 na motility** (%motile sperm) 0 42.9 ± 30,0 na morfology** (%normal sperm) 0 8.3 ± 6,7 na bai** score 20,4 ± 10,1 7.9 ± 5,3 0.003 bdi score * 11 (22) 10.5 (14,2) 1.000 abbreviations: bdi, beck depression inventory; bai, beck anxiety inventory *median (iqr), **mean ± standard deviation (sd) statistically significant p values were written as bold azoospermic group, n = 27 normozoospermic group, n = 30 p value prolidase* (u/i) 36.4 (25,2) 21.7 (12.2) 0.019 tas**, mmol trolox equivalent/l 0.94 ± 0.33 1.30 ± 0.32 0.001 tos*, μmol h 2 o 2 /l 18.7 (3.5) 15.3 (4.0) 0.037 osi** 1.99 ± 0.65 1.23 ± 0.52 0.000 abbreviations: tas, total antioxidant status; tos, total oxidant status; osi, oxidative stress index table 2. seminal plasma oxidative/antioxidative parameters in azoospermic and normozoospermic groups. psychological status in azoospermic men -gumus et al. sexual dysfunction and andrology 297 vol 16 no 03 may-june 2019 298 present study we aimed to evaluate psychological mood of the azoospermic men, and investigate the correlation between psychological mood, and oxidative parametres of blood, and seminal fluid. multiple number of studies which investigated the correlation between infertility, and psychological state of both men, and women have been published. in a meta-analysis, greil et al. analyzed the correlation between infertility, and psychological distress, and indicated that infertility is generally related to psychological distress which may be both the cause, and outcome of infertility(7). the authors also emphasized that the duration of infertility, and treatment should be taken into consideration in studies which would be performed concerning infertility, and psychological distress. very limited number of studies have investigated psychological mood in azoospermia which is a serious etiological cause of infertility. akbal et al. reported increase in symptoms of erectile dysfunction, anxiety, and depression in azoospermic men in whom tese could not find any viable spermatozoa relative to normozoospermic men(20). in recent studies, castro et al. demonstrated presence of a correlation between azoospermia, and neuropsychiatric diseases(21). bak et al. reported that patients with the established diagnosis of nonobstructive azoospermia which signifies absence of sperm production had experienced intense panicky feelings with increased tendency to insomnia, anxiety and depression. (22) in our present study, we found statistically significantly higher anxiety scores in azoospermic men when compared with the normozoospermic group. while depression scores were not so high in azoospermic men. levels of anxiety did not correlate with the duration of marriage, and disease in our study, relatively shorter average duration of marriage, and disease in the azoospermic group may be the reason why we couldn’t find any correlation between these parametres. in groups with longer duration of infertility, more realistic outcomes may be obtained. it is already known that oxidative parameters increase, while antioxidative parameters decrease in both plasma, and seminal fluid of infertile men. in our study, we found increases in oxidative parameters (tos, osi, prolidase), but decreases in antioxidative parameters (tas, thiol) in plasma, and seminal fluid of azoospermic men. despite contradictory arguments made in many studies, as is the case with multiple number of diseases including anxiety, and depression, prolidase has been associated with increased oxidative stress, and decreased antioxidant levels.(23) it has been estimated that this oxidative effect is caused by release of proline mediated by the action of prolidase. in support with the study which detected higher levels of prolidase in anxiety, we found a positive correlation between beck-a scores and levels of tos, and prolidase in the plasma of azoospermic men. besides, prolidase and increased oxidative stress negatively affected sperm counts, motility, and morphology. ozcan et al. reported the presence of a negative correlation between prolidase activity on the wall of the varicocele, and sperm counts in azoospermic men with varicocele.(24) they indicated that this condition might be the result of an oxidative milieu secondary to increased levels of prolidase in the spermatic vein, and duct. in the same study, they reported lack of any correlation between sperm motility, and enzymatic activity of prolidase. thiol is a novel biomarker which can be measured only in blood, and thiols are antioxidant buffers which balance both intracellular, and extracellular oxidative processes.(25) in accordance with decreased antioxidative potential in infertile men, we found lower thiol levels in azoospermic infertile men when compared with normozoospermic individuals. though any relevant study has not been performed in infertile men, some studies have demonstrated antioxidative contribution of thiol levels to oxidative processes. tokgöz et al. detected marked decreases in native, and total thiol levels in the sera of the patients who had undergone prostate biopsies(12). they also indicated that these decreases might be related to acute oxidative stress due to the procedure of prostate biopsies. kozanhan et al. performed a study with health care professionals who had been exposed to anesthetic gases, and reported decreased thiol, but increased disulfide levels(11). they stated that these changes stemmed from oxidative effects of anesthetic gases, and thiol/disulfide balance might be used as a biomarker in the diagnosis of oxidative stress. conclusions infertility is an important health problem which may induce neuropsychiatric disorders as anxiety. anxiety may increase oxidative parametres in both plasma, and seminal fluid. oxidative milieu may impair sperm quality, and affect the success rates of assisted reproductive treatments. we think that in the determination of oxidative potential in infertile men, thiol, and prolidase may be used as biomarkers in infertility. table 3. serum oxidative/antioxidative parameters in azoospermic and normozoospermic groups. azoospermic group, n = 27 normozoospermic group, n = 30 p value prolidase* 8.8 (9.1) 6,5 (1.9) 0.032 tas, mmol trolox equivalent/l 0.87 ± 0.28 1,13 ± 0.35 0.010 tos*, μmol h2o2/l 16.7 (3.3) 14.0 (2.7) 0.003 osi* 1,9 (1.6) 1.25 (0.6) 0.001 native thiol (μmol/l) 403.9 ± 79.4 475.4 ± 86.8 0.007 total thiol (μmol/l) 460.5 ± 79.5 549.2 ± 93.9 0.002 disulphide (μmol/l) 28.3 ± 9.4 36.3 ± 13.5 0.029 disulphide/native thiol ratio 7.3 ± 2.7 7.9 ± 3.2 0.476 disulphide/total thiol ratio 6.3 ± 2.1 6.7 ± 2.3 0.496 native thiol/total thiol ratio 87.4 ± 4.2 86.5 ± 4.6 0.495 abbreviations: tas, total antioxidant status; tos, total oxidant status; osi, oxidative stress index *median (iqr), mean ± sd psychological status in azoospermic men -gumus et al. acknowledgement this study was approved in balikligöl hospital department of urology and yildirim beyazit university, faculty of medicine, department of clinical biochemistry as a research project. conflict of interest the authors report no conflict of interest. references 1. gulum m, gumus k, yeni e, et al. blood and semen paraoxonase—arylesterase activities in normozoospermic and azoospermic men. andrologia. 2017;49. 2. agarwal a, durairajanayagam d, halabi j, peng j, vazquez-levin m. proteomics, oxidative stress and male infertility. reprod biomed online. 2014;29:32-58. 3. macaluso m, wright-schnapp tj, chandra a, et al. a public health focus on infertility prevention, detection, and management. fertil steril. 2010;93:16 e1-0. 4. ng f, berk m, dean o, bush ai. oxidative stress in psychiatric disorders: evidence base and therapeutic implications. int j neuropsychopharmacol. 2008;11:851-76. 5. drosdzol a, skrzypulec v. depression and anxiety among polish infertile couples--an evaluative prevalence study. j psychosom obstet gynaecol. 2009;30:11-20. 6. eisenberg ml, li s, cullen mr, baker lc. increased risk of incident chronic medical conditions in infertile men: analysis of united states claims data. fertil steril. 2016;105:62936. 7. greil al. infertility and psychological distress: a critical review of the literature. soc sci med. 1997;45:1679-704. 8. ercan ac, bahceci b, polat s, et al. oxidative status and prolidase activities in generalized anxiety disorder. asian j psychiatr. 2017;25:118-22. 9. rodrigues r, petersen rb, perry g. parallels between major depressive disorder and alzheimer's disease: role of oxidative stress and genetic vulnerability. cell mol neurobiol. 2014;34:925-49. 10. gecit i, eryilmaz r, kavak s, et al. the prolidase activity, oxidative stress, and nitric oxide levels of bladder tissues with or without tumor in patients with bladder cancer. j membr biol. 2017;250:455-9. 11. kozanhan b, inanli i, deniz cd, et al. dynamic thiol disulphide homeostasis in operating theater personnel exposed to anesthetic gases. am j ind med. 2017;60:1003-9. 12. tokgoz h, tas s, giray o, et al. the change in serum thiol/disulphide homeostasis after transrectal ultrasound guided prostate biopsy. int braz j urol. 2017;43:455-61. 13. erel o, neselioglu s. a novel and automated assay for thiol/disulphide homeostasis. clin biochem. 2014;47:326-32. 14. circu ml, aw ty. reactive oxygen species, cellular redox systems, and apoptosis. free radic biol med. 2010;48:749-62. 15. beck at, ward ch, mendelson m, mock j, erbaugh j. an inventory for measuring depression. arch gen psychiatry. 1961;4:56171. 16. erel o. a new automated colorimetric method for measuring total oxidant status. clin biochem. 2005;38:1103-11. 17. erel o. a novel automated direct measurement method for total antioxidant capacity using a new generation, more stable abts radical cation. clin biochem. 2004;37:277-85. 18. myara i, charpentier c, lemonnier a. optimal conditions for prolidase assay by proline colorimetric determination: application to iminodipeptiduria. clin chim acta. 1982;125:193-205. 19. chinard fp. photometric estimation of proline and ornithine. j biol chem. 1952;199:91-5. 20. akbal c, mangir n, tavukcu hh, ozgur o, simsek f. effect of testicular sperm extraction outcome on sexual function in patients with male factor infertility. urology. 2010;75:598601. 21. castro a, rodriguez f, florez m, et al. pseudoautosomal abnormalities in terminal azfb+c deletions are associated with isochromosomes yp and may lead to abnormal growth and neuropsychiatric function. hum reprod. 2017;32:465-75. 22. bak cw, seok hh, song sh, kim es, her ys, yoon tk. hormonal imbalances and psychological scars left behind in infertile men. j androl. 2012;33:181-9. 23. pirincci n, kaba m, gecit i, et al. serum prolidase activity, oxidative stress, and antioxidant enzyme levels in patients with renal cell carcinoma. toxicol ind health. 2016;32:193-9. 24. ozcan o, malkoc e, cosar a, et al. prolidase enzyme activity in varicose venous walls related to sperm count in patients with varicocele. scand j clin lab invest. 2013;73:97-101. 25. cremers cm, jakob u. oxidant sensing by reversible disulfide bond formation. j biol chem. 2013;288:26489-96. psychological status in azoospermic men -gumus et al. sexual dysfunction and andrology 299 urology journal unrc/iua vol. 2, 44-46 spring 2004 printed in iran 44 miscellaneous the relationship between weight as well as the kind of prostate hypertrophy and the response to tamsulosine, a specific α-blocker mombini h department of urology, ahwaz university of medical sciences, ahwaz, iran abstract purpose: to study the effects of tamsulosine (flowmax) as a specific α-blocker in patients with prostate weighted less than 40 gr and lacked median lobe and to compare them to patients with prostate weighted more than 40 gr with median lobe. materials and methods: forty outpatients with bph were referred to clinic and intentionally enrolled in this study. patients were divided into 2 groups of 20 patients. tamsulosine was daily administered for all of them for 6 weeks. routine tests were performed for all patients, all of which were normal. the probability of prostate cancer was ruled out. the size of prostate and type of hypertrophy were determined by one radiologist via dre, suprapubic ultrasonography and trus-p. patients were divided into a and b groups according to the size of prostate and the lack of median lobe or its presence. prostate size was less than 40 mg in group a and all patients lacked median lobe; whereas, prostate size was more than 40 mg (between 40-60 mg) in group b and patients had some median lobe. results: an increase of 30% in base line q max and a decrease of 25% in base line ipss was seen in 16 patients (80%) of group a, while these were observed only 9 patients (45%) of group b. conclusion: determination of prostate size and the type of hypertrophy seems to be essential before any tamsulosine administration. the weight of prostate is determined by protoscan. key words: prostate size, hypertrophy, tamsulosine introduction before 1980, prostatectomy was regarded as the only acceptable method in the management of benign prostatic hypertrophy (bph). however, complications such as mortality caused by cardiac complications and unsuccessful procedures, urinary system infection, impotency, postoperative hemorrhage and bladder neck and urethral stricture led to the increased tendency toward applying medical treatment. on the other hand, the discovery of modern α blocker drugs with special inhibition characteristic, the decrease of side effects of these medications and the reversibility of complications following the termination of drugs could increase the use of above mentioned medications; as, it was reported that prostatectomy was decreased form 250,000 cases in 1987 to 116,000 cases in 2000; a decline of 55% , which might be due to the use of α adrenergic blockers particularly their specific types such as tamsulosine, doxazosine and alfuzosine. however, one of the disadvantages of such medical treatments is their ineffectiveness in patients with median lobe hypertrophy, which would be discussed later on for the first time. the author believes that the impact of accepted for publication in february 2003 the relationship between weight as well as the kind of prostate hypertrophy and the response to tamsulosine, a specific α-blocker ball valve in median lobe hypertrophy could cause obstructive effects and α receptors have no role in the obstruction caused by contraction of striated muscles of median lobe, so that the use of such drug could not omit this contraction. we studied the effects of tamsulosine (flowmax) as a specific α blocker in patients with prostate weighted less than 40 gr and lacked median lobe and compared them with patients with prostate weighted more than 40 gr with median lobe.(1,2,3) materials and methods forty outpatients with bph at the age of 52-67 years were referred to clinic and entendedly enrolled in this study. patients were divided into 2 groups of 20 patients. tamsulosine capsule 0.4 mg was administered daily for all of them for 6 weeks. patients were morally oriented, no acute urinary retention was reported by them, and they tended to use this medication. routine tests were performed for all patients, all of which were normal. the probability of prostate cancer was ruled out by the measurement of prostatic specific antigen (psa) and digital rectal examination (dre). the size of prostate and type of hypertrophy were determined by one radiologist via dre, suprapubic ultrasonography, and trus-p.(4) lack of bladder stone and hydronephrosis were also assured by performing ultrasonography and urethral stricture was ruled out by inserting a 18 f nelaton catheter. patients were divided into two groups: a and b, according to the size of prostate and the lack of median lobe or its presence. prostate size was less than 40 mg in group a and all patients lacked median lobe; whereas, prostate size was more than 40 mg (between 40-60 mg) in group b and patients had some median lobe. none of the patients used drugs, which interact with the use of specific α blocker. q max and flow rate were measured in all patients before and after treatment and were recorded in particular form, as well. international prostatic symptom score (ipss) was also determined, which was 8-19 (moderate) in both groups. data analysis was conducted by a comparison between ratios using chi-square with spss. following the treatment an increase of 30% in q max from base line and a decrease of 25% in ipss base line were considered positive responses. (2,5,6,7) results an increase of 30% in base line q max and a decrease of 25% in base line ipss was seen in 16 patients (80%) of group a, while these were observed only 9 patients (45%) of group b. four out of these 9 patients had no or small median lobe. discussion by recent introduction of specific α blockers such as tamsulosine, medical treatments have gained particular aspect in treating benign prostate hypertrophy (bph), in addition to various surgical methods. however, it should be noted that the proper selection of patient has on essential impact on the obtained outcome of medical treatment; as, it is stated in this study that the weight of prostate and the kind of hypertrophy (median or lateral lobes hypertrophy) could have an important effect on the improvement of signs and symptoms of prostate enlargement. positive response in the management of bph following tamsulosine administration depends on the size of prostate and the type of hypertrophy. it seems that the use of tamsulosine (a specific α blocker) has no effect in patients with prostate larger than 40 gr, particularly in those with median lobe; but rather, it leads to spending expenses and consuming time of patients and physicians; while, the use of this drug in patients with prostate smaller than 40 gr and with no median lobe could be beneficial. thus, it is recommended to determine prostate size and the type of hypertrophy by the above mentioned methods before any administration of tamsulosine. conclusion determination of prostate size and the type of hypertrophy seems to be essential before any tamsulosine administration. the weight of prostate is determined by protoscan. references 1. john d, conell mc. diagnosis of bph. in: campbell's urology.7th ed. philadelphia: saunders; 1998. p. 1429. 2. hinman f. excision of prostate atlas of urologic surgery. 2nd ed. philadelphia: saunders; 1998. p. 411. 3. mimata h. clinical characteristic of alpha-blocker responder in men with bph. bju 2000; 86: 32. 4. barghi mr, et al. evaluation of ultrasonographic findings in patients with bph and their impact on the treatment. 45 the relationship between weight as well as the kind of prostate hypertrophy and the response to tamsulosine, a specific α-blocker iranian urology journal 2001; 17. 5. okada. h, et al. comparative study of terazosine and tamsulosine for symptomatic bph. bju 2000; 86: 32. 6. christian d. α 1-blockers for bph. eau 1999; 52. 7. desgrandchamps f. importance of individual response in symptom score evalvation. eau 2001; 40: 2. 46 case report rare plasmacytoid urothelial carcinoma of the bladder: two case reports tuba devrim1*, fatih ataç2, canan altunkaya1, ayşe özbek1, gülhan özdemir1, merve eryol1 keywords: plasmacytoid; urothelial carcinoma; cd138; e-cadherin. departments of pathology1, and urology2, faculty of medicine, kırıkkale university, 71450, kırıkkale, turkey. *correspondence: university of kırıkkale, faculty of medicine, department of pathology, kırıkkale, turkey. tel: +90 543 202 2088. fax: +90 318 224 0786. e-mail: tubadevrim@gmail.com. received july 2017& accepted plasmacytoid urothelial carcinoma is a rare and aggressive form of urothelial carcinoma characterized with delayed presentation and poor prognosis. very few cases of this carcinoma have been reported in the literature. here, we report and discuss two cases of bladder plasmacytoid urothelial carcinoma of a 57-year-old male presented with renal colic, and a 33-year-old female presented with macroscopic hematuria. pathologic examinations of the transurethral biopsies revealed urothelial carcinoma with plasmacytoid appearance. subsequently, immunohistochemical evaluation showed positive expression of epithelial markers and cd138. additionally, losing of the membranous expression of e-cadherin verified the diagnosis of plasmacytoid urothelial carcinoma. introduction plasmacytoid urothelial cancer (puc) is an aggressive and quite uncommon form of urothelial carcinoma (uc).(1) it is characterized with late presentation and poor prognosis.(2) microscopically, puc reveals a plasmacytoid morphology appearing with eosinophilic cytoplasm and eccentric nuclei. it also shows a discohesive growth and often extends in the perivesical adipose tissue.(3) additionally it may morphologically resemble plasmacytoma, lymphoma, or carcinoma variants, therefore the appropriate diagnosis in small biopsy samples is very important.(4) figure 1. preoperative appearance of the mass abdomen. a. abdominopelvic tomography. b. cystoscopic appearance. arrows indicate the mass located on the right side of the bladder wall in both cases (case 1: female, case 2: male). case report 86 vol 16 no 01 january-february 2019 87 in the present study, we aimed to report and discuss two uncommon cases of bladder puc of both sexes, which presented with renal colic or macroscopic hematuria to our hospital surprisingly at similar times. case report case 1: a 33-year-old female presented to our hospital with macroscopic hematuria. case 2: a 57-year-old male patient presented to the urology outpatient department with a history of left renal colic. a solid lesion was observed in the right side wall of the bladder of the both cases in cystoscopy examination (figure 1) and incomplete transurethral resections (tur) were performed. therewithal, abdomino-pelvic tomography revealed a mass which constituted a marked wall thickening and extension to the bladder perivesical adipose tissue (figure 1). in both cases, microscopic evaluation of the tur materials showed a high-grade tumor, arranged in discohesive cords and plasmacytoid features; in both cases penetrating the muscle. immunohistochemically, tumors of both cases showed positivity for panck, ck7 and cd138, besides negativity for e-cadherin (figure 2). in the light of these results, radical cystectomy and ileal loop operations were performed. in the pathological evaluations of radical materials, the tumors morphologically resembled the previous tur samples. also, tumors of these materials infiltrated the perivesical fatty tissue. the conditions of the patients were consulted with the oncology department and chemotherapies were planned. after radical cystectomy the male patient was evaluated for distant metastasis by thorax ct and bone scintigraphy. however distant metastasis was not detected. the preoperative evaluation of the female patient for distant metastasis was performed by thoracic ct and eventually no pathological formation was determined. due to the right iliac lap metastasis and perivesical spread determined in the male patient and the tumor infiltrating perivesical fatty tissue and vaginal anterior wall of the female patient, gemcitabine and cisplatin-based combination chemotherapy was administered to both patients. the male patient was given 3 cycles of chemotherapy and there was no pathological involvement in the mr examination of the lower and upper abdomen. he was started to drug-free follow-up after taking the 4th cure chemotherapy. the female patient's 2nd cure chemotherapy is completed. after 3 cycles of systemic chemotherapy, upper and lower abdomen will be reevaluated with mr. if pathological formation is not found, treatment with 4 cycles of chemotherapy will be terminated and the patient will be followed up. discussion puc of urinary bladder is an uncommon malignant neoplasm declared by recent world health organization (who) classification.(5) chung et al. (2017) reported an 8-year retrospective search of the archive at their institution identifying 22 patients with puc. the median age of the cases were stated as 74 years (range 51-86) and only three of them were reported as female. uncommonly, the 33-year-old female case presented in this study was a rare case both in terms of age and sex. also, the researchers reported the percentage of muscle-invasive disease as 86%, and the distant metastases as 9% among the presented puc cases.(6) muscle and perivesical adipose tissue invasion were present in the both cases of the present study. in the male case lymphovascular and perineural invasions of puc were common and significant. moreover, tumor metastasis was detected in 7 out of 22 lymph nodes detected. in another study of retrospective case series the rate of puc was reported as 2.4%, which is the lowest rate among the uc variants. futhermore, puc was accounted for 7% of all deaths from uc at 1 year period.(7) in accordance with the literature, puc cases of the present study were also late presented and unfortunately advanced pathological tumor stage was detected in the radical materials. the morphological similarity of puc to other benign and malign lesions such as cystitis with plasma cell infiltration, plasma cell-derived neoplasms, lymphomas, lymphoepitheliomas and metastatic carcinoma of the breast and stomach is the main cause of misdiagnosis.(8) puc as the rare variant of uc should be considered in order to avoid misdiagnosis. in this regard, immunohistochemistry is an essential technique to make a correct diagnosis on small biopsies. cd138 expression is reported as an important marker for puc. it can be observed in other malignant tumors, such as plasmacytomas, melanomas, rhabdomyosarcomas, and other carcinomas as well as it can be positively staining in all variants of ucs and various other epithelial tumors of the urinary tract.(9) therefore, the pathological diagnosis should be based on the morphological aspect and the differential diagnosis should be considered widely. figure 2. microscopic views of the tumor. hematoxylin-eosin staining: a, b: the appearance of puc as discohesive (a) or groups (b). immunohistochemical stainings: c, d: cd138 positive staining indicating puc. e, f: ck7 positive staining in surface epithelium (e) and in puc (e, f). g, h: e-cadherin positive staining in surface epithelium (g) and lost of membranose staining in puc (g, h). plasmacytoid urothelial carcinoma of bladder-devrim et al. plasmacytoid urothelial carcinoma of bladder-devrim et al. radical treatment must be provided to patients diagnosed with puc. this view is also supported by ohtaka et al. (2016) treated puc successfully with a combination of radical cystectomy and adjuvant chemotherapy. median overall survival of the puc patients is lower than conventional urothelial carcinomas.(11) in this regard, current studies that express survival rates in wide series are limited. cockerill et al. (2017) reported 46 patients with plasmacytoid carcinoma, 27 (59%) died of bladder cancer with a median survival of 1.7 years, and 10 patients died of other causes with a median follow up of 2.2 years. of the 9 surviving patients, the median follow-up was reopted as 10.3 years. in conclusion, consideration of this rare variant by the pathologist is important for correct diagnosis and determining prognosis. thus, the radical resection of this aggressive tumor variant, which is not predicted clinically and radiologically, provides a relatively prolonged survival of the patient. conflict of interest there is no conflict of interest among the authors. references 1. keck b, wach s, stoehr r, et al. plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy. bmc cancer. 2013;13:71. 2. wang z, lu t, du l, et al. plasmacytoid urothelial carcinoma of the urinary bladder: a clinical pathological study and literature review. int. j. clin. exp. pathol. 2012;5:601608. 3. raspollini mr, sardi i, giunti l, et al. plasmacytoid urothelial carcinoma of the urinary bladder: linicopathologic, immunohistochemical, ultrastructural, and molecular analysis of a case series. human pathology. 2011;42(8):1149-1158. 4. nigwekar p, tamboli p, amen mb, osunkoya ao, ben-dor d, amin mb. plasmacytoid urothelial carcinoma: detailed analysis of morphology with clinicopathologic correlation in 17 cases. am j surg pathol. 2009;33(3):417424. 5. moch h, humphrey pa, ulbright tm, reuter v. who classification of tumours of the urinary system and male genital organs. international agency for research on cancer, lyon, france: 2016. 6. chung ad, schieda n, flood ta, et al. plasmacytoid urothelial carcinoma (puc): imaging features with histopathological correlation. can. urol. assoc. j. 2017;11(12):e50–e57. 7. monn mf, kaimakliotis hz, pedrosa ja, et al. contemporary bladder cancer: variant histology may be a significant driver of disease. urologic oncology: seminars and original investigations. 2015;33(18):e15-e20. 8. rahman k, menon s, patil a, bakshi g, desai s. a rare case of plasmacytoid urothelial carcinoma of bladder: diagnostic dilemmas and clinical implications. indian j. urol. 2011;27:144-6. 9. goto k. cd138 expression is observed in the urothelial epithelium and in various urothelial carcinomas, and cannot be evidence for plasmacytoid urothelial carcinoma. int. j. surg. pathol. 2016;24(7):614-619. 10. ohtaka m, kawahara t, kumano y, et al. invasive urothelial carcinoma, lymphomalike/ plasmacytoid variant, successfully treated by radical cystectomy with adjuvant chemotherapy: a case report. j. med. case rep. 2016;10:48. 11. keck b, stoehr r, wach s, et al. the plasmacytoid carcinoma of the bladder—rare variant of aggressive urothelial carcinoma. int. j. cancer 2011;129: 346-354. 12. cockerill pa, cheville jc, boorjian sa, et al. outcomes following radical cystectomy for plasmacytoid urothelial carcinoma: defining the need for improved local cancer control. urology 2017;102:143-147. case report 88 the association of household food insecurity and the risk of calcium oxalate stones hamid shafi1, ahmad-reza dorosty motlagh2, mohammad bagherniya3,atefeh daeezadeh3* mohammad safarian4** purpose: food insecurity has been defined as ‘limited or uncertain availability of nutritionally adequate and safe foods’, which associated with adverse health consequences in human. another alarming condition, which is related to several comorbidities is kidney stone. this study aimed to determine the association of household food insecurity and developing kidney stones (calcium oxalate) in adults referred to medical centers of babol. materials and methods: this case-control study included 200 participants 18-65 years of ages (100 cases, 100 controls). an 18-items food insecurity questionnaire (usda), a valid and reliable 147-item food frequency questionnaire (ffq) and demographic characteristics were obtained via interviewing. results: sixty eight percent of cases and 40% of controls were food insecure, respectively. food insecurity was significantly associated with the risk of kidney stone (p < .05). furthermore, body mass index (bmi) and family history of kidney stone were significantly associated with the risk of kidney stones (p < .05). conclusion: food insecurity and bmi were significantly associated with the kidney stone, which shows the importance of availability of nutritionally adequate and safe foods in prevention of the kidney stone. keywords: food insecurity; kidney stone; diet; case-control study introduction kidney stone is a painful condition(1), which is relat-ed to several comorbidities such as diabetes mellitus, obesity, metabolic syndrome, hypertension, gastric bypass and chronic kidney disease in adults(2,3). the prevalence of kidney stones has been estimated between 8% to 19% and 3% to 5% among males and females, respectively in western countries(4,5). according to a recent study, which analyzed the 2007-2010 national health and nutrition examination survey (nhanes) sample, 8.8% (10.6% of men and 7.1% of women) of the american population suffered from kidney stones(6). the prevalence of this disease increased from 0.9% in individuals who were between 15-29 years of age to 8.2% in older ones who were between 60-69 years of age, in iran(7). it has been previously shown that 80% of kidney stones are calcium oxalate (caox)(5), and the most accessible and requested interventions to reduce the risk of kidney stones is dietary modification(8). following healthy eating, for example, adoption dietary approaches to stop hypertension (dash) diet is recommended to reduce the risk of kidney stone. in addition, it is suggested that obesity, higher bmi and weight gain are independently associated with higher risk of kidney stones formation (9,10). another alarming condition in the world, is food insecurity, which is defined as “limited or uncertain access to adequate food or limited ability to access healthy food through socially acceptable” (11). it has been previously considered that 6.30% of the households in the paris metropolitan area experienced food insecurity and about 2.50% of the households experienced severe food insecurity(12). in the united states, food insecurity existed in about 16% of population(13). another study, which was performed in ontario community in canada has shown that 70% of households were food insecure of which 17% and 53% were categorized in severe and moderate food insecure groups, respectively(14). the prevalence of food insecurity has been estimated between 30.5% to 50.2% in different parts of iran(15-19). although it has been previously shown that 16.3% he1 associate professor, department of urology, babol university of medical sciences, babol, iran. 2department of community nutrition, school of nutritional sciences and dietetics, tehran university of medical sciences, tehran, iran. 3student research committee, department of nutrition, faculty of medicine, mashhad university of medical sciences, mashhad, iran. 4metabolic syndrome research center, faculty of medicine, mashhad university of medical sciences, mashhad, iran. *correspondence: student research committee, department of nutrition, faculty of medicine, mashhad university of medical sciences, mashhad, iran. ** correspondence: metabolic syndrome research center, faculty of medicine, mashhad university of medical sciences, mashhad, iran. associate professor in clinical nutrition department of nutrition faculty of medicine mashhad university of medical sciences (mums), paradise daneshgah, azadi square, mashad, iran. tel: +98 (513) 8002423 (secretary). fax: +98 (513) 8828574 8002321. mobile: +98 (0) 915 3151654 received november 2016 & accpted july 2017 endourology and stone disease endourology and stone diseases 4094 modialysis patients were food insecure(20), to the authors’ knowledge there was no study about the association between prevalence of food insecurity and kidney stones. thus, the aim of this study was to evaluate food insecurity in the patients who suffered from calcium oxalate stones in iranian adult population. materials and methods study design, sample size and participants this case control study was performed among adults who lived in babol, the city located in north of iran in 2014. ethics committee of mashhad university of medical sciences approved the study. the study was founded and supported by mashhad university of medical sciences. to determine sample size in this study, we designed and implemented a pilot study conducted on 24 adults between 18-65 years old, who were selected randomly(12 patients who suffered from calcium oxalate stones and 12 healthy individuals). according to the pilot study, 75% of patients with kidney stones and 50% of the control group were food insecure. therefore, based on the statistical formula and considering 80% power and an α level of 0.05, it was necessary to examine 100 cases (patients who suffered from calcium oxalate stones) and 100 controls (healthy individuals) to compare of food security between two groups. we used purposive sampling method to select participants. 100 cases (with calcium oxalate kidney stone) were assigned after diagnosis of calcium oxalate stone by a urologist using chemical analysis of stone in the laboratory. inclusion criteria for the case group were adults who were between 18-65 years of ages and had kidney stones (only calcium oxalate) according to physician diagnosis without any underlying diseases (such as diabetes, hypertension, hyperlipidemia and so on). after interviewing with cases, we had to find controls who are matched according to sex, age and place of residence. thus, among 8 urban and rural health centers of babol, we selected 5 centers randomly. then, among people who referred to these centers, we chose healthy adult people, who were matched with the case participants. after that, we explained the study objectives completely to them and informed consents were obtained from participants. finally, from a total of 100 adults participated in each group, 65 were men and 35 were women and they were between 18 to 65 years old. in each group 48 participants lived in urban and 52 of them lived in rural. table 2. presents basic data of the study samples. participants in the two groups were matched according to age, sex and place of residence. anthropometric measurement participants' height was measured by the meter strip with a precision of 0.1 cm, while the person was attached to the wall without shoes and looking forward. participants’ weight was measured by a beurer flat digital scale with a precision of 0.1 kg, while the person was wearing minimal clothing without shoes. body mass index (bmi) was calculated as weight in kilograms divided by the square of height in meter. food security assessment household food security status have evaluated by the usda (us department of agriculture) questionnaire, which has been used annually in the u.s. current population survey since 1995(21). the reliability and validity of the questionnaire has evaluated in a previous study in iran(22). this 18 items questionnaire examines household food security status in the last 12 months. we completed the questionnaire by interviewing mothers of households. the studied participants were divided into two classifications of participants based on the scores of the questionnaire: food secure and food insecure groups. food insecure participants were divided into three subgroups: food insecure without hunger, food insecure with moderate hunger and food insecure with severe hunger (table 1). the last two groups (food insecure with moderate hunger and food insecure with severe hunger) were combined in analysis owing to the low percentage of food insecurity with severe hunger, (27% and 6% in case subjects and control ones, respectively). dietary intake to evaluate dietary intakes, a valid and reliable food frequency questionnaire (ffq)(23,24), which contained 147 items of foods and beverage was used. the food consumption converted into food material and its value was calculated in grams. total energy was reported as kilocalorie per day. socio-economic and demographic status demographic characteristics (including age, sex, place of residence, family size, number of children, having children under 18 years of age, and social and economic characteristics) were collected by a general questionnaire. these characteristics were as follows: education and occupational status of the mother and head of household, residential possession ownership status and living facilities. about living facilities, participants were asked that how many items of these 9 items they have (furniture, handcraft carpet, refrigerator, washing machine, dishwasher, microwave, computer, car, and home). having less than or equal to 3 items was considered as a low economic status, 4 to 6 items as moderate economic status and 7 to 9 items as good economic status. about landlord, participants were asked to select one of the options of the private house, rent or mortgage, and living with parents or relatives and others(17). all data were obtained by a well-trained nutritionist who became completely familiar with all questionnaires. food insecurity and calcium oxalate stone-shafi et al. food security status number of positive responses having child under 18 years old having no child under 18 years old food secure 0-2 0-2 food insecure without hunger 3-7 3-6 food insecure with moderate hunger 8-12 7-8 food insecure with severe hunger 13-18 9-10 table 1. classification of the household food security status based on scores vol 14 no 05 september-october 2017 4095 statistical analysis the classes of food security were determined for cases and controls in separate according to the obtained scores. descriptive variables were reported by mean, standard deviation (sd). to detect the relationship between variables and food security or calcium oxalate stone disease chisquared test, independent t-test, pearson and spearman correlation were used. the simple regression method was used to assess the relationship between food security status and all variables. finally, variables were entered into the model step by step forward to fine variables which had a relationship with food insecurity. the multiple regression method was also used to determine the variables which had the most effect on the kidney stone incidence (family history of kidney stone, food insecurity, fat and protein intake). (to reach this goal all variables, which had a significant relation with kidney stone (included: socioeconomic situation, family history of kidney stone, food insecurity, bmi, weight, macronutrient intake (calorie [kilo calories], carbohydrate, fat, protein in grams) were entered into the logistic multiple regression). to analyze the data we used the statistical package for the social sciences (spss), variables case group n=100 control group n=100 p-value age(year) under 30 16 16 30-39 31 31 0.999 40-49 23 23 50 and more 30 30 sex men 65 65 0.999 women 35 35 place of residence village 52 52 0.999 city 48 48 family size under 5 83 83 0.999 5 and more 17 17 number of children under 4 71 78 0.256 4 and more 29 22 having child under 18 yes 63 68 0.457 no 37 32 occupation of the head unemployed 1 2 worker 14 14 government employee 28 29 0.267 self-employed 44 50 retired 13 5 education level of responders pre-university 83 78 0.372 university 17 22 education level of heads pre-university 78 68 0.111 university 22 32 marital status married 90 89 single 10 9 0.845 widow 0 2 economic situation low 24 8 middle 5 9 69 0.011 high 17 23 home ownership 91 95 0.268 other 9 5 family history of kidney stone yes 60 19 < 0.001 no 40 81 food insecurity yes 68 40 < 0.001 no 32 60 bmi* (kg/m2) under weight 3 0 normal 23 39 0.003 overweight 37 46 obese 37 15 dietary intake median(iqr) median(iqr) calorie intake (kilo-calorie) 3702.2(1362.6) 3179.7(1033.4) < 0.001 protein intake (gram) 130.0 (42.2) 107.1(37.3) < 0.001 carbohydrate intake (gram) 573.9(240.4) 493.1(165.6) < 0.001 fat intake (gram) 119.1(46.7) 91.1(42.5) < 0.001 height (cm) 168.0 (17.7) 168.0 (8.0) 0.823 weight (kg) 78.0 (17.38) 74.4(13) 0.008 table 2. basic data of the study participants. food insecurity and calcium oxalate stone-shafi et al. endourology and stone diseases 4096 version 11.5. results sixty eight percent of cases and 40% of controls were food insecure, respectively. forty one percent, 22% and 5% of case subjects were categorized in the food insecurity without hunger, with moderate and severe hunger groups, respectively. in the control subjects, these values were 33%, 7% and 0 %, respectively. no significant differences were found between case and healthy subjects in age, sex, place of residence, family size, number of children, having child under 18, occupation of head, education level of responders and head and marital status. however, there were significant differences in some variables including economic status, history of kidney stone and bmi between individuals within the case and control groups (p < .05). moreover, the median intake of calories and macronutrients including carbohydrate, protein and fat as well as weight were significantly higher among kidney stone patinas in comparison with the health individuals (p < .05) (table 2). the median of daily total calorie and carbohydrate, protein and fat intake were 3702.2 ± 1362.6 kilo calories, 573.9 ± 240.4 grams, 130.0 ± 42.2 grams, 119.1 ± 46.7 grams, respectively in the case subjects. these values were 3179.7 ± 1033.4 kilo calories, 493.1 ± 165.6 grams, 107.1 ± 37.3 grams and 91.1 ± 42.5 grams, respectively in the control group (table 2). among the examined variables, 6 variables including economic status, family history of kidney stone, bmi average, obesity status, food insecurity and dietary intake were significantly associated with the kidney stone (p < .05). according to the multiple regression test, family history of kidney stone and food insecurity were found to be significant predictors for the kidney stone (p < .05) (table 3). furthermore, regression step by step forward model shows that economic status, family size, education level, place of residence and occupation of the household head were significantly related to the food insecurity (p < .05) (table 4). discussion the main finding of the current study is that household food insecurity has a strong correlation with the kidney stone. according to our knowledge, there are a very few studies about the associations between food insecurity and kidney diseases. a previous study, which was conducted among hemodialysis patients, has shown that 16.3% of patients were food insecure(20). in another study, which was conducted by crews et al., food insecurity was related to chronic kidney disease(25). however, it has been shown that food insecurity had a correlation with the chronic diseases(26,27). in their study, fitzgerald et al. showed that food insecurity is associated with increasing type 2 diabetes(28). likewise, a significant association was reported between food insecurity and the risk of type 2 diabetes and between food insecurity and bone density osteoporosis in postmenopausal women in iran(29,30). the results of the current study showed a significant relationship between bmi and the kidney stone. it is earlier suggested that a low calorie dash diet and decrease in fat and protein intake to prevent against kidney stone. in addition, carbohydrate rich in fructose (especially high fructose corn syrup) and sucrose were considered as a risk factor to increase the incidence of kidney stone(31). similarly, in their article, turney et al. have shown that total energy intake was associated with a significant increase risk of developing kidney stones (32). it has been previously shown that food insecure households had low quality diet. indeed, following diet with low vegetables and fruit, grains, and dairy products, and intake of a greater percent of energy from high-sugar foods were more common among food insecure individuals than the food secure ones(33). furthermore, because of financial problems, food insecure households decrease consumption of expensive foods such as fruits, vegetables and dairy and they have low food variety(34), and thus they receive low amount of calcium, citrate and phytate, which are all related to the reduction of the risk of kidney stones(31,35,36). in addition, to meet calorie requirements, consumption of oils and sweets, bread, pasta, and rice are considered as the most cost-efficient way among food insecure households(34), which all could lead to overweight and obesity. as previously have been shown frequently, overweight and obesity were significantly associated with the risk of kidney stones(6,9,10,37). thus, it is not surprising, if considering that food insecurity may lead to the kidney stones. the results of the present study showed that 68% and 40% of participant's household in case and control groups had mild to severe food insecurity, respectively. previous studies, which all were conducted in iran table 3. correlation between kidney stone and effective variables (multiple regression method). independent variable wald odd ratios 95% ci of or p-value food insecurity 5.27 2.44 1.14 5.24 0.022 family history 23.26 5.76 2.83 11.75 <0.001 economic situation low 1.75 2.58 0.63 10.56 0.185 middle 3.34 0.96 0.38 2.45 0.955 high* education level of heads pre-university 0.21 0.81 0.34-1.94 0.647 university* *reference category variable β± se p-value economic situation -1.6 ± 0.5 0.001 family size 1.08 ± 0.3 < 0.001 education level -3.4 ± 0.8 0.001 place of residence 1.9 ± 0.5 0.001 occupation of the head -1.5 ± 0.5 0.005 table 4. correlation between food insecurity and effective variables (regression step by step forward model) food insecurity and calcium oxalate stone-shafi et al. vol 14 no 05 september-october 2017 4097 showed that the prevalence of food insecurity was varied between 50.2% in rey, 30.5% in yazd and 36.6% in isfahan (center part of iran) and 37.6% in dezful placed in south area of the country, which were in line with the results of this study(16-19). the united states department of agriculture (usda) has reported that, 15.8% of the population (49 million adults and children) were food insecure in 2013, concentrated among low income households(38). in india, the prevalence of food insecurity was 77.2% among households(39). possible reasons for the difference between food insecurity among countries might be due to cultural difference, different evaluation instrument, different income and economic factors. another reason could be economic crisis and increased cost of foods. on the other hand, in spite of other countries, industrial countries perform a nutrition program such as food stamp program to help household with low income(40,41). in line with the results of previous studies(15,17,19), in the current study, the prevalence of food insecurity in the households of the first category (low socioeconomic status) was higher than two others category. household food insecurity associated with low household income in seligman et al.(27) and martin-fernandez et al.(12) studies. it seems that, households with higher incomes and better economic conditions can choose various foods and can spend much more part of their income for food supply(17). we found a significant relationship between food insecurity and the place of residence. population who lives in rural areas were more food insecure in comparison with city dwellers, which might be due to inaccessibility to the shopping centers in rural area. however, although the positive association between food insecurity and place of residence was observed in sharafkhani et al. study(42), fallahmadvari et al., found no significant correlation between these factors(40). as previously have been shown frequently(15,19,43-47), in the current study, food insecurity has a significant relationship with family size and number of children. it should be noted that by increasing family size, the need for food will be increased. so, the size and number of meals can also be reduced and food insecurity will appear(17). in this study, there was a significant relationship between food insecurity and job status of the head of household. the findings showed that food security was higher in households whose head were clerks, which is in line with the results of the studies by payab et al.(17) and fallahmadvari et al.(40). moreover, a significant relationship between food insecurity and job status has observed in studies on canadian households and rural households in malaysia(48,49). to interpretation, it should be considered that higher job status often is accompanied by higher income and better socioeconomic situation, which may result in an increment of accessibility to various and nutritious foods. this study showed a significant inverse relationship between food insecurity and education level of the mother and head of household. consistent with this result, previous studies showed a significant relationship between food insecurity and education level of mother and head of household(15,17,19,44,49). absence of adequate education limits job opportunity and reduces the ability to earn money. following the reduction of income, food expenses can be challenging. low education level also reduces people's nutritional knowledge level and affect all stages of the basket to the table (shopping, preparation, cooking and consumption), which can result in the household food insecurity (17). to our knowledge this study was the first that focused on kidney stone patients. in interpreting the existing results, some limitations should be noted. household food insecurity was evaluated in cross-sectional method. therefore, we cannot conclude if food insecurity in the household was continued or temporary. conclusions food insecurity and bmi were significantly associated with the kidney stone, which all show the importance of availability of nutritionally adequate and safe foods in prevention of the kidney stone. since kidney stone disease is related to painfulness and several medical comorbidities, decreasing in the rate of food insecurity across the population might lead to reduction of negative consequences of the kidney stone in the community. acknowledgments the authors wish to thank all participants of this study 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and body composition in ugandans living in urban kampala. j am diet assoc. 2007;107:197882. 45. che j cj. food insecurity in canadian households. health rep 2001;12:11-22. 46. willows nd, veugelers p, raine k, kuhle s. prevalence and sociodemographic risk factors related to household food security in aboriginal peoples in canada. public health nutr.2009; 12:1150-6. 47. foley w, ward p, carter p, coveney j, tsourtos g, taylor a. an ecological analysis of factors associated with food insecurity in south australia, 2002–7. public health nutr. 2010;13:215-21. 48. loopstra r, tarasuk v. severity of household food insecurity is sensitive to change in household income and employment status among low-income families. j nutr. 2013;143:1316-23. 49. shariff zm, khor g. obesity and household food insecurity: evidence from a sample of rural households in malaysia. eur j clin nutr. 2005;59:1049-58. food insecurity and calcium oxalate stone-shafi et al. endourology and stone diseases 5000 urological oncology comparison of different rectal cleansing methods for reducing post-procedural infectious complications after transrectal ultrasound-guided prostate biopsy jong eun lee1, sang soo shin2,3*, taek won kang4, jin woong kim5, suk hee heo2, yong yeon jeong2 purpose: to compare the efficacy of three different rectal cleansing methods for reducing post-procedural infectious complications after transrectal ultrasound (trus)-guided prostate biopsy. materials and methods: a total of 451 consecutive patients who underwent trus-guided prostate biopsy were prospectively included in this study. all patients received targeted antimicrobial prophylaxis and underwent bowel preparation through laxative administration. the patients were divided into three groups on the basis of the method of rectal cleansing immediately before the procedure. group i patients (n =165) underwent cleansing of the perianal skin using povidone-iodine cotton balls; group ii patients (n=116) received an injection of povidone-iodine solution (0.1 g/ml) into the anal and lower rectal canals; and group iii patients (n =170) received direct manual cleansing of the mucosal surface of the anus and lower rectum using povidone-iodine cotton balls. the three groups were compared regarding the incidence of post-procedural infectious complications, re-hospitalization rates, and mean length of hospital stay using one-way anova, the chi-square test, and multiple logistic regression analysis. results: post-procedural infectious complications occurred in %11.2 ,%21.8, and %6.5 of groups i, ii, and iii, respectively (p < .001). the incidence of overall infectious complications was significantly lower in group ii (%95 ci: 0.958–0.232, or = 0.472, p = .038) and group iii (%95 ci: 0.555–0.129, or = 0.267, p < .001) than in group i. re-hospitalization rates were %2.6 ,%9.7, and %0.6 in groups i, ii, and iii, respectively (p < .001). the incidence of re-hospitalization was significantly lower in group ii (%95 ci: 0.869–0.070, or = 0.247, p = .029) and group iii (%95 ci: 0.421–0.007, or = 0.055, p = .005) than in group i. the mean length of hospital stay was significantly longer in group i than in group iii (p = .009). conclusion: combined with targeted antimicrobial prophylaxis, direct manual cleansing of the mucosal surface of the anus and lower rectum using povidone-iodine cotton balls was most effective in preventing post-procedural infectious complications among the three different rectal cleansing methods. keywords: biopsy; infection; prostate; sepsis; transrectal introduction transrectal ultrasound (trus)-guided prostate bi-opsy in patients with suspected prostate cancer is currently the gold-standard procedure for prostate cancer diagnosis.(1) although it is generally recognized as safe and well tolerated, trus-guided prostate biopsy is an invasive method of obtaining prostate tissue samples that may occasionally cause serious complications. whereas the reported overall complication rates after prostate biopsy vary widely in previous studies, ranging from 2% to 10.4%, the rates of infectious complication requiring hospitalization range from 0% to 6.3%.(2-4) indeed, infectious complications are a leading cause of prolonged hospital stay and financial burden after prostate biopsy. therefore, numerous strategies have been proposed to minimize those complications.(5-7) as it was shown to be effective in reducing the rate of 1department of radiology, chonnam national university hwasun hospital, hwasun-gun, jeonnam, south korea. 2 department of radiology, 3 center for aging and geriatrics, 4 department of urology, chonnam national university medical school, gwangju, south korea. 5 department of radiology, chosun university medical school, gwangju, south korea. *correspondence: department of radiology, chonnam national university hospital, chonnam national university medical school, gwangju 61469, south korea. tel: +82 62 2205882, fax: +82 62 2264380, e-mail: kjradsss@gmail.com. received may 2018 & accepted february 2019 infectious complications before colorectal surgery,(8) rectal cleansing before prostate biopsy, along with prophylactic antibiotics, is well known to reduce the risk of infectious complications.(9) a recent systemic review and meta-analysis revealed that rectal cleansing using povidone-iodine before prostate biopsy significantly reduced the rate of infectious complications compared to the control group.(10) when a combination of povidone-iodine and prophylactic antibiotics is used, these effects are further accentuated.(4,10) however, as optimal rectal cleansing methods have not been standardized, various protocols have been used.(11-13) raman et al. reported that soaking the rectum and painting the perianal area with povidone-iodine gauze before prostate biopsy reduced the post-biopsy infectious complications rate from 4.3% to 0.6%.(12) in a study by abughosh et al., the anterior rectal mucosa was directly cleansed using an examiner’s finger and a thin layer of gauze soaked in urology journal/vol 17 no. 1/ january-february 2020/ pp. 42-49. [doi: 10.22037/uj.v0i0.4583] vol 17 no 01 january-february 2020 43 povidone-iodine.(13) to the best of our knowledge, the effectiveness of these various methods of rectal cleansing has not been meticulously compared. therefore, the aim of this study was to compare the efficacy of different rectal cleansing measures for reducing post-procedural infectious complications after trus-guided prostate biopsy. materials and methods patients this study was approved by our institutional review board, and written informed consent was obtained from all patients. during a one-year of study period, 456 consecutive patients from a single tertiary center who underwent trus-guided prostate biopsy under hospitalization were prospectively included in this study. among them, five patients who did not undergo rectal swab culture for the targeted antimicrobial prophylaxis because of the following reasons were excluded from the study: (1) four patients were already hospitalized for the evaluation of bone metastasis of unknown origin, and (2) one patient was already on antibiotic treatment because of a severe urinary tract infection (uti). finally, 451 patients were enrolled in this study. the indications for biopsy were as follows: (1) prostate specific antigen (psa) value greater than 4 ng/ml (n = 407, 90.2%); (2) concerning findings on digital rectal examination such as a nodule, induration, and asymmetry or concerning abnormal lesions on trus or prostate mr imaging (n = 16, 3.5%); (3) the presence of both (1) and (2) (n = 24, 5.3%); and (4) atypia on a previous prostate needle biopsy (n = 4, 0.9%). during the study period, one of three different rectal cleansing methods was used just prior to the procedure. the rectal cleansing method was applied differently every month for randomization. each method was used for a total of four months during the study period of one year. group i patients underwent cleansing of the perianal skin using povidone-iodine cotton balls (figure 1a); group ii patients received an injection of povidone-iodine solution (0.1 g/ml) into the anal and lower rectal canals (figure 1b); group iii patients underwent direct manual cleansing of the mucosal surface of the anus and lower rectum using forceps and povidone-iodine cotton balls (figure 1c). pre-procedural preparations all patients were admitted to the hospital one day prior to the procedure. they received targeted antimicrobial prophylaxis on the basis of the rectal swab culture results. the rectal swab samples were obtained two weeks before the biopsy and cultured on macconkey’s agar (komed) containing 1 μg/ml ciprofloxacin overnight at 37℃ in ambient air. all isolates were subjected to organism identification and antimicrobial susceptibility testing using an automated microbial system (vitek® 2). if quinolone resistance was not observed in the results of the rectal swab culture, the patients received antibiotic prophylaxis consisting of a total of three intravenous injections of ciprofloxacin (400 mg) at morning and evening of day of biopsy, and the morning after the procedure. however, in cases of quinolone resistance, the patients received a total of three intravenous injections of prophylactic ceftriaxone (500 mg) before and after the procedure. all patients also underwent bowel preparation using laxatives the day before the procedure. to minimize pain during the procedure, intravenous dripping of 100 ml of physiologic saline mixed with ketamine (10 mg/ml) was started one hour prior to the biopsy. biopsy protocol the patient was positioned in the left lateral decubitus position with their knees bent. all patients underwent rectal cleansing using one of three different methods immediately before the procedure. trus-guided prostate biopsy was performed using an 18-gauge fully automated biopsy gun with a needle length of 20 cm, cutting notch size of 1.6 cm, and stroke length of 22 mm (acecut; civco medical solutions, kalona, ia, usa) under ultrasonographic guidance (logic e9; ge healthcare, milwaukee, wi, usa) by one experienced radiologist. during the procedure, the biopsy needle was inserted via a steering device attached to the 5.0 to 7.5 mhz transducer to visualize the needle path parallel to the electronic guideline provided by the us images. a total of eight tissue specimens were taken from the prostate gland, with two cores in each of the rectal cleansing methods in prostate biopsy-lee et al. figure 1. illustrations showing the three different rectal cleansing methods. a. group i: cleansing of the perianal skin using povidone-iodine cotton balls. b. group ii: injection of povidone-iodine solution (0.1 g/ ml) into the anal and lower rectal canals. c. group iii: direct manual cleansing of the mucosal surface of the anus and lower rectum using povidone-iodine cotton balls. four regions (right upper, right lower, left upper, and left lower) of the prostate gland. further, in cases with a suspicious focal lesion in the middle part in both prostate glands on ultrasound images, tissue samples were additionally obtained at those portions. immediately after the core tissues were extracted, manual compression of the prostate gland using the us probe was performed to prevent possible post-procedural bleeding. in addition, color doppler us was performed to carefully check for any significant post-biopsy bleeding. the patients were discharged the day after the procedure if there were no complications, and they were routinely followed up on an out-patient basis within one month after discharge. in cases of unexpected complications, they were re-admitted via the emergency department. data analysis the electronic medical records of three groups were meticulously analyzed, including demographic data, prostate volume, psa level, presence of infectious and non-infectious complications, and underlying disease including diabetes mellitus (dm), by one urologist who was blinded to the information regarding the rectal cleansing method applied to the patients. moreover, past history of foley catheter insertion within one month before the procedure, antimicrobial use within three months, uti or prostatitis within three months, hospitalization within six months, prostate biopsy within one year, and fluoroquinolone (fq) resistance were also investigated. the presence or absence of fq resistance was determined by the culture results of the rectal swab samples obtained two weeks before the biopsy. infectious complications after biopsy were considered present if the patients showed asymptomatic bacteriuria or pyuria, symptomatic uti or prostatitis with or without fever (> 37.8 °c), bacteremia, sepsis, or systemic inflammatory response syndrome (sirs) at any time up to one month after the procedure. sirs was defined by the presence of two of the following clinical findings: body temperature higher than 38 °c or lower than 36 °c, heart rate higher than 90/min, hyperventilation evidenced by a respiratory rate higher than 20/ min or paco2 lower than 32 mmhg, and white blood cell count higher than 12,000/μl or lower than 4,000/ μl.(14) re-hospitalization was defined as re-admission to the hospital due to infectious complications related to the trus-guided prostate biopsy. any additional hospitalization due to other diseases was not included in the data analysis. the length of hospital stay was defined as the total number of days spent in the hospital, excluding hospitalized time due to medical conditions other than the trus-guided biopsy. non-infectious complications after the procedure included pain, hematuria, hematospermia, rectal bleeding, and acute urinary retention (aur). the intensity of pain was measured on the evening of the biopsy using the numeric pain raturological oncology 44 table 1. demographics and clinical characteristics of patients. group i (n = 165) group ii (n = 116) group iii (n = 170) p-value age, year; mean ± sd 68.63 ± 8.11 68.94 ± 8.52 67.49 ± 8.54 .282 prostate volume, cc; mean ± sd 45.48 ± 27 41.57 ± 22.51 36.72 ± 15.59 .001 psa level, ng/ml; median (iqr) 6.4 (3.6-10.5) 6.0 (4.2-10.1) 6.7 (4.3-11.9) .083 diabetes mellitus (%) 30 (18.2) 23 (19.8) 33 (19.4) .932 chronic kidney disease (%) 12 (7.3) 15 (12.9) 29 (17.1) .025 foley catheter insertion state (%) 6 (3.6) 2 (1.7) 3 (1.8) .457 recent antimicrobial use (%) 27 (16.4) 24 (20.7) 24 (14.1) .339 recent hospitalization (%) 16 (9.7) 9 (7.8) 10 (5.9) .427 recent history of uti or prostatitis (%) 10 (6.1) 9 (7.8) 13 (7.6) .809 recent history of prostate biopsy (%) 1 (0.6) 1 (0.9) 3 (1.8) .574 fq resistance (%)a 55 (33.3) 53 (45.7) 89 (52.4) .002 rectal swap culture result .102 e. coli (%) 147 (89.1) 106 (91.4) 144 (84.7) k. pneumonia (%) 2 (1.2) 5 (4.3) 8 (4.7) other (%) 9 (5.5) 5 (4.3) 8 (4.7) no growth (%) 7 (4.2) 0 (0) 10 (5.9) biopsy result .140 bph (%) 99 (60) 55 (47.4) 83 (48.8) prostate cancer (%) 59 (35.8) 52 (44.8) 81 (47.6) asap (%) 4 (2.4) 7 (6.0) 5 (2.9) other (%) 3 (1.8) 2 (1.7) 1 (0.6) abbreviations: psa, prostate specific antigen; iqr, interquartile range; uti, urinary tract infection; fq, fluoroquinolone; bph, benign prostate hyperplasia; asap, atypical small acinar proliferation. aoverall fq resistance was 43.7%. group i (n = 165) group ii (n = 116) group iii (n = 170) p-value overall infectious complications (%) 36 (21.8) 13 (11.2) 11 (6.5) < .001 asymptomatic bacteriuria/pyuria 7 (4.2) 9 (7.8) 4 (2.4) .092 uti or prostatitis without fever 13 (7.9) 1 (0.9) 6 (3.5) .015 uti or prostatitis with fever 10 (6.1) 1 (0.9) 0 (0) .001 bacteremia or sepsis or sirs 6 (3.6) 2 (1.7) 1 (0.6) .133 re-hospitalization (%) 16 (9.7) 3 (2.6) 1 (0.6) < .001 mean length of hospital stay, days; mean ± sd 3.42 ± 1.43 3.22 ± 1.41 3.04 ± 0.54 .012 abbreviations: uti, urinary tract infection; sirs, systemic inflammatory response syndrome. table 2. comparison among three groups with respect to post-procedural infectious complications, re-hospitalization, and mean length of hospital stay rectal cleansing methods in prostate biopsy-lee et al. vol 17 no 01 january-february 2020 45 ing scale (nprs), with an 11-point numeric scale ranging from ‘0’ representing ‘no pain’ to ‘10’ representing ‘worst pain imaginable’.(15) other non-infectious complications were defined as events that developed at any time during the follow-up period of one month. statistical analysis comparison of the incidence of post-procedural complications, re-hospitalization rates, and length of hospital stay among the three groups according to the method of rectal cleansing were assessed using one-way anova for continuous variables and the pearson chisquare test for categorical variables. multiple logistic regression analysis was performed to estimate adjusted odds ratios (ors) to investigate which factors among the baseline clinical characteristics (rectal cleansing method, age, prostate volume, dm, foley catheter insertion, recent antimicrobial use, recent hospitalization, recent history of uti, prostatitis, prostate biopsy, and fq resistance) significantly influenced the incidence of post-procedural infectious complications and re-hospitalization rates. all statistical analyses were performed using ibm spss statistics for windows, version 23.0 (ibm corp., armonk, ny, usa). a p value less than 0.05 was considered significant. results a total of 451 patients enrolled in this study were divided into group i (n = 165), ii (n = 116), and iii (n = 170), respectivey. the mean age of the patients was 68.28 ± 8.38 years, the mean prostate volume was 41.17 ± 22.38 cc, and the median psa level (interquatile range) was 6.5 (4.1-10.8) ng/ml. according to the biopsy, the final diagnosis was benign prostate hyperplasia (n=237, 52.5%), prostate cancer (n = 192, 42.6%), atypical small acinar proliferation (asap) (n = 16, 3.5%), and others (n=6, 1.3%). the results of the rectal swab culture performed before the biopsy were e. coli (n = 397, 88%), k. pneumonia (n=15, 3.3%), others (n=22, 4.9%), and no bacterial growth (n=17, 3.8%). overall, fq resistance was observed in 197 (43.7%) patients. the demographics and clinical characteristics of the patients were compared among the three groups based on a method of rectal cleansing (table 1). the mean prostate volume was significantly smaller in group iii than in groups i and ii (p = .001). the incidence of chronic kidney disease was different among the three groups (p = .025). meanwhile, there were no statistically significant differences among the three groups in terms of age, psa level, dm, foley catheter insertion state, recent antimicrobial use, recent hospitalization, recent history of uti or prostatitis, recent history of prostate biopsy, and biopsy results. overall, post-procedural infectious complications occurred in 60 (13.3%) of 451 patients, among which 36 (21.8%), 13 (11.2%), and 11 (6.5%) cases developed in groups i, ii, and iii, respectively (p < .001) (table 2). the incidence of overall post-procedural infectious complications was significantly lower in groups ii (p = .025) and iii (p < .001) than group i. however, there was no significant difference between groups ii and iii. infectious complications consisted of asymptomatic bacteriuria or pyuria (n = 20, 4.4%), uti or prostatitis without fever (n = 20, 4.4%), uti or prostatitis with fever (n = 11, 2.4%), bacteremia, sepsis, or sirs (n = 9, 2%). e. coli was the cause of bacteremia in all cases (n = 9), among which 50% were fq-resistant e coli. among various post-procedural infectious complications, uti or prostatitis occurred more frequently in group i than in groups ii and iii. re-hospitalization rates were 9.7%, 2.6%, and 0.6% in groups i, ii, and iii, respectively (p < .001). sub-group table 3. comparison among three groups with respect to post-procedural non-infectious complications group i (n = 165) group ii (n = 116) group iii (n = 170) p-value pain, nprs; mean ± sd 1.64 ± 0.86 1.54 ± 0.96 1.49 ± 0.62 .211 hematuria (%) 47 (28.5) 41 (35.3) 45 (26.5) .254 hematospermia (%) 1 (0.6) 1 (0.6) 0 (0) .518 rectal bleeding (%) 4 (2.4) 4 (3.4) 2 (1.2) .429 aur (%) 5 (3) 8 (6.9) 2 (1.2) .029 abbreviations: nprs, numeric pain rating scale; aur, acute urinary retention. or p-value 95% ci rectal cleansing methoda group ii 0.472 .038 0.232–0.958 group iii 0.267 < .001 0.129–0.555 age 1.013 .527 0.974–1.053 prostate volume 0.994 .377 0.980–1.008 diabetes mellitus 0.806 .587 0.369–1.757 chronic kidney disease 2.075 .112 0.844–5.099 foley catheter insertion state 5.509 .016 1.380–22.001 recent antimicrobial use 1.036 .943 0.392–2.737 recent hospitalization 1 .026 .964 0.343–3.068 recent history of uti or prostatitis 1.962 .263 0.603–6.388 recent history of prostate biopsy 2.638 .407 0.266–26.124 fq resistance 0.873 .662 0.474–1.608 abbreviations: or, odds ratio; ci, confidence interval; uti, urinary tract infection; fq, fluoroquinolone. athe reference category is group i. table 4. influence of various clinical characteristics on post-procedural infectious complications rectal cleansing methods in prostate biopsy-lee et al. analysis showed that there were significant differences between groups i and ii (p = .028) and groups i and iii (p < .001). however, there was no significant difference between groups ii and iii. the mean length of hospital stay was 3.42 ± 1.43 days, 3.22 ± 1.41 days, and 3.04 ± 0.54 days in groups i, ii, and iii, respectively. while the mean hospital stay was significantly longer in group i than in group iii (p = .009), there was no significant difference between groups i and ii and groups ii and iii. regarding non-infectious post-procedural complications, the overall nprs was 1.56 ± 0.81. the incidence of hematuria, hematospermia, rectal bleeding, and aur after trus biopsy was 29.5% (n = 133), 0.4% (n = 2), 2.2% (n = 10), and 3.3% (n = 15), respectively (table 3). among these non-infectious complications, the incidence of aur was significantly lower in group iii than ii (p = .029). however, there were no significant differences among the three groups in terms of other non-infectious complications. among the various clinical characteristics including rectal cleansing method, age, prostate volume, dm, foley catheter insertion, recent antimicrobial use, recent hospitalization, recent history of uti, prostatitis, prostate biopsy, and fq resistance, the rectal cleansing method and foley catheter insertion were significant factors for the occurrence of post-procedural infectious complication (table 4). the incidence of post-procedural infectious complications was significantly reduced in group ii (or = 0.472, 95% ci: 0.232-0.958, p = .038) and group iii (or = 0.267, 95% ci: 0.1290.555, p < .001) as compared to group i. in addition, foley catheter insertion state (or = 5.509, 95% ci: 1.380-22.001, p = .016) was an independent predictor of infectious complications after trus biopsy. meanwhile, re-hospitalization rates were significantly influenced by the rectal cleansing method, recent history of uti or prostatitis, and recent history of prostate biopsy (table 5). among the three groups, re-hospitalization rates were significantly lower in group ii (or = 0.247, 95% ci: 0.070-0.869, p = .029) and group iii (or = 0.055, 95% ci: 0.007-0.421, p = .005) than in group i. discussion the human gastrointestinal tract normally harbors numerous microbiomes, and the highest concentration of microbiomes is present in the rectum. damage to the barrier function of the rectal mucosa can result in entrance of viable rectal microbiomes and their virulent products into systemic circulation, which may result in sepsis, sirs, multiple organ dysfunction syndrome, and even death. this phenomenon is called “bacterial translocation”, and various rectal procedures and operations can facilitate translocation of normal microbiomes.(16) however, exactly how the bacterial colonies from the rectum enter directly into the bloodstream, urine, or prostate tissue through the biopsy needle and lead to infectious complications remains to be elucidated. several studies comparing transperineal and transrectal prostate biopsy have suggested that these rectal microbiomes may be closely related to the infectious complications of prostate biopsy.(3,17) the transperineal route for prostate biopsy, which represents an alternative pathway to avoid direct contact with the rectal microbiome, has shown a significantly lower incidence of infectious complications compared to the typical transrectal route.(3) according to a study by grummet el al., the rate of re-hospitalization for infection was zero among 245 patients.(17) furthermore, a systemic review of the literature published from 2003 to 2013 found that transperineal prostate biopsy resulted in only a 0.076% re-hospitalization rate for sepsis,(17) which is significantly lower than that reported for transrectal prostate biopsy.(3,4) however, despite the advantage of a decreased rate of serious infectious complications, transperineal prostate biopsy is not widely used because it is difficult to perform under local anesthesia and incurs relatively higher costs, and requires specialized equipment.(17) therefore, methods that have the potential to minimize the effect of rectal microbiomes in transrectal prostate biopsy are relatively preferred. several studies reported that bowel preparation using a disinfectant agent such as povidone-iodine significantly reduced post-procedural infectious complications,(11,18,19) including a previous study showing that rectal cleansing with povidone-iodine effectively reduced the colony count of rectal microbiomes including fq-resistant e.coli owing to its bactericidal activity.(19) moreover, as compared to antibiotic prophylaxis alone, rectal cleansing using povidone-iodine in addition to antibiotic prophylaxis was shown to be more effective in lowering the incidence of infectious complications following prostate biopsy.(3,5,20) however, a prospective randomized trial reported that although rectal cleansing with povidone-iodine before trus-guided prostate biopsy had led to a 42% decrease in the relative risk of post-procedural infectious complications, it was not table 5. influence of various clinical characteristics on re-hospitalization rates or p-value 95% ci rectal cleansing measurea group ii 0.247 .029 0.070–0.869 group iii 0.055 .005 0.007–0.421 age 0.975 .448 0.914–1.040 prostate volume 0.970 .055 0.941–1.001 diabetes mellitus 2.482 .135 0.753–8.184 chronic kidney disease 2.049 .369 0.429–9.789 foley catheter insertion state 0.455 .628 0.019–11.001 recent antimicrobial use 0.745 .698 0.167–3.331 recent hospitalization 0.922 .926 0.166–5.114 recent history of uti or prostatitis 5.934 .006 1.660–21.214 recent history of prostate biopsy 19.024 .030 1.322–273.824 fq resistance 1.232 .697 0.432–3.513 abbreviations: or, odds ratio; ci, confidence interval; uti, urinary tract infection; fq, fluoroquinolone. athe reference category is group i. rectal cleansing methods in prostate biopsy-lee et al. urological oncology 46 vol 17 no 01 january-february 2020 47 statistically significant.(13) currently, american urological association (aua) and european association of urology guidelines recommend rectal cleansing with povidone-iodine plus antibiotic prophylaxis before transrectal prostate biopsy if the local risk of infectious complications is high.(3,21) regarding the rectal cleansing protocol, a variety of pre-procedural rectal preparation methods have been used thus far.(11-13,18,19,22) ghafoori et al. demonstrated that the injection of povidone-iodine solution into the rectum significantly decreased the rate of post-procedural infectious complications.(11) a study by park et al. claimed that soaking the rectum with a povidone-iodine suppository was more effective than a povidone-iodine enema.(19) chen et al. adopted a direct method of cleansing the rectal mucosa overlying the prostate gland using povidone-iodine gauze that showed a 9.6% reduction in the incidence of post-procedural infectious complications.(22) another study reported that this direct cleansing of the rectal vault and perianal area by povidone-iodine reduced the rate of post-procedural infectious complications by decreasing rectal microbial colonization.(18) in our study, we compared the effectiveness of three rectal cleansing methods for reducing post-procedural infectious complications. the incidence of post-procedural infectious complications and re-hospitalization rates were lowest in patients who underwent direct manual cleansing of the mucosal surface of the anus and lower rectum using forceps and povidone-iodine cotton balls. additionally, this group of patients showed the shortest mean length of hospital stay. thus, our results may positively support the expectation that, among various rectal cleansing methods, direct manual rectal cleansing may be the most effective way to yield a bactericidal effect and decrease rectal microbial colonization before trus-guided prostate biopsy. prophylactic antibiotics is one of the well-known methods of minimizing infectious complications caused by rectal microbiomes in trus-guided prostate biopsy. (23,24) according to aua guidelines, antibiotic prophylaxis is recommended in all patients.(23) in general, fq antibiotics are the most preferable choice of drugs.(21) since e. coli is the etiology of most infectious complications following prostate biopsy, the selection of prophylactic antibiotics focuses on this bacteria.(25) however, despite fq-based prophylaxis, a noticeable increase in the prevalence of multi-resistant organisms including fq-resistant organisms has recently been reported, which has contributed to the increased incidence of infectious complications.(26) therefore, the need for a new prophylactic antibiotics regimen has arisen. currently, targeted antibiotics prophylaxis using a rectal swab is considered one of the more effective regimens. (29,30) according to a meta-analysis, the incidence of infectious complications following transrectal prostate biopsy in the targeted antibiotic prophylaxis group was lower than in the empirical group.(31) however, the usefulness of targeted prophylaxis in preventing post-procedural infectious complications remains controversial. a study by liss et al. found no significant difference in the rate of sepsis between groups receiving targeted prophylaxis versus empirical prophylaxis,(32) and all of the causative organisms of sepsis after prostate biopsy were fq-sensitive e. coli despite adequate fq prophylaxis. in our study, the causative organisms of sepsis were always e coli, of which only 50% were fq-resistant e coli. based on these results, it can be assumed that fq prophylaxis for fq-sensitive e. coli found in the rectal flora does not always prevent sepsis. further investigations are necessary to determine which virulence factors besides fq resistance are involved in post-biopsy sepsis despite sufficient antibiotic prophylaxis.(33,34) recent urinary catheterization is one of the known risk factors for post-procedural infectious complications. simsir et al. reported that the presence of a urinary catheter had predictive risk value for sepsis following trus-guided prostate biopsy because the catheter can become an important mediator of microbial colonization.(35) in our study, recent urinary catheterization increased the risk of overall infectious complications by five-fold. however, given that it is frequently used for short periods of time in most clinical situations, the urinary catheter may be more typically associated with minor infectious complications such as bacteriuria.(36) in our study, the mean prostate volume was significantly smaller in group iii. therefore, there would be a possibility that a difference in baseline prostate size could produce bias or influence on the rate of postprocedural infectious complications. however, in multivariate analysis in our study, no significant association between the prostate volume and infectious complications was found. this result is in agreement with other studies.(3,26) our study has several limitations. first, the study design was retrospective. therefore, it was difficult to definitively assure that all patients underwent the same follow-up assessment. and also, future studies including a randomized clinical trial are needed to validate our results. second, although urinalysis was performed in all patients, additional evaluation including urine culture, blood culture, or other laboratory studies were performed only in symptomatic patients. thus, those who were asymptomatic or had mild symptoms did not undergo these additional studies. conclusions combined with targeted antimicrobial prophylaxis, direct manual cleansing of the mucosal surface of the anus and lower rectum using povidone-iodine cotton balls was most effective in preventing post-procedural infectious complications among the three different rectal cleansing methods. acknowledgement this work was supported by the funds from the national research foundation of korea (2018r1d1a3b07043473) and the chonnam national university hospital research institute of clinical medicine in south korea (cri18091-2). conflict of interest the authors report no conflict of interest. references 1. shariat sf, roehrborn cg. using biopsy to detect prostate cancer. rev urol. 2008;10:26280. 2. liss ma, ehdaie mb, loeb s, et al. an update of the american urological association white paper on the prevention and treatment of the more common complications related to rectal cleansing methods in prostate biopsy-lee et al. prostate biopsy. j urol. 2017;198:329-34. 3. walker jt, singla n, roehrborn cg. reducing infectious complications following transrectal ultrasound-guided prostate biopsy: a systematic review. rev urol. 2016;18:73-89. 4. ryu jw, jung si, ahn jh, et al. povidoneiodine rectal cleansing and targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound-guided prostate biopsy are associated with reduced incidence of postoperative infectious complications. int urol nephrol. 2016;48:1763-70. 5. loeb s, van den heuvel s, zhu x, bangma ch, schröder fh, roobol mj. infectious complications and hospital admissions after prostate biopsy in a european randomized trial. eur urol. 2012;61:1110-4. 6. loeb s, carter hb, berndt si, ricker w, schaeffer em. complications after prostate biopsy: data from seer-medicare. j urol. 2011;186:1830-4. 7. loeb s, vellekoop a, ahmed hu, et al. systematic review of complications of prostate biopsy. eur urol. 2013;64:876-92. 8. valverde a, msika s, kianmanesh r, et al. povidone-iodine vs sodium hypochlorite enema for mechanical preparation before elective open colonic or rectal resection with primary anastomosis: a multicenter randomized controlled trial. arch surg. 2006;141:1168-74. 9. williamson da, barrett lk, rogers ba, freeman jt, hadway p, paterson dl. infectious complications following transrectal ultrasound–guided prostate biopsy: new challenges in the era of multidrug-resistant escherichia coli. clin infect dis. 2013;57:26774. 10. pu c, bai y, yuan h, et al. reducing the risk of infection for transrectal prostate biopsy with povidone–iodine: a systematic review and meta-analysis. int urol nephrol. 2014;46:1691-8. 11. ghafoori m, shakiba m, seifmanesh h, hoseini k. decrease in infection rate following use of povidone-iodine during transrectal ultrasound guided biopsy of the prostate: a double blind randomized clinical trial. iran j radiol. 2012;9:67-70. 12. raman jd, lehman kk, dewan k, kirimanjeswara g. povidone iodine rectal preparation at time of prostate needle biopsy is a simple and reproducible means to reduce risk of procedural infection. j vis exp. 2015:e52670. 13. abughosh z, margolick j, goldenberg sl, et al. a prospective randomized trial of povidone-iodine prophylactic cleansing of the rectum before transrectal ultrasound guided prostate biopsy. j urol. 2013;189:1326-31. 14. bone rc, balk ra, cerra fb, et al. definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. chest. 1992;101:1644-55. 15. jensen mp, mcfarland ca. increasing the reliability and validity of pain intensity measurement in chronic pain patients. pain. 1993;55:195-203. 16. roy j, gatt m. causes of surgical sepsis including bacterial translocation. surgery. 2012;30:645-50. 17. grummet jp, weerakoon m, huang s, et al. sepsis and 'superbugs': should we favour the transperineal over the transrectal approach for prostate biopsy? bju int. 2014;114:384-8. 18. gyorfi jr, otteni c, brown k, et al. periprocedural povidone-iodine rectal preparation reduces microorganism counts and infectious complications following ultrasound-guided needle biopsy of the prostate. world j urol. 2014;32:905-9. 19. park ds, oh jj, lee jh, jang wk, hong yk, hong sk. simple use of the suppository type povidone-iodine can prevent infectious complications in transrectal ultrasound-guided prostate biopsy. adv urol. 2009;2009:750598. 20. hwang ec, jung si, seo yh, et al. risk factors for and prophylactic effect of povidone-iodine rectal cleansing on infectious complications after prostate biopsy: a retrospective cohort study. int urol nephrol. 2015;47:595-601. 21. mottet n, bellmunt j, briers e, et al. eauestro-siog guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent. eur urol. 2017;71:618-29. 22. chen p, chang c, wang b-f, et al. standardized protocol in preventing postoperative infectious complications after transrectal ultrasoundguided prostate biopsy: a retrospective study of 246 patients. urol sci. 2016;27:140-3. 23. wolf js, bennett cj, dmochowski rr, hollenbeck bk, pearle ms, schaeffer aj. best practice policy statement on urologic surgery antimicrobial prophylaxis. j urol. 2008;179:1379-90. 24. zani el, clark oac, rodrigues netto jr n. antibiotic prophylaxis for transrectal prostate biopsy. cochrane database syst rev. 2011;5:cd006576. 25. katouli m. population structure of gut escherichia coli and its role in development of extra-intestinal infections. iran j microbiol. 2010;2:59-72. 26. wagenlehner fm, van oostrum e, tenke p, et al. infective complications after prostate biopsy: outcome of the global prevalence study of infections in urology (gpiu) 2010 and 2011, a prospective multinational multicentre prostate biopsy study. eur urol. 2013;63:521-7. rectal cleansing methods in prostate biopsy-lee et al. urological oncology 48 vol 17 no 01 january-february 2020 49 27. cuevas o, oteo j, lázaro e, et al. significant ecological impact on the progression of fluoroquinolone resistance in escherichia coli with increased community use of moxifloxacin, levofloxacin and amoxicillin/ clavulanic acid. j antimicrob chemother. 2011;66:664-9. 28. carignan a, roussy jf, lapointe v, valiquette l, sabbagh r, pépin j. increasing risk of infectious complications after transrectal ultrasound–guided prostate biopsies: time to reassess antimicrobial prophylaxis? eur urol. 2012;62:453-9. 29. taylor ak, zembower tr, nadler rb, et al. targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound guided prostate biopsy is associated with reduced incidence of postoperative infectious complications and cost of care. j urol. 2012;187:1275-9. 30. duplessis ca, bavaro m, simons mp, et al. rectal cultures before transrectal ultrasoundguided prostate biopsy reduce post-prostatic biopsy infection rates. urology. 2012;79:55661. 31. roberts mj, williamson da, hadway p, doi sa, gardiner ra, paterson dl. baseline prevalence of antimicrobial resistance and subsequent infection following prostate biopsy using empirical or altered prophylaxis: a biasadjusted meta-analysis. int j antimicrob agents. 2014;43:301-9. 32. liss ma, kim w, moskowitz d, szabo rj. comparative effectiveness of targeted vs empirical antibiotic prophylaxis to prevent sepsis from transrectal prostate biopsy: a retrospective analysis. j urol. 2015;194:397402. 33. liss ma, johnson jr, porter sb, et al. clinical and microbiological determinants of infection after transrectal prostate biopsy. clin infect dis. 2015;60:979-87. 34. vaezjalali m, azimi h, hosseini sm, taghavi a, goudarzi h. different strains of bk polyomavirus: vp1 sequences in a group of iranian prostate cancer patients. urol j. 2018;15(2):44-8. 35. simsir a, kismali e, mammadov r, gunaydin g, cal c. is it possible to predict sepsis, the most serious complication in prostate biopsy? urol int. 2010;84:395-9. 36. nicolle le. catheter associated urinary tract infections. antimicrob resist infect control. 2014;3:23. rectal cleansing methods in prostate biopsy-lee et al. endourology and stone disease the fate of residual fragments after retrograde intrarenal surgery in long-term follow-up gokhan atis1, eyyup sabri pelit2, meftun culpan3*, bilal gunaydın1, turgay turan1, yavuz onur danacioglu1, asif yildirim1, turhan caskurlu1 purpose: we aimed to describe the natural history of stone fragments ≤ 7 mm that remained after retrograde intrarenal surgery (rirs) in long-term follow-up. materials and methods: we retrospectively reviewed 142 medical records of patients who had residual fragments (rfs) ≤ 7 mm after rirs. patients were divided into 2 groups according to the size of rfs as ≤ 4 mm (group 1) and 5 – 7 mm (group 2). patients’ demographic data, stone characteristics, perioperative data and complications were recorded. re-growth of rfs, spontaneous passage, renal colic, infection and re-operation rates were our main variables. result: a total of 142 patients (86 in group 1 / 56 in group 2) were followed for mean 54.45 ± 14.24 and 56.22 ± 10.28 months. mean size of rfs was 2.85 ± 1.22 mm in group 1 and 6.81 ≤ 2.21 mm in group 2. mean number of rfs were 1.1 ± 0.2 in group 1 and 2.4 ± 1.6 in group 2 (p = .035). spontaneous passage rate of rfs were 30.23% and 17.85% in group 1 and 2, respectively (p = .032). no difference was observed in the re-growth rate of rfs between the two groups (p = .094). although no difference was observed in re-growth of rfs between the groups, patients in group 2 were more likely to experience stone-related events such as renal colic and re-intervention rate (p = .034, p = .029; respectively). conclusion: our results demonstrate that rfs > 4 mm take higher risk in terms of stone-related events and should be followed up more closely. keywords: natural history; renal stone; residual fragments; rirs; spontaneous passage introduction retrograde intrarenal surgery (rirs) have become a widely used modality with low complication and high success in the treatment of kidney stones in recent years.(1) compared to extracorporal shockwave lithotripsy (eswl), rirs has higher success rate with less pain in the treatment of renal stones ≤ 2 cm.(2) because of its low complication rate compared to the percutaneous nephrolithotomy (pcnl), indications of rirs for the treatment of renal stones have expanded for even stones larger than 2 cm.(3-5). in the current literature, stone free rate (sfr) of rirs procedures were varying between 73.6% and 94.1%; on the other hand, rf rates after rirs procedures range from 5.9% to 26.4%.(6) residual stone fragment (rf) is defined as the remaining fragments after any surgical or non-surgical intervention. rf which is asymptomatic, non-infectious, non-obstructive and ≤ 4 mm in size is accepted as clinically insignificant residual fragments (cirf).(7,8) stone growth and recurrence, urinary tract infection, ureteric obstruction are the potential complications of these rfs.(9,10) with the advancement of modern technologies, minimally invasive methods such as eswl, pcnl, rirs 1istanbul medeniyet university, goztepe training and research hospital, department of urology, istanbul, turkey. 2harran university school of medicine, urology, sanliurfa, tr. 3sirnak silopi state hospital, department of urology, silopi sirnak, turkey. *correspondence: department of urology, silopi state hospital, sırnak, turkey. tel: +90 544 4478995, e-mail: mculpan@gmail.com. received august 2017& accepted april 2018 and laparoscopic procedures are all used more effectively for the treatment of renal stones. however, rfs after these minimally invasive procedures are still a problem during the follow-up. in the literature, complication rates due to the rfs are varying between 18.1% and 59% according to the performed procedures.(10,11) in a prospective study published by streem et al., 18.1% of the fragments were experienced re-growth, 41.9% of the residual fragments were not changed at all and 36% spontaneous passage occurred within the first year after the eswl procedure.(11) altunrende et al. found that 22% of the patients who underwent pcnl operation had residual fragments in a 3-year follow-up, 21.1% of these rfs showed an increase in size, 71,1% of rfs stayed stable or decreased in size and 7.9% patients had spontaneous passage.(12) in the study of ozgor et al., 34% re-growth of cirf was observed after rirs operation in 30-month follow-up period.(13) in the literature, there are several studies about the natural course of cirf after eswl, urs, and pcnl; however, there are not enough clinical trials investigating rf after rirs. in this study, we aimed to describe the natural history of stone fragments smaller than 7 mm that remained after rirs procedures in long-term follow-up. vol 16 no 01 january-february 2019 1 materials and methods we retrospectively reviewed the medical records of 1048 patients who underwent rirs at istanbul medeniyet university goztepe training and research hospital from may 2008 to april 2016. of them, 142 patients who had ≤ 7 mm rf after rirs procedures and at least 12 months follow-up were included into the study. the patients who have asymptomatic residual fragments ≤ 7 mm after the rirs operation at 3 months postoperatively were included for the study. the patients who had residual fragments > 7 mm accepted as a treatment failure and excluded from the study. rfs were detected with computed tomography (ct). the size of multiple residual fragments apart from each other was measured with sum of the long axis of each rf. the patients with unsuccessful rirs procedure and who required a repeated stone removal procedure within three months postoperatively were excluded from the study (figure 1). gender, age, history of eswl or stone surgery, and comorbidities were recorded as patients’ characteristics. preoperative parameters such as stone diameter, numbers, burden, laterality, location and opacity, a presence of renal anomalies, grade of hydronephrosis were evaluated with ct. operation time, hospitalization time, fluoroscopy time, postoperative complications, and number, burden, a location of rfs were also recorded. patients were divided into 2 groups according to the size of rf as ≤ 4 mm and 5-7 mm. re-growth of rfs, spontaneous passage, renal colic, infection and re-operation rates were main outcome variables. serum biochemistry, complete blood count, urine analysis and urine culture were performed for all patients prior to surgery. all patients had sterile urine culture prior to surgery. urinary tract infection was treated according to sensitivity results of the urine culture. the procedures were performed in lithotomy position under general anesthesia. we performed semi rigid ureteroscopy firstly to create the ureteral dilation before placing ureteral access sheath (uas). 7.5 fr flexible ureteroscope (flex-x2, tuttlingen, germany) was advanced through the 9.5 -11 fr uas. the f urs was passed over the guidewire in the case of unsuccessful placement of uas. in all cases, 200 or 273 μm laser fiber was used for stone fragmentation. stones were fragmented into pieces as small as possible and were left spontaneous passage. at the end of the procedure, a double-j (4.7 fr) stent was inserted in all cases. double-j stents were removed 2 4 weeks after the operation. table 1. patient demographics, preoperative and perioperative findings. ≤ 4 mm 5-7 mm mean age (year) 45.4 ± 16.6 39.2 ± 11.4 p = .247 gender (male/female) 58/28 24/32 p = .437 stone opacity (opaque/non-opaque) 72/14 46/10 p = .894 stone size before rirs (mm) 16.36 ±7.1 22.08 ± 7.5 p = .028 stone number 1.14 ± 0.4 1.86 ± 1.8 p = .046 hydronephrosis p = .595 none 32 20 grade 1 26 18 grade 2 14 12 grade 3 14 6 operation time (min) 41.17 ± 14.23 56.21 ± 20.17 p = .044 fluoroscopy time (min) 3.02 ± 2.34 3.22 ± 4.07 p = .760 hospitalization time (day) 1.68 ± 2.95 1.81 ± 3.04 p = .685 mean follow-up (month) 54.45 ± 14.24 56.22 ± 10.28 p =. 087 data is presented as mean ± sd or number (percent) ≤ 4 mm 5-7mm mean rf burden (mm) 2.85 ± 1.22 6.81 ± 2.21 p = .004 mean rf number 1.1 ± 0.2 2.4 ± 1.6 p = .035 spontaneous passage 26/86 (30.23%) 10/56 (17.85) p = .032 lower pole 6/36 (16.6%) 2/18 (11.1%) middle/upper pole 10/32 (31.25%) 2/22 (9.09%) multiple calix 4/8 (50%) 2/10 (20%) renal pelvis 6/10 (60%) 4/6 (66.6%) re-growth 18 (20.93%) 12 (21.42%) p = .094 lower pole 7 5 middle/upper pole 4 3 multiple calix 7 4 renal pelvis renal colic 24 (27.90% ) 8 (14.28%) p = .034 urinary infection 6 (6.97%) 4 (7.14%) p = .083 re-operation 16 (18.60%) 18 (32.14%) p = .029 eswl 8 8 pcnl 0 2 f-urs 4 4 urs 2 4 dj stent insertion and delayed urs because of urosepsis 2 0 data is presented as mean ± sd or number (percent) table 2. rf characteristics and postoperative follow-up data. fate of residual fragments after rirs – atis et al. endourology and stone diseases 2 vol 16 no 01 january-february 2019 3 we performed ct in the 3rd months of follow-up. patients were accepted as stone-free when there was no residual fragments on ct on follow-up. the frequency of visits and imaging methods (ct / ultrasonography or kidney-ureter-bladder x-ray) to be used in each visit was determined according to rf burden, localization, and the presence of obstruction and symptoms of patients during the follow-up. if the patient had rf and was asymptomatic, ct scan performed yearly. if available, stone analyses were done and all patients underwent a metabolic evaluation at 1 month postoperatively. dietary suggestions were made for all patients and if necessary patients treated with appropriate medical treatment according to metabolic evaluation or stone analysis. statistical analyses were performed via spss software, version 21.0 (ibm, armonk, ny). the data were expressed as the mean ± standard deviation or frequency. the kolmogorov-smirnov test was used to test the normal distribution of the variables. the categorical variables were compared with the chi squared test, and the continuous variables were compared with an unpaired t test or the mann–whitney u test. a p value ≤ 0.05 was considered to be significant. results in our study rf rate was detected %13.54 (142 / 1048). a total of 142 patients (86 in group 1 / 56 in group 2) were followed for a mean of 54.45 ± 14.24 and 56.22 ± 10.28 months respectively. mean stone size and number before the operation were 16.36 ± 7.1 mm and 1.14 ± 0.4 in group 1, 22.08 ± 7.5 mm and 1.86 ± 1.8 in group 2, respectively (p = .028 / p = .046). the pre-operative and operative characteristics of patients were summarized in table 1. mean size was 2.85 ± 1.22 mm in group 1 and 6.81± 2.21 mm in group 2. mean number of rfs was 1.1 ± 0.2 in group 1 and 2.4 ± 1.6 in group 2 (p = .035). spontaneous passage rate of rfs were 30.23% and 17.85% in group 1 and 2, respectively (p = .032). no differences were observed in the re-growth rate of rfs between the two groups (p = .094). although no difference was observed in re-growth rate between the two groups, patients in group 2 were more likely to experience stone related events such as renal colic and re-intervention (p = .034, p = 0.029; respectively). a total of 16 patients in group 1 and 18 patients in group 2 needed additional procedures (table 2). the stone analysis was available for 60 and 40 patients in group 1 and 2, respectively. the stone analysis results are shown in table 3. discussion rfs that are asymptomatic, non-infectious, non-obstructive and in ≤ 4 mm size is generally accepted as cirf.(7) this term is not accepted as an innocent definition by some authors because almost 59% of these fragments require re-admission to the hospital.(10) however, there are not enough studies evaluating the natural course of rfs after endourological procedures. herein we both evaluated the natural course of rfs after the rirs procedures in long-term follow-up and also compared rfs according to the size in terms of spontaneous passage, stone-related events and reintervention rates. there are several studies describing the natural course of rfs after pcnl and eswl. high stone burdens, multiple access requirements, stone location in different calyces, restriction of visualization due to hemorrhage during the operation were some of the reasons of the rfs after pcnl. fragmentation technique in pcnl (ultrasonic or pneumatic) was another reason of the high rfs rates according to some studies.(14,15) but, conversely to these studies in a prospective research radfar mh et al reported that there were no statistically significant differences in rfs rates between pneumatic and ultrasonic lithotripsy.(16) in a study conducted by ganpule et al., 7.57% rf was observed and, 65.47% of these rfs spontaneously passaged after 3 months. they found that rfs smaller than 25 mm2 and the renal pelvis localization had the highest chance of spontaneous passage.(6) raman et al. reported 8% rfs rate in the patients who underwent pcnl procedure.(17) 42.8% of patients with residual fragments were found to have stone-related symptoms during the follow-up and 26% of these patients required secondary intervention. the rate of symptomatic attack and secondary intervention due to residual fragment was found to be higher in stones localized in renal pelvis and ureter and in patients with rf greater than 2 mm.(17) in our study, similarly to the literature regarding natural course of rfs after pcnl, spontaneous passage rate was higher in patients with rfs smaller than 4 mm and rfs located in the renal pelvis. moreover, the re-intervention rate was higher in rfs larger than 4 mm. the rate of residual fragment detection after eswl procedures is still quite high. it is proved that the stones larger than 20 mm, increased stone number, cystine-brushite-calcium oxalate monohydrate stone types were the negative predictive factors that affect the rf table 3. stone analysis results. stone analysis results ≤ 4 mm 5-7 mm unknown 26 (30.23%) 16 (28.57%) ca oxalate/phosphate 28 (32.55%) 18 (32.14%) uric acid 8 (9.30%) 4 (7.14%) cystine 6 (6.97%) 8 (14.28%) struvite 6 (6.97) 2 (3.57%) mixed 12 (13.95%) 8 (14.28%) figure 1. trial flow diagram fate of residual fragments after rirs – atis et al. rates after eswl procedures.(18,19) in the literature, stone events due to rf after eswl procedures have been reported between 18.1% and 59%.(10,11) in a prospective study published by streem et al., 160 patients with rfs were followed up for 89 months and re-growth of rfs was detected in 18.1% of these patients, 41.9% of the rfs were unchanged and spontaneous passages was observed in 36%.(11) in contrary to the reported natural course of rfs after eswl, re-intervention rates in our study were lower in even rfs ≤ 4 mm group than the reported re-intervention rates after eswl. we thought that higher spontaneous passage rates after rirs compared to eswl may be due to passive ureteral dilatation effect of double-j stent insertion after rirs. since rirs is a new treatment modality, there are not enough studies in the literature regarding the fate of rfs after the rirs procedures. ozgor et al. reported a 34% re-growth rate in 44 patients in 30-month of follow-up period.(13) rebuck et al. showed that 19.6% of the patients with rfs had a stone-related attack in 19.9 months of follow-up period.(20) in a study conducted by chew et al. with the participation of 6 centers, the data of 232 patients with rf after rirs were retrospectively reviewed.(21) fifty six percent of these patients did not need additional intervention and remained asymptomatic, 15% had experienced a stone-related attack without a need of additional intervention and 29% had undergone an additional intervention. moreover, patients with rf larger than 4 mm were found to have a higher risk of recurrence and stone related events. similar to these studies, in our study, we detected a positive correlation between the rf size and the re-intervention rate. however, there was no statistically significant difference in growth rate between the two comparison groups of rf size. this may be explained by the follow-up with appropriate medical treatment. pelvicalyceal anatomy and the calyceal localization of the rfs are well-known factors that may affect the spontaneous passage rate. several studies have shown lower clearance rates in rfs located in the lower calyces than in the middle and/or upper calyces.(22,23) in contrast, rebuck et al. reported that there was no difference in the spontaneous passage rates between the rfs located in lower and non-lower pole.(20) in our study, we observed the highest spontaneous passage rates in renal pelvis than the other calyceal localizations. different fragmentation techniques such as dusting and drilling have been used to treat renal stones ureteroscopically. chew et al. found that patients treated with dusting techniques had a shorter time to a subsequent stone event than patients treated with drilling and basketing technique.(21) in our study group, stones were fragmented into pieces as small as possible and were left spontaneous passage. the superiority of a fragmentation technique over the other technique has not been proven yet in terms of the natural course of rfs. (24) further studies are needed to compare the fragmentation techniques to determine the effect of fragmentation technique over the natural course of rfs. our study has some limitations. the main limitation of the study is its retrospective nature, which may result in differences in follow-up protocol such as frequency of visits and used imaging methods. in addition, despite the same surgical and fragmentation techniques were used in all cases, different surgeons were involved in the procedures. lastly in our study all patients had received dietary instructions and some of them specific medical treatment. this might affect the re-growth rate and the absence of difference between the two groups regarding growth rate might have been the result of the specific medical treatment. despite these limitations, the present study is one of the largest series in the english literature and has the longest follow-up period, which evaluates the natural course of rfs. conclusions our results demonstrate that vast majority of rfs ≤ 4mm passed spontaneously or remained unchanged. however spontaneous passage rates of rfs in 5 7 mm in size were lower and re-intervention rates were higher than rfs ≤ 4 mm in size. moreover, there were no statistically significant differences in re-growth rates and urinary tract infections between the rfs ≤ 4 mm and 5 7 mm. taken together, our results suggest that rfs larger than 4 mm take higher risk in terms of stone-related events and should be followed up more closely. conflict of interest the authors declare that they have no conflict of interest. references 1. van cleynenbreugel b, kilic o, akand m. retrograde intrarenal surgery for renal stones part 1. turk j urol. 2017;43:112–21. 2. javanmard b, kashi ah, mazloomfard mm, jafari aa, saeed a. retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j. 2016;13:2823–8. 3. atis g, culpan m, pelit es, et al. comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery in treating 20-40 mm renal stones. urol j. 2017;14:2995-9. 4. karakoc o, karakeci a, ozan t, et al. comparison of retrograde intrarenal surgery and percutaneous nephrolithotomy for the treatment of renal stones greater than 2 cm. turk j urol. 2015;41:73–7. 5. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015;67:125–37. 6. ganpule a, desai m. fate of residual stones after percutaneous nephrolithotomy: a critical analysis. j endourol. 2009;23:399–403. 7. candau c, saussine c, lang h, roy c, faure f, jacqmin d. natural history of residual renal stone fragments after eswl. eur urol. 2000;37:18–22. 8. delvecchio fc, preminger gm. management of residual stones. urol clin north am. 2000;27:347–54. 9. osman mm, alfano y, kamp s, et al. 5-year-follow-up of patients with clinically fate of residual fragments after rirs – atis et al. endourology and stone diseases 4 vol 16 no 01 january-february 2019 5 insignificant residual fragments after extracorporeal shockwave lithotripsy. eur urol. 2005;47:860–4. 10. khaitan a, gupta np, hemal ak, dogra pn, seth a, aron m. post-eswl, clinically insignificant residual stones: reality or myth? urology. 2002;59:20–4. 11. streem sb, yost a, mascha e. clinical implications of clinically insignificant stone fragments after extracorporeal shock wave lithotripsy. j urol. 1996;155:1186–90. 12. altunrende f, tefekli a, stein rj, et al. clinically insignificant residual fragments after percutaneous nephrolithotomy: mediumterm follow-up. j endourol. 2011;25:941–5. 13. ozgor f, simsek a, binbay m, et al. clinically insignificant residual fragments after flexible ureterorenoscopy: medium-term follow-up results. urolithiasis. 2014;42:533–8. 14. zengin k, sener nc, bas o, nalbant i, alisir i. comparison of pneumatic, ultrasonic and combination lithotripters in percutaneous nephrolithotripsy. int braz j urol. 2014;40:650–5. 15. karakan t, diri a, hascicek am, ozgur bc, ozcan s, eroglu m. comparison of ultrasonic and pneumatic intracorporeal lithotripsy techniques during percutaneous nephrolithotomy. sci world j. 2013;2013:10– 3. 16. radfar mh, basiri a, nouralizadeh a, et al. comparing the efficacy and safety of ultrasonic versus pneumatic lithotripsy in percutaneous nephrolithotomy : a randomized clinical trial. eur urol focus. 2017;3:82–8. 17. raman jd, bagrodia a, gupta a, et al. natural history of residual fragments following percutaneous nephrostolithotomy. j urol. 2009;181:1163–8. 18. skolarikos a, mitsogiannis h, deliveliotis c. indications, prediction of success and methods to improve outcome of shock wave lithotripsy of renal and upper ureteral calculi. arch ital urol androl. 2010;82:56–63. 19. cicerello e, merlo f, maccatrozzo l. management of clinically insignificant residual fragments following shock wave lithotripsy. adv urol. 2012;2012:320104. 20. rebuck da, macejko a, bhalani v, ramos p, nadler rb. the natural history of renal stone fragments following ureteroscopy. urology. 2011;77:564–8. 21. chew bh, brotherhood hl, sur rl, et al. natural history, complications and reintervention rates of asymptomatic residual stone fragments after ureteroscopy: a report from the edge research consortium. j urol. 2016;195:982–6. 22. drach gw, dretler s, fair w, et al. report of the united states cooperative study of extracorporeal shock wave lithotripsy. j urol. 1986;135:1127–33. 23. psihramis ke, jewett ma, bombardier c, caron d, ryan m. lithostar extracorporeal shock wave lithotripsy: the first 1,000 patients. toronto lithotripsy associates. j urol. 1992;147:1006–9. 24. ghani kr, wolf jsj. what is the stone-free rate following flexible ureteroscopy for kidney stones? nat rev urol. 2015;12:281–8. fate of residual fragments after rirs – atis et al. case report 303urology journal vol 6 no 4 autumn 2009 extramammary paget’s disease in prostate amit kumar yadav, richa gupta, usha rani singh urol j. 2009;6:303-5. www.uj.unrc.ir keywords: extramammary paget’s disease, prostatic neoplasms, tissue polypeptide antigen department of pathology, university college of medical sciences, new delhi, india corresponding author: amit kumar yadav, md department of pathology, university college of medical sciences, dilshad garden, new delhi – 110095, india tel: +91 11 2258 6262 e-mail: amityadav7284@yahoo.co.in received october 2008 accepted february 2009 introduction extramammary paget’s disease is a condition morphologically similar to paget’s disease in the breast, but occurs outside the breast. it is an uncommon condition as compared to its mammary counterpart. it most commonly affects the vulva, less commonly the male genital area or the perianal area.(1,2) to the best of our knowledge, extramammary paget’s disease has not been described in prostate previously. we therefore report this particular case. case report a 70-year-old male presented to the surgery outpatient department with complaints of dribbling micturition and nocturia since 2 years earlier. there was also a history of episodes of urinary retention which had been relieved by catheterization. the patient had received medical therapy on 2 occasions; however, it failed to bring any relief to the patient. transrectal ultrasonography showed an enlarged prostate weighed 37 g. serum prostatespecific antigen level was 3.4 ng/ ml. based on the above clinical presentation, a decision to carry out transurethral resection of the prostate was made. multiple prostatic chips together measuring 6 × 4 × 2 cm were received in the histopathology department. microscopic examination predominantly showed features of nodular hyperplasia of the prostate (figure 1), with a single bit of tissue lined by stratified squamous epithelium, showing paget’s cells within the epidermis (figures 2 and 3). these cells were found to be more in number in the lower layers figure 2. single tissue bit lined by stratified squamous epithelium showing paget’s cells in the lower layers of epidermis (× 100). figure 1. morphological features of nodular hyperplasia prostate (× 100). paget’s disease in prostate—yadav et al 304 urology journal vol 6 no 4 autumn 2009 of the epidermis as compared to the upper layers. the paget’s cells were present as single isolated cells or in small groups. they were enlarged and had large nuclei with pale cytoplasm. in view of the above morphological features, a diagnosis of extramammary paget’s disease was made. we considered the possibility of invasion to the urinary bladder, prostate, external genitalia, and anal canal. cystoscopic examination of the bladder did not reveal any visible growth in the bladder. the prostatic tissue submitted in the specimen also did not demonstrate any evidence of malignancy. physical examination of the external genitalia and the anal canal did not reveal any visible growth. immunohistochemistry was then performed on the tissue sections using cytokeratin 7 (ck7) and cytokeratin 20 (ck20) antibodies. the paget’s cells were weakly positive for ck7, interpreted as negative (figure 4) and negative for ck20 (figure 5). based on the above immunohistochemistry findings, a primary prostatic origin of extramammary paget’s disease was suggested. a thorough physical examination and detailed investigations carried out did not reveal any associated pathologic findings. discussion paget’s disease most commonly affects the vulva, and less commonly, the male genital area or the perianal area. in exceptional cases only, the axilla, the region of the ceruminous glands, or that of moll’s glands are reported to be affected by extramammary paget’s disease.(3,4) in cases with the involvement of the axilla, the genital area may also be affected. thus, extramammary paget’s disease involves areas in which apocrine glands are normally encountered. in the rare instances, extramammary paget’s disease is a secondary event caused by extension of an adenocarcinoma either of the rectum to the perianal region, of the cervix to the vulvar region, or of the urinary bladder to the urethra and glans penis, or to the groin.(2,5-8) extramammary paget’s disease has not been reported previously in the prostate (transurethral resection of the prostate chips). however, various authors have reported cases of carcinoma originating in ducts surrounding the prostatic urethra and in intraductal carcinoma. (9,10) ullman and ross(11) described features of hyperplasia, atypia, and carcinoma in situ in prostatic periurethral glands. transitional cell carcinoma has also been reported in the prostate, previously. (12-15) immunohistochemical findings of figure 4. paget’s cells showing weak positivity for cytokeratin 7 (× 400). figure 3. paget’s cells in higher magnification (× 400). figure 5. paget’s cells negative with cytokeratin 20 (× 400). paget’s disease in prostate—yadav et al urology journal vol 6 no 4 autumn 2009 305 ck7/ck20helped us suggest a diagnosis in this case. lopez-beltran and coworkers(16) suggested that a panel of immunostains including ck7/ ck20 might assist in differentiating urothelial carcinoma (ck7+/ck20+) from extramammary paget’s disease of anorectal origin which is known to be ck7+/ck20-. as the present case was negative for both ck7 and ck20, possibility of a prostatic origin was suggested. powell and colleagues(17) suggested that genital extramammary paget’s disease could represent concurrence of two separate malignancies. conflict of interest none declared. references 1. murrell tw, jr., mc mullan fh. extramammary paget’s disease. a report of two cases. arch dermatol. 1962;85:600-13. 2. helwig eb, graham jh. anogenital (extramammary) paget’s disease. a clinicopathological study. cancer. 1963;16:387-403. 3. fligiel z, kaneko m. extramammary paget’s disease of the external ear canal in association with ceruminous gland carcinoma. a case report. cancer. 1975;36:1072-6. 4. whorton cm, patterson jb. carcinoma of moll’s glands with extramammary paget’s disease of the eyelid. cancer. 1955;8:1009-15. 5. mckee ph, hertogs kt. endocervical adenocarcinoma and vulval paget’s disease: a significant association. br j dermatol. 1980;103:443-8. 6. metcalf js, lee re, maize jc. epidermotropic urothelial carcinoma involving the glans penis. arch dermatol. 1985;121:532-4. 7. ikezawa z, ohashi y, nakajima h, nagai r, matsuoka s. an unusual case of extramammary paget’s disease. paget’s disease of the glans penis probably originating from a prostatic duct carcinoma (transitional cell carcinoma of the prostate). j dermatol. 1977;4:19-25. 8. ojeda vj, heenan pj, watson sh. paget’s disease of the groin associated with adenocarcinoma of the urinary bladder. j cutan pathol. 1987;14:227-31. 9. ende n, woods lp, shelley hs. carcinoma originating in ducts surrounding the prostatic urethra. am j clin pathol. 1963;40:183-9. 10. rhamy rk, buchanan rd, spalding mj. intraductal carcinoma of the prostate gland. j urol. 1973;109: 457-60. 11. ullmann as, ross oa. hyperplasia, atypism, and carcinoma in situ in prostatic periurethral glands. am j clin pathol. 1967;47:497-504. 12. karpas cm, moumgis b. primary transitional cell carcinoma of prostate gland: possible pathogenesis and relationship to reserve cell hyperplasia of prostatic periurethral ducts. j urol. 1969;101:201-5. 13. rubenstein ab, rubnitz me. transitional cell carcinoma of the prostate. cancer. 1969;24:543-6. 14. bates hr, jr. transitional cell carcinoma of the prostate. j urol. 1969;101:206-7. 15. johnson de, hogan jm, ayala ag. transitional cell carcinoma of the prostate. a clinical morphological study. cancer. 1972;29:287-93. 16. lopez-beltran a, luque rj, moreno a, bollito e, carmona e, montironi r. the pagetoid variant of bladder urothelial carcinoma in situ a clinicopathological study of 11 cases. virchows arch. 2002;441:148-53. 17. powell fc, bjornsson j, doyle ja, cooper aj. genital paget’s disease and urinary tract malignancy. j am acad dermatol. 1985;13:84-90. the effect of heroin addiction on human sperm parameters, histone-to-protamine transition, and serum sexual hormones levels zohreh nazmara1, mohammad najafi2,3, samira rezaei-mojaz1, mansoureh movahedin4, zahara zandieh1,5, peymaneh shirinbayan6, mohsen roshanpajouh7, hamid reza asgari1, leila hosseini jafari lavasani8, morteza koruji1, 2* purpose: to investigate the effects of heroin on sperm parameters, histone-to-protamine transition ratios in mature sperm, and serum reproductive hormone levels in active heroin users. materials and methods: semen and blood samples were collected from 25 men who used only heroin for at least 12 months and the same number healthy men who did not use any drugs and did not suffer from infertility problems. computer-based analysis, aniline blue staining, and hormonal assessment were performed to provide valuable new information on the relationship between addiction and semen profile and serum reproductive hormone levels. results: our finding showed that semen ph (7.8 vs. 7.75), sperm motility (42.93 ± 3.89% vs. 68.9 ± 2.68%), and viability (73.27 ± 3.85% vs. 86.48 ± 1.05%), and sperm histone replacement abnormalities (32.33 ± 10.89% vs. 5.56 ± 0.85%) were significant differences in addicted group vs. non-exposed ones (p ≤ .05). in addition, serum sex hormone levels were not significantly differed between groups. there was a correlation between the amount of daily heroin consumption and lh level. we also observed that duration of drug dependence is correlated with sperm abnormalities. conclusion: we concluded that heroin consumption affect sperm maturities such as histone-to-protamine ratio and impair semen profile in general and particularly sperm morphology and motility. heroin may be considered as one of the idiopathic male infertility reason. keywords: heroin addiction; histone-to-protamine transition; sexual hormones; sperm parameters introduction addiction as a medical problem in the world is de-veloping among young people(1). based on formal statistics there are more than 2 million addicted people in iran that one-third of them use heroin(2-4). prescription opioid narcotics such as heroin can result in intoxication, medical, and social problems(5). toxins are considered as important risk factors in the reproductive biology(6). however, prescription opioid narcotics as the well-known toxins, may be interfere with male fertility (7) and sperm parameters, specifically sperm motility, decrease with the use of heroin(8). use of illicit drugs appears to have a negative impact on fertility, though more in-depth research in this area is required to make a clear link. previous studies showed that addiction has decreased 1 department of anatomical sciences, school of medicine, iran university of medical sciences, tehran, iran. 2 cellular and molecular research center, iran university of medical sciences, tehran, iran. 3 department of biochemistry, school of medicine, iran university of medical sciences, tehran, iran. 4 anatomical sciences department, faculty of medical sciences, tarbiat modares university, tehran, iran. 5shahid akbarabadi clinical research development unit( shacrdu), iran university of medical sciences, tehran, iran. 6 pediatric neuro-rehabilitation research center, university of social welfare and rehabilitation sciences, tehran, iran. 7 school of behavioral sciences & mental health, tehran psychiatry institute, iran university of medical sciences, tehran, iran. 8 department of microbiology, biology science faculty, north tehran branch, islamic azad university, tehran, iran. *correspondence: cellular and molecular research center & department of anatomical sciences, school of medicine, iran university of medical sciences (iums), hemmat highway, p. o. box 14155-5983, tehran, iran. tel & fax: +98 21 88622689. email: koruji.m@iums.ac.ir. received december 2017 & accepted february 2018 male fertility capacity with damage to sperm motility and normal morphology(9,10). also, it could retard preimplantation development and induces apoptosis in embryos of addicted mice(11). accurate deoxyribonucleic acid (dna) packaging is one of the most important factors in the health of sperm motility and morphology. spermatozoa dna is about ten times more compact than the somatic cells(12). chromatin compaction in mature sperm is facilitated with histone to protamine replacement. in human mature sperm, the histone-to-protamine substitute rate is between 80 to 85%. some reports have demonstrated that cigarette smoking can affect this replacement and result in abnormal sperm morphology and motility(13). kerack and heroin addiction have decreased sperm motility and normal morphology in mice(14,15). sexual dysfunction and andrology sexual dysfunction and andrology 289 vol 16 no 03 may-june 2019 290 on the other hand, the amount of serum sexual hormones is correlated with the usage of illicit drugs. there is controversy in hormonal levels in human studies because of opiate administration route, types of opiate, the amount of usage per day, last time of opiate usage, and history of addiction(9,10). however, in animal studies, many reports have described the correlation between decreased reproductive hormones and addiction (16,17). the aim of this study was to evaluate the effect of heroin on semen quality such as sperm motility and morphology, histone-to-protamine transition, and serum sexual hormone levels among active heroin users. since the correlation among addiction, semen profile and sperm maturity were unknown, we focused on this subject. also, we assessed some new sperm parameters. materials and methods study population the medical ethics committee of iran university of medical science approved this study (code: ir.iums. rec.1394.9211313202). the study requirements were carefully explained to participants and all subjects were interviewed after written informed consent, which was conducted in accordance with the declaration of helsinki. the data on personal information, history of addiction, and medical status were collected via a structured questionnaire. twenty-five 20-50-year-old men with normal body mass index (bmi) were screened for eligibility addiction in the addicted group. they were enrolled from addiction treatment centers before entering to treatment programs. recruited men were required to meet diagnostic and statistical manual of mental disorders (dsmo-v) criteria for addiction. based on their medical records and questionnaires they were just using heroin for at least 12 months and were not taking other drugs during this period. since we did not have any information about their infertility situation before addiction, it was considered as a limitation of the study. in this study we could not follow up the members of addicted group during the biological sample collection. non-exposed group consisted of 25 healthy age-bmi-matched male volunteers without any addiction history. they were healthy male partners of married couples without illicit drug consumption who had attended the shahid akbar-abadi obstetrics and gynecology hospital of the iran university of medical science for female infertility consultation. subjects with medical problems associated with subfertility were excluded from our study. other exclusion criteria were taking of any other illicit-drug in at least 1 year ago in the addicted group and taking of any type of drugs in non-exposed ones. inclusion and exclusion criteria volunteers were participated in the study if they were between 20 and 50 years. none of the participants had known medical or surgical condition that could influence their fertility. in non-exposed group participants had normal semen profile who had attended the shahid akbar-abadi obstetrics and gynecology hospital (tehran, iran) for female infertility consultation. in this group, subjects with a history of any genitourinary surgery, azoospermia, epididymo-orchitis, varicocele, cryptorchidism, and alcohol consumption were excluded from study. in addicted men, all members used only heroin at least for one year. men who consumed heroin and other drugs simultaneously were excluded from study. other exclusion criteria was normal body mass index (18.5 25). andrology parameters in heroin users-nazmara et al. table 1. demographic and seminal data in the study population parameter non-exposed group addicted group p-value mean ± sd (min-max/median) mean ± sd (min-max/median) demographic data age (year) 34.81 ± 1.53 33.15 ± 1.85 .51 bmi (kg/m2) 25.85 ± .70 22.30 ± .36 .001 smoking (yes/no) (4/25) (25/0) .001 duration of dependence (year) (2-32/12) duration of heroin consumption (year) (1-25/5) heroin use (mg/day) (0.5-5/1) seminal parameters semen physical parameters volume (ml) 4.1 ± .45 3.09 ± .35 .08 agglutination (0-2/0) (0-1/0) 0.88 aggregation (0-2/0) (0-3/0) .57 semen ph (7.5-8/7.8) (7.2-7.9/7.75) .001 sperm concentration (×106/ml) 156.77 ± 35.56 158.14 ± 40.34 .98 viability (%) 86.48 ± 1.05 73.27 ± 3.85 .01 sperm motility (%) total 68.9 ± 2.68 42.93 ± 3.89 .001 progressive 38.35 ± 3.5 22.69 ± 3.32 .003 abnormal morphology (%) total 6.67 ± 0.67 88.12 ± 5.1 .001 head 3.67 ± 0.88 74.62 ± 3.47 .001 tail 3 ± 1 13.5 ± 2.51 .037 histone-to-protamine ratios 5.56 ± 0.85 32.33 ± 10.89 .05 appearance of blood cells in semen (×106/ml) wbc 1.48 ± 0.37 9.26 ± 1.86 .001 rbc (0-0.9/ .5) (0-4.1/ .5) .2 appearance of other cells in semen (×106/ml) germ (0-1/0) (0-1/0) .28 round (0-7.9/1.5) (0-11.1/2) .86 semen collection and computer-assisted sperm analysis (casa) analysis: semen was collected in sterile containers from participants by masturbation after 2 to 5 days of sexual abstinence. samples incubated at 37 °c for at least 30 minutes and analyzed by semen collection and computer-assisted sperm analysis (casa) according to 2010 world health organization (who) criteria for semen volume, ph, viscosity, agglutination, aggregation, the appearance of other cells in semen such as blood cells, round cells, and germinal ones, sperm concentration and their vitality, sperm morphology and sperm motility. aniline blue staining aniline blue was used to detect the immature spermatozoa with excessive histones. briefly, 10 µl of washed spermatozoa were spread onto the slides. dried smears were fixed in 3% buffered glutaraldehyde in 0.2 m phosphate buffer (ph 7.2) for 30 minutes. slides were stained with1% aniline blue mixed with 4% acetic acid (ph 3.5) for 5 minutes. then the staining slides were washed in running water for at least 3 minutes and dehydrated in a graded ethanol for 2 minutes in each step. finally, slides were cleared by xylene for at least 30 minutes and were mounting by a drop of entelan and were dried overnight at room temperature. at least 200 sperm cells per slide were evaluated under light microscopy with an objective lens (×100) and the percentage of stained sperm heads was calculated. hormone assessment peripheral blood of participants (5ml) was collected in the morning after eating breakfast and before semen collection. samples centrifuged for 10 min at 4°c and 3000 rpm. the serum concentrations of estradiol (e2), luteinizing hormone (lh), follicle stimulating hormone (fsh), and prolactin (prl) were determined by elisa kits and elisa reader. serum testosterone (t) levels were measured by chemiluminescent enzyme immunoassay. statistical analysis statistical analysis was done with a statistical software package (ver. 16.0, chicago, spss inc.). the parametric distribution was evaluated with kolmogorov-smirnov test. the differences between groups were determined by independent-samples t-test and man-whitney u. the partial correlation analyses were performed between heroin consumption and other parameters. p-value ≤ .05 was proposed to be significant. results demographic information demographic information of study population is shown in table 1. there was no significant difference in the mean age between 2 groups. although bmis were in the normal range in both groups, this parameter in the addicted men (22.3 ± 0.36 kg/m2) was significantly lower than the non-exposed group (25.85 ± 0.7 kg/m2) (p ≤ .01). all subjects in the addicted group were smoker, so there was a statistical difference between groups (p ≤ .01). semen analysis although semen volume and its viscosity, agglutination, aggregation, sperm concentration, the appearance of germ and round cells in semen were the same between groups, the amount of white blood cell (wbc) table 2. partial correlation between duration of dependence, the amount of heroin consumption and some study variables. parameters correlation p-value duration of drug dependence (year) semen ph -0.464 .007 sperm total motility (%) -0.370 .037 lh (miu) -0.428 .018 wbc (%) 0.396 .025 duration of heroin dependence (year) sperm abnormal morphology (%) 0.996 .05 the amount of heroin consumption (mg/day) ph 0.334 .05 lh (miu) 0.408 .025 these correlations were adjusted for age, bmi, and cigarette smoking status. figure 1. aniline blue staining for detection of the histone-to-protamine ratio in sperm nucleus. the sperm cells with increased histone-to-protamine ratios are shown by arrow in (a) healthy and (b) addicted men. positive staining shows the nucleus packaging abnormality in sperms. andrology parameters in heroin users-nazmara et al. sexual dysfunction and andrology 291 vol 16 no 03 may-june 2019 292 in semen and abnormal morphology were statistically different between addicted group and non-exposed ones (9.26 ± 1.86 vs. 1.48 ± 0.37 ×106/ml, 88.12 ± 5.1 vs. 6.67 ± 0.67 % respectively; p ≤ .01). semen ph (7.2-7.9 vs. 7.5-8) and sperm viability and motility (73.27 ± 3.85 vs. 86.48 ± 1.05 % and 42.93 ± 3.89 vs. 68.9 ± 2.68 % respectively) in the addicted group were significantly lower than non-exposed ones (p ≤ .01) (table 1). sperm nuclear histone-to-protamine ratios the sperm cells with increased histone-to-protamine ratios are shown by the arrow in non-exposed (figure 1.a) and addicted group (figure 1. b). there was a significant higher histone replacement abnormality in addicted group than non-exposed ones (32.33 ± 10.89 vs 5.56 ± 0.85 %; p ˂ .01) (table 1). sexual hormones analysis as shown in figure 2, mean serum levels of lh (4.36 ± 0.4 vs. 4.72 ± 0.53 miu/ml), fsh (3.07 ± 0.59 vs. 3.27 ± 0.41 miu/ml), e2 (24.06 ± 2.01 vs. 30.87 ± 3.95 pg/ ml), prl (10.25 ± 1.68 vs. 6.71 ± 1.03 ng/ml), and t (4.42 ± 0.48 vs. 4.43 ± 0.69 ng/ml) erevealed no significant difference between addicted and non-exposed groups. correlations analysis based on partial correlation test semen ph (r -.464, p .007), sperm motility (r-.370, p .037), and the amount of serum lh (r -.428, p .018) were significantly negatively correlated with duration of drug dependence. we also observed a significant positive correlation between wbc and time of drug dependence (r 0.396, p .025). duration of heroin dependence was related to sperm abnormal morphology (r 0.996, p .05). the amount of daily heroin consumption correlated to serum lh level (r 0.408, p .025) when adjusted for age and bmi and cigarette smoking (table 2). discussion considering the role of recreational heroin consumption as one of the potential risk factors of male infertility, we investigated the effect of heroin use on sperm parameters, histone-to-protamine transition ratio, and serum sexual hormone levels as well as these factors’ possible correlations in participants. however, lack of information about their infertility situation before addiction was considered as a limitation of the study. as another limitation, we could not follow up the participants during the biological sample collection. this was the first study that evaluated some clinical aspects of male reproductive parameters in active heroin users. so, semen and blood samples were collected from 25 heroin users and 25 healthy men. then semen analysis, aniline blue staining, and hormones assessment were performed to provide valuable new information on the relationships of addiction and semen profile and serum reproductive hormone levels. our data determined a significant association between heroin consumption and impaired semen parameters and histone-to-protamine transition ratios. confounding factors in this study were controlled by partial analysis. very few studies have done to find out the direct effect of heroin on male infertility. main obstacles on the way of human studies can be legislation and ethical considerations. in the present study, although bmi in the addicted group was in normal range, it was significantly lower than in the non-exposed one. our finding was similar to other previous studies who mentioned illicit drug use decreases body weight in addicted animal(14,17,18) and human(19). the average bmi may affect spermatogenesis. however, partial correlation results showed that heroin can be more effective than bmi in semen parameters. in this study, alteration of semen quality such as reducing ph and increasing wbc were observed. we proposed that wbc in semen can alter semen microenvironment and affect semen ph and semen acidification may affect sperm viability and motility. increasing blood cells in the semen were observed in all addicted men, so we were not able to control confounding factor. previous studies had revealed that the presence of wbcs in semen which in association with ros, may manifest as male factor infertility(20-22). this study showed that duration of dependency was significantly negatively associated with sperm motility. due to the presence of opiate receptors in different regions of the spermatozoa, reduced viability and motility and abnormal sperms can be caused directly by heroin because activation of these receptors leads to an anti-motility effect. based on previous studies, the opioid system may control reproductive function in the central nervous system (cns), the pituitary gland, and the testis, exerting a direct action on the spermatozoa. an adequate level of opiate helps sperm motility but this effect depends on opiates’ concentration(23). in addition, our previous studies showed that cytoskeletal proteins in the sperm tail such as testis-specific gene antigen10 (tsga10), and ion channel proteins (catsper 1-4) in sperm can alter figure 2. comparison amount of reproductive hormone in serum of addicted and non-exposed men. serum levels of lh, fsh, estradiol, testosterone and prolactin were not significant differences between groups (p ≥ .05). andrology parameters in heroin users-nazmara et al. sperm motility(6,14) and antioxidants can help sperm parameters on the inappropriate condition (22). our study indicated that the heroin consumption was associated with a significant increase in head abnormality and histone-to-protamine transition ratios. amini et al. (2014) showed that sperm abnormality increased following kerack administration in mice(14). safarinejad et al. (2013) reported increased sperm dna damage in opiate users. they suggested that opiate has a negative effect on dna integrity through two pathways: first, the hypothalamus and pituitary gland, and second, direct effect on sperm dna integrity(7). our findings are similar to these previous studies(7,13,14). although the molecular mechanisms of opiate-induced nuclear abnormality in human sperm are under investigation, mice model correlated the chromatin damage with semen quality following ethanol consumption(24) or exposure to cigarette smoke(25). considering the importance of histone-to-protamine transition in the dna packaging, each abnormality in this process can be associated with subfertility or infertility in human (13,26). we proposed that in a similar way, opiate may impair the nuclear integrity of sperm. our study showed serum sex hormone levels were not significantly different between groups. correlations demonstrated that addiction and the amount of heroin consumption correlated with lh levels in serum. previous studies demonstrated that opioid narcotics can cause a defect in the hypothalamic-pituitary-testicular axis (9,17). also, the effect of opiate drugs on the amount of serum sexual hormones is also one of the controversial topics in these studies. cushman (1973) reported testosterone level unchanged in heroin users(27). in contrast, a number of studies found a reduction of plasma sexual hormone levels in active opiate addicted men(28,29).also, yilmaz et al. (1999) suggested chronic morphine exposure significantly decreased serum testosterone and lh levels, but not fsh release in male addicted rats(17). differences in sampling lag time (since the last time of drug administration), lifestyle could be the main factors in this heterogeneous data. mirin’s team documented just 10 mg of heroin can cause a fall in the plasma lh and testosterone levels immediately and 4 hours later respectively(30). since time management was possible in animal studies, they showed a significant decline in the amount of serum sexual hormones(18,31). in addition, reproductive hormone levels may be related to opioid-mediated prl release. some studies have revealed the increased prolactin levels in rats who treated with opioids(32), and in heroin users following intravenous self-administration of heroin(33). ellingboe et al. (1980) have shown regular use of heroin leads to tolerance the acute prolactin response(33). based on these data, the male reproductive hormone profile in serum is a time-dependent factor and cannot be a reliable factor for fertility situation(34). conclusions in summary, the present study showed that heroin consumption alters semen parameters and histone-to-protamine transition ratios in addicted men. we also showed a significantly negative correlation between heroin administration and semen parameters. however, it may increase our understanding of the effect of drugs and toxins on male infertility. acknowledgement this study was funded by a grant from iran university of medical sciences (iums), (number: 94-02-3025973) and insf (number: 94017358) for a ph.d. student thesis. conflict of interest the authors report no conflicts of interest. references 1. macleod j, oakes r, copello a, et al. psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies. lancet. 2004;363:157988. 2. shirinbayan p, rafiey h, vejdani roshan a, narenjiha h, farhoudian a. predictors of retention in methadone maintenance therapy: a prospective multi-center study. sci res essay. 2010;5:3231-6. 3. razzaghi em, movaghar ar, green tc, khoshnood k. profiles of risk: a qualitative study of injecting drug users in tehran, iran. harm reduct j. 2006;3:12. 4. yassami m, shahmohammadi d. epidemiology of drug abuse in ir iran. ministry of health and medical education. 2002. 5. akerele e, olupona t. drugs of abuse. psychiatr clin north am. 2017;40:501-17. 6. tajaddini mahani s, behnam b, abbassi m, et al. tsga10 expression correlates with sperm profiles in the adult formalin-exposed mice. andrologia. 2016;48:1092-9. 7. safarinejad mr, asgari sa, farshi a, et al. the effects of opiate consumption on serum reproductive hormone levels, sperm parameters, seminal plasma antioxidant capacity and sperm dna integrity. reprod toxicol. 2013;36:18-23. 8. ragni lauretis l, bestetti o, sghedoni d, aro v. gonadal function in male heroin and methadone addicts. international journal of andrology. 1988;11:93-100. 9. fronczak cm, kim ed, barqawi ab. the insults of illicit drug use on male fertility. j androl. 2012;33:515-28. 10. du plessis ss, agarwal a, syriac a. marijuana, phytocannabinoids, the endocannabinoid system, and male fertility. j assist reprod genet. 2015;32:1575-88. 11. mohammadzadeh e, amjadi f-s, movahedin m, et al. in vitro development of embryos from experimentally kerack-addicted mice. iran j reprod med. 2017;15:413-22. 12. miller d, brinkworth m, iles d. paternal dna packaging in spermatozoa: more than the sum of its parts? dna, histones, protamines and epigenetics. reproduction. 2010;139:287301. andrology parameters in heroin users-nazmara et al. sexual dysfunction and andrology 293 vol 16 no 03 may-june 2019 294 13. yu b, qi y, liu d, et al. cigarette smoking is associated with abnormal histone-toprotamine transition in human sperm. fertil steril. 2014;101:51-7 e1. 14. amini m, shirinbayan p, behnam b, et al. correlation between expression of catsper family and sperm profiles in the adult mouse testis following iranian kerack abuse. andrology. 2014;2:386-93. 15. fazelipour s, tootian z. effect of heroin used in iran on male fertility of mice. int j pharmacol. 2007;3:406-10. 16. clark jt, gabriel sm, simpkins jw, kalra sp, kalra ps. chronic morphine and testosterone treatment. effects on sexual behavior and dopamine metabolism in male rats. neuroendocrinology. 1988;48:97-104. 17. yilmaz b, konar v, kutlu s, et al. influence of chronic morphine exposure on serum lh, fsh, testosterone levels, and body and testicular weights in the developing male rat. arch androl. 1999;43:189-96. 18. fazelipour s, tootian z. effect of heroin used in iran on male fertility of mice. international journal of pharmacology. 2007;3:406-10. 19. diamond f, jr., ringenberg l, macdonald d, et al. effects of drug and alcohol abuse upon pituitary-testicular function in adolescent males. j adolesc health care. 1986;7:28-33. 20. hagan s, khurana n, chandra s, et al. differential expression of novel biomarkers (tlr-2, tlr-4, cox-2, and nrf-2) of inflammation and oxidative stress in semen of leukocytospermia patients. andrology. 2015;3:848-55. 21. agarwal a, mulgund a, alshahrani s, et al. reactive oxygen species and sperm dna damage in infertile men presenting with low level leukocytospermia. reprod biol endocrinol. 2014;12:126. 22. tajaddini s, ebrahimi s, behnam b, et al. antioxidant effect of manganese on the testis structure and sperm parameters of formalintreated mice. andrologia. 2014;46:246-53. 23. subiran n, agirregoitia e, valdivia a, ochoa c, casis l, irazusta j. expression of enkephalin-degrading enzymes in human semen and implications for sperm motility. fertil steril. 2008;89:1571-7. 24. rahimipour m, talebi ar, anvari m, sarcheshmeh aa, omidi m. effects of different doses of ethanol on sperm parameters, chromatin structure and apoptosis in adult mice. eur j obstet gynecol reprod biol. 2013;170:423-8. 25. la maestra s, de flora s, micale rt. effect of cigarette smoke on dna damage, oxidative stress, and morphological alterations in mouse testis and spermatozoa. int j hyg environ health. 2015;218:117-22. 26. hammadeh me, hamad mf, montenarh m, fischer-hammadeh c. protamine contents and p1/p2 ratio in human spermatozoa from smokers and non-smokers. hum reprod. 2010;25:2708-20. 27. cushman p, jr. plasma testosterone in narcotic addiction. am j med. 1973;55:452-8. 28. azizi f, vagenakis ag, longcope c, ingbar sh, braverman le. decreased serum testosterone concentration in male heroin and methadone addicts. steroids. 1973;22:467-72. 29. kolodny rc, masters wh, kolodner rm, toro g. depression of plasma testosterone levels after chronic intensive marihuana use. n engl j med. 1974;290:872-4. 30. mirin sm, mendelson jh, ellingboe j, meyer re. acute effects of heroin and naltrexone on testosterone and gonadotropin secretion: a pilot study. psychoneuroendocrinology. 1976;1:359-69. 31. donnelly gp, mcclure n, kennedy ms, lewis se. direct effect of alcohol on the motility and morphology of human spermatozoa. andrologia. 1999;31:43-7. 32. limonta p, piva f, maggi r, dondi d, motta m, martini l. morphine stimulates prolactin release in normal but not in castrated male rats. j reprod fertil. 1986;76:745-50. 33. ellingboe j, mendelson jh, kuehnle jc. effects of heroin and naltrexone on plasma prolactin levels in man. pharmacol biochem behav. 1980;12:163-5. 34. geoffroy-siraudin c, loundou ad, romain f, et al. decline of semen quality among 10 932 males consulting for couple infertility over a 20-year period in marseille, france. asian j androl. 2012;14:584-90. andrology parameters in heroin users-nazmara et al. xanthogranulomatous orchitis after blunt testicular trauma mimicking a testicular tumor: a case report and comparison with published cases introduction xanthogranulomatous inflammation is one form of chronic inflammation characterized by a cellular infiltrate of lipid-laden macrophages(1). it is considered to be mainly caused by ascending or hematogenous infection, however clear pathogenesis is still unknown(2). in the genitourinary system, xanthogranulomatous inflammation is commonly observed in kidney(3), bladder(4) and prostate(5). it can also occur in the gall bladder(6). xanthogranulomatous orchitis (xgo) is a rare disease and, to our knowledge, only 22 cases have been reported to date. we present a case of xgo after blunt testicular trauma and compared with the published cases. case report a 28-year-old man was hurt when his left testis was pinched in between the bicycle saddle and his left thigh. he had felt a dull pain in his left testis after the trauma, and a month later, he noted a lump in his left testis and visited our department. there was no history of urinary tract infection or urolithiasis. physical examination revealed a thumb head size induration in his left testis. complete blood count and testicular tumor markers were within normal ranges and urinalysis was normal. various imaging tests, such as ultrasound, computed tomography and magnetic resonance imaging, showed a round tumor with distinct boundary between the tumor and the normal testicular tissue in his left testis (figure 1). the right testis was normal. since we suspected benign tumor such as epidermoid cyst in this case, we tried to enucleate the tumor to preserve the testis. the tumor was easily separated from the normal testis. the surgery was completed once the tumor was department of urology, wakayama medical university, wakayama, japan. *correspondence: department of urology, wakayama medical university, 811-1 kimiidera, wakayama 641-8509, japan. tel: +81-73-441-0637. fax: +81-73-444-8085. e-mail: keito608@wakayama-med.ac.jp. received july 2016 & accepted april 2017 shimpei yamashita,* hidetoshi umemoto, yasuo kohjimoto, isao hara xanthogranulomatous orchitis has been reported to be an extremely rare inflammatory change caused by infection and is difficult to distinguish from testicular tumor. we report a 28-year-old man who presented with a lump in his left testis after a blunt testicular trauma. based on a series of imaging tests, we suspected benign tumor such as epidermoid cyst and performed tumor enucleation (testis-sparing surgery) on the patient. histopathological findings showed xanthogranulomatous orchitis. it is assumed that xanthogranulomatous orchitis in this case was caused by blunt testicular trauma and this is the first successful case of xanthoglomatous orchitis in salvaging the testis. case report keywords: testis; testicular tumor; trauma; xanthoglomatous inflammation. figure 1. magnetic resonance imaging showed a round tumor with distinct boundary between the tumor and the normal testicular tissue in the patient’s left testis. (a) t1-weighted image. (b) t2-weighted image. vol 14 no 03 may-june 2017 3094 figure 2. foamy macrophages accompanied by lymphocytes and plasma cell infiltration. he x 100. confirmed benign via rapid pathological diagnosis. the resected specimen was a yellow necrotic mass with a diameter of 2 cm. histological examination revealed the lesion consisted of a dominant infiltrate of foamy macrophages interspersed with a minor component of lymphocytes and plasma cells (figure 2). based on this inflammatory pattern, a diagnosis of xgo was made. discussion we present a case of xgo which was caused by a blunt testicular trauma. table 1 summarizes the data of 22 published cases. median age was 51.3 years old and xgo was considered to be caused by either ascending or hematogenous infection. the whole testis was replaced with fleshy tissue in 21 (95.5%) of the cases and inguinal radical orchiectomy was performed in all cases. in contrast, the present case differs from those previous cases. first, it is assumed that xgo in this case was caused by blunt testicular trauma as the patient experienced dull pain in his left testis since the trauma occurred and subsequently observed a lump a month after. all published xgo cases were caused by infection. however, in the present case, there was no sign of infection and urinalysis was normal. while there was a case of xanthogranulomatous pyelonephritis (xgn) which was reported to be caused by blunt trauma(7), the present case appears to be the first case of xgo caused by trauma. although the exact mechanism of a trauma leading to xanthogranulomatous inflammation is still unknown, the following two hypotheses are considered. one hypothesis is that macrophages have infiltrated the hematoma caused by the trauma, resulting in xgo. the other hypothesis is that macrophages have infiltrated the necrotic tissue caused by blood vessel damage. the exact mechanism for causing xanthogranulomatous inflammation calls for future investigation. second, inflammatory tumor occurred in the normal testicular tissue and the patient underwent testis-sparing surgery. xgn accounts for lesser than 1% of chronic pyelonephritis and is classified into two categories. one is diffuse type in which the whole kidney is replaced with granulomatous tissue (about 85%). the other one is focal type in which granulomatous tissue forms a mass in normal renal tissue (about 15%)(3). the present case suggested that there is also focal type of xgo. almost all the cases of xgo (21/22 cases) were diffuse type where normal testicular tissues were not found. xanthogranulomatous orchitis mimicking tumor-yamashita et al. table 1. summary of 22 published cases of xanthogranulomatous orchitis author journal total age diffuse or infection type treatment patients focal akaza,h. et al. jpn.j.clin.urol. 1997; 31: 1023-1026. 2 64,63 diffuse ascending inguinal radical orchiectomy in both cases iguchi,a. et al. jpn.j.clin.urol. 1985; 31: 1023-1027. 1 51 diffuse hematogenous inguinal radical orchiectomy usamentiaga, e. et al. urology. 1998; 52: 891-892. 1 35 focal ascending inguinal radical orchiectomy vaidyanathan, s. et al. spinal cord. 2000; 38: 769-772. 1 21 diffuse ascending inguinal radical orchiectomy hajiri, m. et al. ann.urol(paris). 2001; 35: 237-239. 7 30-75 diffuse ascending inguinal radical orchiectomy in all cases yap, r. l. et al. urology. 2004; 63: 176-177. 1 64 diffuse ascending inguinal radical orchiectomy nistal, m. et al. arch. pathol. lab. med. 2004; 128: 911-914. 2 58,79 diffuse ascending inguinal radical orchiectomy in both cases dermirci, d.et al. int. j. urol. 2004; 11: 686-688. 1 21 difffuse hematogenous inguinal radical orchiectomy salako, a. a. et al. int. j. urol. 2006; 13: 186-188. 1 24 diffuse ascending inguinal radical orchiectomy al-said, s. et al. int. j. urol. 2007; 14: 452-454. 1 44 diffuse hematogenous inguinal radical orchiectomy hill, j. r. et al. urology. 2008; 72:461. e11-13. 1 68 diffuse ascending inguinal radical orchiectomy rifat mannan, a. a. et al. med. princ. pract. 2009; 18: 418-421. 1 65 diffuse hematogenous inguinal radical orchiectomy val-bernal, j. f. et al. pathol. res. pract. 2012; 208: 62-64. 1 55 diffuse ascending inguinal radical orchiectomy gakiya m. et al. int. j. urol. 2013; 75: 90-94. 1 79 diffuse hematogenous inguinal radical orchiectomy present case 1 28 focal tumor enucleation case report 3095 also, the patients underwent inguinal radical orchiectomy because it was difficult to rule out the possibility of malignant testicular tumor. however, although it was a focal-type xgo in the present case, the patient was initially diagnosed with epidermoid cyst, and was arranged to undergo tumor enucleation, also known as testis-sparing surgery. one focal-type xgo patient was reported to have underwent radical inguinal orchiectomy due to multiple tumors in his testis(8). therefore, to the best of our knowledge, this is the first successful case of xgo in salvaging the testis. the present case suggests that it is highly challenging to distinguish focal-type xgo from epidermoid cyst, which has relatively high generating frequency among benign tumors in the scrotum, based on radiological findings. conclusions the present case suggested that trauma could cause xanthogranulomatous inflammation. as there is a focal type of xgo, it is therefore difficult to clearly differentiate it from epidermoid cyst. hence, if epidermoid cyst is suspected, noting the possibility of a focal type of xgo and performing testis-sparing surgery should be taken into consideration. conflict of interest none declared. references 1. wiener lb, riehl pa, baum n. xanthogranulomatous epididymitis: a case report. j urol. 1987;138:621-2. 2. al-said s, ali a, alobaidy ak, mojeeb e, alnaimi a, shokeir aa. xanthogranulomatous orchitis: review of the published work and report of one case. int j urol. 2007;14:452-4. 3. chlif m, chakroun m, ben rhouma s, et al. xanthogranulomatous pyelonephritis presenting as a pseudotumour. can urol assoc j. 2016;10:e36-40. 4. chung mk, seol my, cho wy, seo hk, kim js. xanthogranulomatous cystitis associated with suture material. j urol. 1998;159:981-2. 5. matsumoto t, sakamoto n, kimiya k, kumazawa j, miyazaki n, hasegawa y. nonspecific granulomatous prostatitis. urology. 1992;39:420-3. 6. reyes cv, jablokow vr, reid r. xanthogranulomatous cholecystitis: report of seven cases. am surg. 1981;47:322-5. 7. murayama k, katsumi t, matsushita s, yoneshima y, watanabe k. [a case of xanthogranulomatous pyelonephritis probably derived from a renal injury]. hinyokika kiyo. 1987;33:592-5. 8. usamentiaga e, val-bernal jf, alonsobartolome p, lopez-rasines g, del valle ji, calabia a. xanthogranulomatous orchitis. urology. 1998;52:891-2. xanthogranulomatous orchitis mimicking tumor-yamashita et al. vol 14 no 03 may-june 2017 3096 a simple, non biological model for percutaneous renal access training ahsen karagozlu akgul1*, dursun unal2, murat demirbas2, sedat oner2, murat ucar1, korhan akgul3, muhammet guzelsoy2, murat aydos2 purpose: percutaneous renal puncture (prp) is one of the most important and critical step of urology, especially while performing percutaneous nephrostomy and percutaneous nephrolithotomy (pcnl). in the learning period of this procedures, there is a need for validated, effective, economical models for such training. this study describes a simple non biological model for learning prp. the aim was to determine the effectivity of this model as a training and assessment tool, and to assess its cost relative to other models. materials and methods: we designed a training box, made of foam and rubber with two open sides and performed radiopaque pelvicalyceal system maquettes to insert inside it. experts in pcnl (i.e., > 100 cases) and novices (i.e., pediatric surgeons and urologists without pcnl experience) performed percutaneous renal puncture. novices performed a pre -test and a post test (i.e., after 2 hour training). data recorded were total procedure time, x ray exposure time, and number of puncture attempts. experts who performed prp successfully were asked to rate the model using a questionnaire. results: five experts and 21 novices completed the study. four experts rated the model as an "excellent" (score 5) training and assessment tool; one expert rated these as "very good" (score 4). comparisons of novices' pre and post test median results revealed significant skill acquisition with shorter procedure time, less x ray exposure, and fewer attempts for successful puncture (all p < .001). conclusion: this new non biological training model is an effective training tool that helps learners improve skills in prp. the model is simple to construct, economical, and highly re-useable compared to others. it provides good visibility and imaging, is portable, and could be used widely in training centres. key words: education; model; percutaneous; kidney; training. introduction percutaneous renal access (pra) is one of the most important attempts in endourological interventions. pra is also the most important step of percutaneous nehprolithotomy (pcnl). the learning curve for pcnl mainly depends on the quality of the pra, which depends on the skills of the individual who performs the pra (i.e. the radiologist or the urologist).(1) an american survey demonstrated that only 11 % of urologists performed percutaneous access by themselves.(2) reasons for this may include lack of training. waterson et al. had evaluated percutaneous access for pcnl obtained by interventional radiologists or a urologist and emphasized that despite similar access difficulty, complications were less and stone free rates were improved during urologist acquired pra.(2) urologist, obtaining access himself/ herself also eliminates requirement and reliance on a second hand. schilling et al. evaluated 49 pcnl procedures performed on live patients by experts and 35 performed by novices, and documented four complications (clavien grade 1-2) in the expert group and 12 complications (clavien grade 3) in the first 20 patients of the novice group.(3) this difference underlines the importance of training on simulators before attempting to perform pcnl on human patients. a review by rosette et al. in 2008 recommended that prp simulation models be developed and validated.(1) there is a clear need for simulators that can enable surgeons to acquire necessary skills. it has been shown that residents who have trained on models demonstrate better surgical skills when operating on live patients. (4,5) animal laboratories (wet lab) and training models can be used to develop these skills; however, the literature indicates that only a few models for pra have been established to date, and these can be categorized as virtual reality simulators (vrss), ex vivo (biological) models, and non biological models.(6) in the literature of the non–biological training models, it was observed 1uludag university faculty of medicine, department of pediatric surgery–division of pediatric urology, bursa, turkey. 2university of health science yuksek ihtisas education and research hospital, department of urology, bursa, turkey. 3cekirge public hospital, department of urology, bursa, turkey. *correspondence: uludag university faculty of medicine, department of pediatric surgery – division of pediatric urology. 16059 görükle, bursa / turkey. tel: +90 532 4123815. fax: +90 224 2950019. email: ahsenkaragozlu@yahoo.com. received december 2016 & accepted june 2017 endourology and stone disease vol 15 no 02 march-april 2018 1 that the most common limitations of the models were the cost and the insufficiency reusable feature of them. we designed a new and simple non–biological training model for percutaneous renal puncture (prp). based on success in preliminary experiments, we designed this study to assess the prp model as a training tool for fluoroscopy-guided pra. we also searched the literature of non–biological models to assess the model’s economic feasibility for clinical use. materials and methods percutaneous renal puncture model the prp model (figures 1 and 2) has two components: a rectangular prism and pelvicalyceal system (pcs) maquettes / units. the prism is 25 cm wide x 31 cm deep x 12 cm high. two sides of the prism are open, which enables the user to see inside when necessary. the prism is constructed of rubber and foam that used to simulate human tissue elasticity. the top portion of the prism consists of three layers with 2 cm thickness that can be changed to simulate different tissue thicknesses. the skin kidney distance could be changed with this three layer design. the skin kidney distance is minimum 6 cm, maximum 12 cm. all layers and walls except portable roof layers were fixed with hot silicone. the second component of the model, the pcs maquette, is made by hand with using play dough by one of the authors (du) who is a senior urologist. they are available as six separate designs (identified as pcs 1 to 6) that simulate different renal case scenarios (figure 3). these designs provide different shapes, different calyx configurations (i.e., 7, 8 or 9 calyces), and different hydro nephrosis statuses. the different configurations were identified from his patients ct images. the total cost of this prp model is $us 25, which includes $us 5 for the outer portion of the structure, $us 15 for play dough, and $us 5 for hot silicone for fixing layers. study design we followed the study design of the study that reported by zang et al. in 2014.(7). the investigation involved assessments by five experts who were defined as experienced at performing pcnl (i.e., individuals who had managed more than 100 clinical pcnl cases(1)) and by 21 novices (i.e., urologists or pediatric surgeons without prior pcnl experience). experts performed pra once using the model, and novices performed pra twice: initially after brief and very basic training for orientation (i.e., a pre-test), and again after two 1 hour training sessions (i.e., a post test). all procedures were done using an 18 g needle and c arm fluoroscopy. training model for percutaneous renal access-karagozlu akgulet al. question no. model characteristic assessed median score* (range) 1 overall appraisal 5 (4 5) 2 simulation of ease/complexity 4 (3 5) 3 quality of x ray images 5 (4 5) 4 training tool 5 (4 5) 5 assessment tool 5 (4 5) *scale: 1 = very poor 2 = poor 3 = good 4 = very good 5 = excellent abbreviation: n: number in group table 1. the experts’ (n = 5) questionnaire results regarding the percutaneous renal puncture model. figure 1. the percutaneous renal puncture model from one open side figure 2. the percutaneous renal puncture model. the view from upside (from the side of the surgeon) with c arm fluoroscopy position on the opposite side and x ray image. endourology and stone diseases 2 the same unit (pcs 1 maquette) was used only during pre and post tests, not during training sessions. the experts were invited to perform pra using the prp model. the objective data collected were procedure time (i.e., total time required to achieve successful puncture beginning from initiation of the first attempt), x ray exposure time, and number of attempts required to achieve successful pra. an observer judged the success of pra; the criterion for this was prp performed in the correct direction through the papilla, not the infundibulum or renal pelvis. the experts who were judged to have performed pra successfully using the model were asked to complete a questionnaire with five questions about the prp model (table 1). each individual novices attempted pra using the model with pcs 1, and performance of pra was evaluated based on the above listed objective parameters. following this, the novices received two 1 hour sessions of supervised training to improve their skills in standard pra using other pcs maquettes (pcs 2, 3, 4, 5, and 6). an expert (so, an urologist, experienced with ˃ 100 pcnl cases) did these training sessions with one day time interval between sessions for each participant. “eye of the needle (bull’s eye)” technique was taught to novices by the senior for accessing. 24 hours later each novice performed pra using pcs 1, the post test objective data (listed above) were recorded. as noted, all tests was done using the same pcs maquette/unit (pcs 1) and all the attempts to puncture were towards the same (posterior inferior) calyx while recording the performance. statistical analysis experts’ results were compared to novices’ results, and novices’ preand post test results were compared to assess skill acquisition. data were analyzed using the software package spss v. 16.0 (spss inc. released 2007. spss for windows, version 16.0. chicago, spss inc.), and the wilcoxon signed rank test and the mann whitney u test were used. p ≤ .05 was considered to indicate statistical significance. with an alpha of 0.05 (two sided) we will need 21 surgeon in novices group to achieve a power of .80. results all five experts performed pra successfully using the prp model, and all completed the questionnaire. complete data sets were collected for 21 novices. regarding the questionnaire findings (table 1), for overall appraisal, all five experts rated the prp model as 4 (i.e., “very good”) or 5 (median score, 5 : excellent). scores for the model’s ability to simulate ease / complexity of the real life procedure ranged from 3 (i.e., “good”) to 5 (median score, 4). four experts rated the model’s performance with respect to x ray images as excellent (score 5) (figure 4). four experts rated the model as an excellent training and assessment tool (score 5 for both), and one assigned a score of 4 for these traits. the test results for the experts and novices are sumtable 2. objective data for the percutaneous renal puncture model: comparison of results for the experts and novices. parameter experts test(n = 5 ) novices pre test (n = 21) novices post test(n = 21) pa value pb value pc value median (min max) median (min max) median(min max) procedure time 63 s (51 120 s) 183 s (52 696 s) 45 s (25 93 s) .005d < .001d .034d x ray exposure time 30 s (25 60 s) 77 s (12 180 s) 15 s (6 45 s) .034d < .001d .028d number of attempts 2 (1 2) 4 (1 8) 1 (1 2) .012d < .001d > .05 a comparison of expert results versus novice pre test results b comparison of novice pre-test versus post test results c comparison of expert’s results versus novice post test results d statistically significant (p < .05) abbreviations: n: number in group, min: minimum, max:maximum, s: second figure 3. the six maquettes that can be used with the percutaneous renal puncture model figure 4. the x ray image of the pcs maquette 1 training model for percutaneous renal access-karagozlu akgulet al. vol 15 no 02 march-april 2018 3 marized in table 2. for each objective parameter, the experts’ results were significantly better than the novices’ pre test results (p = .005, p = .034, and p = .012 for procedure time, x ray exposure time, and number of attempts, respectively). comparisons of the novices’ pre and post test results revealed statistically better post test results for all three parameters (p < .001 for all). the experts’ procedure time and x ray exposure time were significantly longer than the novices’ post test results (p = .034 and p = .028, respectively). there was no significant difference between these two groups with respect to number of attempts. discussion the advent of simulation models in medical education has offered safe ways to improve learners’ surgical skills in settings outside the operating room.(8,9) the literature describes a small number of non biological training models for pra. a 2014 study by zang et al. described validation of another non biological bench model for training in pra. (7). it is constructed of silicone and has three parts: a kidney, a ureteral stump, and non transparent perirenal tissue. the cost of this model is $us550.(7) apart from cost, the main disadvantage of this model is that the trainee is limited to practicing on one pcs, which means that she/he tends to memorize the anatomy. also, only a maximum of six trainees can practice pra on one unit prior to dilation. in a model described by turney et al.(10), the collecting systems from routine computed tomography urograms are extracted and reformatted using specialized software and these images are printed via a 3d printer to create bio models. each of these models costs approximately £8072/€9584/$us12919. the long and demanding preparation period (2-3 days), the need for high technology, and price (even though the authors state that cost is low) are the drawbacks of this tool. in 2008, bruyere et al. published a rapid-prototyping non-biological model for pra that was based on abdominal computed tomography images of a patient scheduled to undergo pcnl.(11) the cost was €2,500 /$us3.690. its disadvantages are high cost, the need of high technology, the long time required for construction, and the fact that each model can tolerate only six practices. in the present study, all five experts performed pra successfully using our prp model. the top of the model is a convertible three layer structure, which allows the user to change the tissue thickness. the experts’ answers to the questionnaire on model performance revealed a rating of excellent (median score, 5) for overall appraisal, x ray imaging, value as an assessment tool, and value as a training tool. a rating of very good (median score, 4) was assigned for the model’s ability to simulate ease/complexity of real life pra. our comparisons of pre and post test data revealed significant improvement (p < .001) in novices’ skills at performing pra using the model. after 2 hours of supervised training, procedure time and x ray exposure time were shorter (both p < .001), which means less x ray exposure for patients in the operating theatre. the training also enabled the novices to achieve successful pra with fewer puncture attempts (p < .001). selecting the correct direction and side of puncture (i.e., successful puncture) decreases the procedure time and associated costs.(12) the trainee can learn how to perform the optimal direction of puncture through the papilla and infundibulum, to use c-arm fluoroscopy, to accurately interpret the fluoroscopic images, and to convert the 2d images into 3d in her or his mind. once a puncture attempt is made, the trainee can view the results inside the model from both sides, understand the reasons for an unsuccessful puncture in detail, and compare the directly visible results to what is apparent on the fluoroscopy images. as well, this model improves hand eye coordination and reduces unnecessary x-ray exposure for patients. we observed that trainees tend to learn the positions of the calyces and anatomy of a pcs as a result of practice, and that learning on only one pcs yields a false sense of skill acquisition / success with pra, which is misleading. it is important to switch pcs maquettes / units after a few successful punctures, and to ensure that the trainee practices with different scenarios and to reform and reduce the ease of the model. our model also allows the supervisor / trainer to remove the pcs maquette from one side of the model and insert the new one without any additional movement. surgical education mainly depends on hands on practice to improve technical skills, and percutaneous renal endoscopic surgery requires advanced surgical skills. the literature indicates that, to become proficient in pcnl, a resident must perform approximately 24 of these procedures during training.(1) competence at pcnl (i.e., expert level) is considered to be reached after 60 pcnl cases, and excellence is acquired at greater than 100 cases.(1) it is difficult to reach these numbers during the training period.(13) the learning curve for pcnl is long, and surgical disasters can occur during the training period.(3) it has been shown that residents who have trained on models demonstrate better surgical skills when operating on live patients.(4,5) training on simulators of pcnl has recently become recommended practice for percutaneous renal surgery; however, time and costs tend to limit the use of these tools. our prp model is highly re useable; in total, 113 puncture attempts were performed on the model during the novices’ pre tests and post tests, and the number of additional attempts made during training sections were not recorded. in addition to being re useable, one key advantage of our prp model is its low cost. the total cost of our prp model is $us25. to our knowledge, this prp model is the most inexpensive model of its type to have been subjected to an assessment study. as with other training models, the current version of this model has some limitations. in this model there is no perirenal and renal cortical tissue and no rib, it cannot simulate the exact tactile feeling and movement while breath. other limitations of this model are that it could not exercise the trainee about accessing though avascular brodel’s line and accessing under ultrasound guidance or direct visualized endoscopic guidance. the complexity of the model had been tried to improve with different pcs units. in our study, the criteria for an expert (individual who had performed more than 100 pcnl) limited the number of expert group. the surgeons from four different hospitals were included the study. the number of experts among these surgeons were only five. the study performed in four different centers using four different c-armed fluoroscopy and because of technical features of machines, the radiation training model for percutaneous renal access-karagozlu akgulet al. endourology and stone diseases 4 dose, used during tests or training, could not be documented. it is a pilot study, we plan to validate the model with increased population size and for the next step of education we plan to design a new model for simulation of all steps of pcnl procedure. conclusions prp is one of the most important attempt for adult and pediatric urology. our findings demonstrate that this prp model is effective as a training tool and is economical for clinical use. this low-cost, re-useable, portable and effective model permits rapid acquisition of prp skills, and can be used as the first step in a surgeon’s learning curve for achieving successful pra. conflict of interest the authors declare that they have no conflict of interest. references 1. rosette jjmch, laguna mp, rassweiler jj, conort p. training in percutaneous nephrolithotomy—a critical review. eau 2008;54:994–1001. 2. watterson jd, soon s, jana k. access related complications during percutaneous nephrolithotomy: urology versus radiology at a single academic institution. j urol. 2006 jul;176(1):142-5. 3. schilling d, gakis g, walcher u, stenzl a, nagele u. the learning curve in minimally invasive percutaneous nephrolitholapaxy: a 1-year retrospective evaluation of a novice and an expert. world j urol 2011;29:749–53. 4. palter vn. comprehensive training curricula for minimally invasive surgery. j grad med educ 2011;3:293-8. 5. stern j, zeltser is, pearle ms. percutaneous renal access simulators. j endourol 2007;21:270-3. review. 6. mishra s, jagtap j, sabnis rb, et al. training in percutaneous nephrolithotomy. current opinion urolithiasis 2013; 23(2):147–51. 7. zang y, yu cf, jin sh, li nc, na yq. validation of a novel non biological bench model for the training of percutaneous renal access. int braz j urol 2014;40:87-92. 8. scott dj, cendan jc, pugh cm, minter rm, dunnington gl and kozar ra. the changing face of surgical education: simulation as the new paradigm. j surg res 2008;147:189-93. 9. wignall gr, denstedt jd, preminger gm, et al. surgical simulation: a urological perspective. urol 2008;179:1690-9. 10. turney bw. a new model with an anatomically accurate human renal collecting system for training in fluoroscopy-guided percutaneous nephrolithotomy access. j endourol 2014;28:360-3. 11. bruyère f, leroux c, brunereau l, lermusiaux p. rapid prototyping model for percutaneous nephrolithotomy training. j endourol 2008;22:91-6. 12. radecka e, brehmer m, holmgren k, palm g, magnusson p, magnusson a. pelvicaliceal biomodeling as an aid to achieving optimal access in percutaneous nephrolithotripsy. j endourol 2006;20:92-101. 13. gill jd, stewart lf, george njr, eardley i. operative experience of urological trainees in the uk. bju int 2012;109:1296-301. training model for percutaneous renal access-karagozlu akgulet al. vol 15 no 02 march-april 2018 5 urological oncology 162 urological oncology cytoreductive and palliative radical prostatectomy, extended lymphadenectomy and bilateral orchiectomy in advanced prostate cancer with oligo and widespread bone metastases: result of feasibility, our initial experience nasser simforoosh*, mehdi dadpour, bahram mofid purpose: to evaluate the feasibility of cytoreductive radical prostatectomy (crp), lymphadenectomy, and bilateral orchiectomy in patients with advanced prostate cancer with oligoand poly-metastases. furthermore, the functional and oncological outcomes of these patients in comparison with the control group that underwent treatment only with systemic therapy (st group) is investigated in a well-selected, prospective cohort study. material and methods: a total of 26 patients were enrolled in crp group and 23 patients in st group. the patients have been followed (9 to 43 months(median:19.5)) with psa (prostate specific antigen), whole body bone scan and other necessary imaging and laboratory tests. functional and oncological outcomes were compared between two groups. results: biochemical relapse occurred in 9 patients (34.6%) in crp group and in 17 patients (73.9%) in st group (p = 0.01). whole-body bone scans showed more reduced metastasis volume in crp group (p = 0.003). there was no voiding dysfunction in 22 patients in crp group post-operatively (84.6%), while in st group trans-urethral resection of prostate or permanent foley catheter was needed in 8 patients (34.7%) and bilateral percutaneous nephrostomy was done in one patient. six patients in crp group (23%) and eight patients in st group (34.7%) died because of prostate cancer and there was no difference between cancer specific survival between the two groups (p = 0.975). conclusion: although surgery doesn’t improve cancer specific survival in patients with skeletal metastatic prostate cancer in the short term, but offers better local control, improves biochemical relapse-free survival, might prevent excessive interventions, and reduce bone pain and metastasis. keywords: prostate neoplasms; metastasis; oligo and wide-spread metastasis; cyto-reductive radical prostatectomy; bilateral orchiectomy; functional and oncologic outcome introduction today, androgen deprivation therapy (adt) is the gold standard treatment for advanced prostate cancer with bone metastases. although radical prostatectomy (rp) is a choice treatment for localized pca (prostate cancer) in men with a life expectancy of more than 10-15 years, there is not sufficient information that surgery could improve survival in patients with bone metastasis(1-5). for many years, it was believed that debulking surgery in metastatic cancer does not affect survival, because not all cancer cells can be eliminated by cytoreductive surgery. now, however, the belief that the development of distant metastasis might be dependent on an intact primary focus has come about(6-8). some studies have demonstrated that cytoreductive cancer surgery can improve the response of the disease to adjuvant systemic therapy and finally improve cancer-specific survival. this hypothesis was proven by clinical trials and meta-analyses in some malignancies like renal cancer, colorectal cancer, and ovarian carcinoma(9-12). the improvement may be because the production of tumor growth factors, immunosuppressive cytokines, and new metastases cells made by the priurology and nephrology research center, shahid labbafinejad hospital, shahid beheshty university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center, shahid labbafinejad hospital, shahid beheshty university of medical sciences, 9th boostan, pasdaran avenue, tehran, iran, tel: +982122588016. e mail: n.simforoosh@gmail.com. received august 2018 & accepted october 2018 mary tumor is reduced (13). it is not yet clear whether or not this hypothesis is true for metastatic prostate cancer. the few studies that have been done in this regard have demonstrated that the role of rp is shifting from low-risk pca to high-risk pca and advanced disease. to achieve a better survival rate, rp with adt may be a frontline treatment option for patients with mpca (metastatic prostate cancer) in the future(6,14,15). on the other hand, because of prostate adhesion to the surrounding tissue in advanced pca and difficult tissue dissection, the safety and feasibility of surgery are unclear. excessive bleeding, rectal injury, sphincter damage, subsequent incontinence and other complications are predictable. more than one third of these patients suffer from problems caused by the local progression of tumor-like urinary retention, bilateral hydronephrosis, and increased creatinine levels(16). permanent foley catheter, bilateral nephrostomy tube placement, repeat channel trans-urethral resection of the prostate, and several other therapies may be needed to re-establish urine flow and prevent complications, but these actions affect quality of life. the current study investigates the feasibility of cytorevol 16 no 02 march-april 2019 163 ductive rp (crp), lymphadenectomy, and bilateral orchiectomy in patients with advanced pca with oligo and poly-metastases. furthermore, the functional and oncological outcomes of these patients in comparison with the control group that underwent treatment only with systemic therapy is investigated in a well-selected, prospective cohort study. case 1 a 52 years old man presented with urinary retention, bilateral severe hydronephrosis and serum creatinine 5 mg/dl and psa 220 ng/dl. trans rectal biopsy of prostate showed adenocarcinoma of prostate. whole body bone scan revealed 3 foci of metastasis in right iliac, right ischium and right pubis. he underwent cyto-reductive radical prostatectomy, extended lymphadenectomy and bilateral orchiectomy (figure1). after 43 months follow up, serum psa is 0.02 ng/dl, hydronephrosis disappeared, creatinine came down to normal range, all the metastases points disappeared in follow up bone scans and the patient is currently continent and voiding well. case 2 a 54 years old man presented with history of obstructive urinary symptoms that was not improved with standard medical treatment. he had bone pain in his back. post-voiding residual urine was 100cc, the serum psa was more than 100 ng/dl. whole body bone scan showed wide-spread bone metastases. trans rectal biopsy of prostate revealed adenocarcinoma of prostate. he underwent rp, extended lnd and bilateral orchiectomy like the previous case. after 30 months follow up, metastatic points decreased significantly in subsequent bone scan and no new metastases appeared. (fig2), the serum psa level is 0.1 ng/dl and the patients has no complaints of bone pain any more. materials and methods a total of 49 patients with mpca and skeletal metastasis were enrolled in the current study from 2014 to 2017. the patients were referred to the surgery and oncology clinic and after consideration of inclusion criteria, the advantages and disadvantages of each type of treatment were described by the surgeon and the oncologist. after discussion and consultation, the patients decided on the treatment method. written informed consent was obtained from all the patients after approval from our institutional review board. twenty-six patients underwent cytoreductive rp, lymphadenectomy, and bilateral orchiectomy (crp group) (figure 1) and were compared with similar patients treated non-surgically with systemic therapy (st group). prostate adenocarcinoma in all these patients was diagnosed by transrectal ultrasound-guided biopsy (12 cores) after an abnormal digital rectal exam or elevated serum prostate-specific antigen (psa). routine pre-treatment laboratory tests and imaging staging procedures, including chest x-ray, abdominal-pelvic computerized tomography (ct scan), magnetic resonance imaging (mri), and whole-body bone scan, were done to evaluate lymphadenopathy, distant metastases, and staging. prostate specific membrane antigen scans (psma scan) were performed in suspicious cases to confirm the diagnosis. inclusion criteria in this study were 1) newly diagnosed prostate cancer with oligometastases and also widespread bone metastases with any elevated psa levels and lymph nodes of any size; 2) imaging and dre (digital rectal exam) confirmation of entirely resectable pca; 3) the absence of visceral metastasis; 4) lack of table 1. patients’ characteristics. group crp group st p value number of patients 26 23 mean age (sd); years 61.5 (7.67) 64.6 (6.18) 0.16 median f/u (range); months 18 (9-42) 21 (14-43) 0.14 mean pre-op psa (sd); ng/dl 108 (73) 84 (61) 0.21 median (iqr) 100(79-113) 69(47-100) mean psa after 6 month (sd) 8.14 (21.3) 38.6 (59.2) 0.003 median (iqr) 0.1(0.05-1.5) 5.4 (0.1-67) mean psa in last f/u (sd) 19.2 (44.5) 75.3 (97.7) 0.003 median(iqr) 0.2(0.05-10.1) 27(0.8-100) type of metastasis; n(%) 0.962 poly-metastasis 16 (61.5%) 14 (60.9%) oligo-metastasis 10 (38.5%) 9 (39.1%) chief complaint; n(%) no symptom 8 (30.8%) 7 (30.4%) 1.00 hematuria 1 (3.8%) 0 obstructive luts 17 (65.4%) 16 (69.6%) figure 1. radical prostatectomy, extended lymphadenectomy and bilateral orchiectomy. radical prostatectomy in metastatic prostate cancer-simforoosh et al. urological oncology 164 significant comorbidities; 5) age under 75 years; and 6) no prior radiation therapy. radical prostatectomy was done in open retro-pubic incision method with an antegrade approach. extended pelvic lymph node dissection (eplnd) was done as excision of fibro-fatty tissue along the external and internal iliac vessels and obturator fossa and common iliac artery bilaterally(17,18). a bilateral orchiectomy was done through a midline incision of the scrotum using the epididymal sparing technique (figure 1). beside the crp group, 23 patients with the same inclusion criteria received the best systemic therapy (adt with antiandrogen drugs) as the standard and traditional treatment group (st group).(19) all data for the crp and st groups was collected prospectively. data collection all pre-operative, peri-operative, and post-operative data, i.e. age, psa, gleason score, tumor stage according to the tnm system, margin status, number of lymph nodes removed, operative time, amount of bleeding, hospitalization duration, catheterization duration, state of continence, and voiding pattern, and any complication that occurred were recorded. all patients were regularly followed every month for the first three months and then every three months. serum psa and other markers that were needed were measured in each visit. patient symptoms and functional outcome, such as urine continence, bone pain, and lower urinary tract symptoms, were evaluated. a whole-body bone scan was done every six months to detect changes in the metastases burden. all other imaging studies were performed if necessary. oligometastatic pca was defined as 5 or fewer metastatic lesions diagnosed by a whole-body bone scan. patients with more than 5 bone metastases were categorized as poly-metastatic (widespread) pca(20-22). time to castration resistance was defined as the time of surgery until the documented confirmation of biochemical progression. cancer-specific survival (css) was defined as the time of diagnosis until death due to pca. overall survival (os) was described as the time of diagnosis until death for any reason(13). complications were evaluated according to clavien grade system(23,24). the independent sample t test and mann-whitney were used to compare normal and non-normal quantitative variables, respectively, in two groups. normality of variables was checked with shapiro wilk test. chi-square test was used to explore the relationship between qualitative variables. survival were explored using log rank test and kaplan-meier plots. results presenting cases characteristics and surgery data a total of 26 patients (crp group) underwent rp, lymphadenectomy, and bilateral orchiectomy. all peri-operative, post-operative and the histopathologic findings are shown in table 2. lymphadenectomy was impossible in one patient because of severe adhesion to the vessels. on average, 16.06 lymph nodes were removed from each patient (range = 6 to 49), of which an average of 8.1 of them showed metastatic cancer (range = 0 to 30). complications and functional outcomes of crp group: recto-vesical fistula occurred in 2 patients because of tumor adhesion to the rectum, and the condition was managed conservatively. one patient needed palliative cystectomy and the placement of bilateral ureterostomy because of a very small, thick, contracted bladder. deep vein thrombosis (dvt) developed in two patients that underwent medical treatment. injury of the external iliac artery during lymphadenectomy occurred in one patient because of adhesive ln, and it was repaired at the same time. one patient developed a significant hematoma in his pelvis and underwent re-exploration to remove hematoma and establish hemostasis. no clavien grade 4 or 5 complication occurred(24). a total of 22 patients voided entirely with continence, and 3 patients used pads because of some degrees of stress incontinence. the patient with a bilateral ureterostomy used table 2. peri-operative and post-operative data. mean operation time 85 mins (75-110) mean blood loss 700 ml (500-1600) mean hospitalization 2.7 days (2-10) mean catheterization 10 days pathology stage pt2b 1 (3.8%) pt2c 1 (3.8%) pt3a 1 (3.8%) pt3b 22 (84.6%) pt4 1 (3.8%) gleason’s score 7 1 (3.8%) 8 2 (7.6%) 9 18 (69.2%) 10 5 (19.2%) margin of surgery positive 26 (100%) negative metastatic lymph node1 yes 24 (92.3%) no 1 (3.8%) 1) lymphadenrctomy in one patient was impossible because of adhession to vessles crp group st group oligo poly oligo poly biochemical relapse 3/10 (30.%) 6/16 (37.5%) 5/9 (55.6%) 12/14 (85.7%) bone pain decrease 2 (20%) 12 (75%) 2 (22.2%) 1 (7.1%) increase 0 1 (6.3%) 4 (44.4%) 7 (50%) no change 8 (80%) 3 (18.8%) 3 (33.3%) 6 (42.9%) metastasis in bone scan decrease 3 (30%) 10 (62.5%) 2 (22.2%) 1 (7.1%) increase 1 (10%) 1 (6.3%) 4 (44.4%) 6 (42.9%) no change 6 (60%) 5 (31.3%) 3 (33.3%) 7 (50%) mortality 1/10 (16.7 %) 5/16 (31.3%) 2/9 (22.2%) 6/14 (42.9%) table 3. outcomes based on the number of metastases. radical prostatectomy in metastatic prostate cancer-simforoosh et al. vol 16 no 02 march-april 2019 165 two urine bags on his abdomen to collect urine. oncologic outcomes of crp group in the mean follow up of 19.2 months (range = 9 to 42 months), 20/26 patients (76.9%) were alive. the six deceased patients had died from cancer. biochemical relapse occurred in 9 patients (34.6%). sixteen patients complained of bone pain before surgery; bone pain was increased in only one patient during the follow-up period. in 14 patients (53.8%), bone pain decreased significantly. serial whole-body bone scans showed an increased burden of metastasis in two (7.7%) patients and a reduced burden in 13 (50%) patients; no changes were seen in the other 11 (42.3%) patients. (table 3) characteristics and oncologic outcomes of st group: in a concurrent evaluation, 23 patients with the same inclusion criteria as the control group (st group) underwent standard systemic therapy (table 1). in the mean follow-up period of 22.8 months (range = 14 to 43 months), 15 patients (65.2%) remained alive. the eight deceased patients died from cancer. biochemical relapse occurred in 17 patients (73.9%). pre-treatment bone pain was found in 4 patients. bone pain occurred or intensified in 11 patients (47.8%) and decreased in only 3 patients. serial whole-body bone scans showed an increased burden of metastasis in 10 (43.5%) patients, a reduced burden in 3 (13%) patients, and no change in the other 10 (43.5%). complications and functional outcomes of st group: because of local progression of the tumor, 4 patients (17.3%) underwent channel transurethral resection of the prostate to resolve signs and symptoms, one (4.3%) patient needed bilateral percutaneous nephrostomy, and 4 (17.3%) patients required the placement of a permanent foley catheter, because their physical condition was too poor to undergo intervention. as mentioned, the data showed a significant decrease in bone pain in patients who underwent surgery, while patients who underwent systemic therapy complained of increasing pain (p < 0.001). whole-body bone scans showed reduced metastasis volume occurred more in crp group (p = 0.003). biochemical relapse occurred in st group significantly higher than in the crp group (p = 0.01). six patients in crp group (23%) and eight patients in st group (34.7%) died because of prostate cancer. kaplan-meier curves are shown in figure 3 to compare the survival between two groups. log rank test shows no difference between cancer specific survival between two groups (p = 0.975). discussion the first aim of this study was to demonstrate the feasibility of rp in patients with oligoand widespread skeletal-metastatic pca. based on the results, rp not only has no major complications, but it also has many advantages. no clavien grade 4 or 5 and no major complication occurred because of surgery. all patients except one were discharged from hospital in good condition after 2 to 5 days. the mortality rate in group crp was 23% (6/26 patients), which was higher than the mortality in similar studies. this difference may be explained by the broad inclusion criteria(13,25). table 3 shows that the mortality rate was higher in patients with more than five metastases (poly-metastatic prostate cancer). to the best of the authors’ knowledge, this is the first prospective cohort study to evaluate cytoreductive rp in patients with both oligoand poly-metastasis in bones, prospectively. only one patient in group crp and two in group st with oligometastasis died because of cancer, as shown in table 3. heidenreich evaluated the data of 23 patients with oligometastatic prostate cancer who underwent cytoreductive rp (group 1) and 38 patients with the same criteria who underwent systemic therapy (group 2), retrospectively(13). patients in group 1 received neoadjuvant adt to decrease the psa to less than 1 ng/dl; otherwise, they were not entered into the study. heidenreich found improvement in the cancer-specific survival rate and time to castration resistance, but no difference was seen in overall survival. the time to castration resistance was increased in the current study, but no improvement was observed in cancer-specific survival or overall survival. although surgery could improve biochemical relapse-free survival (brfs), the overall survival rate was similar between the two groups. another difference between the current study and that of heidenreich was that surgery was performed immediately after diagnosis with any amount of pre-op psa without waiting for neoadjuvant adt. it is speculated that waiting six months before radical surgery might cause the disease to progress. in further contrast with the heidenreich study, those patients in whom psa was not decreased to 1 ng/ ml before surgery were not excluded; surgery was performed on patients with psa over 100 ng/ml. a surveillance, epidemiology, and end results (seer)-based study showed the role of local therapy in the improvement of css and os in patients with metastatic prostate cancer(16,26). further evaluation, however, showed that patients who had undergone surgery were younger, were in better physical condition, and were more likely to have a lower gleason score and clinical stage. this selection bias indicates the importance of figure 2. significant decrease in bone metastasis during follow up whole body bone scan after surgery (almost disappeared) radical prostatectomy in metastatic prostate cancer-simforoosh et al. urological oncology 166 using a prospective study with proper case selection. concerns about functional outcomes are growing, because many patients are diagnosed at earlier ages. quality of life is very important in malignancies(27). despite using drug agents to control luts (lower urinary tract syndrome), 17 patients (65.4%) in the crp group of the current study developed obstructive luts that caused a rise in creatinine levels in some cases. bilateral hydronephrosis occurred in one patient and urinary retention occurred in 4 patients. after surgery, all patients (except one who needed cystectomy) were voiding without difficulty. the bilateral hydronephrosis disappeared, creatinine decreased to within normal range, and 85% of patients were continent. in the st group, 16 patients (69.6%) presented with obstructive luts that caused retention in 3 patients and bilateral hydronephrosis and rise in creatinine in one patient. nine patients required intervention or permanent catheterization to resolve these signs and symptoms. the data shows that even if surgery does not lead to more cancer-specific survival in the short term, it might eliminate problems caused by local progression and increase the quality of life for the patient’s remaining days. as mentioned, the effects of surgery on improving bone pain and metastasis were previously reported; however, the current study did not reveal the same results as reported in the literature. figure 2 reveals the near disappearance of bone metastasis in a follow-up whole-body bone scan after surgery. despite the many benefits that surgery has for such patients, it should be noted that surgery in these patients is more difficult and complicated than a usual radical prostatectomy because of the adhesion of the advanced tumor to neighboring organs like the rectum, the difficulty of dissection, and the risk of bleeding. in contrast with the heidenreich study, patients were included in the crp group of the current study even if their lymph nodes were larger than 3 cm. in such cases, they may be attached entirely to the iliac vessels, and there is a possibility of harm being done to them during lymphadenopathy. this was experienced in one patient of the current study. the external iliac artery was repaired with 6-0 nylon sutures, and the patient had no problems after surgery. it is very important that such surgeries be performed by a surgeon who is very experienced in vascular and pelvic surgery. it is important to note that all operations done during this evaluation were performed by one surgeon; this is one of the positive points of this study. despite the fact that in similar studies a medical agent was used for adt, surgical castration was preferred in the present study. many studies have shown a lower risk of orchiectomy in bone fractures, peripheral arterial disease, cardiac-related complications, and venous thromboembolism in comparison to lhrh agonists 28,29. for such patients, permanent castration is required, and apart from the above-mentioned complications, orchiectomy is easy, less expensive, and does not require the patient to take medications continuously. limitations of this study are low sample size and short follow-up period. another limitation was that patients were not selected in a randomized trial. after receiving a complete explanation of the project, the patients decided how to continue their treatment. to evaluate the advantages and disadvantages of cytoreductive surgery in patients with skeletal oligo and widespread mpca, randomized clinical studies with higher numbers of patients and longer follow-up times are necessary. conclusions although surgery does not seem to improve cancer specific survival rates in patients with skeletal-metastatic prostate cancer in the short term, it does offer better local control, improves biochemical relapse-free survival, might prevent excessive interventions, and reduces bone pain and metastasis volume. the role of rp in advanced pca is increasing, and it may be considered as a standard method instead of systemic therapy in metastatic prostate cancer patients, even in those with skeletal metastasis. conflicts of interest none declared. references 1. james nd, spears mr, clarke nw, et al. survival with newly diagnosed metastatic prostate cancer in the "docetaxel era": data from 917 patients in the control arm of the stampede trial (mrc pr08, cruk/06/019). eur urol. 2015;67:10281038. 2. maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. prostate cancer trialists' collaborative group. lancet. apr 29 2000;355:1491-1498. 3. tangen cm, hussain mh, higano cs, et al. improved overall survival trends of men with newly diagnosed m1 prostate cancer: a swog phase iii trial experience (s8494, s8894 and s9346). j urol. 2012;188:1164-1169. 4. wu jn, fish km, evans cp, devere white rw, dall'era ma. no improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period. cancer. 2014;120:818823. 5. ahmad ae, leao r, hamilton rj. radical prostatectomy for patients with oligometastatic prostate cancer. oncology. 2017;31:794-802. 6. gautam g. is it truly outrageous to consider radical prostatectomy for men with metastatic prostate cancer? indian journal of urology. indian j urol. 2014;30:366-367. 7. becker ja, berg kd, roder ma, brasso k, iversen p. cytoreductive prostatectomy in metastatic prostate cancer: a systematic review. scand j urol. 2017:1-7. 8. sooriakumaran p, karnes j, stief c, et al. a multi-institutional analysis of perioperative outcomes in 106 men who underwent radical prostatectomy for distant metastatic prostate cancer at presentation. eur urol. 2016;69:788-794. 9. flanigan rc, salmon se, blumenstein ba, et al. nephrectomy followed by interferon alfaradical prostatectomy in metastatic prostate cancer-simforoosh et al. vol 16 no 02 march-april 2019 167 2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. n engl j med. 2001;345:1655-1659. 10. bristow re, tomacruz rs, armstrong dk, trimble el, montz fj. survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. j clin oncol. 2002;20:12481259. 11. temple lk, hsieh l, wong wd, saltz l, schrag d. use of surgery among elderly patients with stage iv colorectal cancer. j clin oncol. 2004;22:3475-3484. 12. glehen o, mohamed f, gilly fn. peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. lancet oncol. 2004;5:219-228. 13. heidenreich a, pfister d, porres d. cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. j urol. 2015;193:832-838. 14. thompson im, tangen c, basler j, crawford ed. impact of previous local treatment for prostate cancer on subsequent metastatic disease. j urol. 2002;168:1008-1012. 15. warde p, mason m, ding k, et al. combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. lancet. 2011;378:2104-2111. 16. culp sh, schellhammer pf, williams mb. might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? a seer-based study. eur urol. 2014;65:1058-1066. 17. abdollah f, suardi n, gallina a, et al. extended pelvic lymph node dissection in prostate cancer: a 20-year audit in a single center. ann oncol. 2013;24:1459-1466. 18. joung jy, cho ic, lee kh. role of pelvic lymph node dissection in prostate cancer treatment. korean j urol. 2011;52:437-445. 19. basch e, loblaw da, oliver tk, et al. systemic therapy in men with metastatic castration-resistant prostate cancer:american society of clinical oncology and cancer care ontario clinical practice guideline. j oncol pract. 20 2014;32:3436-3448. 20. singh d, yi ws, brasacchio ra, et al. is there a favorable subset of patients with prostate cancer who develop oligometastases? int j radiat oncol biol phys. 2004;58:3-10. 21. soloway ms, hardeman sw, hickey d, et al. stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. cancer. 1988;61:195-202. 22. kim j, park js, ham ws. the role of metastasis-directed therapy and local therapy of the primary tumor in the management of oligometastatic prostate cancer. investig clin urol. 2017;58:307-316. 23. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009;250:187-196. 24. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-213. 25. gandaglia g, fossati n, stabile a, et al. radical prostatectomy in men with oligometastatic prostate cancer: results of a single-institution series with long-term follow-up. eur urol. 2017;72:289-292. 26. leyh-bannurah sr, gazdovich s, budaus l, et al. local therapy improves survival in metastatic prostate cancer. eur urol. 2017;72:118-124. 27. novicki de, larson tr, andrews pe, swanson sk, ferrigni rg. comparison of the modified vest and the direct anastomosis for radical retropubic prostatectomy. urology. 1997;49:732-736. 28. sun m, choueiri tk, hamnvik op, et al. comparison of gonadotropin-releasing hormone agonists and orchiectomy: effects of androgen-deprivation therapy. jama oncol. 2016;2:500-507. 29. kolinsky m, rescigno p, de bono js. chemical or surgical castration--is this still an important question? jama oncol. 2016;2:437-438. radical prostatectomy in metastatic prostate cancer-simforoosh et al. the role of vitamin e – selenium folic acid supplementation in improving sperm parameters after varicocelectomy: a randomized clinical trial arash ardestani zadeh1,2, davood arab1,2*,naim sadat kia3,sajjad heshmati1, seyed nilofar amirkhalili1 purpose: in this study, we aimed to evaluate the effects of antioxidants including vitamin e-selenium-folic acid (vit e -sefa) on semen parameters following varicocelectomy (vct). materials and methods: sixty patients from 64 infertile male patients diagnosed with varicocele (vc) who underwent sub-inguinal vct were included in the study. following sub-inguinal vct, the patients were randomized into two groups: 30 receiving vit e-se-fa supplementation for six months, and 30 as the control group with supplemental treatment. the post-operative semen parameters of vit e-se-fa receiving group were compared with control group at the end of experiment. the sperm count, percentage of motile and abnormal sperms were considered. results: there were statistically significant differences in terms of count (p = .031) and motility (p = .01) of sperm after six months of receiving vit e-se-fa supplementation comparing with control group. conclusion: vit e-se-fa supplementation can improve sperm parameters (count and motility of sperm) after vct. keywords: antioxidants; sperm parameters; infertility; varicocelectomy introduction infertility, with a prevalence of 15%, is known as the inability to conceive after at least one year of regular and unprotected sexual intercourse, in which male related infertility is defined as unique or contributing factors in about half of the recorded cases.(1,2) several male factors of infertility have been recognized(3) in which the exact cause of infertility could not be detected. varicocele (vc) as a vascular defect in the internal spermatic vein is a most common cause of male infertility. this defect is a source of primary infertility in 35–50% of cases, as well as up to 81% of secondary infertility. (4,5) although, the pathophysiology behind vc-induced infertility has been extensively investigated, the mechanisms for vc related impaired spermatogenesis have not been well established.(6) however, the important mechanisms are scrotal hyperthermia, oxidative stress (os), hormonal disturbances, testicular hypoperfusion and renal and adrenal metabolites reflux.(7) os due to an excess of reactive oxygen species (ros), is now recognized as a major factor in infertility.(8,9) over the last few years, the relation and a directly correlation between semen ros levels and the grade of vc has been well recorded.(7,10,11) thus, removing the os using different approaches may repair vc-related infertility. multi-faceted therapeutic approach including nutrition1 clinical research development center, kowsar hospital, semnan university of medical sciences, semnan, iran. 2 department of surgery, kowsar hospital, semnan university of medical sciences, semnan, iran. 3 social determinants of health research center, semnan university of medical sciences, semnan, iran. *correspondence: clinical research development center, kowsar hospital, semnan university of medical sciences, semnan, iran tel: +98122310059. email:drdavoodarab@yahoo.com. received june 2018 & accepted december 2018 al programs such as antioxidants in combination with operational procedures and assisted reproductive technology (art) can be performed for management of infertility. varicocelectomy (vct) as a main procedure for treatment of patients with vc is associated with various complications including testicular atrophy.(12) recent studies showed that surgical vct reduced the seminal os in infertile men.(13,14) even when seminal analysis do not improve after vct, this surgical procedure enhances the rates of pregnancy and live birth following intrauterine insemination (iui).(15) although, studies reported improvement of semen parametrs after vc repair, there are still conflicting opinions as to whether a vct improves antioxidant defences.(16,17) while antioxidants has been indicated as an approach to increase the antioxidant capacity in the seminal plasma,(18-19) their actual clinical value is unclear. vitamin e (vit e) as a fat-soluble antioxidant neutralizes free radicals and protects the cellular membrane.(20) vit e suppressed the production of ros in infertile male.(21) as well, selenium (se) is known as an antioxidant and necessary trace element in biosynthesis of testosterone and generation of sperm.(22,23) at least 25 selenoproteins have been detected which can help maintain cellular integrity of sperm.(24) additionally, folic acid (fa), the synthetic form of folate, can effectively scavenge free radicals and has been introduced as a factor to reduce andrology urology journal/vol 16 no. 5/ september-october 2019/ pp. 495-500. [doi: 10.22037/uj.v0i0.4653] os in the seminal plasma.(25) this antioxidant has been utilized in combination with zinc following vct to improve semen parameters.(6) although, using antioxidants for sub-fertile patients was suggested in several studies, these approaches were rarley considered after vct. to the best of our knowledge in this study, the combination of vitamin e-selenium-folic acid (vit e -sefa) was used for the first time to improve the semen parameters following vct. the aim of the present study was to investigate the vitamin e-selenium-folic acid (vit e -sefa) supplementation with potential benefit on basic semen parameter results for management of male infertility in patients underwent vct. materials and methods study population in a randomized, single blind clinical trial, between january 2015 and december 2017, 64 infertile patients with vc who underwent sub-inguinal vct at kosar hospital, were included. this investigation was designed to study the influence of vit e-se-fa supplementation on fertility of subjects who underwent sub-inguinal vct. vc was proven by physical examination in a warm room after applying the valsalva maneuver in the standing position.(26) the abnormalities in sperm parameters including count, morphology and motility of sperm were evaluated in two separate semen analyses and patients with vc diagnosis and abnormal sperm parameters were planned for vct. exclusion criteria were usage of supplements, vitamins or alcohol, tobacco smoking, addiction to opium or using the opium during the follow-up period, diabetes mellitus, peptic ulcer history, hormonal disorders (based on clinical history and medical examination), chronic or active genitourinary infection (according to the history, medical examination, urine and semen analysis) and previous reaction to fa, se or vit e. as well, patients with missed follow-up, incorrect usage of drugs, presenting side effects, and delayed complications of vct including recurrent vc, hydrocele or testicular atrophy were excluded from the study. during the study, four patients (n=4) were excluded due to lost to follow-up and thus, the data of 60 patients were evaluated. ethics the aim of research and the methods were explained for each patient. all subjects were aware of receiving vite-se-fa supplementation. before entering to the study, the informed written consent form was signed by all subjects and it was explained that they can exit from study whenever they wanted.the code number of trial was irct2015091223855n2 and it was registered in iranian registry of clinical trials (irct) site (www. irct.ir). study design after performing sub-inguinal vct, the patients were allocated into two groups; supplementation group received daily oral fa (5 mg, iran daru co.), se (200 ug, nature made®) and vit e (400 iu, zahravi co.) for six months, while the remaining 30 subjects with no supplemental treatment during same time as control group. the background, results of physical examination and semen analyses of the patients were investigated to confirm the fertility status. randomization after obtaining informed consent, patients were assigned into two groups to receive supplements or nothing using random block design. in this study, permuted block randomization was used to allocate interventions in a completely random manner to the two treatment groups. six blocks of 4 were defined. structure of each block was four-way combination of two methods of intervention in a perfectly balanced way. random digits table was used for random assignment of blocks to each group. accordingly, a list was prepared. eligible participants were enrolled in the study according to the list, respectively. additional matching did not take place. laboratory specialist and statistic consultant were blinded to treatment assignment (figure 1). surgical procedure in all patients, sub-inguinal vct was performed under general or regional anesthesia using optical magnification (heine cx2.3 binocular loop; dusseldorf, germany) to preserve arteries and lymphatic in the supine position. in each case, an approximately 2 to 3 cm incision was made. the spermatic cord was elevated and placed on a penrose drain. while preserving the arterial and lymphatic vessels, the dilated veins were ligated. in the follow-up period after surgery, semen analysis was done again. semen analysis after 3 or 4 days of sexual abstinence, the semen was obtained from the patients via masturbation. sperm count, motility and morphology were assessed at two points in time before the vct and six months after the vct. semen samples were produced via masturbation into polypropylene containers. within half an hour after sample collection, the samples were liquefied and analyzed according to world health organization (who) manual for semen analysis (2010).(27) all laboratory analyses were performed by specialists blinded to study vitamin e selenium folic acid supplementation after varicocelectomy-ardestani zadeh et al. figure 1. flow chart of study randomization. andrology 496 protocol. sperm parameters were defined as below: sperm count: the number of sperms in 1 ml of semen, determined using hemocytometer method. sperm motility: the percentage of progressive sperms in examined samples, determined using a light microscope. sperm morphology: the percentage of normal featured sperms in examined samples determined using a light microscope. statistical analysis data analyzed using spss-22 software. numeric variables were summarized using mean ± standard deviation (sd). the distribution of the data was evaluated using the kolmogorov–smirnov test. comparisons were performed using parametric test of student’s t-test or non-parametric test of mann-whitney. p-value less than 0.05 was considered as significant level. results in this study, 60/64 infertile patients who undergone vct at kosar hospital, affiliated to semnan university of medical sciences, were enrolled to this study from january 2015 to december 2017. patients were randomly evaluated in two supplement (n = 30) and control groups (n = 30). in table 1, the pre-study data related to basic variables of patients (age, semen analysis and vc grade) were summarized based on control and supplementation groups. according to table 1, there were not statistically significant differences in the pre-study data of two groups, which showed equal characteristics of the two groups and adequacy of randomization. according to table 1, there were statistically significant differences in the sperm count (p = .031) and motility (p = .01) of patients in two groups of study after treatment with supplementation. as well, the pre-op and post-op data based on groups of study were compared and showed that there were no significant differences in the pre and post-op data of control group for sperm count ( p = .084), motility (p = .091) and morphology (p = .441)(table 2). however, significant differences were recorded for sperm count (p = .021) and motility (p = .003) of pre and post-op data in supplement group. discussion in this study, we evaluated the effects of antioxidants including vit e-se-fa on semen parameters six months following vct. although, vc has been suggested to be associated with infertility, its pathogenesis is not completely understood, yet. many theories explained that developing vc is associated with disrupted venous stasis in testes at the presence of impaired venous valves and disrupted hydrostatic pressure difference in the testis at puberty which enhances the venous capacity, resulting in venous varicose.(28,29) consequently, increasing in the venous pressure and reducing in arterial blood flow resulting in hypoxia which leads to ros distribution. recently, it has been recommended that infertility caused by vc had an association with the presence of os.(30,31) failing to restore fertility in patients after vct brings table 1. comparing the pre-study and after treatment data based on groups of study in infertile patients who underwent varicocelectomy at kosar hospital. variables groups p-value supplement control mean ± sd n (%) mean ± sd n (%) age (year) 30.27 ± 4.67 30.47 ± 6.09 0.772 pre-study data i 5 (8.33) 1 (1.66) 0.171 ii 14(23.33) 14 (23.33) iii 11 (18.33) 15 (25) sperm count (106/ml) 35.92 ± 23.14 30.77 ± 22.14 0.069 sperm motility (%) 46.45 ± 16.02 44.17 ± 16.89 0.056 sperm morphology (%) 39.34 ± 18.97 40.69 ± 17.43 0.340 after treatment data sperm count (106/ml) 41.26 ± 24.52 35.83 ± 23.21 0.031 sperm motility (%) 50.29 ± 15.14 46.40 ± 16.51 0.01 sperm morphology (%) 43.15 ± 12.56 41.59 ± 1255 0.315 abbreviations: sd: standard deviation; n: number variables groups supplement (mean ± sd) control (mean ± sd) pre-op sperm count (106/ml) 35.92 ± 23.14 30.77 ± 22.14 post-op sperm count (106/ml) 41.26 ± 24.52 35.83 ± 23.21 p-value 0.021 0.084 pre-op sperm motility (%) 46.45 ± 16.02 44.17 ± 16.89 post-op sperm motility (%) 50.29 ± 15.14 46.40 ± 16.51 p-value 0.003 0.091 pre-op sperm morphology (%) 39.34 ± 18.97 40.69 ± 17.43 post-op sperm morphology (%) 43.15 ± 12.56 41.59 ± 1255 p-value 0.195 0.441 abreviations: sd: standard deviation table 2. comparing the pre-op and post-op data based on groups of study in infertile patients who underwent varicocelectomy at kosar hospital. vitamin e selenium folic acid supplementation after varicocelectomy-ardestani zadeh et al. vol 16 no 05 september-october 2019 497 up the question of the necessity of a supplemental treatment. for improving the sperm characteristics, wirleitner et al.(2012) demonstrated that antioxidants, with no adverse impacts, might be taken by sub-fertile subjects (32). however, raigani et al. (2014) showed no effect of micronutrient supplements, zinc sulphate and fa, on sperm characteristics, despite their antioxidant effects. (33) based on the results of present study, using vit e-sefa supplements for six month could improve sperm count and motility. although, application of antioxidants for sub-fertile patients was suggested in several studies, using these antioxidants after vct were rarley considered according to the literature. as well, there were no reports to show the combined using of vit e -sefa antioxidants after vct. nematollahi‐mahani et al. (2014) conducted a study to evalaute the impacts of fa and zinc sulphate on seminal antioxidant level and endocrine parameters three and six months after surgical repair of varicocele. their results showed a significant increase in peripheral blood inhibin b and improvement in superoxide dismutase (sod) activity in the zinc sulphate/fa group after six months.(6) in a similar study, azizollahi et al. (2013) investigated the effects of zinc sulfate, fa and zinc sulfate/fa on protamine content, acrosomal integrity and sperm quality following vct. they demonstrated that administration of fa increased sperm count. zinc sulfate (zs) improved the sperm morphology. in both zs and fa groups, protamine content and halo formation rate significantly enhanced.(34) in a placebo‐controlled and double‐blind trial, lu et al. (2018) indicated that administration of melatonin as a strong antioxidant three month after varicecelectomy added extra benefit by improving sperm parameters, total antioxidant capacity and hormonal profile.(35) in our study, both sperm count and sperm motility were improved six month after receiving supplementation following vct. these findings showed that the agents with antioxidant capacity can improve the sperm paramaters by reducing the oxidative stress and regulating hormone production. vit e -sefa antioxidants can help to improve the efficiency of sperms by removing the ros from the environment. it has been shown that vit e alone and in combination with other antioxidants has positive impacts on sperm fertility and testis. studies demonstrated that the supplemental prescriptions containing vit e alone can repair the functions of spermatozoa by reducing os impairment.(36,37) no similar studies have done to show the beneficial effects of vit e following vct. however, moslemi et al. (2011) evaluated 690 infertile men with idiopathic asthenoteratospermia who received supplement of vit e (400 iu/daily) in combination with se (200 μg/daily) for at least 100 days and reported 362 cases (52.6%) with total improvement in sperm morphology and/or motility as well, 75 cases (10.8%) with spontaneous pregnancy comparing with control group. (38) gerco et al. (2005) conducted an study to evaluate the effects of a combination of vit e (1 gr) and vit c (1 gr) on infertile men and demonestrated that the level of dna damage was reduced after two months.(39) as well, mortazavi et al. (2014) suggested that supplementation including astaxanthin, vit a and vit e reduced cholesterol levels and serum triglyceride, and improved the semen parameters in obese cases with infertility or sub-fertility.(40) in contrast with studies that show beneficial effects of vit e analogues on sperm parameters, it has been presented that vit e and vit c have toxic impacts and may act as a pro-oxidant instead of an antioxidant, specially when utilized in high doses. in a study evaluating the results of antioxidant supplementation on dna of human sperm integrity during prepartion of percoll, hughes et al. (1998) showed that the combination of acetyl cysteine or ascorbate and alpha tocopherol induced further dna damage.(41) the safe dosages of 100 or 300 mg/daily vit e are recommended, and the dose can be safely raised up to 1000 mg/daily when it is essential. therefore, further investigations are needed to determine the optimal vit e dose in infertile men. in this study, we used 400 iu/daily dose of vit e. to show the impacts of se on semen parameters, placebo-controlled clinical trial were carried out in iran and tunisia. their results demonstrated that se supplementation improved sperm counts, motility and morphology as well as sperm concentration in infertile men.(42,43) safarinejad et al. (2009) investigated the combined effects of se and n-acetyl-cysteine on 468 infertile men with idiopathic oligo-asthenoteratospermia in a 30 weeks treatment period. in response to therapy, the levels of inhibin b and serum testosterone enhanced, but serum follicle-stimulating hormone reduced. furthermore, all semen parameters improved with se and n-acetylcysteine treatment.(42) in the previous studies, fa is also used as adjuvant therapies to enhance the sperm parameters in combination with other antioxidants.(6,34) azizollahi et al. (2013) randomized 112 infertile patients after vct used to repair vc with clinical grade iii into four groups including 32 receiving zs (66 mg/daily) alone, 26 receiving fa (5 mg /daily) alone, 29 receiving zs (66 mg / daily)+ fa (5 mg /daily), and 25 receiving placebo for six months starting immediately after surgery. patients receiving zs therapy showed improvement in only sperm morphology while those receiving fa showed improvement only in sperm concentration. patients receiving combination therapy showed improved sperm concentration, morphology, and motility at the end of six-month treatment. furthermore, increasing the blood inhibin b levels was reported after combination therapy. improvement in seminal sod activity was recorded in both receiving zinc alone and combination therapy. (37) this study was conducted in a limited population. so, we recommended to perform the present study in a large scale population. conclusions in conclusion, vit e -sefa supplementation could improve the sperm parameters including sperm count and motility after vct; however, further studies including larger number of samples are needed to make a proper decision on vit e -sefa supplementation after vct. conflict on interest authors declared no conflict of interest. references 1. monfared mh, akbari m, solhjoo s, et al. inductive role of sustentacular cells (sertoli cells) conditioned medium on bone marrow derived mesenchymal stem cells. int j morphol. 2017;35. vitamin e selenium folic acid supplementation after varicocelectomy-ardestani zadeh et al. andrology 498 2. shokri s, mokhtari t, azizi m, abbaszadeh h-a, moayeri a. nandrolone decanoate administration can increase apoptosis in spermatogenesis cell lines in male rats. jbrms. 2014;1:21-31. 3. ghorbani r, mokhtari t, khazaei m, salahshoor m, jalili c, bakhtiari m. the effect of walnut on the weight, blood glucose and sex hormones of diabetic male rats. int j morphol. 2014;32. 4. witt ma, lipshultz li. varicocele: a progressive or static lesion? urology. 1993;42:541-3. 5. gorelick ji, goldstein m. loss of fertility in men with varicocele. fertil steril. 1993;59:613-6. 6. nematollahi‐mahani s, azizollahi g, baneshi m, safari z, azizollahi s. effect of folic acid and zinc sulphate on endocrine parameters and seminal antioxidant level after varicocelectomy. andrologia. 2014;46:240-5. 7. hamada a, esteves sc, agarwal a. insight into oxidative stress in varicocele-associated male infertility: part 2. nat rev urol. 2013;10:26. 8. said tm, agarwal a, sharma rk, thomas aj, sikka sc. impact of sperm morphology on dna damage caused by oxidative stress induced by β-nicotinamide adenine dinucleotide phosphate. fertil steril. 2005;83:95-103. 9. nayyeri h, latifimehr m. impact of oxidative stress and one-carbon metabolism on male infertility; a mini-review to current trends. journal of ischemia and tissue repair. 2017;1. 10. romeo c, ientile r, santoro g, et al. nitric oxide production is increased in the spermatic veins of adolescents with left idiophatic varicocele. j pediatr surg. 2001;36:389-93. 11. smith r, kaune h, parodi d, et al. increased sperm dna damage in patients with varicocele: relationship with seminal oxidative stress. human reproduction. 2005;21:986-93. 12. diegidio p, jhaveri jk, ghannam s, pinkhasov r, shabsigh r, fisch h. review of current varicocelectomy techniques and their outcomes. bju international. 2011;108:115772. 13. cervellione rm, cervato g, zampieri n, et al. effect of varicocelectomy on the plasma oxidative stress parameters. j pediatr surg. 2006;41:403-6. 14. shiraishi k, naito k. generation of 4-hydroxy2-nonenal modified proteins in testes predicts improvement in spermatogenesis after varicocelectomy. fertil steril. 2006;86:233-5. 15. daitch ja, bedaiwy ma, pasqualotto eb, et al. varicocelectomy improves intrauterine insemination success rates in men with varicocele. j urol. 2001;165:1510-3. 16. evers jl, collins ja. assessment of efficacy of varicocele repair for male subfertility: a systematic review. the lancet. 2003;361:1849-52. 17. naughton ck, nangia ak, agarwal a. varicocele and male infertility: part ii: pathophysiology of varicoceles in male infertility. hum reprod update. 2001;7:47381. 18. agarwal a, majzoub a. role of antioxidants in male infertility. bjui knowledge. 20161-9. 19. rafiee b, morowvat mh, rahimi-ghalati n. comparing the effectiveness of dietary vitamin c and exercise interventions on fertility parameters in normal obese men. urolj. 2016;13:2635-9. 20. brigelius-flohe r, traber mg. vitamin e: function and metabolism. the faseb journal. 1999;13:1145-55. 21. ross c, morriss a, khairy m, et al. a systematic review of the effect of oral antioxidants on male infertility. reprod biomed online. 2010;20:711-23. 22. flohe l. selenium in mammalian spermiogenesis. biol chem. 2007;388:98795. 23. battin ee, brumaghim jl. antioxidant activity of sulfur and selenium: a review of reactive oxygen species scavenging, glutathione peroxidase, and metal-binding antioxidant mechanisms. cell biochem biophys. 2009;55:1-23. 24. mistry hd, pipkin fb, redman cw, poston l. selenium in reproductive health. am j obstet gynecol. 2012;206:21-30. 25. joshi r, adhikari s, patro b, chattopadhyay s, mukherjee t. free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. free radic biol med. 2001;30:1390-9. 26. hudson r. the endocrinology of varicoceles. fertil steril. 1988;49:199-208. 27. organization wh. who laboratory manual for the examination and processing of human semen. 2010. 28. ener k, üçgül ye, okulu e, et al. comparison of arterial blood supply to the testicles in the preoperative and early postoperative period in patients undergoing subinguinal varicocelectomy. scand j urol. 2015;49:16973. 29. sweeney te, rozum js, desjardins c, gore rw. microvascular pressure distribution in the hamster testis. am j physiol heart circ physiol. 1991;260:h1581-h9. 30. cam k, simsek f, yuksel m, et al. the role of reactive oxygen species and apoptosis in the pathogenesis of varicocele in a rat model and efficiency of vitamin e treatment. int j androl. 2004;27:228-33. 31. mostafa t, anis t, el‐nashar a, imam vitamin e selenium folic acid supplementation after varicocelectomy-ardestani zadeh et al. vol 16 no 05 september-october 2019 499 h, othman i. varicocelectomy reduces reactive oxygen species levels and increases antioxidant activity of seminal plasma from infertile men with varicocele. int j androl. 2001;24:261-5. 32. wirleitner b, vanderzwalmen p, stecher a, et al. dietary supplementation of antioxidants improves semen quality of ivf patients in terms of motility, sperm count, and nuclear vacuolization. int j vitam nutr res. 2012;82:391-8. 33. raigani m, yaghmaei b, amirjannti n, et al. the micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men. andrologia. 2014;46:956-62. 34. azizollahi g, azizollahi s, babaei h, kianinejad m, baneshi mr, nematollahimahani sn. effects of supplement therapy on sperm parameters, protamine content and acrosomal integrity of varicocelectomized subjects. j assist reprod genet. 2013;30:5939. 35. azizi m, pasbakhsh p, nadji sa, et al. therapeutic effect of perinatal exogenous melatonin on behavioral and histopathological changes and antioxidative enzymes in neonate mouse model of cortical malformation. int j dev neurosci. 2018. 36. erat m, ciftci m, gumustekin k, gul m. effects of nicotine and vitamin e on glutathione reductase activity in some rat tissues in vivo and in vitro. eur j pharmacol. 2007;554:92-7. 37. yousef m, abdallah g, kamel k. effect of ascorbic acid and vitamin e supplementation on semen quality and biochemical parameters of male rabbits. anim reprod sci. 2003;76:99111. 38. moslemi mk, tavanbakhsh s. selenium– vitamin e supplementation in infertile men: effects on semen parameters and pregnancy rate. int j gen med. 2011;4:99. 39. greco e, iacobelli m, rienzi l, ubaldi f, ferrero s, tesarik j. reduction of the incidence of sperm dna fragmentation by oral antioxidant treatment. j androl. 2005;26:34953. 40. mortazavi m, salehi i, alizadeh z, vahabian m, roushandeh am. protective effects of antioxidants on sperm parameters and seminiferous tubules epithelium in high fatfed rats. j reprod infertil. 2014;15:22. 41. hughes cm, lewis s, mckelvey-martin vj, thompson w. the effects of antioxidant supplementation during percoll preparation on human sperm dna integrity. hum reprod (oxford, england). 1998;13:1240-7. 42. safarinejad mr, safarinejad s. efficacy of selenium and/or n-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. j urol. 2009;181:741-51. 43. keskes-ammar l, feki-chakroun n, rebai t, et al. sperm oxidative stress and the effect of an oral vitamin e and selenium supplement on semen quality in infertile men. arch androl. 2003;49:83-94. vitamin e selenium folic acid supplementation after varicocelectomy-ardestani zadeh et al. andrology 500 prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract manel mellouli1*, slim charfi1, walid smaoui2, rim kallel1, abdelmajid khabir1, mehdi bouacida2, mohamed nabil mhiri2, tahya sellami boudawara1 purpose: to evaluate the impact of lymphovascular invasion on the prognosis of patients treated for upper urinary tract urothelial carcinomas. materials and methods: clinical records of 49 patients treated surgically at our institute for upper urinary tract urothelial carcinomas were reviewed retrospectively. lvi was defined as the presence of cancer cells within an endotheluim-lined space without underlying muscular walls. actuarial survival curves were analysed by kaplan-meier method. multivariate analysis was performed using cox’s proportional hazard model. results: median follow-up was 32 months. lymphovascular invasion was present in 26 (53%) patients. lymphovascular invasion was associated with higher pathological tumor stage (pt) and higher tumor grade. the disease-free and overall survival rates of the patients with lymphovascular invasion were significantly worse than those of the patients without lymphovascular invasion (p < 0.001 and p = 0.027 respectively). multivariate analysis revealed that lymphovascular invasion as well as tumor grade and pathological tumor stage were significant prognostic factors for disease-free and overall survival. conclusion: the presence of lymphovascular invasion was a strong predictor of a poor outcome for utuc. this finding could help identify patients at greater risk for disease recurrence who would benefit from close follow-up and early adjuvant therapy. keywords: transitional cell carcinoma; urinary tract; lymphovascular invasion; prognosis. introduction upper urinary tract urothelial carcinomas (utuc) are rare tumors representing only 5% of all urothelial carcinomas.(1) the estimated incidence of utuc in europe is 1 to 4 cases per 100,000 individuals per year. (1) in tunisia, according to the register of the southern tunisian cancers (2007 edition), the estimated incidence of utuc is 0.21 cases per 100,000 individuals in women and 0.67 cases per 100,000 individuals in men (sellami a, 2007, unpublished data). to date, radical nephroureterectomy (rnu) remains the gold standard treatment for non-metastatic utuc.(2) despite surgery, utuc remains a malignancy with a high potential for local and distant relapse, especially in patients with advanced disease.(3) numerous criteria, such as age, multifocality, tumor stage, grade and architecture, and lymphovascular invasion (lvi) have been established as determinant prognostic factors in utuc.(1) in utuc, lvi is detected in 15 to 20% of cases and is associated with high stage and grade.(3-8) however, the prognostic role of lvi has not still been routinely assessed, checked and described in pathological reports. the aim of the current study was to further delineate the prognostic significance of lvi by analyzing survival outcome for patients with utuc treated by surgery. materials and methods we retrospectively analyzed 49 patients who underwent surgery for utuc between 1992 and 2013 in the chu habib bourguiba of sfax. surgical procedures were performed in one center by various surgeons. all grossly involved lymph nodes were removed during surgery. clinical features clinical data were collected via medical file review. they included age, gender, history of bladder carcinoma or synchronous bladder carcinoma and outcomes. pathological evaluation all surgical specimens (partial ureterectomy, nephrectomy or rnu) were processed according to standard pathologic procedures and all slides were re-reviewed by two pathologists. all specimens were evaluated for tumor location, tumor multifocality, tumor size, tumor architecture, pathological stage, histological grade, presence of lvi, tumor necrosis, concomitant carcinoma in situ (cis), surgical margin status and lymph node status. tumors were staged according to the 2009 american joint committee on cancer–international union against cancer (ajcc/uicc) tnm staging system.(9) tumor grade was assessed according to the 2004 world health organization grading system.(10) multifocality was defined by the presence of two or more synchronous tumors. tumor architecture was defined as 1department of pathology, habib bourguiba hospital, 3029 sfax, tunisia. 2department of urology, habib bourguiba hospital, 3029 sfax, tunisia. *correspondence: department of pathology, habib bourguiba hospital, 3029 sfax, tunisia. tel : 00216 21 027 852. fax : 00216 74 243 427. email : mellouli.manel@yahoo.fr. received august 2016 & accepted may 2017 urological oncology urological oncology 5008 papillary or sessile. lvi was defined, on h&e stained slides, as the presence of tumor cells within an endothelium-lined space without underlying muscular wall. no immunohistochemistry techniques were used to determine the presence of lvi. the extent of lymph node dissection was not standardized and thus was not available for analysis. nodal status was determined by pathological assessment of retrieved lymph nodes at time of surgery. follow-up regimen patients were followed every 3-4 months for the first year following surgery, every 6 months from the second through the fifth years, and annually thereafter. they underwent physical examination, cystoscopy, urine cytology and abdominal-pelvic ct at each visit. recurrence was defined as the disease occurring in the bladder or in the contralateral upper urinary tract. statistical analysis clinicopathologic features of patients were evaluated. in the analysis, age was reclassified into 2 groups: younger than 60 versus 60 or older. tumor size was reclassified into 2 groups: less than 4 cm or more than 4 cm. tumour stage was classified into 2 groups: pta, pt1 and pt2 versus pt3 and pt4. in multifocal tumors, clinicopathologic factors were defined according to the site with the highest stage. qualitative variables were compared by the chi-square test and quantitative variables by the student t-test. patient disease free-survival (dfs) was computed from the day of surgery until lymphovascular invasion in utuc-mellouli et al. table 1. characteristics of 49 patients with utuc. total, n=49 (%) lvi negative, n=23 lvi positive, n=26 p-value age (years) 0.357 <60 18 (36.8) 10 8 >60 31 (63.2) 13 18 sex 0.174 men 41 (83.6) 21 20 women 8 (16.3) 2 6 history of bladder carcinoma 0.319 yes 14 (28.6) 5 9 no 35 (71.4) 18 17 tumor location 0.622 renal pelvis 39 (79.5) 19 20 ureter 10 (20.4) 4 6 tumor size (cm) 0.786 <4 14 (28.5) 7 7 >4 35 (71.5) 16 19 multifocality 0.012 unifocal 34 (69.3) 20 14 multifocal 15 (30.6) 3 12 tumor architecture 0.062 papillary 42 (85.7) 22 20 sessile 7 (14.3) 1 6 pathologic stage 0.117 10 ng/dl) after the saline infusion test.(6) survival analysis showed no statistically significant difference in postoperative relapse-free survival between the two groups (p = .079) (figure 3). discussion the purpose of this report was to compare the postoperative and follow-up outcomes in 2 groups of apa patients who underwent either laparoscopic partial or total adrenalectomy. with advances in surgical techniques, laparoscopic adrenalectomy has gradually become the gold standard for the treatment of unilateral pa.(7-9) however, the method used to cure apa is still controversial, namely laparoscopic partial or total adrenalectomy. laparoscopic partial vs. total adrenalectomy for apa-liu et al. table 3. no improvement of primary aldosteronism in 5 aldosterone-producing adenoma patients who underwent laparoscopic partial adrenalectomy. blood pressure serum potassium levels pac and others case 1 remained hypertensive 3.0 mmol/l at one month after surgery; 2.21 mmol/l at ct confirmed tumor recurrence (fig. 1). 12 months after surgery; continuous oral potassium the pac was 25.7 ng/dl after 36 months of follow-up. supplementation. case 2 remained hypertensive 2.9 mmol/l at one month after surgery; ct confirmed tumor recurrence (fig. 2). continuous oral potassium supplementation. the pac was 15.21 ng/dl after 22 months of follow-up. the pac after the saline perfusion test was 12.59 ng/dl ( >10 ng/dl). case 3 remained hypertensive normal serum potassium. the pac was 20.44 ng/dl after 30 months of follow-up. case 4 remained hypertensive 3.2 mmol/l at one month after surgery; continuous oral the pac was 18.74 ng/dl after 15 months of follow-up. potassium supplementation. case 5 remained hypertensive normal serum potassium. the pac was 21.01 ng/dl after 64 months of follow-up. pac, plasma aldosterone concentration; pac normal value 0.7– 15 ng/dl. figure 1. a. preoperative computerized tomography (ct) demonstrates unilateral single aldosterone-producing adenoma (apa) (arrow). b. pathological results of the postoperative specimen confirmed as adenoma. c. 13 months after surgery, ct showed postoperative tumor recurrence (arrow). unclassified 404 chen et al. reported that the mean operative time for total adrenalectomy in 47 patients with pa was 103.5 minutes, which is almost consistent with the mean operative time determined in our study (105.33 minutes). however, our findings showed that the time for partial adrenalectomy was shorter compared to the time reported in their study (76.16 vs 95.9 minutes).(10) in our study, partial adrenalectomy was performed in younger patients. probably, the surgeon considered partial adrenalectomy for younger patients to retain more adrenal function. however, if older patients have recurrences after surgery, reoperation may be difficult due to physical conditions. so this may be the reason for the difference in age between the two groups. in addition, both surgical procedures were safe, no significant differences were observed in postoperative recovery, and no major complications occurred intraoperatively or postoperatively.(7,11,12) there are controversies between the two surgical methods. the main reason is that laparoscopic partial adrenalectomy has the advantage of retaining part of the ipsilateral adrenal tissue. however, it also has the disadvantage that the tumor may not be completely removed and residual microadenomas may remain after surgery. chen,(10) fu,(11) and al-sobhi(13) et al. reported the results of 16 and 104 laparoscopic partial adrenalectomies. the average follow-up time was 1 year and 8 years, respectively. none of the patients in their studies had recurrent pa and retained more normal ipsilateral adrenal tissue. in addition, none of the patients’ serum cortisol levels were reduced and no exogenous steroid replacement therapy was required after surgery. however, reports on postoperative recurrence of patients with laparoscopic partial adrenalectomy are available. ishidoya et al. reported that postoperative hypertension and hyperaldosteronism did not improve in 2 out of 29 patients who underwent laparoscopic partial adrenalectomy.(14) we performed 65 laparoscopic partial adrenalectomies and experienced 5 cases that did not show improvement of pa after surgery. in 2 of these 5 cases postoperative tumor recurrence was confirmed by ct. in some reports on adrenalectomy in patients with unilateral pa, unilateral single apa was confirmed to account for only 26%-46% by the postoperative pathological results.(5,15,16) although patients were diagnosed by high resolution ct and adrenal vein sampling (avs) before surgery as unilateral single apa, the postoperative pathological results showed that some patients had multiple adenomas/nodules.(11,12) wiel et al. reported that small adrenal gland micro-nodules were frequently ignored by routine histopathology.(17) using hematoxylin and eosin (he)-stained sections combined with ex-vivo mri, macroscopic sections, the pathologist morphologically classified 12 of 15 adrenals as multinodular. in general, partial adrenalectomy may not completely remove microadenomas. residual microadenomas, which secrete aldosterone may cause pa to fail or recur. in our study, 6 out of 31 patients that underwent total adrenalectomy were pathologically confirmed as multiple adenomas after surgery. although all patients that underwent partial adrenalectomy were confirmed as apa before and after surgery, 5 out of 65 patients did not improve or relapse, which might confirm the above viewpoint. laparoscopic total adrenalectomy is safe and feasible for most adrenal diseases.(18) it has fewer perioperative complications and rare postoperative mortality.(19,20) in our study, patients who underwent laparoscopic total and partial adrenalectomy did not require cortisol supplementation therapy after surgery. in the partial adrenalectomy group, a total of 5 patients did not achieve improvement of apa, however, all patients in the total adrenalectomy group were cured. no significant differences were observed in surgical outcome between the figure 2. a. preoperative computerized tomography (ct) demonstrates unilateral single aldosterone-producing adenoma (apa) (arrow). b. pathological results of the postoperative specimen confirmed as adenoma. c. 14 months after surgery, ct showed postoperative tumor recurrence (arrow). figure 3. survival analysis: comparison of relapse-free survival in postoperative follow-up between the two groups. notes: survival analysis showed no statistically significant difference in postoperative relapse-free survival between the two groups (p = .079) laparoscopic partial vs. total adrenalectomy for apa-liu et al. vol 17 no 04 july-august 2020 405 two groups, however total adrenalectomy prevented ipsilateral recurrence due to partial adenoma remnants. although survival analysis showed no statistically significant difference in postoperative relapse-free survival between the two groups (p > .05), the p value was close to a significant level. if the follow-up time is prolonged and the number of cases are increased, there may be statistically significant differences in postoperative recurrence between the two groups. our study has several limitations. first, our study is a retrospective study, and the decision criteria for partial or total adrenalectomy procedure were not randomized. preoperatively, our patients were not selected for avs, and underwent a ct scan, which might have resulted in diagnostic bias. avs is an invasive procedure, and if the preoperative imaging scans confirmed unilateral adrenal masses, avs was not always necessary.(21-22) in our study, we have fewer cases of laparoscopic total adrenalectomy and in both total adrenalectomy and partial adrenalectomy, the follow-up time was relatively short. in future studies, we will increase the number of cases and extend the follow-up time. conclusions this study showed that laparoscopic partial and total adrenalectomy are technically safe and feasible. however, laparoscopic partial adrenalectomy showed a higher no improvement rate (7.7%) for patients with apa. therefore, we selected laparoscopic total adrenalectomy for apa patients. conflict of interest the authors report no conflict of interest. references 1. dick sm, queiroz m, bernardi bl, dall'agnol a, brondani la, silveiro sp. update in diagnosis and management of primary aldosteronism. clin chem lab med. 2018;56(3):360-72. 2. romero dg.clinical practice guideline for management of primary aldosteronism: what is new in the 2016 update?int j endocrinol metab disord 2016;2:. 3. omura m, sasano h, fujiwara t, yamaguchi k, nishikawa t. unique cases of unilateral hyperaldosteronemia due to multiple adrenocortical micronodules, which can only be detected by selective adrenal venous sampling. metabolism. 2002;51:350-5. 4. amar l, plouin pf, steichen o. aldosteroneproducing adenoma and other surgically correctable forms of primary aldosteronism. orphanet j rare dis. 2010;5:9. 5. hennings j, andreasson s, botling j, hagg a, sundin a, hellman p. longterm effects of surgical correction of adrenal hyperplasia and adenoma causing primary aldosteronism. langenbecks arch surg. 2010;395:133-7. 6. funder jw, carey rm, fardella c, gomezsanchez ce, mantero f, stowasser m, et al. case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. j clin endocrinol metab. 2008;93:3266-81. 7. tresallet c, salepcioglu h, godiris-petit g, hoang c, girerd x, menegaux f. clinical outcome after laparoscopic adrenalectomy for primary hyperaldosteronism: the role of pathology. surgery. 2010;148:129-34. 8. rossi h,kim a.primary hyperaldosteronism in the era of laparoscopic adrenalectomy.am surg 2002;68:253-6; discussion 256-7. 9. smith cd,weber cj.laparoscopic adrenalectomy: new gold standard.world j surg 1999;23:389-396. 10. chen sf, chueh sc, wang sm, wu vc, pu ys, wu kd, et al. clinical outcomes in patients undergoing laparoscopic adrenalectomy for unilateral aldosterone producing adenoma: partial versus total adrenalectomy. j endourol. 2014;28:1103-6. 11. fu b, zhang x, wang gx, lang b, ma x, li hz, et al. long-term results of a prospective, randomized trial comparing retroperitoneoscopic partial versus total adrenalectomy for aldosterone producing adenoma. j urol. 2011;185:1578-82. 12. jeschke k,janetschek g,peschel r,et al.laparoscopic partial adrenalectomy in patients with aldosterone-producing adenomas: indications, technique, and results. urology 2003;61:69-72; discussion 72. 13. al-sobhi s,peschel r,bartsch g,et al.partial laparoscopic adrenalectomy for aldosteroneproducing adenoma: short-and long-term results.j endourol 2000;14:497-499. doi:10.1089/end.2000.14.497 14. ishidoya s, ito a, sakai k, satoh m, chiba y, sato f, et al. laparoscopic partial versus total adrenalectomy for aldosterone producing adenoma. the journal of urology. 2005;174(1):40-3. 15. iacobone m, citton m, viel g, boetto r, bonadio i, tropea s, et al. unilateral adrenal hyperplasia: a novel cause of surgically correctable primary hyperaldosteronism. surgery. 2012;152:1248-55. 16. citton m, viel g, rossi gp, mantero f, nitti d, iacobone m. outcome of surgical treatment of primary aldosteronism. langenbecks arch surg. 2015;400:325-31. 17. van de wiel e, küsters b, veltien a, mann r, mukai k, deinum j, et al. perioperative imaging techniques and immunohistochemistry to investigate the feasibility of laparoscopic partial adrenalectomy in primary aldosteronism. european urology supplements. 2018;17. 18. chen y, scholten a, chomsky-higgins k, nwaogu i, gosnell je, seib c, et al. risk factors associated with perioperative complications and prolonged length of stay after laparoscopic adrenalectomy. jama surg. 2018. laparoscopic partial vs. total adrenalectomy for apa-liu et al. unclassified 406 vol 17 no 04 july-august 2020 407 19. sommerey s, foroghi y, chiapponi c, baumbach sf, hallfeldt kk, ladurner r, et al. laparoscopic adrenalectomy--10-year experience at a teaching hospital. langenbecks arch surg. 2015;400:341-7. 20. coste t, caiazzo r, torres f, vantyghem mc, carnaille b, do cao c, et al. laparoscopic adrenalectomy by transabdominal lateral approach: 20 years of experience. surg endosc. 2017;31:2743-51. 21. tan yy, ogilvie jb, triponez f, caron nr, kebebew ek, clark oh, et al. selective use of adrenal venous sampling in the lateralization of aldosteroneproducing adenomas. world j surg. 2006;30:879-85; discussion 86-7. 22. simforoosh n, razzaghy azar m, soltani mh, nourbakhsh m, shemshaki h, et al. staged bilateral laparoscopic adrenalectomy for infantile acth-independent cushing's syndrome (bilateral micronodular nonpigmented adrenal hyperplasia): a case report. urol j. 2017 aug 29;14:5030-5033. laparoscopic partial vs. total adrenalectomy for apa-liu et al. urological oncology laparoscopic versus open partial nephrectomy for stage t1a of renal tumors gholam hossein rezaeetalab1, hormoz karami1,2, farid dadkhah1,3, nasser simforoosh1, nasser shakhssalim1* purpose: partial nephrectomy is the gold standard treatment for small kidney masses. data on the comparison of laparoscopic (lpn) versus open partial nephrectomy (opn) are based on retrospective studies. thus, we planned to compare these two techniques in a prospective trial. materials and methods: the study population consisted of patients over 18 years old with single renal mass of ≤ 4 cm. patients were divided into two groups considering their preference. study arms were matched according to age, gender, tumor size and location and renal nephrometry score. mean operation time, warm ischemia time, hospital stay, peri-operative complications and changes in glomerular filtration rate (gfr) after 1 month were recorded and compared in two groups. patients’ satisfaction score, visual analogue scale and narcotics use to control post-operative pain were also studied. results: 34 and 31 patients underwent lpn and opn, respectively. there was no significant difference between opn and lpn regarding hospital stay (4.1 versus 4.6 days; p = .37), mean hemoglobin drop (2.17 and 1.96 g/dl; p = .62), changes in gfr and positive margin (1 versus 3 p=.40). lpn was accompanied with longer mean surgery time (180 min versus 127 minutes; p < .001) and higher rate of urologic complications (p = .04); nevertheless, patient satisfaction rate was higher (p = .02) and dose of narcotics necessary for controlling post-operative pain was lower (p = .04) in lpn. conclusion: this clinical trial shows that lpn has some benefits over opn, including decreased post-operative pain and higher patient satisfaction. however, extra caution should be considered in the issue of tumor margin and urinary leakage in lpn. key words: kidney neoplasms; laparoscopy; nephron sparing surgery; open partial nephrectomy. introduction nephron sparing surgery (nss) was initially rec-ommended for renal tumors in a solitary kidney, familial and multifocal masses and for those who already suffered from chronic kidney disease.(1). as time elapsed, further studies revealed that radical nephrectomy is a risk factor for chronic kidney disease; and saving as much renal parenchyma as possible would prevent subsequent kidney disease and related morbidities(2). nss provides effective long term benefits in localized renal tumors in terms of cancer control and renal function, and thus it is currently the standard treatment for renal masses under 7 cm (stage t1)(3,4). conversely, based on the evolution and increasing expertise in the field of minimally invasive surgery, a trend towards laparoscopic partial nephrectomy (lpn) in the treatment of small kidney masses has been developing(5,6). those who pioneered the field of lpn, applied it for relatively small and peripheral renal tumors(7). lower blood loss, post-operative pain, and shorter convalescence period alongside small incisions, have been confirmed as the primary advantages of lpn(8). however, there may be some concerns regarding the feasibility, safety, warm ischemia time (wit), long-term changes in renal function and cancer control after lpn(5). open partial nephrectomy (opn) was considered as the gold standard treatment for stage t1a of renal tumors for years(9). several studies has shown similar outcomes for lpn as compared to opn(10). nevertheless, the main concern is that the majority of previous studies in this field are retrospective and there is a paucity of prospective clinical trials. the current study is the first clinical trial to compare the safety, side effects, changes in renal function and post-operative pain control between lpn and opn in stage t1a of renal tumors. materials and methods this study involves a non-randomized prospective trial that was carried out from september 2013 to december 2014 in two medical centers in tehran, iran. the sample size was calculated according to a pilot study to assess the difference in patient’s satisfaction. considering 95% confidence interval and 80% power for the study, a total of 60 patients were needed to achieve the 1 urology and nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2 yazd university of medical sciences, tehran, iran. 3 shahid modarres hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti university of medical sciences, no.103 bustan9 th st ,pasdaran ave, tehran, iran. tel: +9821-22567222. fax:+9821-22567282. e mail: slim456@yahoo.com. received june 2016 & accepted november 2016 vol 13 no 06 november-december 2016 2903 primary aim of the study, which was to compare the ratio of the side effects, patients’ satisfaction and changes in renal function between lpn and opn. all stages of the study were carried out under the supervision and approval of the ethical committee of the iranian urology and nephrology research center. written informed consent was presented to and taken from all patients. the study population included patients of over 18 years old with a single renal mass staged t1an0m0 based on clinical and radiologic examinations. exclusion criteria consisted of glomerular filtration rate (gfr) < 60 cc/min, masses in anatomically or functionally single kidneys, inability to perform partial nephrectomy (such as a tumor in the hilar region) and absolute contra-indication for laparoscopy (bowel obstruction, infection of abdominal wall and aneurysm of great vessels). the study arms were not randomized due to patients’ preference; nevertheless, they were matched considering age distribution, gender, american society of anesthesiologists (asa) classification for health status, tumor size and location (exophytic or endophytic, upper or mid or lower pole) and renal nephrometry score. surgical technique lpn was performed under general anesthesia in lateral decubitus position. a 12 mm port was inserted at the umbilicus using open access approach. then a 5 mm (sub xiphoid), 10 mm (para rectal region parallel to umbilicus), and 5 mm (2 cm medial to anterior superior iliac spine) ports were inserted under direct vision. for right sided operations, the 10 mm port was placed in sub xiphoid. whenever necessary, another 5 mm port was used for liver retraction in the patients with right kidney mass. all patients underwent lpn via a transperitoneal approach. after medial mobilization of the colon and exposure of renal vascular pedicle, main renal artery was clamped using a bulldog. no cooling mechanism was used. the tumor was resected with a safe margin and extracted using an endobag. renal parenchyma was sutured using a 2-0 absorbable polyglactine suture in a running fashion in one layer and bolster was not used routinely. for opn, a flank incision was made in the same position. 11th or 12th rib was resected as required. retroperitoneal approach was used to gain access to the kidney. like lpn, only renal artery was clamped table 1. basic characteristics of the study population. variable opn lpn total p value mean age, years 54.8 50.3 52.4 0.20 gender male 23 23 46 (70.8%) 0.30 female 8 11 19 (29.2%) bmi 27.4 26.9 27.1 0.50 history of smoking 9 (29%) 5 (14.7%) 14 (21.5%) 0.16 chief complaint incidental 12 21 33 (50.7%) flank pain 14 11 25 (38.4%) hematuria 4 2 6 (9.3%) others 1 0 1(1.6) mean tumor size, mm 37.1 33.8 35.4 0.30 tumor ethnicity exophytic 22 23 45 (69.2%) 0.60 endophytic 9 11 20 (30.8%) tumor location upper pole 11 9 20 (30.8%) 0.70 mid pole 7 10 17 (26.1%) lower pole 13 15 28 (43.1%) renal nephrometry score 5.87 5.81 5.84 0.80 abbreviations: opn: open partial nephrectomy; lpn: laparoscopic partial nephrectomy; bmi: body mass index. complication lpn opn urinary leakage 5 0 sepsis 2 0 delayed hemorrhage 1 0 abcess formation 1 0 azothemia 0 1 cva 0 1 pte 1 0 gi bleeding 0 1 overall 10(29%) 3(9.7%) abbreviations: lpn: laparoscopic partial nephrectomy; opn: open partial nephrectomy; cva: cerebro-vascular accident; pte: pulmonary thromboemboli; gi: gastro-intestinal. table 2. frequency of post-operative complications in two groups. lpn vs. opn for stage t1a renal tumors-rezaeetalab et al. urological oncology 2904 and no cooling mechanism was used. following control of small blood vessels with 8-figure knots and repairing the pyelocalyceal system, renorrhaphy was performed the same as laparoscopic approach. whenever there were signs of urinary leakage (fever, flank pain, prolonged ileus and urinary discharge from drain), a double-j (dj) stent was inserted via cystoscopy, and foley catheter was kept until termination of urinary leakage. otherwise, foley catheter was withdrawn the day after surgery and percutaneous drain was removed when its daily output reached lower than 25 cc. patients were subsequently discharged if there was no major complication. variables and statistics complications during surgery and after operation were listed and categorized according to clavien-dindo classification. warm ischemia time (wit), operation time and hospital stay were recorded in all patients. to compute peri-operative bleeding, hemoglobin (hb) changes, blood transfusion rate and estimated intra-operative hemorrhage (according to suction bottle) were used. serum creatinine (cr) and glomerular filtration rate (gfr) was measured before, one day and one month after surgery. post-operative pain was assessed at the time of discharge using visual analogue scale (vas). vas has a score ranging from 0 to 10 in which 0 means no pain and 10 represents the worst possible pain. to control post-operative pain and discomfort, oral or rectal non-steroidal inflammatory drugs (nsaid) were given to the patient. in those patients whose pain did not respond to nsaids, intravenous pethidine (0.25 mg/kg) was injected. the total dosage of pethidine administrated to control post-operative pain was measured in the first 24 hours after the operation and compared in the two study groups. to assess patient satisfaction score after one month, all patients were asked if they were satisfied with the operation; and what type of operation (open or laparoscopy) they would choose if they had the same surgery. spss version 18 was used for data analysis. independent sample t-test and chi-squared test were used to compare variables and ratios between the two groups. p value lower than 0.05 was considered statistically significant. results baseline variables in this study, 31 and 34 patients underwent opn and lpn, respectively. the mean age was 54.8 and 50.3 years in opn and lpn, respectively (p = .20). table 1 illustrates gender distribution, body mass index (bmi), patients' symptoms, tumor size, location and mean renal nephrometry score in the two groups. the mean tumor size was 37.1 and 33.8 mm in opn and lpn groups, respectively (p = .30). mean operation time was significantly higher in lpn than opn (180 versus 127 minutes, respectively, p < .001). there was no significant difference between the two groups regarding hospital stay (4.1 versus 4.6 days for opn and lpn, respectively; p = .38). mean hemoglobin drop one day after surgery was 2.17 and 1.96 g/dl in opn and lpn groups, respectively; which was not statistically significant (p = .62). the mean packed red blood cell transfusion was lower in lpn than in the opn group (0.55 versus 0.41 units), but was not statistically significant (p = .52). estimated blood loss during the operation was measured using suction bottle at the end of surgery, which revealed no significant difference between the two groups (324 ml versus 310 ml for opn and lpn groups respectively; p = .80). peri–operative complications and intra-operative events: eight out of 31 patients (25.8%) in opn group suffered from pleural injury during the surgery, which was sutured and managed using a chest tube. two cases in lpn were converted to open surgery, one of them was due to the injury on renal vein branches. none of the cases in either groups was converted to radical nephrectomy. no cases of bowel or visceral injury was observed. any episode of high body temperature (over 38.5 ° celsius) during hospital admission and after surgery was recorded. although fever was more common among those who had undergone lpn (44% versus 19%), the difference was not statistically significant (p = .09). post-operative complications are shown in table 2. there were only 3 complications associated with opn: 1 cerebrovascular accident, 1 gastrointestinal bleeding and 1 case of azotemia. except for the latter, there was no other urologic complication. however, in lpn group, there were 5 cases of urinary extravasation (later treated with dj insertion), 2 cases of urosepsis and 1 case of delayed hematuria (which was treated by expectant management). the relative frequency of urologic complications was significantly higher in the lpn group (p = .04). positive margin was seen in 3 laparoscopic and 1 open case (8.8% and 3.2% respectively). statistical analysis by fisher’s exact test did not show significant difference between the two groups (p = .40). there was no statistically significant relationship between positive margin and tumor size, location, tumor side and blood loss (p = .50, .20, .60 and .90 respectively). changes in clearance of creatinine: there was an overall increase in mean serum creatinine 24 hours and one month after surgery. the mean changes of serum cr was significantly higher after opn than lpn one day after the operation (+0.266 mg/dl versus +0.084 respectively; p = .002). however, after one month, this difference was not statistically significant (+0.177 versus +0.097; table 3. mean creatinine and gfr changes 1 day and 1 month after the surgery. variable opn lpn p value mean cr changes after 24 hours (mg/dl) +0.266 +0.084 0.002* mean cr changes after 1 month (mg/dl) +0.177 +0.097 0.115 mean gfr changes after 24 hours (ml/min) -14.34 -3.61 0.045* mean gfr changes after 1 month(ml/min) -10.48 -8.56 0.572 abbreviations: cr, creatinine; gfr, glomerular filtration rate; opn, open partial nephrectomy; lpn, laparoscopic partial nephrectomy. lpn vs. opn for stage t1a renal tumors-rezaeetalab et al. vol 13 no 06 november-december 2016 2905 p = .11). as shown in table 3, changes in mean gfr follow the same rule. the mean warm ischemic time (wit) was 19.08 minutes in opn and 20.97 minutes in lpn, which was not significantly different (p = .50). post-operative pain control and patient satisfaction: lower doses of pethidine was needed in lpn group to control patients’ pain in the first 24 hours (16.3 mg versus 27.3 mg pethidine for lpn and opn respectively; p = .04). however, evaluation of mean visual analogue scale (vas) indicated no significant difference between the two groups (p = .70 and p = .35 for vas before and after narcotic administration respectively). further analysis of patient satisfaction (one month later) indicated that patients in the lpn group were more satisfied with the whole operation than those in the opn group (p = .02). discussion current information in the literature on the comparison of lpn and opn in small renal masses are mainly based on retrospective articles and reviews. this study is the first prospective trial in which safety and efficacy of lpn and opn are compared in pathological stage t1a of renal tumors(11). historically, lpn was primarily used for relatively small, peripheral and exophytic kidney masses and retrospective studies were accompanied with a selection bias(7); but in this study, endophytic and mid pole tumors were also included and matched in two comparative groups and renal nephrometry score which indicates surgical difficulty, is also similar in two groups. patients’ performance status and bmi were also matched in two groups. thus this study tried involving a broader spectrum of renal masses in lpn group in order to achieve a more comprehensive conclusion. furthermore, current data on advantages and disadvantages of lpn are complex and controversial. as a minimally invasive approach, it brings out small scar formation and more appealing appearance(12).a study by gill et al. revealed that lpn was accompanied with less intra-operative hemorrhage, earlier hospital discharge, rapid convalescence, and shorter surgery time. wit was longer in lpn group, though. like our study, the margin positive cases were higher in laparoscopic than open group (3 versus zero cases), although the difference was not significant (p = .10)(13).it should be taken into account that the mean size of renal tumors in the study of gill et al. was smaller than the present study (28 mm for lpn and 33 mm for opn) and as such, patients in opn group had significantly larger tumors (p = .005). but in the present study, the mean size of renal masses was not different in the two groups (p = .30). another large retrospective study by gill et al. on 1800 patients indicated that patients with decreased performance status, larger tumors and centrally located kidney tumors had undergone opn rather than lpn. in these cases, lpn was accompanied with shorter surgical time, decreased operative blood loss and shorter hospital stay. however, lpn was associated with longer ischemia time and increased urologic complications. the chance of intraoperative complications and renal function, which changes after 3 months were similar in the two groups(14). similarly, a review article by porpiglia et al. indicated longer wit for lpn than opn(15). a study by gong et al. on patients with stage t1a of renal tumors suggested longer operation and ischemic time for lpn than opn. however, laparoscopy was associated with less blood loss, hospital stay and post-operative complications(16). the results from the italian multicenter “record” project also indicated a longer wit for lpn than opn. nevertheless, gfr was not significantly different after 6 months(17).on the other hand, a literature review on the role of minimally invasive techniques for kidney masses suggested shorter ischemia time, lower complication rate and decreased morbidity for lpn in contrast to opn(18), a multicenter retrospective study by crepel and associates indicated longer surgical time for lpn than opn. intraoperative blood loss and complications were similar in the two groups. laparoscopy was associated with shorter hospital stay, while lpn was done in smaller and more peripheral tumors. therefore, this study suggested that “the indications for laparoscopic partial nephrectomy remain selective”(19). another retrospective study by marszalek et al. demonstrated that wit, hospital stay and surgical time were lower in lpn than opn group. surgical hemorrhage, adverse effects and gfr changes were comparable in the two groups(20). similarly, springer et al. concluded that wit is lower in lpn than opn; but there was no significant difference between long term gfr and oncologic outcomes(21). as stated above, irrespective of whether wit was longer or shorter in lpn than in opn, the mean long term gfr was always comparable to open surgery as shown in several studies(14,15,17,20,21). moreover, this study presents similar results in stage t1a of renal tumors. however, it should be noted that the surgeon’s expertise and tumor accessibility are two important factors that may influence ischemic time(17). most studies suggest that peri-operative complications are similar between lpn and opn. some studies indicated that surgical bleeding is lower during laparoscopy(13, 16, 18). in the study, the mean hemorrhage and hemoglobin drop were not different in two groups. open partial nephrectomy was associated with more cases of pleural injury, which was due to flank surgical approach. however, the rate of urologic complications and urinary leakage was significantly higher in the lpn group. this result is consistent with earlier retrospective studies(8,13,14), and maybe due to difficulty in the repair of pyelocalyceal system and dj insertion during laparoscopy. earlier studies have warned about margin involvement in laparoscopic surgery, which may be attributed to lack of tactile sense during surgery(13,22,23). higher rates of margin positive cases in lpn than opn were observed in this study, although not statistically significant, but suggests extra precision and wider margin excision for laparoscopy to warrant a margin-free pathology. more prospective studies with long-term follow up are needed to evaluate the oncologic outcomes of this difference. this study, as the first clinical trial in this field, is accompanied with several limitations. patient randomization was not possible due to ethical issues and paucity of strong evidence about feasibility of lpn in all types of renal tumors. in addition, relatively small sample size and short follow up may affect the results of this study. more prospective multi-center surveys with long –term follow up and large volume population are necessary to justify the information obtained by this study. conclusions lpn is an acceptable alternative to opn in clinical stage t1a of renal tumors. it has some advantages over opn such as more patient satisfaction lpn vs. opn for stage t1a renal tumors-rezaeetalab et al. urological oncology 2906 scores and better post-operative pain control. the mean hospital stay, wit, intra-operative hemorrhage, peri-operative complications and changes in gfr are comparable to opn. however, while lpn is selected as the primary choice, extra caution is required about tumor margin and urinary leakage. acknowledgements this article has been extracted from the thesis written by dr. gholam hossein rezaeetalab in school of medicine, shahid beheshti university of medical sciences. (registration no: 278m). conflict of interest no conflict of interest is declared. references 1. herr hw. a history of partial nephrectomy for renal tumors. j urol. 2005;173:705-8. 2. ficarra v, secco s, fracalanza s, et al. expanding indication for elective nephronsparing surgery in renal cell carcinoma. arch ital urol androl. 2009;81:86-90. 3. van poppel h, becker f, cadeddu ja, et al. treatment of localised renal cell carcinoma. eur urol. 2011;60:662-72. 4. nguyen ct, campbell sc, novick ac. choice of operation for clinically localized renal tumor. urol clin north am. 2008;35:645-55; vii. 5. johnston wk, 3rd, wolf js, jr. laparoscopic partial nephrectomy: technique, oncologic efficacy, and safety. curr urol rep. 2005;6:1928. 6. berger a, crouzet s, canes d, haber gp, gill is. minimally invasive nephron-sparing surgery. curr opin urol. 2008;18:462-6. 7. novick ac. laparoscopic and partial nephrectomy. clin cancer res. 2004;10:6322s7s. 8. weise es, winfield hn. laparoscopic partial nephrectomy. j endourol. 2005;19:634-42. 9. hadjipavlou m, khan f, fowler s, joyce a, keeley fx, sriprasad s. partial vs radical nephrectomy for t1 renal tumours: an analysis from the british association of urological surgeons nephrectomy audit. bju int. 2015. 10. berger ak, stein rj, aron m, gill is, desai mm. laparoscopic partial nephrectomy: a decade of evolution. j endourol. 2011;25:14550. 11. ljungberg b, bensalah k, canfield s, et al. eau guidelines on renal cell carcinoma: 2014 update. eur urol. 2015;67:913-24. 12. van poppel h. efficacy and safety of nephronsparing surgery. int j urol. 2010;17:314-26. 13. gill is, matin sf, desai mm, et al. comparative analysis of laparoscopic versus open partial nephrectomy for renal tumors in 200 patients. j urol. 2003;170:64-8. lpn vs. opn for stage t1a renal tumors-rezaeetalab et al. 14. gill is, kavoussi lr, lane br, et al. comparison of 1,800 laparoscopic and open partial nephrectomies for single renal tumors. j urol. 2007;178:41-6. 15. porpiglia f, volpe a, billia m, scarpa rm. laparoscopic versus open partial nephrectomy: analysis of the current literature. eur urol. 2008;53:732-42; discussion 42-3. 16. gong em, orvieto ma, zorn kc, lucioni a, steinberg gd, shalhav al. comparison of laparoscopic and open partial nephrectomy in clinical t1a renal tumors. j endourol. 2008;22:953-7. 17. minervini a, siena g, antonelli a, et al. open versus laparoscopic partial nephrectomy for clinical t1a renal masses: a matched-pair comparison of 280 patients with trifecta outcomes (record project). world j urol. 2014;32:257-63. 18. heuer r, gill is, guazzoni g, et al. a critical analysis of the actual role of minimally invasive surgery and active surveillance for kidney cancer. eur urol. 2010;57:223-32. 19. crepel m, bernhard jc, bellec l, et al. [comparison of open and laparoscopic partial nephrectomy: a french multicentre experience]. prog urol. 2007;17:45-9. 20. marszalek m, meixl h, polajnar m, rauchenwald m, jeschke k, madersbacher s. laparoscopic and open partial nephrectomy: a matched-pair comparison of 200 patients. eur urol. 2009;55:1171-8. 21. springer c, hoda mr, fajkovic h, et al. laparoscopic vs open partial nephrectomy for t1 renal tumours: evaluation of long-term oncological and functional outcomes in 340 patients. bju int. 2013;111:281-8. 22. lifshitz da, shikanov sa, deklaj t, katz mh, zorn kc, shalhav al. laparoscopic partial nephrectomy for tumors larger than 4 cm: a comparative study. j endourol. 2010;24:49-55. 23. breda a, stepanian sv, liao j, et al. positive margins in laparoscopic partial nephrectomy in 855 cases: a multi-institutional survey from the united states and europe. j urol. 2007;178:47-50; discussion vol 13 no 06 november-december 2016 2907 reconstructive surgery 272 urology journal vol 6 no 4 autumn 2009 delayed retropubic urethroplasty of completely transected urethra associated with pelvic fracture in girls jalil hosseini, kamyar tavakkoli tabassi, abdollah razi introduction: the objective of the present study was to evaluate the results and the complications of delayed retropubic urethroplasty of completely transected urethra associated with pelvic fracture in girls. materials and methods: from 2002 to 2008, a total of 7 girls with complete urethral disruption after pelvic fracture were referred to our center and all of them underwent delayed retropubic urethroplasty with end-to-end anastomosis of the urethra. results: seven female patients with a median age of 6 years old underwent delayed end-to-end anastomosis. the median time to surgery was 6 months from the trauma. voiding was normal after catheter removal in all of the patients. the median follow-up was 36 months. three patients had mild stress urinary incontinence after catheter removal. conclusion: there are some different strategies for management of complete urethral avulsion in females who have sustained pelvic fracture, including early realignment, bladder flaps, and end-to-end anastomosis. the strategy of delayed end-to-end anastomosis urethroplasty with retropubic approach is sound and produces acceptable results. the use of flexible cystoscope and omental flap is effective in achieving continence after urethroplasty in such cases. urol j. 2009;6:272-5. www.uj.unrc.ir keywords: pelvic bones, bone fractures, female, urethra, urologic surgical procedures, urinary incontinence reconstructive urology center, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran corresponding author: kamyar tavakkoli tabassi, md department of urology, imam-reza hospital, mashhad, iran tel: +98 915 311 6149 e-mail: kamiartt@yahoo.com received january 2009 accepted july 2009 introduction most severe urethral injuries, both in children and adults, occur in males after pelvic fracture.(1) among female patients with pelvic fracture, concomitant urethral injury is rather rare. short length, greater mobility (male membranous urethra, unlike female urethra, is relatively fixed to the pelvic bones), and protection by the bony arch protects the urethra in women and girls against injury during pelvic fracture.(2) trauma to the female urethra is a poorly understood entity that has been reported only sporadically in the literature. trauma to the female urethra is estimated to occur in 4.6% to 6.0% of pelvic fractures,(3,4) and it has been reported more frequently in children than adults.(5,6) there are not any established guidelines for the management of ruptured female urethra in either adults or children. (1) while some surgeons prefer a staged repair, which includes temporary urinary diversion with suprapubic cystostomy and delayed definitive repair after several months, others delayed retropubic urethroplasty in girls—hosseini et al urology journal vol 6 no 4 autumn 2009 273 recommend initial definitive repair, except for cases of extensive urethral destruction, when complex reconstructive procedures are needed. (2,7) however, since female urethral injury is rare, there is a paucity of data about the outcome of different management strategies in the literature; therefore, a consensus has not been established whether a 2-stage or a 1-stage management is preferred. herein, we report our experience with delayed end-to-end anastomosis in 7 young girls with complete distraction defect of the urethra after an injury associated with pelvic fracture. materials and methods from 2002 to 2008, we had 7 young girls with urethral injury after pelvic fracture referred to our center. we had briefly reported 5 of them previously.(8) the median patients’ age at the time of injury was 6 years (range, 4 to 13). all of the patients had complete disruption of the urethra after pelvic fracture and had suprapubic catheter. six patients had pelvic fracture due to car accident and 1 patient after falling down. one of the patients had undergone splenectomy after car accident. a 13-year-old girl had vaginal disruption and hydrometrocolpus after pelvic fracture. she had undergone a prior urethroplasty that had failed. the patients underwent delayed end-to-end anastomosis urethroplasty, about 6 month (5 to 7 months) after the injuries. after incision on the suprapubic area, while the patient was secure in the lithotomy position, the bladder neck was released and, as we reported in male patients previously,(9) fibrous tissue around the proximal urethra was removed under the guide of a flexible cystoscope. then, the distal end of the urethra was identified, and after removal of fibrotic tissue, end-to-end anastomosis with 6 absorbable (3-0) vicryl sutures was performed. in 2 girls—one with noncompetent bladder neck and another with a history of vaginal injuries—we released the omentum and wrapped it around the bladder neck. to release the omentum, the patient underwent midline laparatomy, followed by the release of the omentum on its blood supply. then, the bladder neck was dissected at the suprapubic region, urethroplasty was performed, and the omental flap was wrapped around the bladder neck. in 1 case, there was no proximal urethra and there was only 1 small dimple on flexible cystoscopy. therefore, we incised the bladder at the dimple site under the visual guide of the flexible cystoscope and anastomized the distal urethra to the bladder (not to the obvious bladder neck). after 3 weeks, we removed the urethral catheter, followed by removal of the suprapubic catheter the next week, after making sure there were no voiding problems. we followed our patients at 2 weeks, 1 month, and every 2 months for 6 months, and every 6 months thereafter, by cystoscopy. the mean follow-up period was 36 months (range, 8 to 48 months). results seven girls with a median age of 6 years (range, 4 to 13 years) underwent delayed end-to-end anastomosis following urethral injury. the median delay time was 6 months from trauma (table). during the operation, the lengths of fibrotic tissue between the distal and proximal urethra was 1 cm to 2.5 cm, and after removal of fibrotic tissue, we had enough lengths of the urethra for end-to-end anastomosis. in 1 case, patient age condition delay, mo fibrous gap, cm result follow-up, mo 1 4 complete urethral disruption 6 2.0 normal voiding 48 2 7 complete urethral disruption 6 1.5 mild stress incontinence (transient) 36 3 6 complete urethral disruption 7 1.0 mild stress incontinence (transient) 48 4 9 complete urethral disruption 5 2.5 mild stress incontinence (transient) 48 5 5 complete urethral disruption + spelenectomy 6 1.5 normal voiding 32 6 6 complete urethral disruption 7 2.0 normal voiding 8 7 13 complete urethral disruption + vaginal disruption 6 2.0 urethrovaginal fistula treated by continuous bladder drainage 32 characteristics of girls with urethral injuries who underwent delayed urethroplasty delayed retropubic urethroplasty in girls—hosseini et al 274 urology journal vol 6 no 4 autumn 2009 there was no proximal urethra and there was only a dimple on flexible cystoscope at the bladder neck region. we incised the bladder at the dimple site and anastomosed the distal urethra to the bladder. the patient was continent later presumably because of the external sphincter mechanism. we did not use bladder flap in our cases. one patient had been undergone a previous urethroplasty which had been failed. the median follow-up period was 36 months (range, 8 to 48 months). voiding was normal after catheter removal in all of the patients. three patients had mild stress urinary incontinence after catheter removal that was treated using the kegel exercise and medical treatment. other patients were continent. in one case, in which the patient had vaginal injury, urethrovaginal fistula developed after urethroplasty. we managed it by antibiotic therapy and placement an indwelling foley catheter. the fistula was healed by continuous drainage after 2 months, and we removed the catheter. discussion urethral injuries both in adults and children usually occur in males and are associated with pelvic fractures.(1,10-12) in a review of the literature through 1964, we did not find any case report.(13) however, it is now believed that female urethral rupture occurs in 4.6% to 6.0% of pelvic fractures, more frequently in children than adults.(3,5,6) the true incidence of injuries to female urethra in pelvic fracture remains unclear. overall, with a ratio of 1.5:1, pelvic fractures are more common in females than in males.(13,4) one would expect, therefore, that urethral injury would be common in females. orkin’s review of pelvic fractures(4) showed an incidence of 6%, while perry and husmann(14) found an incidence of 4.6% for urethral injury in females among 130 pelvic fractures. this disagrees with the reports by carter and schafer(15) and antoci and schiff(16) who found no urethral injuries in their series. other case reports and case series usually include one or two cases only. most reported cases of urethral injuries in the literature, so far, have been in young girls. (11,17-20) rather than adults.(13,17,18,21) this would suggest that either adults are less susceptible to this injury,(19) or that adults tend to die more commonly from associated injuries.(13,14) three types of female urethral injury may results from traumatic fracture of the pelvis: simple urethral contusion, complete or partial transection, and urethral injury.(4,13,22) in girls, the most prevalent type of injury seems to be complete rupture of the urethra, which may occur at any level along the urethral course.(13,20,23) in our series, all of the patients had complete urethral disruption. since our patients were referred to us from other centers, we cannot evaluate the prevalence of different types of urethral injuries. in venn and colleagues’ series of 12 patients with urethral injuries, 9 suffered from vaginal injuries and 4 had rectal injuries.(13) podesta and jordan reported associated vaginal injury in 87% of their patients. the injuries in podesta and jordan’s studies varied from partial disruption of the anterior vaginal wall, at the site of the urethral distraction defect, to circumferential vaginal rupture.(22) in our series, 1 patient had undergone splenectomy at the time of trauma and 1 had vaginal injury. the best management strategy for acute urethral disruption in females remained controversial. the debate mostly is between those who favor immediate repair versus those who advocate initial urinary diversion and delayed surgical reconstruction.(5,14,19,24,25) in addition, some authors recommend realignment of the separated urethral ends over a urethral catheter, to avoid tissue dissection or suture placement in the traumatized area.(22,23,26) interestingly, when waterhouse and gross performed primary realignment, according to the method described by banks,(26,27) in 2 girls with complete urethral avulsion at the site of the bladder neck, bladder neck stricture developed in both cases, requiring a repeat surgical procedure. satisfactory urinary control was attained in 5 out of 7 patients in podesta and jordan’s series using a delayed repair strategy. in those series, 1 patient had complete incontinence and another patient had diurnal mild stress incontinence.(22) in venn and colleagues’ report of the 5 patients with avulsion type injury, who underwent reconstruction, 2 required implantation of an artificial urinary sphincter and 1 underwent a delayed retropubic urethroplasty in girls—hosseini et al urology journal vol 6 no 4 autumn 2009 275 rectal fascial sling procedure. all the patients in venn and colleagues’ report were continent 1 to 13 years after the surgery.(13) in our series, 3 patients had mild stress urinary incontinence and were managed by kegel exercise plus medical treatment. the remainders of the patients in our series were completely continent. reasons for high rate of continence in our patients may be the use of flexible cystoscope to guide proper anatomy and the use of omental flap in 2 cases. there was 1 patient who developed urethrovaginal fistula after end-to-end urethroplasty. this patient was successfully managed with conservative management. conclusion in cases of complete urethral avulsion in females who have sustained pelvic fracture, the strategy of delayed end-to-end anastomosis urethroplasty with retropubic approach is sound and produces acceptable results. the use of flexible cystoscope and omental flap is effective in saving continence after urethroplasty in such cases. conflict of interest none declared. references 1. lee yt, lee jm. delayed retropubic urethroplasty of completely transected female membranous urethra. urology. 1988;31:499-502. 2. hemal ak, dorairajan ln, gupta np. posttraumatic complete and partial loss of urethra with pelvic fracture in girls: an appraisal of management. j urol. 2000;163:282-7. 3. black pc, miller ea, porter jr, wessells h. urethral and bladder neck injury associated with pelvic fracture in 25 female patients. j urol. 2006;175:2140-4; discussion 4. 4. orkin la. trauma to the bladder, ureter, and kidney. in: sciarra jj, editor. gynecology and obstetrics. philadelphia: lippincott; 1991. p. 1-8. 5. okur h, kucikaydin m, kazez a, turan c, bozkurt a. genitourinary tract injuries in girls. br j urol. 1996;78:446-9. 6. ahmed s, neel kf. urethral injury in girls with fractured pelvis following blunt abdominal trauma. br j urol. 1996;78:450-3. 7. thambi dorai cr, boucaut hap, dewer pa. urethral injuries in girls with pelvic trauma. eur urol. 1993;24:371-4. 8. hosseini sj, kaviani a, jabbari m, hosseini mm, hajimohammadmehdi-arbab a, simaei nr. diagnostic application of flexible cystoscope in pelvic fracture urethral distraction defects. urol j. 2006;3:204-7. 9. hosseini sj, kaviani a. urethroplasty in female patients. presented in 9th congress of iranian urological association, 2008 tehran. 10. waterhouse k, laungani g, patil u. the surgical repair of membranous urethral strictures: experience with 105 consecutive cases. j urol. 1980;123:500-5. 11. guerriero wg, devine cj jr. urologic injuries. 1st ed. norwalk (ct): connecticut, appleton-century-crofts; 1984. p. 143-5. 12. williams di. rupture of the female urethra in childhood: nine cases. birth defects orig artic ser. 1977;13:239-40. 13. venn sn, greenwell tj, mundy ar. pelvic fracture injuries of the female urethra. bju int. 1999;83: 626-30. 14. perry mo, husmann da. urethral injuries in female subjects following pelvic fractures. j urol. 1992;147:139-43. 15. carter ct, schafer n. incidence of urethral disruption in females with traumatic pelvic fractures. am j emerg med. 1993;11:218-20. 16. antoci jp, schiff m, jr. bladder and urethral injuries in patients with pelvic fractures. j urol. 1982;128:25-6. 17. simpson-smith a. traumatic rupture of the urethra: eight personal cases with a review of 381 recorded rupture. br j surg. 1936;24:309-32. 18. bredael jj, kramer sa, cleeve lk, webster gd. traumatic rupture of the female urethra. j urol. 1979;122:560-1. 19. patil u, nesbitt r, meyer r. genitourinary tract injuries due to fracture of the pelvis in females: sequelae and their management. br j urol. 1982;54:32-8. 20. zein t, sidani m. ruptured urethra in a female. saudi med j. 1992;13:63-4. 21. barach e, martin g, tomlanovich m, nowak r, littleton r. blunt pelvic trauma with urethral injury in the female: a case report and review of the literature. j emerg med. 1984;2:101-5. 22. podesta ml, jordan gh. pelvic fracture urethral injuries in girls. j urol. 2001;165:1660-5. 23. williams di. rupture of the female urethra in childhood. eur urol. 1975;1:129-30. 24. pode d, shapiro a. traumatic avulsion of the female urethra: case report. j trauma. 1990;30:235-7. 25. parkhurst jd, coker je, halverstadt db. traumatic avulsion of the lower urinary tract in the female child. j urol. 1981;126:265-7. 26. waterhouse k, gross m. trauma to the genitourinary tract: a 5-year experience with 251 cases. j urol. 1969;101:241-6. 27. banks h. ruptured urethra: a new method of treatment. br j surg. 1927;15:262. vol 16 no 02 march-april 2019 107 review comparison of supracostal and infracostal access for percutaneous nephrolithotomy: a systematic review and meta-analysis zhaohui he1* fucai tang1,2* zechao lu3* ye he3, genggeng wei4 , fangling zhong2, guohua zeng2, weizhou wu2, lemin yan5, zhibiao li6 purpose: in this meta-analysis, we aimed to compared efficacy and safety of supracostal and infracostal access for percutaneous nephrolithotomy (pcnl). materials and methods: we included eligible studies from pubmed, embase, cochrane library, web of science and china national knowledge infrastructure. literature searching, quality assessment and data extraction were performed by two independent reviewers. data were analyzed by revman software. binary and continuous variables were calculated as odds ratios (or) and mean difference (md). results: two prospective comparative studies and seven retrospective observational studies were included in the meta-analysis, which contained 1,024 cases of supracostal access and 1,249 cases of infracostal access for pcnl. the supracostal access resulted in a significant reduced mean hemoglobin (95% ci: 0.26-3.46, md = 1.86 g/l, p = .02) and a higher incidence of hydrothorax (95% ci: 4.77-22.95: or = 10.47, p < .00001) compared to infracostal access. however, there no difference between supracostal and infracostal access regarding additional procedures (95% ci: 0.70-1.69, or = 1.09, p = .71), stone-free rate (95% ci: 0.80-1.72, or = 1.18, p = .41), length of hospital stay (95% ci: -0.03-0.37, md = 0.17 day, p = .10), and occurrence of fever (95% ci: 0.95-2.03, or = 1.39, p = .09) and blood transfusion (95% ci: 0.45-1.70, or = 0.88, p = .70). no publication bias was identified in the study. conclusion: supracostal access was effective, but not as safe as infracostal access pcnl due to a higher risk of reduced hemoglobin and hydrothorax. therefore, infracostal access should be the preferred safe and effective approach recommended for pcnl. when a supracostal puncture is performed, essential precautions to avoid hemoglobin loss and hydrothorax should be used. key words: infracostal access; supracostal access; percutaneous nephrolithotomy; meta-analysis introduction the use of percutaneous nephrolithotomy (pcnl) was first reported by fernströmand johansson in 1976(1). the overall success rates of pcnl have been > 90% since the 1980s(2). pcnl is the first line choice to treat large or complex kidney stones ( > 2 cm)(3,4), stones obstructing the kidney, hard stones and residual stones following failed shock wave lithotripsy. pcnl is also used as a treatment for kidney stones in patients with skeletal abnormalities, morbidly obese patients and patients with spinal cord injury(5-7). achieving suitable access to the appropriate calyx is one of the most important steps during the pcnl procedure. effective puncture is key for the success of pcnl. many stud1department of urology, the eighth affiliated hospital, sun yat-sen university, shenzhen, china. 2department of urology, minimally invasive surgery center, guangdong provincial key laboratory of urology, the first affiliated hospital of guangzhou medical university, guangzhou, china. 3first clinical college of guangzhou medical university, guangzhou, china. 4department of urology, hongkong university-shenzhen hospital, shenzhen, china. 5college of stomatology, guangzhou medical university, guangzhou, china. 6third clinical college of guangzhou medical university, guangzhou, china. *equal contributors *correspondence: department of urology, the eighth affiliated hospital, sun yat-sen university, shenzhen, 518033. p.r. china. tel: +86 0755 83982222. fax: +86 0755 83980805. e-mail: gzgyhzh@163.com. received august 2018 & accepted january 2019 ies have reported that supracostal access for pcnl is advantageous over infracostal access(8-13). the greatest advantage of supracostal access is the shorter distance, creating the most direct establishment of a percutaneous tract(14). however, pulmonary complications, such as pneumothorax, hydrothorax and lung injury, are more common with the supracostal approach(14). in recent years, with the improvement of clinical skills, more urologists are aware of the limitations of infracostal access and have attempted to use the supracostal approach; however, whether a supracostal or infracostal approach is best remains controversial. to conduct an updated study and provide more evidence that will serve as a basis for clinical decisions, we collected published studies reporting on the treatment of upper urinary calculi using supracostal and infracostal pcnl. a meta-analysis was performed to evaluate the outcomes of the procedures. patients and methods literature search because the current study was a meta-analysis based on the published articles, the consents of patients and approval of institutional review boards were not included. a literature search of pubmed, embase,web of science, cnki and the cochrane library was performed to identify relevant studies. no time or language restrictions were applied. the following subject headings and keywords “percutaneous nephrostomy”, “supracostal” and “supracostal”, were used for each electronic databases. the full electronic search strategy in pubmed that were “(((((((percutaneous nephrostomy) or nephrostomies percutaneous) or percutaneous nephrostomies) or nephrolithotomy percutaneous) or nephrolithotomies percutaneous) or percutaneous nephrolithotomies) or percutaneous nephrolithotomy) and (supracostal or infracostal). ” articles were also identified using the 'related articles’ function. the latest date of this search was 3 march 2017, without lower date limit. the reference lists of retrieved articles were manually searched to identify related articles. the review was limited to the published studies. study selection criteria our search was not restricted to randomized controlled trials (rcts). controlled clinical trials and comparative studies were also included. review articles, meeting abstracts, editorials, case reports and commentaries were excluded. using the patient, intervention, comparison, outcome and study design (picos) method(15), the picos evidence base consisted of the following features: p, patients with upper urinary calculi; i, the use of pcnl or miniaturized percutaneous nephrolithotomy (mpcnl; with an access diameter of 14f-20f); c, comparing supracostal with infracostal access; o, safe and effective operation outcomes. eligible trials included patients harboring upper urinary calculi with an indication for pcnl or mpcnl. there was no restriction on the gender and age of patients. the studies should have included a controlled analysis of supracostal approaches and infracostal approaches for pcnl. the inclusion criteria were as follows:(1) patients with upper urinary calculi;(2) comparing supracostal with infracostal access;(3) relative data that were reported or could be calculated. the exclusion criteria were as follows: (1) conference abstracts, no control group and incomplete data;(2) inclusion criteria were not met. the citations, abstracts and full text of all potentially relevant studies were independently evaluated and independently selected by two reviewers (tang and lu). the final selection of the included studies was achieved through a consensus between the reviewers. data extraction and assessment of study quality the studies were screened according to the inclusion and exclusion criteria. two reviewers (tang and lu) independently assessed, extracted and tabulated data from each article using a predefined data extraction form. data regarding the following factors were obtained: first author, country, year of publication, baseline patient characteristics, intervention, outcome measures, statistical methods and results, and study conclusions. the outcome parameters assessed were additional procedures (such as shock wave lithotripsy, spontaneous passage, flexible ureterorenoscopy and others), length of hospital stay, reduced mean hemoglobin, stone-free, postoperative hydrothorax, fever and blood transfusion. assessment of study quality the methodological quality of the studies was assessed using the newcastle-ottawa scale(16) for observational studies. the scale consists of three domains indicating the study quality as: selection (4 points), comparability (2 points) and outcome (3 points) for a total score of 9 points (with 9 representing the highest quality). studies scoring 0-3 points, 3-6 points, 7-9 points were set as low, moderate and high quality, respectively. statistical analysis review manager (revman 5.0.2: cochrane library software, oxford, uk ) software was used to perform the meta-analysis. outcomes were presented as the mean difference (md) for continuous data and odds ratio (or) for categorical data with 95% confidence intervals (ci). considering the high likelihood of inter-study variance for differences in study design and study population, a random effects model, rather than a fixed eftable1. the basic characteristic of included studies study design age no.of patient mean stone size gender(n) side comparability study supracostal infracostal supracostal infracostal supracostal infracostal male female right left quality (score) r.john 2011(19) r 52.2 ± 13.4 53.5 ± 15.2 154 164 695 ± 629 mm2 596 ± 843 mm2 184 134 182 136 1, 2, 3, 4, 5, 6, 7 ****** difu 2005(20) r 42.4 ± 17.5 45.3 ± 2.35 40 43 7.98 ± 2.29 cm2 7.56 ± 2.35 cm2 na na 1, 2 **** sinha 2016(23) p na 41.05 ± 15.43 366 334 p < .05 na 379 321 1, 5, 6, 7 ****** faruk 2017(25) r 42 ± 15 38 ± 16 49 49 27.1 ± 11.3 mm 27.5 ± 11.1 mm 67 31 na 1, 2, 4 ****** b. lojanapiwat r 51.64 ± 11.93 52.05 ± 12.56 170 294 41.5 ± 18 mm 38.2 ± 15.5 mm 293 171 229 235 1, 2, 3, 7 ****** 2006(14) rohit 2015(24) p 39.84 ± 10.42 39.53 ± 10.23 43 51 39.02 ± 6.27 mm 39.53 ± 7.17 mm 61 33 49 45 2, 3, 4, 5, 6, 7 ****** ravi 2001(26) r 47(7-84) 98 202 na 132 108 106 140 6, 7 **** jing zhang2012(21) r 56.5 ± 9.2 58.1 ± 9.8 70 82 3.78 ± 1.7 3.51 ± 1.5 85 67 73 79 1, 5, 6, 7 ****** yangwen zeng r 42-72 45-78 34 30 0.9-2.5 cm 0.7-2.4 cm 40 24 na 1, 6 ***** abbreviations: r, retrospective; p, prospective; na, not available; 1, stone-free; 2, additional procedure; 3, length of hospital stay; 4, reduced mean hemoglobin; 5, fever; 6, blood transfusion; 7, hydrothrax. comparision of supracostal and infracostal access for pcnl-zhaohui he et al. review 108 vol 16 no 02 march-april 2019 109 fects model, was used in the present study. a statistic for measuring heterogeneity was calculated using the i2 method; 25-50% was considered low-level, 50-75% moderate-level and >75% high-level heterogeneity(17). the z-test was used to analyze the overall effect on or and md, and p < .05 was considered statistically significant. the results of the meta-analysis are expressed using forest plots. in addition, publication bias analysis was visually assessed using funnel plots of effect estimates, and begg’s and egger’s tests(18). the statistical analysis was performed using stata (version 13.0; statacorp lp, college station, tx, usa). results the publication dates of the studies included in the meta-analysis varied from 2001 to 2017, and the reports originated from canada(19), china(20-22), india(23-24), turkey(25), thailand(14) and the usa(26). figure 1 illustrates the process of literature identification and selection as a flow diagram. finally, nine studies(14,19-26) were included in the meta-analysis. two studies(23, 24) were prospective and the remaining studies were retrospective observational studies. the basic characteristics of the included studies are presented in table 1(14,19-26). there were 2,273 patients, of which 1,024 patients underwent pcnl with supracostal access, and 1,249 patients underwent pcnl with infracostal access. two studies performed minimally invasive pcnl(20,25) and one study used the novel prone-flexed position for pcnl(19). for the observational studies, the risk of bias was evaluated using the modified newcastle-ottawa scale. each study included in the meta-analysis was judged on three broad perspectives: the selection of the study cases, the comparability of the study populations and the ascertainment of either the exposure or outcome of interest. four studies(14,21,24,25) received a score of 7 and were considered to be of high quality (table 1). meta-analysis stone-free outcome the data from seven studies(14,19-23,25) were pooled to assess the stone-free outcome between the supracostal access groups and the infracostal access groups. these studies were divided into pcnl and mpcnl subgroups according to whether pcnl or mpcnl was performed. in general, heterogeneity analysis produced i2 = 48% and p = .07. there was no significant difference between supracostal and infracostal groups (95% ci: 0.80-1.72, or = 1.18, p = .41; figure 2). in the mpcnl subgroup, there was no significant difference between the supracostal and infracostal groups (95% ci: 0.48-2.54, or = 1.11, p = .81; figure 2), in the figure 1. flow diagram of studies identified, included and excluded. figure 2. forest plot showing the stone-free rate of supracostal and infracostal access for pcnl comparision of supracostal and infracostal access for pcnl-zhaohui he et al. pcnl subgroup, there was no significant difference between the supracostal and infracostal groups (95% ci: 0.77-2.01, or = 1.24, p = .38; figure 2). additional procedures five studies(14,19,20,24,25) compared the additional procedures between the supracostal and the infracostal access groups. heterogeneity analysis produced i2 = 0%, and p = .60. the meta-analysis of additional procedures showed no difference between the supracostal and infracostal access groups (95% ci,: 0.70-1.69, or = 1.09, p = .71; figure 3). in the mpcnl subgroup, there was no significant difference between the supracostal and infracostal groups (95% ci: 0.42-2.45, or = 1.01, p = .97; figure 3). in the pcnl subgroup, there was no significant difference between the supracostal and infracostal groups (95% ci: 0.59-1.95, or = 1.07, p = .83; figure 3). length of hospital stay the length of hospital stay following supracostal and infracostal access pcnl was compared in three studies(14,19,24,25). a heterogeneity test revealed that no significant heterogeneity existed among the studies (i2 = 0.0% and p = .65). a pooled analysis revealed that no significant difference existed in the length of hospital stay between the supracostal access and the infracostal access groups (95% ci: -0.03-0.37, md = 0.17 day, p = .10; figure 4). reduced mean hemoglobin figure 5 presents a comparison of the hemoglobin decrease between the supracostal and the infracostal access groups. heterogeneity analysis revealed no heterogeneity (i2 = 2.0% and p = .36). a pooled analysis revealed that there was less of a hemoglobin decrease in the infracostal access group compared with the supracostal access group (95% ci: 0.26-3.46, md = 1.86 g/l, p = .02; figure 5)(19,24-25). postoperative complications a heterogeneity test revealed that no significant heterogeneity existed among the studies for each of the postoperative complications analyzed (fever, i2 = 0.0% and p = .86; blood transfusion, i2 = 8.0% and p = .36; hydrothorax, i2 = 0.0% and p = .91).there was no significant difference in the occurrence of fever between the supracostal access and the infracostal access groups (95% ci: 0.95-2.03, or = 1.39; p = .09; figure 6a) (19,21,23,24), or in the occurrence of blood transfusion (95% ci: 0.45-1.70, or = 0.88, p = .70; figure 6b) (19,21-24,26). however, compared with infracostal access, pcnl with supracostal access was associated with a higher risk of hydrothorax (95% ci: 4.77-22.95, or = 10.47, p < .00001; figure 6c)(14,19,21,23,24,26). publication bias publication bias analysis was assessed by the begg’s figure. 3. forest plot showing the additional procedure of supracostal and infracostal access for pcnl figure 4. forest plot showing the length of hospital stay of supracostal and infracostal access for pcnl comparision of supracostal and infracostal access for pcnl-zhaohui he et al. review 110 vol 16 no 02 march-april 2019 111 and egger’s test. visualization of the funnel plot indicated that both begg’ s rank correlation test and egger’ s linear regression yielded non-significant publication bias in the overall meta-analysis of stone-free(begg’ s, p > |z| = .072; egger bias = 2.33, 95% ci: -0.44-8.84, p > |t| = .067), additional procedure (begg’ s, p > |z| = 1.000; egger bias = -1.04, 95% ci: -6.31-3.20, p > |t| = .375) , length of hospital stay(begg’ s, p > |z| = .734; egger bias = -2.08, 95% ci: -5.06-1.77, p > |t| = .174) , reduced mean hemoglobin(begg’ s, p > |z| =1.000; egger bias = 0.45, 95% ci: -21.38-22.96, p > |t| =.729), fever(begg’ s, p > |z| = .734; egger bias= 0.39, 95% ci: -2.75-3.29, p > |t| = .735),blood transfusion(begg’ s, p > |z| = 1.00; egger bias = 0.05, 95% ci: -4.29-4.44, p > |t| = .960) , and hydrothorax(begg’ s, p > |z| = .060; egger bias = -2.05, 95% ci: -16.93-2.53, p > |t| =.109) discussion pcnl has replaced the use of open surgery for removing large and complex renal or upper ureteral calculi, as it is a minimally invasive technique(27). gaining optimal and atraumatic access to the desired calyx is the first step in a successful pcnl. a safe and effective pcnl puncture is defined as one that provides the shortest and straightest access to all calculi, avoiding major vessels, the bowel and lungs, and achieves minimal parenchymal damage(23). access guided by ultrasonography can be effective and safe as it allows clear visualization of the kidney and calyceal system to obtain optimum access to the stone/s(28,29). in the present meta-analysis, supracostal and infracostal access were evaluated to compare their efficacy and safety as approaches for pcnl. nine studies were included in the analysis with a total study population of 2,273 patients. fan et al.(20) previously reviewed the results of 98 mpcnls and their results revealed that there was no negative effect on any intraoperative and postoperative parameters, or any increase complication rates when comparing supracostal and infracostal access. however, ozgor et al.(25) reviewed 83 cases involving treatment with mpcnl and found that there were several advantages of infracostal access, including increased accuracy in establishing a percutaneous tract, safety, speed, convenience and flexibility in moving the patented sheath. sinha et al.(23) performed a retrospective review of 777 patients who underwent pcnl and suggested that the avoidance of the supracostal approach was unnecessary, although there was an increase in thoracic complications when the supra 11th approach (between the 10th and 11th ribs) was used, compared with the infracostal approach. munver et al.(26) retrospectively reviewed the outcomes of 300 patients treated with pcnl. complications included blood transfusion in 7 patients and intraoperative hemothorax/hydrothorax in 5 patients. their report demonstrated that the supracostal approach provided relatively safe access when subcostal angulation was not feasible. lojanapiwat et al.(14) reported on 464 cases treated comparision of supracostal and infracostal access for pcnl-zhaohui he et al. figure 5. forest plot showing the reduced mean hemoglobin of supracostal and infracostal access for pcnl figure 6. forest plot showing the postoperative complications of supracostal and infracostal access for pcnl. a: fever. b: blood transfusion. c: hydrothorax. with pcnl, with subsequent hydrothorax occurring in 26 supracostal puncture cases and 4 subcostal access cases. the rate of pulmonary complications was higher following supracostal access, indicating that supracostal access should be used with caution if unavoidable. honey et al.(19) performed 318 pcnl procedures using the novel prone-flexed patient position pcnl, and confirmed that supracostal access was a safe alternative to infracostal access when the risk of pleural complications was acceptable. singh et al.(24) collected clinical data from 94 patients that underwent pcnl to treat complex renal stones and suggested that upper calyceal puncture through the supra 12th rib was a feasible option in patients with complex/large staghorn calculi, which might minimize lung/pleural injury and obtain a better clearance rate. zhang and zhao(21) reported that supracostal access provided a straight path and the shortest distance to the pelvis, which resulted resulted in a higher rate stone-free status and reduced operating time in 152 pcnl cases. yang et al.(22) retrospectively reviewed 64 patients with upper ureter calculi treated using pcnl. their study also reported that supracostal access pcnl was safe and effective for the treatment of upper ureter stones. to the best of our knowledge, this study was the first meta-analysis to compare the safety and efficacy of supracostal and infracostal access pcnl for the treatment of upper urinary stones. our study showed the was no significant difference between groups in terms of stonefree outcome, additional procedures required, the length of hospital stay and postoperative complications (fever, blood transfusion), which was similar to the findings of previous studies. however, the mean hemoglobin reduction and rate of hydrothorax were significantly increased when using the supracostal approach, compared with infracostal access. these results indicated that supracostal puncture was effective, but not as safe as infracostal access for pcnl. the present study showed that supracostal access was more likely to cause reduced postoperative hemoglobin levels compared to infracostal access (p < 0.05), but the need for blood transfusion was not associated with the postoperative hemoglobin decrease. some studies have reported that blood transfusion rates were up to 17.5% in patients that underwent pcnl(30,31). bleeding was thought to be predominantly caused by intercostal artery injury; however our study revealed that appropriate supracostal puncture did not increase bleeding as a post-operative complication. in our meta-analysis, patients that received pcnl with supracostal access had a higher rate of hydrothorax compared with infracostal access, and lojanapiwat et al.(14) and cocuzza et al.(32) reported similar results in their respective studies. however, many researchers believe that these complications could be reduced to a minimum by using appropriate precautionary techniques(14,33). entering under the 12th rib is the first choice for the establishment of a percutaneous tract for pcnl, and many scholars believe that the infracostal access approach to should be used to avoid thoracic complications, including pneumothorax, hydrothorax and lung injury. however, with infracostal access it can be difficult to achieve a good stone clearance rate for complex upper urinary tract stones, including simple kidney calculi and staghorn calculi. the 11th intercostal access and 10th intercostal access shorten the distance comparision of supracostal and infracostal access for pcnl-zhaohui he et al. required to establish a percutaneous tract. this was also one of the reasons why many scholars advocate using supracostal access(11,13,34). lang et al.(35) reported that the use of supracostal puncture for pcnl had a high stone clearance rate; however, supracostal puncture could increase the rate of complications(36). due to the anatomical locations involved, supracostal puncture can easily penetrate the diaphragm, and might damage the pleura and lungs. some studies have reported that supracostal puncture for pcnl has a risk of pleural injury between 0 and 12.5%(32). however, due to scientific and technological improvements, the complications caused by supracostal access can be tolerated; therefore, an increasing number of clinicians choose to use supracostal access. lojanapiwat et al.(14) reported that intercostal access applied to reach the target calyx had the shortest distance, and this approach can reduce thoracic complications to a minimum. pedro et al.(37) reported that preoperative retrograde or anterograde pyelography can be applied to determine the anatomy of the renal pelvis, and x-ray guidance can reduce the incidence of thoracic complications. lang et al.(35) suggested that by using ct guidance, the application of ureteroscopy for pcnl surgery could reduce the supracostal access complication rate. therefore, taking steps to avoid thoracic complications is key to successful supracostal access for pcnl, which requires more surgical skills. there are certain limitations to our study. firstly, the scarcity of rcts comparing supracostal and infracostal access for pcnl was the main shortcoming when creating this meta-analysis. additionally, the sample size of most studies was highly variable, so the statistical power to identify differences in the outcomes was limited. furthermore, some data were reported in the studies as “range”; these data may not be normally distributed, and the bias of the pooled effect should be considered. finally, we cannot guarantee that all the relevant articles have been searched and included in our study, as nonsignifcant a unpublished. despite these limitations, no publication bias was identified in our study. conclusions in conclusion, infracostal access is the preferred approach recommended for pcnl, and is safe and effective. moreover, the supracostal approach for pcnl did not cause a significant difference in intraoperative and postoperative factors, or complications rates (fever, blood transfusion). supracostal access was effective, but did lead to a higher risk of reduced hemoglobin levels and hydrothorax when compared to infracostal access. therefore, infracostal access should be the preferred option for pcnl surgery. essential precautions to avoid hemoglobin loss and hydrothorax are required when supracostal puncture is chosen. however, further high quality rcts, with larger sample sizes, are required to compare the effectiveness of supracostal and infracostal access and confirm these findings. acknowledgement funding this study was supported by science and technology planning project of guangdong province (no.2017b030314108). ethical statements this is a systematic review and meta-analysis article, all analyses were based on previous published studies. therefor, this article does not conreview 112 vol 16 no 02 march-april 2019 113 tain any studies with human participants or animals performed by any of the authors. thus no ethical approval and patient consent are required. conflict of interest the authors declare that they have no conflict of interest. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol.1976; 10:257-259. 2. alken p, hutschenreiter g, gunther r, marberger m. percutaneous stone manipulation. j urol. 1981;125:463-466. 3. atis g, culpan m, pelit es, et al. comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery in treating 2040 mm renal stones. urol j. 2017;14:29952999 4. sari s, ozok hu, cakici mc, et al. a comparison of retrograde intrarenal surgery and percutaneous nephrolithotomy for management of renal stones > 2 cm. urol j. 2017;14:2949-2954 5. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016;13:2899-2902 6. schultz-lampel d, lampel a. the surgical management of stones in children. bju int. 2001; 87:732-740. 7. mousavi-bahar sh, amirhasani s, mohseni m, daneshdoost r. safety and efficacy of percutaneous nephrolithotomy in patients with severe skeletal deformities. urol j. 2017;14:3054-6058. 8. sukumar s, nair b, ginil kp, sanjeevan kv, sanjay bh. supracostal access for percutaneous nephrolithotomy: less morbid, more effective. int urol nephrol. 2008; 40:263-267. 9. mousavi-bahar sh, mehrabi s, moslemi mk. the safety and efficacy of pcnl with supracostal approach in the treatment of renal stones. int urol nephrol. 2011; 43:983-987. 10. golijanin d, katz r, verstandig a, sasson t, landau eh, meretyk s. the supracostal percutaneous nephrostomy for treatment of staghorn and complex kidney stones. j endourol. 1998; 12:403-405. 11. kekre ns, gopalakrishnan gg, gupta gg, abraham bn, sharma e. supracostal approach in percutaneous nephrolithotomy: experience with 102 cases. j endourol. 2001;15:789-791. 12. jun-ou j, lojanapiwat b. supracostal access: does it affect tubeless percutaneous nephrolithotomy efficacy and safety? int braz j urol. 2010;36:171–176 13. munver r, delvecchio fc, newman ge, preminger gm. critical analysis of supracostal access for percutaneous renal surgery. j urol. 2001;166:1242-1246. 14. lojanapiwat b, prasopsuk s. upper-pole access for percutaneous nephrolithotomy: comparison of supracostal and infracostal approaches. j endourol. 2006;20:491-4. 15. liberati a, altman dg, tetzlaff j, et al. the prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. plos med. 2009; 6:e1000100. 16. ga wells, b shea, d o'connell, et al. the newcastle–ottawa scale (nos) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/ clinical_epidemiology/oxford.asp. accessed 23 nov 2014 17. higgins jp, thompson sg, deeks jj et al. measuring inconsistency in meta-analyses. bmj. 2003; 327: 557. 18. egger m, davey smith g, schneider m, minder c. bias in meta-analysis detected by a simple. graphicaltest.bmj. 1997; 315:629–34. 19. honey rj, wiesenthal jd, ghiculete d, pace s, ray aa, pace kt. comparison of supracostal versus infracostal percutaneous nephrolithotomy using the novel prone-flexed patient position. j endourol. 2011;25:947954. 20. fan d, song l, xie d, et al. a comparison of supracostal and infracostal access approaches in treating renal and upper ureteral stones using mpcnl with the aid of a patented system. bmc urol. 2015;15:102. 21. zhang jing, zhao chunli. applied anatomy and clinical application of supracostal approach for percutaneous nephrolithotomy .university of hebei. 2012. 1367. 22. yang wen-zeng, zhang jing, zhao chunli. to evaluate the safety and efficacy of the supracostal access for pcnl in the treatment of upper ureter calculi. chinese general practice. 2012;15:316-317. 23. sinha m, krishnappa p, subudhi sk, krishnamoorthy v. supracostal percutaneous nephrolithotomy: a prospective comparative study. indian j urol. 2016;32:45-9. 24. singh r, kankalia sp, sabale v, et al. comparative evaluation of upper versus lower calyceal approach in percutaneous nephrolithotomy for managing complex renal calculi. urol ann. 2015;7:31-35. 25. ozgor f, tepeler a, basibuyuk i, et al . supracostal access for miniaturized percutaneous nephrolithotomy: comparison of supracostal and infracostal approaches. urolithiasis. 2017;46:279-283. 26. munver r, delvecchio fc, newman ge, preminger gm. critical analysis of supracostal access for percutaneous renal surgery. j urol. 2001;166:1242-1246. comparision of supracostal and infracostal access for pcnl-zhaohui he et al. comparision of supracostal and infracostal access for pcnl-zhaohui he et al. 27. galvin dj, pearle ms. the contemporary management of renal and ureteric calculi. bju int. 2006;98:1283-1288. 28. basiri a, nouralizadeh a, kashi ah, et al. x-ray free minimally invasive surgery for urolithiasis in pregnancy. urol j. 2016;13:2496-501. 29. hosseini mm, hassanpour a, eslahi a, malekmakan l. percutaneous nephrolithotomy during early pregnancy in urgent situations: is it feasible and safe?. urol j. 2017;14:5034-5037 30. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol 2007.51 (4):899906; discussion 906. 31. aron m, yadav r, goel r, et al. multitract percutaneous nephrolithotomy for large complete staghorn calculi. urol int. 2005;75:327-332. 32. cocuzza m, colombo jr jr, cocuzza al, et al. outcomes of flexible ureteroscopic lithotripsy with holmium laser for upper urinary tract calculi. int braz j urol. 2008;34:143-9. 33. shaban a, kodera a, el ghoneimy mn, orban tz, mursi k, hegazy a. safety and efficacy of supracostal access in percutaneous renal surgery. j endourol. 2008;22:29-34. 34. golijanin d, katz r, verstandig a, sasson t, landau eh, meretyk s. the supracostal percutaneous nephrostomy for treatment of staghorn and complex kidney stones. j endourol. 1998;12:403-405. 35. lang e, thomas r, davis r, et al. risks, advantages, and complications of intercostal vs subcostal approach for percutaneous nephrolithotripsy. urology. 2009;74:751-755. 36. weizer az, auge bk, silverstein ad, et al. routine postoperative imaging is important after ureteroscopic stone manipulation. j urol. 200;168:46-50. 37. pedro rn, netto nr. upper-pole access for percutaneous nephrolithotomy. j endourol. 2009;23:1645-1647. review 114 vol 15 no 03 may-june 2018 5 purpose: transurethral lithotripsy (tul) is a major modality for the endoscopic management of ureteral stones. ureteral spasm makes access for ureters difficult, which causes impaction of the ureteroscope, ureteral dislodge, and a low success rate of endoscopic surgeries. this study described the outcomes of a new endoscopic surgical experience by use of 40-degree warm saline irrigation during tul compaired with routine ambient air irrigation in tul. materials and methods: in this randomized clinical trial from 2014 to 2015, 150 patients with ureteral stone with balanced randomization were divided into two parallel groups. patients underwent tul in the first group with 20–25 degree saline irrigation and in the second group with 40-degree saline irrigation. one surgical team with the same semi-rigid instrument performed all tuls and the other steps were similar in both groups. complete stone fragmentation was measured as the primary outcome and the duration of procedure, retrograde stone migration and all and any intraoperative complications were the secondary measurements. result: while comparing warm saline irrigation with cold saline irrigation, the rate of access to upper ureter was 95% versus 72%, stone retropulsion frequency was 10.7% versus 30.7% and the stone-free rate was 96% versus 76% respectively (p < .05). there was no ureteroscope impaction and ureteral dislodge in both groups. conclusion: using warm saline irrigation in endoscopic surgeries results in better surgical outcomes including a lower ureteral spasm rate, greater ureteral muscle relaxation and better access to the upper ureteral zone, and a lower rate of complications, such as ureteroscope impaction, ureteral dislodge and stone retropulsion. keywords: lithotripsy; ureteroscopy; ureteral dislodge; warm saline; irrigation. introduction endoscopic ureteral surgeries are the most common urologic surgeries, including diagnostic ureterostomy, strictures and obstruction treatments, stone lithotripsy, resection and fulguration of ureteral tumors.(1) urolithiasis is a common urological problem. ureteral stones can cause severe morbidity and pain. after failed medical therapy and if intervention is indicated, then various modalities would be available, such as extra corporeal shock wave lithotripsy (eswl) and ureteroscopic management.(1–3) the choice of intervention depends on many factors, including stone size and location, available instruments and surgical team experience. transurethral lithotripsy (tul) is a major modality for endoscopic management of ureteral stones. one of the risk factors in difficult access of ureters is ureteral spasm, which causes the impaction of the ureteroscope, ureteral dislodge, and a low success rate of endoscopic surgeries. difficult access and retrograde stone migration are two main problems during tul, which could require additional instruments such as ureteral dilators, stone retrieval devices, or additional procedures like re-tul or eswl(4, 5), which can cause additional morbidity and cost. by the invention and use of new endoscopic instruments, ureteral endoscopic surgeries are more common. nowadays, diagnostic ureteroscopy, tul, ureteral stones, treatment of ureteral obstructions and resection and fulguration of ureteral tumors are the 1department of urology, mashhad university of medical sciences, mashhad-iran. 2department of community medicine, mashhad university of medical sciences, mashhad-iran. *correspondence: department of urology, mashhad university of medical sciences,mashhad-iran. tel:09151842487. email: alirezaakhavan30@yahoo.com. received february 2017 & accepted october 2017 most common endoscopic urologic surgeries. transurethral lithotripsy is one of the best modalities for ureteral stone management. tul with semi-rigid ureteroscope is one of the most common techniques for this purpose. however, difficult ureteral access and retrograde stone migration are some of the common problems associated with this method.(5–7) additional medications or interventions like tamsulosin therapy, lidocaine jelly, dj placement, re-tul or eswl could be necessary to manage migrated or residual fragments. (2,9-14) there are some maneuvers, such as the reverse trendelenburg position, to prevent stone retropulsion, and there are some devices like stone baskets, n-trap and stone cone that can solve the problem. all of these entail additional morbidity and costs.(2,4,8,15,16) the thickening of the tip to the end of the ureteroscope instrument may result in ureteral spasm and ureteroscope impaction, and result in ureteral spasm and difficultness in procedures of endoscopic surgery. in such situations, ureteral dislodge may occur as well. since 1993, with the use of the first pneumatic lithoclast device in iran in the urological department of ghaem hospital in mashhad, ureteral endoscopic surgeries began, and everyday, many patients underwent tul and other endoscopic procedures. after a few years, we found out that in cases of cold water irrigation during tul, we had more ureteral spasms around the ureteroscope instrument, which led to lower access to the upper ureter. we also had two endourology and stone disease the evaluation of the result of warm normal saline irrigation in ureteral endoscopic surgeries: a randomized clinical trial mohammadali mohammadzadeh rezaei1, alireza akhavan rezayat1, mahmoud tavakoli1*,lida jarahi2 cases of ureteroscope impaction in the ureter, which resulted in ureteral dislodge during 10 years. in the last two decades, with the use of warm 40-degree saline irrigation during tul, we had better surgical outcomes, and ureteral dislodge or ureteroscope impaction were not seen. in this study, we describe our experience and outcomes of warmed saline irrigation during semi-rigid ureteroscopy and tul in patients with ureteral stone. patients and methods study population the participants of this study were patients who were diagnosed with ureteral stone. from may 2014 to may 2015, 150 consecutive patients with 170 ureteral stones were treated at our urologic department with pneumatic tul (tulp). active urinary tract infection, pregnancy, bilateral stones or single functional kidney were the exclusion criteria. in this study, the criteria for successful operation are the small size of the remaining stone (less than 4 mm) and patients without urinary tract obstruction and hydronephrosis and those totally asymptomatic. sample size was determined based on the study of john tt, with the statistical formula of comparable proportions with a dichotomous outcome between two samples: type i error of 0.05 and type ii error of 0.2, p1 = 0.87 and p2 = 0.68. these resulted in 75 samples in each group. study design this study was a prospective single-center, parallel-group randomized clinical trial with balanced randomization. the block size was 4 and all possible balanced combinations of assignment within the block were calculated. blocks were then randomly chosen to determine the patients’ assignment into the groups: all block sizes were the same and the spss software was used for block randomization. after the local ethics committee’s approval and informed consent, the patients included were randomly allocated into two groups using block randomization method, so that each group contained 75 patients. patients and analyzers were blinded to the randomization group. the co-researcher determined patient allocation and one assistant with the surgeon made the interventions and measured outcomes. patients who underwent tulp with ambient temperature irrigation (22–24°c) were assigned to group 1, and patients who underwent tulp with warmed irrigation fluid (40c) were assigned to group 2. in all patients, routine complete blood count, blodd urea nitrogen, creatinine, urine analysis and culture were performed preoperatively, and prophylactic intravenous antibiotics were administered. using general anesthesia in the lithotomy position, a semi-rigid ureteroscopy was performed (8–8.9 semi-rigid ureteroscope–wolf, germany), and safety wire was placed. after ureteral access and identification of the stone in the ureter, the stone warm saline in tul-mohammadzadeh rezaei et al. table 1. demographic characteristics of patients in the intervention and control groups ambient air group (group 1) 40°c irrigation fluid (group 2) p-value sex female number (%) 32 (42.7) 25 (33.3) 0.23 male number (%) 43 (57.3) 50 (66.7) age, years; mean (sd) 33.4 (8.6) 35.9 (8.8) 0.08 table 2. results of 40°c warmed irrigation fluid versus ambient air group ambient air group (group 1) 40°c irrigation fluid (group 2) p-value stone side right 35 38 0.62 46.7% 50.7% left 40 37 53.3% 49.3% stone location upper ureter 7 8 0.65 9.3% 10.7% mid ureter 23 18 30.7% 24.0% lower ureter 45 49 60.0% 65.3% fragmentation / migration complete with out migration 52 67 0.002 69.3% 89.3% incomplete or migrated 23 8 30.7% 10.7% stenting none 51 65 0.006 68.0% 86.7% dj 24 10 32.0% 13.3% complications no 50 59 0.09 66.7% 78.7% yes 25 16 33.3% 21.3% stone free at 2w free 57 72 < 0.001 76.0% 96.0% residue 18 3 24.0% 4.0% re tul/ eswl no 57 72 < 0.001 76.0% 96.0% yes 18 3 24.0% 4.0% endourology and stone diseases 6 vol 15 no 03 may-june 2018 7 was fragmented by pneumatic device (tulp). all steps were similar in group 1 and 2. the only difference was the irrigating fluid temperature. the duration of the procedure, complete stone fragmentation, retrograde stone migration and any intraoperative complications were recorded for each patient. the next day, kub was performed to assess the probable stone migration or residual stone fragments. two weeks later, patients were re-evaluated by sonography and spiral ct scan. outcome assessment complete stone fragmentation was measured as the primary outcome and the duration of procedure, retrograde stone migration and any intraoperative complications were the secondary measurements. data analysis was performed using spss software (statistical package for the social sciences, v. 16.0; spss inc., chicago, il, usa), by using t-test and chisquared test. a p-value less than 0.05 was considered statistically significant. results of 150 patients, 93 (62%) were male, and 57 (28%) were female. the mean age of the participants was 34.06 years (sd = 9.4), with no significant difference between male and female (table 1). in both groups, the locations of stones were in similar sites of ureter (p =. 65) and the location of stones in both groups was not significantly correlated with the results (table 2). the mean (sd) of stone size in group 1 (cold saline irrigation) was 8.7(1.8) millimeters, while in group 2 (warm saline irrigation), it was 9.8(2.5), (p = .001). since the mean size of stones in the 40-degree irrigation fluid group was greater than in the control group, this showed that even in larger stones, the use of warm saline irrigation was more successful. warmed irrigation fluid improved tulp results. the rates of re-intervention (re tul or eswl) was 24% and 4% in groups 1 and 2 respectively. the mean (sd) time of tulp in group 1 was 27.6 (6.6) minutes while in group 2 it was 24.4 (69), (p = .004). two weeks later, tulp stone-free rates by kub/usg or ct were 76% in group 1 and 96% in group 2. we analyzed data on the time of operation, stone-free rates at two weeks, rates of complications, and need to re-intervene in both groups. the rates of complications (bleeding, failed access, mucosal tear) were 33.3% and 21.32% in groups 1 and 2. the rate of access to the upper ureter with warm saline irrigation was 95% against 72% with cold saline irrigation. lower stone retropulsion with warm saline irrigation was 10.7% against 30.7% with cold saline irrigation. we have not seen any uretrescope impaction and ureteral dislodge in both groups. discussion by using warm saline irrigation in endoscopic surgeries, we described better surgical outcomes: these included lower ureteral spasm rate, more ureteral muscle relaxation, and better access to the upper ureteral zone and lower rate of complications like uretroscope impaction and ureteral dislodge. in this study, we used warmed irrigation fluid during tulp to improve ureteral access, prevent stone retropulsion and increase stone free rate, with minimal cost and morbidity. we compared these outcome measures between two groups. group 1, with ambient temperature irrigation fluid, and group 2, with 40c irrigation fluid. the results were in favor of group 2, which showed better ureteral access, lower stone retropulsion, and a greater stone-free rate. also, the mean operative time was in favor of group 2. this demonstrates warmed irrigation fluid as an effective way to improve tulp results. there were some limitations to our study. we did not have access to flexible ureteroscopy and could not compare our results with it. we also feel that a larger series is required to confirm our results. we did not have a flexible ureteroscope and that was the main limitation of our study. however, flexible ureteroscopy is more expensive, and a well-done tulp could be an acceptable alternative to laser lithotripsy, and is also more cost-effective. the reason of these method success is due to ureteral muscle relaxation with use of warm saline irrigation. this may facilitate ureteroscope passage and better stone access and also no use of high pressure saline irrigation, which may lead to the stone being pushed back. this ureteral dilatation may also facilitate spontaneous passage of small stones.(20) in the study performed by basiri and coworkers, stone removal was performed by the use of balloon for ureteral dilatation and electrohydraulic and basket combination in 60 patients: the rate of success was 84.6%, which was lower than our success rate (96% of our patients were stone-free).(17) in another study by tanagho and coworkers in general urology stone removal by basketing under fluoroscopy, a 60–70% success rate was reported, which, too, was lower than our success rate.(18) in another study by takashi yagisawa and coworkers in 2001, they describe the 91% rate of succession in traditional ureteroscopic pneumatic lithotripsy, which was lower than our success rate as well.(19) according to the same paper with the same method is used in this study, comparison of the results is not possible. conclusions we found that warmed irrigating fluid (40°c) can improve tulp results in terms of ureteral access, preventable 3. comparison of complications between 2 groups complications total none bleeding failed access mucosal tear count group ambient air 50 12 7 6 75 % within group 66.7% 16.0% 9.3% 8.0% 100.0% 40°c count 59 14 0 2 75 % within group 78.7% 18.7% 0.0% 2.7% 100.0% total count 109 26 7 8 150 % within group 72.7% 17.3% 4.7% 5.3% 100.0% warm saline in tul-mohammadzadeh rezaei et al. tion of stone retropulsion, and the stone-free rate. it entails no additional cost or morbidity for patients. conflict of interest the authors declare no conflict of interest. references 1. geavlete p, georgescu d, nita g, et al. complications of 2735 retrograde semirigid ureteroscopy procedures: a single-center experience. j endourol. 2006;20:179-85. 2. singal rk, denstedt jd. contemporary management of ureteral stones. urol clin north am. 1997;24:59-70. 3. sun l, peng fl. simultaneous saline irrigation during retrograde rigid ureteroscopic lasertripsy for the prevention of proximal calculus migration. can urol assoc j. 2013;7:e65-8. 4. chow g, blute m, patterson d, et al. ureteroscopy: update on current practice and long term complications. j urol. 2001;165:71. 5. delvecchio fc, kuo rl, preminger gm. clinical efficacy of combined lithoclast and lithovac stone removal during ureteroscopy. j urol. 2000;164:40-2. 6. hendlin k, weiland d, monga m. impact of irrigation systems on stone migration. . j endourol. 2008;22:453-8. 7. knispel h, klän r, heicappell r, et al. pneumatic lithotripsy applied through deflected working channel of miniureteroscope: results in 143 patients. . j endourol. 1998;12:513-5. 8. sun y, wang l, liao g, et al. pneumatic lithotripsy versus laser lithotripsy in the endoscopic treatment of ureteral calculi. j endourol. 2001;15:587-90. 9. bastawisy m, gameel t, radwan m, et al. a comparison of stone cone versus lidocaine jelly in the prevention of ureteral stone migration during ureteroscopic lithotripsy. ther adv urol. 2011;3:203-10. 10. ambani sn, faerber gj, roberts ww, et al. ureteral stents for impassable ureteroscopy. j endourol. 2013;27:549-53. 11. bourdoumis a, tanabalan c, goyal a, et al. the difficult ureter: stent and come back or balloon dilate and proceed with ureteroscopy? what does the evidence say? urology. 2014;83:1. 12. elashry om, tawfik am. preventing stone retropulsion during intracorporeal lithotripsy. nat rev urol. 2012;9:691-8. 13. fan b, yang d, wang j, et al. can tamsulosin facilitate expulsion of ureteral stones? a meta‐analysis of randomized controlled trials. int j urol. 2013;20:818-30. 14. john tt, razdan s. adjunctive tamsulosin improves stone free rate after ureteroscopic lithotripsy of large renal and ureteric calculi: a prospective randomized study. urology. 2010;75:1040-2. 15. grasso m, beaghler m, loisides p. the case for primary endoscopic management of upper urinary tract calculi: ii. cost and outcome assessment of 112 primary ureteral calculi. urology. 1995;45:372-6. 16. lee h, ryan rt, teichman jm, et al. stone retropulsion during holmium:yag lithotripsy. j urol. 2003;169:881-5. 17. basiri a, simforoosh n. trans ureteral lithotripsy. medical journal of the islamic republic of iran (mjiri). 1990;4:247-52. 18. tanagho e, mcaninch j. smith's general urology, seventeenth edition: mcgraw-hill; 2007. 19. yagisawa t, kobayashi c, ishikawa n, et al. benefits of ureteroscopic pneumatic lithotripsy for the treatment of impacted ureteral stones. j endourol. 2001;15:697-9. 20. church jm. warm water irrigation for dealing with spasm during colonoscopy: simple, inexpensive, and effective. gastrointestinal endoscopy. 2002;56:672-4. warm saline in tul-mohammadzadeh rezaei et al. endourology and stone diseases 8 case report a case report of human infection with dioctophyma renale from iran roghayeh norouzi 1*, arman manochehri 2, mustafa hanifi3 keywords: dioctophyma renale; human infection; iran. a 75-year-old man from kurdistan province, western part of iran was diagnosed with a mass in the right kidney by ultrasound and computed tomography. in operation, a parasitic helminth, 30 cm long and 1.2 cm in diameter consistent with d. renale was found in the right kidney. microscopic examination revealed that the male dioctophyma renale. following removal of worm, the symptoms completely resolved within a few hours. generally, parasitism by d. renale in human is a necropsy finding, nevertheless imaging techniques as ultrasound and computed tomography have been proven to be important tool to achieve diagnosis. 1 department of pathobiology, faculty of veterinary medicine, university of tabriz, tabriz, iran. 2 msc of veterinary parasitology, department of pathobiology, faculty of veterinary medicine, university of tabriz ,tabriz, iran. 3 msc of microbiology, shahid ghazi hospital, kurdistan, iran. *correspondence: department of pathobiology, faculty of veterinary medicine, university of tabriz, tabriz, iran. tel: +98 4136378743. fax: +98 4136378743. e-mail: r.norouzi@tabrizu.ac.ir. received october 2016 & accepted january 2017 introduction dioctophyma renale (giant kidney worm), parasitic roundworm, has been reported in many mammalian spe-cies, including canines, mink, wolves, foxes, jackals, coyotes, skunks, ferrets, weasels, rats, raccoons, wolverines, pumas, cats, seals, pigs, horses and humans, al¬though only rarely.(1,2,3) in its evolutionary cycle, the intermediary is an aquatic oligochaete annelid (lumbriculus variegatus) that ingests eggs of the first stage containing larvae of the parasite and the primary host is infected by ingesting the infected annelid or paratenic host, which can be a fish or frog.(2) it inhabits temperate regions worldwide, particularly areas with freshwater streams and lakes. in these cases, worms were found in various body parts such as the kidneys, scrotum, breasts, thoracic cavity, peritoneal cavity, bladder, and subcutaneous layer.(4,5) female worms can be over 100 cm long and male worms 35 cm, although their size may vary according to the affected species.(1) male worms have a bell-shaped copulatory bursa that does not present rays and has one spicule, but adult female worm that does not present copulatory bursa.(1) humans can also be definitive accidental hosts, and dioctophymatosis is a zoonotic disease, but in the case of humans, locations outside the kidney are frequent.(6,7) although animal infection with this parasite occurs in iran, but human infection rarely in this country. dioctophymatosis has been reported from iran(8) and other parts of the world.(4,6,7,9,10,11) in this study, we report a case of human infection with d.renale in an old man from the bijar city of kurdistan province, western part of iran. figure 1. adult male dioctophyme renale (30 cm long) removed from in the right kidney of a 75-year-old man vol 14 no 02 march-april 2017 3043 human infection with dioctophyma renalenorouzi et al. case report a 75-year-old man from bijar city, kurdistan province, iran, with hematuria and a specific intermittent pain in the right kidney area that persisted for 10 days, presented to the imam hassan hospital, kurdistan, iran on may 2015. he had always lived in an urban habitat, and there was suspicion of ingestion of dirty water. clinical signs suggested nonspecific symptoms including hematuria, nephritis and intermittent pain in the right kidney.the complementary studies, including urine analysis, blood analysis, abdominal x-ray films, and abdominal ultrasonography were carried out. in the urine sample many red blood cells and white blood cells were observed but no eggs were not found in the urinary sediment. the hemogram showed leukocytosis by neutrophilia with left shift toxic granulation neutrophils, lymphopenia, eosinophilia and basophilia. in ultrasound and computed tomography, a mass in the right kidney was demonstrated. in operation, a parasitic helminth, 30 cm long and 1.2 cm in diameter was found in the right kidney. the parasite was placed in a 10% formalin solution. the worm was identified using microscopic examination as the male dioctophyma renale (figure 1). the adult male worm had a bell-shaped copulatory bursa that did not present rays and had one spicule (figure 2). following removal of worm, the symptoms completely resolved within a few hours and remained asymptomatic two week later. discussion dioctophyma renale, the giant kidney worm, is the largest known parasitic nematode.(12) in its evolutionary cycle, the intermediary is an aquatic oligochaete annelid (lumbriculus variegatus) that ingests eggs of the first stage containing larvae of the parasite and the primary host is infected by ingesting the infected annelid or paratenic host, which can be a fish or frog.(13,14) human infections by d. renale have been very rare, and seem to have occurred accidentally. no more than 20 confirmed human cases have been reported worldwide, in which worms were found in various body parts, e.g. the kidneys and peritoneal cavity. these include 4 cases of dioctophymatid larvae found in the subcutaneous nodules. in the case reported here, the patient was a 75yearold man who lived in a small village, near a lake that was used for daily activities, such as bathing, washing clothes, and defecation (both humans and cattle). the etiology of this case was not clear, but it was suspected that he became infected by drinking water. in the context of this zoonosis, several factors in this location pose a risk to the health of the inhabitants: high prevalence of infected canines, high level of surface contamination, and use of the river as a means of transport, recreation and fishing for food (fish, frogs and eels). the continuation of the life cycle of d. renale is directly related to water temperature and egg embryonation.(12) other studies state that this parasitic infection is not very frequent infection in humans, considered to be accidental hosts of the parasite(4). however, according to le bailly et al.(15), parasite has been found in archaeological material dating from 3384 to 3370 bc. although animal infection with this parasite occurs in iran, but human infection rarely in this country. dioctophymatosis has been reported from iran(8) and other parts of the world.(4,6,7,9,10,11) figure 2. a bell-shaped copulatory bursa of adult male worm figure 3. mr urogram showing worm in right kidney of a 75-year-old man case report 3044 the latest publication the parasitism of a domestic dog by d. renale in hamedan, iran reported by zolhavarieh et al.(16) while the nematode has been mainly reported from temperate regions of other parts of the world, the presence of dioctophymatosis in human kurdistan province as a cold region is unusual but the parasitism of a domestic dog by d. renale is very frequent in iran and kurdistan. therefore high prevalence of infected canines and use of the river as a means of transport are several factors in this location pose a risk to the health of the inhabitants. conclusions d. renale infestation in canine and other mammals is high prevalence and transmission of the parasite to human is easy, especially urban region, veterinarians and physicians should consider d. renale infestation in the differential diagnosis of urological disorders and unknown abdominal cystic masses regardless of ecological condition. conflict on interest the authors declare that there is no conflict of interest. references 1. kumar v, vercruysse j, vandesteene r. studies on two cases of dioctophyma renale (goeze, 1782) infection in chrysocyon brachyurus (illiger). acta zool pathol antwerp. 1972; 56: 83-98. 2. samuel wm, kocan aa, pybus mj, davis jw, ed. parasitic diseases of wild mammals, iowa state. 2008; 357-364. 3. tokiwa t, harunari t, tanikawa t, akao n, ohta n: dioctophyma renale (nematoda: dioctophymatoidea) in the abdominal cavity of rattus norvegicus in japan. parasitol int. 2011; 60: 324-6. 4. ignjatovic i, stojkovic i, kutlesic c, tasic s. infestation of the human kidney with dioctophyma renale. urol int. 2003; 70:70-3. 5. verocai gg, measures ln, azevedo fd, correia tr, fernandes ji, scott fb. dioctophyme renale (goeze, 1782) in the abdominal cavity of a domestic cat from brazil. vet parasitol. 2009; 161:342-4. 6. sun t, turnbull a, lieverman ph, sternberg ss. giant kidney worm (dioctophyma renale) infection mimicking retroperitoneal neoplasm. am j surg pathol. 1986; 10: 508-12. 7. urano z, hadçsegawa h, katsumata t, toriyam k, aoki y. dioctophymatid nematode larva found from human skin with creeping eruption. j parasitol. 2001; 87: 462-5. 8. hanjani a.a, sadighian a, nikakhtar b, arfaa f. the first report of human infection with dioctophyma renale in iran. transactions of the royal society of tropical medicine and hygiene. 1968; 62: 647-8. 9. beaver pc, theis jh. diocytophymatid larval nematode in a subcutaneous nodule from man in california. am j trop med hyg. 1979; 28: 206-12. 10. beaver pc, khamboonruang c. dioctophymalike larval nematode in a subcutaneous nodule from man in northern thailand. am j trop med hyg. 1984; 33: 1032-4. 11. fernando ss. the giant kidney worm (dioctophyma renale) infection in man in australia. am j surg pathol. 1983; 7: 281-4. 12. soulsby e.j.l. helminths, arthropods and protozoa of domestic animals, sixth ed. baillie`re, tindall & cassell, london.1978; 326–7. 13. freitas m.g. helmintologia veterina´ria, fourth ed. gra´fica rabelo, belo horizonte. 1980; 267–70. 14. anderson r.c. nematode parasites of vertebrates: their development and transmission, 2nd ed. cab publishing, london, england. 2000; 672. 15. le bailly m, leuzinger u, bouchet f. dioctophymidae eggs in coprolite from neolithic site of arbonbleiche 3 (switzerland). j parasitol. 2003; 89: 1073-6. 16. zolhavarieh sm, norian a, yavari m.dioctophyma renale (goeze, 1782) infection in a domestic dog from hamedan, western iran. iran j parasitol. 2016; 11: 131– 5. human infection with dioctophyma renalenorouzi et al. vol 14 no 02 march-april 2017 3045 vol 16 no 02 march-april 2019 205 sexual dysfunction and andrology the effects of oral 5-alpha reductase inhibitors on penile intracavernosal pressures and penile morphology in rat model sahin kilic1*, engin kolukcu2, fikret erdemir3, ismail benli4, akgul arici5 purpose: benign prostatic hyperplasia (bph), and erectile dysfunction (ed) are urological diseases which affect more than 50 % of men older than 50 years of age. it has been reported that 5-alpha-reductase inhibitors (5-aris) used in clinical studies for the treatment of bph caused ed in 0.8-15.8% of the patients. the aim of this study is evaluation of the effects of oral finasteride and dutasteride on penile intracavernosal pressures and penile morphology in a rat model. materials and methods: thirty wistar albino strain male rats were randomized into control (n = 10), finasteride (n = 10), and dutasteride (n = 10) groups. after 8 weeks of treatment erectile responses were evaluated in all rats measuring intracavernosal pressure (icp) changes during erectile responses to cavernosal nerve electrical stimulation. serum hormone levels were studied and all rats underwent prostatectomy and penectomy. all tissue samples were examined histomorphologically and a semiquantitative scoring system was used for cavernosal tissue collagen density grading. results: approximately 50% decrease was seen in mean icps in the finasteride and dutasteride groups compared to the control group for all voltages (2.5 v, 5 v. 7.5 v). mean icps for 7.5 v were 62.17 ± 30.89 mmhg in control group, 35.27 ± 31.94 in the finasteride, and 36.01 ± 19.20 mmhg in the dutasteride group. but regarding icps there was no statistically significant difference between the groups (p > .05). the serum testosterone (t) concentrations were higher in treatment groups (p < .001). serum dihydrotestosterone (dht), luteinizing hormone (lh) and follicle stimulating hormone (fsh) concentrations were not significantly different between the groups. as a result of histomorphological studies, a statistically significant increase in cavernosal tissue collagen density, and marked atrophic changes in prostatic epithelial tissues were observed in the treatment groups. conclusion: although 5-aris cause marked atrophic changes in prostatic epithelial tissues, and prominent collagen deposition in penile cavernosal tissues, no significant effect on penile icps was seen in this study. the failure to show a statistically significant difference was attributed to higher standard deviations of icp values. the penile morphology evaluation results point to a negative effect of 5-aris on erectile function. keywords: dutasteride; erectile dysfunction; finasteride; intracavernosal pressure; penile morphology; prostate. introduction bph, accepted as a disease of advanced age, which impairs quality of life of the patients, is seen in approximately 50% of men between 51-60 years and approximately 90% over the age of 81 years(1). in the etiology of bph, androgens, estrogens, stromal-epithelial interactions, growth factors, and neurotransmitters can play a role alone or in combination(2). medical treatment methods of bph include use of 5-aris, which target decrease in the prostatic volume. 5-aris ensure decrease in the size of prostate (nearly 30%) by preventing the production of dihydrotestosterone (dht). testosterone enters into prostatic epithelial cells and is converted into dht through the action of 5-alpha re1fethiye state hospital, department of urology, fethiye, mugla. 2tokat state hospital, department of urology, tokat. 3gaziosmanpasa university, faculty of medicine, department of urology, tokat. 4gaziosmanpasa university, faculty of medicine, department of biochemistry, tokat. 5gaziosmanpasa university, faculty of medicine, department of pathology, tokat. *correspondence: fethiye state hospital, department of urology, fethiye, muğla 48300, turkey. telephone: +90 507 240 71 86, fax: +90 252 614 10 02, e-mail: sahinkilic84@hotmail.com received september 2017 & accepted june 2018 ductase enzyme. dht promotes the prostate enlargement by stimulating dna synthesis in nuclei, and cellular growth(3). in animal models, androgen deprivation has been demonstrated to cause deterioration of dorsal nerve structure, and endothelial morphology, decrease in trabecular smooth muscle, increase in extracellular matrix, and penile tissue atrophy. furthermore, androgen deprivation leads to venous leak, and increase in the number of adipocytes in the subtunical region in the corpus cavernosum(4). androgen deprivation inhibits the production of protein, and enzymatic activities of endothelial nitric oxide synthase (enos), and neuronal nitric oxide synthase (nnos) (5). still, as is understood from available data, androgen deprivation leads to a desexual disfunction & andrology 206 crease in the smooth muscles of the corpus cavernosum, and the elastic fibres of the tunica albuginea, and an increase in collagen fibres(6). ed is defined as the persistent inability of a male to achieve and/or maintain a penile erection sufficient to permit satisfactory sexual performance(7). its prevalence ranges between 30-52% in men aged 40-70 years, while it climbs to 80%, among men older than 70 years of age(8). psychogenic, hormonal, neurogenic, and arterial pathologies, iatrogenic causes, systemic, and chronic diseases, and drugs play a role in the etiology of ed(9). as indicated in various studies, the use of 5-aris may cause loss of libido, ejaculatory disorders and erectile dysfunction(10). however, most of the studies investigating the correlation between 5-aris and ed have consisted of clinical research, and an extremely limited number of experimental animal studies investigated cavernosal tissues. as far as we know in english medical literature, finasteride, and dutasteride have not been evaluated in combination in any animal studies. accordingly, our study appears to be the first trial which evaluated the effects of 5-aris on rat cavernosal tissue, prostate morphology, and penile cavernosal response to electrical stimulation in rats. to this end in our study we aimed to evaluate the effects of 5-aris on penile cavernosal pressures, serum androgen levels, and penile tissue. materials and methods a total of 30 10-week-old male wistar albino strain rats weighing 250-300 g (median, 270 g) were used. all procedures were realized in accordance with the stipulations of the 1986 strasbourg universal declaration of animal rights in gaziosmanpaşa university experimental medicine application centre after the approval, and with the support of the gaziosmanpaşa university animal studies ethics committee (2012 hadyek 036). the rats were housed in standard rat cages at 20-23 °c, and under 12-hour dark, and 12-hour light cycles. the rats were fed with special rat pellet, and water ad libitum. the rats were randomized into 3 groups, each containing 10 rats with simple randomization. group 1 was the control group which did not receive any drug therapy. group 2 rats received daily doses of 4.5 mg/kg finasteride via oral gavage for 8 weeks. in group 3 each rat received daily doses of 0.5 mg dutasteride for 8 weeks via oral gavage. measurement of penile cavernosal pressure at the end of 8 weeks rats were anesthesized with intraperitoneal 50 mg/kg ketamine, and 10 mg/kg xylazine. the rats were laid on an operating table warmed at a stable temperature of 36 °c (aot 0811 animal operating table), and through midline scrotal incision of the skin, and prostate and penile roots of the rats were approached. a 25 gauge penile cavernosal pressure needle irrigated with heparin mounted to a pressure transducer (biopac-mp 45 system, usa) integrated to a data gathering system was inserted into the left corpus cavernosum for continuous measurement of intracavernosal pressure (icp). the left major pelvic ganglion, and cavernosal nerve were identified, and bipolar, a stainless steel hook electrode was advanced through the left posterolateral prostate, and placed around the cavernosal nerve. while continuously measuring icp, the cavernosal nerve was stimulated with an electrical nerve stimulator (stn 0211 nerve stimulator) for 30 seconds with 50 hz, 2.5 v, 5 v, and 7.5 v at square wave times of 2 msec to achieve erection. icp, measured before 2.5 v electrical stimulation, was considered as baseline, and maximum changes in icp with reference to baseline icp up to termination of 7.5 v stimulation were recorded for each voltage (2.5 v, 5 v, and 7.5 v, respectively). then intracardiac blood samples of 3cc were drawn from each rat to determine testosterone, dht, fsh and lh levels. subsequently the rats underwent prostatectomy, and penectomy through the previously made midline scrotal incision. at the end of the study all rats were sacrificed by cervical dislocation. biochemical measurements blood samples drawn were centrifuged, and sera were kept at -80 oc pending biochemical analysis. testosterone, dht, fsh, and lh levels of samples were measured using the elisa method (organon teknika reader 230s, austria). for the measurement of serum testosterone, fsh, and lh levels, cayman (cayman chemical company, mi, usa) brand, and for dht levels general (wuhan eiaab science co., ltd, wuhan, china) brand kits were used. histopathological evaluation prostatectomy, and penectomy samples were fixated in a 10% buffered formaldehyde solution, then routinely embedded in paraffin blocks. rat penises were cut in 5 µ sections, and stained with masson trichrome dye so as to evaluate the collagen content in the tissue. smooth muscle collagen ratios in penile cavernosal tissues were histopathologically evaluated. rat prostates were cut in 5 µ sections, and stained with hematoxylin/eosine dye, and examined under a light microscope (nikon eclipse e600) at 100x magnification for the evaluation of muscular, and glandular structures. microscopic images were obtained from a total of 4 serial sections, with 2 sections per slide of each rat. then 16-20 areas were analyzed for each rat in total, with at least 4-5 areas on each section. grading of tissue collagen density was performed based on scoring used by erdemir et al(11). the percentage of collagen concentration in each cut section, and field of examination was determined semiquantitatively and expressed in comparison with blue-stained collagen positive areas. masson trichrome stained areas were graded on a scale between 1 and 4, based on percentages of penile cavernosal collagen content. collagen percentages of < 30%, 30-50%, 51-70%, and > 71% were graded as 1, 2, 3, and 4, respectively. statistical analysis descriptive analyses were performed so as to get information about the general characteristics of the groups. after assessing of the normality, one-way analysis of variance was used for intergroup comparisons of variables. repeated measures analysis of variance was used for comparisons based on changes in variables over time. for two group comparisons tukey hsd test was used as post hoc test of one way analysis of variance. data concerning continuous variables were expressed as mean ± standard deviation. p < .05 was accepted as the level of statistical significance. for statistical calculations commercially available software programs were utilized (ibm spss statistics 19, spss inc., an ibm co., somers, ny). 5-aris effects on intracavernosal pressures and penile morphology kilic et al. vol 16 no 02 march-april 2019 207 results penile cavernosal pressures mean icp values for electrical stimulation of cavernosal nerve with 2.5 v were calculated as 8.05 ± 14.58 mmhg in group 1, 2.86 ± 3.97 mmhg in group 2, and 2.06 ± 2.85 mmhg in group 3. intergroup differences were not statistically significant (p = .278). mean icps for 5 v were estimated as 25.70 ± 30.30 mmhg in group 1, 15.07 ± 15.08 in group 2, and 15.15 ± 13.21 mmhg in group 3 without any statistically significant intergroup difference (p = .438). mean icps for 7.5 v were 62.17 ± 30.89 mmhg in group 1, 35.27 ± 31.94 in group 2, and 36.01 ± 19.20 mmhg in group 3. but intergroup differences were not statistically significant (p = .062). an approximately 50% decrease was seen in mean icps in the finasteride and dutasteride groups compared to the control group for all voltages in qualitative evaluation performed during the procedure. but in statistical analysis, no significant intergroups differences were seen. in one-way repeated measures of variance analysis in intragroup comparisons of mean icp values for all voltages (2.5 v, 5 v. 7.5 v), a statistically significant difference was detected in all groups (p < .001, table 1). generally, in all groups as the voltage of electrical stimulation of the cavernosal nerve increased, increases in mean icp values were seen (figure 1). serum hormone levels the mean serum testosterone level in group 2 was significantly higher relative to group 1 (p < .001). the mean serum testosterone level in group 3 was significantly higher relative to group 1 (p < .001). however no significant intergroup difference was detected for other serum hormone levels (table 2). penile morphology when compared with group 1, prominently increased collagen density was observed in groups 2 and 3 (figure 2). in group 1 grade 3, and 4 collagen densities were not seen, while groups 2 and 3 had no grade 1 collagen density. in group 1, grade 1, and grade 2 collagen densities were observed in 80% and 20% of the specimens, respectively. in group 2, grade 2, grade 3, and grade 4 collagen densities were detected in 50%, 30%, and 20% of the specimens, respectively. in group 3, grade 2, grade 3, and grade 4 collagen densities were observed in 30%, 40%, and 30% of the specimens, respectively. as a result of histomorphological studies, a statistically significant increase in cavernosal tissue collagen density was observed in the treatment groups. (table 3). prostate morphology in group 1 high columnar epithelium, and papillary folds were markedly observed in prostatic glandular tistable 1. mean values for maximum changes in intracavernosal pressures induced by electrical stimulation of cavernosal nerve at each voltage control group (mmhg) (n=10) finasteride group (mmhg) (n=10) dutasteride group (mmhg) (n=10) p* measurement 2.5v 8.05 ± 14.58 2.86 ± 3.97 2.06 ± 2.85 0.278 measurement 5v 25.70 ± 30.30 15.07 ± 15.08b 15.15 ± 13.21d 0.438 measurement 7.5v 62.17 ± 30.89 a 35.27 ± 31.94 c 36.01 ± 19.20 e 0.062 p** < 0.001 0.001 < 0.001 ** one-way repeated measures analysis of variance a a significant correlation was detected between measurements performed at 2.5 v and.5 v b a significant correlation was detected between measurement at 2.5 v c a significant correlation was detected between measurements performed at 2.5 v and.5 v d a significant correlation was detected between measurement performed at 2.5 v e a significant correlation was detected between measurements performed at 2.5 v and.5 v data are given as mean ± sd figure 1. timedependent changes in mean icp values of groups. figure 2.collagen density (blue-stained areas) in penile cavernosal tissues in all groups (mt x 400). 5-aris effects on intracavernosal pressures and penile morphology kilic et al. sexual disfunction & andrology 36 sue (figure 3). however, predominant atrophic changes were seen in prostatic epithelial tissues in groups 2, and 3, being more marked in group 3 (figure 3). discussion effects of androgens on erectile function, libido, and sexual behaviour are very well known(4-6,9). androgens exert their effects in erectile physiology by directly binding to their receptors or via conversion to their more active form of 5-alpha dihydrotestosterone which is mediated by the 5-alpha reductase enzyme. in experimental animal models androgen deprivation has led to morphologic deterioration in the dorsal nerve, and endothelium; decrease in the content of trabecular smooth muscle; increase in connective tissue components, together with atrophy of the penile tissue (4,12). androgen deprivation causes apoptosis of spongious, and cavernosal cells which can be prevented by androgen administration(13). it has been detected that dht prevents disruption of erectile function in castrated rats, and this effect has been correlated partially with an increase in the levels of nitric oxide synthase (nos)(14). in the light of these data the effects of androgens on erectile physiology are apparently very important. 5-aris used in the medical treatment of bph inhibit the conversion of testosterone to more potent androgen dht. as a result of their effects, prostate volume decreases by 20%-30%, and within 6-12 months a nearly 50% decrease in prostate specific antigen (psa) levels is induced(3,15). a decrease in the volume of prostatic glandular tissue caused by 5-aris effects the static component of bph, with a resultant increase in urine flow, and a decrease in bph-related luts, acute urinary retention, and risk of surgery(3,10). also 5-aris decreases the serum levels of dht, which is the major androgen involved in erectile physiology, by 70-90 percent(16-17). many clinical, and experimental studies have revealed the correlation between 5-aris, and erectile dysfunction. the most frequently reported unwanted adverse sexual effect of 5-aris is ed, followed by ejaculatory disorder, and decrease in libido (18). finasteride at a dose of 1 mg is frequently used in dermatology practice, and finasteride-related ed is reported in 0.8-3.8% of these patients, while ed is detected in 3.4-15.8% of the patients who used daily doses of 5 mg finasteride in the treatment of bph(18-21). findings in studies on dutasteride rates of ed are similar to those indicated above. in a double-blind, placebo-controlled study by andriole et al. statistically significantly higher incidence rates of ed have been detected in the dutasteride group (4.7%) when compared with the placebo group (1.7%)(22). the effects of 5-aris on erectile function are clearly seen not only in clinical, but also in experimental studies. within the last four decades, animal experiments have provided evidence demonstrating the key role of dht in erectile physiology(23,24). besides, an animal study has demonstrated that castration induces a 50% decrease in erectile response, and testosterone treatment reverses this effect. however this study has showed that in castrated rats when finasteride is given in combination with testosterone, the erectile response is not improve. when finasteride is administered with dht, improvements in nnos expression, and activity, and erectile response to electrical stimulation are detected(14). this finding underlines the important hormonal role of dht in erectile physiology. in a different study the effects of finasteride (4.5 mg/kg/day for one month), and castration on serum hormone levels, cavernosal, and prostatic morphology, and intracavernosal pressure response to cavernosal nerve stimulation were evaluated(25). in the control, and finasteride group similar testosterone levels were observed, while significantly reduced dht levels were detected in the finasteride, and castration groups. in the castration group the relative proportion of cavernosal smooth muscle markedly decreased, while the mass of connective tissue (collagen) increased prominently, and no change in the smooth muscle/collagen ratio was observed. in the castration group a decreased intracavernosal pressure response to cavernosal nerve stimulation was detected, while no difference was detected between control, and finasteride groups as for the intracavernosal pressure response (25). in another study the effects of long-term (16 weeks) use of finasteride on cavernosal tissues, and erectile response was evaluated table 2. mean hormonal values of all groups control group(n=10) finasteride group (n=10) dutasteride group (n=10) p* fsh (miu/ml) 1.29 ± 0.59 2.04 ± 1.43 1.68 ± 0.70 0.248 lh (miu/ml) 6.80 ± 0.39 6.80 ± 0.35 6.99 ± 0.31 0.377 testosterone (pg/ml) 308.97 ± 146.29 628.40 ± 153.97a 613.64 ± 179.24b < 0.001 dihydrotestosterone (pg/ml) 2.57 ± 1.07 2.90 ± 1.23 2.43 ± 0.96 0.621 * one-way analysis of variance a a significant correlation was found versus control group. b a significant correlation was found versus finasteride group data are presented as mean ± sd grade 1 grade 2 grade 3 grade 4 total group 1 (n) 8 2 0 0 10 group 2 (n) 0 5 3 2 10 group 3 (n) 0 3 4 3 10 total (n) 8 10 7 5 30 since more than %20 of ‘n’ values in each cell of the table is smaller than ‘5’ “’p’ value was not calculated. table 3. grading of collagen density in penile cavernosal tissues 5-aris effects on intracavernosal pressures and penile morphology kilic et al. sexual disfunction & andrology 208 vol 16 no 02 march-april 2019 209 in old (16 months) rats. decreases in cavernosal smooth muscle cells, and cavernosal smooth muscle/collagen ratio were detected. during in vivo evaluation a significant decrease in erectile response was observed(26). in our study, mean icp values in the finasteride, and dutasteride groups are similar and decreased by nearly 50% when compared with the control group, without reaching any level of statistical significance. generally, in all groups as the voltage of electrical stimulation of the cavernosal nerve increased, increases in icp values are seen (p < .001). this indicates that the icp measurements are done correctly. the failure to show a statistically significant difference was attributed to higher standard deviations of icp values. this is in some rats maximum change in icp values were reached after electrical stimulation with 2.5 v, while in some maximum change in icp values were reached after electrical stimulation with 5 v or 7.5 v. we conclude that increasing the sample size and the duration of the treatment can give statistically significant results. when compared with the control group, increase in serum testosterone levels are detected in the finasteride group. however no significant intergroup difference was detected in serum dht levels. in the semiquantitative histopathological evaluation, significant atrophic changes are detected in the prostate tissues, and significantly increased collagen deposition is observed in the cavernosal tissues in the finasteride group versus the control group. effects of 5-aris on penile cavernosal tissue, and prostate have been investigated in many experimental studies. pinsky et al. evaluated the effects of dutasteride on cavernosal tissues, and erectile response in an animal study(27). they observed 86.5% suppression of mean serum dht levels, increased collagen accumulation in cavernosal tissues, a decrease in nnos activity, and in in vivo assessments significant reduction in erectile response in the treatment group. öztekin et al. evaluated the effects of long term dutasteride treatment and treatment withdrawal on cavernosal tissues and erectile responses. they observed that 8 weeks of dutasteride treatment significantly decreased erectile response in in vivo assessments, when compared with the control group, and the group where the dutasteride treatment had been discontinued for 2 weeks after 6 weeks treatment. however erectile responses in the withdrawal group were not so strong as those seen in the control group. the researchers concluded that decreased erectile response caused by dutasteride could persist after its withdrawal(28). in our study, the impact of dutasteride on mean icp values is similar when compared with the finasteride group. furthermore similar to the finasteride group, the serum dht levels decreased relative to the control group without reaching any level of statistical significance. however, in our study, if the prostatic tissue hormone levels were measured instead of the serum hormone levels, it is possible that statistically significant results for dht levels would be obtained(29). on the semiquantitative visual score, collagen accumulation in cavernosal tissues is more markedly observed in the dutasteride group, relative to the control, and finasteride groups. in the evaluation of prostatic tissues, atrophic changes in the dutasteride group are more prominent versus the control, and finasteride groups. these findings demonstrate that even though in clinical studies dutasteride decreases serum dht levels, in the long term when compared with finasteride, in animal tissue studies they indicate that dutasteride can induce prostatic atrophy to a greater extent, and greater amount of collagen deposition in the cavernosal tissues. it should be noted that in clinical studies, similar incidence rates of sexual side effects related to finasteride or dutasteride treatment have been observed. although 5-aris treatment results in marked atrophic changes in epithelial tissues, and prominent collagen accumulation in penile cavernosal tissue, a significant impact on penile cavernosal pressures is not detected. even though 5-aris demonstrate similar efficacy, and side effect profiles, acording to our study dutasteride induces more severe atrophic changes in the prostatic tissue, and more diffuse collegen accumulation in the cavernosal tissue compared with. conclusions androgens are critical for cavernosal smooth muscle integrity. treatment with 5-aris decreases serum dht levels up to 95%. although 5-aris cause marked atrophic changes in prostatic epithelial tissues, and prominent collagen deposition in penile cavernosal tissues, they were not seen to produce a significant effect on penile icps in this study. inability to demostrate a statistically significant difference was attributed to the higher standard deviations of icp values. this condition is a shortcoming of the study. serum testosterone levels were observed to be statistically significantly higher in the treatment groups than in the control group. but there was no significant intergroup difference for serum dht levels. although dutasteride and finasteride have similar efficacy and side-effect profile in clinical studies, in our study dutasteride caused more atrophy in prostatic tissues and caused more intense collagen deposition in cavernosal tissues than finasteride. the penile morphology evaluation results are pointing to a negative effect of 5-aris on erectile function. acknowledgements this study was funded by gaziosmanpaşa university unit of scientific research projects (project no: bap 2013-34). figure 3. prostate tissues in all groups (he x 100). 5-aris effects on intracavernosal pressures and penile morphology kilic et al. conflict of interest the authors report no conflict of interest. references 1. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol. 1984;132:474-9. 2. nicholson tm, ricke wa. androgens and estrogens in benign prostatic hyperplasia: past, present and future. differentiation. 2011;82:184-99. 3. clark rv, hermann dj, cunningham gr, et al. marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. j clin endocrinol metab 2004;89:2179-84. 4. traish a, kim n. the physiological role of androgens in penile erection: regulation of corpus cavernosum structure and function. j sex med. 2005;2:759-70. 5. traish am, goldstein i, kim n. testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. eur urol. 2007;52:54-70. 6. shabsigh r. the effects of testosterone on the cavernous tissue and erectile function. world j urol. 1997;15:21-6. 7. hatzimouratidis k, giuliano f, moncada i et al. european association of urology; male sexual dysfunction. publishing guidelines uroweb. 2016. http://uroweb.org/guideline/ male-sexual-dysfunction/#3. accessed 15 march 2017 8. feldman ha, goldstein i, hatzichristou dg, krane rj, mckinlay jb. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994;151:54-61. 9. yafi fa, jenkins l, albersen m, et al. erectile dysfunction nat rev dis primers. 2016;2:16003 10. o’leary m.p, roehrborn c.g, andriole g et al. improvements in benign prostatic hyperplasiaspecific quality of life with dutasteride, the novel dual 5α-reductase inhibitor. bju int. 2003;92:262-6. 11. erdemir f, firat f, markoc f et al. the effect of pentoxifylline on penile cavernosal tissues in ischemic priapism-induced rat model. int urol nephrol. 2014;46:1961-7. 12. traish am, munarriz r, o’connell l, et al. effects of medical or surgical castration on erectile function in an animal model. j androl. 2003;24:381-7. 13. podlasek ca, meroz cl, korolis h, tang y, mckenna ke, mcvary kt. sonic hedgehog, the penis and erectile dysfunction: a review of sonic hedgehog signaling in the penis. curr pharm des. 2005;11:4011-27. 14. lugg ja, rajfer j, gonzález-cadavid nf. dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat. endocrinology. 1995; 136:1495-501. 15. naslund mj, miner m. a review of the clinical efficacy and safety of 5α-reductase inhibitors for the enlarged prostate. clin ther. 2007;29:17-25. 16. sudduth sl, koronkowski mj. finasteride: the first 5 alpha-reductase inhibitor. pharmacotherapy. 1993;13:309-325. 17. shigehara k, miyagi t, nakashima t, et al. effects of dutasteride on lower urinary tract symptoms: a prospective analysis based on changes in testosterone/dihydrotestosterone levels and total prostatic volume reduction. aging male. 2016;19:128-133. 18. erdemir f, harbin a, hellstrom w. 5-alpha reductase inhibitors and erectile dysfunction: the connection. j sex med. 2008;5:2917-24. 19. nickel jc, fradet y, boake rc, et al. efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the prospect study). proscar safety plus efficacy canadian two year study. cmaj. 1996;155:1251-9. 20. lowe fc, mcconnell jd, hudson pb, et al. long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia. urology. 2003;61:791-6. 21. mcconnell jd, bruskewitz r, walsh p, et al. the effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. finasteride long-term efficacy and safety study group. n engl j med. 1998; 338: 557-63. 22. andriole gl, kirby r. safety and tolerability of the dual 5alphareductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. eur urol. 2003;44:82-8. 23. gray gd, smith er, davidson jm. hormonal regulation of penile erection in castrated male rats. physiol behav. 1980;24:463-8. 24. bradshaw wg, baum mj, awh cc. attenuation by a 5 alpha-reductase inhibitor of the activational effect of testosterone propionate on penile erections in castrated male rats. endocrinology. 1981;109:1047-51. 25. zhang mg, wu w, zhang cm, et al. effects of oral finasteride on erectile function in a rat model. j sex med. 2012;9:1328-36. 26. zhang mg, wang xj, shen zj, gao pj. longterm oral administration of 5α-reductase inhibitor attenuates erectile function by inhibiting autophagy and promoting apoptosis of smooth muscle cells in corpus cavernosum of aged rats. urology. 2013;82:9-15. 27. pinsky mr, gur s, tracey aj, harbin a, hellstrom jg. the effects of chronic 5-alpha5-aris effects on intracavernosal pressures and penile morphology kilic et al. sexual disfunction & andrology 210 vol 16 no 02 march-april 2019 211 reductase inhibitor (dutasteride) treatment on rat erectile function. j sex med. 2011;8: 3066-74. 28. oztekin cv, gur s, abdulkadir na, hellstrom jg. incomplete recovery of erectile function in rat after discontinuation of dual 5-alpha reductase inhibitor therapy. j sex med. 2012;9:1773-81. 29. cook mb, stanczyk fz, wood sn, et al. relationships between circulating and intraprostatic sex steroid hormone concentrations. cancer epidemiol biomarkers prev. 2017;26:1660-6. 5-aris effects on intracavernosal pressures and penile morphology kilic et al. endourology and stone disease ureteral stent removal using an extraction string after uncomplicated ureteroscopy: a cost-benefit analysis hao liu1, weiyun pan2, nan zhang1* purpose: some urologists use the extraction strings for removal of ureteral stent without cystoscopy. while some urologists may have concern about perceived risks, including accidental dislodgement, infection, renal colic and lower urinary tract symptoms. therefore, we performed a retrospective study to help resolve this conflict. materials and methods: patients who had an indwelling ureteral stent with (n = 58) or without (n = 82) extraction strings inserted after ureteroscopy for unilateral ureteral stone were enrolled. for ureteral stent removal, the strings were pulled by physician, no string-stents were removed by cystoscopy. postoperative morbidity was assessed. patients' medical expense due to postoperative morbidity was gathered. results: patients with extraction string had shorter stent dwell time (5.3 ± 1.8 versus 11.2 ± 3.2 days, p = .001) and less costly (8.97 ± 3.07 versus 455 ± 0 cny, p = .001)) for ureteral stent removal. however, six patients with extraction string had an accidental dislodgement, additional medical expenses were 345±137.9 cny. there was no difference in the cost due to urinary tract infection, renal colic and luts between the two groups. the overall cost of patients without an extraction string was significantly more than in patients with an extraction string (86.7 ± 167.7 versus 507.9 ± 147.8 cny, p = .008). conclusion: despite an increase in stent dislodgement related risks to the extraction string, it results in significant cost savings for patients, and the most patients remove with extraction strings might benefit from it. keywords: ureteral stent; cost-benefit analysis; extraction string introduction nowadays, most of the urologists placed an in-dwelling ureteral stent following uncomplicated ureteroscopy(urs). however, ureteral stent may impact quality of life (qol) of patients. and additional suffering due to cystoscopic extraction is even more painful. current ureteral stents are manufactured with a string attached to the distal end, allowing for removal without cystoscopy, which may lead to a reduction of the dwell time(usually less than one week)(1-8). although stent extraction strings have many advantages, more than two-thirds of urologists remove extraction strings prior to their insertion(9). surgeons who do not adopt this method may have concern about perceived risks, including accidental dislodgement, infection, renal colic and lower urinary tract symptoms(luts). but how about incidence rate of the risk aforementioned? does this increase the patient's financial burden compared with patients remove without extraction strings? whether patients remove with extraction strings might benefit from it? therefore, we performed a retrospective study to help address these questions by comparing patients those who underwent ureteric stent placement with and without extraction strings after urs for stone disease. 1department of urology. the second affiliated hospital of zhejiang university school of medicine, zhejiang, china. 2department of ultrasonic. zhejiang cancer hospital, zhejiang, china. *correspondence: department of urology. the second affiliated hospital of zhejiang university school of medicine, hangzhou, zhejiang china. tel: +86 13738078331. fax: +86 13738078331. e-mail: nanzhang@zju.edu.cn. received march 2018 & accepted september 2018 patients and methods study population this study was approved by the ethics review board of the second affiliated hospital of zhejiang university school of medicine. inclusion criteria were patients who had an indwelling ureteral stent with or without extraction strings inserted after urs for unilateral ureteral stones. patients with congenital anomaly of the urinary tract, solitary kidney, renal insufficiency, ureteral stricture, pregnant, underwent bilateral urs or requiring long-term stent placement (>7 days) were excluded(2,4). in total, 140 patients at our institution between january 2017 and september 2017 were enrolled. study design and surgical technique all stents were 6f soft ureteric stents from cook medical(bloomington, in, usa) and the lengths were determined based on patient height. before placed stents with extraction strings, as described by bockholt et al(7) and kim et al(2), the string was cut at the level of the knot and tied with a new air knot 1-2 cm from the stent end, the distal end of the string were left 4cm protruded from the urethral meatus for women to easily find the string, and 10cm for men to have an erection. the stent string was not secured to the patient’s skin. all patients were discharged on the first day after surendourology and stone diseases 329 vol 15 no 06 november-december 2018 330 gery with prescriptions for prophylactic antibiotics and alpha-blockers, and patients were informed that the stents should be removed within one week at the outpatient department. for ureteral stent removal, the string was pulled by continuous and gentle force until the entire stent was out, without use of lidocaine jelly or an analgesic. no string-stents were removed by cystoscopic in which 2% lidocaine jelly was applied to the urethra without any analgesic. outcome assessment demographic and patient characteristics were gathered, including gender and age. other variables included were side, localization of calculus, operative duration, stent dwell time, use of extraction string and the cost for stent remove. postoperative morbidity including accidental dislodgement, infection, renal colic and luts was assessed by review of the medical record for the first three months after urs. dislodgment was identified as the stent leaving the body whether or not intended before prescribed follow up. the urinary tract infection(uti) was defined according to urinalysis of the laboratory department, the second affiliated hospital of zhejiang university school of medicine. and uti was considered as surgical site infection (ssi) if they occurred within one month after stent placement or stent removes(1).we also record the patients' medical expense when they visited the outpatient or emergency department due to postoperative morbidity. spss version 19.0 was used for statistical analysis. numeric data are presented as the mean ± standard deviation and categorical data as counts and percentages. numerical data were compared using student’s t-test. categorical data were analyzed using the χ2 test. statistical significance was set at p < 0.05. results a total of 140 patients were identified with this analysis. of these 140, 58 patients (41.4%) had an extraction string, including 28 females and 30 males. an overview of demographic and patient characteristics is shown in table 1. there were no differences between patients with or without a string in regard to age, gender, side, localization of calculus or operative duration. in general, patients with extraction string had shorter stent dwell time(5.3 ± 1.8 versus 11.2 ± 3.2 days, p = .001) and cost less for ureteral stent removal(8.97 ± 3.07 versus 455 ± 0 cny, p = .001). 6 cases (1 male, 5 females) had an accidental dislodgement representing 10.3% of cases with extraction string and 4.3% of all cases. no dislodgment occurred when extraction string was not used. the stent was dislodged in 3 patients at the inpatient department on postoperative day 1 when the catheter was removed. 3 patients presented to the emergency or outpatient department for accidentally pulled the stent out at home on 1–4 days postoperatively. no patients complained about discomfort except one patient who presented to the emergency department for hematuria. none of these patients required replacement. additional medical expenses including imaging test, laboratory examination table 1. patient characteristics vareable patients with extraction string(n=58) patients without extraction string(n=82) mean age(years) 45.4 ± 14.8 47.1 ± 15.9 gender male(n) 30 46 female(n) 28 36 side right(n) 31 27 left(n) 45 37 localization upper(n) 18 28 middle(n) 20 24 lower(n) 20 30 mean operative duration(min) 49.2 ± 15.8 45.5 ± 20.1 mean stent dwell time(day) 5.3 ± 1.8 # 11.2 ± 3.2 mean cost for stent removal(cny) 8.97 ± 3.07 # 455 ± 0 #p < 0.001, vs without extraction string group. complication patients with extraction string(n=58) patients without extraction string(n=82) dislodgement number(n) 6 0 mean cost(cny) 345 ± 137.9 # 0 ± 0 uti number(n) 3 4 mean cost(cny) 340.3 ± 76.7 387.5 ± 101.6 renal colic number(n) 3 6 mean cost(cny) 519.7 ± 56.1 516.3 ± 55.5 luts number(n) 5 6 mean cost(cny) 75.6 ± 78.9 76.2 ± 70.1 #p < 0.05, vs without extraction string group. table 2. medical expenses due to complication extraction string and cost-benefit analysishao liu et al. and registration fee due to accidental dislodgement are shown in table 2. expenses for patients with an extraction string were significantly more than in patients without an extraction string (345 ± 137.9 versus 0 ± 0 cny). 7 patients had a post-operative uti, including 5.2% and 4.9% of patients with and without extraction string, respectively. most of these patients presented to the emergency department for odynuria and take oral antibiotics for 3-5 days until urinalysis negative. one patient had a febrile uti (>38.0℃) and was administered antibiotics intravenously for 3-7 days until urinalysis negative. medical expenses including laboratory examination, medicines and registration fee are shown in table2. there was no difference in cost due to uti between the two groups(340.3 ± 76.7 versus 387.5 ± 101.6 cny, p = .093). there was no significant difference in the rate of renal colic and luts between the group of patients with and without an extraction string (5.2% versus. 7.3%, p = .082, 8.6% versus. 7.3%, p = .078). all patients who had a renal colic were treated with anticonvulsants and/or analgesic. whether prescribe anticholinergic agents to the patients with luts depended on the physician's judgment. there was no difference in the cost due to renal colic and luts between the two groups(519.7 ± 56.1 versus 516.3±55.5 cny, p = .103, 75.6 ± 78.9 versus 76.2 ± 70.1 cny, p = .098, table 2). the median overall cost was 86.7±167.7 cny for patients with extraction string and 507.9±147.8 cny for patients without extraction string. the cost of patients without an extraction string was significantly more than in patients with an extraction string (p = .008). table 3. discussion although some reports indicate that placement of an indwelling ureteral stent following uncomplicated ureteroscopy(urs) may be unnecessary(10,11), over three-quarters of urologists report stenting after uncomplicated urs for stone disease(12). the main benefit are the prevention of ureteral obstruction, renal colic and facilitation of residual stone fragment passage(5,10,13). however, cystoscopic extraction is time-consuming and laborious, more importantly, it augments the pain of the patients, especially for men. therefore, some urologists used extraction strings to remove stent without cystoscopy, which may lead to a reduction of the dwell time as well as morbidity associated with cystoscopic extraction. but most of the urologists remove extraction strings prior to their insertion(6,14).they may have concern about perceived risks, including accidental dislodgement, infection, renal colic and luts. in our study, we did not observe an increased rate of post-operative infection, renal colic and luts in patients with an extraction string. our study also reveals that 10.3% of patients with strings had an accidental dislodgement and most of these patients were women, presumably due to female hygiene practices and urethral anatomy. the cost of stent removal by cystoscopy is 455 cny in our center, mainly for equipment maintenance, instrument sterilization, medical consumables and personnel salary. by contrast, patients with extraction strings only need to pull the strings until the entire stent was out by their physicians at the outpatient service. therefore, the cost of stent removal in patients with strings was significantly reduced compared with patients without strings. this conclusion has also been confirmed by studies from different countries. bockholt et al(7). found that an estimated $1300 per patient cost associated with cystoscopic stent removal, which would be avoided by using strings. barnes et al(4). reported that stent removed by cystoscopy cost $243.43, and it would have resulted in about $97000 cost savings in their study population if all patients had an extraction string placed. beyond that, when patients could remove stents at home by themselves, it also reduces costs associated with patients travel and registration. they estimated a $68–185 saving per patient on travel costs if patients removed their stents at home. in our study, all extraction strings were pulled by urologists, so we do not count the costs associated with patient travel. some studies have reported that the main complication associated with the use of stent extraction strings was stent dislodgement. these data were supported by our study, which was reported 6 cases of stent dislodgement occurring in patients with extraction strings. most patients do not feel uncomfortable when they had dislodgement. the physician will evaluate the condition through the computed tomography or plain film of the abdomen and urinalysis. althaus et al(6). reported 13 cases with dislodgement, none of these patients required replacement. no patients need intervention except one patient who submitted to the emergency department for flank pain and intravenous pain medication was prescribed. in our study, all 6 patients with dislodgement do not need replacement, and fortunately, don't need medication. the additional medical expenses due to accidental dislodgement were imaging test, laboratory examination and registration fee. the average cost was 345 ± 137.9 chy. some urologists concern for postoperative uti caused by stent extraction strings. based on our study, this concern may be unfounded as we were incapable to find a difference in postoperative uti rate between patients with and without extraction strings. furthermore, there was no difference in the rate of renal colic and luts between groups. our data are in line with previous studies performed by fröhlich et al(1). and barnes et al(4). moreover, the extraction string did not increase the severity of these complications, for example, no difference was noticed when stratifying for febrile uti or urosepsis. therefore≤there was no difference in the cost due to uti, renal colic and luts between the two groups extraction string and cost-benefit analysishao liu et al. table 3. overall cost patients with extraction string(n=58) patients without extraction string(n=82) mean overall cost(cny) 86.7 ± 167.7 # 507.9 ± 147.8 #p < 0.001, vs without extraction string group. endourology and stone diseases 331 vol 15 no 06 november-december 2018 332 overall, patients with extraction string cost less for ureteral stent removal, but they have the potential to pay additional medical expenses caused by stent dislodgement. more importantly, the mean overall cost of patients with an extraction string was much lower than in patients without an extraction string. most of the patients remove with extraction strings might benefit from it. while the present results are supportive evidence for the use of ureteral extraction strings, this should be considered in clinical decision making and patient counseling. in fact this study has several limitations: first of all, it is possible that few patients did not present at our center when postoperative complications occurred, and this part of the data was not collected in our study. secondly, we did not collect the costs associated with patient travel and time taken off work. these data may be gathered in future studies. conclusions despite an increase in stent dislodgement related to the extraction string, it results significant cost savings for patients and the healthcare system, and the most patients remove with extraction strings might benefit from it. however, this must be considered in clinical decision making and patient counseling, and might not be a good option for all patients. acknowledgement this research was supported by zhejiang provincial nature science foundation of china under grant no.y18h050009 conflict of interest the authors report no conflict of interest. references 1. fröhlich m, fehr j, sulser t, eberli d, mortezavi a. extraction strings for ureteric stents: is there an increased risk for urinary tract infections? surg infect (larchmt). 2017;18:936-940. 2. kim dj, son jh, jang sh, lee jw, cho ds, lim ch. rethinking of ureteral stent removal using an extraction string; what patients feel and what is patients' preference? : a randomized controlled study. bmc urol. 2015;15:121. 3. loh-doyle jc, low rk, monga m, nguyen mm. patient experiences and preferences with ureteral stent removal. j endourol. 2015;29:35-40. 4. barnes kt, bing mt, tracy cr. do ureteric stent extraction strings affect stentrelated quality of life or complications afterureteroscopy for urolithiasis: a prospective randomised control trial. bju int. 2014;113:605-609. 5. kuehhas fe, miernik a, sharma v, et al. a prospective evaluation of pain associated with stone passage, stents, and stent removal using a visual analog scale. urology. 2013;82:521extraction string and cost-benefit analysishao liu et al. 525. 6. althaus ab, li k, pattison e, eisner b, pais v, steinberg p. rate of dislodgment of ureteral stents when using an extraction string after endoscopicurological surgery.j urol. 2015;193:2011-2014. 7. bockholt na, wild tt, gupta a, tracy cr. ureteric stent placement with extraction string: no strings attached? bju int. 2012 ;110:10691073. 8. kajbafzadeh am, nabavizadeh b, keihani s, hosseini sharifi sh. revisiting the tethered ureteral stents in children: a novel modification.int urol nephrol. 2015;47:881885. 9. oliver r, wells h, traxer o, et al. ureteric stents on extraction strings: a systematic review of literature.urolithiasis. doi: 10.1007 k/s00240-016-0898-1 10. haleblian g, kijvikai k, de la rosette j, preminger g. ureteral stenting and urinary stone management: a systematic review. j urol. 2008;179:424-430. 11. denstedt jd, wollin ta, sofer m, nott l, weir m, d'a honey rj. a prospective randomized controlled trial comparing nonstented versus stented ureteroscopiclithotripsy. j urol. 2001;165:1419-1422. 12. netto nr jr, ikonomidis j, zillo c. routine ureteral stenting after ureteroscopy for ureteral lithiasis: is it really necessary?j urol. 2001;166:1252-1254. 13. nabi g, cook j, n'dow j, mcclinton s. outcomes of stenting after uncomplicated ureteroscopy: systematic review and metaanalysis.bmj. 2007;334:572. 14. auge bk, sarvis ja, l'esperance jo, preminger gm. practice patterns of ureteral stenting after routine ureteroscopic stone surgery: a survey of practicing urologists.j endourol. 2007;21:1287-1291. vol 15 no 05 september-october 2018 297 case report voluminous urethral stone – a very rare complication after male suburethral sling surgery as a result of sling erosion into proximal urethra ioan scarneciu1,2, cristian andrei2, camelia scarneciu1, aura-mihaela lupu3, ovidiu gabriel bratu4, sorin lupu2* male sling for urinary incontinence is usually accompanied by very good results, with a small number of complications, but, when appear, they may be redundant. voluminous urethral stone developed on suburethral sling as a result of sling erosion into the proximal urethra is an extremely rare complication (following the analysis of cases published on the internet, the authors of this article no longer identified another similar case). we present the case of a patient who presented in our clinic for severe and permanent urinary incontinence, perineal discomfort and pain that was influenced by position. his past medical history showed polytrauma with lumbar fracture and medullary involvement (34 years ago) and transobturator suburethral sling surgery for urinary incontinence about 6 years ago in another urology unit, without relieving symptoms. imaging investigations have showed a voluminous urethral stone developed on polypropylene sling and another small stones in that area. stones surgical extraction was performed by perineal approach (together with the mesh), proximal urethra was closed after excision to apparently healthy urethral tissue (to prevent possibility of later severe incontinence) and a permanent suprapubic cystostomy catheter was inserted. patient is dry at follow-up visits (at 1 and 3 months) and he reported significant improvement in quality of life. the case is spectacular due to the rarity of the complication presented, patient developing urethral erosion without clinical manifestations to suggest this matter (infection or fistula), the symptoms being absent for a long time. introduction urinary incontinence after spinal cord injury is a major problem affecting the quality of life of those patients. patients not responding to drug treatment can benefit from a surgical treatment with inconsistent results(1). suburethral sling, especially from synthetic materials, is most commonly used in patients with stress urinary incontinence as a complication of radical prostatectomy. as a technical option, this procedure can also be used in patients with urinary incontinence after congenital or acquired neurological lesions, being considered second-line therapy after failure of non-surgical methods(1, 2). although the overall rate of success is appreciated between 50 and 85%, with very low frequency of complications, these interventions can sometimes be followed by redundant complications (2,3). 1faculty of medicine, “transilvania” university from brasov, brasov, romania. 2clinic of urology, emergency clinical county hospital from brasov, brasov, romania. 3department of radiology and medical imaging, cfr general hospital, brasov, romania. 4faculty of medicine, university of medicine and pharmacy "carol davila" bucharest, romania. *correspondence: clinic of urology, emergency clinical county hospital from brasov, oltet str., no. 2, brasov, romania. tel: 0040722988921. email: so_lupu@yahoo.com. received july 2017 & accepted february 2018 keywords: male sling; incontinence; sling complications; urethral stone; urethral erosion. figure 1. a. hard and round palpable mass in the perineum. b. voluminous and round radiopaque image in perineum. c. voluminous and round radiopaque image in perineum, with urethral involvement. case report a 62-year-old man was admitted to our clinic for permanent and severe urinary incontinence (without urinary retention), permanent perineal discomfort and intermittent perineal pain (especially in the seated position). symptomatology with an onset of about 6 years and progressive accentuation. his past medical history showed polytrauma as a result of a fall from a height, with lumbar spinal fracture and medullary involvement (34 years ago). in 2010 he had a transobturator suburethral sling surgery for urinary incontinence, in another unit of urology, without relieving symptoms. in 2011 the patient is discovered with a small calcification in the urethra when he has undergone a cystoscopy (in the same unit of urology were was done sling surgery). no treatment was performed for this condition because the patient refused it in that moment and no other urological control has been performed since then until the presentation in our unit. careful physical examination revealed a hard and round palpable mass in the perineum, without inflammatory signs, accompanied by discomfort with palpatory sharpening. pelvic radiography and retrograde urethrocystography showed a voluminous and round radiopaque image in perineum, with urethral involvement (figure 1). abdominal ultrasound was inconclusive (empty bladder). during the current admission, his laboratory data showed normal values. given the degree of urinary incontinence and the marked impact on the quality of life for this patient, after discussing the case in the clinic, definitive suprapubic cystostomy and surgery for removal of the perineal foreign body is considered in order to relieve painful symptoms. after signing the informed consent and adequate pre-operative preparation, surgery was performed. percutaneous placement of a suprapubic cystostomy was done and an incision was made in the perineum, with wide opening of the urethra. the urethra itself was very dilated due to big stone presence (not urethral diverticula). a urethral stone of about 5 cm and smaller ones were extracted, partial resection of excess urethral wall was performed to apparently healthy urethral tissue (to prevent possibility of later severe incontinence), the proximal orifice of the urethra was closed and sutured with absorbable material and parietal planes were closed. on macroscopic examination we observed that the stones were formed around the polypropylene sling (mesh was inside the big stone and were removed together) (figure 2). evolution after surgery was without complications. there was a rapid relieve of perineal pain. the patient was discharged 5 days after surgery with permanent suprapubic catheter. the patient was reviewed at 1 month and 3 months. there have been a significant improvements in the quality of life: absence of perineal pain, without the need to use pads. discussion the rate of urinary incontinence in men is estimated to be between 12 and 17% in the us population, with increasing prevalence with age(4). urinary incontinence secondary to spinal trauma is an important topic that causes marked impairment in patient's quality of life. also, surgery for male urinary incontinence is an extremely important aspect, determined by the large number of patients that remain incontinent due to spinal trauma (increasing the number of accidents) or after urological surgery procedures (after radical prostatectomy or transurethral resection of the prostate)(1, 2, 5). it is estimated that in the us there are more than 250,000 patients with spinal cord injury and about 80% of them have varying degrees of bladder dysfunction(1). surgery techniques and materials used for sling surgery are constantly developing. the type of treatment, medical or surgical, must be individualized according to the degree of incontinence, detrusor contractility and urethral compliance of the patient(3). commonly used methods for sling surgery in men are suburethral bone-anchored slings (bas), retrourethral transobturator slings (rts), and adjustable retropubic slings (ars). identifying the most effective method is still extremely difficult due to the lack of comparative studies and differences in patient follow-up reportings (4). numerous authors published very good and good results, in varying percentages, with the rate of severe complications being below 1% (3,6,7). the lesser results are directly dependent on the surgical technique, but also on associated factors; it is appreciated that history of pelvic radiotherapy or sling surgery could be major risk factors for sling failure(3). it is appreciated that sling procedures are less invasive compared to artificial sphincters. also, the transobturator tape variant is considered to be safer and accompanied by lower complications compared to the retropubic variant(8). although many studies consider to be extremely safe and fast, with excellent results, complications after sling surgery may still exist. the most common complifigure 2. a. intraoperative aspect the stone was found after urethral opening. b. the aspect of very dilated urethra, with another profound stone. c. extracted stones. d. fragmented stones and polypropylene sling from the inside. urethral stone after sling surgery-scarneciu et al. case report 298 vol 15 no 05 september-october 2018 299 cations are: urinary retention, infectious complications, urethral erosion, scrotal pain or numbness, perineal haematoma, need for sling removal. these are generally dependent by the sling surgery type(1,2,3,4,9). except for sling removal, it is estimated that the rest of the complications are transient, appear in a small percentage and disappear after a maximum of 4 months (4). urethral erosion may occur immediately or subsequent after surgery, being secondary to an unrecognized urethral injury during surgery. the solution consists in sling removal. it is also estimated that perineal pain is almost quasi-conscious in most cases, but it resolves spontaneously within a few months(4,9). however, although it is thought that sling surgery is very easy, fast, almost without complications, there are rare situations where complications are surprising. in this report we presented a very rare complication case: the development of a voluminous urethral stone and other smaller ones on a suburethral sling after transobturator tape surgery. the case is spectacular due to the fact that the patient developed an urethral erosion without clinical manifestations to suggest this matter, the symptom being absent for a long time. also, the patient has not developed any obvious fistula or infectious complications over a period of several years, although they would normally have appeared in such a situation. it is strange that the patient did not have the clinical manifestations of a urethral erosion, a possible infection or fistula. patient presentation was totally atypical, only with perineal discomfort, server incontinence and the presence of a hard and round palpable mass in the perineum. the case presented is a particular, exceptional situation, consisting in formation of a voluminous stone on the synthetic material used in sling surgery, by urethral erosion. at least in the studied literature, the authors have never met a case report like this. patients undergoing such sling interventions should be advised, particularly with regard to potential complications, as well as the possibility of failure from a functional point of view. although male sling surgery is considered relatively simple and with low rate complications, it should not be forgotten that any manoeuvre may be accompanied by complications that may affect the quality of life of the patient. conflict of interest the authors report no conflict of interest. grant support & financial disclosures none references 1. al taweel w, seyam r. neurogenic bladder in spinal cord injury patients. res rep urol. 2015; 7: 85–99. 2. herschorn s, et al. com. 13 surgical treatment of urinary incontinence in men, “incontinence”, abrams p, cardozo l, khoury s, wein a (eds), 4th international consultation on incontinence, paris july 5-8, 2008, 4th edition 2009, 1121-1190. urethral stone after sling surgery-scarneciu et al. 3. comiter cv, dobberfuhl ad. the artificial urinary sphincter and male sling for postprostatectomy incontinence: which patient should get which procedure?. investig clin urol. 2016 ; 57: 3–13. 4. landon trost, daniel s. elliott. male stress urinary incontinence: a review of surgical treatment options and outcomes. advances in urology, 2012, 13: 2012. 5. markland ad, richter he, fwu cw, eggers p, kusek jw. prevalence and trends of urinary incontinence in adults in the united states, 2001 to 2008. j urol, 2011:186 : 589–93. 6. welk bk, herschorn s. the male sling for post-prostatectomy urinary incontinence: a review of contemporary sling designs and outcomes. bju int 2012;109:328-44. 7. kretschmer a, buchner a, leitl b, et al. long-term outcome of the retrourethral transobturator male sling after transurethral resection of the prostate. int neurourol j. 2016;20:335-341. 8. siracusano s, visalli f, toffoli l. male incontinence and the transobturator approach: an analysis of current outcomes. arab journal of urology (2013) 11, 331–5. 9. cornel eb, elzevier hw, putter h. can advance transobturator sling suspension cure male urinary postoperative stress incontinence? j urol 2010;183:1459. unclassified the role of npm1 in the invasion and migration of drug resistant bladder cancer chenshuo luo1, ting lei2, man zhao2, qian meng2, man zhang1,2,3* purpose: to study the difference of tumor progression caused by differential expression of npm1 in drug-resistant bladder cancer. materials and methods: the expression of npm1 was analyzed by pcr and western blot. npm1 silencing bladder cancer cells (t24/ddp lv-npm1, pumc-91/ddp lv-npm1) and overexpressing bladder cancer cells (t24/ ddp lv5-npm1, pumc-91/ddp lv5-npm1) were established by lentivirus and limited dilution method. the efficiency of gene interference was detected by fluorescence microscopy and western blot. the migration ability and invasion ability of tumor in vitro were analyzed by wound healing assay and transwell cell invasion test, and the tumorigenic ability in vivo was judged by nude mouse tumorigenicity assay. results: compared with the corresponding negative control group, both npm1 silencing cell lines t24/ddp lv-npm1 and pumc-91/ddp lv-npm1 showed strong migration ability and high invasive ability. at the same time, there was no significant difference in migration ability and the invasive cells proportion between npm1 overexpressing cell line and related negative control group. npm1 silencing bladder cancer cells had obvious tumorigenicity in vivo. conclusion: npm1 silencing cells had significant migration and invasion ability. the silencing of npm1 will accelerate tumorigenicity of drug resistant bladder cancer. differential expression of npm1 is of great value in monitoring the progression of drug-resistant bladder cancer. keywords: bladder cancer; npm1; tumorigenicity; cisplatin introduction bladder cancer is the second most common genito-urinary malignancy, with a growing population of patients globally.(1) because of drug resistance, conventional operation combined with drug perfusion cannot treat bladder cancer well, which makes it easy to recur and difficult to cure.(2) considering the non-invasive and reliability of tumor markers, it is necessary to find a tumor marker that can timely monitor the progress of drug-resistant bladder cancer. in the process of tumor progression, the ability of invasion and migration of drug-resistant tumor is an important factor that can affect the prognosis of patients.(3) nucleocapsmin (npm1) is one of the most important nucleocapsid protein, which can shuttle between nucleolus and cytoplasm.(4,5) abnormal expression of npm1 has been found in colon cancer, lung adenocarcinoma and hematology tumor.(6-8) many studies have shown that npm1 plays a role in many important cell activities and is related to the invasion and migration of tumor cells.(9) npm1 can reflect the therapeutic effect and prognosis of various tumors, such as leukemia.(10) when our laboratory analyzed the urine samples of bladder cancer patients, we identified 14 differential expression protein spots, including npm1.(11) then we found that npm1 is one of the differentially expressed 1clinical laboratory medicine, peking university ninth school of clinical medicine, beijing, 100038, china 2clinical laboratory medicine, beijing shijitan hospital, capital medical university, beijing, 100038, china 3beijing key laboratory of urinary cellular molecular diagnostics, beijing, 100038, china *correspondence: clinical laboratory medicine, peking university ninth school of clinical medicine, beijing shijitan hospital, capital medical university, beijing 100038, china. tel: 0086 010 63926389 fax: 0086 010 63926283 email address: zhangman@bjsjth.cn. received april 2020 & accepted july 2021 proteins between bladder cancer cell lines based on 2d-page proteomics approaches. and then using bladder cancer cell lines against different gradient doses of adriamycin and bladder cancer tissue samples, we showed npm1 was independently associated with drug resistance and recurrent frequency of bladder cancer, suggesting that npm1 was a key regulator in drug-resistant bladder cancer model.(12) to explore the role of npm1 in cell invasion and migration, we analyzed the role of npm1 in the biological characteristics of tumorigenicity in vitro and vivo. this experiment will reveal the influence of npm1 in bladder cancer, and provide guidance for the clinical recognition and intervention of bladder cancer. materials and methods subject and groups bladder cancer cell lines and groups drug resistant cell groups: the cisplatin resistant bladder cancer cell lines (t24/ddp, pumc-91/ddp) were purchased from beijing shijitan hospital affiliated to capital medical university. negative control groups: bladder cancer cell lines t24 and pumc-91. t24 is an american type culture collection (atcc), pumc-91 purchased from the cell biology laboratory of peking union medical college urology journal/vol 18 no. 4/ july-august 2021/ pp. 452-459. [doi: 10.22037/uj.v18i.6087] hospital. npm1 differential expression cell groups npm1 silencing bladder cancer cell lines (t24/ddp lv-npm1, pumc-91/ddp lv-npm1): npm1 silenced stable infection cell line was constructed by lentivirus infection. npm1 silencing negative control groups (t24/ddp lvnc, pumc-91/ddp lv-nc): the infected cell lines were constructed by lentivirus infection. npm1 over-expressing groups (t24/ddp lv5npm1, pumc-91/ddp lv5npm1): the infected cell lines were constructed by lentivirus infection. npm1 over-expressing negative control groups (t24/ ddp lv5-nc, pumc-91/ddp lv5-nc): the infected cell lines were constructed by lentivirus infection. animal groups according to the condition of tumor injection, xenograft model were randomlyized divided into two groups: the negative animal control (lv-nc) and npm1 silencing animal group (lv-npm1). 4 mice in each group. all applicable international, national, and institutional guidelines for the care and use of animals were followed. all procedures performed in studies involving animals were in accordance with the ethical standards of the pecking university ethics committee. (permit number: la2017287) reagents cisplatin (p4394, sigma, usa), rpmi-1640 medium (ae244464298, thermo scientific, usa), fbs table 1. the primer design of real-time quantitative pcr (q-rt-pcr). gene forward primer reverse primer npm1 5'-tggtgcaaaggatgagttgc-3' 5'-gtcatcatcttcatcagcagc-3' β-actin 5'-ctacaatgagctgcgtgtggc-3' 5'-caggtccagacgcaggatggc-3' figure 1. npm1 silencing, npm1 overexpressing stable cell lines and corresponding negative control stable cell lines. (a) the infection efficiency of lentivirus (immunofluorescence microscopy, 10 × 40). (b) the expression of npm1 protein (western blot). (c) the expression level of npm1 silencing stable cell line and npm1 over-expressing stable cell line differential npm1 affects bladder cancer – luo et al. unclassified 453 vol 18 no 4 july-august 2021 454 (1861242, gibco, thermofisher, usa), 0.25% trypsin (17518012, gibco, thermofisher, usa), trizol (84804, gibco, thermofisher, usa), reverse transcription kit (64j00101, dingguo, china). sybr green fluorescent quantitative pcr kits (k20524, transgen biotech, china), polyvinylidene fluoride (pvdf) membranes (iseq00010 sigma, usa), mouse anti-nucleophosmin antibody (ab10530, abcam, usa), mouse igg h&l (hrp) (ab205719, abcam, usa), 96-well plates (e161134l, thermo, usa), npm1-silencing,npm1 over-expressing and negative control lentivirus (genepharma, china), growth factor reduced matrigel (3432-001-01, r&d systems, usa), transwell chambers (140644, thermo, usa) cell culture and subculture t24, pumc-91, t24/ddp and pumc-91/ddp cells were cultured in rpmi-1640 medium containing 15% fetal bovine serum at 37 ℃ and 5% co 2 incubator respectively. after digestion of 0.25% trypsin, they were used for subculture. npm1 expression detection table 2. effect of npm1 differential expression on oncological characteristics of bladder cancer cells. experimental groups the ratio of npm1 protein expression cell migration rate invasive cell count t24/ddp lv-npm1 / t24/ddp lv-nc 0.15 (p <.001) 24h: 73.33% vs 13.83% (p <.001) 1983 vs 788 (p <.001) 48h: 86.53% vs 44.83% (p <.001) pumc-91/ddp lv-npm1 / pumc-91/ddp lv-nc .03 (p <.001) 24h: 20.13% vs 8.47% (p =.046) 755 vs 133 (p <.001) 48h: (90.43% vs 9.76%, p <.001) t24/ddp lv5-npm1 / t24/ddp lv5-nc 1.52 (p =.019) 24h: 8.03% vs 14.80% (p =.261) 503 vs 605 (p =.545) 48h: 20.90% vs 41.00% (p =.064) pumc-91/ddp lv5-npm1 / pumc-91/ddp lv5-nc 1.35 (p =.045) 24h: 10.73% vs 6.70% (p = .102) 139 vs 149 (p =.635) 48h: 15.23% vs 12.33% (p = .630) figure 2. the effect of npm1 silencing and npm1 overexpressing on cisplatin resistant bladder cancer cell migration. with experimental times lasting (0-48 hours), the cell migration rate of npm1 silencing cisplatin resistant bladder cancer cells was higher than that of negative control and npm1 overexpressing bladder cancer cells. differential npm1 affects bladder cancer – luo et al. npm1 gene mrna and protein expression were detected by real-time fluorescent quantitative pcr (q-pcr) and western blot, respectively. q-pcr primer design: primer 5.0 software is used for the primer design (table 1). total rna extraction: when the cells grow to the logarithmic growth stage, discard the medium, wash the cells with pbs for three times, digest the cells with trypsin, and extract the total rna by trizol method. the operation was carried out according to the instructions of the total rna extraction kit. determination of rna concentration and purity: rna concentration and purity were determined by ultraviolet spectrophotometer. the od value of sample rna is between 1.8 and 2.0. cdna synthesis: reverse transcription of rna samples was performed by reverse transcription kit. the total reaction volume of 20 μl. fluorescent quantitative pcr: all operations were carried out according to the instructions of sybr green fluorescent quantitative pcr kit. fluorescent quantitative pcr analysis was carried out by pcr analysis instrument. calculate the corresponding ct value. determination of mrna expression: the relative expression of npm1 gene mrna was analyzed by relative quantitative analysis, and the expression of β-actin was taken as a reference, and the relative expression multiple was n (n = 2-δδct).δδ ct = (mean ct value of target gene in the group mean ct value of β-actin gene in the group) (mean ct value of target gene in the control group mean ct value of β-actin gene in the control group). western blot when cells grew to logarithmic growth phase, they were washed with pbs for 3 times. ripa lysis buffer containing proteinase inhibitor was used to lyse the cells. the volume of the sample was calculated according to the protein mass (20 μg). after sds-page gel electrophoresis, the protein was transferred to the pvdf membrane and sealed with skim milk powder for 2 hours. pvdf membrane was immersed in the diluted antibody of skimmed milk powder for 4 ℃ overnight. the pvdf membrane was cleaned by tbst 3 times. add the corresponding diluted antibody (1: 5000), shake it on the horizontal shaker for 2 hours at room temperature, and clean it with tbst for 3 times at room temperature. dab developer was used for development, and pictures were exposed and saved. image j system was used to analyze the band optical density, the optical density value of the target protein band and β-actin band were compared with that of the control group. the relative optical density value of the control group is set to 1, and calculate the relative optical density value of each target protein. establishment of stable bladder cancer cell line npm1 silenced and npm1 over expressed cell lines figure 3. the effect of npm1 silencing and npm1 overexpressing on the cell invasion of cisplatin resistant bladder cancer cells. 48 hours after the experiment, npm1 silencing cisplatin resistant bladder cancer cells were more invasive than negative control cells. differential npm1 affects bladder cancer – luo et al. unclassified 455 vol 18 no 4 july-august 2021 456 were obtained by lentivirus infection, and stable cell lines were screened by limited dilution method. lentivirus infection: at the logarithmic growth stage of cultured cells, 96 well plates were inoculated with 1 × 103 cells per well. the cells were incubated at 37 ° c for 24 hours. after the cells grew to 50% confluence, they were infected with npm1 silencing lentivirus or npm1 over-expressing lentivirus for 24 hours. meanwhile, the negative control groups were inoculated with corresponding negative control lentivirus. moi value was used to analyze the virus concentration. finally, 106pfu/ml virus concentration was used to infect cells to ensure the maximum infection efficiency and cell survival rate. after virus infection, the cells were cultured in a complete medium. when the cells reached 80% confluence, the cells were transferred to the culture flask for expanded culture. establishment of stable infected cells: the infected cells were screened by limited dilution method. the infected cells were diluted to 0.5-1 cells per 96 well plate. after 3-4 weeks, the cells grew into a visible cell set. the cells expressing gfp fluorescence were further cultured. silencing effect of npm1: western blot was used to confirm the silencing effect of npm1. wound-healing assay in order to evaluate the migration ability of bladder cancer cells, wound-healing assay was performed. the migration ability of cells in each group can be judged by the difference of repair ability of cells in different groups for wound area. the plate was irradiated with ultraviolet for 30 minutes before operation. approximately 3 × 104 infected cells were incubated at 24 holes. wounds were made according to the instructions. after 24 hours low serum concentration medium was used to incubate the cells. rinsed the plate gently with pbs for 2 times after 24 or 48 hours. after that the photos were taken under microscopy (ckx41, olympus, usa). according to the pictures, the rate of cell migration in each group was calculated. the migration rate was the ratio figure 4. tumorigenicity comparison between lv-npm1 and lv-nc cells in nude mice. 35 days after the experiment, nude mice injected with npm1 silencing cells had more pronounced tumor masses than the negative control nude mice. differential npm1 affects bladder cancer – luo et al. of wound width to 0 hour wound area width. transwell invasion assay in order to evaluate the invasion ability of bladder cancer cells, transwell invasion assay was performed. the invasion ability of bladder cancer cells was evaluated by counting the amount of cells which can digest matrigel. matrigel invasion assay was performed using transwell chambers. 1×104 lv-npm1 cells, 1×104 lv5npm1 and the cells were seeded in the upper chamber of a 24-well plate, which was coated with growth factor reduced matrigel. the upper chamber was filled with 500μl serum-free medium. the lower chamber was filled with 500μl medium containing 10% fbs to induce cell invasion. the chamber was incubated at 37°c for 24 hours. at the end of incubation, cells in the upper surface of the membrane were removed with a cotton swab. migrated cells were stained with crystal violet. the images were obtained by microscope and the cells were counted in ten different view fields. the experiment was conducted in triplicate. xenograft growth in nude mice to evaluate the tumorigenicity of lv-npm1 cells, xenograft model was made by subcutaneous injection of lv-npm1 cells in athymic nude mice. male mice (6-8 week old) were randomized into two groups. the mice were inoculated subcutaneously in the left armpit with 100μl serum-free rpmi medium containing 5×107 lvnpm1 cells. they were also inoculated subcutaneously in the right armpit with 100 μl serum-free rpmi medium containing 5×107 lv-nc cells (as the negative control). all the mice were kept in standard laboratory conditions and provided with ad libitum food and water. general health of these animals was daily observed and tumor growth at the injection site was monitored by palpation. tumor volume was measured outside of body by vernier caliper and calculated using the formula: length × (width) 2 × 0.5. after 35 days of the experiment, all nude mice were sacrificed by cervical dislocation and tumors were removed and stored in liquid nitrogen. the experiment was conducted in triplicate. statistical analysis all independent experimental data were expressed as mean values. statistical analysis was performed using graphpad prism 6.0 statistical software. the p-values were calculated by analysis of variance (anova) for two groups. pre-assumptions: h0: there was no significant difference between the experimental group and the control group h1: there was statistical difference between the experimental group and the control group. p-value < .05 indicates a statistically significant result. results the establishment of npm1 silencing cell lines and npm1 over-expressing cell lines the npm1 silencing cell lines and npm1 over-expressing cell lines were obtained by lentivirus infection and limited dilution method. the results of q-pcr and western blot showed that the selected cells by limited dilution method had more than 80% gfp fluorescence efficiency and more than 90% gene efficiency (figure 1a). npm1 silencing stable infection cell line npm1 can be effectively inhibited, and can be long-term inhibited screened. (figures 1b, 1c). the level of npm1 protein in t24/ddp lv-npm1 cell line was only 0.15 times that of the negative control. the level of npm1 protein in pumc-91/ddp lv-npm1 cell line was only 0.03 times that of the negative control. compared with the negative cells, the npm1 protein of the overexpressing cell lines also increased significantly (figures 1b, 1c). the level of npm1 protein in t24/ddp lv5-npm1 cell line was 1.5 times that of the negative control. the level of npm1 protein in pumc-91/ddp lv5-npm1 cell line was 1.35 times that of the negative control. the effect of npm1 silencing and npm1 overexpressing on the cell mobility of cisplatin resistant bladder cancer cells compared with the negative control group, npm1 silencing cell line t24/ddp lv-npm1 showed strong migration ability in 24 hours (73.33% vs 13.83%) and 48 hours (86.53% vs 44.83%). at the same time, there was no significant difference between the overexpressing cell lines (t24/ddp lv5-npm1) and the corresponding negative control cell lines in 24 hours and 48 hours. in the comparison of npm1 silencing cell line pumc91/ddp lv-npm1 and its negative control (pumc-91/ ddp lv-nc), pumc-91/ddp lv-npm1 also showed stronger cell migration ability in 24 hours (20.13% vs 8.47%) and 48 hours (90.43% vs 9.76%). besides, there was no significant difference between the overexpressing cell line and the corresponding negative control cell lines in 24 hours and 48 hours. the results are shown in figure 2. the effect of npm1 silencing and npm1 overexpressing on the cell invasion of cisplatin resistant bladder cancer cells compared with the negative control group, the invasive cells proportion of t24/ddp lv-npm1 cells was higher than lv-nc cells (1983 cells/lp vs 788 cells/lp). at the same time, there was no significant difference in the proportion of cells in the invasive cells proportion between npm1 overexpressing cell line and related negative control group. compared with the negative control group, the invasive cells proportion of pumc-91/ ddp lv-npm1 cells was higher than lv-nc cells (755 cells/lp vs 133 cells/lp). at the same time, there was no significant difference in the proportion of cells in the invasive cells proportion between npm1 overexpressing cell line (pumc-91/ddp lv5-npm1) and related negative control group (pumc-91/ddp lv5-nc). the results are shown in figure 3. the effect of npm1 silencing on the tumorigenicity of cisplatin resistant bladder cancer cells in vivo after 35 days of the experiment, greater masses were observed in animals injected with lv-npm1 cells compared with lv-nc cells. meanwhile, the tumor mass of the nude mice injected npm1 silenced cells was more obvious than that of the negative control nude mice.at 14-35 days (p <.001), as shown in figure 4. discussion drug resistance is the major obstacle to cancer chemotherapy. there is much research about monitoring and avoidance of drug resistance. the accurate judgment of invasion and migration of drug resistant bladder cancer can effectively guide the treatment of bladder cancer and improve the treatment effect. nucleophosmin (npm1) is a nucleolar protein which can provide clinical information for the development of cancers.(13,14) npm1 plays important roles in p53, mdm2 and other signal pathways,(15,16) which means differential npm1 affects bladder cancer – luo et al. unclassified 457 vol 18 no 4 july-august 2021 458 npm1 can affect tumor characteristics and provide important information for drug resistance. the upregulation of npm1 expression will significantly affect the relapse rate and the sensitivity of chemotherapy drugs of leukemia.(17,18) however, the contrary effect of npm1 on therapeutic effect has also been reported. jian et al. found that the abnormal high expression of npm1 may inhibit the growth of tumor cells,(19) which suggested that npm1 might have a positive correlation with the anti-tumor activity. some studies showed that npm1 mutation can change genome stability, which has been described as having both oncogenic and tumor suppressive functions.(20) npm1 overexpression is linked to a poor prognosis.(21) however, in gastric cancer and breast cancer, npm1 is associated with poor prognosis. (19,22) these studies show that the value of npm1 still needs to be further evaluated for different tumors. in general, npm1 is of great value in the progression of non-urinary tumors.(23) myc is one of the protein related to the occurrence and prognosis of tumors.(24) the lack of a functional npm1 was previously associated with increased levels of myc.(25) npm1 regulates c-myc protein stability through its effect on the γ-isoform of the f-box e3 ubiquitin ligase fbw7. this effect of npm1 on fbw7γ is relevant for f its substrates, c-myc, which accumulates in the absence of npm1. in the study of bladder cancer, the activation of myc can go through β-catenin/c-myc signaling pathway and aff4/nf-κb/ myc signaling pathway to increase the ability of cell migration and proliferation.(26) in this experiment, npm1 silencing and npm1 overexpressing bladder cancer cell lines were constructed by lentivirus infection and limited dilution method to evaluate the value of npm1 in drug resistant bladder cancer. in this study, the results showed that the loss of npm1 was correlated with high cell mobility in bladder cancer cells. compared with negative control group, npm1 silencing cell line t24/ddp lv-npm1 showed strong migration ability in 24 hours and 48 hours. in the comparison of npm1 silencing cell line pumc-91/ ddp lv-npm1 and its negative control, pumc-91/ ddp lv-npm1 showed stronger cell migration ability in 24 hours and 48 hours, as shown in table 2. besides, npm1 silencing could make cisplatin resistant bladder cancer aggressive. compared with the negative control, the proportion of the invasive cells of t24/ ddp lv-npm1 cells was higher than lv-nc cells. compared with negative control group, the invasive cells proportion of pumc-91/ddp lv-npm1 cells was higher than lv-nc cells. compared with the above results in vitro, the tumorigenesis experiment also showed similar results in vivo. greater masses were observed in animals injected with lv-npm1 cells compared with lv-nc cells. based on the above experimental results, we confirmed that in the absence of npm1, bladder cancer cells have higher invasiveness and mobility, and may point to poor prognosis and higher risk of recurrence. the experimental results may be related to the explanation of npm1 mechanism. loss of npm1 function has been shown to be associated with increased genome instability. combined with our experimental results, we speculate that the loss of npm1 might promote the activation of myc signal pathway in bladder cancer cells to increase the invasion and migration ability of bladder cancer. these ideas will be further confirmed in future experiments. npm1 shows an important role in the clinical application of tumor markers. npm1 has high sensitivity and specificity, which can monitor the progress of tumor timely and effectively. at the same time, as a tumor related marker, it is associated with a variety of tumor signal pathways, which is of great significance to the study of tumor progression mechanism.(27) unlike many bladder cancer markers, which are susceptible to infection and other factors, npm1 has less interference and can more accurately reflect the changes of tumor in vivo. (28) combined with our results of this study, its clinical value in bladder cancer is worthy of further exploration. as a protein existing in cells, is npm1 easily detected in the urine of patients with bladder cancer? what is the sensitivity of npm1 in clinical noninvasive monitoring of bladder cancer? these questions need to be further confirmed in the clinical research of bladder cancer. conclusions down-regulated expression of npm1 may indicate the poor outcome of bladder cancer, which means that the tumor may be more malignant. monitoring the changes of npm1 in time can effectively adjust the treatment strategy of bladder cancer and treat bladder cancer. acknowledgement this work was supported by enhancement funding of beijing key laboratory of urinary cellular molecular diagnostics (grant number: 2020-js02). conflict of interest the authors report no conflict of interest. references 1. bhanvadia sk. bladder cancer survivorship. curr urol rep. 2018;19:111. 2. martinez rodriguez rh, buisan rueda o, ibarz l. bladder cancer: present and future. med clin (barc). 2017;149:449-455. 3. duff d, long a. roles for rack1 in cancer cell migration and invasion. cell signal. 2017;35:250-255. 4. kim jy, cho ye, an ym, et al. gltscr2 is an upstream negative regulator of nucleophosmin in cervical cancer. j cell mol med. 2015;19:1245-52. 5. endo a, matsumoto m, inada t, et al. nucleolar structure and function are regulated by the deubiquitylating enzyme usp36. j cell sci. 2009;122:678-86. 6. forghieri f, riva g, lagreca i, et al. characterization and dynamics of specific t cells against nucleophosmin-1 (npm1)mutated peptides in patients with npm1mutated acute myeloid leukemia. oncotarget. 2019;10:869-882. 7. liu y, zhang f, zhang xf, et al. expression of nucleophosmin/npm1 correlates with migration and invasiveness of colon cancer cells. j biomed sci. 2012;19:53. 8. he j, xiang z, xiao j, xiao h, liu l. [the poor chemotherapeutic efficacy in lung adenocarcinoma overexpressing c-src and nucleophosmin/b23(npm1)]. j exp hematol. 2016;32:1378-1381. 9. li s, zhang x, zhou z, et al. downregulation differential npm1 affects bladder cancer – luo et al. of nucleophosmin expression inhibited proliferation and induced apoptosis in salivary gland adenoid cystic carcinoma. j oral pathol med. 2017;46:175-181. 10. heath em, chan sm, minden md, et al. biological and clinical consequences of npm1 mutations in aml. leukemia. 2017;31:798807. 11. lei t, zhao x, jin s, et al. discovery of potential bladder cancer biomarkers by comparative urine proteomics and analysis. clin genitourin cancer. 2013;11:56-62. 12. hu h, meng q, lei t, zhang m. nucleophosmin1 associated with drug resistance and recurrence of bladder cancer. clin exp med. 2015;15:361-9. 13. li tt, li j, geng yh, et al. [nras gene expression and its clinical significance in patients with acute myeloid leukemia]. j exp hematol. 2020;28:76-81. 14. jain p, kantarjian h, patel k, et al. mutated npm1 in patients with acute myeloid leukemia in remission and relapse. leuk lymphoma. 2014;55:1337-44. 15. kurki s, peltonen k, latonen l, et al. nucleolar protein npm interacts with hdm2 and protects tumor suppressor protein p53 from hdm2-mediated degradation. cancer cell. 2004;5:465-75. 16. jin a, itahana k, o'keefe k, zhang y. inhibition of hdm2 and activation of p53 by ribosomal protein l23. mol cell biol. 2004;24:7669-80. 17. bertoli s, tavitian s, berard e, et al. more than ten percent of relapses occur after five years in aml patients with npm1 mutation. leuk lymphoma. 2020:1-4. 18. chen s, li x, ma s, et al. chemogenomics analysis of drug targets for the treatment of acute promyelocytic leukemia. ann hematol. 2020. 19. jian y, gao z, sun j, et al. rna aptamers interfering with nucleophosmin oligomerization induce apoptosis of cancer cells. oncogene. 2009;28:4201-11. 20. wang w, budhu a, forgues m, wang xw. temporal and spatial control of nucleophosmin by the ran-crm1 complex in centrosome duplication. nat cell biol. 2005;7:823-30. 21. coutinho-camillo cm, lourenco sv, nishimoto in, kowalski lp, soares fa. nucleophosmin, p53, and ki-67 expression patterns on an oral squamous cell carcinoma tissue microarray. hum pathol. 2010;41:107986. 22. leal mf, mazzotti tk, calcagno dq, et al. deregulated expression of nucleophosmin 1 in gastric cancer and its clinicopathological implications. bmc gastroenterol. 2014;14:9. 23. chang s, yim s, park h. the cancer driver genes idh1/2, jarid1c/ kdm5c, and utx/ kdm6a: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. exp mol med. 2019;51:66. 24. trop-steinberg s, azar y. is myc an important biomarker? myc expression in immune disorders and cancer. am j med sci. 2018;355:67-75. 25. bonetti p, davoli t, sironi c, et al. nucleophosmin and its aml-associated mutant regulate c-myc turnover through fbw7 gamma. j cell biol. 2008;182:19-26. 26. chen jb, zhang m, zhang xl, et al. glucocorticoid-inducible kinase 2 promotes bladder cancer cell proliferation, migration and invasion by enhancing beta-catenin/c-myc signaling pathway. j cancer. 2018;9:47744782. 27. box jk, paquet n, adams mn, et al. nucleophosmin: from structure and function to disease development. bmc mol biol. 2016;17:19. 28. kaufman ds, shipley wu, feldman as. bladder cancer. lancet. 2009;374:239-49. differential npm1 affects bladder cancer – luo et al. unclassified 459 vol 16 no 03 may-june 2019 236 endourology and stone disease are stone density and location useful parameters that can determine the endourological surgical technique for kidney stones that are smaller than 2 cm? a prospective randomized controlled trial adnan gücük1*, burak yılmaz1, sebahat gücük2, uğur üyetürk1 purpose: we aimed to evaluate whether these parameters could be guiding for us in selection between retrograde intrarenal surgery (rirs) and mini-percutaneous nephrolithotomy (pnl) procedures in kidney stones that are smaller than 2 cm. materials and methods: the patients who had kidney stones smaller than two cm and were planned to undergo surgery were randomly distributed into 2 groups prospectively. rirs was performed in the rirs group using a 7.5-f fiberoptic flexible ureterorenoscope while mini-pnl group was dilated up to 16.5f and mini-pnl was performed with 12f nephroscopy. preoperative characteristics, operative and postoperative results were compared in two groups. thereafter, intra and intergroup comparisons were made to determine the effects of hounsfield unit (hu) value indicating the stone density being higher or lower than 677 and stone location on stone-free rates. results: the study involved 60 patients including 30 in each group. the groups’ preoperative values were similar. the hospitalization time and the total duration of scopy were longer in mini-pnl when the postoperative values were compared (p < .0001). in terms of stone densities, hu values that were lower than 677 in the mini-pnl group affected the stone-free rate and reduced it from 100% (> 677hu) to 55.6% (< 677hu), whereas the change was significant (p = .005). lower calyx stones affected the rirs results negatively, whereas multiple calyceal stones affected the mini-pnl group negatively. conclusion: both methods had a similar success rate, but lower pole stones, multiple calyceal stones and stone density parameters affected the stone-free rates significantly, and these may be effective in treatment selection. keywords: density; kidney stones; location; percutaneous nephrolithotomy; retrograde intrarenal surgery introduction percutaneous nephrolithotomy (pnl) and retrograde intrarenal surgery (rirs) have taken the place of shock wave lithotripsy (swl) for treatment of kidney stones as a result of development of minimally invasive techniques and instruments in the last 10-15 years. each procedure has its own advantages and disadvantage (1,2). mini-pnl and rirs are procedures that are preferred for minimally invasive treatment due to their negligible stone-free and complication rates(3,4). rirs has increasingly been used for moderately sized kidney stones in recent years(5,6). however, this technique has limitations such as low success rate in the lower calyx, necessity of using ureteral access sheath, necessity of placing jj stent in case of failure due to inability to gain access in the first session and requirement of a second session, and longer duration of the surgical period as the stone size increases(7,8). it is known that parameters such as stone density, opacity, disorganized settlement and location of the stone generally affect stone-free rates(7,9). the efficacy and safety of using minimally invasive techniques such as rirs or mini-pnl in moderately sized kidney stones is still a debated matter (10,11). the 1 department of urology, abant izzet baysal university faculty of medicine, bolu, turkey. 2 department of family medicine, abant izzet baysal university faculty of medicine, bolu, turkey. *correspondence: abant i̇zzet baysal üniversitesi tıp fakültesi hastanesi, üroloji bölümü, gölköy kampusu, bolu. tel: +905056748193. fax: +90 374 253 46 15. e-mail: gucukadnan@hotmail.com. received november 2017 & accepted may 2018 european association of urology guidelines recommends endourology (all pnl and urs interventions) as the standard treatment option for small to medium (≤ 2cm) renal stones. however, it is not yet clear which endourology option would be more appropriate for this group of stones. in this study, we aimed to compare patients with kidney stones smaller than 2 cm who underwent mini-pnl and rirs and tried to determine if preoperative stone properties affecting the choice of treatment, if any, could be parameters that could lead us to make a choice about these procedures. materials and methods study population patients with kidney stones who visited our clinic between april 2016 and may 2017 were evaluated following the approval of the ethics committee. the patients were evaluated with non-contrast abdominopelvic ct after detailed anamnesis and physical examination. patients who had a kidney stone with a maximum diameter of less than 2 cm and did not prefer to undergo swl were included in the study. patients with anomause of stone density and location for treatment success-gucuk et al. lous kidneys, skeletal deformities, severe obesity (bmi > 35) and those who previously underwent swl treatment for the same stone were excluded from the study. the study was explained to each patient and informed consent was obtained. patients' enrollment algorithm is illustrated in figure 1. in all patients, hemoglobin, platelet, coagulation tests, serum creatinine levels and urine culture tests were performed preoperatively, and treatment was provided according to the findings if necessary. information was recorded on the patients’ age, sex, body mass index (bmi), stone density, stone size and stone location. stone densities and surface areas were obtained as previously described(12). stone location is classified under three categories, lower calyx, upper calyx or multiple. study design this study was a prospective single-center, parallel-group randomized clinical trial with balanced randomization [1:1] which was performed in a referral hospital in bolu, turkey. the patients were randomly divided into 2 groups (mini-pnl and rirs) by a computer software as described in the literature(13). the allocated treatment for each patient was recorded in concealed envelopes. after achieving eligibility criteria and the patient's agreement on participation, the concealed envelopes were opened by one of the researchers and the allocated treatment was performed as explained below(13). the surgeon learned of the randomization group in the operating room before surgery and had no opportunity to schedule patients according to the randomization list. in this study, it was aimed to study a total of 52 subjects with 95% confidence level, 0.80 effect size and 80% power provided that there are at least 26 subjects in each group, and the study was completed with 60 patients. surgical technique all operations were performed or supervised by the same surgeon. right after the patients in mini-pnl group were placed a 5f ureteral catheter with general anesthesia, they were given a prone position and access table 1. patient and stone characteristics. variable mini-pnl group (n = 30) rirs group (n = 30) p-value sex 0.771 male 21 23 female 9 7 mean age (years) 46.1 ± 17.5 46.6 ± 13.5 0.902 mean bmi (kg/m2) 26.4 ± 3.3 27.2 ± 3.7 0.421 stone localization 0.829 upper calices 8 (% 26,7) 8 (26.7) lower calices 14 (% 46.7) 12 (% 40) multipl calices 8 (% 26.7) 10 (% 33.3) mean stone density (hu unit) 845.3 ± 267.5 816.7 ± 251.2 0 .671 stone surface area (mm2) 275.5 ± 75.1 259.1 ± 65.2 0.368 abbreviations: pnl, percutaneous nephrolithotomy; rirs, retrograde intrarenal surgery; bmi, body mass index figure 1. patients’ enrollment algorithm endourology and stones diseases 237 vol 16 no 03 may-june 2019 238 was performed by choosing the optimal calyx to reach the stone after the contrast agent was given. the guide wire was then placed, and the stones were broken with a laser lithotripter using a 12f nephroscope (modular minimally invasive pnl system, karl storz, tuttlingen, germany) following the dilatation using a one step dilator with a 16.5f access sheath. when necessary, the stones were removed using stone removal forceps. right after a 14f nephrostomy tube was inserted and an antegrade pyelography was taken, the operation was completed. following the general anesthesia performed in the rirs group, a safety guide wire was placed and semirigid ureteroscopy (9.5 / 11.5f) was performed to see the ureter and possible pathologies as well as facilitate the placement of the ureteral access sheath. the stones were fragmented using a 270 micrometer laser fiber with the help of a 7.5-f fiber optic flexible ureterorenoscope (storz flex-x2, tuttlingen, germany) after the placement of ureteral access sheaths (9.5 / 11.5 f) (elit flex, ankara, turkey). stone fragmentation was accomplished using a laser energy of 0.5-1.5 j and a rate of 5-15 hz (sphinx jr 30 watt), and this range was adjusted based on stone hardness. stones smaller than 2 mm were left to pass on their own while the larger ones were removed with a basket catheter. a 4.7f jj stent was routinely placed at the end of the operation because of concerns about possible edema and other problems that might be caused by the access sheath. in this group, access sheaths could not be placed in 2 patients due to the small diameter of their ureters, and a jj stent was placed. 2 weeks later, the procedure was performed as it was in the others. the durations of the operation were recorded by adding the durations of 2 procedures. outcome assessment the primary outcome of interest was stone-free rate after rirs and mini-pnl. the stone-free conditions were determined by low-dose spiral ct taken in the third postoperative month. the procedure was considered successful if there were no residual stones. secondary outcomes included the relationship between stone-free rates and parameters of stone density and location, pain after procedures, hospitalization time, operative time, fluoroscopy time and complications. the visual analogue scale (vas; range= 1-10) that was applied in the first hour was used as the pain scale. surgical times were calculated from the beginning of cystoscopy to the end of the procedure carried out by placing a urinary catheter. clavien classifications were used for the complications. firstly, the preoperative and postoperative results of both groups were compared. then the effects of "stone density and location" that could influence the stone-free condition within the groups were evaluated. we used a cutoff value of 677.5 hu that was determined in our previous study to assess the effects of stone density(12). according to this value, we divided the groups into 2 subgroups and looked into the effects of stone density. these subgroups were compared within themselves, and cross comparisons were also made. the effect of stone location on stone-free rates was also assessed. data obtained from this study were analyzed using the spss 20 statistics software. while investigating whether the variables were normally distributed, shapiro wilk's was used due to the number of units. the mann-whitney u test was used for analyzing the diftable 2. operative and postoperative data of mini-pnl and rirs groups and their comparisons parameters mini-pnl group rirs group p mean total operative time (min) 98.3 ± 18.8 109.0 ± 33.8 0.134 mean fluoroscopy time (sec) 121.7 ± 49 24.2 ± 7.9 0.0001 hospitalization time (day) 2.1 ± 2.03 1.6 ± 134 0.0001 stone free rate (%) 86.7 83.3 1 mean pain visual analog score (range: 1-10) 3.1 ± 1.4 3.0 ± 1.4 0.778 complications 12 (%40) 9 (%30) 0.6 none 18 (% 60) 21 (% 70) clavien grade 1 9 (% 30) 6 (% 20) clavien grade 2 3 (% 10) 1 (% 3.3) clavien grade 3 0 2 (% 6.6) abbreviations: pnl, percutaneous nephrolithotomy; rirs, retrograde intrarenal surgery stone free rate (%) parameters mini-pnl group rirs group p fisher's exact stone location 0.24 lower calyx 14 (% 100) 8 (% 66.7) upper calyx 7 (% 87.5) 8 (% 100) multiple 5 (% 62.5) 9 (% 90) stone density 0.22 < 677 hu 5 (% 55.6) 9 (% 81.8) > 677 hu 21 (% 100) 16 (% 84.2) abbreviations: pnl, percutaneous nephrolithotomy; rirs, retrograde intrarenal surgery table 3. the values of the parameters that can affect the stone-free state in the intergroup comparison. use of stone density and location for treatment success-gucuk et al. ferences between the groups due to the non-normal distribution of the variables. the relationship between the categorical variables was analyzed by chi-square test. the results were interpreted using a significance level of .05. results the study was completed with a total of 60 patients including 30 in each group. the preoperative characteristics of the patients and the stones are shown in table 1. there was no difference between the groups with regards to this aspect (p > .05). the groups were similar in terms of patient and stone characteristics. the whole mini-pnl procedure was completed with a single tract in a single session. intercostal intervention was performed in 2 patients with upper calyx stones. the others underwent a subcostal approach. 9 patients in the mini-pnl group and 6 patients in the other group showed temporary fever that was overcome by antipyretics, and this was recorded as clavien grade 1 complication. bleeding that required blood transfusion was observed in 1 patient in the pnl group. 2 patients in the pnl group and 1 patient in the other group showed fever that was overcome in the 2nd day by alternating antibiotics, and this was recorded as clavien grade 2 complicaiton. because of the small ureteral diameter in the 2 patients in the rirs group, the access sheath could not be placed in the 1st session. the procedure was repeated two weeks after the jj stent was inserted. the stent requirement for these 2 patients was stated as clavien 3 complication. the operative and postoperative data of the patients are shown in table 2. the mean duration of fluoroscopy and hospitalization were significantly higher in the mini-pnl group in the intergroup comparison (p = .0001). after the evaluations mentioned above, the effects of stone location and stone density on stone-free rates were evaluated within the groups. in the mini-pnl group, the stone-free rate was found to be 62.5% in the cases of multiple calyceal stones, while it was 87.5% in the cases of upper calyx stones and 100% in the cases of lower calyx stones. multiple caliceal stones decreased the stone-free rate significantly in comparison to the other locations (p = .037). in terms of stone densities, hu values that were lower than 677 in the mini-pnl group affected the stone-free rate and reduced it from 100% (> 677hu) to 55.6% (< 677hu), whereas the difference was significant (p = .005). there was no significant difference in the rirs group in terms of the same parameters (p > .05). after the effects of stone density and location were analyzed within the groups, the results of the intergroup comparisons in terms of the effects of these values are shown in table 3. in this evaluation, it was determined that stone densities of lower than 677 and multiple caliceal stones had significant and negative effects on stone-free rates. although the effect was not statistically significant, it was observed that presence of lower calyx stones affected stone-free status negatively. discussion the european association of urology guidelines recommend using swl or endourology procedures for stones smaller than 2 cm as the first-line treatment(14). the term endourology refers to all pnl and ureterorenoscopic interventions, but no suggestion has been made about which of these might be more appropriate. it was stated that both methods have similar success rates and reliability in studies with this size of stones (1,15). some publications pointed out that mini-pnl methods used for lower pole stones are more advantageous in terms of stone-free rates(1). we prospectively compared these two groups in this study. we predicted that we could partially determine which of these procedures is more appropriate for these groups of stones considering both stone location and stone density. when we compared the operative and postoperative data of our groups, we found that the mean duration of fluoroscopy and hospitalization time were significantly greater in the mini-pnl group (p < .0001). demirbaş et al. compared ultra mini pnl and rirs in their study and found a duration of fluoroscopy of 57 sec corresponding to 185 sec respectively(1). when the total average values were taken into consideration, the duration of fluoroscopy was shorter than those in other studies(1, 15). we think this depended on our experience and praxis of using fluoroscopy. the hospitalization time was also higher in mini-pnl and this agreed with the literature. these data can be considered as a disadvantage of mini-pnl. when the other parameters are considered, similar stone-free rates, hospitalization times and durations of operation were found in the study by schoenthaler et al. while there was no significant difference in pain scores, clavien grade 3 complications were observed in 2 patients in the rirs group. in 2 patients, these complications depended on failure of the placement of the access sheath due to small ureteral diameter in the first session, and the placement of a jj stent to provide passive dilation. an additional surgery was required for the patient about 2 weeks later, and this was a discomfort for both the patient and the surgeon. in fact, in these patients whose rirs operations have begun, if there is no condition that prevents the patient from undergoing mini pnl, it may be a reasonable option to switch to mini-pnl in the same session, and rid the patient of the stone in a single session. the clavien 1 and 2 complications were usually fever-related. while most of these were overcome by antipyretics, some required alternating antibiotics. there was no difference between the groups in terms of these complications, but these were seen more frequently than the minor complications reported in the literature to reach up to 10%(13,16). we believe that this difference in results might have been related to our inability to achieve the same conditions in our operating room every time. in this study, we evaluated the effects of stone density and location that could influence the stone-free status after these comparisons. we classified stone locations under three categories as lower pole, upper pole and multiple. however, at the beginning, we thought of using one of "guy's stone score", "s.t.o.n.e score" or ''resorlu-unsal stone score'' systems for scoring the stone classifications. however, we have seen that these scoring systems are used to predict the outcomes of either pnl or rirs, and they do not consider the factors that are effective in choosing between them. when we considered the effects of stone location on the stone-free rates, in the comparison within the mini-pnl group, we found that stones in multiple calyces and stone densities of lower than 677 affected stone-free rates in a negative way (p < .05). it was found that rirs was affected use of stone density and location for treatment success-gucuk et al. endourology and stones diseases 239 vol 16 no 03 may-june 2019 240 negatively by lower caliceal stones when the 2 groups were compared in terms of stone location (p < .05). we also found that multiple caliceal stones reduced the success of mini-pnl but had no effect on rirs. in another study comparing ultra mini-pnl and rirs, it was stated that lower pole stones negatively affected the rirs results, and the stone-free rate of this group decreased to 42%, and thus ultra mini-pnl might be more effective in such groups(1). there are studies which showed that rirs has similar effectiveness, but ultra-mini pnl seems to make a greater contribution to the stone-free rates in lower pole stones(17,18). additionally, lower pole stones are an ideal indication for pnl because of easy access and low complication rates(17). in fact, if we consider the results of our study, a common scoring system involving stone density parameters may possibly contribute to making the surgeon more objective and successful in cases of lower pole stones and multiple caliceal stones(1,19).the difference between our study and studies in the literature is related to adding the effects of stone density to these evaluations. we have noted in previous studies that reduction in stone density reduced the success of pnl operations and it may be useful to use flexible nephroscopy routinely to eliminate this issue(12,20). thus, we have seen that densities of lower than 677 hu reduced the success of mini-pnl but had no effect on rirs. we attribute this to the difficulty in detecting stones by fluoroscopy, due to the reduction in density and the importance of this difficulty in pnl operations. the most important limitation of our study was the subgroup comparisons included low numbers of patients. if we had access to a sufficient number of patients, we could achieve more reliable results by dividing the cases into density groups and stone location subgroups. another limitation could be that we did not employ a smaller scale percutaneous surgery method (e.g. ultra mini pnl) for comparison. conclusions consequently, lower pole stones of smaller than 2 cm, multiple caliceal stones and stone density parameters affected the stone-free rates significantly. while multiple stones or stone densities of < 677 hu affected success in mini-pnl negatively, lower calyx location affected rirs results negatively. for this reason, a surgical preference that is made by considering the parameters in these groups may contribute optimal usage of these endourological techniques. conflict of interest the authors report no conflict of interest. references 1. demirbas a, resorlu b, sunay mm, karakan t, karagöz ma, doluoglu og. which should be preferred for moderate-size kidney stones? ultramini percutaneous nephrolithotomy or retrograde intrarenal surgery? j endourol. 2016;30: 1285-9. 2. atis g, culpan m, pelit es, et al. comparison of percutaneous nephrolithotomy and retrograde ıntrarenal surgery in treating 20-40 mm renal stones. urol j. 2017;16;2995-9. 3. jacquemet b, martin l, pastori j, et al. comparison of the efficacy and morbidity of flexible ureterorenoscopy for lower pole stones compared with other renal locations. j endourol. 2014;28:1183-7. 4. ferakis n, stavropoulos m. mini percutaneous nephrolithotomy in the treatment of renal and upper ureteral stones: lessons learned from a review of the literature. urol ann. 2015;7:1418. 5. karatag t, buldu i, inan r, istanbulluoglu mo. is micropercutaneous nephrolithotomy technique really efficacicous for the treatment of moderate size renal calculi? yes. urol int. 2015;95:9-14. 6. karakan t, kilinc mf, doluoglu og, et al. the modified ultra-mini percutaneous nephrolithotomy technique and comparison with standard nephrolithotomy: a randomized prospective study. urolithiasis. 2017;45:209213 7. resorlu b, unsal a, gulec h, oztuna d. a new scoring system for predicting stonefree rate after retrograde intrarenal surgery: the "resorlu-unsal stone score" . urology, 2012;80:512518, 8. resorlu b, oguz u, resorlu e, oztuna d, unsal a.the impact of pelvicaliceal anatomy on the success of retrograde intrarenal surgery in patients with lower pole renal stones. urology. 9. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016; 13:2899-2902.2012;79:61-66. 10. desai j, zeng g, zhao z, zhong w, chen w, wu w. a novel technique of ultra-minipercutaneous nephrolithotomy: introduction and an initial experience for treatment of upper urinary calculi less than 2 cm. biomed res int. 2013;2013:490793. 11. wilhelm k, hein s, adams f, schlager d, miernik a, schoenthaler m. ultramini pnl versus flexible ureteroscopy: a matched analysis of analgesic consumption and treatment-related patient satisfaction in patients with renal stones 10-35 m.m. world j urol. 2015; 33: 2131-6. 12. gücük a, uyetürk u, oztürk u, kemahli e, yildiz m, metin a. does the hounsfield unit value determined by computed tomography predict the outcome of percutaneous nephrolithotomy? j endourol.2012; 26: 792-6. 13. javanmard b, kashi ah, mazloomfard mm, ansari jafari a, arefanian s. retrograde ıntrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j. 2016;13:2823-8. 14. turk c, petrik a, sarica k, et al. eau guidelines on diagnosis and conservative use of stone density and location for treatment success-gucuk et al. management of urolithiasis. eur urol. 2016;69:468-74. 15. ozgor f, tepeler a, elbir f, et al. comparison of miniaturized percutaneous nephrolithotomy and flexible ureterorenoscopy for the management of 10-20 mm renal stones in obese patients. world j urol 2016;34: 116973. 16. zengin k, tanik s, karakoyunlu n, et al. retrograde intrarenal surgery versus percutaneous lithotripsy to treat renal stones 2-3 cm in diameter. biomed res int. 2015;2015:914231. 17. kirac m, bozkurt öf, tunc l, et al. comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in management of lower-pole renal stones with a diameter of smaller than 15 mm. urolithiasis. 2013;41: 241-6. 18. lee jw, park j, lee sb, son h, cho sy, jeong h. mini-percutaneous nephrolithotomy vs retrograde intrarenal surgery for renal stones larger than 10 mm: a prospective randomized controlled trial. urology. 2015;86: 873-7. 19. pelit, es, atis g, kati b, et al. comparison of mini-percutaneous nephrolithotomy and retrograde intrarenal surgery in preschoolaged children. urology.2017;101: 21-25. 20. gücük a, kemahlı e, üyetürk u, tuygun c, yıldız m, metin a. routine flexible nephroscopy for percutaneous nephrolithotomy for renal stones with low density: a prospective, randomized study. j urol.2013;190:144-8. use of stone density and location for treatment success-gucuk et al. endourology and stones diseases 241 endourology and stone disease is the homocysteine level a good predictive marker for evaluating kidney function in patients after percutaneous nephrolithotomy? i̇smail karlıdağ1, deniz abat2, adem altunkol2*, volkan i̇zol1, erkan demir1, i̇brahim atilla arıdoğan1 purpose: the purpose of this study is to evaluate the preoperative, early and late postoperative homocysteine levels and its relationship with kidney function in patients after undergoing percutaneous nephrolithotomy (pnl). materials and methods: twenty-three patients with kidney stones underwent pnl and blood samples were taken preoperatively as well as at 48 hours and three months after the operation. the homocysteine level was determined by high pressure liquid chromatography and the fluorometric method in blood samples with ethylenediaminetetraacetic acid. the cockcroft – gault formula was used to calculate the glomerular filtration rate (gfr). non-contrast computed tomography was performed for all patients before surgery. stone burden was calculated as the sum of the area of each stone in mm2. results: fourteen male (60.9%) and nine female (39.1%) patients were recruited for this study, and the median age was 44.3 ± 15.17 (20 – 71) years. there were no statistically significant differences between the preoperative homocysteine level and the level at 48 hours post-operation (p = .460). however, the homocysteine level three months after the operation was significantly lower than the preoperative and 48 hour levels (p = .001 and p = .003, respectively). conclusion: renal function, which deteriorated after the pnl procedure, was preserved or improved over time. homocysteine may be a sensitive indicator to assess the change in renal function pre-and post-pnl. keywords: homocysteine; oxidative stress; percutaneous nephrolithotomy; kidney function. introduction currently, percutaneous nephrolithotomy (pnl), a minimal invasive technique, is a standard method of kidney stone treatment(1). although this operation can cause minimal renal parenchymal damage, reflected in a decrease in the glomerular filtration rate (gfr) after the operation, the gfr later returns to normal(2). homocysteine is a natural amino acid that is contained in mammalian tissues. methionine is an amino acid that contains essential sulfur. homocysteine is produced by methionine transmethylation. kidney function is a significant determinate of the homocysteine level in plasma, and there is a close relationship between the homocysteine level and kidney function. the homocysteine level in patients with renal failure is two to four times higher than healthy population(3). the prevalance of hyperhomocysteinemia is 5-10% in a healthy population and 70-100% in patients with renal failure. there is a cross correlation between gfr and the homocysteine concentration(4). in addition, a close relationship was found between elevated plasma homocysteine and increased oxidative stress in patients with chronic kidney disease(5). in the present study, we evaluated the relationship between preoperative, early and late postoperative homocysteine levels and kidney function in patients after the pnl procedure. according to our knowledge, this is the 1university of çukurova, faculty of medicine, department of urology, adana, turkey 2university of health sciences, adana numune teaching and research hospital, department of urology, adana, turkey. *correspondence: university of health sciences, adana numune teaching and research hospital, department of urology, kurttepe mahallesi, süleyman demirel bulvarı, çukurova, adana, turkey. tel: +905076074572. e-mail: ademaltunkol@hotmail.com. received march 2017 & accepted july 2017 first study regarding the varying homocysteine levels in patient after the pnl procedure. patients and methods study population and study design twenty-three patients with kidney stones underwent the pnl procedure and blood samples were taken preoperatively as well as 48 hours and three months after operation. the blood cell count, homocysteine, folic acid, vitamin b12, blood urea nitrogen, creatinine, glucose, alanine transaminase (alt), aspartate transaminase (ast), gamma glutamyl transferase (ggt), sodium and potassium levels were assessed. the homocysteine level was determined by high pressure liquid chromatography and fluorometric methods in blood samples with ethylenediaminetetraacetic acid. the plasma homocysteine reference distance was 3.3 to 7.2 µmol/l. the cockcroft – gault formula was used to calculate the gfr (gfr ml/min = [ (140 – age) x weight (kg) / serum creatinine (mg/dl) x 72]. the study was approved by the ethics committee of çukurova university, and all patients signed an informed consent form. patient with a solitary kidney, chronic renal failure, diabetes mellitus and/or hypertension for more than five years, renovascular hypertension, previous history of pyelonephritis and previous surgery until at least three months earlier, such as open surgery, shock wave lithotripsy vol 15 no 04 july-august 2018 153 (swl) or percutaneous nephrostomy were excluded from this study. non-contrast computed tomography was performed for all patients before surgery. stone burden was calculated as the sum of the area of each stone in mm2. surgical technique and outcome assessment under general anesthesia, a 6 french (fr) open ended ureteral catheter was placed into the ureter and then fixed to a 14 fr urethral catheter in the lithotomy position. the patient was then turned to the prone position. contrast medium was injected from the ureteral catheter to visualize the collecting system under fluoroscopy. the most appropriate posterior calix was selected and punctured with an 18 gauge percutaneous entry needle to enter the collecting system. a j type guide wire was inserted through the needle and dilation was performed with amplatz dilators (amplatz sheath boston scientific, usa) up to 24 fr. a 24 fr access sheath was placed, and a rigid nephroscope (karl storz, tuttlingen, germany) was used for all patients. stones were cracked with a pneumatic lithotripter (elmed vibrolith, elmed lithotripsy system, ankara, turkey) and extracted with forceps (karl storz, tuttlingen, germany). a 14 fr re-entry malecot was placed at the end of the procedure in all cases except in two patients who underwent a tubeless procedure. the ureteral and urethral catheters were removed 24 hours after the operation in the two patients who underwent a tubeless procedure. the urethral catheter was removed 24 hours after the operation in 21 patients. a kidney-ureter and bladder graphy was performed and the nephrostomy catheter was removed 48 hours after the operation if no hematuria was observed . an antegrade nephrostogram was performed 48 hours after the operation if necessary. patients were discharged after break up of urine leakage. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. statistical analyses data were analyzed using spss software version 20 (spss, inc., chicago, il, usa). categorical variables are shown as number and percent, and quantitative variables are shown as the mean and standard deviation. a p-value < 0.05 was considered significant. comparisons between groups were performed using the t test for normally distributed data. the mann whitney u test and wilcoxon test were used to compare data that were not normally distributed. to evaluate the change in the measurements over the three time points, the repeated measurements analysis was applied. correlations between numerical measures were analyzed using the pearson correlation when assumptions were provided and, when the assumptions were not provided, spearman correlation was used. results fourteen male (60.9%) and nine female (39.1%) patients were recruited for this study and the median age was 44.3 ± 15.17 (20 – 71) years. mean stone burden was calculated as 319.57 ± 313.24 (100 – 1500) mm2. single access was performed in 22 patients and double access in only one patient. the mean operation time was 67.61 ± 31.65 (40 – 180) minutes. one patient received a single unite of red blood cell transfusion during the operation, and one patient received intravenous antibiotics (imipenem/cilastatin) for a high post-operative fewer. the stone free rate was 91% (21 patients), and the clinicaly insignificant residue fragment (< 4 mm) rate was 9% (2 patients). the mean hospitalization time was 2.65 ± 0.71 (1 – 4) days. the homocysteine, hemoglobin, white blood cells, platelet, creatinine, blood urea nitrogen, sodium, potassium, alt, ast, ggt, glucose, folic acid and vitamin b12 levels are shown in tables 1 and 2. preoperative (mean ± sd) 48th hour (mean ± sd) 3rd month (mean ± sd) p value hemoglobin (g/dl) 13.226 ± 2.04 12.26 ± 2.26 12.78 ± 1.95 0.019 folic acid (ng/ml) 7.75 ± 2.86 8.05 ± 3.09 7.20 ± 2.67 0.492 vitamin b12 (pg/ml) 146.65 ± 49.01 127.78 ± 41.62 141.58 ± 35.87 0.096 wbc (x103/ul) 8878.26 ± 3591.39 10086.96 ± 3120.79 9626.09 ± 3539.03 0.218 platelet (x 103/µl) 278.30 ± 95.19 227.48 ± 83.71 230.53 ± 86.94 0.016 glucose (mg/dl) 84.61 ± 13.78 94.43 ± 16.27 81.61 ± 18.50 0.012 ast (u/l) 20.65 ± 6.91 22.04 ± 6.63 21.95 ± 7.67 0.697 alt (u/l) 14.03 ± 7.86 16.43 ± 8.39 18.52 ± 5.20 0.418 ggt (u/l) 14.65 ± 14.09 14.82 ± 14.88 13.04 ± 4.03 0.558 table 1. blood sample results preoperative (mean ± sd ) 48th hour (mean ± sd) 3rd month (mean ± sd ) p value homocysteine (µmol/l) 16.03 ± 5.41 18.26 ± 10.20 9.53 ± 4.60 0.001* 0.003** 0.460*** gfr(ml/min) 134.05 ± 7.9 130.87 ± 11.7 159.1 ± 13.8 0.093* 0.012** 0.123*** bun (mg/dl) 12.09 ± 2.99 11.52 ± 4.12 12.39 ± 3.36 0.528 creatinine (mg/dl) 0.74 ± 0.22 0.82 ± 0.31 0.66 ± 0.25 0.056 *preoperative to 3rd month ** 48th hour to 3rd month *** preoperative to 48th hour table 2. homocysteine levels and gfr levels over time homocysteine level and kidney function after pcnl-karlidag et al. endourology and stone diseases 154 there was no statistically significant difference between the preoperative homocysteine level and the level 48 hours after the operation (p = .460). however, the homocysteine level three months after the operation was lower than the preoperative and 48 hour levels, and this difference was statistically significant (p = .001 and p = .003, respectively)(table 2). the gfr level was calculated as 134.05 ± 7.9 ml/min preoperatively and 130.87 ± 11.7 ml/min 48 hours postoperatively. the decrease in the gfr level was not statistically significant (p = .123). the three month gfr level was 159.1±13.8 ml/min. there was no statistically significant difference between the preoperative gfr and the gfr at three months (p = .093). however, the three month gfr was higher than the 48 hour gfr, and this difference was statistically significant (p = .012)(table 2). the correlation between plasma homocysteine levels and creatinine levels was shown in table 3. distribution of the level of plasma homocysteine-creatinine on preoperative, postoperative 48 th hours and 3rd month are shown in figures 1,2 and 3. discussion management of urinary system stones should be less harmful for the kidney. pnl has some advantages over open surgery, such as a short hospitalization, minimal skin incision, less postoperative pain and better cosmetic results(6). the long and short term effects of pnl on renal function has been assessed in some studies(2,7,8). gfr decreases immediately following the pnl procedure(2). there have been a few studies assessing the decrease in gfr after pnl. some studies have shown that both the treated kidney and the contralateral kidney are affected that the gfr immediately decreases after pnl. the mechanism by which the gfr decrease may be related to activation of the neuronal and/or humoral systems that may occurs during the operation. one way to activate the neuronal and humoral systems is via tissue injury related factors, such as oxidative stress(9). soylemez et al. evaluated the oxidative stress effects of pnl and revealed that oxidative stress is elevated during the pnl procedure(6). according to hoffman, oxidative stress can cause inadequate methionine metabolism leading to increased homocysteine. additionally, some studies revealed that homocysteine demolishes cells, raises lipid peroxidation, causes apoptosis and affects antioxidant defense systems(10). it seems likely that pnl can cause hyperhomocysteinemia by elevating oxidative stress. in the present study, the mean plasma homocysteine level was 16.03 ± 5.41 µmol/l and 18.26 ± 10.20 µmol/l preoperatively and at 48 hours postoperatively, respectively. although an increase in homocysteine was detected in 56% of patients, it was not statistically significant. although not statistically significant, homocysteine level elevation may result from increased oxidative stress during the operation. in addition, the mean plasma homocysteine level was 9.53 ± 4.60 µmol/l three months after the operation. this figure 1. distribution of the level of plasma homocysteine-creatinine preoperatively. figure 2. distribution of the level of plasma homocysteine-creatinine on postoperative 48th hour. creatinine a creatinine b creatinine c homocysteine a pearson correlation 0,003 sig. (2-tailed) 0,988 homocysteine b pearsoncorrelation 0,036 sig. (2-tailed) 0,871 homocysteine c pearsoncorrelation -0,008 sig. (2-tailed) 0,973 a preoperative b 48 hour postoperative c 3rd month after operation table 3. correlation of plasma homocysteine-creatinine homocysteine level and kidney function after pcnl-karlidag et al. vol 15 no 04 july-august 2018 155 value was lower than the homocysteine levels preoperatively and 48 hours postoperatively, and the decrease was statistically significant. we believe that the elevated homocysteine levels return to normal, while oxidative stress is reduced by defense mechanisms over time. some studies revealed that there is a relation between the homocysteine level with folic acid and vitamin b12 (5,10-13). pcnl can cause hyperhomocysteinemia by elevating oxidative stress. in this situation pcnl is the main reason of the hyperhomocysteinemia. on the other hand folic acid or vitamin b depletion may cause some defect in homocysteine metabolism and eventually hyperhomocysteinemia is occurred. in the latter situation, the level of homocysteine may be decreased by folic acid or vitamin b supplementation. however, oxidative stress caused by any situation such as pcnl, folic acid or vitamin b supplementation is not expected to any effect on homocysteine levels. in the present study, preoperative and postoperative level of folic acid and vitamin b12 was not changed significantly. we believe that pcnl is the main reason of the oxidative stress and changing of the homocysteine levels is directly related with pcnl rather than level of folic acid and vitamin b12. the gfr initially decreases after pnl; however, studies have suggested that this procedure has no harmful effect on renal function in the long term. one of the factors that affect renal function in the long time is parenchymal injury caused by multiple accesses and brutal manipulation by the nephroscope. the other factor is renal infarcts caused by angioembolization to prevent excessive bleeding. if these factors do not occur renal function will be preserved or improved over time after pnl(2,14,15). authors have reported that there is a close relationship between decreased kidney function and the homocysteine level(3). the homocysteine level increase, while kidney function progressively deteriorates over time(16). in the present study, the gfr levels decreases initially, but the decrease was not statistically significant. similarly, homocysteine levels increases initially and it was not statistically significant. according to this result, there is an inverse correlation between gfr and the homocysteine level initially. the gfr level then increase over time. also homocysteine levels decreases in late postoperative period rather than the early postoperative period, and this difference was statistically significant. we found a cross correlation between the gfr and homocysteine concentration over time, in the late postoperative period. it seems likely that this situation is dependent on the close correlation between the homocysteine level and kidney function. the limitations of the present study were as follows: the study included a limited number of patients, and featured a short follow-up duration and absence of a control group of healthy volunteers. conclusions renal function which deteriorates after the pnl procedure is preserved or improved over time. homocysteine may be a sensitive indicator to assess changes in renal function immediately after pnl and in the long-term. increased oxidative stress after pnl may affect homocysteine levels. however, we believe that a study with more participants would be useful for statistical analyses. acknowledgement ethical committee approval: ethics committee approval was received from the local committee of çukurova university author disclosure statement the authors report no conflict on interests. financial disclosure: this study was funded by grant no. tf2013ltp27 of the scientific research project of çukurova university. references 1. c. türk, t. knoll, a. petrik, k. et al guidelines associates: s. dabestani, t. drake, n. grivas, y. ruhayel, a.k. tepeler. european association of urology. 2016 guidelines on urolithiasis. 2. nouralizadeh a, sichani mm, kashi ah. impacts of percutaneous nephrolithotomy on the estimated glomerular filtration rate during the first few days after surgery. urol res. 2011 ;39:129-33. 3. kim sj, choi d, ko yg et al. relation of homocysteinemia to contrast-induced nephropathy in patients undergoing percutaneous coronary intervention. am j cardiol. 2011; 108:1086-91. 4. monfared a, azimi sz, kazemnezhad e et al. hyperhomocysteinemia and assessment of its associated factors in renal transplant recipients: a single-center study in northern iran. transplantation. 2014; 98:66-71. 5. chen ch, yang wc, hsiao yh, huang sc, huang yc. high homocysteine, low vitamin b-6 and increased oxidative stress are independently associated with the risk of chronic kidney disease. nutrition. 2016; 32:236-41. 6. söylemez h, bozkurt y, penbegül n et al. time-dependent oxidative stress effects of percutaneous nephrolithotomy. urolithiasis. 2013; 41:65-71. figure 3. distribution of the level of plasma homocysteine-creatinine on postoperative 3rd month homocysteine level and kidney function after pcnl-karlidag et al. endourology and stone diseases 156 7. chatham jr, dykes te, kennon wg. effect of percutaneous nephrolithotomy on differential renal function as measured by mercaptoacetyl triglycine nuclear renography. urology. 2002; 59:522-26. 8. pérez-fentes d, cortés j, gude f. does percutaneous nephrolithotomy and its outcomes have an impact on renal function? quantitative analysis using spect-ct dmsa. urolithiasis. 2014; 42:461-67. 9. handa rk, johnson cd, connors ba, evan ap, lingeman je, liu z. percutaneous renal access: surgical factors involved in the acute reduction of renal function. j endourol. 2016; 30:178-83. 10. hoffman m. hypothesis: hyperhomocystein emia is an indicator of oxidant stress. med hypotheses. 2011; 77:1088-93. 11. solomon lr. low cobalamin (vitamin b12) levels as predictors of cobalamin deficiency: importance of comorbidities associated with increased oxidative stress. am j med. 2016; 129:115.e9-115.e16. 12. dawson sl, bowe sj, crowe tc. a combination of omega-3 fatty acids, folic acid and b-group vitamins is superior at lowering homocysteine than omega-3 alone: a metaanalysis. nutr res. 2016; 36:499-508. 13. bednarska-makaruk m, graban a, sobczyńska-malefora a et al. homocysteine metabolism and the associations of global dna methylation with selected gene polymorphismsand nutritional factors in patients with dementia. exp gerontol. 2016; 81:83-91. 14. wong ka, sahai a, patel a, thomas k, bultitude m, glass j. is percutaneous nephrolithotomy in solitary kidneys safe?. urology. 2013; 82:1013-16. 15. el-tabey na, el-nahas ar, eraky i et al. long-term functional outcome of percutaneous nephrolithotomy in solitary kidney. urology. 2014; 83:1011-15. 16. wu cc, zheng cm, lin yf, lo l, liao mt, lu kc. role of homocysteine in end-stage renal disease. clin biochem. 2012; 45:128694. homocysteine level and kidney function after pcnl-karlidag et al. vol 15 no 04 july-august 2018 157 case report angioemboliziation of internal pudendal artery for treatment of long lasting gross hematuria after transurethral resection of the prostate behkam rezaeimehr1, mona modanloo2, mahdi davoodi3, sayed mohammad sakhaei4, hossein farsavian3, mehdi younesi rostami1* keywords: hematuria; prostatectomy; angio-embolization introduction to our knowledge, vascular lesions such as pseu-doaneurysm and arteriovenous fistula in the arterial supply of the prostate are very rare. although, bleeding is a known complication in prostate surgical procedures such as transurethral resections, however, it is manageable at the time of surgery(1). open surgery is difficult for management of pseudoaneurysm. whereas 1department of urology, school of medicine, mazandaran university of medical sciences, sari, iran. 2pharmaceutical sciences research center, faculty of pharmacy, mazandaran university of medical sciences, sari, iran. 3department of vascular surgery, imam khomeini hospital, mazandaran university of medical sciences, sari, iran. 4department of radiology, school of medicine, mazandaran university of medical sciences, sari, iran. *correspondence: department of urology, school of medicine, mazandaran university of medical sciences, sari, iran. tel: +98 9111159120. e-mail: springbah8@gmail.com. received june 2018 & accepted september 2018 to present a case of recurrent gross hematuria after transurethral resection of the prostate that was refractory to endoscopic and open hemostatic interventions at the bladder neck and prostatic fossa. after performing angiographic evaluation of the pelvic vessels and finding the pseudoaneurysm, percutaneous embolization of arterial supply of the pseudoaneurysm was done. the location and type of lesion were successfully determined by angiography and controlled by angio-embolization of the internal pudendal artery. it seems that angiography can be helpful in the diagnosis and management of refractory bleeding after prostatectomy. endovascular procedures are the first line of treatment in the management of this complication(2-5). we describe a patient who had recurrent massive hematuria following transurethral resections of the prostate. the location and type of lesion were determined by angiography and controlled by angio-embolization. figure 1. angiographic evaluation of the pelvic vessels urology journal/vol 16 no. 5/ september-october 2019/ pp. 517-518. [doi: 10.22037/uj.v0i0.4657] case report we present a 73-year-old man who was under treatment of tamsulosin and finasteride for three years because of obstructive urinary symptoms. in spite of medical treatment, he experienced multiple episodes of gross hematuria. after imaging studies and ruling out urinary tract infection, the patient became candidate for cystoscopy. pre-operative laboratory test results including blood coagulation tests and hemoglobin level were normal. during cystoscopy, we found that the bleeding site originated from the prostatic fossa and observed engorged veins in the bladder neck. transurethral resection of the prostate was done at the same time and about 55 grams of prostatic tissue was resected and was sent to pathology which revealed benign prostatic hyperplasia. the patient was discharged one day after the surgery. but, 4 days later, patient was readmitted because of clot retention. cystoscopy was done and after the evacuation of clots, there were not any arterial bleeding or any significant active bleeding in the prostatic fossa. however, the hematuria repeated again after 4-5 days and we evacuated old clots but we did not observe any active bleeding during cystoscopy. after 2 other episodes of bleeding and receiving 48 units packed red blood cell and 13 bag of fresh frozen, we decided to do an open exploration but we did not find any active bleeding so we ligated the arterial supply of the prostate at the bladder neck. unfortunately, after the surgery, hematuria recurred in a 4-5 days intervals. finally, angiographic evaluation of the pelvic vessels was performed and a pseudoaneurysm was found in the internal pudendal artery (figure 1). hematuria ceased immediately after percutaneous embolization of arterial supply of this pseudoaneurysm. the patient was discharged five days after the procedure and now after six months, the patient is asymptomatic. discussion internal pudendal artery pseudoaneurysm is a rare condition and usually associated with surgical procedures (6,7). in our case, the patient had recurrent gross hematuria following transurethral resection of the prostate. eventually, the diagnosis was made using angiography. concerning the presence of pseudoaneurysm in the internal pudendal artery, angio-embolization was performed for this patient and after the procedure, he had no hematuria. to our knowledge, in the literature, there are some reported cases of internal pudendal artery pseudoaneurysm following prostate surgery presenting with late recurrent hematuria. for example, celtikci et al. reported a 79-year-old patient with massive hematuria following transurethral resection of the prostate for benign prostatic hyperplasia. doppler us and angiography revealed a pseudoaneurysm and arteriovenous fistula originating from the right internal pudendal artery. it was successfully treated with coil embolization (2). beckley et al. treated delayed hemorrhage from an accessory internal pudendal artery pseudoaneurysm after robotic radical prostatectomy using microcoils following super selective catheterization(1). in jeong et al. study, a total of 4 among 563 (0.7%) patients had postoperative bleeding after radical prostatectomy that fit the inclusion criteria. ct angiography revealed active bleeding in all cases. all patients were successfully treated with transarterial embolization without any additional treatment, such as surgical exploration, and there was no treatment-related adverse event(8). in conclusion, results of our study and other studies confirmed that embolization is an efficient method of managing post-operative bleeding due to prostate operations. conflict of interest the authors report no conflict of interest. references 1. beckley i, patterson b, hamaday m, vale j, hrouda d. case report: delayed hemorrhage from an accessory internal pudendal artery pseudoaneurysm after robotic radical prostatectomy: successful management with ct angiography and embolization. journal of endourology. 2007;21:923-5. 2. celtikci p, ergun o, tatar ig, conkbayir i, hekimoglu b. superselective arterial embolization of pseudoaneurysm and arteriovenous fistula caused by transurethral resection of the prostate. polish journal of radiology. 2014;79:352. 3. lopes ri, mitre ai, rocha ft, piovesan ac, costa ofd, karakhanian w. case report: late recurrent hematuria following laparoscopic radical prostatectomy may predict internal pudendal artery pseudoaneurysm and arteriovenous fistula. journal of endourology. 2009;23:297-300. 4. singh sk, wadhwa p, bapuraj j, jha v. transcatheter embolization of internal pudendal artery pseudoaneurysm following traumatic urethral catheterization. international urology and nephrology. 2005;37:93-4. 5. yekeler e, ziylan o, erol b, numan f, ander h. pseudoaneurysm of the bulbourethral branch of the internal pudendal artery presenting as a urethral pseudodiverticulum in a child. pediatric radiology. 2004;34:435-7. 6. wiedeman je. special problems after iatrogenic vascular injuries. surgery, gynecology and obstetrics. 1988;166:323-6. 7. landreneau rj, snyder wh. pelvic abscess or pseudoaneurysm: diagnostic and therapeutic dilemma following iliac arterial trauma. the american journal of surgery. 1992;163:197201. 8. jeong cw, park yh, ku jh, kwak c, kim hh. minimally invasive management of postoperative bleeding after radical prostatectomy: transarterial embolization. journal of endourology. 2010;24:1529-33. treatment of gross hematuria after prostatectomy by angioemboliziation-rezaeimehr et al. case report 518 endourology and stone disease comparison of two different retrograde intrarenal surgical techniques: is it mandatory to use fluoroscopy during retrograde intrarenal surgery? ergun alma1, hakan ercil1* purpose: to evaluate the efficacy and reliability of fluoroscopy-free retrograde intrarenal surgery. materials and methods: a retrospective evaluation was made of the data of 226 patients who underwent rirs as kidney stone treatment between may 2015 and may 2017. when evaluation was made acccording to the exclusion criteria, the study continued with a total of 190 patients including 103 in whom fluoroscopy was used (group 1) and 87 who underwent a fluoroscopy-free procedure (group 2). result: group 1 patients comprised of 56 males and 47 females with a mean age of 41.5 ± 13.9 years. group 2 patients comprised of 48 males and 39 females with a mean age of 42.6 ± 15.2 years. the mean stone size was 14.3 ± 2.7 mm in group 1 and 14.1 ± 2.8 mm in group 2. the mean operating time was calculated as 63.6 ± 8.2 minutes in group 1 and 65.7 ± 9.7 minutes in group 2. in group 1, the success rate was determined as 83.5% on postoperative day 1 and as 92.2% in the postoperative first month. in group 2, these rates were 81.6% and 90.8% respectively. no statistically significant difference was determined between the groups in respect of stone size (p= .752), operating time (p = .108) and postoperative first day (p = .732) and first month success rates (p = .724). conclusion: fluoroscopy-free rirs is a surgical technique with a high rate of success that can be applied safely to be able to protect patients at high risk of radiation and the surgical team, particularly in centers with high patient circulation. keywords: flexible ureteroscopy; fluoroscopy-free rirs; kidney stone; nephrolithiasis; radiation exposure introduction the primary aim of kidney stone treatment is to ob-tain the maximum stone-free rate with minimum morbidity. there have been significant changes in the treatment of kidney stones in the last 30 years. while treatment in the past was only applied with open surgery, treatment options have now become less invasive with percutaneous nephrolithotomy (pcnl), shock wave lithotripsy (swl) and retrograde intrarenal surgery (rirs). in the last decade in particular, the use of rirs has become more popular for reasons including that it is less invasive, patients can be discharged early, there are low complication rates and success rates are high.(1-2) however, the exposure to low-dose radiation with the frequent use of fluoroscopy imaging at different stages of rirs could create potentially harmful effects for the patient and the surgical team in the future. the most significant concern related to ionized radiation is the risk of cancer, which may develop as a result of cellular damage and the expression of affected nuclear material.(3,4) the ionizing radiation (ir) exposure of stone forming patients are depending on three factors. first one is the diagnostic procedures. according to current eau guidelines, non-contract ct scan is the preferable imaging method for the patients with renal colic. 1department of urology, health siences university, adana city training and research hospital, adana, turkey. *correspondence: department of urology, health siences university, adana city training and research hospital, adana, turkey tel: +90 505 4308550, fax+90 322 3440305, e-mail: hakanercil@yahoo.com. received january 2018 & accepted june 2018 secondly, ir exposure of the treatment; all surgical treatment modalities uses ir. third, during follow-up ir exposure is needed. within these factors only modifiable factor is the treatment factor. radiation free treatment modalities such as us-guided swl and pcnl are more preferred to reduce ir doses both in patients and doctors. several urology centres have reported reduced or fluoroscopy-free and flexible ureteroscopic studies to decrease fluoroscopic exposure because of these potential risks.(5,6) the urologists have concerns on flexible ureterorenoscopy(urs) without fluoroscopy guidance. thus, we aimed to compare the feasibility, reliability and outcome of conventional rirs and fluoroscopy free rirs. material and methods study population a retrospective evaluation was made of the data of 226 patients who underwent rirs as kidney stone treatment between may 2015 and may 2017. decision of rirs and the guidance method, with or without fluoroscopy were made by the patient as a result of a patient-doctor consultation. the procedure was performed to patients whom had signed the inform consent. preoperative evaluation of the patients was made based on non-contrast computed tomography (ncct) and kidney-ureurology journal/vol 16 no. 5/ september-october 2019/ pp. 443-447. [doi: 10.22037/uj.v0i0.4382] ter-bladder (kub). all patients were operated by surgeons with at least ten years of endourological surgery experience. one surgeon performed rirs under fluoroscopy guidance (h.e) and the other performed rirs without fluoroscopy (e.a). the patients who were conventionally operated with rirs under fluoroscopy guidance formed group 1 and the patients who were operated with rirs without fluoroscopy fromed group 2. all patients were operated with a flexible ureterenoscopy with 7.5 fr tip and 8.5 fr shaft diameter (karl storz, flex x 2, tutlingen, germany). for both groups, the exclusion criteria were defined as a paediatric age group, coagulation disorder, previous renal or ureter surgery, urinary system obstruction (ureteropelvic or ureterovesical junction obstruction etc.), elevated creatinine level (>2mg/dl), anatomic disorder of the urinary system (double-collecting system, horseshoe kidney etc), those with multiple stones, those with non-opaque stones. when evaluation was made according to the exclusion criteria, the study continued with a total of 190 patients including 103 in whom fluoroscopy was used (group 1) and 87 who underwent a fluoroscopy-free procedure (group 2). the patients were evaluated preoperatively with routine anesthesia tests. stone dimensions were measured preoperatively on ncct and the greatest diameter was calculated with digital measurement. outcome assessment rirs was accepted as successful in patients determined as completely stone-free during follow-up, or with clinically insignificant residue (< 3mm). the treatment was accepted as unsucessful in patients who required additional treatment (swl or urs) because of clinically significant residue (≥ 3mm) or the development of complications due to rirs. when there was a neeed to use fluoroscopy in group 2 patients, the treatment was accepted as unsuccessful. the residual fragments were evaluated with kub on posoperative day 1 and one month later with kub and/or ncct. fluroscopyfree surgical technique all the operations were operated under general anesthesia in the lithotomy position. before rirs, the ureter was evaluated with semi-rigid urs. during diagnostic urs a working guide-wire (0.038-inch superstiff guide-wire, cook urological, bloomington, in, usa) was placed in the renal pelvis by advancement with a 7.0 fr ureteroscope (karl storz, tutlingen, germany) as far as the ureteropelvic junction (upj). during diagnostic urs, the length between the external ureteral meatus and the ureter superior (uml) end was calculated by subtracting the length of the ureteroscope remaining outside the external meatus from the length of the ureteroscope. then, a 9.5/11.5 fr ureteral access sheath (uas) (cook flexor, cook urological, bloomington, in, usa) was placed by advancement according to the defined length. when placing the uas, it was advanced by sliding over the guide-wire only, without applying any tactile force. by advancing a flexible urs (karl storz, flex x 2, tutlingen, germany) within the uas, the upj was passed and the renal pelvis was entered. following examination by direct observation of all the calyces of the kidney, stone fragmentation was fragmented with a ho-yag laser (sphinx, lisa, germany). by using high frequency and low energy (30 hz, 0.5 j) for stone fragmentation, dusting was applied. at the end of fragmentation, a guide-wire (0.038 in floppy tip guide-wire, cook urological) was advanced to the renal pelvis within the flexible urs and the uas was removed together with the ureteroscope for evaluation of ureter damage. at the end of the operation, a double j (dj) stent was applied. these stents were removed after one-month with flexible cystoscope under local anesthesia. the operating time was calculated as the period between the start of urs and the placement of a dj stent. for both procedures, in cases where the ureteroscope could not be advanced to the upj during diagnostic urs (eg, ureteral stricture, ureteral resistance), the operation was terminated by applying a dj stent for passive ureteral dilation and the procedure was reperformed after two weeks. statistical analysis statistical analysis was performed using statistical package for social sciences (spss) 20 software (spss inc.chicago, il). the shapiro wilk test was used to assess the conformity of the data to normal distribution and all normally distributed data were presented as mean ± standard deviation (sd). the student’s t-test was used for parametric variables, and the mann whitney u-test was used for nonparametric variables. for multivariate analyses, the linear regression analysis test table 1. demographics and clinical data characteristicsa group 1(n=103) group 2(n=87) p value age(years) 41.5 ± 13.9 42.6 ± 15.2 0.604 sex male 47 39 0.912 female 56 48 bmi (kg/m2) 23.7 ± 2.6 23.6 ± 2.4 0.954 stone diameter(mm) 14.3 ± 2.7 14.1 ± 2.8 0.752 stone location renal pelvis 59 42 0.622 middle calyx 22 22 upper calyx 9 11 lower calyx 13 12 operation side(%) right 49( 47.57) 41(47.12) 0.951 left 54 (52.42) 46(52.87) abbreviation: bmi, body mass index adata are presented as mean ± sd or number (percent) the need for fluoroscopy during rirsalma et al. endourology and stones diseases 444 was used. a value of p < 0.05 was considered statistically significant. results group 1 patients consisted of 56 males and 47 females with a mean age of 41.5 ± 13.9 years. group 2 patients consisted of 48 males and 39 females with a mean age of 42.6 ± 15.2 years. the mean stone size was 14.3 ± 2.7 mm in group 1 and 14.1 ± 2.8 mm in group 2. in terms of age and stone size, there was no significant differences between two groups. the statistical evaluation of the demographic data and stone parameters is shown in table 1. the uml was calculated as 37.8 ± 2.5 cm in males and 29.1 ± 2.5 cm in females in group 2. a dj stent was placed for passive ureteral dilation because of ureteral resistance during uas placement in 22 patients in group 1 and in 21 patients in group 2. the mean operating time was calculated as 63.6 ± 8.2 minute in group 1 and 65.7 ± 9.7 minute in group 2. in group 1, the success rate was determined as 83.5% on postoperative day 1 and it is increased to 92.2% in the postoperative first month. in group 2, these rates were 81.6% and 90.8% respectively. the mean time of fluoroscopy usage in group 1 was 16.82 ± 6.65 second. for 1 (1.1%) patient of group 2, pyelography had to be applied using fluoroscopy intraoperatively due to stone location in the upper pole of the kidney that could not be visualized. as bifid pelvis was determined in this patient, the operation was continued using fluoroscopy. no statistically significant difference was determined between the groups in respect of operating time, and postoperative first day and first month success rates. the intraoperative and perioperative parameters and the statistical evaluations of these variables are presented in table 2. multivariate linear regression analysis was performed to evaluate the factors which affected success of the operation. as a result of this analysis, stone location in the lower pole of the kidney (p = 0.000) was found to be significant predictive factor for success on postoperative day 1, and mean stone size (p = .001) was a significant predictive factor for success in the first month. in group 1: minimal mucosa injury (clavien 1) developed in 6 (5.8%) patients in group 1. these patients were treated with dj stent insertion which was routinely performed and no further treatment were applied. swl was applied to 5 patients (4.9%) who were accepted as unsuccessful, a second rirs procedure was applied to 2 and in 1 asymptomatic patient with 5.5 mm residual lower pole stone and monitored. postoperative fever (> 38˚c) developed in 5 patients (4.9%), mild hematuria in 10 patients (9.7%) and flank pain in 19 patients (18.4%) who responded to non-steroidal anti-inflammatory treatment. in group 2: minimal mucosa injury (clavien 1) developed in 5 patients (5.7%) in group 2. these patients were treated with dj stent insertion which was routinely performed and no further treatment were applied. swl was applied to 3 patients who were accepted as unsuccessful, a second rirs procedure was applied to 3 and ureteroscopic stone treatment was applied to 1 patient because of ‘steinstrasse’ in the ureter. postoperative fever (> 38˚c) developed in 3 patients (3.4%), mild hematuria in 7 patients (8.04%) and flank pain in 12 patients (13.8%) who responded to non-steroidal anti-inflammatory treatment. the complications for both groups according to the modified clavien’s classification are shown in table 3. discussion fluoroscopic imaging has been used routinely for many years to increase surgical success, collector system anatomy and safety in urological operations. however, in centers with high patient circulation, complications which could develop in the long-term related to the use of fluoroscopy are a source of concern for the whole operating team. the most serious complication which could develop related to fluoroscopy use is cancer, as a result of cellular damage and affected nuclear material(3,4). in studies conducted on this subject, it has been reported that there could be serious side-effects of fluoroscopy usage(7,8). the international commission on radiation protection has reported that exposure to radiation should not exceed 20 msv per year over 5 years and should not exceed 50msv in any single year to avoid the harmthe need for fluoroscopy during rirsalma et al. table 2. perioperative and postoperative findings characteristicsa group 1(n:103) group 2(n:87) p value pud 22 21 0.648 operation time (min) 63.6 ± 8.2 65.7 ± 9.7 0.108 posr on first day (%) 83.5 81.6 0.732 posr on first month (%) 92.2 90.8 0.724 abbreviations: pud, passive ureteral dilatation; posr, postoperative success rate adata are presented as mean ± sd or number (percent) characteristicsa group1(n:103) group 2(n:87) clavien’ score p value fever 5 3 1 0.495 flank pain 19 12 1 0.387 hematuria 10 7 1 0.689 mucozal injury 6 5 1 0.982 adata are presented as mean ± sd or number table 3. postoperative complications vol 16 no 04 september-october 2019 445 ful effects of radiation (8). to protect the surgical team in urological operations from the effects of low-dose radiation, equipments are used such as a scopy apron, gloves, neck guard, testes protector and glasses etc. despite all the biosafety equipment available to medical teams, the cumulative deleterious effects of radioactivity cannot be ignored. fluoroscopes emit doses of approximately 5 rads per minute and minifluoroscopes can cause serious and irreversible damage to health (9,10). in a recent study it was reported that even in optimal conditions, the protective equipment of gloves and glasses could reduce the radiation exposure at the rate of 69.4% and 65.6% respectively (11). in this context, it is evident that all the operating team, especially in centres with high patient circulation are vulnerable to develop complications which are associated with lowdose radiation. as a result of concerns related to fluoroscopy usage in urological stone treatment, firstly, reduced fluoroscopy came into use and recently, there have been publications related to completely fluoroscopy-free operations. in a study by greene et al., the duration of fluorosopy was reduced by 82% during ureteroscopy and it was concluded that similar success rates were achieved with the use of reduced fluoroscopy compared to conventional ureteroscopy and that it was a reliable procedure (12). later, olgin et al. reported that fluoroscopy-free ureteroscopy applied to the upper urinary system was effective and could be applied. thus, the conclusion was reached that exposure to radiation had been completely removed for the patient and operating team and this technique could be applied to pregnant patients, children and patients with recurrent stones(6). in rirs, the use of reduced fluoroscopy or completely fluorosopy-free has come to prominence for reasons such as the developments in laser and optic technology, reduced calibration of the instruments and increased endoscopic experience of urologists. kiraç et al. used single-dose fluoroscopy at the uas placement stage in rirs and reported a success rate of 88.5% in uas placement and 82.9% stone-free rate (sfr). additional fluoroscopic imaging was necessary in only 5.2% (13). peng et al. then described a fluoroscopy-free rirs technique. in that study, the mean stone size was 14±4 mm and 85% sfr was reported on postoperative day 1 and 95.7% sfr in the first month. the mean operating time was 74.5 minute and fluoroscopy was used in only 1 patient because of a double collecting system. it was concluded that fluoroscopy-free rirs is possible and can be employed by experienced surgeons(14). in the current study, the success rates were determined as 83.5% on postoperative day 1 and 92.2% in the first month in group 1 and as 81.6% and 90.8% respectively in group 2. it was necessary to use fluoroscopy intraoperatively in only 1 patient of group 2 (1.1%). in conventional rirs, fluoroscopic imaging is used at different stages of the operation. it is used especially at the stage of uas placement and at the stages of defining the localization of the stone within the kidney and for flexible ureteroscope. under fluoroscopy guidance, the uas is advanced and access to the kidney is provided. fluoroscopic imaging at this stage contributes nothing to the safety of the procedure but only shows the localization of the uas (15). in the technique used in the current study, first diagnostic urs was applied and after calibration of the ureter and determination of the uml, then the uas was placed. the patient group of the current study included patients with a single stone in the kidney, pelvis or any calyx. as the patients only had a single stone, no difficulties were experienced related to the localization of the ureteroscope and the stone within the kidney. however, when there are multiple stones in the kidney, it could be considered more difficult, the fluoroscopy-free rirs technique could still be applied. this would be the subject of a different study. the rates of success in group 2 in the current study are similar in general to the results of conventional rirs in literature (16-18). this is due to the basis of the current study being the visual evaluation of the urinary system at every stage of the operation. it is thought that this visual evaluation could provide the high success rate. complications occurring in rirs are most often related to injuries in the ureter. although the vast majority of injuries are related to the use of uas, it is known that the injury is not directly related to the diameter of the uas used(19). while kiraç et al. reported ureter injury at 1.3%(13). peng et al. reported general complications as 2.9% clavien 1 and 0.7% clavien 2(14). oguz et al. determined a total intraoperative complication rate of 30%, the majority of which were low level. the most frequent intraoperative complication was mild haematuria at 9.5%, followed by superficial mucosal injury at 4.3% and severe mucosal injury at 1.3%(3). in the current study, all the ureter injuries (5.8% in group 1, 5.7% in group 2) were at a treatable level and no additional surgical intervention was necessary in any patient where injury developed (clavien 1). limitations of the current study include the following: the retrospective design, the fact that patients were operated by two surgeons and no inclusion of long-term complications. however, as one of the first studies related to fluoroscopy-free rirs, this study can be considered to contribute to literature in respect of allaying the concerns of all the operating team, particularly in centers with high patient circulation, conclusions fluoroscopy-free rirs is a surgical technique with a high rate of success that can be applied safely to be able to protect patients at high risk of radiation and the surgical team, particularly in centers with high patient circulation. acknowledgement we would like to acknowledge m. resit goren, onur kucuktopcu and asli dilber yildirim for the statistical analyses and intellectual comments. conflict of interest the authors report no conflict of interest. references 1. resorlu b, oguz u, resorlu eb, oztuna d, unsal a. the impact of pelvicaliceal anatomy on the success of retrograde intrarenal surgery in patients with lower pole renal stones. urology. 2012;79:61-6. 2. breda a, ogunyemi o, leppert jt, lam js, schulam pg. flexible ureteroscopy and laser lithotripsy for single intrarenal stones 2 cm the need for fluoroscopy during rirsalma et al. endourology and stones diseases 446 or greater--is this the new frontier? j urol. 2008;179:98:1-4. 3. liu sz. biological effects of low level exposures to ionizing radiation: theory and practice. hum exp toxicol. 2010;29:275-81. 4. tang j, huang y, nguyen dh, costes sv, snijders am, mao jh. genetic background modulates lnc rna-coordinated tissue response to low dose ionizing radiation. int j genomics doi: 10.1155/2015/461038. 5. oguz u, resorlu b, ozyuvali e, bozkurt of, senocak c, unsal a. categorizing intraoperative complications of retrograde intrarenal surgery. urol int. 2014;92:164-8. 6. olgin g, smith d, alsyouf m, et al. ureteroscopy without fluoroscopy: a feasibility study and comparison with conventional ureteroscopy. j endourol. 2015;29:625-9. 7. pierce da, preston dl. radiation-related cancer risks at low doses among atomic bomb survivors. radiat res. 2000;154:178-86. 8. mountford pj, temperton dh. recommendations of the international commission on radiological protection (ircp) 1990. eur j nucl med. 1992;19:77-9. 9. hanel dp, robson db. the image intensifier as an operating table. j hand surg am. 1987;12:322–3. 10. levin pe, schoen jr rw, browner bd. radiation exposure to the surgeon during closed interlocking intramedullary nailing. j bone joint surg am. 1987;69:761–6. 11. hoffler ce, ilyas am. fluoroscopic radiation exposure: are we protecting ourselves adequately? j bone joint surg am. 2015;97:721-5. 12. greene dj, tenggadjaja cf, bowman rj, agarwal g, ebrahimi ky, baldwin dd. comparison of a reduced radiation fluoroscopy protocol to conventional fluoroscopy during uncomplicated ureteroscopy. urology 2011;78:286-90. 13. kirac m, tepeler a, guneri c, et al. reduced radiation fluoroscopy protocol during retrograde intrarenal surgery for the treatment of kidney stones. urol j. 2014;11:1589-94. 14. peng y, xu b, zhang w, et al. retrograde intrarenal surgery for the treatment of renalstones: is fluoroscopy-free technique achievable? urolithiasis 2015;43:265-70. 15. graversen ja, valderrama om, korets r, et al. the effect of extralumenal safety wires on ureteral injury and insertion force of ureteral access sheaths: evaluation using an ex vivo porcine model. urology 2012;79:1011-4. 16. javanmard b, kashi ah, mazloomfard mm, ansari jafari a, arefanian s.retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j. 2016;10:2823-8. 17. grasso m. experience with the holmium laser as an endoscopic lithotrite. urology 1996;48:199–206. 18. breda a, ogunyemi o, leppert jt, schulam pg. flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. eur urol. 2009;55:1190-6. 19. torricelli fc, de s, hinck b, noble m, monga m. flexible ureteroscopy with a ureteral access sheath: when to stent? urology 2014;83:278-81. the need for fluoroscopy during rirsalma et al. vol 16 no 04 september-october 2019 447 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran introduction voiding dysfunction is a bladder emptying disorder and manifested with a complex of lower urinary tract symptoms. voiding dysfunction is common in women so that 14% of females who seek urologic consults have lower urinary tract symptoms. however they would not be diagnosed until they come several times with serious sign and symptoms like recurrent urinary infections or urinary incontinence. evaluation of voiding dysfunction in women and young girls in order to prevent and treat urinary incontinence, retention, urinary tract infection and the renal injury caused by it, is an important matter.(1) several therapeutic methods have been proposed for these patients but the specific anatomy of female's outlet caused limitations in treatment options. female's sphincter almost composed of skeletal muscle (slow-twitch) and an inner layer of smooth muscle which is predominant in the proximal part, but muscle fibers are arranged in an oblique and longitudinal manner and there is no well defined smooth muscle sphincter. effects of thyrotropin-releasing hormone on urethral closure pressure in females with voiding dysfunction hajebrahimi s*, madaen sk, sheikhzadeh p department of urology, imam khomeini hospital, tabriz university of medical sciences, tabriz, iran abstract purpose: to evaluate the effect of intravenous thyrotropin releasing hormone (trh) on the urethral closure pressure (ucp). materials and methods: twenty-two female patients with either bladder outlet obstruction (boo) or detrusor under activity were included in this study. they divided into two study and control groups randomly. twelve patients in study group received 200?gr of trh intravenously and patients in control group received intravenous normal saline as placebo. standard urethral pressure profilometry was performed before injection and after injection at 5, 10, 20 and 30 minutes. functional profile length (fpl), maximum urethral closure pressure (mucp), and urethral closure pressure at the proximal quarter of the fpl (1/4 flp) and at the distal quarter of fpl (3/4 flp) were measured in both groups. results: the mean age of the study and control groups were 41.61±21.7 years and 43.59±19 years respectively .the study and control groups included 5 boo and 6 detrusor under activity and 4 boo and 5 detrusor under activity respectively. the mean peak flow rate was 5.69±8.4 ml/s in the study group and 6.31±81 ml/s in control group. there wasn't significant difference between two groups. mean maximum urethral closure pressure demonstrated no significant difference in two groups before and after trh injection, but a marked reduction in 3/4 ucp and 3/4 fpl in patients after trh injection was seen. conclusion: trh injection significantly reduces the distal urethral pressure. key words: thyrotropin releasing hormone, urethral pressure profilometry, voiding dysfunction-underactive detrusor accepted for publication effects of thyrotropin-releasing hormone on urethral closure pressure in females with voiding dysfunction therapeutic recommendations in evaluating voiding dysfunction in female especially in whom with detrusor hypocontractility are limited and any new information will be interesting. intravenous trh as a diagnostic test for endocrine dysfunction, caused severe urgency in more than 1/3 of patients.(2) in another study on women with stress urinary incontinence, a marked reduction in ucp was seen after trh injection.(3) so it seems that the primary response of lower urinary tract to trh is the relaxation of urethra. this hypothesis encouraged us to study its effects on women with bladder hypocontractility or bladder outlet obstruction. our aim was to evaluate the effects of intra venous trh on ucp in a double-blinded placebocontrolled study. if we can confirm that trh or trh like peptides can relax the female urethra, the long acting pharmacologic products can help these patients with detrusor hypocontractility in order to empty their bladder without using any other therapeutic methods such as cic. materials and methods in this clinical trial 22 female patients with either bladder outlet obstruction (boo) or poor contraction of bladder (detrusor under activity), which were diagnosed based on uroflowmetry and pressure flow study (pfs), were included. patients with detrusor pressure less than 30 cm h2o in peak flow less than 10 ml/sec were diagnosed as underactive detrusor and patients with detrusor pressure more than 60 cmh2o in the same peak flow (<10 ml/sec) were diagnosed as boo. patients with boo caused by anatomic obstruction were excluded from the study. patients were divided into two groups (study and control) randomly. twelve patients in study group received 200 ?gr intravenous trh and the control group patients received intravenous normal saline as placebo. the urethral pressure profile (upp) was done before injection and 5, 10, 20, and 30 minutes after injection. the upp test was done with a mms 2000 urodynamic machine with software version 5.10 the converter 10 french from gaotec model and a fluid with 1009 density was installed with a pump speed of 10mm/sec. the test was done in supine position. at first the transducers were put in bladder completely and then pushed out with 30mm/s speed. the resting profile was recorded (fig. 1). the measured variables were: functional profile length (fpl), maximum urethral closure pressure (mucp), and closure pressure at the proximal quarter of the fpl (1/4 ucp) and at the distal quarter of fpl (3/4 ucp). in addition, blood pressure (bp) and pulse rate (pr) of each group before and after trh injection were measured. in this study we used man-whitney u-test for analysis. 2 fig. 1 fig. 2. urethral closure pressure in 1/4 proximal of functional profile length, chane from base in either group 0 5 0 1 0 0 1 5 0 2 0 0 0 5 1 0 2 0 3 0 t im e a fte r in je c tio n (m in c m h 2 o c on tr ol c ase fig. 3. urethral closure pressure in 3/4 distal of functional profile length, chane from base in either group 0 10 20 30 40 50 60 5 10 20 30 time after injection c m h 2 o case cotrol effects of thyrotropin-releasing hormone on urethral closure pressure in females with voiding dysfunction results the mean age of each study and control group was 41.61±21.7 years and 43.59±19 years respectively. the study group included 6 patients with boo and 6 with underactive detrusor and the control group included 5 patients with boo and 5 with underactive detrusor (p=0.45). the mean peak flow rate in the study and control groups were 5.69±8.4 ml/s and 6.31±81 ml/s respectively. there wasn't any significant difference between the two groups (p=0.67). the fpl and ucp measured for both groups before and after trh injection have no significant differences (table 1). the results of urethral pressure profilometry (upp) after injection are demonstrated in figures 2, 3, and 4. a marked reduction in fpl and ucp in distal 3/4 of the urethra in the study group (after trh injection) compared to the control group (after placebo injection) were seen (p=0.03) and (p=0.02) (fig. 3, 5). the maximum ucp 5 minutes after trh injection in the study group was reduced but it has no significant statistical difference with control group (p=0.35) (fig. 4). in addition, a reduction in (1/4 ucp) 5 minutes after trh injection in the study group was seen but there was no significant difference with the control group either (p=0.29) (fig. 2). after trh injection no increased detrusor pressure was seen and there was no significant difference between two groups in urgency. also no significant difference in bp and pr before and after trh injection was seen (p=0.6). discussion voiding dysfunction is a disorder in bladder emptying in persons who have no urologic problem. in these patients we have an increased activity of external sphincter during voiding which is trained as a habit and differs with detrusor sphincter dyssynergia which results from neurologic disorder or trauma. so terms, psudodyssynergia and behavioral voiding dysfunction were used for explaining this problem.(6) diagnosis of female voiding dysfunction is an important matter because of its role in prevention and treatment of urinary incontinence, retention, and urinary tract infection and the subsequent renal injury. (1) in spite of high incidence of voiding dysfunction in females, there are controversies on its etiology and diagnosis. although many different therapeutic options may be propounded for these patients but the specific anatomy of female outlet is a limitation factor in this way. the female sphincter consists of slow-twitch skeletal muscles(7) and an inner layer of smooth muscle with a majority in proximal part, but these fibers are arranged in a longitudinal and oblique manner and there is no well defined smooth muscle sphincter. therapeutic options in females with voiding dysfunction especially with detrusor hypocontractility are limited. drugs used in underactive detrusor treatment consist of betanechol chloride, distigmine bromide, and e2 and f2 3 fig. 4. maximum urethral closure pressure, chane from base in either group fig. 5. functional profile length, chane from base in either group 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 5 1 0 2 0 3 0 t im e a fte r in je c tio n (m in c m h 2 o c o tr o l c a s e 35 36 37 38 39 40 41 42 43 5 1 0 2 0 3 0 t im e a fte r in je ctio n (m in c m h 2 o c ase c ontrol table 1. mean urethral closure pressure and functional profile length before injection measured variables control group study group p value mucp (cmh2o) 93.98±20.16 93.19±24.98 .35 fpl (cm) 3.96 3.13 .42 ucp in 30% fpl (cmh2o) 72.59±23 68.06±26.3 .29 ucp in 70% fpl (cmh2o) 31.92±21.06 38.03±21.64 .02 effects of thyrotropin-releasing hormone on urethral closure pressure in females with voiding dysfunction prostaglandins that are overused, but studies shows that none of them can help in long term. in males with bladder outlet obstruction (diagnosed by urodynamic) ?-adrenergic blockers are helpful but such a problem in females is rare and it seems these agents (phenoxybenzamin, prazosin, and indoramin) have limited value in treatment of female's urinary outlet obstruction. ?-adrenergic blockers reduce the urine outgoing resistance by affecting proximal smooth muscle sphincter and have marginal effects on females. therefore finding any drug, which affects skeletal muscle sphincter (which is the main part responsible for female's sphincter mechanism) will be important. in a placebo-control trial, trazosin (?-blocker) was used for female with symptoms like prostatism but had no significant clinical effect.(11) trh can have a direct peripheral effect on urethral muscles or a central effect on neural control that can reduces the muscle tone.(10) so we can study its effects on ucp in females with underactive detrusor or boo. abundance of trh receptors and trh like peptides in human's prostate indicates its peripheral effects.(9) rosenthal reported urgency after trh injection in a patient with total spinal cord injury and related it to trh central effects. our study indicated that trh has its maximum effect on ucp and fpl and the most significant alteration is in 3/4 ucp and fpl (fig. 2, 4). although the reason of different effects on distal and proximal parts of urethra is not clear, probably it indicates the openly effect of trh on skeletal muscle of female urethra which is prevalent in the distal part. in addition, as it is shown in table 1, although there is no significant statistical difference between the study and the control group in reduction in (1/4 ucp), compared to control group it is bending to lower pressure. in our study we have no significant difference between the study and the control group in the amount of urgency, blood pressure, and pulse rate before and after trh injection and there was not any other side effects such as nausea and headache. so we can know trh as a low side effect drug. in a study on the effect of trh on muscular contraction of urogenital system in ten woman in comparison with normal saline as placebo, trh increased the pressure of urethra in all of them and increased vaginal pressure in seven, but none of them have any elevation in bladder pressure. on the other hand, the normal saline had no effect on all of them so we can conclude that trh, by central or peripheral effect or both of them, can play a role in the start of skeletal contracture of urogenital system.(25) in a study by derek and coworkers in england, trh injection caused reduction in ucp in females with voiding dysfunction.(10) therapeutic options in the management of female voiding dysfunction is limited, so any new drug would be welcome and if the effect of trh or trh like peptides on relaxation of female's urethra is confirmed, the pharmacological long acting products can help patients with underactive detrusor to empty their bladder without using any other therapeutic options like cic or electrical stimulation of sacral nerve roots. also patients with boo have no need to undergo inconvenient therapeutic procedures like urethral dilatation or bladder neck incision that may cause urinary incontinence. conclusion in summary, trh injection causes reduction in ucp (with the most effect on distal 3/4 of urethra) and knowing how it effects on urethra can open new ways in the evaluation of voiding dysfunction in women. voiding dysfunction in females is relatively common and almost 14% of patients who seek urologic consults have lower urinary tract symptoms, and even sever bladder emptying disorders may be normal from the patients' view and they won't come to clinic seeking treatment. this may cause irreversible injuries like renal failure. so examination, evaluation, and treatment of these patients are very important matters and developments in noninvasive therapeutic procedures could facilitate obtaining this purpose. references 1. everaert k, van laecke e, de muynck m, et al. urodynamic assessment of voiding dysfunction and dysfunctional voiding in girls and women. int urology j 2000; 11 (4): 254-64. 2. steers wd. physiology and pharmacology of 4 effects of thyrotropin-releasing hormone on urethral closure pressure in females with voiding dysfunction the bladder and urethra. in: walsh, retik, vaughan, wein, editors. campbell's urology. 7th ed. philadelphia: w.b saunders company; 1998. p. 872-874. 3. wein aj. pathophysiology and categorization of voiding dysfunction. in: walsh, retik, vaughan, wein, editors. campbell's urology. 7th ed. philadelphia: w.b saunders company; 1998. p.917-925. 4. scanlon mf. thyrotropin-releasing hormone and thyroid-stimulating hormone. vol 2. 4th ed. w.b. saunders company; 2001. p. 12791280. 5. cohen jl. thyroid stimulating hormone and its disorders. in: kenneth l, becker jp, bielezikian, wj, bermner, et al. principles and practice of endocrinology and metabolism. 2nd ed. philadelphia: j.b. lippincott company; 1995. p. 158-159. 6. carlson kv, rome s, nitti vw. dysfunctional voiding in women. j urol 2001 jan; 165 (1): 143-148. 7. gosling ja, dicxon js, humpherson jr. functional anatomy of the urinary tract. london: churchill livingstone; 1983. p. 5, 6-5,11. 8. rosenthal mb. trh and urinary urgency. n engl j med 1974; 291: 1308-1309. 9. gkonos pj, kwok ck, block ni, roos ba. expression of prostatic trh-like peptides differs between species and between malignant and non-malignant tissues. prostate 1993; 29: 135-147, 1993. 10. derek j, rosaria h, woo h, parkhouse h, et al. effect of intravenous thyrotropin releasing hormone on urethral closure pressure in females with voiding dysfunction. eur urol 1995; 28: 64-67. 11. lesley k, carr md, frcs c, george d, webster mb. bladder outlet obstruction in women, urologic clinics of north american 1996 aug; 23 (3): 385-391. 12. farrar dj, whiteside cg, osborn jl, et al. a urodynamic analysis of micturition symptoms in the female. surg gynec obstet 1975; 141: 875. 13. rees dlp, whitefield hn, islam akms, et al. urodynamic finding in adult females with frequency and dysuria. br j urol 1976; 47: 853. 14. roberts m, smith p. non-malignant obstruction of the female urethra. br j urol 1968; 40: 694. 15. gleason dm, bottaccini mr, lattimer jk. what does the bougie a boule calibrate. j urol 1969; 101 (2):114. 16. tessier j, schick e. does urethral instrumentation affect uroflowmetry measurements. br j urol 1990 65: 261. 17. diokno ac, hollander jb, bennett, cj. bladder neck obstruction in women, a red entity. j urol 1984; 132:294. 18. cherrie rj, leach ge, raz s. obstructing urethral value in a women: a case report. j urol 1983; 129: 1051. 19. lepor h, theune c. randomized double-blind study, comparing the efficacy of terazosin versus placebo in women with prostatism-like symptoms. j urol 1996; 154:116. 20. christopher r, chapple, sa. urodynamics made easy. 2nd ed. w.b. saunders company; 2000. p. 5-8. 21. zacur ha, genadry r, rock ja, et al. thyrotropin releasing homrmone-induced contraction of urethral and vaginal muscle. j clin endocrinal metab 1985 oct; 61 (4): 787-9. 22. julian p, shah r. voiding difficulties and retention. in: stantion sl, monga ak. clinical urogynaecology. churchill livingstone; 2000. p. 268-270. 23. almquist s. clinical side effects of trh. front horn res 1972; 1: 38-44. 24. bergman a, bhatia nn, hasen j. effect of thyroid releasing hormone on bladder and urethral pressure. br j urol 1984; 56: 397400. 25. kumar a, mandhani a. functional bladder neck obstruction in females: use of alpha blockers and pediatric resectoscope for bladder neck incisionmillennium international urology congress. 2000 nov; 1306: 200. 5 pediatric urology laser-puncture versus electrosurgery-incision of the ureterocele in neonatal patients predrag ilic1*, mirjana jankovic1, maja milickovic2, slobodan dzambasanovic1, vladimir kojovic1 purpose: to compare the holmium-laser puncture and electrosurgery-incision in neonates with intravesical ureterocele. materials and methods: we retrospectively analyzed the results of laser-puncture of ureterocele (lp group) in 12 patients (mean age 9.8 days, range 4-28) and electrosurgery-incision in 20 patients (es group) (mean age 10.2 days, range 6-28), treated at our institution. patients had their records reviewed for preoperative findings, endoscopic procedure description, and postoperative outcomes. results: there was the need for retreatment in one (8.3%) patient in lp group and in four (20%) patients in es group (p = .626). duration of general anesthesia in lp and es groups was 16 (range, 10-24) minutes and 15 (range, 10-20) minutes, respectively (p = .355). there was no statistically significant difference in terms of hospitalization (lf group one day, es group 1.35 days) (p = .286). complications were not found in lp group. there were two (10%) patients with pyelonephritis after the treatment in es group (p = .516). after one month, obstruction was observed on ultarsound examination in one (8.3%) and two (10%) patients, respectively. after three months, obstruction was not found in any patient in both groups. after six months, vesicoureteral reflux was found in one (8.3%) patient after laser-puncture of the ureterocele and in 13 (65%) patients after electrosurgery-incision (p = .003). conclusion: both laser-puncture and electrosurgery-incision endoscopic techniques are highly effective in relieving the obstruction. there is no significant difference regarding hospitalization, need for retreatment and the occurrence of complications. the incidence of de novo vesicoureteral reflux is significantly lower in patients treated with holmium-laser, as well as the need for upper pole partial nephrectomy. keywords: ureterocele; neonates; laser puncture; electrosurgery incision. introduction ureterocele is a cystic dilation of the distal part of the ureter(1). ureterocele can be located inside the bladder or include the bladder neck and urethra. this anomaly may reflect insufficient ureteral maturation, the fetal process by which the developing ureteral bud separates from the mesonephric duct and moves to the bladder(2). it may be associated with a single or, usually, with duplex system, associated with the upper pole(3). characteristic presenting sign in some patients is prolapse of the ureterocele. pathognomonic clinical sign may be the presence of mucosa-covered intralabial masses with difficult voiding(4). the first clinical sign of the anomaly, sometimes, may be urosepsis. on the other hand, the state is characterized by the absence of clinical signs in some patients(5). prenatal and postnatal ultrasound investigation, magnetic resonance imaging, radionuclide renal scan and voiding cystourethrogram (vcug) are procedures used to define a complex anatomy of the urinary tract of these patients, but the final diagnostic procedure is endoscop(6-11). surgical treatment of ureterocele in neonatal period has to be performed to eliminate the obstruction and uri1urology department, mother and child health care institute of serbia “dr vukan cupic”, belgrade, serbia. 2abdominal surgery department, mother and child health care institute of serbia “dr vukan cupic”, belgrade, serbia. *correspondence: mother and child health care institute of serbia “dr vukan cupic”, belgrade, serbia tel: +381 64 1596523. fax: +381 11 2697232. e-mail: predrag.ilic0410@gmail.com. received july 2017 & accepted october 2017 nary tract infection (uti) and to avoid the occurrence of vesicoureteral reflux, and, also, to preserve renal function and prevent urinary incontinence. the overall procedural morbidity has to be minimized. the options for the treatment are: transurethral incision, excision of ureterocele with (or without) ureterocystoneostomy or ureteroureterostomy, upper pole haeminephroureterectomy. transurethral incision or punctre of the ureterocele may prevent the obstruction and vesicoureteral reflux in majority of patients. also, the necessity for subsequent surgery can be minimized. the endoscopic surgical treatment can be performed with electrosurgery, cold-knife and holmium-laser(12,13). patients and methods study population the study was conducted at mother and child health care institute of serbia “dr vukan cupic“. patients were divided into two groups. in the first group the results of laser-puncture of intravesical ureterocele in 12 patients were analyzed, treated between november 2012 and november 2016 (lp group). in the second group the results of electrosurgery-incision of intravesical ureterocele in 20 patients were analyzed, treated between november 2005 and november 2012 (es group). vol 15 no 02 march-april 2018 27 inclusion criteria: only neonates with intravesical single or double system ureterocele were included in the study. exclusion criteria: patients after neonatal period (older than 28 days), patients with extravesical ureterocele and patients with comorbidities that may affect the outcome of the treatment of ureterocele were excluded. surgical technique ultrasound, vcug and radionuclide renal scan were performed in all patients in order to confirm the diagnosis. urinalysis, urine culture and kidney function tests were evaluated. all patients were under antibiotic prophylaxis. cystoscope 7.5-f was used for the endoscopic evaluation and the treatment. all endoscopic procedures were done under general anesthesia. the source of energy in lp group was holmium: yttrium-aluminum-garnet laser (holmium: yag laser). we used 200 and 550-microm laser probes for ureterocele puncture (figure 1). in er group, electrocautery was used. the size of the probe was 3-f. all anatomic conditions were considered after transurethral placing of the cystoscope: the capacity of the urinary bladder, mucosal appearance, the presence of trigone, ureteral orifices and the presence of ureterocele. the side and the size of ureterocele, its tension and eventual propagation into the urethra were also evaluated. all these conditions were considered with regard to the fulfillment of the bladder. lp group: laser probe was placed through the working channel of the cystoscope near to the bladder floor, to the lowest and medial portion of the ureterocele. we used micro laser fibers generating 0.2 to 1 j at a frequency of 5 hz. a few punctures (4 to 10) were made at the ureterocele wall, while ureterocele has been collapsed. we performed all procedures without placing ureteral stent. foley catheter was placed if there was a risk of bladder neck obstruction. es group: electrocautery probe was placed through the working channel of the cystoscope. front wall of the ureterocele was incised with electrocautery. we have assumed an undisturbed visualization of the ureterocele interior as the sign of obstruction removal. outcome assessment in postoperative period all patients received antibiotic prophylaxis. the level of obstruction was assessed with ultrasound examination on the first postoperative day. during the follow-up period ultrasound examination was performed one and three months after the surgery, and, also, dynamic radionuclide renal scan, in order to confirm the obstruction removal. vcug was performed to evaluate the possibility of vesicoureteral reflux. vcug was a mandatory procedure in all patients in es group, according to the protocol of our institution during the follow-up period for patients in es group. in lp group vcug was not mandatory. protocol was changed in order to avoid negative impact of ionizing radiation during the routine vcug investigation. if there was no urinary tract infection and ultrasound was normal, we performed observation only. results are presented as counts (percents) or median (range). fisher’s exact test and mann-whitney u test were used to assess the differences between groups. spss 20.0 was used for data analysis. all p values less than 0.05 were considered significant. results as mentioned in patients and methods section, twelve patients were included in lp group and twenty patients in ls group. demographic data of the patients in the two study groups have been outlined in table 1. there was no statistically significant difference between the groups regarding clinical parameters, including double/ table 1. preoperative findings in patients characteristicsa lp group (n=12) es group (n=20) p value female 8 (67) 14 (70) 1 age, days; mean ± sd (range) 9.8 ± 6.5 (4-28) 10.2 ± 5 (6-28) 0.409 weight, kg ; mean ± sd (range) 3.6 ± 0.6(2.2-4.4) 3.6 ± 0.4 (2.4-4.0) 0.845 double system ureterocele 9 (75) 16 (80) 1 left side 7 (58) 12 (60) 1 diagnosed prenatally 9 (75) 14 (70) 0.7 abbreviations: n, number of patients; lp, laser-puncture; es, electrosurgery. adata is presented as mean ± sd or number (percent). figure 1. endoscopic view of ureterocele. punction of the ureterocele with laser beam. laser vs. electrosurgery for the ureterocele – ilic et al. pediatric urology 28 single system ratio, type of the ureterocele, side of the ureterocele and diagnosis period (prenatally or postnatally). operative data and postoperative investigations have been illustrated in table 2. puncture of the ureterocele with holmium-yag laser was performed in the total number of 13 procedures in 12 patients in lp group. in es group electrosurgery-incision of ureterocele was performed in the total number of 24 procedures in 20 patients. there was no statistically significant difference between the groups regarding the need for retreatment and duration of general anesthesia. complications were found only in two patients in es group. in both patients pyelonephritis occurred and vcug showed vesicoureteral reflux grade v. there was the difference between groups regarding complications, but without statistical significance. there was no statistically significant difference regarding postoperative obstruction. three months after the surgery ultrasound and radionuclide renal scans showed the absence of obstruction in both groups. there was a significant superiority of laser-puncture technique regarding the occurrence of vesicoureteral reflux: low grade reflux in one patient in lp group (grade iii) and high grade reflux in majority of patients in es group. discussion in majority of patients ureterocele is associated with some other disorder of the urinary tract, like megaureter, duplicated ureter, renal dysplasia, renal parenchyma damage, vesicoureteral reflux, contralateral agenesia, etc. the treatment of the ureterocele represents the treatment of all these disorders(3-5). the reasons for the immediate treatment are the relief of the obstruction, prevention of the urinary tract infections and prevention of vesicoureteral reflux(7). the treatment of the ureterocele enables preservation of renal function. nowadays, prenatal treatment is reality. fetal cystoscopic treatment of the ureterocele is well documented(14,15). ureterocele occurs more often in female. currently, the most complex forms of this anomaly occur in girls(1,7). on the other hand, male urethra in neonate has very small caliber. placing of the endoscopic instruments is very demanding and difficult. the use of adequate equipment is essential. we used cystoscope 7.5-fr in all patients and we didn’t have any problems when passing through the urethra. with the use this cystoscope, an adequate relationship is achieved between patient safety, good visualization, and the ability to perform surgical intervention. here the surgeon's experience plays a very important role. most patients with ureterocele have normal or slightly lower body mass. because of that, the body mass index does not have significant role in the preparation of the patient for the surgical intervention, as well as during the surgical intervention itself(11). in our study, there were no problems related to the body weight of the patients. in recent decades, earlier surgical intervention was suggested to relieve the obstruction in patients with ureterocele and prevent significant damage of the urinary tract. nowadays, some patients are treated prenatally. besides, there are some controversies in the literature: can early treatment protect the urinary tract from serious damage(6,8). in our study, the treatment was performed in neonatal period, immediately after necessary diagnostic procedure. all patients had completed initial surgical treatment (laser-puncture vs. electrosurgery-incision) by the age of 28 days. electrosurgery-incision, cold-knife incision and laser-incision are described surgical techniques for the treatment of ureterocele for relieving the obstruction. the technique in which a few separate punctures on the ureterocele wall are made is also described(10,12,13). the punctures are being made until ureterocele collapses. in our first investigation group (lp group) we decided to perform that technique, using holmium: yttrium-aluminum-garnet laser. a better endoscopic control of the extensibility of the punctures was the reason to perform that endoscopic procedure. on the other hand, in our second investigation group (es group) we performed standard electrosurgery-incision. ureterocele is not a very common anomaly. most studies dealing with initial surgical treatment of ureterocele do not have much more respondents than in our study. in particular, laser-puncture (not incision) of ureterocele is not sufficiently mentioned in the literature, that’s why we can discuss about it like, in a way, relatively new surgical technique(14,15,16). regardless of the small number of patients, when we compare the results of the two techniques in our study, we can preliminary state that there is no significant difference between laser-puncture and electrosurgery-incision in means of relieving the obstruction. after three months all patients are free of obstruction. considering reported decompression rate in most series between 70% and 90%(16,17), it is very clear that both techniques described in our study are highly effective in relieving the obstruction in patients with intravesical ureterocele. de novo vesicoureteral reflux after the endoscopic treatment of ureterocele in neonates is well known. accord table 2. postoperative findings in patients characteristicsa lp group (n=12) es group (n=20) p value no. of retreatments (percentage) 1 (8.3) 4 (20) 0.626 anesthesia, minutes; median ± sd, (range) 16 ± 4 (10-24) 15 ± 2.9 (10-20) 0.355 hospitalization, days; median ± sd (range) 1 ± 0 (1-1) 1.35 ± 1.09(1-5) 0.286 complications none 2 (10%) 0.516 obstruction (after three months) none none 1 vesicoureteral reflux –overall (after six months) 1 (8.3) 13 (65) 0.003 vesicoureteral reflux grade iii 1(8.3) 3 (15) vesicoureteral reflux grade iv none 5 (25) vesicoureteral reflux grade v none 5 (25) abbreviations: n, number of patients; lp, laser-puncture; es, electrosurgery. adata is presented as median±sd or number (percent). laser vs. electrosurgery for the ureterocele – ilic et al. vol 15 no 02 march-april 2018 29 ing to the literature, the incidence of a new reflux ranges from 0% to 75%(16,18,19). during the endoscopic incision it is very difficult to estimate what lengthiness of the incision line is sufficient to relief the obstruction and, at the same time, to prevent reflux. on the other hand, during the laser puncture the moment of collapsing the ureterocele was the sign to stop making the punctures. we presumed that the new punctures may contribute to the reflux. in our series the occurrence of de novo reflux is far more common in patients treated with electrosurgery-incision. it seems to be the main difference between two described endoscopic techniques. the degree of the vesicoureteral reflux is a very important parameter. theoretically, all degrees of reflux may occur in these patients. however, high grade reflux (grade iv and v) is more common. the occurrence of reflux, especially high grade reflux, often determine the necessity of appropriate surgical treatment. currently, surgical technique of the initial endoscopic decompression of the ureterocele should imply prevention of vesicoureteral reflux. according to the literature, laser-puncture provides better protection of reflux(19,20,21). our study also proved this. although this is a small group of respondents, it is very clear that possibility of reflux is lower after laser-puncture. the bottom line is that the puncture with laser beam is well controlled by the surgeon, who can stop to make the punctures immediately after collapsing of the ureterocele. it is supposed to be the critical moment when antireflux mechanism is still preserved. it is still controversial in the literature is vcug a mandatory procedure to all patients. untill 2012 we decided not to perform routine vcug after the ureterocele decompression in order to avoid negative impact of ionizing radiation. if there was no urinary tract infection, ultrasound and radionuclide renal scan were normal, we performed observation only, like many other centers. collapse of the ureterocele and reduction of the upper urinary tract dilation are reliable signs of decompression during the ultrasound examination and dynamic radionuclide renal scan after the endoscopic treatment of ureterocele. if the ureterocele is not collapsed and dilation persists, retreatment has to be performed. about 10% to 30% patients need retreatment(10,17,18). in our series there is the difference between the groups in need for retreatment, but without statistical significance. in lp group retreatment means making a few new punctures on the ureterocele wall until it collapses. in es group the line of the incision was extended 3 to 4 mm. control ultrasound examination and diuretic renal scan showed the absence of the obstruction. it is clear that retreatment solves the problem of the obstruction, but the dilemma is: does it increase the risk of de novo vesicoureteral reflux? it is important for the endoscopic treatment to be as short as possible, given that the procedure is performed in neonates. twenty-three minutes was the median duration of general anesthesia, reported by pagano et al.(20). without significant difference between the groups, our study showed that both laser-puncture and electrosurgery-incision techniques allow the shortest possible patient’s exposure to general anesthesia. expediency of the surgical team plays a major role in this respect. most patients with ureterocele are treated as outpatients. extended hospital stay is reserved for patients with complications after the endoscopic treatment or if some co-existing disorder implies prolonged postoperative follow-up(10,18,21,22). comparing our groups of patients, we found the difference between the groups: extended hospital stay is longer in patients treated with electrosurgery-incision, due to higher rate of postoperative complications, but without statistical significance. de novo vesicoureteral reflux, persistent obstruction, urinary tract infection, incontinence, forming of calculus, etc. are possible complications after the initial endoscopic treatment of ureterocele(3,4,10,18,23,24). obstruction and vur were already discussed. there are many reasons for the occurrence of uti. stasis of urine contributes to the occurrence of uti in any case. it is difficult to find relevant data in the current literature about the complications regarding endoscopic treatment of ureterocele (except vesicoureteral reflux and obstruction). in our series complications were found only in patients treated with electrosurgery-incision. in both patients, acute pyelonephritis was the complication, caused by high grade vesicoureteral reflux. however, we did not find statistically significant difference between the groups regarding complications. it was already mantioned that there are many options for subsequent surgery after the initial treatment of ureterocele. the decision about what kind of surgery is the best choice for the patient depends on the complex anatomy of the urinary tract. upper pole partial nephrectomy is one of the most probable options, if there is no function of the upper pole. besides, there are authors who raise a question about partial nephrectomy(25,26). we performed that procedure only if there were high grade vesicoureteral reflux and urinary tract infections, despite proven nonfunctional upper pole. since there was no high grade reflux in patients treated with laser-puncture, upper pole partial nephrectomy was performed in none of the patients treated with that procedure. that is obviously a very important fact when talking about laser-puncture, like initial treatment of patients with intravesical ureterocele. endoscopic treatment of ureterocele is well documented in the literature. there are also publications about using holmium-laser, but, laser incision (not puncture) was mostly described(20,27). the number of patients in these series is, mainly, too small for detailed analysis. holmium-laser puncture (fenestration) of ureterocele has not been sufficiently discussed(22). on the contrary, using the holmium-laser in the treatment of other disorders of the urinary tract is widely documented, particularly in the treatment of stone-disease(28-30). a laser beam penetrates the soft tissue to the depth of 0.5 mm(28). we decided to perform controlled use of laser beam in the endoscopic puncture of ureterocele, taking into account our experience in holmum-laser lithotripsy(30). conclusions both laser-puncture and electrosurgery-incision endoscopic techniques are highly effective in relieving the obstruction in neonates with intravesical ureterocele. there are no differences regarding hospital stay, the need for retreatment and the occurrence of complications. the incidence of de novo vesicoureteral reflux is significantly lower in patients treated with holmium-laser, as well as the need for upper pole partial nephrectomy. these facts make laser-puncture the preferred surgical technique for the treatment of intravesical ureterocele in neonatal patients. laser vs. electrosurgery for the ureterocele – ilic et al. pediatric urology 30 conflict of interest the authors report no conflict of interest. references 1. zeng l, huang g, zhang j, et al. a new classification of duplex kidney based on kidney morphology and management. 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[epub ahead of print] 23. dada sa, rafiu mo, olanrewaju to. chronic renal failure in a patient with bilateral ureterocele. saudi med j. 2015;36:862-4. 24. penkoff p, bariol s. urethral calculus originating from ureterocele and causing urinary retention. anz j surg. 2015;85:892-3. 25. castagnetti m, vidal e, burei m, zucchetta p, murer l, rigamonti w. duplex system ureterocele in infants: should we reconsider the indications for secondary surgery after endoscopic puncture or partial nephrectomy? j pediatr urol. 2013;9:11-6. 26. hisamatsu e, takagi s, nakagawa y, laser vs. electrosurgery for the ureterocele – ilic et al. vol 15 no 02 march-april 2018 31 sugita y. nephrectomy and upper pole heminephrectomy for poorly functioning kidney: is total ureterectomy necessary? indian j urol. 2012;28:271-4. 27. swana hs, hakky ts, rich ma. transurethral neo-orifice (tuno) a novel technique for management of upper pole obstruction in infancy. int braz j urol. 2013;39:143. 28. sofer m, binyamini j, ekstein pm, et al. holmium laser ureteroscopic treatment of various pathologic features in pediatrics. urology. 2007;69:566-9. 29. atis g, gurbuz c, arikan o, canat l, kilic m, caskurlu t. ureteroscopic management with laser lithotripsy of renal pelvic stones. j endourol. 2012;26:983-7. 30. ilic p, djordjevic m, kojovic v, dzambasanovic s. laser lithotripsy in the treatment of renal stones in children. a singlecenter experience. ann ital chir. 2016;87:32632. laser vs. electrosurgery for the ureterocele – ilic et al. pediatric urology 32 november-december 2018 reviewer of the issue maryam taheri maryam taheri december 2018 maryam taheri, m.d., is assistant professor of urology at urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. dr. taheri completed her urological residency in the year 2010 from labbafinejad medical center, shahid beheshti university of medical sciences and her m.d. degree in the year 2002 from iran university of medical sciences, tehran, iran. she has published more than fifteen papers in international peer reviewed journals. also she was the author of several chapters in different textbooks such as iranian textbook of urology, epidemiology and control of common diseases in iran. currently, she is the head of kidney stone preventive clinic in labbafinejad medical center and contributed in several stone clinic projects as principle investigator or consultant. dr. taheri was chosen as the best reviewer(s) of the issue by editorial board of the urology journal for his valuable and timely review of manuscript”. endourology and stone disease risk factors of infectious complications after flexible uretero-renoscopy with laser lithotripsy cagri senocak,1* cihat ozcan,1 tolga sahin,1 gulden yilmaz,2 ekrem ozyuvali,1 selcuk sarikaya,1 berkan resorlu,3 ural oguz,1 omer faruk bozkurt,1 ali unsal,4 oztug adsan1 purpose: to determine the perioperative risk factors for postoperative infections among patients undergoing flexible uretero-renoscopy with laser lithotripsy (fursll). in addition, the resistance patterns of pathogens isolated from positive preoperative urine cultures were investigated. materials and methods: we retrospectively reviewed data from 492 consecutive patients who had undergone fursll for stone disease in our department. postoperative infection was defined as fever (≥ 38°c) with pyuria (≥ 10 white blood cells per high power field), or systemic inflammatory response syndrome, or sepsis. pre-operative and intra-operative characteristics between patients with and without postoperative infectious complications were compared using univariate analyses. significant variables on univariate analyses were included in a multivariate logistic regression analysis to evaluate risk factors associated with postoperative infection following fursll. results: 42 (8.5%) of 492 patients had postoperative infectious complications after fursll. 59 (12%) of 492 patients had a positive preoperative urine culture. 19 (32.2% of 59) patients had multidrug resistance (mdr) isolates recovered from positive preoperative urine cultures. 75% (9/12 cultures) of the positive preoperative urine cultures of patients in whom a postoperative infectious complication developed consisted of gram-negative pathogens. on multivariate analysis positive preoperative mdr urine culture (or:4.75;95%ci:1.55-14.56; p = .006) was found to be significant with the dependent variable as the postoperative infectious complications despite appropriate preoperative antibiotic therapy. conclusion: we found that positive preoperative mdr urine culture is a significant risk factor for infectious complications after fursll. our findings point to the need for further research on assessment of risk factors for mdr infections to reduce the rate of postoperative infectious complications. keywords: nephrolithiasis; ureteroscopy, laser lithotripsy; urinary tract infections; multi-drug resistance. introduction with the improvement in technology, minimally invasive flexible uretero-renoscopy with laser lithotripsy (fursll) has been recently touted as a tool to improve the outcomes of uretero-renal stone surgery. fursll has become an increasingly favorable option even for patients with renal and proximal ureteral stones less than 20mm.(1,2,3) for these stones, the stonefree rates of fursll are up to 94.1% with 28% overall risk of perioperative complications.(4,5,6) as experience with fursll has grown, one of interesting topic is the increasing rate of infectious complications associated with fursll. infectious complications rates including fever and sepsis in patients undergoing fursll have been reported to vary from 2% to 28% and from 3% to %5, respectively.(4) however, risk factors of infection after fursll have been investigated by limited number of studies and warrant further investigation.(7,8,9) we, therefore, aimed to iden1department of urology, kecioren training and research hospital, ankara, turkey 2department of infectious diseases and clinical microbiology, ankara university school of medicine, ankara, turkey. 3department of urology, ondokuz mayis university school of medicine, samsun, turkey. 4department of urology, gazi university school of medicine, ankara, turkey. *correspondence: department of urology, kecioren training and research hospital, 06380, ankara, turkey, phone: +90 530-926-9784, e-mail: senocakcagri2010@gmail.com. received may 2017 & accepted september 2017 tify possible risk factors for postoperative infection after fursll in this study. we also aimed to evaluate the prevalence and resistance patterns of pathogens isolated from preoperative urine cultures and appropriate empiric therapy for postoperative infections of patients undergoing fursll. materials and methods study design and population after institutional review board approval, we retrospectively analyzed the collected data from 506 consecutive patients treated with fursll for either intrarenal or proximal ureteral stones between january 2010 and october 2014 at the urology department of ankara kecioren training and research hospital. patients with missing data for the clinical baseline records, or without a preoperative urine sample sent for culture, or with postoperative fever due to other potential source of infection were excluded from the study. kidney-ureendourology and stone diseases 158 ter-bladder radiography with or without the use of a contrast medium and ultrasonography/noncontrast-enhanced computed tomography was used for preoperative imaging variables. four urological surgeons experienced with fursll performed the procedures with modifications according to each surgeon’s preferences and experience. a 7.5 f storz flex-x2 was used for flexible urs. a hydrophilic coated ureteral access sheath (9.5/11.5f or 12/14f) was placed under fluoroscopic guidance to maintain low intrarenal pressure and to facilitate extraction of stone fragments. a manual irrigation pump was used to improve visualization during surgery. postoperatively, a double-j stent was placed based at the surgeon’s discretion and removed within two to three weeks. midstream clean catch urine specimens were obtained for each patient. preoperatively, a 7-day appropriate course of antibiotic therapy based on the culture sensitivity was given to the patients with positive preoperative urine culture, and fursll procedures were performed only after achieving a negative urine culture just prior to the procedure. as for intraoperative antibiotic prophylaxis to minimize the potential infectious complications following fursll, a single dose of first generation parenteral cephalosporin antibiotic (cefazolin) was given to the patients with negative preoperative urine cultures during anesthetic induction, while among those with positive preoperative urine cultures, a dose of antibiotic was given intraoperatively based on preoperative antimicrobial susceptibilities. postoperative urine analysis and culture within 30 days following surgery was collected in the presence of fever (≥ 38 °c) or sirs. chest radiography, blood tests and physical examination were performed postoperatively on patients with fever to help rule-out other possible causes of infection. outcome assessment a positive preoperative urine culture was defined as ≥ 50,000 cfu/ml of a pathogenic organism within 30 days before index procedure. the preoperative urine specimen was assumed to be contaminated where there was a mixed culture (growth of more than one isolate), and then a repeat culture was obtained. multidrug resisttable 1. perioperative characteristics of total cohort and by postoperative infectious complications variable total cohort (n = 492) cases (n = 42, 8.5%) controls (n = 450, 91.5%) p age in years, median (iqr) 42 (32-54) 39.5 (25-58) 42 (32-54) 0.333 gender, female, % 43.7 54.7 42.6 0.131 body-mass index, kg/m2 (iqr) 26.4 (24.4-28.2) 26.3 (24-29.5) 26.4 (24.5-28.1) 0.943 diabetes mellitus, % 11.8 21.4 10.9 0.043 stone size, mm, median (iqr) 13 (10-16) 15 (12-21) 12 (10-15) < 0.001 stone number, median (iqr) 1 (1-2) 1 (1-2) 1 (1-2) 0.536 stone location, % 0.656 upper ureteral 18.0 12.0 18.6 renal pelvis 39.2 40.5 39.1 inferior calyx 26.0 26.2 26.0 upper/mid calyx 16.6 21.4 16.2 history of previous stone treatment, % 0.392 none 49.4 64.2 48.0 extracorporeal shock wave lithotripsy 35.5 28.5 36.2 ureterorenoscopy 4.7 2.3 4.9 percutaneous nephrolithotomy 1.4 1.5 open surgery 2.5 2.7 multiple modalities 6.5 4.7 6.7 renal anatomical anomaly, % 4.7 7.1 4.4 0.428 hydronephrosis, % 0.600 none or mild 70.7 64.3 71.3 moderate or severe 29.3 35.7 28.7 preoperative double-j stent, % 22.3 21.4 22.4 0.880 positive preoperative non-mdr urine culture, % 8.1 16.7 7.3 0.034 positive preoperative mdr urine culture, % 3.9 12.0 3.1 0.005 operation time, minutes, median (iqr) 57 (46-70.5) 65 (55-95) 56 (46-70) 0.001 use of ureteral access sheath, % 0.422 none 6.9 9.5 6.6 9.5/11.5f 66.4 71.4 66.0 12/14f 26.6 19.0 27.3 postoperative double-j stent, % 74.8 76.2 74.7 0.828 hospitalization time, days, median (iqr) 1 (1-2) 5 (4-7) 1 (1-2) < 0.001 presence of residual fragments, % 18.7 19.0 18.7 0.952 abbreviations: iqr, interquartile range; mdr, multidrug resistant. isolated pathogens all isolates n=59 mdr isolates n=19 non-mdr isolates n=40 p gram-negative, % escherichia coli 50.8 42.0 55.0 0.355 klebsiella pneumoniae 15.2 22.2 12.5 0.580 pseudomonas aeruginosa 8.5 10.5 7.5 0.697 proteus mirabilis 3.4 5.5 2.5 0.823 gram-positive, % enterococcus species 17.0 21.0 15.0 0.563 staphylococcus species 5.0 0.0 7.5 0.472 table 2. distribution of pathogens with and without multidrug resistance (mdr) isolated from 59 positive preoperative urine culturesa infection after rirs-senocak et al. vol 15 no 04 july-august 2018 159 ance (mdr) gram-negative pathogens in urine cultures were defined as resistance to at least one antibiotic in at least three of the following antibiotic categories (antibiotics used in the analysis given in parenthesis): cephalosporins (ceftriaxone), fluoroquinolones (levofloxacin), penicillins with beta-lactamase inhibitors (amoxicillin/ clavulanate), aminoglycosides (gentamicin or amikacin), carbapenems (meropenem), trimethoprim-sulfamethoxazole, and nitrofurantoin.(10) mdr analysis of gram-positive pathogens with the same criteria was performed for four antibiotic categories: aminoglycosides (gentamycin), fluoroquinolones (levofloxacin), penicillins (ampicillin), glycopeptides (vancomycin). positive mdr culture was defined as any evidence of mdr pathogens in positive urine cultures. positive urine cultures that did not meet the criteria were considered to be positive non-mdr cultures. stone size was determined by measuring the longest diameter on preoperative radiologic investigation; in cases of multiple calculi, stone size was defined as the sum of the longest diameter of each stone. hydronephrosis was graded as either none/mild or moderate/severe using the society of fetal urology grading system.(11) the operative time was calculated from the time of ureteroscope insertion to the end of placing a double-j stent. sirs was defined as the occurrence of at least two of the following criteria: fever ≥ 38 °c or hypothermia ≤ 36.0°c, tachycardia > 90 beats/minute, tachypnea > 20 breaths/minute, leucocytosis > 12,000/µl or leucopoenia < 4,000 µl and sepsis was defined as culture-proven postoperative urinary tract infection together with sirs.(12) in the present study, we used kidney-ureter-bladder radiography and ultrasonography that was performed on the second postoperative day for the assessment of residual fragments (3 mm <). the main outcome of the present study was postoperative infectious complication and was defined as fever (≥ 38 °c) with pyuria (≥ 10 white blood cells per high power field), or sirs, or sepsis. results of concern included the prevalence and resistance patterns of pathogens in urine cultures of patients undergoing fursll and risk factors for postoperative infectious complications. statistical analysis perioperative characteristics between patients with and without postoperative infectious complications were compared using univariate mann-whitney test, chisquare or fisher’s exact test. all significant factors associated with postoperative infectious complications following fursll on univariate analyses (variables with p < .05) were then included in a multivariate logistic regression analysis with a backward stepwise approach to select the significant ones. stata version 11.0 (statacorp, usa) was used for analysis with a two-sided alpha level of < 0.05 being considered statistically significant. results the collected data included patient, stone, and treatment parameters. data also included bacterial species and bacterial resistance to antibiotics used to treat preoperative urine cultures. 4 patients were excluded from the study due to having postoperative fever because of chest infection (n = 2) and tonsillitis (n = 2). we also excluded patients due to missing data on preoperative urine culture (n = 7) and body-mass index (bmi, n = 3). after these exclusions, we obtained 492 patients with complete data to identify predictors of postoperative infectious complications following fursll. of the included 492 patients, 42 patients had the postoperative infectious complications (case group) and other 450 patients did not develop postoperative infection (control group). cohort characteristics of patients with vs. without postoperative infectious complications are shown in table 1. patients in the case group had larger median stone size compared to patients in the control group, though this difference was small and median stone size for both groups was 13mm (p < .001). preoperative double-j stents (n = 110, 22.3% of 492) were inserted in 2 patients with evidence of pyonephrosis, in 3 patients with severe hydronephrosis, and were inserted in the remaining majority (n = 105) to allow for passive ureteral dilation to facilitate the passage of the ureteral access sheath. postoperative double-j stents were inserted for the purpose of facilitating passage of stone fragments in 307 cases (62.4% of 492), while double-j stents were required in all cases with intraoperative complications (n = 61, 12.4% of 492) including mucosal injury of ureter (n = 26, 5.28%), ureteral perforation (n = 4, 0.81%), and mucosal bleeding (n = 31, 6.3%). patients in the case group were more likely to be having a positive preoperative non-mdr urine culture (16.7 vs. 7.3%, p = .034) and mdr urine culture (12 vs. 3.1%, p = .005). overall, 42 (8.5%) patients had postoperative infectious complications after fursll. of the 42 patients with an infectious complication, 14 (33.3%) had fever with pyuria, 23 (54.8%) had sirs, and 5 (11.9%) had septable 3. antibiotic resistance rates among gram-negative and gram-positive pathogens with and without multidrug resistance (mdr) isolated from 59 positive preoperative urine cultures antibiotic resistance rates among gram-negative pathogens antibiotics all isolates n = 46 mdr isolates n = 15 non-mdr isolates n = 31 p amoxicillin-clavulanate 39.1% 80.0% 19.3% < 0.001 ceftriaxone 21.7% 60.0% 3.2% < 0.001 meropenem 0.0% 0.0% 0.0% levofloxacin 24.0% 53.3% 9.7% 0.001 amikacin 2.2% 6.7% 0.0% 0.146 gentamicin 28.3% 66.7% 9.7% < 0.001 trimethoprim-sulfamethoxazole 47.8% 86.7% 29.0% < 0.001 nitrofurantoin 15.2% 33.3% 6.4% 0.017 antibiotic resistance rates among gram positive pathogens antibiotics all isolates n = 13 mdr isolates n = 4 non-mdr isolates n = 9 p ampicillin 38.4% 100.0% 11.1% 0.002 gentamicin 46.1% 100.0% 22.2% 0.009 levofloxacin 38.4 % 100.0% 11.1% 0.002 vancomycin 0.0% 0.0% 0.0% infection after rirs-senocak et al. endourology and stone diseases 160 sis. 59 (12%) of 492 patients had a positive preoperative urine culture. 19 (32.2% of 59) patients had mdr isolates recovered from positive preoperative urine cultures. the distribution of the pathogens in patients with and without mdr preoperative urine cultures is shown in table 2. we did not identify any fungal isolates from preoperative urine cultures. gram-negative pathogens were isolated more often than gram-positive ones in the preoperative urine cultures and the majority of pathogens were escherichia coli and enterococcus species. antibiotic resistance rates among gram-negative pathogens with mdr from positive preoperative urine cultures were significantly greater than those with non-mdr, while all of the isolates were carbapenems susceptible and 97.8% of the isolates were susceptible to amikacin (table 3). postoperative infectious complications after fursll were seen in 30 of 433 (6.9%) patients with negative preoperative urine cultures, 7 of 40 (17.5%) patients with preoperative non-mdr urine cultures, and 5of 19 (26%) patients with preoperative mdr urine cultures. specifically, 75% (9/12 cultures) of the positive preoperative urine cultures of patients in whom a postoperative infectious complication developed consisted of gram-negative pathogens. of the 42 patients with an infectious complication, 12 (28.6%) had a positive postoperative urine culture. in the 12 patients with a positive postoperative urine culture, 7 patients had a positive preoperative urine culture while 3 of 7 were positive for different pathogens. 5 patients experienced sepsis. patients with sepsis were treated on an intensive care unit in collaboration with the infectious diseases specialists. on multivariate analysis positive preoperative mdr urine culture (or: 4.75, 95% ci: 1.55-14.56; p=.006) was found to be significant with the dependent variable as the postoperative infectious complications after controlling for diabetes mellitus, stone size, operative time and positive preoperative non-mdr urine culture (table 4). discussion we examined a single-institution contemporary series of patients undergoing fursll for the management of intrarenal and upper ureteral calculi. infectious complications rate after fursll in the current study was 8.5%, which is in line with the previously reported rates ranging from 2% to 28%.(4) the prevalence of overall mdr pathogens in positive urine cultures prior to fursll was 32.2%. high rates of mdr pathogens in patients with urinary tract infections have also been reported in numerous studies worldwide.(13) unsuitable use of broad-spectrum antibiotics and unnecessary prescription of antibiotics may be responsible for these high rates. in univariate analyses, positive preoperative non-mdr and mdr urine cultures were both associated with higher risk of postoperative infectious complications. after adjusting for clinical and intraoperative significant variables based on multivariate analysis, there was a statistically non-significant but strong trend for association of positive preoperative non-mdr urine cultures with higher risk of postoperative infectious complications. one might think that it would be easy to be accepted that positive preoperative urine cultures itself is a risk factor of postoperative infection after fursll whether the bacteria are mdr or non-mdr. in accordance with this point, very recent published studies demonstrated that a positive preoperative urine culture was the most powerful predictor of postoperative infection in patients undergoing fursll.(8,9) furthermore, we identified positive preoperative mdr urine culture as independent risk factor associated with a 4.75-fold increased risk of postoperative infectious complication after fursll in patients suffering from stone disease despite receiving appropriate preoperative antibiotic therapy. another article highlighting the importance of positive preoperative mdr urine culture in a subset of patients with infectious complications after endoscopic surgery for renal stone disease, pcnl, was recently published by patel et al.(14) their finding that a positive preoperative mdr culture before pcnl increases the risk of development a postoperative infectious complication by 4.89-fold therefore has strong clinical importance and warrants extra caution to postoperative care by urologists. these relevant findings are particularly important because infections caused by mdr pathogens require timely and appropriate treatments including both empirical and definitive antibiotic therapy to reduce postoperative morbidity and costs outcomes. we found that 12 patients with positive preoperative urine cultures still developed postoperative infection complications despite receiving appropriate preoperative antibiotic therapy. we also demonstrated that out of 12 patients with postoperative infectious complications, 3 patients had discordant culture results between positive preoperative and positive postoperative urine cultures. these findings correspond with those of margel et al.(15) who found that 19 of 75 (25%) pcnl-treated patients with a positive stone culture had sterile urine, and the sensitivity of urine culture to predict stone colonization was only 30%. furthermore, antibiotic prophylaxis used in this study failed to eliminate the risk of infection after fursll in 30 of 433 (6.9%) patients with negative preoperative urine cultures. indeed, martov et al.(16) showed in the clinical research office of the endourological society (croes) ureteroscopy (urs) global study that in patients with a negative baseline urine culture undergoing urs for ureteral stones (n = 1141) or renal stones (n = 184), rates of postoperative table 4. multivariate logistic regression analysis of variables associated with postoperative infectious complications after flexible uretero-renoscopy with laser lithotripsy or 95% ci p multivariate analysis diabetes mellitus 1.99 0.85-4.64 0.110 stone size 1.03 0.96-1.10 0.331 operation time 1.01 0.99-1.03 0.094 positive preoperative non-mdr urine culture 2.27 0.88-5.86 0.088 positive preoperative mdr urine culture 4.75 1.55-14.56 0.006 abbreviations: mdr, multidrug resistant; or, odds ratio; ci, confidence interval. infection after rirs-senocak et al. vol 15 no 04 july-august 2018 161 urinary tract infection and fever were not reduced by preoperative antibiotic prophylaxis. possible explanations for these findings might be that cultures obtained from bladder may not accurately reflect the pathogens responsible for the infection found in upper urinary tract urine or in infected stones and antibiotics may not be able to penetrate properly into the infected stone.(17) we found that gram-negative pathogens were isolated more often than gram-positive pathogens among preoperative urine cultures of patients with postoperative infectious complications. similar results in preoperative urine cultures were found by gutierrez et al.,(18) examining 5,354 patients undergoing pcnl. they demonstrated that the prevalence of fever among pcnl-treated patients with a positive preoperative urine culture varied markedly depending on which pathogens were found in their urine cultures. these findings suggest that the risk of infection depends on the predominant pathogens identified in urine cultures of patients undergoing endourological procedures for the treatment of nephrolithiasis including fursll and pcnl. one of the significant findings of our study is the importance of identifying patients with risk factors for infection after fursll in order to select empirical antibiotic therapy. we found that both cephalosporins and fluoroquinolones, types of antibiotics that are commonly used for treating urinary tract infections, cannot be recommended for the empirical treatment of postoperative infections after fursll based on the findings from our local resistance data given the high overall resistance rates among gram-negative pathogens (nearly 25%). furthermore, all tested antibiotics in this study, except carbapenems and amikacin, were not suitable for empiric treatment among patients with a postoperative infectious complication, given that in our study we observed a nearly 5 times risk of postoperative infection in patients with a positive preoperative mdr urine culture and 79% of positive preoperative mdr urine culture consisted of gram-negative pathogens. it is well established that carbapenems has a favorable and acceptable safety profile.(19) amikacin use, however, has been limited due to concerns regarding its toxicity including ototoxicity and nephrotoxicity.(20) our data suggest that choices for empiric antibiotic treatment in patients with postoperative infectious complications should be based on prompt evaluation of common uropathogens relevant to the disease and on local resistance data, given that susceptibility results will take at least 48 hours after a urine culture is reported as positive. although the choice of empiric initial antibiotic therapy for patients with infectious complication will be very much dependent on preoperative cultures and on local resistance data, carbapenems may be appropriate empiric therapy while awaiting the urine culture result in the treatment of postoperative infectious complications for fursll-treated patients. limitations our study has some built-in limitations. first, this is a retrospective observational study in a subset of patients who received fursll. second, our recommendation for empiric antibiotic treatment (carbapenems) in patients with infectious complications after fursll is based on local resistance patterns using our institutional antibiogram that may not be generalizable to other centers where antibiotic resistance patterns may differ. third, no complete data on stone composition, stone culture and upper urinary tract urine culture were available. lastly, we did not consider the possible effect of intraoperative irrigation pressure on postoperative infectious complications, although we observed no difference between patients with and without postoperative infectious complications in ureteral access sheath use which may be helpful for maintaining low intrarenal pressure. conclusions we found that positive preoperative mdr urine culture is a significant risk factor for infectious complications after fursll. our findings point to the need for further research on assessment of risk factors for mdr infections to reduce the rate of postoperative infectious complications. the necessity for well-designed prospective studies is therefore urgent to answer clinical questions of how to treat and for how long to mitigate the infectious complications in the setting of positive preoperative mdr urine culture, such as dosing and duration of antibiotic therapy and the possible benefit of antibiotic combinations versus monotherapy. conflict of interest the authors have no conflict of interest or financial disclosures to declare. references 1. srisubat a, potisat s, lojanapiwat b, setthawong v, laopaiboon m. extracorporeal shock wave lithotripsy (eswl) versus percutaneous nephrolithotomy (pcnl) or retrograde intrarenal surgery (rirs) for kidney stones. cochrane database syst rev. 2014; cd007044. 2. hyams es, monga m, pearle ms et al. a prospective, multi-institutional study of flexible ureteroscopy for proximal ureteral stones smaller than 2 cm. j urol. 2015; 193: 165-169. 3. turk c, knoll t, petrik a, et al. urolithiasis, 2016; guideline / european association of urology. url: http://uroweb.org/guideline/ urolithiasis/ 4. de s, autorino r, kim fj et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015; 67: 125-137. 5. javanmard b, kashi ah, mazloomfard mm, ansari jafari a, arefanian s. retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j. 2016; 13: 2823-2828. 6. kilicarslan h, kaynak y, kordan y, et al. unfavorable anatomical factors influencing the success of retrograde intrarenal surgery for lower pole renal calculi. urol j. 2015; 12: 2065-2068. 7. zhong w, leto g, wang l, zeng g. systemic inflammatory response syndrome after flexible ureteroscopic lithotripsy: a study of risk factors. j endourol. 2015; 29: 25-28. infection after rirs-senocak et al. endourology and stone diseases 162 8. yusuke uchida, ryoji takazawa, sachi kitayama, toshihiko tsujii. predictive risk factors for systemic inflammatory response syndrome following ureteroscopic laser lithotripsy. urolithiasis. 2017; jul 10. doi: 10.1007/s00240-017-1000-3. [epub ahead of print]. 9. blackmur jp, maitra nu, marri rr, housami f, malki m, mcihenny c. analysis of factors' association with risk of postoperative urosepsis in patients undergoing ureteroscopy for treatment of stone disease. j endourol. 2016; 30: 963-969. 10. magiorakos ap, srinivasan a, carey rb, et al. multidrug-resistant, extensively drugresistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. clin microbiol infect. 2012; 18: 268-281. 11. fernbach sk, maizels m, conway jj. ultrasound grading of hydronephrosis: introduction to the system used by the society for fetal urology. pediatr radiol. 1993; 23: 478-480. 12. levy mm, fink mp, marshall jc, et al. 2001 sccm/esicm/accp/ats/sis international sepsis definitions conference. crit care med. 2003; 31: 1250-1256. 13. zowawi hm, harris pn, roberts mj, et al. the emerging threat of multidrug-resistant gram-negative bacteria in urology. nat rev urol. 2015; 12: 570-584. 14. patel n, shi w, liss m, et al. multidrug resistant bacteriuria before percutaneous nephrolithotomy predicts for postoperative infectious complications. j endourol. 2015; 29: 531-536. 15. margel d, ehrlich y, brown n, lask d, livne pm, lifshitz da. clinical implication of routine stone culture in percutaneous nephrolithotomy--a prospective study. urology. 2006; 67: 26-29. 16. martov a, gravas s, etemadian m, et al. postoperative infection rates in patients with a negative baseline urine culture undergoing ureteroscopic stone removal: a matched casecontrol analysis on antibiotic prophylaxis from the croes urs global study. j endourol. 2015; 29: 171-180. 17. korets r, graversen ja, kates m, mues ac, gupta m. post-percutaneous nephrolithotomy systemic inflammatory response: a prospective analysis of preoperative urine, renal pelvic urine and stone cultures. j urol. 2011; 186: 1899-1903. 18. gutierrez j, smith a, geavlete p, et al. urinary tract infections and post-operative fever in percutaneous nephrolithotomy. world j urol. 2013; 31: 1135-1140. 19. linden p. safety profile of meropenem: an updated review of over 6,000 patients treated with meropenem. drug saf. 2007; 30: 657668. 20. peloquin ca, berning se, nitta at, et al. aminoglycoside toxicity: daily versus thriceweekly dosing for treatment of mycobacterial diseases. clin infect dis. 2004; 38: 15381544. infection after rirs-senocak et al. vol 15 no 04 july-august 2018 163 association between marital status and prognosis in patients with prostate cancer: a meta-analysis of observational studies zhenlang guo1, chiming gu1, siyi li1, shu gan1, yuan li1, songtao xiang1, leiliang gong2, shusheng wang1* purpose: the impact of marital status on the prognosis amongst patients diagnosed with prostate cancer remains controversial. thus, a meta-analysis was performed to determine whether marital status can influence the prognosis in patients with prostate cancer. materials and methods: literature search of the medline, psycinfo, embase and cochrane library databases was conducted to identify eligible studies published before april 2020. multivariate adjusted risk estimates and corresponding 95% confidence intervals (cis) were extracted and calculated using the random effects model. results: a total of 11 observational studies comprising 1,457,799 patients diagnosed with prostate cancer were identified. results indicated that unmarried status (separated, divorced, widowed or never married) was associated with an increased risk of all-cause mortality (hazard ratio, hr = 1.39, 95% ci: 1.30–1.50; p < .001; i2 = 92.2%) compared with married status, especially for divorced and never-married patients. similarly, being unmarried had an elevated risk of cancer-specific mortality (hr = 1.29, 95% ci: 1.17–1.41; p < .001; i2 = 82.5%) in patients with prostate cancer. a significant difference was also observed between unmarried status and shorter overall survival (hr = 1.37, 95% ci: 1.20–1.56; p < .001; i2 = 94.5%). conclusion: results demonstrated that unmarried status is associated with a worse prognosis regarding mortality and survival in patients diagnosed with prostate cancer, particularly in divorced and never-married patients. hence, further research should explore the potential mechanisms which can benefit the development of novel, more personalized management methods for unmarried patients with prostate cancer. keywords: marital status; prostate cancer; prognosis; meta-analysis introduction prostate cancer has become a major health problem and a leading cause of morbidity and mortality in men worldwide.(1,2) in the united states in 2018, patients newly diagnosed with prostate cancer reached 164,690, while 26,730 patients with prostate cancer died despite the high overall survival (os) for the disease.(3) however, only a few risk factors for prostate cancer have been identified, including age, family history, race, and certain genetic polymorphisms, thereby limiting the prevention of prostate cancer.(4,5) interestingly, some research demonstrated that being unmarried (never married, separated, widowed or divorced) is associated with shorter survival and higher mortality for several malignancies compared with married status.(6–10) nonetheless, the impact of marital status on the prognosis amongst patients diagnosed with prostate cancer is still inconclusive. several studies revealed that unmarried men have consistently been found to be associated with worse prognosis in patients with prostate cancer,(11,12) whereas other studies reported conflicting results.(13,14) spe1department of urology, the second affiliated hospital of guangzhou university of chinese medicine, guangzhou, china. 2department of mechanical engineering, national university of singapore, kent ridge, singapore. *correspondence: department of urology, the second affiliated hospital of guangzhou university of chinese medicine , guangzhou, 510120, p.r.china. tel: +86 13512704335. e-mail: shushengwanggzy@163.com. received april 2020 & accepted november 2020 cifically, nepple et al.(13) reported that never-married men diagnosed with prostate cancer have an elevated risk of all-cause mortality (acm) compared with those who were married, but this significant association was not observed amongst divorced or widowed men with prostate cancer. in light of these different findings reported in previous literature, we performed a systematic review and meta-analysis to explore how married status influences the prognosis (survival, mortality, etc.) in patients with any form of diagnosed prostate cancer. material and methods this systematic review and meta-analysis was performed in accordance with the cochrane collaboration criterion.(15) our study adhered to the preferred reporting items for systematic reviews and meta-analyses statement guidelines(16) and meta-analysis of observational studies in epidemiology (moose) guidelines. (17) search strategy literature search of the medline (via pubmed), psyurology journal/vol 18 no. 4/ july-august 2021/ pp. 371-379. [doi: 10.22037/uj.v16i7.6197] review cinfo, embase and cochrane library databases was conducted to identify eligible studies from database inception up to april 2020 using a combination of medical subject headings (mesh) and non-mesh terms, including ‘marital status’, ‘marriage’, ‘married’, ‘unmarried’, ‘divorced’ or ‘widowed’ and ‘prostate cancer’, ‘prostate carcinoma’, ‘prostate tumor’ or ‘prostate neoplasms’ and ‘prognosis’, ‘survival’ or ‘mortality’, with no language, region or publication status restriction. furthermore, important citation database such as scopus was searched, and manual searches of reference lists were also performed in relevant original and review articles for additional eligible studies. the main search was carried out independently by the senior investigator (zl. guo). disagreement was resolved by consulting another investigator (ss. wang) who was not involved in the initial search procedure. eligibility criteria all published eligible studies were included if they met the following inclusion criteria; (1) men diagnosed with any stage of prostate cancer only; (2) married stamarital status and prognosis in prostate cancer-guo et al. figure 1. flow diagram of literature searches according to the preferred reporting items for systematic reviews and meta-analyses statement. figure 2. marital status and all-cause mortality in patients with prostate cancer. abbreviations: ci, confidence interval; hr, hazard ratio vol 18 no 4 july-august 2021 372 tus is defined as married and/or living with a partner or family, while unmarried status is defined as widowed, divorced or living alone; (3) original trials regarding the impact of marital status on prognosis (survival or mortality) in patients with any form of diagnosed prostate cancer; (4) studies using an observational study design (i.e. prospective or retrospective cohort, cross-sectional or case-control study); and (5) studies reporting sufficient data on risk estimates (hazard ratio, hr; odds ratio, or; relative risk, rr) with associated 95% confidence intervals (cis) or sufficient raw data for calculation. for studies from the same population, only the largest studies with the longest follow-up period were retained. in addition, certain articles, such as case series, case reports, and review articles were excluded. disagreement was resolved through discussion amongst the investigators. data extraction and methodological quality assessment two investigators (zl. guo and cm. gu) independently extracted data from the eligible studies by using an predefined data extraction form. the following data were extracted: first author, study design, country, bareview 373 figure 3. marital status and cancer-specific mortality in patients with prostate cancer. abbreviations: ci, confidence interval; hr, hazard ratio figure 4. marital status and overall survival in patients with prostate cancer. abbreviations: ci, confidence interval; hr, hazard ratio marital status and prognosis in prostate cancer-guo et al. sic characteristics (i.e. sample size, age, and follow-up), definitive therapy (i.e. radical prostatectomy, androgen deprivation therapy, and radiation therapy), marital status, adjusted confounders, and risk estimates (hr, or or rr) with associated 95% cis or sufficient raw data. if the information reported in the eligible studies were insufficient, we contacted the primary authors to obtain and verify the data. first author study country total participants age, y, follow-up, y, treatments marital outcomes adjustments year design (married, %) mean (range) mean (range) status abdollah f retrousa 163,697 (83.1%) 63 (35-90) na rp married csm age, race, 2011. (21) spective sdw acm socioeconomic status, population never married tumor grade, based cohort and year of surgery aizer aa retrousa 190,648 (76.7%) 63 ± (sd: 12) 3.1 ± (0.1-5.9) mitoxmarried csm demographic factors 2013. (22) spective antrone unmarried (age, race, income, population education, and urban based cohort or rural residence), tumor stage, nodal stage, and whether definitive treatment administered du kl 2012. (23) prospective usa 3,570 (76%) 69.2 (41-48) na radiation married os age, clinical stage, cohort therapy sdw karnofsky performance score (kps), gleason score, prostate specific antigen (psa), biologic effective dose (bed), and type of treatment received gomez sl 2016. (11) retrousa 178,586 (75.4%) na na na married acm cancer site, spective unmarried race/ethnicity, population and treatment based cohort huang tb 2018. (24) retrousa 95,846 (81.6%) na 6.5 ± (sd: 1.9) rp married os age, ethnicity, spective sdw css grade, stage, population gleason scores, based cohort and sequence number khan s 2019. (12) retrousa 3,579 (86.8%) 60.4 na rp married acm age, race, comorbidity spective unmarried status, psa, and cohort csm biopsy gleason grade knipper s 2019. (25) retrousa 433,197 (75.4%) 65.4 (59-71) na rp external married csm prostatic-specific spective beam brachy unmarried antigen value, population therapy age at diagnosis, based cohort year of diagnosis, treatment, clinical tumor stage, and race in all groups lai h 1999. (26) retrousa 261,070 (70%) 65.4 ± (sd: 13.6) na na married sdw age, race, spective os and treatment population based cohort nepple kg retrousa 3,596 (86.9%) na na rp married csm psa, clinical stage, 2012. (13) spective divorced acm and biopsy gleason cohort widowed grade, comorbidity, never married ethnicity, age, and marital status at time of treatment schiffmann retrogermany 8,088 (91.1%) 63.5 (35.8–79.8) 4 ± (3.1) rp married acm psa, biopsy gleason j 2015. (14) spective unmarried score, number of biopsy cohort cores taken, number of positive biopsy cores, clinical tumor stage tyson md retrousa 115,922 (78%) na na na married csm age, ajcc stage, 2013. (27) spective single acm tumor grade, and race population divorced based cohort widowed separated table 1. characteristics of the included studies. abbreviations: acm, all-cause mortality; ajcc, american joint committee on cancer; csm, cancer-specific mortality; css, cancer-specific survival; na, not applicable; os, overall survival; sd, standard deviation; sdw, separated/divorced/widowed; rp, radical prostatectomy; y, year. marital status and prognosis in prostate cancer-guo et al. vol 18 no 4 july-august 2021 374 the methodological quality and risk of bias assessment were performed by two investigators according to the newcastle–ottawa scale (nos),(18) which consists of nine items that evaluate the representativeness of included studies. each item was assessed as either ‘unclear’, ‘yes’ or ‘no’, which corresponded to ‘0’, ‘1’ or ‘0’ in accordance with the information reported by the studies. the total score ranged from 0 to 9, and a study was categorised as follows: a score of 8–9 was considered high quality, a score of 6–7 was considered moderate quality, and a score of ≤ 5 was considered low quality. any disagreements were settled through a discussion amongst the authors. statistical analyses in general, the total risk estimates (hr and rr with associated 95% cis) extracted from the included studies were calculated via stata version 15.0 (serial number: 10699393; statacorp wyb). hr and rr with associated 95% cis were calculated through inverse variance using random or fixed effects models. for consistent definitions, hr with associated 95% cis was used as a common measure because marital status and prostate cancer-related survival or mortality were considered as rare events. the differences amongst the various measures of risk estimates could be generally ignored. hence, the rrs extracted from the included studies could be considered approximations of hrs.(19) i2 was used to assess heterogeneity across studies, with i2 values of 0%, 25%, 50% and 75% representing no, low, moderate and high heterogeneity, respectively.(15) specifically, a severe heterogeneity of i2 ≥ 50% warrants the use of random effects models. otherwise, a fixed effects model should be used.(15) statistical significance was set at p < .05. moreover, weight estimation was conducted in the meta-analysis according to the validity or risk of bias for included studies. note that if all the weights are the same then the weighted average is equal to the mean intervention effect. the bigger the weight given to the study, the more it will contribute to the weighted average. the weights are therefore chosen to reflect the amount of information that each study contains. in the presence of heterogeneity, a random-effects meta-analysis weights the studies relatively more equally than a fixed-effect analysis. subgroup analysis based on different treatments was performed to explore the possible origins of heterogeneity. sensitivity analysis could assess the quality and consistency of the results through omitting each study individually. in addition, meta-regression analysis was conducted to explore the possible sources of heterogeneity in several variables, and restricted maximum likelihood was used in the analysis. however, the application of egger(20) and begg–mazumdar(21) tests was limited because of the low number of studies evaluated. results study identification and selection the search process and study selection are described in figure 1. in general, 569 articles were identified through the initial assessment, and 459 articles were retrieved after duplicates were removed. next, 420 articles were removed after title/abstract evaluation from the remaining articles. finally, 39 articles were evaluated on the basis of the full text, and 28 were excluded for the following reasons: no prostate cancer (6 articles), no marital status (4 articles), no prognostic assessment (14 articles), and not sufficient data for extraction (4 articles). therefore, 11 articles(11–14, 22–28)comprising 1,457,799 patients diagnosed with prostate cancer were identified for systematic review and meta-analysis according to the eligibility criteria. study characteristics and methodological quality the basic characteristics of studies included in this systematic review and meta-analysis are described in table 1. these studies (1 prospective cohort(24) and 10 retrospective cohort studies(11–14, 22, 23, 25–28)) were published between 1999 and 2019. there were 10 studies(11–13, 22–28) from the united states and 1 from germany(14). the sample sizes also varied between 3,570 and 433,197 patients with prostate cancer who were treated with various definitive therapies, including radical prostatectomy (rp), radiation therapy, external beam, brachytherapy, and mitoxantrone. the follow-up duration ranged from 3.1 years to 6.5 years. all the included studies reported risk estimates adjusted for confounding factors. overall, the methodological quality and risk bias assessment of the included studies(11–14, 22–28) was performed according to the nos. five articles(14, 22–24, 26) acquired 8 or 9 points and were considered as high quality, eight articles(11–13, 25, 28) acquired 6 or 7 points and were conreview 375 table 2. results of subgroup analyses. overall acm risk studies, n participants,n hr (95% ci) p value p of heterogeneity i2 (%) 6 910,639 1.39 (1.30–1.50) < 0.001 < 0.001 92.2 different definite therapies rp 4 178,960 1.37 (1.25–1.51) < 0.001 0.006 67.2 other therapies 2 178,586 1.42 (1.25–1.60) < 0.001 < 0.001 98.8 overall csm risk studies, n participants,n hr (95% ci) p value p of heterogeneity i2 (%) 6 473,468 1.29 (1.17–1.41) < 0.001 < 0.001 82.5 different definite therapies rp 3 170,872 1.34 (1.05–1.71) 0.017 0.002 73.3 mitoxantrone 1 190,648 1.35 (1.23–1.49) < 0.001 na na rp external beam brachy therapy 1 433,197 1.19 (1.15–1.24) < 0.001 na na other therapies 1 115,922 1.40 (1.33–1.47) < 0.001 na na abbreviations: acm, all-cause mortality; ci, confidence interval; csm, cancer-specific mortality; hr, hazard ratio; na, not applicable; rp, radical prostatectomy. marital status and prognosis in prostate cancer-guo et al. sidered as moderate quality and one study(27) scored 5 points and was considered as low quality. marital status and mortality in patients with prostate cancer six studies(12,13,22,23,26,28) comprising 910,639 patients diagnosed with prostate cancer used the random effects model (figure 2) and demonstrated that unmarried status (separated, divorced, widowed or never married) was associated with an increased risk of acm (hr = 1.39, 95% ci: 1.30–1.50; p < .001; i2 = 92.2%) compared with married status. specifically, both divorced and never-married men had an excess risk of acm (divorced men, hr = 1.45, 95% ci: 1.39–1.51; p < .001; never-married men, hr = 1.46, 95% ci: 1.05–2.03; p < .001), whereas this significant association was not observed amongst widowed patients (hr = 1.34, 95% ci: 0.83–2.16; p = .23) owing to the limited number of studies included. in the subgroup analyses stratified according to different definitive therapies, unmarried men who were treated with rp was associated with a higher risk of acm (hr = 1.37, 95% ci: 1.25–1.51; p < .001) compared with other treatments (table 2). in six studies(11–14,22,28) comprising 473,468 patients diagnosed with prostate cancer, unmarried men had an elevated risk of cancer-specific mortality (csm) (hr = 1.29, 95% ci: 1.17–1.41; p < .001; i2 = 82.5%) than those married men using a random effects model (figure 3). however, this significant association was not observed in never-married (hr = 1.03, 95% ci: 0.91– 1.17; p = .645) or widowed men (hr = 1.13, 95% ci: 0.15–8.36; p = .905), except for divorced patients (hr = 1.32, 95% ci: 1.22–1.43; p < .001) with prostate cancer. when stratified by different treatments, the results were significant and consistent (table 2). the results of meta-regression analyses regarding the heterogeneity amongst studies for acm and csm revealed that definitive therapy (acm, p = .711; csm, p = .798) could not result in heterogeneity amongst the included studies. therefore, the other important confounding factors such as age should be fully explored in future relevant studies. moreover, the adjusted r-squared values from -11.64% to -8.97% because the regression line is worse than using a horizontal line, which indicated that the regressors slightly contributed to the explanation of the response variables (table 3). when any study was omitted in turn, the stability of the results by sensitivity analysis did not show any significant change for acm and csm (table 4). marital status and survival in patients with prostate cancer three studies(24,25,27) comprising 360,486 patients diagnosed with prostate cancer reported risk estimates of overall survival (os) and marital status. a significant difference was observed between unmarried status and shorter os (hr = 1.37, 95% ci: 1.20–1.56; p < .001; i2 = 94.5%) through a random effects model (figure 4). however, meta-regression and subgroup analyses were limited because of the small number of studies included. notably, the results of sensitivity analysis revealed that the stability of meta-analysis had no significant change after each study was omitted in turn. for cancer-specific survival (css), only one retrospective population-based cohort reporting the risk of css and the impact of marital status was included. huang et al.(25) found that divorced and never-married men were significantly associated with shorter css (hr = 1.61, 95% ci: 1.34–1.93; p < .001 and hr = 1.20, 95% ci: 1.00–1.40; p < .001, respectively). by contrast, this association was not observed amongst widowed men (hr = 1.13, 95% ci: 0.81–1.58; p > .05). discussion main findings the systematic review and meta-analysis identified 11 studies comprising 1,457,799 patients diagnosed with prostate cancer regarding the association between marital status and prognosis in prostate cancer. we found that higher mortality and shorter survival in patients diagnosed with prostate cancer are associated with unmarried status, particularly in divorced and never-married patients, than in married men. however, this significant association does not seem to be validated in widowed populations because of the limited number of relevant studies evaluated. note that the risk estimates table 3. results of meta-regression. covariates exp(b) standard error t p > |t| 95% ci r-squared acm treatment 1.40693 1.242582 0.39 0.711 0.174297 11.35678 -8.97% csm treatment 0.7745458 0.7430051 -0.27 0.798 0.0801535 7.484653 -11.64% abbreviations: acm, all-cause mortality; ci, confidence interval; csm, cancer-specific mortality. study omitted hr 95% ci acm abdollah f 2011. [21] 1.42 1.31 1.54 abdollah f 2011. [21] 1.38 1.26 1.50 gomez sl 2016. [11] 1.41 1.30 1.53 khan s 2019. [12] 1.39 1.29 1.50 nepple kg 2012. [13] 1.38 1.28 1.48 nepple kg 2012. [13] 1.40 1.30 1.50 nepple kg 2012. [13] 1.39 1.29 1.50 schiffmann j 2015. [14] 1.40 1.30 1.50 tyson md 2013. [27] 1.36 1.28 1.43 combined 1.39 1.30 1.50 csm aizer aa 2013. [22] 1.27 1.14 1.42 abdollah f 2011. [21] 1.34 1.22 1.47 abdollah f 2011. [21] 1.28 1.14 1.44 khan s 2019. [12] 1.28 1.16 1.40 knipper s 2019. [25] 1.31 1.18 1.46 nepple kg 2012. [13] 1.28 1.17 1.41 nepple kg 2012. [13] 1.29 1.17 1.42 nepple kg 2012. [13] 1.27 1.16 1.39 tyson md 2013. [27] 1.25 1.13 1.38 combined 1.29 1.17 1.41 abbreviations: acm, all-cause mortality; ci, confidence interval; csm, cancer-specific mortality; hr, hazard ratio. table 4. results of sensitivity analyses. marital status and prognosis in prostate cancer-guo et al. vol 18 no 4 july-august 2021 376 extracted from all included articles were based on the adjustment of confounding factors. finally, sensitivity analysis revealed that the stability of the results had no significant change after each study was omitted in turn, and the meta-regression could not identify the potential confounding factors that might affect the level of heterogeneity between studies. most of the included studies revealed that unmarried men have consistently been found to be associated with worse prognosis in patients with prostate cancer, whereas few studies reported conflicting results.(14, 22) a retrospective cohort comprising 8,088 patients with prostate cancer conducted by schiffmann et al.(14) in germany failed to reveal a significant association between unmarried men and acm (hr = 0.80, 95% ci: 0.40–1.70; p = .6). apart from that, abdollah et al.(22) demonstrated that divorced patients were statistically associated with an increased risk of csm (hr = 1.32, 95% ci: 1.20–1.40; p < .001) compared with married men. by contrast, this significant association was not observed in never-married patients (hr = 1.03, 95% ci: 0.91–1.17; p > .05). in the subgroup analyses stratified by different definitive therapies, unmarried men who have been treated with rp were associated with higher risks of acm and csm compared with those who underwent other treatments. however, of all included studies, three did not report definitive treatments for patients with prostate cancer.(11,27,28) comparison with another previous study one systematic review that assessed a similar topic was published by buja et al.(29). several differences between buja et al. and the current work should be noted. firstly, the previous review included only 3 articles that involved 372,412 patients with prostate cancer and marital status. by comparison, our meta-analysis involved 11 studies comprising 1,457,799 patients diagnosed with prostate cancer. with the added statistical power of 8 studies and at least 1,085,387 cases, our meta-analysis, which was inconsistent with the results of buja et al., was the latest and the most comprehensive review to date. secondly, the association between marital status and prognosis (i.e. survival and mortality) was evaluated amongst patients with prostate cancer treated by any therapy in line with the predefined inclusion criteria. sensitivity analysis and meta-regression failed to identify confounding factors that might affect the level of heterogeneity between studies, thereby reinforcing the main findings. implications for clinical practice some researchers recently suggested that the choice of treatment therapy for prostate cancer in married men may be different from that of unmarried men. for married men, their spouse can encourage them to choose a treatment, such as rp or radiation therapy.(30,31) the association between marriage and treatment for prostate cancer has been confirmed and positively correlated. however, researchers did not evaluate survival or mortality as an endpoint.(30) overall, unmarried status represents an important determinant of a worse prognosis. note that the detrimental influence of unmarried status remains consistent when stratified by different therapies. hence, the negative impact of unmarried status on mortality or survival may still be explained through the later diagnosis or treatments in these unmarried patients. lifestyle choice is also an important risk factor for the prognosis between unmarried and married men. for inreview 377 stance, unmarried men are more likely to abuse tobacco or alcohol than do married men.(33) similarly, married men are more likely to avoid unhealthy habits post-diagnosis because of their responsibility to their spouse and family.(33) therefore, the possible mechanisms by which marriage may potentially influence the prognosis in men with prostate cancer can be shown as follows.(1) patients with prostate cancer may receive more psychological support from their spouse or the society after diagnosis, which can improve their likelihood of survival. (2) the spouse may affect the postoperative compliance (such as follow-up) and reception of adjuvant or secondary treatment, such as androgen deprivation therapy and adjuvant or salvage radiation therapy.(3) the lack of physical activity is more common in men with insufficient emotional support, which may be associated with higher mortality(34–39). nevertheless, our understanding on the association between marital status and different stages of prostate cancer remains unclear because of the lack of studies that examine such a relationship. thus, further research is warranted to investigate the personalised intervention and management methods for unmarried patients with prostate cancer. this systematic review and meta-analysis demonstrated several crucial strengths in multiple ways. firstly, our study comprehensively investigated the association between marital status and prognosis amongst patients with prostate cancer, and subgroup analyses stratified according to definitive therapy were conducted to determine whether this variable moderated such an association and the level of heterogeneity between the studies. secondly, multivariate-adjusted risk estimates were applied to minimise other relevant risk factors that might affect the overall results. finally, sensitivity analysis and meta-regression validated the rationality and reliability of the results for our study. several limitations of this study should be noted. firstly, most of the studies used retrospective cohort design, which has the disadvantages of missing data and risk of bias. secondly, the number of articles included in this study was limited, especially in the subgroup, which may lead to unreliable results and might not reflect the comprehensiveness of the overall results. lastly, significant heterogeneity was observed and the random effects model was applied in the pooled analysis. however, subgroup analysis and meta-regression analyses failed to explore the potential factors leading to significant heterogeneity. therefore, other important factors should be adequately studied in further high-quality researches regarding this topic. conclusions existing evidence indicates that unmarried status is associated with a worse prognosis regarding mortality and survival in patients diagnosed with prostate cancer, particularly in divorced and never-married patients. hence, further research should explore the potential mechanisms which can benefit the development of novel, more personalised management methods for unmarried patients with prostate cancer, who was considered as representatives of high-risk groups. acknowledgements this study was supported by grants from the science and technology research project of guangdong provincial hospital of chinese medicine (no. yn2019ml05). marital status and prognosis in prostate cancer-guo et al. vol 18 no 4 july-august 2021 378 references 1. ferlay j, shin hr, bray f, forman d, mathers c, parkin dm. estimates of worldwide burden of 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bl, kim fj, steiner jf. marriage and ethnicity predict treatment in localized prostate carcinoma. cancer. 2005;103:1819–25. marital status and prognosis in prostate cancer-guo et al. 31. denberg td, glodé lm, steiner jf, et al. trends and predictors of aggressive therapy for clinical locally advanced prostate carcinoma. bju int. 2006;98:335–40. 32. rosengren a, wedel h, wilhelmsen l. marital status and mortality in middle-aged swedish men. am j epidemiol. 1989;129:54–64. 33. umberson d. gender, marital status and the social control of health behavior. soc sci med. 1992;34:907–17. 34. watt rg, heilmann a, sabbah w, et al. social relationships and health related behaviors among older us adults. bmc public health. 2014;14:533. 35. o'shaughnessy pk, laws ta, esterman aj. the prostate cancer journey: results of an online survey of men and their partners. cancer nurs. 2015;38:e1–e12. 36. bellardita l, rancati t, alvisi mf, et al. predictors of health-related quality of life and adjustment to prostate cancer during active surveillance. eur urol. 2013;64:30–6. 37. chamie k, kwan l, connor se, zavala m, labo j, litwin ms. the impact of social networks and partnership status on treatment choice in men with localized prostate cancer. bju int. 2012;109:1006–12. 38. forsythe lp, alfano cm, kent ee, et al. social support, self-efficacy for decision-making, and follow-up care use in long-term cancer survivors. psycho-oncology. 2014;23:788–96. 39. holt-lunstad j, smith tb, layton jb. social relationships and mortality risk: a metaanalytic review. plos med. 2010;7:e1000316. marital status and prognosis in prostate cancer-guo et al. review 379 discrimination of patients with prostate cancer from healthy persons using a set of single nucleotide polymorphisms mir davood omrani1, hossein mohammad-rahimi2, abbas basiri1, milad fallahian3, rezvan noroozi4, mohammad taheri5*, soudeh ghafouri-fard6** purpose: prostate cancer is the second cancer diagnosed in males. it accounts for about 4% of cancer-related mortality in men. several genetic polymorphisms in different genes have been identified that alter the risk of this kind of malignancy. materials and methods: we used the random forest (rf) algorithm for prediction of prostate cancer risk in iranian population using 13 different single nucleotide polymorphisms (snps) in four genes (anril, hotair, il-6 and il-8). the samples were divided into a training set (n=320) and a test set (n=80) to evaluate the generalization power for training algorithm. for hyper-parameters tuning, we used randomized search with 5-fold cross-validation for the following hyper-parameters: (1) number of trees or estimators in the forest (set from 3 to 500); (2) the maximum number of leaf nodes (set from 2 to 32); (3) the maximum number of features used for the best split (set from 5 to 13); and (4) using bootstrap samples in the trees building (true or false). accuracy, sensitivity, specificity, and f1-score in both training and test sets were reported. results: the most important snp was anril-rs1333048: a/a (gini index= 0.096) followed by anril-rs10757278: g/g (gini index= 0.059). training dataset outcomes were as follow: accuracy: 0.896, sensitivity: 0.85, specificity: 0.944 and f1 score: 0.891. test dataset outcomes were as follow: accuracy: 0.787, sensitivity: 0.775, specificity: 0.800 and f1 score: 0.784. the auc scores were 0.966 and 0.841 for training and test datasets, respectively. conclusion: the proposed panels of snps can predict risk of prostate cancer in iranian population with appropriate accuracy. keywords: prostate cancer, single nucleotide polymorphism, il-8, hotair, anril introduction prostate cancer ranks second among the diagnosed cancer in males. it accounts for about 4% of cancer-related mortality in men(1). a comprehensive study in iranian patients has shown that 97% of all cases have been adenocarcinoma. the other defined pathologies have been malignant carcinoma and transitional cell carcinoma(2). at early phases of cancer development, prostate cancer usually does not have any symptoms and progresses in an indolent manner, needing minimal or even no therapeutic intervention. during its course, it can cause difficult urination, increased frequency or urgency in urination, nocturia and urinary retention and back pain in advanced stages, the latter being caused by metastasis(3). genome wide association studies (gwas) conducted in different populations have identified tens 1urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 2dental research center, research institute of dental sciences, shahid beheshti university of medical sciences, tehran, iran. 3faculty of civil engineering, amirkabir university of technology, tehran, iran. 4malopolska centre of biotechnology, jagiellonian university, kraków, poland. 5skull base research center, loghman hakim hospital, shahid beheshti university of medical sciences, tehran, iran. 6department of medical genetics, school of medicine, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. mohammad_823@yahoo.com. ** malopolska centre of biotechnology, jagiellonian university, kraków, poland. s.ghafourifard@sbmu.ac.ir. received june 2020 & accepted may 2021 of genetic polymorphisms that confer risk of this malignancy (4-6). we have recently assessed the role of a number of single nucleotide polymorphisms (snps) in different genes in conferring risk of prostate cancer in iranian population. these snps were located in anril (rs1333045, rs4977574, rs1333048 and rs10757278) (7), hotair (rs12826786, rs1899663 and rs4759314)(8), il-6 (rs1800795 and rs2069845)(9) and il-8 (rs4073, rs2227306 and rs1126647)(10). in the current study, we applied the random forest (rf) algorithm for prediction of risk of prostate cancer based on the genotyping results of these 13 distinct snps. rf algorithm is an ensemble learning method for supervised classification introduced by breiman(11). this nonparametric tree-based approach combines the concepts of adaptive nearest neighbors with bagging(12). rf method has the ability to assess correlation and interaction among varurology journal/vol 18 no. 6/ november-december 2021/ pp. 639-645. [doi: 10.22037/uj.v18i.6337] urological oncology iables. notably, rf can facilitate selection and ranking of variables by calculating variable importance values. these features potentiate rf for evaluation of genomic data and bioinformatics investigation(13). materials and methods we used the rf algorithm for prediction of prostate cancer using 13 different snps. the samples were divided into a training set (n=320) and a test set (n=80) for the purpose of generalizing the outcome of the training algorithm. for hyper-parameters tuning, we used randomized search with 5-fold cross-validation for the following hyper-parameters: (1) number of trees or estimators in the forest (set from 3 to 500); (2) the maximum number of leaf nodes (set from 2 to 32); (3) the maximum number of features used for the best split (set from 5 to 13); and (4) using bootstrap samples in the trees building (true or false). a total of 1000 combination of these hyper-parameters were evaluated on the validation sets. after fixing the hyperparameters, we retrained the whole training set again. totally, 20 percent of the data samples were used as test set. the samples were chosen randomly. for evaluation of the hyperparameters, one fifth of the training set was used as validation set for the 5-fold-cross validation. we did not set a limitation on the maximum depth of the trees. therefore, the nodes were further expanded until all leaves became pure or until all leaves contained fewer samples than the “min samples split” amount. to avoid overfitting, we used the k-fold cross-validation technique. in the current study, we used the python programming language version 3.8.2. for applying the rf algorithm and hyper-parameters randomized search, we implemented python scikit-learn 0.23.0 (https://scikit-learn. org/). accuracy, sensitivity, precision, and f1-score in both training and test sets were reported. precision, sensitivity and f1-score were defined in equations 1-3 (14): where, tp is the number of true positives, fp is the number of false positives, and fn is the number of false negatives. furthermore, we used the receiver operating characteristic (roc) curve and area under curve (auc) score to evaluate the performance of the model. we also presented the most important snps based on the impurity-based feature importance (also known as the gini importance). the gini index measures the importance of a feature by computing the level of the impurity of samples assigned to a node based on a split at its parent (15). gini index was calculated using equation 4: snps for prostate cancer-omrani et al. urological oncology 640 control prostate cancer bph anril-rs1333045 c/t 129 65 57 c/c 57 30 25 t/t 14 5 18 anril-rs1333048 a/a 110 22 27 a/c 50 55 32 c/c 40 23 41 anril-rs4977574 g/g 82 62 65 a/g 82 33 24 a/a 36 5 11 anril-rs10757278 a/g 91 58 65 g/g 84 21 20 a/a 25 21 15 hotair-rs12826786 c/t 108 37 48 c/c 60 25 28 t/t 32 38 24 hotair-rs4759314 a/a 121 61 54 a/g 77 38 44 g/g 2 1 2 rora-rs11639084 c/c 126 59 73 c/t 63 41 23 t/t 11 0 4 rora-rs4774388 t/t 105 64 49 c/t 75 29 41 c/c 19 7 10 il-6-rs2069845 a/g 97 54 44 a/a 82 33 47 g/g 21 13 9 il-6-rs56588968 c/g 87 41 40 g/g 77 30 32 c/c 36 29 28 il-8-rs4073 a/t 96 53 27 t/t 63 34 51 a/a 41 13 22 il-8-rs2227306 c/t 92 52 43 c/c 76 37 35 t/t 32 11 22 il-8-rs1126647 a/t 89 39 37 a/a 72 32 46 t/t 39 29 17 table 1. the frequency and distribution of various polymorphisms. where, n is the number of the total the total samples, nk is the number of samples from class k = {0, 1}, pk is the fraction of nk out of n samples at node τ. we measured the generalization power based on the test data rather than the generalization. the strategy for setting the optimum value of hyperparameters (hyperparameter tuning) was randomized search and k-cross fold-validation. results samples containing at least one nan value were ruled out. the frequency and distribution of various polymorphisms are summarized in table 1. in the hyper-parameter tuning stage, hyper-parameters were set as follow: 1) number of trees = 34; 2) the maximum leaf nodes = 30; 3) the maximum features = 8; and 4) using bootstrap = true. the most important snp was anril-rs1333048: a/a (gini index= 0.096) figure 1. training dataset confusion matrix. the color bar next to the chart shows the frequency. figure 2. test dataset confusion matrix. the color bar next to the chart shows the frequency. figure 3. visualization of the first estimator (decision tree) in our random forest model snps for prostate cancer-omrani et al. vol 18 no 6 november-december 2021 641 followed by anril-rs10757278: g/g (gini index= 0.059). training dataset outcomes were as follow: accuracy: 0.896, sensitivity: 0.85, specificity: 0.944 and f1 score: 0.891. test dataset outcomes were as follow: accuracy: 0.787, sensitivity: 0.775, specificity: 0.800 and f1 score: 0.784. figure 1 shows the training dataset confusion matrix. we also depicted dataset roc curve for both training and test datasets (figures 4 and 5). the auc scores were 0.966 and 0.841 for training and test datasets, respectively. features importance of the assessed snps is shown in figure 6. the best features have been demonstrated for anril-rs1333048: a/a and anril-rs10757278: g/g, respectively. discussion in the current study, we re-analyzed our genotyping data of 13 snps in a population of iranian patients with prostate cancer using the rf method. this method has been previously applied in the analysis of snps in genetic studies. in gwas, rf has been shown to be able in screening of snps with interaction effects. such urological oncology 642 figure 4. training dataset roc curve showing the auc value of 0.966 for the proposed approach in the diagnosis of prostate cancer. figure 5. test dataset roc curve showing the auc value of 0.841 for the proposed approach in the diagnosis of prostate cancer. snps for prostate cancer-omrani et al. method has decreased the number of snps that should be recalled for additional study compared to routine univariate screening strategies(16). rf has been successfully applied for assessment of the effects of 42 snps located in the asthma risk gene adam33 to reach 44% misclassification rate(17). in coronary artery calcification, rf has been applied for predication of the effects of 287 tagged snps and 17 risk elements(18). rf is superior to artificial neural network as it can decrease the high variance from a flexible model such as a decision tree through integrating several trees into one collaborative model. rf provides a different interpretation of a decision tree yet with superior performance. rf classifiers produce a large number of decision trees, without trimming or pruning. for each variable, this approach generates a significance score, which quantifies the variable relative contribution to prediction(19). rf classifiers has been successfully used in various biomedical studies(20-22). in a study by masetic z. et al(23), it has been reported that rf classifiers had better classification performance compared to decision tree, k-nearest neighbor, support vector machine, and artificial neural networks in congestive heart failure detection. in another study by zahangir alam md. et al(21), it has been suggested that other classifiers, unlike rf, do not perform equally well over all used medical datasets. similar to our study, they used k-fold cross validation for the model evaluation. the k-fold cross validation is a tool for evaluating a predictive model that splits the initial dataset into training sets and a validation sets for training and evaluating the model. it can also be used for the purpose for tuning the hyperparameters(24). rf classifiers can also been usedfor analysis of the snps(19). regarding snps, numerous studies used rf algorithm for analysis of the snps(19,25-27). using rf, van dyke a. l, et al.(25) suggested that il1a snp is an important risk factor in predicting risk for nonsmall cell lung cancer among women using snps data. staiano, a. et al(26) used rf algorithm to find snps associated with high cardiovascular risk. rf has a valuable characteristic that enables a prompt calculable internal measure of variable importance. this feature can be applied to rank variables particularly in assessment of high-throughput genomic data. node impurity indices (including the gini index) are frequently used to appraise the importance measures (13). in the current study, we calculated the gini index importance according to the node impurity degree for node splitting. this approach led to the identification of the anril-rs1333048: a/a (gini index= 0.0967) and anril-rs10757278: g/g (gini index= 0.0599) genotypes as the most important genotypes in conferring risk of prostate cancer. the anril rs1333048 snps have been previously shown to be associated with both generalized and localized aggressive periodontitis. moreover, it resides in a common risk locus for coronary artery disease and periodontitis(28). the gg genotype of rs10757278 has been remarkably associated with carotid plaque in female subjects(29). the g allele of this snp interferes with the binding site for stat1. this snp also alters expression of anril and its nearby genes (30,31) in a way that the gg genotype confers the most decreased expression levels(30). this snp also affects alternative splicing of anril(32). future studies are needed to unravel the molecular mechanisms leading to the importance of anril rs1333048 and rs10757278 snps in the susceptibility to prostate cancer in the iranian population. based on outcomes of training and test datasets accuracy, sensitivity, specificity and f1 score values were figure 6. features importance of the assessed snps. snps for prostate cancer-omrani et al. vol 18 no 6 november-december 2021 643 slightly lower in the test dataset. moreover, the auc scores were decreased in test dataset, albeit it remained significant. thus, the proposed panels of snps can predict the risk of prostate cancer in the iranian population with appropriate accuracy. this panel might be used as a screening panel for identification of at risk individuals. further assessment of accuracy of this panel in lager cohorts of patients from different stages of prostate cancer might reveal its significance in the determination of disease course or prognosis. acknowledgments this study was financially supported by urology and nephrology research center. conflict of interest the authors declare they have no conflict of interest. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca: a cancer journal for clinicians. 2018;68:394-424. 2. basiri a, eshrati b, zarehoroki a, golshan s, shakhssalim n, khoshdel a, et al. incidence, gleason score and ethnicity pattern of prostate cancer in the multi-ethnicity country of iran during 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expression contribute to stroke risk and recurrence in a large prospective stroke population. stroke. 2012;43:14-21. snps for prostate cancer-omrani et al. vol 15 no 06 november-december 2018 344 urological oncology the association of shorter interval of biopsy-radical prostatectomy and surgical difficulty shuqiu chen,1,2 guiya jiang,3 ning liu1,2 hua jiang,1,2 lijie zhang,1,2 chao sun,1,2 bin xu,1,2 xiaowen zhang,1,2 yu yang ,1,2 jing liu,1,2 weidong zhu,1,2 ming chen,1,2* purpose: we discuss the safety and perioperative outcomes of a 2-week interval between prostate biopsy and laparoscopic radical prostatectomy (lrp). materials and methods: we retrospectively reviewed the medical records of 182 patients with prostate cancer (pca) who underwent transperitoneal lrp 2 weeks after prostate biopsy between 2012 and 2015. we evaluated the following perioperative outcomes: operative time, estimated blood loss (ebl), infection, conversion to open surgery, positive surgery margins (psm), and complications. we also reviewed studies discussing a shorter interval between biopsy and lrp in peer-reviewed publications. results: the mean operative time and ebl were 100.2 min and 82.2 ml, respectively. there were no rectal injuries or conversions to open surgery, totally 19 (10.4%) patients experienced complications (clavien-dindo grade i and ii): fever occurred in six patients (3.3%), urinary leak in four (2.2%), incomplete paralytic ileus in four (2.2%), deep vein thrombosis in two (1.1%), and postoperative anemia in four. the average bedrest time after surgery was 2.5 days. psm was detected in twenty-one patients (11.5%) . 167 patients (91.7%) recovered continence. follow-up ranged from 13-37 months, the biochemical recurrence (bcr) rate was 10.4% (19/182).the seven peer-reviewed studies we reviewed that a shorter interval was safe and did not influence surgical outcomes. conclusion: our study shows that a 2-week interval between biopsy and lrp is safe and does not negatively affect surgical outcomes. keywords: laproscopic radical prostateectomy;biospy;interval. introduction currently, all of prostate cancers (pca) are diagnosed by transrectal ultrasound (trus)-guided prostatic biopsy. for localized prostate cancer, radical prostatectomy (rp) continues to be a commonly performed and effective treatment. traditionally, urologists recommend an interval of ≥ 6–8 weeks after trus-guided prostatic needle biopsy before rp(1), because of the hypothesis that biopsy can results inflammatory response and bleeding that may take several weeks to subside .(2) however, studies have shown that a shorter interval of 4–6 weeks does not affect immediate operative outcomes such as operative time, estimated blood loss (ebl), and positive surgical margin (psm) status(3). despite this finding, to our knowledge, rarely studies have evaluated the surgical difficulty and operative outcomes of lrp 2 weeks after prostatic biopsy. we retrospectively studied a series of patients who underwent lrp 2 weeks after prostate biopsy, and we aimed to examine whether a shorter interval of 2 weeks between biopsy and lrp was associated with surgical difficulty or operative efficacy. 1urology, zhongda hospital, southeast university,nanjing, 210009, china. 2urological institute of southeast university, nanjing, 210009,china. 3southeast university, medical school. *correspondence: urology, southeast university,zhongda hospital, nanjing, 210009, china. tel: +86 15951815171. fax: +86 25 83272111. e-mail: mingchen6308@163.com. received august 2017 & accepted january 2018 materials and methods study population following ethics committee approval and patient consent, we retrospectively reviewed 182 patients undergoing lrp between february 2012 and december 2015. all the patients underwent the biopsy and lrp in the university hospital. the inclusion criteria were t1, t2 and t3a prostate cancer without distant metastasis. the exclusion criteria included history of pelvic surgery, radiotherapy, having undergone hormonal therapy, fever and severe bleeding of rectum related to biopsy and repeated biopsy. the characteristic of patients and disease has been illustrated in table 1. study design all patients diagnosed with pca basing on trus-guided biopsy (12+x) had a transperitoneal lrp by the same urologist. prophylactic antibiotics was used half an hour before biopsy, and another dose of antibiotic was used 24 hours later. all patients did a pre-biopsy pelvic mri to explore the infiltration of prostate capsule. the preoperative psa level, gleason score, age, body mass index (bmi), operative time, ebl, transfusion rate, length of stay, stage and margin status, conversion to open surgery, rectal injury, incontinence, biochemical recurrence (bcr) were analyzed. to evaluate the safety and effectiveness of short interval between biopsy and lrp. surgical technique all the patients underwent lrp 2 weeks after biopsy. all procedures were performed through a five-port transperitoneal approach. the pelvic peritoneum was incised followed by the vesicle, which was dissected along the vas deferens. the perirectal fatty tissue was then entered. dissection was performed between the rectum and the posterior aspect of denonvilliers’ fascia to avoid rectal injury. fat tissue around the prostate was removed after detaching the bladder, followed by incising the endopelvic fascia to free the prostate and the muscles of pelvic wall. bladder neck incision, ligation of the dorsal venous complex, apical dissection, posterior reconstruction, and urethro-bladder anastomosis were performed with continuous suture. bladder neck suspension to the dorsal venous complex (dvc) was performed to improve continence. obturator triangle lymph node dissection was performed in moderate and high-risk pca patients. outcome assessment anal function exercises three times each day began on the day of urethral catheter removal and continued until recovery of continence or 6 months postoperatively. postoperative continence was defined as being urinary pad-free. patients were followed-up at 2, 4, 6 and 8 weeks postoperatively and every 3 months thereafter. psa level and questions regarding the daily use of urinary pads were assessed at each visit. bcr was defined as two consecutive increases in psa of > 0.2 ng/ml. the classification of complications was evaluated by the clavien-dindo grade as described in previous literature(4). we reviewed the literatures which compared the safety and effectiveness of lrp according to the interval between of biopsy and lrp. statistical analysis was performed using analysis of variance and t-tests with statistical significance set at p < 0.05. result table 1 shows patients’ demographic data and tumour characteristics. all patients included in the study had pathologic stage t1c–t3a n0m0 pca. median operative time and ebl were 100.3 ± 27.5 mins and 82.2 ± 20.2 ml, respectively. there were no conversions to open surgery, and no patients experienced rectal injury. overall, 19 (10.4%) patients experienced postoperative clavien-dindo grade i and ii complications, including fever > 38.5°c in 6 patients (3.3%) who recovered with antibiotic therapy. four patients (2.2%) suffered urinary leakage consisting of urine outflow from the peritoneal drainage tube postoperatively, with the volume of urine leakage ranging from 300–1100 ml per day. all affected patients recovered in 6 days postoperatively with conservative treatment and without additional surgery. four patients (2.2%) suffered incomplete paralytic ileus and recovered in 4-6 days postoperatively with total parenteral nutrition. deep vein thrombosis occurred in two patients (1.1%), and four patients developed unexplained anemia without active bleeding and pelvic hematoma. the average number of days of postoperative bed rest was 2.5 days, and psm was detected in twenty-one patients (11.5%) . no clavien-dindo grade iii to v complications occurred. 142 patients (78%) regained continence within 6 weeks postoperatively, and 167 patients (91.7%) regained continence 6 months postoperatively without requiring urine pads. follow-up ranged from 13–37 months, the bcr rate was 10.4% (19/182), and the mean time to bcr was 24.3 months (table 1). in our literature review(3,5-10), one study of a shorter interval between biopsy and lrp reported a slight increase in perioperative complications. the results from all of other studies that we reviewed showed that performing radical prostatectomy 2–6 weeks after biopsy did not adversely influence surgical difficulty or perioperative efficacy. discussion pca is a major cause of mortality among men worldwide. it is generally considered a relatively slow-progressing malignancy. however, most patients with malignant tumors suffer serious mental anxiety and usually hope to receive treatment as soon as possible. imaging studies such as those using magnetic resonance imaging (mri) after prostate biopsy found that haematoma persisted up to 21 days post-biopsy in 81% of patients, was still present in 49% of patients 28 days later, and in some patients, persisted to 4.5 months post-biopsy(11-13). post-biopsy haematoma is located within the prostate rather than outside of the prostatic capsule, and does not interfere with assessing the prostatic extracapsule using mri(14). post-biopsy prostate haematoma also does not adversely influence intraoperative dissection of the prostate and seminal vesicle. inflammatory adhesions are another factor considered to interfere with surgery due to shorter biopsy-to-surgery intervals. resolution of acute inflammation is followed by tissue proliferation and remodeling. the acute inflammatory table 1. the patient characteristics, perioperative outcomes and complication rates. characteristicsa n=182 age(y) 68.5 ± 7.1 bmi(kg/m2) 24.2 ± 1.7 psa(ng/ml) 18.5 ± 6.7 gleason score ≤ 6 56 = 7 65 ≥ 8 61 operative time (mins) 100.3 ± 27.5 ebl(ml) 82.2 ± 20.2 rectal injury none transfusion none conversion to open none postoperative complications(n) urinary leak 4 pelvic hematoma 0 fever(≥38.5℃) 6 postoperative anemia 4 deep vein thrombosis 2 incomplete paralytic ileus 3 length of bed rest(d) 2.5 positive surgery margin(%) 11.5 pathologic stage(n) ≤ t2a 35 t2b 47 t2c-t3a 100 recovered continence(%) 91.7 bcr(%) 10.4 adata are presented as mean ± sd or number (percent) two weeks between prostatectomy and biopsy is safe and effective-shuqiu et al. urological oncology 345 vol 15 no 06 november-december 2018 346 response usually lasts 24-48 hours but may persist for up to 2 weeks in some patients. tissue remodeling with collagen scar formation begins 3–4 weeks after tissue injury and is followed by resolution of acute inflammation(15,16). in our surgery experience, there were no significant inflammatory adhesions of extracapsule of prostate with an interval of 2 weeks between biopsy and lrp. however, pelvic surgery history resulted in adhesions of periprostate. so, the patients had suffered transurethral resection of prostate previously were excluded(17). we found no haematoma or inflammatory adhesions in the periprostatic tissue or seminal vesicle intraoperatively in our cohort. also, bleeding related to the biopsy was located in prostate and seminal vesicle. these findings were consistent with white et al's report (11) . in this study, we report a new treatment model for pca, and performed 182 cases of lrp within 2 weeks after biopsy, excluding patients in whom the prostatic capsule was invaded by carcinoma on mri. our results showed that operative difficulty and complications were not affected by the shorter interval, consistent with other studies(18,19). in our opinion, bleeding during lrp mainly results from the dissection of dvc and prostate ligament, rather than from dissection of the seminal vesicle and prostatic capsule. as is known, prostatic volume is not a factor in ebl(20), therefore, lrp for localized pca using a shorter interval between biopsy and lrp does not increase ebl. another important keypoint in lrp is psm based on histopathology. the rate of psm reported in the literature is 9-38.8% for localized pca(19), and the independent predictor of psm is clinical stage rather than surgical technique or biopsy-to-lrp interval(5,21). follow-up ranged from 13-37 months, the bcr rate was 10.4%, and the mean time to bcr was 24.3 months, in our study. the shorter interval in our centre did not increase psm or bcr rate. the shorter interval in our study did not increase difficulty dissecting the urethra and dvc. in each lrp surgery performed in our centre, we suspend the bladder neck to the dvc followed by urethral-bladder anastomosis to promote continence. combined with anal function exercises, the incontinence rate 6 months postoperatively was relatively lower in our patient series (8%). in our cohort we excluded the t3b pca because of the high-risk pca result in high rate of incontinence(22). in our literature review, most studies described an interval of 4–6 weeks. only one study reported a serious of 31 cases undergoing a < 2-week interval, and the authors reported this interval was feasible and safe in robotic assisted laparoscopic prostatectomy (ralp) (10). the results of our review also revealed that performing lrp 4–6 weeks after prostate biopsy compared to within 2 weeks does not adversely influence surgical difficulty and perioperative outcomes. park(5) reported longer operative time and larger ebl in longer interval( > 4 weeks) in open surgery(p < 0.05). however there was no significant differences in laparoscopic surgery(p > 0.05)(5) . conversely, george(6) did not recommend early ralp after biopsy because of a greater risk of complications. to our knowledge, our study evaluated the safety and effectiveness of a 2-week interval between prostatic biopsy and lrp; however, there are several limitations in our study. firstly, the relatively small sample size and a long-term follow-up are required for improved statistical power. second, we did not compare the mortality and operative outcomes with more than 2 weeks intervals between biopsy and surgery. conclusions lrp at 2 weeks after prostatic biopsy does not appear to be more technically difficult, increase psm, or affect urinary continence. our data provide reassurance to urologists and patients choosing lrp with a relatively shorter interval after biopsy. using a 2-week interval shortens the waiting time from diagnosis to treatment. acknowledgement the publication fee for this publication was funded in part by the national natural science foundation of china (no. 81370849,81572517), natural science foundation of jiangsu province (no. bk20150642),jiangsu provincial medical innovation team, jiangsu provincial medical talent, jiangsu provincial medical youth talent (no.qnrc2016821) conflict of interest the authors report no conflict of interest. references 1. walsh pc and partin aw. anatomic radical retropubic prostatectomy. campbell-walsh urology, 9th edn. philadelphia: wb saunders, 2007:2959. 2. walsh p: anatomic radical prostatectomy. campbell’s urology. philadelphia, wb saunders, 2002:3107-28. 3. eggener se, yossepowitch o, serio am, vickers aj, scardino pt, eastham ja. radical prostatectomy shortly after prostate biopsy does not affect operative difficulty or efficacy. urology.2007;69:1128-33. 4. clavien p, sanabria j, mentha g, et al. recent results of elective open cholecystectomy in a north american and a european center. ann surg. 1992;216:618-26. 5. park b,choo sh, jeon hg,,et al.interval from prostate biopsy to radical prostatectomy does not affect immediate operative outcomes for open or minimally invasive approach. j korean med sci. 2014;29:1688-93. 6. martin gl, nunez rn, humphreys md, et al. interval from prostate biopsy to robotassisted radical prostatectomy: effects on perioperative outcomes.bju int. 2009;104:1734-7. 7. dell’atti l, capparelli g, papa s, lppolito c. can radical prostatectomy shortly after prostate biopsy affect intra-operative and postoperative outcomes? asian j androl. 2016;18: 496-7. 8. lee dk, allareddy v, o’donnell ma, williams rd, konety br.does the interval between prostate biopsy and radical prostatectomy affect the immediate postoperative outcome? bju int.2006;97:48-50. 9. adiyat kt, murugesan m, katkoori two weeks between prostatectomy and biopsy is safe and effective-shuqiu et al. d, eldefarwy a, soloway ms. total prostatectomy within 6 weeks of a prostate biopsy: is it safe?int braz j urol. 2010;36:17782. 10. lee sh, chung ms, chung yg, park pp, chung bh. does performance of robotassisted laparoscopic radical prostatectomy within 2 weeks of prostate biopsy affect the outcome? int j urol. 2011;18:141-7. 11. white s, hricak h, forstner r, et al. prostate cancer: effect of post biopsy hemorrhage on interpretation of mr images. radiology. 1995;195: 385-90. 12. ikonen s, kivisaari l, vehmas t, et al. optimal timing of post-biopsy mr imaging of the prostate. acta radiol. 2001;42: 70-3. 13. kaji y, kurhanewicz j, hricak h,et al. localizing prostate cancer in the presence of post biopsy changes on mr images: role of proton mr spectroscopic imaging. radiology.1998;206: 785-90. 14. sharif-afshar ar, feng t, koopman s, et al. impact of post prostate biopsy hemorrhage on multiparametric magnetic resonance imaging. canadiam journal of urology.2015;22:7698-702. 15. reinke jm, sorg h.wound repair and regeneration.eur surg res.2012;49:35-43. 16. li j, chen j, kirsner r. pathophysiology of acute wound healing.clinics in dermatology. 2007;25: 9-18. 17. yang y, luo y, hou gl,et al.laparoscopic radical prostatectomy after previous transurethral resection of the prostate in clinical t1a and t1b prostate cancer: a matched-pair analysis.urol j. 2015;12:2154-9. 18. picozzi scm, ricci c, bonavina l, et al. feasiblity and outcomes regarding open and laparoscopic radical prostatectomy in patients with previous synthetic mesh inguinal hernia repair: meta-analysis and sstematic reviewof 7494 patients. world j urol. 2015;33:59-67. 19. robertson c, close a, fraser c, et al. relative effectiveness of robot-assisted and standard laparoscopic prostatectomy as alternatives to open radical prostatectomy for treatment of localised prostate cancer: a systematic review and mixed treatment comparison metaanalysis. bju int. 2103;112: 798-812. 20. sultan mf, merrilees ad, chabert cc, eden cg. blood loss during laparoscopic radical prostatectomy. j endourology. 2009;23: 6358. 21. kasraeian a, barret e, chan j, et al. comparison of the rate, location and size of positive surgical margins after laparoscopic and robot-assisted laparoscopic radical prostatectomy. bju int. 2011;108: 1174-8. 22. hou gl, luo y, di jm,et a.predictors of urinary continence recovery after modified radicalprostatectomy for clinically high-risk two weeks between prostatectomy and biopsy is safe and effective-shuqiu et al. prostate cancer.urol j.2015;12:2021-7. urological oncology 347 preoperative neutrophil-lymphocyte ratio as a predictor of overall survival in patients with localized renal cell carcinoma damian widz1*, przemysław mitura1, paweł buraczyński1, paweł płaza1, marek bar1, michał cabanek1, grzegorz nowak1, anna ostrowska2 , krzysztof bar1 purpose: the neutrophil-to-lymphocyte ratio (nlr), as an indicator of the systemic inflammatory response, predicts adverse outcomes in many malignancies. we investigated its prognostic significance in patients with nonmetastatic renal cell carcinoma. materials and methods: we retrospectively evaluated data of 196 consecutive non-metastatic rcc patients who underwent radical or partial nephrectomy between 2010 and 2012 at a single center. overall survival (os) was assessed using the kaplan-meier method and compared using the log-rank test. we applied univariate and multivariate cox regression models to evaluate the prognostic value of dichotomized nlr for os. results: at a median follow up of 68 months, high nlr (≥ 2,69) correlated with worse survival outcome (p = .006 in log-rank test) and higher tumor stage (p = .035). univariate and multivariate analysis identified elevated nlr (p = .039), as well as age (p = .002), high fuhrmann grade (p = .002) and high pathologic t stage (p < .001), as significantly associated with overall survival. conclusion: in our cohort, an elevated neutrophil-to-lymphocyte ratio is significantly associated with worse os on univariate and multivariate analysis. consequently, the nlr is an easily acquired biomarker, which may be useful in pretreatment patient risk stratification. keywords: inflammation, neutrophil-lymphocyte ratio, prognosis, renal cell carcinoma, survival introduction renal cell carcinoma, representing 2–3% of malig-nancies worldwide(1), has increased in incidence over the last two decades. this medical condition is often identified in western countries, but the frequency of its occurrence in western europe has been stabilized(2). also, due to the wide-spread use of ultrasound (us) and computed tomography (ct) many newly diagnosed renal tumors occur as incidental findings, and are therefore smaller and of lower stage(3,4,5). kidney cancer therapy is a subject of continuous verification and incremental modification to improve oncological outcome while reducing the negative implications of surgical or systemic treatment(6,7,8). researchers are constantly attempting to determine prognostic factors that can accurately predict clinical outcomes of rcc patients. these features are derived from anatomical, histological, clinical and molecular data and are combined into prognostic systems and nomograms(9,10,11,12,13). this constant effort to uncover new factors has focused attention on cancer-associated inflammation, which has an established role in cancer development and progression. pre-operative measurement of inflammatory response markers, such as elevated c-reactive protein levels, hypoalbuminemia or increased white cell, neu1department of urology, medical university of lublin, lublin, poland. 2department of pathology, medical university of lublin, lublin, poland. *correspondence: department of urology, medical university of lublin, jaczewskiego 8, lublin, e-mail address: damian.widz@gmail.com; damianwidz@umlub.pl. received & accepted trophil and platelet counts, allows the prediction of patients’ survival in many cancers(14,15). the neutrophil to lymphocyte ratio (nlr) is a cheap and easily acquired inflammatory marker widely investigated as a prognostic factor in a number of cancers(14,16), including urologic tumors(17). the aim of our study was to evaluate the prognostic significance of preoperative nlr in non-metastatic rcc. this is one of the first cohort studies in this field in our region. materials and methods study population a total of 196 consecutive patients with non-metastatic rcc who had undergone a curative radical or partial nephrectomy at the department of urology at the medical university of lublin between january 2010 and september 2012 were included in this historical cohort study. patients suspected of bone marrow disease (1 case) or lost from follow-up (3 cases) were not involved in the study. study design and evaluations the research was reviewed and approved by medical university of lublin ethics committee. data regarding age, sex, body mass index (bmi), history of hypertension and diabetes were retrieved from medical records urological oncology urology journal/vol 17 no. 1/ january-february 2020/ pp. 30-35. [doi: 10.22037/uj.v0i0.4541] vol 17 no 01 january-february 2020 31urological oncology 349 of the department of urology, clinicopathological parameters including histological rcc subtype, tumor grade (fuhrmann grade), presence or absence (not quantitatively assessed) of histologic tumor necrosis (tn), and tumor size were obtained from the pathology reports from the department of pathology at lublin university hospital. laboratory tests, including peripheral blood cell counts, were performed at 1–7 days before surgery. overall survival was calculated based on the dates of individuals' surgery and death from any cause. dates of death were obtained from the registry of the polish ministry of digital affairs. the objective of the present study was to examine the relationship between pretreatment nlr and the clinicopathological features of rcc in patients who had received radical surgery, as well as the potential effect of nlr on overall survival. nlr was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. statistical analysis the cutoff value for the dichotomization of nlr was calculated using a receiver – operating characteristic curve with survival (death) as a gold standard. the pronlr as a predictor of overall survival in patients with rcc-widz et al. table 1. clinicopathological characteristics of the cohort stratified by preoperative nlr. clinicopathological features nlr < 2,69 n (%) nlr ≥ 2,69 n (%) p-value a age (years) 0.44 < 65 65 (64.4) 56 (58.9) ≥ 65 36 (35.6) 39 (41.1) gender 0.95 male 60 (59.4) 56 (58.9) female 41 (40.6) 39 (41.1) bmi 0.29 < 25 25 (24.75) 30 (31.6) ≥ 25 76 (75.25) 65 (68.4) hypertension 0.15 no 48 (47.5) 55 (57.9) yes 53 (52.5) 40 (42.1) tumor size 0.21 < 7 83 (82.2) 71 (74.7) ≥ 7 18 (17.8) 24 (25.3) histologic subtypes 0.18 clear cell 88 (87.1) 76 (80) non-clear cell 13 (12.9) 19 (20) pt stage 0.04 t1 – t2 73 (72.3) 55 (57.9) t3 – t4 28 (27.7) 40 (42.1) fuhrman grade 0.74 1 – 2 61 (60.4) 54 (58.1) 3 – 4 40 (39.6) 39 (41.9) type of surgery 0.27 nss 27 (26.7) 19 (20) nephrectomy 74 (73.3) 76 (80) tumor necrosis 0.80 no 75 (74.3) 69 (72.6) yes 25 (26.7) 26 (27.4) a the χ2-test abbreviations: bmi – body mass index, nlr – neutrophil-lymphocyte ratio, nss – nephron-sparing surgery, pt stage – pathological tumor stage figure 1. linear correlation analysis of the association between prognosis and nlr values. figure 2. kaplan–meier curves for overall survival in renal cell carcinoma patients categorized by the neutrophil–lymphocyte ratio (low nlr < 2,69; high nlr ≥ 2,69). posed and finally accepted cut-off point was determined to be 2.69. categorical variables were reported as frequencies and percentages. continuous variables were reported as medians and ranges, and then dichotomized according to approximate optimal cutoff points. the relationship between nlr and the clinicopathologic parameters was evaluated by non-parametric tests pearson’s χ2 tests. linear correlation analysis was used to determine the association between prognosis and nlr values. the time of overall survival was calculated using the kaplan-meier method and compared using the log-rank test. cox’s proportional hazard regression model was used to assess the influence on overall survival (os) of age, gender, fuhrmann grade, histologic subtypes of rcc, pathologic t (tumor) stage, tumor size. we decided on a multivariate analysis with variables significant in univariate analysis, as well as including histological subtype, due to its acknowledged role as prognostic factor. all statistical analyses were performed using stata software version 13. p < .05 was considered to be statistically significant. results overall, 196 rcc patients, median age 61 years (interquartile range 24-85), were treated with partial nephrectomy – 46 (23.5%) or nephrectomy – 150 (76.5%). among all the cases, 165 (84.2%) had clear cells, 14 (7.1%) had papillary, 6 (3.1%) had chromophobe, 4 (2%) had cystic, 1 (0.5%) had collecting duct rcc and 6 (3.1%) were not specified. pathologic t stage was t1a in 67 (34.2%), t1b in 52 (26.5%), t2a in 7 (3.6%), t2b in 2 (1%), t3a in 58 (29.6%), t3b in 7 (3.6%) and t4 in 3 (0.2%) patients. tumor fuhrmann grading was grade 1 in 11 cases (5.6%), grade 2 in 103 (52.6%), grade 3 in 55 (28.1%), grade 4 in 24 (12.2%) and in 3 (1.5%) cases not specified. histologic tumor necrosis was reported in 52 (26.5%) patients. the mean neutrophil count was 4.94 ± 1.66, mean lymphocyte count was 1.74 ± 0.64 and mean nlr was 3.18 ± 1.66. using an roc curve we determined the cutoff nlr value of 2.69 to be optimal to differentiate patients’ overall survival and define low (< 2.69) and high nlr (≥ 2.69). overall, there were 101 (51.5%) patients with a low nlr and 95 (48.5%) patients with a high nlr. a high nlr was significantly associated with an advanced tumor stage (p < .05) but not with any other tested clinicopathological feature (table 1). total median follow-up time was 68 months (interquartile range (iqr) 44.5–78). overall, there were 64 deaths from all causes. the prognosis of patients was significantly associated with nlr values (p < .001) (figure 1). kaplan–meier curves for survival probability shown on figure 2 revealed that a high nlr correlates with poor prognosis in rcc patients (p = .006 in log-rank test). for further investigations to determine the prognostic significance of nlr for os, univariate and multivariate cox proportional hazard analyses were performed. age (≥ 65 vs < 65 years, p = .003), gender (male vs female, p = .004), high tumor fuhrmann grade (3+4 vs 1+2, p < .001), high pathologic t stage (t3–t4 vs t1–t2, p < .001), large tumor size (> 7 cm vs ≤ 7 cm, p < .001) and a high nlr (≥ 2.69 vs < 2.69, p = .007) were identified as predictors of poorer outcomes (table 2). in multivariable analyses, after adjusting all the variables, nlr remained significantly associated with os (p = .039), as well as age, gender, high fuhrmann grade, high pathologic t stage, but not tumor size (table 3). discussion the challenge presented by the personalized management of patient care requires constant research for more accurate biomarkers characterizing particular tumors. continuously updated scientific reports on kidney cancer focus to a large extent on molecular research(18). the complexity of molecular alterations in rcc, as well as table 2. univariate analysis of clinicopathological parameters for the prediction of overall survival in patients with rcc. features overall survival hr 95% ci p-value gender (male vs female) 2.287 1.298-4.029 0.004 age (≥ 65 vs < 65) 2.105 1.286-3.445 0.003 the histologic subtypes (clear cell vs non-clear cell) 1.008 0.955-1.064 0.77 pt stage (t3 -t4 vs t1 t2 ) 5.375 3.200-9.028 0.000 nlr ( ≥ 2.69 vs < 2.69) 2.009 1.211-3.334 0,007 tumor size (> 7 cm vs ≤ 7 cm) 3.924 2.380-6.473 0.000 fuhrman grade (3 4 vs 1 2) 3.377 2.015-5.658 0.000 abbreviations: bmi – body mass index, nlr – neutrophil-lymphocyte ratio, pt stage – pathological tumor stage features overall survival hr 95% ci p-value gender (male vs female) 1.755 0.988-3.116 0.06 age (≥ 65 vs < 65) 2.187 1.325-3.611 0.002 the histologic subtypes (clear cell vs non-clear cell) 1.058 0.995-1.125 0.07 pt stage (t3 -t4 vs t1 t2 ) 4.817 2.568-9.035 0.00 nlr ( ≥ 2,69 vs < 2,69) 1.718 1.027-2.874 0.04 tumor size (> 7 cm vs ≤ 7 cm) 1.435 0.819-2.514 0.21 fuhrman grade (3-4 vs 1-2) 2.230 1.343-3.938 0.002 abbreviations: bmi – body mass index, nlr – neutrophil-lymphocyte ratio, pt stage – pathological tumor stage table 3. multivariable analysis of clinicopathological parameters for the prediction of overall survival in patients with rcc. nlr as a predictor of overall survival in patients with rcc-widz et al. urological oncology 32 vol 17 no 01 january-february 2020 33 the intratumor heterogeneity of its genomic landscape, results in time-consuming analyses and is thus associated with high costs(18,19). as a consequence, none of the markers are available for routine testing. nlr is relatively easy to estimate from regularly used blood – based counts, making it an attractive prognostic factor for further evaluation and treatment of rcc patients. nlr has been widely evaluated as an adverse factor for different human cancers, including colorectal, gastric, esophageal, pancreatic, liver, urological and gynecological cancers(1), as well as in non – neoplastic conditions, such as cardiovascular diseases(20,21). graeme j.k. guthrie demonstrated that, regardless of the type of cancer or required treatment approach, nlr was elevated in patients with more advanced or aggressive disease manifested by increased tumor stage, nodal involvement or a higher number of metastatic lesions (14). you luo, in his publication dedicated to urologic tumors defined as renal cell carcinoma, upper tract urothelial carcinoma, bladder cancer and prostate cancer, indicated that patients with a higher nlr had a higher all-cause mortality risk in all the mentioned groups. in terms of cancer specific survival (css) outcome, results showed significant differences, with inferiority of a high nlr, in upper tract urothelial carcinoma and bladder cancer but not in rcc, and no data in prostate cancer(22). renewed interest in the role of nlr as a prognostic factor in rcc patients has developed as a result of new scientific reports. boissier et al. (2017) reviewed the available literature in august 2016 and found that nlr has a prognostic value for all stages of localized or metastatic rcc, including prediction of the response to systemic treatments or cytoreductive nephrectomy in metastatic kidney cancer(22). another study on patients with advanced disease (locally and metastatic) performed by fox et al. showed that the addition of inflammatory markers into prognostic models based on mskcc allows a more accurate prediction of patient survival time. according to this improved classification 25.8% of patients were more appropriately classified. the markers of systemic inflammation used in the study were elevated neutrophil counts, elevated platelet counts and high nlr, defined as > 3(23). there are incoming evidence on the potential benefits of adjuvant systemic therapy in advanced kidney cancer (24,25). due to the fact of a possible toxicity of such treatment, the search for markers enabling proper qualification of patients is underway. motzer et al. showed in their study that nlr may contribute in this field. according to their analysis from the s-trac trial, patients with nlr<3 experienced longer disease free survival with adjuvant sunitinib compared to placebo(24,25). determining the basis of this relation requires further inquiry. the value of nlr in patients with non-metastatic rcc remains under investigation. some studies have already been published, with conflicting results reported. in this cohort study, we found that preoperative nlr is significantly associated with os in univariate and multivariable analyses. we demonstrated that an increased nlr > 2.7 was an independent predictor of poor prognosis. our findings are in agreement with the large european validation study of pichler et al (2013), where they investigated a group of 678 patients with non – metastatic clear cell rcc and reported that nlr was an independent negative predictor for os. they did not find the same relation to css or metastatic free survival (26). their research is in contrast to another prior study by ohno et al (2010) on a smaller cohort of 192 patients with a mean follow-up of 93 months, where they reported that an increased nlr was an independent predictor for recurrence-free survival(27). in his analyses ohno omitted variables such as tumor stage, size, grade or presence of necrosis which has been proven to be highly predictive of tumor recurrence(28). moreover, their study did not include os data. other research projects also do not provide an unambiguous answer about the prognostic role of nlr. using a group of 827 non-metastatic clear cell rcc patients, boyd et al (2014) demonstrated that nlr is an independent predictor of cancer-specific and all-cause mortality. in contrast to many previous studies, and ours, their multivariable analysis is based on continuous nlr(29). this approach, perceived by the authors to be an advantage of the analysis, allows the avoidance of inaccurate setting of the cut-off value and receiving misleading results. however, everyday clinical practice usually requires the establishing of a certain point by which a clinician can identify significant abnormality in a diagnostic test. combination of information received from analyses based on continuous nlr with tests on dichotomized nlr would make it possible to identify a group of patients with a worse prognosis and gradation of their risk. lastly, bazzi et al (2016) evaluated 1970 patients undergoing partial or radical nephrectomy for localized clear cell rcc and found that nlr, as a continuous variable, was significantly associated with worse recurrence free survival (rfs), css, and os; however, in contrast to boyd’s research nlr independently predicted only worse os(30). attempts to explain the relationship between nlr and prognosis, on a pathophysiological basis, lead to the role of inflammation. the interaction between inflammation and carcinogenesis has been studied over the past decades. through various mechanisms, inflammation is involved in oncogenesis. a tumor is not merely a line of cancer cells dividing in an uncontrolled manner. on the contrary, there are many accompanying cells, including those derived from the immune system, influencing tumor behavior. cancer-associated inflammation induces the up-regulation of the innate immune response. it is manifested as a heightened neutrophil dependent reaction, increased tumor macrophage infiltration with concomitant suppression of lymphocytes. elevated proinflammatory cytokines modify the tumor microenvironment, allowing its intense growth and overcoming consecutive barriers in tumor expansion, promoting aggressive tumor behavior(31,32). an elevated neutrophil–lymphocyte ratio reflects, in part, the increased role of the innate immune system; moreover, it is often associated with higher values of proinflammatory cytokines(33,34). our study, as being the historical cohort, is limited by its non-randomized character. no data were available about the cause of death. moreover, nlr is not a disease-specific biomarker and may be influenced by many factors interacting with the immune system. the nlr cut-off point used in our study differs slightly from those used in previous research, as it is always set nlr as a predictor of overall survival in patients with rcc-widz et al. for a certain evaluated cohort. conclusions nevertheless, considering the limitations, our data show that elevated nlr may be recognized as an independent prognostic factor for os in non-metastatic rcc patients undergoing surgical resection of tumors. the nlr might be an easily available and inexpensive biomarker predicting clinical outcomes of rcc patients. however, to establish an accurate nlr value, useful for clinical practice, further prospective research is needed. conflict of interest none declared. references 1. european network of cancer registries: eurocim version 4.0. 200: lyon, france. 2. lindblad, p. epidemiology of renal cell carcinoma. scand j surg, 2004; 93: 88. 3. patard jj, rodriguez a, rioux-leclercq n, guillé f, lobel b. prognostic significance of the mode of detection in renal tumours. bju int. 2002;90(4):358-63. 4. kato m, suzuki t, suzuki y, terasawa y, sasano h, arai y. natural history of small renal cell carcinoma: evaluation of growth rate, histological grade, cell proliferation and apoptosis. j urol, 2004;172:863-6. 5. tsui k-h, shvarts o, smith rb, figlin r, de kernion jb, belldegrun a. renal cell carcinoma: prognostic significance of incidentally detected tumors. j urol, 2000;163:426-430. 6. cai y, li hz, zhang ys. comparison of partial and radical laparascopic nephrectomy: long-term outcomes for clinical t1b renal cell carcinoma. urol j. 2018 mar 18;15(2):1620. doi: 10.22037/uj.v0i0.3913. 7. zhang k, xie wl. urol j. determination of the safe surgical margin for t1b renal cell carcinoma. 2017 jan 18;14(1):2961-2967. 8. nouralizadeh a, ziaee sa, basiri a, simforoosh n, abdi h, mahmoudnejad n, kashi ah. transperitoneal laparoscopic partial nephrectomy using a new technique. urol j. 2009 summer;6(3):176-81. 9. ahmedov v, kizilay f, cüreklibatir i. prognostic significance of body mass index and other tumor and patient characteristics in non-metastatic renal cell carcinoma. urol j. 2018 may 3;15(3):96-103. doi:10.22037/ uj.v0i0.4067. 10. sorbellini m, kattan mw, snyder me, et al. a postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. j urol, 2005;173:4851. 11. patard jj, kim hl, lam js, et al. use of the university of california los angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study. nlr as a predictor of overall survival in patients with rcc-widz et al. j clin oncol. 2004;22(16):3316-22. 12. karakiewicz pi, briganti a, chun fk, et al. multi-institutional validation of a new renal cancer-specific survival nomogram. j clin oncol. 2007;25(11):1316-22. 13. zigeuner r, hutterer g, chromecki t, et al. external validation of the mayo clinic stage, size, grade, and necrosis (ssign) score for clear-cell renal cell carcinoma in a single european centre applying routine pathology. eur urol. 2010;57(1):102-9. 14. guthrie gjk, charles ka, roxburgh csd, horgan pg, mcmillan dc, clarke sj. the systemic inflammation-based neutrophil– lymphocyte ratio: experience in patients with cancer. crit rev oncol hematol. 2013;88(1):218-30. 15. roxburgh cs, mcmillan dc. role of systemic inflammatory response in predicting survival in patients with primary operable cancer. future oncol. 2010;6.1:149–163. 16. acharya s, rai p, hallikeri k, anehosur v, kale j. preoperative platelet lymphocyte ratio is superior to neutrophil lymphocyte ratio to be used as predictive marker for lymph node metastasis in oral squamous cell carcinoma. j invest clin dent. 2017. 8: n/a, e12219. 17. luo y, she d-l, xiong h, fu s-j, yang l. pretreatment neutrophil to lymphocyte ratio as a prognostic predictor of urologic tumors a systematic review and meta-analysis. medicine. 2015; 94(40): e1670. 18. al-ali bm, ress al, gerger a, pichler m. micrornas in renal cell carcinoma: implications for pathogenesis, diagnosis, prognosis and therapy. anticancer res. 2012; 32(9):3727-32. 19. gerlinger m, rowan aj, horswell s, et al. intratumor heterogeneity and branched evolution revealed by multiregion sequencing. engl j med. 2012;366(10):883-892. 20. kim sc, sun kh, choi dh, et al. prediction of long-term mortality based on neutrophillymphocyte ratio after percutaneous coronary intervention. am j med sci. 2016;351(5):467-72. 21. quiros-roldan e, raffetti e, donato f, et al. neutrophil to lymphocyte ratio and cardiovascular disease incidence in hivinfected patients: a population-based cohort study. plos one. 2016;11(5):e0154900. 22. boissier r, campagna j, branger n, karsenty g, lechevallier e. the prognostic value of the neutrophil-lymphocyte ratio in renal oncology: a review. urol oncol. 2017;35(4):135-141. 23. fox p, hudson m, brown c, et al. markers of systemic inflammation predict survival in patients with advanced renal cell cancer. br j cancer. 2013; 109:147–153. 24. ravaud a, motzer rj, pandha hs, et al. adjuvant sunitinib in high-risk renal-cell urological oncology 34 vol 17 no 01 january-february 2020 35 carcinoma after nephrectomy. n engl j med 2016; 375:2246-2254 25. motzer rj, ravaud a, patard jj, et al. adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: subgroup analyses and updated overall survival results. eur urol. 2018;73(1):62-68. 26. pichler m, hutterer gc, stoeckigt c, et al. validation of the pre-treatment neutrophil– lymphocyte ratio as a prognostic factor in a large european cohort of renal cell carcinoma patients. br j cancer. 2013; 108(4): 901–907. 27. ohno y, nakashima j, ohori m, hatano t, tachibana m. pretreatment neutrophilto-lymphocyte ratio as an independent predictor of recurrence in patients with nonmetastatic renal cell carcinoma. j urol. 2010;184(3):873-878. 28. leibovich bc, blute ml, cheville jc, et al. prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma. cancer, 97: 1663–1671. 29. viers br, thompson rh, boorjian sa, lohse cm, leibovich bc, tollefson mk. preoperative neutrophil-lymphocyte ratio predicts death among patients with localized clear cell renal carcinoma undergoing nephrectomy. urol oncol. 2014;32(8):12771284. 30. bazzi wm, tin al, sjoberg dd, bernstein m, russo p. the prognostic utility of preoperative neutrophil-to-lymphocyte ratio in localized clear cell renal cell carcinoma. can j urol. 2016;23: 8151-8154. 31. hanahan d, weinberg ra. hallmarks of cancer: the next generation. cell. 2011;144(5):646-74. 32. lu h, ouyang w, huang c. inflammation, a key event in cancer development. mol cancer res. 2006;4(4):221-33. 33. motomura t, shirabe k, mano y, et al. neutrophil–lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. j hepatol. 2013; 58:58– 64. 34. kantola t, klintrup k, vayrynen jp, et al. stage-dependent alterations of the serum cytokine pattern in colorectal carcinoma. br j cancer. 2012; 107: 1729–1736. nlr as a predictor of overall survival in patients with rcc-widz et al. mucinous adenocarcinoma of the suprapubic cystostomy tract without bladder involvement man libo, li gui-zhong* keywords: cystostomy; adenocarcinoma; urinary bladder neoplasms; neurogenic bladder; suprapubic catheter department of urology, beijing jishuitan hospital, beijing 100035, china. *correspondence: department of urology, beijing jishuitan hospital, beijing 100035, china. tel:8613370156336+, email: lee_gz163@99.com. received august 2016 & accepted june 2017 we present a case of adenocarcinoma developing at the vesicocutaneous edge of a vesicostomy, 8 years after it was created, in a patient who had neurogenic bladder secondary to medullitis. the patient died 6 months after the start of surgery therapy. although transitional and squamous cell carcinoma of a vesicostomy have been reported, to our knowledge, the presence of adenocarcinoma at the vesicostomy edge without bladder involvement has not been reported previously. introduction cutaneous vesicostomy, introduced in 1957, is a wellaccepted form of temporary urinary diversion in select patients.(1) most bladder squamous cell carcinomas have been described in paraplegics or in patients with spinal trauma.(2-8) they are also known to occur in patients with long-term indwelling catheters and during chronic inflammatory states associated with frequent irritation and persistent infection. to our knowledge, only a case of adenocarcinoma of a vesicostomy with bladder involvement have been reported to date.(9) we report the first case of adenocarcinoma developing at the edge of a cutaneous vesicostomy without bladder involvement 8 years after its creation. case report a 63-year-old male patient had a suprapubic foley catheter for 8 years after the formation of a neurogenic bladder secondary to medullitis. a cutaneous vesicostomy was performed at the age of 55 years. the patient presented with new-onset gross hematuria and severe fever. in order to identify the source of hematuria, contrast enhanced computed tomography of the abdomen and pelvis were conducted. on the computed tomographic scan of the abdomen and pelvis, a tumor mass surrounding the suprapubic cystostomy tract was clearly visible. physical examination revealed a hard, erythematous, and inflamed lesion in the abdominal wall envelcase report figure 1. suprapubic mass at presentation. figure 2. wide excision of suprapubic tube, mass, and partial bladder. vol 14 no 04 july-august 2017 4048 adenocarcinoma of the suprapubic cystostomy-libo et al. oping the suprapubic catheter (figure 1). biopsies of the bladder revealed hemorrhagic cystitis and negative for malignancy. ultrasound examination of the kidneys did not show any dilatation. percutaneous biopsy of the bladder mass was performed. histological examination of the biopsy from the mass revealed adenocarcinoma, moderately differentiated. after a negative metastatic workup, the patient underwent wide local excision of the surrounding skin and suprapubic tract and partial cystectomy. intra-operatively, the tumour was closely connected with the periosteum of the pubic symphysis but did not invade abdominal organs (figure 2). histologically, the tumor was diagnosed as infiltrating moderately to poorly differentiated mucinous adenocarcinoma (figure 3). the neoplasm stained intensely positive for cytokeratin (ck) (+), ck20(++), ck7(+), ki67(+), villm(++), vimentin(-), cdx-2(++) and b-catenin(+). the tumor did not appear to be associated with the skin or skin appendages. the tumor probably originated from the vesicocutaneous fistula tract or pseudomyxoma. postoperatively, the patient recovered with no complications except delayed published year author age (y) duration suprapubic pathology bladder t stage treatment survival cystostomy (y) involve ment 2015 present 63 8 adenocarc (-) t4 excision of dead at 6 study inoma the tumour months after surgery 2014 massaro 55 39 scc (+) t4 excision of recurrence within a the tumour year post-resection 2014 massaro 85 1 scc (+) t4 excision of not described the tumour 2013 chung 56 9 scc (+) t4 radiation dead at 6 months after radiation survival at a follow-up of 6months 2011 ito etal 58 35 scc t4 radiation survival at a follow-up of 6months 2013 chung 56 9 scc (+) t4 radiation dead at 6 months after radiation not described 2004 yohannes 42 40 adenocar (+) t2 anterior not described cinoma pelvic exenteration with cutaneous ureterostomy 2000 gupta 40 20 scc (+) t4 radical survival at a cystoprostat follow-up of 3 ectomy , months en bloc pubectomy and excision mass with ileal conduit 1999 schaafsma] 80 5 scc (-) t4 wide excision of dead at 5 months mass and partial after surgery cystectomy 1995 stokes 3rd. 50 25 scc (+) t4 excision dead at 8 months a 1993 stroumbak 80 5 scc (+) radiation and excision not described table 1. the published cases of suprapubic catheter tract carcinoma case report 4049 healing of incision. the patient received no adjuvant treatment. the patient died of pulmonary infection on 6th month after operation. discussion adenocarcinoma of the bladder is a rare form of bladder neoplasia, accounting for only 0.5% to 2% of all cases.(10) the symptoms of adenocarcinoma include hematuria, weight loss, anorexia, irritative voiding symptoms, and suprapubic discomfort. uremia secondary to obstruction of the ureterovesical junction by the mass and passage of a large amount of mucinous mass from the urethra is commonly seen in advanced stages.(10) the average age at diagnosis is 68 years, with higher prevalence in men (m: f, 2–3:1).(11) histologically, adenocarcinomas are classified into signet ring cell, colloid, colonic, clear cell, and glandular, not otherwise specified. primary adenocarcinoma of the bladder is located most frequently on the lateral walls of the bladder of the bladder and the trigone. urachal adenocarcinoma, found most frequently in the dome or anterior wall of the bladder, has also been described and is histologically indistinguishable from primary adenocarcinoma.(10) the prognosis of suprapubic catheter tract adenocarcinoma is comparatively poor because most patients have advanced disease at the time of diagnosis. many predisposing factors have been identified for bladder carcinoma. these include indwelling catheters; calculi, obstruction of the bladder neck, hydronephrosis, chronic irritation and inflammation, infection due to schistosomiasis hematobium, of the bladder and exposure to benzenes, aniline dyes, vinyl chloride, and cyclophosphamides. cystitis glandularis has also been identified as a precursor to adenocarcinoma of the bladder and is associated with brunn epithelial nests in the transitional urothelium, extrophy of the bladder, nephrogenic adenoma, and bladder anatomically altered by surgery.(12) unusual sporadic cases of primary adenocarcinoma in the surgical bladder have been reported in the literature in patients with non-dysfunctioning neurogenic bladder of 10 years’ duration, after urinary ileal conduit diversion, after augmentation cystoplasty, in congenitally duplicated bladder, and in neurogenic bladder secondary to myelomeningocele.(12,13) there are three theories explaining the development of adenocarcinoma of the bladder. the first hypothesis states that cystitis glandularis is the result of embryonic remnants of the urogenital sinus in the bladder, resulting from incomplete separation of the rectum from the urogenital sinus during development.(13) the second theory involves cases of adenocarcinomas associated with augmented bladders. the location of most of these tumors is at the junction of the bladder and intestinal mucosa. therefore, it is believed that the cancer is primarily of bowel origin.(13) the third theory postulates that chronic irritation of the bladder mucosa causes squamous and columnar transformation of the urothelium, which later progresses into adenocarcinoma of the bladder.(14) there are only eight case reports of suprapubic catheter tract carcinoma (two of them with bladder involvement) in the english literature.(2-8) the case reported here is the first case of suprapubic catheter tract adenocarcinoma without bladder involvement and the ninth case of suprapubic catheter tract carcinoma. we present the published cases of suprapubic catheter tract carcinoma in table 1. chronic irritation in neurogenic bladders is a common histologic finding. most series of spinal cord injury patients with bladder cancer show that a high proportion used indwelling catheters (50–100%).(15) polsky et al found a 90% incidence of chronically infected bladder in 3000 neurogenic bladder patients, as well as a subsequent 45% incidence of cystitis glandularis.(16) it is postulated that overdistension in a neurogenic bladder compromises the blood flow to the underlying mucosa, rendering it more susceptible to damage from bacteria circulating in the blood and lymph streams. subsequently, chronic colonization of the bladder mucosa by bacteria leads to the conversion of urinary nitrates to nitrosamine, a well-known carcinogen. animal models have demonstrated that there is an increased production of nitrosamine during infection with bacterial strains of escherichia coli and proteus which causes figure 3. histologic findings from suprapubic mass (hematoxylin and eosin stain, ×200) adenocarcinoma of the suprapubic cystostomy-libo et al. vol 14 no 04 july-august 2017 4050 urothelial hyperplasia and neoplasia.(17) urothelium and low-grade urothelial carcinoma may express ck7 and ck20. in this case, the inflamed urothelium was weakly ck20-positive only in the upper layers, but was strongly positive in the glandular, metaplastic, and neoplastic areas, lending support to the chronic irritation theory of the development of adenocarcinoma. in conclusion, patients with nonfunctioning bladders have a small but definite risk of bladder cancer developing and should be followed closely with regard to this possibility. the tumors that have been reported in this setting have had a high mortality rate, and early detection is therefore of the utmost importance if cure is to be effected. references 1. blocksom bh jr. bladder pouch for prolonged tubeless cystostomy. j urol. 1957; 78:398401. 2. stroumbakis n, choudhury ms, hernandezgraulau jm. squamous cell carcinoma arising from suprapubic cystotomy site without bladder involvement. urology. 1993; 41: 56870. 3. stokes s 3rd, wheeler js jr, reyes cv. squamous cell carcinoma arising from a suprapubic cystostomy tract with extension into the bladder. j urol. 1995; 154:1132-3. 4. schaafsma rj, delaere kp, theunissen ph. squamous cell carcinoma of suprapubic cystostomy tract without bladder involvement. spinal cord. 1999; 37:373-4. 5. gupta np, singh i, nabi g, ansari ms, mandal s. marjolin's ulcer of the suprapubic cystostomy site infiltrating the urinary bladder: a rare occurrence. urology. 2000; 56:330. 6. massaro pa, moore j, rahmeh t, morse mj. squamous cell carcinoma of the suprapubic tract: a rare presentation in patients with chronic indwelling urinary catheters. can urol assoc j. 2014; 8:e510-4. 7. chung jm, oh jh, kang sh, choi s. squamous cell carcinoma of the suprapubic cystostomy tract with bladder involvement. korean j urol. 2013; 54:638-40. 8. ito h, arao m, ishigaki h, et al. a case of squamous cell carcinoma arising from a suprapubic cystostomy tract. bmc urol. 2011; 11:20. 9. yohannes p, hunter w, prasad m. primary adenocarcinoma of cutaneous vesicostomy 40 years later: a rare case. arch pathol lab med. 2004; 128:e58-9. 10. abenoza p, manivel c, fraley ee. primary adenocarcinoma of urinary bladder. clinicopathologic study of 16 cases. urology. 1987; 29:9-14. 11. jacobo e, loening s, schmidt jd, culp da. primary adenocarcinoma of the bladder: a retrospective study of 20 patients. j urol. 1977; 117:54-6. 12. bitar m, mandel e, kirschenbaum am, unger pd. urinary bladder adenocarcinoma arising in a spina bifida patient. ann diagn pathol. 2007; 11:453-6. 13. djavan b, litwiller se, milchgrub s, roehrborn cg. mucinous adenocarcinoma in defunctionalized bladders. urology. 1995; 46:107-10. 14. mostofi fk. potentialities of bladder epithelium. j urol. 1954; 71:705-14. 15. west da, cummings jm, longo we, virgo ks, johnson fe, parra ro. role of chronic catheterization in the development of bladder cancer in patients with spinal cord injury. urology. 1999; 53:292-7. 16. polsky ms, weber ch jr, williams je 3rd, nikolewski rf, barr mt, ball tp jr. chronically infected and postdiversionary bladders: cytologic and histopathologic study. urology. 1976;7:531-5. 17. davis cp, cohen ms, hackett rl, anderson md, warren mm. urothelial hyperplasia and neoplasia. iii. detection of nitrosamine production with different bacterial genera in chronic urinary tract infections of rats. j urol. 1991; 145:875-80. adenocarcinoma of the suprapubic cystostomy-libo et al. case report 4051 editorial comments re: laparoscopic 2-port varicocelectomy with scarless periumblical mini-incision: initial experience in approach and outcomes the authors have presented a nice study about their new technique in laparoscopic repair of varicocele using 2 peri umbilical 5 mm ports. 2 cases of relapse (11%) and 1 case of hydrocele were also reported. pregnancy rates which are the most important outcome in varicocele surgery were not reported. to my opinion the primary outcome of varicocele repair is to promote pregnancy rates. despite being a laparoscopic surgeon, i rarely perform laparoscopy for treatment of varicocele. currently, microsurgical techniques with a small inguinal incision (usually 2 cm or less) can be used for varicocele surgery without need to enter peritoneal cavity. the inherent disadvantage of laparoscopic surgery for varicocele is that it is the laparoscopic equivalent of the high inguinal open surgery for varicocele that is rarely performed nowadays. as the authors correctly pointed out, the paternity rates for microsurgical repair (41 to 44%) is substantially higher than the laparoscopic approach (27%). in addition; recurrence rates have been lower with the microsurgical method (2-9% versus 11%) and the formation of hydrocele is substantially less frequent (0.7% versus 7%)(1). to summarize, higher paternity rates together with less frequency of relapse and hydrocele formation in microsurgical open repair leaves little room for laparoscopy in varicocele repair. references 1. diegidio p, jhaveri jk, ghannam s, pinkhasov r, shabsigh r, fisch h. review of current varicocelectomy techniques and their outcomes. bju int. 2011;108:1157-72. amir h kashi assistant prof of urology hasheminejad kidney center (hkc), iran university of medical sciences, tehran, iran. email: ahkashi@gmail.com editorial comment 64 reply by authors thank you for your comment. as you mentioned, the main limitation of this retrospective study is that we did not look over the known disadvantage of laparoscopic varicocelectomy. authors fully agree that this aspect is very important in the surgical treatment of varicocele. the main purpose of this study was to introduce the initial experience of new surgical technique through scarless periumbilical mini-incision, especially one of the minimally invasive method with good cosmetic result. in addition, the age of the patients was relatively high and the main symptom was not related to pregnancy, so it was difficult to deal with pregnancy related part. authors are well aware of this fact, so we plan to conduct prospective, long-term studies in the future to develop more specific and substantive results related to pregnancy rates. and also, side effects such as recurrence rate and hydrocele incidence were not fully addressed due to the limited number of patients and retrospective study setting. therefore, further prospective comparative studies on the recurrence rate and hydrocele incidence, which are the limitations of laparoscopic varicocelectomy, will require further efforts. despite some of the limitations mentioned, authors hope that this study will contribute to the development of varicocele therapy and further the results of good surgical outcomes as an option for minimally invasive surgery. dr. won ik seo assistant prof of urology urology department of inje university busan paik hospital, south korea. email: bow-boy@hanmail.net. vol 15 no 02 march-april 2018 65 appendixes 298 urology journal vol 5 no 4 autumn 2008 editorial safarinejad mr. urology journal in 2008: a new look, 1 endourology and laparoscopy simforoosh n, soufi majidpour h, basiri a, ziaee sam, behjati s, mohammad ali beigi f, aminsharifi ar. laparoscopic adrenalectomy: 10year experience, 67 procedures, 50 mostafa sa, abbaszadeh s, taheri s, nourbala mh. percutaneous nephrostomy for treatment of posttransplant ureteral obstructions, 79 basiri a, karami h, mehrabi s, javaherforooshzadeh a. laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal ureteral tumor, 120 dhawan dr, ganpule a, muthu v, desai mr. laparoscopic management of calcified paraganglioma of bladder, 126 ilbeigi p, brison d, sadeghi-nejad h. synchronous bilateral laparoscopic radical nephrectomy for solid renal masses using a hybrid approach, 192 inamoto t, azuma h, katsuoka y. re: laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal ureteral tumor, 210 gupta r, modi p, rizvi j. vanishing shaft of a double-j stent, 277 female urology razi a, yahyazadeh sr, sedighi gilani ma, kazemeyni sm. transanal repair of rectourethral and rectovaginal fistulas, 111 infectious diseases yazdani m, shahidi s, shirani m. urinary polymerase chain reaction for diagnosis of urogenital tuberculosis, 46 al-marhoon ms. is there a role for helicobacter pylori infection in urological diseases?, 139 shahbazian h, hajiani e, ehsanpour a. patient and graft survival of kidney allograft recipients with minimal hepatitis c virus infection: a casecontrol study, 178 subject index to volume 5 genetics malekzadeh shafaroudi a, mowla sj, ziaee sam, bahrami ar, atlasi y, malakootian m. overexpression of bmi1, a polycomb group repressor protein, in bladder tumors: a preliminary report, 99 inamoto t, azuma h, katsuoka y. re: overexpression of bmi1, a polycomb group repressor protein, in bladder tumors: a preliminary report, 209 karimianpour n, mousavi-shafaei p, ziaee aa, akbari mt, pourmand g, abedi a, ahmadi a, afshin alavi h. mutations of ras gene family in specimens of bladder cancer, 237 jamshidian h, kor k, djalali m. urine concentration of nuclear matrix protein 22 for diagnosis of transitional cell carcinoma of bladder, 243 infertility roshani a, falahatkar s, khosropanah i, asghari golbaghi mr, kiani sa, akbarpour m. vasal irrigation with sterile water and saline solution for acceleration of postvasectomy azoospermia, 37 naru t, sulaiman mn, kidwai a, ather mh, waqar s, virk s, rizvi jh. intracytoplasmic sperm injection outcome using ejaculated sperm and retrieved sperm in azoospermic men, 106 hikosaka a, iwase y. spermatocele presenting as acute scrotum, 206 heidary m, reza nejadi j, delfan b, birjandi m, kaviani h, givrad s. effect of saffron on semen parameters of infertile men, 255 kidney transplantation khoshdel ar, carney sl. arterial stiffness in kidney transplant recipients: an overview of methodology and applications, 3 zargar-shoshtari ma, soleimani mj, salimi h, mehravaran k. symptomatic lymphocele after kidney transplantation: a single-center experience, 34 ebadzadeh mr, tavakkoli m. lymphocele after kidney transplantation: where are we standing now?, 144 aliasgari m, shakhssalim n, dadkhah f, ghadian subject index to volume 5 299urology journal vol 5 no 4 autumn 2008 a, hosseini moghaddam smm. donor nephrectomy with and without preservation of gonadal vein while dissecting the ureter, 168 kazemeyni sm, esfahani f. influence of hypernatremia and polyuria of brain-dead donors before organ procurement on kidney allograft function, 173 shahbazian h, hajiani e, ehsanpour a. patient and graft survival of kidney allograft recipients with minimal hepatitis c virus infection: a casecontrol study, 178 einollahi b, jalalzadeh m, taheri s, nafar m, simforoosh n. outcome of kidney transplantation in type 1 and type 2 diabetic patients and recipients with posttransplant diabetes mellitus, 248 oncology, adrenal gland simforoosh n, soufi majidpour h, basiri a, ziaee sam, behjati s, mohammad ali beigi f, aminsharifi ar. laparoscopic adrenalectomy: 10year experience, 67 procedures, 50 oncology, bladder heinrich e, gattenloehner s, mueller-hermelink hk, michel ms, schoen g. paraganglioma of urinary bladder, 57 razi a, radmehr a. inflammatory pseudotumor of bladder: report of 2 cases and review of literature, 62 ather mh, alam z, jamshaid a, siddiqui km, sulaiman mn. separate submission of standard lymphadenectomy in 6 packets versus en bloc lymphadenectomy in bladder cancer, 94 malekzadeh shafaroudi a, mowla sj, ziaee sam, bahrami ar, atlasi y, malakootian m. overexpression of bmi1, a polycomb group repressor protein, in bladder tumors: a preliminary report, 99 feizzadeh b, tavakkol afshari j, rakhshandeh h, rahimi a, brook a, doosti h. cytotoxic effect of saffron stigma aqueous extract on human transitional cell carcinoma and mouse fibroblast, 161 dhawan dr, ganpule a, muthu v, desai mr. laparoscopic management of calcified paraganglioma of bladder, 126 inamoto t, azuma h, katsuoka y. re: overexpression of bmi1, a polycomb group repressor protein, in bladder tumors: a preliminary report, 209 karimianpour n, mousavi-shafaei p, ziaee aa, akbari mt, pourmand g, abedi a, ahmadi a, afshin alavi h. mutations of ras gene family in specimens of bladder cancer, 237 jamshidian h, kor k, djalali m. urine concentration of nuclear matrix protein 22 for diagnosis of transitional cell carcinoma of bladder, 243 oncology, kidney rafique m. a primary carcinoid tumor of kidney, 60 moslemi mk. adult mesoblastic nephroma: a case with fatal recurrence, 136 ilbeigi p, brison d, sadeghi-nejad h. synchronous bilateral laparoscopic radical nephrectomy for solid renal masses using a hybrid approach, 192 gangane n, anshu, shende n, sharma sm. mucinous cystadenoma arising from renal pelvis: a report of 2 cases, 197 janitzky a, reiher f, porsch m, grube c, evert m, liehr ub. an unusual case of birt-hogg-dube syndrome with renal involvement, 272 oncology, prostate sevinc c, akpinar h, tufek i, obek c, kural ar. radical retropubic prostatectomy as a solo therapy for treatment of adult rhabdomyosarcoma, 203 basiri a, radfar mh. conservative management of early bladder rupture after postoperative radiotherapy for prostate cancer, 269 oncology, testis ghadiany m, attarian h, hajifathali a, khosravi a, molanaee s. relapse of acute myeloid leukemia as isolated bilateral testicular granulocytic sarcoma in an adult, 132 oncology, ureter basiri a, karami h, mehrabi s, javaherforooshzadeh a. laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal ureteral tumor, 120 inamoto t, azuma h, katsuoka y. re: laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal ureteral tumor, 210 subject index to volume 5 300 urology journal vol 5 no 4 autumn 2008 oncology, others zare s, parvin m, ghohestani sm. retroperitoneal ganglioneuroma, 232 pediatric urology ziaee sam, javaherforooshzadeh a. priapism in a 15-year-old boy with major beta-thalassemia, 55 basiri a, zare s, shakhssalim n, hosseini moghaddam sm. ureteral calculi in children: what is best as a minimally invasive modality?, 67 seyedzadeh a, kompani f, esmailie e, samadzadeh s, farshchi b. high-grade vesicoureteral reflux in pfeiffer syndrome, 200 bazmamoun h, ghorbanpour m, mousavibahar sh. lubrication of circumcision site for prevention of meatal stenosis in children younger than 2 years old, 233 reconstructive surgery razi a, yahyazadeh sr, sedighi gilani ma, kazemeyni sm. transanal repair of rectourethral and rectovaginal fistulas, 111 durazi mh, jalal aa. penile prosthesis implantation for treatment of postpriapism erectile dysfunction, 115 zargar-shoshtari ma, mehravaran k, salimi h, kaffash nayyeri r. retroperitoneal ureterocyctoplasty in bilaterally functioning kidneys, 123 hosseini sj, kaviani a, vazirnia ar. internal urethrotomy combined with antegrade flexible cystoscopy for management of obliterative urethral stricture, 184 hosseini j, tavakkoli tabassi k. surgical repair of posterior urethral defects: review of literature and presentation of experiences, 215 hosseini j, kaviani a, golshan ar. clean intermittent catheterization with triamcinolone ointment following internal urethrotomy, 265 sexual dysfunction akgül t, karakan t, ayyıldız a, germiyanoğlu c. comparison of sertraline and citalopram for treatment of premature ejaculation, 41 durazi mh, jalal aa. penile prosthesis implantation for treatment of postpriapism erectile dysfunction, 115 mehraban d, naderi gh, yahyazadeh sr, amirchaghmaghi m. sexual dysfunction in aging men with lower urinary tract symptoms, 260 wadhera s, patidar n, odiya s, ghanghoria a, mathur r, kumar gupta a. true hermaphrodism presenting as pelvic abscess, 275 stone diseases kumar p. radiation safety issues in fluoroscopy during percutaneous nephrolithotomy, 15 darabi mahboub mr, shakibi mh. percutaneous nephrolithotomy in patients with solitary kidney, 24 etemadian m, haghighi r, madineay a, tizeno a, fereshtehnejad sm. delayed versus same-day percutaneous nephrolithotomy in patients with aspirated cloudy urine, 28 basiri a, zare s, shakhssalim n, hosseini moghaddam sm. ureteral calculi in children: what is best as a minimally invasive modality?, 67 wadhera s, mathur rk, odiya s, raikwar rs, girish g. solo extracorporeal shock wave lithotripsy for management of upper ureteral calculi with hydronephrosis, 84 rabbani smr. treatment of steinstrasse by transureteral lithotripsy, 89 hadjzadeh mr, mohammadian n, rahmani z, behnam rassouli f. effect of thymoquinone on ethylene glycol-induced kidney calculi in rats, 149 ketabchi aa, aziziolahi ga. prevalence of symptomatic urinary calculi in kerman, iran, 156 soufi majidpour h, yousefinejad v. percutaneous management of urinary calculi in horseshoe kidneys, 188 others nadjafi-semnani m, simforoosh n, ghanbarzadeh n, miri mr. real-time point-to-point wireless intranet connection: first implication for surgical demonstration and telementoring in urologic laparoscopic surgery in khorasan, 74 rokni yazdi h, moharamzad y. endovascular treatment of renal arteriovenous fistula following a stab wound, 129 rafique m. intravesical foreign bodies: review and current management strategies, 223 rajaian s, kumar s, gopalakrishnan g. persistent multiple vesicocutaneous fistulas or watering-can abdomen, 280 madineh sma. avicenna’s canon of medicine and modern urology: part i: bladder and its diseases, 284 vol 16 no 02 march-april 2019 115 endourology and stone disease the effect of percutaneous nephrostomy implementation on the outcome of ureteroscopic stone treatment fuat kızılay1*, adnan simsir1, barıs altay1, oktay nazlı1, i̇brahim cüreklibatır1, bülent semerci1 purpose: we aimed to investigate the effect of percutaneous nephrostomy (pcn) implementation on the second ureteroscopy (urs) outcomes after a failed urs. materials and methods: the data of four hundred forty-eight patients with an unsuccessful urs history were evaluated. patients were divided into two groups; patients who underwent pcn before second urs (group a) and patients who did not (group b). we compared the stone access rate in the second urs between the two groups according to patient and stone characteristics and operative data. then, group a was subdivided into two groups according to stone access as; access succeeded (group a1) and access failed (group a2). we also compared stone access rates between these two groups in terms of gender, age, body mass index, stone size, side, location, grade of hydronephrosis and pcn duration. all data were available immediately after surgery and obtained from patient files and the outcome assessment was performed during the study period. results: stone access rate was higher in group a than group b (143/196 vs 41/252, p = .0018). mean nephrostomy duration and mean hydronephrosis grade were significantly higher and mean stone size was significantly lower in group a1 than group a2 (18.74 vs 9.62 days, p < .001; grade 3.25 vs 1.21, p = .038; and 7.286 vs 12.631 mm p < .001, respectively). conclusion: pcn is a favourable intervention after a failed urs and increases the success rate of the second operation with ease of implementation and minimal morbidity. keywords: percutaneous nephrostomy; ureterolithiasis; ureteroscopy; urinary diversion introduction ureteroscopy (urs) has begun with hugh hamp-ton young's observation of a child’s over-dilated ureter with a posterior urethral valve (puv) in 1912, using a pediatric cystoscope (1) and has now been widely utilized in ureterolithiasis treatment. the most common indication for urs is a symptomatic ureteral calculus with a very low likelihood of spontaneous passage(2). rigid urs has begun to be used in the 1980s for the first time in the treatment of ureteral stones. despite the wide calibrated urss (> 10 fr), high success rates were reported(3). with the development of new technologies in the past three decades, a new era has started in endourology. thin and flexible urss has rapidly changed the endourology practice(4). however, the flexible urs device is expensive and fibre optics require frequent repair(5) and is not widely available in our country. percutaneous nephrostomy (pcn) has been used since 1955 for the treatment of postrenal obstruction or before an endourological intervention with the intent of urinary diversion(6,7). pcn decompresses the urinary tract in the presence of ureter stone with high success and low complication rates(8). indwelling a double j stent (djs) is another method that is as effective as pcn for decompressing purpose. 1department of urology, ege university school of medicine, izmir 35100, turkey. *correspondence: urology department, ege university school of medicine, bornova, 35100, izmir, turkey tel:+90 232 390 25 15 . fax: +90 232 374 65 52. e-mail: fuatkizilay@gmail.com. received november 2017 & accepted march 2018 it has been shown that the first urs fails and subsequent urs is required in 10-15% of cases(9). it is a preferred method to indwell a djs and to treat the stone with a second urs after a while when the urologist cannot access the stone in the first urs. however, sometimes it is not possible to indwell a djs probably due to the guidewire being unable to pass through an impacted stone. in this case, it is a rational option to decompress the collecting system with a pcn and perform the second urs after a while. we proposed that the pcn might facilitate the second urs after a failed urs and we aimed to evaluate whether pcn implementation after a failed urs facilitates the second operation in the present study. we hypothesized that pcn would induce a passive dilation in the ureter, decompress the collecting system and facilitate the second ureterorenoscopy by reducing intrapelvic and intraureteral pressures and increasing pelviureteric peristalsis as shown in figure 1. patients and methods study population patients older than 18 years with symptomatic ureteral stones detected by imaging methods (non-contrast computerized tomography [ncct], ultrasonography [usg], x-ray) and who had a failed urs story were percutaneous nephrostomy and ureteroscopy-kızılay et al. included in the study and the data of these patients were analyzed. in the vast majority of patients (398/448, 88.8%), ncct, which is accepted as the gold standard for the urinary system stone diagnosis, had been used. additional opaque imaging with ct-urography had been performed in 22 patients with ureteral stricture suspicion. intravenous urography (ivu) had not been used in any patient. all patients had surgical indications and did not benefit from medical treatment. patients with urethral or ureteral stricture, urinary diversion story and pregnancy were not included (n = 28). after the first failed urs, 19 patients who passed the stones spontaneously had not been also included in the study. informed consent had been obtained at least 48 hours before the operations. all patients had hydronephrosis in varying grades on ncct. classification of hydronephrosis was made from grade 1 to 4 according to the system of the society for fetal urology(10). since this classification was most often made according to usg findings, all patients included in the study had undergone renal usg. study design this historical cohort study included 448 patients who had undergone a second operation after a failed urs between january 2010 and july 2017. in the same period, a total of 6228 urs operations had been performed in our clinic. first, the patients were divided into two groups; those who underwent pcn (group a, n = 196) and those who did not undergo pcn (group b, n = 252). the two groups were compared in terms of stone access rate. subsequently, the group a was subdivided into two groups: access succeeded (group a1, n = 143) and access failed (group a2, n = 53). antegrade djs or antegrade flexible urs had been planned for the 53 patients with failed second urs after pcn implementation. in group b, pcn and re-urs had been planned for 211 patients whose stone was inaccessible in the second urs. factors affecting successful access in the two groups were compared. figure 2 shows the study flowchart. the study was conducted in accordance with the declaration of helsinki. surgical technique the informed consent form was obtained from the patients and sterile urine culture was provided prior to the ureteroscopy procedure. intravenous 1 gr cefazolin was administered to patients following spinal anaesthesia. in the lithotomy position, 5% lidocaine gel was applied to the urethra. all the procedures were performed by semirigid ureteroscopes with 8 or 9 fr distal tip (storz®, tuttlingen, germany). 8 fr ureteroscope was used in 296 of 448 patients (66.1%) and 9 fr ureteroscope was used in 152 patients (33.9%). a 0.038 in ×150 cm sized polytetrafluoroethylene (ptfe) coated guidewire (boston scientific®, usa) with 3 cm flexible tip was used routinely to guide ureteroscope. a sensor dual-flex ptfe-nitinol guidewire with hydrophilic figure 1. a schematic view of the impact of a percutaneous nephrostomy. the urine in the collecting system is taken out by the catheter bag in the direction of the blue arrows, so that the intrapelvic pressure indicated by the yellow star decreases figure 2. study flowchart. aureteroscopy bpercutaneous nephrostomy endourology and stones diseases 116 vol 16 no 02 march-april 2019 117 tip (boston scientific®, usa) was used as a second alternative when the first guidewire could not pass. all ureteroscopies were performed in a retrograde manner. if stone access achieved, a stonelight® holmium laser lithotripter was used for stone fragmentation. if the stone could not be accessed, the absence of a ureteral stricture was confirmed by administering a diluted opaque substance with saline solution with low pressure from the lumen of the ureteroscope under the fluoroscopy view. a 16 fr foley’s catheter was introduced to the bladder with the completion of the operation and was taken on the same day or one day later. the ureteroscopy procedure and instrumentation are shown in figure 3. after the first urs, 196 patients (group a) underwent pcn on day 1 postoperatively. our criteria for implementing a pcn in the postoperative period were the presence of lumbar pain resistant to medical treatment, hydronephrosis at varying grades, and the patient's acceptance of the procedure. because it is an interventional procedure, the informed consent form was taken from the patients. eight fr pcn tube (rüsch teleflex®, usa) was inserted by interventional radiology. five ml of 2% prilocaine was injected into the planned access tract before implementation. the patient was placed in the prone position on the ultrasound table. then a pillow was placed under the access side to allow the kidney to move upwards. after 10 minutes, pcn was introduced into more dilated renal calyx under ultrasound guidance. a percutaneous nephrostomy view is schematized in figure 1. patients had been discharged after a period of observation (in terms of haemorrhage and fever) on the same day following the implementation of pcn. an appointment had been made for the second urs and re-urs had been applied at the date of the appointment. dates had been determined for second urss and patients underwent re-urss on acquisition dates. patients had been left with pcns until the second operations. in urs, success had been defined according to stone access. in the third month follow-up, patients had undergone ncct to assess the residual fragments or strictures. the presence of stones smaller than 4 mm or absence of any residual fragment had been defined as "stone free". outcome assessment our primary outcome measurement was successful access to the stone in the second urs and comparison of two groups (group a and b) in terms of patient and stone characteristics. secondary outcome measurement was to evaluate factors affecting successful access in group a in terms of gender, age, body mass index (bmi), stone size (mm), side (right or left), location (proximal, middle and distal), grade of hydronephrosis and pcn duration (day). all data were recorded and retrospectively collected from patient files. categorical data were examined with the mann–whitney u, chi-square and ficher’s exact tests. shapiro-wilk test was performed for the evaluation of the normal distribution of numerical data. independent two group t-tests were used for numerical data as the data were normally distributed. roc analysis was performed to establish cut-off values predictive for stone access in 75% of the patients. a two-tailed p value less than 0.05 was considered statistically significant. all analyses were performed using ibm spss® statistics 23.0. results a total of 448 patients who had undergone a failed urs were enrolled in the study. the reasons for failure in the first urs were as follows; unable to pass the guidewire proximally to the stone in 322 patients, to approach to the stone with ureteroscope allowing efficacious stone fragmentation in 62 patients and displacement of distal located ureteral stone to proximal ureter with the ef group a (n = 196) group b (n = 252) p-value (mean ± standard) age (year) mean 34.97 ± 1.23 35.47 ± 0.65 .663a range 18-54 19-59 gender male 130 (66.7%) 164 (65.4%) .322b female 66 (33.3%) 88 (34.6%) body mass index male 23.11 ± 1.44 24.19 ± 1.21 .242a female 21.96 ± 1.18 22.75 ± 1.03 .319a laterality right 114 (58.3%) 137 (54.5%) .653c left 82 (41.7%) 115 (45.5%) location proximal 73 (37.5%) 100 (40.0%) middle 77 (39.5%) 73 (29.1%) .451c distal 46 (22.9%) 79 (30.9%) stone sizea (mm) 8.73 ± 1.18 9.95 ± 1.34 .326 operation timea (min) 24.45 ± 0.56 23.66 ± 1.22 .524 hydronephrosis gradea 2.23 ± 1.16 2.42 ± 1.05 .128 time to second ureteroscopya (day ) 28.36 ± 0.85 26.66 ± 1.28 .216 access to stone in the second ureteroscopy 143/196 (72.91%) 41/252 (16.36%) .0018 table 1. characteristics and clinical data of the patient groups. values are given as mean ± standard deviation or number % a independent-samples t-test b fisher's exact test c pearson chi-square percutaneous nephrostomy and ureteroscopy-kızılay et al. fect of pressurised saline fluid and failure to proceed proximally with ureteroscope in 64 patients. in the first operation, 38 patients had grade i (mucosal injury, n = 18; hematuria, n = 20), 51 patients had grade ii (urinary tract infections) and 64 patients had grade iiia (proximal stone migration) complications according to clavien-dindo classification. overall, the mean age of the patients was 35.22 (18-59) years and 66.5% of the patients were male. stone access rate was significantly higher in group a (p = .0018). in the nephrostomy-implemented group, 72.91% of the stones could be accessed, while only 16.36% of the stones could be accessed in the non-nephrostomy group. in group a, the second urs had failed in 11 patients, because the guidewire could not be passed proximally to the stone and the stone had been pushed-back to the collecting system in 42 patients. in grup b, urs had failed in 176 patients, because of being unable to pass the guidewire proximally to the stone and the push back phenomenon in 35 patients. in the second operation, complications were grade i in 26 patients (mucosal injury, n = 12; hematuria, n = 14), grade ii in 44 patients and grade iiia in 77 patients. demographic and clinical data of the patients are shown in table 1. then, we divided the pcn-group (group a) into two groups; stone access succeeded (group a1, n = 143) and stone access failed (group a2, n = 53). we performed a subgroup analysis comparing these two groups in terms of patient and stone characteristics, pcn duration and hydronephrosis grade. mean hydronephrosis grade was significantly higher in group a1 than group a2 (3.25 ± 0.76 vs 1.21 ± 1.09, p = .038). mean time between pcn implementation and urs was significantly longer in group a1 (18.74 ± 1.14 vs 9.62 ± 0.97, p < .001). there was an inverse relationship between the groups regarding the stone size, as follows, it was significantly larger in group a2 than group a1 (12.631 ± 0.88 vs 7.286 ± 1.02 mm, p < .001). table 2 summarizes the comparison of subgroups of group a (groups a1 and a2). since the stone size and pcn duration were important factors affecting stone access in comparison of group a1 and a2, we performed roc analysis to determine the predictive values of stone access in 75% of the patients as shown in table 3. the area under the roc curve (95% ci) for the prediction of stone access was 0.990 (0.970–1.000) for the stone size. the optimal cutoff value in the prediction of stone access was 9 mm for the stone size, with 91.4% sensitivity and 92.3% specificity. likewise, the area under the roc curve (95% ci) for the prediction of stone access was 0.985 (0.956– 1.000) for the pcn duration. the optimal cut-off value in the prediction of stone access was 13 days for the pcn duration, with 94.3% sensitivity and 100% specificity. we determined 9 mm and 13 days for stone size and pcn duration, respectively, as predictive values for successful stone access in 75% of patients. discussion urs is frequently used in the treatment of ureterolithiasis and provides high success rates. shield et al. reported a 14.6% failure rate in the initial urs(9). urs outcomes of high-volume centres were shown to be better than low-volume centres(11). in our clinic, during the study period, a total of 6228 patients underwent urs due to ureteral stone and 448 urs failed, our failure rate was 7.19%. normally the pcn requirement rate for djs failure is < 1%, and pcn is used to treat septic complications and to relieve symptoms of patients. in table 2. demographic and clinical data of group a1 (stone access succeeded) and group a2 (stone access failed) group a1 group a2 p-value n = 143 n = 53 age (year) mean 32.86 ± 1.86 34.45 ± 1.08 .982a range 18-49 21-54 gender male 84 (58.7%) 30 (56.6%) .170b female 59 (41.3%) 23 (43.4%) body mass index male 22.81 ± 1.24 23.42 ± 0.89 .121a female 21.12 ± 1.43 22.81 ± 1.22 laterality right 65 (45.4%) 23 (43.4%) .701c left 78 (54.6%) 30 (56.6%) location proximal 43 (30.1%) 21 (39.6%) .669c middle 51 (35.7%) 19 (35.8%) distal 43 (34.2%) 13 (24.6%) stone size (mm) 7.286 ± 1.02 12.631 ± 0.88 < .001a nephrostomy duration (day) 18.74 ± 1.14 9.62 ± 0.97 < .001a hydronephrosis grade 3.25 ± 0.76 1.21 ± 1.09 .038a values are given as mean ± standard deviation or number % a independent-samples t-test b fisher's exact test c pearson chi-square auc 95% ci sensitivity specificity p-value stone sizea 0.990 0.970–1.000 91.4% 92.3% < .001 pcn durationb 0.985 0.956–1.000 94.3% 100% < .001 abbreviations: auc, area under curve; ci, confidence interval. a for stone size < 9 mm b for nephrostomy duration longer than 13 days table 3. roc analysis of stone size and percutaneous nephrostomy duration for successful stone access in 75% of the patients percutaneous nephrostomy and ureteroscopy-kızılay et al. endourology and stones diseases 118 vol 16 no 02 march-april 2019 119 our series, this rate is quite high (43.8%) because we did not use pcn for therapeutic purposes in these patients, we applied the pcn with the prediction that pcn will facilitate the second urs. currently, there are two methods to decompress the renal collecting system: ureteral stents and percutaneous nephrostomy tube. both methods have similar success rates. pcn placement is a frequently used method in urology practice for both malignant and benign pathologies(12-15). kwon et al.(16) evaluated the effectiveness of pcn during urs in the treatment of upper ureteral stones. they divided the subjects into two groups depending on the presence of a pcn at the time of surgery and they found significantly better outcomes in terms of operative time (57.4 minutes vs 68.1 minutes) and success rate (92.9% vs 78.6%) with similar complication rate in the pcn group. in our study, the mean operation time of the two groups was similar, but the success rate was significantly higher in the pcn group comparable to this study. although the proximal stones were much more than the distal stones (46 vs 40) in group a1, the difference was not significant and we found that stone localization had no effect on success rates. the same authors assessed the efficacy of pcn during flexible urs in the treatment of renal stones. they enrolled 130 patients and divided them into two groups depending on the presence of pcn during the surgery. they concluded that pcn provided higher stone-free rates in flexible urs treatment without increasing the operation time and complication rates(17). in the case of sepsis, which is caused by an obstructing stone, urgent decompression of the collecting system is required(18). the choice between pcn and stent is based on factors such as disease severity, stone size, localization of stone, planned stone treatment method, and the presence of interventional radiology. none of our patients had sepsis or pyonephrosis during the first urs, but all had hydronephrosis at varying grades. our patients underwent pcn for the purpose of facilitating second urs by decompressing the collecting system, not for emergency intervention. but in this way, we may have prevented the emergency case that the obstructed stone may cause in our patients afterwards. the quality of life (qol) of patients undergoing djs or pcn is also an important issue. mokhmalji et al. concluded that both methods negatively affect the qol of patients and this effect has been shown to be similar (19). while stents lead to mostly lower urinary tract complaints such as irritative voiding symptoms and hematuria, pcn may lead to ergonomic problems such as inconvenience of carrying the nephrostomy tube and bag, poor cosmetic image and perhaps the most important one, easy dislocation of the tube. although we did not make a detailed inquiry for the inconvenience of pcn in our patients, we observed only mild pain in three of them. our centre is a national referral centre for treatment of ureterolithiasis. flexible urs is also available in our clinic. but when this fragile and expensive device breaks down, the repair process takes a long time since our hospital is a public university hospital and the complicated bureaucratic procedures last long. so, we have to treat the majority of our patients with semi-rigid urs. also, we do not have a thinner urs with 4 or 6 fr diameter. we occasionally come across the problem of inaccessibility to the stone during urs treatment in our high case volume clinic. when we can not access the stone and indwell a djs in initial urs, we prefer to place a pcn expecting to alleviate hydronephrosis, prevent sepsis and facilitate the second urs. the pathophysiology of ureteral colic has not been fully elucidated. but it is an accepted view that ureteral spasm inhibits organized antegrade peristalsis by leading to a significant increase in tonic smooth muscle contraction and two main factors that facilitate the stone passage are the increase of the hydrostatic pressure in the proximal part of the stone and the relaxation of the ureter muscles where the stone is located. in their experimental studies, meini et al.(20) have shown that peristalsis can be both antegrade and retrograde route. during ureteral colic, each cell may induce an action potential in response to depolarization and as a result, disorganized peristalsis may occur consequently. lennon et al.(21) compared the effects of double pigtail ureteric stent and pcn on stone transit and ureteric motility in 12 dogs. they concluded that djs induces ureteric dilatation, diminishes peristalsis and impairs stone passage and proximal pcn tube drainage can facilitate spontaneous stone passage by preventing ureteral dilation and maintaining antegrade peristalsis. they emphasized that in the initial phase, increasing hydrostatic pressure is probably the most important factor figure 3. ureteroscopy procedure and instrumentations. a) photograph of semi-rigid ureteroscope used in operations, b) fluoroscopic image of a guidewire pushed forward from the left distal ureter to the proximal ureter, c) fluoroscopic image of a guidewire, which could not be pushed forward to proximal due to an impacted stone in the left ureter, black arrow shows the impacted stone, d) endoscopic view of fragmentation of the stone in the ureter with holmium laser lithotripsy percutaneous nephrostomy and ureteroscopy-kızılay et al. determining stone passage. in this case, it is proper to express that pcn can facilitate stone passage and access to stones by leading to relaxation in ureteral muscles and preventing ureteral dilatation. the results of these studies and the pathophysiological mechanisms they emphasize, almost clarify the outcome “pcn facilitates the second urs” that we achieved in our study. with the results we have obtained, we also consider that pcn may facilitate the ureteroscopy or allow spontaneous stone passage by providing this effect in the human ureter. although it is thought that pcn may have a preventive role in the expulsion of the stones by reducing proximal urinary system pressure, this view did not apply to our study. because we consider that the ureter should be entirely evaluated due to its anatomical and physiological properties. the effect on the proximal as distal as the stone is also important, and we propose that pcn will prevent dilation of the entire ureter and also inhibit ureteral muscle spasm. although we found that pcn facilitates the second urs and revealed important parameters affecting the success rate, our study has some limitations; 1) the design of our study was retrospective, 2) urs operations were performed by different urologists. the experience of the surgeon is an important factor affecting the outcome of an operation. conclusions our data suggest that decompressing renal collecting system with a pcn is a logical choice to facilitate reurs when ureteral stone access has failed in an initial urs. 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solvig j, johansen teb. singlecentre review of radiologically guided percutaneous nephrostomy using “mixed” technique: success and complication rates. eur j radiol. 2011;80:553-8. 8. lynch mf, anson km, patel u. percutaneous nephrostomy and ureteric stent insertion for acute renal deobstruction consensus based guidance. br j med surg urol. 2008;1:120-5. 9. shields jm, bird vg, graves r, gómez-marín o. impact of preoperative ureteral stenting on outcome of ureteroscopic treatment for urinary lithiasis. j urol. 2009;182:2768-74. 10. beetz r, bökenkamp a, brandis m, et al. diagnosis of congenital dilatation of the urinary tract. consensus group of the pediatric nephrology working society in cooperation with the pediatric urology working group of the german society of urology and with the pediatric urology working society in the germany society of pediatric surgery. urologe a. 2001;40:495. 11. kandasami sv, mamoulakis c, el-nahas ar, et al. impact of case volume on outcomes of ureteroscopy for ureteral stones: the clinical research office of the endourological society ureteroscopy global study. eur urol. 2014;66:1046-51. 12. lee wj, patel u, patel s, pillari gp. emergency percutaneous nephrostomy: results and complications. j vasc interv radiol. 1994;5:135-9. 13. avritscher r, madoff dc, ramirez pt, et al. fistulas of the lower urinary tract: percutaneous approaches for the management of a difficult clinical entity. radiographics. 2004;24:s217-s36. 14. kanou t, fujiyama c, nishimura k, tokuda y, uozumi j, masaki z. management of extrinsic malignant ureteral obstruction with urinary diversion. int j urol. 2007;14:689-92. 15. nariculam j, murphy d, jenner c, et al. nephrostomy insertion for patients with bilateral ureteric obstruction caused by prostate cancer. br j radiol. 2009;82:571-6. 16. kwon sy, choi jy, kim bs, kim ht, yoo es, park yk. efficacy of percutaneous nephrostomy tube during ureteroscopy for upper ureter stone management. j endourol. 2013;27:1209-12. 17. kwon sy, kim bs, kim ht, park yk. efficacy of percutaneous nephrostomy during flexible ureteroscopy for renal stone management. korean j urol. 2013;54:689-92. 18. lynch mf, anson km, patel u. current opinion amongst radiologists and urologists in the uk on percutaneous nephrostomy and ureteric stent insertion for acute renal unobstruction: results of a postal survey. bju int. 2006;98:1143-4. 19. mokhmalji h, braun pm, portillo fjm, siegsmund m, alken p, köhrmann ku. percutaneous nephrostomy versus ureteral stents for diversion of hydronephrosis caused percutaneous nephrostomy and ureteroscopy-kızılay et al. endourology and stones diseases 120 vol 16 no 02 march-april 2019 121 by stones: a prospective, randomized clinical trial. j urol. 2001;165:1088-92. 20. meini s, santicioli p, maggi ca. propagation of impulses in the guinea-pig ureter and its blockade by calcitonin gene-related peptide (cgrp). naunyn schmiedebergs arch pharmacol. 1995;351:79-86. 21. lennon g, thornhill j, grainger r, mcdermott t, butler m. double pigtail ureteric stent versus percutaneous nephrostomy: effects on stone transit and ureteric motility. eur urol. 1997;31:24-9. percutaneous nephrostomy and ureteroscopy-kızılay et al. comparison of the ratio of the lenght of the second and fourth digits in subgroups of fertile and infertile cases purpose: to identify any relationship between known reasons of male infertility and 2d:4d ratio. materials and methods: a total of 371 males were included in the study. the cases were grouped into 6 groups including sperm count < 5 million/ml, sperm count ≥ 5 million/ml, klinefelter syndrome, hypogonadotropic hypogonadism, vasal agenesis and control. groups were compared with each other in terms of 2d:4d ratios and groups with a 2d:4d ratios below 1 and equal/above 1 were compared. results: the greatest ratios were in the vasal agenesis and hypogonadotropic hypogonadism groups and analysis of the data with logistic regression analysis showed that there was a significant difference in terms of 2d:4d ratios for these groups when comparing with control group. the other groups showed no statistically significant differences. conclusion: the results of the present study showed some significant difference between 2d:4d ratios for the subgroups of the fertile and infertile cases. although, 2d:4d ratio is not an unaccompanied parameter to reveal causes of male infertility, it can be associated with some situations that are related with male infertility. keywords: 2d:4d; digit lenght ratio; fluctuation asymmetry; hox gene; infertility. introduction in vertebrates homeobox (hox) gene family is nec-essary for development of limbs and genitalia(1,2). the members of hox gene family, hoxa and hoxd, are needed for differentiation of the genital bud and growth and formation of the digits(3). it has been suggested that the relationship between those 2 distinct body parts is not solely the common genetic control during their developmental stages, but also other factors may be effective. among those factors, prenatal sex steroids are the most commonly studied. differences in prenatal hormone levels in female and male fetuses cause their genital developments to progress in different directions after a certain step. in men second digit is typically shorter than 4th digit whereas second digit in women is generally equal to or longer than 4th digit. hence, length of the 2nd digit to that of 4th digit (2d:4d ratio) is less than 1 in majority of men and equal to or greater than 1 in most women(4). we aimed in this study, by hypothesizing that 2d:4d ratio could be related to infertility, to identify any relationship between known reasons of male infertility and 2d:4d ratio. materials and methods study design a non-interventional, prospective and cross sectional study was designed in erciyes university urology department between april 2011 and may 2013. study population a total of 331 men who attended to our clinic with comdepartment of urology, medical faculty, erciyes university, melikgazi, kayseri, 38280, turkey. *correspondence: department of urology, medical faculty, erciyes university, melikgazi, kayseri, 38280, turkey. tel: +90 532 5881646. fax: +90 352 4375285. e-mail: emreakinsal@hotmail.com. received july 2016 & accepted may 2017 plaints of infertility and 40 men who fathered at least one child were included the study. cases with congenital or acquired digit deformity in 2nd or 4th digit of the right or left hand were excluded. evaluations palmar surfaces of the right and left hand of the cases were transferred to digital medium with the help of a scanner (hewlett packard® scanjet g3110). lengths of 2nd and 4th digit were measured with a digital caliper with a sensitivity of 0.01 mm (mitutoyo®). to measure the length of 2nd digit, the distance between the midpoint of the proximal line separating the digit stem from palm and the tip of the index digit was used. to measure the length of 4th digit, the distance between the midpoint of the proximal line separating the digit stem from palm and the tip of the fourth digit was used. the distances were measured in millimeters and recorded. next, the ratio of 2nd digit to 4th digit (2d:4d) was calculated and recorded for both hands in each case. at a later stage of the study, a semen analysis was performed in cases other than those in fertile control group at least one time and preferably 2 times and the analysis was evaluated according to the world health organization (who) 2010 criteria(5). outcomes with laboratory and physical examination findings, the cases were grouped into 6 groups: 46 xy-genotype cases with nonobstructive azoospermia and severe oligoastenozoospermia (sperm count less than 5 million/ ml) (n = 115), cases with a sperm count above 5 million/ml (n = 90), cases with klinefelter syndrome (n = sexual dysfunction and infertility emre can akinsal*, abdullah demirtas, oguz ekmekcioglu sexual dysfunction and infertility 3081 65), cases with hypogonadotropic hypogonadism (n = 27), cases with vasal agenesis (n = 34), and the control group with children (n = 40). groups were compared with each other in terms of 2d:4d ratios and groups with a 2d:4d ratios below 1 and equal/above 1 were compared. ethics informed consent was obtained from all cases. the study was approved by the ethics committee. statistical analysis: all statistical analyses were performed using spss 20.0 for windows® statistical software package (chicago,usa). categorical variables were compared using logistic regression analysis. a p value less than .05 was considered statistically significant. results assessment of cases with a 2d:4d ratio in right hand equal to or greater than 1 with other cases in their group revealed that this condition is present in 11 of 115 cases (9.6%) with sperm count < 5 million/ml (group 1), 13 of 90 cases (14.4%) with a sperm count above 5 million/ ml (group 2), 5 of 65 cases (7.7%) with klinefelter syndrome (group 3), 5 of 27 cases (18.5%) with hypogonadotropic hypogonadism (group 4), 10 of 34 cases (29.4%) with vasal agenesis (group 5), and 4 of 40 cases (10%) in the control group (group 6). distribution of the groups for right hand was shown in table 1. the greatest ratios were in the vasal agenesis and hypogonadotropic hypogonadism groups and analysis of data with logistic regression analysis showed that there was a significant difference between control group and vasal agenesis group in terms of 2d:4d ratios (p = .041)(table 2). 2d:4d ratios were also assessed in left hand. number of cases with a 2d:4d ratio equal to or above 1 were 18 (15.7%) in group 1, 17 (18.9%) in group 2, 7 (10.8%) in group 3, 7 (25.9%) in group 4, 9 (26.5%) in group 5, 2 (5%) in group 6 (table 1). like the right hand, higher ratios were detected in hypogonadotropic hypogonadism and vasal agenesis groups. both groups showed statistically significant differences when compared with the control group. p values were .025 and .019 respectively (table 2). discussion this clinical study compared infertile case groups with fertile control group separately in right and left hand in terms of that the digit ratio is below 1, or equal to or greater 1. the percentage of cases with a 2d:4d ratio equal to or greater than 1 was specially higher among vasal agenesis and hypogonadotropic hypogonadism groups and some statistically significant differences were detected. the discovery that hox genes are necessary for develvol 14 no 02 march-april 2017 3029 table 1. distribution of the groups according to 2d:4d ratio. right 2nd and 4th digit ratio left 2nd and 4th digit ratio group no groups < 1 ≥ 1 < 1 ≥ 1 n, (%) n, (%) n, (%) n, (%) total 1 sperm count < 5 million/ml 104 (90.4) 11 (9.6) 97 (84.3) 18 (15.7) 115 2 sperm count ≥ 5 million/ml 77 (85.6) 13 (14.4) 73 (81.1) 17 (18.9) 90 3 klinefelter syndrome 60 (92.3). 5 (7.7) 58 (89.2) 7 (10.8) 65 4 hypogonadotropic hypogonadism 22 (81.5) 5 (18.5) 20 (74.1) 7 (25.9) 27 5 vasal agenesis 24 (70.6) 10 (29.4) 25 (73.5) 9 (26.5) 34 6 control group 36 (90.0) 4 (10.0) 38 (95.0) 2 (5.0) 40 total 323 (87.1) 48 (12.9) 38 (95.0) 60 (16.2) 371 right hand p left hand p or (95%ci) or (95%ci) control group 1.00 1.00 group 1 0.95 (0.29-3.18) .936 3.53 (0.78-15.93) .102 group 2 1.52 (0.46-4.99) .490 4.43 (0.97-20.16) .055 group 3 0.75 (0.19-2.98) .682 2.29 (0.45-11.63) .316 group 4 2.05 (0.50-8.44) .323 6.65 (1.26-35.05) .025 group 5 3.75 (1.05-13.35) .041 6.84 (1.36-34.33) .019 table 2. comparison of the subgroups according to 2d:4d ratio with logistic regression analysis. digit ratios in male infertility-akinsal et al. vol 14 no 03 may-june 2017 3082 opment of genital bud and growth of the digits followed by demonstration of hox gene expression products in spermatozoa after meiotic division has led to the idea that hox genes and hence digit characteristics may be related with fertility(6). manning et al. studied the relationship between 2d:4d ratio and sperm count. they compared 12 males with germ cell failure with 46 males with normal semen parameters in terms of right and left hand 2d:4d ratios. they reported a significant difference in right hand ratios and an insignificant difference in left hand ratios(7). the number of cases and subgroups in our study was much greater than this study. in this way, some comments can be done about which male infertility reason is more relevant with digit ratios. the studies supporting the relationship between fertility and digit ratio are also not scarce. wood et al. conducted a study with 44 cases to explore this relationship. among their study population, 16 cases had nonobstructive azoospermia, 4 had bilateral vasal agenesis, and 24 previously fertile vasectomized cases had azoospermia. the authors investigated the relationship between the success of surgical sperm extraction and 2d:4d ratios in these groups. furthermore, they also compared the rates of having children and clinical pregnancy rates with 2d:4d ratios in cases with a successful sperm extraction procedure. this study found that 2d:4d ratios were lower in previously fertile vasectomized patients compared with nonobstructive azoospermic cases. cases with nonobstructive azoospermia who had a successful sperm extraction procedure had a lower 2d:4d ratio in right hand than those with an unsuccessful procedure. none of the cases with a successful sperm extraction procedure had a left hand 2d:4d ratio greater than 1. the pregnancy success in cases with successful surgical extraction was not affected by 2d:4d ratio(8). to our opinion, the most important point in this study that can be criticized is that the cases with bilateral vasal agenesis were not assessed as a separate group but rather included in a larger group, largely because their number was low. that is because the cases were divided into two large groups as congenital and acquired azoospermic cases and the cases with bilateral vasal agenesis were assessed as a whole with nonobstructive azoospermia and compared with vasectomized cases.. the pathology in cases with vasal agenesis is the absence of ductus deferens. most of the testicular functions are intact in these cases and the chance of finding sperms surgically is high(9). therefore, the presence of this small group that has a high rate of sperm extraction in that study with an already small sample group may highly influence the results. in addition, the criticism of small sample size made for similar studies also applies to that study. if the number of cases in this group was higher and these cases were evaluated as a separate group, the results would be clearer. examining the situation from a different perspective may be more clarifying to assess the relationship between digit ratios and fertility. that perspective is whether there is a relationship between digit ratios and sex hormones. the evidence from majority of these studies have suggested that differences in androgen and estrogen levels during development are indirectly related with 2d:4d ratio(10). it is currently unknown how sex steroids influence the developmental stages in digit development and how prenatal androgen and estrogens play a role in the gender difference between digit ratios. experimental animal studies have been conducted to partly elucidate this relationship. the study that has drawn the most attention was that conducted on mice. according to this animal study, 2d:4d ratio is determined by a balance of prenatal testosterone and prenatal estrogen signalization within a short period of fetal life. an important result of that study was that external hormones and receptor antagonists applied postnatally did not alter 2d:4d ratio at the postnatal development period, but it did affect anogenital distance. therefore, it has been suggested that 2d:4d ratio is determined during embryonic period and remains constant for a life time(11). percent of cases with hypogonadotropic hypogonadism that had 2d:4d ratio equal to or greater than 1 was high in our study and a significant difference was detected for left hand when the cases with hypogonadotropic hypogonadism were compared with fertile males. this may be related to a hormonal irregularity at their intrauterine micro medium during prenatal period. like digit length ratio, fluctuation asymmetry is also considered to be related with many physiological and pathological conditions. bilateral paired morphologic features show excellent symmetry and stability during developmental process. however, random deviations from symmetry may take place during development and this phenomenon is called the fluctuation asymmetry, which is assessed by measuring the differences between morphologic features showing symmetry (ears, index digits, wrists, ankles etc.) with different methods(12). a study by firman et al. investigated whether semen quality is reliably reflected by digit length ratios and the fluctuation asymmetry. fifty cases aged 18-35 years were included. cases underwent semen analysis, fluctuation asymmetry measurements, and 2nd-4th digit length measurements to calculate 2d:4d ratio. the results showed a significant relationship between body fluctuation asymmetry and total sperm count, sperm motility, and sperm head length. however, no significant relationship was evident between 2d:4d ratio and semen parameters for both hands(13). the fluctuation asymmetry and differences in digit length ratios which may be related with physiologic and/or pathologic conditions may actually be morphologic features partly reflecting the functionality or disorder of the same common developmental mechanisms. in this context, fluctuation asymmetry and 2d:4d ratio could be a predictor for vasal agenesis which can be regarded as a developmental mechanism disorder. our control group was composed of men who fathered at least one child and they were assumed as fertile cases. no semen analysis was performed for this group because of the costs and the ethical reasons. however, it is possible for a father having an abnormal spermiogram. creating a control group from individuals with normal semen analysis could give more clear results. so, this was a limitation of our study. conclusions the results of the present study showed some significant difference between 2d:4d ratios for the subgroups of the fertile and infertile cases. nevertheless, 2d:4d ratio is not an unaccompanied parameter to reveal all causes of male infertility. because the number of factors that have a role in this condition is probably more than known. however, 2d:4d ratio may be a good predictor for some rare subgroups of infertile men like digit ratios in male infertility-akinsal et al. sexual dysfunction and infertility 3083 vassal agenesis and hypogonadotropic hypogonadism. future large scale studies may identify more specific relationships among these situations and 2d:4d ratio. acknowledgements this study has not been funded by any person or institution. conflict of interest the authors declare no conflict of interest. references 1. herault y, fraudeau n, zakany j, duboule d. ulnaless (ul), a regulatory mutation inducing both loss-of-function and gain-of-function of posterior hoxd genes. development. 1997;124:3493-500. 2. peichel cl, prabhakaran b, vogt tf. the mouse ulnaless mutation deregulates posterior hoxd gene expression and alters appendicular patterning. development. 1997;124:3481-92. 3. kondo t, zakany j, innis jw, duboule d. of fingers, toes and penises. nature. 1997;390:29. 4. baker f. anthropological notes on the human hand. american anthropologist. 1888;a1:51-76. 5. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. hum reprod update. 2010;16:231-45. 6. erickson rp. post-meiotic gene expression. trends genet. 1990;6:264-9. 7. manning jt, scutt d, wilson j, lewis-jones di. the ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. hum reprod. 1998;13:3000-4. 8. wood s, vang e, manning j, et al. the ratio of second to fourth digit length in azoospermic males undergoing surgical sperm retrieval: predictive value for sperm retrieval and on wubsequent fertilization and pregnancy rates in ivf/icsi cycles. j androl. 2003;24:871-7. 9. qiao d, wu hf, qian lx, song nh, feng nh. [clinical features & diagnostic and therapeutic strategies of congenital absence of the vas deferens]. zhonghua nan ke xue. 2005;11:818-21. 10. honekopp j, bartholdt l, beier l, liebert a. second to fourth digit length ratio (2d:4d) and adult sex hormone levels: new data and a metaanalytic review. psychoneuroendocrinology. 2007;32:313-21. 11. zheng z, cohn mj. developmental basis of sexually dimorphic digit ratios. proc natl acad sci u s a. 2011;108:16289-94. 12. livshits g, kobyliansky e. fluctuating asymmetry as a possible measure of developmental homeostasis in humans: a review. hum biol. 1991;63:441-66. 13. firman rc, simmons lw, cummins jm, matson pl. are body fluctuating asymmetry and the ratio of 2nd to 4th digit length reliable predictors of semen quality? hum reprod. 2003;18:808-12. digit ratios in male infertility-akinsal et al. vol 14 no 03 may-june 2017 3084 1 urology journal unrc/iua vol. 1, 1-4 winter 2004 printed in iran introduction primary urethral carcinoma in males is responsible for less than 1% of their malignant diseases.(1) approximately 50% to 75% of these lesions are originated from posterior urethra (prostatic, membranous, and bulbar urethra), anterior urethra, and mostly from meatus and fossa vanicularis.(2) in males, if the tumor remainders originate from anterior urethra, the most common symptom will be difficult urination and nodule sensation. in more advanced stages signs would be urinary obstruction or incontinence secondary to bladder overflow. hematuria, purulent discharges, decrease in caliber and urinary pressure, straining during urination, dysuria, abscess around urethra, and fistula formation are also seen.(2) in large lesions of anterior urethra, a mass on the ventral surface of penis may be palpable.(2) painful ejaculation, priapism, penile ulcer, and sexual dysfunction could be the causes of referral. size of penis could be increased due to tumor, indurations, and edema. loss of appetite, weight loss, and malaise are later complaints of the disease secondary to chronic infection. the duration between the beginning of symptoms and diagnosis may even be 3 years that is most often due to patient embarrassment and sometimes because of misdiagnosis. sever hemorrhage is an important symptom of urethral cancer in patients who undergo urethral stricture treatment with gentle dilation. medical examination and earlier cystoscopy could decrease mistakes in diagnosis.(3) penile examination should be systematically performed, beginning from the end of penis towards urogenital diaphragm. palpation of corpus spongiosum and corpus cavernosum to detect any mass, hardness, or both could be of help in estimating the severity of disease.(3) case report a 66-year old married farmer form rafsanjan, southeast of iran, with chief complaint of decrease of urinary force, hematuria, clot in the urine, sensation of mass, and hardness at the end of penis and both groins. herniorrhaphy had been conducted for the patient 2.5 years before, after which he had developed acute urinary retention followed by open prostatectomy. he had suffered from urinary retention after the removal of catheter. he had been catheterized again, hospitalized for a while, and finally after a period his catheter had been removed. no urinary complication was reported till a few months before our visit. he had no history of smoking or any other disease. he used pest poison for his trees 2-3 times annually without considering protective measures. he had 10 healthy children. in clinical examination, a 4×4 cm2 hard oval mass at the end of penis with no extension to skin and meatus was palpated. in the right inguinal region a 4×4 cm2 and in the left inguinal region a 3×3 cm2 mobile hard mass with no pain and redness were observed (fig.1). mild leukocytosis, hematuria, and pyuria were reported in his laboratory tests. his urine culture was negative. other hematological, biochema case of primary urethral carcinoma and inguinal lymphatic metastasis with partial penectomy and limited inguinal lymphadenectomy najafi semnani m department of urology, birjand university of medical sciences, birjand, iran key words: urethral carcinoma, inguinal lymphatic metastasis, partial penectomy accepted for publication a case of primary urethral carcinoma and inguinal lymphatic metastasis with partial penectomy and limited inguinal lymphadenectomy ical, and liver and kidney function tests were normal. he had normal dre and ivu too. cystoscopy was done under anesthesia. the whole 4 cm glandular urethra was invaded by the tumor. proximal urethra was normal. the bladder was totally examined and there was no lesion. biopsies were taken from the bladder wall, bladder neck, and finally form the tumor. pathology results were normal for bladder samples and showed undifferentiated scc in the mass. consequently, the patient underwent partial penectomy with bilateral superficial inguinal lymphadenectomy. a circumferential incision was made 2 cm proximal to the tumor. the penis was cut 6.5 cm distally and a biopsy was taken form the proximal margin of urethra (samples a and b). then left and right superficial and limited inguinal lymphadenectomy was conducted. palpable lymph nodes were removed and sent to pathology as seven groups (samples c-i). results of pathology of penis sample indicated infiltrative tumor with a dimension of 3×3×4 cm3 and an invasion to corpus cavernous, which is 4 mm beneath the skin and 8 mm from meatus. microscopic analysis showed vessel invasion in a section of tumor. proximal margin of surgery was reported normal. diagnosis of tumor (scc) was again confirmed. biopsy of the rest urethral margin was normal (b). all lymph nodes were tumorless except for that of superior right inguinal region (d). macroscopic examination of sample d indicated a 2×3×5 cm3 creamy tissue, which included 4 cm (0.5-2.7) lymph nodes, two of which were tumoral, of whom one demonstrated perinodal with extracapsular invasion. the patient was refered to an oncologic surgical center for classic right inguinal lymphadenectomy. however, he refrained from referral. to date, 60 months after surgery, no local recurrence was observed in examination and inguinal regions were normal (fig. 2). according to the patient, the length of the penis was adequate to void straightly and intercourse. in the mri taken 44 months post-operatively, pelvic and inguinal regions were tumorless. discussion most often primary urethral tumor occurs at the age of 60 to 80 years and the mean age at diagnosis is 60 years.(4) no precise etiologic factor has been reported but long-term urethral infection, urethral stricture, chronic inflammation, sexually transmitted diseases, urethritis, and trauma are proposed as risk factors. this patient had no history of urethral infection or stricture and only a long-term catheterization following herniorrhaphy and prostatectomy was reported. a considerable number of patients have a history of exposure to carcinogens or cigarette smoking. nonetheless, there is still no epidemiologic study concerning these factors as a causative mechanism for urethral cancer.(4) the patient had no smoking history. however, he was in contact with pesticides. in males if the tumor develops at anterior urethra, the most common complaint would be difficult urination and nodal sensation. sever hemor2 fig. 1. a hard mass at the end of penis and the right and left inguinal regions is observed. fig. 2. the rest of the penis and the scar of bilateral superficial inguinal lymphadenectomy 60 months after surgical treatment a case of primary urethral carcinoma and inguinal lymphatic metastasis with partial penectomy and limited inguinal lymphadenectomy rhage is one of the primary symptoms of urethral cancer in patients who undergo gentle dilatation for urethral stricture. early cystoscopic examination could reduce mistakes in diagnosis.(2) this patient was referred with low urinary flow, hematuria, hardness, and mass sensation at the end of penis and inguinal regions. the examination of penis should begin from its end towards urogenital diaphragm. bimanual examination should be done for detecting prostate lesions, invasion to trigone, and adhesion to the pelvic wall. systematic examination of inguinal region should be done to detect their involvements. urethroscopy and cystoscopy should be performed. pelvic ctscan should be conducted in the cases of all tumors except for superficial and most distal ones. ivu is essential for urethral tcc. taking ample biopsies from the lesions is very important which is mostly conducted through urethra. treatment has two parts: a. treatment of tumor: according to the tumor location and size, there are four general treatment options: 1. conservative treatment and local excision; 2. partial penectomy; 3.radical penectomy; 4. total removal of penis, urethra, scrotom, and anterior pubis associated with cystoprostatectomy. since patient had a limited tumor at the end of penis and at least 2 cm of normal urethra could be removed in a way that patient could void straightly, partial penectomy was done. a biopsy was taken separately which was tumorless and the study of sample indicated that surgical margin was also without tumor. sixty months later, no local recurrence was noted and the patient had satisfactory intercourse. b. lymph nodes treatment: urethral cancer tends to local lymphatic invasion, which is occurred before distant metastasis. lymph nodes of anterior urethra are directly drained into deep and superficial inguinal lymphatic glands. several principals should be considered in the treatment of lymph nodes: 1. it is confirmed by several researchers that if lymph nodes are palpable, there will be a high risk of nodal involvement. this is contrary to scc of penis in which palpable inguinal masses may have no tumoral involvement and patient is recommended for lymphadenectomy after antibiotic therapy.(3, 6) 2. inguinal lymphadenectomy could be a definite treatment in male urethral cancer; therefore, any case of palpable lymphatic gland should be treated by classic and complete lymphadenectomy. limited lymphadenectomy is recommended for patients who refrain from classic lymphadenectomy after the confirmation of nodal involvement. this may indicate that limited and superficial lymphadenectomy could be a successful treatment, which leads to long-term survival with minimal involvement of inguinal lymphatic glands. superficial inguinal lymphadenectomy in this patient led to definitive treatment 60 months later. of course, most researchers believe that if there is no palpable inguinal node, prophylactic lymphadenectomy will be of no value.(3, 6) some applied radiotherapy successfully to treat primary tumor of urethra and lymph nodes metastasis(4), while, some others believe that radiotherapy is met with unacceptable results.(3) reference 1. dalbagnai g, zhang zf, et al. male urethral carcinoma: analysis of treatment outcome. urology 1999; 53: 1126-32. 2. mostofi fk, davis cj, et al. carcinoma of the male and female urethra. urol clin north am 1992; 19: 347-48. 3. zeidman ej, desmond p, et al. surgical treatment of carcinoma of the male urethra. urol clin north am 1992; 19: 359-67. 4. foeman jd, lichter as. the role of radiation therapy in the management of the male and female urethra. urol clin north am 1992; 19: 383-9. 5. vapnek jm, hricak h. recent advances in imaging studies for staging of penile and urethral carcinoma. urol clin north am 1992; 19: 257-66. 6. levine rl. urethral cancer. cancer 1980; 45: 1956-72. 3 review a systematic review evaluating the effect of vitamin b6 on semen quality saleem a. banihani* purpose: this review systematically discusses and summarizes the effect of vitamin b6 on semen quality. material and method: to achieve this contribution, we searched the pubmed, scopus, and web of science databases for english language papers from 1984 through 2017 using the key words “sperm” versus “vitamin b6”, “pyridoxine”, and “pyridoxal”. also, the references from selected published papers were included, only if relevant. result: to date, as revealed by rodent studies, high doses of vitamin b6 impair semen quality and sperm parameters. while in humans, it is suggested, but not yet directly approved, that seminal vitamin b6 levels may alter sperm quality (i.e., sperm quantity and quality), and that vitamin b6 deficiency may trigger the chemical toxicity to sperm (i.e., hyperhomocysteinemia, oxidative injury). conclusion: the adverse effect of vitamin b6, when used at high doses, has been revealed in experimental animals, but not yet directly approved in humans. consequently, in vitro studies on human ejaculate as well as clinical studies that investigate the direct effect of vitamin b6 on semen quality seem very significant. keywords: pyridoxine; pyridoxal-5' phosphate; semen quality, sperm; vitamin b6. introduction vitamin b6 is a water-soluble vitamin and a mem-ber in the vitamin b group essential for normal growth and development(1,2). it is present in a variety of foods with a high content in walnuts, meat products, soybeans, and chicken breasts(3,4). the important known role of vitamin b6 in the developing human body is in metabolism, particularly of the neurotransmitters(1,5). the common biologically active form of vitamin b6 is pyridoxal-5' phosphate, which is a coenzyme for more than 100 known enzymatic reactions, mainly those of amino acid and carbohydrate metabolism(1,6). in point of fact, the important biochemical function of vitamin b6 in the human body suggests it has a role in sperm maturation and sperm parameters. therefore, several studies have linked vitamin b6 with semen quality; this effect, however, has yet to be summarized and collectively discussed. this review systematically discusses and summarizes the up-to-date evaluation of the effect of vitamin b6 on semen quality. material and methods information source to accomplish this contribution, we searched the pubmed, scopus, and web of science for english language articles from 1984 through 2017. search strategy we performed an inclusive electronic search until june 2017 using the key words “sperm” versus “vitamin b6”, “pyridoxine”, and “pyridoxal” in the above databases. additionally, certain relevant references were *correspondence: department of medical laboratory sciences, jordan university of science and technology, irbid 22110, jordan. phone: +962-27201000. fax: +962-2-7201087. e-mail: sabanihani@just.edu.j. received december 2016 & accepted november 20, 2017 included to support the empirical results and the mechanistic discussion. eligibility criteria this review included animal and human studies. the abstracts or full texts of all articles from the systematic search were extracted and carefully studied. each included article was carefully assessed based on its full text that directly or indirectly introduces the effect of vitamin b6 on semen quality. the articles that do not present the effect of vitamin b6 on semen quality were excluded (not related). in addition, reviews and non-english abstracts/full texts were also excluded. results the literature searches retrieved a total of 23 potential records (figure 1). after abstract and full text reading, a total of 12 articles met our inclusion criteria (table 1). the majority of the included research studies that have directly linked vitamin b6 with semen quality were nonclinical (i.e., rodent studies) (8 studies). the human studies in this context were only four articles. we could not conduct meta-analysis in this systematic review because of the heterogeneity of the data. summary of selected study and design the in vivo system studies were conducted in japan (6 studies), united kingdom (1 study), and switzerland (1 study) (table 1). while the human studies were conducted in netherlands (2 studies), canada (1 study), and france (1 study). seven studies from the in vivo system ones were conducted on rats, and only one study was conducted on mice. vol 15 no 01 january-february 2017 1 primary outcomes the primary outcomes of the included studies were sperm parameters (e.g., count, motility, morphology, and volume), histological changes in the testes and male reproductive organs, and certain seminal enzymes and biomolecules. effect of vitamin b6 on semen quality and testicular function wistar male rats injected high doses (≥ 125 mg kg-1 day-1) of pyridoxine hydrochloride for six weeks had lower weights of the epididymis, and lower weights of the testis, prostate gland, and seminal vesicle, and decreased mature spermatid counts at ≥ 500 mg kg-1 day-1(7). in addition, at 1000 mg kg-1 day-1 dose, the activity of testicular enzymes such as ldh-x, a lactate dehydrogenase enzyme, activity was significantly decreased (8), whereas cytochrome p-450 and cytochrome b5 content, and beta-glucuronidase activity were significantly increased(9). histological investigations by the same group showed degeneration of elongated spermatids, delay in spermiation, sertoli cell alterations, and germ cell degeneration at 500 mg kg-1 day-1 and 1000 mg kg-1 day-1(10). in a different way, at 125 and 250 mg kg-1 day-1 (5 times per week for 6 weeks), sperm motility and count of wistar rats were significantly decreased(9,11). moreover, at 250 and 500 mg kg-1 day-1 for 2 weeks’ treatment, only very slight histopathological changes were observed(9). while, at the same doses, but for 4and 6-week treatments, decreased sperm motility, fertility index, epididymis weight, testicular proteins, and some histopathological alterations in the testes such as germ cells degeneration were observed(12). further, sd-slc male rats at six-week of age treated intraperitoneally for four weeks with pyridoxine in saline at 500 mg kg-1 day-1 had sperm morphological and physiological changes (i.e., sperm motility)(13). sperm motility and morphology markedly decreased in male rats treated with pyridoxine after 4-9-week treatment (14). in addition, after 4 weeks, histological change in the testes confirmed by a reduction in sperm count was observed leading to a marked testicular atrophy at 8-9 weeks(14). in humans, pyridoxine was found to be present in seminal plasma, and that it is inversely associated with the ejaculate volume(15). in addition, pyridoxal-5' phosphate was found to activate the monoamine oxidase (mao), an enzyme that catalyzes the oxidation of monoamines (deamination), in human semen(16). it is important to mention that the activity of monoamine oxidase was found to be higher in infertile men compared to fertile (16). discussion effect of vitamin b6 on seminal homocysteine vitamin b6 acts as a coenzyme for cystathionine-≥-synthase enabling the transsulphuration of homocysteine into cystathionine and cysteine(17,18). a deficiency in vitamin b6 causes accumulation of homocysteine or hyperhomocysteinemia(19,20). it was reported that b vitamin deficiencies, including vitamin b6, are linked with hyperhomocysteinemia and gonadal abnormalities in males, such as altered spermatogenesis(19,21). therefore, normal levels of vitamin b6 in men seems important to protect the integrity of semen quality and maintain normal sperm parameters. though, this suggestion requires more investigation, mainly by clinical studies. vitamin b6 and gonadal function in 1984, symes and co-workers have shown that vitamin b6 has a function in the action of steroid hormones, mainly testosterone, and vitamin b6 deficient male rats have a reduced synthesis of testosterone(22). table 1. summary of the studies that investigated (directly and indirectly) the effect of vitamin b6 or its derivatives on semen quality. ref. location affecter population outcome (7) japan pyridoxine hydrochloride wistar male rats -lower weights of the epididymis, testis, prostate gland, and seminal vesicle. -decreased mature spermatid count. (8) united kingdom pyridoxal 5'-phosphate male mouse -decreased testicular lactate dehydrogenase (9) japan pyridoxine wistar male rats -reduced spermatogenesis -decrease in reproductive organ weights -increase in testicular markers: beta-glucuronidase activity, cytochrome p-450 content and cytochrome b5 content (11) japan vitamin b6 wistar male rats -decreased sperm count -decreased sperm motility phagocytosis of mature spermatids by sertoli cells (10) japan pyridoxine wistar male rats -alteration in testicular cells -delay in spermiation (12) japan pyridoxine male jcl: sd rats -decreased sperm motility -decrease in testicular proteins -histopathological alterations in the testes -decrease in epididymis weight (13) japan pyridoxine sd-slc male rats -sperm morphology alteration -sperm physiology alteration (14) switzerland pyridoxine male rats -sperm motility changes -sperm morphology changes -histopathological alterations in the testes (15) netherlands pyridoxine men of couples -change in semen volume undergoing in vitro fertilization or intracytoplasmic sperm injection treatment (16) canada pyridoxal-5' phosphate humans -activation of seminal monoamine oxydase (19) france vitamin b6 humans -altered spermatogenesis (21) netherlands vitamin b6 humans -change in seminal homocysteine vitamin b6 and semen quality-banihani review 2 the mechanism by which this occurs is may be by recycling the testosterone receptors from the nucleus into the cytosol after primary translocation(22). later study has confirmed these results and found that vitamin b6 deficiency may alter in gonadal function since it is involved in synthesis of testosterone, follicle-stimulating hormone, and luteinizing hormone(23). another in vivo system study, in male rats, showed that the depression of gonadal development kept in constant darkness was improved by receiving normal amounts of vitamin b6 and vitamin b1, and a high amount of pantothenic acid (24). therefore, this evidence may indicate a valuable role of vitamin b6 in maintaining normal gonadal function, and hence normal semen quality. vitamin b6 in oxidative stress conditions vitamin b6 has been found to have potent antioxidant activity(25-27). compared to vitamins c, pyridoxine appears to quench singlet oxygen radical(25). mechanistically, it has been shown that the chromophoric moiety (3-hydroxypyridine) of vitamin b6 establishes an exceptional model that mimics the dynamic behavior of this vitamin as an antioxidant against riboflavin-generated reactive oxygen species(28). for instance, the protein lysozyme was photo-protected by vitamin b6 from riboflavin-sensitized photo-degradation(28). further, independently of the homocysteine-lowering effect, it has been reported that patients with acute ischemic stroke supplemented b-vitamins, including vitamin b6, had lower oxidative stress, an imbalance between pro-oxidants and antioxidants to the favor of the former(29), indicating the immediate antioxidant activity of these vitamins(30). therefore, given that higher levels of free radicals, particularly reactive oxygen species, in semen lead to oxidative stress, and thus to sperm injury (31-33), then vitamin b6, once normally present in semen, may enhance the molecular defense mechanism against oxidative damage to sperm, thereby protects the normal sperm physiology, particularly sperm motility. though, further research studies in this context seem important to endorse this suggestion. moreover, glutathione system, including glutathione, glutathione reductase, and glutathione peroxidase, was found to be present in mammalian and human semen (34,35). the function of this system appears to neutralize free radicals and protect the sperm against oxidative injury(34,35). it is well known that vitamin b6 deficiency affects glutathione level and reduces the glutathione/ oxidized glutathione ratio in the blood(36-38). it has been recognized that the intracellular sperm glutathione system is altered in infertile men compared to fertile(39). based on this evidence, vitamin b6 deficiency may alter glutathione system, thereby affecting the antioxidant defense mechanism against oxidative damage to sperm, which may ultimately alter sperm parameters. seminal monoamine oxidase it has been shown that adding monoamine oxidase to human semen in vitro induced seminal plasma cytotoxicity, which may affect negatively semen quality(40). given that pyridoxal-5' phosphate activates the monoamine oxidase enzyme(16), then adding pyridoxal-5' phosphate to human semen is suggested to trigger semen toxicity, which may lead to sperm injury. conclusions only from rodent studies (8 studies), it is obvious that high doses of vitamin b6 impair semen quality, mainly sperm count and motility, and cause significant histopathological changes such as germ cells degeneration. in humans, vitamin b6 has been approved to be present in normal semen, even though the available studies failed to show its direct relationship with normal sperm parameters. while, indirectly, it is suggested that a deficiency in vitamin b6 may lead to hyperhomocysteinemia, which may alter sperm parameters. in addition, it can be suggested that vitamin b6 may enforce the seminal antioxidant reservoir, which could be favorable to sperm function. still, in vitro and clinical studies that investigate the direct effect of vitamin b6 on semen quality appear significant, and may contribute to the etiology of male subfertility. declaration of interest the author declares no conflict of interest. the corresponding author alone is responsible for the content and writing of this work. references 1. bowling fg. pyridoxine supply in human development. semin cell dev biol. 2011;22:611-8. 2. craig jp, bekal s, hudson m, domier l, niblack t, lambert kn. analysis of a horizontally transferred pathway involved in vitamin b6 biosynthesis from the soybean cyst nematode heterodera glycines. mol biol evol. 2008;25:2085-98. 3. esteve mj, farre r, frigola a, garciacantabella jm. determination of vitamin b6 (pyridoxamine, pyridoxal and pyridoxine) in pork meat and pork meat products by liquid chromatography. j chromatogr a. 1998;795:383-7. 4. engler pp, bowers ja. b-vitamin retention in meat during storage and preparation. a figure 1. literature search and selection diagram. vitamin b6 and semen quality-banihani vol 15 no 01 january-february 2017 3 review. j am diet assoc. 1976;69:253-57. 5. coburn sp. vitamin b-6 metabolism and interactions with tnap. subcell biochem. 2015;76:207-38. 6. gregory jf, deratt bn, rios-avila l, ralat m, stacpoole pw. vitamin b6 nutritional status and cellular availability of pyridoxal 5'-phosphate govern the function of the transsulfuration pathway's canonical reactions and hydrogen sulfide production via side reactions. biochimie. 2016;126:21-6. 7. mori k, kaido m, fujishiro k, inoue n. testicular damage induced by megadoses of pyridoxine. j uoeh. 1989;11:455-9. 8. gould kg, engel pc. modification of mouse testicular lactate dehydrogenase by pyridoxal 5'-phosphate. biochem j. 1980;191:365-71. 9. mori k, kaido m, fujishiro k, inoue n, koide o. effects of megadoses of pyridoxine on spermatogenesis and male reproductive organs in rats. arch toxicol. 1992;66:198203. 10. kaido m, mori k, ide y, inoue n, koide o. testicular damage by high doses of vitamin b6 (pyridoxine) in rats: a light and electron microscopical study. exp mol pathol. 1991;55:63-82. 11. ide y, kaido m, koide o. changes in spermatozoa due to large doses of pyridoxine (vitamin b6). acta pathol jpn. 1992;42:861-9. 12. tsutsumi s, tanaka t, gotoh k, akaike m. effects of pyridoxine on male fertility. j toxicol sci. 1995;20:351-65. 13. takizawa s, katoh c, inomata a, horii i. flow cytometric analysis for sperm viability and counts in rats treated with trimethylphosphate or pyridoxine. j toxicol sci. 1998;23:15-23. 14. plassmann s, urwyler h. improved risk assessment by screening sperm parameters. toxicol lett. 2001;119:157-71. 15. boxmeer jc, smit m, utomo e, et al. low folate in seminal plasma is associated with increased sperm dna damage. fertil steril. 2009;92:548-56. 16. roberge ag, moufarege a, lavoie j, roberge c, tremblay rr. biochemical properties and kinetic parameters of monoamine oxydase in human seminal plasma. int j fertil. 1984;29:180-5. 17. boers gh, smals ag, drayer ji, trijbels fj, leermakers ai, kloppenborg pw. pyridoxine treatment does not prevent homocystinemia after methionine loading in adult homocystinuria patients. metabolism. 1983;32:390-7. 18. lievers kj, kluijtmans la, blom hj. genetics of hyperhomocysteinaemia in cardiovascular disease. ann clin biochem. 2003;40:46-59. 19. forges t, monnier-barbarino p, alberto jm, gueant-rodriguez rm, daval jl, gueant jl. impact of folate and homocysteine metabolism on human reproductive health. hum reprod update. 2007;13:225-38. 20. waly mi, ali a, al-nassri a, almukhaini m, valliatte j, al-farsi y. low nourishment of b-vitamins is associated with hyperhomocysteinemia and oxidative stress in newly diagnosed cardiac patients. exp biol med (maywood). 2016;241:46-51. 21. vujkovic m, de vries jh, dohle gr, et al. associations between dietary patterns and semen quality in men undergoing ivf/icsi treatment. hum reprod. 2009;24:1304-12. 22. symes ek, bender da, bowden jf, coulson wf. increased target tissue uptake of, and sensitivity to, testosterone in the vitamin b6 deficient rat. j steroid biochem. 1984;20:1089-93. 23. ebadi m. regulation and function of pyridoxal phosphate in cns. neurochem int. 1981;3:181-205. 24. hanai m, esashi t. the interactive effect of dietary water-soluble vitamin levels on the depression of gonadal development in growing male rats kept under disturbed daily rhythm. j nutr sci vitaminol (tokyo). 2012;58:230-9. 25. ehrenshaft m, bilski p, li my, chignell cf, daub me. a highly conserved sequence is a novel gene involved in de novo vitamin b6 biosynthesis. proc natl acad sci u s a. 1999;96:9374-8. 26. wang jl, fu lc, zhou sw, et al. [the interaction of vitamin b6 with the human serum albumin]. guang pu xue yu guang pu fen xi. 2005;25:912-5. 27. tunali s. the effects of vitamin b6 on lens antioxidant system in valproic acidadministered rats. hum exp toxicol. 2014;33:623-8. 28. natera j, massad w, garcia na. the role of vitamin b6 as an antioxidant in the presence of vitamin b2-photogenerated reactive oxygen species. a kinetic and mechanistic study. photochem photobiol sci. 2012;11:938-45. 29. mhaidat nm, alzoubi kh, khabour of, tashtoush nh, banihani sa, abdul-razzak kk. exploring the effect of vitamin c on sleep deprivation induced memory impairment. brain res bull. 2015;113:41-7. 30. ullegaddi r, powers hj, gariballa se. b-group vitamin supplementation mitigates oxidative damage after acute ischaemic stroke. clin sci (lond). 2004;107:477-84. 31. banihani sa. omeprazole and semen quality. basic clin pharmacol toxicol. 2016;118:1813. 32. banihani sa. effect of captopril on semen quality. andrologia. 2016. 33. mayorga-torres bj, camargo m, cadavid ap, du plessis ss, cardona maya wd. are vitamin b6 and semen quality-banihani review 4 oxidative stress markers associated with unexplained male infertility? andrologia. 2016. 34. li tk. the glutathione and thiol content of mammalian spermatozoa and seminal plasma. biol reprod. 1975;12:641-6. 35. ghorbani m, vatannejad a, khodadadi i, amiri i, tavilani h. protective effects of glutathione supplementation against oxidative stress during cryopreservation of human spermatozoa. cryo letters. 2016;37:34-40. 36. choi ey, cho yo. effect of vitamin b(6) deficiency on antioxidative status in rats with exercise-induced oxidative stress. nutr res pract. 2009;3:208-11. 37. dubick ma, gretz d, majumdar ap. overt vitamin b-6 deficiency affects rat pancreatic digestive enzyme and glutathione reductase activities. j nutr. 1995;125:20-5. 38. lamers y, o'rourke b, gilbert lr, et al. vitamin b-6 restriction tends to reduce the red blood cell glutathione synthesis rate without affecting red blood cell or plasma glutathione concentrations in healthy men and women. am j clin nutr. 2009;90:336-43. 39. garrido n, meseguer m, alvarez j, simon c, pellicer a, remohi j. relationship among standard semen parameters, glutathione peroxidase/glutathione reductase activity, and mrna expression and reduced glutathione content in ejaculated spermatozoa from fertile and infertile men. fertil steril. 2004;82 suppl 3:1059-66. 40. allen rd, roberts tk. role of spermine in the cytotoxic effects of seminal plasma. am j reprod immunol microbiol. 1987;13:4-8. vitamin b6 and semen quality-banihani vol 15 no 01 january-february 2017 5 kidney transplantation effect of age on conversion to everolimus with calcineurin inhibitor minimization at a late post-transplant stage junji uchida1*, shunji nishide1, kazuya kabei1, hisao shimada1, akihiro kosoku1, tomoaki iwai1, nobuyuki kuwabara1, toshihide naganuma1, norihiko kumada2, yoshiaki takemoto1, tatsuya nakatani1 purpose: the purpose of this study was to identify the risk factors for everolimus discontinuation in kidney transplant recipients converted to everolimus with calcineurin inhibitor (cni) minimization at a late post-transplant stage. materials and methods: an observational retrospective cohort study was conducted on a total of 38 recipients of kidney transplantation at our institution from june 2012 to march 2015 who were converted from antimetabolites to everolimus at a late post-transplant stage and followed for 1 year. we divided the patients into two groups to evaluate the factors affecting everolimus discontinuation after conversion: everolimus continuation group (n = 23), patients in whom everolimus maintained, and everolimus discontinuation group (n = 15), patients in whom everolimus were stopped within 1 year after conversion. results: age at conversion was significantly older in the everolimus discontinuation group compared to the everolimus continuation group (57.9 ± 12.0 years in the everolimus discontinuation group vs 45.7 ± 11.2 years in the everolimus continuous group; p = .0062). multivariate cox proportional hazard regression analysis revealed that age at conversion significantly correlated with everolimus discontinuation (p = .012). receiver operating characteristic curve of age at conversion showed that the cut-off value was 55 years old for the everolimus discontinuation group [area under curve 0.804, 95% confidence interval (0.654-0.954), sensitivity 86.7%, specificity 65.2%]. conclusion: our results indicated that late conversion to everolimus with cni minimization in elderly recipients older than 55 years of age may be associated with more frequent adverse events and discontinuations. keywords: age; calcineurin inhibitor minimization; everolimus; immunosuppressive agent; kidney transplantation introduction kidney transplantation is the most preferable renal replacement therapy in improving life expectancy and quality of life for patients with end-stage renal disease. the central issue in kidney transplantation remains to be the suppression of allograft rejection. the aim of immunosuppression therapy is to reduce the risk of rejection and to prolong patient and graft survival. current immunosuppressive protocols, consisting of calcineurin inhibitors (cnis), mycophenolate mofetil (mmf), and steroid, have appreciably improved short and medium-term graft survival(1). however, improvements in long-term graft survival are restricted by nephrotoxicity associated with cni administration(2). immunosuppressive regimens that minimize exposure to cnis following kidney transplantation have been widely investigated in order to reduce the burden of cni-related complications(3). among them, there have been several published clinical studies on conversion to everolimus in maintenance transplants. the acertain study revealed that conversion to everolimus with cni minimization or elimination at a late post-transplant stage was associated with more frequent adverse effects and discontinuation(4). our previous pilot study showed that recipients with good graft function may benefit from conversion to everolimus with 1department of urology, osaka city university graduate school of medicine, osaka, japan. 2department of urology, suita municipal hospital, suita, japan. *correspondence: department of urology, osaka city university graduate school of medicine 1-4-3, asahi-machi, abeno-ku, osaka, 545-8585, japan. phone: +81-6-6645-3857, fax: +81-6-6647-4426. e-mail: m9492120@msic.med.osaka-cu.ac.jp. received december 2017 & accepted july 2018 cni minimization at a late post-transplant stage, as an improvement in graft function compared to baseline was observed in everolimus maintenance patients(5). everolimus plus cni minimization may provide some advantage to the renal function of recipients in whom everolimus could be maintained. the aim of this study was to identify the risk factors for everolimus discontinuation after conversion to everolimus with cni minimization at a late post-transplant stage. materials and methods study population we began to convert patients on mmf to everolimus with cni minimization at our institution in june 2012. we have also applied everolimus to abo-incompatible kidney transplant recipients(6) and patients with relatively good graft function(5). for this study, a total of 38 recipients of kidney transplantation at our institution from june 2012 to march 2015 who were converted from antimetabolites to everolimus for 1 year ending in march 2016 were investigated. the inclusion criteria for conversion were as follows:(1) at least 3 months after transplantation,(2) renal function defined as a serum creatinine (s-cr) value < 2.5 mg/dl,(3) no acute rejection episodes for more than 3 months, and(4) normal or slightly increased albuminuria defined as a urinary alkidney transplantation 266 vol 15 no 05 september-october 2018 267 bumin excretion rate (the ratio of spot urine albumin to cr)< 300 mg/g cr. treatment with everolimus was stopped due to adverse events in 15 patients (39.5%). seven patients with general fatigue, 2 with interstitial pneumonia, 2 with peripheral edema, 1 with menoxenia, 1 with redness and itching of face, 1 with colon diverticulitis, and 1 with cholecystitis were led to discontinuation of everolimus. median time from conversion to discontinuation was 119 days, with a range between 17 and 271 days. there were no graft failures or apparent clinical rejection during the observation period. this study analyzed retrospectively the risk factors for everolimus discontinuation after late conversion of stable kidney transplant recipients from antimetabolites with standard exposure cnis to everolimus with very low exposure cnis as a 1-year pilot study. we retrospectively compared the clinical parameters such as age at conversion, gender, estimated glomerular filtration rate at conversion, urinary albumin excretion at conversion, type of calcineurin inhibitors, dialysis duration, and period from transplantation to conversion between the two groups to analyze the risk factors for everolimus discontinuation. we divided the patients into two groups to evaluate the factors leading to everolimus discontinuation: the everolimus continuation group (n = 23), patients in whom everolimus was maintained for 1 year after conversion, and the everolimus discontinuation group (n = 15), patients in whom everolimus was stopped within 1 year after conversion. the number of patients at month 1, 3, 6, and 12 in the everolimus continuation group and the everolimus discontinuation group is shown in table 1. protocols of conversion to cni minimization on the day of conversion, mmf or mizoribine was discontinued and everolimus was started at a dose of 1.5 mg/day (0.75 mg, twice a day) in the patients who received cyclosporine (csa group) or 3.0 mg/day (1.5 mg, twice a day) in the patients who received tacrolimus (tac group). the cni dose was simultaneously reduced to 40-60% below baseline values. dose adjustments started from 1 week onward to target an everolimus trough level of 3 to 8 ng/ml and a csa trough level of 25-50 ng/ml or a tac trough level of 2-4 ng/ ml. everolimus trough levels were assessed at 1 week and every month until 1 year after conversion. baseline doses of methylprednisolone were continued unaltered in all patients. clinical and biochemical measurement and concentration of cnis and everolimus at baseline, clinical parameters including age, gender, cause of end-stage renal disease, duration of dialysis, time to transplantation, donor type, and abo-compatibility were collected. at baseline and at 1, 3, 6, and 12 months after conversion, fasting blood samples were obtained in the early morning for biochemical studies, including total cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and trough levels of cni and everolimus. estimated glomerular filtration rate (egfr) was calculated using the modified modification of diet in renal disease equation using the new japanese coefficient(7). urinary albumin excretion rate (the ratio of spot urine concentrations of albumin to creatinine) was measured at baseline and at 1, 3, 6, and 12 months after conversion. we evaluated these clinical parameters at baseline compared to 12 months after conversion between the two groups. all subjects provided informed consent prior to enrollment in this study, which was approved by the human ethics committee of osaka city university hospital. all procedures were in accordance with the helsinki declaration of 1975. statistical analysis statistical analysis was conducted using ezr (saitama medical center, jichi medical university, saitama, japan), which is a graphical user interface for r (the r foundation for statistical computing, vienna, australia). more precisely, it is a modified version of r commander designed to add statistical functions frequently used in biostatistics(8). the results are expressed as mean ± standard deviation or median with ranges and as proportions for categorical variables. changes were evaluated with the paired t test or wilcoxon test. differences between the two groups were analyzed by student’s t-test or mann-whitney u-test. categorical variables were compared using chi-squared analysis or fisher's exact test. univariate association between variables was assessed by cox proportional hazard regression analysis, and multivariate cox proportional hazard regression analysis was performed to determine the factors related to everolimus discontinuation. cut-off values of the factors related to everolimus discontinuation were calculated by the receiver operating characteristics curve (roc curve). statistical significance was set as p < 0.05. table1. number of patients postconversion everolimus everolimus continuation group discontinuation group month 1 36 2 month3 34 4 month 6 27 11 month 12 23 15 figure 1. changes in estimated glomerular filtration rate and urinary albumin excretion before and after conversion. recipients in whom everolimus was maintained for 1 year after conversion (everolimus continuation group) or recipients in whom everolimus was stopped (everolimus discontinuation group). ns=not significant age at conversion to everolimus with cni minimization-uchida et al. results baseline patient characteristics the demographic and clinical characteristics at baseline of the everolimus continuation and discontinuation groups are presented in table 2. age at transplant and conversion was significantly older in the everolimus discontinuation group compared to the everolimus continuation group. no significant differences were observed between the two groups with regard to the other clinical parameters. renal function and urinary albumin excretion (figure 1) there were no significant differences in egfr and urinary albumin excretion at baseline between the two groups (table 2). in the everolimus continuation group, the mean egfr value was significantly elevated from 46.7±12.6 ml/min/1.73m2 at baseline to 49.8 ± 14.3 ml/min/1.73m2 at 12 months after conversion. in the everolimus discontinuation group, there was no significant difference in the mean egfr between baseline and 12 months after conversion. furthermore, there was a significant difference in the change of egfr between the two groups. in the everolimus continuation group, the log [urinary albumin excretion] was significantly increased from 1.06 ± 0.29 at baseline to 1.29 ± 0.44 at 12 months after conversion. in the everolimus discontinuation group, there was no change in the log [urinary albumin excretion] between baseline and 12 months after conversion. lipid profile there were no significant differences in total cholesterol and low-density lipoprotein at baseline between the two groups. there were no significant differences in total cholesterol and low-density lipoprotein between baseline and 12 months after conversion in both groups. relationship between everolimus discontinuation and clinical parameters univariate cox proportional hazard regression analysis revealed that discontinuation of everolimus correlated with urinary albumin excretion and age at conversion. we selected age at conversion, urinary albumin excretion, and egfr as variables associated with everolimus discontinuation for the multivariate analysis. age table 2. comparison of clinical parameters between everolimus continuous and discontinuous group everolimus continuation group everolimus discontinuation group p-value n 23 15 age at transplant (year) 45.7 ± 11.2 57.9 ± 12.0 .00622 gender (male: female) 13:10 10:5 .736 hd duration (months) 7 7.2 ± 100 67.6 ± 73.8 .786 calcineurin inhibitor 14:9 9:6 1.0 (cyclosporin: tacrolimus) cause of end stage renal disease cgn; 5, iga n; 6, cgn; 3, iga n; 1, dm n; 3, .415 dm n; 2, renal sclerosis; 2, adpkd; 0, renal sclerosis; 1, unknown; 5, others; 1 adpkd; 2, unknown; 5, others; 2 donor age (year) 55.0 ± 11.8 56.9 ± 9.7 .634 donor type (living: deceased) 19:4 14:1 .63 donor relation spouses; 10, parent/child; 8, sister;1 spouses; 11, parent/child; 3, sister;0 .344 hla mismatch (antigen) 3.5 ± 1.1 4.1±1.6 .0675 abo-compatibility compatible; 13, incompatible; 10 compatible; 4, incompatible; 11 1.0 period from transplant to conversion (months) 41.7 ± 54.5 44.8 ± 32.1 .848 age at conversion (year) 48.9 ± 12.0 61.9 ± 11.5 .00563 egfr (ml/min/1.73m2) 46.7 ± 12.6 47.9 ± 12.6 .786 urinary albumin excretion (mg/g cr) 13.8 ± 7.4 20.9 ± 13.4 .0776 total cholesterol (mg/dl) 201.8 ± 26.9 198.8 ± 34.5 .779 triglyceride (mg/dl) 121.5 ± 52.2 108.8 ± 42.9 .464 low density lipoprotein (mg/dl) 103.3 ± 26.0 106.4 ± 17.0 .692 high density lipoprotein (mg/dl) 65.8 ± 16.0 68.1 ± 20.6 .734 abbrebiations: hd, hemodialysis; cgn, chronic glomeronephritis; iga n, iga nephropathy; dm n, diabetic nephropathy; adpkd, autosomal dominant polycystic kidney disease; hla, human leukocyte antigen; egfr, estimated glomerular filtration rate. adifferences between the two groups were analyzed by student’s t-test or mann-whitney u-test. bcategorical variables were compared using chi-squared analysis or fisher's exact test. figure 2. a threshold of age at conversion associated with discontinuation of everolimus by use of receiver operating characteristic curve analysis. age at conversion to everolimus with cni minimization-uchida et al. kidney transplantation 268 vol 15 no 05 september-october 2018 269 at conversion was selected as a variable by the backward model. previous reports showed that conversion to everolimus was advised in patients with proteinuria or not good graft function(4,9). multivariate cox proportional hazard regression analysis indicated that age at conversion was independently associated with discontinuation of everolimus (table 3). cut-off value of everolimus discontinuation the roc curve of age at conversion for the everolimus discontinuation group showed that the cut-off value was 55 years old [area under curve 0.804, 95 % confidence interval (0.654-0.954), sensitivity 86.7 %, specificity 65.2%] (figure 2). discussion in this study, the risk factors for everolimus discontinuation after conversion to everolimus with cni minimization in the kidney transplant recipients with good renal function were analyzed. age at conversion was significantly older in the everolimus discontinuation group (average age: 61.9 years) compared to the everolimus continuation group and significantly correlated with discontinuation of everolimus by multivariate analysis. moreover, we revealed that late conversion to everolimus with cni minimization in elderly recipients older than 55 years of age may be associated with more frequent adverse events and discontinuations by the roc curve, although the specificity was relatively low because of the small sample size. to our knowledge, there have been no reports on the safety and efficacy of everolimus in elderly recipients, although the cut-off point for elderly patients differs among various countries. our results may be useful to explore patients who could be converted to everolimus with cni minimization at a late post-transplant stage. increasing age is associated with structural and functional changes in body compartments and tissue that alter absorptive capacity, volume of distribution, hepatic metabolic function, and ultimately drug disposition. age-related changes may appear in most organs and can alter pharmacodynamics responses to medications(10). although no data have been published on elderly changes, elderly recipients may be more susceptible to developing adverse effects related to immunosuppressive drugs, especially everolimus. that is, elderly recipients may not be eligible for conversion from mmf to everolimus at a late post-transplant stage. the present study showed that egfr in the everolimus continuation group was significantly improved compared with that at baseline. moreover, there was a significant difference in the change in egfr between the two groups. in the post hoc analysis of the zeus study, the renal benefit increased slightly from year 1 for living donor kidney transplant recipients who remained on everolimus-maintained immunosuppression, and for living donor kidney transplant recipients who discontinued everolimus, the renal benefit was lost(11). our study showed that selected recipients with good renal function may acquire renal benefit, if they remained on everolimus-maintained immunosupression. the nephrotoxic effect of cnis can limit long-term survival(2). recent strategies to avoid or reduce exposure to cnis have focused on immunosuppressive drugs that are generally considered non-nephrotoxic, such as mtor inhibitors. everolimus has shown potent antiproliferative effects and has prevented allograft rejection in preclinical models(12). in experimental models, everolimus has been shown to ameliorate progression of chronic allograft nephropathy, not only when administered prophylactically from the time of transplantation but also in advanced disease(13,14). even conversion to everolimus in maintenance transplants may lead to renal benefit. however, late conversion everolimus in recipients with high baseline proteinuria has been reported to induce a decline in graft function and poor graft prognosis in previous clinical trials(15). the introduction of everolimus with cni minimization at a late post-transplant stage may have some benefits due to its pleiotropic effects. everolimus exhibits anti-neoplastic, anti-viral, anti-atherosclerotic, and anti-proliferative properties. it is well known that kidney transplant recipients receiving mtor inhibitors have a lower risk of developing cytomegalovirus infection(16). the convert trial revealed that mtor inhibitor-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with cni-based immunosuppression(17,18). chronic antibody-mediated rejection is considered to play a major role in late allograft loss(2,19). although everolimus-based immunosuppression in early conversion from cni was reported to be associated with an increased risk of developing denovo donor-specific antibodies and antibody-mediated rejection(20), a recent review demonstrated that late conversion to cni-free immunosuppressive regimen with mtor inhibitors did not appear to affect the risk of denovo donor-specific table 3. cox hazard regression analysis of risk factors associated with everolimus discontinuation univariate multivariate variable hazard ratio (95% ci) p-value hazard ratio (95% ci) p-value gender 1.478 (0.505-4.327) .476 age at conversion 1.080 (1.025-1.136) .00416 1.075 (1.016-1.137) .012 period from transplant to conversion (months) 1.001 (0.992-1.011) .815 hd duration 0.999 (0.993-1.004) .626 csa/tac 1.023 (0.364-2.877) .965 donor age 0.978 (0.921-1.04) .468 hla mismatch 1.508 (0.961-2.361) .074 abo-incompatiblity 2.808 (0.893-8.84) .077 egfr at conversion 1.003 (0.965-1.042) .252 1.017 (0.934-1.062) .454 urinary albumin excretion 1.041 (1.003-1.079) .0318 1.028 (0.988-1.068) .173 abbreviations: hd, hemodialysis; csa, cyclosporin; tac, tacrolimus; egfr, estimated glomerular filtration rate. age at conversion to everolimus with cni minimization-uchida et al. antibodies(21). moreover, in human cell cultures, it was reported that everolimus was equally effective as tacrolimus in suppressing humoral alloimmunity(22). late conversion to everolimus may be a favorable strategy in the expectation of avoiding mmf toxicity or reducing cni-associated long-term toxicities, because it may not elicit the development of denovo donor-specific antibodies, if the patient remained on everolimus treatment. the recipients who remained on everolimus in this study showed a significant increase in urinary albumin excretion compared to the recipients in whom everolimus was stopped. mtor inhibitor use has been associated with proteinuria/albuminuria in kidney transplant recipients(23). potential mechanisms for mtor-associated proteinuria/albuminuria include decreased vascular endothelial growth factor synthesis and inhibition of key podocyte proteins that comprise the glomerular slit diaphragm, including nephrin(23). in kidney transplant recipients, microalbuminuria predicts graft loss and all-cause mortality(24). however, the impact of mtor inhibitor-induced proteinuria/albuminuria on graft outcome has remained unclear. in this study, albuminuria was slightly elevated after late conversion to everolimus in patients in whom everolimus was maintained (median value of urinary albumin excretion: 16 mg/g cr (6-126 mg/g cr)). slightly increased albuminuria may well induce an undesirable effect for long-term graft and patient survival. the present study might have limitations because of the small sample size and because it is a retrospective study. however, there have been few reports on everolimus in elderly patients receiving kidney transplantation. it is not yet established whether everolimus is safe and effective for elderly recipients. to our knowledge, this is the first demonstration to identify the possible risk factors for discontinuation of everolimus at late conversion by multivariate analysis, although the present study is a pilot. further prospective well-controlled and longterm follow-up trials with a larger number of patients are needed to confirm our results. conclusions in conclusion, the present study identified the possibility that late conversion to everolimus with cni minimization in elderly recipients older than 55 years of age may be associated with more frequent adverse events and discontinuations. the recipients enrolled in this study had relative good graft function with less albuminuria. therefore, recipients whose ages are less than 55 years and who have relatively good graft function with little chronic allograft damage may be available for late conversion to everolimus. our results may be useful to explore patients who could be converted to everolimus with cni minimization at a late post-transplant stage. conflict of interest the authors report no conflict of interest. references 1. xie x, jiang y, lai x, xiang s, shou z, chen j. mtor inhibitor versus mycophenolic acid as the primary immunosuppression regime combined with calcineurin inhibitor for kidney transplant recipients: a meta-analysis. bmc nephrol. 2015;16:91. 2. nankivell bj, borrows rj, fung cl, o'connell pj, allen rd, chapman jr. the natural history of chronic allograft nephropathy. n engl j med. 2003;349:2326-33. 3. golshayan d, pascual m. minimization of calcineurin inhibitors to improve long-term outcomes in kidney transplantation. transpl immunol. 2008;20:21-8. 4. holdaas h, rostaing l, serón d, et al. conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. 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2011;92:303-10. 19. gaston rs, cecka jm, kasiske bl,et al. evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. transplantation. 2010;90:68-74. 20. liefeldt l, brakemeier s, glander p, et al. donor-specific hla antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation. am j transplant. 2012;12:1192-8. 21. grimbert p, thaunat o. mtor inhibitors and risk of chronic antibody-mediated rejection after kidney transplantation: where are we now? transpl int. 2017;30:647-657. 22. eleftheriadis t, pissas g, sounidaki m, antoniadi g, antoniadis n, liakopoulos v, stefanidis i. in human cell cultures, everolimus is inferior to tacrolimus in inhibiting cellular alloimmunity, but equally effective as regards humoral alloimmunity. int urol nephrol. 2017;49:1691-1697. 23. biancone l, bussolati b, mazzucco g, et al. loss of nephrin expression in glomeruli of kidney-transplanted patients under m-tor inhibitor therapy. am j transplant. 2010;10:2270-8. 24. halimi jm, buchler m, al-najjar a, et ak. urinary albumin excretion and the risk of graft loss and death in proteinuric and nonproteinuric renal transplant recipients. am j transplant. 2007;7:618-25. age at conversion to everolimus with cni minimization-uchida et al. the correlation of gene expression of inflammasome indicators and impaired fertility in rat model of spinal cord injury: a time course study banafsheh nikmehr1, mahshid bazrafkan1, gholamreza hassanzadeh1, abdolhossein shahverdi2, mohammad ali sadighi gilani3, sahar kiani4, tahmineh mokhtari5, farid abolhassani1* purpose: expression assessment of the inflammasome genes in the acute and the chronic phases of spinal cord injury (sci) on adult rat testis and examination of associations between inflammasome complex expression and sperm parameters. materials and methods: in this study, 25 adult male rats were randomly divided into 5 groups. sci surgery was performed at t10-t11 level of rats’ spinal cord in four groups (sci1, sci3, sci7, and sci56). they were sacrificed after 1day, 3days, 7days and 56 days post sci, respectively. one group remained intact as control (co). casa analysis of sperm parameters and qrt-pcr (asc and caspase-1) were made in all cases. results: our data showed a severe reduction in sperm count and motility, especially on day 3 and 7. asc gene expression had a non-significant increase on day 1 and 56 after surgery compared to control group. caspase-1 expression increased significantly on day 3 post injury versus the control group (p = .009). moreover, caspase-1 overexpression, had significant correlations with sperm count (r = -0.555, p = .01) and sperm progressive motility (r = -0.524, p = .02). conclusion: inflammasome complex expression increase following sci induction. this overexpression correlates to low sperm parameters in sci rats. keywords: spinal cord injury; infertility; testis, inflammasome; asc; caspase-1. introduction spinal cord injury (sci) is a devastating clinical issue affecting 40 to 80 new cases per million population each year throughout the world and up to 90% of these cases are due to traumatic causes(1). according to a study conducted by a specialized spinal cord injury center in tehran, iran, the incidence of sci is up to 2.36 persons per 10000 population with an average age of 29.1 years. sci patients are at higher risk of morbidity and mortality because of complications related to the injury. iran has younger sci cases more than other developing countries and about 80% of whom are male. sci people are usually at reproductive age, so fatherhood is a grave issue for this population(2). about 85% to 97% of sci men suffer from impaired fertility caused by erectile dysfunction and ejaculatory problems(3). there are some assisted methods such as penile vibration (pvs) and electroejaculation (eej) to obtain the semen from these patients. however, most sci men have a low semen quality(4-6). although testicular tissue becomes involved post-sci, a limited number of studies have addressed this issue. impaired spermatogenesis, vast germ cell apoptosis, inflammatory cytokines elevation, blood-testis barrier disruption and leukocytes influx have been demonstrated as abnormal changes in testis after sci inducing an inflammatory environment and unstable niche in this tissue(7-9). the inflammasome is a multi-protein complex that is a part of the innate immunity. the main component of this complex is called nucleotide oligomerization domain–like receptor (nlr), an inter-cellular receptor for pathogenic and non-pathogenic signals. the other parts of complex consist of an adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (asc), and caspase-1 (casp-1). the inflammasome activation induces auto-cleavage of pro-caspase-1 into the it’s active form that leads to converting pro-interleukin-1β (pro-il-1β) and pro-interleukin-18 (pro-il-18) to the biological active forms (il-1β and il-18). these pro-inflammatory cytokines trigger other inflammatory cascades playing 1department of anatomy, school of medicine, tehran university of medical sciences, tehran, iran. 2department of embryology, reproductive biomedicine research center, royan institute for reproductive biomedicine, acecr, tehran, iran. 3department of urology, school of medicine, tehran university of medical sciences, tehran, iran. 4department of stem cells and developmental biology at cell science research center, royan institute for stem cell biology and technology, acecr, tehran, iran. 5department of anatomy, school of medicine, semnan university of medical sciences, semnan, iran. *correspondence: department of anatomy, school of medicine, tehran university of medical sciences, poursina avenue, 1417613151, tehran, iran. tel: +98 (21) 88953008, fax: +98 (21) 66419072, e-mail: abolhasf@sina.tums.ac.ir. received july 2017 & accepted september 2017 sexual dysfunction and andrology sexual dysfunction and infertility 5057 an important role in the innate immunity(10,11). however, higher activity of the inflammasome complex and resulted inflammation can induce damages in the involved tissues and cause a rapid pro-inflammatory form of cell death (pyroptosis)(12). in 2011, dulin et al. revealed disruption in blood-testis-barrier (btb) and immune cell infiltration into the rat testis tissue following sci. accordingly, they found the elevation of il-1β 72h post-injury(9). in a recent study, fortune et al. assessed gene expression pattern and metabolomics in acute (24h) and chronic (3 months) phases of sci in rat testis. they detected many transcripts and metabolites related to inflammatory, oxidative stress and apoptotic pathways. therefore, they concluded that an unstable niche have been established in testis after sci causing sci-dependent male infertility(13). based on this background, sci promotes an inflammatory microenvironment in the testis tissue leading to a large germ cells apoptosis. inflammasome activation has not been reported in testis post-sci in the literature. therefore, we launched a time course study (acute and chronic phases of sci) regarding the role of essential genes (asc and casp-1) responsible for inflammasome complex in rat testis. materials and methods experimental animals in this study, 25 male wistar rats (weight 200-250 g, age 8–10 weeks) were used in a random sampling design. all animals were kept and maintained at 20–24 °c, 55 ± 10 % humidity and on a 12-hour light/dark cycle at the animal laboratory core facility of royan institute, tehran, iran. they were fed by standard diet ad libitum, with access to tap water. all animal handlings, surgeries and cares were managed in compliance with the tehran university of medical sciences ethics committee. the animals acclimatized to the laboratory at least one week before surgery. study design the rats were randomly divided into 5 groups and sci induction and sacrifices were performed based on the study time-line (figure 1). contusion injury model at t10-t11 levels was chosen because there is no direct innervation from these levels to testes. also, this model has the most similarity to traumatic injuries of the sci patients in the clinics. surgeries for contusion injury induction were done at four groups: sci 1, sci 3, sci 7 and sci 56. rats in each group were killed and analyzed at a specific time point that is to say one day, three days, seven days and 56 days after surgery. one group remained intact as control (co). sci surgery the rats were anesthetized with an intraperitoneal administration of ketamine (80 mg/ kg) and xylazine (10 mg/kg) mixture. a dissection along the midline of the cord was performed on the 10th to 11th thoracic (t10– t11) vertebrae to create a 4mm longitudinal cut. after cutting the muscles and tissues, the laminectomy was performed. the vertebrae around t10 were stabilized and the contusion injury model was induced by nyu mascis (new york university multicenter animal spinal cord injury study) impactor (14,15). a 10-gram rod was dropped from a height of 25 mm. complete contusion injury was obtained on spinal cord after 1-3 minutes (figure 2). after surgery for recovery time, all rats were placed on a warm plate (38°c) for an hour. manual bladder emptying was daily done from the day after surgery to remove residual urine, blood or any infection until the return of reflexive control of bladder function. behavioral test from day one, all sci rat models were functionally examined. open field locomotor test was performed by the non-invasive, basso, beattie, bresnahan (bbb) locomotor rating scale(16). all animals with bbb scoring less than 2 were kept and others were removed from our study because of insufficient damage of spinal cord. epididymis sampling the cauda epididymis was dissected before perfusion to avoid negative effects on sperm motility. this procedure was done with care without any damage to vessels in that area. epididymis, after one or two incision, minced in 1 ml pre-warmed ham's f-10 medium (st. louis, mo, usa) fortified with bovine serum albumin (bsa, sigma, louis, usa) for 30 to 45 min in a 37◦c incubator. semen analysis after 30-45 min incubation, epididymal sperm released from the tissue and swim up into the medium. sperm parameters were analyzed with a computer-assisted sperm analyzer (casa) as pointed out by krause(17). the casa system consisted of a phase contrast microscope (eclipse e-200, nikon co., japan) with a heat plate equipped with sperm class analyzer® software inflammasome gene expression in rat testes following sci-nikmehr et al. table 1. standard terminology for variables measured by computer-assisted sperm analyzer (casa) systems. parameters unit description curvilinear velocity (vcl) μm/seconds time-averaged velocity of a sperm head along its actual curvilinear path. straight-line velocity (vsl) μm/seconds time-averaged velocity of a sperm head along the straight line between its first detected position and its last average path velocity (vap) μm/seconds time-averaged velocity of a sperm head along its average path linearity (lin) % the linearity of a curvilinear path, vsl/vcl straightness (str) % linearity of the average path, vsl/vap. wobble (wob) % a measure of oscillation of the actual path about the average path, vap/vcl. target gene primer sequence (5′–3′) annealing temperature(◦c) gene bank code product size(bp) caspase-1 forward ctttctgctcttcaacaccag 59.61 nm_012762.2 122 caspase-1 reverse aatgtcctccaagtcacaaga 59.64 asc forward cccatagacctcactgataaact 59.55 nm_172322.1 127 asc reverse gctccagactcttccataatctt 60.13 table 2. the sequences of rat specific primers for caspase-1 and asc cdna. all primers were designed by perlprimer v1.1.21. vol 14 no 06 november-december 2017 5058 (sca, full research version 5.1, microptic co., barcelona, spain). in order to make sperm analysis, 4 μl sperm samples were placed in a standard count analysis chamber (leja, nieuw vennep co., netherlands). specimens were observed with a nikon microscope 10x/0.25 negative phase contrast field ph1 bm, with an intermediate magnification of 0.7 and a green filter. at least 400 spermatozoa were counted for each sample. (table1) testis sampling and rna extraction at each of the time points of study, the tissue reperfusion was done with normal saline to eliminate blood from all tissues especially testes. after 45-60 min, testes were dissected and cut into the three parts. each part was snap frozen in liquid nitrogen and stored individually in -80◦c, for further investigation. rna extraction procedures were done under an rnase-free condition. total rna was isolated from testis samples using trizol reagent (sigma, st. louis, mo, usa), based on the manufacturer’s protocol. briefly, samples were warmed at lab temperature. then, they were placed in 1.5 ml rnase free tubes and homogenized thoroughly with a needle. afterward, 800 μl (1 ml per 50 to 100 mg tissue) trizol® reagent was added to each tube and homogenized by hand with a tissue-homogenizer tip until tissue was completely dissociated. then, 200 μl chloroform was added to each tube, capped tightly and shaken firmly. after 3 min incubation in lab temperature, the tubes were centrifuged at 12000 rpm, 15min, and 4◦c. the aqueous (top) phase (containing rna) was decanted in another rnase-free tube and the same volume of 100% isopropanol was added to the tube for rna precipitation. tubes are placed in -20◦c for an hour and centrifuged (12000 rpm, 15min, and 4◦c). the pellet was washed with 70% ethanol, air dried and dissolved in diethyl pyrocarbonate (depc) treated water. the extracted rna was quantitated at 260 nm (nanodrop 2000 spectrophotometer, thermo scientific, wilmington, de). quantitative real-time pcr the isolated rna was reversely transcripted to complementary dna (cdna) using primescript rt reagent kit (takara bio inc., otsu, japan) according to the manufacturer guidelines. primers were designed by perlprimer software version 1.1.21 (marshall, 2004) and the sequences were listed in table 2. the mrna expression levels of the genes (asc and casp-1) were quantified using abi/steponeplus real-time pcr system (applied biosystems). all real-time pcr assays were run in a total reaction volume of 20 μl. the result was shown as relative gene expression by the comparative ct method ( 2─∆∆ct )(18). all ct values were determined and normalized in comparison to a housekeeping gene (b-actin). relative quantification was calculated by steponetm real-time pcr software version 2.2 (thermo fisher scientific, waltham, ma). statistical analysis all data were analyzed using spss statistical software version 22.0 (spss inc., chicago, il). results were expressed as mean ± standard error of the mean (s.e.m). analyses of the parametric data were done by one-way analysis of variance (anova) with turkey’s post hoc statistical tests. non-parametric data were analyzed statistically using kruskal-wallis test (nonparametric anova) and dunn's multiple comparisons for posttest. in all analyses, p < .05 was set as a significant level. results semen analysis sperm parameters were evaluated by recruiting casa system and statistically analyzed compared to those of the control group and p < 0.05 was considered statistically significant (table 3). sperm concentration was significantly lower in comparison to the control group, on day 1, 3 and 7 after sci (p = .034, p = .002 and p figure 1. the time line of the study. there were four groups that have undergone sci surgery. rats in each group were killed at a specific time point (day1, day3, day7 and day56) post injury and epididymis (for sperm analysis) and testis (for real-time pcr) were dissected. groups co sci 1 sci 3 sci 7 sci 56 count (106 /ml) 27.64 ± 2.33 15.38 ± 1.41* 9.92 ± 0.77* 14.99 ± 1.47* 24.13 ± 4.95 total motility (%) 83.22 ± 3.52 52.09 ± 9.39 44.28 ± 4.58* 57.66 ± 0.93 52.19 ± 15.67 progressive motility (%) 64.11 ± 7.68 31.66 ± 7.44 19.11 ± 2.89* 28.02 ± 1.36* 42.24 ± 14.26 non-progressive motility (%) 19.10 ± 4.59 20.42 ± 4.82 25.16 ± 1.99 29.62 ± 0.70 9.72 ± 1.66 immotile sperms (%) 16.79 ± 3.52 47.91 ± 4.70 55.71 ± 4.58* 42.34 ± 0.93 47.78 ± 15.64 vcl (%) 107.40 ± 12.61 53.71 ± 6.57* 35.65 ± 9.07* 41.03 ± 9.85* 76.60 ± 20.20 vsl (%) 28.62 ± 1.61 13.02 ± 3.69* 5.87 ± 1.20* 8.56 ± 2.74* 15.78 ± 5.30 vap (%) 47.41 ± 3.96 26.37 ± 4.84 14.80 ± 4.24 16.99 ± 4.76 37.53 ± 10.78 lin (%) 27.76 ± 3.60 23.30 ± 3.79 17.89 ± 1.98 18.72 ± 3.09 18.95 ± 2.84 *p < 0.05 compared to co table 3. effects of sci on sperm parameters in rats, on day 1, 3, 7 and 56 after injury. (mean ± standard error) inflammasome gene expression in rat testes following sci-nikmehr et al. sexual dysfunction and infertility 5059 = .028, respectively). after 56 days post injury, sperm count had returned almost to amount of control group. total motility (%) had a decline in all groups, but it was significant just on 3 day group, compared to control group (p = .02). sperm progressive motility was reduced significantly on day 3 and 7 after sci (p = .01 and p=.034, respectively). non-progressive motility had no significant differences at any time points, compared to that of control. the most immotile sperm number was observed on day 3, although there was a non-significant growth in immotile sperm percent at four-time points. vcl and vsl (%) significantly reduced on day 1, 3 and 7, respectively. but the most reduction was seen on day 3. there was a decrease in vap and lin levels at every mentioned time points post-injury, but the changes were not significant. asc and casp-1 mrna gene expression asc and casp-1 mrna expression in rat testes of the control group, without any intervention, was at a low basic level (figure 3, co). in one day group the amount of mrna expression level for asc increased, but it was not significant. the asc had a non-significant expression peak again, 56 days after sci (figure 3). casp-1 also had an increased expression only one day after sci. the peak level of casp-1 was on day 3 (p = .009). after that, the expression level became lower, even on 56 days post-sci. the correlation of gene expression and sperm parameters the correlations were assessed between sperm parameters and gene expression (figure 4). sperm count correlated negatively to casp-1 expression (r = -0.555, p = .01). moreover, there is a significant negative correlation between sperm progressive motility and caspase-1 expression (r = -0.524, p = .02) discussion impaired fertility is a common feature of men with sci that is attributed to erectile and ejaculation dysfunctions. in most cases, these problems are solvable with some methods like pvs and eej. however, semen quality of these patients is often poor. the majority of the studies have emphasized that low sperm motility and viability, leukocytospermia, and high sperm dna fragmentation are common among sci men. many reports indicate that sperm count remained unchanged following sci(6,19). in the present study, we examined sperm parameters of sci rats at the acute (1,3,7 days after injury) and the chronic (56 days after injury) phases. interestingly, sperm count fell by half just after one figure 2. rat model of spinal cord injury (t10-t11): a. exposed spinal cord following a dorsal laminectomy procedure. b. bruising of the spinal cord after contusion induction figure 3. effects of sci on gene expression of asc and caspase-1 in rat testis, on day, 1, 3, 7 and 56 post injury (*p < .05 compared to co). inflammasome gene expression in rat testes following sci-nikmehr et al. vol 14 no 06 november-december 2017 5060 day and a third after 3 days post-injury. this severe reduction was significant in the acute phase (1,3 and 7 days) but after 56 days (chronic phase) it had rebounded almost to the control group level. sperm motility had a sharp decline after injury, as well. total motility decreased in the acute (1,3 and 7 days after injury) and the chronic (56 days after injury) phases of sci but it was statistically significant just on day 3. the most effect of sci was on progressive motility with a significant reduction on day 3 and 7. sci caused a large increase in the percent of immotile sperm, especially on day 3 with a threefold increase. most studies have analyzed sperm parameters post-sci in human samples, and few researches have been conducted on the experimental models. in this field, the majority of studies indicated that sperm count after sci was normal and most changes happen in sperm motility and viability(19). interestingly, our study showed a rapid decline in sperm count in the acute phase of sci. low sperm motility in our research is in concordance with previous studies that they have been mentioned it as one of the most important causes of impaired fertility following sci(19,20). however, some investigations have claimed seminal plasma of sci men is toxic to sperm, and cauda epididymis and vas deferens(21,22) have sperm with better quality(23,24). in the present study, we analyzed sperm from caudal part of epididymis, to diminish toxic effects of ejaculated semen on sperm motility after sci. intriguingly, total motility dropped rapidly just after one day, and it remained low after 56 days from surgery. it seems that the greatest effect of sci is on progressive motility, especially on day 3 and 7 post-injury (acute phase). although many reasons have been raised for male subfertility following sci, spermatogenesis defects, large germ cell apoptosis and inflammatory conditions in testicular tissue are not well-defined. in this regard, only a few investigations have been performed on experimental models. huang et al. carried out a time course study (3, 7, and 14 days after the sci induction) on spermatogenesis abnormalities following sci on male rats. they showed delayed spermiation and vacuolization of the nucleus of spermatids just 3 days after sci. other spermatogenic abnormalities were observed on day 14 group. also, they demonstrated that hormone alteration is not the only reason for the impaired spermatogenesis following sci(25). choobineh et al. reported exogenous testosterone therapy after sci in adult mice could not compensate sexual hormone insufficiency and it caused reduction in natural testosterone production of testes(26). for the first time, dulin et al. (2011) illustrated that blood-testis barrier (btb) integrity was disrupted after sci on male sprague-dawley rats. in that study, btb became permeable to immunoglobulin g at both 72 hours and 10 months post sci. the results indicated immune cell infiltration into the testis tissue and high expression of the pro-inflammatory cytokine il-1β. moreover, widespread germ cell apoptosis was observed at 72 h after sci(9). in 2016, fortune et al. showed many pathological events in testis in both acute and chronic phases of sci. they revealed a pro-inflammatory environment established after sci in rat testis. afterwards, other inflammatory cascades are activated resulting cell cycle dysregulation and apoptosis within the seminiferous tubules(13). inflammasome is an inflammatory complex that is activated under pathogenic and non-pathogenic conditions. association of this complex with many diseases was previously detected(23-25), but it is not clearly defined in male infertility. ibrahim et al. (2013) showed higher concentrations of some inflammasome indicators including il-1◦, il-18, casp-1 and asc in the semen of sci affected men with chronic injury and even the inflammasome suppression treatments have been applied to improve the semen quality in sci patients(27,28). in this study, we evaluated the expression of asc and casp-1 in rat testis at the acute (1,3 and 7 days) and the chronic (56 days) phases of sci. interestingly, both of two genes were expressed higher than the control group, just after one day post-injury. asc expression was high on day 1, dropped on day 3 and 7 and again raised on day 56 after injury but it was not significant at of the four time points of study. asc is an adaptor protein that makes a connection between nlrs and casp1. however, recent investigations showed that some nlrs can be attached to casp-1 directly without asc (29). it means that asc overexpression can indicate inflammasome activation but is not necessary. casp-1 is the best-known type of the inflammatory caspases and it is an indispensable component of inflammasome complex. there are some pathways to activate the inflammasome complex (canonical and non-canonical), but in all pathways, casp-1 is necessary for inflammasome formation and activation(30,31). in this study, casp-1 expression increased more than two-fold on day 1 after injury and peaked on day 3 with a fourfold increase, compared to the control group. following that, casp-1 expression dropped on day 7 and remained figure 4. the correlation of casp-1 expression and sperm parameters of rat model of spinal cord injury. a. casp-1 overexpression was significantly correlated to decline in sperm count (r = -0.555, p = .01). b. sperm progressive motility reduced with increase in casp-1 expression (r = -0.524, p = .02). inflammasome gene expression in rat testes following sci-nikmehr et al. sexual dysfunction and infertility 5061 unchanged on day 56 after injury. since the casp-1 is a direct marker of the inflammasome, it seems the sci could activate inflammasome gene expression. our data showed there are significant correlations between some sperm parameters and inflammasome gene expression. casp-1 expression negatively correlated with sperm count and progressive motility. the expression of casp-1 elevated after one day, and it was in the highest level on day 3 post-injury. as we know casp-1 is the critical enzyme of the inflammasome complex (interleukin-1◦/18 converting enzyme or ice) activating pro-inflammatory cytokines of il-1◦ and il18. these cytokines have been known as the negative factors on the sperm parameters, especially on motility (22). in the current study, a sharp decline in sperm progressive motility was detected on day 3 and 7 after injury. it seems that this reduction could happen secondary to the casp-1 overexpression on day 1 and 3. identification of gene expression pattern of inflammasome in testis during the acute and the chronic phases of sci is essential to therapeutic purposes. conclusions asc and casp-1 are two inflammasome specific genes and are not related to other signaling pathways. therefore, the expression of those genes on rat testis following sci can indicate an abnormal cell situation. with these data, it seems there is a pattern in inflammasome gene expression in both acute and chronic phases of sci. such a pattern has been specified in other tissues but not in testis. moreover, sci had negative effects on sperm progressive motility that correlated negatively with casp-1 overexpression. acknowledgement this study was supported by research grant no. 29326 from tehran university of medical sciences. we would like to thank royan institute (the embryology department and the electrophysiology laboratory) for their technical assistance. conflict of interest the authors declare they have no conflict of interest. references 1. organization wh, society isc. international perspectives on spinal cord injury. world health organization; 2013. 2. derakhshanrad n, yekaninejad m, vosoughi f, fazel fs, saberi h. epidemiological study of traumatic spinal cord injuries: experience from a specialized spine center in iran. spinal cord. 2016;54:901-7. 3. brackett nl, ferrell sm, aballa tc, et al. an analysis of 653 trials of penile vibratory stimulation in men with spinal cord injury. j urol. 1998;159:1931-4. 4. ibrahim e, lynne c, brackett n. male fertility following spinal cord injury: an update. androl. 2016;4:13-26. 5. brackett nl, santa-cruz c, lynne cm. sperm from spinal cord injured men lose motility faster than sperm from normal men: the effect is exacerbated at body compared to room temperature. j urol. 1997;157:2150-3. 6. momen mn, fahmy i, amer m, arafa m, zohdy w, naser ta. semen parameters in men with spinal cord injury: changes and aetiology. asian j androl. 2007;9:684-9. 7. sánchez-ramos a, vargas-baquero e, martinde francisco f, et al. early spermatogenesis changes in traumatic complete spinal cordinjured adult 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the weight-drop rod. paper presented at: world congress on medical physics and biomedical engineering 20062007. 16. basso dm, beattie ms, bresnahan jc. a sensitive and reliable locomotor rating scale for open field testing in rats. j neurotrauma. 1995;12:1-21. 17. krause w. computer-assisted semen analysis systems: comparison with routine evaluation and prognostic value in male fertility and assisted reproduction. hum reprod. 1995;10(suppl 1):60-66. 18. livak kj, schmittgen td. analysis of relative gene expression data using real-time quantitative pcr and the 2− ◦◦ct method. methods. 2001;25:402-8. 19. patki p, woodhouse j, hamid r, craggs m, shah j. effects of spinal cord injury on semen parameters. j spinal cord med. 2008;31:2732. 20. padron of, brackett nl, sharma rk, lynne cm, thomas aj, agarwal a. seminal reactive oxygen species and sperm motility and morphology in men with spinal cord injury. fertil steril. 1997;67:1115-20. inflammasome gene expression in rat testes following sci-nikmehr et al. vol 14 no 06 november-december 2017 5062 21. de lamirande e, leduc be, iwasaki a, hassouna m, gagnon c. increased reactive oxygen species formation in semen of patients with spinal cord injury. fertil steril. 1995;63:637-42. 22. cohen dr, basu s, randall jm, aballa tc, lynne cm, brackett nl. sperm motility in men with spinal cord injuries is enhanced by inactivating cytokines in the seminal plasma. j androl. 2004;25:922-5. 23. brackett nl, davi rc, padron of, lynne cm. seminal plasma of spinal cord injured men inhibits sperm motility of normal men. j urol. 1996;155:1632-5. 24. brackett nl, lynne cm, aballa tc, ferrell sm. sperm motility from the vas deferens of spinal cord injured men is higher than from the ejaculate. j urol. 2000;164:712-5. 25. huang h, linsenmeyer t, li m, et al. acute effects of spinal cord injury on the pituitary‐ testicular hormone axis and sertoli cell functions: a time course study. j androl. 1995;16:148-57. 26. choobineh h, gilani mas, pasalar p, jahanzad i, ghorbani r, hassanzadeh g. the effects of testosterone on oxidative stress markers in mice with spinal cord injuries. int j fertil steril. 2016;10:87. 27. zhang x, ibrahim e, de rivero vaccari jp, et al. involvement of the inflammasome in abnormal semen quality of men with spinal cord injury. fertil steril. 2013;99:118-24. e112. 28. ibrahim e, castle s, aballa t, et al. neutralization of asc improves sperm motility in men with spinal cord injury. hum reprod. 2014:deu230. 29. man sm, kanneganti td. regulation of inflammasome activation. immunol rev. 2015;265:6-21. 30. lamkanfi m, dixit vm. mechanisms and functions of inflammasomes. cell. 2014;157:1013-1022. 31. man sm, kanneganti t-d. converging roles of caspases in inflammasome activation, cell death and innate immunity. nat rev immunol. 2016;16:7-21. inflammasome gene expression in rat testes following sci-nikmehr et al. sexual dysfunction and infertility 5063 miscellaneous effects of 1% lidocaine instillation on overactive bladder induced by bladder outlet obstruction in rats hyo jin kang,1,2 sang woon kim,1yong seung lee,1 sang won han,1 jang hwan kim1* purpose: lidocaine is a common local anesthetic and antiarrhythmic drug that acts via the local anesthetic effect of blocking voltage-gated sodium channels in peripheral neurons. to evaluate lidocaine as a therapeutic agent, we investigated optimal concentrations and effects of intravesical lidocaine instillation in a bladder outlet obstruction (boo)-induced rat model of overactive bladder (oab). materials and methods: to determine the therapeutic dosage of lidocaine, 16 female sprague-dawley (sd) rats (mean weight = 200 ± 20 g) were divided into four treatment groups: those receiving saline, 0.5% lidocaine, 1% lidocaine, and 2% lidocaine (n = 4 per group). twenty-four additional sd rats were divided into two groups to investigate the effect of 1% lidocaine treatment in rats with boo and normal rats (n = 12 per group). cystometry was performed by infusing physiological saline and lidocaine into the bladder at a slow infusion rate (0.04 ml/ min). cystometric parameters were analyzed using powerlab®. the expression of c-fos, a protein expressed by c-fibers in the spinal cord (l6), was investigated via western blotting. results: among the test lidocaine doses, only 1% lidocaine increased the intercontraction interval (ici) (control mean = 500.56 ± 24.4 s; treatment mean = 641.0 ± 49.3 s; p < .01) without changes in threshold pressure and basal pressure. in the boo-induced oab group, the ici increased significantly after instillation of 1% lidocaine (control mean = 135.8 ± 12.87 s; oab-group mean = 274.2 ± 33.21 s; p < .01). detrusor overactivity and non-voiding contraction were observed in the control group but not in rats with boo after lidocaine instillation. the expression of c-fos in c-fibers in the spinal cord (l6) decreased significantly after 1% lidocaine treatment in rats with boo. conclusion: intravesical instillation of 1% lidocaine improves cystometric parameters without deterioration of contractility by blocking excessive c-fiber activity in the rat model of boo-induced oab. therefore, instillation of 1% lidocaine has minimal effects on normal nerves while blocking nerves that contribute to oab. our findings suggest that intravesical instillation of 1% lidocaine is a useful treatment for oab. keywords: bladder outlet obstruction; cystometry; lidocaine; overactive bladder; unmyelinated c-fibers introduction overactive bladder (oab) is a storage and voiding dysfunction related to urinary urgency, with or without urgency incontinence, frequency, and nocturia. (1-4) the oab symptoms are caused either by obstruction of, or secondary effects of obstruction on the bladder. in some patients, the symptoms are accompanied by uncontrolled contractions of the detrusor muscle during bladder filling, known as detrusor overactivity (do).(5-7) prior investigations have shown that myelinated aδ-fibers and unmyelinated c-fibers of the afferent nerve are important for the regulation of micturition. c-fibers convey input signals from the periphery to the central nervous system; these fibers respond to mechanical, thermal, and chemical stimuli.(8,9) the activation of c-fibers, which are silent in normal bladders, is regarded as a major cause of oab, triggering micturition in unstable bladders.(10) we surveyed neuroinhibitors that might specifically inhibit only activated c-fibers during oab. these included lidocaine, a common local anes1department of urology, severance hospital, urological science institute, yonsei university college of medicine, seoul, korea. 2medical science research institute, seoul national university bundang hospital, seongnam, korea. *correspondence: dept. of urology, school of medicine, yonsei university, 134 shinchon-dong, seodaemoon-gu, seoul, korea, 120-752 telephone: +82-2-2228-2319. fax: +82-2-312-2538. e-mail address: jkim@yuhs.ac. received january 2019 & accepted august 2019 thetic and antiarrhythmic drug(11-13) that blocks the influx of sodium ions through direct binding of neuronal voltage-gated sodium membrane channels, thereby producing an analgesic effect by inhibiting the excitation of nerve endings or by blocking conduction in peripheral nerves.(14,15) in addition, lidocaine is a widely used local anesthetic because of its rapid onset of action and intermediate duration of efficacy.(12,16) in previous reports, intravesical instillation of lidocaine was shown to provide immediate relief of pain, as well as improve urgency and frequency, in patients with interstitial cystitis/bladder pain syndrome.(13,17) yokoyama et al. reported that lidocaine blocked the action potentials of small unmyelinated c-fibers more easily than those of large myelinated aδ-fibers.(14) the effects of intravesical lidocaine instillation for therapeutic treatment of oab have not been elucidated. lidocaine is a candidate drug for oab treatment because it has already been approved for clinical use as an anesthetic, and its safety has been established(18). therefore, we evaluated various doses of lidocaine in normal rats urology journal/vol 17 no. 3/ may-june 2020/ pp. 306-311. [doi:10.22037/uj.v0i0.5111] to detect concentrations that could inhibit only c-fibers without affecting aδ-fibers. in addition, we confirmed the therapeutic effect of selected lidocaine doses in a bladder outlet obstruction (boo)-induced rat model of oab. materials and methods animals six-week-old female sprague-dawley (sd) rats (mean weight = 200 ± 20 g) purchased from orient bio (seongnam, korea) were cared for in accordance with guidelines of the association for assessment and accreditation of laboratory animal care international. the institutional animal care and use committee of yonsei university college of medicine (seoul, korea) approved these animal experiments. sixteen sd rats were divided into the following four groups (n = 4 per group) to determine the optimum lidocaine dose: the control group and groups that received 0.5%, 1%, and 2% lidocaine. twenty-four additional sd rats were divided into the following two groups (n = 12 per group): the control group with normal rats and the group of rats with boo. boo was induced by using methods described in a previous study.(2) briefly, rats were anesthetized with a mixture of zoletil (30 mg/kg; virbac, carros cedex, france) and rompun (10 mg/kg; bayer korea ltd., seoul, korea), and the bladder and proximal urethra were exposed via a lower midline abdominal incision. the proximal urethra was carefully freed from the vaginal wall to avoid injury to periurethral blood vessels. a polyethylene-50 (pe-50) catheter (clay adams, parsippany, nj, usa) with an inner diameter of 1.40 mm was inserted into the urethra. the proximal urethra was then tied loosely with 3/0 silk, thus enabling the catheter to move freely. after the catheter was removed, intramuscular antibiotics were injected postoperatively. the silk ligatures were removed from the rats with boo before cystometry. cystometry the cystometry study design is shown in figure 1. two animal experiments were performed: determination of optimum lidocaine concentration and evaluation of effects of 1% lidocaine on boo. at 4 weeks after boo surgery, rats were anesthetized with a mixture of zoletil figure 1. schematic illustration of the design of the current study. a) cystometry for determination of lidocaine concentration. b) cystometry after instillation of 1% lidocaine in rats with bladder outlet obstruction (boo)-induced overactive bladder (oab). figure 2. cystometric analysis of lidocaine dosage in normal rats. cystometric parameters were analyzed for rats instilled with saline (a), 0.5% lidocaine (b), 1% lidocaine (c), and 2% lidocaine (d). room-temperature saline or lidocaine was instilled by the intravesical route for 30 min (0.04 ml/min). in the lidocaine-treatment groups, lidocaine was replaced with saline for 2 h. intercontraction intervals (icis) increased in rats instilled with 0.5% (a) and 1% lidocaine (b), compared with rats instilled with saline instillation (c); however, bp, tp, and mp values did not differ significantly among groups. d) in rats instilled with 2% lidocaine, all cystometric parameters increased relative to those of rats instilled with saline. 1% lidocaine effects on overactive bladder-kang et al. vol 17 no 03 may-june 2020 307 and rompun (1 ml/kg), and the bladder was exposed. a pe-50 tube, filled with saline and with its end flared by heat, was inserted into the bladder through the dome and the 3/0 silk ligatures were released. after the abdominal incision was closed, the rats were placed in a restraining cage and allowed to recover from anesthesia for 2–3 h until they awakened. the catheter was connected to a pressure transducer and syringe pump via a three-way stopcock. cystometry was performed by infusing physiological saline into the bladders of normal rats and rats with boo at a slow infusion rate (0.04 ml/min). cystometric variables were measured during saline infusion for 2 h to evaluate bladder function. after a minimum number of stable micturition cycles was analyzed, the saline was replaced with lidocaine hydrochloride (jeil pharmaceutical, daegu, korea) and infusion was continued for 30 min. the intravesical lidocaine was washed out for 30 min and bladder pressure was immediately monitored using a powerlab®/ labchart7 instrument (adinstruments, bella vista, australia). continuous cystometry was performed, and at least five reproducible micturition cycles were analyzed. intercontraction intervals (icis) were defined as the intervals between large amplitude spontaneous bladder contractions. threshold pressure (tp) was defined as the bladder pressure immediately prior to micturition, relative to basal pressure (bp; the lowest bladder pressure during filling). micturition pressure (mp) was defined as the maximum bladder pressure during micturition. drug administration the stock solution of 2% lidocaine hydrochloride (jeil pharmaceutical) was neutralized by mixing it with 8.4% sodium bicarbonate solution (jeil pharmaceutical) at a 1:1 ratio. to generate 1% and 0.5% lidocaine solutions, 2% lidocaine was diluted with normal saline at 1:1 and 1:2 ratios, respectively. the ph of neutralized lidocaine was between 7.4 and 7.6. western blotting spinal cord tissues were homogenized using proprep lysis buffer (intron, seoul, korea), and the concentration of cellular protein was determined using the bio-rad assay reagent (bio-rad, hercules, ca, usa). briefly, samples with equal concentrations of cellular protein were mixed with 4ι sample buffer (gendepot inc., barker, tx, usa), heated at 95°c for 10 min, and separated using electrophoresis on 10% sodium dodecyl sulfate–polyacrylamide gels. proteins were then transferred onto polyvinylidene difluoride membranes (amersham life science, arlington heights, il, usa) in tris-glycine transfer buffer (invitrogentm, carlsbad, ca, usa). the membranes were blocked for 1 h at room temperature with 5% skim milk in tris-buffered saline with tween-20. the membranes were incubated at 4°c overnight with anti-c-fos antibody (santa cruz biotechnology, santa cruz, ca, usa), and then incubated with horseradish peroxidase-conjugated anti-mouse igg (santa cruz biotechnology) for 1 h at room temperature. the membranes were washed and then incubated using a west-q chemiluminescent substrate plus kit (gendepot inc.). the intensities of protein bands were determined using multi gauge software (version 3.0; fuji photo film, tokyo, japan); relative densities were expressed as ratios of control values. statistical analysis quantitative data are expressed as the means ± standard deviations. differences between lidocaine-concentration groups were evaluated using one-way anova analysis of variance followed by dunnett’s t3 and multiple comparison post hoc tests. paired student’s t-tests were used to compare cystometric parameters before and after 1% lidocaine treatment. differences with p values < .05 were considered statistically significant. statistical analyses were performed using graphpad prism software (version 5.01; graphpad inc., la jolla, ca, usa). results cystometry for determination of lidocaine concentration the ici increased significantly in rats instilled with 1% and 2% lidocaine, compared with that of rats instilled with saline, indicating that a relatively high concentration of lidocaine delayed micturition. bp and tp increased significantly in rats instilled with 2% lidocaine, compared with those of control rats; bp and tp values in the other groups were nearly identical to those of the control group. the mp trend differed from those of other cystometric parameters-mp increased in rats instilled with 0.5% lidocaine but decreased in rats 1% lidocaine effects on overactive bladder-kang et al. miscellaneous 308 saline 0.5% lidocaine 1% lidocaine 2% lidocainecystometric parameters ici (intercontraction interval, s) 500.5 ± 24.4 606.3 ± 45.2 641.0 ± 49.3** 598.6 ± 26.4** bp(basal pressure, cmh 2 o) 3.28 ± 0.19 2.51 ± 0.31 3.49 ± 0.19 5.17 ± 0.40*** tp (threshold pressure, cmh 2 o) 5.83 ± 0.37 6.61 ± 0.85 5.97 ± 0.55 7.45 ± 0.64* mp (micturition pressure, cmh 2 o) 21.69 ± 0.61 28.73 ± 2.15*** 21.09 ± 0.50 18.71 ± 0.74** table 1. cystometric parameters after instillation of various concentrations of lidocaine in normal rats. data are shown as the means ± standard deviations. *, p < .05 compared with the control; **, p < .01; ***, p < .001 normal normal/lidocaine boo boo/lidocaine cystometric parameters ici (intercontraction interval, s) 358.2 ± 70.02 508.9 ± 71.03** 135.8 ± 12.87 274.2 ± 33.21** bp (basal pressure, cmh 2 o) 3.56 ± 0.58 3.32 ± 0.63 5.35 ± 0.32 5.71 ± 0.62 tp (threshold pressure, cmh 2 o) 9.02 ± 0.77 11.28 ± 1.59 10.16 ± 0.66 12.86 ± 1.75 mp (micturition pressure, cmh 2 o) 23.36 ± 1.39 24.58 ± 0.65 34.29 ± 5.23 36.98 ± 4.93 data are shown as the means ± standard deviations. **, p < .01. table 2. cystometric parameters of normal rats and rats with bladder outlet obstruction (boo) after instillation of 1% lidocaine. instilled with 2% lidocaine. furthermore, instillation of 1% lidocaine had no effect on mp (table 1; figure 2). thus, instillation of 1% lidocaine had minimal effects on most cystometric parameters in normal rats and only increased micturition interval. cystometric parameters in normal rats and the boo-induced rat model of oab at 4 weeks postoperatively, the mean ici was significantly shorter in rats with boo, such that the frequency of micturition was more than two times greater than normal in rats with boo. bp, tp, and mp increased in rats with boo, but these differences were not statistically significant (table 2). cystometry after instillation of 1% lidocaine in the boo-induced rat model of oab after instillation of 1% lidocaine, the mean ici of the boo group was significantly longer than that of the boo group before lidocaine treatment; bp, tp, and mp did not differ significantly between groups (table 2). cystometric analysis indicated that instillation of 1% lidocaine induced recovery of frequent micturition. in addition, persistent do and non-voiding overactivity disappeared after intravesical instillation of 1% lidocaine in rats with boo (figure 3). although the instillation of 1% lidocaine seemed to have no effects on bp, tp, and mp according to parametric analysis, it has been shown via graph monitoring to have more influence on these parameters and improve the urination interval. expression of c-fos in the boo-induced rat model of oab expression of c-fos was analyzed via western blotting. in this analysis, the intensities of the blots were determined via densitometric scanning, and relative densities were expressed as ratios relative to the control value. the results of western blotting revealed that the expression of c-fos proteins increased in rats with boo compared with normal rats. after intravesical instillation of 1% lidocaine, c-fos expression decreased significantly in rats with boo (figure 4). discussion persistent oab is a urological condition that causes problems with urination and highly prevalent in the general population(19-21). prescription drugs for oab treatment, such as anticholinergics, are moderately effective and cause side effects that include dry mouth, constipation, and drowsiness, which can limit their usefulness(21,22). therefore, new therapeutic agents are needed to avoid the side effects of current treatments and address the underlying causes of oab. the activation of silent c-fibers is regarded as a major cause of oab, as this process triggers detrusor contraction in unstable bladders(10,14,23). blocking c-fiber activation may thus be an effective treatment for oab patients. previous studies showed that lidocaine is a non-selective blocker of voltage-gated sodium channels in peripheral neurons, and that unmyelinated c-fibers are more easily affected than myelinated aδ-fibers(14,24). prior investigators reported that intravesical instillation of lidocaine reduces various symptoms of oab and increases bladder cafigure 3. the results of cystometry before and after instillation of 1% lidocaine in rats with boo. the mean ici increased significantly after instillation of 1% lidocaine (b) compared with instillation of saline (a) in rats with boo. bp, tp, and mp values remained unchanged. b) after instillation of 1% lidocaine, oab symptoms and non-voiding contractions were absent. figure 4. expression of c-fos protein in the spinal cords (l6) of normal and boo rats. a) according to western blotting analysis, the expression of c-fos proteins was higher in rats with boo compared with normal rats. after intravesical instillation of 1% lidocaine, c-fos expression decreased significantly in rats with boo. b) blot intensities were analyzed via densitometric scanning, and relative densities were expressed as ratios relative to control values. data are expressed as the means ± standard deviations. 1% lidocaine effects on overactive bladder-kang et al. vol 17 no 03 may-june 2020 309 pacity(10). however, intravesical instillation of lidocaine has not been established as a clinical treatment option for oab. therefore, we investigated lidocaine as a candidate for oab treatment. in addition, lidocaine has been used as an anesthetic agent; because of its mechanism of action and stability, it may have advantages as a candidate therapeutic agent for clinical application. however, the concentration of lidocaine currently used in clinical applications is intended to induce anesthesia; thus, it simultaneously blocks both aδ-fibers and c-fibers. to evaluate the feasibility of treating oab with lidocaine, an adequate concentration is needed to block c-fibers without affecting aδ-fibers. we investigated changes in bladder sensation during cystometry after intravesical instillation of 0.5%, 1%, and 2% lidocaine. after the instillation of 2% lidocaine, the ici, bp, and tp increased significantly, whereas mp decreased. thus, intravesical instillation of 2% lidocaine may cause serious disturbances in the contraction of bladder smooth muscle; it may block both sensory and motor neurons and is therefore an excessive dose. we propose that instillation of 2% lidocaine should be limited to use as an anesthetic, rather than as a therapeutic agent for treatment of oab. following instillation of 1% lidocaine, the results of cystometric analysis revealed that the ici increased significantly, whereas other parameters did not differ significantly. this suggests that instillation of 1% lidocaine reduces the sensation of bladder filling by blocking sensory neurons. previous studies have indicated that desensitization of c-fibers does not affect cystometric parameters or bladder capacity in normal individuals(25,26), but we found that cystometric parameters changed after intravesical instillation of lidocaine in our experiment. we presume that our findings were related to the ability of lidocaine to effectively block both myelinated aδ-fibers and unmyelinated c-fibers because it is a non-selective sodium-channel blocker. hence, our results suggest that 1% lidocaine blocks the action potentials of sensory neurons and is therefore a suitable concentration for therapeutic treatment of oab. to demonstrate the therapeutic effect of intravesical instillation of 1% lidocaine on oab, cystometry was performed at 4 weeks after boo induction of oab in a rat model. the results of cystometric analysis showed that icis were significantly longer in rats with boo treated with lidocaine than in non-treated rats with boo, whereas bp, tp, and mp did not differ significantly different between groups. cystometric monitoring showed that the voiding pattern after instillation of 1% lidocaine was very similar to that of normal voiding contractions. persistent do and non-voiding overactivity, which were present in the boo-induced oab group, disappeared after instillation of 1% lidocaine. edlund et al. reported that the voiding pattern instability in oab patients was markedly reduced after intravesical instillation of lidocaine(28). therefore, our current results suggest that intravesical instillation of 1% lidocaine is an attractive treatment for oab based on its ability to block voltage-gated sodium channels in c-fibers. for clinical trials, the establishment of a suitable lidocaine concentration lower than that needed for anesthesia is necessary. to confirm whether instillation of 1% lidocaine blocks the activation of c-fibers, we investigated the expression of c-fos protein, a known c-fiber marker, before and after instillation of 1% lidocaine. western blotting analysis showed that the expression of c-fos protein increased in rats with boo, compared with normal rats; c-fos expression decreased significantly after instillation of 1% lidocaine in rats with boo. our results suggested that the activation of unmyelinated c-fibers might be associated with do in the boo model, and that instillation of 1% lidocaine might improve do by blocking voltage-gated sodium channels in unmyelinated c-fibers. the instillation of 1% lidocaine may be an effective treatment option for use in clinical settings. moreover, the effects of intravesical instillation of lidocaine are limited to the bladder, thereby avoiding the development of side effects associated with current medications used for treatment of oab. instillation of lidocaine is relatively inexpensive, which may reduce medical costs for patients with oab. notably, patients can perform self-instillation of lidocaine by using clean intermittent catheterization. importantly, our study had some limitations. we did not evaluate the duration of the effects of instillation of 1% lidocaine. the frequency of instillation needed for a therapeutic effect is important for patients with oab. in future studies, it will be necessary to evaluate the tolerance and adverse effects of repeated instillation of lidocaine. conclusions lidocaine is widely used in clinical fields as an anesthetic but has not been regarded as a therapeutic agent. in the current study, we investigated lidocaine instillation at various concentrations for oab treatment and demonstrated its effectiveness. we found that instillation of 1% lidocaine has minimal effects on normal urination and alleviates symptoms of oab via blocking voltage-gated sodium channels in unmyelinated c-fibers. although further evaluation is needed to support its use in clinical applications, instillation of 1% lidocaine may constitute a new strategy for oab treatment. acknowledgments this study was supported by a grant of the korean health technology r&d project, ministry of health and welfare, republic of korea (hi10c2020). conflicts of interest there are no conflicts of interest to declare. references 1. chuang fc, hsiao sm, kuo hc. the overactive bladder symptom score, international prostate symptom scorestorage subscore, and urgency severity score in patients with overactive bladder and hypersensitive bladder: which scoring system is best? int neurourol j. 2018;22:99-106. 2. emami m, shadpour p, kashi ah, choopani m, zeighami m. abobotulinumιa toxin injection in patients with refractory idiopathic detrusor overactivity: injections in detrusor, trigone and bladder neck or prostatic urethra, versus detrusor-only injections. int braz j urol. 2017;43:1122-1128. 3. song m, heo j, chun jy, et al. the paracrine miscellaneous 310 1% lidocaine effects on overactive bladder-kang et al. effects of mesenchymal stem cells stimulate the regeneration capacity of endogenous stem cells in the repair of a bladder-outletobstruction-induced overactive bladder. stem cells dev. 2014;23:654-663. 4. jun jh, kang hj, jin mh, et al. function of the cold receptor (trpm8) associated with voiding dysfunction in bladder outlet obstruction in rats. int neurourol j. 2012;16:69-76. 5. leron e, weintraub ay, mastrolia sa, schwarzman p. overactive bladder syndrome: evaluation and management. curr urol. 2018;11:117-125. 6. rahnama'i ms, van koeveringe ga, van kerrebroeck pe. overactive bladder syndrome and the potential role of prostaglandins and phosphodiesterases: an introduction. nephrourol mon. 2013;5:934-945. 7. lee wc, chiang ph, tain yl, wu cc, chuang yc. sensory dysfunction of bladder mucosa and bladder oversensitivity in a rat model of metabolic syndrome. plos one. 2012;7:e45578. 8. juszczak k, ziomber a, wyczolkowski m, thor pj. urodynamic effects of the bladder c-fiber afferent activity modulation in chronic model of overactive bladder in rats. j physiol pharmacol. 2009;60:85-91. 9. craig ad. how do you feel? interoception: the sense of the physiological condition of the body. nat rev neurosci. 2002;3:655-666. 10. steers wd. pathophysiology of overactive bladder and urge urinary incontinence. rev urol. 2002;4 suppl 4:s7-s18. 11. daykin h. the efficacy and safety of intravenous lidocaine for analgesia in the older adult: a literature review. br j pain. 2017;11:23-31. 12. ragsdale ds, mcphee jc, scheuer t, catterall wa. common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated na+ channels. proc natl acad sci u s a. 1996;93:9270-9275. 13. henry ra, morales a, cahill cm. beyond a simple anesthetic effect: lidocaine in the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. urology. 2015;85:1025-1033. 14. yokoyama o, komatsu k, kodama k, yotsuyanagi s, niikura s, namiki m. diagnostic value of intravesical lidocaine for overactive bladder. j urol. 2000;164:340-343. 15. guerios sd, wang zy, boldon k, bushman w, bjorling de. lidocaine prevents referred hyperalgesia associated with cystitis. neurourol urodyn. 2009;28:455-460. 16. cummins tr. setting up for the block: the mechanism underlying lidocaine's usedependent inhibition of sodium channels. j physiol. 2007;582:11. 17. colaco ma, evans rj. current 1% lidocaine effects on overactive bladder-kang et al. recommendations for bladder instillation therapy in the treatment of interstitial cystitis/ bladder pain syndrome. curr urol rep. 2013;14:442-447. 18. klein ja, jeske dr. estimated maximal safe dosages of tumescent lidocaine. anesth analg. 2016;122:1350-1359. 19. aoki y, brown hw, brubaker l, cornu jn, daly jo, cartwright r. urinary incontinence in women. nat rev dis primers. 2017;3:17097. 20. son yj, kwon be. overactive bladder is a distress symptom in heart failure. int neurourol j. 2018;22:77-82. 21. okui n. efficacy and safety of non-ablative vaginal erbium:yag laser treatment as a novel surgical treatment for overactive bladder syndrome: comparison with anticholinergics and beta3-adrenoceptor agonists. world j urol. 2019; doi:10.1007/s00345-019-026447. 22. campanati a, gregoriou s, kontochristopoulos g, offidani a. oxybutynin for the treatment of primary hyperhidrosis: current state of the art. skin appendage disord. 2015;1:6-13. 23. lee sr, hong ch, choi yd, kim jh. increased urinary nerve growth factor as a predictor of persistent detrusor overactivity after bladder outlet obstruction relief in a rat model. j urol. 2010;183:2440-2444. 24. offiah i, dilloughery e, mcmahon sb, o'reilly ba. prospective comparative study of the effects of lidocaine on urodynamic and sensory parameters in bladder pain syndrome. int urogynecol j. 2019;30:1293-1301. 25. silva c, ribeiro mj, cruz f. the effect of intravesical resiniferatoxin in patients with idiopathic detrusor instability suggests that involuntary detrusor contractions are triggered by c-fiber input. j urol. 2002;168:575-579. 26. lazzeri m, beneforti p, turini d. urodynamic effects of intravesical resiniferatoxin in humans: preliminary results in stable and unstable detrusor. j urol. 1997;158:20932096. 27. edlund c, peeker r, fall m. lidocaine cystometry in the diagnosis of bladder overactivity. neurourol urodyn. 2001;20:147155. vol 17 no 03 may-june 2020 311 transurethral resection of a large urinary bladder leiomyoma: a rare case report introduction bladder's benign mesenchymal tumors are quite rare, and constitute 1-5% of all bladder tumors.(1,2) benign tum-ors that form in the bladder are myoma, leiomyoma, rhabdomyoma, fibroma, angioma, osteoma and myxoma. (3) bladder leiomyoma is the most frequently observed benign mesenchymal tumor of the bladder, constituting 35% within this group. therefore, bladder leiomyoma constitutes less than 0.5% of all bladder tumors.(4,5) until now, there have been about 250 case reports of bladder leiomyoma. based on its localization, bladder leiomyoma can be endovesical (63%), extravesical (30%), or intramural (7%). (6,7) complaints from patients with bladder leiomyoma may consist of obstructive symptoms, irritative symptoms, and gross hematuria. sometimes, however, patients may be asymptomatic.(7) since the endovesical form is more symptomatic compared to forms at other localizations, it is usually diagnosed at an earlier stage.(5) since the disease is rarely encountered, we wished to present the findings of a case with bladder leiomyoma diagnosed at the urology department of adıyaman university. university of health sciences, dişkapi yildirım beyazit training and research hospital, department of urology, ankara, turkey. *correspondence: university of health sciences, dişkapı yildirim beyazit training and research hospital, department of urology, ankara, turkey. tel: +90 532 603 11 81. fax: +90 312 318 66 90. e-mail: alper_gok@hotmail.com. received october 2016 & accepted may 2017 alper gök bladder leiomyoma constitutes less than 0.5% of all bladder tumors. until now, there have been about 250 case reports of bladder leiomyoma. we present a case of large bladder leiomyoma, that was treated successfully with transurethral resection. the patient presented to our clinic with both obstructive and irritative urinary complaints. cystoscopy showed a mass lesion completely obstructing the bladder neck at the junction of right lateral wall and floor, which did not extend to ureteral orifices. a transurethral resection was performed at the same session of cystoscopy. at the postoperative 3rd month control visit, the patient's obstructive symptoms were completely healed but her irritative symptoms continued. a repeat cystoscopy revealed residual tumoral tissue remaining at the floor of the previous surgical area. transurethral resection was performed, and these tissues were completely resected. at the control visit that was 3 months after the second transurethral resection procedure, the patient was free from any urinary complaints. in conclusion, large bladder leiomyomas can be treated successfully with endoscopic approaches. case report keywords: benign neoplasms; bladder; diagnosis; leiomyoma; transurethral resection figure 1. cystoscopy image of the tumor from bladder neck. vol 14 no 04 july-august 2017 4052 case report a forty-six year old female patient presented to our clinic with both obstructive and irritative urinary complaints. her laboratory workup and abdominal physical examination was normal, bimanual vaginal examination indicated a solid mass near the bladder neck. she did not have any comorbidity. transvaginal ultrasonographic examination revealed a 9x6 cm tumoral lesion localized to the junction of right lateral wall and floor of the bladder. renal ultrasonography showed that the kidneys were bilaterally normal. cystoscopy showed a mass lesion completely obstructing the bladder neck at the junction of right lateral wall and floor, which did not extend to ureteral orifices (figure 1). the epithelial lining of the bladder covering the mass lesion appeared normal. upon the patient's consent, bipolar energy was used for transurethral resection of bladder tumor (turbt) at the same session with cystoscopy. there was no significant bleeding during the turbt so the lesion was completely resected as far as can be seen. on the postoperative 2nd day, the urethral catheter was removed and the patient was discharged without any problems. in histopathological examination of the specimen that was obtained with turbt, staining for alpha-smooth muscle antigen (sma) and desmin were positive (figures 2 and 3). there was no staining for panck at the tumoral area, but the surface epithelium stained positive. in addition, hematoxylin-eosin section showed a normal transitional epithelium, while the muscle fibers were in continuity with lamina propria under epithelial invaginations. these findings were consistent with leiomyoma. at the postoperative 3rd month control visit, the patient's obstructive symptoms were completely healed but her irritative symptoms continued. a repeat cystoscopy revealed residual tumoral tissue remaining at the floor of the previous surgical area. turbt was performed, and these tissues were completely resected. at the control visit that was 3 months after the second turbt procedure, the patient was free from any urinary complaints. discussion benign mesenchymal tumors constitute a very small group within all bladder tumors. leiomyoma is the most frequently encountered type among benign mesenchymal tumors of bladder. the size of a leiomyoma can range from a few millimeters to 30 cm.(8,9) goluboff et al.(7) reviewed 37 reported cases of leiomyoma and found that these patients most commonly presented with obstructive urinary symptoms (49%), irritative symptoms (38%), hematuria (11%), or flank pain (13%); while 19 percent were asymptomatic. in that series, most patients were treated with open resection (62%), whereas 30 percent were treated with transurethral resection.(7) among those 37 patients, 76% were female and their age ranged between third and sixth decades. on the other hand, there are studies reporting equal distribution of gender among cases with bladder leiomyoma.(10,11) the exact cause of bladder leiomyoma is unclear. there are 4 factors held responsible in its etiology including hormonal disturbances, dysontogenesis, perivascular inflammation, and infection at the bladder's muscle layer.(4,12) imaging techniques that can be used for diagnosing bladder leiomyoma include transabdominal ultrasonography, transvaginal ultrasonography, computed tomography, and magnetic resonance imaging. some authors claim ultrasonography is a superior technique compared to other methods for imaging bladder leiomyoma, because it is better at revealing tumor's localization and its relation with neighboring organs.(13,14) treatment of bladder leiomyoma is surgical resection. while turbt is generally preferred for small-sized tumors with endovesical localization, partial cystectomy and segmental resection are preferred for larger tumors. asymptomatic patients can be followed without surgery since there is no evidence that bladder leiomyoma can undergo malignant transformation.(8,9,15) here, we presented a case with large bladder leiomyoma, a rarely encountered disease that was treated successfully with turbt. based on the experience of this case, we think, endoscopic resection of bladder leiomyoma cause less bleeding than the endoscopic resection of other bladder tumor forms, and so the turbt can be a good option for surgical resection of the bladder leiomyoma even in large tumors with endovesical localization. conflict of interest the author report no conflict of interest. tur of large urinary bladder leiomyoma-gok a. case report 4053 figure 2. muscle fibers appearing positively stained for x100 sma figure 3. positive staining for x200 desmin references 1. campbell ew, gislason gj. benign mesothelial tumors of the urinary bladder: review of literature and a report of a ease of leiomyoma. j. urol. 1953;70:733–742. 2. melicow mm. tumors of the urinary bladder. j. urol. 1937;37:117. 3. goktug hg, ozturk u, sener nc, tuygun c, bakirtas h, imamoglu am. transurethral resection of a bladder leiomyoma: a case report. can urol assoc j 2014; 8: 111-113 4. nazih k, ghazi s. bladder leiomyoma: presentation, evaluation and treatment. arab journal of urology 2013; 11:54-61 5. cornella jl, larson tr, lee ra, magrina jf, kammerer-doak d. leiomyoma of the female urethra and bladder: report of twenty-three patients and review of the literature. am. j. obstet. gynecol. 1997;176:1278–1285. 6. knoll ld, segura jw, scheilhauer bw. leiomyoma of the bladder. j. urol. 1986;136:906–913. 7. goluboff et, o’toole k, sawczuk is. leiomyoma of bladder: report of case and review of literature. urology. 1994;43:238– 241. 8. kim iy, sadeghi f, slawin km. dyspareunia: an unusual presentation of leiomyoma of the bladder. rev urol. 2001;3:152–4. 9. broessner c, klingler ch, bayer g, pycha a, kuber w. a 3,500-gram leiomyoma of the bladder: case report on a 3-year follow-up after surgical enucleation. urol int. 1998;61:175–7. 10. mutchler rw, gorder jl. leiomyoma of the bladder in a child. br. j. radiol. 1972;45:538– 540. 11. katz rb, waldbaum rs. benign mesothelial tumors of the bladder. urology. 1975;5:236– 238. 12. teran az, gambrell rd. leiomyoma of the bladder. int. j. fertil. 1989;34:289–292. 13. fernandez a, dehesa tm. leiomyoma of the urinary bladder floor: diagnosis by transvaginal ultrasound. urol. int. 1992;48:99. 14. illescas ff, baker me, weinerth jl. bladder leiomyoma. advantages of sonography over computed tomography. urol. radiol. 1986;8:216–218. 15. bai sw, jung hj, jeon mj, jung da j, kim sk, kim jw. leiomyomas of the female urethra and bladder: a report of five cases and review of the literature. int urogynecol j pelvic floor dysfunct. 2007;18:913–7 tur of large urinary bladder leiomyoma-gok a. vol 14 no 04 july-august 2017 4054 endourology and stone disease the association of encrustation and ureteral stent indwelling time in urolithiasis and kub grading system ibrahim guven kartal1*, burhan baylan1, alper gok1, azmi levent sagnak1, nihat karakoyunlu1, mehmet caglar cakici1, serafettin kaymak1, osman raif karabacak1, hikmet topaloglu1, hamit ersoy1. purpose: to evaluate the management of prolonged indwelling ureteral stents and the newly developed kub (kidney, ureter, and bladder) grading system for the classification of encrusted stents in urolithiasis. method: this study involved 69 patients that had indwelling and forgotten ureteral stents for more than 6 months after urolithiasis treatment. they were categorized into 4 groups based on indwelling time and were reviewed retrospectively. patients whose ureteral stent could not be removed with simple cystoscopy were graded according to stone surface area and the kub system. results: the mean stent indwelling time was 23.1 months. stone burden in kub and, in proportion to that, total kub (t) score showed increased association that was directly proportional to indwelling time (p < 0.001, p = 0.008). surgical intervention was required in 73.9% of patients. among patients requiring surgery, 78.4% were treated in a single session and multi-modal interventions were performed in 70.5%. k score ≥ 3 was found to be associated with multiple surgery requirements (odds ratio [or];11.25, %95 confidence interval [ci]:2.132-59.375), multi-modal procedure requirements (or;16.50, %95 ci:3.434-79.826 ), and lower stone-free rates (p = 0.04). b score ≥ 3 was associated with multi-modal procedure requirements (or;8.90, %95 ci:1.052-75.462). u score ≥ 3 and t score ≥ 9 were associated with an operating time >180 minutes (p < 0.001, p = 0.008). conclusion: prolonged indwelling time of the ureteral stent in urolithiasis is associated with increased encrustation and stone burden. since the kub system specifies stone burden and its particular localization, it can be used as a simple, convenient method for the planning treatment of encrusted ureteral stents. keywords: bladder; kidney; stent; ureter; urolithiasis introduction after entering the armamentarium of urologists, the ureteral stent has provided very valuable contributions and has become an irreplaceable tool. the risk factors for encrustation vary from patient to patient, and include prolonged indwelling time, urinary tract infection, previous history of stone disease, lack of health insurance, pregnancy, chemotherapy, chronic kidney disease, and metabolic or congenital anomalies(1,2). various strategies exist for the timely removal of a ureteral stent; however, it is not always possible to remove a stent on time or to prevent encrustation(3). prolonged stent indwelling time can lead to the development of a broad range of complications from hematuria, obstructive symptoms due to occlusion, migration, encrustation to serious complications like renal failure, uretero-iliac artery fistula, and even death(4). considering the affected renal functions, it is obvious that treatment of encrusted stents is a requirement. ureteral stent encrustation and stone formation start with bacterial adhesion, colonization, and biofilm formation. the biofilm layer protects the bacteria from the immune system and antibiotics(5). encrustation can occur in both sterile and infected urine depending on urinary ph, bacterial enzymes, and stent biomaterials(6). department of urology, university of health sciences, diskapi yildirim beyazit training and research hospital, ankara, 06110, turkey. *correspondence: university of health sciences, diskapi yildirım beyazit training and research hospital, department of urology, ankara, 06110, turkey. phone: +905556298424. email: igk84@hotmail.com. received may 2018 & accepted july 2018 el-faqih et al. reported that the increase in encrustation was directly proportional to stent indwelling time, which was present in 76.3% after 12th week(7). consistent with this, kawahara et al. also found similar results, which was present in 75.9% of the patients after 3rd month(2). several grading systems have been described to predict the difficulty of treatment due to the difficulty of the surgery level of encrusted stents(8,9). arenas et al. designed a better kub grading system in order to predict surgical difficulty and to aid in management of patient expectations(10). they reported that this system was reliable and convenient for predicting surgical session requirement, modality requirement, operation time and stone-free rates. in our study, we employed the kub grading system that included a classification system by sing et al. this system is based on the volume and a localization component for each patient. the present study was designed to evaluate management of prolonged stent applications and as per our knowledge it is the first study regarding the clinical use of kub grading system in urolithiasis. materials and methods we retrospectively reviewed patients that presented to our tertiary care urolithiasis treatment center from janendourology and stone diseases 323 vol 15 no 06 november-december 2018 324 uary 2007 to july 2017 with indwelling and forgotten ureteral stents for longer than 6 months following urolithiasis treatment. although, etiologically, there are cases where stents were placed for other reasons and encrustation took place, due to its distinctive pathophysiology, only patients that had prolonged ureteral stents following urolithiasis treatment were included in the study. for each patient, kidney-ureter-bladder (kub) radiography, blood biochemistry, and urinary culture were performed. patients with positive urinary culture results were treated via hospitalization if necessary, and the procedures were performed afterwards. at the end of the first month after treatment, creatinine levels were measured, both kub and ultrasound were performed in each patient, and additional investigations were made as necessary. in cases with prolonged ureteral stent, the presence of encrustation was assessed with kub ± non-contrast computed tomography (ncct). ncct was performed as an ancillary imaging when ureteral stent could not be removed using simple cystoscopy and if encrustation was suspected. encrustations were categorized according to localization as kidney, ureter, and bladder areas. stone surface areas were calculated with kub using the formula: length x width. after calculattable 1. kub grading criteria k-kidney 1-absence of calcification at the coil at the renal end 2-presence of calcification with width ≤5 mm, apparent at the coil at the renal end, but not filling the coil 3-presence of calcification with width >5mm, apparent at the coil at the renal end, but not filling the coil 4-presence of calcification filling the coil at the renal end, and its extent from the coil ≤5 mm 5-presence of calcification filling the coil at the renal end, and its extent from the coil >5mm (including staghorn stones) u-ureter 1-absence of calcification along the ureter 2-presence of calcification at only one area along the ureter, and its width ≤5 mm 3presence of calcification at only one area along the ureter, and its width >5 mm 4-presence of multiple calcifications occupying less than 50% of the total length of ureter, and their widths >5 mm 5-presence of multiple calcifications occupying more than 50% of the total length of ureter, and their widths >5 mm b-bladder 1-absence of calcification at the coil at the vesical end 2-presence of calcification with width ≤5 mm, apparent at the coil at the vesical end, but not filling the coil 3presence of calcification with width >5 mm, apparent at the coil at the vesical end, but not filling the coil 4presence of calcification filling the coil at the vesical end, and its extent from the coil is ≤5 mm 5presence of calcification filling the coil at the vesical end, and its extent from the coil is >5 mm figure 1. a 30-year old female patient presenting with a urinary tract infection had a ureteral stent present for 33 months. the kub score was 13 (k=5, u=3, b=5) and the stone surface area was calculated as 360 mm² in the kidney, 90 mm² in the ureter, 624 mm² in the bladder. the patient underwent transurethral cystolithotripsy, semi-rigid urs, and flexible urs in a multi-modal fashion in a single session, and stent-free and stone-free status was achieved. figure 2. management of forgotten ureteral stents in urolithiasis encrusted ureteral stent’s new grading system-kartal et al. ing encrustation areas with kub, they were graded; < 100 mm², 100-400 mm² and > 400 mm². the grading of encrustation was made according to the kub grading system developed by arenas j.l. et al(10). appropriate treatment modality was decided after evaluating radiological examinations and patient’s clinical condition. all calculations and surgical procedures were done by the three endourologists at our clinic. non-encrusted stents were removed in the outpatient setting, under local anesthesia, and in a non-traumatic way using a forceps with the help of simple cystoscopy. patients requiring surgery were examined separately. for each patient, the number of surgical sessions required evaluation of multi-modal procedures performed in a session, operating time, postoperative complications, and stonefree rates. multi-modal surgery was defined as 2 or more modalities combined in a surgical session. if more than one surgical session was performed, the operating time was calculated as the sum of operating times of each surgery. post-operative complications were categorized according to the modified clavien-dindo classification. additionally, the ability of the kub degree to predict the possible difficulties encountered in the treatment was evaluated. stones ≥4 mm were defined as residual stones. statistical analysis data analysis was carried out with ibm spss statistics 17.0 (ibm corporation, armonk, ny, usa) package software. normality assessment for distribution of continuous numerical variables was made with kolmogorov-smirnov test, and homogeneity of variance was assessed using the levene test. descriptive statistics was expressed as mean ± standard deviation or median (minimum-maximum) for numerical variables, and case number and (%) for categorical variables. the significance of the difference between the groups for continuous numerical variables was analyzed with one way analysis of variance (one-way anova) for parametric data, or kruskal wallis test for non-parametric data. if the kruskal wallis test result was statistically significant, the condition(s) causing the difference was detected using conover’s multiple comparison test. correlation of tscore with stone burden and ureteral stent indwelling time was analyzed with spearman’s rank numbers correlation test. categorical variables were analyzed with pearson’s chi-square, fisher’s exact probability, and continuity correction chi-square or probability ratio tests. the ability of the kub component scores and t score to predict prognosis was analyzed by calculating odds ratio and 95% ci. a p-value of less than 0.05 was accepted as statistically significant. results a retrospective review covering the time from january 2007 to october 2017 yielded 69 patients that had a prolonged ureteral indwelling stent placed for treatment of urolithiasis. mean age of the patients was 48 ± 16 years. mean indwelling stent time was 23.1 months (7102). indications for placing ureteral stent were swl in 4 cases (5.8%), semi-rigid ureteroscopy (urs) in 30 cases (43.5%), flexible urs in 33 cases (47.8%), and percutaneous nephrolithotomy (pnl) in 2 cases (2.9%). primary presenting complaints were pain in 37 cases (53.7%), infection in 20 cases (28.9%), hematuria in 6 cases (8.7%), and 6 cases (8.7%) were detected incidentally. eighteen patients (26.1%) were treated by removing the ureteral stent under simple cystoscopy guidance only with no need for additional procedures. the remaining 51 patients (73.9%) were accepted as encrusted, and additional procedures were made. surgical modalities included transurethral cystolithotripsy, percutaneous cystolithotripsy, semi-rigid urs, flexible urs, pnl, swl, and for one patient, open pyelolithotomy. the median operating time in patients with encrusted table 2. clinical properties of patients with encrusted ureteral stent 6-12 months (n=5) 13-24 months (n=20) 25-36 months (n=16) > 36 months (n=10) p-value total (n=51) age 55.0 ± 12.9 50.3 ± 17.4 47.4 ± 16.0 40.9 ± 16.3 0.374† 48.0 ± 16.5 gender 0.039‡ male 5 (100.0%)a 15 (75.0%) 9 (56.3%) 4 (40.0%)a 33 (64.7%) female 0 (0.0%)a 5 (25.0%) 7 (43.8%) 6 (60.0%)a 18 (35.3%) affected side 0.900‡ right 2 (40.0%) 10 (50.0%) 8 (50.0%) 6 (60.0%) 26 (51.0%) left 3 (60.0%) 10 (50.0%) 8 (50.0%) 4 (40.0%) 25 (49.0%) ct scan 5 (100.0%) 14 (70.0%) 16 (100.0%) 10 (100.0%) 45 (88.2%) stone burden in kub < 0.001‡ < 100 mm² 4 (80.0%)a,b 9 (45.0%) 2 (12.5%)b 0 (0.0%)a 15 (29.4%) 100-400 mm² 1 (20.0%) 11 (55.0%) 5 (31.3%) 3 (30.0%) 20 (39.2%) > 400 mm² 0 (0.0%)a,b 0 (0.0%)c,d 9 (56.3%)b,c 7 (70.0%)a,d 16 (31.4%) kub score k 3.2 ± 0.45 2.7 ± 1.62 3.5 ± 1.09 4.1 ± 1.28 0.086¶ 3.3 ± 1.39 u 1.6 ± 0.55 1.9 ± 1.07 2.2 ± 1.33 2.6 ± 1.07 0.247¶ 2.1 ± 1.14 b 1.4 ± 0.55 1.6 ± 1.09 2.8 ± 2.01 2.9 ± 1.85 0.160¶ 2.2 ± 1.64 t 6.2 ± 0.45a,b 6.2 ± 2.77c,d 8.5 ± 2.68b,c 9.6 ± 2.59a,d 0.008¶ 7.6 ± 2.87 hospital stay length 0 (0-2)a,b 0 (0-11)c,d 3 (0-8)b,c 5 (0-15)a,d < 0.001¶ 1 (0-15) number of 2 (1-3) 2 (1-3) 2 (1-3) 2 (1-4) 0.190¶ 2 (1-4) modalities number of surgeries 2 (1-2) 2 (1-2) 2 (1-3) 1 (1-3) 0.708¶ 2 (1-3) † one-way anova, ‡ likelihood ratio test, ¶ kruskal wallis test, a: statistically significant difference between 6-12 months group and >36 months group (p < 0.05), b: statistically significant difference between 6-12 months group and 25-36 months group (p < 0.05), c: statistically significant difference between 13-24 months group and 25-36 months group (p < 0.05), d: statistically significant difference between 13-24 months group and > 36 months group (p < 0.05), e: statistically significant difference between 25-36 months group and >36 months group (p = 0.009). encrusted ureteral stent’s new grading system-kartal et al. endourology and stone diseases 325 vol 15 no 06 november-december 2018 326 stent was 75 minutes, and operating times varied from 15 to 360 minutes. the single surgical session was adequate in 40 of 51 patients (78.4%) and multi-modal interventions were required in 36 of 51 patients (70.5%). the median number of surgeries required to achieve a stent-free state was 1 (minimum: 1 and maximum: 3). stone-free status was achieved in 40 patients (78.4%). twelve patients (17.3%) developed 13 complications following removal of the ureteral stent. these complications were urinary tract infection, postoperative fever, blood transfusion, sepsis, and drainage lasting more than 12 hours after pnl, urinary retention, urinoma, and sepsis. according to the modified clavien-dindo classification, 2 complications (15.4%) were grade 1; 5 (38.6%) were grade 2; 4 (30.8%) were grade 3a; 1 (7.6%) was grade 4a; and 1 (7.6%) was grade 4b. the median hospital stay length was 3 days (min: 1 – max: 15). two patients presenting with pain and fever were evaluated with ncct and were diagnosed with infective hydronephrosis. their treatment was initiated with percutaneous nephrostomy prior to definitive treatment. encrustation was graded according to the kub grading criteria (table 1 and figure 1). after the patients were distributed to groups based on their stent indwelling times as 6-12, 13-24, 25-36 and >36 months, they were compared in terms of their clinical properties as seen in table 2. the distribution of gender showed a statistically significant difference based on stent indwelling time (p = 0.039). this difference was caused by a higher frequency of female patients in the group with stent indwelling time greater than 36 months compared to the 6-12 months group (p = 0.044). distribution of stone burden in kub showed statistically significant difference according to stent indwelling time (p < 0.001). when comparing the groups stratified according to stent indwelling time, each of the mean k, u, or b component scores showed an increase in parallel with indwelling time. however, the differences were not statistically significant (p = 0.086, p = 0.247, and p = 0.160, respectively). conversely, there was a statistically significant difference in terms of t score that represents total stone burden (p = 0.008). there was statistically significant difference between stent indwelling time groups in regards to hospital stay length (p < 0.001). the patients were then evaluated regarding the effects of the kub score on the prognosis in the case of encrusted ureteral stents as shown in table 3. of the kub scores, only the k component was found to be significant in the prediction of multiple surgery sessions. k and b components were significant in predicting the multi-modal procedure requirement. for predicting an operating time of ≥ 180 minutes, the u component of the kub scores and t score were found to have significance. since there was no patient with a u score < 3 and operating time ≤180 minutes, the odds ratio and 95% ci was not applicable (shown as “na” in table 3). for predicting complete stone-free status/residual stones after treatment, only the k score was found to have any significance (p = 0.04), whereas u and b components or t scores did not have statistically significant predicting power (p > 0.05) discussion there is no consensus on how long a stent should be kept in place after treatment for urolithiasis. indwelling time for commonly used polymer-based stents should not exceed 3-6 months(11). because our study sample included patients whose stents could not be removed with only a simple cystoscopy after 7 months indwelltable 3. effect of kub score on prognosis in patients with an encrusted ureteral stent multiple surgery sessions requirement multimodal procedure requirement no (n=22) yes (n=29) p-value or (95% ci) no (n=15) yes (n=36) p-value or (95% ci) k 0.004† < 0.001‡ < 3 10 (45.5%) 2 (6.9%) 1.000 9 (60.0%) 3 (8.3%) 1.000 ≥ 3 12 (54.5%) 27 (93.1%) 11.250 (2.132-59.375) 6 (40.0%) 33 (91.7%) 16.500 (3.434-79.286) u > 0.999† 0.333‡ <3 15 (68.2%) 20 (69.0%) 1.000 12 (80.0%) 23 (63.9%) 1.000 ≥ 3 7 (31.8%) 9 (31.0%) 0.964 (0.292-3.180) 3 (20.0%) 13 (36.1%) 2.261 (0.538-9.508) b > 0.999† 0.040‡ < 3 16 (72.7%) 20 (69.0%) 1.000 14 (93.3%) 22 (61.1%) 1.000 ≥ 3 6 (27.3%) 9 (31.0%) 1.200 (0.353-4.083) 1 (6.7%) 14 (38.9%) 8.909 (1.052-75.462) t 0.859† 0.184† < 9 13 (59.1%) 19 (65.5%) 1.000 12 (80.0%) 20 (55.6%) 1.000 ≥ 9 9 (40.9%) 10 (34.5%) 0.760 (0.242-2.387) 3 (20.0%) 16 (44.4%) 3.200 (0.769-13.315) operating time ≥180 minutes complete stone-free status after treatment no (n=44) yes (n=7) p-value or (95% ci) yes (n=40) no (n=11) p-value or (95% ci) k 0.177‡ 0.040‡ < 3 12 (27.3%) 0 (0.0%) 1.000 12 (30.0%) 0 (0.0%) 1.000 ≥ 3 32 (72.7%) 7(100.0%) na 28 (70.0%) 11 (100.0%) na u <0.001‡ 0.288‡ < 3 35 (79.5%) 0 (0.0%) 1.000 29 (72.5%) 6 (54.5%) 1.000 ≥ 3 9 (20.5%) 7 (100.0%) na 11 (27.5%) 5 (45.5%) 2.197 (0.556-8.688) b 0.174‡ 0.264‡ < 3 33 (75.0%) 3 (42.9%) 1.000 30 (75.0%) 6 (54.5%) 1.000 ≥ 3 11 (25.0%) 4 (57.1%) 4.000 (0.772-20.727) 10 (25.0%) 5 (45.5%) 2.500 (0.625-9.996) t 0.008‡ 0.291‡ < 9 31 (70.5%) 1 (14.3%) 1.000 27 (67.5%) 5 (45.5%) 1.000 ≥ 9 13 (29.5%) 6 (85.7%) 14.308 (1.564-130.928) 13 (32.5%) 6 (54.5%) 2.492 (0.640-9.699) abbreviations: or, odds ratio; ci, confidence interval; na, not analyzed † continuity corrected chi-square test), ‡ fisher’s exact test) encrusted ureteral stent’s new grading system-kartal et al. ing time, we categorized patients in 4 groups starting from 6 months. encrusted stents present serious challenges for urologists since they have been known to cause complications that can even lead to death(12,13). in addition, their treatment is difficult and costly(14). researchers have described several classification methods for encrusted stents in order to provide guidance to urologists facing these challenges(8-10). as reported by many previous studies, increased stent indwelling time results in increased encrustation and stone burden, which makes treatment more difficult and complex(15-18). for evaluation of our patients with an encrusted stent, we classified our patients in various ways. the classification described by sing et al., which considers the total stone burden, has categories including < 100 mm², 100-400 mm², and > 400 mm². these do not specify localization of encrustation, and it overlooks an important component of treatment planning(9). in their study, weedin et al. used the fecal (forgotten, encrusted, calcified) grading system described by acosta-miranda to determine both the size and the localization of the stone. they reported that treatment became more difficult when encrustation was localized at the proximal. furthermore, they showed that localization of the stone was important when planning the treatment(19). disadvantages to the fecal grading system is that it was described in a very small sample during its development, which does not account for some possible scenarios of stent encrustation(10). there is a need for a grading system that will take every possible scenario into account. it must describe stone localization, stone burden, and encrustation in proximal and distal coil in a simple manner. furthermore, the consideration of the fact that the stone burden, especially localized at the proximal makes treatment difficult. based on these criteria, arenas et al. defined the kub grading system. it was advocated that by specifying the localization, burden, and grade of encrustation in the kub radiography and kub grading can predict possible challenges in treatment(10). previous studies have shown that encrustation is most frequent at the proximal coil(2,19). weedin et al. reported that proximal stone burden was particularly of significance in stent removal because of the requirement for multiple surgeries. in their series, they found that patients with stone burden > 400 mm² were 18 times more likely to require multiple surgeries(19). arenas et al. also reported that patients with a k score showing proximal stone burden as ≥ 3 had 3.59 times higher probability of multiple surgery requirement(10). in our study, we found that only the k component of kub scores was significant in predicting multiple surgery requirements, and that multiple surgery session risk was 11.25 times higher in those with a k score ≥ 3. for predicting the multi-modal procedure requirement, which is another factor related to the difficulty and costliness of treatment, we found that the k score and b score had significance, which is contradictory to what arenas et al. reported. unlike the studies by weedin et al. and arenas et al., patients with higher b scores had a higher probability of multimodal surgery requirement. however, the b score was not found to influence the number of surgical sessions, operating time >180 minutes, stone-free status, or morbid procedure requirement in proximal stones such as complicated ureteroscopy and pnl. therefore, our results are consistent with the literature. thus, it can be deduced that the b score does not have a significant effect on the difficulty of surgery. however as the b score increases, the more modalities will be required. this will have negative effect on the cost. in the kub system, the k score specifies the proximal stone burden and patients with a k score ≥ 3 have less stone-free rates. this was statistically significant and consistent with the study by arenas et al(10). for predicting an operating time of 180 minutes or longer, the u component of the kub scores and t score were found to have a significance. in the light of all these findings, it can be said that the k score is associated with multiple surgeries, multi-modal surgery requirement, and lower stone-free rate. the u score is associated with longer operating time and the b score is associated with more treatment modalities. higher t score has been associated with longer stent indwelling time and longer operating time. therefore, it can be used in planning. as t score has a statistical significance with regard to surgical difficulty, the u and b scores should not be ignored. one of the limitations of the study is its retrospective design. current guidelines do not give any recommendations about the management and treatment of encrusted stents. the lack of systematic treatment approach constitutes an impediment in previous and future studies related with encrusted stent. presently, there is no systematic approach to the treatment principle as shown in figure 2. in addition, several studies recommended that treatment planning for encrusted ureteral stents should be made from the distal to the proximal direction(20,21). therefore, we generally adopted this principle in our selection of treatment other than swl. no ideal stent exists at the market for the moment. when we consider that the material and thickness of the stent can influence encrustation, another limitation of the study is that the stent types were not identified. additionally, some of the patients were referred from different centers, and the treatment was administered by surgeons that had different endourological experiences. in our study, stent encrustation occurred after treatment for urolithiasis, and this helped to increase homogeneity to some extent. conclusions prolonged indwelling time of ureteral stents leads to increased encrustation and makes the treatment more difficult. good planning and multi-modal endoscopic approaches when necessary can help to achieve high treatment success. the kub system can be used as an ancillary tool for the management of encrusted ureteral stents and in the prediction of surgical 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ar, see malekzadeh shafaroudi a, 99 basiri a, karami h, mehrabi s, javaherforooshzadeh a. laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal author index to volume 5 ureteral tumor, 120 basiri a, radfar mh. conservative management of early bladder rupture after postoperative radiotherapy for prostate cancer, 269 basiri a, zare s, shakhssalim n, hosseini moghaddam sm. ureteral calculi in children: what is best as a minimally invasive modality?, 67 basiri a, see simforoosh n, 50 bazmamoun h, ghorbanpour m, mousavibahar sh. lubrication of circumcision site for prevention of meatal stenosis in children younger than 2 years old, 233 behjati s, see simforoosh n, 50 behnam rassouli f, see hadjzadeh mr, 149 birjandi m, see heidary m, 255 brison d, see ilbeigi p, 192 brook a, see feizzadeh b, 161 c carney sl, see khoshdel ar, 3 d dadkhah f, see aliasgari m, 168 darabi mahboub mr, shakibi mh. percutaneous nephrolithotomy in patients with solitary kidney, 24 delfan b, see heidary m, 255 desai mr, see dhawan dr, 126 dhawan dr, ganpule a, muthu v, desai mr. laparoscopic management of calcified paraganglioma of bladder, 126 djalali m, see jamshidian h, 243 doosti h, see feizzadeh b, 161 durazi mh, jalal aa. penile prosthesis implantation for treatment of postpriapism erectile dysfunction, 115 e ebadzadeh mr, tavakkoli m. lymphocele after kidney transplantation: where are we standing now?, 144 ehsanpour a, see shahbazian h, 178 author index to volume 5 302 urology journal vol 5 no 4 autumn 2008 einollahi b, jalalzadeh m, taheri s, nafar m, simforoosh n. outcome of kidney transplantation in type 1 and type 2 diabetic patients and recipients with posttransplant diabetes mellitus, 248 esfahani f, see kazemeyni sm, 173 esmailie e, see seyedzadeh a, 200 etemadian m, haghighi r, madineay a, tizeno a, fereshtehnejad sm. delayed versus same-day percutaneous nephrolithotomy in patients with aspirated cloudy urine, 28 evert m, see janitzky a, 272 f falahatkar s, see roshani a, 37 farshchi b, see seyedzadeh a, 200 feizzadeh b, tavakkol afshari j, rakhshandeh h, rahimi a, brook a, doosti h. cytotoxic effect of saffron stigma aqueous extract on human transitional cell carcinoma and mouse fibroblast, 161 fereshtehnejad sm, see etemadian m, 28 g gangane n, anshu, shende n, sharma sm. mucinous cystadenoma arising from renal pelvis: a report of 2 cases, 197 ganpule a, see dhawan dr, 126 gattenloehner s, see heinrich e, 57 germiyanoğlu c, see akgül t, 41 ghadian a, see aliasgari m, 168 ghadiany m, attarian h, hajifathali a, khosravi a, molanaee s. relapse of acute myeloid leukemia as isolated bilateral testicular granulocytic sarcoma in an adult, 132 ghanbarzadeh n, see nadjafi-semnani m, 74 ghanghoria a, see wadhera s, 275 ghohestani sm, see zare s, 232 ghorbanpour m, see bazmamoun h, 233 girish g, see wadhera s, 84 givrad s, see heidary m, 255 golshan ar, see hosseini j, 265 gopalakrishnan g, see rajaian s, 280 grube c, see janitzky a, 272 gupta r, modi p, rizvi j. vanishing shaft of a double-j stent, 277 h hadjzadeh mr, mohammadian n, rahmani z, behnam rassouli f. effect of thymoquinone on ethylene glycol-induced kidney calculi in rats, 149 haghighi r, see etemadian m, 28 hajiani e, see shahbazian h, 178 hajifathali a, see ghadiany m, 132 heidary m, reza nejadi j, delfan b, birjandi m, kaviani h, givrad s. effect of saffron on semen parameters of infertile men, 255 heinrich e, gattenloehner s, mueller-hermelink hk, michel ms, schoen g. paraganglioma of urinary bladder, 57 hikosaka a, iwase y. spermatocele presenting as acute scrotum, 206 hosseini j, kaviani a, golshan ar. clean intermittent catheterization with triamcinolone ointment following internal urethrotomy, 265 hosseini j, tavakkoli tabassi k. surgical repair of posterior urethral defects: review of literature and presentation of experiences, 215 hosseini j, kaviani a, vazirnia ar. internal urethrotomy combined with antegrade flexible cystoscopy for management of obliterative urethral stricture, 184 hosseini moghaddam smm, see basiri a, 67 hosseini moghaddam smm, see aliasgari m, 168 i ilbeigi p, brison d, sadeghi-nejad h. synchronous bilateral laparoscopic radical nephrectomy for solid renal masses using a hybrid approach, 192 inamoto t, azuma h, katsuoka y. re: laparoscopic distal ureterectomy and boari flap ureteroneocystostomy for a low-grade distal ureteral tumor, 210 inamoto t, azuma h, katsuoka y. re: overexpression of bmi1, a polycomb group repressor protein, in bladder tumors: a preliminary report, 209 iwase y, see hikosaka a, 206 j jalal aa, see durazi mh, 115 jalalzadeh m, see einollahi b, 248 jamshaid a, see ather mh, 94 author index to volume 5 303urology journal vol 5 no 4 autumn 2008 jamshidian h, kor k, djalali m. urine concentration of nuclear matrix protein 22 for diagnosis of transitional cell carcinoma of bladder, 243 janitzky a, reiher f, porsch m, grube c, evert m, liehr ub. an unusual case of birt-hogg-dube syndrome with renal involvement, 272 javaherforooshzadeh a, see basiri a, 120 k kaffash nayyeri r, see zargar-shoshtari ma, 123 karakan t, see akgül t, 41 karami h, see basiri a, 120 karimianpour n, mousavi-shafaei p, ziaee aa, akbari mt, pourmand g, abedi a, ahmadi a, afshin alavi h. mutations of ras gene family in specimens of bladder cancer, 237 katsuoka y, see inamoto t, 192 katsuoka y, see inamoto t, 209 kaviani a, see hosseini sj, 184 kaviani a, see hosseini j, 265 kaviani h, see heidary m, 255 kazemeyni sm, esfahani f. influence of hypernatremia and polyuria of brain-dead donors before organ procurement on kidney allograft function, 173 kazemeyni sm, see razi a, 111 ketabchi aa, aziziolahi ga. prevalence of symptomatic urinary calculi in kerman, iran, 156 khoshdel ar, carney sl. arterial stiffness in kidney transplant recipients: an overview of methodology and applications, 3 khosravi a, see ghadiany m, 132 khosropanah i, see roshani a, 37 kiani sa, see roshani a, 37 kidwai a, see naru t, 106 kompani f, see seyedzadeh a, 200 kor k, see jamshidian h, 243 kumar gupta a, see wadhera s, 275 kumar p. radiation safety issues in fluoroscopy during percutaneous nephrolithotomy, 15 kumar s, see rajaian s, 280 kural ar, see kural ar, 203 l liehr ub, see janitzky a, 272 m madineay a, see etemadian m, 28 madineh sma. avicenna’s canon of medicine and modern urology: part i: bladder and its diseases, 284 malakootian m, see malekzadeh shafaroudi a, 99 malekzadeh shafaroudi a, mowla sj, ziaee sam, bahrami ar, atlasi y, malakootian m. overexpression of bmi1, a polycomb group repressor protein, in bladder tumors: a preliminary report, 99 mathur r, see wadhera s, 275 mathur rk, see wadhera s, 84 mehraban d, naderi gh, yahyazadeh sr, amirchaghmaghi m. sexual dysfunction in aging men with lower urinary tract symptoms, 260 mehrabi s, see basiri a, 120 mehravaran k, see zargar-shoshtari ma, 34 mehravaran k, see zargar-shoshtari ma, 123 michel ms, see heinrich e, 57 miri mr, see nadjafi-semnani m, 74 modi p, see gupta r, 277 mohammad ali beigi f, see simforoosh n, 50 mohammadian n, see hadjzadeh mr, 149 moharamzad y, see rokni yazdi h, 129 molanaee s, see ghadiany m, 132 moslemi mk. adult mesoblastic nephroma: a case with fatal recurrence, 136 mostafa sa, abbaszadeh s, taheri s, nourbala mh. percutaneous nephrostomy for treatment of posttransplant ureteral obstructions, 79 mousavi-bahar sh, see bazmamoun h, 233 mousavi-shafaei p, see karimianpour n, 237 mowla sj, see malekzadeh shafaroudi a, 99 mueller-hermelink hk, see heinrich e, 57 muthu v, see dhawan dr, 126 n naderi gh, see mehraban d, 260 nadjafi-semnani m, simforoosh n, ghanbarzadeh n, miri mr. real-time point-to-point wireless intranet connection: first implication for surgical demonstration and telementoring in urologic laparoscopic surgery in khorasan, 74 nafar m, see einollahi b, 248 naru t, sulaiman mn, kidwai a, ather mh, author index to volume 5 304 urology journal vol 5 no 4 autumn 2008 waqar s, virk s, rizvi jh. intracytoplasmic sperm injection outcome using ejaculated sperm and retrieved sperm in azoospermic men, 106 nourbala mh, see mostafa sa, 79 o obek c, see kural ar, 203 odiya s, see wadhera s, 84 odiya s, see wadhera s, 275 p parvin m, see zare s, 232 patidar n, see wadhera s, 275 porsch m, see janitzky a, 272 pourmand g, see karimianpour n, 237 r rabbani smr. treatment of steinstrasse by transureteral lithotripsy, 89 radfar mh, see basiri a, 269 radmehr a, see razi a, 62 rafique m. a primary carcinoid tumor of kidney, 60 rafique m. intravesical foreign bodies: review and current management strategies, 223 rahimi a, see feizzadeh b, 161 rahmani z, see hadjzadeh mr, 149 raikwar rs, see wadhera s, 84 rajaian s, kumar s, gopalakrishnan g. persistent multiple vesicocutaneous fistulas or watering-can abdomen, 280 rakhshandeh h, see feizzadeh b, 161 razi a, radmehr a. inflammatory pseudotumor of bladder: report of 2 cases and review of literature, 62 razi a, yahyazadeh sr, sedighi gilani ma, kazemeyni sm. transanal repair of rectourethral and rectovaginal fistulas, 111 reiher f, see janitzky a, 272 reza nejadi j, see heidary m, 255 rizvi j, see gupta r, 277 rizvi jh, see naru t, 106 rokni yazdi h, moharamzad y. endovascular treatment of renal arteriovenous fistula following a stab wound, 129 roshani a, falahatkar s, khosropanah i, asghari golbaghi mr, kiani sa, akbarpour m. vasal irrigation with sterile water and saline solution for acceleration of postvasectomy azoospermia, 37 s sadeghi-nejad h, see ilbeigi p, 192 safarinejad mr. urology journal in 2008: a new look, 1 salimi h, see zargar-shoshtari ma, 34 salimi h, see zargar-shoshtari ma, 123 samadzadeh s, see seyedzadeh a, 200 schoen g, see heinrich e, 57 sedighi gilani ma, see razi a, 111 sevinc c, akpinar h, tufek i, obek c, kural ar. radical retropubic prostatectomy as a solo therapy for treatment of adult rhabdomyosarcoma, 203 seyedzadeh a, kompani f, esmailie e, samadzadeh s, farshchi b. high-grade vesicoureteral reflux in pfeiffer syndrome, 200 shahbazian h, hajiani e, ehsanpour a. patient and graft survival of kidney allograft recipients with minimal hepatitis c virus infection: a casecontrol study, 178 shahidi s, see yazdani m, 46 shakhssalim n, see basiri a, 67 shakhssalim n, see aliasgari m, 168 shakibi mh, see darabi mahboub mr, 24 sharma sm, see gangane n, 197 shende n, see gangane n, 197 shirani m, see yazdani m, 46 siddiqui km, see ather mh, 94 simforoosh n, soufi majidpour h, basiri a, ziaee sam, behjati s, mohammad ali beigi f, aminsharifi ar. laparoscopic adrenalectomy: 10year experience, 67 procedures, 50 simforoosh n, see nadjafi-semnani m, 74 simforoosh n, see einollahi b, 248 soleimani mj, see zargar-shoshtari ma, 34 soufi majidpour h, yousefinejad v. percutaneous management of urinary calculi in horseshoe kidneys, 188 soufi majidpour h, see simforoosh n, 50 sulaiman mn, see ather mh, 94 sulaiman mn, see naru t, 106 author index to volume 5 305urology journal vol 5 no 4 autumn 2008 t taheri s, see einollahi b, 248 taheri s, see mostafa sa,79 tavakkol afshari j, see feizzadeh b, 161 tavakkoli m, see ebadzadeh mr, 144 tavakkoli tabassi k, see hosseini j, 215 tizeno a, see etemadian m, 28 tufek i, see kural ar, 203 v vazirnia ar, see hosseini sj, 184 virk s, see naru t, 106 w wadhera s, mathur rk, odiya s, raikwar rs, girish g. solo extracorporeal shock wave lithotripsy for management of upper ureteral calculi with hydronephrosis, 84 wadhera s, patidar n, odiya s, ghanghoria a, mathur r, kumar gupta a. true hermaphrodism presenting as pelvic abscess, 275 waqar s, see naru t, 106 y yahyazadeh sr, see mehraban d, 260 yahyazadeh sr, see razi a, 111 yazdani m, shahidi s, shirani m. urinary polymerase chain reaction for diagnosis of urogenital tuberculosis, 46 yousefinejad v, see soufi majidpour h, 188 z zare s, parvin m, ghohestani sm. retroperitoneal ganglioneuroma, 232 zare s, see basiri a, 67 zargar-shoshtari ma, mehravaran k, salimi h, kaffash nayyeri r. retroperitoneal ureterocyctoplasty in bilaterally functioning kidneys, 123 zargar-shoshtari ma, soleimani mj, salimi h, mehravaran k. symptomatic lymphocele after kidney transplantation: a single-center experience, 34 ziaee sam, javaherforooshzadeh a. priapism in a 15-year-old boy with major beta-thalassemia, 55 ziaee sam, see simforoosh n, 50 ziaee sam, see malekzadeh shafaroudi a, 99 ziaee aa, see karimianpour n, 237 november-december 2018 reviewer of the issue i̇lter tüfek i̇lter tüfek december 2018 i̇lter tüfek is associated professor of urology at acibadem mehmet ali aydınlar university medical school urology department, istanbul, turkey. he is also practicing at acibadem maslak hospital, istanbul, turkey. dr tüfek earned his medical degree from istanbul university medical school (1994). he performed his urology residency at istanbul university, cerrahpasa medical school between 1994 and 1998. in 2005, he started robotic surgery. since then he is dealing with robotic urology. also he is interested in laparoscopic urology and endourology. he is a fellow of european board of urology since 2014. he has published more than thirty papers in international peer reviewed journals. he is a member of american urologic association, endourology society and national urological associations. “i am glad to be a reviewer for urology journal. hence you are able to improve yourself and contribute to the journal. during review you can have the chance to be aware of the most recent literature about the subject. you can guide the authors to achieve highest quality standards for the paper.” dr. tüfek was chosen as the best reviewer(s) of the issue by editorial board of the urology journal for his valuable and timely review of manuscript”. evaluation of ros-tac score and dna damage in fertile normozoospermic and infertile asthenozoospermic males akram vatannejad1,2, heidar tavilani3, mohammad reza sadeghi4, saeid amanpour5, somayeh shapourizadeh6, mahmood doosti1* purpose: the aim of study was to evaluate reactive oxygen species (ros), total antioxidant capacity (tac) and ros-tac score as indicator for oxidative stress status as well as 8-hydrodeoxyguanosine (8-ohdg) levels as a marker for dna damage in the seminal plasma of asthenozoospermia patients compared to normozoospermia samples. materials and methods: the semen samples of 28 fertile normozoospermic donors and 25 infertile men with asthenozoospermia were analyzed according to world health organization (who) criteria. ros production was measured in neat semen samples by the chemiluminescent assay. plasma levels of tac was measured by commercially available colorimetric assays. the levels of dna oxidative damage were measured by seminal plasma levels of 8-ohdg using elisa method. ros-tac score was measured using principal component analysis. results: asthenozoospermic men had a higher ros levels compared to the normozoospermic men (p = .01). however, no significant difference was observed in tac levels between the groups. ros-tac score in asthenozoospermic men was lower than normozoospermic men (p = .02). the levels of 8-ohdg in the asthenozoospermic men were higher than normozoospermic men (p = .01). conclusion: the present study demonstrated a decrease in ros-tac score and, a high dna damage in asthenozoospermia compared to normozoospermia. ros-tac score can predict the oxidative damage of semen samples of astenozoospermic infertile males. keywords: asthenozoospermia; dna damage; reactive oxygen species; ros-tac score; total antioxidant capacity; 8-ohdg. introduction asthenozoospermia is one of the common causes of male infertility which is characterized by poor sperm motility because of various etiology such as physiological, anatomical, medical, genetic and dietary factors (1,2). physiological amount of reactive oxygen species (ros) is required for motility promotion, hyperactivation, capacitation, acrosome reaction, nuclear condensation as well as gamete fusion(3-5). nevertheless, ros in pathological levels can damage sperm’s function and male fertility by reduction in sperm motility mostly through depletion of intracellular atp and lipid peroxidation of plasma membrane(6,7). excessive concentrations of ros in semen can be scavenged by the cumulative sum of the enzymatic and 1department of clinical biochemistry, faculty of medicine, tehran university of medical sciences, tehran, iran. 2student’s scientific research center, tehran university of medical sciences, tehran, iran 3urology and nephrology research center, hamadan university of medical sciences, hamadan, iran. 4monoclonal antibody research center, avicenna research institute, acecr, tehran, iran. 5cancer biology research centre, tehran university of medical sciences, tehran, iran. 6payame noor university, tehran, iran. *correspondence: department of clinical biochemistry, faculty of medicine, tehran university of medical sciences, tehran, iran. tel: +98 21 64053265. fax: +98 21 64053385. email: doostimd@sina.tums.ac.ir. received november 2016 & accepted january 2017 non-enzymatic antioxidants called total antioxidant capacity (tac)(8). some studies showed a positive correlation between tac levels and normal semen parameters (9,10). when generation of ros exceeds, the balance between ros generation and tac could be distributed, and consequently, oxidative stress (os) would be occurred. ros-tac score as a marker of seminal os is calculated from seminal ros level and seminal plasma tac values. so, ros-tac score calculation, over the use of only ros or tac, is recommended for prediction of male fertility potential as well as differentiation between fertile and infertile patients. ros-tac score shows os status in the infertile men. in more levels of ros-tac score, the possibility of os is lower(11,12). available evidence suggests that os leads to dna sexual dysfunction and infertility sexual dysfunction and infertility 2973 damage, lipid peroxidation, poor sperm function, and difficulties in fertilizing potential of spermatozoa(13). oxidative damage to dna can occur in the form of base modification, deletions, dna cross-links, dna strand breaks, frame shifts or with rearrangement of chromosomes(13). so, the oxidized base, 8-hydrodeoxyguanosine (8-ohdg) is mostly considered as a marker of os damage to dna(14,15). some studies have shown that high 8-ohdg levels in sperm are associated with male infertility(2,16-18). besides, 8-ohdg levels are correlated with sperm motility and morphology(19). because of multifactorial nature of male infertility and low prediction capacity of the spermogram, a more powerful test based on os measurement is required for assessing male factor infertility as well as basic semen analysis(20-23). since, ros assays to evaluate male factor infertility have sensitivity and specificity of 68.8% and 93.8%, respectively(23), therefore, the aim of study was to evaluate os status by measurement of seminal ros, tac levels and ros-tac score as well as dna damage by evaluating 8ohdg levels in seminal plasma of asthenozoospermia samples compared to normozoospermia ones. materilas and methods study population the ethical committee of tehran university of medical sciences approved the study and informed consent was obtained from all subjects. 28 fertile normozoospermic donors and 25 infertile asthenozoospermic (sperm motility less than %35) men aged 25-35 years, who recruited at treatment center of omid clinic were enrolled. all of the participants underwent semen analysis. the infertile group was the people who visited the clinic for infertility problem. the fertile group was chosen among the ones who visited the clinic for embryo donation or sex selection. fertility of the normozoospermic donors was confirmed by the history of at least one child in the last two years and normal sperm parameters according to world health organization (who) criteria(24). procedures ejaculates were obtained by masturbation following 48 to 72 hours of sexual abstinence. after semen liquefaction (30 min at 37 °c), concentration (haemocytometer), motility and morphology of sperm (papanicolaou staining method) as well as semen volume were determined according to who manual(24). the exclusion criteria were leukocytospermia (leukocyte concentration greater than 1×106/ml), men with history of smoking, excessive alcohol consumption, endocrine disorders such as diabetes, drug intake such as vitamins supplements, carotene, ascorbate and tocopherol or minerals such as selenium, zinc, and those with varicocele. an aliquot of well-liquefied neat semen was taken for immediate ros evaluation by chemiluminescence assay. the remaining portion of neat semen was centrifuged (500g× 10 min) to separate clear seminal plasma from spermatozoa. then, stored at -80°c for the measurement of the tac and 8-ohdg analysis. measurement of seminal ros ros production was measured in neat semen samples by chemiluminescence assay. 2 μl of 5 mm freshly prepared solution of luminol (5-amino-2,3-dihyparametera group normozoospermia (n=28) asthenozoospermia (n=25) p sperm concentration (106/ ml) 47.24 ± 4.29 39.23 ± 4.36 .2 motility (%) 62.1 ± 3.05 21.18 ± 4.84 < .0001 morphology (%) 11.47 ± 2.89 7.52 ± 1.81 .2 leukocyte (106/ ml) 0.57 ± 0.08 0.61 ± 0.09 ns table 1. sperm parameters in normozoospermic and asthenozoospermic men. abbreviation:ns, non significant adata are presented as mean ± se using the independent t test. group variablea normozoospermia (n=28) asthenozoospermia (n=25) p ros (rlu/20*106) 162.89 ± 41.57 588.22 ± 152.56 .01 tac (μm) 796.38 ± 86.45 996.34 ± 62.77 .06 ros-tac 50 ± 2.95 39.75 ± 3.26 .02 abbreviation:ns, not significant a values are mean ± se. independent student's t-test was used for the analysis table 2. comparison of oxidative stress indices (ros, tac, and ros-tac scores) between normozoospermic and asthenozoospermic men. ros-tac score and male infertility-vatannejad et al. vol 14 no 01 january-february 2017 2974 dro-1,4-phthalazinedione; sigma chemical co.,st. louis, mo) in dimethyl sulfoxide was added to 80 μl of the liquefied neat semen. chemiluminescence was measured integrally for 15 minutes using a luminometer (lumo luminometer, autobio labtec instruments co. ltd., zhengzhou, china). number of ros production was expressed as relative light units (rlu) per minute per 20 × 106 spermatozoa (rlu/min/20 × 106)(23,25). total antioxidant assay an antioxidant assay kit (dianbioassay co. iran) was applied to evaluate tac in the seminal plasma samples. aliquots of the seminal plasma stored at -80°c were thawed at room temperature and assessed according to manufacturer’s instructions. each seminal plasma was diluted 1:10 with deionized water. this method is based on the ability of seminal plasma antioxidants to inhibit oxidation of the more stable abts (2,20-azino-di-[3 ethylbenzthiazoline sulphonate]) to abts+. briefly, 20 μl of sample or standard was added to 180 μl of reagent i and the first absorbance was read quickly at 660 nm. after adding 20 μl of reagent ii and incubation in dark place during 10 minutes, the second absorbance was read at 660 nm. then, the difference between the first and second absorbance was determined and values of seminal plasma tac (μm) were calculated using a standard curve. ros-tac score calculation ros-tac score was calculated using principal component analysis (pca) in order to obtain standard index of oxidative stress(12). ros-tac score minimizes the variance of the individual variables of os marker (ros alone or tac alone)(13). briefly, ros and tac levels were normalized to the same distribution. then, the ros-tac score was calculated according to linear combinations which was yielded by pca that is described by mahfouz et al(12). 8-ohdg assay the levels of 8-ohdg (pg/ml) in seminal plasma were measured using a competitive elisa kit (cayman chemical, cat# 589320, ann arbor, mi, usa) according to the manufacturer’s protocol. after reading at 450 nm, the concentration of each sample was determined using the equation obtained from the standard curve. statistical analysis results were expressed as mean ± se. variables were compared using independent student's t-test among the groups. the linear correlation between two variables were calculated using the pearson correlation coefficients. statistical significance was defined as p ≤.05. results sperm parameters according to the groups are presented in table 1. semen samples in both groups had a concentration and morphology score of more than 15×106 cells/ml and 4%, respectively. total motility was significantly lower in the asthenozoospermic men compared to the normozoospermic men (p < .001). according to microscopic observation, samples containing more than 1×106 leukocyte per milliliter semen were excluded to avoid a potential source of ros generation. oxidative stress detection in neat semen seminal levels of ros, seminal plasma tac levels and calculated ros-tac score in the study groups are illustrated in table 2. asthenozoospermic men had a significantly higher ros levels compared to normozoospermic men (p = .01). however, no significant difference was detected in seminal plasma levels of tac among the groups (p = .06). ros-tac score in asthenozoospermic men was significantly lower than normozoospermic men (p = .02). 8-ohdg assay the seminal plasma levels of 8-ohdg were 84.36 ± 3.29 and 102.82 ± 6.24 (pg/ml) in the normozoospermic and asthenozoospermic men, respectively (figure 1). the levels of 8-ohdg were found to be significantly higher in the asthenozoospermic men compared to the normozoospermic men (p = .01). correlation analysis correlations of ros-tac score, ros and 8-ohdg with semen parameters in total population are shown in ros-tac score and male infertility-vatannejad et al. table 3. correlations between ros-tac score, ros and 8ohdg with sperm parameters. sperm concentration motility morphology 8ohdg ros-tac score ros variable r p r p r p r p r p r p ros-tac score 0.2 .1 0.18 .3 0.13 .4 0.22 .1 -0.5 < .0001 ros -0.3 .05 -0.33 .05 -0.17 .3 -0.28 .07 -0.5 < .0001 8ohdg 0.28 .09 -0.12 .4 0.19 .2 0.22 .17 0.28 .07 figure 1. seminal plasma concentration of 8-ohdg in normozoospermic and asthenozoospermic men. results are expressed as mean ± se. *p < 0.05. sexual dysfunction and infertility 2975 table 3. ros levels negatively correlated with motility (r = -0.33, p = .05) and sperm concentration (r = -0.3, p = .05). in the present study, no significant correlation was demonstrated between ros-tac score and sperm parameter in the groups. also, no significant relationship was found between the 8-ohdg levels with the ros-tac score and ros. discussion we demonstrated a decrease in ros-tac score from asthenozoospermia compared to the normozoospermia. the dna oxidation levels were also found to be higher in asthenozoospermia. asthenozoospermia is an extremely common cause of male infertility(26). even though the sperm motility is dependent on ros generation in physiological levels and consequently oxygen and atp consumption, ros in pathological levels appears to have a significant role in reduction of motility due to atp depletion and lipid peroxidation of sperm membrane(27-30). the sperm motility was also found to be lower in asthenozoospermia which was in agreement with the results of previous works(6,31). an elevation in os in human spermatozoa with lower percentage of motility and morphology in comparison to proven donors have been reported previously(32,33). in the current study, also ros levels were increased in asthenozoospermia compared to normozoospermia which is consistent with previous observations(12,34,35). contradictory results have been reported on the seminal plasma tac levels between infertile and fertile males(9,12,34,36). in the present study, tac levels were higher in the asthenozoospermia compared to normozoospermia, but the data were very variable so that statistical significance was not achieved. one possible explanation is that the seminal tac in the initial os occurrence attempts to scavenge the elevating levels of ros and therefore the levels of tac might not be decreased(6,12,37). some studies have shown a positive correlation between high seminal ros levels and lower percentage of motile sperm in infertile males(12,34,35). indeed, a majority of ros production seen in populations of impaired sperm motility is related to the onset of os which is inconformity with the current study that is probably because of no significant decrease in tac levels of asthenozoospermia. in the present study, ros levels were elevated in asthenozoospermia, however; there was no sufficient increase in tac levels to compensate os. indeed, a balance between ros generation and tac is disrupted which may be involved in the pathophysiology of male infertility. although, ros and tac were measured alone like previous studies, calculating of ros-tac score as an accurate index of os, gives more valuable information about male infertility(12,34). we found a significant lower ros-tac score in asthenozoospermia compared to normozoospermia which could lead to os in asthenozoospermia. according to our result, the occurrence of os in infertile asthenozoospermic men is more likely affected by increase of ros(38). therefore, the impairment in sperm-fertilizing ability after different treatments may be due to the factors not tested during routine semen analysis, such as os status. in agreement with our results, mahfouz et al. revealed that infertile men with high seminal ros levels have a significant lower ros-tac score compared to the men with physiological seminal ros levels. however, there was no any significant decrease in tac levels of infertile men with high seminal ros levels(12). therefore, it can be concluded that ros-tac score is a more accurate and valid marker of os than ros or tac values alone in male infertility. however, to date there are still a few studies in the field of male infertility which investigated ros-tac score. os may have negative effects on sperm function through impairment in membrane fluidity and integrity, and dna integrity(39,40). in the present study, the 8-ohdg levels of sperm dna showed a significant increase in asthenozoospermia compared to normozoospermia which is in line with the previous reports (16,33). it seems that os, by inducing damage to the sperm dna, decreases chance of successful fertilization and embryo development after ivf and icsi(41). in conclusion, the present study demonstrated a decrease in ros-tac score and, a high dna damage in asthenozoospermia compared to normozoospermia. ros-tac score can predict the oxidative damage of semen samples of asthenozoospermic infertile males. acknowledgement we thank the omid clinic, particularly dr. saeidi for providing samples. this study was funded by the tehran university of medical sciences, tehran, iran (grant numbers 21660 and 30756). conflict of interest the authors report no conflict on interest. references 1. wei y-h, kao s-h. mitochondrial dna mutation and depletion are associated with decline of fertility and motility of human sperm. zoological studies. 2000;39:1-12. 2. shen s, wang j, liang j, he d. comparative proteomic study between human normal motility sperm and idiopathic asthenozoospermia. world j urol. 2013;31:1395-401. 3. aitken rj, clarkson js. cellular basis of defective sperm function and its association with the genesis of reactive oxygen species by human spermatozoa. j reprod fertil. 1987;81:459-69. 4. henkel r. the impact of oxidants on sperm function. andrologia. 2005;37:205-6. 5. athayde ks, cocuzza m, agarwal a, et al. development of normal reference values for seminal reactive oxygen species and their correlation with leukocytes and semen parameters in a fertile population. j androl. 2007;28:613-20. 6. agarwal a, makker k, sharma r. clinical relevance of oxidative stress in male factor infertility: an update. am j reprod immunol. 2008;59:2-11. 7. pasqualotto ff, sharma rk, nelson dr, thomas aj, agarwal a. relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing infertility investigation. fertil steril. 2000;73:459-64. ros-tac score and male infertility-vatannejad et al. vol 14 no 01 january-february 2017 2976 8. doustimotlagh ah, dehpour ar, nourbakhsh m, golestani a. alteration in membrane protein, antioxidant status and hexokinase activity in erythrocytes of ccl4induced cirrhotic rats. acta med iran. 2014;52:795803. 9. hosseinzadeh colagar a, karimi f, jorsaraei sg. correlation of sperm parameters with semen lipid peroxidation and total antioxidants levels in asthenoand oligoasheno teratospermic men. iran red crescent med j. 2014;15:780-5. 10. pahune pp, choudhari ar, muley pa. the total antioxidant power of semen and its correlation with the fertility potential of human male subjects. j clin diagn res. 2013;7:9915. 11. pasqualotto fbf, sharma rk, pasqualotto eb, agarwal a. poor semen quality and ros-tac scores in patients with idiopathic infertility. urol int. 2008;81:263-70. 12. mahfouz r, sharma r, thiyagarajan a, et al. semen characteristics and sperm dna fragmentation in infertile men with low and high levels of seminal reactive oxygen species. fertil steril. 2010;94:2141-6. 13. ko ey, sabanegh es, jr., agarwal a. male infertility testing: reactive oxygen species and antioxidant capacity. fertil steril. 2014;102:1518-27. 14. hiroshi kasaii, peter svoboda, sayumi yamasaki, kawai k. simultaneous determination of 8-hydroxydeoxyguanosine, a marker of oxidative stress, and creatinine, a standardization compound, in urine. industrial health. 2005;43:333-6. 15. aitken rj, de iuliis gn. on the possible origins of dna damage in human spermatozoa. mol hum reprod.16:3-13. 16. nakamura h, kimura t, nakajima a, et al. detection of oxidative stress in seminal plasma and fractionated sperm from subfertile male patients. eur. j. obstet. gynecol. reprod. biol. 2002;105:155-60. 17. kodama h, yamaguchi r, fukuda j, kasai h, tanaka t. increased oxidative deoxyribonucleic acid damage in the spermatozoa of infertile male patients. fertil steril. 1997;68:519-24. 18. chen s-s, huang wj, chang ls, wei y-h. 8-hydroxy-2'-deoxyguanosine in leukocyte dna of spermatic vein as a biomarker of oxidative stress in patients with varicocele. j urol. 2004;172:1418-21. 19. ni zy, liu yq, shen hm, chia se, ong cn. does the increase of 8-hydroxydeoxyguanosine lead to poor sperm quality? mutat res. 1997;381:77-82. 20. inhorn mc, patrizio p. infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. hum reprod update. 2015;dmv016. 21. kini s, morrell d, thong kj, kopakaki a, hillier s, irvine ds. lack of impact of semen quality on fertilization in assisted conception. scott med j. 2010;55:20-3. 22. guzick ds, overstreet jw, factor-litvak p, et al. sperm morphology, motility, and concentration in fertile and infertile men. n engl j med. 2001;345:1388-93. 23. agarwal a, sharma rk, sharma r, et al. characterizing semen parameters and their association with reactive oxygen species in infertile men. reprod biol endocrinol. 2014;12:33. 24. world health o. who laboratory manual for the examination of human semen and sperm-cervical mucus interaction: cambridge university press; 1999. 25. mahfouz r, sharma r, lackner j, aziz n, agarwal a. evaluation of chemiluminescence and flow cytometry as tools in assessing production of hydrogen peroxide and superoxide anion in human spermatozoa. fertil steril. 2009;92:819-27. 26. chemes he, olmedo sb, carrere c, et al. ultrastructural pathology of the sperm flagellum: association between flagellar pathology and fertility prognosis in severely asthenozoospermic men. hum reprod. 1998;13:2521-6. 27. aitken rj, baker ma, sawyer d. oxidative stress in the male germ line and its role in the aetiology of male infertility and genetic disease. reprod biomed online. 2003;7:6570. 28. o'flaherty cn, de lamirande e, gagnon c. positive role of reactive oxygen species in mammalian sperm capacitation: triggering and modulation of phosphorylation events. free radic biol med. 2006;41:528-40. 29. agarwal a, said tm. role of sperm chromatin abnormalities and dna damage in male infertility. hum reprod update. 2003;9:33145. 30. de lamirande e, jiang h, zini a, kodama h, gagnon c. reactive oxygen species and sperm physiology. rev reprod. 1997;2:48-54. 31. tavilani h, doosti m, saeidi h. malondialdehyde levels in sperm and seminal plasma of asthenozoospermic and its relationship with semen parameters. clin chim acta. 2005;356:199-203. 32. agarwal a, saleh ra, bedaiwy ma. role of reactive oxygen species in the pathophysiology of human reproduction. fertil steril. 2003;79:829-43. 33. kao sh, chao ht, chen hw, hwang ti, liao tl, wei yh. increase of oxidative stress in human sperm with lower motility. fertil steril. 2008;89:1183-90. 34. pasqualotto ff, sharma rk, pasqualotto eb, agarwal a. poor semen quality and ros-tac ros-tac score and male infertility-vatannejad et al. sexual dysfunction and infertility 2977 scores in patients with idiopathic infertility. urol int. 2008;81:263-70. 35. agarwal a, bragais fm, sabanegh e. assessing sperm function. urol clin north am. 2008;35:157-71. 36. siciliano l, tarantino p, longobardi f, rago v, de stefano c, carpino a. impaired seminal antioxidant capacity in human semen with hyperviscosity or oligoasthenozoospermia. j androl. 2001;22:798-803. 37. agarwal a, nallella kp, allamaneni ss, said tm. role of antioxidants in treatment of male infertility: an overview of the literature. reprod biomed online. 2004;8:616-27. 38. zini a, lamirande e, gagnon c. reactive oxygen species in the semen of infertile patients: levels of superoxide dismutaseand catalase-like activities in seminal plasma. int j androl. 1993;16:183-8. 39. aitken rj, clarkson js, fishel s. generation of reactive oxygen species, lipid peroxidation, and human sperm function. biol. reprod. 1989;41:183-97. 40. alvarez jg, touchstone jc, blasco l, storey bt. spontaneous lipid peroxidation and production of hydrogen peroxide and superoxide in human spermatozoa. superoxide dismutase as major enzyme protectant against oxygen toxicity. j androl. 1987;8:338-48. 41. saleh ra, agarwal a, nada ea, et al. negative effects of increased sperm dna damage in relation to seminal oxidative stress in men with idiopathic and male factor infertility. fertil and steril. 2003;79:1597-605. ros-tac score and male infertility-vatannejad et al. vol 14 no 01 january-february 2017 2978 reconstructive surgery 276 urology journal vol 6 no 4 autumn 2009 the use of unaltered appendix transfer in ileal continent reservoir 10 years experience, a novel technical modification nasser simforoosh, abbas basiri, seyed amir mohsen ziaee, farzaneh sharifiaghdas, ali tabibi, ahmad javaherforooshzadeh, reza sarhangnejad, emad-adin moudi, farzad tajali introduction: we report a new modified technique of unaltered appendix transfer to ileal pouch and preserving ileocecal segment. this modification enables us to use ileum as the popular type of enteric segment instead of ileocecal segment while using appendix as a catheterizable stoma. materials and methods: forty-five patients (30 men) who needed reconstruction of the lower urinary tract were enrolled for using appendix as a catheterizable stoma. reservoir was reconstructed using ileal segment. the appendix was circumcised from its base over its pedicle. the spatulated appendix tip was exteriorized as a catheterizable stoma to the skin, preferably umbilicus, and its base was implanted to the ileal pouch. results: follow-up records of 38 of 45 patients were available. the median follow-up period was 29 months. the mean intermittent catheterization interval was 4.19 ± 1.6 hours. urodynamic parameters were evaluated for 18 out of 38 patients. the median maximal pouch capacity determined as 380 ml. the median appendiceal closure pressure was 61 cm h2o. no pouch perforation occurred. stomal stenosis occurred in 3 patients. they did not catheterize their appendiceal stoma because they restarted catheterization through the urethra. conclusion: this novel approach enabled us to use ileum as today’s more popular type of bowel segment to reconstruct enteric pouch rather than using ileocecal segment, while using appendix as a catheterizable stoma. one of the unique advantages of this technique is that the postponement of clean intermittent catheterization will not result in pouch perforation since the urine will leak when the pouch become overfill. urol j. 2009;6:276-82. www.uj.unrc.ir keywords: appendix, ileum, urinary reservoirs, urinary diversion methods urology and nephrology research center and shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran iran corresponding author: nasser simforoosh, md department of urology, shahid labbafinejad medical center, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2258 8016 fax: +98 21 2258 8016 e-mail: simforoosh@iurtc.org.ir received may 2009 accepted september 2009 introduction continent urinary diversion improves the quality of life for many patients with incontinence or low complaint bladder.(1) a specific technique to restore lower urinary tract function is a catheterizable continent stoma.(2) since patients with advanced urethral problems are not candidates for orthotopic continent urinary diversion, surgeons usually tend to perform cutaneous continent urinary diversion. to date, several organs have been used as catheterizable stoma. the use of appendix as a continent vesicostomy was initially described by mitrofanoff in 1980 and subsequently modified by duckett and synder.(3,4) woodhouse appendix transfer in ileal continent reservoir—simfoosh et al urology journal vol 6 no 4 autumn 2009 277 and colleagues used all of the available narrow tubes—the appendix, ureter, fallopian tube, and a length of tailored intestine—and tunneled them into several types of reservoirs.(3,4) although the most appropriate organ for continent diversion seems to be the appendix,(5) the fashioning of continent cutaneous stoma still remains the most challenging aspect of continent urinary diversion. (2) bissada initially introduced the reconstruction of cutaneous continent diversion with in situ appendix using reinforcing sutures.(6) by omitting the reinforcing sutures, we previously made a modification to the above technique. (7) riedmiller and associates modified the mitrofanoff’s technique with embedment of in situ appendix in the anterior tenia of the cecum.(8) the ileocecal segment has important physiologic functions. this segment is regularly removed in the majority of the above techniques, which could lead to bowel dysfunction in long-term, especially in children. also today, the ileum is becoming the most popular enteric segment used for pouch reconstruction, since it is more flexible and has the advantage of easier bowel anastomosis compared with ileocolic anastomosis. therefore, we designed a study to use the ileum as reconstructed pouch, while by transferring the unaltered appendix over its pedicle to the pouch, we were able to use the appendix as an excellent catheterizable stoma. to our knowledge, this is the first report of transferring the unaltered appendix to the ileal pouch or to the ileal patch of the augmented bladder while preserving the ileocecal segment intact. materials and methods forty-five patients who needed reconstruction of the lower urinary tract underwent continent cutaneous urinary diversion using unaltered appendix transfer with preservation of the ileocecal segment, during a 10-year period (1998 to 2008). we reconstructed the reservoir with the ileal segment conserving at least 20 cm of the distal ileum and the ileocecal valve. the appendix was circumcised carefully from the cecal base, preserving its blood supply. the proximal end of the appendix was anastomosed to the reservoir without submucosal tunneling (figure 1), and its spatulated distal end was brought out as a cutaneous stoma (figure 2). the appendix was placed as a straight tube to facilitate catheterization (figure 3). as we previously reported,(7) in contrast to other techniques,(6,10) we do not manipulate the proximal end of the appendix and simply implant to the reservoir with the advantages described before. the umbilicus was usually used as the exit site to the skin (figures 4 and 5). in patients with bladder extrophy, stoma was created at a midway point, between the xyphoid and the symphysis pubis or at the right lower quadrant area, depending on the appendix length. urodynamic variables in 18 of 38 patients were figure 1. appendix anastomosis to the ileal pouch. figure 2. distal end of the appendix was brought out as a cutaneous stoma. appendix transfer in ileal continent reservoir—simfoosh et al 278 urology journal vol 6 no 4 autumn 2009 evaluated in the supine position, 3 months postoperatively. three patients died because of metastatic cancer. for urodynamic studies, we utilized an 8-f 3-lumen catheter in the empty reservoir, while using a rectal balloon to measure the intra-abdominal pressure. the pressures of the filling pouch (pouchometry) were recorded using infusion of sterile saline at a rate of 20 ml/ min on average. the appendicular pressure profile (app) was also performed using infusion of sterile saline at a rate of 2 ml/min and the pull-out device with a rate of 2 mm/sec. we measured these parameters: maximal pouch capacity (mpc), which is the sense of abdominal discomfort or reaching the pouch pressure to 40 cm h2o; pouch pressure at maximal capacity (ppmc); maximal appendiular pressure (map) which is the peak of the curve of app; maximal appendicular closing pressure (macp) which is the difference between map and pouch pressure; and functional appendicular length (fal) which is the length over which appendicular pressure remained higher than reservoir pressure. after lowering the pouch volume to a half, we removed the catheter of the appendix and left the rectal balloon in place. the patients were asked to do the valsalva maneuver or to perform the crede maneuver in order to measure the appendicular leak point pressure (alpp) as an estimation of abdominal leak point pressure. results records of 45 patients, including 30 men (66.6%) and 15 women (33.3%), were reviewed in this study. during the follow-up period, 7 patients (6 men and 1 woman) were lost. the mean age of the patients was 23.1 ± 4.0 years (range, 2 to 69 figure 3. location of the appendiceal stoma with catheter. figure 4. the appendix and ileal segment resections with preservation of the ilocecal segment. figure 5. ileal reservoir configuration and unaltered appendix transfer. appendix transfer in ileal continent reservoir—simfoosh et al urology journal vol 6 no 4 autumn 2009 279 years). the underlying diseases of these patients are shown in table 1. the median follow-up duration was 29 months (range, 1 to 62 months). we used 10-f catheters in 14 patients (36.8%), 12-f catheters in 19 (50.0%), and 14-f catheters in 5 (13.2%) for pouch catheterization via the appendicular stoma. the stoma was created in the umbilicus in 26 patients (68.4%), at the midpoint between the xyphoid and the symphysis pubis (in case of bladder extrophy) in 7 (18.4%), and at the right lower quadrant area in 5 (13.2%). during the follow-up period, we had no perioperative complications. the mean clean intermittent catheterization interval was 4.19 ± 1.6 hours. thirty-five patients (92.1%) were continent. urodynamic findings are shown in table 2. the median mpc was 380 ml. the median ppmc, fal, map, and macp were 19.5 cm h2o, 5 cm, 85 cm h2o, and 61 cm h2o, respectively. all of the patients had an alpp higher than 84 cm h2o. complications included umbilical parastomal hernia in 1 patient; and 3 patients (7.8%) developed stomal stenosis. they were those who performed clean intermittent catheterization through the urethra instead of the appendicular stoma. we did not revise the stoma of these 3 patients because of adequate reservoir drainage. reservoir calculus developed in 5 patients (13.2%). no pouch perforation occurred during the follow-up period. we could see appendiceal stoma with and without catheter in 1 patient, 10 years after the surgery (figures 6 and 7). diagnosis patients (%) extrophy/epispadiasis 9 (20.0) neurogenic bladder dysfunction 23 (51.1) bladder carcinoma 5 (11.1) end-stage bladder neck destruction 4 (8.8) undiversion from ileal conduit 1 (2.2) large vesicovaginal fistula with small contracted bladder 3 (6.6) table 1. patients’ diagnoses patients mpc, ml ppmc, cm h2o map, cm h2o alpp, cm h2o macp, cm h2o fal, cm 1 500 17 55 > 110 45 4.0 2 430 8 45 > 95 37 4.0 3 340 28 82 118 57 3.0 4 690 15 67 > 97 44 5.0 5 415 25 95 > 131 75 13.0 6 400 25 84 > 107 76 5.0 7 120 40 114 > 122 82 5.0 8 400 19 114 > 84 73 7.0 9 860 28 131 > 139 90 8.0 10 550 11 85 107 58 5.5 11 1284 14 105 > 176 80 8.0 12 360 20 105 > 92 90 7.0 13 700 20 76 > 98 55 5.0 14 130 15 85 > 108 65 5.0 15 126 11 100 > 88 85 5.0 16 200 9 72 > 121 55 6.0 17 150 21 59 > 103 45 5.0 18 250 23 88 > 98 50 5.5 *mpc indicates maximal pouch capacity; ppmc, pouch pressure at maximal capacity; map, maximal appendicular pressure; alpp, appendicular leak-point pressure; macp, maximal appendicular closure pressure; and fal, functional appendix length. table 2. urodynamic variables of patients who underwent bladder reconstruction figure 6. appendiceal stoma without catheter 10 years after surgery. appendix transfer in ileal continent reservoir—simfoosh et al 280 urology journal vol 6 no 4 autumn 2009 discussion continent catheterizable stomas for simple catheterization to achieve socially acceptable dry intervals are important for patients with cutaneous continent urinary diversion.(9) initially, mitrofanoff reported the appendicovesicostomy technique using submucosal tunneling. despite the fact that continence outcomes in mitrofanoff’s procedure are good (more than 90%), the reoperation rate for conduit complications has been reported about 30%, due to stomal stenosis and failure of continence mechanism. (2,4) moreover, rupture of reservoir possibly caused by lack of “pop-off” mechanism has been reported.(10,11) in this study, postponement of clean intermittent catheterization was associated with urine leakage; therefore, we did not have any pouch perforation in our series. others have reported such experience previously.(7) in contrast to the classic mitrofanoff procedure, we exteriorated the distal part of the spatulated appendix as stoma and anastomosed the cecal base to the ileal reservoir. there are several advantages of this innovation. wider lumen in the base of appendix makes appendicoreservoir anastomosis simpler. we anastomosed the spatulated tip of appendix to the abdominal wall (umbilicus or lower quadrants) without any manipulation or making skin flaps.(7) interestingly, stomal stenosis was not common following this method. this is due to intermittent dilatation naturally occurs during intermittent catheterization via appendix, which is the routine elected method of pouch emptying. since, the meso-appendix is usually fanned out in the base and mid portion; exterioration of the distal part seems more feasible, specifically in obese patients. in 1993, bissada used in situ appendix as a continent catheterizable stoma in 20 adult patients. he used reinforcing silk sutures in patients with intra-operative leak pressure lower than 75 cm h2o to 80 cm h2o. (6) five years later, we reported the above technique without using the reinforcing suture with similar success.(7) in our previous report, we used ileocecal segment as pouch and the distal tip of the appendix was brought out to skin as stoma. today, the use of the ileum as augumenting patch or urinary pouch has become more popular comparing ileocecal segment. because of discrepancy in lumen size of ileum and colon, ileocolonic anastomosis seems technically more difficult than ileo-ileal one. moreover, by preserving ileocecal segment, long-term complications like chronic diarrhea, megaloblasitc anemia, biliary stone, neuropathic disorders, and steatorrhea could be prevented.(12) that is why we made this new modification to our previously reported technique.(7) to be able to use the ileum, we decided to transfer the appendix to the ileal pouch as we described in our new modification to previous report.(7) with creation a window in the mesoappendix, riedmiller and colleagues made a modification to the mitrofanoff technique and embedded in situ appendix in the tenia of cecum.(8) the abdominal leak point pressure has not been standardized with respect to bladder volume. some have recommended using near capacity volumes,(13) whereas others have suggested filling to 250 ml or half the functional capacity.(14,15) in the urethra, it is generally accepted that with abdominal leak point pressure lower than 60 cm h2o and/or maximum urethral closure pressure lower than 20 cm h2o, some degrees of intrinsic sphincter deficiency may develop. (16,17) although the appendix has usually lower internal diameter comparing with the urethra, alpp and macp measured more than above limits in all patients. moreover, in our technique, the appendix was not located in a dependent position. therefore, these characteristics, together figure 7. appendiceal stoma with catheter 10 years after surgery. appendix transfer in ileal continent reservoir—simfoosh et al urology journal vol 6 no 4 autumn 2009 281 with compliance improvement, could explain the excellent continence rate of this procedure (92.1%), if regular pouch emptying was employed. furthermore, adequate appendiceal length, higher appendiceal pressure than reservoir pressure and external compressive force toward appendix secondary to intra-abdominal pressure could help to the continence mechanisms. to reduce the rate of appendicular stomal stenosis, subramaniam and coworkers used an antegrade continence enema stopper in catheterizable channels and followed the patients for 3 to 6 months postoperatively. they showed the beneficial effects of this stopper to eliminate the occurrence of stomal stenosis.(18) we think that the effect of this stopper is like clean intermittent catheterization for prevention of stomal stenosis. in this study 3 patients (7.8%) developed stomal stenosis. this low incidence seems secondary to little manipulation of appendix and its vasculature, and especially due to intermittent catheterization (every 4 hours) which acts as regular dilatation. this hypothesis is strengthened by observing that the 3 patients who stopped clean intermittent catheterization by the time (reduction of urethral problem during follow up period) developed appendicular stomal stenosis further confirmed by subramaniam and colleagues’ study. development of a small parastomal hernia in one of our cases, who refused to perform herniorraphy, sounds related to obesity. conclusion our novel technique of transferring the appendix to the ileal neobladder seems to be safe, simple, and successful. it is associated with little manipulation of appendix, the “pop-off” mechanism, and intact ileocecal segment. also, one of the distinct advantages of our technique of transferring appendix is that the procedure enables us to use ileum as the popular type of bowel as pouch rather than ileocecal segment, while enjoying the use of appendix as an excellent catheterizable stoma. although our experience has been limited to 38 patients, the clinical and urodynamic outcome of the procedure was satisfactory in various situations. further studies with higher number of patients and longer follow up will determine whether this new procedure would be associated with a long-term success and lower rate of complications. conflict of interest none declared. references 1. de ganck j, everaert k, van laecke e, oosterlinck w, hoebeke p. a high easy-to-treat complication rate is the price for a continent stoma. bju int. 2002;90: 240-3. 2. lorenzo jl, castillo a, serrano ea, gonzalez-blanco s, andrade c, moreno j. urodynamically based modification of mitrofanoff procedure. j endourol. 1997;11:77-81. 3. woodhouse cr, malone pr, cumming j, reilly tm. the mitrofanoff principle for continent urinary diversion. br j urol. 1989;63:53-7. 4. woodhouse cr. the mitrofanoff principle for continent urinary diversion. world j urol. 1996;14:99-104. 5. ahmed s. urinary tract reconstruction augmentation cystoplasty. saudi med j. 2003;24:s45-6. 6. bissada nk. characteristics and use of the in situ appendix as a continent catheterization stoma for continent urinary diversion in adults. j urol. 1993;150:151-2. 7. simforoosh n, razzaghi mr, danesh ak, sharifi fa, gholamrezaie hr, mousavi h. continent ileocecal diversion with an unaltered in situ appendix conduit. j urol. 1998;159:1176-8. 8. riedmiller h, burger r, muller s, thuroff j, hohenfellner r. continent appendix stoma: a modification of the mainz pouch technique. j urol. 1990;143:1115-7. 9. monti pr, de carvalho jr, arap s. the monti procedure: applications and complications. urology. 2000;55:616-21. 10. woodhouse cr, macneily ae. the mitrofanoff principle: expanding upon a versatile technique. br j urol. 1994;74:447-53. 11. elder js, snyder hm, hulbert wc, duckett jw. perforation of the augmented bladder in patients undergoing clean intermittent catheterization. j urol. 1988;140:1159-62. 12. steiner ms, morton ra. nutritional and gastrointestinal complications of the use of bowel segments in the lower urinary tract. urol clin north am. 1991;18: 743-54. 13. bump rc, elser dm, theofrastous jp, mcclish dk. valsalva leak point pressures in women with genuine stress incontinence: reproducibility, effect of catheter caliber, and correlations with other measures of urethral resistance. continence program appendix transfer in ileal continent reservoir—simfoosh et al 282 urology journal vol 6 no 4 autumn 2009 for women research group. am j obstet gynecol. 1995;173:551-7. 14. haab f, zimmern pe, leach ge. female stress urinary incontinence due to intrinsic sphincteric deficiency: recognition and management. j urol. 1996;156:3-17. 15. nitti vw, combs aj. correlation of valsalva leak point pressure with subjective degree of stress urinary incontinence in women. j urol. 1996;155:281-5. 16. summitt rl, jr., bent ae, ostergard dr, harris ta. stress incontinence and low urethral closure pressure. correlation of preoperative urethral hypermobility with successful suburethral sling procedures. j reprod med. 1990;35:877-80. 17. pajoncini c, costantini e, guercini f, bini v, porena m. clinical and urodynamic features of intrinsic sphincter deficiency. neurourol urodyn. 2003;22: 264-8. 18. subramaniam r, taylor c. the use of an antegrade continence enema stopper in catheterizable channels virtually eliminates the incidence of stomal stenosis: preliminary experience. j urol. 2009;181:299-301. vol 15 no 03 may-june 2018 59 case report first experience of inserting a metallic mesh stent (uventa stent) in malignant ureteral obstruction in iran mohammad ali ghaed,1*, maziar daniali,2 mohammad ebrahimian3 malignant ureteral obstruction is usually caused by an extrinsic compression including intra-abdominal cancers. one of the treatment modalities decompressing the obstruction is applying stent to open the ureter. metallic stent is an effective instrument which we used for the first time in iran in our patient who had a metastatic colon cancer with a single kidney and we used a novel, double-layered, coated, self-expandable metallic mesh stent (uventa stent) to keep the ureter open. after six months of follow up with ureteroscopy, there was no obstruction any more. 1department of urology, rasoul-e-akram hospital, iran university of medical sciences, tehran, iran. 2resident of surgery, iran university of medical sciences, tehran, iran. 3student research committee, faculty of medicine, iran university of medical sciences, tehran, iran. *correspondence: department of urology, rasoul-e-akram hospital, iran university of medical sciences, tehran, iran. email: maghaed@yahoo.com. received july 2017 & accepted october 2017 keywords: malignant ureteral obstruction; treatment; stent; case report. introduction a variety of pelvic, retroperitoneal or metastatic malignancies may cause ureteral obstruction. ureteral ob-struction secondary to malignancy presents a challenging management scenario for the urologist. traditional treatment modalities such as polymeric ureteral stents and percutaneous nephrostomy (pcn) tubes, an unwilling procedure because of daily life limitations, may be impaired by the progression of tumor.(1,2) we report a 68-year-old man with metastatic colon cancer and right single kidney that we found his malignant ureteral obstruction due to colon cancer by ureteroscopic evaluation. this report was approved by the ethics committee of iran university of medical sciences. an informed consent was taken from the patient. case report a 68-year-old man with metastatic colon cancer referred to our clinic because of hydro-uretero-nephrosis and raised creatinine last year. he had a flank pain but no tenderness without any other symptoms. he had a past surgical history of left nephrectomy 10 years ago because of left kidney cancer and also a total colectomy+ileosigmoid anastomosis three years ago. his serum creatinine was 2.2 mg/dl. pre-operation imaging including ultrasonography and computed tomography (ct) scan made us suspicious to internal stricture of the ureter. proving the figure 1. fluoroscopic view of the stricture during surgery. figure 2. ureteroscopic view of the stricture during surgery. existence of stricture and accessing the exact length of it, we performed uretersocopy. on ureteroscopy, he had a stricture in the middle of ureter. we inserted a temporary double j (dj) stent which did not help to solve the obstruction and creatinine rised. after that we used the uventa stent, a double-layered, coated, self-expandable metallic mesh stent in the middle of the right ureter to open the stricture. (figures 1, 2) after placing the stent, patient’s creatinine decreased. we requested an intravenous pyelogram (ivp) after the surgery which seemed to be good. (figure 3) six months later, we re-evaluated the patient by ureteroscopy. there was no stricture anymore and the stent was in the correct position. patient had no more complain of flank pain. serum creatinine was in the normal range. then we requested an ivp for the patient. (figure 4) discussion using a metal stent is not a common way to open the obstruction of ureter secondary to malignancy.(3) uventa stent, a type of metal stent, is a nickel-titanium alloy, segmental, thermally expandable stent.(4) being thermoand self-expandable and providing less frequent complications including irritation are considered to be the advantages of uventa stent.(4,5) chung et al. believed that using uventa metal stent is an effective option to decrease malignant obstruction of ureter’s symptoms.(4) as we reviewed in literatures, uventa stent for ureteral stricture was manufactured since 2013 and a few countries like italy, spain and north korea used this stent recently. the total number of the patients in whom the uventa ureteral stents were inserted is less than a hundred.(6) although long term follow up of these patients are not available, but short and middle term follow up show the efficacy and safety of these stents. after stent insertion, the patient should be under close follow up with ivp or ureteroscopy due to delayed stricture. the stent should figure 3. intravenous pyelography after the surgery. figure 4. intravenous pyelography 6 months after the procedure. be removed 12 months later.(7) no severe complications are mentioned but some minor complications like persistent flank pain, lower urinary tract infection and stent migration are considered in previous studies.(8) our patient had no minor and major complications and six month ureteroscopic follow up demonstrated the patency of the metallic stent. re-evaluating the patient using ureteroscopy had some reasons including confirming the patency of the stent and excluding stent encrustation. as stent failure is a result of tumor progression in other parts of the ureteral segment, long term follow up of our patient is obligatory. in conclusion, there are different treatment strategies for the management of malignant ureteral obstruction. due to complications and patient’s complains, inserting a ureteral metal stent (such as uventa stent) seems to be a safe and efficient treatment for these patients. references 1. kanou t, fujiyama c, nishimura k, tokuda y, uozumi j, masaki z. management of extrinsic malignant ureteral obstruction with urinary diversion. int j urol. 2007;14:689-92. 2. lingam k, paterson p, lingam m, buckley j, forrester a. subcutaneous urinary diversion: an alternative to percutaneous nephrostomy. j urol. 1994;152:70-2. 3. liatsikos e, kallidonis p, kyriazis i, et al. ureteral obstruction: is the full metallic double-pigtail stent the way to go? eur urol. 2010;57:480-7. 4. chung kj, park bh, park b, et al. efficacy and safety of a novel, double-layered, coated, selfexpandable metallic mesh stent (uventa™) in malignant ureteral obstructions. j endourol. 2013;27:930-5. metallic mesh in malignant ureteral obstruction-ghaed et al. case report 60 vol 15 no 03 may-june 2018 61 5. kim m, hong b, park hk. longterm outcomes of double-layered polytetrafluoroethylene membrane-covered self-expandable segmental metallic stents (uventa) in patients with chronic ureteral obstructions: is it really safe? j endourol. 2016;30:1339-46. 6. hendlin k, korman e, monga m. new metallic ureteral stents: improved tensile strength and resistance to extrinsic compression. j endourol. 2012;26:271-4. 7. kim ks, choi s, choi ys, et al. comparison of efficacy and safety between a segmental thermo-expandable metal alloy spiral stent (memokath 051) and a self-expandable covered metallic stent (uventa) in the management of ureteral obstructions. j laparoendosc adv surg tech a. 2014;24:550-5. 8. wang hj, lee ty, luo hl, et al. application of resonance metallic stents for ureteral obstruction. bju int. 2011;108:428-32. metallic mesh in malignant ureteral obstruction-ghaed et al. case report 129urology journal vol 5 no 2 spring 2008 endovascular treatment of renal arteriovenous fistula following a stab wound hadi rokni yazdi, yashar moharramzadeh urol j. 2008;5:129-31. www.uj.unrc.ir keywords: arteriovenous fistula, kidney, angiography, embolization, treatment outcome, stab wounds department of radiology and imaging, imam khomeini hospital, tehran university of medical sciences, tehran, iran corresponding author: hadi rokni yazdi, md department of radiology and imaging, imam khomeini hospital, tohid sq, tehran, iran tel: +98 912 197 5457 fax; +98 21 6694 5117 e-mail: rokniyaz@sina.tums.ac.ir received may 2007 accepted september 2007 introduction renal arteriovenous fistula (avf) due to a noniatrogenic penetrating trauma is uncommon. in most reported cases, renal avf has been one of the complications of interventional urologic procedures.(1) most cases secondary to percutaneous needle biopsy of the kidney are resolved spontaneously in contrast to those caused by traumas.(2) angiographic renal embolization has been reported to be effective in the treatment of penetrating renovascular injuries as an alternative to other possible options such as direct vascular repair or partial nephrectomy.(3,4) we report a case of renal avf following a stab wound, which was treated by endovascular coiling. case report a 42-year-old man presented to our department with gross hematuria for 20 days after a single stab wound to the left flank area. he was hemodynamically stable, but the hemoglobin level had decreased to 9 g/dl. the patient underwent selective left renal digital subtraction angiography (advantex, general electric medical system, milwaukee, illinois, usa) via the right femoral artery with a 5-f cobra ii catheter (cordis corporation, miami, florida, usa). a moderate-sized avf was detected in the lower pole of the kidney (figure 1). the arterial branch of the avf was then selectively catheterized (figure 2), and was completely occluded by a 5-mm soft platinum coil (cook corp, bloomington, figure1. digital subtraction angiography of the left kidney shows avf in the lower pole of the kidney with feeding artery (black arrow) and draining vein (white arrows). avf indicates arteriovenous fistula. endovascular treatment of renal arteriovenous fistula—rokni yazdi and moharramzadeh 130 urology journal vol 5 no 2 spring 2008 indiana, usa; figure 3). after embolization, less than 10% of the kidney tissue showed vascular deprivation (figure 4). no complication was noted. urine became clear in the recovery room after 3 hours. no clinical sign of recurrence or hypertension was found after 2.5 years of follow-up. discussion traumatic renal avf is mostly iatrogenic, typically as a complication of percutaneous biopsy of the kidney. to our knowledge, less figure 3. left, selective coiling of the feeding artery of the arteriovenous fistula with a 5-mm soft platinum coil. right, control angiography after selective occlusion of the arteriovenous fistula feeding artery (only the proximal portion of the coiled artery can be seen as a more dense part due to superimposition of 2 parallel arteries. note a small meniscus of clot just proximal to the coil; late arterial phase). figure 2. selective catheterization of the feeding artery of avf. avf indicates arteriovenous fistula. figure 4. control angiography after selective occlusion of the arteriovenous fistula feeding artery in capillary (nephrogram) phase shows a small infarction (white arrow) in less than 10% of the renal parenchyma. endovascular treatment of renal arteriovenous fistula—rokni yazdi and moharramzadeh urology journal vol 5 no 2 spring 2008 131 than 20 cases of renal avf after stab wounds have been reported in the literature.(5) in the majority of these cases, renal injuries are self-limiting and conservative treatment is accepted as the preferred approach to most injuries to the kidneys.(6,7) however, continuous gross hematuria and decreasing hemoglobin necessitates intervention for controlling hemorrhage in these patients. color doppler ultrasonography can be a diagnostic tool. also, due to real-time visualization of the avf, some authors have used ultrasonography-guided compression treatment for low-flow thrombosing fistulas.(8) however, angiography remains the “gold standard” method for diagnosis of the renovascular injuries with the additional advantage of the potential for therapeutic intervention.(9) since their first use in 1973 for management of an avf due to kidney biopsy,(4) endovascular techniques have been used to manage a variety of renovascular injuries with much success, whereas aggressive surgeries such as vascular repair or nephrectomy have resulted in only 25% to 35% renal salvage rate.(10) complications of catheter therapy are relatively rare. renal artery dissection has been described in up to 7.5% of the patients. postembolization syndrome, a form of hyperpyrexia after embolization which usually occurs after tumor ablation, has also been described in patients treated by selective embolization with polyvinyl alcohol particles and gelatin sponges. coils can migrate to nontargeted points, usually to the lungs, especially when they are smaller than the size of the avf. arterial hypertension is a rare complication that in most cases, resolves spontaneously. there is no evidence to show that the incidence of renal hypertension might increase after superselective renal embolization.(11) in conclusion, selective embolization is a quite useful technique for the treatment of a traumatic renal avf. conflict of interest none declared. references 1. srivastava a, singh kj, suri a, et al. vascular complications after percutaneous nephrolithotomy: are there any predictive factors? urology. 2005;66:38-40. 2. heyns cf, van vollenhoven p. increasing role of angiography and segmental artery embolization in the management of renal stab wounds. j urol. 1992;147:1231-4. 3. fisher rg, ben-menachem y, whigham c. stab wounds of the renal artery branches: angiographic diagnosis and treatment by embolization. ajr am j roentgenol. 1989;152:1231-5. 4. corr p, hacking g. embolization in traumatic intrarenal vascular injuries. clin radiol. 1991;43:262-4. 5. benson da, stockinger zt, mcswain ne jr. embolization of an acute renal arteriovenous fistula following a stab wound: case report and review of the literature. am surg. 2005;71:62-5. 6. velmahos gc, demetriades d, cornwell ee 3rd, et al. selective management of renal gunshot wounds. br j surg. 1998;85:1121-4. 7. armenakas na, duckett cp, mcaninch jw. indications for nonoperative management of renal stab wounds. j urol. 1999;161:768-71. 8. hung m, chang h, cherng w. diagnosis and ultrasond-guided compression of iatrogenic inferior epigastric arteriovenous fistula. j med ultrasound. 1999;7:48-51. 9. reilly kj, shapiro mb, haskal zj. angiographic embolization of a penetrating traumatic renal arteriovenous fistula. j trauma. 1996;41:763-5. 10. tillou a, romero j, asensio ja, et al. renal vascular injuries. surg clin north am. 2001;81:1417-30. 11. dinkel hp, danuser h, triller j. blunt renal trauma: minimally invasive management with microcatheter embolization experience in nine patients. radiology. 2002;223:723-30. 403 forbidden
editorial comments re: laser-puncture versus electrosurgery-incision of the ureterocele in neonatal patients abdol-mohammad kajbafzadeh1* behnam nabavizadeh1 1pediatric urology and regenerative medicine research center, children's medical center, tehran university of medical sciences, tehran, iran *correspondence: a m. kajbafzadeh pediatric urology and regenerative medicine research center, children's medical center, tehran university of medical sciences, no.62, dr. gharib's street, keshavarz boulevard, tehran, iran. p.o. box: 1419733151 tel: + 98-21-66565400. fax: + 98-21-66565500. email: kajbafzd@tums.ac.ir. the authors present an interesting comparison between two groups of neonates with intravesical ureterocele treated by two distinct methods. while the approaches are not novel, the study was able to clarify the benefits and drawbacks of each technique. timely and proper management of neonatal ureterocele is of paramount importance in pediatric urology which can relieve life-threatening complications. according to their experience, ureterocele puncture using holmium yag laser was superior to electrocautery incision in neonates in terms of formation of iatrogenic vesicoureteral reflux. other prominent parameters including pyelonephritis, rate of reoperation, and duration of hospital stay was not significantly different between groups. the latter might be partly due to the small number of cases in their observation as they stated. a special care must be taken not to damage the surrounding tissue and bladder wall while using laser, especially in unexperienced hands. our experience is congruent with their results that ureterocele incision is associated with significant complications. we use a technique of ureterocele surgery consisting of creating two punctures into the poles of ureterocele. subsequently, we insert a double-j stent passing inside the ureterocele and then fulgurate the collapsed walls (1,2). the long-term results of this study with larger number of cases are also awaited. references 1. kajbafzadeh a, salmasi ah, payabvash s, arshadi h, akbari hr, moosavi s. evolution of endoscopic management of ectopic ureterocele: a new approach. j urol. 2007;177:1118-23; discussion 23. 2. nabavizadeh b, nabavizadeh r, kajbafzadeh a-m. mp61-18 evolution in endoscopic management of ureterocele: long-term outcomes of ureterocele double puncture as a promising technique. j urol. 2017;197:e806. editorial comment 66 reply by authors thank you very much for your editorial comment about our article „laser-puncture versus electrosurgery-in-cision of the ureterocele in neonatal patients“. i read it carefully and i agree with all facts, mantioned in your text. your technique, published last year, is very interesting. all these techniques are attempts to find the best choice for the treatment of neonates with ureterocele. i hope that we'll have more relevant results of these techniques with a larger number of patients in the comming period. the essence is to find an optimal surgical minimally invasive method to relieve the obstruction, prevent vesicoureteral reflux and to avoid subsequent extensive surgery of the urinary tract, if possible. best regards predrag ilic, md, phd mother and child health care institute of serbia “dr vukan cupic” pediatric surgery clinic, urology department medical faculty, university of belgrade belgrade, serbia phone: +381 11 3108 123. cell: +381 64 159 6523. fax: +381 11 2697 232. e-mail: predrag.ilic0410@gmail.com. www.imd.org.rs vol 15 no 02 march-april 2018 67 pediatric urology effects of different anesthetic agents on surgical site hemorrhage during circumcision derya karasu1*, canan yilmaz1, seyda efsun ozgunay1, isra karaduman2, demet ozer3, mete kaya4 purpose: to investigate the effects of ketamine+midazolam and propofol+sevoflurane anesthesia on surgical site hemorrhage during circumcision procedures. materials and methods: the boys undergoing circumcision surgery were included in the study. the patients were divided into two groups. in group 1 (n = 50), 0.01 mg/kg midazolam and 2 mg/kg iv ketamine were administered. in group 2 (n = 50), 1 µg/kg fentanyl, 1 mg/kg lidocaine 2%, and 2–3 mg/kg iv propofol were administered, and patency of airway was ensured with a laryngeal mask airway. the intraoperative bleeding scale was recorded during the procedure to evaluate surgical site bleeding. hemorrhage was checked for the first three hours using the postoperative bleeding scale to follow the amount of hemorrhage. results: intraoperative bleeding scores were significantly higher in group 1 as compared to group 2. however, there was no significant difference between the groups regarding frequency of postoperative hemorrhage. the mean blood pressure values measured at 5th, 10th, 15th minutes and recovery room were significantly higher in group 1. conclusion: the intraoperative bleeding scores were significantly higher with ketamine+midazolam compared to propofol+sevoflurane. on the other hand this hemorrhage can be controlled easily with appropriate hemostasis, and the amount of blood loss was not clinically significant. we think that our study makes a positive contribution to the literature about the effects of anesthetics on the surgical site bleeding during circumcision. clinical trials registration: actrn12616000189426 keywords: circumcision; hemorrhage; ketamine; midazolam; propofol. introduction circumcision, is one of the most widely performed surgical procedures worldwide. circumcision is performed at varying rates in various populations and age groups. (1,2) currently, approximately one quarter of men in the world are circumcised largely concentrated in the usa, canada, countries in the middle east and asia with muslim population and large portions of africans.(3,4) in a study conducted in usa, estimated circumcision prevalence was 80.5% and prevalence varied significantly by year of birth, race/ethnicity, health insurance type, and family income.(5) it is most commonly performed for religious reasons and it may also be performed for medical reasons, including prevention of phimosis, paraphimosis, urinary tract infections, and various other types of infections (i.e. balanitis xerotica obliterans).(2,6) the most common early complications of circumcision include pain, hemorrhage, swelling, and inadequate skin removal. hemorrhage is the most common complication, with a 0.1–35% incidence rate. this type of hemorrhage is very mild and can be controlled by applying direct pressure to the site for a few minutes.(6) 1department of anesthesiology and reanimation, bursa yuksek ihtisas training and research hospital, bursa 16290, turkey. 2department of anesthesiology and reanimation, gaziemir government hospital, izmir 35410, turkey. 3department of anesthesiology and reanimation, savsat government hospital, artvin 08700, turkey. 4department of pediatric surgery, bursa yuksek ihtisas training and research hospital, bursa 16290, turkey. *correspondence: department of anesthesiology and reanimation, bursa yuksek ihtisas training and research hospital, mimar sinan street yildirim bursa 16290, turkey. tel: +90 505 7281175, e-mail: drderyatopuz@gmail.com. received february 2017& accepted october 2017 it has been reported that circumcision can be performed without anesthesia in the neonatal period or with local anesthesia in older individuals as day surgery. the widely accepted opinion suggests the use of general anesthesia or sedation, considering the psychological impact of this painful and stressful procedure on a child. the ideal anesthesia should ensure appropriate analgesia, amnesia, sedation, inactivity, and early recovery from anesthesia without cardiovascular or respiratory depression, nausea/vomiting, or agitation.(8) several anesthetic agents and their combinations have been used for those purposes. one of the most commonly preferred agents is propofol, which acts by facilitating gaba inhibitory neurotransmission. however, propofol may cause cardiovascular and respiratory depression. ketamine acts via direct sympathetic stimulation and reuptake inhibition of norepinephrine from the postganglionic sympathetic system. this agent also induces functional dissociation between the limbic and cortical systems, called “dissociative anesthesia”. due to its high therapeutic index and ability to maintain airway protective reflexes during sedation, ketamine is considered appropriate for sedoanalgesia.(8) in our literature review, we did not find any studies vol 15 no 02 march-april 2018 21 about the effects of anesthetics on surgical site hemorrhage during circumcision. as such, in this study, we aimed to compare the effects of ketamine+midazolam and propofol+sevoflurane anesthesia on surgical site hemorrhage during circumcision procedures. materials and methods study design this study was a prospective single center study. it was conducted in accordance with the principles of the declaration of helsinki. the patients’ families were interviewed in the anesthesia outpatient clinic during the preoperative period to obtain approval for their children’s participation in the study. a written informed consent was obtained from each patient’ families. the study protocol was approved by the local ethics committee and australian new zealand clinical trials registry (ref: actrn12616000189426). study population study participants were boys undergoing circumcision surgery in bursa yuksek ihtisas training and research hospital from october 2014 to january 2015. patients were enrolled in the study after a routine preoperative evaluation. inclusion criteria were boys undergoing circumcision surgery. patients who showed contraindications for general anesthesia (malignant hyperthermia history, toughness, etc.); instead of a history of allergy to anesthetic drugs or known bleeding diathesis; instead of abnormalities in coagulation tests; instead of american society of anesthesiologists (asa) physical status was iii–iv; or whose circumcision was performed with another surgeon were excluded from the study. patients’ enrollment algorithm has been illustrated in figure 1. procedures following 4–6 hours of fasting and premedication with 0.01–0.02 mg/kg iv midazolam (zolamid®, defarma, ankara, turkey), the patients were taken to the operating room. mean blood pressure (mbp), heart rate (hr), and peripheric oxygen saturation were monitored and recorded for all patients in the preoperative and intraoperative periods, as well as in the recovery room. in group 1 (n = 50), 0.01 mg/kg midazolam and 2 mg/ kg iv ketamine (ketalar®, pfizer, istanbul, turkey) were administered by an anesthesiologist, and the patients were given 2–3 l/minute o2 through an oxygen mask. a sedation score of 3 was determined according to the ramsay sedation scale. when an additional dose was needed during the operation, 0.5 mg/kg ketamine was administered. in group 2 (n = 50), 1 µg/kg fentanyl (talinat®, vem, istanbul, turkey), 1 mg/kg lidocaine 2% (jetmonal®, adeka, istanbul, turkey), and 2–3 mg/kg iv propofol (propofol 2%®, fresenius kabi, bad hamborg, germany) were administered. the patency of airway was ensured with a laryngeal mask airway (lma). anesthesia was maintained using 2–3% sevoflurane (sevorane®likit 100%, abbvie, queenborough kent, england), 1 l/minute o 2 and 1 l/minute nitrous oxide (n 2 o). surgical technique all circumcisions were performed by one surgeon, who was unaware of the groups in this study. after appropriate surgical site cleaning, a dorsal penile nerve block was performed with 2 ml 0.5% bupivacaine (bustesin®, vem, ankara, turkey) in both groups. the skin and mucosa were then separated, a circumferential incision was made on the outer prepuce at the level of the corona, and hemostasis was ensured with bipolar cautery. the wound edges were sutured with 5/0 polyglactin 910 (vicryl rapide™, ethicon). the procedure was completed with loose dressing. additional drug requirements and duration of the operations were recorded. the intraoperative bleeding scale defined by kumari et al. was used (table 1).(9) evaluations length of recovery room stay was recorded for each patient, and a faces pain scale (fps) was used for pain assessment (0:no hurt, 1:hurts little bit, 2:hurts little more, 3:hurts even more, 4:hurts whole lot, 5:hurts worst). when the modified aldrete’s score (mas) was 9–10, the patients were transferred to the ward.(10) hemorrhage and pain were followed up in the ward. hemorrhage was checked for the first three hours using the postoperative bleeding scale (table 1). when fps was ≥ 2, 10 mg/kg paracetamol suppository (paranox s®, sanofi aventis) was administered. total postoperative analgesic requirements and intraoperative and postoperative complications were recorded. surgical site hemorrhage during circumcisionkarasu et al. table 1. intraoperative and postoperative bleeding scale. intraoperative postoperative 0 no hemorrhage no hemorrhage 1 slight hemorrhage; no compression via gauze of blood required slight hemorrhage: small amount of staining at the incision line 2 slight hemorrhage; occasional compression via gauze required. surgical field not threatened moderate hemorrhage: bleeding stains the dressing 3 slight hemorrhage; frequent compression via gauze required. hemorrhage threatened surgical severe hemorrhage: bleeding continues despite of dressing field but a few seconds after compression via gauze bleeding was removed 4 moderate hemorrhage; frequent compression via gauze required. hemorrhage threatened surgical field directly after gauze compression was removed variables group 1 (n = 50) group 2 (n = 50) p-value age, year; mean ± sd (range) 5.82 ± 2.23 (1-8) 5.48 ± 2.24 (1-8) .448 weight, kg; mean ± sd (range) 20.09 ± 5.27 (9-31) 21.14 ± 7.32 (8-36) .413 asa* i / ii; n 46 /4 47 / 3 operation time, minute; mean ± sd (range) 14.12 ± 3.7 (10-25) 15.3 ± 3 (10-20) .087 *asa: american society of anesthesiologists table 2. demographic characteristics of groups. pediatric urology 22 outcomes primer outcomes: the score of intraoperative bleeding scale, and postoperative bleeding scale were evaluated. seconder outcomes: mbp, hr, and peripheric oxygen saturation were evaluated in the preoperative intraoperative periods, and in the recovery room. fps, total postoperative analgesic requirements, intraoperative and postoperative complications were also assessed. statistical analysis statistical package 21.0 for windows (spss inc., armonk, ny, usa) was used for statistical analyses. the shapiro-wilk test was used to analyze normal distribution of the data. t-test was used to compare two groups with normally distributed data and quantitative variables. the wilcoxon sign-rank test was used to compare the dependent samples. in the analysis of repeated measures, percentage changes from baseline were calculated and compared using these values. the pearson's chi-square, and fisher's exact chi-square were used to analyze categorical data. mean ± standard deviation, frequency, and percentage were used for definitive statistics of the data. if the p value was < .05, the results were considered statistically significant. based on our pilot data, sample size was calculated with a power of 0.8 and a risk of for type 1 error to detect 0.5 effect size of intraoperative bleeding score for both groups. at least 50 patients per group were required. results of 187 patients assessed for eligibility, 79 patients did not meet the inclusion criteria, five patients declined to participate in the study, and three patients (early discharge from hospital) were excluded for other reasons. of the 100 patients included, 50 were allocated to group 1 and 50 to group 2. none of the patients dropped out during the study (figure 1). there were no significant differences between the two groups with respect to age, weight, asa class, or duration of operation (p > .05, table 2). primary outcomes: intraoperative bleeding scores were significantly different between the groups (figure 2, p = .001). although hemorrhage was controlled with appropriate hemostasis, the prevalence of hemorrhage that could fill the surgical site was significantly higher in group 1 compared to group 2. however, there was no significant difference between the groups regarding postoperative bleeding scores (group 1: 0.14 ± 0.4, group 2: 0.04 ± 0.19, p = .120). secondary outcomes: figure 1. trial flow diagram. figure 2. bleeding scale of the groups. surgical site hemorrhage during circumcisionkarasu et al. vol 15 no 02 march-april 2018 23 the mbp values measured at 5th, 10th, 15th minutes and recovery room were significantly higher in group 1 (p < .05, figure 3). the hr values measured at 15th, and 20th minutes were significantly higher in group 1 (p < .05, figure 4). no statistically significant differences in spo2 levels during surgery or in the recovery room were found between groups 1 and 2 (p > .05). the additional ketamine dose requirement during circumcision was 58% in group 1. there was no significant difference in length of recovery room stay between the two groups (group 1: 14 ± 2.3 minutes and group 2: 15 ± 1.8 minutes, p > .05). when mas was considered, there was no difference in time to reach a 9–10 mas score between the groups (group 1: 13.2 ± 3.3 minutes, group 2: 14.4 ± 1.6 minutes, p > .05). there was no statistically significant difference between the groups in fps measured in the recovery room (group 1: 1.23 ± 0.32, group 2: 1.284 ± 0.30, p > .05). similarly, no significant difference was detected statistically between the groups in fps measured during the stay in the ward (group 1: 1.14 ± 0.35, group 2:1.14 ± 0.35, p > .05). six patients in group 1 and seven patients in group 2 had fps scores ≥ 2. a 10 mg/kg paracetamol suppository was administered in the postoperative period to those patients. postoperative analgesic requirement was ≤ 18% in both groups. no severe anesthesia-related or surgery-related complication developed in any of the patients during or after the operation. in group 1, we observed the following complications: decrease of spo 2 levels below 95% in 2% of patients, excessive secretion in 6% of patients, vomiting in 4% of patients, laryngospasm and cough in 2% of patients, and allergy in 2% of patients. in group 2, we observed the following complications; decrease of spo 2 levels below 95% in 2% of patients, laryngospasm in 8% of patients, cough in 4% of patients, and allergy in 6% of patients and waking up late in 6% of patients. the incidence of complications was higher in group 2, but this difference between groups was not statistically significant. discussion we investigated the effects of ketamine+midazolam and propofol+sevoflurane anesthesia on surgical site hemorrhage during circumcision procedures. our main finding from our study was that the intraoperative bleeding scores were higher in the ketamine+midafigure 4. value of heart rate (hr). figure 3. values of mean blood pressure (mbp). surgical site hemorrhage during circumcisionkarasu et al. pediatric urology 24 zolam group compared to propofol+sevoflurane group, but postoperative bleeding scores were not significantly difference between the groups. there was no difference in the length of recovery room stay between two groups. while circumcision is mostly performed as a religious ritual, it may be also performed to reduce risks of urinary tract infections, penile malignancy, and sexually transmitted illnesses. besides, circumcision does carry a risk of complications. there are several factors involved in the development of complications, such as anatomical abnormalities, additional diseases, surgical technique, and patient’s age(11) it has been reported that even in experienced hands, the rate of complications associated with circumcisions is 2–10%. while hemorrhage is the most common complication of circumcision, other problems include insufficient or excessive foreskin removal, adhesions, injury to the urethra, necrotizing fasciitis, and amputation.(12) hemorrhage is mostly related to overlooked control of hemostasis during the procedure.(11) the current study was planned as a result of observations of this procedure suggesting that hemorrhage tendency might vary depending on the method of anesthesia. in the present study, we preferred to use the intraoperative bleeding scale that kumari et al. used for day case surgeries.(9) we did not need to follow hemoglobin level, test of bleeding time to detect intraoperative and postoperative hemorrhage as we do not expect major hemorrhage during circumcisions. in our study, the intraoperative bleeding scores were significantly higher in group 1 than in group 2. in addition, the prevalence of hemorrhage that could fill the surgical site but could be controlled with appropriate hemostasis was significantly higher in group 1. there was no significant difference in postoperative hemorrhage between the groups. therefore, hemodynamic parameters were implicitly analyzed in order to identify the effects of the anesthetic agents administered to the patients. for ketamine, the peak effect starts in 2–3 minutes, the distribution half-life is 8–9 minutes, and the elimination half-life lasts for 2.2–2.9 hours.(13) this might be the reason for high blood pressure at 5 th, 10 th, and 15 th minutes, as well as the significant increase in intraoperative bleeding scores that we found in this study. direct and indirect effects of ketamine may lead to an increase in hemorrhage tendency. depending on its dose, ketamine stimulates the sympathetic system directly and causes a secondary release of norepinephrine by depressing the baroreceptor reflex activity.(13-16) that may be the reason why intraoperative hemorrhage was significantly higher in group 1. when ketamine was used in patients carrying a risk of hemorrhage, the patients were followed closely. further studies are needed to reveal the effect of ketamine on the amount of hemorrhage. in addition, there was no significant difference in hemorrhage during the postoperative period between the groups, which might be due to the transient effects of ketamine. blood pressure levels returned to normal during follow up in the ward. in our study, the blood pressure levels measured at 5, 10, and 15 minutes after operation in the intraoperative period and in recovery room were higher in group 1 compared to group 2. these differences may be due to the continuity of high blood levels of ketamine. in group 2 the propofol+sevoflurane anesthesia lead to a hypotensive condition, which might account for the low hemorrhage tendency in the intraoperative period. perioperative and postoperative effects of ketamine have previously been reported. in a retrospective study, vomiting, decreased spo 2 levels to 90%, agitation, and bronchospasm were reported as the complications of ketamine in day-case circumcision surgeries, at rates of 7.9%, 4.3%, 2%, and 1%, respectively.(17) in the present study, we administered 2 mg/kg ketamine and observed the following complications: decrease of spo2 levels below 95% in 2% of patients, laryngospasm and cough in 2% of patients, vomiting in 4% of patients, increased secretion in 6% of patients, and allergy in 2% of patients. the incidence of complications was higher in group 2, but this difference between groups was not significant. an important limitation of the present study was the subjective bleeding scale. the amount of blood loss was not measured quantitatively such as comparison to preoperative and postoperative hemoglobin levels. because the population of our study was children, we did not want to make invasive procedure. the other limitation was using a scale used in ear, nose, and throat surgery. no surgical bleeding scale used for circumcision was identified by our screening. in addition, a ketamine+propofol or ketamine+dexmedetomidine combination could have been used instead of ketamine+midazolam to minimize the increasing effect of ketamine on blood pressure. conclusions although propofol+sevoflurane is accompanied by less intraoperative blood loss compare to ketamine+midazolam during circumcision, this type of hemorrhage can be controlled easily with appropriate hemostasis and the amount of blood loss was not clinically significant. ketamine + midazolam anesthesia have some superiority to propofol+sevoflurane as a continuation of spontaneous breathing, not using the other airway tools (lma, endotracheal tube) and no prolongation in the length of recovery room stay. the results of this study demonstrate that ketamine + midazolam anesthesia can be a good alternative for circumcision. we think that our study makes a positive contribution to the literature about the effects of anesthetics on the surgical site bleeding during circumcision. conflict of interest the authors report no conflict of interest. references 1. loban ah, ibrahim me, alauddin j, ferdous kmn. circumcision with intravenous (iv) ketamine, thiopentone and penile block: a safe and cost-effective anesthetic technique. hosp med coll. 2013;12:34-7. 2. bhat na, hamid r, rashid ka. bloodless, sutureless circumcision. afr j paediatr surg. 2013;10:252-4. 3. al-shamsi mm, al-zamili ah. the frequency of circumcision in infants and children in diwaniah. karbala j med. 2008;2:323-30. 4. moses s, bailey rc, ronald ar. male circumcision: assessment of health benefits surgical site hemorrhage during circumcisionkarasu et al. vol 15 no 02 march-april 2018 25 and risks .sex transm infec 1998;74:368-73. 5. introcaso ce, xu f, kilmarx ph, zaidi a, markowitz le. prevalence of circumcision among men and boys aged 14 to 59 years in the united states, national health and nutrition examination surveys 2005-2010. sex transm dis. 2013;40:521-5. 6. shen j, shi j, gao j, et al. a comparative study on the clinical efficacy of two different disposable circumcision suture devices in adult males. urol j. 2017;14:5013-7. 7. balkan e, kilic n. circumcision and complications. j current pediatrics. 2005;2:223. 8. gulec h, sahin s, ozayar e, degerli s, bercin f, ozdemir o. ketamine-propofol sedation in circumcision. rev bras anestesiol. 2015;65:367-70. 9. kumari i, naithni u, bedi v, gupta s, gupta r, bhuie da. comparison of clonidine versus midazolam in monitored anesthesia care during ent surgery– a prospective, double blind, randomized clinical study. anaesth pain&intensive care. 2012;16:157-64. 10. white pf, song d. new criteria for fasttracking after outpatient anesthesia: a comparison with the modified aldrete's scoring system. anesth analg. 1999;88:106972. 11. krill aj, palmer ls, palmer js. complications of circumcision. the scientific world journal. 2011;11:2458-68. 12. ozkan a, ozorak a, oruc m. retrospective investigation complications in nineteen hundred cases of circumcision. konuralp medical j. 2012;4:8-12. 13. sawynok j. topical and peripheral ketamine as an analgesic. anesth analg. 2014;119:1708. 14. lin c, durieux me. ketamine and kids: an update. paediatr anaesth. 2005;15:91-7. 15. beyaz sg. preemptive analgesic effect of ketamine in children with lower abdominal surgery. balkan med j. 2011;28:179-83. 16. ozdamar d, hosten t, gurkan y, toker k, solak m. magnetic resonance imaging of propofol and ketamine sedation in children. turk j anaesth reanim. 2010;38:91-100. 17. ozkan a, okur m, kaya m, et al. sedoanalgesia in pediatric daily surgery. int j clin exp med. 2013;6:576-82. surgical site hemorrhage during circumcisionkarasu et al. pediatric urology 26 editorial comment an updated iranian model in kidney transplantation: rewarded gifting a practical solution to kidney shortage crisis ghahramani has presented a biased aspect of iranian model in kidney transplantation(1). he ignores the advantages and the recent upgrade of this model that has been appreciated by others around the world(2,3). kidney shortage is a global problem and is growing alarmingly(2). countries with the most sophisticated and expensive health care systems, including those with full support of the deceased program have not been able to eliminate living transplantation. the waiting list consists of more than 100000 recipients in the u.s. and 4000 recipients have died each year while on the list. advocates of “only deceased and related transplantations” ignore the lives of recipients who die while on the waiting list(2,3). the iranian model and first living unrelated transplantation program started at shahid labbafinejad hospital (from spouse and other unrelated donors). all transplant cases are registered at the cts registry in heidelberg (simforoosh et.al.)(4). successful results in other centers have been achieved due to using the iranian model. there is no doubt that iran, with using living related and unrelated kidney transplantation, has the shortest waiting list in the world due to the use of all potential sources for kidney transplantation(2,3). the exception is the program in shiraz, iran, which has the longest waiting list in iran, approximately two years. many recipients from the shiraz province have had transplantations in shahid labbafinejad hospital center as well as other centers; because they could no longer wait for a deceased donor in shiraz. in contrast to the conclusion made by ghahramani(1), our experience reveals that having regulated paid living donation does not inhibit deceased donor program growth. last year, with a total of 4500 kidney transplantations in our center we transplanted 123 cadaver transplants with 122 living unrelated transplantations which were all done by laparoscopic donor nephrectomy with excellent results in both groups. patients in our list receive transplantations in just a few months, and for many recipients, especially children, pre-emptive kidney transplantation is performed without performing dialysis(5). in brief the “upgraded iranian model of kidney transplantation” includes the following characteristics: -transplantation for citizens of other countries is strictly illegal except for countries with no transplant program like afghanistan, which needs written permission from the ministry of health (moh). -cadaver transplantations are the first priority. -living kidney transplantations, related or unrelated, is also performed to further decrease the time on the waiting list. -kidney transplantations are only done at the university and governmental hospitals. private hospitals are banned by law to undertake kidney transplantations in iran. -donors are paid by the government and recipients under control of the moh and the dialysis and transplant patient association (datpa) encourage donation program. hospitals and medical teams are not allowed to have any financial intervention in donations. the ministry of health and education and the datpa control the system. we recommend other countries to consider the above model to save the lives of thousands of recipients currently on the waiting list. references 1. ghahramani n. paid living donation and growth of deceased donor programs. transplantation. 2016 ; 100: 1165-9 2. bastani b. the worsening transplant organ shortage in usa; desperate timesdemand innovative solutions.j nephropathol. 2015; 4: 105-9. 3. rosenbergt. need a kidney? not iranian? you'll wait. the new york times. 2015http://opinionator.blogs. nytimes.com/2015/07/31/need-a-kidney-not-iranian-youll-wait. 4. simforoosh n, basiri a, fattahi mr, einollahi b, firouzan a, pour-reza-gholif, nafar m, farrokhi f. living unrelated versus living related kidney transplantation: 20 years' experience with 2155 cases. transplant proc. 2006; 38: 422-5. 5. pour-reza-gholi f, nafar m, simforoosh n, einollahi b, basiri a, firouzan a, alipourabedi b, farhangi s. is preemptive kidney transplantation preferred? updated study. urol j. 2007; 4: 155-8 nasser simforoosh, m.d professor of urology and kidney transplantation e mail: simforoosh@iurtc.org.ir. www.iurtc.org.ir. editorial comment 2803 pediatric urology further evidence of the association of the diacylglycerol kinase kappa (dgkk) gene with hypospadias kamil k. hozyasz,1* adrianna mostowska,2 andrzej kowal,3 dariusz mydlak,3 alexander tsibulski2, paweł p. jagodziński2 purpose: hypospadias is a common developmental anomaly of the male external genitalia. in previous studies conducted on west european, californian, and han chinese populations the relationship between polymorphic variants of the diacylglycerol kinase kappa (dgkk) gene and hypospadias have been reported. the aim was to study the possible associations between polymorphic variants of the dgkk gene and hypospadias using an independent sample of the polish population. materials and methods: ten single nucleotide polymorphisms in dgkk, which were reported to have an impact on the risk of hypospadias in other populations, were genotyped using high-resolution melting curve analysis in a group of 166 boys with isolated anterior (66%) and middle (34%) forms of hypospadias and 285 properly matched controls without congenital anomalies. results: two dgkk variants rs11091748 and rs12171755 were associated with increased risk of hypospadias in the polish population. these results were statistically significant, even after applying the bonferroni correction for multiple comparisons (p < .005). all the tested nucleotide variants were involved in haplotype combinations associated with hypospadias. the global p-values for haplotypes comprising of rs4143304-rs11091748, rs11091748rs17328236, rs1934179-rs4554617, rs1934183-rs1934179-rs4554617 and rs12171755-rs1934183-rs1934179rs4554617 were statistically significant, even after the permutation test correction. conclusion: our study provides strong evidence of an association between dgkk nucleotide variants, haplotypes and hypospadias susceptibility. keywords: dgkk; diacylglycerol kinase kappa; haplotypes; hypospadias; polymorphism. introduction in hypospadias, the external urethral opening is po-sitioned abnormally between the glans and the perineum, thus allowing the classification of hypospadias as anterior (distal), middle (midshaft) and posterior (proximal). anterior hypospadias is described as glandular (the meatus on the ventral surface of glans penis), coronal, or subcoronal. in middle hypospadias the urethra opens into ventral surface of penis. in posterior hypospadias the urethral opening is located in the penoscrotal junction, scrotum, or perineum(1). the majority of cases are isolated, i.e. individuals are not affected by other congenital anomalies. hypospadias is the second most common human birth defect with an incidence of 1 in 250 live male births and its pathogenesis is complex, multifactorial, and determined by genetic, endocrine, and environmental causes(1-5). previous studies demonstrated familial reoccurrence for the anterior and middle forms of those malformations but not for posterior types, displaying the importance of genetic predisposition for hypospadias(5). many linkage analyses, aiming to elucidate the molecular genetic basis of hypospadias were performed in the past, but they have met with only limited success. in part, this limited suc1department of paediatrics, institute of mother and child, warsaw, poland. 2department of biochemistry and molecular biology, poznan university of medical sciences, poznan, poland. 3department of paediatric surgery, institute of mother and child, warsaw, poland. *correspondence: department of paediatrics institute of mother and child, 17a kasprzaka str. 01-211 warsaw, poland. tel. +48223277190. fax +48223277043. e-mail: khozyasz@verco.com.pl; kamil.hozyasz@imid.med.pl. received july 2017 & accepted november 2017 cess can be attributed to the complexity of the disease, as well as to the selection of not homogenous populations for investigations(4). recently, two genome-wide association studies based on dna samples from west european cases(5,6), as well as two case-control studies conducted in the california population composed primarily of hispanic and caucasian individuals(7) and in the han chinese population(8), showed that common polymorphic variants of the dgkk gene can increase the risk of hypospadias. the dgkk gene (omim *300837) located on chromosome xp11.22 encodes the diacylglycerol kinase kappa. this enzyme is involved in the down-regulation of diacylglycerol signalling since it phosphorylates diacylglycerol, converting it to phosphatidic acid(9). determination of the exact associations between polymorphic variants of candidate genes and hypospadias risk might provide very important insight into the cause of hypospadias(4,10-12). expression of dgkk in preputial tissue is lower in boys with the hypospadias risk allele of rs1934179(5). recently, shen et al.(13) reported that the enzyme dgkk appears to be a mediator during development of mouse external genitalia. the global burden incurred from hypospadias in terms of physical morbidity, health care expenses, emotional pediatric urology 272 vol 15 no 05 september-october 2018 273 distress, and social dysfunction is significant for affected individuals, their families, and the health care system overall(2,11,14). hypospadiology remains a constantly evolving discipline with plenty of discrepancies among epidemiologic studies(1,11). identifying the underlying aetiology of this condition is crucial for improving prevention strategies and genetic risk counselling. the primary aim of our case-control study was to investigate the contribution of previously reported cases of polymorphic variants of the candidate dgkk gene to the incidence of hypospadias in a homogenous polish population. this study is the first to represent patients with hypospadias of east european origin as part of a replicate sample to the previously described studies. the secondary aim was to test the association between common dgkk haplotypes and hypospadias susceptibility using different risk models. methods patients and controls considering apparent etiologic heterogeneity of hypospadias, only isolated anterior and middle cases were included in the current case-control study(5). a total of 166 unrelated boys (13 months to 10 years old) presenting with non-syndromic hypospadias and 285 unrelated healthy boys (13 months to 10 years old) with no family history of hypospadias or other structural anomalies were recruited from the institute of mother and child in warsaw. the control group was matched by age and place of birth. case eligibility to the study was ascertained using the detailed medical records of each patient. the non-syndromic designation was based on diagnosis of isolated hypospadias with no other apparent cognitive and structural anomalies. of the 166 boys ultimately enrolled, there were 110 (66%) anterior and 66 (34%) middle forms of hypospadias. the ancestry contributions were estimated to be 100% of caucasian, polish descent in both the hypospadias cases and the control group. samples were obtained between january 2013 and june 2015. dna was isolated from peripheral blood lymphocytes using the salting-out extraction procedure. the study was approved by the local ethics committee. written and oral consent was obtained from the legal guardians of all the participants. single nucleotide polymorphism selection and genotyping single nucleotide polymorphisms (snps) are defined as loci with alleles that differ at a single base, with the rarer allele having a frequency of at least 1% in a random set of individuals in a population(15,16). ten snps in dgkk gene, previously detected to be associated with hypospadias(5-8), were evaluated in this study (table 1). table 1. characteristics of polymorphisms genotyped in the dgkk gene. gene rs no. locationa allelesb snp functionc protein effect mafd dgkk rs4074320 chrx:50119085 a / g (rev) missense p.asp1118asn 0.29 rs4143304 chrx:50146570 c / t (fwd) cds-synon p.leu368leu 0.39 rs11091748 chrx:50157984 a / g (fwd) intron 0.39 rs17328236 chrx:50168209 a / g (fwd) intron 0.28 rs12171755 chrx:50179749 c / t (fwd) intron 0.35 rs1934183 chrx:50181014 g / t (rev) intron 0.39 rs1934179 chrx:50182184 c / t (rev) intron 0.36 rs4554617 chrx:50203402 a / c (fwd) intron 0.37 rs4826634 chrx:50208239 g / t (fwd) intron 0.37 rs7063116 chrx:50235002 a / g (fwd) n/a (upstream) 0.37 ancbi build 37 / hg19. bunderline denotes the minor allele (based on whole sample). caccording to the single nucleotide polymorphism database (dbsnp) dmaf, minor allele frequency calculated from the control samples abbreviations: fwd, forward; rev, reverse strand. gene rs no. alleles2 primers for pcr amplification (5’ – 3’) annealing temp. (°c) pcr product length (bp) melt. temp. range (°c) dgkk1 rs4074320 a / g f: gggaatacaggaagctgcac 55 128 80 95 r: acctgagcaagatccaccag rs4143304 c / t f: tgcagtctttgcttgctctc 55 96 78 93 r: tcaccagattcacacccatc rs11091748 a / g f: accctacaggactggaccatag 58 147 80 95 r: gagacagccttgtcacctagaac rs17328236 a / g f: tcaccacatcaaggctctacc 55 62 70 85 r: gccacccaatggtgaatg rs12171755 c / t f: ggggtaggccaggtaagtaatg 58 122 75 90 r: ggaagtcagaaggccagaaca rs1934183 g / t f: ctgggaagaggcagtagtgg 61 135 80 95 r: gttcttctcccccacagga rs1934179 c / t f: catttttctatcaattggctcct 55 136 75 90 r: tccaaatctacactcctttttgc rs4554617 a / c f: ttcattcccctctactcttgga 61 149 80 95 r: ccctcaagcacgtgtaggat rs4826634 g / t f: ccatgggctttgatgagg 58 111 74 89 r: ggacagtgaccccagataatg rs7063116 a / g f: tggaccttggttgttgatg 55 169 71 86 r: cacagttgaaatctgttttaggaac 1genomic dna for molecular analyses was isolated from peripheral blood lymphocytes by a standard salt-out extraction procedure. 2underline denotes the minor allele (based on whole sample). table 2. high-resolution melting curve analysis (hrm) conditions for the identification of polymorphisms genotyped in the data set . association of the dgkk gene with hypospadias–hozyasz et al. the genotyping was carried out by high-resolution melting curve analysis (hrm) on the lightcycler 480 system (table 2). for quality control, approximately 10% of randomly selected samples were re-genotyped. samples that failed genotyping were not repeated and were removed from statistical calculations. statistical methods for each snp, the hardy-weinberg (hw) equilibrium was evaluated in both patients and controls using chi-square (χ2) test. statistically significant deviation from hw expectations was interpreted as p-value < .05. the differences in allele frequencies between cases and controls were determined using standard χ2 test. the strength of association was estimated by odds ratio (or) and corresponding 95% confidence intervals (95% cis). the bonferroni correction was applied to account for multiple comparisons, and p-values < .005 (.05 / 10 snps) were interpreted as statistically significant. the haplotype-based association analysis was performed using plink v1.07 (http://pngu.mgh.harvard. edu/~purcell/plink/). the omnibus haplotype test (jointly estimating all haplotype effects at a given location) for sliding windows of 2 to 4 snps across the gene was conducted using logistic regression. significant p-values were corrected using the 1,000-fold permutation test. the detailed haplotype analysis was conducted for snp combinations with statistically significant omnibus test p-values. haplotype-specific odds ratios (ors) were calculated and the most common haplotypes were used as the reference. only haplotypes with frequencies ≥ 0.01 in either cases or controls were tested. results first, we analyzed the dgkk snps independently. none of the tested snps showed evidence of deviation from hardy-weinberg equilibrium in neither the cases nor the controls. after correction for multiple testing, statistically significant results of increased risk for hypospadias were observed only for carriers of the dgkk rs11091748 and rs12171755 variants (table 3). the or for individuals with the rs11091748 g allele compared to a allele carriers was 1.87 (95% ci = 1.27 2.76, p = .0015). six other snps showed a trend toward association with hypospadias. the dgkk nucleotide variants demonstrated moderate linkage disequilibrium (ld). d’ and r2 values, calculated from the genotype data of the control samples, ranged from 0.607 to 1.000 and 0.131 to 0.984, respectively (figure 1 and table 4). subsequently, we tested the common dgkk haplotypes for their association with the risk of hypospadias. the global p-values for the two two-markers haplotypes (rs11091748_rs17328236, rs1934179_rs4554617), the one three-markers haplotype (rs1934183_rs1934179_ rs4554617), and the one four-markers haplotype (rs12171755_rs1934183_rs1934179_rs4554617) were statistically significant even after permutation correction. detailed analysis of those haplotypes is presented in table 5. all tested snps were involved in haplotype combinations associated with hypospadias. however, the haplotype combination (rs1934179_rs4554617) with the best global p-value (pcorr = .007, table 5) does not include the two snps (rs11091748 and rs12171755) highly linked with hypospadias in the single markers analysis (table 3). table 3. association of dgkk gene snps with the risk of hypospadias. rs no. allelesa allele counts in casesb maf in cases allele counts in controlsb maf in controls or (95% ci)c p value rs4074320 a / g 63 / 103 0.38 (a) 82 / 196 0.29 (a) 1.46 (0.97 2.19) .0660 rs4143304 c / t 85 / 79 0.48 (c) 108 / 171 0.39 (t) 1.70 (1.15 2.52) .0072 rs11091748 a / g 89 / 76 0.46 (a) 109 / 174 0.39 (g) 1.87 (1.27 2.76) .0015 rs17328236 a / g 63 / 99 0.39 (g) 78 / 201 0.28 (g) 1.64 (1.09 2.47) .0176 rs12171755 c / t 79 / 82 0.49 (t) 98 / 182 0.35 (t) 1.79 (1.21 2.66) .0037 rs1934183 g / t 86 / 78 0.48 (t) 112 / 173 0.39 (g) 1.70 (1.15 2.51) .0069 rs1934179 c / t 79 / 86 0.48 (t) 102 / 178 0.36 (t) 1.60 (1.08 2.37) .0175 rs4554617 a / c 77 / 81 0.49 (c) 103 / 176 0.37 (c) 1.63 (1.10 2.43) .0147 rs4826634 g / t 50 / 115 0.30 (t) 106 / 178 0.37 (t) 0.73 (0.48 1.10) .1320 rs7063116 a / g 73 / 91 0.45 (a) 105 / 180 0.37 (a) 1.37 (0.93 2.03) .1096 statistically significant results (p-value < 0.005) are highlighted in bold font. aunderline denotes the risk allele. bthe order of alleles d / d (d is the minor allele in the control samples). callelic model: d vs d (d is the risk allele). abbreviations: maf, minor allele frequency; or, odds ratio; ci, confidence interval. d' above diagonal r2 below diagonal rs4074320 rs4143304 rs11091748 rs17328236 rs12171755 rs1934183 rs1934179 rs4554617 rs4826634 rs7063116 rs4074320 0.861 0.849 0.963 0.757 0.766 0.752 0.750 0.746 0.607 rs4143304 0.489 1.000 1.000 0.983 0.889 0.984 0.952 0.891 0.763 rs11091748 0.469 0.984 1.000 0.982 0.869 0.983 0.948 0.917 0.757 rs17328236 0.850 0.604 0.594 0.882 0.889 0.879 0.878 0.962 0.730 rs12171755 0.448 0.816 0.792 0.558 0.982 1.000 0.984 0.909 0.818 rs1934183 0.372 0.777 0.756 0.468 0.796 0.983 0.966 0.892 0.758 rs1934179 0.415 0.870 0.848 0.521 0.940 0.851 0.984 0.913 0.774 rs4554617 0.406 0.827 0.802 0.512 0.896 0.835 0.954 0.942 0.805 rs4826634 0.131 0.283 0.300 0.203 0.247 0.295 0.266 0.291 0.740 rs7063116 0.276 0.513 0.503 0.366 0.638 0.498 0.590 0.627 0.178 table 4. linkage disequilibrium between markers of the dgkk gene in the control samples. association of the dgkk gene with hypospadias–hozyasz et al. pediatric urology 274 vol 15 no 05 september-october 2018 275 discussion identifying the major genetic alternations leading to hypospadias will have an impact on genetic counselling and will lead to a greater understanding of the male urinary tract development. our study builds on previous publications which have reported that the genetic susceptibility of hypospadias may be associated with common variants of the dgkk gene(5-8). in our mono-ethnic sample, the dgkk haplotypes were found to be strongly associated with hypospadias and provided further evidence that dgkk may be an important disease-promoting gene(10,11,15,16). the high odds ratios and level of significance provide compelling support for the observed haplotypes associations, despite the small numbers of participants. for the two investigated snps (rs4826634 and rs7063116), in the presented polish sample of patients, evidence of association with hypospadias was found only using haplotypes testing. the lack of association in the single marker analysis may be attributed to a lack of power, secondary to small sample size. an alternative explanation might be that the analyzed variants do not target the causal variant in the polish population adequately, due to the presence of differing haplotypic structures in specific mono-ethnic populations(4,10,15). in accordance with our study, carmichael et al.(7) have previously found evidence of association between two blocks of dgkk haplotypes and the hypospadias risk in californian population. in their study, an 8-snps block contained rs12171755, rs19341179 and rs19341179, which were also associated with increased risk of being born with hypospadias in the polish population. in contrast to our results, ma et al.(8) did not observe the association between dgkk haplotypes and hypospadias susceptibility in the han chinese population. however, a very recent study by xie et al.(17) from china, similarly to our results, showed strong association of haplotypes including rs4554617 with the susceptibility to hypospadias. these findings support the assumption that the functional variants associated with these risky snps of dgkk are likely to be regulatory in nature. more in-depth investigations are necessary to explore the functional and mechanistic table 5. haplotype analysis of snps genotyped in the dgkk gene. omnibus haplotype test frequency polymorphisms p-value corrected p-valuea haplotype cases controls odds ratiob p-valuec 2-marker window rs4074320_rs4143304 .0561 .2777 rs4143304_rs11091748 .0017 .0150 c-a 0.466 0.620 referent t-g 0.522 0.376 1.84 (1.39 2.44) < 0.0001 c-g 0.012 0.004 4.29 (0.78 23.68) .0883d rs11091748_rs17328236 .0084 .0440 a-a 0.466 0.616 referent g-g 0.391 0.270 1.92 (1.41 2.61) < 0.0001 g-a 0.143 0.114 1.66 (1.08 2.55) .0208 rs17328236_rs12171755 .0134 .0719 rs12171755_rs1934183 .0210 .1089 rs1934183_rs1934179 .0142 .0749 rs1934179_rs4554617 .0004 .0070 c-a 0.459 0.627 referent t-c 0.446 0.362 1.68 (1.26 2.25) .0004 c-c 0.044 0.007 8.507 (2.75 26.29) < 0.0001d t-a 0.051 0.004 19.444 (4.41 85.68) < 0.0001d rs4554617_rs4826634 .0502 .2418 rs4826634_rs7063116 .0568 .2867 3-marker window rs4074320_rs4143304_rs11091748 .0241 .1149 rs4143304_rs11091748_rs17328236 .0104 .0559 rs11091748_rs17328236_rs12171755 .0130 .0709 rs17328236_rs12171755_rs1934183 .0201 .1019 rs12171755_rs1934183_rs1934179 .0290 .1469 rs1934183_rs1934179_rs4554617 .0023 .0180 t-c-a 0.442 0.591 referent g-t-c 0.430 0.364 1.58 (1.17 2.13) .0026 g-c-a 0.019 0.030 0.85 (0.32 2.21) .7357 g-t-a 0.051 0.004 18.09 (4.10 79.77) < 0.0001d g-c-c 0.039 0.004 13.56 (2.99 61.45) < 0.0001d t-t-c 0.013 0.004 4.52 (0.82 0 24.99) .0785d rs1934179_rs4554617_rs4826634 .0397 .1928 rs4554617_rs4826634_rs7063116 .1930 .7243 4-marker window rs4074320_rs4143304_rs11091748_rs17328236 .0394 .1928 rs4143304_rs11091748_rs17328236_rs12171755 .0187 .0959 rs11091748_rs17328236_rs12171755_rs1934183 .0741 .3526 rs17328236_rs12171755_rs1934183_rs1934179 .0377 .1808 rs12171755_rs1934183_rs1934179_rs4554617 .0076 .0430 c-t-c-a 0.438 0.591 referent t-g-t-c 0.431 0.349 1.67 (1.23 2.26) .0008 c-g-c-a 0.020 0.030 0.87 (0.33 2.28) .7816 c-g-t-c 0.007 0.015 0.58 (0.12 2.78) .7302d t-g-t-a 0.046 0.004 16.30 (3.65 72.73) < 0.0001d c-g-c-c 0.013 0.004 4.66 (0.84 25.74) .0734d t-t-t-c 0.013 0.004 4.66 (0.84 25.74) .0734d t-g-c-c 0.020 0.000 20.91 (1.12 391.39) .0086d rs1934183_rs1934179_rs4554617_rs4826634 .0985 .4555 rs1934179_rs4554617_rs4826634_rs7063116 .0509 .2428 detailed haplotype analysis was presented only for snp combinations with statistically significant omnibus test p-values. ap-value calculated using permutation test and a total of 1,000 permutations. bthe most common haplotype was used as the reference. cchi-square test. dfisher exact test. association of the dgkk gene with hypospadias–hozyasz et al. role of dgkk in the male urinary system. rigorously establishing the genetic risk for any multifactorial disorder is important but inherently difficult(4,10). conclusions our study represents a step forward in understanding the genetic basis of isolated hypospadias. the study provides strong evidence of an association of dgkk haplotypes with the susceptibility to hypospadias. further testing in independent populations and meta-analyses are needed to clarify the role of nominally significant polymorphic variants of the dgkk gene association with hypospadias. acknowledgments we want to thank numerous families for their generous participation in our study that made this research possible. this work was supported by grant no. 510-06-53 from institute of mother and child, warsaw, poland. conflict of interest the authors state that there are no conflicts of interest regarding the publication of this article. references 1. george m, schneuer fj, jamieson se, holland aj. genetic and environmental factors in the aetiology of hypospadias. pediatr surg int. 2015; 31: 519-27. 2. gite va, nikose jv, bote sm, patil sr. anterior urethral advancement as a singlestage technique for repair of anterior hypospadias: our experience. urol j. 2017;14: 4034-37. 3. kalfa n, paris f, philibert p, et al. is hypospadias associated with prenatal exposure to endocrine disruptors? a french collaborative controlled study of a cohort of 300 consecutive children without genetic defect. eur urol. 2015; 68:1023-30. 4. choudhry s, baskin ls, lammer ej, et al. genetic polymorphisms in esr1 and esr2 genes and risk of hypospadias in a multiethnic study population. j urol. 2015;193:1625-31. 5. van der zanden lf, van rooij ia, feitz wf, et al. common variants in dgkk are strongly associated with risk of hypospadias. nat genet. 2011;43: 48-50. 6. geller f, feenstra b, carstensen l, et al. genome-wide association analyses identify variants in developmental genes associated with hypospadias. nat genet. 2014;46:95763. 7. carmichael sl, mohammed n, ma c, et al. diacylglycerol kinase k variants impact hypospadias in a california study population. j urol. 2013;189: 305-11. 8. ma q, tang y, lin h, et al. diacylglycerol kinase k (dgkk) variants and hypospadias in han chineses: association and meta-analysis. bju int. 2015;116: 634-640. 9. shionoya t, usuki t, komenoi s, isozaki t, sakai h, sakane f. distinct expression and localization of the type ii diacylglycerol kinase isozymes δ, η and κ in the mouse reproductive organs. bmc dev biol. 2015;15: 6. 10. wu c, li s, cui y. genetic association studies: an information content perspective. curr genom. 2012;13: 566-73. 11. palmsten k, chambers cd. hypospadias: one defect, multiple causes, acting through shared pathways. curr epidemiol rep. 2015; 2: 1322. 12. polat h, gulacti u. the ideal use of catheters in hypospadias repair: an experimental study. urol j. 2016; 13: 2856-9. 13. shen j, liu b, sinclair a, cunha g, baskin ls, choudhry s. expression analysis of dgkk during external genitalia formation. j urol. 2015; 194:1728-36. 14. snodgrass wt, bush nc. hypospadias. in: snodgrass wt, editor. pediatric urology. evidence for optimal patient management. new york: springer; 2013. p.117-52. 15. liu n, zhang k, zhao h. haplotypeassociation analysis. adv genet. 2008; 60: 335-405. 16. clark ag. the role of haplotypes in candidate gene studies. genet epidemiol. 2004; 27: 32133. 17. xie h, lin x-l, zhang s, et al. asssociation between diacylglycerol kinase kappa variants and hypospadias susceptibility in a han chinese population. asian j androl. 2017; doi: 10.4103/aja.aja_13_17. association of the dgkk gene with hypospadias–hozyasz et al. pediatric urology 276 case report end to end urethroplasty after urethral uventa stent stricture: the first case report jalil hosseini1, ali tayebi-azar2,3, amir hossein rahavian2, saleh ghiasy2,4* nowadays there is not any specific technique for repairing the recurrent urethral stricture with retained urethral stent. we report a 49 year-old man with history of end to end urethroplasty 11 years ago who was referred with urethral stricture. he refused to undergo urethroplasty again, so the stricture was managed by uventa stent insertion which failed after six months. finally the patient underwent end to end urethroplasty with complete excision of the obstructed urethra, stent and surrounding periurethral fibrosis. end to end urethroplasty post uventa stent stricture is an available option with good postoperative outcomes. keywords: urethroplasty; strictures; uventa stent; spongiofibrosis introduction in 1988, milroy et al introduced the urethral stents and their usage in treatment of urethral strictures(1). first of all urolume stent placement was popular among urologists in the 1990’s as a minimally invasive therapy for short bulbar strictures with promising early results in the absence of extensive periurethral fibrosis(2). but long-term follow up revealed a high failure rate(2). after introduction of urolume stent, so many different urethral stents like wallstent(3), self-expandable, self-reinforced poly-l-lactic acid urethral stent(4) were introduced with controversial results. the most important complications of these stents are restenosis, recurrent genitourinary infections, stone encrustation, pain, and sexual complaints(5). finally taewoong medical instrument company in south korea described uventa urethral stent in 2016 (figure 1). nowadays there is not a definite management for recurrent urethral stricture with retained urethral stent. different techniques has been described up to the surgery circumstances and surgeons’ preference (6). this report describes the surgical challenges for management of a patient with a history of end to end urethroplasty followed by stent placement that was complicated with stricture and in-growing tissue, which was successfully re-operated. case presentation a 49 year-old man, known case of urethral stricture due to straddle injury during cycling at the age of 15, underwent end to end urethroplasty 11 years ago. this data was gained throughout patient's history and medical reports. one year after operation, anastomotic site stricture was diagnosed, so he underwent direct vision urethrotomy once and cystoscopy-dilatation for six times. two years ago, regarding to recurrence of stricture, the patient was suggested to undergo urethroplasty again, but he did not accept; so uventa urethral stent was inserted. six months after stent insertion, the patient was candidate for stent extraction which failed after two attempts. trochar cys1reconstructive urology department, shohada e tajrish hospital, shahid beheshti medical science university, iran. 2infertility and reproductive health research center (irhrc), shahidbeheshti medical scienceuniversity, iran. 3nephrology and kidney transplant research center, urmia university of medical sciences, urmia , iran 4department of urology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: infertility and reproductive health research center (irhrc), shahid beheshti medical science university, iran. telfax +98 2122712234, mob +98 9128198037. email;saleh.ghiasy@sbmu.ac.ir. received october 2018 & accepted may 2019 figure 1. uventa™ urethral stent (taewoong medical instrument company, south korea) urology journal/vol 17 no. 4/ july-august 2020/ pp. 429-431. [doi: 10.22037/uj.v0i0.4914 ] tostomy was performed. a complete workup including flexible cystoscopy and rug-vcug (figure 2a) was done. . finally he underwent end to end urethroplasty and excision of stent. complete excision of the obstructed urethra containing the stent (figure 2b) with the surrounding periurethral fibrosis was done followed by one-stage end to end urethroplasty (figure 2c). we took a written consent from patient to report his images and information for promotion of knowledge. discussion in literature, delayed surgery with primary anastomosis is introduced as the best option with high success rate for treatment of post urethroplasty urethral strictures, however the patient did not accept to undergo urethroplasty before stenting. hussain et al. reported that the prevalence of stent related complications is 55%. the most common complications were re-stenosis and post-void dribbling (32%) and recurrent urinary tract infection (27%); whereas perineal pain and dysuria were other complications. in total, 45% of their patients had more than one complication, and 45% of them required operative intervention. open stent extraction was required in 8.3%(2). previous case series revealed that 33% of patients whom underwent post stent extraction urethroplasty had acceptable outcomes in the short-term follow-up(7). commonly buccal mucosal graft urethroplasty is used for patients with urethral stenosis without obstruction while in our patient, the urethral lumen was blind and because of the length of stricture. we could not perform augmented urethroplasty. the decision about how to perform stent retrieval is difficult and the management of these patients is different and depends on some factors such as the severity of fibrosis, the length of stricture and the patient concrete topography(6,8).with respect to which is the most optimal technique to extract the retained stent at the time of a definitive reconstruction, en-block urethral excision was better than urethral preservation and removal(6). conclusions to our knowledge we report the first end to end urethroplasty post uventa stent stricture by complete excision of the obstructed urethra containing the stent and surrounding periurethral fibrosis. commonly buccal mucosal graft urethroplasty is used for patients with urethral stenosis without obstruction while in our patient, the urethral lumen was blind and because of the length of stricture, we could not perform augmented urethroplasty. our final decision regarding to patient's consent was end to end urethroplasty. our experience confirms that a single stage urethroplasty after stricture recurrence in these patients is an available option with significantly improved postoperative clinical and patient-reported outcomes, as well as acceptable success rates. acknowledgements we appreciate reconstructive urology department of shohada e tajrish hospital staff and vahid shahabi who helped using data collection. references 1. milroy e, cooper j, wallsten h, et al. a new treatment for urethral strictures. the lancet. 1988;331:1424-7. 2. hussain m, greenwell tj, shah j, mundy a. long‐term results of a self‐expanding wallstent in the treatment of urethral stricture. bju int. 2004;94:1037-9. 3. baert l, verhamme l, van poppel h, vandeursen h, baert j. long-term consequences of urethral stents. j urol. 1993;150:853-5. 4. isotalo t, tammela tl, talja m, valimaa t, tormala p. a bioabsorbable self-expandable, self-reinforced poly-l-lactic acid urethral stent for recurrent urethral strictures: a preliminary report. j urol. 1998;160:2033-6. 5. palminteri e, gacci m, berdondini e, poluzzi m, franco g, gentile v. management of urethral stent failure for recurrent anterior urethral strictures. eur urol. 2010;57:615-21. 6. angulo jc, kulkarni s, pankaj j, et al. urethroplasty after urethral urolume stent: an international multicenter experience. urology. 2018. 7. fisher mb, santucci ra. extraction of urolume endoprosthesis with one-stage urethral reconstruction using buccal mucosa. urethroplasty after uventa stent-hosseini et al. case report 430 figure 2. a) urethral stricture at the site of stent in rug (white arrow), b) stenthyperplasic overgrowth (white arrow), c) end to end urethroplasty. vol 17 no 04 july-august 2020 431 urology. 2006;67:423. e9-. e10. 8. gobbi d, leon ff, gnech m, et al. management of congenital urethral strictures in infants. case series. urol j. 2019. urethroplasty after uventa stent-hosseini et al. laparoscopic urology 176 urology journal vol 6 no 3 summer 2009 transperitoneal laparoscopic partial nephrectomy using a new technique akbar nouralizadeh, seyed amirmohsen ziaee, abbas basiri, nasser simforoosh, hamidreza abdi, nastaran mahmoudnejad, amir h kashi introduction: we report our experience with a new technique for transperitoneal laparoscopic partial nephrectomy with the kidney turned upside down intraoperatively. materials and methods: laparoscopic partial nephrectomy was performed in 10 patients with upper pole lesions through a transperitoneal approach. once complete mobilization of the kidney was achieved, it was rotated 180 degrees around the horizontal axis, so that the upper pole was positioned inferiorly. after performing partial nephrectomy, the resection bed was sutured by 2-0 polyglactin sutures and application of hem-o-lok clips. then, the kidney was returned into its normal position and fixed to the abdominal wall. results: we performed laparoscopic partial nephrectomy on 9 patients with a contrast-enhancing upper pole kidney mass and 1 patient with a nonfunctioning upper pole. the median tumor size was 58 mm (range, 41 mm to 92 mm). the median operative time was 206 minutes (range, 114 to 262 minutes) and the mean warm ischemia time was 30 minutes (range, 22 to 35 minutes). one patient underwent surgical exploration due to bleeding 6 hours after the operation. prolonged urine leakage (more than 7 days) was observed in 1 patient, which responded to ureteral stent insertion. surgical margins were negative in all of the patients. renal cell carcinoma was histologically diagnosed in patients with a kidney tumor. conclusion: laparoscopic upper pole partial nephrectomy had acceptable results while the kidney was turned upside down intraoperatively, in terms of operative time and complications. this approach facilitates the procedure by achieving a better field of vision. urol j. 2009;6:176-81. www.uj.unrc.ir keywords: nephrectomy, laparoscopy, renal cell carcinoma, urologic surgical procedures urology and nephrology research center and shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: akbar nouralizadeh, md urology and nephrology research center, no 101, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2277 0954 e-mail: nouralizadeh@yahoo.com received april 2009 accepted july 2008 introduction laparoscopic partial nephrectomy (lpn) is an acceptable alternative option for small kidney tumors,(1-3) and similar long-term outcomes in terms of oncology have been shown with lpn when compared to open partial nephrectomy (opn).(4) however, greater intraoperative technical complexity of this operation and its perioperative complications have limited the spread of indications for lpn.(5) laparoscopic upper pole partial nephrectomy (luppn) is associated with difficulties in tumor visualization and resection.(1,3) some authors have proposed modifications to facilitate luppn.(1) since the inferior and anterior kidney masses are accessible for laparoscopic surgery with a good field of vision, we speculated that rotation of the transperitoneal laparoscopic nephrectomy—nouralizadeh et al urology journal vol 6 no 3 summer 2009 177 kidney for operations on upper pole posterior tumors can provide the surgeon with the benefits from the advantages of operating laparoscopically on the inferior and anterior tumors. we present our experience with this new technique of rotating the kidney to facilitate tumor visualization and resection during luppn. materials and methods patients between september 2003 and october 2007, 9 patients with a contrast-enhancing upper pole mass in the kidney (figure 1) and 1 patient with a nonfunctioning upper pole kidney and kidney calculus underwent luppn using a new technique. we had the experience of 246 laparoscopic radical nephrectomies and 56 lpns through the study period and before then, and to facilitate luppn attempted a modified technique of rotating the kidney for the operation. the patients were evaluated preoperatively by history taking, physical examination, chest radiography, urinalysis, abdominal computed tomography (ct), and serum biochemistry tests including creatinine, calcium, phosphorus, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and the total and direct bilirubin. surgical technique our surgical approach was transperitoneal lpn. the patients were secured in the flank position. four trocars (5 mm and 10 mm) were placed through the umbilicus, pararectal, subcostal, and midline areas. after mobilization of the colon, the renal artery and vein were exposed. the surrounding tissues were dissected from the kidney and the kidney was mobilized. the perinephric fat was dissected off the kidney except for the fat overlying the tumoral tissue. a bulldog clamp was applied on the renal artery before rotating the kidney. then, we rotated the kidney 180 degrees over its pedicular axis, so that the upper pole was located inferiorly (figure 2). as a result, the posterior upper pole mass was located anteriorly and inferiorly, allowing complete visualization of the tumor and easy recognition of the dissection plane that facilitated dissection by rigid laparoscopic instruments. the tumor mass was dissected off the kidney by a cold knife, maintaining a safety margin of 5 mm. the specimen was extracted by an endobag. the adrenal gland was removed together with upper pole nephrectomy in patients with upper pole renal mass. resection bed was sutured by polyglactin 2-0 sutures and application of hem-o-lok clips. the pyelocaliceal system was repaired by freehand suturing with 4-0 polyglactin sutures. no bolster or ureteral stent is used in the lpn operations performed in this center, as indicated before.(6) the clamp on the renal artery was removed and after confirming homeostasis, the kidney was returned to its original position (figure 3), and it was sutured to the abdominal wall with 2-0 polyglactin sutures. figure 1. computed tomography showed an upper pole left kidney mass. figure 2. complete excision of the tumor while the kidney was rotated upside down. a indicates the upper pole after excision of tumor and b, the lower pole. transperitoneal laparoscopic nephrectomy—nouralizadeh et al 178 urology journal vol 6 no 3 summer 2009 follow-up kidney specimens were evaluated and renal cell carcinoma (rcc) was graded according to the fuhrman grading system.(7) the patients were visited at the urology clinic 2 weeks after discharge. in patients with rcc, follow-up visits included clinic visits 6 and 12 months after the operation, and then every year. abdominal ct was done 12 months after the operation and then every year in order to assess local recurrence. chest radiography and biochemical laboratory studies including serum calcium, phosphorus, aspartate aminotransferase, alanine aminotransferase, alkaline phsophatase, and direct and total bilirubin were tested in every clinic visits. results the table outlines characteristics of the patients and their perioperative and pathology data. the patients were 5 men and 5 women and their median age was 45 years (range, 34 to 70 years). the side of the operation was right in 5 patients and left in 5. indications for lpn were elective in all patients, and no imperative indications were recorded. the median of the greatest diameter of the tumor on pathology examination was 58 mm (range, 41 mm to 92 mm). all of the tumors were larger than 40 mm. the median operative time was 206 minutes (range, 114 to 262 minutes), and the median hospital stay was 6 days (range, 4 to 16 days). the median warm ischemia time in the h em og lo bi n, g /d l s er um c re at in in e, m g/ dl p at ie nt a ge , y s ex h os pi ta l s ta y, d o pe ra tiv e tim e, m in c la m p ti m e, m in p re op er at iv e p os to pe ra tiv e p re op er at iv e p os to pe ra tiv e tu m or si ze , m m tr an sf us io n, u p at ho lo gy 1† 44 f 16 23 8 28 12 .3 9. 2 1. 1 0. 6 51 2 r c c , g ra de 2 2 58 f 12 24 2 25 10 .0 8. 3 0. 6 0. 7 44 2 le io m yo m a 3 36 m 4 17 8 30 15 .0 13 .4 1. 1 2. 1 92 0 r c c , g ra de 2 4 34 m 8 23 5 24 16 .2 13 .2 1. 1 1. 6 45 2 r c c , g ra de 2 5‡ 45 m 4 20 6 … 15 .1 14 .3 1. 2 1. 4 … 0 n u p 6 40 f 5 17 6 35 13 .2 9. 8 1. 2 1. 3 58 0 r c c , g ra de 2 7 45 f 6 11 4 32 13 .5 9. 0 0. 9 1. 3 62 0 r c c , g ra de 2 8 50 f 6 20 6 30 14 .2 12 .1 1. 0 1. 3 41 0 r c c , g ra de 2 9 70 m 6 14 4 22 10 .9 9. 7 1. 4 1. 4 62 0 r c c , g ra de 2 10 45 m 6 26 2 35 13 .4 9. 5 1. 1 1. 5 71 0 r c c , g ra de 2 d em og ra ph ic a nd p er io pe ra tiv e d at a* *r c c , i nd ic at es r en al c el l c ar ci no m a; f , f em al e; m , m al e; n u p, n on fu nc tio ni ng u pp er p ol e ki dn ey . † t hi s pa tie nt u nd er w en t s ur gi ca l e xp lo ra tio n 6 ho ur s af te r op er at io n du e to c on tin ue d bl ee di ng fr om th e h em ov ac d ra in . ‡ t hi s pa tie nt u nd er w en t l ap ar os co pi c pa rt ia l n ep hr ec to m y fo r a no nf un ct io ni ng u pp er p ol e ki dn ey , a nd th e re na l a rt er y w as n ot c la m pe d. figure 3. rotating the kidney to its normal position after excision of the tumoral mass. transperitoneal laparoscopic nephrectomy—nouralizadeh et al urology journal vol 6 no 3 summer 2009 179 patients with renal tumor was 30 minutes (range, 22 to 35 minutes). the median hemoglobin drop until the 2nd postoperative day was 2.55 g/dl (range, 0.8 g/dl to 4.5 g/dl). three patients required transfusion (two units for each one), based on the judgment by the anesthesiologist. one patient with grade 2 rcc underwent surgical exploration due to bleeding and hemoglobin drop on the operation day (6 hours after operation). the bleeding source was a tiny artery located in the adrenal bed. in this patient, urinary leakage lasted more than 1 week and led to ureteral stent insertion. pathology diagnoses are shown in the table. surgical margins were free of tumor in all of the patients. one of the tumors was a renal leiomyoma and other tumors were rcc. figure 4 depicts proper function and anatomy of the remaining kidney mass in one patient 8 weeks after operation. follow-up data including ct on the 1st postoperative year and later was indicated in 8 patients with rcc. no local recurrence was observed in the follow-up studies. no complications were observed in follow-up studies of the two patients with nonfunctioning upper pole and leiomyoma. discussion currently nephron-sparing surgery is considered the standard therapy for small kidney masses.(2,8,9) long-term tumor control has been reported not different with laparoscopic radical nephrectomy,(8,10-12) and lpn has been introduced as an alternative option to opn for small tumors.(1,3) recently, lpn has expanded its indications to include larger t1b tumors.(2) however, intraoperative difficulties and perioperative complications has limited lpn acceptance as the standard treatment for nephronsparing surgery.(5) complications rate lpn were reported by gill and coworkers to be higher than that in opn.(13) the tumor location plays an important role in the complexity of the operation and its postoperative complications. it has been reported that lpn for upper pole kidney tumors is associated with higher complications relative to lower pole and middle pole tumors.(12,14) achieving a good field of vision for resection of upper pole kidney tumors results in longer operative time and more bleeding.(1) limited field of vision and difficulties in kidney positioning for suturing of the resection bed are important impediments for surgery of these tumors.(3) because of the endoscope angle, these tumors are not easily found by rigid laparoscopes and their resection and suturing is more complicated.(1) as a result of the aforementioned difficulties, some urologists prefer to perform laparoscopic radical nephrectomy or opn for tumors amenable to management by laparoscopic nephron-sparing surgery.(15) some authors have proposed methods to tackle these challenges. kim and associates used a gauze sling in their report of 2 cases to elevate the kidney from its bed, in order to achieve a better field of vision for the laparoscopic operation of upper pole kidney masses.(1) large tumors are not suitable for percutaneous and ablative procedures.(16,17) retroperitoneal approach may be promising for posterior tumors, but not suitable for upper pole tumors as they will not be easily accessible in this approach. the necessity of a direct vision in robotic surgery makes suturing of upper pole resection bed difficult. laparoscopic partial nephrectomy for lower pole tumors and anterior tumors has been associated with least intraoperative complexity and postoperative complications.(12,14) based on this idea, if the kidney is rotated 180 degrees over its pedicular figure 4. intravenous urography of the patient presented in figure 3, eight weeks after the operation. upper pole removal is evident with intact middle and lower pole calyxes. transperitoneal laparoscopic nephrectomy—nouralizadeh et al 180 urology journal vol 6 no 3 summer 2009 axis, the upper/posterior pole tumors are located inferiorly and anteriorly, and their surgery will be accomplished with considerable ease. therefore, after clamping the renal artery and completely mobilizing the kidney, we used a180-degree rotation of the kidney around its pedicular axis to locate the upper pole posterior tumors in an inferior and anterior location. one patient was explored by open surgery 6 hours after the operation, because of continued bleeding from the hemovac drain. this patient was the first who was operated on using this technique. bleeding originated form an artery in adrenal resection bed. all tumors operated by this technique were larger than 40 mm. patard and coworkers reported longer operative time, more bleeding and transfusion, and more frequent urinary fistula for partial nephrectomy of tumors larger than 40 mm compared to smaller tumors.(12) longer warm ischemia time and pyelocaliceal system repair were reported by simmons and associates(2) in lpn of tumors larger than 40 mm, compared to smaller tumors. in their study, however, statistical significance was not observed for operative time and bleeding volume. warm ischemia time and operative time in this series is comparable and slightly shorter compared with the figures reported by simmons and colleagues(2) for lpn of tumors larger than 40 mm (32 minutes versus 38 minutes and 210 minutes versus 228 minutes, respectively). however, transfusion frequency in this study was more than that in many reported series. nevertheless, all patients who received blood transfusion were the first 4 patients operated on using the new technique. no transfusion was needed in the last 6 patients. prolonged leakage (more than 7 days) was observed in 1 patient, which responded to ureteral stent insertion. two patients had urine leakage from the peritoneal drain for 5 days. other patients had no leakage or leakage duration shorter than or equal to 5 days. follow-up ct scans were uneventful in all of the patients. we learned the following tips in our experience: first, the ureter should be dissected free from the surrounding tissues up to the ureteropelvic junction. this makes kidney rotation easier and eliminates the need to release the distal ureter in order to compensate for ureter length shortage in kidney rotation. second, dissecting the adrenal gland free from the surrounding tissues and rotating it with the tumor facilitates kidney rotation. conclusion we described a new technique for lpn for upper pole kidney tumors by rotating the kidney 180 degrees over its pedicular axis. we reported satisfactory results in 10 patients. we believe that this technique will bring considerable ease in surgery of upper pole kidney tumors, and its intraoperative and postoperative results are acceptable. we admit that this technique needs to “come to maturity” and should be attempted in larger series. conflict of interest none declared. references 1. kim ts, hattori r, yoshino y, et al. laparoscopic partial nephrectomy in upper-pole apical renal tumor using gauze sling and flexible laparoscope. j endourol. 2007;21:879-82. 2. simmons mn, chung bi, gill is. perioperative efficacy of laparoscopic partial nephrectomy for tumors larger than 4cm. eur urol. 2009;55:199-208. 3. zorn kc, gong em, mendiola fp, et al. operative outcomes of upper pole laparoscopic partial nephrectomy: comparison of lower pole laparoscopic and upper pole open partial nephrectomy. urology. 2007;70:28-34. 4. moinzadeh a, gill is, finelli a, kaouk j, desai m. laparoscopic partial nephrectomy: 3-year followup. j urol. 2006;175:459-62. 5. gerber gs, stockton br. laparoscopic partial nephrectomy. j endourol. 2005;19:21-4. 6. simforoosh n, noor-alizadeh a, tabibi a, et al. bolsterless laparoscopic partial nephrectomy: a simplification of the technique. j endourol. 2009. 7. fuhrman sa, lasky lc, limas c. prognostic significance of morphologic parameters in renal cell carcinoma. am j surg pathol. 1982;6:655-63. 8. hafez ks, fergany af, novick ac. nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and tnm staging. j urol. 1999;162:1930-3. 9. lerner se, hawkins ca, blute ml, et al. disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. j urol. 1996;155:1868-73. transperitoneal laparoscopic nephrectomy—nouralizadeh et al urology journal vol 6 no 3 summer 2009 181 10. leibovich bc, blute ml, cheville jc, lohse cm, weaver al, zincke h. nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. j urol. 2004;171:1066-70. 11. pahernik s, roos f, rohrig b, wiesner c, thuroff jw. elective nephron sparing surgery for renal cell carcinoma larger than 4 cm. j urol. 2008;179:71-4. 12. patard jj, shvarts o, lam js, et al. safety and efficacy of partial nephrectomy for all t1 tumors based on an international multicenter experience. j urol. 2004;171:2181-5. 13. gill is, matin sf, desai mm, et al. comparative analysis of laparoscopic versus open partial nephrectomy for renal tumors in 200 patients. j urol. 2003;170:64-8. 14. venkatesh r, weld k, ames cd, et al. laparoscopic partial nephrectomy for renal masses: effect of tumor location. urology. 2006;67:1169-74. 15. best s, ercole b, lee c, fallon e, skenazy j, monga m. minimally invasive therapy for renal cell carcinoma: is there a new community standard? urology. 2004;64:22-5. 16. finley ds, beck s, box g, et al. percutaneous and laparoscopic cryoablation of small renal masses. j urol. 2008;180:492-8. 17. malcolm jb, berry tt, williams mb, et al. single center experience with percutaneous and laparoscopic cryoablation of small renal masses. j endourol. 2009;23:907-11. vol 16 no 03 may-june 2019 318 case report primary hyperaldosteronism induced by aldosterone-producing adenoma co-existing with a left suprarenal accessory spleen: two case reports and a review of the literature wen-zhi li1,*, xiang wan1*, long li1*,bin xu1, zhong wang1 keywords: adrenal adenoma; hyperaldosteronism; accessory spleen 1department of urology, shanghai ninth people’s hospital, shanghai jiao tong university school of medicine *correspondence: department of urology, shanghai ninth people’s hospital, shanghai jiao tong university school of medicine, no.639, zhizaoju road in huangpu district, shanghai, 200011, china. fax: (86-21) 63136856. email: chxb2004@126.com, zhongwang2000@sina.com *these authors have contributed equally. received september 2017 & accepted february 2018 we encountered 2 patients (a 33-year-old woman and a 66-year-old man) with an aldosterone-producing adenoma (apa) and a left accessory spleen. the patients’ primary symptoms were hypertension and hypokalemia, and both had elevated serum aldosterone levels. preoperative computed tomography a left suprarenal retroperitoneal mass and laparoscopic left adrenalectomy was performed in both cases. the postoperative microscopic examination revealed splenic tissue. both patients experienced relief of their hypertension and hypokalemia, with an uneventful recovery. introduction ectopic splenic tissue can exist in two forms: an accessory spleen or splenosis. an accessory spleen is normal splenic tissue that has evolved from embryological remnants of splenic tissue(1), and is typically asymptomatic, although it may grow to the size of a normal spleen after splenectomy is performed(2). the co-existence of an aldosterone-producing adenoma (apa) with a left accessory spleen would be difficult to diagnose, and we are not aware of any reported cases of primary hyperaldosteronism (pha) that were induced by apa and a left accessory spleen. thus, we report our experience with two cases of apa and a left accessory spleen that was identified after laparoscopic adrenalectomy. figure 1. preoperative abdominal computed tomography of case 1 (a, c) and case 2(b, d). case report case 1 a 33-year-old woman (table 1) had previously undergone splenectomy and was subsequently referred to our hospital because of hypertension (170/110 mmhg) and hypokalemia (3.16 mmol/l). abdominal computed tomography (ct) revealed a left retroperitoneal suprarenal mass with approximate dimensions of 4 × 3.5 cm (figure 1). laboratory testing revealed a serum aldosterone level of 158.65 pg/ml, a renin level of 0.19 ng/ ml/h, an angiotensin level of 1,187.49 pg/ml, a cortisol level of 166.23 ng/ml, an adrenocorticotrophic hormone level of 25.90 pg/ml, a urinary aldosterone level of 3.5 µg/24 h, and a urinary cortisol level of 69.65 µg/24 h. the patient had a pale complexion and finger beds, and received a 1-week treatment using α-receptor blockers (phenoxybenzene) and spironolactone, which controlled her blood pressure, serum potassium level, and heart rate (< 80 beats/min). during this period, the patient did not exhibit paroxysmal hypertension, but developed warm fingers and toes, pink nail beds, and nasal obstruction. left laparoscopic adrenalectomy was performed under general anesthesia, and revealed that the suprarenal mass had a distinct capsule (figures 2,3). no uncontrollable hypotension was encountered during or after the surgery (blood pressure: 153/102 mmhg), and the patient did not report experiencing postoperative discomfort. a pathological evaluation revealed that the mass was non-malignant ecchymotic splenic tissue (figure 4). the patient recovered uneventfully and was discharged on postoperative day 5. at the 6-month follow, the patient had normal values for blood pressure, urinary aldosterone, and renin, as well as normal findings from ct and routine blood testing of liver and kidney functions. case 2 a 66-year-old man (table 1) presented to our hospital with hypertension (181/119 mmhg) and hypokalemia (2.98 mmol/l). the patient had undergone total splenectomy at the age of 25 years because of a traffic accident. preoperative ct revealed a 4 × 3 cm mass in the left retroperitoneal suprarenal region (figure 1). laboratory testing revealed a renin level of 2.65 ng/ml/h, an angiotensin level of 1,190.36 pg/ml, an aldosterone level of 202.96 pg/ml, a cortisol level of 175.83 ng/ml, an adrenocorticotrophic hormone level of 30.32 pg/ml, a urinary aldosterone level of 27.8 µg/24 h, and a urinary cortisol level of 60.53 µg/24 h. the patient had a pale complexion and nail beds, and received a 1-week treatment using phenoxybenzene and spironolactone, which controlled his blood pressure, serum potassium level, and heart rate (< 80 beats/min). the patient also developed warm fingers and toes, pink nail beds, and nasal obstruction. laparoscopic left adrenalectomy was performed under general anesthesia (figures 2,3), and his blood pressure remained stable during and after the surgery (145/98 mmhg). the postoperative pathological results suggested that the removed mass was accessory spleen tissue (figure 4). the patient recovered well and was subsequently discharged from the hospital. at the 6-month follow-up, the patient had normal values for blood pressure, urinary aldosterone level, and renin level, as well as normal findings from routine blood testing of liver and kidney functions. suprarenal accessory spleen –li and wan et al. table 1. basic information of the 2 patients. case1 case2 normal value gender female male age 33 66 splenectomy yes yes blood pressure(mmhg) 170/110 181/119 140-90/90-60 serum potassium(mmol/l) 3.16 2.98 3.5-5.5 mass location left suprarenal left suprarenal mass size(cm*cm) 4*4 4*3 serum aldosterone(pg/ml) 158.65 202.96 45-175 serum renin(pg/ml/h) 0.19 2.65 0.55 ± 0.09 serum angiotensin(pg/ml) 87.49 90.36 26.0 ± 1.9 serum cortisol(ng/ml) 166.23 175.83 66-286 serum acth(pg/ml) 25.9 175.83 5-50 urine aldosterone(ug/24h) 3.5 27.8 2.0-13.3 urine cortisol(ug/24h) 69.65 60.53 36-455 figure 2. the left adrenal area mass was discovered during laparoscopic surgery (case 1: a, case2: b). case report 319 vol 16 no 03 may-june 2019 320 surgical technique the retroperitoneal approach was used in case 1 and the intraperitoneal approach was used in case 2. in case 1, a roughly 4 × 3.5 cm round mass was discovered at the left adrenal area. the mass had an intact capsule and was closely attached to the adrenal gland. in case 2, a mobile round mass was discovered near the left adrenal gland and behind the pancreas. that mass also had an intact capsule but was farther away from the left adrenal, compared to the first mass (figure 2). in both cases, the masses were completely removed and sent for pathological examination. the sectioned surfaces exhibited a homogenous solid structure with a “fish meat” appearance, and no cavity or hematoma was observed within the structure. thus, the post-operative pathological diagnoses were accessory spleens with chronic congestion. discussion twenty percent of the population has an accessory spleen, which is supplied by vessels from the splenic hilum and is usually discovered adjacent to the spleen in the peritoneum(3). between 1 and 4 wandering accessory spleens can be detected in a patient, and they usually have a diameter of 1–3 cm(4). the manifestations of these accessory spleens can mimic an adrenal, pancreatic, gastrointestinal, or even testicular tumor. surgical intervention is not necessary in asymptomatic cases, although laparoscopic resection is recommended if the patient experiences anemia, pain, rupture, or infarction(5). we are only aware of three reported cases of an accessory spleen in the suprarenal region. rosenblatt et al.(6) performed laparoscopic adrenalectomy for a 72-yearold woman with a suspected adrenal tumor, although postoperative microscopic examination revealed splenic tissue that included lymphoid follicles. tsuchiya et al.(7) reported the case of a 66-year-old woman who underwent laparoscopic adrenalectomy because of a suspected non-functional adrenal tumor, although the surgical specimen was not a tumorous lesion. chen et al.(8) performed laparoscopic resection for a patient with a suspected adrenal tumor, although the pathological report confirmed the diagnosis of an accessory spleen. however, we are not aware of any reports regarding pha induced by apa and an accessory spleen. during plain or contrast-enhanced ct, the accessory spleen has the same density as normal splenic tissue(7), and an adrenal mass with a high-intensity t2-weighted signal is generally a malignant tumor. magnetic resonance angiography could provide more detailed anatomical information to facilitate the diagnosis, and damaged red blood cells during scintigraphy can be used to identify a small asymptomatic accessory spleen. figure 3. the removed mass of case 1 (a) and case 2(b). figure 4. the post-operative pathological diagnoses were accessory spleens with chronic congestion. (case 1: a, case2: b) suprarenal accessory spleen –li and wan et al. furthermore, in patients who have undergone splenectomy, the absence of howell-jolly bodies and surface indentations on erythrocytes can reveal the immunological and physiological effects of the accessory spleen(9). scintigraphy using 99mtc-nanocolloid provides high specificity for confirming the presence of spleen tissue in patients who had experienced splenic trauma. in the present cases, we performed laparoscopic surgery based on the assumption that the pha had been induced by apa, but did not consider the possibility of an accessory spleen. this is because the patients’ symptoms and serum aldosterone levels fulfilled the pha diagnostic criteria, which led to our misinterpreting the significance of the masses during the preoperative imaging. furthermore, the patients’ histories of splenectomy made it impossible to compare the accessory spleen to their spleen during the ct. therefore, clinicians should be aware of the possibility of an accessory spleen when an adrenal mass is detected using conventional imaging techniques. intraoperative findings of a dark-red mass with a smooth surface may also indicate the presence of an accessory spleen. references 1. perry kt jr., zisman a, singer j, schulam p. splenosis presenting as a right suprarenal retroperitoneal mass. j urol. 2002; 168: 644645. 2. rao kg, fitzer pm. left suprarenal mass following splenectomy: case reports. j urol. 1984; 132: 323-325. 3. kato y, murayama k, taniguchi n, et al. a case of accessory spleen presenting as retroperitoneal tumor. hinyokika kiyo. 1998; 44: 711-714. 4. wadham bm, adams pb, johnson ma. incidence and location of accessory spleens. n engl j med. 1981; 304: 1111. 5. velanovich v, shurafa m. laparoscopic excision of accessory spleen. am j surg. 2000; 180: 62-64. 6. rosenblatt gs, luthringer dj, fuchs gj. enlargement of accessory spleen after splenectomy can mimic a solitary adrenal tumor. urology. 2010; 75: 561-562. 7. tsuchiya n, sato k, shimoda n, et al. an accessory spleen mimicking a nonfunctional adrenal tumor: a potential pitfall in the diagnosis of a left adrenal tumor. urol int. 2000; 65: 226-228. table 2.reports of accessory spleen in the adrenal region. no. reporter year age gender location size(cm) splenectomy chief preoperative treatment pathology history complaint diagnosis 1 rosenblatt 2010 72 female left adrenal 5*5 yes abdominal adrenal laparoscopic splenic et al pain tumor left adrenalectomy tissue 2 tsuchiya 2000 66 female left adrenal 2*2 no asymptomatic adrenal tumor laparoscopic splenic et al left adrenalectomy tissue 3 chen et al 2005 41 male left adrenal 7*6 no asymptomatic adrenal gland cancer laparoscopic splenic tissue left adrenalectomy suprarenal accessory spleen –li and wan et al. case report 321 8. chen ch, wu hc, chang ch. an accessory spleen mimics a left adrenal carcinoma. medgenmed. 2005; 7: 9. 9. pearson ha, johnston d, smith ka, touloukian rj. the born-again spleen. return of splenic function after splenectomy for trauma. n engl j med. 1978; 298: 1389-1392. reconstructive surgery comparison of urethral dilation with amplatz dilators and internal urethrotomy techniques for the treatment of urethral strictures onur karsli1, murat ustuner1*, omur memik1, emre ulukaradag1 purpose: the most common option for the management of urethral stricture (us) is direct visual internal urethrotomy (dviu), because it is an easy and minimally invasive technique but the low success and high recurrence rates of this technique make urologists research for different types of therapeutic alternatives in stricture treatment. in this study we aimed to compare the internal urethrotomy with amplatz dilation for the treatment of male us. materials and methods : a total of sixty patients, who have been operated due to urethral stricture were enrolled into this study. group 1 was treated with amplatz renal dilators and the group 2 was treated with cold knife urethrotomy. all patients were evaluated for qmax preoperatively and at the first, 3rd, 9th and 12th months postoperatively. results: in the 3 month uroflowmetry results, mean q max values were 15.6 ± 2 ml/sec in amplatz group and 15.5 ± 1.6 ml/sec in dviu group. there was no statisticaly difference between the two groups. however the q max values in the postoperative 9 and 12 months were significantly decreased in the dviu group. in the dviu group 9 recurrences (36%) appeared and 2 of these reccurrences were in the first 3 months, whereas in the amplatz group no recurrences appeared in the first 3 months. the urethral stricture recurrence rate up to the 12 month follow up was statistically significant for group 1 when it is compared with group 2. conclusion: in our experience, amplatz dilation is a good option as the initial treatment for urethral stricture. keywords: amplatz dilators; internal urethrotomy; urethral strictures; urethral strictures recurrences; uretral strictures treatment introduction urethral stricture (us) is one of the oldest known issue of urology due to the difficulty of diagnosis, treatment and risk of recurrence. us disease is defined as narrowing of the urethral lumen because of fibrosis, which occurs in urethral mucosa and surrounding tissues. the etiology could be idiopathic, iatrogenic, post-traumatic and also includes infectious and lichen sclerosus(1). although it is rare, familial stricture especially seen in adults can be considered in etiology(2). treatment of the stricture depends on the localization, length and type(3). although urethral dilation is one of the oldest modality, the most common option for the management of us is direct visual internal urethrotomy (dviu), because it is an easy and minimally invasive technique(4). endoscopic urethrotomy was first described in 1974 by sachse with the use of a cold-knife technique to incise the stricture segments(5). despite its widespread acceptance as the first-line option, the success rates after initial dviu is reported to be 8%–76% (6-8). low success and high recurrence rates of this technique make urologists research for different types of therapeutic alternatives in stricture treatment (9). recently akkoc et al. described amplatz dilation techniques university of health sciences, derince training and research hospital, department of urology, kocaeli, turkey. *correspondence: university of health sciences, derince training and research hospital, department of urology, kocaeli, turkey. tel: +905065021260. fax : +902622334641. e-mail: muratustuner@gmail.com. received june 2018 & accepted january 2019 for the treatment of us as an effective and safe technique(10). in this study we aimed to compare internal urethrotomy with amplatz dilatation for the treatment of us. to the best of our knowledge, this is the first clinical trial in the literature comparing the outcomes of amplatz dilation with dviu. materials and methods study population in this retrospective study, we analyzed the data from 60 patients who were diagnosed with us and operated in our department between 2016 and 2017. the diagnose of us was made by clinical history, uroflowmetry and urethrography. the records of patients’, physical examination, complete blood count, serum biochemical analysis, urine analysis and urine culture were retrospectively reviewed. the patients with active urinary infection were treated with the appropriate antibiotics before the operation. all patients were evaluated by urethrography preoperatively and the stricture lengths were measured. exclusion criterias of the study were stricture longer than 2 cm, meatal stenosis, posterior urethral strictures, and history of us treatment. patients were informed about a new dilatation technique. the urology journal/vol 17 no. 1/ january-february 2020/ pp. 68-72. [doi: 10.22037/uj.v0i0.4662] vol 17 no 01 january-february 2020 69 patient was operated with amplatz dilation in case he accepted this technique. as a result, there were two groups of patients and each group had 30 patients. the patients in group 1 were treated with amplatz renal dilators and group 2 were treated with dviu. all patients were re-evaluated by uroflowmetry at the first, 3rd, 9th and 12th month postoperatively and qmax values were recorded. during the follow-up period, if the patients had complaints of voiding difficulty and the maximum flow rate (qmax) was < 10 ml/s, urethroscopy and urethrography were planned. if urethral strictures were present at urethroscopy and urethrography, these were accepted as recurrent strictures and the same procedure was performed again. the procedure was accepted as a successful one when the patient did not complain of any voiding difficulty and the qmax was greater than 12 ml/sec(11). the primary endpoint measures of the study was determined as an increase of qmax. the secondary endpoint of the study was determined as the recurrence time of the stenosis. surgical technique written information consent was obtained from patients for both surgical procedure. all patients were operated by the same surgeon. all the patients underwent into urethrotomy under spinal or general anesthesia in the lithotomy position. cephazolin sodium 1 g. i.v. was administered for preoperative antibiotic prophylaxis. a 20.5 f urethrotome was used for the cold knife urethrotomy group. a safety guide wire was first passed through the stricture and the urethrotomy was performed at 12 o’clock. for all patients, a 20 f foley urethral catheter was inserted and left in the bladder for 7 days at the end of the procedure. for amplatz dilation, all patients underwent cystoscopy at lithotomy position under spinal or general anesthesia. a 0.038-inch hydrophilic guidewire was introduced into the working channel after the location of the stenosis was seen with the cystoscope (figure 1). the cystoscope was then removed and amplified renal dilators between 10f to 22f were sequentially delivered to the bladder over the guide wire (figure 2 and 3). after the dilation procedure, the urethra was evaluated with cystoscopy and the procedure ended by attaching a 20f foley urethral catheter and removed at postoperative 7th day (figure 4). statistical analysis independent-samples t test, and fisher’s exact test were used for comparing the groups of patients. p < 0.05 was considered statistically significant. the computer software that was used was statistical package for social sciences (spss 12.0.1; spss inc., chicago, il, usa). results there were two groups of patients treated for urethral stricture. group 1 was the amplatz dilation group and the group 2 was cold knife urethrotomy group. in both two groups there were 30 patients. the mean age of group 1 was 60.7 ± 6.3 years and in group 2 was 59.3±4.6 years. the etiology of urethral strictures were idiopathic in 20 (33,3%) and iatrogenic in 40 (66,6%) patients. iatrogenic causes were attributed to transurethral resection of prostate, transurethral resection of bladder tumor and urethral catheterization. there was no statistically significant difference between the two groups for age (p = .79). the mean preoperative qmax values for group 1 and 2 were 4.9 ± 0.8 and 4.6 ± 0.4 ml/sec, respectively (p = .22). there was no statistically difference between two groups (table 1). mean operation time was shorter in amplatz group (15 ± 1.8 minutes) when compared with cold-knife group (15.9 ± 3.5 minutes) but it was not statistically significant (p = .21). when we compared the 3 month uroflowmetry results, mean q max values were 15.6 ± 2 ml/sec in amplatz group and 15.5 ± 1.6 ml/sec in dviu group. there was no statisticaly difference between the two groups (p = .89). however the q max values in the postoperative 9 and 12 months were significantly decreased in the dviu group (p = .001) (table 2). in the cold knife group 9 recurrences appeared and 2 of these reccurrences were in the first 3 months, whereas in the amplatz group no recurrences appeared in the first 3 months. recurrence-free rate at 3 months was similar between two (p = .23). the urethral stricture recurrence rate up to the 12 month follow up was statisparameters amplatz group dviu group p age 60.7 ± 6.3 59.3 ± 4.6 0.79 a preoperative qmax value (ml/sec) 4.9 ± 0.8 4.6 ± 0.4 0.22 a operative time (min) 15 ± 1.8 15.9 ± 3.5 0.21 b recurrence/no recurrence, n (%), 3th month 0/30 2/28 0.49 b recurrence/no recurrence, n (%), 12th month 4/25 9/21 0.02 b table 1. characteristics in study groups and comparability of groups treated. a: independent samples t test. b: fisher’s exact test. qmax group before the operation 3th months 9thmonths 12thmonths amplatz 4.9 ± 0.8 15.6 ± 2 15 ± 1.8 14.2 ± 1.3 dviu 4.6 ± 0.4 15.5 ± 1.6 13.4 ± 1.4 11.9 ± 1.2 p 0.22* 0.89* 0.001* 0.0001* * independent samples t test. table 2. operative outcomes table 3. surgical technique and complication operation time complication group min bleeding n(%) uti n(%) amplatz 15±1.8 1 (3.3) 1(3.3) dviu 15.9±3.5 3 (10) 2(6.6) p 0.21 0.61 0.55 urethral strictures and amplatz dilationkarslı et al. tically significant for group 1 when it is compared with group 2 (p = .02) (table 1). the major postoperative complications were urethral bleeding and urethral tract ınfections (uti). for the amplatz group, only one patient reported as one episode of urethral bleeding. however, in the dviu group, 3 patients had urethral bleeding (table 3). discussion in this study we compared amplatz dilation and dviu, and as a result we found that amplatz dilation is more safe and effective technique for urethral stricture. in our experience, amplatz dilation a is good option as the initial treatment for urethral stricture. the first known treatment modality of urethral stricture in history was dilation(12). metal or bougie urethral dilation offers several advantages over internal urethrotomy. they avoid the need for general, spinal or intravenous anesthesia. it is a simpler, less-invasive, and potentially office-based procedure that requires less degree of surgical expertise and equipment(12,13). because the traditional dilatation procedure is performed in a blind fashion and potential technical complications at the time of the procedure such as excessive bleeding, urethral perforation with extravasation, rectal injury, and false path(14). to prevent these complications several modalities have been developed. gelman et al. described direct vision balloon dilation for the trament of us and they suggested this technique(14).yu et al reported high-pressure balloon dilation for male anterior urethral stricture and they found that this technique was effective and safe. moreover they suggested such an alternative treatment modality for anterior urethral stricture disease(15). the amplatz dilation method have been described by akkoc et al.(10) which we used in this study. the principle of conventional dviu is to achieve epithelial regrowth by the incision of the scar tissue. the major disadvantage of dviu is that the depth of the scar tissue cannot be estimated accurately during the procedure and resulting in imprecise incision of the scar tissue. it is possible that the incision of the urethral stricfigure 1. the image of hydrophilic guidewire which was introduced into the uretrhral stenosis area under cystoscopy figure 3. the image of 22 f amplatz dilator which was introduced from external meatus to the bladder by using guide wıre for the urethral stenosis area figure 2. the image of 10 f amplatz dilator which was introduced from external meatus to the bladder by using guide wıre for the urethral stenosis area figure 4. the image of post dilatation procedure urethral strictures and amplatz dilationkarslı et al. reconstructive suegery 70 vol 17 no 01 january-february 2020 71 ture may not reach the healthy tissue, so that it can not minimize the stricture recurrence effectively. urethral epithelium metaplasia (stratified squamous) is seen as the primary change after urethral incision is more fragile than normal pseudostratified columnar epithelium (16). on the other hand, by incising the urethra via a cold knife, the underlying corpus spongiosum might be injured, which would lead to postoperative hemorrhage. the destroyed vascularity within the corpus spongiosum and focal urinary extravasation through fissures on the mucosa might exacerbate the spongiofibrosis and finally turn to stricture recurrence(17). there are many investigations about use of therapeutic agents such as steroids, to avoid recurrence of stricture (18,19). yıldırım et. al. have show that the use of local steroids injections with dviu seems to decrease the high stricture recurrence rate following dviu(20). in another study conducted by sinanoglu et al., use of oral colchicine showed reducement of the recurrence of stenosis (21). even if the results are controversial routine repeated dilations after dviu are suggested by urologists to prevent urethral stricture recurrence. tian et al. argued that close follow-up by after dviu is more effective than recurrent dilatations in preventing recurrence of stricture(22). there are limited randomised and prospective trials that comparing the efficacy of dilatation versus internal urethrotomy as initial treatment for urethral strictures. in one study which was a retrospective study of 199 men with strictures treated at the mayo clinic, 101 (67%) patients underwent dilation and 39 (26%) patients underwent direct vision internal urethrotomy. at a median follow-up of 3.5 years, the probability of not requiring re-treatment within 3 years was 65% for dilation and 68% for urethrotomy, indicating that these procedures were equally efficacious as an initial treatment of bulbar strictures(13). jw steenkamp and cf heyns and ml de kock who also compared and showed that dilation and dviu are equally effective for initial treatment of us(23). in our study, the recurrence rate was 6 % for the amplatz dilation during the 18 months follow up period. in the cold knife group, recurrence rate was 36 % during the 18 months follow up period. “time to recurrence” is also an important parameter in urethral stricture disease(24). in the dviu group, 2 of 30 (6,6 %) recurrences appeared within the first 3 months, whereas in the dilation group no recurrences appeared within the first 3 months in our study. santucci et al. evaluated the success rate of dviu as a treatment for simple male urethral strictures(8) and they found the stricture free rate after the first dviu 8% with a median time to reccurence of 7 months. this result shows a lower success rate from the previously published studies which have reported the dviu success rates to vary from 20% to 95% (25-28) and they indicate that urethrotomy is popular for being an easy technique and it is not a successful procedure. in our study we found the dviu success rate is lower than amplatz dilation and these results encourages us to suggest that the initial treatment of us should be amplatz dilation because of the higher success rate than dviu. there are some important limitations to our study. one of them is that we did not do the measures of strictures. the other one at the end of dviu is that we didn't measure the urethral caliber. another limitation is the shortness of our follow-up period. finally our study is retrospective. conclusions treatment modality of anterior urethral stricture disease by using guidewire-assisted urethral dilation with amplatz renal dilators is safe, effective and a minimally invasive method for the treatment of urethral strictures. it also avoids the risks which is associated with blind dilatation techniques. when it is compared with cold knife technique, it provides a better recurrence free rates during the early period. in our experience, amplatz dilation is a good option as the initial treatment for urethral stricture. further randomized studies comparing dilatation using amplatz renal dilators with dviu are warranted. conflict of interest none declared. references 1. mundy ar, andrich de: urethral strictures. bju int. 2011;107:6–26. 2. hosseini j, kazemzadeh azad b, aliakbari f, tayyebi azar a, hosseini ma. familial urethral stricture, five adult patients overview. urol j. 2019 ;16:515-516. 3. hızlı f, berkmen f, günes ̧ mn, yürür h. outcomes of internal urethrotomy after transurethral resection related urethral strictures and literature review. türk üroloji dergisi. 2005;31:417-22. 4. van leeuwen ma, brandenburg jj, kok et, et al. management of adult anterior urethral stricture disease: nationwide survey among urologists in the netherlands. eur urol. 2011, 60:159-66. 5. sachse h. zur behandlung der harnröhren striktur: die transurethrale schlitzung unter sicht mit scharfem schnitt. fortschr med. 1974;92:12–15. 6. de kock ml, allen fj. guidelines for the treatment of urethral strictures. s afr j surg. 1989;27:182-4. 7. chilton cp, shah pj, fowler cg, tiptaft rc, blandy jp. the impact of optical urethrotomy on the management of urethral strictures. br j urol. 1983;55:705-10. 8. santucci ra, eisenberg l. urethrotomy has a much lower success rate than previously reported. j urol. 2010; 183:1859–62 9. cecen k, karadag ma, demir a, kocaaslan r. plasmakinetictm versus cold knife internal urethrotomy in terms of recurrence rates: a prospective randomized study. urol int. 2014; doi: 10.159/000363249. 10. akkoc a, aydin c, kartalmıs m, et al. use and outcomes of amplatz renal dilator for treatment of urethral strictures. int braz j urol. 2016; 42: 356-64 . 11. koca o, sertkaya z, gunes m, et al. internal urethrotomy versus plasmakinetic energy for urethral strictures and amplatz dilationkarslı et al. surgical treatment of urethral stricture (article in turkish). turkish j urol. 2011; 37:30-33. 12. vicente j, salvador j, caffaratti j. endoscopic urethrotomy versus urethrotomy plus ndyag laser in the treatment of urethral stricture. eur urol. 1990;18:166-8. 13. stormont tj, suman vj, oesterling je. newly diagnosed bulbar urethral strictures: etiology and outcome of various treatments. j urol. 1993;150:1725-8. 14. gelman j, liss ma, cinman nm. direct vision balloon dilation for the management of urethral strictures. j endourol. 2011;25:124951. 15. yu s, wu h, wang w, et al. high-pressure balloon dilation for male anterior urethral stricture: single-center experience. j zhejiang univ-sci b (biomed & biotechnol). 2016 17:722-7 16. chambers rm, baitera b. the anatomy of the urethral stricture. br j urol. 1977; 49: 545-51. 17. isen k, nalcacioglu v. direct vision internal urethrotomy by using endoscopic scissors. int urol nephrol. 2015 ;47:905-8. 18. kumar s, garg n, singh sk, mandal ak. efficacy of optical internal urethrotomy and intralesional injection of vatsala-santosh pgi tri-inject (triamcinolone, mitomycin c, and hyaluronidase) in the treatment of anterior urethral stricture. adv urol. 2014; 2014:192710. 19. mazdak h, meshki i, ghassami f. effect of mitomycin c on anterior urethral stricture recurrence after internal urethrotomy. eur urol. 2007; 51:1089-92. 20. yıldırım me, kaynar m, ozyuvali e, et al. the effectiveness of local steroid injection after internal urethrotomy to avoid recurrence. arch ital urol androl. 2015;87:295–8. 21. sinanoglu o, kurtulus fo, akgün fs. long term effect of colchicine treatment in preventing urethra stricture recurrence after internal urethrotomy. urol j. 2018;15:204-8. 22. tian y, wazir y, wang j, li h. prevention of stricture recurrence following urethral internal urethrotomy: routine repeated dilations or active surveillance? urol j. 2016;13:2794-6. 23. steenkamp jw, heyns cf, de kock ml. internal urethrotomy versus dilation as treatment for male urethral strictures: a prospective, randomized comparison. j urol. 1997 ;157:98-101. 24. atak m, tokgoz h, akduman b, et al. lowpower holmium:yag laser urethrotomy for urethral stricture disease: comparison of outcomes with the cold-knife technique. kaohsiung j med. 2011; 27:503-507. 25. greenwell tj, castle c, andrich de et al: repeat urethrotomy and dilation for the treatment of urethral stricture are neither clinically effective not cost-effective. j urol. 2004; 172: 275. 26. naude am and heyns cf. what is the place of internal urethrotomy in the treatment of urethral stricture disease? nat clin pract urol. 2005; 2: 538. 27. heyns cf, steenkamp jw, de kock ml et al: treatment of male urethral strictures: is repeated dilation or internal urethrotomy useful? j urol. 1998; 160: 356. 28. morey a: urethral stricture is now an open surgical disease. j urol 2009; 181: 953. urethral strictures and amplatz dilationkarslı et al. reconstructive suegery 72 vol 19 no 1 january-february 2022 138 urological oncology the role of kallikrein10 (klk10) polymorphism in prostate cancer susceptibility seda gulec yılmaz1, faruk yencılek2 , asıf yıldırım3, fatma tuba akdeniz1, altay burak dalan1, zerrin barut4, turgay isbır1* purpose: the present study aims to investigate the potential role of kallikrein 10 (klk10) genotype and allele frequencies in predisposition to prostate cancer. materials and methods: klk10 (rs7259451) gene polymorphisms were determined by real-time polymerase chain reaction analysis in patients with prostate cancer (n = 69) and controls (n = 76). results: klk10 gene frequencies were significantly different in the case and control groups (p = .028). gg carriers were significantly higher in the control group (p = .034), whereas tt carriers were higher in the prostate cancer group (p = .033). furthermore, the patients with gg genotype had the lowest psa levels while tt carriers had the highest (p = .005). conclusion: according to the results, we suggested that carrying variant t allele and also carrying homozygote tt genotype could be a potential risk, while ancestral homozygote gg genotype and g allele are risk reducing factors for prostate cancer. keywords: klk10 gene; polymorphism; prostate cancer; psa; rs7259451 introduction prostate cancer is the most common cancer among men aged over 40 years. moreover, after lung cancer, it is the second most common mortality factor in cancer-related deaths. incidence rates of prostate cancer have more than doubled in the last decades, because of great improvements in diagnostic assets and hightech screening methods(1). although prostate cancer is a multifactorial disease with several potential risk factors, such as smoking, obesity, age, diabetes and environmental changes, recent advances in genetics have contributed in understanding its pathological metabolism. however, prostate cancer etiology is still vague and investigations about genetic polymorphisms enable to display individual differences and predispositions (2). thanks to recent improvements in genetic analysis, many genes and their variations have been demonstrated in cancer research. there are many polymorphisms associated with prostate cancer tendency(3,4). these genetic relations help to understand the molecular basis of the disease as well as provide a clinical diagnostic utility. the protein function and effectiveness could be altered by genomic variations, called polymorphism. these variations have different impacts on cancer and cancer prognosis. they also give rise to predispositions via initiating a physiological process indirectly(5,6). 1department of medical biology, faculty of medicine, yeditepe university, istanbul, turkey. 2department of urology, faculty of medicine, yeditepe university, istanbul, turkey. 3department of urology, göztepe education and research hospital, istanbul, turkey. 4department of basic medical science, faculty of dentistry, antalya bilim university, antalya, turkey *correspondence: turgay isbır; department of medical biology, faculty of medicine, yeditepe university, istanbul, turkey. yeditepe universitesi yerleskesi, inonu cad. 26 agustos yerleskesi, 34755 kayısdagı-atasehir, istanbul, turkey. tel: +90 5332823726/ +90 2165780000-1263, e-mail: turgay.isbir@yeditepe.edu.tr. received august 2020 & accepted march 2021 human kallikrein-related peptidases, catalyse peptide bond hydrolysis, are a member of the serine peptiases family. kallikrein 3 (klk3), the most wellknown family member, named as prostate-specific-antigen (psa), is a well-known kallikrein (klk) and has great importance in prostate cancer prognosis and high psa levels could lead the biochemical failure which predisposes the patients to metastasis(7). another family member, called kallikrein10 (klk10), is a protein that is involved in steroid hormone stimulation via affecting hormone-receptor complexes. the human tissue klk is located on chromosome 19q13.4 and encoded by steroid hormone-regulated genes. it has been demonstrated that dysregulation of klk expression is associated with multiple diseases, such as cancer(8). human klk was determined as eligible biomarker for diagnosis and prognosis for many cancer types, such as ovarian, breast and prostate. investigations have focused on understanding the relationship between prostate cancer and the polymorphisms of several klk genes. therefore, this study is aimed to investigate the potential role of klk10 genotype and allelic frequencies in the tendency to prostate cancer (pc). materials and methods the study population consisted of 69 patients who reurology journal/vol 19 no. 1/ january-february 2022/ pp. 41-44. [doi: 10.22037/uj.v18i.6425] curred from yeditepe university urology department and 76 age-matched healthy controls. control group consisted of healthy individuals with age 40 -80 years, they were not diagnosed with this disease, following a clinical examination. the patients' group consisted of individuals who had prostate cancer with age range between 40-80 years old. the diagnosis of prostate cancer was demonstrated by the clinical, and pathological examinations. the tumor differentiation status was evaluated using gleason score criteria. the clinical examinations classified t -stage as early -stage (t1 and t2) and late -stage (t3 and t4). pathologic t -stage was classified as t2a, t2b, t2c, t3a, and t3b. all patients and control groups gave their informed consent following a detailed explanation of the protocol of the study. blood samples from all individuals were collected in tubes containing edta. clinical and demographic information’s of patients and controls obtained from hospital records. genomic dna extraction from 350µl of whole blood was performed by invitrogen iprep purelink gdna blood isolation kit (invitrogen, life technologies, carlsbad, california, usa). dna samples were measured with nanodrop 2000 (thermoscientific, waltham, massachusetts, usa). determination of klk10 gene (rs7259451) polymorphism was performed in applied biosystems 7500 fast real time pcr instrument (applied biosystems, foster city, ca, usa) by using taqman genotyping assay and taqman genotyping master mix (taqman reagents, applied biosystems, foster city, ca, usa). the reactions were carried out with primer sequence as 5’-taaggcaagactcaggataaaacac[g>t] gtggtgtggccgggagcggtggctc-3’. due to the minor allele frequency (maf) analysis, allele frequencies considered as g wild type and t mutant form. statistical analyses were performed using spss ver. 23 software (spss inc, chicago, il, usa). the significant difference between groups was examined by student’s t and one way anova tests, also demographic and clinic data were compared by chi square and fisher’s exact tests. risk estimations were examined with odds ratio (or) at 95% confidence interval (ci). p < 0.05 is denoted as statistically significant. results demographic and clinical properties are summarized in table 1. there were no differences between the patients and controls in mean ages. there were also no significant difference regarding bmi and smoking habits between the groups, although diagnosis for diabetes, coronary artery disease (cad) and hypertension were significantly higher in the pc group (p < .001). the patients with pc had significant a statistically higher level of psa when compared to the control group (p = .006). the genotypic and allelic frequencies of klk10 in pc klk10 in prostate cancergüleç yılmaz et al. urological oncology 42 table 1. the comprehensive comparison of sensitivity parameters prostate cancer (n=69) control (n=76) p-value age (years), mean±sd 68.52 ± 7.36 66.49 ± 8.45 0.867 body mass index (kg/m2), mean±sd 27.01 ± 3.71 27.28 ± 3.55 0.773 smoking status n (%) 52 (76.5%) 16 (23.5%) 0.415 diabetes mellitus n (%) 6 (66.7%) 3 (33.3%) < 0.001* cad n (%) 1 (25%) 3 (75%) < 0.001* hypertension n (%) systolic blod pressure >140 17 (81%) 3 (19%) < 0.001* diastolic blod pressure >90 psa (ng/ml) mean±sd 25.94 ± 41.14 3.0 3± 2.66 0.006* gleason score, mean±sd 7.74±0.88 pathological t-stagen (%) t2a 9 (13 %) t2b 10 (14.5 %) t2c 29 (42 %) t3a 11 (15.5 %) t3b 10 (15 %) clinical t-stage n (%) early (t1+t2) 61 (88,4 %) late (t3+t4) 8 (11.6 %) *p values less than 0.05 denoted statistical significance. .χ2: chi square used for comparison of patients with pc and control group; student t test is used for comparing quantitative data abbreviations: cad:coronary artery disease, psa: prostate-spesific antigen, n: number of individuals, sd: standart deviation. prostate cancer (n=69) n (%) control (n=76) n (%) p value χ2 or 95 % ci genotype p = .028* χ2 =7.178 gg 26 (37.7 %) 42 (55.3 %) .034* 4.489 0.489 0.252-0.951 gt 35 (50.7 %) 32(42.1 %) .298 1.081 1.415 0.735-2.727 tt 8 (11.6 %) 2 (2.6 %) .033* 4.524 4.852 0.993-23.703 allelic count n (%) g allele 87 (63.1 %) 64 (64%) 0.033* 4.524 0.206 0.042-1.007 t allele 51 (36.9 %) 36 (36%) 0.034* 4.489 2.043 1.051-3.970 table 2. kallikrein10 (klk10) rs7259451 genotypic and allelic frequencies in prostate cancer and control group. *p values less than 0.05 denoted statistical significance. χ2: chi square and fisher's exact test used for comparison of patients with pc and control group; abbreviations: n:number of individuals; χ2:chi-square; or:odds ratio; ci:confidence interval vol 19 no 1 january-february 2022 138 and control groups are given in table 2. there were significant differences between the groups in the frequency of klk10 genotypes (p = .028). the frequency of the gg homozygote genotype was significantly higher in the control group than the patient group and those with gg genotype were ~2 fold likely to be healthy control than patients (χ2 = 4.489, %95 ci= 0.252-0.951, or= 0.489, p = .034). there were no statistically significant correlations between the groups regarding the gt heterozygote genotype (p = .298), however, the tt homozygote genotype was significantly higher in the patient group when compared to the control group (p = .033). ancestral g allele frequency was significantly higher in controls than patients with pc(p = .033), while mutant t allele frequency was significantly higher in the patient group (p = .034). sixty-four percent of healthy control participants were carrying the g allele, whereas 36% of them had the t allele. as it is shown in table 3, although there was no statistically difference between klk10 genotypes regarding prostate volume (p = .236), the homozygote mutant allele (tt) group displayed the highest prostate volume. according to psa levels genotype groups are significantly different. the patients with klk10 gg genotype carriers had the lowest and tt carriers had highest psa levels (p = .005). while there was no statistical difference in allele distributions (p = .486), we found that t allele carriers had higher psa levels than g allele carriers (table 3). discussion in the last decades, polymorphism, expression and genome-wide studies have undergone a great improvement; however, there is no particular evidence to identify prostate cancer susceptibility. on account of this, new studies should be performed in population-based case-control studies. owing to its tumor suppressing effect, the klk10 gene accounts for the prediction of cancer prognosis(9). the human klk10 gene and its potential role have been investigated in various cancer types in different populations. the present study aims to investigate the associations between klk10 polymorphism and prostate cancer in a turkish population. klk genes and klk proteins have structural characteristics, such as localization on the same chromosomal domain. they also have analogue translational sites, stop and start codons. klk genes have five peer exons and four codons with no association with other genes located on the same gene region. altered klk gene expressions vary in different cancer types; moreover, it has been asserted that klk proteins participate in proliferation, angiogenesis and metastasis(8,10). several studies indicated that the klk protein family, the best known of which is klk3, also known as psa, is widely used for prostate cancer diagnosis(10). klk family members has been investigated as novel serum biomarkers, although there is unclear evidence regarding klk gene expression and protein levels(11). bayani et al. (2008) demonstrated that dysregulated klk expression levels in breast, ovary and prostate are associated with increased klk protein levels. they indicated that unbalanced translocations associated with altered protein levels. furthermore, they showed that there was a relation between cancer progression and klk protein levels(12). although there have been several investigations into the klk protease family, the association between physiological role and genetic variations is still unclear. angelopoulou et al. (2009) demonstrated klk mrna expressions of cancer tissues. they found that klk9 and klk10 have the highest expression levels among cancerous mammary tissues. thus, it has been suggested that klk9 and klk10 participate in proteolytic cascades(13). klk proteins are initially translated as preproenzymes that carry signal peptide on n-terminus and mature active enzyme takes place after a short propeptide. the signal cleaves from propeptide domains, and forms a mature enzyme complex. human klks participate in different biological processes, such as regulating neural development, regulating blood pressure, semen liquefaction and also cell proliferation(14). therefore, several studies have been conducted on the role of human klks in diverse cancer types. yousef et al. (2005) showed the relation between klk10 and endocrine related malignancies in silico analyses. although klk genes had different expression profiles in various tissues, klk10 gene expression significantly downregulated in ovarian, breast, testicular and prostate cancer lines. consequently, the klk10 gene represented a tumour suppressor function, especially in endocrine-related malignancies and klk10 could be considered as a cancer biomarker gene(15). the potential biomarker role of klk10 gene was documented in human breast, ovary and prostate cancer cell lines by sidiropoulus et al. (2005). they investigated epigenetic alterations on the tumor suppressor role of klk10 mrna expression. however, various mechanisms account for downregulating gene expressions; hypermethylation of cpg islands on the klk10 gene could explain the specific tumor suppressing mechanism of klk10 expression profile in cancer cells(16). another study demonstrated the tumor biomarker role of altered klk10 serum level in patients with various malignancies. although the relation between gene regulation and serum protein level is still unclear, luo et al. (2001) showed a positive correlation with serum klk10 level and ovarian cancer severity(17). * p = values less than 0.05 denoted statistical significance. student t test and one way anova test used used for comparison of genotypes and alleles abbreviations: psa: prostate-spesific antigen; sd: standart deviation prostate volume (ml) mean±sd psa (ng/ml) mean±sd gg 45.05 ± 29.79 26.39 ± 7.16 gt 39.00 ± 13.28 p = .236 40.49 ± 13.57 p = .005* tt 47.77 ± 19.11 81.08 ± 70.79 g allele 42.29 ± 17.00 p = .972 33.44 ± 15.80 p = .486 t allele 43.07 ± 15.38 40.54 ±3 5.69 table 3. klk10 ( rs7259451) genotype variations and prostate volume and psa levels in patient with prostate cancer klk10 in prostate cancergüleç yılmaz et al. vol 19 no 1 january-february 2022 43 urological oncology 44 the relation between single nucleotide polymorphisms in human klk10 gene and endocrine-related malignancies, such as prostate, testicular, breast and ovarian cancer, was investigated by bharaj et al. (2002). five coding regions of klk10 gene sequencing analysis performed in different human tumour tissues were obtained from cancer patients and the sequence analysis showed that the mutant variant was significantly higher in prostate tumours than adjacent normal tissues. thus, they identified human klk10 gene polymorphisms at codon 50 associated with pc risk(18). in silico analysis of klk10 single nucleotide polymorphisms (snps) demonstrated that klk10 expression could be altered by intronic snps via regulating transcription factors. intronic snps could change not only gene expressions, but also hormone response element binding domains. batra et al. (2010) performed klk10 gene sequencing to analyse possible association between klk10 and cancer survival. the analysis showed that klk10 rs 7259451 polymorphism located on the 5’utr intronic region where upstream of androgen response elements (ares) clustered. in addition, they asserted that intronic snps could regulate translation via epigenetic factors, such as hypermethylation and microrna alterations(19). their results support the present study as regard the importance of klk10 (rs 7259451) gene polymorphism on pc susceptibility. conclusions although the present study has limitations, such as small sample size, to the best of our knowledge, it was the first in vivo study which investigated the association between pc susceptibility and klk10 intronic snp. our results implicated that homozygote ancestral gg genotype and carrying g allele could be protective from pc. besides not only carrying mutant homozygote genotype tt, but also having t allele, could be a potential risk factor for pc. conflict on interest the authors declare that they have no conflict of interest. references 1. siegel rl, miller kd, jemal a. ca cancer j clin 2016; 66: 7–30. 2. cintra hs, pinezi jc, machado gd, et al. investigation of genetic polymorphisms related to the outcome of radiotherapy for prostate cancer patients. dis markers. 2013;35:701-10. 3. ostrander ea, stanford jl. genetics of prostate cancer: too many loci, too few genes. am j hum genet. 2000;67:1367-75. 4. lai j, kedda ma, hinze k, et al. psa/klk3 arei promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility. carcinogenesis 2007,28: 1032-39. 5. rahimi n, azizi m, bahari g, narouie b, hashemi m. association of egln2 rs10680577 polymorphism with the risk and clinicopathological features of patients with prostate cancer.. asian pac j cancer prev. 2020;21:1221-26. 6. shaik ap, jamil k, das p. cyp1a1 polymorphisms and risk of prostate cancer: a meta-analysis. urol j. 2009;6,78-86. 7. simforoosh n, dadpour m, mousapour p, shafiee a, hashemi bm. factors predicting prostate specific antigen failure following radical prostatectomy: experience with 961 patients. urol j. 2020;17, 486-91. 8. borgoño ca, michael ip, diamandis ep. human tissue kallikreins: physiologic roles and applications in cancer. mol cancer res. 2004;2: 257-80. 9. zhang y, bhat i, zeng m, et al. human kallikrein 10, a predictive marker for breast cancer. biol chem. 2006;387:715-21. 10. planque c, aïnciburu m, heuzé-vourc'h n, régina s, monte m, courty y. expression of the human kallikrein genes 10 (klk10) and 11 (klk11) in cancerous and non-cancerous lung tissues. biol chem. 2006;387:783-8. 11. yousef gm, polymeris me, yacoub gm, et al. parallel overexpression of seven kallikrein genes in ovarian cancer. cancer res. 2003; 63: 2223-27. 12. bayani j, paliouras m, planque c, et al. impact of cytogenetic and genomic aberrations of the kallikrein locus in ovarian cancer. mol oncol. 2008;2:250-60. 13. angelopoulou k, karagiannis gs. the canine kallikrein-related peptidases 9 and 10: structural characterization and expression in mammary cancer. mamm genome. 2009; 20:758-67. 14. shaw jl, diamandis ep. distribution of 15 human kallikreins in tissues and biological fluids. clin chem. 2007;53:1423-32. 15. yousef gm, white nm, michael ip, et al. identification of new splice variants and differential expression of the human kallikrein 10 gene, a candidate cancer biomarker. tumour biol. 2005;26: 227-35. 16. sidiropoulos m, pampalakis g, sotiropoulou g, katsaros d, diamandis ep. downregulation of human kallikrein 10 (klk10/nes1) by cpg island hypermethylation in breast, ovarian and prostate cancers. tumour biol. 2005;26:324-36. 17. luo ly, bunting p, scorilas a, diamandis ep. human kallikrein 10: a novel tumor marker for ovarian carcinoma? clin chim acta. 2001;306:111-18. 18. bharaj bb, luo ly, jung k, stephan c, diamandis ep. identification of single nucleotide polymorphisms in the human kallikrein 10 (klk10) gene and their association with prostate, breast, testicular, and ovarian cancers. prostate 2002;51: 35-41. 19. batra j, tan ol, o’mara t, et al. kallikreinrelated peptidase 10 (klk10) expression and single nucleotide polymorphisms in ovarian cancer survival. int j gynecol cancer 2010;20:529-36. klk10 in prostate cancergüleç yılmaz et al. miscellaneous the effect of interfascial injection on obturator nerve block compared with nerve stimulating approach by ultrasound-guide: a randomized clinical trial yong beom kim,1 hee yeon park,1 kyung mi kim,1 hyeon ju shin,2 su bin kim,1 mi geum lee1* purpose: this study was conducted to evaluate whether the ultrasound-guided interfascial injection technique is really compatible with the ultrasound-guided nerve stimulating technique for obturator nerve block (onb) at the inguinal crease after bifurcation of the obturator nerve. materials and methods: a total 62 onbs were performed for transurethral resection of bladder tumors under spinal anesthesia, and were divided into two groups, that is, to an ultrasound-guided onb with nerve stimulation control group (the us-ns group) or an ultrasound-guided interfascial injection experimental group (the us-ifi group). in the us-ifi group, complete onb was confirmed using a nerve stimulator at 5 min after completing the injection, and if residual twitching remained, another local anesthetic was injected; in such cases blocks were considered to have ‘failed’. during turb surgeries, two urology assistants determined obturator reflex grade (i-iv) at 15 min after injection completion in both groups. results: we assumed that the us-ns group achieved complete onb in all cases. six cases in the us-ifi group failed to achieve complete onb (failure rate: 0% versus 19.4%, p = .012). there was one case of grade ii obturator reflex in each group. conclusion: the ultrasound-guided interfascial injection technique was not compatible with the ultrasound-guided nerve stimulating technique for onb at the inguinal crease. keywords: bladder tumor; nerve block; obturator nerve; transurethral resection; ultrasound introduction transurethral resection of bladder tumor (turb) is an essential treatment for bladder tumors,(1) but direct electrical stimulation of the obturator nerve (on) during turb can trigger an inadvertent adductor muscle spasm, which can cause a serious complication like bladder perforation.(2,3) the majority of bladder cancer patients are elderly and have various comorbidities, which increase the risk of complications after general anesthesia.(4) furthermore, even general anesthesia with muscle relaxants does not eliminate the risk of adductor muscle spasm.(2) spinal anesthesia using a selective obturator nerve block (onb) offers an alternative means of anesthesia for turb, but adductor muscle spasm can be induced when onb is incomplete.(2,3) nerve stimulators have been used under ultrasound guidance to enhance the efficacy of onb,(2,5,6) though recently, it has been reported onb can be performed by interfascial injection under ultrasound guidance without a nerve stimulator with similar efficacies.(7,8) basically, the on is known to divide into two branches after exiting the obturator canal. the anterior branch is located in fascial planes among adductor longus, 1department of anesthesiology and pain medicine, gil medical center, gachon university college of medicine, incheon, republic of korea. 2department of anesthesiology and pain medicine, korea university anam hospital, seoul, republic of korea. *correspondence: department of anesthesiology and pain medicine, gachon university college of medicine, gil medical center, , incheon 21565, republic of korea tel: +82-32-460-3637, fax: +82-32-469-6319, e-mail: mikeum2@gilhospital.com. received january 2018 & accepted september 2018 adductor brevis, and pectineus muscles, whereas the posterior branch is located between the adductor brevis and adductor magnus muscles at the inguinal crease.(7,8) therefore, onb has been performed using anterior and posterior branch blocks at the inguinal crease level.(4,7,8) but many clinicians are reluctant to perform onb caused by varied anatomic locations.(9) moreover, on itself is very thin and generally embedded in an intermuscular septum, so it is difficult to be found even in ultrasound image and also difficult to be electrically stimulated.(5) therefore, we were interested in ultrasound-guided interfascial injection, which only needs to distinguish interfascial layers, not on, and does not need to use nerve stimulator. since incomplete block can cause direct harm to patients, we thought that decreasing the rate of incomplete block was important for generalization of that injection clinically. in this study, we sought to determine whether ultrasound-guided interfascial injection is really compatible with ultrasound-nerve stimulation for turb under spinal anesthesia. urology journal/vol 16 no. 4/ july-august 2019/ pp. 407-411. [doi: http://dx.doi.org/10.22037/uj.v0i0.4386] vol 16 no 04 july-august 2019 408 materials and methods study population written informed consent was obtained from all patients after obtaining approval from our institutional ethics committee (gairb2014-337) and registering in the university hospital medical information network (umin) clinical trials registry (umin000020534). this study was performed in accordance with the consort 2010 checklist. inclusion and exclusion criteria sixty-two american society of anesthesiologists physical status (asa) i or ii patients were enrolled in the study, who underwent spinal anesthesia with onb for elective turb due to bladder tumors. the exclusion criteria were as follows: diabetes or peripheral neuropathy, motor or sensory deficits in the lower extremities, asa of iii or greater, a coagulation disorder, anticoagulant medication, known allergy to local anesthetics, contraindication for spinal anesthesia (infection at injection site, severe scoliosis, or fusion surgery), lack of cooperation, and refusal to participate. we conducted a randomized, controlled, parallel group study (figure 1). written, informed consent was obtained on the day before the surgery. patients were assigned into 1 of 2 groups randomly, that is, an ultrasound-guided onb with nerve stimulation control group (the us-ns group) or an ultrasound-guided interfascial injection experimental group (the us-ifi group) to receive onb in the inguinal crease using random integer set generator (http://www.random.org/). the ratio of allocation was 1:1. the researcher not involved in performing the block generated the randomization set, and enrolled participants. all the performances were conducted in the operating room of gil medical center, gachon university college of medicine, incheon, korea, from jan 2016 to march 2016. procedures routine monitoring was begun and spinal anesthesia with hyperbaric 0.5% bupivacaine 12-15 mg was administered to achieve a level of anesthesia above t 10 (at least t10 to t4) in all patients. after setting the patient in a supine position, an anesthetic nurse who is unrelated in this study closed the curtain in front of the patient’s face to hide the procedure. and the patient’s affected leg was slightly abducted and rotated externally without knee flexion,(9) and figure 1. patients’ enrollment algorithm. figure 2. obturator nerve block sites. the fascial planes of the adductor muscles and the pectineus muscle are identified (a). the target of anterior branch block is arrowed ①, and that of the posterior branch block is also arrowed ②. separation of target muscles for anterior branch block (b) and posterior branch block (c) is shown. the arrowhead indicates the needle. al, adductor longus muscle; ab, adductor brevis muscle; am, adductor magnus muscle; p, pectineus muscle. ultrasound-guided obturator nerve block-lee et al. the inguinal region was prepared with a povidone iodine solution. a 10 mhz linear probe (zonare medical systems, california, usa) was equipped with a sterile plastic cover and gel, and the transducer was positioned parallel to the inguinal crease at 90° to the skin and the image depth was set at 4-5 cm. the inguinal region was examined laterally from the femoral vein until the pectineus muscle was identified with the adductor longus, adductor brevis, and adductor magnus medially at the inguinal crease (figure 2a). in the us-ns group, a 22-gauge, 120-mm stimulating needle (stimuplex insulated needle; d plus b. braun, melsungen, germany) attached to a nerve stimulator (stimuplex hns12; b. braun, melsungen, germany) was advanced via an ultrasound in-plane approach in a lateral to medial direction to position the needle tip at the junction of adductor longus, adductor brevis, and pectineus muscles within the fascia for an anterior branch block (figure 2a, arrow ①). the nerve stimulator was then turned on, and if adductor muscle twitching was observed even at 0.3 ma, 10 ml of local anesthetic (la; 1.5% lidocaine + epi 1:200,000) was slowly injected into the muscle interface after negative aspiration (figure 2b), and then the needle was positioned at the junction of adductor brevis and adductor magnus muscles within the fascia for a posterior branch block (figure 2a, arrow ②); 10 ml of la was injected in the same manner (figure 2c). if adductor muscle twitching did not occur at these locations, additional needling was performed to locate the target branch within the fascia. transducer tilting cranially 0°-20° was also allowed if twitching did not occur with the transducer normal to skin. if la misdistributed into muscle, the needle was redirected until the correct spread of la was visualized. in the us-ifi group, the same amount of la was injected at anterior and posterior branch sites within fascia without a nerve stimulator. five minutes after the main branches block,(10) the needle was re-advanced to search for residual twitching by the same anesthesiologist.(11) if twitching was still observed in both the medial aspect of thigh and the sonogram even at 0.5 ma, another 5 ml of la was injected into the twitching site and block was documented as a failure. after the la injection on both groups, we were able to confirm that the adductor muscle twitching disappeared. all blocks were performed by one anesthesiologist with experience of more than 60 onbs. evaluations the primary outcome was failure rate of onb confirmed with nerve stimulator only according to this study design. in the us-ns group, failure rate was assumed zero in all cases because we confirmed the twitch of adductor muscles was disappeared when we injected the la. in us-ifi group, the performer blocked the first injection using only the anatomical landmark on the us image, and then blocked with nerve stimulator at the second injection for evaluating the twitches on the first injection site, the failure rate. therefore, we made sure that the same researcher performed both injections, and made other researchers who unknown group assignments confirmed images, and check the success or failure of onb. it can also introduce performer bias, but different approaches were necessary in this study. the secondary outcome was the extent of adductor motor block measured with obturator reflex grade. after onb, two urologic assistants who were unaware of the group assignments entered the operating room, and patients were positioned in a lithotomy position. neoplasm endoscopic resection was started using a bipolar resectoscope (electrical current: 280 w) and endovesical irrigation with a normal saline solution. surgery was performed by either of six surgeons at random. we requested two urologic assistants to perform obturator reflex grading 15 min after completing injection on both groups as described by lee et al.(10): gr i no movement or palpable muscle twitching, gr ii palpable muscle twitching without movement, gr iii slight movement of the thigh not interfering with the surgical procedure, and gr iv vigorous movement interfering with the surgical procedure. table 1. patients’characteristics in two groups. variables us-ns group (n = 31) us-ifi group (n = 31) p-value age, year; mean ± sd 70 ± 11 68 ± 14 .461 sex (m/f); n 25/6 25/6 .625 height, cm; mean ± sd 166.3 ± 6.3 164.1 ± 7.6 .226 weight, kg; mean ± sd 63.1 ± 10.2 61.9 ± 11.3 .655 asa class (i/ii); n 11/20 7/24 .201 abbreviations: m, male; f, female; asa, american society of anesthesiologists physical status; us-ns group, ultrasound-guided nerve stimulator group; us-ifi group, ultrasound-guided interfascial injection group. variables us-ns group (n = 31) us-ifi group (n = 31) p-value duration of surgery, min; mean ± sd 71.9 ± 40.6 69.4 ± 42.1 .807 dose of 0.5% hyperbaric marcaine, mg; mean ± sd 13.8 ± 1.4 13.9 ± 1.1 .762 spinal level (t10/t8/t6/t4); n 1/3/18/9 5/4/15/7 .343 side (right/left); n 15/16 17/14 .400 failure rate; n (percentage) 0 (0)a 6 (19.4) .012b obturator reflex grade (i/ ii/ iii / iv); n 30 / 1 / 0 / 0 30 / 1 / 0 / 0 abbreviations: t, thoracic level; us-ns group, ultrasound-guided nerve stimulator group; us-ifi group, ultrasound-guided interfascial injection group. a nerve stimulator is the only tool in confirming the complete onb before turb surgery. thus, it is assumed complete onb is achieved in all cases in the us-ns group. b statistical significance is accepted for p values < .05. table 2. obturator nerve block data for the two groups. ultrasound-guided obturator nerve block-lee et al. miscellaneus 409 vol 16 no 04 july-august 2019 410 statistical analysis results are presented as mean ± standard deviations, unless otherwise indicated. the statistical analysis was performed using the statistical package for social sciences software (spss 12.0 for windows; spss inc., chicago, il, usa). the chi-squared test or the fisher’s exact test were used to analyze categorical data (gender, asa status, block site, spinal level, failure rate, and reflex grade), and the student’s unpaired t-test was used to compare continuous data (age, height, weight, surgery time, and marcaine doses). statistical significance was accepted for p values < .05. in a preliminary study, success was achieved in 7 of 10 patients who underwent ultrasound-guided interfascial injection. twenty eight blocks were required per group for an α value of 0.05 and a power of 90%, and 31 blocks were determined necessary assuming a dropout rate of 10%. results in all, 62 patients were included in the present study. patients’ enrollment algorithm has been illustrated in figure 1. group demographic data are shown in table 1, and data regarding the onb procedure in table 2. the number of skin punctures to onb was one for all 62 blocks. no vascular puncture or blood aspiration occurred during procedures, and no neurologic, vascular or infection-related complications were detected by follow-up urology chart reviews. nerve stimulator was the only tool in confirming the success or failure of onb before turb surgery. thus, we assumed that complete onb was achieved in all cases in the us-ns group, and six cases in the us-ifi group failed to achieve complete onb. one case in each group exhibited grade ii obturator reflex during the surgery, but with no other complication. no case in either group required general anesthesia to complete surgery. discussion our results show that the ultrasound-guided interfascial injection technique is not compatible with the ultrasound-guided nerve stimulating technique for onb at the inguinal crease. block was not achieved in six cases in the us-ifi group. two types of residual twitching were found in failed cases, that is, four cases of twitching on the inner part of the fascial layers beyond the area of la spread (2 cases of anterior branch block, 2 cases of posterior branch block), and two cases of another form of twitching near an la injected site when the transducer was changed slightly (1 case of anterior and posterior branch block, 1 case of anterior branch block). in this study, we decided to target fascia, not an on,(9) which is very small and difficult to image.(2,4,5,7) on echogenicity within fascia is not distinguishable from fascia in many cases.(9) in us-ifi group, we confirmed la spread along the adjacent interfascial layers, not stagnating on a spot of injection. initially, we supposed that the us-ifi group would be compatible with us-ns group, but twitching points beyond the area of la spread were observed in some cases. it has been well-established incomplete onb is due to inadequate la diffusion despite a correct electrical end point.(7,8) at the inguinal crease, many muscle layers are near the on pathway, which is intertwined and complicated,(12) and thus, slight tilting of the transducer can result in missing the pathway. for example, in some cases there was no twitching when the probe was held perpendicular to skin, but twitching occurred when the probe was tilted 10° cranially. saranteas t et al. addressed the dynamics of nerve position and found that probe angulations can change nerve position within the anatomic line.(13) we allowed 10-20° angulation of the probe, because high transducer angles make onb technically difficult and increasing the risk of serious complications.(2,12) reports about anterior branch block cite success rate of more than 90%,(3,6,10) and other interfascial techniques also have been reported to have good success rates.(7,8) however, even one failed-case should be avoided because of the seriousness of bladder perforation.(11) interfascial injection is a volumetric technique that relies on diffusion of the injected drug, and it has been shown the anterior and posterior divisions of on have multiple branching patterns that are widely distributed among the adductor muscles.(9,10,12,13) the authors of a study showing the compatibility of interfascial injection approach on onb stated that using nerve stimulator showed better accuracy in blocking the posterior branch.(7) we reapplied the nerve stimulator for searching the failed-cases of us-ifi group, and additional la was injected for patients’ safety. just once, stimulation of electric resectors to the bladder walls for checking the block quality can cause a strong contraction of the adductor muscles and induce a bladder perforation.(7) so we used sufficiently low level of stimulant current (0.30.5 ma) to confirm that the needle tip was placed as close as possible to the nerve and for the safety reasons. (11) in this study, we could not prevent obturator reflex totally even when complete onb had been achieved. we tend to be nervous about even slight muscle contraction due to severity of bladder perforation, but in practical situations, operators need to be aware that even complete onb does not guarantee complete adductor motor block because innervations from the femoral and sacral plexus also dominate contribute to adductor motor strength.(8) definitions of complete onb have not been standardized, and in clinical situations, evaluation of onb is time-consuming and difficult.(7,12) we assumed that complete onb was achieved in all cases in the us-ns group, and counted failed cases in the us-ifi group, which can introduce bias. this study cannot be categorized as a double-blind study, which is one of the limitations of this study. the performers were not blinded to the group assignments (one injection for us-ns group or. two injections for us-ifi group), even though urologic assistants who evaluate obturator reflex were unaware of the group assignments because they entered the operating room after onb. conclusions in conclusion, the ultrasound-guided interfascial injection technique was not compatible with the ultrasound-guided nerve stimulating technique for onb at the inguinal crease, and thus, we suggest that combined use of ultrasound and nerve stimulator for onb. finally, we emphasize successful onb does not guarantee complete adductor motor block. ultrasound-guided obturator nerve block-lee et al. conflict of interest none declared. references 1. ong el, chan st. transurethral surgery and the adductor spasm. ann acad med singapore. 2000;29:259-62. 2. moningi s, durga p, ramachandran g, murthy pv, chilumala rr. comparison of inguinal versus classic approach for obturator nerve block in patients undergoing transurethral resection of bladder tumors under spinal anesthesia. j anaesthesiol clin pharmacol. 2014;30:41-5. 3. thallaj a, rabah d. efficacy of ultrasoundguided obturator nerve block in transurethral surgery. saudi j anaesth. 2011;5:42-4. 4. shah nf, sofi kp, nengroo sh. obturator nerve block in transurethral resection of bladder tumor: a comparison of ultrasoundguided technique versus ultrasound with nerve stimulation technique. anesth essays res. 2017;11:411-5. 5. helayel pe, da conceicão db, pavei p, knaesel ja, de oliveira filho gr. ultrasoundguided obturator nerve block: a preliminary report of a case series. reg anesth pain med. 2007;32:221-6. 6. fujiwara y, sato y, kitayama m, shibata y, komatsu t, hirota k. obturator nerve block using ultrasound guidance. anesth analg. 2007;105:888-9. 7. manassero a, bossolasco m, uques s, palmisano s, de bonis u, coletta g. ultrasound-guided obturator nerve block: interfascial injection versus a neurostimulationassisted technique. reg anesth pain med. 2012;37:67-71. 8. sinha sk, abrams jh, houle tt, weller rs. ultrasound-guided obturator nerve block: an interfascial injection approach without nerve stimulation. reg anesth pain med. 2009;34:261-4. 9. soong j, schafhalter-zoppoth i, gray at. sonographic imaging of the obturator nerve for regional block. reg anesth pain med. 2007;32:146-51. 10. lee sh, jeong cw, lee hj, yoon mh, kim wm. ultrasound guided obturator nerve block: a single interfascial injection technique. j anesth. 2011;25:923-6. 11. akata t, murakami j, yoshinaga a. lifethreatening haemorrhage following obturator artery injury during transurethral bladder surgery: a sequel of an unsuccessful obturator nerve block. acta anaesthesiol scand. 1999;43:784-8. 12. anagnostopoulou s, kostopanagiotou g, paraskeuopoulos t, chantzi c, lolis e, saranteas t. anatomic variations of the obturator nerve in the inguinal region: implications in conventional and ultrasound regional anesthesia technique. reg anesth pain med. 2009;34:33-9. 13. saranteas t, paraskeuopoulos t, alevizou a, et al. identification of the obturator nerve divisions and subdivisions in the inguinal region: a study with ultrasound. acta anaesthesiol scand. 2007;51:1404-6. miscellaneus 411 ultrasound-guided obturator nerve block-lee et al. female urology pelvic floor muscle training with or without tibial nerve stimulation and lifestyle changes have comparable effects on the overactive bladder. a randomized clinical trial lina bykoviene1*, raimondas kubilius1, rosita aniuliene2, egle bartuseviciene2, arnoldas bartusevicius2 purpose: to compare effects of transcutaneous posterior tibial nerve stimulation (tptns) and pelvic floor muscle training (pfmt) in women with overactive bladder syndrome (oab). material and methods: we randomized 67 women ≥ 18 years with oab to three parallel groups: group i (n = 22) received life-style recommendations (lsr) only; group ii (n = 24) had lsr + pfmt and group iii (n = 21) had lsr + pfmt + tptns. urgency, evaluated by a 3-day voiding diary before treatment and six weeks later, was the main outcome measure. the king‘s college health questionnaire was also administered. results: urgency was significantly reduced in all three groups from 5.1 ± 3.7 to 3.8 ± 3.2 episodes/day, p = .016 in group i, from 5.2 ± 3.6 to 3.2 ± 2.9, p = .006 in group ii and from 6.8 ± 3.1 to 4.4 ± 3.5 in group iii, p = .013. there were no intergroup differences. the questionnaire results improved significantly only in group iii as regards general health perception, role limitation, physical and social limitations without intergroup differences. women improved their micturition frequency in two groups from 8.9 ± 3.2 to 7.5 ± 2.3 episodes/per day, p = .025 in group ii, and from 8.8 ± 2.3 to 7.4 ± 2.0, p = .001 in group iii, but only in group ii was a significant reduction of urinary incontinence seen from 3.8 ± 4.6 to 2.9 ± 4.8 episodes/day, p = .045. conclusion: all three treatments lead to effective short-term reduction of urgency in women with oab, but longterm efficacy evaluation is required. keywords: multimodal treatment; overactive bladder; pelvic floor muscle training; posterior tibial nerve; transcutaneous electrical nerve stimulation. introduction according to the international continence society (ics) and international urogynecological association (iuga), overactive bladder syndrome (oab) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology(1). this is a chronic condition affecting millions of women worldwide and morbidity increases with age(2). though not life-threatening, it has a great impact on quality of life (qol)(3, 4). while oab pathogenesis is still not well understood, the main purpose of treatment is to reduce oab symptoms and thus improve patient‘s qol. in older age groups co-morbidities and medications affect both pharmaceutical and invasive treatment options. therefore, there is a demand to develop more tolerable and effective treatments to manage overactive bladder states. all guidelines recommend pelvic floor muscle training (pfmt) as a first-line treatment for patients with oab or urge urinary incontinence(5–7), but the evidence for effectiveness is limited. the rationale is that increased pfm strength would allow better urge control by interfering with urethral–detrusor reflexes, thus producing inhibition of pathological detrusor contractions. another well tolerated, non-invasive new treatment option is transcutaneous posterior tibial nerve stimu1department of rehabilitation, lithuanian university of health sciences, kaunas, lithuania. 2department of obstetrics and gynecology, lithuanian university of health sciences, kaunas, lithuania. *correspondence: rehabilitation department, lithuanian university of health science, eiveniu st. 2, lt50161, kaunas, lithuania. tel: +37065606533, fax: +37037326324, e-mail: lina.bykoviene@lsmuni.lt. received september 2017 & accepted march 2018 lation (tptns)(8-14). as the s2-s4 nerve roots (mainly s3) provide motor supply to the bladder and the posterior tibial nerve contains s3 fibres, the hypothesis is that retrograde impulses during tptns reach the sacral micturition centre and thus cause detrusor relaxation by inhibiting parasympathetic motor neurons. evidence for the effectiveness of tptns has grown and may be similar or even better than antimuscarinics such oxybutynin(8,9). as pfmt (reducing urge incontinence) and tptns (reducing urgency) act in different ways, their combination could lead to summation effects. schreiner at al.(10) evaluated pfmt and tptns in combination and their results supported this. our objective was to evaluate pfmt and tptns combination efficacy for women with oab and to compare it with the effects of pfmt alone. material and methods study design a randomized multi-arm parallel-group clinical trial with balanced randomization (1:1:1 for three groups) was conducted from april 2015 to june 2017 at the department of rehabilitation of lithuanian university of health sciences in kaunas, lithuania. the study was approved by the kaunas regional biomedical research ethics committee (no be-2-8) and all participants signed an informed consent. all new outpatients who female urology 186 came during that time to the rehabilitation department were assessed for eligibility. the study group allocation was by a sequentially running computer-generated(16) block randomization list (prepared by the statistician from lithuanian university of health sciences) as blocks of three unique numbers/block, ranging from 1 to 3 unsorted. women were evaluated for eligibility and assigned to the groups by the same person. on the basis of the reduction rate of urgency incontinence after the pfmt by 27% and after the pfmt+tptns by 76%(10) we conducted a test with a significance level of 0.05 and power of 0.80 and anticipated that groups of equal size were required. we concluded that at least 19 women were needed in each group. inclusion and exclusion criteria inclusion criteria were as follows: non-pregnant women ≥ 18 years with clinical complaints of oab (urgency, urinary frequency, nocturia, and/or urgency incontinence) or mixed urinary incontinence with predominant urgency urinary incontinence type. exclusion criteria were: positive urine analysis and culture, residual urine ≥ 100ml, measured before for all women by bladder scanning, pelvic organ prolapse higher than grade ii by the pop-q quantification system, inability to perform the kegel exercises, presence of tptns contraindications (active implants (including cardiac pacemakers), malignancy, tissue bleeding or skin damage in the stimulation site). oab and non-invasive treatment-bykoviene at al. table 1. pre-treatment demographic and clinical evaluation data among groups. variables control (n = 22) pfmt (n = 20) pfmt+tptns (n = 19) p-value age, years 59.36.1 ±10.47 63.95 ± 10.75 63.95 ± 9.87 .262a bmi, kg/m2 30.54 ± 5.42 30.12 ± 5.66 28.43 ± 6.06 .470a duration of the oab symptoms, years 6.05 ± 5.41 4.95 ± 5.70 10.93 ± 13.75 .093a presence of menopause 18 (82) 17 (85) 16 (84) 1.00b menopause duration, years 10.58 ± 6.74 13.06 ± 8.99 12.44 ± 7.89 .614a presence of abdomen or pelvis operations 16 (73) 14 (72) 17 (90) .293b dominant mode of delivery vaginal vaginal vaginal .715b (vaginal or caesarean section) 19 (95) 16 (89) 16 (89) presence of perineal lesion 20 (91) 15 (71) 15 (79) .377b (rupture, episiotomy) during labour newborn weight, kg 3.83 ± 0.42 3.41 ± 0.52 3.61 ± 0.35 .019*a pfm power 1.95 ± 1.20 2.25 ± 0.72 1.89 ± 0.88 .462a pfm endurance, s 7.43 ± 3.16 8.45 ± 2.50 6.79 ± 3.17 .217a pfm repetition 8.57 ± 2.06 9.65 ± 0.88 9.58 ± 0.90 .030*a pfm fast repetition 18.19 ± 12.03 16.85 ± 5.47 17.58 ± 7.18 .887a abbreviations: pfmt, pelvic floor muscle training; bmi, body mass index; oab, overactive bladder; pfm, pelvic floor muscle; tptns, transcutaneous posterior tibial nerve stimulation; values are given as mean ± sd or number (percentage); a p value based on anova; b p value based on fisher’s exact test; * statistically significant difference among groups. figure 1. patient flow chart of the clinical study. vol 15 no 04 july-august 2018 187 evaluations in an initial interview age, duration of oab symptoms, menopause status, parity with birthweight(s), mode of delivery, perineal birth trauma or episiotomy, abdominal or pelvic operations were recorded. the king‘s health questionnaire (khq), validated for the lithuanian language, was used to evaluate qol. it consists of nine domains: general health perceptions, incontinence impact, role limitations, physical limitations, social limitations, personal relationships, emotions, sleep/energy, severity measures. each domain is evaluated from 0 to 100% (0% – the best qol, 100% – the worst qol). clinical examination included body mass index (bmi) and functional assessment of the pelvic floor muscles (pfm) by the perfect scheme(15). the latter was performed with the women in the supine position with her knees flexed and apart. pfm functions were evaluated by one-finger intravaginal palpation. the pfm contraction power (p) was graded according to the modified oxford grading system (from 0 meaning no contraction to 5 meaning strong contraction). the pfm contractions endurance (e) (in seconds), repetition (r) and fast repetition (f) were evaluated as numerical variables. the three-day voiding diary provided the number of daytime urinary frequency, urgency, nocturia, and urinary incontinence measured as the numerical variables (calculated as means of three days). interventions the treatment was as follows: control group i: participants were provided with written common lifestyle changing recommendations (lsr) regarding weight loss, fluid intake, decreasing caffeine and alcohol intake as well as smoking cessation, limiting spicy food, sour, gassy products, artificial sweeteners, increasing fiber-rich food, physical activity and kegel exercises (common, not individualized written instructions were provided to the women). patients were encouraged to follow these recommendations for six weeks. group ii: pfmt participants were provided with the same recommendations as in the control group. according to the perfect scheme evaluation records, they were instructed via digital palpation to perform an individualized pfmt program at home. for example, if the perfect scheme was 2/5/6/11 (p/e/r/f), the participant was instructed to hold submaximal to maximal pfm contractions for 6 seconds and repeat this seven times with a 4 second rest period after each contraction, and after oab and non-invasive treatment-bykoviene at al. table 2. khq results within and among groups. domain (%): control (n=22) pfmt (n = 20) pfmt+tptns (n=19) pb-value d general health perceptions before 51.14 ± 14.39 50.00 ± 11.47 51.32 ± 19.50 .958 after 53.41 ± 17.75 43.75 ± 13.75 46.05 ± 17.21 .143 .054 pa-value .427 .056 .042* d .099 .361 .203 incontinence impact before 65.59 ± 30.82 68.33 ± 25.38 73.77 ± 23.75 .623 after 69.77 ± 25.04 66.67 ± 26.56 63.18 ± 24.66 .711 .036 pa-value .394 .716 .082 d .105 .045 .317 role limitations before 54.52 ± 34.55 54.10 ± 24.75 63.16 ± 23.99 .536 after 58.32 ± 22.91 45.82 ± 28.04 42.07 ± 23.85 .098 .082 pa-value .504 .231 .001* d .092 .235 .626 physical limitations before 61.35 ± 31.44 52.48 ± 35.55 64.95 ± 27.71 .453 after 67.42 ± 24.38 47.43 ± 30.18 53.53 ± 29.23 .066 .065 pa-value .293 .522 .019* d .153 .111 .284 social limitations before 35.55 ± 30.25 25.28 ± 23.37 36.81 ± 24.84 .327 after 36.31 ± 28.71 20.29 ± 25.28 25.67 ± 26.61 .154 .049 pa-value .893 .298 .016* d .018 .145 .306 personal relationships before 22.70 ± 35.17 43.37 ± 41.03 16.67 ± 29.64 .193 after 26.70 ± 33.49 39.58 ± 45.37 22.92 ± 34.43 .859 .054 pa-value .359 .593 .598 d .084 .062 .138 emotions before 58.06 ± 31.11 52.78 ± 32.27 62.01 ± 30.67 .655 after 56.52 ± 34.34 45.02 ± 27.40 49.09 ± 35.42 .513 .024 pa-value .779 .172 .058 d .033 .183 .276 sleep/energy before 49.26 ± 34.24 44.98 ± 28.06 55.28 ± 25.52 .559 after 50.03 ± 26.22 40.78 ± 22.56 49.09 ± 29.69 .471 .024 pa-value .874 .361 .087 d .018 .117 .158 severity measures before 50.95 ± 22.20 56.32 ± 16.63 56.14 ± 24.45 .652 after 51.61 ± 27.13 49.67 ± 20.95 49.09 ± 29.48 .948 .030 pa-value .842 .062 .120 d .019 .249 .184 abbreviations: khq, king‘s health questionnaire; pfmt, pelvic floor muscle training; tptns, transcutaneous posterior tibial nerve stimulation values are given as mean ± sd; p value based on anova; pa within groups; pb between groups; * statistically significant difference. female urology 188 few minutes to perform 12 fast contractions. all women were instructed to practice this regimen five times daily (in the lying, standing, and sitting position alternately with the legs apart). the women were also instructed to contract their pfms during an urge to void. after three weeks participants re-evaluation by the perfect scheme was done and a new exercise program established with reference to this new records. compliance over the six weeks time was monitored. group iii: pfmt + tptns these women were provided with the same recommendations as patients in the control group and in the pfmt group. in addition, they had 18 tptns procedures at the department of rehabilitation, i.e. 30 min, three times/week over six weeks. tptns was performed by a rehabilitation nurse who used a programmed device for urge incontinence (“btl-5000“, program no e-5781, www.btlnet.com), programmed for 10 hz frequency, 300 µs pulse width with a work/rest regimen to cover work – 10 s, rest – 15 s, ramp up – 3 s, ramp down – 2 s. intensity was adjusted to the highest level (10 – 50 ma), but lower than possibly causing pain or discomfort to the patient. two surface electrodes (5 x 5 cm) were placed along the posterior tibial nerve path on each leg: one surface electrode was placed behind the medial malleolus (negative) and another was placed 10 cm above the first one (positive). outcome assessment all patients completed the khq and the 3-day voiding diary before treatment and after six weeks by themselves. primary outcomes of efficacy were urgency episodes/day (from the voiding diary) as the most bothersome and most significant symptom of oab. secondary outcomes: qol changes measured by khq questionnaire, other voiding diary variables (daytime urinary frequency, nocturia and urinary incontinence episodes/day), pain in lumbosacral, pelvic or perineal regions during pfmt and skin irritation, allergic reactions, pain under the electrodes or intolerance of electrical currents during tptns. statistical analysis statistical analysis was performed using the spss software package. the reliability of the khq was investigated by cronbach‘s coefficient alpha (α) using data provided by the total baseline sample and after treatment. descriptive analysis was carried out using frequencies, means, and standard deviations. for comparison between groups, we used chi-squared or fisher’s exact test if an expected chi-value was < 5 for categorical variables. student’s t-test used for independent samples to verify differences between means. to compare the means before and after intervention in each group, we used the student’s t-test for paired samples. the anova was used for repeated measures and tukey’s test for multiple comparisons. p < .05 was considered significant. results a total of 67 women were randomized and 61 completed the study. six patients failed to comply with the study protocol and were excluded from trial: four from the pfmt group (two refused because of time needed for treatment, two had long-lasting exacerbation of co-morbidities) and two women from the pfmt + tptns group refused participation because of time needed for treatment. withdrawal rate – 9%. a study overview for the per-protocol analysis is shown in figure 1. prior the treatment, there were no significant differences between groups for most characteristics and clinical evaluation variables, except birthweight of the women´s children (i vs ii group, 3.83 ± 0.42 kg vs 3.41 ± 0.52 kg, respectively, p = .014) and pfm repetition from the perfect scheme (p = .030) (table 1). there were no significant differences among groups in all khq oab and non-invasive treatment-bykoviene at al. table 3. voiding diary results within and among groups. voiding diary variables: control (n=22) pfmt (n=20) pfmt+tptns (n=19) pb-value d fluid intake/day (ml) before 1574.55 ± 643.85 1704.44 ± 579.86 1540.86 ± 461.03 .637 after 1347.91 ± 468.98 1485.37 ± 452.47 1431.24 ± 465.11 .626 .015 pa-value .017 .054 .301 d .285 .299 .169 urination amount/day (ml) before 1988.82 ± 1041.85 1887.03 ± 577.01 1728.51 ± 427.95 .540 after 1845.62 ± 1107.11 1597.98 ± 645.32 1553.57 ± 547.73 .471 .016 pa-value .501 .036* .137 d .094 .334 .255 urinary frequency/day before 9.83 ± 6.92 8.86 ± 3.24 8.81 ± 2.31 .733 after 8.58 ± 4.58 7.52 ± 2.30 7.36 ± 2.04 .427 .017 pa-value .109 .025* .001* d .151 .338 .471 incontinence episodes/day before 2.06 ± 2.46 3.84 ± 4.62 1.78 ± 2.16 .055 after 2.27 ± 3.07 2.89 ± 4.83 1.58 ± 2.14 .516 .061 pa-value .616 .045* .608 d .053 .142 .066 urgency epizodes/day before 5.14 ± 3.73 5.24 ± 3.64 6.76 ± 3.12 .278 after 3.79 ± 3.22 3.17 ± 2.87 4.43 ± 3.49 .485 .033 pa-value .016 .006* .013* d .274 .447 .523 nocturia epizodes/day before 2.17 ± 1.96 1.55 ± 1.80 1.93 ± 1.00 .480 after 1.82 ± 1.35 1.60 ± 1.54 1.56 ± 1.04 .787 .019 pa-value .226 .819 .170 d .147 .021 .270 abbreviations: pfmt, pelvic floor muscle training; tptns, transcutaneous posterior tibial nerve stimulation values are given as mean ± sd; p value based on anova; pa within groups, pb between groups. * statistically significant difference. vol 15 no 04 july-august 2018 189 domains (table 2) or 3-day voiding diary variables (table 3). both pfmt and pfmt+tptns groups accomplished their individualized pfmt home program in 82% and 83% respectively, p = .875. khq questionnaire khq internal consistency was high with the cronbach α-values ranging from 0.861 of baseline data to 0.886 after six weeks treatment. the questionnaire results improved significantly only within group iii as regards general health perception, role limitation, physical and social limitations without intergroup differences (table 2). voiding diary women in all three groups had significantly reduced urgency after treatment without a difference among them (table 3). urinary frequency had decreased significantly after treatment within groups ii and iii, but only group ii showed significantly reduced urinary incontinence episodes/day within group (table 3). women significantly reduced fluid intake after treatment within control group: 14% = 227ml/day, p = .017. there were no significant differences in all voiding diary variables after treatments as compared between the three study groups. no side effects were noticed with the pfmt or tptns therapies. discussion women in all groups improved significantly according to the voiding diary assessment. however, only in the control (lsr) group did women significantly decrease the fluid intake by the end of the treatment period. hashim et al. evaluated fluid management for patients with oab and reported that a 25% reduction in fluid intake was associated with improved daily urgency, frequency and nocturia episodes(17). the control women reduced just one oab symptom, urgency, by 25% / day. the lsr+pfmt and lsr+pfmt+tptns groups decreased the fluid intake by 13% (219 ml/day) and 7% (110 ml/day), respectively, compared to 14% (227 ml/ day) among the controls, but still reduced their urgency episodes by 40% and 34%, respectively. while urgency can be reduced by life-style regulation, greater reductions are achieved by combining this with pfmt. the difference between the groups were, however, small and not of clinical significance. urgency reduction by combination of pfmt and tptns for women with oab has, however, not been evaluated before. an important aspect in oab management is the patient’s appreciation of their quality of life. there are several validated and reliable questionnaires to measure urinary symptom impact on qol. according to the european association of urology guidelines on urinary incontinence(6) khq is valid, reliable and responsive as a means to measure change over time. only the women treated by the combination of lsr, pfmt and tptns most effectively improved their qol, i.e. in four of nine khq domains. in contrast, within groups i and ii, lsr alone or when added to pfmt had no significant impact on khq domains after six weeks of treatment. schreiner’s at al.(10) study revealed significantly greater improvement in the similar multimodal (pfmt + tptns) group than in the pfmt group in several khq fields, including impact of urinary incontinence, limitations of daily activities, physical limitations, emotions, sleep/provision, and measures of severity. the multimodal group was in their study significantly superior to the pfmt group in reducing urgency incontinence episodes and nocturia and reduction was significantly greater than the pfmt group, but changes of urgency were not measured. we could not reveal differences in voiding diary variables. both our and schreiner’s studies had relatively small study groups of older women by mean age with the long lasting oab symptoms, but schreiner’s study had no control group, treatment duration was twice as long, tptns was used in continuous electrical current mode once a week and pfmt regimen was less intensive and not individualized. supposedly, schreiner at al. study showed greater improvements than ours due to longer treatment duration or continuous electrical current mode of tptns procedure. there is no study that compares interrupted stimulation with continuous mode during tptns procedure. in another study(18) three different treatments for women with oab with a similar pfmt arm were compared (n = 34). women were instructed to perform an individualized pfmt according to the perfect scheme, but at least three times daily and for six weeks longer than in our study. all khq domains were improved, but voiding diaries were incomplete contrasting with our study where they were fully completed. scaldazza et al. investigated similar multimodal (pfmt and non-invasive electrical stimulation) treatment, showing significantly improved women’s qol according to the oab-q sf questionnaire, but not a significant reduction of oab symptoms according to 3-day micturition diary, using intravaginal electrical stimulation with different parameters instead of posterior tibial nerve stimulation(19). though intravaginal stimulation has been considered effective for reduction of oab symptoms and improvement of quality of life(18,20–22), tptns may be more acceptable than intravaginal treatment in some cultures, such as ours, and it is also a cheaper approach. tptns has not been compared with intravaginal stimulation for oab treatment. a novel treatment approach used in our study was the bilateral tptns. the decision to stimulate both legs at the same time was made because it is unclear which leg should be stimulated for better results. tptns has an inhibitory effect on involuntary detrusor contractions through inhibition of somatic sacral and lumbar nerve fiber depolarization without affecting the micturition reflex(13). possibly, stimulation of both tibial nerves could lead to better inhibitory effects as highlighted recently(23). adding bilateral tptns to pfmt we most effectively improved participants’ quality of life, but results were not superior to the pfmt or lsr alone. pfmt can also modulate overactive bladder syndrome. increased urethral pressure can inhibit the sacral preganglionic innervation to the bladder through the guarding reflex(24). moreover, pfm contraction can stimulate the sympathetic nerve fibers of the internal urethral sphincter thereby causing a decrease in detrusor muscle pressure(25). it has been shown that pfmt improves urinary incontinence more often than no treatment(26) and greater efficacy could be achieved by increasing intensity(6), but there is limited evidence about efficacy to patients with oab(27). a limitation of our study was the short treatment duration with interrupted electrical current mode during the tptns procedure as well as unknown long-term oab and non-invasive treatment-bykoviene at al. female urology 190 oab and non-invasive treatment-bykoviene at al. effects of all three treatments. the study groups were also relatively small, but this also applies to the other studies referred to above(10,14,18-19). despite random allocation we were not able to conceal group assignment during the evaluation procedures. however, the women answered all questionnaires by themselves and the evaluator could not influence this. conclusions tptns and pfmt require an investment of time and effort by the patient and clinician to achieve maximum benefits, but the results show that the benefits are marginal in the short term and they do not add much to simpler advice forms while conferring similar improvements to oab symptom, urgency. more sustained study for longer periods still appear indicated in order to fully assess two treatment modes which have the benefit of lacking invasiveness and may be of help to some of the patients who suffer from an overactive bladder. acknowledgement the authors of the manuscript would like to thank prof. reynir tómas geirsson for his assistance in writing this paper. conflict of interest the authors declare that they have no conflict of interest. references 1. haylen bt, de ridder d, freeman rm, swift se, berghmans b, lee j, et al. an international urogynecological association (iuga)/ international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. int urogynecol j 2010 ;21:5-26. 2. eapen rs, radomski sb. gender differences in overactive bladder. can j urol 2016 ;23(suppl 1):2-9. 3. sexton cc, coyne ks, thompson c, bavendam t, chen ci, markland a. prevalence and effect on health-related quality of life of overactive bladder in older americans: results from the epidemiology of lower urinary tract symptoms study. j am geriatr soc 2011 ;59:1465-70. 4. abrams p, kelleher cj, kerr la, rogers rg. overactive bladder significantly affects quality of life. am j manag care 2000 ;6(11 suppl):s580-90. 5. gormley ea, lightner dj, faraday m, vasavada sp, american urological association, society of urodynamics, female pelvic medicine. diagnosis and treatment of overactive bladder (non-neurogenic) in adults: aua/sufu guideline amendment. j urol 2015 ;193:1572-80. 6. lucas mg, bosch rj, burkhard fc, cruz f, madden tb, nambiar ak, et al. eau guidelines on assessment and nonsurgical management of urinary incontinence. eur urol 2012 ;62:1130-42. 7. national collaborating centre for women's and children's health (uk). urinary incontinence in women: the management of urinary incontinence in women. london: royal college of obstetricians and gynaecologists (uk); 2013 sep. (nice clinical guidelines, no. 171.) available at: https://www.ncbi.nlm. nih.gov/books/nbk247723/ 8. souto sc, reis lo, palma t, palma p, denardi f. prospective and randomized comparison of electrical stimulation of the posterior tibial nerve versus oxybutynin versus their combination for treatment of women with overactive bladder syndrome. world j urol 2014 ;32:179-84. 9. manriquez v, guzman r, naser m, aguilera a, narvaez s, castro a, et al. transcutaneous posterior tibial nerve stimulation versus extended release oxybutynin in overactive bladder patients. a prospective randomized trial. eur j obstet gynecol reprod biol 2016 ;196:6-10. 10. schreiner l, dos santos tg, knorst mr, da silva filho ig. randomized trial of transcutaneous tibial nerve stimulation to treat urge urinary incontinence in older women. int urogynecol j 2010;21:1065-70. 11. de seze m, raibaut p, gallien p, evenschneider a, denys p, bonniaud v, et al. transcutaneous posterior tibial nerve stimulation for treatment of the overactive bladder syndrome in multiple sclerosis: results of a multicenter prospective study. neurourol urodyn 2011;30:306-11. 12. ammi m, chautard d, brassart e, culty t, azzouzi ar, bigot p. transcutaneous posterior tibial nerve stimulation: evaluation of a therapeutic option in the management of anticholinergic refractory overactive bladder. int urogynecol j 2014;25:1065-9. 13. amarenco g, ismael ss, even-schneider a, raibaut p, demaille-wlodyka s, parratte b, et al. urodynamic effect of acute transcutaneous posterior tibial nerve stimulation in overactive bladder. j urol 2003;169:2210-5. 14. svihra j, kurca e, luptak j, kliment j. neuromodulative treatment of overactive bladder--noninvasive tibial nerve stimulation. bratisl lek listy 2002;103:480-3. 15. laycock j, jerwood d. pelvic floor muscle assessment: the perfect scheme. physiotherapy 2001;87:631-42. 16. urbaniak gc, pluos s. research randomizer (version 4.0) [computer software]. 2013; available at: https://www.randomizer.org/. accessed 04/28, 2015. 17. hashim h, abrams p. how should patients with an overactive bladder manipulate their fluid intake? bju int 2008;102:62-6. 18. wang ac, wang yy, chen mc. singleblind, randomized trial of pelvic floor muscle training, biofeedback-assisted pelvic floor vol 15 no 04 july-august 2018 191 muscle training, and electrical stimulation in the management of overactive bladder. urology 2004;63:61-6. 19. scaldazza cv, morosetti c, giampieretti r, lorenzetti r, baroni m. percutaneous tibial nerve stimulation versus electrical stimulation with pelvic floor muscle training for overactive bladder syndrome in women: results of a randomized controlled study. int braz j urol 2017;43:121-6. 20. wang ac, chih sy, chen mc. comparison of electric stimulation and oxybutynin chloride in management of overactive bladder with special reference to urinary urgency: a randomized placebo-controlled trial. urology 2006;68:999-1004. 21. ozdedeli s, karapolat h, akkoc y. comparison of intravaginal electrical stimulation and trospium hydrochloride in women with overactive bladder syndrome: a randomized controlled study. clin rehabil 2010;24:342-51. 22. franzen k, johansson je, lauridsen i, canelid j, heiwall b, nilsson k. electrical stimulation compared with tolterodine for treatment of urge/urge incontinence amongst women--a randomized controlled trial. int urogynecol j 2010;21:1517-24. 23. slovak m, chapple cr, barker at. noninvasive transcutaneous electrical stimulation in the treatment of overactive bladder. asian j urol 2015;2:92-101. 24. chai tc, steers wd. neurophysiology of micturition and continence in women. int urogynecol j pelvic floor dysfunct 1997;8:85-97. 25. shafik a, shafik ia. overactive bladder inhibition in response to pelvic floor muscle exercises. world j urol 2003;20:374-77. 26. dumoulin c, hay-smith j. pelvic floor muscle training versus no treatment for urinary incontinence in women. a cochrane systematic review. eur j phys rehabil med 2008;44:47-63. 27. greer ja, smith al, arya la. pelvic floor muscle training for urgency urinary incontinence in women: a systematic review. int urogynecol j 2012;23:687-97. oab and non-invasive treatment-bykoviene at al. female urology 192 urological oncology association of macrophage inhibitory factor 173gene polymorphism with biological behavior of prostate cancer mohammad reza razzaghi1, mohammad mohsen mazloomfard1, 2*, sheida malekian3, zahra razzaghi1 purpose: chronic inflammation is an important factor in the etiology of prostate cancer. macrophage migration inhibitory factor (mif) plays an important regulatory role in inflammatory responses. the aim of this study was to investigate the potential association between mif-173 g/c polymorphism, and both biological behavior and incidence of prostate cancer. materials and methods: analysis of polymorphic variants for mif was performed using the polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) method in 128 subjects with prostate cancer and 135 controls. results: the frequency of mif-173 *c allele was significantly (or = 2.18, 95% ci = 1.32-3.61) higher in patients with prostate cancer (19.5%) than in healthy individuals (10%). prostate cancer patients with gleason scores ≥ 7 had higher frequency of mif-173 *c allele than gleason scores < 7 (86.1% vs. 27.1%, p = 0.003, or = 3.18, 95% ci = 1.46-6.95). the frequency of mif-173 *c allele was significantly different in patients with t1, t2 and ≥t3 clinical stages of prostate cancer (15.2% vs. 42.6% and 47.8%, p = 0.003). conclusion: our data suggest that mif-173 polymorphisms may be associated with a higher incidence of prostate cancer compared to controls. we believe that mif-173 gc+cc genotype can be used as a predictive factor for aggressive behavior of prostate cancer including pathological stage and gleason scores as well as metastatic potential. keywords: macrophage migration inhibitory factor (mif); prostate specific antigen; polymorphism; prostate cancer introduction prostate cancer (cap) is the most common malig-nancy in males aside from skin cancer and is the second leading cause of cancer mortality in the united states. the incidence of prostate cancer in iran is close to that of asian countries and remarkably lower than developed countries(1). the aggressiveness and metastatic behavior of cap is variable, with a spectrum that ranges from indolent cancer confined to the prostate, to cases with rapid, extra-prostatic extension and distant metastasis(2). previous studies suggested that clinical progression of cap may be influenced by changes in expression and response to cytokine and growth factor receptors, which can be modulated by inflammatory signals(2). macrophage migration inhibitory factor (mif) is a member of the transforming growth factor-β (tgf-β) superfamily, which is considered a pleiotropic cytokine that is a central regulator of innate immunity acts as an upstream regulator of many other inflammatory cytokines(3). it is suggested that an association exists between mif genotypes that result in increased mif protein production and an increased risk of prostate cancer(4-5). 1laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran. 2cancer research center, shahid beheshti university of medical sciences, tehran, iran. 3 internal medicine department, shohada-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: shohada-e-tajrish hospital, tajrish sq, tehran, iran tel: +98-21-22718021. email: mazloomfard@gmail.com. received may 2017 & accepted july 2018 a -173 g/c substitution results in a single nucleotide polymorphism (snp) which influences mif gene expression(6). there is accruing evidence for the relevance of this polymorphism as high-expression mif alleles may influence biological behavior and metastasis of prostate cancer(7-8). although the exact physiologic function of mif in tumor progression is unknown, macrophage-derived angiogenic activity may have a role(9). the aim of this study was to examine the association between mif -173 g/c polymorphism and the stage and grade of prostate cancer. patients and methods study population a total of 128 subjects with prostate cancer and 135 benign prostatic hyperplasia controls were consecutively recruited from tajrish hospital between january 2013 and december 2016. sample size was calculated with pass-11 software, with 0.9 study power and or =2.9.(7) all urology clinic patients with diagnosed prostate cancer who consented to participate in the study, donated 5 ml of blood. ultrasound-guided transrectal needle biopsy of prostate (13-fold biopsy), psa (free urological oncology 32 vol 16 no 01 january-february 2019 33 and total), physical and other auxiliary examinations were performed for all cases. gleason score of surgery specimen was used for patients who underwent radical prostatectomy. control subjects were recruited from other patients with lower urinary tract symptoms and were frequency-matched to cases on age and smoking status. any controls with abnormal appearance of pathology, prostate-specific antigen test > 2.5 ng/ml, abnormal digital rectal examination, other previous cancer diagnosis, history of urinary tract infection and urethral stricture disease were excluded from the study. patients with complaint of pain in the perineum, testicles, tip of the penis, blow the wrist in pubic and bladder area, pain during urination or during or after ejaculation were also excluded. written informed consent was provided for each participant. the research protocol was approved by the institutional review board of shahid beheshti university of medical sciences. genotyping five ml of peripheral blood was collected from the study subjects to edta tubes; lymphocytes were obtained from these samples and were used to isolate dna by a salting-out procedure with minor modifications (10). analysis of polymorphic variants for mif was performed using the polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) method. pcr reaction used oligonucleotide pairs restricting the polymorphic site of the studied gene to the following sequence: mif173: f; 5’actaagaaagacccgaggc-3’, mif173: r; 5’ggggcacgttggtgttta-3’. briefly, pcr reaction was carried out in a total volume of 25 μl containing 1 μl of genomic dna solution, 20 mmol/ltris–hcl (ph 8.3), 100 mmol/l kcl, 3 mmol/l mgcl2, 500 μmol/l of each dgtp, datp, dttp, and dctp, 1 μl of each forward and reverse primers, and 0.1 u taq polymerase/ml. the condition of pcr was as follows: initial denaturation at 94 ̊c for 3 min followed by 30 amplification cycles at 94 ̊c for 30 sec, 55 ̊c for 30 sec, and 72 ̊c for 60 sec, and a final extension at 72 ̊c for 5 min. amplified pcr product (3 μl) was digested in a 10-μl final reaction volume using 1 μl of 10˟ reaction buffer 2 and 4 units of alu i restriction enzyme, at 37°c overnight. the digested products were resolved on a 3% agarose gel stained with ethidium bromide and visualized using uv transillumination. statistical analysis data were analyzed using the spss software (statistical package for the social sciences, version 20.0, spss inc, chicago, il). chi-square test and fisher’s exact test were used to compare dichotomous variable between two groups. independent t-test was used to comparing continuous variable between two groups. hardy–weinberg equilibrium was tested by chi-square test for both study groups. a p-value of < 0.05 was considered statistically significant. table 1. baseline characteristics of patients of both groups characteristics a cases (n = 128) controls (n = 135) p value median age, year ± sd 72.6 ± 8.9 70.4 ± 8.1 0.07 smoker, n(%) 44 (34.4) 34 (25.2) 0.1 positive family history for cancer, n(%) 8 (6.3) 6 (4.4) 0.5 mean psa, ng/ml ± sd 30.1 ± 56.6 1.1 ± 0.8 < 0.001 psa, ng/ml n(%) < 10 46 (35.9) 10-20 41 (32) > 20 41 (32) gleason sum n(%) < 7 61 (47.7) ≥ 7 67 (52.3) clinical stage n(%) localized (t1-t2) 70 (54.7) locally advanced (t3-t4) 19 (14.8) metastatic (n+ and/or m+) 39 (30.5) a data is presented as mean ± sd or number (percent) mif -173 g>c (%) cases (n = 128) a controls (n = 135) a p-valueb or (95% ci) number percent number percent gg 84 65.6 110 81.5 0.01 ref. gc 38 29.7 23 17 2.16 (1.20-3.90) cc 6 4.7 2 1.5 3.93 (0.77-9.96) gc+cc 44 34.4 25 18.5 0.003 2.3 (1.31-4.07) g allele 206 80.5 243 90 0.002 ref. c allele 50 19.5 27 10 2.18 (1.32-3.61) a the observed frequencies among the prostate cancer and control subjects were in agreement with the hardy-weinberg equilibrium (x2 = 0.394, p = 0.529 and x2 = 0.386, p = 0.534) b chi-square test for either genotype distributions or allele frequencies between the cases and controls. table 2. genotype and allele frequencies of mif polymorphisms among the cases and controls mif polymorphisms in prostate cancer-razzaghi et al. results the general demographic characteristics of the case and control groups are shown in table 1. the mean ± sd age of the prostate cancer and control groups was 72.61 ±8.9 years and 70.91 ± 9.34 years respectively (p = 0.07). there was no difference in smoking history as well as first degree relative history for cancer between prostate cancer and control groups. the mean ± sd of serum total psa levels were 30.1 ± 56.6 ng/ml in prostate cancer and 1.1±0.8 ng/ml in control subjects (p < 0.001). sixty one (47.7%) prostate cancer patients had gleason sum < 7 and 67 (52.3%) had gleason sum ≥ 7. pelvic ct scan was positive for lymphadenopathy in 14 (10.9%) patients and 35 (27.3%) cases had metastasis in whole body bone scan. treatment modalities were active surveillance and watchful waiting in 9 (7%), radical prostatectomy in 48 (37.5%), radiation in 13 (10.2%), hormone therapy in 39 (30.5%), radical prostatectomy followed by hormone therapy in 12 (9.4%), radiotherapy plus hormone therapy in 7 (5.5%) and chemotherapy in 2 (1.6%) prostate cancer patients. the allele and genotype distribution at position-173 of the mif gene in the prostate cancer and control groups are shown in table 2. no evidence of departure from hardy-weinberg equilibrium in in the prostate cancer and control groups was seen. the frequency of mif173 *c allele was significantly higher in patients with prostate cancer (19.5%) than in healthy individuals (10%). the genotype distribution at position-173 of the mif gene according to gleason score and clinical stages are shown in table 3. prostate cancer patients with gleason scores ≥ 7 had higher frequency of mif-173 gc+cc genotype than gleason scores < 7 (44.9% vs. 21.3%, p = 0.003, or = 0.32, 95% ci = 0.14-0.68). the frequency of mif-173 gc+cc genotype was significantly different in patients with t1, t2 and ≥ t3 clinical stages of prostate cancer (15.2% vs. 42.6% and 47.8%, p = 0.003). the frequency of mif-173 gc+cc genotype in cases with regional lymph node involvement in imaging or pelvic lymph node dissection and patients with metastasis were 57.1% and 60% respectively (p=0.075 and < 0.001, or=0.35 ci = 0.11-1.07 and or=0.22 ci = .09-0.49, respectively). discussion in the present study we investigated the association between the mif -173 g/c polymorphism and both incidence and behavior of prostatic carcinoma. mif is a multifunctional cytokine which has a regulatory role in inflammatory response(11) and stimulates secretion of other proinflamatory mediators such as tnf α and il1(12). because the correlation between chronic inflammation and cancer has been established(13) and also angiogenic effects of mif(14), the association of mif and cancers was studied in some investigations. the correlation between mif and prostate (2,7), gastric(15), breast (16) and bladder(17) cancer and acute lymphoblastic leukemia(4) has been shown in some studies. it seems that mif promotes tumor survival by inducing an angiogenic response, but mif is not directly angiogenic. prostatic adenocarcinoma is the most commonly diagnosed non-cutaneous malignant tumor. some studies have reported higher expression of mif gene in prostate cancer tissue than in normal prostate tissue(18). meyer-siegler and colleagues found enhanced mif mrna levels in metastatic adenocarcinoma of prostate in comparison with normal prostatic tissues(19). they postulated that this cytokine plays a role in the development of metastasis and it may represent a prognostic factor for prostate cancer. in another study they showed higher mif expression in metastatic adenocarcinoma than in the normal prostate, bph or focal prostate adenocarcinoma(20). this increased serum mif concentrations in patients with prostatic adenocarcinoma was irrespective of treatment modality indicating that continuing mif secretion by the prostate cancer epithelial cells may not be regulated hormonally. the association between mif expression and tumor grading and prognosis of prostate cancer was identified in another study (21). the mif -173 g/c polymorphism was identified and higher serum mif levels were found in subjects with mif -173 *c compared to the mif -173 gg genotype (22-23). meyer-siegler at al.(2) evaluated the correlation between -173c and -794 7-catt polymorphism and prostate cancer. they reported that mif gene polymorphism was associated with incidence and also grading of prostate cancer. individuals with -173*c genotype had a higher grade (gleason score ≥7) prostate cancer when compared to those that had the g/g genotype [or=9.69; 95%ci: 2.20-42.66]. gg (n = 84) gc+cc (n = 44) p value or (95% ci) number percent number percent psa (ng/ml) < 10 38 45.2 8 18.2 <0.001 ref. 10-20 29 34.5 12 27.3 0.51 (0.18-1.41) > 20 17 5.9 24 9.1 0.15(0.06-0.40) gleason sum < 7 48 57.1 13 29.5 0.003 ref. ≥ 7 36 42.9 31 70.5 0.32 (0.14-0.68) clinical stage localized (t1-t2) 66 78.5 4 9.1 0.003 ref. locally advanced (t3-t4) 7 8.4 12 27.2 <0.001 1.16(0.44-3.06) metastatic (n+ and/or m+) 11 13.1 28 63.7 0.22(0.09-0.49) table 3. frequency distributions among gleason scores and clinical stages of prostate cancer between the genotypes of the mif polymorphisms mif polymorphisms in prostate cancer-razzaghi et al. urological oncology 34 vol 16 no 01 january-february 2019 35 ding and colleagues(7) evaluated the association of mif -173 polymorphism with incidence and gleason score, clinical stage and psa value of prostate cancer. they showed that c allele carriers are at higher risk for prostate cancer [or=3.27; 95%ci: 2.13-4.47]. this suggests that mif -173 polymorphism may play a role in the etiology of prostate cancer. they considered mif may contribute in tumorogenesis through its ability to antagonize p53 which was previously shown in some studies(24-26). moreover mif over-expression due to mif polymorphism may promote chronic inflammatory response and the resultant cancer(13). arisawa et al.(27) evaluated 229 patients with gastric cancer and 428 subjects with no evidence of gastric malignancies on the upper gastro-duodenal endoscopy and reported an association between the -173c mif allele and gastric cancer in patients older than 60 years [or=1.71; 95%ci: 1.03-2.84]. ziino et al.(28) failed to find a significant association between the mif −173g/ c polymorphism and prednisone poor response in childhood all. xue et al(4) compared 346 acute lymphoblastic leukemia (all) cases and 516 cancer-free controls and showed that the variant genotype gc and the combined genotypes gc/cc were associated with a significantly higher risk of childhood all [or=1.39, 95% ci:1.01-1.93 for gc and adjusted or=1.38, 95% ci:1.01-1.89 for gc/cc]. vera and meyer-siegler(3) in a meta-analysis suggested that the -173c mif promoter polymorphism is associated with an increase in the risk of solid tumor cancer, particularly for prostate cancer but not for “non-solid” tumors (leukemia). in contrast, yuan et al(17) compared 325 patients with bladder cancer with 345 cancer-free controls and found that mif173c alleles associates with decreased risk of bladder cancer [or = 0.57, 95% ci, 0.41-0.79]. sadjadi and his colleagues showed that based on geographical distribution, the prevalence of prostate cancer in iran is lower than in western countries(1). however, after one decade from that research, pakzad et al. found that there was a significant increase in the incidence of pca, with annual percentage increase of 17.3%(29). these finding have led us to explore further research on cellular genetics of prostate cancer in our country. we found correlation between mif -173*c genotype and higher gleason scores and psa values and advanced clinical stages which were similar to meyer-siegler(2) and ding’s study(7). our results suggest that mif -173c polymorphism may have predictive value for behavior of prostate cancer. low number of patients in both prostate cancer and control groups was a major limitation of our study. conclusions in this study we showed the association between mif -173c polymorphism and incidence and behavioral characteristics of prostate cancer such as gleason score and clinical stage. we believe that mif -173c polymorphism correlates with higher incidence of prostate cancer and also can be used as a predictive marker for aggressive behavior of prostate cancer independent of gleason score and clinical stage. however our findings support the need for larger studies underlining the predictive value of mif -173c polymorphism in prognosis of prostate cancer. acknowledgement this study was approved in laser application in medical sciences research center, shahid beheshti university of medical sciences, as a research project. conflict of interest the authors report no conflict of interest. references 1. sadjadi a, nooraie m, ghorbani a. et al. the incidence of prostate cancer in iran: results of a population-based cancer registry. arch iran med 2007;10:481-5. 2. meyer-siegler kl, vera pl, iczkowski ka. et al. macrophage migration inhibitory factor (mif) gene polymorphisms are associated with increased prostate cancer incidence. genes immun 2007;8:646-52. 3. macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis. kim kw, kim hr. korean j intern med. 2016;31:634-42. 4. xue y, xu h, rong l. et al. the mif -173g/c polymorphism and risk of childhood acute lymphoblastic leukemia in a chinese population. leuk res 2010;34:1282-6. 5. zhang x, weng w, xu w, wang y, yu w, tang x et al. the association between the migration inhibitory factor -173g/c polymorphism and cancer risk: a metaanalysis. onco targets ther. 2015 10;8:60113. 6. donn rp, shelley e, ollier we, thomson w. a novel 5'-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. arthritis rheum 2001;44:1782-5. 7. ding gx, zhou sq, xu z. et al. the association between mif-173 g>c polymorphism and prostate cancer in southern chinese. j surg oncol 2009;100:106-10. 8. meyer-siegler kl, iczkowski ka, leng l, bucala r, vera pl. inhibition of macrophage migration inhibitory factor or its receptor (cd74) attenuates growth and invasion of du-145 prostate cancer cells. j immunol 2006;177:8730-9. 9. white es, strom sr, wys nl, arenberg da. non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity. j immunol 2001;166:7549-55. 10. miller sa, dykes dd, polesky hf. a simple salting out procedure for extracting dna from human nucleated cells. nucleic acids res 1988;16:1215. 11. naujokas mf, arneson ls, fineschi b. et al. potent effects of low levels of mhc class ii-associated invariant chain on cd4+ t cell development. immunity 1995;3:359-72. 12. lue h, kleemann r, calandra t, roger t, mif polymorphisms in prostate cancer-razzaghi et al. bernhagen j. macrophage migration inhibitory factor (mif): mechanisms of action and role in disease. microbes infect 2002;4:449-60. 13. balkwill f, mantovani a. cancer and inflammation: implications for pharmacology and therapeutics. clin pharmacol ther 2010;87:401-6. 14. nishihira j, ishibashi t, fukushima t, sun b, sato y, todo s. macrophage migration inhibitory factor (mif): its potential role in tumor growth and tumorassociated angiogenesis. ann n y acad sci 2003;995:171-82. 15. xia hh, yang y, chu km, et al. serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer. cancer 2009. 16. xu x, wang b, ye c, et al. overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer. cancer lett 2008;261:147–57. 17. yuan q, wang m, zhang z, zhang w. macrophage migration inhibitory factor gene -173g>c polymorphism and risk of bladder cancer in southeast china: a case-control analysis. mol biol rep 2011. 18. nakamura t, scorilas a, stephan c. et al. quantitative analysis of macrophage inhibitory cytokine-1 (mic-1) gene expression in human prostatic tissues. br j cancer 2003;88:1101-4. 19. meyer-siegler k, hudson pb. enhanced expression of macrophage migration inhibitory factor in prostatic adenocarcinoma metastases. urology 1996;48:448-52. 20. meyer-siegler k, fattor ra, hudson pb. expression of macrophage migration inhibitory factor in the human prostate. diagn mol pathol 1998;7:44-50. 21. del vecchio mt, tripodi sa, arcuri f. et al. macrophage migration inhibitory factor in prostatic adenocarcinoma: correlation with tumor grading and combination endocrine treatment-related changes. prostate 2000;45:51-7. 22. donn r, alourfi z, de benedetti f. et al. mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. arthritis rheum 2002;46:2402-9. 23. de benedetti f, meazza c, vivarelli m. et al. functional and prognostic relevance of the -173 polymorphism of the macrophage migration inhibitory factor gene in systemiconset juvenile idiopathic arthritis. arthritis rheum 2003;48:1398-407. 24. hudson jd, shoaibi ma, maestro r, carnero a, hannon gj, beach dh. a proinflammatory cytokine inhibits p53 tumor suppressor activity. j exp med 1999;190:1375-82. 25. damico r, simms t, kim bs. et al. p53 mediates cigarette smoke-induced apoptosis of pulmonary endothelial cells: inhibitory effects of macrophage migration inhibitor factor. am j respir cell mol biol 2011;44:323-32. 26. jung h, seong ha, ha h. direct interaction between nm23-h1 and macrophage migration inhibitory factor (mif) is critical for alleviation of mif-mediated suppression of p53 activity. j biol chem 2008;283:3266979. 27. arisawa t, tahara t, shibata t. et al. functional promoter polymorphisms of the macrophage migration inhibitory factor gene in gastric carcinogenesis. oncol rep 2008;19:223-8. 28. ziino o, d’urbano le, de benedetti f, et al. the mif −173g/c polymorphism does not contribute to prednisone poor response in vivo in childhood acute lymphoblastic leukemia. leukemia 2005;19:2346–7. 29. pakzad r, rafiemanesh h, ghoncheh m, et al. prostate cancer in iran: trends in incidence and morphological and epidemiological characteristics. asian pac j cancer prev. 2016;17:839-43. mif polymorphisms in prostate cancer-razzaghi et al. urological oncology 36 case report primary repair of extensive rectal injury during urethroplasty in children without bowel preparation: report of two cases abbas basiri1, mehdi dadpour1 today, there are several methods to repair colon and rectal injury such as primary repair, stoma, resection with anastomosis and damage control only. to our best knowledge, there is no definite method published in literature about iatrogenic rectal injury during perineal urethroplasty in children. here, we explain two 10 and -12year old boys with iatrogenic rectal injury during perineal urethroplasty who underwent primary repair. based on our experience, primary repair of rectum in such condition is feasible, successful and can be a good choice to avoid placing colostomy and secondary repair. keywords: complication; rectal injury; perineal urethroplasty; primary repair introduction today, there are several methods to repair colon and rectal injury such as primary repair, stoma, resection with anastomosis and damage control only(1). the method of choice to repair the injury is controversial, however, primary repair has been more preferred in recent years.(2-4) to our best knowledge, there is no standard method in the literature for repairing iatrogenic rectal injury during perineal urethroplasty in pediatrics. here we explain two 10 and 12-year old cases with primary repair of iatrogenic rectal injury during perineal urethroplasty without any bowel preparation. case report a 10-year-old boy was referred to our center with a totally blunt urethra and inability to void. he had undergone pelvic fixation, urethroplasty and repair of the bladder two years ago, after an extensive pelvic damage due to a car accident. he underwent internal urethrotomy three times during the past two years because of urethral stenosis recurrence (figure 1). after placing a cystostomy, he became a candidate to repeat urethroplasty (perineal end to end anastomotic urethroplasty). no bowel preparation and rectal washing was performed before the surgery. in lithotomy position, after perineal exploration, the urethra was found but because of adhesion and fibrosis band and difficult tissue dissection, the rectum was perforated about 5cm (figure 2). after washing the field of surgery with adequate amount of normal saline and replacement of surgical draping and instruments, we repaired the rectum with vicryl and silk sutures in 2 layers. then urethroplasty was performed using the standard method.(5) 1urology and nephrology research center, shahid beheshti university of medical science, shahid labbafinejhad hospital, department of urology, tehran, iran. *correspondence: shahid labbafinejhad hospital, department of urology, tehran, iran tel: 00982123602152. fax: 0982122567282. email: mehdi_dadpour@yahoo.com. received may 2018 & accepted november 2018 figure 1. blunt urethra in urethrogram and evidence of previous surgery. figure 2. digital rectal exam: tip of the finger that comes out of the rectal tear site shows the extent of injury. figure 2. urethrogram after 6 months of surgery. urology journal/vol 17 no. 2/ march-april 2020/ pp. 213-214. [doi: 10.22037/uj.v0i0.4594] this scenario was repeated for a 12-year old boy with a history of epispadias, bladder exstrophy, mega penis and perineal surgery for urethral stricture and fistula. his extended iatrogenic rectal injury during dissection was also repaired in 2 layers after cleaning the field of surgery. the patients were allowed to start diet 6 hours after surgery. no evidence of rectal bleeding, ileus, abdominal pain and any related complications were observed. foley catheter was removed after 10 days and voiding and defecation were uneventful afterward. figure 3 shows the bladder and urethra after 6 months of surgery. there was no voiding problem at the patients’ last follow up visits (6 months). discussion to the best of our knowledge, this is the first experience of primary repair of rectal injury during perineal urethroplasty in pediatrics. gobbi et al. reported repairing congenital urethral strictures in seven infants(6). jianpo et al. reported a successful perineal urethroplasty in a nine-year old boy with long pelvic fracture and urethral distraction(7). however, there was no experience of rectal injury during surgery in either papers. former experiences in adults have shown primary repair of rectum and placing colostomy as logical and available in patients with iatrogenic rectal injury. in agreement, aragon et al. indicated primary repair as a safe procedure in the evaluation of 481 patients with abdominal trauma and colon injury(2), however burak veli et al. did not find any difference in outcomes after primary repair and colostomy placement(8). in the evaluation of 10 patients, papadopoulos et al. observed that colonic diversion should only be considered if the colon or rectal tissue were inappropriate due to severe ischemia or edema(9). surgery during 6 hours and in hemodynamically stable patients had a lower risk of complication. past studies have shown that hypotension and unstable hemodynamics increase the incidence of collections and abscesses (10,11). many of these studies are conducted on patients with abdominal trauma and trans-peritoneal approach. hosseini et al. evaluated erectile function in 65 adult patients with a history of perineal urethroplasty.(12) qiang fu et al. reported 28 out of 573 patients with rectal injury who underwent urethroplasty, all of which were primarily repaired, and a few of them underwent temporarily colostomy placement.(13) finally, it is worthy of note that we performed no bowel preparation and rectal washing was performed before surgery. the patients started diet 6 hours after the surgery without any problem. although it is better to perform bowel preparation before these surgeries, we aimed to show the feasibility of primary repair without stoma in this situation. conclusions based on our experience, primary repair of rectal injury during perineal urethroplasty in children is feasible and can be a preferable alternative in order to avoid colostomy placement and secondary repair. references 1. steele sr, wolcott ke, mullenix ps, et al. colon and rectal injuries during operation iraqi freedom: are there any changing trends in management or outcome? dis colon rectum. 2007;50:870-7. 2. salinas-aragon le, guevara-torres l, vacaperez e, belmares-taboada ja, ortiz-castillo fde g, sanchez-aguilar m. primary closure in colon trauma. cir cir. 2009;77:359-64. 3. levine jh, longo we, pruitt c, mazuski je, shapiro mj, durham rm. management of selected rectal injuries by primary repair. am j surg. 1996;172:575-8; discussion 8-9. 4. choi wj. management of colorectal trauma. j korean soc coloproctol. 2011;27:166-72. 5. joshi p, kaya c, kulkarni s. approach to bulbar urethral strictures: which technique and when? turk j urol. 2016;42:53-9. 6. ulger bv, turkoglu a, oguz a, uslukaya o, aliosmanoglu i, gul m. is ostomy still mandatory in rectal injuries? int surg. 2013;98:300-3. 7. papadopoulos vn, michalopoulos a, apostolidis s, et al. surgical management of colorectal injuries: colostomy or primary repair? tech coloproctol. 2011;15 suppl 1:s63-6. 8. bostick pj, heard js, islas jt, et al. management of penetrating colon injuries. j natl med assoc. 1994;86:378-82. 9. gonzalez rp, falimirski me, holevar mr. further evaluation of colostomy in penetrating colon injury. am surg. 2000;66:342-6; discussion 6-7. 10. hosseini j, soleimanzadeh ardebili f, fadavi b, haghighatkhah h. effects of anastomotic posterior urethroplasty (simple or complex) on erectile function: a prospective study. urol j. 2018;15:33-7. 11. fu q, zhang j, sa yl, jin sb, xu ym. recurrence and complications after transperineal bulboprostatic anastomosis for posterior urethral strictures resulting from pelvic fracture: a retrospective study from a urethral referral centre. bju int. 2013;112:e358-63. 12. gobbi d, fascetti leon f, gnech m, midrio p, gamba p, castagnetti m. management of congenital urethral strictures in infants. case series. urol j. 2019;16:67-71. 13. jianpo z, jianwei w, guizhong l, et al. successful perineal urethroplasty for long pelvic fracture urethral distraction defect (pfudd) in a 9 year-old boy. urol j. 2016;13:2576-8. extensive rectal injury during urethroplastybasiri et al. case report 214 andrology the effect of aerobic training on serum levels of adiponectin, hypothalamic-pituitary-gonadal axis and sperm quality in diabetic rats mohammad parastesh1*, abbas saremi1, akbar ahmadi2, mojtaba kaviani3 purpose: the present study aims to investigate the effects of aerobic training on adiponectin, sex hormones, and sperm parameters in streptozotocin–nicotinamide induced diabetic rats. material and methods: in this experiment, 52 eight-week-old sprague dawley rats (200-250 g) were randomly assigned to four groups: healthy control, diabetic control, diabetic with aerobic training and healthy with aerobic training. diabetes was induced by intraperitoneal injection of nicotinamide and streptozotocin solution. the aerobic training protocol was performed for ten weeks. finally, blood serum samples were obtained to assess fsh, lh, testosterone, and adiponectin levels. results: results showed an increase in serum adiponectin levels in aerobic training group which led to a significant difference between aerobic training group and diabetic control group. in addition, aerobic training caused significant increase in serum testosterone level and lh in diabetic aerobic training group, so that significant differences were observed between serum testosterone, lh and fsh of diabetic aerobic training group and healthy control group. sperm parameters in the diabetic aerobic training group including sperm count, motility and viability presented significant differences compared to diabetic control group. conclusion: short term aerobic training can improve serum adiponectin levels and sperm parameters, including sperm count and sperm motility through increasing serum testosterone, lh and fsh levels in type 2 diabetic rats. keywords: adiponectin; diabetes mellitus type 2; aerobic training; sex hormones; sperm parameters. introduction diabetes mellitus (dm) is one of the greatest threats to current worldwide health. in a study in 2017, the number of diabetics in the world was 451 million which is anticipated to increase to 693 million in 2045(1). dm may influence male reproductive function at multiple levels as a result of its impacts on endocrine control of spermatogenesis, spermatogenesis itself or by damaging penile erection and ejaculation(2). data from animal studies strongly suggests that dm impairs male fertility(3). on the other hand, fertility is regulated by two gonadotropic hormones, luteinizing hormone (lh) and follicle-stimulating hormone (fsh) which modulate testosterone synthesis in leydig cells and its aromatization to estradiol in sertoli cells, respectively(4). in a study by aziz et al. in 2018, remarkable differences between the levels of testicular and pituitary hormones in diabetic rats compared with non-diabetic rats were recognized(5). the findings regarding sperm quality in diabetic rats indicate a decrease in sperm motility and sperm count and an increase in sperm abnormalities(6). adiponectin plays an important role in metabolic disorders such as obesity, type 2 diabetes, coronary heart disease, and metabolic syndrome(7). discovery of the metabolic adiponectin hormone has been a main development not only in energy balance, but more generally 1department of sport physiology, faculty of sport sciences, arak university, arak, iran. 2department of sport sciences, sanandaj university, kordestan , iran. 3faculty of pure & applied science, school of nutrition and dietetics, acadia university, wolfville, ns, canada. *correspondence: faculty of sport sciences, department of sports physiology and pathology, arak university, arak, iran. postal code: 38156-879 tel: +98 9331528384. fax: +988634173492. e-mail: m-parastesh@araku.ac.ir. received august 2018 & accepted november 2018 in fields including reproduction, inflammation, and immunology(8). regarding the relationship between serum level of adiponectin and its possible effect on fertility, a few studies have been conducted. in 2007, francisca et al. suggested that the pituitary constitutes a relevant place of action for adiponectin and supports a role for adipokines as a connection in the regulation of metabolism, growth, and reproduction(9). in 2008, olga et al. also indicated that adiponectin and its receptors are expressed in the chicken testis, where they are likely to affect steroidogenesis, spermatogenesis, sertoli cell function as well as spermatozoa motility(10). exercise training (et) is believed to be an important element in the treatment strategy for rats with type 2 diabetes(11). physical exercise increases glucose disposal into contracting muscles, leading to a significant decrease in blood glucose concentration(12). despite the beneficial effects of physical exercise on different metabolic aspects of diabetic rats, to the best of our knowledge no study has been conducted to study the effects of physical exercise on fertility of diabetic rats. therefore, it can be noteworthy to investigate the effect of a period of aerobic training on serum levels of adiponectin, sex hormones and sperm parameters in type 2 diabetic rats. urology journal/vol 16 no. 6/ november-december2019/ pp. 592-597. [doi: 10.22037/uj.v0i0.4728] vol 16 no 06 november-december2019 593 materials and methods experimental animals and protocols fifty four eight-week-old sprague dawley rats (200250g) were housed in cages in groups of controlled temperature (22 ± 2˚c) and light/dark (12/12h) conditions with free access to water and rat chow. all experimental procedures were guided by regulations approved by the iranian ministry of health. the rats were randomly divided to four groups: control (c) (n = 12), diabetic control (dc) (n = 15), diabetic with aerobic training (dat) (n = 15) and healthy with aerobic training (hat) (n = 12) groups. the groups were treated according to the experimental protocol for a duration of 60 days. all experiments were operated in the medical science university of arak. the code of ethics is also included in the description (ir.arakmu.rec.1394.329) in the ethics committee of the research projects of arak university of medical sciences. diabetic induction diabetes was induced after a 12 hour fast. the rats were injected with nicotineamid (sigma chemical co) dissolved in normal saline at a dose of 120 mg/kg, and after 15 minutes, streptozotocin (stz, sigma chemical co) dissolved in 0.1 m citrate buffer at a dose of 65 mg/kg was given in a single intraperitoneal injection. 72 hours after injection, animals’ blood glucose levels were evaluated. those animals that had blood glucose levels higher than 250mg/dl were considered diabetic. blood glucose levels of the rats were being measured by a glucometer after a 12 h fast. further, the healthy control rats were given intraperitoneal injections of normal saline at a dose of 1cc to be in the same condition as diabetic groups(13). aerobic training protocol the aerobic exercise was performed on a rodent motor-driven treadmill at a 0˚ slope. the rats exercised for 5 d/w for 10 weeks. training blocks consist of 3 phases of familiarization, overload, and finally preservation and stabilization of exercise intensity. in the familiarization phase (first week), the rats walked on treadmill at a speed of 8m/min for 10-15 min every day. in the overload phase (second to fourth weeks), the rats initially ran on treadmill at a speed of 27 m/min for 20 min, and then during 3 weeks the time of exercise increased (2min in each session) gradually until reached 60 minutes. finally, in the preservation and stabilization stage of exercise intensity, the rats did the aerobic exercise for 7 weeks with a speed of 27m/min for 60 min (table 1). each exercise session began with 5min of warm up (16m/min) and 5min was allocated to cooling down (16m/min and gradual decrease of intensity to the least amount)(14). procedure twenty four hours after the last exercise session, all of the rats were anaesthetized by the injection of chloroform and sacrificed. blood samples were collected by cardiac puncture (5cc) and centrifuged at 3500rpm for 10 min and the serum samples were stored at -70˚c for future analysis. serum levels of testosterone, lh, fsh, adiponectin and insulin were assayed using various kits according to their manufacturer's instructions. testosterone (rat elisa kit, eastbiopharm cat. no cke90243, china, sensitivity: 0.25nmol/l, assay range: 0.5-100nmol/l), lh (rat elisa kit, eastbiopharm cat. no ck-e90904, china, sensitivity: 0.11miu/l, assay range: 0.2-60miu/l), fsh (rat elisa kit, eastbiopharm cat. no cke30597, china, sensitivity: 0.12miu/l, assay range: 0.2-60miu/l), adiponectin (rat elisa kit, eastbiopharm cat. no ck-e30584, china, sensitivity: 0.16mg/l, assay range: 0.2-60mg/ l) and insulin (rat elisa kit, eastbiopharm cat. no ck-e30620, china, sensitivity: 0.5miu/l, assay range: 0.1-40 miu/l). sperm count the excised left testis was weighed and the dissected epididymis was transferred into 5cc (dmem) medium and cut into small slices in order to swim out the sperm into the medium. after 10 min of diffusion in 27˚c temperature, 1ml of the solution was diluted with 9ml table 1. aerobic training (at) protocol (14) weeks day at 1 20 min, 27 m/min week1 2 22 min, 27 m/min 3 24 min, 27 m/min 4 24 min, 27 m/min 5 28 min, 27 m/min 6 30 min, 27 m/min week2 1 32 min, 27 m/min 2 34 min, 27 m/min 3 36 min, 27 m/min 4 38 min, 27 m/min 5 40 min, 27 m/min 6 42 min, 27 m/min week3 1 44 min, 27 m/min 2 46 min, 27 m/min 3 48 min, 27 m/min 4 50 min, 27 m/min 5 52 min, 27 m/min 6 54 min, 27 m/min week4 1 56 min, 27 m/min 2 58 min, 27 m/min 3 60 min, 27 m/min 4 60 min, 27 m/min 5 60 min, 27 m/min 6 60 min, 27 m/min week5-10 1-6 60min, 27 m/min to end of 10th week groups body weight (g) fasting blood glucose (mg/dl) testis weight left (g) pre test post test pre test post test hc 242.9(± 21) 280.3 (± 35) 88.4 (±10) 100.2 (±12) 1.58 (± 0.19) dc 232.6 (± 36) 253.2 (± 46) 299.3 (±46)a 366.4 (±102)a 1.31 (± 0.25)a dat 238.7 (± 20) 227.4 (± 38)a 354.2 (±86)a 188.8 (±115)b 1.34 (± .32) hat 248.7 (± 19) 250.1 (± 25)a 85.6 (±8)c 76.1 (±4)b 1.57 (± .17)b a. the significant difference with healthy control group (p < 0.05). b. the significant difference with diabetic control group (p < 0.05). c. the significant difference with diabetic aerobic training group (p < 0.05). abbreviations: hc, healthy control group; dc, diabetic control group; dat, diabetic aerobic training group; hat, healthy aerobic training group. table 2. body and left testis weight (means±sd) the effect of training on adiponectin, sex hormone and sperm quality in diabetic rats-parasteh et al. formaldehyde fixative. the diluted solution was transferred into each chamber of neubauer hemocytometer and sperm heads were manually counted under a microscope. sperm count was carried out according to who guidelines and data were expressed as the number of sperm per ml(15). sperm motility measurement of sperm motility was performed according to who protocol. 10μl of the sperm suspension was located on a microscope slide and covered. a minimum of five microscope fields were investigated to evaluate sperm motility on at least 200 sperm for each animal, then the percentage of sperm motility was computed(15). sperm viability eosin-nigrosin staining was used to evaluate sperm viability according to who protocol. in this protocol, eosin (1%, merk, germany) and nigrosin (10%, merk, germany) were prepared in distilled water. at first, one volume of sperm suspension was blended with two volume of 1% eosin, then after 30 seconds an equal volume of nigrosin was added to this mixture. finally, thin smears were assembled and observed under a light microscope with a magnification of 100x and the ratio of the live sperms percentage in different groups was computed. in this method, viable sperms appeared white while nonviable sperms stained purple(15). sperm morphology before morphologic investigation of the sperm of each group, smears prepared from sperm suspension stained by the way of papanicolao and then were air dried and utilized according to who. in each sample, 100 sperms with a magnification of 100x were investigated and existing abnormalities were reported as a percentage(15). statistical analysis a shapiro-wilk test was applied to determine the normality of distribution of measures which were found to be normally distributed. then a leven test indicated that the variances were homogeneous. a one-way analysis of variance (anova) and post hoc test (tukey) was performed to determine differences among the groups. data were expressed as means ± sd and significance was set at the alpha level p < .05. correlation between variables was also determined by pearson correlation coefficient. results during the implementation of the training, 3 rats were excluded from the study because of diabetic complications in the diabetic control group, 2 rats died during the training protocol and 1 rat was removed from the diabetic aerobic training due to failure to perform the training protocol. fasting blood glucose, body weight, and left testis weight for each animal, body weight was recorded at the beginning and end of a 70-day period. comparison of weight factor in posttest showed a significant difference between healthy control group with diabetic training group (p = .012) and healthy training group (p = .032) (table 2). also, there was significant difference in the mean left testis weight of rats in the healthy control group compared to diabetic control group (p = .021) (table 2). there was no significant difference in fasting blood glucose level of diabetic control group and diabetic aerobic training group in the beginning of the period (p = .311), but after 10 weeks of aerobic training there was a significant decrease in fasting blood glucose of diabetic aerobic training group compared to diabetic control group (p = .013) (table 2). sperm count the results showed a significant decrease in epididymal sperm number of diabetic control group compared to healthy control group (p = .001). the results also showed that the average sperm number of diabetic aertable 3. epididymal sperm number, sperm motility, sperm viability, and sperm morphology in studied groups. groups sperm count(106) sperm viability (%) sperm motility (%) sperm morphology (%) hc 39.3 (±13) 77.5 (±4.6) 60.8 (±6.5) 95.4 (±1.3) dc 11.75 (±5.7) a 29.78 (±16.2) a 32.5 (±1.1) a 85.25 (±7.5) a dat 26 (±13.2) ab 41.7 (±7.2) ab 40 (±6.5) a 88 (±8.8) hat 46.2 (±3.3) bc 87.8 (±2.9) abc 66.1 (±4.1)abc 90.4 (±9.1)bc a. the significant difference with healthy control group (p < .05). b. the significant difference with diabetic control group (p < .05). c. the significant difference with diabetic aerobic training group (p < .05). abbreviations: hc, healthy control group; dc, diabetic control group; dat, diabetic aerobic training group; hat, healthy aerobic training group. groups lh (miu/ml) fsh (miu/ml) testosterone (nmol/l) adiponectin (mg/l) insulin (miu/l) hc 5.6 (±2.8) 4.4 (±1) 6.6 (±1.8) 5.6 (±2.2) 3.4 (± .52) dc 3.9 (± .7)a 3.5 (±1.1) 4.6 (±1.6)a 1.6 (± .6)a 4.5 (± .96)a dat 4.7 (±1) 5.9 (±5) 5.7 (±2.3) 3.8 (±1.1)ab 3.1 (± .58)b hat 9.8 (±1.6)abc 4.3 (±1) 7.9 (±1.7)bc 5.3 (± .7)bc 3.3 (±.78)bc a. the significant difference with healthy control group (p < .05). b. the significant difference with diabetic control group (p < .05). c. the significant difference with diabetic aerobic training group (p < .05). abbreviations: hc, healthy control group; dc, diabetic control group; dat, diabetic aerobic training group; hat, healthy aerobic training group. table 4. the level of follicle stimulating hormone (fsh), miu/ml; luteinizing hormone (lh), miu/ml; testosterone, nmol/l; adiponectin, mg/l and insulin, (miu/l) in different groups of rats. the effect of training on adiponectin, sex hormone and sperm quality in diabetic rats-parasteh et al. andrology 594 vol 16 no 06 november-december2019 595 obic training group (26 ± 13×(106)) was significantly higher than that of diabetic control group (11.75 ± 5×(106)) (p = .03). furthermore, the difference between healthy control group and diabetic aerobic training group was not significant (p = .065) (table 3). sperm viability the mean percentage of viable sperms in the diabetic control group was significantly lower than that of the healthy control group (p = .001). also, there was a significant increase in sperm viability in diabetic aerobic training group compared to the diabetic control group (p = .001). (table 3). sperm morphology there was a significant difference in the mean percentage of morphologic natural sperms between the rats of healthy control group and diabetic control group (p = 0.007), but the difference between diabetic control group and diabetic aerobic training group was not significant (p = .566) (table 3). sperm motility the mean percentage of sperm motility in diabetic control group was significantly lower than that in healthy control group (p = .001), while there was a significant increase in sperm motility in diabetic aerobic training group compared to diabetic control group (p = .041) (table 3). adiponectin and hormonal levels the mean serum testosterone (p = 0.028) and lh (p = 0.047) concentrations decreased significantly in the diabetic control group compared with the healthy control group. the differences between means serum testosterone (p = .117), lh (p = .746) and fsh (p = .596) concentrations in the healthy control group and diabetic aerobic training group were not significant. unlike the healthy control group, the mean serum adiponectin level of the diabetic control group decreased significantly (p = .001). also the differences between means serum adiponectin concentrations in the healthy control group and diabetic aerobic training group were not significant (p = .269). therefore, after a 10 week protocol, aerobic training increases serum adiponectin of diabetic rats (table 4). the mean serum insulin level of diabetic control group increased significantly compared to the healthy control group (p = .008). the difference between means serum insulin concentrations among the healthy control group and diabetic aerobic training group were also not significant (p = .12). therefore, 10 weeks aerobic training reduced serum levels of insulin in diabetic rats (table 4). correlation of serum adiponectin and hormonal levels significant correlations were observed between serum adiponectin and serum lh (r = .495, p = .049) and serum testosterone (r = .406, p = .014) in diabetic type 2 rats (table 5). discussion the present study examined the effect of 10 weeks of aerobic training on serum levels of adiponectin and the sex hormones (testosterone, lh, and fsh) as well as sperm parameters in type 2 diabetic rats. during the last decade, diabetes and infertility have increased simultaneously(16). however, scientific reports regarding the relationship between diabetes and infertility are limited. the results generally affirm that diabetes has a negative effect on sperm parameters(3). according to who, sperm parameters include sperm count, sperm viability, sperm motility and sperm morphology(17). also confirmed that sperm parameters in the diabetic control group were significantly lower than those in healthy control group(18). the proposed mechanism is such that diabetes induces testicular changes through apoptosis, atrophy of seminal tubes, decreasing the diameter of seminal tubes, and decreasing the cellular complex of spermatogenesis, and the harmful effects on the production of natural sperm and spermatogenesis(19). also experimental studies have shown that diabetes and insulin resistance result in a decrease in gnrh, lh, fsh, and testosterone via the effect on hypothalamic-pituitary-gonadal axis(20). the increase of blood glucose results in a decrease in sex hormones including testosterone and sperm parameters through mechanisms such as an increase in oxidative stress in testis tissue and destroying productive cells of gnrh in hypothalamus (21). the present study also revealed that the amount of reproductive hormones of lh, fsh, and testosterone in diabetic rats was lower than that of healthy rats. these results are in agreement with the results of mohamed et al(22) and erdemir et al(21). in fact, our study supports the idea that a reduction in androgenic hormones is probably one of the main mechanisms in disrupting fertility of diabetic rats. this experiment showed that 10 weeks of aerobic training caused a significant reduction in blood glucose of the experimental group. physical exercise has been suggested as an effective and non-medicinal strategy in preventing and treating infertility. observing consumed calories, adopting a healthy diet and a moderate physical activity help improve the quality of sperm(23). alhashem et al. also reported that fattening rats with a highcalorie diet decreased their fertility capacity and a following aerobic training improved their spermatogenesis(24). in sum, studies have indicated that exercise at a moderate intensity can increase male fertility, probably through mechanisms such as improving endocrine system status, oxidative stress and body composition(25). the current study indicated that aerobic training in diabetic rats increases sex hormones (testosterone and lh) significantly when compared to non-training diabetic group. in other words, a decrease in blood glucose after ten weeks of aerobic training was associated to the return of testosterone and lh hormones to normal levels and no significant difference between the healthy control group and the experimental group was observed. the study also revealed a significant increase in sperm parameters, including sperm count and sperm viability in diabetic aerobic training group when compared to diabetic control group. the findings of the research indicate that performing exercise increases the efficiency of sperm fertility in diabetic rats probably through improving blood glucose levels and sex hormone status. in line with aforementioned findings in non-diabetic subjects(25,26) , our results showed that exercise improves fertility in diabetic rats. taken together, our results are in agreement with the reports which state physical exercises at moderate intensity may cause improvement in metabolic function and sex hormones, including testosterone(27). the findings also showed that adiponectin serum has positive effects on fertility. kasimanickam and colleagues showed that the concentration of adiponectin and testosterone were greater in high fertility bulls the effect of training on adiponectin, sex hormone and sperm quality in diabetic rats-parasteh et al. compared with average and low fertility bulls. furthermore, sperm dna fragmentation index was greater in low fertility compared with both average and high fertility bulls. they also concluded that the mrna abundance of adiponectin and its receptors, adipor1 and adipor2, were greater in high fertility bulls compared with average and low fertility bulls(28). our study demonstrated that serum adiponectin levels of diabetic rats were significantly lower in comparison to healthy rats, which is confirmed by previous reports(29,30), and possibly indicating that low levels of adiponectin may be an effective factor in type 2 diabetes disease. the effect of aerobic training on serum adiponectin levels of diabetic rats was investigated and indicated that adiponectin levels increase following a period of aerobic training. the results showed no significant difference between serum adiponectin levels of the diabetic aerobic training group and the healthy control group indicating the beneficial effects of aerobic training on adiponectin concentrations. also, our study also showed that there is a positive and significant correlation between serum adiponectin, lh and testosterone in rats. therefore, it seems that a decrease in adiponectin concentration due to diabetes may contribute to infertility. the emergence of the metabolic hormone of adiponectin as a key endocrine signal is a major improvement not only in energy balance, but also in areas such as reproduction, inflammation, and immunology. adiponectin, regulating pleiotropic, has a large number of biological functions, including gonadal steroidogenesis (8). as mentioned before, the means of testosterone, lh and adiponectin concentrations were higher after the aerobic training. these findings are in line with the findings of kasimanickam et al (2013). they reported that adiponectin and testosterone concentrations are greater in high fertility bulls(28). in the present study, there were improvements on fertility of diabetic rats after 10 weeks of aerobic training. our findings indicated that in addition to changes in sex hormones and sperm parameters, the effects of serum adiponectin may also be associated with these improvements. the present study suggests that a short period of aerobic training improves the profile of sex hormones and serum adiponectin concentrations which can lead to an increase in fertility capacity of diabetic rats. therefore, it is suggested that this research be replicated on diabetic rats with other kinds of exercises which decline diabetes effects following changes in serum levels of adiponectin and sex hormones in order to find suitable strategies in improving fertility of diabetic rats. also, the limitations of this study can be our diabetic model, so that streptozotocin–nicotinamide induced diabetes is a type i imitation, and this model does not exactly simulate type ii diabetes in humans. although various pathophysiological and molecular aspects of type 1 and type ii diabetes are prevalent, some of the characteristics may vary and generally restrict this pattern to type ii diabetes and insulin resistance. conclusions serum adiponectin, testosterone and lh concentrations were higher in trained diabetic rats. in addition, the quality of sperm regarding the parameters of count and viability were improved in the trained diabetic rats. in the present study, increasing adiponectin was associated with increased gonadotropic steroidogenesis (increased serum testosterone concentration). acknowledgments the present research is based on a research project approved by the deputy director of research and technology at arak university. also, the authors declare their gratitude to all those who helped us along the way. conflict of interest the authors report no conflict of interest. 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zohoori e, karamian m. hypoglycemic effects of three iranian edible plants; jujube, barberry and saffron: correlation with serum adiponectin level. pakistan journal of pharmaceutical sciences. 2015 nov 1;28(6). comorbid psychiatric disorders in children and adolescents with nocturnal enuresis pediatric urology shahrokh amiri, ali reza shafiee-kandjani* , roghayeh naghinezhad, sara farhang, salman abdi purpose: the present study was conducted with the aim of identifying the frequency of comorbid psychiatric disorders in children and adolescents with nocturnal enuresis (ne). materials and methods: in this descriptive-analytical study, 183 children and adolescents aged 5-18 years with ne referred to psychiatric clinics at tabriz university of medical sciences were selected in 2015. a structured clinical diagnostic interview, the kiddie-schedule for affective disorders and schizophrenia (k-sads), was employed based on the diagnostic and statistical manual of mental disorders (dsm-iv-tr) for the diagnosis of ne and comorbid psychiatric disorders. results: in this study, 39 participants (21.3%) were female and 144 (78.7%) were male. the mean age of participants was 8.69 ± 2.34 years. the lifelong incidence of mental disorders among enuretic children and adolescents was 79.23%. the highest incidence belonged to attention deficit/hyperactivity disorder (adhd) with 74.9%, oppositional-defiant disorder (odd) with 53%, and tic disorders with 12% (motor tics together with a single case of vocal tic). the lowest incidence was for conduct disorder, bipolar affective disorder, and post-traumatic stress disorder (ptsd) with 5%. based on the fisher exact test, there was no significant difference between girls and boys in terms of psychiatric disorders incidence (p > .05). conclusion: comorbid psychiatric disorders with ne are common among children and adolescents. therefore, in-depth examination of other psychiatric disorders needs to be carried out in enuretic children and adolescents, which will affect the treatment and prognosis of ne. keywords: attention deficit-hyperactivity disorder; comorbidity; nocturnal enuresis; prevalence; psychiatric disorders. introduction nocturnal enuresis (ne) is a common disorder in children defined as an often involuntary diurnal or nocturnal urination in one's bed or clothes by children who are normally expected to have gained bladder control and who lack manifest physical abnormalities(1). ne is diagnosed when a child wets his/her bed or clothes at least 2 times a week for 3 consecutive months, or when bedwetting creates a clinically important anxiety and frustration in the life(2). the incidence of ne has been reported in approximately 10% of 5-year olds and 3-5% of 10-year old children. meanwhile, 1% of adolescents aged 15-18 suffer from the disease(1). in a meta-analysis, the incidence of ne in boys (11.2-16.7 years) and girls (6.3-10.6 years) was reported to be 13.9% and 8.4%, respectively, and the overall incidence (9.2-12.8 years) was reported as 11.01%(3). the incidence of ne and day time incontinence was reported to be 18.7 and 5.5%, respectively (4). there is no general consensus regarding the cause of ne, with such factors as delayed puberty and nervous system development, reduced bladder capacity, and impaired antidiuretic hormone (adh) secretion (which results in water absorption by the kidneys) being sugresearch center of psychiatry and behavioral sciences, tabriz university of medical sciences, tabriz, iran. *correspondence: department of psychiatry, razi mental hospital, el goli boulevard, po box: 5456, tabriz, iran. tel/fax: +98 41 33803351. email: shafieear@tbzmed.ac.ir. received july 2016 & accepted december 2016 gested(5). since ne is not regarded as a disease but as a mere symptom by a number of authorities, numerous physical and psychological factors have been identified as the cause of this condition. since ne is observed in the majority of childhood psychiatric disorders, enuretic children struggle with multiple psychiatric problems (6). in this regard, in a study in kashan, iran, the incidence of comorbid psychiatric disorders has been reported as high as 89% (7). a study on pre-school children revealed that up to 9.1% had at least one subtype of incontinence (8.5% had nocturnal enuresis, 1.9% daytime urinary incontinence and .8% fecal incontinence). 6.4% had attention deficit/hyperactivity disorder (adhd), 6.2% had oppositional-defiant disorder (odd) and 2.6% were affected by to adhd and odd. 10.3% of the children with any kind of incontinence had adhd while 10.3% had odd. children with both adhd and odd having higher rates of incontinence than children with only one disorder(8). other reports reveal that 17.5% of children and adolescents with adhd suffer from ne(9). it has also been observed that odd in adhd children is predictive of ne(10). accordingly, screening comorbid psychiatric disorders with ne is of great significance(11). vol 14 no 01 january-february 2017 2968 pediatric urology 2969 a review of previous studies demonstrates that psychiatric disorders exhibit great comorbidity with ne. on the other hand, previous studies lack correspondence with regard to the incidence of psychiatric disorders. based on the clinical experiences, we have realized that the parents of ne children in iran are unwilling to report bedwetting to avoid psychiatric stigmata. therefore, data in this field is so scarce that the evaluation of etiology, prevalence and risk factors is much justified and may be of great importance to gain a thorough understanding of psychiatric problems involved in ne. it also meets scientific needs and facilitate therapeutic interventions in dealing with ne. the present study was therefore conducted with the aim of determining the comorbid psychiatric disorders with ne in children and adolescents in a referral center in north western iran. materials and methods this descriptive cross-sectional study was conducted in 2015. study population 183 children and adolescents aged 5-18 years with ne referred to psychiatric clinics at tabriz university of medical sciences were selected through the convenience sampling method. as the mentioned university clinics are the places in which several referred and outpatient children are visited from all over the province, the population may be considered as the representative of the existing society. inclusion criteria were parental consent for the participants, the first diagnosis of ne based on dsm-iv-tr criteria, lack of previous treatment, and being 5-18 years of age. daytime urinary incontinence and fecal incontinence were excluded. in case of urinary tract infection, diabetes insipidus, or other physical illnesses leading to urinary incontinence, the participants were excluded from the study. patients with intellectual disability were also excluded. procedure data pertaining to family medical histories as well as individual and family characteristics were respectively collected by medical records and interviews with parents. k-sads semi-structured diagnostic interview was used for the diagnosis of ne and lifelong comorbid psychiatric disorders. evaluations kiddie schedule for affective disorders and schizophrenia (k-sads) k-sads is a semi-structured diagnostic interview psychiatric disorders in enuretic children-amiri et al. frequency percentage children's birth order first 125 68.3 second 36 19.7 third or higher 22 12 children's level of education not entered into school 26 14.2 primary school student 141 77 junior and high school student 19 8.8 history of ne in the family brother 9 4.9 sister 9 4.9 mother 15 8.2 father 37 20.2 both parents 4 2.2 the family's place of residence urban areas 152 83.1 rural areas 31 16.9 parents' level of education illiterate 9 4.9 primary school 47 25.7 junior school 46 25.1 high school diploma 48 26.2 university 33 18 mothers' level of education illiterate 7 3.8 primary school 39 21.3 junior school 53 29 high school diploma 64 35 university 20 10.9 table 1. patients' individual and family characteristics designed based on dsm-iii-r and dsm-iv criteria, which is filled by a psychiatrist through interviews with parents and children. k-sads is scored using a 0-3 point rating scale. zero score indicates lack of adequate information, score one indicates presence of symptoms, score two represents sub-threshold level of symptoms and score three represents the threshold criteria(12). in iran, ghanizadeh et al.(13) reported the reliability of the persian version of k-sads: .81 through the test-retest method and .69 through inter-rater method. statistical analysis data were analyzed using spss v.21. descriptive statistics (frequency distribution, percentage, mean score, and standard deviation) were used to describe the variables and estimate the prevalence of comorbid psychiatric disorders. fisher's exact test was utilized to examine the prevalence variation of ne among boys and girls. a significance level lower than .05 was considered significant. results 183 children and adolescents including 39 girls (21.3%) and 144 boys (78.7%) participated in this study. the mean age of participants was 8.6 ± 2.3 years, with the youngest and oldest being 5 and 18 years, respectively. the onset of ne was 5.2 ± .9 years, with a minimum and maximum of 2 and 11 years. the mean frequency of ne within the last 3 months was 27.1 ± 23.7 times. the mean frequency of ne during the last week was 2.7 ± 1.6 times. the mean age of mothers and fathers at time of participation in the study were 35.3 ± 5.5 and 40.2 ± 6.5 years, respectively. the youngest mother was 23 and for the father it was 29 years old. the oldest counterparts were 50 and 70, respectively. according to table 1, which displays the individual and family characteristics of participants, the majority of children were firstborn in terms of birth order, and were primary school students. the siblings exhibited similar histories of ne as the majority of fathers had a history of ne. most parents lived in urban areas and had high school diplomas as their highest level of education. the incidence of lifelong psychiatric disorders in children and adolescents with ne was 79.23%. as shown in table 2, the highest incidence rates of lifelong psychiatric disorders comorbid with ne were adhd with 74.9%, odd with 53%, chronic tic disorders (motor tics together with a single case of vocal tic) with 12%. the lowest incidence was related to conduct disorder, bipolar affective disorder, and ptsd with .5%. according to results from the fisher's exact test, there was no significant difference between boys and girls in terms of psychiatric disorders incidence (p > .05). discussion according to the results, the majority of patients were primary school student boys, which corresponds to the findings of previous studies(3,8,14). in this study, the history of ne was more prevalent among the fathers (20.2 %). it is in contrary to a study conducted in turkey in which the mothers were more suffering from the condition(15). overall, the parents and siblings may also have had the similar experiences in childhood periods(16,17). in contrast to previous studies, the majority of children were firstborns(15). although the relationship between table 2. the incidence of lifelong psychiatric disorders comorbid with ne in children and adolescents psychiatric disorders fisher's exact test n (%) boy girl p no yes no yes adhda 137 (74.9) 34(23.6) 110 (76.4) 12(30.8) 27 (69.2) .83 .36 oddb 97 (53) 66(45.8) 78 (54.2) 20(51.3) 19 (48.7) .36 .59 chronic tic disorders 22 (12) 123(85.4) 21 (14.6) 38(97.4) 1 (2.6) 4.19 .051 generalized anxiety disorder 17 (9.3) 132(91.7) 12 (8.3) 34(87.2) 5 (12.8) .73 .36 obsessive-compulsive disorder 14 (7.7) 132(91.7) 12 (8.3) 37(94.9) 2 (5.1) .44 .73 separation anxiety disorder 12 (6.6) 133(92.4) 11 (7.6) 38(97.4) 1 (2.6) 1.29 .46 specific phobia 11 (6) 134(93.1) 10 (6.9) 38(97.4) 1 (2.6) 1.04 .46 tourette syndrome 7 (3.8) 137(95.1) 7 (4.9) 39(100) 0 1.97 .34 fecal incontinence 3 (1.6) 141(97.9) 3 (2.1) 39(100) 0 .82 1 social phobia 2 (1.1) 143(99.3) 1 (.7) 38(97.4) 1(2.6) .99 .38 conduct disorder 1 (.5) 143(99.3) 1 (.7) 39(100) 0 .27 1 bipolar mood disorder i 1 (.5) 144(100) 0 38(97.4) 1 (2.6) 3.71 .21 ptsdc 1 (.5) 143(99.3) 1 (.7) 39(100) 0 .27 1 a: attention deficit hyperactivity disorder; b: oppositional-defiant disorder; c: post-traumatic stress disorder. psychiatric disorders in enuretic children-amiri et al. vol 14 no 01 january-february 2017 2970 pediatric urology 2971 birth order and ne cannot be well-specified, parental stress during the early life of first born children as well as rigorous disciplinary measures by parents for their firstborns might impose a stressful situation and result in ne(18). in the present study, 74.9% of enuretic patients exhibited adhd. in another study conducted in iran, a 40% incidence of the same disorder was reported(7). it has also been reported that there is a strong comorbidity between adhd and ne(14,10,19). the severity of ne appears to play a key role in adhd comorbidity (20). accordingly, enuretic children from the tertiary care samples have a much higher rate of adhd comorbidity than those referred to non-tertiary care settings(19). a study reported a reduction in the frequency of ne by stimulant medications(21). also, a number of comorbid psychiatric problems such as language disorders play a key role in developing resistance to ne treatments(22). therefore, considering comorbid psychiatric disorders is of great importance in therapeutic approaches(11). a common disorder in children with ne is odd, which corresponds to the findings of this study; albeit with a lower-than-12% incidence in previous studies(7,20). variations in statistical populations and geographical locations are the possible reasons behind different results. like some studies, a significant comorbidity was found between ne, adhd, and odd(23), with a probable biological and neurological link between them. no difference was observed between girls and boys in terms of psychiatric disorder incidence, which corresponds to previous studies(7). therefore, although boys are more vulnerable to ne, both sexes are equally affected by comorbid psychiatric disorders with ne. this points to the significance of equal attention to both genders in terms of therapeutic interventions for the purpose of dealing with comorbid psychiatric issues. the lifelong psychiatric disorders incidence in children and adolescents with ne was 79.23%. therefore, it is highly probable that ne could be deeply involved in psychiatric problems. in addition to chronicity of the disease, comorbidity undermines the significance of clinical interventions in dealing with other comorbid psychiatric disorders. a small sample size and more narrow population was utilized in the study which accounts for a multi-centric study. in the present study, various subtypes of enuresis (24) have not been classified which should be considered in the future studies. conclusions comorbid psychiatric disorders with ne are common among children and adolescents which accounts for a thorough examination to figure out psychiatric disorders in cases of enuretic children. acknowledgement the authors are thankful to all parents and children participating in this study. the paper was adopted from doctoral dissertation of dr roghayeh naghinezhad with the reg. no. of 54.6240 from tabriz university of medical sciences. conflict of interest the authors declare that they have no competing interests. references 1. sadock bj, sadock va. kaplan &sadock's comprehensive textbook of psychiatry, 9th ed. new york: lippincott williams & wilkins. 2009; pp: 3560-79. 2. hockenberry m, wang d, wilson d. wong'snursing care of in fants and children. translated bypuran sami. tehran: boshratohfe; 2009: 269-400. 3. hadinezhadmakrania, moosazadeh m, nasehi mm, abedi g, afshari m, farshidi f, aghaei s. prevalence of enuresis and its related factors among children in iran: a systematic review and meta-analysis. int j pediatr. 2015;3:995-1004. 4. mahmoodzadeh h, amestejani m, karamyar m, nikibakhsh a. prevalence of nocturnal enuresis in school aged children. iran j pediatr. 2013;23:59–64. 5. gur e, turhan p, can g, akkus s, sever l, guzeloz s, citcili s, arvas a, enuresis: prevalence, risk factors andurinary pathology among children in istanmbul turkey. pediatrint. 2004;46:58-63. 6. ellington ee, mcguinness tm. mental health considerations in pediatric enuresis. j psychosocnursment health serv. 2012;50:405. 7. sepehrmanesh z, and moravvaji a. comorbidity of psychiatric disorder in children with nocturnal enuresis. daneshvarmed. 2014; 21 :23-28 8. niemczyk j, equit m, braun-bither k, klein am, von gontard a. prevalence of incontinence, attention deficit/hyperactivity disorder and oppositional defiant disorder in preschool children. eur child adolesc psychiatry. 2015;24:837-43. 9. amiri s, shafiee-kandjani ar, fakhari a, abdi s, golmirzaei j, akbari rafi z, safikhanlo s.psychiatric comorbidities in adhd children: an iranian study among primary school students. arch iran med. 2013;16:513-7. 10. ghanizadeh a. comorbidity of enuresis in children with attention-deficit/hyperactivity disorder.j attendisord. 2010;13:464-7. 11. niemczyk j, equit m, hoffmann l, von gontard a.incontinence in children with treated attention-deficit/hyperactivity disorder. j pediatr urol. 2015;11:141.e1-6. 12. kaufman j, birmaher b, brent d, rao u, flynn c, moreci p, williamson d, ryan n: schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (k-sads-pl): initial reliability and validity data. j am acad child adolesc psychiatry. 1997; 36:980-8. 13. ghanizadeh a. adhd, bruxism and psychiatric disorders: does bruxism increase the chance of a comorbid psychiatric disorder psychiatric disorders in enuretic children-amiri et al. in children with adhd and their parents?. sleep breath. 2008;12:375-80. 14. shreeram s, he jp, kalaydjian a, brothers s, merikangas kr.prevalence of enuresis and its association with attention-deficit/ hyperactivity disorder among u.s. children: results from anationally representative study. j am acad child adolesc psychiatry. 2009;48:35-41. 15. dolgun g, savaser s, balci s, yazici s. prevalence of nocturnal enuresis and related factors in childrenaged 5-13 in istanbul. iran j pediatr. 2012;22:205-12. 16. ozden c, ozdal ol, altinova s, oguzulgen i, urgancioglu g, memis a.prevalence and associated factors of enuresis in turkish children. int braz j urol. 2007;33:216-22. 17. esezobor ci, balogun mr, ladapo ta.prevalence and predictors of childhood enuresis in southwest nigeria: findings from a cross-sectional population study. j pediatr urol. 2015;11:338.e1-6. 18. de bruyne e, van hoecke e, van gompel k, verbeken s, baeyens d, hoebeke p, vande walle j. problem behavior, parental stress and enuresis. j urol. 2009;182(4 suppl):2015-20. 19. baeyens d, roeyers h, d'haese l, pieters f, hoebeke p, vandewalle j.the prevalence of adhd in children with enuresis: comparison between a tertiary and non-tertiary care sample. actapaediatr. 2006;95:347-52. 20. joinsonc, heron j, emond a, butler r. psychological problems in children with bedwetting and combined (day and night) wetting: a uk population-based study. j pediatrpsychol 2007; 32:605-16. 21. williamsonl, gower m, and ulzen t. clinical case rounds in child and adolescent psychiatryenuresis and adhd in older children and an adolescent treated with stimulant medication: a case series j can acad child adolesc psychiatry. 2011; 20: 53–5. 22. ferrara p, de angelis mc, caporale o, malamisura m, del volgo v, vena f, gatto a, chiaretti a. possible impact of comorbid conditions on the persistence of nocturnal enuresis: results of a long-term follow-up study. urol j. 2014;11:1777-82. 23. zavadenko nn, kolobova nm, suvorinovaniu. attention deficit hyperactivity disorder and enuresis in children and adolescents. zhnevrolpsikhiatrim s skorsakova. 2010;110:50-5. 24. zink s, freitag cm, von gontard a.behavioral comorbidity differs in subtypes of enuresis and urinary incontinence. j urol. 2008;179:295-8. psychiatric disorders in enuretic children-amiri et al. vol 14 no 01 january-february 2017 2972 urological oncology revisiting vesicourethral anastomosis during open radical retropubic prostatectomy; a simple and reproducible technique: a single center experience with 200 cases abbas basiri1,2*, seyed hossein hosseini sharifi2 purpose: vesicourethral anastomosis (vua) represents a challenging step of open radical prostatectomy (orp) because of limitation of space in the depth of male pelvis, lack of control on knots during tightening which subsequently causes inadequate coupling of vua or breakdown of knots, and also extremely difficult reapplication of sutures. to facilitate this step of orp, we have developed a simple and reproducible technique and reported our 8-year experience. materials and methods: we used two extra-long debakey tissue forceps to approximate the bladder neck to the urethral stump. we found it more beneficial than babcock clamp especially in obese patients with excess fatty tissue in the pelvic area. in this technique, the surgeon's assistant creates more space for the surgeon’s hand by sweeping the fatty tissue away from the anastomotic area and then pushes the reconstructed bladder neck down while the sutures are being tied. results: we analyzed data from 200 patients with prostatic cancer who underwent open radical prostatectomy performed from 2009 to 2017. there were only 2 sutures disrupted during knot tying. in two cases (1%), drain output was more than 30 ml/day on postoperative day 2 and drainage was left in place for a longer duration. with the help of medications, time voiding and dedicated pelvic floor exercise whenever needed,.the goal of full urinary continence (01 pad/day) was achieved in 85%, 94% and 98% of patients immediately after catheter removal, 3 months and 6 months after surgery, respectively. eight patients (4%) developed urethral stricture. conclusion: the surgical technique has been shown to be an independent predictor of urinary continence. we introduce a new simple modification of vesicourethral anastomosis during rp. using this technique; in addition to reducing anastomotic disruption rate and increasing knot tying control, postoperative urinary continence after orp may also be improved. keywords: vesicourethral anastomosis; open radical prostatectomy; follow up introduction radical prostatectomy (rp) is the gold standard treatment for prostate cancer. perioperative complication rates have been reported between 7.8% and 17.9%, which include prolonged vesicourethral anastomotic leak in up to 3.5% of cases and anastomotic stricture in up to 4.9% of patients during follow-up.(1,2) a key step during the procedure is the formation of a watertight vesicourethral anastomosis (vua). this maneuver, however, remains one of the most challenging parts of the surgery, requiring significant training and experience and is commonly a time consuming task even in the hands of an experienced surgeon. the impact of urethral stricture and urinary incontinency on patient’s quality of life can be devastating even in the case of an oncologically perfect surgery. for these reasons, this step must be mastered by any urologist who wants to perform impeccable radical prostatectomy. (3) in laparoscopic rp, running anastomosis is usually used which is quicker and technically less challenging than interrupted anastomosis. for open radical prosta1urology and nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti university of medical sciences (sbmu), tehran, iran. 2department of urology, erfan hospital, tehran, iran. *correspondence: urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. tel: +98 21 2256 7222. e mail: basiri@unrc.ir. received september 2018 & accepted november 2018 tectomy(orp), most surgeons perform vesicourethral anastomosis using interrupted sutures because of the difficulty of continuous suturing.(4) there are numerous studies comparing suturing techniques (i.e. interrupted versus continuous suturing) for vesicourethral anastomosis but it seems that limitation of space in the depth of male pelvis, especially in obese patients, and lack of control on knots during tightening are important factors that should be addressed first. to facilitate this step of orp we have developed a feasible and reproducible technique and aim to report our 8 year experience. materials and methods between january 2009 and june 2017, 200 consecutive patients with organ confined prostate cancer regardless of patient’s characteristics such as age, bmi and comorbidities underwent open retropubic radical prostatectomy for clinically localized prostate cancer and were selected for the novel modified vesicourethral anastomosis technique , which was approved by the ethical committee of the institution. urology journal/vol 16 no. 5/ september-october 2019/ pp. 475-477. [doi: 10.22037/uj.v0i0.4800] vesicourethral anastomosis was performed using an interrupted suturing technique. we used six 3-0 vicryl sutures starting by tightening the anterior one then moving on to the 10-, 8-, 6-, 4and 2-o’clock positions. we used two long debakey tissue forceps to approximate the bladder neck to the urethral stump. we found it more beneficial than a single babcock clamp in the midline which all sutures are tied, especially in obese patients with excess fatty tissue in the pelvic area. by using this technique, the surgeon's assistant can sweep the fatty tissue away from the anastomotic area and create more working space for the surgeon and then push the reconstructed bladder neck down and hold it close to the urethra while the sutures are being tied. we found it beneficial to prevent tension on sutures as it could avert suture breakdown. (figures 1 & 2) results we analyzed data from 200 patients with prostatic cancer who underwent rp performed from 2009 to 2017. only 2 sutures were disrupted while tying in the initial experience. in two cases (2%), we encountered drain output more than 30 ml/day on postoperative day 2 and the drain was left in place for a longer duration. the goal of full urinary continence (01 pad/day) was achieved in 85%, 94% and 98% of patients immediately after catheter removal, 3 months and 6 months after surgery, respectively, with the aid of medications, time voiding and dedicated pelvic floor exercise. eight patients (4%) developed urethral stricture. discussion vua represents a challenging step of orp because of low depth of the male pelvis, lack of control on knots during tightening and subsequent inadequate coupling of vua or breakdown of knots and also extremely difficult reapplication of sutures. the vesicourethral anastomosis creates watertight closure with urethral realignment and mucosal coaptation. disruption of the vesicourethral anastomotic sutures while tying is not uncommon and reapplication of sutures is often difficult(5). it seems that suture breakdown during vesicourethral anastomosis is not a rare experience for surgeons who perform radical prostatectomy. imperfect vesicourethral anastomosis can cause significant postoperative urinary extravasation which results in a longer catheterization time, increased risk of long-term anastomotic strictures and longer hospital stay. due to the high number of radical prostactemy operations being performed annually in the world, even small differences in surgical outcomes and complications can possibly affect a great number of patients. the rate of urinary incontinence after rp is significantly affected by the surgeon’s experience, surgical technique and definition of continence. the surgical technique has been shown as an independent predictor of urinary continence. beyond any technique used to improve the result of vesicourethral anastomosis for short term and long term continence rate, feasibility, convenience and simplicity are the most important factors that should be addressed initially.(6) several technical modifications have been introduced to improve postoperative urinary continence. most studies that address increasing the quality of vesicourethral anastomosis focus on comparing suture techniques (continous and interrupted), bladder neck reconstruction and reducing anastomosis time.(7,8) in this study we introduced a simple technique to facilitate vesicourethral anastomosis. primarily, we did not intend to evaluate the continence rate and urethral stricture but the results are comparable with those obtained using standard techniques. ficarra et al. reported the 12-month urinary incontinency rate to range from 4% to 31% and also stricture-related complications after open radical prostatectomy was reported by sujenthiran et al. to be 6.9% .(9,10) figure 1. using two extra-long debakey forceps to approximate the bladder neck to the urethral stump figure 2. surgeon's assistant can sweep the fatty tissue posteriorly away from anastomotic area vesicourethral anastomosis following open radical retropubic prostatectomy-basiri et al. urological oncology 476 vol 16 no 04 september-october 2019 477 conclusions although the quality of the vesico-urethral anastomosis is unlikely to have an impact on the oncological outcome of radical prostatectomy, it undoubtedly affects functional outcome and quality of life(11). using this simple modified technique helps to prepare more space in the cramped and confined pelvic space to apply proper knot placement and better tissue apposition. this is a preliminary study and we admit that without appropriate randomization, studies are prone to confounding bias and could overestimate or underestimate outcomes of interest. references 1. tewari a1, sooriakumaran p, bloch da, seshadri-kreaden u, hebert ae, wiklund p.positive surgical margin and perioperative complication rates of primary surgical treatments for prostate cancer: a systematic review and meta-analysis comparing retropubic, laparoscopic, and robotic prostatectomy. eur urol. 2012;62:1-15 2. jacobsen a, berg kd, iversen p, brasso k, røder ma. anastomotic complications after robot-assisted laparoscopic and open radical prostatectomy. scand j urol. 2016; 50274-9. 3. simone albisinni, fouad aoun, alexandre peltier, roland van velthoven. the singleknot running vesicourethral anastomosis after minimally invasive prostatectomy: review of the technique and its modifications, tips, and pitfalls. prostate cancer. 2016; 2016: 1481727. 4. ju hyun lim, chang myon park, han kwon kim, jong yeon park. comparison of perioperative outcomes between running versus interrupted vesicourethral anastomosis in open radical prostatectomy: a singlesurgeon experience. korean j urol. 2015; 56: 443–8 5. swami ks1, lam t, nabi g. a novel circumferential bladder neck suture to facilitate vesicourethral anastomosis during radical retropubic prostatectomy. bju int. 2011 ;107:2006-10. 6. ficarra v1, novara g, rosen rc, artibani w, carroll pr, costello a, menon m, montorsi f, patel vr, stolzenburg ju, van der poel h, wilson tg, zattoni f, mottrie a. systematic review and meta-analysis of studies reporting urinary continence recovery after robotassisted radical prostatectomy. eur urol. 2012; 62:405-17 7. kowalewski kf, tapking c, hetjens s et al. interrupted versus continuous suturing for vesicourethral anastomosis during radicalprostatectomy: a systematic review and meta-analysis. eur urol focus. 2018: s2405-4569(18)30143-3 8. yuri tolkach, 1 , 2 konstantin godin, 3 sergey petrov. a new technique of bladder neck reconstruction during radical prostatectomy in vesicourethral anastomosis following open radical retropubic prostatectomy-basiri et al. patients with prostate cancer int braz j urol. 2015; 41: 455–65 9. ficarra v1, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012;62:405-17. 10. sujenthiran a1, nossiter j1, parry m et al. national cohort study comparing severe medium-term urinary complications after robot-assisted vs laparoscopic vs retropubic open radical prostatectomy. bju int. 2018; 121:445-52. 11. liss ma, osann k, canvasser n, et al . continence definition after radical prostatectomy using urinary quality of life: evaluation of patient reported validated questionnaires. j urol 2010;183:1464–8. case report an unusual complication of suprapubic catheter migration into the left ureter wang shuaibin, mu haiqi, feng qin, yu haifeng* keywords: suprapubic catheter; complication; migration into ureter; pyelonephritis. suprapubic cystostomy is a widely employed procedure that is used to drain the bladder. despite being a safe procedure, suprapubic cystostomy has been reported to present multiple intraand postoperative complications. serious and unusual complications can occur during changing of the suprapubic catheter (spc) in patients with neuropathic bladder. in this work, we report an elderly patient with neuropathic bladder suffering from an unusual complication involving migration of the spc into the ureter during changing of the spc, leading to ureteric obstruction and left pyelonephritis. department of urology, the second affiliated hospital of wenzhou medical university, wenzhou, zhejiang 325027, people’s republic of china. *correspondence: department of urology, the second affiliated hospital of wenzhou medical university, wenzhou, zhejiang 325027, people’s republic of china tel: +86-577-88002815. fax: +86-577-88002855. e-mail: 691898478@qq.com. received june 2017 & accepted october 2017 introduction suprapubic catheters (spcs) are commonly used to drain the bladder. early studies show that suprapubic cysto-stomy is an effective and well-tolerated method for patients with neuropathic bladder. the method can accelerate renal deterioration and prevent urinary tract complications, including stones, recurrent infections, and blocked catheters(1). although suprapubic cystostomy is a safe procedure in most cases, unusual complications may occur either immediately after suprapubic cystostomy or several years after the procedure(2,3). herein, we report an elderly male patient with senile dementia who suffered from an unusual complication of spc migration into the ureter during spc change. suprapubic cystostomy was performed on the patient 3 years prior to this report. case report an 80-year-old chinese man with neurogenic bladder and benign prostatic hyperplasia was referred to the urology department of our hospital in october 2015. his past history included experiencing a stroke ten years prior to reporting and suffering from senile dementia. thus, the patient exhibited difficulty in communicating with others and expressing his feelings. preoperative ultrasound scan showed an enlarged prostate (50 mm × 39 mm × 37 mm in size). urodynamics performed on 21 october 2015 showed weak contractility of the detrusor and moderate obstruction of the bladder neck. the patient was treated through turp (transurethral prostate resection) figure 1. computed tomography,performed on 14 may 2017, (a left picture)the dilated ureter and the tip of foley catheter was located in ureter(white arrow) .(b right picture)the balloon of foley catheter had been inflated in distal end of dilated ureter(white arrow). case report 62 vol 15 no 03 may-june 2018 63 and suprapubic cystostomy. during the first month after operation, the patient continued to experience serious urinary incontinence. his spc was changed every four weeks in the urology unit after surgery. twelve days after a catheter change in may 2017, which was uneventful, his family noticed that the drainage catheter showed hematuria and pyuria per urethra. moreover, the patient experienced incontinence and fever (tympanic temperature, 38.2 °c). he was brought directly to our accident and emergency department, where laboratory investigations showed an elevated peripheral white blood cell (wbc) count of 25.4 × 109/l (normal range: 4–10 × 109/l), neutrophil ratio of 96%, and elevated c-reactive protein of 186 mg/l (normal range: 0–8 mg/l). serum creatinine and blood urea nitrogen were 104 µmol/l (normal range: 50–133 µmol/l) and 8.38 mmol/l (normal range: 2.9–8.2 mmol/l), respectively. the patient developed an increasing degree of left renal pain. computed tomography and ultrasound examination of the abdomen and pelvis revealed that the spc tube had migrated into the ureteral orifice and ureter. the tip of the foley catheter was lying about 4cm from the ureterovesical junction (figure 1). more significantly, hydronephrosis of the left kidney without hydroureter was found. given the findings on the ct scan and the patient’s symptoms, diagnostic imaging demonstrated ureter obstruction and left pyelonephritis. the spc (18 french) was changed under ultrasonography guidance, and the patient was prescribed 2 g of ceftriaxone administered intravenously every day for five days. hematuria and pyuria subsided after 72 h. the patient was discharged in a stable condition after a week. discussion suprapubic cystostomy catheter drainage is considered a valid and useful adjunct in various scenarios. most commonly applied in urology practice, this drainage is vital in patients with long-term catheters (because of various causes) and many postoperative situations(4). a meta-analysis comparing spc tubes with transurethral catheter drainage revealed that the suprapubic route is more acceptable to patients and reduces microbiological complications(5). our patient used spc instead of urethral catheterization after transurethral resection of the prostate and did not develop any problems in the following 30 months. although suprapubic cystostomy is a well-established procedure, complications do occur. multiple common complications, such as bacteriuria, bleeding, and bladder calculi, have been reported(6,7). however, several rare and unusual complications of suprapubic cystostomy have also been reported. these complications include bowel perforation, expulsion through bladder, entero-cutaneous fistula, knotting of the catheter, and catheter migration in a gaping ureter. vaidyanathan et al.(8) reported a serious complication during suprapubic cystostomy change in a spina bifida patient; in this case, inadvertent positioning of the spc in the urethra led to urine drainage failure of the spc. the patient developed an increasing degree of pain, swelling in the suprapubic region, and hematuria. hourglass deformity of urinary bladder is another unusual late complication of suprapubic cystostomy reported in patients with neuropathic bladder. singh and colleagues reported a case of left pyelonephritis secondary to catheter insertion for traumatic urethral stricture in a young male in 2001(9). cystographic evaluation revealed the contrast entering the left ureter with bilateral hydronephrosis. the author hypothesized the possibility of catheter migration into a gaping ureter with bilateral hydronephrosis. in 2010, dangle and colleagues(10) reported another case of spc migration into the left ureteral orifice that led to ureter obstruction and hydronephrosis. the patient who possessed a solitary kidney with neurogenic bladder and voiding dysfunction was managed with spc drainage. these reports suggest that, for patients with a solitary kidney, diagnosis of such a condition is crucial to provide immediate relief to the obstructed kidney. in the present paper, we report an elderly male patient with senile dementia whose spc had migrated into a previously normal non-gaping ureter. given the communication barrier, the drainage color and volume changes per urethra were not discovered in time by his family, leading to serious complications of ureteric obstruction, left pyelonephritis, and a slight degree of renal damage. by reviewing this case report, we can postulate that the presence of bladder dysfunction in elderly patients combines detrussor overactivity and a patulous ureteral orifice, leading to migration of the catheter tip into the ureteral orifice and ureter. ureter obstruction could lead to unilateral upper urinary hydroceles and pyelonephritis, whereas normal ureters may cause bladder incontinence. diagnosing such a condition is crucial to immediately rectify the incorrect placement of the spc and relieve the obstructed kidney; prescription of antibacterial agents may help promote healing. we suggest that the spc be anchored securely to reduce the occurrence of migration of the catheter tip into the ureter and accidental dislodgment of the catheter. in case of difficulty, ultrasound guidance should be employed when performing catheter exchange. conclusions spc migration into ureter is a poorly reported complication that must be reported. health professionals should be vigilant when inserting a catheter through the suprapubic track. a learning point from this case is as follows: suprapubic catheters should be anchored securely to reduce the occurrence of the migration of the catheter into ureter and accidental catheter dislodgment. conflict of interest none declared. references 1. vaidyanathan subramanian, soni bakul, hughes peter, et al. preventable long-term complications of suprapubic cystostomy after spinal cord injury: root cause analysis in a representative case report. patient saf surg. 2011;5:27. 2. szolnoki j m, puskas f, sweeney d m, et al. hyponatremic seizures after suprapubic catheter placement in 7-year-old child. paediatr anaesth. 2006;16:192-4. 3. vaidyanathan subramanian, soni bakul m, singh gurpreet, et al. fatality due to septicemia and hemorrhage in a patient with spinal cord injury and ischemic heart disease with the need for long-term catheter drainage. an unusual complication of suprapubic catheter-shuaibin et al. adv ther. 2006;23:354-8. 4. ananthakrishnan krishnan, ayyathurai rajinikanth, chiran j k, et al. an unusual complication of suprapubic catheter insertion. scientificworldjournal. 2006;6:2433-5. 5. mcphail m j w, abu-hilal m, johnson c da meta-analysis comparing suprapubic and transurethral catheterization for bladder drainage after abdominal surgery. br j surg. 2006;93:1038-44. 6. katsumi h k, kalisvaart j f, ronningen l d, et al. urethral versus suprapubic catheter: choosing the best bladder management for male spinal cord injury patients with indwelling catheters. spinal cord. 2010;48:325-9. 7. nomura s, ishido t, teranishi j, et al. longterm analysis of suprapubic cystostomy drainage in patients with neurogenic bladder. urol int. 2000;65:185-9. 8. vaidyanathan subramanian, hughes peter l, soni bakul m, et al. inadvertent positioning of suprapubic catheter in urethra: a serious complication during change of suprapubic cystostomy in a spina bifida patient a case report. cases j. 2009;2:9372. 9. vaidyanathan subramanian, hughes peter l, soni bakul m, et al. hourglass urinary bladder in a spinal cord injury patient unusual late complication of suprapubic cystostomy: a case report. cases j. 2009;2:6866. 10. dangle pankaj p, tycast james, vasquez evalynn, et al. suprapubic cystostomy: a bizarre complication of catheter migration causing ureteric obstruction. can urol assoc j. 2010;4:e127-8. an unusual complication of suprapubic catheter-shuaibin et al. case report 64 a comparative study on the clinical efficacy of two different disposable circumcision suture devices in adult males junwen shen1*, jihan shi2, jianguo gao1, ning wang1, jianer tang1, bin yu1, weigao wang1, rongjiang wang1 purpose: we evaluated the safety and efficacy of two different kinds of disposable circumcision suture devices in adult men. materials and methods: adult male patients (n = 179; mean age: 23.7 years) with redundant prepuce and/or phimosis were included in a clinical trial from july 2015 to august 2016. patients were divided into 2 groups: group a using the langhe disposable circumcision suture device (n = 89), and group b using the daming disposable circumcision suture device (n = 94). results: intraoperative and postoperative bleeding were more serious in the group a of disposable circumcision suture device compared with the group b of disposable circumcision suture device (4.21 ± 1.31 ml) versus (2.56 ± 1.45 ml). patients in the group b of disposable circumcision suture device had a longer swelling time (group a versus group b: 11.7 ± 0.9 days versus 14.5 ± 1.4 days), the postoperative pain score in the 7 days after surgery (group a versus group b: 2.9 ± 0.9 versus 3.8 ± 1.5), and higher postoperative infection rate (group a versus group b: 4.7% versus 13.8%), the differences were statistically significant (p < 0.05). conclusion: postoperative complications of the two kinds of disposable circumcision suture devices are different. we should pay attention to the risk of postoperative bleeding when the patients use the langhe disposable circumcision suture device, while the patients who use the langhe disposable circumcision suture device will have a longer healing time, and postoperative pain and the risk of infection cannot be ignored after the surgery. key words: disposable circumcision suture devices, redundant prepuce, postoperative complications. introduction redundant prepuce and phimosis are common male external genital diseases, and circumcision acts as the first-choice therapy for such diseases(1). the traditional circumcision surgery is featured by long operation duration, large intraoperative blood loss and prolonged postoperative healing course(2-4). disposable circumcision suture devices appeared in china in 2013 and have been widely applied since then. by drawing on the experience of intestinal anastomat cutting principle, circumcision suture devices can simultaneously fulfill foreskin cutting and suturing(5). at present, two different disposable circumcision suture devices, both of which are based on the cutting principle of intestinal anastomat, are used in our clinical practice while differ in varied processes for foreskin anastomosis. in clinical use, the effects of these two circumcision suture devices have been shown significantly different in their application to adult males. in this paper, the intraoperative and postoperative data of these two circumcision suture devices will be summarized to compare their differences in the treatment effects. methods study population the data was collected from july 2015 to august 2016. two different disposable circumcision suture devices surgeries were conducted in adult patients with redundant prepuce or phimosis in our department, where the choice of surgical method followed patient's preference. the informed consent was signed before the surgery and the postoperative routine follow-up lasted 1 month. for those with postoperative complications, the follow-up was extended to the incision healing. all adult male patients (older than 18 years) having complete follow-up record were enrolled. a total of 179 patients were enrolled in the study and then divided into two different groups (group a that used langhe circumcision suture devices and group b that used daming circumcision suture devices) according to their surgical instrument. as a result, 85 cases were assigned to the group a and 94 cases to the group b. procedures medical devices foreskin stapler type a: from jiangxi langhe medical instrument co., ltd., see figure 1. foreskin stapler type b: jiangsu changshu henry medical instrument co., ltd., see figure 2. surgical methods first, the adherent part of foreskin was separated. in the case of ostium praeputiale stenosis, a sharp incision 1 departments of urology, the first people's hospital of huzhou, zhejiang province,china. 2 departments of anesthesiology, the first people's hospital of huzhou, zhejiang province, china. *correspondence: departments of urology, the first people's hospital of huzhou, zhejiang province,china. tel: 0086 135 6722 8765. e mail: 13567228765@163.com. received december 2016 & accepted july 2017 pediatric urology vol 14 no 05 september-october 2017 5013 pediatric urology 5014 could be performed by scissors, followed by lifting the ostium praeputiale and placing the stapler onto the balanus. with the frenulum loosened, the bell handles was spanned to the back of the frenulum, forming an angle of about 45°. then the ostium praeputiale was fixed to the bell pole using tie, where the bell pole should be inserted into the center of the housing carefully. the adjustment knob was installed and tightened clockwise to align to end of bell pole with the top of adjustment knob. the safety catch was removed; the handles were hold for 15-20 seconds and then released. the adjustment knob was turned counterclockwise and the bell stand was removed. the adherent foreskin was cut off. the entire bell stand was detached and the circular anastomotic site was pressed for 2 min, followed by pressure bandaging of the surgical wound. the pressure bandage was opened 3 days after surgery, and the wound was cleaned every day until healing(6-8). evaluations 1. operation duration: the time spent from the onset of anesthesia to the end of surgery. 2. pain scores: with the scale set between 0 points and 10 points, visual analogue pain score (vas) was used for pain scoring to record the intraoperative pain, pain within 24 hours after surgery, and pain within 1 week after surgery respectively. 3. blood loss: calculated by 5cm×5cm gauzes that could suck 5ml blood. 4. postoperative complications assessment: including postoperative infection, bleeding, incision dehiscence, second operation and other surgical complications. 5. wound healing period: the time from the day of surgery to the day of complete wound healing. 6. appearance satisfaction: upon patients' visit to our department for review 1 month after surgery, their postoperative foreskin condition was recorded, including incision healing, cutting edge neatness, residual foreskin symmetry, penile erection restriction; the patient satisfaction was reported as "satisfactory" and "dissatisfactory". 7. the situation of staple shedding after surgery was recorded to identify whether the patient needed to visit the hospital for manual removal of staples. statistical analysis spss19.0 statistical software was used to process the data, t test was adopted for numerical data comparison and χ2 test for categorical data comparison, where p < .05 was defined as statistically significant difference. results average age in group a was 23.2 ± 2.6 years, while average age in group b was 24.0 ± 3.1 years. 74 patients in group a had redundant prepuce, and 11 patient had phimosis. at the same time, 80 patients in group b had redundant prepuce and 14 patients had phimosis.. the intraoperative and postoperative recovery situations were compared between two groups (table 1). the comparison of intraoperative and postoperative outcomes between two groups showed that the intraoperative blood loss of group a was higher than of group b and 2 cases from group a underwent second operation for suture hemostasis due to postoperative active bleeding. group b was featured by longer staple-shedding time after surgery and thereby higher probability of visiting the hospital for removing staples; besides, these patients also suffered longer postoperative edema, greater postoperative pain degree as well as higher incidence of postoperative infection. discussion as male genital diseases commonly seen in urology, redundant prepuce and phimosis may increase the risk of urinary tract infection. surgical excision of the redundant foreskin to expose the penis serves as the mainstream regime at present. furthermore, excision of redundant foreskin can also reduce the risk of hiv infection(2,9-12). conventional surgical circumcision had been used widely in past decades, however disposable circumcision suture devices had been recognized by the more and more urology doctors in the recent years. comparing the two surgical methods, disposable circumcision suture devices has the advantages of short comparison of two circumcision devicesshen et al. figure 1. langhe disposable circumcision suture device. figure 2. daming disposable circumcision suture device. operation time, less operation pain and less blood loss this method benefits both the doctor and patients. that is the reason why it had been used widely in the recent years. however, with the extensive use of the disposable circumcision suture devices, we found some problems in the surgical procedures themselves, such as postoperative incision edema, infection, local incision dehiscence, especially the longer time for staple shedding after surgery; those, whose staples fail to shed, need to visit the hospital for manual removal. all of this increase the patient's pain and mental stress(13-16). two different types of disposable circumcision suture devices are currently used in our medical center. although both of them are based on the principle of intestinal anastomat and can simultaneously fulfill foreskin cutting and suturing, the intraoperative and postoperative efficacy of these two surgical instruments have been shown differently (figures 3-4). compared with patients using foreskin stapler type b, those using foreskin stapler type a were associated with more obvious intraoperative blood loss and higher risk of postoperative bleeding. of 85 patients, obvious oozing within 6 hours after surgery was reported in 2 cases, who underwent second operation for cut suturing to achieve hemostasis. by comparing these two different disposable circumcision suture devices, it was demonstrated that stapler type b incorporates a pressure by plastic sheet upon the incision wound and the staples fix the wound outside the plastic sheet (figure 4). on the contrary, the surgical instrument type a directly fixes the incision wound with the staples (figure 3). it is precisely this difference that leads to the fact that instrument type b has more ideal intraoperative and postoperative compression hemostasis effect as well as significantly reduced intraoperative and postoperative bleeding risk. at the same time, we also found that the patients undergoing operation type b were characterized by longer postoperative recovery time. first, the postoperative edema time of patients undergoing operation type b was found to be significantly longer than those undergoing operation type a, so was the case with postoperative pain degree and postoperative infection rate. we believe that the cause resulting in the 3 differences above is the process used by surgical instrument type b. as mentioned before, the work principle of surgical instrument type b is to press the wound with a plastic sheet while the staples are used to fix the wound and plastic sheet. therefore, it is more likely to cause wound compression and incarceration, further leading to local edema and inflammation, especially on the site of frenulum of prepuce, which appears to be the position most likely to develop edema. edema may accelerate incarceration and cause local pain or even local inflammation (figures 5-6). secondly, the comparison of staple shedding indicated that the staple shedding time of group b was longer than group a (n=85) group b (n=94) p-value operation duration (minutes) 8.1 ± 2.0 7.6 ± 2.2 > 0.05 blood loss (ml) 4.21 ± 1.31 2.56 ± 1.45 < 0.01 intraoperative pain (score) 2.8 ± 1.1 2.7 ± 1.5 > 0.05 pain within 24 hours after surgery (score) 3.8 ± 1.7 4.0 ± 1.4 > 0.05 second operation 2 0 < 0.001 period of complete staple shedding (days) 14 ± 3 21 ± 4 < 0.001 pain within 7 days after surgery (score) 2.9 ± 0.9 3.8 ± 1.5 < 0.001 incision edema time (days) 11.7 ± 0.9 14.5 ± 1.4 < 0.001 cases requiring manually removing staples 7/85 18/94 < 0.05 cases reporting dissatisfactory appearance 8 7 > 0.05 cases of postoperative incision infection 4(4.7) 13(13.8) < 0.05 table 1. comparison of two different operations’ clinical outcome and complications. data is presented as mean ± sd, n, n(%) or % figure 3. surgical outcomes in group a. figure 4. surgical outcomes in the group b. comparison of two circumcision devicesshen et al. vol 14 no 05 september-october 2017 5015 group a and associated with more cases of manually removal. in our opinion, the tendency of group b to cause postoperative incision edema will lead to the incarceration of circular plastic sheet in the edema tissue, which impedes staple shedding. meanwhile, the comparison of the specific postoperative incarceration situation of stapling between two groups reported two differences. for group a, the residual staples were usually single and isolated; the staples were often embedded by the surrounding skin and difficult to remove due to deeply stapling into skin. for group b, the residual staples after surgery were often segmental, and the common situation was that several or a row of staples failed to shed, which led to the incomplete shedding of plastic sheet; however, the staples were easy to remove since the stapling depth was relatively shallow. according to the investigation on postoperative adverse symptoms and causes of two surgery procedures, we summarize that the different postoperative complications of two disposable circumcision suture devices were derived from their different processes, which requires us to take corresponding measures to reduce such adverse symptoms based on these two set of conditions. for circumcision suture devices type a, absorbable suture can be used for intermittent reinforcement of the wound after intraoperative foreskin anastomosis, and the patients will also be asked to reduce physical activity within 24 hours after surgery so as to lower the risk of postoperative bleeding. for circumcision suture devices type b, the clearance of circular plastic sheet among the staples can be cut with scissors. in general, we cut at three positions, namely, the 12 o'clock, 4 o'clock and 8 o'clock, to reduce the possibility of plastic sheet incarceration in the incision after surgery. besides, the patients are also informed of the fact that the postoperative edema may last slightly longer so as to relieve their postoperative anxiety. however, if the pain remains obvious 24 hours after surgery, then prompt hospital visit will be recommended to observe whether the plastic sheet is incarcerated in the incision and, if necessary, manually removal as early as possible. conclusions in conclusion, these two namely are featured by different postoperative recovery situations due to process differences. langhe circumcision suture devices is associated with greater intraoperative and postoperative blood loss and higher risk of secondary bleeding, while daming circumcision suture devices may lead to longer postoperative edema and slower postoperative recovery. although difficult postoperative staple shedding is reported in both of them, daming stapler has a higher incidence, and the patient needs to visit the hospital for manual removal if the staples fail to shed within one month after surgery. finally, we found that the postoperative recovery can be improved if differentiated treatment is conducted regarding the postoperative recovery characteristics of these two staplers. for patients reporting postoperative stapler incarceration, the plastic sheet and staples should be removed promptly. references 1. dunsmuir, w. d. & gordon, e. m. the history of circumcision. bju int 1993; 83 suppl 1, 1-12. 2. hayashi, y. & kohri, k. circumcision related to urinary tract infections, sexually transmitted infections, human immunodeficiency virus infections, and penile and cervical cancer. int j urol 2013: 769-75. 3. williams, n. & kapila, l. complications of circumcision. br j surg 1993: 1231-6. 4. ahmed, a., mbibi, n. h., dawam, d. & kalayi, g. d. complications of traditional male circumcision. ann trop paediatr 1999 : 113-7. 5. gu, c. et al. introducing the quill device for modified sleeve circumcision with subcutaneous suture: a retrospective study of 70 cases. urol int 2015 : 255-61. 6. pan, f. et al. circumcision with a novel disposable device in chinese children: a randomized controlled trial. int j urol 2013: 220-6. 7. mohta, a. editorial comment from dr mohta to circumcision with a novel disposable device in chinese children: a randomized controlled trial. int j urol 2013: 228-9. 8. millard, p. s., wilson, h. r., goldstuck, n. d. & anaso, c. rapid, minimally invasive adult voluntary male circumcision: a randomised pediatric urology 5016 figure 5. edema of frenulum of prepuce was likely to be most serious. figure 6. edema may accelerate incarceration. comparison of two circumcision devicesshen et al. comparison of two circumcision devicesshen et al. vol 14 no 05 september-october 2017 5017 trial of unicirc, a novel disposable device. s afr med j 2013: 52-7. 9. shaffer, d. n. et al. the protective effect of circumcision on hiv incidence in rural low-risk men circumcised predominantly by traditional circumcisers in kenya: two-year follow-up of the kericho hiv cohort study. j acquir immune defic syndr 2007: 371-9. 10. kelly, r. et al. age of male circumcision and risk of prevalent hiv infection in rural uganda. aids 1999: 399-405. 11. gray, r. et al. the effectiveness of male circumcision for hiv prevention and effects on risk behaviors in a posttrial follow-up study. aids 2012: 609-15. 12. bitega, j. p., ngeruka, m. l., hategekimana, t., asiimwe, a. & binagwaho, a. safety and efficacy of the prepex device for rapid scaleup of male circumcision for hiv prevention in resource-limited settings. j acquir immune defic syndr 2011: 127-34. 13. zhang, z. et al. application of a novel disposable suture device in circumcision: a prospective non-randomized controlled study. int urol nephrol 2016: 465-73. 14. ren, y. & yan, j. j. [modified circumcision with a disposable suture device]. zhonghua nan ke xue = national journal of andrology 2015: 541-4. 15. huo, z. c. et al. use of a disposable circumcision suture device versus conventional circumcision: a systematic review and metaanalysis. asian j androl, 2017: 362-7. 16. cao, d. h., dong, q. & wei, q. commentary on "disposable circumcision suture device: clinical effect and patient satisfaction". asian j androl 2015: 516. robotic & laparoscopic urology symptom resolution and recurrence outcomes after partial versus total laparoscopic adrenalectomy: 13 years of experience with medium-long term follow up nasser simforoosh, mohammad hossein soltani, hamidreza shemshaki*, milad bonakdar hashemi, mehdi dadpour , amir h kashi** purpose: partial adrenalectomy (pa) is an emerging modality typically performed for the treatment of hereditary and sporadic bilateral tumors, to reduce the risk of adrenal failure. in this study, we evaluated the recurrence and functional outcomes after partial and total adrenalectomy (ta). materials and methods: from march 2005 to july 2018, 284 patients with functional tumor or > 5 cm adrenal mass underwent clipless and sutureless laparoscopic partial or total adrenalectomy (pla and tla). patients with a pathological diagnosis of pheochromocytoma, cushing or conn’s disease and more than two year follow up were included in this study. pre-operative and operative variables were collected retrospectively and functional outcomes and recurrence were gathered prospectively. results: one hundred forty patients (mean age: 43±5.1years) were included in the study. pla and tla were performed for pheochromocytoma (total n=78; pla=12 (15%), tla=66 (85%)), cushing syndrome (toal n=17; pla = 4 (24%), tla = 13 (76%)), and conn’s disease (total n=45; pla=7 (16%), tla=38 (84%)). in pheochromocytoma patients, improvement of hypertension, palpitation, and headache was not different between patients who underwent pla versus tla (all p > 0.05). two recurrences were observed in patients with pheochromocytoma who had undergone tla. in patients with cushing disease, central obesity, fascial plethora, and hypertension were improved in all patients six months after treatment, muscle weakness was improved one year after surgery, and acne and hyperpigmentation only improved two years after surgery. the length of time for resolution of symptoms was not different in patients who underwent pla versus tla. in conn’s disease hypertension was resolved in all patients and no patient required potassium supplements post-operatively. in follow up no recurrence was observed in patients with a pathological diagnosis of cushing or conn’s disease. conclusion: in our experience, pla can provide excellent control of the symptoms parallel with tla and with no statistically significant difference in recurrence making pla an attractive option in patients with an adrenal mass. keywords: adrenalectomy; laparoscopy; partial; adrenal sparing surgery; cortical sparing surgery; recurrence introduction adrenal masses are relatively common among the general population, with an autopsy series of 3–5%(1). most of these lesions, when they are first detected, are benign nonfunctioning adrenal adenomas, but they can also be functional and secretory(2). laparoscopic total adrenalectomy—first introduced by dr. gagner(3)—is an acceptable method for treating these adrenal masses. simforoosh et al.(4) reported the first laparoscopic adrenalectomy in iran. however, the adrenal insufficiency that follows bilateral adrenalectomy results in a lifelong risk of morbidity due to addisonian crisis (35%), which, in turn, can compromise a patient’s quality of life(5). consequently, over the last two decades, increasing enthusiasm has been created in partial adrenalectomy (pa). although pa has produced successful results, the risk of the recurrence of the tumor remains a concern, as urology nephrology research centre (unrc) , shahid labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology nephrology research centre, shahid labbafinejad hospital, boostan 9th st., pasdaran ave, po box 1666679951, tehran, iran. tel: +98.21.23602280. email: hshemshaki@sbmu.ac.ir. ** urology and nephrology research center (unrc), shahid labbafinejad medical center, shahid beheshti, university of medical sciences (sbmu), tehran, iran. ahkashi@gmail.com. received june 2020 & accepted october 2020 this risk and the associated efforts to detect recurrences require lifelong clinical and biochemical surveillance. previous studies have revealed that cases of conn’s adenoma seem to be a reliable indication of pa due to its benign behavior and eccentric location and that curative biochemicals seem to be the result of pa in almost all cases(5,6). compared with conn’s syndrome patients, experiences with pa are minimal in cushing’s syndrome patients. walz and colleagues(7) evaluated pa in 22 patients with adrenal neoplasia, including four patients with cushing’s adenoma. recurrence was not observed in any patients after a median follow up of 6.5 years. data on the recurrence of inherited pheochromocytoma after pa are inconsistent. following adrenal sparing surgery, inabnet et al.(8) reported relapse in three of five patients, and van heerden et al.(9) observed relapses in two patients. however, others found no relapses or only one relapse in larger series. urology journal/vol 18 no. 2/ march-april 2021/ pp. 165-170. [doi: 10.22037/uj.v16i7.6338] vol 18 no 2 march-april 2021 138 due to these limited and controversial data regarding the efficacy and safety of pa versus ta in adrenal masses, this study was conducted to evaluate the efficacy and safety of these surgical approaches in the treatment of pheochromocytoma, cushing and conn’s disease. materials and methods patients and settings this was a retrospective-prospective study conducted from march 2005 to july 2018. all patients with radiologically confirmed adrenal masses underwent clinical examination and biochemical evaluations. ultrasonography and abdominal ct scan were preoperatively performed for all patients. mri was performed if ct scan was inconclusive. routine biochemical tests such as serum sodium and potassium levels, fasting blood sugar, and endocrine analyses such as serum cortisol, acth, mineralocorticoids, and 17-hydroxyprogesterone, and 24-hour urinary vma were also performed when indicated. patients who had biochemically active adrenal masses or clinically unapparent adrenal mass more than five cm were scheduled for pa or ta. patients with a pathological diagnosis other than pheochromocytome, cushing or conn’s disease were excluded from the study. patients were also excluded if surgery was planned as open surgery from the outset or if surgery was converted to open surgery or whether follow up duration was less than two years. the study was approved by the ethics committee at shahid beheshti university of medical sciences. all of the surgeries were performed by expert endourologists. surgical procedure transperitoneal laparoscopic total adrenalectomy (tla) was carried out as previously described and is summarized below(10). patients received oral phenoxybenzamine for adequate alpha blockade in case of high preoperative cathecholamines or when there was preoperative suspicion of pheochromocytoma. under general anesthesia, the patients were positioned in flank position with an angle of about 60 degrees. a small umbilical incision was created under direct visualization to enter the abdominal cavity and pneumoperitoneum was then rapidly created with co 2 . three 5 mm trocars were inserted under direct vision. for right-side adrenalectomy, we inserted another 5 mm trocar to retract the liver. we used bipolar cautery to coagulated adrenal partial vs. total adrenalectomy-simforoosh et al. endourology and stones diseases 130 veins and then divided veins by cold scissors. no vascular staplers, clips, or any other energy sources were used for the closure of adrenal vessels as described earlier(10). adrenal glands were separated from the surrounding tissue by sharp or blunt dissection and use of bipolar cautery. specimens were retrieved from the abdominal cavity using an endobag through enlargement of the umbilical or lower quadrant port sites. for partial adrenalectomy, the same protocol was used. adrenal masses were identified and divided from the rest of normal adrenal tissue by cold scissors and bleeding was controlled by bipolar cautery. patients’ follow-up a retrospective chart review was designed to obtain demographic, biochemical, hormonal, operative, and postoperative parameters, including the length of hospital stay, surgical time, major complications, and steroid dependence at follow-up of pa. the size of the resected adrenal mass was determined by pathologic reports. follow-up consisted of abdominal ct or magnetic resonance imaging, clinic visits, plasma or 24-hour measurement of adrenal hormones as indicated by pathology reports 3-6 months after the operation and then annually. in conn’s disease follow-up included the measurement of the blood pressure and serum potassium. in cushing’s disease, patients were investigated for cushing's symptoms or signs in each follow up visit. patients were asked to report symptoms that they experienced before surgery and symptoms that they had at follow up visits. in case of symptom resolution, patients were asked to estimate the duration of symptom presence after surgery. the survey also inquired if patients were on steroids in bilateral cases and for how long steroids were required postoperatively. specific questions related to the management of diabetes and hypertension were also included, looking specifically at how their disease was currently treated and whether or not they were on medication or dietary modifications for this condition. diabetes and hypertension resolution were also verified by patient chart review, looking at blood pressure measurements, serum glucose measurements, and medication profiles whenever possible. statistical analysis we used an independent t test for normally distributed data. chi-squared test was implemented to compare nominal data. statistical analysis was performed using table 1. patient demographics (primary vs. secondary ralp) variables partial adrenalectomy total adrenalectomy p-value total pathologies, n=140 n=23 n-117 age (years) 39.05 ± 12.26 41.18 ± 13.38 0.78 gender, male/female 13 / 10 52 / 65 0.56 side, right/left 12 / 11 83 / 34 0.08 tumor size (cm) 4.32 ± 3.09 5.44 ± 3.08 0.12 operative time, min 103 ± 15 112 ± 10 0.23 pheochromocytome, n=78 n=12 n=66 htn improvement, n(%) 11(89) 60(91) 0.62 palpitation improvement, n(%) 11(89) 57(86) 1.0 headache resolution, n(%) 8(66) 48(72) 0.73 recurrence, n(%) 0(0) 2(3) 1.0 cushing syndrome, n=17 n=4 n=13 bilateral adrenalectomy, n(%) 1(25) 2(15) 1.0 recurrence, n(%) 0(0) 0(0) 1.0 conn’s syndrome, n=45 n=7 n=38 htn improvement, n(%) 4(100) 38(100) 1.0 potassium supplement, n(%) 0(0) 0(0) 1.0 recurrence, n(%) 0(0) 0(0) 1.0 vol 18 no 2 march-april 2021 166 spss version 18.0 software. statistical significance was set at p < 0.05. results a total of 284 patients were operated for adrenal mass during the study period. a number of 144 patients were excluded for not having a pathologic report of pheohromoytoma, cushing or conn’s disease (n=133), or for short follow-up (n=11). finally, 140 patients were followed for a mean follow-up of 65 months. the demographics of patients, their operative and postoperative parameters are illustrated in table 1. pheochromocytoma seventy-eight patients underwent laparoscopic surgery due to phaeochromocytoma. ninety percent of our patients had hypertension (mean: 230 ± 11 mmhg) preoperatively, and 87% of them were improved post-operatively (mean: 130 ± 7 mmhg) (p = 0.001). patients went from a mean of 2.8 ± 0.7 antihypertensive medications pre-operatively to 0.8 ± 0.2 medications (p < 0.001). eighty seven percent of our patients had palpitation preoperatively, and 83% of them improved post-operatively (p < 0.001). twenty three percent of our patients had headache preoperatively, and 73% of them improved post-operatively (p = 0.02). improvement of hypertension, palpitation, and headache was not statistically different between patients who underwent pla versus tla (table 1). six cases (4 cases in ta group and 2 cases in pa) in pheochromocytoma underwent bilateral adrenalectomy. none of the patients who underwent pa required permanent steroid supplements post-operatively while patients who underwent bilateral tla were on steroid replacement. after a six-year follow-up, two cases who underwent tla were visited in our clinic because of hypertension and biomarker recurrence. their images showed recurrence of pheochromocytoma in the site of surgery and they were scheduled for tumor resection. after a second operation, they did not have recurrence in a one-year follow-up. cushing’s syndrome seventeen patients underwent laparoscopic surgery due to cushing’s disease, of these, 4 (24%) underwent pa and 13 (76%) patients underwent ta. after a sixmonth follow-up, symptoms such as central obesity, fascial plethora, and hypertension were improved in all patients. ninety-two percent reported dramatic changes. but symptoms such as muscle weakness, acne, and hyperpigmentation did not improve completely. after a one-year follow-up, symptoms such as muscle weakness improved in all patients and 90% reported dramatic changes. these changes were not significant between the two study groups (p = 0.46). nevertheless, acne and hyperpigmentation did not resolve completely. in the second year after surgery, patients were evaluated for symptoms such as acne and hyperpigmentation almost at a similar time interval. symptoms were resolved in both groups similarly. figure 1 outlines the time line of symptom resolution in patients after cushing surgery. there was no recurrence in patients with a pathology diagnosis of cushing. three cases (2 cases in tla group and 1 case in pla) in cushing underwent bilateral adrenalectomy. the case of pla did not require permanent steroid supplements post-operatively. finally, the patients had persistent symptoms including diabetes (81%), hyperpigmentation (89%), obesity (61%), and hypertension (62%). using a univariate analysis, we compared all of the patients who had unresolved symptoms after adrenalectomy to those that had a complete response, and we were unable to identify any factor that could be predictive of failure to respond to adrenalectomy. evaluated factors included age (p = 0.51), gender (p = 0.07), diagnosis (p = 0.24), treatment pre-operatively with adrenolytic medication (p = 0.50), serum cortisol level (p = 0.12), and urine cortisol level (p = 0.34). the time of symptom resolution varied from weeks to up to eighteen months (figure 1). most changes in physical examination were observed within a mean of six months after the operation. however, hyperpigmentation took an average of thirteen months for resolution. there was significant variability among patients in how figure 1. symptom resolution after adrenalectomy in cushing disease. partial vs. total adrenalectomy-simforoosh et al. robotic and laparoscopic urology 167 long it took for symptoms to resolve. conn’s syndrome forty-five patients underwent laparoscopic surgery due to conn’s syndrome; 7 (16%) underwent pa and 38 (84%) patients underwent ta. the maximum mean systolic blood pressure measured was 207 ±25.7 mmhg and the maximum mean diastolic pressure was 114±18.7 mmhg. elevated blood pressure had first been diagnosed 6.5 ± 2.5 years before the operation. thirty-two patients (71%) suffered from hypokalemia with a mean minimal level of 2.6 ± 0.3 mmol/l. in a retrospective analysis, hypokalemia was first detected 1.8 ± 2.1 years before surgery. in the first follow up after surgery, no patient required potassium supplements and all patients in the two groups showed improvement in hypertension. after an eight-year follow up, there was no recurrence in the two groups. discussion in this series, we observed no statistically significant differences between the pla and tla groups in terms of the mean operative time, intra-operative blood loss, duration of hospital stay, complications, or postoperative morbidity. also, the functional results for pa and ta were comparable in the treatment of adrenal tumors. while no recurrences were detected at the 65-month (on average) follow-up for patients with cushing’s adenoma and conn’s syndrome, two recurrences were observed in patients in the pheochromocytoma group who underwent ta. most of the time, pheochromocytoma is a non-familial sporadic tumor. however, it can present itself as a genetic disease with an autosomal dominant inheritance of high penetrance that can occur either in isolation or in combination with other pathologies(11). patients with bilateral pheochromocytomas are treated with total bilateral adrenalectomy. despite the fact that cortical-sparing adrenalectomy was introduced in 1999, it is still a relatively underutilized procedure(12,13). a recent meta-analysis(14) reported that pa can reduce the need for steroid replacement therapy and has a low risk of recurrence. however, this knowledge is based mainly on retrospective case series with small sample size. overall, there is little evidence supporting the use of partial adrenalectomy in treatment of bilateral pheochromocytomas, leading to a paltry recommendation in the recent guidelines on the management of pheochromocytoma(14,15). however, we have shown that the functional outcomes of pla and tla were comparable in the treatment of pheochromocytoma. indeed, while functional outcomes of surgery are encouraging, the data regarding recurrences need to be critically evaluated. in our cohort, tumors recurred in two patients. recurrence in pheochromocytoma can be a true recurrence due to positive surgical margins, recurrence due to multifactorial nature of the disease in pla surgeries, or a de novo lesion. a relatively high rate of “recurrence” in a hereditary pheochromocytoma population might merely reflect the multifocal nature of the disease rather than a “true” recurrence at the site of resection(16). hereditary pheochromocytomas have recurrence rates ranging from 0–100%(17,18). walz et al. suggest that this wide range may be due to the different follow-up times employed in different studies, as recurrences are often seen more than 10 years after the initial tumor is removed(13). the rate of recurrence in the hereditary disease might also be a result of detection and screening biases, as these patients are likely to undergo periodic radiographic surveillance. the small number of recurrences in our study (two out of 78 patients) limit our ability to identify patients who are at risk for recurrence. it is unclear if any specific tumor type or lesion size is more likely than others to be associated with recurrences within the ipsilateral gland. the adverse side effects associated with chronic steroid dependence have led surgeons to endorse a pa procedure in the treatment of adrenal tumors. too little steroid replacement can lead to addisonian crisis and death and too much can cause osteoporosis, diabetes, and hypertension. the amount of residual adrenal cortical tissue to be left in situ to maintain acceptable cortical functioning while ensuring adequate tumor clearance is a topic of debate. most authors suggest that a margin of at least 3-5 mm is necessary to attain good results (16). a recently published review indicates that 5.3% of patients require long-term steroid replacement therapy(16). most patients who require steroid replacement therapy had suffered from bilateral disease, although some had only unilateral adrenal involvement. although only 5.3% of patients require long-term steroid replacement, yip et al. found that approximately 35% of patients undergoing pa for bilateral resection were steroid dependent(19). nevertheless, our findings related to steroid dependence agree with the data presented in a recently published review article(16). this meta-analysis showed that patients in pa groups were less dependent on steroids than ta patients. cushing’s syndrome is a result of excess cortisol, which lead to devastating metabolic, physical, and mental changes. in our study, we included only those patients who underwent adrenalectomy as part of their treatment. therefore, our patient population might not be generalizable to all patients with cushing’s syndrome. specifically, our findings might not be relevant to patients with pituitary cushing’s syndrome who underwent successful transsphenoidal resection treatment. in a follow-up, we found that after six months, measurable symptoms, such as central obesity, facial plethora, and hypertension, had improved in all patients. after a one-year follow-up, symptoms such as muscle weakness had improved. acne and hyperpigmentation were resolved after two years. fu et al.(20) conducted a randomized trial on conn’s disease by comparing pa and ta. they demonstrated that pa had a shorter operative time than ta, but this difference was not statistically significant. however, the intraoperative blood loss observed in the pa group was significantly higher than in the ta group. for the pa cohort, a decreased dose of antihypertensive medication was prescribed at the final follow-up. we found that the levels of intraoperative blood loss were comparable between the two groups. perhaps this is because of the experience in laparoscopic adrenalectomy procedures. adrenal surgical expertise is not widespread, as less than 30 percent of all surgeons perform more than four adrenalectomies per year(21). partial adrenalectomy needs even higher surgical expertise and, therefore, should be performed by very experienced adrenal surgeons. partial vs. total adrenalectomy-simforoosh et al. vol 18 no 2 march-april 2021 168 ishidoya et al.(22) recommended the use of ta over pa for patients with unilateral aldosterone-producing adenoma and primary hyperaldosteronism. all patients who underwent ta recovered from hypertension, suppressed plasma renin activity, and high plasma aldosterone. however, two of the 29 patients treated with pa or enucleation still experienced hypertension with high plasma aldosterone. nevertheless, our results agree with the data provided in a recently published meta-analysis that demonstrated an aldosterone-producing adenoma recurrence rate of 2%. also, 97% of the considered patients were steroid independent, indicating that pa is efficacious in alleviating conn’s syndrome. the present study had several limitations. the retrospective portion of the study did not allow for uniform data collection for some variables. however, the design employed enabled us to perform a longitudinal follow-up and include a large sample size, which would be impossible in a purely prospective study of this rare disease. moreover, our survey study design had limitations, including the potential for patient recall bias and response bias in the evaluation of cushing’s syndrome symptoms and their resolution time after surgery. also, because of the small number of recurrences, it was not possible for us to determine which factors are likely associated with recurrences. furthermore, the non-randomized nature of this study renders it prone to selection bias. patients with larger tumors or more aggressive tumors could have a higher chance of undergoing tla. nonetheless, this series is a large series with a moderate-long term follow up indicating the safety of pla for pheochromocytoma, cushing and conn’s disease. conclusions in our experience, pla can provide excellent control of the symptoms parallel with tla and with no statistically significant difference in recurrence making pla an attractive option in patients with an adrenal mass. conflict of interest no competing financial interests exist. references 1. kloos rt, korobkin m, thompson nw, francis ir, shapiro b, gross md. incidentally discovered adrenal masses. cancer treat res. 1997;89:263-92. 2. johnson pt, horton km, fishman ek. adrenal mass imaging with multidetector ct: pathologic conditions, pearls, and pitfalls. radiographics. 2009;29(5):1333-51. 3. gagner m, lacroix a, bolte e. laparoscopic adrenalectomy in cushing's syndrome and pheochromocytoma. n engl j med. 1992;327(14):1033. 4. simforoosh n, ahmadnia h, ziaee am, moradi m. laparoscopic adrenalectomy: a report of the first experience in iran. urol j. 2004;1(2):77-81. 5. dineen r, thompson cj, sherlock m. adrenal crisis: prevention and management in adult patients. ther adv endocrinol metab. 2019;10:2042018819848218. 6. bhat hs, tiyadath bn. management of adrenal masses. indian j surg oncol. 2017;8(1):67-73. 7. walz mk, peitgen k. laparoscopic partial adrenalectomy. surg endosc. 2000;14(11):1089-90. 8. inabnet wb, caragliano p, pertsemlidis d. pheochromocytoma: inherited associations, bilaterality, and cortex preservation. surgery. 2000;128(6):1007-11;discussion 11-2. 9. van heerden ja, sheps sg, hamberger b, sheedy pf, 2nd, poston jg, remine wh. pheochromocytoma: current status and changing trends. surgery. 1982;91(4):367-73. 10. simforoosh n, shakiba b, dadpour m, mortazavi se, hamedibazaz hr, mahdavi m. feasibility and safety of clipless and sutureless laparoscopic adrenalectomy: a 7-year single center experience. urol j. 2020;17(2):143-5. 11. silvinato a, bernardo wm, branco aw. total and partial laparoscopic adrenalectomy. rev assoc med bras (1992). 2019;65(10):1240. 12. asari r, scheuba c, kaczirek k, niederle b. estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2a. arch surg. 2006;141(12):1199-205; discussion 205. 13. walz mk, peitgen k, diesing d, petersenn s, janssen oe, philipp t, et al. partial versus total adrenalectomy by the posterior retroperitoneoscopic approach: early and longterm results of 325 consecutive procedures in primary adrenal neoplasias. world j surg. 2004;28(12):1323-9. 14. nagaraja v, eslick gd, edirimanne s. recurrence and functional outcomes of partial adrenalectomy: a systematic review and metaanalysis. int j surg. 2015;16(pt a):7-13. 15. lenders jw, duh qy, eisenhofer g, gimenezroqueplo ap, grebe sk, murad mh, et al. pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. j clin endocrinol metab. 2014;99(6):1915-42. 16. kaye dr, storey bb, pacak k, pinto pa, linehan wm, bratslavsky g. partial adrenalectomy: underused first line therapy for small adrenal tumors. j urol. 2010;184(1):1825. 17. lee je, curley sa, gagel rf, evans db, hickey rc. cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. surgery. 1996;120(6):1064-70; discussion 701. 18. brauckhoff m, gimm o, thanh pn, bar a, ukkat j, brauckhoff k, et al. critical size of residual adrenal tissue and recovery from impaired early postoperative adrenocortical function after subtotal bilateral adrenalectomy. surgery. 2003;134(6):1020-7; discussion 7-8. 19. yip l, lee je, shapiro se, waguespack sg, sherman si, hoff ao, et al. surgical management of hereditary pheochromocytoma. j am coll surg. 2004;198(4):525-34; discussion 34-5. 20. fu b, zhang x, wang gx, lang b, ma x, li hz, et al. long-term results of a prospective, randomized trial comparing partial vs. total adrenalectomy-simforoosh et al. robotic and laparoscopic urology 169 vol 18 no 2 march-april 2021 170 retroperitoneoscopic partial versus total adrenalectomy for aldosterone producing adenoma. j urol. 2011;185(5):1578-82. 21. gimm o, duh qy. challenges of training in adrenal surgery. gland surg. 2019;8(suppl 1):s3-s9. 22. ishidoya s, ito a, sakai k, satoh m, chiba y, sato f, et al. laparoscopic partial versus total adrenalectomy for aldosterone producing adenoma. j urol. 2005;174(1):40-3. partial vs. total adrenalectomy-simforoosh et al. pediatric urology evaluation of the intravesical ureters after failed endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid in children via light and transmission electron microscopic analysis. a matched case-control study volkan izol1, yurdun kuyucu2, arbil acikalin3, mutlu deger1*, ibrahim atilla aridogan1, sait polat2, nihat satar1 introduction: the cytokine profile and the ultrastructural changes of refluxing ureterovesical junctions(uvjs) of children treated with failed dextranomer/hyaluronic-acid (dx/ha) injections were investigated using immunohistochemical methods and transmission electron microscopy(tem). patients and methods: eighteen children who had undergone injection for reflux were included the study. the smooth muscle arrangement of the ureteral wall, transforming growth factor-β (tgf-β1),vascular-endothelial-growth factor (vegf) and cd34 were evaluated immunohistochemically, and the results were compared with 10 age-matched autopsy specimens as controls. the ultrastructural evaluation and morphological description was made semi-quantitatively and compared with published data. result: four of the patients (22%) were male, and 14 (78%) were female. the mean age of the patients was 105.4 ± 44.5(48-184) months. there was no correlation between the vesicoureteral reflux (vur) grade and age (p = 0.85). the mean vegf and cd34 scores were 16.2 ± 9.6 (0-90) cells per hpf and 10.2 ± 3.5 (4-16) vessels per hpf in ureters with reflux; these values were 60.6±16.4 (32-84) cells per hpf and 17.8 ± 4.1 (12-24) vessels per hpf in the control group. the amount of vegf and cd34 were significantly decreased in patients compared with the control group (p < 0.001, p < 0.001).the tgf-β1 levels were significantly higher in patients with vur compared with the control group (34.2 ± 19.9 vs 5.0±1.9; p=0.001).the amount of vegf, cd34, and tgf-β1 were not correlated with the grade of reflux (p = 0.26, p = 0.94, and p = 0.42, respectively). ultrastructural changes in the muscle cells were observed in all the vur specimens (grade ii-iv). conclusion: refluxing ureters exhibited immune-histopathological abnormalities and ultrastructural changes of the muscle cells in all vur specimens in the ureterovesical junctions of children treated with failed dx/ha injections for reflux. keywords: dextranomer/hyaluronic acid; transmission electron microscopy; ureterovesical junctions; vesicoureteral reflux introduction vesicoureteral reflux (vur) is characterized by the retrograde flow of urine from the bladder into the upper urinary tract because of an anatomic and/or functional disorder. moderate to severe reflux is responsible for potentially serious consequences such as renal scarring, hypertension, and renal failure. antibiotic prophylaxis and surgical management by ureteroneocystostomy have been the traditional treatments of choice for vur since the 1970s(1-3) . in the early 1980s, a less invasive technique of endoscopic injections (ei) of bulking agents was first described by matouschek et al.(4) this technique became popular after o’donnell and puri(1986) published their successful initial report on the endoscopic correction of primary reflux(4-8) . dextranomer/hyaluronic acid(dx/ha) is formed from cross-linked dextranomer microspheres suspended in 1 department of urology,faculty of medicine, university of çukurova, adana, turkey. 2 department of histology and embryology, faculty of medicine, university of çukurova, adana, turkey. 3 department of pathology ,faculty of medicine, university of çukurova, adana, turkey. *correspondence: university of çukurova, faculty of medicine. department of urology, 01330, adana, turkey. phone: +90 322 3386305. fax: +90 322 4598050. e-mail: drmutludeger@gmail.com. received november 2017 & accepted june 2018 a carrier gel of stabilized sodium hyaluronate. this finding was first described by stenberg and lackgren in 1995(9). the food and drug administration (fda) approved this material for use in children with primary grade i-iv vur in 2001.since then, several clinical investigations have been published with high success rates that range from 68% to 89% (8,10-12) . very rare complications have been reported(13-14). the histopathological effects of dx/ha on the intravesical ureters have been investigated by only a limited number of studies(15-19) .there are no data in the literature regarding the evaluation of ultrastructural changes in the intravesical ureters by transmission electron microscopy (tem) in patients with failed ei. to our knowledge, this is the first study to evaluate the ultrastructural changes using tem in the ureterovesical junctions(uvj) of children treated with failed dx/ha injections for reflux. additionally, cytokines play significant roles in vur pediatric urology 279 vol 16 no 03 may-june 2019 280 pathophysiology. tgf-β1 is involved in many cellular functions, including cell growth, proliferation, differentiation and apoptosis. increased levels of this cytokine may induce apoptosis in smooth muscle cells, leading to contractile dysfunction and structural abnormalities (20) .vegf is a signal protein and produced by muscle and endothelial cells to stimulate vasculogenesis and angiogenesis, is important for regulating tissue growth, nerve coordination and gap junction metabolism. vegf is typically less abundant in poorly developed uvjs(20). cd34 is an endothelial antigen whose function is unknown. the anti-cd34 antibody is often used as a marker to determine microvessel density, which has been previously studied to determine the role of hypoxia in pathogenesis (21) . in this study, cytokine profile, including the transforming-growth-factor-β1 (tgf-β1), vascular-endothelial-growth factor (vegf), and cd34 of the distal ureters were evaluated quantitatively by immunohistochemical methods, and the ultrastructural evaluation and morphological description was made semi-quantitatively and compared with published data. patients and methods between january 2013 and august 2014, 18 children who underwent ureteroneocystostomy for vur following failed injection therapy with dx/ha were included this prospective a case control study. the indications for surgery in the study group were reflux persistency or greater reflux on voiding cystourethrography and recurrent upper urinary tract infections. after obtaining informed consent from all patients’ families, urodynamic studies were performed in all patients to rule out neurogenic bladder and voiding dysfunction before the operation. patients who had a history of previous open reimplantation for reflux or any other ureteral diseases were excluded from the study. after obtaining the necessary approvals from the local ethics committee (approval number-march 1,2012;6/4), the parents or legal guardians of the patients were informed that the clinical and laboratory data would be used for scientific purposes, and written consent was obtained. histopathological and ultrastructural evaluations 28 distal intravesical ureters were dissected sharply without cauterization during ureteroneocystostomies for histopathological and ultrastructural evaluations. each sample contained an intramural portion of the ureter with the ureteric orifice. the size of the specimen approximately 15 mm. depending on the order of excision, the preparations were placed in vials that contained formaldehyde for histopathological evaluation or vials that contained a 5% glutaraldehyde solution for ultrastructural evaluation with an electron microscope. all the vials were numbered and evaluated by a single pathologist and histologist. the ureterovesical junctions of 5 age-matched autopsy specimens was done faculty of medicine, university of çukurova between january 2013 and august 2014 without history or evidence of any urological disease (2 with respiratory distress syndrome,1 with aspiration pneumonia and 2 who experienced sudden death) served as the control group and were used only for histopathologic and immunohistochemical evaluations. electron microscopic examination the specimens of the distal intravesical ureteric segments for electron microscopic examination were fixed for 4 hours with 5% glutaraldehyde in millonig phosphate buffer at ph 7.4 and post-fixed with 1% osmium tetroxide in the same phosphate buffer for 2 hours at 4 °c. the samples were dehydrated in a graded series of ethanol and embedded in araldite. semi-thin sections were taken with reichert ultracut-s ultramicrotome and stained with toluidine-blue, and the appropriate areas for electron microscopic observation were determined. thin sections were taken from the selected areas and stained with uranyl acetate and lead citrate. they were examined with a jeol jem 1400 transmission electron microscope. the ultrastructural evaluation and morphological description was made semi-quantitatively. light microscopy study for the histopathological evaluation, formaldehyde-fixed, paraffin-embedded tissues were cut transversely at a 5-μm thickness. hematoxylin and eosin (he) stained slides were examined under light microscopy (nikon-e600,tokyo,japan).the smooth muscle arrangement of the ureteral wall was scored as oswald et al.(23) described in their study that was based on the absence of a muscular coat, the replacement of muscle fibers with fibrotic tissue, and the enhancement of interstitial collagen: score 0-absent, 1-mild (≤ 25%), 2-moderate (26-50%), 3-severe (51-75%), and 4-extremely severe (> 75%).the results were compared with the control group. immunohistochemical examination immunohistochemistry was performed on formalin-fixed, paraffin–embedded 5 μm thick tissue sections using a manual streptavidin-biotin complex immunoperoxidase procedure with antibodies against human vegf (monoclonal mouse, dako,m7273; denmark), tgf-β1 (polyclonal rabbit,santa-cruz,sc-146), and cd34 (monoclonal mouse,dako,m7165, denmark). for all the antibodies tested, antigen retrieval treatment for 15 min in 0.01 m citrate buffer solution (ph 6.0) using a microwave oven was performed, and the immune complexes were then visualized by aec. the slides were counterstained with mayer’s hematoxylin and mounted.the positive controls were angiosarcoma, tonsil, and, hemangioma. the negative controls were obtained by omitting the primary antibody. all vegf and tgf-β1-positive cells were counted from 10 randomly selected high-power fields (hpfs) at 400x magnification. the urothelial and intraluminal cells were not counted. microvessel densities were evaluated by counting positively stained endothelial cells or cell clusters in 10 randomly selected hpfs. the results were compared with the control group and between each grade. statistical analysis a data analysis was performed using spss software, version 15 (spss,inc.,chicago,il). the chi-square test, t-test and one-way analysis of variance(anova) were used for analysis. in all the tests, the statistical significance level was set at p<0.05. results of the patients, 4 (22%) were male and 14 (78%) were female. the mean age of the patients was 105.4 ± 44.5(48-184) months. the reflux was grade ii in 6, grade iii in 12, and grade iv in 10 ureters, according to the international reflux study(22) (table 1). none of evaluation of the intravesical ureters after failed endoscopic treatment-izol et al. the patients had grade v vur. there was no correlation between the vur grade and age (p = 0.85). 10 patients had bilateral vur, and 8 had unilateral vur. the mean injected volume for each ureter was 1.0 cc, and the mean time from ei to surgical intervention ranged from 3 to 10.2 ± 7.9 months. the mean injection number was 1,07 ± 0,26 times. no preoperative or postoperative complications were observed. electron microscopic evaluation the surface urothelium, lamina propria, and adventitia were observed as normal in all grade vur specimens (figure 1a). ultrastructural changes of the muscle cells were observed in all the vur specimens (grade ii-iv). intercellular edema and increased cytoplasmic density of some smooth muscle cells were observed in all the specimens (figure 1b, 2a, 2b). heterochromatins clumping in the nucleus and perinuclear cisternae enlargement were observed in grade iii-iv vur specimens (figure 1b, 2a). swollen endoplasmic reticulum cisternae and mitochondria, cristae disorganization in mitochondria, and vacuoles that include membranous whorl structures in some areas and empty spaces that characterize edema in the cytoplasm of the smooth muscle cells were prominent in all the vur specimens (grade ii-iv) (figure 1a, 2a, 2b). the degree of degeneration was similar in patients with the same grade vur who were different ages. histopathology dx/ha material was located in the adventitia in 22 (78.6%) cases and in the muscle fibers in 6 (21.4%) cases. a fibrous pseudocapsule surrounding the dx/ha material was present in only two (14.3%) cases, which were located in the muscle fibers. a giant cell reaction was rapid in 26 (92.9%) of the 28 cases. in three (21.4%) cases, eosinophilic infiltration was increased compared to the other cases. no calcification or rapid inflammation was observed. in most of the vur cases, the smooth muscle coat was disorganized and widely absent compared to the control group. collagen and edema was replaced instead of smooth muscle. the mean smooth muscle scores in grade ii to iv vur were 1.6 ± 0.5 (1-2), 1.0 ± 0.6 (0-2), and 1.0 ± 1.4 (0-3), respectively. no significant correlation was found between the reflux grade and the smooth muscle disarrangement score (p = 0.86). when we compared the results with the control group, the difference was significant (p < 0.001). there was no sign of inflammation, operative injury or cautery artifact in the specimens. immunohistochemistry there was a significant difference in the amount of cytokines between the patients and the controls (figure 3). the mean vegf and cd34 scores were 16.2 ± 9.6 (0-90) cells per hpf and 10.2 ± 3.5(4-16) vessels per hpf in ureters with reflux; these values were 60.6 ± 16.4 (32-84) cells per hpf and 17.8 ± 4.1 (12-24) vessels per hpf in the control group. the amount of vegf and cd34 were significantly decreased in patients comevaluation of the intravesical ureters after failed endoscopic treatment-izol et al. table 1. sample distribution by reflux grade. reflux grade number of ureteral units right left i ii 4 2 iii 4 8 iv 2 8 v total 10 18 grade (n) ii(n=6) iii(n=12) iv(n=10) p vegf 14.0 ± 3.0 4.8 ± 4.3 31.2 ± 35.5 0.26 (6-26) (0-10) (2-90) cd34 14.8 ± 2.0 10.1 ± 2.9 8.0 ± 3.1 0.94 (12-16) (6-14) (4-12) tgf-β1 33.3 ± 15.2 34.6 ± 24.7 34.4 ± 20.1 0.42 (20-50) (8-60) (12-60) sms 1.6 ± 0.5 1.0 ± 0.6 1.2 ± 1.3 0.86 (1-2) (0-2) (0-3) * vegf = vascular-endothelial-growth factor *tgf-β1= transforming growth factor-β1 *sms = smooth muscles scores table 2. cytokine profile of the patients. figure 1a. the sting procedure applied group. grade 4. normal transitional epithelial cells (ec) are observed. nucleus (n), mitochondrion (m). bar=0,5 μm. figure 1b. the sting procedure applied group. grade 4. intercellular edema is observed in the muscular layer (black arrow). heterochromatin clumping (white arrow) in the nucleus (n) and perinuclear cisternae enlargement (arrow head) in the smooth muscle cells are observed. swollen mitochondria (m), cristae disorganization in the mitochondria and vacuoles (v) that include membranous whorl structures in the cytoplasm are observed. collagen (col). bar=0,5 μm. pediatric urology 281 vol 16 no 03 may-june 2019 282 pared with the control group (p < 0.001, p < 0.001). the tgf-β1 levels were significantly higher in patients with vur compared with the control group (34.2 ± 19.9 vs 5.0 ± 1.9; p = 0.001).the amount of vegf, cd34, and tgf-β1 were not correlated with the grade of reflux (p = 0.26, p = 0.94, and p = 0.42, respectively) (table 2). discussion several bulking agents have been used for the endoscopic treatment of vur, and we know that an ideal injectable biomaterial must be easy to inject, nontoxic, and stable without migration to vital organs(8,10-12) .one of these agents, dx/ha, is formed from cross-linked dextranomer microspheres suspended in a carrier gel of stabilized sodium hyaluronate. the diameters of the microspheres are 80 to 250 μm, and this large size. the histopathological effects of dx/ha on the intravesical ureters have been evaluated by a few studies, but no electron microscopic study regarding this issue exists in the literature(15-19,24). the normal ultrastructure of the uvj in humans was first described by hanna et al. in 1976(25). in one rare study by sofikerim et al. 24 distal intravesical ureteric segments were examined using tem, reporting normal, similar structures for the tunica mucosa, submucosa and the tunica adventitia in all patients irrespective of the grade of vur, and pathological findings were observed in only muscular layers(26) . increasing degree of intercellular edema with increasing grade of vur and intracytoplasmic vacuoles in grades iv-v were shown semi-quantitatively in the smooth muscle layer and smooth muscle cell structure. it was noted that this degeneration was correlated with the grade of vur, and the age of the patient had no effect on the results. in our study, using tem, ultrastructural changes such as intercellular edema in the muscular layer, degeneration and increased cytoplasmic density in the smooth muscle cells were shown in grades ii-iv reflux. these 2 studies demonstrate that there is damage to the muscular layer of the uvj in patients with and without endoscopic injection, and these changes may lead to the dysfunction of cells and their organelles and result in reflux. consequently, we proposed that this condition might affect the spontaneous resolution of vur, especially in highgrade patients. figure 2a. (right) the sting procedure applied group. grade 3. heterochromatin clumping (arrow) in the nucleus (n) and perinuclear cisternae enlargement (arrow head) in the smooth muscle cells are observed. swollen granular endoplasmic reticulum cisternae (ger) and mitochondria (m), cristae disorganization in the mitochondria and vacuoles (v) that include membranous whorl structures in the cytoplasm are observed. bar=0,5 μm. figure 2b. (left) the sting procedure applied group. grade 2. swollen mitochondria (m) and cristae disorganization and vacuoles (v) that include membranous whorl structures in the cytoplasm are observed. collagen (col). bar=1 μm. figure 3. the expression of vegf, cd34, and tgf-β1 in the control group and patients with reflux. “*” and “¥” indicate statistical significance. significance was tested using an anova table and a linearity test. evaluation of the intravesical ureters after failed endoscopic treatment-izol et al. the histopathological effect of dx/ha injections on distal ureters was first investigated by stenberg and lackgren in animal models(19). afterwards, the first clinical study was performed by the same authors and included 13 patients with a history of failed endoscopic treatment and 10 patients who had not received dx/ha; the patients underwent open ureteral implantation and were compared to one another. they concluded that dx/ ha injection is associated with an inflammatory reaction of the giant cell type (100%), chronic periureteral inflammation(33%), and fibrotic pseudo-encapsulation (43%) of the implant(15). routh et al. evaluated 16 children who underwent ureteroneocystostomy after failed dx/ha injection(17). this was the first study to use the immunohistochemical methods such as cd3, cd20, and mib-1 staining to examine lymphocyte infiltration and nuclear turnover. they reported slightly increased periureteral inflammation with time and low cell turnover rates (mib-1), indicating that there was no increase in nuclear proliferation. ben-meir et al. investigated the cause of failure of the endoscopic dx/ha injections(16).malpositioning of the dx/ha injections were found in 95% of the examined ureters(16,17) . in our study, misplacement of the dx/ha implants was observed in all cases; pseudocapsule formation around the dx/ha material occurred in 14.3% of the cases in our study, and it was not as frequent as in previously reported studies (43-75%)(15, 17). we concluded that an abnormal position of the material can explain the failure of endoscopic treatment, but it is difficult to say that this is the exact mechanism. misplacement of the implant, loss of graft volume by phagocytosis and migration of the injection material were other reported causes of failures(8,16,18,27). to our knowledge, there is no data showing the histological findings and the localization of the injection material in patients successfully treated with endoscopic procedures. schwentner et al. evaluated the extracellular microenvironments and cytokine profiles of uvjs in children with vur (20). they reported that the amount of tnf-α and tgf-β1 were significantly higher in patients with reflux compared to the control group, while igf-1, ngf, and vegf were more abundant in the normal healthy ureters. none of the markers were correlated with age or the vur grade. in our study, the tgf-β1 levels were significantly higher in patients with vur compared with the control group (p = 0.001).the amounts of vegf and microvessel density were significantly lower in patients with reflux than the control group (p < 0.001,and p < 0.001, respectively). the lack of vegf in the distal intravesical ureters with reflux may be associated with primary vur because of the smooth muscle disappearance and impaired microperfusion(23, 28, 29). these results were in parallel to the literature and support the hypothesis regarding the role of ischemia in vur(20, 21, 26-28). no significant correlation was observed between the degree of reflux and the amount of vegf, cd34, and tgf-β1(p = 0.26, p = 0.94, and p = 0.42,respectively). we presumed that primary vur led to this cytokine profile, but it was not possible to show the effect of dxha injections on the cytokine profile in this study. in our cases, previous endoscopic injection treatment did not cause significant difficulty during the ureteral re-implantation procedures. this result was similar to published data(10,30). the bulking agents were typically easily removed en-bloc or in pieces, and care must be taken during the ureteral dissection to avoid ureteral injury. the limitations of this study include the small sample size, the lack of a control group for ultrastructural investigation, evaluation of autonomic innervations and gene mutations as well as limited marker profiles due to restricted financial resources. conclusions in this study, light and tem were used to examine the histopathologicaland ultrastructural changes in the ureterovesical junctions of children treated with failed dx/ ha injections for reflux. subsequently, refluxing ureters exhibits immune-histopathological abnormalities and ultrastructural changes of the muscle cells in all vur specimens similar to previous reports as menitoned above. it is not easy to determine if these changes were due to the dx/ha injections or to primary vur. in further studies, we will examine the distal intravesical ureters of patients with no history of previous endoscopic or open surgery, and we will compare those results with these data. acknowledgements this study is supported by the academic research projects unit of the university of çukurova with grant number tf2012bap24. after obtaining the necessary approvals from the local ethics committee (approval number-march 1,2012;6/4), the patients’ parents were informed that the clinical and laboratory data would be used for scientific purposes, and their written consent was obtained. conflict of interest the authors report no conflict of interest. references 1. normand ic and smellie jm. prolonged maintenance chemotherapy in the management of urinary infection in childhood. br med j 1965; 1: 1023–1026. 2. politano va and leadbetter wf. an operative technique for the correction of vesicoureteral reflux. j urol 1958; 79: 932–41. 3. glenn jf and anderson ee. distal tunnel ureteral reimplantation. j urol 1967; 97: 623– 6. 4. matouschek e. new concept for the treatment of vesico-ureteral reflux. endoscopic application of teflon. arch esp urol 1981; 34: 385-8. 5. o'donnell b and puri p. endoscopic correction of primary vesicoureteric reflux. br j urol1986; 58: 601-4. 6. puri p, pirker m, mohanan n, dawrant m, dass l and colhoun e. subureteral dextranomer/hyaluronic acid injection as first line treatment in the management of high grade vesicoureteral reflux. j urol 2006; 176: 1856-60. 7. stenberg a, hensle tw and lackgren g. vesicoureteral reflux: a new treatment evaluation of the intravesical ureters after failed endoscopic treatment-izol et al. pediatric urology 283 vol 16 no 03 may-june 2019 284 algorithm. cur urol rep. 2002; 3: 107-14. 8. kirsch aj, perez-brayfield m, smith ea and scherz hc. the modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. j urol. 2004; 171: 2413-6. 9. stenberg a and läckgren g. a new bioimplant for the endoscopic treatment of vesicoureteral reflux: experimental and short-term clinical results. j urol 1995; 154: 800-3. 10. lackgren g, wahlin n, skoldenberg e and stenberg a. long term follow up of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. j urol 2001; 166: 1887-92. 11. routh jc, vandersteen dr, pfefferle h, wolpert jj and reinberg y. single center experience with endoscopic management of vesicoureteral reflux in children. j urol 2006; 175: 1889-92. 12. lavelle mt, conlin mj andskoog sj. subureteral injection of deflux for correction of reflux: analysis of factors predicting success. urology 2005; 65: 564-7. 13. bedir s, kilciler m, ozgok y, deveci g and erduran d. long term complication due to dextranomer based implant: granuloma causing urinary obstruction. j urol 2004; 172: 247-8. 14. snodgrass wt. obstruction of a dysmorphic ureter following dextranomer/hyaluronic acid copolymer. j urol 2004; 171: 395-6. 15. stenberg a, larsson e and lackgren g. endoscopic treatment with dextranomerhyaluronic acid for vesicoureteral reflux: histological findings. j urol 2003; 169: 10913. 16. ben-meir d, morgenstern s, sivan b, efrat r and livne pm. histology proved malpositioning of dextranomer/hyaluronic acid in submucosal ureter in patients after failed endoscopic treatment of vesicoureteral reflux. j urol 2012; 188: 258-61. 17. routh jc, ashley ra, sebo tj, vandersteen dr, slezak j and reinberg y. histopathological changes associated with dextranomer/hyaluronic acid injection for pediatric vesicoureteral reflux. j urol 2007; 178: 1707-10. 18. broderick k, thompson jh, khan ar and greenfield sp. giant cell reaction with phagocytosis adjacent to dextranomerhyaluronic acid (deflux) implant: possible reason for deflux failure. j pediatrurol 2008; 4: 319-21. 19. stenberg a, larsson e, lindholm a, ronneus b and lackgren g. injectable dextranomer-based implant: histopathology, volume changes and dna-analysis. scand j urolnephrol 1999; 33: 355-61. 20. schwentner c, oswald j, lunacek a, pelzer evaluation of the intravesical ureters after failed endoscopic treatment-izol et al. ae, fritsch h, schlenck b, karatzas a, bartsch g and radmayr c. extracellular microenvironment and cytokine profile of the ureterovesical junction in children with vesicoureteral reflux. j urol 2008;180: 694700. 21. miettinen m. immunohistochemistry of soft tissue tumours review with emphasis on 10 markers. histopathology 2014; 64: 101-8. 22. lebowitz rl, olbing h, parkkulainen kv, smellie jm andtamminen-möbius te. international reflux study in children: international system of radiographic grading of vesicoureteric reflux. pediatrradiol 1985; 15: 105–9. 23. oswald j, brenner e, schwentner c, deibl m, bartsch g, fritsch h and radmayr c. the intravesical ureter in children with vesicoureteral reflux: a morphological and immunohistochemical characterization. j urol2003; 170: 2423-7. 24. alkan m, ciftci ao, talim b, senocak me, caglar m and buyukpamukcu n. histological response to injected dextranomer-based implant in a rat model. pediatr surg int 2007; 23: 183-7. 25. hanna mk, jeffs rd, sturgess jm and barkin m. ureteral structure and the ultrastructure. part 1. the normal human ureter. j urol1976; 116: 718–24. 26. sofikerim m, sargon m, oruc o, dogan hs and tekgul s. an electron microscopic examination of the intravesical ureter in children with primary vesico-ureteric reflux. bju int 2007; 99: 1127-31. 27. lee ek, gatti jm, demarco rt and murphy jp. long-term follow up of dextranomer/ hyaluronic acid injection for vesicoureteral reflux: late failure warrants continued follow up. j urol 2009; 181: 1869-74. 28. oswald j, schwentner c, brenner e, deibl m, fritsch h, bartsch g and radmayr c. extracellular matrix degradation and reduced nerve supply in refluxing ureteral endings. j urol2004; 172: 1099-102. 29. schwentner c, oswald j, lunacek a, schlenck b, berger ap, deibl m, fritsch h, bartsch g and radmayr c. structural changes of the intravesical ureterin children with vesicoureteral reflux—does ischemia have a role? j urol 2006; 176: 2212-8. 30. herz d, hafez a, baglı d, capolicchio g, mclorie g and khoury a. efficacy of endoscopic subureteral polydimethylsiloxane injection for treatment of vesicoureteral reflux in children: a north american clinical report. j urol 2001; 166: 1880–6. vol 16 no 03 may-june 2019 274 urological oncology effect of treatment modality on long term renal functions in patients with muscle invasive bladder cancer nurullah hamidi1*, evren suer2, mete ozkidik2, mehmet ilker gokce2, erdem ozturk2, cihat ozcan2, kadir turkolmez2, yasar beduk2, sumer baltaci2 purpose: to compare of changes in glomerular filtration rate (gfr) in patients who underwent radical cystectomy (rc) and multimodal treatment (mmt). materials and methods: we identified 472 consecutive patients who underwent rc or treated with mmt for muscle invasive bladder cancer (mibc) at our institution, between january 1995 and december 2010. after excluding the patients who died within 5 years or without 5 years of follow-up, 175 and 59 patients who were treated with rc and mmt, respectively were included to the study. gfr was measured before treatment and every 6 months after treatment till the end of 60th month. results: the mean age and mean baseline gfr were 66.5±5.7 years and 85.1±18.2 ml/min/1.73m2, respectively for all patients. we detected statistically significant higher decrease rates for gfrs in mmt group compared to rc group at every follow up period till 42nd month. renal function decreasing was found to be more prominent during first year of follow-up (79.1 to 65.9 ml/min/1.73m2) in mmt group. however, gfr decreased more regularly in rc group (~4 ml/min/1.73m2 per year). mmt, lower baseline gfr, diabetes mellitus, hypertension, and ureteroenteric anastomotic stricture development were associated with low gfr under 60 and 45 ml/min at the end of five years. conclusion: decreased renal function is noted in many mibc patients after rc or mmt in the long-term follow-up. renal function deterioration is more prominent within the first year after mmt. keywords: bladder cancer; multimodal treatment; radical cystectomy; renal deterioration; urinary diversion introduction bladder cancer (bc) is the eleventh most common-ly diagnosed cancer in both genders and approximately 25% of bc patients present with muscle invasive disease.(1) standard treatment of muscle invasive bladder cancer (mibc) is radical cystectomy (rc) with urinary diversion (ud). furthermore, bladder preservation with multimodal treatment (mmt) including radiotherapy, chemotherapy and complete transurethral resection of bladder tumor is recommended in unwilling patients or patients who were unfit for rc. to date, several ud techniques were described by many authors and two mostly used ud types are ileal conduit diversion (icd) and orthotopic neobladder (on).(2) the choice of ud type depends on many factors including patient preference, age, tumor stage, presence of urethral recurrence risk, surgeon experience, patient’s neurological and psychological disorders.(3) patient’s renal function is also another important parameter for choosing the type of ud. on is recommended in patients who have less than 1.7 to 2.2 mg/dl of serum creatinine level or greater than 40 ml/min of the glomerular filtration rate (gfr).(4) another important issue is renal deterioration after treatment in mibc patients. renal deterioration develops in most patients regardless of the treatment modal1ankara atatürk training and research hospital, department of urology, ankara, turkey. 2ankara university school of medicine, department of urology, ankara, turkey. *correspondence: ankara atatürk training and research hospital, department of urology, ankara, turkey bilkent mah, no: 1, postal code: 06430, tel: +90 553 205 0307, fax: +90 312 508 2147 mail: dr.nhamidi86@gmail.com. received november 2017 & accepted july 2018 ity.4 the risk of renal impairment after treatment depends on many factors including, preoperative patient co morbidities and renal function, age-related renal function loss, stricture of ureteroenteric anastomosis, urinary stone development after rc and nephrotoxic chemotherapeutic drugs used during mmt.(2,5,6) to the best of our knowledge, there is no publication comparing renal function impairment after rc and mmt for mibc patients. in this study, we aimed to evaluate the changes in gfr values in bladder cancer patients who had minimal 5 years of follow-up period after rc (with either icd or on) and mmt. materials and methods we included 472 consecutive patients who underwent rc or treated with mmt for mibc at our institution, between january 1995 and december 2010. patients who died within 5 years (143 patients after rc, 64 after mmt), lost to follow-up (17 patients after rc, 2 patients during mmt), gfr value under 60 ml/min per 1.73 m2 (12 patients), were excluded. finally, 175 and 59 patients who were treated with rc or mmt, respectively were included to the study. data of age, gender, baseline gfr (immediately before treatment), tumor histology, tumor stage, co morbidity history, presence of hydronephrosis (before treatment), carcinoma in situ (cis) and postoperative co morbidities (ureteroenteric stricture, pyelonephritis) were recorded. ethical approval for this retrospective study was obtained from the institutional review board (irb no: 15.08.2016246). the study was conducted in compliance with the principles of the declaration of helsinki. surgical techniques all procedures were performed by three experienced surgeons (kt, yb, sb). bricker procedure was performed for icd. we have isolated 15-20 cm ileal segment about 25-30 cm proximally from ileocecal valve. both ureters dissected proximally and anastomosed separately in a standard end-to-side technique by two running absorbable 4/0 or 5/0 sutures. ileal segment anastomosed to the skin in a nipple fashion. in patients who had on, studer and mainz pouch ii procedures were performed in 39 and 20 patients, respectively. selection of diversion type was performed based on patient’s age, comorbidity, neurological and psychological impairment, serum creatinine value and patient’s preference. multimodal treatment: after maximal transurethral resection of bladder tumor, patients received 64-66 gy (fraction dose, 200 cgy/day) radiation to the pelvis over 4 weeks time with concurrent cisplatin (20 mg/day for 5 days) based chemotherapy during the first and fourth weeks of rt. mmt response was evaluated by computed tomography (ct) scan, cystoscopy, urine cytology and tumor site biopsy. clinical complete response was defined as no tumor palpable on bimanual examination under anesthesia (beua), no tumor visible on cystoscopy, negative tumor site biopsy and negative urine cytology. patients who had complete response were followed with cystoscopy, tumor site biopsy, beua, urine cytology and ct scan. follow-up periods and renal function assessment for bc patients, follow-up period is usually 4 times for the first 2 years, 2 times for the next 3 years and then annually at outpatient clinic. at each visit, we evaluated renal function tests (including serum creatinine, blood urea nitrogen) serum electrolytes, complete blood cell count, urine analysis and urine culture, residual urine volume (in patients with on), renal ultrasonography and computed tomography of abdomen and chest. gfr was calculated with the modification of diet in renal disease (mdrd) equation:(7) gfr (ml/min per 1.73 m2)= 175x(serum creatinine)-1.154 x(age)-0.203 x(0.742 if female) we also recorded the patients who had gfr below 60 and 45 ml/min per 1.73 m2 at follow up periods. this study was retrospective and most patients had irregular follow-up visits. thus, we considered gfr values between 3-9 months after treatment as first gfr measurement (6 months after treatment) and gfr values between 9-15 months as second gfr measurement (12 months after treatment). all subsequent gfr measurements were obtained at every 6 months. gfr change was calculated according to formula= gfrchange (gfrfollow-up timegfrbaseline)/ gfrbaseline pyelonephritis was defined as hospitalization by both a febrile episode and flank pain tenderness with a positive urine culture (>105 colony-forming units) after excluding other indications for fever. ureteroenteric anastomotic stricture was defined as newly developed hydronephrosis by ultrasonography and/or ct. statistical analysis: all statistical analysis was done with spss 16.0(ibm company chicago, illinois, usa). student t test was used for comparison of parametric variables. mann-whitney and chi square tests were used to compare non-parametric variables. percentage change of gfrs were compared with wilcoxon test and logistic regression analyses were performed to determine predictive factors of gfr decrease. for statistical significance p values of < .05 was accepted. results we evaluated data of 234 patients (130 and 45 of them underwent rc with icd, and on, respectively and 59 of them were treated with mmt) retrospectively. the mean age, mean baseline gfr and mean follow-up were 66.5 ± 5.7 years, 85.1 ± 18.2 ml/min and 71 ± 8 treatment modality and long term renal function in mibc-hamidi et al. table 1. patients’ characteristics. characteristic total (n=234) rc group (n=175) mmt group (n=59) p value mean age ± sd 66.5 ± 5.7 65.3 ± 6.2 67.4 ± 4.9 .07a baseline gfr, mean ± sd 85.1 ± 18.2 91.8 ± 18.8 79.1 ± 16.3 *.001b gender male, n (%) 197 (84.2) 132 (73.7) 41(69.4) .6c female, n (%) 37(15.8) 43(26.3) 18 (30) histological type .07c transitional cell carcinoma, n (%) 210 (89.7) 157 (89.7) 53 (89.8) squamous cell carcinoma, n (%) 13 (5.5) 7 (4) 6 (10.2) transitional cell carcinoma with 6 (2.6) 6 (3.4) squamous differentiation, n (%) adenocarcinoma, n (%) 3 (1.3) 3 (1.7) other, n (%) 2 (0.9) 2 (1.2) comorbidity hypertension, n (%) 88 (37.6) 60 (34.3) 28 (47.5) .07c diabetes mellitus, n (%) 62 (26.5) 40 (22.8) 22 (37.3) *.03c hyperlipidemia, n (%) 30 (12.8) 23 (13.1) 7 (11.9) .8c preoperative hydronephrosis, n (%) 47 (20.1) 37 (21.1) 10 (16.9) .49c presence of cis, n (%) 32 (13.7) 20 (11.4) 6 (10.1) .8c *statistically significant abbreviations: cis, carcinoma in situ; gfr, glomerular filtration rate; mmt, multimodal treatment; rc, radical cystectomy a student t test was used for statistical analysis b mann whitney test was used for statistical analysis c chi-square test was used for statistical analysis urological oncology 275 vol 16 no 03 may-june 2019 276 months, respectively for all patients. patient characteristics were given in table 1. pathological stage t0, ta1, t2 and t3+4 disease were detected in 13 (5.6 %), 24 (10.3 %), 137 (58.5 %) and 60 (25.6 %) rc patients, respectively. in mmt group, clinical stage t2 and t3+4 diseases were detected in 35 (59.3 %) and 24 (40.7 %) patients. in rc group, 30 (17.1 %) patients received platinum based chemotherapy during the perioperative period. after surgery, we detected ureteroenteric stricture in 9.1% (16 patients) of rc patients with icd and 6.7% (2 patients with studer, 2 patients with mainzii procedure) of rc patients with on. pyelonephritis occurred in 6.2% (11 patients) and 3.3% (2 patients in studer procedure) of patients with icd and on, respectively. in mmt group, unilateral ureteral stricture and bladder contracture developed in 4 (6.6%) and 5 (8.4%) patients, respectively. two patients underwent salvage cystectomy for severe bladder contracture. the mean baseline gfrs were 91.8 and 79.1 in rc and mmt groups, respectively. the mean gfr was statistically significant lower in mmt group compared to rc group at baseline(p < 0.001). therefore, we compared two groups based on percentage change from baseline at follow up periods. we detected statistically significant higher decrease rates for gfrs in mmt group compared to rc group at every follow up period till 42nd months. decrease rates of gfrs similar between two groups after 42nd months. for two groups, mean gfrs and percentage change of gfrs from baseline were detailed in table 2 and figure 1. during follow-up, we detected gfr below 60 ml/ min/1.73 m2 in 52 (40%), 23 (51%) and 28 (47.5%) patients in subgroup 1, 2 and 3, and gfr below 45 ml/ min/1.73 m2 in 17 (13%), 8 (17.8%) and 14 (23.7%) patients in subgroup 1, 2 and 3, respectively. logistic regression analyzes including age, baseline gfr, gender, comorbidity status, treatment method (mmt or rc), presence of cis, presence of preoperative hydronephrosis, ureteroenteric anastomotic stricture development and pyelonephritis development variables were performed to determine factors associated with gfr under 60 and 45 ml/min/1.73 m2 at the end of five years. advanced age, lower baseline gfr, treatment with mmt, ureteroenteric anastomotic stricture development, presence of diabetes mellitus or hypertension history were found to be associated with with gfr under 60 and 45 ml/min/1.73 m2 at the end of five years in univariate analysis. on multivariate logistic analysis; lower baseline gfr, treatment with mmt, ureteroenteric anastomotic stricture development, diabetes mellitus and hypertension were associated with gfr under 60 and 45 ml/min/1.73 m2 at the end of five years (table 3). table 2. mean glomerular filtration rates and comparison of percentage change from baseline between two groups. gfr rates total (n=234) rc group (n=175) mmt group (n=59) percentage change percentage change p value (ml/min/1.73 m2) from baseline in from baseline in rc group mmt group baseline, mean ± sd 85.1 ± 18.2 91.8 ± 18.8 79.1±16.3 -a 6 months after, mean ± sd 84.8 ± 19 88.7 ± 17.9 73.2 ± 17.8 3.4% 7.5% *.001a 12 months after, means ± sd 81.4 ± 20.6 87.1 ± 17.7 65.9 ± 20.1 5.1% 16.7% *<.001a 18 months after, means ± sd 79 ± 20.8 82.6 ± 18 65.1 ± 24.9 10.1% 17.7% *.001a 24 months after, means ± sd 78.2 ± 20.9 82.1 ± 17.8 65 ± 25 10.6% 17.8% *.001a 30 months after, means ± sd 77.5 ± 20.7 81.1 ± 18.3 64.8 ± 23.8 11.7% 18.1% *.001a 36 months after, means ± sd 75 ± 20.9 78.3 ± 19.1 64.4 ± 23 14.7% 18.6% *.004a 42 months after, means ± sd 73.4 ± 21 76.6 ± 19.8 63.7 ± 21.8 16.6% 19.5% *.01a 48 months after, means ± sd 70.9 ± 21.6 74 ± 21 62 ± 21 19.4% 21.7% .08 a 54 months after, means ± sd 68.7 ± 21.9 71.7 ± 59.6 59.6 ± 19.4 21.9% 24.7% .24 a 60 months after, means ± sd 64.9 ± 21.8 67.5 ± 22.3 57.2 ± 18.3 26.5% 27.7% .4a *statistically significant abbreviations: gfr, glomerular filtration rate; mmt, multimodal treatment; rc, radical cystectomy. awilcoxon test was used for statistical analysis gfr under 60 ml/min/1.73 m2 gfr under 45 ml/min/1.73 m2 variables or 95% ci p value or 95% ci p value age (older) 1.1 0.952-1.458 .9 1.2 1.131-3.941 .6 sex(female) 0.9 0.530-1.882 .86 1.3 1.202-1.536 .5 lower baseline gfr 2.6 1.4625.639 *.001 2.2 1.088-4.414 *.04 treatment with mmt 3.2 1.248-5.481 *< .001 2.8 1.106-4.982 *.02 presence of cis 1.3 0.526-3.289 .6 1.1 0.224-4.816 .9 presence of preoperative hn 1.1 0.824-2.268 .8 1.9 0.674-5.474 .2 diabetes mellitus history(+) 4.9 2.5759.706 *< .001 4.7 1.380-8.143 *< .001 hypertension history(+) 3.6 2.019-6.552 *< .001 4.2 1.562-7.898 *< .001 hyperlipidemia history(+) 1.6 0.512-4.166 .2 1.1 0.538-16.192 .7 ureteroenteric anastomotic stricture development 3 1.46-6.074 *.001 3.2 1.264-5.872 *< .001 pyelonephritis development 1.2 0.52-1.241 .7 1 0.434-2.162 .8 *statistically significant abbreviations: ci, confidence interval; cis, carcinoma in situ; hn, hydronephrosis; mmt, multimodal treatment; or, odds ratio table 3. multivariate analysis according to decrease in glomerular filtration rates under 60 and 45 ml/min/1.73 m2 at the end of five years treatment modality and long term renal function in mibc-hamidi et al. discussion many studies regarding renal function deterioration after rc have been published; however data regarding the effect of mmt on renal function is scarce.(8-10) the most common blamed factors of renal function deterioration after rc are patient comorbidities such hypertension or diabetes mellitus, lower baseline renal function, history of cisplatin-based chemotherapy in perioperative period, stricture of ureteroenteric anastomosis, pyelonephritis and development of urinary stones.2,5,6 primary aim of this study was to compare of renal functions of mibc patients who had rc and mmt. eisenberg et al. reported renal function outcomes of 1631 rc (76% underwent incontinent diversion and 24% underwent continent diversion) patients who were alive at least 10 years after rc.8 they defined renal deterioration as a decrease in gfr >10 ml/min/1.73 m2 before and after rc. median gfrs were 62, 55 and 51 ml/min/1.73 m2 at baseline, 5 and 10 years of follow-up, respectively. similar to eisenberg’s study, in another study, renal deterioration was defined as a decrease in gfr >10 ml/min/1.73m2.(9) they reported that 36% of rc patients with icd and 21% of rc patients with on had renal function deterioration at 10 years of follow-up. in nishikawa et al`s study the mean gfr (169 patients) declined from 69.6 to 55.9 ml/min/1.73 m2 during follow-up (median 106 months) and renal deterioration was observed in 46.2 % of patients.(10) more recently, makino et al. reported their renal function outcomes after rc with ud.(11) they emphasized that rapid decline of gfr observed in the first year after rc (65.1 to 58.9 ml/min/1.73 m2) followed by a continuous decline of ~1.0 ml/ min/1.73 m2 per year thereafter. in our study, patients were treated with mmt or rc either with icd or on and mean gfr in the whole group declined from 85.1 to 64.9 ml/min/1.73 m2 at the end of five years. the rate of mean gfr decrease in our study is consistent with those reported in previous studies.8-11 to the best of our knowledge, in our study, for the first-time comparison of renal function impairment after rc and mmt is performed. we observed higher decrease rate of gfr values in mmt group. in this group, renal function deterioration was found to be more prominent during the first year of follow-up (79.1 to 65.9 ml/min/1.73 m2). on the other hand, gfr decreased more regularly in rc group (~4 ml/ min/1.73 m2 per year). studies focusing on long-term renal function deterioration after mmt are scarce. renal function deterioration due to radiation seems to be related to bladder contracture and ureteral stricture. in a retrospective review of long-term survivors in patients who underwent trimodal therapy, zietman et al. reported 21% of bladder hypersensitivity, involuntary detrusor contractions and incontinence.(12) rödel et al. demonstrated 3% of bladder contracture and 2% of salvage cystectomy due to bladder contracture.(13) our study exhibited significantly higher decline in renal function in the mmt group compared to rc group. this can be related to several factors. in our study, 4 patients (6.6%) developed unilateral ureteral stricture and 5 (8.4%) developed bladder contracture due to radiation. two patients underwent salvage cystectomy for bladder contracture. all these complications occurred in the first year of treatment, which may explain the sharp decrease in mean gfr in the mmt group. on the other hand, higher rates of diabetes mellitus in mmt group at the beginning of treatment may play a role for this finding. according to previous studies, several factors have been identified to be associated with the decline in renal function after rc such as older age, patients’ co morbidities, pre-op gfr, post-op hydronephrosis or anastomotic strictures.9,11 makino et al. evaluated renal function deterioration in the early and late postoperative period.11 ureteroenteric anastomotic stricture was identified as a sole significant predictive factor of early postoperative (one year after rc) renal function deterioration, whereas diabetes mellitus and pyelonephritis episodes were identified as factors resulting late renal function decline. perioperative chemotherapy and hypertension were not associated with the risk of renal function decline. differently from makino’s study, jin et al. identified chronic hypertension (p = 0.001, hr 1.2) as independent predictive factor for renal deterioration.9 in our study, ureteroenteric anastomotic stricture occurred in 20 patients who underwent rc and this parameter was found to be a significant factor for renal function deterioration on multivariate analysis. the present study is limited by its retrospective nature. there was heterogeneity between groups. as known, figure 1. mean glomerular filtration rates of radical cystectomy and multimodal treatment groups treatment modality and long term renal function in mibc-hamidi et al. urological oncology 277 vol 16 no 03 may-june 2019 278 other significant important factor on renal deterioration after rc is reflux development. we could not obtain documentation related to refluxing after rc. the time frame of the study was large and several developments took place for both treatment modalities. we were unable to obtain 10 year of renal function outcomes due to inadequate follow-up, which may demonstrate the long-term renal function better. finally, 19 patients (17 patients after rc, 2 patients during mmt) lost to follow-up. this situation has reduced the number of our patients conclusions decreased renal function is noted in many mibc patients after rc or mmt in the long term follow-up. renal function deterioration is more prominent within the first year after mmt. in the long term, mmt, development of ureteroenteric anastomotic stricture, diabetes mellitus and hypertension were found to be significant factors associated with lower gfr levels. acknowledgements none declared. references 1. ferlay j, steliarova-foucher e, lortettieulent j, et al. cancer incidence and mortality patterns in europe: estimates for 40 countries in 2012. eur j cancer. 2013; 49: 1374-403. 2. kassouf w, hautmann re, bochner bh, et al. a critical analysis of orthotopic bladder substitutes in adult patients with bladder cancer: is there a perfect solution? eur urol. 2010; 58: 374-83. 3. skinner ec, skinner dg, stein jp. orthotopic urinary diversion. in: wein aj, kavoussi lr, novick ac, editors. campbell-walsh urology, 10th edn. philadelphia; elsevier saunders; 2012. p. 2479-2496. 4. hautmann re. urinary diversion: ileal conduit to neobladder. j urol. 2003; 169: 834-42. 5. hautmann re, volkmer bg, schumacher mc, et al. long-term results of standard procedures in urology: the ileal neobladder. world j urol. 2006; 24: 305-14. 6. perimenis p, burkhard fc, kessler tm, et al. ileal orthotopic bladder substitute combined with an afferent tubular segment:long-term upper urinary tract changes and voiding pattern. eur urol. 2004; 46: 604-9. 7. nyman u, grubb a, sterner g, et al. the ckd-epi and mdrd equations to estimate gfr: validation in the swedish lund-malmo study cohort. scand j clin lab invest. 2011; 71: 129-38. 8. eisenberg ms, thompson rh, frank i, et al. long-term renal function outcomes after radical cystectomy. j urol. 2014; 91: 619-25. 9. jin xd, roethlisberger s, burkhard fc, et al. long-term renal function after urinary diversion by ileal conduit or orthotopic ileal bladder substitution. eur urol. 2012; 61: 4917. 10. nishikawa m, miyake h, yamashita m, et al. long-term changes in renal function outcomes following radical cystectomy and urinary diversion. int j clin oncol. 2014; 19: 1105-11. 11. makino k, nakagawa t, kanatani a, et al. biphasic decline in renal function after radical cystectomy with urinary diversion. int j clin oncol. 2017; 22: 359-65. 12. zietman al, sacco d, skowronski u, et al. organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors. j urol. 2003; 170: 1772-6. 13. rödel c, grabenbauer gg, kuhn r, et al. combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. j clin oncol. 2002; 20: 3061-71. treatment modality and long term renal function in mibc-hamidi et al. case report a case of masson’s tumor of the penis presenting as chronic pelvic pain syndrome krasimir yanev1, aleksander krastanov1, marincho georgiev1, andrian tonev1, alexander timev1, angel elenkov1* keywords: masson’s tumor; penis; chronic pelvic pain. introduction the intravascular papillary endothelial hyperplasia (ipeh) or masson’s tumor is an unusual and rare benign disease, first described in 1923 by pierre masson(1). it is histologically characterized by papillary and anastomosing channel-like structures lined by proliferating endothelium(2). we present a rare case of ipeh at the base of the penis, visible only on mri, causing chronic pelvic pain and erectile dysfunction. radical excision of the formation cured the condition. case report a 48-year-old male presented with constant pain in the area around the symphysis, perineum and the base of the penis. the pain was associated with sudden onset 6 years ago during sexual intercourse. it gradually became more intensive especially during erection which lead to disturbance of the sexual function. during this period numerous clinical examinations revealed no evidence of urologic disease explaining the symptoms. the patient had been diagnosed with prostatodynia and treated with different pain medications with no effect. when an mri of the pelmedical university sofia, bulgaria. *correspondence: department of urology, medical university sofia, bulgaria. tel.: +359 884 73 88 33. e-mail: a.elenkov@abv.bg. received february 2017 & accepted september 2017 the intravascular papillary endothelial hyperplasia (ipeh) or masson’s tumor is an unusual and rare benign disease. it is histologically characterized by papillary and anastomosing channel-like structures lined by proliferating endothelium. radiologically, it is usually presented as a heterogenic solid mass with contrast enhancement, with areas resembling necrosis and thrombosis. these signs can easily be attributed to malignancy. the urogenital tract is extremely rarely affected with only 8 cases described in the kidneys and one of the penis. we present a rare case of ipeh at the base of the penis, visible only on mri, causing chronic pelvic pain and erectile dysfunction. according to available english literature our case is the first in this pelvic location and only the second to affect the penis. radical excision of the formation cured the condition. figure 1. coronal and sagittal t2-weighted images through the penis and scrotum, showing hyper intense mass consisting of deformed, varicose vessels at the base of the penis (arrows). it shows association with the dorsal vein and projects from the crural attachments down to the level of the symphysis where lumens are narrowed. vol 15 no 04 july-august 2018 217 vic area was performed, a hyper intense varicose mass was seen to extend from the base of the penis to the crural attachments (figure 1). based on the mri find findings surgical excision of the mass was proposed to the patient. under spinal anesthesia, arch-shaped incision in the base of the penis was performed. the dorsal neurovascular bundle was mobilized and many cystic masses were found to intimately coalesce with it and the surrounding tissues. they extended from crura penis to the symphysis. the masses were excised and the neurovascular bundle was kept intact (figure 2 a,b,c). a redon drainage was kept until the 2nd postoperative day. the patient was discharged on 4th postoperative day. the histological examination revealed benign lesion with typical characteristics of ipeh (figure 2d). on the 20th postoperative day control, pain in the pelvis had disappeared and sexual function was restored on the 20th postoperative day at a control exam the pain in the pelvis had disappeared and sexual function was restored. on follow-up at postoperative 3rd, 6th, 12th and 18th month, no clinical abnormalities were detected. discussion ipeh is a very rare condition and can be localized in every blood vessel most commonly in the veins of the head, neck, fingers and the trunk and less frequently in upper respiratory and gastrointestinal tracts(3,4). the urogenital tract is extremely rarely affected with only 8 cases described in the kidneys(5). our case is the first in this pelvic location and the second in the available literature to affect the penis. only in one case, skin of the shaft has been affected(6). as a rare disease, ipeh has no distinct radiological appearance. it is usually presented as a heterogenic solid mass with contrast enhancement, with areas resembling necrosis and thrombosis. these signs can easily be attributed to malignancy(5,7,10). diagnosis of ipeh can be verified only histologically. at present it is believed to be a means of reactive vascular proliferation secondary to traumatic vascular stasis and is associated with thrombus formation and organization(2). there are three forms of ipeh: primary; secondary and extravascular(8). the extravascular form is rarely seen and is due to extravascular hematoma organization(9,10). the pathological report of our specimen showed signs of the extravascular form dissemination of the process was observed in the surrounding soft tissues around the neurovascular bundle which most probably is caused by rupture of venous vessels. in our case, the onset of the disease was sudden during sexual intercourse. the trauma had lead led to hematoma formation which had been organized and recanalised with simple endothelial proliferation. this masson’s tumor started compressing the branches of the pudendal nerve and the pelvic periosteum leading to the above described symptoms. radical excision of the formation cured the condition. conflict of interest the authors report no conflict of interest. references 1. masson p. hemangioendothelioma vegetant intra-vasculaire. bull soc anat paris 1923;93:517–23 2. liu yy, chiang ph. adrenal intravascular papillary endothelial hyperplasia: a case report and literature review. urological science. 2013;24:129–30. 3. makos cp, nikolaidou aj. intravascular papillary endothelial hyperplasia (masson’s tumor) of the oral mucosa. presentation of two cases and review. oral oncol extra. 2004;40:59–62. 4. meadows mc, sun x, dardik m, tarantino dr, chamberlain rs. intraabdominal intravascular papillary endothelial hyperplasia (masson’s tumor): a rare and novel cause of gastrointestinal bleeding. case rep gastroenterol. 2010;4:124–32. 5. alkan e, sağlıcan y, özkanlı ao, balbay md. the first recurrent intravascular papillary endothelial hyperplasia (masson’s tumor) of the kidney. turk j urol. 2016; 42: 202–5. 6. dekio s, tsujino y, jidoi j. intravascular papillary endothelial hyperplasia on the penis: report of a case. j dermatol. 1993;20:657-9. 7. johraku a, miyanaga n, sekido n, ikeda h, michishita n, saida y, et al. a case of intravascular papillary endothelial hyperplasia (masson’s tumor) arising from renal sinus. jpn j clin oncol. 1997;27:433–6. 8. guvenc mg, derekolylu l, korkut n, oz f, oz b. intravascular papillary endothelial hyperplasia (masson lesion) of the hypopharynx and larynx. ear nose throat j 2008;87:700-1. 9. modi a, moorjani n, pontefract d, livesey s. isolated papillary endothelial hyperplasia in the left atrial appendage. interact cardiovasc thorac surg 2008;7:1204-6. 10. arai e, shimizu m, ogawa f, hirose t, figure 2. (a) ipeh masses during the operation, and (b) after their excision. (c) masson’s tumors after excision measuring 36/6 mm and 42/7mm with total weight of 7g. (d) a venous vessel with obliteration due to recanalized thrombus. (e) higher magnification shows marked endovascular proliferation and formation of a secondary lumen lined with endothelial cells and filled with erythrocytes (van-gieson,100x). penis masson tumor presenting as cpps-yanev et al. case report 218 ohbayashi h, taguchi s, et al. exteravascular papillary endothelial hyperplasia of the palm masquerading as an angiosarcoma. j dermatol 2008;35:238-41. penis masson tumor presenting as cpps-yanev et al. vol 15 no 04 july-august 2018 219 the respiratory induced kidney motion: does it really effect the shock wave lithotripsy? mehmet ozgur yucel1, serkan ozcan2 , gokhan tirpan3, murat bagcioglu3, arif aydin3, arif demirbas3, tolga karakan3* purpose: to investigate the effect of respiratory induced kidney mobility on success of shock wave lithotripsy (swl) with an electrohydraulic lithotripter. materials and methods: between may 2013 and april 2015, 158 patients underwent swl treatment for kidney stones with an electrohydraulic lithotripter. the exclusion criteria were presence of a known metabolic disease (such as cystinuria), non-opaque stones, need for focusing with ultrasonography, abnormal habitus, urinary tract abnormalities, and inability to tolerate swl until the end of the procedure. stones greater than 20 mm, and lower pole stones were also excluded. the movement of the kidneys were measured with fluoroscopy guidance. results: the procedure was successful in 66.7% of the males, and 56.9% of the females. the mean stone size was 11 ± 3 mm in the successful group, and it was 14 ± 4 mm in the unsuccessful group. the mean stone mobility rate was 32 ± 10 in the successful group and 40 ± 11 in the unsuccessful group. multivariate analysis showed that stone size and kidney mobility affected the success rate significantly, however hounsfield unit (hu) did not. conclusion: the current study shows the significant effect of kidney motion on the success of swl. further studies with different lithotripters are needed to determine the significance of kidney mobility. keywords: kidney motion; kidney stone; shockwave lithotripsy; urolithiasis. introduction shock wave lithotripsy (swl) was first described in 1980s, and it has become the milestone in the treatment of upper urinary tract stone disease(1). its use increased gradually, and currently it has been used even in the treatment of complex stones. a number of factors affect the success rates of swl. they include stone-related factors including the type and localization of the stone, and its density on computerized tomography (ct); and patient-related factors including body habitus, the skin-stone distance (ssd), hydronephrosis and renal functions(2-4). one of the most important problems in swl is the difficulty to focus on the stone. focusing is particularly difficult in kidneys that are hypermobile with respiration. a number of factors including anesthesia, pain, respiratory disorders, and body habitus affect respiration-related mobility of the kidneys. in this study, we aimed to investigate the effect of the kidney motion on success of swl in a lithotripter with an ellipsoid focus, and a focal zone of 7.5x22 mm. patients and methods study design after obtaining approval of the ankara training and research hospital local ethics committee, 158 patients that had swl between may 2013 and april 2015 were prospectively included in the study. preoperative imaging included kidney, ureter, and bladder (kub) x-ray 1department of urology, adiyaman university , adiyaman, turkey. 2department of urology, izmir katip çelebi university, izmir, turkey. 3department of urology, ankara training and research hospital, ankara, turkey. *correspondence: ankara hastanesi, sukriye mah., ulucanlar cd., 06340, ankara, turkey. phone/fax : +90 541 5752706/ +90 312 363 3396. e-mail: tolgakarakan@yahoo.com. received november 2016 & accepted november 2017 endourology and stone disease and non-contrast enhanced computerized tomography (ncct). swl procedure was employed while the patient was in supine position, using elmed multimed classic (elmed medical systems, ankara, turkey) electrohydrolic device. this device has an ellipsoid focus, the size of its focus is 7.5x22 mm, and its focus length is 135 mm (table 1). focusing was done by an experienced urologist, under fluoroscopy and continuous monitoring (flouroscopy targeting and monitoring every 250 pulses). the procedure was done under intramuscular analgesia (diclofenac sodium). the patients were administered 2000 shocks in every session, at 14-18 kv with stepwise voltage ramping, and 60 pulses/min. the patients' body was fixed to the tables with markers to avoid body movement during sessions. the patients were examined with kub and ultrasonography to determine stone disintegration, and the degree of hydronephrosis one week after every session. swl was done up to 3 sessions if there was no progression in hydronephrosis, and the patient was willing to keep up with swl. none of the patients had more than 3 swl sessions. the procedure ended when stone disintegration was achieved, ant the patient was stone free on follow up. both kub and ultrasonography were obtained on follows up visits of the patients performed 1 and 3 months after the last successful swl session, and ncct was obtained when needed. the patients with insignificant residual stone fragments (< 3 mm residual fragments) vol 15 no 01 january-february 2017 11 were regarded as stone free. study population patients with stone size less than 20 mm were included in the study. the exclusion criteria were presence of a known metabolic disease (such as cystinuria), nonopaque stones, need for focusing with ultrasonography, abnormal habitus, urinary tract abnormalities, previous renal surgery and inability to tolerate swl until the end of the procedure. the stones greater than 20 mm and lower pole stones were also excluded. lower pole stones excluded due to its high swl failure. measurements the size of the stone was calculated taking the longest axis of the stone on kub into consideration. the ratio of the size of the stone measured on kub and the size of the stone measured on fluoroscopy was calculated. the center of the stone and the center of the fluoroscopy were marked when the patient was monitored with fluoroscopy. then, cranial and caudal motion of the stone was marked on fluoroscopy, and the motion of the kidney on fluoroscopy was calculated by comparing it with the stone size (figure 1). the size of the stone was not measured between the sessions. only the motion values measured at the first measurement were taken into consideration in the study. the movements of the kidney were measured three times at the beginning, middle and end of the procedure. in the next swl sessions measurement was not done considering the disintegration of the stones. statistical analysis statistical analysis of data was performed with spss ibm pasw 18. descriptive statistics were given as mean, standard deviation, frequency, and percent. the normality of distribution was tested with shapiro wilks test for continuous variables. student t test was used if the distribution was normal, and mann whitney u test was employed if the distribution was not normal. categorical variables were analyzed with fisher’s exact test. univariate and multivariate regression analysis models were used to analyze the effects of different factors on the success rate of swl. the results that were significant (p value < 0.05 statistically significant) and near significant variables on univariate analysis were analyzed with multivariate logistic regression test. results the patient characteristics and demographic data are presented in table 2. the success rate of swl was analyzed statistically in relation with the mean age, sex, side of the kidney with stone, localization of the stone, (hounsfield unit) hu of stone, and kidney motion. the mean age was 39 ± 11 years in the patients with a successful result, and 46 ± 13 years in the ones with an unsuccessful result. the procedure was successful in 66.7% of the males, and 56.9% of the females. presence of the stone in the right or the left kidneys, in the upper or renal pelvis were not found as significant factors for the success of treatment. the successful and unsuccessful groups were similar for age and gender as well as the side and localization of the stone. univariate analysis showed that size of the stone, hu of the stone, and kidney motion affected the success of swl significantly. multivariate analysis showed that stone size and kidney motion affected the success rate significantly, however hu did not. discussion advances in endourological procedures such as retrograde intrarenal surgery (rirs) and percutaneous nephrolithotomy (pnl), and high success rates obtained with those procedures make one ask whether swl loses its value as a gold standard treatment modality(5-7). therefore, it is important to know the success rate of swl in different patient groups. stone parameters, patient characteristics, and types of lithotripters have been investigated for their effects on the success of swl(8-10). some of the most important factors that affect the success of swl are correct focusing on the stone, and monitoring the stone with fluoroscopy. the kidney motion table 1. descriptive analysis of patients and treatment parameters age* (year) 42 ± 1.5 (22-73) mean stone hu* 662 ± 14.7 (369-1453) stone size* (mm) 12.2 ± 0.2 (6-20) mean kidney mobility* (mm) 35 ± 0.8 (10-67) success rate % (n) %62.7 (99) size of focal area (mm) 7.5x22 mean shockwaves number 1752 ± 321 ( 412-2000) mean energy (kv) * 15.01 ± 0.3(12-18) shock wave rate (per minute) 60 mean shockwave session 2.68 abbreviations: hu, hounsfield unit * mean ± sd (range) univariate analysis multivariate analysis success failure p value or 95%ci p value age* (year) 39 ± 11 46 ± 13 0.057 1.03 0.98-1.09 0.234 gender (%) 0.463 female, n(%) 37 (56,92%) 28 (43,08%) male, n(%) 62 (66,66%) 31(33,34%) side (%) 0.711 right, n(%) 49 (49,5%) 31 (52,5%) left, n(%) 50 (50,5%) 28 (47,5%) stone size* (mm) 11 ± 3 (6-20) 14 ± 4 (8-20) < 0.001 1.62 1.19-2.21 0.002 mean stone hu* 771 ± 194 (369-1453) 829 ± 141(418-981) 0.012 1.01 0.99-1.01 0.534 mean kidney mobility* (mm) 32 ±10 (10-67) 40 ±11(15-60) < 0.001 1.12 1.04-1.21 0.003 stone location (%) 0.064 0.24 0.05-1.16 0.077 upper/mid calyceal, n(%) 42 (42,4%) 34 (57,7%) renal pelvis/upj, n(%) 57 (57,6%) 25 (42,3%) table 2. patients demographics and analysis of swl success rate. abbreviations: swl, shock wave lithotripsy; hu, hounsfield unit; * mean ± sd (range) respiration induced kidney mobility in swl-yucel et al. endourology and stone diseases 12 due to respiration usually makes difficult to keep the stone in the focal zone of the lithotripter. kidney motion due to respiration may be up to 5-50 mm, and this shows that more than 50% of the shock waves remain out of the focal zone of the lithotripter(11-15). an in vitro study made with a lithotripter with a focal zone of 4.5 mm showed that fragmentation effect decreased significantly when motion was more than 10 mm(16). a recent magnetic resonance imaging (mri) study showed that the motion was 8.9 mm for the right, and 8.48 mm for the left kidneys in awake individuals, and those values were greater in the individuals under general anesthesia .(14) correct focusing of the swl shock waves on the stone is important both for swl success and prevention of parenchymal injury(17). in these studies, kidney mobility was measured by ultrasound, mri and ct which is dissimilar to our study. although the measurement used in our study is an analytical measurement, the greatest advantage is that the measurements are made during the process. various systems have been developed for continuous localization before shock wave firing, such as ultrasonography and tracking algorithms to solve respiration-related focusing problems(17,18). performing swl under general anesthesia, and controlling and coordinating the respiratory movements of the patient with the swl sequences are the main measure to prevent respiratory movements which impair success of swl. a number of studies showed better results with general anesthesia compared to sedation(19-22). the success rates under sedoanalgesia were reported as 5272% in those studies. other parameters that affect the success of swl are ssd, type of the stone, and stone hu. various studies showed the effects of ssd on the success of swl on kidney stones. studies reported that the success of swl decreased when ssd was >10 cm(23,24). another mechanism that affects the success of swl is the focal zone of the device. in vitro studies showed that the lithotripters with broader focal zones had higher capacities to break the stones(25,26). however, it must be kept in mind that injury to neighboring tissues increases as the focal zone gets broader. two different zones may be used in modulith slx-f2 urologic workstation (storz-medical, kreuzlingen, switzerland). the broader focal zone (50x9 mm) is used in kidney stones, and the narrow focal zone (28x6 mm) is used in the ureteral stones. however, the clinical results did not show any improvement in the effectivity(26). in a very recent study, harrogate et al. investigated kidney motion, and found stone motion secondary to respiration as 7.7±2.9 mm for kidney stones, and 3.6 ± 2.1 mm for ureteric stones in patients who were not under anesthesia(27). different from other studies, in that study it was suggested that respiration-related motion was less in conscious patients without any anesthesia. another study that investigated swl success in relation with respiration-associated movement in 10 patients reported mean motion as 1.5 ± 0.3 cm with ultrasonography, and it was seen that approximately 40% of the shock waves missed the stone(28). we found a greater mean motion in this study. this difference may be related to different measurement methods of movements among studies, including ultrasonography, mri and ct instead of fluoroscopy in other studies. in addition, in our study we calculated the sum of cranial and caudal movements. a number of hypotheses have been proposed for stone disintegration. broader focal zone, slower pulse rate, adequate coupling of shock wave head, and active monitoring increase success of swl(25). the main limitations of our study are use of a single lithotripter, and absence of ssd data and stone analysis. another limitation is making measurements under fluoroscopy without any electronic measurement, chasing the movements visually, and manual measurement of the points and distances with maximum movement. however, there are only scarce reports in the literature that have investigated respiration-related motion on the success of swl. to our knowledge, this is one of the first studies that included the highest number of patients, and analyzed a number of parameters in relation with motion. conclusions in our study, we observed a statistically significant relationship between kidney motion and success of swl. further comparative studies using lithotripters with different focal zones are needed to determine the significance of kidney motion on different focal zones and different devices. conflict of interest the authors report no conflict on interest. figure 1. the method used to measure the actual mobility (m). a: craniocaudal size of the stone on kidney-ureter-bladder x-ray, b: the size of the stone under fluoroscopy, c: the mobility of the stone with respiration. m=axc/b (calculation of actual mobility by calculating the ratio of the actual size of the stone on kidney-ureter-bladder x-ray and its size on fluoroscopy). respiration induced kidney mobility in swl-yucel et al. vol 15 no 01 january-february 2017 13 references 1. chaussy c, brendel w, schmiedt e. extracorporeally induced destruction of kidney stones by shock waves. lancet 1980;13;2:1265-8. 2. wiesenthal jd, ghiculete d, ray aa, honey rj, pace kt. a clinical nomogram to predict the successful shock wave lithotripsy of renal and ureteral calculi. j urol. 2011; 186:556-62. 3. gupta np, ansari ms, kesarvani p, kapoor a, mukhopadhyay s. role of computed tomography with no contrast medium enhancement in predicting the outcome of extracorporeal shock wave lithotripsy for urinary calculi. bju int. 2005; 95:1285-8. 4. semins mj, matlaga br. strategies to optimize shock wave lithotripsy outcome: patient selection and treatment parameters. world j nephrol. 2015; 6;4:230-4. 5. donaldson jf, lardas m, scrimgeour d, stewart f, maclennan s, lam tb. systematic review and meta-analysis of the clinical effectiveness of shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy for lower-pole renal stones. eur urol. 2015; 67:612-6 6. resorlu b, unsal a, ziypak t, diri a, atis g, guven s. comparison of retrograde intrarenal surgery, shockwave lithotripsy, and percutaneous nephrolithotomy for treatment of medium-sized radiolucent renal stones. world j urol. 2013; 31:1581-6 7. telli o, haciyev p, karimov s, sarici h, karakan t, ozgur bc, demirbas a, resorlu b, soygur t, burgu b. does previous stone treatment in children generate a disadvantage or just the opposite? urolithiasis 2015; 43:1415. 8. wiesenthal jd, ghiculete d, ray aa, honey rj, pace kt. a clinical nomogram to predict the successful shock wave lithotripsy of renal and ureteral calculi. j urol. 2011; 186:556-62. 9. ordon m, ghiculete d, pace kt, honey rj. does the radiologic technologist or the fluoroscopy time affect treatment success with shockwave lithotripsy? j endourol. 2012; 186:556-62. 10. bhojani n, lingeman je. shockwave lithotripsy-new concepts and optimizing treatment parameters. urol clin north am. 2013; 40:59-66. 11. davies sc, hill al, holmes rb, halliwell m, jackson pc. ultrasound quantitation of respiratory organ motion in the upper abdomen. br j radiol. 1994;67:1096-102. 12. balter jm, ten haken rk, lawrence ts, lam kl, robertson jm. uncertainties in ctbased radiation therapy treatment planning associated with patient breathing. int j radiat oncol biol phys. 1996; 1;36:167-74. 13. schwartz lh, richaud j, buffat l, touboul e, schlienger m. kidney mobility during respiration. radiother oncol. 1994; 32:84-6 14. song r, tipirneni a, johnson p, loeffler rb, hillenbrand cm. evaluation of respiratory liver and kidney movements for mri navigator gating. j magn reson imaging 2011; 33:1438. 15. sorensen md, bailey mr, shah ar, hsi rs, paun m, harper jd. quantitative assessment of shockwave lithotripsy accuracy and the effect of respiratory motion. j endourol. 2012; 26:1070-4. 16. cleveland ro, anglade r, babayan rk. effect of stone motion on in vitro comminution efficiency of storz modulith slx. j endourol. 2004; 18:629-33 17. orkisz m, farchtchian t, saighi d, bourlion m, thiounn n, gimenez g. image based renal stone tracking to improve efficacy in extracorporeal lithotripsy. j urol. 1998; 160:1237-40. 18. bohris c, bayer t, lechner c. hit/miss monitoring of eswl by spectral doppler ultrasound. ultrasound med biol. 2003; 29:705-12. 19. sorensen c, chandhoke p, moore m, wolf c, sarram a. comparison of intravenous sedation versus general anesthesia on the efficacy of the doli 50 lithotriptor. j urol. 2002;168:35-7. 20. eichel l, batzold p, erturk e. operator experience and adequate anesthesia improve treatment outcome with third generation lithotripters. j endourol. 2001;15:671-3. 21. hosking dh, smith we, mccolm se. a comparison of extracorporeal shock wave lithotripsy and ureteroscopy under intravenous sedation for the management of distal ureteric calculi. can j urol. 2003;10:1780-4. 22. pareek g, hedican sp, lee ft jr, nakada sy. shock wave lithotripsy success determined by skin-to-stone distance on computed tomography. urology 2005; 66:941-4 23. patel t, kozakowski k, hruby g, gupta m. skin to stone distance is an independent predictor of stone-free status following shockwave lithotripsy. j endourol. 2009; 23:1383-5. 24. pareek g, hedican sp, lee ft jr, nakada sy. shock wave lithotripsy success determined by skin-to-stone distance on computed tomography. urology 2005; 66:941-4. 25. rassweiler jj, knoll t, köhrmann k-u, et al. shock wave technology and application: an update. european urology 2011; 59:784-96. 26. de sio m, autorino r, quarto g, mordente s, giugliano f, di giacomo f, et al. a new transportable shock-wave lithotripsy machine for managing urinary stones: a single-centre experience with a dual-focus lithotripter. bju int. 2007 ;100:1137-41. 27. harrogate s, yick s, williams jc, cleveland respiration induced kidney mobility in swl-yucel et al. endourology and stone diseases 14 r, turney bw. quantification of the range of motion of kidney and ureteric stones during shockwave lithotripsy in conscious patients. j endourol. 2016;30:406-10. 28. sorensen md, bailey mr, shah ar, hsi rs, paun m, harper jd. quantitative assessment of shockwave lithotripsy accuracy and the effect of respiratory motion. j endourol. 2012;26:1070-4. respiration induced kidney mobility in swl-yucel et al. vol 15 no 01 january-february 2017 15 urological oncology does mantoux test result predicts bcg immunotherapy efficiency and severe toxicity in non-muscle invasive bladder cancer wojciech krajewski1*, romuald zdrojowy1, jędrzej grzegrzółka2, piotr krajewski1, michał wróbel3, mateusz łuczak1, anna kołodziej1 purpose: to evaluate on a large group of patients whether mantoux tuberculin skin test (tst) result is associated with bcg immunotherapy effectiveness and whether it can predict occurrence of moderate to severe toxicity. materials and methods: we analysed group of 823 patients with intermediate and high risk nmibcs who were treated with bcg. the study included 412 patients with the history tst and 411 without tst. a standard dose of statens serum institute tuberculin rt23 was used. the reaction was read 48-72 hours later by evaluating the diameter of palpable induration. the size of the induration was considered positive when the measurement was greater than or equal to 6 mm and excessively positive when bigger than 26 mm. whole bcg immunotherapy schedule consisted of 27 instillations. results: the patients were followed for median 61 months. the 5-year recurrence and progression free survival (rfs, pfs) did not differ between the groups in both total study population and in tumour subgroup analysis. tst result in both total study population and in subgroups was not statistically associated with rfs, pfs and cancer specific survival. the moderate-to-severe toxicity was observed in 181(44%) tst patients, and in 196(47%) patients without tst. incidence of toxicity was not statistically different and also not statistically associated with tst result in any of the tumour subgroups of tst group. conclusion: this study shows, that tst does not have value in prediction of bladder cancer recurrence, progression nor cancer specific survival. also it doesn’t have a value in predicting therapy toxicity. keywords: bacillus calmette-guerin; mantoux test; non-muscle-invasive bladder cancer; progression; recurrence introduction standard of care in non-muscle invasive bladder can-cer (nmibc) includes transurethral resection of bladder tumour (turb) and subsequent intravesical therapy, which, depending on the cancer risk level, may be a single cytostatic agent instillation with or without bacillus calmette-guerin (bcg) immunotherapy regimen(1,2). bcg therapy has been proven to be effective for lowering the recurrences and progression rates of nmibc including carcinoma in situ (cis) treatment(3-5). the bcg therapeutic effect is largely associated with cellular immunological mechanism, however, its precise way of action is still unidentified(6). despite the fact, that bcg immunotherapy is a widely accepted management of medium and high risk nmibcs, there are many uncertainties with regard to treatment protocol, reduction of side effects and mechanism of action (6,7). the mantoux tuberculin skin test (tst), also known as test for purified protein derivative (ppd), is the standard method of tuberculosis diagnosis. the tst is performed by intradermal injection of tuberculin ppd into 1department of urology and oncological urology, wrocław medical university, wrocław, poland. 2department of histology and embryology, wroclaw medical university, wrocław, poland. 3department of urology and oncologic urology, lowersilesian specialistic hospital, wrocław, poland. *correspondence: department of urology and oncological urology, wrocław medical university, borowska 213, wrocław, poland. tel/fax: 71 733 1010. email: wk@softstar.pl. received april 2018 & accepted september 2018 the inner surface of the forearm. subsequently, the skin reaction (induration) is read between 48 and 72 hours after administration and the result is interpreted depending on induration size and one’s risk of being infected with tuberculosis(8). prognostic value of tst reactivity in patients treated with bcg has been evaluated in some studies. correlation between tumor free status and the presence of positive tst have been observed in these reports, however, the studies were based on small groups of patients receiving short bcg regimens(9-11). the aim of the study was to analyse whether tst result was associated with bcg immunotherapy effectiveness and whether it could predict occurrence of moderate or severe side effects on a large group of bcg patients. material and methods study population and inclusion criteria we retrospectively analysed group of 823 patients with intermediate and high eortc risk nmibc who were treated in our outpatient bcg department between 1998 and 2016(12). one team of three physicians qualified all urology journal/vol 16 no. 5/ september-october 2019/ pp. 458-462. [doi: 10.22037/uj.v0i0.4542] vol 16 no 04 september-october 2019 459 patients for immunotherapy and one physician administered majority of instillations (ak). patients observed for minimum 12 months with introduction and any maintenance courses (≥7 instillations) were included in the study analysis. four hundred and twelve patients (80f/332m, age 64,2+/-9,2y) received tst before bcg immunotherapy introduction and 411 (81f/330m, age 66,4+/-9,4y) did not. during first three years of outpatient department functioning all patients were qualified for tst. later, qualification for the test was random, however not purposely randomized, basing on test kits availability. procedures tst was performed before bcg immunotherapy introduction. a standard dose of statens serum institute (ssi) tuberculin rt23 was used. the reaction was read 48 to 72 hours later by evaluating the diameter (millimetres) of palpable, raised and hardened area in the forearm. in case of erythema without induration, the result was read as "0 mm". the size of the induration was considered to be positive when the measurement was greater than or equal to 6 mm. induration bigger than 26 mm was considered excessively positive(13). before first instillation every patient had chest x-ray, urine culture performed and complete blood count, creatinine, got and gpt levels measured. bcg instillations were introduced at least 14 days following the last invasive bladder procedure. patients received immediate single instillation with a chemotherapeutic agent after primary turb according to eau guidelines (doxorubicine, mitomycin). a restaging turb was also performed according to guideline recommendations. whole bcg immunotherapy schedule consisted of 27 instillations divided into introducing course and seven maintenance courses. introducing course was composed of 6 weekly given instillations. maintenance courses were comprised of three weekly given instillation administered after 3, 6, 12, 18, 24, 30 and 36 months(14). before each course urine culture and got and gpt levels were measured. chest x-ray and usg were performed every 6 months. cystoscopy (cs) was performed every 3 months during first two years following turb and then every 6 months. after five years cs was performed annually. urine cytology was performed every 3 months if the primary tumour was poorly differentiated (hg, g3 and some g2) or in case of concomitant cis or mucosal dysplasia. bladder wall biopsy was performed i every case of recurrence suspicion and positive cytology. in case of primary cis mapping biopsy was performed routinely after first maintenance course. the patients were analysed in terms of toxicity occurrence, recurrence free (rfs), progression free (pfs), cancer specific (css) and overall survival (os). times to events were calculated taking the date of initiating bcg as time zero. toxicity was defined as clinical state requiring administration of anti-mycobacterial agents (fluoroquinolones, rifampicin, isoniazid etc.) and/or dose reduction and/or cessation of therapy. a recurrence was defined as a reoccurrence of tumor of any stage and grade confirmed by turbt and histologic or cytological assessment. progression was defined as a rise to t2 or higher tumour stage. statistical analysis all statistical analyses were performed using prism 5.0 software (graphpad, ca, usa). for correlations of tst implementation and results with clinical endpoints chi-square test and fisher exact test tests were used. for analysis of survival periods the kaplan meyer curves were performed and mantel cox test was used. results were considered as statistically significant when p < 0.05 in all analyses. results the baseline patients’ characteristics are included in table 1. the study included 412 patients (80 female/ 332 male) with the history tst procedure and 411 (81f/330m) patients without tst who were age and gender matched. average number of bcg instillations given was 18,98 in tst group and 19,22 in group without tst. the difference was not statistically significant. the groups did not differ statistically in terms of presence of muscle layer in histopathological specimen, the mantoux test and bcg efficiency and toxicity – krajewski et al. table 1. the patients baseline characteristics according to tst status with tst without tst primary diagnosis ta 194 (47%) 106 (25.8%) t1 167 (40.5%) 231 (56.2%) hg 170 (41.3%) 239 (58.2%) lg 242 (58.7%) 172 (41.8%) talg 166 (40%) 66 (16%) tahg 28 (6.7%) 40 (9.7%) t1hg 91 (22%) 199 (48.4%) t1lg 76 (18.4%) 32 (7.8%) cis 51 (12.5%) 74 (18%) gender male 332 (80.5%) 330 (80.3%) female 80 (19.5%) 81 (19.7%) median age (mean; range; median) 64.3; 27-85; 65 65.4. 28-89. 66 toxicity 181 (44%) 196 (47%) observation time (mean; range; median) 102.4; 12-242; 94 43.8; 12-257; 34 muscle in primary turb specimen (y/n/missing) 317 (76.9%)/50 (12.1%)/45 (11%) 328 (79.8%)/76 (18.5%)/7 (1.7%) concomitant cis (y/n) 60 (14.6%)/301 (73%) 66 (16.1%)/271 (65.9%) number of tumours (solitary/multiple/cis/missing data) 111 (26.9%)/246 (59.7%)/51 (12.4%)/4 (1%) 142 (34.5%)/188 (45.8%)/74 (18%)/7 (1.7%) tumour size (<3cm/ł3cm) 214 (51.9%)/147 (35.6%) 216 (52.5%)/121 (29.4%) newly diagnosed/recurrent tumours 177 (43%)/235 (57%) 223 (54.3%)/188 (45.7%) tst result negative/positive/excessively positive 130 (31.6%)/77 (18.7%)/205 (49.7%) concomitants cis, tumour focality and tumour size. the groups were not matched in terms of primary diagnosis (p < 0.001), therefore, subgroup analyses were performed. the patients were followed for median 61 months [range 12-257, sd 55]. the groups were not matched in terms of observation time, so we performed a survival analysis, avoiding direct comparison of frequencies of observational end-points. the observation time difference is caused by the fact, that during earlier years of bcg outpatient department functioning, tst test was performed more frequently than in recent years. the recurrence was observed in 139 pts. (33,8%) in group without tst and in 194 pts. with tst (47%). thirty-nine pts. (9%) experienced the recurrence more than once during study follow-up in group without tst and 64 pts. in group with tst (15,5%). progression of the cancer was observed in 70 pts. (17%) without and 113 pts. (27,4%) with tst. there were 31 (7,5%) and 72 (17,5%) cancer specific deaths in without tst and with tst groups respectively. results of mantel cox analysis of survival according to tst status are showed in table 2, and analysis of survival according to tst result (negative/positive) in table 3. none of the analysed parameters were statistically correlated. the tst result (negative/positive/excessively positive) in both total study population and in subgroups was not statistically associated with rfs, pfs, os and css (table 4). in the total study population analysis rfs for 12, 24 and 60 months concerned 81,1%, 73,4% and 62% of patients with tst and 80,9%, 73,9% and 62,1% of patients of without tst, respectively. pfs for 12, 24 and 60 months for all tumours concerned 91,5%, 87,3% and 79,7% patients in group with tst and 90,7%, 87% and 80,1% of patients without tst, respectively. those results did not differ statistically for both overall and subgroup analysis. the toxicity was observed in 181 (44%) of tst patients, and in 196 pts. (47%) in group without tst. in group with tst 115 pts. (28%) underwent dose reduction, 99 pts. (24%) needed fluoroquinolones administration, 68 pts. (16%) required more potent tuberculostatic agent, and in 83 pts. (20%) bcg immunotherapy was stopped because of toxicity. in group without tst 113 pts. (27%) experienced dose reduction, in 144 pts. (35%) fluoroquinolones were administered, 44 pts. (10%) needed potent tuberculostatic agent, and in 87 pts. (21%) bcg was detained because of toxicity. in the analysis of toxicity occurrence, when chi-square test was performed, there was no statistical differences between group without tst and patients with positive and negative result of the tst (p = 0.547). when fisher’s exact test was performed in tst group for patients with positive and negative tst result, the subgroups where not statistically different (p = 0.915). discussion in this study we analysed the possible association between tst result with bcg efficiency and occurrence of moderate to severe toxicity in 823 patients with nmibc. the bcg immunotherapy is a widely accepted standard of care in intermediate and high risk nmibcs. its efficiency has been proved in numerous papers and its use is advocated by international clinical guidelines. however, despite the fact that bcg in nmibc treatment was introduced more than 40 years ago, there are still many unknowns(15). precise way of action, the best administration schedule, optimal dosage as well as makers of response and risk factors for complications still remain a conundrum. table 2. mantel cox analysis of survival according to tst status. overall survival cancer specific survival recurrence free survival progression free survival tst performed vs. hazard 95% ci p value hazard 95% ci p value hazard 95% ci p value hazard 95% ci p value not performed ratio ratio ratio ratio total study 1.1 0.8-1.5 0.548 1.0 0.6-1.6 0.993 1.0 0.8-1.3 0.949 1.0 0.8-1.3 0.949 population cis 1.0 0.5-2.0 0.925 0.9 0.3-2.5 0,770 1.1 0.4-3.0 0.827 1.1 0.5-2.4 0.753 t1hg 0.7 0.5-1.2 0.227 0.8 0.4-1.5 0,471 1.0 0.4-2.5 0.910 0.7 0.4-1.1 0.131 t1lg 1.3 0.5-3.3 0.646 0.7 0.11-4.5 0,709 1.2 0.5-2.9 0.672 0.8 0.3-2.6 0.735 tahg 0.6 0.2-1.4 0.216 0.6 0.2-2.0 0,408 0.5 0.1-2.1 0.349 0.9 0.2-2.0 0.735 talg 0.6 0.3-1.2 0.1292 0.4 0.1-1.5 0,181 0.7 0.3-1.4 0.332 0.6 0.3-1.4 0.268 bold values (p < 0.05) are statistically significant. abbreviations: ci, confidence interval. overall survival cancer specific survival recurrence free survival progression free survival tst result positive vs. hazard 95% ci p value hazard 95% ci p value hazard 95% ci p value hazard 95% ci p value negative ratio ratio ratio ratio total study population 1.0 0.7-1.4 0.987 1.0 0.7-1.4 0.883 1.2 0.9-1.6 0.333 0.9 0.6-1.5 0.756 cis 1.0 0.5-2.1 0.951 1.0 0.3-3.0 0.958 1.0 0.3-2.9 0.959 0.9 0.3-2.6 0.871 t1hg 1.1 0.6-2.2 0.662 1.3 0.5-3.2 0.606 1.0 0.4-2.5 0.910 1.0 0.5-2.2 0.876 t1lg 1.2 0.5-2.5 0.706 1.0 0.2-4.3 0.975 1.2 0.5-2.9 0.672 1.2 0.4-3.4 0.739 tahg 2.4 0.5-11.8 0.292 3.2 0.4-27.0 0.277 1.6 0.1-18.0 0.725 2.4 0.5-11.8 0.292 talg 0.8 0.5-1.3 0.315 0.6 0.2-1.6 0.328 0.8 0.5-1.5 0.551 0.8 0.4-1.6 0.474 bold values (p < 0.05) are statistically significant. abbreviations: ci, confidence interval. table 3. mantel cox analysis of survival according to tst result (negative/positive). the mantoux test and bcg efficiency and toxicity – krajewski et al. urological oncology 460 vol 16 no 04 september-october 2019 461 it is well known that bcg action is based on immunological response. components of the bcg instillation such as attenuated bacteria, dead bacilli and subcellular debris are characterized by powerful immunological properties. increased immunological activity in the bladder after bcg instillation leads to the activation and migration of cytotoxic lymphocytes, macrophages and natural killer (nk) cells which finally results in tumor eradication(6). earlier papers indicated possible association between tst result and bcg efficiency and toxicity. yet, these studies were performed on small group of patients, with various administration schedules and with short follow-up. ultimately, there are no studies in populations with high risk of possible tuberculosis exposition. shortly after world war ii, which was the time when the majority of current bc patients in poland were born, poland was a country with one of the highest incidence of tuberculosis in europe. at present, despite the significant decrease in the number of cases, the differences between poland and western europe are still visible. the regulations concerning the bcg compulsory vaccinations and the bacterial strain were different among various european countries. in poland, until 1950 only the dutch strain was used and after the introduction of the compulsory vaccination in 1955 the strain was changed for brazilian moreau. it is unclear what is the effect of the immunization during vaccination. vast majority of our study population underwent compulsory vaccination with bcg vaccine during their life-time. all abovementioned factors make the polish population very different in terms of tuberculosis immunization from the patients in other countries, especially, north america(16,17). in the analysis of this study population, it was shown that preformation of tst was not associated with reduced risk of tumour recurrence. in the survival analysis, statistical significance was not reached in any tumour group (total study population, talg, tahg, t1hg, t1lg, cis) for neither 12, 24 nor 60 months rfs. also, the median times to recurrence were not statistically different for subgroup analysis. tst result (negative/positive/excessively positive) in both total study population and in subgroups was not statistically associated with rfs. influence of tst on progression was also analysed. it was shown that that preformation of tst was not associated with reduced risk of cancer progression neither in total study population nor in subgroup analysis. pfs for 12, 24 and 60 months did not differ statistically. the median times to progression in subgroup analysis were also not statistically different. similarly, as in recurrence analysis, tst result was not statistically associated with pfs neither for total study population, nor for subgroups. finally, os and css were not proved to be dependent on tst preformation. statistical significance was not reached for neither total study population nor tumour subgroups. what is more, tst result did not influence neither os nor css. however, a number of reported deaths was not big and may by not statistically representative. for the purposes of this analysis, the moderate and sever toxicity were defined as clinical situation requiring administration of antimycobacterial agents (fluoroquinolones, riphamazide, izoniazide etc.) and/or dose reduction and/or cessation of the therapy. the toxicity was observed in 181 tst patients, and in 196 patients without tst. the difference was not statistically different. incidence of toxicity was also not statistically associated with tst result in any of the tumour subgroups of tst group. this study has some limitations that ought to be disclosed. firstly, this study is limited by its retrospective nature. the long period of the observation raises doubts about whether a cohort effect may occur with present-day high-risk patients being dissimilar from those from early part of the study. however, during 20 years of the course, none of qualification, therapeutic and maintenance details did change. what is more, to avoid biases, only one team of physicians qualified all patients and one physician administered almost all of instillations (ak). additionally, only two nurses were included in the treatment protocols. secondly, our department is referral in urooncology, only one in the voivodeship which offers bcg immunotherapy. therefore, population of our patients underwent resections in various centres. for that reason, turbs and histopathological assessment could be performed with different quality. however, majority of the specimens were originally or were re-evaluated by our team of pathologists to avoid incorrect qualification. thirdly, despite random patient allocation, the study did not have precise randomization protocol for whole period. lastly, talg tumors represent big part of cases. however, all of those tumours were in intermediate risk group according to eortc grading (e.g. because of size, multifocality and/or recurrent character). for that reason, subgroup analysis was performed. notwithstanding limitations our study has some clear strengths. firstly, we present big centro-european population which was not previously included in bcg trials. the study population is homogeneous in terms of immunization, vast majority of our patients underwent compulsory vaccination with bcg vaccine during their life-time. secondly, our group have long and meticulous follow-up with minimal loss to observation. thirdly, our patients received maintenance courses in 6+3 manner, which was not studied in previous reports. table 4. mantel cox analysis of survival according to tst result: negative/positive/excessively positive (p-values). tst result overall survival cancer specific survival recurrence free survival progression free survival negative/positive/excessively positive cis 0.256 0.202 0.838 0.347 t1hg 0.894 0.835 0.993 0.866 t1lg 0.899 0.999 0.876 0.662 tahg 0.578 0.558 0.936 0.688 talg 0.337 0.479 0.481 0.677 bold values (p < 0.05) are statistically significant the mantoux test and bcg efficiency and toxicity – krajewski et al. finally, to our knowledge, this is the biggest study analysing aspect of tst in population of nmibc receiving bcg immunotherapy. conclusions this study shows that the mantoux tuberculin skin test does not have value in prediction of bladder cancer recurrence, progression nor cancer specific survival. also, it doesn’t have a value in predicting therapy toxicity. conflict of interest the authors report no conflict of interest. references 1. babjuk m, burger m, zigeuner r, et al. eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. eur urol. 2013;64:639-53. 2. kamat am, bellmunt j, galsky md, et al. society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. j immunother cancer. 2017;5:68. 3. duchek m, johansson r, jahnson s, et al. bacillus calmette-guerin is superior to a combination of epirubicin and interferonalpha2b in the intravesical treatment of patients with stage t1 urinary bladder cancer. a prospective, randomized, nordic study. eur urol. 2010;57:25-31. 4. jarvinen r, kaasinen e, sankila a, rintala e, finnbladder g. long-term efficacy of maintenance bacillus calmette-guerin versus maintenance mitomycin c instillation therapy in frequently recurrent tat1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised finnbladder i study with a 20-year follow-up. eur urol. 2009;56:260-5. 5. sylvester rj, brausi ma, kirkels wj, et al. long-term efficacy results of eortc genitourinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus calmette-guerin, and bacillus calmette-guerin plus isoniazid in patients with intermediateand high-risk stage ta t1 urothelial carcinoma of the bladder. eur urol. 2010;57:766-73. 6. redelman-sidi g, glickman ms, bochner bh. the mechanism of action of bcg therapy for bladder cancer--a current perspective. nat rev urol. 2014;11:153-62. 7. poletajew sa, majek a, magusiak p, ledzikowska k, dybowski b, radziszewski p. availability and patterns of intravesical bcg instillations. urol j. 2017;14:5068-70. 8. nayak s, acharjya b. mantoux test and its interpretation. indian dermatol online j. 2012;3:2-6. 9. torrence rj, kavoussi lr, catalona wj, ratliff tl. prognostic factors in patients treated with intravesical bacillus calmetteguerin for superficial bladder cancer. j urol. 1988;139:941-4. 10. bilen cy, inci k, erkan i, ozen h. the predictive value of purified protein derivative results on complications and prognosis in patients with bladder cancer treated with bacillus calmette-guerin. j urol. 2003;169:1702-5. 11. luftenegger w, ackermann dk, futterlieb a, et al. intravesical versus intravesical plus intradermal bacillus calmette-guerin: a prospective randomized study in patients with recurrent superficial bladder tumors. j urol. 1996;155:483-7. 12. sylvester rj, van der meijden ap, oosterlinck w, et al. predicting recurrence and progression in individual patients with stage ta t1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials. eur urol. 2006;49:466-5; discussion 757. 13. menzies d. interpretation of repeated tuberculin tests. boosting, conversion, and reversion. am j respir crit care med. 1999;159:15-21. 14. lamm dl, blumenstein ba, crissman jd, et al. maintenance bacillus calmette-guerin immunotherapy for recurrent ta, t1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized southwest oncology group study. j urol. 2000;163:1124-9. 15. morales a, eidinger d, bruce aw. intracavitary bacillus calmette-guerin in the treatment of superficial bladder tumors. j urol. 1976;116:180-3. 16. biot c, rentsch ca, gsponer jr, et al. preexisting bcg-specific t cells improve intravesical immunotherapy for bladder cancer. sci transl med. 2012;4:137ra72. 17. zbar b, rapp hj. immunotherapy of guinea pig cancer with bcg. cancer. 1974;34:suppl:1532-40. the mantoux test and bcg efficiency and toxicity – krajewski et al. urological oncology 462 the epigenetic assessment of human spermatogenic cells derived from obstructive azoospermic patients in different culture systems maria zahiri1,2, mansoureh movahedin1*, seyed javad mowla3, mehrdad noruzinia4, morteza koruji 5,6, mohammad reza nowroozi7, zahra bashiri5,6 purpose: generating functional gametes for patients with male infertility is of great interest. we investigated different cultural systems for proliferation of sscs derived from obstructive azoospermic patients. materials and methods: testicular cells were obtained from men with obstructive azoospermia. after enzymatic digestion process, cells were assigned to various groups: culture of sscs in the dish without cover (control group), co-culture of sscs with infertile sertoli cells (i), co-culture of sscs with fertile sertoli cells (ii), culture of sscs on nanofiber (covered with laminin) (iii), culture of testicular cell suspension (iv). then cells were cultured and colony formation, gene-specific methylation (by msp), quantitative genes expression of pluripotency (nanog, c-myc, oct-4) and specific germ cell (integrin α6, integrin β1, plzf) genes were evaluated in five different culture systems. results: our findings indicate a significant increase in the number and diameter of colonies in iv group in compare to control group and other groups. expression of germ specific genes in iv group were significantly increased (p ≤ 0.05) and levels of expression of pluripotency genes were significantly decreased in this group (p ≤ 0.05) compared with other groups. gene-specific pattern of methylation of examined genes showed no changes in culture systems during the culture era. conclusion: a microenvironment capable of controlling the proliferation of cell colonies can be restored by testicular cell suspension. keywords: spermatogonial stem cells; proliferation; epigenetic; testicular cell suspension; obstructive azoospermia introduction fertility in men depends on the spermatogenesis pro-cess leading to the production of fertile male gametes. a specialized microenvironment (niche) affects the balance of self-renewal and spermatogonial stem cells (sscs) differentiation(1,2). niches include various types of somatic cells, including sertoli cells, myoid (peritubular) and leydig cells and also extracellular matrix (ecm) that contribute to the development of spermatogenesis by producing various growth factors(3). for example, sertoli cells support the proliferation of sscs by producing glial cell-derived neurotrophic factor (gdnf). in addition, leydig and peritubular cells secrete colony-stimulating factor 1 (csf1) that appears to be playing a role in the sscs proliferation. ecm proteins, including laminin, have been reported to be involved with spermatogonia and therefore are considered an important component of the niche(4-6). about 15% of couples are infertile, and male factor infertility affects around half of them. infertility has made 1department of anatomical sciences, medical sciences faculty, tarbiat modares university, tehran, iran. 2department of anatomical sciences, school of medical sciences, bushehr university of medical sciences, bushehr, iran. 3department of molecular genetics, faculty of biological sciences, tarbiat modares university, tehran, iran. 4department of medical genetics, school of medicine, tarbiat modares university, tehran, iran. 5department of anatomical sciences, school of medicine, iran university of medical sciences, tehran, iran. 6cellular and molecular research center, iran university of medical sciences, tehran, iran. 7department of urology, uro-oncology research center, tehran university of medical sciences, tehran, iran. *correspondence: department of anatomical sciences, faculty of medical sciences, university of tarbiat modares, jalale‐ale‐ahmad highway, p. o. box: 14115‐175, tehran, iran. tel.: +9821 8801 1001, ext 4502; fax: +9821 8801 3030. e mail: movahed.m@modares.ac.ir. received april 2020 & accepted november 2020 due to genetic variants and segregating alleles, epigenetic factors and environmental pollution and factors that are not known yet. it has been reported that azoospermia comprises 25% of male infertility cases(7). in vitro spermatogenesis may be useful in the treatment of patients with non-obstructive azoospermia (noa), e.g. patients with sertoli cell abnormalities and spermatogenesis arrest. assisted reproductive technologies (art) generally treat obstructive fertility problems by eliminating pregnancy barriers, but in many noa patients, male germ cells are either absent or underdeveloped or incomplete and therefore not suitable for art. transfer of cells from the in vivo damaged environment into a culture medium can help better maturation and production of viable sperm(8). there are a limited number of sscs in a testicle tissue removed from a testis. this makes it necessary to use in-vitro propagation of sscs for repopulation of adult human testes. on the other hand, there are no valid surface-specific isolation markers for sscs, therefore, in vitro characterization of spermatogenesis that allows andrology urology journal/vol 18 no. 2/ march-april 2021/ pp. 214-224. [doi: 10.22037/uj.v16i7.6092] in vitro propagation of human sscs is the goal of researchers. accordingly, there is a major need for culture systems that mimic the natural situation and provide functional testicular cells(9). however, functional sperm production in humans has not yet been achieved in vitro(10). various techniques have been proposed for in vitro propagation of human sscs, including different cultural systems, such as various feeder layers, improvement of niche, different culture substrates, addition of serum or using feederand serum-free medium, using different growth factors and supplements(11). three-dimensional (3d) culture has been introduced very recently and has been hypothesized to be able to mimic seminiferous epithelium developing male germ cells better. previous studies have been able to obtain morphologically healthy sperm in a 3d matrix material, maturated by support from somatic testicular cells and the presence of gonadotrophins(12). as suggested, the applicability of this culture technique requires further research(13,14). while 3d culture has been shown to support spermatogenesis, it's optimal conditions remain unknown. during culture, the genetic and epigenetic stability of human sscs should be considered. in this study, the effectiveness of various cultures in the propagation and enrichment of human sscs derived from oa patients was investigated in order to provide an efficient system. materials and methods sample collection human testicular samples have been obtained from men with oa that were recourse to shayan-mehr clinic (tehran-iran) for the treatment of infertility under the testicular sperm extraction (tese) program and the remaining tissue was used. the use of human testicular biopsy samples and all steps of this research study were conducted with the authorization of the tarbiat modares university research ethics committee (5212037-tehran, iran). written consent was received from those who would like to participate in the study. the demographic table related to the conditions for patients to enter the research is given in table 1. isolation and cultivation of human sscs one hour after biopsy, tissue samples were transferred to dulbecco’s modified eagle medium (dmem; gibco, paisley, uk), supplemented with 14 mm nahco 3 (sigma, st louis, mo, usa), 100 iu/ml penicillin, single-strength non-essential amino acids and 100µg/ ml streptomycin and then were brought to the laboratory. samples were enzymatically subjected to two stages: the samples were incubated in a medium containing 0.5 mg/ml collagenase, 0.5 mg/ml trypsin, 0.5 mg/ml hyaluronidase, and 0.05 mg/ml dnase, for 30 minutes at 37 ° c. during this time, samples were pipetted several times by sampler. every enzyme is bought from sigma, usa. tubes and spermatogenic cells were deposited using gradient gravity. the result of the first phase of enzyme digestion was the parts of seminal tubes entering the second stage of digestion for further digestion. for further removal of interstitial cells, the second digestion stage (45 min at 37°c) was performed in dmem by adding fresh enzymes to seminiferous tubular fragments. the cells that are in the tubes, including spermatogonia and sertoli, were released by centrifugation at 1500 rpm for 4 minutes at 37 ° c. due to the small number of sscs in initial biopsies to evaluate the different cultivation systems of sscs, after enzymatic digestion process, the cells were cultured for 2 weeks in five cultural systems. in order to unify cultures, biopsy samples were weighed before enzymatic digestion and 2×105 cells were placed per 12-well culture plate. after cell isolation, all specimens were incubated for two weeks in culture 34-stempro with its complement (invitrogen), 6 mg/ml –d (±) glucose, 100 µg/ml transferrin, 60 µm putrescine, 25 µg/ml human insulin, 30 µg/ml pyruvic acid, 30 nm sodium selenite, 60 ng/ml progesterone, 1 µ/ml –dl lactic acid, 5 mg/ml bovine serum albumin, 2 µm l-glutamine, 10 ng/ml glial cell line-derived neurotrophic factor (gdnf), mem solepigenetic assessment of spermatogenic cells-zahiri et al. andrology 215 table 1. the demographic table related to the conditions for patients to enter the research. clinical and pathologic data of azoospermic men inclusion criteria exclusion criteria fsh levels (miu/ml) 15-1 ≥31 testicular volume (ml) 15-6 ≤5 ≥16 testicular histologic findings dynamic biopsy motile sperm(+) motile sperm(-) pathology assessment all spermatogenic cells(+) maturation arrest or sco sertoly cell only syndrome gene name primer sequence gene bank code band size (bp) integrin α6 for: 5′agt gtt tat act atg gaa gtg tgg-3′ nm_000210.1 106 rev: 5′tac tat gca tca gaa gta agc ct-3′ integrin β1 for: 5′tcc aaa cta cgg acg taa agc-3′ nm_033668.1 75 rev: 5′ccc tca tac ttc gga ttg acc-3′ plzf for: 5′gta cct cta cct gtg cta tgt g-3′ nm_001018011 80 rev: 5′tgt cat agt cct tcc ttc atc tc-3′ c-myc for: 5′tgt aaa ctg cct caa att gga c-3′ nm_001198530.1 177 rev: 5′gga ttg aaa ttc tgt gta act gct-3′ nanog for: 5′cct tgg ctg ccg tct ctg-3′ nm_058176.2 131 rev: 5′gca aag cct ccc aat ccc-3′ oct-4 for: 5′tct cgc ccc ctc cag gt-3′ nm_001173531.1 202 rev: 5′gcc cca ctc caa cct gg-3′ tbp for: 5′cca gca tca ctg ttt ctt gg-3′ nm_003194 151 rev: 5′ggc tgt tgt tct gat cca tg-3′ table 2. sequence of primers designed for quantitative pcr analysis in culture evaluation. uble vitamins, 10-4 ascorbic acid, 10 µg/ml -d biotin, -25×10-5 mercaptoethanol, 30 ng/ml beta-estradiol, 20 ng/ml human epidermal growth factor, 10 ng/ml basic fibroblast growth factor (bfgf), 10 ng/ml human leukemia inhibitory factor (lif). in order to evaluate different culture systems in sscs proliferation, after enzymatic digestion, these cells were cultured for two weeks in medium mentioned above in 5 different culture systems: culture of sscs in the dish without cover (control group), co-culture of sscs with infertile sertoli cells (i), co-culture of sscs with fertile sertoli cells (ii), culture of sscs on nanofiber (covered with laminin) (iii), culture of testicular cell suspension (iv). culture of sscs in the culture dish without cover supernatants from the previous centrifugation were transferred to the dishes containing the culture medium and incubated for one night at 37 ° c. after incubation, sertoli cells are adhering to the dish floor while others are in suspension. then the cell suspension was collected and counted by a specific cell counting slide and about 3 wells per 12 well plates were cultured. cultivation of sscs with infertile sertoli cells in order to prepare this group, the cell suspension derived from the second phase of the enzyme was divided and cultured in at 37°c for overnight. then, the upper cell suspension of one part of the sample was transtable 3. sequence of methylated and non-methylated primers specific for genes used in msp. gene name primer sequence gene bank code band size (bp) integrin α6 ttgtagttttcggaattaggatttc 100 integrin α6 mf aataataccctacactaaaccgtcg integrin α6 mr tgtagtttttggaattaggattttg 101 integrin α6 uf taataataccctacactaaaccatcac integrin α6 ur integrin β1 ttttttttcgattttcggtc 203 integrin β1mf aaataccgcgacctttaacg integrin β1mr ttttttttgatttttggttgg 203 integrin β1uf taaaaataccacaacctttaacacc integrin β1ur plzf gaagtcgtttttaagtttcgg 125 plzf mf ctacaacgtccaaccaaacg plzf mr tgaagttgtttttaagttttgg 130 plzf uf ctaactacaacatccaaccaaacaa plzf ur c-myc gaaattttgtttatagtagcgggc 140 c-myc mf aaaaaaacgaatcctaacaacgac c-myc mr aaattttgtttatagtagtgggtgg 140 c-myc uf caaaaaaacaaatcctaacaacaac c-myc ur oct-4 gaaaaagggaaagtttcgttttc 105 oct-4 mf gtaccatactccaaaccaacgta oct-4 mr aagaaaaagggaaagttttgttttt 109 oct-4uf acataccatactccaaaccaacata oct-4ur figure 1. a and c: human sscs colony (a: scale bars=100 µm and c: scale bars=20 µm), b: immunofluorecent staining of sscs, detected oct-4 positive under immune fluorescence microscope (scale bars =100 µm), d: immunofluorecent staining of sscs, detected plzf positive under immune fluorescence microscope (scale bars=20 µm), e: human sertoli cells, (scale bars=300 µm). and f: immunofluorecent staining of sertoli cells, detected vimentin, (scale bars=20 µm). epigenetic assessment of spermatogenic cells-zahiri et al. vol 18 no 2 march-april 2021 216 ferred to another dish that after removal of the upper cell suspension, sertoli cells were attached. cultivation of sscs with fertile sertoli cells in order to isolate the sertoli cells in this group, samples of the testicular biopsy were taken from fertile persons, who were undergoing orchidotomy according to the diagnosis of urologist. in order to prepare this group, the same method as the two groups mentioned, was used from cellular supernatants obtained from second-generation enzymatic digestion of healthy persons. culture of sscs on nanofiber, covered with laminin nanofibers were sterilized by immersion in 70% ethanol for 2 hours or sterilized by ultraviolet light, and then 20µg/ml laminin(sigma-aldrich) was added and covered nanofiber incubated for 2 hours until one night in 37 ° c. before use, they were washed 1 to 2 times with phosphate-buffered saline (pbs) and they were ready for cell culture. in this group, cell suspension containing sscs was used. the cells were load in such a way that in the beginning, the cells were mixed with 30 landa of medium and about 3.5×105 cells/ml fiber were added slowly over fiber and then placed in incubator. after two hours, when cells were adhering to the fibers, the new medium was added to the laminin-coated dishes. the medium was replaced every other day. culture of testicular cell suspension in order to prepare this group, the medium containing cells and seminiferous tubule components obtained from the first enzymatic digestion was centrifuged for 5 minutes at 1500 rpm (equivalent to 1500 rpm). the medium containing the enzyme was added to the cell sediment and the steps were continued in the order explained. in the end, after centrifugation, cell sediment was collected and all testicular tissue cells were cultured without isolation. andrology 217 figure 2. comparison of colony number and diameter within cultural groups. a: significant differences with day 3 in each group (p ≤ 0.05). b: significant differences with day 7 in each group (p ≤ 0.05). c: significant differences with day 10 in each group (p ≤ 0.05). epigenetic assessment of spermatogenic cells-zahiri et al. confirmation of sertoli and sscs immunocytochemistry was used for the identification of the sertoli and sscs. initially, for fixing cells, 4% paraformaldehyde was used. after permeabilization with 0.2% triton x100 and blocking with 10% goat serum (vector, burlingame, ca), the dishes received overnight incubation using mouse monoclonal anti-vimentin antibody (sigma-aldrich, usa) at room temperature (dilution ratio= 1:200). then rabbit antihuman oct-4 and promyelocyte leukemia zinc-finger factor (plzf) antibody (dilution ratio=1:100) was added at 4°c. after extensive washing with pbs, it was incubated at 4°c for 2 hours in the dark using the fluorescent-labeled secondary antibody (dilution ratio=1:100; sigma-aldrich, usa). the control dishes were under similar conditions but did not have the first antibody. evaluation of survival and cell proliferation in order to determine the percentage of live cells, trypan blue and neobar slides were used and live and dead cells were counted in the leukocyte counter cells and the ratio and percentage were calculated. also, to determine the total live cells in the sample, the live cells were counted in 1 mm3 sample. evaluation of colony formation of sscs colonies derived from sscs, cultured over two weeks in all groups were studied on days 3, 7, 10 and 14 in terms of the number and diameter of the colony. colonies’ diameter was measured with an inverted microscope (zeiss, germany), equipped with graded eyepiece. observations were repeated three times and mean and standard deviation were measured and analyzed. identity confirmation of sscs quantitative analysis of gene expression: figure 3. gene expression pattern of integrin α6 (a), β1 (b), plzf (c), nanog (d), c-myc (e), and oct-4 (f) during sscs culture in the studied groups. in each group, the expression level of gene in each sample is normalized to tbp, as an internal control. the level of expression of each sample is also calibrated to a calibratore (the cells derived from second enzymatic digestion). (n:3, mean ± sd, p ≤ 0.05) epigenetic assessment of spermatogenic cells-zahiri et al. vol 18 no 2 march-april 2021 218 according to previous studies, assessment of spermatogonial genes expression was used to determine the presence of sscs in culture. as a positive control, the total rna was isolated from the testis, sscs that were cultured on uncoated dishes, and sscs derived from all cultures, using an rnx-plus tm (cinnagen, iran) according to the recommendations of the manufacturer. genomic dna contamination was removed from extracted rna, using dnase i (fermentase) and rna concentrations have been determined, using uv spectrophotometer (eppendorf, germany). treated rna was reverse-transcribed, using revertaidtm first-strand cdna synthesis kit (fermentase) with oligo dt primer according to the recommended protocols. oligonucleotide pcr primers specific for alpha-6-integrin, beta-1 integrin, plzf, c-myc, nanog, oct-4 and tbp (internal control) genes were adapted from other primers and synthesized by genfanavaran company. pcr master mix (cinnagen) and sybr green were used for pcr reactions in a thermal cycler (applied biosystems, stepone tm, usa). the cycling conditions included initial melting cycle (95°c for 5 sec) for polymerase activation, 40 cycles of melting (95°c for 30 sec), annealing (58-60°c for 30 sec), and annealing for an extended 30 seconds at 72 °c. melt-curve analysis was used to confirm the quality of pcr reactions. to determine the efficiency, the standard curve for each gene was prepared, using serial dilution of cdna from the testis. the reference and target genes for each sample were amplified simultaneously. the target genes have been normalized by the reference gene and expressed in relation to the calibrator. the comparative cycle threshold (ct) method was used to determine the gene expression ratio. primers are listed in table 2. epigenetic assessment dna extraction: dna of the sscs in all groups were extracted using dna extraction kit (roche co.) based on the suggested guideline at the end of the second week in a mechanical form, under reverse microscope guide. at the end of the second week, the cultured cells were isolated by trypsin and suspended after rinsing in 200 ml pbs. then 200 ml binding buffer and 40 µl k proteinase were added and incubated in 70oc. then, 100 µl isopropanol was added and centrifuged after being transformed into filtered tube. finally, 50 µl elusion buffer was added and centrifuged. the quality of dna extraction was tested on agarose gel by absorption in 260-280 nm wavelength. methylation of dna by sss1 enzyme: to guide the methylate primers to dna, sss1 methylase enzyme (biolabs co, new england) was used according to the instructions and after treatment with sodium bisulfate (sbs), methylated primers were used for pcr. enzyme stock 32 mmol was converted to 1600 mmol and incubated at 37oc for 1.5 hours. heating up to 65oc for 20 minutes stops the reaction. then methylated dna was extracted using the kit and treated with sbs, before methylation-specific pcr (msp) with m andrology 219 figure 4. results of msp-pcr for methylation of genes: integrin α6, β1, plzf (a), c-myc, and oct-4 (b). epigenetic assessment of spermatogenic cells-zahiri et al. primer. finally, methylated dna has been used as positive control in msp with methylated primer (m). methylation-specific pcr (msp): msp was performed with two primers: m primer with methylated dna-modified sequence with sbs and, and u primer with non-methylated dna-modified sequence with sbs. proliferation with m primer showed methylation in cpg zones inside primer sequences and proliferation with u primer showed no methylation, while proliferation with both primers showed partial methylation in cpg zones inside primer sequences. in the present research, msp with methylated and non-methylated primers was performed on integrin α6, integrin β1, plzf, c-myc, and oct-4. primers are listed in table 3. statistical analysis the quantitative variables were described as the mean and standard deviation (mean± sd) and categorical variable were expressed as the frequency and percentage. the results of cell proliferation by repeated measure analyses. to analyze the data of real-time pcr, first, the raw data were changed to reportable data through available formulas and then analyzed by one-way anova. statistical analyses were conducted in spss v.16 and graphs were prepared in microsoft excel 2007 software. the difference was considered statistically if p ≤ 0.05. results the identification of colonies testicular biopsy specimens of oa patients after receiving were subjected to two stages of enzymatic digestion. in the first stage, the interstitial tissue was removed and in the second stage, the tubes were crushed and a suspension containing germ and sertoli cells was obtained. trypan blue staining of the isolated cells indicated viability of vast majority (> 90 %) of the cells. for the identification of colonies (figure 1-a, c), we detected the expression levels of oct-4 and plzf by immunocytochemistry in different groups (figure 1-b, d). the results showed that these markers were expressed in colonies after two weeks in proliferation media. sertoli cells were used as a feeder for co-culture with sscs (figure 1-e), and were identified by vimentin (figure 1-f). the results show the presence of this marker in the cytoplasm around the nucleus of sertoli cells. assessment of colonization the diameter and number of colonies in 5 culture systems were evaluated at days 7, 10 and 14. the colony count was significantly different between groups on different days; on day 7, mean colony count was higher in testicular suspension culture (30.9 ± 1.44), while it was lowest in simple culture group (6.2 ± 1.13) (p < 0.05). mean colony count was 22 ± 1.15 in self-sertoli culture, 18.4 ± 1.42 in healthy sertoli cells, and 13.4±1.49 in culture on nanofiber covered with laminin. on day 10, mean colony count was higher in testicular suspension culture (34.2 ± 1.22) (p < 0.05), while it was lowest in simple culture group (9 ± 1.7). mean colony count was 24.2±1.13 in self-sertoli culture, 20.7 ± 1.49 in healthy sertoli cells, and 13.8 ± 1.39 in culture on nanofiber covered with laminin. on day 14, mean colony count was higher in testicular suspension culture (p < 0.05), while it was lowest in simple culture group (11.7 ± 1.41). mean colony count was 27.1 ± 0.87 in self-sertoli culture, 23.3 ± 1.49 in healthy sertoli cells, and 13.9 ± 1.19 in culture on nanofiber covered with laminin. also, there was an increasing trend in suspension culture and self-sertoli cells in the consecutive days, which increased significantly on 7th, and 10th day than the third day (p < 0.05) and 14th day than 7th day, while it was not statistically significant on 14th day than 10th day (p > 0.05). in culture on nanofiber, there was a slight increase that was not statistically significant (p > 0.05). mean colony count in simple culture group also increased from the 7th and 10th day than the 3rd day and 14th day than 7th day (p < 0.05); also, the increase on 10th than 7th day, and 14th than 10th day was not statistically significant (p > 0.05) (figure 2a). the colony diameter was significantly different between groups on different days; on day 7, mean colony diameter was significantly different among testicular suspension culture (169.4 ± 4.42), culture on nanofiber (100.9 ± 4.3), simple culture group (61.5 ± 3.86) (p < 0.05). mean colony diameter was not significantly different among other groups; 149.2 ± 2.73 in self-sertoli culture, 143.1 ± 2.5 in healthy sertoli cells (p > 0.05). on day 10, mean colony diameter was significantly different among testicular suspension culture (186.6 ± 4.5), culture on nanofiber (102 ± 4.5), simple culture group (64 ± 4.7) (p < 0.05) and was highest in testicular suspension culture group (p < 0.05), while there was no statistically significant difference between self-sertoli culture (163 ± 4.3), and healthy sertoli cells (156.3 ± 6.11). on day 14, mean colony diameter was higher in testicular suspension culture (203.8 ± 7.4) than other groups (p < 0.05), while there was no statistically significant difference in colony diameter in self-sertoli (174.5±6.9) than healthy sertoli cells (167.6 ± 4.4) (p > 0.05) (fig.2 b). also, there was an increasing trend in testicular suspension culture, simple culture, and culture on nanofiber in the consecutive days (p > 0.05), while means colony diameter significantly increased in self-sertoli cells and healthy sertoli cells on each day than the previous assessment day (p < 0.05). results of quantitative pcr for integrin-α6, plzf, integrin β1, nanog, c-myc and oct-4 gene in the second week of culture, integrin α6 expression and plzf gene were significantly highest in testicular suspension cells culture (2.26 ± 0.05, 1.83 ± 0.02 respectively) and lowest in simple culture group (0.83 ± 0.04, 1.03 ± 0.002 respectively) than other groups (p < 0.05). in addition, although integrin α6 expression was significantly higher in self-sertoli culture (1.82 ± 0.06) than healthy sertoli cells (1.73 ± 0.06), this difference was not statistically significant (p > 0.05) (figure 3-a, b). integrin β1 gene expression was expressed the highest in testicular suspension cells (2.25 ± 0.04) and lowest in culture on nanofiber (0.55 ± 0.06) group (p < 0.05), but was similar self-sertoli (1.2 ± 0.01), healthy sertoli (1.2 ± 0.07), and simple culture (1.28 ± 0.02) groups without significant difference (p > 0.05) (fig. 3-c). expression of c-myc gene and nanog were highest in simple culture (0.71 ± 0.03, 1.27 ± 0.03 respectively) and lowest in testicular cells group (0.50 ± 0.02, 0.38 ± 0.08 respectively) (p < 0.05), while it was not significantly different among selfsertoli cells (0.59 ± 0.01, 0.83 ± 0.03) and healthysertoli cells (0.60 ± 0.02, 0.59 ± 0.04), and nanofiber culture (0.64 ± 0.03, epigenetic assessment of spermatogenic cells-zahiri et al. vol 18 no 2 march-april 2021 220 0.87 ± 0.03) (p > 0.05) (fig. 3-d, e). oct-4 gene expression was highest in simple culture (0.65 ± 0.04) (p < 0.05). although oct-4 gene expression in nanofiber (0.40 ± 0.02) was lower than sertoli cells groups (0.54 ± 0.04 in selfsertoli and 0.44 ± 0.03 in healtysertoli), the difference was not statistically significant (p > 0.05) (figure 3-f). results of msp the methylation pattern of integrin α6, integrin β1, plzf, c-myc, oct-4 genes were evaluated during the sscs culture using specific methylation pcr technique (msp). accordingly, msp test was performed on the treated dna of sscs after the second week with methylated and nonmethyl primers. the results with methylated primer for integrin α6, β1, and plzf gene in cells in all studied culture systems follow a similar pattern and remained negative. however, msp results for the non-methylated primer for these genes were positive in all groups. the size of the proliferation fragment for integrin α6 for methylated primers was 100 bp and for non-methylated primers 101 bp, which were 203, and 205 bp, respectively, for integrin β1 gene, and 125, and 130 bp, respectively, for plzf gene. at the end of the second week, methylation pattern did not also change in c-myc and oct-4 gene during culture and it remained in partial methylation. the size of the proliferation fragment was 140 bp for methylated and non-methylated primers in plzf gene and 105 bp for oct-4 (figure 4). discussion in this research, we were able to show that the suspension of testicular cells could increase the forming of sscs colony relative to other cultures. spermatogenesis is a process that occurs in seminiferous tubules and controls several interactions between germ cell growth and the microenvironment surrounding it. microenvironments are constituted by direct contact of the germ cells with somatic cells and acellular components that mediate proliferation and/or differentiation signaling to germ cells during spermatogenesis(3). to rescue the fertility of patients with azoospermia, experimental approaches such as ssc transplantation, testicular tissue transplantation or in vitro germ cell maturation are under intense research development. most researchers were therefore searching for structures of culture that can sustain this form of cellular interaction(15-18). one of the problems in modeling the process of spermatogenesis is that until now, a suitable culture system has been not provided for the enrichment and proliferation of sscs which could maintains nature and controlled ability of these cells. the co-culture of these cells or use of 3d scaffolds might be one way to achieve such goals(1,19) in this study, in order to establish an effective approach to human spermatogenesis in vitro, we investigated different culture systems to prolifrateand enrichment of sscs derived from oa patients. in this study, five different systems of culture were used to proliferation of sscs: simple culture system and culture of testicular cell suspension and co-culture system of sscs with donor sertoli cells, co-culture of sscs with fertile sertoli cells and culture of sscs on laminin-coated nanofibers. all systems relatively supported propagation and enrichment of sscs, but the systems of testicular, sertoli, and nano-fibers cells had more support, respectively. andrology 221 it is noteworthy that in our study, the fate of sscs was examined in a period of fourteen days and it is possible that different results will be obtained in longer cultures. another point is that in this study, only six genes have been studied. obviously, commenting on the efficiency of the selected cultural system to support cell proliferation or differentiation requires the study of a wider range of known genes and it is hoped that this will be considered in future research. our result showed significant differences in colony count among the groups with the highest values in testicular suspension, followed by self-sertoli groups, and the lowest in the control group. also, mean colony diameter was higher in testicular suspension group on day 7, and 10, compared to culture on nanofiber and simple culture but there was not significantly different among other groups; on day 14, in testicular suspension culture, the average colony diameter was higher than other groups (p < 0.05), while there was no significant statistical difference in colony diameter in self-sertoli than healthy sertoli cells (p > 0.05). although some of the p-values were statistically insignificant, these results indicate higher colony diameter in all days in testicular suspension group than other groups. gene expression of germ cell genes showed significantly highest expression of integrin α6 and plzf in testicular suspension cells and lowest in simple culture group than other groups (p < 0.05), and integrin β1 gene expression was highest in testicular suspension cells and lowest in nanofiber group, which confirmed that testicular suspension cells could effectively purify and enrich the functional human sscs. gene expression of pluripotency genes showed the lowest expression of c-myc gene and nanog in testicular suspension cells, especially during second week in all groups (p < 0.05). nevertheless, expression of oct-4 gene was not significantly different among groups (p > 0.05). the results of gene expression also showed the superiority of testicular culture. germ-cell gene expression in testicular suspension cells increased with time, while pluripotency gene expression decreased by time. different researchers have used various culture systems and have evaluated expression of various genes. mirzapour and colleagues reported the largest number of colonies in the control group and the largest colony diameter in the presence of basic fibroblast growth factor (bfgf) and human leukemia inhibitory factor (lif) on human sertoli cells and positive sscs markers, such as oct4, stra8, piwil2, and vasa, but negative for nanog. they have suggested this technique efficient for human ssc colonization(20). other researchers have likewise suggested the favorable role of growth factors on human ssc culture(21), which could justify the results of the present study, indicating lower colonization in the control group (simple culture). gfr-α1 (gdnf receptor) regulates sscs niches and spermatogenesis maintenance through map kinase, nf-kb and ikb signal pathways(22). the findings of the current study, in line with the above-mentioned studies, confirm that gdnf supplies the necessary items for growth and maintenance of human sscs in medium. moreover, we found that pluripotency gene expression did not improve under the experimented culture conditions, while germ-cell gene expression increased. in addition, sscs characteristics did not change and cells were not differentiated that shows the stability of this epigenetic assessment of spermatogenic cells-zahiri et al. vol 18 no 2 march-april 2021 222 culture technique, which could be due to the protective effect of gdnf against differentiation(23). besides the addition of other growth factors (e.g., egf, fgf, lif), feeder layer (such as vero cells, mouse fetal fibroblasts (mef), and leydig and sertoli cells) has also been identified as an important factor on human sscs cultures(24). according to the results of this study, the sscs / sertoli cells co-culture was better compared to the control group. for normal spermatogenesis, direct cell-cell interaction between the germ cell and feeder cell is important, and this relationship is not present in the monocultures of germ cell. germ cell monocultures reduce survival and proliferation compared with co-culture of germ-feeder cells. few studies have addressed the efficacy of co-culture with sertoli cells. jabbari and colleagues used a soft agar system to amplify human sscs by co-culturing with sertoli cells. they concluded that the system reduces apoptosis and increases the proliferation of human sscs(25). koruji et al. reported increasing the diameter and number of human ssc colonies by co-culturing sscs with sertoli cells(26). in short-term co-culture with sertoli cells, tajik et al examined the effects of gnrh analog on ssc colonization(27). bahadorani et al demonstrated a shortterm feeder-free culture of ssc for only one week in goat(28) which is consistent with the current study findings. pramod and abhijit(29) and others(20) the presence of stable colonies without any differentiation has been confirmed. this suggests that the long-term use of sertoli cells as feeders may be appropriate for the spread of goat sscs. nowroozi et al. obtained biopsy samples from 47 infertile patients who had noa and grown in single-layer sertoli cells. the size and number of colonies were assessed on days 8, 13 and 18. they observed that the process of differentiation and maturation of sscs was stopped by increasing the colony size(30). other groups used 2d testicular monoand co-cultures to show the required interaction between sertoli and peritubular cells in the regulation of ecm expression as well as the testicular cell reorganization capabilities in vitro. other groups used 2d testicular monoand co-cultures to demonstrate the mutual interaction between sertoli and the peritubular cells in regulating expression of ecm components and ability to reconstruct testicular cells in vitro(31,32). by inhibition caused by cell proliferation, the proliferation of sertoli cells is reduced and fsh can restore this effect(33). the superiority of co-culture with sertoli cells in the present study is justifiable through gdnf-secreting sertoli cells acting as sscs renewal regulator. because sertoli cells derived from donor patient is homologous with human sscs therefore it might be most suitable for culturing human sscs and establishes a foundational feeder layer for the short-term goal of stable human sscs cultures. the use of 3d culture on nanofiber in the present study showed the superiority of this method than simple culture, regarding colony count and germ-cell specific gene expression. the three-dimensional culture, with the aid of the ecm, enables cells to organize properly and imitate spermatogonial epithelium. various ecm has been used in three-dimensional cultures, like soft agar(34), and collagen gel matrix. poly l-lactic acid (plla), used in the present study, has been previousepigenetic assessment of spermatogenic cells-zahiri et al. ly used for other stem cells and has recently been used in human sscs as one of the most promising biodegradable and biocompatible polymers approved by the us food and drug administration agency which can form a three-dimensional non-woven network easily by electrospinning(1). eslahi et al. (2013) compared frozen-thawed sscs seeded onto plla with the control groups (with no seeding on plla) and suggested the colony formation of human sscs in the culture system can be increased by the plla, but may cause them to differentiate during cultivation(1) . sadri-ardakani et al. succeed to reproduce a large number of human testicle spermatogonia cells in the presence of 34-stempro medium. sscs cells were able to hold germ cells for 28 weeks and 15 passages in the lab using laminin-plated dishes. it was observed that is induced the process of differentiation by placing sscs on laminin(35,36). lim et al. documented the proliferation of isolated sscs from obstructive and non-obstructive patients in the presence of growth factors such as gdnf, lif, egf and fgf on laminin-coated plates (37). koruji et al. used laminin-ecm-coated dishes with gdnf, egf, lif, and bfgf supplements to improve the human culture sscs culture results(36). in this study, which is consistent with the findings of the above-mentioned studies, we successfully used 3d nanofiber culture with laminin surface. some procedures, including cellular isolation and cultivation, can affect the ssc's integrity. the genome, epigenum, or both can alter in manipulated cells. reports show that genetic stability exists in other populations of stem cells during in vitro culture. since ssc is the cells that convey genetic information to the next generation, ssc's genetic stability is more important than somatic cells. shinohara and colleagues showed that in vitro culture of mouse spermatogonia for more than 24 months was associated with karyotype and imprinting stability. the recipient mice's offspring were fertile and also had a typical imprinting pattern. however, the genetic and epigenetic changes of human ssc cultivated have not yet been determined. in agreement with other culture reports(21,38), and epigenetic studies showed the testicular cell suspension group as the best group, this group is regarded the most similar to testes’ micro-environment. the results of our on other culture groups, such as sertoli and nanofiber, which kept the nature of human sscs also confirms the importance of presence of ecm, micro-environment, and their signaling. conclusions despite the scientific development in stem cells, human ssc culture is still a controversial issue. although our study has significant limitations due to the combined use of two-dimensional in vitro culture system, our results indicate that co-culture of human sscs with testicular cells improved the germ cell ratio in vitro and could maintain a cell-specific genetic and epigenetic content. thus, the results indicate the ability of proliferation of functional cells in suspension culture. however, further research is necessary for the evaluation of long-term human sscs proliferation in vitro models. recent reports have examined 3d in-vitro systems as an alternative to this study's 2d in-vitro culture model, which can mimic the natural niche of the sscs and pave the way for in vitro spermatogenesis. testicular cell culture in three-dimensional systems could be used as an alternative way of restoring infertile patients' fertility. the results of the present study can dynamically add to the knowledge of researchers and clinicians and be an important step towards future clinical use for male infertility. acknowledgement the authors would like to thank the shayan-mehr clinic (tehran-iran) for their cooperation throughout the period of study. conflict on interest authors declare that there are no financial or conflict of interest exist. references 1. eslahi n, hadjighassem mr, joghataei mt, et al. the effects of poly l-lactic acid nanofiber scaffold on mouse spermatogonial stem cell culture. int. j. nanomedicine. 2013;8:4563. 2. sadri-ardekani h, mizrak sc, van daalen sk, et al. propagation of human spermatogonial stem cells in vitro. jama. 2009;302:2127-34. 3. jones dl, wagers aj. no place like home: anatomy and function of the stem cell niche. nat. rev. mol. cell biol. 2008;9:11. 4. yoshida s, sukeno m, nabeshima y-i. a vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. science. 2007;317:1722-6. 5. oatley jm, brinster rl. the germline stem cell niche unit in mammalian testes. physiol. rev. 2012;92:577-95. 6. fayomi ap, orwig ke. spermatogonial stem cells and spermatogenesis in mice, monkeys and men. stem cell res. 2018;29:207-14. 7. sun m, yuan q, niu m, et al. efficient generation of functional haploid spermatids from human germline stem cells by threedimensional-induced system. cell death differ. 2018;25:747. 8. hunter d, anand-ivell r, danner s, ivell r. models of in vitro spermatogenesis. spermatogenesis. 2012;2:32-43. 9. riboldi m, rubio c, pellicer a, gil-salom m, simón c. in vitro production of haploid cells after coculture of cd49f+ with sertoli cells from testicular sperm extraction in nonobstructive azoospermic patients. fertil. steril. 2012;98:580-90. 10.oliver e, stukenborg jb. rebuilding the human testis in vitro. andrology. 2020 jul;8:825-34. 11. nagano mc. techniques for culturing spermatogonial stem cells continue to improve. biol. reprod. 2011;84:5-6. 12. stukenborg j-b, schlatt s, simoni m, et al. new horizons for in vitro spermatogenesis? an update on novel three-dimensional culture systems as tools for meiotic and post-meiotic differentiation of testicular germ cellsmol. hum. reprod. 2009;15:521-9. 13. lee j-h, gye mc, choi kw, et al. in vitro differentiation of germ cells from nonobstructive azoospermic patients using three-dimensional culture in a collagen gel matrix. fertil. steril. 2007;87:824-33. 14. sun m, yuan q, niu m, et al. efficient generation of functional haploid spermatids from human germline stem cells by threedimensional-induced system. cell death differ. 2018;25:749-66. 15. galdon g, atala a, sadri-ardekani h. in vitro spermatogenesis: how far from clinical application? curr. urol. rep. 2016;17:49. 16. giudice mg, de michele f, poels j, vermeulen m, wyns c. update on fertility restoration from prepubertal spermatogonial stem cells: how far are we from clinical practice? stem cell res. 2017;21:171-7. 17. shams a, eslahi n, movahedin m, izadyar f, asgari h, koruji m. future of spermatogonial stem cell culture: application of nanofiber scaffolds. curr stem cell res t. 2017;12:544-53. 18. von kopylow k, schulze w, salzbrunn a, et al. dynamics, ultrastructure and gene expression of human in vitro organized testis cells from testicular sperm extraction biopsies. mol hum reprod. 2018;24:123-34. 19. ganjibakhsh m, mehraein f, koruji m, aflatoonian r, farzaneh p. three-dimensional decellularized amnion membrane scaffold as a novel tool for cancer research; cell behavior, drug resistance and cancer stem cell content. mater. sci. eng. c. 2019;100:330-40. 20. liu s, tang z, xiong t, tang w. isolation and characterization of human spermatogonial stem cells. reprod. biol. endocrinol. 2011;9:1. 21. kanatsu-shinohara m, ogonuki n, inoue k, et al. long-term proliferation in culture and germline transmission of mouse male germline stem cells. biol. reprod. 2003;69:612-6. 22. huleihel m, fadlon e, abuelhija a, haber ep, lunenfeld e. glial cell line-derived neurotrophic factor (gdnf) induced migration of spermatogonial cells in vitro via mek and nf-kb pathways. differentiation. 2013;86:38-47. 23. sada a, hasegawa k, pin ph, saga y. nanos2 acts downstream of glial cell line‐derived neurotrophic factor signaling to suppress differentiation of spermatogonial stem cells. stem cells. 2012;30:280-91. 24. tournaye h, dohle gr, barratt cl. fertility preservation in men with cancer. lancet. 2014;384:1295-301. 25. jabari a, gilani mas, koruji m, et al. three-dimensional co-culture of human spermatogonial stem cells with sertoli cells in soft agar culture system supplemented by growth factors and laminin. acta histochem. 2020;122:151572. 26. koruji m, movahedin m, mowla s, gourabi h, arfaee a. efficiency of adult mouse spermatogonial stem cell colony formation under several culture conditions. in vitro cell. dev. biol. anim. 2009;45:281. 27. tajik p, kohsari h, qasemi-panahi b, sohrabihaghdoost i, barin a, ghasemzadeh-nava h. effects of gonadotropin releasing hormone (gnrh) on bovine spermatogonial stem cell epigenetic assessment of spermatogenic cells-zahiri et al. andrology 223 vol 18 no 2 march-april 2021 224 proliferationatogonial stem cells proliferation. ijvst. 2015;6:11-20. 28. bahadorani m, hosseini s, abedi p, et al. short-term in-vitro culture of goat enriched spermatogonial stem cells using different serum concentrations. j. assist. reprod. genet. 2012;29:39-46. 29. pramod rk, mitra a. in vitro culture and characterization of spermatogonial stem cells on sertoli cell feeder layer in goat (capra hircus). j. assist. reprod. genet. 2014;31:9931001. 30. nowroozi mr, ahmadi h, rafiian s, mirzapour t, movahedin m. in vitro colonization of human spermatogonia stem cells: effect of patient's clinical characteristics and testicular histologic findings. urology. 2011;78:1075-81. 31. richardson ll, kleinman hk, dym m. basement membrane gene expression by sertoli and peritubular myoid cells in vitro in the rat. biol. reprod. 1995;52:320-30. 32. mincheva m, sandhowe-klaverkamp r, wistuba j, et al. reassembly of adult human testicular cells: can testis cord-like structures be created in vitro? mol hum reprod. 2017;24:55-63. 33. schlatt s, de kretser dm, loveland kl. discriminative analysis of rat sertoli and peritubular cells and their proliferation in vitro: evidence for follicle-stimulating hormonemediated contact inhibition of sertoli cell mitosis. biol. reprod. 1996;55:227-35. 34. stukenborg jb, wistuba j, luetjens cm, et al. coculture of spermatogonia with somatic cells in a novel three‐dimensional soft‐agar‐ culture‐system. j. androl. 2008;29:312-29. 35. delgado-rivera r, harris sl, ahmed i, et al. increased fgf-2 secretion and ability to support neurite outgrowth by astrocytes cultured on polyamide nanofibrillar matrices. matrix biol. 2009;28:137-47. 36. koruji m, shahverdi a, janan a, piryaei a, lakpour mr, sedighi mag. proliferation of small number of human spermatogonial stem cells obtained from azoospermic patients. j. assist. reprod. genet. 2012;29:957-67. 37. lim j, sung sy, kim h, et al. long‐term proliferation and characterization of human spermatogonial stem cells obtained from obstructive and non‐obstructive azoospermia under exogenous feeder‐free culture conditions. cell prolif. 2010;43:405-17. 38. chikhovskaya j, jonker m, meissner a, breit t, repping s, van pelt a. human testis-derived embryonic stem cell-like cells are not pluripotent, but possess potential of mesenchymal progenitors. hum. reprod. 2011;27:210-21. epigenetic assessment of spermatogenic cells-zahiri et al. reconstructive surgery efficacy of using non-tunneled dialysis catheters during arteriovenous fistula till its maturation: a retrospective study gholamhossein kazemzadeh1, maziar bazrafshan1*, mohammad mahdi kamyar1, adeleh hashemi fard1 purpose: due to high prevalence of diabetes mellitus and subsequent nephropathy, the need for access to start and continue dialysis has been increased. in this study, we aim to study the efficacy and complications of non-tunneled catheters (ntc) till fistula maturation because of being easy and cheap implementation as well as similar complications compared to tunneled catheters (tc). materials and methods: in this retrospective observational study, 247 patients with first-time avf creation referred to vascular surgery centre of mashhad university of medical sciences, iran, were recruited since march 2016 to december 2017. only 153 patients who have completed the study, and were monitored every two weeks in case of un-maturation along with the status of temporary catheters. results: mean age of patients was 49.9 ± 7.74 years, and 75 (49%) were females, which was comparable with literature. preference of ntc implementation was at right jugular because of the easy access to central vein and less chance of complications. catheter location was at right internal jugular in 61.4% of the patients. out of 24 femoral cases, 18 was done at femoral. avf location was done at left/right cubital in most cases (52.3%). the rate of infection was 15.0%, which was less than ntc’s infections reported in the literature. conclusion: use of non-tunneled catheter in the form of outpatient in the period of avf maturation time is recommended due to similar complication rate. keywords: avf; catheter; ckd; dialysis; esrd introduction chronic kidney disease (ckd) and end-stage renal disease (esrd) are increasingly common diagnoses as the population age and the incidence of diabetes rise. data from the united states renal data system (usrds) showed that 117,162 new patients began therapy for esrd in 2015, whereas the prevalent dialysis population reached 661,648(1). central venous catheters play an important role in the treatment of patients with end-stage renal disease. despite initiatives to improve fistula creation, more than 80% of patients initiated hemodialysis with a catheter(2). hemodialysis catheters can be categorized into two groups: non-tunneled catheters (ntc) and tunneled (or cuffed) (tc). non-tunneled catheters have been modified significantly over time. there are conflicting reports on what a safe duration for the use of these catheters is, and recommendations vary from one to few weeks. for example, the national kidney foundation (nkf) recommends <1 week as a safe duration and never advised to be >3 weeks. however, there are reports from certain parts of the world of much longer use and indeed using them for long-term dialysis as well(3). ntc should be placed only in hospitalized patients and used for a short duration, usually less than 4 weeks(4). the potential complications related to placement of ntc are similar to tc. however, because of short duration of tc usage, long-term complications are less vascular and endovascular surgery research center, mashhad university of medical sciences, mashhad, iran. *correspondence: vascular and endovascular surgery research center, mashhad university of medical sciences, mashhad, iran. postal code: 91738-56693. fax: (98) 51 3851 3258. phone: +985118525311. e-mail: bazrafshanm951@mums.ac.ir. received january 2019 & accepted july 2019 frequent but infectious complications are more common. some complications of the catheters are: arterial puncture, venous laceration/perforation, myocardial injury, and the associated hemorrhage and hematoma (5% of patients). the risk of above complications seems to be similar between ntc and tc(5). cardiac arrhythmias are potentially serious complications of all central venous catheter insertions(6). air embolism is a rare but fatal complication. this is often observed in situations associated with difficulty in placing the catheter through the peel-away sheath and usually occurs in the interval between the removal of the dilators and the peeling away of the sheath. therefore, this seems to be seen more frequently in ntc(7). central venous stenosis usually occur after long-term placement of catheters specially in subclavian vein, duration of dialysis and number of catheter replacement(8-10). pneumothorax and hemothorax are developed after catheter insertion and are seen more often in subclavian placement (11,12). kinking or acute bends in the catheter were common in the past with catheters made with stiffer materials (13). infection is the most common complication of catheterization and observed more frequently in ntc than tc. treatment is usually initiated with empiric antibiotics and some suggest that ntc should be removed immediately if there is catheter related blood-stream infection (14-17). in overall, other complications than infection is less common in ntc compared to tc. however, the folurology journal/vol 16 no. 6/ november-december2019/ pp. 578-580. [doi: 10.22037/uj.v0i0.5120] vol 16 no 06 november-december2019 579 lowing should be added to difficulty of using tc: time of operation that sometimes needs to sedation, need for fluoroscope for proper insertion, and the total cost. this study aims to survey patients with avf creation and simultaneously need dialysis, or because of need to urgency dialysis, ntc is inserted and they have been referred for avf creation. we used ntc at this time until avf maturation and analyzed the results. in this paper, we would like to assess using ntc over tc due to easy implementation and easy management procedure till fistula maturation. we aim to show the superiority of ntc over tc due to less complications. materials and methods in this retrospective observational study, 247 patients with first time avf creation referred to vascular surgery centre of mashhad university of medical sciences, iran, from march 2016 to december 2017 were recruited. only 153 patients have been monitored routinely for a duration of 6-month since avf creation. clinical characteristics were measured at baseline, oneweek after surgery, three-week after surgery and 5-6 weeks after surgery. the patients were monitored every two weeks in case of un-maturation. the status of temporary catheters were checked at various time points. the patients and dialysis centers have been trained of needed actions to be taken to send the patients to emergency unit in case of infection symptoms or issues with catheters functioning. the placement of avf in forearm or antecubital, and etiology of esrd had no effect on the study. therefore, patients who had catheter before avf creation were also included in the study. exclusion criteria were: history of neck surgery or neck radiotherapy, history of anticoagulant consumption, history of previous avf, age under 14 years, history of pulmonary and mediastinal pathology, presence of remote infection, history of steroid and immunosuppressive medications, issues with catheters functioning and un-maturation of ivf, patients’ preference for tunneled cuff catheter, and death or immigration. routine approaches including appropriate filter, proper length and speed of the dialysis and patient’s general health were used to have a successful dialysis while using ntc instead of kt/v(18). data analysis was performed using ibm spss statistics for windows version 24 (armonk, ny: ibm corp). clinical characteristics were reported as mean ± standard deviation and frequency (percentage) for continuous and categorical variables, respectively. results after one year from recruitment, 153 patients have completed the study. mean age of patients was 49.9 ± 7.74 years, and 75 (49%) were females, which was comparable with the reported numbers in literature as the age in our paper was reported at the start date of dialysis. catheter location determination was right internal jugular and left internal jugular based on priority, and if it was not successful, left/right subclavian or left/ right femoral were considered. catheter location was at right internal jugular in 61.4% of the patients. out of 24 femoral cases, 18 were done at femoral because temporary catheter placement was not possible at left/ right jugular. avf location was done at left/right cubital in most cases (52.3%). however, preference of avf location was at either snuff box or forearm if there was potential arterial and venous at either locations. about fifty percent of patients had dm, most of avf was in left upper extremity, and average time to maturation was 57 days. the rate of infection was 5.03% (table 1). discusion one of the ways to do hemodialysis is catheter insertion either tc or ntc. as mentioned, it seems that the risk of complication is more in the tc due to longer use of catheter, however the infection rate is higher in ntc. in this study, incidence of infection was 23 cases (15.0%). this result is greater in comparison to other studies in tc context (infection rate for tc: 13.6 %)(19), but the change was not significant in period of maturation time. however, it seems that the risk of infection would increase if a longer period of catheter is used. although the lower incidence of infection (compared to another study regarding ntc (32.6%)(19)) may be due to use of aseptic field and procedure in operation room, catheter care instructions at dialysis center and better homecare could be other reasons. total number of catheter change was 63 (41.18%) that interestingly is below 50% of replacement due to catheter infection. other reasons included: dysfunction, catheter base fracture due to change of neck position, catheter spontaneous coming out; and 2 cases for intentional catheter removal because of psychological attacks. the symptoms for diagnosis of infection were fever and chill in dialysis time and puss discharge from tc exit site. unlike tc, we did not rule out other etiology for fever in ntc, and only fever started after dialysis onset was considered as catheter related infection and catheter replacement was done. after replacement, fever recovered in all cases without need to prescribe antibiotics. this result can confirm the accuracy of our approach in ntc insertion efficiency to some extent. other important complication of catheter insertion is central vein (brachiocephalic and superior vena cava) stenosis. after developing of stenosis of near to total occlusion, the symptoms begin to appear. the most common symptoms are limb and neck swelling, and arm, shoulder and chest wall collateral veins become prominent. this is confirmed by venography. the incidence of symptomatic central vein stenosis was 2.6% (4 cases), in whom the catheter insertion duration was over table 1. baseline demographics and clinical features (n=153) variable mean ± sd / frequency (%) age (year) 49.9 ± 7.74 gender male 78 (50.98) female 75 (49.02) diabetes 77 (50.33) catheter site right jugular 94 (61.44) left jugular 29 (18.59) right femoral 18 (11.76) left femoral 6 (3.92) right subclavian 2 (1.31) left subclavian 4 (2.61) catheter replacement 63 (41.18) maturation time (day) 64 ± 15.2 avf site left snuff box 46 (30.06) left forearm 19 (12.41) left antecubital 67 (43.79) right snuff box 8 (5.22) right forearm 1 (0.6) right antecubital 13 (8.49) catheter infection 23 (15.03) non-tunneled dialysis catheters during arteriovenous-kazemzadeh et al. 80 days in all four cases. this incidence of central vein stenosis was less (4.3%) compared to another study(20). the reason can be shorter duration of ntc used compared to tc, insertion of ntc in internal jugular vein as first choice and lesser ntc diameter than tc. also, the incidence of 4.3% in other study is the result of all central vein accesses insertion, such as picc, which may be inserted from subclavian vein. the cost of tc is far more expensive than ntc. also because of using ultrasound for catheter insertion and distal jugular vein insertion, no complications such as pneumothorax are found. average time for avf maturation in our study was 54.3 days, and we had maximum of two catheter replacements without pneumothorax or hemothorax over this time period. a limitation of this retrospective study is the lack of a comparison group where the efficacy of ntc could be compared with alternative approaches. hence, more investigation for this matter is needed using prospective studies. conclusions in our practice, use of ntc for temporary dialysis until the maturation of the avf has not been accompanied by significant major complications. if there are available possibilities such as ultrasound in operation room, employment of complete aseptic field when inserting a catheter and proper training for dialysis centers and patients for catheter maintenance, we recommend that ntc is used over tc in period of avf maturation time. also, we recommend that right internal jugular vein is considered as a catheter insertion site. conflict of interest the authors report no conflict of interest. references 1. sidawy ap, preler ba. rutherford’s vascular surgery and endovascular therapy, vol 2, 9th edition. elsevier; 2018. p. 175-2288 2. u.s. renal data system: usrds 2011 annual data report: atlas of end-stage renal disease in the united states. bethesda, md: national institutes of health, national institute of diabetes and digestive and kidney diseases; 2011. available at: http://www. usrds.org/ 2011/view/default.asp. accessed april 2, 2012 3. national kidney foundation k/doqi clinical practice guidelines for vascular access: update 2000.am j kidney dis.2001;37:s137-s181. available at: http://www.kidney.org/ professionals/kdoqi/guideline_uphd_pd_ va/index.htm. accessed april 2, 2012. 4. vascular access 2006 work group. clinical practice guidelines for vascular access. am j kidney dis. 2006; 48:s176–s273. 5. vats hs. complications of catheters: tunneled and non-tunneled. adv chronic kidney dis. 2012;19:188-194. 6. fiaccadori e, gonzi g, zambrelli p, tortorella g. cardiac arrhythmias during central venous catheter procedures in acute renal failure: a prospective study. j am soc nephrol. 1996;7:1079-84. 7. bessereau j, genotelle n, chabbaut c, et al. long-term outcome of iatrogenic gas embolism. intensive care med. 2010; 36:1180-7 8. levit rd, cohen rm, kwak a, et al. asymptomatic central venous stenosis in hemodialysis patients. radiology. 2006;238:1051-6. 9. khwaja a. kdigo clinical practice guidelines for acute kidney injury. nephron clin pract. 2012;120:c179-c184. 10. barrett n, spencer s, mclvor j, brown ea. subclavian stenosis: a major complication of subclavian dialysis catheters. nephrol dial transplant. 1988; 3:423–5 11. borja ar. current status of infra-clavicular subclavian vein catheterization: review of the english literature. ann thorac surg. 1972;13:615-24 12. farrell j, walshe j, gellens m, martin kj. complications associated with insertion of jugular venous catheters for hemodialysis: the value of post procedural radiograph. am j kidney dis. 1997; 30:690-2. 13. from division of nephrology, department of medicine, university of wisconsin school of medicine and public health, madison, wi. advances in chronic kidney disease, vol 19, no 3 (may), 2012: pp 188-194 14. chan mr. hemodialysis central venous catheter dysfunction. semin dial. 2008;21:51621. 15. maya id. antibiotic lock for treatment of tunneled hemodialysis catheter bacteremia. semin dial. 2008; 21:539-41. 16. lok ce,mokrzycki mh. prevention and management of catheter-related infection in hemodialysis patients. kidney int. 2011; 79:587-98. 17. oliver mj, callery sm, thorpe ke, schwab sj, churchill dn. risk of bacteremia from temporary hemodialysis catheters by site of insertion and duration of use: a prospective study. kidney int. 2000;58:2543-45. 18. barzegar h, moosazadeh m, jafari h, esmaeili r. evaluation of dialysis adequacy in hemodialysis patients: a systematic review. urol j. 2016; 13(4):2744-9. 19. stevenson kb, hannah el, lowder ca, adcox mj, davidson rl, mallea mc, et al. epidemiology of hemodialysis vascular access infections from longitudinal infection surveillance data. am j kidney dis. 2002;39:549-55. 20. lee ay, levine mn, butler g, webb c, costantini l, gu c, et al, incidence, risk factors, and outcomes of catheter-related thrombosis in adult patients with cancer. j clin oncol. 2006;24:1404-8. non-tunneled dialysis catheters during arteriovenous-kazemzadeh et al. reconstructive surgery 580 urological oncology genetic polymorphism of mismatch repair genes and susceptibility to prostate cancer paniz khooshemehri 1#, seyed hamid jamaldini1, 2 #, seyed amir mohsen ziaei3, mahdi afshari 4, mahshid sattari1, behzad narouie 5, mehdi sotoudeh 3, vahideh montazeri6, negar sarhangi 2, mandana hasanzad1,2* purpose: mismatch repair (mmr) is one of the dna repair systems that correct mispaired bases during dna replication errors. polymorphisms in genes can increase susceptibility to the development of prostate cancer (pca). in this study, we investigated mutl homolog 1 (mlh93(1g>a (rs1800734) and muts homolog 3 (msh3) (rs26279) polymorphisms with the risk of pca. materials and methods: in this study of iranian population, 175 histopathologically confirmed (pca) patients and 230 benign prostate hyperplasia (bph) as the controls were recruited. the genotypes of mlh1 and msh3 were determined by polymerase chain reaction and restriction fragment length polymorphism (pcr-rflp) method. results: there was no significant difference of mlh1 (p = 0.4) and msh3 (p = 0.5) genotype distributions among pca cases and controls. and also patients with pca were not significant differences compared to those without in stage of cancer, grade of tumor, perineural invasion, and vascular invasion. conclusion: our results did not show adequate evidence for any significant association of mlh1 and msh3 polymorphisms and pca . keywords: prostate cancer; msh3; mlh1; polymorphism; pcr-rflp. introduction prostate cancer (pca) is the most commonly diag-nosed malignancy among aging males after skin cancer and is the sixth leading cancer resulting in mortality in males (1). although the reason of pca is still unclear, epidemiological studies have suggested that it is a multifactorial disease with a genetic basis(2). there are a number of studies being carried out to identify biomarkers in patients with high risk of adverse pca outcomes(3). dna repair systems reduce any risks conferred by mutations from risk factors, including etiologic and environmental leading to exit somatic mutations that may be important for initiation of late onset diseases(4). a highly conserved mismatch repair (mmr) functions to boost replication accuracy by correcting and deleting base pair mismatch during dna replication(5). the mmr system consists of seven mismatch repair genes, including msh2, msh3, msh6, mlh1, pms1, pms2, and mlh3. the heterodimers which are 1 medical genomics research center, tehran medical sciences, islamic azad university, tehran, iran. 2 personalized medicine research center, endocrinology and metabolism clinical sciences institute, tehran university of medical sciences, tehran, iran. 3urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 4department of community medicine, zabol university of medical sciences, zabol, iran. 5 department of urology, zahedan university of medical sciences, zahedan, iran. 6 department of toxicology and pharmacology, faculty of pharmacy, tehran university of medical science, tehran, iran. # both authors share the first authorship in this paper *correspondence: medical genomics research center, tehran medical sciences, islamic azad university, tehran, iran. postal code: 1916893813. tel: +98-21-22008065. fax: +98-21-22600714. email: mandanahasanzad@yahoo.com. received january 2019 & accepted december 2019 formed by msh2-msh6 (mutsα) and msh2-msh3 (mutsß) mismatch repair complexes identify mispaired bases. the function of mutsα complex is to investigate and repair the base-base and insertion/deletion (i/d) mispairs. mutsα is also likely to be associated with another heterodimer of mlh1 and pms2 (mutlα) (6). defects in this mmr pathway result in a considerable rate of mutation or genetic instability, which in turn leads to variation in genes that regulate cell proliferation and death(7). numerous mutations and polymorphisms have been distinguished in mmr genes(8). genetic polymorphisms of mutl homolog 1 (mlh1) have a detrimental effect on the mmr capacity and cancer risk. the mlh1 gene, which is located on chromosome 3p contains 19 exons and it is shown to cover a region of up to 100 kilo bases (kb)(9). the mlh1 -93g>a (rs1800734) polymorphism is closely linked to several cancers, including tobacco-related oral carcinoma, colorectal, and lung cancer (10-12). the muts homolog 3 (msh3) protein acts as one of the important compourology journal/vol 17 no. 3/ may-june 2020/ pp. 271-275. [doi: 10.22037/uj.v0i0.5051] nents of the mismatch repair system, which is encoded by the msh3 gene and located on chromosome 5q in humans. it possesses 1137 amino acid residues with the molecular mass of approximately 128 kilodaltons (kda) (13). currently, scientists have reported at least 180 single nucleotide polymorphisms (snps) in msh3 gene. among all of these snps, rs26279 g>a polymorphism is frequently investigated and has been recently thought to be carcinogenic. some studies showed that this polymorphism is associated with the risk of different types of cancer, including breast cancer, colorectal cancer, bladder cancer, pca and ovarian cancer (14-18). considering the importance of mlh1 and msh3 in the carcinogenic process, several case-control studies have been patients in patients in order to investigate the possible correlation between mentioned two polymorphisms and the risk of pca. methods sample collection this case-control study consisted of 175 patients with pca and 230 controls with benign prostatic hyperplasia (bph). the patients were selected between february 2010 and april 2015 from the department of urology of shahid labbafinejad medical center, tehran, iran. written informed consent was obtained from all of the participants and details of the consent form was approved by the ethics committee. demographic and clinical data were collected, including age, body mass index (bmi), history of pca in 1st-degree relatives, blood group, total and free prostate-specific antigen (psa) level, staging and grading by questioners. open laparoscopic or radical prostatectomy was used to determine the tumor stage, grade, vascular and perineural invasion. tumor stage and tumor grade were determined by tnm staging (pathologic tumor stage, nodal invasion, metastasis) and the gleason scoring (gs >7, gs ≤ 7) system, respectively (19,20). the control group with bph had to fulfill the following inclusion criteria for decreasing the likelihood of misdiagnosed prostate cancer: 1) either serum psa < 4.0 ng/ml or pathological reports of no malignancy of transrectral ultrasound-guided prostate biopsy if there was a serum psa > 4.0 ng/ ml. 2) normal digital rectal examination. 3) negative pathological report of malignancy in resected prostatic tissues from open surgical prostatectomy. the exclusion criteria for patients with pca were a family history of pca in the control group, consuming any psa decreasing medication, hormone therapy, orchiectomy and non-adenocarcinoma of the prostate. dna extraction and genetic analysis peripheral blood samples from bph and pca were collected before surgery in a tube containing edta, and dna extraction was performed by using dngtm plus dna extraction kit (cinnagen, iran) and maintained at +4°c. the rs1800734 polymorphism of mlh1 and rs26279 polymorphism of msh3 genes was determined using polymerase chain reaction and restriction fragment length polymorphism (pcr-rflp) methods. pcr was performed in a total 50µl reaction volume mlh1 and msh3 in prostate cancer-khooshemehri et al. table 1. demographic and behavioral characteristics of cases and controls factor prostate cancer healthy individuals p-value smoking status no no (%) 71 (57.72) 108 (81.82) < 0.0001 yes no (%) 52 (42.28) 24 (18.18) having 3 or more sons older than 40 ≤ 2 no (%) 72 (98.63) 103 (94.50) 0.1 >2 no (%) 1 (1.37) 6 (5.5) history of marriage no no (%) 2 (1.94) 0 0.2 yes no (%) 101 (98.06) 130 (100) family history no no (%) 93 (87.74) 125 (98.43) 0.001 yes no (%) 13 (12.26) 2 (1.57) age mean (sd) 62.38 (7.59) 70 (8.64) 0.0001 bmi mean (sd) 24.87(2.88) 24.74(3) 0.6 gene (polymorphism) genotypes cases no (%) controls no (%) p-value crude or(95% ci) adjustedor(95% ci) aa 29 (16.76) 29 (12.61) 1 mlh1 (rs 1800734) ag 83 (47.98) 122 (53.04) 0.4 0.68 (0.38-1.22) 0.71 (0.30-1.72) gg 61 (35.26) 79 (34.35) 0.77 (0.42-1.43) 0.69 (0.28-1.68) msh3 (rs26279) aa 82 (47.40) 99 (43.04) 1 ag 81 (46.82) 112 (48.70) 0.5 0.87 (0.58-1.31) 0.71 (0.36-1.38) gg 10 (5.78) 19 (8.26) 0.63 (0.28-1.44) 0.24 (0.06-0.97) mlh1, mutl homolog 1; msh3, muts homolog 3 table 2. crude and adjusted associations between different polymorphisms and prostate cancer. urological oncology 272 vol 17 no 03 may-june 2020 273 containing 2mm mgcl2, 25 mm kcl, 5 mm trishcl (ph 8.4), 0.23 mm each of deoxyribonucleotide triphosphate (dntp), and 1 unit of taq polymerase. the primers used for amplification of mlh1 were forward 5’ ttt cag ctt tca ggc aca gtt – 3' and reverse primer 5’ cct tcc agc tct ttt gac tt – 3’. the polymorphic site of the msh3 gene was amplified by the use of each primer: forward primer, 5’ ttt cag ctt tca ggc aca gtt – 3’, and reverse primer, 5́ cct tcc agc tct ttt gac tt – 3'. the cycling condition for mlh1 and msh3 were 95°c for 5min of one cycle; 95°c for 1 min ,58°c (mlh1) and 55°c (msh3) for 1min and 72°c for 1min for 35 cycles and final elongation cycle of 72°c for 5min. after pcr, rflp method was used for mlh1 and msh3 with pvuii and hhai restriction enzymes, respectively (thermo v scientific), and pcr products were digested at 37°c for 16 hr. the three genotypes were identified according to their size for both genes: mlh1 aa (373bp), gg (285+88bp), and ag (373+285+88bp), msh3 aa (200bp), gg (151+49bp) and ag (200+151+49bp). statistical analysis categorical variables were compared between cases and controls using chi-square test. the comparison of continues variables was conducted by mann–whitney u test and independent t-test. crude and adjusted (adjusted for age, family history of pca and smoking status) logistic regression models were used to investigate the association between genotypes and pca. all data analyses were performed using stata ver.11 software. p-value less than 0.05 were considered statistically significant. results totally 405 subjects were recruited in the study, including 230 (56.79%) healthy subjects and 175 (43.21) patients suffering from pca. mean (sd) age of them was 66.57 (9.01) years. frequencies of smoking habit (42.28% vs. 18.18% respectively; p < 0.0001) and familial history of cancer (12.26% vs. 1.57% respectively; p = 0.001) were higher among prostatic cancer patients compared to healthy subjects. in addition, these patients were significantly younger than controls (mean age: 62.38 vs. 70 respectively; p = 0.0001). no significant differences were found between two groups regarding marital status (p = 0.2), having more than 40-year-old son (p = 0.1) and mean bmi (p = 0.6) (table 1). as illustrated in table 2, frequencies of ag and gg genotypes of mlh1 polymorphism among patients with and without pca were 47.98% vs. 53.04% and 35.26% vs. 34.35%, respectively (p = 0.4). corresponding figures for ag and gg genotypes of msh3 polymorphism were 46.82% vs. 48.70% and 5.78% vs. 8.26% respectively (p = 0.5). crude and adjusted odds ratios between the presence of ag genotype of mlh1 polymorphism and developing pca were 0.68 (p = 0.2) and 0.72 (p = 0.4), respectively. corresponding odds ratios for gg genotype were 0.77 (p = 0.4) and 0.69 (p = 0.4), respectively. crude and adjusted odds ratios representing the effect of different genotypes of msh3 polymorphism on developing cancer were 0.87 (p = 0.5) and 0.71 (p = 0.3) respectively, for ag genotype and 0.63 (p = 0.3) and 0.24 (p = 0.04), respectively for gg genotype (table 2). g allele of mlh1 polymorphisms was observed among 59.25% and 60.88% of cases and controls, respectively (p = 0.6). the odds ratio between the presence of this allele and pca was 0.93 (p = 0.6). moreover, 29.19% of cases and 32.61% of controls carried g allele of msh3 polymorphism (p = 0.3). the odds ratio between the presence of this allele and pca was 0.85 (p = 0.3). polymorphisms and staging of cancer the frequencies of different genotypes of mlh1 polymorphism among patients with initial stages of cancer compare to those with advanced stages were 40.54% vs. 68% respectively for ag genotype and 37.84% vs. 24% respectively for gg genotype (p = 0.1). corresponding figures for genotypes of msh3 polymorphism were 48.65% vs. 52% respectively for ag genotype and 5.41% vs 4% respectively for gg genotype (p = 1) (table 3). polymorphisms and grading of tumor table 3 represents that 45.87% of low tumor grade patients and 45.87% of high tumor grade patients had ag genotype of mlh1 polymorphism. corresponding rates for gg genotype were 28.13% and 39.45% respectively (p = 0.3). moreover, ag and gg genotypes of msh3 polymorphism among patients with lower grade of the tumor were 45.31% and 9.38% respectively, while these genotypes were carried by 47.71% and 3.67% of patients with high-grade tumor respectively (p = 0.3) (table 3). polymorphisms and perineural invasion of cancer among patients who developed perineural invasion, frequencies of ag and gg genotypes of mlh1 polymorphism were 50% and 31.43%, respectively, while corresponding frequencies for those without invasion were 41.67% and 31.43% respectively (p = 0.8). in addition, 42.86% and 41.67% of patients with and without perineural invasion had ag genotype respectively, while, this genotype was presented among 8.57% and 8.33% of patients with and without perineural invasion respectively (p = 1) (table 3). polymorphisms and vascular invasion of cancer only ag genotype of mlh1 polymorphism was found among patients with vascular invasion of the tumor (88.89%). presence of ag and gg genotypes of this polymorphism was observed among 47.06% and 35.29% of patients without vascular invasion respectively (p = 0.7). the frequencies of the ag genotype of msh3 polymorphism among patients with and without vascular invasion were 55.56% and 41.18% respectively. gg genotype was observed only among patients without vascular invasion of the tumor (p = 0.4) (table 3). discussion pca is one of the most common malignancy in males and leading causes of cancer mortality. there are few studies that are investigated the relationship between the mlh1 rs1800734 and msh3 rs26279 polymorphisms and risk of pca. mmr deficiency has been reported to be associated with increased risk of several types of cancer (21). until now, there are a large number of publications have demonstrated investigated the association of mlh1 and msh3 polymorphisms mlh1 and msh3 in prostate cancer-khooshemehri et al. and cancer susceptibility. msh3 rs26279 and mlh1 rs1800734 polymorphisms are most widely studied for their association with cancer risk among those genetic variations. however, the results of these studies were controversy. berndt et al. and muniz-mendoza et al. founded that msh3 rs26279 and mlh1 rs1800734 polymorphisms have been extensively investigated for their correlation with the risk of colorectal cancer(14,22). in contrast, smith et al. did not observe any significant association between msh3 rs26279 polymorphism and the risk of breast cancer(17). chen h et al. reported that there was not persuasive evidence showing that snps of rs1800734 were related to colorectal cancer susceptibility(23). in this study, we realized that gg genotype of msh3 polymorphism was significantly less common among patients with pca compared to patients with bph. additionally, we observed that there was not a remarkable relationship between presence of mlh1 and msh3 polymorphisms and different characteristics of the tumor. although homozygote and heterozygote genotypes of mlh1 polymorphism decreased the odds of developing pca approximately 30%, these effects were not statistically significant. therefore, this polymorphism is not a protective factor for pca. among different genotypes of mlh3 polymorphism, only homozygote genotype showed a significant association with pca, so that the presence of this genotype caused a 76% decrease in the odds of cancer. the considerable change between crude and adjusted estimates indicates that factors such as age, family history of pca and smoking status can confound this association. to assess the effect of mlh1 and msh3 polymorphisms on different characteristics of pca, we compared the frequencies of various genotypes of these polymorphisms between patients with different stages, grades and invasions of cancer. it was observed that patients with advanced phases of cancer and invasive situation of the tumor had higher rates of mlh1 polymorphism. however, these differences were not statistically significant. genotypes of msh3 polymorphism were relatively different among patients with various stages and grades of the tumor, although still, these differences were not significant. therefore, these two polymorphisms cannot be considered as protective or risk factors for progression of the pca. a meta-analysis, which was done by xu jl et al. suggested that mlh1 -93g >a polymorphism could be a possible biomarker of cancer susceptibility(24). in a study which was carried out by hiroshi hirata et al. for the first the association of msh3 gene polymorphisms in pca was reported. these results suggested that the msh3 polymorphism may be a risk factor for pca (15). ting wang et al. indicated that the mlh1 -93g>a polymorphism could contribute to individual susceptibility to colorectal cancer and act as a risk factor for microsatellite instability-colorectal cancer(25). a pooling analysis of hmlh1 polymorphisms revealed that hmlh1 polymorphisms may be associated with cancer risk, especially in asians(26). a meta-analysis in 2015 showed that msh3 rs26279 variant is associated with an increased risk of overall cancer(27). according to our result, the mlh1 and msh3 polymorphisms did not show any significant association with prostate cancer. we also found an association of smoking habits and familial history of cancer among prostatic cancer patients. in addition, these patients were significantly younger compared to healthy subjects. moreover, investigations should be carried out to detect the exact effects of such genetic factors on developing pca and its severity. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin. 2011;61:69-90. 2. bostwick dg, burke hb, djakiew d, et al. human prostate cancer risk factors. cancer. 2004;101:2371-490. 3. salinas ca, koopmeiners js, kwon em, et al. clinical utility of five genetic variants for predicting prostate cancer risk and mortality. the prostate. 2009;69:363-72. 4. park jy, huang y, sellers ta. single nucleotide polymorphisms in dna repair genes and prostate cancer risk. cancer epidemiol. 2009361-85. 5. li g-m. mechanisms and functions of dna mismatch repair. cell research. 2008;18:8598. 6. iyer rr, pluciennik a, burdett v, modrich pl. dna mismatch repair: functions and mechanisms. chem rev. 2006;106:302-23. 7. kinzler kw, vogelstein b. gatekeepers and caretakers. nature. 1997;386. 8. peltomäki p, vasen h. mutations associated with hnpcc predisposition—update of icghnpcc/insight mutation database. dis markers. 2004;20:269-76. 9. han h-j, maruyama m, baba s, park j-g, nakamura y. genomic structure of human mismatch repair gene, hmlh1, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (hnpcc). hum mol genet. 1995;4:237-42. 10. jha r, gaur p, sharma sc, das sn. single nucleotide polymorphism in hmlh1 promoter and risk of tobacco-related oral carcinoma in high-risk asian indians. gene. 2013;526:2237. 11. raptis s, mrkonjic m, green rc, et al. mlh1–93g> a promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. j natl cancer inst. 2007;99:463-74. 12. shih c-m, chen c-y, lee l, kao w-t, wang y-c. a polymorphism in the hmlh1 gene (-93g→ a) associated with lung cancer susceptibility and prognosis. int j mol med. 2010;25:165. 13. risinger ji, umar a, boyd j, berchuck a, kunkel ta, barrett jc. mutation of msh3 in endometrial cancer and evidence for its functional role in heteroduplex repair. nat genet. 1996;14:102-5. 14. berndt si, platz ea, fallin md, thuita lw, mlh1 and msh3 in prostate cancer-khooshemehri et al. urological oncology 274 vol 17 no 03 may-june 2020 275 hoffman sc, helzlsouer kj. mismatch repair polymorphisms and the risk of colorectal cancer. int j cancer. 2007;120:1548-54. 15. hirata h, hinoda y, kawamoto k, et al. mismatch repair gene msh3 polymorphism is associated with the risk of sporadic prostate cancer. j urol. 2008;179:2020-4. 16. kawakami t, shiina h, igawa m, et al. inactivation of the hmsh3 mismatch repair gene in bladder cancer. biochem biophys res commun. 2004;325:934-42. 17. smith tr, levine ea, freimanis ri, et al. polygenic model of dna repair genetic polymorphisms in human breast cancer risk. carcinogenesis. 2008;29:2132-8. 18. song h, ramus sj, quaye l, et al. common variants in mismatch repair genes and risk of invasive ovarian cancer. carcinogenesis. 2006;27:2235-42. 19. epstein ji, allsbrook jr wc, amin mb, egevad ll, committee ig. the 2005 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma. am j surg pathol. 2005;29:1228-42. 20. hoedemaeker rf, vis an, van der kwast th. staging prostate cancer. microscopy research and technique. 2000;51:423-9. 21. xiao x, melton dw, gourley c. mismatch repair deficiency in ovarian cancer—molecular characteristics and clinical implications. gynecol oncol. 2014;132:506-12. 22. muniz-mendoza r, ayala-madrigal m, partida-perez m, et al. mlh1 and xrcc1 polymorphisms in mexican patients with colorectal cancer. genet mol res. 2012;11:2315-20. 23. chen yc, hunter dj. molecular epidemiology of cancer. ca cancer j clin. 2005;55:45-54. 24. xu j-l, yin z-q, huang m-d, et al. mlh1 polymorphisms and cancer risk: a metaanalysis based on 33 case-control studies. asian pac j cancer prev. 2012;13:901-7. 25. wang t, liu y, sima l, et al. association between mlh1-93g> a polymorphism and risk of colorectal cancer. plos one. 2012;7:e50449. 26. li s, zheng y, tian t, et al. pooling-analysis on hmlh1 polymorphisms and cancer risk: evidence based on 31,484 cancer cases and 45,494 cancer-free controls. oncotarget. 2017;8:93063. 27. miao hk, chen lp, cai dp, kong wj, xiao l, lin j. msh3 rs26279 polymorphism increases cancer risk: a meta-analysis. int j clin exp pathol. 2015;8:11060-7. mlh1 and msh3 in prostate cancer-khooshemehri et al. vol 16 no 02 march-april 2019 221 case report a new technique of scrotoplasty following total scrotal destruction by raised rotated perineal flaps with de epithelialized borders seyyed mohammad ghahestani¹*, pooya hekmati¹, sara karimi² in this article we present a two-year-old male patient who had history of fournier gangrene of scrotum. extensive perineal and scrotal debridement with suprapubic cystostomy tube insertion had been done for him in the emergency setting. one year later his parents brought him back for scrotal reconstruction. a novel technique by using rotational perineal flap was used. the cosmetic result of one-month and three-month follow up is presented in the article. keywords: scrotoplasty; perineal flap; scrotum; reconstruction introduction total scrotoplasty may be needed in congenital scrotal agenesis or cases of scrotal skin loss due to trauma or necrotizing fasciitis (fournier gangrene)(1). scrotal agenesis is also an extremely rare anomaly of scrotum in which various grafts and/or flap techniques may be used(2). in the cases of scrotal agenesis several reconstructive techniques including use of myocutaneous flaps such as gracilis flap, split thickness free skin graft, and preputial flap have been mentioned(1-4). tissue expanders are also suggested(5-7). in this article we present a two-year-old male child with history of fournier gangrene of scrotum. a novel technique by rotational perineal flap is introduced. the cosmetic results during follow-ups till one year are presented. 1department of pediatric urology, children medical center hospital, tehran university of medical sciences, tehran, iran. 2department of female urology, shahid hasheminejad hospital, iran university of medical sciences, tehran, iran. *correspondence: department of pediatric urology, children medical center hospital, tehran university of medical sciences, tehran, iran. e mail: mgrosva@gmail.com. received september 2017 & accepted april 2018 figure 1. a)total scrotal destruction; b &c) marking incision lines of flaps; d) flaps are raised and anchored by stay sutures; e &f) upper borders of flaps are de-epithelialized to enhance the eventual cosmetic result; g &h) lower border of flaps are sutured together by 6-0 pds sutures producing a protuberated scrotal appearance. case report a two-year-old boy was referred to the clinic suffering from idiopathic spontaneous necrotizing fasciitis. the infectious process had been started suddenly from an eruption on the groin and progressed to the scrotum within hours. intravenous antimicrobial agents were instituted and the patient was promptly taken to the operation room. aggressive debridement preserving the intact testes was done. technique a cystostomy tube was also inserted and fixed in the bladder. the wound was left for secondary healing. one year later the parents brought him back for scrotal reconstruction and orchidopexy. the incision lines were marked. both testes and cords were freed from their location at distal inguinal canals. the upper borders of the flaps were de-epithelialized. the flaps were freed from downside and lateral aspect but the upper borders were attached. the testes were fixed at midlevel of the flaps. the lower horizontal sides of the flaps were sutured and attached together with 6-0 pds sutures. this is an important step in this technique which makes an out-pouching and protruding appearance like a normal scrotum. the other lines of incision were also closed except the de-epithelalized borders which were left for secondary healing as skin folds and borders of scrotum. follow-up after twenty days, three months, and one year follow up, an acceptable scrotal appearance close to the normal shape was achieved. discussion scrotoplasty may be needed in cases of scrotal agenesis or scrotal loss either due to trauma or necrotizing infection (1, 2). various techniques using preputial flap, gracilis flap, split thickness skin graft and use of tissue expanders were explained in the literature(1-4). each technique may have a profile of cons and pros. use of preputial skin has a prerequisite of uncircumcised preputium that may be unavailable in cases of fournier or trauma that may also be older(6). on the other hand, the reconstructed small pouch may also be inadequate for large testes(5). meshed split thickness grafts may lack the redundant appearance and the testes may not be mobile(4). the reconstructed scrotum may also have a skinny appearance. use of tissue expanders would have multiple sessions of expander and for reconstruction would need minimally two sessions(5-7). an advantage of our technique is its applicability in circumcised patients. it is also single-stage procedure. the testes are relatively mobile inside the neo-scrotum. no implantation of a foreign body is necessary as seen in the cases by tissue expanders. in this case there were some concerns about the implantation of a foreign body that may flare a reaction similar to the first fournier episode. because of the thick nature of the flaps, the appearance will not be skinny. nevertheless the neo-scrotum in patient would lack rogation. overall the resultant appearance is acceptable and the parents were satisfied with the outcomes of the surgery. this new technique of scrotoplasty with raised perineal flaps and de-epithelialized border is a good option in cases of scrotal destruction and agenesis and does not require an uncircumcised condition. a new technique of scrotoplasty-ghahestani et al. case report 222 figure 2. 1) demarcating incision lines, 2) raising flaps and releasing the testes to mobilize them down, 3) de-epithelializing upper border to facilitate flap rotation, 4) rotating flaps and juxtaposing lower border with separate sutures. upper de-epithelialized border is left un-sutured. figure 3. follow up after twenty days and also after three months vol 16 no 02 march-april 2019 223 acknowledgement the authors are indebted to miss m khalifa for elegant medical illustration and miss m pashaii operating room technician in taking and modification of photos. references 1. lucas jw, lester km, chen a, simhan j. scrotal reconstruction and testicular prosthetics. transl androl urol. 2017;6:71021. 2. lin ct, chang sc, chen sg, tzeng ys. reconstruction of perineoscrotal defects in fournier's gangrene with pedicle anterolateral thigh perforator flap. anz j surg. 2016;86:1052-5. 3. wallner c, behr b, ring a, mikhail bd, lehnhardt m, daigeler a. reconstructive methods after fournier gangrene. urologe a. 2016;55:484-8. 4. chen sy, fu jp, wang ch, lee tp, chen sg. fournier gangrene: a review of 41 patients and strategies for reconstruction. ann plast surg. 2010;64:765-9. 5. bonitz rp, hanna mk. correction of congenital penoscrotal webbing in children: a retrospective review of three surgical techniques. j pediatr urol. 2016;12:161.e1-5. 6. el-sabbagh ah. coverage of the scrotum after fournier's gangrene. gms interdiscip plast reconstr surg dgpw. 2018;7:doc01. 7. kuzaka b, wróblewska mm, borkowski t, et al. fournier's gangrene: clinical presentation of 13 cases. med sci monit. 2018;24:548-55. a new technique of scrotoplasty-ghahestani et al. figure 4. one-year appearance at final follow-up unclassified the feasibility of open prostatectomy in patients with previous prostate surgery amir reza abedi1, farzad allameh2*, seyyed ali hojjati3, saleh ghiasy3, mohammad pouri4, saeed montazeri5 purpose: benign prostatic hyperplasia (bph) is one of the most common problems in elderly men. transurethral resection of the prostate (turp) can be performed for most patients who need re-do prostate surgery, but open prostatectomy should be considered in patients with prostate size larger than 70 grams. this study assessed the feasibility of open prostatectomy (op) after previous turp in patients whose prostate size was larger than 70 grams. materials and methods: we subdivided patients into two groups: group 1 included patients who had a history of prostate surgery presented with severe voiding symptoms and a large prostate (>70 gram). patients who were candidate for open simple prostatectomy without a history of prostate surgery were allocated to group 2. results: between june 2007 and april 2018, 2700 patients underwent turp or open prostatectomy in our department. 152 of 2700 patients came to us because of severe voiding symptoms after previous prostate surgery, but only 30 patients met the criteria to be enrolled in this study. perioperative complication (capsular perforation) occurred in 4 (13.3%) patients in group 1 whereas none of the patients in the group 2 had capsular perforation. hemoglobin drop in group 1 was not significantly different from patients in group 2. the rate of blood transfusion did not differ between the groups (2 [6.6%] patients in group 1 and 41 (5.6%) patients in group 2). after 6-12 months, re-operation rate because of urethral/bladder neck stricture was done in 10 (30%) patients in group 1 and 15 (2%) patients in group 2 (p < 0.05). four (13.3%) patients in group 1 complained of urinary leakage (more than one pad per day) 6 months after the operation whereas 5 patients in group 2 used more than one pad per day (0.7%) (p > 0.05). hospital stay was slightly longer in patients in group 1. six months after the operation, the patients’ quality of life was better in group 2 compared with group 1 (p < 0.05). conclusion: open simple prostatectomy was a feasible procedure in patients with large prostate after previous turp, but it was associated with more complications in the long term. keywords: prostatectomy; reoperation; transurethral prostate resection of the prostate introduction benign prostatic hyperplasia (bph) is a common problem in elderly men(1). open prostatectomy (op) and transurethral resection of the prostate (turp) are common procedures for removing the prostate in patients with bph. indications for bph surgery include: refractory urinary retention, overflow incontinence, recurrent urinary tract infections, bladder stones or gross hematuria due to bph(2). turp is considered as a gold standard treatment in patients whose prostates are smaller than 70-80 grams(3,4). its efficacy decreases in patients whose prostates are large(5). therefore, european and american urology guidelines recommend considering open prostatectomy in patients whose prostates are large (www.eau. 1clinical research development unit of shohada-e tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 2urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 3department of urology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 4men’s health and reproductive health research center, shahid beheshti university of medical sciences, tehran, iran. 5laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center, no 103, 9th boustan, pasdaran, tehran, iran. postal code: 1666697751, email: farzadallame@gmail.com, cell: +989123885545, fax: +982122736386 received september 2020 & accepted january 2022 org, www.aua.org). moreover, op is still being performed for patients in many developing countries(6). compared with op, robotic prostatectomy, is associated with equivalent functional outcomes, but a significant reduction in the transfusion rate and a decreased hospital stay has been reported(7). given that we do not have a robotic system in our country; we prefer to perform open simple prostatectomy in patients with a large prostate. the retreatment rate is the most important factor that should be considered in the terms of long-term efficacy (8). re-do surgery rate was 12.7% for turp and 8.8% for op during 8 years(8). the re-turp rate after primary turp was 8.3% whereas it was 4.3% after open prostatectomy(9). given that more extensive prostate tissue is urology journal/vol 19 no. 2/ march-april 2022/ pp. 148-151. [doi: 10.22037/uj.v18i.6468] vol 19 no 2 march-april 2022 149 removed during op, the rate of repeat prostatectomy after turp is more than that expected after op(10). in the terms of cost, the benefit of turp overbalanced five years after the operation that because of higher reoperation rate in patients with turp(11). in this study, we assess the feasibility of open simple prostatectomy in patients who need re-intervention after previous turp. materials and methods between june 2007 and april 2018, 2700 patients underwent turp or open prostatectomy in our department. we included patients whose prostates size were larger than 70 grams and complained of voiding symptoms, were unpleased with medical treatment, and had a history of turp. patients with suspicious digital rectal examination and those with pathology report indicated complications other than bph were excluded from the study. we excluded patients with urethral/bladder neck stricture. the study was approved by the ethical committee of shahid beheshti university of medical sciences (ir.sbmu.retech.rec.1400.563), and informed consent was sought from all patients. we subdivided patients into two groups: group one included patients with severe voiding symptoms who had a history of prostate surgery, outflow obstruction was reported by uds (urodynamic study), prostate larger than 70 grams was reported by abdominal ultrasonography, and urethral stricture was ruled out by cystoscopy. 30 patients were in group 1. patients who had a history of severe urinary symptoms and large prostate, and they did not have a history of prostate surgery were enrolled in group 2 (n=720 patients). indications for open prostatectomy included: lower urinary tract symptoms despite maximal medical therapy, frequent urinary tract infections, recurrent hematuria due to bph, uremia, and urinary retention more than one episode. history taking and physical examination including digital rectal examination were done in the urology department. serum level of creatinine, prostate specific antigen (psa), urine analysis and culture were checked. ultrasonography of the kidneys, the bladder, and the prostate were also done. after that, cystoscopy was scheduled to rule out urethral stenosis. patients with high serum level of psa underwent trans-rectal ultrasound guided biopsy of the prostate. urodynamic study was done to prove bladder outlet obstruction. open trans-vesical prostatectomy was performed by two senior urology residents. when symptom scores improved and were more than 5 points from its baseline, it is considered as ipss improvement. this was a retrospective and cross-sectional study. complications such as surgical site infection and incontinence, international prostate symptom score (ipss), patients’ quality of life, and the peak flow rate (qmax) were recorded. the patients’ quality of life was assessed by the quality of life (qol) questionnaire (12). the institutional review board of the department of urology and the ethics committee of shahid beheshti university of medical sciences approved the study (code: sbmu.retech.rec.1400.563). statistical analysis statistical analysis was done by spss software (statistical package for the social science, version 16.0, chicago, illinois, usa). categorical variables were analyzed by chi-square or fisher’s exact tests as appropriated. quantitative variables were analyzed by t test or mann-whitney test. no subgroup analysis was planned. two-sided p values less than 0.05 were considered statistically significant. results between june 2007 and april 2018, 2700 patients unvariable op patients without history of surgery op with history of turp p value age, years 67 ± 6.2 75.2 ± 7.2 0.21 prostate size in ultrasonography 85 ± 12 79 ± 8 0.54 ipss 26.2 ± 6.1 25.2 ± 5.2 0.86 peak flow rate, ml/s 6 (0 to 8) 7 (0 to 9) 0.75 psa (mg/dl) 3.4 ± 1.2 2.7 ± 1.4 0.32 table 1.data of patients before surgery op: open prostatectomy; turp: transurethral resection of the prostate, ipss: international prostate symptom score, psa: prostate specific antigen variable op patients without history of surgery op with history of turp p value anesthesia: spinal /general 670/50 28/2 0.31 blood transfusion 41 (5.7 %) 2 (6.66%) 0.13 postoperative fever 31 (4.3%) 2 (6.66%) 0.13 time to catheter removal, days 7 (5 to 10) 9(7 to 12) 0.07 incontinent patients six months after surgery 5 (0.69%) 4 (13.3%) 0.032 uti (epididymitis, cystitis) 60 (8.3%) 3(10%) 0.31 ipss after surgery 5.1±2.2 4.2±2.1 0.43 mean qol score at 6-12 months 24.2±2.3 44.3±3.4 0.01 op: open prostatectomy, turp: transurethral resection of the prostate, uti: urinary tract infection, ipss: international prostate symptom score, qol: quality of life. data are presented as n, mean ± sd, or median. table 2. data of patients during or after surgery prostatectomy in with previous prostate surgery-abedi et al. unclassified 150 derwent monopolar turp or open prostatectomy in our department. 720 patients underwent op without a history of turp. 152 (5.6%) patients who had undergone prostate surgery came to us because of voiding symptoms, and urethral/ bladder neck stricture was ruled out. most of them underwent turp, but op was performed for 30 patients who had a large prostate. the mean±sd duration from the time of the previous transurethral resection of the prostate (turp) to the time of op was 36±5 months. patients’ demographic characteristics before the operation are shown in table 1. american society of anesthesiology risk score categories 1, 2, and 3 were observed in 2, 21, 7 patients in group 1 and 60, 504, 156 patients in the group 2. perioperative and late postoperative data is shown in table 2. perioperative complications (capsular perforation) occurred in 4 (13.3%) patients in group 1; however, none of the patients in group 2 had capsular perforation. in three cases, we were able to repair the perforation, and the suprapubic catheter was inserted for one week but the cystostomy catheter was kept for three weeks in one patient. difficult enucleation was reported in 12 (40%) patients in group 1 and 10 (1.3%) patients in group 2 (p < 0.05). early postoperative complications (during hospitalization) were observed in 3 (10%) patients in group 1 (urinary leak in two patients and gastrointestinal bleeding in one patient) whereas 20 (2.7%) patients in group 2 had urinary leak (p < 0.05). one patient in group 1 with an anesthesiology risk score of 3 experienced myocardial infarction two days after surgery. hemoglobin drop was not significantly different between the groups two days after surgery, and the rate of blood transfusion was not significantly different (two [6.6%] patients in group one and 41 [5.6%] patients in group two). six months after surgery, urethral/bladder neck stricture was reported in 10 (30%) patients in group one and 15 (2%) patients in group 2 (p<0.05). urinary incontinence was observed in 8 (26.6%) patients in group 1 and 21 (2.9%) patients in group 2 after surgery (p < 0.05). however, six months after surgery, 4 (13.3%) patients of the group 1 complained of urinary leakage more than one pad per day whereas 5 (0.7%) patients of group 2 complained of urinary leakage more than one pad per day (p > 0.05). after 6-12 months, re-operation rate due to urethral/ bladder neck stricture was done in 10 (30%) patients of the group 1 and 15 (2%) patients of group 2 (p < 0.05). the patients in group 1 compared to the patients in group 2 needed longer hospitalization. the patients’ quality of life in group 2 was significantly better than the patients of group 2, 6-12 months after the operation (p < 0.05). discussion to date, little information has been published about the surgical and functional outcome of patients who underwent open prostatectomy after previous turp. transurethral resection of the prostate has been considered as the standard treatment for prostates less than 70 to 80 grams(3,4,13). although op is associated with more morbidity(14), it provides more ipss and qmax improvement(14), less re-operation rate(15), and less dysuria(16). re-turp should be considered in patients who need prostate surgery after previous turp, but its results are disappointing in patients who have large prostate (9,14). several minimally invasive surgeries such as holmium laser enucleation of the prostate (holep) has been described as feasible alternatives to open simple prostatectomy, and are is associated with excellent long-term efficacy(17-19) and should be considered in patients with previous prostate surgery, but its steep learning curve and cost are reasons for not using holep in the world (20,21). 1.1% of patients who had undergone holep needed re-do holep, which is comparable to that of op(22). secondary-holep procedure seems to be safe and technically feasible with comparable functional outcomes as those of primary-holep(22), but its cost has limited its wide implementation in our country. semmens and colleagues analyzed a western australian database of 19,598 men who underwent surgery during 1980-1995(23). after 8 years, the re-turp rate was 6.6% for primary turp vs 3.3% for op(23). reoperation rate in our study was about 6% that was comparable with other studies(23). in this study, prostate size larger than 60 gr despite previous turp indicated that primary prostate size must be large, and previous turp was incomplete, so adenoma left in prostatic fossa began to grow slowly afterwards. op in the setting of previous prostate surgery is a feasible procedure, but it is associated with a higher complication rate such as difficult enucleation and capsular perforation. in the long term, most of our patients are pleased with the results of prostatectomy; however, some patients suffered from frustrating complications such as urinary incontinence and urethral stricture more than usual. our study showed that hospital stay in patients with previous turp was longer, and immediate and late postoperative complication of op after previous turp was significantly higher compared with op in patients without previous prostate surgery. the anatomy of patients after turp is technically difficult, and identification of the plane between prostate capsule and adenoma is fairly difficult(14,24). therefore, op in patients with a history of turp should be done by an experienced urologist, and it is associated with increased complications such as capsular perforation. re-turp and holep are alternative options for patients who develop obstructive symptom due to regrowth of prostate adenoma after previous prostate surgery(23), but the results of turp in patients with large prostate seem to be less successful than op(14); on the other hand, the cost of holep limited its wide implementation in our country. our study showed that op was a feasible option in patients with large prostate after previous turp. further study is necessary to compare the functional outcome between turp and open simple prostatectomy in patients who present with severe luts and large prostate after turp. it seems that performing open simple prostatectomy is more logical in patients who have large prostate size because it is possible that turp ends in incomplete prostate resection, but our study cannot determine the prostate size cut-off to perform open simple prostatectomy. unfortunately, we do not have robot in our country; therefore, we prefer to do simple open prostatectomy in cases with a large prostate, so the role of robotic simple prostatectomy should be assessed in the other studies. conclusions open simple prostatectomy is a feasible procedure in prostatectomy in with previous prostate surgery-abedi et al. vol 19 no 2 march-april 2022 151 patients whose prostate is larger than 70 grams after previous turp, but it is associated with more immediate and late complications. acknowledgements we express our appreciation to the operation room personnel of shohada-e tajrish hospital. conflict of interest the authors have no conflicts of interest to announce. references 1. irwin de, kopp zs, agatep b, milsom i, abrams p. worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. bju int. 2011;108:1132-8. 2. foster he, barry mj, dahm p,et al. surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: aua guideline. j urol. 2018;200:612-9. 3. de la rosette jj, alivizatos g, madersbacher s, et al. eau guidelines on benign prostatic hyperplasia (bph). eur urol. 2001;40:256-63. 4. reich o, gratzke c, stief cg. techniques and long-term results of surgical procedures for bph. eur urol. 2006;49:970-8. 5. hoekstra rj, van melick hh, kok et, bosch jr. a 10-year follow-up after transurethral resection of the prostate, contact laser prostatectomy and electrovaporization in men with benign prostatic hyperplasia; long-term results of a randomized controlled trial. bju int. 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pourmomeny aa, zargham m, fani m. reliability and validity of the quality of life questionnaire in iranian patients with lower urinary tract symptoms. luts: low urin tract symptoms. 2018;10:93-100. 13. simforoosh n, abdi h, kashi ah, et al. open prostatectomy versus transurethral resection of the prostate, where are we standing in the new era? a randomized controlled trial. urol j. 2010;7:262. 14. porpiglia f, terrone c, renard j, et al. transcapsular adenomectomy (millin): a comparative study, extraperitoneal laparoscopy versus open surgery. eur urol. 2006;49:120-6. 15. nestler s, bach t, herrmann t, et al. surgical treatment of large volume prostates: a matched pair analysis comparing the open, endoscopic (thuvep) and robotic approach. world j urol. 2019;37:1927-31. 16. sorokin i, sundaram v, singla n, et al. robotassisted versus open simple prostatectomy for benign prostatic hyperplasia in large glands: a propensity score–matched comparison of perioperative and short-term outcomes. j endourol. 2017;31:1164-9. 17. naspro r, suardi n, salonia a, et al. holmium laser enucleation of the prostate versus open prostatectomy for prostates> 70 g: 24-month follow-up. eur urol. 2006;50:563-8. 18. salonia a, suardi n, naspro r, et al. holmium laser enucleation versus open prostatectomy for benign prostatic hyperplasia: an inpatient cost analysis. urology. 2006;68:302-6. 19. jones p, alzweri l, rai bp, somani bk, bates c, aboumarzouk om. holmium laser enucleation versus simple prostatectomy for treating large prostates: results of a systematic review and meta-analysis. arab j urol. 2016;14:50-8. 20. robert g, cornu jn, fourmarier m, et al. multicentre prospective evaluation of the learning curve of holmium laser enucleation of the prostate (ho lep). bju int. 2016:495-9. 21. demir a, günseren kö, kordan y, yavaşçaoğlu i̇, vuruşkan ba, vuruşkan h. open vs laparoscopic simple prostatectomy: a comparison of initial outcomes and cost. j endourol. 2016;30:884-9. 22. elshal am, elmansy hm, elhilali mm. feasibility of holmium laser enucleation of the prostate (holep) for recurrent/residual benign prostatic hyperplasia (bph). bju int. 2012;110:845-50. 23. leslie s, de castro abreu al, chopra s, et al. transvesical robotic simple prostatectomy: initial clinical experience. eur urol. 2014;66:321-9. 24. welliver c, helo s, mcvary kt. technique considerations and complication management in transurethral resection of the prostate and photoselective vaporization of the prostate. transl androl urol. 2017;6:695. prostatectomy in with previous prostate surgery-abedi et al. increased level of c-kit in semen of infertile patients with varicocele sexual dysfunction and infertility guorong jin1, jianrong liu2*, qin qin1, songdan gao1, fang zhang1, yuehong ma1, caiyun ding1, lina dong1, haizhen yin1, yimin wang1 purpose: varicocele is the most common risk factor for male infertility, however, not all males with varicocele experience infertility. in fact, most patients with varicocele have normal spermatogenesis. the molecular mechanism of varicocele-associated infertility is yet to be completely understood. the aim of this study is to assess the association of a number of fertility regulatory factors on varicocele associated infertility and to throw light on the mechanism of varicocele-associated infertility. materials and methods: semen from 30 infertile patients with varicocele and 30 fertile men with varicocele were collected. the concentrations of the following factors in seminal plasma were determined by elisa: follicle stimulating hormone (fsh), luteinizing hormone (lh), testosterone (t), androgen binding protein (abp), transferrin (trf), inhibin b (inhb) and stem cell factor (scf). the expression level of c-kit in seminal precipitate of patients with varicocele was detected by real-time pcr. results: the concentrations of sexual hormones, fsh, lh and t, had no differences between infertile patients with varicocele and fertile men with varicocele (p > 0.05). factors secreted by sertoli cells, abp, trf, inhb and scf, showed no significant differences between the two groups (p > 0.05). interestingly, the expression of c-kit was significant higher in infertile patients with varicocele than that in fertile men with varicocele (p < 0.01). conclusion: neither the sexual hormones nor the sertoli cells was responsible for the infertility induced by varicocele. the aberrant expression of c-kit in infertile patients with varicocele may provide new insight into the mechanism of varicocele-associated infertility. keywords: c-kit; infertility; sertoli cell; varicocele. introduction varicocele is prevalent worldwide and is considered by the world health organization (who) as the first cause for male infertility. however, varicocele is not only a frequent finding in infertile men, but that it is also found in fertile men(1). in fact, most patients with varicocele have normal spermatogenesis. the exact mechanism of varicocele-associated infertility remains unclear(2). many studies have shown that varicocele have negative effect on spermatogenesis(3). spermatogenesis is a complex process and is controlled by hormones and many regulatory factors. it is well known that spermatogenesis is under the control of hypothalamic-pituitary-gonadal axis(4). hypothalamus secretes gnrh, which stimulates hypophysis to secrete follicle stimulating hormone (fsh) and luteinizing hormone (lh). fsh has an effect on maturation of testis and promotes sperm maturation. lh stimulates leydig cells to secrete testosterone (t), which is necessary for spermatogenesis. 1central laboratory, shanxi provincial people's hospital, affiliate of shanxi medical university, taiyuan, china. 2 department of reproductive medicine, shanxi provincial people's hospital, affiliate of shanxi medical university, taiyuan, china. *correspondence: department of reproductive medicine, shanxi provincial people's hospital, affiliate of shanxi medical university, 29 shuangta street, taiyuan 030012, china. phone: (+86)-351-4960-046. e-mail address: liujianrong3@sina.com. received august 2016 & accepted february 2017 in the testis, sertoli cells play important roles on spermatogenesis. they are responsible for the secretion of numerous proteins into the seminiferous tubular lumen, such as androgen binding protein (abp), transferrin (trf) and inhibin b (inhb). abp binds androgens with high affinity and transports them to the epididymis. trf is thought to play a critical role in the delivery of iron from the somatic compartment to the germ cells, which is necessary for cell proliferation, differentiation, and metabolism(5). inhb is a glyco-protein that modulates fsh secretion via a negative feedback loop(6). it is considered as a biomarker of testicular toxicity(7). all of these factors play necessary roles in spermatogenesis. during testicular development, stem cell factor (scf) and c-kit are critical for reproductive events and important for germ-cell development(8). fsh secreted by the pituitary stimulates sertoli cells to secrete scf, which binds to its tyrosine kinase receptor, c-kit, on the surface of differentiating germ cells, where it induces proliferation and differentiation(9). the c-kit receptor forms a dimer by binding scf, and as a result, tyrosine kinase vol 14 no 02 march-april 2017 3023 sexual dysfunction and infertility 3024 activity is induced(10). the interaction of scf and c-kit plays an essential role in primordial germ cell migration and survival, and in spermatogonial adhesion, proliferation(11). in this study, we detected these relating hormones and regulatory factors, including fsh, lh, t, abp, trf, inhb, scf and c-kit, in infertile patients with varicocele and fertile men with varicocele. the aim of this study is to assess the association of a number of fertility regulatory factors on varicocele associated infertility. materials and methods patients we included 60 patients with varicocele aged between 25 and 30 years attending reproductive medicine department of shanxi provincial people’s hospital between may 2014 and march 2015. patients were divided into two groups: infertile patients with varicocele (n=30) and fertile men with varicocele (n=30). inclusion criteria: all patients exhibited grade ii or grade iii clinical varicocele. the following standard grading system was used: grade ii, easily palpable, but not visible; and grade iii, easily visible. for the group of fertile men with varicocele, they had given birth to children in a year and the sperm count was >39×106/ ejaculation, sperm concentration was >15×106/ml. for the group of infertile patients with varicocele, their wives did not get pregnant after more than 1 year of sexual life without contraceptives and the sperm count was <39×106/ejaculation; sperm concentration was <15×106/ml. female infertility was excluded: normal follicular development was monitored by transvaginal ultrasound (tvus); and patency of the fallopian tube was determined by transvaginal ultrasonography. exclusion criteria: patients with reproductive tract infections, gonad function abnormality, abnormal chromosome karyotype, radioactive and other special professionals, taking drugs which disrupt sperm production and sperm motility, patients with serious cardiovascular, liver, kidney and hematopoietic system disease, or mental illness. informed consent was obtained from each patient and approval for the study protocol was granted by the institutional review board of shanxi provincial people’s hospital. sperm examination in all cases, after 3-5 days of sexual abstinence, semen samples were collected by masturbation. then total sperm counts were determined 30 minutes after ejaculation using computer-aided semen analysis (casa). the sperm examination was performed in accordance with the who fifth version of human semen examination standards. elisa semen samples were collected as previously described and centrifuged to separate seminal plasma and seminal precipitate. the seminal plasma concentration of fsh, lh, t, abp, trf, inhb and scf were examined using commercially available elisa kits (jianglaibio, shanghai, china). the experiment was performed according to the manufacturer's instructions. the optical density of color development was read by a photometer and the concentration was calculated by gen5 software (biotek, winooski, usa). real-time pcr total rna from seminal precipitate was isolated using a takara minibest universal rna extraction kit (takara bio, inc., shiga, japan) and 500ng rna was reverse transcribed to cdna using primescript rt master mix (perfect real time) (takara bio, inc., shiga, japan). real-time pcr was performed using the sybr premix ex taq ii (takara bio, inc., shiga, japan) following the manufacturer's instructions for the cfx96 real-time pcr detection system (bio-rad laboratories, inc., hercules, usa). the used primers were: the forward primer 5’-tcctcgcctccaagaattgt-3’ and the reverse primer 5’-tcacaggtagtcgagcgttt-3’. the expression of beta-actin was used as a loading control. relative transcript abundance was quantified by the 2-δδct method. statistical analysis all statistical analysis was carried out using spss version 19.0 (spss, chicago, il, usa). values are presented as mean ± standard deviation. levels of significance for comparisons between groups were determined by student’s t-test. p value of < 0.05 was considered statistically significant. results patients patients with varicocele were collected as previously described. the mean age of the infertile patients with varicocele was 27.2 ± 2.3 years; and that of fertile men with varicocele was 26.9 ± 2.1 years. there was no difference in the mean age of the two groups (p > 0.05). semen analysis the semen from patients with varicocele was analyzed in accordance with the who fifth version of human semen examination standards. the result showed that both fertile men with varicocele and infertile patients with varicocele had normal semen volume and showed no difference (p > 0.05). infertile patients with varicocele had significant lower sperm concentration than increased c-kit in infertile patients with varicocele-jin et al. group n sperm volume (ml) sperm concentration (*106/ml) sperms with forward motility (a+b) (%) fertile men with varicocele 30 2.72 ± 0.79 45.73 ± 14.51 34.27 ± 16.76 infertile patients with varicocele 30 2.57 ± 0.85 6.88 ± 4.12 20.28 ± 18.28 p value 0.86 < 0.01 0.02 table 1. semen parameters in patients with varicocele data is presented as mean ± sd. fertile men with varicocele (p < 0.01). sperms with forward motility significantly decreased in infertile patients with varicocele when compared with fertile men with varicocele (p < 0.05) (table 1). concentrations of sexual hormones we detected the concentrations of sexual hormones including lh, fsh and t in the seminal plasma of patients with varicocele using elisa. the result showed that all of the detected sexual hormones showed no differences between fertile men with varicocele and infertile patients with varicocele (p > 0.05) (table 2). factors secreted by sertoli cells sertoli cells secrete many factors which are crucial for spermatogenesis. we examined the secretory function of sertoli cells by detecting the factors secreted by sertoli cells including abp, trf, inhb and scf, in the seminal plasma of patients with varicocele. the result indicated that none of the factors showed significant difference between fertile men with varicocele and infertile patients with varicocele (p > 0.05) (table 3). expression of c-kit c-kit is important regulator in spermatogenesis. we detected the expression of c-kit in seminal precipitate of patients with varicocele using real-time pcr. the result showed that the expression of c-kit in infertile patients with varicocele was significantly higher than that in fertile men with varicocele (p < 0.01) (figure 1). discussion though it is well known that varicocele is the first cause for infertility, it has been found that a portion of patients with severe varicocele do not present with infertility. the cause-effect relationship between varicocele and infertility has not been conclusively established yet. based on the current knowledge about negative effect of varicocele on spermatogenesis, we postulate that spermatogenesis failure may be responsible for varicocele-associated infertility. spermatogenesis is under control of the hypothalamic-pituitary-gonadal axis. it is well known that fsh and lh are the pivotal endocrine regulators of testicular sex steroids production and spermatogenesis. lh stimulated t production of leydig cells is the key endocrine stimulus of spermatogenesis(12). studies have reported that varicocele may be associated with increased fsh and low levels of t(13,14). in this study, we detected the seminal plasma concentration of fsh, lh and t in patients with varicocele. the reason why we detected the hormones in the seminal plasma is that the operational sites of these hormones are in the testis, not the serum. the seminal plasma concentration of fsh, lh and t may be more valuable for evaluate their roles on spermatogenesis than serum content. our result showed that there were no differences in the seminal plasma concentrations of fsh, lh and t between infertile patients with varicocele and fertile men with varicocele. it seems that fsh, lh and t may not participate in the process that varicocele induces infertility. spermatogenesis is supported and regulated by sertoli cells. sertoli cells provide nutritional as well as morphogenetic support for germ cells during spermatogenesis. they are responsible for the secretion of numerous proteins into the seminiferous tubular lumen, such as abp, trf and inhb, which regulates or responds to pituitary hormone release and further influences spermatogenesis(15,16). to evaluate whether the secretory function of sertoli cells is changed in infertile patients with varicocele, we detected the key secretions of sertoli cells in seminal plasma of patients with varicocele. the result table 2. concentration of sexual hormones group lh (ng/l) fsh (iu/l) t (nmol/l) fertile men with varicocele 45.63 ± 7.27 7.27 ± 0.76 7.01 ± 0.96 infertile patients with varicocele 43.91 ± 6.27 7.07 ± 0.88 7.23 ± 1.38 p value 0.46 0.40 0.61 data is presented as mean ± sd. group abp (ng/ml) trf (nmol/l) inhb (ng/l) scf (pg/ml) fertile men with varicocele 6.84 ± 1.34 403.82 ± 78.74 31.58 ± 5.47 87.25 ± 54.69 infertile patients with varicocele 6.42 ± 1.28 385.2 ± 61.86 31.53 ± 5.30 75.41 ± 24.52 p value 0.30 0.41 0.98 0.31 data is presented as mean ± sd. table 3. concentration of factors secreted by sertoli cells figure1. the expression of c-kit in patients with varicocele data represent the mean of triplicate measurements and are reported as the mean fold change (x-fold) ± sd. increased c-kit in infertile patients with varicocele-jin et al. vol 14 no 02 march-april 2017 3025 showed that none of these factors, abp, trf and inhb, had statistically significant difference between infertile patients with varicocele and fertile men with varicocele. this indicated that sertoli cells were not damaged in infertile patients with varicocele and sertoli cells may be not involved in the process of infertility induced by varicocele. scf/c-kit system plays an important role in the production of gametes. the interaction of scf with c-kit is required for germ cell survival and growth, and abnormalities in the activity of the scf/c-kit system have been associated with human infertility(17). we detected the concentration of scf and c-kit, and the result showed that scf was not altered while c-kit was increased in infertile patients with varicocele compared with fertile men with varicocele. scf is secreted by sertoli cells and c-kit is expressed on spermatogonia a1 to a4, spermatocytes and round spermatids. the result of stable expression of scf is in accordance with the postulation that sertoli cells may be not responsible for varicocele associated infertility. ectopic expression of c-kit in infertile patients with varicocele suggests that germ cells may be involved in the process of varicocele associated infertility. varicocele may cause damage to germ cells and induce infertility. c-kit may be helpful to predict whether varicocele will harm spermatogenesis, and induce infertility clinically. for patients with varicocele who might develop infertility, preventive measures may be taken, such as surgery and sperm freezing. conclusions taken together, we screened the sexual hormones, factors secreted by sertoli cells, and scf/c-kit system to clarify the mechanism of infertility induced by varicocele. neither the sexual hormones nor the sertoli cell was responsible for varicocele-associated infertility. a valuable finding was that the expression of c-kit was significant higher in infertile patients with varicocele than fertile men with varicocele. the aberrant expression of c-kit in infertile patients with varicocele may provide new insight into the mechanism of varicocele-associated infertility. acknowledgments this work was supported by national natural science foundation of china (no. 81373650), shanxi natural science foundation (no. 2009011057-3 and no. 2012011045-4) and science foundation of shanxi provincial health department (no. 201201061). references 1. templeton a. varicocele and infertility. lancet. 2003;361:1838-9. 2. sheehan mm, ramasamy r, lamb dj. molecular mechanisms involved in varicoceleassociated infertility. journal of assisted reproduction and genetics. 2014;31:521-6. 3. neto ft, bach pv, najari bb, li ps, goldstein m. spermatogenesis in humans and its affecting factors. seminars in cell & developmental biology. 2016. 4. schlatt s, ehmcke j. regulation of spermatogenesis: an evolutionary biologist's perspective. seminars in cell & developmental biology. 2014;29:2-16. 5. yamaguchi k, ishikawa t, kondo y, fujisawa m. cisplatin regulates sertoli cell expression of transferrin and interleukins. molecular and cellular endocrinology. 2008;283:68-75. 6. hayes fj, pitteloud n, decruz s, crowley wf, jr., boepple pa. importance of inhibin b in the regulation of fsh secretion in the human male. the journal of clinical endocrinology and metabolism. 2001;86:5541-6. 7. dere e, anderson lm, coulson m, mcintyre bs, boekelheide k, chapin re. sot symposium highlight: translatable indicators of testicular toxicity: inhibin b, micrornas, and sperm signatures. toxicological sciences : an official journal of the society of toxicology. 2013;136:265-73. 8. lennartsson j, ronnstrand l. stem cell factor receptor/c-kit: from basic science to clinical implications. physiological reviews. 2012;92:1619-49. 9. bhattacharya i, pradhan bs, sarda k, gautam m, basu s, majumdar ss. a switch in sertoli cell responsiveness to fsh may be responsible for robust onset of germ cell differentiation during prepubartal testicular maturation in rats. american journal of physiology endocrinology and metabolism. 2012;303:e886-98. 10. blechman jm, lev s, barg j, et al. the fourth immunoglobulin domain of the stem cell factor receptor couples ligand binding to signal transduction. cell. 1995;80:103-13. 11. rossi p, sette c, dolci s, geremia r. role of c-kit in mammalian spermatogenesis. journal of endocrinological investigation. 2000;23:609-15. 12. huhtaniemi i. a short evolutionary history of fsh-stimulated spermatogenesis. hormones. 2015;14:468-78. 13. younes ak. improvement of sexual activity, pregnancy rate, and low plasma testosterone after bilateral varicocelectomy in impotence and male infertility patients. archives of andrology. 2003;49:219-28. 14. shakhov ev, artifeksov sb, ryzhakov iu d. the endocrine function of the hypophysealgonadal system in varicocele. urologiia i nefrologiia. 1993:28-30. 15. grover a, sairam mr, smith ce, hermo l. structural and functional modifications of sertoli cells in the testis of adult folliclestimulating hormone receptor knockout mice. biology of reproduction. 2004;71:117-29. 16. johnson l, thompson dl, jr., varner dd. role of sertoli cell number and function on regulation of spermatogenesis. animal reproduction science. 2008;105:23-51. 17. figueira mi, cardoso hj, correia s, maia cj, socorro s. hormonal regulation of c-kit receptor and its ligand: implications for human increased c-kit in infertile patients with varicocele-jin et al. sexual dysfunction and infertility 3026 infertility? progress in histochemistry and cytochemistry. 2014;49:1-19. increased c-kit in infertile patients with varicocele-jin et al. vol 14 no 02 march-april 2017 3027 endourology and stone disease does mild hydronephrosis induced by full-bladder improve outcomes in patients undergoing shock wave lithotripsy for lower calyceal stones?: a prospective randomized study ismet aydın hazar1, basri cakiroglu2, orhun sinanoglu3, feride sinem akgün4, ersan arda5*, ilkan yuksel5, hakan akdere5 purpose: to compare the outcomes, sessions and shock wave numbers in patients undergoing standard procedure shock wave lithotripsy (swl) and patients undergoing swl with mild hydronephrosis induced by full-bladder following oral hydration before swl procedure for lower calyceal stones. materials and methods: between january 2014january 2016 a total of 371 patients who underwent swl, for lower pole calyceal stones ≤ 2 cm, were included into the study. 127 patients were treated in the supine position (group a), 123 in the prone position (group b) and 121 in the prone position with full bladder and mild hydronephrosis checked by ultrasound before procedure (group c). there were 286 men and 85 women with a mean ± sd age of 36 ± 11 years results: the mean (sd) stone sizes within the group a, group b and group c were 11 mm (±3 mm), 12 mm (±4.1 mm) and 11 mm (± 3.8 mm) respectively. no significant difference was found in age (p = .18) and stone size between 3 groups (p = .07). the median interquartile range (iqr) number of shocks within the group a, group b and group c were 7600 (3855), 6500 (4300) and 6700 (4915) respectively. significant difference was found in number of shock waves among 3 groups (p < .01). the difference between groups according to stone expulsion rate was found significant in all sessions (p = .01). conclusion: the present study suggests that mild hydronephrotic status induced by full-bladder before swl can lower cost and patient discomfort by decrease in number of sessions and increase in stone clearance. keywords: hydronephrosis; lower pole calyx stones; shock wave lithotripsy; stone free rate. introduction shock wave lithotripsy (swl) is a non-invasive treatment method for kidney stones less than 2 cm in diameter and is recommended in urological guidelines. the number of lower calyceal kidney stones treated with swl has been increasing as the technique of devices becomes elaborated.(1) however, the difficult clearance of lower calyceal stones after swl remains to be an important issue.(2) to solve the underlying problem of poor drainage in lower pole renal calices with consequent poor stone clearance rates, auxiliary methods consisting of diuresis and various patient positions have been suggested to increase urine production by high fluid intake or diuretic administration just before the swl session to flush out stone fragments, and to use gravity force favoring displacement of stone fragments by placing the patient in the prone and/or trendelenburg position.(3,4) despite several reports supporting the benefits of diuresis and patient position, the prone position is studied for ureteral stones and diuresis is assured either with water drinking and/or diuretics before procedure. to the best of our knowledge, a study 1department of urology, taksim research and training hospital, istanbul, turkey. 2department urology, hisar intercontinental hospital, istanbul, turkey. 3department of urology, maltepe university, istanbul, turkey. 4department of emergency clinic, maltepe university, istanbul, turkey. 5department of urology, trakya university, edirne, turkey. *correspondence: trakya university medical faculty, balkan campus, edirne, turkey. tel: +905323204814. fax: +902165241300. email: ersanarda@gmail.com. received march 2017 & accepted december 2017 comparing the outcomes of swl in supine position, prone position and prone position with hydronephrosis induced by full bladder has not been published. the present study compared the stone free (sf) rates, session and shock wave numbers for lower pole kidney stones in patients receiving swl among these 3 groups. methods study population between january 2014january 2016 a total of 371 patients who underwent swl, for lower pole calyx stones ≤ 2 cm, were included into the study. the study protocol was reviewed and approved by the institutional ethics committee. inclusion and exclusion criteria the inclusion criteria are as follows: age of 18 years or more, solitary renal lower calyceal calculi between 4 and 20 mm, and consent to randomization. exclusion criteria were non-lower calyceal stones of the same side, renal anatomical deformities such as urethral stricture or ureteropelvic junction obstruction, concomitant endourology and stone diseases 14 vol 15 no 03 may-june 2018 15 distal obstruction, renal insufficiency or grade 3 hydronephrosis of the affected kidney, pregnancy, bleeding diathesis, significant cardiac conditions or uncontrolled hypertension. flow diagram of the study are summarized in figure 1. study design and procedures all subjects included into this single-blind prospective study were simply randomized to supine (group a), prone (group b) and prone plus hydronephrosis induced by bladder fullness (group c). swl was performed with storz modulite fx by the attending urologist using real time ultrasound for stone localization. treatment was initiated at 14 kv, and the energy gradually increased between 20 and 24 kv, depending on the maximum level that the patient could tolerate. the numbers of shock waves (sw) used were determined by calyceal stone sizes; 4-10mm stones (1500 sw), 11-15 mm (2000 sw), and 16-20 mm (2500 sw). outcome assessments patients’ follow-up visits were scheduled immediately at weeks 1, 4, 10, and 6 months after swl therapy, with an evaluation using plain film of the kidney, ureter, and bladder and ultrasound imaging. the radiologists who performed ultrasonography or reported kub were totally blind to the study objectives and protocols. the cumulative of patients who became sf at each week designated our total sfr. cases were accepted as sf if there were no radiological and ultrasonographic evidence of stone as confirmed by a blinded radiologist. stone free status was defined as having no visible residual stone or fragment. sf were recorded in all follow-up visits. complications during and after treatment were recorded. statistical analysis data were checked and analyzed using spss software (spss, chicago, il). quantitative data were expressed as meanstandard deviation if the normality assumption was satisfied in groups otherwise they were expressed as median (interquartile range =iqr), whereas qualitative data were expressed with frequencies and proportions. one way analysis of variance (anova) was employed for comparison between groups if the normality assumption was met and kruskal-wallis test was employed otherwise. fisher’s exact test and chi-square test were used to compare groups with respect to nominal variables. the marascuillo procedure was employed to simultaneously test the differences of all pairs of proportions where a difference is considered statistically significant if its value exceeds the critical range value. p = .05 was considered significant. results the mean standard deviation (sd) of stone sizes within the group a, group b and group c were 11 mm (± 3 mm), 12 mm (± 4.1 mm) and 11 mm (± 3.8 mm) respectively. using a chi-square test, no difference was found in gender proportion between 3 groups (p = .5). no significant difference was found in age, body mass index, stone size, stone density and skin to stone distance between 3 groups (table 1). the median interquartile range (iqr) number of shocks within the group a, group b and group c were 7600 (± 3855), 6500 (± 4300) and 6700 (± 4915) respectively. using kruskal wallis rank sum test, significant difference was found in number of shocks between 3 groups (p = .01) (table 2). after one session, stone expulsion rate of 13% (17 out of 127patients) was observed in group a, 28% (34 out of 123 patients) was observed in group b and 40% (48 out of 121 patients) was observed in group c. the difference between groups was found significant using a chi-square test (p = .01). after the second session, stone expulsion rate of 48% (62 out of 127patients) was observed in group a, 67% (82 out of 123 patients) was observed in group b and 80% (97 out of 121 patients) was observed in group c. the difference between groups was found significant using a chi-square test (p = .01). after the third session and more, stone expulsion rate of 67% (115 out of 127patients) was observed in group a, 86% (101 out of 123 patients) was observed in group b and 87% (106 out of 121 patients) was observed in group c. the difference between groups was found significant using a chi-square test (p = .01). the stone expulsion rate in all sessions was found significantly different between group a and group b and between group a and group c. both group b and c showed a statistical advantage over group a in terms of stone expulsion rate in all sessions. (table 2) marascuillo procedure states that the stone expulsion rate after three or more sessions were found significantcharacteristics group a(n=127) group b(n=123) group c(n=121) p value patients’ gender (m/f) 98/29 97/24 91/32 0.5 patients’ age mean ± sd 35 ± 11 35 ± 11 37 ± 11 0.18 body mass index (kg/m3) 25.4 ± 3.7 26.1 ± 4 25.9 ± 3.9 0.3 stone size(mm) mean ± sd 11 ± 3 12 ± 4.1 11 ± 3.8 0.07 skin to stone distance (cm) 10.7 + 1.5 10.8 + 1.6 10.7 + 1.6 0.6 stone density (hounsfield units) 565 ± 153 589 + 168 577 + 166 0.59 table 1. patients 'and stones 'characteristics. swl parameters group a(n=127) group b (n=123) group c (n=121) p value number of shockwaves median(iqr) 7600 ( ± 3855) 6500 ( ± 4300) 6700 ( ± 4915) < 0.01 stone free after first session, n(%) 17 (13%) 34 (28%) 48 (40%) < 0.01 stone free after second session, n(%) 62 (49%) 82 (67%) 97 (80%) < 0.01 stone free after third session, n(%) 85 (67%) 101 (82%) 106 (88%) < 0.01 abbreviation: iqr, inter quartile range table 2. shock wave lithotripsy treatment parameters and the results of treatment swl for hydronephrotic lower pole stones with full bladder-hazar et al. ly different between group a and group c. group c showed a statistical advantage over group a in terms of stone expulsion rate after three or more sessions (table 3). discussion achieving sf status for renal lower pole stones after swl treatment remains a controversial issue. swl is a noninvasive and ambulatory modality for removal of lower calyceal stones. according to the european guidelines for urolithiasis management, swl is considered the treatment of choice in the absence of unfavorable factors for calyceal stones smaller than 20 mm.(5) in order to achieve complete clearance of stones after swl, supportive measures are attempted to overcome unfavorable condition of the lower calyx.(6) parenteral or oral hydration, inversion and pharmacologic diuresis have been utilized to dislodge stone fragments and all these are well tolerated by patients after swl.(7) in several previous series, patients which were placed into prone trendelenburg position at 45o-70º, were administered diuretics and oral hydration immediately before therapy, underwent flank percussion. the results suggest the contributing effect of auxiliary methods in stone fragments expulsion.(7,8) in this study, we prospectively evaluated the combined effect of both hydronephrosis induced by full-bladder and prone positioning in improving the clearance of fragmented lower calyceal stones and overall sf rates. the aim was to enhance the effect of gravity by prone positioning with fragment flushing by induced hydronephrosis during swl avoiding the discomfort in exagerated inverted position previously reported in other series. the positioning of the patient for all urinary stone locations remains to be a controversial issue; there is a debate about the positioning of patients during swl. some authors believe that supine position is cost effective with low morbidity. on the other hand, some authors are in favor of prone positioning.(9) beside the role of prone or supine positioning, higher fluid amount with lower viscosity in calyces is of utmost important not only to increase pressure for easy expulsion of fragments but also for sufficient acoustic cavitation to assure fragmantation. in order to understand this effect, one must remember that swl acts through four mechanisms; compressive fracture, spallation, acoustic cavitations, and dynamic fatigue.(10) cavitation is the leading mechanism of swl action in fragmentation. this acoustic phenomena requires high amount of fluid with low viscosity. in the actual disintegration process, the high-speed imaging analysis displays the progress of stone fragmentation related to time. first cracks appear to be produced by the initial shockwave. then, after the surrounding fluid penetrates the cracks, the actual disintegration of stone substance occurs as a result of collapsing cavitation bubble.(11) in the present study as well, we tried to increase hydrostatic pressure in the renal calyces and pelvis through oral hydration and full-bladder without causing positional discomfort to the patient. there are some limitiations to our study; first, we did not classify the sf rates according to stone sizes, second, lack of data on stone composition. conclusions the prone position and naturally induced hydronephrosis seem to have significantly adjunct effect on swl treatment of lower calyceal stones. therefore, we suggest that prone position with bladder fullness coincide with better outcomes in swl patients. conflict of interest none declared. references 1. lingeman je, siegel yi, steele b, et al. management of lower pole nephrolithiasis: a critical analysis. j urol. 1994; 151: 663-7. 2. raman jd, pearle ms. management options for lower pole renal calculi. cur opin urol. 2008; 18: 214-9. 3. albanis s, ather hm, papatsoris ag, et al. inversion, hydration and diuresis during extracorporeal shock wave lithotripsy: does it improve the stone-free rate for lower pole stone clearance? urol int.2009; 83: 211-216. 4. cakiroglu b, sinanoglu o, tas t, hazar ia, balci mbc. the effect of inclined position on stone free rates in patients with lower caliceal stones during swl session. arch ital urol androl. 2015; 87: 38-40. table 3. post hoc analyses for expulsion proportions within each week 1st session 2nd session 3rd or later session absolute difference critical range absolute difference critical range absolute difference critical range a versus b 0.15* 0.12 0.04 0.15 0.03 0.12 a versus c 0.27* 0.13 0.05 0.15 0.11* 0.10 b versusc 0.12 0.15 0.01 0.15 0.08 0.10 *: significant difference figure 1. flow diagram of the study. swl for hydronephrotic lower pole stones with full bladder-hazar et al. endourology and stone diseases 16 vol 15 no 03 may-june 2018 17 5. turk c, knoll t, petrik a, et al. eau guidelines for urolitihiasis.2014 6. leong ws, liong ml, liong yv, et al. does simultaneous inversion during extracorporeal shock wave lithotripsy improve stone clearance: a long-term, prospective, singleblind, randomized controlled study. urology. 2014; 83:40-4. 7. chiong e, hwee st, kay lm, liang s, kamaraj r, esuvaranathan k. randomized controlled study of mechanical percussion, diuresis and inversion therapy to asist passage of lower pole renal calculi after shock wave lithotripsy. urology. 2005;65:1070-4. 8. pace kt, tariq n, dyer sj, et al. mechanical percussion, inversion and diuresis for residual lower pole fragments after shock wave lithotripsy: a prospective, single blind, randomized controlled trial. j urol 2001; 166: 2065–71. 9. elahian a, ghorbani n, tavoosi a. comparison of the effect of body position, prone or supine, on the result of extracorpreal shock wave lithotripsy in patients with stones in the proximal ureter afshar zomorrodi. saudi j kidney dis transpl 2007; 18: 200-5 10. zomorrodi a, golivandan j, samady j. effect of diuretics on ureteral stone therapy with extracorporeal shock wave lithotripsy. saudi j kidney dis transpl 2008; 19(3): 397-400. 11. azm ta, higazy h. effect of diuresis on extracorporeal shockwave lithotripsy treat¬ment of ureteric calculi. scand j urol nephrol. 2002; 36(3): 209-12. swl for hydronephrotic lower pole stones with full bladder-hazar et al. vol 16 no 03 may-june 2019 260 urological oncology impact and predictive value of prostate weight on the outcomes of nerve sparing laparoscopic radical prostatectomy in patients with low risk prostate cancer dong-gen jiang1, chu-tian xiao2, yun-hua mao2, jian-guang qiu2, jie si-tu2, min-hua lu2, xin gao2* purpose: to investigate the impact of prostate weight on outcomes of nerve sparing laparoscopic radical prostatectomy (lrp) and assess its predictive value on postoperative continence and potency recovery. materials and methods: we conducted a retrospective study on the clinical data of 165 patients with low risk prostate cancer (pca) who underwent nerve sparing lrp. all the patients included had normal preoperative urinary and sexual function. the association of prostate weight with perioperative data was assessed using spearman correlation coefficient. univariate and multivariate cox regression analyses were employed to identify prognostic predictors for continence and potency recovery. results: increased prostate weight was significantly associated with older age, higher prostate-specific antigen (psa), lower biopsy and pathological t stage and gleason score, longer operative time, and higher estimated blood loss (p < .05). the continence rates at the 3rd, 6th, and 12th month after surgery were 63.6% (105/165), 87.9% (145/165), and 95.8% (158/165); and the potency rates were 44.8% (74/165), 62.4% (103/165) and 77.6% (128/165), respectively. furthermore, multivariate cox analysis showed that patient age (hr = 0.52, 95% ci: 0.350.76) and prostate weight (hr = 0.54, 95% ci: 0.34-0.86) were independent predictors for continence recovery, while only patient age (hr = 0.66, 95% ci: 0.45-0.96) could independently predict potency recovery. conclusion: larger prostate size was correlated with older age, higher psa, lower tumor stage and grade, longer operative time, and more intraoperative blood loss in low risk pca patients. increased prostate weight may independently predict poor continence recovery after nerve sparing lrp. keywords: erectile dysfunction; prostatectomy; prostatic neoplasms; prostate size; prognosis; treatment outcome; urinary incontinence introduction following the introduction of anatomic radical pros-tatectomy (rp) by walsh pc,(1) this procedure has become a routine treatment modality for localized prostate cancer (pca) worldwide. however, incontinence and erectile dysfunction after rp for early stage pca can significantly affect the quality of life (qol) of patients, especially for those with preoperative normal potency.(2) the intrafascial approach nerve sparing rp has been reported to be apply to low risk pca patients,(3-5) which enables the dissection of the prostate with limited trauma to the surrounding fascias and the enclosed neurovascular bundle (nvb). patients who underwent nerve sparing laparoscopic radical prostatectomy (lrp) could achieve accelerated rehabilitation of continence and potency to a high percentage, without unfavorable effect on the oncological outcomes.(5) as the introduction of prostate-specific antigen (psa) screening and the prevalence of active surveillance, men diagnosed with clinically organ-confined pca have presented with larger prostate weight.(6) the application of external-beam radiation therapy and brachytherapy in pca with large gland size is technical1department of urology, the seventh affiliated hospital of sun yat-sen university, no.628 zhenyuan road, shenzhen 518107, china. 2department of urology, the third affiliated hospital of sun yat-sen university, no.600 tianhe road, guangzhou 510630, china. *correspondence: department of urology, the third affiliated hospital of sun yat-sen university, no.600 tianhe road, guangzhou 510630, china. tel: + 86 20 85252990. fax: +86 20 85252678. e-mail: urogx@hotmail.com. received december 2017 & accepted may 2018 ly limited, which makes rp the treatment of choice.(7,8) nevertheless, rp for larger prostates is associated with longer operative time, greater blood loss, and higher surgical difficulty.(9-11) there are several published data analyzing the impact of prostate size on perioperative and functional outcomes of rp,(9-14) while no consensus has been reached. to date, the effect of prostate size on outcomes of nerve sparing lrp remains unclear. the purpose of our study was to explore the association of prostate weight with perioperative data of patients with low risk pca, and assess the predictive value of prostate weight on continence and potency recovery after nerve sparing lrp. materials and methods enrollment this study was conducted after the approval of the ethics committee of the third affiliated hospital of sun yat-sen university (no. [2015] 2-130). we retrospectively reviewed the records of pca patients from the pca database of our hospital, and those without completed clinical data were excluded from the research population. between january 2002 and december 2014, a total of 967 men underwent lrp at our institution, 165 consecutive low risk pca patients with preoperative normal urinary and sexual function who received nerve sparing lrp were included in the study. low risk pca was identified according to the d'amico risk stratification scheme (clinical t stage ≤ ct2a, psa < 10 ng/ml, and a gleason score < 7).(15) the 2002 american joint committee on cancer tnm staging system was applied for both clinical and pathological staging. gleason score was evaluated according to the international society of urological pathology 2005 guidelines. (16) lrp specimen was submitted in their entirety and prostate weight, which included the prostate, seminal vesicles, and vasa deferentia stumps, was measured at the time of pathological examination by the pathologist. no patient had contraindications for general anesthesia and all the procedures were performed by one experienced surgeon (xin gao). written consent from patients of the study cohort was considered, while as this was a retrospective study in which most of the data were obtained more than 5 years ago and all data were analyzed anonymously, it was considered not needed. surgical technique the patient positioning, trocar placement, and the major steps of the surgery have been previously described in detail.(5,17) we focus here on the pivotal surgical essentials of our technique. all the patients included received a bilateral intrafascial nerve sparing approach, the intrafascial plane is developed between the prostatic fascia and the capsule after the posterior plane is developed. the prostatic fascia is incised by sharp and athermic dissection from prostate capsule to facilitate complete mobilization and lateralization of the nvb off the prostate. to be noted, the dissection is initiated at the middle of the prostate and continued in a retrograde direction towards the base of prostate to completely detach the nvb from the prostatic pedicles. then the prostatic pedicles are clipped by hem-o-lok® clips and detached with athermic scissor without injuring the nvb. subsequently, the dissection plane is continued in a descending manner towards the apex. before vesicourethral anastomosis, an approximate 15-cm long absorbable self-retaining suture (quilltm srs) with one fiveeighths arc needle is prepared. the bladder neck is firstly narrowed with running suture from the dorsal edge to form a “tennis racket” shape. then the continuous suture of the anastomosis is initiated by passing the needle from the outside in on the full thickness of bladder neck and then from the inside out on the full thickness of the urethra at 4 o’clock position. subsequently, the running suture is continued at 6, 8, 10, 12 and 2 o’clock position, respectively, to complete the vesicourethral anastomosis. postoperative care the urethral catheter was removed in case no anastomotic leakage was detected using cystography. after catheter removal, patients were guided to carry out daily pelvic floor muscle training. all the patients received phosphodiesterase 5 inhibitors (pde5-is) (sildenafil 25mg per day) for the first eight weeks postoperatively and thereafter as subjectively needed. besides, rehabilitation using vacuum erection device was also recommended 3 weeks after the surgery once they returned to continence. outcomes assessment urinary and sexual functions were evaluated with self-administered validated questionnaires preoperatively and at the 3rd, 6th, and 12th month after surgery, and then simultaneously during the follow-up visits or telephone interviews. all answers were collected by a special independent research staff member. urinary function was assessed using international continence society questionnaire and continence was defined as no pad or a protective pad daily. sexual function was evaluated by the use of sexual health inventory for men (shim) questionnaire,(18) which is a shortened five-question version of the international index of erectile function. potency was defined as shim score ≥ 21, with or without the use of oral pde5-is. comimpact of prostate weight on nerve sparing lrp-jiang et al. table 1. correlation between prostate weight and preoperative characteristics of the 165 patients with low risk prostate cancer. variables total (%) prostate weight r p-value < 75 g (%) ≥ 75 g (%) all cases 165 (100) 124 (75.2) 41 (24.8) age (year) .369 < .001 < 65 89 (53.9) 80 (64.5) 9 (22.0) ≥ 65 76 (46.1) 44 (35.5) 32 (78.0) bmi ( kg/m2) -.116 .137 < 24 72 (43.6) 50 (40.3) 22 (53.7) ≥ 24 93 (56.4) 74 (59.7) 19 (46.3) preoperative psa (ng/ml) < 7 78 (47.3) 65 (52.4) 13 (31.7) .179 .021 7-10 87 (52.7) 59 (47.6) 28 (68.3) comorbidities .010 .901 0 54 (32.7) 41 (33.1) 13 (31.7) 1 79 (47.9) 59 (47.6) 20 (48.8) ≥ 2 32 (19.4) 24 (19.3) 8 (19.5) clinical t stage -.166 .034 ≤ ct1c 115 (69.7) 81 (65.3) 34 (82.9) ct2a 50 (30.3) 43 (34.7) 7 (17.1) biopsy gleason score < 6 29 (17.6) 17 (13.7) 12 (29.3) -.177 .023 6 136 (82.4) 107 (86.3) 29 (70.7) abbreviations: bmi, body-mass index; psa, prostate-specific antigen. urological oncology 261 vol 16 no 03 may-june 2019 262 plications occurring during the surgical procedure or within 3 months after surgery were documented and classified according to the modified clavien grading system.(19) positive surgical margin (psm) was defined as the presence of tumor tissue on the inked surface of the specimen. statistical analysis the data were analyzed using ibm statistical package for the social science (spss inc, chicago, illinois, usa) version 20.0. continuous parametric variables were presented as the median value and interquartile range. the association between prostate weight and perioperative data of the patients were evaluated by spearman correlation coefficient. univariate and multivariate analysis using cox proportional-hazards regression model were performed to identify independent prognostic predictors for continence and potency recovery during the follow-up. all tests of significance were two sided, and p < .05 indicated statistical significance. results association between prostate weight and preoperative characteristics the median patient age was 65 (61-68) years, body mass index (bmi) was 24 (22-27) kg/m2, preoperative psa was 6.9 (5.3-8.6) ng/ml, and prostate weight was 48 (27-74) g. as showed in table 1, after assessing by spearman correlation coefficient, prostate weight was found to be significantly associated with patient age (r = .369, p < .001), preoperative psa level (r = .179, p = .021), clinical t stage (r = -.166, p = .034) and biopsy gleason score (r = -.177, p = .023). patients with large prostate weight were likely to have older age, higher psa level, and earlier tumor stage. however, no remarkable correlation was observed between prostate weight and bmi, as well as preoperative comorbidities (p > .05). correlation of prostate weight with perioperative and pathological outcomes the perioperative patient data and pathological outcomes are demonstrated in table 2. the median operative time was 207 (185-236) mins, estimated blood loss was 245 (150-400) ml, hospital stay was 12 (11-14) days and catheterization time was 9 (8-11) days. the bilateral nerve sparing procedures were conducted in all cases. despite the described strict inclusion criteria, tumors with pathological t stage > pt2b were demonstrated in 25 (15.2%) patients. similarly, tumors with pathological gleason score > 7 were found in 9 (5.5%), while the incidence of psm was only 9.7% (16/165). in the spearman correlation coefficient analysis, larger prostate weight was remarkably correlated with longer operative time (r = .221, p = .004), more estimated blood loss (r = .179, p = .022), lower pathological t stage (r = -.168, p = .031) and gleason score (r = -.181, p = .020). whereas no significant association was found between prostate weight and blood transfusion, hospital stay, catheterization time, perioperative complications, and psm (p > .05). predictive value of prostate weight on continence and potency recovery the median follow-up was 44 months with a range of 13-113 months. during the follow-up period, the contitable 2. association of prostate weight with perioperative and pathological outcomes of the 165 patients after lrp. variables total (%) prostate weight r p-value < 75 g (%) ≥ 75 g (%) all cases 165 (100) 124 (75.2) 41 (24.8) operative time (min) .221 .004 < 200 80 (48.5) 68 (54.8) 12 (29.3) ≥ 200 85 (51.5) 56 (45.2) 29 (70.7) estimated blood loss (ml) .179 .022 < 250 86 (52.1) 71 (57.3) 15 (36.6) ≥ 250 79 (47.9) 53 (42.7) 26 (63.4) blood transfusion .062 .429 no 160 (97.0) 121 (97.6) 39 (95.1) yes 5 (3.0) 3 (2.4) 2 (4.9) hospital stay (day) .095 .226 < 12 82 (49.7) 65 (52.4) 17 (41.5) ≥ 12 83 (50.3) 59 (47.6) 24 (58.5) catheterization time .060 .441 < 9 73 (44.2) 57 (46.0) 16 (39.0) ≥ 9 92 (55.8) 67 (54.0) 25 (61.0) perioperative complications .122 .119 none 134 (81.2) 104 (83.9) 30 (73.2) clavien i-ii 27 (16.4) 18 (14.5) 9 (22.0) clavien iii-iv 4 (2.4) 2 (1.6) 2 (4.8) pathological t stage -.168 .031 pt2a 92 (55.8) 63 (50.8) 29 (70.7) pt2b 48 (29.1) 40 (32.3) 8 (19.5) ≥ pt2c 25 (15.2) 21 (16.9) 4 (9.8) pathological gleason score -.181 .020 < 7 122 (73.9) 86 (69.4) 36 (87.8) 7 34 (20.6) 30 (24.2) 4 (9.8) ≥ 8 9 (5.5) 8 (6.4) 1 (2.4) positive surgical margin .127 .104 no 149 (90.3) 114 (92.0) 35 (85.4) yes 16 (9.7) 10 (8.0) 6 (14.6) abbreviations: lrp, laparoscopic radical prostatectomy. impact of prostate weight on nerve sparing lrp-jiang et al. nence rates at the 3rd, 6th, and 12th month after surgery were 63.6% (105/165), 87.9% (145/165), and 95.8% (158/165); and the potency rates were 44.8% (74/165), 62.4% (103/165) and 77.6% (128/165), respectively. for univariate and multivariate cox proportional hazards analysis, the first subgroup of each variable has been set as the reference (comparative level). as demonstrated in tables 3 and 4, both univariate and multivariate cox analysis indicated that patient age (hr = 0.52, 95% ci: 0.35-0.76, p = .001) and prostate weight (hr = 0.54, 95% ci: 0.34-0.86, p = .009) were independent predictors for continence recovery, while only patient age (hr = 0.66, 95% ci: 0.45-0.96, p = .029) could independently predict potency recovery. since prostate weight was strongly correlated with patient age in the spearman correlation coefficient analysis, data were further evaluated by stratified models, aiming to confirm predictive value of prostate weight independent of patient age. we also performed cox regression analysis according to subgroups of patient age (data not shown). the p value for prostate weight in continence recovery prediction in the stratified model was .011, which confirmed that prostate weight was an independent predictor for continence recovery. discussion widespread psa screening, combined with the technical improvement of prostate biopsy, has resulted in increased diagnosis of pca and detection of lower grade and earlier stage disease. the morbidity and mortality of pca in china, although not as high as those in the table 3. univariate and multivariate analysis of prognostic factors for continence. variables univariate multivariate hr (95%ci) p-value hr (95%ci) p-value age (< 65 vs. ≥ 65 years) 0.48 (0.34-0.66) < .001 0.52 (0.35-0.76) .001 bmi (< 24 vs. ≥ 24 kg/m2) 1.31 (0.96-1.80) .087 0.73 (0.52-1.02) .063 preoperative psa (< 7 vs. 7-10 ng/ml) 0.70 (0.51-0.96) .026 0.83 (0.58-1.19) .310 prostate weight (< 75 vs. ≥ 75 g) 0.50 (0.34-0.72) < .001 0.54 (0.34-0.86) .009 clinical t stage (≤ ct1c vs. ct2a) 0.70 (0.50-0.99) .041 0.70 (0.49-1.01) .053 biopsy gleason score (< 6 vs. 6) 0.84 (0.56-1.26) .387 0.68 (0.44-1.07) .095 operative time (< 200 vs. ≥ 200 mins) 0.98 (0.72-1.34) .900 1.20 (0.85-1.69) .295 estimated blood loss (< 250 vs. ≥ 250 ml) 0.83 (0.61-1.23) .224 0.84 (0.60-1.17) .290 perioperative complications .105 .181 none 1 (reference) 1 (reference) clavien i-ii 0.70 (0.46-1.08) .109 0.73 (0.46-1.18) .201 clavien iii-iv 0.46 (0.17-1.25) .129 0.44 (0.15-1.30) .135 pathological t stage .270 .487 pt2a 1 (reference) 1 (reference) pt2b 1.19 (0.83-1.69) .342 1.20 (0.81-1.75) .364 ≥ pt2c 0.79 (0.50-1.24) .304 0.88 (0.51-1.51) .639 pathological gleason score .494 .322 < 7 1 (reference) 1 (reference) 7 1.00 (0.68-1.47) .993 1.13 (0.74-1.73) .572 ≥ 8 0.66 (0.34-1.31) .238 0.61 (0.28-1.31) .202 positive surgical margin (no vs. yes) 0.53 (0.30-0.94) .029 0.62 (0.34-1.15) .128 abbreviations: bmi, body-mass index; psa, prostate-specific antigen; hr, hazard ratio; ci, confidence interval. variables univariate multivariate hr (95%ci) p-value hr (95%ci) p-value age (< 65 vs. ≥ 65 years) 0.63 (0.46-0.87) .005 0.66 (0.45-0.96) .029 bmi (< 24 vs. ≥ 24 kg/m2) 0.84 (0.61-1.15) .271 0.90 (0.64-1.27) .560 preoperative psa (< 7 vs. 7-10 ng/ml) 0.85 (0.62-1.16) .290 1.11 (0.79-1.56) .539 prostate weight (< 75 vs. ≥ 75 g) 0.89 (0.62-1.28) .528 0.93 (0.58-1.50) .763 clinical t stage (≤ ct1c vs. ct2a) 0.73 (0.52-1.03) .072 0.79 (0.55-1.15) .224 biopsy gleason score (< 6 vs. 6) 0.97 (0.64-1.46) .881 1.04 (0.67-1.62) .854 operative time (< 200 vs. ≥ 200 mins) 0.72 (0.53-0.99) .004 0.73 (0.52-1.03) .077 estimated blood loss (< 250 vs. ≥ 250 ml) 1.19 (0.87-1.63) .280 1.22 (0.87-1.72) .251 perioperative complications .243 .100 none 1 (reference) 1 (reference) clavien i-ii 1.13 (0.74-1.71) .574 1.02 (0.65-1.60) .923 clavien iii-iv 0.40 (0.13-1.27) .121 0.27 (0.08-0.90) .034 pathological t stage .362 918 pt2a 1 (reference) 1 (reference) pt2b 0.96 (0.68-1.37) .840 0.94 (0.64-1.37) .741 . ≥ pt2c 0.72 (0.45-1.14) .158 0.92 (0.56-1.51) .738 pathological gleason score .045 .085 < 7 1 (reference) 1 (reference) 7 1.06 (0.73-1.56) .756 0.92 (0.61-1.41) .707 ≥ 8 0.39 (0.18-0.83) .015 0.39 (0.17-0.90) .026 positive surgical margin (no vs. yes) 1.31 (0.75-2.27) .343 1.31 (0.72-2.39) .380 abbreviations: bmi, body-mass index; psa, prostate-specific antigen; hr, hazard ratio; ci, confidence interval. impact of prostate weight on nerve sparing lrp-jiang et al. table 4. univariate and multivariate analysis of prognostic factors for potency. urological oncology 263 vol 16 no 03 may-june 2019 264 western countries, were increasing markedly during the past decade.(20) rp has been established as the most durable treatment option for patients with clinically localized pca, especially for those with good life expectancy. following the first performance of lrp by gao et al. in china,(21) this procedure has become a routine treatment modality for localized pca in large medical centers of the country. actually, the development of minimally invasive surgical techniques has resulted in greater focus on achieving optimal functional outcomes and qol in patients after rp. hence, the effect of various patient characteristics on outcomes of the surgery, especially for younger patients with preoperative potency, needs to be assessed comprehensively to provide valuable guidance for surgeons and patients. although lrp is generally safe in patients with large prostates, removal of larger gland is commonly believed to be more technically challenging.(9-11) the current study analyzed the impact of prostate weight on outcomes of nerve sparing lrp for treatment of low risk pca, and assessed the predictive value of prostate weight for postoperative continence and potency recovery. to our knowledge, no standard definition of a large prostate has ever been demonstrated, while the prostates of > 75 g versus those < 75 g were reported to be significantly different in surgical margin status, estimated blood loss and psa failure-free survival rate.(12,13) thus we divided the patients into two groups, according to the prostate weight of < 75 g or ≥ 75 g, for the data analyzing in our research. most series have reported that patients with larger prostates experienced longer operative time, higher intraoperative blood loss, and lower pathological stage than those with smaller prostates, while there is no consistence with regard to the influence of prostate weight on psm and transfusion rate.(913) in our study series, the psm rate was 9.7% (16/165), and 84.8% (140/165) of the cases had a pathological t stage of ≤ pt2b, which were both more improved than those presented in the above series. the main reason might be that all cases included in the present research were low risk localized pca. in addition, our data showed that older patients tend to have lager prostate weight. actually, it is common that pca patients have a comorbidity of benign prostatic hyperplasia, which occurred in 50% of men 60 years or older and 80% of men 80 years or older,(22) this may explain why older patients were likely to have larger prostate weight in our study. similarly, we found that increased prostate weight was significantly associated higher psa level, lower biopsy and pathological t stage and gleason score in the low risk pca cohort. this result is not surprising, the increased psa production from enlarged adenoma tissue may lead to earlier detection and biopsy in the natural history of pca, making the diagnosis of comparatively lower risk tumor. furthermore, it is easy to understand that increased prostate weight was associated with longer operative time and higher intraoperative blood loss. as the poor visualization caused by a large prostate size makes it more challenging to expose and dissect surrounding tissues of the gland, which might lead to either direct or indirect injuries to blood vessels. the central goal of rp is complete extirpation of the primary tumor, while patients’ qol could be negatively influenced by the presence of urinary incontinence and erectile dysfunction. therefore, more effective prognostic predictors for continence and potency recovery after rp are required to provide professional consultation for patients before surgery. in the multivariate cox regression analysis, we identified larger prostate weight as an independent predictor for poor continence recovery, which is in line with our previous research(23) conducted in high risk pca patients. moreover, we found that smaller patient age could predict better continence and potency recovery. this finding is in accordance with the results of the study conducted in 3,477 patients by kundu sd et al.(24) urinary incontinence and erectile dysfunction after lrp are multifactorial including neurogenic and vasculogenic injuries due to traction, direct transaction, thermal injury or incorporation into haemostatic sutures with clips.(25, 26) the postoperative continence and potency recovery may therefore be compromised, especially in patients with large prostate as the technical challenge during the procedures. in the present study, the continence rates at the 3rd, 6th, and 12th month after surgery were 63.6%, 87.9%, and 95.8%; and the potency rates were 44.8%, 62.4% and 77.6%, respectively. our results compared favorably with the majority of recently published series of patients treated with nerve sparing rp,(3-5) as we have conducted a precise anatomical intrafascial nerve sparing approach during the surgeries. the prostatic fascia, lateral pelvic fascia, and anterior layer of denonvillier’s fascia fuse with each other posterolateral to the prostate, and form a potential triangular space containing nvb. (27, 28) the intrafascial plane is the plane between the prostate capsule and the prostatic fascia, which could preserve almost all nvb fibers even if they distribute in a more dispersed shape.(3-5) besides, we have performed a retrograde dissection approach in our nerve sparing lrp, as it could identify and release nvb from the prostate before ligation of the prostatic pedicles to avoid traction and potential injuries to nvb by any subsequent manipulation of the prostate. the major strengths of the present study include the use of validated questionnaires to assess functional outcomes. furthermore, all lrps of the series were performed by one single surgeon, maintaining consistency of all surgical techniques. simultaneously, there are certain limitations in our study. first, the weak point of the present study is inherent in its retrospective nature. in addition, the relatively small number of patients included is also the shortcoming. however, it’s enough to guarantee statistical significance. conclusions in summary, our data suggested that increased prostate weight was significantly associated with older patient age, higher preoperative psa level, lower tumor stage and grade, longer operative time, and higher intraoperative blood loss in patients with low risk pca. larger prostate weight might be an independent prognostic predictor for poor continence recovery after nerve sparing lrp, and it could be beneficial for patient counseling on the functional outcomes after surgery. acknowledgements the authors acknowledge financial support received from the national natural science foundation of china (81572503, 81772722), the clinical medical research and transformation centre projects of guangzhou, china (201604020006), and the science and technology planning project of guangdong province impact of prostate weight on nerve sparing lrp-jiang et al. (702206453235). conflicts of interest none declared. references 1. walsh pc. anatomic radical prostatectomy: evolution of the surgical technique. j urol. 1998;160:2418-24. 2. donovan jl, hamdy fc, lane ja, et al. patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. n engl j med. 2016;375:1425-37. 3. stewart gd, el-mokadem i, mclornan me, stolzenburg ju, mcneill sa. functional and oncological outcomes of men under 60 years of age having endoscopic surgery for prostate cancer are optimal following intrafascial endoscopic extraperitoneal radical prostatectomy. surgeon. 2011;9:65-71. 4. stolzenburg ju, kallidonis p, do m, et al. a comparison of outcomes for interfascial and intrafascial nerve-sparing radical prostatectomy. urology. 2010;76:743-8. 5. stolzenburg ju, rabenalt r, do m, et al. intrafascial nerve-sparing endoscopic extraperitoneal radical prostatectomy. eur urol. 2008;53:931-40. 6. feneley mr, landis p, simon i, et al. today men with 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gl, luo y, di jm, et al. predictors of urinary continence recovery after modified radical prostatectomy for clinically high-risk prostate cancer. urol j. 2015;12:2021-7. 24. kundu sd, roehl ka, eggener se, antenor ja, han m, catalona wj. potency, continence and complications in 3,477 consecutive radical retropubic prostatectomies. j urol. 2004;172:2227-31. 25. kumar a, tandon s, samavedi s, mouraviev v, bates as, patel vr. current status of various neurovascular bundle-sparing techniques in robot-assisted radical prostatectomy. j robot surg. 2016;10:187-200. 26. mustafa m, davis jw, gorgel sn, pisters l. robotic or open radical prostatectomy in men with previous transurethral resection of prostate. urol j. 2017;14:2955-60. 27. ganzer r, stolzenburg ju, wieland wf, impact of prostate weight on nerve sparing lrp-jiang et al. urological oncology 265 vol 16 no 03 may-june 2019 266 brundl j. anatomic study of periprostatic nerve distribution: immunohistochemical differentiation of parasympathetic and sympathetic nerve fibres. eur urol. 2012;62:1150-6. 28. alsaid b, karam i, bessede t, et al. tridimensional computer-assisted anatomic dissection of posterolateral prostatic neurovascular bundles. eur urol. 2010;58:2817. impact of prostate weight on nerve sparing lrp-jiang et al. the effect of urinary catheters on microbial biofilms and catheter associated urinary tract infections sahra kırmusaoğlu1*, seyhun yurdugül2, ahmet metin3, suphi vehid4 purpose: the aims of this study were to determine relationship between biofilm producer microorganisms attached to urinary catheters (ucs) and urinary catheter-associated urinary tract infections (cautis), to determine the rate of cauti development and the relationship between cauti and catheterization period in catheterized patients. materials and methods: urinary catheters from 143 inpatients who were hospitalized in abant izzet baysal university hospital urinary service, and urine samples of these patients before and after catheterization of urinary catheter were collected. culture-based microbiological evaluation of urinary catheters removed from inpatient and urine samples collected from inpatients were performed before and after catheterization of urinary catheter to identify various organisms and determine biofilm production by them. results: the incidence of cautis was 13% (18/143) in catheterized inpatients. biofilm producer microorganisms such as escherichia coli (e. coli ), klebsiella pneumoniae, pseudomonas aeruginosa, proteus mirabilis that were isolated from ucs removed from inpatients were found to cause cauti (p < .001). conclusion: incidence of cautis is increased by the usage of ucs and prolonged catheterization period. keywords: urinary catheter; biofilm; catheter-associated urinary tract infection; escherichia coli; klebsiella pneumonia; pseudomonas aeroginosa; proteus mirabilis. introduction biofilm infections cause problems in hospitalized and immunocompressed patients.(1) indwelling device related urinary tract infections are one of the most common biofilm infections of the urinal system.(2,3) in europe, the mortality rate of nosocomial infections is 10%, 97% of which are related with catheters.(4) approximately 80% of nosocomial urinary tract infections are associated with indwelling urinary catheters.(5) urinary bladder infection that is associated with biofilm causes failure in the drainage of urine due to congestion of catheter lumen that can be caused by crystalline debris of biofilms.(4) biofilm embedded bacterial communities can be made up of heterogeneous cells that can resist immune defence and antibiotics because of their low metabolic activity caused by nutrient and oxygen limitations at the lower parts of the biofilm, decreased penetration of antibiotics through biofilm caused by binding of antibiotics to the structural contents of the biofilm matrix.(1) biofilms have an important role in the pathogenesis of bacteria in indwelling device related infections. biofilms are formed by bacteria, which attach to biotics such as, tissues, or abiotic surfaces such as, medical devices and are slime-like glycocalyx. after colonization of bacteria, mature biofilms disperse 1 department of molecular biology and genetics, faculty of arts and sciences, t.c. haliç university, sütlüce-beyoğlu/istanbul 34445, turkey. 2 department of biology, faculty of arts and sciences, abant izzet baysal university, bolu 14030, turkey. 3 department of urology, faculty of medicine, abant izzet baysal university, bolu 14030, turkey. 4 department of public health, cerrahpaşa faculty of medicine, istanbul university istanbul 34098, turkey. *correspondence: department of molecular biology and genetics, faculty of arts and sciences, t.c. haliç university, sütlüce-beyoğlu/istanbul 34445, turkey. tel: +90 212 924 24 44-1148. fax: +90 212 999 78 52. e-mail: kirmusaoglu_sahra@hotmail.com. received october 2016 & accepted march 2017 which leads to bacterial spread to the whole body.(6, 7,8) antimicrobial resistant indwelling device related infections can cause chronic and recurrent infections. (1) untreated urinary tract infection (uti) can lead to acute pyelonephritis, chronic renal infection, bacterial vaginosis, chronic bacterial prostatitis, bacteraemia and death.(3) enterococcus spp. especially enterococcus faecalis, methicillin resistant staphylococcus aureus (mrsa), escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, proteus mirabilis, staphylococcus epidermidis, providencia stuartii and morganella morganii are the main urinary pathogens that cause biofilm related urinary tract infections.(3,9) the aims of this study were to determine relationship between biofilm producer microorganisms attached to urinary catheters (ucs) and urinary catheter associated urinary tract infections (cautis), to determine the rate of cauti development and the relationship between cauti and catheterization period in catheterized patients. materials and methods study population all patients who had been hospitalized in urology miscellaneous miscellaneous 3028 clinics of abant izzet baysal university faculty of medicine hospital due to health problems which did not include urinary tract infections (uti) in a period of 6 months, were included in study. study participants were inpatients who used urinary catheter, did not have uti, were not immunosuppressed, had no other diseases, and did not take antibiotic prophylaxis before taking catheter out of the body. inclusion criteria was presence of urinary catheter. exclusion criteria were uti, being immunosuppressed, having other diseases, and antibiotic prophylaxis before taking catheter out of the body. informed consent was obtained from all the inpatients participated in the study. this study was approved by ethics committee of clinical studies of t.c. haliç university, institute of health sciences. urine samples of those patients were collected before and after catheterization of urinary catheter to evaluate urine analysis and urine cultures. approximately 4-5 cm long tips of foley urinary catheters were cut by sterile scalpel and transferred to the sterile urine container to culture and detect whether biofilms were formed by microorganisms grew. urine samples taken from the patients before and after the catheterization of urinary catheter were cultured. these samples were processed and evaluated microbiologically and biochemically in abant izzet baysal university department of biology biochemistry laboratory.(table 1) study design and evaluation this study which was performed in prospective single center and on random inpatients was conducted in urology clinics of abant izzet baysal university faculty of medicine hospital in bolu, turkey. inpatients who had urinary catheters participated in this study in the period of 6 months. after informed consent was obtained from all the inpatients participated in the study, and being approved by ethics committee, the study proceeded as explained below. not only development of biofilm producer uropathogens on ucs, but also positivities of urinalysis test that contains leukocyte, nitrite and microorganism, and development of biofilm producer uropathogens in urine were defined as cautis. procedures analysis of urinary catheters and urine urinary catheters were transferred into tryptic soy broth (tsb) (merck tm) and incubated for 24 hours at 37o c. then, after observing microbial growth, a subsequent transfer was done into the blood and emb agars and incubated for 24 hours at 37o c.(10) urines were also inoculated into the blood and emb agar and incubated for 24 hours at 37o c. then, the microorganisms isolated from urinary catheters and urines were identified. the capability of biofilm production of microorganisms was determined by congo red agar method, tube method and microtiter plate assay.(11,12) since not only microbiological growth and development of bacteriuria (higher than 105 cfu/ml of microorganisms grown in urine cultures)(5,13), but also the posithe effect of ucs on microbial biofilms and cautiskırmusaoğlu et al. table 1. all processes of methods urine sample before catheterization urine sample after catheterization urinary catheter culturation of urines culturation of urines culturation of tips of catheters identification of isolates identification of isolates identification of isolates antibiotic susceptibility tests antibiotic susceptibility tests antibiotic susceptibility tests assessment of biofilm production assessment of biofilm production assessment of biofilm production a) qualitative determination of biofilm a) qualitative determination of biofilm a) qualitative determination of biofilm congo red agar method (cra) congo red agar method (cra) congo red agar method (cra) tube method (tm) tube method (tm) tube method (tm) b) quantitative determination of biofilm b) quantitative determination of biofilm b) quantitative determination of biofilm microtiter plate assay microtiter plate assay microtiter plate assay urinalysis test urinalysis test number percentage % urinary catheter / patient 143 100 catheter colonized 75 52 catheter uncolonized 68 48 total microorganisms isolated from catheters 88 100 the incidence of biofilm producer microorganisms in whole microorganisms 18 21 (18/88) the incidence of biofilm related uti 18 13 (18/143) the incidence of biofilm producer microorganisms in catheters colonized 18 24 (18/75) table 2. status of catheters and incidences vol 14 no 02 march-april 2017 3029 tivities of leukocyte (higher than 10 leukocytes per mm3 of urine(14)) and nitrite, and the observation of microorganism in urine microscopy(15) were criterias for the definition of cauti, the complete urinalysis including ph, nitrite, and microscopic (leukocyte, bacteria, crystals) were also performed. identification of microorganisms after incubation of urines and urinary catheters, microorganisms that grow on blood and emb agar media were determined whether they are gram positive or negative according to gram staining. identification of s. aureus was based upon colony morphology on blood and mannitol-salt agar, catalase and coagulase tests. identifications of gram negative bacteria was based upon colony morphology on emb agar, imvic test, and api systems.(10) assessment of mrsa and mrse methicillin resistance of s. aureus and s. epidermidis is determined by cefoxitin by kirby bauer disk diffusion method and broth microdilution method according to the clinical laboratory standards institute criteria 2013 (clsi). bacterial suspensions of staphylococcal strains were prepared in tryptic soy broth (tsb), and adjusted to 0.5 mcfarland (1.108 cfu/ml). the staphylococcal strains from bacterial suspensions were inoculated by the spread plate method to mueller hinton agar, and 30 µg cefoxitin disks were put on the inoculated plate. zone diameters of cefoxitin were measured after incubation in 24 hours at 37°c. the zone measurements were categorized into sensitive (≥ 22 mm), or resistant (≤ 21 mm for cefoxitin) categories.(16) assessment of biofilm production a) qualitative determination of biofilm congo red agar method (cra). the strains isolated from urinary catheters and urines were inoculated to congo red agar media (cra) (merck tm) as described by freeman et al. (1989) to identify whether strains were biofilm producer or not.(11) the cra medium was constructed by mixing 0.8 g of congo red and 36 g of sucrose (sigma, missouri, eua) to 37g/l of brain heart infusion (bhi) agar (oxoid, basingstoke, hampshire, england). after an incubation period of 24 hours at 37°c, morphology of colonies that undergone to different colours were differentiated as biofilm producers or not. black colonies with a dry crystalline consistency indicated biofilm producers, whereas colonies that remained pink were non-biofilm producers. tube method (tm). the biofilm formation of strains that were isolated from urinary catheters and urines was also detected by tube method described by christensen et al. (1985). the strains were inoculated in polystyrene test tube which contained tsb and incubated for 24 h at 37°c.(12) the sessile strains of which biofilms adhered on the walls of polystyrene test tube were stained with saphranin for 1 hour, after planktonic cells were discharged by washing twice with phosphate buffered saline (pbs). then, saphranin stained polystyrene test tube was washed twice with pbs to discharge saphranin stain. after air drying of the test tube, the occurence of visible film lining the walls and the bottom of the tube indicates biofilm production.(12) b) quantitative determination of biofilm preparation of bacterial suspension bacterial suspensions of strains that were isolated from urinary catheters and urines were prepared and adjusted to 0.5 mcfarland (1.108 cfu/ml). this bacterial suspensions were twenty fold (1/20) diluted to gain 5.106 cfu/ml. bacterial suspension was adjusted by ten fold dilution (1/10) in such a way as the final concentration become 5.105 cfu/ml. microtiter plate assay 180 µl of tsb and 10 µl of bacterial suspensions were inoculated into 96-well flat-bottomed sterile polytable 3. microorganisms isolated in urinary catheters and urine samples urinary catheter urine (after catheterization) cauti microorganisms microbial growth biofilm producer microbial growth biofilm producer no % no % no % no % no % s. epidermidis mrse 19 22 14 26 0 0 0 0 0 0 msse 2 2 1 2 0 0 0 0 0 0 s. aureus mrsa 18 20 9 17 0 0 0 0 0 0 mssa 2 2 2 4 0 0 0 0 0 0 e. coli 29 33 18 34 14* 78 14* 78 14* 78 klebsiella pneumonia 4 5 1 2 1* 6 1* 6 1* 6 candida albicans 8 9 4 8 0 0 0 0 0 0 streptococcus spp. 3 3 1 2 0 0 0 0 0 0 pseudomonas aeroginosa 2 2 2 4 2* 11 2* 11 2* 11 proteus mirabilis 1 1 1 2 1* 6 1* 6 1* 6 total 88 100 53 100 18* 100 18* 100 18* 100 abbreviations: %, percentage; no, number. * parameters which defines cauti were compared by pearson χ2 test (χ2: 49.685, p < .001). the effect of ucs on microbial biofilms and cautiskırmusaoğlu et al. miscellaneous 3030 styrene microplate (lp italiana spa tm) to obtain 5.105 cfu/ml as a final concentration (ten fold dilution (1/10)). uninoculated wells containing sterile tsb were used as negative controls. microplates incubated at 24 h at 37°c. the sessile isolates of which biofilms formed on the walls of wells of microplate were stained with saphranin for 1 hour, after planktonic cells in wells of microplate had discharged by washing twice with phosphate-buffered saline (pbs) (ph 7.2) and wells had dried at 60 °c for 1 h.(12) then, saphranin stained wells of microplates were washed twice with pbs to discharge saphranin stain. after air drying process of wells of microplate, biofilms lined the walls of the microplate were measured spectrophotometrically at 595 nm by a microplate reader (thermo instruments tm). the studies were repeated in triplicates. uninoculated table 4. the catheterization periods and microorganisms that caused catheter-associated uti microorganisms isolated in urinary catheters microorganisms isolated in urines urinalysis cath sex per. m.o.s biofilm m.o.s biofilm m.o.s in urine (cfu/ml) leuko. (per mm3 of urine) ph nitrite 1 f p. aeroginosa positive p. aeroginosa positive > 105 > 10 6.5 + 1 f e. coli positive e. coli positive > 105 > 10 5 + (esbl +) 1 m e. coli positive e. coli positive > 105 > 10 5 + (esbl +) 1 m e. coli positive e. coli positive > 105 > 10 8 + (esbl +) 2 f e. coli positive e. coli positive > 105 > 10 6.5 + 2 m e. coli positive e. coli positive > 105 > 10 6.5 + 2 f p. positive p. aeroginosa aeroginosa positive > 105 > 10 6.5 + 2 m k. pneumonia positive k. positive > 105 > 10 5 + pneumonia 3 f e. coli positive e. coli positive > 105 > 10 6.5 + 4 m e. coli positive e. coli positive > 105 > 10 6.5 + (esbl +) 4 f e. coli positive e. coli positive > 105 > 10 6.5 + 4 f e. coli positive e. coli positive > 105 > 10 6.5 + 7 f e. coli positive e. coli positive > 105 > 10 7.5 + (esbl +) 7 m e. coli positive e. coli positive > 105 > 10 6.5 + 7 f e. coli positive e. coli positive > 105 > 10 6.5 + 7 m e. coli positive e. coli positive > 105 > 10 5 + (esbl +) 8 m proteus positive proteus positive > 105 > 10 6.5 + mirabilis mirabilis 21 m e. coli positive e. coli positive > 105 > 10 5.5 + abbreviations: cath. per., catheterization periods; m.o.s, microorganisms; leuko, leukocytes; f, female; m, male. the effect of ucs on microbial biofilms and cautiskırmusaoğlu et al. vol 14 no 02 march-april 2017 3031 wells containing sterile tsb that were considered to be the negative controls used as blanks. the blank absorbance values were used to identify whether biofilm formation of isolates exist or not. the wells of isolates of which od values are higher than blank well are considered to be biofilm producers. the statistical analysis the data were analyzed by the spss software version 21 that is licensed to istanbul university. pearson χ2 test was used to detect existence of significance between the cultures of urinary catheter and urine, and between urine samples that were taken before and after catheterization. as a result of which existence of significance between the urinary catheter and biofilm related urinary tract infection were detected. all results were considered statistically significant if the p-value was equal to or less than 0.05. results 143 urinary catheter samples were collected from inpatients (age ranges from 20 to 75, 33 female, 110 male) who had been hospitalized in urology clinics of abant izzet baysal university faculty of medicine hospital due to health problems which did not include urinary tract infections (uti) in a period of 6 months. 88 strains of microorganisms were isolated from urinary catheters of 68 patients among 143 (table 2). 18 strains of microorganisms were isolated from the urines that were taken after catheterization of inpatients, but, on the other hand, no microorganisms were found in any urine samples taken before catheterization. the strains of e. coli, klebsiella pneumonia, pseudomonas aeroginosa and proteus mirabilis were isolated from the urines that were taken after catheterization of inpatients (table 3). not only growth of definite species in biofilms of urinary catheters were observed, but also heterogeneous microorganisms grew in biofilms of urinary catheters. heterogeneous microorganisms that grew in biofilms of urinary catheters were, mostly, candida albicans, mrsa and e. coli. some of the isolates from the urinary catheters including e. coli, klebsiella pneumonia, candida albicans, streptococcus spp., mrsa, mssa, mrse and msse were found to be biofilm producers only; on the other hand, some of the isolates of e. coli, klebsiella pneumonia, pseudomonas aeroginosa and proteus mirabilis were found to be both biofilm producers and cause catheter-associated utis (cautis) (tables 3 and 4) (p < .001). six of e. coli strains were found to be the extended spectrum beta-lactamase producers (esbl). the values of complete urinalysis of catheterized inpatients such as positivity of leukocyte and nitrite, and bacteria seen in urine microscopy supported cautis of catheterized inpatients (table 4). the incidences of e. coli, pseudomonas aeroginosa, klebsiella pneumonia and proteus mirabilis that caused cautis were 78%, 11%, 6% and 6%, respectively (table 3). the incidences of cautis were 27% (9/33) and 8% (9/110) among female and male, respectively. the incidences of cautis caused by e. coli and pseudomonas aeroginosa were 21% (7/33) and 6% (6/33) among female, respectively. the incidences of cauti caused by e. coli, klebsiella pneumonia and proteus mirabilis were 6% (7/110), 1% (1/110) and 1% (1/110) among male, respectively (table 4). although, four strains of e. coli, four strains of candida albicans, one strain of streptococcus spp. and 26 strains of s. aureus and s. epidermidis isolated from urinary catheter of patients were biofilm producers, they were not found to cause utis (table 3). 18 strains of microorganisms isolated from urinary catheters of patients were found to be biofilm producers and caused biofilm or cautis. the incidence of biofilm related uti was 13% (18/143) in catheterized inpatients. the incidence of biofilm producer microorganism was 21% (18/88) among all microorganisms that were isolated from colonized urinary catheters (table 2). leukocytes and microorganisms were observed in urine microscopy, nitrite were positive, and at least 104 cfu/ml of microorganisms grow in urine cultures of these 18 catheterized inpatients who also showed clinical symptoms of uti. these data show that biofilm producer microorganisms that can adhere to urinary catheters facilitate adhesion, colonization of microorganisms and cause uti in catheterized patients (p < .001). the incidence of cauti in patients who were catheterized four days and below, and above four days were 9% (12/127) and 38% (6/16), respectively (table 5). 91 percent of inpatients who were catheterized four days and below and 62 percent of inpatients who were catheterized four days and above did not have cauti. discussion in our study, escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, proteus mirabilis were found to be the main urinary pathogens that cause catheter-associated urinary tract infection (cautis). alves et al., as well as kucheria et al. also concluded that these pathogens were the main urinary pathogens(3,17) (table 3). urinary tract infection is caused by bacteria that colonize urinary catheters produce biofilm and disperse to the bladder. diagnosis of symptomatic cauti varies. cauti is defined based on microbiological growth, development of bacteriuria and uti symptoms during and after catheterisation period.(5) stenzelius defined cauti as bacteriuria higher than 105 cfu/ml of microorganisms grown in urine cultures and urinary symptoms during and after catheterization period.(18) thibon defined table 5. the percentages of cautis according to catheterization periods catheterization days inpatient with cauti inpatient without cauti total inpatient ≤ 4 9% (12/127)* 91% (115/127)* 127 > 4 38% (6/16)* 62% (10/16)* 16 abbreviations: cauti, catheter-associated urinary tract infection * parameters which defines cauti were compared by pearson χ2 test (χ2: 20.232, p < .001). the effect of ucs on microbial biofilms and cautiskırmusaoğlu et al. miscellaneous 3032 uti as bacteriuria (higher than 105 cfu/ml of microorganisms grown in urine cultures) with higher than 10 leukocytes per mm3 of urine.(14) karchmer defined uti as bacteriuria equal and higher than 105 cfu/ml of microorganisms grown in urine cultures.(13) according to the center for disease control and prevention (cdc), the positivities of leukocyte, and nitrite, the observation of microorganism in urine microscopy, and at least 104 cfu/ml of microorganisms grown in urine cultures of catheterized patients indicates cautis.(15) in our study, these parameters were positive in inpatients who had cautis, and they also showed clinical symptoms of uti. however, high and rising of urine ph leads crystallization in urine that promotes biofilm formation.(19) in our study, urine phs of inpatients who had cauti ranged 5-8. urine phs of two inpatients who had cauti elavated from 5 and 5.5 to 8 and 7.5, respectively. rising of ph in urine can be due to the ability of urease production of bacteria that colonize urinary catheter.(19) although four strains of e. coli, four strains of candida albicans, one strain of streptococcus spp. and 26 strains of s. aureus and s. epidermidis that were isolated from urinary catheters of inpatients and found to be biofilm producers, these isolates were not present in urine samples of patients, and inpatients did not show clinical symptoms of uti. so, these isolates did not cause urinary tract infection. the reason for this may be due to undetachment of biofilm, so sessile microorganism did not disperse from catheter to urine and did not cause uti till that time. when the biofilm embedded microorganism are detached and dispersed, they cause uti. it is hard to identify microorganism and biofilm in urine before uti due to the down-regulation of phenol soluble modulins (psms) since microorganisms are just identified in the dispersal stage of biofilm that is caused by psms.(20,21,22) another reason might be due to ph of urines that are not optimum for microbial growth. generally, ph of the urine ranges between 5 to 8.5. above ph 7.5, and below ph 6.5 bacteria can not grow effectively. the optimum ph for bacteria and yeast growth ranges from 6.5 to 7.5 and from 5 to 6, respectively.(23) this result can also be explained by short catheterization period. decreased catheterization period of patient reduces the risk of cauti. prolonged catheterization period of patient increased the incidence of cauti.(24) if catheterization period of these inpatients were prolonged, risk of cauti would be increased. in our study, six patients that had cauti were catheterized more than 4 days. one patient that had cauti was catheterized for a period of 21 days. twelve patients that had cauti were catheterized below 4 days (table 4). the incidence of cauti in patients who were catheterized four days and below, and above four days were 9% (12/127) and 38% (6/16), respectively (table 5). according to our study, prolonged catheterization period increases the risk of cauti (p < 0.05). incidence of bacteriuria development in patients who has urinary catheter is 5%. when catheterization period prolonges to more than 7 and 14 days, incidence of bacteriuria development rises to 35% and 70 %, respectively.(5) crouzet et al. reported that termination of catheterization at the fourth day decreased the incidence rate of cauti from 10.6 to 1.1.(24) dohnt et al. found that incidence rate of cauti of short term (to 7 days) and long term catheterized patients (28 days) were approximately 50% and 100%, respectively.(25) in our study, biofilm the effect of ucs on microbial biofilms and cautiskırmusaoğlu et al. producer proteus mirabilis that was isolated in urinary catheter was also isolated in urine of an inpatient who was catheterized for 8 days (table 4). proteus mirabilis that does not cause uti in short catheterization period, causes uti in prolonged catheterization.(4) in addition to prolonged catheterization period, the risks of cauti of inpatients, may be enhanced with older age, female sex and immunosuppression due to other diseases.(26) in our study, patients who had cauti were not immunosuppressed, had no other diseases, and half of the patients were female. another study revealed that, before taking catheter out of the body, antibiotic prophylaxis decreased the incidence of uti (27, 28), while antibiotic resistance can be emerged by prophylaxis.(29) in our study, antibiotic prophylaxis was not given to catheterized inpatients before taking catheter out of the body. conclusions according to this study, incidence of cautis is increased by the usage of urinary catheters and prolonged catheterization period. to prevent incidence rate of cautis increased by the usage of urinary catheters and prolonged catheterization period, urinary catheters must be inserted to patient with the aseptic techniques. urinary catheters must be also removed and frequently renewed with a new ones to prevent cauti especially in immunosuppressed patients. urethral injury facilitating bacterial adhesion can be prevented by the usage of lubricant during the insertion of catheter. antimicrobial incorporated catheters can be used to decrease risks of cauti. references 1. bjarnsholt t, moser c, jensen po and hoiby n. biofilm infections. new york dordrecht heidelberg london: springer science business media, llc; 2011. pp. 215-225. 2. jacobsen sm, stickler dj, mobley hlt and shirtliff me. complicated catheter-associated urinary tract infections due to escherichia coli and proteus mirabilis. clin microbiol rev. 2008;21:26-59. 3. alves mj, barreira jc, carvalho i, et al. propensity for biofilm formation by clinical isolates from urinary tract infections: developing a multifactorial predictive model to improve antibiotherapy. j med microbiol. 2014;63:471-7. 4. stickler dj. clinical complications of urinary catheters caused by crystalline biofilms: something needs to be done. j intern med. 2014;276:120-9. 5. lam tbl, omar mi, fisher e, gillies k, maclennan s. types of indwelling urethral catheters for short-term catheterisation in hospitalised adults. cochrane database of syst rev. 2014;9:1-92. art. no.: cd004013. 6. archer nk, mazaitis mj, costerton jw, et al. staphylococcus aureus biofilms: properties, regulation, and roles in human disease. virulence. 2011;2:445-59. 7. donlan rm and costerton jw. biofilms: vol 14 no 02 march-april 2017 3033 the effect of ucs on microbial biofilms and cautiskırmusaoğlu et al. survival mechanisms of clinically relevant microorganisms. clin microbiol rev. 2002;15:167-93. 8. otto m. staphylococcal biofilms. bacterial biofilms. springer berlin heidelberg. 2008. pp. 207-228. 9. stickler dj. bacterial biofilms in patients with indwelling urinary catheters. nat clin pract urol. 2008;5:598-608. 10. bilgehan h. klinik mikrobiyolojik tanı. fakülteler kitapevi, barış yayınları. 2009. 11. freeman dj, falkiner fr and keane ct. new method for detecting slime production by coagulase negative staphylococci. j clin pathol. 1989;42:872-4. 12. christensen gd, simpson wa, younger jj, et al. adherence of coagulase-negative staphylococci to plastic tissue culture plates: a quantitative model for the adherence of staphylococci to medical devices. j clin microbiol. 1985;22:996-1006. 13. karchmer tb, giannetta et, muto ca, strain ba, farr bm. a randomized crossover study of silver-coated urinary catheters in hospitalized patients. arch intern med. 2000;160:3294–8. 14. thibon p, le coutour x, leroyer r, fabry j. randomized multi-centre trial of the effects of a catheter coated with hydrogel and silver salts on the incidence of hospitalacquired urinary tract infection. j hosp infect. 2000;45:117–24. 15. parida s and mishra sk. urinary tract infections in the critical care unit: a brief review. indian j crit care med: peer-reviewed, official publication of indian society of critical care medicine. 2013;17:370. 16. clsi. performance standards for antimicrobial susceptibility testing; twentythird informational supplement. clsi document m100-s23. wayne, pa: clinical and laboratory standards institute; 2013. 17. kucheria r, dasgupta p, sacks s, khan m and sheerin n. urinary tract infections: new insights into a common problem. postgrad med j. 2005;81:83. 18. stenzelius k, persson s, olsson ub, stjarneblad m. noble metal alloy-coated latex versus silicone foley catheter in shortterm catheterization: a randomized controlled study. scand j urol nephrol. 2011;45: 258– 64. 19. broomfield rj, morgan sd, khan a, and stickler dj. crystalline bacterial biofilm formation on urinary catheters by ureaseproducing urinary tract pathogens: a simple method of control. j med microbiol. 2009;58:1367-75. 20. farsi hm, mosli ha, al-zemaity mf, bahnassy aa and alvarez m. bacteriuria and colonization of double-pigtail ureteral stents: long-term experience with 237 patients. j endourol. 1995;9:469-72. 21. djeribi r, bouchloukh w, jouenne t and menaa b. characterization of bacterial biofilms formed on urinary catheters. am j infect control. 2012;40:854-9. 22. kırmusaoğlu s. staphylococcal biofilms: pathogenicity, mechanism and regulation of biofilm formation by quorum sensing system and antibiotic resistance mechanisms of biofilm embedded microorganisms. in: microbial biofilms importance and applications. dhanasekaran d, thajuddin n, editors. intech, croatia; 2016. p. 189-209. 23. tortora gj, funke br and case cl. microbiology: an introduction, 12th edition, usa: pearson education; 2015. p. 960. 24. crouzet j, bertrand x, venier ag, et al. control of the duration of urinary catheterization: impact on catheter-associated urinary tract infection. j hosp infect. 2007;67:253-7. 25. dohnt k, sauer m, müller m, et al. an in vitro urinary tract catheter system to investigate biofilm development in catheter-associated urinary tract infections. j microbiol methods. 2011;87:302-8. 26. lee ng, marchalik d, lipsky a, et al. risk factors for catheter-associated urinary tract infections in a pediatric institution. j urol. 2016;195:1306-11. 27. zegers b, uiterwaal c, kimpen j, et al. antibiotic prophylaxis for urinary tract infections in children with spina bifida on intermittent catheterization. j urol. 2011;186:2365-71. 28. pfefferkorn u, sanlav l, moldenhauer j, et al. antibiotic prophylaxis at urinary catheter removal prevents urinary tract infections: a prospective randomized trial. ann surg. 2009;249:573-5. 29. nazarko l. should antibiotics be prescribed when urinary catheters are removed?. br j community nurs. 2011;16:374-80. 30. tambyah pa and oon j. catheter-associated urinary tract infection. curr opin infect dis. 2012;25:365-70. miscellaneous 3034 endourology and stone disease comparison of the efficacy of intravenous and intramuscular lornoxicam for the initial treatment of acute renal colic: a randomized clinical trial ahmet soylu1*, mehmet sarier2, bulent altunoluk3, haluk soylemez4, yasar can baydinc5 purpose: we aimed to find out if there was any difference between intramuscular and intravenous administration of lornoxicam in terms of efficacy and side effects. materials and methods: this study was a single-blind parallel-group randomized clinical trial. a total of 51 patients who were diagnosed with acute renal colic at our clinic were included in the study. pain severity prior to treatment was rated using the visual analogue scale (vas). patients were randomized into 2 groups: group 1 (n = 27) received intramuscular 8mg lornoxicam and group 2 (n=24) received intravenous 8mg lornoxicam. pain severity was reassessed 30 minutes after the treatment. preand post-treatment vas scores and the mean change in the vas scores of the 2 groups were statistically compared. results: the mean vas scores decreased significantly from 7.65 to 2.07 in group 1, from 7.96 to 1.38 in group 2, and from 7.79 to 1.75 in total (p < 0.001). no statistically significant difference was observed between groups 1 and 2 in terms of vas score reduction (p = 0.128). none of the patients suffered any side effects except for 1 (2%) patient who had dyspepsia. conclusion: parenteral lornoxicam provides significant pain relief in patients with acute renal colic. however, no significant difference was found between intramuscular and intravenous administration in terms of analgesic efficacy. keywords: lornoxicam; parenteral treatment; acute renal colic; urolithiasis introduction pain is one of the most common presenting com-plaints in the emergency department (ed).(1) renal colic is a common cause of pain and patients usually present with severe flank and/or abdominal pain which requires immediate analgesic treatment in the ed.(2) about 85% of renal colic cases are caused by urolithiasis, but renal colic may also arise from different etiologies such as extrinsic ureteral compression, urinary neoplasms, and anatomic anomalies.(3) the prevalence of renal colic varies between 5-15% throughout the world.(4) providing pain relief is the most important step of the treatment and various types of medications are used for pain relief in the clinical practice. when selecting first-line analgesic drugs in the ed, the efficacy, safety, and rapid applicability of the drug, and the logistics involved are taken into consideration.(5) given their prostaglandin synthesis-inhibiting effects and the current evidence on their efficacy, international guidelines recommend the use of non-steroid anti-inflammatory drugs (nsaid) as first-line analgesic treatment.(6,7) however, to date, no gold standard protocol has been established for pain management in patients with renal colic. lornoxicam is an nsaid 1department of urology, gozde akademi hospital, malatya, turkey. 2department of urology, medical park hospital, antalya turkey. 3department of urology, medical palace hospital, kayseri, turkey. 4department of urology, aile hospital, istanbul, turkey. 5occupational physician, izmir, turkey. *correspondence: department of urology, gozde akademi hospital, malatya, turkey. tel: +90 532 485 8110. fax: +90 422 238 2626. e-mail: drsoylu@gmail.com. received march 2018 & accepted may 2018 which belongs to the oxicam class and has analgesic and antipyretic properties. like the other members of the oxicam class, lornoxicam acts by inhibiting prostaglandin synthesis. it has a short plasma elimination half-life of 3-4 hours, which makes it eligible for treating acute pain.(8) previous studies have shown that the analgesic efficacy of nsaids is at least as potent as opioids.(9,10) parenteral lornoxicam can be administered via intramuscular (im) and intravenous (iv) routes. we aimed to find out if there was any difference between intramuscular and intravenous administration of lornoxicam in terms of efficacy and side effects. patients and methods study population after local ethics committee approval was obtained, fifty-one patients who presented to the ed of i̇nönü university turgut özal medical center between february 1, 2006, and april 30, 2006, with severe flank pain and whose radiological findings were indicative of urolithiasis were included in the study. the study was carried out in compliance with the helsinki declaration of 1964 and its later amendments. endourology and stone diseases 16 vol 16 no 01 january-february 2019 17 inclusion and exclusion criteria the exclusion criteria for this randomized controlled study were as follows: history of analgesic use within the last 2 hours prior to presentation, active urinary tract infection and pyuria accompanying renal colic, age < 18 or >65 years, history of gastrointestinal bleeding or ulcer, liver failure, coagulopathies, moderate or severe renal failure, severe heart failure, pregnancy, lactation, hypovolemia and dehydration, known or suspected cerebrovascular bleeding, known allergies to lornoxicam or other nsaids. procedures and evaluations blood and urine samples were obtained from each patient. complete blood count, blood urea nitrogen, serum creatinine and electrolyte levels, urine dipstick testing, and urine microscopy results were recorded for each patient. all patients underwent plain abdominal radiography and urinary ultrasonography. in patients whose plain abdominal radiography and urinary ultrasonography results were negative, a non-contrast computerized tomography was performed to confirm the stone. the blood pressure, heart rate, respiratory rate and body temperature of all patients were recorded. the severity of pain was evaluated using the visual analogue scale (vas) score.(11) the vas is a 100 mm horizontal line, marked from 0 to 10 at 10mm intervals, with 0 representing "no pain" and 10 representing "worst possible pain". patient randomization and all vas measurements were performed by the same physician. informed consent was obtained from each patient prior to treatment. this study was a single-blind parallel-group randomized clinical trial. the parallel design, which is the most popular design in randomized clinical trials, was used. patients were randomly allocated into 2 groups using a random numbers table.(12-13) group 1 (n=27) received im and group 2 (n=24) received iv 8mg lornoxicam (nycomed gmbh, austria) which was diluted in distilled water. the duration of iv of injection was at least 15 seconds and the duration of im administration was at least 5 seconds. all patients were monitorized before administration and were followed-up for 1 hour to observe any side effects and complications. on the 30th minute, pain was reassessed using the vas score and vital signs were measured. statistical analysis all statistical analyses were performed using the spss statistical software (spss for windows, version 22.0; spss, inc., chicago, il, usa). preand post-treatment vas scores were compared using the non-parametric wilcoxon signed ranks test. the age and vas scores of the two groups were evaluated using the non-parametric mann whitney u test. a p-value<0.05 was considered statistically significant. results the mean age was 37.4 ± 1.9 years (range 18-65). the mean age in groups 1 and 2 were 38.2 ± 2.7 and 36.7 ± 2.7 years, respectively. no statistically significant difference was found between the two groups in terms of age (p = 0.799). the characteristics of patient groups are presented in table 1. all patients had flank and/ or abdominal pain, costovertebral angle tenderness, and some patients had abdominal tenderness on the affected side. on the 30th minute, the mean vas scores decreased significantly: from 7.79 to 1.75 in the whole study group; from 7.65 to 2.07 in group 1; and from 7.96 to 1.38 in group 2 (p < 0.001) (table 2). the decrease in group 2 was greater than group 1 but the difference was not statistically significant (p = 0.128). in 5 patients from group 1 and in 8 patients from group 2, the vas score decreased to zero. four patients from group 1 whose pain scores did not decrease below 4 were given rescue analgesics. none of the patients from group 2 required rescue analgesia. none of the patients developed any allergic reactions or complications. side effects were observed in only one (2%) 60-year-old female who developed dyspepsia. a single dose of im or iv lornoxicam was well-tolerated by all patients. none of the patients in the intramuscular or intravenous groups experienced any perioperative coagulopathies due to lornoxicam use. discussion renal colic is a condition which mostly stems from urinary stone disease and it is the most painful and the most commonly encountered urologic disease in the ed.(14) according to the results of our study, lornoxicam was found to be an effective nsaid in the treatment of renal colic, both through im and iv routes. table 1. patient characteristics. group 1 (im) group 2 (iv) p-value total number, (male-female) 27 (15-12) 24 (12-12) age (years), mean±sd 38.2 ± 2.7 36.7 ± 2.7 0.799 stone location (kidney-urether) 5-22 8-16 urea (mg/dl) mean±sd 15.5 ± 5.1 16.2 ± 5 0.807 creatinine (mg/dl) mean±sd 1 ± 0.2 1 ± 0.3 0.972 hydronephrosis n(%) 17 (63) 17 (71) groups pre-treatment vas score post-treatment vas score p-value amount of decrease in pain (%) group 1 (im, n:27) mean ± sd 7.65 ± 1.32 2.07 ± 1.54 < 0.001 72.9% group 2 (iv, n:24) mean ± sd 7.96 ± 1.12 1.38 ± 1.20 < 0.001 82.7% total (n:51) mean ± sd 7.79 ± 1.23 1.75 ± 1.42 < 0.001 77.6% abbreviations: vas,visual analogue scale; im, intramuscular; iv, intravenous; sd, standard deviation. table 2. the vas scores of the patients in the study group. efficacy of parenteral lornoxicam for acute renal colic-soylu et al. in patients with renal colic, pain is generated by the increased urinary tract wall pressure and ureteral smooth muscle spasms caused by the ureteral obstruction. the edema, inflammation, and increased peristalsis and pressure caused by the stone contribute to the pain.(15) in addition, there is an increased sensitivity to pain in these patients.(16) the inflammation and obstruction of the urinary tract induces the local release of prostaglandins, and leads to diuresis and vasodilation and results in an increase in the intrarenal pressure.(17,18) the prostaglandin synthesis-inhibiting effects of the nsaids explain their high efficacy in the analgesia of patients with renal colic.(19) however, given the lack of a gold standard treatment approach, the optimal treatment is still unclear. in the past, opioid drugs, which act through the central nervous system, were accepted as the first-line treatment for renal colic. however, physicians were often reluctant to administer additional doses to achieve sufficient analgesia, given the risk of adverse events.(20) extensive use of opioids may lead to various side-effects, such as ventilatory depression, drowsiness, sedation, nausea, vomiting and urinary retention.(21) there are numerous studies stating that parenteral nsaids bear the advantage of possessing analgesic properties similar to those of opioid analgesics, without causing the undesirable opioid-related side effects.(9,10,20) however, it should be kept in mind that nsaids have their own side effect profile and may cause gastric irritation, gastrointestinal hemorrhage, coagulopathy, and nephrotoxicity.(21) in this context, an nsaid with a low side effect profile, high efficacy and rapid onset of action might well be the optimal analgesic for the initial treatment of acute renal colic. lornoxicam has been on the market for over two decades and its benefit/risk profile is considered to be validated.(22) in 2009, its analgesic effects in acute pain were analyzed by a cochrane systematic review.(23) an important side effect of nsaids is gastrointestinal bleeding. in a placebo-controlled study by warrington et al which evaluated the gastrointestinal effects of lornoxicam, patients were treated with either lornoxicam 4 mg twice daily or indomethacin 50 mg twice daily for 28 days.(24) no difference was observed between the groups in terms of fecal blood loss, and no lornoxicam-induced ulcers were detected on endoscopic evaluation. similarly, safety studies on the human gastrointestinal system indicate that single doses of lornoxicam (up to 160 mg) do not cause any serious side effects.(25) another side effect of nsaids is reduced platelet function. lornoxicam inhibits platelet aggregation like other non-selective nsaids. however, its effects on perioperative bleeding are clinically insignificant.(22) in a prospective randomized study by isik et al., adult patients undergoing tonsillectomy received either lornoxicam 8 mg iv or 50 mg tramadol iv just before the induction of general anesthesia, and none of the patients experienced significant bleeding with lornoxicam.(24) in another study by mowafi et al, no significant differences were found between iv 16 mg lornoxicam and normal saline in terms of intraoperative bleeding in patients undergoing tonsillectomy.(26) lornoxicam is distinguished from the other members of the oxicam class with its short elimination half-life of 3-5 h.8 its short elimination half-life makes lornoxicam an effective analgesic for patients with acute pain such as renal colic and also renders the drug more tolerable compared to other nsaids. however, there are only a limited number of studies on the use of lornoxicam in patients with renal colic. bilir et al found that the analgesic effect of a single dose of iv lornoxicam 8 mg is significantly better compared to tenoxicam 20 mg and placebo. in another study, cevik et al. compared iv lornoxicam, tenoxicam, and dexketoprofen trometamol in patients with renal colic in terms of efficacy and safety. (27) the fastest vas score reduction was achieved with lornoxicam, which provided pain relief within 30 minutes. in accordance with the literature, both the iv and the im groups in our study demonstrated vas score reductions 30 minutes after the administration of lornoxicam. this outcome suggests that intravenous administration is faster in terms of pain reduction, and thus, slightly superior to intramuscular administration. in patients with renal colic, iv route is preferred over oral, rectal or im administration due to its more rapid effect and ease of titration.(28) in our study, it is worth noting that no difference was found between the iv and im routes in terms of vas score reduction. however, all 4 (7.8%) of the patients who required rescue analgesia were in the im group. in the light of the above data, we speculate that the analgesic effects of im lornoxicam may start later compared to iv lornoxicam. thus, when using the im route, it might be wise to wait longer before administering rescue analgesia. we believe that future studies with larger sample sizes will help enlighten this issue. other than its efficacy in renal colic, lornoxicam has also been shown to exhibit potent analgesic effects in patients undergoing various urologic procedures. mazrais et al. found that lornoxicam is superior to paracetamol in terms of postoperative analgesia in patients undergoing open retropubic prostatectomy.(29) similarly, ozkan et al. reported that lornoxicam is superior to paracetamol and tramadol in patients undergoing shock wave lithotripsy.(24) this study has some limitations. firstly, vas scores were not evaluated after the 30th minute. secondly, the parenteral administrations of lornoxicam were not compared with oral administration. the absence of a placebo control group also constitutes a limitation of this study. however, this study is significant in terms of showing that lornoxicam is a well-tolerated drug which is equally effective via the im and iv routes in terms of providing analgesia within 30 minutes. conclusions the parenteral use of lornoxicam, which is an nsaid that belongs to the oxicam class, provides effective pain relief in patients with acute renal colic. however, no significant difference was found between im and iv administration in terms of analgesic efficacy. acknowledgements this study was done while all the authors were working at inonu university, malatya, turkey. conflict of interest no potential conflict of interest was reported by the authors. efficacy of parenteral lornoxicam for acute renal colic-soylu et al. endourology and stone diseases 18 vol 16 no 01 january-february 2019 19 references 1. mozafari j, masoumi k, forouzan a, et al. sublingual buprenorphine efficacy in renal colic pain relief: a randomized placebo-controlled clinical trial. pain ther. 2017;6:227-34. 2. sin b, cao j, yang d, ambert k, punnapuzha s. intravenous lidocaine for intractable renal colic unresponsive to standard therapy. am j ther. 2018;2:1. 3. valerio m, doerfler a, chollet y, schreyer n, guyot s, jichlinski p. [emergency management of renal colic]. rev med suisse. 2009;5(228):2457-2461. http://www.ncbi. nlm.nih.gov/pubmed/20088121. 4. marx j, walls r, hockberger r. rosen’s emergency medicine-concepts and clinical practice, vol. 2. 8th ed. elsevier health sciences; 2013. p. 1336–42. 5. pathan sa, mitra b, romero l, cameron pa. what is the best analgesic option for patients presenting with renal colic to the emergency department? protocol for a systematic review and meta-analysis. bmj open. 2017;7(4):1-5. doi:10.1136/bmjopen-2016-015002. 6. türk c, petřík a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016;69(3):468-474. doi:10.1016/j. eururo.2015.07.040. 7. emergency department management of renal colic and suspected renal calculus. irish association for emergency medicine clinical guidelines 3, version 1; may 2014. http:// www.iaem.ie/wp-content/ uploads/2015/08/ iaem-cg3-ed-management-ofsuspectedrenal-colic-suspected-renal-calculus.pdf. 8. olkkola kt, brunetto a v., mattila mj. pharmacokinetics of oxicam nonsteroidal anti-inflammatory agents. clin pharmacokinet. 1994;26(2):107-120. doi:10.2165/00003088-199426020-00004. 9. mentes o, bagci m. postoperative pain management after inguinal hernia repair: lornoxicam versus tramadol. hernia. 2009;13(4):427-430. doi:10.1007/s10029009-0486-1. 10. zhao h, ye th, gong zy, xue y, xue zg, huang wq. application of lornoxicam to patient-controlled analgesia in patients undergoing abdominal surgeries. chin med sci j. 2005;20(1):59-62. 11. basiri a, kashi ah, zeinali m, et al. limitations of spinal anesthesia for patient and surgeon during percutaneous nephrolithotomy. urol j. 2018 jan 8. doi: 10.22037/uj.v0i0.3993. [epub ahead of print] 12. sadeghi bazargani h, hajebrahimi s. evidence-based urology: how does a randomized clinical trial achieve its designed goals? urol j. 2011, spring;8(2):88-96. 13. maghsoudi r, farhadi-niaki s, etemadian m, et al. comparing the efficacy of tolterodine and gabapentin versus placebo in catheter related bladder discomfort after percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2018 feb;32(2):168-174. doi: 10.1089/end.2017.0563. epub 2018 jan 26. 14. the british association of urological surgeons. section of endourology: stone guidelines. first published: december 2008; reviewed and updated february 2012. http://www.baus. org.uk/_userfiles/ pages/files/publications/ revisedacutestonemgtguidelines.pdf. 15. davenport k, timoney ag, keeley fx. conventional and alternative methods for providing analgesia in renal colic. bju int. 2005;95(3):297-300. doi:10.1111/j.1464410x.2005.05286.x. 16. serinken m, karcioglu o, turkcuer i, ozkan hi, keysan mk, bukiran a. analysis of clinical and demographic characteristics of patients presenting with renal colic in the emergency department. bmc res notes. 2008;1. doi:10.1186/1756-0500-1-79. 17. holdgate a, pollock t. systematic review of the relative efficacy of non-steroidal antiinflammatory drugs and opioids in the treatment of acute renal colic. bmj. 2004;328:1401. doi:10.1136/bmj.38119.581991.55 [doi]\ rbmj.38119.581991.55 [pii]. 18. golzari se, soleimanpour h, rahmani f, et al. therapeutic approaches for renal colic in the emergency department: a review article. anesthesiol pain med. 2014;3(3):e16222. doi:10.5812/aapm.16222. 19. manthey david e, nicks bret a. urologic stone disease. in: tintinalli je, stapczynski js, cline dm, ma oj, cydulka rk, meckler gd, editors. tintinalli's emergency medicine: a comprehensive study guide; 2010. p. 651-6. 20. rosenow de, albrechtsen m, stolke d. a comparison of patient-controlled analgesia with lornoxicam versus morphine in patients undergoing lumbar disk surgery. anesth analg. 1998;86(5):1045-1050. doi:10.1097/00000539-199805000-00026. 21. bilir a, gulec s, turgut m, cetinkaya d, erkan a, kurt i. lornoxicam in extracorporeal shockwave lithotripsy; comparison with tenoxicam and placebo in terms of analgesic consumption. scand j urol nephrol. 2008;42(2):143-147. doi:10.1080/00365590701225988. 22. hillstrom c, jakobsson jg. lornoxicam: pharmacology and usefulness to treat acute postoperative and musculoskeletal pain a narrative review. expert opin pharmacother. 2013;14(12):1679-1694. doi:10.1517/146565 66.2013.805745. 23. hall pe, derry s, moore ra, mcquay hj. single dose oral lornoxicam for acute postoperative pain in adults. cochrane efficacy of parenteral lornoxicam for acute renal colic-soylu et al. database syst rev. 2009;(4):cd007441. doi:10.1002/14651858.cd007441.pub2. 24. warrington sj, debbas nm, farthing m, et al. lornoxicam, indomethacin and placebo: comparison of effects on faecal blood loss and upper gastrointestinal endoscopic appearances in healthy men. postgrad med j. 1990;66(778):622-626. http://www.ncbi.nlm. nih.gov/pubmed/2217030. accessed march 7, 2018. 25. radhofer-welte s, rabasseda x. lornoxicam, a new potent nsaid with an improved tolerability profile. drugs of today. 2000;36(1):55-76. doi:10.1358/ dot.2000.36.1.566627. 26. mowafi ha, telmessani l, ismail sa, naguib mb. preoperative lornoxicam for pain prevention after tonsillectomy in adults. j clin anesth. 2011;23(2):97-101. doi:10.1016/j. jclinane.2010.07.002. 27. cevik e, cinar o, salman n, et al. comparing the efficacy of intravenous tenoxicam, lornoxicam, and dexketoprofen trometamol for the treatment of renal colic. am j emerg med. 2012;30(8):1486-1490. doi:10.1016/j. ajem.2011.12.010. 28. tramèr mr, williams je, carroll d, wiffen pj, moore ra, mcquay hj. comparing analgesic efficacy of non-steroidal antiinflammatory drugs given by different routes in acute and chronic pain: a qualitative systematic review. acta anaesthesiol scand. 1998;42(1):71-79. http://www.ncbi.nlm.nih. gov/pubmed/9527748. 29. mazaris em, varkarakis i, chrisofos m, et al. use of nonsteroidal anti-inflammatory drugs after radical retropubic prostatectomy: a prospective, randomized trial. urology. 2 0 0 8 ; 7 2 ( 6 ) : 1 2 9 3 1 2 9 7 . d o i : 1 0 . 1 0 1 6 / j . urology.2007.12.039. efficacy of parenteral lornoxicam for acute renal colic-soylu et al. endourology and stone diseases 20 endourology and stone disease comparison of hemodynamic stability and pain control in lateral and prone positions in patients undergoing percutaneous nephrolithotomy: a randomized controlled trial fatemeh roodneshin1, mahtab poor zamany nejat kermany1*, pooya rostami2, narges ahmadzadeh3, babak gharaei1, mohammad reza kamranmanesh1 purpose: percutaneous nephrolithotomy (pcnl) is the preferred surgical treatment in many cases of kidney stones which is performed in different positions such as prone, lateral, and supine. this study was designed to evaluate whether patient position (lateral versus . prone) has an effect on the need for analgesia and onset of pain after surgery. materials and methods: patient with confirmed kidney stones (size ≥ 2 cm) who were candidates for pcnl were enrolled in this study. the required biochemical analyses were performed preoperatively. all patients underwent spinal anesthesia by the same anesthesiologists and then were randomly divided into two separate groups as lateral (l) and prone (p) positions. the operations’ start and end time, required time for proper access into target calyces, additional need for analgesic or cardiac drugs, duration of analgesia, and onset of pain after pcnl were carefully recorded and then compared between the two groups. results: in total, 51 patients were evaluated of whom 39 were men and 12 were women. mean duration of analgesia after pcnl surgery in p group (173 ± 8 min) was significantly longer than in l group (147±12 min) (p = .001). furthermore, the amount of ephedrine usage in l group (3.6 ± 1.5mg) was significantly lower than in the p group (16.4 ± 12mg), suggesting more hemodynamic variations in the p group during the operation. conclusion: our randomized control trial study shows that choosing the optimal position in the pcnl technique depends on patient's condition. if hemodynamic control is of matter to the anesthesiologist, then lateral position is more appropriate. however, if control of pain and longer time of analgesia are important, prone position may be preferred. keywords: analgesia; lateral position; percutaneous nephrolithotomy; prone position. introduction percutaneous nephrolithotomy (pcnl) is a routine surgical technique for removing kidney stones which is performed by a minimally invasive intervention through a small incision in the flank area(1,2). in comparison with other therapeutic procedures for kidney calculi such as shock wave lithotripsy (swl), pcnl has considerable advantages such as high stone– free rate of up to 95%, shorter post-surgical recovery period, and similar recurrence rate. nevertheless, pcnl has lower surgical risks and lower surgical infection(3-5). therefore, pcnl has great clinical utility and is the preferred choice for removing kidney stones especially in patients with staghorn calculi larger than 20 mm(5). choosing the proper position for patients undergoing pcnl is an important issue(6,7). it has been strongly suggested that an appropriate position can help anesthetists to keep normal airway circulation, and support optimal analgesia and better control of pain during operation (8). also, it allows direct access to the kidneys for urologists leading to shorter duration of operation and lower incidence of hemodynamic problems i.e. bleeding and 1labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2department of anesthesiology, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. 3mofid medical center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: labbafinejad medical center, shahid beheshti university of medical sciences,tehran, iran. tel: +989121062215. email: drpoorzamany@yahoo.com. received october 2018 & accepted september 2019 hypovolemia(6,9). in 2016, mak and colleagues demonstrated that prone position is followed by more hemodynamic changes than supine position, though it reduces the risk of visceral organ injury during operation(10). in 2018, gan and coworkers reported that lateral position in patients undergoing pcnl significantly reduces the duration of operation, decreases the need to transfusion after operation and provides greater stone clearance(11). however, there have been no prior rct studies directly comparing these two methods. therefore, in this randomized controlled trial study, we have compared the two positions of lateral and prone position concerning the onset of pcnl-induced pain and hemodynamic changes in patients undergoing pcnl operation. materials and methods study population our study was a randomized clinical trial conducted from december 2015 to december 2016 in the urology unit of labbafinejad university hospital, tehran, iran. the inclusion criteria were patients aged between 1865 years with kidney stones (size ≥ 2 cm) who were urology journal/vol 17 no. 2/ march-april 2020/ pp. 124-128. [doi: 10.22037/uj.v0i0.4915] scheduled for pcnl with an informed consent for spinal anesthesia. the exclusion criteria were age < 18 years or > 65 years, patients with cardiovascular or respiratory disorders, coagulopathy disorders, any history of addiction, current pregnancy, and patients with scattered stones that required multiple access tracts, and considerable rise of blood pressure (30% from baseline) or heart rate (30% from baseline) during the operation. the study was approved by the ethics committee of shahid beheshti university of medical sciences and each patient provided informed consent before inclusion in the study. the study was registered at www. clinicaltrials.gov (nct03966599). initially, 112 patients were enrolled in the study but 61 were excluded from the final analysis. of those 61 patients who were excluded, 15 were younger than 18 years old, 10 had coagulopathy disorders, 6 had multiple stones that required several access tracts, and 30 patients had cardiovascular or respiratory disorders. the remaining 51 patients were included in the final sample and were randomly divided into two groups with respect to position (lateral: 26 patients, prone: 25 patients). randomization was performed using a table of random numbers generated by random allocation software(12). all of the surgeries were performed by senior fellows under direct supervision of an expert endourologist. table 1 summarizes the preoperative baseline characteristics for the patients in the two groups. before pcnl prior to surgery, patients fasted for at least 8 hours. complete biochemical analysis including cbc (complete blood cell count), ct (clotting time), cr (creatinine), urea, bt (bleeding time), bg (blood group) and rh, u/a (urine analysis) and u/c (urine culture) was performed on the blood and urine samples collected from patients. also, the size and location of calculi were precisely detected by ct scan (computed topography scan) and ivp (intravenous pyelogram) techniques. hemodynamic parameters including hr (heart rate), bp (blood pressure), sbp (systolic blood pressure), dbp (diastolic blood pressure) and spo2 (peripheral capillary oxygen saturation) were monitored carefully before, during, and after the surgery. anesthesia process after injection of normal saline (500ml), the patients were spinally anesthetized using bupivacaine (%5; 4ml) into l2-l4 of spinal cord. then some patients (group l) were positioned into the lateral state same side to calculi for 5 minutes, but the other patients (group p) were not. finally, all the patients (group l&p) were positioned into supine and lithotomy states respectively for intra-ureter catheterization under guide of cystoscopy. pcnl procedure initially, in the lithotomy position and under cystoscopy guide, a catheter (6f) was inserted into the ureter through urinary tract and after that all of the patients were positioned into prone state. then, after checking the precise stone location using c-arm through the abdominal wall, access needle guide (18 gauge) was inserted into the calyx by fornix. after confirming the urine output, the guide wire (0.35 inch j-tip) was inserted into the targeted calyx. for the patients with hydronephrosis, normal saline (50ml) was injected through the catheter to create more contrast. the nephrostomy tract was then dilated using amplatz of f30 or f28 and then, f30 sheath was directed to the target location. in case of any considerable reduction (30% from baseline) in hr or bp or sbp (systolic bp), patient was given an intravenous ephedrine and atropine (10 mg and 0.02 mg/kg, respectively). patient who had significant rise (more than 30% of patient’s baseline value) in hr or map (mean arterial pressure) were excluded from the study. furthermore, in case of shivering or pain during pcnl, pethidine (0.55mg/kg) and fentanyl (1µg/ kg) were administered respectively. after pcnl in the recovery room, return of sensation was assessed by pinprick test and as soon as any feeling of pain was sensed, the exact time was recorded. 48 hours after pcnl, all patients were monitored by kub (kidney, ureter, and bladder) x-ray and ultrasonography examinations regarding any possible remaining stones in kidneys and urinary residues in the bladder. primary outcome our primary outcome was the first recorded time of lateral and prone positions in pcnl surgeryroodneshin et al. table 1. demographic data of patients undergoing pcnl surgery lateral position prone position p-value total number (n) 26 25 male (n) 21 18 .46 female (n) 5 7 age ,years mean (sd) 43.5 ± 10 42.8 ± 11 .8 weight(kg) mean (sd) 72.8 ± 7 74.8 ± 7 .3 lateral (n= 26) prone (n= 25) p-value stone location low position 24 21 .3 high position 2 4 size of kidney stone(mm) mean (sd) 33.0±7.6 29±5.9 .1 mean number of attempts (sd) 1.1±0.3 1.0±0.3 .7 abbreviations: mm, millimeter table 2. size and location of calculi and number of attempts for reaching the stones vol 17 no 02 march-april 2020 125 pain sensation in the recovery room and need for analgesic injection. secondary outcome hemodynamic changes including blood pressure and pulse rate changes during recovery room were the secondary outcomes. statistical analysis at first, a pilot study was designed to determine the exact sample size. after evaluation of the patients, we determined the onset of pain sensation in lateral group as 130 min and in the prone group as 170 min. considering a level of a = 0.05, study power of 80%, , and a 20% possibility of failure, a sample size of at least 15 patients was considered for each group. normal distribution of data was assessed by kolmogorov–smirnov test. then, the data were analyzed via oneway anova in spss software with p ≤ .05 considered as a significant difference. results the consolidated standards of reporting trials (consort) diagram in figure1 shows the process for participant inclusion. the two groups were similar in their baseline characteristics (table 1). in 92% of the l group and 86% of the p group patients, kidney stones were in a low position. the mean size of the stone was 29 ± 5.9 and 33.0 ± 7.6 mm in p and l groups. the mean number of total attempts to accessing the calculi under ultrasonography monitoring was 1.0±0.3 in p and 1.0 ± 0.3 times in l groups, which had no significant difference (table 2). at t6 level, 69% of the l and 68% of the p groups, and at the t5 level, 26% from the l and 28% from the p groups experienced returned sensation 20 min after anesthesia, showing no significant difference in the extension of sensation after surgery (table 3). the first recorded time of pain sensation in the recovery room was 147 ± 12 and 173 ± 8 min in l and p groups respectively, indicating a significant difference between the groups (p = .01) (figure 2). the patients in the l group received more fentanyl (15 ± 2.3µg) than p group (10 ± 2µg), indicating higher pain occurrence in the l group compared to the p group . however, prone positioned patients received more ephedrine (16.4±12mg) than laterally positioned patients (3.6 ± 1.5 mg), implying greater hemodynamic changes in the p group (p = .001) (table 3). endourology and stones diseases 126 table 3. sensory levels after 20 min, first pain sensation and need for fentanyl and ephedrine in the prone and lateral position groups lateral (n= 26) prone (n= 25) p-value sensory level after 20 min t4 1 1 .99 t5 7 7 t6 18 17 recorded time of first pain/sense ( min) mean (sd) 147 ± 12 173 ± 8 .001 fentanyl(µg) mean (sd) 15 ± 2.3 10 ± 2 .01 ephedrine(mg) mean (sd) 3.6 ± 1.5 16.4 ± 12 .001 figure 1. distribution of sensation at various levels of spinal cord at the same time after anesthesia figure 2. kaplan-meyer showing survival time of analgesic drugs effects in the two groups of prone and lateral positions. as seen, patients with prone position analgesic drugs had a longer duration lateral and prone positions in pcnl surgeryroodneshin et al. discussion choosing the proper position in the pcnl technique depends on patient's conditions. this study showed if hemodynamic control matters to the anesthesiologist, the lateral position is more appropriate; however, if the control of pain and longer time of analgesia are important, the prone position should be preferred. pcnl is a common low-intervention surgery for removing complex and large kidney calculi (9). however, operation duration, hospitalization period, post-operative narcotic analgesic need and cost were found to be significantly lower in the sa group. in the light of this data, it was shown that pnl can be performed more effectively, safely and with a lower cost using spinal anesthesia(9,13). our study reached the conclusion that bupivacaine, which is a local anesthetic agent with long-lasting ef¬fects, decreases pain scores only in the second postoperative hour. while no significant difference was found among the groups in terms of the total amount of analgesics used, there was a tendency to need low¬er amounts of narcotic analgesia in patients provided with a higher concentration of bupivacaine. the an¬algesic administration frequency was reduced signifi¬cantly in both dosages of bupivacaine(9,14). the traditional position for patient undergoing pcnl is prone which is used by most urologists(7). however, other positions such as lateral and supine have been suggested to possibly reduce the pain and provide better access to stones during the operation(6). in the current trial study, we evaluated the outcomes of two positions as lateral and prone in need for analgesia drugs and the onset time of pain after pcnl surgery. our results demonstrated that pcnl operation in the prone position may delay the onset of post-surgical pain and decrease the need for analgesia as compared with patients undergoing pcnl in the lateral position. however, more hemodynamic variations were observed with the prone position. karami and coworkers in 2013 reported that pcnl in both supine and flank positions are as effective and safe as prone position(15). they found that these positions do not make any significant difference regarding the time of operation, mean access duration, and pyelocaliceal perforation during pcnl(15). we did not find any strong evidence comparing lateral and prone positions with regards to the onset of pain and need for analgesia after pcnl. our study demonstrated for first time that lateral position in patient undergoing pcnl surgery can provide more analgesia using the same dose of analgesic drugs as compared with patients positioned in the prone state. this outcome was accompanied by the same sensations at spinal levels indicating that the lateral position can only delay the onset of pain sensation and does not affect sensory signals. dasgupta et al. in 2013 suggested that lateral position may provide better allowance for anesthesiologists to control airways, although they concluded that there is no obvious superiority for a position and it is dependent on the patient conditions (e.g. lateral position for obese subjects)(16). in none of the previous articles, the level of analgesia and onset of pain after surgery were examined and our finding is novel in this regard. hemodynamic changes in prone and supine positions have been compared in a study(17). in 2012, khoshrang et al. , stated that hemodynamic changes are less in the supine status as compared to the prone after comparing 40 patients (17). however, no study compared hemodynamic changes between the two groups of prone and lateral positions. as ephedrine was used more in the p group than in l group in our study, it seems that prone position is followed by more hemodynamic variations, although it needs further investigations. there are several strengths in this study. the study was designed as rct which prevent biases from sampling and retrospective studies. all spinal procedures were done with the same anesthesiologist. as to our knowledge, this is the first study that compared pain control and hemodynamic stability outcomes in lateral and prone positions in pcnl. low sample size was our limitation. conclusions proper positioning is a key issue in patients undergoing pcnl surgery. in this randomized controlled trial study, and for the first time, we have successfully demonstrated that lateral position provides more analgesia and delays the onset of post-surgical pain after pcnl. overall, according to anesthesiologists, prone position is preferred due to lower post-surgical pain and delayed onset of pain after pcnl. however, concerning hemodynamic variations, lateral position is preferred to prone. it is again emphasized that, in the view of the anesthetists; choosing the right position depends on the priorities. for more comprehensive results, further clinical trials are still required. conflict of interest the author declares no conflict of interest in this study. references 1. lahme s, bichler k-h, strohmaier wl, götz t. minimally invasive pcnl in patients with renal pelvic 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surgeryroodneshin et al. vol 17 no 02 march-april 2020 127 which position? bju int. 2012;110:e1018-e21. 7. giusti g, de lisa a. pcnl in the prone position vs pcnl in the modified supine double-s position: is there a better position? a prospective randomized trial. urolithiasis. 20181-7. 8. wu p, wang l, wang k. supine versus prone position in percutaneous nephrolithotomy for kidney calculi: a meta-analysis. int urol nephrol. 2011;43:67-77. 9. zhao z, fan j, liu y, de la rosette j, zeng g. percutaneous nephrolithotomy: position, position, position! urolithiasis. 2018;46:7986. 10. mak dk-c, smith y, buchholz n, elhusseiny t. what is better in percutaneous nephrolithotomy–prone or supine? a systematic review. arab j urol. 2016;14:101-7. 11. gan jjw, gan jjl, gan jjh, lee kt. lateral percutaneous nephrolithotomy: a safe and effective surgical approach. indian j urol. 2018;34:45. 12. saghaei m. random allocation software for parallel group randomized trials. bmc med res methodol. 2004;4:26. 13. solakhan m, bulut e, erturhan ms. comparison of two different anesthesia methods in patients undergoing percutaneous nephrolithotomy. urol j. 2019;16:246-50. 14. dundar g, gokcen k, gokce g, gultekin ey. the effect of local anesthetic agent infiltration around nephrostomy tract on postoperative pain control after percutaneous nephrolithotomy: a single-centre, randomised, double-blind, placebocontrolled clinical trial. urol j. 2018;15:306-12. 15. karami h, mohammadi r, lotfi b. a study on comparative outcomes of percutaneous nephrolithotomy in prone, supine, and flank positions. world j urol. 2013;31:1225-30. 16. dasgupta r, patel a. percutaneous nephrolithotomy: does position matter?– prone, supine and variations. curr opin urol. 2013;23:164-8. 17. khoshrang h, falahatkar s, ilat s, et al. comparative study of hemodynamics electrolyte and metabolic changes during prone and complete supine percutaneous nephrolithotomy. nephro-urology monthly. 2012;4:622. endourology and stones diseases 128 lateral and prone positions in pcnl surgeryroodneshin et al. the safety and efficacy of adjuvant hemostatic agents during laparoscopic nephron-sparing surgery: comparison of tachosil and floseal versus no hemostatic agents senol tonyali*, artan koni, sertac yazici, cenk y. bilen purpose: to compare the effectiveness of tachosil and floseal during laparoscopic nephron-sparing surgery (lnss), and to evaluate postoperative complications, especially hemorrhage and urinary leakage. materials and methods: the medical records of all patients that underwent lnss for a small renal mass (srm) performed by the same experienced surgeon were retrospectively analyzed. the patients were divided into the following 3 groups, based on hemostatic agent: group 1: no adjuvant hemostatic agent (no aha); group 2: tachosil; group 3: floseal. results: the study included 79 patients; no aha group: n = 18; tachosil group: n = 25; floseal group: n = 36. the 3 groups were similar in terms of diameter [29.6 ± 11.5 mm, 26.4 ± 13.4 mm and 30.4 ± 9.6 mm, respectively (p = .218)] and padua scores [6.9 ± 0.9, 6.7 ± 1 and 6.9 ± 0.9, respectively (p =.540)]. mean duration of surgery was significantly shorter in the floseal group (120.9 ± 23.1 minutes) than in the no aha group (156.6 ± 34.4 minutes). mean ischemia time was longest in the no aha group (24.3 ± 4 minutes) and shortest in the floseal group (21.3 ± 4.3 minutes). intra-abdominal (ia) catheter drainage on postoperative day 1 was significantly higher in the no aha group than in the tachosil and floseal groups [156.9 ±78.3 ml vs. 72.6 ± 64.5 and 60.8 ± 30.2 ml, respectively (p < .05)]. mean duration of hospitalization was 3.2 ± 0.5 days in the no aha group that was significantly longer than in the floseal group (2.8 ± 0.7 days) (p = .043). there were not any differences in intraoperative complications, the transfusion rate, surgical margin positivity, or postoperative complications between the 3 groups (p = .596, p = .403, p = 1.0, p = .876, respectively). however, pseudoaneurism as a late term complication occurred in 27.7% patients in the no aha group. conclusion: tachosil and floseal are safe and effective adjuvant treatments for patients undergoing lnss. they might be useful especially in preventing pseudo aneurisms, shortening intraoperative ischemia time and hospital stay and decreasing postoperative drainage. shortened operation and warm ischemia time may also be attributed to long learning curve of lnss. keywords: floseal; tachosil; nephron-sparing surgery; laparoscopy; nephrectomy; hemostatic agent. introduction laparoscopic nephron-sparing surgery (lnss) has been used since 1990’s and yields similar oncologic results as the open approach(1,2). lnss is a challenging technique with a shallow learning curve that requires constant technical support. lnss is associated with potential complications such as urinary leakage and bleeding that requires transfusion(3). adjuvant hemostatic agents (ahas) and tissue sealants have been used since late 1970’s and are known to be safe(4,5). numerous studies have shown that use of ahas during lnss reduces the complication rate(6-10). despite the increasing use of minimally invasive surgery, intraand postoperative kidney hemorrhage following tumor resection remains a challenge. the current standard hemostatic method is suturing, although ahas are also widely used. ahas consist of topical hemostats, sealants, and adhesives. gelatin, collagen, and cellulose can also be use to achieve hemostasis (11). among ahas, floseal and tachosil are both well known. tachosil acts via creation of a fibrin clot at the surgical site upon contact with blood or other fluids and have shown to decrease intraoperative time to hemostasis(11,12). floseal plays a role in fibrin formation, promotes coagulation thus minimizes blood loss(13). although many ahas are currently in use, head-tohead comparative data are lacking; therefore, it is difficult for surgeons to choose one agent over another. the present study aimed to retrospectively evaluate the impact of using tachosil and floseal on surgical outcomes of lnss such as operation time, intraoperative ischemia time, hospital stay and postoperative complications, especially hemorrhage and urinary leakage. materials and methods study population and design the medical records of all patients that underwent lnss for a small renal mass (srm) performed by the hacettepe university school of medicine, department of urology, ankara, turkey. *correspondence: hacettepe university, school of medicine, department of urology, sihhiye 06100 ankara, turkey. tel: +90 312 305 1885. e-mail: senoltonyali@hotmail.com. received august 2017 & accepted december 2017 laparoscopic urology vol 15 no 01 january-february 2017 21 laparoscopic urology 22 same experienced laparoscopic surgeon between july 2007 and june 2015 were retrospectively reviewed. demographic data, body mass index (bmi), american society of anesthesiologists (asa) score, anatomic characteristics of renal masses [preoperative aspects and dimensions used for an anatomical score (padua)] and preper-, and postoperative data were retrospectively reviewed. all patients underwent lnss with elective, relative or imperative indications were included the study. patients whom all data was not available were excluded. preoperative imaging suggested renal malignancy in all patients. the standard diagnostic method for renal cell carcinoma (rcc) computerized tomography (ct) was performed in every patient. although most of the patients had stage t1b or lower renal masses, lnss was performed whenever surgical resection was possible. aha was not used for initial surgeries because of the lack of aha. available aha in the operation room was used in consequent patients without a tendency. the patients were divided into the following 3 groups, based on hemostatic agent: group 1: no adjuvant hemostatic agent (no aha); group 2: tachosil; group 3: floseal. follow-up abdominal ultrasonography was performed at postoperative 3rd, 6th, 12th months. abdominal ct was performed annually. serum cr levels was measured at postoperative 1st, 3rd, 6th, 12th months then annually. surgical technique each patient was positioned for surgery according to renal mass characteristics the modified flank position for transperitoneal lnss and the flank position for retroperitoneal lnss. the same experienced surgeon performed each surgery using the same surgical principles. in all groups the renal pedicle was controlled using a satinsky clamp in cases of central and endophytic masses, and selective clamping of the renal artery with a bulldog clamp was used in cases of peripheric and exophytic masses. following tumor resection using cold scissors, the tumor bed was sutured using 2.0 vicryl for hemostasis of vessels and closure of the collecting system. thereafter, parenchymal hemostasis was achieved by approximating both edges using continuous 1.0 vicryl sutures around a surgicel (ethicon inc., somerville, nj) bolster placed in the tumor bed. tachosil or floseal was layered before placement of a surgicel bolster. after the hilar was unclamped, a 20 f sump drainage catheter was inserted and the procedure was terminated via closing the layers anatomically. statistical analysis mean ± standard deviation (sd), minimummaximum values and percentages were used to describe the quantitative variables. comparison of quantitative measurements among the groups was assessed with the non-parametric independent samples kruskalwallis test. dual comparisons between the groups were investigated with chi-square test. statistical analysis was performed via ibm spss statistics version 21 and p-value of less than .05 was considered significant. results in total, 79 patients underwent lnss for srm: no aha group: n = 18; tachosil group: n = 25; floseal group: n = 36. patient demographics are shown in table 1. there were not any significant differences in gender distribution, tumor side and diameter, padua score, vessel alteration, or clinical stage between the 3 groups (p > .05), but age, bmi and asa score differed significantly (p < .05). mean tumor diameter based on ct was 29.6 ±11.5 mm, 26.4 ±13.4 mm, and 30.4 ± 9.6 mm in the no aha, tachosil, and floseal groups, respectively. although the preoperative creatinine level was significantly higher in the no aha group (p = .017) (table 1), the postoperative creatinine level was similar in all groups (p = .184) after a mean follow-up of 13 months. mean duration of surgery was significantly shorter in the floseal group than in the no aha group (120.9 ± 23.1 versus 156.6 ± 34.4 minutes) (p = .004), whereas mean duration of surgery was similar in the floseal and tachosil groups (table 2). intraoperative estimated blood loss (ebl) was lower in the no aha group (72.7 ± 24.4 ml) than in the tachosil (118 ±112.3 ml) and floseal (130 ± 203 ml) groups which was not statistically significant (p = 0.995). mean ischemia time was longest in the no aha group (24.3 ± 4 minutes) and shortest in the floseal group (21.3 ± 4.3 minutes). there weren’t any differences in intraoperative complications (adjacent organ and vessel injury, pneumothorax, etc.), the transfusion rate, surgical margin positivity, or postoperative complications between the 3 groups (p = .596, p = .403, p = 1.0, p = .876, respectively). in all, 3 patients in the floseal table 1. patient demographics and tumor characteristics variables no aha tachosil floseal p sex 0.64 male, n 12 (66.7%) 17 (68%) 28 (77.8%) female, n 6 (33.3%) 8 (32%) 8 (22.2%) age (years) 55.7 ± 8.6 57.2 ± 9.6 51.2 ± 11.7 0.043 mean bmi (kg/m2) 24.8 ± 3.2 29.5 ± 5 25.3 ± 3.3 0.000 mean asa 1.6 ± 0.7 1.4 ± 0.5 1.2 ± 0.4 0.042 tumor side 0.56 right 10 (55.6%) 16 (64%) 18 (50%) left 8 (44.4%) 9 (36%) 18 (50%) mean tumor diameter based on ct (mm) 29.6 ±11.5 26.4 ± 13.4 30.4 ± 9.6 0.218 mean padua score 6.9 ± 0.9 6.7 ± 1 6.9 ± 0.9 0.540 vessel alteration 0.717 1 artery, 1 vein 13 (72.2%) 20 (80%) 30 (83.3%) other 5 (27.8%) 5 (20%) 6 (16.7%) clinical stage 0.48 t1a 12 (66.7%) 21 (84%) 28 (77.8%) t1b 6 (33.3%) 4 (16%) 8 (22.2%) mean presurgical creatinine level (mg/dl) 1.13 ± 0.4 0.85 ±0.1 0.86 ± 0.1 0.017 laparoscopic nephron-sparing surgery-tonyali et al. group had hematuria on first or second postoperative day, which lowered the hemoglobin level and was treated conservatively with blood transfusion. additionally, 1 patient in the tachosil group required blood transfusion due to a rectus hematoma on the trocar tract. intra-abdominal (ia) catheter drainage on postoperative day 1 was significantly higher in the no aha group than in the tachosil and floseal groups [156.9 ±78.3 ml vs. 72.6 ±64.5 and 60.8 ±30.2 ml, respectively (p < .05)]. mean duration of hospitalization was 3.2 ± 0.5 days in the no aha group, versus 2.9 ± 0.7 days in the tachosil group and 2.8 ± 0.7 days in the floseal group; the difference between the floseal and no aha groups was significant (p = .043)(table 2). late-term complications (after 3 months) following hospital discharges were observed in 5 patients (27.7%) in the no aha group and in 1 patient (2.77%) in the floseal group. in the aha– group 5 patients developed pseudoaneurism: 2 were treated successfully with angio embolization, 1 patient was followed-up conservatively, and 1 patient underwent angio embolization 2 times during the first year following lnss (radionuclide examination showed a non-functioning kidney after the second embolization). the fifth patient in the no aha group was misdiagnosed as rcc recurrence during routine follow-up and underwent radical nephrectomy at another hospital; histopathological examination showed not only a stage t0 tumor, but also pseudo aneurism. in the floseal group 1 patient developed a pseudo aneurism that was treated successfully with angio embolization. none of these late complications were observed in the tachosil group. discussion open nephron-sparing surgery yields oncologic outcomes comparable with open radical nephrectomy and long-term preservation of renal function in patients with small renal tumors. along with technological advancements, refinement of surgical tools, and surgical experience, lnss has become a feasible alternative to open partial nephrectomy(1,2). lnss is a challenging surgical technique with a shallow learning curve and is associated with potentially troublesome complications. achieving hemostasis and repair of the collecting system are the most challenging aspects of the procedure, whereas intraoperative and postoperative bleeding and urine leakage are well-known complications that occur in 1.2%-9.5 % and 1.2%-4.5 % of patients, respectively (3,14). the use of ahas during lnss has become more wide spread since 2000’s, as it is associated with reductions in postoperative bleeding and urinary leakage. several studies have reported these aha benefits and that the use of ahas was superior to the standard procedure, in terms of the rates of hemorrhage and urine leakage(3,14). several ahas are currently available, but there are no comparative data concerning their effectiveness. tachosil (takeda nycomed, linz, austria) is a readyto-use fibrin sealant patch consisting of equine collagen coated with human fibrinogen and thrombin. it helps to achieve hemostasis in 3-5 min via creation of a fibrin clot at the surgical site upon contact with blood or other fluids, and it can also be use for tissue sealing(11,15). many studies report that tachosil is a safe and effective hemostatic agent(12,16,17). in an open randomized, prospective study conducted with 185 patients tachosil was observed to be superior to standard suturing during nephron-sparing surgery and time to hemostasis was significantly shorter in the tachosil group than in the standard suturing group (5.3 min vs. 9.5 min, respectively)(12). similarly, fanari et al.(17) reported that mean time to hemostasis using tachosil was 5.5 min (range: 3-16 min). tachosil can be used safely regardless of patient age. in a preliminary study mele et al.(16) observed that tachosil was safe and effective for achieving hemostasis, as well as sealing the collecting system in children undergoing nephron-sparing surgery. some researchers reported that combined manual suturing and aha use might be the best method for achieving hemostasis during laparoscopic partial nephrectomy. falsaperia et al.(18) reported that tachosil is safe and effective, and easy to apply, even when surgery is performed without hilar clamping. use of tachosil might reduce the cost of surgery. a relaparoscopic nephron-sparing surgery-tonyali et al. table 2. operation characteristics and postoperative course no aha(n = 18) tachosil (n = 25) floseal (n = 36) p approach 0.030 transperitoneal, n 12 (66.6%) 19 (76%) 34 (94%) retroperitoneal, n 6 (33.3%) 6 (24%) 2 (6%) mean duration of surgery (min) 156.6 ±34.4 137.4 ± 42.4 120.9 ± 23.1 * 0.004 mean ebl (ml) 72.7 ±24.4 118 ±112.3 130 ± 203 0.995 mean ischemia time (min) 24.3 ±4 23.1 ± 6.3 21.3 ± 4.3 0.101 intraoperative complications 0.596 no, n 17 (94.4%) 25 34 (94.4%) yes, n 1 0 2 surgical margin 1.00 positive, n 1 (5.6%) 1 (4%) 1 (2.8%) negative, n 17 (94.4%) 24 (96%) 35 (97.2%) postsurgical complications 0.876 ≤ clavien 2, n 3 (16.6%) 5 (20%) 5 (13.8%) > clavien 2, n 1 (5.5 %) 0 1 (2.7%) transfusion required 0.403 yes, n 0 1 (4%) 3 (8.3%) no, n 18 (100%) 24 (96%) 33 (91.6%) mean 1st d ia catheter drainage (ml) 156.9 ±78.3 72.6 ± 64.5* 60.8 ± 30.2* 0.000 mean duration of hospitalization (d) 3.2 ±0.5 2.9 ± 0.7 2.8 ± 0.7* 0.043 mean postsurgical creatinine level (mg/dl) 1.28 ±0.8 0.96 ± 0.2 1.17 ±1.1 0.184 abbreviations: d, day; ia, intraabdominal; aha, adjuvant hemostatic agent; ebl, estimated blood loss vol 15 no 01 january-february 2017 23 laparoscopic urology 24 cently published review by colombo et al.(19) examined the economic effect of tachosil. they screened studies that included patients that underwent hepatic, cardiac, and renal surgery with the use of tachosil. they observed that time to hemostasis, duration of hospitalization (2.01 days vs. 3.58 days), and the postoperative complication rate were lower in the tachosil group than in the standard technique group. in accordance with colombo et al., mean durations of hospitalization were 4 and 5.5 days in earlier studies(17,18). in the present study mean duration of surgery, postoperative catheter drainage time, and duration of hospitalization were lower (but not significantly) in the tachosil group than in the no aha group. moreover, serious postoperative bleeding and late complications were not observed in the tachosil group. floseal (baxter corp., deerfield, il) consists of a cross-linked bovine gelatin matrix and human-derived thrombin. its use in ear, nose, and throat, cardiac, and vascular surgery is well known. it also can be used for urological surgery, including both open and laparoscopic procedures such as radical-partial nephrectomy and prostatectomy(20). floseal use during lnss can have a positive effect on the surgical procedure and outcome, including warm ischemia time, estimated blood loss, duration of surgery, duration of hospitalization, and hemorrhagic complications. gill et al.(6) retrospectively compared floseal and their standard technique without aha, and there was not any significant difference in duration of surgery, warm ischemia time, estimated blood loss, or duration of hospitalization between the 2 techniques. nonetheless, floseal was associated with fewer procedural and hemorrhagic complications. wille et al.(21) reported that floseal is a safe and reproducible tool that reduces warm ischemia time and precludes damage induced by sutures. they used floseal to achieve hemostasis, and used suturing only to repair the collecting system or to occlude the great vessels damaged during deep excision via scissors or a harmonic scalpel (ethicon endo-surgery, livingston, west lothian, uk). mean clamping time was 25.8 minutes, mean duration of surgery was 201 minutes (range: 110-355 minutes), and mean estimated blood loss was 181 ml. a recent systematic review reported that floseal use during various surgical procedures reduces the time to obtain hemostasis, duration of hospitalization, and intraoperative and postoperative bleeding(13). another study compared the safety and efficacy of floseal and a surgeon-prepared gelatin hemostatic agent. median duration of surgery was similar in both groups (150 min), whereas median warm ischemia time was shorter in the floseal group (16 min vs. 20 min). the postoperative transfusion rate was 0% in the floseal group, versus 4.8% in surgeon-prepared gelatin hemostatic agent group (p = .33). both ahas exhibited similar safety and efficacy profiles, whereas the surgeon-prepared material reduced the cost of treatment per case by $200-$450(22). antonelli et al.(23) compared the efficacy of floseal, tachosil, and no hemostatic agent during both open and laparoscopic partial nephrectomies. in all, 48 procedures were minimally invasive (tachosil: n = 18; floseal; n = 14; no hemostatic agent: n = 16) and 150 were open procedures. the researchers reported that the hemostatic agents did not provide any clinical benefit in terms of medical and surgical complications, transfusion, and reinterventions. moreover, estimated blood loss was highest in the floseal group. the researchers concluded that it was not possible to confirm the efficacy of ahas, as compared to standard suturing. the study by antonelli et al. seems similar to our study at first sight however there were main differences between the methodology and outcomes of the two studies. first of all both open and minimal invasive operations were included that prospective, multi-institutional study. to use or not to use ha, the type of used ha and surgical approach was decided on centers’ and surgeons’ preference on that study which might cause a selection bias and affect surgical outcomes. we reported the results of the consecutive lnns’s of a single surgeon in a retrospective fashion and found ha to be useful in lnss. similarly, to that study intraoperative ebl was highest in floseal group in our study. the present study’s findings in the floseal group are consistent with most of the aforementioned studies. mean duration of surgery, duration of hospitalization, and postoperative drainage were significantly lower in the present study’s floseal group than in the no aha group. mean ischemia time was also lower, but not significantly, in the floseal group. on the other hand, postoperative bleeding that reduced the hemoglobin level was observed in 3 patients in floseal group. in addition, 27.7% patients in the no aha group had a pseudo aneurism as a late complication, which shows the importance of ahas during lnss. use of ahas in the present study provided many advantages during lnss, such as shorter duration of surgery, duration of hospitalization, and warm ischemia time (not significant), and a decrease in postoperative drainage. in terms of duration of surgery and hospitalization, and warm ischemia time, floseal was superior to tachosil, whereas postoperative drainage was similar in the floseal and tachosil groups. although all procedures were performed by the same experienced laparoscopic surgeon, shortened operation and warm ischemia time may also be attributed to long learning curve such that our first cases were mainly in no aha group. the present study has some limitations, including its retrospective design and relatively small patient population. the patients were divided into 3 groups, sequentially. the first cases were performed without aha because of the lack of aha in the operation room. after than the supply of aha available aha in the operation room was used in consequent patients without a tendency. although many features of the tumors and patients were similar, including clinical stage, size, and padua score, others differed. additional randomized prospective studies with larger numbers of patients matched according to demographics and tumor characteristics are required to confirm the present findings. conclusions in conclusion, both tachosil and floseal can be considered safe and effective, and easy to use adjuvant treatments during lnss. they might be useful especially in preventing pseudo aneurisms, decreasing postoperative drainage and shortening intraoperative ischemia time and hospital stay. shortened operation and warm ischemia time may also be attributed to long learning curve of lnss such that our first cases were mainly in no aha group. laparoscopic nephron-sparing surgery-tonyali et al. conflict of interest the authors declare there are no conflicts of interest financial or otherwise related to the material presented herein. references 1. haber gp, gill is. laparoscopic partial nephrectomy: contemporary technique and outcomes. eur urol 2006;49:660-5. 2. gill, i. s., matin, s. f., desai et al. comparative analysis of laparoscopic versus open partial nephrectomy for renal tumors in 200 patients. j urol 2003;170:64-8. 3. ramani, a. p., desai, m. m., steinberg, a. p. et al. complications of laparoscopic partial nephrectomy in 200 cases. j urol 2005;173:427. 4. urlesberger h, rauchenwald k, henning k. fibrin adhesives in surgery of the renal parenchyma. eur urol 1979;5:260-1. 5. hidas g, lupinsky l, kastin a, moskovitz b, groshar d, nativ o. functional significance of using tissue adhesive substance in nephronsparing surgery: assessment by quantitative spect of 99m tc-dimercaptosuccinic acid scintigraphy. eur urol 2007;52:785-9. 6. gill, i. s., ramani, a. p., spaliviero, m. et al. improved hemostasis during laparoscopic partial nephrectomy using gelatin matrix thrombin sealant. urology 2005;65:463-6. 7. aron m, gill is. minimally invasive nephronsparing surgery (minss) for renal tumours part i: laparoscopic partial nephrectomy. eur urol 2007;51:337-46; discussion 46-7. 8. pruthi rs, chun j, richman m. the use of a fibrin tissue sealant during laparoscopic partial nephrectomy. bju int 2004;93:813-7. 9. richter, f., schnorr, d., deger, s. et al. improvement of hemostasis in open and laparoscopically performed partial nephrectomy using a gelatin matrix-thrombin tissue sealant (floseal). urology 2003;61:737. 10. klingler ch, remzi m, marberger m, janetschek g. haemostasis in laparoscopy. eur urol 2006;50:948-56; discussion 56-7. 11. toro a, mannino m, reale g, di carlo i. tachosil use in abdominal surgery: a review. j blood med 2011;2:31-6. 12. siemer, s., lahme, s., altziebler, s. et al. efficacy and safety of tachosil as haemostatic treatment versus standard suturing in kidney tumour resection: a randomised prospective study. eur urol 2007;52:1156-63. 13. echave m, oyaguez i, casado ma. use of floseal(r), a human gelatine-thrombin matrix sealant, in surgery: a systematic review. bmc surg 2014;14:111. 14. breda, a., stepanian, s. v., lam, j. s. et al. use of haemostatic agents and glues during laparoscopic nephron-sparing surgery-tonyali et al. laparoscopic partial nephrectomy: a multiinstitutional survey from the united states and europe of 1347 cases. eur urol 2007;52:798803. 15. matonick jp, hammond j. hemostatic efficacy of evarrest, fibrin sealant patch vs. tachosil(r) in a heparinized swine spleen incision model. j invest surg 2014;27:360-5. 16. mele e, ceccanti s, schiavetti a, bosco s, masselli g, cozzi da. the use of tachosil as hemostatic sealant in nephron sparing surgery for wilms tumor: preliminary observations. j pediatr surg 2013;48:689-94. 17. fanari m, serra s, corona a, de lisa a. [use of tachosil in laparoscopic enucleoresection of renal masses smaller than 4 cm: our preliminary experience of 41 cases]. urologia 2012;79 suppl 19:131-3. 18. falsaperla, m., autorino, r., puglisi, m. et al. haemostatic agents during laparoscopic nephron-sparing surgery: what about tachosil? bju int 2009;104:270-1. 19. colombo, g. l., bettoni, d., di matteo, s. et al. economic and outcomes consequences of tachosil(r): a systematic review. vasc health risk manag 2014;10:569-75. 20. user hm, nadler rb. applications of floseal in nephron-sparing surgery. urology 2003;62:342-3. 21. wille ah, johannsen m, miller k, deger s. laparoscopic partial nephrectomy using floseal for hemostasis: technique and experiences in 102 patients. surg innov 2009;16:306-12. 22. guzzo tj, pollock ra, forney a, aggarwal p, matlaga br, allaf me. safety and efficacy of a surgeon-prepared gelatin hemostatic agent compared with floseal for hemostasis in laparoscopic partial nephrectomy. j endourol 2009;23:279-82. 23. antonelli, a., minervini, a., mari, a. et al. trimatch comparison of the efficacy of floseal versus tachosil versus no hemostatic agents for partial nephrectomy: results from a large multicenter dataset. int j urol 2015;22:47-52. vol 15 no 01 january-february 2017 25 urological oncology multiparametric mri for the diagnosis of tumor type in patients suspicious of inner gland prostate cancer zahra ghane1,2, fariborz faeghi3*, mahyar ghafoori4, abolfazl payandeh5 purpose: the current study aimed to evaluate multiparametric mri for the diagnosis of type of tumor (benign or malignant) in patients suspicious of inner gland prostate cancer. materials and methods: this cross-sectional study was conducted on 44 consecutive patients with a clinical impression of prostate cancer who were referred to the mri department of payambaran hospital, tehran, iran for confirmative diagnostic evaluation. cases suspected of tumor relapse and those who previously underwent treatment for prostate cancer were excluded. multiparametric mri was performed for every patient by using a 1.5 tesla device with an integrated endorectal and pelvic-phased array coil. all patients subsequently underwent mri transrectal ultrasound fusion biopsy. the diagnostic value of each sequence was then investigated individually and in combination with other techniques by comparing the results with histological findings from mri–trus fusion biopsy. results: among the techniques, t2-weighted imaging (t2w) had the highest sensitivity and specificity while dynamic contrast enhanced (dce) technique had the least. diffusion-weighted imaging (dwi) and magnetic resonance spectroscopy (mrs) had a similar sensitivity and specificity and did not significantly differ from t2w. adding functional techniques to t2w did not improve diagnostic indices compared to t2w alone. quantitative evaluation of apparent diffusion coefficient (adc), dwi, and mrs showed that all techniques were able to differentiate between benign and malignant tumors. however, the quantitative combination of these sequences decreased diagnostic performance. conclusion: t2w is the best technique for the diagnosis of type of tumor in terms of benignancy or malignancy in patients suspicious of inner gland prostate cancer. adding functional imaging measurements to t2w does not improve its diagnostic value. keywords: multiparametric mri; prostate cancer; zone; t2 weighted imaging. introduction cancer has become a major public health problem and accounts for the third leading cause of death in iran. specifically, prostate cancer has turned into an important issue in the world especially in developing countries. it is the second most prevalent cancer in the world and the sixth most prevalent in iran. the most common histology observed in prostate cancer is adenocarcinoma which is also associated with a shorter life span.(1) regarding zonal origin, 65% of prostate tumors originate from the peripheral zone while about 30% of them develop from the transition zone. the presence of transition zone tumors plays a significant role in the progression and mortality of the disease. thus, the early diagnosis is essential.(2) prostate cancer is initially diagnosed by measuring 1department of radiology technology, school of allied medical sciences, shahid beheshti university of medical sciences, tehran, iran. 2iran social security organization. 3department of radiology technology, school of allied medical sciences, shahid beheshti university of medical sciences, tehran, iran. 4radiology technology department, full professor, school of allied medical sciences, iran university of medical sciences, tehran, iran. 5department of biostatistics and epidemiology, school of health, zahedan university of medical sciences, zahedan, iran. *correspondence: tehran shemiran tajrish ghods square darband street school of allied medical sciences. postal code: 1971653313, telefax: +98. 2122722150, tel: +98.2122718506. email: f_faeghi@sbmu.ac.ir. received december 2018 & accepted october 2019 prostate-specific antigen (psa) level and performing digital rectal exam (dre). definite diagnosis is made through transrectal ultrasound-guided (trus) biopsy. however, these diagnostic techniques have some drawbacks. low sensitivity and low positive predictive value (ppv) of dre, low specificity of psa measurement, and inefficacy of systemic biopsy in diagnosing cancers of the anterior part of the prostate are some of the limitations related to these methods. hence, identifying a non-invasive and more precise method for early diagnosis of prostate cancer is crucial.(3) in the mid-1980s, for the first time t1-weighted (t1w) and t2-weighted (t2w) imaging techniques of mri were used for prostate imaging. gradually, by adding functional imaging (dwi, dce, and mrs) to the anatomic sequence (t2w), it became possible to examine urology journal/vol 16 no. 6/ november-december2019/ pp. 552-557. [doi: 10.22037/uj.v0i0.4998] vol 16 no 06 november-december2019 553 the physiological properties of tissues. among these functional parameters, dynamic contrast enhanced (dce) is efficient for assessing microvascular properties, diffusion weighed imaging (dwi) is sensitive to the restriction of water molecule diffusion movement and magnetic resonance spectroscopy (mrs) is valuable for evaluating biochemical changes within the prostate tissue. however, none of these functional techniques are sufficient for the diagnosis of prostate cancer individually. moreover, heterogeneous appearance and overlap enhancement of bph nodules originating from the transition zone complicates the detection of tumors originating from this zone.(3,4) the current study was conducted to evaluate the efficacy of multiparametric mri (mpmri) for the diagnosis of type of tumor in the inner prostate gland (transition, central, and fibromuscular zone). also, we aimed to compare the results obtained from mri with the results of mri-trus fusion biopsy as it is considered the golden standard of diagnosis. materials and methods study design, sample and population this cross-sectional study was performed during 2017 on patients clinically suspicious of prostate cancer who were referred to the mri department of medical imaging center of payambaran hospital, tehran, iran for further diagnostic evaluation. sample size was computed by using pass software (version 11.0.4). a sample size of n=44 was required to achieve 80% power for the two-sided binomial test to detect a change in sensitivity from 0.5 to 0.8. the probability of type one error (（) was considered to be 0.05. also, based on previous studies, the prevalence of prostate cancer was estimated to be 0.50.(5) the present research was approved by the ethics committee of shahid beheshti university of medical sciences, tehran, iran (ethics code: ir.sbmu. retech.rec.1396.828). inclusion and exclusion criteria this study included men ≥ 50 years old with a clinical suspicion of prostate cancer who were referred by an urologist for mri imaging and prostate biopsy. the primary diagnosis was based on an increase in the serum level of psa (psa> 3ng/ml) or an abnormal dre. exclusion criteria included tumor relapse, having already undergone treatment, and having contraindications for receiving endorectal coil such as presence of severe hemorrhoid or severe inflammatory bowel disease, sensitivity to latex, or history of rectal resection. subjects who were contraindicated for mri imaging (i.e. presence of ferromagnetic implants and cardiac pacemakers) or gadolinium contrast agent injection (i.e. active asthma, allergy to gadolinium, severe allergy, and gfr < 30 ml/min) were also excluded from the study. in addition, cases whose obtained images were not satisfactory (e.g. multiple artifacts due to total hip replacement or patient movements) were also not included. procedures in this study, an mri scanner with a field strength of 1.5 tesla (magnetom avanto, siemens) along with combined endorectal and pelvic phased-array coils was used. multiparametric sequences including t2w, dwi, dce, and mrs were performed for all patients. the detail of each protocol is shown in table 1. for dce mri, 0.1 mmol/kg gadolinium contrast agent was admpmri for the detection of inner gland prostate cancer-ghane et al. pulse sequences t1-w (tra) t2-w(tra-sag-cor) dwi (tra) dce (tra) mrs (3d-csi) time repetition (ms) 600 8000 4400 4.96 650 time echo (ms) 12 109 82 1.69 120 (mm)slice thickness 3 3 3 3 matrix size 256×192 320×320 102×50 192×138 number of section 24 24 30 28 10 field of view(mm) 175×175 175 ×175 175×85 250×250 190×190 flip angle 150 150 12 90-180-180 average (nex) 1 1 6 1 8 (mm) voxel size 0.9×0.7×3 0.5×0.5×3 1.7×1.7×3 1.9×1.4×3 10×10×10 temporal resolution 11s b-value(s/mm2) 50-400-800-1200 table 1. details and parameters of the sequences figure 1. classification of dce i: slow entrance of the contrast agent and contrast is kept being enhanced and having the same signal with background tissue ii: rapid entrance and relatively rapid exit of the contrast agent from tissue iii: very rapid entrance and exit of the contrast agent from tissue ministered with an injection rate of 2-3 ml/s followed by 20 ml normal saline flush. the temporal resolution was equal to 11 seconds. evaluations initially, an experienced radiologist interpreted the mri images and correlated the lesions observed in t2w with functional sequences. diagnostic characteristics for the detection of tumoral lesions included lesion morphology and homogeneous low signal intensity in t2w, restricted diffusion in dwi, early enhancement and wash out of the contrast agent in dynamic imaging, and increase in the choline + creatinine to citrate ratio (cho + cr/ci) in mr spectroscopy. according to the pi-rads v2 scoring system, findings of t2w and dwi were assessed on a 5-point category scale with 5 being most likely to represent clinically significant prostate cancer. mrs was also assessed with a score from 1 to 5. dce was evaluated based on the shape of the curves (figure1 and 2). mritrus fusion biopsy was considered as the gold standard of diagnosis. considering the correlation between the imaging scores and the results obtained from fusion biopsy, the scores of 1 and 2 were considered as negative, score 4 and 5 as positive, and the score of 3 was considered negative for t2w and dwi and positive for mrs. as for the dce technique, asymmetry and focal early enhancement were assumed to be positive along with the shape of plateaus and washout. in the second stage of evaluation, quantitative and semi-quantitative values were obtained using the syngo mri software (siemens medical solutions), spectroscopy software, and mean curve. quantitative factor of diffusion coefficient, the ratio of metabolites in mrs and tic pattern diagrams were considered as quantitative and semi-quantitative values. advanced ultrasound devices that were equipped with special software and hardware to accurately match mri images with ultrasound images were used for tissue sampling. with the help of the sensors connected to the ultrasound probe and the patient's body, the probe's position relative to the prostate was detected at any time and by moving the probe in different directions within the rectum, an ultrasound image was provided on the monitor as well as an equivalent mri image. by marking the suspicious mass on the mri image, the same area was automatically marked on the ultrasound image, and the corresponding software specified the needle pathway to obtain a tissue sample from the mass. then, samples were sent for pathological evaluation. statistical analysis analysis was performed using spss software version 20 (ibm, chicago, illinois, usa) and medcalc version 12.1.4 (medcalc software bvba, mariakerke, belgium). diagnostic indices including the sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv), accuracy, roc curve, and area under the curve (auc) of each sequence was calculated separately. mcnemar’s test was employed for the comparison of diagnostic values and logistic regression model was used for the evaluation of combined mri sequences. p-value < .05 was considered as statistically significant. results a total of 44 male patients suspicious of prostate cancer with a mean age (sd) of 65.1(5.9) years old (range: 53 – 80) and a serum psa level > 3 ng/ml were included in the study. based on histological examination, 22 patients (50%) were diagnosed with malignancy with a gleason score ≥ 6 and the rest had benign tumors. regarding the ability of each technique to detect the type of tumor separately, results obtained from imaging with t2w, dce, dwi and mrs (qualitative) sequences were not compatible with histologic findings in 5,19,9, and 9 cases, respectively. table 2 reports the diagnostic indices of these sequences when performed in isolation. there was a significant difference between the specificity of dce and t2w techniques only (p = .004). as shown in figure 3, t2w had a greater auc compared to the other techniques. the estimated auc was equal to 0.89 (p < .001), 0.57 (p = .44), 0.80 (p = .001), and 0.80 (p = .001) for t2w, dce, dwi, and mrs sequences, respectively. the results for double, triple, and quadruple combinations of the aforementioned techniques (t2w+dwi, t2w+mrs, t2w+dce, t2w+dwi+dce, t2w+dwi+mrs, t2w+dwi+dce +mrs) were found to be similar to those of t2w alone (p > 0.05). in other words, by adding functional sequences to t2w, no changes were observed in terms of diagnostic indices. the techniques of dwi, adc, and mrs were also investigated quantitatively (table 3). quantitative investigation of dwi, adc map showed that the results obtained from these parameters were not compatible with histological findings in 14 cases (31.8%). sensitivity, specificity, ppv, npv, and accuracy were reported to be 63.6, 72.7, 70, 66.7, and 68.2%, respectively. considering the roc curve, the auc was calculated as 0.73, which was statistically significant (p = .003). on this basis, 648 × 10-6 was determined as the cut-off point for differentiation of benign lesions table 2. diagnostic indices of t2-w, dce, dwi, and mrs sequences sensitivity specificity positive predictive value negative predictive value precision t2-w 81.8% (18/22) 95.5% (21/22) 94.7% (18/19) 84% (21/25) 88.6% (39/44) dwi 72.7% (16/22) 86.4% (19/22) 84.2% (16/19) 76.0% (19/25) 79.5% (35/44) dce 59.1% (13/22) 54.5% (12/22) 56.5% (13/23) 57.1% (12/21) 56.8% (25/44) mrs 71.4% (15/21) 90.5% (19/21) 88.2% (15/17) 76.0% (19/25) 81.0% (34/42) abbreviations: t2-w: t2-weighted; dwi: diffusion weighted imaging; dce: dynamic contrast enhanced; mrs: magnetic resonance spectroscopy descriptive indices mean adc1 quantity of mrs2 mean 684.6×10-6 1.14 standard deviation 138.9×10-6 1.47 minimum 402×10-6 0.02 maximum 978×10-6 7.16 1: apparent diffusion coefficient; 2: magnetic resonance spectroscopy table 3. descriptive indices for mean adc and quantity of mrs mpmri for the detection of inner gland prostate cancer-ghane et al. urological oncology 554 vol 16 no 06 november-december2019 555 from malignant ones. the quantitative investigation of mrs showed that the results were not compatible with pathology findings in 11 cases. sensitivity, specificity, ppv, npv, and accuracy were reported as 68.2, 81.8, and 78.8, 72, and 75%, respectively. considering the roc curve, the auc was calculated as 0.73 which was statistically significant (p = .004). based on this result, 0.91 was determined as the cut-off point for differentiation of benign lesions from malignant types. our results showed that there was no significant difference between adc and mrs in diagnosing the type of tumor (p = .97). the mean adc and the quantity of mrs were combined together. the results of this combination in diagnosing the type of tumor were not compatible with the pathology findings in 18 cases. sensitivity, specificity, ppv, npv, and accuracy were reported to be 59.1%, respectively. the auc was also estimated as 0.59, which was not statistically significant (p = .23) (figure 4). discussion the current study was carried out to evaluate the diagnostic indices of mpmri for detection of malignant or benign type of tumor in patients suspicious of inner gland prostate cancer. our results indicated that t2w had the highest sensitivity and specificity while dce had the least. the sensitivity and specificity of qualitative dwi and mrs techniques were found to be similar. dwi and mrs were not significantly different compared to t2w. however, dce specificity had a significant difference compared to t2w. each of these techniques might report false positive results because of the difficult differentiation between prostate cancer and benign hyperplasia due to the hypervascularity of bph in dce and the low amount of adc in dwi and adc maps, there is an overlap between the amounts of adc in stromal bph with the amounts in prostate cancer.(4,6,7) in addition, based on the data obtained from dce imaging, 9 of the 22 cases with malignant lesions had persistent enhancement which might be attributed to the presence of fewer arteries in the tumor.(8) in mrs, the different amount of metabolites in various parts of the prostate (such as the difference in the peri-urethral zone from other zones or the higher citrate concentrafigure 2. classification of mrs i: cho is significantly lower than citrate (<<) ii: cho is elevated but still lower than citrate (<) iii: cho is approximately on the same level as citrate (=) iv: cho is elevated compared to citrate (>) v: cho is significantly elevated compared to citrate (>>) figure 3. roc curve for comparison of the diagnostic value of the three sequences of dwi, dce, and mrs with the sequence of t2 in diagnosing the type of tumor figure 4. roc curve for comparison of mean adc, mrs, and combination of mean adc, mrs mpmri for the detection of inner gland prostate cancer-ghane et al. tion in glandular proliferation) as well as the extensive range of metabolites in tumors of the internal portion of prostate may result in false positive results.(9,10) the sensitivity and specificity of t2w were the highest which could be due to anatomical characteristics.(11) nonetheless, benign lesions such as chronic inflammation of the prostate, atrophy, scar, benign hyperplasia of the prostate, post-biopsy bleeding, and the effects of hormone therapy or radiotherapy can mimic the tumor tissue in t2w. in this study, the number of false positive cases in t2w reduced with the use of mri at appropriate time intervals with respect to previous biopsy and also elimination of patients who had received previous treatment. our findings also indicated that adding functional techniques to t2w does not improve diagnostic indices of the inner gland. regarding mpmri, our results are in agreement with the studies by delongchamps et al.(3) and hoeks et al.(2) li et al. (2006) indicated that adding dce to t2w increased the diagnostic precision of prostate cancers within the transition zone.(12) puech and colleagues investigated the diagnostic value of dce and the consequences of its elimination from mpmri. they showed that this technique is able to identify undetectable lesions on t2w and dwi.(13) however, in the present study, dce had the lowest diagnostic value and its addition to t2w did not increase diagnostic performance. meanwhile, based on the results, there was no lesion identified by dce which had not been observed on t2w. hong li et al. considered monotonous low intensity signal on t2w, homogeneous enhancement in dce, and irregular margins between the lesion and the central zone on t2w and dce which could not be easily detected in t2w, sometimes, in favor of cancer. however, in the present study, the diagnostic value of dce was based on the tic curve, ascribing to the differences in methodologies. the results of this study indicated that t2w and dwi techniques were appropriate for detection of type of tumor within the transition zone, but dce did not provide any further information. meanwhile, gadolinium increases the time and cost of the test.(14-17) in the present study, in addition to the qualitative investigation of dwi, the intensity of the signal was achieved by drawing regions of interest (roi) on adc maps of the lesion. this measure shows the degree of diffusion of water molecules. in scientific terms, the diffusion of water molecules is more restricted in malignant lesions and so, the signal intensity decreases in greater quantities.(2) this quantitative evaluation stated that the mean adc is useful in differentiating between benign and malignant tumors which is in line with a qualitative study by schimoller et al (2014).(18) our findings also revealed that quantitative mrs was able to differentiate between benignancy and malignancy. the comparison between mean adc and mrs quantity indicated that the two techniques were not significantly different in diagnosing the tumor type. in addition, the combination of mean adc and mrs quantity showed weakness in differentiating benign from malignant lesions. however, more data is needed for a more accurate report. there were some limitations in the present study. our sample size was restricted due to the fact that the prevalence of transition zone tumor is much less than peripheral zone tumor which makes it difficult to collect more samples in a limited time. second, the results of dce and tic curve obtained from mean curve software might have been different if another type of software was used. the third limitation was related to the gold standard diagnosis method. mpmri trus fusion biopsies improve the detection of clinically significant cancers compared to systematic trus-guided biopsies, however, fusion biopsies alone fail to diagnose 8.3% of cancers including 6.7% of significant cancers.(19) conclusions the results of this study showed that t2w is the best mri imaging technique for the diagnosis of type of tumor in the inner gland of prostate. adding functional techniques did not increase the diagnostic value of tumor detection in this zone. acknowledgement the authors would like to thank the staff of medical imaging center of payambaran hospital, tehran, iran for their support during data collection of this study. the authors also acknowledge the valuable comments and suggestions of the reviewers, which improved the quality of this paper. conflict of interest the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this paper. references 1. pakzad r, rafiemanesh h, ghoncheh m, et al. prostate cancer in iran: trends in incidence and morphological and epidemiological characteristics. asian pac.j.cancer prev.2016;17:839-43. 2. hoeks cm, hambrock t, yakar d, et al. transition zone prostate cancer: detection and localization with 3-t multiparametric mr imaging. radiology. 2013;266:207-17. 3. delongchamps nb, rouanne m, flam t, et al. multiparametric magnetic resonance imaging for the detection and localization of prostate cancer: combination of t2-weighted, dynamic contrast-enhanced and diffusion-weighted imaging. bju int. 2011;107:1411-8. 4. haider ma, van der kwast th, tanguay j, et al. combined t2-weighted and diffusionweighted mri for localization of prostate cancer. am j roentgenol. 2007;189:3238. 5. obuchowski na, zhou xh. prospective studies of diagnostic test accuracy when disease prevalence is low. biostatistics. 2002;3:477-92. 6. noworolski sm, vigneron db, chen ap, kurhanewicz j. dynamic contrast-enhanced mri and mr diffusion imaging to distinguish between glandular and stromal prostatic tissues. magn reson imaging. 2008;26:107180. 7. padhani ar, gapinski cj, macvicar da, et al. dynamic contrast enhanced mri of prostate cancer: correlation with morphology and mpmri for the detection of inner gland prostate cancer-ghane et al. urological oncology 556 vol 16 no 06 november-december2019 557 tumour stage, histological grade and psa. clin radiol. 2000;55:99-109. 8. josefsson a, wikstrom p, granfors t, et al. tumor size, vascular density and proliferation as prognostic markers in gs 6 and gs 7 prostate tumors in patients with long followup and non-curative treatment. eur urol. 2005;48:577-83. 9. mueller-lisse ug, scherr mk. proton mr spectroscopy of the prostate. eur j radiol. 2007;63:351-60. 10. hoeks cm, barentsz jo, hambrock t, et al. prostate cancer: multiparametric mr imaging for detection, localization, and staging. radiology. 2011;261:46-66. 11. akin o, sala e, moskowitz cs, et al. transition zone prostate cancers: features, detection, localization, and staging at endorectal mr imaging. radiology. 2006;239:784-92. 12. li h, sugimura k, kaji y, et al. conventional mri capabilities in the diagnosis of prostate cancer in the transition zone. am j roentgenol. 2006;186:729-42. 13. puech p, sufana-iancu a, renard b, lemaitre l. prostate mri: can we do without dce sequences in 2013? diagn interv imaging. 2013;94:1299-311. 14. chesnais al, niaf e, bratan f, et al. differentiation of transitional zone prostate cancer from benign hyperplasia nodules: evaluation of discriminant criteria at multiparametric mri. clin radiol. 2013;68:e323-30. 15. scialpi m, rondoni v, aisa mc, et al. is contrast enhancement needed for diagnostic prostate mri? transl androl urol. 2017;6:499-509. 16. junker d, steinkohl f, fritz v, et al. comparison of multiparametric and biparametric mri of the prostate: are gadolinium-based contrast agents needed for routine examinations? world j urol. 2019;37:691-9. 17. thestrup kc, logager v, baslev i, moller jm, hansen rh, thomsen hs. biparametric versus multiparametric mri in the diagnosis of prostate cancer. acta radiol open. 2016;5:2058460116663046. 18. schimmoller l, quentin m, arsov c, et al. mr-sequences for prostate cancer diagnostics: validation based on the pi-rads scoring system and targeted mr-guided in-bore biopsy. eur radiol. 2014;24:2582-9. 19. kaushal r, das cj, singh p, dogra pn, kumar r. multiparametric magnetic resonance imaging-transrectal ultrasound fusion biopsies increase the rate of cancer detection in populations with a low incidence of prostate cancer. investig clin urol. 2019;60:156-61. mpmri for the detection of inner gland prostate cancer-ghane et al. female urology assessing the reliability and validity of the persian version of the chronic pelvic pain questionnaire in women mahboubeh mirzaei1, azar daneshpajooh1, mohammadali bagherinasabsarab1*, fatemeh bahreini2 , fatemeh yazdanpanah2 purpose: there is a need for developing a standard and approved tool to assess chronic pelvic pain (cpp) in iranian women. the aim of this study was to investigate the reliability and validity of the persian version of the pelvic pain and urinary/frequency (puf) questionnaire in iranian women with cpp. materials and methods: this cross-sectional study was performed on 50 females with cpp referred to the urology clinic of kerman university of medical sciences from 2018 to 2019. initially, the puf questionnaire was translated into persian and then back translated into english. the face validity of the tool was evaluated by being tested on 50 patients who had different literacy levels to ensure its understandability and acceptability by patients. the construct validity was evaluated through both exploratory and confirmatory factor analyses. the internal consistency was also analyzed by determining cronbach's alpha coefficient and test-retest method. results: the persian version of the questionnaire was compatible with the original english version. the kisser sampling adequacy index was calculated on the data before extracting the factors indicating good factor accessibility of the questionnaire statements. the construct validity of the questionnaire was confirmed using exploratory and confirmatory factor analyses. the internal consistency parameters were also acceptable. cronbach's alpha coefficient of the whole questionnaire, as well as the coefficients of the "signs/symptoms" and "unpleasant feelings" domains were 77%, 74%, and 78%, respectively. conclusion: the developed persian version of the puf questionnaire retrieved a good validity and reliability. keywords: iran; pelvic pain; reproducibility of results; surveys and questionnaires; women introduction chronic pelvic pain (cpp) is one of the most com-mon women’s health problems in today's society, especially at the reproductive age which seems to be more prevalent during this period. any pelvic pain unrelated to pregnancy, menstruation, and intercourse lasting for at least six months or more is defined as cpp.(1-3) diagnosis and treatment of cpp accounts for about 10% of visits by obstetricians and gynecologists. (2) although gynecological, urological, gastrointestinal, musculoskeletal, and socio-psychosocial parameters have been generally associated with this problem,(1,3,4) more than 60% of cpp patients are not definitely diagnosed due to the complexity of the disease, especially in those with musculoskeletal problems,(4,5) the frequency of cpp in different communities has been reported between 3.8% and 39% according to the characteristics of study populations and methodology. there has been only one cross-sectional study in iran which reported a high rate (10.2%) of cpp among women working in two medical centers.(6) recent studies suggest the necessity of therapeutic interventions in a significant number of patients with cpp. in fact, alleviating pain is one of the top priorities in all diseases.(7) primary evaluation of pain is of the 1department of urology, kerman university of medical sciences, kerman, iran. 2kerman university of medical sciences, kerman, iran. *correspondence: department of urology, kerman university of medical sciences, kerman, iran. tel: +98 34 32239188. fax: +98 34 32239188. e-mail: ma_bagherinasab_md@yahoo.com received may 2020 & accepted september 2020 most important aspects of pain management. as pain is a psychological-clinical phenomenon, standard tools should be used for its evaluation. in fact, improper evaluation of pain may lead to bias in the physician's estimation of pain severity and ultimately impairment in the treatment process.(8) the pelvic pain and urinary/frequency (puf) questionnaire is a simple tool to diagnose interstitial cystitis or cpp syndrome in women.(9) this questionnaire consists of two main dimensions (signs/symptoms and unpleasant feelings) consisting of 7 and 4 questions, respectively. the questionnaire has been widely used by researchers as it evaluates a wide range of clinical symptoms from urgency of urination and pelvic pain to symptoms of sexually transmitted diseases.(10) in addition, the puf questionnaire has been shown to be well-correlated with the results of the intravenous potassium allergy test which is positive in most patients with ic/pbs.(11-15) the puf questionnaire which is used to assess pelvic pain also addresses symptoms related to sexually transmitted diseases, urinary tract obstruction, and interstitial cystitis.(15) in order to use foreign-language questionnaire in another country, it is necessary to evaluate its validity (extent of target measurability) and reliability (reproducibility). urology journal/vol 18 no. 3/ may-june 2021/ pp. 326-329. [doi: 10.22037/uj.v16i7.6212] vol 18 no 3 may-june 2021 327 although the puf questionnaire has been approved in english-language nations, it needs to be also translated and validated for iranians,(9,16,17) to determine if it has the same applicability as the original version to be used in target populations.(18) chronic pain usually affects individuals’ attitudes toward life.(19) and in some cases, theirs and their friends’ and family members’ quality of life.(20) due to the clinical significance, high prevalence, and impact of cpp on patients’ quality of life, and also the lack of appropriate tools to screen and follow-up these patients in iran and other persian-speaking countries, this study was conducted to validate the puf questionnaire as a simple and reliable tool to be used in clinic and research. materials and methods this cross-sectional study was conducted in kerman from 2018 to 2019. considering the prevalence of cpp reported in similar studies, 50 patients referred to the urology clinic of kerman university of medical sciences were enrolled in the study. the subjects consecutively entered the study, and verbal consent was acquired after explaining the purpose of the study to them. the 12-question puf questionnaire was used to collect the data after being translated into persian. in the first step, two iranian native speakers who were fluent in english translated the tool into persian. after that, the text was back-translated to english by two other people who had lived in english-speaking countries for more than 10 years and were professionally engaged in translating texts. in the first phase of translation, the word-toword strategy was used, and in case of inapplicability and mismatches, the text was conceptually translated. (21) to make sure that the questionnaire phrases were understandable, they were compared between the two english versions. inclusion criteria patients who had a definite diagnosis of cpp, were native persian-speaker, age over 18 years, and had ability to read and write. assessing validity to do this, both face and construct validities of the questionnaire were assessed. the face validity assesses the audience's view on the appearance of the questionnaire's statements. the construct validity answers that to what extent the structure of the questionnaire is consistent with its primary purpose. factor analysis was used to group variables and ascertain correlational patterns between them which are expected to follow a logical pattern. the face validity of the instrument was assessed by filling the questionnaire by 15 patients with different literacy levels in order to determine if it was understandable and acceptable. to evaluate the construct validity, the factorial structure was examined by paf analysis and direct oblimin circulation. this method, which is a type of exploratory factor analysis, was performed to determine the validity of the persian version of the questionnaire. to ensure acceptable construct validity, confirmatory factor analysis (cfa) with a maximum estimated trueness approach was used. assessing reliability the internal consistency of the questionnaire was measured to ascertain its reliability by calculating cronbach's alpha coefficient and test-retest method. for this, the questionnaire was refilled by the participants after 7 days of the first test. ethical approval the study was approved by the ethics committee of kerman university of medical sciences (ir.kmu. ah.rec.1397.084). statistical analysis to analyze the data, statistical methods for assessing reliability and validity, as well as frequency and relative frequency were used. spss 20 software was utilized for this purpose. results a total of 50 women with cpp were examined. the patients’ mean age was 39.81 ± 8.23 years, and the response rate was 98%. the translated questionnaire was approved by the translators in terms of agreement with the original version. construct validity the kaiser’s measure of sampling adequacy (msa) index which was calculated before extracting the factors was obtained as 0.89. the two-factor model using the eigenvalue values and the scree chart was the best extractable model accounting for 65% of the total variance. the signs/symptoms and unpleasant feelings domains included 7 and 4 questions, respectively. reliability and validity of the persian version of the cpp questionnaire-mirzaei et al. questions/dimensions test re-test mean sd mean sd question 1 0.24 0.04 0.3 0.04 question 2a 1.06 0.08 1.18 0.08 question 2b 0.90 0.08 0.84 0.08 question 3 1.10 0.03 1.10 0.03 question 4a 0.68 0.06 0.71 0.06 question 4b 0.64 0.06 0.78 0.06 question 5 1.12 0.05 1.12 0.05 question 6 0.79 0.07 0.82 0.07 question 7a 1.53 0.06 1.51 0.05 question 7b 0.91 0.06 0.95 0.07 question 8a 1.40 0.05 1.45 0.06 question 8b 1.18 0.08 1.24 0.07 signs/symptoms 7.41 1.82 7.93 2.32 unpleasant feeling 3.92 1.70 4.30 1.78 total 11.40 3.10 12.31 3.71 table 1. the mean scores of the questions and dimensions of the pelvic pain and urinary/frequency questionnaire . the mean scores of the signs/symptoms dimension were 7.41 ± 1.82 and 7.93 ± 2.32 at test and re-test phases, respectively. in the unpleasant feelings dimension, the mean scores were 3.92 ± 1.7 and 4.30 ± 1.78 at test and retest phases, respectively. the total mean scores were obtained as 11.4 ± 3.10 and 12.31 ± 3.71 at test and re-test, respectively (table 1). therefore, it seems that, under similar conditions, the questionnaire will deliver relatively similar scores. the correlation coefficients between the questions were 0.924 (p < 0.001) in the signs/symptoms and 0836 (p < .001) in the unpleasant feeling dimensions, as well as 0.905 in total scale (p < .001) (table 2). therefore, it can be said that the questions had the necessary correlations and alignments. the two-factor model of cfa showed a root mean square error of approximation (rmsea) index of 0.92, the comparative fit index (cfi) of 0.95, and the chisquare/degree of freedom ratio of 2.6. all these indicated acceptable fitness. reliability the internal consistency of the questionnaire was appropriate. the correlations between all the items were above 0.4 in both dimensions (signs/symptoms and unpleasant feeling). while the whole questionnaire’s cronbach's alpha coefficient was 77%, those of the signs/symptoms and unpleasant feeling dimensions were 78% and 74%, respectively. the re-test phase also showed a high correlation between the questions indicating a good reliability. both the cronbach's alpha calculation and test-retest methods indicated acceptable internal compatibility and reliability of the questionnaire. in other words, the questions had necessary correlation and compatibility retrieving similar scores if being repeated under similar conditions. discussion many epidemiological and interventional studies are concerned with determining frequency and monitoring progression of cpp.(22) instruments designed to measure cpp should have three characteristics: 1) being clinically applicable, 2) having good validity, and 3) having acceptable reliability. a short and simple translation makes the tool understandable and increases its applicability. on the other hand, the high level of participation of the studied population can be in favor of the acceptance of questionnaire by patients.(23) so far, studies have been conducted on the validity and reliability of persian versions of other questionnaires. for example, a study by hajebrahimi et al. in 2012 validated the persian version of the international consultation on incontinence questionnaire-urinary incontinence short form (iciquisf) as a simple and valid tool in patients with urinary incontinence.(19) another study in 2015 by sari-motlagh et al. showed that the persian version of the international questionnaire consultation on incontinence questionnaire in over active bladder (iciq-oab) can be a strong and simple tool for researches to monitor persian-speaking patients.(20) in the present study, the puf questionnaire was validated as a brief questionnaire in which queries are juxtaposed in a relatively identical format. because of having a few descriptive words and a simple language structure,(22) the persian translation of the original questionnaire was relatively easy and fluent. the translations of this questionnaire into other languages including spanish(22) and brazilian(23)were also reported to be easy. in our study, the mean scores of the signs/symptoms and unpleasant feeling dimensions were obtained as 7.93 and 4.30, respectively. the total mean score was also recorded as 12.31 which was almost the same as the study of minaglia et al. who validated the spanish version of the questionnaire in 2005.(22) in 2015, victal et al. also validated the brazilian version of the questionnaire reporting good validity and reliability.(23) the cfa and efa approaches were used to determine construct validity of the questionnaire. the efa method was used to extract the constituents of the questionnaire retrieving two factors consistent with the those proposed by the developers of the questionnaire. in some studies; however, the extracted factors were not the same as those of the original version.(7) in the cfa method, the questionnaire dimensions proposed by its developers were re-evaluated to check if they met the required criteria and to confirm the construct validity of the translated questionnaire. in the present study, the cfa highlighted one indicator. a good-fitness in a model is met when the rmsea is not larger than 0.2, the cfa is > 0.9, and the chi-square/ degree of freedom ratio is less than 3 or even 5. in this study, using the amos software, the data showed a good fitness in the two-factor model. most studies have used the efa method to determine the construct validity of the cpp questionnaire.(22) however, other experts have noted that the cfa may be more appropriate to test the proposed model.(22) overall, one of the strengths of this study was using a variety of methods to evaluate the validity and reliability of the questionnaire. the reliability of the puf questionnaire was analyzed by two methods (i.e. cronbach's alpha calculation and test-retest method). this indicated appropriate internal compatibility and reliability of the tool. in other words, the questions had adequate correlation and alignment retrieving relatively similar scores after being retested under similar conditions. the results of this study were parallel to the studies on spanish and brazilian versions of the questionnaire which reported good validity and reliability.(22,23) considering the above-mentioned, it seems that the developed persian version of puf questionnaire can be used for clinical and research purposes. questions/dimensions correlation coefficient p value question 1 0.756 < 0.001 question 2a 0.931 < 0.001 question 2b 0.940 < 0.001 question 3 1 < 0.001 question 4a 0.883 < 0.001 question 4b 0.905 < 0.001 question 5 0.849 < 0.001 question 6 0.888 < 0.001 question 7a 0.813 < 0.001 question 7b 0.921 < 0.001 question 8a 0.821 < 0.001 question 8b 0.885 < 0.001 signs/symptoms 0.924 < 0.001 unpleasant feeling 0.836 < 0.001 total 0.905 < 0.001 table 2. internal correlation coefficients between questions of the two dimensions of pelvic pain and urinary/frequency questionnaire at two time points (test/retest). reliability and validity of the persian version of the cpp questionnaire-mirzaei et al. female urology 328 conclusions considering the comprehensibility, as well as acceptable validity and reliability of the developed persian version of the puf questionnaire, it can be used by iranian researchers in related fields. conflicts of interest none declared. references 1. van os-bossagh p, pols t, hop wc, nelemans t, erdmann w, drogendijk ac, et al. questionnaire as diagnostic tool in chronic pelvic pain (cpp): a pilot study. european journal of obstetrics & gynecology and reproductive biology. 2002;103:173-8. 2. wenof m, perry p. understanding the principles of chronic pelvic pain. the international pelvic pain society. 1991. 3. zondervan kt, yudkin pl, vessey mp, dawes mg, barlow dh, kennedy sh. the prevalence of chronic pelvic pain in women in the united kingdom: a systematic review. bjog: an international journal of obstetrics & gynaecology. 1998;105:93-9. 4. cheong y, stones rw. doctors and the chronic pelvic pain patient. minerva ginecologica. 2007;59:613-8. 5. latthe p, latthe m, say l, gülmezoglu m, khan ks. who systematic review of prevalence of chronic pelvic pain: a neglected reproductive health morbidity. bmc public health. 2006;6:177. 6. dehghan mf, ghanbari z, foroutan m, kouhpayehzadeh ej, moshtaghi z. chronic pelvic pain frequency among a group of iranian employed women. 2009. 7. brewer me, white wm, klein fa, klein lm, waters wb. validity of pelvic pain, urgency, and frequency questionnaire in patients with interstitial cystitis/painful bladder syndrome. urology. 2007;70:646-9. 8. macdiarmid sa, sand pk. diagnosis of interstitial cystitis/painful bladder syndrome in patients with overactive bladder symptoms. reviews in urology. 2007;9:9. 9. parsons cl, dell j, stanford ej, bullen m, kahn bs, waxell t, et al. increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity. urology. 2002;60:573-8. 10. dell jr. chronic pelvic pain of bladder origin: a focus on interstitial cystitis. international journal of fertility and women's medicine. 2003;48:154-62. 11. parsons cl. evidence-based strategies for recognizing and managing ic. contemp urol. 2003;15:22-35. 12. parsons cl, bullen m, kahn bs, stanford ej, willems jj. gynecologic presentation of interstitial cystitis as detected by intravesical potassium sensitivity. obstetrics & gynecology. 2001;98:127-32. 13. parsons cl, dell j, stanford ej, bullen m, kahn bs, willems jj. the prevalence of interstitial cystitis in gynecologic patients with pelvic pain, as detected by intravesical potassium sensitivity. american journal of obstetrics and gynecology. 2002;187:1395400. 14. parsons cl, greenberger m, gabal l, bidair m, barme g. the role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. the journal of urology. 1998;159:1862-7. 15. parsons cl, zupkas p, parsons jk. intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome. urology. 2001;57:428-32. 16. berry jw. introduction to methodology. handbook of cross-cultural psychology. 1980;2:1-28. 17. sperber ad, devellis rf, boehlecke b. cross-cultural translation: methodology and validation. journal of cross-cultural psychology. 1994;25:501-24. 18. brislin rw. translation and content analysis of oral and written materials. methodology. 1980:389-444. 19. hajebrahimi s, nourizadeh d, hamedani r, pezeshki mz. validity and reliability of the international consultation on incontinence questionnaire-urinary incontinence short form and its correlation with urodynamic findings. urology journal. 2012;9:685-90. 20. sari motlagh r, hajebrahimi s, sadeghi‐ bazargani h, joodi tutunsaz j. reliability and validation of the international consultation on incontinence questionnaire in over active bladder to p ersian language. luts: lower urinary tract symptoms. 2015;7:99-101. 21. graziottin a. psychogenic causes of chronic pelvic pain, and its impact on psychological status. chronic pelvic pain. 2011:29-39. 22. minaglia s, özel b, nguyen jn, mishell jr dr. validation of spanish version of pelvic pain and urgency/frequency (puf) patient symptom scale. urology. 2005;65:664-9. 23. victal ml, d’ancona cal, junqueira rg, da silva dc, oliveira hc, de moraes lopes mhb. test-retest reliability and discriminant validity for the brazilian version of “the interstitial cystitis symptom index and problem index” and “pelvic pain and urgency/frequency (puf) patient symptom scale” instruments. translational andrology and urology. 2015;4:594. reliability and validity of the persian version of the cpp questionnaire-mirzaei et al. vol 18 no 3 may-june 2021 329 case report bilateral primary renal lymphoma presented as homogenous renal enlargement and acute interstitial nephritis lei wei, hanmin wang, di wang, feng ma, li li, shiren sun* department of nephrology, xijing hospital, xi'an, shaanxi 7100032,china. *correspondence: department of nephrology, xijng hospital, no.127, changle road, xi'an, shaanxi7100032, p. r. china. e-mail: sunshiren@medmail.com.cn. received may 2018 & accepted december 2018 primary renal lymphoma(prl) is an extremely rare form of extranodal lymphoma andexhibitsas single (10-20%), multifocal nodules (60%), renal invasion from contiguous retroperitoneal disease (25-30%), diffuse infiltration (20%) or perirenal involvement (10%)[1] .here we report a case of bilateral primary renal lymphoma in a 13 yearold boy who presented with homogenous nephromegaly and acute interstitial nephritis(ain).the renal biopsy revealed primary renal t lymphoblastic lymphoma. hyper-cvad regimen was initiated and the renal function had been recovered after the first round of chemotherapy. to our knowledge, there have only been three reports of primary renal t lymphoblastic lymphoma including ours so far. all the three patients were young and showed as ain and bilateral renal enlargement. we also reviewed 16 cases of prl presenting with ain and enlarged kidneys that have been reported since 1997. although prl is quite rare, it must be taken into account when making a differential diagnosis of ain. renal biopsy is the gold standard and intensive chemotherapy can preserve the renal function. keywords: lymphoma; renal mass; interstitial nephritis introduction primary renal lymphoma (prl) is an extremely rare form of extranodal lymphoma and exhibits as single (10-20%), multifocal nodules (60%), renal invasion from contiguous retroperitoneal disease (25-30%), diffuse infiltration (20%) or perirenal involvement (10%)(1). here we report a case of bilateral primary renal lymphoma in a 13 year-old boy who presented with homogenous nephromegaly and acute interstitial nephritis(ain).the renal biopsy revealed primary renal t lymphoblastic lymphoma. hyper-cvad regimen was initiated and the renal function had been recovered after the first round of chemotherapy. to our knowledge, there have only been three reports of primary renal t lymphoblastic lymphoma including ours so far. all the three patients were young and showed as ain and bilateral renal enlargement. we also reviewed 16 cases of prl presenting with ain and enurology journal/vol 17 no. 3/ may-june 2020/ pp. 317-320. [doi: 10.22037/uj.v0i0.4596] figure 1. histopathological examination of core biopsy specimen showing diffuse infiltration of interstitium by monomorphous atypical lymphocytes(h&e, x200 magnification) figure 2. immunohistological stainings showed that the neoplastic cells were positive for cd3+, cd1a+ and ki-67 and negative for tdt. (x200 magnification). larged kidneys that have been reported since 1997. although prl is quite rare, it must be taken into account when making a differential diagnosis of ain. renal biopsy is the gold standard and intensive chemotherapy can preserve the renal function. case report a 13-year old boy without any medical history was admitted to our department for fatigue, anorexia, arthralgia and weight loss. careful physical examination revealed an low-grade fever (38.2° c) and boggy swelling of his joints. there was no peripheral lymphadenopathy or hepatosplenomegaly. the routine blood tests showed elevated serum creatinine of 3.31mg/dl, uric acid of 42.62mg/dl and lactate dehydrogenase of 367u/l. he had hemoglobin of 103g/l, platelet count 185×109/l, white blood cell count 10.01×109/l with a differential of 70.4% neutrophils. twenty-four hour urinary protein was 385mg/dl. urine analysis revealed the trace protein and no red blood corpuscle. the peripheral blood smear showed no abnormal findings. abdominal ultrasonography revealed bilateral renal symmetrical enlargement with lengths of 14cm and medulla spongy appearance. the renal biopsy was performed and showed a diffuse interstitial infiltration with lymphomatous cells compressing tubules and surrounding preserved glomeruli. additional staining confirmed t-lymphoblastic lymphoma with cd3+ and cd1a+. ki-67 stained more than 90% of the cells indicating a high-growth fraction (figure 1). fdg pet-ct showed a diffusely intense fdg uptake in both kidneys with a standard uptake value of 4.84 and intense patchy uptake in the bone marrow of multiple bones in axial and appendicular skeleton case report 413 figure 3. pet demonstrated enlarged kidneys with abnormal intense cortical fdg accumulation and intense patchy uptake in the bone marrow of multiple bones in axial and appendicular skeleton. age/sex clinical manifestations scr (mg/dl) ua (mg/dl) pro (mg/d) ldh (u/l) renalsize(cm) histology treatment renal function follow-up ref. 57/m dyspnoea, anemia dlbcl r-chop ↑ 9 27/f nausea, vomiting, fever 5.18 9.23 644 dlbcl r-chop 10 14/m headache, flank pain, 5.4 17.2 622 28/26 dlbcl ccg-5942 ↑ alive at 11 emesis, weight loss 2 weeks 68/f flank pain , dysuria 2.4 472 1820 14/14.5 dlbcl ↓ died at 12 10 days 5/m hypertension 2.0 10.3 6354 16.6/17.4 t-lbl ccg-1961 died at 7 2 months 21/f fever, weight loss, 14.60 1124 13.6/13.7 dlbcl vacop-b 13 abdominal pain 47/m fever, weakness 1.79 390 16.7/14.6 dlbcl chop ↑ alive at 14 1 year 28/m asymptomatic 9.11 408 dlbcl r-chop ↑ alive at 15 3 months 70/m confusion 9.42 b-lbl 16 23/m chest pain, weight loss 230 15/15 t-lbl vdclp ↑ alive at 8 2 year 62/m lumbar pain, oliguria, 8.0 1220 919 dlbcl 17 renal failure 17/m weight loss, joint pain, 5.3 9.2 696 20.7/19.8 nhl of cop+ ↑ 18 flank pain, fever b cells copadm 52/m ankleswelling , 4.11 400 15/15 t cell vapec-b ↑ 19 weight gain , lymphoma 22/m fever, weight loss 3.8 528 15/15 b-lbl copadem ↑ died at 1 20 year 11/f anorexia, vomitting, 5.79 10.1 17/17 birkitt’s cop+ ↑ died 21 weight loss, flank pain lymphoma copadm 6/f abdominal pain, fever 2.8 peripheral t 22 cell lymphoma abbreviations: -, not provided; n, normal;↑, improved; ↑, worsened; scr, serum creatinine; ua, uric acid; pro, proteinuria; ldh, lactate dehydrogenase; dlbcl, diffuse large b cell lymphoma; b-lbl, b lymphoblastic lymphoma; t-lbl, t lymphoblastic lymphoma; nhl, non-hodgkin's lymphoma; r-chop, cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab;vdclp, vincristin,prednisolone,daunorubicin, cyclophosphamide, l-asparaginase, prednisolone; cop, cyclophosphamide, vincristine, prednisolone; copadm, cyclophosphamide, vincristine, prednisolone, adriamycin, methotrexate; ref., reference. table 1. literature review of the 16 cases of bilateral primary renal lymphoma presenting with acute interstitial nephritis since 1997. primary renal lymphoma-wei l et al. case report 318 vol 17 no 03 may-june 2020 319 (figure 2). bone marrow biopsy evaluation identified 16% lymphoblasts. flow cytometry of the bone marrow identified a large population of cells expressing cd1a and tdt. cerebrospinal fluid specimen analysis was interpreted as unremarkable. combining the clinical and pathological findings, the patient was diagnosed with primary renal t cell lymphoblastic lymphoma. intensive systemic chemotherapy with hyperfractionated cyclophosphamide, vincristine, therarubicin and dexamethasone (hyper-cvad) and intrathecal chemotherapy were determined as appropriate treatment. three weeks after the chemotherapy, a repeated ultrasonography showed the lengths of both kidney decreased to 11cm. his serum creatinine was 1.23mg/dl and uric acid was 6.65mg/dl. the patient’s renal function and uric acid kept normal until the last visit. unfortunately, he died of pulmonary infection after allogeneic bone marrow transplantation at 17 months after diagnosis. discussion acute interstitial nephritis has a large variety of etiologies including drugs, infections, autoimmune disorders and hematological diseases. although extremely rare, acute interstitial nephritis can be a primary clinical manifestation of renal lymphoma. drug-induced or allergic interstitial nephritis and other systemic diseases (igg4 related disease, sjogren syndrome etc.) should be considered in the differential diagnosis with prl presenting with massive lymphomatous infiltration. criteria to diagnose prl can be concluded by the following four features: renal enlargement, lymphomatous infiltration, no nodal or extra-nodal involvement, and improved renal function after chemotherapy(2,3). plr is quite rare as no more than 70 cases have been reported so far(4). due to a relatively aggressive behavior and delayed diagnosis, most of the patients had a poor prognosis(5). therefore, the early diagnosis and rapid intensive treatment are essential to preserve the renal function. majority of patients with t-lbl present with stage iv disease (80%), b symptoms (50%) and elevated serum lactate dehydrogenase (ldh) levels(6)`. there have been only two cases of primary renal t lymphoblastic lymphoma(7,8), both with young age and enlarged kidneys, which were similar with ours. our patient had severe hyperuricemia without hyperkalemia, hyperphosphatemia or hypocalcemia, are probably due to the high metabolite state of tumor cells, other than the tumor lysis syndrome. fdg pet-ct is unspecific tool for the diagnosis of lymphoma due to that physiologic fdg excretion in the kidneys makes the interpretation of the tracer uptake in this organ difficult. however, it shows superiority on the diagnosis of primary renal lymphoma by excluding the nodal or extra-nodal lymphoma and staging of the disease. the present study reviewed 16 cases of bilateral primary renal lymphoma presenting with acute interstitial nephritis since 1997(7-22)(table 1). there were more male patients than female patients, with a gender ratio of 11:5. these patients aged from 5 to 70 years old, of which 10 were young patients (age < 28 years). weight loss (7/16), fever (7/16) and flank or abdominal pain (5/16) are most common symptoms. the average renal size was 15.6cm. most of the patients had increased ldh level. three patients had co-infection with hcv, hbv or hiv infections. preponderance of the cases (11/16) are b-cell lineage, and diffuse large b cell lymphoma are the most common histological type (8/16). after chemotherapy, most patients had improved renal functions. however, their prognoses were not clear with limited information. it was postulated that the pre-existing inflammation recruits lymphoid cells into the renal parenchyma(23). however, the exact mechanisms underlying the different patterns of malignant cells infiltrating the kidney (diffuse or focal, bilateral or unilateral) remain unknown. bilateral primary renal lymphoma presented as acute interstitial nephritis and symmetrical nephromegaly is believed to be a unique entity with specific 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s. primary bilateral t-cell renal lymphoma presenting with sudden loss of renal function. nephrol dial transplant. 2001;16:1487-9. 20. stallone g, infante b, manno c, campobasso n, pannarale g, schena fp.primary renal lymphoma does exist: case report and review of the literature.j nephrol. 2000;13:367-72. 21. sieniawska m, bialasik d, jedrzejowski a, sopylo b, maldyk j.bilateral primary renal burkitt lymphoma in a child presenting with acute renal failure.nephrol dial transplant. 1997;12:1490-2. 22. neuhauser ts, lancaster k, haws r, et al.rapidly progressive t cell lymphoma presenting as acute renal failure: case report and review of the literature.pediatr pathol lab med. 1997;17:449-60. 23. heggermont wa, verhoef g, evenepoel p, et al.clinical case report: a rare cause of acute kidney failure tissue is the issue. acta clin belg. 2017;72:201-204. primary renal lymphoma-wei l et al. urological oncology 152 urological oncology second transurethral resection of bladder tumor: is it necessary in all t1 and/or high-grade tumors? mohsen ayati1, erfan amini1, reza shahrokhi damavand1*, mohammad reza nowroozi1, mohammad soleimani2 , ehsan ranjbar1, ali nowroozi1 purpose: to evaluate the role of second transurethral resection of bladder tumor (turbt) in patients with t1 and/ or high-grade bladder tumor regarding tumor size, multiplicity, and presence or absence of muscle in specimens of initial resection. materials and methods: a total of 107 patients with either primary t1 or high-grade urothelial bladder cancer underwent second turbt within 6 weeks after initial surgery and prior to starting intravesical immunotherapy. we assessed the incidence of residual disease and upstaging in second turbt. results: upstaging was noted in 11 (10.3%) patients and residual tumor was evident in 29 (27%) patients. disease upstaging had a statistically significant association with tumor size, multifocality, and absence of muscle at initial resection in univariate analysis. presence of residual tumor in second resection also showed significant association with tumor size and absence of muscle at initial resection but not multifocality. multivariate logistic regression analysis revealed that absence of muscle at initial resection independently predicts disease upstaging during second turbt (or = 8.123, 95% ci: 1.478-44.632). furthermore, both tumor size (or = 13.573, 95% ci: 3.104-59.359) and absence of muscle (or = 21.214, 95% ci: 6.062-74.244) were independent predictors of residual disease in second turbt. conclusion: we showed that second turbt in a subset of patients with single, small t1 and/or high-grade tumor who underwent complete initial resection might be of limited value. keywords: residual tumor; second-look surgery; transurethral resection; upstaging; urinary bladder neoplasms introuction bladder cancer is the most common malignancy involving the urinary system and the ninth most common cancer throughout the world(1). based on globocan data, about 430,000 new cases diagnosed in 2012 with mortality rate of 3.2 and 0.9 per 100,000 men and women respectively(2). approximately 70% of urothelial bladder cancers are non-muscle-invasive at presentation. of these 70% present as stage ta, 20% as t1 and 10% as carcinoma in situ(3). transurethral resection of bladder tumor (turbt) is the initial procedure in the diagnosis and treatment of these tumors. different studies have reported presence of residual disease in about 40% of high-grade ta and up to 55% of patients with t1 tumors, after initial resection (4-7). moreover, there is significant potential for risk of understaging in patients with high-grade non-muscle-invasive tumors in the initial resection especially those with t1 tumors(8,9). so, many investigators recommended that patients with ta high-grade and or t1 tumors should undergo second turbt. however, despite the fact that many retrospective studies showed a high rate of residual tumor and under1 department of urology, uro-oncology research center, tehran university of medical sciences, tehran, iran. 2 department of urology, shahid modarres hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: department of urology, uro-oncology research center, tehran university of medical sciences, tehran, iran. tel: +98 21 66903063. fax: +98 21 66903063. e-mail: rshahrokhi@razi.tums.ac.ir. received july 2018 & accepted august 2018 staging after repeat turbt, several factors including surgeon experience and quality of initial resection in addition to tumor characteristics might affect the results of these reports(10-12). some of these studies included patients with even macroscopic residual tumor. presence of macroscopic residual tumor may lead to erroneous conclusions in such studies and overestimate the significance of second turbt. furthermore, only few investigators have evaluated the role of second turbt in a subgroup of patients with single and small t1 and/ or high-grade tumors and those who underwent initial complete turbt.(6,11,13) because of ongoing debate concerning the indications of second turbt and to identify groups of patients who may benefit most from a second turbt, we evaluated the role of second turbt in a series of 107 patients with high-grade non-muscle-invasive bladder tumor who had a second turbt regarding tumor size, multiplicity and presence or absence of muscle in specimens of initial resection. patients and methods study population using our institutional review board-approved bladder vol 16 no 02 march-april 2019 153 cancer database, we retrospectively evaluated all patients who underwent second turbt between 2011 and 2015. definition of second turbt was based on undergoing second resection within 6 weeks from initial surgery. tumor size was determined based on the ultrasonography findings. in this retrospective analysis of prospectively collected data, patients with macroscopic residual disease after initial turbt according to the surgeon’s subjective observation were excluded from enrollment. in addition, patients with muscle invasive disease after initial resection who underwent second turbt (i.e. as a part of bladder preservation protocol) were excluded from enrollment. receiving intravesical immunotherapy after initial turbt and prior to second resection was also an additional exclusion criterion. administration of intravesical mitomycin after turbt was done based on the decision of treating urologist. a total of 107 patients met inclusion criteria and were enrolled in the analysis. surgical technique initial turbts were performed by a limited number of expert urologists and visible tumors with adequate margin were resected separately in fractions. during the second turbt, all visible tumors and scars from previous surgery were resected. all turbts were performed using monopolar loop electrocautery employing distilled water as solution. staging was performed according to the tnm 2009 system of the american joint committee on cancer (ajcc) and tumors were graded based on 2004 who grading classification. outcome assessment the incidence of residual disease, tumor upstaging, and upstaging to muscle-invasive disease were the outcome measures of the study. the collected data were analyzed using spss software (version 16, spss inc, chicago, il, usa). categorical data were compared using chisquare or fisher’s exact test and quantitative variables were compared using t-test. multivariate logistic regression analysis was used to determine variables that independently predict risk of upstaging/residual disease. results among 107 patients, 90 (84%) were male and 17 (16%) female. the mean age was 59±12 years (range from 24 to 80). ninety-two patients had a single tumor and the remaining (14%) had multifocal tumors. histopathological evaluation after initial turbt revealed 4 highgrade ta and 103 t1 tumors. residual tumor was detected in 29 (27%) patients after second resection and upstaging occurred in 11 (10.3%) cases. upstaging to muscle-invasive disease occurred in 7 patients of whom 6 patients did not have muscle in the initial specimen. table 1 shows pathologic findings in second turbt stratified according to various tumor characteristics in initial surgery. the association of tumor size, multifocality, and absence of muscle in initial resection with the risk of residual disease and upstaging has been shown in table 2. disease upstaging had a statistically significant association with tumor size, multifocality, and absence of muscle at initial resection in univariate analysis. presence of residual tumor in second resection also showed significant association with tumor size and absence of muscle at initial resection but not multifocality. multivariate logistic regression analysis (table 3) revealed that absence of muscle at initial resection can independently predict disease upstaging during second turbt. furthermore, both tumor size and absence of muscle were independent predictors of residual disease in second turbt. among 59 patients with single, small (≤ 3cm) tumors who underwent adequate initial resection, identified by the presence of muscularis properia in the specimen, upstaging was not found and only 3 patients showed residual disease in second turbt. discussion approximately 70% of patients who present with bladsecond turbt in t1 and/or high grade tumors-ayati et al. first turbt tumor stage at second turbt tumor characteristics distribution no. (%) t0, no. (%) ta, no. (%) t1, no. (%) t2, no. (%) size ≤ 3 cm 87(81.3) 73(84) 10(11.5) 3(3.4) 1(1.1) >3 cm 20(18.6) 5(25) 8(40) 1(5) 6(30) multifocality single 92(86) 69(75) 16(17.3) 3(3.2) 4(4.3) multiple 15(14) 9(60) 2(13.3) 1(6.6) 3(20) muscle in present 73(68.2) 67(91.8) 4(5.4) 1(1.4) 1(1.4) the specimen absent 34(31.7) 11(32.3) 14(41.1) 3(8.8) 6(17.6) overall 107(100) 78(72.9) 18(16.8) 4(3.7) 7(6.5) table 1. pathologic findings at second turbt stratified according to tumor characteristics during initial resection. tumor characteristics residual tumor (%) p-value upstaging to p-value upstaging (%) p-value in first turbt muscleinvasive disease (%) tumor size ≤3 cm 14 (16.1) < 0.001 1 (1.1) < 0.001 4 (4.6) < 0.001 >3 cm 15 (75.0) 6 (30) 7 (35.0) tumor multifocality single 23 (25.0) 0.226 4 (4.3) 0.023 7 (7.6) 0.024 multifocal 6 (40.0) 3 (20) 4 (26.7) presence of muscle present 6 (8.2) < 0.001 1 (1.4) 0.002 2 (2.7) < 0.001 in the specimen absent 23 (67.6) 6 (17.6) 9 (26.5) table 2. association between baseline tumor characteristics and disease upstaging/residual disease. urological oncology 154 der cancer have non-muscle-invasive disease and turbt remains the treatment of choice in these patients. adequate resection of bladder tumor during turbt is of utmost importance. all macroscopic tumors with underlying muscle as well as edge of the resection area, preferably in fractions, should be removed. this allows the histopathologist to accurately stage the disease and decreases risk of understaging and inadequate treatment. klan et al demonstrated that patients who initially had a fractionated turbt had a reduced rate of residual tumor (36.7%) compared to patients who did not undergo resection of the tumor bed (56%)(14). the results of the second turbt mainly reflect the quality of initial resection. however, because of factors such as anatomic inaccessibility, tumor multiplicity, excessive tumor volume or medical instability requiring premature cessation, complete tumor removal is not always possible. recent studies have suggested that initial turbt may be incomplete in a significant number of cases(4,12,14,15). therefore, presence of residual tumor or upstaging during second turbt could be a consequence of incomplete initial resection. furthermore, several prognostic factors i.e. multifocality, tumor size and absence of muscle in the first resection might also impact the outcome of second turbt. most data on second turbt come from studies, which did not specifically analyze aforementioned prognostic factors in the first resection which are also important. risk of residual disease and upstaging in second turbt vary from 26 to 83% and 1.3 to 64% in different studies, respectively(13,16-20). although the term second turbt should not be used for the repeat resection after incomplete turbt with macroscopic residual disease, several studies addressing significance of second turbt are retrospective with the potential of including patients with incomplete initial resection. in a series of 58 patients with g2-3 pt1 bladder cancer a rate of 74% of residual tumors in second turbt has been reported. however, information regarding the quality of first resection was not available. in addition, muscle was not present at initial resection in about 40% of patients, questioning the quality of resection(18). to evaluate the value of second turbt for t1 bladder cancer, schwaibold et al reported 52% residual disease in 136 patients who underwent second turbt because of t1 urothelial cancer in initial resection. however, the study population consisted of relatively high-risk patients as more than 25% of patients had recurrent disease(21). as mentioned before, multifocality and tumor size may influence the risk of residual tumor and/or upstaging in second turbt. in a randomized prospective study investigators performed complete and correct resection during the first turbt and showed a rate of 33.3% of residual tumor in 105 patients who underwent re-turbt, 2-6 weeks following primary diagnosis of t1 disease(11). patients with no muscle tissue in the specimen were excluded from the study. in patients with solitary tumor, they reported 22.6% and 5.7% residual mass and upstaging respectively. also in tumors less than 3cm, the rate of residual disease and upstaging in second turbt was 18.9% and 2.7% respectively. these results are similar to our findings and corroborate with our observations (table 2). similarly, in a prospective study, the authors reported a rate of 36.8% of residual tumor in 38 patients with single tumor versus 64.3% in patients with multifocal disease(22). in the present study, we also noted that 25% of patients with single tumor had residual cancer in second turbt, whereas risk of residual disease was 40% in patients with multiple tumors; however the difference was not statistically significant. several investigators showed that absence of detrusor muscle in initial specimen significantly increases the risk of residual disease and upstaging in second resection(17,18). our findings in this study support this notion. of 73 patients with muscle in the initial resection, 6 (8.2%) had residual tumor. of these, only 2 patients had upstaging. on the other hand, 23 of 34 patients (67.6%) without muscle at first resection had residual tumor, and upstaging occurred in 26.5% of them. a major problem associated with turbt is undersatging. in a retrospective study 27% of t1 tumors were upstaged after radical cystectomy (rc)(23). similarly, stein reported that one-third of patients believed to have non-muscle-invasive cancer at the time of cystectomy were found to have muscle-invasive disease(24). the risk increased to 50% in some rc series(25). however, these findings are not attributable to all high-grade or t1 tumors in second turbt as the majority of patients with non-muscle-invasive disease in rc cohorts may harbor poor prognostic clinical and radiological features including multiple large tumors or refractory to intravesical therapy(17). performing turbt according to a “well-standardized strategy” decreases the likelihood of residual tumor and upstaging in patients with superficial disease. this issue has been confirmed in recent studies with report of 2643% and 1.3-8.2% residual tumor and upstaging respectively (13,15,19,20,26,27). in our study, residual tumor was also detected in 27% of patients and upstaging occurred in 10.3%. nevertheless, present study questioned the importance of second turbt in a subset of patients with single and small tumors (≤ 3cm), especially when muscle is present in first specimen. it should be considered that omitting second turbt in this subgroup of patients is not equal to overlooking follow up evaluations. actually these patients will undergo cystoscopy within 3 months after turbt and all potential residual tumors can be detected at that time. limitation of this study is mainly related to the retrospective nature of the study. it comprised patients with relatively low-risk disease as 81.3% and 86% of second turbt in t1 and/or high grade tumors-ayati et al. tumor characteristics risk of residual p-value risk of upstaging to p-value risk of p-value in first turbt tumor, or [95% ci] muscle-invasive upstaging, disease, or [95% ci] or [95% ci] tumor size (>3 cm vs. ≤3 cm) 13.573 [3.104-59.359] 0.001 17.069 [1.632-178.482] 0.018 4.707 [0.990-22.379] 0.052 tumor multifocality (multifocal vs. single) 2.048 [0.285-14.736] 0.476 2.508 [0.443-14.203] 0.299 muscle in the specimen (absent vs. present) 21.214 [6.062-74.244] <0.001 6.517 [0.641-66.206] 0.113 8.123 [1.478-44.632] 0.016 table 3. multivariate regression analysis to predict risk of residual tumor and disease upstaging. vol 16 no 02 march-april 2019 155 patients had small (≤ 3 cm) and single tumors respectively. low incidence of disease upstaging could also be a result of clinical characteristics of the study cohort. in addition, in this multi-institutional study specimens were assessed in different pathology departments and slides were not re-reviewed for the purpose of the study. another limitation of this cohort is the very low sample size of high-grade ta. however, it should be considered that our finding for t1 tumors (majority of them were also high grade) can be generalized to ta tumors. ta tumors are probably associated with even lower risk of residual disease and upstaging in second turbt. finally, we couldn’t assess the site of initial tumors in bladder, because it is not recorded in our data registry. nevertheless, our study showed that subjecting all patients with t1 and/or high-grade urothelial cancer to repeat turbt has the potential to impose unnecessary risk and additional financial burden. further studies are needed to identify subgroups of patients that may benefit most from second turbt. conclusions we showed that absence of muscle in first resection can independently predict risk of upstaging and residual disease in second turbt. according to our findings, second turbt might be overtreatment in a significant proportion of patients with high-grade and/or t1 disease and in contrast to prior reports it does not seem to be necessary in all patients with t1 and/or high-grade tumors. we noted that second turbt in patients with single, small t1 and/or high-grade tumors who underwent adequate initial resection is not associated with upstaging or residual disease. conflict of interest the authors declare that they have no conflict of interest. references 1. ploeg m, aben kk, kiemeney la. the present and future burden of urinary bladder cancer in the world. world j urol. 2009;27:289-93. 2. organization wh. globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. lyon, france: international agency for research on cancer. 2014. 3. kirkali z, chan t, manoharan m, et al. bladder cancer: epidemiology, staging and grading, and diagnosis. urology. 2005;66:434. 4. grimm mo, steinhoff c, simon x, spiegelhalder p, ackermann r, vogeli ta. effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. j urol. 2003;170:433-7. 5. divrik rt, yildirim u, zorlu f, ozen h. the effect of repeat transurethral resection on recurrence and progression rates in patients with t1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. j urol. 2006;175:1641-4. 6. lazica da, roth s, brandt as, bottcher s, mathers mj, ubrig b. second transurethral resection after ta high-grade bladder tumor: a 4.5-year period at a single university center. urol int. 2014;92:131-5. 7. vasdev n, dominguez-escrig j, paez e, johnson mi, durkan gc, thorpe ac. the impact of early re-resection in patients with pt1 high-grade non-muscle invasive bladder cancer. ecancermedicalscience. 2012;6:18. 8. gendy r, delprado w, brenner p, et al. repeat transurethral resection for non-muscleinvasive bladder cancer: a contemporary series. bju int. 2016;4:54-9. 9. el-barky e, sebaey a, eltabey m, aboutaleb a, hussein s, kehinde eo. the importance of second-look transurethral resection for superficial bladder cancer. journal of clinical urology. 2015;8:299-305. 10. brausi m, collette l, kurth k, et al. variability in the recurrence rate at first follow-up cystoscopy after tur in stage ta t1 transitional cell carcinoma of the bladder: a combined analysis of seven eortc studies. eur urol. 2002;41:523-31. 11. divrik rt, sahin af, yildirim u, altok m, zorlu f. impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pt1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. eur urol. 2010;58:185-90. 12. dalbagni g, herr hw, reuter ve. impact of a second transurethral resection on the staging of t1 bladder cancer. urology. 2002;60:8224. 13. divrik t, yildirim u, eroglu as, zorlu f, ozen h. is a second transurethral resection necessary for newly diagnosed pt1 bladder cancer? j urol. 2006;175:1258-61. 14. klan r, loy v, huland h. residual tumor discovered in routine second transurethral resection in patients with stage t1 transitional cell carcinoma of the bladder. j urol. 1991;146:316-8. 15. schips l, augustin h, zigeuner re, et al. is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer? urology. 2002;59:220-3. 16. miladi m, peyromaure m, zerbib m, saighi d, debre b. the value of a second transurethral resection in evaluating patients with bladder tumours. eur urol. 2003;43:241-5. 17. dutta sc, smith ja, shappell sb, coffey cs, chang ss, cookson ms. clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. the journal of urology. 2001;166:490-3. 18. herr hw. the value of a second transurethral resection in evaluating patients with bladder tumors. j urol. 1999;162:74-6. second turbt in t1 and/or 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et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001;19:666-75. 25. fritsche hm, burger m, svatek rs, et al. characteristics and outcomes of patients with clinical t1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. eur urol. 2010;57:300-9. 26. vogeli ta, grimm mo, simon x, ackermann r. [prospective study of effectiveness. reoperation (re-tur) in superficial bladder carcinoma]. urologe a. 2002;41:470-4. 27. jakse g, algaba f, malmstrom pu, oosterlinck w. a second-look tur in t1 transitional cell carcinoma: why? eur urol. 2004;45:539-46. urological oncology 156 second turbt in t1 and/or high grade tumors-ayati et al. endourology and stone disease effect of irrigation solution temperature on complications of percutaneous nephrolithotomy: a randomized clinical trial seyed reza hosseini1*,mohammad ghasem mohseni2,seyed mohammad kazem aghamir3, hamed rezaei4 purpose: many factors affecthypothermia and shivering during percutaneous nephrolithotomy and in recovery. hence this study was carried out to determine the effect of irrigation solution temperature on complications of percutaneous nephrolithotomy. materials and methods: in this randomized clinical trial, 60 patients undergoing pcnl in sina university hospital were enrolled. the patients were randomly assigned in three groups according to simple random manner. the groups included three groups of room temperature fluid (24 degree), warm solution (37 degree), and cold fluid (20 degree) during nephroscopy. results: although the initial core temperature was alike across the groups (p > .05); the hypothermia rate occured in all 20 patients in the cold fluid group (p = .012). there was significant difference between the groups in terms of final temperature and alteration amount (p = .001). the mean vas scores were significantly lower in the warm fluid group compared with the others groups at recovery, and 8hrs post-operatively (p = .03). assessment of shivering rates revealed that 3(15%) patients in warm solution group shivered compared to8 (40%) patients in cold fluid group (p = .018). conclusion: warm irrigation solution during pcnl results in significantly decreased hypothermia, mean postoperative pain score and shivering. hence use of warm irrigation fluid for this matter is recommended. keywords: hypothermia; irrigation fluid; percutaneous nephrolithotomy introduction percutaneous nephrolithotomy (pcnl) is a routine treatment for stones larger than two centimeters, staghorn calculi, and resistant to extracorporeal shockwave lithotripsy (eswl). it is usually done by fluoroscopy or ultrasonography via the calyceal system. even for the most experienced urologist, major complications can still occur in up to 7% of patients undergoing pnl and minor complications may be encountered in up to 25% of patients. hemorrhage is the most significant complication of pcnl, with transfusion rates reported to be from less than 1% to 10%. (1,17) during nephroscopy, continuous irrigation of pyelocalyceal system with fluids is required to develop good visual field. the irrigation fluid temperature is studied in different endoscopic procedures showing controversial results. postoperative hypothermia may result in hazardous complications such as myocardial ischemia, coagulopathy, surgical wound infection, decreased drug metabolism, and shivering(2).to our knowledge, only one study about hypothermia in pcnl has evaluated the anesthetic complications of hypothermia.(3) the optimal temperature of irrigation solution is not clear and not evidence based. use of warm intra-operative solution may be effective for reduction of postoperative hypothermia risk. on the other hand use of cold 1associate professor, department of urology, tehran university of medical sciences ,tehran, iran. 2professor, department of urology, tehran university of medical sciences ,tehran, iran. 3associate professor, department of urology, tehran university of medical sciences, tehran, iran. 4resident of urology, tehran university of medical sciences ,tehran, iran. *correspondence: department of urology, sina hospital, imam khomeini ave., tehran, iran. e mail: rhosseinim@yahoo.com. received january 2018 & accepted january 2019 fluid may result in better intra-operative homeostasis due to peripheral blood vessel vasoconstriction. finding the appropriate temperature for irrigation fluid would result in better surgical outcomes and decreased intra-operative complications such as bleeding and would prepare better visual appearance during nephroscopy, and may result in less hypothermia and related complications. accordingly, in this study, intra-operative and post-operative complications in pcnl were compared across three groups including those receiving solution with room temperature, warm fluid, and cold solution. materials and methods study population in this randomized clinical trial, 60 patients undergoing pcnl in sina university hospital were enrolled. the subjects had an age range of 18 to 60 years old. in our department, pcnl is performed in patients with kidney stones more than 2 cm in diameter, stones refractory to extracorporeal shock wave lithotripsy, proximal ureteral stones larger than 1.5 cm in diameter, diverticular stones, and stones producing distal obstruction. the exclusion criteria wasmedium to high cardiovascular risk, coagulation disorder, renal failure, hepatic failure, diabetes mellitus, and hypothyroidism. the helsinki decurology journal/vol 16 no. 6/ november-december2019/ pp. 525-529. [doi: 10.22037/uj.v0i0.4399] laration was respected during the study and informed consent form was signed by all patients. also, the study was approved by the ethical committee of tehran university of medical sciences. patients’ enrollment algorithm is illustrated in figure 1. routine laboratory exams (fbs,cbc,bun.creatinine,urine culture) were perfomed before surgery. study design a randomized multi-arm parallel-group clinical trial with balanced randomization (1:1:1) was conducted at the de¬partment of urology of tehran university of medical sciences in tehran, iran. the study group allocation was by a sequentially running computer-generated block randomization list as blocks of three unique numbers/block, ranging from 1 to 3 unsorted. sample size was calculated considering a 5 percent expected difference between core temperature in three groups as the primary outcome of interest. we conducted a test with a significance level of 0.05 and power of 0.80 and an¬ticipated that groups of equal size were required. we concluded that at least 20 pateints were needed in each group. the groups included three groups of room temperature fluid (24°c), warm solution (37°c), and cold fluid (20°c) during nephroscopy. demographic data, previous medical history, stone-related data, and operation data were recorded in three groups. surgical technique the patients were not warmed before operation. all patients were transferred to operation room and anesthetized with general method during 20-minute period. the core temperature was assessed and recorded just before initiation of anesthesia. esophageal temperature probes were planted to measure core temperature. the probe was connected to the monitoring system continuously, during the operations, and monitored the patients’ temperature constantly. however, core temperature recorded its average every 10 minutes. temperature of the operating room was constantly set at 23 ± 1°c, by a central thermostat. six patients were excluded before operation due to preoperative hypothermia (core temperature less than 36°c). the operations were carried out by single practiced surgeon endourologist. the irrigation fluid volume and duration of operation (just prone pcnl time) were also recorded. after general anesthesia, a 5f urethral catheter was placed cystoscopically and percutaneous access was obtained while the patient was placed in a prone position. then the access to calyceal system was developed by shiba needle under fluoroscopy guide and it was dilatated with plastic dilatator up to 30f. then amplatz sheath was inserted and stones were removed using nephroscope 26f and pneumatic lithoclast. distilled water was used as irrigation fluid in pressure of 60 mmhg. to ensure patient safety, core temperature was measured during the procedure; if patients suffered severe hypothermia, the surgeon stopped the irrigation and patient warming using blanket and warmer was performed. outcome assessment the core temperature as the primary outcome of interest was recorded again just after operation. the rest of data were secondary outcome. then, the patients were transferred to the recovery room and underwent routine monitoring for at least one hour. the shivering at recovery room was recorded. post-operative pain scores were evaluated using a 10-cm self assessed visual analog scale (vas) with 0 indicating no pain and 10 representing the worst pain experienced by the patient in the recovery room and 8 hours after pcnl. the reader(fourth author; urology resident) was blinded to both patient groups. after operation, routine labexamination and plain abdominal radiography were performed. also, the abdominal ct-scan was done as indicated. stone-free was defined as stone diameter less than 4 mm. the complications were categorized to five levels by modified clavien system.(4) data analysis was performed by spss (version 24.0) software [statistical procedures for social sciences; chicago, illinois, usa]. fisher exact and kruskal wallis tests were used and were considered statistically significant at p values less than .05. results three groups of patients consisting of 20 patients in each were compared . the age, body mass index (bmi), hemoglobin decrease, irrigation volume, stone size, surgical duration, and hospital stay were similar in terms of a number of background variables (table 1). although the initial core temperature was alike across the groups (p > .05); there was significant difference between groups for final temperature and alteration amount (table 2). males comprised 80%, 65%, and 70% of patients in the room temperature fluid, warm solution, and cold fluid group, respectively (p = .563). seventy percent, 80%, and 80% were stone-free in irrigation solution temperature and complications of pcnl-hosseini et al. table 1. background data across the groups. variable room temperature fluid body temperature fluid cold fluid p value age 45.9 ± 11.9 44.9 ± 12.2 39.9 ± 16.6 0.345 bmi (kg/m²) 26.5 ± 3.4 25.6 ± 2.1 24.8 ± 3.6 0.241 hemoglobin decrease (g/dl) 1.6 ±1.1 1.5 ± 0.9 2.1 ± 1.0 0.132 irrigation volume (liter) 12.1 ± 2.8 12.6 ± 3.3 12.8 ± 3.2 0.768 stone size (cm) 3.1 ± 0.9 3.2 ± 1.1 3.6 ± 1.3 0.331 operation duration (min) 85.0 ± 31.2 85.7 ± 38.7 86.5 ± 30.1 0.988 hospital stay (day) 5.2 ± 2.5 4.8 ± 1.4 5.1 ± 2.3 0.778 creatinine increase(mg/dl) 0.5 ± 0.2 0.4 ± 0.1 0.6 ± 0.4 0. 11 variable room temperature fluid body temperature fluid cold fluid p value initial temperature 36.8 ± 0.4 36.7 ± 0.4 36.6 ± .4 0.259 final temperature 35.7 ± 0.9 36.1 ± 0.6 35.0 ± 1.1 0.001 temperature alteration 1.1 ± 0.8 0.6 ± 0.4 1.6 ± 0.9 0.001 table 2. core temperature across the groups. endourology and stone diseases 526 groups of room temperature fluid, warm solution, and cold fluid, respectively (p = .700). assessment of shivering rates revealed that patients in the warm solution group shivered less compared with other groups although it was not statistically significant (table 3) (p = .198). the mean vas scores were significantly lower in warm fluid group compared with the others groups at recovery, and 8hrs post-operatively (table 3) (p = .03). clavein complications grading was same across the groups (table 4). the hypothermia significantly occurred in cold fluid group (table 5) (p = .021). discussion the main finding of the present study is that warm irrigation solution could significantly decrease hypothermia, the mean postoperative pain score and shivering. previous studies showed that cardiovascular, hemorrhagic and infectious complications are significantly more frequent in hypothermic than in normothermic patients(2). lots of studies have proved that cold stress could influence the immune responses by elevating the levels of inflammatory cytokines, including proand anti-inflammatory cytokines. it has been reported that many proinflammatory cytokines, such as tnf-a, il-1, il-6, significantly increased under cold stress. for minimally invasive procedures like pcnl, this response is concerned with regional pain.(5) the effects of fluid temperature on core temperature in patients under endoscopic surgeries has been assessed in different studies. the effects on bleeding volume and homeostasis of cold solution are established in some investigations. the effects of experimental lowering of temperature on decreased blood flow are reported by some animal studies(6). also, it has been demonstrated in human studies such as prostatectomy procedures, resulting in appropriate hemostasis.(7) the bleeding time more than two times after superficial lowering of the temperature is reported in human volunteers (8). use of warm irrigation fluid has also been studied in some reports. in the study by parodi et al.(9), use of warm fluid for irrigation during arthroscopy had no effect on reduction of hypothermia in shoulder joint but it had an significant effect in the hip joint. this difference in a single study may also explain variations in different studies. as in our study, jin and colleagues(10) recommended the use of warm irrigation solution to reduce hypothermia and shivering and also intra-operative blood loss after endoscopics surgeries.althoughin our study, hemoglobin level differences were not significant. the isothermal solution led to further fluid overload after operation due to decreased viscosity(11). there are few studies discussing this issue in endoscopic urological procedures. mirza et al. reported that hypothermia is common after endoscopic urological procedures which isrelated to duration of operation, weight, irrigation fluid volume, and type of procedure. (12) rezaei et al. showed that using warm saline irrigation in ureteral endoscope results in better surgical outcomes including a lower ureteral spasm rate, greater ureteral muscle relaxation and better access to the upper ureteral zone, and a lower rate of complications, such as ureteroscope impaction, ureteral dislodge and stone retropulsion.(13) regarding these confounding factors, we matched all of these variables across the groups of the current study. also, warm and isothermal irrigation fluids were effective to reduce the hypothermia rate after turp (14). use of isothermal fluid was also effective on hypothermia reduction in another study.(15) similar results were also reported by tekgul and colleagues(3) compared to the irrigation fluid with room temperature and warm solution in pcnl and reported that lower hypothermia and shivering were seen in the warm fluid group. compared to this study, longer follow-up was made in our study during hospitalization to discharge. in line with the mentioned study,, using warm irrigation fluid resulted in lower hypothermia after procedure, but the complications that could be related to hypothermia, as surgical site infection or coagulopathy were not seen more frequently in patients suffering from hypothermia. this may be due to shortness of surgical time or limited number of patients studied in this survey. actually, longer operation time may exaggerate the impact of irrigation fluid temperature on core body temperature and subsequently such complications. also in the present study, the mean vas score was significantly lower in the warm fluid group compared tothe other groups in the recovery and 8hrs post-operatively. in our recently published article, we showed that pain score after pcnl has an important role in needing analgesic drugs. (16) therefore, warm fluid group may be received low dose analgesic drugs compare other groups. some of limitation of our study were small sample size and limited temperature range of irrigation solutions to compare because of there was no distinct evidence that support to use extreme temperatures in practice . fu table 3. complications across the groups. variable room temperature fluid body temperature fluid cold fluid p-value test shivering* 5 (25%) 3 (15%) 8 (40%) 0.198 fever 1 (5%) 3 (15%) 3 (15%) 0.68 fisher exact dvt -- -- 1 (5%) 1.000 fisher exact angioembolization 1 (5%) -- --1.000 fisher exact transfusion 1 (5%) 1 (5%) 1 (5%) 1.000 -- grade room temperature fluid body temperature fluid cold fluid p-value of kruskal wallis 1 2 (10%) 1 (5%) 1 (5%) 0.910 2 2 (10%) 3 (15%) 4 (20%) 3 1 (5%) --- --- negative 15 (75%) 16 (80%) 15 (75%) table 4.clavein complications grading across the groups. irrigation solution temperature and complications of pcnl-hosseini et al. vol 16 no 06 november-december2019 527 ther studies recommended more patients to attain more reliable results. conclusions overall, according to our study, it was concluded that use of warm irrigation solution during pcnl results in significantly less hypothermia, mean postoperative pain score and shivering. hence, use of warm irrigation fluid for this matter is recommended. however, further studies with larger sample size and multi-center sampling are required to attain more definite results with higher reliability and potency for generalization. references 1. preminger gm, assimos dg, lingeman je, et al. chapter 1: aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005;173:1991– 2000. 2. torossian a, brauer a, hocker j, bein b, wulf h, horn ep. preventing inadvertent perioperative hypothermia. deutsches arzteblatt international. 2015; 112:166-72. 3. tekgul zt, pektas s, yildirim u, et al. a prospective randomized double-blind study on the effects of the temperature of irrigation solutions on thermoregulation and postoperative complications in percutaneous nephrolithotomy. j anesth. 2015; 29:165-9. 4. tefekli a, ali karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified claviengrading system: looking for a standard. eur urol. 2008; 53:184-90. 5. guo jr, li sz, fang hg. different duration of cold stress enhances pro-inflammatory cytokines profile and alterations of th1 and th2 type cytokines secretion in serum of wistar rats. j anim vet adv. 2012; 11:1538– 1545 6. venjakob aj, vogt s, stockl k, tischer t, jost pj, thein e. local cooling reduces regional bone blood flow. journal of orthopaedic research: official publication of the orthopaedic research society.2013; 31:1820-7. 7. zorn kc, bhojani n, gautam g, shikanov s, gofrit on, jayram g. application of ice cold irrigation during vascular pedicle control of robot-assisted radical prostatectomy: enseal instrument cooling to reduce collateral thermal tissue damage. j endourol.2010 24:1991-6. 8. romlin b, petruson k, nilsson k.moderate superficial hypothermia prolongs bleeding time in humans. acta anaesthesiol scand.2007;51:198-201. 9. parodi d, valderrama j, tobar c, besomi j, lopez j, lara j. effect of warmed irrigation solution on core body temperature during hip arthroscopy for femoroacetabular impingement. arthroscopy: the journal of arthroscopic & related surgery: official publication of the arthroscopy association of north america and the international arthroscopy association. 2014; 30: 36-41. 10. jin y, tian j, sun m, yang ka. systematic table 5. hypothermia across the groups. grade mild (34-36 degree) moderate (32-33.9 degree) negative true p-value of kruskal wallis room temperature fluid 11 (55%) 1 (5%) 8 (40%) 0.021 body temperature fluid 6 (30%) -- 14 (70%) cold fluid 13 (65%) 3 (15%) 4 (20%) figure 1. patient flowchart irrigation solution temperature and complications of pcnl-hosseini et al. endourology and stone diseases 528 vol 16 no 06 november-december2019 529 review of randomised controlled trials of the effects of warmed irrigation fluid on core body temperature during endoscopic surgeries. j clin nurs. 2011; 20:305-16. 11. kim ys, lee jy, yang sc, song jh, koh hs, park wk. comparative study of the influence of room-temperature and warmed fluid irrigation on body temperature in arthroscopic shoulder surgery. arthroscopy: the journal of arthroscopic & related surgery : official publication of the arthroscopy association of north america and the international arthroscopy association. 2009; 25:24-9. 12. mirza s, panesar s, auyong kj, french j, jones d, akmal s.the effects of irrigation fluid on core temperature in endoscopic urological surgery. j perioper pract 2007; 17:49-51. 13. mohammadzadeh rezaei ma, akhavan rezayat a, tavakoli m, jarahi l. evaluation the result of warm normal saline irrigation in ureteral endoscopic surgeries. urol j. 2018; 15:83-86. 14. okeke li. effect of warm intravenous and irrigating fluids on body temperature during transurethral resection of the prostate gland. bmc urol. 2007; 7:15. 15. pit mj, tegelaar rj, venema pl. isothermic irrigation during transurethral resection of the prostate: effects on peri-operative hypothermia, blood loss, resection time and patient satisfaction. br j urol. 1996; 78:99103. 16. hosseini sr, imani f, shayanpour g, khajavi mr. the effect of nephrostomy tract infiltration of ketamine on postoperative pain and peak expiratory flow rate in patients undergoing tubeless percutaneous nephrolithotomy: a prospective randomized clinical trial. urolithiasis. 2017 ;45:591-595. 17. maghsoudi r, etemadian m, kashi ,ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016 8;13:2899-2902. irrigation solution temperature and complications of pcnl-hosseini et al. urological oncology detection of the prostate cancer bone metastases: is it feasible to compare 18f-fluorocholine pet/ct, 18f-fluorodeoxyglucose pet/ct and 99mtc–methyl diphosphonate bone scintigraphy? agata karolina pietrzak1*, rafal czepczynski2, ewa wierzchoslawska3, witold cholewinski3 purpose: the objective was to compare the efficacy of 99mtc-mdp-bs, 18f-fdg-pet/ct and 18f-fch-pet/ ct in detecting bone metastases in prostate cancer patients. materials and methods: 56 patients diagnosed with prostate cancer underwent 99mtc-methylendiphosphonates bone scintigraphy (99mtc-mdp-bs) and fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18f-fdg-pet/ct) or fluorine-18-fluorocholine pet/ct (18f-fch-pet/ct) within six weeks. there were 27 patients examined with 99mtc-mdp-bs + 18f-fdg (mean age 67.96 ± 9.04 years) and 29 patients examined with 99mtc-mdp-bs + 18f-fch (mean age 73.93 ± 8.75 years). the r factor in scintigraphy and semi quantitative analysis with standardized uptake value (suv) in the pet/ct were used using semi automatic methods of bone lesions’ contouring. the r factor was calculated as the total count rate in bone metastasis and the total count rate in contralateral area ratio. for further analysis, the mean pixel and the total surface of lesion product in scintigraphy, the total lesion glycolysis (tlg) in the 18f-fdg-pet/ct and the total lesion activity (tla) in the 18f-fch-pet/ct were evaluated. results: the average maximal suv (suvmax) value was significantly higher in patients who underwent 18f-fch-pet/ct than in 18f-fdg-pet/ct (5.17 ± 2.24, 3.71 ± 1.56, p < .05). the r factor differences in both groups (patients who underwent bs and 18f-fdg-pet/ct, bs and 18f-fch-pet/ct) were insignificant (1.92 ± 0.87, 2.03 ± 0.57, respectively, p > .05). there was no statistically significant correlation (pearsons’ correlation coefficient rp) between the r factor and the suvmax within examined groups (rp = .42; p = .31) and between the r factor and the suvmean (rp = .43; p = .28). a high rp between measured total surface in the bs and volume in the pet/ct of the metastatic lesion was found. in patients who underwent bs + 18f-fdg-pet/ct and bs + 18f-fch-pet/ct, rp equaled .95 and .70. conclusion: 99mtc-mdp-bs, 18f-fdg-pet/ct and 18f-fch-pet/ct occurred as comparable imaging methods in bone metastases detection in the prostate cancer patients and provide complementary clinical conclusions. keywords: bone scintigraphy; computed tomography; fluorine-18-fluorocholine; fluorine-18-fluorodeoxyglucose; positron emission tomography; prostate cancer. introduction prostate cancer is one of the most common cancer diseases in elder men, especially over age 65 years. the important issue in prostate cancer staging, restaging and response to treatment evaluation is to diagnose and monitor the bone metastases. the probability of bone metastatic lesion occurrence and their incidence depends on many factors, i.e: age, general health condition, gleason score value (higher than 6) and prostate –specific antigen (psa) level (higher than 20 ng/ml) (1) or metastatic bone microenvironment(2). metastatic bone disease is associated with several health ailments and affects mortality, thus their management seems to be critical(3-5). jeong et al. claim that main cause of tumor bone metastases is the high stromal cells activity within bone tissue, resulting in physiologic imbalance between number of osteoblasts and osteoclasts 1nuclear medicine dep., greater poland cancer centre, poznan, poland. 2department of endocrinology, poznan university of medical sciences, poznan, poland. 3electroradiology dep., university of medical science, poznan, poland. *correspondence: nuclear medicine department, greater poland cancer centre, garbary 15 street, 60 – 101 poznan, poland. tel. +48 663196699. e-mail: agata.pietrzakk@gmail.com. received july 2017 & accepted december 2017 in skeleton. osteolytic bone metastases are connected with bone resorption and osteoblastic with tumor growth(2,6). osteoblastic bone metastases developing with prostate cancer progression are the less aggressive and slow growing in comparison to mixed or osteolytic metastases from breast cancer(6). the methods of first choice in the metastatic bone lesions monitoring are most often the bone scintigraphy (bs), using 99mtc – diphosphonates (99mtc-mdp bs) or positron emission tomography/computed tomography with the fluorine -18fluorodeoxyglucose (18f-fdg pet/ct). although the 18f-fdg is not a tumor – specific agent, the 18f-fdg pet/ct is commonly recognized as sensitive, specific and accurate imaging method in detecting bone metastases as a consequence of advanced stage of various cancer diseases(7-10). the growing knowledge about the prostate cancer cells resulted in extraction of several highly speurological oncology 242 vol 15 no 05 september-october 2018 243 cific tracers, i.e. fluorine-18-fluorocholine (18f-fch). 18f-fch seems to be superior to 18f-fdg according to relatively high specificity in prostate cancer cells uptake(11). multiply nuclear medicine departments worldwide constantly perform 18f-fdg pet/ct as a standard protocol in prostate cancer patients due to its availability and advantages in comparison to other imaging techniques, such as single computed tomography (ct). the main difference between 18f-fdg and 18f-fch is that choline accumulates mostly in prostate tumors. the uptake is regulated by choline kinase capture of lecithin (phosphatidylcholine) and the tracer’s utilization is not connected with cells proliferation (the uptake does not depend on proliferative activity while increasing choline utilization reflects the cells division intensity due to membrane lipid synthesis estimation). as a result, the 18f-fch pet/ct reveals relatively higher than 18f-fdg specificity in detecting prostate cancer tumors and metastases(5,12). prostate cancer is diagnosed also with the biomolecular markers, i.e. psa. the role of psa depends on few factors such as age, body mass index (bmi) and prostate gland size. it is used to detect and to monitor the prostate cancer but it has some limitations: dependency on multiply factors and decreased specificity in low from high grade tumors differentiation. however, it has been proven that psa serum level significantly increases with either prostate cancer, prostatitis or benign prostatic hyperplasia (bph), thus the psa cannot be used as a single cancerous marker(12-17). evaluation of prostate cancer bone metastases is the crucial clinical issue and needs complex and fast management with imaging and biomolecular methods. the aim of this research article was to compare the planar bone scintigraphy with technetium-99m methyl diphosphonate bone scintigraphy (99mtc-mdp bs), fluorine-18-fluorodeoxyglucose pet/ct (18f-fdg pet/ct) and fluorine-18-fluorocholine pet/ct (18f-fch pet/ct) in detecting prostate cancer bone metastases. materials and methods dataset characteristics the study was performed upon receiving of the patients’ informed consent in writing and all requirement of local bioethical committee were fulfilled. we diagnosed 56 male prostate cancer patients with 99mtc-mdp bs and pet/ct scans (18f-fdg pet/ ct or 18f-fch pet/ct) within six weeks. there were 27 patients examined with 99mtc-mdp bs + 18f-fdg (mean age 67.96 ± 9.04 years, age range: 52-80 years) and 29 with 99mtc-mdp bs + 18f-fch (mean age 73.93 ± 8.75 years, age range: 57-85 years). the differences between age, number of patients and number of lesions occurred as statistically insignificant, thus groups were homogenic and comparable. we compared one metastatic bone lesion with bone scintigraphy and the pet/ct technique. we used the semi automatic method of the metastatic bone lesions contouring in the bs and semi automatic with 50% background cut-off to delineate malignant findings in the pet/ct. we evaluated the r factor in the 99mtc-mdp bs and the suvmax and suvmean values to characterize bone metastases. we have calculated the r factor with the following equation: the semiquantitative assessment of tracer uptake in the pet/ct was based on the standardized uptake value (suv) calculation. the suvmax value of the metastatic bone lesion was based on the equation(18-19): for further analysis, we evaluated the mean pixel and the lesions’ total surface product in the bone scintigraphy, the total lesion glycolysis (tlg) in the 18f-fdg pet/ct and the total lesion activity (tla) in the 18f-fch pet/ct. the mean pixel, tlg and tla were calculated with following equations: study protocols we performed bone scans with dual – head gamma figure 1. 99mtc-mdp bs and 18f-fdg pet/ct scans in prostate cancer patient. prostate cancer cells activity – pietrzak et al. camera (brightview xct, philips, cleveland) 2.5 3h p.i. of the 99mtc–mdp (methylenodiphosphonian) with activity up to 800mbq (range: 650-800mbq). a total body scans were performed in anterior and posterior projections with low–energy and highresolution collimators (lehr) with the 256x1024 pixels matrix and table scan speed of 15 cm/min. special patient preparation was not required. we performed the whole body 18f-fgd pet/ct scans (gemini tf 16, philips, cleveland) 60 min p.i. of the 18f-fdg with activity up to 400mbq (range: 250400mbq). as a preparation protocol, patients fasted for 6h before the examination, avoided cold environment and exercises 48h before the tests. the water intake before the examination was required. the patients laid supine on the pet scanner table with arms above the head and neck up to 30min of scanning. ct was performed before pet acquisition with 120 kvp and 100 mas. emission images were acquired for 1:30min per table(20-21). the whole body 18f-fch pet/ct static scans were performed with gemini tf 16, philips, cleveland, 6-10min p.i. of the 18f-fluorocholine with activity up to 300mbq (range: 200-300mbq). acquisition was performed in the same position as in above described 18f-fdg pet/ct. technical conditions were similar in the 18f-fdg pet/ct and the 18f-fch pet/ct. methods of contouring we used the semi automatic method of contouring with 50% background cut–off to delineate structures and to calculate the volume of the metastatic bone lesions in the pet/ct scans. we delineated the abnormal findings in the 99mtc-mdp bs semi automatically (figure1,2). statistical analysis we compared several factors in two groups of patients in the interval scale (values were comparable, the differences between them were crucial for analysis). we assumed there is none known direction of values fluctuation; the basic hypothesis was there are no significant differences between compared groups in every single condition of the analysis. we compared groups of dependent (two factors in same patients, for example in patients who underwent 99mtc-mdp bs and 18f-fdg pet/ct) and the independent variables (i.e.: suvmax value in patients who underwent 18f-fdg pet/ct and 18f-fch pet/ct). all measured parameters had the gaussian distribution according to the shapiro – wilk test’s results, thus we used the t-test to evaluate statistical significance. the variances in every analysis were equal (the tendency was unpredictable). the investigators calculated the pearsons’ correlation coefficient an used the materiality level of p < .05. the authors used statistica (statsoft) commercial software for the statistical analysis. results the dataset characteristics we have analyzed 56 prostate cancer patients who underwent 99mtc-mdp bs and 18f-fdg pet/ct with several factors. the psa marker data (table 1) were included. the differences between the psa level before the bs and the pet/ct were statistically insignificant (p = .09). analysis the average r factor, suvmax and suvmean values in patients who underwent 99mtc-mdp bs + 18f-fdg pet/ct were 1.92 ± table 1. patients’ and lesions’ characteristics. variables 99mtc-mdp bs + 18f-fdg pet/ct 99mtc-mdp bs + 18f-fch pet/ct p-value age, year; mean ± sd (range) 67.96 ± 9.04 (52-80) 71.93 ± 8.75 (57-85) .10 psa level before bs, ng/ml; mean ± sd (range) 25.86 ± 36.31 (5.16-146.50) 195.69 ± 301.19 (1.49-934.60) .34 psa level before pet/ct, ng/ml; mean ± sd (range) 37.42 ± 62.76 (5.16-320.90) 230.07 ± 308.74 (6.07-934.60) .26 r factor, mean ± sd 1.92 ± 0.87 2.03 ± 0.57 .58 max pixel, mean ± sd 103.44 ± 69.84 142.52 ± 57.45 .03 total surface, mm2; mean ± sd 1165.78 ± 1267.22 583.16 ± 468.62 .01 suvmax; mean ± sd 3.71 ± 1.56 5.17 ± 2.24 .01 suvmean; mean ± sd 2.20 ± 0.97 3.30 ± 1.39 .00 volume, mm3; mean ± sd 6966.34 ± 8017.14 5952.55 ± 5442.08 .59 abbreviations: psa, prostate specific antigen; bs, bone scintigraphy; pet/ct, positron emission tomography/computed tomography abbreviations: tlg, total lesion glycolysis; tla, total lesion activity a tlg for the 18f-fdg pet/ct b tla for the 18f-fch pet/ct variables bs + 18f-fdg pet/ct bs + 18f-fch pet/ct p-value r factor and suvmax value .42 .43 r factor and suvmean value .31 .28 rp r factor and suvmax value .42 .43 r factor and suvmean value .31 .28 tlga, tlab and ‘mean pixel x total surface’ .37 .46 table 2. statistics for correlation between studied diagnostic methods. prostate cancer cells activity – pietrzak et al. urological oncology 244 vol 15 no 05 september-october 2018 245 0.87, 3.71 ± 1.56 and 2.20 ± 0.97, respectively and in the 99mtc-mdp bs + 18f-fch pet/ct: 2.03 ± 0.57, 5.17 ± 2.24, 3.30 ± 1.39, respectively (table 1). according to the t – test’s results the differences between suvmax and suvmean were statistically significant (p < .05). the suvmax value in the 18f-fdg pet/ct and the 18f-fch pet/ct: p = .01, suvmean value in 18f-fdg pet/ct and 18f-fch pet/ct: p < .001. the differences between the r factors obtained with 99mtc-mdp bs in both groups were insignificant (p = .58). according to the pearsons’ correlation coefficient (rp) analysis, we found no significant correlation between the r factor and the suvmax value within examined groups (rp = .42; p = .31) or between the r factor and the suvmean value (rp = .43; p = .28) (table 2). the high correlation coefficient between total surface obtained with 99mtc-mdp bs and volume in pet/ct of the metastatic bone lesions was found. in patients who underwent 99mtc-mdp bs + 18f-fdg pet/ct and 99mtc-mdp bs + 18f-fch pet/ct correlation coefficients were .95 and .70, respectively (p < .05). the volume differences between 18f-fdg pet/ct and 18f-fch pet/ct were statistically insignificant, p = .57, however 18f-fch seems to be more precise in the lesion edge detection in prostate cancer bone metastases. furthermore, there was no correlation between psa level and r factor or suvmax values in both groups. the analysis of tlg within metastatic bone lesions in comparison with contralateral in 99mtc-mdp bs mean pixel multiplied by the total surface showed no significant correlation in both groups (99mtc-mdp bs + 18f-fdg pet/ct, rp = .37; 99mtc-mdp bs+18ffch pet/ct, rp = .46). there was no significant correlation between measured indices within analysed groups (tlg and the mean pixel multiplied by the total surface in the 99mtc-mdp bs + 18f-fdg pet/ct and tlg, tla and the mean pixel multiplied by the total surface in the 99mtc-mdp bs + 18f-fch pet/ ct; .37, .43, respectively). discussion 18f-fdg is a commonly used radiopharmaceutical in the oncology, however several studies have shown its limitations in the prostate cancer lesions assessment because of relatively low metabolic activity of prostate cancer cells. according to some authors(22-24), the 18f-fdg will most likely be useful in the prostate cancer patients with hormone-resistant low-differentiated cell types and can be promising in the bone metastases detection and monitoring. 18f-fch occurred as highly lesion-specific radiotracer: useful in every stage of the prostate cancer, especially in detecting the disease cells regardless localization, however metastatic bone lesions can be reliably monitored with both tracers. moreover, commonly performed in metastatic bone lesions assessment sodium fluoride 18f-naf pet/ct does not significantly increase the specificity of the prostate cancer bone metastases detection. the sensitivity, specificity and the accuracy of each method: 99mtc-mdp bs, 18f-fdg pet/ct, 18f-fch pet/ct, 18f-naf pet/ ct, is high and exceeds 90% (25-27). 18f-naf seems to be superior to 99mtc-mdp bs in detection osteoblastic metastases because of, i.e., higher affinity of 18f-naf for bone tissue than diphosphonates(27). several imaging methods are useful in the prostate cancer metastatic bone lesions monitoring as planar bone scintigraphy and single photon emission tomography/ computed tomography (spet/ct) technique. spet/ ct is predictively more meaningful in particular bone findings monitoring of known localization, while in many conditions, patients who underwent bone scintigraphy are suspected of having metastatic disease or have numerous bone metastases. the sensitivity of the 99mtc-mdp bs and the spet/ct was recognized as 79%, 89%; specificity 91%, 94%; accuracy 87%, 93%, respectively(28). the tlg or the tla are the volume-based prognostic markers, used for, i.e., preoperative assessment and metastatic bone disease treatment monitoring in various types of cancers. tlg emerged from 18f-fdg pet/ct as a prognostic factor in preand posttreatment monitoring of the cancer patients. tla as a corresponding to tlg parameter might be used in pet/ ct technique as an additional volume and suv-based clinical index(28,29). in this paper, we compared imaging methods with several factors. to find the connection between obtained using each technique indices, we multiplied the mean pixel multiplied by the total surface of the metastatic bone lesions in the 99mtc-mdp bs. we evaluated the tlg or the tla in the pet/ct methods and the rp, however no significant correlation have been found, what leads to conclusion that the bone scintigraphy and the pet/ct provide valuable and complementary clinical informations. in this research article, we have found cognitively interesting to evaluate and to compare described groups of patients with the 99mtc-mdp bs + 18f-fdg pet/ct and the 99mtcmdp bs + 18f-fch pet/ct and did not focus on the sensitivity, specificity and accuracy of the methods as it had been widely investigated before but on the feasibility to compare metabolic and osteoblastic activity of the figure 2. 99mtc-mdp bs and 18f-fch pet/ct scans in prostate cancer patient. prostate cancer cells activity – pietrzak et al. metastatic bone lesions assessed with three molecular imaging techniques within two groups of patients. research has been limited by number of patients who underwent the 99mtc-mdp bs and the pet/ct in short period of time, thus sample could be too small to find significant correlation between measured parameters. conclusions in conclusion, 99mtc-mdp bs, 18f-fdg pet/ct and 18f-fch pet/ct reveal complementarity in metastatic bone disease. it provides information that it is highly valuable to use all these methods to diagnose bone metastases in the prostate cancer patients. acknowledgements all patients were admitted and consulted in greater poland cancer centre, poznan, poland between 20102016. conflict of interest the authors report no conflict of interest. references 1. caldarella c, treglia g, giordano a, giovanella l. when to perform positron emission tomography/computed tomography or radionuclide bone scan in patients with recently diagnosed prostate cancer. cancer manag res. 2013;5:123-31 2. jeong hm, cho sw, park si. osteoblasts are the centerpiece of the metastatic bone microenvironment. endocrinol metab (seoul). 2016;31:485-92 3. coleman re . bone cancer in 2011: prevention and treatment of bone metastases. nat rev clin oncol. 2011;9:76-8 4. nieder c, haukland e, mannsåker b, norum j. impact of intense systemic therapy and improved survival on the use of palliative radiotherapy in patients with bone metastases from prostate cancer. oncol lett. 2016;12:2930-5 5. cook gj, azad g, padhani ar. bone imaging in prostate cancer: the evolving roles of nuclear medicine and radiology. clin transl imaging. 2016;4:439-47 6. hoefeler h, duran i, hechmati g, et al. health resource utilization associated with sekeltal – related events in patients with bone metastases: results from a multinational retrospective – prospective observational study – a cohort from 4 european countries. j bone oncol. 2014;3:40-48 7. vojtíšek r, jiří ferda j, fíneka j. effectiveness of pet/ct with 18f-fluorothymidine in the staging of patients with squamous cell head and neck carcinomas before radiotherapy. rep pract oncol radiother. 2015;20:210-6 8. huang ye, huang yj, ko m, hsu cc, chen cf. dual-time-point 18f-fdg pet/ct in the diagnosis of solitary pulmonary lesions in a region with endemic granulomatous diseases. ann nucl med. 2016;30:652-8 9. azad gk, cook gj. multi-technique imaging of bone metastases: spotlight on pet/ct. clin radiol. 2016;71:620-31 10. suenaga h, chen j, yamaguchi k, et al. mechanobiological bone reaction quantified by positron emission tomography. j dent res. 2015; 94:738-44 11. jadvar h. prostate cancer: pet with 18f-fdg, 18for 11c-acetate, and 18f-or 11c-choline. j nucl med. 2011;52:81-9 12. sollini m, pasqualetti f, perri m, et al. detection of a second malignancy in prostate cancer patients by using [(18)f]choline pet/ ct: a case series. cancer imaging. 2016;16-27 13. aparici cm, seo y. functional imaging for prostate cancer: therapeutic implications. semin nucl med. 2012;42:328-42 14. sarwar s, adil ma, nyamath p, ishaq m. biomarkers of prostatic cancer: an attempt to categorize patients into prostatic carcinoma, benign prostatic hyperplasia, or prostatitis based on serum prostate specific antigen, prostatic acid phosphatase, calcium, and phosphorus. prostate cancer. 2017;2017:5687212. epub. 15. chinea fm, lyapichev k, epstein ji, et al. understanding psa and its derivatives in prediction of tumor volume: addressing health disparities in prostate cancer risk stratification. oncotarget. 2017. epub:14903 16. pentyala s, whyard t, pentyala s, et al. prostate cancer markers: an update. biomed rep. 2016;4:263-8 17. shariat sf, semjonow a, lilja h, savage c, vickers aj, bjartell a. tumor markers in prostate cancer i: blood-based markers. acta oncol. 2011;50 supp.1:61-75 18. heinisch m, dirisamer a, loidl w, et al. positron emission tomography/computed tomography with f-18-fluorocholine for restaging of prostate cancer patients: meaningful at psa <5ng/ml? mol imaging biol. 2006;8:43-8 19. heindel w, gübitz r, vieth v, weckesser m, schober o, schäfers m. the diagnostic imaging of bone metastases. dtsch arztebl int. 2014; 111: 741-7 20. hahn s, heusner t, kümmel s, et al. comparison of fdg-pet/ct and bone scintigraphy for detection of bone metastases in breast cancer. acta radiol. 2011; 52: 100914 21. okada m, sato n, ishii k, matsumura k, hosono m, murakami t.fdg pet/ct versus ct, mr imaging, and 67ga scintigraphy in the post-therapy evaluation of malignant lymphoma. radiographics. 2010; 30: 939-57 22. vali r, loidl w, pirich c, langesteger w, beheshti m. imaging of prostate cancer with prostate cancer cells activity – pietrzak et al. urological oncology 246 vol 15 no 05 september-october 2018 247 pet/ct using 18f-fluorocholine. am j nucl med mol imaging. 2015;5:96-108 23. how kit n, dugué ae, sevin e, et al. pairwise comparison of 18f-fdg and 18f-fch pet/ ct in prostate cancer patients with rising psa and known or suspected second malignancy. nucl med commun. 2016;37:348-55 24. ouyang q, duan z, lei j, jiao g. comparison of meta-analyses among elastosonography (es) and positron emission tomography/ computed tomography (pet/ct) imaging techniques in the application of prostate cancer diagnosis. tumour biol. 2016;37:2999-3007 25. jambor i, kuisma a, ramadan s, et al. prospective evaluation of planar bone scintigraphy, spect, spect/ct, 18f-naf pet/ct and whole body 1.5t mri, including dwi, for the detection of bone metastases in high risk breast and prostate cancer patients: skeleta clinical trial. acta oncol. 2016; 55:59-67 26. minamimoto r, loening a, jamali m, et al. prospective comparison of 99mtcmdp scintigraphy, combined 18f-naf and 18f-fdg pet/ct, and whole – body mri in patients with breast and prostate cancer patients. j nucl med. 2015;56:1862-8 27. langsteger w, rezaee a, pirich c, beheshti m. 18f-naf-pet/ct and 99mtc-mdp bone scintigraphy in the detection of bone metastases in prostate cancer. semin nucl med. 2016;46;491-501 28. ryu is, kim js, roh jl, et al. prognostic significance of preoperative metabolic tumour volume and total lesion glycolysis measured by 18f-fdg pet/ct in squamous cell carcinoma of the oral cavity. eur j nucl med imaging 2014;41:452-61 29. moon sh, hyun sh, choi jy. prognostic significance of volume-based pet parameters in cancer patients. korean j radiol. 2013;14:112. prostate cancer cells activity – pietrzak et al. kidney transplantation 194 urology journal vol 6 no 3 summer 2009 postnephrectomy changes in doppler indexes of remnant kidney in unrelated kidney donors abolfazl bohlouli,1 mohammad kazem tarzamni,2 afshar zomorrodi,1 sedigeh abdollahifard,1 bahram hashemi,3 nariman nezami4,5 introduction: we aimed to evaluate the intralobar renal arteries indexes using the doppler ultrasonography indexes, which have become the established method of kidney monitoring, in living unrelated kidney donors during the postnephrectomy period. materials and methods: in this prospective study, we evaluated and followed up 34 living unrelated kidney donors. the doppler ultrasonography indexes, including resistive index, pulsatility index, and peak systolic velocity, along with the grey-scale ultrasonographic indexes of cortical thickness, length, and anteroposterior diameter of the kidney were determined before nephrectomy, and then, 1 week and 3 months after nephrectomy. in addition, glomerular filtration rate were assessed simultaneously. results: the resistive index and pulsatility index did not change 1 week and 3 months after nephrectomy (p = .66 and p = .38, respectively). the peak systolic velocity at 1 week was significantly higher than its prenephrectomy value (p = .02). also, the peak systolic velocity at 3 months was significantly higher than that prior to nephrectomy (p < .001). indexes of the kidney size all increased during the follow-up period. the estimated glomerular filtration rate increased decreased 1 week after nephrectomy, but it reach to a level comparable with its preoperative values after 3 months. conclusion: results of the present study showed an increased peak systolic velocity in association with unaltered resistive index and pulsatility index in the remnant kidney of donors, during the short-term follow-up. this finding indicates the increased blood flow and kidney size in the remnant kidney of donors, following nephrectomy. urol j. 2009;6:194-8. www.uj.unrc.ir keywords: kidney transplantation, nephrectomy, kidney physiology, doppler ultrasonography 1department of transplantation, tabriz university of medical sciences, tabriz, iran 2department of radiology, tabriz university of medical sciences, tabriz, iran 3department of medical researches, tabriz university of medical sciences, tabriz, iran 4young researchers club, tabriz islamic azad university, tabriz, iran 5drug applied research center, tabriz university of medical sciences, tabriz, iran corresponding author: nariman nezami, md clinical pharmacy laboratory, drug applied research center, tabriz university of medical sciences, pashmineh, daneshgah st, tabriz 5165665811, iran tel: +98 411 333 8789 fax: +98 411 336 3231 e-mail: dr.nezami@gmail.com received january 2009 accepted july 2009 introduction the need for kidney transplantation continues to increase as a result of rising numbers of patients with endstage renal disease.(1,2) living donor kidney transplantation is one of the solutions with proven efficacy and safety for its recipients. however, the postoperative outcome of the donors has been subjected to little investigation.(3) although medical literature indicates that kidney donation is currently a safe procedure with low morbidity and mortality,(4,5) several studies have claimed that living kidney donation has calculable long-term risks and complications that may not be apparent in the short-term.(6-8) however, the potential risks of living kidney donation are still controversial,(7) and there are few published reports examining the extended outcome after donor nephrectomy, especially postnephrectomy changes in unrelated kidney donors—bohlouli et al urology journal vol 6 no 3 summer 2009 195 in unrelated kidney donors.(2) living donor kidney transplantation has become more common in the past few years in iran. thus, we need more investigations on postnephrectomy outcome of donors and regular follow-ups to identify at-risk populations. ultrasonography examination of the kidneys is relatively inexpensive and provides a way to assess location, contour, and size of the kidneys.(9-11) in addition, color doppler ultrasonography (cdu) has been validated as a noninvasive method to evaluate hemodynamic features of renal blood flow in patients with various renal diseases,(10) and currently, cdu velocimetry of interlobar renal arteries has become an established method of screening of kidney allograft donors and monitoring of recipients.(12-14) we designed the present study to evaluate the health condition of donors’ remnant kidney using the cdu indexes of interlobar renal arteries before, 1 week, and 3 months after nephrectomy. materials and methods in this prospective study, we evaluated and followed up 34 living unrelated kidney donors who underwent nephrectomy between july 2006 and august 2008 at imam reza hospital in tabriz, iran. all of the participants provided informed consent. furthermore, the whole work was supervised and approved by the ethic committee at tabriz university of medical sciences, and compliance with the helsinki declaration was considered. permission for donation was done by the nephrologists and the urologists responsible for transplant program. receiving any medication that might affect renal blood flow and kidney function, surgical complications, and loss of follow-up were the exclusion criteria. of 105 donors, 47 accepted to participate in the study and signed consent form, but only 34 donors remained in the study. two donors were excluded because of surgical complications and 11, because of lost to follow-up. all of the participants underwent cdu before nephrectomy, and then, 1 week and 3 months after nephrectomy, and the results were compared with each other. the ultrasonographies were all performed by a hitachi model eub 525 (hitachi medical corp, tokyo, japan) using convex probes (3.5 mhz and 7.5 mhz) by one radiologist (mkt). the cdu indexes including resistive index (ri), pulsatility index (pi), and peak systolic velocity (psv), and the grey-scale ultrasonogrphic indexes including cortical thickness, length, and anteroposterior diameter of the kidney were recorded for both kidneys’ prior to nephrectomy and the remnant kidney after the operation. after visualization of the interlobar arteries of the upper, middle, and lower pole by cdu, the indexes were determined in the interlobar arteries of each pole by pulsed doppler ultrasonography, and then, the mean of the values were reported. in the interlobar renal arteries, the ri and pi were calculated from the doppler spectra using the following equations: ri = peak systolic velocity – end-diastolic velocity/peak systolic velocity pi = peak systolic velocity – end-diastolic velocity/mean velocity in addition to the cdu indexes, systolic and diastolic blood pressure, glomerular filtration rate (gfr), serum creatinine, and blood urea levels were determined, simultaneously. the estimated gfr was calculated according to the cockroftgault formula. serum creatinine and blood urea levels were determined by the jaffe method (mg/ dl) and a commercial kit (mg/dl), respectively. blood pressure was measured using a manual sphygmomanometer. statistical analyses were performed by the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa). the results were presented as mean values ± standard deviation for continuous variables. statistical significance between the times of evaluation was estimated using the 1-way repeated measures analysis of variance, the friedman, and the bonferroni tests. also, correlation of variables was studied by the pearson correlation coefficient test. a p value less than .05 was considered significant. results the mean age of the donors was 25.56 ± 2.31 years and 8 of them (23.5%) were women. nephrectomies were right-sided and left-sided in 11 and 23 cases, postnephrectomy changes in unrelated kidney donors—bohlouli et al 196 urology journal vol 6 no 3 summer 2009 respectively. clinical parameters and cdu indexes are outlined in the table. blood pressure and blood urea hovered around the normal ranges with no significant alterations. a slight increase in serum creatinine, and subsequently a decrease in gfr, was seen 1 week postoperatively, which was corrected after 3 months. constant increases in the kidney’s length, anteroposterior diameter, and cortical thickness were recorded at the 1st week and the 3rd months after nephrectomy. concerning the function of the remnant kidney compared to its function before nephrectomy of the contralateral kidney, the estimated gfr increased up to 63% and 91% after 1 week and 3 months after nephrectomy, respectively. the ri did not change significantly after nephrectomy (figure 1; p = .66). there was no significant alterations in the pi, either (figure 2; p = .38). however, the psv increased 3months after nephrectomy to a significant level (figure 3; p < .001). measurements before and after nephrectomy p parameters before 1 w after 3 m after before vs 1 w 1 w vs 3 mo before vs 3 mo overall † systolic bp, mm hg 96.78 ± 6.38 100.35 ± 3.07 98.21 ± 6.38 .14 .34 .45 .34 diastolic bp, mm hg 64.64 ± 4.58 67.01 ± 2.15 62.14 ± 2.56 .15 .27 .35 .31 serum creatinine, mg/dl 0.85 ± 0.19 1.06 ± 0.22 0.90 ± 0.14 .03 .01 .10 .02 blood urea, mg/dl 17.53 ± 3.88 20.50 ± 5.14 19.50 ± 1.01 .07 .42 .67 .12 gfr, ml/min 123.68 ± 17.99 101.20 ± 14.75 118.43 ± 13.03 .003 .004 .09 .003 kidney length, mm 108.93 ± 6.93 112.25 ± 4.37 115.53 ± 6.53 .01 .005 < .001 < .001 kidney ap diameter, mm 41.46 ± 3.21 45.14 ± 4.09 48.54 ± 4.41 .18 .005 .04 < .001 cortical thickness, mm 8.59 ± 1.77 12.20 ± 5.97 14.18 ± 4.44 .02 < .001 .003 .001 resistive index 0.61 ± 0.04 0.60 ± 0.03 0.61 ± 0.04 .31 .43 .65 .66 pulsatility index 1.10 ± 0.17 1.06 ± 0.14 1.10 ± 0.21 .06 .40 .37 .38 peak systolic velocity 21.10 ± 2.43 23.38 ± 2.37 29.22 ± 3.66 .02 .009 < .001 < .001 clinical and laboratory findings in kidney allograft donors before and after nephrectomy* *bp indicates blood pressure; gfr, glomerular filtration rate; and ap, anteroposterior. †compared with repeated measures analysis of variance. figure 1. changes in the resistive index of the interlobar renal arteries. figure 2. changes in the pulsatility index of the interlobar renal arteries. figure 3. changes in the peak systolic velocity of the interlobar renal arteries. postnephrectomy changes in unrelated kidney donors—bohlouli et al urology journal vol 6 no 3 summer 2009 197 discussion the aim of the present study was to evaluate and compare the cdu findings of the remnant kidney in living unrelated kidney donors at 1 week and 3 months after nephrectomy. to the best of our knowledge, this is the first report on the cdu indexes of the remnant kidney in living unrelated kidney donors. results of this study revealed that psv values of the donors significantly increased 3 months after nephrectomy, while the ri and pi did not change significantly. we also found that the size and function of the remnant kidney consistently increased during the follow-up period, despite a slight decrease in gfr 1 week after nephrectomy. several studies have reported that surgical ablation of the kidney tissue such as unilateral nephrectomy leads to an increase in the gfr from half the preoperative level to an average of about 75% of the 2-kidney performance within 2 to 4 weeks after nephrectomy, and around 85% after 2 to 6 years.(15,16) the functional compensation is obviously seen in the increase of the remaining functional volume of donors’ kidneys after nephrectomy.(17) in the present study, although the prenephrectomy gfr was higher than its value at 1 week or 3 months after the operation, the estimated gfr was the result of only one functioning kidney. hence, despite a decline in gfr after 1 postnephrectomy week, considering the prenephrectomy gfr as a result of both kidneys’ function and half of its value as a marker of the remnant kidney’s function, the calculated gfr for the remnant kidney is supposed to have an increase of about 63% after 1 week and 91% after 3 months (table). in fact, the loss of one kidney due to either a disease or surgical removal results in compensatory changes in the remaining kidney.(18) primary studies have reported similar results and shown that the creatinine clearance increases by 72% to 78%, compared to the preoperative creatinine clearance, within several weeks postoperatively, and then, stabilizes or increases very slightly for more than 10 years after nephrectomy.(19,20) examination of donors by technetium tc 99m mercaptoacetyl triglycine renal showed a functional increase of the remaining kidney of 20% in the mean tubular excretion rate levels compared to the values of healthy carriers of two kidneys.(21) circulatory changes reflected in doppler waveforms of the intralobar renal arteries predict possible adverse outcomes.(22,23) the ri, pi, and psv has proved as doppler waveforms in screening and mentoring of various renal pathophysiologic conditions.(24-26) the increasing volume of psv during the follow-up period of our study showed the increase in the remnant kidney’s blood flow. this finding, as well as the increased kidney size, demonstrates the compensatory phase of the remnant kidney, which confirms “the demand and supply law” of basic medical physiology.(27) moreover, the unaltered systolic and diastolic blood pressure during the postnephrectomy period indicates that increased psv is a result of unilateral nephrectomy, and subsequently, shifting the removed kidney’s blood flow to the remnant kidney. the unchanged ri and pi in our study demonstrated unchanged resistance in the interlobar renal arteries. on the other hand, presence of constant ri and pi in association with increased psv and kidney size, all described net compensatory increase in kidney volume and function which continued up to the 3rd month postnephrectomy. consistent with the present study results, khosroshahi and colleagues(11) did not show any changes in the ri and pi of the interlobar renal arteries of the remnant kidney, 6 to 12 months after donation. in case of serum creatinine level, although its levels increased 1 week and 3 months after nephrectomy, such rising volumes all were in normal limits. previous studies also have reported that the serum creatinine level usually increases up to 20% above the baseline, while remaining within the normal range.(28) conclusion our study showed an increase in psv in association with unaltered ri and pi in the remnant kidney of donors in short-term. this finding indicates the increased blood flow of the remnant kidney. although the gfr decreased and serum creatinine increased within postnephrectomy changes in unrelated kidney donors—bohlouli et al 198 urology journal vol 6 no 3 summer 2009 normal range values 1 week after nephrectomy, considering the fact that there is only one kidney left functioning in the body of donors, we can assume that function of the remnant kidney even has increased up to 63% to 90% at 1 week and 3 months after nephrectomy. conflict of interest none declared. references 1. textor sc, taler sj, driscoll n, et al. blood pressure and renal function after kidney donation from hypertensive living donors. transplantation. 2004;78:276-82. 2. goldfarb da, matin sf, braun we, et al. renal outcome 25 years after donor nephrectomy. j urol. 2001;166:2043-7. 3. lima dx, petroianu a, hauter hl. quality of life and surgical complications of kidney donors in the late post-operative period in brazil. nephrol dial transplant. 2006;21:3238-42. 4. ota k. current status of organ transplantations in asian countries. transplant proc. 2003;35:8-11. 5. jordan j, sann u, janton a, et al. living kidney donors’ long-term psychological status and health behavior after nephrectomy a retrospective study. j nephrol. 2004;17:728-35. 6. ellison md, mcbride ma, taranto se, delmonico fl, kauffman hm. living kidney donors in need of kidney transplants: a report from the organ procurement and transplantation network. transplantation. 2002;74:1349-51. 7. azar sa, nakhjavani mr, tarzamni mk, faragi a, bahloli a, badroghli n. is living kidney donation really safe? transplant proc. 2007;39:822-3. 8. gracida c, espinoza r, cancino j. can a living kidney donor become a kidney recipient? transplant proc. 2004;36:1630-1. 9. el-agroudy ae, sabry aa, wafa ew, et al. long-term follow-up of living kidney donors: a longitudinal study. bju int. 2007;100:1351-5. 10. galesic k, brkljacic b, sabljar-matovinovic m, morovic-vergles j, cvitkovic-kuzmic a, bozikov v. renal vascular resistance in essential hypertension: duplex-doppler ultrasonographic evaluation. angiology. 2000;51:667-75. 11. khosroshahi ht, tarzamni mk, gojazadeh m, bahluli a. color doppler findings in transplanted kidneys and remnant kidneys of donors 6 to 12 months after kidney transplantation. transplant proc. 2007;39:816-8. 12. avasthi ps, voyles wf, greene er. noninvasive diagnosis of renal artery stenosis by echo-doppler velocimetry. kidney int. 1984;25:824-9. 13. krumme b, blum u, schwertfeger e, et al. diagnosis of renovascular disease by intraand extrarenal doppler scanning. kidney int. 1996;50:1288-92. 14. krumme b, rump lc. colour doppler sonography to screen for renal artery stenosis--technical points to consider. nephrol dial transplant. 1996;11:2385-9. 15. davison jm, uldall pr, walls j. renal function studies after nephrectomy in renal donors. br med j. 1976;1:1050-2. 16. pabico rc, mckenna ba, freeman rb. renal function before and after unilateral nephrectomy in renal donors. kidney int. 1975;8:166-75. 17. even-sapir e, gutman m, lerman h, et al. kidney allografts and remaining contralateral donor kidneys before and after transplantation: assessment by quantitative (99m)tc-dmsa spect. j nucl med. 2002;43:584-8. 18. wesson lg. compensatory growth and other growth responses of the kidney. nephron. 1989;51:149-84. 19. vincenti f, amend wj, jr., kaysen g, et al. longterm renal function in kidney donors. sustained compensatory hyperfiltration with no adverse effects. transplantation. 1983;36:626-9. 20. talseth t, fauchald p, skrede s, et al. long-term blood pressure and renal function in kidney donors. kidney int. 1986;29:1072-6. 21. hamscho n, wilhelm a, dobert n, et al. residual kidney function after donor nephrectomy. assessment by 99mtc-mag3-clearance. nuklearmedizin. 2005;44:200-4. 22. krumme b, grotz w, kirste g, schollmeyer p, rump lc. determinants of intrarenal doppler indices in stable renal allografts. j am soc nephrol. 1997;8:813-6. 23. allen ks, jorkasky dk, arger ph, et al. renal allografts: prospective analysis of doppler sonography. radiology. 1988;169:371-6. 24. trillaud h, merville p, tran le linh p, palussiere j, potaux l, grenier n. color doppler sonography in early renal transplantation follow-up: resistive index measurements versus power doppler sonography. ajr am j roentgenol. 1998;171:1611-5. 25. bruno s, ferrari s, remuzzi g, ruggenenti p. doppler ultrasonography in posttransplant renal artery stenosis: a reliable tool for assessing effectiveness of revascularization? transplantation. 2003;76:147-53. 26. buckley ar, cooperberg pl, reeve ce, magil ab. the distinction between acute renal transplant rejection and cyclosporine nephrotoxicity: value of duplex sonography. ajr am j roentgenol. 1987;149:521-5. 27. guyton ac, hall je. overview of the circulation, medical physics of pressure, flow, and resistance. in: guyton ac, hall je, editors. textbook of medical physiology. philadelphia: elsevier saunders; 2006. p. 161-70. 28. najarian js, chavers bm, mchugh le, matas aj. 20 years or more of follow-up of living kidney donors. lancet. 1992;340:807-10. vol 19 no 1 january-february 2022 138 prognostic value of hpv dna in urothelial carcinoma of the bladder: a preliminary report of 2-year follow-up results mehmet sarier1,7*, sibel sürmen usta2, hasan turgut3, sefa alperen öztürk4, ahmet soylu5, mestan emek6, erdal kukul7, hakan bozcuk8, nevgun sepin9 purpose: the association between the human papillomavirus (hpv) and anogenital carcinomas is well established. however, despite its anatomic adjacency, the relationship between hpv and urothelial carcinoma of the bladder (ucb) is less clear. recent meta-analysis and case-control studies demonstrated a significant relationship between the presence of hpv dna and ucb. the aim of this clinical study was to compare the 2-year follow-up results of hpv-positive and hpv-negative ucb patients to evaluate the prognostic value of hpv dna positivity in ucb. methods: the study included patients with stage pta and pt1 ucb who underwent polymerase chain reaction (pcr) analysis of hpv dna between january 1 and november 30, 2018. based on their pcr results, 19 hpv-positive and 38 hpv-negative ucb patients who had regular follow-up in our clinic were evaluated in terms of tumor recurrence and disease progression over a 2-year follow-up period. results: there was no significant difference between the groups in terms of age, follow-up time, smoking, or tumor grade (p = .576, p = .368, p = .080, and p = .454). tumor recurrence was observed at least once in 47.3% (n=9) of the 19 hpv-positive patients and 36.8% (n=14) of the 38 hpv-negative patients (p = .445). there was no difference in disease progression between the groups during follow-up. conclusion: in our sample of ucb patients, the presence of hpv dna was associated with a trend toward higher recurrence rate during the 2-year follow-up, though the difference was not statistically significant. no difference in disease progression was observed based on hpv dna positivity. keywords: urothelial carcinoma; bladder; hpv; prognosis; pcr introduction human papillomavirus (hpv) is a double-stranded dna virus and currently the most common sexually transmitted pathogen worldwide. according to epidemiological studies, the annual global prevalence of hpv is as high as 11.7%.(1) the main reason for this high prevalence is that most hpv infections are asymptomatic or subclinically controlled by host adaptive immunity and become undetectable over time. the oncogenic nature of hpv is another reason that it presents a serious global socioeconomic burden. hpv is one of the most important viruses implicated in infection-related cancers and is thought to be responsible for 7 to 8% of all human malignancies.(2) over 200 different hpvs have been identified to date, of which more than 40 are responsible for anogenital infections and hpv-associated malignancies.(3,4) squamous cell carcinoma is the most common histologic type of cancer associated with 1department of urology, istinye university istanbul turkey. 2department of obstetrics and gynaecology, medical park hospital antalya turkey. 3faculty of health sciences, avrasya university, trabzon turkey. 4department of urology, medical faculty, suleyman demirel .university, isparta. 5department of urology, atlas university, istanbul turkey. 6department of public health,medical faculty, akdeniz university, antalya turkey. 7department of urology, medical park hospital, antalya turkey. 8department of oncology, medical park hospital, antalya turkey. 9department of clinical microbiology and infectious disease, training and research hospital antalya turkey. *correspondence: medical park hospital department of urology muratpaşa, antalya, 07110 turkey. tel: +905333324960. fax: +902423143030. email: drsarier@gmail.com received august 2020 & accepted january 2021 hpv due to hpv tropism for squamous epithelium. the relationship between hpv and cervical cancers, as well as anogenital and certain head and neck carcinomas, has been unequivocally demonstrated. hpv coexistence is reported in 96% of cervical cancers, 64% of anal cancers, 36% of penile cancers, and 41% of head and neck cancers.(5,6) however, the relationship between hpv and bladder cancer has remained a subject of controversy, despite its anatomic adjacency. coexistence of hpv and primary bladder cancer has been reported at rates ranging from 0 to 100% (overall prevalence 16.8%).(7,8) this lingering uncertainty can be largely attributed to methodological limitations of previous studies, namely limited case series, lack of fresh tissue sampling, and not following a case-control design.(9,10) therefore, sarier et al.(11) recently conducted a case-control study with fresh samples and demonstrated a strong correlation between ucb and hpv infection (odds ratio 4.24, urological oncology urology journal/vol 19 no. 1/ january-february 2022/ pp. 45-49. [doi: 10.22037/uj.v18i.6429] 95% ci 1.63-12.34). however, to our knowledge there are no studies in the literature investigating the relationship between the presence of hpv dna and bladder cancer prognosis. the aim of this clinical study was to compare 2-year follow-up results of hpv-positive and hpv-negative ucb patients to determine the prognostic value of hpv dna positivity in ucb. patients and methods case selection and ethical approval the study included patients who were diagnosed as having a primary or recurrent bladder tumor by ultrasound and/or cystoscopic examination in the urology outpatient clinic and underwent transurethral resection of bladder tumor (tur-bt) between january 1 and november 30, 2018. before surgery, first morning urine and urethral swab samples were collected for hpv dna testing by polymerase chain reaction (pcr) analysis. patients with clinical stage pt2 disease or higher and those with carcinoma in situ or non-urothelial carcinoma of the bladder according to their tur-bt pathology results were excluded from the study. patients with stage pta and pt1 ucb were grouped according to their pcr results. information regarding the patients’ demographic characteristics, smoking history, and tumor grade were collected. intravesical immunotherapy was administered to patients with intermediateand high-risk tumors for 1 year following tur-bt.(12) during follow-up, control cystoscopy was performed every 3 months for the first year and every 6 months thereafter. a total of 19 hpv-positive and 38 hpv-negative ucb patients who regularly attended follow-up in our clinic were evaluated in terms of tumor recurrence and progression. local ethics committee approval was obtained (number 005/2018) and all patients provided written informed consent. the study was carried out in keeping with the declaration of helsinki. molecular analysis first morning urine samples (15 ml) were obtained and urethral samples collected using a cotton-tipped swab before surgery. all samples were stored at -80°c until analysis. dna was extracted from the samples using the prepna plus and prep-gs plus extraction kits (dna technology®, moscow, russia) as per the manufacturer’s instructions. the samples were analyzed for hpv dna using a dt prime 5 real-time pcr device (also manufactured/programmed by dna technology®). the samples were analyzed for low-risk (types 6, 11, 44) and high-risk (types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82) hpv. statistical analyses all statistical analyses were performed using open epi® version 3.01 (atlanta, ga, usa). shapiro–wilk test was performed to determine whether the data followed normal distribution. continuous variables were expressed as means and standard deviation, and comparisons between groups were done using mann–whitney u test. chi-square test was used to evaluate relationships between categorical variables. p values less than 0.05 were considered statistically significant. results there were no statistical differences between the 19 hpv-positive ucb patients and 38 hpv-negative ucb patients in terms of age (p = .576), follow-up duration (p = .368), smoking history (p = .080), and tumor grade (p = .454) (table 1). during follow-up, at least 1 tumor recurrence was observed in 47.3% (n = 9) of the hpv-positive patients and 36.8% (n = 14) of the hpv-negative patients (p = .445). no progression in tumor grade or clinical stage was detected in the patients during the follow-up period. high-risk hpv types were detected in 94.7% (n = 18/19) and low-risk hpv types were detected in 5.3% (1/19) of the hpv-positive patients. pcr revealed dna from multiple hpv types in 4 patients. distribution of the detected hpv types is shown in table 2. discussion bladder carcinomas are the fourth most common type of cancer in men and the seventh most common type of cancer in women worldwide, and the prognosis is poor in some cases despite advances in treatment.(13) although factors such as tumor size, histological grade, and clinical stage are routinely used to predict recurrence and prognosis, these factors are usually inadequate to determine tumor course.(14) therefore, studies are ongoing to investigate recurrence and prognosis prediction in bladder carcinomas and understand the effectiveness of treatment methods. the utility of various prognostic biomarkers such as epidermal growth factor receptor, p53, retinoblastoma (rb), and p16 tumor suppressor genes has been investigated for prognostic stratification of patients.(14) however, none of these biomarkers has been widely adopted as a prognostic factor in bladder carcinoma. in the literature, one large study demonstrated that 39.1% of patients had tumor recururological oncology 46 prognostic value of hpv in urothelial carcinoma of the bladder–sarier et al. table 1. demographic structure and distribution of follow-up results in patients with urothelial bladder carcinoma according to human papillomavirus (hpv) status. hpv(n=38) hpv+ (n=19) p-value age (years) 64.7 ± 11.5 61.4 ± 13.9 .576 male 31 (81.5%) 17 (89.4%) .703 female 7 (18.5%) 2 (10.6%) smoking history 21 (55.2%) 15 (78.9%) .080 high-grade tumor 18 (47.4%) 11 (57.9%) .454 low-grade tumor 20 (52.6%) 8 (42.1%) clinical stage pta 19 (50.0%) 13 (68.4%) .180 clinical stage pt1 19 (50.0%) 6 (31.6%) tumor recurrence 14 (36.8%) 9 (47.3%) .445 follow-up time (months) 26.1 ± 6.9 27.5 ± 7.3 .368 results expressed as mean ± standard deviation or frequency (percentage) vol 19 no 1 january-february 2022 138 rence without progression while 33.0% showed disease progression over a 10-year follow-up period despite intravesical immunotherapy/chemotherapy and surgical treatments.(15) comparing the results of that study with our own, the recurrence rate among hpv-negative patients in our study was 36.4%, similar to the literature, while we observed a higher rate of 47.3% in hpv-positive patients. hpv is known to act as an oncogene via viral oncoproteins e6 and e7.(16) e6 protein inhibits the function of the tumor suppressor protein p53, while e7 contributes to oncogenesis by inactivating rb1 protein, which is encoded by another tumor suppressor gene, rb. the resulting disruptions in cell cycle control and dna repair compromise the genomic stability of cells and increase the likelihood of malignant transformation.(17) e7 overexpression also leads to epigenetic remodeling of the p16 gene locus, which results in high levels of nonmutated functional p16.(18) however, as opposed to the normal consequence of p16 overexpression, which is cell cycle arrest, proliferation continues in hpv-transformed cells due to the nonfunctional rb pathway.(19) today, p16 is widely used as a surrogate biomarker in hpv-related anogenital and head and neck carcinomas. there are numerous studies investigating the relationship between hpv and urinary tract cancers. unlike penile cancer, no significant relationship has been observed between hpv and prostate, testicular, or kidney cancers in previous studies.(20) however, this is not the case for bladder cancer. two hypotheses have been proposed to explain the association between hpv and bladder cancer. one is that the urethra is the first point of contact during sexual transmission of the virus. the urethra provides a reservoir for the virus as well as a direct connection and natural route of entry to the urinary bladder from the genital area. the other hypothesis is based on the epithelial tropism exhibited by hpv.(21) the prognostic value of hpv infection in the cancers with which it is associated has also been investigated for many years. published meta-analyses have indicated that hpv positivity is a favorable prognostic factor in cervical, anal, and head and neck cancers.(22,23,6) in addition, hpv positivity was associated with better response to radiotherapy and chemotherapy in head and neck cancers, resulting in better prognosis.(24) it is not clear how hpv positivity improves prognosis in these carcinomas. however, compared to hpv-positive cancers, highly metastatic hpv-negative primary cancers were found to have more aggressive p53 mutations that cause more severe growth dysregulation and poorer prognosis.(14) the present study is the first to evaluate the effect of hpv dna on prognosis in ucb. although we observed no statistically significant difference between the hpv-positive and hpv-negative groups in terms of disease progression at the end of follow-up, hpv-positive ucb patients tended to have higher frequency of tumor recurrence, unlike in other hpv-associated carcinomas. while this finding suggests that hpv-positive patients might have a higher risk of recurrent disease, at least in the short term, it must still be determined whether this is related to hpv infection. cell character might be a factor in this. cancers commonly associated with hpv are characteristically squamous cell carcinomas. however, ucb has different histopathological features. we believe that this study should be regarded as a preliminary study on the prognostic utility of hpv coexistence in urothelial carcinoma. in the future, investigating the expression of tumor suppressor genes such as p53, rb, and especially p16, which is known to play a role in bladder carcinogenesis along with hpv, may help elucidate the prognostic value of hpv positivity. tumor grade is the most important predictor of progression in bladder cancer. previous studies have also yielded discrepant results regarding the relationship tumor grade and hpv. hpv dna positivity was correlated with low-grade tumors in a study by tenti et al.(25), while cai et al.(26) and javanmard et al.(8) reported a correlation with high-grade tumors. in contrast to these studies, sarier et al.(11) observed no statistical correlation between tumor grade and hpv dna positivity. these three conflicting results show that it is too early to draw any conclusions about the relationship between hpv infection and tumor grade. the distribution of hpv types detected in patients with ucb is another noteworthy finding from this study. types 16 and 18 are known to be the predominant high-risk types responsible for the largest proportion of hpv-associated anogenital carcinoma cases.(20,27,28) however, developments in multiplex pcr technology have enabled the investigation of more genotypes, thus revealing a greater variety of high-risk genotypes.(26,29,30) in this study, types 16 and 18 together constituted only 23% of the detected hpv types. we consider this an important finding demonstrating the diversity of highrisk hpv types in ucb. this study has some important limitations to address. firstly, the case series could have been larger, which may have provided better coordination between clinical findings and statistical results. secondly, this study evaluated 2-year results, but a follow-up period of at least 5 years would increase the significance of the study. in addition, investigating hpv-associated tumor suppressor genes in tumor tissues by immunohistochemical methods will be a guide to better demonstrate the prognostic value of hpv positivity. conclusions hpv-positive and hpv-negative patients with pta and pt1 ucb showed no significant difference in disease progression over a 2-year follow-up period. hpv-positive patients tended to have higher tumor recurrence rate, though the difference did not reach statistical significance. future studies with larger series and longer follow-up times will provide more guidance on this subject. hpv type patients, n (%) type 16 3 (11.5%) type 18 3 (11.5%) type 26 1 (3.9%) type 39 3 (11.5%) type 45 1 (3.9%) type 51 2 (7.7%) type 53 3 (11.5%) type 56 1 (3.9%) type 66 2 (7.7%) type 68 2 (7.7%) type 82 2 (7.7%) type 6 3 (11.5%) total 100% table 2. human papillomavirus (hpv) types detected by polymerase chain reaction in patients with urothelial carcinoma of the bladder prognostic value of hpv in urothelial carcinoma of the bladder–sarier et al. vol 19 no 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papillomavirus types 16, 18, 31, 33, and 45 in the majority of cervical carcinomas. j clin microbiol. 2006;44:1310-1317. 18. mclaughlin-drubin me, crum cp, münger k. human papillomavirus e7 oncoprotein induces kdm6a and kdm6b histone demethylase expression and causes epigenetic reprogramming. proc natl acad sci u s a. 2011;108:2130-2135. 19. mclaughlin-drubin me, park d, munger k. tumor suppressor p16ink4a is necessary for survival of cervical carcinoma cell lines. proc natl acad sci u s a. 2013;110:16175-16180. 20. heidegger i, borena w, pichler r. the role of human papilloma virus in urological malignancies. anticancer res. 2015;35:25132519. http://www.ncbi.nlm.nih.gov/ pubmed/25964524. accessed november 30, 2018. 21. visalli g, facciolà a, aleo fd, et al. hpv and urinary bladder carcinoma : a review of the literature. wcrj. 2018;5(1):1-12. 22. liu h, li j, zhou y, hu q, zeng y, mohammadreza mm. human papillomavirus as a favorable prognostic factor in a subset of head and neck squamous cell carcinomas: a meta-analysis. j med virol. 2017;89:710-725. 23. li p, tan y, zhu lx, et al. prognostic value of hpv dna status in cervical cancer before treatment: a systematic review and metaanalysis. oncotarget. 2017;8:66352-66359. 24. kobayashi k, hisamatsu k, suzui n, hara a, tomita h, miyazaki t. a review of hpvrelated head and neck cancer. j clin med. 2018;7:241. 25. tenti p, zappatore r, romagnoli s, et al. p53 overexpression and human papillomavirus infection in transitional cell carcinoma of the urinary bladder: correlation with histological parameters. j pathol. 1996;178:65-70. 26. cai. human papillomavirus and non-muscle invasive urothelial bladder cancer: potential relationship from a pilot study. oncol rep. 2011;25(2). doi:10.3892/or.2010.1083 27. zampronha r de ac, freitas-junior r, murta efc, et al. human papillomavirus types 16 and 18 and the prognosis of patients with stage i cervical cancer. clinics (sao paulo). 2013;68:809-814. 28. mai s, welzel g, ottstadt m, et al. prognostic relevance of hpv infection and p16 overexpression in squamous cell anal cancer. int j radiat oncol biol phys. urological oncology 48 prognostic value of hpv in urothelial carcinoma of the bladder–sarier et al. vol 19 no 1 january-february 2022 138 2015;93:819-827. 29. jørgensen kr, høyer s, sørensen mm, jensen jb. human papillomavirus types 44, 52, 66 and 67 detected in a woman with squamous cell carcinoma of the urinary bladder. scand j urol. 2017;51:85-86. 30. polesel j, gheit t, talamini r, et al. urinary human polyomavirus and papillomavirus infection and bladder cancer risk. br j cancer. 2012;106:222-226. prognostic value of hpv in urothelial carcinoma of the bladder–sarier et al. vol 19 no 1 january-february 2022 49 urology for people 309urology journal vol 6 no 4 autumn 2009 what’s up in urology journal, autumn 2009? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. the persian translation of this article is available from www.uj.unrc.ir. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2009;6:309. www.uj.unrc.ir bladder muscle cells culture modern medicine has stepped into the area of re-building the impaired organs of the body. for instance, scientists try to build a new bladder for patients who have lost their bladder or part of it because of diseases, surgeries, injuries, etc. culture of the cells is one way to achieve a complete intact tissue. dr sharifiaghdas and her iranian colleagues are experts in this area, and in their recent article, they described the growth of muscle cells of the bladder of mice on a natural matrix. culture of cells needs a matrix on which new cells can be fed and grow. there are artificial matrixes and also natural ones. dr sharifiaghdas tried the amnion, the membrane around the fetus in mother’s womb, as a matrix. she reported successful growth of cells on the amnion which was more promising than their growth on other matrixes. these basic research projects are hoped to be the basis of the near future of a change in the paradigm of medical treatment. see page 283 for full-text article laparoscopy for large tumors laparoscopy has been popularized in the world and made more tolerable the nightmare of pain, staying in bed, infections, and large scars after surgeries. instead of the surgeons’ hands, delicate instruments are inserted into the body’s cavities for the operation. therefore, there is no need to make large incisions on the body. but, for large tumors, handling this method of surgery is very difficult that many surgeons prefer to do their own conventional operations. some experienced pioneer surgeons, however, take the risk of approaching larger and larger tumors and expand their limitations in laparoscopy. dr sharma and his colleagues in india did so for tumors of the adrenal gland, a gland on the top of the kidneys, which were larger than 5 cm in diameter (7 cm on average). they reported that with enough care and experience, these tumors can be removed by laparoscopy, as well. see page 254 for full-text article do all men benefit from viagra and its friends? viagra is now a well-known drug that effectively solves the erectile problem of men. however, there are some men whose problem cannot be resolved even with the maximum allowed doses of viagra and a newer drug of this family, called vardenafil. physicians have to discuss other treatments in this step, such as using injections, prosthesis, or vacuum devices. the most recently released drug of this kind, tadalafil (known as cialis), is more effective than its older generation. so, the physician may offer cialis to men whose treatment has failed. a group of researchers from turkey tested this hypothesis that cialis can help men to gain proper erection for intercourse, if other similar drugs have failed. they prescribed cialis for men who did not benefit from sildenafil (viagra) and vardenafil. however, this new drugs was not effective either. so the research team recommended that changing the drug may not be helpful and the physician may have to discuss other options with the patient. see page 267 for full-text article case report 126 urology journal vol 5 no 2 spring 2008 laparoscopic management of calcified paraganglioma of bladder divya ratna dhawan, arvind ganpule, veermani muthu, mahesh r desai urol j. 2008;5:126-8. www.uj.unrc.ir keywords: paraganglioma, pheochromocytoma, bladder neoplasms, urinary bladder, laparoscopy department of urology, muljibhai patel urological hospital, nadiad, gujarat, india corresponding author: mahesh r desai, ms, frcs, frcs department of urology, muljibhai patel urological hospital, dr virendra desai rd, nadiad, gujarat, india 387001. tel: +91 268 252 0323 fax: +91 268 252 0248 e-mail: mrdesai@mpuh.org received august 2007 accepted octorber 2007 introduction paraganglioma (pheochromocytoma) of the bladder is a rare entity accounting for less than 0.5% of the bladder tumors and 1% of all pheochromocytomas.(1,2) extraadrenal pheochromocytoma is diagnosed in case of high suspicion, especially in bladder lesions with calcification. we report a similar case which was managed laparoscopically. case report a 26-year-old man presented with recurrent painless total gross hematuria with amorphous clots for the past 6 months, a single episode of syncopal attack 5 days prior to presentation, and occasional postmicturition headaches. he was previously diagnosed with a bladder calculus. cystoscopy revealed an oval wide-based solid mass involving the right posterolateral bladder wall. tissue sample was taken for histopathology examination and open surgery was contemplated, but the patient developed severe hypertension on skin incision. therefore, the procedure was abandoned. he required intensive care and blood transfusion with assisted ventilation for 1 day. whole body metaiodobenzylguanidine scan was normal and the 24-hour urinary value of vanillylmandelic acid was 10.7 mg (reference range, 1.5 mg to 10.6 mg). examination of the biopsy specimen revealed paraganglioma. abdominal radiography showed semilunar calcification in the pelvis and ultrasonography revealed a 3.4 × 2.4-cm soft tissue lesion on the right posterolateral wall of the bladder with calcification. no extravesical spread was noted on contrast-enhanced computed tomography (ct) scan. doppler ultrasonography confirmed the extensive vascularity of the lesion (figure 1). the patient was prepared with long-acting alpha-blockers and beta-blockers. five standard laparoscopic ports (three 5-mm and two 10-mm ports) were placed in fan-ray configuration. using the laparoscopic ultrasonography, the bladder mass was delineated. then, the bladder was partially distended by saline solution and the mass was excised with an adequate margin (figure 2). the bladder was then closed (figure 3) and a 20-f foley catheter was placed periurethrally. no hypertensive crisis was observed intra-operatively. the operation lasted for 150 minutes and no blood transfusion was required. the postoperative laparoscopic management of calcified paraganglioma of bladder—dhawan et al urology journal vol 5 no 2 spring 2008 127 recovery was unremarkable. blood pressure returned to baseline immediately after the operation. the catheter was removed once cystography documented no leak. the 24-hour urine vanillylmandelic acid at 1 month follow-up was 5.6 mg. histopathology and immunohistochemistry (figure 4) confirmed the diagnosis of pheochromocytoma. at 4-month follow-up, the patient still had a normal blood pressure. figure 3. intracorporeal suturing after resection of the mass.figure 2. resected specimen. c indicates calcification; t, soft tissue; and b, bladder margin. figure 4. top, nests of spindle to polygonal cells with granular eosinophilic cytoplasm and hyperchromatic nuclei with mild pleomorphism are seen (a, hematoxylin-eosin 10; b, hematoxylin-eosin 40). c, tumor cells were negative for cytokeratin. d, tumor cells were positive for chromogranin. figure 1. left, reconstructed computed tomography image shows a vesical mass with calcification. right, doppler ultrasonography shows high vascularity of the lesion. laparoscopic management of calcified paraganglioma of bladder—dhawan et al 128 urology journal vol 5 no 2 spring 2008 discussion vesical pheochromocytoma is a unique surgical challenge due to its presentation and potential catecholamine surge during the operative manipulation. radiological studies, including ct scan, demonstrate ring-like calcifications of the tumor. this rare finding is suggestive of pheochromocytoma not only in the bladder but also in other sites.(3) any bladder mass with calcification or a calculus whose position does not change should be completely evaluated with suspicion to this diagnosis. cystoscopy may be considered when ct does not provide details. when this procedure is ignored even in patients with normal blood pressure before surgery, severe life-threatening cardiovascular complications including death can occur because of excessive catecholamine release.(4) indiscriminate biopsy of pheochromocytomas may trigger a catastrophic crisis and must be avoided.(5) in most cases, the diagnosis is initially missed and subsequent review of the histopathological material reveals pheochromocytoma. transurethral resection of the tumor is not an ideal treatment since hemorrhage can be severe and uncontrollable.(3) laparoscopic partial cystectomy for bladder pheochromocytoma has been sparingly attempted.(3,6-8) as intravesical intervention entails greater risk of catecholamine surge, solely extravesical (laparoscopic) approach and mapping of the tumor with laparoscopic ultrasonography may be a more attractive option. shorter hospital stay, less intra-operative blood loss, and early recovery are other advantages of the laparoscopic approach. conflict of interest none declared. references 1. grignon dj. neoplasms of the urinary bladder. in: bostwick dg, eble jn, editors. urologic surgical pathology. st louis: mosby-year book; 1997. p. 214305. 2. singh dv, seth a, gupta np, kumar m. calcified nonfunctional paraganglioma of the urinary bladder mistaken as bladder calculus: a diagnostic pitfall. bju int. 2000;85:1152-3. 3. cheng l, leibovich bc, cheville jc, et al. paraganglioma of the urinary bladder: can biologic potential be predicted? cancer. 2000;88:844-52. 4. samaan na, hickey rc, shutts pe. diagnosis, localization, and management of pheochromocytoma. pitfalls and follow-up in 41 patients. cancer. 1988;62:2451-60. 5. blake ma, kalra mk, maher mm, et al. pheochromocytoma: an imaging chameleon. radiographics. 2004;24:s87-99. 6. bozbora a, barbaros u, erbil y, kiliçarslan i, yildizhan e, ozarmagan s. laparoscopic treatment of hypertension after micturition: bladder pheochromocytoma. jsls. 2006;10:263-6. 7. dilbaz b, bayoglu y, oral s, cavusoglu d, uluoglu o, dilbaz s. laparoscopic resection of urinary bladder paraganglioma: a case report. surg laparosc endosc percutan tech. 2006;16:58-61. 8. [no authors listed]. combined laparoscopic and transurethral partial cystectomy for juxta-ureteral pheochromocytoma of the bladder. minim invasive ther allied technol. 2002;11:19-22. sexual dysfunction and andrology artificial neural network for the prediction of chromosomal abnormalities in azoospermic males emre can akinsal1*, bulent haznedar2, numan baydilli1, adem kalinli3, ahmet ozturk4, oğuz ekmekçioğlu1 purpose: to evaluate whether an artifical neural network helps to diagnose any chromosomal abnormalities in azoospermic males. materials and methods: the data of azoospermic males attending to a tertiary academic referral center were evaluated retrospectively. height, total testicular volume, follicle stimulating hormone, luteinising hormone, total testosterone and ejaculate volume of the patients were used for the analyses. in artificial neural network, the data of 310 azoospermics were used as the education and 115 as the test set. logistic regression analyses and discriminant analyses were performed for statistical analyses. the tests were re-analysed with a neural network. results: both logistic regression analyses and artificial neural network predicted the presence or absence of chromosomal abnormalities with more than 95% accuracy. conclusion: the use of artificial neural network model has yielded satisfactory results in terms of distinguishing patients whether they have any chromosomal abnormality or not. keywords: artificial neural network; azoospermia; chromosomal abnormality; infertility; prediction. introduction since to first introduction of artificial neural network (ann) to andrology by niederberger in 1993,(1) there are scarce papers in this area. andrology is a special field with the opportunity for mathematical modelling. generally, at least in our country-turkey, somewhat complicated cases are referred to tertiary care clinics without providing sufficient information to the patient/couple. computer technology is used widely worldwide. simple diagnostic tools might help the clinician in seconds to find out satisfactory information. producing diagnostic tools using statistical or ann models is the duty of academicians. azoospermia is still a frustrating condition and needs to be diagnosed adequately and quickly to be able to make an explanation to the couple. the male has to be examined with lots of diagnostic tests. as known, there are some clinical and laboratory parameters showing the cause/s of azoospermia. whether the males should be genetically evaluated and the required genetical evaluations should be practically decided. it might seem as an easy problem. if the male is azoospermic, with very little testicles and taller than general population, the diagnosis is a kind of hypogonadism most probably before any test is performed. all of the following questions might irritate the clinician: in all azoospermic males, is it necessary to perform genetical tests, what are their costs, are the duration of the tests increase the distress of the couple? the aim of this study is to develop an ann model which may predict which azoospermic 1department of urology, faculty of medicine, erciyes university, kayseri, turkey. 2department of computer engineering, faculty of engineering, hasan kalyoncu university, gaziantep, turkey. 3department of computer engineering, faculty of engineering, erciyes university, kayseri, turkey. 4department of biostatistics and medical informatics, faculty of medicine, erciyes university, kayseri, turkey. *correspondence: department of urology, faculty of medicine, erciyes university, melikgazi, kayseri, 38280, turkey. tel: +90 532 5881646, fax: +90 352 4375285, e-mail: emreakinsal@hotmail.com. received june 2017 & accepted october 2017 male with cytogenetic evaluation requirements. materials and methods study design a non-interventional, retrospective study was designed in erciyes university, department of urology. study population the data of pellet negative azoospermic males were evaluated retrospectively. if the evaluated parameters which might help the diagnosis were complete, the data of 425 patients were taken into consideration by the below-mentioned exclusion criteria: exclusion criteria a) absence of one or two testicles, b) the presence or history of cryptorchidism (with or without surgery), c) the presence of significant testicular atrophy of one or two testicles later on life d) size discrepancy between the testicles more than 50%, e) prior chemo and/or radiation therapy for any reason/region, f) any hormonal treatment which could have effected the testicular volumes or hormones, g) history of mumps orchitis. evaluations all patients were evaluated in the same clinic and generally by the same physician (oe). the height (cm) and body weight (kg) of the patients were measured and recorded. testicular volumes were determined by using prader orchidometer. all semen analyzes were done in the same laboratory. semen samples were obtained after a 3 to 5 days period of ejaculatory abstisexual dysfunction and andrology 44 vol 15 no 03 may-june 2018 45 nence, and semen analyzes were performed according to 2010 world health organization (who) guidelines. (2) semen analyzes were performed at least twice and pelleting was performed. patients with negative pellet test were considered as azoospermic. some males could not ejaculate (especially hypogonadothropic ones), their ejaculate volumes were taken as zero. all hormonal evaluations were performed in the laboratory of our center. peripheral blood samples were used for cytogenetical examinations and at least 20 metaphases have been evaluated. total testicular volume (right and left), body weight, height, body mass index (bmi), total testosterone (tt), follicle stimulating hormon (fsh), luteinizing hormon (lh), prolactin (prl), estradiol (e2) and ejaculate volume were the intended to evaluate data. these data were evaluated one by one with binary logistic regression analysis whether they could help the diagnosis. if not, they were not used in artificial neural network (ann) and other statistical analyses. there were 425 eligible azoospermic cases. among them, 310 were chosen as the education set and 115 as test set randomly for the ann evaluation. all statistical evaluations were made for these sets separately and as whole group. multilayer perceptron neural networks multilayer perceptron (mlp), called also multilayer feed forward neural network, is one of the most popular ann architectures. the mlp is very efficient for function approximation in high dimensional spaces. the architecture of the mlp with a three layer topology. an mlp network is composed of neurons connected to each other. the input signal propagates from the input layer to the output layer. the number of neurons in the input and the output layers depend on the number of input and output variables, respectively. the number of hidden layers and the number of neurons in each hidden layer affect the generalisation capability of the network. the performance of an mlp network depends mainly on the weights of its connections. the training process of an mlp network involves finding values of the connection weights, which minimise an error function between the actual network output and the corresponding target values in the training set. the knowledge is represented and stored by the strength (weights) of the connections between the neurons. after the mlp network is satisfactorily trained and tested, it is able to generalize rules and will be able to respond to unseen input data to predict required output, within the domain covered by the training examples. application of mlps to the problem the mlp neural model used in predicting genetic anomaly is shown in figure 1. the network employed consists of input layer, hidden layers and output layer. the input layer has six neurons since there are six input variables with height, total testicular volume, ejaculate volume, fsh, lh and total testosterone. each hidden layer contains eight neurons which were found after many trials, and the output layer has got one neuron which is a measure of probability of genetic anomaly presence. the tangent hyperbolic and sigmoid nonlinear activation functions are used in the neurones of the first and second hidden layers respectively, and the linear activation function is used in the output neuron. the input data tuples were scaled between –2.0 and +2.0 and the output data tuples were also scaled between 0.0 and 1.0 before training. an estimated probability of less than 0.5 indicated no genetic anomaly, whereas an estimated probability of greater than 0.5 suggested the presence of genetic anomaly. outcomes total 425 data sets were used. 310 of data sets were used for training the network, and the remaining 115 data sets were used for the testing. in this study, levenberg-marquardt algorithm that combines the best features of gauss-newton and gradient descent methods was used to train the proposed network.(3,4) the learning phase is carried out after the presentation of each set until the calculation accuracy of the network is deemed satisfactory according to a maximum allowable number of training cycles. the number of training cycles was taken to be 1000 epoches. after proper training, the network was tested with 115 data sets. ethics the study was approved by the ethics committee. results the distribution of the patients according to the diagnosis and training and test sets were shown in table 1. following logistic regression analyses, height, total testicular volume, fsh, lh, tt and ejaculate volume produced significant differences to discriminate whether the patients had sex chromosome abnormalities. afterwards, only these six variables were used for ann evaluations(table 2). the evaluated parameters revealed non-significant differences between the training and test sets. table 1. the distribution of the patients according to the diagnosis and training and test diagnosis training test total n n n nonobstructive azospermia 158 60 218 klinefelter's syndrome 70 25 95 vasal agenesia 29 11 40 unidentified 19 7 26 epididymal obstruction 12 4 16 hypogonadothropic hypogonadism 11 4 15 other chromosomal abnormalitiesa 8 3 11 distal ejaculatory duct obstruction 3 1 4 total 310 115 425 asignificant sex chromosome abnormalities like 46xx, 46xy /45x0. trainin seta test seta p-value n 320 115 age (years) 31.0 + 5.5 31.4 + 5.7 0.41 height (cm) 173.0 + 7.6 174.5 + 8.5 0.11 total testicular volume (ml) 22.9 + 14.8 22.9 + 14.7 0.85 ejaculate volume (ml) 2.2 + 1.5 2.3 + 1.4 0.51 fsh (miu/ml) 20.9 + 17.1 19.0 + 15.7 0.30 lh (miu/ml) 10.8 + 8.6 9.9 + 9.0 0.22 total testosterone (ng/dl) 377.1 + 229.6 364.6 + 214.1 0.65 a data is presented as mean ± sd abbreviations: fsh, follicle stimulating hormone; lh, luteinizing hormone. table 2. variables used both in the ann and logistic regression analsyes. artificial neural network in azoospermia–akinsal et al. in logistic regression analyses, total testicular volume with lh had the highest power to find out who requires sex chromosome evaluation with the expressiveness ratio of 96.5% and 95.2% in the test and the training sets, respectively. in ann with all parameters in training set the accuracy was 100%. in test set, the ratio was 97%. discussion azoospermia is diagnosed in approximately 1% of all men and up to 15% of infertile men, depending upon the demographic nature of the infertile cohort.(5) men with azoospermia should be evaluated in an effort to discover the underlying etiology of their condition, which will guide the formulation of a therapeutic plan. (6) in about 15% of male and infertile subjects, genetic abnormalities may exist, including chromosome aberrations and single gene mutations.(7) the frequency of karyotypic abnormalities in 1790 males with infertility was detected to be high as 12.67% in azoospermia and 4.6% in oligozoospermia, respectively.(8) genetic risks for couples undergoing in vitro fertilization (ivf) and intracytoplasmic sperm injection (icsi) are related to transmission of constitutional genetic abnormalities, genetic alterations present only in sperm, or de-novo generated genetic disorders. therefore, the identification of genetic factors has become a good practice for appropriate management of the infertile couple.(7) azoospermia is still a frustrating condition and needs to be diagnosed adequately and rapidly to be able to provide an explanation to the couple. the prediction of a genetical abnormality with physical examination and some simple tests are important for the physician. a simple and cheap predictive tool will provide convenience for both patients and physicians. thus, we attempted to create a diagnostic tool by using artificial neural network. neural networks have become popular tools in urological research. these systems are now being investigated as predictive methods in many areas, such as bladder cancer research, detection of prostate cancer, spontaneous stone passage in stone disease and bladder outlet obstruction in men with lower urinary tract symptoms. (9-12) andrology and infertility are special areas with the opportunity for mathematical modelling. in this field, scarce studies (not more than 20) are present and the studies generally focused on assisted reproductive techniques. this is the first study to determine the cytogenetical abnormalities with the help of ann, in azoospermic males. neural computation is a nonlinear modelling technique that adopts features of the physiological function of the biological neuron to inspire its mathematical models.(13) the most common ann model used in clinical medicine is a special class of ann, namely the mlp. this model is well suited for solving clinical diagnostic classification problems.(14) ann and classical statistical methods were used together and compared with each other in several previous studies. we used logistic regression analysis for classical method and it worked as a guide for ann. we determined the parameters that we used for input layers by logistic regression analysis. following logistic regression analyses, height, total testicular volume, fsh, lh, tt and ejaculate volume produced significant differences to discriminate whether the patients had sex chromosome abnormalities. then only these six variables were used for ann evaluations. both logistic regression analyses and ann predicted the presence or absence of chromosomal abnormalities more than 95%. total testicular volume and lh had the highest power to find out who requires sex chromosome evaluation in the current study. contrary to the expectations, the power of the fsh was not so high. this situation may be associated with different subgroups included in our study population. artificial neural network and the logistic regression analyses worked well in the problem presented here. this problem seems easy to resolve practically. however, we need practical predictor programmes in phones, computers and etc. this study is also a beginning of the other studies. with the same parameters, we will try to perform multicenter studies whether the predictor works in a same way. in this way, the physcians who work at primary centers will be able to evaluate their patients easier and more accurately. in previous studies, the researchers produced some ann models to predict outcomes of some procedures at infertility management such as presence of spermatazoa in testes and ivf/icsi outcomes. designed ann models demonstrated high accurate prediction rates. (15-17) moreover, some other biomarkers associated with spermatogenesis (inhibin b, leptin) had been combined with ann models to prediction of sperm retrieval.(18) combination of ann models for the management of each step of azoospermic males would be very beneficial for both patients and physicians. to design such a system will not be too difficult with recent technologies. infertility management is still a challenging process due to its cost, time consuming and uncertainty of results. ann models may save time and reduce costs by avoiding from unnecessary tests. in addition, predicting outcomes accurately and further informing the couple may make their expectations of treatment more realistic and abstain from unnecessary frustrations. although azoospermia may be due to genital tract obstruction, defective spermatogenesis, ejaculatory duct dysfunction or hypogonadotrophism, it is currently classified as obstructive and non-obstructive. this is because, hypogonadotrophic azoospermia and ejaculatory duct dysfunction are rare causes of azoospermfigure 1. the mlp neural model used to predict genetic anomaly. artificial neural network in azoospermia–akinsal et al. sexual dysfunction and andrology 46 vol 15 no 03 may-june 2018 47 ia, accounting for about only 2% of azoospermia.(19) defective spermatogenesis in 60% and genital tract obstruction in 40% of 102 patients with azoospermia evaluated with testicular biopsy and distal vasography were reported.(20) none of the patients in this series had ejaculatory dysfunction or hypogonadotrophic hypogonadisim. in our study population, some disorders are very rare (table 1). the other intended study is to predict the exact reason of azoospermia. if we may be able to reach a higher number of patients, we might stratify them more easily. if an ann model that may predict the cause of azoospermia is produced, some patients may not require cytogenetical evaluation. there is some limitations of our study. all eligible patients were included in the study. if power analysis was performed and the sample size was determined, our results could be more reliable statistically. some sub-analyzes may be performed by increasing the number of patients. in this way, a possible relationship between lh and testicular volume may be evaluated and even a cut-off value for lh may be detected to predict the patients with the requirement of chromosomal evaluation. conclusions the use of ann model has given satisfactory results, in terms of distinguishing patients whether they have any chromosomal abnormality. as more specific input variables become available and number of cases increase, it might be possible to predict the exact diagnosis. artificial intelligence based models are difficult to train, however easy to use. possible combinations of ann models might reduce the treatment cost and predict treatment outcomes. conflict of interest the authors report no conflict of interest. references 1. lamb dj, niederberger cs. artificial intelligence in medicine and male infertility. world j urol. 1993; 11:129-36. 2. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. hum reprod update 2010; 16: 231-45. 3. hagan mt, menhaj mb. training feedforward networks with the marquardt algorithm. ieee trans. neural netw. 1994; 5: 989-93. 4. chen s, billings sa, grant pm. non-linear system identification using neural networks. int j control. 1990; 51: 1191–215. 5. practice committee of american society for reproductive medicine in collaboration with society for male reproduction and urology. evaluation of the azoospermic male. fertil steril. 2008; 90 suppl 5: 74–7. 6. sigman s, lipshultz l, howards s. office evaluation of the subfertile male; in: lipshultz l, howards s, niederberger c (eds). infertility in the male. 4th ed. new york: cambridge university press, 2009; pp 153–76. 7. foresta c, ferlin a, gianaroli l, dallapiccola b. guidelines for the appropriate use of genetic tests in infertile couples. eur j hum genet. 2002; 10: 303-12. 8. nakamura y, kitamura m, nishimura k, et al. chromosomal variants among 1790 infertile men. int j urol. 2001; 8: 49–52. 9. parekattil sj, fisher ha, kogan ba. neural network using combined urine nuclear matrix protein-22, monocyte chemoattractant protein-1 and urinary intercellular adhesion molecule-1 to detect bladder cancer. j urol. 2003; 169: 917-20. 10. kalra p, togami j, bansal bsg, et al. a neurocomputational model for prostate carcinoma detection. cancer. 2003; 98: 184954. 11. cummings jm, boullier ja, izenberg sd, kitchens dm, kothandapani rv. prediction of spontaneous ureteral calculous passage by an artificial neural network. j urol. 2000; 164: 326-8. 12. wadie bs, badawi am, abdelwahed m, elemabay sm. application of artificial neural network in prediction of bladder outlet obstruction: a model based on objective, noninvasive parameters. urology. 2006; 68: 1211-4. 13. niederberger c. neural computation in urology: an orientation. mol urol. 2001; 5: 133-9. 14. hinton ge. how neural networks learn from experience. sci am. 1992; 267: 144-51. 15. samli mm, dogan i: an artificial neural network for predicting the presence of spermatozoa in the testes of men with nonobstructive azoospermia. j urol. 2004; 171: 2354-7. 16. wald m, sparks a, sandlow j, van-voorhis b, syrop ch, niederberger cs. computational models for prediction of ivf/icsi outcomes with surgically retrieved spermatozoa. reprod biomed online. 2005; 11: 325-31. 17. ramasamy r, padilla wo, osterberg ec, et al. a comparison of models for predicting sperm retrieval before microdissection testicular sperm extraction in men with nonobstructive azoospermia. j urol. 2013; 189: 638-42. 18. ma y, chen b, wang h, hu k, huang y. prediction of sperm retrieval in men with nonobstructive azoospermia using artificial neural networks: leptin is a good assistant diagnostic marker. hum reprod. 2011; 26: 294-8. 19. hull mg, glazener cm, kelly nj, et al. population study of causes, treatment and outcome of infertility. br med j (clin res ed). 1985; 291: 1693-7. 20. matsumiya k, namiki m, takahara s, et al. clinical study of azoospermia. int j androl. 1994; 17: 140-2. artificial neural network in azoospermia–akinsal et al. vol 15 no 03 may-june 2018 1 effect of polygonum aviculare l. on nephrolithiasis induced by ethylene glycol and ammonium chloride in rats jamileh saremi1 , hossein kargar jahromi2 , mohammad pourahmadi1* purpose: nephrolithiasis is a common urinary tract disease, in addition to the pain and treatment costs, there may be significant complications resulting from the stones. this study intended to investigate the effects of polygonum aviculare l. aqueous extract (pae) on urolithiasis induced by ethylene glycol (eg) and ammonium chloride (ac) in rats. materials and methods: sixty-four male wistar rats were randomly divided into eight groups (n = 8). rats in the normal control group (i) received no treatment. the sham groups (iii and iv) were given pae. at 100 and 400 mg/kg by gavage for 28 days. the disease control group (ii), the prevention groups ( v and vi), and the therapeutic groups (vii and viii), received 1% eg and .25 ac in their drinking water for 28 days. the prevention groups (from the start of eg administration), and the therapeutic groups (from the 14th day of eg administration), received pae at 100 and 400 mg/kg by gavage. at the end of the experiment, kidneys were examined for caox deposits and tubulointerstitial changes. results: the number of caox crystals and tubulointerstitial changes increased significantly in group ii rats compared to groups i, iii, and iv (p < .001). the number of caox crystals (p < .001) and tubulointerstitial changes (p < .001) in the prevention groups, and the number of caox crystals (p < .05) and interstitial changes (p < .05) in the therapeutic groups declined significantly compared to group ii. conclusion: results show aqueous extract of polygonum aviculare l. is effective in the prevention and treatment of kidney stones. keywords: ammonium chloride; calcium oxalate; ethylene glycol; nephrolithiasis; polygonum aviculare; urolithiasis. introduction nephrolithiasis is the third common disease of the urinary tract after urinary infection and pathological disorders of the prostate gland.(1) in 2005, the prevalence of kidney stones was reported to be 5.7% in iran (5.3% in females and 6.1% in males).(2) different substances in the body influence the process of stone formation, and about 80-85% of the total urinary stones are calcium stones. urinary calcium stones usually result from increases in urine calcium, uric acid, and urinary oxalates, and from reductions in urine citrate levels.(1) recurrence of kidney stones is also highly probable. in 2005, the 1-, 5-, and 10-year recurrence rates of kidney stone were reported to be 16, 32, and 53%, respectively.(2) symptoms and signs of urinary stone include colic pain, nausea, vomiting, and hematuria. moreover, acute urinary tract obstruction, hydronephrosis, and renal damage occur.(1) treatment of urinary stones includes use of oral drugs, removal of stones by using an ureteroscope, extracorporeal shock wave lithotripsy, removal of stones through the skin, and open surgery.(1) treatment of kidney stones by using medicinal plants has been common for a long time. considering the risk of recurrence of urinary stones, the high costs of treatment, and the complications resulting from surgical operations, use of medicinal plants can be a suitable alternative in the prevention and treatment of kidney stones. polygonum aviculare l. has numerous medicinal properties. in traditional iranian medicine, this plant is considered useful for improving urinary problems, removal of kidney stones, and is used for treating kidney, bladder, and urinary tract infections.(3) polygonum aviculare contains alkaloids, tannins, saponins,(4) large quantities of phenolic and flavonoid compounds,(5) and has antibacterial,(4) antioxidant,(5) antihypertensive, diuretic,(6) and anti-obesity properties.(7) since the effects of aqueous extract of polygonum aviculare on kidney stones had not been studied yet, this research investigated the effects of this extract on the prevention and treatment of kidney stones induced by ethylene glycol and ammonium chloride in male wistar rats. 1research center for noncommunicable diseases, jahrom university of medical sciences, jahrom, iran. 2zoonoses research center, jahrom university of medical sciences, jahrom, iran. *correspondence: research center for noncommunicable diseases, jahrom university of medical sciences. blvd, jahrom, iran. postal code: 7418814765. tel : 071 54336085. fax: 071 54340405. email: zahed1340@yahoo.com. received january 2017 & accepted september 2017 endourology and stone disease materials and methods ethical statement the study protocol was approved by the ethics committee of jahrom university of medical sciences (jums. rec.1393.006). study design rats were randomized into eight groups by using a random number table. experimental procedures the polygonum aviculare plant was collected in spring from the shiraz garden (shiraz, iran) and was identified by amir borjian (phd of plant systematic, jahrom islamic azad university (jahrom, iran) (voucher number: 2537). the leaves were cleaned and dried in the shadow at 25˚c and powdered by mechanical grinder. the powders were soaked in distilled water. after 72 hours, the extract was filtered and then condensed by a rotary evaporator under vacuum at 50°c temperature. the powders were soaked in distilled water. after 72 hours, the extract was filtered and then condensed by a rotary evaporator under vacuum at 50°c temperature. based on previous studies,(7,8) two doses of 100 and 400 mg/kg of aqueous extract of polygonum aviculare l. was used to see its dose depended action. the groups studied during the 28 days(9) of the research were as follows: group i (normal control group): did not receive any treatment during the study. group ii (disease control group): received 1% ethylene glycol and .25% ammonium chloride in their drinking water during the study. sham groups (iii and iv): received aqueous extract of polygonum aviculare l. at 100 mg/kg (group iii) and 400 mg/kg (group iv) by gavage during the study. prevention groups (v and vi) : received 1% ethylene glycol and .25% ammonium chloride in their drinking water from the first day to the last day of the study, and were given aqueous extract of polygonum aviculare l. at 100 mg/kg (group v) and 400 mg/kg ( group vi) by gavage for 4 weeks. therapeutic groups(vii and viii): received 1% ethylene glycol and .25% ammonium chloride in their drinking water from the first day to the last day of the study, and were given aqueous extract of polygonum aviculare l. at 100 mg/kg ( group vii) and 400 mg/kg (group viii) by gavage from the 14th day of the study. experimental animals this was an animal experimental study. male wistar rats ( 200 ± 10 g) were included. housing and husbandry rats were kept in clean cages under standard conditions at 23 ± 2 ˚c and 12h light/12h dark cycles at relative humidity of 50-55%, and had free access to standard food and tap water during the study. sample size sixty four rats were divided into eight 8-member groups. (10) allocation to groups: rats were randomly divided into eight groups including: group i (normal control group), group ii (disease control group), sham groups (iii and iv), sham groups (iii and iv), prevention groups (v and vi), therapeutic groups(vii and viii). outcomes at the end of the study (on the 29th day), the rats were killed by carbon dioxide inhalation, and their kidneys were quickly removed and fixed in 10% formalin buffer. after dehydration, the tissues were embedded in paraffin, and 5µm thick serial sections were prepared, stained using the h&e method,(9) and studied under a model olympus light microscope (at 10x magnification). twenty slides (each containing 2 sections) from each kidney were prepared. the numbers of calcium oxalate crystals in 10 microscopic fields were counted and reported as mean ± standard error. tubulointerstitial changes such as tubular necrosis, tubular dilation, and interstitial inflammation were studies using the semi-quantitative approach: 0 = none, 1 = trace ( < 10%), 2 = mild (10-25%), 3 = moderate (26-50%), and 4 = marked ( > 50%).(11,12) statistical analysis spss 17 was used to analyze the data. caox deposits and tubulointerstitial changes were normally distributed as tested by kolmogorov-smirnov test. differences between groups were assessed by one-way anova, following which tukey test was performed. the results were expressed as mean standard error. the differences between the groups were significant at the 5% level (p < .05). results pathology study was carried out to detect damages inflicted on the kidneys, and the numbers of counted calcium oxalate crystals. in group i: all tissue sections were studied under the microscope, but no caox crystals or tissue damage was observed in any of the sections. in group ii: calcium oxalate crystals were deposited in large numbers (19.9 ± 1.90) in kidney tissues, including the proximal tubules, the henle’s loops, the distal tubules, and the collecting ducts. the number of calcium oxalate crystals(p < .001) and interstitial changes(p < .001), increased significantly compared to group i. the sham groups (groups iii and iv) as in the case of the normal control group, neither calcium oxalate crystals, nor any tissue damage was detected. (table 1 and figure 1) the prevention groups (v and vi): the number of caox crystals (group v, p < .001, group vi, p < .001) table 1. effect of polygonum aviculare l. on calcium oxalate deposits and tubulointerstitial changes in rats. group i group ii group iii group iv group v group vi group vii group viii (normal control) (disease control) (sham 100mg/kg) (sham 400mg/kg) (preventive 100mg/kg) (preventive 400mg/kg) (curative 100mg/kg) (curative 400mg/kg) calcium oxalate 0 19.9 ± 1.9 0 0 10.06 ± 1.89 11.71 ±1.59 6.74 ± 1.42 6.98 ± 1.09 a*** b*** b*** a*** b*** a*** b*** a** b*** a** b*** tubulointerstitial damage 0 1.91 ± .12 0 .02 ± .01 1.27 ± .16 1.31 ± .14 1.31 ± .17 1.3 ± .14 a*** b*** b*** a*** b** a*** b* a*** b* a*** b* polygonum aviculare l. on urolithiasis saremi et al. endourology and stone diseases 2 vol 15 no 03 may-june 2018 3 and tissue damage (group v, p = .007, group vi, p = .015) decreased considerably compared to the disease control group. moreover, calcium oxalate deposit and tissue damage were significantly different (p < .001) from those of the normal control group and sham groups, but no significant differences were observed with the therapeutic groups (p > .05). furthermore, there was no significant difference between the groups v and vi(p > .05). the therapeutic groups (vii, viii): caox crystal deposit (group vii, p < .001, group viii, p < .001) and tubulointerstitial damage (group vii, p = .015, group viii, p = .012) were significantly different from those of the disease control group. moreover, the caox deposit and tubulointerstitial damage were significantly different from those of the normal control group (p < .001) and from those of the sham groups, moreover, group vii showed no significant difference with group viii (p > .05). discussion results indicated that aqueous extract of polygonum aviculare l. at concentrations of 100 and 400 mg/kg significantly reduced the number of caox crystals and the extent of interstitial damage in the prevention and therapeutic groups. no studies have been carried out so far regarding the effects of polygonum aviculare l. on kidney stones. therefore, it is impossible to express anything definite on how polygonum aviculare l. affects kidney stones and on its possible mechanisms of action. calcium stones form in various stages, including accumulation of calcium oxalate and calcium phosphate, and crystal nucleation, growth, accumulation, and retention.(13) low volume of urine, low ph value of urine, calcium, sodium, oxalate, and urea promote stone formation.(13) in a study conducted on rats fed cholesterol and a highfat diet, some metabolic disorders were observed including hyperoxaluria, hypercalciuria, nephrocalcinosis and hyperlipidemia; in other words, disorder in serum fats prepared the ground for the mentioned changes and for kidney stone formation.(14) polygonum aviculare l. has fatreducing effects,(7) which may be the reason for some of its effects in preventing kidney stone formation and in removal of these stones. calcium stones in the kidneys may result from infections. nanobacteria can also cause crystal nucleation and growth. they may cause damage to the epithelium of renal tubules, obstruct tubules, cause chronic infections, resulting in tissue damage and the formation of kidney stones.(15) polygonum aviculare l. has antibacterial properties;(4) therefore, part of its effects on curing kidney stones may be is due to its antibacterial characteristics. calcium oxalate crystals, can damage kidney epithelial cells, which causes cells to secrete materials such as free radicals. these products may promote stone formation by inducing heterogeneous crystal nucleation and agglomeration.(16) antioxidant administration may prevent crystal nucleation and retention.(17) studies have shown polygonum aviculare l. contains alkaloids, saponins(4) and large quantities of phenolic and flavonoid compounds.(5) phenolic and flavonoid compounds have antioxidant properties.(18) moreover, saponins have antioxidant, antifungal, and antiviral characteristics, and are hypocholesterolemic. (19) research has indicated saponins have protective effects against oxidative damage and renal interstitial fibrosis,(20) and play an important role in preventing the formation of kidney stones.(21) therefore, polygonum aviculare l. prevents heterogeneous nucleation and crystal accumulation probably because it contains saponins and has antioxidant effects. medicinal herbs are not only cost-effective, but also contain chemical compositions that can be served as starting points for treatment of nephrolithiasis. despite of these, medicinal herbs are not without disadvantages. like synthetic drugs, they may have negative side effects. besides, they may interact with other herbs or drugs. there is a limited data about safety, efficacy and compositions of extracts. therefore, further studies need to investigate their efficacy, pharmacological qualities, safety and also drug interactions. additionally, most of research on urolithiasis carried out in rat models because of its similarities to human in caox deposition, location of stones, and also cortex to medulla volume ratio.(22) in spite of this, there are some differences between rat and human kidney including: size, weight, number of papilla and nephrons.(22) thus, these studies are not still applicable for treatment of urolithiasis in human. in this regard, further scientific assessment and systematic reviews are required to relate animal models to human clinical trial. conclusions in this research, aqueous extract of polygonum aviculare l. at doses of 100 and 400 mg/kg significantly reduced accumulation of calcium oxalate crystals and kidney tissue damage in the two prevention and therapeutic groups. there were no significant differences between the different doses and prevention and therfigure 1. photomicrographs of the rat kidney stained with h&e. a, c, d, e, g, i, k, m, o and q(x10). b, f, h, j, l, n, p and r (x40). (a & b) group i (normal control), (c-f) group ii (eg+ac), (g&h) group iii (sham 100mg/kg), (i&j) (sham 400mg/kg), (k&l) group v (preventive 100mg/kg), (m&n) group vi (preventive 400mg/ kg), (o&p) groupvii (curative 100mg/kg), (q&r) group viii (curative 400mg/kg). tubular stones (white arrows), tubulointerstitial damage (dilation, hyaline cast, tubular atrophy, interstitial inflammation and tubular cell necrosis) (black arrows). polygonum aviculare l. on urolithiasis saremi et al. apeutic groups. therefore, it seems aqueous extract of polygonum aviculare l. is effective in prevention and treatment of kidney stones in rat models because it contains compounds such as saponins and phenolic and flavonoid substances, and has fat-reducing, anti-oxidant, antibacterial and diuretic effects, although more research is needed to determine the mechanisms related to these effects. acknowledgement we would like to express our gratitude to the research deputy of jahrom university of medical sciences for the financial support we received to carry out this research (grant no. 649/d/p). conflict of interest the authors report tehat they have no conflict of interest. references 1. stoller ml. urinary stone disease. in: tanagho ea, mcaninch jw, editors. smith's general urology. 17th ed. new york: mcgraw-hil; 2008. p.246-77.. 2. safarinejad mr. adult urolithiasis in a population-based study in iran: prevalence, incidence, and associated risk factors. urol res. 2007;35:73--82. 3. kianmehr h. tashkhise giyahaneh darooii [recognition of medical herbs]. tehran: aiij publications; 2008. [in persian] 4. salama hm, marraiki n. antimicrobial activity and phytochemical analyses of polygonum aviculare l.(polygonaceae), naturally growing in egypt. saudi j biol sci. 2010;17:57-63. 5. hsu c-y. antioxidant activity of extract from polygonum aviculare l. biol res. 2006;39:281-8. 6. yin mh, kang dg, choi dh, kwon to, lee hs. screening of vasorelaxant activity of some medicinal plants used in oriental medicines. j ethnopharmacol. 2005;99:113-7. 7. sung y-y, yoon t, yang w-k, kim sj, kim d-s, kim hk. the antiobesity effect of polygonum aviculare l. ethanol extract in high-fat diet-induced obese mice. evid based complement alternat med. 2013;2013. 8. haeng ps, sung y, jin nk, kyoung kh. antiatherosclerotic effects of polygonum aviculare l. ethanol extract in apoe knock-out mice fed a western diet mediated via the mapk pathway. j ethnopharmacol. 2014;151:1109. 9. khalili m, jalali mr, mirzaei-azandaryani m. effect of hydroalcoholic extract of hypericum perforatum l. leaves on ethylene glycol-induced kidney calculi in rats. urol j. 2012;9:472. 10. hadjzadeh m-a-r, khoei a, hadjzadeh z, parizady m. ethanolic extract of nigella sativa l seeds on ethylene glycol-induced kidney calculi in rats. urol j. 2009;4:86-90. 11. cho hj, bae wj, kim sj, et al. the inhibitory effect of an ethanol extract of the spores of lygodium japonicum on ethylene glycolinduced kidney calculi in rats. urolithiasis. 2014;42:309-15. 12. saremi j, kargar-jahromi h, pourahmadi m. effect of malva neglecta wallr on ethylene glycol induced kidney stones. urol j. 2015;12:2387--90. 13. basavaraj dr, biyani cs, browning aj, cartledge jj. the role of urinary kidney stone inhibitors and promoters in the pathogenesis of calcium containing renal stones. eau-ebu update series. 2007;5:126-36. 14. schmiedl a, schwille p, bonucci e, erben r, grayczyk a, sharma v. nephrocalcinosis and hyperlipidemia in rats fed a cholesterol-and fat-rich diet: association with hyperoxaluria, altered kidney and bone minerals, and renal tissue phospholipid–calcium interaction. urol res. 2000;28:404-15. 15. kajander eo, ciftcioglu n, aho k, garciacuerpo e. characteristics of nanobacteria and their possible role in stone formation. urol res. 2003;31:47-54. 16. khan s, thamilselvan s. nephrolithiasis: a consequence of renal epithelial cell exposure to oxalate and calcium oxalate crystals. mol urol. 1999;4:305-12. 17. thamilselvan s, khan sr, menon m. oxalate and calcium oxalate mediated free radical toxicity in renal epithelial cells: effect of antioxidants. urol res. 2003;31:3-9. 18. rice-evans ca, miller nj, paganga g. structure-antioxidant activity relationships of flavonoids and phenolic acids. free radic biol med. 1996;20:933-56. 19. franchis g, kerem z, makkar h, becker k. the biological action of saponins in animal systems. br j nutr. 2002;88:587-605. 20. xie x-s, liu h-c, yang m, zuo c, deng y, fan j-m. ginsenoside rb1, a panoxadiol saponin against oxidative damage and renal interstitial fibrosis in rats with unilateral ureteral obstruction. chin j integr med. 2009;15:133-40. 21. patel pk, patel ma, vyas ba, shah dr, gandhi tr. antiurolithiatic activity of saponin rich fraction from the fruits of solanum xanthocarpum schrad. & wendl.(solanaceae) against ethylene glycol induced urolithiasis in rats. j ethnopharmacol.. 2012;144:160-70. 22. khan s. animal models of kidney stone formation: an analysis. world j urol. 1997;15:236-43. polygonum aviculare l. on urolithiasis saremi et al. endourology and stone diseases 4 urological oncology prognostic value of platelet counts in patients with metastatic prostate cancer treated with endocrine therapy kenji shimodaira1, jun nakashima1,2,3, yoshihiro nakagami1, yosuke hirasawa1, takeshi hashimoto1, naoya satake1, tatsuo gondo1, kazunori namiki1, makoto ohori1, yoshio ohno1 purpose: the endocrine therapy is effective for patients with advanced prostate cancer, but the disease eventually becomes refractory to treatment. the aim of this study was to investigate prognostic factors and to develop a risk stratification model for survival in patients with advanced prostate cancer undergoing endocrine therapy. materials and methods: this study included 197 patients with stage iv prostate cancer who were treated with endocrine therapy as primary treatment at tokyo medical university, tokyo, japan, between january 1999 and november 2012. prognostic values including baseline clinical laboratory values before endocrine therapy for stage iv prostate cancer were examined. patients (n = 30) who were not followed or for whom data were unavailable or who were treated with radiotherapy were excluded from the study. excluding these patients, we retrospectively analyzed 167 patients who were treated with endocrine therapy as the primary treatment. disease-specific survival (dss) was evaluated using the kaplan-meier method, and prognostic factors were identified using the cox proportional hazard model analysis. results: in univariate analyses, patients with a performance status (ps) ≥ 2, platelet count ≥ 3.0× 105 µ/l, prostate specific antigen (psa) > 50 ng/ml, alkaline phosphatase (alp) > 350 u/l, lactate dehydrogenase (ldh) > 240 iu/l, and gleason score (gs) ≥ 8, hemoglobin (hb) < 12 g/dl, extent of disease (eod) ≥ 3 and poorly differentiated adenocarcinoma showed significantly lower dss than their respective counterparts. neutrophil-to-lymphocyte ratio (nlr), platelet-to-lymphocyte ratio (plr) and white blood cell (wbc) count were not significantly associated with dss. in a multivariate cox proportional hazard model, ps and platelet count were independent prognostic factors. based on the hazard rate (hr) calculated by the following formula: hr = exp (0.82 × ps + 1.38 × platelet count) patients were stratified into 3 risk groups. the differences in dss rates among the 3 groups were statistically significant. conclusion: these results suggest that ps and platelet count are independent prognostic factors and that a combination of these factors can be used to stratify metastatic prostate cancer patients treated with endocrine therapy according to their dss risk. keywords: advanced prostate cancer; endocrine therapy; platelet counts; prognostic value; risk stratification introduction although, endocrine therapy is initially effective for patients with advanced prostate cancer, some of them have an unfavorable prognosis; these patients need innovative therapeutic strategies to improve their prognosis, and they may be candidates for participation in clinical trials of novel therapies. therefore, it is important to investigate prognostic factors and to develop a risk prediction model for survival in patients with advanced prostate cancer undergoing endocrine therapy in order to identify patients with a poor prognosis. it has been reported that alkaline phosphatase (alp), gleason score (gs), hemoglobin (hb) and extent of disease (eod) are associated with prognosis in patients with advanced prostate cancer(1,2) in univariate analyses. in multivariate analyses, alp and performance status (ps)(3), platelet-to-lymphocyte ratio (plr)(4) and neu1department of urology, tokyo medical university, tokyo, japan. 2department of urology, sanno hospital, tokyo, japan. 3international university of health and welfare, clinical medicine research center, tokyo, japan. *correspondence:department of urology, tokyo medical university 6-7-1 nishishinjuku, shinjuku-ku, tokyo 160-0023, japan. tel: +81-3-3342-6111. fax: +81-3-3344-4813. e-mail: kenji-shimo@tune.ocn.ne.jp. received august 2018 & accepted february 2019 trophil-to-lymphocyte ratio (nlr)(5), were shown to be prognostic factors. soloway et al. suggested that men with metastatic prostate cancer enrolled in trials designed to evaluate the impact of treatment on survival should be stratified based upon their eod, as determined using a bone scan. their analysis also indicates that patients in the eod iv (super bone scan or similar super bone scan; equal to or more than 75% of total bone) category have particularly poor prognosis and may be candidates for alternative treatments. however, these studies did not develop tools for predicting prognosis, such as a risk stratification model, and it may therefore be difficult to accurately predict the prognosis.(1) few reports have attempted to set up a risk stratification model for metastatic prostate cancer. although eod, alp, gs, hb, and ps are considered to be prognostic factors for survival, the oncologic significance of other potentially relevant variables such as peripheral urology journal/vol 17 no. 1/ january-february 2020/ pp. 36-41. [doi: 10.22037/uj.v0i0.4735] vol 17 no 01 january-february 2020 37 blood cell counts including platelet counts has not been fully evaluated. platelet count has been reported to be a significant prognostic factor in renal tumors, malignant mesothelioma , diffuse large b cell lymphoma, upper tract urothelial carcinoma, epithelial ovarian cancer.(611) in several studies, platelets play a significant part in prostate cancer progression.(12) however, to our knowledge, no report to date has investigated the relationship between platelet count and prognosis and developed a risk stratification model using platelet count. in the present study, we sought to investigate prognostic factors including peripheral blood cell counts and to develop a risk stratification model for survival in patients with advanced prostate cancer undergoing endocrine therapy. materials and methods this study was conducted at tokyo medical university. the medical records of 197 patients who were treated with endocrine therapy as primary treatment at tokyo medical university, tokyo, japan, between january 1999 and november 2012 were retrospectively reviewed after the study was approved by our facility’s ethics committee. prognostic values including baseline clinical laboratory values before endocrine therapy for stage iv prostate cancer were examined. patients (n = 30) who were not followed or for whom data were unavailable or who were treated with radiotherapy were excluded from the study. excluding these patients, we retrospectively analyzed 167 patients who were treated with endocrine therapy as the primary treatment (table1). endocrine therapy was lhrh analogue monotherapy or lhrh analogue with first-generation antiandrogen. baseline demographic, clinical, and laboratory data were collected retrospectively for all patients. prostate cancer was diagnosed by using needle biopsy. the indication for a needle biopsy included an elevation of serum psa level, a nodule felt on a digital rectal examination, and the existence of a low echoic lesion on transrectal ultrasonography (trus). needle biopsy of the prostate was performed under trus guidance. blood biochemistry was measured before the start of hormone therapy. primary prostate cancer was evaluated by rectal examination, magnetic resonance imaging (mri), and trus. lymph node metastasis and distant metastasis were evaluated using computed tomography (ct) or mri. the eod, as determined using a bone scan was classified according to the method reported by soloway et al. (1) ps was divided according to ecog ps. (13) we evaluated clinical and laboratory data before the start of hormone therapy retrospectively. baseline clinical data showed tnm stage, presence of bone metastasis, presence of positive lymph node, gs of biopsy on diagnosing prostate cancer, and histological differentiation. baseline clinical laboratory data including platelet, prostate specific antigen (psa), alp, lactate dehydrogenase (ldh), hb, white blood cell (wbc), nlr, and plr before endocrine therapy were collected retrospectively for all patients. disease-specific survival (dss) defined the percentage of patients who have not died due to a specific disease at a certain point in the research participants or the treated group. we used dss curves were constructed using the kaplan-meier method. univariate analysis was performed using the log-rank test, and multivariate analysis was performed using the cox regression analysis. to develop the risk stratification model, the optimal cut-off point was selected as the range of the 10th percentile to the 90th percentile for the distribution. continuous variables were categorized by setting up effectual cutoff values(14). we categorized effective cut-off values as described by atzpodien j et al. using the minimum p value approach, the selected cut-off value for all data was analyzed as a dichotomous variable. we identified significant prognostic factors in the multivariate analysis using a stepwise selection procedure. therefore, all possible prognostic factors were evaluated in the multiprognostic value with metastatic prostate cancer-shimodaira et al. urological oncology 353 table1. demographic and clinical characteristics characteristics number of patients (%) age, year; mean ± sd (range) 74.838 ± 0.629 (52-92) t stage t1 19 (11.4) t2 63 (37.7) t3 67 (40.1) t4 18 (10.8) n stage n0 85 (50.9) n1 82 (49.1) m stage m0 32 (19.2) m1 135 (80.8) tnm stage tanyn1m0 32 (19.2) tanyn0m1 85 (50.9) tanyn1m1 50 (29.9) bone metastasis (+/-) + 135 (80.8) 32 (19.2) lymph node (+/-) + 99 (59.3) 68 (40.7) performance status, mean (range) 0.898 ± 0.089 (0-4) ≥ 2 49 (29.3) ≤1 118 (70.7) platelet, mean (range) (241.329 ± 6.634) × 10³ (6.168.2× 10³) ≥ 3.0× 105 /µl 32 (19.2) < 3.0× 105 /µl 135 (80.8) psa, mean (range) 849.941 ± 185.612 (4.9-18910.0) ≥ 50 ng/ml 109 (65.3) < 50 ng/ml 58 (34.7) alkaline phosphatase, mean (range) 589.874 ± 74.888 (106-7467) > 350 u/l 62 (37.1) ≤ 350 u/l 105 (62.9) lactate dehydrogenase, mean (range) 252.698 ± 48.431 (86-8248) > 240 iu/l 24 (14.4) ≤ 240 iu/l 143 (85.6) gleason score, mean (range) 8.281 ± 0.077 (6-10) ≥ 8 132 (79.0) ≤ 7 35 (21.0) hemoglobin, mean (range) 13.286 ± 0.146 (7.1-19.2) ≥12 133 (79.6) < 12 34 (20.4) white blood cell (wbc), mean (range) (6.52 ± 1.84) × 10³ (2.8-12.6)× 10³ > 7.5 × 10³ /µl 134 (80.2) ≤ 7.5× 10³ /µl 33 (19.8) neutrophil-to-lymphocyte ratio (nlr) 2.757 ± 2.549 (0.883-27.059) > 3.5 34 (20.4) ≤ 3.5 133 (79.6) platelet-to-lymphocyte ratio (plr) 150 ± 73 (53-437) > 150 64 (38.3) ≤ 150 103 (61.7) extent of disease (eod) 1.653 ± 1.241 (0-4) ≥ 3 43 (25.7) ≤ 2 124 (74.3) histological differentiation poorly 80 (47.9) well-moderately 87 (52.1) abbreviations: psa: prostate specific antigen variate analysis and a stepwise selection procedure was used. we calculated hazard rate (hr) of prognostic factors for dss and developed a risk stratification model for survival by using the significant prognostic factors in patients with advanced prostate cancer treated with endocrine therapy as reported previously.(15,16) in all analyses, p < 0.05 was considered statistically significant. analyses were performed with statview. results the mean follow-up period was 54.3 months (range, table 2. result of univariate and multivariate analyses parameter univariate multivariate p value coefficient hazard ratio 95%ci p value ps (≥ 2 vs ≤1) 0.0129 0.82 2.27 1.36-4.21 0.0045 plt (≥ 3.0× 105 vs < 3.0× 105) < 0.0001 1.38 3.97 1.96-6.08 < 0.0001 psa (> 50 vs ≤ 50) 0.0088 alp (> 350 vs ≤ 350) 0.0486 ldh (> 240 vs ≤ 240) 0.0082 gs (≥ 8 vs ≤ 7) 0.0141 hb (≥ 12 vs < 12) 0.0179 eod (≥ 3 vs ≤ 2) 0.0102 poorly vs well or moderately 0.0294 nlr (> 3.5 vs ≤ 3.5) 0.3772 plr (> 150 vs ≤ 150) 0.0502 wbc (> 7500 vs ≤ 7500) 0.713 abbreviations: ps: performance status, plt: platelet, psa: prostate specific antigen, alp: alkaline phosphatase, ldh: lactate dehydrogenase, gs: gleason score, hb: hemoglobin, eod: extent of disease, nlr: neutrophil-to-lymphocyte ratio, plr: platelet-to-lymphocyte ratio, wbc: white blood cell figure 1. 1-a) performance status (ps) and disease-specific survival, 1-b) platelet (plt) and disease-specific survival, 1-c) prostate-specific antigen (psa) and disease-specific survival, 1-d) alkaline phosphatase (alp) and disease-specific survival, 1-e) lactate dehydrogenase (ldh) and disease-specific survival, 1-f) gleason score (gs) and disease-specific survival, 1-g) hemoglobin (hb) and disease-specific survival, 1-h) poorly differentiated adenocarcinoma and disease-specific survival, 1-i) extent of disease (eod) and disease-specific survival prognostic value with metastatic prostate cancer-shimodaira et al. urological oncology 38 vol 17 no 01 january-february 2020 39 0–192 months). the mean survival time was 65.0 months. the mean age was 74.8 years (range, 52– 92 years). the mean initial psa was 849.9 ng/ml (range, 4.9–18910.0 ng/ml). t stage was t1 in 19 cases (11.4%), t2 in 63 cases (37.7%), t3 in 67 cases (40.1%), and t4 in 18 cases (10.8%); n stage was n0 in 85 (50.9%) cases, n1 in 82 cases (49.1%); and m stage was m0 in 32 cases (19.2%) and m1 in 135 cases (80.8%). t any n1m0 was 32 cases (19.2%), t any n0m1 was 85 cases (50.9%), and t any n1m1 was 50 cases (29.9%). lhrh analogue monotherapy was performed in 9 cases versus an lhrh analogue with first-generation anti-androgen in 158 cases. in univariate analyses, patients with ps ≥ 2, platelet count ≥ 3.0 × 105 /µl, psa > 50 ng/ml, alp > 350 u/l, ldh > 240 iu/l, and gs ≥ 8, hemoglobin < 12 g/ dl, eod ≥ 3 and poorly differentiated adenocarcinoma showed significantly lower dss rates than their respective counterparts (figure 1). nlr, plr and wbc count were not significantly associated with dss. in a multivariate cox proportional hazard model, ps (hr = 2.27, 95% confidence interval [ci]: 1.36 –4.21, p = 0.0045) and platelet count (hr = 3.97, 95%ci: 1.96 –6.08, p < 0.0001) were independent prognostic factors (table 2). we calculated the hr for dss by using the following formula: hr = exp (0.82 × ps + 1.38 × platelet count). in this equation, ps was assigned a value of 1 or 0 for ≥ 2 or ≤ 1, respectively. platelet count was assigned a value of 1 or 0 for ≥ 3.0 × 105 /µl or < 3.0 × 105 /µl, respectively. based on their ps and platelet count, patients were stratified into 3 risk groups: low-risk (hr = 1, ps ≤ 1 and platelet count < 3.0 × 105 µ/l), intermediate-risk (1 < hr ≤ 5, ps ≥ 2 and platelet count < 3.0 × 105 /µl or ps ≤ 1 and platelet count ≥ 3.0 × 105 /µl), and high-risk (hr > 5, ps ≥ 2 and platelet count ≥ 3.0 × 105 /µl). the differences in dss rates among the 3 groups were statistically significant (figure 2). discussion in previous reports, alp, gs, hb and eod were related to prognosis in patients with advanced prostate cancer(1,7) in univariate analyses. in the present study, in univariate analyses, ps, platelet count, psa, alp, ldh levels, and gs were significantly associated with dss rates, and in a multivariate cox proportional hazard model, ps and platelet count were independent prognostic factors. interestingly, platelet count was a prognostic factor in patients with metastatic prostate cancer treated with endocrine therapy. leblanc et al. revealed that patients with bone metastases (the most frequent in prostate cancer) have higher platelet count and bad prognosis.(17) in other malignancies, platelet count is also a prognostic factor. bensalah et al. reported a correlation between platelet count and renal tumor characteristics, and evaluated the potential prognostic value of thrombocytosis in localized and metastatic tumors. the significance of the prognostic factors associated with survival was retained in multivariate analysis, suggesting that tnm stage, fuhrman grade, tumor size, eastern cooperative oncology group score, and platelet count are independent prognostic factors in renal cell carcinoma.(6) zhou et al. reported that high pretreatment platelet count resulted in poor overall survival in malignant mesothelioma.(7) ochi y et al. reported that platelet count and albumin levels are useful prognostic factors with diffuse large b cell lymphoma.(8) georgios et al. assessed the impact of perioperative platelet count on recurrence-free survival after radical nephroureterectomy for upper tract urothelial carcinoma. in a comparison between patients with normal preoperative platelet counts and those with elevated platelet counts, the 5-year recurrence-free survival was significantly different for upper tract urothelial carcinoma.(9) it was also reported that a group of patients with epithelial ovarian cancer and higher platelet counts had a significantly shorter median time to disease progression than a group of patients with normal platelet counts;(10) platelet counts were related to platelet derived growth factor, which may be the growth factor driving the pathogenesis of epithelial ovarian cancer. (11) platelet-derived growth factors (pdgfs) and their receptors (pdgfrs) are key regulations of mesenchymal cells in the tumor microenvironment and have been associated with unfavorable outcomes in several cancers. a high expression of pdgfr-β, which was a specific manner with tyrosine kinase receptors of pdgfr family, is associated with biochemical recurrence in prostate cancer after radical prostatectomy. (18) pdgf-bb reportedly shows a significant predictive ability for prostate cancer.(19) it was also reported that thrombocytosis was associated with prognosis in patients with renal cell carcinoma.(20,21) pardo et al. reported that higher platelet counts were associated with a poorer prognosis for those patients with hypopharyngeal cancer.(22) platelet count has also been reported to predict postoperative survival in patients with gastric cancer.(23) likewise, in the present study, patients with higher platelet counts showed significantly lower dss rates than did those with lower platelet counts. in the past, it is revealed that platelets were related to prostate cancer progression.(12) in this study, ps and platelet count were independent prognostic factors in patients with metastatic prostate cancer. recently, it has been reported that circulating tumor cells (ctc) counts have prognostic value in patients with castrafigure 2. disease-specific survival rates according to 3 risk groups. using two statistically significant prognostic factors (plt and ps), patients were stratified into 3 risk groups: a low-risk group, consisting of patients with neither of two unfavorable factors; an intermediate-risk group, consisting of patients with one of two unfavorable factors; and a high risk-group, consisting of patients with two of two unfavorable factors. prognostic value with metastatic prostate cancer-shimodaira et al. tion-resistant prostate cancer (crpc).(24) future studies are expected to evaluate novel possible prognostic factors including ctc. we have calculated the hr of ps and platelet count and have successfully stratified patients with metastatic prostate cancer into 3 groups, using these prognostic factors based on the hr. the differences in dss rates among the 3 groups were statistically significant. no reports to date have attempted to set up a risk stratification model using platelet count for metastatic prostate cancer. to our knowledge, the present study may be the first to establish a risk stratification model using ps and platelet count. in recent years, it has been reported that abiraterone acetate(25,26) and enzalutamide(27) significantly prolong overall survival in patients with advanced prostate cancer. our stratification model may facilitate more accurate predictions of unfavorable prognosis and identify patients who may be candidates for clinical trials of new strategies such as early induction of novel chemotherapeutics and hormonal agents that may eventually improve patients’ dss. we have demonstrated that platelet count is a novel prognostic factor and should be taken into consideration along with ps in the management of metastatic prostate cancer. although this study provides important insights into the prognosis of patients with metastatic prostate cancer, it has several limitations. first, since it was a retrospective analysis of data collected from a single institution; the number of included cases was relatively small. second, it is difficult to evaluate new strategies. it is not well known what new therapies are effective for metastatic prostate cancer patients with poor ps and a high platelet count treated with endocrine therapy at the primary treatment. the sequencing of metastatic castration-resistant prostate cancer (mcrpc) therapies was recently presented.(28) furthermore, it is necessary to develop a novel treatment for patients with intermediateor highrisk patients on the risk stratification to improve their prognosis. further prospective studies are expected to validate externally the significance of our stratification model of dss in patients with metastatic prostate cancer treated with endocrine therapy. conclusions these results suggest that ps and platelet count are independent prognostic factors and that a combination of these factors can be used to stratify dss risks in patients with metastatic prostate cancer treated with endocrine therapy. acknowledgement this study was supported by tokyo medical university in 2018. conflict on interest the authors report no conflict of interest. references 1. soloway ms, hardeman sw, hickey d,et al. stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. cancer. 1988; 61: 195-202. 2. l.j. emrich, r.l. priore, g.p. murphy, et al. prognostic factors in patients with advanced stage prostate cancer. cancer res 1985; 45: 5173-9. 3. tomioka a, tanaka n, yoshikawa m, et al. risk factors of psa progression and overall survival in patients with localized and locally advanced prostate cancer treated with primary androgen deprivation therapy. bmc cancer 2015; 15: 420. 4. wang y, xu f, pan j, et al. platelet to lymphocyte ratio as an independent prognostic indicator for prostate cancer patients receiving androgen deprivation therapy. bmc cancer 2016; 16: 329. 5. templeton aj, pezaro c, omlin a, et al. simple prognostic score for metastatic castrationresistant prostate cancer with incorporation of neutrophil-to-lymphocyte ratio. cancer 2014; 120: 3346-52. 6. bensalah k, leray e, fergelot p, et al. prognostic value of thrombocytosis in renal cell carcinoma. j urol 2006; 175: 859-63. 7. zhuo y, lin l, zhang m, et al. pretreatment thrombocytosis as a significant prognostic factor in malignant mesothelioma: a metaanalysis. platelets 2016; 16: 1-7. 8. ochi y, kazuma y, hiramoto n, et al. utility of a simple prognostic stratification based on platelet counts and serum albumin levels in elderly patients with diffuse large b cell lymphoma. ann hematol 2017; 96: 1-8. 9. georgios g, hans-martin f, fahmy h, et al. prognostic relevance of postoperative platelet count in upper tract urothelial carcinoma after radical nephroureterectomy. eur j cancer 2014; 50: 2583-91. 10. stone rl, nick am, mcneish, et al. paraneoplastic thrombocytosis in ovarian cancer. n engl j med 2012; 366: 610-8. 11. dabrow mb, francesco mr., mc breaty fx, et al. the effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium. gynecol oncol 1998; 71: 29-37. 12. reeves f, sapre n, corcoran n et al. tumor vascularity in prostate cancer: an update on circulating endothelial cells and platelets as noninvasive biomarkers. biomark med. 2013; 7: 879-91. 13. oken, m.m, creech, r.h, tormey, d.c, et al. toxicity and response criteria of the eastern cooperative oncology group. am j clin oncol. 1982; 5:649-55. 14. atzpodien j, royston p, wandert t, et al. metastatic renal carcinoma comprehensive prognostic system. br j cancer 2003; 88: 34853. 15. mizuno r, nakashima j, mukai m, et al. tumour length of the largest focus predicts prostate-specific antigen-based recurrence after radical prostatectomy in clinically localized prostate cancer. bju 2009; 104: prognostic value with metastatic prostate cancer-shimodaira et al. urological oncology 40 vol 17 no 01 january-february 2020 41 1215-8. 16. ohno y, nakashima j, ohori m, et al. pretreatment neutrophil-to-lymphocyte ratio as an independent predictor of recurrence in patients with nonmetastatic renal cell carcinoma. j urol 2010; 184: 873-8. 17. leblanc r, peyruchaud o. the role of platelets and megakaryocytes in bone metastasis. j bone oncol 2016; 5: 109-11. 18. nordby y, richardsen e, rakaee m, et al. high expression of pdgf-β in prostate cancer stroma is independently associated with clinical and biochemical prostate cancer recurrence. sci rep 2017; 7: 43378. 19. skarmoutsos a, skarmoutsos i, katafigiotis i, et al. detecting novel urine biomarkers for the early diagnosis of prostate cancer: platelet derived growth factor-bb as a possible new target. curr urol 2018; 1: 13-9. 20. jae y, young h, phil h. clinical significance of preoperative thrombocytosis in patients who underwent radical nephrectomy for nonmetastatic renal cell carcinoma. original article-urological oncology 2016; 57: 324-9. 21. katsuki i, kei k, shunichi s, et al. prognostic significance of thrombocytosis in renal cell carcinoma patients. international journal of urology 2004; 11: 364-7. 22. parado l, valero c, lopez m, et al. the prognostic value of pretreatment platelet count in patients with head and neck squamous cell carcinoma. auris nasus larynx 2017; 44 : 313-8. 23. ishizuka m, oyama y, abe a, et al. combination of platelet count and neutrophil to lymphocyte ratio is useful predictor of postoperative survival in patients undergoing surgery for gastric cancer. j surg oncol 2014; 110: 935-41. 24. zheng y, zheng c, wu j, et al. prognostic value of circulating tumor cells in castration resistant prostate cancer: a meta-analysis. urol j 2016; 13: 2881-8. 25. fizazi k, scher hi, molina a, et al. abiraterone acetate for treatment of metastatic castrationresistant prostate cancer: final overall survival analysis of the cou-aa-301 randomised, double-blind, placebo-controlled phase 3 study. lancet oncol 2012; 13: 983-92. 26. ryan, cj, smith mr, fizazi k, et al. abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapynaive men with metastatic castration-resistant prostate cancer (cou-aa-302): final overall survival analysis of a randomised, doubleblind, placebo-controlled phase 3 study. lancet oncol 2015; 16: 152-60. 27. beer tm, andrew ja, dana er, et al. enzalutamide in metastatic prostate cancer before chemotherapy. n engl j med 2014; 371: 424-33. prognostic value with metastatic prostate cancer-shimodaira et al. case report robotic excision of the vagina in a 46 xx dsd male patient. first pediatric report giovanni torino1, ottavio adorisio2*, giovanni cobellis3, francesca mariscoli3, antonio zaccara2 1pediatric urology unit, "santobono-pausilipon" children's hospital, naples, italy. 2department of pediatric surgery, pediatric surgery unit, bambino gesù children’s hospital, research institute, palidoro, rome, italy. 3pediatric surgery and urology unit, “g. salesi” children’s hospital, marche polytechnic university, ancona, italy. *correspondence: department of pediatric surgery children’s hospital “bambino gesù children’s hospital, via della torre di palidoro 50, palidoro, rome, italy received september 2020 & accepted april 2021 the disorders of sex differentiation (dsd) represent a wide range of congenital anomalies of the genitalia. surgical treatment of these cases may become a challenge. we present a case of a 16-year-old boy with 46 xx dsd, sry negative, presented with persistent dribbling incontinence, recurrent uti, and perineal pain. past medical history included right orchiectomy, laparoscopic excision of uterus, fallopian tubes, and left streak gonad at another institution at the age of 2 years. the native vagina was left in place. vcug confirmed the presence of the residual vagina (8 cm in maximum length), connected with the bulbar urethra. robotic-assisted laparoscopic excision of the vagina was performed with satisfying short and long-term results. keywords: robotic surgery; dsd; uti; pelvic surgery; minimally invasive surgery introduction robotic removal of the vagina in a pediatric male patient has not yet been reported to date. we report a case of a 16-year-old boy affected by 46 xx dsd with a residual vagina removed using the robotic approach. case report a16-year-old boy with 46 xx dsd, sry negative, presented with persistent dribbling incontinence, recurrent febrile uti, and perineal pain. he was raised as a male by his parents. his past medical history included: right inguinal orchiectomy for ovotestes, laparoscopic excision of the uterus, fallopian tubes and intra-abdominal left streak gonad at another institution at the age of 2 years (the native vagina was left in place), two-stage repair of scrotal figure 1. preoperative vcug showing the vagina (8 cm), filling up during micturition. urology journal/vol 18 no. 4/ july-august 2021/ pp. 466-468. [doi: 10.22037/uj.v18i.6470] hypospadias when he was 3-year-old, bilateral mastectomy at the age of 13 years. because of the persistence of recurrent febrile uti and perineal pain, a voiding cystourethrogram (vcug) was performed, confirming the presence of a residual vagina (8 cm maximum length) (figure 1). the decision to perform a vaginectomy was taken. the patient was placed in a combined lithotomy/supine position to perform simultaneously the robotic surgery and vaginoscopy. the preliminary cystoscopy showed a normal urethra, without stenosis, with the vagina opening at the level of the bulbar urethra. the 12-mm optical port was inserted via the umbilicus, and two other 8-mm robotic working ports were placed on the para-rectal lines and at the level of the transverse umbilical line. the bladder was suspended to the anterior abdominal. the light of the cystoscope, into the vagina, was used as guidance to separate the vagina from the surrounding tissues (figure 2a-b). dissection was performed between the vagina and the surrounding tissues. suspension of the vagina, good magnification ensured by the robotic approach, and the trendelenburg position allowed us to avoid injuries to the sacral plexus. the vagina was transected as close as possible to the urethra leaving in place a little sidewall of the vagina near the urethra. this opening was closed with an absorbable stitch, avoiding urethral strictures (video 1). the specimen was then removed from the optical port. the pathologic examination confirmed the removal of the vagina. the operative time was 240 minutes. the post-operative period was uneventful. the patient was discharged 7 days after the procedure the foley catheter was removed on the 20th post-operative day. a post-operative vcug showed neither significant remnants at the level of the bulbar urethra or leakage with normal bladder emptying (figure 3). after a two-year follow-up, the patient shows a complete resolution of the symptoms. discussion surgical removal of a residual vagina may be a real challenge in the pediatric population due to the proximity to the pelvic nerves, rectum, ureters, bladder, rectal sphincters, and because of the narrow surgical space(1,2,3). there is a gaining consensus about robotic surgery feasibility and efficacy in the pediatric population due to an increasing number of appreciable surgical results reported in the literature in a wide range of congenital anomalies(1). in the case of pelvic anomalies, open surgery often needs a combined approach with two incisions at the level of the abdomen and perineum respectively. the laparoscopic approach, despite shorter hospitalization and good control of post-operative pain, rarely allows safe access to the perineal space (4,5). the minimally invasive approach, based on robotic surgery, has been recommended in several reports(4,6,7) because of the clearer view of the deep pelvic structures. robotic-assisted surgery has been successfully used to obtain a complete removal of a large utricle in a pediatric patient who had previously undergone a laparoscopic procedure(8). in the present case, the previcase report 413 robotic excision of the vagina in a child-torino et al. figure 2 a-b. separation of the vagina from the surrounding structures using the light of the cystoscope as guidance. figure 3. post-operative vcug showing the removal of the vagina with a little stump close to the urethra. case report 467 vol 18 no 4 july-august 2021 138 ous laparoscopic approach did not allow the complete removal of the vagina. for this reason, we opted for robotic-assisted laparoscopy in the redo procedure to combine the advantages of laparoscopy with the improved three-dimensional (3d) visualization associated with high instruments dexterity(9). this technique has been previously used in transgender adults(10). to our knowledge, no cases of robot-assisted excision of the residual vagina in a pediatric dsd male patient has been described in the literature to date. in conclusion, because of the excellent magnification, the high dexterity ensured by robotic instruments, the low risk of iatrogenic lesions, the short hospital stay and the low postoperative pain, robotic-assisted surgery should be considered also in pediatric patients. conflict of interest the authors declare no conflict of interest. references 1. goruppi i, avolio l, romano p, raffaele a, pelizzo g. robotic-assisted surgery for excision of an enlarged prostatic utricle. int j surg case rep. 2015;10:94-6. 2. alqahtani a, albassam a, zamakhshary et al. robot-assisted pediatric surgery: how far can we go? world j surg, 2010;34:975-8. 3. matthews ca. applications of robotic surgery in gynecology. j womens health (larchmt), 2010;19.863-7. 4. onal b, diamond da, retik ab, cendrom m, nguyen ht. robot-assisted laparoscopic excision of symptomatica retrovescical cyst in boys and young adults. j urol. 2011;186:23722378. 5. estrada cr, passerotti cc. robotic surgery in pediatric urology. arch. esp. urol. 2007;60:471-479. 6. benmohamed b, chaker k, obringer l et al. duplicated collecting system with ectopic prostatic implantation: therapeutic conservative robot assisted approach, about a case report. urol case rep. 2019 nov 6;30. 7. lima m, maffi m, di salvo n et al. robotic removal of müllerian duct remnants in pediatric patients: our experience and a review of the literature. pediatr med chir. 2018 may 30;40. 8. ferong k, waterschoot m, sinatti c et al. rare and special robotic surgery indications in the pediatric population: ectopic organs and differences of sexual development. world j urol. 2019 aug 22. 9. benmohamed b, chaker k, obringer l et al. duplicated collecting system with ectopic prostatic implantation: therapeutic conservative robot assisted approach, about a case report. urol case rep. 2019 nov 6;30. 10. cohen od, dy gw, nolan it, maffucci f, et al. robotic excision of vaginal remnant/ urethral diverticulum for relief of urinary symptoms following phalloplasty in transgender men. urology. 2020;136:158161. case report 212case report 428 vol 18 no 3 may-june 2021 468 robotic excision of the vagina in a child-torino et al. notice 296 urology journal vol 5 no 4 autumn 2008 notice of inadvertent duplicate publications the editors wish to draw attention to 3 articles published in the urology journal that have also appeared in other journals. as noticed in the summer 2007 issue (volume 4, number 3), a paper by nikoobakht and colleagues, “the relationship between lipid profile and erectile dysfunction,” which was published in volume 2, number 1, page 40 (winter 2005) of the journal, is similar to an article by the same authors and same title, published in the international journal of impotence research 2005;17:523-6. the other 2 papers are: “urinary tamm-horsfall protein and citrate: a casecontrol study of inhibitors and promoters of calcium stone formation” by pourmand and colleagues which is published in volume 2, number 2, page 79 (spring 2005) of this journal and also in the urology international 2006;76(2):163-8 and “the role of ureteroscopy in the treatment of renal transplantation complications” by basiri and colleagues which is published in volume 1, number 1, page 27 (winter 2004) of this journal and also in the scandinavian journal of urology and nephrology 2006;40(1):53-6. these inadvertent duplicate publications have occurred as a result of misinterpretation of local journals and a different group of readers when the urology journal had just been lunched in english; before march 2007, our journal was not being indexed in the international indexing systems and used to be considered as a local publication, with limited audience. it was also because the journal had just changed its language from persian to english. moreover, many authors were not familiar with the regulations of acceptable secondary publication. these cases were detected by the déjà vu website (www.spore.swmed. edu/dejavu/). the editors contacted the corresponding authors and it was confirmed that they had inadvertently duplicated their publication and the mistake was a result of a misunderstanding of the regulations by authors. the situation was also explained to the déjà vu team and they accepted to remove these papers from the category of duplicate publication. urol j. 2008;5:296. www.uj.unrc.ir erratum in volume 5, number 3 of the urology journal (summer 2008), the new section, urology for people was inaugurated. on page 212, an article was reviewed in this section entitled “avicenna and his modern scientific viewpoint.” however, the referred article’s publication had been postponed up to the current issue. therefore, the whole article on avicenna is published in this issue and not the summer issue. the editors regret this error in the past issue. endourology and stone disease simultaneous treatment of renal and upper ureteral stone and cysts with percutaneous nephrolithotomy and cyst laser intrarenal incision and drainage xiaohui hu†, kehua jiang†, hongbo chen*, shenliang zhu, chunxiong zhao purpose: to assess the feasibility and safety of percutaneous nephrolithotomy (pcnl) combined with cyst laser intrarenal incision and drainage in the management of renal and upper ureteral stones with ipsilateral renal cyst. materials and methods: between march 2011 and march 2016, 28 patients with ipsilateral renal cyst in renal and upper ureteral stones underwent pcnl combined with cyst laser intrarenal incision and drainage. the perioperative evaluated variables included operation time, cyst size after surgery, complications and stone-free rate(sfr). results: all patients successfully underwent the operation without conversion to open surgery. the mean operative time was 64.4±30.1 minutes; the mean hemoglobin reduction was 7.9±1.6 g/dl; the mean time to removal of nephrostomy tube and double j ureteral stent was 3.0±1.0 days, and 30.3±7.0 days; the mean hospital stay was 8.5±2.0 days. the sfr of all the patients was 89.3%(25/28), and no serious perioperative complications occurred. conclusion: pcnl combined with cyst laser intrarenal incision and drainage is a feasible and safe approach for treatment of renal and upper ureteral stones with ipsilateral renal cyst. keywords: percutaneous nephrolithotomy; laser intrarenal incision and drainage; renal stone; upper ureteral stone; renal cyst introduction kidney stone and renal cyst both are one of the most common diseases in urinary surgery, with high incidence and recurrence rates. at present, the therapies of kidney stone include extracorporeal shock wave lithotripsy (swl), percutaneous nephrolithotomy (pcnl) and flexible ureteroscopy and holium laser lithotripsy, among which pcnl is the main method in the treatment of the larger calculi(1-3). for renal cyst, the treatments mainly consist of ultrasound-guided puncture drainage and laparoscopic unroofing decompression, but puncture drainage easily causes relapse. with regard to a patients with both kidney stone and renal cysts which both need surgery, staging surgery is the general treatment but patients are faced with increased numbers and risks of surgeries(4). in recent years, some reports showed that flexible ureteroscopy with laser incision and drainage treatment of renal cyst unraveled a good curative effect, as well as percutaneous nephrolithotomy combined with unroofing decompression. but both their curative effect and safety need further evaluation. based on this situation, for patients in the urology department in whom the kidney stone was associated with renal cyst, the authors performed pcnl combined with cyst laser intrarenal incision and drainage at the same time, which achieved the goal of curing two diseases at the same time and relieving the suffering of the patients with multiple surgeries, and evaluated its efficacy and safety. † these authors contributed equally to this work. department of urology, the central hospital of enshi tujia and miao autonomous prefecture, enshi, hubei province, china. *correspondence: department of urology, the central hospital of enshi tujia and miao autonomous prefecture, enshi, hubei province, china. tel: 86-718-8263186. fax:86-718-8263186. e-mail: jkh_urol@163.com. received november 2016 & accepted june 2017 patients and methods study population from march 2011 to march 2016, a total of 28 patients-16 men and 12 womenwith renal and upper ureteral stones and ipsilateral renal cyst were identified for this study. this approach was approved by ethic committee of the central hospital of enshi tujia and miao autonomous prefecture. patients' information included gender, age, body mass index (bmi), operative time and length of hospital stay(los) were recorded. preoperative ultrasound of urinary tract system, plain films of kidney, ureteral, bladder, intravenous urography(ivu), and contrast-enhanced ct scans of renal and ureter were perfomred to evaluate the cyst and stone size and location. ct scan disclosed renal or upper ureter stones combined with ipsilateral renal cyst (figures 1,2). renal cyst size, stone size, and renal cyst bosniak classification was measured by ct scan. the sfr after surgery was also measured by ct scan and plain films of kidney, ureteral, bladder. follow up duration was 6-24 months. surgical technique all procedures were performed under continuous epidural anesthesia or general anesthesia with the patients in the lithotomy position. a 5f ureteral catheter was inserted under direct cystoscopic vision. then we placed the patient in the oblique supine position. then three steps were processed as followed. the first one was to determine the relationship of stones and cyst by ultrasound imaging and ct scans, which made perendourology and stone diseases 6 cutaneous access possible to simultaneously process calculi and cyst, then an 18-gauge access needle was successfully punctured into the desired target calyx with the guidance of ultrasound imaging. collecting system entry was confirmed by methylene blue instillation through the ureteral catheter, a flexible 0.035inch zebra guidewire (boston scientific corporation) was passed into the renal collecting system through the needle sheath, then needle was removed and the nephrostomy tract was dilated to 18f by fascial dilators and a matched peel-away sheath passed. holmium laser lithotripsy was initiated after passing an 8/9.8 rigid nephroscope placed inside the access sheath with normal saline irrigation (figure 3a). the stone fragments were flushed out by the forceful pulse flow. third step: we found out the renal cystic wall which was convex in the inner of kidney, the wall of cyst fluctuating with water current could be seen (figure 3b), and the cystic wall was cauterized from the bottom of cyst at the avascular area by holmium laser in order to decompress, then the inner cyst fluid outflowed (figure 3c). we resected and removed the wall of cyst, the nephroscope was introduced into the interior of the cyst and the entire wall of the cyst was inspected (figure 3d), then a double-j stent was placed into the cyst and a nephrostomy tube was placed routinely. results ct scans and ivus were performed in all patients and patient gender age bmi side stone preoperative bosniak surgical stone complication los remove dj cyst size 3m follow up number (year) kg/m2 size(cm) cyst size(cm) classification time(min) residual (days) after surgery (cm) (month) 1 male 33 18.4 right 2.1 3.6 i 84 no 10 20 0.5 24 2 male 56 30.9 left 1.1 2.3 ii 35 no 9 30 0 24 3 male 54 25.4 left 2.6 1.9 i 79 no 8 27 0 11 4 male 19 22.3 right 3.1 2.2 i 80 yes fever 12 30 0 24 5 male 50 25.1 left 1.7 1.6 i 75 no 8 30 0 24 6 male 34 20.6 left 3.4 4.1 ii 103 yes transfusion 10 40 1.0 10 7 male 59 22.7 right 1.1 3.6 i 29 no 8 20 0.8 24 8 male 30 26.7 left 2.5 4.0 i 62 no 7 30 1.0 24 9 male 22 25.8 right 1.8 3.0 i 36 no 7 26 0 8 10 male 53 25.7 left 2.0 2.7 i 38 no 7 18 0 24 11 male 27 23.6 left 1.8 2.8 i 29 no 7 40 0 24 12 male 56 18.9 right 1.5 2.7 ii 34 no 8 30 0 24 13 male 72 21.3 right 3.1 2.2 i 73 no 7 34 0 24 14 male 52 25.4 left 2.0 1.8 i 64 no 6 30 0 24 15 male 63 23.4 left 2.4 3.0 i 74 no 7 20 1.0 24 16 male 51 27.3 left 2.7 1.7 i 62 no 7 30 0 24 17 female 26 22.5 left 3.2 3.5 i 126 yes fever 14 45 0 12 18 female 59 29 right 1.9 3.6 i 71 no 9 30 0 24 19 female 55 20.3 left 1.8 1.6 i 41 no 7 35 0 24 20 female 18 19 left 1.6 2.9 ii 34 no 12 35 0 12 21 female 34 23 left 1.8 3.4 i 78 no 6 43 0 24 22 female 64 25.9 left 2.3 2.0 i 104 no 11 30 0 6 23 female 32 27.7 right 4.0 4.1 i 132 no 10 26 1.0 24 24 female 62 21 left 1.9 2.8 i 45 no 7 30 0 24 25 female 55 24.2 left 1.0 1.9 i 28 no 9 30 0 24 26 female 35 20.7 left 1.5 2.6 i 36 no 7 30 0 24 27 female 26 18.5 right 1.8 3.4 i 44 no 8 30 0.5 18 28 female 20 23.5 left 2.2 1.8 i 108 no 10 30 0 24 table 1. demographic characteristics and surgical statistics. figure 1. computed tomography in a ureteropelvic joint stone with ipsilateral renal cyst. figure 2. computed tomography in multiple renal and upper ureteral stones with ipsilateral renal cyst. treatment of renal and upper ureteral stone and cysts -hu et al. vol 15 no 01 january-february 2017 7 the presence of renal and upper ureteral stones with ipsilateral renal cyst were confirmed (figures 1, 2). all the patients underwent successful pcnl combined with percutaneous nephroscopic cyst holmium laser intrarenal incision and drainage. their mean age was 43.5 ± 16.4 years and their body mass index was 23.8 ± 4.7 kg/m2. all of the patients complained of varying degrees of flank pain. two patients had hematuria, three patients had renal colic. the mean stone size was 21 ± 16mm, the mean cyst size was 27 ± 13mm, 24 patients belong to grade i of bosniak classification and 4 patients belong to grade ii of bosniak classification. in all patients, urine culture was negative, and no patient had pyuria; three patients had a history of previous stone surgery. demographic parameters of patients' data were collected from medical charts and were listed in table 1. the kub and ct scans performed 1 month after surgery assessed the sfr (figure 4). double j ureteral stent was removed after 3 months. patients were discharged after removal of the nephrostomy tubes. they were followed up every 3 months in the first year and annually thereafter. stone-free status or the presence of asymptomatic fragments < 4mm and renal cyst disappearance on postoperative ct and kub were both recorded as successful outcomes. postoperative follow-up lasted for 6-24 months; renal ultrasound showed no hydronephrosis in all patients. we found that both the stones and cyst did not relapse. operative characteristics are also listed in table 1. all operations were performed successfully. no major complications occurred. one patient needed blood transfusion; two patients had fever after operation and the fever subside with antibiotics. all the patients had a single tract for pcnl. the mean operative time was 64.4 ± 30.1 minutes; the mean time to double j ureteral stent removal was 30.3 ± 7.0 days. the mean hospital stay was 8.5 ± 2.0 days. the sfr of all the patients was 89.3%(25/28). three patients had residual stones in kidneys after operation; one patient had to undergo a second phase pcnl, and two patients had to undergo swl. discussion nowadays, symptomatic renal calculus is generally treated by pcnl, flexible ureteroscopy, swl or open surgery. the treatment applied depends on stone location, stone size and the degree of hydronephrosis. renal cyst is mainly treated by percutaneous aspiration, laparoscopic renal cyst unroofing decompression, flexible ureteroscopic intrarenal incision and percutaneous nephroscopic renal cyst unroofing decompression(5-7). the decision of therapeutic strategy depends on cyst size, patient symptoms and cyst location. ultrasonic guiding percutaneous aspiration is applied as an effective approach for renal cysts but is limited by high rate of relapse and significant complications. laparoscopic approach is recognized as the gold standard approach due to its good surgical field and curative effect. however, when compared with flexible ureteroscopy and percutaneous approach, it has some weaknesses, such as more port sites, extensive dissection and longer operative time(8,9). retrograde ureteroscopic management is the least invasive approach and has a low complication rate(10-12). however, percutaneous technique has also been applied for treatment of renal cysts(7). many studies reported percutaneous marsupialization as a safe and efficient approach for treatment of renal cyst(13,14). with regard to a patient with both kidney stone and renal cyst, qiu et al.(15) reported single-session retroperitoneoscopic renal cyst decortication and retroperitoneoscopy-assisted pcnl for simultaneous treatment of renal cyst and stones. chen et al.(16) reported percutaneous intrarenal cyst marsupialization and simultaneous nephrolithotomy for patients with renal cyst and ipsilateral calculi. the results showed that this method could decrease the costs and the potential injury risks. in our center, we also applied pcnl combined with percutanefigure 3. pcnl combined with percutaneous nephroscopic laser intrerenal incision for treatment of renal stones and cyst. (a) percutaneous nephroscopic holmium laser lithotripsy. (b) (c) the cyst wall was incised by holmium laser from intrarenal. (d) the nephroscope was introduced into the interior of the cyst and the entire wall of the cyst was inspected. figure 4. postoperative plain abdominal x-ray image and computed tomography (ct) show the double-j stent in the correct position, and demonstrate clearance of stones and disappearance of renal cyst in right kidney. treatment of renal and upper ureteral stone and cysts -hu et al. endourology and stone diseases 8 ous nephroscopic laser intrarenal incision and drainage for these patients. the main difference between chen and our approach is whether 18-gauge needle puncture is passed through the cyst into the target calyx. if the cyst wall is thin, a needle is passed through the cyst into the target calyx which may cause urine leakage. however, we applied 18-gauge access needle which was punctured into the desired target calyx without injuring renal cyst with the guidance of ultrasound imaging, and the tract was dilated to 18f by fascial dilators, then the cystic wall was cauterized and cut open from the bottom of cyst at the avascular area by holmium laser in order to decompress. then the incision was enlarged 2-4cm by holmium laser to achieve internal marsupialization, and at last the cyst was interconnected with collecting system. a 5f double-j stent was placed within the proximal end of the cyst. our results showed the mean operative time was lower than those reported by chen (64.4 ± 30.1 minutes vs 68 minutes). the mean time to removal of double-j ureteral stent was 30.3 ± 7.0 days. the mean hospital stay was 8.5 ± 2.0 days. the mean sfr was 89.3%(25/28). the key point of our creation is that we choose a suitable puncture route without injuring external wall of renal cyst, which is selected carefully with important and precise information from preoperative ct and ivu to remove calculi and process intrarenal incision and drainage to decompress the cyst. it demonstrates that pcnl combined with percutaneous nephroscopic laser intrarenal incision and drainage is a safe and efficient approach in the management of renal and upper ureteral stones with ipsilateral renal cysts. also, our method has some deficiencies. firstly, when faced with multiple renal cysts and excessive haemorrhage, it is difficult to deal with the cysts and calculi in one session because of risk of potential damage. secondly, the prolonged placement time of double-j stent may affect the patient’s quality of life and increase stent-related symptoms. common symptoms include abdominal pain, frequent micturition, urinary urgency, hematuria, infection and so on. in addition, our approach is limited by its relatively small sample size and lack of a control group and limited follow-up. thus, in subsequent study, we will assess the curative effect of pcnl combined with percutaneous nephroscopic laser intrarenal incision and drainage with larger sample and longer-term follow-up for treatment of renal and upper ureteral stones with ipsilateral renal cyst. conclusions pcnl combined with cyst laser intrarenal incision and drainage is proved to be a safe, feasible and helpful procedure in management of renal and upper ureteral stoned with ipsilateral renal cyst. acknowledgement this study was funded by hubei province health and family planning scientific research project (number: wj2017m257) and natural science foundation of hubei province of china (number: 2014cfc1068). conflict of interest the authors report no conflict of interest. references 1. ghani kr, andonian s, bultitude m, et al. percutaneous nephrolithotomy: update, trends, and future directions. eur urol. 2016;70:382-96. 2. de s ar, kim fj, zargar h, laydner h, balsamo r, torricelli fc, di palma c, molina wr, monga m, de sio m. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015;67:125-37. 3. kang dh, cho ks, ham ws, et al. comparison of high, intermediate, and low frequency shock wave lithotripsy for urinary tract stone disease: systematic review and network meta-analysis. plos one. 2016;11:e0158661. 4. topaktas r, tepeler a. how should we treat renal calculi accompanying to simple renal cyst? urology. 2015;85:484. 5. yu w, zhang d, he x, et al. flexible ureteroscopic management of symptomatic renal cystic diseases. j surg res. 2015;196:11823. 6. hoenig dm lr, amaral jf, stein bs. laparoscopic unroofing of symptomatic renal cysts：three distinct surgical approaches. j endourol. 1995;9(1)::55-8. 7. hamedanchi s, tehranchi a. percutaneous decortication of cystic renal disease. korean j urol. 2011;52:693-7. 8. busato wf jr bl. percutaneous endocystolysis, a safe and minimally invasive treatment for renal cysts: a 13-year experience. j endourol. 2010;24:1405-10. 9. mai h lj, zhao l, qu n, wang y, huang c, chen b, li y, chen l, zhang x. efficacy investigation of transpostceliac single-port 3-channel laparoscope in the treatment of complex renal cyst. int j clin exp med. 2015;8:10031-5. 10. mao x, xu g, wu h, xiao j. ureteroscopic management of asymptomatic and symptomatic simple parapelvic renal cysts. bmc urol. 2015;15:48. 11. li ec hj, yang lb, yuan hx, hang lh, alagirisamy kk, li dp, wang xp. pure natural orifice translumenal endoscopic surgery management of simple renal cysts: 2-year follow-up results. j endourol. 2011;25:75-80. 12. basiri a hs, tousi vn, sichani mm. ureteroscopic management of symptomatic, simple parapelvic renal cyst. j endourol. 2010;24:537-40. 13. shao zq, guo ff, yang wy, et al. percutaneous intrarenal marsupialization of symptomatic peripelvic renal cysts: a singlecentre experience in china. scand j urol. 2013;47:118-21. 14. tehranchi a, hamedanchi s, badalzadeh a. treatment of renal and upper ureteral stone and cysts -hu et al. vol 15 no 01 january-february 2017 9 percutaneous unroofing of renal simple cysts: experience from one centre. arab journal of urology. 2011;9:255-7. 15. qiu j, wang d, chen x, et al. simultaneous treatment of renal cysts and stones with single-session retroperitoneoscopic renal cyst decortication and retroperitoneoscopyassisted percutaneous nephrolithotomy. urol int. 2012;88:395-9. 16. chen h ql, zu x,liu l,cao z,zeng f,niu j,cui y,wang l. percutaneous intrarenal cyst marsupialization and simultaneous nephrolithotomy in selected patients: killing two birds with one stone? urology. 2014;84:1267-71. treatment of renal and upper ureteral stone and cysts -hu et al. endourology and stone diseases 10 pediatric urology 180 pediatric urology the differences between preterm and term birth affecting initiation and completion of toilet training among children: a retrospective case-control study dilek yildiz1, derya suluhan1*,berna eren fidanci1,merve mert1, turan tunç2, bülent altunkaynak3 purpose: this study seeks to investigate the possibility the existence of a difference in terms of start and end dates of toilet training between term and preterm children as well as the possible determining factors. materials and methods: this study was conducted as a 5-year retrospective case (children born preterm-(32 to <37 weeks) – and control (children born at term (>37 weeks + 1 day)) study. the data were collected with a form consisted of questions about demographic data (12 questions) and toilet traning features (10 questions) through face-to-face interviews with the mothers. a chi-square test and logistic regression analysis were conducted to examine the data. odds ratio was used as a measure of the relation between levels of the dependent variable. results: the study examined a total of 133 children including 59 preterm children and 74 children born at term including 60 (45.1%) boys and 73 (54.9%) girls. the possibility of starting toilet training at or before 24 months was found to be 6.4 times greater in full-term children than preterm children (or = 6.493). the logistic regression analysis, which aimed at identifying any variables that might affect end date of toilet training, found that despite the tendency to consider preterm birth as a factor prolonging the duration of toilet training, the difference was not found to be statistically significant (p = .07). conclusion: this study compared full-term and preterm children in terms of start and end dates of toilet training and found that preterm children start toilet training later than full-term children. based on the results of the study, it is possible to say that preterm birth, gender and birth order affect start date of toilet training. however there is no difference between term and preterm babies on the end date of toilet training. keywords: toilet training; preterm birth; parents introduction while toilet training is a challenging experience for parents, it constitutes one of the most significant developmental tasks of childhood.(1-3) smooth accomplishment of this task is critically important for both the child and the parents. a multitude of factors influences—either by enabling or obstructing—the start and achievement of the child’s toilet training. parent-related factors include educational attainment, family sociocultural structure, income level, living environment, type of toilet, methods used, and parents’ knowledge/ experience of the subject, while factors such as age, gender, physical and mental readiness, gestational age at birth, and birth weight are cited among the child-related factors.(3-7) a review of the existing literature shows that very few studies have looked into the effect of gestational age on start and completion of toilet training.(8-9) in drillien’s study on the growth and development of prematurely-born infants, the researcher reported on child-rearing practices and bladder control develop1 department of pediatric nursing, gülhane faculty of nursing, saglik bilimleri university, ankara, 06010, turkey. 2 department of pediatrics, memorial ataşehir hospital, istanbul, 34758, turkey. 3 department of department of statistics, gazi university, faculty of science, ankara, 06500, turkey. *correspondence: department of pediatric nursing, gülhane faculty of nursing, saglik bilimleri university, ankara, 06010, turkey. tel: +90 506 3311738, fax: +90 312 3043907, e-mail: derya.suluhan@sbu.edu.tr. received october 2018 & accepted march 2019 ment.(9) toilet-training, and the age at which children became reliably dry both day and night, was related to prematurity, impairment, socioeconomic conditions, and sex. small, prematurely-born children acquired sphincter control later than full-term-born children. the researcher also pointed out that girls were more advanced in gaining bladder control than boys. largo et al. reported that developing bladder and bowel control is not affected by prematurity, adverse perinatal events, or mild-to-moderate neurological impairment, nor is it related to psychomotor development or socioeconomic conditions.(8) this study seeks to answer the following questions: 1) do preterm children and full-term children differ with respect to the start date of toilet training? ; 2) do preterm children and full-term children differ with respect to the end date of toilet training? methods setting this study was conducted as a 5-year retrospective case study with a control group, examining preterm children vol 16 no 02 march-april 2019 181 and full-term children in a training and research hospital in turkey from march 1, 2015, through january 1, 2016. subjects the data used in the study pertained to children admitted as inpatients to the neonatal intensive care unit due to preterm birth during the one-year period between january 2010 and january 2011; these data were reviewed retrospectively, and the contact information of the patients was accessed. the cases were selected according to gestastional age. preterm birth is defined as “babies born alive before 37 weeks of pregnancy are completed”. sub-categories of preterm birth are based on weeks of gestational age: extremely preterm (<28 weeks), very preterm (28 to <32 weeks), and moderate to late preterm (32 to <37 weeks).(10) the case group consisted of moderate to late preterm babies, and the control group consisted of full-term babies (>37 weeks + 1 day). the case group consisted of 59 preterm children in the then-current age group of 4-6 years with no neurological, genetic, or metabolic diseases that impacted their cognitive and motor development. extremely preterm and very preterm babies were excluded due to common prematurity complications. the control group comprised 74 children born full-term between january 2010 and january 2011 who were hospitalized for a different reason. the control group was selected after matching for age and gender with the case group. in both groups, the children were evaluated by a doctor with a voiding dysfunction symptom score. children with voiding dysfunction were not included in the study. the files of children in the control group were reviewed, and their contact information was accessed. data collection the contact information obtained in the file review was used to invite parents in the case and control groups to the hospital to fill out data collection forms. these forms were filled out in 10-15 minutes through faceto-face interviews with the mothers. the data collection forms were developed by the researcher through a review of the literature.(1,3,5,11-14) the form consisted of a total of 22 questions, including 12 questions about sociodemographic data (the parent’s age, the child’s age and gender, the parent’s educational attainment and employment status, the number of children, and the family structure) and 10 questions on toilet training (child’s age when toilet training started, duration of training, training methods used by parents, and any problems encountered). data analysis spss v22 (statistical package for social sciences) was employed to analyze the data obtained in the study. a chi-square test and a logistic regression analysis were conducted to examine the data. numbers and percentages were used for interpretation in chi-square tables. odds ratio was used to measure the relation between levels of the dependent variable. throughout the analyses, p < 0.01 and p < 0.05 values were considered statistically significant. the dependent variables were ‘‘start date of toilet training’’ and ‘‘duration of toilet training’’. the independent variables were the child’s gender, birth order, the mother’s educational attainment, her perception of income level, and family type. though there is no specific age at which toilet training should begin, it is advised table 1. comparison of start date of toilet training in preterm (n=59) and full-term (n=74) children by sociodemographic characteristics start date of toilet training characteristics before 24 months after 24 months child’ characteristics gender number (n) percent (%) number (n) percent(%) χ2 p girl preterm (n=35) 12 34.3 23 65.7 9.90 full-term (n=38) 27 71.1 11 28.9 < .001b boy preterm (n=24) 2 8.3 22 91.7 8.94 full-term (n=36) 16 44.4 20 55.6 < .001b birth order χ2 p first-born preterm (n=28) 11 39.3 17 60.7 5.47 full-term (n=43) 29 67.4 14 32.6 0.02a later born preterm (n=31) 3 9.7 28 90.3 9.81 full-term (n=31) 14 45.2 17 54.8 < .001b mother’s characteristics χ2 educational attainment p 11 years or less preterm (n=34) 6 17.6 28 82.4 15.37 full-term (n=53) 32 60.4 21 39.6 < .001b more than 11 years preterm (n=25) 8 32.0 17 68.0 1.96 full-term (n=21) 11 52.4 10 47.6 0.16 family’s income level χ2 p less income than preterm (n=19) 8 42.1 11 57.9 3.08 expenses full-term (n=20) 14 70.0 6 30.0 .08 balanced income preterm (n=40) 6 15.0 34 85.0 14.73 and expenses or more < .001b full-term (n=54) 29 53.7 25 46.3 χ2 p family type nuclear family preterm (n=50) 10 20.0 40 80.0 17.16 < .001b full-term (n=69) 40 58.0 29 42.0 other preterm (n=9) 4 44.4 5 55.6 full-term (n=5) 3 60.0 2 40.0 *ap < .05; b p< .001 the differences between preterm and term birth about toilet training -yildiz et al. pediatric urology 182 for parents to start at 18-24 months in healthy children. (15,16) ‘‘start date of toilet training’’ was defined as ş 24 months and > 24 months, allowing the variable to be discrete and thus enabling logistic regression. ethical considerations permission from hospital’s board of ethics and written consent from the participating mothers were obtained (1491-678-10/1539). results the study examined a total of 133 children, 59 preterm children and 74 full-term children, including 60 (45.1%) boys and 73 (54.9%) girls. the median age was 4.3±0.8 years. all parents consist of mothers whose median age was 35.08±5.63 years. in terms of mother’s educational attainment, duration of education was ≤11 years for 75 (56.4%) mothers and >11 years for 58 (43.6%) mothers. 119 children (89.5%) lived in a nuclear family, 9 (6.8%) lived in an extended family, and 5 (3.8%) lived in a single-parent family. 39 mothers (29.3%) had lower income than their expenses, 88 (66.2%) mothers had as much income as their expenses, and 6 (4.5%) had more income than their expenses. table 1 compares toilet training start date in preterm and full-term children by sociodemographic characteristics. in both genders, start of training at ≤ 24 months was found to be significantly higher for children born full-term (p < 0.001 and p < 0.001) than children born preterm. in terms of birth order, the number of firstborn full-term children who started toilet training at ≤ 24 months was significantly higher than that of nonfirst-born children. the share of children who started training >24 months was found to be significantly higher in the preterm group regardless of birth order (p = 0.02 and p < 0.001). the number of full-term children of mothers with an educational attainment of ş11 years who started toilet training at ≤ 24 months was found to be significantly higher (p < 0.001) than those of preterm children of similarly-educated mothers; this difference was not found for full-term children with mothers with an educational attainment of >11 years (p = 0.16). in terms of family income level, in families with income-expense balance or a higher income, the number of children who start toilet training ≥ 24 months was found to be significantly higher (p < 0.001) in the preterm group than the full-term group; this difference did not exist in families with lower income (p = 0.08). rates of late start dates were found to be higher in preterm children living in nuclear families (p < 0.001) (table 1). a comparison of toilet training completion by demo completion of toilet training characteristics 2-30 days longer than 30 days child’ characteristics gender number (n) percent (%) number (n) percent (%) χ2 p girl preterm 21 60.0 14 40.0 .40 .53 full-term 20 52.6 18 47.4 boy preterm 17 70.8 7 29.2 4.05 .04a full-term 16 44.4 20 55.6 birth order χ2 p first-bornpreterm 18 64.3 10 35.7 3.41 .07 full-term 18 41.9 25 58.1 later born preterm 20 64.5 11 35.5 .27 .60 full-term 18 58.1 13 41.9 mother’s characteristics χ2 educational attainment p 11 years or less preterm 23 67.6 11 32.4 3.51 .06 full-term 25 47.2 28 52.8 more than 11 years preterm 15 60.0 10 40.0 .27 .60 full-term 11 52.4 10 47.6 family’s income level χ2 p less income than preterm 9 47.4 10 52.6 .23 expenses .63 full-term 11 55.0 9 45.0 balanced income and preterm 29 72.5 11 27.5 6.45 expenses or more .01a full-term 25 46.3 29 53.7 family type χ2 p nuclear family preterm 33 66.0 17 34.0 3.30 .07 full-term 34 49.3 35 50.7 other preterm 5 55.6 4 44.4 full-term 2 40.0 3 60.0 a p < 0.05 table 2. comparison of completion times of toilet training in preterm (n=59) and full-term (n=74) children by sociodemographic characteristics the differences between preterm and term birth about toilet training -yildiz et al. vol 16 no 02 march-april 2019 183 graphic characteristics of children and mothers shows that the rates of toilet training lasting >30 days were significantly higher with preterm children in families with income-expense balance or with a higher income (p = .01) and in boys (p = 0.04) (table 2). a logistic regression analysis was conducted to identify any variables that might affect toilet training start date. preterm birth, gender, and birth order were found to be statistically significant. the possibility of starting toilet training at ≤ 24 months was found to be 6.493 times greater with full-term children than with preterm children (or=1/0.154=6.493). the ratio was found to be 4 times higher in girls than boys (or=4.009). similarly, the share of start dates ≤ 24 months was found to be 3.8 times higher in first-born children than in children with a birth order of 2 or later (or=3.886) (table 3). the logistic regression analysis also aimed to identify any variables that might affect toilet training end date; it found that, despite the tendency to consider preterm birth as a factor prolonging toilet training duration, the difference was not found to be statistically significant (p = 0.07). other variables were not found to have a statistically significant effect on duration (table 4). discussion this study seeks to investigate a possible difference in toilet training start and end dates between full-term and preterm children, as well as potential determining factors. preterm birth, gender, birth order, socio-economic status, family structure, and the mother’s educational attainment were found to be correlated with the start date of toilet training. a logistic regression analysis was carried out to identify the factors that had an actual effect. the analysis showed that preterm birth, gender, and birth order are the only determining factors and that all three variables delay the start date of toilet training. drillien et al. showed that preterm birth and gender are factors that influence toilet training.(9) it is worth noting that rates of start dates >24 months is high in both genders in the preterm group. regardless of birth order, late start was observed in the preterm group. also, despite family socio-economic status and the child being a boy correlating with duration of toilet training, such a link was not validated by the logistic regression analysis. however, literature has shown that low socioeconomic status has an effect on toilet training.(17) toilet training start date varies from one society to another. while it was common in the 1940s to start toilet training before 18 months in the us and europe, recent studies show start dates as late as 21-36 months.(14) the american academy of pediatrics and the canadian paediatric society recommend a child-centered toilet training approach, which starts at 18-24 months.(10,17) mothers with a lower socio-economic status are known to have a higher risk of preterm birth.(8) this could be one factor that might influence delayed toilet training. largo et al. showed that preterm children start toilet training earlier (<18 months) than full-term children and that they are subject to more frequent training. the same study reports that start date and intensity of the training are not related to socioeconomic status. the study also maintains that gestation week at birth does not affect bladder and bowel control.(8) similarly, this study did not find a correlation between socioeconomic status and toilet training start date. however, as opposed to other studies, our study found that preterm children start toilet training later than full-term children. the reason could be mothers’ belief that a preterm birth will result in delayed acquisition of the skill. while one of the factors influencing toilet training start date is gender, earlier bladder and bowel control among girls is known to be linked with maturation. additionally, a number of studies have found that both full-term and preterm girls start toilet training at a younger age than boys.(2,7,8,12,15-17) one study reports that preterm girls (both sga (small for gestational age) and aga (appropriate for gestational age)) start toilet training at a younger age than boys, predominantly between 1218 months. the same study reports that gender has no impact on start date of toilet training at ≥24 months.(8) it should be noted that as in largo’s study, our study found that preterm children start toilet training >24 months regardless of gender. these findings are in line with the results of other studies found in the literature, and one reason could be faster maturational development in girls. (7,19-20) the current study also investigated the possibility of birth order being a determining factor affecting toilet training start date. no relevant data was found in the literature. the study found that being the second child or table 3. result of last step of backward logistic regression analysis for determining the variables that affect on the time to start toilet training b s.e. df sig. unadjusted or (95% ci) adjusted or (95% ci) birth -1.871 .458 1 .000 .224 (.105 to .478) .154 (.063 to .378) gender 1.389 .449 1 .002 2.676 (.1305 to 5.491) 4.009 (1.663 to 9.665) birth order 1.357 .431 1 .002 3.416 (1.648 to 7.080) 3.886 (1.670 to 9.046) family type .806 .458 1 .078 2.182 (1.022 to 4.658) 2.239 (.913 to 5.492) constant -2.039 1.204 1 .090 .130 note: binary dependent variable is “the time to start toilet training” (before 24 months; after 24 months). note: binary dependent variable is “the completion of toilet training” (2-30 days; longer than 30 days). b s.e. df sig. unadjusted or (95% ci) adjusted or (95% ci) birth .647 .358 1 .071 1.910 (.947 to 3.851) 1.910 (.947 to 3.851) constant 1 .240 .591 1 .036 table4. result of last step of backward logistic regression analysis for determining the variables that affect on the completion of toilet training the differences between preterm and term birth about toilet training -yildiz et al. pediatric urology 184 later delayed the toilet training start date (>24 months) in the preterm group. the reason could be mothers’ belief that preterm birth may delay acquisition of toilet skills, despite their experience in child care. in the full-term group, first-born children started toilet training earlier, whereas later children did not show such a difference. the reason could be the family’s desire to start toilet training at a later age for later-born siblings, either due to difficulties encountered with their firstborn child or due to parents’ level of experience. horn et al. compared toilet training start date by caregivers’ educational attainment and showed that fullterm children of parents with lower levels of educational attainment start toilet training earlier.(17,21) in our study, mothers with lower levels of educational attainment were also found to delay toilet training for their preterm children. however, no correlation was found between educational attainment and the timing of toilet training. the reason could be that timing of toilet training varies in different societies, or that mothers believe a preterm birth might delay acquisition of toilet skills and it would not be good to force their child to achieve this developmental task too early. however, a comparison of toilet training end dates shows that, despite a relatively shorter toilet training duration in preterm children in families with lower levels of educational attainment, the difference was not found to be statistically significant. the reason could be that later start dates result in shorter durations, due to maturation. family socio-economic status may be another determining factor affecting toilet training start date. koc et al. reported in their study that parents with a higher socioeconomic status start toilet training at a later age. (22) in another study that compared full-term and preterm children, socioeconomic status was not found to impact toilet training start date in preterm children.(21) our study did not find any correlation between socioeconomic status and the timing of toilet training, in accordance with the existing literature. one of the limitations of this study was the use of retrospective data. this might have affected the participants’ recollections of some of the details of their experience in toilet training their child. another limitation is that toilet training methods were not taken into account. toilet training methods are one of the important factors that affects duration of toilet training, but it was not evaluated in our study. this study is the first study to examine the relationship between family type and toilet training. it can be argued that family structure does not have an impact on start and end dates of toilet training in preterm children. conclusions this study compared full-term and preterm children in terms of start and end dates of toilet training, and it found that preterm children start toilet training later than full-term children. based on the results of the study, it can be said that preterm birth, gender, and birth order affect the toilet training start date. although one may argue that being born preterm creates a tendency to shorten the duration of toilet training, no statistically significant relation was identified. more extensive research on larger groups of patients is needed to obtain reliable data on the subject. we recommend to parents or caregivers of children born preterm that gestational age at birth does not affect the occurrence of the child's initiative nor the development of bladder and bowel control. acknowledgement we would like to thank the registered nurses, merve demirhan for her help with collected data. conflict on interest the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. references 1. van aggelpoel t, de wachter s, van hal g, van der cruyssen k, neels h, vermandel a. parents' views on toilet training: a crosssectional study in flanders. nurs child young people. 2018 ;30:30-35. 2. brazelton tb, christophersen er, frauman ac, et al. instruction, timeliness, and medical influences affecting toilet training. pediatrics. 1999;103 (supplement 3):1353-8. 3. mota dm, barros aj. toilet training: methods, parental expectations and associated dysfunctions. j pediatr (rio j). 2008;84:9-17. 4. vermandel a, van kampen m, van gorp c, wyndaele jj. how to toilet train healthy children? a review of the literature. neurourol urodyn. 2008;27:162-6. 5. bakker e, van gool j, van sprundel m, van der auwera c, wyndaele j. results of a questionnaire evaluating the effects of different methods of toilet training on achieving bladder control. bju int. 2002;90:456-61. 6. klassen tp, kiddoo d, lang me, et al. the effectiveness of different methods of toilet training for bowel and bladder control. evid rep technol assess (full rep). 2006 ;(147):157. 7. schum tr, mcauliffe tl, simms md, walter ja, lewis m, pupp r. factors associated with toilet training in the 1990s. ambul pediatr. 1999;158:115-22. 8. largo r, molinari l, von siebenthal k, wolfensberger u. development of bladder and bowel control: significance of prematurity, perinatal risk factors, psychomotor development and gender. eur j pediatr. 1999;158:115-22. 9. drillien cm. a longitudinal study of the growth and development of prematurely and maturely born children. arch dis child. 1961;36:515-25. 10. toilet training guidelines: parents—the role of the parents in toilet training. pediatrics. 1999 ;103(6 pt 2):1362-1363. 11. clifford t, gorodzinsky f. toilet learning: anticipatory guidance with a child-oriented approach. paediatr child health. 2000;5:33344. the differences between preterm and term birth about toilet training -yildiz et al. vol 16 no 02 march-april 2019 185 12. stadtler ac, gorski pa, brazelton tb. toilet training methods, clinical interventions, and recommendations. pediatrics. 1999;103 (supplement 3):1359-61. 13. blum nj, taubman b, nemeth n. relationship between age at initiation of toilet training and duration of training: a prospective study. pediatrics. 2003;111:810-4. 14. gorodzinsky f. toilet learning: anticipatory guidance with a child-oriented approach. paediatr child health. 2000 ;5:333-44. 15. kaerts n, vermandel a, van hal g, wyndaele jj. toilet training in healthy children: results of a questionnaire study involving parents who make use of day-care at least once a week. neurourol urodyn. 2014;33:316-23. 16. joinson c, heron j, von gontard a, butler u, emond a, golding j. a prospective study of age at initiation of toilet training and subsequent daytime bladder control in school-age children. j dev behav pediatr. 2009;30:385-93. 17. horn ib, brenner r, rao m, cheng tl. beliefs about the appropriate age for initiating toilet training: are there racial and socioeconomic differences? j pediatr. 2006 ;149:165-8. 18. koc i, camurdan a, beyazova u, ilhan m, sahin f. toilet training in turkey: the factors that affect timing and duration in different sociocultural groups. child care health dev. 2008 ;34:475-81. 19. bloom da, seeley ww, ritchey ml, mcguire e. toilet habits and continence in children: an opportunity sampling in search of normal parameters. j urol. 1993 ;149:108790. 20. taubman b. toilet training and toileting refusal for stool only: a prospective study. pediatrics. 1997;99:54-8. the differences between preterm and term birth about toilet training -yildiz et al. vol 13 no 05 september-october 2016 2744 association study of klotho gene polymorphism with calcium oxalate stones in the uyghur population of xinjiang, china abdusamat ali1†, halmurat tursun2†, alim talat1,akpar abla1, erpan muhtar1,tao zhang1, murat mahmut1* purpose: the aim of the present study was to investigate the correlation between klotho gene polymorphisms and calcium oxalate stones in xinjiang uyghur people. materials and methods: we compared 128 patients with calcium oxalate stones (case group) and 94 healthy people (control group), detected the genotype and allele distributions of single-nucleotide polymorphisms (snps) of the klotho gene (rs3752472, rs650439, and rs1207568) by reverse transcription polymerase chain reaction. results: the distributions of the genotype and allele frequencies of the snps were consistent with the hardy– weinberg equilibrium in the two groups. there were statistically significant differences between the genotype and allele distributions of rs3752472 between the case and control groups; the allele frequencies in the case/control groups were c = 240 (93.7%)/151 (80.3%) and t = 16 (6.3%)/37 (19.7%). there was no statistically significant difference in the genotype distribution of rs650439 between the case and control groups, but there was a difference in the allele distribution; the allele frequencies in the case/control groups were a = 202 (78.9%)/143 (57.2%) and t = 54 (21.1%)/107 (42.8%). there were no statistically significant differences in genotype and allele distributions between the case and control groups of rs1207568; the allele frequencies in the case/control groups were c = 194 (71.3%)/145 (77.1%) and t = 78 (28.7%)/43 (22.9%). in rs3752472, the risk for patients with the c and a alleles increased by 3.675 and 2.799 times, respectively. conclusion: the rs3752472 and rs650439 snps are related to the risk of calcium oxalate stones in xinjiang uyghur people, and might be one of the risk factors. keywords: case-control studies; genotype; klotho gene; polymorphism; urolithiasis. introduction urolithiasis is one of the three major diseases of the human urinary system and it is common in the worldwide. etiology of urolithiasis is affected by numerous factors, including genetic and environmental factors, abnormal metabolism, race, and living habits(1); therefore, the exact mechanism by which urinary calculi form remains unclear. with the development of molecular biology techniques such as polymerase chain reaction–restriction fragment length polymorphism (pcr-rflp), the molecular pathogenesis of urolithiasis has become a focus of research, and the correlation between susceptibility to urolithiasis and gene polymorphism has received particular attention. xinjiang, a multi-ethnic region that is the main residence of the uyghur people, has a high incidence of urolithiasis. clinical diagnosis has revealed that urolithiasis is more prevalent in uyghur patients than in patients of other races living in the same region(2). research has shown that levels of the klotho enzyme are related to 1department of urology, the second affiliated hospital of xinjiang medical university, urumqi ,xinjiang, china. 2department of urology, the first affiliated hospital of xinjiang medical university, urumqi ,xinjiang, china. †these authors contributed equally to this work. *correspondence: department of urology, the second affiliated hospital of xinjiang medical university, urumqi ,xinjiang, china. tel: +8613999118109. fax: +86-13999118109. e-mail: mekit@126.com. received july 2016 & accepted september 2016 the risk of urolithiasis(3,4). in order to investigate the correlation between klotho gene polymorphisms and the risk of renal calculi in xinjiang uyghur people, we studied the distribution of three snps (rs3752472, rs650439, and rs1207568) in uyghur people and investigated the correlation between polymorphic loci and calcium oxalate stones, as well as the molecular mechanisms that cause them. materials and methods subjects between january 2013 and september 2013, patients with urinary calcium oxalate stones who were treated at the department of urinary surgery of the first affiliated hospital of xinjiang medical university and the second affiliated hospital of xinjiang medical university were enrolled in the study. the study population was composed of 128 uyghur patients and 94 healthy volunteers. all the patients and volunteers were biologically unrelated uyghur people. the patients had an avvol 14 no 01 january-february 2017 2939 endourology and stone disease erage age of 43 ± 10 years. seventy-six patients (59%) harbored kidney stones, thirty-two patients (25%) had ureteral stones, and the other thirty patients (16%) were diagnosed with bladder stones. sixty-seven patients 67 (52.3%) reported a family history of stones and forty-four patients (34.3%) had recurrent stones. according to clinical symptoms, x-ray plain film results, and b-mode analyses, patients with urinary calculi received surgery or extracorporeal shock wave lithotripsy treatment, and the samples taken from them contained calcium oxalate stones. stone analysis was performed using shimadzu fourier transform infrared spectrophotometer 8300 manufactured by shimadzu corporation, japan. the control group consisted of 94 healthy volunteers with an average age of 46 ± 9 years without diagnosis or history of urinary calculi. there were no significant differences in the sex or age distribution between the case and control groups (all p > .05). we measured serum concentrations of total creatinine (cr), lactate dehydrogenase (ldh), calcium, phosphate, sodium, potassium, magnesium and pth (parathyroid hormone) as well as 24-hour urine excretions of cr, calcium, phosphate, sodium, potassium and magnesium in both groups. in the present study, we only analyzed the levels of serum calcium, phosphate, and cr and the 24-hour urinary excretions of calcium and phosphate. laboratory data and clinical characteristics of 222 subjects were presented in table 1. patients with calcium oxalate stones were included in this study. exclusion criteria for patients and controls were the presence of chronic urinary tract infections, renal tubular acidosis, renal failure, hyperparathyroidism, osteoporosis, cancer and using drugs that effect calcium and hormone metabolism, such as diuretics, calcium and vitamin d supplements. patients using anti-diabetic and anti-hypertensive agents were also excluded from the study. the study protocol was approved by the ethics committee of the first and second affiliated hospital of xinjiang medical university (approval number: iacuc-20140221097). written informed consent for research was obtained from the participants. genomic dna extraction blood (3 ml) was drawn from the antecubital veins of subjects in the case and control groups using ethylenediaminetetraacetic acid as an anticoagulant, and the samples were stored at -20°c. dna was extracted using a blood genomic dna extraction kit (k5017500; biochain science & technology, inc, beijing, china). agarose gel electrophoresis was used to confirm genomic dna integrity. klotho gene polymorphism in urolithiasis-ali et al. table1. general characteristics of the subjects (n = 222). variables patients(n=128) controls(n=94) p value age, years, mean ± sd 43 ± 10 46 ± 9 .536 gender, no (%) .349 male 83(64.8) 66(70.2) female 45(35.2) 28(29.8) bmi, kg/m2, mean ± sd 24.9±3.7 24.1 ± 3.1 .552 smoking, no (%) 52 (40.6) 44 (46.8) .511 family history, no (%) 67 (52.3) --- ---recurrence (n) 44 (34.3) --- ---serum calcium (mg/dl) 9.2 ± 0.6 9.1 ± 0.5 .039* serum phosphate (mg/dl) 3.5 ± 0.6 3.6 ± 0.6 .0001* urine calcium (mg/24h) 242.8 ± 145.3 107.5 ± 87.0 .0001* urine phosphate(mg/24h) 355.0 ± 239.8 291.6 ± 132.5 .045* urine ph 6.1 ± 0.6 6.0 ± 0.6 .400 creatinine (μmol/l) 91.6 ± 31.8 82.4 ± 23.5 .027* abbreviations: bmi, body mass index; sd, standard deviation. * p < .05 generated by comparison between healthy controls and stone patients. table 2. pcr primer sequences. upstream primer (5′-3′) downstream primer (5′-3′) length of gene segment rs3752472 cctcctttacctgaaaatcgg ggcttggtgagactgctgatt 104 bp rs650439 aggacgaccagctgagggtgtat tctggtgacataaccttcaggagct 104 bp rs1207568 tggacgctcaggttcattct cctctaggatttcggccagt 243 bp endourology and stone diseases 2940 pcr amplification primers the pcr amplification primers were designed according to the complete sequences in genbank and the study by (xu et al. 2013) (table 2). pcr amplification and genotype detection the total volume of the pcr reactants was 15 μl, which comprised the following: the upstream and downstream primers (0.2 μl each), template dna (0.5 μl), deoxyribonucleotide triphosphate (dntp) (10 mm), and distilled h2o (11 μl). the pcr amplification conditions were as follows: pre-degeneration at 95°c for 5 min; degeneration at 95°c for 30 s, annealing at 68°c for 45 s, and extension at 72°c for 60 s for a total of 40 cycles; and extension at 72°c for 6 minutes. the lengths of the amplified molecules were 122 bp (rs3752472), 104 bp (rs650439) and 243bp (rs1207568); they were analyzed using 3% agarose gel electrophoresis and an imaging system. the products of the pcr were sequenced by the life sciences corporation. statistical analysis the polymorphism allele frequencies were found to be consistent with hardy-weinberg equilibrium. genotypes, differences in genotype frequency distribution, and the correlation of specific genotypes with the occurrence and development of calcium oxalate stones were analyzed by the chi-squared test. the measurement data was expressed as mean ± standard deviation (sd). all data was analyzed on the spss software platform (v.17.0; spss inc., chicago, il, usa). p value < .05 was considered to be statistically significant. results genotype detection the pcr analyses revealed the presence of polymorphisms at the specific sites rs3752472 (mutant t/t (162 bp), wild type c/c (121,41 bp), and heterozygote c/t (162, 121, 41bp) phenotypes were obtained; figure 1, and rs650439 (mutant t/t (97,47 bp), wild type a/a(144 bp), and heterozygote a/t (144, 97, 47 bp) phenotypes; figure 2, and rs l207568 (mutant t/t (147, 96 bp), wild type c/c (243 bp), and heterozygote c/t (243, 147, and 96 bp) phenotypes ; figure 3. comparison of genotype and allele frequency for the rs3752472 snp, the results of genotype detection were as follows: or = 3.707, 95%ci: 1.861-7.384, x2 = 14.912; v = 1; and p < .01. people carrying the c/c genotype had a significantly higher risk of developing calcium oxalate stones (3.707 times higher) than people carrying the c/t+t/t genotype. there was a significant difference in the genotype frequency between the case and control groups. people carrying the c allele had a higher risk of developing calcium oxalates stones (table 3). for the rs650439 snp, the results of genotype detection were as follows: or = 1.169, 95%ci: 0.677-2.020, χ2 = 0.315, v = 1, p = .575. there was a significant difference in the distribution of a and t alleles between the case and control groups. people carrying the a allele were at higher risk of developing calcium oxalate stones (2.799 times higher) than those carrying the t allele (table 4). figure 1. genotyping of the rs 3752472 polymorphism site in the klotho gene. figure 2. genotyping of the rs 650439 polymorphism site in the klotho gene. klotho gene polymorphism in urolithiasis-ali et al. vol 14 no 01 january-february 2017 2941 for the rs1207568 snp, the results of genotype detection were as follows: or = 0.741, 95%ci: 0.428–1.285, χ2 = 1.140, v = 1, p = .286. there was no significant difference between the two groups (table 5). discussion urinary calculi affect many people globally, with a 1–5% prevalence and a 50% recurrence rate over 10 years. extensive research has shown that a disorder in calcium phosphate metabolism is related to urinary calculi, particularly calculi containing calcium. many genes, including the klotho gene, are involved in the development of urinary calculi. klotho was discovered by kuro-o et al.(5), and is mainly expressed in the renal tubules and choroid plexus as a type-i trans-membrane protein containing 1014 amino acids.(6-7) to a lesser extent, the protein is also expressed in the pituitary, parathyroid, pancreas, ovary, testis, and placenta. the klotho protein is not only found in the organs that regulate calcium balance, such as in the renal and parathyroid systems, and the choroid epithelial cells of the ventricles, but is also present in the blood and cerebrospinal fluid because its extracellular domain is usually involved in digestion.(6,8) human klotho is a type-i trans-membrane glycoprotein with β-glucuronidase catalytic activity, and is a regulator of calcium and phosphate levels.(9-10) there has been intensive international research into klotho gene polymorphisms and the calcium–phosphorus metabolic balance. xu et al.(4) found that there was a significant association between the rs3752472 snp in klotho and the risk of calcium oxalate nephrolithiasis. the risk attributed to the homozygote cc genotype was twice that of the heterozygote ct and homozygote tt genotypes, while the rs650439 snp was not related to the risk of calcium oxalate nephrolithiasis. we investigated klotho gene polymorphisms in xinjiang uyghur people by comparing case and control groups; in the rs3752472 snp, there was a significant difference between the risk for people carrying the c/c genotype (3.707 times more likely) compared with those carrying the t/t+t/c genotype (or = 3.707, 95%ci = 1.861–7.384, p < .01). the risk of developing calcium oxalate nephrolithiasis was 3.675 times greater for people carrying the c allele than for those carrying the t allele. however, in the rs650439 snp there was no significant difference between the genotype frequencies, but the distribution of a and t alleles was significantly different. the risk of calcium oxalate nephrolithiasis for the people carrying the a allele was 2.799 times higher than for those carrying the t allele (or = 2.799, 95%ci: 1.893–4.138, p < .01). telci et al.(3) studied the g395a, f252v, and c1818t polymorphisms of the klotho gene and found that only g395a was significantly associated with the risk of calcium oxalate nephrolithiasis. people carrying the gg genotype of the g395a klotho polymorphism were twice as likely to develop calcium oxalate nephrolithiasis as those with the homozygous aa or the heterozygote ga genotypes, while those with the a allele were at higher risk of the disorder and presented more obvious symptoms such as hypercalcemia and hypophosphatemia. yamada et al.(11) considered that the klotho gene g395a polymorphism was associated with prefigure 3. genotyping of the rs l207568 polymorphism site in the klotho gene. cases (n = 128) control (n = 94) or 95%ci p genotype (%) c/c 113 (88.3) 63 (67.0) 1 c/t 14 (10.9) 25 (26.0) t/t 1 (0.78) 6 (7.0) c/t+t/t 15 (11.7) 31 (33.0) 3.707 1.861–7.384 p < .01 allele (%) c 240 (93.75) 151 (80.3) 1 t 16 (6.25) 37 (19.7) 3.675 1.976–9.838 p < .01 table 3. comparison of genotype and allele frequencies of rs3752472. klotho gene polymorphism in urolithiasis-ali et al. endourology and stone diseases 2942 menopausal and postmenopausal bone mineral density, and the gg genotype was a risk factor for its reduction. xu et al.(12) found no significant differences in allele and genotype frequencies of the klotho gene g395a polymorphism (rs1207568) in their experimental and control groups. moreover, we also found no relationship between the klotho gene g395a polymorphism (rs1207568) and the risk of calcium oxalate nephrolithiasis when we compared patients and healthy volunteers from the xinjiang uyghur region. these results are influenced by race, the methods used, and the sample size, and further research is required. we found that polymorphisms resulting from klotho gene mutations had an effect on normal calcium and phosphorus metabolism, and led to a loss of ca2+, an increase in urinary calcium, an interaction with urinary matrix proteins, and high risk of lithogenesis. alapont pérez et al.(13) found that the risk of calcium oxalate nephrolithiasis was related to hot and dry climates. people living in the xinjiang region experience long days and consequently high levels of vitamin d. the klotho gene(14) and klotho mrna expression(15) are regulated by vitamin d receptors and vitamin d receptor elements, leading to an increase in intestinal calcium absorption and urinary calcium excretion. all of these factors have an effect on calcium and phosphorus metabolism. the situation is exacerbated by urinary concentration, which is one of the causes of calcium oxalate nephrolithiasis in xinjiang uyghur people. in this study, we found that the klotho gene rs3752472 and rs650439 snps are associated with the risk of calcium oxalate nephrolithiasis in uyghur people from the xinjiang region, and might be risk factors for the disorder. acknowledgement research supported by the national natural science foundation of china (grant #81460139). conflict of interest the authors report no conflict on interest. references 1. gürel a, üre i̇, temel h e, et al. the impact of klotho gene polymorphisms on urinary tract stone disease. world j urol; 2015: 1-6. 2. qian b, zheng l, wang q, et al. correlation between apoe gene polymorphisms and the occurrence of urolithiasis. exp ther med, 2015, 9: 183-6. 3. telci d, dogan au, ozbek e, et al. klotho gene polymorphism of g395a is associated with kidney stones . am j nephrol. 2011; 33: 337-43. 4. xu c, song rj, yang j, et al. klotho gene polymorphism of rs3752472 is associated with table 4. comparison of genotype and allele frequencies of rs650439. cases (n = 128) control (n = 94) or 95%ci p genotype (%) a/a 81 (63.3) 56 (59.6) 1 a/t 40 (31.3) 31 (33.0) t/t 7 (5.4) 7 (7.4) a/t+t/t 47 (36.7) 38 (40.4) 1.169 0.677–2.020 .575 allele (%) a 202 (78.9) 143 (57.2) 1 t 54 (21.1) 107 (42.8) 2.799 1.893–4.138 p < .01 cases (n = 128) control (n = 94) or 95%ci p genotype (%) c/c 74 (57.8) 61 (64.9) 1 c/t 46 (35.9) 23 (24.5) t/t 8 (6.3) 10 (20.6) c/t+t/t 54 (42.2) 33 (35.1) 0.741 0.428–1.285 .286 allele (%) c 194 (71.3) 145 (77.1) 1 t 78 (28.7) 43 (22.9) 0.738 0.480–1.134 .165 table 5. comparison of genotype and allele frequencies of rs1207568. klotho gene polymorphism in urolithiasis-ali et al. vol 14 no 01 january-february 2017 2943 the risk of urinary calculi in the population of han nationality in eastern china. gene. 2013;526: 494-7. 5. kuro-o m, matsumura y, aizawa h, et al. mutation of the mouse klotho gene leads to a syndrome resembling ageing. nature 1997; 390: 45-51. 6. matsumura y, aizawa h, shiraki-iida t, et al. identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein . biochem biophys res commun 1998;242: 626-30. 7. shiraki-iida t, aizawa h, matsumura y, et al. structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein . febs lett. 1998; 424: 6-10. 8. chen cd, podvin s, gillespie e, leeman se, abraham cr. insulin stimulates the cleavage and release of the extracellular domain of klotho by adam10 and adam17 . proc natl acad sci u s a 2007;104: 19796-801. 9. razzaque ms , lanske b. the emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. j endocrinol. 2007;194: 1-10. 10. tohyama o, imura a, iwano a, et al. klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides . j biol chem. 2004; 279: 9777-84. 11. yamada y, ando f, niino n, shimokata h. association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in japanese women . j mol med (berl). 2005; 83: 50-7. 12. xu c, song rj, wang xl , zhang w. the association among vitamin d receptor gene,klotho gene polymorphisms and calcium urolithia-sis. zhonghuashiyanwaikezazhi 2013;30: 2554-7 13. alapont pf, galvez cj, varea hj, colome bg, olaso oa, sánchez b.j. epidemiology of urinary lithiasis . actas urol esp. 2001; 25: 341-9. 14. whitfield gk, remus ls, jurutka pw, et al. functionally relevant polymorphisms in the human nuclear vitamin d receptor gene . mol cell endocrinol. 2001; 177: 145-59. 15. alexander rt, woudenberg-vrenken te, buurman j, et al. klotho prevents renal calcium loss . j am soc nephrol. 2009;20: 2371-9. klotho gene polymorphism in urolithiasis-ali et al. endourology and stone diseases 2944 sexual dysfunction and andrology the effects of nocturnal blood pressure patterns and autonomic alterations on erectile functions in patients with hypertension ercan yuvanc1*, mehmet tolga dogru2, vedat simsek2, hüseyin kandemir2, devrim tuglu1 purpose: hypertension (ht) is known to be of the main risk factors for erectile dysfunction (ed). but non-dipping (<%10 drop in the night) of ht is not investigated truly. the aim of this study was to test the hypothesis that the non-dipper hypertensive patients are more prone to develop erectile dysfunction. materials and methods: this was a cross-sectional clinical study. 70 ht patients diagnosed by ambulatory blood pressure monitoring (abpm) were classified into 3 groups (no ed, mild to moderate and severe) according to their international index of erectile function (iief) scores. all three groups were compared for their dipping status by abpm, heart rate variability (hrv) by holter monitoring. results: in our study non-dipper hypertensives had statistically more erectile dysfunction (p = 0.004). also severe ed patients with non-dipping pattern had decreased dipping blood pressure levels then those of ed(-) patients with non-dipping ht (p = .003) conclusion: autonomic dysfunction especially sympathetic overactivity is associated with both non dipping pattern of ht and erectile dysfunction as a common pathologic pathway, besides there might be an association between ed and non dipping ht. keywords: erectile dysfunction; non-dipper hypertension; sympathetic overactivity; heart rate variability; iief. introduction erectile dysfunction (ed) is one of the most com-mon health problems especially in the elderly male.(1) inadequate release and increased enzymatic destruction of nitric oxide (no) or altered response of penile vascular smooth muscle cells to no are the main etiologic factors of ed.(2) nevertheless, many of factors which may have an effect on endothelial and regulatory autonomic functions can cause erectile dysfunction.(2) from that point of view, ed can be regarded as a marker of vascular and autonomic dysfunction. virtually all cardiovascular risk factors including age, hypertension, diabetes mellitus, hyperlipidemia, smoking and obesity are risk factors which has a proven role on developing endothelial dysfunction.(3) hypertension has a higher prevalence than the other cardiovascular risk factors and as a result of this, hypertension is one of the most important risk factor for ed. it seems that increasing in both severity and duration of hypertension can be a cause of endothelial dysfunction.(4) on the other hand, hypertension could also show complex characteristics and especially subtypes which are determined by nocturnal blood pressure alterations.(5) patients whose blood pressure does not decrease at least 10% during nocturnal period have been defined as non-dippers.(5) many studies have shown that patients with essential hypertension with a non-dipper blood pressure pattern show an increased frequency of target 1 department of urology, kirikkale university, faculty of medicine, kirikkale 71100, turkey. 2 department of cardiology, kirikkale university, faculty of medicine, kirikkale 71100, turkey. * correspondence: kirikkale university, school of medicine, department of urology, kirikkale, turkey tel: +90 318 225 28 20. fax: +90 318 225 28 19 . email: ercanyuvanc@gmail.com. received september 2017 & accepted march 2018 organ damage.(6,7) it has also been suggested that there is more apparent endothelial dysfunction in hypertensive patients with a non-dipper profile.(8) non-dippers have been shown to have lower levels of endothelium dependent vasodilatation than dippers, due to lower levels of no release.(9) although there is extensive data about high ed prevalence in hypertensive patients. there is limited data about the relationship between circadian blood pressure alterations and erectile dysfunction.(10) in the present study we aimed to determine the relationship between the blood pressure patterns and erectile dysfunction in hypertensive patients and possible associations of circadian autonomic changes. material and methods this is a cross-sectional study. 110 male patients who admitted to the cardiology department for hypertension prediagnosis were screened in andrology department for erectile dysfunction. the study was carried out between april 2016 and april 2017 at the medical faculty of kırıkkale university. the study design was approved by the local ethics committee. detailed information was given to enrolled patients, and informed consent forms were signed by all participants. patient selection those with systolic blood pressure above 140 mmhg sexual disfunction & andrology 198 vol 16 no 02 march-april 2019 199 and those with diastolic blood pressure above 90 mmhg were included in the study as hypertensive patients. exclusion criteria were acute coronary syndromes, systolic heart failure (ef < 50%), coronary and peripheral artery disease , secondary hypertension, congenital heart disease, moderate and severe valvular heart disease, , thoracic/ abdominal aortic aneurysm, acute or a history of treatment for or diagnosis of carotid artery stenosis, chronic renal dysfunction (serum creatinine level >1.5 mg/dl), diabetes mellitus (fasting blood glucose level ≥126 mg/dl), malignancies, morbid obesity (body mass index [bmi] ≥ 40 kg/m2), asthma or chronic obstructive lung disease, infections, connective tissue disorders, neurological problems, psychiatric diseases (psychotic and major depressive patients and the patients with anxiety disorders), endocrine disease, alcohol and drug abuse and use of medications for hormonal treatment. forty patients were excluded because of progression of any exclusion criteria during the study period. in the present study, a total of 70 participants (minimum age: 24, maximum age: 82, mean age: 55.0 ± 12.7 years) were enrolled into the study. laboratory a fasting blood sample was drawn between 09.00 and 10.00 hours. laboratory work-up involved detailed biochemical analysis including complete blood count, fasting blood glucose, urea, creatinine, alt, ast and serum lipid profile (total cholesterol, ldl cholesterol, hdl cholesterol, triglyceride). serum hormone levels were determined by electrochemiluminescence immunoassay with the roche elecsys 2010 immunoassay analyzer using roche kit (roche diagnostic corporation, germany). in case of necessity for differential diagnosis of erectile dysfunction hormonal analyses (luteinizing hormone (lh), prolactin, total testosterone (tt), free testosterone (ft), estradiol (e2) and dehydroepiandrostenedione-sulphate (dhea-s))were performed additionally by using electrochemiluminescence immunoassay with the roche elecsys 2010 immunoassay analyzer using roche kit (roche diagnostic corporation, germany). urologic and andrologic evaluation erectile function evaluation: a specific turkish-translated version of the international index of erectile function (iief) questionnaire, i.e. erectile function (ef) domain, was used as the assessment instrument for measurement of ef and interventional efficacy.(11) the iief form was applied in all subjects for the assessment of sexual satisfaction by the department of urology.(12) as the gold standard instrument, the iief is an extensively used and highly validated instrument for the evaluation of sexual function in men especially in clinical trials.(13) the ef domain is a six-item version of the iief questionnaire that grades ef by responses to six specific questions of the iief questionnaire; question 1–5 are related to ef segment of iief and the last question concerns erectile confidence, i.e. question 15 of the iief.(12,13) if iief score was less than 26, these patients were accepted as ed. according to iief values, erectile dysfunction is evaluated as following classification: iief score ≥26: no ed, iief score 17–25: mild ed, iief score 11–16: moderate ed, and iief score < 10: severe ed. additionally, for the purpose of more detailed statistically analysis we also classified the scores of ed domain of iief as following: erectile dysfunction (ed) groups: group 1[ed (-)]: iief score ≥26: no ed group 2 [ed (+)]: iief score 11-25: mild -moderate ed group 3[ed (+)]: iief score < 10: severe ed cardiologic evaluation: after obtaining detailed medical history, physical examination including blood pressure measurement in both arms by using sphygmomanometer was done in all subjects. 12-channel electrocardiography (ecg) recordings and transthoracic echocardiography (ge-vivid 7 pro, general electric; fl, usa) were performed. ambulatory blood pressure monitoring we diagnosed essential hypertension by using ambulatory blood pressure monitoring (abpm) (ge tonoport, berlin, germany). abpm device was programmed to perform the measurement per 30 minutes in daytime (06:00-22:00) and per 60 minutes in nighttime (22:00-06:00). after 24 hour blood pressure monitoring, recordings were processed by using ge tonoport programme®. after that, evaluation of blood pressure levels were performed according to esc/esh 2013 hypertension guidelines.(14) after the hypertension diagnosis, all participants were splited up as to dropping levels of blood pressure at the nighttime. dropping levels of blood pressure is named as ‘’ dipping’’. additionally, the patients whose systolic blood pressure drop was over >%10 during the night period, were classified as ‘’dipper hypertension’’, and the remainders were classified as ‘’nondipper hypertension’’(15). dipping is calculated by following formula: systolic blood pressure dipping = [1( )]x100 we also calculated diastolic blood pressure dipping by using mean diastolic blood pressure night and daytime values in mentioned formula. in the present study, 47 dipper and 23 nondipper patients were detected and then admitted the study. heart rate variability (hrv) measurements nbp effect in erection in htn-yuvanc et al. patient characteristics mean ± standard deviation(sd) dipper hypertension nondipper hypertension p n:43 n:27 age (years) 54.97 ± 12.65 53.30 ± 12.68 57.63 ± 12.37 ns height (h)(cm) 172.04 ± 5.83 171.9 ± 5.5 172.2 ± 6.4 ns weight(w)(kg) 79.71 ± 9.95 79.8 ± 9.7 79.5± 10.5 ns body mass index (w/h2)(kg/m2) 26.94 ± 3.16 27.02 ± 3.20 26.79 ± 3.15 ns waist circumference (cm) 97.31 ± 11.76 97.7± 12.0 96.8± 11.4 ns abbreviations: ns, statistically nonsignificant table 1. the statistically comparisons about anthropometric characteristics of patients with dipper and nondipper hypertension. hrv measurements are related with r-r variations of a certain time period. it is well known that these measurements can reflect changes in autonomic states indirectly.(16) measurement of 24-hour hrv: after the clinical and laboratory tests ended, a holter device was affixed and starting time was adjusted to second sensitivity and when the recording time ends (24 hours) measurement of 24 hour hrv was performed. recordings were performed with 24-hour holter monitoring and analyzed with delmar-impresario system (delmar –impresario medical systems, irvine, california, usa).while evaluating the analyzed data, standard measurement criteria was utilized as stated by task force report in 1996.(16) rmssd was analyzed as the time domain hrv variables. rmssd was described as square root of the mean differences between successive rr intervals. the unit of the time domain measurement is milliseconds (msec).(16) power spectral (frequency) analysis of hrv was also performed using a fast fourier transform to break down the time series to its underlying periodic function. total power (tp) was defined as the energy in the heart period power spectrum from 0 to 0.40 hz. frequencies. the very low frequency (vlf) , low frequency (lf) and high frequency (hf) powers were defined as the energy in the heart period power spectrum between 0.003 0.04 hz.,0.04 -0.15 hz and 0.15 0.40 hz, respectively. the unit of the frequency domain measurements is millisecond square (msec) 2 .(16) then we calculated lf/hf (24 hour) lf / hf ratio (daytime), lf / hf ratio (nighttime), lf / hf ratio (daytime/nighttime) ratios. rmssd reflects parasympathetic activity as the hf power in frequency domain data. lf/hf reflects sympathovagal balance and increasing in this ratio is considered that reflect increased sympathetic activity.(16) in the present study, we used lf and hf, lf/hf ratio values as the frequency domain data and rmssd value as the time domain data of hrv. statistical analysis all statistical analysis was performed using spss version 20.0 (spss; chicago, il, usa). the normally distributed data are presented as mean ± standard deviation (sd) and non-normally distributed data are expressed as median (25%-75%). for continuous data student t table 2. the statistically comparisons about anthropometric characteristics among erectile dysfunction groups. patient characteristics group 1 ed(-) no ed n:28 group 2 ed(+) mild-moderate n:27 group 3 ed(+) severe n:15 p age(years) 48.07 ± 11.02 57.44 ± 11.97 63.40 ± 10.29 < 0.001 height(h) (cm) 173.79 ± 5.35 171.59 ± 6.97 169.60 ± 3.09 0. 0.069 weight(w)(kg) 81.04 ± 9.41 79.59 ± 11.01 77.47 ± 9.13 0.539 body mass index (w/h2)(kg/m2) 26.87 ± 3.23 27.00 ± 3.07 26.96 ± 3.39 0.989 waist circumference (cm) 95.00± 10.74 98.96 ± 12.34 98.66 ± 12.56 0.410 abbreviations: ns, statistically nonsignificant; ed, erectile dysfunction. patient characteristics dipper hypertension n:43 nondipper hypertension n:27 p ambulatory blood pressure monitoring (abpm) measurement mean systolic blood pressure (24 hour)(mmhg) 144.5 ± 13.5 146.7 ± 7.9 0.447 mean diastolic blood pressure (24 hour) (mmhg) 87.0 ± 11.3 88.2 ± 6.3 0.618 mean systolic blood pressure (daytime) (mmhg) 148.1 ± 13.1 147.1 ±7.6 0.676 mean diastolic blood pressure (daytime) (mmhg) 89.8 ± 11.1 89.4 ± 6.9 0.872 mean systolic blood pressure (nighttime) (mmhg) 131.2 ± 11.5 144.3 ± 12.0 < 0.001 mean diastolic blood pressure (nighttime) (mmhg) 78.0 ± 11.9 84.4 ± 7.8 0.019 *mean systolic pressure dipping (%) 13.66 (11.62-15.17) 0.40 (2.52 6.30) < 0.001 *mean diastolic pressure dipping(%) 14.73 (9.00-18.31) 3.18 (0.90 -11.71) 0.001 heart rate variability measurements (frequency domain) *low frequency (lf) (24 hour) (msec) 2 238.0 (137.5-603.2) 347.6 (157.4-554.5) 0.629 *high frequency (hf)(24 hour) (msec) 2 111.2 (48.3-181.5) 111.28 (80.26-226.7) 0.463 *lf/hf (24 hour) 2.75 (1.50 4.44) 2.31(1.75-3.98) 0.963 *low frequency (lf) (daytime)(msec) 2 267.1(131.9-500.3) 284.8 (122.53-451.5) 0.668 *high frequency (hf)(daytime)(msec) 2 62.6 (26.4-113.8) 75.4 (36.7-128.5) 0.663 *lf/hf (daytime) 4.44 (3.08-6.20) 3.15 (1.92-4.28) 0.014 *low frequency(lf)(nighttime)(msec) 2 378.6 (175.5-627.0) 316.6 (135.1-194.7) 0.405 *high frequency(hf)(nighttime)(msec) 2 159 (121.4-182.6) 179.4 (136.9-435.9) 0.132 *lf/hf (nighttime) 1.89 (1.42-2.65) 3.50 (1.74-4.69) 0.050 *lf/hf (daytime/ nighttime ratio) 2.20 (1.36-3.37) 0.83 (0.56-1.39) <0.001 heart rate variability measurements (time domain) * rmssd(24 hour) (msec) 28.0 (19.0-37.0) 26.0 (22.5-38.0) 0.810 * rmssd(daytime) (msec) 42.7 (28.2-72.8) 37.5 (23.9-51.2) 0.777 * rmssd(nighttime) (msec) 48.7 (25.5 80.4) 39.3(27.8-60.8) 0.145 iief score iief 23.28 ± 6.56 14.33 ± 9.56 < 0.001 abbreviations: ns, statistically nonsignificant; abpm, ambulatory blood pressure monitoring; iief, international index of erectile function. student t test, mean ± sd, p < 0.05, *mann whitney u test, median (75%-25%),p < 0.05, table 3. the statistically comparisons about ambulatory blood pressure monitoring (abpm) measurements, heart rate variability and iief scores of patients with dipper and nondipper hypertension. nbp effect in erection in htn-yuvanc et al. sexual disfunction & andrology 200 vol 16 no 02 march-april 2019 201 test with was used for comparing normally distributed data. mann whitney u test was used for comparing non-normally distributed data. pearson and spearman tests were used for correlation analysis. univariate analysis type iii was also performed for the evaluation of the factors which were of important associations with ed. a p value of < 0.05 was accepted as statistically significant. multivariate analyses were performed for comparing groups to show the effect of confounders and even interaction. results in the present study, a total of 70 participants were enrolled into the study (minimum age: 24 , maximum age : 82, mean age 55.0 ± 12.7 years). tables 1 and 2 shows that anthropometric characteristics of the patients that were admitted to the study. there were no differences in anthropometric measures, hormonal and biochemical tests between the patients with dipper and nondipper hypertension. besides we did not detect any statistically significant between same measurements except age among the ed groups ((p>0.05 and for age characteristic) p < 0.001, student t test, tables 1 and 2). in study group, there were 43 patients (%61.4) with dipper hypertension, 27 patients (%38.6) with nondipper hypertension. we detected that, there were 28 patients (%40.0) with normal erectile functions, 27 patients (%38.6) with mild-moderate erectile dysfunction and 15 patients (%21.4) with severe erectile dysfunction. there were only 6 patients with nondipper hypertension have normal erectile functions. furthermore, in the patient group which have severe erectile dysfunction (15 patients) , there were 11 patients with nondipper hypertension. we determined that, there was statistically significant association between the presence of severe erectile dysfunction and nondipper hypertension (p = 0.004, pearson chi-square). there are statistically significant differences about mean systolic and diastolic pressure dipping between dipper and nondipper hypertension groups (p < 0.001 and p = 0.001, student t test, respectively). we also determined that there are statistically significant differences about lf / hf ratio (daytime ), lf / hf ratio (nighttime ), lf / hf ratio (daytime/nighttime) values between dipper and nondipper hypertension groups ( p = 0.014, p = 0.050 and p < 0.001, student t test, respectively) . additionally, we found that the patients with dipper hypertension have higher iief scores than those of the patients with nondipper hypertension (p = 0.001, student t test)(table 3). when we evaluated the ed groups, there are statistically significant differences about mean systolic and diastolic pressure dipping among ed groups (p = 0.004, kruskal wallis test). after bonferroni adjustment, we found that the patients with severe ed have lower dipping blood pressure measures than those of ed (-) group (p = 0.002)(table 4). we also determined that there are statistically significant differences about lf / hf ratio (nighttime) and lf / hf ratio (daytime/nighttime) values among ed groups (p = 0.050 and p < 0.001, kruskal wallis test, respectively) (table 4). correlation analyses we performed partial correlation analyses of iief scores with hrv and abpm measurements. after contable 4. the statistically comparisons about ambulatory blood pressure monitoring (abpm) measurements, heart rate variability and iief scores erectile dysfunction (ed) groups. patient characteristics group 1 ed(-) group 2 ed(+) group 3 ed(+) p no ed n:28 mild-moderate n:27 severe n:15 ambulatory blood pressure monitoring (abpm) measurements mean systolic bp (mmhg)(24 hour) 146.0 ± 11.95 142.29 ± 10.31 150.39 ± 11.42 0.096 mean diastolic bp (mmhg) (24hour) 89.19 ± 10.18 85.09 ± 9.27 89.55 ± 8.12 0.223 mean systolic bp (mmhg)(daytime) 148.08± 10.56 144.74 ±9.72 1 52.10± 11.84 0.099 mean diastolic bp (mmhg) (daytime) 92.45 ± 10.37 86.79 ± 8.53 90.82 ± 8.82 0.109 mean systolic bp(mmhg) (nighttime) 129.72± 10.55 133.24 ± 13.57 144.15 ± 14.36 0.003 mean diastolic bp(mmhg) (nighttime) 80.11 ± 9.25 78.34 ± 11.94 85.95 ± 9.18 0.095 *mean systolic pressure dipping (%) 13.03 (10.66-13.04) 10.98 (1.58 -13.79) 4.28(1.70 -10.85) 0.004 *mean diastolic pressure dipping (%) 13.15 (7.33-18.05) 11.74 (1.16 -17.38) 4.49(1.66-11.76) 0.045 heart rate variability measurements (frequency domain) *low frequency (lf) (24 hour)(msec) 2 359.2 (174.9-577.3) 231.8 (124.3-668.6) 234.1(134.8-531.5) 0.629 *high frequency (hf) (24 hour)(msec) 2 136.3(93.0-263.2) 108.1(38.4-187.1) 101.4 (51.7-163.3) 0.463 *lf/hf (24 hour) 2.17(1.55-3.83) 3.11 (1.86-5.15) 2.31 (1.07-5.12) 0.963 *low frequency (lf) (daytime)(msec) 2 284.8 (140.1-470.1) 307.7 (126.6-533.5) 196.8 (102.5-389.8) 0.668 *high frequency (hf) (daytime)(msec) 2 75.4 (28.2-143.3) 61.7 (33.8-121.5) 67.6 (24.4-113.8) 0.663 *lf/hf (daytime) 3.77 (3.12-6.0) 3.83 (2.60-4.44) 3.09 (1.86-4.69) 0.014 *low frequency (lf) (nighttime)(msec) 2 349.4 (173.4-510.9) 347.6 (208.0-688.4) 293.7 (106.4-488.8) 0.405 *high frequency (hf)(nighttime)(msec) 2 217.4 (63.3-321.1) 203.8 (85.1-330.9) 59.1(31.3-184.9) 0.132 *lf/hf (nighttime) 1.66 (1.24-2.43) 1.98 (1.45-4.16) 3.70 (2.65-5.14) 0.050 *lf/hf (daytime/ nighttime ratio) 2.36 (1.36-3.34) 1.88 (1.01-3.27) 0.72 (0.35-1.64) <0.001 heart rate variability measurement (time domain) *rmssd(24 hour) (msec) 29.0 (23.0-321.1) 26.0 (17.5-33.5) 25.0(18.0-41.0) 0.810 * rmssd(daytime) (msec) 40.2 (25.8-62.9) 27.0 (20.6-43.3) 27.3(20.2-39.5) 0.777 * rmssd(nighttime) (msec) 48.3 (31.5-80.7) 37.1 (26.2-53.4) 30.6(22.0-51.5) 0.145 iief score iief 28.0 ± 1.9 18.9 ± 4.4 6.1 ± 3.7 < 0.001 abbreviations: ns, statistically nonsignificant, bp: blood pressure. abpm, ambulatory blood pressure monitoring; iief, international index of erectile function. one way anova test, mean ± sd, p < 0.05, *kruskal wallis test, median (75%-25%), p < 0.05, nbp effect in erection in htn-yuvanc et al. sexual disfunction & andrology 202 trolling the effects of age, weight, height, body mass index and waist circumference measures, there were positive correlation between iief scores and lf/hf ratio (daytime/nighttime) and mean systolic blood pressure dipping (r: 0.371, p = 0.014; r: 0.453, p = 0.002, partial correlation analysis, respectively). there was negative correlation between iief scores and mean systolic blood pressure nighttime values (r:0.398, p = 0.008; partial correlation analysis, respectively). we also performed univariate analysis to reveal the associations between iief scores and hrv and abpm results. according to univariate model which is of controlling the statistically affects of age, weight, height, body mass index, waist circumference, mean systolic blood pressure dipping measures, lf/hf daytime/ nighttime ratios ; we determined that iief scores have still shown statistically significant associations with mean systolic blood pressure dipping and lf/hf daytime/nighttime ratio measures, age (f: 11.204, p = 0.001; f: 6.199, p = 0.015 and f: 4.458, p = 0.039, univariate analysis type iii, p < 0.05, respectively). we used a multivariate analysis model, including iief score, age, height, weight, waist circumference, daytime and nighttime lf/hf ratios (sympathetic tonus), systolic and diastolic daytime and nighttime mean blood pressure ratios, daytime and nighttime hf (parasympathetic tonus) (table 5). we determined that there is a close statically association between ed severity and blood pressure dipping levels at nighttime (f (wilks’ lambda): 31.957)(p < 0.001) (pairwise comparisons, p= 0.004). the odds ratio of ed for abpm results were 6.36 (2.15-18.85)(p < 0.001). discussion in the present study, we found that there was statistically significant relationship between the presence of ed and dipping characteristics of blood pressure in the patients with hypertension. according to our results, the patients with nondipper hypertension which has strong association with more endothelial dysfunction and target organ damage have more severe erectile dysfunction symptoms than those of the patients with dipper hypertension. we also determined that both the patients with nondipper hypertension and severe ed has higher sympathetic tonus compared to the patients with dipper hypertension. besides, in our study, we detected that sympathetic overactivity may have a role in both nondipper hypertension and erectile dysfunction in the same time. additionally, the most important result of our study about circadian autonomic dysfunction both in severe ed and nondipper hypertension was decreased ratio of lf/hf daytime / lf /hf nighttime measures which reflects circadian sympathetic balance of autonomic nervous system. endothelial and autonomic functions have a key role to perform cardiovascular and metabolic functions with observable and measurable clinical and biochemical characteristics. relaxation and contraction capacities of arteries, peripheral and pulmonary vascular resistance and elasticity, blood pressure regulation, releasing and balancing of coagulant and anticoagulant agents, hormonal, metabolic and erectile functions are only a few of the processes that are made by contribution of vascular endothelial layer and autonomic nervous system. the relationship between endothelial dysfunction and hypertension is a well studied issue in last decade.(15, 17) there are a lot of studies in which endothelial dysfunction was to be one of the main pathophysiological process in hypertension and its related end organ damage.(15,17-19) hypertension is one of the most common diseases that is based on endothelial and autonomic dysfunctions. additionally, it is well known that, endothelial and autonomic dysfunctions are also two of the most important reasons of erectile dysfunction. there are a lot of studies in the literature which reveal the high prevalence of erectile dysfunction in patients with hypertension.(20-23) nondipper hypertension is a clinical type of systemic hypertension that shows less than %10 decreases in nocturnal blood pressure levels. it is also related with high incidence of clinical complications which associate with target organ damages. many of studies have shown that nondipper hypertension has a close association with endothelial dysfunction left ventricular hypertrophy, increased proteinuria, secondary forms of hypertension, increased insulin resistance, and increased fibrinogen level.(24-25) however, nondipper hypertension is not only related with endothelial and metabolic functions. in spite of having some contradictory results, it might depend on autonomic imbalance and pathological higher sympathetic activity in the patients with nondipper hypertension composed to those of dippers.(26-28) additionally, it is a well known fact that erectile dysfunction is also closely related with autonomic dysfunction. decreased parasympathetic and increased sympathetic activity are important factors of erectile dysfunction pathogenesis. penile erection of nocturnal and early morning time which shows healthy erectile functions which closely depend on healthy autonomic functions that reveal higher parasympathetic and lower sympathetic activity during nocturnal period.(29,30) according to our data, there was a statistically significant positive association between the presence of nondipper hypertension and severe ed. the patients with severe ed have both higher mean nocturnal systolic and diastolic blood pressure levels and nondipper blood pressure pattern. in our study, when we evaluated table 5. the results of multivariate analysis. patient characteristics fvalues pvalues age (years) 0.169 0.845 height (h) (cm) 2.688 0.082 weight (w)(kg) 2.857 0.071 waist circumference (cm) 1.925 0.161 high frequency (hf)(daytime)(msec)2 3.178 0.054 low frequency (lh) / high frequency (hf) (daytime) 0.399 0.674 high frequency (hf)(nighttime)(msec)2 2.738 0.078 lf/hf (nighttime) 1.905 0.236 lf/hf(daytime/ nighttime ratio) 0.787 0.463 ed severity 31.957 < 0.001 nbp effect in erection in htn-yuvanc et al. vol 16 no 02 march-april 2019 203 the heart rate variability measures, we also found that there were higher nocturnal sympathetic activity which is reflected by lf/hf ratio both in the patients with nondipper hypertension and severe ed. moreover, partial correlation analysis and univariate analysis results have shown that there were statistically significant associations between iief scores and mean systolic blood pressure dipping and lf/hf daytime/nighttime ratio measures after controlling the effects of anthropometric characteristics. this data leads us to think that, both nondipper hypertension and erectile dysfunction is closely related with autonomic dysfunction and higher incidence of erectile dysfunction in the patients with nondipper hypertension might depend on autonomic dysfunction. limitations: we consider that major limitation of the present study is the absence of serum no levels and being a small scale study. conclusions in this study, we determined that, autonomic dysfunction might be effective on pathological processes of both nondipper hypertension and ed. besides, lower iief scores of the patients with nondipper hypertension depend on autonomic dysfunction as a common pathological pathway. conflict of interest the authors report no conflict of interest. references 1. gareri p, castagna a, francomano d, et al. erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives. int j endocrinol. 2014; 2014: 878670. 2. dean rc, lue tf. physiology of penile erection and pathophysiology of erectile dysfunction. the urologic clinics of north america. 2005; 32: 379-95. 3. javaroni v, neves mf. erectile dysfunction and hypertension: impact on cardiovascular risk and treatment. int j hypertens. 2012; 2012: 627278. 4. quyyumi a., patel s. endothelial dysfunction and hypertension cause or effect? hypertension. 2010; 55: 1092-94. 5. routledge fs, mcfetridge-durdle ja, dean c. night-time blood pressure patterns and target organ damage: a review. the canadian journal of cardiology. 2007; 23: 132-38. 6. cicconetti p, morelli s, ottaviani l, et al. blunted nocturnal fall in blood pressure and left ventricular mass in elderly individuals with recently diagnosed isolated systolic hypertension. am j hypertens. 2003; 16: 900–5. 7. cuspidi c, meani s, salerno m, et al. cardiovascular target organ damage in essential hypertensives with or without reproducible nocturnal fall in blood pressure. jhypertens 2004; 22: 273–80. 8. alioglu e, turk uo, bicak f, et al.vascular endothelial functions, carotid intima-media thickness, and soluble cd40 ligand levels in dipper and nondipper essential hypertensive patients. clin res cardiol. 2008; 97: 457-62. 9. higashi y, nakagawa k, kimura m, et al. circadian variation of blood pressure and endothelial function in patients with essential hypertension: a comparison of dippers and non-dippers. j am coll cardiol. 2002; 40: 2039-43. 10. erden i, ozhan h, ordu s, et al. the effect of non-dipper pattern of hypertension on erectile dysfunction. blood press. 2010; 19: 249-53. 11. öztürk m i̇, koca o, keleş m o, question for a questionnaire: the international index of erectile function international journal of impotence research 2011: 23: 24–6. 12. rosen rc, cappelleri jc, gendrano iii n. the international index of erectile function (iief): a state-of-the-science review. int j impot res 2002; 14: 226–44. 13. cappelleri jc, rosen rc, smith md et al. diagnostic evaluation of the erectile function domain of the international index of erectile function. urology 1999; 54: 346. 14. mancia g, fagard r, narkiewicz k, et al.2013 esh/esc guidelines for the management of arterial hypertension: the taskforce for the management of arterial hypertension of the european society of hypertension (esh) and of the european society of cardiology (esc). j hypertens. 2013; 31:1281-357. 15. park k-h, park wj. endothelial dysfunction: clinical implications in cardiovascular disease and therapeutic approaches. journal of korean medical science. 2015; 30: 121325. 16. heart rate variability: standards of measurement, physiological interpretation, and clinical use. task force of the european society of cardiology (esc) and the north american society of pacing and electrophysiology (naspe) circulation 1996; 93: 1043-65. 17. dinh qn, drummond gr, sobey cg, et al. roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. biomed research international. 2014; 2014: 406960. 18. adam harvey, augusto c. montezano, et al vascular biology of ageing—implications in hypertension j mol cell cardiol. 2015; 83: 112–21. 19. rubattu s, pagliaro b, pierelli g, et al pathogenesis of target organ damage in hypertension: role of mitochondrial oxidative stress int j mol sci. 2015 ; 16: 823–39. 20. delay k, haney n, hellstrom w. modifying risk factors in the management of erectile dysfunction: a review world j mens health. nbp effect in erection in htn-yuvanc et al. sexual disfunction & andrology 204 2016; 34: 89–100. 21. maiorino m, bellastella g, esposito k. diabetes and sexual dysfunction: current perspectives. diabetes metab syndr obes. 2014; 7: 95–105. 22. salonia a, capogrosso p, clementi mc. is erectile dysfunction a reliable indicator of general health status in men? arab j urol. 2013; 11: 203–11. 23. tiftikcioglu bi, bilgin s, duksal t et al. autonomic neuropathy and endothelial dysfunction in patients with impaired glucose tolerance or type 2 diabetes mellitus medicine (baltimore) 2016; 95: e3340. 24. pusuroglu h, cakmak ha, erturk m. assessment of the relation between mean platelet volume, non-dipping blood pressure pattern, and left ventricular mass index in sustained hypertension med sci monit. 2014; 20: 2020–26. 25. ryu j, cha r, kim dk. the clinical association of the blood pressure variability with the target organ damage in hypertensive patients with chronic kidney diseasej korean med sci. 2014; 29: 957–64. 26. mcgregor do, olsson c, lynn kl. autonomic dysfunction and ambulatory blood pressure in renal transplant recipients. transplantation. 2001; 71: 1277-81. 27. liu m, takahashi h, morita y. non-dipping is a potent predictor of cardiovascular mortality and is associated with autonomic dysfunction in haemodialysis patients. nephrol dial transplant. 2003; 18: 563-69. 28. nakano y, oshima t, ozono r, et al. nondipper phenomenon in essential hypertension is related to blunted nocturnal rise and fall of sympatho-vagal nervous activity and progress in retinopathy. auton neurosci. 2001; 88: 181–86. 29. pereira de souza neto e, fernández ea, abry p, application of cardiac autonomous indices in the study of neurogenic erectile dysfunction. urol int. 2011; 86: 290-97. 30. chen cj, kuo tb, tseng yj, combined cardiac sympathetic excitation and vagal impairment in patients with non-organic erectile dysfunction. clin neurophysiol. 2009; 120: 348-52. nbp effect in erection in htn-yuvanc et al. urological oncology osteopontin and angiogenic factors as new biomarkers of prostate cancer tomasz wiśniewski1,2*, agnieszka żyromska1,3, roman makarewicz1, ewa żekanowska4 purpose: the novel biomarkers that would identify patients at risk for relapse and metastatic spread are needed. the aim of this study was the evaluation of serum levels of osteopontin (opn) and tumor endogenous angiogenic factors such as vascular–endothelial growth factor (vegf), vascular-endothelial growth factor receptor 2 (vegf r2), endostatin, angiostatin and thrombospondin 1, in prostate cancer (pc) patients. material and methods: blood concentrations of the analyzed parameters were determined in 40 prostate cancer patients eligible for radiotherapy as well as in a control group consisting of 25 volunteers. commercial elisa kits were used for the analysis. results: significantly higher levels of opn (101.49 ng/ml vs 59.88 ng/ml; p < .001), endostatin (252.60 ng/ ml vs. 223.55 ng/ml; p = .043), angiostatin (47 ng/ml vs. 13 ng/ml; p = .047), vegf (262.1 pg/ml vs. 138.0 pg/ml; p = .056) and vegf r2 (11188.81 pg/ml vs. 9377.50 pg/ml; p = .047) were detected in pc patients compared with the control group. in pc patients we showed a positive correlation between opn level and tnm clinical stage (r = 0.36; p = .02) and negative correlation between opn level and hemoglobin concentration (r=0.33; p = .04). conclusion: the study showed higher levels of the angiogenic factors in pc patients compared with the control group and identified opn as an indicator of the pc clinical stage as well as a decreased hemoglobin level. keywords: osteopontin; angiogenesis factors; prostate cancer. introduction prostate cancer is the second most common malig-nancy in men. despite an overall good prognosis for prostate cancer patients it is estimated that among radically treated patients as many as 25% will experience recurrence of the disease during the first 3 years after treatment. there is now an ongoing intense search for factors responsible for the increased risk of relapse in individual patients, including osteopontin (opn) or angiogenic factors as potential cancer aggressiveness predictors. in the cancer progression a process of angiogenesis plays an important role being critical in the phenomena of an invasion and metastasising. pc is recognizable by a low vessel density and a slow cell proliferation. production of numerous anti-angiogenic factors such as: angiostatin, endostatin, prostate specific antigen (psa), thrombospondin 1, interleukin 10 (il-10), interferons and retinoids may be responsible for such a pc characteristic.(1) presently these factors are a subject of both pre-clinical and clinical studies. the prominent pc propensity to bone metastasis indicates that bone metabolism markers may be potentially utilized as prognostic factors. there is a special interest in osteopontin (opn) which is a representative of a sia1department of oncology and brachytherapy, nicolaus copernicus university collegium medicum, bydgoszcz, poland. 2radiotherapy department of franciszek lukaszczyk oncology center, bydgoszcz, poland. 3amethyst radiotherapy centre, zgorzelec, poland. 4department of pathophysiology, nicolaus copernicus university collegium medicum, bydgoszcz, poland. *correspondence: department of oncology and brachytherapy, nicolaus copernicus university collegium medicum, ul dr. i. romanowskiej 2, 85-796 bydgoszcz, poland tel.: +48 52 374 3320 ; e-mail: wisniewskitomasz9@gmail.com. received december 2017 & accepted may 2018 loprotein family. in healthy individuals it is involved in such processes as: an early immune response, inhibition of a cellular apoptosis as well as a stress or pressure induced bone modelling.(2) opn increased concentration has been observed in numerous pathological conditions. it is responsible for an initiation and progression of atherosclerotic lesions as it facilitates a deposition of calcium in vascular walls. presumably, the protein plays a role in a recurrent coronary stenosis. it also affects the growth and proliferation of tumour cells, and makes metastasising easier by promoting binding tumour cells with integrins. on the other hand suppressed expression of opn significantly inhibited cell invasiveness and anchorage-independent growth.(3) opn involvement in the formation of new vessels is still under investigation.(4,5) opn can stimulate angiogenesis because it promotes the endothelial cell survival due to interaction with αvβ3 integrin.(5) other investigators found that opn produced by nontumor cells plays a host protective role in prostate tumor development.(6) there are also pre-clinical evidence suggesting that opn is involved in inducing chemoresistance.(5) the aim of this study was the analysis of serum levels of opn and tumour angiogenic factors including: angiostatin, endostatin, thrombospondin, vascular-endothelial growth factor (vegf) and its receptor 2 (vegf urological oncology 134 vol 16 no 02 march-april 2019 135 r2) in pc patients. we analysed a relationship between baseline levels of the estimated parameters and classic prognostic factors including: clinical stage, histological grade, psa level as well as patient age, prostate volume and haemoglobin concentration. we also determined a connection between the levels of osteopontin and the angiogenic factors. patients and methods study population the study included 40 prostate cancer patients eligible for radical radiotherapy. inclusion criteria were adult male with pathologically confirmed prostate cancer and written informed consent. patients with distant metastases, previous oncological treatment due to another cancer or previous radiotherapy to the pelvis area were excluded from the study. before the treatment, all patients underwent blood tests, prostate biopsy, magnetic resonance imaging (mri) of the pelvis as well as per rectum examination in order to determine classic prognostic factors including a maximum psa level, clinical stage according to the tnm classification and a tumour grade according to the gleason scoring system. additionally, in each patient the prostate volume was determined based on computed tomography (ct) performed for radiotherapy planning. the control group was recruited from healthy men who responded to an invitation letter for prophylactic tests in our oncology center. after excluding prostate cancer (based on psa level and per rectum examination) a randomly chosen 25 men were proposed to participate in our study as a control group. patients with previous oncological treatment due to another cancer were excluded from a study. the study protocol was approved by the bioethical committee of ludwik rydygier collegium medicum in bydgoszcz of nicolaus copernicus university in torun. all the individuals participating in the project were given an informed written consent. the european union “program of the development of collegium medicum of nicolaus copernicus university” and a grant for young researchers (mn-5/wl/sd) were the sources of the study funding. the concentration of hemoglobin was tested on the first day of radiotherapy. the peripheral blood was taken between 7.30 and 8.30 a.m. from the basilic vein of the forearm to sterile vacutainers (becton dickinson, franklin lakes, new jersey, usa) with 3.2% citrate solution as well as to clot. test-tubes were centrifuged for 15 minutes in 4°c at the speed of 1500 x g. prior to the analysis the blood samples were divided into eppendorf sterile tubes and stored in 80°c. concentrations of the analysed biomarkers were measured with the enzyme-linked immunosorbent assays. detailed data of the test are given in table 1. statistical analyses statistical analyses were performed using statistica commercial software (version 9.0; statsoft, tulsa, oklahoma, united states). p-values less than 0.05 were considered statistically significant. the shapiro–wilk test was used to evaluate a normality of individual parameters, and, due to the absence of normal distribution, the results were presented as medians (me) as well as a lower (q1) and upper quartile (q3). a difference between the tested parameters in individual groups was estimated using the non-parametric u mann-whitney test. in the case of a correlation between parameters that did not present a normal distribution the spearman coefficient (r) was applied. results a clinical characteristics of the patients is presented in table 2. an average age was 67 years (range: 56 – 81) in the tested group and 64 years (range: 51 – 77) in the control group (p = .4). the most significant difference considered opn measurements. a median level of opn in the pc patients was 101.49 ng/ml compared with 59.88 ng/ml in the healthy men (p < .001). these results are presented in figure 1. in the pc group we determined a relationship between a baseline level of the tested parameters and classic prognostic factors(tnm clinical stage, gleason score, psa level) as well as other clinical features such as: patient’s age, prostate volume and hemoglobin concentration. in the tested group we prove a positive correlation between a baseline level of opn and clinical stage (r=0.36; p = .02) (figure 2) and a negative correlation between opn level and hemoglobin concentration (r=-0.33; p = .04) (figure 3). only the median level of thrombospondin 1 was lower in the tested group than in the controls, however the difference was not significant (27111.1ng/ml vs. 31246.4ng/ml; p = .615) (figure 1). a significantly higher median value of vegf r2 was noted in the patients compared with the control group (11188.81 pg/ ml vs. 9377.50 pg/ml; p = .047). also the median level of vegf was about twice as high in the tested group as in the healthy men although the difference was at the limit of a statistical significance (262.1 pg/ml vs. 138.0 pg/ml; p = .056) (figure 4). the analysis of the angiogenic inhibitors showed that in the cancer patients the median concentration of endostatin was significantly higher than in the control group (252.60 ng/ml vs. 223.55 ng/ml; p = 0.043). similarly, the median level of angiostatin was more than three times higher (47 ng/ ml vs. 13 ng/ml; p = 0.047) in the treatment group (figure 5). we did not find any correlation between the baseline levels of the angiogenic factors and such clinical factors as: gleason score, psa level, patient’s age and prostate new biological markers in prostate cancer wiśniewski et al. table 1. types of the tests used in the study. factor material name of the test company city, state country vegf serum human vegf immunoassay r&d systems minneapolis, minnesota usa vegf r2 serum human soluble vegf r2 immunoassay r&d systems minneapolis, minnesota usa osteopontin plasma human osteopontin immunoassay r&d systems minneapolis, minnesota usa endostatin plasma human endostatin immunoassay quantikine (dnst0) r&d systems minneapolis, minnesota usa angiostatin plasma human angiostatin elisa kit raybiotech norcross, georgia usa trombospondin 1 plasma human thrombospondin-1 immunoassay r&d systems minneapolis, minnesota usa volume. there was also no correlation between the angiogenic factors and osteopontin. discussion the aim of this study was to evaluate the levels of endogenous factors regulating tumour angiogenesis in prostate cancer patients. due to contradictory reports on the matter we decided to take into consideration a wide range of tested parameters in order to evaluate their relationship with clinical prognostic factors and to obtain a starting point for further tests in a larger group of patients. biomarkers that distinguish highly aggressive from moderately aggressive tumours and complement psa measurements are still required. our study proved almost twice as high level of osteopontin in the prostate cancer patients compared to the healthy men (me=101.49 ng/ml vs. 59.88 ng/ml; p < .001) which is compliant with a number of published reports on an increased osteopontin level in the course of different tumours. the results indicate that opn is a cancer biomarker and is related to a diseases clinical stage, histologic grade and early tumour progression in multiple cancer types. it is also a predictor of disease-free and overall survival in various malignancies.(7) it is noteworthy that there were significant discrepancies in opn levels in individual researchers which may result from a diverse biology of particular types of cancers. on the other hand, vordermark et al. conducted an experiment in which available elisa tests for opn determination generated diverse outcomes in the same blood sample which makes comparing results between researchers using different diagnostic kits practically impossible. (8) the overexpression of opn in prostate cancer cell lines induced their proliferation, invasion and, most notably, enhanced ability to intravasate blood vessels.(9) in prostate cancer patients an increased expression of vegf and opn are each associated with an increased frequency of biochemical failureand they also correlate with each other.(10) in our study there was no correlation between the levels of vegf and opn, probably due to the small amount of patients. opn levels are also higher in patients with bone metastases and it was suggested that opn could be a predictor of treatment response in metastatic castrate-resistant prostate carcinoma after chemotherapy.(11,12) in the presented study we showed a correlation between a baseline osteopontin concentration in pc patients and tnm stage (r=0.36; p = .02). in the literature there is no data which could be compared to our results. clinical observations on opn levels in other types of cancers are close to our results. in the study including head and neck cancer patients snitcovsky et al. showed higher levels of opn in higher clinical stages (p = .009). (13) by contrast, hui et al. did not show correlation between opn and clinical stage in nasopharyngeal cancer patients. however, the authors observed higher levels of the protein in individuals with distant metastases compared to controls (me=894 ng/ml vs. 513 ng/ml; p = .005).(14) the correlation between opn levels and a tumour grade was found in bladder cancer patients.(15) table 2. clinical characteristics of the tested group. characteristic value age (years), mean (range) 67 (56 81) maximum psa level before radiotherapy (ng/ml), mean (range) 23 (4.4 100) histological grade gleason score median (range) 6 (3 9) divided by groups, n (%) 2-6 31 (77.5) 7 4 (10) 8-10 5 (12.5) clinical stage according to tnm classification, n (%) t2an0m0 7 (17.5) t2bn0m0 10 (25) t2cn0m0 6 (15) t3an0m0 14 (35) t3bn0m0 3 (7.5) prostate volume (cm3), mean (range) 69 (26.9 – 143.3) haemoglobin level (ng/dl), mean (range) 13.8 (11.7 – 16.8) figure 1. osteopontin and trombospondin-1 levels in prostate cancer patients and control group patients. new biological markers in prostate cancer wiśniewski et al. urological oncology 136 vol 16 no 02 march-april 2019 137 an increase of osteopontin expression could possibly be connected with an oncogenic transformation of the prostate epithelial cells.(9) in a recently published experimental trial it has been proven that an overexpression of opn isoform b and c may lead to the prostate cancer cells resistance to the docetaxel based chemotherapy.(16) in the presented study the increased concentration of opn was correlated with lower hemoglobin levels (r=-0.33; p = .04). in pc patients there is no available research to which our results might be related. consistently to our findings snitcovsky et al. found a negative correlation between opn and hemoglobin concentrations (r=-0.39; p = .04) in head and neck cancer patients.(13). the authors suggested that opn may be an indicator of tumor hypoxia. le et al. confirmed this conclusion proving a negative correlation between opn and tumor oxygen partial pressure (po2) (r = -0.42; p = .003) determined with the eppendorf microelectrode in head and neck cancer patients. le also demonstrated that an average opn level in von hippel lindau disease patients was significantly higher compared with healthy volunteers (447 ng/ml vs. 318 ng/ml, p = .002).(17). such patients are characterized by the mutated expression of vhl gene which is involved in a cell reaction to hypoxia. two dahanca (danish head and neck cancer group) studies, both conducted in head and neck cancer patients, offered more proof to support the thesis that osteopontin may be a marker of tumour hypoxia. in the study by nordsmak et al. opn levels correlated negatively with tumour po 2 measured with an electrode before treatment.(18) in the randomized dahanca 5 study by overgaard et al. opn expression correlated negatively with the prognosis of irradiated patients. the prognosis improved after nimorazole treatment, an agent which sensitizes hypoxic cells to ionizing radiation. the researchers concluded that opn level may help to select potential beneficiaries of the nimorazole treatment.(19) moreover, an experimental study showed that opn expression increased under the influence of hypoxia in a culture of human glioblastoma multiforme cells.(20) in 34 head and neck carcinoma patients the opn concentration at normal hemoglobin values was almost 3 times higher compared with decreased hemoglobin levels (p = .02).(21) in a literature only one study was found to show that hypoxia does not influence the opn expression. four nasopharyngeal cancer cell lines were incubated in hypoxic conditions and with western blot technologies the intracellular hif-1 α protein concentration as well as opn level were evaluated. a significant increase of hif-1 α was noted, whereas the opn level remained the same. it was also shown that reoxygenation of previously hypoxic cancer cells did not influence the opn concentration.(14) in a prostate cancer cell line study riemann et al. evaluated an influence of hypoxia and extracellular acidosis on genes expression. they demonstrated that the expression of mrna for opn had decreased in hypoxic conditions and increased in an acid environment.(22) the above results prove that the influence of hypoxia on the opn level is not unequivocally confirmed and more studies are necessary in this field. among the five angiogenesis regulators we tested a figure 2. correlation between clinical stage according to tnm classification and osteopontin level (ng/ml). (tnm groups correspond to: 1 – t2an0m0, 2 – t2bn0m0, 3 – t2cn0m0, 4 – t3an0m0, 5 – t3bn0m0). figure 3. correlation between haemoglobin level (mg/dl) and osteopontin level (ng/ml) in the tested group of patients. figure 4. vegf and vegf r2 levels in prostate cancer patients and control group patients. new biological markers in prostate cancer wiśniewski et al. urological oncology 138 significantly increased level of two inhibitors including endostatin and angiostatin as well as one activator, vegf r2, was noted in cancer patients compared with the control group. the difference in the vegf level between the two groups was at the limit of a statistical significance (p = .056). reference literature data based on immunohistochemical studies suggest that healthy prostate tissue and tissue in patients with the benign prostatic hyperplasia contain a small amount of vegf, while a significant amount of this compound is present in pc cells.(23) it has been proven that patients with distant prostate cancer metastases have higher levels of vegf compared with patients without metastases and with healthy volunteers, but this evidence did not appear to be useful in predicting pc progression.(24,25) our study concerned only a few selected regulators of angiogenesis in pc, however we managed to show a prevalence of the inhibitors of this process. this may reflect a relatively negligible process of forming new vessels in prostate cancer. it is also suggested that high concentrations of angiogenesis inhibitors may block a development of dormant metastases.(26) in the presented study we did not confirm correlation between vegf level and such clinical factors as: psa level, gleason score or patient’s age which is in compliance with the results obtained by other researchers (1). only duque et al. observed significantly higher levels of vegf in patients with psa level > 20 ng/ml and a trend towards higher vegf values in patients with a high gleason score eg. 8-10.(24) the immunohistochemistry of prostate cancer shows a 100% vegf r1 expression, whereas vegf r2 expression is changeable and its intensity depends on a tumour grade.(27) in our cancer patients group no correlation was observed between vegf r2 level and the classic prognostic factors. it may result from the fact that vegf r2 has also an affinity to vegf c and d which both play an important role in lymphangiogenesis while prostate cancer disseminates rather via blood than lymphatic vessels. in the tested group we observed significantly increased endostatin levels compared with the controls. so far, increased levels of circulating blood endostatin were detected in patients with carcinomas of the breast, kidney, liver, ovarian, prostate, head and neck as well as in non-hodgkin lymphomas and soft tissue sarcomas. tests on rats and mice demonstrated that a high endostatin concentration resulted in a regression of a number of tumours, including prostate cancer.(28) to add, according to hasle et al., down syndrome patients who, due to 3 copies of the col18a1 gene, have high endostatin levels, are characterized by a decreased incidence of prostate cancer and other tumours.(29) a recently published research showed that endostatin may influence prostate cancer not only by impeding angiogenesis but also by blocking the androgen receptor.(30) in the case of angiostatin it was in vitro demonstrated that prostate cancer cells show the ability to transform plasminogen into angiostatin while, at the same time, they are not able to produce it without exogenous plasminogen.(31) it was shown that plasminogen is connected to the surface of cancer cells via β-actin, while angiostatin cannot bind to the cell membrane as it does not contain the necessary kringle 5 domain.(32) in vitro, psa, being a serine protease, transforms plasminogen into an active form of angiostatin through the proteolysis of glu 439-ala 440 binding.(33) we did not demonstrate a correlation between angiostatin and psa level, however, it may result from including maximum psa values into the analysis or from a small size of the tested group. additionally, psa is not the only enzyme generating angiostatin from plasminogen.(31) we found that in prostate cancer patients the level of thrombospondin 1 was close to its level in the healthy men. a literature on this issue is scarce. cell line tests showed that healthy prostate cells secrete large amounts of tsp-1, while low tsp-1 levels were observed in prostate cancer cell cultures.(23) the tsp-1 down-regulation correlates with a progression in proliferative diseases.(34) rofstad et al. consider thrombospondin 1 a positive factor in irradiated patients since it increases the efficiency of radiotherapy by lowering the fraction of tumour hypoxic cells and sensitizing tumour endothelial cells to ionizing radiation.(35) conclusions on the basis of the obtained results we assume that the process of tumor angiogenesis plays an important role in the prostate cancer pathogenesis. among the analysed parameters the greatest difference between the pc patients and healthy individuals was shown forosteopontin levels. the protein expression correlated positively with prostate cancer clinical stage and negatively with hemoglobin concentration. opn should be considered a novel biomarker which may complement psa measurements and improve a diagnostic and prognostic accuracy. acknowledgement funds necessary to perform the study were obtained from a scholarship financed by the european union as a part of the european social fund – the “program of development of collegium medicum of nicolaus copernicus university” as well as a grant for research facilitating the development of young researchers (mn5/wl/sd) ; granted to tw. figure 5. endostatin and angiostatin levels in prostate cancer patients and control group patients. new biological markers in prostate cancer wiśniewski et al. vol 16 no 02 march-april 2019 139 conflict of interest the authors report no 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with prostate cancer. prostate 2007;67:330-40. 12. thoms jw, dal pra a, anborgh ph, et al. plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response. br j cancer. 2012;107:840-6. 13. snitcovsky i, leitão gm, pasini fs, et al. plasma osteopontin levels in patients with head and neck cancer undergoing chemoradiotherapy. arch otolaryngol head neck surg. 2009;135:807–11. 14. hui ep, sung fl, yu bk, et al. plasma osteopontin, hypoxia, and response to radiotherapy in nasopharyngeal cancer. clin cancer res. 2008;14:7080–7. 15. ang c, chambers af, tuck ab, winquist e, izawa ji. plasma osteopontin levels are predictive of disease stage in patients with transitional cell carcinoma of the bladder. br j urol int. 2005;96:803–5. 16. nakamura kd, tilli tm, wanderley jl, et al. osteopontin splice variants expression is involved on docetaxel resistance in pc3 prostate cancer cells. tumour biol. 2016;37:2655-63. 17. le qt, sutphin pd, raychaudhuri s, et al. identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas. clin cancer res. 2003;9:59– 67. 18. nordsmark m, eriksen jg, gebski v, alsner j, horsman mr, overgaard j. differential risk assessments from five hypoxia specific assays: the basis for biologically adapted individualized radiotherapy in clinical head and neck cancer patients. radiotheroncol. 2007;83:389–97. 19. overgaard j, eriksen jg, nordsmark m, et al. danish head and neck cancer study group. plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the dahanca 5 randomised doubleblind placebo-controlled trial. lancet oncol. 2005;6:757–64. 20. said hm, hagemann c, staab a, et al. expression patterns of the hypoxia-related genes osteopontin, ca9, erythropoietin, vegf and hif-1alpha in human glioma in vitro and in vivo. radiotheroncol. 2007;83:398–405. 21. bache m, reddemann r, said hm, et al. immunohistochemical detection of osteopontin in clinical head-and-neck cancer: prognostic role and correlation with oxygen electrode measurements, hypoxia-inducible-factor-1 – related markers and hemoglobin levels. int j radiatoncolbiol phys. 2006;66:1481–7. 22. riemann a, ihling a, reime s, gekle m, thews o. impact of the tumor microenvironment on the expression of inflammatory mediators in cancer cells. adv exp med biol. 2016; 923:105-11. 23. doll ja, reiher fk, crawford se, pins mr, campbell sc, bouck np. thrombospondin-1, vascular endothelial growth factor and fibroblast growth factor-2 are key functional regulators of angiogenesis in the prostate. prostate. 2001;49:293–305. 24. duque jl, loughlin kr, adam rm, kantoff pw, zurakowski d, freeman mr. plasma new biological markers in prostate cancer wiśniewski et al. urological oncology 140 levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer. urology. 1999;54:523–7. 25. botelho 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clin cancer res. 2001;7:2750–6. 32. wang h, doll ja, jiang k, et al. differential binding of plasminogen, plasmin, and angiostatin 4.5 to cell surface betaactin: implications for cancer-mediated angiogenesis. cancer res. 2006;66:7211–5. 33. heidtmann hh, nettelbeck dm, mingels a, jäger r, welker hg, kontermann re.generation of angiostatin-like fragments from plasminogen by prostate-specific antigen. br j cancer. 1999;81:1269–73. 34. firlej v, mathieu jr, gilbert c et al. thrombospondin-1 triggers cell migration and development of advanced prostate tumors. cancer res. 2011;71:7649–58. 35. rofstad ek, henriksen k, galappathi k, mathiesen b. antiangiogenic treatment with throm-bospondin-1 enhances primary tumor radiation response and prevents growth of dormant pulmonary micrometastases after curative radiation therapy in human melanoma xenografts. cancer res. 2003;63:4055–61. new biological markers in prostate cancer wiśniewski et al. urology for people 294 urology journal vol 5 no 4 autumn 2008 what’s up in urology journal, autumn 2008? urology for people is a new section in the urology journal for providing people a summary of what is published in this journal and describing urological entities in a simple language. it is the second issue in which this section is added. the persian translation of this article is available from www.uj.unrc.ir. it is noteworthy that the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2008;5:294-5. www.uj.unrc.ir objects in bladder several surgeons have reported detection of an object called foreign body in the bladder. these can be surgical instruments or fragments of catheters, intrauterine contraceptive devices that are migrated to the bladder, and objects inserted into the urethra. dr rafique from pakistan has reported his 16 patients with such objects in their bladder and has reviewed all the related reports around the world. most of the foreign bodies were surgical gauze remained in the bladder after an operation (mistake by the surgical team) or intrauterine contraceptive devices migrated from the uterus in women. self-insertion of the objects is another common cause, which is mostly seen in mentally challenged patients. also, insertion of a thermometer in females, whose urethra is short, may lead to slipping of the device into the bladder. dr rafique has also described the methods to extract the objects attempted by the surgeons so far. most of the foreign bodies can be removed by endoscopic methods; an instrument called cystoscope is inserted into the bladder and the object is removed through the urethra. women should be careful about using intrauterine device, and if lost, they should consult with their physician to make sure it has not migrated into other organs. if they refer late, a stone may be formed around the device that makes its removal difficult. also, parents and care givers to mentally challenged patients should be cautious about this problem and take any prolonged urinary complaint seriously. see page 223 for full-text article how to minimize complications after circumcision circumcision in boys is a common surgical operation, especially in moslem nations. the operation is safe and usually, no problem occurs thereafter. however, a small number of boys with circumcision may suffer from narrowing of the tip of their urethra. dr bazmamoun and his colleagues in hamedan decided to advise a group of parents whose boys were circumcized to rub a lubricant jelly on circumcision site each time they change the child’s diaper. they compared children in this group with other circumcised boys and found that a smaller percentage of the children in the first group developed narrowing of the urethral tip (namely, meatal stenosis) and infection of the wound. lubrication of the circumcision site has been recommended by some surgeons; however, its benefits had not been clearly shown in any studies before dr bazmamoun reported their study results. parents can discuss what they are required to do after circumcision of their children, and lubrication is an option that should be done urology for people urology journal vol 5 no 4 autumn 2008 295 according to the recommendations of their surgeon. see page 233 for full-text article do genes have a role in bladdr cancer? you might have heard that some factors like smoking can increase the risk of bladder cancer. recently, genetic variations or disorders have also been added to the list of such factors. however, in contrast to the matter of smoking, the role of genes has not been confirmed yet, and scientists are still working on a series of genes that may cause, or let’s say attribute to the development of bladder cancer. dr karimianpour and associates assessed the ras gene in a group of patients with bladder cancer in tehran, and surprisingly, they found no impaired ras gene in their patients. this gene has been suggested by many researchers around the world to have a role in bladder cancer, and the study by dr karimianpour shows that in iranian patients, ras gene might not be a cause. however, studies on a larger number of patients are required to make a stronger conclusion. see page 237 for full-text article diabetic kidney transplant patients diabetes mellitus has been always a challenge for the physicians. it not only affects the native kidneys of the patients, but also continues its damaging effect on a transplanted kidney. so, there are concerns about transplantation in patients with diabetes mellitus. dr einollahi and his colleagues in bqiyatollah hospital in tehran have addressed this issue. they found that the overall chance of survival of the patient and the transplanted kidney is lower among diabetic patients. this poorer outcome of transplantation is more prominent in those who have type 1 diabetes mellitus, which is the insulin-dependent type that usually develops in younger ages. it should be noted that the above concerns are not a barrier to transplantation in diabetic patients. however, dr einollahi’s study suggests that both the physician and the patient be more careful about diabetes, and a close monitoring of blood sugar and the transplanted kidney function must be considered after transplantation. see page 248 for full-text article saffron for infertility? herbal medicine is popular in folk medicine, but its efficacy should be assessed by scientific methods. recently, a trend has been observed in iran, and also the world, towards using herbs in modern medicine. in iran, saffron is an attractive herb in folk medicine, with a long list of its benefits. to scrutinize the potential usage of saffron, dr heidary and his research team carried out a study on infertile men. they prescribed saffron, solved in milk, for 3 months and found that the number and quality of the sperm of the participants improved to a great extent. this interesting finding can be the primary step for further studies. the effect of saffron can be confirmed in a study of a larger number of patients when compared with a control group of infertile men who do not use saffron. this local herb may have a role in the future of modern medicine, but it would be an expensive drug! see page 255 for full-text article avicenna and his modern scientific viewpoint avicenna, a great iranian scientist has written the most famous medical book in the history. a thousand years ago, he donated a treasure to the world named canon of medicine. dr madineh, a urologist interested in this book, has selected some chapters of the canon that are about bladder and its diseases. in his article, he shows the similarities of avicenna’s theories with modern theories. readers may find it interesting that 10 centuries ago, avicenna could through away the superstitious beliefs in medicine and substitute them with experimental methodology we believe in now. see page 284 for full-text article urological oncology il-6 genomic variants and risk of prostate cancer mohammad taheri1, rezvan noroozi2,3, azadeh rakhshan4, molud ghanbari5, mir davood omrani1*, soudeh ghafouri-fard2* purpose: to evaluate the role of interleukin-6 (il-6) single nucleotide polymorphisms in prostate cancer (pca) and benign prostate hyperplasia (bph). materials and methods: we genotyped two il-6 intronic variants (rs1800795 and rs2069845) in pca cases, bph cases and healthy men referred to labbafinejad and shohadaye tajrish medical centers using tetra arms-pcr method. results: the study included 130 pca cases, 200 bph cases and 200 healthy men. the c allele of rs1800795 was associated with pca risk in the assessed population (or (95% ci) = 1.45 (1.06-1.98)). however, the frequency of rs2069845 variants was not significantly different between pca, bph and control groups. the a c haplotype (rs2069845 and rs1800795 respectively) was associated with pca and bph risk (or (95% ci) = 1.67 (1.122.48); or (95% ci)= 1.78 (1.25 – 2.54)). besides, the a g haplotype (rs2069845 and rs1800795 respectively) has a protective effect against both pca and bph in the assessed population (or (95% ci) = 0.63 (0.46-0.87); or (95% ci)= 0.6 (0.45-0.79)). conclusion: consequently, the results of the current study provide further evidence for contribution of il-6 in prostate cancer. keywords: il-6; prostate cancer; benign prostate hyperplasia introduction prostate cancer (pca) and benign prostate hyperpla-sia (bph) are two androgen-dependent pathological conditions with shared inflammatory elements as well as common genetic and epigenetic changes(1). both diseases have been associated with bk virus (bkv) infection(2). expression of certain matrix nuclear proteins can differentiate these two conditions(3). the high prevalence of these disorders among aged males has surged researchers to find genetic susceptibility loci(4-6) with possible application as biomarkers or therapeutic targets(7). a recent meta-analysis of literature has shown the age-standardized rate of prostate cancer was 9.11 in iran(8). inflammatory responses have a well-documented role in cancer pathogenesis through modulation of tumor microenvironment, distortion of cytokine balance and production of reactive oxygen species(9). among cytokine, the role of interleukin (il)-6 in prostate cancer pathogenesis has been vastly evaluated. multiple lines of evidence point to its role in this type of malignancy. first, serum il-6 levels have been correlated with pca burden as defined by serum prostate specific antigen (psa) levels or clinically apparent metastases(10). moreover, its higher levels might be an indicator of irresponsiveness to hormone ablation therapy(11). il-6 act 1urogenital stem cell research center, shahid beheshti university of medical sciences, tehran, iran. 2department of medical genetics, shahid beheshti university of medical sciences, tehran, iran. 3phytochemistry research center, shahid beheshti university of medical sciences, tehran, iran. 4cancer research center, shahid beheshti university of medical sciences, tehran, iran. 5department of clinical biochemistry, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. *correspondence: department of medical genetics, shahid beheshti university of medical sciences, tehran, iran. emails: soudeh ghafouri-fard: s.ghafourifard@sbmu.ac.ir. mir davood omrani: davood_omrani@yahoo.co.uk received & accepted as a paracrine factor that modulates pca autophagy and neuroendocrine differentiation(12). the regulatory role of il-6 on is exerted through the ampk/mtor pathway(13). the role of il-6 in induction of cell proliferation and prevention of apoptosis is exerted through various cancer-associated signal pathways such as the janus tyrosine family kinase (jak)-signal transducer and activator of transcription (stat) pathway, the extracellular signal-regulated kinase 1 and 2 (erk1/2)-mitogen activated protein kinase (mapk) pathway and the phosphoinositide 3-kinase (pi3-k) pathway(9). experimental studies have shown that il-6 induces and/or augments the conversion of prostate cancer cells from an androgen-dependent to an androgen-independent phenotype(14). functional variants within il-6 coding gene including the rs1800795 and rs2069845 single nucleotide polymorphisms (snps) have been previously shown to alter circulating il-6 levels(15-17). moreover, the c allele of rs1800795 has been associated with increased risk of pca in an american population but the association did not remain significant after accounting for multiple tests(18). the gg genotype of this snp has been associated with an increased risk of metastasis of primary breast cancer(19). considering the role of il-6 in pca pathogenesis as well as the presence of comurology journal/vol 16 no. 5/ september-october 2019/ pp. 463-468. [doi: 10.22037/uj.v0i0.4543] mon inflammatory mechanisms in pca and bph, we aimed at evaluation of the associations between two functional polymorphisms within this gene (rs1800795 and rs2069845) and risk of pca and bph in an iranian population. the current study is the first association study of il-6 polymorphisms in iranian patients with pca and bph. materials and methods patients the appropriate sample size was calculated for rs2069845 with minor allele frequency of 0.25 assuming the study power of 70% and significance level of 5% to be 120 cases and 120 controls. the current case-control study recruited 130 newly diagnosed pca cases, 200 newly diagnosed bph cases and 200 healthy men referred to labbafinejad and shohadaye tajrish medical centers. the diagnosis was established based on pathological examination of biopsied samples. the study protocol has been approved by ethical committee of shahid beheshti university of medical sciences. all study participants signed the informed consent forms. control subjects were selected from men seeking routine health assessment during 2016 and were matched to patients. men attributed to control group had no history of lower urinary tract symptoms, inflammatory disease of prostate, prostate enlargement or family history of pca. controls had normal psa levels. pca or bph was diagnosed through evaluation of clinical prostate biopsies by an expert pathologist especially in bph patients with high psa levels (4.0 ng/ml or more). exclusion criteria were inadequate pathologic sample, history of former malignancies in other organs and previous chemo-radiotherapy. blood samples were collected from patients in edta tubes before commencement of any therapy such as surgery, radiotherapy, and chemotherapy. clinicopathological data were collected through filling questionnaires and assessment of medical reports. genotyping genomic dna was extracted from blood samples of all study participants using standard salting out method. the rs2069845 and rs1800795 intronic variants within il-6 gene were genotyped using tetra-primer armspcr technique and were visualized after staining on 2% agarose gel. the amplification program was started with denaturation step at 95 ºc for 5 minutes followed by 35 cycles of 95 ºc for 45 seconds, specific annealing temperatures for 35 seconds, and 72 ºc for 35 seconds and a final extension step in 72 ºc for 10 minutes. ten percent of samples were sequenced using abi 3730xl dna analyzer (macrogen, korea) to confirm the results of tetra-primer arms-pcr. the nucleotide sequences of primers used for genotyping are shown in table 1. table 1. the nucleotide sequences of primers used for genotyping (snp: single nucleotide polymorphism, bp: base pair). snp primer sequence tm annealing temperature pcr product size (bp) rs2069845 forward inner primer (g allele): 5′ gtttcccagtcctctttacaccaacg 66 °c 62 °c 197 bp (g allele) reverse inner primer (a allele): 5′ 66 °c 292 bp (a allele) tttatgatctgttgaaagaccactgacct forward outer primer: 5′ 66 °c 434 bp catcctgcctctgccatttctacttaa (two outer primers) reverse outer primer: 5′ 66 °c attctgacatctgagataatgcctgg rs1800795 forward inner primer (c allele): 5′ 68 °c 61 °c cacttttccccctagttgtgtcttccc 206 bp (c allele) reverse inner primer (g allele): 5′ 68 °c 155 bp (g allele) attgagcaatgtaacgtcctttagcttc forward outer primer: 5′ 68 °c 306 bp (two outer primers) caatacatgccaatgtgctgagtcacta reverse outer primer: 5′ agaatgatcctcagtcatctccagtcct 68 °c variables prostate cancer group bph group controls age (mean ± sd) 66.54 ± 9.5 67.96 ± 3.97 64 ± 5.12 bmi (mean ± sd) 25.06 ± 2.14 24.97 ± 3.47 25.7 ± 1.2 prostate weight (gr) (mean ± sd) 58 ± 98.31 61.87 ± 29.52 psa (ng/ml) (mean ± sd) 9.13 ± 9.28 8.94 ± 7.2 < 4 <4 25 (19.23%) 39 (19.5%) 200 (100%) 4-10 73 (56.15%) 94(47%) 0 >=10 32 (24.61%) 67 (33.5%) 0 smoking never smoker (%) 69 (53.1%) 121 (60.5%) 124 (62%) current or former smoker (%) 61 (46.9%) 79 (39.5%) 76 (38%) gleason score <=6 68 (52.3%) >6 62 (47.7%) abbreviations: sd: standard deviation, psa: prostate specific antigen, bmi: body mass index). table 2. demographic and clinical data of study participants (bph: benign prostate hyperplasia, il-6 variants in prostate cancer-taheri et al. urological oncology 464 vol 16 no 04 september-october 2019 465 statistical analysis the agreement of genotype frequencies with the hardy– weinberg equilibrium was assessed using chi-square test. the associations between genotype frequencies and pca or bph were evaluated in three inheritance models including recessive, dominant and co-dominant using pearson's chi-square test. the p values were corrected through multiplying by the number of snps. p values less than 0.05 were regarded as significant. the linkage between rs1800795 and rs2069845 variants were assessed using d’ and r values. haplotype block frequencies and their associations with pca and bph were computed using partition-ligation–expectation-maximization (pl-em) algorithm(20) (snpanalyzer 2.0 software) with supposition of 0.01 minimum frequencies for blocks. the results were stated as odds ratios (or) and 95% confidence interval of or (95% ci), p-value and bonferroni adjusted p-values. patients were matched to control group in variables such as bmi and smoking history. results demographic and clinical data of study participants table 2 shows the demographic and clinical data of pca, bph and healthy subjects participated in the study. pca and bph patients were age-matched (p = 0.061). the three study groups were not significantly different in smoking (p = 0.39) and bmi (p = 0.79). genotyping the distributions of alleles and genotypes of the assessed snps were in accordance with hwe in the three study groups. table 3 shows the results of evaluation of hwe. figure 1 and 2 show the results of arms-pcr for genotyping the mentioned snps. the c allele of rs1800795 was associated with pca risk in the assessed population (or (95% ci) = 1.45 (1.061.98), adjusted p = 0.04). however, the frequency of rs2069845 variants was not significantly different between pca, bph and control groups. (table 4) we also assessed the frequencies of il-6 haplotypes in the three study groups and found significant over-presentation of a c haplotype (rs2069845 and rs1800795 respectively) in both pca and bph groups compared with control subjects (or (95% ci)= 1.67 (1.122.48), adjusted p = 0.04; or (95% ci)= 1.78 (1.25 – 2.54), adjusted p = 0.006 respectively). besides, the a g haplotype (rs2069845 and rs1800795 respectively) has been shown to exert protective effect against both pca and bph in the assessed population (or (95% ci)= 0.63 (0.46-0.87), adjusted p = 0.02; or (95% ci)= 0.6 (0.45-0.79), adjusted p = 0.001 respectively). table 5 shows the detailed information of haplotype analytable 3. exact test for hardy-weinberg equilibrium. snp rs2069845 p-value rs1800795 p-value aa ag gg gg gc cc pca 46 69 15 0.15 39 55 36 0.08 bph 78 91 31 0.60 61 91 48 0.22 control 82 97 21 0.32 77 87 36 0.19 abbreviations: snp: single nucleotide polymorphism, bph: benign prostate hyperplasia, pca: prostate cancer figure 1. the results of arms-pcr for genotyping the rs1800795 and rs2069845 snps. figure 2. the results of arms-pcr for genotyping the rs2069845 snps. il-6 variants in prostate cancer-taheri et al. sis) no strong linkage disequilibrium (ld) has been observed between the analyzed polymorphic sites (ld analysis, d′ = 0.14; r = 0.01; p = 0.5). discussion the role of il-6 in the pathogenesis of pca has been extensively evaluated. however, associations between genomic variants of il-6 gene and risk of pca have not been assessed in different populations. in the present study we assessed associations between two functional variants of il-6 and prostate disorders in a cohort of iranian patients with prostate disorders. we found significant over-presentation of the rs1800795 c allele in pca patients compared with healthy subjects. we did not find any difference in allele or genotype frequencies of this snp between bph patients and controls which might rule out its contribution in the pathogenesis of bph despite its putative role in pca. although the c allele of rs1800795 has been associated with higher circulating il-6 levels in human subjects(15,17,21), the association between this allele and pca risk in american patients did not remain significant after multiple testing correction. however, authors suggested further evaluation of the association between this genomic variant and pca risk(18). consequently, our results provide additional support for their observation. moreover, the c allele of rs1800795 has been associated with higher concentrations of circulating c reactive protein (crp) (16), which has been regarded as a negative predictor of survival in pca (22). so this polymorphism might exert its effects in pca pathogenesis through multiple mechanisms including alterations in il-6 and crp levels. however, despite previous studies demonstrated higher il-6 in carriers of minor allele of rs2069845(17), we did not find significant difference in allele and genotype frequencies of rs2069845 between pca, bph and control groups. notably, we found significant over-presentation of a c haplotype (rs2069845 and rs1800795 respectively) in both pca and bph groups compared with control subjects. on the other hand, the a g haplotype (rs2069845 and rs1800795 respectively) has been shown to exert protective effect against both pca and bph in the assessed population. such data further supports the significance of rs1800795 and unimportance of rs2069845 variants in conferring pca or bph risk. however, the implication of other functional variants within these haplotypes cannot be ruled out. as no differences have been found in haplotype frequencies between bph and pca groups, assessment of haplotypes cannot differentiate between these two conditions. although most of previous studies have demonstrated the usefulness of il-6 concentrations as predictive biomarkers in pca patients, some inconsistencies exist. for instance, nakashima et al. reported serum il-6 level as a major prognostic factor for prostate cancer and its extent of disease(23). in line with their study, alcover et al. highlighted the effectiveness of il-6 in predicting the biochemical progression of prostate cancer (25). on the other hand, pierce et al. failed to detect any association between circulating il-6 concentration and pca risk and proposed that rs1800795 may alter pca risk through other mechanisms(19) among which might be modulation of crp levels. alternatively, they suggested that the variability in il-6 levels or the insufficiency of a single assessment of il-6 as an indicator of long-standing blood levels might result in failure of table 4. association analysis of rs2069845 and rs1800795 polymorphisms and risk of pca and bph (p*: adjusted p value). snp model sample size (%) pca vs. control bph vs. control pca vs. bph pca (%) bph (%) control (%) or (95% ci) p p* or (95% ci) p p* or (95% ci) p p* rs2069845 allele g vs. a 99 (38) 153 (38) 139 (35) 1.15 (0.83-1.60) 0.38 0.77 1.16 (0.87-1.55) 0.30 0.61 1.00 (0.0.72-1.37) 0.96 1.00 161 (62) 247 (62) 261 (65) co-dominant gg vs 15 (12) 31 (15.5) 21 (10.5) 1.26 (0.6-2.70) 0.59 1.00 1.59 (0.82-2.94) 0.33 0.66 1.54 (0.85-2.78) 0.35 0.7 aa ag vs 69 (53) 91 (45.5) 97 (48.5) 1.26 (0.79-2.04) 0.99 (0.64-1.49) 1.11 (0.75-1.64) aa dominant gg+ag 84 (64.6) 122 (61) 118 (59) 1.27 (0.8-2.00) 0.31 0.61 1.09 (0.73 -1.62) 0.68 1.00 1.17 (0.74-1.85) 0.51 1.00 vs aa 46 (35) 78 (39) 82 (41) recessive gg vs 15 (12) 31 (15.5) 21 (10.5) 1.11 (0.55-2.24) 0.77 1.00 1.56 (0.86-2.83) 0.14 0.27 0.71 (0.37-1.38) 0.31 0.62 ag +aa 115 (88.5) 169 (84.5) 179 (89.5) rs1800795 allele c vs g 127 (49) 187 (47) 159 (40) 1.45 (1.06-1.98) 0.02 0.04 1.33 (1.00-1.76) 0.05 0.09 1.09 (0.8-1.49) 0.6 1.00 133 (51) 213 (53) 241 (60) co-dominant cc vs 36 (27.7) 48 (24) 36 (18) 1.96 (1.09-3.57) 0.08 0.16 1.69 (0.97.-2.94) 0.16 0.32 2.44 (1.37-4.35) 0.74 1.00 gg cg vs 55 (42.3) 91 (45.5) 87 (43.5) 1.25 (0.75-2.08) 1.32 (0.85-2.08) 1.3 (0.87-1.92) dominant cg+cc 91 (70) 139 (69.5) 123 (61.5) 1.46 (0.91-2.34) 0.11 0.23 1.42 (0.94-2.16) 0.09 0.18 1.02 (0.63-1.66) 0.92 1.00 vs gg 39 (30) 61 (30.5) 77 (38.5) gg recessive cc vs 36 (27.7) 48 (24) 36 (18) 1.74 (1.03-2.95) 0.04 0.07 1.44 (0.89-2.34) 0.14 0.28 1.21 (0.73-2.00) 0.45 0.9 cg+gg 94 (72.3) 152 (76) 164 (82) rs2069845 rs1800795 pca bph control pca vs. control bph vs. control pca vs. bph or (95% ci) p p* or (95% ci) p p* or (95% ci) p p* a g 0.35 0.31 0.47 0.63 (0.46-0.87) 0.005 0.02 0.6 (0.45-0.79) 3.6 e-4 0.001 1.06 (0.77-1.46) 0.73 1.00 g c 0.22 0.16 0.22 1.07 (0.75 – 1.53) 0.71 1.00 0.89 (0.64 – 1.24) 0.5 1.00 1.2 (0.83– 1.72) 0.33 1.00 a c 0.27 0.31 0.18 1.67 (1.122.48) 0.01 0.04 1.78 (1.25 – 2.54) 0.001 0.006 0.94 (0.65 – 1.35) 0.73 1.00 g g 0.16 0.22 0.13 1.23 (0.752.01) 0.41 1.00 1.64 (1.072.49) 0.02 0.08 0.75 (0.47 – 1.19) 0.22 0.87 table 5. the frequencies of haplotype blocks in the three study groups (p*: adjusted p value). il-6 variants in prostate cancer-taheri et al. urological oncology 466 vol 16 no 04 september-october 2019 467 detecting the expected association(18). taken together, the rs1800795, or another variant in ld with it might confer pca risk possibly through modulation of il-6 rna and protein levels or even other independent mechanisms. considering the short plasma half-life of il-6(25) and the presence of a circadian rhythm for this cytokine due to the circadian alterations of cortisol(26), we propose assessment of genomic variants within this gene as an alternative to evaluation of its serum concentrations. such studies would elaborate the role of il-6 in pca risk and pave the way for designing personalized therapeutic options. our study had some limitations including sample size. due to relative small sample size, we could not assess associations in subgroups of patients including different grades of pca. moreover, we did not have the data about serum level of il-6 in study participants. conclusions the rs1800795, or another variant in ld with it is associated with pca risk possibly through modulation of il-6 rna and protein levels or even other independent mechanism. acknowledgement the current study was supported by a grant from shahid beheshti university of medical sciences. conflict on interest none declared. references 1. miah s, catto j. bph and prostate cancer risk. indian j urol. 2014;30:214-8. 2. vaezjalali m, azimi h, hosseini sm, taghavi a, goudarzi h. different strains of bk polyomavirus: vp1 sequences in a group of iranian prostate cancer patients. urol j. 2018;15:44-8. 3. pourmand g, safavi m, ahmadi a, et al. epca2.22: a silver lining for early diagnosis of prostate cancer. urol j. 2016;13:2845-8. 4. ghafouri-fard s, ousati ashtiani z, sabah golian b, hasheminasab sm, modarressi mh. expression of two testis-specific genes, spata19 and lemd1, in prostate cancer. arch med res. 2010;41:195-200. 5. taheri m, habibi m, noroozi r, et al. hotair genetic variants are associated with prostate cancer and benign prostate hyperplasia in an iranian population. gene. 2017;613:20-4. 6. taheri m, pouresmaeili f, omrani md, et al. association of anril gene polymorphisms with prostate cancer and benign prostatic hyperplasia in an iranian population. biomark med. 2017;11:413-22. 7. faramarzi s, ghafouri-fard s. expression analysis of cancer-testis genes in prostate cancer reveals candidates for immunotherapy. immunotherapy. 2017;9:1019-34. 8. hassanipour s, fathalipour m, salehiniya h. the incidence of prostate cancer in iran: a systematic review and meta-analysis. prostate international. 2017. 9. nguyen dp, li j, tewari ak. inflammation and prostate cancer: the role of interleukin 6 (il-6). bju int. 2014;113:986-92. 10. adler hl, mccurdy ma, kattan mw, timme tl, scardino pt, thompson tc. elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. j urol. 1999;161:182-7. 11. wise gj, marella vk, talluri g, shirazian d. cytokine variations in patients with hormone treated prostate cancer. j urol. 2000;164:7225. 12. delk na, farach-carson mc. interleukin-6: a bone marrow stromal cell paracrine signal that induces neuroendocrine differentiation and modulates autophagy in bone metastatic pca cells. autophagy. 2012;8:650-63. 13. chang pc, wang ty, chang yt, et al. autophagy pathway is required for il-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer lncap cells. plos one. 2014;9:e88556. 14. lee so, lou w, hou m, de miguel f, gerber l, gao ac. interleukin-6 promotes androgenindependent growth in lncap human prostate cancer cells. clinical cancer research. 2003;9:370-6. 15. brull dj, montgomery he, sanders j, et al. interleukin-6 gene -174g>c and -572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. arterioscler thromb vasc biol. 2001;21:1458-63. 16. walston jd, fallin md, cushman m, et al. il-6 gene variation is associated with il-6 and c-reactive protein levels but not cardiovascular outcomes in the cardiovascular health study. hum genet. 2007;122:485-94. 17. ljungman p, bellander t, nyberg f, et al. dna variants, plasma levels and variability of interleukin-6 in myocardial infarction survivors: results from the airgene study. thromb res. 2009;124:57-64. 18. pierce bl, biggs ml, decambre m, et al. c-reactive protein, interleukin-6, and prostate cancer risk in men aged 65 years and older. cancer causes control. 2009;20:1193-203. 19. abana co, bingham bs, cho jh, et al. il-6 variant is associated with metastasis in breast cancer patients. plos one. 2017;12:e0181725. 20. qin zs, niu t, liu js. partition-ligationexpectation-maximization algorithm for haplotype inference with single-nucleotide polymorphisms. am j hum genet. 2002;71:1242-7. 21. kelberman d, fife m, rockman mv, brull dj, woo p, humphries se. analysis of common il-6 promoter snp variants and the il-6 variants in prostate cancer-taheri et al. antn tract in humans and primates and effects on plasma il-6 levels following coronary artery bypass graft surgery. biochimica et biophysica acta-molecular basis of disease. 2004;1688:160-7. 22. liu zq, chu l, fang jm, et al. prognostic role of c-reactive protein in prostate cancer: a systematic review and meta-analysis. asian journal of andrology. 2014;16:467-71. 23. nakashima j, tachibana m, horiguchi y, et al. serum interleukin 6 as a prognostic factor in patients with prostate cancer. clin cancer res. 2000;6:2702-6. 24. alcover j, filella x, luque p, et al. prognostic value of il-6 in localized prostatic cancer. anticancer research. 2010;30:4369-72. 25. febbraio ma, ott p, nielsen hb, et al. hepatosplanchnic clearance of interleukin-6 in humans during exercise. am j physiol endocrinol metab. 2003;285:e397-402. 26. vgontzas an, bixler eo, lin hm, prolo p, trakada g, chrousos gp. il-6 and its circadian secretion in humans. neuroimmunomodulation. 2005;12:131-40. il-6 variants in prostate cancer-taheri et al. urological oncology 468 special feature 245urology journal vol 6 no 4 autumn 2009 relevance of levels of evidence to the urologist j chandra singh,1 philipp dahm2 urol j. 2009;6:245-8. www.uj.unrc.ir keywords: urology, evidence-based medicine, guidelines 1department of urology, christian medical college, vellore, india 2department of urology, college of medicine, university of florida, gainesville, florida, usa corresponding author: j chandra singh, md department of urology, christian medical college, vellore 632 004, tn, india tel: +91 416 228 2055 fax: +91 416 223 2035 e-mail: chandrasingh@cmcvellore.ac.in received march 2009 accepted may 2009 introduction while caring for patients, urologists have to make several clinical decisions. to counsel and give appropriate care for a single patient, various aspects including prevention, natural history, diagnosis, treatment options, prognosis and health economics may need to be addressed. for informed and shared decision making to arrive at the treatment plan, knowledge of the strongest evidence from literature on each of these aspects is essential. the best available clinical evidence is clinically relevant research, which may be from the basic sciences of medicine, but especially that derived from clinical research that is patient centered, that evaluates the accuracy and precision of diagnostic tests and prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens.(1) evidence-based practice addresses each question or decision making individually based on the strongest evidence available on that particular aspect. one of the guiding principles of evidencebased medicine is the concept of a hierarchy of evidence. this refers to the fact that certain study designs are more likely than others to provide an unbiased result and represent the “truth.” levels of evidence is a particular ranking system used to describe the strength of the results measured in a clinical trial or research study that is widely used.(2) the table enlists the levels attributable to studies addressing various parameters. this level of evidence rating system, adapted from the orthopedic surgery literature(3) and the center of evidence based medicine,(4) was used to assess the type and levels of evidence found in the urological literature.(5) we found that only a small subset of studies published in the urological literature, approximately 1 in 7 studies, provided “high-quality evidence,” even if levels i and ii combined are considered. one should note that a similar study design may be assigned different levels, depending upon the type of question addressed by the study. clinical scenarios levels of evidence a higher level of evidence is available for many pharmacological interventions, as multicenter randomized trials have been performed to prove efficacy. for example, in lower urinary tract symptoms related to benign prostatic hyperplasia, tamsulosin has been shown to give better improvement in symptom score and flow rate compared to placebo. (6) furthermore, a dose of 0.8 mg has been shown to have significantly higher adverse effects without a proportionately higher benefit (level i evidence). there levels of evidence in urology—singh and dahm 246 urology journal vol 6 no 4 autumn 2009 is level i evidence demonstrating the superiority of intravesical immunotherapy with bacillus calmette-guerin in delaying tumor recurrence compared to trans-urethral resection alone.(7,8) other closely related questions, for example, the evidence for intravesical bacillus calmetteguerin and progression of transitional cell carcinoma of the bladder is questionable.(9) the role of bacillus calmette-guerin in low-grade bladder cancer, comparison of bacillus calmetteguerin with other intravesical agents, intravesical bacillus calmette-guerrin versus transurethral resection alone therapeutics, etc, have been studied; however, the evidence is not similarly strong. (9) the role of bisphosphonates in advanced prostate cancer is another area that has been widely studied. one thousand nine hundred and fifty-five patients from 10 studies were included in a systematic review and meta-analysis. the study provided level i evidence for reduction of refractory bone pain and reduction of skeletalrelated events in those with metastatic prostate cancer.(10) however, the evidence is not strong on choice of bisphosphonates, schedule, and costbenefit implications. surgical interventions with level i evidence for benefit or absence of it are limited.(11,12) it has been suggested that typically the surgeon has a personality and temperament that does not always lead to well-developed cooperation and team skills.(13) furthermore, recruitment of surgical patients who fulfill the inclusion criteria and are amenable to randomization is another difficulty. the sample size of an adequately powered surgical trial may be large, necessitating recruitment from many centers, and with the plethora of operative choices, several challenges need to be overcome before executing a surgical trial that can provide level i evidence. another issue specific to surgical interventions and urological devices is that of the learning curve. one proposed solution to this issue is expertise-based trials. in this study design for randomized controlled trials of surgical interventions, participants are randomized not only to a form of treatment (ie, roboticassisted laparoscopic prostatectomy versus open retropubic prostatectomy), but also to an expert surgeon who is experienced in that technique.(14) levels of evidence in urological literature several authors have highlighted the critical need level therapy/prevention/ etiology/harm prognosis diagnosis economic decision analyses i ● rct significant difference no significant difference (narrow confidence interval) ● systematic review† of level i rcts (homogenous) ● prospective cohort study‡ ● systematic reviews† level i‡ ● testing of previously developed diagnostic criteria in series of consecutive patients (with universally applied gold standard) ● systemic review of level i‡ ● clinically sensible costs + alternatives, multi-way analysis; many studies used ● systematic review level i† ii ● prospective cohort§ ● poor-quality rct limited follow-up, dropout ● systematic review level ii nonhomogenous level i ● retrospective cohort study║ ● study of untreated controls from previous rct ● systematic review† level ii ● development of diagnostic criteria on basis of consecutive patients (with universally applied gold standard) ● systematic review level ii† ● clinically sensible costs + alternative; limited studies used ● systematic review level ii† iii ● case-control# ● retrospective cohort║ ● systematic review level iii … ● study of nonconsecutive patients (no gold standard) ● systematic review level iii† ● limited alternatives + costs, poor estimates ● systematic review level iii† iv ● case series (no or historical controls) ● case series ● poor quality retrospective cohort study ● case-control study ● poor reference standard ● no sensitivity analyses level of evidence rating system* *adapted from the center of evidence-based medicine website, and the journal of bone and joint surgery. †a study of results from 2 or more previous studies. ‡all patients enrolled at the same point in the disease course (inception cohort) with greater than 80% follow-up. §study was initiated after treatment was performed. ║patients with a particular outcome were compared to those who did not have the outcome (surgeries that failed versus succeeded) and look back for exposure, etc. #patients were compared with a control group of patients treated at the same time and institution. levels of evidence in urology—singh and dahm urology journal vol 6 no 4 autumn 2009 247 for evidence-based guidelines in urology. (5,13) it was also noted that most articles, even in established urology journals, were retrospective case series without a control group, representing level iv evidence.(13) several journals of other specialties have sought to raise awareness for this issue by providing a level of evidence rating with every published article. journals such as the british journal of urology international have been regularly identifying the type of study and the level of evidence that a given study provides, which enables the readers to assign appropriate importance to the findings.(5) grade of recommendation and levels of evidence evidence-based clinical practice guidelines have been recognized as playing an important role in guiding clinical practice. they are also among the most well-known evidence-based resources that urologists are aware of and actually use.(15) clinical practice guidelines have a special place in the organization of evidence as summaries that integrate the best available evidence for a full range of management options for a given disease.(16) to do so, they provide specific recommendations for typical index patients. the strength of such recommendations is inherently linked to the quality of available evidence that addresses a given specific question. although several guidelines, such as those that are being developed by the european association of urology,(17) provide such an explicit link between the grade of recommendation and the quality of evidence, their underlying methodology has been recently drawn in to question based on research advances in guidelines methodology.(18) specifically, the grading of recommendations assessment, development, and evaluation (grade) system for grading evidence and grading recommendations represents a major advance in guidelines methodology. the grade system is being increasingly used by major professional organizations including the world health organization.(19) an advantage of the grade system is that for any evidence that has been allocated a grade based on study design, not only it has explicit comprehensive criteria for downgrading and upgrading the quality of evidence ratings based on the study limitations, but also it considers other issues such as magnitude of the effect size, the underlying precision, and the relevance of the endpoint to the patient.(20) the american urological association has recently adopted a modified version of the grade system to develop their guidelines, which represents a major step forward. conclusion understanding the levels of evidence is an essential prerequisite for an evidence-based practice of urology, by allowing the reader to place a given clinical research study into context. having unified validated levels of evidence and grade of recommendation facilitates translation of research findings to patient care. that being said, it is important to be aware of the second guiding principles of evidence-based practice, which is that “evidence alone is never enough” but needs to be integrated with an individual patient’s-specific circumstances, values, and preferences.(21) going forward, an increasing number of evidence-based resources will be becoming available, including high-quality clinical practice guidelines, to guide an evidence-based practice of urology. conflict of interest none declared. references 1. straus se, sackett dl. using research findings in clinical practice. bmj (clinical research ed. 1998 aug 1;317(7154):339-42. 2. national cancer institute [homepage on internet]. levels of evidence [cited 2009 feb 9]. available from: http://www.cancer.gov/templates/db_alpha. aspx?cdrid=446533 3. wright jg, swiontkowski m, heckman jd. levels of evidence. the journal of bone and joint surgery. 2006 sep;88(9):1264. 4. centre for evidence-based medicine. oxford centre for evidence-based medicine levels of evidence (march 2009) [cited 2009 feb 9]. available from: http:// www.cebm.net/?o=1025 5. borawski km, norris rd, fesperman sf, vieweg j, preminger gm, dahm p. levels of evidence in the urological literature. the journal of urology. 2007 oct;178(4 pt 1):1429-33. 6. wilt tj, mac donald r, rutks i. tamsulosin for benign prostatic hyperplasia. cochrane database of systematic reviews (online). 2003(1):cd002081. levels of evidence in urology—singh and dahm 248 urology journal vol 6 no 4 autumn 2009 7. shelley md, wilt tj, court j, coles b, kynaston h, mason md. intravesical bacillus calmette-guerin is superior to mitomycin c in reducing tumour recurrence in high-risk superficial bladder cancer: a metaanalysis of randomized trials. bju international. 2004 mar;93(4):485-90. 8. shelley md, court jb, kynaston h, wilt tj, coles b, mason m. intravesical bacillus calmette-guerin versus mitomycin c for ta and t1 bladder cancer. cochrane database of systematic reviews (online). 2003(3):cd003231. 9. hall mc, chang ss, dalbagni g, et al. guideline for the management of nonmuscle invasive bladder cancer (stages ta, t1, and tis): 2007 update. j urol. 2007;178:2314-30. 10. yuen kk, shelley m, sze wm, wilt t, mason md. bisphosphonates for advanced prostate cancer. cochrane database of systematic reviews (online). 2006(4):cd006250. 11. dall’oglio mf, srougi m, antunes aa, crippa a, cury j. an improved technique for controlling bleeding during simple retropubic prostatectomy: a randomized controlled study. bju international. 2006 aug;98(2):384-7. 12. aus g, abrahamsson pa, ahlgren g, hugosson j, lundberg s, schain m, et al. three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial. bju international. 2002 oct;90(6): 561-6. 13. mansson w. evidence-based urology--a utopia? european urology. 2004 aug;46(2):143-6. 14. devereaux pj, bhandari m, clarke m, montori vm, cook dj, yusuf s, et al. need for expertise based randomised controlled trials. bmj (clinical research ed. 2005 jan 8;330(7482):88. 15. dahm p, preminger gm, scales cd, jr., fesperman sf, yeung ll, cohen ms. evidence-based medicine training in residency: a survey of urology programme directors. bju international. 2009 feb;103(3):290-3. 16. haynes rb, hart le. evidence in context: one person’s poison is another’s acceptable risk. acp journal club. 2008 nov 18;149(5):2-3. 17. fall m, baranowski ap, fowler cj, lepinard v, malone-lee jg, messelink ej, et al. eau guidelines on chronic pelvic pain. european urology. 2004 dec;46(6):681-9. 18. dahm p, yeung ll, gallucci m, simone g, schunemann hj. how to use a clinical practice guideline. the journal of urology. 2009 feb;181(2):472-9. 19. guyatt gh, oxman ad, kunz r, vist ge, falck-ytter y, schunemann hj. what is “quality of evidence” and why is it important to clinicians? bmj (clinical research ed. 2008 may 3;336(7651):995-8. 20. dahm p, kunz r, schunemann h. evidence-based clinical practice guidelines for prostate cancer: the need for a unified approach. current opinion in urology. 2007 may;17(3):200-7. 21. sackett dl, rosenberg wm, gray ja, haynes rb, richardson ws. evidence based medicine: what it is and what it isn’t. bmj (clinical research ed. 1996 jan 13;312(7023):71-2. vol 15 no 05 september-october 2018 261 kidney transplantation evaluation of the quality and accessibility of available websites on kidney transplantation saeideh valizadeh-haghi1, shahabedin rahmatizadeh2* purpose: (i) to assess the quality of health websites on kidney transplant and (ii) to evaluate the accessibility of these websites and their concordance with the existing guidelines. materials and methods: the terms “kidney transplantation” and “renal transplantation” were searched in the three most popular search engines google, yahoo, and bing. 58 unique websites were eligible for the analysis . the websites accessibility was evaluated using the achecker tool. kruskal–wallis test was performed to examine any significant difference between accessibility issues across different domains. the eligible websites were screened for quality based on the honcode of conducts. moreover, the daily traffic data of each website was determined by alexa. the correlation of known accessibility problems with website popularity was examined too. result: the main reported known problems belonged to “scripts must have functional text,” “text equivalents,” “accessible forms,” and “text links for server-side image map”. although the mean accessibility errors in governmental (10.25 ± 7.274) and organizational (12.31 ± 9.469) websites were less than those in the other domains, the differences were not significant (p = 0.60). findings showed no significant correlation (p > 0.05) between the extent of known problems (16.50 ± 12.18) and alexa ranking (253675.07 ± 534690.947). furthermore, most websites on kidney transplant were not certified by the honcode. conclusion: the health websites designers should be aware of accessibility problems, because there is a growing population of potential users with disabilities. this study indicated the need to ensure the compliance of kidney transplant websites with accessibility guidelines such as section 508. furthermore, most surveyed websites were of poor quality and unreliable. therefore, physicians should warn their patients about unqualified online health information and guide them to websites which are more reliable. keywords: kidney transplantation; consumer health information; web accessibility; honcode; health education; health informatics; website popularity; alexa ranking introduction end-stage renal disease (esrd), which causes an irreversible impairment in renal function, may be fatal if transplantation or dialysis is discarded(1). despite major advances in diagnostic and surgical methods for kidney transplant, the associated complications remain a major clinical problem, which can improve the risk of hospitalization and morbidity and increase medical costs (3). therefore, the patients who need a kidney transplant should decide informatively. to do so, in addition to medical consultations, they need extra information about the conditions, side effects and postsurgical care. health information can be obtained from various sources and a person’s choice of the source of information would affect their future health-related decisions(4). following the increasing demand for health awareness, the internet has become a vital source of information. this highlights the need for reliable health websites that help users understand their health status and make appropriate decisions (5). despite its advantages, e.g., availability, online health information may not always be reliable(6). previous 1assistant professor, department of medical library and information sciences, school of allied medical sciences, shahid beheshti university of medical sciences, tehran, iran. 2assistant professor, department of health information technology and management, school of allied medical sciences, shahid beheshti university of medical sciences, tehran, iran. *correspondence: 4th floor, no 21, darband st., tajrish sq., tehran. iran; email: sh.rahmatizadeh@sbmu.ac.ir. received november 2017 & accepted march 2018 studies have reported the poor quality of many websites due to the dissemination of misleading, inaccurate, incomplete, and inappropriate information. grewal and alagaratnam assessed the quality of colorectal disease websites for colorectal cancer. their study showed that colorectal cancer websites were potentially unreliable(7). in another study, haymes assessed the quality of health information regarding rhinoplasty on the internet. the findings showed that, the quality of information available on the internet with regard to rhinoplasty was generally of low quality and unreliable(8). in another study, the information on total ankle replacement (tar) available to the general public through the internet were evaluated. the study has demonstrated a low quality of tar information available across all website types(9). considering the significant effects of the use of online health information on an individual’s overall health, the provision of unreliable or inappropriate information would increase the risk of negative consequences, such as ineffective treatments or delays in seeking medical care(10). therefore, evaluation and identification of the quality of health websites are necessary. however, considering the growing number of potential users with disabilities(11), the accessibility of many health websites to physically challenged users is very limited(12). through web accessibility, people can comprehend, navigate, and interact with the internet, regardless of their limitations(13). therefore, web designers should take accessibility into account to satisfy needs of such users. to understand the accessibility barriers of health websites, web accessibility evaluation is needed, which refers to the evaluation of internet use by physically challenged individuals. currently, there are no studies assessing the quality and accessibility of health websites on kidney transplant. in this study, by considering the internet as an information source for patients, we (i) assessed the quality of health websites on kidney transplant and (ii) evaluated the accessibility of these websites and their concordance with the existing guidelines. materials and methods the terms “kidney transplantation” and “renal transplantation ” were searched in the three most popular search engines, i.e., google, yahoo, and bing. the first three pages of search results provided by each of the above-mentioned search engines (180 urls) were evaluated in this study. all urls were analyzed, and redundant websites (containing links to portable document files, repeated unreachable addresses, non-english websites, and advertising websites) were excluded. after exclusion, 58 unique websites were eligible for the analysis . each retrieved website was classified as governmental (.gov), educational (.edu), commercial (.com), and organizational (.org). in this study, website accessibility was evaluated using the achecker automatic tool(16), because it has been accredited by the world wide web consortium and has been introduced in the consortium portal (“web accessibility evaluation tools list,” n.d.). furthermore, achecker is a reliable, cost-effective tool and has been used in several studies to examine website accessibility(17,18). achecker defines three levels of problems, including “known,” “likely,” and “potential”. known problems are identified as certain accessibility barriers and should be resolved by website owners. likely problems are identified as probable barriers, which should be identified by an individual. finally, potential problems cannot be identified by achecker and require a human decision(19). in this study, known problems were reported as per the section 508 guidelines. non-parametric kruskal–wallis test was performed to examine any significant difference between accessibility issues across different domains. the eligible websites were sequentially screened for quality based on the honcode of conducts, which has set regulations to make website developers adhere to ethical standards in presenting information and to assist readers in identifying the purpose and source of data. for this purpose, hon principles were applied using the honcode toolbar (http://www.hon.ch)(20). this toolbar function, which has been used and examined in different studies, is considered valid(21). kruskal–wallis test was performed to examine possible differences in the mean ranking of known problems between honcode-verified and unverified websites. moreover, the daily traffic data of each website, determined by alexa as an index of popularity of websites, was used by the researchers. alexa’s traffic ranks are based on the traffic data provided by users in alexa’s global data panel over a 3 month rolling period (22). to examine the correlation of known accessibility problems with website popularity, non-parametric spearman’s test was conducted. for statistical analyses, spss version 24 was used. the level of statistical significance was set at p < 0.05 . results all urls were analyzed, and redundant websites were excluded. after exclusion, 58 unique websites were eligible for the analysis . four out of 58 websites were not responsive to online evaluation. the most frequent accessibility error types reported by achecker, along with the percentage of websites with these errors, are presented in table 1. the main reported known problems belonged to: “scripts must have functional text,” “text equivalents,” “accessible forms,” and “text links for server-side image map” (table 2). to investigate the relationship between the extent of actable 1. most frequent accessibility error types check id description error category webpages (%) 90 script must have a nonscript section script must have functional text *91.4 1 img element missing alt attribute text equivalents 56.9 57 input element, type of "text", missing an associated label accessible forms 46.6 7 image used as anchor is missing valid alt text text equivalents 36.2 91 select element missing an associated label accessible forms 8.6 58 image used for input element is missing alt text accessible forms 6.9 121 input element, type of "radio", missing an associated label accessible forms 3.4 91 select element missing an associated label accessible forms 3.4 118 input element, type of "password", missing an associated label accessible forms 1.7 13 client-side image map missing duplicate text links text links for server-side image map 1.7 119 input element, type of "checkbox", missing an associated label accessible forms 1.7 *most of the websites showed error in check90. error category websites n (%) script must have functional text 53 (91.4%) text equivalents 41 (70.7%) accessible forms 30 (51.7%) text links for server-side image map 1 (1.7%) table 2. accessibility error rate by category evaluation of kidney transplant websitesvalizadeh haghi et al. kidney transplantation 262 vol 15 no 05 september-october 2018 263 cessibility errors and domain of studied websites, first, quantitative normalization of the extent of errors was investigated by smirnov–kolmogorov test. considering the absence of normal distribution, comparisons were made by kruskal–wallis test in different domains. according to table 3, although the mean accessibility errors in governmental (10.25 ± 7.274) and organizational (12.31 ± 9.469) websites were less than those in the other domains, the differences were not significant (p = 0.60). spearman’s correlation coefficient test showed no significant correlation (p > 0.05) between the extent of known problems and alexa ranking. most websites on kidney transplant (70.7%) were not certified by the honcode toolbar. the mean of known problems was lower in the hon-verified websites (11.41 ± 7.78) than in the verified websites (18.61 ± 13.10). differences were statistically significant (x2 = 4.428; p = 0.035 on kruskal–wallis test; table 4). table 4. kruskal–wallis test results comparing verified and unverified websites discussion to the best of our knowledge, this is the first study to investigate the status of accessibility as well as quality of websites containing information regarding kidney transplant. generally, websites with complex interaction modalities and user interfaces expose physically challenged people to new opportunities as well as challenges(23). currently, attention to the issue of website accessibility is very important. adherence to the guidelines of web accessibility is essential to reduce the gap between digitally underserved (e.g., physically challenged people) and information-affluent people(24). unfortunately, several websites are inaccessible to most people. overall, web accessibility status is largely unknown, particularly in health information websites, because limited studies have assessed the level of compliance of health websites. accordingly, the present study aimed to examine the current status of accessibility to health websites on kidney transplant for people with disabilities. the accessibility status of health websites is variable, depending on different health topics. the results of accessibility evaluation in prostate cancer websites showed that the majority of websites (92%) were accessible(25). the results of accessibility evaluation of aortic aneurysm treatment websites also showed moderate quality in terms of accessibility(26). some other studies on health website accessibility in different subjects have shown that most health websites are not accessible enough to people with disabilities(27). similarly, the present research showed that the majority of kidney transplant websites (96.6%) had accessibility barriers to physically challenged people. findings are discouraging because most kidney transplant websites do not fulfill the criteria. the majority of accessibility problems, particularly those related to scripts, are addressed by web developers(28). similarly, the present study revealed that most of health websites on kidney transplant (91.4%) have problems in “script must have functional text” category. therefore, health website designers should use scripting languages (for displaying content or creating interface elements), which can be read using assistive technologies(29). a developer can increase website accessibility by including alternate texts for video files, images, and audio files; the idea is to present a textual description(30). the present study revealed that 70.7% of surveyed websites had accessibility issues in the “text equivalent” category, mainly “img element missing alt attribute” error type (table 2). therefore, in health websites on kidney transplant, textual equivalents should be presented for all non-text elements that convey information to make the websites more accessible to physically challenged people. moreover, providing alternate texts for image maps is necessary(30). client-side image maps, instead of server-side maps, should be used to improve accessibility ad in the present study, most websites had taken this point into account. in fact, without a text alternative for each section, server-side image maps are not accessible(29). special considerations should be taken regarding the design of health website accessible forms since much of the information retrieved from the internet is gathered in online forms(29). however, our study showed that 51.7% of surveyed websites had problems in “accessible forms” category (table 2). therefore, physically challenged users may encounter problems while using these websites. since government-sponsored websites and educational institutions present reliable health information and are trustable(31), it is expected that people, including physically challenged patients, use these types of websites more than the commercial and private ones. therefore, it is expected that designers of these health websites consider equal access to the information for all users. zeng and bambang (2003) revealed that governmental and educational health websites exhibit better performance on web accessibility than other domains(32). in the present study, governmental and educational websites were speculated to show better performance retable 3. mean and standard deviation of known problems of website accessibility across domains domain number of known problems websites (n) mean standard deviation commercial (com) 19 22.16 12.807 educational (edu) 9 19.44 15.018 organizational (org) 26 12.31 9.469 governmental (gov) 4 10.25 7.274 total 58 16.50 12.180 hon not verified hon verified p-value known problem mean (sd) median mean (sd) median 0.035 18.61 (13.10) 19.00 11.41 (7.78) 8.00 table 4. kruskal–wallis test results comparing verified and unverified websites evaluation of kidney transplant websitesvalizadeh haghi et al. garding accessibility. nevertheless, the results showed no significant differences among various domains with regard to accessibility barriers (table 3). in this study, accessibility barriers exist in all categories of websites (e.g., educational and governmental), especially commercial websites. because physically challenged people prefer to use websites with less accessibility barriers, they may visit accessible websites, which contain unreliable health information and can negatively affect their health. in general, accessibility may have positive effects on a website’s popularity(24). nevertheless, in the present study, the results revealed that the correlation between accessibility barriers and website popularity is not significant (r = 0.172, p = 0.205). this implies that people with disabilities may encounter accessibility barriers, even if they visit popular websites. because physically challenged people are among the internet users, popular websites should pay special attention to the accessibility guidelines to make their websites more accessible; this can in turn increase the website visits and popularity. based on the results, various factors may be responsible for the limited compliance of websites with accessibility guidelines. in some studies, one of the main problems was that many developers did not prioritize accessibility(33). another reason is that websites may not be evaluated or modified after the design, based on accessibility guidelines. while web design strategies should be in line with accessibility needs assessment of users with different disabilities (e.g., cognitive, visual, auditory, and motor disabilities)(34). in addition to accessibility, quality of health websites is important, because it may affect the patients’ decision-making. therefore, we assessed the quality of health websites on kidney transplant, as well. our study showed that kidney transplant websites are of poor quality, as only 17 out of 58 (29.3%) websites were hon-verified, which is in line with the studies in various health topics(8,9); therefore, patients should use these websites with more caution. moreover, accessibility errors in hon-verified websites were fewer than the unverified ones, and differences were statistically significant (p = 0.035). authoritative websites on kidney transplant had made more efforts to make their websites more accessible. therefore, physically challenged people who use authoritative websites to fulfill their information needs on kidney transplant, are able to use assistive technologies more effectively and encounter fewer barriers while obtaining health information. conclusions the health websites designers, as well as owners, should be aware of accessibility problems, because there is a growing population of potential users with disabilities. this study indicated the need to ensure the compliance of kidney transplant websites with accessibility guidelines such as section 508. furthermore, because most surveyed websites were of poor quality and unreliable, there is a need to pay special attention to this problem. physicians should warn their patients about unqualified online health information and guide them to websites which are more reliable. because limited studies have examined the accessibility of health websites, besides the present study, it is recommended to pay more attention to the assessment of website accessibility on different topics. this effort is expected to increase awareness on web accessibility issues in health information websites. acknowledgement the authors would like to thank dr. mir davood omrani, and appreciate his kindly supports for this study. this article is extracted from the research project (code 13886) which is funded by the school of allied medical sciences, shahid beheshti university of medical sciences. conflict of interest the authors report no conflict of interest. references 1. abbasi ma, chertow gm, hall yn. endstage renal disease. bmj clin evid. 2010. 2. garcia gg, harden p, chapman j, world kidney day steering 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open transvesical prostate surgery; prostate; transurethral resection of the prostate introduction benign prostatic hyperplasia (bph) is the most common benign tumor in men, leading to problems such as disturbance in the urinary flow. the best treatment modality for this disease depends on different factors such as severity of symptoms, size of the prostate and patient’s general condition(1-3). these treatment modalities range from medical and pharmacological therapies to surgical procedures such as transurethral resection of the prostate (turp), open prostatectomy (op) or minimally invasive surgeries(1-3). turp and op and laser prostatectomy (holep) is currently a standard treatment are three standard surgical procedures in 1department of urology, faculty of medicine, kurdistan university of medical sciences, sanandaj, iran 2clinical research development center, kowsar hospital, kurdistan university of medical sciences, sanandaj, iran. 3student research committee, kurdistan university of medical sciences, sanandaj, iran. 4department of epidemiology, school of public health, hamadan university of medical sciences, hamadan, iran. 5student research committee, shahid beheshti university of medical sciences, sanandaj, iran *correspondence: clinical research development center, kowsar hospital, kurdistan university of medical sciences, pasdaran ave, sanandaj, iran. tel: +988733131366, email: rasouli1010@gmail.com. received june 2020 & accepted october 2020 patients with bph(2,4,5). for patients with bph who have a prostate weight of less than 70-80 grams, turp has been recommended as the standard method of treatment. for larger prostates or in the case of presence of large bladder stones, open prostatectomy has been suggested as the preferred method(6-8). however, there have been few studies directly comparing op and turp in a parallel study for prostate sizes of 40-65 grams(7,9). herein, we aim to compare the safety and efficiency of transvesical open prostatectomy versus turp in patients with bph and a prostate weight of 40-65 grams. urology journal/vol 18 no. 3/ may-june 2021/ pp. 289-294. [doi:10.22037/uj.v16i7.6342] materials and methods study design and participants this was a retrospective study performed on 160 consecutive patients with bph who had undergone turp (n=80) or op surgery (n=80) during 2006-2017 in tohid and kowsar hospitals, sanandaj, iran. inclusion criteria were: confirmed presence of bph, definite indication for prostatectomy, prostate weight between 4065 grams, and consent to participate in the study. indications for prostate surgery included recurrent urinary tract infection, persistent lower urinary tract symptom despite medical treatment, increased creatinine and bilateral hydronephrosis that significant reduce following urinary catheterization, frequent urinary retention (need to evacuate and catheterize the patient after surgery for one year), and hematuria due to prostate enlargement despite receiving medical treatment. criteria for being excluded from the study included: previous history of urinary tract surgery, prostate surgery or concurrent presence of bladder stones, patients with diabetes, patients with a history of discopathy and known cases of bladder neurogenesis. patients’ data including age, prostate weight and voleffectiveness and safety of op versus turp-sofimajidpour et al. endourology and stones diseases 130 ume, length of hospital stay, and need for re-operation was collected. the volume (cc) of the prostate was measured by ultrasound before surgery and the weight (gram) of the prostate was assessed post-surgery. shortterm post-operative complications such as fever, dysuria, requirement for blood transfusion, clot formation and need for catheter replacement within the first three days after surgery as well as long-term complications such as urinary retention, urinary incontinence, impotence, retrograde ejaculation (re) and urinary catheterization within the first year after surgery were also investigated. furthermore, patients’ peak flow rate (q max) and international prostate symptom score (ipss) was assessed at different time points: before surgery until 12 months post-surgery. patients’ medical history and physical examination (including digital rectal exam) was evaluated by the same urologist. laboratory parameters including plasma creatinine (cr), blood urea nitrogen (bun), complete blood count (cbc), serum sodium and potassium, urinary analysis (u/a), urinary culture (u/c), prostate-specific-antigen (psa) were measured. in addition, renal, bladder and prostate transabdominal ultrasound were performed to determine prostate volume and size table 1. comparing operative and postoperative variables in op and turp patients. variable turp (n=80) op (n=80) pvalue age (year), mean ± sd 62.4 ± 3.7 (57-76) 67.2 ± 4.6 (62-78) < 0.001 body mass index (bmi) 23.7 ± 3.2 24.1 ± 3.7 .46 prostate weight, mean ± sd 46.6 ± 5.7 (45-65) 45.3 ± 4.8 (40-65) .10 prostate size, g, mean ± sd 41.6 ± 2.7 (30-65) 42.1 ± 3.6 (40-65) .32 duration of hospitalization (hour) 36.2 ± 2.8 (24-50) 73.1 ± 2.6 (72-120) < 0.001 cr 1.40 ± 0.27 (1.21.6) 1.38 ± 0.33 (1.1-1.6) .83 psa 3.61 ± 0.44 (3-4.2) 3.72 ± 0.51 (3.1-4.3) .14 short complications after surgery postoperative fever, n (%) 52 (65) 47 (58.7) .41 blood transfusion 4 (5) 7 (8.7) .25 dysuria week 2 27 (33.7) 3 (3.7) < 0.001 week 4 26 (32.5) 4 (5) < 0.001 week 8 24 (30) 3 (3.7) < 0.001 month 3 26 (32.5) 5 (6.2) < 0.001 month 4 22 (27.5) 3 (3.7) < 0.001 month 5 21 (26.2) 2 (2.5) < 0.001 month 6 22 (33.8) 2 (2.5) < 0.001 month 12 27 (33.7) 1 (1.3) < 0.001 clot retention and need for catheter replacement 6 (7.5) 0 (0) .01 within the first three days after surgery hemodynamic changes and decrease in serum 0 (0) 0 (0) sodium level long-term complications after surgery urinary retention and requirement for urinary 10 (12.5) 0 (0) < 0.01 catheterization (year 1) incontinence after 3 months 0 (0) 0 (0) impotence after 3 months 0 (0) 0 (0) retrograde ejaculation 65 (81.2) 80 (100) < 0.01 re-operation (27 procedures on 19 patients) 27 (33.7) 0 (0) < 0.01 peak flow rate (q max), mean ± sd (range) before 9.3 ± 1.2 (8-11) 9.2 ± 1.3 (8-11) .61 after 1 month 14.1±1.6 (10-17) 14.3 ± 1.5 (13-16) .41 after 3 month 13.3 ± 1.5 (11-15) 16.4 ± 2.3 (15-18) < 0.001 after 6 month 13.3 ± 2.2 (11-13) 17.2 ± 2.4 (16-19) < 0.001 after 9 month 12.6 ± 1.7 (11-13) 17.1 ± 2.2 (16-19) < 0.001 after 12 month 13.4 ± 2.2 (12-15) 17.3 ± 1.6 (16-19) < 0.001 international prostate symptom score (ipss) before 28.4 ± 3.2 (23-30) 29.2 ± 3.1 (27-32) .11 after 3 month 21.3 ± 2.8 (19-23) 18.4 ± 2.6 (16-20) < 0.001 after 6 month 21 ± 3.1 (19-23) 17.5 ± 2.4 (16-20) < 0.001 after 12 month 21.6 ± 2.5 (18-23) 17.3 ± 2.4 (16-20) < 0.001 abbreviations: op, open prostatectomy; turp, transurethral resection of the prostate; sd, standard deviation; ipss, international prostate symptom score robotic and laparoscopic urology 290 vol 18 no 3 may-june 2021 291 before surgery. on the day of surgery, cystoscopy was performed for all patients and the approximate size of the prostate was recorded. foley catheter was removed in turp group after lightening of urine color 3-5 days after surgery. in the op group, skin incision of 7-10 cm was given, sutures was removed on the tenth day. no wound infection or dehiscence was seen in the suture line. the cystostomy was removed on day 2 or 3 after confirming the absence of clot and foley catheter was removed on day 7-9 after surgery. in the turp group, an average of 25 mg of pethidine was given (first day) to relieve pain, and in the op group, 50 mg of pethidine was given to relieve the patients' pain (first day) and then oral acetaminophen 500 mg, 4 times a day for 7-10 days was administered similarly in both groups. patients were followed up for at least one year. op and turp were performed by the same experienced urologist with more than 25 years of experience and history of performing more than 4000 tur operations. ethical considerations this study was approved by the ethics committee of kurdistan university of medical sciences (ir.muk. rec.1398.174). statistical analysis categorical variables are expressed as frequency (percentage) and continuous variables are reported as mean ± standard deviation (sd). t-test was used for comparison of continuous data and categorical was compared by using chi-square test and fisher exact test. all statistical analysis was performed by stata software version 14. p-value <0.05 was considered as statistically significant. results the mean ± sd age of patients in the turp and op groups was 62.4 ± 3.7 and 67.2 ± 4.6 years old, respectively. the mean ±sd prostate weight in the turp and op groups was 46.6 ± 5.7 and 45.3 ± 4.5 grams, respectively and the mean prostate volume was 41.1 and 42.5 cc (respectively). the mean duration of hospitalization was 36.2 hours in the turp and 73.1 hours in the op group. there were no differences between the two groups in terms of postoperative complications including: hemodynamic changes and decrease in serum sodium level was not reported in either group, fever, the need for transfusion was reported in four cases (5%) in the turp group and seven cases (8.7%) who underwent open surgery. dysuria was reported more frequently in the turp group compared with the op group from week two to 12 months post-surgery, showing a statistically significant difference between the two groups (table 1). we observed six cases (7.5%) with clot retention and need for catheter replacement within the first three days after surgery in the turp group while no cases developed this complication in the op group. regarding long-term complications, the frequency of urinary retention and requirement for urinary catheterization within the first year was significantly different between the two groups with 10 cases (12.5%) in the turp group and no cases in the op group (p < .001). in the turp group, 19 patients underwent reoperation in 27 procedures, including three patients with meatal stenosis who underwent meatotomy. nine patients were diagnosed with bulbar uretheral stenosis, for whom three patients underwent dilatation and internal uretherotomy once, and for six patients, for whom dilatation and internal uretherotomy were performed twice. two patients had residual tissue in prostatic fossa who underwent re-tur in the fourth month. five patients were diagnosed with bladder neck fibrosis. two patients underwent tuip, one patient underwent bladder neck dilatation once and two patients underwent bladder neck dilatation twice. of note, no patients in the op group required a second surgery. urinary incontinence and impotence was not reported in any patients of both groups. re was observed in 65 cases (81.2%) of the turp group and 80 cases (100%) of the op group. if the turp group includes all patients, q max shows a significant difference with the open group in 1, 3, 6, 9 and 12 months (table 1). however, if 19 patients in the turp group who need reoperation are removed from this group, the rate of q max in the two groups is not significantly different (table 2). based on the ipss, a significant improvement in symptoms was seen after surgery in the op group compared with the turp group, (the turp group includes all patients) (table 1). however, if 19 patients in the turp group who need reoperation are removed from this group, the rate of ipss in the two groups is not significantly different (table 2). table 2. comparing peak flow rate (q max) and international prostate symptom score (ipss) variables in op and turp group without re-operation. variable turp (n=61) op (n=80) pvalue peak flow rate (q max), mean ± sd (range) before 9.1 ± 1.3 (8-11) 9.2 ± 1.3 (8-11) 0.61 after 1 month 14.2 ± 1.5 (10-16) 14.3 ± 1.5 (13-16) 0.99 after 3 month 16 ± 1.6 (13-17) 16.4 ± 2.3 (15-18) 0.25 after 6 month 16.7 ± 2.2 (13-18) 17.2 ± 2.4 (16-19) 0.48 after 9 month 16.7 ± 1.9 (14-18) 17.1 ± 2.2 (16-19) 0.23 after 12 month 17 ± 2.4 (14-19) 17.3 ± 1.6 (16-19) 0.14 international prostate symptom score (ipss) before 28.4 ± 3.2 (23-30) 29.2 ± 3.1 (27-32) 0.11 after 3 month 19.3 ± 2.8 (17-22) 18.4 ± 2.6 (16-20) 0.53 after 6 month 17.6 ± 3.1 (15-19) 17.5 ± 2.4 (16-20) 0.93 after 12 month 17.5 ± 2.5 (15-19) 17.3 ± 2.4 (16-20) 0.82 abbreviations: op, open prostatectomy; turp, transurethral resection of the prostate; sd, standard deviation; ipss, international prostate symptom score effectiveness and safety of op versus turp-sofimajidpour et al. in order to relieve the pain at the incision site and the surgical site in the op group, on the first day, pethidine injection of 25 mg more than the turp group was required, and then oral acetaminophen 500 mg, 4 times a day for 7-10 days was administered similarly in both groups. at monthly follow-up of patients, no incision site pain was reported in patients. at monthly follow-up of patients, pain at the incision site was not reported in patients in the op group. discussion turp and op are two accepted surgical procedures in patients with bph(7). turp is one of the most common methods, performed in 60 to 97% of cases with bph (7,10). due to the high prevalence of benign prostatic hyperplasia and the importance of this issue, in this study, we aimed to investigate the efficacy and safety of these two surgical approaches in comparison with each other. the results of our study showed that the mean prostate weight and volume was not significantly different between the two groups who underwent turp and op. this finding was consistent with the results of a previous study conducted by simforoosh et al.(7). in another study by nnabugwu and colleagues, the prostate volume was significantly different between turp and op groups(11). in the present study, patients with similar prostate weight and volume were selected so that selection bias could be minimized. in the present study, the duration of hospitalization in individuals with turp and op methods was 36.2 and 73.1 hours, respectively, which was comparable with the results of another study by ou et al.(12). in a similar study by kwon et al., the duration of hospitalization in patients who underwent monopolar turp, bipolar turp and op was 9.4, 6.3 and 12 days, respectively (1); however, in accordance with our study, the mean hospital stay in the op group was higher than that of turp group. however, in our opinion and in the opinion of our patients, 36 hours of longer hospitalization was not important for this age group under prostate surgery. the results of the present study showed that the need for re-operation was significantly higher in the turp group compared with patients who underwent open surgery that is consistent with the results of a study by simforoosh et al.(7). some studies have reported the rate of reoperation as less than 5% per year, depending on the duration of follow-up period and number study showed that the need for reoperation in the turp group was higher than the open method and this difference was statistically significant. it was consistent with the results of a study by simforoosh et al.(7). in some other studies, reoperation was reported to be less than 5% per year, which varied according to the patient's follow-up period and the number of recurrences(13,14). in this study, urinary incontinence and impotence was not reported in any patients of either groups at three months post-surgery but re was higher in the op group compared with the turp group. dysuria was a more frequent complaint in patients of the turp group from week two to one-year post surgery; 27 cases (33.7%) of the turp group versus one case (1.3%) in the op group had dysuria at the first-year after surgery which was statistically significant. in line with this finding, in a study by simforoosh et al.(7), a significant difference existed between the two groups, with 28% of cases suffering from dysuria in the op group compared with 71% in the turp group. urinary incontinence was statistically significant, which is consistent with the results of the present study(7). in a study by long et al., incontinence and urinary tract infection was more prevalent in patients with op compared with transurethral plasmakinetic resection of the prostate (pkrp) while the need for catheterization method was more frequently reported in the pkrp group than the tvp group. based on the findings of this study, the main reason for temporary urinary incontinence may be related to local inflammation and edema, difficulties with the external sphincter mechanism, instability or decreased bladder adaptation or excessive stretching of the external sphincter(15). urinary incontinence and other irritative symptoms have been reported in some other studies and in patients undergoing turp surgery(16,17). in general, irritative symptoms are a major problem after surgery of damaged tissues and these symptoms may become resistant to treatment(7). recovery time and resolution of these symptoms depends on the type and duration of the operation and also patients’ general condition and amount of compliance. in our study, if the turp group includes all patients, q max shows a significant difference with the open group in 1, 3, 6, 9 and 12 months. however, if 19 patients in the turp group who need reoperation are removed from this group, the rate of q max in the two groups is not significantly different. in the study by long and colleagues, it was shown that during the follow-up period, q max improved in both of the study groups (pkrp and tvp)(15). park argued that the reason for higher q max in the op method compared with turp is that with complete removal of the adenoma, the proximal duct becomes wider and more symmetrical(18). ou et al. demonstrated that at six and 12 months post-surgery, there was no significant difference between turp and op groups in terms of q max rate(12). the results of these studies, in agreement with the results of our study. in the present study, the need for transfusion in the op group was slightly higher. in the study by park, only 0.8% of patients in the turp group required blood transfusions(18). in the study of kwon et al., need for transfusion with monopolar turp, bipolar turp and op was observed in 15.7%, zero and 33.3% of patients, respectively, showing a statistically significant difference (1). in the study of kader et al., the need for transfusion in the turp and transurethral incision of the prostate (tuip) groups was 5% and 0%, respectively; however, this difference was not statistically significant (19). in the present study, clot formation and catheter replacement within the first three days of surgery was more frequently observed in the turp group in comparison with the op group. gupta et al reported this rate as 8% in patients who underwent turp and 0% with open surgery (20). simforoosh and colleagues found this rate to be 12% in the turp group and 0% in the op group(7). these reports are consistent with the results of our study. based on the ipss, a significant improvement in symptoms was seen after surgery in the op group compared with the turp group, (the turp group includes all patients). however, if 19 patients in the turp group who need reoperation are removed from this group, the rate of ipss in the two groups is not significantly different. nnabugwu and colleagues showed no difference beeffectiveness and safety of op versus turp-sofimajidpour et al. laparoscopic and robotic urology 292 vol 18 no 3 may-june 2021 293 tween turp and op at 12 months after surgery (11). in the study of simforoosh et al., ipss did not have a statistically significant difference between op and turp groups(7). conclusions although turp is the standard method of treatment for bph in patients with a prostate weight between 4065 grams, the results of our study showed that op is a safer and more effective method with less short-term and long-term complications compared with turp. furthermore, the need for re-operation seems to be significantly higher in patients with turp. op has an easy learning curve and does not require specialized equipment and apparatuses. thus, we recommend open surgery as the preferred method for treatment of bph in prostate weighing between 40-65 grams. acknowledgement the study was sponsored by the deputy of research and technology of kurdistan university of medical sciences, sanandaj, iran. the authors wish to thank the clinical research development center at kowsar hospital, sanandaj, iran for their collaboration. conflict on interest the authors declare that there is no conflict of interest. references 1. kwon js, lee jw, lee sw, choi hy, moon hs. comparison of effectiveness of monopolar and bipolar transurethral resection of the prostate and open prostatectomy in large benign prostatic hyperplasia. korean journal of urology. 2011;52:269-73. 2. robbani ag, salam m, islam aa. transurethral resection (turp) versus transurethral incision (tuip) of the prostate for small sized benign prostatic hyperplasia: a prospective randomized study. taj: journal of teachers association. 2006;19:50-6. 3. stoelting rk. stoelting's anesthesia and coexisting disease: elsevier health sciences; 2012. 4. zwergel u, wullich b, lindenmeir u, rohde v, zwergel t. long-term results following transurethral resection of the prostate. european urology. 1998;33:476-80. 5. woo mj, ha y-s, lee jn, kim bs, kim ht, kim t-h, et al. comparison of surgical outcomes between holmium laser enucleation and transurethral resection of the prostate in patients with detrusor underactivity. international neurourology journal. 2017;21:46. 6. hanson ra, zornow mh, conlin mj, brambrink am. laser resection of the prostate: implications for anesthesia. anesthesia & analgesia. 2007;105:475-9. 7. simforoosh n, abdi h, kashi ah, zare s, tabibi a, danesh a, et al. open prostatectomy versus transurethral resection of the prostate, where are we standing in the new era? a randomized controlled trial. urology journal. 2010;7:262-9. 8. singhania p, nandini d, sarita f, hemant p, hemalata i. transurethral resection of prostate: a comparison of standard monopolar versus bipolar saline resection. international braz j urol. 2010;36:183-9. 9. wei s, cheng f, yu w. the clinical application of combination suprapubic prostatectomy with transurethral resection of the prostate (turp) in patients with large volume benign prostatic hyperplasia (bph). urologia journal. 2020;87:65-9. 10. meier de, tarpley jl, imediegwu oo, olaolorun d, nkor s, amao e, et al. the outcome of suprapubic prostatectomy: a contemporary series in the developing world. urology. 1995;46:40-4. 11. nnabugwu i, ugwumba f, udeh e, ozoemena o. learning transurethral resection of the prostate: a comparison of the weight of resected specimen to the weight of enucleated specimen in open prostatectomy. nigerian journal of clinical practice. 2017;20:1590-5. 12. ou r, deng x, yang w, wei x, chen h, xie k. transurethral enucleation and resection of the prostate vs transvesical prostatectomy for prostate volumes> 80 ml: a prospective randomized study. bju international. 2013;112:239-45. 13. madersbacher s, lackner j, brössner c, röhlich m, stancik i, willinger m, et al. reoperation, myocardial infarction and mortality after transurethral and open prostatectomy: a nation-wide, long-term analysis of 23,123 cases. european urology. 2005;47:499-504. 14. reich o, gratzke c, stief cg. techniques and long-term results of surgical procedures for bph. european urology. 2006;49:970-8. 15. long z, zhang y-c, he l-y, zhong k-b, tang y-x, huang k. comparison of transurethral plasmakinetic and transvesical prostatectomy in treatment of 100–149 ml benign prostatic hyperplasia. asian journal of surgery. 2014;37:58-64. 16. meyhoff h, nordling j. long term results of transurethral and transvesical prostatectomy: a randomized study. scandinavian journal of urology and nephrology. 1986;20:27-33. 17. tubaro a, carter s, hind a, vicentini c, miano l. a prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. the journal of urology. 2001;166:172-6. 18. park s-w, chung m-k. the results of retropubic prostatectomy and transu-rethral resection of prostate; compare both results, and then investigate the cause of different results. investigative and clinical urology. 2004;45:309-14. 19. abd-el kader o, el den km, el nashar a, hussein a, yehya e. transurethral incision versus transurethral resection of the prostate in small prostatic adenoma: long-term followup. african journal of urology. 2012;18:2933. 20. gupta s, solanki mi, maharaul hh. a effectiveness and safety of op versus turp-sofimajidpour et al. comparative study of post operative complications of open prostatectomy (fryer’s) versus trans urethral resection of prostate. 2015. effectiveness and safety of op versus turp-sofimajidpour et al. laparoscopic and robotic urology 294 female urology introduction signs and symptoms related to urine storage and voiding are resulted from dysfunctions of lower urinary tract system. these may include detrusor over-activity, sphincter weakness or sensory bladder disorders(1).the international sub-committee of standardization of urinary incontinence has classified lower urinary tract symptoms (luts) into three sub-groups including those related to urine storage, voiding and post-micturation. luts also presents with pain in lower urinary tract system. luts may be associated with overactive bladder or urine incontinence(2). luts is especially seen after the age of 40, and its frequency increases with age affecting many individuals older than 70 years old(3). based on the predictions on the aging of world’s population, the worldwide prevalence of luts is gradually raising(4). the prevalence of luts is variable in different populations depending on the age, gender, types of symptoms and cultural aspects of the societies(5). epidemiological studies have shown the prevalence of 40-70% of luts among women. among these, nocturia has been reported as a common symptom affecting 45-70% of women (1,4-6). luts negatively affects the quality of life leading to depression, anxiety, exasperation, stress, and reduced sexual activity and satisfaction. despite this, not all people visit physicians due to feelings shame and embarrassment(7). gathering information regarding the true the prevalence of lower urinary tract symptoms (luts) and incontinence in iranian women mahtab zargham1, abbas ali pourmomeny2*, masa soltanmohamadi2 purpose: lower urinary tract symptoms (luts) affect many women worldwide. the prevalence of luts among iranian women has not been reported. the aim of the present study was to evaluate the prevalence of lower urinary tract symptoms and its bother rate among women ≥20 years old living in isfahan, a central province of iran. materials and methods: this was a descriptive cross-sectional study. the data was collected using a population-based survey on women aged ≥ 20 years selected from the general population of isfahan (a central province of iran. a total of 2609 women were approached for the study. after obtaining demographic features, the participants completed the persian version of the international consultation on incontinence modular questionnaire for female lower urinary tract symptoms (iciq-fluts). results: 95.5% of the participants had at least one lower urinary tract symptoms. the most common symptoms were urgency (82.4%) and stress urinary incontinence (44.5%). nocturia (one or more occasions) was also noted in 60.7%. the highest bother rate was related to urgency. conclusion: the prevalence of lower urinary tract symptoms was high in the studied women. among lower urinary tract symptoms, urgency and nocturnal enuresis were the most and the least frequent symptoms. however, the bother rate of the symptoms was relatively low. keywords: iran; lower urinary tract symptoms (luts); prevalence; women 1pelvic floor research center, urology department of school medicine, isfahan university of medical sciences, isfahan, iran 2pelvic floor research center, school of rehabilitation sciences, isfahan university of medical sciences, isfahan, iran. *correspondence: pelvic floor research center, school of rehabilitation sciences, isfahan university of medical sciences, isfahan, iran. tel: + 98 3137925018, fax:+98 31 37925000 e-mail: pourmomeny@gmail.com. received january 2019 & accepted july 2019 prevalence of these symptoms can help to implement therapeutic and preventive measures. there are few epidemiological evidences about the prevalence of luts among iranian women. therefore, the aim of present study was to assess the prevalence of luts among women older than 20 years old in isfahan, a central province of iran. we then referred the women with incommodious symptoms to specialized health care centers for further management. materials and methods this was a descriptive and cross-sectional population-based survey performed on women within 2016 to 2018 in isfahan, a city in central region of iran. considering the report of the statistical center of iran on the isfahan’s population in the latest population and household survey in iran (2016), and taking into account a 10% drop in data gathering phase, the final sample size was decided as 3000. these women were randomly selected from 15 districts of isfahan. the study was approved by the local ethics committee of isfahan university of medical sciences (ir.mui.rec.1396.3251). the inclusion criterion was age ≥ 20 years. all the participants were requested to sign a written informed consent before entering to the study. luts was assessed using a standardized protocol based on the international continence society (ics) definitions. we particularly emphasized on the storage and voiding symptoms. after filling out the consent and the urology journal/vol 17 no. 3/ may-june 2020/ pp. 276-280. [doi: 10.22037/uj.v0i0.5053] vol 17 no 03 may-june 2020 277 demographic form, the participants were asked to complete the international consultation on incontinence modular questionnaire for female lower urinary tract symptoms (iciq-fluts) previously validated in persian (cronbach’s alpha & icc= 0.83)(8). in addition to the assessment of symptoms by likert scale (never, occasionally, sometimes, most of the time, all of the time), the iciq-fluts questionnaire also estimates the bother score of the symptoms considering the score of 0 for no suffering and 10 for maximum suffering. according to the ics guidelines, responding “occasionally” or “sometimes” to any response was regarded as positive. also, voiding more than 8 times per day and one or more times at night were interpreted as positive symptom of daytime frequency and nocturia, respectively. characteristics of the study population, prevalence of luts and other syndromes were presented as numbers and/or percentages with 95 % confidence intervals (cis). also mean values with standard deviation (sd) and median values with interquartile ranges (iqr) were calculated. all the statistical analyses were performed using spss v16.0 software (spss, chicago, il, usa). results a total of 3000 individuals were approached for the study, in order to enroll a sample of 2609. thus, the response rate was 87%. the overall mean age of the participants was 40.5 ± 12.24 years old(20-87). the number of deliveries was between 0 to 10 while 87% of participants reported less than 4 deliveries. the participants’ demographic features have been presented in table 1. the total missing data was 6.9%. 95.5%, and 79.9% of the subjects responded “occasionally” and “sometimes” to one or more symptoms, respectively, and 110 (4.5%) reported no symptoms by marking the “never” for all the queries. the prevalence of the symptoms has been noted in table 2. among storage related symptoms, the most frequent was urgency (82.4%) following by nocturia (60.7%)and daytime frequency (9.6%). among incontinence symptoms, stress urinary incontinence (sui) constituted the most encountered symptom (44.5%) following by urgency urinary incontinence (uui) (36.3%), unexplained incontinence (16.2%) and nocturnal enuresis (5.8%). among voiding symptoms, intermittency (44.8%), hesitancy (31.5%), and straining (21.3%) constituted the most common encountered issues (table 2). the mean age of the individuals with luts(40.37±12.22) was higher in comparison with those without luts (36.38 ± 12.70); however, the difference was not statistically significant(p = 0.065). the prevalence of the symptoms was obtained 92.9% among 20-29 years old women. this showed an increasing trend with aging; however, a decrease was observed in the prevalence of the symptoms in ≥70 years old group (table 3). nocturia, which was defined based on the ics definition (waking up at least one time at night to urinate) was observed in 60.7% and 18.4% of the participants voided at least twice per night. furthermore; 66.5%, 23.8% and the prevalence of fluts in iranian women-zargham et al. table 1. sample demographic information (n=2609). variables n (%) bmi: ≥25 1237 (51.2) <25 1044 (48.8) educational background: primary school 866 (33.6) high school 791 (30.7) university 919 (35.7) job: housewife 1799 (69.4) employer & student 690 (26.6) self-employment 105 (4) marital status: single 2185 (84.6) married 398 (15.4) menstrual status : premenopausa 1928 (75.4) menopausal 628 (24.6) delivery: vaginal cesarean section 958 (37.2) vaginal delivery & cesarean 819 (31.8) nulliparity 237 (9.2) pregnant 558 (21.7) 73 (2.8) medical history: pelvic malignancy uterus, ovary and vaginal surgery 21 (0.8) diabetes 183 (7) urinary tract infection and medical 107 (4.1) care 316 (12.1) neurologic condition 13 (0.5) symptom never (0) occasionally( 1) sometimes (2) most of the time(3) always(4) n (%, 95%ci) n (%, 95%ci) n (%, 95%ci) (4) n (%, 95%ci) n* (%y, 95%ci) urgency 449 975 834 234 61 ( 17.6%,14-21.1) (38.2%,35.1-41.2) (32.7%,29.5-35.8) (9.2%,5.5-12.9) (2.4%,0-6.2) pain 1408 656 412 58 16 (55.2%,52.6-57.8) (25.7%,22.3-29) (16.2%,12.6-19.7) (2.3%,0-6.1) (0.6%,0-4.3) hesitancy 1737 501 237 37 22 (68.5%,66.3-70.6) (19.8%,16.3-23.2) (9.4%,5.6-13.1) (1.5%,0-5.4) (0.9%,0-4.8) straining 1997 333 162 36 10 (78.7%,76.9-80.5) (13.1%,9.4-16.7 ) (6.4%,2.6-10.31) (1.4%,0-5.2) (0.4%,0-4.3) intermittency 1401 707 322 92 14 (55.2%,52.6-57.8) (27.9%,24.5-31.2) (12.7%,9-16.3) (3.6%,0-7.4) (0.6%,0-4.6) urgency incontinence 1620 525 331 50 17 ( 63.7%,61.3-66) (20.6%,17.1-24) (13%,9.3-16.6) (2%,0-5.8) (0.7%,0-4.6) stress incontinence 1410 582 377 116 56 (55.5%,52.9-58) (22.9%,19.4-26.3) (14.8%,11.2-18.3) 4.6%,0.7-8.4) (2.2%,0-6) unexplained 2130 238 143 23 9 incontinence ( 83.8%,82.2-85.3) (9.4%,5.6-13.1) ( 5.6%,1.8-9.3) (0.9%,0-4.7) ( 0.4%,0-4.5) nocturnal enuresis 2400 99 40 5 3 (94.2%,93.2-95.1) (3.9%,0-7.7) (1.6%,0-5.4) (0.2%,0-4.1) (0.1%,0-3.6) table 2. prevalence(%,95ci) each symptom according likert score. 9.6% of the participants noted 1-6, 7-8, and more than 8 times daily urinations, respectively. according to ics definition, 21.69% of the studied women had overactive bladder (oab) syndrome with 54.1% of them suffering from uui. according to the patients’ self-reports, the history of urinary tract infection needing urologist appointment was observed in 12.1%within the past six months. among these, the urgency, uui, and daytime frequency were identified with respective frequencies of 88.3%, 44.2%, and 15.9%. the highest bother score belonged to urgency and sui with mean score of 2.45 and 1.84 respectively. the lowest bother score belonged to nocturia enuresis ( mean score :0.37). discussion the aim of the present study was to ascertain the prevalence of urinary symptoms in the general population of iran. in our study a normal distribution was observed in age. in present study, in 95.5% of the population, however, luts were either evidently or silently observed. urgency showed the highest frequency and bother score in comparison with other symptoms. in other studies, this symptom has also been reported as either the first or second common presentation (12.8-35%)(5,7,9). the high prevalence of this symptom may be related to dietary regimens and consuming stimulant beverages, the lack of mobility, depression and anxiety(10,11). the roles of such factors need to be further investigated. abnormal daytime frequency (more than 8 times per day) was found in 9.6% of our studied population. this has been reported as 7-57.1% in other studies(5,12-15). however, precaution should be taken reporting such values as there has been no information on the daily liquid intake and also drug usage history neither in our study nor in other epidemiological studies(1,5). the frequency and means bother scores of sui was higher than uui in our study which is in line with previous reports(1,5,7,9,16).on the other hand, in van breda hm et al. report, the frequencies of sui and uui were as 3.1% and 3.8%, respectively(7).this disagreement can be related to the difference in the mean age of the participants. 21.69% of our participants showed oab from whom 54.1% had uui. the prevalence of this syndrome was reported 18.2% in the study of safarinejad mr. et al.(17) which was lower compared with our study. this may be explainable by the overall increment observed in the symptoms during 2009 to 2018. the prevalence of this syndrome has been reported in the range of 2% to 53% in various studies(18-21). in present study, nocturia comprised the second most common symptom after urgency. also, nocturia claimed the highest bother score after urgency and sui. in their study, hajebrahimi s. et al. reported nocturia (at least one per night) as the most common symptom (43.5%) among women with the mean age of 21.11 years(23). some studies have suggested nocturia of one time per night as a normal phenomenon(5,7). these implications suggest the one night-time nocturia as a normal phenomenon rather than a disorder. this hypothesis may be further supported by the relatively low mean bother score of 1.6 in individuals with this problem. nonetheless, by using the modified definition of nocturia, the storage symptoms still retained higher frequencies than voiding symptoms. irwin de. et al. asserted an increasing trend in luts(4). these researchers reported at least one luts symptom in 45.2% of subjects older than 20 years old in 2008. they further predicted an increasing ratio of 18.4% of luts symptoms to reach 63.6% in 2018. these ratios were obtained 95.5% and 94.3% in the present report and the study of van breda et al(7) respectively indicating a close proximity despite different age spectrums of the participants. a history of visiting urologists within the past three months was recorded in 11.1% of our participants. regarding cultural dissimilarities among societies, this ratios have been variable in different countries with reported values of 22% in brazil(23) and 4% in china(24). among muslims, some of factors deterring physician appointments are shame, religious issues (excrements avoidance), and considering incontinence as a normal sequela of aging(25). a history of seeking physician due to urinary tract infections within the past six months was noted in 12.1%. respective to the overall value, these individuals showed higher rates of uui, urgency and daytime frequency. nevertheless, in our study, the diagnosis of the infections was decided based on the patients’ claims rather than the paraclinical finding which is a limitation of the study. at least one symptom of luts was identified in 95.5% of our studied population. however, 88.9% of these individuals stated no complaints and did not visit physicians. this brought up the question that when a lower urinary tract symptom should be considered as a complaint? and why the majority of people did not seek medical assistance for their problems? do they regard these symptoms as normal? the epidemic nature of the table 3. prevalence each symptom in different age groups. symptoms 20-39yrα (n=1307) 40-59yrα n=1019 60≥ yrα n=251 nocturia 51.15 69.8 82.6 urgency 79.5 84 86 bladder pain 45 48 34.2 frequency β 9.1 12.1 10.2 hesitancy 29.5 32.2 41.5 straining 22.5 22 28.4 intermittency 42.1 48.2 52 urge incont. 24.1 48.4 64.5 stress incont 32.1 55.6 65 unexplained incont. 9.3 24.2 28.2 nocturnal enuresis 2.9 9 14 every luts 93.7 96.3 97.6 α: age group and weight (%) , β: more than 8 times per day the prevalence of fluts in iranian women-zargham et al. female urology 278 vol 17 no 03 may-june 2020 279 symptoms, the lack of knowledge, unwillingness, and shame may largely contribute to this phenomenon. a symptom being considered as intolerable is mainly dependent on the level of agony and reduction in life quality. it is probable that the most of women assessed in present study suffered from hidden symptoms. the essential factor is individual’s attitude toward these symptoms. without any doubt, these symptoms are often resulted from functional disorders rather than pathologies like infections or urinary system tumors. limitations of this study include the cross-sectional design, and not considering the relationship of incontinence with other associated diseases, time-dependent alternations in the symptoms, and the possible impacts of dietary habits. these may be addressed in future studies. conclusions according to the ics definitions, our results demonstrated that luts were highly prevalent but had relatively low bother score. this may indicate hidden or silent luts in adult women in isfahan. nevertheless, the most frequent symptom was urgency. acknowledgement we thank the deputy of research of isfahan university of medical sciences, health centers, health section of isfahan municipality, as well as the isfahan education department for their kind cooperation. conflict on interest the authors report no conflict of interest. references 1. coyne ks, sexton cc, thompson cl, milsom i, irwin d, kopp zs, et al. the prevalence of lower urinary tract symptoms (luts) in the usa, the uk and sweden: results from the epidemiology of luts (epiluts) study. bjui 2009;104:352-60. 2. abrams p, cardozo l, fall m, griffiths d, rosier p, ulmsten u, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub_ committee of the international continence society. neurourol. urodyn. 2002;21:167-78. 3. sexton cc, coyne ks, thompson c, bavendam t, chen ci, markland a. prevalence and effect on health-related quality of life of overactive bladder in older americans: results from the epidemiology of lower urinary tract symptoms study. j am geriatr soc. 2011;59:1465-70. doi: 10.1111/j.15325415.2011.03492.x. epub 2011 jun 30. 4. irwin de, kopp zs, agatep b, milsom i, abrams p. worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. bjui 2011;108:1132-8. 5. irwin de, milsom i, hunskaar s, reilly k, kopp z, herschorn s, et al. population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the epic study. eur. urol. 2006;50:1306-15. 6. boyle p, robertson c, mazzettac, keech m, hobbs fdr, fourcade r, et al. the prevalence of lower urinary tract symptoms in men and women in four centres. the urepik study. bjui 2003;92:409-14. 7. van bredahm, bosch jr, de kort lm. hidden prevalence of lower urinary tract symptoms in healthy nulligravid young women. iuj. 2015;26:1637-43. 8. pourmomeny aa, rezaeian zs, soltanmohamadi m. translation and linguistic validation of the persian version of the bristol female lower urinary tract symptoms instrument. iuj. 2017;28:1329-33. 9. pathiraja r, prathapan s, goonawardena s. urinary incontinence of women in a nationwide study in sri lanka: prevalence and risk factors. urol j. 2017 23;3075-80. 10. coyne ks, kaplan sa, chapple cr, sexton cc, kopp zs, bush en, et al. risk factors and comorbid conditions associated with lower urinary tract symptoms: epiluts. bjui 2009;103:24-32. 11. zhang w, song y, he x, xu b, huang h, he c, et al. prevalence and risk factors of lower urinary tract symptoms in fuzhou chinese women. eur urol. 2005;48:309-13. 12. chuang fc, kuo hc. prevalence of lower urinary tract symptoms in indigenous and nonindigenous women in eastern taiwan. jfma 2010;109:228-36. 13. liao ym, dougherty mc, biemer pp, boyington ar, liao ct, palmer mh, et al. prevalence of lower urinary tract symptoms among female elementary school teachers in taipei. int urogynecol j. 2007;18:1151-61. 14. liao ym, yang cy, kao cc, dougherty mc, lai yh, chang y, et al. prevalence and impact on quality of life of lower urinary tract symptoms among a sample of employed women in taipei: a questionnaire survey. int j nurs stud 2009;46:633-44. 15. pinnock cb, marshallvr. troublesome lower urinary tract symptoms in the community: a prevalence study. med. j. aust.1997;167:725. 16. nojomi m, amin eb, rad rb. urinary incontinence: hospital-based prevalence and risk factors. j res med sci 2008;13:22-8. 17. safarinejad mr. prevalence of the overactive bladder among iranian women based on the international continence society definition: a population-based study. int urol nephrol. 2009;41:35-45. 18. milsom i, irwin de. a cross-sectional, population-based, multinational study of the prevalence of overactive bladder and lower urinary tract symptoms: results from the epic study. european urology supplements 2007;6:4-9. 19. temml c, heidlers, ponholzer a, the prevalence of fluts in iranian women-zargham et al. madersbacher s. prevalence of the overactive bladder syndrome by applying the international continence society definition. european urology 2005;48:622-7. 20. milsom i, abrams p, cardozo l, roberts rg, thuroff j, wein aj. how widespread are the symptoms of an overactive bladder and how are they managed? a population based prevalence study. bjui 2001;87:760-6. 21. lapitan mc, chyeon plh. the epidemiology of overactive bladder among females in asia: a questionnairesurvey. international urogynecology journal .2001;12:226-31. 22. haj se, mostafaie h, torabi z, beighzali s, parnianfard n, bagheri z. s36 prevalence of lower urinary tract symptoms (luts) and urinary incontinence among iranian young adult and correlation of their knowledge with current evidences. european urology supplements 2013;12:e1144-e1s36. 23. rios aa, cardoso jr, rodrigues ma f, de almeida shm. the help-seeking by women with urinary incontinence in brazil. international urogynecology journal 2011;22:879-84. 24. ng sf, lok mk, pang sm, wun yt. stress urinary incontinence in younger women in primary care: prevalence and opportunistic intervention. journal of women's health 2014;23:65-8. 25. altaweel w, alharbi m. urinary incontinence: prevalence, risk factors, and impact on health related quality of life in saudi women. neurourol. urodyn. 2012;31:642-5. symptoms bother score (mean) median (iqr) nocturia 1.55 0 (0-2) urgency 2.45 1 (0-4) pain 1.47 0 (0-2) daytime frequency 1.69 0 (0-2) hesitancy 0.86 0 (0-0) straining 0.70 0 (0-0) intermittency 1.05 0 (0-1) urgency incontinence 1.53 0 (0-2) stress incontinence 1.84 0 (0-2) unexplained incontinency 0.72 0 (0-0) nocturnal enuresis 0.37 0 (0-0) α=interquartile range supplementary table: bother score (mean, median and iqrα) in each symptom according to analog scale the prevalence of fluts in iranian women-zargham et al. female urology 280 point of technique 214 urology journal vol 6 no 3 summer 2009 percutaneous drainage of a late-onset giant posttraumatic urinoma ali asghar ketabchi, mahsa ketabchi, mohsen barkam urol j. 2009;6:214-6. www.uj.unrc.ir keywords: kidney injuries, drainage, urine department of urology, shafa hospital, physiology research center, kerman university of medical sciences, kerman, iran corresponding author: ali asghar ketabchi, md department of urology, shafa hospital, kerman, iran tel: +98 341 245 6665 e-mail: mrketabchi@yahoo.com received april 2008 accepted april 2009 introduction urinoma or pararenal pseudocyst is defined as an encapsulated collection of extravasated urine in the perirenal space. extravasation of urine into the perirenal fat triggers lipolysis and inflammatory reactions, which lead to formation of a fibrous sac around the collected urine.(1) urinomas occur most commonly following trauma to the kidneys.(1) although posttraumatic urine extravasation is common (2% to 18%), urinoma develops only in few cases.(2) other major causes include obstructive uropathy (eg, posterior urethral valve and ureteropelvic junction obstruction), iatrogenesis in endosurgical procedures, and rarely, pregnancy.(3-5) we report a young man with a giant urinoma following falling which had caused left-flank blunt trauma 1 month earlier. treatment with percutaneous drainage was done successfully. case report a 25-year-old man was referred to our hospital due to a large abdominal mass, with a history of a blunt trauma to his left flank in a falling injury 1 month earlier. computed tomography revealed injury to the left kidney that had caused parenchymal laceration extending through the renal cortex, medulla, and collecting system, with trivial contrast medium extravasation and perirenal hematoma (organ figure 1. left, transverse computed tomography scan of a large left cystic mass (giant urinoma). right, giant urinoma in the left is seen with multiple septa. drainage of a giant urinoma—ketabchi et al urology journal vol 6 no 3 summer 2009 215 injury scale grade 4). on the 1st day of admission, he had mild hematuria which gradually subsided to microscopic hematuria without the need for blood transfusion. during the hospital stay, his vital signs were stable, and he was treated conservatively. ultrasonography on day 7 revealed no sign of perirenal extravasation or hematoma, and the patient was discharged. on the 2nd admission, 1 month after the 1st admission, he had a large mass in the left side of his abdomen. he had no significant symptoms, except for filling a little heaviness and vague discomfort in his left side of the abdomen. abdominal ultrasonography and computed tomography revealed an 11 × 9-cm cyst with multiple septa (figure 1) without any contrast medium extravasation in the perirenal area or in the cystic mass. the left kidney was located in the lower limit position (figure 2), and had signs of parenchymal fracture in one of slides (figure 3). technique by the guide of ultrasonography, an 18-gauge needle was advanced into the urinoma and about 3500 ml of clear urine was aspirated. then the tract was dilated over a guide wire to 12 f in size, and a 10-f pigtail catheter was inserted and left for continuous drainage for 3 days. results about 30 days after the blunt trauma to the left flank, a large urinoma had been gradually formed, which was documented by computed tomography as a lubolated cystic mass with parenchymal renal laceration (grade 4). following percutaneous aspiration of about 3.5 l of clear urine, the patient was discharged on day 4 of the 2nd admission. at discharge, ultrasonography showed no sign of extravasation or hematoma in the left perirenal space. on the follow-up visits after 2 weeks and 1 month, no abnormalities or symptoms were reported. discussion urine extravasation is a common finding in grades 4 and 5 kidney injuries with an expectation of resolution in 87.1% of patients.(6) however, if it persists and causes urinoma, drainage is recommended for prevention of serious complications, such as abscess formation and sepsis. drainage is a reasonable first-step treatment before any corrective interventions. among drainage modalities, percutaneous drainage is recommended when the patients are hemodynamically stable and figure 2. intravenous urography shows the left kidney in a lower position than the right kidney because of the left urinoma (arrow). figure 3. left kidney paranchymal laceration (arrow) on computed tomography scan. drainage of a giant urinoma—ketabchi et al 216 urology journal vol 6 no 3 summer 2009 their urinomas are fixed. hence, this method will be an effective and safe therapy for these patients and will help to relieve symptoms. nonetheless, there has been little information in the literature to date on the late-onset urinoma following trauma to the kidneys. usually, the delayed formed urinomas, according to unal and colleagues, are more complicated and often need operative drainage.(7) however in our case, we did not find any significant complication or hemodynamical instability. therefore, we managed it by percutaneous catheter drainage. conflict of interest none declared. references 1. ito s, ikeda m, asanuma h, shishido s, nakai h, honda m. a giant urinoma in a neonate without obstructive uropathy. pediatr nephrol. 2000;14:831-2. 2. srinath n, sood r, rana kvs, madhusoodhanan p. urinoma following blunt renal trauma. mjafi. 2000;56:3446. 3. connor jp, hensle tw, berdon w, burbige ka. contained neonatal urinoma: management and functional results. j urol. 1988;140:1319-22. 4. thompson im, ross g, jr., ezzard j, habib h, amoury ra. experiences with 16 cases of pararenal pseudocyst. j urol. 1976;116:289-92. 5. ushioda n, matsuo k, nagamatsu m, kimura t, shimoya k. maternal urinoma during pregnancy. j obstet gynaecol res. 2008;34:88-91. 6. matthews la, smith em, spirnak jp. nonoperative treatment of major blunt renal lacerations with urinary extravasation. j urol. 1997;157:2056-8. 7. unal b, basar h, karadeniz bilgili my, et al. lateonset ureteric urinoma with intermittent jet flow as a complication of ureterolithotomy. j clin ultrasound. 2004;32:264-6. miscellaneous the effects of diuresis, duration of dialysis and age on lower urinary tract function in urologically healthy male patients on the waiting list for kidney transplant roman zachoval1,5,6*, vladimír borovicka1, tomáš marada2, ondřej viklický3, jiří froněk2, jan krhut4, libor janoušek2, janka slatinská3, petr nencka6 purpose: this work investigated the effects of diuresis, duration of dialysis and age on lower urinary tract function in urologically healthy males on the waiting list for kidney transplant. materials and methods: the study included all men who had kidney transplants at our centre between january 2009 and december 2014 who had normal urological findings prior to inclusion on the list. diuresis, the duration of haemodialysis, age, and parameters of function of the lower urinary tract as determined by filling and voiding cystometry were evaluated. results: the study included 127 men (median age, 59 years; median diuresis, 250 ml; median duration of dialysis, 469.5 days). we found that greater diuresis was accompanied by significantly higher fdv, fdv/cmax, ndv, cmax and compliance and by significantly lower pdet.max, pdetqmax and booi. longer duration of dialysis was accompanied by significantly lower fdv, ndv and cmax, compliance and qmax.p and with significantly higher pdet.max, pdetqmax and booi. older age was associated with significantly higher pdet.max and with significantly lower compliance. worsening of the basic parameters of the storage function of the lower urinary tract occurred when diuresis decreased to 500–750 ml, when the duration of dialysis was one year and when patients were older than 54 years. conclusion: in healthy male patients on the waiting list for kidney transplant, there were connections between the occurrence of dysfunctions of the lower urinary tract and diuresis, duration of dialysis and age. patients should be monitored for dysfunctions of the lower urinary tract before and after transplantation. key words: age; diuresis; dialysis; kidney transplant; lower urinary tract dysfunction; male; waiting list. introduction in patients who are on the waiting list for kidney trans-plants, changes caused by deterioration of renal function and degenerative processes lead to worsening of the functions of the lower urinary tract (lut)(1). however, correct function of the lut is essential for the patient and for graft function following transplantation(2). although several studies have evaluated the functions of the lut in patients prior to and after transplantation, the exact relationships between diuresis, duration of haemodialysis and patient age and the occurrence of dysfunctions of the lut are not yet known. this has not been clarified even in male patients in whom dysfunctions of the lut could cause an especially serious danger for the graft. this work investigated the connections between diuresis, duration of dialysis, and age on lower urinary tract function in urologically healthy males who were on the waiting list for kidney transplant. a second objective was to determine the diuresis values, duration of dial1department o urology, thomayer hospital, prague, czech republic. 2department of transplantation surgery, institute of clinical and experimental medicine, prague, czech republic. 3department of nephrology, institute of clinical and experimental medicine, prague, czech republic. 4department of urology, university hospital in ostrava. 5department of urology, general faculty hospital and 1st faculty of medicine of charles university in prague. 6department of urology, kralovske vinohrady faculty hospital and 3rd faculty of medicine of charles university in prague. *correspondence: department of urologythomayer hospitalvidenska 800 140 59 prague 4 czech republic tel: +420 261083196. fax: +420 261083688. e-mail: roman.zachoval@ftn.cz. received february 2017 & accepted auguat 2017 ysis and age at which the individual parameters of the function of the lut substantially deteriorated, if indeed they did so. the bigger goal is the identification of male patients without urological diseases and symptoms who are most at risk of developing lut disorders. materials and methods the analysis included all men who underwent kidney transplants between january 2009 and december 2014 at our centre who were sent for urological examination and exhibited normal urological findings, except for possible reduced diuresis, before being put on the waiting list for a kidney transplant. the following men were excluded from the study: those whose case histories contained information about surgery of the lut those who at the present time or in the past (for patients with diuresis less than 500 ml) demonstrated medium or serious voiding difficulties based on the questionnaire of the international prostate symptom vol 15 no 02 march-april 2018 49 miscellaneus 50 score (i.e. ipss > 7 on a scale of 0 – 35) those who had urological diseases that had potential effects on the lut those for whom uroflowmetry showed a maximal flow rate (qmax) less than < 15 ml/s (examined only for patients with diuresis greater than 500 ml); the minimum voiding volume in the examination was > 150 ml those on pharmacotherapy for lut symptoms those who suffered from neurological diseases or other diseases that might impact lut function the following were evaluated for all men: 1. diuresis (ml), which was determined as the average value from a 7-day voiding diary 2. the duration of haemodialysis (days) 3. age (years) 4. the parameters of function of the lut as evaluated by urodynamic examination performed according to the good urodynamic practice recommendations: a. storage function parameters as determined by filling cystometry i. first desire to void (fdv) (ml) ii. first desire to void/maximal capacity (fdv/ cmax) (normal value > 50% cmax) iii. normal desire to void (ndv) (ml) iv. normal desire to void (ndvcmax) (normal value > 75% cmax) v. maximal cystometric capacity (cmax) (normal value > 350 ml) vi. detrusor compliance (normal value > 30) vii. maximal detrusor pressure (pdet.max) (cm h 2 o ) viii. the presence of uninhibited detrusor contractions b. voiding parameters as determined using voiding cystometry i. maximal flow rate (ml/s) ii. post-voiding residual as measured by ultrasound (ml) iii. detrusor pressure at maximal flow rate (pdetqmax) (cm h2o) iv. bladder outlet obstruction index (booi = pdetqmax – 2 × qmax) (normal value < 40) v. bladder contractility index (bci = pdetqmax + 5 × qmax) (normal value > 100) statistical analysis the following data were evaluated statistically: descriptive patient data that were related to diuresis, age and individual urodynamic parameters the correlation between diuresis and urodynamic parameters the correlation between the duration of dialysis and urodynamic parameters and the correlation between age and urodynamic parameters for parameters for which the borderline between normal and pathological values is clearly defined according to the international continence society. study outcomes: the area under the curve (auc = area under roc curve (receiver operating characteristis curve) is signifying excellent, good, and worthless tests. the accuracy of the test depends on how well the test separates the group being tested into those with and without the disease in question. accuracy is measured by the area under the roc curve. an area of 1 represents a perfect test; an area of .5 represents a worthless test. a rough guide for classifying the accuracy of a diagnostic test is the traditional academic point system: • .90-1 = excellent (a) • .80-.90 = good (b) • .70-.80 = fair (c) • .60-.70 = poor (d) • .50-.60 = fail (f) ) and confidence intervals (confidence interval (ci) is a type of interval estimate that is computed from the observed data, confidence level is the frequency of possible confidence intervals that contain the true value of their corresponding parameter) were evaluated for diuresis, duration of dialysis and age. when the lower confidence interval for these parameters was less than 0.5, the cut-off values were determined, since these parameters showed the greatest specificity and sensitivity in distinguishing between normal and pathological values for the given parameter. the odds ratios were determined for these parameters. the basic statistical information, such as averages, standard deviations, scatter, medians, interquartile ranges, and minimum and maximum values were determined for the measured parameters in the entire data set. selected statistical data were also graphed using box & whisker plot diagrams. spearman’s correlation coefficient was used to determine the relationship of the investigated parameters with the non-gaussian distribution of these variables. variation in the parameters over time was tested using both the paired wilcoxon test and also the friedman anova test. these results were then controlled using parametric scatter analysis table 1. results of descriptive data for the storage and voiding functions of the lower urinary tract. parameters median lower qurtile upper quartile minimum maximum fdv (ml) 89 56 137 5 291 fdv/c max (%) 42 29 58 3 427 ndv (ml) 138 98 213 26 213 ndv/c max (%) 71 55 85 16 713 c max (ml) 211 144 341 22 914 compliance 14,1 4,4 32,5 0,2 320 pdet.max (cm h 2 o) 35 17 65 2 221 qmax.p (ml/s) 15,4 11,2 17,7 9,6 25,2 pvr (ml) 11 0 80 0 910 pdetqmax (cm h2o) 52 35 72 12 163 booi 37 15 60 6 155 bci 92 76 113 36 183 effect of diuresis, duration of dialysis and age on luts-zachoval et al. (repeated design). the differences in the investigated parameters between the monitored groups were tested using the double-selection wilcoxon test or the kruskal-wallis test. differences in the categorical variables between the tested groups were determined using the chi-squared test or fisher’s exact test. the statistical significance was determined using the limit of alpha = 0.05. the statistical analyses were performed using sas software (sas institute inc., cary, nc, usa) and statistica software (statsoft, inc., tulsa, ok, usa). the graphs were drawn using sw statistica (statsoft, inc.) results the study cohort included 127 male patients who had complete information for all of the considered parameters. the median age was 59 years (lower quartile 50 – upper quartile 65). the cause of chronic kidney disease was glomerulonephritis for 21 patients, hypertension nephropathy for 20, diabetic nephropathy for 19, tubulointerstitial nephritis for 19, iga nephropathy for 12, renal polycystosis for 12, focal segmental glomerulosclerosis for 4 and other or unclear causes for 21. median diuresis was 250 ml (lower quartile 100–upper quartile 1,000). the median duration of dialysis was 469.5 days (lower quartile 248–upper quartile 1,004). descriptive data for parameters determined by urodynamic examination descriptive data for the storage and voiding functions of the lut are shown in table 1. uninhibited detrusor contraction was present in 51 patients (40%). correlations between diuresis and urodynamic parameters table 2 shows the relationships between diuresis and the urodynamic parameters related to lut functions. evaluation of the storage phase showed that increasing diuresis was accompanied by significant increases in fdv volume, fdv/cmax, ndv and cmax and with significantly greater compliance and significantly lower pdet.max. evaluation of the voiding phase indicated that the greater the diuresis, the lower the pdetqmax and booi values. correlations between the duration of dialysis and urodynamic parameters table 3 shows the relationships between the duration of dialysis and the urodynamic parameters of the lut function. evaluation of the storage phase showed that increasing duration of dialysis was accompanied by significantly lower volumes for fdv, ndv and cmax, with significantly lower compliance and with significantly greater pdet.max. evaluation of voiding showed that greater duration of dialysis was associated with significantly lower qmax.p and with significantly higher pdetqmax and booi values. correlations between age and urodynamic parameters table 4 shows the relationships between age and the urodynamic parameters of the lut function. evaluation of the storage function showed that increasing patient age was accompanied by significantly higher pdet. max and with significantly lower compliance. evaluation of the voiding function showed no significant dependence between age and the parameters of the voiding function of the lut. evaluating the specificity, sensitivity, roc curve, area under the curve (auc) and the odds ratio values for diuresis, the confidence intervals were greater than 0.5 for cmax and compliance. the cut-off value for distinguishing between normal and pathological values of cmax was 750 ml, with a sensitivity of 84.2%, a table 2. the relationships between diuresis and the urodynamic parameters table 3. the relationships between the duration of dialysis and the urodynamic parameters parameters p fdv (ml) < .0001 fdv/c max (%) .08 ndv (ml) < .0001 ndv/c max (%) .0098 c max (ml) < .0001 compliance < .0001 pdet.max (cm h 2 o) .0005 qmax.p (ml/s) .35 pvr (ml) .33 pdetqmax (cm h 2 o) .03 booi .04 bci .16 parameters p fdv (ml) .001 fdv/c max (%) .2 ndv (ml) .0001 ndv/c max (%) .15 c max (ml) .0001 compliance .0002 pdet.max (cm h 2 o) .0004 qmax.p (ml/s) .0058 pvr (ml) .97 pdetqmax (cm h 2 o) .0357 booi .0161 bci .64 figure 1. roc curve for residual diuresis. effect of diuresis, duration of dialysis and age on luts-zachoval et al. vol 15 no 02 march-april 2018 51 miscellaneus 52 specificity of 55.6% and an odds ratio of 6.7 at this sensitivity and specificity, patients with diuresis that is less than 750 ml have a 6.7-fold greater risk of having pathological cmax values than patients with diuresis greater than 750 ml. the cut-off for distinguishing between normal and pathological values of compliance was 500 ml, with a sensitivity of 81.4%, a specificity of 53.3% and an odds ratio of 12.8. at this sensitivity and specificity, patients with diuresis less than 500 ml have a 12.8-fold greater risk of having pathological compliance values than patients with diuresis greater than 500 ml. the results are shown in figure 1. to evaluate the duration of dialysis, the confidence interval was greater than 0.5 for cmax and booi. the cut-off for distinguishing between normal and pathological values of cmax was 267 days, with a sensitivity of 81.9%, a specificity of 61.5% and an odds ratio of 7.3. at this sensitivity and specificity, patients with duration of dialysis greater than 267 days have a 7.3-fold greater risk of having pathological cmax values than patients with dialysis duration less than 267 days. the cut-off for distinguishing between normal and pathological booi values was 307 days, with a sensitivity of 75.5%, a specificity of 50.0%, and an odds ratio of 3.1. at this sensitivity and specificity, patients with duration of dialysis greater than 307 days have a 3.1-fold greater risk of having pathological booi values than patients with dialysis duration less than 307 days. the results are shown in figure 2. for the age evaluation, the confidence interval was greater than 0.5 for compliance. the cut-off for distinguishing between normal and pathological compliance values was 54 years, with a sensitivity of 76.1%, a specificity of 41.7%, and an odds ratio of 5.2. at this sensitivity and specificity, patients older than 54 years have a 5.2-fold greater risk of pathological compliance values than patients younger than 54 years. the results are shown in figure 3. discussion the underlying mechanism of lut dysfunctions in ckd patients have not been completely elucidated yet, however several etiological and risk factors have been discussed. changes in the diuresis volume, different compound concentration in urine, chronic inflammation, chronic ischaemia, lack of proliferative and protective factors in urine and different reflex between urinary bladder and lower urinary tract outlet might contribute to these effects(2). dysfunction of the lut that causes long-term high intravesical pressure and significant post-voiding residual volume can cause vesicoureteral reflux into transplanted kidney and can pose a risk to graft function. consequently, it is advantageous to diagnose these disorders as soon as possible, ideally prior to transplantation(2). notably, patients with serious lut dysfunction, such as reduced maximal detrusor capacity less than 100 ml, have significantly lower graft survival compared to other patients, independent of the patient’s immunological status(1). the number of patients in the dialysis program is constantly increasing, primartable 4. the relationships between age and the urodynamic parameters. parameters p fdv (ml) .51 fdv/c max (%) .18 ndv (ml) .28 ndv/c max (%) .16 c max (ml) .14 compliance .0008 pdet.max (cm h2o) .0013 qmax.p (ml/s) .69 pvr (ml) .7 pdetqmax (cm h2o) .73 booi .89 bci .63 figure 2. roc curve for duration of dialysis. figure 3. roc curve for age. effect of diuresis, duration of dialysis and age on luts-zachoval et al. ily because of the greater number of older patients, both men and women(3,4). compared to women, men have a greater risk of the occurrence of serious lut obstruction and other dysfunctions(5,6) . experimental and clinical studies have repeatedly demonstrated that prolonged reduced diuresis leads to lut storage and voiding dysfunctions. when this happens, repeated urinary infections or other pathological changes in the bladder can lead to structural rebuilding of all of the layers of the lut and to serious morphological and functional disorders, such as a contracted bladder with minimal capacity(1) . as a result of reduced diuresis, the patient and also the examining physician frequently do not notice any pathological changes in detrusor capacity and compliance in cases of progressing end stage kidney disease (eskd). following successful kidney transplant, lut dysfunction and its symptoms can be fully manifested along with all of their negative consequences(7). some authors have found that anuria and oliguria are the most important risk factors for urological complications following kidney transplantation (8). zermann et al. reported that 38% of patients (both men and women) with reduced diuresis who were on the waiting list for kidney transplantation were at risk of low bladder compliance, and 48% were at risk of detrusor hyperactivity(9) . tsunoyama et al. found that patients with eskd and reduced diuresis who were on the waiting list for kidney transplantation suffered from reduced fs, ns and ss compared to the normal population, while 27% showed detrusor hyperactivity(10). maximal detrusor capacity less than 100 ml was found for 14% and 34% of patients with reduced diuresis in the studies by song et al. and chen et al., respectively(11,12). the voiding function can also be disrupted in patients with reduced diuresis who are on the waiting list for kidney transplantation. in the set of patients studied by habib kashi et al., the greatest worsening of lut function was found for parameters related to both storage and voiding functions(1) . chen et al. found lut obstruction in 51% of patients(12). this observation is in accordance with our results, as almost all of the storage function parameters and some of the voiding function parameters showed a statistically significant dependence on diuresis volume. we were able to determine a cut-off value for the diuresis volume at which the probability of storage function dysfunction significantly increased. we found that when diuresis decreased to less than 500–750 ml, there was a 6to 12-fold greater probability of reduced maximal detrusor capacity and compliance. previous studies showed that morphological and functional changes in the lut are dependent on the duration of reduced diuresis(10). the maximal detrusor capacity and compliance also increase with the duration of oliguria or anuria(12-14). according to martin et al., the capacity of the detrusor decreases to 300 ml after 5 years and to 150 ml after 15 years in patients with eskd and reduced diuresis(13). according to dion et al., reduced detrusor compliance after 1 and 10 years of dialysis occurs in 31% and 77% of patients, respectively(14). these conclusions are in accordance with our results in that we also that found that the duration of dialysis and the pathological values of most of the parameters related to storage function showed significant associations with parameters related to voiding function. we found that the risk of the development of reduced bladder capacity was significant—up to 7-fold—when dialysis lasted longer than 1 year. aging occurs at many levels and includes changes at the molecular, cellular and organ levels as well as in cerebral function and in the organism as a whole. the changes associated with aging occur at different times in different individuals; consequently, individuals differ more from each other when they are older versus when they are younger. lut aging is typically characterized by pathological changes like detrusor hyperactivity, reduced detrusor contractibility and the presence of subvesical obstruction. the very complicated changes associated with lut aging are frequently complicated by concomitant diseases that significantly affect lut, including vascular, degenerative, metabolic and neurological diseases(16). a number of studies have evaluated the dependence of storage and voiding dysfunction on age. one study that evaluated asymptomatic men and women found that cystometric capacity, maximal detrusor pressure and maximal voiding flow decrease substantially in both sexes with aging(17). balslev jorgensen et al. investigated uroflowmetry parameters and found that all of the parameters decrease with age, even in asymptomatic individuals(18). madersbacher et al. evaluated differences between the sexes by monitoring lut dysfunction during aging in a symptomatic population. they found a substantial increase in post-voiding residual volume and a decrease in qmax and detrusor capacity in both sexes during aging(19). some studies investigated reduced contractility and found a dependence on age(20), while others found no age dependence(19,21). our results confirmed those of studies that demonstrated the dependence of storage function parameters on age. we found that detrusor compliance was significantly dependent on patient age and that the risk of deterioration of detrusor compliance increased approximately 5-fold for men who were over 54 years of age. some studies that evaluated the occurrence of some types of dysfunction and their dependence on age found differences between men and women. the study by madersbacher et al. found an increase in detrusor hyperactivity that was only dependent on age in men. among men aged 40 to 60 years, 23% had detrusor hyperactivity, as did 47% of the men who were over 80 years of age(19). studies of voiding function have repeatedly reported that qmax is reduced in men over 50 years of age(22,23). some studies have reported a decrease in qmax of 1–2 ml/s/5 years(24-26). our study only included asymptomatic men who were on the waiting list for kidney transplantation; thus, some of the results may be specific to men. another potential limitation was our failure to distinguish patients based on the causes of eskd. however, it was not possible to evaluate these parameters because of the statistically insufficient number of patients. conclusions our results demonstrated that in healthy male patients who were on the waiting list for kidney transplants, there were connections between the occurrence of dysfunctions of the lut and diuresis, duration of dialysis and age. the basic parameters of the storage function of the lut worsened when diuresis decreased to 500 – 750 ml, when dialysis was performed for approximately one year and when patients were older than 54 years. particular care should be taken when examining these effect of diuresis, duration of dialysis and age on luts-zachoval et al. vol 15 no 02 march-april 2018 53 miscellaneus 54 patients, and they should be monitored for dysfunction of the lut before and after transplantation. conflict of interest none declared. references 1. habib kashi s., wynne ks, sadek sa, et al. an evaluation of vesical urodynamics before renal transplantation and its effect on renal allograft function and survival. transplantation. 1994;57:1455–1457. 2. zermann dh. disorders of micturition. in: schrier r, ed. diseases of the kidney, 7th ed. philadelphia: lippincott-williams and wilkins, 2001: vol. 1, 663-694. 3. barzegar h, moosazadeh m, jafari h, esmaeili, r. evaluation of dialysis adequacy in hemodialysis patients: a systematic review. urol j. 2016; 13: 2744-2749. 4. tumin m, satar nhm, zakaria rz et al. determinants of willingness to became organ donors among dialysis patients´ family members. urol j. 2015; 12:2245-2250. 5. ounissi m., gargah t, bacha mm, et al. malformative uropathies and kidney transplantation. transplant proc. 2011; 43: 437-440. 6. zhang y, wang y, zhang p, et al. extendedrelease doxazosin for treatment of renal transplant recipients with benign prostatic hyperplasia. transplant proc. 2009; 41: 37473751. 7. hurst fp, neff rr, falta em et al. incidence, predictors, and associated outcomes of prostatism after kidney transplantation. clin j am soc nephrol. 2009; 4: 329-336. 8. tillou x, lee-bion a, deligny bh et al. does daily urine output really matter in renal transplantation? ann transplant. 2013; 18: 716-720. 9. zermann dh, loffler u, reichelt o, wunderlich h, wilhelm s, schubert j. bladder dysfunction and end stage renal disease. int urol nephrol. 2003; 35: 93-97. 10. tsunoyama k, ishida h, omoto k, shimizu t, shirakawa h, tanabe k. bladder function of end-stage renal disease patients. int urol nephrol. 2010; 17: 791-795. 11. song m, park j, kim yh et al. bladder capacity in kidney transplant patients with end-stage renal disease. int urol nephrol. 2015; 47: 101-106. 12. chen jl, lee mc, kuo hc. reduction of cystometric bladder capacity and bladder compliance with time in patients with endstage renal disease. journal of the formosan medical association. 2012; 111: 209-213. 13. martin x, aboutaieb r, soliman s, el essawy a, dawahra m, lefrancois n. the use of long-term defunctionalized bladder in renal transplantation: is it safe? eur urol. 1999; 36: 450-453. 14. ushigome h, sakai k, suzuki t et al. kidney transplantation for patients on long-term hemodialysis. transplant proc. 2008; 40: 2297-2298. 15. dion m, cristea o, langford s, luke ppw, sener a. debilitating lower urinary tract symptoms in the post-renal transplant population can be predicted pretransplantation. clinical and translational research. 2013; 95: 589-594. 16. hald t, horn t. the human urinary bladder in aging. br. j urol. 1998; 82, suppl 1: 59-64. 17. homma y, imajo c, takabashi s, kawabe k, aso y. urinary symptoms and urodynamics in a normal elderly population. scand j urol nephrol suppl. 1994; 157: 27-30. 18. balslev jorgensen j, jensen kme, mogensen p. longitudinal observation on normal and abnormal voiding in men over the age of 50 years. br j urol. 1993; 72: 413-420. 19. madersbacher s, pycha a, schatzl g, mian c, klingler ch, marberger m. the aging lower urinary tract: a comparative urodynamic study of men and women. adult urology. 1998; 51: 206-212. 20. bosch jlhr, kranse r, van mastrigt r, schroeder fh. dependence of male voiding efficiency on age, bladder contractility and urethral resistence: development of a voiding efficiency nomogram. j urol. 1995; 154: 190194. 21. malone-lee j, wahedna i. characterisation of detrusor contractile function in relation to old age. br j urol. 1993; 72: 873-880. 22. abrams ph. prostatism and prostatectomy: the value of urine flow rate measurement in the preoperative assessment for operation. j urol. 1977; 117: 70-71. 23. andersen jt, jacobsen o, worm-petersen j et al. bladder function in healthy elderly males. scand j urol nephrol. 1978; 12:123-127. 24. drach gw, layton tn, binard wj. male peak urinary flow rate: relationships to volume and age. j urol. 1979; 122: 210-214. 25. gammelgaard j. micturition patterns in normal adults. ugeskr laeger. 1974;48: 26752678. 26. ball aj, feneley rcl, abrams ph. the natural history of untreated prostatism. br j urol. 1981. 53:613-616. effect of diuresis, duration of dialysis and age on luts-zachoval et al. successful laparoscopic removal of a self-inflicted thermometer that spontaneously migrated into the peritoneal cavity jovo bogdanović 1,2, vuk sekulić1,2*, tijana koković3, senjin djozić1, dragan vulin4 keywords: adult; bladder; bladder perforation; foreign body; laparoscopy. 1clinic of urology, clinical center of vojvodina, novi sad, serbia. 2faculty of medicine novi sad, university of novi sad, novi sad, serbia. 3radiology center, clinical center of vojvodina, novi sad, serbia. 4clinic of abdominal & endocrine surgery, clinical center of vojvodina, novi sad, serbia. *correspondence: clinical center of vojvodina, hajduk veljkova str 1-9, novi sad 21000, serbia. phone +381 63 515010. fax + 381 21 529929. e mail: vuk.sekulic@mf.uns.ac.rs. received january 2017 & accepted august 2017 a sixty-three-year-old caucasian male was referred to emergency service 10 hours after self-infliction of a mercury glass thermometer into the urethra. the patient presented without abdominal or voiding symptoms. radiological imaging confirmed the presence of a thermometer in the peritoneal cavity, without signs of contrast leakage from the bladder. the patient underwent suture of the perforation site with a subsequent successful removal of the foreign body using laparoscopic approach. recovery was uneventful. to the best of our knowledge, we are not aware of any previous report of laparoscopic removal of a mercury glass thermometer from the peritoneal cavity. laparoscopic removal of fragile items, such as a thermometer, is obviously feasible but associated with substantial risks. introduction there is a myriad of reported foreign bodies in the bladder(1). sexual pleasure is the main reason for insertion, followed by inquisitiveness and mental or psychiatric disorders(2). however, an occasional item, such as a thermometer, inadvertently slips into the bladder. intraperitoneal migration of this foreign body is a rare event, and there are only a few reports in the literature(3,4). case report a sixty-three-year-old caucasian male was referred to emergency service 10 hours following inadvertent self-infliction of a mercury glass thermometer through the urethra. the patient denied abdominal or voiding symptoms. his past history did not reveal the treatment of serious health conditions including psychiatric diseases. physical examination was unremarkable. there were no signs of urethrorrhagia or macroscopic hematuria. urinalysis rvealed 10 to 15 red blood cells in the high power field. although the thermometer was shown frankly on plain x-ray of case report figure 1. cystogram confirming an absence of extravasation of contrast from the bladder and the thermometer in the peritoneal cavity in the coronal (figure 1a) and oblique plane (figure 1b). figure 2. ct scan showing intraperitoneal localization of the thermometer and an absence of contrast extravasation from the bladder. case report 5071 a "ghost" thermometer-bogdanović et al. the pelvis, an ultrasound surprisingly failed to show it in the bladder. thereafter, a cystogram with 300 ml saline and 30 ml of iodine contrast showed no signs of contrast extravasation from the bladder (figures 1a&b). a ct scan confirmed this finding (figure 2). the patient requested a laparoscopic removal of the foreign body despite possible risk of potential intraperitoneal spillage of mercury. the decision to attempt laparoscopic removal was made following several successful removals of similar items from the laparoscopic training box. the procedure was performed under general anesthesia using three trocars: a 10 mm camera port was placed beneath the umbilicus and additional two ports (5 and 12 mm) were placed bilaterally in the middle of the line between umbilicus and spina iliaca anterior superior, taking care to avoid injury to epigastric vessels. a small tear of parietal peritoneum near the median umbilical ligament was sutured. the thermometer was found in the peritoneal cavity. it was inserted into the 12 mm port and both items together were pulled out undamaged. after half-hour the procedure was completed leaving a peritoneal drain and three-way 18-fr foley catheter in the bladder. the drain and the catheter were removed on postoperative day 3 and 7, respectively. recovery was uneventful. discussion the medical thermometer has not been an unusual foreign body in the bladder(1). insertion of this device into the bladder was more frequent in females, due to the short urethra and common attempts to measure a basal core temperature in the vagina or urethra for reproductive reasons. passage of a thermometer through the male bladder is more difficult due to the length and curvatures of the urethra(1,2). diagnosis of the thermometer in the bladder or peritoneal cavity is not challenging because glass and mercury are clearly radiopaque on x-ray. however, sometimes it may be difficult to prove radiologically a route of passage of the foreign body, because of the lack of contrast extravasation. all reported foreign bodies have been removed safely by the open surgical procedures(3,4). to the best of our knowledge, laparoscopic removal of a mercury glass thermometer from the peritoneal cavity has not been reported previously. the technique of laparoscopic removal is quite easy. however, this procedure is associated with a risk of injury of surrounding organs with glass fragments as well as spillage of mercury into the peritoneum, and potential systemic toxic effects of mercury on the central nervous system and kidneys. furthermore, enterocutaneous and rectal fistulas, granuloma formation and intestinal obstruction following intraperitoneal mercury exposure have been reported previously(5,6). some of these risks can be lowered by usage of a retrieval bag. conflict of interest the authors report no conflict on interest. acknowledgement the authors are thankful to mrs. giorgia solaja for help in improving writing style of the manuscript. references 1. van ophoven a, de kernion jb. clinical management of foreign bodies of the genitourinary tract. j urol 2000; 164: 274-87. 2. bogdanović j, sekulić v, trivunić-dajko s, herin r. re: palmer et al.: urethral foreign bodies: clinical presentation and management urology. 2017; 100; 256-8 3. kiriyama t, motonaga i, ichikawa t: foreign body migration from the bladder. j urol 1976;115: 530-1. 4. nie j, zhang b, duan ycet al.. intestinal obstruction due to migration of a thermometer from bladder to abdominal cavity: a case report. world j gastroenterol. 2014;20:24268. 5. mazer-amirshahi m, bleecker ml, barrueto, fjr. intraperitoneal elemental mercury exposure from a mercury-weighted bougie. j med toxicol. 2013; 9: 270–3. 6. haas ns, shih r, gochfeld m. a patient with postoperative mercury contamination of the peritoneum. j toxicol clin toxicol. 2003;41:175–80 vol 14 no 06 november-december 2017 5072 novel anatomic mapping of pelvic plexus at prostatic and periprostatic region on fresh frozen cadaveric setting purpose: we aimed to investigate the exact localization of neural pathway and the frequency of nerve fibers, which are located in the pelvic facial layers in the prostate and periprostatic regions. materials and methods: we used four fresh frozen cadavers in this trial. anatomical layers of anterior rectus fascia and abdominal rectus muscle were dissected to reach the retropubic area. prostate, visceral and parietal pelvic fascia, levator ani muscle and puboprostatic ligaments were identified. nine tissue samples, each 1x1 cm in size, were obtained from each cadaver and grouped separately. the locations of these samples are as follows. group g i from 12 o’clock (apical region), g ii from right prostatic apex, g iii from 2 o’clock, g iv from right far pelvic lateral, g v from 5 o’clock, g vi from 7 o’clock, gvii from left far pelvic lateral, g viii from 10 o’clock and g ix from left prostatic apex. nerve distribution, frequency and diameters of these 9 groups were compared to each other. results: 36 specimens were obtained from 4 cadavers. mean number of nerve fibers was 14.1. the number of nerve fibers in each location were not statistically different from each other (p = .9). mean nerve diameter was 89.1 μm. mean diameter of nerves was statistically different between groups ii, iii iv and vi and viii (p = .001). no difference was seen amongst others. conclusion: the distributions of nerve fibers at prostate and peri-prostatic region were homogeneous while the nerve diameters varied amongst the different regions. keywords: cadaver; cavernous nerve; neural mapping; pelvic plexus; prostate. introduction pelvic plexus or inferior hypogastric plexus (ihp) is a diffuse neural network situated in periprostatic space covering the prostate. the nerve fibers and ganglia, that surround the prostate capsule, form this neural network. in these fields, nerve fibers course with the vascular structures as neuro-vascular bundle (nvb). nvb contains nerve fibers directly associated with prostate, seminal vesicle, all parts of urethra (prostatic, membranous and spongious), ejaculatory duct, cavernous and spongious bodies, bulbourethral gland and might be dissected anatomically from posterolateral surface of prostate.(1) these neural structures innervate the urogenital organs in the pelvic region. however, the main part of the ihp gives rise to the cavernous nerve (cn), which is responsible for erectile function.1 cn and ihp generally run in a caudal direction. the distribution of nerve fibers at the prostate level, adjacent tissues and far pelvic region is variable. possessing knowledge of this distribution is important to achieve good functional outcomes following radical prostatectomy, which is a treatment modality for organ-confined prostate cancer. nerve injuries can cause erectile dysfunction and incontinence after radical prostatectomy. (2) nerve distribution of prostate gland and its' surrounding tissues is still a debated issue. in our study, after open pelvic cadaveric dissection, nerve distribution of 1department of urology, department of urology, hacettepe university school of medicine, ankara, turkey. 2department of anatomy, hacettepe university school of medicine, ankara, turkey. 3department of pathology, hacettepe university school of medicine, ankara, turkey. *correspondence: hacettepe university, faculty of medicine, department of urology, 06100 sihhiye/ankara/turkey. phone: 0 312 305 19 69. e-mail: emrehuri@hacettepe.edu.tr. received october 2016 & accepted august 2017 prostate gland and periprostatic tissue is analyzed based on their glandular location. we aimed to map the neural distribution of anterior, anterolateral, posterolateral sides of prostate, far lateral pelvic tissues and classify them according to their frequency and size parameters. materials and methods preparation for dissection four fresh frozen cadavers, having no previous dissection of the pelvic region, were included to the study. cadavers were removed from the preservation tank one day prior to dissection, and then prepared accordingly. open surgical set, sterile draping, retractors and optimal lighting systems were available. 2.5x surgical loop (heiner) was used for fine dissection and surgical field control. dissection technique a urologist and an anatomist performed the dissections together. we performed retropubic radical prostatectomy as described by walsh.(3) subumbilical median incision was performed between pubic symphysis and umbilicus. after incision, each anatomic landmark was identified. they are as follows: skin, subcutaneous tissue, fascia of camper, fascia of scarpa, arcus tendineous of levator ani,, arcuate line of rectus sheath, semilunar line, fascia of rectus muscle, abdominal rectus muscle, transverse fascia, iliopsoas muscle, bladder, emre huri1, mustafa f. sargon2, ilkan tatar2, makbule cisel aydın3, mehmet ezer1, figen söylemezoglu3 miscellaneous vol 14 no 06 november-december 2017 5064 prostate, perivesical space, superficial dorsal vein, deep dorsal vein, visceral pelvic fascia, parietal pelvic fascia, internal obturator muscle, levator ani muscle, prostatic fascia, prostatic capsul, denonvillier's fascia, puboprostatic ligaments, pubovesical ligaments, arcus tendineus, seminal vesicles, vas deferens, cavernous penile nerve, external urethral sphincter and urethra. tissue sampling and evaluation 10x10 mm tissue samples were collected during the dissection from prostate and far prostate fields and put into 10% formaldehyde solution. nine tissue samples were taken from each cadaver. tissue samples classified to nine groups as gi to gix. tissue samples contain fascial tissues adjacent to prostate and further away from prostate. the location from which tissue samples were taken were planned so that all of the area between prostatic apex and vesicoprostatic junctions could be sampled. the fragments were made by considering clockwise anatomical neighborhoods, in this way tissue was removed from each area in equal proportions. schematic illustration of clockwise sampling areas is shown in figure 1. a total of nine tissue samples were taken. these samples were grouped clockwise. samples were taken from 12 o'clock (group i), right apex (group ii), 2 o'clock (group iii), right lateral pelvic wall (group iv), 5 o'clock (group v), 7 o'clock (group vi), left lateral pelvic wall (group vii), 10 o'clock (group viii) and left apex (group ix). the specimens were fixed in 10% formaldehyde solution and then, embedded into paraffin blocks. 5 μm thick sections from paraffin blocks were stained with h&e and visualized by one researcher with 100x magnification under the light microscope at department of pathology. in every section, diameter of the peripheral nerve fibers from pelvic plexus was measured and filed with oculometric method. the nerve fiber frequency according to different fields, its relation with dimensions of the fibers and diameter changes according to regions were evaluated statistically. statistical analysis the post-hoc test reveals which specific groups cause the differences between groups. in this study, post-hoc test was performed to find the groups which make differences between the nerve diameters. kruskal-wallis test was used for comparing interregional nerve fiber numbers and one-way anova was used for comparing nerve fibers diameters. p value was 0.05 and confidence bounds were 95%. results thirty-six specimens were obtained from four cadavers. mean nerve frequency in these groups were 13.2 (gi), 16 (gii), 18.7 (giii), 12 (giv), 13.5 (gv), 19.2 (gvi), 9.5 (gvii), 12.7 (gviii) and 12 (gix). distribution of peripheral nerve fibers and their diameters of different prostatic regions are shown in table 1. the frequency of nerve fibers in regions were not statistically different among groups (p = 0.991). the diameters of nerves were 88.4 (gi), 79.5 (gii), 93.5 (giii), 78.6 (giv), 100.5 (gv), 74.4 (gvi), 87 (gvii), 121.5 (gviii), 84.3 (gix) clockwise. nerve diameters were significantly different between gviii and gii (p = 0.04) and gviii and giii (p = 0.01), gviii and giv (p = 0.02), gviii and gvi (p = 0.001) no significant difference was seen amongst the other groups. according to the microscopic analysis on the images, periprostatic nerve fiber diameters at 10 o’clock (gviii) (figure 2a) were higher than right prostatic apex (figure 2b), 2 o’clock (giii) (figure 2c), right far lateral pelvic field (giv) (figure 2d), and 7 o’clock(figure 2e) (gvi), respectively. discussion our findings suggest that nerve fibers were distributed homogenously, which contradict with their results of the literature. however, we took samples from between ventrolateral and dorsolateral sides of the prostate. we didn't take samples from the ventral side. the reason miscellaneous 5065 regions (group) number of peripheric nerves, n, *mean ± sd (min-max) diameter of peripheric nerves, (µm), **mean ± sd (min-max) 12 o’clock (g1) 13.2 ± 19.8 (0-42) 88.4 ± 45.1 (19-224) right apical (g2) 16.0 ± 20.8 (2-47) 79.5 ± 43.7 (16-189) 2 o’clock (g3) 18.7 ± 22.2 (4-51) 93.5 ± 111.6 (13-821) right lateral pelvic wall (g4) 12.0 ± 8.0 (3-21) 78.6 ± 51.3 (18-245) 5 o’clock (g5) 13.5 ± 11.1 (6-30) 100.5 ± 60 (35-344) 7 o’clock (g6) 19.2 ± 18.5 (5-46) 74.4 ± 42.5 (7-200) left lateral pelvic wall (g7) 9.5 ± 5.9 (2-16) 87.0 ± 56.0 (23-244) 10 o’clock (g8) 12.7 ± 13.2 (3-31) 121.5 ± 109.6 (39-608) left apical (g9) 12.0 ± 12.6 (0-28) 84.3 ± 64.7 (15-411) table 1. distribution of peripheric nerve fibers and their diameters according to the prostatic regions. *p = 0.991 (sd = standard deviation) figure 1. schematic view of tissue sampling regions and difference between the regions for nerve fiber’s diameters cadaveric neural mapping of pelvis and prostate-huri et al. for that is the previous studies in literature clearly show that there is limited to no functional nerve fibers in the anterior region. we believe that the nerve distribution in our groups were similar due to our comparison of a different set of regions. our findings also suggest that mean nerve diameter at 10 o'clock is higher than other regions. this is the first such finding in literature. also, increased mean nerve diameter was higher in the left side, which shows that nerve distribution of the periprostatic area is not symmetric. since the first description radical prostatectomy by walsh(4), there has been important changes in nerve sparing radical prostatectomy technique.(3,5,6) these modifications increased functional and structural importance of anatomical landmarks. as of today, radical prostatectomy has satisfactory oncological outcomes. although the long-term cancer-specific survival rate is high, it is clear that functional outcomes are still not satisfactory.(7) different imaging techniques have been used to visualize the neurovascular bundle to improve the functional outcomes of radical prostatectomy.(8-10) yadav et al. examined the prostate tissue of rats with a multiphotone microscope and showed that microscopic findings were similar to that of pathologic findings. they were able to visualize the neural fibers in the periprostatic region of the live tissue.(11) we have used light microscope for dissection and then sent the tissue for pathological analysis. however, our method is not proven to be a reliable method for visualization of nerve fibers. inferior hypogastric plexus is responsible for erection and urinary continence.(12) this plexus is made up of sympathetic and parasympathetic nerve fibers originating from t11-l2 and s3-4 segments of spinal cord. these nerve fibers make up cavernosal penile nerve at the distal end.(12,13) clarebrough et al. reported that neural tissue is mainly posterolateral to prostate and nerve frequency decreased from the base of the prostate to the apex.(9) ganzer et al. studied the topographic anatomy of prostate capsule and periprostatic nerve distribution. they have reported similar findings regarding the decreased nerve frequency at the prostatic apex. in addition, they reported that nerve frequency was higher at the ventrolateral and dorsal side of the prostate.(14) other studies in literature have reported that nerve frequency decreased from the prostatic base to apex, (9,14-16 )which contradicted with our results. kiyoshima et al. conducted a study in which they mapped the periprostatic nerve fibers. they used 79 prostatectomy specimens. in 52% of specimens, they have seen fat tissue between prostatic fascia and prostate capsule, and nvb was not identifiable. in 48% of specimens, prostatic fascia and prostate capsule were stuck to one another, and nvb could be identified. they also reported that periprostatic nerve anatomy varied between specimens (17) alsaid et al. used a computer enhanced anatomic dissection technique to visualize the neurovascular bundle. their findings suggest that periprostatic nerve frequency of apex was higher in the anterior and anterolateral region.8 costello et al. performed a immunohistochemistrical investigation of periprostatic area. they have reported that the nerve frequency of anterior of prostate was minimal and consequently lateral dissection of prostate would be sufficient to spare the neurovascular bundle.18 similar to aforementioned studies, our results also show that the neural distribution of pelvic plexus varies from patient to patient. this anatomic variability of nvb could be used to explain why nerve-sparing is not successful in some patients. the weakness of our study lies in the limited sample size. we didn't use a proven imaging method for viscadaveric neural mapping of pelvis and prostate-huri et al. figure 2. a. the light microscopic photograph of peripheral nerves at left 10 o’clock localization (g8-x10, h&e) b. the light microscopic photograph of peripheral nerves in the right prostatic apex (g2-x10, h&e) c. the light microscopic photograph of peripheral nerves at right 2 o’clock localization (g3-x10, h&e) d. the light microscopic photograph of peripheral nerves at right far lateral pelvic field (g6-x10, h&e) e. the light microscopic photograph of peripheral nerves at left 7 o’clock localization (g7-x10, h&e) vol 14 no 06 november-december 2017 5066 ualization of nvb during dissection. in live surgery surgical instruments such as clips and thermal coagulation devices damage the neurovascular supply of the prostate and adjacent tissues. since we used cold incisions for dissection, cadaveric setting enables us to do pathological analysis without the tissue damage. in our study, we didn't do an analysis of the nerve fibers of the prostatic capsule, however we believe that it should be the subject of a future study. conclusions the nerve fibers that originate from pelvic plexus are homogenously distributed in the periprostatic region. mean nerve diameter is higher in the caudal region, towards the apex. pelvic fascia is the key anatomic landmark foe nerve-sparing during radical prostatectomy. a similarly conducted study with higher volume in a preferably live setting is needed to confirm these findings. conflict of interests none of the contributing authors have any conflict of interest, including specific financial interest or relationship and affiliations relevant to the subject matter or materials discussed in the manuscript. references 1. cumhur m, y. n., tuncel m: temel anatomi, 1 ed: odtü geliştirme vakfı yayıncılık ve i̇letişim a.ş., p. 488, 2001 2. dauber, w., feneis, h., feneis, h. et al.: pocket atlas of human anatomy founded by heinz feneis. in: thieme electronicbook library, 5th rev. ed. stuttgart ; new york: georg thieme verlag,, p. 545 p., 2007 3. walsh, p. c.: anatomic radical prostatectomy: evolution of the surgical technique. j urol, 160: 2418, 1998 4. walsh, p. c.: radical prostatectomy for the treatment of localized prostatic carcinoma. urol clin north am, 7: 583, 1980 5. lepor, h.: a review of surgical techniques for radical prostatectomy. reviews in urology, 7: s11, 2005 6. walsh, p. c., marschke, p., catalona, w. j. et al.: efficacy of first-generation cavermap to verify location and function of cavernous nerves during radical prostatectomy: a multiinstitutional evaluation by experienced surgeons. urology, 57: 491, 2001 7. haglind, e., carlsson, s., stranne, j. et al.: urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: a prospective, controlled, nonrandomised trial. eur urol, 68: 216, 2015 8. alsaid, b., bessede, t., diallo, d. et al.: division of autonomic nerves within the neurovascular bundles distally into corpora cavernosa and corpus spongiosum components: immunohistochemical confirmation with three-dimensional reconstruction. eur urol, 59: 902, 2011 9. clarebrough, e. e., challacombe, b. j., briggs, c. et al.: cadaveric analysis of periprostatic nerve distribution: an anatomical basis for high anterior release during radical prostatectomy? j urol, 185: 1519, 2011 10. walsh, p. c., donker, p. j.: impotence following radical prostatectomy: insight into etiology and prevention. j urol, 128: 492, 1982 11. yadav, r., mukherjee, s., hermen, m. et al.: multiphoton microscopy of prostate and periprostatic neural tissue: a promising imaging technique for improving nervesparing prostatectomy. j endourol, 23: 861, 2009 12. mauroy, b., demondion, x., drizenko, a. et al.: the inferior hypogastric plexus (pelvic plexus): its importance in neural preservation techniques. surg radiol anat, 25: 6, 2003 13. baader, b., herrmann, m.: topography of the pelvic autonomic nervous system and its potential impact on surgical intervention in the pelvis. clin anat, 16: 119, 2003 14. ganzer, r., blana, a., gaumann, a. et al.: topographical anatomy of periprostatic and capsular nerves: quantification and computerised planimetry. eur urol, 54: 353, 2008 15. eichelberg, c., erbersdobler, a., michl, u. et al.: nerve distribution along the prostatic capsule. eur urol, 51: 105, 2007 16. lee, s. b., hong, s. k., choe, g. et al.: periprostatic distribution of nerves in specimens from non-nerve-sparing radical retropubic prostatectomy. urology, 72: 878, 2008 17. kiyoshima, k., yokomizo, a., yoshida, t. et al.: anatomical features of periprostatic tissue and its surroundings: a histological analysis of 79 radical retropubic prostatectomy specimens. jpn j clin oncol, 34: 463, 2004 18. costello, a. j., dowdle, b. w., namdarian, b. et al.: immunohistochemical study of the cavernous nerves in the periprostatic region. bju int, 107: 1210, 2011 cadaveric neural mapping of pelvis and prostate-huri et al. miscellaneous 5067 miscellaneous the association of phosphodiesterase 5 inhibitor on ischemia-reperfusion induced kidney injury in rats jong kil nam1*, jung hee kim2, sung woo park1,and moon kee chung1 purpose: ischemia-reperfusion (ir) causes various damage in renal tissues. the aim of the present study was to evaluate the renoprotective effect of phosphodiesterase 5 inhibitor (pde5i) on ir induced renal injury in a rat model. materials and methods: thirty adult male, -12week-old, sprague-dawley rats were divided into three groups. renal ir injury was induced by occlusion of the bilateral renal pedicle for 45 min followed by reperfusion for 24 h. the rats were sacrificed for collecting blood and tissue specimens. ir rats were administered daily oral tadalafil (group i) or no pills (group ii), while sham-operated animals were treated with no pills (sham group). the pill was diluted with distilled water and administered to rats for 15 days, orally. renal histopathology, function, proinflammatory and inflammatory cytokines and mediators were assessed by serum creatinine, western blot assay and immunohistochemistry. results: compared with sham group, rats that underwent renal ir operation exhibited a significant increase in concentration in serum creatinine (p < .01) and tissue pro-inflammatory and inflammatory mediators. in group i, however, tadalafil significantly suppressed elevation of the serum creatinine and increased the levels of endothelial nitric oxide synthase and decreased the level of intercellular adhesion molecule1(icam1-) compared to group ii (p < .05). moreover, tadalafil prevented ir-induced expression of pro-inflammatory mediators such as monocyte chemotactic protein1(mcp1-) (p < .05). conclusion: tadalafil significantly promotes functional recovery after renal ir injury and effectively inhibits the induction of pro-inflammatory and inflammatory mediators. the results substantiate tadalafil as a protective agent against ir-induced renal injury. keywords: kidney; ischemia; reperfusion; tadalafil; nephrectomy introduction ischemia is an irreversible tissue injury process in which there is a loss of blood supply in a tissue due to impeded arterial flow or reduced venous drainage.(1) reperfusion after the ischemic period can cause severe tissue injury, which is termed ischemia reperfusion (ir) injury.(2) ir-induced renal injury, which occurs in various conditions, such as renal transplantation, nephron sparing surgery, renal angioplasty, shock and heart failure, is a common cause of acute renal insufficiency.(3,4) although several decades of research have greatly improved the understanding of the mechanisms underlying renal ir injury, effective drugs for treating it are still unavailable. the mechanisms of renal ir injury include hypoxia, vascular endothelial injury, infiltration of inflammatory cell, accumulation of free radicals such as reactive oxygen species (ros) and generation of inflammatory mediators. ir aggravates renal structural damages.(5,6) sildenafil citrate, vardenafil hcl and tadalafil are wide1department of urology, research institute for convergence of biomedical science and technology, pusan national university yangsan hospital, yangsan, korea. 2research institute for convergence of biomedical science and technology, pusan national university yangsan hospital, yangsan, korea. *correspondence: dept. of urology, pusan national university yangsan hospital, pusan national university school of medicine, beomo-ri, mulgeum-eup, yangsan, gyeongnam 626-770, korea. tel: +82 55 3602134, fax: +82 55 3602164, e-mail: toughkil76@naver.com. received september 2017 & accepted october 2019 ly used primary treatment of erectile dysfuncion and various other disorders including hypertension, prostatic hyperplasia and coronary heart disease.(7,8) these drugs are phosphodiesterase 5 inhibitors (pde5is); they enhance cyclic guanosine monophosphate and nitric oxide (no)-mediated vasodilation with resulting improvement of erectile dysfunction.(7,8) experimental studies have demonstrated that pde5is improve endothelial function and reduce infarct size in rat models of myocardial infarction.(8) hence, these inhibitors may also be nephroprotective in renal ir injury. a recent study using a renal ir model demonstrated that pde5is improve endothelial function and protect nephrons.(9) in this study, we further explored the protective effects of a pde5i (tadalafil) in a rat model of renal ir injury. materials and methods pde5i tadalafil powder (eli lilly and company, indianapourology journal/vol 17 no. 1/ january-february 2020/ pp. 91-96. [doi: 10.22037/uj.v0i0.4173] lis, id) was dissolved in dimethyl sulfoxide (dmso, 10mg/ml) and diluted 1:100 in ethanol. the dilution was added to 28 ml of drinking water (28ml). tadalafil was administered to rats every day for 15 days. the animal house technicians ensured that the tadalafil-laden water was completely consumed each day. tadalafil dosing for 15days was 5 mg/kg/day.(10) rat model the experimental study was carried out after obtaining the approval of the ethics committee [irb no. 06-2014006]. thirty adult, male, 12-week-old sprague-dawley rats were allowed free access to food and drink, and were housed under the specific pathogen-free conditions in alternating 12 h periods of light and dark, with 35-75% humidity at 20-26℃. renal ir injury was induced by clamping of the bilateral renal pedicle and subsequently with reperfusion.(11,12) in brief, rats were anesthetized using an intramuscular injection of ketamine 100mg/kg. with each rat in the supine position, midline incision was conducted and the both kidneys were subjected to 45minutes of ischemia by both renal pedicles clamping with atraumatic method followed by reperfusion for 24 h. the rats were sacrificed and then, immediately blood and tissue specimens were gathered and stored at -75℃. the rats were allocated to three experimental groups at random. the rats in group i and ii underwent ir injury surgery, with oral tadalafil supplied (group i) or not supplied (group ii). rats in sham group underwent a sham operation with no medication. assessment of renal function the diagnosis of clinical acute kidney injury (aki) due to ir injury is typically based on an elevation in plasma creatinine. there is a lag period between the onset of kidney injury and the rise in creatinine; typically, creatinine levels peak 6-24 h after the ischemic insult. prior experimental data showed that 45 min of bilateral renal pedicle ischemia resulted in a significant rise in serum creatinine at 6-24 h.(13) therefore we measured serum creatinine level and mediators at 24 h. the samples were measured using a technicon ra-1000 autoanalyzer (bayer, tarrytown, ny). immunohistochemical staining and western blot assay immunohistochemical staining was performed according to the manufacturer’s instructions. paraffin-embedded renal tissues were cut into 3 µm thickness, deparaffinized and hydrated. the antibodies against intercellular adhesion molecule-1, (icam-1, 1:1000; santa cruz biotechnology, santa cruz, ca), endothelial nitric oxide synthase (enos, 1:1000; santa cruz biotechnology) or monocyte chemotactic protein-1 (mcp-1, 1:1000; santa cruz biotechnology) used for immunohistochemical staining. the immunohistochemical staining protocols by shi et al. were used.(14,15) total protein in rat kidney was withdrawn with radioimmunoprecipitation assay lysis buffer containing 1% phenylmethanesulfonyl fluoride (beyotime, nanjing, china). a kit (beyotime) was used to extract nuclear and cytoplasmic protein antibody against icam-1, enos, mcp-1 or β-actin (all 1:1000; santa cruz biotechnology), or to glyceraldehyde-3-phosphate dehypde5i protects from ir induced kidney injurynam et al. figure 1. the effects of tadalafil on renal function during renal ir. serum creatinine was less increased by tadalafil pre-treatment (group i) compared by group ii. group ii compared with the group i and sham group. *; p < .05. figure 2. the effect of tadalafil on enos during renal ir detected by immunohistochemical staining (x400) and western blot. at 24 h after reperfusion, the expression of enos was enhanced by tadalafil (a). immunohistochemical staining (b) and western blot results (c) showed the expression of enos in group i was increased compared by group ii and sham group. *; p < .05, ** p < .01. miscellaneous 92 vol 17 no 01 january-february 2020 93 drogenase (gapdh, 1:500; santa cruz biotechnology) were used for western blot assay. membranes were then examined with hrp-conjugated secondary antibody (1:1,000; santa cruz biotechnology). by using an enhanced ecl detection system (millipore), target proteins were visualized and by using quantity one 4.6.2 software (bio-rad, hercules, ca), band densitometries were quantified. the western blot protocol by mahmood et al. were used.(16,17) statistical analysis the statistical data were analyzed using statistical package for the social sciences version 13.0 for windows software (spss, chicago, il). one-sample kolmogorov smirnov tests were used to determine that the quantitative data for every group were normally distributed. statistical significance for multiple comparisons was analyzed by one-way analysis of variance test. statistical test results were considered significant at a p-value < .05. results effect of tadalafil on renal function after ir injury to investigate the protective effect of the tadalafil on renal function caused by ir injury, plasma creatinine levels were measured 24 h after renal reperfusion. plasma creatinine concentrations were significantly higher in group i and ii than in the sham group. compared with the group ii, group i rats exhibited a significant difference in concentration in creatinine level (figure 1) (p = .008). effect of tadalafil on enos after ir injury enos concentrations in the renal tissue were markedly increased after reperfusion, and remained at significantly higher level than in sham operated group (figure 2a) (p < .01). this was significantly different relative to group i and ii (p = .032). ir injury increased the expression of enos in the kidneys compared to the sham operated group. pre-treatment with tadalafil enhanced the increase in enos concentration (figure 2a, b and c). after reperfusion, the numbers of positive cells stained with enos antibodies were increased compared with the sham group (figure 2 b and c). effect of tadalafil on icam-1 after ir injury pro-inflammatory mediators, such as icam-1, amplify the inflammatory response and oxidative stress injury, and deteriorate tissue damage. presently, the icam-1 concentrations in the renal tissue were markedly increased after reperfusion, and remained significantly higher than in the sham operated group (figure 3a, b and c) (p < .05). group ii displayed significantly higher levels than group i (p = .021). icam-1 was significantly decreased by tadalafil pre-treatment. typical photographs of renal tissue are shown in figure 3b. compared with group ii, group i displayed obvious down-regulation of the expression of icam-1. effect of pde5i on mcp-1 after ir injury pro-inflammatory factors, such as mcp-1, reportedly play an important role in renal injury induced by ir. presently, mcp-1 concentrations in the renal tissue were increased after reperfusion, with group i being significantly lower than group ii (figure 4a). group i and ii displayed significantly higher mcp-1 expression than the sham operated group (figure 4a, b and c). the tadalafil pre-treatment group displayed significantly lower decrease than group ii. these findings indicated that tadalafil lowered the local inflammatory response. discussion the present study demonstrated that enos and icam1 antibodies were markedly increased compared with the sham group. compared with ischemia reperfusion group (group ii), tadalafil pretreated group (group i) displayed obvious down-regulation of the expression of icam-1 and up-regulated expression of enos. moreover, mcp-1 in the tadalafil pre-treatment group displayed significantly lower decrease than ischemia reperfusion only group. these findings indicated that tadalafil lowered and attenuated the local inflammatory response. recovery of renal function following nephron sparing surgery is associated with reduced ischemic damage during operation, pre-operative preparation and post-operative management. minimally invasive techniques have been developed to reduce warm ischemia time and to preserve functional renal volume in nephron sparing surgery. however, nephron sparing surgery of difficult cases are usually conducted in long ischemia to allow for tumor resection and renal reconstruction. long-standing ischemia compromises renal function due to ischemia reperfusion injury. some patients with solitary kidney and renal insufficiency may need acute or even permanent dialysis. (18) the definition of the ideal ischemia time threshold during nephron sparing surgery is still debatable. based on data from animal models and small, retrospective clinical studies,(19) a warm ischemia time of less than 30 minutes has been historically thought to allow full recovery of kidney function. current evidence suggests that warm ischemia time and residual functional parenchyma after nephron sparing surgery correlates with postoperative renal function. preoperative preparation for protection against renal ir injury introduces many substances.(20-24) however, currently they are not used clinically because of a lack of data, particularly clinical studies. methylene blue,(20) melatonin,(21) dexamethasone,(22) sufosalazine(23) and beta-carotene(24) have been studied for their efficacy in preventing destruction in experimental renal ir injury models. phosphodiesterase 5 (pde5) is the predominant phosphodiesterase in the corpus cavernosum. pde5i blocks degradative action of cgmp by pde5, increasing blood flow to the penis during sexual stimulation. in addition, novel therapeutic indications have emerged with the discovery that pde5 is expressed in various other tissues, such as arterial and venous vasculatures, skeletal and visceral muscles, and platelets.(25) ir induced renal injury occurring with ischemia and restoration of blood flow to post-ischemic tissue may be associated with microvascular injury, particularly due to increased permeability of arterioles and capillaries, leading to an increase of diffusion and an induction of fluid exudation across the tissues.(1) the sterile inflammatory response induced by ir is characterized by marked recruitment of neutrophils and the production of cytokines, chemokines, and other proinflammatory stimuli. activated endothelial cells produce more ros following reperfusion, which promote leukocyte adhesion to capillaries and venules and subsequent emigrapde5i protects from ir induced kidney injurynam et al. tion into the tissues.(2) damage to the cell membrane can release more free radicals. such reactive species may also act indirectly in redox signaling to stimulate apoptosis. leukocytes and endothelial cell adhesive interactions may also bind to the endothelium of small capillaries, which precipitate the development of microvascular dysfunction.(1,2,26) although ir injury triggers the toxic and inflammatory cascades leading to alteration of renal function. interestingly, in our study, after administration of tadalafil, serum creatinine levels decreased significantly. in addition, our data demonstrate that pre-treatment with tadalafil is renoprotective against ir injury, with affects evident at the serum creatinine level as well as for inflammatory mediators. the up-regulated expression of enos and the down-regulated expression of icam-1 and mcp-1 were largely modified after pre-treatment. this may reflect tadalafil-mediated inhibition of inflammatory factors at the inflammatory sites. no synthases (noss) are a group of enzymes that catalyze the production of no from l-arginine. no produced by enos is a vasodilator identical to the edrf (endothelium-derived relaxing factor) produced in response to increased blood flow in arteries. this expands blood vessels by relaxing of vascular smooth muscle in linings.(27) enos is the main regulator of vascular smooth muscle tone.(27) enos-mediated no production plays a pivotal protective role in ir injury.(27,28) presently, tadalafil significantly enhanced enos in the treated rats compared with non-treated rats. in contrast, others showed that sildenafil has a protective effect that is independent of the no/cgmp pathway in an ir model. (29) this indicates that other protective pathways involving sildenafil could exist. their identity requires further studies. icam-1 is an endothelialand leukocyteassociated transmembrane protein that stabilizes intercellular interaction and promotes leukocyte endothelial transmigration. when activated, leukocytes bind to endothelial cells and then transmigrate into tissues. particularly, icam-1 signaling seems to recruit inflammatory immune cells including macrophages and granulocytes. figure 3. the effect of tadalafil on icam-1 during renal ir detected by immunohistochemical staining (x400) and western blot. at 24 h after reperfusion, the expression of icam-1 was suppressed by tadalafil (a). immunohistochemical staining (b) and western blot results (c) showed the expression of icam-1 in group i was decreased compared by group ii. *; p < .05, ** p < .01. figure 4. the effect of tadalafil on mcp-1 during renal ir detected by immunohistochemical staining (x400) and western blot. at 24 h after reperfusion, the expression of mcp-1 was enhanced by tadalafil (a). immunohistochemical staining (b) and western blot results (c) showed the expression of icam-1 in group i was decreased compared by group ii. *; p < .05. pde5i protects from ir induced kidney injurynam et al. miscellaneous 94 vol 17 no 01 january-february 2020 95 (30,31) this finding, as well as the increased expression of icam-1, has been corroborated by experiments on cultured endothelial cells exposed to ir injury. in our study, icam-1 level was significantly decreased by pre-treatment with tadalafil. the findings indicate the effectiveness of tadalafil in reducing leukocyte endothelial transmigration and decreasing the inflammatory response. mcp-1, also termed chemokine ligand 2, has been implicated in pathogenesis of several diseases characterized by monocytic infiltrates.(32) adminstration of anti-mcp-1 antibodies in a model of glomerulonephritis reduced the infiltration of macrophages and t cells, and reduced scarring, renal impairment and crescent formation.(33) presently, tadalafil pre-treatment significantly reduced the expression of mcp-1. this finding indicates that tadalafil can alleviate the inflammatory response of the kidney during renal ir by reducing the local inflammatory response. previous several studies confirmed the efficacy of some premedication in preventing renal damage in animal models of ir injury.(20-24) however, none of the agents are currently used in adjuvant therapy in humans because of lack of clinical data on safety and their restricted availability. in contrast, pde5i is commonly used and readily available; the current data support its use for reducing ir injury. clinical studies are still necessary to evaluate the therapeutic properties of pde5 inhibitors in prevent ir injury. limitation to our study, such as the relatively short period of ischemia (45 min) and reperfusion (24 h), leave the prolonged real function unclear. also, the mechanisms to explain the renoprotective effects are ambiguous because of missing evaluation of free radicals such as ros. furthermore, we did not examin the histologic damage such as, inflammatory cell count and the number of apoptotic cells in renal tissue were increased concomitantly in ir injury. further studies are needed to resolve the controversy in the present and previous studies. conclusions in our study, tadalafil improved the recovery of renal injury during ir by enhancing enos expression, and decreasing icam-1 and mcp-1 expression. these findings showed that tadalafil lowered the local inflammatory response and enhanced ischemic tolerance. tadalafil pre-treatment has the potential to attenuate the ir induced renal injury in nephron sparing surgery. acknowledgements this study was supported by research institute for convergence of biomedical science and technology (30-2015-026), pusan national university yangsan hospital conflict of interest the authors report no conflict of interest. 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symptoms secondary to benign prostatic hyperplasia: a review of clinical data in asian men and an update on the mechanism of action. ther adv urol. 2015;7:249-64. 8. kukreja rc. sildenafil and cardioprotection. curr pharm des. 2013;19:6842-7. 9. küçük a, yucel m, erkasap n, et al. the effects of pde5 inhibitory drugs on renal ischemia/reperfusion injury in rats. mol biol rep. 2012;39:9775-82. 10. vignozzi l, filippi s, morelli a, et al. effect of chronic tadalafil administration on penile hypoxia induced by cavernous neurotomy in the rat. j sex med. 2006;3:419-31. 11. esposito e, mondello s, di paola r, et al. glutamine contributes to ameliorate inflammation after renal ischemia/reperfusion injury in rats. naunyn schmiedebergs arch pharmacol. 2011;383:493-508. 12. chatterjee pk, di villa bianca rd, sivarajah a, mcdonald mc, cuzzocrea s, thiemermann c. pyrrolidine dithiocarbamate reduces renal dysfunction and injury caused by ischemia/ reperfusion of the rat kidney. eur j pharmacol. 2003;482:271-80. 13. guan z, miller sb, greenwald je. zaprinast accelerates recovery from established acute renal failure in the rat. kidney int. 1995;47:1569-75. 14. shi sr, key me, kalra kl. antigen retrieval in formalin-fixed, paraffinembedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. j histochem cytochem. 1991;39:741-8. 15. robertson d, savage k, reis-filho js, isacke cm. multiple immunofluorescence labelling of formalin-fixed paraffin-embedded (ffpe) tissue. bmc cell biol. 2008;9:13. 16. mahmood t, yang p-c. western blot: technique, theory, and trouble shooting. n am j med sci. 2012 sep;4(9):429-34. pde5i protects from ir induced kidney injurynam et al. 17. alegria-schaffer a, lodge a, vattem k. performing and optimizing western blots with an emphasis on chemiluminescent detection. methods enzymol. 2009;463:573-99. 18. dulabon lm, kaouk jh, haber gp, et al. multi-institutional analysis of robotic partial nephrectomy for hilar versus nonhilar lesions in 446 consecutive cases. eur urol. 2011;59:325-30. 19. novick ac. renal hypothermia: in vivo and ex vivo. urol clin north am. 1983;10:637-44. 20. weinbroum aa. methylene blue attenuates pancreas ischemia-reperfusion (ir)-induced lung injury: a dose response study in a rat model. j gastrointest surg. 2009;13:1683-91. 21. sener g, sehirli ao, keyer-uysal m, arbak s, ersoy y, yeğen bc.the protective effect of melatonin on renal ischemia-reperfusion injury in the rat. j pineal res. 2002;32:120-6. 22. rusai k, prokai a, juanxing c, et al. dexamethasone protects from renal ischemia/ reperfusion injury: a possible association with sgk-1. acta physiol hung. 2013;100:173-85. 23. cámara-lemarroy cr, guzmán-de la garza fj, alarcón-galván g, cordero-pérez p, fernández-garza ne. effect of sulfasalazine on renal ischemia/reperfusion injury in rats. ren fail. 2009;31:822-8. 24. hosseini f, naseri mk, badavi m, ghaffari ma, shahbazian h, rashidi i. protective effect of beta carotene pretreatment on renal ischemia/reperfusion injury in rat. pak j biol sci. 2009;12:1140-5. 25. schwarz er, kapur v, rodriguez j, rastogi s, rosanio s. the effects of chronic phosphodiesterase-5 inhibitor use on different organ systems. int j impot res. 2007;19:13948. 26. carden dl, granger dn. pathophysiology of ischaemia-reperfusion injury. j pathol.2000;190:255-66. 27. yamasowa h, shimizu s, inoue t, takaoka m, matsumura y. endothelial nitric oxide contributes to the renal protective effects of ischemic preconditioning. j pharmacol exp ther. 2005;312:153-9. 28. yamashita j, ogata m, itoh m, et al. role of nitric oxide in the renal protective effects of ischemic preconditioning. j cardiovasc pharmacol. 2003;42:419-27. 29. elrod jw, greer jj, lefer dj. sildenafilmediated acute cardioprotection is independent of the no/cgmp pathway. am j physiol heart circ physiol. 2007;292:h342-7. 30. etienne-manneville s, chaverot n, strosberg ad, couraud po. icam-1-coupled signaling pathways in astrocytes converge to cyclic amp response element-binding protein phosphorylation and tnf-alpha secretion. j immunol. 1999;163:668-74. pde5i protects from ir induced kidney injurynam et al. 31. ichikawa h, flores s, kvietys pr, et al. molecular mechanisms of anoxia/ reoxygenation-induced neutrophil adherence to cultured endothelial cells. circ res. 1997;81:922-31. 32. xia m, sui z. recent developments in ccr2 antagonists. expert opin ther pat. 2009;19:295-303. 33. lloyd cm, minto aw, dorf me, et al. rantes and monocyte chemoattractant protein-1 (mcp-1) play an important role in the inflammatory phase of crescentic nephritis, but only mcp-1 is involved in crescent formation and interstitial fibrosis. j exp med. 1997;185:1371-80. miscellaneous 96 the effect of time to castration resistance on overall survival and success of docetaxel treatment in castration resistant prostate cancer patients evren suer1, nurullah hamidi2, cagri akpinar1*, mehmet ilker gokce1, omer gulpinar1, kadir turkolmez1, yasar beduk1, sumer baltaci1. purpose: to investigate the prognostic role of time to castration resistance(ttcr) in patients who have received solely docetaxel chemotherapy regimen(dcr) for castration resistant prostate cancer(crpc). methods: between jan 2004 and dec 2015, data of 162 patients who have received dcr for crpc were gathered. patients were divided into three groups according to ttcr: group 1(≤ 12 months), group 2(13-24 months), and group 3(>24 months). data of age, clinical stage, gleason grade(gg), previous treatments, site of metastases, prostate-specific antigen (psa) values, ttcr, overall survival, biochemical progression free survival(pfs) and psa response to docetaxel were recorded. result: the mean age of the 162 patients was 74.4 ± 8.5 years. data on mean age, type of castration, adding estramustine to docetaxel, secondary hormonal manipulation, gleason grade, clinical t stage at initial diagnosis and site of metastases were comparable between three groups. psa values were higher in group 1 than other groups. psa response to docetaxel was 59.2% in all patient and it was worse in group 1 than other groups (p = .009). two years overall survival rates were 7.6%, 25% and 32.3% in group 1, 2 and 3, respectively. median survival rates were 7, 14 and 23 months in group 1, 2 and 3, respectively, and this difference was statistically significant (p=.016). on multivariate analysis, ttcr was found to be independent prognostic factor for overall survival and response to docetaxel treatment. conclusion: ttcr appears to be an independent prognostic factor for patients who are candidates for dcr. keywords: castration; chemotherapy; docetaxel; prostate cancer; survival introduction androgen deprivation therapy (adt) is the main treatment option for metastatic prostate cancer.(1) after an initial response, resistance to adt occurs in most patients, with the result that the median survival among patients with metastatic prostate cancer is approximately 3 years.(2) eventually most of the patients will progress to castration resistant prostate cancer (crpc). previously docetaxel chemotherapy regimen (dcr) was the mainstay treatment for crpc patients. (3) the therapeutic armamentarium for metastatic crpc has rapidly expanded in recent years. recently new agents with diverse mechanisms of action (sipuleucel-t, abiraterone acetate, enzalutamide and radium-223) were shown to prolongoverall survival.(4-7) although abiraterone and enzalutamide are widely used, cytotoxics continue to play an important role in the manage¬ment of metastatic crpc. the best timing for the use of cytotoxic chemotherapy remains questionable and varies among patients. in patients with disease progres¬sion and who are symptomatic or harbour visceral metastases, cytotoxic chemo¬therapy may have a role to play earlier in the dis¬ease course. 1 ankara university school of medicine, department of urology, ankara, turkey. 2ankara atatürk research and training hospital, department of urology, ankara, turkey. *correspondence: ankara university school of medicine, department of urology, ankara, turkey tel: +90 541 738 76 38, fax: +90 (312) 508 21 47. akpinar.cagri89@gmail.com. received march 2018 & accepted september 2018 due to emerging treatment options for crpc, it is important to define predictive markers to categorise patients suitable for dcr and prevent the ineffectiveness, costs and side effects of this treatment. time to castration resistance (ttcr) was defined as a predictive factor for secondary endocrine treatment and mixed chemotherapy regimens in previous studies.(8,9) we aimed to investigate the prognostic role of ttcr in patients who have received solely dcr for crpc. materials and methods in this retrospective study we have evaluated our metastatic prostate cancer database. between jan 2004 and dec 2015, a total of 211 patients who have received dcr for crpc were detected. to prevent the flare up phenomenon, antiandrogen was started 10 days before lhrh agonist started and then patients received only lhrh agonist therapy. psa and testosterone levels were measured once every 3 months during adt therapy. crpc was defined as biochemical or radiological disease progression on adt with castrate testosterone levels (< 50 ng/dl). biochemical progression was defined as a 50% increase in two of three consecutive psa urological oncology urology journal/vol 16 no. 5/ september-october 2019/ pp. 453-457. [doi: 10.22037/uj.v0i0.4497] measurements taken at 1 week intervals, provided that the psa value was > 2 ng/ml. forty nine patients were excluded from the study due to; indeterminate starting dates for primary adt or chemotherapy (n=24), discontinuation of chemotherapy due to patient incompliance or preference (n=11), significant lack of follow-up data (n=10) and multiple cancer diagnosis (n=4). therefore, the remaining 162 patients were eligible for the final analysis. clinical t stage at initial diagnosis was evaluated in patients and is shown in table 2. docetaxel was administered i.v. at the standard dose of 75 mg/m2 every 3 weeks as a 1-h infusion with dexamethasone prophylaxis and oral prednisolone 5 mg twice daily as described previously.(3) prostate specific antigen (psa) response rates were measured using prostate cancer working group (pcwg) 2 criteria.(9) as recommended by the pcwg 2, psa response was defined as 50% declines from baseline and a 25% increase confirmed with a second psa reading a minimum of 3 weeks later was used to determine psa progression and response duration. blood tests, including psa, were measured every three weeks, and radiological assessments, including computed tomography scans of the thorax, abdomen and pelvis and bone scans, were table 1. patient characteristics and comparison of patient characteristics of three groups patient characteristics age, mean ± std 74.4 ± 8.5 median follow up time, , month (median(range) and iqr) 40 (9-120) , 36 gleason grade at initial diagnosis, n(%) <8 18 (11) ≥8 144 (89) clinical t stage at initial diagnosis, n(%) ≤t2 44 (27.2) t3-4 118 (72.8) type of castration, n(%) medical 114 (70.3) surgical 48 (29.7) adding estramustine to docetaxel, n(%) 33 (20.3) secondary hormonal manipulation, n(%) none 82 (50.6) anti-androgen withdrawal 38 (23.4) switch to another anti-androgen 42 (26) presence of bone metastases, n(%) 149 (92) presence of lymph node metastases, n(%) 62 (38.3) presence of liver metastases, n(%) 18 (11) presence of lung metastases, n(%) 18 (11) time to castration resistance, month (median(range) and iqr) 18 (3-86) , 23 parameters group 1 (n=52) group 2 (n=48) group 3 (n=62) p value age, mean ± std 75.7 ± 8.2 73.3 ± 8.5 74.2 ± 8.8 0.84 gleason grade at initial diagnosis, n(%) 0.21 <8 6 (11.5) 2 (4.2) 10 (16.2) ≥8 46 (88.5) 46(95.8) 52 (83.8) clinical t stage at initial diagnosis, n(%) 0.72 ≤t2 15 (29.8) 14 (29.2) 16 (25.9) t3-4 37 (71.2) 34 (70.8) 46 (74.1) type of castration, n(%) 0.25 medical 32 (61.5) 34 (70.8) 48 (77.4) surgical 20 (38.5) 14 (29.2) 14 (22.6) adding estramustine to docetaxel, n(%) 10 (19.2) 11 (22.9) 12 (19.3) 0.78 secondary hormonal manipulation, n(%) 0.48 none 28 (53.8) 23 (47.9) 33 (53.2) anti-androgen withdrawal 11 (21.2) 10 (20.7) 16 (25.8) switch to another anti-androgen 13 (25) 15 (31.2) 13 (21) metastases 0.64 m1b presence of bone metastases , n(%) 48 (92.3) 47 (97) 54 (87) 0.62 m1a, presence of lymph node metastases, n(%) 26 (50) 10(20.8) 26 (42) 0.54 m1c, presence of liver metastases, n(%) 4 (7.6) 4 (8.3) 10 (16.1) 0.68 presence of lung metastases, n(%) 6 (11.5) 4 (8.3) 8 (13) 0.72 median follow-up,month 46 43 47 0.58 median nadir psa value during adt, (range) 17.7 (0.12-150) 2.3 (0.03-19) 1.2 (0.008-7.3) *0.014 median psa value immediately before docetaxel, (range) 93.4 (4-526) 63.7(4.42-196) 78.1(1.5-1092) *0.024 median nadir psa value during docetaxel, (range) 65.9 (0.7-400) 34.8 (0.03-161) 18 (0.3-120) *0.026 median highest psa value after starting docetaxel, (range) 153 (4-617) 102.7 (3.2-231) 88.2 (5-490) *0.037 median os, month(range) 7 (3-26) 14(8-38) 23(6-39) *0.016 2 years os rate, % 7.6 25 32.2 *0.029 median biochemical pfs, month(range) 3(1-7) 6(1-13) 10(2-19) *0.04 psa response to docetaxel, n(%) 16(30.7) 32(66.6) 44(71) *0.009 abbreviations: adt, androgen deprivation therapy; os, overall survival; pfs, progression free survival; psa, prostate specific antigen *statistically significant time to castration resistance and survival in crpc-suer et al. urological oncology 454 carried out after psa progression were detected. follow-up data, including time to biochemical progression and date of death, were available for all patients. time to castration resistance (ttcr) was calculated from the time of adt initiation irrespective of stage until confirmation of crpc. data on patient and characteristics, were collected from a retrospective review of medical records. the following variable were recorded for analysis; age, stage, gleason grade(gg), previous treatments, site of metastases, psa value and ttcr. biochemical progression and death due to any reason were considered as events. kaplan meier analysis were performed to obtain estimates for overall survival (os) (figure 1). cox regression analysis was performed to define independent prognostic factors. variables that were significant in univariate analysis or close to p value 0,05 although not statistically significant, were included in the cox regression analysis. p value < 0.05 was accepted the statistical significance criteria. spss 17.0 was used for the analysis. results the mean age of the 162 patients was 74.4±8.5 years. patient characteristics are listed in table 1. thirty men (18.5 %) had received prior local therapy for prostate cancer with curative intent. of these 30 men, 20 and 10 had received radical prostatectomy and radiotherapy, respectively. median nadir psa value during adt, median psa value immediately before docetaxel, median nadir psa value during docetaxel, median highest psa value after starting docetaxel were 3.2 (range: 0.008-150), 78.7 (range: 1.51092), 38.4 (0.03-400), 113.3 (range: 3.2-617), respectively. median survival (minimum survival was 3 months and maximum survival 39 months. when this data is ranked from lowest to highest, the median value in the middle is the median value, which is calculated 15) and 2 years survival rate were 15 month and 18.5%, respectively. psa response to docetaxel was 59.2%. patients were divided into three groups according to ttcr: group 1(≤12 months), group 2(13-24 months), and group 3(> 24 months). data on patient and disease characteristics of three groups were compared. data on mean age, type of castration, adding estramustine to docetaxel, secondary hormonal manipulation, gleason grade,clinical t stage at initial diagnosis and site of metastases were comparable between three groups (table 1). median nadir psa value during adt (p = .014), median psa value immediately before docetaxel (p =.024), median nadir psa value during docetaxel (p = .026), and median highest psa value after starting docetaxel (p =.037) were statistically significant higher in group 1 than other groups. median survival rates were 7, 14 and 23 months in group 1, 2 and 3, respectively, and this difference was statistically significant (p = .016). psa response to docetaxel treatment were worse in group 1 than other groups (p = .009). median biochemical pfs rates were 3, 6, and 10 months in group 1, 2 and 3 respectively, and this difference was statistically significant (p =.04). there was no statistically significant difference between the 3 groups in terms of the median follow-up time (table 1). all comparisons were detailed in table 2. two years os rates were 7.6%, 25% and 32.3% in group 1, 2 and 3, respectively (table 1) and in the kaplan meier analysis found overall survival in group 1 was statistically significant worse than group 2 and group 3 (figure 1). on multivariate analysis, ttcr was found to be independent prognostic factor for overall survival (95% ci: 1.924-3.282, hr = 2.8 p = .001,) and response to docetaxel treatment (95% ci: 1.156-4.086, hr= 1.9, p = .001) (table 2). discussion dcr was established as the standard care in crpc after the outcomes of two randomized studies.(3,10) the results of these two phase iii studies showed that time to castration resistance and survival in crpc-suer et al. table 2. multivariate analysis for prediction of overall survival and response to docetaxel treatment variables overall survival response to docetaxel treatment hr 95% ci p value hr 95% ci p value ≥8 gleason grade at initial diagnosis 2.2 1.230-3.547 .001 1.8 1.486-4.342 .003 higher median nadir psa value during adt 0.9 0.702-1.131 0.54 0.9 0.842-1.236 0.5 higher median psa value immediately before docetaxel 1.2 0.562-1.634 0.31 1.2 0.674-1.938 0.3 higher median nadir psa value during docetaxel 2.3 1.288-5.142 .01 1.9 1.084-4.046 .02 visceral metastasis 3 1.062-4.328 .001 3.2 1.812-6.326 .001 time to resistance to adt 2.8 1.924-3.282 .001 2.2 1.156-4.086 .001 abbreviations: adt, androgendeprivationtherapy; psa, prostate-specificantigen figure 1. kaplan meier curves for overall survival two years os rates were 7.6%, 25% and 32.3% in group 1, 2 and 3, respectively. kaplan-meier analysis showed statistically significant difference between os rates of three groups (p < .001 for comparison of group 1 and 2; p <.001 for group 1 and 3; p =.038 for group 2 and 3). vol 16 no 04 september-october 2019 455 docetaxel in a 3-weekly regimen improved os, which was the primary endpoint of both trials. additionally, dcr offered better palliation and quality of life. however, the side effects of chemotherapy and the relatively elder crpc population was the basis for tailoring the therapy. a nomogram was formed using independent prognostic factors in tax 327 study to simplify important clinical decisions such as when to start cytotoxic chemotherapy. these prognostic factors were presence of liver metastases, number of metastatic sites, clinically significant pain, karnofsky performance status, type of progression, pretreatment psa doubling time, baseline psa, tumor grade, baseline alkaline phosphatase, and baseline hemoglobin.(11) furthermore, in the tax 327 secondary analysis study, four independent risk factors were defined, risk groups were developed and validated for predicting psa decline and os in men with mcrpc. these independent risk factors are pain, visceral metastases, anaemia, and bone scan progression.(12) the approval of abiraterone and enzalutamide in pre-docetaxel setting enhanced the need for the identification of patients who may have greater benefit by the use of chemotherapy. high gleason score at the time of diagnosis and patients who had a short response to prior adt (<16 months) had poor psa responses when treated with secondary hormonal therapies such as abiraterone and enzalutamide.(13,14) loriot et al. evaluated median duration of response to initial adt in patients treated with androgen receptor axis targeted drugs. in this study patients who had longer initial adt response demonstrated better responses for secondary treatments and 12 months was the cut-off.(9) bellmunt et al. examined cou-aa-301 and cou-aa-302 patients and demonstrated the positive effects of longer exposure to prior adt on survival.(15) however, the clinical benefit of abiraterone was maintained in all groups. zheng et al. evaluated the prognostic effects of circulating tumor cells (ctc). in this meta-analysis demonstrated that ctc positivity indicates poor prognosis in patients with crpc and can be used as an independent prognostic factor of survival rate in patients with crpc.(16) also a case of penic metastasis in a 70-year-old geriatric male patient with prostatic adenocarcinoma is reported. who was treated with cabazitaxel chemotherapy beyond 20 cycles with a good response and acceptable minimal toxicity.(17) in an era of shifting paradigms in crpc with multiple options becoming available prior to dcr, prior response to adt may serve to discriminate between patients who benefit most from docetaxel chemotherapy as first-line treatment. the cell cycle is important because many chemotherapy drugs work only on cells that are actively reproducing. docetaxel is a mitotic inhibitor and based on this information we expected better responses in shorter ttcr. however,in our study shorter ttcr was associated with lower psa response and survival. particularly in patients who have ttcr < 12 months demonstrated the worse prognosis. shorter ttcr is also associated with short doubling time and fast cell cycle, which is also a poor prognostic parameter.(18) the outcomes of this study confirm the previous study published by bournakis et al.(8) in a series which have included docetaxel and non-docetaxel regimens, they have demonstrated < 2 year of ttcr as an independent prognostic factor for pfs and os. according to these results we can accept ttcr as a prognostic factor, without relating to any therapy. the process for the secondary therapy must concern quality of life and side effects of the therapy. this study has several limitations. in this retrospective study we did not have adequate data to evaluate radiological pfs and pain scores. although all of the patients were treated with dcr, a significant number of patients received estramustin in their regimen which causes some heterogeneity. due to the health insurance restriction, none of our patients were treated in predcr setting with novel drugs such as abiraterone acetate and enzalutamide. only the minority of the patients received abiraterone acetate after the development of unresponsiveness of chemotherapy. conclusions ttcr appears to be an independent prognostic factor for patients who are candidates for dcr. although utilizing chemotherapy instead of secondary hormonal treatments seem to be reasonable in patients who have developed early castration resistance , the patients must be informed of the lower response rates for chemotherapy. acknowledgement thanks are due to ankara university health research and practice center support for the preparing of this manuscript. conflict of interest the authors have declared no conflict of interest. references 1. horwich a, hugosson j, de reijke t, wiegel t, fizazi k, kataja v. prostate cancer: esmo consensus conference guidelines 2012. ann oncol. 2013;24:1141-62. 2. tangen cm, hussain mh, higano cs, et al. improved overall survival trends of men with newly diagnosed m1 prostate cancer: a swog phase iii trial experience (s8494, s8894 and s9346). j urol. 2012;188:1164-9. 3. tannock if, de wit r, berry wr, et al. docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. n engl j med. 2004;351:1502-12. 4. beer tm, armstrong aj, sternberg cn, et al. enzalutamide in men with chemotherapynaive metastatic prostate cancer (mcrpc): results of phase iii prevail study. j clin oncol. 2014;32:lba1-lba. 5. fizazi k, scher hi, molina a, et al. abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the cou-aa-301 randomised, double-blind, placebo-controlled phase 3 study. lancet oncol. 2012;13:983-92. 6. kantoff pw, higano cs, shore nd, et al. sipuleucel-t immunotherapy for castrationresistant prostate cancer. n engl j med. 2010;363:411-22. 7. sartor o, coleman r, nilsson s, et al. effect of radium-223 dichloride on symptomatic time to castration resistance and survival in crpc-suer et al. urological oncology 456 vol 16 no 04 september-october 2019 457 skeletal events in patients with castrationresistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. lancet oncol. 2014;15:73846. 8. bournakis e, efstathiou e, varkaris a, et al. time to castration resistance is an independent predictor of castration-resistant prostate cancer survival. anticancer res. 2011;31:1475-82. 9. loriot y, eymard jc, patrikidou a, et al. prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer. eur j cancer. 2015;51:194652. 10. petrylak dp, tangen cm, hussain mh, et al. docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. n engl j med. 2004;351:1513-20. 11. armstrong aj, garrett-mayer es, yang yc, de wit r, tannock if, eisenberger m. a contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a tax327 study analysis. clin cancer res. 2007;13:6396-403. 12. armstrong aj, tannock if, de wit r, george dj, eisenberger m, halabi s. the development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for psa decline and survival. eur j cancer. 2010;46:517-25. 13. heidenreich a, pfister d. treatment decisions for metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy: the role of cabazitaxel in the continuum of care. eur urol. 2012;62:1201-4. 14. loriot y, massard c, albiges l, et al. personalizing treatment in patients with castrate-resistant prostate cancer: a study of predictive factors for secondary endocrine therapies activity. j clin oncol. 2012;30:213. 15. bellmunt j, kheoh t, yu mk, et al. prior endocrine therapy impact on abiraterone acetate clinical efficacy in metastatic castration-resistant prostate cancer: post-hoc analysis of randomised phase 3 studies. eur urol. 2016;69:924-32. 16. zheng y, zhang c, wu j, et al. prognostic value of circulating tumor cells in castration resistant prostate cancer: a meta-analysis. urol j. 2016;13:2881-8. 17. atag e, semiz hs, kazaz sn, et al. response to cabazitaxel beyond 20 cycles in a patient with penile metastasis of prostate cancer: a case report. urol j. 2017;14:2985-8. 18. stewart aj, scher hi, chen mh, et al. prostate-specific antigen nadir and cancerspecific mortality following hormonal therapy for prostate-specific antigen failure. j clin oncol. 2005;23:6556-60. time to castration resistance and survival in crpc-suer et al. case report yang-monti principle in bridging long ureteral defects: cases report and a systemic review jun sheng bao#, qiqi he#, yuzhuo li, wei shi, gongjin wu, zhongjin yue* keywords: reconstruction; ileal ureteral replacement; long ureteral defect; yang-monti principle. ureteric substitution using the yang-monti principle was reported as a modification of simple ileal ureter replacement. during april 2013 to june in 2015, 2 patients underwent ileal ureteral substitution using a reconfigured ileal segment of yang monti principle in our clinical center. some slight modifications were made and then follow-up were carried out up to 12 months. for these 2 cases, no significant intra/post-operative complications occurred. in 1 year follow up, serum creatinine (scr) and blood urea nitrogen (bun) of both patients decreased to normal. glomerular filtration rate (gfr), renogram and pyelogram showed a stable split renal function. to better understand the yang-monti principle and potential risks and complications, we conduct an systemic review by searching pubmed, google scholar and the cochrane library database from january 1996 through june 2016. 10 out of 644 publications were identified, which included 269 patients from cohort studies. the most usual indications for yang-monti therapy were iatrogenic stricture and retroperitoneal fibrosis. infection and ileus were indicated as the main short time postoperative complications while the fistula and re-strictures happened in long-term. in general, we believe yang-monti principle is a safer and efficient technique for clinical partial and complete ureteral defects if patients and potential risks could be well prepared. introduction ureteral loss represents a surgical challenge to provide low pressure drainage while avoiding urinary stasis and reflux. the ideal replacement should optimize drainage while minimizing absorption, allowing for ureteral repair of varied lengths and locations with maximal preservation of the urinary tract. long-segment ureter defects usually appeared in surgery of severe ureteric obstruction or ureteric stricture, which might be caused by neoplasms, retroperitoneal fibrosis, iatrogenic injuries during open or endourological surgeries, radiation/chemical damage and chronic inflammation. various techniques have been described in literature to handle such problems posed by a shortened ureter not amenable to repair by direct re-anastomosis. one modifications is the application of yang-monti principle which allows the creation of a long tube from short bowel segment after its re-configuration. department of urology, key laboratory of disease of urological system, gansu nepho-urological clinical center, second hospital of lanzhou university, lanzhou, gansu, china, 730030 #these two authors contribute equally to the work. *correspondence: department of urology, key laboratory of disease of urological system, gansu nepho-urological clinical center, second hospital of lanzhou university, 80 cuiying rd,chengguan district lanzhou, china ,730000. e-mail: yuezhongjin@sina.com. received april 2017 & accepted june 2017 case report 4055 figure1: antegrade angiography images preoperative and postoperative a.pre-op (m) b.pre-op (f) c.post-op (m) d.post-op (f). first coined in 1996 to describe using small bowel for ureteric replacement got widely acceptance, which was applied for ureteral replacement first in dogs(1) then clinically(2) in few case reports. the feasibility of constructing a long tube from short segments of ileum was evaluated clinically(3,4) and experimentally(5). due to the excellent functional outcome, the technique was applied in the clinical setting. however, potential postoperative risk of urine leakage, peritonitis and urine reflux occur occasionally , which need to take into account. moreover, experiences of yang-monti in china/asia remain rare. we believe some paucity of modification could facilitate and thus report our experiences on 2 patients in our center. moreover, we performed a systemic review on the outcome, risks and complications of surgery. report of cases two cases were performed during april 2013 to june in 2015 in our clinical center. both patients underwent preoperative evaluation in the form of careful history taking, medical examination and laboratory investigations which included complete routine blood tests, urine analysis, blood renal function, coagulation function, sodium, potassium, and chloride estimation (tables 1 and 2). radiological investigations to visualize the upper urinary tract included renal ultrasonography, intravenous urography (ivu) or computerized tomographic urography(ctu). glomerular filtration rate (gfr) / renal isotope scanning(ris) were performed to estimate the split renal function. all patients underwent preoperative colonic preparation for 24 hours. the study was approved by the ethical committee of second hospital of lanzhou university (2015a-078). both patients were consented for approval of surgery. case 1: 75 year-old male a 75 year-old man presented to us with a chief comyang-monti principle in ureteral defects-bao et al. case 1 case 2 gender male female age 75 41 etiology urothelium carcinoma of solitary kidney iatrogenic stricture locations of defect right mid-ureter left upper-ureter length of defect (cm) 22 15 surgery time(min) 384 302 hospitalization(d) 23 15 antibody time(d) 11 7 d-j tube removal(w) 4 6 table 1. the basic information of two cases abbreviation: cm: centimeters, min:minutes, d:days, w:weeks case 1:ureteral carcinoma (m) case 2: ureteral obstruction (f) pre-op post-op pre-op post-op wbc (×109/l) 8.7 4.32 6.86 7.33 hgb (g/l) 127 106 140 126 hct(l/l) 0.387 0.335 0.420 0.388 u-rbc (/ul) 3722.5 10-20/hpf 37.4 1-3/hpf u-wbc (/ul) 301.5 0-2/hpf 1295.3 0-2/hpf ph (-) 6.5 6.5 6.5 6.0 bun 84 4.7 6.0 12.3 scr 1200 67 68 86 sodium 143.6 138.7 141.7 147.8 potassium 3.5 3.86 3.9 4.33 chloride 104.2 112.2 102.5 115.0 abbreviations: pre-op: preoperative examination, post-op: postperative examination, wbc: white blood cell, hgb: hemoglobin, hct: hematocrit, srf: scrum renal function, scr: scrum creatinine, table 2: basic laboratory findings of two cases vol 14 no 04 july-august 2017 4056 plaints of for intermittent hematuria lasting for 5-6 weeks and anuria for 1 week. he also had a history of left nephrectomy 10 years ago. on admission, no comorbidities were found, personal and family histories were negative for previous cancers. a high level of scr (1200umol/l) was observed (table 2) and the non-contrast enhanced ctu images delineated an upper right dilated ureter. right nephrostomy was performed to decrease the creatinine. antegrade imaging via nephrostomy tube demonstrated ureter obstruction located in the level of the anterior superior iliac spine. (figure 1) we thus performed ureterscopic biopsy and pathology showed low-grade urothelium carcinoma. with these findings, a diagnosis of urothelium carcinoma was made. the patient strongly claimed for treatment. concase report 4057 sidering his solitary kidney, after all palliative therapy options discussed, we offered the patient two surgery choices: 1. keeping nephrostomy tube after radical ureteral resection and surveillance; 2. ileal ureteral substitution after radical ureteral resection and surveillance. the patient finally decided to choose the latter option. case 2: 41 year-old female patient the other case was a 41 year-old female patient referred for left flank pain and intermittent fever. she had history of ureteroscopy and lithotripsy for left proximal ureteral calculus and bladder-musculature flap surgery due to ureteral stricture 1 year before admission. on admission, laboratory findings were normal (table 2). the non-contrast enhanced ct scan, nephrostomy, antegrade imaging and cystoscopy were performed in sequence. the results confirmed left proximal upper tract ureteral obstruction, combined with hydronephrosis. the left ureteric orifice was not detected in cystoscopic examination. all treatment options were discussed, however, we had no choice but to perform ileal ureteral substitution surgery of yang-monti principle owing to a 15 cm ureter defects of bladder-musculature flap surgery history. (figure 1) surgery technique was basically according to with previous yang-monti principle demonstration(6). the differences existed in anastomosis. we used malposed suture method and a non-refluxing lich-gregoir technique to reduce the risk of re-stricture and calculus formation. malposed suture method focused on non-direct 3m follow-up 6m follow-up 12m follow-up case 1: uc (m) wbc (×109/l) 3.97 5.25 9.18 hgb (g/l) 108 110 92 hct(l/l) 0.340 0.365 0.378 u-rbc (/ul) 75.7 1-3/hpf 0-2/hpf u-wbc (/ul) 23.7 0-2/hpf 0-1/hpf ph (-) 6.5 6.5 6.5 bun 5.7 6.3 4.8 scr 170 121 146 case 2: us (f) wbc (×109/l) 7.14 6.56 4.23 hgb (g/l) 128 122 118 hct(l/l) 0.396 0.412 0.384 u-rbc (/ul) 16.4 0/hpf 0/hpf u-wbc (/ul) 28.2 0-1/hpf 0-1/hpf ph (-) 6.0 6.5 6.5 bun 4.6 6.3 5.1 scr 87 75 78 gfr(ml/min) l: 24.9, r: 61.1 l: 26.6, r:,73.1 abbreviations: uc: ureteral carcinoma, us: ureteral stricture, pre-op: preoperative examination, post-op: postperative examination, m: months, wbc: white blood cell, hgb: hemoglobin, hct: hematocrit, srf: scrum renal function, scr: scrum creatinine, gfrşglomer,ular filtration rate table 3: follow-up information of two cases figure2: the malposed suthure of ileal segments ----suturing line yang-monti principle in ureteral defects-bao et al. suture line forming “t-shaped” anastomotic stomas which generate less suture corners compared to “crossshaped” stomas of traditional suture method and decrease the potential risks of urine leakage from suture corners, which might be of benefit for urine leakage prevention.(figure 2) at the end of the procedure, nephrostomy tube, double-j stent, drainage tube for retroperitoneal cavity and urethral catheter were inserted. postoperative fluid infusion and intermittent bladder washing were carried out for 2 weeks. drainage tubes were removed 2-3 days after operation and double j tube were maintained for 4-6 wks. antegrade imaging was performed at 4 weeks after operation which revealed fluent drainage of ileal ureteral substitutions. figure 3: samples(m) and recunstroction ct(f) of patients. author (years) country type n mean age (y.o) followup post-op long-term (> 3m) evidence patients: time camplications complications level ali-el-dein b(2003)3 egypt cohort 10 48.7 10/10: 12m urinary leakage reflux: 1/10 2c urinary tract infection 4/10 b l.chung(2006)11 uk cc & cohort 52 48.6 52/52: 72m pyelonephritis: 4/52 reflux failure: 3/52 2b wound infection: 1/16 stricture: 2/16 sa. armatys(2008)10 us cohort 91 46.8 91/91: 36m infection: 23/91 fistula: 9/91 2b bowel obstruction: 15/91 stricture: 7/91 steffens ja(2010)15 german cohort 18 47.4 18/18: 50m infection and paralytic infections & fistula: 4/18 2b ileus: 9/18 m.esmat(2013)6 egypt cohort 16 35.0 ± 8.0 9/16: 44m urinary leakage: 1/16 none 2b infection: 4/16 ordorica r(2014)13 u.s cohort 16 45 16/16: 44m none ureteral fistula: 1/16 2b bilateral obstruction: 1/16 m.takeuchi(2014)16 japan cohort 8 43.6 8/8: 60m metabolic acidosis: 3/8 fistula: 2/8 2c stricture: 1/8 s.s nazir(2015)14 india cohort 9 35.0 9/9: 36m urinary leakage: 1/9 none 2c wound infection:1/9 ym xu(2015)9 china cohort 44 41.0 43/44: 69m intestinal obstruction: 2/43 none 2c maigaard(2015)7 danmark cohort 5 47 5/5: 41m urinary leakage: 3/5 ureter stricture: 1/5 2b abbreviation: cc: case-control; yo: years old; post-op: post operation; m: month table 4: studies characteristicts of yang-monti principle and ileal ureteral reconstruction (1996-2016) yang-monti principle in ureteral defects-bao et al. vol 14 no 04 july-august 2017 4058 the hydronephrosis severity of the first case was greatly improved. nephrostomy tubes were removed under the evidences of no fever or flank pain observed after tube clamping. (figures 1 and 3) we appointed three follow up visits at 3, 6 and 12 months after operation to evaluate the recovery of these patients. blood routine tests, urine analysis, blood renal function, ivu and gfr test were thus performed. the male patient refused to take radioactive tests while the female patient accepted all after informed consent. during follow-up, no urine leakage, obstruction, excess mucus production, metabolic abnormalities, frequency, oliguria or odynuria were observed. ivu revealed fluently drainage in both patients 3 month after operation. the differential gfr of the female patient for left and right kidneys were 24.9ml/min and 61.1 ml/min on 6-month follow up and promoted to 26.6ml/min(left) and,73.1ml/min(right) on 12-month follow up. (table 3). systemic review search strategy of systemic review for systemic review, we used the picos method according to the prisma statement (crd42015019212; http://www.crd.york.ac.uk/prospero). a search for articles published from january 1996 through june 2016 using 3 databases, pubmed, google scholar, and the cochrane library database was conducted for potentially eligible studies using a reproducible strategy. the search was limited to 20 years because the yang-monti principle firstly applied in dogs starting in 1996. the following separate searches were conducted using medical subject heading (mesh) terms to maximize the search results. the search resulted in 644 citations. duplicates and experts reviews were removed. the laparoscopic/robotic surgery, pediatrics and few cases report (cases less than 3) were excluded. studies with inconsistent/insufficient data or errors, conferences abstract and unpublished reports were also excluded. studies selection a total of 644 potential relevant abstracts in medline (n = 15), google scholar (n = 629), the cochrane library (n = 0) were examined. 631 were duplicates, unrelated, 1-3 cases report, pediatrics or not original articles; two papers(7,8) did not mainly focus on yang-monti principle and postoperative complications, one(9) probably involved the same patients. the remaining 10 publications(10) published during 2003-2015 were included in our systemic reviews. (figure 4) studies characteristics a total of 269 patients were recruited across all 10 cohort studies. considering the different states of patients and medical levels, etc. might generate the high heterogeneity, we just demonstrated the clear information extracted from publications and the vague information was excluded. among all 269 cases, 9.67% (26/269) were from africa, 27.8%(75/269) were from europe, 22.68%(61/269) were from asia and 39.78%(107/269) were from the u.s. the most usual indication for operation was iatrogenic stricture (approximate 51.46% ş123/239) and then retroperitoneal fibrosis (approximate 16.73%, 40/239) (data not shown). regularly, the antibodies were performed 1-2 weeks and dj tubes were dilated for 2-5 weeks. the short time postoperative complications were infections (27.9%, 75/269) and ileus (9.6%, 26/269). fistula (4.7%, 12/251) and strictures (4.1%,11/269) were more probably to appear after 3 months(table 4). the approximate percentages we used were not accurate but close to the result of larger sample research(8, 9) when we performed analysis respectively. discussion in 1993, yang was the first to describe two small previously detubularized ileal segments to develop transverse tube in a patient undergoing radical cystectomy. the patient remained continent and had no difficulties figure 4: flow chart of studies and patients search strategy yang-monti principle in ureteral defects-bao et al. case report 4059 with catheterization. unfortunately, the main topic of publication focused on the investigator’s creation of an antireflux mechanism needle on the ileal wall but not the construction technique. there was no reference to the conception of the new tube in the title or abstract of the publication. perhaps this was the reason why the technique continued to be unknown until 1997, when monti et al. described independently the detailed construction of single and double ileal tubes in dogs(1). yang monti technique was thus widely recognized and accepted. other following reports presented different bowel segments (intestinal or colon) for ureteric replacement. the merits of the ileal segment are its mobility, small diameter, and constant blood supply. however, common postoperative risks were urine leakage, peritonitis, colic, strictures and infections(11,12). in addition, drawbacks mostly attributed to the absorbing and secreting characteristics of the involved bowel segments such as hyperchloremic metabolic acidosis and excess mucus production and also to the wide caliber refluxing ileal ureter with subsequent progressive dilatation, functional obstruction and recurrent uti(13,14). in our two cases, we made slight modifications:(1). we located ureteric replacement in the retroperitoneum, which is more accordant to the initial physiological characteristics and can decrease the interference in abdomen. in additional, urine leakage or localized infections associated with postoperative complications might be much easier to drain out due to cavity space limitation, which would notably decrease peritonitis, strictures and infections and benefit for eras (enhanced recovery after surgery).(2). we used a non-antireflux mechanism in the distal end-to-end anastomosis between bladder and ureter. lich-gregoir methods also generate strictures(15,16), the patients with calculus and stricture history might be better without antireflux mechanism. in these two cases, direct anastomosis made our surgery more simple and less time consuming, and also could significantly reduce the ureteric ileal segment replacement and ureteral path. the less secretion of succus entericus might be of benefit for maintaining the normal function, efficient urine drainage and fast recovery of the newly reconstructed urinary tracts.(3). the malposed suture method was employed in the ileal segments for end-to-end anastomosis in these two cases, which might be efficient to decrease the occurrence of urine leakage after operation. however, this procedure needs more evidence. during follow-up, no complaint of stricture, fistula, excess mucus production was observed by others(17,18). these might be an advantage of slight modifications and most probably due to the marked reduction in the size of the secreting surface area in comparison with simple ileal ureters that may be associated with mucous obstruction in some cases. in addition, hyperchloremic metabolic acidosis was not observed, which was reported in varying percentages by some studies(14). absence of metabolic disorders among our cases might have contributed to proper surgery timing selecting (serum creatinine ≤100mmol/l), reduction of the size of absorbing surface area might decrease the contact of urine with the ileal mucosa. our systemic review, to our knowledge, is the most comprehensive review on the topic at present. we had to admit that systemic review of these no-control and cohort prospective/retrospective studies might have high heterogeneity due to limited cases, different etiologies and similar outcomes in literature, which would generate multiple potential biases. therefore, extracted data of these ten publications did not fit for a meta-analysis. we just presented the publications to show clear and brief information. we suppose some preventive measures could be taken into account to prevent some potential complications, i.e. maintaining temporary urinary diversion through preoperative nephrostomy tube, postponing removal of double-j tube to 12-24 weeks, maintaining great blood supply of ileal segments in surgery and proper antibiotics, which might efficiently reduce the possible occurrence of short-term infection, ileus and leakage after surgery as well as fistula and stricture in a long run. nevertheless, although our two patients had different clinical courses and we were convinced that we provided them with optimal treatment at that time, long-term follow-up and more cases are needed, particularly in the evaluation of non-antiflux influence in certain patients with similar clinical causes. we believe that widespread of the kind of yang-monti principle is necessary and should be perform in caution. our work might be helpful to some urologists who identify or develop new modification surgery setting and can benefit appropriate patients. conclusions in general, we believe yang-monti principle is a safer and efficient technique for clinical partial and complete ureteral defects if patients and potential risks could be well prepared. our cases experiences and review findings might be helpful to some urologists and may benefit proper patients. multi-center experiences and longterm follow-up remain necessary in future. conflict of interest the authors declare no conflict of interest. acknowledgments we apologize to those investigators whose original work could not be cited owing to the space and searching limitations. the study was supported by grants (201306180078) from the china scholarship council and the authors thank all the medical staffs participated in this work. references 1. monti pr, lara rc, dutra ma, de carvalho jr. new techniques for construction of efferent conduits based on the mitrofanoff principle. urology. 1997;49:112-5. 2. ghoneim ma, alieldein b. replacing the ureter by an ileal tube, using the yang-monti procedure. bju int. 2005;95:455-70. 3. alieldein b, ghoneim ma. bridging long ureteral defects using the yang-monti principle. j urol. 2003;169:1074-7. 4. castellan m, gosalbez r. ureteral replacement using the yang-monti principle: long-term follow-up. urology. 2006;67:476-9. 5. tscholl r, tettamanti f, zingg e. ileal substitute of ureter with reflux-plasty by yang-monti principle in ureteral defects-bao et al. vol 14 no 04 july-august 2017 4060 terminal intussusception of bowel animal experiments and clinical experience. urology. 1977;9:385-9. 6. esmat m, abdelaal a, mostafa d. application of yang-monti principle in ileal ureter substitution: is it a beneficial modification? int braz j urol. 2012;38:779. 7. wagner m, bayne a, daneshmand s. application of the yang-monti channel in adult continent cutaneous urinary diversion. urology. 2008;72:828-31. 8. ma l, liu l, shen h, dan d, wang l, deng yh. the perioperative and convalescence nursing of 5 cases of monti ileovesicostomy. international journal of clinical & experimental medicine. 2015;8:2887-92. 9. xu ym, qian l, qiao y, et al. ileal ureteric replacement with an ileo-psoas muscle tunnel antirefluxing technique for the treatment of long segment ureteric strictures. bju int. 2008;102:1452-6. 10. [no authorlisted]. !!! invalid citation !!! 11. ali-el-dein b, ghoneim ma. bridging long ureteral defects using the yang-monti principle. j urol. 2003;169:1074-7. 12. ordorica r, wiegand lr, webster jc, lockhart jl. ureteral replacement and onlay repair with reconfigured intestinal segments. j urol. 2014;191:1301-6. 13. verduyckt fj, heesakkers jp, debruyne fm. long-term results of ileum interposition for ureteral obstruction. eur urol. 2002;42:181-7. 14. takeuchi m, masumori n, tsukamoto t. ureteral reconstruction with bowel segments: experience with eight patients in a single institute. korean journal of urology. 2014;55:742-9. 15. baston c, harza m, preda a, et al. comparative urologic complications of ureteroneocystostomy in kidney transplantation: transvesical leadbetterpolitano versus extravesical lich-gregoir technique. paper presented at: transplantation proceedings, 2014. 16. maigaard t, kirkeby hj. yang–monti ileal ureter reconstruction. scand j urol. 2015;49:313. 17. defoor jr wr, reddy pp. minimally invasive techniques to approach complications of enterocystoplasty and continent catheterizable channels. pediatric endourology techniques: springer; 2014:28799. 18. lopes ri, dénes ft, padovani g, sircili mh, srougi m. monti's principle in the treatment of congenital uterovesical fistula. urology. 2014;83:1170-2. yang-monti principle in ureteral defects-bao et al. case report 4061 endourology and stone disease management of large proximal ureteral calculi: a three-year multicenter experience of simultaneous supine percutaneous nephrolithotomy and retrograde ureterolithotripsy yu-chen chen1,2,hao-wei chen1,2,yung-shun juan3, ing-shiang lo1, ming-chen paul shih4,wen-jeng wu3, jhen-hao jhan1, tsung-yi huang1* purpose: to share our multicenter experience using a safe and effective method for treating large proximal ureteral calculus by simultaneous supine percutaneous nephrolithotomy (spcnl) and retrograde ureterolithotripsy (ursl) in the galdakao-modified supine valdivia position. materials and methods: between december 2014 and august 2017, all patients with large proximal ureteral stones (> 15 mm) who underwent simultaneous spcnl and retrograde ursl at three medical centers were retrospectively reported. the ureter stone was pushed back (retrograde) with the ureteroscope and was retrieved using forceps with a nephroscope through an amplatz sheath. surgical methods and outcomes were described to improve our experience and management of large proximal ureteral calculi. results: a total of 31 patients underwent simultaneous spcnl and retrograde ursl. the mean patient age, stone size, operating time, and postoperative hospital stay were 57 years (range, 32–74 years), 20.1 mm (range, 15.0–37.9 mm), 81 minutes (range, 30–150), and 3.2 days (range, 2–7 days), respectively. there were 10 modified clavien grade i and five grade ii complications. no blood transfusions were necessary in this series. all patients were treated with double-j stents without a nephrostomy tube. only one patient did not achieve stone-free status because of the strict stone impaction into the ureteral wall. this patient received auxiliary ursl after two months. thereafter, the overall stone-clearance rate at three months was 100%. conclusion: our preliminary data showed that this modified method is safe and effective for treating large proximal ureteral stones. keywords: endoscopes; percutaneous nephroscopy; supine position; upper ureteral stone; ureteroscopic lithotripsy introduction ureteroscopic lithotripsy (ursl) and extracorpor-eal shock wave lithotripsy (eswl) were proposed by the latest american urological association (aua) guidelines as first-line treatments for managing proximal ureteral calculi(1). however, eswl has a poor stone-free outcome rate and requires multiple sessions in cases of upper ureteral stones > 10 mm(2). rigid ursl, when approaching large proximal ureter stones, is often associated with a long operative time, the migration of stones or fragments, and further auxiliary procedures such as flexible ursl and eswl. according to the 2016 european association of urology (eau) guidelines, percutaneous nephrolithotomy (pcnl) can be considered in cases of large (> 10 mm) impacted proximal ureteral calculi(3), but bleeding is generally commonly reported with an overall 7% need 1department of urology, kaohsiung medical university hospital, kaohsiung medical university, kaohsiung, taiwan. 2graduate institute of clinical medicine, college of medicine, kaohsiung medical university, kaohsiung, taiwan. 3department of urology, kaohsiung municipal ta-tung hospital, kaohsiung, taiwan. 4department of radiology, kaohsiung medical university hospital, kaohsiung medical university, kaohsiung, taiwan. *correspondence: department of urology, kaohsiung medical university hospital, no. 100, tz-you 1st road, kaohsiung 807, taiwan. tel: 73121101 886+, ext. 6694, fax: 73211033 886+, e-mail: jennis7995@hotmail.com. received december 2017 & accepted april 2018 for transfusion(4). since each technique has its own limitations, large proximal ureteral stones are challenging to treat with minimally invasive techniques and the optimal management of large proximal ureteral stones (> 15 mm) has yet to be defined. here we report a multicenter experience describing a safe and effective method of treating large proximal ureteral calculi by simultaneous supine pcnl (spcnl) and retrograde semi-rigid ursl in the galdakao-modified supine valdivia (gmsv) position. patients and methods study population and study design between december 2014 and august 2017, all patients who underwent simultaneous spcnl and ursl for a large proximal ureteral calculus at the kaohsiung medical university hospital, kaohsiung municipal siaogang hospital, and kaohsiung municipal ta-tung urology journal/vol 16 no. 5/ september-october 2019/ pp. 433-438. [doi: 10.22037/uj.v0i0.4328] hospital were retrospectively reviewed. inclusion and exclusion criteria the inclusion criteria were the presence of a large proximal ureteral calculus, length on standard imaging ≥ 15 mm, and ureteral stone located between the ureteropelvic junction and the lower border of the fourth lumbar vertebra. patients with a large proximal ureteral calculus combined with other ureteral, renal, or bladder stones were excluded. patients with untreated urinary tract infections who were pregnant or had an abnormal interposition of visceral organs (retrorenal colon), a potential malignant renal tumor, or a bleeding tendency were excluded from the study. patients who could not be placed in the gmsv position because of bone deformity or muscle contracture were also excluded(5). this study was approved by the institutional review board of the kaohsiung medical university hospital (id: kmuhirb-e(i)-20170273). informed consent was obtained from all patients, after educating them about the residual stones and double j stent placement. preoperative preparation all patients underwent preoperative urine culture; serum biochemistry and routine blood tests; radiographic examination of the kidneys, ureters, and bladder (kub); and computerized tomography urography (ctu) evaluation(6). stone size was determined by measuring the length and the width during preoperative radiologic investigations. the stone surface area was calculated using the formula described by tiselius and andersson (length × width × 3.14 × 0.25)(7). all patients were administered intravenous preoperative antibiotics, and urine culture was performed before administration of prophylactic antibiotics. patients were admitted to our urology ward two days before the operation for preoperative and anesthetic assessment according to the hospital protocols and health insurance indications in taiwan. under local anesthesia with intramuscular injection of pethidine, patients were placed in the prone position. renal puncture was performed with an 18g chiba biopsy needle and radifocus® hydrophilic guidewire was introduced into the targeted calyx under fluoroscopic guidance by a radiologist on the day before the operation. an antegrade pyelogram delineating the pelvicalyceal system was used to confirm the position of stone, guidewire, and percutaneous nephrostomy pigtail. surgical technique on the day of the operation, the patient was placed in the gmsv position (figure 1), with one leg ipsilateral to the stone in extension and the other in flexion. two surgeons performed the spcnl and retrograde semi-rigid ursl, simultaneously. after tract dilatation with an ultraxxtm nephrostomy balloon through the radifocus® hydrophilic guidewire, a 30 french (fr) amplatz sheath was introduced. one surgeons placed a 24 fr nephroscope (richard wolf, knittlingen, germany) at the ureteropelvic junction and waited for the other surgeon to approach in a retrograde manner the proximal ureteral stone with a 6 fr semi-rigid ureteroscope (richard wolf, knittlingen, germany). although the main length of the ureteral stone required for inclusion in the study was ≥ 15 mm, patients were further separated into two groups based on the width of ureteral stones measured on radiologic images. stones with width < 10 mm were pushed back in a retrograde manner with the ureteroscope and retrieved using forceps with the nephroscope through the amplatz sheath. the 30 fr amplatz sheath allows the passage of the stones with width < 10 mm (figure 3). stones with a width > 10 mm were disintegrated by a holmium: yag laser and then pushed retrograde and removed in an anterograde manner by forceps through an amplatz sheath. baskets were unnecessary during all procedures. at the end of the operation, a double-j stent was positioned in retrograde fashion, which was subsequently removed as an outpatient procedure 2-4 weeks postoperatively depending on the outcome of stone clearance. outcome assessment and postoperative care the primary outcome of interest was stone-free clearance, which was defined as the absence of fragments or a single fragment of ≤ 4 mm on standard radiography at the 1and 3-month follow-up examinations(8). secondary outcomes included operating time, hospital stay, and complications, which were graded according to the modified clavien classification(9). the operating time was defined as the time between the pcn tract dilatation and the end of the operation (foley insertion), which excluded the time required for anesthesia and patient’s positioning. postoperative labora table 1. patient demographics and clinical data patient characteristicsa number of patients (n = 31) sex, male/female, n 23/8 median age, year (range) 57 ± 8.7 (32–74) body mass index, kg/m2 (range) 27 ± 4.4 (21.2–41.7) bun, mg/dl (range) 20.2 ± 18.1 (11.1–109) creatinine, mg/dl (range) 1.11 ± 0.35 (0.58–2.41) egfr, ml/min/1.73m2 (range) 74.7 ± 23.8 (29–119) stone laterality, right/left, n 17/14 stone size length, mm (range) 20.1 ± 6.3 (15–37.9) stone burden, mm2 (range) 205 ± 94.9 (57.8–403) abbreviations: bun, blood urea nitrogen; egfr, estimated glomerular filtration rate. a data presented as number or mean ± standard deviation figure 1. lateral-frontal view of the patient with a left proximal ureter stone placed in the galdakao-modified supine valdivia (gmsv) position with the left leg in extension and the other in flexion. the c-arm and fluoroscopic instrument were placed contra-laterally to the left ureteral stone. management of large proximal ureteral calculi-chen et al. endourology and stones diseases 434 vol 16 no 04 september-october 2019 435 tory data were collected to investigate for active bleeding. continuous bladder irrigation was administered for one night if gross hematuria was present, and the foley catheter was removed if there was no evidence of hematuria. kub radiography was arranged to confirm the postoperative stone clearance. we discharged the patient if there was no evidence of fever, anemia, or persistent pain. all patients were under urologic outpatient clinic follow-up after discharge. results a total of 31 consecutive patients (23 men, 8 women) with a single large proximal ureteral calculus underwent simultaneous spcnl and ursl. percutaneous lithotomy tract provided access mainly through the lower calyx in 16 cases, while in the remaining 15 cases, access was achieved through the middle calyx. patient demographics and stone characteristics are described in table 1. the mean stone length on standard imaging was 20.1 mm (range, 15.0–37.9 mm); the stones were > 20 mm in 15 patients and 15–20 mm in 16 patients. intraoperative and postoperative findings are reported in table 2. the mean operating time was 81 minutes (range, 30–150 minutes). ureteral stents without a nephrostomy tube (tubeless method) were used in all cases. there were 16 patients who experienced modified clavien class i and five patients who experienced class ii postoperative complications. among class i complications, nine patients had transient gross hematuria, five patients experienced flank pain, and two patients experienced urethral pain. overall, five patients developed a postoperative fever (class ii complication), which was controlled with appropriate antibiotics and supportive treatment. notably, no blood transfusion was needed in this series, and no urinary tract perforation or adjacent organ injury occurred during the procedures. we discontinued bladder irrigation in 22 patients within six hours after the operation; however, for nine patients, bladder irrigation continued beyond this time due to postoperative gross hematuria. in these nine cases, bladder irrigation was discontinued one day after the operation due to improved hematuria. the postoperative stone stone-free rate at 1-month follow-up was 96.8%, with one patient not achieving stone-free status; this patient had a small (5 mm) residual stone revealed by postoperative follow-up kub due to severe angulation and strict stone impaction into the ureteral wall. this patient received ursl two months after the simultaneous spcnl and ursl (a double j stent was placed following the simultaneous table 2. intraoperative parameters and postoperative outcomes intraoperative resultsa operating time, minutes (range) 81 ± 28 (30–150) postoperative outcomesa postoperative hospital stay, days (range) 3.2 ± 1.3 (2–7) postoperative stone-free status, n (%) 30/31 (97) stone clearance at 3 months, n (%) 31/31 (100) complications: modified clavien classification grade i, n (%) 10/31 (32) hematuria 9 flank pain 5 urethral pain 2 modified clavien classification grade ii, n (%) 5/31 (16) postoperative fever more than 38.0 with antibiotics 5 further treatment, n (%): 1/31 (3) auxiliary eswl 1 adata presented as mean ± standard deviation or number (%) abbreviations: eswl, extracorporeal shock wave lithotripsy. figure 2. fluoroscopic images under c-arm showing the (a) right upper ureter stone (arrow) simultaneously approached by antegrade nephroscope and retrograde ureteroscope; and the left percutaneous nephrostomy in situ with the (b) right double-j stent without residual stones postoperatively. management of large proximal ureteral calculi-chen et al. spcnl and ursl for two months). postoperatively radiographic imaging revealed no residual stone after the second operation. the overall stone-clearance rate at three months was 100%. discussion before the 1980s, ureteral stones were managed by open ureterolithotomy. with the advent of eswl, small-caliber semi-rigid ureteroscopes with holmium lasers, flexible ureterorenoscopes, and laparoscopic procedures, the management of ureteral calculi has changed dramatically. eswl, ursl, pcnl, laparoscopic ureterolithotomy, and open surgery are methods currently available for the treatment of proximal ureteral calculi. most upper ureteral stones, especially those < 10 mm in length, can be managed with a minimally invasive approach with excellent surgical outcomes. however, large impacted upper ureteral stones remain challenging to manage, and the optimal treatment for large proximal ureteral calculi located between the ureteropelvic junction and the lower border of the fourth lumbar vertebra is controversial. according to the 2016 eau guidelines for urolithiasis, eswl and ursl are the first-line treatment modalities for the management of proximal ureteral stones (1). however, each technique has limitations. eswl requires multiple sessions and has a dramatically decreased stone-free rate for stones > 10 mm(2,10). retrograde ursl also requires several passages with the ureteroscope to remove all the stone fragments after intracorporeal lithotripsy, which has been reported to be associated with an increased risk of ureteral perforation. moreover, continuous high-pressure irrigation may also result in stone migration back into the renal pelvis or calyx with a reported incidence of 28–60%(11), furthermore, the stone may become unreachable and require further use of a rigid or semi-rigid ureteroscope. although some studies have used an anti-retropulsion device such as a basket during rigid ursl, there is no space available for passage of the device wire when managing large impacted stones(12). moreover, the procedure could be converted to pcnl, laparoscopic, or open ureterolithotomy in some cases such as a tortuous ureter or unusual ureter angulation. a flexible ureteroscope (furs) is considered a new trend and was suggested by the 2016 american urological association (aua) guidelines for the surgical management of stones, which indicate the use of urs for proximal ureteral stones(1). however, furs is not commonly available worldwide because of its high costs, skill-dependence, and long operative time. therefore, according to the 2016 eau guidelines, pcnl is to be considered for managing large proximal ureteral stones (> 10 mm)(3). since the 1980s, pcnl has been gradually widely used as a minimally invasive treatment for large proximal ureteral stones because of its high stone-free rate. a meta-analysis performed in 2017 reported that pcnl was superior to ursl for stone clearance and but showed no significant difference in pain or ureterostenosis despite pcnl being more invasive(13). pcnl produced its advantages via an antegrade tract, which could avoid stone migration by acting as an effective anti-reputation device. however, pcnl was commonly associated with a high risk of bleeding requiring blood transfusion (0–23%), adjacent organ injury (0.4%), and infectious complications (33%) (14,15). laparoscopic ureterolithotomy has been recommended by some randomized controlled studies due to its excellent stone-free rates, especially for proximal ureteral stones > 15 mm when compared to ursl (16-18). nonetheless, laparoscopic ureterolithotomy is relatively invasive. there are two entry points for laparoscopic ureterolithotomy. transperitoneal entry has been associated with postoperative ileus and the possible risk of damaging intraperitoneal structures, thus contributing to the morbidity rates(19); retroperitoneal entry has been associated with fewer intraperitoneal complications, but steeper surgical learning curves. thus, it remains to be seen which treatment modality is ideal for patients with large proximal ureteral stones. a new approach to pcnl using a modified lithotomy position called the gmsv position has recently been proposed(5). the gmsv position is more comfortable for the anesthetist, especially in cases of obese or highrisk anesthesia patients and supports a versatile antero-retrograde approach to the upper urinary tract, which opens the possibility of endoscopic combined intrarenal surgery (ecirs)(20,21). ecirs in the gmsv position is a synergic and a single step approach combining pcnl and retrograde intrarenal surgery using furs(22). however, furs is not currently available in many hospitals in developing countries due the high equipment costs. figure 3. views under nephroscopy revealed (a) a ureter stone pushed back to ureteropelvic junction by the retrograde ureteroscope (b) after retrieving the stone in an antegrade manner; the ureteroscope is visible at the ureteropelvic junction (arrow). management of large proximal ureteral calculi-chen et al. endourology and stones diseases 436 vol 16 no 04 september-october 2019 437 therefore, surgeons prefer to use semi-rigid ureteroscopes because of their durability and affordable price. hence, herein we propose a new technique using simultaneous supine pcnl and retrograde semi-rigid ursl in the gmsv position for large proximal ureteric calculi. in this study, the postoperative stone-free rate was approximately 97%. due to the strict stone impaction into the ureteral wall, one patient did not reach stonefree status as a small fragment remained positioned along the upper ureter. this patient received ursl two months after the simultaneous spcnl and ursl procedure and achieved stone-free status postoperatively. overall, the stone-clearance rate at 3 months was 100%. also in our study, percutaneous lithotomy tract was achieved mainly through the lower calyx (n = 16) and middle calyx (n = 15). large-scale studies are warranted to better examine the optimal calyx for puncture; however, our current experience suggests that the middle and lower-calyx renal accesses represent safe and easy approaches to the creation of a correct tract to the collecting system. the results of our study suggest that simultaneous spcnl and ursl may be a new strategy worth exploring for the safe and effective treatment of upper tract urolithiasis. this approach creates an open low-pressure system that reduces the absorption of irrigation fluid into the circulation. if needed, the stone can be disintegrated first and then pushed back, or directly pushed back to the renal pelvis by retrograde ureteroscopy and then retrieved via forceps with a nephroscope through an amplatz sheath, in a single procedure without the need for baskets, thus reducing the risk of ureteral injury and bleeding. in the case of a stone width of < 10 mm, the operation time was extremely short due to the use of an amplatz sheath, which allows the removal of stone fragments of up to 10 mm. the spcnl and ursl procedures were performed by two surgeons simultaneously, and once the ureteroscope approached the upper ureteral stone, the operation was finalized within seconds, easily and efficaciously after stone removal using an antegrade renoscope. our study also demonstrated less intraoperative blood loss with none of the patients requiring a blood transfusion. the cause of reduced bleeding was probably due to the shorter operative time required. we also believe that given the shorter operation time and the reduced blood loss, patients return to their daily activities much sooner. in addition, during withdrawal of the ureteroscope, the ureter and bladder can be revaluated for any residual stone fragments, bleeding, or blood clots. moreover, this approach also offers the possibility of treating concurrent ipsilateral renal stones with the same percutaneous access during the same session. our study has some limitations. first, a small number of cases were included in the study and our design was retrospectively descriptive rather than comparative. however, our multicenter results of simultaneous spcnl and ursl seem promising for treating large proximal ureteral stones. second, due to the limitations placed by our hospital protocols and health insurance system in taiwan, all patients were admitted 2 days before operation for preoperative laboratory studies and preoperative anesthesia assessment to be performed on the first day of hospitalization, and renal access puncture was performed by interventional radiologists on the second management of large proximal ureteral calculi-chen et al. day. thus, in accordance with our hospital protocols, all patients underwent two-stage pcnl (renal access was done by radiologists), rather than a single-stage procedure in one session. conclusions simultaneous spcnl and ursl represents significant progress in the treatment of large proximal ureteral stones. based on the low blood transfusion rate, no major complications, a high stone-free rate, and short postoperative stay duration, we believe that simultaneous supine pcnl and retrograde ursl is a safe and effective treatment. it is likely that, with more experience using this method, this approach will gain increasing acceptance among urologists in the coming years. however, more clinical trials are required to confirm the outcomes of the present study. acknowledgements this study was approved by the institutional review board of the kaohsiung medical university hospital. both kaohsiung municipal siaogang hospital and kaohsiung municipal ta-tung hospital are part of the kaohsiung medical university hospital system. conflict of interest the authors have no competing interests. references 1. dean a, amy k, nicole lm, et al. surgical management of stones: american urological association / endourological society guideline. available from: http://www. auanet.org/education/guidelines/surgicalmanagement-of-stones. accessed december 15, 2016. 2. preminger gm, tiselius hg, assimos dg, et al. eau/aua nephrolithiasis guideline panel. j urol. 2007;178:2418-34. 3. türk c, knoll t, petrik a, et al. guidelines on urolithiasis. eau. 2016. available at: http:// uroweb.org/guideline/urolithiasis/. accessed december 15, 2016. 4. kallidonis p, panagopoulos v, kyriazis i, liatsikos e. complications of percutaneous nephrolithotomy: classification, management, and prevention. curr opin urol. 2016;26:8894. 5. scoffone cm, cracco cm, cossu m, grande s, poggio m, scarpa rm. endoscopic combined intrarenal surgery in galdakaomodified supine valdivia position: a new standard for percutaneous nephrolithotomy? eur urol 2008;54:1393-403. 6. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016:8;13:2899-902. 7. tiselius h-g, andersson a. stone burden in an average swedish population of stone formers requiring active stone removal: how can the stone size be estimated in the clinical routine? eur urol 2003;43:275-81. 8. srisubat a, potisat s, lojanapiwat b, setthawong v, laopaiboon m. extracorporeal shock wave lithotripsy (eswl) versus percutaneous nephrolithotomy (pcnl) or retrograde intrarenal surgery (rirs) for kidney stones. cochrane database syst rev 2009;(4):cd007044 9. tefekli a, ali karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol 2008;53:184-90. 10. white w, klein f. five-year clinical experience with the dornier delta lithotriptor. urology. 2006;68:28-32. 11. chow gk, patterson de, blute ml, segura jw. ureteroscopy: effect of technology and technique on clinical practice. j urol. 2003;170:99-102. 12. bozkurt ih, yonguc t, arslan b, et al. minimally invasive surgical treatment for large impacted upper ureteral stones: ureteroscopic lithotripsy or percutaneous nephrolithotomy? can urol assoc j. 2015;9:e122-5. 13. wang q, guo j, hu h, et al. rigid ureteroscopic lithotripsy versus percutaneous nephrolithotomy for large proximal ureteral stones: a meta-analysis. plos one. 2017;12:e0171478. 14. seitz c, desai m, häcker a, et al. incidence, prevention, and management of complications following percutaneous nephrolitholapaxy. eur urol. 2012;61:146-158 15. ritter m, krombach p, michel ms. percutaneous stone removal. eur urol suppl 2011;10:433-9. 16. kumar a, nanda b, kumar n, kumar r, vasudeva p, mohanty nk. a prospective randomized comparison between shockwave lithotripsy and semirigid ureteroscopy for upper ureteral stones > 2 cm: a single center experience. j endourol. 2015;29:47-51. 17. kadyan b, sabale v, mane d, et al. large proximal ureteral stones: ideal treatment modality? urol ann. 2016;8:189-92. 18. torricelli fc, monga m, marchini gs, srougi m, nahas wc, mazzucchi e. semi-rigid ureteroscopic lithotripsy versus laparoscopic ureterolithotomy for large upper ureteral stones: a meta analysis of randomized controlled trials. int braz j urol. 2016;42:64554. 19. liu y, zhou z, xia a, dai h, guo l, zheng j. clinical observation of different minimally invasive surgeries for the treatment of impacted upper ureteral calculi. pak j med sci. 2013;29:1358-62. 20. derosette jj, tsakiris p, ferrandino mn, et al. beyond prone position in percutaneous nephrolithotomy: a comprehensive review. eur urol. 2008;54:1262-9. 21. cracco cm, scoffone cm. ecirs (endoscopic combined intrarenal surgery) in the galdakao-modified supine valdivia position: a new life for percutaneous surgery? world j urol. 2011;29:821-7. management of large proximal ureteral calculi-chen et al. endourology and stones diseases 438 miscellaneous extracorporeal shockwave therapy combined with drug therapy in chronic pelvic pain syndrome : a randomized clinical trial seyed mansoor rayegani1, mohammadreza razzaghi2 , seyed ahmad raeissadat3, farzad allameh4*, dariush eliaspour1, amirreza abedi5 , atefeh javadi1, amirhossein rahavian5 purpose: chronic prostatitis/ chronic pelvic pain syndrome (cp/cpps) is a nonspecific pelvic pain in the absence of signs of infection or other obvious local pathology for at least three of the last 6 months. evidence for treatment approach is limited. so the aim of this study is to investigate the effect of extracorporeal shock wave therapy (eswt) combined with pharmacotherapy in the treatment of cp/cpps. materials and methods: in this randomized clinical trial, 31 patients with cp/cpps were investigated in two groups: the intervention group (n=16) was treated with a combination of an alpha-blocker, an anti-inflammatory agent, a muscle relaxant and a short course of antibiotic in combination with 4 sessions of focused eswt (a protocol of 3000 impulses, 0.25 mj/mm2 and 3 hz of frequency). the control group (n=15) received the aforementioned pharmacotherapy with 4 sessions of sham-eswt . follow-up was performed 4 and 12 weeks following eswt by using the visual analogue scale (vas), international index of erectile function (iief) 5, national institutes of health-chronic prostatitis symptom index (nih-cpsi) and international prostate symptom score (ipss) questionnaires. post void residual (pvr) urine and maximum flow rate (qmax) were also assessed in both groups. results: the patients mean age was 43.7 ±12.6 years. in both groups, the mean scores of nih-cpsi (total and sub-domains) and vas showed statistically significant improvements after 4 and 12 weeks compared to the baseline (p < .001). in the intervention group, ipss (mean difference: 4.25) and qmax (mean difference: 2.22) were also significantly improved (p < .001). there was a significant improvement in nih-cpsi (mean difference: 1.1) and vas scores (mean difference: 1.1) in the intervention group as compared to the control group (p < .01). qmax, pvr and iief score were not statistically different in the two groups. conclusion: eswt in combination with pharmacotherapy could improve the treatment outcome in patients with cp/cpps. keywords: chronic pelvic pain syndrome; erectile dysfunction; extracorporeal shock wave therapy; pain management; prostatitis introduction chronic prostatitis /chronic pelvic pain syndrome (cp/cpps) is the most frequent urological disorder in men younger than 50 and the third most common urological finding in men over 50 years old.(1) according to the national institute of health (nih), chronic pelvic pain syndrome (cpps) is a chronic or persistent pain that lasts 3 months in the last 6 months and is perceived in structures related to the pelvis which is associated with symptoms suggestive of lower urinary tract, sexual, bowel or pelvic floor dysfunction and causes negative emotional and cognitive consequences. 1physical medicine and rehabilitation research center, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 2laser application in medical sciences research center, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 3clinical development research center of shahid modarres hospital, physical medicine and rehabilitation research center, shahid beheshti university of medical sciences, tehran, iran. 4center of excellence in training laser application in medicine, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 5department of urology, shahid beheshti university of medical sciences, tehran, iran. *correspondence: center of excellence in training laser application in medicine, shohada-e-tajrish hospital, tajrish sq., tehran, iran. tel: +989123885545. fax: +982122736386. email: farzadallame@gmail.com. received july 2018 & accepted april 2019 (2,3) the prevalence of cpps is between 3–10 % that affects nearly 15% of all urologic outpatient visits.(4,5) despite its high prevalence and its impact on quality of life (qol), the pathogenesis of the cpps is hardly understood. numerous etiologies are proposed including infection, pelvic floor hyperactivity, local chemical alterations, neurologic components (central sensitization), and perfusion disturbances.(6,7) it is important to exclude other genital and pelvic disorders present with pelvic pain before the diagnosis of cpps.(8) the determination of the severity of the disease, its urology journal/vol 17 no. 2/ march-april 2020/ pp. 185-191. [doi: 10.22037/uj.v0i0.4673] progression and treatment response can be assessed by means of reliable questionnaires such as international prostate symptom (ipss) score and national institutes of health-chronic prostatitis index (nih-cpsi).(2,9,10) unknown pathogenesis leads to limitations in the treatment of cpps. the most common therapeutic approaches are α-receptor blockers, like tamsulosin, antibiotics which cover gram negative germs, analgesics such as nonsteroidal anti-inflammatory drugs (nsaids) and 5-αreductase inhibitors used as monoor combination therapy.(11-13) the second-line treatment protocols include physical therapy, trigger-point massage, electromagnetic treatment, acupuncture, prostate massage, and intraprostatic injection of botulinum toxin a.(14,15) there are many challenging issues in the management of patients with cpps, such as the possibility of treatment failure by monotherapy or pharmacological side effects in long-term use.(16) although extracorporeal shock wave therapy (eswt) has been successful for other indications such as orthopedic pain syndromes,(17) there is limited evidence whether this approach is also effective for patients with cpps. a number of mechanisms have been suggested including the increasing of local microvascularization, decreasing passive muscle tone, hyperstimulating nociceptors, interrupting the flow of nerve impulses, or influencing the neuroplasticity of the pain memory.(18,19) eswt is an outpatient procedure without significant side effects that can be simply applied. according to the mentioned challenges in cpps treatment and the fact that there is no conclusive data about the effectiveness of combining eswt and drug therapy, we conducted a sham-controlled randomized clinical trial to study the effects of eswt and oral pharmacological treatment combination therapy in patients with cpps, which, to the best of our knowledge, has not been performed before.(20) materials and methods we performed this single-blind randomized controlled clinical trial from may 2017 to february 2018. inclusion and exclusion criteria all patients with chronic prostatitis type iiib/chronic pelvic pain syndrome who were referred to the urology clinic of shohada-e-tajrish hospital and met our inclusion criteria were enrolled in this study. the study inclusion criteria were as follows: patients older than 18 years of age diagnosed with type iiib prostatitis (criteria according to nih classification)(3), patients with pain that lasted 3 months in the last 6 months without clear abnormalities upon urological examination and no evidence of bacteria in urinary and seminal fluid culture tests, and patients who were not addicted to drugs and narcotics. the exclusion criteria of this study included being under treatment by another method at the beginning of the study, other diagnoses such as varicocele, hernia or prostate cancer during workup, psa > 4, bleeding diathesis, history of urethral stricture or hematuria or urinary tract infection in the last year. the diagnosis of patients was made by a single urologist based on a comprehensive history and physical examination including digital rectal examination, psa measurement, urine analysis and culture, semen analysis and two-cup test. a combination of an alpha blocker (tamsulosin 0.4mg daily), an nsaid (diclofenac sustained release 100mg daily), a muscle relaxant (baclofen 10mg/bd) for 12 weeks and a short term antibiotic (ofloxacin 300mg/bd for 2 weeks) were started for all patients. in this situation, no one was deprived from the treatment. for each patient the questionnaires including iief5, ipss and nih-cpsi were completed and the degree of pain was assessed using vas to achieve baseline chareswt in chronic pelvic pain syndrome-rayegani et al. figure 1. consort 2010 flow diagram miscellaneous 186 vol 17 no 02 march-april 2020 187 acteristics by a blind investigator. we tried to have a consistent environment for participants and trained the participants well for rating the questionnaires to increase the reliability of our assessments. we also calculated the cronbach’s alpha for each questionnaire. uroflowmetry was also done to obtain maximum flow rate (qmax) and post void residual urine (pvr). we used pc based wireless uroflowmeter by mms from netherland. table 1. demographic and baseline data in both groups. group n mean std. deviation p value age (years) case 16 44.38 13.846 .77 control 15 43.07 11.708 marriage status case 16 8(50%) 1.00 (number of married) control 15 7(53.3%) ejaculation per week case 16 1.50 1.033 .4 control 15 1.80 0.941 body mass index (kg/m2) case 16 29.25 6.382 .98 control 15 29.20 6.656 duration case 16 11.37 5.251 .95 (months) control 15 11.26 5.885 iief a 5 case 16 16.38 6.131 .66 control 15 15.47 5.153 ipss b case 16 15.69 6.610 .90 control 15 15.40 6.208 nih c pain part case 16 13.06 6.298 .44 control 15 14.67 5.052 nih urination part case 16 4.75 2.817 .89 control 15 4.87 1.767 nih qol d part case 16 7.69 2.750 .44 control 15 8.33 1.759 nih total score case 16 25.50 8.989 .42 control 15 27.87 7.259 pvr e (ml) case 16 14.7500 9.83531 .72 control 15 16.1333 11.84945 qmax (ml/s) case 16 14.825 6.7752 .87 control 15 15.233 7.0605 vas f case 16 6.44 1.263 .94 control 15 6.40 1.805 a iief: international index of erectile function, b ipss: international prostate symptom score, c nih: national institute of health, d qol: quality of life, e pvr: post void residue, f vas: visual analog scale table 2. mean difference of variables before and after treatment in intervention and control groups after 4 and 12 weeks intervention group after 4 weeks after 12 weeks mean difference p value mean difference p value iief a 5 0.38 0.45 -0.81 .35 ipss b 1.88 0.006 4.25 .0001 nih c pain 4.25 0.0001 5.06 .0001 nihurine 2.25 0.0001 2.19 .001 nihqol d 3.75 0.0001 4.88 .0001 nih total 10.25 0.0001 12.12 .0001 qmax -2.22 0.004 -1.8 .04 pvr e 2.88 0.056 4.2 .14 vas f 3.81 0.0001 3.63 .0001 control group after 4 weeks after 12 weeks mean difference p value mean difference p value iief 5 0.74 0.22 -0.80 .26 ipss 0.73 0.6 1.40 .06 nih pain 2.67 0.001 3.14 .0001 nihurine 0.87 0.003 0.87 .0001 nihqol 2.4 0.0001 2.33 .0001 nih total 5.94 0.0001 6.34 .0001 qmax -0.59 0.17 0.65 .20 pvr 1.67 0.10 0.08 .92 vas 1.73 0.0001 2.07 .0001 a iief: international index of erectile function, b ipss: international prostate symptom score, c nih: national institute of health, d qol: quality of life, e pvr: post void residue, f vas: visual analog scale. eswt in chronic pelvic pain syndrome-rayegani et al. miscellaneous 188 then using random number table, the participants were randomly divided into two groups using opaque envelopes to guarantee the allocation concealment. in this protocol all patients were blind about the future procedure. procedure in the intervention group, patients were treated by eswt once a week for 4 weeks. each time 3000 impulses, with 0.25 mjoules/mm2 and 3 hertz of frequency were delivered. after each 500 pulses, the probe position was changed. in this study, we used standard focused electromagnetic duolith sd1 t-top by storz medical from switzerland. the treatment was performed in supine position. in the sham group, the same protocol was applied for patients but the probe was turned off. outcome assessment the primary outcomes were pain reduction and improvement in urinary symptoms which were evaluated using vas, nihcpsi and ipss questionnaires. the secondary outcomes included sexual performance which was assessed by iief5 questionnaire, objective urinary conditions (qmax and pvr) and treatment complications. the follow-up assessments were done 4 and 12 weeks following the first eswt session. the follow-up study included clinical examinations and filling the questionnaires and taking a focused history of patients’ complaints by the same blind person who evaluated the participants at the beginning of the study, besides measuring qmax and pvr by uroflowmetry. the study protocol was performed in accordance with the declaration of helsinki and approved by the ethics group n mean std. deviation p value iief a 5 case 16 16.00 5.177 .45 control 15 14.73 3.918 ipss b case 16 13.81 4.679 .64 control 15 14.67 5.473 nih c pain part case 16 8.81 3.351 .02 control 15 12.00 3.982 nih urination part case 16 2.50 1.366 .01 control 15 4.00 1.690 nih qold part case 16 3.94 1.340 .001 control 15 5.93 1.624 nih total score case 16 15.25 4.282 .001 control 15 21.93 5.391 qmax case 16 17.044 4.8814 .54 control 15 15.827 6.1762 pvr e case 16 11.8750 6.66208 .42 control 15 14.4667 10.63597 vas f case 16 2.63 1.500 .001 control 15 4.67 1.447 a iief: international index of erectile function, b ipss: international prostate symptom score, c nih: national institute of health, d qol: quality of life, e pvr: post void residue, f vas: visual analog scale. table 3. comparison of outcomes between intervention and control groups after 4 weeks group n mean std. deviation p value iief a 5 case 16 17.19 2.713 .34 control 15 16.27 3.327 ipss b case 16 11.44 3.669 .93 control 15 14.00 4.536 nih c pain part case 16 8.00 3.899 .01 control 15 11.53 3.980 nih urination part case 16 2.56 1.094 .003 control 15 4.00 1.363 nih qol d part case 16 2.81 1.047 .0001 control 15 6.00 1.309 nih total score case 16 13.38 4.703 .0001 control 15 21.53 4.533 qmax case 10 14.600 3.8038 .40 control 12 16.333 5.4249 pvr e case 10 14.5000 4.30116 .80 control 12 13.5000 11.63459 vas f case 16 2.81 1.167 .004 control 15 4.33 1.543 a iief: international index of erectile function, b ipss: international prostate symptom score, c nih: national institute of health, d qol: quality of life, e pvr: post void residue, f vas: visual analog scale. table 4. comparison of outcomes between intervention and control groups after 12 weeks. eswt in chronic pelvic pain syndrome-rayegani et al. vol 17 no 02 march-april 2020 189 committee of shahid beheshti university of medical sciences and it is registered on irct database with the following code: irct2017082635911n1. the informed consent was obtained after all patients were informed of the treatment methods and also about publishing the data without disclosure of their names. it must be mentioned that there was no deviations from the study protocol in all phases of the project. statistical analysis the data were analyzed by spss (version 23). the biostatistician was blind about treatment groups. statistical analyses such as chi-square, paired t-test and independent t-test were used. p value less than 0.05 implied statistical significance. results thirty-one male patients were randomly assigned to the intervention group (n=16) and control group (n=15). the consort flow diagram is shown in figure 1. the mean age of the patients in the intervention and sham groups were 44.3 ± 13.8 and 43.07 ± 11.7 years, respectively. the demographic data were summarized in table 1. at baseline, the mean scores of iief5, vas, ipss and nih-cpsi were not statistically different in the two groups. the mean scores of objective parameters including qmax (14.825 ± 6.77 versus 15.23 ± 7.06, p = .87) and pvr (14.75 ± 9.83 versus 16.13 ± 11.84, p = .72) were also similar in both groups. with respect to within-group data analysis, vas score, total nih-cpsi and all subdomains were significantly improved in both groups. the difference became statistically significant 4 and 12 weeks after treatment. (table 2). ipss and qmax were significantly improved in the intervention group (p < .006) but insignificantly improved in the sham group, 4 and 12 weeks after treatment. in addition, iief5 scores and pvr were not improved in either group at any follow-up time points. regarding between-group analysis, the scores of nih-cpsi subdomains including pain, urinary symptoms and qol became significantly different in the two groups at week 4. total nih-cpsi and vas scores at this follow-up time point were also significantly different in favor of the intervention group(table 3). after 12 weeks, the difference between the two groups was also noted and the mean ± sd nih-cpsi total scores including pain, urinary symptoms and qol subdomains were 13.38 ± 4.70 in the intervention group and 21.53 ± 4.53 in the sham group (p = .0001). vas score was different in the two groups and the mean was 2.81 ± 1.16 versus 4.33 ± 1.54 in the intervention and control group, respectively (p = .004). but the mean scores of qmax (14.6 ± 3.80 versus 16.33 ± 5.42, p = .40) and pvr (14.5 ± 4.30 cc versus 13.50 ± 11.63 cc, p = .80) were not significantly different. also, the mean of iief5 (17.19 ± 2.71 versus 16.27 ± 3.32, p = .34) and ipss (11.44 ± 3.66 versus 14 ± 4.53, p = .93) were not different in the two populations (table 4). there were only 18% (n = 4) and 13% (n = 2) loss to follow-up in intervention and control groups respectively, yet all the questionnaires were filled by interview on phone and only uroflowmetry was not performed. in this study, four patients in the intervention group experienced minor complications that included transient hematuria and hematospermia which were not statistically and clinically noteworthy. discussion our study showed that eswt and drug therapy could improve urinary symptoms, pain and qol of patients with cpps. numerous studies in other fields of medicine such as cardiology and orthopedics have shown that eswt is effective and has no significant side effects.(17,21) this issue was confirmed in the present study. furthermore, eswt is effective to alleviate pain and help heal tissue. this can be explained by local muscle relaxation and eswt–induced neovascularization.(22,23) a randomized double-blind study of eswt in patients with cpps performedby zimmermann et al.(19) showed that all outcome parameters improved significantly in the treatment group at month 3 (ipss: 25% decrease; iief: 5.3% increase; nih-cpsi: 17% decrease; vas: 50% decrease), with no improvement in the sham-treatment group. this study was the first study to recommend level 1 evidence for eswt in patients with cpps.(19) in the study of 80 cpps patients,(24) there was a significant improvement in pain, qol and total nih-cpsi scores in the eswt group compared to the sham group. in our study, an improvement in symptoms was observed in both intervention and sham groups that can be in line with the sham effect and also the medications used in both groups. however, the difference became significant at weeks 4 and 12 after treatment for vas and nih-cpsi total and subdomain scores in favor of eswt. yet ipss was not significantly different in each follow-up time. in most studies(23,25,26), identical to the present research, focused eswt was used, with the exception of only one study.(27) in this randomized controlled study, a radial shock wave device was used in cpps patients and the outcomes were compared with the second group in which pharmacological treatment was administrated. a significant improvement of pain and qol was reported in the first group. in the present study, qmax and pvr were not significantly different in the two groups in each follow-up time, while the study conducted by pajovic et al.(25) showed statistically significant improvement in both pvr and qmax after receiving a combination of triple drug therapy and eswt, which could be due to the longer duration of treatment (12 sessions of eswt, once-weekly) although, in this study, the mean score of iief at the baseline was similar to some previous studies, there were no significant changes in our follow-up study, contrary to the findings of above-mentioned studies. (19,28,29) the average of follow-up in most studies was 12 weeks after eswt(19,24,26,27) but some studies extended their follow-up ranging from 24 weeks to one year.(25,29,30) moayednia et al.(30) showed that at week 24 of follow-up, the mean scores of pain, urinary symptoms, qol and total nih-cpsi score were not statistically different from baseline in the eswt group. while in another study,(29) the efficacy of shock wave was proven for one year after treatment. it seems that further studies are needed to determine its long-term efficacy. although our data looks very promising, some limiting factors in our study need to be considered: the study period of only 3 months is short, therefore, the durability of this approach is unknown. eswt in chronic pelvic pain syndrome-rayegani et al. the lack of side-effects specific to eswt make it possible to repeat the eswt cycle at any time. in the future, it might be possible to significantly extend the treatment sessions possibly to achieve a long-lasting treatment effect. conclusions eswt is an outpatient and easy procedure that in combination with pharmacotherapycould improve treatment outcomes in patients with cp/cpps. acknowledgements we would like to thank the laser application in medical sciences research center personnel for their cooperation and compassion. conflict of interest it should be mentioned that the authors had no conflict of interest during this mission. references 1. collins mm, stafford rs, o'leary mp, barry mj. how common is prostatitis? a national survey of physician visits. j urol. 1998;159:1224-8. 2. fall m, baranowski ap, elneil s, engeler d, hughes j, messelink ej, et al. eau guidelines on chronic pelvic pain. eur urol. 2010;57:3548. 3. krieger jn, nyberg jr l, nickel jc. nih consensus definition and classification of prostatitis. jama. 1999;282:236-7. 4. bartoletti r, cai t, mondaini n, dinelli n, pinzi n, pavone c, et al. prevalence, incidence estimation, risk factors and characterization of chronic prostatitis/chronic pelvic pain syndrome in urological hospital outpatients in italy: results of a multicenter case-control observational study. j urol. 2007;178:2411-5. 5. marszalek m, wehrberger c, hochreiter w, temml c, madersbacher s. symptoms suggestive of chronic pelvic pain syndrome in an urban population: prevalence and associations with lower urinary tract symptoms and erectile function. j urol. 2007;177:18159. 6. korkmaz s, karadag ma, hamamcioglu k, sofikerim m, aksu m. electrophysiological identification of central sensitization in patients with chronic prostatitis. urol j. 2015;12:2280-4. 7. pontari ma, ruggieri mr. mechanisms in prostatitis/chronic pelvic pain syndrome. j urol. 2008;179:s61-s7. 8. yanev k, krastanov a, georgiev m, tonev a, timev a, elenkov a. a case of masson’s tumor of the penis presenting as chronic pelvic pain syndrome. urol j. 2018. 9. litwin ms, mcnaughton-collins m, fowler jr fj, nickel jc, calhoun ea, pontari ma, et al. the national institutes of health chronic prostatitis symptom index: development and validation of a new outcome measure. j urol. 1999;162:369-75. 10. delavierre d, rigaud j, sibert l, labat j. symptomatic approach to chronic prostatitis/ chronic pelvic pain syndrome. prog urol. 2010;20:940-53. 11. weidner w, wagenlehner f, marconi m, pilatz a, pantke k, diemer t. acute bacterial prostatitis and chronic prostatitis/ chronic pelvic pain syndrome: andrological implications. andrologia. 2008;40:105-12. 12. propert kj, alexander rb, nickel jc, kusek jw, litwin ms, landis jr, et al. design of a multicenter randomized clinical trial for chronic prostatitis/chronic pelvic pain syndrome1. urology. 2002;59:870-6. 13. nickel jc, downey j, ardern d, clark j, nickel k. failure of a monotherapy strategy for difficult chronic prostatitis/chronic pelvic pain syndrome. the journal of urology. 2004;172:551-4. 14. chuang y-c, chancellor mb. the application of botulinum toxin in the prostate. j urol. 2006;176:2375-82. 15. anderson ru, wise d, sawyer t, chan c. integration of myofascial trigger point release and paradoxical relaxation training treatment of chronic pelvic pain in men. j urol. 2005;174:155-60. 16. tiselius hg. urology: shock wave therapy in practice: level 10; 2013. 17. schmitz c, császár nb, milz s, schieker m, maffulli n, rompe j-d, et al. efficacy and safety of extracorporeal shock wave therapy for orthopedic conditions: a systematic review on studies listed in the pedro database. br med bull. 2015;116:115. 18. wess oj. a neural model for chronic pain and pain relief by extracorporeal shock wave treatment. urol res. 2008;36:327-34. 19. zimmermann r, cumpanas a, miclea f, janetschek g. extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome in males: a randomised, double-blind, placebo-controlled study. eur urol. 2009;56:418-24. 20. marszalek m, berger i, madersbacher s. low-energy extracorporeal shock wave therapy for chronic pelvic pain syndrome: finally, the magic bullet? european urology. 2009;56(3):425-6. 21. wang j, zhou c, liu l, pan x, guo t. clinical effect of cardiac shock wave therapy on patients with ischaemic heart disease: a systematic review and meta‐analysis. eur j clin invest. 2015;45:1270-85. 22. yan x, yang g, cheng l, chen m, cheng x, chai y, et al. effect of extracorporeal shock wave therapy on diabetic chronic wound healing and its histological features. zhongguo xiu fu chong jian wai ke za zhi. eswt in chronic pelvic pain syndrome-rayegani et al. miscellaneous 190 vol 17 no 02 march-april 2020 191 2012;26:961-7. 23. zimmermann r, cumpanas a, hoeltl l, janetschek g, stenzl a, miclea f. extracorporeal shock‐wave therapy for treating chronic pelvic pain syndrome: a feasibility study and the first clinical results. bju int. 2008;102:976-80. 24. zeng x, liang c, ye z. extracorporeal shock wave treatment for non-inflammatory chronic pelvic pain syndrome: a prospective, randomized and sham-controlled study. chin med j. 2012;125:114-8. 25. pajovic b, radojevic n, dimitrovski a, vukovic m. comparison of the efficiency of combined extracorporeal shock-wave therapy and triple therapy versus triple therapy itself in category iii b chronic pelvic pain syndrome (cpps). aging male. 2016;19:202-7. 26. vahdatpour b, alizadeh f, moayednia a, emadi m, khorami mh, haghdani s. efficacy of extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome: a randomized, controlled trial. isrn urol. 2013;2013. 27. nikolaevich km. radial shock wave therapy in chronic pelvic pain syndrome (cpps). urology. 2013;6. 28. guu s-j, geng j-h, chao i-t, lin h-t, lee y-c, juan y-s, et al. efficacy of lowintensity extracorporeal shock wave therapy on men with chronic pelvic pain syndrome refractory to 3-as therapy. am j mens health. 2018;12:441-52. 29. al edwan gm, muheilan mm, atta onm. long term efficacy of extracorporeal shock wave therapy [eswt] for treatment of refractory chronic abacterial prostatitis. ann med surg (lond). 2017;14:12-7. 30. moayednia a, haghdani s, khosrawi s, yousefi e, vahdatpour b. long-term effect of extracorporeal shock wave therapy on the treatment of chronic pelvic pain syndrome due to non bacterial prostatitis. j res med sci. 2014;19:293. eswt in chronic pelvic pain syndrome-rayegani et al. miscellaneous investigation of a new catheter on relieving pain during male cystoscopy – a randomized clinical trial xiong yongjiang, liu jiaji, zhao tao* purpose: to investigate the pain intensity and tolerability of a new catheter applied for urethral surface anesthesia during rigid cystoscopy in male patients, and explore the prospects of its application and the anesthetic method in hospitals at primary levels. materials and methods: 252 adult male patients were randomly divided into the experimental group and the control group.1% lidocaine solution was irrigated into the posterior urethra of the experimental group using the new catheter before cystoscopy, while the control group was administered with lidocaine gel. both groups were assessed by visual analogue scale(vas) with their pain perceived during administration of lidocaine (control group) /during insertion of catheter and administration of lidocaine (experimental group) (t1),during the insertion of cystoscope (t2),at the beginning of cystoscopy (t3),the third minute of cystoscopy (t4), during the first urination after the procedure (t5), as well with the maximum pain (pmax) perceived during the whole procedure. the fluctuations of blood pressure and heart rate in each group before, after and during the procedure were recorded, and the anesthesia costs in both groups were calculated. results: except a slightly higher score in t1, the scores of vas in experimental group were lower than those of control group in t2,t3 and t4. the pmax of the control group was 4.92(sd=1.20), which was higher than in the experimental group of 3.89 (sd = 0.95, p < 0.01).there was no significant difference on blood pressure variation in both groups. while heart rate variation in experimental group was lower than that in control group (16.3%, sd=3.4 vs. 22.6%,sd=5.0, p < 0.01).no obvious complications were found in both groups. the anesthesia cost of the experimental group is about 1.53 dollars, with 1.75 dollars lower than that of the control group. conclusion: it is tolerable and beneficial to apply the new catheter for male urethral anesthesia. it can significantly relieve the pain during rigid cystoscopy in male patients, and is low in cost and easy in operation. thus this method is worth being recommended to hospitals, especially at community hospitals or primary hospitals. keywords: cystoscopy; male; catheter; anesthesia; pain introduction the most basic endoscopic technique in urology, cystoscopy is an essential step for operations such as ureteral retrograde catheterization, retrograde pyeloureterography, ureteral stent extraction, etc(1).however, cystoscopy has been reported by patients to maintain an inevitable pain. pain is more intense in male patients than in female patients(2). during cystoscopy, the most painful part is the insertion of cystoscopy into the urethra, especially when the cystoscopy passes through the external urethral sphincter(3).however ,the commonly used clinical methods for perfusion through the external urethral orifice or application of drug to the surface of the sheath cannot take sufficient effect on the posterior urethra, resulting in unsatisfactory pain relief(4-6). it has always been the topic of discussion for urologists as for how to reduce the patient's pain during cystoscopy. our aim was to explore a new method by using a new catheter technology to fully apply the topical anesthetic department of urology,yongchuan hospital of chongqing medical university,xuan hua road,yongchuan district, chongqing,402160,china. correspondence: department of urology, yongchuan hospital of chongqing medical university,xuan hua road,yongchuan district, chongqing,402160,china. ph:+8613527491151,email:zhaotao_1999@163.com. received january 2019 & accepted december 2019 to the male urethral mucosa before performing cystoscopy. patients and methods study population ethical approval for the study was granted by the institutional review board at yongchuan hospital of chongqing medical university. according to the design formulas, we calculated the sample size by considering the expected accuracy, attrition rate and the cost of the experiment. 230 adult male patients from june 2016 to august 2017 who underwent cystoscopy in our department were selected as the research objectives, and were randomly divided into the experimental group (120 patients) and the control group (110 patients) based on a randomization generator available at randomization.com by a nurse. exclusion criteria: those who are allergic to anesthetic urology journal/vol 17 no. 3/ may-june 2020/ pp. 312-316. [doi: 10.22037/uj.v0i0.5130] lidocaine; those who have used analgesics within the past 24 hours; those with sensory deficits (such as paraplegia); patients with severe cardiovascular and cerebrovascular diseases; other patients who were not eligible for cystoscopy, such as those suffering from acute cystitis, urethritis, prostatitis, urethral stricture, severe bladder contracture and so on. a total of 41 patients in both groups had undergone transurethral operation with general anesthesia or spinal anesthesia before, such as turp and turbt, while the rest were examined for the first time. the clinical data of the two groups of patients were not statistically significant and hence were comparable. surgical technique control group: 10g of lidocaine gel was injected into the urethra, and the perineal urethra was massaged slightly. the cystoscopy was performed 5 minutes later. experimental group: using a new fr16 catheter (figure 1 and figure 2) for urethral surface anesthesia, and the method is as follows: the catheter is fully lubricated, then inserted into the patient's urethra until it enters the bladder. afterwards, 5ml of physiological saline was injected from the channel⑤ so as to fill the balloon⑤. when gently pulled back, the balloon would be stuck at the bladder neck. 10ml 1% lidocaine solution was further injected into the channel⑤ and the solution gradually overflowed from the small holes⑤ into the prostatic and membranous urethra. 1 minute later, the physiological saline in the balloon was completely withdrawn. and then,the catheter was pulled out slowly while 2 ml of lidocaine solution was injected into the channel⑤ so as to take effect on the mucosa in other area. cystoscopy was performed 5 minutes later. both groups of patients underwent rigid cystoscopy were operated by two urologists. they worked together to confirm that the same procedures were practiced on each group. the amount of bladder perfusion was not more than 200 ml. each cystoscopy was performed with a rigid cystoscope with 22 fr sheet and 30 degree lens. data collection and analysis both groups of patients were evaluated by a specialized nurse using the visual analogue scale (vas) to assess the analgesic effect in urology cystoscopy room. the nurse recorded the vas scores during different moments, i.e, t1: during administration of lidocaine (control group) /during insertion of catheter and administration of lidocaine (experimental group), t2: during the insertion of cystoscope, t3: at the beginning of cystoscopy, t4: the third minute of cystoscopy, t5: during the first urination after the procedure, and the maximum pain score(pmax) experienced by the patient during the whole operation. all the data were accurate to the nearest tenth. the vas scores were: 1-3 for mild pain, 4-6 for moderate pain, 7-9 for severe pain, and 10 for extreme pain. the fluctuations of blood pressure and heart rate before and during the examination were monitored. blood pressure variation = (maximum systolic blood pressure systolic blood pressure at rest before examination) / systolic blood pressure at rest before examination × 100%. heart rate variation = (maximum heart rate static heart rate before examination) / static heart rate before examination × 100%. 24 hours later, the patient was followed up by telephone and asked if he had taken analgesic drugs and developed other complications such as dysuria, urinary retention, and systemic allergy. the patient's required anesthesia costs were calculated separately. all patients were informed and signed consent to participate in the study. randomization was performed by a nurse before the patient went into the operating room. when the preoperative anesthesia was performed by the nurse, the urologists, but not the patient, were informed of which group the patient in. the two doctors did not participate in the randomization, and they were unaware of the study-group assignments. during the operation, both groups of patients were evaluated by another nurse using the visual analogue scale (vas) to assess the analgesic effect. continuous variables are presented as means and standard deviations, and binary variables as numbers and percentages. vas scores of two groups are response variables of multiple paired samples. friedman test was used to compare the vas scores of two groups at different time points. student-t test was used to compare the mean age and operation time. pearson’s chi-square test was used for counts, as appropriate. two-sided p values of less than 0.05 were considered to indicate statistical significance. all calculations were performed with the use of excel 2013 (microsoft), sas software. characteristics control experimental p value mean age, years (sd) 52.2(15.3) 54.0(14.2) 0.29 hematuria(%) 20/122(16.4) 26/130(20.0) 0.34 bladder tumor(%) 31/122(25.4) 28/130(21.5) retrograde ureteral catheterization(%) 13/122(10.7) 20/130(15.4) postoperative re-examinatio(%) 31/122(25.4) 22/130(16.9) urethral stent extraction(%) 27/122(22.1) 34/130(26.2) operation time >3min(%) 77/122(63.1) 68/130(52.3) 0.08 operation time (min) 5.83 ± 0.66 5.19 ± 0.37 0.28 table 1. comparison of patients in experimental and control group abbreviation: sd = standard deviation s control experimental p value t1(sd) 3.02(1.09) 3.44(0.89) 0.21 t2(sd) 4.61(1.82) 3.51(1.48) <0.01 t3(sd) 3.57(1.44) 2.67(0.95) <0.01 t4(sd) 2.96(1.38) 2.07(1.01) <0.01 t5(sd) 1.28(0.76) 1.16(0.59) <0.01 pmax 4.92(1.20) 3.89(0.95) <0.01 abbreviations: sd=standard deviation, vas=visual analogue scale table 2. vas scores of two groups at different time points. a new catheter on relieving pain-yongjiang et al. vol 17 no 03 may-june 2020 313 results a total of 252 male patients were enrolled and underwent randomization from june 2016 to august 2017. the baseline characteristics of the patients were similar in the two groups (table 1). all of them completed the operation without serious complications such as systemic anaphylaxis, induced asthma, urinary retention, hypertensive crisis, severe arrhythmia and other serious adverse reactions. no postoperative analgesic drugs were administered. two patients in each group had urinary frequency and dysuria on the second day after operation,and their urine routine indicated a significant increase in white blood cells. they were cured after oral antibiotic was administered. overall comparison (two-factor repeated measures analysis of variance) showed that there was a significant difference among different time points on vas (p<0.05). except that at t1, the vas score of the control group was slightly lower than that of the experimental group, those of control group at other time points were invariably higher than those of the experimental group (table 2). the pmax vas score of the control group was 4.92(sd = 1.20), which was higher than that of the experimental group with 3.89(sd = 0.95, p < 0.01). the blood pressure variation in control group was 12.9%(sd = 3.7),similar with the experimental group of 11.2%(sd = 3.2, p = 0.12). while heart rate variation in experimental group(16.3%,sd = 3.4) was lower than that in control group(22.6%,sd = 5.0, p < 0.01). as per calculation, the anesthetic cost per patient in the control group was about 3.28 dollars, which was higher than the 1.53 dollars in the experimental group. discussion as a commonly used examination item in urology, cystoscopy can be used to observe the presence of stones, tumors, foreign bodies, and deformities in the bladder and urethra. it can also be used for ureteral retrograde catheterization, retrograde pyeloureterography, ureteral stent extraction, etc. due to the long male urethra, there are three physiological stenoses and flexions. male patients often experience pain during cystoscopy and even fear of examination. the pain caused by cystoscopy is mainly due to(1) the pain caused by the squeezing of the urethra by the endoscope. in the anterior urethra, this pain is mainly caused by the somatosensory afferent nerve, and when the endoscope sheath is inserted into the posterior urethra, it is mixed with the stimulation of the visceral nerves and hence the more severe pain, which cannot be avoided nor be effectively relieved without drug intervention(3). (2) the pain caused by the pulling and stimulation of the visceral nerves, which is a result of the full bladder due to the use of large amount of perfusate(7). this pain can be relieved by improving the operation skills and reducing the intravesical pressure. at present, the commonly applied clinical practice includes general anesthesia, spinal anesthesia, pre-loaded analgesics, urethral surface anesthesia, etc., which are used to relieve pain in patients during cystoscopy(8). for the first two methods, due to their complicated operation, high requirements for cardiopulmonary function, more complications, high cost, etc., it is not easy to be widely used, especially in outpatient patients. pre-treatment pain medications are not sufficiently effective and are accompanied with significant gastrointestinal side effects. the urethral surface anesthesia works by directly acting on the urethral mucosa through local anesthetic drugs, and has the advantages of simple and convenient operation and small side effects. david et al. found that intraurethral instillation of lidocaine gel reduced the likelihood of moderate to severe pain during cystoscopy(9). shahram et al. performed a double-blind, randomized clinical trial in 2016. they concluded that combined glandular lidocaine injection and intraurethral lidocaine gel significantly reduced pain perception after cystoscopy compared to the use of intraurethral lidocaine gel alone(10). however, other scholars demonstrated no benefit from the use of an anesthetic gel in cystoscopy(4). although the debate over the use of lidocaine for urethral surface anesthesia continues, the commonly used clinical methods for perfusion through the external urethral orifice or application of drug to the surface of the sheath cannot take sufficient effect on the posterior urethra, resulting in unsatisfactory pain relief(4-6). poletajew's study of anaesthesia of the posterior urethra indicated that after 6 h patients in the experimental group were more likely to declare that the cystoscopy was painless (81.8% vs.70.2%, relative risk = 1.17)(11). some scholars claim miscellaneous 314 a new catheter on relieving pain-yongjiang et al. figure 1. sketch of the new catheter. the perimeter of the catheter is 14mm and the tip④ is a closed end. there is a non-return valve④ at the end of channel④. figure 2. photo of the new catheter. that flexible cystoscopy, compared with rigid cystoscopy, can reduce pain in patients(12). however, no matter flexible or rigid cystoscope, it will invariably cause significant pain and discomfort when passing through the urethra, especially the posterior urethra(13). neither is flexible cystoscope ideal for relieving the pain of patients. gee gr(14) observed the pain degree of flexible and rigid endoscope examination via vas score, which of flexible endoscope group and rigid group were 1.4 and 1.8 respectively, without significant difference. in addition, flexible cystoscopes are expensive, easily damaged, and unsuitable for beginners. it is more difficult to promote them in basic medical institutions. a simple, easy-to-apply technology that facilitates its promotion among basic medical institutions to enable effective anesthetic agents to act on the entire urethra, especially the posterior urethra, and to minimize patient suffering is thus a subject worthy of exploring. for these reasons, we designed and invented a new type of catheter. the tip of the catheter is a blind end. there are numerous small holes near the distal end of the balloon within 5 cm. the anesthetic agent can evenly act on the posterior urethra through the small holes; the role of the balloon is to close the inner urethra and prevent the anesthetic from rapidly leaking into the bladder so as to extend the drug action time. in this study, the vas score of the control group at t1 was slightly lower than of the experimental group, which may be related to the increased urethral pressure after catheter stimulation of the urethra and insufficient smoothness around the small holes of the catheter due to the technical reasons of the manufacturer, but the difference was not statistically significant. although the patients in the experimental group increased the process of urethral catheterization, the pain caused by the urethral catheterization was very slight and did not cause special discomfort to the patient, the main disadvantage of which was a slight increase the time for anesthesia. while at t2, t3, t4, and t5,the moments when the patients are more sensitive to the pain perceived, the scores of the experimental group were significantly lower than those of the control group, and so was pmax, the maximum pain value during the examination. it is indicated that the anesthetic can be fully applied to the posterior urethra through the new catheter, hence effectively relieve pain in patients with cystoscopy. we also found that in both the experimental group and the control group, the pmax for most patients occurred when the sheath was inserted into the posterior urethra, while for a small proportion of the patients, it occurred in the initial stage of the examination when the endoscope moved in large amplitude. this indicates that the urinary tract stimuli are the most important cause of pain in cystoscopy, as reported by losco g(15). it also shows that although the use of new catheters can significantly reduce the pain of patients, the operation skills are still factors that cannot be ignored(16). most of the patients who underwent cystoscopy were middle-aged or elderly patients and often had hypertension, diabetes, arrhythmia, and atherosclerosis. severe pain can lead to a dramatic increase in blood pressure, heart rate, and even fecal incontinence, triggering cardiovascular events even serious adverse reactions(17). this experiment showed that there was no significant fluctuation in blood pressure between the two groups during the examination, but the heart rate change was lower in the experimental group than that in the control group. this fact not only shows that the analgesic effect of the experimental group is better, but also confirms that the method used in the experimental group is safe and reliable, and has less impact on the cardiovascular function of the patient, hence lower potential risk. in addition, the new catheter used in the experimental group is simple and novel in design, low in cost, and can reduce the economic burden of patients to some extent. we know that our study have limitations about the lack of smoothness around the small holes of the catheter. so it is necessary to improve the technical process after communicating with the manufacturer to avoid bias and to obtain a definitive conclusion. conclusions application of this new catheters can effectively relieve pain in the cystoscopy of male patients. the operation is simple and convenient, and it is safe and economical. it is worthy of promotion and adoption in the majority figure 3. patients’ enrolment algorithm. a new catheter on relieving pain-yongjiang et al. vol 17 no 03 may-june 2020 315 of primary medical institutions. acknowledgement this study was sponsored by a grant from the chongqing health and family planning commission(no:2016msxm055).we thank dr zhang xuan,dr zhao dejian,dr luo huaming,dr zhang jiamo for their dedicated work;ms wei chunqi and ms wang hongmei for preparatory work and logistics;mr liu ming and ms qi li for assistance with statistical analysis. conflict of interest we declare that we have no conflicts of interest. references 1. stein m, lubetkin d, taub hc, skinner wk, haberman j, kreutzer er. the effects of intraurethral lidocaine anesthetic and patient anxiety on pain perception during cystoscopy. j urol. 1994;151:1518-21. 2. greenstein a, greenstein i, senderovich s, mabjeesh nj. is diagnostic cystoscopy painful? analysis of 1,320 consecutive procedures. int braz j urol. 2014;40:533-8. 3. taghizadeh ak, el madani a, gard pr, li cy, thomas pj, denyer sp. when does it hurt? pain during flexible cystoscopy in men. urol int. 2006;76:301-3. 4. cano-garcia mdel c, casares-perez r, arrabal-martin m, merino-salas s, arrabalpolo ma. use of lidocaine 2% gel does not reduce pain during flexible cystoscopy and is not cost-effective. urol j. 2015;12:2362-5. 5. kobayashi t, nishizawa k, mitsumori k, ogura k. instillation of anesthetic gel is no longer necessary in the era of flexible cystoscopy: a crossover study. j endourol. 2004;18:483-6. 6. matsuda d, irie a, shimura s, et al. [uncertain analgetic efficacy of intraurethral instillation of anesthetic jelly in rigid cystoscopy for men]. nihon hinyokika gakkai zasshi. 2005;96:617-22. 7. hanno pm, wein aj. anesthetic techniques for cystoscopy in men. j urol. 1983;130:10702. 8. palit v, ashurst hn, biyani cs, elmasray y, puri r, shah t. is using lignocaine gel prior to flexible cystoscopy justified? a randomized prospective study. urol int. 2003;71:389-92. 9. aaronson ds, walsh tj, smith jf, davies bj, hsieh mh, konety br. meta-analysis: does lidocaine gel before flexible cystoscopy provide pain relief? bju int. 2009;104:506-9; discussion 9-10. 10. gooran s, pourfakhr p, bahrami s, et al. a randomized control trial comparing combined glandular lidocaine injection and intraurethral lidocaine gel with intraurethral lidocaine gel alone in cystoscopy and urethral dilatation. urol j. 2017;14:4044-7. 11. poletajew s, bender s, pudelko p, et al. anaesthesia of the posterior urethra and pain reduction during cystoscopy a randomized controlled trial. wideochir inne tech maloinwazyjne. 2017;12:75-80. 12. choe jh, kwak kw, hong jh, lee hm. efficacy of lidocaine spray as topical anesthesia for outpatient rigid cystoscopy in women: a prospective, randomized, doubleblind trial. urology. 2008;71:561-6. 13. cano-garcia mdel c, casares-perez r, arrabal-martin m, merino-salas s, arrabalpolo ma. [perception of pain in flexible cystoscopy using intraurethral lidocaine]. arch esp urol. 2016;69:207-11. 14. gee jr, waterman bj, jarrard df, hedican sp, bruskewitz rc, nakada sy. flexible and rigid cystoscopy in women. jsls. 2009;13:135-8. 15. losco g, antoniou s, mark s. male flexible cystoscopy: does waiting after insertion of topical anaesthetic lubricant improve patient comfort? bju int. 2011;108 suppl 2:42-4. 16. chen yt, hsiao pj, wong wy, wang cc, yang ss, hsieh ch. randomized doubleblind comparison of lidocaine gel and plain lubricating gel in relieving pain during flexible cystoscopy. j endourol. 2005;19:163-6. 17. goldfischer er, cromie wj, karrison tg, naszkiewicz l, gerber gs. randomized, prospective, double-blind study of the effects on pain perception of lidocaine jelly versus plain lubricant during outpatient rigid cystoscopy. j urol. 1997;157:90-t4. miscellaneous 316 a new catheter on relieving pain-yongjiang et al. sexual dysfunction and infertility 199urology journal vol 6 no 3 summer 2009 pattern of compensatory hypertrophy in contralateral testis after unilateral orchiectomy in immature rabbits kamyar tavakkoli tabassi,1 sakineh amoueian,2 elena saremi3 introduction: our aim was to evaluate effects of hemicastration in immature rabbits on the histology of the contralateral testis after puberty. materials and methods: eighteen immature male rabbits were randomly divided into two groups. the first group underwent right or left hemicastration and the second, sham operation. after their puberty, the rabbits underwent the second operation. in the former group the contralateral testis and in the latter, the right or left testis was removed and sent for pathologic examination. the two groups were compared in terms of leydig cell count, testis volume, and seminiferous tubule count and diameter. results: the mature rabbits’ mean weight at the orchiectomy time, seminiferous tubule count, and seminiferous tubules diameter did not show significant differences between two groups. however, testis volumes and leydig cell count were significantly higher in the first group with hemicastration prior to puberty. the mean testis volume was 3.24 ± 2.06 ml in the first group and 1.4689 ± 0.85701 ml in the second group (p = .03), and the mean leydig cell count in every 5 microscopic high-power fields was 86.22 ± 54.96 and 42.00 ± 18.09, respectively (p = .04). conclusion: our research demonstrated that prepubertal hemicastration in rabbits led to the compensatory hypertrophy in the contralateral testis after puberty and an increase in the number of the leydig cells. urol j. 2009;6:199-203. www.uj.unrc.ir keywords: orchiectomy, rabbits, testis, leydig cells, seminiferous tubules 1department of urology, imamreza hospital, mashhad university of medical sciences, mashhad, iran 2department of pathology, imamreza hospital, mashhad university of medical sciences, mashhad, iran 3department of surgery, imamreza hospital, mashhad university of medical sciences, mashhad, iran corresponding author: kamyar tavakkoli tabassi, md department of urology, imam-reza hospital, mashhad, iran tel: +98 915 311 6149 e-mail: kamiartt@yahoo.com received march 2009 accepted july 2009 introduction the testicular volume consists mainly of seminiferous tubules, where spermatogenesis completes, and the leydig cells (5% to 12%), which have the role of originating the testosterone.(1,2) different circumstances such as trauma, testicular torsion, tumors, undescended testis, and congenital anorchia may result in testicular vanishing at different years of age. the effects of a vanished testis on the morphologic and functional factors of the other one, in proportionate to its vanishing age, has been the point of concern. however, respecting the ethics of human rights, studies on this issue has been done on animals. functional compensation of the remnant testis after hemicastration has been investigated in rats, rabbits, sheep, pigs, and cattle.(3-10) in rats, sheep, pigs, and cattle, it has been reported that hemicastration in prepubertal period causes hypertrophy of the contralateral testis.(3,8-10) hemicastration in mature rats does not cause contralateral hypertrophy after orchidectomy—tavakkoli tabassi et al 200 urology journal vol 6 no 3 summer 2009 hypertrophy of the remnant testis,(3) but it does in sheep.(7) according to mombeini and colleagues, hemicastration in mature rabbits does not cause hypertrophy of the contralateral testis.(11) in two other studies on prepubertal rabbits, there are different results about hemicastration effects on the contralateral testis, one eventuates in hypertrophy of the contralateral testis,(12) whereas the other one does not.(5) based on the aforementioned facts, we decided to evaluate the hemicastration effects on the histology of the contralateral testis in immature rabbits. material and methods animals and castration this study was supplied with 18 immature male albino rabbits (20 to 25 days old) by razi institution. the study protocol was approved by the ethical committee of mashhad university of medical sciences. the immaturity of the rabbits was confirmed by one veteran based on the examination of the undescended testes. the rabbits were randomly divided into 2 groups of case and control. in the case group, right or left hemicastration was performed randomly and the specimens were sent for pathologic examination. immature testicular pattern was confirmed on the examinations. general anesthesia was done with xylazine, 5 mg/kg, and ketamine, 44 mg/ kg, and complemented with local anesthesia using lidocaine. unilateral castration was performed through a scrotal incision with an abdominal extension on the covert testis. in the control group, sham operation was performed, consisting of a scrotal incision and its simple repair. all of the rabbits were hospitalized after the operations in the same environmental situation. the rabbits’ room temperature was kept between 13°c and 19°c. they were fed by their routine nourishments in the animal house center. then, the rabbits underwent the second operation after their onset of puberty, 4 months after the first operation. the remnant testis in the case group and the right or the left testis in the control group was hemicastrated. the specimens were embedded in paraffin, fixed immediately by immersion in 10% boan, and sent for pathology examination. at the end of the study, all of the animals were scarified by administration of high doses of anesthetic drugs. pathology examination first, testis length and width were measured using a laboratory clippers and testis volume was calculated using the formula for a prolate sphere (4.19 × a × b2, where a is the longest radius and b, the shortest radius). for enumeration of the seminiferous tubules on the tissue sections, 2 serial sections were cut with microtome from each of the paraffin blocks per testis (thickness, 3 μm to 4 μm). they were stained with periodic acid-schiff reagent and counterstained with harris hematoxylin. the fields for microscopic examination were selected randomly. the leydig cells and the seminiferous tubules were counted in 20 and 10 random high-power field of microscope, respectively, and then, the average values were determined. for measuring the diameters of the tubules, a micrometer was used located on the objective lens of microscope. statistical analyses statistical analyses were performed using the spss software (statistical package for the social sciences, version 16.0, spss inc, chicago, illinois, usa). the data were expressed as mean ± standard deviation. according to the kolmogorov-smirnov test our variables had normal distribution. the two groups were compared in terms of leydig cell count, mean diameter, seminiferous tubules count, testis volume, and rabbit’s weight, using independent sample t test for continuous variables and the chisquare test for categorical variables. a p value of less than .05 was considered significant. results the pathological assessments of the immature rabbits’ testes showed no spermatogenesis in all the 9 specimens and thereby immature patterns of the testes obtained from the case group (figure 1). four months after the first operation, the body weight of the mature rabbits at the orchiectomy time was 1731.22 ± 77.79 mg and 1705.56 ± 124.81 contralateral hypertrophy after orchidectomy—tavakkoli tabassi et al urology journal vol 6 no 3 summer 2009 201 mg in the case and the control groups, respectively (p = .61). changes in the testes parameters after hemicastration in comparison with those in the control group were as follows: the mean testis volume was 3.24 ± 2.06 ml in the case group and 1.4689 ± 0.85701 ml in the control group (p = .03). the mean leydig cell count in every 5 microscopic high-power fields was 86.22 ± 54.96 and 42.00 ± 18.09, respectively in the case and the control group (p = .04; figures 2 and 3). the mean seminiferous tubules count in the case group was 22.56 ± 6.37 and 28.11 ± 8.02 in the control group (p = .12; figures 2 and 3). the mean seminiferous tubules diameter in the case group was 160.00 ± 46.90 μm and 150.00± 7.817 μm in the control group (p = .58). discussion the effects of unilateral castration on the histological factors of the contralateral testis and also the hormonal changes in men have drawn researchers’ attention. they have tried to find the answer by considering various ages of hemicastration in different animal species. after puberty in the majority of the studied species, hemicastration resulted in compensatory hypertrophy of the contralateral testis. this fact was fully demonstrated in those studies performed on dogs and rabbits.(11,12) in the study by mombeini and colleagues, 10 mature rabbits were unilaterally castrated, and after puberty, the contralateral testis was castrated. testes weight and histological parameters were compared to the formerly castrated ones. owing to the fact that there were not any significant differences in leydig cell count and size of the seminiferous tubules, it was concluded that a testis did not have evidently the potential ability of compensatory hypertrophy after puberty.(11) hemicastration effects before maturity presented different consequents. various investigations on rats, lambs, pigs, cattle, and dogs have demonstrated that unilateral castration before puberty leads up to the compensatory hypertrophy in the contralateral testis after puberty.(3,10,13-22) however, it has not been always the same in those studies performed on rabbits. sanefuji reported a double increase in seminiferous tubules count and testis figure 1. testis of an immature rabbit (harris hematoxylin, × 100). figure 2. testis of a rabbit 4 months after hemicastration of the contralateral testis (harris hematoxylin, × 40). figure 3. testis of a mature rabbit in the control group (harris hematoxylin, × 100). contralateral hypertrophy after orchidectomy—tavakkoli tabassi et al 202 urology journal vol 6 no 3 summer 2009 weight of the contralateral testis 4 weeks after hemicastration in immature rabbits.(12) in contrast, berger and coworkers’ study showed no hypertrophy in the contralateral testis of 1to 50-day-old rabbits after hemicastration; however, the authors did not give the contralateral testes enough time, ie, 10 days, for any probable hypertrophy.(6) similarly in another investigation, 30 male rabbits were divided into 5 separate groups, whereby no operation was performed on one of the groups, and the rest were hemicastrated at the ages of 35, 49, 77, and 105 days. in all the rabbits the contralateral testis was castrated at the age of 8 months to be evaluated.(5) this investigation, as well, did not show any significant differences between the testis parameters; eg, mean testis weight of 3.53 in hemicastrated rabbits at the age of 35 days compared to 2.52 in those in the control group. hence, the compensated hypertrophy was doubtful. sham operation, however, was not done on the first group and each of groups consisted of only 6 rabbits. therefore, we decided to give the testes more time for any possible changes. thus, the results were significant in our study, similar to other animal-based studies, demonstrating compensatory hypertrophy of the contralateral testis in hemicastrated immature rabbits. during prepubertal development in most animal species, normal testicular growth is associated with dramatic proliferation of the leydig cells in the interstitium and an increased number of the sertoli and germ cells within the seminiferous epithelium.(1,23-25) in most species, compensatory hypertrophy has been associated with increased diameter and length of the seminiferous tubes and increased number of the germ cells and sertoli cells.(9, 26-30) thus, the proliferation response to prepubertal unilateral castration is often used as a model for studying those factors influencing testicular development. although neither the number nor the diameter of the seminiferous tubes had a significant change in our study, the enlargement of the seminiferous length is possible due to an increase of the remaining testis volume. changes in the leydig cells are less discussed in compensatory hypertrophied testis of hemicastrated rabbits. in a study performed on boars, increased number of leydig cell and total leydig cell mass in compensatory hypertrophied testes was demonstrated; the younger the age at hemicastration, the more obvious increase in the number of leydig cells.(31) in our study, increase in leydig cell count in every 5 light microscopic high-power field of testis samples, and therefore, in the total testis mass was an integral part of hypertrophied rabbit’s testis. however, we could not measure the hormonal levels and also the insulin-like growth factor, which would help us better interpret our findings. conclusion our research demonstrated that prepubertal hemicastration in rabbits led to the compensatory hypertrophy in the contralateral testis after puberty. this process includes at least the increase in leydig cell count and testis volume. conflict of interest none declared. references 1. christensen ak. leydig cells. in: hamilton dw, greep ro, editors. handbook of physiology. baltimore: american physiological society, william & wilkins; 1975. p. 57-94. 2. kaler lw, neaves wb. attrition of the human leydig cell population with advancing age. anat rec. 1978;192:513-8. 3. cunningham gr, tindall dj, huckins c, means ar. mechanisms for the testicular hypertrophy which follows hemicastration. endocrinology. 1978;102:1623. 4. furuya t. onset of compensatory hypertrophy of interstitial tissue and leydig cells in rats hemicastrated around the time of puberty. biol reprod. 1990;42:491-8. 5. thompson tl, berndtson we. testicular weight, sertoli cell number, daily sperm production, and sperm output of sexually mature rabbits after neonatal or prepubertal hemicastration. biol reprod. 1993;48:952-7. 6. berger m, jean-faucher c, de turckheim m, veyssiere g, jean c. the effect of unilateral castration on plasma and testicular testosterone in rabbits from birth to 60 days. arch int physiol biochim. 1978;86:799-808. 7. hochereau-de reviers mt, loir m, pelletier j. seasonal variations in the response of the testis and lh levels to hemicastration of adult rams. j reprod fertil. 1976;46:203-9. contralateral hypertrophy after orchidectomy—tavakkoli tabassi et al urology journal vol 6 no 3 summer 2009 203 8. waites gm, wenstrom jc, crabo bg, hamilton dw. rapid compensatory hypertrophy of the lamb testis after neonatal hemiorchidectomy: endocrine and light microscopical morphometric analyses. endocrinology. 1983;112:2159-67. 9. kittok rj, kinder je, johnson rk. effect of castration on plasma luteinizing hormone concentrations in prepubertal boars. j anim sci. 1984;58:1271-7. 10. schanbacher bd, fletcher pw, reichert le, jr. testicular compensatory hypertrophy in the hemicastrated calf: effects of exogenous estradiol. biol reprod. 1987;36:1142-8. 11. mombeini h, mosapour s, aghaee a. [the evaluation of hormonal and histologic changes in contralateral testis after unilateral orchidectomy in white rabbits]. iran j urol. 2001;29:29-33. persian. 12. sanefuji t. [tissue culture studies on compensatory testicular hypertrophy of the young rabbit after hemicastration]. hinyokika kiyo. 1988;34:585-91. japanese. 13. orth jm, higginbotham ca, salisbury rl. hemicastration causes and testosterone prevents enhanced uptake of [3h] thymidine by sertoli cells in testes of immature rats. biol reprod. 1984;30:263-70. 14. brown jl, dahl kd, chakraborty pk. effects of follicular fluid administration on serum bioactive and immunoactive fsh concentrations and compensatory testicular hypertrophy in hemicastrated prepubertal rats. j endocrinol. 1991;130:207-12. 15. brown jl, chakraborty pk. comparison of compensatory pituitary and testicular responses to hemicastration between prepubertal and mature rats. j androl. 1991;12:119-25. 16. brown jl, schoenemann hm, chakraborty pk. follicular fluid administration delayed, but did not prevent, the hemicastration-induced increase in follicle-stimulating hormone secretion and compensatory testicular hypertrophy in ram lambs. biol reprod. 1994;50:44-8. 17. walton js, evins jd, hillard ma, waites gm. follicle-stimulating hormone release in hemicastrated prepubertal rams and its relationship to testicular development. j endocrinol. 1980;84:141-52. 18. walton js, evins jd, waites gm. feedback control of follicle-stimulating hormone in pre-and postpubertal rams as revealed by hemicastration. j endocrinol. 1978;77:75-84. 19. hochereau-de reviers mt, blanc mr, courot m, gamier dh, pelletier j, poirier jc. hormonal profiles and testicular parameters in the lamb. in: steinberger a, steinberger e, editors. testicular development, structure, and function. new york: raven press; 1980. p. 237-47. 20. brown jl, stuart ld, chakraborty pk. endocrine profiles, testicular gonadotropin receptors and sperm production in hemi-castrated ram lambs. j anim sci. 1987;65:1563-70. 21. mirando ma, hoagland ta, woody co, jr., riesen jw. the influence of unilateral castration on testicular morphology and function in adult rams. biol reprod. 1989;41:798-806. 22. tsutsui t, kurita a, kirihara n, hori t, kawakami e. testicular compensatory hypertrophy related to hemicastration in prepubertal dogs. j vet med sci. 2004;66:1021-5. 23. sharpe rm, walker m, millar mr, et al. effect of neonatal gonadotropin-releasing hormone antagonist administration on sertoli cell number and testicular development in the marmoset: comparison with the rat. biol reprod. 2000;62:1685-93. 24. mccoard sa, lunstra dd, wise th, ford jj. specific staining of sertoli cell nuclei and evaluation of sertoli cell number and proliferative activity in meishan and white composite boars during the neonatal period. biol reprod. 2001;64:689-95. 25. johnson l. increased daily sperm production in the breeding season of stallions is explained by an elevated population of spermatogonia. biol reprod. 1985;32:1181-90. 26. voglmayr jk, mattner pe. compensatory hypertrophy in the remaining tests following unilateral orchidectomy in the adult ram. j reprod fertil. 1968;17:179-81. 27. boockfor fr, barnes ma, kazmer gw, halman rd, bierley st, dickey jf. effects of unilateral castration and unilateral cryptorchidism of the holstein bull on plasma gonadotropins, testosterone and testis anatomy. j anim sci. 1983;56:1376-85. 28. kosco ms, loseth kj, crabo bg. development of the seminiferous tubules after neonatal hemicastration in the boar. j reprod fertil. 1989;87:1-11. 29. orth jm. the role of follicle-stimulating hormone in controlling sertoli cell proliferation in testes of fetal rats. endocrinology. 1984;115:1248-55. 30. hochereau-de reviers mt, land rb, perreau c, thompson r. effect of season of birth and of hemicastration on the histology of the testis of 6-month-old lambs. j reprod fertil. 1984;70:157-63. 31. lunstra dd, wise th, ford jj. sertoli cells in the boar testis: changes during development and compensatory hypertrophy after hemicastration at different ages. biol reprod. 2003;68:140-50. vol 16 no 01 january-february 2019 37 urological oncology a comparison of eortc and cueto risk tables in terms of the prediction of recurrence and progression in all non-muscle-invasive bladder cancer patients ayhan dalkilic1, göksel bayar2, muhammet fatih kilinc3* purpose: to compare the prediction accuracy of the european organization for research and treatment of cancer (eortc) and the spanish urology association for oncological treatment (cueto) risk tables in all non-muscle invasive bladder cancer patients. material and methods: recurrence and progression-free survival of all patients were assessed according to the eortc and the cueto risk tables for each patient and the concordance index was used to indicate discriminative ability. statistical analyses were performed, at 1 and 5 years, to the whole group and separately to those treated or not treated with bacillus calmette-guerin (bcg) . results: the study included 400 patients. one-year bcg maintenance therapy was applied to 181 patients (45.3%). the recurrence rate was higher than in cueto, and similar to eortc. the eortc was determined to provide better discrimination than cueto in the whole patient group and in those treated or not treated with bcg. the concordance indices for these groups were 0.777, 0.705; 0.773, 0.669; and 0.823, 0.758, respectively . the progression rate was similar in this study to the rate defined in both risk tables. the discrimination power was similar in eortc and cueto for all the groups. the concordance indices were 0.801, 0.881; 0.915, 0.930; and 0.832, 0.806, respectively. conclusion: the eortc has more power than cueto to discriminate each recurrence risk group and both risk tables can successfully discriminate progression risk groups in all patients. keywords: cueto; eortc; progression; recurrence; bladder cancer; non-muscle invasive introduction in developed countries, bladder cancer is the sixth most common cancer in males and the seventeenth most common cancer in females (1). it is the most common malignancy of the urinary tract(2). nearly 80% of urothelial carcinoma of the bladder presents as non-muscle-invasive bladder cancer (nmibc). however, 70-80% of cases with nmibc recur after transurethral resection of the bladder tumor (turb), and 20-30% of patients progress to muscle-invasive cancer, despite additional intravesical chemotherapy or immunotherapy(3). risk tables can be used for the prediction of recurrence and especially progression(4). the european organization for research and treatment of cancer (eortc) developed a risk table, which provides a scoring system for recurrence and progression risk. the eortc risk table includes these factors: number of tumors, tumor size, prior recurrence rate, t stage, presence of carcinoma in situ (cis), and grade for nmibc patients not treated by maintenance bacillus calmette-guerin (bcg) instillation therapy(5). the spanish urology association for oncological treatment (cueto) later 1department of urology, sisli hamidiye etfal training and research hospital, istanbul, turkey. 2department of urology, idil state hospital , sirnak, turkey. 3department of urology, ankara training and research hospital, ankara, turkey. *correspondence: ankara training and research hospital, 06340, ankara, turkey phone/fax: +90 312 595 3724 / +90 312 363 3396. e-mail: mdfatihkilinc@yahoo.com. received august 2017 & accepted january 2018 proposed a modified model to be used for patients only treated with bcg instillation. this risk tables includes these factors: age, gender, recurrent tumor, number of tumors, t stage, cis, and grade(6). although there is a new eortc risk table that can be used for nmibc patients treated with bcg, it is not yet in routine use in general practice(7). the rationale of this study was to evaluate the power of eortc and cueto risk tables on all patients who had undergone all the necessary stages in current practice, including maintenance bcg, single-dose immediate intravesical chemotherapy and second-look turb. the main aim of this study was to compare the utility of the eortc and cueto risk tables in all patients, and separately in patients treated or not treated with bcg. patients and methods study population and design a retrospective analysis was made of data from 491 patients who had undergone turb for primary or recurrent bladder cancer and received a histopathological diagnosis as non-muscle invasive bladder cancer, at a single institution between 2007 and 2016. the study was retrospective but was based on a prospective cohort study, which means that most patients underwent more than one turb procedure between 2007-2016. the patient database screening was begun prospectively from january 2007. therefore, turb data which was closest to january 2007 were recorded as patient characteristics, and other turb records (histopathologically proven) were accepted as recurrence or progression. patients were excluded from the study if they had primary cis, were upgraded to muscle-invasive disease after second-look turb, had non-urothelial carcinoma of the bladder, concomitant upper urinary tract tumor, or could not be contacted for whatever reason. this trial is registered with clinicaltrials.gov, number nct03174912. surgery and after surgery procedure patients diagnosed with primary or recurrent bladder cancer were treated with turb, and were staged according to the 2002 tnm classification and the 1973 world health organization grading system. one single immediate intravesical instillation of chemotherapy with mitomycin-c was administered in all cases by the operating urologist when there were no contraindications. second-look turb was performed 2-6 weeks after the first turb to patients with pathological stage t1 or grade 3, or initial incomplete turb. bcg induction and maintenance therapy of at least one year was applied to patients with one of t1, grade-3, or cis or all the factors of multiple, recurrent, large tumor (>3cm). no intravesical induction or maintenance therapy was given to patients with no risk factors. intravesical chemotherapy, mitomycin-c 6-weekly, were also applied to patients with one or two risk factors that were not high risk (large, multiple or recurrent tumor). bcg treatment was not applied to some patients who were high risk due to adverse effects, or had contraindications to bcg medication or on patient request. patients were evaluated every 3 months during the first 2 years, and every 6 months thereafter with cystoscopies, cytology, and if necessary, biopsy or turb. upper urinary tract assessment was performed to all intermediate and high-risk patients annually. pathological investigations were made by a uropathologist at a single-center and the review pathology investigation was made by the same pathologist. patients were followed up for at least 60 months if progression was not determined. outcome assessment recurrence was defined as non-muscle invasive or muscle invasive and progression as muscle-invasive tumor determined from cystoscopy and turb and then proven histopathologically. the primary end point for recurrence was accepted as the occurrence of the first recurrence or progression. the primary end point for progression was accepted as occurrence of progression. follow-up was continued in terms of progression for patients with a recurrent tumor. surveillance data were also obtained, including pathologically proven recurrence or progression, and the time to first recurrence or muscle-invasive cancer, which was defined as the time period between the date of initial diagnosis and the date of recurrence or progression. patients without recurrence were evaluated at the time of the last cystoscopy for recurrence analysis and those without recurrence were evaluated at the time of the last cystoscopy for progression. patients known to have died from causes unrelated to all patients patients not treated with bcg patients treated with bcg p value number of patients (n) 400 219 (54.8%) 181 (45.2%) age (years) <6 146 (36.5%) 84 (38.4%) 62 (34.2%) 0.366 60-70 142 (35.5%) 71 (32.4%) 71 (39.2%) >70 112 (28%) 64 (29.2%) 48 (26.5%) gender male 327 (81.7%) 179 (81.7%) 148 (81.8%) 0.993 female 73 (18.3%) 40 (18.3%) 33 (18.2%) prior recurrence rate primary 223 (55.7%) 127 (58%) 96 (53%) 0.043 ≤1/ year 95 (23.7%) 57 (26%) 38 (21%) >1/ year 82 (20.6%) 35 (16%) 47 (26%) number of tumors 1 231 (57.8%) 132 (60.3%) 99 (54.7%) 0.063 2-3 49 (12.3%) 28 (12.8%) 21 (11.6%) 4-7 41 (10.2%) 25 (11.4%) 16 (8.8%) >7 79 (19.7%) 34 (15.5%) 45 (24.9%) tumor size ≤3 cm 183 (45.8) 109 (49.8) 74 (40.9%) 0.076 >3 cm 217 (54.2) 110 (50.2) 107 (59.1%) t stage ta 170 (42.5) 101 (46.1) 69 (38.1%) 0.107 t1 230 (57.5) 118 (53.9) 112 (61.9%) grade 1 36 (9%) 18 (8.2%) 18 (10%) 0.184 2 177 (44.3%) 106 (48.4%) 71 (39.2%) 3 187 (46.7%) 95 (43.4%) 92 (50.8) carcinoma in situ yes 32 (8%) 9 (4%) 23 (12.8%) 0.002 no 368 (92%) 210 (96%) 158 (87.2%) single dose mitomycin-c yes 365 (91.2%) 205 (93.6%) 160 (88.4%) .066 no 35 (8.8%) 14 (6.4%) 21 (11.6%) table 1. patients’ characteristics. eortc versus cueto in all nmibc-dalkilic et al. urological oncology 38 vol 16 no 01 january-february 2019 39 bladder cancer were excluded from the analysis. statistical analysis was performed separately on the whole patient group, and patients treated or not treated with bcg. the patients in the current study were classified into four groups according to the eortc and cueto risk tables. this classification was performed by one urologist and confirmed by a different urologist. the time to first recurrence and progression was determined for each risk group. a kaplan-meier survival analysis plot was generated for cumulative recurrence and progression analysis. the probabilities of 1 and 5-year cumulative incidence were analyzed with a 95% confidence interval (ci). cumulative incidence probability results were divided into three groups. the first group was the probability results equal to the original risk tables with one standard deviation (sd), the second group was with two sd. the third group was the probability results lower or higher than the risk tables with two sd. the concordance index (c index) was applied after multinomial logistic regression analysis. a value of p < .05 was accepted as statistically significant. spss 17 package software for windows (chicago, il) was used for all statistical processes. table 2. comparison of expected outcome in terms of recurrence according to the eortc and cueto risk tables scoring versus observed outcomes in the current study. recurrence rate at 1 year (95% ci) recurrence rate at 5 years (95% ci) risk all patients not patients treated risk all patients not patients treated tables patients treated with bcg with bcg tables patients treated with bcg with bcg eortc recurrence groups i (0) 15 (10-19) 0 0 * 31 (24-37) 11 (4-17) 22 (18-26) * ii (1-4) 24 (21-26) 19 (15-24) 19 (15-24) 19 (15-24) 46 (42-49) 60 (54-65) 52 (47-57) 69 (63-75) iii (5-9) 38 (35-41) 47 (42-52) 48 (44-52) 46 (41-51) 62 (58-65) 80 (72-87) 76 (70-81) 85 (75-94) iv (10-17) 61 (55-67) 76 (70-81) 81 (74-88) 70 (62-77) 78 (73-84) 94 (88-99) 92 (85-99) 97 (92-99) concordance index 0.777 0.773 0.823 cueto recurrence groups i (0-4) 8 (6-10) 27 (20-33) 29 (21-37) 24 (16-31) 21 (17-25) 63 (53-72) 60 (55-65) 66 (57-75) ii (5-6) 12 (8-16) 44 (36-51) 47 (37-57) 39 (33-45) 36 (29-42) 78 (69-77) 76 (70-81) 80 (72-88) iii (7-9) 25 (20-31) 64 (56-71) 67 (56-77) 62 (55-68) 48 (41-55) 85 (78-92) 76 (70-81) 93 (84-99) iv (10-16) 42 (28-56) 46 (36-55) 60 (54-65) 38 (31-45) 68 (54-82) 85 (75-93) 80 (75-85) 88 (80-95) concordance index 0.705 0.669 0.758 green: outcomes of reference studies, dark blue: outcomes are equal with one standard deviation, light blue: outcomes are equal with two standard deviations, red: outcomes are not equal with two standard deviations (*: there is no patient to analyze). figure 1. kaplan-meier survival curves of risk of recurrence according to the eortc (a) and cueto risk tables (b), risk of progression according to the eortc (c), and cueto risk tables (d) of all patients. in the recurrence analysis, the eortc model (1a) showed a significant difference in all groups (p <.001), but in the cueto model (1b), the groups showed a significant difference except between groups with scores of 7-9 and 10-16 (p = .45). in the progression analysis, eortc (1c) and cueto (1d) showed a significant difference (p < .001). figure 2. kaplan-meier survival curves of risk of recurrence according to the eortc (a) and cueto risk tables (b), risk of progression according to the eortc (c), and cueto risk tables (d) of patients not treated with bcg. in the recurrence analysis, the eortc model (fig 2a) showed a significant difference in all groups (p < .001), but in the cueto model (fig 2b), a significant difference was seen only between patients with 0-4 score and the others (p < .001). in the progression analysis, both risk tables showed a significant difference (p < .001) in all groups except the groups with 0 and 2-6 scores for eortc (2c) and groups with 0-4 and 5-6 for cueto (2d). eortc versus cueto in all nmibc-dalkilic et al. results of a total 491 patients, 400 patients were included in this study after exclusion of 91 patients because of lack of follow-up (n=14), incomplete data (n=16), concomitant upper urothelial tract carcinoma (n=6) or detection of invasive carcinoma on second-look tut-bt (n=55). second-look turb was performed on 268 patients, and the final pathology was reported as non-invasive carcinoma in 55 patients who were then excluded from the study. the overall mean follow-up period of the whole patient group was 60.6 ± 27.6 months and for patients not determined with progression,70.2 ± 14.3 months. the mean age of the patients was 63.7 ± 10.8 years (range: 23-91 years). immediate post-operative single dose mitomycin-c instillation was applied to 365 (91.2%) patients. bcg therapy of 6-week induction and 1-year maintenance was applied to 181 patients (45.3%). intravesical instillation treatment of mitomycin-c was applied to 124 patients (31%) at 6-week intervals. no intravesical therapy except the single dose post-operative instillation of mitomycin-c was applied to 95 patients (23.8%). the distribution of the numbers of patients in terms of risk factors according to eortc and ceuto is shown in table 1. the prior recurrence frequency (p = .043) and cis (p = .002) rates were significantly different in the two groups of bcg treated or not treated. the number of the patients who did not receive single dose mitomycin-c was similar in the two groups. the 1 and 5-year rates for recurrence and progression of the eortc and cueto risk tables and the results obtained in this study with these rates are shown in tables 2 and 3. the tables are colored according to the proximity of the data obtained in this study with the data of the reference risk tables. recurrence analyze recurrence occurred in 154 (38.5%) and 285 (71.3%) of all patients in the 1 and 5-year follow-up periods respectively. the recurrence rates of all the risk groups according to the eortc and cueto risk tables in all patients are shown in table 2. figures 1a and 1b show cumulative hazard curves for each of the four groups for the time to recurrence using eortc and cueto in all the patients. the number of patients not treated with bcg was 219 (54.8%). recurrence occurred in 88 (40.2%) and 147 (67.1%) of all patients not treated with bcg in the 1 and 5-year follow-up periods respectively. figures 2a and 2b show cumulative hazard curves for each of the four groups for the time to recurrence using eortc and cueto in the patients not treated with bcg. the number of patients treated with bcg was 181 (45.2%). recurrence occurred in 66 (36.5%) and 138 (76.2%) of all patients treated with bcg in the 1 and 5-year follow-up periods respectively. figures 3a and 3b show cumulative hazard curves for each of the four groups for the time to recurrence using eortc and cueto in the patients treated with bcg. progression analyze progression occurred in 50 (12.5%) and 116 (29%) of all patients in the 1 and 5-year follow-up periods respectively. the progression rates of all the risk groups according to the eortc and cueto risk tables in all patients are shown in table 3. figures 1c and 1d show the cumulative hazard curves of each of the four groups for the time to progression using eortc and cueto in all the patients. progression occurred in 19 (8.7%) and 59 (26.9%) of all patients not treated with bcg in the 1 and 5-year follow-up periods respectively. figures 2c and 2d show the cumulative hazard curves of each of the four groups for the time to progression using eortc and cueto in the patients not treated with bcg. progression occurred in 31 (17.1%) and 57 (31.5%) of all patients treated with bcg in the 1 and 5-year follow-up periods respectively. figures 3c and 3d show the cumulative hazard curves of each of the four groups for the time to progression using eortc and cueto in the patients treated with bcg. discussion in the current study, the recurrence rates may be high, but when patients were grouped according to the points of the eortc risk table, it was observed that as the risk increased so the recurrence rate directly increased (figures 1a, 2a, 3a). in contrast, just as the recurrence predictions in the cueto risk table were not compatible with those of the current study, no clear difference was observed between the four groups in the classification table 3. comparison of expected outcome in terms of progression.according to the eortc and cueto risk tables scoring versus observed outcomes in the current study progression rate at 1 year (95% ci) progression rate at 5 years (95% ci) risk all patients not patients treated risk all patients not patients treated tables patients treated with bcg with bcg tables patients treated with bcg with bcg eortc progression groups i (0) 0.2 (0-0.7) 0 0 * 0.8 (0-1.7) 0 0 * ii (2-6) 1.0 (0.4-1.6) 7.4 (3-12) 2 (1-3) 14 (10-18) 6 (5-8) 8 (4-11) 2 (0.5-3.5) 16 (12-20) iii (7-13) 5 (4-7) 14 (6-22) 7 (4-10) 21 (16-26) 17 (14-20) 34 (29-39) 30 (26-34) 39 (30-47) iv (14-23) 17 (10-24) 28 (20-36) 28 (21-35) 28 (22-34) 45 (35-55) 70 (60-79) 79 (70-87) 61 (50-71) concordance index 0.801 0.915 0.832 cueto progression groups i (0-4) 1.2 (0.2-2.2) 3.5 (2-5) 4.5 (3-6) 6.6 (5-8) 3.7 (1.9-5.6) 4 (2-6) 1 (0.5-1.5) 8 (4-12) ii (5-6) 3 (0.8-5.2) 9 (5-14) 3(2-4) 22 (17-27) 12 (7.6-16) 15 (10-20) 6 (3-9) 27 (20-34) iii (7-9) 5.5 (2.7-8.4) 17 (11-23) 13 (9-17) 23 (17-29) 21 (16-27) 48 (41-55) 51 (46-56) 44 (38-50) iv (10-14) 14 (6.6-21) 29 (25-33) 32 (26-37) 27 (23-31) 34 (23-44) 69 (64-74) 77 (70-84) 64 (59-69) concordance index 0.881 0.930 0.806 green: outcomes of reference studies, dark blue: outcomes are equal with one standard deviation, light blue: outcomes are equal with two standard deviations, red: outcomes are not equal with two standard deviations (*: there is no patient to analyze). eortc versus cueto in all nmibc-dalkilic et al. urological oncology 40 vol 16 no 01 january-february 2019 41 made (figures 1b, 2b, 3b). the cueto risk table was considered to be insufficient in the risk classification and the prediction of recurrence in the current series. in the progression rates, especially in the high-risk patients, the 5-year progression rates of the current study were seen to be higher than those of the risk tables. the c index values of the eortc and cueto tables for the whole patient group, those not receiving bcg and those receiving bcg were found to be 0.801, 0.881; 0.915, 0.930 and 0.832, 0.806, respectively. although the progression rates were higher than those of the tables, when patients were grouped according to the points, the risk groups were significantly differentiated from each other in all 3 groups (the whole patient group, those not receiving bcg and those receiving bcg) of both the eortc and cueto (figures 1c, 1d, 2c, 2d, 3c, 3d). despite the higher progression rates determined in the current series compared to the reference risk tables, it can be considered that both the eortc and the cueto risk tables could be used for the prediction of progression and risk classification in patients treated and not treated with bcg. the 5-year cancer specific survival in muscle-invasive bladder cancer patients with nmibc history has been reported to be 35% and 60% in patients without nmibc history(8,9). a delay in definitive treatment, particularly in high-risk patients, could be a reason for missing the opportunity for treatment at the local stage of the disease. risk tables can give an idea of the prediction of recurrence and especially progression. in the studies made when forming the eortc risk table, approximately 78% of the patients received intravesical chemotherapy and 10% bcg therapy, while none received bcg maintenance(5). in contrast, all the patients in the cueto study received bcg therapy(6). in nmibc patients, bcg therapy is known to decrease recurrence and progression(4,10). therefore, while the eortc prediction of recurrence and progression of high-risk patients receiving bcg is higher than normal, in the cueto table, the prediction is lower than for high-risk patients not receiving bcg. previous studies have been published related to the compatibility of risk tables with local patient groups, the general accuracy and comparisons with each other. in two different studies of the validation of eortc in a local patient group, the recurrence prediction accuracy rate was similar but there was not full compatibility in respect of progression(11,12). there is no urology clinic in the world where no patient is given maintenance bcg treatment or all patients are given bcg maintenance treatment. therefore, in addition to investigating the accuracy of the risk tables, comparisons with each other have been made and even the accuracy of eortc for those receiving bcg and the accuracy of cueto for those not receiving bcg have been examined(13,14). in a study, which examined the accuracy of the eortc risk tables in patients receiving maintenance bcg, there was high accuracy in respect of both recurrence and progression. however, as the maintenance bcg period was 3 months in that study, it has drawn criticism that the treatment period was not sufficient(13). the reliability of the cueto risk table for patients not receiving bcg has been examined and it was reported that the eortc risk table predicted recurrence and progression with more accuracy than the cueto in patients not receiving maintenance bcg following turb(14). in another comparative study of patients receiving maintenance bcg for at least 1 year and those not receiving maintenance bcg following turb, both recurrence and progression were predicted to be higher in both risk tables, especially in high-risk patients, and this difference was seen to be more evident in patients receiving bcg especially in the eortc risk table(15). when the patients were grouped according to the risk points, there was seen to be no significant differentiation between the groups of the eortc and cueto risk tables in the prediction of recurrence and progression. that only 11% of the patients in that study were receiving bcg suggests that the treatment was not sufficient. the reason for this view is that it was a multi-center study and included the data of patients from the year 2000. the recurrence rates obtained in the current study were similar to those of the eortc table but higher than those of the cueto risk table. the 5-year recurrence rates of the patients receiving bcg in both the eortc and cueto risk tables were lower than the 5-year recurrence rate results obtained in the current study. the c index values for eortc and cueto for the whole patient group, those not treated with bcg and those treated with bcg were 0.777, 0.705; 0.773, 0.699; and 0.823, 0.758, respectively. although the recurrence rates of the patients receiving bcg were not similar to the risk tables, the high c index value is explained by the clear difference between the groups. it has been previously reported in literature that insufficient intravesical treatment following turb increases the recurrence and progression rates and this could be a cause of incorrect results in the risk table predictions (16). in a study which included only primary nmibc pafigure 3. kaplan-meier survival curves of risk of recurrence according to the eortc (a) and cueto risk tables (b), risk of progression according to the eortc (c), and cueto risk tables (d) of patients treated with bcg. in the recurrence analysis, the eortc model (fig 3a) showed a significant difference (p < .001) in all groups, but in the cueto (fig 3b) model, a significant difference was seen only between patients with 0-4 score and the others (p < .001). in the progression analysis, eortc (fig 3c) and cueto (fig 3d) risk tables showed a significant difference (p < .001) in all groups. eortc versus cueto in all nmibc-dalkilic et al. tients receiving and not receiving maintenance bcg, it was shown that the recurrence predictions of both the eortc and the cueto risk tables remained insufficient and only high-risk patients could be differentiated (17). in the analysis of only the patients receiving bcg in that same study, the results were reported to be worse. while 36.8% of the patients were in the moderate and high-risk group, only 23% received maintenance bcg and approximately 50% of those receiving bcg were in the low risk group. it was a multi-center study and the patient data was from 1998-2001, again raising the question of whether standard and sufficient intravesical treatment was applied to patients following turb(17). the maintenance bcg therapy rate is known to be as low as it should be(18). in the current study, some of the high-risk patients were not treated with bcg, for reasons of patient preference, adverse events, unavailability etc. that this study was retrospective could be seen as a limitation, but retrospective data were obtained from both the eortc and the cueto risk tables(5,6). later validation studies were also conducted with a retrospective method(11-13). as the primary outcome points were highly objective and all the patients were applied with the same treatment and follow-up plan, apart from the loss of data, the retrospective nature cannot be considered to have caused any limitation to the features of the study. that the study was conducted in a single-center and the intravesical instillation and follow-up protocol were standardized as a single type can be considered to have increased the power of the study. this is the first single-center study which has applied a standard intravesical treatment and follow-up protocol and performed an analysis of all patients and separately of those who received and did not receive bcg according to the eortc and cueto risk tables. in conclusion, the eortc risk table differentiated recurrence risk groups from each other more successfully than the cueto risk table in patients receiving and not receiving bcg. both risk tables yielded similar results in the prediction of progression. there is undoubtedly a need for a new risk table. when creating this table, the data should be used from centers where a current, standard treatment and follow-up protocol has been applied in the proper manner. conflict of interest the authors report no conflict of interest. acknowledgements we express our gratitude to mrs. caroline jane walker for her support in the proofreading the manuscript. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin 2011;61:69–90 2. ferlay j, shin hr, bray f, forman d, mathers c, parkin dm. estimates of worldwide burden of cancer in 2008: globocan 2008. int j cancer 2010;127:2893-917. 3. edward m. messing, md. urothelial tumors of the urinary tract. in campbell’s urology, eight edition, 4th volume w.b. saunders, usa 2002: 2723-84. 4. sylvester rj, van der meijden ap, lamm dl. intravesical bacillus calmette-guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. j urol 2002;168:1964-70. 5. sylvester rj, van der meijden ap, oosterlinck w, witjes ja, bouffioux c, denis l, et al. predicting recurrence and progression in individual patients with stage tat1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials. eur urol 2006;49:466-77. 6. fernandez-gomez j, madero r, solsona e, et al. predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus calmette-guerin: the cueto scoring model. j urol 2009;182:2195203. 7. cambier s, sylvester rj, collette l, et al. eortc nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in 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2013;109:1460-6. 16. lammers rj, palou j, witjes wp, janzingpastors mh, caris ct, witjes ja. comparison of expected treatment outcomes, obtained using risk models and international guidelines, with observed treatment outcomes in a dutch cohort of patients with non-muscle-invasive bladder cancer treated with intravesical chemotherapy. bju int 2014;114:193-201. 17. vedder mm, márquez m, de bekker-grob ew, et al. risk prediction scores for recurrence and progression of non-muscle invasive bladder cancer: an international validation in primary tumours. plos one 2014;6;9:e96849. 18. poletajew sa, majek a, magusiak p, ledzikowska k, dybowski b, radziszewski p. availability and patterns of intravesical bcg instillations. urol j. 2017;4;14:5068-70. eortc versus cueto in all nmibc-dalkilic et al. introduction the first laparoscopic prostatectomies were per-formed via an intra-peritoneal and ante-grade route in 1992 by schuessler et al.,(1) and in 1997 by gaston et al..(2) then, several teams have amplified these approaches.(3–5) in 1997, raboy et al. performed laparoscopic prostatectomy using an extra-peritoneal approach with ante-grade dissection.(6) in 1999, the extra-peritoneal approach was being developed simultaneously by bollens et al.,(7) using ante-grade dissection, and in lyon (france),(8,9) where we introduced an original, not only completely extra-peritoneal approach, but also with a retrograde prostate-semino-rectal dissection combined with the ascending dissection of the erectile neurovascular bundles, from the apex up to the bladder neck, commonly used in conventional surgery and which, paradoxically, had not been described until then in laparoscopic surgery. rassweiler et al.(10) initiated a retrograde dissection via the intra-peritoneal route. radical prostatectomy was proven perfectly adapted to the treatment of prostate cancer, but laparoscopic procedures were initially performed via an intra-peritoneal route, contrary to the more logical and natural approach to the planes of anatomical dissection used during conventional open surgery, and were associated with certain risks that can be avoided by preserving the peritoneum.(11) we then developed a simplified retrograde extra-peritoneal laparoscopic technique. this technique, while providing a largely sufficient dissection space (figure 1), enables the initial approach to the apico-urethro-fascial, sphincteral, erectile and rectal junction, then prostato-semino-rectal cleavage up to the bladder neck, combined with the ascending dissection of the erectile neurovascular bundles (figure 2). this technique exactly renders the open procedure, and enables the surgeon to focus immediately on the essential step on which oncologic risks (apical dissection) and functional consequences (neuro-vascular bundles and sphincter preservation) depend (figure 3). we already published 47 cases in 2002,(8) and 143 cases in 2003.(9) the objective is to present the oncologic and functional results of the first 1,000 patients operated with this technique. laparoscopic and robotic urology retrograde extraperitoneal laparoscopic prostatectomy (relp). a prospective study about 1,000 consecutive patients, with oncological and functional results pierre dubernard1, pierre chaffange1, philippe pacheco1, elie pricaz1, nader vaziri1, maxime vinet1, philippe chalabreysse2, charles-henry rochat3, grégoire ficheur4, emmanuel chazard4* purpose: usual laparoscopic surgery of localized prostate cancer uses antegrade dissection. we describe and evaluate the original relp (retrograde extraperitoneal laparoscopic prostatectomy). materials and methods: a prospective cohort of 1005 patients with clinically localized cancer prostate who were operated on from december 1999 to september 2013, in lyon (france), and followed up to 172 months (median: 60 months). patients encountered a relp procedure, a totally extra-peritoneal approach with a retrograde dissection from the apex to the bladder neck, and ascending dissection of the erectile neurovascular bundles, facilitated by the 30° optic telescope. adjunctive treatments were: immediate radiotherapy (9.2%), salvage radiotherapy (13.4%), androgen deprivation therapy (10.8%), chemotherapy (1.4%), no treatment (75.8%). results: the mean age was 63.4 years, the gleason score was 4+3 or worse in 24.9%, there were 2.3% unifocal tumors. the pathology stages were pt2a (8.71%), pt2b (2.80%), pt2c (69.0%), pt3a (13.1%), and pt3b (6.41%). there were 60.8% negative margins (r0) in total (90.1% for basal locations, and 75.8% for apical locations). the mean operating time was 115 minutes for the last 100 patients. the bpfsr (biological progression free survival rate, psa ≤ 0.10 ng/ml) was 71.9% at 5 years, and 61.4% at 10 years. the cancer specific survival rate was 99.4% at 5 years, and 98.3% at 10 years. after 12 months, 88.6% of patients did not require an incontinence pad, and 67.0% retained the pre-operative quality of their erection. conclusion: relp yields good oncologic results and quality of life, as good as robot-assisted surgery. keywords: functional results; laparoscopy; oncological results; prostatectomy; prostatic neoplasms; retrograde extraperitoneal laparoscopic prostatectomy 1hôpital privé jean mermoz, centre lyonnais d'urologie bellecour (club), lyon, france. 2md-cypath. cabinet médical de pathologie, lyon, france. 3clinique générale beaulieu, geneva, switzerland. 4univ. lille, chu lille, ulr 2694, cerim, public health dept, f-59000 lille, france. *correspondence: cerim ulr 2694. 1 av oscar lambret. f-59045 lille cedex. france. phone: +33 3 20 62 69 69. fax: +33 3 20 62 68 81. email: emmanuel.chazard@univ-lille.fr received may 2020 & accepted may 2021 urology journal/vol 18 no. 5/ september-october 2021/ pp. 503-511. [doi: 10.22037/uj.v18i.6233] material and methods population from december 1999 to september 2013, a total of 1,005 patients with a clinically localized prostate cancer were operated in the club, a private center in lyon, using the relp technique. five patients were excluded (4 per-operative conversions, and one death due to cardiac failure). the 1,000 remaining patients were all included, followed-up, and analyzed. we collected data about their characteristics at the inclusion (surgeon, date, age, preoperative prostate specific antigen psa, and erection status), the characteristics of the prostate tumor (pathological report, gleason relp prostatectomy: a 1,000 patient cohort-dubernard et al. laparoscopic and robotic urology 504 figure 2. initial approach to the erectile neurovascular bundles. figure 1. pelvis exposure with the relp technique (1: peritoneum, 2: bladder, 3: prostate, 4: neurovascular ilio-obturator axes). score, tnm staging), follow-up, and treatment (psa recurrence, adjuvant treatments, complications, and intercurrent diseases). psa recurrence was defined rigorously as a post-operative psa value greater than 0.10 ng/ml. the study was conducted in accordance with french regulation. as it consisted of the secondary use of routine care data, it did not require any ethical approval by an internal review board. the patients were informed their anonymized data could be reused for research purposes, and none objected. ethnicity data could not be collected. the principles outlined in the declaration of helsinki were followed. surgical technique and postoperative protocol the complete operative protocol is provided as online supporting information. the surgical approach for prostate dissection benefited greatly from anatomic and technical descriptions,(12–14) which made it possible to define the relationships between the apico-urethral junction and the various fasciae, the peri-urethral-musculo-sphincteral sleeves, the erectile neurovascular bundles, and the anterior wall of the rectum. the anatomic landmarks are thus better defined at the apex,(15) and the dissection planes much more natural there than at the base of the prostate to allow for easier posterior musculofascial reconstruction.(16) the surgical team has now an experience of more than 1,500 cases operated in the club. during all these procedures, a senior urologist was always present, according to the “mentoring” principle. at the inclusion, all the patients underwent a primary prostatectomy, excluding previous radiotherapy. affigure 3. retrograde apical dissections, neurovascular bundles, and sphincter preservation. figure 4. proportion of patients having a given tumor location. relp prostatectomy: a 1,000 patient cohort-dubernard et al. vol 18 no 5 september-october 2021 505 ter the surgeon systematically examined the prostate macroscopically, subsequently the specialist anatomic pathologist determined the tumor margins (location, extent, dimensions and number). the tumor was qualified r0 in the absence of tumor margin, r1 if there was one focus < 3 mm, even infra-millimetric, or r2 if there was one focus ≥ 3 mm or more than one focus of any size. in case of r2 positive margins with an ascending post-operative psa>0.10 ng/ml, an adjuvant radiotherapy was proposed within 6 to 9 months postoperatively according to the patient’s acceptance. furthermore, the patients were followed-up every 6 months, and a secondary radiotherapy was proposed for those with initial positive margins and a subsequently two times rising psa. adt was proposed in case of failure of radiotherapy. data collection the data were collected in the course of medical consultations by the surgeons who operated the patients. a spreadsheet was used. during the study period, the data were gathered and controlled every week by the first author and, when necessary, the information was checked in the patient's paper file. a final check was carried out at the time of the statistical analysis and revealed no anomaly. statistical analysis descriptive univariate statistics were computed in the whole database. for quantitative variables, the mean and standard deviation (sd) were computed. in case of figure 5. margins as function of the tnm tumor stage. figure 6. proportion of patients having a given tumor location, and the corresponding margin location. relp prostatectomy: a 1,000 patient cohort-dubernard et al. laparoscopic and robotic urology 506 non-normal distribution, median, first and third quartiles were computed (respectively q2, q1 and q3). for qualitative and binary variables, counts and proportions were reported. the 95% confidence intervals of means were computed using the normal distribution when appropriate (n ≥ 30 or normal distribution). the 95% confidence intervals of proportions were computed with the exact binomial test. the khi² test was used to test the independency between categorical variables (with theoretical counts ≥ 5). linear regressions were used to draw the learning curves of the surgeons. the time-dependent events were analyzed using survival methods. descriptive survival curves were drawn using the kaplan-meier estimate, with normal estimation of confidence intervals. cox model with stepwise covariate selection was used for inferential analyses. survival analyses were performed including all the patients who underwent surgery: the objective was to quantify the survival after the comprehensive protocol (surgery with or without adjuvant or secondary radiotherapy), and not to assess the surgery alone. we only tested covariates that were available before or immediately after the surgery, and included all of them: surgeon name, age of the patient, year, gleason score, gleason ≥ 7 (4+3), tumor stage, tumor volume, margins, each location of the margins (apical, basal, etc.), capsule infiltration, nerve sheaths infiltration, and presence of lymph nodes metastasis. we did not include covariates that were a consequence of the results of the surgery (e.g. radiotherapy, hormonotherapy or chemotherapy), to avoid the indication bias. a bidirectional step procedure was used to automatically filter covariates. the post-operative erection status and the urinary continence of the patients was only evaluated for the patients who were followed up at least 12 months, for a sufficient recovery delay. all the tests were double-sided and interpreted with a 5% significance threshold. data management and statistical computations were performed with r statistical computing software. missing values were studied, but not imputed. results one thousand patients were analyzed and followed up during 0 to 172 months. the median follow up time was 60 months [19; 95] (table 1). patients’ background the mean age was 63.4 (sd = 6.44). the median psa before the surgery was 6.7 ng/ml [4.94; 9.30], with 75.4% (n = 754) having psa<10, 18.1% (n=181) having 10 < psa < 20, and 6.50% (n = 65) having psa > 20. the clinical stage (only available for patients n°1 to 324) was ct1a-b for 2.47% (n = 8), ct1c for 59.3% (n = 192), ct2a-b for 34.6% (n = 112), and ct3a for 3.70% (n = 12). characteristics of the tumor and extension assessment according epstein’s classification of gleason score,(17) patients can be classified as follows: 24.1% (n=241) of group 1 (gleason ≤ 6), 50.9% (n = 509) of group 2 (gleason 3+4), 18.2% (n=182) of group 3 (gleason 4+3), 5.6% (n = 56) of group 4 (gleason 8), and 1.1% (n=11) of group 5 (gleason 9 or 10). the score was 4+3 or worse in 24.9% (n = 249) of patients. the tumor volume, determined using planimetric measure, was < 25% of the prostate in 37.8% (n = 378), 2550% of the prostate in 39.2% (n = 392), 50-75% of the follow-up proportion (n) lost to follow-up (beginning of period) [0,30] months 36.5% (365) 0% ]30,60] months 14.6% (146) 36.5% ]60,90] months 20.0% (200) 51.1% ]90,120] months 18.7% (187) 71.1% ]120,150] months 8.4% (84) 89.8% ]150,180] months 1.8% (18) 98.1% table 1. characteristic of the study included in this systematic review. figure 7. learning curve (y=proportion of r0 margins, x=years, pt2 only). left: main surgeon. right: team of five surgeons relp prostatectomy: a 1,000 patient cohort-dubernard et al. vol 18 no 5 september-october 2021 507 prostate in 19.6% (n = 196), and 75-100% of the prostate in 3.4% (n = 34). most tumors were multifocal 87.9% (n = 879) or bifocal 9.8% (n = 98), and 2.3% (n = 23) were unifocal. relatively to the total number(3,810) of all the single and multifocal locations, the distribution was apical in 23.3% (n = 888), lateral medial in 24.3% (n = 925), posterior in 13.8% (n = 526), basal in 14.1% (n = 536), anterior in 11.3% (n = 113), and transitional in 5.1% (n=195). relatively to the patients, tumor locations are presented on figure 4. the prostatic capsule was intact in 59.1% (n = 589) cases, infiltrated in 22.6% (n = 225) cases, and passed through in 18.4% (n = 183) cases. the nerve sheaths were intact in 48.1% (n = 479) cases, penetrated in 40.6% (n = 104) cases, and passed through in 11.4% (n = 113) cases. regarding lymphatic involvement, 61.3% (n = 613) did not have any lymphadenectomy due to a psa value lower than 10 ng/ml and gleason score ≤ 7 (3+4). among the 387 pelvic lymph node dissection, 99.2% (n = 384) were negative, and 0.78% (n = 3) were positive. according to the tnm pathological classification, the tumor stage was pt2a in 8.71% (n = 87) cases, pt2b in 2.80% (n = 28) cases, pt2c in 69.0% (n = 689) cases, pt3a in 13.1% (n = 131) cases, and pt3b in 6.41% (n = 64) cases. there was no pt0 stage. the margins of the tumor were r0 in 60.8% (n = 608), r1 (one focus < 3 mm, including margins < 1mm) in 23.6% (n = 236), and r2 (one focus ≥ 3 mm or more than one focus of any size) in 15.6% (n = 156). those proportions were respectively 66.3%, 20.9%, and 12.8% for pt2 tumors, and 37.9%, 34.9%, and 27.2% for pt3 tumors (p = 1.5e-12). (figure 5) the patients had an apical margin in 21.5% (n = 215), a lateral medial margin in 15% (n = 150), a posterior margin in 9.7% (n = 97), a basal margin in 5.3% (n=53), and an anterior margin in 3.1% (n = 31) (an individual patient may account for several margin locations. (figure 6) the “success rate”, defined as the proportion of patients without margins for a given location among patients review 149 complications n comments intra-operative: conversion 6 4 to achieve prostatectomy (excluded) 2 for open ureteric re-implantation (included) rectal injury 6 5 immediately recognised and sutured 1 secondary temporary diversion ureteral section 4 2 immediate and 1 secondary open re-implantation; 1 laparoscopic suture ureteral stenosis 3 2 double j stent; 1 secondary open re-implantation ureteral meatus eversion 1 secondary open re-implantation bladder wall injury 4 sutured without any consequences immediate post-operative: death 1 cardiac failure anastomosis fistula 9 during more than 2 weeks pelvic hematoma 6 ureteric stenosis 3 2 treated percutaneously; 1 secondary open re-implantation tardive: stenosis of the anastomosis 3 urethralstenosis 6 table 2. complications (out of 1005 cases) figure 8. biological progression free survival rate (x in months, event: psa>0.10 ng/ml) relp prostatectomy: a 1,000 patient cohort-dubernard et al. laparoscopic and robotic urology 500laparoscopic and robotic urology 508 having that tumor location, was 100% for transitional locations, 92.8% for anterior locations, 90.1% for basal locations, 88.4% for posterior locations, 83.8% for lateral medial locations, and 75.8% for apical locations. surgical procedure the mean operating time decreased from 206 minutes (patients 1 to 100 for the original surgeon), to 145 minutes (patients 225 to 324 for the original and next surgeon), and 115 minutes for the last 100 patients (patients 901 to 1000 for 4 surgeons). the mean weight of the specimen was 42,5g (range14-125 g). a continuous improvement of surgeon performance (figure 7) was observed: 43.2% (n = 433) of the surgical procedures were performed by the first author from his age 55 to 68. for that cohort, the pt2a, pt2b and pt2c tumors, the proportion (y) of r0 versus r1&r2 as a function of the year (x) was estimated y = 0.0344 x + 0.454 (p = .0002, n = 348), which means the proportion of r0 increased by 3.44% every year in average. the final team of 5 surgeons did not have equal experience. they participated as part of the team on an alternating basis. the proportion of r0 was estimated y = 0.0154 x + 0.491(p = .0005, n = 1000). complications and morbidity surgical conversion occurred in six patients. there were 15 per-operative complications, 19 immediate post-operative complications, and nine tardive complications (table 2). according to clavien classification,(18) we observed: one grade v, 15 grade iiia, and 12 grade iiib complications. other treatments and follow-up among the patients, 75.8% (n = 758) did not require any complementary treatment. in case of rising psa > 0.10 ng/ml: 9.2% (n = 92) received immediate adjuvant external beam radiotherapy (ebrt); 13.4% (n = 134) secondary ebrt; 10.8% (n = 108) received adt (androgen deprivation therapy), and 1.4% (n = 14) received a chemotherapy. during their follow up, 23.7% (n = 237) encountered a psa recurrence (defined as a value greater than 0.10 ng/ml), with a median value of 0.21 [0.17; 0.30] in case of recurrence. the biological progression free survival rate (bpfsr) is presented in figure 8. it reaches 96.1% [94.9; 97.4] at 1 year, 90.1% [88.1; 92.1] at 2 years, 80.5% [77.7; 83.4] at 3 years, 71.9% [68.6; 75.3] at 5 years, and 61.4% [56.8; 66.5] at 10 years. the following covariates had an adjusted significant impact on the bpfsr: the margins (reference: no margin): r2 margins with hr=3.35 [2.43; 4.62] (n=151), and r1 margins with hr=2.04 [1.48; 2.80] (n=232) a gleason score of 7= 4+3 or greater, with hr=1.97 [1.49; 2.59] (n = 247) infiltration of nerve sheaths (reference: no infiltration): extra-capsular infiltration with hr=1.76 [1.13; 2.74] (n = 112), and intra-capsular infiltration with hr=1.45 [1.07; 1.97] (n = 399) presence of lymph node metastasis, with hr=8.00 [1.10; 58.3] (n = 3) t3 stage of the tumor versus t2, with hr=1.55 [1.08; 2.22] (n = 192) the following variables were found significant in bivariate analyses, but were not independent predictors in cox model: year of surgery, tumor volume, and capsule infiltration. during their follow up, 3.1% (n = 31) patients died, including 0.9% (n = 9) who died from prostate cancer. the cancer specific survival rate was 99.7% [99.4; 1.00] at 1 year, 99.4% [98.8; 1.00] at 5 years, and 98.3% [97.1; 99.5] at 10 years. the following covariates had a significant adjusted impact on the cancer survival: the tumor volume (where 1 means 75%-100% of the prostate), with hr=118.63 [2.459; 5724.24] t3 stage of the tumor (versus t2), with hr=10.8 [1.21; 97.4] (n = 192) the following variables were found significant in bivariate analyses, but were not independent predictors in cox model: year of the surgery, gleason score, surgical margins, capsule infiltration, and nerve sheaths infiltration. functional results for the 813 patients who had follow up during of at least 12 months (with 1.3% missing values), 75.0% (n = 610) had a perfect continence, 13.6% (n = 111) had some seldom and minor leaks but did not need any protection, 5.9% (n = 48) used one light pad per day, 3.32% (n = 27) used several pads per day. of this later group, 14/27 finally had a sling implantation. total incontinence occurred in 1.97% (n = 16). of this group, 15/16 had an artificial urinary sphincter implantation. preoperative erectile function was evaluated in 876/1000 patients via our own formal but non validated questionnaire: 81.3% (n = 712/876) of patients could obtain a normal erection without any treatment, 7.08% (n=62/876) spontaneously had an erection insufficient for penetration but were successfully treated pre-operatively for erectile dysfunction (ed), and 11.6% (n = 102) were unable to attain any erection either with or without treatment. for the 770/876 patients with at least 12 months follow-up, the preceding percentages were respectively: 23.8% (n = 183/770), 35.1% (n = 270/770), and 41.2% (n = 317/770). among the 712/876 patients with normal pre-operative erectile function, 549/712 were followed at least 12 months: 29.3% (n = 161/712) retained normal erections, 37.7% (n = 207/712) had an insufficient erection but were treated successfully for ed, and 33.0% (n=181/712) had no erection with or without treatment. thus erectile function was maintained in 67.0% (n=368/712). among the 33% (n = 181/712) patients who had normal erection pre-operatively but ed post-operatively, 55.2% (n = 100/181) stated that this was not a concern to them. this group was significantly older (mean age 66.6 versus 63.9, p = .0046). discussion this cohort has similar baseline data to previously published series,(19–21) with at least 1,000 consecutive patients and a mean follow up of 5 years. the margins rate (pt2-pt3): 32.9 % (r1: 23.6%, even unifocal infra-millimetric, and r2: 15.6%) need a comparative analysis with others series (8.7% to 51.4%). (22,23) we speculate that the retrograde dissection might have a significant favorable impact on the location rate (apical in 21.5% and basal in 5.3%) with a “success rate” of 75.8% for apical locations and 90.1% for basal locapfmt on incontinence after rp-rangganata et al. vol 18 no 5 september-october 2021 509 tions.(24,25) our rate of systematic lymph node dissection rate (38.7%) is consistent with previously published series. (26,27) the duration of surgery decreased regularly with experience. the rate of negative margins for the four “companion” surgeons increased by 3.44% every year. in spite of the margins rate and a psa threshold ≤ 0.10 ng/ml, the bpfsr remains similar to others series: 71.9% at 5 years, 61.4% at 10 years,(28) and the cancer specific survival rate is: 99.4% at 5 years, 98.3% at 10 years. with a median follow up of 60 months, 75.8% patients have not required any complementary treatment. at 12 months follow up, 88.6% do not require any incontinence pad.(29) of those patients with normal pre-operative erectile function, 67.0% maintain normal erectile function, with or without oral treatment. most importantly, this procedure is perfectly adaptable to the rarp (robotic assisted radical prostatectomy). to the best of our knowledge no report of robot assisted radical retrograde extraperitoneal laparoscopic prostatectomy (r-relp) has been published except by this group.(30) we believe that the retrograde approach has significant advantages, as demonstrated in a detailed step by step supplemental description with video presentation published online. we hope that this article will assist interested robotic surgeons in applying this technique to their surgical armamentarium. the r-relp is now the subject of a clinical trial. robotic-assisted laparoscopic prostatectomy (r-relp) using the da vinci system can be reproduced to an equal standard using the relp technique.(30) three-dimensional vision via the 30° telescope and articulated instruments, with their 90° mobility, are particularly suited to retrograde dissection, and make easier for the urologists to give up the open surgery. this is the ideal application to exploit the specific capacities of the robot to their fullest as well as with the less expansive 3d column. conclusions this report demonstrates that relp technique yields acceptable oncologic and quality of life outcomes. this technique is adaptable to rarp. acknowledgements the authors express their appreciation to aurélien belot, phd, london school of hygiene and tropical medicine, london, united kingdom, who has initiated the statistical analysis of the first cohort of patients. they would like to thank richard j macchia, md, cleveland clinic florida, for his assistance in the preparation of the english language version of this publication pierre dubernard had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. conflict of interest the authors report no conflict of interest. references 1. schuessler ww, schulam pg, clayman rv, kavoussi lr. laparoscopic radical prostatectomy: initial short-term experience. urology. 1997;50:854-7. 2. curto f, benijts j, pansadoro a, et al. nerve sparing laparoscopic radical prostatectomy: our technique. eur urol. 2006;49:344-52. 3. guillonneau b, cathelineau x, barret e, rozet f, vallancien g. laparoscopic radical prostatectomy: technical and early oncological assessment of 40 operations. eur urol. 1999;36:14-20. 4. abbou cc, salomon l, hoznek a, et al. laparoscopic radical prostatectomy: preliminary results. urology. 2000;55:630-4. 5. hoznek a, salomon l, olsson le, et al. laparoscopic radical prostatectomy. the créteil experience. eur urol. 2001;40:38-45. 6. raboy a, ferzli g, albert p. initial experience with extraperitoneal endoscopic radical retropubic prostatectomy. urology. 1997;50:849-53. 7. bollens r, vanden bossche m, roumeguere t, et al. extraperitoneal laparoscopic radical prostatectomy. results after 50 cases. eur urol. 2001;40:65-9. 8. dubernard p, som p, hamza t, benchetrit s. radical prostatectomy by simplified extra peritoneal laparoscopic technique. preliminary results on 47 cases. j urol. 2002:348. 9. dubernard p, benchetrit s, chaffange p, hamza t, van box som p. [retrograde extraperitoneal laparoscopic prostatectomy (r.e.i.p). simplified technique (based on a series of 143 cases]. prog urol. 2003;13:16374. 10. rassweiler j, sentker l, seemann o, hatzinger m, rumpelt hj. laparoscopic radical prostatectomy with the heilbronn technique: an analysis of the first 180 cases. j urol. 2001;166:2101-8. 11. yang y, liu z, guo y, et al. the efficiency and safety of transperitoneal versus extraperitoneal robotic-assisted radical prostatectomy for patients with prostate cancer: a single center experience with 1-year follow-up. urol j. 2020;17:480-5. 12. walsh pc. anatomic radical prostatectomy: evolution of the surgical technique. j urol. 1998;160:2418-24. 13. poon sa, scardino pt. open radical retropubic prostatectomy. in: eastham ja, schaeffer em, editors. radical prostatectomy. springer, new york; 2014:107-29. 14. barré c. open radical retropubic prostatectomy. eur urol. 2007;52:71-80. 15. walz j, epstein ji, ganzer r, et al. a critical analysis of the current knowledge of surgical anatomy of the prostate related to optimisation of cancer control and preservation of continence and erection in candidates for radical prostatectomy: an update. eur urol. 2016;70:301-11. 16. simone g, papalia r, ferriero m, guaglianone s, gallucci m. laparoscopic “single knot– single running” suture vesico-urethral anastomosis with posterior musculofascial reconstruction. world j urol. 2012;30:651-7. pfmt on incontinence after rp-rangganata et al. laparoscopic and robotic urology 502laparoscopic and robotic urology 510 17. epstein ji, zelefsky mj, sjoberg dd, et al. a contemporary prostate cancer grading system: a validated alternative to the gleason score. eur urol. 2016;69:428-35. 18. dindo d, demartines n, clavien p-a. classification of surgical complications. ann surg. 2004;240:205-13. 19. hull gw, rabbani f, abbas f, wheeler tm, kattan mw, scardino pt. cancer control with radical prostatectomy alone in 1,000 consecutive patients. j urol. 2002;167:528-34. 20. roehl ka, han m, ramos cg, antenor jav, catalona wj. cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. j urol. 2004;172:910-4. 21. coelho rf, rocco b, patel mb, et al. retropubic, laparoscopic, and robot-assisted radical prostatectomy: a critical review of outcomes reported by high-volume centers. j endourol. 2010;24:2003-15. 22. barré c, thoulouzan m, aillet g, nguyen j-m. assessing the extirpative quality of a radical prostatectomy technique: categorisation and mapping of technical errors. bju int. 2014;114:522-31. 23. vora aa, marchalik d, kowalczyk kj, et al. robotic-assisted prostatectomy and open radical retropubic prostatectomy for locallyadvanced prostate cancer: multi-institution comparison of oncologic outcomes. prostate int. 2013;1:31-6. 24. ploussard g, drouin sj, rode j, et al. location, extent, and multifocality of positive surgical margins for biochemical recurrence prediction after radical prostatectomy. world j urol. 2014;32:1393-400. 25. cathelineau x, cahill d, widmer h, rozet f, baumert h, vallancien g. transperitoneal or extraperitoneal approach for laparoscopic radical prostatectomy: a false debate over a real challenge. j urol. 2004;171:714-6. 26. leyh-bannurah s-r, budäus l, pompe r, et al. north american population-based validation of the national comprehensive cancer network practice guideline recommendation of pelvic lymphadenectomy in contemporary prostate cancer. prostate. 2017;77:542-8. 27. fossati n, willemse p-pm, van den broeck t, et al. the benefits and harms of different extents of lymph node dissection during radical prostatectomy for prostate cancer: a systematic review. eur urol. 2017;72:84109. 28. boorjian sa, eastham ja, graefen m, et al. a critical analysis of the long-term impact of radical prostatectomy on cancer control and function outcomes. eur urol. 2012;61:664-75. 29. erauso a, perrouin-verbe m-a, papin g, et al. [urinary continence following laparoscopic radical prostatectomy: qualitative analysis]. prog urol. 2012;22:945-53. 30. rochat c-h, dubernard p. the retrograde extraperitoneal approach: robotic retrograde extraperitoneal laparoscopic prostatectomy (rrelp). in: hemal ak, menon m, editors. robotics in genitourinary surgery. springer london; 2011:307-18. pfmt on incontinence after rp-rangganata et al. vol 18 no 5 september-october 2021 511 effects of opium dependency on testicular tissue in a rat model: an experimental study hassan jamshidian1, erfan amini1*, mohsen karvar1, elnaz ayati1,2, mohsen ayati1, farhad pishgar1, mansoor jamali zavarehei3, farid azmoudeh ardalan3, zahra khazaeipour4,saeid amanpour5, seyed majid aghamiri1. purpose: this study is aimed to evaluate the effects of opium dependency on testicular tissue in a rat model. methods: thirty-two wistar male rats (aged 30 days and weighing 200-250 grams) were randomized into two groups. group a, consisting of 16 rats, received dissolved oral opium tablets in drinking water for 45 days, whereas group b (control group) consisted of 16 rats that received opium-free water. after 45 days vertical and horizontal diameters of testis, number of seminiferous tubules, mean seminiferous tubule diameter, number of germ cells, height of germinal epithelium, percentage of degenerating leydig and germ cells and glutathione density of testicular tissue (µmol/g of tissue) were compared between study groups. results: morphological evaluation of testicular tissue revealed a significantly higher percentage of degenerating leydig and germ cells in the treated group compared to control group. (10.08 ± 0.351 vs. 1.83 ± 0.88, 4.50 ± 0.769 vs. 0.607 ± 0.118, respectively) (p-value<0.001 for each) interestingly, vertical and horizontal diameter of testis, the average number of germ cells, height of germinal epithelium and number of seminiferous tubules, were significantly higher in the treated group compared to control group. seminiferous tubule diameter and glutathione density of testicular tissue were not statistically significantly different between the groups. conclusion: applying a rat model, we noted that opium has a substantial effect on testicular structure and function. a significantly higher proportion of leydig and germ cells were degenerated in treated rats despite an increase in the average number of seminiferous tubules and germ cells. these findings support the hypothesis that opium consumption adversely affects male fertility. keywords: animal models; infertility; opium; testis introduction opioids has been used widely for their analgesic effects. furthermore, opioid abuse is common in some regions in the world and have been postulated to be associated with infertility in men.(1) the opioid system, including endogenous opioid peptides and opioid receptors, modifies secretion of gonadotropin-releasing hormone (gnrh), and subsequently alters the serum levels of follicle-stimulating hormone (fsh) and luteinizing hormone (lh). it has been shown that activation of opioid receptors is associated with decreased serum lh levels, whereas, opioid antagonists, including naloxone, increase serum lh levels.(2,3) opioids may modulate gonadal functions via binding to opioid receptors in the hypothalamus, the pituitary gland, and the testes(4,5). several studies have demonstrated acute and chronic effects of endogenous and exogenous opioids in regulating sex hormone secretion, includ1 uro-oncology research center, tehran university of medical sciences, tehran, iran. 2department of obstetrics and gynecology, tehran university of medical sciences, tehran, iran. 3department of pathology, tehran university of medical sciences, tehran, iran. 4brain and spinal cord injury research center, neuroscience institute, tehran university of medical sciences, tehran, iran. 5vali-e-asr reproductive health research center, tehran university of medical sciences, tehran, iran. * correspondence: assistant professor of urology, uro-oncology research center, imam khomeini hospital complex, end of keshavarz blv., tehran university of medical sciences, tehran, iran. postalcode: 1419733141. phone: +98 21 66903063. fax: +98 21 66903063. email: amini.erfan@gmail.com. received july 2017 & accepted september 2018 ing testosterone and estradiol. opioid dependency has been shown to decrease serum levels of testosterone, lh, and fsh, and consequently may be associated with decreased libido, erectile dysfunction, and infertility in men.(6,7) decreased sperm motility after morphine administration has also been observed in some studies, a finding that underscores potential role of opioid system in regulating sperm motility.(4,8) besides endocrine effects, opioids might also directly damage testicular and ovarian tissues. some studies with contradicting findings have evaluated role of opioid agonists and antagonists in oxidative stress in different organs.(9-11) despite extensive evaluations addressing endocrine effects of opioids, studies evaluating the histomorphological and oxidative-related effects of opium on testicular tissue are insufficient. we conducted this experimental study to assess the impact of opium on testicular tissue in a rat model. sexual dysfunction and andrology urology journal/vol 16 no. 4/ july-august 2019/ pp. 375-379. [doi: http://dx.doi.org/10.22037/uj.v0i0.4066] materials and methods animals thirty-two wistar male rats (aged 30 days and weighting 200-250 grams) were randomly assigned into two groups. group a (treated group, n=16) consisted of 16 rats that received dissolved oral opium tablets in drinking water for 45 days. group b (control group, n=16) received opium-free water. both groups were kept in a 12/12 hours dark/light cycle, air-conditioned environment with controlled temperature and humidity, and were treated with food and tap water ad libitum throughout the study. international standards for the care of laboratory animals were followed and the protocol of this experimental study was approved by institutional ethical committee (approval number: 9003-114-15256). opium dependency in rats of group a, addiction was induced by treating with dissolved oral opium tablets in drinking water for 45 days. each tablet contained 100 mg opium (10 mg morphine). at the beginning of the study, opium tablets were added to drinking water in group a to a concentration of 1 mg/ml. opium concentration increased by 1 mg/ml every 48 hours to the maximum concentration of 4 mg/ml, which was continued to the end of the study. rats in group b were maintained in similar condition and received opium-free water. the changes in the daily amount of water intake was also recorded in all rats. to assess opium dependency, two rats from each group were randomly selected and received 2 mg/ kg intra-peritoneal naloxone. opium dependency was confirmed 20 minutes after injection of naloxone by occurrence of withdrawal symptoms, including writhing, ptosis, diarrhea, jumping, teeth chattering, head and wet-dog shaking, and paw tremor in rats of group a. after 45 days, the rats were killed with co 2 asphyxiation and bilateral orchiectomy was performed through a midline scrotal incision. immediately after the operation, one testis was placed in bouin's solution for histological evaluation and another testis was stored at –80°c for biochemical assays. histopathological studies histopathological assessment of testicular tissues was performed by a blinded pathologist. after preparation of paraffin blocks, tissue sections with 5 µm thickness from the mid-portion of testicular tissue was provided and stained with hematoxylin and eosin. examination with an optical microscope under magnification of 10-100 times with standard technique was carried out. sertoli cell only syndrome was diagnosed in one rat in control group which was excluded from the study. testicular length and width were measured by ocular micrometer microscope. tubules were counted in an area of 1500 µm × 1500 µm centered in the middle of the field. the seminiferous tubule diameter, number of germ cells, height of germinal epithelium and the percentage of degenerating germ cells were recorded in 20 seminiferous tubules. percentage of degenerating leydig cells was also assessed in 20 inter-tubular spaces. biochemical studies frozen testicular tissues were homogenized, centrifuged and prepared for measuring glutathione concentration as an index of oxidative damage after morphine administration. measurement of glutathione concentration of testicular tissue was performed applying bioxytech® gsh-400 kit (oxis international, inc., portland, or, usa). the results were recorded as µmol per gram (µmol/g) of tissue. statistical analysis data were analyzed using spss (spss, inc., chicago, illinois) version 15. we used the chi-square or fisher’s exact test to compare qualitative data. student’s t test, and mann-whitney u test were applied to compare quantitative data. p-value < 0.05 was considered as statistically significant. results in the course of the study, weight of rats in both groups and the amount of daily water intake were recorded. average weight of rats and their mean water intake were comparable between the study groups. furthermore, no significant change was observed in the amount of water effects of opium on testicular histomorphology-jamshidian et al. table 1. comparison of histopathological parameters between study groups. opium-treated rats, group a (n=16) control rats, group b (n=15) p-value number of germ cells 109.50 ± 4.63 82.47 ± 4.96 < 0.001 seminiferous tubule diameter 229.38 ± 20.63 216.20 ± 16.79 0.062 height of germinal epithelium 76.63 ± 3.83 73.27 ± 1.79 < 0.001 number of seminiferous tubules 35.50 ± 4.90 27.60 ± 3.20 < 0.001 vertical diameter of testis (mm) 12.468 ± 0.670 10.383 ± 1.671 < 0.001 horizontal diameter of testis (mm) 8.796 ± 0.922 7.258 ± 0.535 < 0.001 data are shown in mean ± sd. figure 1. histopathological evaluations of testicular damage in opium-dependent rats. histopathological evaluation of testicular tissue revealed significant cell degeneration in the opium treated group (c, d) compared to control group (a, b). vol 16 no 04 july-august 2019 376 intake in group a, as the concentration of morphine in drinking water increased. morphological evaluation of testicular tissue revealed a significantly higher percentage of degenerating leydig and germ cells in the treated group compared to control group (10.08 ± 0.351 vs. 1.83 ± 0.88, 4.50 ± 0.769 vs. 0.607 ± 0.118, respectively) (p-value < 0.001 for each). the proportion of degenerating cells was noted to be more than 5 times in rats of group a compared to group b (figure 1). despite degeneration of leydig and germ cells, we found that vertical and horizontal diameters of testis, the average number of germ cells, height of germinal epithelium and number of seminiferous tubules, were significantly higher in group a. moreover, seminiferous tubule diameter was comparable between rats of the study groups. table 1 compares various histopathological parameters between study groups. however, we did not find a statistically significant difference in glutathione density of testicular tissues between two groups of the study (16 ± 1.5 vs. 15 ± 1.4 µmol/g in group a and b, respectively; p-value=0.818). discussion endocrine effects of opioids have been extensively reviewed in the literature, however, our study was one of the few studies to assess the effects of opium on histomorphological parameters of testis. our results revealed that opium consumption is associated with significant detrimental effects on testicular histomorphology and produces degenerative changes in testicular tissue. opioid peptides are postulated to play an important role in regulation of testicular function. animal studies have shown that opiate receptors exist in sertoli cells and opioids are capable of modifying the response of sertoli cells to fsh.(12-14) endogenous opioid peptides also bind to opioid receptors on gonadotropic cells, in the pituitary gland, and inhibit gnrh release. therefore, endogenous opioid peptides are involved in controlling reproductive function at different stages.(15) in a study evaluating the effects of morphine sulfate injection on rat reproductive system, investigators showed decreased serum lh and testosterone levels, as well as reduction in spermatogenic cells. although testicular weight was not affected by morphine administration, prostate and seminal vesicle weights decreased significantly. spermatid development was also affected in morphine treated rats with reduced counts of both early and late spermatids. furthermore, they noted decreased tubular diameter and sertoli cell counts as a consequence of morphine administration.(16). in a similar study, abdellatief et al. reported that chronic consumption of tramadol in rats, leads to decrease in serum lh, fsh and testosterone levels. they also noted that rats treated with tramadol have more destruction of seminiferous tubules, separation of tubular basement membrane, decrease in seminiferous tubules diameter and germinal epithelial height.(17) additionally, el sawy et al. noted that administration of tramadol for one month could lead to suppression of spermatogenesis and exfoliation of germ cells inside the lumina of the tubules.(18) in the present study we noted an increase in the average number of germ cells, although this increase was concurrent with significant increases in number of degenerated cells. increased number of germ cells in our study, although statistically significant, does not seem to be of clinical implication and does not preclude toxic effects of opioids on testicular tissue. simultaneous presence of hyperplasia and degenerative processes have been reported in several studies addressing histopathological changes in various tissues.(19,20) these findings highlight the hypothesis that observed increases in number of germ cells might be more attributable to tissue responses against opioid toxic effects, rather than benign histopathological changes. some studies have also assessed impacts of opioid antagonists on testicular tissue. naloxone, as an opioid antagonist, has been reported that can increase release of gonadotropin-releasing hormone (gnrh) and block inhibitory effects of stress on testosterone production in rats. it is also reported that naloxone treated rats have more spermatozoids and sertoli cells, as well as increased tubular length, sexual cords, sperm production and testicular weight.(21-23) although studies concerning the effects of opioid agonists on testicular tissue are insufficient, several reports have investigated effects of these substances on the hypothalamic pituitary gonadal axis, both in animals and humans.(15,16,24,25) yilmaz et al. have reported that chronic consumption of opioids does not affect seminiferous tubules and leydig cells, but it can suppress releasing gnrh, lh and testosterone hormone, without altering serum fsh level. later, padmanabham et al. confirmed fsh can be released without gnrh stimulation.(26) besides the alterations in endocrine regulation, opium consumption may result in oxidative damages to testicular tissues. opium induced oxidative damage has not been evaluated in the literature. however, studies have shown detrimental effects of cocaine and cigarette smoke on testicular tissue. li et al. evaluated cocaine induced oxidative damage in testicular tissue in a rat model. they showed that cocaine impacts on spermatogenesis, reduces testicular level of glutathione, an antioxidant agent, and induces apoptosis in rat testes. (27) similarly, cigarette smoke affected testicular antioxidant enzyme levels and impaired spermatogenesis in rats.(28,29) in a similar paper, kushwaha et al. reported that nicotine abuse augments testicular toxicity in diabetic rats.(30) in the present study, we assessed effects of opium on testicular glutathione density in opium dependent rats. no significant difference was noted in glutathione density in opium dependent rats compared to control group. however, it should be considered that lack of difference in glutathione density between study groups may be pertinent to the limited power of the study. applying a rat model, we noted that opium has a substantial effect on testicular structure and function. a significantly higher proportion of leydig and germ cells were degenerated in treated rats despite an increase in the average number of seminiferous tubules and germ cells. these findings support the hypothesis that opium consumption adversely affects male fertility. however, our study is associated with certain limitations including limited sample size and lack of re-review of pathology slides and further studies are required to confirm our findings. acknowledgments none conflict of interests authors declare that there are no competing interests. sexual dysfunction and andrology 377 effects of opium on testicular histomorphology-jamshidian et al. references 1. fronczak cm, kim ed, barqawi ab. the insults of illicit drug use on male fertility. j androl. 2012;33:515-28. 2. cicero tj, schainker ba, meyer er. endogenous opioids participate in the regulation of the hypothalamus-pituitaryluteinizing hormone axis and testosterone's negative feedback control of luteinizing hormone. endocrinology. 1979;104:1286-91. 3. cicero tj, schmoeker pf, meyer er, miller bt. luteinizing hormone releasing hormone mediates naloxone's effects on serum luteinizing hormone levels in normal and morphine-sensitized male rats. life sci. 1985;37:467-74. 4. albrizio m, guaricci ac, calamita g, zarrilli a, minoia p. expression and immunolocalization of the mu-opioid receptor in human sperm cells. fertil steril. 2006;86:1776-9. 5. subiran n, casis l, irazusta j. regulation of male fertility by the opioid system. mol med. 2011;17:846-53. 6. vuong c, van uum sh, o'dell le, lutfy k, friedman tc. the effects of opioids and opioid analogs on animal and human endocrine systems. endocr rev. 2010;31:98-132. 7. daniell hw. narcotic-induced hypogonadism during therapy for heroin addiction. j addict dis. 2002;21:47-53. 8. agirregoitia e, valdivia a, carracedo a, et al. expression and localization of delta-, kappa-, and mu-opioid receptors in human spermatozoa and implications for sperm motility. j clin endocrinol metab. 2006;91:4969-75. 9. almansa i, barcia jm, lopez-pedrajas r, muriach m, miranda m, romero fj. naltrexone reverses ethanol-induced rat hippocampal and serum oxidative damage. oxid med cell longev. 2013;2013:296898. 10. costa-malaquias a, almeida mb, souza monteiro jr, macchi bde m, do nascimento jl, crespo-lopez me. morphine protects against methylmercury intoxication: a role for opioid receptors in oxidative stress? plos one. 2014;9:e110815. 11. samarghandian s, azimi-nezhad m, afshari r, farkhondeh t, karimnezhad f. effects of buprenorphine on balance of oxidant/ antioxidant system in the different ages of male rat liver. j biochem mol toxicol. 2015;29:249-53. 12. fabbri a, tsai-morris ch, luna s, fraioli f, dufau ml. opiate receptors are present in the rat testis. identification and localization in sertoli cells. endocrinology. 1985;117:25446. 13. orth jm. fsh-induced sertoli cell proliferation in the developing rat is modified by beta-endorphin produced in the testis. endocrinology. 1986;119:1876-8. 14. zhou zf, xiao bl, zhang gy, zhuang lz. a study of the effect of b-ep and naloxone on the function of the hypothalamopituitary-testicular axis of the rat. j androl. 1990;11:233-9. 15. fabbri a, jannini ea, gnessi l, ulisse s, moretti c, isidori a. neuroendocrine control of male reproductive function. the opioid system as a model of control at multiple sites. j steroid biochem. 1989;32:145-50. 16. james rw, heywood r, crook d. effects of morphine sulphate on pituitary-testicular morphology of rats. toxicol lett. 1980;7:6170. 17. abdellatief rb, elgamal da, mohamed ee. effects of chronic tramadol administration on testicular tissue in rats: an experimental study. andrologia. 2015;47:674-9. 18. m. el sawy m, abdel malak h. effect of tramadol abuse on testicular tissue of adult albino rats: a light and electron microscopic study. vol 38; 2015. 19. pop ot, cotoi cg, plesea ie, et al. correlations between intralobular interstitial morphological changes and epithelial changes in ageing testis. rom j morphol embryol. 2011;52:339-47. 20. sula b, ekinci c, ucak h, et al. effects of hyperbaric oxygen therapy on rat facial skin. hum exp toxicol. 2016;35:35-40. 21. akinbami ma, taylor mf, collins dc, mann dr. effect of a peripheral and a central acting opioid antagonist on the testicular response to stress in rats. neuroendocrinology. 1994;59:343-8. 22. da silva va, jr., vieira ac, pinto cf, et al. neonatal treatment with naloxone increases the population of sertoli cells and sperm production in adult rats. reprod nutr dev. 2006;46:157-66. 23. gerendai i, nemeskeri a, csernus v. naloxone has a local effect on the testis of immature rats. andrologia. 1983;15:398-403. 24. hosseini sy, amini e, safarinejad mr, soleimani m, lashay a, farokhpey ah. influence of opioid consumption on serum prostate-specific antigen levels in men without clinical evidence of prostate cancer. urology. 2012;80:169-73. 25. yilmaz b, konar v, kutlu s, et al. influence of chronic morphine exposure on serum lh, fsh, testosterone levels, and body and testicular weights in the developing male rat. arch androl. 1999;43:189-96. 26. padmanabhan v, brown mb, dahl ge, et al. neuroendocrine control of follicle-stimulating hormone (fsh) secretion: iii. is there a gonadotropin-releasing hormone-independent component of episodic fsh secretion in ovariectomized and luteal phase ewes? effects of opium on testicular histomorphology-jamshidian et al. vol 16 no 04 july-august 2019 378 endocrinology. 2003;144:1380-92. 27. li h, jiang y, rajpurkar a, tefilli mv, dunbar jc, dhabuwala cb. lipid peroxidation and antioxidant activities in rat testis after chronic cocaine administration. urology. 1999;54:925-8. 28. ozyurt h, pekmez h, parlaktas bs, kus i, ozyurt b, sarsilmaz m. oxidative stress in testicular tissues of rats exposed to cigarette smoke and protective effects of caffeic acid phenethyl ester. asian j androl. 2006;8:18993. 29. peltola v, mantyla e, huhtaniemi i, ahotupa m. lipid peroxidation and antioxidant enzyme activities in the rat testis after cigarette smoke inhalation or administration of polychlorinated biphenyls or polychlorinated naphthalenes. j androl. 1994;15:353-61. 30. kushwaha s, jena gb. effects of nicotine on the testicular toxicity of streptozotocininduced diabetic rat: intervention of enalapril. hum exp toxicol. 2014;33:609-22. andrology parameters in heroin users-nazmara et al. sexual dysfunction and andrology 379 case report familial urethral stricture, five adult patients overview jalil hosseini1, babak kazemzadeh azad1*, fereshteh aliakbary1, ali tayyebi azar1, mohammad ali hosseini2 congenital stricture, specifically with manifestation in adulthood is extremely a rare cause of urethral stricture and is not associated with known etiologies. it was first described by cobb et al., and to our knowledge only 5 families were reported in english literatures to have familial urethral stricture. we report two families with urethral stricture including five male patients referred to our tertiary reconstructive urology department during 1994 to 2017. the age and severity of symptoms at presentation are variable; as are the surgical interventions required. there are no phylogenetic, familiar or racial relationship between the two families described. keywords: urethral stricture; bulbar stricture; urethroplasty; cobb’s urethral stenosis introduction the term urethral stricture mainly refers to an anterior urethral disease occurring for the most part secondary to pelvic trauma, inflammatory conditions, iatrogenic or surgical interventions including urethral instrumentation.(1, 2) familial stricture, specifically with presentation in adulthood, is an extremely rare cause of urethral stricture. this phenomenon was described by cobb et al. (1968), who proposed that the obstacle forms from partial fusion of the anterior and posterior urethra. the fusion arises from incomplete opening of the urogenital membrane during the embryonic phase of development.(3) we report two families with familial urethral stricture, referred to our tertiary reconstructive urology department during 1994 to 2017. to the best of us knowledge, only 5 families have been reported in the literature.(4-7) 1infertility and reproductive health research center shahid beheshti university of medical sciences, tehran, iran. 2student research committee, qazvin university of medical sciences, qazvin, iran. *correspondence: reconstructive urology fellowship, infertility and reproductive health research center shahid beheshti university. tel: 09121712141, fax: 22716383, e-mail: b.kazemzadehazad@sbmu.ac.ir. received may 2018 & accepted august 2018 figure 1. retrograde urethrography of patients. urology journal/vol 16 no. 5/ september-october 2019/ pp. 515-516. [doi: 10.22037/uj.v0i0.4547] case report series 1 three brothers presented, all with complaints of difficult voiding. the youngest brother’s obstructive urinary symptoms started 25 years ago (at 27 year old age), but he did not have any intervention until he referred to our clinic due to severity of symptoms. retrograde urethrogram (rug) plus, simultaneous voiding cystogram showed a small stricture in the mid bulbar urethra. (figure a) he underwent direct vision internal urethrotomy (dviu); and there was no symptom recurrence during one year follow up. (figure b) the second brother (55-years-old) underwent two urethral dilatations in the last 5 to 7 years, also due to mid-bulbar urethral stricture. the oldest brother (65-year-old) presented to the clinic 9 years ago following an unsuccessful urethral catheterization after an acute urinary retention. rug showed bulbar urethral stricture. (figure c) dviu was done and there was no recurrence of stricture. (figure d) all three brothers of this family underwent close follow up postoperatively without any self-catheterization order and so far, they are happy with their micturition.(8) series 2 the second series was a family with two brothers. the older brother, (56 years old), underwent dviu in 1984 for a web-shaped mid-bulbar stricture without any known etiology. he had history of 10 dviu procedures within 15 years due to his refusal to consent to open surgery. he underwent end-to-end bulbar urethroplasty in 2001. the younger brother (47-year-old) had a webshaped bulbar stricture which initially presented at 31 years old. he underwent dviu every 2 years before he was referred to our hospital in 2006 for open surgery and an end-to-end urethroplasty revealed a 2 cm bulbar stricture. although he was asymptomatic for about 1 year after the surgery, but his bulbar urethra progressively narrowed and he had repeat urethral dilatations in 2008, 2010 and 2014. discussion the overwhelming majority of congenital urethral strictures are referred to as a variety of posterior urethral valve (puv) disorders. familial puvs are rarely reported.(9) the stenosis in the above cases is called cobb’s collar, which is a membranous stricture of the bulbar urethra distal to the external urethral sphincter. the location differentiates this issue from puv(10,11). although presentation in adulthood suggests a trauma or inflammation history, the site of strictures in the above cases exactly matches the definition of cobb’s. the similarity of symptoms, age of incidence and response to the treatment in the above individuals suggests a familial disease.(5) there are no phylogenetic or familiar relationship between the two families described. moreover, since other reported cases have a world-wide distribution, racial factors do not seem to be involved in these presentations. the age and severity of symptoms at presentation are variable(4); as are the surgical intervention required. as seen in our cases, differs from a minimally invasive dviu to urethroplasty and multiple urethral dilatations. references 1. latini jm, mcaninch jw, brandes sb, chung jy, rosenstein d. siu/icud consultation on urethral strictures: epidemiology, etiology, anatomy, and nomenclature of urethral stenoses, strictures, and pelvic fracture urethral disruption injuries. urology. 2014;83:s1-s7. 2. hosseini j, tabassi kt. surgical repair of posterior urethral defects: review of literature and presentation of experiences. urol j. 2008;5:215-22. 3. cobb bg, wolf jr ja, ansell js. congenital stricture of the proximal urethral bulb. the j urol. 1968;99:629-31. 4. pal p, ray s, talukdar a, sonthalia n, chakraborty s. cobb's collar occurring in two brothers in a family: a rare entity revisited. indian j radiol. 2014;24:87. 5. jindal t, pal p, sinha rk, karmakar d. familial bulbar urethral strictures. bmj case reports. 2014;2014:bcr2013202857. 6. schreuder mf, van der horst hj, bökenkamp a, beckers g, van wijk ja. posterior urethral valves in three siblings: a case report and review of the literature. birth defects research part a: clinical and molecular teratology. 2008;82:232-5. 7. snell ja. congenital bulbar urethral strictures occurring in three brothers: comment. aust and new zealand j surg. 1997;67:573-. 8. tian y, wazir r, wang j, wang k, li h. prevention of stricture recurrence following urethral internal urethrotomy: routine repeated dilations or active surveillance? urol j 2016;13:2794-6. 9. kajbafzadeh a. congenital urethral anomalies in boys. part i: posterior urethral valves. urol j. 2009;2:59-78. 10. levin tl, han b, little bp. congenital anomalies of the male urethra. ped radiol. 2007;37:851-62. 11. dewan pa, goh dg. variable expression of the congenital obstructive posterior urethral membrane. urology. 1995;45:507-9. familial urethral stricture-hosseini et al. case report 516 urological oncology the evaluation of the relationship between bladder cancer and oxidative stress using nrf-2/keap-1 pathway, zinc and copper levels cağri doğan1*, cenk murat yazıcı1, murat akgül1, polat türker1 purpose: it has been shown that copper and zinc contribute to the structure of the antioxidant enzymes. in addition, nrf-2 and keap-1 complex have a powerful effect on the intracellular organization of the antioxidants. we evaluated the relation of copper, zinc, nrf-2, and keap-1 complex regarding the oxidative stress with tumor stage grade in patients with bladder cancer. materials and methods: a total of 52 patients (32 bladder cancer and 20 control group) were included in the study. the demographic properties of groups were identical. serum nrf-2, keap-1, cu, and zn levels were compared by elisa method between the groups, and tissue nrf-2, keap-1, cu and zn levels were evaluated also by elisa method in cancer patients. results: serum levels of nrf-2 and keap-1 of the bladder cancer patients were found to be higher than the control group (p = 0.004 and p = 0.001, respectively). on the other hand serum levels of copper and zinc were found to be lower than the control group (p = 0.008 and p = 0.001, respectively). however, the subgroup analysis according to the stages and grades of the tumour showed no difference. the copper level obtained from the tissue analysis was detected to be considerably decreased with tumour stage and grade. conclusion: bladder cancer patients had higher serum nrf-2 and keap-1 levels and lower serum copper and zinc levels. in addition, the copper levels decreased with the tumour stage and grade. studies with larger number of patients are needed to demonstrate the efficacy of these markers. keywords: bladder cancer; nrf-2; keap-1; urinary markers department of urology, tekirdag namik kemal university school of medicine, tekirdag, turkey. *correspondence: assistant professor at department of urology, tekirdağ namık kemal university medical school. e-mail: phone number:00905558908805. drcagridogan@gmail.com. adress: tekirdag namık kemal university, urology department, süleymanpaşa, tekirdağ, turkey, 59030. received september 2020 & accepted april 2021 introduction bladder cancer (bc) is the 9th most frequently de-tected and 13th most-lethal common malignancy worldwide. in addition, non-muscle invasive bladder cancer (nmibc) accounts approximately for 75% of the patients at admittance(1). the important risk factors known for the aetiology include smoking, exposure to aromatic amines and polycyclic hydrocarbons, genetic predisposition, and chronic irritation(2). the gold standard method for the diagnosis and treatment of bc is cystoscopy. although several diagnostic markers have also been identified to minimize this invasive procedure, none of them could get ahead of cystoscopy(3-4). exposure to toxic metabolites such as aromatic amines and oxidative stress appear to be important factors in carcinogenesis. the changes caused by these factors at the cellular level lead to the initiation of the oncological process and chronicity. reactive oxygen radicals (ror) are the most important radical type formed by living systems originated from the reduction of the molecular oxygen(5). ror play a significant role in the different complex course of carcinogenesis. a higher value of ror concentration is associated with the presence of tumours. there are a lot of epidemiologic evidences for ror in cancer pathogenesis. ror have also close relationship with bc. it has been demonstrated that ror is one of the important reasons for the presence and recurrence of bc(6,7). when the cell is exposed to oxidative stress, it activates its own antioxidant systems in the first stage. these systems might be mediated via enzymatic or non-enzymatic pathways, and exert activity to limit the catabolic effects of the ror(8). trace elements in the structure of the enzymes responsible for the antioxidant system as co-factors are as functionally important as the enzymes themselves against oxidative stress. the imbalance of these elements may lead to lack of limitation of the oxidative stress(9). copper and zinc are the essential molecules which contribute to the structure of the antioxidant enzymes as co-factors and play an important role in the metabolism of oxidative stress(10). the abnormal changes in the levels of the trace elements may cause mutation and cancer by affecting the structural characteristics of the antioxidant enzymes(11). the presence of an association between trace elements and bc is also observed in the previous studies. the imbalance of these important trace elements might play an important role in bc induction(12). total antioxidant capacities have close relationship in the presence of carcinogenesis. novel studies reported that antioxidants could prevent the initiation and promotion of carcinogenesis(7). the physiological role of urology journal/vol 18 no. 4/ july-august 2021/ pp. 422-428. [doi: 10.22037/uj.v18i.6439] antioxidants is to prevent damage to cellular components that may arise as a result of chemical reactions involving ror. nuclear transcription factor erythroid 2p45 related factor 2 (nrf-2) and ketch-like ech related protein 1 (keap-1) complex have an important effect on the intracellular organization of the antioxidant system(8). when the cell is exposed to oxidative stress, nrf-2 is separated from keap-1 and translocated to the nucleus, and provides the transcriptional activation of the detoxification enzymes and antioxidant molecule genes(13). schematic diagram of the ‘nrf2 keap1 antioxidant response element’ signaling pathway is shown in figure 1(14). in addition to protecting the normal cells, this complex may also protect the cancer cells exposed to stress and prolong the survival of the cancer cells(15). while its relation with several types of cancer has been evaluated in the literature, there is no study evaluating the relationship between the bc and nrf-2/ keap-1 complex. in this trial, we aimed to assess the level of nrf-2, keap-1 molecules and copper and zinc levels associated with oxidative stress. furthermore, we evaluated the place of nrf-2, keap-1, zinc, and copper molecules in the diagnosis of bc, which may be possible bc markers. patients and methods all procedures in this cross-sectional study were performed in accordance with the ethical standards of the institutional / national research committee with the standards of helsinki declaration. this study was approved by the local / national ethics committee (no: 2015/12/01/12) and all patients gave written informed consent prior to surgery and the study. the sample size was calculated based on the formula according to the previously published works(6,7,12). the sample size estimation was 35 cases. for this reason we included 35 patients to the study, however, 3 patients were excluded from the study because of unacceptable values. while patients with < 2 cm of mass in their bladder were included in the trial, patients with a history of non-bladder cancer, chronic inflammatory disease, and rheumatic disease were excluded. transurethral resection of bladder tumour (tur-b) was performed under general anaesthesia. patients diagnosed with a bc type other than transitional cell carcinoma were excluded from the trial. approximately 0.5cm3 tumour tissue pieces were collected from the bladder mass, and stored for analysis at -86°c in freezer condition. moreover, 8 ml of blood samples were collected to the serum separating gel tubes and centrifuged at 3000 rpm for 10 minutes. the resultant sera, then, were taken into eppendorf tube and stored in a -86°c freezer to analyse the levels of nrf-2, keap-1, copper, and zinc. no tissue sample was collected from the patients in this group due to ethical reasons. the control group was composed of totally healthy individuals. both the patient and the control group were similar patterns for age, sex, smoking status and region of living area. we performed cystoscopy to the control group as a gold standard to exclude bc. the individuals to whom cystoscopy was performed were included as a control group for different evaluations such as benign prostate hypertrophy (bph) etc. without ethical restriction. the cystoscopy of these individuals was also normal for bph and other diseases. the exclusion criteria in the study group were also applied to the control group. bladder tumour tissue samples were homogenized in saline buffer solution. following the homogenization, nrf-2 levels (cusabio brand kit with the lot number of csb-el 015752hu) and keap-1 levels (cusabio brand kit with the lot number of csb-el 012147hu) in the tissue were measured by elisa method. tissue samples for measuring copper and zinc levels were boiled with 2 ml nitric acid at 100°c for 1 hour and table 1. the demographics of patients and control group. control bladder group tumour group number 20 32 median age (± sd) 60.2 ±11.2 67.7 ± 10.95 gender (female / male) 5/15 4/28 comorbidity (dm/ht) 2/2 6/5 control group average values (min.-max.) bladder tumour group average values (min.-max.) p value keap-1 (serum) pg/ml 577 (193-1843) 1133 (150-10897) 0.004 nrf-2 (serum) pg/ml 3227 (2340-5150) 5708 (1463-20645) 0.001 copper serum pg/ml 126 (80-247) 101 (38-219) 0.008 zinc serum pg/ml 180 (135-326) 146 (61-279) 0.001 table 2. the correlation between parameters of serum levels in bladder tumour group and control group. figure 1. schematic diagram of the nrf2-keap1-are signaling pathway. nrf2 is constantly ubiquitinated through keap1 and degraded in the proteasome. after exposure to oxidative stress, keap1 is inactivated and nrf2 becomes phosphorylated. phosphorylated nrf2 (p-nrf2) accumulates in the nucleus and binds to antioxidant response element sites. it subsequently activates other genes including antioxidants, detoxifying enzymes, and transport molecules. bladder cancer and oxidative stress-doğan et al. urological oncology 423 vol 18 no 4 july-august 2021 424 digested, and then 2 ml of perchloric acid (60%) was added. the digested material was diluted with deionized water and the levels of copper and zinc were measured using flame atomic absorption spectrophotometry (tm shimadzu aa-6800). for the analysis of the data, spss version 20.0 software was used. the normality of the data was checked using shapiro-wilk test. as the variables do not distribute normally, non-parametric statistical tests were preferred. mann-whitney u test was used for the comparison of two independent groups. for the comparisons of more than two independent groups, kruskal-wallis test was used. mann-whitney u test was used for the comparison of subgroups. the receiver operating curve analysis (roc) was performed to detect the predictive accuracy of the studied markers (nrf-2 and keap-1). the results were expressed as median and minimum-maximum values using marginal or cross tables. p < 0.05 value was accepted to be statistically significant. results a total of 32 patients with the diagnosis of bc were included in the trial. twenty-eight (87.5%) of the patients were male, 4 (12.5%) of them were female, and the mean age of the patients was 67.7 ± 10.9 years. six (18%) of the patients had diabetes mellitus (dm) and 5 (15%) had hypertension (ht) (table 1). after the resection, 2 (6%) of the patients were detected to have carcinoma in situ (cis), 7 (21%) of them were found to have ta/low grade, 3 (9%) of them had ta/high grade, 9 (28%) of them had t1/low grade, 5 (15%) of them had t1/high grade, and 6 (18%) of the patients were found to have t2/high grade tumour. a total of 20 healthy individuals were included in the control group for the trial. fifteen (75%) of the patients in this group were male and 5 (25%) of them were female. the mean age was 60.2 ± 11.2 years. two (10%) of the patients in the control group had diabetes mellitus and 2 (%10) patients were detected to have hypertension (table 1). a serum median levels of nrf-2 and keap-1 in the study group were 5708 pg/ml (min:1463-max:20645) and 1133 pg/ml (min:150-max:10897), respectively. on the other hand, serum median level of nrf-2 was 3227 pg/ml (min:2340-max:5150) and keap1 was 577 pg/ml (min:193-max:1843) at the control group. the study group values of nrf-2 and keap-1 were found to be significantly higher than the control group (p = 0.001 and p = 0.004). the roc analysis for the serum nrf-2 and keap-1 in bc patients was shown in figure 2. the cut-off value for serum nrf2 was 4291 pg/ml (sensitivity: 75%specificity: 55%) (auc=0.800, p < 0.0001, %95 ci (0.679-0.931)). in addition the cut-off value for serum keap-1 was 913 pg/ml (sensitivity: 65%specificity: 60%) (auc = 0.741, p < 0.004, %95 ci (0.606-0.875)). the normal value of serum total copper level in healthy population was 63.7-140.12 pg/ml. a serum median level of total copper value in bc patients was 101 (min:38-max:219) pg/ml (min:1463-max:20645) and in control group was 126 pg/ml (min:80-max:247). a serum median level of zinc in bc patients was 146 pg/ ml (min:61-max:279) and in control group was 180 pg/ml (min:135-max:326). serum levels of copper and zinc were found to be statistically significantly lower than the control group (p=0.008 and p=0.001, respectively) (table 2). subgroup analysis performed based on the stages of the bc showed no difference in the staging and grading of the tumours caused by serum levels of zinc and copper (p = 0.26 and p = 0.89, respectively). in addition, tissue levels of nrf-2 and keap-1 were detected to cause no significant difference in the staging and grading of the tumours. the only significant difference between bc stages/grades was found in the tissue copper level (p : 0.038). when we analysed the subgroups for tissue copper level, this significance only occurred between ta low grade versus t2 (p : 0.001), ta high grade versus t2 (p : 0.02), and cis versus t2 (p : 0.04) stages (table 3). values and statistical analyses of the trial data for serum and tissue copper, zinc, nrf-2, and keap-1 according to table 3. the comparison of copper levels in bladder cancer tissue for significant subgroups. bladder tumour staging/grading n (%) cu tissue values (pg/ml) p value ta low grade versus 7 (21%) 9.96 (3.7-119.8) 0.001 t2 high grade 6 (28%) 2.8 (1.1-3.7) cis versus 2 (6%) 11.1 (10.8-11.3) 0.04 t2 high grade 6 (28%) 2.8 (1.1-3.7) ta high grade versus 3 (9%) 4.6 (4.3-4.9) 0.02 t2 high grade 6 (28%) 2.8 (1.1-3.7) bladder tumour staging n (%) average values (min-max) p value keap-1 (serum) pg/ml ta low grade 7 (21%) 1025 (150-10897) 0.67 cis 2 (6%) 3452 (1154-5750) ta high grade 3 (9%) 975 (788-1960) t1 low grade 9 (28%) 1088 (383-3050) t1 high grade 5 (15%) 2175 (375-4160) t2 high grade 6 (28%) 1038 (420-4160) keap-1 (tissue) pg/ml/mgprt ta low grade 7 (21%) 130 (8-600) 0.62 cis 2 (6%) 166 (68-265) ta high grade 3 (9%) 37 (25-106) t1 low grade 9 (28%) 50 (19-185) t1 high grade 5 (15%) 111 (22-219) t2 high grade 6 (28%) 70 (22-219) table 4. the correlation between bladder tumour stage and keap-1 levels. bladder cancer and oxidative stress-doğan et al. the stages and grades are shown in tables 4 to 7. discussion the dysregulation of the ror mechanism may play a role in the pathology of tumorigenesis. it activates the abnormal introduction of the signalling pathway that triggers the tumor formation. the uncontrolled growth of the cells leads to the development of the cancer mass with the help of the reactive oxygen-nitrogen species, signal transduction, transcription factors, and kinases/ phosphatases cascades(16). copper and zinc are some of the fundamental molecules involved in oxidative stress. they contribute to the structure of antioxidant enzymes as co-factors(10). previous studies have shown that oxidative stress may be an important factor in the development of bc(7,16-19). it has known that the intake of vitamins and antioxidants decreases bc recurrence (20). mazdak et al. also stated that the distribution of total antioxidant activity did not show normal pattern in patients with bc. they revealed that the patients with bc had a lower level of total antioxidant activity(7). nfr-2/keap-1 complex has also an important role in antioxidant activity. nfr-2 is a transcription factor belonging to cap’n’collar family (cnc) in this complex and has a close interaction with keap-1. keap-1 is another molecule of this complex. it acts as a sensor to identify the oxidant and electrophilic compound(8). when the cell is exposed to oxidative stress, it separates from keap-1. the free nrf-2 quantity increases in the cytoplasm. when a certain concentration is achieved, nrf-2 molecules translocate to the nucleus and bind to antioxidant response element (are) region. are is present in the promotor region of many antioxidant enzymes. this region provides the transcriptional activation of the detoxifying enzymes and antioxidant molecules in the cells exposed to oxidative stress(15). while its relation with several types of cancer has been evaluated in the literature, there is no study evaluating the relationship between the bc and nrf-2/keap-1 complex. the somatic mutation of the nrf-2 prevents it from being identified by keap-1, and leads to nrf-2 up-regulation. this mechanism has been demonstrated to play a role in pulmonary, head/neck, and oesophagus cancer(21-23). similarly, keap-1 mutations had been detected in pulmonary and gallbladder carcinoma tissues(24-25). keap-1 mutations cause over-expression of nrf-2 in the cancer cells and activation of the cytoprotective proteins in response. similar findings are also thought to be in association for bc. in our trial, when the bc and the control groups are compared, serum nrf-2, keap-1, copper and zinc levels were observed to have statistically significant differences. being an important part of the oxidative stress, trace elements in the serum were detected to be significantly reduced in patients with bc. we believe that this reduction may be associated with the fact that trace elements such as zinc and copper are used as co-factors of the enzymes acting to prevent oxidative stress or used for system activation. furthermore, nrf-2 and keap-1 increased in bc patients that show the presence of oxidative stress indirectly. the increase of nrf-2 and keap-1 was statistically considerable in patients with bc compared to the control group. it suggests that oxidative stress is an important factor in the development of bc. similar trials are showing the relationship between bc and copper and zinc levels in the serum(10,12,26). when the results of these studies are examined, different data are obtained. in the previous studies, the serum levels of zinc have been found to be generally low in cases with bc and in the meta-analysis by song et al. this reduction was found to be significant (10). consistent with the literature findings, in the prestable 5. the correlation between bladder tumour stage and nrf-2 levels. bladder tumour staging average values (min-max) p value nrf-2 (serum) pg/ml ta low grade 7500 (1462-206445) 0.73 cis 17261 (5771-28750) ta high grade 4875 (3938-9800) t1 low grade 5438 (1916-15250) t1 high grade 10875 (1875-20800) t2 high grade 5188 (2100-20800) nrf-2 (tissue) pg/ml/mgprt ta low grade 6598 (1056-74967) 0.65 cis 20785 (8457-33113) ta high grade 4685 (3094-13282) t1 low grade 6287 (2358-23114) t1 high grade 13902 (2748-27366) t2 high grade 8801 (2723-27366) bladder tumour staging average values (min-max) p value copper (serum) pg/ml ta low grade 101 (38-146) 0.89 cis 106 (97-114) ta high grade 88 (86-1467) t1 low grade 100 (63-219) t1 high grade 115 (98-146) t2 high grade 105 (84-155) copper (tissue) pg/ml/mgprt ta low grade 10 (4-120) 0.03 cis 11.07 (10.84-11.31) ta high grade 4.59 (4.29-4.87) t1 low grade 4.32 (1.68-11.50) t1 high grade 3.99 (2.97-13.59) t2 high grade 2.75 (1.06-3.74) table 6. the correlation between bladder tumour stage and copper levels. bladder cancer and oxidative stress-doğan et al. urological oncology 425 vol 18 no 4 july-august 2021 426 ent trial, the serum levels of zinc of the cases with bc were found to be significantly lower. the relationship between bc and the serum level of copper has been reported in varying degrees in the literature. the general opinion is that the serum levels of copper in cases with bc are increased compared to the control group. in the meta-analysis by song et al., serum level of copper was detected to be increased in patients with bc.(10) in our study, the serum level of copper was detected to be considerably lower than the control group which is not consistent with the literature data(12). on the other hand, there were some studies that state no relationship between bc and control groups(26,27). the subgroup heterogeneity of bc for stage and grade might be one reason for this inconstancy. we choose most of our cases from high-risk nmibc and muscle invasive bc. the status of stage and grade might affect the copper levels. in addition, the copper level may also be involved in different mechanisms in this patient group. we believe that this inconsistency is associated with the fact that there are not enough studies to conduct a meta-analysis on this subject. in our study, we found that only the tissue level of copper was significant for bc and this significance only occurred between ta low versus t2, ta high versus t2, and cis versus t2 stages. we could not find any correlation between t1 and other stages. it might be due to the invasion of lamina propria (t1) is the transition layer for muscle invasion. for this reason, table 7. the correlation between bladder tumour stage and zinc levels. bladder tumour staging median values (min-max) p value zinc (serum) pg/ml ta low grade 140 (102-179) 0.26 cis 202 (193-211) ta high grade 130 (112-147) t1 low grade 159 (61-204) t1 high grade 143 (129-164) t2 high grade 150 (116-279) zinc (tissue) pg/ml/mgprt ta low grade 36 (13-148) 0.06 cis 67 (48-87) ta high grade 16 (6-36) t1 low grade 21 (4-127) t1 high grade 20 (9-76) t2 high grade 11 (2-25) the results might show only significant results with distinct stages. the serum levels of nfr-2 and keap-1 in cases with bc were found to be considerably higher than those of the control group. while there are no data regarding the bc, the serum levels of nrf-2 and keap-1 were found to be increased in patients with prostate, breast, and pulmonary cancers(28). the blood levels of these molecules that are the active components of the antioxidant system were also found to be increased in our study. we also evaluated the position of serum and tissue zinc, copper, nrf-2 and keap-1 molecules as bc markers. no relationship was detected between these molecules and the pathological stages except the copper tissue levels of the bc. while there is no study regarding the bc, there are some studies showing the relationship between nrf-2 and keap-1 molecules, and other urological cancers(29). nrf-2 levels differ in benign and malignant prostate tissue with being significantly more expressed in tissues with prostate cancer compared to benign tissue. furthermore, a correlation was detected between the stage of the prostate cancer and nrf-2 levels(29). limited number of participants and the non-homogeneous distribution of the bc stages were the negative aspects of this trial. the highly broad reference ranges of nrf-2 and keap-1 were also the other negative aspects of the study. in addition, the patient and control figure 2. the roc curve for serum nrf-2 and keap-1 in bladder cancer patients. bladder cancer and oxidative stress-doğan et al. group could not have exactly similar patterns for the type of ror stress, the region of inhabitance of participants and the duration of exposure to agents. we know that copper and zinc had previously been studied in bc, however, as nrf-2 and keap-1 had not been studied before, we hope that this trial paves the way for future trials. we think that conducting much larger, comprehensive, new trials on this timely subject will give way to make the follow-up protocol of the patients with bc less invasive and more cost effective. conclusions the serum levels of zinc and copper were found to be significantly decreased and the serum levels of nrf2 and keap-1 were found to be increased in patients with bc. for the prediction of the stage of the bc, it was detected that only the tissue level of copper was significant and this significance only occurred between ta low grade versus t2, ta high grade versus t2, and cis versus t2 stages. other variables were observed to be non-significant for the prediction of the tumour stage. in this regard, we believe that the tissue level of copper may aid other markers and cystoscopy in the diagnosis and follow-up of the patients. acknowledgement this investigation was supported by tekirdağ namık kemal university scientific research projects committee with project number nku-bap.00.20.tu.15.01. conflict of interest we have no conflict of interest to declare. references 1. antoni s, ferlay j, soerjomataram i, znaor a, jemal a, bray f. bladder cancer incidence and mortality: a global overview and recent trends. eur urol. 2017; 71: 96-108. 2. cumberbatch mgk, jubber i, black pc, esperto f, figueroa jd, kamat am, kiemeney l, lotan y, pang k, silverman dt, znaor a, catto jwf. epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018. eur urol. 2018 ;74:784-795 3. babjuk m, burger m, compérat e, gontero p, mostafid ah et al. eau guidelines on nonmuscle-invasive (ta, t1 and cis) bladder cancer, in eau guidelines. 2020, european association of urology guidelines office arnhem, the netherlands. 4. tan ws, tan wp, tan my, khetrapal p, dong l, dewinter p, feber a, kelly jd. novel urinary biomarkers for the detection of bladder cancer: a systematic review. cancer treat rev. 2018 ;69:39-52. 5. valko m, leibfritz d, moncol j, cronin mt, et al. free radicals and antioxidants in normal physiological functions and human disease. int j biochem cell biol 2007;39:4484. 6. mazdak, h., mirkheshti, n., movahedian, a., yazdekhasti, f., & shafian, m. (2009). manganese, chromium and the oxidation status in bladder cancer. trace elements & electrolytes, 26(2). 7. mazdak h, tolou_ghamari z, gholampour m. bladder cancer: total antioxidant capacity and pharmacotherapy with vitamin-e. international urology and nephrology, 1-6. 8. nur a. resveratrolün hipoksi-reoksijenasyonu ile i̇ndüklenen i̇n vitro endotel hücresi hasarına etkisinin ve nrf-2 'nin olası rolünün araştırılması (tez). i̇zmir dokuz eylül üniversitesi 2012 9. hoekstra wg, suttie jw, ganther hg, mentz w (1974) trace elements metabolism in animals. university park press, baltimore, 61 10. song m. songming h..zinc and copper levels in bladder cancer: a systematic review and meta-analysis.bioltrace elem res (2013) 153:5–10 11. navarro ss, rohan te (2007) trace elements and cancer risk: a review of the epidemiologic evidence. cancercauses control 18:7–27 12. mazdak, h., yazdekhasti, f., movahedian, a., mirkheshti, n., & shafieian, m. (2010). the comparative study of serum iron, copper, and zinc levels between bladder cancer patients and a control group. international urology and nephrology, 42, 89-93. 13. kwak mk, itoh k, yamamoto m, et al. enhanced expression of the transcription factor nrf2 by cancer chemopreventive agents: role of antioxidant response elementlike sequences in the nrf2 promoter. mol cell biol 2002;22:2883-92. 14. oh, y. s., & jun, h. s. (2018). effects of glucagon-like peptide-1 on oxidative stress and nrf2 signaling. international journal of molecular sciences, 19(1), 26. 15. taguchi, k., & yamamoto, m. (2017). the keap1–nrf2 system in cancer. frontiers in oncology, 7, 85. 16. mazdak h, gholampour m, tolou ghamri z. a quick review of redox state in cancer: focus to bladder the gulf journal of oncology, 2020, 1:59-62. 17. akcay t, saygili i, andican g, yalcin v (2003) increased formation of 8-hydroxy-2′ deoxyguanosine in peripheral blood leukocytes in bladder cancer. inturol 71:271–274. 18. willett wc, macmahon b (1984) diet and cancer—an overview. n engl j med 310:697– 703 19. nelson rl (1992) dietary iron colorectal cancer risk. freeradicbiolmed 12:161–168. 20. mazdak h, zia h (2012) vitamin e reduces superficial bladder cancer recurrence: a randomized controlled trial. int j prev med 3:110–115. 21. shibata t, ohta t, tong ki et al. cancer related mutations in nrf2 impair its recognition by keap1–cul3 e3 ligase and promote malignancy. proc. natlacad. sci. usa 2008; 105; 13568–13573. 22. padmanabhan b, tong ki, ohta t et al. structural basis for defects of keap1 activity provoked by its point mutations in lung cancer. mol. cell 2006; 21; 689–700. 23. kim yr, oh je, kim ms et al. oncogenic bladder cancer and oxidative stress-doğan et al. urological oncology 427 vol 18 no 4 july-august 2021 428 nrf2 mutations in squamous cell carcinomas of oesophagus and skin. j. pathol. 2010; 220; 446–451. 24. singh a, misra v, thimmulappa rk et al. dysfunctional keap1– nrf2 interaction in non-small-celllungcancer. plosmed. 2006; 3; e420. 25. shibata t, kokubu a, gotoh m et al. geneticalteration of keap1 confersconstitutive nrf2 activation and resistance to chemotherapy in gallbladder cancer. gastroenterology 2008; 135; 1358–1368. 26. gecit i, kavak s, demir h, gunes m, pirincci n, cetin c, ceylan k, benli e, yildiz i (2011) serum trace element levels in patients with bladder cancer. asianpac j cancer p 12:3409– 3413 27. golabek t, darewicz b, borawska m, socha k, markiewicz r, kudelski j (2012) copper, zinc, and cu/zn ratio in transitional cell carcinoma of the bladder. urol int 89:342–347 28. hartikainen jm, tengstrom m, kosma vm, kinnula vl, mannermaa a, soini y. genetic polymorphisms and protein expression of nrf-2 and sulfiredoxin predict surivival outcomes in breast cancer.cancerres 2012; 72:5537-46. 29. nuclear factor erythroid 2-related factor-2 activitycontrols 4-hydroxynonenal metabolism and activity in prostate cancer cellsp. pettazzoni, e. ciamporcero, c. medana, s. pizzimenti, f. dal bello, v.g. minero, c. toaldo, r. minelli, k. uchida, m.u. dianzani, r. pili, g. barrera .freeradic. biol. med., 51 , pp. 1610–1618 bladder cancer and oxidative stress-doğan et al. miscellaneous protective effects of colchicine on testicular torsion/detorsion-induced ischemia/reperfusion injury in rats kerem han gozukara1*, oguzhan ozcan2, tumay ozgur3, yusuf selim kaya1, okan tutuk4 purpose: to evaluate the short-term use of colchicine on preventing ischemia-reperfusion injury after surgery in an experimental animal model. materials and methods: a total of 40 rats were divided into five groups (n = 8). sham (sh), ischemia-reperfusion (i/r), i/r and colchicine-treated for once per-operatively (i/rc1), i/r and colchicine-treated for 5 days postoperatively (i/rc5), and i/r and placebo given for 5 days (i/rp) groups. testicular torsion was created by rotating the testicle 720o in clockwise direction and held for 3 hours. in group i/rc1 30 minutes before detorsion, p.o. 1 mg/kg ml infusion of colchicine was given only once. in group i/rc5, colchicine continued p.o. once daily for five days. tissue malonyldialdehite (mda), superoxide dismutase (sod), glutathione peroxidase (gpx) and catalase (cat) were measured for evaluating the oxidative stress. apoptosis levels shown with caspase-3 staining and mean seminiferous tubular diameter (mstd), germinal epithelial cell thickness (gect), and mean testicular biopsy score (mtbs) were used to evaluate the germ cell damage. results: decreased protein mda levels therewithal increased sod, cat and gpx levels achieved in i/rc5 group when compared to i/r group and did not differ from the i/rp group (p < 0.05). mstd, gect, and js were better in i/rc5 than i/rp which showed the natural course of i/r damage in testis (p < 0.005). caspase 3 positivity, as an apoptosis indicator, were significantly lower (p < 0.05) in i/rc5 group in comparison with i/r, i/rc1, and i/rp groups. conclusion: the usage of colchicine as a complementary treatment after definitive surgery reduce early-onset ischemia-reperfusion damage and diminishes apoptosis. keywords: colchicine; perfusion; injury; rat; torsion introduction as a urologic emergency, testicular torsion is seen in 4,5/100000 males aged 1-25.(1) this situation may result in testicular atrophy in the absence of definitive surgery within hours. detorsion of the testis causes ischemia/reperfusion (i/r) injury. the primary indicators of i/r injury are lipid peroxidation and apoptosis arisen from neutrophil recruitment, reactive oxygen species (ros) and proinflammatory cytokines.(2) low concentrations of ros promotes sperm capacitation but excessive production acts quite the contrary.(3) high levels of ros degrade polyunsaturated lipids which are found in the plasma membrane of spermatozoa, forming malondialdehyde (mda) that is an indicator of oxidative stress. on the other side, several protective anti-oxidant scavenger enzymes such as superoxide dismutase (sod), glutathione peroxidase (gpx) and catalase (cat) neutralize free radicals. in the presence of excessive ros production cellular dysfunction and related apoptosis begin. 1 urology department , mustafa kemal university school of medicine, turkey. 2 biochemistry department , mustafa kemal university school of medicine, turkey. 3 pathology department, mustafa kemal university school of medicine, turkey. 4 physiology department, mustafa kemal university school of medicine, turkey. *correspondence: mustafa kemal university, school of medicine, tayfur ata sokmen hospital urology department 4th floor /19, 31010, serinyol, hatay, turkey. phone : 903262900-3379 (int.) mobile: 905057462464. e-mail: keremgozukara@gmail.com. received october 2018 & accepted june 2019 apoptosis is a physiologic mechanism used to eliminate nonfunctioning and undifferentiated cells.(4) apoptosis occurs in two important pathways, intrinsic and extrinsic whom the caspases are the unique markers of entire processes. the cell death cascade was initiated either with the death receptor-mediated namely extrinsic way or with the mitochondrion-mediated procaspase-activation pathway known as the intrinsic way.(5) in caspase family, caspase-3 is a significant mediator of both apoptotic and necrotic cell death by inhibiting proteins that are vital for repairing dna injury, intercellular signal transmission, cell cytoskeleton and continuation of the cell cycle.(6) colchicine is a tricyclic alkaloid of the colchicum autumnale plant which is a member of colchicaceae plant family, one of the oldest therapeutic substances known to mankind. it has been used for gout disease, familial mediterranean fever, acute pericarditis, acute arthritis, and behçet's disease.(7) the suppressing effect of colchicine on inflammation has not been enlightened precisely yet, but the prevailing opinion is inhibition of urology journal/vol 17 no. 3/ may-june 2020/ pp. 294-300. [doi: 10.22037/uj.v0i0.4918] the neutrophils and endothelial adhesion molecules by disrupting microtubule polymerization in leucocytes.(8) we hypothesize that the anti-inflammatory effect of colchicine may be beneficial in i/r injury which is closely related to leucocyte accumulation, apoptosis, and increased tissue ros levels. therefore, we aimed to evaluate the protective effect of colchicine treatment on ischemia-reperfusion damage in a testicular torsion rat model by caspase-3 staining. materials and methods experimental design the study was conducted in mustafa kemal university school of medicine animal laboratory by local ethical committee approval (date and decision number: 2015.02.19 / 8). a total of 40 wistar albino adult male rats weighing 320-440 g were included in the study. rats were caged individually in a controlled environment at 200c to 220c room temperature, 50% to 55% relative humidity, and light/dark cycles of 12 hours and were fed ad libitum. they were acclimatized for ten days. in all procedures that were applied to the animals according to local ethical committee laboratory rules and rules of guidelines for the care and use of laboratory animals of the us national institutes of health (washington, dc) was obeyed. rats were randomly divided into five groups (n:8). intramuscular ketamine hydrochloride (50 mg/kg ketalar; eczacıbasi, istanbul, turkey( and xylazine hydrochloride were used for anesthesia. rats were placed in a effectiveness of colchicine in testis torsion-gozukara et al. figure 1. caspase-3 staining in groups figure 2. morphology and spermatogenesis in group 4, 5. a: impaired and aborted spermatogenesis (→) with disorganised epitelium, some germ cells absent, necrotic or degenerated in group 5 (hematoxylen&eosinx200). b: preservation of spermatogenesis in some of the seminifer tubules with regular and compact germ cells (→) in group 4 (hematoxylen&eosinx200). vol 17 no 03 may-june 2020 295 miscellaneous 296 dorsal recumbent position in a sterile condition. under anesthesia the scrotal area was shaved and cleaned, disinfected by povidone-iodine solution and a scrotal midline incision was done. torsion was performed by rotating the spermatic cord 720 degrees clockwise along the longitudinal axis and fixed in the scrotal pouch by 5/0 nontraumatic absorbable suture.(9) the scrotal incision was covered with a moist, warm sterile cover for 3 hours and the surgical technique was the same for all groups. in the sham group, only a scrotal incision was performed. in i/r group, after 3 hours of testicular torsion, testicle was detorsioned and reperfusioned for 3 hours and then orchiectomy was done. in i/rc1, following 3 hours of ischemia; p.o. 1mg/kg ml colchicine (recordati pharmaceutical industry and trade inc., esenyurt, istanbul) was given 30 minutes prior to detorsion, and then the testicle was removed after 3 hours of reperfusion. in i/rc5 group, p.o. 1mg/kg ml colchicine was given 30 minutes before detorsion and continued for five days postoperatively, and the testicle was removed. in i/rp, all procedures were followed the same as the i/rc5 group; only placebo (0,2 ml of serum physiologic; %0.9 p.o.) was given instead of colchicine. at the end of the experiment, under the general anesthesia, for histologic and biochemical evaluation 5-6 cc blood was taken from the heart of the rats and euthanasia was applied by exsanguination. the biochemical examination was performed for determining the oxidative stress levels and studying antioxidant agents in the blood and tissue specimens over mda, sod, cat, and gpx. pathology methods a pathologist -blinded to the study protocolevaluated prepared slides, the mean seminiferous tubular diameter (mstd), germinal epithelial cell thickness (gect), and mean testicular biopsy score (mtbs) were used to evaluate in 20 seminiferous tubules of each section. (10) the mstd was calculated using an eyepiece micrometer (za3262, u-ocmc, 24 mm cross, 10/100x) mounted within one of the eyepiece objectives. at 400x power the field is 0.44 mm x 0.44 mm, yielding an area of approximately 0.19 mm2. the mstd of each testis was determined in microns. gect was determined by counting the number of epithelial cells from the basement membrane to the lumen at 90°, 180°, 270°, and 360°, and averaged. the mtbs was graded using johnsen's score.(11) a score of 1 to 10 was given to each tubule according to epithelial maturation: 10, complete spermatogenesis, with many spermatozoa, and germinal epithelium organized with a regular thickness, leaving an open lumen; 9, many spermatozoa present but germinal epithelium disorganized with marked sloughing or obliteration of the lumen; 8, only a few spermatozoa (fewer than 5 to 10) present; 7, no spermatozoa but many spermatids present; 6, no spermatozoa and only a few spermatids (fewer than 5 to 10) present; 5, no spermatozoa and no spermatids but several or many spermatocytes present; 4, only a few spermatocytes (fewer than 5) and no spermatids or spermatozoa present; 3, spermatogonia the only germ cells present; 2, no germ cells, but sertoli cells present; and 1, no cells present in tubular section. table 1. the body and testicular weights of the rats for all 5 groups n weight g testis weight g sham 8 350.5 ± 26 0.72 ± 0.17 a i/r 8 379.37 ± 29 0.58 ± 0.11 i/rc1 8 350.5 ± 26 0.57 ± 0.09 i/rc5 8 376.63 ± 30 0.49 ± 0.15 i/rp 8 367.37 ± 28 0.49 ± 0.08 p values > 0.005 .009 findings of the parameters were expressed as mean ± standart deviation. only statistically significant groups were marked with the letter of the alphabet ap =.012 sham vs i/rc5; p = .014 sham vs i/rp n mdaprot nmol/g sodprot u/g catprot k/mg protein gpxprot u/ g protein sham 8 113.4 ± 22,6a 1401.5 ± 189.5e 0.12 ± 0.017 h 277.6 ± 31.6 l i/r 8 336.4 ± 62.8 b 790.9 ± 177.2f 0.067 ± 0.011i 141.37 ± 26.1m i/rc1 8 364.1 ± 65.2 c 910.5 ± 136.4g 0.069 ± 0.01j 141.8 ± 31.6n i/rc5 8 188.1 ± 74.9 1246.4 ± 232.1 0.11 ± 0.019 k 215.8 ± 43 i/rp 8 359.6 ± 87.3d 978 ± 171.1 0.069 ± 0.026 151.4 ± 36.4 p values < 0.001 < 0.001 < 0.001 < 0.001 mdaprot, tissue malonyldialdehite; sodprot, tissue superoxide dismutase; catprot, tissue catalase; gpxprot, tissue glutathione peroxidase. findings of the parameters were expressed as mean ± standart deviation. only statistically significant groups were marked with the letter of the alphabet. ap < 0.001 sham vs i/r; p < 0.001 sham vs i/rc1; p = .001 sham vs irp bp = .007 ir vs irc5 cp = .002 i/rc1 vs i/rc5 dp = .008 i/rp vs i/rc5 ep < 0.001 sham vs i/r; p < 0.001 sham vs i/rc1; p = .003 sham vs irp fp = .006 ir vs irc5 gp = .04 i/rc1 vs i/rc5 hp < 0.001 sham vs i/r; p < 0.001 sham vs i/rc1; p < 0.001 sham vs irp ip = .004 ir vs irc5 jp = .005 i/rc1 vs i/rc5 kp = .006 i/rp vs i/rc5 lp < 0.001 sham vs i/r; p < 0.001 sham vs i/rc1; p < 0.001 sham vs irp mp = .01 ir vs irc5 np = .0016 i/rc1 vs i/rc5 table 2. biochemical results of all 5 groups effectiveness of colchicine in testis torsion-gozukara et al. immunohistochemistry section of 3-4 mm thickness was cut from the paraffin blocks of these preparations and then was de-paraffinized and rehydrated through a graded series of alcohol, microwave antigen retrieval method was used, endogenous peroxidase was blocked in 5% h2o2 at room temperature for 8 minutes, followed by washing with pbs three times. the slices were then incubated with caspase 3 (cpp32-ab-4) (prediluted polyclonal rabbit primer antibody, thermo scientific, freemont, ca, usa.) immunohistologic staining (ihs) was applied, followed by washing with pbs three times. subsequently, the slices were incubated with biotinylated goat anti-polyvalent/labvision secondary antibodies at room temperature for one h, washed with pbs three times, followed by incubation with dab reagent for 8 min at room temperature. nuclear staining in tonsil tissue was accepted as the positive control. caspase-3 positive cells were count in one mm2 of the tissue modified from the study of mosadegh et al.(12) biochemical methods testis tissues were weighed and homogenized in icecold phosphate-buffered saline at ph 7.4 (10% w / v). after centrifugation at 10 000 rpm for 20 minutes, all supernatants were removed for biochemical analysis. protein levels of supernatants and homogenates were measured by the bradford method using bovine serum albumin as a standard.(13) the mda levels of homogenates were measured by the double heating method of draper and hadley.(14) mda equivalents (1,1,3,3-tetramethoxypropane, lot no, mkbp9901v, sigma-aldrich) were used as standards, and mda results were expressed as nmol / g-protein. catalase activities were assayed by the aebi method. (15) the decomposition of the substrate h 2 o 2 was spectrophotometrically monitored at 240 nm (shimadzu uv 1601, japan). absorption reduction was measured and expressed as k / mg protein. gsh-px activity was measured by paglia and valentine method.(16) the enzymatic reaction was initiated by the addition of h 2 o 2 to the reaction mixture containing reduced glutathione, reduced nicotinamide adenine dinucleotide phosphate and glutathione reductase. a spectrophotometer monitored the absorbance change at 340 nm. one unit of gsh-px is defined as nadph micromoles oxidized per minute. the activity was given as units per g protein. total (cu-zn and mn) sod activity values were obtained from sun et al.(17) and durak et al.(18) a unit of sod, nitro blue tetrazolium (nbt), was defined as the amount of enzyme causing 50% inhibition at the reduction rate. the results are expressed in units per g protein. statistical analysis kolmogorov-smirnov test was performed to determine whether the distribution of the data obtained was normal or not. weigth, testicular weight gect, mstd, caspase 3 staining, mdaprot, sodprot, catprot and gpxprot values were analysed with one-way analysis of variance and as a post-hoc test tukey’s was used to determine the group that caused statistical difference between groups. kruskall wall test was used to analyse johnsen score values. bonferonni corrected mann whitney u test was used to compare two by two groups regarding to johnsen scores to determine statistically different groups. each test group was compared with the appropriate control groups and p values less than 0.05 were considered as significant except johnsen groups where p = 0.005 were considered as significant. the results were expressed as mean + standard error mean or median and 25-75 percentile values. spss v21.0 program was used for statistical analysis. results the mean body and testicle weights of the rats were not statistically different between groups. (table 1) the biochemical and histopathological findings were given in table 2, and 3. in the 5-day colchicine given the group, the protein mda levels were significantly lower than i/r and i/rp groups (p < 0.002) which were reached the significantly highest levels. table 3. histopathologic results of all 5groups n johnsen score gect mstd sham 8 9.6 ± 0.52 b 8.5 ± 0.53 f 12.5 ± 1.93 j i/r 8 7 ± 0.54 c 7.1 ± 0.84 g 9.1 ± 1.36 k i/rc1 8 6.6 ± 0.52 d 6.9 ± 0.64 h 9.4 ± 0.91l i/rc5 8 6.4 ± 0.74 e 6.6 ± 0.74 i 7.1 ± 0.84 m i/rp 8 4.3 ± 0.52 4.5 ± 1.07 4.9 ± 0.84 p values < 0.001 < 0.001 < 0.001 gect, germinal epithelial cell thickness; mstd, mean seminiferous tubular diameter findings of the parameters were expressed as mean ± standart deviation. only statistically significant groups (p=0.005) were marked with the letter of the alphabet bp< 0.001 sham vs i/r; sham vs i/rc1; sham vs i/rc5; sham vs irp cp< 0.001 i/r vs i/rp dp< 0.001 i/rc1 vs i/rp ep< 0.001 i/rc5 vs i/rp fp = .018 sham vs i/r; p = .001 sham vs i/rc5; p< 0.001 sham vs irp gp = .001 i/r vs i/rp hp< 0.001 i/rc1 vs i/rp ip = .005 i/rc5 vs i/rp jp = .013 sham vs i/r; p = .017 sham vs i/rc1; p < 0.001 sham vs i/rc5; p < 0.001 sham vs irp kp = .036 i/r vs i/rc5; p < 0.001 i/r vs i/rp lp = .001 i/rc1 vs i/rc5; p < 0.001 i/rc1 vs i/rp mp = .001 i/rc5 vs i/rp effectiveness of colchicine in testis torsion-gozukara et al. vol 17 no 03 may-june 2020 297 miscellaneous 298 gpx, cat, and sod levels were higher in sh and i/ rc5 groups (p < 0.05). also, antioxidant levels (sod, cat) in i/rc5 group did not differ from the sh group statistically (p > 0.05). as a positive indicator of apoptosis, caspase-3 positivity was higher in group i/r, i/rc1, and i/rp than group sh and i/rc5. i/rc5 group had lower caspase-3 positivity than group i/r (p < 0.05). (figure 2) when comparing johnsen’s scores in i/rc5 group with i/r and i/rc1 groups, there was no statistical difference (p = .211 and p = .905, respectively) that implies to an alleviation in tissue deterioration. also, i/rp group’s johnsen’s scores were significantly lower than the others (p < 0.001). the mean seminiferous tubular diameter and germinal epithelial cell thickness were affected negatively in all groups but group sh. with the use of colchicine in the postoperative period, in i/rc5 group, mstd and gect measurements were significantly better than group i/rp (p < 0.005) which showed the natural course of ischemic events and not statistically differed from the group i/r. (figure 1) discussion testicular torsion is a urological urgency that's incidence peaks in 2 periods of life (neonatal and prepubertal), resulting in testicular infarct if not immediately treated. the first-line treatment is surgery(19), but testicular salvage and postoperative changes do not only depend on operation. because atrophy can be seen in one-fourth of the torsion cases that are treated in time. (20) logically an additional medical salvage therapy should be considered in the postoperative period. in this respect, numerous substances like vardenafil, sildenafil, rosuvastatin, coenzyme q10, different surgical, and interventional techniques showed positive results on preserving testis from ischemia-reperfusion damage.(221-23) however, none of these studies discuss their subjects for postoperative usage. from this point of view, our study revealed that oxidative stress was reduced in rats which colchicine usage was started peroperatively and continued for five days after the operation. additionally, the levels of anti-oxidative agents such as sod, cat, and gpx kept their levels in 5-day colchicine group postoperatively. total antioxidant capacity and total oxidative stress findings were also significantly better with the short term colchicine usage (p < 0.005). this favorable effect of colchicine may be explained with leucocyte interaction. chappey et al.(24) determined the colchicine deposition dynamics in leucocytes and revealed that colchicine rises to the plasma peak level at 1-hour after application and accumulates mostly in leukocytes. mitsui et al.(25) showed increased major proinflammatory cytokines which lead to leucocyte accumulation in the tissues in the first hours of the torsion. so colchicine could be easily accumulated in migrated leucocytes. after this, the main anti-inflammatory effect of colchicine occurs by inhibiting the assembly and polymerization of microtubules which are the keystones in cell migration, secretion of cytokines, maintenance of the cytoskeleton and cell shape.(26) additionally, colchicine suppresses the tnf-alpha production from macrophages that generated after tissue necrosis induced by lipopolysaccharides.(27,28) in the present study, short term colchicine treatment group; sod, cat, and gpx molecules which are endogenous antioxidants commissioned to protect the steady-state of the cell against oxidative stress were found significantly higher as the sham group (p < 0.005). the high levels of endogenous anti-oxidants can be explained by the suppression of inflammation, which is triggered by many stress pathways, rather than increasing the generation of these molecules. the other possible protective mechanism of colchicine may be related to lipid peroxidation, cytosolic ca+2, and oxidative stress. testicular injury increases linearly with the degree and duration of torsion.(29) due to ischemia, new acidic environment induces ca+2 influx into cells in various ways. increased intracellular ca+2 levels trigger the activation of inflammatory markers and cell death especially over mitochondria.(30,31) at this point, korkmaz et al.(32) reported that colchicine has a reducing effect on cytoplasmic ca+2 release in neutrophils. in this way, colchicine reduces the oxygen radicals generated by mitochondria which are most damaging cellular macromolecules, lipids in particular. one of the most critical indicators of lipid peroxidation and the secondary index of oxidative stress is mda.(33) mda interacts with dna and proteins per the aldehyde component, which is toxic to the structure at high levels and causes irreversible damage linked to dna fragmentation, protein denaturation. we found that mda levels were significantly lower in the colchicine-treated group compared to other untreated groups (p < 0.005). caspase is one of the cysteine endoprotease families and plays a regulatory role in cell death and inflammation.(6) they have classified into two groups; apoptotic and inflammatory, and apoptotic caspases work as initiator or executioners. caspase 3 is a well-known executioner apoptotic caspase and proteolytically processed to the active form that is essential for apoptosis. (34-36) the active form of caspase 3 causes cell death by dna damage and protein degradation.(37) in our study, we found that caspase 3 staining in the 5-day colchicine-treated group was significantly lower (p < 0.005) when compared to groups without colchicine treatment and this score was not statistically different from the sham group, and even lower scores were obtained. this finding also emphasizes the less dna fragmentation and cell death with short term colchicine usage like forementioned mda. colchicine may trigger controlled apoptosis by stopping the cell cycle in the g2/m phase and contribute to planned cell death by microtubule depolymerization.(26) because of this feature, it has been tried for some cancer treatments(26) but not preferred due to its high side-effect profile. however, with the secondary necrosis or apoptosis which is seen in testicle torsion, the inflammatory, and immunogenic activity of colchicine become prominent; thus uncontrolled apoptosis is precluded(38). to our knowledge, long term usage of colchicine harms sperm cell maturation.(39) however, the sustained benefit of short-term colchicine treatment on torsioned-detorsioned testis survival is unknown and side effects arising from short term usage are still presumptive. in our study, when compared with the placebo group the johnsen score was better with 5-day colchicine treatment group. similar results were found with the gect and mtbs scores. the most significant damage to testicular tissue was created with the activation of inflammatory and apoptotic cascades.(40) these results have allowed us to concentrate on the potent aneffectiveness of colchicine in testis torsion-gozukara et al. vol 17 no 03 may-june 2020 299 ti-inflammatory effect of colchicine. in an overall perspective, the benefits outweigh the possible danger of short-term colchicine treatment in patients with torsion. experimental design and relatively small sample size are the major limitations of our study. however, this is one of the few studies related to colchicine treatment on testicular torsion. conclusions colchicine is a highly active and fructuous molecule on ischemia-reperfusion injury in testicle torsion animal model with short-term usage and may be a convenient option for this patient group over its noticeable anti-inflammatory effect. but further experimental animal studies are required to determine the drug dose, duration, and way of administration of colchicine in patients with testicular torsion. references 1. karaguzel e, kadihasanoglu m, kutlu o. mechanisms of testicular torsion and potential protective agents. nat rev urol. 2014;11:3919. 2. cuzzocrea s, riley dp, caputi ap, salvemini d. antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. pharmacol rev. 2001;53:135-59. 3. agarwal a, saleh ra, bedaiwy ma. role of reactive oxygen species in the pathophysiology of human reproduction. fertil steril. 2003;79:829-43. 4. oropesa avila m, fernandez vega a, garrido maraver j, et al. emerging roles of apoptotic microtubules during the execution phase of apoptosis. cytoskeleton (hoboken). 2015;72:435-46. 5. shoorei h, khaki a, khaki aa, hemmati aa, moghimian m, shokoohi m. the ameliorative effect of carvacrol on oxidative stress and germ cell apoptosis in testicular tissue of adult diabetic rats. biomed pharmacother. 2019;111:568-78. 6. choudhary gs, al-harbi s, almasan a. caspase-3 activation is a critical determinant of genotoxic stress-induced apoptosis. methods mol biol. 2015;1219:1-9. 7. slobodnick a, shah b, pillinger mh, krasnokutsky s. colchicine: old and new. am j med. 2015;128:461-70. 8. leung yy, yao hui ll, kraus vb. colchicine--update on mechanisms of action and therapeutic uses. semin arthritis rheum. 2015;45:341-50. 9. soltani m, moghimian m, abtahi-eivari sh, shoorei h, khaki a, shokoohi m. protective effects of matricaria chamomilla extract on torsion/ detorsion-induced tissue damage and oxidative stress in adult rat testis. int j fertil steril. 2018;12:242-8. 10. shokoohi m, shoorei h, soltani m, abtahieivari sh, salimnejad r, moghimian m. protective effects of the hydroalcoholic extract of fumaria parviflora on testicular injury induced by torsion/detorsion in adult rats. andrologia. 2018;50:e13047. 11. johnsen sg. testicular biopsy score count--a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. hormones. 1970;1:2-25. 12. mosadegh m, hasanzadeh s, razi m. nicotine-induced damages in testicular tissue of rats; evidences for bcl-2, p53 and caspase-3 expression. iran j basic med sci. 2017;20:199-208. 13. bradford mm. a rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. anal biochem. 1976;72:248-54. 14. draper hh, hadley m. malondialdehyde determination as index of lipid peroxidation. methods enzymol. 1990;186:421-31. 15. aebi h. catalase in vitro. methods enzymol. 1984;105:121-6. 16. paglia de, valentine wn. studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. j lab clin med. 1967;70:158-69. 17. sun y, oberley lw, li y. a simple method for clinical assay of superoxide dismutase. clin chem. 1988;34:497-500. 18. durak i, yurtarslanl z, canbolat o, akyol o. a methodological approach to superoxide dismutase (sod) activity assay based on inhibition of nitroblue tetrazolium (nbt) reduction. clin chim acta. 1993;214:103-4. 19. kapoor s. testicular torsion: a race against time. int j clin pract. 2008;62:821-7. 21. miklós á, bajor fz. a review of main controversial aspects of acute testicular torsion. journal of acute disease. 2016;5:1-8. 24. ustun h, akgul kt, ayyildiz a, et al. effect of phospodiesterase 5 inhibitors on apoptosis and nitric oxide synthases in testis torsion: an experimental study. pediatr surg int. 2008;24:205-11. 25. erol b, bozlu m, hanci v, tokgoz h, bektas s, mungan g. coenzyme q10 treatment reduces lipid peroxidation, inducible and endothelial nitric oxide synthases, and germ cell-specific apoptosis in a rat model of testicular ischemia/ reperfusion injury. fertil steril. 2010;93:2802. 26. karakaya e, ates o, akgur fm, olguner m. rosuvastatin protects tissue perfusion in the experimental testicular torsion model. int urol nephrol. 2010;42:357-60. 27. chappey on, niel e, wautier jl, et al. colchicine disposition in human leukocytes after single and multiple oral administration. clin pharmacol ther. 1993;54:360-7. 28. mitsui y, okamoto k, martin dp, effectiveness of colchicine in testis torsion-gozukara et al. miscellaneous 300 schmelzer jd, low pa. the expression of proinflammatory cytokine mrna in the sciatic-tibial nerve of ischemia-reperfusion injury. brain res. 1999;844:192-5. 29. bhattacharyya b, panda d, gupta s, banerjee m. anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin. med res rev. 2008;28:155-83. 30. rao p, falk la, dougherty sf, sawada t, pluznik dh. colchicine down-regulates lipopolysaccharide-induced granulocytemacrophage colony-stimulating factor production in murine macrophages. j immunol. 1997;159:3531-9. 31. li z, davis gs, mohr c, nain m, gemsa d. inhibition of lps-induced tumor necrosis factor-alpha production by colchicine and other microtubule disrupting drugs. immunobiology. 1996;195:624-39. 32. sessions ae, rabinowitz r, hulbert wc, goldstein mm, mevorach ra. testicular torsion: direction, degree, duration and disinformation. j urol. 2003;169:663-5. 33. sanada s, komuro i, kitakaze m. pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures. am j physiol heart circ physiol. 2011;301:h1723-41. 34. huang sh, song jp, qin j, rong j, wu zk. dynamics of interstitial calcium in rat myocardial ischemia reperfusion injury in vivo. j huazhong univ sci technolog med sci. 2014;34:37-41. 35. korkmaz s, erturan i, naziroglu m, uguz ac, cig b, ovey is. colchicine modulates oxidative stress in serum and neutrophil of patients with behcet disease through regulation of ca(2)(+) release and antioxidant system. j membr biol. 2011;244:113-20. 36. spirlandeli al, deminice r, jordao aa. plasma malondialdehyde as biomarker of lipid peroxidation: effects of acute exercise. int j sports med. 2014;35:14-8. 37. mcilwain dr, berger t, mak tw. caspase functions in cell death and disease. cold spring harb perspect biol. 2013;5:a008656. 38. crompton m, heid i. the cycling of calcium, sodium, and protons across the inner membrane of cardiac mitochondria. eur j biochem. 1978;91:599-608. 39. crompton m. the mitochondrial permeability transition pore and its role in cell death. biochem j. 1999;341 ( pt 2):233-49. 40. woo m, hakem r, soengas ms, et al. essential contribution of caspase 3/cpp32 to apoptosis and its associated nuclear changes. genes dev. 1998;12:806-19. 41. savill j, bebb c. apoptotic cell phagocytosis. in: cameron rg, feuer g, eds. apoptosis and its modulation by drugs. berlin, heidelberg: effectiveness of colchicine in testis torsion-gozukara et al. springer berlin heidelberg; 2000:151-77. 42. ehrenfeld m, levy m, margalioth ej, eliakim m. the effects of long-term colchicine therapy on male fertility in patients with familial mediterranean fever. andrologia. 1986;18:420-6. 43. lysiak jj, nguyen qa, kirby jl, turner tt. ischemia-reperfusion of the murine testis stimulates the expression of proinflammatory cytokines and activation of c-jun n-terminal kinase in a pathway to e-selectin expression. biol reprod. 2003;69:202-10. editorial guidelines for urological surgeries in the covid-19 pandemic: is it time for revision? amir h kashi1, seyyed mohammad ghahestani2* a few months after the advent of covid 19, urology and health bodies around the world issued various recom-mendations and practice lines about urology procedures with the aim of helping urologists to encounter this unexpected situation. the emphasis in such issues was on scheduling surgical operations with an aim to postpone them to a better situation in which the disease has presumably subsided and medical facilities, personnel, and equipment are eased. most of these guide lines endowed 1 to 3-month delays for elective and non-urgent operations.(1) twelve months after the start of covid-19, we are able to look at the national incidence patterns of this disease. we considered biweekly cases as active infections impacting the health sector and society, smoothing daily fluctuations(2). the following biweekly incidence patterns were observable: in some countries with an almost swift lockdown response, the study happened as projected. these countries followed a pattern in which secondary surges were smoother than the first one. germany, italy, singapore, switzerland, and the uk are included in this category (figure 1a). however, many other countries including countries with a high incidence of covid-19 in primary surge are not classified into the above category of as projected pathway. in these countries, the subsequent surges after the primary surge were either stronger or were totally merged into a constant rising pattern after the primary surge. curves of biweekly cases in the czech republic, france, iran, netherlands, romania, spain, and the us reveal second surges stronger than the primary surge (figure 1b, 1d). the second surges in these countries were observed one to three months after the primary surge when elective postponed operations had been scheduled primarily. intriguingly in japan, the philippines, and south korea with a brilliant response to the primary surge of covid-19, still, the secondary surges were greater than the primary surge (figure 1d). release of first surge national restrictions and less compliance of people with covid-19 protocols in the chronic phase of disease could be speculated as reasons for the observable strong second surge. in iran, according to formal governmental declarations, the adherence to covid-19 protocols by the general population decreased from 77% in the first two months of covid-19 to less than 22% after three months.(3) therefore, after the postponement period advocated by surgical guidelines, in many countries, the situation had been often no better, if not worse. since the european association of urology guideline committee, rapid reaction group issued its guideline on 21st april 2020, three months later in countries of figure 1b which include many european countries the situation is either the same or aggravating. we recognize the fact that the very first impact was so startling that this postponement was the only way to concentrate the facilities on the new situation and provide a time for deployment but the continuation of such a policy and universal adoption of these recommendations may be inappropriate in many countries of figures 1b, 1c, and 1d. it is interesting to mention that during the time of writing this letter two countries namely the netherlands and the uk moved from within category 1a into category 1b denoting the necessity of a dynamic vigilance. in iran, secondary surges show a fluctuating course, and the situation forecast will not be better in the upcoming months. we had examples of patients who were a candidate for elective prostatectomy due to urinary retention who could not tolerate our recommendation of operation postponement and keeping foley catheter for several weeks and individually opted to undergo elective surgery in other remote centers with fewer resources(4). recommendation treatise of iranian urology association prudently incorporated these epidemiologic data into the pamphlet(iua-ctp)(5). the authors recognized the wide variation of epidemiologic situations in different provinces and considered this fact in their document. this is especially important in the countries with the vast area and population distribution demonstrating a great difference with european countries. we think that postponement is not a panacea for dealing with sequential surges of covid-19 and the decision to postponement may culminate in doing the surgery in a worse situation. instead, the decision to perform an elective operation should be dependent on the availability of hospital beds, icu beds, personal protective equipment, and other necessary resources in a country or a province and the exact time the patient is visited. national or regional committees can formulate contemporary guidelines on elective operations based on the availability of regional/national medical resources rather than adopting a universal guideline. production of effective vaccines may change the landscape. nevertheless, in many countries, mass vaccination may happen several months later and till then, the protocols are based on previous assumptions. this again reiterates the difference in circumstances. monitoring of the situation and considering imminent vaccination in newly evolving protocols are paramount. we stipulate iua-ctp under the auspices of the iranian urology association 1urology and nephrology research center (unrc), shahid labbafinejad hospital, shahid beheshti ,university of medical sciences (sbmu), tehran, iran. 2urology department ,children medical center hospital ,tehran university of medical sciences, ,tehran,iran. *correspondence: urology department ,children medical center hospital ,tehran university of medical sciences, ,tehran,iran. e mail: mgrosva@gmail.com. received december 2020 & accepted december 2020 urology journal/vol 17 no. 6/ november-december 2020/ pp. 560-561. [doi: 10.22037/uj.v16i7.6610] can be preached as a paragon in the countries facing the escalating phase of the outbreak. references 1. heldwein fl, loeb s, wroclawski ml, sridhar an, carneiro a, lima fs, et al. a systematic review on guidelines and recommendations for urology standard of care during the covid-19 pandemic. eur urol focus. 2020. 15;6(5):1070-1085. 2. school om. https://ourworldindata.org/ g r a p h e r / b i w e e k l y c o n f i r m e d c o v i d 1 9 c a s e s ? t a b = c h a r t & c o u n t r y = ~ d e u 2020. access date: oct 4th, 2020. 3. farhadi m. mehrnewsagency. 2020 10th june. available from: https://www.mehrnews.com/ news/4946139. access date: oct 10th, 2020. 4. kashi ah. covid-19, urologists and hospitals. urol j. 2020. 16;17(3):327. 5. ghahestani sm, hashemi mb, kandevani ny, borumandnia n, dadpour m, sharifiaghdas f. iranian urology association coronavirus disease 2019 (covid-19) taskforce pamphlet (iua-ctp) recommended practice based on national epidemiologic analysis. uro j. 2020 nov 4. doi: 10.22037/uj.v16i7.6445. figure 1. biweekly covid-19 cases in countries based on their pattern. a) countries in which secondary surges were weaker than the primary surge. b) countries experiencing a second surge stronger than the primary surge. c) countries with a brilliant lockdown response to covid-19 primary surge which experienced secondary surges however mild relative to many other countries but still stronger than their primary surge. d) biweekly covid-19 cases in the united states. review 561 prediction of proximal ureteral stone clearance after extracorporeal shock wave zi-hao xu, shuang zhou, chun-ping jia, jian-lin lv* purpose: the cumulative effect of measurable parameters on proximal ureteral stone clearance following extracorporeal shock wave lithotripsy (eswl) was assessed via the application of an artificial neural network (ann). methods and patients: from january 2015 to january 2020, 1182 patients with upper ureteral stone underwent eswl in the supine position. the corresponding significance of each variable inputted in this network was determined by means of wilks’ generalized likelihood ratio test. if the connection weight of a given variable could be set to zero while maximizing the accuracy of the network classification, the variable was not considered as an important predictor of stone removal. results: a total of 1174 cases (after excluding 8 cases) were randomly assigned into a training group (813 cases), testing group (270 cases), and keeping group (91 cases). we performed ann analysis of the stone clearance rate in the training group, and it showed a predictive accuracy of 93.2% (482/517 cases). however, the predictive accuracy for the stone clearance rate in the training group was 75.3% (223 cases/296 cases). the order of importance of independent variables was stone length > course (d) > patient’s age > stone width > ph value. conclusion: the ann possesses a huge prediction potential for the invalidation of eswl. keywords: prediction; proximal ureteral stones; artificial neural network introduction urolithiasis is one of the most common urological diseases. according to the european association of urology (eau) guidelines for urolithiasis, extracorporeal shock wave lithotripsy (eswl) remains the primary treatment for symptomatic upper ureteral stone(1). however, all stones do not respond to this treatment. the early eswl suitable stones will guide doctors to choose another treatment to avoid unnecessary eswl. for this purpose, it is necessary to establish or construct a prediction model that includes all variables that may affect the stone-free state. artificial neural network (ann) is a computational method based on a large number of neurons, which loosely simulates the way in which biological brains solve the problem of large clusters of biological neurons connected by axons. any neuron can have a summation function, which is capable of combining all of its input values. this system is self-learning and training, not explicitly programmed, and performs well in areas where traditional computer programs have difficulty in expressing solutions or feature detection. the network is able to recall the appropriate output for a particular set of inputs after training, which can infer the correct output of a pattern that has never been encountered before. the ann, as a form of artificial intelligence technology, has been widely used in various fields. tsao department of urology, the affiliated jiangning hospital with nanjing medical university, nanjing, jiangsu 211100, china. *correspondence: department of urology, affiliated jiangning hospital of nanjing medical university, no. 168 gushan road, dongshan street, nanjing 211100, china. tel: +86-25-52178496. fax: +86-25-52178496. e-mail: ljlls01@163.com received september 2020 & accepted february 2021 et al.(2) used both neural networks and logistic regression algorithm to predict the clinical stage of prostate cancer indicated by prostate specific antigen levels and gleason grade. in this study, we hypothesized that the ann could be a more powerful tool than logistic regression algorithm to predict potential capsular invasion by cancer. the ann is also a more powerful tool than regression analysis for predicting the survival of liver cancer patients(3). therefore, in this study, we used an ann to assess the cumulative effect of all measurable parameters that affect the removal of stones in the proximal ureter following eswl. materials and methods from january 2015 to january 2020, patients with upper ureteral stone who underwent eswl in the supine position were included in this study. all procedures performed in the study were in accordance with the ethical standards of the affiliated jiangning hospital of nanjing medical university and the 1964 helsinki declaration and its later amendments or comparable ethical standards. this study was approved by the ethics committee of the jiangning hospital, nanjing medical university. the proximal ureter was defined as the segment extending from the pyeloureteral junction to the lower edge of the fourth lumbar spine. the stones were initially diagnosed by abdominal ultrasound and abdomurology journal/vol 18 no. 5/september-october 2021/ pp. 491-496. [doi: 10.22037/uj.v18i.6476] endourology and stone disease inal roentgenogram of the kidney, ureter, and bladder (kub). if felt necessary, a simple computed tomography (ct) scan was performed. the lithotripter adopted in this study was electromagnetic dornier compact delta ii uims (dornier medical systems, germany). in this work, the stones were fragmented under ultrasonic or fluoroscopic guidance. in each group, shock waves were delivered at 60-90 sw/min. the energy of this machine can be divided into 9 levels ((a, b, c, 1-6), and we usually applied 3-5 levels. the stone free rate (sfr) was measured on a kub film obtained 3 months after surgery. treatment failure was defined as radiologically confirmed persistence of stones (> 4 mm) without rupture after the second session of swl. the minimum follow-up period was 3 months. spss 22 for windows software was used to process the acquired data. spss software was used to establish a feed-forward and back-propagation error-adjusted neural network. an ann was used to study the effect of 18 factors on the stone-free state. these factors included sex, age, stone position (left/right), stone length, stone width, body mass index, alpha receptor blocker or calcium channel blocker, urinary tract infection, hydronephrosis, daily drinking, hypertension, diabetes, coronary heart disease, ph, course of the disease, history of ipsilateral endoscopy, and ipsilateral stone discharge. when a category existed, an input neuron was allocated to each category value of the category variable, with a value of 1, otherwise 0. the output layer comprised 1 neuron, and the stone-free state was defined as the class value 1, and the nonstone-free state was defined as the class value 0. the value of network output was actually in the range of 0 and 1, and then it was converted to class 0 (if the output was not more than the decision threshold) or class 1 (if the output was more than the decision threshold) based on the decision threshold. in a separate test set, using the cascade learning paradigm, the number of hidden nodes were selected to obtain the optimal performance. in our study, patients were randomly allocated by the spss software; 69.25% of patients were classified into the total training group, 23.00% into the testing group, and 7.75% into the keeping group. the relative importance of each input variable in the network was determined by means of wilks’ generalized likelihood ratio test. if the connection weight of a given variable could be set to 0 while retaining the accuracy of network classification, the variable was not considered to be a significant predictor of stone removal. mean ± standard deviation (m ± s.d.) was used to express the result of data. p < 0.05 was defined as statistically significant. results a total of 1174 cases (after excluding 8 cases) were allocated into the training group (813 cases), testing group (270 cases), and keeping group (91 cases). in 813 cases (69.2%), the stones were excreted, and the remaining 361 cases (30.8%) needed other treatment due to an inadequate response to lithotripsy. there was no statistical difference in the background data among the three groups. univariate analysis showed that daily water intake, course of the disease (d), length, width, and age of patients were significantly correlated with stone excretion. the overall accuracy of the ann analysis in predicting stone removal was 93.2% (482/517 cases) and 75.3% (223 cases out of 296 cases), respectively. the predicted stone removal curve is shown in figure 1. the area under the receiver operating characteristic figure 1. probability prediction graph prediction of proximal ureteral stones clearance-xu et al. endourology and stones diseases 492 (roc) curve of the applied ann analysis model was 0.935 (figure 2). the relative weights of the 18 key variables were assigned by the ann analysis for predicting proximal ureteral stone clearance (figure 3), the importance of independent variables was as follows: the length of stone > course (d) > patient’s age > stone width > ph value. the cumulative and gain plots predicted by anns for proximal ureteral stone clearance figure 2. receiver operating characteristic curve for stone-free status (area under the curve = 0.935) figure 3. independent variable importance graph prediction of proximal ureteral stones clearance-xu et al. vol 18 no 5 september-october 2021 493 are shown in figures 4 and 5. discussion proximal ureteral stone is one of the most common stone diseases in modern society. stones smaller than 4-6 mm can initially be treated by monitoring. eswl is generally the first choice for the treatment of an upper ureteral stone, especially for stones less than 1 cm. however, effective treatment management decisions depend on the nature of the stones, as well as patient factors. the patient's position also affects the stone clearance after eswl(4). although eswl has been found to be effective for treating ureteral stones, some ureteral stones do not respond to this treatment. wherfigure 5. the gain graph for stone expulsion figure 4. the cumulative gain graph for stone expulsion prediction of proximal ureteral stones clearance-xu et al. endourology and stones diseases 486endourology and stones diseases 494 ever possible, allowing the stone to pass spontaneously is probably the most popular option. accurate prediction of the passage of a stone in an individual’s body will allow timely intervention in patients who need it. an accurate prediction can also prevent unnecessary surgery and potential complications in patients who do not require stone management or lithotripsy. it is crucial to identify patients with failed eswl and ensure earlier and better treatment options, which can be achieved by building predictive models. among a wide range of expert systems (es), an ann may be suitable for the stone channel prediction of eswl for upper ureteral stone. the ann analysis is a complex nonlinear mathematical model, which is inspired by the closely connected parallel structure inside the human brain. the ann analysis is capable of stimulating the human brain to process, analyze, and learn relationships between data without the need to provide any known associations or rules(5-9). anns can assist in building prediction models, classifing biomedical events, and making a decision. on the other hand, some applications of neural networks have been applied in many fields of urology(10-12). complicated interactions and relationships among individual predictive variables could be detected via an ann. although expert systems are based on accurate expert-defined rules, there is no need for neural networks to know the data in advance(13,14). they learned by exposure to data and expected responses so that after the learning and testing phases, the ann can be applied to be a decision-making helper. compared with the statistical method, the ann has several advantages. predictions of individuals, rather than assumptions about correlations among variables, and determination of relationships among variables are important to the results. the ann can accurately predict 2 classes with a higher average classification rate (sensitivity + specificity)/2, which can take into account the ability of the model to predict the two categories, regardless of the number of cases per category(15). the ann analysis can be used as an assistant for making a clinical decision, and on that basis a trained ann can usually provide better prediction than standard multiple regression analysis. in the current study, we analyzed the application of the ann analysis to predict the proximal ureteral stone clearance rate following extracorporeal shock wave lithotripsy. the accuracy of the neural network in predicting stone removal reached an unprecedented 93.2% (482 out of 517 cases), and the overall accuracy was 75.3% (223 out of 296 cases). through the gain diagram, we found that the predicted success rate of stone removal will be increased by more than 2.5 times. the area under the roc curve was 0.935. in this study, an ann analysis was performed to specify the relative weights of the 18 key variables for the prediction of proximal ureteral stone clearance. the results of the constructed neural network indicated that the length, course, age, width, ph value, and body mass index were the most relative variables affecting the output decision. the correlation ranged from large to small: stone length, course of the disease, patient age, stone width, urine ph value, and body mass index. on further validation in a prospective group of patients, the ann could help guide the selection of patients with ureteral stones treated with eswl. however, the results of the current study are only preliminary explorations. identification and inclusion of more critical variables in the input, such as rock brittleness, may improve the efficiency and usefulness of the neural network. however, further prospective studies are needed to assess the potential of ann analysis for the prediction of the proximal ureteral stone clearance rate. conclusions the accuracy of the neural network in predicting the removal of upper ureteral stone after eswl is high. in the analysis of prognostic variables, the model of stone clearance was determined by ann analysis. the length of stone was the strongest predictor of stone clearance, followed by the course of the disease, patient’s age, and stone width. identification and inclusion of more critical variables in the input may improve the efficiency and usefulness of the neural network. however, it needs to be validated by other researchers, preferably by using a prospective randomized approach. conflict of interest the authors declare no conflict of interest. references 1. türk c, petřík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur. urol. 2016;69:475-82. 2. tsao c-w, liu c-y, cha t-l, et al. artificial 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8. robert m, marotta j, rakotomalala e, muir g, grasset d. piezoelectric extracorporeal shockwave lithotripsy of lower pole nephrolithiasis. eur. urol. 1997;32:301-4. 9. pace kt, tariq n, dyer sj, weir mj, d'a. honey rj. mechanical percussion, inversion and diuresis for residual lower pole fragments after shock wave lithotripsy: a prospective, single blind, randomized controlled trial. j. urol. 2001;166:2065-71. 10. lamb d, niederberger c. artificial intelligence in medicine and male infertility. prediction of proximal ureteral stones clearance-xu et al. vol 18 no 5 september-october 2021 495 world j. urol. 1993;11:129-36. 11. moul jw, snow pb, fernandez eb, maher pd, sesterhenn ia. neural network analysis of quantitative histological factors to predict pathological stage in clinical stage i nonseminomatous testicular cancer. j. urol. 1995;153:1674-7. 12. zlotta ar, remzi m, snow pb, schulman cc, marberger m, djavan b. an artificial neural network for prostate cancer staging when serum prostate specific antigen is 10 ng./ ml. or less. j. urol. 2003;169:1724-8. 13. gomha ma, sheir kz, showky s, abdelkhalek m, mokhtar aa, madbouly k. can we improve the prediction of stone-free status after extracorporeal shock wave lithotripsy for ureteral stones? a neural network or a statistical model? j. urol. 2004;172:175-9. 14. cummings jm, boullier ja, izenberg sd, kitchens dm, kothandapani rv. prediction of spontaneous ureteral calculous passage by an artificial neural network. j. urol. 2000;164:326-8. 15. michaels ek, niederberger cs, golden rm, brown b, cho l, hong y. use of a neural network to predict stone growth after shock wave lithotripsy. urology. 1998;51:335-8. prediction of proximal ureteral stones clearance-xu et al. endourology and stones diseases 496 notice 296 urology journal vol 5 no 4 autumn 2008 notice of inadvertent duplicate publications the editors wish to draw attention to 3 articles published in the urology journal that have also appeared in other journals. as noticed in the summer 2007 issue (volume 4, number 3), a paper by nikoobakht and colleagues, “the relationship between lipid profile and erectile dysfunction,” which was published in volume 2, number 1, page 40 (winter 2005) of the journal, is similar to an article by the same authors and same title, published in the international journal of impotence research 2005;17:523-6. the other 2 papers are: “urinary tamm-horsfall protein and citrate: a casecontrol study of inhibitors and promoters of calcium stone formation” by pourmand and colleagues which is published in volume 2, number 2, page 79 (spring 2005) of this journal and also in the urology international 2006;76(2):163-8 and “the role of ureteroscopy in the treatment of renal transplantation complications” by basiri and colleagues which is published in volume 1, number 1, page 27 (winter 2004) of this journal and also in the scandinavian journal of urology and nephrology 2006;40(1):53-6. these inadvertent duplicate publications have occurred as a result of misinterpretation of local journals and a different group of readers when the urology journal had just been lunched in english; before march 2007, our journal was not being indexed in the international indexing systems and used to be considered as a local publication, with limited audience. it was also because the journal had just changed its language from persian to english. moreover, many authors were not familiar with the regulations of acceptable secondary publication. these cases were detected by the déjà vu website (www.spore.swmed. edu/dejavu/). the editors contacted the corresponding authors and it was confirmed that they had inadvertently duplicated their publication and the mistake was a result of a misunderstanding of the regulations by authors. the situation was also explained to the déjà vu team and they accepted to remove these papers from the category of duplicate publication. urol j. 2008;5:296. www.uj.unrc.ir erratum in volume 5, number 3 of the urology journal (summer 2008), the new section, urology for people was inaugurated. on page 212, an article was reviewed in this section entitled “avicenna and his modern scientific viewpoint.” however, the referred article’s publication had been postponed up to the current issue. therefore, the whole article on avicenna is published in this issue and not the summer issue. the editors regret this error in the past issue. female urology autologous muscle-derived cell injection for treatment of female stress urinary incontinence: a single-arm clinical trial with 24-months follow-up farzaneh sharifiaghdas1ǂ, farshad zohrabi1,2ǂ, reza moghadasali3,4, soroosh shekarchian3, neda jaroughi3, tina bolurieh3, hossein baharvand3,4, nasser aghdami3* purpose: this clinical study evaluated the effect of autologous muscle-derived cell (mdc) injection for the treatment of female patients with pure stress urinary incontinence (sui). materials and methods: a total of 20 women with sui received transurethral injections of autologous mdcs. baseline and follow-up evaluations consisted of physical examinations (cough stress tests), one-hour pad test, incontinence impact questionnaire-7 (iiq-7), and urogenital distress inventory (udi-6) scoring. the patients were followed one week as well as 1, 3, 6, 9, 12, and 24 month(s) after the procedure. multichannel urodynamic study were performed before and 24 months after the intervention. the incidence and severity of adverse events (ae) were also recorded at each follow-up visit. results: a total of 20 eligible female patients with the chief complaint of sui that was unresponsive to conservative management, was enrolled in the trial, 17 of whom completed all follow-up visits. at 12th months, 10 (59%) patients had complete response, whereas 2 (12%) and 5 (29%) patients had partial and no response, respectively. at 24th months, relapse of sui in 5 out of 10 complete responders (29%) and 2 out of 2 partial responders to the treatment, respectively. the intervention produced no serious ae during the trial. conclusion: according to our results, though obtained from a limited number of patients, mdc therapy was a minimally invasive and safe procedure for treatment of female patients with pure sui. however, currently, the efficacy of this type of treatment for sui is not sufficiently high and multi-center randomized clinical trials are required to be conducted before reaching a concrete conclusion. keywords: urinary incontinence, stress; urethra; celland tissue-based therapy; muscle-derived stem cell introduction stress urinary incontinence (sui) is a common health problem in women. it has been reported that 25-35% of women over 18 years of age suffer from urinary incontinence(1). the international continence society defined sui as involuntary leakage of urine on exertion/ effort, coughing, or sneezing. sui is categorized into two subtypes: urethral hypermobility which is a result of weak anatomical support, and intrinsic sphincter deficiency (isd) which occurs due to the weakness of striated external sphincters and control mechanisms within the bladder neck and urethra(2,3). the initial management of sui is comprised of a conservative approach that includes lifestyle modification, biofeedback, pelvic floor physiotherapy, electrical stimulation, and pharmacotherapy. however, surgery is the mainstay method 1urology and nephrology research center (unrc), department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences. tehran, iran. 2department of urology, school of medicine, bushehr university of medical sciences, bushehr, iran. 3department of regenerative medicine, cell science research center, royan institute for stem cell biology and technology, acecr, tehran, iran. 4department of stem cells and developmental biology, cell science research center, royan institute for stem cell biology and technology, acecr, tehran, iran. ǂ contributed equally *correspondence: royan institute for stem cell biology and technology, shaghayegh alley, banihashem st., banihashem sq., p.o. box: 19395-4644, tehran, iran. tel: +982122436300 fax: +982122413790 e-mail:nasser.aghdami@royaninstitute.org. received august 2018 & accepted april 2019 employed for non-responsive cases (4). urethral slings are the most popular surgical options which repair the anatomical defects regardless of sui pathophysiology. related postoperative complications include erosions, permanent urinary retention, bladder perforation, urethral trauma, persistent suprapubic and groin pain, wound infection and dehiscence, and dyspareunia(5,6). tissue engineering and cell therapy are novel interventions developed to overcome the sphincteric deficiency. some clinical studies evaluated the safety and efficacy of intraurethral injection of adult stem cells for treatment of sui (7,8). we previously reported the safety of muscle-derived cell (mdc) injection in female patients with isd and urethral epispadias (9). thought many studies were conducted on the efurology journal/vol 16 no. 5/ september-october 2019/ pp. 482-487. [doi: 10.22037/uj.v0i0.4736] vol 16 no 04 september-october 2019 483 fect of mdc injection for treatment of female sui (9,17,19,19,23,24 , few clinical studies completed a follow up of ≥2 years(25,29). the current clinical trial evaluated the safety and potential efficacy of adult mdc injection in 20 women suffering from pure sui, during a 24 months follow-up period. materials and methods from september 2013 to march 2016, this single-center prospective study enrolled 20 women with sui unresponsive to conservative management. in this trial, sui patients with urethral hypermobility with valsalva leak point pressure (vlpp) of 60-90 cm h 2 o, were included. exclusion criteria consisted of the history of anti-incontinence surgery in the past 12 months, evidence of acute vulvovaginitis, grade 3 (or higher) cystoceles, active urinary tract infection, urogynecologic malignancies, coagulopathies, grade 3 (or higher) rectocele, diabetes mellitus (dm), hypertension (htn), smoking, post–void residual volume of ≥100 ml as assessed by ultrasound scan, abnormal cystourethroscopic findings (diverticula, mass, etc.), and abnormal urodynamic study results (low capacity, low compliance, and detrusor over activity). the ethics committee of the urology and nephrology research center of shahid beheshti university of medical sciences (tehran, iran) approved this study with the registration no. nct02156934. all patients received information about the process of the clinical study and provided written informed consent. in baseline and follow-up evaluations, medical history and results of physical examination, cough-induced stress test in lithotomy and upright position, urinalysis (u/a) and culture, urinary tract ultrasound, one-hour pad test, multichannel urodynamic study, and cystourethroscopy, were recorded. the patients were visited at week 1, and at the end of month(s) 1, 3, 6, 9, 12 and 24 after cell injection. maximal urethral closure pressure (mucp) and maximal flow rate were assessed before and 24 months after the intervention. hypermobility during valsalva maneuver was defined as a ≥45º change in the angle between the horizontal line and urethra. the degree of pelvic organ prolapse was graded according to the pelvic organ prolapse quantification system(10). urine analysis and culture, and urinary tract ultrasound evaluations were performed at baseline and 1 week after the cell injection. the severity of symptoms were scored according to the incontinence impact questionnaire (iiq-7) and urogenital distress inventory (udi-6)(11). a multichannel urodynamic study was performed by using a dual-lumen 6 fr catheter according to the standards proposed by the international continence society(12). eligible patients underwent an open biopsy of the quadriceps femoris muscle under local anesthesia. a 5×5 mm square of the muscle was excised, collected, and transferred to the clean room in a cold box. all procedures performed on human participants were conducted in accordance with the ethical standards of the institutional and national research committee and the 1964 declaration of helsinki, related amendments or comparable ethical standards. muscle-derived cell (mdc) processing human mdcs were isolated by the fiber enzymatic dissociation technique described in our previous phase-i study(9). briefly, the biopsy specimens were minced into approximately 1 mm pieces. tissues were subjected to enzymatic dissociation using a solution of collagenase xi (sigma, cat. # c7657) and 1 mg/ml dispase (gibco, cat. # 17105-041), plated in collagen-i-coated flasks (sigma-aldrich, cat. # 7624), and incubated at 37°c with 5% co2. quality control tests included karyotyping for the chromosomes; immunofluorescence for the expression of desmin as a popular muscle marker; and flow cytometric evaluation of the expressions of cd34 (as a general stem cell marker), cd56 (as muscle progenitor marker), and cd45 (which was used to rule out the hematopoietic origin of these cells). samples safety was assessed using the following assays: microbial test, mycoplasma test, and limulus amebocyte lysate (lal) gel clot assay for endotoxin detection. autologous muscle-derived cell (mdc) transplantation the final culture of mdcs was suspended in normal saline, counted, and loaded into 10-ml sterile syringes. for each patient, at least 50×106 cells were injected endoscopically and submucosal at 5 and 7 o'clock positions approximately 1-1.5 cm distal to the bladder neck, at the presumed level of external sphincter with the aid of a flexible 23-gauge needle of 5.7 french (fr) in diameter and 8 mm in lengths (cook williams medical company). response assessment all patients were followed for 24 months after cell table 1. patients’ demographic data. patients race age (years) weight (kg) number of deliveries 01 caucasian 32 78 1 02 caucasian 48 72 2 03 caucasian 59 69 3 04 caucasian 44 74 2 05 caucasian 45 76 2 06 caucasian 54 69 3 07 caucasian 30 66 0 08 caucasian 53 71 3 09 caucasian 60 74 4 10 caucasian 60 71 5 11 caucasian 65 79 5 12 caucasian 46 81 2 13 caucasian 51 84 3 14 caucasian 60 69 5 15 caucasian 48 86 3 16 caucasian 51 73 3 17 caucasian 70 73 3 18 caucasian 46 69 2 19 caucasian 53 83 2 20 caucasian 44 68 3 patient parameters baseline week 1 visit urinary tract ultrasound anatomic anomaly neg neg pvr urine (cc) 10-20 10-20 hydronephrosis neg neg u/a neg neg rbc (number) 0-2 0-2 wbc (number) 0-1 0-1 prot neg neg u/c neg neg abbreviations: pvr: post-void residual; u/a: urine analysis; rbc: red blood cell; wbc: white blood cell; prot: protein; u/c: urine culture.neg: negative. table 2. patients’ parameters at baseline and one week following the cell injection. mdcs in sui-sharifiaghdas et al. transplantation. objective response was assessed by the cough stress test and one-hour pad test. subjective response was assessed by the iiq-7 and udi-6 questionnaires. complete response or cure was defined as: negative cough stress test for all positions and one-hour pad test result of below 2 g. decrease in one-hour pad test weight and negative cough stress test in the lithotomy position (with positive cough test in the upright position) were defined as partial response. pad test grades were defined based on their weight, as follows: 1 (< 2 g); 2 (2-10 g); 3 (10-20 g); and 4 (> 20 g). primary and secondary endpoints primary endpoint was a complete response after 12 months as assessed by subjective criteria (iiq7-udi6) and objective criteria (cough test and pad test). severity and incidence of adverse events (aes) related to cell injection were secondary endpoints. statistical analysis we used mean and standard deviation (sd) for data presentation. a p-value ≤ 0.05 was considered statistically significant. paired t-test was used for comparison of quantitative and qualitative variables, respectively. to compare the mean age between complete, partial and non-responders, anova test has been used. the non-parametric wilcoxon test was used for data with abnormal distribution. spss version 19 was used statistical analyses. results we initially evaluated 51 females and then, recruited 20 eligible patients to participate in this trial (table1) of those, 17 were followed for 24 months. two patients did not complete the follow-up period due to lack of attendance and no phone response within the first 3 months. two weeks after the intervention, one patient was diagnosed with breast cancer, and received systemic chemotherapy and could not attend the follow-up visits. the mean age of participants was 51.5 (ranging from 30 to 70) years. 12 months after injection, 10 (59%) patients had complete response, 2 (12%) patients showed partial response, and in 5 (29%) subjects, treatment failed (figure 1a). at the end of 2-year follow-up, there was a recurrence of sui in 5 out of 10 cured patients as well as 2 out of 2 partial responders. there was no statistically significant difference (p =.33) in mean age among complete (52.4 ± 9.9 years), partial (51.5 ± 10.6 years), and non-responders (49.8±13.8 years). the mean number of normal vaginal deliveries was not statistically different (p = .33) among patients who completely responded (3), partially responded(2), and had no response(2). the mean of maximum flow rate (qmax), measured by urodynamic tests, decreased at the final follow-up visit from 20.506 ml/s to 18.572 ml/s in all patients (table 3, p = .0.35). however, statistically significant decrease in mean qmax changes was only observed in complete responders (19.5 ml/s to 16.21 ml/s; p = .002; table 3). mean mucp was 51.19 ± 5.1 cm h 2 o (range 44-59 cm h2o) at baseline and 51.69±4.9 cm h 2 o (range 47-59 cm h 2 o) at the end of 24-months follow-up (p = .136). an improvement in the cough–induced stress test (only in the upright position) was observed 3 months post–injection in complete responders; however, at the end of 24-month follow-up, a negative cough stress test was recorded in these patients. there was a decrease in the one-hour pad test at third month and negative result (<2 g) at the end of 24-months follow-up in complete responders (figure 1b). improvements in udi-6 and table 3. mean maximum flow rate in patients at baseline and 24 months after the muscle-derived cell (mdc) injection. baseline 24th months follow-up p-value* mean qmax all patients (ml/s) 20.5 (±4.2) 18.5 (±1.6) 0.035 mean qmax complete response patients (ml/s) 19.5 (±2.2) 16.2 (±1.3) 0.002 mean qmax partial response patients (ml/s) 20.1 (±2.3) 18.6 (±2.0) 0.8 mean qmax no response patients (ml/s) 22.8 (±7.1) 18.9 (±2.0) 0.1 abbreviations: qmax: maximum flow rate; ml/s: milliliters per second * as evaluated by paired t-test. figure 1. (a) the rates for complete, partial, and no response to the muscle-derived cell (mdc) injection at baseline and month(s) 1, 3, 6, 9, 12, and 24 after the injection. (b) one-hour pad test at baseline and month(s) 1, 3, 6, 9, 12, and 24 after the cell injection. * p < 0.003 and ** p < 0.0001 as compared to the baseline. mdcs in sui-sharifiaghdas et al. female urology 484 vol 16 no 04 september-october 2019 485 iiq-7 scores were recorded at 3and 6-months follow-up visits, which lasted up to 24 months (figures 2a and 2b). we observed complete response (as the primary endpoint) in 10 out of 17 (59%) patients at 12 months. the site of the muscle biopsy healed after one week in all patients. two years after cell injection, we detected no serious aes (as the secondary endpoint) related to the intervention following comprehensive patient examination with respect to urinary tract infections, urinary retention, pain, hematoma, or infection at the site of muscle biopsy and cell injection. table 1 lists the patients’ demographic data and reveals patients’ parameters assessed by urinary tract ultrasound (related to bulking agent effects), and urine analysis and culture. discussion our study revealed the potential efficacy and safety of transurethral injection of mdcs in female patients suffering from sui who were unresponsive to conservative management, during a 2-year follow-up period. in this trial, we observed a gradual process of healing and improvement that started three months after the cell transplantation. although at 12th month follow-up visit results were promising, half of the cured patients and all partial responders experienced sui recurrence during the second year. in 2000, chancellor et al. for the first time, reported the positive effect of myoblasts transplantation for treatment of sui in a rat model(13). several preclinical studies followed this concept and demonstrated the efficacy of cell therapy for treatment of urethral sphincter injuries(13). yokoyama et al. indicated that labeled mdcs differentiated into myotubes and myofibrils in the bladder wall of a rat model(14). injection of mdcss into the periurethral regions of a mice model of sui resulted in significant improvement of lpp in comparison with the control group(15,16). in 2008, mitterberger et al. reported that the formation of new myofibrils after a single injection of myoblasts into a guinea pig with sui, produced no inflammation, infection, nor scar at the injection site. another remarkable finding of this study was the direct correlation between increment of lpp and the amount of injected cells, suggesting that a sufficient number of cells is required to improve sui(8). along with preclinical experiments, clinical trials that assessed the effect of mdcs as treatment of sui have shown promising results. injection of mdcs in sui patients was found to be safe, which was further supported by lack of aes in our study(8,17-27). in another study, 12 women with a history of failed surgical intervention for treatment of sui, received mdcs; results showed complete response in 3 and partial response in 7 patients after 12 months of follow-up(23). although the results of the current study indicated an acceptable improvement rate at one year follow up, half of these individuals experienced sui recurrence. stangel-wojcikiewicz et al. reported that injection of 0.6 to 25×106 mdcs in 16 sui women caused complete and partial response in 50 and 25% of the patients, respectively after 2 years of follow-up, which indicated a response rate similar to that observed in our study(25). improved thickness, contractility and electro-activity of the rhabdosphincter confirmed integration of mdcs into the rhabdosphincter 2 years after the mdcs injection in 20 women with sui(24). the efficacy of an intraurethral injection of fresh skeletal muscle in 35 women with uncomplicated and complicated sui was reported. uncomplicated sui cases had a cure rate 25% and 63% improvement whereas the complicated group had a 7% cure rate and 57% improvement,(19) which was nearly comparable to the findings of the present trial. of note, the efficacy results might be attributed to the quantity of injected cells. carr et al. reported that injection of 18-22×106 mdcs improved 5 and cured 1 patient out of 8 subjects with sui. they indicated that the improvement began 3 and 8 months after the cell injection. this trend was in line with our results(17). later, they confirmed the positive effect of higher numbers of injected cells in 30 patients(28). therefore, to ensure a positive effect, all patients received at least 5×107 cells. in addition, injection of mdcs led to a complete response in 50% and partial response in 25% of 16 sui women, which was in line with the results of the current study(25). on the other hand, a larger single-arm trial performed on 123 female patients with sui, reported complete response in 79% of the patients after a single injection of 3.8×107 fibroblasts and 5.1×106 myoblasts, which were considerably higher numbers of cells compared to our trial, but with almost the same response rate. also, mitterberger et al. showed that in most patients, continence score, urinary incontinence quality of life scale (i-qol) and the thickness, contractility, and electromyographic activity of the rhabdosphincter were significantly improved(27). subsequently, it was shown that injection of mdcs positively impacted the quality of life of female patients with sui, 2 and 4 years after the injection(29). figure 2. (a) changes in urogenital distress inventory (udi-6) scores from the baseline to the end of 24th months follow-up in stress urinary incontinence (sui) patients. *: p < 0.05 and **: p < 0.0001 as compared to the baseline. (b) changes in incontinence impact questionnaire-7 (iiq-7) scores from baseline to the end of 24th months follow-up in sui patients. * p < 0.001 and ** p < 0.0001 as compared to the baseline. mdcs in sui-sharifiaghdas et al. in the majority of trials, cells were directly injected into the damaged sphincteric area. both subjective and objective assessments reported that the cure rate in these trials ranged from 13 to 50%, and indicated 50-86% improvement at short-to-medium term follow-up periods. in 2018, cui et al. compared the effect of muscle-derived stem cells (mdscs) and adipose tissue-derived stem cells (adscs) for treatment of sui in a rat model. also, after cell injection, rats were killed and their urethra was studied. histologic analysis showed that the mdscsand adscs-treated groups had significantly higher myosin and α-smooth muscle actin (α-sma) content compared to the control group(30). conclusions mdc therapy was found to be a minimally invasive and safe procedure for 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long-term structural and functional effects of autologous muscle precursor cell therapy in a nonhuman primate model of urinary sphincter deficiency. j urol. 2013;190:1938-45. 22. torrente y, belicchi m, marchesi c, et al. autologous transplantation of muscle-derived cd133+ stem cells in duchenne muscle patients. cell transplant. 2007;16:563-77. 23. sebe p, doucet c, cornu jn, et al. intrasphincteric injections of autologous muscular cells in women with refractory stress urinary incontinence: a prospective study. int urogynecol j. 2011;22:183-9. 24. mitterberger m, pinggera gm, marksteiner r, et al. adult stem cell therapy of female stress urinary incontinence. eur urol. 2008;53:16975. 25. stangel-wojcikiewicz k, jarocha d, piwowar m, et al. autologous muscle-derived cells for the treatment of female stress urinary incontinence: a 2-year follow-up of a polish investigation. neurourol urodyn. 2014;33:324-30. 26. kuismanen k, sartoneva r, haimi s, et al. autologous adipose stem cells in treatment of female stress urinary incontinence: results of a pilot study. stem cells transl med. 2014;3:936-41. 27. mitterberger m, marksteiner r, margreiter e, et al. autologous myoblasts and fibroblasts for female stress incontinence: a 1-year follow-up in 123 patients. bju int. 2007;100:1081-5. 28. carr lk, robert m, kultgen pl, et al. autologous muscle derived cell therapy for stress urinary incontinence: a prospective, dose ranging study. j urol. 2013;189:595-601. 29. stangel-wojcikiewicz k, piwowar m, jach r, majka m, basta a. quality of life assessment in female patients 2 and 4 years after muscle-derived cell transplants for stress urinary incontinence treatment. ginekol pol. 2016;87:183-9. 30. cui l, meng q, wen j, et al. a functional comparison of treatment of intrinsic sphincter deficiency with muscle‐derived and adipose tissue‐derived stem cells. iubmb life. 2018;70:976-84. mdcs in sui-sharifiaghdas et al. urological oncology the association of a number of risk factors with depression in patients with prostate cancer undergoing androgen deprivation therapy chang hee kim, kwang teack kim, jin kyu oh, kyung jin chung, tae beom kim, han jung, sang jin yoon, khae hawm kim* purpose: to identify factors affecting depressive symptoms in patients undergoing androgen-deprivation therapy (adt) to treat prostate cancer. materials and methods: the patients with prostate cancer visiting the psychiatry department without referral because of depressive symptoms while undergoing adt participated. to assess depressive symptoms, the beck depression inventory (bdi) was used. to identify the risk factors affecting depressive symptoms, univariate regression and multiple linear regression analyses were implemented. results: the mean (± sd) age, age when initiating adt, duration of adt, serum testosterone level and bdi scores of participants (n = 45) were 73.9 ± 7.9 years, 72 ± 8.5 years, 33 ± 31.6 months, 214.9 ± 219.5 ng/dl and 18 ± 13.5 points. the androgen dependent and independent were 26 and 9 patients. eight of these androgen-independent patients underwent concurrent chemotherapy. twenty-one patients were treated with bicalutamide and 24 with leuprolide. of the clinical variables affecting bdi scores, the type of adt drug (p < 0.001), serum testosterone level (p = 0.003), and age at diagnosis (p < 0.001) were significant. conclusion: efforts to diagnose and treat depression appropriately, especially if depressive symptoms change in patients undergoing adt to treat prostate cancer who are using an lhrh agonist (leuprolide), have low testosterone level, or are older at the age when initiating adt. keywords: androgen-deprivation therapy; depression; prostate cancer; quality of life. introduction prostate cancer is one of the most common cancers among men, with approximately 240,000 men being newly diagnosed with prostate cancer in the us(1). androgen-deprivation therapy (adt) has been historically used only in advanced stage cases, but has been increasingly selected as a treatment method in patients with asymptomatic metastasis, node-positive status, and elevation of prostate specific antigen (psa) after treatment(2-4). the known side effects of adt include loss of libido, gynecomastia, erectile dysfunction, anemia, cardiovascular disease, osteoporosis, and depression(5). specifically, depression has been shown to have an association with adt(6,7). depressive symptoms in patients with cancer are closely associated with a variety of complications, ranging from cancer recurrence to decreased compliance with treatment(8). nevertheless, oncologists do not readily recognize psychiatric problems like depression and, subsequently, patients requiring psychiatric treatment are not properly managed(9,10). recently, the quality of life of patients has become particularly important as the survival of prostate cancer patients undergoing adt has increased and depressive symptoms greatly influence quality of life. however, there have been few studies that have investigated the factors affecting depressive symptoms in prostate cancer patients department of urology, gachon university gil medical center, gachon university school of medicine, incheon, republic of korea. *correspondence: department of urology, gachon university gil medical center, gachon university school of medicine, incheon, republic of korea. tel: +82-32-460-3331. fax: +82-32-460-8340. received august 2017 & accepted january 2018 undergoing adt. the present study aimed to identifying factors affecting depressive symptoms occurring in patients undergoing adt, as the number of patients treated with adt increases, to promote an increase in quality of life through proper management and diagnosis. materials and methods demographic and clinical characteristics the inclusion criteria of this study were as follows. patients with prostate cancer histologically confirmed at gachon university gil medical center between may 2005 and june 2016 who visited the psychiatry department without consultation of the oncology staff due to depressive symptoms while receiving adt. all participants had an elementary school education or higher, and were married. patients with the following exclusion criteria were excluded: prior to adt, the patients had a history of psychiatric disorders, including depression, neurological disorder involving the brain, or hypogonadism, they were diagnosed with or treated for cancer beyond prostate cancer, or they used male hormones for cancer treatment purposes. depending on the adt schedule, the patients received an lhrh agonist (leuprolide depot 11.25 mg) intramuscularly every 12 weeks or an anti-androgen agent urological oncology 26 vol 15 no 03 may-june 2018 27 (bicalutamide 150 mg) orally daily. those treated with leuprolide also took bicalutamide 50 mg for a month to prevent disease flare-ups that may occur during the initial leuprolide administration. this study was approved by the institutional review board (irb no. gcirb 2014-274) of our institution. measures of depressive symptomatology the beck depression inventory (bdi) is a 21-item self-report used to evaluate the severity of depressive symptoms, to screen for depression, and to assess the severity of depressive symptoms, even in cases with symptomatology overlap with neurovegetative symptoms(11). the total score range from 0 to 63, with higher scores indicating more severe depressive symptoms. the bdi is a reliable tool to measure the severity of depressive symptoms. lee et al. showed that the cronbach’s alpha for bdi total score was 0.89 and the correlation between the bdi and the patient health questionnaire-9 was strong (r = 0.75)(12). participants completed the bdi with the aid of a trained psychiatric nurse. variables affecting depressive symptoms univariate regression analysis was performed to identify the factors affecting depressive symptoms at the bdi score in patients undergoing adt after diagnosis of prostate cancer, current age, age when initiating adt, type and length of adt, disease response to adt, androgen dependence, serum testosterone level and use of concurrent chemotherapy with adt. generally, a step wise multiple linear regression analysis was then performed with backward elimination to select an appropriate model, and a p value > 0.20 was used for removal. however, we analyzed for all variables by the multivariate regression analysis. because the number of variables affecting depressive symptoms occurring in patients undergoing adt was relatively small, (only eight variables, in this study). disease response status (responder/stable disease or progressive) was determined per the recommendation of the prostate specific antigen (psa) working group. patients stable or responding to adt were defined as androgen-dependent and those in whom prostate cancer progressed despite adt treatment were defined as androgen-independent(13). there have been some studies of the relationship between testosterone level and depressive symptoms in prostate cancer patients. barrett connor et al. found that the bdi score was significantly and inversely associated with testosterone (p < 0.007) independent of weight change and physical activity in prostate cancer patients(14,15). results forty-five patients with prostate cancer visiting the psychiatry department without referral because of depressive symptoms while undergoing adt participated in this study. the mean (± sd) age of participants was 73.9 ± 7.9 years and the mean age at diagnosis was 72 ± 8.5 years. the mean duration of adt treatment was 33 ± 31.6 months. twenty-one patients were treated with bicalutamide and 24 with leuprolide. thirty-six patients were defined as being androgen-dependent and 9 as being androgen-independent. eight of these androgen-independent patients underwent concurrent chemotherapy. the mean serum testosterone level was 214.9 ± 219.5 ng/dl among all participants. the mean bdi score across all participants was 18 ± 13.5 points, respectively (table 1). the results of the univariate regression analysis were shown in table 2. however, we analyzed for all clinical variables (current age, age when initiating adt, type and length of adt, disease response to adt, androgen dependence, serum testosterone level, use of concurrent chemotherapy with adt) with the bdi score by the multivariate regression analysis, because of the relatively small number of variables. the results showed that among the tested variables, the type of adt drug (p < 0.001), serum testosterone (p = 0.003), and age at initiating adt (p < 0.001) were statistically significant (table 3). discussion this study was conducted to investigate the conditions affecting depressive symptoms occurring during treatment with adt. the severity of depressive symptoms was measured with the bdi, and indicated that depression is likely to be severe in patients undergoing adt to treat prostate cancer who are using an lhrh agonist table 1. characteristics of patients undergoing adt characteristica value mean age (years) 73.9 ± 7.9 mean age at diagnosis (years) 72 ± 8.5 period of adt (months) 33 ± 31.6 type of adt drug (bicalutamide or leuprolide) 21/24 (47/53) androgen dependence (androgen-dependent or androgen-independent) 36/9 (80/20) disease response to current treatment (responder/ stable disease or progressive disease) 36/9 (80/20) treatment with concurrent chemotherapy (yes or no) 8/37 (82/18) serum testosterone (ng/dl) 214.9 ± 219.5 beck depression inventory (score) 18 ± 13.5 abbreviations: adt: androgen deprivation therapy; bdi: beck depression inventory avalues are presented as the mean (± sd) or number (%). table 2. association of bdi scores with clinical variables by univariate analyses. variables β ± se p-value current age 0.261 ± 0.203 0.204 type of adt drug 4.696 ± 3.158 0.144 length of adt -0.102 ± 0.049 0.044 age when initiating adt 0.334 ± 0.184 0.078 serum testosterone -0.007 ± 0.007 0.342 disease response to adt 7.306 ± 3.882 0.067 androgen dependence 7.306 ± 3.882 0.067 concurrent chemotherapy -6.811 ± 4.096 0.104 abbreviations: adt, androgen deprivation therapy; se, standard errors depression following adt for prostate cancer-kim et al. (leuprolide), have low testosterone level, or are older at the age of initiating adt. in prostate cancer treatment, lhrh agonists are commonly used to substantially decrease levels of serum testosterone, and anti-androgen agents are commonly used because they act on androgen receptors. lhrh agonists generate a biphasic response by initially causing elevation of luteinizing hormone and follicle-stimulating hormone levels, followed by downregulation of the release of gonadotropin-releasing hormone in the hypothalamus and gonadotropins in the anterior pituitary gland, which subsequently give rise to the inhibition of androgen synthesis in the testes(16). on the other hand, anti-androgen agents compete with androgens for binding to the androgen receptor, suppressing the effects of androgen in prostate cancer cells. therefore, anti-androgen agents do not cause decreases in the serum testosterone level(17). the effect of adt on depressive symptoms has yet to be elucidated. the studies have reported that adt affects depression for other reasons, such as through the involvement of neurochemicals such as serotonin(18). another study indicated that adt worsens depressive symptoms by affecting pro-inflammatory cytokines such as il-1 and il-6(19). we believe that a low testosterone level is related to depression, as testosterone reduction leads to a worsening of depressive symptoms, even in healthy men(20). additionally, a study that compared a group undergoing treatment with adt for prostate cancer with several control groups showed that depressive symptoms increased as testosterone level decreased in the adt group(21,22). we found that the testosterone reduction was significantly correlated with a worsening of depressive symptoms in the patients treated with leuprolide, an lhrh agonist. it has been reported that various psychiatric disorders in the elderly (elderly patients) are not properly recognized. furthermore, they are not properly identified due to the presence of other physical symptoms(23). therefore, if depressive symptoms worsen in elderly patients undergoing adt, their quality of life will likely be negatively affected. however, because of difficulties in diagnosis, it is important to pre-screen elderly patients undergoing adt in whom depression is at high risk of worsening, and to diagnose and treat appropriately. the elderly with depression have a few characteristics. in many cases, depression is accompanied with medical comorbidities, impaired sleep quality, and cognitive impairment, responsiveness to initial treatment of depression is low due to a spouse's death or reduced psychosocial resources, and it is difficult to treat for a sufficient period(24,25). accordingly, the elderly who experience depression for the first time require a long treatment period to achieve remission and have a higher recurrence rate (7% vs. 15%); thus, the prognosis is unfavorable(26,27). particularly, in patients over age 70 who experience depression for the first time, it very frequently recurs with concurrent cognitive impairment, and the suicide rate is very high. thus, they should be diagnosed and treated with accuracy(28). in the present study, the results of the analysis conducted to identify factors affecting depressive symptoms of patients undergoing adt showed that the older the patients are at age initiating adt, the more severe the depressive symptoms (p < 0.001). therefore, medical staff who administer adt should always be aware that the likelihood of patients with risk factors for developing depression is high and prompt and appropriate diagnosis and treatment when depression occurs is paramount to prevent a decrease in their quality of life. hence, we have the following recommendations for the medical staff treating patients with risk factors for depression (table 4). first, before initiating treatment with adt, the patient's disease history should be ascertained and a detailed physical examination should explore the history of depression and identify co-occurring illnesses. as mentioned, it is often difficult to diagnose depression in cancer patients or elderly patients because of the presence of comorbidities(29). therefore, medical staff should try to recognize worsening of depressive symptoms during treatment with adt by thoroughly understanding the comorbidities or physical abnormalities of the patients. second, changes in depressive symptoms in patients with risk factors should be followed up while receiving adt, by for example, administering a self-reporting questionnaire. in a study that studied patients undergoing adt, depressive symptoms increased after adt was administered and around the time when testosterone level precipitously dropped(21). if it is difficult to confirm depressive symptoms, the patient can be referred to a psychiatrist with the recommendation that they visit the department for screening on a regular basis. third, if depressive symptoms worsen in a patient with risk factors, they should be diagnosed and treated by psychiatrists. with an increase in the elderly population, diverse treatment approaches have been introduced to treat depression in the elderly who experience the disorder for the first time. recently, many treatment approaches appropriate for elderly patients have been introduced and we believe that an appropriate diagnosis can improve treatment outcomes(30). this study had some limitations. as the study participants were patients who voluntarily visited a psychiatrist due to changes in depressive symptoms while undergoing adt, the sample size was small. based on the current findings, a study investigating factors affecting changes in depressive symptoms in patients undergoing adt is underway. as a follow-up study, we are planning to present an approach to help patients undergoing adt lead a healthier life, physically and mentally, by table 3. association of bdi scores with clinical variables by multiple linear regression analyses. parameters variables β ± se partial r2 p-value type of adt drug 51.537 ± 11.818 0.178 < 0.001 serum testosterone 0.087 ± 0.027 0.134 0.003 age when initiating adt 0.757 ± 0.160 0.154 < 0.001 abbreviations: adt, androgen deprivation therapyse, standard errors 1 the patient’s disease history and a detailed physical examination before initiating treatment with adt 2 administering a self-reporting questionnaire 3 referred to psychiatry department for proper treatment abbreviations: adt: androgen deprivation therapy table 4. recommendations to minimize the risk of depression in patients undergoing adt depression following adt for prostate cancer-kim et al. urological oncology 28 vol 15 no 03 may-june 2018 29 complementing the limitations of the present study. conclusions we believe that efforts should be taken to diagnose and treat depression appropriately, especially if depressive symptoms change in patients undergoing adt to treat prostate cancer who are using an lhrh agonist (leuprolide), have low testosterone level, or are older at the age of initiating adt. acknowledgement this work was supported in part by the grants from the national research foundation of korea (nrf2013r1a1a1063509). conflict of interest the authors report no conflict of interest. references 1. howlader n, noone a, krapcho m, et al. seer cancer statistics review, 1975–2009 (vintage 2009 populations), national cancer institute. bethesda, md. based on november 2011 seer data submission, posted to the seer web site, april 2012; 2012. 2. smith mr. androgen deprivation therapy for prostate cancer: new concepts and concerns. curr opin in endocrinol. 2007;14:247. 3. barrass b, thurairaja r, persad r. more should be done to prevent the harmful effects of long‐term androgen ablation therapy in prostate cancer. bju int. 2004;93:1175-6. 4. choi h, chung h, park jy, lee jg, bae jh. the influence of androgen deprivation therapy on prostate size and voiding symptoms in prostate cancer patients in korea. int neurourol j. 2016;20:342. 5. gooren lj. clinical review: ethical and medical considerations of androgen deprivation treatment of sex offenders. j clin endocrinol metab. 2011;96:3628-37. 6. casey rg, corcoran nm, goldenberg sl. quality of life issues in men undergoing androgen deprivation therapy: a review. asian j androl. 2012;14:226-31. 7. rosenblatt de, mellow a. depression during hormonal treatment of prostate cancer. j am board fam pract. 1995;8:317-20. 8. osborn rl, demoncada ac, feuerstein m. psychosocial interventions for depression, anxiety, and quality of life in cancer survivors: meta-analyses. int j psychiat med. 2006;36:13-34. 9. fallowfield l, ratcliffe d, jenkins v, saul j. psychiatric morbidity and its recognition by doctors in patients with cancer. brit j cancer. 2001;84:1011. 10. passik sd, dugan w, mcdonald mv, rosenfeld b, theobald de, edgerton s. oncologists' recognition of depression in their patients with cancer. j clin oncol. depression following adt for prostate cancer-kim et al. 1998;16:1594-600. 11. kathol rg, mutgi a, williams j, clamon g, noyes r, jr. diagnosis of major depression in cancer patients according to four sets of criteria. am j psychiatry. 1990;147:1021-4. 12. lee e-h, lee s-j, hwang s-t, hong s-h, kim j-h. reliability and validity of the beck depression inventory-ii among korean adolescents. psychiat invest. 2017;14:30-6. 13. antonarakis es, kibel as, evan yy, et al. sequencing of sipuleucel-t and androgen deprivation therapy in men with hormonesensitive biochemically recurrent prostate cancer: a phase ii randomized trial. clin cancer res. 2017;23:2451-9. 14. barrett-connor e, von mu ̈hlen dg, kritzsilverstein d. bioavailable testosterone and depressed mood in older men: the rancho bernardo study. the journal of clinical endocrinol metab. 1999;84:573-7. 15. pirl wf, siegel gi, goode mj, smith mr. depression in men receiving androgen deprivation therapy for prostate cancer: a pilot study. psycho‐oncology. 2002;11:518-23. 16. goa kl, spencer cm. bicalutamide in advanced prostate cancer. drug aging. 1998;12:401-22. 17. furr b, tucker h. the preclinical development of bicalutamide: pharmacodynamics and mechanism of action. urology. 1996;47:1325. 18. meyers b, d'agostino a, walker j, kritzer m. gonadectomy and hormone replacement exert region-and enzyme isoform-specific effects on monoamine oxidase and catecholo-methyltransferase activity in prefrontal cortex and neostriatum of adult male rats. neuroscience. 2010;165:850-62. 19. aragon-ching jb, williams km, gulley jl. impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer. front biosci. 2007;12:71. 20. amore m, innamorati m, costi s, sher l, girardi p, pompili m. partial androgen deficiency, depression, and testosterone supplementation in aging men. int j endocrinol. 2012;2012. 21. lee m, jim hs, fishman m, et al. depressive symptomatology in men receiving androgen deprivation therapy for prostate cancer: a controlled comparison. psycho‐oncol. 2015;24:472-7. 22. shin m-s, chung kj, ko i-g, et al. effects of surgical and chemical castration on spatial learning ability in relation to cell proliferation and apoptosis in hippocampus. int urol nephrol. 2016;48:517-27. 23. reynolds k, pietrzak rh, el-gabalawy r, mackenzie cs, sareen j. prevalence of psychiatric disorders in us older adults: findings from a nationally representative survey. world psychiatry. 2015;14:74-81. 24. murphy e. the prognosis of depression in old age. brit j psychiatry. 1983;142:111-9. 25. alexopoulos gs, meyers bs, young rc, et al. recovery in geriatric depression. arch gen psychiatry. 1996;53:305-12. 26. reynolds cf, frank e, dew ma, et al. treatment of 70+-year-olds with recurrent major depression: excellent short-term but brittle long-term response. am j geriatric psychiatry. 2000;7:64-9. 27. beekman at, geerlings sw, deeg dj, et al. the natural history of late-life depression: a 6-year prospective study in the community. arch gen psychiatry. 2002;59:605-11. 28. charney ds, reynolds cf, lewis l, et al. depression and bipolar support alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life. arch gen psychiatry. 2003;60:66472. 29. roose sp, sackeim ha, krishnan krr, et al. antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial. am j psychiatry. 2004;161:2050-9. 30. roose sp, sackeim ha, krishnan kr, et al. antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial. am j psychiatry. 2004;161:2050-9. depression following adt for prostate cancer-kim et al. urological oncology 30 special feature 74 urology journal vol 5 no 2 spring 2008 real-time point-to-point wireless intranet connection first implication for surgical demonstration and telementoring in urologic laparoscopic surgery in khorasan mohammad nadjafi-semnani,1 nasser simforoosh,2 nahid ghanbarzadeh,1 mohammad reza miri1 urol j. 2008;5:74-8. www.uj.unrc.ir keywords: laparoscopy, telemedicine, computer communication networks, distance education 1birjand university of medical sciences, birjand, iran 2department of urology, shahid labbafinejad medical center and urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: mohammad nadjafi-semnani, md po box: 493 birjand, iran tel: +98 561 222 9129 fax: +98 561 223 2622 e-mail: monadjafi@gmail.com this article has been presented as an abstract in the engineering and urology society’s annual meeting in anaheim, california, may 18, 2007 and has been presented as a poster in the 25th world congress of endourology, cancun, mexico, november 1, 2007. received december 2007 accepted march 2008 introduction using communication technologies, physicians have the benefit of telemedicine to better deliver healthcare.(1) telemedicine has been used by different specialties since 1950s, initially for forwarding the medical records of patients, and later, for other purposes such as education, training, counseling, and mentoring.(2) telesurgical telementoring is an advanced form of telemedicine. utilizing current video technology, medical robots, and high-bandwidth telecommunications, experienced surgeons can guide and teach practicing surgeons new operative techniques.(1) surgical sciences have been revolutionized by the continuous advancement of laparoscopic, endoscopic, and minimally invasive procedures during the past two decades.(3) urology has been in the forefront of this innovation; the endourologic and laparoscopic techniques have renovated this specialty.(3) the first report of telementoring in urologic laparoscopic surgery was published in 1996.(4) in this procedure, the mentor in the remote area sees the real-time video of the surgeon’s performance at the operation room in their office and can talk and guide them accordingly. we describe the first academic report of telementoring in urologic laparoscopic surgery from iran. this study was conducted to examine the technologic facilities in iran for a setup of point-topoint wireless intranet connection for telementoring. we could provide adequate video and audio teleconferencing and image quality to support remote real-time surgical demonstration and telementoring. telementoring setup we conducted a telementoring procedure with 2 multimedia workstations communicating with each other over the university’s local area network (lan). laparoscopic extraperitoneal trigonoplasty was selected for telementoring as an educational event during the national seminar on neonatal circumcision in birjand, a city in khorasan province, iran, in december 15, 2005. laparoscopic procedure laparoscopic extraperitoneal trigonoplasty was first reported by simforoosh and colleagues in shahid labbafinejad medical center in tehran.(5) the mentor was the innovator of this procedure and the real-time intranet connection for telementoring—nadjafi-semnani et al urology journal vol 5 no 2 spring 2008 75 laparoscopic surgeon was an experienced fellow of endourology and urolaparoscopic surgery practicing in birjand, a city in the northeast of iran. the patient was a 10-year-old boy who presented with abdominal and flank pain and hematuria. the intravenous urography revealed right hydronephrosis and a 22-mm calculus in the right pelvis. voiding cystourethrography revealed bilateral vesicoureteral reflux (vur). grade 3 vur was seen in the right and grade 1 in the left side. he had undergone right-side percutaneous nephrolithotomy in emam reza hospital, birjand 30 days earlier and became stone free. then, the patient presented for the therapy of vur. his parents were informed on the different method of antireflux surgery we had planned, and they opted to undergo laparoscopic repair of his reflux. informed consent was obtained from the parents. the technique and results of this novel laparoscopic procedure had previously been reported.(5) this laparoscopic procedure duplicates exactly the same principles and steps which were introduced by gil-vernet trigonoplasty antireflux operation.(6) we performed laparoscopic trigonoplasty as follows: an 11-mm incision was made over the lower crease of the umbilicus. the rectus fascia was opened transversely at the midline. fibrous adhesion bands between the anterior and posterior layers of the rectus sheaths up to the arcuate line were cut with scissors. next, a finger was introduced under the rectus muscle, and the extraperitoneal space between the bladder, rectus muscles, and lateral abdominal wall was developed by posterior and lateral finger movements. this space was further developed by balloon dilation. the first trocar (10 mm) was placed by open technique in this space. under carbon dioxide insufflations and direct vision, 3 trocars (5 mm) were placed. the bladder was opened at low midline for about 3 cm to 4 cm with laparoscopic scissors. the ureteral orifices were then identified and 2 trimmed ureteral catheters were inserted intracorporeally into the ureters. a superficial transverse incision was made with laparoscopic scissors through the mucosa between the ureters 2 mm lateral to the orifices. extending this incision in a u fashion around the medial aspect of the ureteral orifices, the medial aspect of both ureters was cleared of the muscles and attachments. two 4-0 polyglactin horizontal mattress sutures were placed through both ureteral walls and the waldeyer’s sheath near the orifices, and the ureters were approximated in the midline. at this stage, both ureteral orifices were advanced medially across the previously incised mucosal trough, and thus, their submucosal tunnels were lengthened. superior and inferior to the horizontal mattress suture, two 4-0 polyglactin sutures were placed to bring together the epithelium and convert the horizontal mucosal incision to a vertical closure line. the ureteral catheters were removed. the bladder was closed with a 2-0 polyglactin running suture. a drain was placed through the lower port. multimedia workstations configuration although advanced commercially prepared packages were available for establishing this telecommunication, due to limited resources, we decided to use another efficient cost-effective setup for laparoscopic telementoring. two multimedia workstations were setup in birjand university of medical sciences main conference hall and emam reza medical center operating room (table). these two workstations were 5 hardware operating room conference hall network standards lan (10/100) ip/h323 lan (10/100) ip/h323 video input adaptor maxtor 100 capturing card none external camera sony dcr-pc 109e none video hardware panasonic vcr none wireless transmission rate 27 mbps 27 mbps microphone software sony wireless sony wired operating system windows xp windows xp telecommunication software windows netmeeting windows netmeeting video image transferring software windows media encoder windows media encoder technical details of 2 interactive multimedia workstations real-time intranet connection for telementoring—nadjafi-semnani et al 76 urology journal vol 5 no 2 spring 2008 km away from each other and were connected at a transmission rate of 27 mbps through the university lan by wireless point-to-point intranet connection device (linksys inc, taipei, taiwan) as shown in the figure. the laparoscopic mentor (professor simforoosh), who was the chairman of this educational event, and the audience of the seminar in the main conference hall of the university could see, hear, and talk to the laparoscpic surgeon interactively. the laparoscopic (internal body view) or an externally mounted camera (overview of the operating room) videos were projected alternatively on the screen. the laparoscopic surgeon could hear the mentor and the questions asked by the audience and talked to them interactively, but he did not have their pictures. the data was transmitted through the optic fiber between the computer center of the university and the conference hall and by a category 6 cable from the operating room to the computer center in emam reza hospital. the windows netmeeting (microsoft, redmond, washington, usa), two microphones, and a sony camcorder were used for live interactive telecommunication (audio and overview of the operating room). for fast transmission of high-quality video images over the lan, the windows media encoder (microsoft, redmond, washington, usa) was used. this software has many advantages including adjustment of transmission rate, ability of different lan users to see simultaneously the transmitted videos over the lan by free windows media player software, and that the capability of broadcasting the streaming videos on the internet. after installing the windows media interactive computing multimedia workstations configuration. real-time intranet connection for telementoring—nadjafi-semnani et al urology journal vol 5 no 2 spring 2008 77 encoder on the computers in both workstations, the user in the conference hall, knowing the ip address and port number of the operating room computer, could see the videos online and project them on the conference hall screen by a video projector. video image captures routine laparoscopic images were first transferred to the monitor in front of the surgeon, then to the video recorder and from the video recorder to the capturing card of the operating room computer. for capturing and transmitting the laparoscopic and external video images to the lan without frame drop, professional maxtor 100 capturing card (matrox electronic systems ltd, dorval, quebec, canada) in the real time was used. sony camcorder dcr-pc 109e (sony inc, tokyo, japan) was used as externally mounted camera and connected alternatively to the capturing card to transmit the external video images from operation room and surgical team. image evaluation for evaluating the quality of the transmitted images, the opinion of the laparoscopic mentor was sought. in addition, to evaluate further, the effect of transmitting laparoscopic video images, 5 paired local and remote digital still images were “grabbed” from the video feed as previously described by broderick and associates.(7) these images were pasted to digital graphic editing software, and then, they were opened in the access program (microsoft office, microsoft, redmond, washington, usa). these images were presented in a blinded fashion separately and later together as paired pictures to the laparoscopic surgeon and he was asked to evaluate the images with regard to his ability to identify the captured images and the quality of the images and to score them (scale 1 to 10 as poor to excellent). by the setup of point to point wireless intranet connection over the university’s lan, demonstration of a novel laparascopic antireflux technique for the participants of an iranian national congress became possible. through this connection, the teleconference with adequate audio and video quality and live real-time broadcast of laparoscopic surgery from the operating room to the university conference hall was accomplished. in addition, this connection was able to allow adequate transmission of high-quality video images to be seen by the laparoscopic mentor for surgical decision making and telementoring. the mentor in the conference hall was able to identify the waldeyer’s sheath over the bared ureteral wall and the transmitted images were evaluated as excellent quality by him. it has been suggested by simforoosh and colleagues that the long-term success in this laparoscopic technique depends entirely on the suturing of the ureteral walls and the waldeyer’s sheaths to each other.(5) in addition, evaluation of the grabbed images from the operating room and the conference hall by the laparoscopic surgeon revealed that all images received the scale of 9 to 10, and he was not able to differentiate the origin of the images. discussion telementoring is defined as active real-time teaching and requires videoconferencing between the local and remote surgeons. this interaction depends on transmission of audiovisual signals simultaneously in both directions.(3) the remote surgeon acts as a preceptor to provide guidance through difficult operations. laparoscopic surgery requires long-term practice and mentorship, and it has a steep learning curve. telementoring would be a good answer to this demand. telementoring can potentially enhance surgeons’ education, increase patients’ access to experienced surgeons, and decrease the likelihood of complications resulted from lack of experience with new techniques.(1) telementoring may also be useful because it allows surgeons to teach their colleagues without any inconveniences such as traveling to the teaching seminar venues.(8) the first published telementored laparoscopic procedures were performed by a group at johns hopkins in 1996 who successfully telementored 22 of 23 laparoscopic procedures including simple and radical laparoscopic nephrectomies.(4) successful early telementoring experiences have encouraged extensive and wider application.(8) abdirad and colleagues recently have published real-time intranet connection for telementoring—nadjafi-semnani et al 78 urology journal vol 5 no 2 spring 2008 the first academic telemedicine in the field of pathology from iran.(9) to our best knowledge, this is the first report from iran regarding telementoring in laparoscopic urologic surgery. we used a practical setup of software and lan. we first tested the microsoft netmeeting software for this live telecommunication. although it was very useful for live interactive conversation and teleconference, as was used in our study for interactive communication between laparoscopic surgeon and his mentor, due to its low quality of transmitted video images, it was not suitable for telementoring. instead, we found that high-speed transmission of video images by windows media encoder was a very efficient and cost-effective telecommunication means. transmitted video images can be seen in any place over lan by the media player software. our study revealed that the quality of transmitted video images is very suitable for telementoring. we think this setup is especially useful in residency and fellowship programs in teaching hospitals where the responsible attending surgeon has to care for different surgeries in different operating rooms at the same time while sitting in his office in the main operating room. they can also continue this surveillance in all places where the lan is accessible. moreover, laparoscopic video images have been employed for teaching anatomy to medical students and surgical residents.(10) this setup is also useful in teaching anatomy to medical students as the transmitted image can be seen in different departments simultaneously. unavailability of telestrator video sketchpad in our study is one of our setup limitations. this device would be very instrumental for the mentor to illustrate the operative plan to the laparoscopic surgeon and the audience in the seminar.(3) however, our setup of connection through the university lan could provide adequate video and audio teleconferencing and image quality to support remote real-time surgical demonstration and telementoring. this is especially useful for developing countries where due to the limited resources, they cannot afford commercially prepared packages for telementoring in laparoscopic surgeries. conflict of interest none declared. acknowledgement the authors would like to acknowledge the help and support of dr tohid azizi for accomplishing this study. references 1. lee br, bishoff jt, janetschek g, et al. a novel method of surgical instruction: international telementoring. world j urol. 1998;16:367-70. 2. rosser jc, jr., gabriel n, herman b, murayama m. telementoring and teleproctoring. world j surg. 2001;25:1438-48. 3. varkarakis im, rais-bahrami s, kavoussi lr, stoianovici d. robotic surgery and telesurgery in urology. urology. 2005;65:840-6. 4. moore rg, adams jb, partin aw, docimo sg, kavoussi lr. telementoring of laparoscopic procedures: initial clinical experience. surg endosc. 1996;10:107-10. 5. simforoosh n, nadjafi-semnani m, shahrokhi s. extraperitoneal laparoscopic trigonoplasty for treatment of vesicoureteral reflux: novel technique duplicating its open counterpart. j urol. 2007;177:321-4. 6. gil-vernet jm. a new technique for surgical correction of vesicoureteral reflux. j urol. 1984;131:456-8. 7. broderick tj, harnett bm, doarn cr, rodas eb, merrell rc. real-time internet connections: implications for surgical decision making in laparoscopy. ann surg. 2001;234:165-71. 8. pande ru, patel y, powers cj, d’ancona g, karamanoukian hl. the telecommunication revolution in the medical field: present applications and future perspective. curr surg. 2003;60:636-40. 9. abdirad a, sarrafpour b, ghaderi-sohi s. static telepathology in cancer institute of tehran university: report of the first academic experience in iran. diagn pathol. 2006;1:33. 10. satava rm. surgical education and surgical simulation. world j surg. 2001;25:1484-9. endourology and stone disease is absence of hydronephrosis a risk factor for bleeding in conventional percutaneous nephrolithotomy? hee youn kim, hyun-sop choe, dong sup lee, je mo yoo, seung-ju lee* purpose: there is conflict of evidence regarding whether absence of hydronephrosis is a risk factor for bleeding in percutaneous nephrolithotomy (pnl). moreover, among the stone complexity scoring systems used for pnl (guy’s stone score, the s.t.o.n.e. nephrometry and the croes nomogram), only the s.t.o.n.e. nephrometry score incorporates hydronephrosis as a risk factor. therefore, this study aimed to compare perioperative outcomes according to the presence or absence of hydronephrosis in percutaneous nephrolithotomy (pcnl) patients and to investigate whether absence of hydronephrosis is a risk factor for blood transfusion rate. materials and methods: 281 patients who had undergone pcnl between december 2009 and april 2017 were divided according to the absence or presence of hydronephrosis (group i and group ii, respectively). perioperative outcomes were compared between the two groups. a multivariable regression analysis was performed to investigate whether hydronephrosis was a risk factor for blood transfusion rate. results: patients without hydronephrosis showed significantly longer operation time and admission period, lower stone-free rate and higher blood transfusion rate compared to patients with hydronephrosis (p < 0.05, p = 0.002, p = 0.011, and p < 0.05, respectively). multivariate logistic regression analysis showed that hydronephrosis was a significant risk factor for blood transfusion (or, 95% ci and p value was 0.353, 0.163-0.761 and 0.008, respectively). conclusion: based on the results of the current study, we found that absence of hydronephrosis was a significant risk factor for blood transfusion in conventional pcnl. keywords: percutaneous nephrolithotomy; hydronephrosis; blood transfusion; urolithiasis introduction percutaneous nephrolithotomy (pcnl) remains an integral part of treatment for large complex renal stones. in studies where practice patterns of urolithiasis were surveyed, more than 80% of urologic practitioners responded that they performed pcnl(6,7). despite its wide use, complication rates are still relatively high. a large prospective study using the modified clavien-dindo classification system reported an overall complication rate of 20.5% (8,9). bleeding is the most significant complication of pcnl, with reported rates of bleeding requiring blood transfusion ranging between 0 and 20% (10). numerous studies have attempted to elucidate the risk factors for bleeding (11-14). among those factors, we focused on hydronephrosis. the presence or absence of hydronephrosis is associated with various steps in the pcnl procedure, especially during the initial renal access. in the absence of hydronephrosis, iatrogenic hydronephrosis is usually made via ureteral catheter, which can assist in successful renal access and theoretically, bleeding should not be a problem. nevertheless, there is conflicting evidence in the literature on whether the presence or absence of department of urology, st. vincent’s hospital, college of medicine, the catholic university of korea, suwon, republic of korea. *correspondence: department of urology, st. vincent’s hospital, college of medicine, the catholic university of korea, 93, jungbu-daero, paldal-gu, suwon-si, gyeonggi-do 16247, republic of korea. tel: 82 31 249 7473, fax: 82 31 253 0949, e-mail: seungju@catholic.ac.kr. received september 2018 & accepted january 2019 hydronephrosis affects bleeding during pcnl (11,13-15). some claim that hydronephrosis did not have any effect on blood loss, while others claim that absence of hydronephrosis was a significant risk factor for severe bleeding. moreover, among the stone complexity scoring systems used for pnl (guy’s stone score (16), the s.t.o.n.e. nephrometry (17) and the croes nomogram (18)), only the s.t.o.n.e. nephrometry score incorporates hydronephrosis as a risk factor. therefore, the aim of this study was to compare perioperative outcomes according to the presence or absence of hydronephrosis in pcnl patients and to investigate whether absence of hydronephrosis is a risk factor for blood transfusion. patients and methods study population and design the institutional review board of st. vincent’s hospital, the catholic university of korea, approved the study protocol. this was a retrospectively case-control study. chart review of all patients who underwent pcnl with a follow up period of at least 3 months between december 2009 and april 2017 was investigaturology journal/vol 17 no. 1/ january-february2020/ pp. 8-13. [doi: 10.22037/uj.v0i0.4826] vol 17 no 01 january-february 2020 09 ed. the following patients were excluded: patients who underwent bilateral pcnl, patients with kidney anomalies (including horseshoe kidney), patients who underwent another operation simultaneously, patients who had multiple tracts, and patients with a preexisting percutaneous nephrostomy tract through which renal access was achieved. a total of 281 patients were eligible for the current study. the following information was recorded as patient characteristics: age, sex, body mass index (bmi), history of diabetes mellitus (dm), history of hypertension, and history of chronic kidney disease (ckd). the following information was recorded as stone characteristics: laterality, absence or presence of hydronephrosis, guy’s stone score(16), stone volume(19) and staghorn stone. staghorn stones were excluded for stone volume calculation. finally, the following information was recorded as perioperative outcomes: operation time (minutes), admission period (days), stone-free rate (%), blood transfusion rate (%) and infectious complication rate (%). operation was considered successful when the follow up image showed no residual stones or clinically insignificant residual fragments (cirfs). in the current study, cirfs were considered to be ≤ 4mm, nonobstructing, noninfectious, and asymptomatic residual fragments(20). additionally, only microbiologically or radiographically confirmed febrile urinary tract infection was recorded as an infectious complication; simple postoperative fever was not included. the study population was divided into two groups: group i was defined as patients without hydronephrosis and group ii as patients with hydronephrosis. surgical technique urine culture with an antibiotic susceptibility test was done in every patient planned for pcnl. if the urine culture result was positive, then susceptible oral antibiotics were administered for one week before admission. otherwise, a prophylactic antibiotic was administered just before surgery. after general endotracheal anaesthesia, a ureteral occlusion balloon catheter was inserted via cystoscope with the patient in lithotomy position. the patient was then turned to the prone position. percutaneous renal access was achieved with fluroscopic assistance. the access tract was dilated with a balloon dilator and a 30f amplatz sheath was inserted. a rigid 26f nephroscope was inserted and the stone was fragmented with an ultrasonic lithotripter and removed with forceps. at the end of the operation, an antegrade ureteral catheter was inserted and a 20f nephrostomy tube was placed. data analysis spss (ibm corp. released 2012. ibm spss statistics for windows, version 21.0. armonk, ny: ibm corp.) was used for the statistical analysis. descriptive statistics were used to describe the results. the comparison of continuous variables was performed using the unpaired t-test or the mann-whitney test based on the result of the shapiro-wilk test for normality. the comparison of categorical variables was performed using the chi-square test or fisher’s exact test. a multivariate logistic regression analysis was conducted to investigate whether hydronephrosis was a risk factor for blood transfusion. p values < 0.05 were considered statistically significant. results baseline patient and stone characteristics are described in table 1. of the 281 patients, the number of patients without hydronephrosis (group i) was 95 (33.8%) and the number of patients with hydronephrosis (group ii) was 186 (66.2%). there were no significant differences in age, sex, bmi, history of dm, history of hypertension, history of chronic kidney disease or stone laterality. a significant difference was noted in guy’s stone score, as the percentage of grade 2 stones was higher in table 1. comparison of baseline patient and stone characteristics between group i (patients without hydronephrosis) and group ii (patients with hydronephrosis) group i group ii p value n (%) 95/281 (33.8%) 186/281 (66.2%) age (years, mean ± sd) 54.9 ± 10.6 53.8 ± 12.3 0.4531 sex (%) 0.1232 male 51/95 (53.7%) 118/186 (63.4%) female 44/95 (46.3%) 68/186 (36.6%) bmi (kg/m2, mean ± sd) 25.2 ± 3.1 25.4 ± 3.6 0.7443 dm (%) 27/95 (28.4%) 42/186 (22.6%) 0.3072 hypertension (%) 36/95 (37.9%) 59/186 (31.7%) 0.3512 ckd (%) 4/95 (4.2%) 7/186 (3.8%) 1.0004 laterality (%) 0.7032 left 57/95 (60.0%) 107/186 (57.5%) right 38/95 (40.0%) 79/186 (66.2%) guy’s stone score (%) <0.053 grade 1 19/95 (20.0%) 54/186 (29.0%) grade 2 18/95 (18.9%) 88/186 (47.3%) grade 3 40/95 (42.1%) 43/186 (23.1%) grade 4 18/95 (18.9%) 1/186 (0.5%) stone burden (mm3, mean ± sd) 153.7 ± 123.0 207.0 ± 146.2 0.0103 staghorn stone (%) 50/95 (52.6%) 22/186 (11.8%) 0.0012 1 unpaired t-test 2 chi-square test 3 mann-whitney test 4 fisher’s exact test sd = standard deviation, bmi = body mass index, dm = diabetes mellitus, ckd = chronic kidney disease hydronephrosis as a risk factor for bleeding in pcnl-kim et al. group ii (p < 0.05) and the percentage of grade 3 and grade 4 stones was higher in group i (p = 0.001 and p < 0.05, respectively), implying that the group without hydronephrosis contained patients with more complex stones. the stone volume was significantly higher in group ii (p = 0.01), but this was because staghorn stones were not included for stone burden calculation. the proportion of staghorn stones was significantly higher in group i (p = 0.001). the comparison of perioperative outcomes between group i and group ii is described in table 2. significant differences were found in operation time, admission period, stone-free rate, and the blood transfusion rate between group i and group ii (p < 0.05, p = 0.002, p = 0.011, and p < 0.05, respectively). in short, patients without hydronephrosis showed longer operation time and admission period, lower stone-free rates, and higher blood transfusion rate compared to patients with hydronephrosis. to determine whether hydronephrosis was a risk factor for transfusion, a univariate and multivariate logistic regression analysis was performed (table 3). absence of hydronephrosis was a significant risk factor for blood transfusion, with an odds ratio of 0.353, a confidence interval of 0.163-0.761, and a p value of 0.008. discussion the current study sought to investigate whether hydronephrosis was a significant risk factor for blood transfusion rate. the implication of hydronephrosis on surgical outcomes, especially bleeding, in pcnl is not well established. previous studies showed conflicting results. kukreja et al. reported in their prospective study in 2004 that hydronephrosis did not have any effect on blood loss (13). however, in their study, the pcnl procedure was staged for a large stone burden, prolonged operation time and the occurrence of significant complications such as perforation or bleeding, which could have affected their results. in a study by akman et al. in which factors affecting bleeding during pcnl were studied(11), hydronephrosis was not a significant factor, although the p value nearly showed significance (p = 0.06). in contrast, lee et al. and senocak et al. found out that the absence of hydronephrosis was a significant risk factor for bleeding during pcnl(14,15). moreover, among the stone complexity scoring systems used for pcnl (guy’s stone score (16), the s.t.o.n.e. nephrometry(17) and the croes nomogram(18)), only the s.t.o.n.e. nephrometry score incorporates hydronephrosis as a risk factor, again showing that hydronephrosis is not thought of as an important factor during pcnl. in the current study, the absence of hydronephrosis was found to be a significant risk factor for blood transfusion after pcnl. several hypotheses can be proposed for the current result. first, the difference in guy’s stone score between the two groups may be the main reason. patients without hydronephrosis tended to have higher guy’s stone scores, indicating more complex stones, which is thought to be due to diverticular and staghorn stones in the group without hydronephrosis. the higher proportion of higher complexity stones may have caused the higher transfusion rate in the group without hydronephrosis. this result is validated by other studies as increased guy’s stone scores were associated with increased complication rates (21). one interesting finding from the result of the current study is that even with the same guy’s stone score, blood transfusion rate can vary depending on the presence or absence of hydronephrosis, suggesting that guy’s stone score alone may be insufficient to predict the complication rate of pcnl. this may imply that hydronephrosis should be included hydronephrosis as a risk factor for bleeding in pcnl-kim et al. table 2. comparison of perioperative outcomes between group i (patients without hydronephrosis) and group ii (patients with hydronephrosis) group i group ii p-value operation time (minutes, mean ± sd) 103.4 ± 47.4 82.7 ± 36.1 < 0.051 admission period (days, mean ± sd) 3.9 ± 1.9 3.5 ± 1.6 0.0221 stone-free rate (%) 60/95 (63.2%) 145/186 (78.0%) 0.0112 transfusion rate (%) 27/95 (28.4%) 21/186 (11.3%) < 0.052 infectious complication rate (%) 3/95 (3.2%) 4/186 (2.2%) 0.6923 1 mann-whitney test 2 chi-square test 3 fisher’s exact test sd = standard deviation variables univariate multivariate or (95% ci) p value or (95% ci) p value sex 2.483 (1.319-4.677) 0.005 2.315 (1.152-4.649) 0.018 bmi 0.832 (0.750-0.924) 0.001 0.823 (0.733-0.925) 0.001 guy score grade 1(reference) 0.302 0.036 grade 2 1.699 (0.621-4.651) 0.005 3.212 (1.034-9.975) 0.044 grade 3 4.027 (1.531-10.592) 0.012 5.050 (1.696-15.035) 0.004 grade 4 5.154 (1.436 (18.500) 0.000 3.925 (0.923-16.685) 0.064 hydronephrosis 0.321 (0.170-0.606) 0.000 0.353 (0.163-0.761) 0.008 or = odds ratio, ci = confidence interval, bmi = body mass index table 3. univariate and multivariate logistic regression analysis to determine independent predictor of transfusion with regard to percutaneous nephrolithotomy endourology and stones diseases 10 vol 17 no 01 january-february 2020 11 in scoring systems to predict outcomes for pcnl. the only scoring system used for pcnl that includes hydronephrosis is, as previuously mentioned, the s.t.o.n.e. nephrometry score (17). however, although this system has been validated for its predictive ability of the stonefree rate, the utility of this scoring system for stratifying complication rates has not been asserted(22). further study is needed in this aspect. the second possible reason for the result of the current study is that the absence of hydronephrosis may have led to increased bleeding due to vascular injury during initial renal access. the ideal location for initial renal access is through the calyceal fornix because this will avoid the interlobar (infundibular) arteries adjacent to the calyceal infundibula and the arcuate arteries along the renal pyramid (23). in the presence of hydronephrosis, this process is relatively straightforward because of the dilated calyces. however, in the absence of hydronephrosis, the calyceal fornix may be missed and puncture through the infundibulum or directly into the renal pelvis may occur, leading to massive bleeding. in addition, with little hydronephrosis, repeated attempts may be necessary to puncture the desired calyx, which can be a significant risk factor for bleeding in pcnl(24). the third possible reason is that the absence of hydronephrosis affords less space for manipulation within the kidney, leading to traumatic injury of the renal vasculature and parenchyma(15). several suggestions can be made to reduce bleeding complications during pcnl in patients without hydronephrosis. first, the utilization of ultrasound guidance for initial renal access may help reduce bleeding during pcnl. in a meta-analysis that compared fluoroscopy and ultrasound guidance during initial renal access, ultrasound was found to be superior in terms of puncture time, the success rate of first puncture, blood loss, and transfusion requirements (25,26). however, utilizing ultrasound alone for renal access can be difficult because of poor imaging of the renal anatomy in patients with a nondilated collecting system(27). combining ultrasound and fluoroscopy can overcome this problem and help decrease bleeding by reducing puncture attempts and access time(28). second, the utilization of smaller caliber access sheaths may reduce bleeding. compared to conventional pcnl that uses a 30f amplatz sheath, mini-pcnl utilizes smaller-sized sheaths, ranging between 11-20f. several studies have reported the advantage of mini-pcnl over conventional procedure in terms of a reduced hemoglobin drop and the need for blood transfusion(29). third, staging the procedure for patients with a large stone burden may reduce blood loss(13). lastly, utilizing rirs in well-selected patients with large renal stones may be helpful. several studies have found that rirs was a good alternative treatment to pcnl in patients with 2-4cm renal stones(30,31). the current study also showed significant results for other outcomes. the operation time and admission period were significantly longer and the stone-free rate was significantly lower in the group without hydronephrosis. again, a higher proportion of more complex stones in the group without hydronephrosis may have caused this result as guy’s stone score is known to be associated with surgical outcomes in pcnl. infectious complications did not show significant difference between the two groups. several studies have implicated hydronephrosis as one of the risk factors for infectious complications after pcnl(32-34). one possible reason for our result is the strict definition of infectious complication in the current study. unlike other studies that included a simple febrile episode as an infectious complication, only microbiologically or radiographically confirmed febrile urinary tract infections were included in the current study. lastly, urine leakage was not investigated in this study because both the nephrostomy tube and the ureteral catheter were routinely inserted at the end of the operation. there were several limitations in the current study. because of the retrospective nature of the study, there supplementary table 1. comparison of baseline patient and stone characteristics between patients who did not receive transfusion and patients who received transfusion. no transfusion transfused p value n (%) 233/281 (82.9%) 48/281 (17.1%) age (years, mean ± sd) 54.2 ± 12.0 54.0 ± 10.4 0.9301 sex (%) 0.0042 male 149/233 (63.9%) 20/48 (41.7%) female 84/233 (36.1%) 28/48 (58.3%) bmi (kg/m2, mean ± sd) 25.7 ± 3.3 23.8 ± 3.5 0.0013 dm (%) 59/233 (25.3%) 10/48 (20.8%) 0.5112 hypertension (%) 80/233 (34.3%) 15/48 (31.3%) 0.6812 ckd (%) 7/233 (3.0%) 4/48 (8.3%) 0.0994 laterality (%) 0.7442 left 137/233 (58.8%) 27/48 (56.3%) right 96/233 (41.2%) 21/48 (43.8%) guy’s stone score (%) < 0.053 grade 1 19/95 (20.0%) 54/186 (29.0%) grade 2 18/95 (18.9%) 88/186 (47.3%) grade 3 40/95 (42.1%) 43/186 (23.1%) grade 4 18/95 (18.9%) 1/186 (0.5%) stone burden (mm3, mean ± sd) 192.1 ± 139.7 2 13.2 ± 169.2 0.7823 staghorn stone (%) 48/233 (20.6%) 24/48 (50.0%) < 0.052 1 unpaired t-test 2 chi-square test 3 mann-whitney test 4 fisher’s exact test sd = standard deviation, bmi = body mass index, dm = diabetes mellitus, ckd = chronic kidney disease hydronephrosis as a risk factor for bleeding in pcnl-kim et al. could have been selection bias. another potential bias is misclassification bias, where patients may have been included into a wrong group especially when hydronephrosis is not distinct. also, some data that could have been valuable for the purpose of the study were not available, such as the time taken for initial renal access and the number of puncture attempts. in addition, surgical experience was not taken into account in the analysis, which may have caused higher a transfusion rate in our early cases. a relatively small number of study population is another limitation. conclusions based on the results of the current study, we found that absence of hydronephrosis was a significant risk factor for blood transfusion in conventional pcnl. conflict of interest the authors report no conflicts of interest. references 1. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 2. ghani kr, andonian s, bultitude m, et al. percutaneous nephrolithotomy: update, trends, and future directions. eur urol. 2016;70:382-96. 3. falahatkar s, ghasemi a, gholamjani moghaddam k, et al. comparison of success rate in complete supine versus semi supine percutaneous nephrolithotomy: (the first pilot study in randomized clinical trial). urol j. 2017;14:3000-7. 4. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 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pelvi-calyceal perforations. urol j. 2017;14:4020-3. 10. seitz c, desai m, hacker a, et al. incidence, prevention, and management of complications following percutaneous nephrolitholapaxy. eur urol. 2012;61:146-58. 11. akman t, binbay m, sari e, et al. factors affecting bleeding during percutaneous nephrolithotomy: single surgeon experience. j endourol. 2011;25:327-33. 12. keoghane sr, cetti rj, rogers ae, walmsley bh. blood transfusion, embolisation and nephrectomy after percutaneous nephrolithotomy (pcnl). bju int. 2013;111:628-32. 13. kukreja r, desai m, patel s, bapat s, desai m. factors affecting blood loss during percutaneous nephrolithotomy: prospective study. j endourol. 2004;18:715-22. 14. lee jk, kim bs, park yk. predictive factors for bleeding during percutaneous nephrolithotomy. korean j urol. 2013;54:44853. 15. senocak c, ozbek r, bozkurt of, unsal a. predictive factors of bleeding among pediatric patients undergoing percutaneous nephrolithotomy. urolithiasis. 2017. 16. thomas k, smith nc, hegarty n, glass jm. the guy's stone score--grading the complexity of percutaneous nephrolithotomy procedures. urology. 2011;78:277-81. 17. okhunov z, friedlander ji, george ak, et al. s.t.o.n.e. nephrolithometry: novel surgical classification system for kidney calculi. urology. 2013;81:1154-9. 18. smith a, averch td, shahrour k, et al. a nephrolithometric nomogram to predict treatment success of percutaneous nephrolithotomy. j urol. 2013;190:149-56. 19. tiselius hg, andersson a. stone burden in an average swedish population of stone formers requiring active stone removal: how can the stone size be estimated in the clinical routine? eur urol. 2003;43:275-81. 20. muslumanoglu ay, tefekli a, karadag ma, tok a, sari e, berberoglu y. impact of percutaneous access point number and location on complication and success rates in percutaneous nephrolithotomy. urol int. 2006;77:340-6. 21. mandal s, goel a, kathpalia r, et al. prospective evaluation of complications using the modified clavien grading system, and of success rates of percutaneous nephrolithotomy using guy's stone score: a single-center experience. indian j urol. 2012;28:392-8. 22. wu wj, okeke z. current clinical scoring systems of percutaneous nephrolithotomy outcomes. nat rev urol. 2017;14:459-69. hydronephrosis as a risk factor for bleeding in pcnl-kim et al. endourology and stones diseases 12 vol 17 no 01 january-february 2020 13 23. sampaio fj, zanier jf, aragao ah, favorito la. intrarenal access: 3-dimensional anatomical study. j urol. 1992;148:1769-73. 24. el-nahas ar, shokeir aa, el-assmy am, et al. post-percutaneous nephrolithotomy extensive hemorrhage: a study of risk factors. j urol. 2007;177:576-9. 25. liu q, zhou l, cai x, jin t, wang k. fluoroscopy versus ultrasound for image guidance during percutaneous nephrolithotomy: a systematic review and meta-analysis. urolithiasis. 2016. 26. hosseini mm, hassanpour a, eslahi a, malekmakan l. percutaneous nephrolithotomy during early pregnancy in urgent situations: is it feasible and safe? urol j. 2017;14:5034-7. 27. park s, pearle ms. imaging for percutaneous renal access and management of renal calculi. urol clin north am. 2006;33:353-64. 28. agarwal m, agrawal ms, jaiswal a, kumar d, yadav h, lavania p. safety and efficacy of ultrasonography as an adjunct to fluoroscopy for renal access in percutaneous nephrolithotomy (pcnl). bju int. 2011;108:1346-9. 29. mishra s, sharma r, garg c, kurien a, sabnis r, desai m. prospective comparative study of miniperc and standard pnl for treatment of 1 to 2 cm size renal stone. bju int. 2011;108:896-9; discussion 9-900. 30. akman t, binbay m, ozgor f, et al. comparison of percutaneous nephrolithotomy and retrograde flexible nephrolithotripsy for the management of 2-4 cm stones: a matchedpair analysis. bju int. 2012;109:1384-9. 31. bryniarski p, paradysz a, zyczkowski m, kupilas a, nowakowski k, bogacki r. a randomized controlled study to analyze the safety and efficacy of percutaneous nephrolithotripsy and retrograde intrarenal surgery in the management of renal stones more than 2 cm in diameter. j endourol. 2012;26:52-7. 32. mariappan p, smith g, bariol sv, moussa sa, tolley da. stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study. j urol. 2005;173:1610-4. 33. chen l, xu qq, li jx, xiong ll, wang xf, huang xb. systemic inflammatory response syndrome after percutaneous nephrolithotomy: an assessment of risk factors. int j urol. 2008;15:1025-8. 34. sharma k, sankhwar sn, goel a, singh v, sharma p, garg y. factors predicting infectious complications following percutaneous nephrolithotomy. urol ann. 2016;8:434-8. hydronephrosis as a risk factor for bleeding in pcnl-kim et al. vol 15 no 05 september-october 2018 277 pediatric urology urethral meatus and glanular closure line: normal biometrics and clinical significance tariq o abbas1,2,3*, mansour ali1 purpose: the aim of this study is to explore the normal external urethral meatal and glans closure line in normal boys, and to investigate the correlation between these glans biometrics and the age of the participants. material and method: 103 male children were asked to participate in the study during ritual circumcision. parents of 94 of them (mean age 5.9 years, range 0.6–13) accepted while remaining 9 did not. glans biometrics were measured using digital calipers. result: 100% of the study participants had a vertical slit-like meatal opening located at the tip of the glans. the length of the meatal opening was 5.3 (± 1) mm and of ventral glans closure was 4.8 (±1.1) mm. significant correlation between both the external meatal opening and closure lines lengths and age was observed. moreover, the meatal opening size was correlated to the glans closure line as well (r = 0.36, confidence interval 0.14–0.54, p < .001). conclusion: the site and size of the meatus opening in normal male children is consistent, and ventral glans closure is equal to or slightly less than meatal length. these findings could aid in glanular reconstruction configuration during hypospadias surgery. keywords: hypospadias; meatus; glans closure 1department of pediatric surgery, hamad general hospital, doha, qatar. 2college of medicine, qatar university, doha, qatar. 3weill cornel medical college-qatar, doha, qatar. *correspondence: hamad general hospital, pediatric surgery department, pediatric surgery department, hamad general hospital, doha, qatar. tel: (+974) 55093651; email: tariq2c@hotmail.com. received january 2018& accepted june 2018 introduction significant improvements have been achieved in the field of hypospadias repair over the last 3 decades with noticeable reduction of complications and adverse outcomes. the ultimate aim of the different surgical operations for hypospadias repair is to achieve a near-normal glans and penis anatomy with a specific consideration to get a slit-like meatus and satisfactory glanular approximation.(1–4) likewise, it was put forward that having better understanding of the penile anatomy and standardization of the procedures applied would bring better outcomes.(5,6) to date, it has been in pure discretion and judgment of the operating surgeon to assess the pattern of “normal” glans configuration in regards to meatus length and the extent of glanular closure line with scarce studies in this field.(2) the aim of this study is to provide a base of “nomogram” for the meatal and glanular closure dimensions on which the future hypospadias reconstructive procedures can depend on. materials &methods between january 2015 and december 2016, 103 patients who were asking for ritual circumcision in circumcision clinic of hamad medical corporation, doha, qatar were included in this prospective analytical study. overall, 94 male children (mean age 5.9 years, range 0.6–13) participated and remaining candidates did not proceed because either the child or parents declined. patients with known genitourinary anomaly, or previous penile surgery were excluded from the study. all the patients were examined under general anesthesia just prior to the commencement of the surgical procedure of circumcision. longitudinal meatal length (ab) and vertical glans closure lines (bc) were measured using digital caliper following gentle retraction of the foreskin (figure 1). results were expressed as mean ± standard deviation (sd) and spearman’s rank correlation between meatus length and closure line and between meatus length and the age of the patients; 95% ci were calculated and p ≤ 0.05 was considered statistically significant. the study was approved by the medical research centre institutional review boards of hamad medical corporation, doha, qatar (protocol no. 16/16090) and also approved by irb committee of the medical research centre, hamad medical corporation 3050, doha, qatar, tel: 0097444392440. results 100% of the study participants had a vertical slit-like meatal opening located the tip of the glans penis and ran ventrally (figure 1). the length of the meatal opening (ab) was (5.3, ± 1) mm and of ventral glans closure was (4.8, ±1.1) mm. the ab/bc ratio was calculated and found to be 1.1 – 1.3. significant correlation between both the external meatal opening (r = 0.52, ci 0.22– 0.61, p < 0.04) and closure lines lengths and age of the participants was observed. moreover, the meatal opening size was correlated to the glans closure line as well (r = 0.36, confidence interval 0.14–0.54, p < .001). (figure 2) discussion towards the direction of “perfection” in hypospadias repair, several significant milestones have been accomplished. however, the “normal” dimensions of glanular configurations had not gain much attention so far. although one of the key components of hypospadias surgery is to get a slit-like meatus opening,(7) no objective normative data exist to guide the surgeon to reconstruct the different “topographical” elements. the findings of the present study present objective data that can help the surgeon in the process of decision making during glanular reconstruction in hypospadias cases as well as other penile anomalies including: bladder exstrophy-epispadias complex, cloacal exstrophy, disorders of sexual development and traumatic penile injuries. the size of the meatus opening in normal male children is consistent, and ventral glans closure is equal to or slightly less than meatal length. this is similar to what have been reported by hutton et. al.(8) however, it has been recently shown that the structure of the ventral closure line separating the two glanular wings is a septum and not a glanular tissue.(9) on the other hand, our data show significant correlation between the length of the meatal opening and age similar to previous reports. (8,10) besides the size of the meatus, it has been suggested that the ideal location of the meatal opening should be aimed to locate at the tip of the glans following analysis of 300 boys.(11) therefore, creation of a slit-like apical meatal opening can be considered a s a criterion for successful hypospadias repair.(12) however, it is interesting that in most distal hypospadias cases the anatomical landmarks (hillocks) of the meatal opening are well preserved and should be marked prior to incision.(13) creating a longer glans closure could lead to meatal stenosis and increase the risk of urethra-cutaneous fistula. on the other hand, defining the diagnostic criteria of meatal stenosis is considered a clinical challenge as no consensus exists in this regard. however, failure to pass 5f catheter in boys 5-10 years old has been chosen by some authors and happens with high frequency that reaches up to 20% in circumcised children.(14) meatal stenosis has the potential to cause lower urinary tract obstruction with its subsequent complications.(15,16) moreover, about one quarter of patients with meatal stenosis are considered asymptomatic(17). it was also shown that 11.1 % of patients with asymptomatic meatal stenosis have hydronephrosis and vesicoureteric reflux.(14) the present study findings can help defining the size of the meatus in proportion to the age of the patients in more accurate manner and facilitate noninvasive diagnosis of mild forms of meatal stenosis during that can be utilized for screening purposes as well. limitations of the study include the relatively small number of the study cohort and not correlating the meatal length and closure line to other biometric measurements of the penis including the size of the glans. in conclusion, the findings of the present study can help in decision making of glanular topographic proportions during glanular reconstruction, facilitate objective assessment of cosmetic post-operative outcomes, help in defining the features of abnormal meatal shape to ease the clinical diagnosis of meatal stenosis. the size of the meatus opening in normal male children is consistent, and ventral glans closure is equal to or slightly less than meatal length. figure 1. photograph of one of the participants penis showing the different landmarks used for data measurements. point (a) is the distal extent of the meatal opening, point (b) is the proximal extent of the meatal opening and distal limit of glanuar closure line, and point (c) is the proximal limit of glanular closure line. therefore, a to b is the length of the meatal opening while b to c is the extent of the vertical glanular closure line. figure 2. graphical data distribution of different variables. urethral meatus and glanular closure line-abbas et al. pediatric urology 278 vol 15 no 05 september-october 2018 279 acknowledgements this study is supported by medical research centre at hamad medical corporation, qatar (mrc proposal # 16090/16). references 1. snodgrass w, bush n. primary hypospadias repair techniques: a review of the evidence. urol ann. 2016;8(4):403–8. 2. springer a, tekgul s, subramaniam r. an update of current practice in hypospadias surgery. eur urol suppl. 2017;16(1):8–15. 3. keays ma, dave s. current hypospadias management: diagnosis, surgical management, and long-term patient-centred outcomes. can urol assoc j. 2017;11:s48–53. 4. boddy sa, samuel m. mathieu and “v” incision sutured (mavis) results in a natural glanular meatus. j pediatr surg. 2000 mar;35(3):494–6. 5. adams j, bracka a. reconstructive surgery for hypospadias: a systematic review of long-term patient satisfaction with cosmetic outcomes. indian j urol. 2016;32(2):93–102. 6. beaudoin s, delaage p-h, bargy f. anatomical basis of surgical repair of hypospadias by spongioplasty. surg radiol anat. 2000;22(3– 4):139–41. 7. snodgrass w, bush n. primary hypospadias repair techniques: a review of the evidence. urol ann. 2016;8(4):403–8. 8. hutton kar, babu r. normal anatomy of the external urethral meatus in boys: implications for hypospadias repair. bju int. 2007;100(1):161–3. 9. ozbey h, kumbasar a. glans wings are separated ventrally by the septum glandis and frenulum penis: mri documentation and surgical implications. türk üroloji dergisi/ turkish j urol. 2017;43(4):525–9. 10. litvak as, morris ja, mcroberts jw. normal size of the urethral meatus in boys. j urol. 1976 jun;115(6):736–7. 11. genç a, taneli c, oksel f, balkan c, bilgi y. analysis of meatal location in 300 boys. int urol nephrol. 2001;33(4):663–4. 12. baskin l. hypospadias: a critical analysis of cosmetic outcomes using photography. bju int. 2001;87(6):534–9. 13. babu r. glans meatus proportion in hypospadias versus normal: does marking reference points impact outcome? j pediatr urol. 2014;10(3):459–62. 14. joudi m, fathi m, hiradfar m. incidence of asymptomatic meatal stenosis in children following neonatal circumcision. j pediatr urol. 2011;7(5):526–8. 15. robson wl, leung ak. the circumcision question. postgrad med. 1992;91(6):237–42, 244. 16. american academy of pediatrics: report of the task force on circumcision. pediatrics. 1989;84(2):388–91. 17. mahmoudi h. evaluation of meatal stenosis following neonatal circumcision. urol j. 2005;2(2):86–8. urethral meatus and glanular closure line-abbas et al. september-october 2017 reviewer of the issue hamidreza abdi hamidreza abdi october 2017 dr. hamidreza abdi graduated from tehran university of medical sciences in 2001, and completed his residency training in urology at shahid beheshti medical university in tehran. in 2008, he achieved second grade of excellence in the iranian national urology board exam and has been a fellow of european board of urology since 2009. dr. abdi practiced urology in northern part of iran near caspian sea for 3 years, and then decided to move to canada to enhance his knowledge and surgical skills. after moving to canada, he undertook a urologic oncology fellowship (research and clinical) at the vancouver prostate centre at the university of british columbia. his was focused primarily on the use of mri in the diagnosis and treatment of prostate cancer. he also contributed to the development of clinical databases for patients with bladder and prostate cancer, and is interested in biomarker discovery and validation in uro-oncology. dr. abdi has been involved in multicentre research projects working with the international bladder cancer network, hiroshima university, and the international young urologists association. in order to be eligible for licensure in canada, dr. abdi began urology residency at the university of ottawa in 2015, and he is currently pgy-3. he has been involved in the residentdriven global surgery educational project in which residents across the world discuss interesting cases and exchange their ideas. he continues to be a clinical reviewer for several peer-reviewed journals including urology journal, urology, cytotherapy journal, the journal of urology ,plos one, bmc urology, world journal of urology, urologic oncology: seminars and original investigations. “it would be my great pleasure to review articles for urology journal. being a reviewer will allow me to be aware of new ideas in urology research from different parts of the world, limitations of conducting research projects, and important clinical questions or hot topics. being a reviewer also presents a great opportunity to exchange knowledge during the review process. i would like to thank the editorial board of urology journal for the invitation to serve as a reviewer.” dr abdi was chosen as the best reviewer of the issue by editorial board of the urology journal for his valuable and timely review of manuscript. andrology 150 unclassified investigating the outcome of surgery in patients with penile fracture hamid mazdak, hanieh salehi, zahra tolou ghamari, reza kazemi* purpose: the aim of study was to investigate the outcome of surgery in patients with penile fracture in al-zahra hospital. materials and methods: this cross sectional study was conducted on 187 patients with penile fracture underwent surgery in al-zahra hospital during 20162020. data such as penile fracture causes, erectile dysfunction, time of surgery after penile fracture, degree of penile curvature and etc were extracted from medical records. results: the most common reason of penile fracture in these patients was manipulation and trauma with frequency 70 (37.4%) and 69 patients (36.9%), respectively. lower urinary tract symptom, urinary tract injury, penile curvature, penile nodule and erectile dysfunction were observed in 1 (0.54 %), 2(1.06 %), 76 (40.64%), 75 (40.1%), 43 (23%) patients, respectively. mild and moderate erectile dysfunction was seen in 38 (88.3%) and 5 (11.62%) patients, respectively. there was a significant relationship between erectile dysfunction with the degree of penile curvature, surgical time and size of defect (p < .01). furthermore, significant relation was observed between penile nodules and suture type (p = .000). conclusion: according to findings, erectile dysfunction was observed in 23 % of patients; however most of these patients had mild erectile dysfunction. moreover, erectile dysfunction was influenced by penile curvature, surgical time and size of defect. therefore, early surgery and special attention to patients with severe penile curvature are proposed for prevention of erectile dysfunction in these patients. keywords: erectile dysfunction; penile curvature; penile fracture; penile nodule introduction penile fracture is defined as disruption of tunica al-buginea of corpus cavernosum(1). this rare injury may occur due to anal intercourse, vigorous vaginal, forceful manipulation, gunshot wounds, masturbation, or any other mechanical trauma(2,3). other reasons of penile fracture include rolling in bed on the erect penis(4) and using collagenase clostridium histolyticum in treatment of peyronie’s disease(5). the most common reason of this injury in europe and united states is trauma during sexual intercourse(1,6). approximately 8 % of the cases of penile fracture in iran were attributed to sexual intercourse and remaining cases were related to self-manipulation and other factors(7,8). the events following this injury includes popping and cracking sound accompanied with sudden pain, quick detumescence, deviation of the penis to the opposite side of the injury and swelling and ecchymosis(9). recognized physical findings including edema, penile deformity, ecchymosis and patient history often indicate the diagnosis, and additional imaging procedures are often not necessary(9). various imaging modalities such as ultrasound(10), mri(11) and cavernosography(1) have shown different levels of utility in cases of equivocal diagnosis. treatment contains the use of anti-inflammatory drugs and cold compresses(1). but these forms of treatments department of urology, isfahan university of medical sciences, isfahan, iran. *correspondence: department of urology, isfahan university of medical sciences, isfahan, iran. rezakazemi201978@gmail.com received june 2020 & accepted december 2020 are not acceptable, due to high rate of complications(3). today, prompt surgical repair is accepted as choice therapy in these patients(12-14). surgical management includes hematoma evacuation, penile exploration, local defect in the tunica albugine, and urethra with subsequent repair of those injuries. prompt repair of penile fracture prevents urinary incontinence, penile dyspareunia, or pain during intercourse (3). however, postoperative common complications include penile nodules, lower urinary tract symptom and urinary tract injury and erectile dysfunction. but other studies reported that penile fracture repair has no effect on sexual function. they also reported that lower complication rate in these patients is due to immediate surgical correction of the penile(15). prevalence of penile fracture in recent years is increasing and few studies have been conducted regarding the outcome of surgery in patients with penile fractures in our country. moreover, no study is conducted regarding the role of postoperative surgical time and degree of penile curvature on erectile dysfunction in our region, therefore, the aim of current study was to investigate the outcome of surgery in patients with penile fracture in educational hospital of isfahan. urology journal/vol 19 no. 2/ march-april 2022/ pp. 144-147. [doi: 10.22037/uj.v18i.6347] vol 19 no 2 march-april 2022 100 materials and methods study population this cross sectional study was conducted on 187 patients with penile fracture who underwent surgery in al-zahra hospital, isfahan, iran during 20162020. before collecting samples, this study was approved by isfahan university of medical sciences (number: ir.mui.med.rec.1399.058). inclusion and exclusion criteria all patients with penile fractures were included in the study. moreover, exclusion criteria were penile curvature, urinary symptoms and sexual impotence. in addition, patients with incomplete information were excluded from study. procedure all patients with penile fracture underwent surgery in alzahra hospital, isfahan, iran. all patients were followed up 3 months after surgery. data such as age, size of defect, penile fracture causes (manipulation, intercourse, trauma), marital status, side of fracture, sound of fracture, location of injury, erectile dysfunction, sexual impotence, penile nodules, urinary tract injury, suture type and lower urinary tract symptom were extracted from medical records and entered to questionnaire. in addition, other data including time of surgery after penile fracture, duration of hospitalization, time of the first intercourse after surgery and degree of penile curvature were entered to questionnaire. extent of penile deviation was measured through images which are taken of the penis in the state of erection. in addition, erectile function was assessed by international index of erectile function (iief), based on ed questionnaire. statistical analysis data were entered to spss, version 19. qualitative variables were shown as frequency and quantitative parameters as mean± sd. relation between erectile dysfunction with parameters was assessed by chi-square test. then, for determination of coefficient correlation, we used lambda coefficient correlation. p<0.05 was assumed significant. results frequency and mean quantitative parameters of patients with penile fracture in terms of characteristics such as penile fracture causes, marital status and etc is shown in table 1. as shown in table 1, erectile dysfunction and penile outcome of surgery in patients with penile fractures-mazdak et al. table 1. frequency and mean quantitative parameters of patients with penile fracture in terms of penile fracture parameters frequency (percent) reason of penile fracture trauma* 69 (36.9) intercourse 48 48 (25.7) manipulation 70 70 (37.4) total 187 (100) marital status single 84 (44.9) married 103 (55.1) total 187 (100) fracture side right 72 (38.5) left 90 (48.1) ventricle 21 (11.2) dorsal 4 (2.1) total 187 (100) the sound of a fracture yes 145 (77.5) no 42 (22.5) total 187 (100) location of injury proximal 56 (29.9) medial 99 (52.9) distal 29 (15.5) proximal and distal 3 (1.6) total 187 (100) sexual impotence (erectile dysfunction) no 144 (77) yes 43 (23) total 187 (100) erectile dysfunction mild 38 (88.3) moderate 5 (11.62) total 43 (100) penile nodule no 112 (59.9) yes 75 (40.1) total 187 (100) the size of defect (cm) ≤ 2 161 (86.09) >2≤4 22 (11.77) > 4 4 (2.14) total 4 (2.14) urinary tract injury no 185 (98.94) yes 2 (1.06) total 187 (100) suture type monocryl 86 (46) vicryl 101 (54) total 187 (100) surgical cleft circumcision 167 (90.4) longitudinal 18 (9.6) total 187 (100) lower urinary tract symptom no 186 (99.46) yes 1 (0.54) total 187 (100) penile curvature yes 76 (40.64) no 111 (49.3) time of the first intercourse after surgery (day) less than 30 days 17 (9.09) after 30 days 170 (90.9) age, year; mean ± sd (range) 32.91 ± 12.69 (16-75) time of surgery after penile 9.96 ± 11.32 (3-72) fracture hours; mean ± sd (range) duration of hospitalization; 1.09 ± 0.33 (1-3) day; mean ± sd (range) *manipulation: fracture by the person by manipulation during erection intercourse: fractures when the penis enters the vagina trauma: anything other than the above two parameters mean ± sd (range) erectile dysfunction p-value correlation coefficient degree of penile curvature group 1: 3.78 ± 6.59 35-0 )) .000 group 2: 21.6±15.8 45-0 )) 0.41 postoperative surgical time group 1: 8.06±7.54 (48-3 ) .004 group 2: 16.30±17.89 (48-4 ) 0.25 size of defect group 1: 1.37±0.59 (0.5-5) .008 group 2: 2.33± 1.3 (0.7—7) 0.30 table 2. relation between erectile dysfunction with parameters group 1: without erectile dysfunction; group 2: erectile dysfunction vol 19 no 2 march-april 2022 145 unclassified 146 curvature was seen in 23 % and 40.64 % of patients, respectively. relation between erectile dysfunction with degree of penile curvature, postoperative surgical time, size of defect and surgical cleft is shown in table 2. relation between erectile dysfunction with parameters was assessed by chi square. lambda coefficient correlation was used for determining coefficient correlation. p < 0.05 was assumed significant. as shown in table 2, there was significant relation between erectile dysfunction with degree of penile curvature, postoperative surgical time, and size of defect (p < .01). furthermore, significant relation was observed between penile nodules and suture type (p = .000, coefficient correlation=0.68). discussion management of penile fracture with emergency surgical repair is the most effective approach in these patients. however, postoperative complications including erectile dysfunction, penile nodules, penile curvature and painful erection or intercourse are common in penile fracture patients(16). the most reason of penile fracture in this study was manipulation. ibrahim et al., reported the most common cause of penile fracture in egypt was sexual intercourse(17). jack et al., reported that only 19 % of causes of penile fracture in japan is sexual intercourse and other causes of penile fracture are rolling over in bed onto an erect penis and masturbation(18). shafi et al., conducted a study on patients of babol province and reported that masturbation is a main reason of penile fracture in this area(3). kochakarn et al., reported that the most common cause of penile fracture was sexual intercourse (83%) and masturbation (16. 6%)(14). reise et al., in a study in brazil reported that the most dangerous condition for penile fracture was sexual intercourse in status of woman on top(16). other studies reported that the cause of half of cases of penile fracture in middle east is manual bending of erected penis for achieving detumescence. they believed that this is due to lack of sexual education or cultural belief in this area as evidenced by the extensive practice. shafi et al., conducted a study on patients of babol province and reported that masturbation is a main reason of penile fracture in this area(3). therefore, it seems that the cause of penile fracture is mainly related to geographic area and cultural circumstances(3). postoperative erectile dysfunction was also seen in 23 % of patients of our study. in this regard, 38 patients had mild erectile dysfunction and 5 had moderate erectile dysfunction. in addition, we observed a significant relation between postoperative erectile dysfunction and surgical time. nason et al., assessed the outcome of sexual function following penile fracture in 21 patients and observed 1 patient with symptoms of mild erectile dysfunction (ed) and 1 patient with mild to moderate ed (19-24). in addition, 14 patients did not demonstrate evidence of erectile dysfunction. they also reported that sexual satisfaction in long term was promising. swanson et al., assessed penile fracture in 29 patients in northwestern memorial hospital and reported 9 patients (31 %) with mild erectile dysfunction. the incidence of erectile dysfunction in this study was higher than our study. el-salami et al., assessed erectile dysfunction in 180 patients with penile fracture after 106 months follow-up and observed 3.8 % patients with mild erectile dysfunction and 2.2 % with moderate erectile dysfunction (25). it seems that the difference between our study and el-salami's study may be due to the difference in age range of patients(26) and surgical time. muentener et al., in a study evaluated patients with penile fracture who underwent surgery and observed good outcome in 92% of patients. immediate surgery leads to excellent findings and is superior to non-operative treatment in patients with penile fracture(2). other research and guidelines are strongly proposed prompt surgical therapy of penile fracture due to early return of sexual activity and less morbidity(27). in addition, degree of penile curvature affected sexual impotence in our study. burri et al., also reported that men with stronger curvature had more overall sexual dissatisfaction, which was consistent with our study(28). urai et al., reported no significant relation between penile curvature severity and comorbidities in men with peyronie's disease(29). therefore, more studies are needed regarding the role of penile curvature and sexual impotence. furthermore, size of defect was another parameter that affected erectile dysfunction in our study. few studies have been performed considering erectile dysfunction and size of defect, but levine et al., reported that size of defect did not affect erectile dysfunction (30). kati et al., reported that the size of defect in patients with penile fracture was in the range 0.3-3.6 cm; however, they did not assess relation of erectile dysfunction and defect size(31). it seems that more studies should be conducted in this regard. in our study, postoperative penile nodules were observed in 40.1 % of patients. atyeh et al., conducted a study on patients with penile fracture and observed that penile nodules as the most common postoperative complications were seen in 41.7 % of patients(32). these findings were almost like to our study. kominsky et al., reported that penile nodules were observed in 13.7 % of patients(1). according to the findings of our study, one of the influential factors on penile nodules was suture type. in this regard, vicryl led to more nodules than monocryl. regan et al., also compared monocryl (poliglecaprone-25) and vicryl (polyglactin-910) in patients with penile fracture and observed superiority of monocryl than vicryl, regarding penile nodules(33). this finding was consistent with our study. niessen et al., compared poligecaprone-25 and polyglactin-910 and found that poligecaprone-25 led to less hypertrophic scars(34). therefore, it is proposed to pay more attention to the type of suture in the surgery of patients with penile fractures. conclusions according to these findings, erectile dysfunction was observed in 23 % of patients; however, most of the patients had mild erectile dysfunction. moreover, erectile dysfunction was also influenced by penile curvature, surgical time and size of the defect. therefore, early surgery and special attention to patients with severe penile curvature are proposed for prevention of erectile dysfunction in these patients. conflict of interest there is no conflict of interest. references 1. kominsky h, beebe s, nayan shah n, et al. surgical reconstruction for penile fracture: a outcome of surgery in patients with penile fractures-mazdak et al. vol 19 no 2 march-april 2022 100 systematic review. sexual med j 2019; 2: 1-9. 2. muentener m. long term experience with surgical and conservative treatment of penile fracture. j urol 2004; 172:576-589. 3. shafi h, ramaji a, kasaeeian a, et al. report of 84 cases of penile fracture in beheshti hospital center. j mazandaran univ med sci 2005; 15:37-43 4. ateyah a, mostafa t, nasser ta, et al. penile fracture: surgical repair and late effects on erectile function. j sex med 2008; 5:1496– 502. 5. beilan ja, wallen jj, baumgarten as, et al. intralesional injection of collagenase clostridium histolyticum may increase the risk of late-onset penile fracture. sex med rev 2018; 6:272–8. 6. mydlo jh. surgeon experience with penile fracture. j urol 2001; 166: 526–8. 7. jack g, garraway i, reznichek, r. current treatment options for penile fractures. rev urol 2004; 6(3):114-20. 8. zargooshi j. penile fracture in kermanshah, iran: report of 172 cases. j urol 2000;164: 364-366. 9. karadeniz t, topsakal m. penile fracture: differential diagnosis, management and outcome. british j urol 1996; 77:279–81. 10. hassali ma, nouri ai, hamzah aa, et al. role of penile doppler as a diagnostic tool in penile fracture. j med ultrasound 2018; 26:48–51. 11. klein fa, smith v, miller n. penile fracture: diagnosis and management. j trauma. 1985;25:10901092. 12. mydlo, j. surgeon experience with penile fracture. j urol 2001; 166: 526. 13. zargooshi, j. penile fracture in kermanshah, iran: the longterm results of surgical treatment. bju int 2002; 89: 890-97. 14. kochakarn, w, viseshsindh, v, muangman, v. penile fracture: long-term outcome of treatment. j medassoc thai 2002; 85: 179182 15. bolat m. effects of penile fracture and its surgical treatment on psychosocial and sexual function. int j impotence res 2017; 29; 244– 49. 16. reise l. mechanisms predisposing penile fracture and long-term outcomes on erectile and voiding functions. advances in urol 2014; 1-9. 17. ibrahiem el, el-tholoth h, mohsen t. ahmed el-assmy. penile fracture: long-term outcome of immediate surgical intervention. urology 2019; 75: 108–111. 18. jack g, garraway i, reznichek r, rajfer j. current treatment options for penile fractures. reviews urol 2004; 6: 114-120. 19. nason g. barry b. mcguire. sexual function outcomes following fracture of the penis. cite as: can urol assoc j 2013;7: 252-7. 20. o’leary mp, fowler fj, lenderking wr. a brief male sexual function inventory in urology. urology 1995;46: 697-706. 21. assmy a, tholoth hs, mohsen t. does timing of presentation of penile fracture affect outcome of surgical intervention? urology 2011; 77:1388-91. 22. ibrahiem hi, tholoth hs, mohsen t. penile fracture: long-term outcome of immediate surgical intervention. urology 2010;75:10811. 23. garcagomez b, romero j, villacampa f, et al. early treatment of penile fractures: our experience. arch esp urol 2012; 65:684-8. 24. koifman l, barros r, jonior ra. penile fracture: diagnosis, treatment and outcomes of 150 patients. urology 2010; 76: 1488-92. 25. assmy el. risk factors of erectile dysfunction and penile vascular changes after surgical repair of penile fracture. int j impot res 2012; 24: 20-5. 26. joe a. management of erectile dysfunction. am fam physician 2010 ;81(3):305-12 27. ahmad a. majzoub, onder canguven, and talib a. raidh. alteration in the etiology of penile fracture in the middle east and central asia regions in the last decade; a literature review. urol ann 2015; 7: 284–288. 28. burri a, hartmut porst. the relationship between penile deformity, age, psychological bother, and erectile dysfunction in a sample of men with peyronie’s disease. sexual med j 2018; 30:171–78. 29. usta m. relationship between the severity of penile curvature and the presence of comorbidities in men with peyronie's disease. j urol 2004; 177-181. 30. levine l, greenfield j, estrada c. erectile dysfunction following surgical correction of peyronie's disease and a pilot study of the use of sildenafil citrate rehabilitation for postoperative erectile dysfunction. j sex med 2005; 2: 241-7. 31. kati b. penile fracture and investigation of early surgical repair effects on erectile dysfunction. urologia 2019; 86: 207-10. 32. atiyeh a. mostafa t. penile fracture: surgical repair and late effects on erectile function. sex med 2008;5:1496–150. 33. regan t. comparison of poliglecaprone-25 and polyglactin-910 in cutaneous surgery. dermatol surg 2013; 39:1340–44. 34. niessen fb, spauwen ph, kon m. the role of suture material in hypertrophic scar formation: monocryl vs vicryl-rapid. ann plast surg 2000; 39:254–60. outcome of surgery in patients with penile fractures-mazdak et al. vol 19 no 2 march-april 2022 147 endourology and stone disease the effects of aqueous extract of eryngium campestre on ethylene glycol-induced calcium oxalate kidney stone in rats hamidreza safari1, sajjad esmaeili2, mohammad sadegh naghizadeh1, mehran falahpour2, mohammad malekaneh3, and gholamreza anani sarab4* purpose: this study aimed to evaluate the anti-inflammatory effect of e. campestre using the aqueous extracts, obtained from the aerial parts, on ethylene glycol (eg)-induced calcium oxalate kidney stone in rats. materials and methods: 64 male wistar rats were randomly divided into 8 groups. group i was considered as negative control and received normal saline for 30 days, group ii as kidney stone control received eg for 30 days, groups iii to vi as prophylactic treatment received eg plus 100, 200 or 400 mg/kg extracts for 30 days and groups vi to viii received eg as therapy from day one and 100, 200 or 400 mg/kg extract from the 15th day. on the 30thday from the start of induction, rats were euthanized. blood was collected and the kidneys were immediately excised. slides from each one’s kidneys were prepared and stained with hematoxylin & eosin method. also levels of interleukin-1 beta (il-1β) and interleukin-6 (il-6) were determined in rat’s serum by competitive elisa kit. results: e. campestre reduced il-1β and il-6 levels, showing a significant reduction for both cytokines in all prophylactic groups, especially at the dose of 400 mg/kg (p-value < .001). moreover, il-1β (p = .011) reduced significantly in the therapy groups in 400 mg/kg dose. crystal count reduction was seen in all prophylactic and therapy groups in comparison with group ii. conclusion: these results suggest that the e. campestre extract has potent suppressive effect on pro-inflammatory cytokine production in rat. also, e. campestre decreases crystal deposition in the kidney of the hyperoxaluric rat. keywords: cytokines; e. campestre; inflammation; kidney stone introduction kidney stone is among the oldest and the most common diseases known to human and the third most prevalent disorder of the urinary tract that affects 10-15% of the total population around the world(1). the prevalence of kidney stones in iran was 5.7% in 2005, with slight increase prevalence in men (6.1%) than women (5.3%)(2-4). there are several risk factors related to the formation of urinary calculi, such as gender, genetics, dietary habits and climate. also, metabolic acidosis, hypertension and urinary tract infections are associated with urinary tract stone. calculi usually form when urine becomes supersaturated with particular calcium salts such as calcium oxalate(5). based on chemical composition, the most common types of kidney stones are calcium, magnesium ammonium phosphate, uric acid, and cysteine. in this regard, calcium-containing stones constitute about 75% of all the urinary calculi and can exist as either calcium oxalate or calcium phosphate (apatite), or a mixture of both(6,7). calcium oxalate (caox) stones are responsible for a large proportion of calculi in primary and secondary forms of hyperox1msc student of immunology, immunology department, birjand university of medical sciences, birjand, iran. 2student research committee, birjand university of medical sciences, birjand, iran. 3cellar and molecular sciences research centre, birjand university of medical sciences, birjand, iran. 4infectious diseases research center, birjand university of medical sciences, birjand, iran. *correspondence: infectious diseases research center, birjand university of medical sciences, birjand, iran mobile: 989151605847+. fax: 985631631600+. e-mail address: ghansa@yahoo.com. received november 2017 & accepted august 2019 aluria(8,9). current therapy approaches for kidney stone are mainly supportive like drinking plenty of water and the use of anti-inflammatory drugs. although,stone pieces may discharge naturally, but bigger pieces should be removed by surgery. also, ultrasound shock waves are used to break the larger stones into tiny pieces. however, this has been associated with a number of undesirable side-effects, such as tubular necrosis, hemorrhage and kidney fibrosis(10). herbal medicine recently attracted research attention to avoid the adverse effects of current anti-urolithiasis therapies(11-14). the genus eryngium, belonging to the subfamily saniculoidea of apiaceae, consist of approximately 317 species around the world and are well-known to possess acetylenes, flavonoids, coumarins and triterpensaponins(15).eryngiumcampestre l. (apiaceae) (field eryngo) is scattered in spain, france, germany, balkan peninsula and some countries in africa and asia including iran(16). also, it has been used in european herbal medicine as an infusion to treat kidney and urinary tract inflammations.(17) urology journal/vol 16 no. 6/ november-december2019/ pp. 519-524. [doi: 10.22037/uj.v0i0.4287] this study aimed to evaluate the anti-inflammatory effect of e.campestre, using the aqueous extracts obtained from the aerial parts, on ethylene glycol-induced caox kidney stone in rats. materials and methods preparation of extract e.campestre was collected from the northern parts of iran and its herbarium code was determined at the school of pharmacy and pharmaceutical sciences, mazandaran university of medical sciences (code: 1442). aerial parts were separated, dried in shade and powdered to a fine grade using a grinder. thirty grams of powder was dissolved in distilled water in a volume of 600 ml and stirred by a stirrer for 24 hours in the room temperature. the resulting mixture passed through sterilized gauze and subsequently purified with whatman paper. finally, the extract was placed in an incubator at 40 °c to completely dry. three grams of dry extract (10 percent) obtained from every 30 grams of dried plant powder. the extract was kept in a refrigerator and the doses of the extract were prepared in distilled water before oral administration to rats. experimental protocol this experimental study was conducted in 2017 in 30 days in birjand university of medical sciences. this study received an ethics code (code: ir.bums. rec.1396.76) from the university ethics committee. a total of 64 male wistar rats weighing 200–250 g were divided randomly into8 groups (each group contained 8 rats). rats were housed under controlled standard conditions at a temperature of 25 ± 2 °c and 12-hour darkness and lightning cycles with free access to standard food and drinking water. ethylene glycol (eg) was used to induce hyperoxaluria in rats(18). the followings are the details of the experimental procedure, adopted for the study: group i or negative control (nc): the standard diet and drinking water; they received 1 ml of normal saline by oral gavage once daily. group ii or kidney stone control (ksc): standard diet and 0.1 % of eg in drinking water during the study period; they received 1 ml of normal saline by oral gavage once daily. group iii (prophylactic 100): standard diet and 0.1 % of eg in drinking water during the study period; they received 100mg/kg of extract by oral gavage once daily for 30 days in the final volume of 1 ml. group iv (prophylactic 200): standard diet and 0.1 % of eg in drinking water during the study period; they received 200mg/kg of extract by oral gavage once daily for 30 days in the final volume of 1 ml. group v (prophylactic 400): standard diet and 0.1 % of eg in drinking water during the study period they received 400mg/kg of extract by oral gavage once daily for 30 days in the final volume of 1 ml. group vi (therapy 100): standard diet and 0.1 % of eg in drinking water during the study period, and from the 15th day until the end of the study they received the extract at a dose of 100mg/kg daily in the final volume of 1 ml. group vii (therapy 200): standard diet and 0.1 % of eg in drinking water during the study period, and from the 15thday until the end of the study they received the extract at a dose of 200mg/kg daily in the final volume of 1 ml. group viii (therapy 400): standard diet and 0.1 % of eg in drinking water during the study period, and from the 15thday until the end of the study they received the extract at a dose of 400mg/kg daily in the final volume of 1 ml. eryngium campestre for calcium oxalate kidney stone-safari et al. table1: effect of e. campestre on caox crystal deposits in urolithiasis induced rat. control groups prophylactic groups therapy groups parameter nc ksc p100 p200 p400 t100 t200 t400 caoxcrystals 0.7 ± 0.6* 33.5 ± 9.1 17 ± 8.5* 5.8 ± 2.6* 5.31± 1.5* 19 ± 5.1* 12 ± 6.9* 9.9 ± 4.2* * the mean differences in comparison with ksc group is significant at the < 0.01 level. figure 1: photomicrographs of h&e stained paraffin sections of rat kidney tissues. a. there were no deposits of crystals in the normal control group. e. ksc group showed significantly increased levels of crystal deposits. b, c, d. prophylactic group (doses 100,200and 400 mg/kg, respectively) had significantly decreased crystals in comparison to ksc group. f, g, h. interventiongroup (doses 100,200and400 mg/kg, respectively) also had a significant decrease of crystals in comparison with ksc group. original magnification x40.abbreviations: ksc, kidney stone control. endourology and stone diseases 520 vol 16 no 06 november-december2019 521 histopathologic examination and cytokine measurement on the 30th day from the start of eg induction, the animals were anesthetized and euthanized. blood was collected and the kidneys were immediately excised and washed in ice-cold saline and placed in 10% formalin; they were then embedded in paraffin and on each slide, 3 sections of 5μm were stained by hematoxylin & eosin. the caox crystal deposition, induced by eg in tissue kidney, was studied by the pathologist, using the light microscopy with a magnification of ×40 in 10 microscopic fields. serum was separated by centrifugation at 3000×g for 15 minutes. levels of il-1β and il-6 were determined in all groups by rat competitive elisa kit (eastbiopharm, china, lot number: e20170620008) according to the manufacturers’ instructions (eastbiopharm.com inc.). statistical analysis all data was analyzed using spss version 18.0 (new york: mcgraw-hill) and are expressed as mean ± sd. one-way anova (lsd post hoc test) was used to compare the mean values of the cytokines. a p-value < 0.05 was considered statistically significant for the differences. results histopathologic examination the histopathologic status of calcium deposits in rats' kidneys paraffin sections was analyzed in the field view of ×40 magnification (figure 1). almost no caox deposits were found in group i. table 1 provides information about the average distribution of caox deposits in kidneys of rats in different groups. the mean numbers of caox deposits in the kidney specimens of both prophylactic and therapy groups were significantly lower than that in the kidney stone control group (p < .001). rats who received 200 or 400 mg/kg extract had shown more decline in crystal deposits (average number of crystal deposits = 8.25) compared to those who received 100 mg/kg extracts daily with average number of crystal deposit being 18 in prophylactic and therapy groups. in total, crystal deposits in prophylactic groups were lower (mean crystals = 9.3) compared to therapy groups (mean crystals = 13.63). serum analysis based on the serum levels of il-1β and il-6 presented in table 2, the values of normal control group were significantly lower than their values in eg administered ksc group (p < .001). the il-1β and il-6 serum levels of rats received 400 mg/kg extracts in prophylactic groups showed a significant decrease in comparison with the ksc group (p < .001). furthermore, the reduction of il-1β and il-6 levels remained significant at lower doses of extracts (100 & 200 mg/kg) in the prophylactic groups. while the reduction of il-1 in treatment groups was significant in 400 mg/kg dose (p = .01), it remained unchanged for il-6 in these groups. from the values, it was evident that both doses (200 and 400 mg/kg) of the extract are effective in reducing the serum levels of inflammatory cytokines in prophylactic groups (figure & table 2). the results clearly demonstrated that the high dose of 400 mg/kg extract is more table2: effect of the aqueous extract of e. campestre on serum levels of il-1 and il-6 in different groups in comparison to ksc groups il1 il6 il1(p-value compare to ksc) il6 (p-value compare to ksc) mean standard mean standard deviation deviation ksc 1012.26 182.48 130.80 19.80 t100 821.90 142.15 101.24 38.55 0.206 0.142 t200 803.38 182.09 94.27 20.31 0.123 0.030 t400 734.07 135.58 102.12 16.68 0.011 0.168 p100 772.68 112.09 89.75 20.75 0.046 0.009 p200 745.80 133.34 81.06 24.29 0.017 0.001 p400 654.82 191.08 71.71 12.26 p < 0.001 p < 0.001 nc 592.62 98.62 56.80 8.50 p < 0.001 p < 0.001 abbreviations: t, therapy group; p, prophylactic group; nc, normal control; ksc, kidney stone control. figure 2. effect of the aqueous extract of e. campestre on serum levels of il-1 and il-6 in different groups in comparison to kidney stone control (ksc) (*, p < 0.05; **, p < 0.01; ***, p < .001). abbreviations: t, therapy group; p, prophylactic group; nc, normal control; ksc, kidney stone control. eryngium campestre for calcium oxalate kidney stone-safari et al. effective in reducing the serum levels of il-1β and il-6 inflammatory cytokines. discussion nephrolithiasis incidence and prevalence is reported to be increasing annually around the world, along with a decrease in the age of onset, probably because of changes in lifestyle, diet, and climate(19).in the present study, eg was used to produce hyperoxaluria in male wistar rats. as the urinary system of male rats resembles that of humans, kidney stone formation in eg fed rats is frequently used to mimic the urinary calculi formation in human(20). preceding studies showed that 14 days administration of eg, increases oxalate concentration in urine which leads to the formation of renal calculi(21). the pathological process of stone formation involves crystal nucleation, growth, aggregation and their retention in the kidneys. although the triggers and the exact mechanisms of crystal formation are not well understood, crystal deposition has been linked with intra-renal inflammation(22,23).from previous histopathological findings, eg causes tissue damage in the renal tubular epithelium and tubules dilatation. enhancement of renal tubular epithelial cell damage leads to emptying the contents of the cell, attracting inflammatory cells, and thereby inflammatory response in the renal tissue(24). inflammation leads to the development of collagen deposit and epithelium transformation which is conducive to biomineralization processes in the tubular basement membrane(24). the pharmacological effects of eryngium species correlated with the presence of high triterpenoid saponin content(25), flavonoids(26,27), phenolic acids(28) coumarin derivatives(29), acetylenes(30,31), rosmarinusacid, and chlorogenic acid, known as antioxidants(32,33).exclusively, phytochemical analysis revealed significant concentrations of sterols and anti-inflammatory effects(34). e. campestre contained high amounts of sitosterol and stigmasterol, while cholesterol was detected in small amounts(31). phytosterols (sitosterol, stigmasterol, and campesterol) are responsible for antioxidant effects in some diseases(35). e. campestre extracts showed very significant inhibition of the bone marrow acute phase response by reducing the phagocytic leukocytes count and by lowering neutrophils and monocytes infiltrates(34). in spite of the extensive usage of eryngium species in the treatment of inflammatory disorders around the world, the number of scientific investigations evaluating the anti-inflammatory or anti-nociceptive activity of eryngium is limited. in this study, microscopic examination of kidney sections obtained from eg induced urolithic rats showed crystal deposition in the kidneys of lithogenic groups along with inflammation, which might be attributed to oxalate. based on the findings, the administration of extract in a prophylactic regimen (100, 200 & 400 mg/kg) reduced caox crystal deposition in the kidney (table1). in the therapy groups (group vi to viii), the extract at the dose of 200 mg/kg also reduced the count of crystal deposition significantly (table1). crystal nucleation induced by super saturation of urine with caox and crystal growth caused by oxidative stress, resulted from renal epithelial exposure to caox crystals(36). the antioxidant or anti-inflammatory potential of e. campestre extract showed a protective effect against crystal deposition in the kidney of rats that received the extracts. e. campestre extracts reduced the level of il-1β and il-6 cytokines significantly in all prophylactic groups(p < 0.001) (figure & table2). moreover, e. campestre extract possessed the inhibitory effects on il-1β at the high dose of 400 mg/kg in the treatment groups compared with the negative control group (p < 0.01). however, all the prophylactic groups (group iii to v) exhibited a marked decrease in il-1β and il-6 levels at a high dose (400 mg/kg) of extract in comparison to treatment groups. therefore, the results revealed the significant anti-inflammatory activity of e. campestre extracts in eg-induced inflammation in rats with a prophylactic regimen. considering the activation of the inflammasome by a wide variety of triggers during the inflammatory conditions, the extracts may interfere with the inflammasome-dependent il-1β signaling pathway, which warrants further studies(37). simona conea et.al. showed that the anti-inflammatory activities of the extract were supported by inhibition of phagocytes and nitro-oxidative stress reduction. the effect is likely related to a synergic activity of the detected sterols, triterpenoid saponins, and polyphenolic compounds(37). overall, the results obtained in the present study are consistent with the anti-inflammatory effects of the eryngium reported in the previous studies(34,38). since inflammatory cytokines have significantly decreased in the treatment group compared with the ksc group, it is suggested to measure anti-inflammatory cytokines such as il-10 and il-4 in future studies. also, additional tests such as flow cytometry and western blotting can be further examined to assess the effects of this extract on inflammation and eginduced calcium oxalate kidney stones. conclusions e. campestre canlower the level of proinflammatory cytokines such as il-1β and il-6 in rats, demonstrating a potent bioactive potential to suppress the inflammatory response. also, e. campestre decreased crystal deposition in the kidney of the hyperoxaluric rat. this study suggests e. 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on ligatureinduced rat periodontitis. digest journal of nanomaterials and biostructures. 2015;10:693-704. 35. kimura y, yasukawa k, takido m, akihisa t, tamura t. inhibitory effect of some oxygenated stigmastane-type sterols on 12-o-tetradecanoylphorbol-13-acetateinduced inflammation in mice. biological and pharmaceutical bulletin. 1995;18:1617-9. 36. naghii mr, mofid m, hedayati m, khalagi k. antioxidants inhibition of high plasma androgenic markers in the pathogenesis of ethylene glycol (eg)-induced nephrolithiasis in wistar rats. urolithiasis. 2014;42:97-103. 37. conea s, parvu a, taulescu m, vlase l. effects of eryngium planum and eryngium campestre extracts on ligature-induced rat periodontitis. digest journal of nanomaterials and biostructures. 2015;10:693-704. 38. nebija f, stefkov g, karapandzova m, stafilov t, panovska tk, kulevanova s. chemical characterization and antioxidant activity of eryngium campestre l., apiaceae from kosovo. macedonian pharmacology bulletin. 2009;55:22-32. eryngium campestre for calcium oxalate kidney stone-safari et al. endourology and stone diseases 524 andrology short abstinence may have paradoxical effects on sperms with different level of dna integrity: a prospective study serajeddin vahidi1, nima narimani2*, taha ghanizadeh1, fatemeh yazdinejad1, maryam emami2, kaveh mehravaran2, hossein saffari2, farhood khaleghimehr2,laleh dehghan marvast1 purpose: to investigate the effect of short abstinence on sperm function tests and semen parameters. materials and methods: this prospective study included 65 male patients with increased dna injury in their ejaculated sperm and a history of recurrent pregnancy loss and/or assisted reproductive techniques failures. the effects of antioxidants medical therapy and short abstinence on semen quality were assessed (tunel test and cma3 staining). results: antioxidants have statistically significant effects on mean sperm concentration (untreated, 67.51 ± 44.40 million/ml, vs. treated, 56.09 ± 37.85 million/ml; p-value=0.005) and mean tunel score (untreated, 24.56% ± 9.49%, vs. treated, 20.64% ± 10.28%; p-value = 0.013). moreover, a short abstinence period might have positive effects as shown on the tunel assay (20.64% ± 10.28 vs. 17.38% ± 8.59 ; p-value = 0.028) and cma3 staining (47.79% ± 20.78, vs. short 41.92% ± 18.49; p-value = 0.019), when considering all study subjects. however, different results were obtained using more precise analysis based on a tunel cutoff score of 20%. the analysis showed that short abstinence might improve sperm dna integrity in patients with tunel score > 20% (mean tunel score from 27.85% ± 8.32% to 19.14% ± 8.90% ; p-value =0.001%). however, it might have deleterious effects on sperm dna integrity in patients with tunel score < 20% (mean tunel score from 11.89% ± 3.21% to 15.17% ± 7.79%; p-value = 0.045%) conclusion: our results showed that short abstinence may not be beneficial in all infertile males, and it should only be used in selected patients with abnormal dna integrity. keywords: cma3; male infertility; short abstinence; sperm dna integrity; tunel 1department of urology, research & clinical center for infertility, shahid sadoughi university of medical sciences, yazd, iran. 2department of urology, hashemi nejad kidney center (hkc), iran university of medical sciences (iums), tehran, iran. *correspondence: assistant professor of urology, department of urology, hashemi nejad kidney center (hkc), iran university of medical sciences (iums),tehran, iran. tel: (+98 21) 81161,fax: (+98 21) 88644441, email: narimani.n@iums.ac.ir, nima_dr2001@yahoo.com. received october 2020 & accepted july 2021 introduction male fertility and sperm production ability have been traditionally assessed using conventional semen analysis(1). the latest world health organisation (who) guideline(2) recommends abstinence of 2 to 7 days prior to semen collection. on the other hand, some reports recommend a single day of abstinence as optimal for semen parameters(3). in the era of assisted reproductive technology, special consideration needs to be given to sperm dna integrity along with semen analysis. it has been estimated that 15% of infertile men with normal semen analysis (presumed to have idiopathic infertility) have increased sperm dna injury(4). a higher level of sperm dna fragmentation index (dfi) is associated with lower natural pregnancy rate and decreased assisted reproductive technology (art) outcome(5). in a state of oxidative stress, reducing the epididymal transit effect may lead to better semen quality. this goal may be achieved via two means: short abstinence and testicular sperm retrieval(6). the effect of short abstinence on sperm dna have been widely assessed by different groups, yet controversy remains. short abstinence is usually considered as abstinence less than 24 hours (instead of recommended abstinence of 2-7 days). many reports(6,7) have shown positive effects for short abstinence on sperm dna quality and art outcomes, while others have reported contrasting data(8,9). this discrepancy may be due to selection bias, difference in sample size, or type of the tests used. in this context, the question to be addressed is whether the standard abstinence period(2) is only effective in men with normal sperm dfi or if it is applicable in all infertile males. the present study assessed the effects of short abstinence ( ejaculation after 24 hours of abstinence) on semen and sperm dna quality in a group of infertile men with previous recurrent pregnancy loss and/or art failure and elevated sperm dfi. materials and methods following the approval by our institutional review board (ref number: ir.ssu.rsi.rec.1398.004), 85 urology journal/vol 18 no. 6/ november-december 2021/ pp. 682-687. [doi: 10.22037/uj.v18i.6515] vol 18 no 6 november-december 2021 683 infertile men who provided written informed consent to take part in the study were enrolled (referred to yazd center for infertility and research, yazd, iran, between december 2018 and may 2019). the yazd center of infertility and research is a high-volume center with approximately 30 outpatient visits per day in the andrology clinic, most of which are referred from all over the country due to recurrent pregnancy loss or art failure. the primary inclusion criteria were (i) couples with recurrent early abortion (more than two abortions in the first trimester) and (ii) recurrent failed art (more than three intrauterine inseminations (iui) or more than two in vitro fertilisation (ivf) sessions and more than two intracytoplasmic sperm injection (icsi) sessions). among them, men with disturbed dna integrity, as assessed using terminal deoxynucleotidyl transferase-mediated dutp nick end labelling (tunel) test, and/or increased level of chromomycin a3 (cma3) staining (tunel score > 20% and/or cma3 score > 30) were selected(10) and treated with antioxidant medical therapy for 3 months (folic acid 1 mg/day, once daily selenium plus-eurho® vital selen plus capsule, euro otc pharma gmbh, and once daily /250 mg l-carnitine ). because these tests have not been standardised yet, the cutoff values were chosen based on previous studies (10-14). at the end of the third month, the participants provided us with two semen samples as described below (in the semen collection section). exclusion criteria were (i) a history of smoking, (ii) opium addiction, (iii) multiple sexual partners, (iv) known hormonal abnormality, (v) clinically detected varicoceles, or (vi) cryptorchidism. the same andrologist performed a complete physical examination, evaluated the past medical history and recorded the results. finally, 21 patients were excluded, and 64 patients were enrolled. semen collection each patient provided three semen samples: (i) the first sample before antioxidant medical therapy (with abstinence of 2–7 days based on the who recommendation) was considered as unntreated sample; (ii) the second sample (treated sample ) after 3 months of antioxidant medical therapy (with abstinence of 3 days) and (iii) the third sample with 24 hrs of abstinence after the second sample, was considered as the short abstinence (short ejaculation) sample. semen analysis and sperm dna integrity semen samples were obtained and analysed based on who guidelines (2010)(2). motility was classified as (i) progressive, (ii) nonprogressive and (iii) immotile. sperm morphology was reported based on strict criteria. two different sperm dna and chromatin tests were performed on each semen sample: (i) a terminal deoxynucleotidyl transferase-mediated dutp nick end labelling (tunel) test, which directly measures sperm dfi, and (ii) chromomycin a3 staining (cma3), which evaluates sperm dna protamination (or compaction). tunel test in brief, after fixation with paraformaldehyde, the samples were washed and treated with pbs and a mixture of methanol and 3% h 2 o 2 . in the next step, after being immersed in triton x-100 and sodium citrate, the samples were washed with pbs and then stained with a mixture of enzyme and fluorescently labelled dutp solution. finally, they were assessed using an in situ cell death detection kit (roche diagnostics gmbh, mannheim, germany) and fluorescence microscopy (bx51, olympus, tokyo, japan) (15). at least 200 sperms were counted and considered as containing damaged dna if they turned bright green. chromomycin a3 cma3 is a guanine–cytosine binding fluorochrome which competes with protamine for the same binding locus. therefore, cma3 staining assesses chromatin integrity (protamination). briefly, air-dried samples were fixed with carnoy’s solution, stained with cma3 for 20 min, rinsed and then mounted with glycerol buffer, and finally stored at a low temperature overnight. the next morning, the samples were assessed using a fluorescence microscope(16). sample size calculation considering the following formula, the estimated sample size for this before-after study, was 64 samples: where type i error rate (α), and power (1-β) were 0.05, 0.35 and 0.8, respectively(17) statistical methods continuous variables are reported as mean (standard deviation) and categorical data are presented as frequency (percentage). in order to assess the difference between two variables for the same subject, paired sample t test was used for continuous variables. also the association between age, body mass index, smoking, alcohol consumption, duration of infertility and the results of sperm dfi were assesed using repeated measures anova. p-value < 0.05 was considered as statistically significant. statistical analysis was performed using spss version 25.0 (ibm, chicago, illinois, usa). variables untreated group (n= 64) mean ± sd treated group (n=64) mean ± sd p-value volume (ml) 3.40 ± 1.41 3.62 ± 1.44 0.161 concentration (mil/ml) 67.51 ± 44.40 56.09 ± 37.85 0.005* progressive (%) 39.69 ± 12.50 38.76 ± 11.85 0.512 nonprogressive (%) 10.55 ± 4.26 10.73 ± 3.34 0.787 immotile (%) 50.02 ± 10.75 50.47 ± 11.59 0.746 morphology (%) 3.54 ± 1.86 3.50 ± 1.66 0.837 tunel (%) 24.56 ± 9.49 20.64 ± 10.28 0.013* cma3 (%) 48.75 ± 15.96 47.79 ± 20.78 0.769 table 1. effect of antioxidants on semen parameters, sperm dna integrity and chromatin compaction *p-value < 0.05 considered as significant short abstinence and dna integrity-vahidi et al. results a total of 64 male patients were evaluated with a mean age of 34.7 ± 4.66 yrs (range: 27–49 yrs). the data indicate that antioxidants have statistically significant effects on mean sperm concentration (untreated, 67.51 ± 44.40 million/ml, vs. treated, 56.09 ± 37.85 million/ml; p-value = 0.005) and the mean tunel score (untreated, 24.56% ± 9.49%, vs. treated, 20.64% ± 10.28%; p-value = 0.013). however, there was no significant relationship between antioxidant treatment and other semen parameters, including cma3 staining (table 1). the effects of short abstinence on semen parameters and sperm dna integrity are demonstrated in table 2. short abstinence had a statistically significant negative effect on semen volume (recommended abstinence, 3.62 ± 1.44 ml, vs. short abstinence, 2.92 ± 1.43 ml; p-value < 0.001) but positive (decreasing) effects on tunel score (recommended abstinence, 20.64% ± 10.28%, vs. short abstinence, 17.38% ± 8.59%; p-value =0.028) and cma3 score (recommended abstinence, 47.79% ± 20.78%, vs. short abstinence, 41.92% ± 18.49%; p-value = 0.019). its effect on other semen parameters was not statistically significant (p-value >0.05). antioxidant drugs may improve ( decreased tunel test) or may have no effect on dna integrity (tunel test remains constant or even increase ). therefore after three months of antioxidants medical therapy, the samples may have tunel score below (responder) or above (non-responder) normal cutoff ( 20%). in this step, we tried to assess the effect of short abstinence on sperm with normal tunel score (< 20%) and sperm with abnormal dfi( tunel score > 20%) for further robust evaluation of the effects of short abstinence on sperms with normal or increased sperm dna integrity, table 2 were re-analysed based on a tunel cutoff score of 20% as proposed by sharma and the colleagues.(10), and the results are presented in table 3. at the tunel cutoff score of 20%, 28 samples had low (tunel score < 20%) and 36 others had high (tunel score > 20%) sperm dfi. short abstinence had a negative (increasing) effect on samples with low sperm dfi (mean tunel score increased from 11.89% ± 3.21% to 15.17% ± 7.79%; p-value = 0.045) and a positive (decreasing) effect on samples with abnormal (high) sperm dfi (mean tunel score decreased from 27.85% ± 8.32% to 19.14% ± 8.90%; p-value < 0.001). discussion the present study showed that a short abstinence period could improve sperm dna integrity in patients with increased sperm dna damage. to the best of our knowledge, the present study is the first to show that short abstinence may have a paradoxical effect on sperm dfi as evidenced by baseline dna integrity status. in subjects found to have low dna damage using tunel test (tunel score < 20%), short abstinence not only failed to cause further improvement but also had certain deleterious effects. therefore, short abstinence is probably not applicable to all cases (as recommended elsewhere)(3) and should be reserved for selected infertile men with increased dfi. in a functioning spermatogenesis system, epididymis may act as a screening tool and may eliminate immature sperms due to its oxidative stress effects (induced by epididymis epithelial cells, leukocytes, immature sperms themselves, etc.). therefore, epididymal passage may lead to subsequent improved semen quality and seminal sperm dfi. in such systems, decreasing epididymal passage time may result in increased sperm dfi as explained in the current study (and in patients with normal sperm dfi). on the other hand, in a malfunctioning system ( e.g. due to incomplete protamination), epidiymal passage may lead to additional stress on the vulnerable sperms and therefore may induced sperm dna injury apart from oxidative stress. in such systems, short abstinence or testicular sperm extraction may have great benefit in preserving sperm dna intable 2. effect of short abstinence on semen parameters and sperm dna integrity and chromatin compaction after previous medical therapy in all the patients. variables treated group (n=64) mean ± sd short abstinence (n=64) mean ± sd p-value volume (ml) 3.62 ± 1.44 2.92 ± 1.43 < .001 count (mil/ml) 56.09 ± 37.85 54.02 ± 37.51 0.699 progressive (%) 38.76 ± 11.85 38.42 ± 11.32 0.887 nonprogressive (%) 10.73 ± 3.34 11.32 ± 4.10 0.245 immotile (%) 50.47 ± 11.59 50.08 ± 9.58 0.656 morphology (%) 3.50 ± 1.66 3.38 ± 1.43 0.729 tunel (%) 20.64 ± 10.28 17.38 ± 8.59 0.028* cma3 (%) 47.79 ± 20.78 41.92 ± 18.49 0.019* *p-value < 0.05 considered as significant. figure 1. tunel test, sperm with injured dna depicted as bright green. short abstinence and dna integrity-vahidi et al. andrology 684 vol 18 no 6 november-december 2021 685 tegrity. nevertheless, in the current study, short abstinence had statistically significant effects on semen volume. it also decreased sperm concentration, percentage of immotile and progressive sperms, sperms with normal morphology and the percentage of non-progressive motility, although with no statistical significance (p-value > 0.05). in the case of a longer abstinence period, three important events occur. sperms are stored in the epididymis (with presumable stress effects )(18) , the seminal level of reactive oxygen species (ros) may increase(8) and the antioxidant capacity of axillary sexual glands secretions (prostate and seminal vesicle) may decrease significantly(19). these changes may indicate better semen quality in an efficient spermatogenesis process (act as a screening tool) but may lead to increased sperm dna fragmentation and subsequent infertility in a non-efficient system which is pathologically vulnerable to environmental stressors (e.g. due to abnormal sperm chromatin compaction) or in the oxidative stress status (excessive production of ros or decreased levels of seminal antioxidants). multiple ejaculations with short abstinence periods may increase semen antioxidant capacity and decrease seminal ros, especially those originating from the epididymis(6). there are a few inconsistent reports regarding the effects of a short abstinence period on semen quality; the discrepancies may be due to differences in the number of recruited participants, fertility status and inclusion/ exclusion criteria. agrawal and his colleagues, in their study on seven healthy men with unproven fertility, showed that sperm dfi increased concomitantly with an increase in the abstinence period. they reported that mean sperm dfi increased from 9.9% in cases of short abstinence period (less than 2 days) to more than 17% in cases with long abstinence period (9–11 days). their conclusion should be cautiously interpreted as their cohort included only a small number of normospermic men(6). on the other hand, a study conducted by de jong and colleagues on 11 healthy volunteers and another study by mayorga-torres and colleagues on six healthy volunteers, using scsa techniques, found that a shorter abstinence period might not affect sperm dfi(9,20). furthermore, de jong et al. reported that a shorter abstinence period might negatively affect sperm chromatin compaction, making them susceptible to environmental stressors (not observed in the present study). this difference may be due to differences in sample size, type of sperm dfi test used, and fertility status of the recruited men. even if the small sample size in the above study is not considered, results obtained from healthy participants cannot be attributed to subfertile and infertile men. our findings are in agreement with those of pons and co-workers and sanchez and colleagues, who used the sperm chromatin dispersion test and reported positive effects of short abstinence on semen quality in 36 and 40 infertile men, respectively(21,22). the result of previously published studies (in pubmed) on the effect of a short abstinence period on sperm dfi are summaraized in table 4. table 3. effect of short abstinence on sperm dna integrity based on baseline low or high level of sperm function tests (tunel test). variables treated group (n=64) mean ± sd short abstinence mean ± sd p-value tunel < 20% (n = 28 samples) 11.89 ± 3.21 15.17 ± 7.79 0.045 tunel > 20% (n = 36 samples) 27.85 ± 8.32 19.14 ± 8.90 <.001 study number of abstinence dfi chromatin semen sperm progressive morphology participants time assessment compaction volume concentration motility assessment de jong et al. 2004(9) 11 24 hours scsa: scsa(hds): decreased decreased no change no change no change increased gosalvez et al, 2011 (29) 33 3 hours scd: not mentioned not not not mentioned not mentioned and decreased mentioned mentioned 24 hours pons et al. 2013 (21) 34 24 hours scd: not mentioned decreased decreased decreased not mentioned decreased sanchez martin et al. (22) 21 12 hours scd: not mentioned decreased no change no change not mentioned decreased mayorga torres et al.(2015)(20) 6 24 hours scsa: not mentioned decreased no change no change not mentioned no change mayorga torres et al.(2016)(8) 3 2 hours scsa: not mentioned decreased decreased decreased not mentioned decreased agrawal et al. 2016(6) 7 24 hours tunel: not mentioned decreased decreased no change no change decreased uppangala et al. 2016 (30) 16 24 hours scd: anilline blue: increased decreased decreased no change no change decreased comar et al, 2017(31) 2458 less than tunel: cma3:increased decreased decreased increased no change 2 days decreased shen et al., 2018(32) 167 1-3 hours scsa: scsa:increased decreased increased increased not mentioned decreased borges et al. 2019 (7) 818 4.15± 2.72 scd: not mentioned decreased decreased no change no change days decreased table 4. the results of the previous studies about the effects of short abstinence on sperm dna. short abstinence and dna integrity-vahidi et al. the present study also showed that antioxidants, despite showing statistically significant improvement in tunel tests, could not remarkably improve chromatin compaction. it may be due to the fact that ros, although are harmful in high amounts, considered as physiologic in small quantity, and are essential for sperm maturation (chromatin compaction)(23). antioxidant overuse, especially in cases with normal seminal ros levels, may eliminate such physiologic amount and may lead to decreased sperm maturation ( disturbed chromatin compaction). this is so-called reductive stress phenomenon(24,25). this may be the reason for decreased semen quality after antioxidants therapy in some patients. measurement of the ros level has not been performed in our center, possibly leading to antioxidant overprescription and related side effects. menezo and co-workers previously reported a similar finding. in their cohort of 54 patients using the scsa technique, they reported a significant decrease in sperm dfi (32.4% to 26.2%; p-value < 0.05) and increase in sperm decondensation rate (17.5% to 21.5%; p-value < 0.05) after antioxidant therapy(26). because increased sperm dfi may lead to a lower art outcome(27), methods that improve sperm dna integrity appear necessary. nonresponders to antioxidant therapy (those with disturbed sperm dna integrity) could be treated with a simple, cost-effective, noninvasive approach (short abstinence) instead of invasive/expensive alternatives (such as testicular sperm extraction, magnetic activated cell sorting and physiologic intracytoplasmic sperm injection). there are some limitations in the current study. first, the present study showed that short abstinence might improve both sperm dfi and chromatin compaction status, but its probable positive effect on art outcome remains to be elucidated. second, in the current study, the sperm dna integrity was assessed by tunel test and cma3 staining, using a fluorescence microscope. since this method may be operator dependent, our results need to be further assessed with flow cytometric techniques, in future studies. third, it has been reported that testicular sperms have a higher rate of chromosomal aneuploidy in comparison with that in ejaculated samples(28); the question of whether this is true in cases of short abstinence will be addressed in future studies. finally, the present study mainly included men with subfertility (increased dfi with approximately normal semen analysis) and having no control group. future studies are anticipated assessing the effects of short abstinence on males with abnormal semen parameters and sperm dna integrity. conclusions the present study showed that short abstinence ( abstinence time less than 24 hours) would improve sperm dna integrity in patients with high sperm dfi and previous attempts of failed medical therapy. however, because the effects of such a strategy on art outcome and chromosomal aneuploidy are 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the effect of sperm dna damage on in vitro fertilization and intracytoplasmic sperm injection outcome. asian j androl. 2017;19:80-90. 28. moskovtsev si, alladin n, lo kc, jarvi k, mullen jb, librach cl. a comparison of ejaculated and testicular spermatozoa aneuploidy rates in patients with high sperm dna damage. syst biol reprod med. 2012;58:142-8. 29. gosalvez j, gonzalez-martinez m, lopezfernandez c, fernandez jl, sanchez-martin p. shorter abstinence decreases sperm deoxyribonucleic acid fragmentation in ejaculate. fertil steril. 2011;96:1083-6. 30. uppangala s, mathai se, salian sr, et al. sperm chromatin immaturity observed in short abstinence ejaculates affects dna integrity and longevity in vitro. plos one. 2016;11:e0152942. 31. comar va, petersen cg, mauri al, et al. influence of the abstinence period on human sperm quality: analysis of 2,458 semen samples. jbra assist reprod. 2017;21:30612. 32. shen zq, shi b, wang tr, et al. characterization of the sperm proteome and reproductive outcomes with in vitro fertilization after a reduction in male ejaculatory abstinence period. mol cell proteomics. 2018. short abstinence and dna integrity-vahidi et al. miscellaneous clinical and bacterial risk factors for development of post-prostate biopsy infections amir hasanzadeh1,2, peter black3, mohammad reza pourmand*2, gholamreza pourmand4 purpose: to research on clinical and bacterial risk factors and their relationship with post-prostate biopsy infection (pbi). materials and methods: in this prospective cohort study, rectal swabs were collected from 158 men prior to prostate biopsy and cultured selectively for identify ciprofloxacin-resistant (fq-r) gram-negative bacteria. the patient characteristics, phylogenetic background, sequence typing and pulsed field gel electrophoresis (pfge) pattern were compared in two groups of fq-r escherichia coli rectal and clinical isolates. results: in total, pbi was observed in 20 (12.5%) cases; the most of these subjects were fq-r-colonized. (17/73 [24%] vs 3/85 [3.5%]; p < 0.001). fq-r colonization, diabetes, hospitalization and uti were independent risk factors (95% ci: 1.1-20.1, or = 4.73; 95% ci: 1.7-25.3, or = 6.57; 95% ci: 1.9-27.5, or = 7.22; and 95% ci: 1.2-14.3, or = 4.05; respectively), that increased the rate of pbi (all p < 0.05). despite the increase in infections among patients colonized with strains of e. coli st131, its prevalence was near significance between colonized and infected groups (p = 0.07). the pfge patterns and antimicrobial susceptibility profiles of rectal and clinical isolates in 13 patients were similar which is remarkably important and informative. conclusion: the most pbis originate from fq-r e. coli rectal colonization. rectal culture screening and assessment of clinical risk factors can predict the incidence of pbi in patients. keywords: biopsy; drug resistance; iinfection; prostate introduction transrectal ultrasound-guided prostate biopsy (trus-bx) is considered a standard method to diagnose prostate cancer. therefore, millions of people around the world are evaluated by this approach. post-prostate biopsy infection (pbi) is an important adverse event that is potentially life threatening for patients(1). hence, the american urological association and the european association of urology (eau) recommend the preoperative use of fluoroquinolone (fq) antibiotics before prostate biopsy to prevent infections(2,3). the most prevalent bacterium responsible for pbi is eschericia coli that most likely originates from the rectum of patients during biopsy(4,5). in recent years, there have been concerns regarding the expansion of a pandemic clonal group known as e. coli sequence type 131 (st131); most members of this group are resistant to fq and some of them express the extended-spectrum （-lactamases(6). e. coli st131 belongs to phylogenetic group b2, which is associated with greater virulence than other phylogenetic groups and can be colonized in the intestine with high density(7,8). e. coli st131 is an important cause of extraintestinal infections such as sepsis, meningitis and urinary tract infections that are commonly multidrug resistant (mdr)(9). recent studies have shown that e. 1department of microbiology, maragheh university of medical sciences, maragheh, iran. 2department of pathobiology, school of public health, tehran university of medical sciences, tehran, iran. 3 vancouver prostate centre, university of british columbia, vancouver, b.c., canada. 4urology research center, tehran university of medical sciences, tehran, iran. *correspondence: department of pathobiology, school of public health and biotechnology research center, tehran university of medical sciences, tehran, iran. tel: +98 21 88954910, fax: +98 21 66472267, e-mail address: mpourmand@tums.ac.ir. received may 2018 & accepted february 2019 coli st131 is responsible for more than 40% of bloodstream infections after prostate biopsy, indicating the importance of this type of e. coli in rectal colonization (6,7,10,11). to our knowledge, there are no reports indicating the prevalence of e. coli st131 in patients undergoing prostate biopsy in iran. in this study, therefore, we have investigated the following: (i) comparison of characteristics in one uninfected and one infected group of patients after prostate biopsy, (ii) determination of the phylogenetic background and the prevalence of st131 among fq-r e. coli isolates, (iii) co-resistance profile, and, finally, (iv) molecular epidemiology and comparison of pfge pattern of the fq-r e. coli rectal colonization versus clinical isolates take at the time of pbi. patients and methods study population and study design in total, 185 patients referred to the urology research center, sina hospital, iran, between march 2015 and february 2016, for the purpose of evaluation for prostate cancer using trus-bx. study design, inclusion and exclusion criteria, method for the isolation of fluoroquinolone resistant bacteria and the antibiotic susceptibility test is clearly explained in our previous work (12). urology journal/vol 16 no. 6/ november-december2019/ pp. 603-608. [doi: 10.22037/uj.v0i0.4603] molecular typing in continuation of the previous study, the fq-r e. coli from rectal and clinical isolates was categorized into seven phylogenetic groups using a quadruplex polymerase chain reaction (pcr)-based method (new clermont method) (13). for isolates belonging to group b2, the st131 status was determined by pcr-based detection of snps (single-nucleotide polymorphisms) associated with st131 in mdh and gyrb housekeeping genes. twenty seven randomly selected putative st131 isolates underwent confirmatory 7-locus multilocus sequence typing (mlst) based on partial sequences for pura, fumc, mdh, icd, gyrb, reca, and adk (http://mlst. ucc.ie/mlst/dbs/e. coli ); all isolates were confirmed as st131. the pcr-based detection was applied to identify h30 and h30-rx st131 subclones(14,15). pulsed-field gel electrophoresis analysis the genetic relationship of the fq-r e. coli in rectal and clinical isolates was assessed by xbai pulsed field gel electrophoresis (pfge) analysis according to a standard protocol(16). the bionumerics software (applied maths, v7.6 saint-matins-latem, belgium) was employed to gel analysis. the cluster analysis was performed using dice similarity value ≥ 94% with a band position tolerance 1% based on the unweighted pair group method with bionumerics to classify profiles into distinct pulsetypes(16). the study was designed and performed according to the helsinki declaration and was approved by the ethics committee of the tehran university of medical sciences (28848-27-01-94). informed consent was obtained from all individual participants included in the study. statistical methods we conducted multiple comparisons to meet the objectives of this study. the normally distributed variables were compared between the infected and non-infected groups using the student t test. the mann-whitney u test was also used as non-parametric analogous, when appropriate. moreover, the categorical variables were compared between aforementioned groups through using the chi-squared test; and fisher exact test was also applied when the data sparsity was expected. to predict post-prostate biopsy infection, the univariable analyses were initially conducted and those variables with p-value < 0.1 were imported into the multivariable model. finally, it can be said that the strength of associations between predictors of interest and outcome studied were reported as odds ratio (or) with 95% confidence interval (ci). the ibm spss statistics 21.0 software was used for data analysis. risk factors for development of pbi hasanzadeh et al. table 1. clinical characteristics including potential independent risk factors for development of infection after prostate biopsy clinical characteristics no infection (n = 138) infection (n = 20) p value age, y, mean ± sd 64.2 ± .7 65.6 ± 2 .113* body mass index, kg/m2, mean ± sd 25.7 ± 13.3 26.2 ±11.8 .249** psa,ng/ml,mean ± sd 16.1 ± 18 23.1 ± 34.7 .158** prostate volume, mm3, mean±sd 46.5 ± 16 52.9 ± 26.8 .357* hospitalization in past 1 year (%) 15 (10.9) 9 (45) < .001† presence of a catheter (%) 17 (12.3) 4 (20) .310† prostatitis in past 4 months (%) 20 (14.5) 10 (50) < .001† uti in past 4 months (%) 32 (23.2) 14 (70) < .001† previous biopsy (%) 21 (15.2) 5 (25) .21† hypertension (%) 33 (23.9) 8 (40) .125† diabetes (%) 19 (13.8) 11 (55) < .001† pre-biopsy enema (%) 45 (32.6) 6 (30) .800† smoking (%) 22 (15.9) 6 (30) .128† fluoroquinolone-resistant colonization (%) 56 (40.6) 17 (85) < .001† abbreviations: psa, prostate specific antigen; sd, standard deviation. *continuous variables: t test. **continuous variables: mann-whitney. †categorical variables: pearson chi-square. figure 1. xbaipulsed-field gel electrophoresis (pfge) profiles of 71 fluoroquinolone-resistant escherichia coli rectal isolates in patients undergoing transrectal ultrasound prostate biopsy.data columns, from left to right, show strain number, e. coli phylogenetic group, st131 status, occurence of infection after prostate biopsy and ciprofloxacin mic by etest. dashes demonstrate negative results. miscellaneous 604 vol 16 no 06 november-december2019 605 results risk factor for pbi almost all the patients had been infected with fq-r bacteria. despite the fact, a patient was coinfected with 2 fq-r and fq-sensitive e. coli isolates. fq-r e. coli grew in the rectal culture of all but 3 patients with pbi. the rate of pbi was 24% [17/73] in patients with a positive rectal culture versus 3.5% [3/85] in those with a negative rectal culture (p < 0.001). table 1 shows the relationship between potentially independent risk factors and pbi levels according to the univariable analysis. the most important risk factors associated with an increased pbi included (i) history of hospitalization in the last 1 year (p < 0.001), (ii) prostatitis and uti during the last 4 months (p < 0.001), (iii) diabetes (p < 0.001) and fq-r colonization (p < 0.001). on multivariable analysis using logistic regression (table 2), fq-r colonization, and history of hospitalization, utis and diabetes remained statistically significant (all p<0.05). determination of phylogenetic groups, st131 status and st131 subclones we indicates the compared molecularly the 16 available fq-r clinical e. coli isolates from men who did develop pbi with the 53 available fq-r rectal e. coli isolates from men who did not develop pbi. table 3 distribution of phylogenetic groups of fq-r e. coli stratified by presence in rectal culture or in culture taken at the time of pbi (“clinical”). the phylogenetic group b2 was the most dominant phylogroup among rectal and clinical isolates (36/54 [67%] vs. 13/16 [81.2%], respectively (p = 0.47). the st131 status was determined in all isolates belonging to group b2 (42/49 [85.7%] ). despite the increase in infections among patients colonized with strains of e. coli st131, its prevalence was near significance between colonized and infected groups (29/42 [53.7] vs. 13/16 [81.3]: p = 0.07). generally, all e. coli st131 strains belonged to the h30 st131 subclone, and no difference was found in the prevalence of the h30-rx st131 subclone between rectal and clinical isolates (4/29 [14%] vs. 4/13 [31%]; respectively; p = 0.24). genomic relationships of 74 fq-r gram-negative rectal isolates, 71 (96%) e. coli isolates (out of 70 patients) were selected to perform pfge. pfge analysis showed that these rectal isolates were genomically diverse. the 42 e. coli st131 strains clustered separately relative to the nonst131 strains. nonst131 strains demonstrated greater genomic heterogeneity than the st131strains (figure 1). of 70 patients with rectal fq-r e. coli isolates, pbi was diagnosed in 16 (24%), and 13 (81%) of these cases showed an e. coli st131 isolate. among the remaining 54 patients, 29 (54%) cases had st131 isolates. of 17 patients with diagnosed infections, 13 cases had both clinical and rectal isolates available for genomic comparison. the pfge pattern between rectal and clinical isolates was indistinguishable in all cases. however, three cases with expanded infection had two different clinical strains. thus, two patients were infected with two fq-r e. coli strains, with both strains of the first patients (patient a, strains 8 and 11, figure 2) and one of the strains of the second patient matched with the rectal isolates (patient h, strain 6, figure 2). one patient was infected with both an fq-r and fq-sensitive strain of e. coli, but only the fq-r isolate matched the rectal strain (patient m, strain 17; figure 2). discussion table 2. multivariate logistic regression analysis of independent risk factors for infection after prostate biopsy risk factors adjusted odds ratio 95% ci p value diabetes 6.57 1.7-25.3 .006 hospitalization in past 1 year 7.22 1.9-27.46 .004 prostatitis in past 4 months 1.51 .52-4.4 .448 uti in past 4 months 4.05 1.214.3 .029 fluoroquinolone-resistant colonizationa 4.73 1.1-20.1 .035 abbreviation: ci, confidence interval. variables with p < 0.1 in the univariable analysis were used in the multivariable model. a indicated by a positive prebiopsy rectal culture. 70 fq-r e. coli isolates, no. (%) phylogenetic group or sequence type pretrus-bx rectal isolates with not develop pbi (n=54) post-tpb infection (clinical isolate) (n=16) p* a 6 (11.1) 1 (6.2) < 0.001 b1 2 (3.7) 0 < 0.001 b2 36 (66.6) 13 (81.3) 0.473 e 5 (9.2) 0 < 0.001 f 1 (1.9) 0 < 0.001 c 1 (1.9) 2 (12.5) < 0.001 d 3 (5.5) 0 < 0.001 st131 29 (53.7) 13 (81.3) .07 abbreviation: trus-bx, transrectal ultrasound-guided prostate biopsy; st131, sequence type 131; ci, confidence interval. * the p values were calculated using mcnemar test. table 3. phylogenetic distribution of fq-r escherichia coli isolates risk factors for development of pbi hasanzadeh et al. miscellaneous 606 in this study, based on the recommendations of the american urological association, a fluoroquinolone was used for antibiotic prophylaxis before trus-bx (2). pre-trus-bx rectal cultures in ciprofloxacin-enriched selective media revealed fq-r gram negative bacteria in 46.2% of patients, which is higher than the 10%-36% prevalence reported in developed countries(4,17,18), but similar to one report from east asia(21). it is possible that asian ethnicity and patterns of antibiotic use in developing countries could influence rectal colonization with fq-r organisms(12). the risk of pbi in iranian patients appeared to be increased by a similar proportion compared to the risk described in developed countries. most previous studies from developed countries have reported the rate of infectious complications after trus-bx to be between 1% and 5% in patients using fq prophylaxis, although one study reported a rate as high as 10% (20,21). the pbi rate in our study was 12.5%, implying a high rate of infection, but this is not surprising in light of the high rate of rectal colonization with fq-r bacteria. of course differences in the definitions of pbi and the methods by which pbi were captured can affect the rates of pbi. consistent with the rates of colonization with fq-r bacteria and of pbi, we found that the value of the presence of fq-r bacteria in rectal culture as a risk factor for subsequent pbi was similar in our population (odds ratio = 4.7) compared to prior reports in developed countries(22). as expected, fq-r e. coli was by far the most frequent isolate from the rectum and also the most frequent cause of pbi in our study, with 44.3% of patients carrying this bacterium in their rectum. we were able to confirm by pfge patterns in rectal and clinical isolates that the fq-r e. coli causing the pbi likely originated from the rectum. prostate biopsy needles can play a role in the transmission of resistant isolates (especially fq-r e. coli) from rectal to bloodstream, urine and prostate. hence, screening rectal culture seems to be a major step forward in identifying bacteria and their properties, as in our study, rectal culture screening succeed to identify rectal carriage in all men who developed post biopsy infection with fq-r e. coli. most information on the prevalence and distribution of pathogenic strains of e.coli is derived from developed countries(6). e. coli st131 is one of the newly emerging pathogens and the majority of its members are fqr and mdr(6). we have therefore studied the distribution of phylogenetic groups as well as the prevalence of st131, h30 and h30-rx subclones in rectal and infected isolates in iran for the first time. in the present study, prevalence e. coli st131 was near significance between colonized and infected groups (53% vs. 81%, p = .07). due to its high prevalence and widespread resistance to several antibiotics in the colonized and infected isolates, measures need to be taken to reduce the risk of infection from fq-r e. coli st131. at stated before, the screening rectal culture and antibiogram results obtained before trus-bx may be useful in determining an appropriate antibiotic prophylaxis. the identification of rectal bacteria that can cause pbi is a necessity, but is not sufficient. most patients with pathogenic fq-r e. coli will still not develop a pbi because pbi results from a balance between multiple host and pathogen factors (22,23). according to the above, we have therefore also considered patient characteristics as risk factors for pbi. in the study of liss et al., it was observed that the history of hospitalization in last year and colonization with fluoroquinolone-resistant bacteria are two important and independent factors for increasing infections after prostate biopsy. in numerous other studies, going to international travel and the history of using antibiotics and admission before prostate biopsy were introduced as independent risk factors for increasing pbi. interestingly, in other studies, diabetes and chronic obstructive pulmonary disease as an independent risk factor were introduced. however, according to our findings, diabetes, recent hospitalization and prior uti were independent risk factors for developing pbi, in addition to fq-r colonization on rectal culture. some of these are potentially modifiable factors (e.g. more stringent blood glucose management or delay of pnbx after uti) and this knowledge can be used to reduce the risk of pbi. limitations of this study include the relatively small sample size, and it will be necessary to perform a larger study in our country. strengths of this study include (i) use of selective media that works better in isolating the rectal fq-r organisms(17) while also saving laboratory costs and time; and, (ii) careful patient follow-up after prostate biopsy. conclusions the most of post-prostate biopsy infections occur in patients colonized with fq-r bacteria who have used fluoroquinolone alone as antibiotic prophylaxis. fq-r e. coli, particularly the st131 group, is the most important pathogen in the context of rectal colonization and pbis. therefore, it is necessary to understand better this clonal group. an increase in the fq-r rectal carriage is associated with elevated post biopsy infection, which rectal culture screening and assessment of clinical risk figure 2. comparison of xbai pulsed-field gel electrophoresis (pfge) patterns of paired fluoroquinolone-resistant escherichia coli from rectal and clinical isolates from 13 patients with post– prostate biopsy infection (pbi). despite two distinct urine isolates explained in the text, clonal similarity for 13 patients with rectal and clinical isolates suggested that most pbis originate from rectal colonization of fq-r e. coli. risk factors for development of pbi hasanzadeh et al. vol 16 no 06 november-december2019 607 factors can predict the incidence of pbi in patients. acknowledgement the authors would like to thank the urology research center of sina hospital for their cooperation and the technicians of the department of laboratory medicine for their technical contributions. this research was supported by tehran university of medical sciences, tehran, iran (grant number: 28848). conflict on interest the authors report no conflict on interest references 1. wagenlehner fm, van oostrum 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multidrug-resistant escherichia coli. clin infect dis. 2013;57:26774. 6. rogers ba, sidjabat he, paterson dl. escherichia coli o25b-st131: a pandemic, multiresistant, community-associated strain. j antimicrob chemother. 2011;66:1-14. 7. johnson jr, johnston b, clabots c, kuskowski ma, castanheira m. escherichia coli sequence type st131 as the major cause of serious multidrug-resistant e. coli infections in the united states. clin infect dis. 2010;51:28694. 8. williamson da, freeman jt, porter s, et al. clinical and molecular correlates of virulence in escherichia coli causing bloodstream infection following transrectal ultrasoundguided (trus) prostate biopsy. j antimicrob chemother. 2013;68:2898-906. 9. dehghani b, mottamedifar m, khoshkharamroodmajani h, hassanzadeh a, zomorrodian k, rahimi a. sds-page analysis of the outer membrane proteins of uropathogenic escherichia coli isolated from patients in different wards of nemazee hospital, shiraz, iran. iran j med sci. 2016;41:399-405. 10. assimacopoulos a, johnston b, clabots c, johnson jr. post-prostate biopsy infection with escherichia coli st131 leading to epididymo-orchitis and meningitis caused by gram-negative bacilli. j clin microbiol. 2012;50:4157-9. 11. williamson da, roberts sa, paterson dl, et al. escherichia coli bloodstream infection after transrectal ultrasound–guided prostate biopsy: implications of fluoroquinolone-resistant sequence type 131 as a major causative pathogen. clin infect dis. 2012;54:1406-12. 12. hasanzadeh a, pourmand mr, alizadeh a, pourmand g. prevalence and significance of fluoroquinolone-resistant bacteria carriage in patients undergoing transrectal ultrasound prostate biopsy. urol j. 2017;14:3085-90. 13. clermont o, christenson jk, denamur e, gordon dm. the clermont escherichia coli phylo‐typing method revisited: improvement of specificity and detection of new phylo‐ groups. environ microbiol rep. 2013;5:5865. 14. banerjee r, robicsek a, kuskowski ma, et al. molecular epidemiology of escherichia coli sequence type 131 and its h30 and h30rx subclones among extended-spectrum（-lactamase-positive and-negative e. coli clinical isolates from the chicago region, 2007 to 2010. antimicrob agents chemother. 2013;57:6385-8. 15. colpan a, johnston b, porter s, et al. escherichia coli sequence type 131 (st131) subclone h30 as an emergent multidrugresistant pathogen among us veterans. clin infect dis. 2013;57:1256-65. 16. johnson jr, porter sb, zhanel g, kuskowski ma, denamur e. virulence of escherichia coli clinical isolates in a murine sepsis model in relation to sequence type st131 status, fluoroquinolone resistance, and virulence genotype. infect immun. 2012;80:1554-62. 17. liss ma, chang a, santos r, et al. prevalence and significance of fluoroquinolone resistant escherichia coli in patients undergoing transrectal ultrasound guided prostate needle biopsy. j urol. 2011;185:1283-8. 18. steensels d, slabbaert k, de wever l, vermeersch p, van poppel h, verhaegen j. fluoroquinolone‐resistant e. coli in intestinal flora of patients undergoing transrectal ultrasound‐guided prostate biopsy—should we reassess our practices for antibiotic prophylaxis? clin microbiol infect. 2012;18:575-81. 19. tsu jh-l, ma w-k, chan wk-w, et al. prevalence and predictive factors of harboring fluoroquinolone-resistant and extended-spectrum β-lactamase–producing risk factors for development of pbi hasanzadeh et al. miscellaneous 608 rectal flora in hong kong chinese men undergoing transrectal ultrasound-guided prostate biopsy. urology. 2015;85:15-22. 20. minamida s, satoh t, tabata k, et al. prevalence of fluoroquinolone-resistant escherichia coli before and incidence of acute bacterial prostatitis after prostate biopsy. urology. 2011;78:1235-9. 21. mosharafa aa, torky mh, el said wm, meshref a. rising incidence of acute prostatitis following prostate biopsy: fluoroquinolone resistance and exposure is a significant risk factor. urology. 2011;78:511-4. 22. liss ma, johnson jr, porter sb, et al. clinical and microbiological determinants of infection after transrectal prostate biopsy. clin infect dis. 2015;60:979-87. 23. lindert ka, kabalin jn, terris mk. bacteremia and bacteriuria after transrectal ultrasound guided prostate biopsy. j urol. 2000;164:76-80. risk factors for development of pbi hasanzadeh et al. transplantation of spermatogonial stem cells suspension into rete testis of azoospermia mouse model arefeh jafarian1, niknam lakpour2, mohammad reza sadeghi3, sheida salehkhou2, mohammad mehdi akhondi2* purpose: the loss of spermatogonia following chemo-or radiotherapy leading to temporary or permanent infertility of the patient is a well known and unwanted side effect of many oncological therapies. materials and methods: in this study, germ cells were isolated from 4 days old mouse testis cells. busulfan treatment was used to the eliminate proliferating cells in the testis of recipient mice. the donor cells suspended in dmem, were introduced into the rete testis of recipient mice via microinjection method. to distinguish the progeny of the transplanted donor stem cells from endogenous germ cells, brdu-labeled cells were used. in addition, real time pcr was performed to determine expression levels of ngn3 and lin28 (spermatogonia stem cells markers) before and after transplantation. western blot analysis was further performed to detect an increase in ngn3 expression after transplantation. results: transplantations of stem cells into rete testis of the recipients was done. our results clearly showed a significant increase in spermatozoa number in epididymal luman spermatogonial stem cells (sscs) did not show alkaline phosphatase activities while ngn3 and lin28 were clearly expressed. ngn3 and lin28 expression were reduced after busulfan treatment compared to untreatmented mice. however, the expression of ngn3 and lin28 increased after transplantation . brdu-labeled testis cells were successfully transplanted into rete testis of recipient mice. these cells remained in rete testis of all recipient mice up to two months after transplantation. conclusion: the present study clearly confirme that a regeneration after cytotoxic treatment was based on morphological criteria. we demonstrated the increase in stem cell numbers during regeneration and after transplantation.. transplantation of spermatogonial stem cells suspension by the injection of cells via the rete testis of recipient azoospermia model considerably enhances the efficiency of this procedure. keywords: rete testis; spermatogonial stem cells; transplantation. introduction germ cell transplantation technique has tremen-dous applications in a wide range of species. it was used to study spermatogonial stem cells (sscs) biology, production of valuable transgenic animals and restore fertility in different animal species. although recent progress in spermatogonial stem cell transplantation has been shown to restore fertility in sterile animals(1). some major problems are associated with stem cells enrichment, freezing methods and transplantation. to date, differentiation of sscs into mature spermatozoa has not been demonstrated in vitro culture systems, and new strategies in germ cell transplantation has not been successful to produce enough mature sperm(2). it has been reported in previous studies,sscs culture before transplantation into recipient testes could increase the number of mature sperm production. sscs transplantation is a promising strategy to preserve sterility, especially in pre pubertal boys treated with anti-cancer therapy(3). isolating and cryo freezing of sscs in a boy with cancer is an important theoretical way to restore reproductive potential. this strategy, has been successful in animal models systems, however, it has not yet been applied in humans yet(4).spermatogenesis is a complex biological process that takes place in seminiferous tubules where diploid spermatogonial divided by mitosis, meiosis and spermiogenesis process to produce mature sperm. the period required for spermatogenesis is different between various species. it takes approximately 74 days in human, 52 days in rat and 35 days in mice(5). the process of spermatogenesis is divided into three different phases: spermatocytogenesis, meiosis and spermiogenesis. during the spermatocytogenesis, type a spermatogonia are divided mitotically to produce type b spermatogonia that rest on the basement membrane. in meiosic phase the primary spermatocytes undergo first meiotic division and become secondary spermatocytes and then the spermatid cells produced by second meiotic division. during spermiogenesis, the spherical and haploid spermatids develop into final product, spermatozoa. spermatozoa are released into the lumen of the seminiferous tubule and carried toward the epididymis to achieving motility and become 1immunology, asthma and allergy research institute (iaari) , tehran university of medical sciences, tehran, iran. 2reproductive biotechnology research center, avicenna research institute, acecr, tehran, iran. 3monoclonal antibody research center, avicenna research institute, acecr, tehran, iran. *correspondence: reproductive biotechnology research center, avicenna research institute, acecr, p.o. box: 196151177, tehran, iran. tel.: +98 21 22432020. fax: +98 21 22432021. e-mail: akhondi@avicenna.ac.ir. received november 2016 & accepted july 2017 sexual dysfunction and andrology sexual dysfunction and andrology 40 capable of fertilization. a relationship between sertoli cells in somniferous epithelium has an important role in regulation of sscs self renewal and spermatogonia optimal number(6). growth factors produced by the sertoli cells have regulatory roles in induction or inhibition of self renewal and differentiation of germ cells(7,8). one of the important advantages of germ cell transplantation is diagnosis of colons that is created from a single cell(9). the most important cells that affected in radiation or chemotherapy are undifferentiated population of spermatogonia with mitotic activity. recent studies have revealed that lin28 and neurog3 are expressed by undifferentiated stem cells and progenitor spermatogonia, including asingle, apaired, and aaligned 4–16(10,11). lin28 expression is associated with pluripotency and is not expressed in adult mouse testis(12). ngn3 is a class b bhlh transcription factor that have main function in the early steps of spermatogenesis(10). therefore, lin28 and ngn3 could have ideal factors for transplantation assessment.transplantation of male germ line stem cells opens another exciting strategy for fertility preservation(13). potential clinical applications of germ cell transplantation includes restoration of fertility in patients who undergo sterilizing treatments for malignancy or genetic defects in testicular somatic cells(14). efficient germ cells transplantation is dependent on the number of sscs number, cell survival and hormonal regulation(15). spermatogonial cell transplantation is an efficient technique that can help to study of sscs multiplication and renewal leading to to restoration of spermatogenesis(16). in a previous study, we reportsuccessful transplantation of neonatal mouse donor testis cells into recipient seminiferous tubules(17). while, in the present study, we used rete testis transplantation to increase the efficiency of sscs transplantation. therefore, the aim of this study is to evaluate the effect of rete testis transplantation on postnatal testicular germ cell proliferation following stem cell transplantation. materials and methods cell isolation and culture c57bl/6 mice were purchased from the pasteur institute (tehran, iran) and were kept in conditions consistent with requirements of the local commission for ethical matters of animal experimentation. testis were isolated from neonatal mice (2 to 4 days old afterdecapsulation under a dissection microscope, cells were suspended in dmem minimum containing; 0.5 mg/ml collagenase/dispase, 0.5 mg/ml trypsin and 0.05 mg/ml dnase supplemented with 14 mm nahco 3 (sigma), non-essential amino acids, 100 iu/ml penicillin, 100 μg/ml streptomycin and 40 μg/ml gentamycin (all from figure 2. alkaline phosphatase reactivity a. the colony did not show alkaline phosphatase reactivity. control groups including b. blood neutrophils cells; c. mouse intestine was alkaline phosphatase positive and d. negative control. magnification: × 20. figure 1. spermatogonial stem cell culture and labeling a: a) sscs proliferation, b) scs colonization b: sscs were positive with monoclonal anti-brdu antibody in culture media. a) single sscs b) negative control c) colony of sscs. magnification: ×20 sscs transplantation in azoospermic mice-jafarian et al. vol 15 no 01 january-february 2017 41 invitrogen, carlsbad, calif, usa). they were incubated for 45 min at 37 °c with shaking and gentle pipetting. then the supernatant containing the leydig cells was removed and the cells were incubated in dmem medium containing collagenase (1.5 mg/ml), hyaluronidase (1.5 mg/ml), trypsin (0.5 mg/ml), and dnase (1 μg/ml) for 20-30 min at 37°c and 5% co2. subsequently, the cells were cultured at 32 °c in 5% co 2 at a concentration of 10×106 cells/dish. after trypsin digestion the cells washed and seeded onto new dishes with dmem medium for transplantation into recipient testes. total cell number and viability were determined before transplantation(18). the schematic flowchart of methods is shown in figure 1. alkaline phosphatase (ap) activity after 3 days cultured cells were fixed in 4% paraformaldehyde at room temperature for 1 min and washed twice with pbs then stained with alkaline phosphatase substrate solution (sigma) for 30 min at 37°c. then ap-activity was detected colorimetrically by visual analysis of the stained cells red bright color indicating expression of alkaline phosphatase against a yellow background. tissue cryosections was used as a positive control(19). figure 4. testis histology and the regeneration of spermatogenesis after busulfan injection busulfan is a chemotherapeutic agent that induced azoospermia, testicular atrophy and depletion in spermatogenic cells a) wildtype c57bl/6 mouse testis (control), b) busulfan treated testis at a dose of 30 mg/ kg 35 days after injection, c) busulfan-treated testis at a dose of 30 mg/ kg 70 days after injection d) busulfantreated testis at a dose of 30 mg/ kg 100 days after injection, e) capsular thickness in normal testis, f) capsular thickness in azoospermia mouse testis. the results showed that testis capsular thickness was increased after busulfan treatment, g) changes in testis size after injection of busulfan. busulfan decreased the testis size and depleted spermatogenesis. a) normal testis, b) neonatal mouse testis, c) busulfan treated mouse testis magnification: × 20 figure 5. brdu staining following spermatogonial stem cell transplantation (a) spermatogonial stem cell detection in transplanted testis cryosection staining. (b) negative control of brdu staining in testis tissue. magnification: × 40 figure 3. : immunostaining of cytokeratin and ngn3 a) a) cytokeratin was detected in the neonatal sertoli cells b) negative control. b) b) ngn3 immunoreactivity was positive for the sscs. magnification: × 20 b) ngn3 immunoreactivity was positive for the sscs. a) sscs with hrp conjugated anti mouse igg as secondary antibody, b) sscs with fitc conjugated anti mouse igg as secondary antibody, c) colony of sscs, d) negative control. magnification: × 20 sscs transplantation in azoospermic mice-jafarian et al. sexual dysfunction and andrology 42 immunohistochemical localization of cytokeratin sertoli cells were studied using an antibody to cytokeratin-18 (ck-18). isolated cells were centrifuged at 30 × g for 5 min in a cytospincentrifuge (shandon, cheshire, uk) and fixed in 4% paraformaldehyde (pfa) in pbs (ph 7.4) for 20 minutes. then the cells washed 3 times with pbs containing 0.5 % triton x100 and 10% rabbit serum. unspecific site was blocked with 10% sheep serum in pbs for 30 min at room temperature. subsequently, the cells were incubated at 37 °c for 1 hr with 1:100 dilution of mouse primary monoclonal anticytokeratin pan (boeringer-mannheim, germany) antibody. the cells were washed and incubated with fitc-coupled (1:50) anti mouse igg as secondary antibody (sigma) for 45 min.. the slides were visualized under a fluorescence microscope (nikon.us). all experiments were repeated at least two times(20). immunocytochemical staining of ngn3 the cells were fixed in 4% paraformaldehyde (pfa) in pbs (ph 7.4) for 20 minutes and washed 3 times with pbs containing 0.5 % triton x100 and 10% rabbit serum. unspecific site was blocked with 10% sheep serum in pbs for 30 min at room temperature. subsequently, the cells were incubated at 37 °c for 1 hr with 1:100 dilution of mouse primary anti ngn3 monoclonal antibody (santa cruz biotechnology, santa cruz, ca, usa). then the cells were washed in pbs and incubated with 1:50 dilution of horse radish peroxidase (hrp) conjugated anti mouse igg as a secondary antibody (sigma) for 45 min. after washing with tbs/ bsa the color was developed by the addition of 3, 3’-diaminobenzidine (dab; sigma) for 8-10 min and, the slides were assessed with an optical microscope(20). incorporation of 5-bromo-2 deoxyuridine (brdu) in spermatogonial stem cells to trace the transplanted cells, the cells were incorporated with 5-bromo-2´-deoxyuridine (brdu, sigma) before transplantation. after reaching approximatly 70% confluency, brdu incorporation was performed by adding 0.1 mm brdu to the culture medium for 24 hr. then, the brdu incorporated cells were centrifuged at 500g for 4 min. after fixation in ice-cold acetone, the cells were washed in pbs containing 1% bsa, 0.05% tween 20, and 0.1% sodium azide. dna denaturation was done by 2n hcl for 30 minutes at 37 °c. monoclonal anti brdu antibody (sigma1:500) was added to figure 6. qrt-pcr analysis of ngn3 and lin28 in azoospermia mouse sscs a) the ngn3 was exclusively expressed in testis cells of adult mouse, 3-6 days old mice testis but decreased busulfan treated mouse testis after transplantation its expression increased. p value < 0.05 b) lin28 expression decreased in adult busulfan treated mouse testis. results revealed that lin28 expression increased after transplantation. . p value < 0.05 figure 7. serum level of testosterone and germ cells numbers two months after transplantation a) testosterone level and b) number of haploid cells percent were shown to have an increase in transplanted mice in compared to the control group (p < 0.0005) sscs transplantation in azoospermic mice-jafarian et al. vol 15 no 01 january-february 2017 43 sexual dysfunction and andrology 44 the cells for 2 hr at 37 °c. subsequently, the cells were incubated for 45 min with horse radish peroxidase (hrp)-conjugated anti mouse igg (1:50) as a secondary antibody. then, 10% dab solution was applied for 10 min. the brdu positive cells were observed under inverted phase contrast microscope. preparation of recipient mice busulfan was used to deplete endogenous germ cells and degeneration of spermatogenesis in order to prepare recipients. adult male c57bl/6 mice (6 weeks of age) were kept at stable temperature (22 °c) and light–dark cycle of 12 h light/12 h darkness with free access to food and water. busulfan (sigma chemical, dorset, uk) was dissolved in dimethyl sulphoxide (dmso; sigma), and an equal volume of sterile distilled water was added to provide final concentrations of 30 mg/ kg. adult mice received a single intraperitoneal injection of busulfan(15). transplantation and testicular tissue collection the donor spermatogonia and sertoli cells in suspension were suspended in a volume of approximately 15 μl of dmem/ fcs (fetal calf serum) and transplanted into rete testis of recipient mice with a microinjection needle. the recipient mice were anesthetized for transplantation. transplantation was carried out a week after culturing. for testicular injections, the cells (1x 106) were maintained on ice and then microinjected into the rete testes using glass needle in one of the testes of each recipient mice; and another testis was used as an internal control. the testes of the recipient mice were collected and fixed in 10% neutral buffered formalin (merck, darmstadt, germany) or kept in −80 °c for paraffin sections and spermatogenic markers were detected immediately after the injection at 4 and 8 weeks. for evaluation of spermatogonial stem cell colonization, recipient mice testes were analyzed with brdu stainingthe transplanted testis sections with 5 μm thickness were immunostained with a primary anti-brdu in order to visualize the donor-derived spermatogenesis. rna extraction and quantitative real-time rtpcr total rna was extracted from fresh testis tissues using trizol (invitrogen) according to the manufacturer’s instructions. the first strand cdna was synthesized with 50 ng of total rna by random hexamer priming using high capacity cdna synthesis kit (intron, korea) at 42°c for 60 min and at 70°c for 5 min. quantitative real-time pcr was performed with a sybr-green kit (takara, korea) according to the manufacturer’s instructions and using the abi light cycler (abi step one) in a total reaction volume of 10μl to analyze the expression of ngn3 and lin28. all reactions were performed in triplicate and results were normalized to gapdh (internal control) to correct rna input in refigure 8. serum level of testerone and germ cells numbers. figure 9. ngn3 detection by western blot in mouse testis western blot analysis detected presence of ngn3 protein in the normal testis. busulfan treatment caused complete depletion of germ cells, and after transplantation ngn3 expression was showed in recipient mouse testis. sscs transplantation in azoospermic mice-jafarian et al. actions. the following primers were used for rt-pcr: lin28 primers: agaccaaccatttggagtgc and aatcgaaacccgtgagacac;ngn3primers: gttggtgagcccctggagaccatat and ctggcccctggcccctgggcac ;gapdhprimers: aaggtcatcccagagctgaaand ctgcttcaccaccttcttga. determination of testosterone levels and germ cells number for measurement of testosterone, the mice were anaesthetized with 0.64 mg/ kg xylazin (alfasan, woerden, and the netherlands) and 20 mg/ kg ketamine (alfasan). serum testosterone level was measured by a chemiluminescence analyser (diasorin kit; italy). the blood of animal was collected by cardiac puncture. the serum after separation was stored at 20 °c for testosterone level detection. for dna flow cytometry, freshly harvested testicular tissue was separated and placed in phosphate-buffered saline (pbs). enzymatic digestion of testicular tubules was performed after testicular tissue dissection according to the technique of dym et al. with minor modifications . to remove residual cells, tissue fragments were washed twice with phosphate buffer. then, 1 ml of cold 70% ethanol was added drop by drop to the obtained sediment. after centrifugation (10 min in 500 g), the supernatant was discarded. then, 0.5 ml of nucleic acid staining solution consisting of 8.5 ml of staining buffer (0.1% bsa in pbs), 0.1% rnase (sigma) and 0.5 ml of stock solution of propidium iodide (1 ng/ ml; sigma) was added to the pellet. dna histograms were obtained by a flow cytometer (becton-dickinson, fac scan, san jose, ca, usa), and analysis was performed by cell quest programs (becton-dickinson) (15). sds-page and western blotting proteins were extracted from the testis of 6 weeks old mice (control) and busulfan-treated mice using radioimmunoprecipitation assay (ripa) buffer containing 10mm tris-hcl (ph = 8.0), 1% np-40, 10% glycerol, 0.1% sds,1mm edta and 100mm nacl with protease inhibitor cocktail (roche diagnostic, gmbh, germany). 50 μg of total protein was heated to 95°c for 5 min and separated by 12% sodium dodecyl sulfate-polyacrylamide (sds-page) gel and blotted on to a polyvinylidene fluoride (pvdf) membrane (amersham biosciences). protein binding sites were blocked for 2 hrs in 3% nonfat skim milk in tris-buffered solution with 0.1% tween 20 (tbst) at room temperature (rt). the membrane was incubated overnight at 4 °c in 1 % bsa solution containing 1:300 dilution of primary antibody (ngn3 monoclonal antibody, santa cruz) the membrane was diluted with 1:10,000 hrp conjugated rabbit anti mouse immunoglobulins (sigma) 1hr at room temperature after 3 times of washing with tbst, bands were visualized using enhanced chemiluminescence (ecl) reagent (ariyatous biotech, iran) according to the manufacturer’s instructions and were compared with ≥-actin. statistical analysis the values are presented as the mean ± sem. results were analyzed by one-way anova and bonferroni’s post-hoc test was used for comparison of experimental groups with control by graph pad prism5 software. p-value less than .05 was considered statistically significant. results cell culture and labeling approximately before 1 week several small colonies were observed on top of the monolayer of testicular cells (figure 2a). isolated sscs was incubated in medium with 0.1 mm brdu and the brdu labeled cells were used for transplantation. to in vitro detection of these cells after rete testis transplantation, monoclonal anti-brdu antibody was used in culture medium and brdu positive cells were observed by optical micscope (figure 2b). alkaline phosphatase (ap) activity cultured spermatogonial stem cells did not show any alkaline phosphatase activity. althogh, alkaline phosphatase is highly expressed in the mouse intestine, as well as blood noutrophil cells that served as a positive control(figure 3). immunostaining of cytokeratin and ngn3 immunocytochemical evaluation using an antibody against cytokeratin showed cytoplasmic localization of ck-18 in sertoli cells (figure 4a). figure 4b clearly showes a positive expression of ngn3 in sscs compared to control. recipient mice four weeks after the injection of mice with busulfan, most of the endogenous germ cells were removed (figure 5a). histological analysis showed that 70 and 100 days after injection of 30 mg/ kg busulfan, the regeneration of spermatogenesis occurred in a few tubules, while it was not effective to return fertility in azoospermia mice (p = 0.005) (figure 5b,c). on the other hand, evaluation by optical microscopy demonstated increase in capsular thickness after busulfan treatment compared to the control group (figure 5d). donor cells in recipient seminiferous tubules two months after transplantation of cells into rete testis, most of the donor cells were observed in tubule cross-sections of recipient mice as detected by immonohistochemistry for brdu (figure 6a). no brdu positive cells were found in the non-transplanted group (figure 6b). expression of spermatogenic molecular markers in recipient testicular tissue the known molecular markers of spermatogonial stem cells and spermatogonia ngn3 and lin28 were detected in adult (control group), 3-6 days old, busulfan treated and recipient mice testes as determined by q rt-pcr. expressions of ngn3 and lin28 at relatively high levels were detected 8 weeks after transplantation in recipient mice (p < .05) (figure 7). testosterone concentration and cycle analysis two months after transplantation, testosterone level and number of haploid cells percentage were shown to have an increase in transplanted mice compared to control group (p = .0005) (figure 8a, b). detection of ngn3 protein level by western blot in spermatogonial stem cells western blot analysis detected the presence of ngn3 protein in the testis. the ngn3 antibody recognized a single protein band of ~ 23 kda in normal mice. western blot results indicated no detectable ngn3 protein in busulfan treated testis. as a result, busulfan treatment sscs transplantation in azoospermic mice-jafarian et al. vol 15 no 01 january-february 2017 45 sexual dysfunction and andrology 46 caused a complete depletion of germ cells, and thus these animals were used as recipients for germ cell transplantation (figure 9). discussion the germ cell transplantation technique has provided a new treatment approach in restoration of fertility in oncological patient. in this propose, azoospermic mice are a good model for development of this new technology. in the past, there was not an appropriate in vitro culture condition to support proliferation and differentiation of sscs for a long time. although, a complete in vitro spermatogenesis has not been obtained in any species(21). in the mature testis, 2-3 stem cells exist in 104 testicular cells. therefore, in this study we used testes from immature mice to provide a large number of undifferentiated sscs(22). stem cell expansion following busulfan treatment and before transplantation had effective role in cell population. before autologous transplantation and treatment of infertility, expansion of sscs is necessary. according to recent reports, c-kit is express in differentiating spermatogonia (aa116 and possibly aa18 ) and undifferentiated sscs are c-kit negative(10,23,24). while, ngn3 and lin28 are expressed by spermatogonial stem cells and early steps of spermatogenesis(11). so, we used ngn3 and lin28 to characterization of cultured sscs. in the present study, germ cell transplantation from rete testis of azoospermia mouse model copuld lead to an increase in efficiency of transplantation. the results of busulfan injection to deplete endogenous germ cells confirmed the regeneration is based on stem cell expansion after cytotoxic treatment. after busulfan injection and destraction of primitive germ cells that account for less than 1% of the total number of testis cells(25,26), nearly all of the differentiated progenitor cells remained and continued their differentiation with normal kinetics. however, due to the absence of self-renewal activity in sscs they gradually got mature and disappeared by 35 days(27,28). therefore, as the stem cell numbers continued to recover, the number of differentiated germ cells decreased, and the ratio of stem cells to differentiated germ cells markedly changed during regeneration. our results apparently revealed the number of stem cells decreased and reached the lowest value four weeks after the injection of 30 mg/kg busulfan. however, stem cells then started to increase and histological analysis showed the regeneration of spermatogenesis in a few tubules between 70 and 100 days after injection of 30 mg/ kg busulfan while, stem cell regeneration was not effective. because it has been reported that busulfan is a potent agent that can destroy sertoli cells in testis environment(29). so, abnormal testis environment may decrease spermatogenesis efficacy. in the present study, we used neonatal or prepubertal donor testis cells with most of undifferentiated cells in suspension. so, 25-30 μl of fresh cell suspension (~ 2/5×106 cells/ml) was slowly injected into the rete testis if azoospermicmouse. then, sscs migration into the niche or basement membrane of seminiferouse tubules and donor derived spermatogenesis was detected two month after transplantation. previouse studies showed spermatogonial stem cells numbers in donor cell suspension is an important factor in colonization. an increase in sscs population rather than differentiated cells could increase spermatogenesis efficacy. indeed, cell cycle stages had a main role in regulating ssc migration to the niche(30). in this study, further cell cycle analysis detected the presense of the most cells in the g2/m phase after transplantation that showed an success in homing of transplanted cells and progression into differentiation cycle. although, the mechanism that promotesscs homing, replicattion and differentiation into mature spermatoza is complicated(31). on the other hand, busulfan treatment induced stem cell degradation and testis tissue became approximately empty of sscs. in this regard, two months after transplantation, the presence of transplanted cells was investigated by examination of ngn3 and lin28 expression. increased expressions of ngn3 and lin28 could confirm the existence of new cells in testis of azoospermia mouse model. based on recent finding, ngn3 and lin28 were specifically expressed in the spermatogonia and busulfan could induce morphological damage to undifferentiated sscs and sperm production. in our study, transplanted sscs into rete testis of azoospermia mice, could to lead the cell suspension in near all of the tubules and that revealed by anti-brdu staining. it was better to use gfp-donor mice to better distinguish testis resettlement, but it was limitations of our study. two months after transplantation, an increase in ngn3 and lin28 expressions revealed the success in sscs homing and beginning of donor derived spermatogenesis in the recipient seminiferous tubules. we could success to evaluate sscs transplantation in rete testis of azoospermia mouse model by cellular and molecular analysis. while, we need more time to check functional sperm in the ejaculate. conclusions germ cell transplantation was initially developed in rodents and had great potential and promising initial results. number of important factors including isolation of donor cells, delivery to recipient testes and recipient animal preparation related to the success rate of the technique and making this procedure as a viable option for application. clinical applications include preservation of fertility in patients undergoing potentially sterilizing treatments for cancer therapy and rare animals. in the practice the introduction of genetic modifications into the germline of domestic animals is most applications of sscs transplantation. rete testis transplantation of germ cells is newer approach that enhances our understanding of testis function, preserve fertility, study and manipulates spermatogenesis in a variety of mammalian specie references 1. ogawa t, dobrinski i, 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transfer into rat, bovine, monkey and human testes. human reproduction. 1999;14:144-50. 19. anderson wa. cytochemistry of sea urchin gametes: iii. acid and alkaline phosphatase activity of spermatozoa and fertilization. journal of ultrastructure research. 1968;25:114. 20. heidari b, gifani m, shirazi a, et al. enrichment of undifferentiated type a spermatogonia from goat testis using discontinuous percoll density gradient and differential plating. avicenna journal of medical biotechnology. 2014;6:94. 21. guerin j. [testicular tissue cryoconservation for prepubertal boy: indications and feasibility]. gynecologie, obstetrique & fertilite. 2005;33:804-8. 22. bellve ar, cavicchia j, millette cf, o'brien da, bhatnagar y, dym m. spermatogenic cells of the prepuberal mouse: isolation and morphological characterization. the journal of cell biology. 1977;74:68-85. 23. oatley jm, kaucher av, avarbock mr, brinster rl. regulation of mouse spermatogonial stem cell differentiation by stat3 signaling. biol reprod. 2010;83:42733. 24. zhang m, zhou h, zheng c, et al. the roles of testicular c-kit positive cells in de novo morphogenesis of testis. sci rep. 2014;4:5936. 25. kramer mf, de rooij dg. the effect of three alkylating agents on the seminiferous epithelium of rodents. ii. cytotoxic effect. virchows arch b cell pathol. 1970;4:276-82. 26. bellve ar. purification, culture, and fractionation of spermatogenic cells. methods enzymol. 1993;225:84-113. 27. de rooij dg, russell ld. all you wanted to know about spermatogonia but were afraid to ask. j androl. 2000;21:776-98. 28. meistrich ml. effects of chemotherapy and radiotherapy on spermatogenesis. eur urol. 1993;23:136-41; discussion 42. 29. hemsworth bn, jackson h. effect of busulphan on the developing gonad of the male rat. j reprod fertil. 1963;5:187-94. 30. ishii k, kanatsu-shinohara m, shinohara t. cell-cycle-dependent colonization of mouse spermatogonial stem cells after transplantation into seminiferous tubules. j reprod dev. 2014;60:37-46. 31. cheung hh, rennert om. generation of fertile sperm in a culture dish: clinical implications. asian j androl. 2011;13:618-9. sscs transplantation in azoospermic mice-jafarian et al. vol 15 no 01 january-february 2017 47 reconstructive surgery is there a difference in platelet-rich plasma application method and frequency to protect against urethral stricture? arif aydin1, mehmet giray sonmez1, pembe oltulu2, rahim kocabaş3, leyla öztürk sonmez4,5, hakan hakkı taşkapu1, mehmet balasar1 purpose: to determine the efficacy of instillation frequency and submucosal injection of platelet-rich plasma (prp) after urethral trauma to prevent urethral inflammation and spongiofibrosis. materials and methods: sixty-five rats were used in the study; 50 rats were randomized into 5 groups with 10 rats in each group and 15 rats were allocated for prp preparation. the urethras of all rats were traumatized with a pediatric urethrotome knife at 6 and 12 o’clock positions, except in the sham group. group 1 was the sham group and had only urethral catheterization daily for 15 days, group 2 was given 0.9% saline (physiologic saline [(ui+ps]) once a day after urethral injury (ui+ ps), group 3 was injected with prp submucosally after urethral injury, group 4 was given prp once a day as intraurethral instillation using a 22 ga catheter sheath with urethral injury, and group 5 was given prp twice a day as intraurethral instillation using a 22 ga catheter sheath with urethral injury. each administration of prp was administered as 300 million platelets/150 microliters. on day 15, the penises of the rats were degloved to perform penectomy. histopathologic evaluation was made for spongiofibrosis, inflammation, and congestion in vascular structures. results: when the sham group, ui+ps, ui+prpx1, ui+prpx2 and ui+prps groups are compared in total, there were significant differences identified for parameters other than edema. when the ui+ps, ui+prpx1, ui+prpx2 and ui+prps groups are compared, the ui+ps group was observed to have significantly more inflammation (mucosal inf. 2.42 ± 0.53) and spongiofibrosis (2.42 ± 0.53). all the prp groups were identified to have significantly less mucosal inflammation (ui+prps 1 ± 0, ui + prpx1; 1.4 ± 0.51, prpx2; 1.33 ± 0.5) and spongiofibrosis (ui+prps; 1.57 ± 0.53, prpx1; 1.2 ± 0.42, prpx2; 1.55 ± 0.52). the group with the lowest spongiofibrosis was the prpx1 group. conclusion: this study showed that prp significantly reduced mucosal inflammation and spongiofibrosis, independent of the administration route, when applied to the urethra after urethral trauma. keywords: urethral stricture; prp; urethral fibrosis; urethral inflammation; urethral healing introduction urethral stricture forms due to narrowing of the lu-men in any region of the urethra linked to fibrosis development due to trauma, infection, or idiopathic causes.(1) prevalence appears to be 0.9% in males, and it is a disease with very high treatment costs.(2) currently, the most common cause of the urethral stricture etiology is iatrogenic interventions as a result of increasing endoscopic interventions, with the most common development after tur-p.(3,4) urethra stricture is a disease affecting all age groups and the quality of life of the patient, with minimally invasive treatments and high recurrence rates.(1,2,5) however, congenital urethral strictures are exceedingly rare in infants.(6) whatever the etiology of stricture, excessive inflammation in the injury region and increased accumulation of type 3 collagen 1neü meram medicine faculty department of urology, konya, turkey. 2neü meram medicine faculty department of pathology, konya, turkey. 3neü meram medicine faculty konüdam exp. medicine&app. res. center, konya, turkey. 4selcuk university, department of physiology, konya, turkey. 5beyhekim state hospital, department of emergency medicine, konya, turkey. *correspondence: department of urology, neü meram medicine faculty, konya, turkey. tel.: +903322237441. mobile: +905055566988. e-mail: aydinarif@gmail.com. received april 2020 & accepted october 2020 as a result of this inflammation are considered to cause fibrosis.(7) to date, many agents have been studied to prevent formation of fibrosis, increase success rates of surgical treatments or reduce recurrence; however, none have entered routine use.(8) platelet-rich plasma (prp) is a preparation of autologous plasma enriched with platelet concentrations above that normally found in whole blood.(9) prp increases the speed of wound healing due to containing many growth factors. the synthesis of type 3 collagen causing fibrosis reduces with the effect of these factors. (10-12) due to this effect of prp, it is considered that it will have a significant effect on urethral healing. however, there is no information about whether this effect will be enhanced by the easily applied method of instillation, or by submucosal injection of prp. this study investigated the effects on urethral healing, inflammaurology journal/vol 18 no. 6/ november-december 2021/ pp. 663-669. [doi: 10.22037/uj.v16i7.6100] tion, and fibrosis of prp administered as intraurethral instillation and as submucosal injection in an experimentally-induced urethra injury model in rats and compared the administration methods. the aim of this study is to develop new treatment modalities for urethral stricture that may form after urethral injury by evaluating the effect of prp and the efficacy of the prp administration form. materials and methods this study was completed in n.e. university konüdam experimental medicine application and research center after receiving permission from the local animal ethics committee. rats and anesthesia a total of 65 wistar male albino rats weighing 250-300 g were used in the study. the animals were kept in separate cages at room temperature (22 °c) with 50% humidity during preoperative and postoperative periods. on the day of the experiment, rats were administered anesthesia with ketamine (50 mg/kg) under sterile conditions. rats other than wistar albino species, female rats, those below 250 g and younger than 3 months were not included in the study. table 1. pathologic parameters and ratios between groups. (μ: chi-square test) pathologic group-1 group-2 group-3 urethral injury group-4 group-5 total p value parameters sham n(%) urethral injury + +submucozal prp injection urethral injury + urethral injury + n(%) all groupsμ saline daily (ui+ prps) n(%) prp x1 (ui+prpx1) prp x2 (ui+prpx2) (ui+ps) n(%) n(%) n(%) mucosal inflammation < 0,001 0 2 (22.2%) 0 0 0 0 2 (5%) 1 7 (77.8%) 0 7(100%) 6(60%) 6 (66.7%) 26(62%) 2 0 4 (57.1%) 0 4(40%) 3 (33.3%) 11(26%) 3 0 3 (42.9%) 0 0 0 3 (7%) spongiofibrosis < 0.001 0 3 (33.3%) 0 0 0 0 3(7.1%) 1 3 (33.3%) 0 3 (42.9%) 8(80%) 4(44.4%) 18(42.9%) 2 3 (33.3%) 4 (57.1%) 4 (57.1%) 2(20%) 5(55.6%) 18(42.9%) 3 0 3 (42.9%) 0 0 0 3(7.1%) edema 0.627 0 5(55.6%) 3 (42.9%) 2 (28.6%) 3(30%) 2 (22.2%) 15 (35.7%) 1 4(44.4%) 3 (42.9%) 5 (71.4%) 6(60%) 7 (77.8%) 25 (59.5%) 2 0 1 (14.3%) 0 1(10%) 0 2 (4.8%) serosal inflammation 0.003 0 6 (66.7%) 3 (42.9%) 0 0 0 9 (21.4%) 1 3 (33.3%) 4 (57.1%) 4 (57.1%) 3(30%) 2(22.2%) 16 (38.1%) 2 0 0 2 (28.6%) 4(40%) 4(44.4%) 10 (23.8%) 3 0 0 1 (14.3%) 3(30%) 3(33.3%) 7 (16.7%) figure1: the study protocol atraumatization of rat’s urethra with pediatric uretrotome, badministration of the prp into the urethra with using a 24 ga catheter cadministration of the submucozal injection of the prp to the urethra d-dissection of the rat penis until its proximal part prp treatment in urethral injury-aydin et al. reconstructive surgery 664 vol 18 no 6 november-december 2021 665 preparation of platelet-rich plasma (prp) platelet-rich plasma (prp) was prepared daily from the blood taken from a male (wistar albino) rat. to take the sample for prp, blood was taken from the heart under anesthesia and then the animal was euthanized (with the cervical dislocation method). blood samples were taken in tubes containing sodium citrate (blood/sodium citrate 3.8% = 9:1) and gently mixed. then the first centrifugation procedure (440 xg, 10ı, 20 ℃) was completed. the supernatant was obtained, transferred to a new tube and the second centrifugation was completed (800 xg, 12ı, 20 ℃). after the second centrifugation, nearly 2 ml of the upper section was removed with a pipette. the remaining prp was gently mixed and platelet count measurement was performed (~2x106/mm3). the measured prp was used in applications. all procedures were completed under sterile conditions.(13) prp was prepared fresh before administration and the procedure. the prp preparation process including taking blood took nearly 60 minutes. internal urethrotomy model and prp application in the study, a pediatric internal urethrotomy scalpel was used to induce a urethral injury model and a longitudinal 0.5 cm incision was made in the 12 o’clock direction from 0.5 cm proximal around the urethra to encompass muscles and corpus spongiosum. then intraurethral instillation was performed with a 22 ga catheter sheath in the groups. submucosal prp injection was performed with a ppd injector (figure 1). study groups at the beginning of the study, 15 rats were separated for preparation of prp and prp was prepared daily. later, 50 rats were randomized into 5 groups, with 10 rats in each group. group 1 was the sham group and only underwent daily urethral catheterization, group 2 was given instillation of intraurethral 0.9% saline once a day using a 22 ga catheter sheath after urethral injury (urethral injury + physiologic saline [(ui+ps]) group 3 was given submucosal injection of prp after urethral injury (ui+prps). submucosal prp was injected at 150 microliters (300 million platelets/administration). group 4 was given instillation of intraurethral prp once a day using a 22 ga catheter sheath after urethral injury (ui+prpx1). prp was administered into the urethra of rats as an instillation and one application of 300 million platelets/150 microliters was given for 15-days duration. group 5 was given instillation of intraurethral prp twice a day using a 22 ga catheter sheath after urethral injury (ui+prpx2). prp was administered into the urethra of rats as an instillation and two applications of 300 million platelets/150 microliters were given for 15-days duration. final evaluation on day 15, the penises of the rats were degloved to perform penectomy. rat penises were placed in 10% formaldehyde and sent to the pathology department for histopathologic analysis. at the end of the study, 1 rat in the sham group (n = 9), 3 rats in the ui+ps group (n = 7), 3 rats in the ui+prps group (n = 7), and 1 rat in the ui+prpx2 group (n = 9) died due to anesthesia and environmental factors, so the study was completed with the remaining 42 rats. histopathologic analysis histopathologic analysis was performed under light microscope by a single independent pathologist blinded to the study groups. until the day of macroscopic examination, the urethral tissues were fixed in 10% formalin in a separate dish for each rat. during the macroscopic examination, the tissue samples were cut into squares at 3-mm intervals and embedded in paraffin blocks. slices of 4-micron thickness were cut from the paraffin blocks and stained with hematoxylin and eosin (he) and with masson trichrome for histochemical examination. the preparates were examined under light microscope at x100 and x200 magnification. for the histopathologic examination of the tissues, spongiofibrosis, inflammation, and congestion in vascular structures were evaluated. spongiofibrosis was examined with masson tritable 2. histopathological scores of groups and total p values (α kruskal-wallis test) pathologic parameters group-1 group-2 group-3 group-4 group-5 p value sham urethral injury + urethral injury + urethral injury + urethral injury + all groupsα (mean value ±sd) sf daily (ui+sf) submucozal prp prp x1 prp x2 (mean value ±sd) injection (ui+ prps) (ui+prpx1) (ui+prpx2) (mean value ±sd) (mean value ±sd) (mean value ±sd) mucosal inflammation 0.77 ± 0.44 2.42 ± 0.53 1± 0 1.4 ±0.51 1.33±0.50 < 0.001 spongiofibrosis 1 ± 0.86 2.42 ± 0.53 1.57 ± 0.53 1.2 ±0.42 1.55±0.52 0.004 edema 0.44 ± 0.52 0.71 ± 0.75 0.71 ± 0.48 0.8 ±0.63 0.77±0.44 0.664 serosal inflammation 0.33 ± 0.50 0.57 ± 0.53 1.57 ± 0.78 2 ± 0.81 2.11±0.78 < 0.001 pathologic parameters sham sham vs sham vs ui+ sham vs ui+ps ui+prpx1 prpx2 (p value)* vs ui+prps (p value)* (p value)* (p value)* mucosal inflammation < 0.001 0.012 0.024 0.207 spongiofibrosis 0.001 0.524 0.12 0.149 edema 0.414 0.204 0.165 0.312 serosal inflammation 0.375 < 0.001 < 0.001 0.002 table 3. p values between sham group and experiment groups (*independent t test) prp treatment in urethral injury-aydin et al. chrome staining for histochemical examination. spongiofibrosis was evaluated as 0 = none; 1 + ≤ 10% tissues with fibrosis; 2 + = 10%-49% tissues with fibrosis; and 3 + ≥ 50% tissues with fibrosis. inflammation was evaluated as: 0 = none; 1+ = 5-10 lymphocytes/x200 magnification; 2+ = 11-50 lymphocytes/x200 magnification; and 3 + = > 50 lymphocytes/ x200 magnification. congestion in vascular structures was calculated by counting the number of vessels with congestion in the tissue at each x100 magnification and dividing this by the number of total x100 magnification areas in the tissue: 0: none, 1 + = 1-3, 2 + > 3-6, and 3 + = > 6-10. hyperemia and edema were evaluated according to their presence in biopsy samples (figure 2). while inflammatory cells in subepithelial tissue were assessed for identification of mucosal inflammation, identification of serosal inflammation assessed inflammatory cells in the tunica adventitia. the results of this assessment identified that rats receiving prp treatment had fewer inflammatory cells observed in the submucosal area compared to the serosal area. all procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted. approval for the study was granted by the local ethics committee. the study was performed in the experimental animals laboratory of n.e. unv. medical faculty. (no: 2017011) statistical analysis statistical analysis was performed with spss, v.23.0 statistical software (spss, inc. chicago, il, usa). chi square tests were used to understand if distributions of categoric variables were different across groups. categoric variables are described by frequencies and percentages. continuous variables are presented as mean and standard deviations. the independent samples t-test and kruskal wallis test were used for the comparison of continuous variables among groups. a p value < 0.05 was considered statistically significant. results during intraurethral administration, no side effects were observed in rats. during the study, 8 rats died due to anesthesia and environmental factors, while 42 rats survived. penectomies were performed on the 15th day and rats were sacrificed. forty-two rats were included in the assessment. rats included in the assessment were evaluated histopathologically for mucosal inflammation, urethral spongiofibrosis, edema, serosal inflammation, and congestion. all sections were monitored for mucosal hemorrhage but this was not scored. histopathologic assessment was evaluated and compared based on percentages and scoring. when all groups are compared with each other, the lowpathologic parameters ui+ps ui+ps ui+ps ui+prpx1 ui+prpx1 ui+prpx2 vs vs vs vs vs vs ui+prpx1 ui+prpx2 ui+prps ui+prpx2 ui+prps ui+prps (p value)* (p value)* (p value)* (p value)* (p value)* (p value)* mucosal inflammation 0.001 0.001 < 0.001 0.779 0.061 0.102 spongiofibrosis < 0.001 0.006 0.011 0.121 0.130 0.953 edema 0.803 0.836 1.0 0.931 0.768 0.789 serosal inflammation 0.001 0.001 0.017 0.766 0.297 0.193 table 4. p values between experiment groups (*independent t test) figure 2. h&e,x100;subepithelial, mucosal fibrosis and inflammation, a) 0.9% saline group, b) prpx1 group, c) prpx2 group, d) prps group; the urethral wall layer is shown with black arrow and line. h-e, x400; inflammation in the serosal section above the wall layer (black line and arrow) e) 0.9% saline group ( red arrow), f) prpx1 group ( red arrow), g) prpx2 group(red arrow) h) prps group (red arrow) prp treatment in urethral injury-aydin et al. reconstructive surgery 666 vol 18 no 6 november-december 2021 667 est values for mucosal inflammation, spongiofibrosis, edema, and serosal inflammation were measured in the sham group, while the highest values for mucosal inflammation, spongiofibrosis, and edema were measured in the ui+ps (0.9% saline) group. for serosal inflammation, the highest value was measured in the ui+prpx2 group. when all groups are compared, there were significant differences found for mucosal inflammation, spongiofibrosis, and serosal inflammation. no significant difference was identified for edema. the analyses of percentages and scoring for the groups are shown in table 1. the sham group was identified to have the lowest score values for all histopathologic parameters. data for comparisons between the sham group and other groups are shown in table 2. the urethral injury+ 0.9% saline (ui+ps) group was observed to have the highest values in terms of mucosal inflammation, spongiofibrosis, and edema. when the ui+ps group is compared with the prp groups, mucosal inflammation and spongiofibrosis were observed to be significantly greater in the ui+ps group. the highest significant difference for spongiofibrosis was identified in the ui+prpx1 group. there were no significant differences between the ui+ps group and the prp groups in terms of edema. when the ui+ps group is compared with the prp groups in terms of serosal inflammation, it was significantly less in the ui+ps group compared to all prp groups. when the prp groups (ui+prpx1, ui+prpx2, ui+prps) are compared with each other, there were no significant differences observed in terms of mucosal inflammation, spongiofibrosis, edema, and serosal inflammation. however, mucosal inflammation and serosal inflammation were observed to be lower in the ui+prps group, while spongiofibrosis was less in the ui+prpx1 group (table 3). urethral congestion was observed to be similar in all groups and no differences were identified. discussion urethra stricture is a disease with high cost disrupting quality of life and with frequent recurrence. there are many factors in the etiology led by trauma, urethra infections, cardiac surgeries, endoscopic interventions or foley catheter insertion. with the increase in endoscopic treatment especially in recent years, there is an increase in the incidence of iatrogenic urethra stricture. (14) after urethra stricture has formed once, it has high recurrence rates and may be treated with repeated minimal invasive procedures, self-dilatation and/or complex surgeries like urethroplasty.(15-17) as a result, it is very important to find a medical treatment modality that will prevent the formation of urethra stricture and/or lengthen recurrence duration. there is still no medical treatment available in spite of the increase in the prevalence of urethra stricture in recent years, the effect on patient quality of life, and high cost, with experimental applications not going beyond preventive agents. when the literature is examined, many agents have been trialed for the prevention of urethra stricture and different administration methods have been used. administration methods vary according to the effect mechanism of the agent; however, to date, there is no study about the administration method and administration frequency for a certain agent. in our study, different from the literature, the efficacy of prp administration was compared in terms of administration route and dose for the first time. as expected, intraurethral prp treatment was shown to be protective against urethral stricture, with the pathologic assessment results of the prp groups determined to be superior to the sham and saline groups. though no significant difference was identified for pathologic assessment of the prp subgroups of ui+prpx1, ui+prpx2 and ui+prps, interestingly the ui+prpx1 group had the lowest spongiofibrosis scores. the lowest scores for serosal and mucosal inflammation were identified in the ui+prps group. based on these results, we believe that more than one administration of prp is not superior. the low incidence of spongiofibrosis especially leads to the consideration that intraurethral and single-dose administration of prp may be more effective to prevent urethral stricture. urethra stricture was identified to have a high recurrence risk due to abnormal fibrosis increase.(7) studies observed fibrotic areas causing urethral stricture have 32% increases in type 3 collagen concentrations.(18) to prevent this abnormal increase in fibrosis, a variety of experimental and clinical studies were performed about the administration of medications or materials with antifibrotic effects.(19-21) the first studies on the prevention of urethra stricture clinically administered steroid treatments like triamcinolone, but were not very successful. (20,22) in rat models, periurethral botox-a injection, mitomycin-c, and dexpanthenol instillation were administered and the 3 agents were shown to reduce fibrosis and inflammation.(19,23,24) in fact, mitomycin-c was clinically injected in the submucosa in anterior urethra stenosis and shown to reduce fibrosis.(25) the increasing costs of urethral stricture continue to be a focus of interest. in clinical studies, caprotil gel, halofuginone, hyaluronic acid, and carboxymethyl cellulose were identified to reduce the recurrence of stenosis and postoperative pain when administered as instillations. (21,26,27) as seen in the literature, clinical and animal studies were performed with many agents and different methods, and different administration methods were used and all were shown to be effective in different studies. however, there is no study showing which administration method is more effective in a single study. additionally, none of these treatments have entered routine use to prevent urethral stricture. platelet-rich plasma (prp) contains high amounts of growth factors. the most important of these growth factors is platelet-derived growth factor (pdgf), which is a factor repairing connective tissue and initiating wound healing. pdgf is the first factor initiating processes including mitogenesis, angiogenesis and macrophage activation. many growth factors contained in prp increase the speed of regenerative processes and reduce inflammatory factors, reducing fibrosis development. studies with autologous prp showed that prp increases the rate of wound healing, closes wounds more easily in open diabetic wounds and reduces inflammation. due to these effects, autologous prp is routinely used in many clinics like plastic surgery and orthopedics.(1012,17,22-24) autologous prp contains many growth factors like endothelial growth factor, insulin-like growth factor, transforming growth factor and fibroblast growth factor expressed by mesenchymal stem cells. these growth factors prevent excessive accumulation of type prp treatment in urethral injury-aydin et al. prp treatment in urethral injury-aydin et al. 3 collagen in tissues reducing fibrosis development. linked to the effect of these growth factors, prp was shown to be effective for the prevention of fibrosis following urethral injury.(28,29) tavukçu et al. administered prp into the urethras of rats with induced experimental urethra injury and determined that it reduced type 3 collagen synthesis in urethra stenosis and protected against fibrosis.(28) however, no study was performed with prp or any other agent using different administration methods and numbers of administrations like urethral instillation and submucosal injection to identify the optimal treatment protocol. this study compared the protective effect of prp with intraurethral and submucosal administration for urethral stricture developing after iatrogenic induced urethra trauma. in conclusion, prp was seen to significantly reduce urethral spongiofibrosis independent of the method of administration. in the three prp groups, prps, prpx1, and prpx2, spongiofibrosis was identified to be low, with spongiofibrosis score lowest in the prpx1 group and highest in the prps group. additionally, the prp group with instillation 1 time per day had lower score values for urethral fibrosis than the prp group with instillation 2 times per day; however, there was no statistical difference identified. this situation shows that the increase in the number of prp administrations was not effective for protection from stenosis, and that a single dose was sufficient. there are a range of studies about wound healing related to prp. massara et al.(10) showed prp has increasing effect on healing in ischemic and diabetic foot wounds. nikopulos et al.(11) performed a study showing the efficacy of prp use for pubourethral ligament restoration in stress urinary incontinence. guinot et al.(12) used a platelet-rich fibrin membrane for closure after urethroplasty for distal hypospadias and there are publications about reduced fistula development. arnalich et al.(30) used solid prp as osd in the eye and showed it was an effective and safe preparate for corneal ulcers and perforations in eye surgery. mohammadi et al.(31) showed effective wound healing in rats. as seen in these studies, prp was even used in the eye and positively affected wound healing and reduced fibrosis due to containing many growth factors without identified side effects. in our study, it was identified to be more effective on fibrosis when administered as urethral instillation. in this study, the efficacy of prp administered as intraurethral instillation 1 and 2 times per day and as submucosal injection 1 time per day was compared in rats with urethral injury. when compared with intraurethral 0.9% saline instillation after urethra injury, all prp groups were identified to have significant degrees of reduction in mucosal inflammation and urethral fibrosis. prp is a current topic, coming to the fore as a cheap and easily applicable method without autologous side effect profile. in our study, the administration method in rats with experimental urethra injury induced was compared with the ui+ps group. in our study, all administration methods for prp were identified to be effective, aid in healing urethral tissue and reduce inflammation parameters. when the administration route is compared, administration as urethral instillation 1 time per day was most effective on spongiofibrosis and reduced it most. as a result, it is considered that this method may be chosen for clinical administration due to ease of administration to patients. in summary, prp affects synthesis of type 3 collagen especially and increases normal wound healing due to containing many growth factors. it is a simple, cheap, and effective preparate with no side effects that can be obtained by autologous means routinely used in other disciplines in medical practice. it may be used as routine instillation to protect against iatrogenic urethra stricture and/or to prevent recurrence after treatment. prp administered through intraurethral instillation and submucosal route is a promising preparate that may prevent the development of fibrosis and inflammation as a result of urethral injury and increase the speed of normal urethral healing. however, administration of prp as instillation 1 time per day was observed to be more effective than submucosal administration and administration as instillation 2 times per day in our study. administration of prp as 1 daily intraurethral instillation to protect against urethral stricture may be chosen due to easy application. however, there is a need for clinical and experimental studies about the long-term outcomes to better evaluate the effect of prp. the most important limitation of the study is the short follow-up period for an animal experiment. this follow-up duration was not sufficiently long to determine fibrosis that may develop in the long term and possible side effects. conflict of interest none of the authors have any potential conflict of interest. references 1. mccammon ka, zuckerman jm, jordan gh. surgery of the penis and urethra. in: wein aj, kavoussi lr, partin aw,peters ca,eds. campbell-walsh urology 11th ed. philadelphia:elsevier;2016;40:907–45.e4. 2. das sk, jana d, ghosh b, et al. a comparative study between the outcomes of visual internal urethrotomy for short segment anterior urethral strictures done under spinal anesthesia and local anesthesia. turk j urol. 2019 1;45:431-36. 3. palminteri, e., berdondini e, verze p, et al. contemporary urethral stricture characteristics in the developed world. urology, 2013. 81:191. https://www.ncbi. nlm.nih. gov / pubmed/23153951 4. gül m, altıntaş e, kaynar m, et al. the predictive value of platelet to lymphocyte and neutrophil to lymphocyte ratio in determining urethral stricture after transurethral resection of prostate. turk j urol. 2017 ;43:325-29. 5. santucci r, eisenberg l. urethrotomy has a much lower success rate than previously reported. j urol. 2010;183:1859–62. 6. gobbi, dalia; leon, francesco fascetti; gnech, michele; et al. management of congenital urethral strictures in infants. case series. urol j. 2019 feb 21;16:67-71. 7. hofer md, cheng ey, bury mi, et al. analysis of primary urethral wound healing in the rat. urology. 2014;84.246.e1. 8. kilinc mf, doluoglu og, eser pe, et al. reconstructive surgery 668 vol 18 no 6 november-december 2021 669 intraurethral erythropoietin to prevent fibrosis and improve urethral healing: an experimental study in a rat model. urology. 2019 ;123:297.e9-297.e14. 9. peter i-kung wu , robert diaz, joanne borgstein platelet-rich plasma phys med rehabil clin n am. 2016 ;27:825-53. 10. massara m, barillà d, de caridi g, et al. application of autologous platelet-rich plasma to enhance wound healing after lower limb revascularization: a case series and literature review.semin vasc surg. 2015 ;28:195-200. 11. nikolopoulos ki, pergialiotis v, perrea d, et al. restoration of the pubourethral ligament with platelet rich plasma for the treatment of stress urinary incontinence.med hypotheses. 2016; 90:29-31. 12. guinot a, arnaud a, azzis o, et al. preliminary experience with the use of an autologous platelet-rich fibrin membrane for urethroplasty coverage in distal hypospadias surgery. j pediatr urol. 2014;10:300-5. 13. aydın a, sönmez mg, oltulu p, et al. “histopathologic evaluation of the effects of intraurethral platelet rich plasma in urethral trauma experimentally induced in rat model.” .urology. 2020 jul;141:187.e9-e14. 14. dubey d. the current role of direct vision internal urethrotomy and self-catheterization for anterior urethral strictures. indian j urol. 2011 27:392-6. 15. ferguson gg, bullock tl, anderson re, et al. minimally invasive methods for bulbar urethral strictures: a survey of members of the american urological association. urology. 2011 ;78:701-6. 16. akyuz m, sertkaya z, koca o, et al. adult urethral stricture: practice of turkish urologists. int braz j urol. 2016;42:339-45. 17. greenwell tj, castle c, andrich de, et al. repeat urethrotomy and dilation for the treatment of urethral stricture are neither clinically effective nor cost-effective. j urol. 2004;172:275-7 18. da-silva ea, sampaio fj, dornas mc, et al. extracellular matrix changes in urethral stricture disease. j urol. 2002;168:805-7. 19. sahinkanat t, ozkan ku, ciralik h, et al. botulinum toxin-a to improve urethral wound healing: an experimental study in a rat model. urology. 2009;73:405-9 20. hebert pw. the treatment of urethral stricture: transurethral injection of triamcinolone. j urol. 1972 ;108:745-7 21. chung jh, kang dh, choi hy, et al. the effects of hyaluronic acid and carboxy methylcellulose in preventing recurrence of urethral stricture after endoscopic internal urethrotomy: a multicenter, randomizedcontrolled, single-blinded study. j endourol. 2013 ;27:756-62. 22. cole at, curtis ga, gill wb, the use of a hydrocortisone antibacterial urethral insert in the treatment of urethral strictures: a preliminary report. j urol. 1972;108:742-44. 23. ibrahim yardimci, tolga karakan, berkan resorlu, et al. the effect of intraurethral dexpanthenol on healing and fibrosis in rats with experimentally induced urethral trauma urology. 2015 ;85:274.e9-13. 24. ayyıldız a, nuhoglu b, gulerkaya b, et al. effect of intraurethral mitomycin-c on healing and fibrosis in rats with experimentally induced urethral stricture. int j urol. 2004;11:1122-26. 25. mazdak h, meshki i, ghassami f. effect of mitomycin c on anterior urethral stricture recurrence after internal urethrotomy. eur urol. 2007 ;51:1089-92; discussion 1092. epub 2006 nov 27. 26. shirazi m, khezri a, samani sm, et al. effect of intraurethral captopril gel on the recurrence of urethral stricture after direct vision internal urethrotomy: phase ii clinical trial. int j urol. 2007 ;14:203-8. 27. nagler a, gofrit o, ohana m, et al. the effect of halofuginone, an inhibitor of collagen type-i synthesis, on urethral strictureformation: in vivo and in vitro study in a rat model. j urol. 2000 ;164:1776-80. 28. tavukcu hh, aytaç ö, atuğ f, et al. protective effect of platelet rich plasma on urethral injury model of male rats. neurourol urodyn. 2018;37:1286-93. 29. wang k, guan y, liu y, et al. fibrin glue with autogenic bone marrow mesenchymal stem cells for urethral injury repair in rabbit model. tissue eng part a. 2012;18:2507–17. 30. arnalich f, rodriguez ae, luque-rio a, et al. solid platelet rich plasma in corneal surgery. ophthalmol ther. 2016;5:31-45. 31. mohammadi r, mehrtash m, hassani n, et al. effect of platelet rich plasma combined with chitosan biodegradable film on fullthickness wound healing in rat model. bull emerg trauma. 2016;4:29-37. prp treatment in urethral injury-aydin et al. case report 220 urology journal vol 6 no 3 summer 2009 neurofibromatosis presenting as painless clitoromegaly nicholas g cost,1 fabian s sanchez,1 arthur g weinberg,2 korgun koral,3 linda a baker1 urol j. 2009;6:220-2. www.uj.unrc.ir keywords: neurofibroma, neurofibromatosis 1, clitoris, genitalia abnormalities, sex differentiation disorders 1department of urology, southwestern medical center and children’s medical center, dallas, texas, usa 2department of pathology, southwestern medical center and children’s medical center, dallas, texas, usa 3department of radiology, southwestern medical center and children’s medical center, dallas, texas, usa corresponding author: nicholas g cost, md department of urology, ut southwestern medical center at dallas, j8.148, 5235 harry hines blvd, dallas, tx 75390-9110, usa tel: +1 214 648 2278 fax: +1 214 648 8786 e-mail: nicholas.cost@sbcglobal.net received june 2008 accepted september 2008 introduction neurofibromatosis is an autosomal dominant progressive disorder with an incidence of approximately 1 in 3000 live births.(1) its recognized features include hyperpigmented skin lesions (cafe-au-lait spots), neurofibromas, iris hamartomas, macrocephaly, central nervous system tumors, defects of the skull and facial bones, and vascular lesions. involvement of the external genitalia is extremely unusual.(1,2) we present a case of a neurofibroma of the dorsal clitoral hood and its management. case report a 3-year-old girl presented to the pediatric urology clinic with the complaint of 8 months of painless clitoromegaly. she had been referred for concern of ambiguous genitalia and intersex state. the past medical and family history was unremarkable. examination revealed a healthy female with multiple cafe-au-lait spots. superficially, the clitoris appeared enlarged, but with further inspection, there was actually a 1.5 × 1.0-cm rubbery mobile mass of the dorsal clitoral hood lying over the normal glans clitoris. the patient’s karyotype was determined to be 46,xx. given the initial concern for ambiguous genitalia, a thorough endocrine evaluation was done which ruled out precocious puberty, congenital adrenal hyperplasia, and other hormonal causes of clitoromegaly. her bone age was found to be appropriate and blood laboratory examination results were as follows: sodium, 138 meq/l; potassium, 4.0 meq/l; bicarbonate, 22 meq/l; chloride, 105 meq/l; urea, 12 mg/dl; creatinine, 0.4 mg/dl; free thyroxin, 1.4 ng/dl (reference range, 0.65 ng/dl to 2.30 ng/dl); thyroid-stimulating hormone, 2.45 μu/ml (reference range, 0.35 μu/ml to 6.16 μu/ ml); 17-hydroxyprogesterone, < 10 ng/dl (reference, < 10 ng/dl); androstenedione, < 10 ng/dl (reference, < 10 ng/dl); and testosterone, < 3.0 ng/dl (reference range, < 10 ng/dl). pelvic magnetic resonance imaging revealed a 1.8 × 0.8 × 2.0-cm well-circumscribed, pedunculated, nonlipomatous soft tissue mass within the subcutaneous tissues of the clitoral hood (figures 1 and 2). of note, no other pelvic masses or bladder lesions were noted. the patient was examined under anesthesia by cystoscopy, and resection was attempted. during cystoscopy, no lesions were found within the bladder. however, the mass was found to be adherent to neurofibromatosis and painless clitoromegaly—cost et al urology journal vol 6 no 3 summer 2009 221 the clitoral corpora, but resection was possible without injury to the clitoris or the neurovascular bundle. pathology examination revealed an infiltrating plexiform neurofibroma (figure 3). based on the presence of cafe-au-lait spots and the plexiform neurofibroma, the patient was diagnosed with neurofibromatosis 1. additional imaging of the abdomen and brain did not reveal any further involvement. at 1-year follow-up, no recurrence was detected. discussion literature review demonstrated 27 previous reports of clitoral neurofibromas; however, only 1 was the involvement of the clitoral hood.(1,3) the other reports are of neurofibromas of the glans clitoris. the first description of clitoral neurofibroma was by haddad and jones in 1960.(4) a later report by rink and mitchell suggested that any child with genital neurofibromatosis be evaluated for bladder neurofibromas based on a few cases with involvement of both external genitalia and bladder.(1,2) given the precision of the current imaging techniques, it is unclear if cystoscopy is still necessary. in cases of neurofibromas involving the female external genitalia, examination generally reveals clitoral enlargement resembling a phallus, and some patients report pain if presenting after puberty. occasionally, this enlargement masquerades as an intersex disorder and is confused with virilizing congenital adrenal hyperplasia. of the two pathological subtypes of neurofibromatosis, discrete nodular and plexiform neuromas, the plexiform subtype is more common in urogenital involvement.(5) overall, the incidence of malignant degeneration of neurofibromas ranges from 13% to 29%, which increases with age.(2) thomas and colleagues reported a case of clitoral involvement by malignant schwannoma and described treatment with total surgical removal of the gross tumor. figure 1. coronal view of t2 magnetic resonance imaging of the pelvis demonstrating the mass arising from the dorsal clitoral hood figure 2. axial view of t2 magnetic resonance imaging of the pelvis. note the lack of bladder or pelvic involvement by neurofibromatosis figure 3. tangential and cross-sections of enlarged nerve trunks form a plexiform mass in the clitoral tissue (hematoxylin-eosin, × 40). neurofibromatosis and painless clitoromegaly—cost et al 222 urology journal vol 6 no 3 summer 2009 behavior of the malignant schwannoma is similar to other soft tissue sarcomas with a tendency towards local recurrence despite wide surgical excision and hematogenous spread.(6) after review of this case and the existing literature, we recommend that management of a clitoral neurofibroma consist of excision with all attempts to preserve the clitoris and its adjacent neurovascular structures. we also recommend regular postoperative surveillance to monitor for local recurrence. however, no local recurrences have been described to date. conflict of interest none declared. references 1. griebel ml, redman jf, kemp sf, elders mj. hypertrophy of clitoral hood: presenting sign of neurofibromatosis in female child. urology. 1991;37:337-9. 2. rink rc, mitchell me. genitourinary neurofibromatosis in childhood. j urol. 1983;130:1176-9. 3. yüksel h, odabaşi ar, kafkas s, onur e, turgut m. clitoromegaly in type 2 neurofibromatosis: a case report and review of the literature. eur j gynaecol oncol. 2003;24:447-51. 4. haddad hm, jones hw jr. clitoral enlargement simulating pseudohermaphroditism. ama j dis child. 1960;99:282-7. 5. kaneti j, lieberman e, moshe p, carmi r. a case of ambiguous genitalia owing to neurofibromatosis-review of the literature. j urol. 1988;140:584-5. 6. thomas wj, bevan he, hooper dg, downey ej. malignant schwannoma of the clitoris in a 1-year-old child. cancer. 1989;63:2216-9. an up-to-date meta-analysis of coffee consumption and risk of prostate cancer jia-dong xia1, jie chen2, jian-xin xue1, jie yang1, zeng-jun wang1* purpose: results of the association between coffee consumption (cc) and the risk of prostate cancer (pc) are still controversy. based on published relevant studies, we conducted an up-to-date meta-analysis to investigate this issue. materials and methods: the protocol used in this article is in accordance with the prisma checklist. eligible studies were screened and retrieved by using pubmed and embase as well as manual review of references up to july 2016. we calculated the pooled relative risk (rr) with 95% confidence interval (ci) with random effect models. the dose-response relationship was assessed by generalized least-squares trend estimation analysis. results: totally, we included twenty-eight studies (14 case-control and 14 cohort studies) on cc with 42399 pc patients for the final meta-analysis. no significant association of pc was found for high versus non/lowest cc, with rr = 1.07 (95% ci: 0.96-1.18). in subgroup meta-analysis by study design, there were no significant positive associations between cc and pc in case-control studies (rr = 1.19, 95% ci: 1.05-1.35) or in the cohort studies (rr = 0.97, 95% ci: 0.84-1.12). additionally, rr with different quality of studies were respectively 1.15 (95% ci: 0.99-1.34) and 1.28 (95% ci: 1.03-1.58) for high and low quality in the case-control studies; while were respectively 1.02 (95% ci: 0.88-1.20) and 0.81 (95% ci: 0.57-1.14) in the cohort studies. when analyzed by geographic area, we found no association between cc and pc, with rr = 1.06 (95% ci: 0.86-1.30) for 10 studies from europe, 1.06 (95% ci: 0.94-1.20) for 13 studies conducted in america; 1.12 (95% ci: 0.70-1.79) for 4 studies from asia. however, in subgroup analysis by subtype of the disease, there was a significant negative (beneficial) association in the localized pc (rr = 0.90, 95% ci: 0.84-0.97), but not for the advanced pc (rr = 0.90, 95% ci: 0.70-1.16). additionally, rr = 0.99 (95% ci: 0.98-0.99) for an increment of one cup per day of coffee intake shows significant association with the localized pc. conclusion: our results indicate that cc has no harmful effect on pc. on the contrary, it has an effect on reducing the localized pc risk. further prospective cohort studies of high quality are required to clarify this relationship. keywords: prostate cancer; coffee consumption; dose-response; stage-specific; meta-analysis. introduction since the introduction of prostate specific antigen testing, the rate of men diagnosed with prostate cancer (pc) has increased, which makes pc the most frequently diagnosed tumor and the second leading cause of death from cancer in men(1). in general, the incidence of pc in western countries is approximately six-fold higher than that of non-western countries. some of this discrepancy may be caused by increased screening, but it has been hypothesized that differences in dietary intake may also account for it, though much of the research has no explicit conclusions(2-4). coffee is one of the most widely consumed beverages in the world. it is a complex chemical mixture that contains many compounds, which have been suggested to have potential genotoxic, mutagenic and anti-mutagenic activities in lower organisms(5). coffee is also a main source of dietary methylxanthines, e.g. caffeine(6). it has been reported that caffeine has obvious effects on a variety of physiologic, cellular and molecular systems, which is fundamental in basic and clinical research(7). since the 1980s, many epidemiologic studies have es1department of urology, the first affiliated hospital of nanjing medical university, nanjing, china. 2department of obstetrics and gynecology, nanjing drum tower hospital, nanjing medical university, nanjing, china. *correspondence: department of urology, the first affiliated hospital of nanjing medical university, 300 guangzhou road, nanjing, china. e-mail: zengjunwang2002@sina.com. received august 2016 & accepted july 2017 timated the association between coffee consumption (cc) and pc risk with inconsistent results. so far, meta-analyses have been conducted on this issue, yet with opposite conclusions(8-10). however, most of them were methodologically defective—neither of them carried out meta-regressions to examine dose-response analysis, nor did they include all the published studies available at the time of their compilations(11). furthermore, some large prospective cohort studies with high quality have examined the association between cc and pc risk as well as stage-specific (localized or advanced). additionally, we used multiple subgroup analysis to assess the association between cc and pc, which is different from the previous meta-analysis, and we used generalized least-squares trend estimation analysis to assess the dose-response relationship, which could complicate the interpretation of the pooled results. therefore, the aim of the present study is to provide a quantitative assessment on this topic, we systematically performed a meta-analysis by summarizing all available data of both case-control and cohort studies, besides, we also conducted the meta-analysis to see the review vol 14 no 05 september-october 2017 4079 coffee consumption and risk of prostate cancer-xia et al. table 1. characteristics of studies included in the meta-analysis of coffee consumption and prostate cancer risk authors study study study cases/ coffee adjusted or/rr nos adjustments (publication year) design country period noncases consumption (95% ci) score all pca local pca advanced pca talamini et al. case-control 1992 (32) hospital based italy 1986 1990 271/685 1 low 1.0 na na 6 age, area of residence, education, and bmi. 2 inter-mediate 1.12 (0.78-1.62) na na 3 high 1.34 (0.93-1.93) na na 0 cups/ 1.00 na 1.00 slattery et al. case-control usa 1983 week 1993 (33) population based 1986 362/685 1-20 cups 0.99 na 1.39 5 age /week (0.68-1.47) (0.67-2.87) >20 cups 1.09 na 1.04 /week (0.75-1.60) (0.47-2.26) gronberg et al. case-control 1959406/1218 0 cups/day 1.00 na na specific food items, smoking 1996 (34) population based sweden 1989 1-2 cups/day 1.77 na na habits and alcoholic (0.65-5.09) 7 consumption 3-5 cups/day 1.99 na na (0.78-5.46) 6-9 cups/day 1.91 na na (0.73-5.30) key et al. case-control 1997 (35) population based england 1989328/328 0 cups/day 1.00 na na 7 energy intake 1992 1 cups/day 0.92 (0.60-1.42) na na 2 cups/day 1.41 (0.89-2.21) na na ≥ 3 cups/day 0.94 (0.59-1.51) na na jain et al. case-control 1998 (36) population based canada 1989617/636 0 g/day 1.00 na na 6 age and total energy intake 1993 0-500 g/day 0.84 (0.58-1.22) na na > 500 g/day 0.97 (0.65-1.44) na na hsieh et al. case-control greece 19941999 (37) hospital based 1997 320/246 0 cups/day 1.00 na na 5 age, height, bmi, < 1 cups/day 0.38 and years of schooling (0.15-0.99) na na 1-2 cups/day 0.72 (0.35-1.45) na na 2-3 cups/day 0.57 (0.29-1.12) na na > 3 cups/day 1.15 (0.53-2.47) na na villeneuve et al. case-control 1999 (19) population based canada 19941623/1623 0 cups/day 1.0 na na 6 age, province of residence, 1997 < 1 cups/day 0.8 race, years since quitting (0.6-1.1) na na smoking, cigarette pack-years, 1-4 cups/day 1.0 alcohol, grains (0.7-1.3) na na ≥4 cups/day 1.1 (0.8-1.5) na na sharpe et al. case-control 2002 (37) population based canada 1979399/476 0 1.00 na na age, ethnicity, respondent 1985 drinks/day status, family income, bmi, 1-2 1.1 na na cumulative cigarette smoking, drinks/day (0.6-1.9) 5 alcohol consumption 3-4 1.1 na na drinks/day (0.6-1.9) ≥ 5 0.9 na na drinks/day (0.5-1.7) chen et al. case-control 2005 (38) hospital based china 1996237/481 no 1.00 na na 6 age and bmi 1998 yes 1.88 (1.07-3.30) na na gallus et al. case-control italy 1991219/431 1st tertile 1.0 na na 5 age, study center, 2007 (39) hospital based 2002 2nd tertile 1.3 (0.8-2.1) na na education, occupational 3rd tertile 1.9 (1.2-3.0) na na physical activity at 30 –39 years, bmi, family history, and total energy intake ganesh et al. case-control 1999 no 1.0 na na 5 age, religion and education 2011 (40) hospital based india 2001 123/167 yes 1.3 (0.6-2.7) na na review 4080 deneo-pellegrini case-control et al. hospital based uruguay 1996 tertile i 1.0 na na 5 age, residence, urban/rural 2012 (41) 2004 326/652 tertile ii 1.54 na na status, education, family (0.91-2.59) history of prostate cancer tertile iii 1.37 na na among first degree relatives, (0.82-2.29) bmi and total energy intake geybels et al. case-control usa 2002 ≤ 1/week 1.0 1.0 1.0 age,race, 2013 (22) population-based 2005 892/863 2-6/week 1.22 1.25 1.01 first-degree family history (0.88-1.69) (0.89-1.76) (0.55-1.83) of prostate cancer, smoking 1 /day 1.13 1.07 1.27 status, and history of prostate (0.84-1.51) (0.97-1.47) (0.77-2.11) 6 cancer screening 2-3 /day 1.16 1.13 1.23 (0.90-1.50) (0.86-1.49) (0.78-1.61) ≥ 4/day 1.16 1.12 1.33 (0.82-1.63) (0.78-1.93) (0.74-2.38) wilson et al. case-control sweden 2001 < 1 1.00 1.00 1.00 2013 (18) populationbased 2002 1499/1112 cup/day age, region, smoking, bmi, 1-<2 0.97 0.88 0.70 education, and intake of cups/day (0.62-1.52) (0.59-1.31) (0.40-1.23) calcium, zinc, and total energy 2-<4 0.98 0.98 0.83 cups/day (0.65-1.49) (0.71-1.35) (0.53-1.29) 7 4-5 1.06 1.01 1.02 cups/day (0.69-1.62) (0.72-1.42) (0.64-1.62) > 5 0.97 0.89 0.73 cups/day (0.60-1.57) (0.59-1.35) (0.41-1.30) jacobsen et al. cohort norway 19671986 (13) 1969 205/13664 ≤2 cups/day 1.00 na na age, residence, 3-4 cups/day 0.83 na na cigarette smoking (0.59-1.15) 6 5-6 cups/day 0.78 na na (0.53-1.15) ≥7 cups/day 0.74 na na (0.47-1.25) nomura et al. cohort usa 1965108/7355 0 cups/day 1.00 na na 8 age 1986 (14) 1968 1-2 cups/day 1.21 na na (1.02-1.43) 3-4 cups/day 1.06 na na (0.88-1.26) >5 cups/day 1.43 na na (1.20-1.69) severson et al. cohort usa 1965174/7999 ≤1 time 1.00 na na 8 age 1989 (42) 1978 /week 2-4 times 0.96 na na /week (0.39-2.37) ≥5 times/ 0.92 na na week (0.59-1.44) hsing et al. cohort usa 19661990 (43) 1986 149/17633 ≤3 cups/day 1.00 na na 6 age 3-4 cups/day 0.8 na na (0.6-1.2) ≥5 cups/day 1.0 na na (0.6-1.6) marchand et al. cohort usa 19751994 (44) 1980 198/20316 1 quantile 1.0 na na 8 age, ethnicity and income 2 quantile 0.9 (0.6-1.4) na na 3 quantile 1.2 (0.8-1.8) na na 4 quantile 1.1 (0.7-1.7) na na stensvold et al. cohort norway 1977 ≤2 cups/day 1.00 na na age, cigarettes per day and 1994 (45) 1982 177/21735 3-4 cups/day 0.3 na na county of residence (0.13-1.10) 7 5-6 cups/day 0.6 na na (0.30-1.71) ≥7 cups/day 0.4 na na (0.23-1.44) ellison et al. cohort canada 1970145/3400 0 ml/day 1.00 na na 7 five-year age group and wine 2000 (46) 1993 0-250 ml/day 1.14 na na consumption (0.66-1.97) 250-500 1.42 na na ml/day (0.80-2.52) 500-700 1.35 na na ml/day (0.77-2.61) > 750 1.42 na na ml/day (0.77-2.61) iso et al. cohort japan 19882007 (47) 1997 161/43500 ≤1-2/month 1.00 na na 8 age and area of study 1-4/week 0.96 na na (0.48-1.92) 1/day 1.19 na na (0.71-1.97) ≥2/day 1.13 (0.73-1.75) na na coffee consumption and risk of prostate cancer-xia et al. vol 14 no 05 september-october 2017 4081 nilsson et al. cohort sweden 1992653/32425 < 1 occ/day 1.00 na na 8 age, bmi, smoking, education and 2010 (20) 2007 1-3 occ/day 0.92 na na recreational physical activity (0.70-1.21) ≥4 occ/day 1.03 na na (0.77-1.38) wilson et al. cohort usa 19865035/47911 none 1.00 1.00 1.00 8 2011 (15) 2006 < 1 cup/day 0.94 1.01 0.81 (0.85-1.05) (0.88-1.15) (0.64-1.02) 1-3 cups/day 0.94 0.99 0.75 race, height, bmi, vigorous (0.86-1.04) (0.87-1.12) (0.60-0.93) physical activity, smoking, 4-5 cups/day 0.93 1.02 0.73 diabetes, family history of (0.83-1.04) (0.88-1.18) (0.56-0.95) prostate cancer, multivitamin ≥6 cups/day 0.82 0.93 0.47 use, intake of processed (0.68-0.98) (0.74-1.16) (0.28-0.77) meat, tomato sauce, calcium, alpha linolenic acid, supple mental vitamin e, alcohol intake and history of psa testing shafique et al. cohort england 1970318/6017 0 cups/day 1.00 na na age at screening, cholesterol, 2012 (21) 2007 1-2 cups/day 0.84 8 systolic blood pressure, bmi, (0.60-1.21) na na alcohol intake, tea ≥3 cups/day 0.74 consumption, smoking status, (0.47-1.16) na na social class discacciati et al. cohort sweden 19983801/ 0 na 1.13 0.96 2013 (23) 2010 44613 (0.93-1.27) (0.68-1.35) < 1cup/day na 1.00 0.97 tea, alcohol, bmi, personal (0.86-1.16) (0.78-1.21) history of diabetes, family 1-3 cups na 1.00 1.00 history of pca, smoking /week status, physical activity education and total energy 4-5 cups/day na 0.93 0.95 intake (0.83-1.03) (0.79-1.14) ≥ 6 cups/day na 0.81 0.87 (0.69-0.96) (0.66-1.16) bosire et al. cohort usa 199523335/ 0 cup/day 1.00 1.00 1.00 8 2013 (17) 2007 288391 < 1 cup /day 1.03 1.03 1.10 (0.98-1.08) (0.97-1.09) (0.95-1.28) age, race, height, bmi, 1 cup /day 1.00 1.01 0.97 physical activity, smoking, (0.95-1.06) (0.95-1.07) (0.83-1.14) history of diabetes, family 2-3 cups/day 1.00 1.01 0.98 history of prostate cancer , (0.96-1.05) (0.96-1.07) (0.86-1.12) psa testing, intakes of toma 4-5cups/day 1.00 0.99 1.08 to sauce, alpha-linolenic acid, (0.94-1.06) (0.93-1.06) (0.92-1.27) and total energy intake ≥ 6 0.94 0.92 1.15 cups/day (0.87-1.02) (0.84-1.01) (0.92-1.43) li et al. cohort japan 1995318/18853 0 cups/day 1.0 1.0 1.0 7 age, education level, bmi, 2013 (16) 2005 < 1 cup/day 0.81 0.89 1.26 time engaging in sports or (0.61-1.07) (0.48-1.65) (0.73-2.16) exercise, marital status, time 1-2 cups/day 0.73 1.16 0.73 status, family history of (0.53-1.01) (0.61-2.20) (0.38-1.39) cancer, consumption of ≥3 cups/day 0.63 0.54 0.90 spent walking, smoking (0.39-1.00) (0.18-1.66) (0.38-2.12) tea, job status, daily total energy intake, passive smoking, alcohol drinking, daily consumption of miso soup coffee consumption and risk of prostate cancer-xia et al. abbreviations: or/rr, odd ratio/rate ratio; c, confidence interval; nos, newcastle-ottawa scale; bmi, body mass index (kg/m2); occ, occasion; psa, prostate specific antigen; na, not available, pca; prostate cancer review 4082 relationship of cc with stage-specific prostate cancer incidence. material and methods publication search we systematically reviewed the literature by electronically searching pubmed and embase up to july 2016. the search terms included the keywords “coffee”, “caffeine”, “diet”, combined with “prostate cancer”, “prostate carcinoma”, “prostate neoplasm”. all of the references in the relevant articles were screened for any further articles that were not identified in the initial search. two reviewers (jx and jc) independently searched and extracted the data according to the defined inclusion and exclusion criteria. inclusion and exclusion criteria inclusion criteria were as follows:(1) studies had a case-control or cohort design;(2) the outcome of interest was primary prostate cancer;(3) the exposure of interest was cc; and(4) relative risk (rr) and their 95% confidence intervals (ci) could be extracted or calculated from relevant articles. exclusion criteria were as follows:(1) incomplete data availability;(2) duplicated or updated data;(3) non-inclusion of their own data, such as reviews, comments, editorials, letters and congress. data extraction two reviewers (jx and jc) independently extracted and recorded the following information: first author’s surname, year of publication, study design, study country, follow-up period or study period, number of participants (cases or controls/subjects), the exposure to cc, the odds ratios (or, from case-control studies) or rate ratios (rr, from cohort studies) estimated with 95% ci for each category of cc of all pc and stage-specific (localized or advanced), and variables adjusted for in the analysis . if 95% ci were not provided, but the numbers of cases and controls (or person-time) in exposure categories were reported(12-14), these data were used to calculate the standard error of the crude rr, and then approximate ci for the reported adjusted rr. for several rrs from age-adjusted model to different multivariate models(15-23), we chose the rrs from multivariate models with the most complete adjustment for potential confounders. disagreements were resolved through consensus with a third reviewer (xj). quality assessment of included studies two independent reviewers (jx and jc) systematically performed the methodological quality assessment of selected studies according to the newcastle-ottawa scale (nos)(24). the quality criteria assessed were as follows: the representative and applicability of study groups, comparability of the groups, evaluation of outcomes, and adequacy of follow-up. since standard criteria have not been stated, we defined scores as ≥6 for case-control table 2. summary relative risk estimates and 95% for coffee consumption and prostate cancer risk. study no. of studies no. of cases relative risk (95% ci) p value heterogeneity test q p i2 (%) highest vs. lowest all studies 28 42399 1.07 (0.96-1.18) 0.228 54.40 0.001 52.2 study design case-control studies 14 7622 1.19(1.05-1.35) 0.005 12.12 0.518 0.0 cohort studies 14 34777 0.97(0.84-1.12) 0.668 34.10 0.001 64.8 hospital based case-control studies 6 1496 1.50 (1.21-1.85) 0.000 2.72 0.743 0.0 population based case-control studies 8 6126 1.06 (0.91-1.23) 0.445 2.54 0.924 0.0 study geographic area europe 10 4396 1.06 (0.86-1.30) 0.586 16.60 0.055 45.8 america 13 33363 1.06 (0.94-1.20) 0.361 28.04 0.005 57.2 asia 4 839 1.12 (0.70-1.79) 0.635 9.03 0.029 66.8 methodological quality of study case-control study high quality 8 5873 1.15 (0.99-1.34) 0.060 6.58 0.474 0.0 low quality 6 1749 1.28 (1.03-1.58) 0.026 4.96 0.421 0.0 cohort study high quality 8 6647 1.02 (0.88-1.20) 0.781 24.30 0.001 71.2 low quality 5 994 0.81 (0.57-1.14) 0.221 7.46 0.114 46.4 stage-specific localized pca 6 26064 0.90 (0.84-0.97) 0.006 4.07 0.539 0.0 case-control studies 2 1745 1.01 (0.77-1.33) 0.922 0.67 0.413 0.0 cohort studies 4 24319 0.90 (0.83-0.97) 0.004 2.65 0.448 0.0 advanced pca 7 5304 0.90 (0.70-1.16) 0.399 12.83 0.046 53.2 case-control studies 3 584 0.99 (0.69-1.44) 0.976 2.07 0.356 3.2 cohort studies 4 4720 0.84 (0.58-1.21) 0.340 10.71 0.013 72.0 increment of 1 cup/day all studies 19 36985 0.99 (0.98-1.00) 0.046 56.21 0.542 0.0 study design case-control studies 9 6446 1.01 (0.95-1.06) 0.825 29.97 0.269 3.9 cohort studies 10 30539 0.99 (0.98-1.00) 0.012 23.12 0.810 0.0 stage-specific localized pca 6 26064 0.99 (0.98-0.99) 0.003 15.4 0.800 0.0 case-control studies 2 1745 1.01 (0.96-1.06) 0.680 2.76 0.907 0.0 cohort studies 4 24319 0.99 (0.98-0.99) 0.002 11.86 0.539 0.0 advanced pca 7 5304 0.98 (0.94-1.02) 0.410 27.62 0.231 0.2 case-control studies 3 584 1.02 (0.96-1.08) 0.539 6.74 0.664 0.0 cohort studies 4 4720 0.97 (0.91-1.02) 0.263 19.20 0.117 2.6 abbreviations: ci, confidence interval; pca, prostate cancer coffee consumption and risk of prostate cancer-xia et al. vol 14 no 05 september-october 2017 4083 studies and ≥8 for cohort studies being of high methodological quality, otherwise being of low quality(8). statistical analysis study-specific log (rate ratio) for cohort studies and log (or) for case-control studies were combined to compute a pooled rr and its 95% ci for the highest versus non/lowest category of coffee consumption from each study with the dersimonian and larid random effects models(25). the heterogeneity of effect size among studies was tested by q statistics (p < .10 indicated the presence of heterogeneity), and inconsistency was quantified by i2 statistics (i2 > 50% is considered significant)(26,27). in situations with substantial heterogeneity, the subgroup analysis was used to explore the sources of heterogeneity based on the characteristics of the studies (study design, geographic region, study quality, stage-specific), and a sensitivity analysis was performed to assess the stability of the results. based on the method developed by greenland and longnecker(28,29), we applied generalized least-squares trend estimation analysis to examine dose-response relationship between different categories of coffee intake using the random-effects model. for all studies, the median cups of cc for each category were calculated as the average consumption by assigning the midpoint of upper and lower boundaries. if the upper bound was not provided, we assumed that the average consumption had the same amplitude of intake as the preceding category. this method requires that the distributions of case patients and control subjects (or person-time) and the risk estimates with their variance estimates for at least three quantitative exposure categories, so studies providing no cutoff or median of coffee intake in each category, or reporting only two categories of exposure, or lacking the number of cases and non-cases in each exposure category were excluded. for studies using units or milliliter other than cups for consumption, we roughly converted them into cups per day as a standard measure (1 time/occasion/drink=1 cup, 125 ml= 1 cup, 250 g =1 cup). ultimately, we evaluated the possibility of publication bias through a funnel plot and with the begg’s and egger’s tests(30,31). a two-tailed p < .05 was considered statistically significant. all statistical analyses were performed with stata (version 11.0; stata crop). results study characteristics a total of 114 potentially eligible studies were initially identified, most of which were excluded because the exposure or endpoint was not relevant to our analysis. the study identification and selection progression were summarized in figure 1. finally, we identified 28 eligible studies in our meta-analysis,(12-23,32-47) including 14 case-control studies and 14 cohort studies. the former included 7622 cases of pc and 9603 controls, while the latter involved 34777 cases of pc and 573812 participants. particularly, one study only reported the stage-specific rr but not all the pc(23). of these 28 studies, 13 were conducted in america (usa, canada and uruguay), 11 in europe (sweden, england, greece, italy and norway) and 4 in asia (china, india and japan). among the case-control studies, 6 used hospital-based controls and 8 applied population-based controls. the rrs of most studies were adjusted for age or body mass index (bmi, kg/m2), which are the most likely confounder of relationship between coffee intake and pc. general characteristics in the studies included in this meta-analysis were shown in table 1. high versus non/lowest coffee consumption figure 2 and table 2 present the multivariable-adjusted rrs in each study and the pooled rr of pc for the highest versus non/lowest categories of coffee intake. the combined summary rr from all the studies was 1.07 (95% ci: 0.96-1.18, p = .228). in the subgroup analysis by study design, the summary rrs from case-control studies and cohort studies were respectively 1.19 (95% ci: 1.05-1.35, p = .005) and 0.97 (95% ci: 0.84-1.12, p = .668). when separating the hospital-based case-control studies from the population-based case-control figure 1. flow diagram of the studies identified in the meta-analysis figure 2. forest plot of case-control and cohort studies assessing the association between high coffee consumption (high versus non/lowest) and prostate cancer risk. horizontal lines indicate 95% confidence interval (ci); diamonds indicate summary relative risk estimate with its corresponding 95% ci. coffee consumption and risk of prostate cancer-xia et al. review 4084 studies, we found an apparent difference between them ((hospital based rr: 1.50 (95% ci: 1.21-1.85, p < .001); population-based rr was 1.06 (95% ci: 0.911.23, p = .445)). based on different geographic regions, the summary rrs were 1.06 (95% ci: 0.86-1.30, p = .586) for the studies conducted in europe, 1.06 (95% ci: 0.93-1.20, p = .361) for the studies performed in america, and 1.12 (95% ci: 0.70-1.79, p = .635) for the studies carried out in asia. according to the quality of studies, the pooled rrs for high quality and low quality were respectively 1.15 (95% ci: 0.99-1.34, p = .060), 1.28 (95% ci: 1.03-1.58, p = .026) in the case-control studies; and respectively 1.02 (95% ci: 0.88-1.20, p = .781), 0.81 (95% ci: 0.57-1.14, p = .221) in the cohort studies. based on the studies, which explored the relationship of cc with stage-specific pc, the meta-analysis showed that the pooled rrs were 0.90 (95% ci: 0.69-1.16, p = .399) in the advanced pc, but 0.90 (95% ci: 0.84-0.97, p = .006) in the localized pc. there was some evidence of heterogeneity among all the studies of cc overall (p = .001, i2 = 52.2%), and the heterogeneity mainly existed in the cohort studies (p = .001, i2 = 64.8%). as the heterogeneity was remarkable, we conducted a sensitivity analysis with any single study omitted in all the studies. the results showed that the pooled rrs and 95% ci changed little, which indicated that the meta-analysis results were stable (figure 3). to explore the source of heterogeneity among the cohort studies, we did the subgroup analysis by characteristics of studies. when stratified by study geographic area and methodological quality of study, the heterogeneity of the cohort studies reduced slightly but not significantly (table 2). dose-response meta-analysis we incorporated nineteen studies (nine case-control studies(12,18,19,22,33-37) and ten cohort studies(13,15-17,20,21,42,44,46,47) into the dose-response analysis of cc and risk of pc (table 2), because other remaining studies reported only 2 quantitative exposure categories (38,40), or did not provide cutoff of coffee intake in each category (32,39,41,44), or did not reveal the number of cases and non-cases in each exposure category(41,43). there was marginally statically significant departure from linearity (p = .049). the pooled rr for a one cup per day increment in cc was 0.99 (95% ci: 0.981.00), which was evident for cohort studies (rr = 0.99, 95% ci: 0.98-1.00, p = .012) , but not significant in the case-control studies (rr = 1.01, 95% ci: 0.95-1.06, p = .825). when grouped by stage-specific prostate cancer, the pooled rr for studies conducted in localized pc was 0.98 (95% ci: 0.98-0.99, p = .003), but 0.98 (95% ci: 0.94-1.02, p = .410) in advanced pc. publication bias no evidence of publication bias was found from either visualization of funnel plot, begg’s test (p = .632), or egger’s test (p = .229) (figure 4). there was no significant indication of publication bias for the sixteen studies, which were included in the dose-response analysis (begg’s p = .629; egger’s p = .152). discussion based on the published results from 14 case-control and 14 cohort studies, our meta-analysis assessed the potential association between cc and pc. the overall pooled rr of pc for high versus non/lowest coffee consumption was 1.07 (95% ci: 0.96-1.18), which indicates that cc is not associated with an increased risk of pc. stratified by study design, the meta-analysis showed cc increased the risk of pc in the case-control studies, but did not increase in the cohort studies. the discrepancy of the results between case-control and cohort studies may be explained with potential biases of case-control studies, such as selection bias and recall bias. additionally, it is worth noting that when subgrouped by the control characteristics or quality of case-control studies, there was not an increased risk of pc in population-based or high quality of case-control studies despite its presence in hospital-based and low quality of case-control studies. generally, population-based case-control studies are considered more reliable because their subjects are more representative as controls than those of hosfigure 3. the sensitivity analysis diagram for each study used to assess the relative risk estimates for coffee consumption and prostate cancer risk in the cohort studies. figure 4. publication bias in all the studies. both visualization of funnel plot and begg’s test (p = .632), or egger’s test (p = .229) test indicated no publication bias in the studies included in the meta-analysis. coffee consumption and risk of prostate cancer-xia et al. vol 14 no 05 september-october 2017 4085 pital-based case-control studies. as we know, the design and methodology of studies could affect the efficacy outcome differently. hence, these results above suggested that there is no causal relationship between coffee drinking and increased pc. on the contrary, the dose-response relationship analysis showed that there was an inverse dose-response relationship between a one cup per day increment and decreased risk of pc (p = .049), which was more significant in cohort studies (p = .012). more interestingly, in the subgroup of stage-specific pc of both high versus non/lowest cc and dose-response meta-analysis, we found that cc could substantially reduce the localized, rather than advanced prostate cancer incidence. therefore, based on the results of our analyses, we could conclude that cc could not increase the incidence of pc, but reduce the risk of localized prostate cancer. compared with the previous meta-analyses, our meta-analysis has some advantages. firstly, it is well known that the inclusiveness of all relevant studies for the meta-analyses is very important. in park et al. ’ meta-analysis (8), they totally included twelve studies (eight case-control studies and four cohort studies) and found rr of 1.16 (95% ci: 1.01–1.33) for highest versus lowest coffee drinkers. in another one, it only contained five prospective cohort studies and shows an inverse association of pc risk with high coffee intake (rr 0.79, 95% ci: 0.61–0.98)(9). recently, there is another meat-analysis demonstrating a borderline significant inverse association between cc and pc risk based on cohort studies. altogether, these results are inconsistent and confusing. we include all the published studies available as possible as we could, and the number of total cases included in the meta-analysis was more massive (14 case-control and 14 cohort studies). secondly, because cutoffs for the highest coffee categories varied from each study, the dose–response relationship analysis is especially important. the dose– response relationship is to describe the change in effect on an organism caused by differing levels of exposure (or doses) to a stressor after a certain exposure time, and it is critical for determining “safe” and “hazardous” levels and dosages for drugs, potential pollutants, and other substances to which humans or other organisms are exposed(48). we did a dose-response meta-analysis, which was not carried out specially in either of the previous meta-analyses. thirdly, as we know, publication bias is much of concern in a meta-analysis, and there was little evidence of publication bias in our meta-analysis. finally and the most importantly, to the best of our knowledge, in the meta-analysis, we first evaluate subgroups based on the stage of pc, finding that there is an inverse association with the incidence of localized rather than advanced pc. coffee is produced by infusing ground, roasted coffee beans, with the most common forms being coffea arabica and coffea canephoria var. robusta(49). coffee contains more than a thousand different chemicals. while it has caffeine and methylglyoxal with potentially carcinogenic effects, some other chemicals have been suggested to have potentially chemo-preventive effects, such as chlorogenic, caffeic acids, diterpenes cafestol and kahweol(7,50-52). our analyses have found that coffee drinking could reduce the risk of localized but not advanced pc. this is an investing finding. it has been reported that other environmental agents, like chemical, physical or microbial agents, could enhance or suppress coffee on the carcinogenic effect, depending on the carcinogen it is used with, the type of host cell, and the stage of cell cycle in which it is introduced(53). it is hypothesized that coffee drinking may be associated with increased levels of sex hormone-binding globulin (shbg) and total testosterone levels, which might play a role in pc(54). however, a recent randomized trial showed that consumption of caffeinated coffee had no evident effect on shbg levels, but significantly increased total testosterone and decreased both total and free estradiol in men(55). at the same time, cc is also associated with reductions in the levels of inflammation-related molecule, which have an important role in prostatic carcinogenesis(56). furthermore, an animal study showed that caffeine treatment increased the percentage of mitotic tumor cells undergoing lethal mitosis, which indicated oral administration of caffeine might be an effective strategy for the prevention of pc progression(57). despite these advantages, there are still some limitations. firstly, heterogeneity among studies may have been involved because of methodological differences among studies, including different methods of coffee preparation, misclassification of cc, differences in serving size and brew strength. furthermore, the individual rr estimate included in our meta-analysis was adjusted for different covariates in the different studies. nevertheless, the results did not change substantially after the sensitivity analysis. secondly, unfortunately, because of the small number of studies investigating the relationship between cc and subtypes of pc, our meta-analysis could only evaluate subgroups based on tumor stage, but not on gleason grade or prostate cancer-specific mortality. lastly, most of the studies in this meta-analysis were conducted in europe, the united states, canada and japan; thus the data should be extrapolated to other populations with caution. conclusions in summary, although data from low quality case-control studies suggest that coffee is a risk factor for pc, there is no association between cc and increased pc based on the results of high quality of case-control studies and cohort studies and dose-response analysis. on the contrary, according to the stage-specific prostate cancer, subgroups analysis showed that cc could be a protective exposure that reduces the localized pc risk. however, prospective studies, focusing on more detailed results, including subtypes of coffee, taking a broad range of confounders into account, are required to clarify this relationship. acknowledgments this work was supported in part by the project of the national 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introduction: our aim was to evaluate the natural behavior, growth pattern, morphology, and specific features of human bladder smooth muscle cells (hbsmcs) on two different matrixes, including human amniotic membrane (ham) and collagen. materials and methods: the hbsmcs were obtained from 6 children with primary vesicoureteral reflux undergoing open antireflux surgery, and they were isolated from the anterior wall of the bladder. the specimens were cultured on a tissue culture plate of bovine dermal collagen serving as control and on decellularized ham. histological, transmission electron microscopy, and immunocytochemical examinations were done, thereafter. results: on ham, very few hbsmcs slowly migrated from explant tissue on the 7th day of culture. all the cells were placed at the same direction, and in some parts, formed multilayer. after 35 to 40 days, the confluency rate was 75% and the cells were orderly arranged. on collagen, cell migration from explant culture took place as rapidly as the 3rd to 4th day of culturing. on days 30 to 40, the confluency rate was 100%. immunocytochemical staining was positive for anti-actin and antidesmin antibodies. on transmission electron microscopy, cell organelles of hbsmcs exhibited the same features of the natural smooth muscle cells. they were tightly attached to each other and the underlying layer basement membrane. conclusion: a well-designed growth pattern of hbsmcs on ham with abundant cell-to-cell adhesions encourages us to use it as a competent tissue for reconstruction of relatively damaged or diseased bladders. undoubtedly, further clinical studies should be performed to replicate our results. urol j. 2009;6:283-8. www.uj.unrc.ir keywords: cell culture techniques, bladder, smooth muscles, amnion 1department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran 3department of stem cells, royan institute, tehran, iran 4department of infectious diseases and tropical medicine, shahid beheshti university of medical sciences, tehran, iran corresponding author: farzaneh sharifiaghdas, md urology and nephrology research center, no 103, 9th boustan st, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2277 0954 e-mail: fsharifiaghdas@yahoo.com received june 2009 accepted august 2009 introduction congenital abnormalities, cancer, trauma, infection, inflammation, iatrogenic injuries, and several other conditions may lead to genitourinary organ damage or loss, requiring eventual reconstruction. (1) finding a suitable material to reconstruct the genitourinary tract has been a challenging task. over the past few decades, the use of several bladder-wall substitutes has been attempted with both synthetic and organic materials.(2) the first application of a free tissue graft for bladder replacement was reported by neuhof in 1917, when fascia was used to augment bladders in dogs. (3) since that first report, numerous other free graft materials have been culturing human bladder smooth muscle—sharifiaghdas et al 284 urology journal vol 6 no 4 autumn 2009 used experimentally and clinically including the bladder allograft, pericardium, dura, placenta, peritoneum, and omentum.(4-9) generally, 3 classes of biomaterials have been utilized for engineering genitourinary tissues: naturally derived materials, acellular tissue matrices, and synthetic polymers.(10) most of the attempts have usually failed due to either mechanical, structural, functional, or biocompatibility problems.(2) our goal in present study is to evaluate and compare the natural behaviors, growth pattern, morphology, and specific features of human bladder smooth muscle cells (hbsmcs) on 2 different matrixes including human amniotic membrane (ham) and collagen, in order to achieve a suitable, costeffective, abundant matrix for further studies and reconstruction of the bladder. materials and methods harvesting and preparation of bladder cells bladder smooth muscle cells were obtained from 6 children with a mean age of 6 years old (range, 2 to 10 years) with primary vesicoureteral reflux undergoing open antireflux surgery. they had no evidence of bladder dysfunction on history, physical examination, imaging studies, and urodynamic studies. informed consent was obtained from the parents before the operation. at the time of operation, a 0.5 × 0.5-cm fullthickness biopsy of the anterior wall of the bladder was obtained. the adherent perivesical fat and urothelium were removed with fine scissors. the sample was immediately put in the cold phosphate-buffered saline (pbs; gibco, cat no 21600-051) containing penicillin, 100 u/ml; streptomycin, 100 μg/ml (gibco, cat no 15070); and ofloxacin, 0.3% (0-8757, sigmaaldrich, st louis, mo, usa), and transported to the laboratory. after 2 times washing of the specimen with pbs, the muscle cubes were divided into 1 × 1-mm pieces, washed again with pbs, and put in a humidified incubator at 37°c with 5% co2. the cells were reefed with fresh medium m199 (gibco, cat no 31150), 10% fetal bovine serum (gibco, cat no 10270-106), and l-glutamine, 2 mm (gibco, cat no 25030), 2 days thereafter, and subsequently, on alternate days. passaging and subculturing of the cells was performed as per routine. the hbsmcs were cultured on a tissue culture plate of bovine dermal collagen (nalgene, cat no 5409), serving as control and on decellularized ham as test. preparation of decellularized human amniotic membrane the sample of ham was harvested from seronegative maternal donors. under sterile conditions, the placental membrane was thoroughly washed and placed in pbs containing penicillin/streptomycin (gibco-invitrogen, grand island, ny, usa) and ofloxacin (o-8757, sigma-aldrich, st louis, mo, usa). then, to obtain a decellularized membrane, the epithelial cells were isolated by trypsinization (trypsin ethylenediamine tetraacetic acid, gibco, cat no 25300). immunocytochemistry for immunostaining, the hbsmcs were washed twice with pbs and fixed with 4% paraformaldehyde for 24 hours at 4ºc. these cells were permeabilized and blocked in pbs containing 0.2% triton x-100 (sigma-aldrich, st louis, mo, usa; cat no t8787) and 10% goat serum for 10 minutes and 30 minutes, respectively. thereafter, the hbsmcs were incubated in primary antibody diluted in 0.5% bovine serum albumin at 37ºc for 1 hour. the antibodies used in this study were desmin (sigma, cat no d1033) and α-smooth muscle actin (sigma, cat no a5228). at the end of the incubation time, the cells were washed twice with pbs plus 0.05% tween 20 and incubated with the fluorescence isothiocyanate-conjugated antimouse immunoglobulin (fitc, chemicon, ap308f and abcam, ab6785-1), respectively diluted in 0.5% bovine serum albumin for 60 minutes at 37ºc. after washing twice with pbs plus 0.05% tween 20, the specimens were examined under fluorescence microscope (bx51, olympus, japan). culturing human bladder smooth muscle—sharifiaghdas et al urology journal vol 6 no 4 autumn 2009 285 transmission electron microscopy for transmission electron microscopy, the specimens were fixed using 2.5% glutaraldehyde in 0.1-m pbs (ph, 7.4) for 2 hours. after washing with pbs, they were postfixed with 1% osmium tetroxide for 1.5 hour, again washed in pbs, dehydrated in an acetone series, and then, embedded in epoxy resin. after resin polymerization, sections of approximately 50 nm were cut and double-stained with uranyl acetate and lead citrate. electron micrographs were taken using a zeiss em 900 transmission electron microscope (carl zeiss, oberkochen, germany). (11) results culture primary cultures of hbsmcs were successfully established and passaged from biopsies obtained before. we did not inspect any abnormal morphologic features or cessation of growth in both matrixes. culturing was continued for 40 days. during this time, we observed growth pattern, confluency rate, and cell morphology, on a daily basis. immunocytochemical staining was performed on each cell strain periodically for the duration of these experiments and in all instances, staining was positive for all strains utilized. morphological examination and immunocytological staining with desmin and α-smooth muscles actin antibodies were used to confirm smooth muscle cells phenotype (figure 1). collagen matrix cell migration from explant culture took place as rapidly as the third to fourth day. all the cells had the typical spindle-shaped morphology with centrally located round-to-oval nuclei. they continued to migrate from the explant tissue till the second week and had a confluency rate of approximately 25% at this time. multiple pseudopodia emanated from the cells until they made contact with the adjacent cells, forming a “hill and valley” appearance. multilayer formation was clearly seen in different parts (figure 2). on the 30th to 40th day, the confluency rate was figure 1. morphological examination and immunocytological staining with desmin antibody was used to confirm smooth muscle cells phenotype (15th day). left, desmine. middle, hoechst. right, merge. figure 2. human bladder smooth muscle cells on collagen matrix. left, migration of smooth muscle cells from explant tissue on the 7th day. middle, multilayer formation of cells on the 14th day. right, final appearance of cells on collagen matrix on the 35th day. culturing human bladder smooth muscle—sharifiaghdas et al 286 urology journal vol 6 no 4 autumn 2009 100%. the cells did not exhibit contact inhibition. human amniotic membrane very few hbsmcs slowly migrated from the explant tissue on the 7th day. the confluency rate after 3 weeks reached to 25% and the cells displayed characteristic spindle-shaped morphology as discussed earlier. surprisingly, all of the cells were placed at the same direction, and in some parts, formed multilayer. after about 35 to 40 days, the confluency rate was 75%, and we had a well-designed sheet of cells (figure 3). transmission electron microscopy cell organelles in the hbsmcs, both on ham and the collagen matrix, exhibited the same features of the natural smooth muscle cells. the hbsmcs on ham had formed 2 to 3 layers in some parts. they were tightly attached to each other and also to the underlying basement membrane layer by cellular junctions. interdigit formation of cells on this matrix was seen as well (figure 4). discussion many injuries may lead to damage or loss of the bladder, necessitating eventual replacement or repair of the organ.(12) these injuries include congenital abnormalities, iatrogenic injuries (eg, vesicovaginal fistula due to a pelvic surgery), cancer, trauma, infection, and inflammations. (1) gastrointestinal segments are frequently used as donor tissue for augmentation cystoplasty or for making urinary reservoirs (pouches) after radical cystectomy for bladder cancer. however, several complications can ensue, such as metabolic disturbances, urolithiasis, increased mucous production, and malignant transformation.(13, 14) these complications made many investigators attempt to use alternative methods, materials, and tissues for replacement or repair of the bladder.(12) many materials have been used for free grafts including the skin, bladder, submucosa, omentum, dura, peritoneum, placenta, seromuscular graft, and small intestinal submucosa. synthetic materials like polyvinyl sponge matrixes, vicryl matrixes, resin-sprayed paper, and silicon were used, as well.(12) however, as mentioned before, these biomaterials have figure 3. human bladder smooth muscle cells on human amniotic membrane matrix. left, primary culture of smooth muscle cells on the 14th day. middle and right, final appearance and orderly arrangement of the cells on the 40th day. figure 4. transmission electron microscopy (35th day). left, the hbsmcs on collagen matrix. middle, the hbsmcs on human amniotic membrane matrix matrix. right, interdigit formation of cells on human amniotic membrane matrix matrix. c, indicates caveola; m, mitochondrion; n, nucleus; v, vacuole; and am, amniotic membrane. culturing human bladder smooth muscle—sharifiaghdas et al urology journal vol 6 no 4 autumn 2009 287 many mechanical, structural, functional, or biocompatibility problems. permanent synthetic materials will have mechanical failure; urinary calculus formation and using degradable materials lead to fibroblast, scaring, graft contracture and reduced reservoir volume.(12) the ideal biomaterial used to engineer a tissue should be biocompatible, since the formation of new tissue would strongly depend on the interaction of the biomaterial with the transplanted or ingrowing cells. the biomaterial should not only be nontoxic to the cells, but also elicit bioactive cellular responses. (15) it must also be capable of controlling the structure and function of the engineered tissue in a predesigned manner, by interacting with transplanted cells and/or the host cells. this ideal biomaterial should be biocompatible, promote cellular interaction and tissue development, and possess mechanical and physical properties.(10) to the present time, a cellular collagen matrix derived from donor bladder submucosa has been successfully used both experimentally and clinically for bladder and urothelial replacement in many centers. it has been described as a useful matrix due to its proper characteristics and ease of processing. nevertheless, it is an expensive matrix, encouraging researchers to look for a cost-benefit medium with the same or even better qualities.(11) in 1993, baskin and colleagues(16) separated and cultured hbsmcs for the first time. since then, several studies have evaluated the morphology and pattern of growth of smooth muscle cells on collagen matrix.(15, 17) according to the good results of these studies in utilizing collagen, we decided to choose it as a control matrix in our study. our hbsmc culture on collagen had promising results. the cell migration from explant tissue, morphology, and growth pattern were all acceptable. we may simply use this semiliquid material (collagen plus hbsmc) for treatment of vesicoureteral reflux or incontinence as a “viable bulking agent”; however, the high cost of collagen serves as a limiting factor. the amniotic membrane comprises the innermost layer of the placenta. amniotic membrane transplantation has been used in many different types of reconstructive surgeries.(18) amniotic membrane transplantation became important because of its ability to diminish the occurrence of adhesions and scarring, its ability to enhance wound healing and epithelialization, and its antimicrobial potential. the amniotic membrane expresses incomplete human leukocyte antigen classes a, b, c, and dr,(19) which may account for the fact that immunological rejection after transplantation has not been observed. in 1940, de rotth used a fresh fetal membrane as a graft for conjunctival surface reconstruction with limited success.(20) sorsby and colleagues reported in 1946 and 1947 the successful use of amniotic membrane as a patch graft in the treatment of acute ocular burns.(21,22) using the ham for urological purposes is a young technique. the ham was successfully used for culturing mouse urothelial cells.(11) the present study, to our knowledge, is the first report of successful hbsmc culturing on ham. the classic spindle-shaped morphology, abundant cell-to-cell and cell-o-basement membrane junctions exactly resembled a normal bladder smooth muscle layer. we could see multilayer and interdigit formation of cells in some parts. surprisingly, hbsmcs cultured on ham were all located at the same direction in good order, but the same cells were randomly arranged on collagen matrix. this may encourage us to use the ham as a competent tissue for reconstruction of relatively damaged or diseased bladders. whether this special arrangement or configuration helps us in achieving better results in vivo remains unclear and needs to be examined in future studies. conclusion a well-designed growth pattern of hbsmcs cultured on ham with abundant cell-to-cell adhesions as well as a tight adherence of cells to the underlying basement membrane were detected. conflict of interest none declared. references 1. atala a. tissue engineering in urology. curr urol rep. 2001;2:83-92. culturing human bladder smooth muscle—sharifiaghdas et al 288 urology journal vol 6 no 4 autumn 2009 2. falke g, caffaratti j, atala a. tissue engineering of the bladder. world j urol. 2000;18:36-43. 3. neuhof h. fascial transplantation into visceral defects an experimental and clinical study. surg gynecol obstet. 1917;25:383. 4. fishman ij, flores fn, scott fb, spjut hj, morrow b. use of fresh placental membranes for bladder reconstruction. j urol. 1987;138:1291-4. 5. kambic h, kay r, chen jf, matsushita m, harasaki h, zilber s. biodegradable pericardial implants for bladder augmentation: a 2.5-year study in dogs. j urol. 1992;148:539-43. 6. kelami a, ludtke-handjery a, korb g, rolle j, schnell j, danigel kh. alloplastic replacement of the urinary bladder wall with lyophilized human dura. eur surg res. 1970;2:195-202. 7. tsuji i, ishida h, fujieda j. experimental cystoplasty using preserved bladder graft. j urol. 1961;85:42-4. 8. moriya k, kakizaki h, murakumo m, et al. creation of luminal tissue covered with urothelium by implantation of cultured urothelial cells into the peritoneal cavity. j urol. 2003;170:2480-5. 9. baumert h, simon p, hekmati m, et al. development of a seeded scaffold in the great omentum: feasibility of an in vivo bioreactor for bladder tissue engineering. eur urol. 2007;52:884-90. 10. atala a. tissue engineering for the replacement of organ function in the genitourinary system. am j transplant. 2004;4 suppl 6:58-73. 11. sharifiaghdas f, hamzehiesfahani n, moghadasali r, ghaemimanesh f, baharvand h. human amniotic membrane as a suitable matrix for growth of mouse urothelial cells in comparison with human peritoneal and omentum membranes. urol j. 2007;4:71-8. 12. atala a, bauer sb, soker s, yoo jj, retik ab. tissueengineered autologous bladders for patients needing cystoplasty. lancet. 2006;367:1241-6. 13. mcdougal ws. metabolic complications of urinary intestinal diversion. j urol. 1992;147:1199-208. 14. soergel tm, cain mp, misseri r, gardner ta, koch mo, rink rc. transitional cell carcinoma of the bladder following augmentation cystoplasty for the neuropathic bladder. j urol. 2004;172:1649-51. 15. pariente jl, kim bs, atala a. in vitro biocompatibility evaluation of naturally derived and synthetic biomaterials using normal human bladder smooth muscle cells. j urol. 2002;167:1867-71. 16. baskin ls, howard ps, duckett jw, snyder hm, macarak ej. bladder smooth muscle cells in culture: i. identification and characterization. j urol. 1993;149:190-7. 17. kropp bp, zhang y, tomasek jj, et al. characterization of cultured bladder smooth muscle cells: assessment of in vitro contractility. j urol. 1999;162:1779-84. 18. trelford jd, trelford-sauder m. the amnion in surgery, past and present. am j obstet gynecol. 1979;134:833-45. 19. akle ca, adinolfi m, welsh ki, leibowitz s, mccoll i. immunogenicity of human amniotic epithelial cells after transplantation into volunteers. lancet. 1981;2:1003-5. 20. de rotth a. plastic repair of conjunctival defects with fetal membranes. arch ophthalmol. 1940;23:522. 21. sorsby a, symons hm. amniotic membrane grafts in caustic burns of the eye: (burns of the second degree). br j ophthalmol. 1946;30:337-45. 22. sorsby a, haythorne j, reed h. further experience with amniotic membrane grafts in caustic burns of the eye. br j ophthalmol. 1947;31:409-18. vol 16 no 03 may-june 2019 312 miscellaneous the epidemiology of symptomatic catheter-associated urinary tract infections in the intensive care unit: a 4-year single center retrospective study renyu ding*, xiaoxia li, xiaojuan zhang, zhidan zhang, xiaochun ma* purpose: catheter-associated urinary tract infection (cauti) occurs frequently in critical illness with significant morbidity, mortality, and additional hospital costs. the epidemiology of symptomatic ward-acquired cauti (within 48 hours of intensive care unit [icu] admission) has not been carefully examined. the objective of our study was to identify the patient characteristics and microbiology of symptomatic cauti in critical illness. materials and methods: a 4-year retrospective observational study (2013-2016) was conducted at a single adult icu with 30 beds in a tertiary hospital in northeast china. the enrolled patients were over 18 years of age and had been diagnosed as having symptomatic cautis in the icu from january 2013 to december 2016. the information of clinicopathological characteristics (such as age, sex, underlying diseases, hospital admission diagnosis, icu admission source, severity of illness, duration of urinary catheterization, use of antibiotics, duration of icu stay, and icu mortality) was recorded in an electronic database by senior clinicians who were blinded to the study purpose and design. microbiological data were retrieved from the computerized hospital database. results: between january 2013 and december 2016, 4115 patients were admitted to the icu. ninety-eight symptomatic cauti cases were enrolled in this study, including 29 patients who had ward-acquired cauti and 69 patients who had icu-acquired cauti. patients with ward-acquired symptomatic cauti had significantly shorter overall icu length of stay and shorter urinary catheterization time, and the overall icu mortality was significantly higher in patients who had icu-acquired symptomatic cauti. more third-generation cephalosporins and carbapenems were used prior to cauti in the patients with icu-acquired symptomatic cauti. escherichia coli and acinetobacter baumannii were the most common bacteria causing ward-acquired and icu-acquired cauti, respectively. there were a higher number of cases of non-candida albicans infections in patients with icu-acquired symptomatic cauti than in patients with ward-acquired symptomatic cauti. conclusion: clinical characteristics, microbiological characteristics, and prognosis were different between ward-acquired and icu-acquired symptomatic cauti. patients with icu-acquired symptomatic cauti had higher overall icu mortality. keywords: catheter-associated urinary tract infections; intensive care unit; critical illness; candiduria; bacteriuria introduction catheter-associated urinary tract infection (cauti) occurs frequently in critical illness with significant morbidity, mortality, and additional hospital costs.(1,2) many studies have been conducted to investigate the epidemiology, surveillance, and prevention of intensive care unit (icu) acquired cauti.(3-5) owing to impaired consciousness and/or systemic inflammation, the diagnosis of cauti can be challenging in critically ill patients.(6,7) the diagnoses of cauti have been different across previous studies.(2) moreover, an observational study was conducted on critically ill patients to determine the epidemiology of bacteriuria and candiduria, but asymptomatic and symptomatic bacteriuria/candiduria could not be differentiated.(8) in contrast, the epidemiology of symptomatic ward-acquired cauti in critical illness (within 48 hours of icu admission) has not been carefully examined. the department of intensive care unit, the first hospital of china medical university, nanjing bei street 155, shenyang 110001, liaoning province, p.r. china. *correspondence: department of intensive care unit, the first hospital of china medical university, nanjing bei street 155, shenyang 110001, liaoning province, p.r. china tel: (+86) 024-83282261, fax: (+86) 024-83282631. e-mail: renyuding@126.com. received november 2017 & accepted april 2018 objective of our study was to identify the patient characteristics and microbiology of symptomatic cauti in critical illness. the differences between icuand ward-acquired cauti, as well as differences between icu-acquired symptomatic bacteriuria and candiduria, were also analyzed. materials and methods study population a 4-year retrospective study was conducted at the first affiliated hospital of china medical university. all adult patients admitted to the selected icus between january 2013 and december 2016 were included in this study. inclusion and exclusion criteria the enrolled patients were over 18 years of age and had been diagnosed as having symptomatic cautis in icu. patients with symptomatic cauti were defined as follows:(1) when a patient who had an indwelling urinary catheter for more than 2 days developed one or more of the following symptoms: fever > 38°c, urgency, frequency, suprapubic tenderness, or dysuria;(2) positive urine cultures containing ≥ 105 colony forming units per ml of no more than two microorganisms; and (3) a clinician diagnosis of cauti in the patient’s record. the exclusion criteria were as follows: (1) patients who were re-admitted to the icu, (2) patients who were transferred from the icu of another hospital, or (3) patients who stayed in the icu longer than 6 months. procedures there has been an electronic database in the icu of our hospital since 2012, and patients who were catheterized upon admission or during their stay in icu were screened daily for the acquisition of cautis. patients diagnosed as having symptomatic cautis were recorded prospectively. in this study, we retrospectively collected the clinical information of patients diagnosed as symptomatic cautis from the electronic database. the clinicopathological characteristics including age, sex, underlying diseases (such as diabetes mellitus, chronic liver disease, chronic renal disease, chronic respiratory disease, chronic cardiovascular disease, and solid tumor), hospital admission diagnosis (such as cardiovascular disease, trauma, sepsis, gastrointestinal/ liver disease, respiratory disease, neurologic disease), and the severity of illness were recorded in an electronic database by senior clinicians who were blinded to the study purpose and design. the duration of urinary catheterization, use of antibiotics, duration of icu stay, and icu mortality were also collected. microbiological data were retrieved from the computerized hospital database. the study was approved by the ethics committee of the first hospital of china medical university for screening, inspection, and data collection of the patients. evaluations acute physiology and chronic health evaluation ii (apache ii) score and sequential organ failure assessment (sofa) score were used to evaluate the severity of illness on icu admission. the icu admission sources were grouped as follows: surgery ward, medical ward, and emergency department. ward-acquired cauti was defined as the first positive urine culture occurring within 48 hours of icu admission, and icu-acquired cauti was defined as the first positive urine culture occurring after 48 hours of icu stay.(8) sepsis was defined as the presence of both infection and epidemiology of cauti in critical illness-ding et al. miscellaneous 313 table 1. comparison of characteristics of critically ill patients with wardand icu-acquired symptomatic cauti. variables a ward-acquired (n =29) icu-acquired (n = 69) p-value age, year; median (iqr) 69 (61, 80) 65.8 (53, 79) .50 sex, male; n (%) 13 (44.83) 36 (52.17) .51 underlying diseases; n (%) diabetes mellitus 12 (41.38) 24 (34.78) .54 chronic liver disease 1 (3.45) 2 (2.9) .86 chronic renal disease 6 (20.69) 9 (13.04) .25 chronic respiratory disease 7 (24.14) 11 (15.94) .34 chronic cardiovascular disease 17 (58.62) 35 (50.72) .48 solid tumor 8 (27.59) 16 (23.19) .68 hospital admission diagnosis; n (%) cardiovascular disease 5 (17.24) 9 (13.04) .59 trauma 1 (3.45) 7 (10.14) .27 sepsis 8 (27.59) 35 (50.72) .04 gastrointestinal/liver disease 6 (20.69) 4 (5.8) .03 respiratory disease 4 (13.79) 3 (4.35) .10 neurologic disease 3 (10.34) 6 (8.7) .75 others b 2 (6.9) 5 (7.25) n/a icu admission sources; n (%) surgery 11 (37.93) 33 (47.83) .73 medicine 12 (41.38) 19 (27.54) .18 emergency department 6 (20.69) 17 (24.64) .67 severity of illness; median (iqr) apache ii score c 16.38 (13, 20) 18.36 (14, 23) .19 sofa score c 5.72 (3, 7) 7 (5, 10) .08 duration of urinary catheterization prior to cauti, days; median (iqr) 4 (3, 7) 9 (5, 21) < .001 antibiotic use prior to cauti; n (%) third generation cephalosporin 7 (24.14) 32 (46.38) .04 levofloxacin or moxifloxacin 9 (31.03) 23 (33.33) .825 carbapenems 6 (20.69) 30 (43.48) .033 vancomycin or linezolid 5 (17.24) 16 (23.19) .167 antifungal drugs 6 (20.69) 24 (34.78) .513 icu outcomes icu los, days; median (iqr) 17.14 (6, 22) 39.01 (17, 50) < 0.001 icu los after cauti, days; median (iqr) 16.59 (6, 22) 25.86 (9, 31) .16 icu mortality; n (%) 2 (6.9) 24 (34.78) .01 abbreviations: icu, intensive care unit; iqr, interquartile range; apache ii score, acute physiology and chronic health evaluation ii score; sofa score, sequential organ failure assessment score; los, length of stay; cauti, catheter-associated urinary tract infections. a continuous variables were compared by independent samples t-test. mann-whitney u test was employed to analyze variables with non-normal distribution. chi-square and fisher exact tests were used to determine whether differences existed between groups of categorical variables. b other includes renal disease, metabolic disorder, poisoning c values of apache ii score and sofa score were recorded at the admission of icu vol 16 no 03 may-june 2019 314 a systemic inflammatory response.(9) duration of icu stay and icu mortality were evaluated as patient outcomes. statistical analysis continuous data are reported as medians and interquartile ranges (iqr). categorical data are presented as frequency distributions. differences in continuous variables between groups were compared using the t-test and mann-whitney u test. chi-squared and fisher exact tests were used to determine whether differences existed between groups of categorical variables. all the tests were 2-tailed, and a p value < 0.05 was determined to represent statistical significance. all statistical analyses were performed using spss version 23.0 (ibm corp., armonk, ny, usa). results between january 2013 and december 2016, 4115 patients were admitted to the icu; 107 patients were diagnosed as having symptomatic cauti. four patients who were re-admitted to the icu, three patients who were transferred from the icu of another hospital, and two patients who stayed in the icu longer than 6 months were excluded. for subsequent analysis, 98 patients with symptomatic cauti were enrolled. for each patient, if cauti occurred multiple times during the icu stay, only the first epidemiological recording was considered in the analysis. characteristics of critically ill patients with ward and icu-acquired symptomatic cauti table 1 shows the characteristics of the 29 patients with ward-acquired symptomatic cauti and the 69 patients with icu-acquired symptomatic cauti. in terms of age, sex, underlying diseases, and admission source or illness severity, no significant differences were found between the two groups. the patients with ward-acquired symptomatic cauti had a significantly shorter overall icu length of stay (los) (median icu los, 17.14 days [iqr 6-22] vs. 39.01 days [iqr 17-50], p < .001); however, there was no significant difference in icu los after cauti between both groups. the overall icu mortality was significantly higher in patients who had icu-acquired symptomatic cauti than in those who had ward-acquired symptomatic cauti (34.78% vs. 6.9%, p = .01). in terms of the diagnosis at hospital admission, the icu-acquired symptomatic cauti group had a higher number of patients with sepsis, and the ward-acquired symptomatic cauti group had a higher number of patients with gastrointestinal/ liver disease. the duration of urinary catheterization prior to cauti in the group of ward-acquired symptomatic cauti was significantly shorter than that in the icu-acquired group (median, 4 days [iqr 3-7] vs. 9 days [iqr 5-21], p < .001). antibiotic use prior to cauti is described in table 1. more third-generation cephalosporins (46.38% vs. 24.14%, p =.04) and carbapenems (43.48 vs. 20.69%, p = .033) were used prior to cauti in patients with icu-acquired symptomatic cauti. there was no significant difference between groups in the use of levofloxacin or moxifloxacin, vancomycin or linezolid, and antifungal drugs prior to cauti. microbiological characteristics of wardand icu-acquired symptomatic cauti for each patient, when multiple isolates were obtained, only the first isolate was considered in the analysis. table 2 presents pathogens causing wardand icu-acquired symptomatic cauti. thirty-two pathogens were isolated from 29 ward-acquired cauti patients. of these, 25% (8/32) were from the enterobacteriaceae family, with escherichia coli being the most frequently occurring bacteria (7/15 isolated bacterial strains, 46.7%) (table 2). furthermore, 53.1% were identified as candida spp., with candida albicans being the most frequently occurring yeast (14/17 isolated candida spp., 82.4%) (table 2). seventy-six pathogens were isolated from 69 icu-acquired cauti cases. candida spp. were the most frequently isolated microorganism (46.1%), with c. albicans infection representing 22.4% (17/76) of cases. there was a higher number of non-c. albicans infection cases in patients with icu-acquired cauti than in those with ward-acquired cauti (18/35 vs. table 2. microbiological characteristics of wardand icu-acquired symptomatic cauti. pathogens a ward-acquired (n =32) icu-acquired (n =76) p-value enterobacteriaceae; n (%) 8 (25) 11 (14.5) .19 escherichia coli 7 (21.9) 5 (6.6) .03 klebsiella pneumonia 1 (3.1) 4 (5.3) .63 enterobacter 0 (0) 2 (2.6) n/a pseudomonas aeruginosa; n (%) 1 (3.1) 3 (3.9) .83 enterococcus; n (%) 4 (12.5) 10 (13.2) .96 e. faecalis 0 (0) 2 (2.6) n/a e. faecium 4 (12.5) 8 (10.5) .77 acinetobacter baumannii; n (%) 2 (6.3) 11 (14.5) .23 corynebacterium diphtheroides; n (%) 0 (0) 2 (2.6) n/a burkholderia cepacia; n (%) 0 (0) 1 (1.3) n/a candida spp.; n (%) 17 (53.1) 35 (46.1) .50 candida albicans 14 (43.8) 17 (22.4) .03 candida glabrata 2 (6.3) 8 (10.5) .48 candida parapsilosis 1 (3.1) 4 (5.3) .63 candida tropicalis 0 (0) 4 (5.3) n/a candida guilliermondii 0 (0) 1 (1.3) n/a candida lusitaniae 0 (0) 2 (2.6) n/a trichosporon asahii; n (%) 0 (0) 2 (2.6) n/a abbreviations: icu, intensive care unit; cauti, catheter-associated urinary tract infections. a chi-square and fisher exact tests were used to determine whether differences existed between groups of categorical variables. epidemiology of cauti in critical illness-ding et al. 3/17, p = .02); specifically, cases of candida glabrata (10.5%), candida parapsilosis (5.3%), and candida tropicalis (5.3%) infection were noted in icu-acquired cauti patients. however, e. coli infection comprised only 6.6% of the cases (5/76) in icu-acquired cauti patients, which was lower than that in ward-acquired cauti patients (21.9%, p = .03). finally, 3 (10.3%) ward-acquired cauti patients and 7 (10.1%) icu-acquired cauti patients had polymicrobial infection. icu-acquired symptomatic candiduria and icu-acquired symptomatic bacteriuria of the 69 patients with icu-acquired symptomatic cauti, 2 patients had trichosporon asahii infection, and 4 exhibited both candiduria and bacteriuria during their icu admissions and were excluded from this comparison. as shown in table 3, no significant differences were observed between the two groups in terms of age, sex, underlying diseases, admission source, illness severity, or outcome. in terms of the diagnosis at hospital admission, cardiovascular disease was more frequent among the patients with icu-acquired symptomatic candiduria than among those with icu-acquired symptomatic bacteriuria. discussion in this study, we reported the epidemiology of symptomatic cauti diagnosed in critically ill patients. although many studies concerning the epidemiology, surveillance, and prevention of cauti have focused on icu-acquired cauti, few studies have investigated the difference between symptomatic icu-acquired and ward-acquired cauti in critically ill patients. for example, aubron et al. compared the clinical characteristics of critically ill patients who had wardand icu-acquired positive urine cultures.(8) they found that age, acute physiology and chronic health evaluation (apache) iii score, underlying diseases (chronic liver disease or hepatic failure), primary diagnosis (trauma or neurological findings), microbiological patterns, and the hospital or icu los were significantly different between groups. however, they were unable to differentiate between asymptomatic and symptomatic bacteriuria/candiduria.(8) asymptomatic bacteriuria is defined as bacteriuria in patients without urinary tract signs or symptoms.(10) the differentiation between symptomatic and asymptomatic urinary tract infections (uti) is clinically important, because asymptomatic catheter-associated bacteriuria and funguria rarely result in adverse outcomes (e.g., pyelonephritis, perinephric abscess, and bacteremia) and generally do not require treatment. patients with candiduria are mostly asymptomatic; a large multicenter study showed that only 4% of patients had symptomatic uti.(11) bacteriuria in indwelling urinary catheterized patients is usually asymptomatic.(12) in january 2009, the national healthcare safety network (nhsn), the centers for disease control and prevention’s surveillance system on patients’ safety, significantly revised the definition of cauti: symptomatic and bacteremic cases were included as cauti but asymptomatic bacteriuria was removed.(13,14) we compared the icu and ward-acquired symptomattable 3. comparison between critically ill patients with icu-acquired candiduria and with icu-acquired bacteriuria. variables a candiduria (n = 31) bacteriuria (n = 32) p-value age, year; median (iqr) 67.48 (60,78) 62.75 (49,79) .26 gender, male; n (%) 13 (41.9) 21 (65.63) .06 underlying diseases; n (%) diabetes mellitus 13 (41.9) 9 (28.13) .25 chronic liver disease 2 (6.5) 0 (0) n/a chronic renal disease 4 (12.9) 4 (12.5) .96 chronic respiratory disease 6 (19.4) 5 (15.6) .70 chronic cardiovascular disease 17 (54.8) 14 (43.8) .38 solid tumor 6 (19.4) 8 (25) .59 hospital admission diagnosis; n (%) cardiovascular disease 7 (22.6) 1 (3.1) .02 trauma 2 (6.5) 5 (15.6) .25 sepsis 16 (51.6) 14 (43.8) .53 gastrointestinal/liver disease 1 (3.2) 3 (9.4) .32 respiratory disease 0 (0) 3 (9.4) n/a neurologic disease 4 (12.9) 2 (6.3) .37 others b 1 (3.2) 4 (12.5) n/a icu admission source; n (%) surgery 13 (41.9) 16 (50) .52 medicine 8 (25.8) 10 (31.3) .63 emergency department 10 (32.3) 6 (12.8) .22 severity of illness; median (iqr) apache ii score c 18.8 (15, 22) 18.13 (12.75, 23) .71 sofa score c 7(4.5, 9.5) 6.8 (4.75, 10) .79 icu outcomes icu los, days; median (iqr) 39.1 (16, 54) 41.4 (18.5, 57) .77 icu los after cauti, days; median (iqr) 28.7 (9, 42) 25.1 (9, 25) .50 icu mortality, n (%) 11 (35.5) 10 (31.3) .72 abbreviations: icu, intensive care unit; iqr, interquartile range; apache ii score, acute physiology and chronic health evaluation ii score; sofa score, sequential organ failure assessment score; los, length of stay; cauti, catheter-associated urinary tract infections. a continuous variables were compared by independent samples t-test. mann-whitney u test was employed to analyze variables with non-normal distribution. chi-square and fisher exact tests were used to determine whether differences existed between groups of categorical variables. b other includes renal disease, metabolic disorder, poisoning c values of apache ii score and sofa score were recorded at the admission of icu epidemiology of cauti in critical illness-ding et al. miscellaneous 315 vol 16 no 03 may-june 2019 316 ic cauti cases in critical illness. our results showed that the overall icu los was significantly shorter in patients who had ward-acquired symptomatic cauti, whereas the overall icu mortality was significantly higher in patients who had icu-acquired symptomatic cauti (no significant difference was found in terms of the disease severity on icu admission). this difference could be explained by the prevalence of different kinds of diseases in the two groups: the icu-acquired symptomatic cauti group had a higher number of patients with sepsis than did the ward-acquired group. in previous studies, gram-negative bacilli were reported to be the most commonly isolated bacterial pathogens in icu-acquired positive urine cultures, with e. coli being the most frequently isolated bacteria.(5,15) the comparison between icu and ward-acquired symptomatic cauti in critical illness showed that e. coli was more prevalent in ward-acquired symptomatic cauti, whereas acinetobacter baumannii was more prevalent in icu-acquired cauti in our study population. acinetobacter baumannii isolated from patients in the icu may be highly resistant to multiple antibiotic classes. the difference in the pathogenic bacteria spectrum between the two groups can be potentially explained by the longer icu los, prolonged catheterization period, and more frequent use of broad-spectrum antibiotics in the group of icu-acquired cauti.(16-18) recently, some studies indicated that cauti might be associated with microbial biofilm, and the biofilm formation might be related to the production of drug-resistant bacteria in cauti.(17-18) in our study, candida spp. were the most commonly isolated microorganisms in both wardand icu-acquired symptomatic cauti. aubron et al. reported that 55% of the positive urine cultures in critical illness were caused by candida spp.;(8) our results were consistent with their results. compared with previous studies that reported that c. albicans and other candida species cause 1/3 of all icu-acquired utis, this rate is regarded as high.(19) during the period of critical illness, high rates of candiduria have been related to the frequent use of systemic antibiotics.(20,21) previous studies showed that risk factors for candiduria include female sex, advanced age, icu hospitalization, surgery, and preexisting diabetes mellitus.(22,23) however, in the present study, a comparison of icu-acquired candiduria with bacteriuria showed no significant differences between groups in terms of the aforementioned risk factors. as mentioned earlier, patients with icu-acquired candiduria had a longer icu los and higher apache iii score in a previous study.(8) our results showed that there were no significant differences between icu-acquired candiduria and bacteriuria in terms of illness severity or icu los. finally, there was a higher number of cases of non-c. albicans infection in patients with icu-acquired symptomatic cauti. interestingly, in contrast to our findings, c. albicans has been reported to be the most common candida spp. in icu-acquired cauti cases in other studies.(22,24) although candiduria reporting has been eliminated from the 2015 nhsn definition of cauti,(25) the diagnosis of cauti with candida and whether to treat catheter-related candiduria in critical illness are still controversial. a meta-analysis that included 11 studies and 2745 icu patients with cauti suggested that 34% of cauti cases in icu patients were caused by epidemiology of cauti in critical illness-ding et al. fungal sources. in infectious disease society of america-2016 guidelines,(26) barring high-risk patients (neutropenic patients and patients undergoing urologic manipulation), patients with asymptomatic candiduria are not recommended to undergo treatment with antifungal agents. antifungal agents are recommended in patients with symptomatic candiduria.(26) the results of our study also showed that, in terms of the diagnosis at hospital admission, cardiovascular disease was more frequent among patients with icu-acquired symptomatic candiduria than among those with icu-acquired symptomatic bacteriuria. there are no similar reports in previous literature. this correlation needs to be confirmed by further studies in a larger sample. there are several limitations in our study. first, there was a lack of representativeness; the present study was only performed in one tertiary-care hospital, although it included multiple icu populations. second, due to the retrospective nature of our study, we depended on the clinicians’ judgment to investigate the cause of fever. these limitations might introduce bias in the results. conclusions this is the first study to analyze the differences between wardand icu-acquired symptomatic cauti in critical illness. the clinical characteristics, microbiological characteristics, and prognosis were different between the two groups. no significant differences between icu-acquired symptomatic candiduria and bacteriuria were found. our study’s findings suggest that both icu-acquired symptomatic candiduria and bacteriuria should receive more attention because icu-acquired symptomatic cauti might be associated with poor prognosis. acknowledgements we thank hailong wang of china medical university for the advice on statistical analysis. conflicts on interest the authors report no conflict of interest. references 1. leone m, garnier f, avidan m, martin c. catheter-associated urinary tract infections in intensive care units. microbes infect. 2004;6:1026-32. 2. chant c, smith om, marshall jc, friedrich jo. relationship of catheter-associated urinary tract infection to mortality and length of stay in critically ill patients: a systematic review and meta-analysis of observational studies. crit care med. 2011;39:1167-73. 3. richards mj, edwards jr, culver dh, gaynes rp. nosocomial infections in medical intensive care units in the united states. national nosocomial infections surveillance system. crit care med. 1999;27:887-92. 4. van der kooi ti, de boer as, manniën j, et al. incidence and risk factors of deviceassociated infections and associated mortality at the intensive care in the dutch surveillance system. intensive care med. 2007;33:271-8. 5. burton dc, edwards jr, srinivasan a, fridkin sk, gould cv. trends in catheter-associated urinary tract infections in adult intensive care units-united states, 1990-2007. infect control hosp epidemiol. 2011;32:748-56. 6. chenoweth ce, gould cv, saint s. diagnosis, management, and prevention of catheterassociated urinary tract infections. infect dis clin north am. 2014;28:105-19. 7. tedja r, wentink j, o’horo jc, thompson r, sampathkumar p. catheter-associated urinary tract infections in intensive care unit patients. infect control hosp epidemiol. 2015;36:13304. 8. aubron c, suzuki s, glassford nj, garciaalvarez m, howden bp, bellomo r. the epidemiology of bacteriuria and candiduria in critically ill patients. epidemiol infect. 2015;143:653-62. 9. bone rc, balk ra, cerra fb, et al. definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. the accp/sccm consensus conference committee. american college of chest physicians/society of critical care medicine. chest. 1992;101:1644-55. 10. hooton tm, bradley sf, cardenas dd, et al. diagnosis, prevention and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the infectious diseases society of america. clin infect dis. 2010;50:625-63. 11. kauffman ca, vazquez ja, sobel jd, et al. prospective multicenter study of funguria on hospitalized patients. clin infect dis. 2000;30:14-8. 12. tambyah pa, maki dg. catheter-associated urinary tract infection is rarely symptomatic: a prospective study of 1,497 catheterized patients. arch intern med. 2000;160:678-82. 13. dudeck ma, horan tc, peterson kd, et al. national healthcare safety network (nhsn) report, data summary for 2009, deviceassociated module. am j infect control. 2011;39:349-67. 14. press mj, metlay jp. catheter-associated urinary tract infection: does changing the definition change quality? infect control hosp epidemiol. 2013;34:313-5. 15. lewis ss, knelson lp, moehring rw, chen lf, sexton dj, anderson dj. comparison of non-intensive care unit (icu) versus icu rates of catheter-associated urinary tract infection in community hospitals. infect control hosp epidemiol. 2013;34:744-7. 16. ellis d, cohen b, liu j, larson e. risk factors for hospital-acquired antimicrobial-resistant infection caused by acinetobacter baumannii. antimicrob resist infect control. 2015;4:40. 17. kirmusaoglu s, yurdugül s, metin a, vehid s. the effect of urinary catheters on microbial biofilms and catheter associated urinary tract infections. urol j. 2017;14:3028-34. 18. sabir n, ikram a, zaman g, satti l, gardezi a, ahmed a, ahmed p. bacterial biofilm-based catheter-associated urinary tract infections: causative pathogens and antibiotic resistance. am j infect control. 2017;45:1101-5. 19. inan d, saba r, yalcin an, et al. deviceassociated nosocomial infection rates in turkish medical-surgical intensive care units. infect control hosp epidemiol. 2006;27:3438. 20. weinberger m, sweet s, leibovici l, pitlik sd, samra z. correlation between candiduria and departmental antibiotic use. j hosp infect. 2003;53:183-6. 21. paul n, mathai e, abraham oc, michael js, mathai d. factors associated with candiduria and related mortality. j infect. 2007;55:450-5. 22. padawer d, pastukh n, nitzan o, et al. catheterassociated candiduria: risk factors, medical interventions, and antifungal susceptibility. am j infect control. 2015;43:e19-22. 23. colodner r, nuri y, chazan b, raz r. community-acquired and hospital-acquired candiduria: comparison of prevalence and clinical characteristics. eur j clin microbiol infect dis. 2008;27:301-5. 24. sievert dm, ricks p, edwards jr, et al. antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2009-2010. infect control hosp epidemiol. 2013;34:1-14. 25. urinary tract infection (catheter-associated urinary tract infection [cauti] and noncatheter-associated urinary tract infection [uti] and other urinary system infection [usi]) events. centers for disease control and prevention website. http://www.cdc.gov/ nhsn/pdfs/pscmanual/7psccauticurrent.pdf. published 2015. accessed february 15, 2015. 26. pappas pg, kauffman ca, andes dr, et al. clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of america. clin infect dis. 2016;62:e1-50. epidemiology of cauti in critical illness-ding et al. miscellaneous 317 urological oncology predictors of secondary bladder cancer in patients with prostate cancer treated with brachytherapy: a single-institution study of a japanese cohort kiyoshi takahara1, makoto sumitomo1, masayuki ito2, fumitaka ito2, masashi nishino1, takuhisa nukaya1, masashi takenaka1, kenji zennami1, kosuke fukaya1, manabu ichino1, naohiko fukami4, hitomi sasaki1, mamoru kusaka4, shinya hayashi2, hiroshi toyama3, ryoichi shiroki1 purpose: the incidence of secondary bladder cancer after treatment for localized prostate cancer (pca) remains unclear. in this study, pca cases treated with brachytherapy (bt) were evaluated to assess the incidence of a second malignancy of bladder cancer in a japanese cohort. materials and methods: overall, 969 patients treated with bt at our hospital between july 2006 and january 2019 were included in the study cohort. the incidence and predictors of secondary bladder cancer were also assessed. results: the incidence of secondary bladder cancer was 1.5% (n = 14). of the seven factors (age, pretreatment psa, gleason score, ctnm stage, prostate volume, total activity, and combined external beam), prostate volume and total activity showed significant differences between the cohorts with and without secondary bladder cancer (p = .03 and p = .001, respectively). upon comparison of the seven parameters for the 969 patients treated with bt, we found that only the total activity factor was affected by the incidence of secondary bladder cancer in the multivariate analysis (p = .007). conclusion: the incidence of secondary bladder cancer was evaluated after bt for pca. total activity was associated with the incidence of secondary bladder cancer in japanese patients who received bt. keywords: brachytherapy; prostate cancer; secondary bladder cancer introduction prostate cancer (pca) ranking is the second most fre-quent cancer and the fifth leading cause of cancer death in men(1). pca has recently become a common type of cancer globally. however, owing to widespread psa detection, pca has often been discovered at a localized stage(2,3). many management strategies are available for localized pca, including active surveillance, radical prostatectomy (rp), robot-assisted radical prostatectomy, and radiation therapy. a systematic review showed that external beam radiation therapy (ebrt), brachytherapy (bt), and rp are effective monotherapies for localized pca; bt has a similar biochemical progression-free survival rate as rp in patients with a low to moderate risk of pca(4). multiple prospective studies have assessed patient-reported toxicity differences among the three major definitive therapy options: rp, ebrt, and bt(5,6). with high survival rates associated with each of these therapies, men and their partners often make treatment decisions based on their understanding of quality of life differences between each treatment modality(7). as mentioned above, bt is a valid treatment option 1department of urology, fujita health university school of medicine, toyoake, aichi, japan. 2department of radiation oncology, fujita health university school of medicine, toyoake, aichi, japan. 3department of radiology, fujita health university school of medicine, toyoake, aichi, japan. 4department of urology, okazaki medical center, fujita health university, okazaki, japan. *correspondence to: kiyoshi takahara, m.d., ph.d., department of urology, fujita health university school of medicine, 1-98 dengakugakubo, kutsukakecho, toyoake, aichi 470-1192, japan. tel: 81-562-93-2600, fax: 81-562-93-4593, e-mail: takahara@fujita-hu.ac.jp. received february 2021 & accepted october 2021 for localized pca. bt has been found to be a highly effective and safe treatment, providing a good alternative to the surgical removal of the prostate, breast, and cervix, while reducing the risks of some long-term side effects(8). however, the long-term risk of secondary malignancy, especially the risk of bladder cancer, is a potential late effect of bt. this study aimed to evaluate localized pca patients treated with bt at our hospital to assess the incidence and predictors of secondary bladder cancer in a japanese cohort. materials and methods study design in the current study, we retrospectively reviewed the clinicopathological data of 969 patients treated with bt at our hospital between july 2006 and january 2019. for all patients, serum psa levels were checked; ctnm stage was assigned by computed tomography, magnetic resonance imaging, and whole-body bone scan. prostate volume was assessed using transrectal ultrasound at the time of the prostate biopsy. the study design was approved by the ethics commiturology journal/vol 19 no. 3/ may-june 2022/ pp. 209-213. [doi:10.22037/uj.v18i.6718] tee of our hospital (approval number of fujita health university school of medicine: hm18-089). the need for informed consent from all patients included in this study was waived because of the retrospective design. treatment classification the d’amico risk classification(9) was used to determine the bt treatment. as a general rule, bt alone was performed for low-risk, combination of bt and ebrt for intermediate-risk, and trimodality treatment consisting of hormonal therapy, ebrt, and bt for high-risk pca patients. patient selection among the 969 localized pca patients who received bt, 581 were treated with a 160 gy permanent interstitial iodine-125 (i-125) implant alone by real-time intraoperative planning; 388 were treated with a 110 gy permanent seed implantation, followed by a 45 gy supplemental intensity-modulated radiation therapy to the prostate and seminal vesicles 2 months later. the current approach for bt dose calculation is based on the aapm tg-43 dosimetry formalism, with recent advances in acquiring single-source dose distributions (10). follow-up evaluations follow-up evaluations were performed at 3to 6-month intervals for 5 years and yearly thereafter. the clinical data of each patient were collected from medical records. secondary bladder cancer was diagnosed by transurethral resection of the bladder. pathological findings, including grade and pt stage, were also obtained. statistical analysis for statistical analysis, the comparison between two groups was performed using mann-whitney's u test, chi-square test, or fisher’s exact test. the prognostic secondary bladder cancer after bt-takahara et al. table 1. patient characteristics. table 2. incidence of secondary bladder cancer and patient characteristics. urological oncology 210 vol 19 no 3 may-june 2022 211 significance of certain factors was assessed using univariate and multivariate analyses. all data were analyzed using ibm spss statistics version 23 (spss japan inc., tokyo, japan), and a p-value < 0.05, which was considered significant in all statistical analyses. results the clinical characteristics of 969 japanese patients with localized pca treated with bt included in this study are summarized in table 1. the median age was 70 years; the median serum psa level was 7.1. regarding the ctnm stage and gleason score, ct2n0m0 and table 3. patients’ characteristics with and without secondary bladder cancer. table 4. univariate and multivariate analyses of seven factors. secondary bladder cancer after bt-takahara et al. urological oncology 212 gleason score < 6 were observed in 56.3% and 48.3% of patients, respectively. in the context of d’amico risk classification, the low-risk group was most frequently observed in 40.1%. we then evaluated the incidence of secondary bladder cancer in 969 pca patients treated with bt, which was observed in 14/969 (1.5%) patients. upon histological grading, g2 was observed most frequently in 71.4% of cases; all cases of pt stage were under pt1 (table 2). to investigate the effect on the incidence of secondary bladder cancer, we focused on seven factors (age, pretreatment psa, gleason score, ctnm stage, prostate volume, total activity, and combined external beam) related to pca and bt in the 969 patients treated with bt. prostate volume and total activity showed significant differences between cohorts with and without secondary bladder cancer (p = .03 and p = .001, respectively) (table 3). among these seven factors, we evaluated which factor was associated with the incidence of secondary bladder cancer in 969 pca patients treated with bt. univariate analysis showed that prostate volume and total activity were independent factors for the incidence of secondary bladder cancer (p = .014 and .006, respectively). in the multivariate analysis, total activity was the only factor directly associated with the incidence of secondary bladder cancer (p = .007) (table 4). discussion the potential side effects and long-term toxicities of treatment for pca are important considerations in selecting the best therapy for patients(11-14). a second primary cancer is generally considered to be radiation-induced if (i) it is diagnosed after a latency period (usually considered to be 5 years or more) following irradiation; (ii) it occurs within the radiation field (for prostate radiotherapy, this includes the rectum, bladder, anus, prostate, soft tissues, bones, or joints of the pelvis and pelvic lymphoma); (iii) it is a different histological type from the original cancer; and (iv) the second tumor was not evident at the time of radiotherapy(15,16). rather than using this definition, we opted for a more inclusive strategy, as suggested by others(17). several recent studies have reported the incidence of secondary bladder cancer among pca treatments, including rp, ebrt, and bt. a previous study using the surveillance, epidemiology, and end results database from 1973 to 2011 showed that the relative risk of developing bladder cancer after 10 years was significantly higher following bt than after ebrt or ebrt and bt(18). another study showed that pca patients treated with any radiation therapy were 1.70 times more likely to develop secondary bladder cancer compared with rp alone(19). however, zelefsky et al. reported that the 10year likelihood of bladder cancer that developed after treatment in the rp, bt, and ebrt cohorts was 1.4%, 1.0%, and 1.2%, respectively, with no significant differences(20). collectively, these findings suggest that the prognostication of each pca treatment for secondary bladder cancer should be conducted. accordingly, in the current study, we focused on localized pca patients treated with bt to investigate the incidence and predictors of secondary bladder cancer in a japanese cohort. in this study, 969 japanese patients who underwent bt for localized pca treatment were evaluated. the incidence of secondary bladder cancer was observed in 14/969 (1.5%) patients. in the context of histological findings of secondary bladder cancer after bt treatment, g2 and g3 were observed in 85.7% of cases; pt stage in all cases was under pt1. our histological results were consistent with a previous report that the majority of bladder cancers following bt were of high grade and low stage at diagnosis, most of which demonstrated luminal immunophenotype(21). to evaluate which factors influenced the incidence of secondary bladder cancer after bt therapy in japanese patients with localized pca, several analyses were performed with the seven factors (age, pretreatment psa, gleason score, ctnm stage, prostate volume, total activity, and combined external beam). between cohorts with and without secondary bladder cancer, prostate volume and total activity showed significant differences. since the total activity was dependent on the prostate volume in order to deliver 160 gy, except combining extra beam, our analysis between cohorts with and without secondary bladder cancer was acceptable. interestingly, in the multivariate analysis, total activity was the only factor directly associated with the incidence of secondary bladder cancer. in this study, bt was not performed for pca with a large prostate volume; total activity was decreased when the extra beam was combined. furthermore, only total activity remains an important factor for the incidence of secondary bladder cancer. moreover, the combination of bt and external beam therapy was not associated with the incidence of secondary bladder cancer in our japanese cohort. in the current study, we reported that the incidence of secondary bladder cancer after bt for localized pca patients was 1.5%, within a median follow-up of 81 months. total activity was an important predictor of the incidence of secondary bladder cancer in japanese patients who received bt. this study has some limitations. first, this was a retrospective, single-institution study. in addition, since patient characteristics were not fully obtained, well-designed analyses were lacking. in particular, the population of patients who had a history of smoking should be selected, considering that tobacco smoking is the best-established risk factor for bladder cancer in both men and women(22). further studies are needed to validate our assessment of the predictors of secondary bladder cancer in patients with pca and bt. conclusions in conclusion, the incidence of secondary bladder cancer after bt for localized pca treatment was evaluated. total activity was the only significant independent predictive factor for the incidence of secondary bladder cancer in japanese patients who received bt. conflicts of interest the authors have no conflict of interest to declare regarding this study. references 1. global burden of disease cancer c, fitzmaurice c, allen c, et al. global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted lifeyears for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of secondary bladder cancer after bt-takahara et al. vol 19 no 3 may-june 2022 213 disease study. jama oncol. 2017;3:524-48. 2. andriole gl, crawford ed, grubb rl, 3rd, et al. mortality results from a randomized prostate-cancer screening trial. n engl j med. 2009;360:1310-9. 3. schroder fh, hugosson j, roobol mj, et al. screening and prostate-cancer mortality in a randomized european study. n engl j med. 2009;360:1320-8. 4. wolff rf, ryder s, bossi a, et al. a systematic review of randomised controlled trials of radiotherapy for localised prostate cancer. eur j cancer. 2015;51:2345-67. 5. chen rc, basak r, meyer am, et al. association between choice of radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance and patient-reported quality of life among men with localized prostate cancer. jama. 2017;317:1141-50. 6. sanda mg, dunn rl, michalski j, et al. quality of life and satisfaction with outcome among prostate-cancer survivors. n engl j med. 2008;358:1250-61. 7. hamdy fc, donovan jl, lane ja, et al. 10year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. n engl j med. 2016;375:1415-24. 8. skowronek j. current status of brachytherapy in cancer treatment short overview. j contemp brachytherapy. 2017;9:581-9. 9. d'amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998;280:969-74. 10. nath r, anderson ll, luxton g, weaver ka, williamson jf, meigooni as. dosimetry of interstitial brachytherapy sources: recommendations of the aapm radiation therapy committee task group no. 43. american association of physicists in medicine. med phys. 1995;22:209-34. 11. laing r, uribe j, uribe-lewis s, et al. lowdose-rate brachytherapy for the treatment of localised prostate cancer in men with a high risk of disease relapse. bju int. 2018;122:6107. 12. liauw sl, sylvester je, morris cg, blasko jc, grimm pd. second malignancies after prostate brachytherapy: incidence of bladder and colorectal cancers in patients with 15 years of potential follow-up. int j radiat oncol biol phys. 2006;66:669-73. 13. siegel rl, miller kd, jemal a. cancer statistics, 2018. ca cancer j clin. 2018;68:730. 14. suriano f, altobelli e, sergi f, buscarini m. bladder cancer after radiotherapy for prostate cancer. rev urol. 2013;15:108-12. 15. cohen wg. sarcoma arising in irradiated bone; report of 11 cases. cancer. 1948;1:3-29. 16. sale ka, wallace di, girod da, tsue tt. radiation-induced malignancy of the head and neck. otolaryngol head neck surg. 2004;131:643-5. 17. boorjian s, cowan je, konety br, et al. bladder cancer incidence and risk factors in men with prostate cancer: results from cancer of the prostate strategic urologic research endeavor. j urol. 2007;177:883-7; discussion 7-8. 18. keehn a, ludmir e, taylor j, rabbani f. incidence of bladder cancer after radiation for prostate cancer as a function of time and radiation modality. world j urol. 2017;35:713-20. 19. abern mr, dude am, tsivian m, coogan cl. the characteristics of bladder cancer after radiotherapy for prostate cancer. urol oncol. 2013;31:1628-34. 20. zelefsky mj, pei x, teslova t, et al. secondary cancers after intensity-modulated radiotherapy, brachytherapy and radical prostatectomy for the treatment of prostate cancer: incidence and cause-specific survival outcomes according to the initial treatment intervention. bju int. 2012;110:1696-701. 21. au s, keyes m, black p, villamil cf, tavassoli p. clinical and pathological characteristics of bladder cancer in post brachytherapy patients. pathol res pract. 2020;216:152822. 22. humans iwgoteocrt. tobacco smoke and involuntary smoking. iarc monogr eval carcinog risks hum. 2004;83:1-1438. secondary bladder cancer after bt-takahara et al. november-december 2017 reviewer of the issue jovo r. bogdanović jovo r. bogdanović december 2017 jovo r. bogdanović, md, ph.d., is associate professor of urology at the faculty of medicine novi sad, university of novi sad, serbia. he earned medical degree at the faculty of medicine, university of zagreb, croatia. he completed his urological residency under professor jovan d. stojkov at the clinical center of novi sad, serbia. currently, he is holding a position of head of department of stone treatment at the clinic of urology, clinical center of vojvodina. since 2001, he has participated in the teaching process at the faculty of medicine novi sad, university of novi sad. dr bogdanović has published more than twenty papers in international per reviewed journals. also he was the author of several chapters in different textbooks. he holds an active membership in the european association of urology, serbian medical society and serbian association of urology. his work has been awarded by society of physicians of vojvodina. “being a reviewer for urology journal is a great honor, as you are allowed to contribute to the scientific level of this journal. careful and fair-minded evaluation of scientific articles is an important scholarly contribution and a gratifying duty in academics. peer review is a vital process for any journal and enables publication of innovative research that meets the highest standards of quality. jovo r. bogdanović, was chosen by editorial board of the urology journal for his valuable and timely review of manuscript”. sexual dysfunction in premenopausal women with obstructive sleep apnea zahide yilmaz1*, pinar bekdik sirinocak1, bekir voyvoda2, levent ozcan2 purpose: sexual functions in the males with obstructive sleep apnea syndrome (osas) have been well investigated in the literature; however sexual functions in the premenopausal women with osas have been studied to a lesser extent. materials and methods: the study included 22 premenopausal women diagnosed as osas by the polysomnographic (psg) evaluation. the control group included 13 premenopausal women suspected of sleep-related respiratory disorder, but whose psg tests were determined to be normal. both groups were administered epworth sleep scale (ess), beck depression scale (bds), and female sexual function index (fsfi) questionnaire forms. relations between disease parameters, and the total fsfi score, and scores of the six fsfi parameter were analyzed. results: the total fsfi score in the cases with osas, was determined to be significantly lower than that of the control subjects (p = .031). scores of the desire, arousal, and orgasm were determined to be significantly lower in the patient group, compared to control group (p = .034; p = .048; p = .039). the total fsfi scores, and scores of the desire, arousal, lubrication, orgasm, satisfaction and pain subscales in the cases did not correlate significantly with the apnea-hypopnea index (ahi), non-rapid eye movement 1 (nrem1)%, nrem2%, nrem3%, rem%, the time spent with saturation o 2 < 90%, minimum oxygen saturation (%), ess scores, and bds scores (all p > .05). conclusion: women with osas experience sexual dysfunction when compared with normal population. clinical evaluation has to include also the evaluation of sexual life in women. key words: obstructive sleep apnea; sexual dysfunction; women. introduction female sexual dysfunction (fsd) is a highly preva-lent and often underestimated problem in the general community.(1) fsd may occur at any age, and it affects roughly 40% of women at some point in their lifetime, with 12% of women reporting afflictive sexual problems.(2) fsd is a public health problem, but little epidemiological data are available regarding its extent and magnitude of the psychogenic and organic causes of decreased sexual desire, arousal, and orgasm, as well as pain, which all cause personal distress. previous studies discovered that factors, such as age, obesity, menopausal status, educational level, financial income, psychological factors, hormonal dysfunction, particularly thyroid disease, and physical health status of women, could affect women’s chances of having fsd. (3-5) among the multitude of factors influencing the sexual integrity of women, the different aspects of lifestyle are considered to play a significant role in the genesis of fsd.(6,7) however effect of obstructive sleep apnea syndrome (osas) on sexual dysfunction in premenopausal women has not been well defined yet. osas is a chronic disease characterized by the repetitive episodes of apnea and upper airway collapse during sleep. osas affects the middle-aged men nearly by 4%, and the middle-aged women by 2%.(8) osas has been known for more than 30 years. as it is the case in many chronic diseases, sexual functions are affected by sleep apnea both in the males and females. especially erectile dysfunction has been a frequently reported sexual dysfunction in the males with osas. these patients have been shown to improve by the continuous positive airway pressure (cpap) treatment.(8,9) female sexual dysfunction is vastly under-recognized but has been previously described in chronic disease states. sexual dysfunction in male patients with osas is well described, but not in females. in light of these informations we aimed in this study to evaluate sexual dysfunction by the use of female sexual function index (fsfi), in the premenopausal women diagnosed with sleep apnea. materials and methods study design patients who were newly diagnosed with osas at the sleep and sleep disorders laboratory of the neurology clinic of kocaeli derince education and research hospital, turkey between 2015 and 2016 were included 1derince training and research hospital, department of neurology, kocaeli, turkey. 2 derince training and research hospital, department of urology, kocaeli, turkey. *correspondence: derince training and research hospital, department of neurology, 41900 derince, kocaeli, turkey. tel: (+90) -262-317 8000. fax: (+90)262233 4641. e-mail: yilmazzahide@hotmail.com. received february 2017 & accepted june 2017 urological oncology 5051 sexual dysfunction and andrology in the study. ethical approval an informed consent was obtained from each participant.the study protocol was approved by the local ethics committeeof kocaeliuniversty non-intervational clinical researches ethics board with the permission number and date of ku gokaek-2017/11. the study was conducted in accordance with the principles of the declaration of helsinki. study population participants who had no sexual activity within the past month were not included in the study. participants with sexual problems, including decreased libido, a history of sexual abuse; organic, and/or psychiatric disorders were excluded from the study. periand postmenopausal women, psychoactive medication users, and patients with depression, diabetes and cancer were also excluded. sample size the study included a total of 22 premenopausal women diagnosed with osas by the psg results. the control group included 13 premenopausal women suspected of sleep-related respiratory disorder, but whose psg results were found to be normal. measurements patients were questioned for the following variables : sexual dysfunction and sleep apnea-yilmaz et al. table 1.evaluation of descriptive characteristics of the groups. total (n=35) patient (n=22) control (n=13) p age (year) min-max (median) 35-54(42) 35-51 (44) 35-54 (40) a0,100 meant ± sd 42.06 ± 5.60 43,59 ± 4,82 40.54 ± 5.70 bmi (kg/m2) min-max (median) 21,5-46,9 (32,5) 21,9-46,9 (33,9) 21,5-43,3 (31,3) a0,116 meant ± sd 32,91 ± 6,88 34,24 ± 6,65 30,65 ± 6,92 education (year) elementary 26 (74,3) 16 (72,7) 10 (76,9) b0,698 secondary 7 (20,0) 4 (18,2) 3 (23,1) high school 2 (5,7) 2 (9,1) 0 (0) operations none 16 (45,7) 11 (50,0) 5 (38,5) b0,904 once 11 (31,4) 7 (31,8) 4 (30,8) twice 6 (17,1) 3 (13,6) 3 (23,1) 3 times 2 (5,7) 1 (4,5) 1 (7,7) parity none 2 (5,7) 0 (0) 2 (15,4) b0,022* once 4 (11,4) 1 (4,5) 3 (23,1) twice 11 (31,4) 10 (45,5) 1 (7,7) 3 times 13 (37,1) 7 (31,8) 6 (46,2) ≥ 4 times 5 (14,3) 4 (18,2) 1 (7,7) hypertension 6 (17,1) 2 (9,1) 4 (30,8) c0,106 diabetes 10 (28,6) 7 (31,8) 3 (23,1) c0,576 copd 2 (5,7) 1 (4,5) 1 (7,7) c1,000 cardiac disease 1 (2,9) 0 (0) 1 (7,7) smoking habit 18 (51,4) 13 (59,1) 5 (38,5) c0,305 abbreviations: bmi, body mass index; dm, diabetes mellitus; copd, chronic obstructive pulmonary disease. amann whitney u test; bfisher-freeman-halton test; cfisher’s exact test; *p < 0,05. total (n=35) patient (n=22) control (n=13) ap nrem1 % min-max (median) 1,5-34,3 (7,5) 1,5-34,3 (7,3) 1,8-32,8 (7,7) 0,322 mean ± sd 9,68 ± 8,44 8,56 ± 7,73 11,56 ± 9,55 nrem2 % min-max (median) 2,9-49,1 (20,4) 2,9-47,2 (20,6) 3,1-49,1 (16,4) 0,733 mean ± sd 21,39 ± 14,27 20,12 ± 12,21 23,55 ± 17,54 nrem3 % min-max (median) 12,1-77,3 (48) 14,5-77,3(53,3) 12,1-75,7(35,6) 0,306 mean ± sd 47,24 ± 19,66 50,05 ± 18,63 42,48 ± 21,17 rem % min-max (median) 0-22,8 (11,9) 4,2-22,8 (13,9) 0-18,8 (10,9) 0,068 meant ± sd 11,35 ± 5,10 12,47 ± 4,77 9,46 ± 5,27 time so 2 < %90 % min-max (median) 0-22,5 (0) 0-22,5 (0) 0-0 (0) 0,009** mean ± sd 1,94 ± 5,95 3,09 ± 7,32 0,00 ± 0,00 min so2 % min-max (median) 67,8-95 (90) 67,8-93 (88,5) 91-95 (93) 0,001** mean ± sd 89,05 ± 5,59 86,81 ± 5,97 92,85 ± 1,14 ess min-max (median) 0-17 (7) 0-17 (6) 0-17 (11) 0,266 mean ± sd 7,69 ± 5,06 6,91 ± 4,77 9,00 ± 5,45 beck min-max (median) 0-38 (19) 0-38 (21) 2-27 (17) 0,047* mean ± sd 18,66 ± 7,99 20,50 ± 8,17 15,54 ± 6,89 disease duration(year) min-max (median) 0,33-20 (4) 1-20 (5) 0,33-10 (3) 0,346 mean ± sd 5,58 ± 5,20 6,45 ± 5,84 4,10 ± 3,66 ahi min-max (median) 0,7-102,7 (7,4) 5,2-102,7(12,1) 0,7-4,4 (1,9) mean ± sd 14,29 ± 20,27 21,44 ± 22,96 2,18 ± 1,11 disease severity; n (%) normal 13 (37,1) 0 (0) 13 (100) mild 13 (37,1) 13 (59,1) 0 (0) moderate 4 (11,4) 4 (18,2) 0 (0) severe 5 (14,3) 5 (22,7) 0 (0) abbreviations: nrem, non-rapid eye movement; rem, rapid eye movement; time so 2 < %90, time saturation oxygen <%90;min so 2 , minimum saturatin oxygen; ess, epworth sleep scale; bds, beck depression scale; ahi,apnea-hypopnea index amann whitney u test; byates continuity correction test; cfisher’s exact test; *p < 0,05; **p < 0,01 table 2. evaluation of disease variables in the groups. vol 14 no 06 november-december 2017 5052 age, body mass index (bmi), number of obstetric-gynecologic operations, parity, hypertension (ht), diabetes mellitus (dm), cardiac disease, chronic obstructive pulmonary disease (copd), disease duration, and smoking habit. in addition, psg parameters were recorded. both groups were administered the epworth sleep scale (ess), beck depression scale (bds), and fsfi questionnaire forms. all patients were grouped as mild, moderate, and severe osas based on the apnea-hypopnea index (ahi). mild, moderate, and severe sleep apneas were defined as (ahi) 5-15/hour, 15-30/hour, and 30 and over/hour, respectively. the fsfi questionnaire was previously validated in the native language of the participants(10) and partner version of the premature ejaculation profile scale (pep) for the assessment of sexual function. the women filled the pep form (in turkish) themselves. the fsfi includes a total of 19 questions in six categories: desire, arousal, lubrication, orgasm, satisfaction, and pain. scores range from 2 to 36, and lower scores indicate more severe female sexual dysfunction.(11) patients were also administered bds. this scale includes 21 questions. higher scores indicate higher levels of clinical signs related with depression.(12) the patients and control subjects underwent psg analysis all night long (embla n 7000). the psg evaluation included electroencephalogram, electrooculogram, chin, and tibial electromyogram, electrocardiogram, snoring, oro-nasal thermistor, nasal pressure transducer, finger pulse oximeter, thoracic and abdominal respiratory movements, and body position. scoring was performed according to the criteria of the american academy of sleep medicine (aasm), 2007. apnea was defined as a reduction in the amplitude of oro-nasal thermistor signal by ≥ 90% for at least 10 sec, compared to the baseline. hypopnea was defined as a reduction in the amplitude of nasal cannula signal by ≥50 % for at least 10 sec, compared to the baseline, a decline in oxygen saturation by ≥ 3 %, or it was considered to be related with arousal. statistical analysis statistical analyses were performed using the number cruncher statistical system(ncss, 2007) (kaysville, utah, usa) software. descriptive data were expressed in mean, standard deviation (sd), median, frequency, percentage, and minimum and maximum values. the mann-whitney u test was used to compare abnormally distributed quantitative variables between the two groups. qualitative data were compared using the fisher-freeman-halton test, fisher’s exact test, and yates’ continuity correction test (yates corrected chi-square). relations between the variables were evaluated using the spearman’s correlation analysis. p values of < 0.01 or < 0.05 were considered statistically significant. results the study included a total of 35 participants (22 patients and 13 controls) with a mean age of 42.06 ± 5.60 (range: 32 to 54) years. the mean age and bmi did not differ significantly between the groups (p > 0.05). only the rate of two-childbearing (higher parity) was higher in the patient group (p = .022). education status, number of obstetric-gynecologic operations, and comorbidities such as ht, dm, and copd, and smoking habit also did not show significant differences between the groups (p > .05). demographic data of the osas and control groups are presented in table 1. the bds scores were statistically significantly higher in the patient group, compared to the control group (p sexual dysfunction and sleep apnea-yilmaz et al. urological oncology 5053 table 3. evaluation of groups with regard to the fsfi scale. total (n=35) patient (n=22) control (n=13) ap desire min-max (median) 2-10 (5) 2-7 (5) 2-10 (6) 0,034* meant ± sd 4,94 ± 1,98 4,36 ± 1,59 5,92 ± 2,25 arousal min-max (median) 0-19 (11) 0-16 (9,5) 6-19 (11) 0,048* meant ± sd 10,31 ± 4,32 9,14 ± 4,26 12,31 ± 3,77 lubrication min-max (median) 0-20 (13) 0-20 (12) 8-20 (14) 0,100 mean ± sd 12,54 ± 5,65 11,27 ± 6,28 14,69 ± 3,66 orgasm min-max (median) 0-14 (10) 0-13 (9) 4-14 (11) 0,039* mean ± sd 8,86 ± 3,99 7,82 ± 4,28 10,62 ± 2,75 satisfaction min-max (median) 2-15 (10) 2-15 (9,5) 3-15 (10) 0,547 mean ± sd 9,37 ± 3,72 8,95 ± 4,02 10,08 ± 3,17 pain min-max (median) 0-15 (11) 0-15 (10,5) 3-15 (11) 0,201 mean ± sd 9,46 ± 4,64 8,59 ± 5,10 10,92 ± 3,45 total fsfi score min-max (median) 5-85 (56) 5-77 (54) 35-85 (63) 0,031* mean ± sd 54,74 ± 20,53 48,95 ± 21,64 64,54 ± 14,45 abbreviations: fsfi, female sexual function index amann whitney u test; *p < 0,05 mild (n=13) moderate+severe (n=9) ap n=22 mean ± sd (median) mean ± sd (median) desire 4,23 ± 1,48 (4) 4,56 ± 1,81 (5) 0,539 arousal 9,77 ± 3,79 (10) 8,22 ± 4,94 (9) 0,421 lubrication 11,23 ± 4,55 (11) 11,33 ± 8,51 (15) 0,402 orgasm 8,08 ± 3,40 (9) 7,44 ± 5,53 (10) 0,638 satisfaction 9,92 ± 2,75 (10) 7,56 ± 5,22 (9) 0,439 pain 9,46 ± 3,71 (10) 7,33 ± 6,67 (11) 0,813 total fsfi score 51,69 ± 15,97 (54) 45,00 ± 28,58 (56) 0,894 abbreviations: fsfi, female sexual function index amann whitney u test table 4. evaluation of fsfi scale scores with regard to disease severity. = .047). disease variables of both groups are shown in table 2. the mean scores of desire, arousal, and orgasm were found to be significantly lower in the patient group, compared to the control group (p = .034; p = .048; p = .039). the mean scores of lubrication, satisfaction, and pain did not differ significantly between the groups (p > .05). the mean value of total fsfi score in the patient group was significantly lower, compared to the control group (p = .031). evaluation of the patient and control groups with regard to the fsfi subscales is shown in table 3. the mean scores of the desire, arousal, lubrication, orgasm, satisfaction, and pain, which are the fsfi subscales, did not show statistically significant differences among the patients, depending on the disease severity (p > .05). the mean value of total fsfi score also did not differ significantly between patients, depending on disease severity (p > .05). evaluation of fsfi scale with regard to disease severity is presented in table 4. no statistically significant correlations between the values of total fsfi scores of the patients, and the ahi, non-rapid eye movement 1 (nrem1) %, nrem2 %, nrem3 %, rapid eye movement(rem) %, time spent with saturation oxygen (o 2 ) < 90%, minimum saturation oxygen(min so 2 ) %, ess scores, bds scores, and bmi were seen (p > 0.05). scores of fsfi subscales, which are the sexual desire, sexual arousal, lubrication, orgasm, satisfaction and pain, did not correlate significantly with the ahi, nrem1 %, nrem2 %, nrem3 %, rem %, time spent with so 2 < 90%, min so 2 %, ess scores, bds, disease duration, age, and bmi in the patient group (p > .05). in addition, we found no significant correlations between the values of total fsfi scores of the cases and the disease duration (p > .05). evaluation of correlations between the fsfi subscale scores and total scores, and the other variables in the patient group, are shown in table 5. discussion in this study, by excluding postmenopausal or perimenopausal women, we excluded the potential effects of menopause or estrogen deficiency itself as well as that of aging, both of which are independent factors of fsd. our results shows a high prevalance of sexual dysfunction in pre-menopausal women with osas compared to healthy controls. sexual function in females is related with complex neurophysiological and psychological processes. the pathophysiology of sexual dysfunction in females with osas is multifactorial. endothelial dysfunction has been demonstrated to play a critical role.(13-15) the genital tract is primarily innervated by the pudendal nerve. the integrity of the pudendal nerve is important for the normal female sexual function. it has been reported that peripheral neuropathy may develop in osas, which is related with severity of the chronic intermittent nocturnal hypoxia.(16) in addition, cpap treatment has been shown to improve neural functions in males.(17) levels of testosterone have been shown to be lower in the women with osas, which was found to be related with the severity of disease.(18) the quality of life, and the mood may also contribute to sexual dysfunction in women.(8) sexual dysfunction has been well defined in the males with osas. the rate of sexual dysfunction has been reported to be 30 to 50 % in the men with osas.(19,20) there is a considerably limited number of studies related to sexual dysfunction in the females with osas. in a prospective study on pre-menopausal women with osas in turkey, koseoglu et al.(21) found a high prevalence of impaired sexual function.they also found that all scores in sexual function domains except enjoyment and pain decreased significantly with increasing severity of osas. in our study, the total fsfi score in the patient group was significantly lower than that of the control group. the patient group had significantly lower scores of sexual desire, sexual arousal, and orgasm, compared to the controls. in our study, the total fsfi scores, and the scores of desire, arousal, lubrication, orgasm, satisfaction, and pain subscales were not found to be significantly correlated with the ahi, nrem1 %, nrem2%, nrem3 %, sexual dysfunction and sleep apnea-yilmaz et al. desire arousal lubrication orgasm satisfaction pain total n=22 r p r p r p r p r p r p r p ahi 0,046 0,840 -0,208 0,354 0,120 0,596 0,030 0,894 -0,186 0,408 -0,064 0,777 0,007 0,974 nrem1 0,033 0,885 -0,091 0,688 -0,161 0,475 -0,071 0,752 -0,051 0,821 0,011 0,961 -0,131 0,561 % nrem2 0,035 0,876 0,092 0,684 -0,176 0,433 0,112 0,619 -0,073 0,747 0,034 0,880 0,084 0,709 % nrem3 -0,196 0,382 -0,057 0,802 -0,044 0,847 -0,237 0,288 -0,014 0,952 -0,007 0,974 -0,094 0,676 % rem % -0,201 0,370 0,219 0,327 0,110 0,627 0,060 0,790 0,246 0,269 0,195 0,384 0,197 0,380 so 2 <90 0,051 0,821 -0,164 0,467 0,096 0,671 0,054 0,813 -0,190 0,396 0,083 0,715 0,076 0,736 % min so 2 -0,059 0,796 0,041 0,858 -0,137 0,542 -0,047 0,835 0,183 0,414 -0,262 0,239 -0,166 0,461 % ess -0,153 0,496 0,127 0,573 0,051 0,820 -0,002 0,992 -0,076 0,738 0,403 0,063 0,169 0,453 disease duration -0,112 0,619 -0,100 0,657 0,120 0,595 0,117 0,603 -0,250 0,261 0,131 0,560 0,039 0,864 (year) age -0,033 0,883 -0,093 0,679 -0,136 0,546 -0,073 0,745 -0,210 0,347 -0,051 0,820 -0,076 0,735 bmi 0,052 0,819 -0,027 0,904 0,019 0,933 0,083 0,713 -0,044 0,845 0,024 0,917 0,071 0,753 (kg/m2) table 5.evaluation of relations between the fsfi subscale scores and total scores, and the other variables in the patient group. abbreviations: r, spearman’s coefficient of correlation; ahi,apnea-hypopnea index; nrem, non-rapid eye movement; rem, rapid eye movement; time so 2 < %90, time saturation oxygen<%90; min so 2 , minimum saturatin oxygen; bmi, body mass index vol 14 no 06 november-december 2017 5054 rem %, time spent with so 2 < 90 %, min so 2 , and ess scores. in the study of stavaras et al.(22), minsat was found to be correlated with all fsfi subscales, except the sexual desire. koseoğlu et al.(21) found that minsat was determined to be significantly correlated with only orgasm. however, we were unable to find such a correlation, possibly due to the small sample size in our study. in our study, the total fsfi scores in the patient group did not show statistically significant correlation with the time spent with so 2 < 90%. fanfulla et al.(23) reported in 2013, osas group existing with sexual dysfunction had a longer time spent with so 2 < 90 %, than the patients with osas who did not have sexual dysfunction. our patient group included 22 cases; of these, 13 patients had mild, and nine patients had moderate-to-severe osas. this may be the reason for low values of time spent with so 2 < 90% in our study. we believe that, with a larger number of patients with severe osas, such a correlation can be demonstrated. in the present study, scores of desire, arousal, lubrication, orgasm, satisfaction, and pain subscales of fsfi in the cases, did not differ significantly depending on disease severity. the degree of disease also did not significantly affect the total fsfi score in the patient group. in accordance with our results, onem et al.(14) found that osas presented with sexual dysfunction in women, although the degree of sexual dysfunction was not related with osas severity. the authors concluded that this might be due to the relations of sexual dysfunction in women with osas, with both organic and psychogenic problems. on the contrary, stavaras et al.(22) found an association between the severity osas and sexual dysfunction in women. additional factors including depression are also known to affect sexual dysfunction.(24,25) in several studies, the prevalence of depression has been found to be higher in patients with osas.(26) in our study, we found a statistically significant relationshipbetween the bds scores and osas in the patient group; however total fsfi scores did not correlate with the scores of bds. in addition, in our study, the total fsfi scores in the patient group did not correlate with bmi, consistent with previous study findings.(8,23) nonetheless, the limited number of cases in both groups is the main limitation to our study. the reason of this issue is the lesser frequency of osas in premenopausal women. conclusions in conclusion, there is a relationship between osas and sexual dysfunction in women. we, therefore, recommend sexual life evaluation during clinical examination in patients with osas. conflict of interest none declared. acknowledgements we acknowledge that all authors have made substantial contribution to the work, and all have read and approved the final manuscript. references 1. raina r, pahlajani g, khan s, gupta s, agarwal a, zippe cd. female sexual dysfunction: classification, pathophysiology, and management. fertilsteril. 2007; 88, 1273– 84. 2. kammerer-doak d, rogers rg. female sexual function and dysfunction. obstetgynecolclin north am. 2008; 35:169–83. 3. addis ib, van den eeden sk, wassel-fyr cl, vittinghoff e, brown js, thom dh. sexual activity and function in middle aged and older women. obstet gynecol. 2006; 107:755–64. 4. chedraui p, perez-lopez fr, san miguel g, avila c. assessment of sexualityamong middleaged women using the female sexual function index. climacteric. 2009;12:213–21. 5. pasquali d, maiorino mi, renzullo a, bellastella g, accardo g, esposito d et al. female sexual dysfunction in women with thyroid disorders. j endocrinol invest. 2013 . 6. salonia a, munarriz rm, naspro r, nappi re, briganti a, chionna r et al. women’s sexual dysfunction: a pathophysiological review. bju int. 2004; 93: 1156–64. 7. imbimbo c, gentile v, palmieri a, longo n, fusco f, granata am et al. female sexual dysfunction: an update on physiopathology. j endocrinol invest. 2003; : 102-104. 8. subramanian s, bopparaju s, desai a, wiggins t, rambaud c, surani s.sexual dysfunction in women with obstructive sleep apnea. sleep breath. 2010;14:59-62. 9. goncalves ma, guilleminault c, ramos e, palha a, paivat. erectil dysfunction, obstructive sleep apnea syndrome and nasal cpap treatment. sleep med. 2005; 6: 333-9. 10. oksuz e, malhan s. prevalence and risk factors for female sexual dysfunction in turkish women. j urol. 2006; 175: 654–658. 11. rosen r, brown, c, heiman j, leiblum s, meston c, shabsigh r et al. the female sexual function index (fsfi): amultidimensional self-report instrument for the assessment of female sexual function. j sex marita.lther. 2000; 26, 191–208. 12. michele d,marleide da mota g. obstructive sleep apnea (osa) and depressive symptoms. arq. neuro-psiquiatr. 2009 67. 13. popovic rm, white dp. upper airway muscle activity in normal women: influence of hormonal status. j appl physio.1998;84:1055-62. 14. onem k, erol b, sanli o, kadioglu p, yalin as, canik u et al. is sexual dysfunction in women with obstructive sleep apnea-hypopnea syndrome associated with the severity of the disease? a pilot study. j sex med. 2008; 5: 2600-9. 15. jurado-gámez b, fernandez-marin mc, gómez-chaparro jl, muñoz-cabrera l, lopez-barea j, perez-jimenez f, et sexual dysfunction and sleep apnea-yilmaz et al. urological oncology 5055 al.relationship of oxidative stres and endothelial dusfunction in sleep apnoea. eurrespir j. 2011;37:873-9. 16. mayer p, dematteis m, pépin jl, wuyam b, veale d, vila aet al.peripheral neuropathy in sleep apnea: a tissue marker of the severity of nocturnal desaturation. am j cirt care med.1999;159: 213-9. 17. dziewas r, schilling m, engel p, boentert m, hor h, okegwoaet al. treatment for obstructive sleep apnoea; effect on peripheral nerve function. j neurolneurosurgpsychiatry 2007;78:295-7. 18. behan m, wenningerjm.sexs steroidal hormones and respiratory control. respirphysiolneurobiol. 2008; 164:213-21. 19. fanfulla f, malaguti s, montagna t, salvini s, bruschi c, crotti pet al. erectile dysfunction in men with obstructive sleep apnea: an earlysign of nevre involvement. sleep. 2000; 23:775-80. 20. karkoulias k, perimenis p, charokopos n, efremidis g, sampsonas f, kaparianosaetal. does cpap therapy improve erectile dysfunction in patients with obstructive sleep apnea syndrome? clin ter. 2007; 158: 515-8. 21. koseoğlu n, koseoğlu h, itil o, oztura i, baklan b, ikiz ao et al. sexual function status in women with obstructive sleep apnea syndrome. j sexmed 2007; 4:1352-7. 22. stavaras c, pastaka c, papala m, gravas s, tzortzis v, melekos m et al. sexual function in pre-and post-menopausal women with obstructive sleep apnea syndrome. int j impot res. 2012;24:228-233. 23. fanfulla f, malaguti s, montagna t, salvini s, bruschi c, crotti p, et al. erectile dysfunction in men with obstructive sleep apnea: an earlysign of nevre involvement. sleep. 2000;23:775-80. 24. reynaert c, zdanowicz n, janne p, jacques d. depression and sexuality. psychiatrdanub. 2010; 22(sppl 1): s: 111-3. 25. shindel aw, eisenberg ml, breyer bn, sharlip id, smith jf. sexual function and depressive symptomsamong female north american medical students. j sex med. 2011;8:391-9. 26. harris m, glozier n, ratnavadiel r, grunstein rr. obstructive sleep apnea and depression. sleep med rev. 2009; 13:437-44. sexual dysfunction and sleep apnea-yilmaz et al. vol 14 no 06 november-december 2017 5056 vol 17 no 03 may-june 2020 112 financial burden of prostate cancer screening: changing trends after health sector reform in a developing country mohammad reza nowroozi, erfan amini*, farhad pishgar, mohsen ayati, hassan jamshidian, seyed majid aghamiri uro-oncology research center, tehran university of medical sciences, tehran, iran. * correspondence: assistant professor of urology, department of urology, uro-oncology research center, tehran university of medical sciences. tehran, iran. telephone: +98 21 6690 3063, fax: +98 21 6690 3063, e-mail address: e-amini@sina.tums.ac.ir; amini.erfan@gmail.com. iranian health system has experienced several reforms in past decades, including establishment of primary health-care network as well as the family physician program and the social protection scheme in rural areas.(1) the new government, elected in june 2013, took health as the top priority and conducted health sector transformation plan (hstp) on may 5, 2014, with the aims of improving health service quality in government hospitals, providing insurance to uninsured iranians, and lowering out-of-pocket payments. upon launch of the hstp, it was welcomed both by patients and health care workers and public satisfaction rate increased to 75%. however, as the program progressed several obstacles emerged, mostly related to the financial burden of the plan, lack of health-related facilities and hospital beds, as well as overuse of services.(1,2) uninformed and unselected opportunistic prostate cancer screening has increased during the implementation of the hstp. prostate cancer does not seem to be a leading cause of death among iranians and the mortality rate has been estimated to be 2.3 deaths per 100,000, far away from the reported rate in the united states.(3) however, an increasing number of men with elevated serum prostate-specific antigen level are being screened for prostate cancer as a consequence of the significant reduction in out-of-pocket payments. since the implementation of the hstp, we have noted 30% increase in prostate biopsies in our institution, a referral center in the field of urologic oncology, resulting in substantial increase in the diagnosis of indolent prostate cancer. prostate cancer overdiagnosis exposes men to the potential morbidities of unnecessary treatments, lowers quality of life, and imposes additional costs to the healthcare system.(4,5) prioritizing of the problems and the solutions is an inevitable part in the planning of health sector reforms. the absence of a well-organized health information system in iran prevents the efficient assessment of health status in addition to impeaching development of national clinical guidelines. preparing such guidelines as a part of the hstp has the potential to overcome overdetection, overtreatment of diseases, and decreases the financial burdens of the plan. economic burden of hstp on the public budget has already raised concerns about the sustainability of the program. the government has invested vast sums in the healthcare system; however, government budget deficits and the fragmented pooling of health insurance funds(6) have led to unpaid wages for up to six months among health workforces in some government hospitals. strict monitoring of the reform process, health information system improvement, developing national guidelines and precise prioritizing of the health challenges are crucial for the sustainability of the hstp and implementing health reforms properly. references 1. moradi-lakeh m, vosoogh-moghaddam a. health sector evolution plan in iran; equity and sustainability concerns. int j health policy manag. 2015;4:637. 2. karami matin b, hajizadeh m, najafi f, homaie rad e, piroozi b, rezaei s. the impact of health sector evolution plan on hospitalization and cesarean section rates in iran: an interrupted time series analysis. international journal for quality in health care. 2018;30:75. 3. mousavi sm, gouya mm, ramazani r, davanlou m, hajsadeghi n, seddighi z. cancer incidence and mortality in iran. ann oncol. 2009;20:556. 4. heijnsdijk ea, wever em, auvinen a, et al. quality-of-life effects of prostate-specific antigen screening. n engl j med. 2012;367:595. 5. loeb s. will changes to prostate cancer screening guidelines preserve benefits and reduce harm? eur urol. 2016. 6. bazyar m, rashidian a, kane s, vaez mahdavi mr, akbari sari a, doshmangir l. policy options to reduce fragmentation in the pooling of health insurance funds in iran. int j health policy manag. 2016;5:253. letter urology journal/vol 17 no. 3/ may-june 2020/ pp. 325-325. [doi: 10.22037/uj.v0i0.4738] pediatric urology the management of phimosis seen after circumcision with thermocautery osman akyüz1, kamil cam2* purpose: one of the most frequent complications after circumcision by thermocautery is phimosis. in this study, we aimed to present the functional and cosmetic results of the modified sleeve technique for the correction of this iatrogenic phimosis. materials and methods: the study group included iatrogenic phimosis cases who underwent circumcision using thermocautery during the last eight years. initially, steroid creams were applied on these patients for six weeks. patients who did not respond to this treatment underwent surgery using the modified sleeve technique. control visits were performed at the first and fourth postoperative weeks. results: a total of 32 patients with a median age of 5.1 ± 1.1 years out of 13285 circumcisions by thermocautery were included in the study. no positive treatment outcomes were obtained by topical steroids, and all patients proceeded to surgery by modified sleeve technique. median operative time was 25 ± 2.3 minutes. cosmetic and functional outcomes were satisfactory in all cases. conclusion: there is no place for topical steroids in management of iatrogenic phimosis after thermocautery, thus early surgery is advised to avoid emotional stress. our modified sleeve technique can achieve maximum cosmetic and functional outcomes without leading to extreme shortening of the penile skin and mucosa. keywords: cautery; circumcision; modified sleeve; phimosis introduction circumcision is the surgical excision and removal of the foreskin to expose glans penis.(1) it is one of the most common surgical procedures throughout the world. one of the most important complications of circumcision is the development of phimosis. especially when thermocautery is used during circumcision, this risk of phimosis significantly increases.(2) by definition, a hard fibrotic ring develops during phimosis that entraps the penis. in some cases, glans penis or external meatus is almost indiscernible. this condition usually leads to development of infections, and occasionally causes voiding problems and may even progress to infravesical obstruction. when response is not achieved with application of steroid creams, phimosis is surgically corrected. since the fibrotic ring is much harder in these iatrogenic cases than that seen with congenital phimosis, even under general anesthesia, forceful retraction of the foreskin cannot expose glans penis. the classical dorsal slit technique for the management of phimosis may result in excessive tissue loss in circumcision associated cases. particularly, an inexperienced surgeon may try to expose the glans by a dorsal slit, which may increase tissue loss when an inadequate length of penile skin remained from the original circumcision. in our study, we modified the sleeve technique to man1 asistant professor of urology, department of urology, school of medicine, biruni university, istanbul. 2 professor of urology, department of urology, school of medicine, marmara university, istanbul. *correspondence: department of urology, school of medicine, biruni university, özel medicine hospital, hoca ahmet yesevi cad. no:149 güneşli, bagcılar, istanbul tel: +90 0532 7919430. fax: +90 0212 4963658. e-mail:akyuzosman@hotmail.com, kamilcam@hotmail.com. received february 2019 & accepted october 2019 age such iatrogenic phimosis. our aim was to provide maximum functional and cosmetic outcomes without unnecessary tissue loss of penile skin and mucosa by this technique. the objective of this study was to define the outcome of our modified sleeve technique for the management of phimosis related to circumcision by thermocautery. materials and methods study population a total of 13285 circumcisions were performed at our institution between september 2009 and september 2017. among them, 48 iatrogenic phimoses developed. however, 16 of these were treated by another physician and were excluded from the study. a total of 32 patients who were surgically treated in our institution for phimosis secondary to circumcision with thermocautery were included. phimosis was graded based on the classification by kikiros et al., described for patients with congenital phimosis.(3) before surgical intervention, topical application of clobetasol propionate (0.05%) cream was tried twice daily for a period of six weeks. when corticosteroid therapy failed, surgical revision was recommended to the patients. the characteristics of the patients are summarized in table 1. at all stages of the study, the families were informed about the procedure, and their urology journal/vol 17 no. 1/ january-february 2020/ pp. 50-54. [doi: 10.22037/uj.v0i0.5138] vol 17 no 01 january-february 2020 51 informed consent forms were obtained. this study was carried out in accordance with the helsinki declaration. approval for conducting the study was granted by our institutional ethics committee (register no: 2018/1530). surgical technique all interventions were performed in the operating room under general anesthesia by the same urologist (dr. o.a.). the sleeve method described for circumcision was modified to a “short double slit method,” and used for all patients in the study. the starting point was the stenotic ring. the foreskin was retracted delicately backwards till the stenotic ring was exposed. first the superficial layer of the stenotic ring was incised circumferentially, and the penile skin was dissected without loss of any intact tissue (figures 1a and 1b). then, the stenotic ring was incised using a scalpel deeply for 1-2 mm at the 12 o’clock position to expose the glans penis (figure 1c). after exposure of the glans penis and identification of penile mucosa, the internal aspect of the stenotic ring was incised circumferentially (figure 1d). in other worlds, the first and the second circumferential incisions performed through the healthy skin in the proximal end of the fibrotic ring, and through the healthy mucosa in the distal end of the fibrotic ring, respectively. consequently, the stenotic ring between the two lines of incision was excised circumferentially and then removed (figure 1e). afterwards skin and mucosa were re-sutured with absorbable sutures (figure 1f). follow-up: all patients were discharged on the day of surgery. as an anti-inflammatory analgesic, ibuprofen in a dose of 5 mg/kg was given at 8-hour intervals. dressing with 0.2% nitrofurazone ointment was initiated. control visits at the first and fourth weeks postoperative were performed. results a total of 13285 circumcisions by thermocautery under local anesthesia were performed in our institution during the period studied. all patients had follow-up two control visits at first and four weeks after the procedure, respectively. a total of 48 (0.36%) patients developed phimosis after circumcision by thermocautery. among them, 16 cases had been treated and followed up by other physicians and were excluded. the median age was 5.1±1.1 years (range, between one and eight years) of the remaining 32 iatrogenic phimosis cases. phimosis developed in the four weeks after circumcision in all cases. physical examination assessed the phimosis as grade 5 in 20 patients and grade 4 in 12 patients, based on the classification by kikiros et al.(3) the other complications in the whole group with thermocautery were surgical site infection in 13 patients, meatal stenosis in management of iatrojenic phimosis-akyuz et al. table 1. the characteristics of the patients number (%) total number of the circumcision 13285 the number of iatrogenic phimosis 48 (0.36%) the number of surgically treated phimosis cases (study group) 32 (0.24%) 1 –8 years (mean 5.1±1.1 years) age range of phimosis underwent surgical correction the severity of phimosis* grade 5 20 (0.15%) grade 4 12 (0.09%) * according to kikiros at al. figure 1. the flowchart of patients with phimosis after thermocautery. 3 patients, epidermal cyst in 2 patients and inadequate skin removal 1patient. there was no bleeding requiring surgical intervention. no perceptible response to topical steroids was observed in the grade 5 cases. only three patients with grade 4 phimosis had a transient and limited downgrade of phimosis to grade 3, but all these patients then progressed back to grade 4 in two weeks despite prolonged steroid treatment. in conclusion medical treatment with topical steroids showed no efficacy in the management of phimosis associated with thermocautery, and all patients proceeded to surgery. the modified sleeve technique as described above was performed for correcting the phimosis in all cases. the mean operative time was 25 ± 2.3 minutes (range, between 18 and 40 minutes). no intraoperative or postoperative complications developed. the preand post-operative appearances of the penises are shown in figures 2a, and 2b, respectively. significant constriction of the stenotic ring on the glans is seen in figure 2b (arrow). notably, in cases with shortened penile skin from the original circumcision, maximum cosmetic and functional outcomes were achieved without further shortening of the penile skin by this modified technique. the consequence of patients in each step is summarized in figure 1. discussion circumcision is one of the most ancient surgical interventions, and still among the most frequently applied surgical procedures throughout the world.(4) it has been postulated that approximately 30% of males over 15 years of age in the world have had circumcision surgery. although the majority of these men are muslims, if one also considers the social and medical reasons for circumcision in the non-muslim world, the rate of circumcision can rise to 33% throughout the world.(5) in our country, almost all boys are circumcised due to religious considerations. our hospital is located in a crowded region; several organizations sponsor circumcisions for children from low income circumstances. therefore, approximately 20 to 30 circumcisions are performed daily at our institution, increasing during the summer when these organizations are more active. as a consequence, we were able to include such a large number of patients in this study. on the other hand, physiologic phimosis is described as the inability to retract the foreskin due to adhesions between the foreskin and the glans. this condition accounts for 96% of the cases seen during the neonatal period, and with age it disappears down to 1%.(6)pathologic phimosis develops as a result of inadequate hygiene, recurrent episodes of balanitis or balanoposthitis, or forceful retraction of the foreskin, all of which lead to scarring of the preputial orifice.(7) however, phimosis is also observed as a frequent complication following circumcision, particularly with the use of thermocautery during the procedure, resulting in extremely thicker and harder stenotic rings than those with physiologic phimosis. this condition may be related to the surgical intervention itself or it may occur due to energy sources such as the thermocautery. in eastern societies, greater numbers of circumcisions are performed, mostly under local anesthesia, because of extremely large numbers of children to be circumcised pediatric urology 52 figure 2. (a) appearance before surgical intervention. (b) appearance after surgical intervention . (b arrow sign) the mark left on glans penis by stenotic ring. figure 3. the flowchart of patients with phimosis after thermocautery. management of iatrojenic phimosis-akyuz et al. vol 17 no 01 january-february 2020 53 and insufficient hospital beds and operating rooms to accommodate them. therefore, an easy to perform and cost-effective procedure for circumcision under local anesthesia would gain great popularity. thermocautery is one such method and has been used widely in eastern societies. the greatest advantage of thermocautery is that it is associated with minimal or no bleeding at all. karaman et al. have demonstrated that even in patients with bleeding diathesis, thermocautery can be safely used for circumcision.(8). there are no adequate clinical or experimental studies in the literature on histopathological changes following circumcision with thermocautery. according to a histopathological examination, the depth of the thermal effect on the cortical tissue was reported to be only 0.1 mm.(9) in a recent study performed on rats, the authors have shown that use of thermocautery for circumcision is a safe method resulting in better wound healing and without any notable complications.(10) however, they observed more intense collagen proliferation and granulation than that of monopolar and bipolar incisions. examination was carried out at the fifth day after surgery, while a longer time period would be required to develop a stenotic ring, based on this higher granulation and collagen deposition. another advantage thermocautery is that it provides a reasonable approximation and adhesion of wound edges without suturing, especially in small children. arslan et al. reported that they did not use sutures with thermocautery in 3,420 small children out of 5,870 circumcision procedures.(11) the most frequently encountered complication after circumcision by thermocautery is the development of phimosis. this outcome is more frequently seen in cases with a concealed (buried) penis. secondary to the development of phimosis, the glans penis is trapped, and in some cases, almost imperceptible. aydoğdu et al. indicated that phimosis developed in 20% of the cases of circumcision by thermocautery, and all of these cases underwent surgical correction.(12) however, they did not specify the kind of surgical approach they used. in our research, we observed a rate of 0.36% for phimosis after thermocautery. as in the case of congenital phimosis, steroid creams can be tried for healing phimosis. in this study we applied a potent steroid cream preoperatively for six weeks in all patients. however, no persistent healing of phimosis was observed in any patient. on the other hand, in cases with congenital phimosis, steroid creams with low potency can relieve phimosis in the majority of cases. esposito et al. reported success rates from 65% to 95% using steroid creams in cases of congenital phimosis.(13) therefore, early surgical treatment should be suggested for these cases to avoid emotional disturbances resulting from delaying medical treatment. in the past, we used a dorsal slit to treat phimosis associated with thermocautery. however in cases with a shorter foreskin and/or mucosa, the dorsal slit method could lead to unnecessary tissue loss. furthermore, particularly in cases with trapped penis, the length of the mucosa, and thickness of the stenotic ring cannot be determined. contrary to stenotic rings seen in congenital phimosis, fibrotic rings with up to 7-8-mm thickness may develop in these iatrogenic cases. therefore, a more optimal and standard technique than the dorsal slit is required for the correction, based on our previous unpleasant experiences. this new technique is in fact a modification of the sleeve method for circumcision. in this method, the skin is incised circumferentially and then excised, with the aim of preserving as much skin length as possible. the mucosa was incised at the 12 o’clock position and glans penis exposed. mucosa of a suitable length was retained and incised circumferentially. the thick stenotic ring in between was removed and then re-sutured. with this modified method, excessive shortening of the foreskin is avoided and an optimal cosmetic appearance is achieved. this is the first report in the literature describing the modified sleeve technique for treating phimosis associated with thermocautery. as this problem usually emerges soon after circumcision, both the families and the children can experience serious psychological trauma. therefore, an early and easy treatment approach with reasonable cosmetic results should be advised for these patients. this study provides an optimal surgical approach for these patients, and suggests that medical treatment with topical steroids has no place in cases of phimosis associated with thermocautery. conclusions in this study, we first document that topical steroids have no role in the management of iatrogenic phimosis associated with circumcision by thermocautery. consequently, early surgery is required to minimize emotional disturbances. additionally, phimosis associated with thermocautery has much thicker and harder stenotic rings. finally, we describe the modified surgical method for the first time in the literature for treating phimosis associated with thermocautery. the modified sleeve excision of phimosis in these cases allows the preservation of a longer foreskin and/or mucosal length and a better cosmetic result. conflicts of interest there are no conflicts of interest. references 1. blank s, brady m, buerk e, carlo w, diekema d, freedman a, et al. american academy of pediatrics, task force on circumcision: male circumcision. pediatrics. 2012; 130: e756–85. 2. akyüz o, bodakçi mn, tefekli ah, thermal cautery-assisted circumcision and principles of its use to decrease complication rates. j pediatr urol. 2019 ; 19. pii: s1477-5131(19)30005-1. 3. kikiros cs, beasley sw, woodward aa. the response of phimosis to local steroid application. pediatr surg int. 1993; 8: 329-32. 4. dunsmuir wd, gordon em. the history of circumcision. bju international. 1999; 83: 1-12. 5. who/unaids: male circumcision: global trends and determinants of prevalence, safety and acceptability. world health organization 2008. 6. qster j. further fate of the foreskin. incidence of preputial adhesions, phimosis and smegma among danish schoolboys. arc dis child. 1968; 43: 200-03. management of iatrojenic phimosis-akyuz et al. 7. pedersini p, parolini f, bulotta al, alberti d. "trident" preputial plasty for phimosis in childhood. j ped urol. 2017; 13: 278 -82. 8. karaman mi, zulfikar b, caskurlu t, ergenekon e. circumcision in hemophilia: a cost-effective method using a novel device. j pediatr surg. 2004; 39: 1562 -4. 9. abdel hay s. the use of thermal cautery for male circumcision. 2009; jkau med sci. 2009; 16: 89-93. 10. tuncer aa, bozkurt mf, bayraktaroğlu a, koca h, doğan i, çetinkursun s, et al. examination of histopathological changes of scalpel, monopolar, bipolar, and thermocautery applications in rat experimental circumcision model. am j transl res. 2017; 9: 2306 -13. 11. arslan d, kalkan m, yazgan h, unuvar u, sahin c. collective circumcision performed in sudan:evaluation in terms of early complications and alternative practice. pediatric urology. 2013; 81: 864 -8. 12. aydoğdu b, tireli ag, demirali o, güvenç o, beşikbaşdaş c, sander s. sünnet komplikasyonlarında klinik deneyimimiz. jopp derg. 2011; 3:64-67. 13. esposito c, centonze a, alicchio f, savanelli a, settimi a. topical steroid application versus circumcision in pediatric patients with phimosis: a prospective randomized placebo controlled clinical trial. world j urol 2008, 26: 187-90. management of iatrojenic phimosis-akyuz et al. pediatric urology 54 urological oncology discrepancies between biopsy gleason score and radical prostatectomy specimen gleason score: an iranian experience shahaboddin dolatkhah1, maryam mirtalebi1, parnaz daneshpajouhnejad2,3, ahmadreza barahimi4, hamid mazdak5, mohammad hossein izadpanahi6, mehrdad mohammadi5, diana taheri1,7* purpose: considering the importance of treatment decisions for prostate cancer (pca) and the utility of gleason scoring system (gs) in this field, we aimed to assess the percent of agreement and disagreement between needle biopsy (nb) gleason score and radical prostatectomy (rp) specimen gleason score. materials and methods: in this retrospective study, consecutive patients with pca, who underwent nb and subsequently rp were enrolled. gs of both nb and rp specimens were recorded for each patient. patients were classified according to the gs as low-grade (≤ 3+3), intermediate-grade (3+4 and 4+3), and high-grade (gs．810). the levels of agreement and discrepancy of nb gs was compared to its corresponding rp gs using kappa coefficient of agreement. over-grading and under-grading of nb gs were also determined. result: a total of 100 embedded rp and corresponding nb were analyzed. the rate of discrepancy for group and individual scoring of gs was 41% and 56%, respectively. the rate of under and over-grading was 34% and 7%, respectively. kappa value for group and individual scoring was .443 (95%ci: .313 .573) and .411 (95%ci: .291 .531), respectively. conclusion: the findings of our study indicate that though the agreement between nb gs and rp gs are fair to moderate, but the feature of discrepancy, i.e. under-grading in low and intermediate grades and over-grading in high grades of nb gs, could help us in making more appropriate clinical decision especially considering other biochemical and pathological factors such as the level of psa or peri-neural invasion. keywords: gleason score; grading; needle biopsy; prostate cancer; radical prostatectomy introduction prostate cancer (pca) is considered as the most fre-quent cancer in men according to the annually-updated cancer statistics from the national cancer institute (1). pca is the second leading cause of cancer-related deaths in men. it is estimated that the rate of new cases of pca and its related deaths would be 1.7 million and 499000 by 2030 in the world(2). one study in iran showed the standardized incidence of pca in 2003 to 2009 to be 5.4, 7.24, 9.22, 9.57, 10.91, and 12.80 cases per 100,000 people, respectively, which shows a continuous increase in its incidence in recent years(3). the gleason scoring system (gs) which was first described by gleason and mellinger in 1960, is the most commonly used practical evaluation tool for patients with pca. this histological grading tool is considered as the most powerful prognostic method to predict pa1department of pathology, school of medicine, isfahan university of medical sciences, isfahan, iran. 2student research committee, isfahan medical students’ research center, school of medicine, isfahan university of medical sciences, isfahan, iran. 3department of pathology, isfahan kidney disease research center, isfahan university of medical sciences, isfahan, iran. 4department of medical mycology, school of medicine, tarbiat modares university, tehran, iran. 5department of urology, school of medicine, isfahan university of medical sciences, isfahan, iran. 6department of urology, isfahan urology and kidney transplantation research center, isfahan university of medical sciences, isfahan, iran. 7isfahan kidney diseases research center, isfahan university of medical sciences, isfahan, iran. *correspondence: department of pathology, isfahan kidney diseases research center, isfahan university of medical sciences, isfahan, iran. tel: +989131061773, e-mail: d_taheri@med.mui.ac.ir. received september 2017 & accepted june 2018 tients' clinical outcomes and to determine an appropriate treatment strategy for patients with pca(4). gs is currently used for both needle biopsy (nb) and radical prostatectomy (rp) specimens. although the rp gs represents the “true” grade of pca(5), the use of nb gs has recently increased as a diagnostic and therapeutic alternative to rp(6). some characteristics of gs such as ease of learning and reproductivity make this system as an appropriate diagnostic tool for prognostic and therapeutic manage¬ment of pca(7). however, previous studies in this field have reported a significant discrepancy between the gs of nb and rp specimens (8). factors such as multifocal nature of pca and the inherent sampling error of diagnostic nb could explain the causes of this discrepancy(9). present evidence indicates that depending on the series and the periods of examination, nb gs underestimates and overestimates the rp gs in 18%-60% and 6%-25% of cases, respectively(10,11). urological oncology 56 vol 16 no 01 january-february 2019 57 moreover, it seems highly beneficial to evaluate the correlation between nb and rp gs in an iranian population with different clinical settings and pca causes compared to developed countries(12). thus, considering the increasing rate of pca and its related morbidity and mortality among iranian males(7), and the differences in clinical settings in iran, we aimed to evaluate the discrepancy between nb gs and rp gs in a series of iranian patients with pca undergoing prostate nb and subsequent rp. to our knowledge, no previous studies have been performed in iran on this topic. the results of this study would definitely be useful in treatment decisions especially between active surveillance and curative intent therapy, as well as the utility of gs in this field(13). materials and methods study population in this retrospective study, all consecutive patients diagnosed with pca, who underwent radical retro-pubic prostatectomy in al-zahra hospital, which is affiliated to isfahan university of medical sciences, isfahan, iran, from may 2009 to may 2012, were enrolled with simple sampling method. the protocol of this study was approved by regional ethics committee of isfahan university of medical sciences. inclusion and exclusion criteria: inclusion criteria were the availability of both preoperative nb and corresponding rp pathologic specimens. all patients underwent nb prior to rp. patients with a history of neoadjuvant or adjuvant hormone therapy were excluded in order to eliminate bias in the histopathologic evaluation of samples and defining the gleason score. procedures and evaluations all selected pathological specimens were reviewed by the same expert genitourinary pathologist to avoid inter-observer variability. the uropathologist was blinded for the patient’s identity and for the original diagnosis and outcome (including any additional np or rp biopsy results). clinicopathologic characteristics of selected patients including the clinical stage of pca, pre-biopsy psa level and presence of peri-neural invasion (pni) were recorded. the updated gs of both nb and rp specimens were determined and recorded for each patient. patients were classified according to the international society of urological pathology (isup) criteria on gleason grading of pca(14) as low-grade (gs ≤ 3 + 3), intermediate-grade (3 + 4 and 4 + 3) and high-grade (gs ≥ 8 10). the levels of agreement and discrepancy for each patient nb gs were assessed aligned with their corresponding rp gs. over-grading and under-grading were defined as nb gs higher and lower than rp gs, respectively. specimens’ preparation the nb specimens were performed using conventional trans-rectal, ultrasound-guided (trus) procedure under general anesthesia with antibiotic cover by the same surgeon. after placing the patient in the left lateral position, an ultrasound probe (bk medical pro-focus 2202; bk medical, mileparken, denmark) was placed in the rectum to visualize the prostate. then, 12-24 trus guided core biopsies were taken from the right and left peripheral zones at the surgeon’s discretion. all biopsies were stained with hematoxylin and eosin. rp specimens were formalin fixed, paraffin-embedded sections which stained with hematoxylin and eosin. the specimens were sectioned at 4 mm intervals from apex to base. gs for both nb and rp specimens was assigned based on the sum of their primary and secondary tumor patterns. table 1. clinicopathologic characteristics of patients with prostate carcinoma clinocopathologic characteristic number (%) number of patients 100 (100%) mean age in years ± standard deviation (sd) (range) 63.0 ± 6.9 (42-78) number of patients at a clinical stage t1 2 (2%) t2a 45 (45%) t2b 18 (18%) t3 19 (19%) t4 16 (16%) mean ± sd pre-biopsy psa* in each stage group (ng/ml) t1 9.0 ± 6.3 t2a 12.1 ± 9.4 t2b 10.2 ± 6.2 t3 19.1 ± 16.7 t4 20.1 ± 11.3 mean ± sd pre-biopsy psa in the total population (ng/ml) 14.3 ± 11.5 biopsy gleason score (%) ≤ 3 + 3 78 (78%) 3 + 4 13 (13%) 4 + 3 5 (5%) 8 – 10 4 (4%) radical prostatectomy gleason score (%) ≤ 3 + 3 63 (63%) 3 + 4 24 (24%) 4 + 3 9 (9%) 8 – 10 4 (4%) positive perineural invasion (%) 75 (75%) *‘psa, prostatic-specific antigen. all values expressed in numbers (percentages) unless expressed otherwise. needle biopsy and radical prostatectomy gleason score-dolatkhah et al. statistical analysis obtained data were analyzed using spss software ver.21 (spss inc., chicago, il, u.s.a.) and student's t-test and the chi-square test was used for comparing quantitative and qualitative variables, respectively. the concordance between nb and rp gss was evaluated through the coefficient of the agreement, the kappa and weighed kappa statistic. 95% confidence intervals (cis) are also reported. the kappa statistic is a measure of agreement between two observations and considers the chance agreement(15). kappa was calculated for each individual(2-10) gss also. kappa agreement was calculated using graphpad software (2015 graphpad prism software, california, usa). a p-value less than 0.05 was considered statistically significant. results in this study, a total of 100 embedded rp and corresponding nbs were analyzed according to the updated gleason system. clinicopathologic characteristics of studied patients are presented in table1. mean age of subjects was 63.0 ± 6.9 ranging from 42 to 78 years. mean of psa level was 14.3 ± 11.5 before taking biopsy. the median gs of all nbs was 6, whereas for rp it was 7. discrepancies between the gleason scores of the biopsies and prostatectomy specimens are illustrated in table 2. it is reported that among the 55 patients with gleason score of ≤ 3 + 3 on nb, an accuracy of 61.8% for gleason scores of ≤ 3 + 3 is seen. of the 27 patients with gleason scores of 3 + 4 and 4 + 3 on nb, 48.1% were graded correctly, while 48.1% were under-graded and 3.7% were over-graded. from 18 cases with highgrade tumor in nb, 66.7% were graded correctly and reminder were under-graded. overall rate of under and over-grading was 34% and 7%, respectively. the rate of concordance, over-grading and under-grading of gleason score from nbs compared with rps are presented in figure 1. for group scoring, the number of observed agreements was 59 (59%). the reliabilty of biopsy for group scoring using kappa statistics yielded a value of .374 (95% ci: .240 .509) reflecting fair agreement beyond chance. weighted kappa value was .443 (95% ci: .313 .573), which represent moderate agreement. for individual scoring, the number of observed agreements was 44 (44%). the reliabilty of biopsy for group scoring using kappa statistics yielded a value of .290 (95% ci: .173 .406), reflecting fair agreement beyond chance. weighted kappa value was .411 (95% ci: .291 .531), which represent moderate agreement. we considered the weighted kappa, because most of the discrepancies are related to closer scores. the pni was presented in 23 (62.2%), 23 (74.2%) and 30 (93.7%) of low, moderate and high-grade pca according to the rp gs, respectively. pni was presented in 41 (74.5%), 21 (77.8%) and 14 (77.8%) of low, moderate and high-grade pca according to the nb gs, respectively. mean of psa in low, moderate and high-grade pca according to the rp gs was 13.1 ± 10.7, 17.3 ± 11.6 and 20.2 ± 11.1, respectively. mean of psa in low, moderate and high-grade pca according to the nb gs was 9.0 ± 5.1, 11.0 ± 5.3 and 22.1 ± 10.6, respectively. discussion in this study, we have evaluated the discrepancies between nb and rp gs scoring in our center. we have found a 41% and 56% discrepancies between group and individual scoring of the two methods of gs scoring, respectively. most cases of discrepancies were related to low and intermediate grade of nb gs and were mainly represented with under-grading for low and intermediate-grades. whereas, for high-grade scoring, all of the discrepancies were represented as over-graded nb gs. recently, in accordance with the introduction of different therapeutic alternatives to rp, the use of bioptic gs has become as an important issue in the diagnosis and management of pca (6). on the other hand, several studtable2. comparison of number of cases in each group of gleason score from needle biopsies (nb gs) and radical prostatectomy (rp gs) specimens. nb gs low grade intermediate high grade total rp gs ≤ 3 + 3 4 + 3 and 3 + 4 ≥ 8 10 37 (37.0%) low grade ≤ 3 + 3 34 (61.8%) 1 (3.8%) 2 (11.1%) intermediate 4 + 3 and 3 + 4 14 (25.5%) 13 (48.1%) 4 (22.2%) 31 (31.0%) high grade ≥ 8 10 7 (12.7%) 13 (48.1%) 12 (66.7%) 32 (32.0%) total 55 (100%) 27 (100%) 18 (100%) 100 (100%) figure 1. the rate of concordance, over-grading and under-grading of gleason score (gs) from needle biopsies compared to radical prostatectomy in different groups of gs based on needle biopsy results needle biopsy and radical prostatectomy gleason score-dolatkhah et al. urological oncology 58 vol 16 no 01 january-february 2019 59 ies have investigated the correlation between bioptic gs and rp gs and reported discrepancies between the two mentioned gs. thus, it is suggested that in order to optimize the utility of bioptic gs in the management of pcs, evaluating the discrepancies of the two methods in each center and its related factors, could provide us with baseline information to minimize the discrepancies and improve the diagnostic utility of nb gs. several studies with different designs have investigated the discrepancy and over and under-grading rates of nb gs compared with rp gs. in a study in norway among 1116 patients with pca, reported correlation between the two grading methods was 53%, and under-grading and over-grading were 38% and 9%, respectively(8). arrabal-polo et al. in spain also have reported similar results(16). in our study the rate of concordance, under-grading and over-grading was 59%, 34%, and 7%, respectively. our results were similar to most of the reported studies in this field(17). noguchi et al. have reported lower rate of concordance (36%) and higher rate of over (18%) and under (46%) grading(18). the largest series of patients have been investigated by epstein et al. by analyzing 7643 patients for the correlation between nb and rp gs. they reported a 36.3% undergrading for gs 5-6 and a 58% similar results for gs 9-10(19). rajinikanth and colleagues in the usa showed that most of under-graded cases in nb gs were related to gs ≤ 6 and over grading were more in nb gs of 8-10(20). the results of our study were similar to this study. in our study 6 of 7 cases of over-grading, were for nb gs of 8-10 and 1 was for nb gs of 7. recently, walker et al. in canada have investigated the trend and change in discordance rates between nb and rp after implementation of active surveillance and updating of the gleason scoring protocol by the international society of urologic pathology in 2005. they indicated that the rate of discordance have decreased since 2005 in a way that the proportion of under-grading by nb has decreased for 50%(21). it seems that under-grading of nb gs is considered to be the most important part of reported discrepancies. some factors including pathologic diagnosis error or experience of the pathologist, borderline cases, sampling error and reverse sampling error could explain the finings as well as the higher rate of its related under-grading(22). there are evidences that increasing the number of biopsies would decrease the rate of discrepancy(23). in a regional experience in australia, ooi et al. have reported a concordance rate of 43% and under-grading rate of 46%. they concluded that the number of biopsies could improve scoring accuracy(24). in a population-based study, rapiti and colleagues have investigated the degree of concordance between nb and rp gs in 371 cases of pca, in geneva, switzerland. they used kappa statistic for evaluating the concordance. their findings indicated that in 67% of studied population the grading was similar and in 26% was under-graded by nb gs. the kappa agreement was 0.42. they also indicated that the concordance rate would be improved by increasing the number of biopsy cores(22). kappa agreement in our study was similar to the mentioned study. another explanation for obtained discrepancy is the time interval between biopsy and rp. evidences suggest that increasing the time period between biopsy and rp, could increase the rate of under-grading especially for cases with lower grade tumors(25). it is worth to mention that in our study we used trus biopsy method in evaluation of pca. one study has compared transperineal template prostate biopsy to trus and concluded that transperineal template prostate biopsy results in an almost 4-fold higher rate for pca detection compared to trus biopsy(26). another study has also suggested transperineal sector biopsy as a first-line diagnostic strategy which can be used as a safe and effective approach with high cancer detection rates compared to trus biopsy(27). in this study, pni was reported in 75% of all cases and the rate had increasing trend with increasing the grade of pca. the trend was more significant by using rp gs. mean of psa was also higher in higher grade of pca both in nb gs and rp gs. it seems that in cases with lower grade of pca, clinical condition of the patients in accordance with factors such as pni and level of psa could help us for making more appropriate treatment approach. the limitations of this study were small sample size of studied population, single center evaluation and retrospective design of the study. furthermore, we have not recorded the number of biopsies in each nb and rp, core length of biopsy and prostate weight due to missing data in the medical files of the patients. previous studies showed that the concordance between nb and rp gs scoring is higher in a larger number of biopsy specimens. reis et al. in brazil have reported the association between core length of biopsy as well as prostate weight (inverse relation) with rp gs up-grading(28). moreover, due to the small sample size we could not investigate the role of different factors such as age, level of psa, size of the gland, etc. in predicting the discrepancies between nb and rp gss. the small sample size further resulted in a low number of cases with gc > 7 which may under power the findings of our study in generalizability to high-grade tumor patients. conclusions the findings of our study indicated that though the agreement between nb gs and rp gs are fair to moderate, the feature of discrepancy, i.e. under-grading in low and intermediate grades and over-grading in high grades of nb gs, could help us for making more appropriate clinical decision specially if other biochemical and pathological factors such as the level of psa or pni are considered. this study has utmost advantage for interpretation of results in our center, and urges us to improve the biopsy techniques and pathology reports in our center to be able to rely more on the pathology readings for patient on active surveillance. it is recommended to plan future studies to determine factors which could predict discrepancies between the two methods as well as strategies to reduce it in order to provide more appropriate treatment strategies using nb gs. acknowledgement this study was approved and under financial support by isfahan university of medical sciences as a research project. conflict of interest the authors report no conflict of interest. needle biopsy and radical prostatectomy gleason score-dolatkhah et al. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2015. ca: ca cancer j clin. 2015;65:5-29. 2. ferlay j. globocan 2008, cancer incidence and mortality worldwide: iarc cancerbase no. 10. http://globocan/. iarc. fr. 2010. 3. pakzad r, rafiemanesh h, 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significance for men with nonpalpable prostate cancer. j urol.. 2001;166:104-10. 19. epstein ji, feng z, trock bj, pierorazio pm. upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified gleason grading system and factoring in tertiary grades. eur urol. 2012;61:1019-24. 20. rajinikanth a, manoharan m, soloway ct, civantos fj, soloway ms. trends in gleason score: concordance between biopsy and prostatectomy over 15 years. urology. 2008;72:177-82. 21. walker r, lindner u, louis a, et al. concordance between transrectal ultrasound guided biopsy results and radical prostatectomy final pathology: are we getting better at predicting final pathology? can urol assoc j. 2014;8:47. 22. rapiti e, schaffar r, iselin c, et al. importance and determinants of gleason score undergrading on biopsy sample of prostate cancer in a population-based study. bmc urol. 2013;13:19. 23. divrik rt, erogˇlu a, şahin a, zorlu f, özen h. increasing the number of biopsies increases the concordance of gleason scores of needle biopsies and prostatectomy specimens. paper presented at: urologic oncology: seminars and original investigations, 2007. 24. ooi k, samali r. discrepancies in gleason scoring of prostate biopsies and radical prostatectomy specimens and the effects of multiple needle biopsies on scoring accuracy. a regional experience in tamworth, australia. anz j surg. 2007;77:336-8. 25. eroglu m, doluoglu og, sarici h, telli o, ozgur bc, bozkurt s. does the time from biopsy to radical prostatectomy affect gleason score upgrading in patients with clinical t1c urological oncology 60 vol 16 no 01 january-february 2019 61 prostate cancer? korean j urol. 2014;55:3959. 26. nafie s, wanis m, khan m. the efficacy of transrectal ultrasound guided biopsy versus transperineal template biopsy of the prostate in diagnosing prostate cancer in men with previous negative transrectal ultrasound guided biopsy. urol j. 2017;14:3008-12. 27. eldred-evans d, kasivisvanathan v, khan f, et al. the use of transperineal sector biopsy as a first-line biopsy strategy: a multiinstitutional analysis of clinical outcomes and complications. urol j. 2016;13:2849-55. 28. reis lo, sanches bc, de mendonça gb, et al. gleason underestimation is predicted by prostate biopsy core length. world j urol. 2015;33:821-6. needle biopsy and radical prostatectomy gleason score-dolatkhah et al. urological oncology prostate specific antigen nadir after radical cystoprostatectomy in patients with benign prostatic tissue: a benchmark to define biochemical recurrence after radical prostatectomy seyed yousef hosseini1, mohsen alemi2 *, erfan amini3, naser riazi4 purpose: biochemical failure after radical prostatectomy has been defined based on retrospective studies in men who underwent rp for localized prostate cancer. nevertheless, retrospective strategy and possibility of extra-prostatic extension overshadowed the accurateness of the aforementioned cut-off value. to define a more precise psa nadir value, we estimated serum psa after cystoprostatectomy in cases with bladder urothelial cancer and no evidence of prostate cancer. materials and methods: study population consists of 52 subsequent patients who underwent radical cystoprostatectomy for muscle-invasive bladder cancer between december 2010 and december 2013. patients with prostate adenocarcinoma and/or high grade prostate intraepithelial neoplasia were excluded from enrollment. other exclusion criteria were prostate involvement with urothelial carcinoma, neoadjuvant or adjuvant chemotherapy and radiation therapy. between all cases, 41 were enrolled for study. serum psa level was measured using immunochemiluminescence method from 6 months to 3 years after operation in study participants. results: forty-one patients with mean age of 66.4 ± 8.9 years were assessed in this study. average serum psa level after radical cysto-prostatectomy was: 037 ± .031 ng/ml (from .002 to .1). serum psa level was not impressed with type of diversion or interval between operation and psa measurement. average serum psa level in this study was meaningfully lesser than .2 ng/ml which is contemplated as psa nadir value after rp. conclusion: serum psa level of 0.2 ng/ml as the definition for biochemical recurrence after rp may delay salvage treatment. our results showed that cut off value of （0.1 ng/ml may be more precise in the era of early salvage treatment. keywords: biochemical recurrence; nadir; prostate specific antigen; radical cystectomy; radical prostatectomy. introduction with the advent of prostate specific antigen (psa) in 1980, clinicians were able to recognize prostate cancer at an early stage when the disease is amenable to definitive treatments.(1) psa is also a valuable biomarker for early detection of disease recurrence after initial definitive treatment i.e. radical prostatectomy and radiation therapy. psa increase to a certain threshold after radical prostatectomy, biochemical recurrence, may predict local or distant recurrence in future. the natural history after biochemical recurrence is variable and biochemical recurrence does not translate to metastatic disease and death in all patients.(2) the median time from biochemical recurrence to metastatic disease has been reported to be 8 years.(3) definition of biochemical recurrence may be of utmost importance in the diagnosis of treatment failure and timely use of salvage treatments. some investigators have proposed a cut-off value of .4 ng/ml for definition of biochemical recurrence.(4,5) according to american urological as1department of urology, shahid modarres hospital, and urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 2urology and nephrology research center, hamadan university of medical sciences, hamadan, iran. 3department of urology, uro-oncology research center, tehran university of medical sciences, tehran, iran. 4department of urology, shahid mohammadi hospital, hormozgan university of medical sciences, bandar abbas, iran. *correspondence: department of urology, shahid beheshti hospital, hamadan university of medical sciences, hamadan, iran. telefax:+98-8138380155, e-mail: mohsenalemi@yahoo.com. received april 2018 & accepted march 2019 sociation and american society of clinical oncology guidelines an initial and confirmatory psa value of ≥ .2 ng/ml after radical prostatectomy is considered as biochemical recurrence.(6) national comprehensive cancer network has defined biochemical failure as a detectable psa (while it was undetectable after surgery) and 2 subsequent rises. however there is no definition of detectable psa.(7) therefore, there is no consensus on the definition of biochemical recurrence after radical prostatectomy in the literature; in addition, the presence of benign prostatic tissue after radical prostatectomy, and extra-prostatic sources of psa may interfere with postoperative psa measurements and precise definition of biochemical recurrence. we conducted this study to assess postoperative psa in men who underwent radical cystoprostatectomy for urothelial bladder cancer and no pathological evidence of prostate cancer. the distribution of psa values in this population can be used as a benchmark for determining the optimal nadir value as well as defining detection threshold in the era of ultrasensitive psa. urology journal/vol 16 no. 6/ november-december2019/ pp. 563-566. [doi: 10.22037/uj.v0i0.4551] materials and methods all consecutive patients who underwent radical cystoprostatectomy with curative intent between december 2010 and december 2013 were considered for enrollment in this prospective cohort. patients with prostate adenocarcinoma or high grade intraepithelial neoplasia in the final cystoprostatectomy specimen were excluded from enrollment. additional exclusion criteria were prostate involvement with urothelial carcinoma, neoadjuvant or adjuvant chemotherapy and radiation therapy. it should be noted that all surgeries were performed by or under supervision of one urologist (syh). histopathological evaluation of prostatic tissue in cystoprostatectomy specimens was performed in slices with 3 micrometers in thickness. any evidence of prostatic adenocarcinoma and/or high grade prostatic intraepithelial neoplasia were considered as exclusion criteria. a total of 41 patients were eligible for the study. the serum psa level was measured by eclia (electro chemi luminesence immunoassay) between 6 months and 3 years after surgery. institutional review board approved the study and written informed consent was obtained from all participants. statistical analysis statistical analysis was performed using spss version 16 (spss inc., chicago, il, usa). frequency of patients with undetectable psa was determined. different cut-off values were used to define undetectable psa. using t-test, mean value of serum psa after cystoprostatectomy was compared to 0.2 as the threshold of biochemical recurrence. in addition, the effect of age, disease stage, and time elapsed from surgery as well as type of urinary diversion on postoperative serum psa was evaluated. p value of less than 0.05 was considered as statistically significant. results a total of 41 patients with mean age of 65.1 ± 8.7 (range from 48 to 83) were evaluated in this study. mean serum psa after radical cystoprostatectomy was .037 ± .031 ng/ml ranging from .002 to .1. when compared to cut off values .1 and .2 (current definition of biochemical recurrence after radical prostatectomy), the mean value of serum psa after cystoprostatectomy was significantly lower (p < .001, one sample t-test). neither of patients had serum psa above .1 and 30 of 41 patients (73.2%) had serum psa less than .05. we also noted that 20 (48.8%) and 13 (31.7%) patients had psa ≤ .03 and ≤ .01 respectively. no correlation was found between postoperative psa value and interval between surgery and psa measurement (r = .036, p = .821; pearson correlation). to assess the effect of age on postoperative serum psa level, patients were dichotomized into 2 groups (younger and older than 65). mean serum psa was comparable between different age groups (table 1). similarly, we did not find any association between either pathologic stage of urothelial cancer or type of urinary diversion and serum psa level (table 1). discussion according to our findings the majority of patients after cystoprostatectomy have undetectable serum psa level and applying ultrasensitive psa assay showed that more than 70% of patients had psa less than .05 and neither of patients had psa greater than .1 ng/ml. based on these findings we expect similar psa nadir values in patients with localized prostate cancer who undergo radical prostatectomy. therefore, applying ultrasensitive psa to detect biochemical recurrences after radical prostatectomy provides an opportunity to initiate early salvage treatment in eligible patients. despite improvements in surgical methods and case selection, about 25% to 41% of patients will show prostate specific antigen (psa) relapse 10 years after operation. (8-10) the likelihood of recurrence is even higher when radical prostatectomy is performed in patient with high risk advanced prostate cancer. therefore, a significant proportion of patients after radical prostatectomy require adjuvant treatment and determining proper cut off values for initiation of salvage treatment is of utmost importance. a measureable psa level after operation may be secondary to residual benign tissue rather than residual malignancy or existence of micrometastatic disease.(4,11) measuring psa after cystoprostatectomy in patients with benign prostatic tissue provides an opportunity to assess the role of benign residual tissue and/or extra-prostatic sources of psa in post radical prostatectomy nadir value. according to our findings remaining benign tissue and/or extraprostatic sources of psa is not associated with values greater than .1 and remains below .05 in majority of patients. several studies have investigated the importance of psa nadir value after radical prostatectomy. sokoll et al. in a study assessing 754 men who underwent radical prostatectomy showed that a lower psa nadir value (i.e .01 vs. .1 ng/ml) is an independent predictor of biochemical recurrence.(12) other studies also showed that in the range of .01 and .1, higher psa nadir is associated with increased risk of biochemical relapse.(13,14) psa nadir value has also been shown to be an independent predictor of biochemical recurrence in the range of .001 and .01 ng/ml. in another study kang et al. using ultrasensitive psa astable 1. association between post-cystectomy serum psa level and patient characteristics patient characteristics no. (%) mean serum psa level (ng/ml) p-value age ≤ 65 18 (43.9) .042 ± .040 .703a > 65 23 (56.1) .034 ± .027 type of urinary diversion ileal conduit 18 (43.9) .033 ± .027 .906b orthotopic neobladder 17 (41.5) .040 ± .038 continent cutaneous pouch 6 (14.6) .042 ± .040 pathologic stage t1 14 (34.1) .037 ± .042 .566b t2 18 (43.9) .042 ± .029 t3 9 (22.0) .030 ± .027 abbreviations: psa, prostate specific antigen. a mann whitney test b kruskal wallis test psa nadir after radical cystectomy-hosseini et al. urological oncology 564 vol 16 no 06 november-december2019 565 say, proposed that cut-off value of .03 is an independent predictor of biochemical recurrence. this ultrasensitive psa relapse criterion of ≥ .03 ng/ml predicted all eventual relapses with high sensitivity (100%) and specificity (96%) and provided a median 18 months lead time advantage over the standard definitions of psa relapse. (15) lowering the threshold and applying advanced ultrasensitive psa assays that detect concentrations as low as .001 ng/ml are associated with a high rate of false positive findings. in addition, it is not necessary to measure extremely low values as residual benign and malignant cells produce higher amounts of psa. some investigators have questioned the accuracy of ultrasensitive psa at cut-off values in the .01 .1 ng/ml range as overlap of psa values was found in recurrent and non-recurrent patient groups.(16) despite all limitations associated with the use of ultrasensitive psa, current definition of psa failure may be flawed. in the era of early salvage treatment values less than .2 ng/ml should not be considered undetectable. using ultrasensitive assays and lowering the cut-off value for the definition of biochemical recurrence provide an opportunity to detect the biochemical recurrence sooner when salvage treatment might be more effective. mir et al. evaluating different cut off values for defining biochemical recurrence, proposed psa ≥ .05 ng/ml as a criteria for therapy(14). our findings also showed that majority of patients had psa less than 0.05 after cystoprostatectomy. one limitation in the present study was the absent of re-review of pathology slides to confirm the absence of prostate cancer in the specimens; however, all specimens were assessed by a limited number of uropathologists who are expert in the field of urologic oncology. more recently there has been interest in using salvage radiation therapy instead of adjuvant treatments in patients with adverse pathologic features after radical prostatectomy. although 3 different randomized trials showed improved outcomes in patients with adverse pathologic features who receive adjuvant radiation therapy compared to “wait and see” approach(17-19), recent evidence questions the benefit of adjuvant compared to salvage radiation therapy in a subset of patients. one study showed that only 17% of men with adverse pathologic features after radical prostatectomy progressed to biochemical recurrence.(20) therefore, applying salvage radiation instead of adjuvant treatment has the potential to prevent overtreatment in a significant proportion of patients. applying ultrasensitive psa has also the potential to safely prevent unnecessary adjuvant treatments. the definition of biochemical recurrence also should be refined to prevent delays in salvage treatment. conclusions by determining the serum level of psa in patients whose prostate tissue is completely removed and have no malignancy, we can achieve an accurate definition for psa nadir value, which is comparable to a successful curative radical prostatectomy without micrometastasis. psa nadir in the present study was less than 0.1 ng/ml in all patients indicating that a lower cut-off value might be more accurate compared to the current definition of biochemical recurrence and prevents delays in salvage therapy. conflict of interest the authors declare no conflict of interest. references 1. moul jw. prostate specific antigen only progression of prostate cancer. j urol. 2000;163:1632-42. 2. boorjian sa, thompson rh, tollefson mk, et al. long-term risk of clinical progression after biochemical recurrence following radical prostatectomy: the impact of time from surgery to recurrence. eur urol. 2011;59:893-9. 3. pound cr, partin aw, eisenberger ma, chan dw, pearson jd, walsh pc. natural history of progression after psa elevation following radical prostatectomy. jama. 1999;281:15917. 4. amling cl, bergstralh ej, blute ml, slezak jm, zincke h. defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? j urol. 2001;165:1146-51. 5. stephenson aj, kattan mw, eastham ja, et al. defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. j clin oncol. 2006;24:3973-8. 6. buti s, ciccarese c, iacovelli r, et al. inside the 2016 american society of clinical oncology genitourinary cancers symposium: part 2–prostate and bladder cancer. future medicine; 2016. 7. mohler jl, armstrong aj, bahnson rr, et al. prostate cancer, version 1.2016. j natl compr canc netw. 2016;14:19-30. 8. amling cl, blute ml, bergstralh ej, seay tm, slezak j, zincke h. long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. j urol. 2000;164:101-5. 9. hull gw, rabbani f, abbas f, wheeler tm, kattan mw, scardino pt. cancer control with radical prostatectomy alone in 1,000 consecutive patients. j urol. 2002;167:528-34. 10. roehl ka, han m, ramos cg, antenor jav, catalona wj. cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. j urol. 2004;172:910-14. 11. diamandis e, yu h. prostate-specific antigen and lack of specificity for prostate cells. lancet. 1995;345:1186. 12. sokoll lj, zhang z, chan dw, et al. do ultrasensitive prostate specific antigen measurements have a role in predicting longterm biochemical recurrence-free survival in men after radical prostatectomy? j urol. 2016;195:330-6 . 13. eisenberg ml, davies bj, cooperberg mr, cowan je, carroll pr. prognostic implications of an undetectable ultrasensitive prostate-specific antigen level after radical prostatectomy. eur urol. 2010;57:622-30. psa nadir after radical cystectomy-hosseini et al. 14. mir mc, li j, klink jc, kattan mw, klein ea, stephenson aj. optimal definition of biochemical recurrence after radical prostatectomy depends on pathologic risk factors: identifying candidates for early salvage therapy. eur urol. 2014;66:204-10. 15. kang jj, reiter re, steinberg ml, king cr. ultrasensitive prostate specific antigen after prostatectomy reliably identifies patients requiring postoperative radiotherapy. j urol. 2015;193:1532-8. 16. taylor iii ja, koff sg, dauser da, mcleod dg. the relationship of ultrasensitive measurements of prostate‐ specific antigen levels to prostate cancer recurrence after radical prostatectomy. bju int. 2006;98:540-3. 17. wiegel t, bottke d, steiner u, et al. phase iii postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pt3 prostate cancer with postoperative undetectable prostatespecific antigen: aro 96-02/auo ap 09/95. j clin oncol. 2009;27:2924-30. 18. thompson im, tangen cm, paradelo j, et al. adjuvant radiotherapy for pathological t3n0m0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. j urol. 2009;181:956-62. 19. bolla m, van poppel h, tombal b, et al. postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (eortc trial 22911). lancet. 2012;380:2018-27. 20. kang jh, ha y-s, kim s, et al. concern for overtreatment using the aua/astro guideline on adjuvant radiotherapy after radical prostatectomy. bmc urol. 2014;14:30. psa nadir after radical cystectomy-hosseini et al. urological oncology 566 vol 16 no 02 march-april 2019 193 female urology salvage autologous fascial sling after failed anti-incontinence surgeries: long term follow up farzaneh sharifiaghdas, nastaran mahmoudnejad*, mehdi honarkar ramezani, hamidreza shemshaki, fatemeh ameri purpose: to evaluate long term outcomes of autologous pubovaginal fascial sling (afpvs) as a salvage procedure following different types of failed anti-incontinence surgeries. material and method: we retrospectively reviewed medical records of patients who had undergone salvage afpvs after any kind of anti-incontinence surgery from 2005-2015 at our medical center. patients were contacted by telephone. revised urinary incontinence scale (ruis) was used to determine the success rate. result: a total of 40 patients out of 51 were successfully contacted. mean patient age was 50.8 ± 9.8 years (range30-75) and mean follow up was 62.6 ± 32.4 months (range12-120). of 40 patients, 14(35%) had pure sui and 26(65%) complained of mixed urinary incontinence. a total of 15(37.5%) patients had a failed burch colposuspention, 5(12.5%) tvt, 8(20%) tot, 3 (7.5%) afpvs and five (12.5%) patients had history of failed mini-sling procedure. four (10%) patients had undergone more than one anti incontinence surgeries. overall success rate was 65% in our study. new onset urge urinary incontinence was detected in 25% of patient which was negatively associated with satisfaction and recommendation. there was no statistically significant correlation between mixed urinary incontinence, type or number of previous failed surgeries with success however presence of pure sui had a strong conclusion: autologous pubovaginal fascial sling might be considered as a safe and efficacious salvage surgical option following failed midurethral slings, burch colposuspention and even afpvs itself. it will provide reasonable long term results with no major complications. keywords: stress urinary incontinence; salvage fascial sling; failed midurethral sling; anti-incontinence surgery; redo sling introduction stress urinary incontinence (sui) is a common con-dition which affects up to 40% of women(1). sui is defined as involuntary urinary leakage on effort or exertion or on sneezing or coughing. this condition might be due to intrinsic sphincter deficiency (isd) and/or urethral hypermobility(2). the surgical treatment of female sui has evolved over the last century with different techniques and modalities. these include pubovaginal slings (pvs), urethral bulking agents, transvaginal urethral suspensions, retro pubic suspensions and most recently, mid urethral slings (mus)(3). in spite of the wide spectrum of options available, treatment fails in 10-20% of patients(4). patients who have failed a prior anti-incontinence surgery for sui, represent a challenging population. although several studies have been published, to date there is no general consensus on the procedure of choice for treating recurrent sui (rsui)(5). given lack of quality data on the optimal management and "rescue" procedure for treatment of rsui, most surgeons rely on their own experience or 1 shahid labbafi nejad medical center, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. correspondence: shahid labbafi nejad medical center, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. e mail: nastaran.mahmoudnejad@gmail.com. received april 2017 & accepted november 2018 opinion(6). autologous fascial pvs (afpvs) was first described in the early 20th century and was brought into popular use again by mcguire and lytton in 1978(3-7). success rates of salvage procedures for rsui including mus, burch colposuspention and pvs are respectively 68.5%, 76% and 82.5% (5). in the present study, we evaluated the clinical usefulness and success rate of afpvs as a salvage surgery for management of rsui following antiincontinence procedures. to our best knowledge this is the first study assessing success rate of redo afpvs in traditional and new techniques simultaneously. materials and methods we retrospectively reviewed medical records of all patients who had undergone salvage afpvs after any kind of anti-incontinence surgery from 2005-2015 at our medical center. failure was defined as either rsui or mixed urinary incontinence. the patients with history of previous pelvic radiation therapy, diabetes mellifemale urology 194 tus and those with concomitant surgery were excluded from the study. all patients underwent physical and pelvic examination, urodynamic study (uds), q-tip test, cough stress leak (marshall) test and cystoscopic evaluation. before performing salvage afpvs, all the patients were offered conservative treatments like lifestyle advise on weight loss, adequate fluid intake, kegel exercises and they received appropriate medical treatment (such as anticholinergic drugs, alpha-adrenoreceptor agonists, tricyclic antidepressants or selective serotonin reuptake inhibitors) as needed for at least three months. recorded parameters included: age and body mass index (bmi) at the time of salvage surgery, parity, type and number of previous failed surgeries, history of pelvic organ prolapse repair, presence of mixed urinary incontinence, menopause and comorbidities (asthma, chronic obstructive pulmonary disease). all information regarding the surgery including time, hospital stay, kind of anesthesia, foley catheter removal and probable periand post-operative complications was obtained as well. salvage afpvs was carried out using a harvested 2x8 cm rectus fascial strip through a pfannensteil incision. the urethrovesical junction was exposed transvaginally through a submucosal tunnel in anterior vaginal wall. the endopelvic fascia was perforated and sharp dissection was used to develop the retro pubic space up to the abdominal wall. we used no.1 vicryl sutures at either end of the strip for suspending the fascial graft through a tunnel behind the pubis bone. the strip was anchored on to the rectus sheath without any tension and with two finger breadths distance from symphysis pubis. then the urethra was examined with a 16 french single use nelaton catheter to rule out any angulation of the urethra. follow up evaluation was performed via telephone call using validated revised urinary incontinence scale (ruis) questionnaire (unpublished data)(8-9) for assessing urinary continence status and satisfaction of the patients. the ruis is a short, reliable and valid five item scale questionnaire that can be used to assess urinary incontinence and to monitor patient outcomes following treatment. it was originally developed by selecting the best performing urinary incontinence items which were included in a large community survey of 2,915 australians in 2006. the ruis has recently been validated in clinical settings(10-11). these studies have shown that the ruis is a valid and reliable measure of urinary incontinence. with only 5 items the ruis is short and simple to use and score. most patients will only take a minute to complete it. a score of less than 3 indicates that the patient has no urinary incontinence. a score of 4-8 is considered mild, a score of 9-12 is considered moderate and a score of 13 or above indicates severe incontinence symptoms. we used spss 22.0 (ibm. armonk, ny) for statistical evaluation with p-values reported for two tailed assessments and groups were compared utilizing standard x2 and student's t-test. normality for quantitative variables were assessed by kolmogorov-smirnov (k-s) test and descriptive analysis was reported as mean and standard deviation. results a total of 51 patients were identified with rsui or mixed urinary incontinence after anti incontinence surgeries (burch colposuspention, mus or pvs). forty patients who had undergone salvage afpvs without concomitant surgery, were successfully contacted by telephone and completed the planned study. mean patient age was 50.8 ± 9.8 years (range30-75) and mean follow up was 62.6 ± 32.4 months (range12-120). none of them had comorbidities like asthma or chronic obstructive pulmonary disease. demographic and clinical data is summarized in (table 1). a total of 15(37.5%) patients had a failed burch colposuspention, 5(12.5%) tvt, 8(20%) tot, 3 (7.5%) pvs and five (12.5%) patients had history of failed mini-sling procedure. four (10%) patients had undergone more than one anti incontinence surgeries. these included two patients with prior failed mini-sling and burch colposuspention, one with failed tvt, tot, pvs and one patient with history of failed tot, mini-sling, pvs and burch colposuspention. based on uds, eight (20%) women had detrusor over activity. maximum urinary flow rate was 17.9 ± 3.9 ml/ sec (range 10-25). cystoscopic evaluation and vaginal examination was done for all patients. cough stress leak test was positive in lithotomy position in 37 (92.5%) patients and it was positive in remaining three (7.5%) patients in upright position. average operational time including positioning and preparation of the patients was 124.5±35.6 (range 70220) minutes. there were no perioperative blood transfusions. we had one perforation of the bladder at the table 1. demographic and clinical information according to ruis score. variables overall sample (n = 40) ruis score unsuccessful (n = 14) ruis score successful (n = 26) p-value age(years) 50.8 ± 9.8 (30-75) 50.8 ± 8.1 (33-67) 50.8 ± 10.7 (30-75) 0.99 bmi 27.8 ± 4.5 (20-36) 28.1 ± 4.7 (21-34) 29.1 ± 4.4 (20-36) 0.52 follow up length(months) 62.6 ± 32.4 (12-120) 54.9 ± 25.8 (24-108) 66.8 ± 35.2 (12-120) 0.27 time from initial to salvage 71.2 ± 73.9 (3-300) 49.3 ± 50.2 (3-144) 83 ± 82.4 (4-300) 0.17 surgery(months) parity 3.7 ± 1.8 (0-9) 3.9 ± 1.8 (0-6) 3.6 ± 1.9 (1-9) 0.66 menopause at the time of surgery 21 (52.5%) 8 (38%) 13 (62%) 0.66 previous popa repair 5 (12.5%) 2 (40%) 3 (60%) 0.81 prior abdominal hysterectomy 9 (22.5%) 4 (44.5%) 5 (55.5%) 0.50 prior vaginal hysterectomy 1 (2.5%) 1 (100%) 0.45 mixed urinary incontinence(yes) 26 (65%) 11 (42%) 15 (58%) 0.53 pure sui(yes) 14 (35%) 3 (21%) 11 (79%) 0.00 a: pelvic organ prolapse salvage pubovaginal fascial sling: long term follow up-sharifiaghdas et al. vol 16 no 02 march-april 2019 195 time of surgery and 4 patients had postoperative fever and subsequent wound infection due to subcutaneous seroma collection that required surgical intervention and drainage. three women had urinary retention, two of them were treated well with 2 weeks intermittent catheterization and one of them underwent urethral dilatation and urethrolysis. ten (25%) patients suffered from de novo urge urinary incontinence. we did not have any delayed postoperative complications (table 2). vaginal exposure of tot mesh was detected in one patient and it was removed at the time of the salvage surgery. success rate was defined by rius score less than eight. according to ruis score, 10(twenty five percent) patients were completely cured (ruis≤3) and 40 %( 16 women) had mild urinary incontinence (ruis 4 to 8). overall success rate was 65% in our study. nine (22.5%) patients had ruis score of 9 to 12 who were considered to have moderate urinary incontinence symptoms. five (12.5%) women had ruis score more than 13 which means they suffered from severe urinary incontinence symptoms. failure was defined by ruis score more than 9(35%) in our study. fourteen (35%) patients were not satisfied with the surgery, while14 (35%) were partially satisfied and 12(30%) women were completely satisfied with outcome of the procedure. twenty-two (55%) patients recommended the salvage afpvs to others. assessing sexual function needs validated questionnaires before and after the surgery. there was no significant association of age, bmi, parity, previous hysterectomy or pop repair with success. unfortunately, we didn't have any recorded data about sexual function of the patients prior to salvage surgery but we asked them about sexual satisfaction after the procedure and surprisingly all of them mentioned no change in their sexual life. there was no statistically significant correlation between mixed urinary incontinence, type or number of previous failed surgeries with success however presence of pure sui had a strong correlation with success (p = 0.005). the association of ruis score with hypermobility of the urethra and urodynamic findings including vlpp value or presence of detrusor over activity didn’t reach statistical significance. de novo urge urinary incontinence was negatively associated with satisfaction and recommendation (p < 0.005). discussion according to our results, pure sui might be a good predictor of success rate even in complex cases. like many other studies, we didn't find any correlation between age, parity, bmi, menopause and previous pop surgeries with success rate (13,16,29,30). persistence of urge urinary incontinence was not a major cause of dissatisfaction, however new-onset urge urinary incontinence seemed to be a very important and bothersome factor affecting satisfaction and recommendation. therefore, appropriate pre-operation counselling of the patients to set realistic outcomes is highly recommended. finding a suitable surgical technique for management of rsui is a very challenging topic. available options for these patients include: a repeat mesh sling, afpvs or urethral bulking agents. a recent systematic review and meta-analysis of randomized controlled(rct) trials on the surgical management of rsui, examined data on 350 women in 10 rct trials with a mean follow up of 18.1 months. the authors of this review concluded that there is "a poor level of evidence in this field"(12). however there are no prospective randomized trials assessing the optimal treatment approach for rsui. in present study we decided to choose afpvs as salvage procedure for treatment of rsui hoping for a different and durable outcome. there is a paucity of data to strongly recommend one salvage treatment over another(13-15). afpvs is typically not considered as first line treatment for uncomplicated sui as it is more invasive than mus but it is our choice when mus or other surgical procedures have failed since theoretically placing a sling more proximally and correcting isd should cure the residual incontinence (16). however afpvs is not without potential complications. in the literature the most common post-operative complications include urgency and obstruction, with rates ranging between 1627% for urgency and 14-18% for obstruction requiring intermittent catheterization(1,17,18). despite a reported high success rate for tot and tvt slings, in the most recent cochrane review, complications are significant and likely under reported(19-20). recurrent or persisted sui occurs after mus in up to 12-20% of cases(20-21). mus also occasionally requires removal or division due to complications such as obstruction, mesh exposure or vaginal pain(20,22,23). in a recent review of literature by nadeau et al, success rate of pvs in the patient population who failed other procedures was reported to be 66-90% (2,24-26). bulking agents are another available option for treatment of rsui. they may provide short-term improvement in symptoms but no cure(27). their favorable side effect profile and minimally invasive nature make them a viable alternative for "carefully selected" patients(2). petrou et al. have reported a success rate of 76.2% in 21 patients with median follow up of 74 months following salvage afpvs(13). variables overall sample(n=40) urodynamic evaluation oaba (yes) 8 (20%) vlppb≤60 2 (5%) vlpp (61-89) 21 (52.5%) vlpp≥90 17 (42.5%) maximum flow rate ml/sec 17.9±3.9(10-25) surgical information operation time (minute) 124.5±35.6 (70-220) general anesthesia (yes) 4 (10%) spinal anesthesia (yes) 36 (90%) hospital stay (days) 2.2±0.9 (1-4) catheterization (days) 2.1±0.8 (1-5) periand post-operative complications bladder perforation 1 (2.5%) fever 4 (10%) wound infection 4 (10%) urinary retention 3 (7.5%) need for cicc 3 (7.5%) urethrolysis 1 (2.5%) table 2. para-clinic and surgical information a: overactive bladder b: valsalva leak point pressure c: clean intermittent catheterization salvage pubovaginal fascial sling: long term follow up-sharifiaghdas et al. female urology 196 in a large retrospective study, milose et al. reported 69.7 % overall sui cure rate of afpvs after failed mus slings in 66 women with mean follow up of 436 days. complete cure of all incontinence was achieved in 37.9% patients(16). welk and herschorn identified 33 patients treated with salvage pvs after failure of a median of 2 prior anti incontinence surgeries. median follow up was 16 months and success rate was reported to be 64%(3). walsh ca. et al in a separate series of 7 patients contacted retrospectively, reported a cure rate of 71% with 86% satisfaction of the patients with their outcome (28). our overall success rate in the present study is 65% which is comparable to previous available studies in this era. it is logical to consider that second line surgical procedures are likely to be inferior to first line treatment, both in terms of reduced benefit and increased risk of harm(2,27). most of the patients in our study were referred to us from other medical centers and we didn’t have a background or clinical evaluation of their initial surgeries. presuming that they were all appropriate candidates for their previous surgeries, our success rate would be acceptable. although there was no statistically significant correlation between type or number of previous surgeries, we noticed 10 out of 15 patients with history of burch colposuspention and all of the women with previous failed pvs had ruis score ≤8, which means redo afpvs is not only suitable for more recently invented procedures (mus) but also can serve as a reasonable option for treatment of traditional surgeries or even failed pvs itself. our relatively long term follow up time (mean: 62.6, range12-120 months) indicates that positive effects of redo afpvs is durable. we performed uds for all patients however, symptoms of overactive bladder were only seen in 20% of them. we didn't find any statistical correlation between uds findings and our success rate in this study. perhaps it is time to design a powerful prospective study to reevaluate the usefulness of performing uds as a routine para-clinical test in "all" incontinent patients with history of failed anti-incontinence procedures. the major limitations of the present study are its retrospective design and subjective outcomes. relatively large sample size from single institution and long term follow up are the strengths of our study. conclusions appropriate management of recurrent stress urinary incontinence after anti-incontinence surgeries is a challenging topic. our retrospective study supports the use of afpvs in complex patients. our data imply that salvage afpvs provides durable and acceptable continence rates. there are no serious periand post-operative complications. since there is no general consensus on the procedure of choice for treating recurrent sui, well-designed prospective studies and collaboration in multi-center studies are highly recommended to choose a reasonable approach. acknowledgements the authors would like to thank dr. janet sansoni (associate professor at centre for health service development, university of wollongong, australia) for her official permission to use ruis questionnaire in this study. conflict of interest the authors have no conflicts of interest to declare. references 1. parker wp, gomelsky a, padmanabhan p. autologous fascia pubovaginal slings after prior synthetic anti-incontinence procedures for recurrent incontinence: a multiinstitutional prospective comparative analysis to de novo autologous slings assessing objective and subjective cure. neurourol urodyn. 2016; 35: 604-8. 2. nadeau g, herschorn s. management of recurrent stress incontinence following a sling. curr urol rep. 2014; 15: 427. 3. welk bk, herschorn s. the autologous fascia pubovaginal sling for complicated female stress incontinence. can urol assoc j. 2012; 6:36-40. 4. chaikin dc, rosenthal j, blaivas jg. pubovaginal fascial sling for all types of stress urinary incontinence: long-term analysis. j urol. 1998; 160:1312-6. 5. nikolopoulos ki, betschart c, doumouchtsis sk. the surgical management of recurrent stress urinary incontinence: a systematic review. acta obstet gynecol scand. 2015; 94:568-76. 6. zimmern pe, gormley ea, stoddard am, et al. management of recurrent stress urinary incontinence after burch and sling procedures. neurourol urodyn. 2016; 35:344-8. 7. mcguire ej, lytton b. pubovaginal sling procedure for stress incontinence. j urol. 1978; 119:82-4. 8. sansoni j, hawthorne g, marosszeky n, et al (2011); the technical manual for the revised incontinence and patient satisfaction tools. centre for health service development, university of wollongong 9. sansoni j, hawthorne g, k moore, et al (2011); validation and clinical translation of the revised continence and patient satisfaction tools: final report. centre for health service development, university of wollongong. 10. sansoni j, marosszeky n, sansoni e ,et al (2006); refining continence measurement tools (final report). centre for health service development, university of wollongong and the department of psychiatry, university of melbourne. 11. hawthorne g, sansoni j, hayes l m, et al (2006); measuring patient satisfaction with incontinence treatment (final report). centre for health service development, university of wollongong and the department of psychiatry, university of melbourne. 12. agur w, riad m, secco s, et al. surgical treatment of recurrent stress urinary incontinence in women: a systematic review and meta-analysis of randomized controlled trials. eur urol 2013; 64:323–36. 13. petrou sp, davidiuk aj, rawal b, et al. salvage pubovaginal fascial sling: long term follow up-sharifiaghdas et al. vol 16 no 02 march-april 2019 197 salvage autologous fascial sling after failed synthetic midurethral sling: greater than 3-year outcomes. int j urol. 2016; 23:178-81 14. scarpero hm, dmochowski rr. sling failures: what’s next? curr. urol. rep. 2004; 5:389–96 15. patil a, moran p, duckett j. how do urogynaecologists treat failed suburethral slings? experience from the british society of urogynaecology database and literature. j. obstet. gynaecol. 2011; 31: 514–7. 16. milose jc, sharp km, he c, et al. success of autologous pubovaginal sling after failed synthetic mid urethral sling. j urol. 2015; mar; 193(3):916-20. 17. jeon mj, jung hj, chung sm. comparison of the treatment outcome of pubovaginal sling, tension-free vaginal tape, and transobturator tape for stress urinary incontinence with intrinsic sphincter deficiency. am j obstet gyncol 2008; 199:1– 4. 18. albo me, richter he, brubaker l. burch colposuspension versus fascial sling to reduce urinary stress incontinence. n engl j med 2007; 356:2143–55. 19. blaivas jg, purohit rs, weinberger jm, et al. salvage surgery after failed treatment of synthetic mesh sling complications. j urol. 2013; 190:1281-6 20. ogah j, cody jd, rogerson l. minimally invasive synthetic suburethral sling operations for stress urinary incontinence in women. cochrane database syst rev. 2009: :cd006375 21. merlin t, arnold e, petros p, et al: a systematic review of tension-free urethropexy for stress urinary incontinence: intravaginal slingplasty and the tension-free vaginal tape procedures. bju int 2001; 88: 871. 22. daneshgari f, kong w, swartz m. complications of mid urethral slings: important outcomes for future clinical trials. j urol 2008; 180: 1890 23. tamussino kf, hanzal e, kolle d, et al. tension-free vaginal tape operation: results of the austrian registry. obstet gynecol 2001; 98: 732 24. groutz a, blaivas jg, hyman mj, et al. pubovaginal sling surgery for simple stress urinary incontinence: analysis by an outcome score. j urol. 2001;165:1597-600 25. breen jm, geer be, may ge. the fascia lata suburethral sling for treating recurrent urinary stress incontinence. am j obstet gynecol. 1997; 177:1363-5; discussion 1365-6. 26. blaivas jg, jacobs bz. pubovaginal fascial sling for the treatment of complicated stress urinary incontinence. j urol. 1991; 145:12148 salvage pubovaginal fascial sling: long term follow up-sharifiaghdas et al. 27. lucas mg, bosch rj, burkhard fc, et al. eau guidelines on surgical treatment of urinary incontinence. european association of urology. eur urol. 2012; 62:1118-29. 28. walsh ca, parkin k, moore kh. rectus fascia pubovaginal sling for recurrent stress urinary incontinence after failed synthetic mid-urethral sling: letter. can urol assoc j 2012;16:429 29. jeong sj, lee hs, lee jk, et al. the long term influence of body mass index on the success rate of midurethral sling surgery among women with stress urinary incontinence or stress predominant mixed incontinence: comparisons between retropubic and transobturator approaches. plos one. 2014; 9(11):e113517. 30. haverkorn rm, williams bj, kubricht ws , et al. is obesity a riskfactor for failure and complications after surgery for incontinence and prolapse in women? j urol. 2011; 185:987-92 urological oncology evaluation of two ureter sealing methods during radical nephroureterectomy kun pang1,2#, bo chen1#, bo jiang1, zhenduo shi1, lin hao1, zhiguo zhang1,2, jianjun zhang3, longcun cai3, tian xia4, zhenningwei#5, kun fang6, dianjun yu7, conghui han1,2*, xiaowen sun8** purpose: to investigate the safety of electrocoagulation and thulium laser (tm-laser) sealing methods of distal ureter resection during radical nephroureterectomy (nfu) in a porcine model. methods: 9 pigs were used in the study: 6 were used to measure the bursting pressure (bp) and 3 were used to measure the highest pressure during nfu. twelve ureters were to measure bp after being sealed by electrocoagulation or tm-laser (n = 6, each). six experimental nfus were performed in 3 pigs to measure the intraluminal pressure of all procedures. results: the mean bp in the electrocoagulation group (104.3 ± 25.0 cmh2o) was similar to that of the tm-laser group (74.8 ± 23.3 cmh2o, p > .05). the peak intraluminal pressure (35.9 ± 7.6 cmh 2 o) during nfu was significantly lower than the bp (p < .05). conclusion: the effectiveness of the sealing was confirmed using both electrocoagulation and tm-laser during nfu. keywords: bursting pressure; distal ureter and bladder cuff resection electrocoagulation; experimental porcine model; pluck technique; thulium laser introduction upper tract urothelial carcinoma (utuc) is a rela-tively uncommon disease that accounts for 5–7% of all renal tumors and 5–10% of all urothelial tumors, with an estimated annual incidence of 1–2 cases per 100,000(1). utuc is encountered in approximately 25% of ureteral cancer cases and is subject to a high risk of local recurrence that ranges from 30% to 75%(2). radical nephroureterectomy (nfu) with distal ureter and bladder cuff (dubc) resection is the standard treatment for utuc (3). a large number of endourologic techniques have become promising alternatives to open dubc resection(4) during nfu. however, existing clinical trial evidence regarding their effectiveness and safety is inconclusive(5). in 1998, keeley and tolley(6) reported 1department of urology, xuzhou central hospital, 199 jie fang nan road, xuzhou, 221009, china. 2department of urology, the third affiliated hospital of soochow university, no.185, juqian street, changzhou city, jiangsu province china. 3the affiliated suqian hospital of xuzhou medical university. no.138 huanghe south road, sucheng district, suqian city, jiangsu province. 4xuzhou medical university, no. 209 tongshan road, xuzhou, jiangsu, 221004, p. r. china. 5school of medicine, jiangsu university, 301 xuefu road, zhenjiang city, jiangsu province, china. 6 nanjing university of traditional chinese medicine, no. 138 xianlin avenue, qixia district, nanjing, jiangsu, china. 7 li huili hospital, no. 57, xingning road, yinzhou district, ningbo, zhejiang, china. 8department of urology, shanghai first people’s hospital affiliated to shanghai jiaotong university. no.100 haining road, hongkou district, shanghai 200080, china. # kun pang, bo chen, bo jiang, cong-hui han, and xiaowen sun contributed equally to this work. *correspondence: department of urology, xuzhou central hospital, 199 jie fang nan road, xuzhou, 221009, china. tel: +8618952172133 e-mail: 479920288@qq.com. **correspondence: department of urology, school of medicine, shanghai first people’s hospital affiliated to shanghai jiaotong university, no.100 haining road, hongkou district, shanghai 200080, china. e-mail: sunxiaow1973@163.com. received december 2018 & accepted may 2019 a cystoscopic detachment of dubc during laparoscopic nfu that offered patients an additional benefit of a minimally invasive technique. however, it is related to a high potential for local relapse, which is hypothesized to be because of local tumor cell spillage(7). oncological safety concerns arise from nonmechanically sealed ureteral openings(8). it may be that the high intraluminal pressure during the nfu after endoscopic manipulation could lead to a breakage in the seal and result in tumor cell spillage. thus, the effectiveness of electrocoagulation and laser methods in sealing the ureteral orifice is controversial. as the pressure to the dubc cannot be measured during nfu in patients, we designed a porcine nfu model to measure the peak pressure to the dubc and comurology journal/vol 17 no. 2/ march-april 2020/ pp. 152-155. [doi: 10.22037/uj.v0i0.4920] pared it to the bursting pressure (bp) of the ureteral openings that were sealed by either electrocoagulation (ec) or a tm-laser. materials and methods laboratory animals the institutional animal research committee at the sixth people’s hospital of shanghai municipality approved the study protocol (scxk[sh]2007-0013). nine shanghai white pigs, each weighing 60 ± 5 kg, were purchased from shanghai nanhui special farm (license gb/t 8473-1987). six pigs were used to determine the bp of the sealed ureters, and 3 pigs underwent experimental nfu. sample size the sample size calculation followed the equation: n1=n2=2[(tα/2+tβ)s/δ] 2. we defined α = 0.05, and 1-β = 0.2. according to a chinese article, we found that the human ureteral sealing pressure was 192.25 ± 14.27 cmh 2 o; we sealed 3 human ureters by tm-laser in vitro, and the burst pressure was 165.42 ± 12.50 cmh 2 o. therefore, the sample size was calculated to be 5.90. study design six pigs were euthanized to harvest ureter specimens (n = 12). these specimens were equally and randomly divided into ec and tm-laser groups. for the ec group, the distal ureteral segment was placed into a metal container full of 5% mannitol, to the bottom of which an electrode pad was attached. the ureteral orifice was sealed under direct vision using an electrosurgical hook (lisa laser products ohg, katlenburg-lindau, germany) at 45 w for 8-10 s. for the tm-laser group, the distal ureteral segment was placed into a metal container full of normal saline. a medical tm-laser system (wavelength, 2.01 µm; maximum output power, 110 w; lisa laser products ohg, katlenburg-lindau, germany) was used for laser coagulation in the continuous-wave mode. the ureteral orifice was sealed under direct vision using a 550-µm end-firing percufib fiber (lisa laser products ohg, katlenburg-lindau, germany) at a set power of 70 w for 5-7 s. measurement of bp the bp limit of the ureteral orifice after sealing was performed as previously described(1). for real-time monitoring of the intraluminal dynamic pressure, a 5-cm segment of the excised distal ureter was transected, and the stump was connected to a tri-way adapter, which was also connected to a piezometer (y-50, wuxi, china) and a 20-ml syringe. the distal ureteral segment was continuously perfused with saline containing methylene blue (baxter, suzhou, china) via the syringe at a flow rate of 0.1 ml/s. the bp was defined as the ureter sealing methods for radical nephroureterectomy-pang et al. table 1. intraluminal pressure over nfu. stage intraluminal pressure, cmh 2 o incising the subcutaneous tissue 7.3 ± 4.5 identifying the ureter 28.6 ± 8.2 locating simulated tumor and ligating ureter 35.9 ± 7.6* after ligating the ureter 33.1 ± 7.4 on mobilizing and ligating renal pedicle 30.0 ± 7.3 on dissecting the kidney 29.6 ± 9.1 dissecting the ureter 35.0 ± 8.8 plucking the ureter 33.1 ± 7.0 * the peak pressure was during locating the simulated tumor figure 1. key stages of the experimental nfu: (a) cannulation of bilateral ureteral orifices; (b) connection to the piezometer via the tri-way adapter; (c) location of the simulated tumor and ligation of the ureter; and (d) en bloc resection of the ureter and the kidney. vol 17 no 02 march-april 2020 153 intraluminal pressure at the time that the blue-stained saline leaked from the sealed orifice, which was the primary experimental outcome. experimental nfu the experimental nfu was performed. under general anesthesia, the animal was placed in a supine position, and a lower median abdominal incision was made to expose the bladder. the bilateral ureteral orifices were located, and two flexible cannulas were inserted into the bilateral orifices (figure 1a) and connected to the piezometer via the tri-way adapter (figure 1b). the orifices were secured using silk sutures to maintain hermetic. the simulated tumor was located at the level paralleling the lower polar of the kidney, and the proximal ureteral segment was ligated using silk sutures 0.5 cm distally to the renal pelvis (figure 1c). the ureter and kidney were moved to the level of the renal pedicle, and the renal vessels were securely ligated. the ureter was plucked, and the piezometer was disconnected to remove the nfu specimen en bloc (figure 1d). the baseline pressure was defined as the intraluminal pressure before surgical manipulation, and the intraluminal pressure was recorded at intervals of 3s, when plucking the ureter, and at its maximum. statistical analysis sas v8.02 software (sas, cary, nc, usa) was used for statistical analyses. all continuous data are expressed as the mean ± standard deviation. a normality test was performed, and the measurement data that conformed to normal distributions were analyzed by t-tests to determine if the variances were equal, and t-test was used if the variances were unequal. the burst pressure between the two groups and the comparison between the peak pressure and the burst pressure was evaluated using t-test. p-value < 0.05 was considered statistically significant. results the bps between the ec (104.3 ± 25.0 cmh 2 o) and tm-laser (74.8 ± 23.3 cmh2o) groups were not significantly different (variances were equal, t=2.11, p = .0606). during nfu, the mean intraluminal pressure fluctuated significantly from 7.3 ± 4.5 cmh2o when incising the subcutaneous tissue to 35.9 ± 7.6 cmh2o when locating the simulated tumor and ligating the ureter (table 1). in the tm-laser group, the peak pressure was 35.9 ± 7.6 cmh 2 o, which was significantly lower than the bp (74.8 ± 23.3 cmh 2 o) and the difference was statistically significant (variances were unequal, t = 4.13, p = .009). discussion radical nfu with dubc resection is the standard treatment for utuc(3). the dubc are sealed by either electrocoagulation or a thulium laser (tm-laser) before nfu to prevent the dissemination of tumor cells along the urinary tract(1,9). these two sealing methods have been shown to have comparable perioperative and oncological outcomes(9), which were consistent with our previous research(1). dubc resection is an effective and safe procedure in terms of disease recurrence and overall survival(10). compared with open resection, the endoscopic management of dubc resection significantly shortens the operative time(11), reduces intraoperative bleeding, and expedites postoperative recovery (9). however, intraoperative tumor cell seeding is a risk factor for local recurrence(12-14). current clinical studies do not agree on the relative risk of urine spillage and tumor cell seeding between the pluck technique and open resection method(15). is the sealing pressure safe for preventing urine spillage and tumor cell seeding? our porcine biomechanical study was designed to assess whether the intraluminal pressure would exceed the bp of the ureteral orifice when sealed by either electrocoagulation or tm-laser. we found that the burst pressures between the ec and tm-laser groups were not significantly different, indicating that the sealing effectiveness was equal between the two methods. we also found that the peak pressure was significantly lower than bp during nfu. the intraluminal pressure at each stage of the experimental nfu was well below the bp of the ureteral orifices, regardless of the sealing technique. therefore, it is very unlikely that intraoperative manipulation in nfu will burst the sealed ureteral orifice and result in tumor cell spillage. this study was limited in that the bp was measured ex vivo rather than in vivo. besides, the experimental nfu was performed on pigs, whose urinary system anatomy differs from that of humans to some extent. finally, no actual oncological safety test was conducted, and tumor cell spillage might occur even in the absence of bursting the sealed urethral openings. conclusions in conclusion, the efficacy of electrocoagulation and tm-laser methods in sealing the ureteral orifice was similar, and the sealed ureteral orifice could withstand the pressure throughout the entire experimental nfu procedure. acknowledgment this article is funded by national natural science fund (81774089); jiangsu province, the medical innovation team (cxtda2017048); jiangsu province key research and development program (be2017635); jiangsu province, natural science research projects (17kjb360001); jiangsu province, young medical talents (qnrc2016386); jiangsu provincial traditional chinese medicine bureau of science and technology project (yb2017055) and ningbo natural science foundation (2017a610194). the authors acknowledge editorial support from american journal experts. references 1. pang k, liu sb, wei hb, et al. two-micron thulium laser resection of the distal ureter and bladder cuff during nephroureterectomy for upper urinary tract urothelial carcinoma. lasers med sci. 2014;29:621-7. 2. zhang xk, yang p, zhang zl, hu wm, cao y. preoperative low lymphocyte-to-monocyte ratio predicts poor clinical outcomes for patients with urothelial carcinoma of the upper urinary tract. urol j. 2018;15:348-54. 3. annan ac, stevens ka, osunkoya ao. urothelial carcinoma involving the ureteral orifice: a clinicopathologic analysis of 93 cases. hum pathol. 2017;65:101-6. 4. fragkoulis c, pappas a, papadopoulos urological oncology 154 ureter sealing methods for radical nephroureterectomy-pang et al. gi, stathouros g, fragkoulis a, ntoumas k. transurethral resection versus open bladder cuff excision in patients undergoing nephroureterectomy for upper urinary tract carcinoma: operative and oncological results. arab j urol. 2017;15:64-7. 5. elawdy mm, osman y, taha de, elhalwagy s, el-mekresh m. coincidental bladder cuff transitional cell carcinoma in nephroureterectomy specimens: risk factors, prognosis and clinical implementation. urol j. 2018;15:256-60. 6. keeley fx, jr., tolley da. laparoscopic nephroureterectomy: making management of upper-tract transitional-cell carcinoma entirely minimally invasive. j endourol. 1998;12:13941. 7. mellouli m, charfi s, smaoui w, et al. prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract. urol j. 2017;14:500812. 8. upfill-brown a, lenis at, faiena i, et al. treatment utilization and overall survival in patients receiving radical nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma: evaluation of updated treatment guidelines. world j urol. 2018. 9. raman jd, park r. endoscopic management of upper-tract urothelial carcinoma. expert rev anticancer ther. 2017;17:545-54. 10. lai wr, lee br. techniques to resect the distal ureter in robotic/laparoscopic nephroureterectomy. asian j urol. 2016;3:120-5. 11. giannakopoulos s, toufas g, dimitriadis c, et al. laparoscopic transvesical resection of an en bloc bladder cuff and distal ureter during nephroureterectomy. scientificworldjournal. 2012;2012:658096. 12. ito a, shintaku i, satoh m, et al. intravesical seeding of upper urinary tract urothelial carcinoma cells during nephroureterectomy: an exploratory analysis from the thpmg trial. jpn j clin oncol. 2013;43:1139-44. 13. schwartzmann i, pastore al, sacca a, et al. upper urinary tract urothelial carcinoma tumor seeding along percutaneous nephrostomy track: case report and review of the literature. urol int. 2017;98:115-9. 14. tan p, xie n, yang l, liu l, tang z, wei q. diagnostic ureteroscopy prior to radical nephroureterectomy for upper tract urothelial carcinoma increased the risk of intravesical recurrence. urol int. 2018;100:92-9. 15. pai a, hussain m, hindley r, emara a, barber n. long-term outcomes of laparoscopic nephroureterectomy with transurethral circumferential excision of the ureteral orifice for urothelial carcinoma. j endourol. 2017;31:651-4. ureter sealing methods for radical nephroureterectomy-pang et al. vol 17 no 02 march-april 2020 155 miscellaneous improvement of erection related incision pain in circumcision patients using interrupted rapid eye movement sleep: a randomized controlled study a-juan dai1, miao li2, li-li wang3, ting liu3, xiao-hua wang2*, yu-hua huang2** introduction: postoperative pain from male circumcision (mc) is common especially in the sleep-related erection period. this study aims to explore the effect of interrupted rapid eye movement (irem) sleep on relieving sre-related incision pain and the improvement of other clinical outcomes. materials and methods: this simple randomized controlled study was conducted between may and november 2016. approval was obtained from the local ethical committee on 5 may 2016. ninety participants who underwent male circumcision were divided into the interrupted rapid eye movement sleep group and the control group. the times and the cumulative time of erection-related moderate and severe pain in minutes at night for 3 days after the operation were observed and compared. we also compared the condition of the incision swelling and healing. sleep time at night was used to evaluate the safety of interrupted rapid eye movement sleep. results: for the first 3 days after the operation, the times of sleep-related erection pain were significantly decreased in the irem sleep group (p = .010). five patients reported that there was no pain during night. the cumulative time of erection-related moderate and severe pain was statistically decreased in the interrupted rapid eye movement sleep group (p = .034). after 3 days, there was no moderate and severe pain related to sleep-related erection in the 2 groups. there were no significant differences in incision swelling (p = .768), healing (p = .626), and sleep time (p = .231). conclusion: interrupted rapid eye movement sleep is an effective, simple, and free treatment to relieve incision pain of sleep-related erections. keywords: rapid eye movement; interrupt; sleep-related erection; pain; circumcision. introduction male circumcision (mc), being usually performed on adults in china(1,2), is one of the most common surgical procedures, whose benefit is a reduction in urinary tract infections and improvement of sexual performance (3,4), especially with regard to sex drive and mental erection confidence(5). although regarded as routine and minor, it is a painful procedure which, compounded by general anesthesia, can prove to be a particularly distressing event(6). the incidences of moderate and severe pain during the first and third day after circumcision were reported as occurring in up to 96% and 78% of patients, respectively, in china(7). these episodes of pain would be worsened when nocturnal erection caused by increased circulating testosterone occurred(8). almost all patients complained of worsened incision pain when they were undergoing nocturnal erections in our hospital. currently, the main treatment for incision pain resulting from sleep-related erections (sres) is a hormone-related regimen such as diethylstilbestrol and acetaminophen in china(9). in addition, a number of analgesic and anesthetic methods such as opioids and dorsal penile nerve block using clonidine and fentanyl have 1division of anesthesia surgery, the first affiliated hospital of soochow university, no.188 shizi street, suzhou 215006, china. 2department of urology, the first affiliated hospital of soochow university, no.188 shizi street, suzhou 215006, china. 3school of nursing, soochow university, no.1 shizi street, suzhou 215006, china. *correspondence: hospital of soochow university, no.188 shizi street, suzhou 215006, china. tel: +8618913752992; fax: +8651265221447; e-mail: docxiaohuawang@163.com **correspondence: hospital of soochow university, no.188 shizi street, suzhou 215006, china. tel: +8618913752992; fax: +8651265221447; e-mail: dr_huangyuhua@126.com. received may 2017 & accepted october 2017 been widely used for male circumcision(10-12), but there can be side effects from using these kinds of pain-relief methods(13). however, this is not suitable for preventing the pain of mc patients. hence, it was necessary to explore more reasonable and effective ways of relieving postoperative pain related to mc(13). sleep-related erections (sres) refer to the erections occurring spontaneously during sleep with rapid eye movement (rem)(14).there are 4 to 5 episodes of sres during one night, each episode lasts 30 to 45 minutes, with a total time of 80 to 180 minutes in healthy men. in a young adult male, the erection begins near the onset of rem sleep, increases quickly to full tumescence, persists throughout the rem sleep episode, and then ends in rapid detumescence at the end(8). with the extension of sleep time, the frequency and duration of rems gradually extends. sleep-related penile erections (sre) are naturally occurring, physiologically normal, occur several times on any given night, and are stable across time,(15) but in mc patients, sres could increase the pain and result in bleeding and suture avulsion. therefore, we aimed to find a reasonable method to relieve this problem. according to the association between the circadian miscellaneous 48 vol 15 no 03 may-june 2018 49 rhythmicity of sleep and the regular pattern of sre, we designed the regimen of interrupted rapid eye movement (irem) sleep for mc patients. the irem sleep in this study meant that patients who underwent circumcision were awoken a few times a night at the beginning of rem sleep and kept awake for 10-minute intervals, during three nights after the operation. based on this intervention, we assumed that the total time of sleep-related erections would be decreased by decreasing the time of rems or interrupting rem sleep. thus, incision pain and edema would be relieved and wound healing would be accelerated. materials and methods study design and population this randomized controlled study was approved by the ethics committee of the first affiliated hospital of soochow university (clinical trial identifier:2016023). from may to november 2016, patients were recruited from the operating room of the outpatient department of the first affiliated hospital of soochow university. eligible patients were(1) scheduled for circumcision,(2) aged 14 to 60 years,(3) fully conscious,(4) able to clearly express their feelings,(5) previously having an erection every morning, and(6) able to voluntarily participate in the study. patients were not eligible if they had(1) too low a threshold of pain, with numerical rating scale (nrs) > 5 points at preoperative anesthesia,(2) a history of chronic insomnia or psychological diseases,(3) sexually transmitted diseases or male genitalia inflammation, and(4) other chronic diseases or cancers. a power analysis determined that 22 is the least amount of sample (effect size 0.1, alpha 0.05)(7). finally, we enrolled 45 participants for each group. procedures there were 2 researchers (a physician who performed the circumcisions with stapler for all the participants in this study and a nurse who was responsible for data collection and delivering the intervention). patients who were willing to participate in this study were informed about the study by the physician and provided signed informed consent when patients visited him first time at clinic. patients were randomly assigned in to the irem sleep group or control group by the physician according to the computer-generated random number sequence. the nurse presented the rights of withdrawal and confidentiality to eligible participants when patients were admitted for the operation. baseline information, including demographics, history of previous morning erections and current clinical data, were collected. to ensure the participants’ full understanding of the meaning of the numbers of the nrs that was used to evaluate incision pain, the nurse provided education concerning the nrs scale to all the participants before the operation. patients were also educated regarding the evaluation methods for edema, time of sleep, and other irregular conditions which the patients might experience. then the nurse ordered the participants to take down these data in detail. in addition, patients in the irem sleep group were given a booklet on irem sleep and one-on-one education, which took about 15 minutes. all these procedures were conducted in the waiting area of the operating room. interventions the research physician performed the incisions and dressings for all the participants. the participants underwent wound dressing at day 3 and day 7 after the operation. control group the participants in the control group received regular care, including telling them the incision pain during night, how to identify severe bleeding and edema which would require a physician visit, and the scheduled time to attend hospital for wound dressing. irem sleep group pilot study first, we examined whether the regimen of irem sleep schedule was reasonable for 5 patients as follows: sleep for 120 minutes, awake for 10 minutes, for 2 cycles; then sleep 60 for minutes, awake for 10 minutes, for 2~3 cycles. the results indicated that the 120-minute sleep period was too long for 3 patients. therefore, we modified the schedule of irem sleep schedule: sleep for 90 minutes, awake for 10 minutes, for 3 cycles; then sleep for 60 minutes, awake for 10 minutes, for 2~3 cycles. booklet a booklet for patients in the irem sleep group was developed by our research group, including urologists, nurses, and venereological experts. the content of the booklet was as follows:(1) brief description of the male circumcision procedure and the expected discomfort aftable 1. comparison of demographic and clinical characteristics. groups intervention (n = 33) control (n = 42) t/z/x2 p age (years) 25.52 ± 6.11 26.81 ± 5.94 -0.925a 0.358 education (years) 15.00 (12.00,16.00) 13.82 (11.75,16.00) -1.226b 0.220 bmi (kg/m2) 22.60 ± 2.63 23.95 ± 4.83 -1.439 a 0.154 hr (times/min) 86.37 ± 16.23 87.21 ± 12.97 -0.246 a 0.806 sbp (mmhg) 123.99 ± 24.38 125.52±8.51 -0.380 a 0.705 dbp (mmhg) 74.91 ± 7.99 73.79 ± 6.88 0.647 a 0.519 other diseases diabetes (yes) 0 (0%) 1(2.4%) 0.796 c 1.000 others (yes) 0 (0%) 1(2.4%) 0.796 c 1.000 baseline nrs 4.00 (3.00,5.00) 4.00 (3.00,5.00) -0.050 b 0.960 abbreviations: bmi, body mass index; hr, heart rate; sbp and dbp, systolic and diastolic blood pressure; nrs, numerical rating scale. education and baseline nrs were presented as median (interquartile range). the item of other diseases was presented as count (proportion). others were presented as mean and standard deviation. a: t test; b: wilcoxon rank-sum test; c: fisher’s exact test. interrupted rem sleep improved male circumcision pain-dai et al. terward,(2) description of the association between rem sleep and sleep-related erection,(3) introduction to the evaluation of the nrs with regard to pain and edema, (4) introduction to the purpose of irem sleep,(5) introduction to the irem sleep method (the alarm was set before sleep). the schedule of irem sleep was: sleep for 90 minutes, awake for 10 minutes, for 3 cycles; then sleep for 60 minutes, awake for 10 minutes, for 2~3 cycles. if a patient was still troubled by sre pain, he could shorten the time awake. education of irem sleep in the one-on-one education session, the nurse and the patient reviewed the booklet together, with emphasis on the knowledge and methods needed for irem sleep. in the waiting area of the operating room, patients were taught the waking time intervals during the night and the skills to set the phone alarm clock. this education took approximately 15 to 20 minutes. data collection on the next morning after operation, we collected the data of pain, edema and sleep on the first day of the night after the operation, by the participants’ self-report using telephone. at day 3 and day 7 post operation, the nurse collected the rest data when the patients came to the hospital for wound dressing. measurements pain assessment pain was assessed with the nrs(16). the scores ranged from 0 to 10; 0 indicated no pain, and 10 indicated the most intense pain. the pain classification was as follows: 4-6 and 7-10 indicated moderate pain and severe pain (msp), respectively. in further detail, the score with nrs ≥ 4 meant msp. the total time of msp was taken as the cumulative time during the night. the times of sre pain imply the times of msp related to sre. incision edema and healing the degrees of edema severity resulting from the penis incision were classified as 3 levels. level 1 indicated striae-present edema, level 2 indicated striae-absent edema without blister, and level 3 indicated severe edema with blister and high skin temperature(7), respectively counted score 1, 2 or 3. the level of incision healing was evaluated by the physician at 1 week after the incision. the levels of incision healing were classified into 3 levels: level a indicated primary healing of the incision without any adverse reactions, level b indicated poor healing, but the incision did not become infected, and level c indicated that the incision was infected and needed drainage(7). duration of sleep to observe the side effects of irem sleep, we recorded the duration of sleep at night. in this study, the duration of sleep means the cumulative time of night time sleep that was observed. outcomes the primary outcomes were the times of sre-related msp and the cumulative time of msp at night during first 3 days after operation. the secondary outcomes were the levels of swelling and condition of incision healing during the second and third day. the cumulative times of sleep at night during first 3 days were safety indicator. statistical analysis all analyses were performed with spss 16.0 (spss, inc., chicago, illinois). continuous variables are presented as mean and standard deviation (sd) when normally distributed on visual inspection of their histograms and as median (interquartile range) when not normally distributed. categorical variables are summarized as count (proportion). data from the participants who withdrew from the study were not included in these analyses. the baseline characteristics were compared using t test, wilcoxon rank sum test, repeated measure and fisher’s exact test. the level of statistical significance was 0.05. table 2. comparison of times of sre-related msp and the cumulative time of msp at night. groups (n) times of msp the cumulative time of msp(min) 1d 2-3d 1-3d intervention (33) 2.00 ± 1.28 2.00 (1.50,3.50) 28.00 (11.00,50.50) control (42) 2.86 ± 1.93 3.47 (2.00,6.25) 55.00 (13.75,220.00) f/z 6.944 -2.125 p 0.010a * 0.034b * 1d: the first day after operation; 2-3d: the second and third day after operation; 1-3d: first 3 days after operation. the times of sre-related msp at 1d was presented as mean and standard deviation (sd), that of 2-3d and the total time of msp were presented as median (interquartile range). a: repeated measure; b: wilcoxon rank sum test. *: p value < 0.05. groups (n) level of swelling(2-3d) level of incision healing (7d) level a level b intervention(33) 2.00 (1.00,2.00) 32 (97.0%) 1(3.0%) control (42) 2.00 (1.75,2.00) 39 (92.6%) 3 (7.4%) z/x2 -0.295 0.619 p 0.768a 0.626b level of swelling (2-3d) was presented as median (interquartile range) and level of incision healing at 7d was presented as count (proportion). 2-3d: the second and third day after operation; 7d:the seventh day after operation. a: wilcoxon rank sum test; b: fisher’s exact test. table 3. comparison of levels of swelling and condition of incision healing. interrupted rem sleep improved male circumcision pain-dai et al. miscellaneous 50 vol 15 no 03 may-june 2018 51 results baseline characteristics ninety mc patients were recruited to this study, of whom 45 were randomly allocated to the irem sleep group and 45 to the control group (figure 1). twelve participants in the irem sleep group and 3 in the control group withdrew during the study, leaving 33 in the intervention group and 42 in the control group. there were several different reasons to withdraw from this study in the irem sleep group, 4 participants did not like to influence another family member’s sleep, 6 forgot to set the alarm clock, 1 was unwillingly to answer the phone, and 1 was excluded due to a sustained erection. in the control group, 1 was wound re-suturing and 2 did not answer the phone. demographic parameters were similar between both groups (table 1). the pain scores between two groups were not significantly different at baseline (table 1). times, the cumulative time, and incidences of sre-related msp at night during the first 3 days after the operation, the times of sre-related msp in the irem sleep group were significantly fewer than the control group (p = .010). five patients reported that there was no pain during the night. the cumulative time of sre-related msp was significantly decreased in the irem sleep group (p = .034) (table 2). at day 1 after the operation, the incidences of sre-related msp in the irem sleep group was 66.7%, while in the control group, it was 81.6%. incision swelling and healing there were no statistical differences in incision swelling (p = .768) and healing (p = 0.626) after the operation between the 2 groups (table 3). the cumulative time of sleep at night we recorded the cumulative time of sleep at night for 3 days after the operation. the results indicated that there was a little longer sleep time in the irem sleep group than in the control group. but this was not significantly different (p = .231) (table 4). discussion in this study, we found that the incidence of incision msp was 81.6%, which was lower than that reported by xiao-mei et al, who found the incidence of msp was 96%(7). the reason might be that we only collected the data of msp related to sre, while xiao-mei et al. included all the patients’ pain data. in addition, we found that mc patients in the nonintervention group experienced about 3 times the incidence of sre-related msp, with the total time of msp lasting for about 1 hour, and even up to 13 hours. the results above indicated that the postoperative pain status of patients with mc is not well noticed. although there have been related studies that reported the association between irem sleep and erection(17), we have not found existing reports using irem sleep for sre-pain intervention in mc patients. from our pilot study, we first designed the regimen of irem sleep, and then tested the effect of this method. we found that irem sleep improved sre-related msp for mc patients. we also found the times of sleep-related erection were noticeably fewer, and thus, the occurtable 4. comparison of cumulative time of sleep at night (h) ( ± s) groups (n) 1d 2d 3d intervention (33) 6.50 ± 1.51 6.39 ± 1.57 6.69 ± 1.22 control (42) 5.72 ± 2.05 6.11 ± 1.81 6.21 ± 1.79 f 1.456 p 0.231 1d, 2d and 3d: the first night, the second night and the third night after operation, respectively. p values were derived from repeated measure. figure 1. patients' flow diagram. interrupted rem sleep improved male circumcision pain-dai et al. rence of msp was improved. the beneficial effects of irem sleep on relieving sre-incision pain could also be observed on the third postoperative day. as the times of sre-related msp decreased, the cumulative time of msp decreased. some patients even reported that there was no pain at night after the operation. this phenomenon indicated that irem sleep effectively interrupted the occurrence of rem sleep in mc patients, leading to decrease times of erection, and therefore, the incision pain was effectively improved. although this method was good, the adherence to the irem sleep schedule was a problem. we understand that some patients had not paid the attention to the likelihood of sre-related pain; hence, we should increase the educational time and improve its effectiveness in the future. some other patients had a shorter sleep cycle, while the human normal sleep cycle lasts from 80 minutes to120 minutes(14), which resulted in the irem sleep intervention being invalid. the reasons might be associated with limited time of education (about 20 to 30minutes), as well as the sub-optimal time at which the education program was performed (just before the operation). at that time, the patients were anxious, and they paid more attention to the operation than the irem sleep intervention education; hence, the adherence of patients to the education might be affected. in addition, we did not pay attention to patients’ caring to interrupt their family members’ sleep, which resulted in four patients’ noncompliance. in further studies, we should modify the regimen of irem sleep according to the patients’ condition, arrange reasonable educational time and consider risk factors to affect the compliance. some patients in the control group kept themselves awake all night to avoid sleep-related incision pain, after they once experienced severe erection-related pain. hence, they had less sleep time. in this study, we recorded the cumulative time of sleep during the first 3 days. the results found that there were shorter sleep times in the control group than that of irem sleep group, although the result was not significantly different. therefore, irem sleep is one of the safe and effective methods for relieving sre pain. incision healing is another indicator of the advantages and disadvantages of circumcision [10]. the occurrence of sre after mc usually exacerbates incision swelling, which then delays the time of healing. xu et al found that the incidence of moderate and severe incision swelling was up to 44% at the third day after the operation, which could affect patient outcomes. hence, we explored the effect of irem sleep on improving incision swelling and healing.(7) however, we did not find that irem sleep could improve these indicators. the reason might be that sres provided adequate engorgement of the corpora cavernosa, which then led to increased tissue oxygenation(18), and thus promoted incision healing. the interrupted rapid eye movement sleep is an effective, safe, and free method of treatment to relieve incision pain of sleep-related erections. limitations: in this study, we did not perform blinded measurements, and the erection-related msp using nrs and the time of sleep was by patients’ self-report; therefore, these measurements were somewhat subjective, and a measuring bias might exist. we did not perform the intentionality analysis, and therefore a selection bias might exist. there was limited education time which might result in poor adherence to our intervention program. the limited sample was given in this study. in a further study, we could perform an individualized regimen of irem sleep, which may bring more benefits to the mc patients. conclusions we proposed the method of interrupted rapid eye movement sleep, then explored the effect of pain-relieving on male circumcision. we found that the interrupted rapid eye movement sleep is an effective, simple, and free treatment to relieve incision pain of sleep-related erections. acknowledgments this study was sponsored by the national science foundation of china (grant no. 81172347). conflict of interest the authors report no conflict of interest. references 1. morris bj, wamai rg, henebeng eb, et al. estimation of country-specific and global prevalence of male circumcision. popul health metr. 2016;14:1-4. 2. zeng m, wang l, chen c, et al. factors associated with knowledge of and willingness for adult male circumcision in changsha, china. plos one. 2016;11:e0148832. 3. malone j, thompson j. circumcision circumspection. n engl j med. 1997;336:1244-5. 4. peng yf, cheng y, wang gy, et al. clinical application of a new device for minimally invasivecircumcision. asian j. androl. 2009;10:447-54. 5. yang mh, tsao cw, wu st, et al. the effect of circumcision on young adult sexual function. kaohsiung j med sci. 2014;30:3059. 6. tree-trakarn t, pirayavaraporn s. postoperative pain relief for circumcision in children: comparison among morphine, nerve block, and topical analgesia. anesthesiology. 1985;62:519-22. 7. xu xm, xu zh. therapeutic effects on compound lidocaine cream in relieving incision pain of circumcision. nurs j chin pla. 2010;27:1131-2. 8. hirshkowitz m, schmidt mh. sleep-related erections: clinical perspectives and neural mechanisms. sleep med rev. 2005;9:311-29. 9. li pc, cai m, li zl, et al. diethylstilbestrol and acetaminophen ring effect of penile erection and complications after transurethral resection of the foreskin. national journal of andrology. 2010;16:174-5. 10. ma q, fang l, yin wq, et al. chinese shang ring male circumcision: a review. urol. int. 2017. interrupted rem sleep improved male circumcision pain-dai et al. miscellaneous 52 vol 15 no 03 may-june 2018 53 11. sandeman dj, reiner d, dilley av, bennett mh, kelly kj. a retrospective audit of three different regional anaesthetic techniques for circumcision in children. anaesth intensive care. 2010;38:519-24. 12. naja za, ziade fm, al-tannir ma, abi mansour rm, el-rajab ma. addition of clonidine and fentanyl: comparison between three different regional anesthetic techniques in circumcision. paediatr anaesth. 2005;15:964. 13. karakoyunlu n, polat r, aydin gb, ergil j, akkaya t, ersoy h. effect of two surgical circumcision procedures on postoperative pain: a prospective, randomized, double-blind study. j pediatr urol. 2015;11:124.e1-5. 14. mann k, pankok j, connemann b, röschke j. temporal relationship between nocturnal erections and rapid eye movement episodes in healthy men. neuropsychobiology. 2003;47:109-14. 15. song ys, song es, lee kh, park yh, shin wc, ku jh. sleep-related nocturnal erections and erections during midazolam-induced sedation in healthy young men. int j impot res. 2006;18:522-6. 16. da sf, de oliveira sm, nobre mr. a randomised controlled trial evaluating the effect of immersion bath on labour pain. midwifery. 2009;25:286-94. 17. voss u. functions of sleep architecture and the concept of protective fields. rev neurosci. 2006;15:33-46. 18. montorsi f, oettel m. testosterone and sleep‐ related erections: an overview. j sex med. 2005;2:771-84. interrupted rem sleep improved male circumcision pain-dai et al. urological oncology prognostic significance of the neutrophil-to-lymphocyte ratio in patients with non-muscle invasive bladder cancer treated with intravesical bacillus calmette–guérin and the relationship with the cueto scoring model jae-wook chung1,6†, jin woo kim1†, eun hye lee2, so young chun3, dong jin park4, kyeong hyeon byeon1, seock hwan choi5,7, jun nyung lee1,7, bum soo kim5,7, hyun tae kim5,7, eun sang yoo5,7, tae gyun kwon1,6,7, yun-sok ha1,6,7*, tae-hwan kim1,7* purpose: in this study, we evaluated the predictability of a modified club urológico español de tratamiento oncológico (cueto) scoring model and preoperative neutrophil-to-lymphocyte ratio (nlr) in patients with non-muscle invasive bladder cancer (nmibc). materials and methods: from august 2005 to may 2016, a total of 281 patients received intravesical bacillus calmette–guérin therapy after transurethral resection of a bladder tumor. the pathologic stage of all patients was ta or t1. of 281 patients, 84 (29.9%) experienced recurrence and 14 (5.0%) developed progression. the mean follow-up period was 46 months. the cut-off value for nlrs was 2.29. results: one hundred-eight patients (38.4%) displayed a high nlr (> 2.29). in kaplan–meier curve analysis, a high nlr was associated with lower recurrence-free survival (rfs) (p < .001) and progression-free survival (pfs) (p = .002). cueto scores were associated with rfs (p < .001), but not with pfs (p = .423). a combination of nlrs and the cueto risk model correlated with rfs (p < .001) and pfs (p = .002). in multivariate analysis, female gender, concomitant carcinoma in situ (cis), tumor number >3, recurrent tumors, and a high nlr were independent factors predicting recurrence (all p < .05). concomitant cis, recurrent tumors, and a high nlr were independent factors for predicting progression (all p < .05). conclusion: in patients with nmibc, an nlr >2.29 was identified as a significant factor for predicting tumor recurrence and progression. the inclusion of preoperative nlr enhanced the accuracy of the cueto model to predict disease progression. keywords: neutrophil-to-lymphocyte ratio; bacillus calmette–guérin; club urológico español de tratamiento oncológico risk model; survival introduction the most common malignant tumor of the urinary tract is bladder cancer, and the fourth-most common cancer among males in developed countries.(1) three-quarters of bladder cancer patients are diagnosed with non-muscle invasive bladder cancer (nmibc), which includes tis, ta and t1 pathologic stages.(2) transurethral resection of bladder tumor (tubrt) is a primary surgical treatment used to treat patients with nmibc.(3) after initial turbt, immunotherapy with 1 department of urology, school of medicine, kyungpook national university, kyungpook national university chilgok hospital, daegu, republic of korea. 2 joint institute for regenerative medicine, kyungpook national university hospital, daegu, republic of korea. 3 biomedical research institute, kyungpook national university hospital, daegu, republic of korea. 4 department of urology, dongguk university school of medicine, gyeongju, korea.. 5 department of urology, school of medicine, kyungpook national university, kyungpook national university hospital, daegu, republic of korea. 6 joint institute for regenerative medicine, kyungpook national university hospital, daegu, republic of korea. 7 department of urology, school of medicine, kyungpook national university, daegu, republic of korea. † these authors contributed equally to this work. *correspondence: department of urology, school of medicine, kyungpook national university, kyungpook national university chilgok hospital, daegu, republic of korea: dr. tae-hwan kim, e-mail: doctork@knu.ac.kr, department of urology, school of medicine, kyungpook national university, kyungpook national university chilgok hospital, daegu, republic of korea. e-mail: yunsokha@gmail.com. received march 2021 & accepted september 2021 intravesical instillation of bacillus calmette–guérin (bcg) is the most effective adjuvant therapy for intermediateand high-risk nmibc.(4) despite the effectiveness and safety of bcg, recurrence rates are 32.6% to 42.1% and progression rates are 9.5% to 13.4%.(5) the major treatment challenge with nmibc is preventing progression to muscle invasive bladder cancer (mibc), which rapidly worsens prognoses.(6) thus, it is significant to predict risk factors for disease recurrence and progression in nmibc patients according to individual characteristics, including pathology and choose urology journal/vol 19 no. 4/ july-august 2022/ pp. 281-288. [doi: 10.22037/uj.v18i.6765] optimal treatment modalities to enhance oncologic outcomes. to predict recurrence of nmibc and progression to mibc, numerous clinical and pathological factors are commonly used to assign patients to different risk groups. of these risk models, a scoring model developed by the club urológico español de tratamiento oncológico (cueto, or spanish urological club for oncological treatment) is considered the most reliable. the cueto model was developed as a risk-scoring tool that predicts the probability of disease recurrence and progression in bcg-treated patients at 1, 2, and 5 years.(7) it is now recognized that increased systemic inflammatory responses induced by tumor microenvironments trigger alteration of acute-phase reactive proteins and hematologic parameters.(8) among these serum markers are neutrophil and lymphocyte counts, which can indicate relative neutrophilia and lymphocytopenia. in various tumor patients, a higher percentage of neutrophils than lymphocyte is associated with reduced cancer-free and overall survival.(9-11) we evaluated the efficiency of a modified cueto scoring model combined with preoperative nlrs to predict recurrence and progression of disease in nmibc patients. patients and methods ethics statement this study was approved by the institutional review board of kyungpook national university, hospital, daegu, republic of korea (irb number knuh 202003-042). the study was carried out in agreement with the applicable laws and regulations, good clinical practices, and ethical principles as described in the declaration of helsinki. the institutional review board of kyungpook national university chilgok hospital waived because of the retrospective nature of the study. study design the study was a single institution, retrospective observational trial. from august 2005 to may 2016, a total of 281 patients who underwent bcg induction therapy after complete turbt were included in this study. they had not previously received intravesical bcg and showed no side effects of bcg or signs of recurrence during bcg therapy. all patients were diagnosed as histologically ta or t1. a second tur was performed 2 to 4 weeks after initial resection if a bladder tumor specimen did not include detrusor muscle or when a high-grade tumor was detected. patients with only carcinoma in situ (cis) were excluded, as were those significance of the nlr with cueto model-chung et al. total n = 281 nlr ≤ 2.29 n = 173 nlr > 2.29 n = 108 p-value recurrence 84 (29.9%) 35 (20.2%) 49 (45.4) < 0.001 progression 14 (5.0%) 3 (1.7%) 11 (10.2%) 0.002 gender 0.952 male 245 (87.2%) 151 (87.3%) 94 (87.0%) female 36 (12.8%) 22 (12.7%) 14 (13.0%) age, years 67.38 ± 10.58 68.00 ± 9.87 66.40 ± 11.60 0 .218 age, categorical 0.340 < 60 63 (22.4%) 34 (19.7%) 29 (26.9%) 60 ~ 70 98 (34.9%) 64 (37.0%) 34 (31.5%) > 70 120 (42.7%) 75 (43.4%) 45 (41.7%) body mass index, kg/m2 23.88 ± 3.37 23.94 ± 3.07 23.79 ± 3.81 0.727 follow-up periods, months 46.65 ± 20.80 45.25 ± 19.14 48.89 ± 23.13 0.173 t stage 0.239 ta 105 (37.4%) 60 (34.7%) 45 (41.7%) t1 176 (62.6%) 113 (65.3%) 63 (58.3%) tumor grade 0.327 low 30 (10.7%) 16 (9.2%) 14 (13.0%) high 251 (89.3%) 157 (90.8%) 94 (87.0%) concomitant carcinoma in situ 0.098 no 257 (91.5%) 162 (93.6%) 95 (88.0%) yes 24 (8.5%) 11 (6.4%) 13 (12.0%) tumor size 0.779 ≥ 3 cm 195 (69.4%) 119 (68.8%) 76 (70.4%) > 3 cm 86 (30.6%) 54 (31.2%) 32 (29.6%) tumor number 0.293 ≥3 215 (76.5%) 136 (78.6%) 79 (73.1%) > 3 66 (23.5%) 37 (21.4%) 29 (26.9%) recurrent tumor 0.792 no 240 (85.4%) 147 (85.0%) 93 (86.1%) yes 41 (14.6%) 26 (15.0%) 15 (13.9%) cueto score according to recurrence (non-categorical) 5.58 ± 2.13 5.57 ± 2.08 5.59 ± 2.20 0.938 cueto score according to recurrence (categorical) 0.826 1~4 92 (32.7%) 55 (31.8%) 37 (34.3%) 5~6 106 (37.7%) 67 (38.7%) 39 (36.1%) 7~9 66 (23.5%) 42 (24.3%) 24 (22.2%) 10~16 17 (6.1%) 9 (5.2%) 8 (7.4%) cueto score according to progression (non-categorical) 8.27 ± 2.26 8.35 ± 2.20 8.15 ± 2.37 0.462 cueto score according to progression (categorical) 0.453 1~4 22 (7.8%) 12 (6.9%) 10 (9.3%) 5~6 42 (15.0%) 22 (12.7%) 20 (18.5%) 7~9 120 (42.7%) 78 (45.1%) 42 (38.9%) 10~14 97 (34.5%) 61 (35.3%) 36 (33.3%) table 1. characteristics of patients with nmibc. data are presented as mean ± sd or number (percent) vol 19 no 4 july-august 2022 282 urological oncology 283 found to have advanced bladder or ureteral tumors or non-urothelial carcinoma at the first tur. patients with hematologic malignance and acute or chronic infection were also excluded. preoperative nlr was calculated by a complete blood count with differential. preoperative nlr was measured once at least 2 weeks before surgery. the best cutoff value of nlr was computed to be 2.29 in accordance with the receiver operating characteristic (roc) curve. and the area under the roc curve was 0.651 (95% ci 0.578–0.724; p < .001) (sensitivity: 59.5%, specificity: 69.5%) (figure 1). the follow-up period of patients was calculated from the first turbt to the last cystoscopy examination. we performed urine cytology, cystoscopy, chest x-ray, and abdominopelvic computed tomography (ct) scans for follow-up study. during the first year after turbt, follow-up study was conducted at 3, 6, and 12 months. cystoscopy and urine cytology were performed every 6 months until 2 years after turbt, and yearly thereafter. imaging analyses, including chest x-ray and ct scans were examined every 6 months from 1 to 5 years, and annually thereafter. recurrence of disease was defined as a newly patho¬logical confirmed bladder cancer regardless of stage after completion of bcg induction therapy. progression of disease was defined as from ta or t1 to stage t2 or higher disease (mibc). intravesical bacillus calmette–guérin instillation in all patients, bcg tice strain 12.5 mg (oncotice) was used. a bcg suspension with 50 ml of 0.9% normal saline was instilled into the bladder via a 10 fr urethral catheter. patients were advised not to urinate for two hours. induction bcg therapy was initiated 2 weeks after tur and repeated once a week for 6 weeks. we did not perform bcg maintenance therapy. there were no patients who received immediate postoperative instillation of chemotherapy. club urológico español de tratamiento oncológico scoring model scoring tumor recurrence and progression were calculated according to the cueto scoring model, which includes age, gender, previous recurrence status, tumor stage (2002 tnm classification) and grade, multiplicity, and concomitant cis. in accordance with the 2004 world health organization (who) grading system, we classified tumor grades as low or high. statistical analysis non-continuous variables of patient characteristics, including gender, t stage, tumor grade, concomitant cis, size (≤ 3 cm vs > 3 cm), number (≤ 3 vs > 3), recurrence status and cueto risk model (categorical) were analyzed using the chi-square test. student’s t-test was used to analyze continuous variables such as age, body mass index (bmi), cueto risk model (non-categorical) and follow up periods. in addition, univariate and multivariate cox re¬gression model was used for analysis of tumor recurrence and progression, and kaplan– meier curves via a log-rank test were used for analysis of recurrence-free survival (rfs) and progression-free survival (pfs). statistical analysis was performed using spss 16.0 for windows (spss inc., chicago, il, usa), and a p value < .05 was con¬sidered statistically significant. results table 1 lists the characteristics of patients with nmibc. a total of 173 patients had an nrl ≤ 2.29 (61.6%) and 108 (38.4%) had an nlr > 2.29. eighty-four patients (29.9%) experienced recurrence and 14 (5.0%) showed progression after tur followed by bcg therapy. female patients accounted for 12.8% (36/281) of the study groups. no significant differences were evident in gender, age, bmi, and follow-up periods between the two nlr groups. there were no significant differences in tumor t stage, grade, concomitant cis, size, number, and prior recurrence status between the two nlr groups. no significant differences were found in categorical or non-categorical cueto scores between the two nlr groups. table 2 shows subgroup analysis of high risk nmibc patients (n = 251). high risk group was defined if any high grade tumor or cis is present. (12) subgroup analysis of high risk group showed similar results to the overall group. table 2. characteristics of patients with high risk patients with nmibc. total n = 251 nrl ≤ 2.29 n = 159 nlr > 2.29 n = 95 p-value recurrence 78 (30.7%) 34 (21.4%) 44 (46.3%) < 0.001 progression 14 (5.5%) 3 (1.9%) 11 (11.6%) 0.001 gender 0.814 male 223 (87.8%) 139 (87.4%) 84 (88.4%) female 31 (12.2%) 20 (12.6%) 11 (11.6%) age, years 67.59 ± 10.61 68.16 ± 9.96 66.64 ± 11.61 0 .270 body mass index, kg/m2 23.82 ± 3.44 23.91 ± 3.11 23.68 ± 3.94 0.607 data are presented as mean ± sd or number (percent) no recurrence recurrence p-value neutrophil count (x103) 3.97 ± 1.47 4.50 ± 1.44 0.006 lymphocyte count (x103) 2.03 ± 0.61 1.86 ± 0.69 0.039 nlr 2.11 ± 1.01 2.69 ± 1.17 < 0.001 no progression progression p-value neutrophil count (x103) 4.11 ± 1.49 4.59 ± 1.14 0.238 lymphocyte count (x103) 1.99 ± 0.64 1.65 ± 0.62 0.054 nlr 2.25 ± 1.09 2.98 ± 0.99 0.013 data are presented as mean±sd or number (percent) table 3. absolute neutrophil, lymphocyte count and nlr according to recurrence and progression. significance of the nlr with cueto model-chung et al. table 3 shows absolute neutrophil, lymphocyte count and nlr according to recurrence and progression. nrl was significantly higher in patients who showed recurrence or progression. table 4 shows univariate and multivariate cox proportional hazards regression model for predicting recurrence. female gender, concomitant cis, multiplicity (> 3) and an nlr > 2.29 were independent prognostic factors for tumor recurrence (hazard ratio [hr], 2.103; 95% confidence internal [ci], 1.175–3.450; p = .011 / hr, 2.550; 95% ci, 1.362–4.774; p = .033 / hr, 2.275; 95% ci, 1.424–3.635; p = .009 / hr, 2.514; 95% ci, 1.657–3.483; p = .001, respectively). table 5 shows univariate and multivariate cox proportional hazards regression model for predicting progression. concomitant cis, prior recurrence status and an nlr > 2.29 were independent prognostic factors for progression (hr, 10.254; 95% ci, 2.919–36.018; p < .001 / hr, 8.628; 95% ci, 2.446–30.437; p = .041 / hr, 6.119; 95% ci, 1.975–21.622; p = .008, respectively). kaplan–meier curve analyses with a log-rank test are shown in figure 2, 3, and 4. a high nlr (> 2.29) were associated with significantly low rfs and pfs (p < .001, p = .002) (figure 2). a high cueto was associated with a significantly low rfs (p < .001), but there was no significant association between cueto scores and pfs (p = .423) (figure 3). after combining nlrs (cutoff value = 2.29) and cueto scoring (cut-off value = 7), the modified risk model showed that high nlr and cueto scores were significantly associated with low rfs and pfs (p < .001, p = .002) (figure 4). discussion this study identified nlr as a significant factor for predicting tumor recurrence and progression, and inclusion of preoperative nlr enhanced the accuracy of the cueto model to predict progression in patients with nmibc. in the early stages, nmibc is not life-threatening, but it will recur in more than half of patients and progress from 10% to 20% to mibc.(13) although numerous efforts have been made to predict and prevent tumor recurrence and progression, the exact characteristics of nmibc are unknown due to its heterogeneity. the european organization for research and treatment of cancer (eortc) has developed a simple scoring system that uses information such as tumor size and number, prior recurrence rate, stage, and concomitant cis and who grade based on data of 2596 patients with nmibc, to predict the risk of relapse and progression. (14) the cueto scoring model was created to compensate for the eortc with low rates of bcg treatment, using information from 1062 patients who received bcg treatment.(7) compared to eortc, where most of the 78% patients received intravesical chemotherapy, all patients in the cueto study received bcg instillation, and 15% of them received mitomycin c. intravesical instillation of bcg is a standard treatment for cis and an adjuvant option for t1 and higher-grade ta bladder tumors after tur.(15) the cueto model is thought to be more suitable for patients treated with bcg. in this study, as with the cueto study, we included patients who completed 6 bcg instillations. however, compared with the cueto scoring model, only female gender, concomitant cis, multiplicity (> 3), and prior recurrence status were significant factors for predicting tumor recurrence (all p < .05). about tumor progression, only concomitant cis and prior recurrence status were significant factors (all p < .05). a kaplan–meier curve analysis demonstrated that the cueto score was associated with rfs (p < .05), but not with pfs (p = .423). we, therefore, decided to add the nlr ratio to the cueto scoring model if inclusion of an nlr would enhance the predictability of cueto scoring. preoperative nlr has proven to be a useful marker and a high nlr has been linked to higher tumor stages table 4. univariate and multivariate cox proportional hazards regression model for predicting recurrence. p-value hr (95% ci) univariate multivariate age 0.015 0.271 body mass index 0.935 gender (male vs. female) 0.005 0.011 2.103 (1.175-3.450) t stage (ta vs t1) 0.035 0.236 tumor grade (low vs high) 0.475 presence of carcinoma in situ (no vs. yes) 0.024 0.033 2.550 (1.362-4.774) multiplicity (≤ 3 vs > 3) 0.004 0.009 2.275 (1.424-3.635) tumor size (≤ 3 vs > 3) 0.715 prior recurrence status (no vs. yes) 0.080 nlr (≤ 2.29 vs. > 2.29) < 0.001 0.001 2.514 (1.657-3.483) p-value hr (95% ci) univariate multivariate age 0.089 body mass index 0.722 gender (male vs. female) 0.141 t stage (ta vs t1) 0.225 tumor grade (low vs high) 0.193 presence of carcinoma in situ (no vs. yes) < 0.001 < 0.001 10.254 (2.919-36.018) multiplicity (≤ 3 vs > 3) 0.645 tumor size (≤ 3 vs > 3) 0.670 prior recurrence status (no vs. yes) 0.022 0.041 8.628 (2.446-30.437) nlr (≤ 2.29 vs. > 2.29) 0.002 0.008 6.119 (1.975-21.622) table 5. univariate and multivariate cox proportional hazards regression model for predicting progression. significance of the nlr with cueto model-chung et al. vol 19 no 4 july-august 2022 284 urological oncology 212 and adverse oncologic outcomes in numerous cancers, including not only the gastrointestinal cancer but genitourinary tract cancer, such as urothelial carcinoma of the bladder.(16-19) although the pathophysiology is not understood clearly, relative neutrophilia may increase inflammatory markers that include proangiogenic factors, growth factors, proteases, and antiapoptotic markers, which facilitate tumor growth and progression.(20) in addition, lymphocytopenia may destroy cell-mediated immune responses and therefore worsen prognoses.(21) in bladder tumors, several previous studies have evaluated the predictive value of nlrs(22); most focused on mibc and were conducted mainly on patients who underwent radical cystectomy.(23-26) in 2014, viers et al. evaluated 899 patients who underwent radical cystectomy without neo-adjuvant chemotherapy and who had a preoperative nlr. an elevated preoperative nlr (> 2.7) was associated with a significantly higher risk of a locally advanced disease as well as subsequent disease recurrence and cancer-specific and all-cause mortality. in 2012, can et al. demonstrated that among 80 nmibc patients and 102 patients with mibc, an nlr > 2.57 was a predictor of invasive urothelial carcinoma. according to a 2014 study by potretzke et al., among 102 consecutive patients undergoing radical cystectomy, nlr was significantly related to pathologic tumor staging and to upstaging of non-organ confined disease (≥ pt3). similarly, krane et al. reported that, among figure 1. the best cut-off nlr value according to the roc curve. figure 2. kaplan–meier curve analysis for recurrence-free survival (a) and progression-free survival (b), according to nlrs. significance of the nlr with cueto model-chung et al. urological oncology 285 68 consecutive cases of radical cystectomy for mibc, an nlr >2.5 was associated with poor overall and cancer-specific survival, suggesting that such patients may benefit from neo-adjuvant chemotherapy. when focusing on nmibc, several trials(8,16,27,28) evaluated the predictive value of the nlr. in 2015, mano et al. revealed that an nlr > 2.41 was an independent predictor of disease progression and recurrence in 107 patients with nmibc treated with tur. according to favilla et al.’s study in 2016, an nlr ≥ 3 was associated with worse disease recurrence (hr, 2.84; p < .01) in 178 patients with ta or t1 bladder tumor who underwent tur. the 5-year rfs was 49% and 62% in patients with an nlr ≥ 3 and < 3 (p < .01). a prospective study of albayrak et al. in 2016 found that a higher nlr was associated with recurrence and progression of ta or ta bladder tumors, although, and in contrast with the finding of previous studies, a significant relationship with nlr was lost after correcting for age. another prospective trial by getzler et al. in 2018 demonstrated that an nlr > 2.5 was a significant predictor of disease recurrence and a worse rfs in 113 patients with nmibc, particularly those treated with bcg. as with the studies described above, we found that an nlr > 2.29 was associated with higher tumor recurrence (hr, 2.451; 95% ci, 1.567–3.834; p < .001) and tumor progression (hr, 5.911; 95% ci, 1.579–22.126; p = .008) according to a multivariate cox proportional hazards regression model. kaplan–meier curve analysis showed that an nlr > 2.29 showed significantly low rfs and pfs (p < .001 and < .002, respectively). however, the four studies mentioned above were not restricted to patients treated with bcg. when narrowing the scope of predictive values of nlrs in all bcg treated patients, racioppi et al. (2019)(29) evaluated whether an nlr ratio can predict the response to bcg in high-risk nmibc patients. one hundred consecutive patients with newly diagnosed figure 3. kaplan–meier curve analysis for recurrence-free survival (a) and progression-free survival (b), according to cueto scores. figure 4. kaplan–meier curve analysis for recurrence-free survival (a) and progression-free survival (b), according to a combination of nlrs and cueto scores. significance of the nlr with cueto model-chung et al. vol 19 no 4 july-august 2022 286 high-risk nmibc were analyzed retrospectively. all received an induction course of intravesical immu¬notherapy with bcg followed by a maintenance course for at least a year. forty-eight patients underwent radical cystectomy for high-grade recurrence or pro¬gression to muscle invasive disease (bcg non-responder group). the mean nlr was 2.61 ± 0.77 in the bcg responder group and 3.65 ± 1.16 in the bcg non-responder group (p = .01). the nlr was associated with both recurrence (p = .01) and progression (p = .01). a kaplan–meier analysis with a log-rank test showed statistically significant differences between the curves for an nlr < 3 and an nlr ≥ 3 (p < .05). based on the ability of the nlr to predict tumor recurrence and progression, we added the nlr to the cueto scoring model. using the cueto scoring model alone, a significant association was observed with low rfs (p < .001), but not with pfs (p = .423) (figure 2). however, after combining the nlr (cut-off value 2.29) and cueto scoring model (cut-off value 7), the resulting modified risk model showed that a high nlr and high cueto score were significantly associated with both low rfs and pfs (p < .001 and p = .002, respectively) (figure 3). other combined risk models have been shown to enhance the predictability of each risk model.(8,21) getzler et al. provided statistical evidence that an nlr > 2.5 may improve the predictive power of an eortc score when the two are calculated together. in 2019, aydin et al. evaluated the correlation between nlr and eortc recurrence and progression scores. they reported that as the nlr increased, recurrence (p < .001) and progression (p = .034) scores increased significantly. nevertheless, this study is the first to analyze the prognostic significance of the nlr and its synergic relation with the cueto scoring model in patients with nmibc after intravesical bcg instillation. furthermore, interestingly, there were no differences in the clinical and pathological findings between the two nlr groups. and this highlights that the biological properties of tumor cells may be very different from the pathological and anatomical characteristics of the tumor. as such patients within a specific pathological classification may have differing prognosis due to differing biological properties such as the degree of immune dysfunction. there were several limitations to be considered in this study. first, it was based on a retrospective analysis of the records of patients treated at a single institution with unavoidable selection biases. small numbers and heterogeneous patients are also weak points. it should also be noted that in many previous studies, various nlr cut-off values were evaluated and utilized.(30) each study’s results should be interpreted carefully. because the idealized and generalized nlr have not yet been established, each study selected cut-off values with different sensitivities and specificities. furthermore, the main limitation concerning nlrs is the volatile counts of neutrophils and lymphocytes. although we excluded patients with hematologic malignances and acute or chronic infections, it is possible that individual chronic medications, herbs, or antibiotics affected the nlr value. as the nlr is a dynamic parameter (unlike standard pathological parameters), the dynamic changes of nlr after various treatments of bladder cancer may be important in the clinical day-to-day management of patients. few studies have been reported on the nlr measured after turbt or bcg instillation, therefore, studies comparing nlr before and after treatment of bladder cancer or optimal timing of nlr determination are also essential, either. a prospective study with a larger cohort is required to solidify the place of nlr in predicting disease recurrence and progression in patients with nmibc in the future. conclusions our study showed that in patients with nmibc, the nlr was identified as a significant factor for predicting tumor recurrence and progression. furthermore, inclusion of a preoperative nlr enhanced the accuracy of the cueto model to predict disease progression. nlr is promising and inexpensive hematologic biomarker which can be applied to clinical decision making and estimation of oncologic outcomes in the bladder cancer patients. we therefore recommend that patients with a high nlr receive more aggressive management. acknowledgements this research was supported by the basic science research program through the national research foundation of korea (nrf), and was funded by the korean government (msit) (2016r1c1b1011180), (2019r1h1a1079839), (2019r1f1a1044473), (2019r1a2c1004046), (2018r1c1b5040264), (2020r1a2b5b03002344) and (2020r1i1a3071568). conflict of interests none of the authors has any personal or financial con¬flict of interest. references 1. ferlay j, soerjomataram i, dikshit r, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer. 2015;136:e359-86. 2. babjuk m, burger m, zigeuner r, et al. eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. eur urol. 2013;64:639-53. 3. babjuk m, bohle a, burger m, et al. eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. eur urol. 2017;71:447-61. 4. malmstrom pu, sylvester rj, crawford de, et al. an individual patient data meta-analysis of the long-term outcome of randomised studies comparing 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2014;66:1157-64. 24. can c, baseskioglu b, yilmaz m, colak e, ozen a, yenilmez a. pretreatment parameters obtained from peripheral blood sample predicts invasiveness of bladder carcinoma. urol int. 2012;89:468-72. 25. potretzke a, hillman l, wong k, et al. nlr is predictive of upstaging at the time of radical cystectomy for patients with urothelial carcinoma of the bladder. urol oncol. 2014;32:631-6. 26. krane ls, richards ka, kader ak, davis r, balaji kc, hemal ak. preoperative neutrophil/lymphocyte ratio predicts overall survival and extravesical disease in patients undergoing radical cystectomy. j endourol. 2013;27:1046-50. 27. favilla v, castelli t, urzi d, et al. neutrophil to lymphocyte ratio, a biomarker in nonmuscle invasive bladder cancer: a singleinstitutional longitudinal study. int braz j urol. 2016;42:685-93. 28. albayrak s, zengin k, tanik s, et al. can the neutrophil-to-lymphocyte ratio be used to predict recurrence and progression of nonmuscle-invasive bladder cancer? kaohsiung j med sci. 2016;32:327-33. 29. racioppi m, di gianfrancesco l, ragonese m, palermo g, sacco e, bassi pf. can neutrophil-to-lymphocyte ratio predict the response to bcg in high-risk non muscle invasive bladder cancer? international braz j urol. 2019;45:315-24. 30. marchioni m, primiceri g, ingrosso m, et al. the clinical use of the neutrophil to lymphocyte ratio (nlr) in urothelial cancer: a systematic review. clin genitourin cancer. 2016;14:473-84. significance of the nlr with cueto model-chung et al. vol 19 no 4 july-august 2022 288 letter adjuvant vs. salvage radiation therapy after radical prostatectomy: role of decipher® in the era of personalized medicine ali nowroozi1,2, amirali karimi1,2, sanam alilou1,2, erfan amini1* prostate cancer (pca) is the most common and the second cause of cancer-related deaths among men, with in-creasing incidence and burden, nationally and globally.(1,2) radical prostatectomy (rp) has substantially influenced pca management, providing excellent results in treating the patients.(3) however, likelihood of biochemical recurrence (bcr) remains high, especially in patients with adverse pathological features and these patients should receive postoperative adjuvant radiation therapy (art) according to the guidelines. there are some uncertainties about receiving immediate art after rp in men with adverse pathological features versus salvage radiation therapy (srt) after bcr. unlike art, srt provides time for urinary and sexual recovery, though it might be associated with undertreatment and risk of disease progression in a subset of patients. in the era of personalized medicine, molecular diagnosis has the potential to distinguish patients with higher risk of progression and metastasis who may benefit from art. decipher® (genomedx biosciences) is a semi-quantitative genomic classifier (gc) with the potential to predict the risk of pca metastasis after rp in men at high risk of recurrence. the test is based on gene-expression microarray analysis of 22 rna biomarkers and produces scores ranging between 0 and 1. results are also classified into low-risk, intermediate-risk, and high-risk groups (for scores < 0.45, between 0.45 and 0.6, and > 0.6, respectively). (3) the probability of recurrence at 10 years after rp has been reported to be 2.6% and 13.6% in men with low risk and high risk decipher scores respectively.(3) analyzing data from the leuven and grid cohorts also revealed that for every 10% growth in decipher test score, 10-year metastasis odds increased 53% and 31%, respectively(4) decipher has been found to be predictive of 5-year prostate cancer-specific mortality (pcsm) rate. mortality rates among men with low and intermediate decipher scores were found to be 0%, compared to 9.4% for high-risk patients.(5) in a recent meta-analysis,(6)10-year incidence of metastasis based on decipher score in low-risk, intermediate-risk and high-risk patients were 5.5%, 15.0% and 26.7%, respectively. the national comprehensive cancer network (nccn) classifies intermediate-risk pca patients into two favorable and unfavorable intermediate risk groups (fir and uir respectively). although regression-free survival is statistically comparable between fir and low risk (lr) groups, odds of adverse pathology in fir patients is significantly higher compared to very low (vl) and lr men.(7) therefore, it is yet to be determined whether waitand-see followed by srt is beneficial in the fir group. herlemann et al.(8) conducted a retrospective study on 647 patients who were classified as vl/lr (427, 66%) or fir (220, 34%) risk groups. rp was their initial treatment and decipher analysis was performed to assess if this genomic test can predict the presence of adverse pathology. fir patients with low or intermediate risk decipher scores demonstrated statistically same odds for harboring adverse pathology as nccn vl/lr groups; however, adverse pathology was observed at significantly higher rates in decipher high risk fir patients compared to vl/lr groups (or = 6.8, p < 0.001). one study in patients with low risk disease based on decipher testing (score<0.4) showed that receiving srt compared to art is not associated with decline in 5-year metastasis free survival; however, art decreased 5-year metastasis rate from 23% to 6% in patients with scores ≥ 0.4.(9) in order to better identify the appropriate treatment for each patient, dalela et al.(10) proposed a novel scoring system (ranging 0-4) by merging genomic and histopathology data. based on their nomogram, when patients with high decipher scores and aggressive disease characteristics (overall score ≥ 2) received art rather than srt, an absolute decrease of 17.3% and 32% in clinical recurrence was noted, 5 and 10 years following rp, respectively. while proposing radiotherapy is aimed for pca relapse prevention, shortand long-term side effects and complications must be taken into account. treatment-associated cost is also a salient criterion to consider in decision-making. in comparison with 100% adjuvant radiotherapy, decipher engenders more qalys and is more effective whilst being more cost-effective. due to imperfect implementation of the guidelines (which suggest art for all patients with adverse pathologic features), and subsequent diminished use of art, decipher-based treatment happens to be the superior side in qaly and outcomes of the patients, but more expensive than usual care. the incremental cost-effectiveness ratio (icer) of gc-based care is $90,833 per qaly, which is within reasonable thresholds ($100,000 to $150,000).(11) decipher has shown to be capable of predicting disease recurrence, metastasis and pcsm in multiple studies and 1uro-oncology research center, tehran university of medical sciences, tehran, iran. 2school of medicine, tehran university of medical sciences, tehran, iran. *correspondence: associate professor of urology, department of urology, uro-oncology research center, tehran university of medical sciences. tehran, iran. tel. +98 21 66903063, fax: +98 21 66903063, . e-mail address: amini.erfan@gmail.com; e-amini@sina.tums.ac.ir received october 2020 & accepted november 2020 urology journal/vol 18 no. 3/ may-june 2021/ pp. 349-350. [doi: 10.22037/uj.v16i7.6526] has the potential to predict subgroup of patients who might benefit from art after rp; however, further investigations are required to prove decipher’s role in clinical outcome improvement in patients receiving decipher-based treatment compared with those receiving usual care. references 1. pishgar, f., et al., global, regional and national burden of prostate cancer, 1990 to 2015: results from the global burden of disease study 2015. j urol, 2018. 199: p. 1224-32. 2. basiri, a., et al., incidence, gleason score and ethnicity pattern of prostate cancer in the multi-ethnicity country of iran during 20082010. urol j, 2020. 3. glass, a.g., et al., validation of a genomic classifier for predicting post-prostatectomy recurrence in a community based health care setting. j urol, 2016. 195: p. 1748-53. 4. van den broeck, t., et al., validation of the decipher test for predicting distant metastatic recurrence in men with high-risk nonmetastatic prostate cancer 10 years after surgery. eur urol oncol, 2019. 2: p. 589-96. 5. nguyen, p.l., et al., ability of a genomic classifier to predict metastasis and prostate cancer-specific mortality after radiation or surgery based on needle biopsy specimens. eur urol, 2017. 72: p. 845-52. 6. spratt, d.e., et al., individual patient-level meta-analysis of the performance of the decipher genomic classifier in highrisk men after prostatectomy to predict development of metastatic disease. j clin oncol, 2017. 35: p. 1991-8. 7. aghazadeh, m.a., et al., national comprehensive cancer network(r) favorable intermediate risk prostate cancer-is active surveillance appropriate? j urol, 2018. 199: p. 1196-201. 8. herlemann, a., et al., decipher identifies men with otherwise clinically favorableintermediate risk disease who may not be good candidates for active surveillance. prostate cancer prostatic dis, 2019. 9. den, r.b., et al., genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. j clin oncol, 2015. 33: p. 944-51. 10. dalela, d., et al., genomic classifier augments the role of pathological features in identifying optimal candidates for adjuvant radiation therapy in patients with prostate cancer: development and internal validation of a multivariable prognostic model. j clin oncol, 2017. 35: p. 1982-90. 11. lobo, j.m., et al., cost-effectiveness of the decipher genomic classifier to guide individualized decisions for early radiation therapy after prostatectomy for prostate cancer. clin genitourin cancer, 2017. 15: p. e299-e309. letter 350 urological oncology the association of a number of predictive factors for the recurrence of papillary urothelial neoplasm of low malignant potential: prognostic analysis from multiple academic centers ki hong kim1, seung hwan lee2, sun il kim3, byung ha chung4, kyo chul koo4, jin seon cho5, woo jin bang5, jong yeon park6, sung joon hong2* purpose: to identify clinically useful predictors for the recurrence of papillary urothelial neoplasm of low malignant potential (punlmp), we reviewed the clinical information of patients who were diagnosed and treated in multiple tertiary-care academic facilities. materials and methods: between february 2007 and april 2015, 95 patients diagnosed with punlmp after transurethral resection of bladder (turb) were included in this study. age, gender, body mass index, smoking history, the presence or absence of previous history of urothelial neoplasm, the presence or absence of gross hematuria, cytological results at the time of diagnosis, tumor diameter, and multiplicity of tumor were estimated as variables for analysis. cox regression tests were used for identifying predictive factors for recurrence of punlmp. results: sixty-nine cases of punlmp were de novo primary bladder punlmps without known urothelial lesions in the urinary tract, and 26 punlmps were identified on surveillance biopsies of patients with a previous history of urothelial neoplasm. during the follow-up period, recurrences developed in 13 patients (13.7%). recurrence rates were 4.2% and 9.5% at 12 and 24 months, respectively. on univariate and multivariate cox regression analyses, previous history of urothelial neoplasm [95% confidence interval (ci): 0.057-0.604, hazard ratio (hr) = 0.185, p = .005] and multiplicity of tumors [95% ci = 0.064-0.584, hr = 0.193, p = .004] were identified as independent predictors for recurrence-free survival of patients with punlmp. conclusion: tumor multiplicity and previous history of urothelial neoplasm are independent prognostic factors for prediction of recurrence of punlmp. more careful and closer follow-up should be recommended for pulnmp patients with tumor multiplicity or a previous history of urothelial neoplasm. keywords: papillary urothelial neoplasm of low malignant potential; recurrence rate; prognosis; prediction factor introduction the term ‘papillary urothelial neoplasm of low ma-lignant potential’ (punlmp) was introduced at the 1998 world health organization/international society of urological pathology (who/isup) meeting(1) in 2004, who/isup separated the noninvasive papillary neoplasms into four categories: urothelial papilloma, punlmp, low-grade urothelial carcinoma, and highgrade urothelial carcinoma.(2) these four categories replaced the 1973 who classification in which urothelial papilloma was categorized according to carcinoma grades 1 to 3,(1,3) and this system has been widely used in the clinical or pathologic fields.(4-6) histologically, punlmp was defined as a ‘papillary urothelial lesion with an orderly arrangement of cells within papillae with minimal architectural abnormalities and minimal 1department of urology, soonchunhyang university cheonan hospital, soonchunhyang university college of medicine, cheonan, korea. 2department of urology, shinchon severance hospital, yonsei university college of medicine, seoul, korea. 3department of urology, ajou university school of medicine, suwon, korea. 4department of urology, gangnam severance hospital, yonsei university college of medicine, seoul, korea. 5department of urology, hallym university college of medicine, chuncheon, korea. 6department of urology, gangneung asan hospital, university of ulsan college of medicine, gangneung, korea. *correspondence: department of urology, urological science institute, yonsei university college of medicine, 134 shinchon-dong, seodaemun-gu, seoul 120-752, republic of korea. tel: +82-2-2228-2313. fax: +82-2-312-2538. e-mail: sjhong346@yuhs.ac. received april 2018 & accepted january 2019 nuclear atypia irrespective of cell thickness.(1) several studies about punlmp demonstrate that the risk rate of recurrence ranges from 17.9% to 60%, and the histological progression rate is 1.9% to 29.0%.(48) clinical predictors for recurrence of punlmp have been shown to include age, tumor size, and tumor multiplicity.(4,6,7,9) histopathologic predictors include mitoses, chromatin organization state, global acetylation, methylation changes, and subtle architectural disorder. (4,10-14) the histopathologic predictive factors that have been identified to date have the limitation that they cannot be applied easily in the clinical field. additionally, previous studies about clinical predictors of punlmp have the limitation that they were relatively small-scale studies that were performed in single center. these limitations indicate that further efforts for identifying urology journal/vol 16 no. 6/ november-december2019/ pp. 558-562. [doi: 10.22037/uj.v0i0.4519] vol 16 no 06 november-december2019 559 prognostic factors of punlmp are needed. the current study was therefore conducted to investigate clinically useful predictors for the recurrence of punlmp in patients who were diagnosed and treated in multiple tertiary-care academic facilities. patients and methods patients five korean institutions (shinchon severance hospital, yonsei university college of medicine; ajou university school of medicine; gangnam severance hospital, yonsei university college of medicine; hallym university college of medicine; gangneung asan hospital, university of ulsan college of medicine) contributed data to this study. between february 2007 and april 2015, 95 patients who were diagnosed with punlmp after transurethral resection of bladder (turb) were included in this study. the patients were assessed by urine cytology and cystoscopy every 3 months for 2 years after turb, every 6 months for the next 3 years, and yearly thereafter. the patients also had a computed tomography scan yearly. recurrence was defined as the histopathologically proven reappearance of any urothelial neoplasm during the follow-up period, and progression was defined as recurrence to a higher-grade neoplasm. histopathologic diagnosis was classified using the 2004 who/isup criteria.(1,15) the medical ethics committee of severance hospital, yonsei university health care system (seoul, korea) approved this retrospective study. after receiving institutional review board approval, we conducted a retrospective chart review of included patients. clinical data and statistical analysis age, gender, body mass index, smoking history, the presence or absence of previous history of urothelial neoplasm, the presence or absence of gross hematuria, cytological results at the time of diagnosis, tumor diameter, and multiplicity of tumor were estimated as variables for analysis. gross hematuria was defined as the case in which the hematuria was visually confirmed, and tumor multiplicity was defined as the presence of tumors at 2 or more sites in the cystoscopy. the end point of the study was recurrence-free survival (rfs), and rfs defined as the time interval between inital turb and first recurrence. statistical analyses to identify independent predictors for rfs of punlmp were performed using univariate and multivariate cox’s proportional hazard regression analyses. variables that were significant in the univariate analysis (p<0.05) were entered into the multivariate model. all statistical analyses were performed using spss statistics version 20.0.0 (ibm corp., armonk, ny, usa). for all analyses, a two-sided p-value of < 0.05 was considered to indicate statistical significance. results the median follow-up period after being diagnosed with punlmp after turb was 25.3 months, and all included patients had tumors that were classified as noninvasive (ta) punlmp. baseline characteristics of included patients are outlined in table 1. 69 patients had de novo primary bladder punlmps without known urothelial lesions in the urinary tract. 26 punlmps were diagnosed with surveillance biopsies on patients with a previous history of urothelial neoplasm. of 26 patients, 5 and 21 patients were classified as t1 and ta, respectively. all of 26 patients were diagnosed with low-grade urothelial carcinoma. during the follow-up period, recurrences developed in 13 patients (13.7%). recurrence rates were 4.2% and 9.5% at 12 and 24 months, respectively. histologic grade progression developed in seven patients (7.4%), and none of the included patients developed stage progression (> pta). all of patients who progressed in histologic grade were diagnosed as having low-grade urothelial carcinoma. of recurred patients, there were none who progressed to high-grade or either to pt1. five patients died during the follow-up period from dislow malignant potential papillary urothelial neoplasm-kim et al. table 1. patient characteristics. number of patients 95 gender male 74 female 21 age at being diagnosed with punlmp, median (years old, iqr) 63.00 ( 53.00 – 71.00) bmi, median (kg/m2 , iqr) 24.40 (22.30 – 26.10) smoking history presence 45 absence 41 unknown 9 previous history of urothelial neoplasm presence 26 absence 69 gross hematuria presence 56 absence 39 cytologic result inadequate 1 negative 66 atypia, favor benign 10 atypia, favor neoplastic 7 suspicious malignancy 0 malignancy 3 not estimated 8 tumor multifocality presence 17 absence 78 tumor diameter, median (cm, iqr) 0.50 (0.50 – 1.00) abbreviations: punlmp, papillary urothelial neoplasm of low malignant potential; bmi, body mass index; iqr, interquartile range eases other than an urothelial malignancy. univariate and multivariate cox regression analyses were conducted to identify independent predictive factors for rfs of patients with punlmp (table 2). on univariate and multivariate cox regression analyses, previous history of urothelial neoplasm [95% confidence interval (ci) = 0.057-0.604, hr = 0.185, p = .005] and multiplicity of tumors (95% ci = 0.064-0.584, hr = 0.193, p = .004) were identified as independent predictors for rfs of patients with punlmp. the rfs of groups who were categorized by previous history of urothelial neoplasm and multiplicity were calculated using the kaplan-meier method (figure 1). the differences in rfs between groups were statistically significant (p < 0.001) as determined by the log rank test. discussion punlmp has the histopathologic feature which requires clinical follow-up even though it has limited biologic aggressiveness, and it may seem evident that it is generally regarded as malignancy because of the character that the recurrence and the progression might develop in punlmp.(16) however, it has been not categorized as malignancy. reducing the psychological and financial hardship of patients who were diagnosed as cancer is one of the reasons that clinicians and pathologists do not regard punlp as carcinoma.(16) for the reason, clinicians should recommend regular follow-up for patients who have punlmp because of its clinically ambiguous characteristics. traditionally, most clinicians have had difficulty in planning follow-up because the obvious prognosis of punlmp has not yet been identified. several studies for identifying the prognosis and histopathologic predictive factors for recurrence or progression of punlmp have been conducted to improve this situation. montironi et al. reported that chromatin organizational state is a predictive factor for the recurrence of punlmp,(10,11) and mazzucchelli et al. reported that global acetylation and methylation changes predict the recurrence of punlmp.(12) it has also been reported that subtle architectural disorder detected by quantitative analysis in daxx (death domain-associated protein)-immunostained tissue sections in recurrent cases of punlmp may play a role in recurrence of this disorder.(13) pich et al. reported that proliferative activity is the most significant predictor of recurrence in nonintable 2. predictors for recurrence free survival of punlmp variables hr 95%ci p univariate analysis age at being diagnosed with punlmp 0.998 0.940-1.059 0.948 gender relative to male female 0.409 0.069-2.435 0.326 bmi 1.609 1.060-2.442 0.025 smoking history relative to absence presence 0.932 0.037-23.247 0.966 gross hematuria relative to absence presence 0.886 0.225-3.486 0.862 previous history of urothelial neoplasm relative to absence presence 0.050 0.009-0.294 0.001 cytologic result relative to ≤atypia, favor benign ≥atypia, favor neoplastic 1.726 0.224 – 13.293 0.600 multifocality relative to absence presence 0.075 0.016-0.361 0.001 tumor size 1.200 0.440-3.269 0.722 multivariate analysis bmi 1.110 0.903-1.365 0.323 previous history of urothelial neoplasm relative to absence presence 0.185 0.057-0.604 0.005 multifocality relative to absence presence 0.193 0.064-0.584 0.004 abbreviations: punlmp, papillary urothelial neoplasm of low malignant potential; hr, hazard ratio; ci, confidence interval; bmi, body mass index figure 1. a) kaplan-meier curve for recurrence (%) in group with previous history of urothelial neoplasm and group without previous history of urothelial neoplasm. b) kaplan-meier curve for recurrence (%) in group with tumor multiplicity and group without previous history of urothelial neoplasm. low malignant potential papillary urothelial neoplasm-kim et al. urological oncology 560 vol 16 no 06 november-december2019 561 vasive punlmp and grade 1 papillary carcinomas of the bladder.(14) however, this study has the limitation that it combines patients with both noninvasive punlmp and grade 1 papillary carcinoma. although these studies identified histopathologic predictive factors for recurrence of punlmp, the factors are not easily assessed and applied to predictions of recurrence in the most clinical fields. clinical data for identifying the prognosis and the prognostic factor of punlmp have also been reported. fujii et al. studied the long-term outcome of bladder punlmp(8) and reported that the 2-, 5-, and 10-year recurrence free rates were 66%, 51%, and 36%, respectively. maxwell et al. also reported results identified from long-term follow-up periods.(5) although these clinical studies have the strength of long-term follow-up periods, they did not suggest any predictive factor for the recurrence of punlmp. several authors reported that tumor multiplicity, tumor size, and prior recurrence rate are significant prognostic factors for prediction of recurrence in non-muscle-invasive urothelial neoplasm that contain punlmp.(7,9) however, again these studies have the limitation that they did not include cases of punlmp exclusively. it has also been reported that the size of the initial tumor in patients with recurrences was significantly higher compared with those from patients with no recurrence, but this factor was not confirmed in multivariate analysis.(6) recently, zhang et al. identified age, tumor multiplicity, and mitosis as significant prognostic factors for the recurrence of punlmp through multivariate analysis. (4) even though this report has a relatively small scale, it is important because the significant prognostic factors suggested in this study can be easily applied in clinical fields. tumor multiplicity has been known as one of the prognostic factors for rfs of superficial urothelial carcinoma that has developed in bladder.(17) patients with multiple tumors may have had increased risk because the probability of incomplete resection and microscopic tumor dissemination increase with the number of tumor.(18) the current study also indicates that tumor multiplicity is a prognostic predictor for recurrence of punlmp, like the result reported by zhang et al. the fact that these two studies show tumor multiplicity as a predictor of recurrence of punlmp indicates that punlmp should not be clinically regarded as a purely benign neoplasm. the prior recurrence rate has also been known as one of the predictive factors for the recurrence of stage ta t1 bladder cancer.(17) similarly, the current study results indicate that a previous history of urothelial neoplasm is one of the significant prognostic factors in punlmp. this similarity of results suggests punlmp is similar to a malignancy. although the proportion of punlmp cases with a previous history of urothelial neoplasm in most published studies has not been mentioned, punlmp cases with a previous history of urothelial neoplasm are not rare clinically. the study that was reported by lee et al. showed that 29 of 63 patients with punlmp had a previous history of urothelial neoplasm.(6) a strength of the current study, in contrast with previous reported studies, is that the enrolled patients included patients with a previous history of urothelial neoplasm. these results suggest that more careful and closer follow-up should be recommended in patients with pulnmp who have a previous history of urothelial neoplasm. the results of the current study also show that tumor multiplicity and the previous history of urothelial neoplasm, which are prognostic factors of noninvasive urothelial carcinoma, can be applied as prognostic factors for the recurrence of punlmp. the results reported in the current study need to be confirmed and validated by analyzing data from a larger prospective study because they may have been affected by the retrospective nature of the study and the small number of enrolled patients. conclusions in the current study, we found that tumor multiplicity and previous history of urothelial neoplasm are independent prognostic factors for the prediction of recurrence of punlmp. clinicians should recommend careful and close follow-up of punlmp patients who have tumor multiplicity or previous history of urothelial neoplasm. acknowledgement this manuscript was prepared with the assistance of bioscience writers, an englishlanguage, scientific editing company. conflict of interest the authors report no conflict of interest. references 1. epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998;22:1435-1448. 2. jones td, cheng l. papillary urothelial neoplasm of low malignant potential: evolving terminology and concepts. j urol. 2006;175:1995-2003. 3. montironi r, mazzucchelli r, scarpelli m, lopez-beltran a, cheng l. morphological diagnosis of urothelial neoplasms. j clin pathol. 2008;61:3-10. 4. zhang xk, wang yy, chen jw, qin t. bladder papillary urothelial neoplasm of low malignant potential in chinese: a clinical and pathological analysis. int j clin exp pathol. 2015;8:5549-5555. 5. maxwell jp, wang c, wiebe n, yilmaz a, trpkov k. long-term outcome of primary papillary urothelial neoplasm of low malignant potential (punlmp) including punlmp with inverted growth. diagn pathol. 2015;10:3. 6. lee tk, chaux a, karram s, et al. papillary urothelial neoplasm of low malignant potential of the urinary bladder: clinicopathologic and outcome analysis from a single academic center. hum pathol. 2011;42:1799-1803. 7. pan cc, chang yh, chen kk, yu hj, sun low malignant potential papillary urothelial neoplasm-kim et al. ch, ho dm. prognostic significance of the 2004 who/isup classification for prediction of recurrence, progression, and cancerspecific mortality of non-muscle-invasive urothelial tumors of the urinary bladder: a clinicopathologic study of 1,515 cases. am j clin pathol. 2010;133:788-795. 8. fujii y, kawakami s, koga f, nemoto t, kihara k. long-term outcome of bladder papillary urothelial neoplasms of low malignant potential. bju int. 2003;92:559562. 9. chen z, ding w, xu k, et al. the 1973 who classification is more suitable than the 2004 who classification for predicting prognosis in non-muscle-invasive bladder cancer. plos one. 2012;7:e47199. 10. scarpelli m, montironi r, tarquini lm, et al. karyometry detects subvisual differences in chromatin organisation state between nonrecurrent and recurrent papillary urothelial neoplasms of low malignant potential. j clin pathol. 2004;57:1201-1207. 11. montironi r, scarpelli m, lopez-beltran a, et al. chromatin phenotype karyometry can predict recurrence in papillary urothelial neoplasms of low malignant potential. cell oncol. 2007;29:47-58. 12. mazzucchelli r, scarpelli m, lopez-beltran a, et al. global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence: a quantitative analysis. int j immunopathol pharmacol. 2011;24:489-497. 13. castellini p, montironi ma, zizzi a, et al. recurrent papillary urothelial neoplasm of low malignant potential. subtle architectural disorder detected by quantitative analysis in daxx-immunostained tissue sections. hum pathol. 2014;45:745-752. 14. pich a, chiusa l, formiconi a, et al. proliferative activity is the most significant predictor of recurrence in noninvasive papillary urothelial neoplasms of low malignant potential and grade 1 papillary carcinomas of the bladder. cancer. 2002;95:784-790. 15. miyamoto h, miller js, fajardo da, lee tk, netto gj, epstein ji. non-invasive papillary urothelial neoplasms: the 2004 who/isup classification system. pathol int. 2010;60:1-8. 16. maclennan gt, kirkali z, cheng l. histologic grading of noninvasive papillary urothelial neoplasms. eur urol. 2007;51:889897; discussion 897-888. 17. sylvester rj, van der meijden ap, oosterlinck w, et al. predicting recurrence and progression in individual patients with stage ta t1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials. eur urol. 2006;49:466-465; discussion 475-467. 18. thalmann g. organ preservation for t1g3 bladder cancer: is it feasible? eur urol. 2008;53:27-29. low malignant potential papillary urothelial neoplasm-kim et al. urological oncology 562 endourology and stone disease the impact of sheath size in miniaturized percutaneous nephrolithotomy in adult patients; a matched-pair analysis akif erbin1*, burak ucpinar1, alkan cubuk1, ozgur yazici1, harun uysal2, metin savun1, seref basal1, mehmet fatih akbulut1 purpose: the miniaturized percutaneous nephrolithotomy (mpnl) can be performed by using a very wide range of different access sheaths (14-22 fr). it has been well known that tract size is one of the main parameters affecting the complication rates in pnl. we aimed to compare 21 fr with 16.5 fr mpnl tract sizes in adult patients. materials and methods: from may 2013 to april 2018, 604 patients with kidney stone underwent mpnl in our department. the study was designed as retrospective and match-pair analysis was the preferred method for the formation of groups. the 21 fr mpnl cases were matched with 16.5 fr mpnl cases at a 1:1 ratio, according to the patients’ age, gender, body mass index, american society of anesthesiologists (asa) score, stone characteristics (stone size, opacity and localization) and hydronephrosis. patients with solitary kidney, renal anomalies, musculoskeletal abnormalities, and pediatric patients (< 18 years old) were excluded from the study. both groups (21 fr and 16.5 fr) were compared in terms of demographics, stone characteristics, operative data and post-operative outcomes. results: a total of 260 patients were included in the study (130; 21 fr mpnl group and 130; 16.5 fr mpnl group). the operation time was significantly shorter in 21 fr group (21 fr; 85.2 ± 37.5, 16.5 fr; 101.7 ± 37.7 minutes, p = 0.001). complete stone clearance rates were 76.9% and 62.3% in 21 fr and 16.5 fr mpnl, respectively (p = 0.01). there was no significant difference between the groups in terms of overall operative and post-operative complications. however, in subgroups analysis, post-operative fever was higher in 16,5 fr mpnl (4 patients in 16.5 fr, no patients in 21 fr group, p = 0.044); steinstrasse, renal colic and post-operative jj stent requirement rates were higher in 21 fr mpnl procedure (p: 0.018, p: 0.031 and p: 0.046, respectively). the hospitalization time was significantly higher in 21 fr (p = 0.01). conclusion: although 21 fr mpnl procedure has advantages such as better success rates and shorter operation time, some post-operative complications (steinstrasse, renal colic, post-operative jj stent requirement) are against of 21 fr mpnl when compared with 16.5 fr mpnl procedure. further randomized prospective studies with larger patient volume are needed to confirm these results. keywords: kidney stone; miniaturized; nephrolithiasis; percutaneous nephrolithotomy; sheath sizes introduction main treatment modalities for urinary tract stones are extracorporeal shockwave lithotripsy (eswl), ureterorenoscopy (urs), percutaneous nephrolithotomy (pnl) and open or laparoscopic surgery. with technological advancements, endourologic procedures (urs and pnl) have gained more popularity among other surgical treatments. since its first description in 1976, percutaneous nephrolithotomy (pnl) has become the mainstay of treatment for large kidney stones(1). the european association of urology (eau) guidelines on urolithiasis recommends pnl as the first treatment of choice for kidney stones larger than 2 cm(2). in standard pnl, renal access is obtained through 2430 fr access sheaths. attempts to minimize the blood loss during pnl by reducing the sheath size and hence, decreasing the area of parenchymal and infundibular 1department of urology, haseki traning and research hospital, istanbul, turkey. 2department of anesthesiology, bezmialem vakif university, istanbul, turkey. *correspondence: department of urology, haseki traning and research hospital, istanbul, turkey. tel: +90 506 543 1062. fax: +90 212 529 4400. e-mail: akiferbin@hotmail.com. received july 2018 & accepted december 2018 injury, gave rise to the concept of miniaturization. although a clear definition does not exist in the literature, the miniaturized pnl (mpnl) is accepted as the use of 14-22 fr access sheaths by eau urolithiasis guidelines panel(3). the mpnl technique was introduced by jackman et al in 1998(4). recently, systems with even smaller diameters, such as ultra mini-pnl (11–13 fr) and microperc (4.8–10 fr), have been introduced as alternative techniques to reduce procedure-related morbidity(5,6). smaller access sheaths were initially introduced for paediatric use, but are now widely utilised for the adult patients. the mpnl can be performed by using a very wide range of different access sheaths (14-22 fr). the primary goal of pnl is to achieve maximal stone clearance with minimal morbidity. it has been well known that tract size is one of the main parameters affecting the complication rates in pnl. however, reducing the urology journal/vol 16 no. 6/ november-december2019/ pp. 536-540. [doi: 10.22037/uj.v0i0.4676] tract size may adversely affect some procedure-related factors such as operation time(3). there is no clear data on which tract size has more advantages in adult mpnl procedures. the aim of the study was to compare 21 fr with 16.5 fr mpnl tract sizesin adult patients, using 1:1 match pair analysis. material and methods study design the study protocol was approved by the institutional review board at haseki training and research hospital. from may 2013 to april 2018, 604 patients with kidney stone which have underwent mpnl in our department were evaluated for inclusion. the study was designed as retrospective and match-pair analysis was the preferred method for the formation of groups. we used our stone database to identify the procedures which were applied through 21 and 16.5 fr access sheaths. the 21 fr mpnl cases were matched with 16.5 fr mpnl cases at a 1:1 ratio, according to the patients’ age, gender, body mass index (bmi), american society of anesthesiologists (asa) score, stone characteristics (stone size, stone opacity, stone localization) and hydronephrosis (hn) (7,8). patients with solitary kidney, renal anomalies, musculoskeletal abnormalities, and pediatric patients (< 18 years old) were excluded from the study. patients who had missing data during follow up period were also excluded. both groups (21 fr and 16.5 fr) were compared in terms of demographics, stone characteristics, operative data and post-operative outcomes. treatment success was defined as ‘complete stone clearance’ with no residual fragments. operative and post-operative complications were evaluated according to the satava and modified clavien-dindo classification system, respectively(9,10). satava classification system was introduced in order to define the possible operative complications. in the following years, it has been widely used for many endourological procedures. preoperative evaluation before surgery, all patients signed an informed consent form. patient assessment included medical history, physical examination, complete blood count, coagulation tests, serum biochemistry, urinalysis and urine culture. anticoagulant drugs were discontinued at least 7-10 days before the operation. all patients were evaluated preoperatively by intravenous urography and/or non-contrast abdominal computed tomography (ct). stone size was determined by the measurement of the stones’ longest diameter. in case of multiple calculi, the sum of the greatest diameter of each stone was calculated. all patients had sterile urine culture prior to surgery. second generation cephalosporins were administered as antibiotic prophylaxis. the first dose was administered intravenously when anesthesia was initiated, and the second dose was given 12 hours later. pnl technique after the induction of general anesthesia, a 5 fr ureteral catheter was placed to the ureter and fixed on the foley catheter in the lithotomy position. the patient was then repositioned to the prone position. percutaneous access was achieved under c arm fluoroscopy (sire mobil compact, siemens) guidance. the puncture was performed with an 18 gauge percutaneous access needle (boston scientific corporation, natick ma). after achieving access to the pelvicalyceal system (pcs), a 0.035 inch guidewire (boston scientific corporation, natick ma) was advanced through the needle into the pcs or ureter. the track was dilated sequentially using fascial dilators and the 16.5 or 21 fr metallic sheaths (karl storz, tutlingen, germany) were advanced over their metal dilators under fluoroscopic guidance. a rigid 12 fr nephroscope (karl storz, tuttlingen, germany) was advanced through the sheath. stone disintegration was achieved using a holmium yag laser lithotripter (sphinx, lisa laser, usa) and 550 μm laser fibers at an energy of 1.0–1.5 j and a rate of 8–10 hz. stone fragments were removed with tipless nitinol stone baskets(boston scientific, natick, ma, usa).at the end of the procedure, retrograde pyelography was performed to assess the integrity of the pelvicalyceal system. if no sign of perforation was detected under fluoroscopy and if there was no sign of evident bleeding, procedures were terminated in a tubeless fashion and the incision at the access tract site was sutured (tubeless mpnl) with or without placing a jj stent. otherwise, a nephrostomy tube was left in place. all procedures were performed miniaturized percutaneous nephrolithotomy size-erbin et al. table 1. demographic data and stone characteristics of patients included in the study. 21fr mpnl (n:130) 16.5fr mpnl (n:130) p sex (female/male)* 40/90 48/82 .296 age (years) * 46.6 ± 12.9 45.6 ± 12.4 .550 bmi (kg/m2)* 27.1 ± 4.3 27.6 ± 4.5 .379 asa score* 2.0 ± 1.0 1.8 ± 1.1 .712 previous eswl / surgery eswl 33 (25.4%) 26 (20.0%) .302 pnl 31 (23.8%) 27 (20.8%) .553 open surgery 13 (10.0%) 12 (9.2%) .834 stone opacity (opaque / non-opaque)* 120/10 116/14 .393 stone localization * .938 isolated lower calyx 27 27 isolated middle calyx 6 6 isolated upper calyx 7 7 isolated pelvis 30 30 multiple calyx 57 59 partial staghorn 3 1 stone size (mm) * 26.0 ± 8.6 26.3 ± 8.6 .323 hydronephrosis (mild/severe) * 91/39 95/35 .584 operation side (right / left) 71/59 63/67 .323 * 1:1 matching parameters abbreviations: bmi; body mass index asa; american society of anesthesiologists eswl; extracorporeal shockwave lithotripsy vol 16 no 06 november-december2019 537 by two experienced urologistsat the tertiary referral center. post-operative evaluation a complete blood count and renal function test according to the glomerular filtration rate measured by the cockroft-gault formulawere obtained from all patients within 6 hours after the operation. on first post-operative day, a plain x-ray of the kidneys, ureters and bladder was obtained. in cases with a nephrostomy tube, the tube was removed on first or second post-operative day after obtaining an antegrade nephrostography which was performed to prove the lack of obstruction in ipsilateral ureter. if leakage from the nephrostomy tract persists longer than 48 hours, this situation was defined as ‘prolonged urine leakage’ and a jj stent was placed. all patients were evaluated with renal function tests and a non-contrast abdominal ct 1 month after the operation. statistical analysis data were analysed by using statistical package for the social sciences software package version 20 (spss inc., chicago, il, usa). quantitative data were expressed as mean ± standard deviation on tables and categorical data were expressed with frequency (n) and percentages (%). the distribution of the variables was measured by the kolmogorov smirnov test. independent t test was used to compare independent groups. pearson correlation test was used to examine the relationship between variables. pearson chi-square and fisher exact tests were used to compare the categorical data. the data were analysed at 95% confidence level and the threshold forstatistical significance was accepted as p < 0.05 for all analyses. results a total of 260 patients were included in the study (130; 21 fr mpnl group and 130; 16.5 fr mpnl group). patient demographics and stone characteristics were similar between groups and are demonstrated in table 1. table 2 summarizes the operative data. nephrostomy tube and jj stent placement rates were significantly higher in 16.5 fr. there was no significant difference between the groups in terms of intraoperative complications, which were classified according to the satava classification system. overall intraoperative complications occurred in 4 patients (3,1%) in 21 fr and 2 patients (1.6%) in 16.5 fr (p: 0.693). grade 2a complication (pelvicalyceal system perforation proven by contrast media extravasation) observed in 3 patients in 21 fr and 1 patient in 16.5 fr. these patients were treated with prolonged ureteral stenting up to 4 weeks. grade 2b complication (severely bleeding requiring termination of the procedure) observed only 1 patients in 16.5 fr. this patient was treated with blood transfusion and supportive treatment. complications and post-operative outcomes are summarized in table 3. when post-operative complications were compared according to the modified clavien-dindo classification, overall and subgroup complication rates were comparable between groups. grade 4 or grade 5 complications were not observed in any patient. fever was observed in 4 patients in 16.5 fr during post-operative period, whereas, none of the patients in table 2. operative details of patients included in the study. 21 fr mpnl (n:130) 16.5 fr mpnl (n:130) p operation time (min) 85.2 ± 37.5 101.7 ± 37.7 .001 fluoroscopy time (min) 5.0 ± 3.5 3.5 ± 3.1 .001 access .225 solitary lower pole 109 (83.8%) 104 (80.0%) middle pole 11 (8.5%) 7 (5.4%) upper pole 4 (3.1%) 11 (8.5%) multiple access 6 (4.6%) 8 (6.2%) intercostal access 7 (5.4%) 14 (10.8%) .112 nephrostomy placement 89 (68.5%) 114 (87.7%) .001 jj stent placement 21 (16.2%) 44 (33.8%) .001 intraoperative complic ation .693 21 fr mpnl 16.5 fr mpnl p overall complications, n (%) 28 (21.5%) 23 (17.7%) 0.437 complications, n (%) fever (>38 °c) 0 4 (3.1%) .044 renal colic 9 (6.9%) 2 (1.5%) .031 steinstraisse 10 (7.7%) 2 (1.5%) .018 urine leakage 11 (8.5%) 6 (4.6%) .211 post-operative dj placement 19 (14.6%) 9 (6.9%) .046 pleural effusion 1 (0.8%) 2 (1.5%) .563 hemoglobin drop (gr/dl) 1.9 ± 3.4 1.1 ± 3.0 .051 blood transfusion 3 (2.3%) 3 (2.3%) .000 embolization 0 1 (0.8%) .318 modified clavien-dindo classification .238 grade 0 103 (79.2%) 107 (82.3%) .531 grade 1 5 (3.8%) 8 (6.2%) .395 grade 2 3 (2.3%) 2 (1.5%) .653 grade 3a 0 2 (1.5%) .157 grade 3b 19 (14.6%) 11 (8.5%) .120 hospitalization time (hours) 68.1 ± 32.7 51.3 ± 31.6 .001 complete stone clearance, n (%) 100 (76.9%) 81 (62.3%) .010 table 3. comparison of post-operative outcomes of 21 fr mpnl and 16.5 fr mpnl groups. miniaturized percutaneous nephrolithotomy size-erbin et al. endourology and stone diseases 538 vol 16 no 06 november-december2019 539 21 fr experienced fever (p = 0.044). steinstrasse was encountered in 10 (7.7%) patients in 21 fr and 2 (1.5%) patients in 16.5 fr (p = 0.018). renal colic during post-operative period was more common among 21 fr, as well (p:0.031). post-operative jj stent placement was required in 19 patients (14.6%) in 21 fr and 9 patients (6.9%) in 16.5 fr (p = 0.046). both groups were similar in terms of hemoglobin drop, blood transfusion rates and bleeding which requires angioembolization. the hospitalization time was significantly higher in 21 fr (68.1 ± 32.7 vs 51.3 ± 31.6 hours, p = 0.01). complete stone clearance was achieved in 100 patients (76.9%) in 21 fr and 81 patients (62.3%) in 16.5 and the difference was statistically significant (p = 0.01). discussion different types and sizes of instruments are available for pnl procedure and selection between these different instruments are dependent on surgeons’ preference. we compared two different sheath sizes, 21 fr and 16.5 fr, which were both classified under the name of mpnl and found out that21 fr had higher operation success rates with decreased operation duration, whereas, 16.5 fr had shorter fluoroscopy duration. in terms of complications; steinstrasse, renal colic and need for post-operative jj stent placement was more common among 21 fr, whereas, fever was more common among 16.5 fr. the duration of an operation is an important parameter especially in high-risk patients. application of general anesthetic agents for a prolonged duration may have negative impacts on patients’ overall health(11).percutaneous nephrolithotomy procedure is performed under continuous irrigation. so, prolonged operation time may increase the intrapelvic pressure, especially in mpnl, and thereby increase the risk of pelvicalyceal rupture, septic and metabolic complications. many studies have demonstrated the limitation of mpnl procedures as longer operation times when compared with conventional pnl procedure(3). laser lithotripters are the commonly preferred method for stone fragmentation in mpnl cases and laser fragmentation of stones during mpnl is quite time consuming. in addition to laser lithotripters, miniaturized ultrasonic and pneumatic lithotripters, with or without aspiration mechanisms, can also be preferred for stone fragmentation. however, stone fragmentation and aspiration with these instruments during mpnl cases is not as fast as fragmentation with large-bore instruments during conventional pnl cases. additionally, fragmentation of stones into very small pieces (dusting) is required, since bigger fragments can not be expelled out via smaller access sheaths. we emphasized that using a 21 fr sheath instead of a 16.5 fr sheath, allows bigger fragments to be expelled out and thereby, may shorten the operation time by decreasing the duration of laser fragmentation. the fluoroscopy time was longer in 21 fr mpnl. we use serial fascial and metallic dilators for tract dilatation. fluoroscopy is most needed during tract dilatation. traction dilatation occurs at more steps in 21 fr operations and this causes prolonged fluoroscopy time. the majority of urologists utilize fluoroscopy to obtain renal tract access. but radiation exposure is the major drawback both for surgeon and patient. ultrasound guidance access can be preferred to minimize radiation exposure(12). many studies have compared the effectiveness of mpnl and conventional pnl. a meta-analysis including 18 studies (2 randomized controlled trials, 6 non-randomized comparative studies, and 10 case series) have demonstrated the equal effectivity of mpnl and conventional pnl(3). in a recently published randomized prospective study, equal effectivity of mpnl and conventional pnl have been shown for the treatment of large kidney stones(9). even though there are some studies which have compared mpnl with conventional pnl in the literature, there are no studies which have compared different sheath sizes of mpnl in adult patients. in our study, 21 fr was significantly superior to 16.5 fr in terms of complete stone clearance. we have emphasized that, effective retrieval of stone fragments from a larger access sheath was the reason of higher stone free rates. a major advantage of mpnl over conventional pnl is its’ less hemoglobin drop and less transfusion requirement(12). operating through smaller access sheaths decrease the injury on renal parenchyma and thereby, decrease the amount of bleeding during surgery. even though our procedures were classified under mpnl, our sheath sizes were different between groups and bleeding was an important parameter in our study. however, no significant difference was detected between groups, in terms of hemoglobin drop, transfusion requirement and necessity of angioembolization. besides bleeding, additional complications may be encountered during and after pnl surgeries. operative complications can be listed as major bleeding and pelvicalyceal system perforation during surgery. performing the percutaneous access and dilation through an appropriate calyx at an appropriate angle lowers these complications, so, tract size can be considered as a determinant factor for these complications. but, in our study, we have detected no difference between 21 fr and 16.5 fr and concluded that they are both equally safe in terms of operative complications. a wide range of post-operative complications can be encountered after pnl surgery. according to recent eau guidelines, complications like fever can be encountered as frequent as 10.8% of all patients and other complications can be listed as bleeding, pelvi-calyceal perforations, prolonged urinary leakage, thoracic complications, sepsis, organ injury and death(2). in our study, overall post-operative complications were similar between groups. however, there were significant differences when complications were evaluated individually. fever was encountered in 3.1% of patients in 16.5 fr. in contrast, none of the patients in 21 fr group experienced fever. nephrostomy and/or jj stent placement rates were higher in 16.5 fr group due to higher rates of residual calculi detected at the end of each operation.we have emphasized that, higher rates of instrumentation (nephrostomy or jj stent) resulted in higher rates of fever during post-operative period. additionally, decreased drainage of irrigation fluid and increased intrapelvic pressure in 16.5 fr group might have resulted in this significant difference. in our study, we have detected significantly higher rates of steinstrasse, renal colic and necessity of post-operative jj stent placement in 21 fr group. steinstrasse is one of the bothersome complications, which may result in renal colic episodes, prolonged urinary leakage and prolonged hospitalization times. we have emphasized that,higher rates of steinstrasse was due to the creation miniaturized percutaneous nephrolithotomy size-erbin et al. of bigger stone fragments in 21 fr group and migration of these stone fragments into the ureter before effective clearance. if spontaneous passage of these fragments could not achieved, post-operative jj stent placement was inevitable. this was the main reason of increased hospital stay in 21 fr group. contrary to the fact that the present study is a matched pair study, it has some limitations, mainly related to its retrospective nature and non-randomization. the other important limitation of our study was the lack of our usage of flexible ureteroscope during surgery. flexible instruments might haveincreased the final stone free status rates and decrease the need for a second-look procedure. although the total number of patients was sufficient, the number of data was small in effectively comparing some parameters (eg. complications) and this can be listed as another limitation of our study. conclusions the 21 fr mpnl procedure has significantly higher success rates and shorter operation time when compared with 16.5 fr mpnl. although overall operative and post-operative complications were similar between groups, operative nephrostomy and jj stent placement and post-operative fever rates were higher in 16.5 fr, whereas; steinstrasse, renal colic, post-operative jj stent requirement rates and hospitalization time were higher in 21 fr mpnl procedure. although this is the first study which evaluates different sheath sizes of mpnl in adult patients, future prospective randomized studies are required to clarify which sheath size is more advantageous in mpnl. conflict of interest the authors report no conflict of interest. references 1. fernström i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol 1976;10:257-9. 2. türk c, petrík a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol2016;69:468-74. 3. ruhayel y, tepeler a, dabestani s, et al. tract sizes in miniaturized percutaneous nephrolithotomy: a systematic review from the european association of urology urolithiasis guidelines panel. eur urol. 2017;72:220-235. 4. jackman sv, docimo sg, cadeddu ja, et al. the "mini-perc" technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol1998;16:371-4. 5. desai j, solanki r. ultra-mini percutaneous nephrolithotomy (ump): one more armamentarium. bju int2013;112:1046-9. 6. desai mr, sharma r, mishra s, et al. single-step percutaneous nephrolithotomy (microperc): the initial clinical report. j urol2011;186:140-5. 7. karalar m, tuzel e, keles i, okur n, sarici h, ates m. effects of parenchymal thickness and stone density values on percutaneous nephrolithotomyoutcomes, med sci monit. 2016; 22:4363-4368. 8. maghsoudi r, etemadian m, kashi ah, ranjbaran a. associaton of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016;13:2899-2902. 9. satava rm. identification and reduction of surgical error using simulation. minim invasive ther technol 2005;14:257–261. 10. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg 2004;240:205-13. 11. abbas basiri , amir h kashi, mahdi zeinali , mahmoudreza nasiri , reza valipour, reza sarhangnejad. limitations of spinal anesthesia for patient and surgeon during percutaneous nephrolithotomy. urol j. 2018;15:164-167 . 12. guler a, erbin a, ucpinar b, et al. comparison of miniaturized percutaneous nephrolithotomy and standard percutaneous nephrolithotomy for the treatment of large kidney stones: a randomized prospective study. urolithiasis. 2018 [epub ahead of print]. miniaturized percutaneous nephrolithotomy size-erbin et al. endourology and stone diseases 540 277urology journal vol 5 no 4 autumn 2008 case report vanishing shaft of a double-j stent rahul gupta, pranjal modi, jamal rizvi urol j. 2008;5:277-9. www.uj.unrc.ir keywords: indwelling catheters, foreign bodies, stents, iatrogenic disease institute of kidney diseases and research centre, ahmedabad, gujarat, india corresponding author: rahul gupta, md institute of kidney diseases and research centre, ahmedabad, gujarat, india tel: +91 942 760 9778 e-mail: rajaguptadr@rediffmail.com introduction “forgotten” indwelling stents can result in complications such as encrustation, pyelonephritis, recurrent obstruction, and stent migration and breakage.(1,2) we report a case of forgotten stent with encrustation of the proximal and distal ends, spontaneous disappearance of the middle segment, and an associated hourglass pelvic stenosis resulting in hydronephrosis. case report a 56-year-old man presented with the history of frequency, urgency, and dysuria for 2 months. he had undergone right open pyelolithotomy 10 years earlier. on evaluation, serum urea and creatinine values were within normal limits. urinalysis revealed microscopic pyuria and hematuria. urine culture was positive for escherichia coli. ultrasonography of the kidney revealed a normal left kidney, but figure 1. plain abdominal radiography shows coiled double j stent in the kidney and bladder region with encrustation (arrows). figure 2. intravenous urography shows good function of the right kidney. vanishing shaft of a double-j stent—gupta et al 278 urology journal vol 5 no 4 autumn 2008 moderate hydronephrosis with a lower calyceal calculus (1 × 1 cm) in the right kidney. bladder ultrasonography revealed a calculus, as well. plain abdominal radiography revealed coiled ends of a polyurethane double-j stent in the right kidney and bladder region with encrustation; however, the entire shaft of the stent was missing (figure 1). intravenous urography revealed normal left renal unit, but in the right side, delayed excretion of the contrast medium and presence of moderate hydronephrosis was seen. no contrast medium was noted beyond the ureteropelvic junction (figure 2). the patient was treated by antibiotics according to the microbial sensitivity test results. cystolithotripsy and right percutaneous nephrostomy were then performed. antegrade and retrograde imaging study were suggestive of hourglass pelvic stenosis (figure 3). the patient was subjected to right percutaneous nephrolithotomy followed by transperitoneal laparoscopic pyelopyeloplasty (figure 4). his postoperative recovery was uneventful. nephrostography on the 7th postoperative day showed prompt drainage with no evidence of extravasation. intravenous urography at the 6th week revealed prompt drainage of the contrast medium (figure 5). discussion various problems with indwelling stents have been reported, one of the most prevalent of which is “forgotten stents.(1,2)” the rate of encrustation figure 4. left, line diagram demonstrates the hourglassshaped pelvic stricture. middle, excision of the stricture segment. right, final appearance after pyelopyeloplasty using 5-0 vicryl suture. figure 5. follow-up intravenous urography shows good function and drainage of the right kidney. figure 3. bidirectional contrast study reveals pelvic stenosis. vanishing shaft of a double-j stent—gupta et al urology journal vol 5 no 4 autumn 2008 279 is significantly related to the duration of stenting or dwelling time. el-faqih and colleagues noted a 9.6% encrustation rate for stents of less than 6 weeks duration, which increased to 47.5% for those of 6 to 12 weeks and 76.3% for those of more than 12 weeks of duration; therefore, they recommended early removal of the stents.(1) patients with encrusted long-standing stents may require endourological procedures, extracorporeal shock wave lithotripsy, or laparoscopy for the removal of their stents.(3-5) spontaneous and procedure-induced stent fragmentation have been reported.(6,7) kumar and colleagues showed stent fragmentation into multiple pieces over a mean indwelling time of 3.5 months.(8) our patient had a retained stent for 10 years. the distal and proximal coils of the stent were encrusted, probably due to the prolonged period of contact with urine in the bladder and renal pelvic stenosis leading to urine stasis, respectively. we believe that due to encrustation, both ends of the stent were retained in situ and the central shaft was degraded and vanished. in addition, the bidirectional contrast study revealed an hourglass pelvic stricture, which would have resulted from the previous open pyelolithotomy and aggravated by the inflammatory reaction caused by encrusted retained stent fragment. laparoscopic pyeloplasty has been effective for secondary ureteropelvic junction obstruction.(9) instead of conventional pyeloplasty, we opted for pyelopyeloplasty because of good vascularity of both cut ends of the pelvis and good patency of the ureteropelvic junction. in order to prevent leakage of the urine in early postoperative days, antegrade stenting was performed intra-operatively. the stent was removed after 3 weeks. in conclusion, hourglass deformity of the renal pelvis is rare and retention of both ends of the stents and its vanishing shaft is uncommon. combined endourological and laparoscopic approach is a good alternative to manage such cases without morbidity. to our knowledge, this is the first case report of laparoscopic pyelopyeloplasty for hourglass deformity of the renal pelvis. conflict of interest none declared. references 1. el-faqih sr, shamsuddin ab, chakrabarti a, et al. polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. j urol. 1991;146:1487-91. 2. monga m, klein e, castaneda-zuniga wr, thomas r. the forgotten indwelling ureteral stent: a urological dilemma. j urol. 1995;153:1817-9. 3. aravantinos e, gravas s, karatzas ad, tzortzis v, melekos m. forgotten, encrusted ureteral stents: a challenging problem with an endourologic solution. j endourol. 2006;20:1045-9. 4. lam js, gupta m. tips and tricks for the management of retained ureteral stents. j endourol. 2002;16:733-41. 5. bhansali m, patankar s, dobhada s. laparoscopic management of a retained heavily encrusted ureteral stent. int j urol. 2006;13:1141-3. 6. adsan o, guner e, ozturk b, ataman t, cetinkaya m. spontaneous fragmentation of a double j stent. int urol nephrol. 1997;29:307-11. 7. ilker y, turkeri l, dillioglugil o, akdas a. spontaneous fracture of indwelling ureteral stents in patients treated with extracorporeal shock wave lithotripsy: two case reports. int urol nephrol. 1996;28:15-9. 8. kumar m, aron m, agarwal ak, gupta np. stenturia: an unusual manifestation of spontaneous ureteral stent fragmentation. urol int. 1999;62:114-6. 9. levin bm, herrell sd. salvage laparoscopic pyeloplasty in the worst case scenario: after both failed open repair and endoscopic salvage. j endourol. 2006;20:808-12. case report primary epidermoid cyst of the clitoris in adult female population: three case reports and introducing a safe surgical approach. nastaran mahmoudnejad1*, peyman mohammadi torbati2 , alireza zadmehr3 1assistant professor of urology, fellowship of female urology, shahid labbafinejad hospital, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. 2associate professor of pathology, shahid labbafinejad hospital, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. 3resident of urology, shahid labbafinejad hospital, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. *correspondence: assistant professor of urology, fellowship of female urology, shahid labbafinejad hospital, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. 9th boustan st., pasdaran ave.tehran, iran. postal code: 16666 tel/fax: +98-21-22588016. email: nastaran.mahmoudnejad@gmail.com. received june 2020 & accepted october 2020 epidermoid cyst (epc) of the clitoris is a very rare cause of non-hormonal acquired clitoromegaly. clitoral epcs are extremely uncommon without prior history of genital surgery, trauma, circumcision, or piercing. surgical removal with special care to avoid compromising neurovascular bundle of the clitoris is the preferred treatment. to our best knowledge, only three cases of adult female clitoral epc without history of genital surgery, female circumcision, or medications including oral or implantable contraceptives have been reported. herein, we describe three cases of primary epc of the clitoris, their management, unique histopathology report, safe surgical approach, and their follow up course. keywords: clitoromegaly; epidermoid cyst; spontaneous; clitoral cyst; case report; ciliated metaplasia introduction clitoromegaly can be classified into two distinct categories. it can be acquired or congenital. acquired clitoro-megaly may have hormonal or non-hormonal etiologies.(1) epc of the clitoris is an infrequent cause of non-hormonal acquired clitoromegaly. these cysts are formed when the epidermis is traumatically transplanted, or idiopathically present in the dermis or the subcutis. epcs are usually solitary, round, and elevated tumors commonly found on the back, chest, neck, face, or scalp. they often urology journal/vol 18 no. 3/ may-june 2021/ pp. 343-346. [doi: 10.22037/uj.v16i7.6348] figure 1. 1a: supra meatal inverted-u incision. 1b: removal of the cyst with blunt and sharp dissection. stop growing after reaching a size of 1-5 cm in diameter. external genitalia can also be involved with clitoral, labial, or scrotal implantation. the cyst is characterized by an outer wall of epidermis with a center filled with keratinaceous material arranged in laminated layers.(2,3) clitoral epcs are extremely rare without prior anterior surgical excision, infibulation, circumcision, or genital piercing with epidermal clitoral inclusion involved.(4) due to exclusive role of the clitoris in female orgasm and sexual activity, any kind of surgery at this site should be performed with special care. to our best knowledge, only three cases of adult female clitoral epc without history of genital surgery, female circumcision, or medications including oral or implantable contraceptives have been reported. three cases of primary epc of the clitoris, their management, unique histopathology report, safe surgical approach, and their follow up course are described in this article. case report case one: a 45-year-old female presented with a sixmonth history of progressively painless enlarging clitoral mass. she did not have any history of genital surgery or genitourinary symptoms. pelvic examination revealed a mobile, non-tender, soft, well defined clitoral mass measuring approximately 5×2 cm. general physical examination was normal and there was no sign of hyperandrogenism. routine lab tests were within normal limits. the patient was scheduled for surgical exploration and excision of the mass. under a spinal anesthesia, a foley urethral catheter was inserted and a supra-meatal inverted-u incision was made. (figure1a) the cyst was removed with combination of sharp and blunt dissection (figure 1b). special care was given to avoid compromising the neurovascular bundle of the clitoris. hemostasis was achieved and the incision was repaired with interrupted case report 413 primary epidermoid cyst of the clitoris in adult female population-mahmoudnejad et al. figure 2. 2a: stratified keratinizing squamous epithelium, keratin material in lumina and dense fibro-connective tissue of the cyst wall. (×100 h&e staining) 2b: mixture of secretory cells, intercalated cells, and ciliated cells (×400 h&e staining) figure 3. 3a: gross appearance of the clitoral cyst. 3b: excised specimen of the cyst. case report 344 3-0 absorbable sutures. the patient was discharged the same day and the post-operative period was uneventful. the histopathology report revealed a 5 × 1.5 × 0.5 epidermoid cyst. the cystic structure in the majority of areas was lined with stratified keratinizing epithelium (figure 2a), which was supported by chronically inflamed dense fibro-connective tissue. at one focus features of tubal metaplasia including ciliated cells (clear cytoplasm, abundant apical cilia), secretory cells (non-ciliated with eosinophilic apical cytoplasmic protrusions but not mucin vacuoles) and intercalated cells were identified. (figure 2 b) no evidence of nuclear atypia and/or dysplasia was seen. at two-week office visit, the incision was healed completely with excellent cosmetic appearance. at six-month follow up visit, tactile and sexual sensation were preserved and there was no recurrence at the surgical site. case two: a 35-year-old female was consulted for a two-year history of non-tender clitoral mass. she complained about difficulty in voiding and also some degrees of dyspareunia, lately. medical history was unremarkable. she didn’t mention any history of genital trauma, piercing, or surgery. there was no sign of virilization. on local examination, a mobile, fluctuant, and firm cystic lesion was palpated at the clitoral site. (figure 3a). lab investigations were within normal limits. during the operation, the cyst was excised through a supra-meatal inverted-u incision. the ventral wall of the cyst was densely attached to the base of the clitoris. some amount of sebaceous material leaked from the cyst during dissection. the cyst was removed without compromising the neurovascular bundle of the clitoris. (figure 3b) the incisional site was closed with separate 3-0 absorbable sutures and the patient was discharged at the same day. histopathology report of the specimen confirmed a 3 ×1.5 ×1 epidermoid cyst lined with stratified squamous epithelium containing keratinous debris. at one-month post-operative evaluation, genitourinary symptoms of the patient were all disappeared. twoyear follow up of the patient was satisfactory. case three: a 25-year-old virgin female patient presented with gradual swelling of the clitoral region since two years ago. she did not mention any history of genital trauma or hormonal treatment. she complained of urinary frequency and difficult voiding. in physical examination. we detected a 5×2 cm, round and slightly tender clitoral mass with surface ecchymosis. (figure 4) there was no signs of hyperandrogenism. routine blood tests seemed to be normal. microscopic hematuria was found in urine analysis. urine culture did not show urinary tract infection and urine cytology was negative for malignancy. bladder and kidneys ultrasound study was normal. under spinal anesthesia, the patient underwent cystourethroscopy which was normal. at the same session a supra-meatal inverted-u incision was made and the clitoral lesion excised completely. the histopathology report revealed a 5 ×1.5 ×1 epidermoid cyst of the clitoris. urinary symptoms of the patient were disappeared in onemonth post-operative visit. sensory content of the clitoral region was preserved and there was no visible scar tissue at the surgical incision site. in four years follow up course, there was no recurrence at the surgical area. the patient had sexual intercourse and she did not mention any problems. discussion tumors of the clitoris are uncommon. they include a variety of benign, malignant, and rarely metastatic lesions.(5) female external genitalia may have a multitude of cysts. such cysts can be vaginal (hymenal), para-urethral, or clitoral. clitoral cysts are most infrequent of these. they are usually presented as painless, soft, and mobile mass in the absence of any virilization sign.(6) epcs of the clitoris are commonly seen after type i genital mutilation/female circumcision performed in some ethnic communities in africa and west asia.(7) pure adult spontaneous epcs without infibulation, genital cutting, or piercing are extremely rare.(8) three cases of primary epc of the clitoris following contraceptive implants or pills have been reported.(1,8,9) only one case of pregnancy-associated clitoral epidermoid cyst has been described by jing w. hughes et al.(10) to our best knowledge, three cases of primary epc of the clitoris non-related to any medication, genital trauma, or pregnancy in adult females have been reported in the literature.(6,7,11) pre-operative evaluation of the patients in the literature consisted of hormonal and chromosomal analysis, abdominopelvic or trans-vaginal ultrasonography, or even pelvic mri.(1,3,5,7,12) in our opinion, in the absence of hyperandrogenism signs, these types of lesions should be differentiated from clitoromegaly. therefore, a detailed history and performing a complete physical examination before the surgical removal would be the only required course of action. imaging studies will not add further essential information and should be restricted to complicated situations. knowing the anatomy of the vulva and clitoris is critical prior to performing any case report 212case report 428 figure 4. clitoral cyst with surface ecchymosis. primary epidermoid cyst of the clitoris in adult female population-mahmoudnejad et al. vol 18 no 3 may-june 2021 345 kind of surgery. the major goals of surgery involving the clitoris include preservation of sensory function for future sexual health and restoration of normal anatomy. various surgical techniques in management of clitoromegaly have been described, previously.(12) cystectomy with total clitoridectomy was the surgical option as described by some authors.(4) however, this resulted in significant sensory loss. we believe a supra-meatal inverted – u incision is a very safe approach toward the clitoral lesions. the clitoral body is substantial in length, mostly lying superficially under the clitoral hood and mons pubis. the dorsal nerves of the clitoris are large and superficial, terminating at or near the base of the clitoral glans.(13) regarding the superficial location of the terminal branches of the dorsal clitoral nerve, performing the surgical incision over the clitoral skin may harm these structures. almost all reported cases made vertical, elliptical or inverted – v incision over the clitoral skin, clitoral hood, or the cyst itself.(2,7,11,14) in supra-meatal approach, we can safely preserve the neurovascular bundle of the clitoris. there would be no need to trimming the skin, or reconstruction of labia minora or clitoris. excellent cosmetic results, no scar formation, and preserving the tactile and sexual sensation are the advantages of this approach. special care should be given to the urethra. insertion of a urethral catheter and meticulous dissection should be considered. complete surgical removal of the clitoral cysts is the ideal therapeutic approach and definite diagnosis is made by histopathology report. in case one a focal point of tubal metaplasia including ciliated cells was identified on microscopic examination. the origin of cysts lined by ciliated or mucinous epithelium, is debated, and they may be of müllerian, wolffian, or urogenital sinus origin, or may represent metaplasia or heterotopia.(15) this is the first report of primary epc of the clitoris with focal ciliated tubal metaplasia. conclusions even though the primary epc of the clitoris in female adult population is very rare, it should be considered as one of the differential diagnosis of any soft, non-tender and mobile mass of the clitoris. in the absence of hyperandrogenism signs, a detailed medical history and careful physical examination facilitates the diagnosis and prevents unnecessary hormonal or chromosomal analysis. in most cases, imaging studies would not add further helpful information and should be performed only in complicated cases. since the definitive diagnosis is made by histopathology, immediate surgical excision would be a complete diagnostic and therapeutic approach of these lesions. a supra-meatal inverted-u incision will provide a safe access to the clitoral masses without compromising the neurovascular bundle of the clitoris. conflict of interest statement the authors declare that there is no conflict of interest. references 1. fedele l, fontana e, bianchi s, frontino g, berlanda n. an unusual case of clitoromegaly. letters to the editor. eur j obstet gynecol reprod biol. 2008; 140: 287-288. 2. celik n, yalcin s, gucer s, karnak i. clitoral epidermoid cyst secondary to blunt trauma in a 9-year-old child. turk j pediatr. 2011; 53:108. 3. anderson-muellar be, laudenschlager md, hansen ka. epidermoid cyst of clitoris: an unusual case of clitoromegaly in a patient without history of previous female circumcision. j ped adolesc gynecol. 2009; 22: e130. 4. al-ojaimi eh, abdulla mm. giant epidermoid inclusion cyst of the clitoris mimicking clitoromegaly. j low genit tract dis. 2013;17:58-60 5. schmidt a, lang u, kiess w. epidermal cyst of the clitoris: a rare cause of clitorimegaly. eur j obstet gynecol reprod biol. 1999; 87: 163-165. 6. arun nayak, meenal sarmalkar, madhuri mehendale, shrutika shah. spontaneous nontraumatic epidermoid cyst of the clitoris: a rare case report. int j reprod contracept obstet gynecol. 2015 dec; 4:2081-2083. 7. vandana bhuria, vani malhotra, smiti nanda, meenakshi chauhan, bhawana goel. epidermoid cyst of the clitoris: an unusual case. j gynecol surg. volume 30, number 1, 2014. 8. lambert b. epidermoid cyst of the clitoris: a case report. j low genit tract dis 2011; 15:161y2. 9. robin g. marcelli f. agberta n. guerin du masgenet b. goeusse p. contribution of sonography to the diagnosis of non-hormonal acquired clitoromegalia: a case report. ann endocrinol (paris). 2006; 67:613-6. 10. jing w. hughes, marsha k. guess, adam hittelman, sallis yip, john astle, lubna pal, silvio e. inzucchi, antonette t. dulayclitor. epidermoid cyst presenting as pseudoclitoromegaly of pregnancy. ajp rep. 2013; 3: 57–62. 11. linck d, hayes mf. clitoral cyst as a cause of ambiguous genitalia. obstet gynecol. 2002; 99: 963966. 12. johnson lt, lara-torre e, murchison a, garcia em. large epidermal cyst of the clitoris: a novel diagnostic approach to assist in surgical removal. j pediatr adolesc gynecol. 2013 apr; 26: e33-5. 13. joseph a kelling, cameron r erickson, jessica pin, paul g pin. anatomical dissection of the dorsal nerve of the clitoris. aesthet surg j. volume 40, issue 5, may 2020, pages 541–547. 14. cindy wu, lynn damitz, kimberly m. karrat, alice mintz, kalyani avva, denniz zolnoun. clitoral epidermal inclusion cyst resection with intra-operative sensory nerve mapping technique. female pelvic med reconstr surg. 2016; 22: e24–e26. 15. heller, debra. benign tumors and tumor-like lesions of the vulva. clin obstet gynecol. 2015; 58: 526-535. primary epidermoid cyst of the clitoris in adult female population-mahmoudnejad et al. case report 346 review 139urology journal vol 5 no 3 summer 2008 is there a role for helicobacter pylori infection in urological diseases? mohammed s al-marhoon introduction: helicobacter pylori (h pylori) infection is a focus of attention nowadays. it has been found to cause gastrointestinal disorders and also extraintestinal disorders. the aim of this paper is to explore the role of h pylori in urological diseases and to keep urologists up to date in this subject. materials and methods: medline and pubmed were searched from 1950 to december 2007 for the following combined terms: helicobater pylori together with urology, urological diseases, kidney, kidney cancer, ureter, bladder, bladder cancer, prostate, prostate cancer, benign prostatic hyperplasia, urethra, seminal vesicle, testis, and testicular cancer. results: accumulating evidence is appearing in the literature relating h pylori infection to urological diseases. the most obvious is the implication of h pylori in inducing chronic cystitis leading to bladder lymphoma. in addition, some epidemiological studies have shown significant associations between infective chronic prostatitis and prostatic carcinoma. conclusion: a simple hypothetical model relating h pylori infection to prostate and bladder diseases is proposed to stimulate the collaborative work between the urologists and scientists to explore this field which is underinvestigated to date. if h pylori is found to have a significant role in urological diseases, prevention of bladder and prostate cancers by eradication of h pylori infection may become a reality like what happened in the treatment of peptic ulcer disease and gastric cancer. urol j. 2008;5:139-43. www.uj.unrc.ir keywords: helicobacter pylori, prostatic neoplasms, urinary bladder neoplasms, lymphoma, prostatitis department of urology, mansoura university, urology and nephrology center, mansoura, egypt corresponding author: mohammed s al-marhoon, phd, mrcsed, md, bsc department of urology, mansoura university, urology and nephrology center, mansoura, egypt tel: +20 16 670 7732 fax: +20 50 226 3717 e-mail: almarhoon@hotmail.com introduction today, helicobacter pylori (h pylori) infection is a focus of attention. it has been found to cause gastrointestinal disorders and extra-intestinal disorders, too. the gastrointestinal disorders include gastric adenocarcinoma, gastric lymphoma, duodenal ulcer, and chronic atrophic gastritis.(1-4) whereas, the extraintestinal disorders include vascular, respiratory, liver, skin, and kidney diseases.(5-9) the possibility that a bacterium could cause gastritis, peptic ulcer, and cancer was a difficult concept to accept, especially as it would change the whole concept of the pathophysiology of ulcer disease which was based on acid etiology. it is now clear that infection with h pylori is associated with peptic ulcer disease and gastric cancer. helicobacter pylori has been designated a group 1 (definitive) carcinogen by the world health organization.(10) the pathways by which h pylori leads to gastric cancer have been shown by models of gastric carcinogenesis. correa’s multistep model(11) showed that h pylori infection is a triggering helicobacter pylori infection in urological diseases—al-marhoon 140 urology journal vol 5 no 3 summer 2008 factor in the process of increasingly severe gastric lesions progressing from chronic active gastritis to atrophy, intestinal metasplasia, dysplasia, and gastric cancer. earlier, we proposed a model indicating the initial changes induced by h pylori infection that play a role in protecting the organism and enhancing its colonization in the stomach that may lead to gastric cancer.(12) the aim of this paper is to explore the role of h pylori in urological diseases through a review of published articles and to keep the urologists up to date on this subject. new discoveries about the role of bacteria in urological neoplasms and other diseases may change the concepts of treatment in urology like what happened in the treatment of peptic ulcer disease and gastric cancer. materials and methods medline and pubmed were searched from 1950 to december 2007 for the following combined terms: helicobater pylori together with urology, urological diseases, kidney, kidney cancer, ureter, bladder, bladder cancer, prostate, prostate cancer, benign prostatic hyperplasia, urethra, seminal vesicle, testis, and testicular cancer. a total of 124 articles were found, of which 27 that were relevant to our subject were reviewed. there were 6, 16, and 5 articles on h pylori related to the kidneys, bladder, and prostate, respectively. no title was found on the subject in relation to the ureters, seminal vesicles, urethra, or testes. helicobacter pylori helicobacter pylori is a spiral gram-negative rod. it has 2 important strains based on their genetic characteristics: vacuolating toxin gene (vaca) and cytotoxin associated gene (caga). the caga strains are more virulent than vaca strains.(13) helicobacter pylori infection triggers local and systemic inflammatory response. it may cause chronic inflammation and stimulate chronic systemic inflammatory response through the production of various inflammatory metabolites, such as tumor necrosis factor-α (tnf-α), interferon-γ (ifn-γ), interleukin 1β (il-1β), interleukin 6 (il-6), interleukin 8 (il-8), and interleukin 10 (il-10).(14,15) these mechanisms and the latest findings on h pylori infection and its relation with urinary tract and urological diseases are discussed below. prostatitis it has long been known that certain infectious agents that affect specific areas of the body can also have systemic sequelae. a typical example of this is infection with beta-hemolytic streptococcus group a. these bacteria frequently cause acute or chronic tonsillitis, which can also lead to glomerulonephritis. helicobacter pylori might also be a cause of infections distant from the stomach. chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is the most common form of the prostatitis syndromes.(16) the etiology of cp/cpps is unknown in most of the cases, although some of the microorganisms including escherichia coli, mycoplasma genitalium, or chlamidya trachomatis are accused as the etiology of cp/cpps.(17) chronic prostatitis might have been triggered by secondary inflammatory reactions to an unknown antigen. in cp/ cpps, no organism could be exactly found by conventional methods of microbiology. there are many measurable proinflammatory cytokines and chemokines in human semen such as il-1β, il-6, il-8, il-10, ifn-γ, and tnf-α that show high levels in seminal, plasma, and/or expressed prostatic secretion of men with cp/cpps.(18) one could hypothesize that chronic infection with h pylori may be an occult etiological factor in the pathogenesis of cp/cpps by inducing the secretion of il-1β, il-6, il-8, il-10, ifn-γ, and tnf-α. thus, finding a relationship between h pylori infection and chronic prostatitis may help in finding new approaches for the diagnosis and treatment of cp/cpps. it has been demonstrated that the prostate does not harbor normal bacterial flora by the absence of bacterial genomes in histologically normal prostates.(19) the etiology of the chronic prostatitis/pelvic pain syndrome remains controversial, some believing that bacteria are present but do not appear on conventional aerobic cultures. a molecular technique to detect bacteria that do not grow in such cultures is to use polymerase chain reaction assay for bacterial 16s rdna. bacterial dna sequences were helicobacter pylori infection in urological diseases—al-marhoon urology journal vol 5 no 3 summer 2008 141 found to be present in prostate biopsy specimens in 77% of men with chronic prostatitis/pelvic pain syndrome.(20) also, 78% of prostatectomy specimens from men who had prostate cancer or benign prostatic hyperplasia (bph) were positive for bacterial dna.(19) prostate cancer in 1999, a case of the association of prostatic adenocarcinoma with adenocarcinoid of the ileum and gastric mucosa-associated lymphoid tissue (malt) lymphoma with h pylori infection was reported in the literature.(21) carcinoma of the prostate is the most frequently diagnosed malignancy of men in the western countries. (22) it has been hypothesized that prostatic infection and inflammation might be a cause of prostatic carcinoma. epidemiological studies show significant associations between infection and prostatic carcinoma.(23,24) proliferative inflammatory atrophy could be a connection between prostatitis and prostatic carcinoma in a progressive process from proliferative inflammatory atrophy to prostatic intraepithelial neoplasm,(23,25,26) induced by infection and inflammation causing cellular damage by free radicals or genetic alterations.(27,28) the findings associating infection with prostatic carcinoma include detection of bacteria in prostatic specimens and experimental studies in mice.(29-31) bacterial dna sequences of urogenital pathogens and bacterial sequences not reported previously were detected in 19.6% of patients with prostate cancer and 46.4% of those with cpps.(30) on the other hand, in an experimental study on a mouse model of chronic bacterial prostatitis induced by escherichia coli, it was shown that chronic inflammation leads to severe dysplasia and atypical hyperplasia in the prostate.(31) benign prostatic hyperplasia prostatitis and bph are the most common benign diseases of the prostate gland.(32) it is also well recognized by both urologists and pathologists that bph and prostatitis can coexist.(33) the national institute of health’s classification of prostatitis includes the following categories: category i is acute bacterial prostatitis; category ii, symptomatic chronic bacterial prostatitis; category iii, chronic pelvic pain syndrome (chronic nonbacterial prostatitis/prostatodynia); and category iv, asymptomatic prostatitis (bacterial or nonbacterial). the association between prostatic inflammation and bph and the bacterial presence in association with bph has been documented.(35) the clinical significance of asymptomatic category iv chronic prostatitis associated with bph has yet to be determined.(36) interstitial cystitis to date, most of the studies have not supported any role for h pylori in the pathogenesis of interstitial cystitis.(37,38) bladder cancer there are some reports of malt lymphoma arising in the bladder.(39,40) since a history of chronic cystitis is common among patients with malt lymphoma of the bladder,(41) a relation between chronic antigenic stimulation with infectious agents and the occurrence of this malignancy has been postulated. a large body of data have implicated h pylori in the pathogenesis of bladder malt lymphoma, and regression of malt lymphoma by eradication of h pylori has been reported.(42) since the success of eradication by antibiotic therapy is hampered by the occurrence of antibiotic-resistant strains, it has been hypothesized that intravesical vaca-based vaccines against h pylori may protect against the development of bladder malt lymphoma in patients with chronic cystitis, who are at high risk of developing this tumor.(43) on the other hand, in an animal study, researchers transurethrally inoculated h pylori into the mouse urinary tract and observed that the organism established infection and induced inflammation in the urinary bladder and the pelvis.(44) kidney diseases the prevalence of h pylori infection in kidney transplant recipients is quite variable. some authors have found it to be quite low (38%),(45) while others have reported its incidence rate up to 80%.(46) in uremic patients who are known to be infected with h pylori, it has been recommended helicobacter pylori infection in urological diseases—al-marhoon 142 urology journal vol 5 no 3 summer 2008 to eradicate h pylori infection prior to kidney transplantation to avoid a long-term significant increase of gastric and/or duodenal peptic ulcer disease.(47) a primary malt lymphoma of the kidney was reported in a 50-year-old man who was infected with h pylori.(48) conclusion based on the above summary of the literature, a model relating h pylori infection to prostate and bladder diseases can be hypothesized (figure). however this proposed model has many gaps to be proved and investigated. this model has been proposed to stimulate the collaborative work between the urologists and other scientists to explore this field which is underinvestigated and full of knowledge gaps. if h pylori is found to have a significant role in urological diseases, prevention of bladder and prostate cancers by eradication of h pylori infection may become a reality like what happened in the treatment of peptic ulcer disease and gastric cancer. conflict of interest none declared. references 1. forman d, newell dg, fullerton f, et al. association between infection with helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. bmj. 1991;302:1302-5. 2. bayerdorffer e, neubauer a, rudolph b, et al. regression of primary gastric lymphoma of mucosaassociated lymphoid tissue type after cure of helicobacter pylori infection. malt lymphoma study group. lancet. 1995;345:1591-4. 3. tytgat gn. review article: treatments that impact favourably upon the eradication of helicobacter pylori and ulcer recurrence. aliment pharmacol ther. 1994;8:359-68. 4. correa p. the epidemiology and pathogenesis of chronic gastritis: three etiologic entites. front gastrointest res. 1980;6:98-108. 5. patel p, mendall ma, carrington d, et al. association of helicobacter pylori and chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. bmj. 1995;311:711-4. 6. kanbay m, kanbay a, boyacioglu s. helicobacter pylori infection as a possible risk factor for respiratory system disease: a review of the literature. respir med. 2007;101:203-9. 7. pellicano r, mazzaferro v, grigioni wf, et al. helicobacter species sequences in liver samples from patients with and without hepatocellular carcinoma. world j gastroenterol. 2004;10:598-601. 8. rebora a, drago f, picciotto a. helicobacter pylori in patients with rosacea. am j gastroenterol. 1994;89:1603-4. 9. nagashima r, maeda k, yuda f, kudo k, saitoh m, takahashi t. helicobacter pylori antigen in the glomeruli of patients with membranous nephropathy. virchows arch. 1997;431:235-9. 10. [no author listed]. schistosomes, liver flukes and helicobacter pylori. iarc working group on the evaluation of carcinogenic risks to humans. lyon, 7-14 june 1994. iarc monogr eval carcinog risks hum. 1994;61:1-241. 11. correa p. human gastric carcinogenesis: a multistep and multifactorial process--first american cancer society award lecture on cancer epidemiology and prevention. cancer res. 1992;52:6735-40. 12. al-marhoon ms, nunn s, soames rw. the association between caga+ h. pylori infection and distal gastric cancer: a proposed model. dig dis sci. 2004;49:1116-22. 13. atherton jc. the clinical relevance of strain types of helicobacter pylori. gut. 1997;40:701-3. 14. el-omar em. the importance of interleukin 1beta in helicobacter pylori associated disease. gut. 2001;48:743-7. 15. crabtree je. role of cytokines in pathogenesis of helicobacter pylori-induced mucosal damage. dig dis sci. 1998;43:46s-55s. 16. schneider h, wilbrandt k, ludwig m, beutel m, weidner w. prostate-related pain in patients with chronic prostatitis/chronic pelvic pain syndrome. bju int. 2005;95:238-43. 17. khadra a, fletcher p, luzzi g, shattock r, hay p. interleukin-8 levels in seminal plasma in chronic prostatitis/chronic pelvic pain syndrome and nonspecific urethritis. bju int. 2006;97:1043-6. 18. li lj, shen zj, lu yl, fu sz. the value of endotoxin concentrations in expressed prostatic secretions for the diagnosis and classification of chronic prostatitis. hypothetical model for the relation of helicobacter pylori infection to urological diseases. helicobacter pylori infection in urological diseases—al-marhoon urology journal vol 5 no 3 summer 2008 143 bju int. 2001;88:536-9. 19. hochreiter ww, duncan jl, schaeffer aj. evaluation of the bacterial flora of the prostate using a 16s rrna gene based polymerase chain reaction. j urol. 2000;163:127-30. 20. krieger jn, riley de, roberts mc, berger re. prokaryotic dna sequences in patients with chronic idiopathic prostatitis. j clin microbiol. 1996;34:3120-8. 21. mcgregor dh, cherian r, weston ap, lawson l, mcanaw mp. adenocarcinoid of ileum and appendix, incidentally discovered during exploratory laparotomy for gastric malt lymphoma, with subsequent diffuse prostatic metastases: report of a case with light, immunohistochemical, and electron microscopic studies. dig dis sci. 1999;44:87-95. 22. sakr wa, grignon dj, crissman jd, et al. high grade prostatic intraepithelial neoplasia (hgpin) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. in vivo. 1994;8:439-43. 23. dennis lk, lynch cf, torner jc. epidemiologic association between prostatitis and prostate cancer. urology. 2002;60:78-83. 24. roberts ro, bergstralh ej, bass se, lieber mm, jacobsen sj. prostatitis as a risk factor for prostate cancer. epidemiology. 2004;15:93-9. 25. de marzo am, marchi vl, epstein ji, nelson wg. proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. am j pathol. 1999;155:1985-92. 26. shah r, mucci nr, amin a, macoska ja, rubin ma. postatrophic hyperplasia of the prostate gland: neoplastic precursor or innocent bystander? am j pathol. 2001;158:1767-73. 27. bostwick dg, alexander ee, singh r, et al. antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer. cancer. 2000;89:123-34. 28. zheng sl, augustsson-balter k, chang b, et al. sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the cancer prostate in sweden study. cancer res. 2004;64:2918-22. 29. wagenlehner fm, elkahwaji je, algaba f, et al. the role of inflammation and infection in the pathogenesis of prostate carcinoma. bju int. 2007;100:733-7. 30. krieger jn, riley de, vesella rl, miner dc, ross so, lange ph. bacterial dna sequences in prostate tissue from patients with prostate cancer and chronic prostatitis. j urol. 2000;164:1221-8. 31. elkahwaji je, zhong w, hopkins wj, bushman w. chronic bacterial infection and inflammation incite reactive hyperplasia in a mouse model of chronic prostatitis. prostate. 2007;67:14-21. 32. collins mm, stafford rs, o’leary mp, barry mj. how common is prostatitis? a national survey of physician visits. j urol. 1998;159:1224-8. 33. nickel jc. prostatic inflammation in benign prostatic hyperplasia the third component? can j urol. 1994;1:1-4. 34. national institutes of health. summary statement: national institutes of health/national institute of diabetes and digestive and kidney disease workshop on chronic prostatitis. bethesda: national institutes of health; 1995. 35. gorelick ji, senterfit lb, vaughan ed, jr. quantitative bacterial tissue cultures from 209 prostatectomy specimens: findings and implications. j urol. 1988;139:57-60. 36. nickel jc, downey j, young i, boag s. asymptomatic inflammation and/or infection in benign prostatic hyperplasia. bju int. 1999;84:976-81. 37. haq a, mattocks s, wong l, et al. incidence of helicobacter pylori in patients with interstitial cystitis. eur urol. 2001;40:652-4. 38. agarwal m, dixon ra. a study to detect helicobacter pylori in fresh and archival specimens from patients with interstitial cystitis, using amplification methods. bju int. 2003;91:814-6. 39. kempton cl, kurtin pj, inwards dj, wollan p, bostwick dg. malignant lymphoma of the bladder: evidence from 36 cases that low-grade lymphoma of the malt-type is the most common primary bladder lymphoma. am j surg pathol. 1997;21:1324-33. 40. bates aw, norton aj, baithun si. malignant lymphoma of the urinary bladder: a clinicopathological study of 11 cases. j clin pathol. 2000;53:458-61. 41. al-maghrabi j, kamel-reid s, jewett m, gospodarowicz m, wells w, banerjee d. primary low-grade b-cell lymphoma of mucosa-associated lymphoid tissue type arising in the urinary bladder: report of 4 cases with molecular genetic analysis. arch pathol lab med. 2001;125:332-6. 42. van den bosch j, kropman rf, blok p, wijermans pw. disappearance of a mucosa-associated lymphoid tissue (malt) lymphoma of the urinary bladder after treatment for helicobacter pylori. eur j haematol. 2002;68:187-8. 43. pastuszka a, slusarczyk k, koszutski t, kudela g, kawalski h. intravesical vaccination against helicobacter pylori in patients with chronic cystitis may confer protection against malt-type lymphoma of the bladder. med hypotheses. 2007;69:1160-1. 44. isogai h, isogai e, kimura k, fujii n, yokota k, oguma k. helicobacter pylori induces inflammation in mouse urinary bladder and pelvis. microbiol immunol. 1994;38:331-6. 45. yildiz a, besisik f, akkaya v, et al. helicobacter pylori antibodies in hemodialysis patients and renal transplant recipients. clin transplant. 1999;13:13-6. 46. hruby z, myszka-bijak k, gosciniak g, et al. helicobacter pylori in kidney allograft recipients: high prevalence of colonization and low incidence of active inflammatory lesions. nephron. 1997;75:25-9. 47. cocchiara g, romano m, buscemi g, maione c, maniaci s, romano g. advantage of eradication therapy for helicobacter pylori before kidney transplantation in uremic patients. transplant proc. 2007;39:3041-3. 48. colovic m, hadzi-djokic j, cemerikic v, colovic r, jankovic g, dacic m. primary malt lymphoma of the kidney. hematol cell ther. 1999;41:229-32. endourology and stone disease prediction of the energy required for ho:yag laser lithotripsy of urinary stones volkan selmi1*, unal oztekin1, mehmet caniklioglu1, levent isikay1 purpose: in this study, we aimed to find a more accurate predicting constant value of energy per mm3xhounsfield unit (hu) to ablate urinary stones by endoscopic stone treatment. material and methods: the files of 142 patients who underwent rigid or flexible ureteroscopic laser lithotripsy in our clinic between december 2018 and march 2020 were evaluated retrospectively. total energy administered for the ablation of the stone was obtained from the registry of the ho:yag laser and recorded to the follow-up forms. the constant value was calculated for each stone, and the final mean value was figured out by calculation of the mean of all constant values. results: the study was conducted with 142 patients; 102 males and 40 females. the mean age of the population was 46.61 ± 14.58 years. the number of stones was 1.27 ± 0.67. the mean constant value of energy needed per mm3xhu for urinary stones was 22.87 milliwatt. conclusion: this study was conducted to report a predictive constant value and is the very first study evaluating the energy prediction per mm3xhu. the data of the study showed that the constant value is 22.87 mw/mm3xhu. urologists may estimate the required energy and plan the surgery according to the outcomes of the study. as a future aspect of our study, the constant value may represent predictive information about the time and accuracy of the operation. keywords: laser lithotripsy; urolithiasis; energy; ureteroscopy introduction the laser lithotripsy has been used as a treatment option for urinary stone disease for three decades after the development of the holmium: yttrium–aluminium–garnet (ho:yag) laser(1). pulsed lithotripter characteristic of ho:yag laser made it possible to use these devices for removal of urinary stones. early on, pneumatic or ultrasonographic lithotripters were used during ureteroscopy. however, the development of flexible ureteroscopes and more powerful laser fibers allowed surgeons to access and remove the stones regardless of stone size and location in the urinary tract. a new treatment option has been popular because of these technologic developments: flexible ureteroscopy (furs). nowadays, there are emerging studies evaluating thulium-fiber lasers (tfl) as lithotripters for urinary stones(2). although percutaneous nephrolithotomy (pnl) is recommended as the gold standard treatment option for renal stones greater than 20 mm, current studies in the literature report stone-free rates as high as pnl provides(3). besides, furs has lower complication rates, including fewer high-grade complications compared to pnl. so, there is an increasing trend towards furs for urinary stone treatment even for larger stones. however, there are still some controversial points when to opt for furs. in the literature, it has been reported that the complication rate increases when the stone burden or 1yozgat bozok university, faculty of medicine, department of urology, yozgat, turkey. correspondence: volkan selmi, yozgat bozok university, faculty of medicine, urology department, yozgat, turkey. tel: +90 532 748 07 57 fax: +90 354 217 10 72. e-mail: volkanselmi@hotmail.com. received september 2020 & accepted february 2021 density is high or the operation time is extended. several studies stated that the complication rates surged when the hounsfield unit (hu) of the stone increased, which also induced the extended operation time(4-7). it is crucial to decide which surgical procedure would be better for both patient and surgeon, and which one provides better success. thus, choosing the treatment modality should be based on achieving high success rates and low complication rates. to accomplish these, calculating the estimated operation time and the need for energy can provide a foresight if furs procedure is the right option. in the literature, some studies evaluated the required energy for urinary stone removal regarding the size and the density of the stone(8-11). in this study, we aimed to find a more accurate predicting constant value of energy per mm3xhu to ablate urinary stones by ureterorenoscopy. material and methods the files of 142 patients who underwent endoscopic laser lithotripsy in our clinic between december 2018 and march 2020 were evaluated retrospectively, after the approval from the institutional review board (decision number: 2020-kaek-189_2020.05.19_11). age, gender, stone number, stone size, stone burden, stone density and stone localization were obtained from the follow-up forms. also, all the perioperative and postopurology journal/vol 18 no.3/may-june 2021/ pp.284-288. [doi: 10.22037/uj.v18i.6442] vol 18 no 3 may-june 2021 285 erative data like operation time, stone-free status, total energy administered, complications and hospitalization time were investigated. the patients who were between 18 and 85-year-old and did not have urinary anomaly, history of urinary tract infection or urinary surgical intervention within the last six months, dj stent before surgery and stated as stone-free after the first procedure, were included in the study. the patients who had a urinary anomaly, history of urinary tract infection, dj stent or urinary surgical intervention, residual stone fragments greater than 3 mm and furs procedures in which uas was not used were excluded. routine preoperative assessment tests were performed before the operation. patients were evaluated by computerized tomography (ct). the stone size was measured as the longest diameter of the stone on the ct. the sum of all longest dimensions was recorded as the stone size in case of multiple stones. the stone burden was calculated according to the ellipsoid formula (stone volume = π*l*w*d*0.167), where length (l), width (w), and depth (d) are stone diameter measured in three axes (12). the stone density was assessed in hu by ct. the time between starting endoscopy and end of dj stent insertion was defined as operation time. intravenous first-generation cephalosporin was administered 30 minutes before the surgery for the surgical prophylaxis. all procedures were performed under general anesthesia. urs was preferred for stones in the distal, mid or proximal ureter. and furs was the choice for renal stones. firstly, the surgeon accessed the ureter by a 9.5 f ureteroscope (karl storz®, tuttlingen, germany) for a safe dilatation under the guidance of a guidewire. the 7.5 f ureteroscope was used to reach the stone in urs procedure. ureteral access sheath (elite flex®, ankara, turkey) was placed in the ureter in all furs cases. a 7.5 f flexible ureteroscope (flex-x2®, karl storz, tuttlingen, germany) was used for furs. a 200 µm laser fiber (ho yag laser; dornier medtech®; munich, germany / dornier med-tech gmbh, medilas h20 and hsolvo, wessling, germany) was used for laser lithotripsy. the energy of the laser was chosen between 0.8 – 1.5 joule and 8 – 15 hz. at the end of the operation, a ureteral stent was placed in all patients. operation time was defined from the beginning of cystoscopy to the end of ureteral stent placement. stone ablation time was defined as the time between starting fragmentation and total ablation of the stone. intraoperative data were recorded. patients who had no complication were discharged on the first postoperative. total energy administered for the ablation of the stone was obtained from the registry of the ho:yag laser and recorded to the follow-up forms. then, the constant value of energy per mm3xhu was calculated according to the formula the constant value was calculated for each stone, then the mean of all constant values was given as the final mean value. all analyses were done using spss 25.0 statistical software (spss, chicago, usa). to describe data, frequencies and percentages or means ± standard deviations were used. results the study was conducted with 142 patients; 102 males and 40 females. the mean age of the population was 46.61 ± 14.58-year-old. the number of stones was 1.27 ± 0.665. mean stone volume was 553.10 ± 667.34 mm3, and the mean density of the stones was 990.13 ± 302.63 hu. sixty-six patients had renal stones (superior calyx: 3, middle calyx: 9, lower calyx: 20, renal pelvis: 29 and multi-calyceal: 5), 76 had ureteral stones (proximal ureter: 29, mid ureter: 17 and distal ureter: 30). mean operation time and mean stone ablation time was 58.91 ± 31.08 min and 32.08 ± 25.96 min, respectively. the demographic data and the stone characteristics were shown in table 1. fifteen patients encountered surgical and postoperative complications. eleven patients had hematuria which resolved with immobilization and hydration. one patient had fever exceeding 38°c for only 24 hours and resolved with antipyretics. three patients had urinary tract infections. although two of them cured with empiric antibiotics, one of the had urosepsis and died because of sepsis. mean required energy to ablate urinary stones was 11009.76 watts. the mean constant value of energy needed per mm3xhu for urinary stones was 22.87 milliwatt (mw). the perioperative outcomes and the mean constant value were shown in table 2. discussion the success rate of endoscopic urinary stone treatment has been increased from the introduction of flexible ureteroscopes and laser lithotripters. thus, these instruments have been preferred for large stones. in the literature, there are several studies evaluating the success rates for the stones larger than 20 mm and reporting that furs is safe and efficient for these stones(3,13). there is a lack of studies evaluating the needed energy to remove the urinary stones. regarding the impact of the stone size on the operation success, panthier et al. evaluated how much energy required to ablate 1mm3 of stone by laser lithotripsy and categorized the needed energy according to the stone composition. they found that calcium oxalate monohydrate stones need 35.9 ± 20 joules, cystine stones required 101.1± 47 joules and uric acid stones needed 126.2 ± 30 joules(8). however, it is not possible to know the stone composition before table 1. demographic data of patients and stone characteristics variable gender (n=142) (%) male 102 (71.8%) female 40 (28.2%) the mean age (years) (mean ±sd) 46.61 ±14.58 stone number (mean ±sd) 1.27 ±0.665 stone size (mm) (mean ±sd) 12.70 ±6.68 stone volume (mm3) (mean ±sd) 553.10 ±667.34 stone density (hu) (mean ±sd) 990.13 ±302.63 stone localization n(%) upper calyx 3 (2.1%) middle calyx 9 (6.3%) lower calyx 20 (14.1%) renal pelvis 29 (20.4%) proximal ureter 29 (20.4%) mid ureter 17 (12.0%) distal ureter 30 (21.1%) multi-calyceal 5 (3.5%) energy required for laser lithotripsy-selmi et al. the operation, but a prediction can be made according to the density of the stone. in another study, ventimiglia et al. reported that 19 j was required per mm3 for urinary stones(14). it was lower than our results but this variation may depend on the theory which did not consider the density of stone as a co-factor influencing the required energy. although there are various required energy amounts reported in the literature, none of them reckoned the density of stone into calculation of the required energy. so, we conducted this study in another point of view on how much energy is needed to ablate per mm3xhu. the results showed that 22.87 mw of energy is required per mm3xhu to ablate urinary stone. furs and ho:yag laser lithotripsy were mostly studied for renal stones, especially for lower caliceal stones (15). current studies have shown that furs is almost safe and efficient as other procedures. bozkurt et al. evaluated the patients with 15-20 mm lower pole renal stones and reported 89.2% stone-free rate (sfr) after the first session of furs. the sfr was increased to 94.6% with additional procedures(16). in another study, it is reported that the sfr three months after the surgery was 82.1% and comparable to pnl for the stones up to 20 mm(17). on the other hand, in a meta-analysis, it is stated that sfr varies between 73.9% and 93.3% for stones greater than 20 mm(18). in this study, only the patients who were stone-free after the first session were included in the study. recent studies identified the stone size and volume as an independent predictive factor affecting the success of ureteroscopy(19-22). yamashita et al. stated that increasing stone size was the only independent predicting factor for auxiliary procedures(23). in addition, goldberg et al. reported that sfr for furs decreases significantly when the diameter of the stone is greater than 15 mm (24). in another study, staged operation is recommended in order to achieve success if the stone size is ≥ 20 mm (25). the other influence of stone size and volume is on the complication rate of furs. it is reported that larger stones (>30mm) were associated with higher complication rates(26). another factor affecting the success rate is the density of the stone. there are studies evaluating the correlation between the density of the stone and the success. all showed that the sfr increases when hu of the stone decreases(27,28). operative time can predict the operation difficulty and complexity. on the other hand, stone burden and density are correlated with the operation time, which affects the stone-free rate. a retrospective analysis reported that larger stone volume and higher hu increase the operation time; thus, the complication rate soars up(29). also, it is stated as a predicting factor for higher complication rates(30). sorokin et al. reported that stone volume has the most substantial impact on operation time (6). mekayten et al. stated that more time is necessary for dusting the stone those had higher density even for more powerful laser lithotripters(10). in this study, mean stone volume and density were 553.10 ± 667.34 mm3 and 990.13 ± 302.63 hu, respectively. the mean operation time in our study was 58.91 ± 31.08 minutes. the complication rate was 10.6% and similar, as stated in the literature. it is crucial to predict how much energy is needed to remove the complete stone and how long will the operation take before the surgery. as a result of this, the surgeon and the patient can discuss the operation time and estimated complication and success rate even for another treatment option or possible second procedure. this is beneficial when choosing the operation method and also satisfies both sides. multiplying the stone volume and density and division of the constant value of energy will give the estimated energy needed for stone removal. by calculating the estimated energy, the urologist can decide the pulse energy and frequency of the ho;yag laser lithotripter and can calculate the estimated time to dust the stone. although correlation analysis has not been performed, this constant value can be used as a predictive tool and will give the chance to select another treatment option if the operation takes longer. however, this study has limitations. retrospective nature and the small amount population of the study are the major limitations. also, we did not categorise the stones according to the composition. conclusions estimating the need of laser energy and time to dust the whole stone would facilitate the urologists' work, so a constant value stating the requirement of laser energy should be used as a predictive tool for urinary stone treatment. thus, this study was conducted to report a predictive constant value and is the very first study evaluating the energy prediction per mm3xhu. the data of the study showed that the constant value is 22.87 mw/ mm3xhu. urologists may estimate the required energy and plan the surgery according to the outcomes of the study. as a future aspect of this study, the constant value may represent predictive information about the time and accuracy of the operation. further prospective randomised trials with more patient population should be performed to verify the outcomes of this study. references 1. kronenberg p, somani b. advances in lasers for the treatment of stones-a systematic table 2. the perioperative outcomes and the mean constant value standard deviation the mean operation time (minute) 58.91 ±31.08 the mean flouroscopy time (second) 13.51 ±10.58 the mean stone ablation time (minute) 32.08 ±25.96 the mean energy required (watts) 11009.76 ±15713.73 the mean hospitalization time (day) 1.63 ±2.28 complications no 127 (89.4%) fever 1 (0.7%) haematuria 11 (7.7%) urinary tract infection 3 (2.1%) the mean constant value (milliwatt/mm3xhu) 22.87 ±23.75 energy required for laser lithotripsy-selmi et al. endourology and stones diseases 286 vol 18 no 3 may-june 2021 287 review. curr urol rep. 2018;19:45. 2. enikeev d, taratkin m, klimov r, et al. thulium-fiber laser for lithotripsy: first clinical experience in percutaneous nephrolithotomy. world j urol. 2020. 3. barone b, crocetto f, vitale r, et al. retrograde intra renal surgery (rirs) versus percutaneous nephrolithotomy (pcnl) for renal stones >2cm. a systematic review and meta-analysis. minerva urol nefrol. 2020. 4. knipper s, tiburtius c, gross aj, netsch c. is prolonged operation time a predictor for the occurrence of complications in ureteroscopy? urol int. 2015;95:33-7. 5. komeya m, odaka h, asano j, et al. development and internal validation of a nomogram to predict perioperative complications after flexible ureteroscopy for renal stones in overnight ureteral catheterization cases. world j urol. 2019. 6. kuroda s, ito h, sakamaki k, et al. a new prediction model for operative time of flexible ureteroscopy with lithotripsy for the treatment of renal stones. plos one. 2018;13:e0192597. 7. sugihara t, yasunaga h, horiguchi h, et al. a nomogram predicting severe adverse events after ureteroscopic lithotripsy: 12 372 patients in a japanese national series. bju int. 2013;111:459-66. 8. panthier f, ventimiglia e, berthe l, et al. how much energy do we need to ablate 1 mm(3) of stone during ho:yag laser lithotripsy? an in vitro study. world j urol. 2020. 9. patel sr, nakada sy. quantification of preoperative stone burden for ureteroscopy and shock wave lithotripsy: current state and future recommendations. urology. 2011;78:282-5. 10. mekayten m, lorber a, katafigiotis i, et al. will stone density stop being a key factor in endourology? the impact of stone density on laser time using lumenis laser p120w and standard 20 w laser: a comparative study. j endourol. 2019;33:585-9. 11. ofude m, shima t, yotsuyanagi s, ikeda d. stone attenuation values measured by average hounsfield units and stone volume as predictors of total laser energy required during ureteroscopic lithotripsy using holmium:yttrium-aluminum-garnet lasers. urology. 2017;102:48-53. 12. jain r, omar m, chaparala h, et al. how accurate are we in estimating true stone volume? a comparison of water displacement, ellipsoid formula, and a ct-based software tool. j endourol. 2018;32:572-6. 13. al busaidy ss, kurukkal sn, al hooti qm, alsaraf ms, al mamari sa, al saeedi ak. is rirs emerging as the preferred option for the management of 2 cm-4 cm renal stones: our experience. can j urol. 2016;23:8364-7. 14. ventimiglia e, pauchard f, gorgen arh, panthier f, doizi s, traxer o. how do we assess the efficacy of ho:yag low-power laser lithotripsy for the treatment of upper tract urinary stones? introducing the joules/mm(3) and laser activity concepts. world j urol. 2020. 15. cabrera jd, manzo bo, torres je, et al. mini-percutaneous nephrolithotomy versus retrograde intrarenal surgery for the treatment of 10-20 mm lower pole renal stones: a systematic review and meta-analysis. world j urol. 2019. 16. bozkurt of, resorlu b, yildiz y, can ce, unsal a. retrograde intrarenal surgery versus percutaneous nephrolithotomy in the management of lower-pole renal stones with a diameter of 15 to 20 mm. j endourol. 2011;25:1131-5. 17. bai y, wang x, yang y, han p, wang j. percutaneous nephrolithotomy versus retrograde intrarenal surgery for the treatment of kidney stones up to 2 cm in patients with solitary kidney: a single centre experience. bmc urol. 2017;17:9. 18. bader mj, gratzke c, walther s, et al. efficacy of retrograde ureteropyeloscopic holmium laser lithotripsy for intrarenal calculi >2 cm. urol res. 2010;38:397-402. 19. erbin a, tepeler a, buldu i, ozdemir h, tosun m, binbay m. external comparison of recent predictive nomograms for stone-free rate using retrograde flexible ureteroscopy with laser lithotripsy. j endourol. 2016;30:11804. 20. mursi k, elsheemy ms, morsi ha, ali ghaleb ak, abdel-razzak om. semi-rigid ureteroscopy for ureteric and renal pelvic calculi: predictive factors for complications and success. arab j urol. 2013;11:136-41. 21. ito h, kawahara t, terao h, et al. utility and limitation of cumulative stone diameter in predicting urinary stone burden at flexible ureteroscopy with holmium laser lithotripsy: a single-center experience. plos one. 2013;8:e65060. 22. ito h, sakamaki k, kawahara t, et al. development and internal validation of a nomogram for predicting stone-free status after flexible ureteroscopy for renal stones. bju int. 2015;115:446-51. 23. yamashita s, kohjimoto y, iba a, kikkawa k, hara i. stone size is a predictor for residual stone and multiple procedures of endoscopic combined intrarenal surgery. scand j urol. 2017;51:159-64. 24. goldberg h, golomb d, shtabholtz y, et al. the "old" 15 mm renal stone size limit for rirs remains a clinically significant threshold size. world j urol. 2017;35:1947-54. 25. takazawa r, kitayama s, tsujii t. appropriate kidney stone size for ureteroscopic lithotripsy: when to switch to a percutaneous approach. world j nephrol. 2015;4:111-7. 26. bas o, tuygun c, dede o, et al. factors affecting complication rates of retrograde flexible ureterorenoscopy: analysis of 1571 procedures-a single-center experience. world j urol. 2017;35:819-26. 27. joseph p, mandal ak, singh sk, mandal p, energy required for laser lithotripsy-selmi et al. sankhwar sn, sharma sk. computerized tomography attenuation value of renal calculus: can it predict successful fragmentation of the calculus by extracorporeal shock wave lithotripsy? a preliminary study. j urol. 2002;167:1968-71. 28. gupta np, ansari ms, kesarvani p, kapoor a, mukhopadhyay s. role of computed tomography with no contrast medium enhancement in predicting the outcome of extracorporeal shock wave lithotripsy for urinary calculi. bju int. 2005;95:1285-8. 29. ito h, kuroda s, kawahara t, makiyama k, yao m, matsuzaki j. clinical factors prolonging the operative time of flexible ureteroscopy for renal stones: a single-center analysis. urolithiasis. 2015;43:467-75. 30. sorokin i, cardona-grau dk, rehfuss a, et al. stone volume is best predictor of operative time required in retrograde intrarenal surgery for renal calculi: implications for surgical planning and quality improvement. urolithiasis. 2016;44:545-50. energy required for laser lithotripsy-selmi et al. endourology and stones diseases 288 artificial ureter in patients with extensive ureteral damage mohammad yazdani, amir javid*, mehrdad mohammadi sichani, mohammad reza gharaati, emad yazdani purpose: loss of significant lengths of ureter when substitution with bowel or bladder fails is a disaster in urology. this study is conducted to evaluate the results of subcutaneous nephron-vesical bypass (snvb) in ureteral damage of different etiologies. materials and methods: seventeen snvb were employed in patients with ureteral injuries. we employed a device consisted of an internal silicone tube covered by a coiled ptfe tube to replace the ureter. this is called artificial ureter (au). proximal end of the au was introduced in the kidney percutaneously, the tube was passed through a subcutaneous tunnel, while the distal end was inserted in the bladder through a small suprapubic incision. results: follow-up ranged from six months to ten years. we removed the prosthetic ureter in one patient due to gross hematuria two months after insertion. one of the patients was reoperated two days after the procedure because of urinary leakage. in all other patients, the procedure was safe and effective. conclusion: subcutaneous nephron-vesical bypass is a safe and appealing alternative to a nephrostomy tube. this is a permanent device with no need for exchange. the technique can be applied in ureteral injuries due to various causes. keywords: flap; malignancy; trauma; transplantation ureter. isfahan university of medical sciences, isfahan, iran. *correspondence: isfahan university of medical sciences, isfahan, iran. tel & fax & email received september 2016 & accepted april 2017 introduction ureter may be damaged in a variety of contexts, i.e., trauma, cancer, iatrogenic, allograft, radiation, etc. there are several methods to remedy ureteral loss in these cases. for decades, when end-to-end anastomosis has not been technically feasible, replacement of a long segment of the ureter has been a real challenge to urologists. different techniques were suggested to overcome this problem, including boari flap and psoas bladder hitch alone or in combination, downward mobilization of the involved kidney, complete or partial ileal replacement of the ureter, and renal autotransplantation.(1-4) nowadays, minimally invasive techniques are the initial procedures to repair the ureteral loss.(5) sometimes, particularly in metastatic cancers with ureteral involvement and/or after radiation therapy, none of these procedures is feasible.(6) these patients have to bear the burden of permanent nephrostomy tubes and countless exchanges. materials and methods our first case of snvb was in a transplanted kidney ten years ago. the patient had distal ureteral stenosis after transplantation and reconstructive surgery was unsuccessful. the snvb procedure was uneventful in this patient and renal function has been preserved ever since. of the 17 cases who received the au, nine were secondary to cancer and radiation therapy, five had allograft anastomotic stricture, and three cases were postmiscellaneous figure 1. insertion of artificial ureter into the kidney. miscellaneous 3091 artificial ureter outcomesyazdani et al. traumatic. all patients had previously undergone reconstructive ureteral surgery with recurrence of obstruction. at the time of surgery, all patients had suffered from nephrostomy tube for at least 3 months. operative technique a detour double tube system was used for nephron-vesical bypass. it consists of two coaxial tubes: a porous 27 f polytetrafluoroethylene outer tube and an inner 17 f silicone tube. the procedure was performed under general anesthesia. the existing nephrostomy tract was serially dilated with metal dilatators to 30f and was used for placing the proximal end of the au. (figure 1) under general anesthesia and in modified flank position, a 2-cm incision was made in the suprapubic region to access the bladder. a tunneling device was used to create a subcutaneous tract between the nephrostomy site and the suprapubic incision. (figure 2) the proximal end of the silicone tube was placed in a calyx so that the radiopaque ring marker was positioned at the junction of the calyx and the renal parenchyma. the distal end of the au was then brought to the suprapubic incision using the tunneling device and the tunneling device was removed. the length of the au tube was adjusted for each patient, and any excess length was removed, and the outer tube was peeled away for 2 cm at the distal end to expose the inner silicone tube. the bladder was distended via a foley catheter and a small region of bladder dome was exposed. the distal end of the inner silicone tube was fenestrated and introduced into the dome of the bladder through a small incision. the outer ptfe layer was fixed to bladder serosa using absorbable sutures. results the first case of au was performed in a transplanted kidney about ten years ago and it is still functioning. one au had to be removed due to refractory hematuria. so, snvb was effective in preserving renal function in 16 of our 17 patients. urinary leakageusually from bladder anastomosis was one of the complications that usually responded well to conservative management with anticholinergics, antibiotics and prolonged bladder drainage with a foley catheter. we exchanged the device in one patient because of refractory urinary leakage. hematuria following this procedure was mostly microscopic and exertional. most patients experienced mild frequency and urgency that responded to anticholinergics. the youngest patient was a seven-year-old girl and the oldest was a 79-year-old man. we used this procedure in three patients with iatrogenic ureteral trauma: ureteral avulsion (figure 3), ureteral injury following total colectomy and the third case was following laparotomy for trauma. after three to five years of follow up, all three patients are well satisfied with the au, with only one patient complaining of gross hematuria after heavy exercise. we had five cases of prostatic adenocarcinoma which developed ureteral stenosis after radiation therapy (figure 4), two cases of invasive rectal carcinoma with colostomy and two cases of adenocarcinoma of the cervix. three of these patients died of metastatic cancer 2 to 5 years after the procedure. our patient population also included five patients with allograft ureteral stricture, and in all these cases we were able to save the transplanted kidney after applying this procedure. au is a foreign body and incrustation and stone formation is the main long term disadvantage. although we encountered 4 cases of stone formation, all of the stones were in the bladder and they were managed with transurethral lithotripsy. discussion au is basically a simple alloplastic tube connected to the urinary tract by end-to-end sutures or by intubafigure 3. a case of ureteral avulsion. vol 14 no 03 may-june 2017 3092 figure 2. subcutaneous bypass of the artificial ureter. tion and closure. au may be considered for a selected population of patients with ureteral injuries after failure of primary repair or when open surgery is likely to be hazardous because of general conditions. it should be emphasized that this procedure is not recommended as an initial attempt after ureteral injury but only when open surgery for repairing the ureter fails and there is no other way to save the ureter. antireflux devices and peristaltic mechanisms are not necessary.(7-9) in the 1960s and early 1970s, the first attempts were undertaken to bypass the obstructed ureteral segments with silicone prostheses. problems with extravasation, obstruction at the anastomotic sites and incrustation were gradually overcome by changes in material, design, and surgical techniques. subcutaneous ureteral replacement with au, including a coaxial assembly of an inner silicone and outer expanded polytetrafluoroethylene tube, has produced good results.(10-12) in our experience, this technique was effective and safe in ureteral injuries that ensued from different etiologies. our results demonstrate that this technique should be considered in ureteral obstruction caused by advanced prostatic adenocarcinoma, particularly when it occurs after pelvic radiation therapy. additionally, in patients with radical cystectomy and enterocystoplasty, placement of au can be attempted as a last resort. a normal bladder function is obviously an essential prerequisite. in the future, we are likely to see bioengineered neo-tissue combined with highly porous and infection-resistant alloplasts to create better and more functional neo-organs. tissue engineering and acellular matrix grafts have produced impressive early results.(7) conclusions artificial ureteral replacement by subcutaneous nephron-vesical bypass offers a reasonable alternative to open ureteral reconstruction. this procedure has been used in ureteral obstruction caused by malignancies and radiation therapy, allograft ureteral stricture, and ureteral trauma. references 1. ahn m, loughlin kr. psoas hitch ureteral reimplantation in adults: analysis of a modified technique and timing of repair. urology 2001; 58:184–7. 2. benson mc, ring ks, olsson ca. ureteral reconstruction and bypass: experience with ileal interposition, the boari flap-psoas hitch and renal autotransplantation. j urol 1990; 143:20–3. 3. castillo oa, sanchez-salas r, vitagliano g, et al. laparoscopy-assisted ureter interposition by ileum. j endourol 2008; 22:687–92. 4. eisenberg ml, lee kl, zumrutbas ae, et al. long-term outcomes and late complications of laparoscopic nephrectomy with renal autotransplantation. j urol 2008; 179:240–3. 5. seideman ca, huckabay c, smith kd, et al. laparoscopic ureteral reimplantation: technique and outcomes. j urol 2009; 181:1742–6. 6. zaman f, chowdhury a, masood j, nargund v. re: management of ureteral obstruction due to advanced malignancy: optimizing therapeutic and palliative outcomes: e. kouba, e. m. wallen and r. s. pruthi j urol 2008; 180: 444-450. j urol. 2009 mar;181(3):15056. 7. desgrandchamps f1, griffith dp. the prosthetic ureter. j endourol. 2000 feb;14(1):63-77. 8. wang y1, wang g1, hou p, et al. subcutaneous nephrovesical bypass: treatment for ureteral obstruction in advanced metastatic disease. oncol lett. 2015 jan;9(1):387-390. 9. desgrandchamps f1, duboust a, teillac p, idatte jm, le duc a. total ureteral replacement by subcutaneous pyelovesical bypass in ureteral necrosis after renal transplantation. transpl int. 1998; 11 suppl 1:s150-1. 10. hennebert pn. [prostheses implanted in the urinary tract]. acta urol belg. 1977 apr;45(2):115-259. 11. nissenkorn i1, gdor y. nephrovesical subcutaneous stent: an alternative to permanent nephrostomy. j urol. 2000 feb;163(2):52830. 12. yazdani m, gharaati mr, zargham m. subcutaneous nephrovesical bypass in kidney transplanted patients. int j organ transplant med. 2010;1(3):121-4. artificial ureter outcomesyazdani et al. figure 4. nephrostography in a patient after radiation therapy: ureteral obstruction is clear. miscellaneous 3093 appendixes 310 urology journal vol 6 no 4 autumn 2009 acknowledgement reviewers in volume 6 the editorial team of the urology journal would like to acknowledge a depth of gratitude to colleagues who have done us the great favor of peer reviewing of the submitted manuscripts over the past year: abdi hr, iran ahmadnia h, iran aliasgari m, iran amin sharifi ar, iran ardestani me, iran argani h, iran arshadi h, iran asgari sa, iran asle-zare m, iran ather mh, pakistan barghi mr, iran carrier s, canada castillo oa, chile castillo oa, chili cohanzad sh, iran dadkhah f, iran danesh ak, iran djaladat h, iran etemadian m, iran falahatkar s, iran ghanaati m, iran gholamrezaei hr, iran hosseini mm, iran hosseini sy, iran inan k, turkey irani d, iran karami h, iran kashi ah, iran kaviani a, iran kazemeini sm, iran kazemi b, iran keshvari m, iran khayamfar f, iran khoshdel ar, iran lashei ar, iran lu hs, china madaen sk, iran madinei ma, iran maghsoudi r, iran mahboobi ah, iran malek hosseini r, iran mehrsaei ar, iran miladipour h, iran mohamadi cichani m, iran mohseni gh, iran mousavi bahar sh, iran naseri s, iran nikoobakht mr, iran nouralizade a, iran parvin m, iran pourmand g, iran razavi ss, iran razi a, iran sadeghi-nejad mr, usa salehipour m, iran seyedzadeh a, iran shadpour p, iran shakeri s, iran shamsa a, iran soleimani m, iran tadayon f, iran tavakoli tabasi k, iran torbati p, iran tugcu v, turkey yamamoto s, japan yari p, iran zand s, iran zare s, iran ziaee sam, iran zolfagari a, iran endourology and stone disease initial prospective study of ambulatory mini-percutaneous nephrolithotomy on upper urinary tract calculi ye tian, xiushu yang*, guangheng luo*, yandong wang, zhaolin sun purpose: to explore the feasibility and safety of ambulatory mpcnl (mini percutaneous nephrolithotomy) on upper urinary tract calculi. methods: clinical data of 18 patients who received ambulatory mpcnl during auguest 2017 to january 2018 and 23 patients who were treated with routine inpatient mpcnl of the corresponding period were collected. all the patients included received 16fr channel pcnl under the guidance of doppler ultrasound. a 6fr double j stent was placed in the ureter for internal drainage, and either an indwelling 14fr open nephrostomy tube was placed or the puncture channel was filled with absorbable hemostatic materials alone, depending on the bleeding condition of the puncture channel and the intraoperative conditions. preoperative parameters and surgery time, complications, total hospitalization costs and hospital stay time between the two groups were compared. results: preoperative parameters regarding age (p = 0.057), sex distribution (p = 0.380), asa score (p = 0.388), calculi ct value (p = 0.697), and the s.t.o.n.e. score (p=0.122) were comparable between the two groups. maximum diameter of calculi (cm) of the conventional hospitalization group, however, was larger than the ambulatory surgery group (p = 0.041). there were no significant differences in the mean surgery time (p = 0.146), postoperative hemoglobin drop (p = 0.865), calculi-free rate on the next day after surgery (p = 0.083) and postoperative fever rate (p=0.200) between the two groups. with regard to tubeless rate (p < 0.001), total hospitalization costs (p = 0.003) and hospital stay time (p < 0.001), there were significant advantage favoring ambulatory mpcnl. conclusion: for patients with simple upper urinary tract calculi and relatively good performance status, ambulatory mpcnl is feasible as it’s equally safe and efficient as compared with routine inpatient mpcnl. moreover, ambulatory mpcnl decreases hospitalization costs and hospital stay time. nevertheless, perioperative management should be carefully conducted, and well-designed studies are warranted. keywords: ambulatory surgery; mpcnl; renal calculi; safety introduction urinary calculi are commonly encountered in the field of urology. the incidence of calculi in inpatients with urological diseases is more than 50% in high prevalence areas(1). calculi in the kidney and proximal ureter are typically treated via percutaneous nephrolithotomy (pcnl). compared with conventional open surgery, pcnl causes less trauma, has superior reproducibility, less influence on renal function, and an equivalent or even better calculi extraction rate. furthermore, the occurrence of perioperative complications associated with pcnl has been greatly reduced by the recent development of mpcnl, and the technique has been rapidly promoted(2,3). while patients undergoing pcnl traditionally require planned inpatient admission, there is a growing evidence to support its potential feasibility as an ambulatory approach(4). however, these studies are extensively criticized for design flaws, such as the retrospective study design or a single arm report. to our knowledge, there were no reports of ambulatory mpcnl safety or efficiency with a control study. this department of urology, guizhou provincial people’s hospital, guiyang, guizhou, p.r.china. *correspondence: department of urology, guizhou provincial people’s hospital, guiyang, guizhou, p.r.china tel: +86-173-8501-5539. fax: +86-851-8562 1836. e-mail: 584500474@qq.com received september 2018 & accepted january 2019 is a prospective study of the clinical data from 18 patients who underwent mpcnl in our hospital, with the aim of evaluating the safety and feasibility of mpcnl as ambulatory surgery, as well as providing a reference for the further development of ambulatory mpcnl. materials and methods clinical data from august 2017 to january 2018, 18 patients diagnosed with calculi in the kidney or proximal ureter underwent mpcnl as ambulatory surgery (same-day procedures, ambulatory surgery group), while 23 were conventionally hospitalized for mpcnl (conventional hospitalization group). this study was approved by the local medical ethics committees of guizhou provincial people’s hospital (no. 2017040). the clinical features of both groups are summarized in table 1. preoperative assessments all included patients were diagnosed with urinary calculi, and underwent mpcnl. patients in the ambulatory surgery group agreed to undergo mpcnl as ambulatourology journal/vol 17 no. 1/ january-february 2020/ pp. 14-18. [doi: 10.22037/uj.v0i0.4828] vol 17 no 01 january-february 2020 03 ry surgery, and underwent the following preoperative examinations in the outpatient clinic: routine blood and urine examinations, coagulation function tests, liver and kidney function tests, electrolyte levels, fasting blood glucose levels, electrocardiography, chest and abdominal radiography, and urinary ct scan. after preoperative examination, an anesthesia risk assessment was completed for each patient in the anesthesia clinic. the conventional hospitalization group underwent similar routine preoperative checks. exclusion and inclusion criteria exclusion criteria were: insufficiencies of the heart, lung, liver or other vital organs; hypertension; uncontrolled diabetes mellitus (those with satisfactory blood pressure and blood glucose control were included); systemic bleeding disorders or other surgical contraindications; pregnancy; severe anatomical deformity; severe obesity; intolerance of the prone position; severe mental illness; uncontrolled urinary tract infection; or other conditions that rendered the patient unsuitable for pcnl. the advantages and disadvantages of ambulatory surgery were thoroughly explained to the patients (and their guardians) who were candidates for mpcnl preoperatively. for patients suitable for (asa score ≤ 2 and s.t.o.n.e. score ≤ 7) and willing to accept ambulatory mpcnl were include in the ambulatory surgery group. postoperatively, the ambulatory surgery group were monitored by specifically designated nurses who understood the major complications that could potentially occur; it was also ensured that the patients were able to reach the hospital within 30 minutes from their residences. patients with poorer physical condition, complex calculi or unwilling to accept ambulatory mpcnl were include in the conventional hospitalization group. surgical methods after induction of general anesthesia, each patient was placed in the lithotomy position. a cystoscope or ureteroscope was used to place a 5fr ureteral catheter into the ipsilateral ureter, and to place an indwelling 16fr foley catheter. after moving the patient to the prone position, the target renal pelvis was punctured under the guidance of doppler ultrasound. a zebra guidewire was used to guide a fascial dilator, which was expanded gradually from 8fr to 16fr, and then pushed into the sheath. a 12fr nephroscope was then introduced for examination. after identifying the target calculi, a holmium laser was used to crush the calculi and the fragments were flushed out of the body. after satisfactory calculi removal, a 6fr double j stent was placed in the ureter for internal drainage. the nephroscope and outer sheath were removed under the guidance of the safety guidewire. in accordance with the bleeding condition of the puncture channel and the intraoperative conditions, either an indwelling 14fr open nephrostomy tube was placed or the puncture channel was filled with absorbable hemostatic materials alone. discharge standards patients were discharged when the following criteria were satisfied: stable vital signs; no obvious postoperative infection and/or bleeding; no discomfort after eating semi-liquid food; no or mild abnormalities in routine blood examination, hepatic and renal function tests, and electrolyte levels; good positioning of the double j stent on plain abdominal radiography; and the presence of family members to accompany the patient. follow-up all patients had at least one telephone follow-up per day for 2 weeks after discharge. the follow-up included questions regarding general patient condition, surgical area symptoms and wound condition, presence of fever, amount and color of urine, and other special situations. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. patients (and their guardians) met the ambulatory mpcnl criteria would discuss the advantages and disadvantages of ambulatory surgery preoperatively, and informed consents were obtained. no formal consents were required with the patients in the conventional hospitalization group. statistical analysis the spss 21.0 statistical software package was used for statistical analysis. measurement data accord with normal distribution were expressed as the mean ± standard deviation. the t-test for two independent samples was used for intergroup numerical data comparisons, while the intergroup count data were analyzed using the χ2 test. the significance level of the hypothesis test was set at α = 0.05. results the mean surgery time in the ambulatory surgery group tended to be slightly shorter than that in the conventional hospitalization group, but this difference was not significant (p = 0.146, table 2). there was no significant difference between the two groups in the postoperative hemoglobin decrease (p = 0.865), calculi-free rate (p table 1. clinical features of the ambulatory surgery group and the conventional hospitalization group parameters ambulatory surgery group (n=18) conventional hospitalization group (n=23) p value age (y) 42.9 ± 9.6 52.3±11.5 0.057 sex [male/female] 14/4 15/8 0.380 asa score 1.44 ± 0.12 1.61±0.14 0.388 maximum diameter of calculi (cm) 1.92 ± 0.72 2.74±0.94 0.041 calculi ct value (hu) 1093 ± 290 1147±326 0.697 s.t.o.n.e. score 6.44±0.17 6.95±0.26 0.122 ambulatory surgery group: patients who underwent percutaneous nephrolithotomy for urinary calculi as ambulatory surgery; conventional hospitalization group: patients who underwent percutaneous nephrolithotomy for urinary calculi as hospital inpatients. ambulatory mpcnl on upper urinary tract calculi-tian et al. vol 17 no 01 january-february 2020 15 = 0.083), or incidence of fever on postoperative day 1 (p = 0.200, table 2). compared with the conventional hospitalization group, the ambulatory surgery group had a significantly greater incidence of tubeless rate (p < 0.001), shorter hospital stay (p < 0.001), and significantly lesser total hospitalization cost (p = 0.003, table 2). no complications of clavien grade ⅲ and above were encountered in both groups. one patient in the ambulatory surgery group required an indwelling nephrostomy tube due to the detection of mild bleeding during intraoperative examination of the puncture channel; the drainage fluid was red-tinged at 4 hours postoperatively, and the patient was discharged with the tube in place. at the third day postoperatively, the patient returned to the hospital for removal of the nephrostomy tube, and there was no bleeding or extravasation of urine. two patients in the conventional hospitalization group had postoperative fever, which may have been related to their older age, larger of calculi, and slightly longer surgery time; these patients were discharged after effective anti-infection and symptomatic treatment. discussion ambulatory surgery originated in the western world and has since been widely promoted worldwide. as a new medical service model, ambulatory surgery has standardized the management of certain conditions that have relatively little variation in patients without severe comorbid diseases, which maximizes efficiency, shortens hospital stay, and improves medical expenses and hospital service levels. pcnl is an important treatment method for upper urinary tract calculi, but is considered a high-risk surgery due to potential perioperative complications such as bleeding, infection, and damage to adjacent organs(5). however, the emergence of mpcnl has greatly reduced the perioperative hemorrhage risks(6,7), and created conditions conducive to percutaneous nephroscopic ambulatory surgery. the performance of mpcnl as ambulatory surgery requires stricter control and management methods compared with other established ambulatory surgery procedures. the patients in the ambulatory surgery group in the present study were included in accordance with detailed inclusion/exclusion criteria, discharge standards, and strict follow-up monitoring to ensure maximal perioperative safety. the results of the present preliminary study showed that there were no significant difference regarding the safety and efficiency parameters between the two groups, and the ambulatory surgery group had a significantly reduced hospital stay and total hospital costs compared with the conventional hospitalization group. the key issue that restricts the performance of pcnl as ambulatory surgery is the monitoring and treatment of postoperative complications. generally, patients in our hospital received pcnl were required to stay for about 3 days postoperatively for observation of complications. the most common and potentially fatal complications of pcnl include postoperative infection and bleeding(2). postoperative infection manifest as fever, chills, and increased white blood cell count, severe cases may present with septic shock-related manifestations such as decreased blood pressure, decreased urine output, disturbance of consciousness, and circulatory failure. if timely treatment is not administered, the patient’s life may be endangered. risk factors for severe infection include preoperative urinary tract infection, females (especially postmenopausal females), diabetes mellitus and anemia, large numbers of calculi, long surgery time, high irrigation pressure, poor renal function, and an immunosuppressed status(8). hence, preoperative screening is critical for patients requiring pcnl. clinicians should be very cautious when selecting ambulatory surgery for patients with severe infection. we consider that patients with more than two of the abovementioned risk factors for infection should not undergo pcnl as ambulatory surgery. education and follow-up for patients and their families are also very important, so that they understand the potential risks of severe postoperative infections. if severe complications occur, patients must promptly return to hospital for treatment. according to our experience and that reported in the literature, the vast majority of serious post-pcnl infections occur intraoperatively and within 8 hours postoperatively(9,10). therefore, we believe that nearly 24 hours of observation after the surgery is sufficient for most patients, if not all. in our series, two patients in the conventional hospitalization group had postoperative fever, which were discharged after effective anti-infection and symptomatic treatment. no serious infections were encountered. bleeding after pcnl is another serious potential complication. severe bleeding can manifest as fresh hematuria outflow in the catheter or nephrostomy tube; in table 2. operative details of patients included in the study. parameters ambulatory surgery group conventional hospitalization group p value surgery time (min) 74.4 ± 35.7 96.2 ± 31.4 0.146 hemoglobin drop (g/l) 15.3 ± 6.9 14.8 ± 8.0 0.865 tubeless rate 17/18 4/23 < 0.001 immediate calculi-free rate after surgery (%) 94.4 (17/18) 73.9 (17/23) 0.083 hospital stay (h) mean 18.3 ± 3.6(14-23) 132.7 ± 31.9(98-253) < 0.001 median 17.5 154.0 25 percentile 15.5 127.8 75 percentile 21.5 214.3 total hospitalization cost (us dollar) 2114 ± 275 3097±854 0.003 major complications blood transfusion 0 0 fever 0 2 (clavien grade ⅱ) 0.200 ambulatory mpcnl on upper urinary tract calculi-tian et al. endourology and stones diseases 16 ambulatory surgery group: patients who underwent percutaneous nephrolithotomy for urinary calculi as ambulatory surgery; conventional hospitalization group: patients who underwent percutaneous nephrolithotomy for urinary calculi as hospital inpatients. vol 17 no 01 january-february 2020 17 severe cases, a large number of blood clots can be seen in the drainage bag. routine blood examination often reveals a progressive decrease in hemoglobin concentration, which can lead to hemodynamic instability and hemorrhagic shock. the two peak times at which postoperative bleeding usually occurs are within 24 hours postoperatively and within a few weeks postoperatively(5,11). for patients at relatively high risk of bleeding, the selection of ambulatory surgery should be made cautiously, and detailed education should be given to day surgery patients and their families. in addition, it is essential to maintain smooth and effective communication between the patient and the hospital staffs so that patients can quickly return to the hospital for treatment if serious bleeding occurs. the main purposes of the indwelling nephrostomy tube include urinary drainage, compression of the puncture channel to reduce bleeding, and secondary treatment of renal lesions. nevertheless, insertion of the nephrostomy tube tends to be thought of a practice of the surgeon rather than a real need. tubeless pcnl can reduce hospital stay, postoperative pain, use of analgesics, urinary leakage and hospitalization costs. many studies have confirmed the safety of tubeless pcnl for relatively simple calculi(12-14). compared with the standard channel pcnl, the use of mpcnl in the present study greatly reduced the incidence of postoperative hemorrhage. most patients of our study in the ambulatory surgery group had relatively simple calculi, and the intraoperative treatment was satisfactory. postoperatively, puncture channel bleeding was checked using conventional direct vision under the guidance of the safety guidewire. hemostasis was achieved by tamping the surgicel fibrillar™ absorbable hemostat (ethicon inc., johnson and johnson, sommerville, nj, usa) with a working sheath, except in cases with obvious substantial bleeding. compared with the control group, the use of tubeless pcnl in the ambulatory surgery group did not increase complications such as postoperative bleeding, which further confirmed the safety and feasibility of tubeless mpcnl. most of the ambulatory pcnl studies in the literature were retrospectively design and with a standard percutaneous renal access(4,15). we believe several aspects of our study could be helpful for further ambulatory pcnl study. to our knowledge, this is the first prospective report of pcnl as ambulatory surgery, which minimized the systematic errors. secondly, we introduced microchannel pcnl for ambulatory surgery for the first time, which we believe caused less trauma and bleeding risks. furthermore, we used absorbable hemostat for puncture channel tamping to reduce bleed and postoperative urinary leakage, which could be used for reference in the clinical practice. compared with the conventional hospitalization group, the patients included in the ambulatory surgery group were younger, had fewer comorbidities and lower asa score, simpler and smaller calculi, shorter operative time, better postoperative recovery, and no serious complications such as severe bleeding or infection that required readmission of further intervention. the present results confirm that performing mpcnl as ambulatory surgery can effectively reduce hospital stay and hospitalization costs without increasing perioperative risks in appropriate patients, and indicates that up to 24 hours of postoperative observation can rule out most complications, making mpcnl ambulatory surgery safe and feasible for selected patients. however, this present study is observational with inherent limitations and confounders. and the maximum diameter of calculi was lower in ambulatory surgery group, as the sample size is relatively small and it is difficult to control the confounding. effect the results should be carefully interpreted as the lack of randomization and the small sample size. further efforts including miniaturization of the sheath size(16), anaesthesia(17) and improvements on postoperative analgesia(18) could be made to ease ambulatory pcnl recovery. conclusions ambulatory mpcnl is generally safe and feasible. considering the potentially fatal complications, this approach should only reserve for highly selected patients in centers with sufficient case volume. well-designed studies are needed to confirm the safety and economic and social benefits of mpcnl as ambulatory surgery. conflict of interest the authors declare no conflict of interest. acknowledgments this study was funded by health and family planning commission of guizhou province foundation (no. gzwjkj2017-1-032) and doctoral foundation of guizhou provincial people’s hospital (no. gzsybs[2016]11). we thank kelly zammit, bvsc, from liwen bianji, edanz group china (www.liwenbianji.cn/ac), for editing the english text of a draft of this manuscript. references 1. yang y, deng y, wang y. major geogenic factors controlling geographical clustering of urolithiasis in china. sci total environ. 2016; 571: 1164-71. 2. wei c, y zhang, g pokhrel, et al. research progress of percutaneous nephrolithotomy. int urol nephrol. 2018; 50: 807-17. 3. mousavi-bahar sh, amirhasani s, mohseni m, daneshdoost r. safety and efficacy of percutaneous nephrolithotomy in patients with severe skeletal deformities. urol j. 2017; 14: 3054-8. 4. jones p, g bennett, a dosis, et al. safety and efficacy of day-case percutaneous nephrolithotomy: a systematic review from european society of uro-technology. eur urol focus. 2018. https://doi.org/10.1016/j. euf.2018.04.002. 5. wollin da, gm preminger. percutaneous nephrolithotomy: complications and how to deal with them. urolithiasis. 2018; 46: 87-97. 6. lei h, wang d, luo j, qiu j. use of an exvivo porcine kidney model to compare the blood loss of different size of nephrostomy tracts. chinese j exp surg. 2011; 28: 2090-1. 7. hennessey db, nk kinnear, a troy, d angus, dm bolton, dr webb. mini pcnl for renal calculi: does size matter? bju int. 2017; 119: 39-46. ambulatory mpcnl on upper urinary tract calculi-tian et al. 8. kreydin ei, bh eisner. risk factors for sepsis after percutaneous renal stone surgery. nat rev urol. 2013; 10: 598-605. 9. ran g, luo j, hu m, zhao z. analysis on curative effect of 37 patients with septic shock after percutaneous nephrolithotomy. j clin res. 2014; 31: 139-41. 10. xiao c, li z, ding x, xiao j, kang f, fu l. septic shock following percutaneous nephrolithotomy: a 6 cases report. jiangxi med j. 2013; 48: 1216-8. 11. li x, wang p, liu y. clinical analysis of 11 cases undergoing selective renal artery embolization for severe post-percutaneous nephrolithotomy hemorrhage. j clin urology (china).2014; 29: 903-5. 12. tirtayasa pmw, p yuri, p birowo, n rasyid. safety of tubeless or totally tubeless drainage and nephrostomy tube as a drainage following percutaneous nephrolithotomy: a comprehensive review. asian j surg. 2017; 40:419-23. 13. yang x, wang q, hu h, et al. tubeless versus standard percutaneous nephrolithotomy: an update meta-analysis. bmc urol. 2017; 17:102-18. 14. aghamir s, salavati a, hamidi m, fallahnejad a. primary report of totally tubeless percutaneous nephrolithotomy despite pelvicalyceal perforations. urol j. 2017; 14: 40203. 15. bechis sk, ds han, je abbott, et al. outpatient percutaneous nephrolithotomy: the uc san diego health experience. j endourol. 2018; 32: 394-401. 16. lahme s. miniaturisation of pcnl. urolithiasis. 2018; 46: 99-106. 17. basiri a, kashi ah, zeinali m, nasiri mr, valipour r, sarhangnejad r. limitations of spinal anesthesia for patient and surgeon during percutaneous nephrolithotomy. urol j. 2018; 15: 164-7. 18. dundar g, gokcen k, gokce g, gultekin ey. the effect of local anesthetic agent infiltration around nephrostomy tract on postoperative pain control after percutaneous nephrolithotomy: a single-centre, randomised, double-blind, placebocontrolled clinical trial. urol j. 2018; 15: 306-12. endourology and stones diseases 18 ambulatory mpcnl on upper urinary tract calculi-tian et al. urological oncology does the new proposal for prostate cancer grading correlate with capra score? levent isikay1 , senol tonyali1*, gulden aydog2 purpose: to determine if there is a correlation between the newly proposed gleason grading system by the international society of urological pathology and the cancer of the prostate risk assessment (capra) score. material and methods: the records of all patients that underwent radical prostatectomy at our hospital between 2007 and 2013 were retrospectively reviewed. the study parameters included patient demographics, the percentage of pre-operative prostate biopsies positive for pca, biopsy gleason score (gs), and preand post-operative psa values. result: the study included 146 patients with complete medical records and follow-up data. mean age of the patients was 66.6 ± 6.08 years. according to the newly proposed gleason grading system, 97 (66.4%) patients were grade 1, 20 (13.7%) were grade 2, 8 (5.5%) were grade 3, 11 (7.5%) were grade 4, and 10 (6.8%) were grade 5. the distribution of capra scores was as follows: 1: n = 43 (29.5%); 2: n = 53 (36.3%); 3: n = 22 (15.1%); 4: n = 14 (9.6%); 5: n = 8 (5.5%); 6: n = 4 (2.7%); 7: n = 1 (0.7%); 8: n = 1 (0.7%). correlation analysis showed that the capra score was significantly correlated with gs based on the newly proposed gleason grading system (correlation coefficient=0.361, p < 0.001). conclusion: as a strong correlation was noted between these 2 independent grading systems, we think clinicians that seek to predict the prognosis in pca patients should take into consideration both the newly proposed isup grading system and the capra score. keywords: biochemical recurrence; capra; gleason pattern; pathologic examination; prostatectomy introduction prostate cancer (pca) is the most common solid neoplasm in europe, with an incidence of 214 cases per 1000 men(1). nowadays, patient counseling and patient-oriented treatment form the core of pca treatment, because each treatment modality can have serious effects on patient quality of life;(2) as such, stratification and grading of pca continue to increase in importance. the treatment of pca is based on clinical stage and risk status, and treatment options for localized pca include active surveillance, radical prostatectomy (rp), radiation therapy, brachytherapy, cryosurgical ablation, and high-intensity focused ultrasound (hifu)(1). the gleason grading system is the most common system used to grade prostate cancer aggressiveness. the system uses a scale of 1 to 5 to calculate the gleason score (gs) (range: 2-10), which is the sum of the most common and second most common grade patterns. the most commonly reported gss in clinical practice is ≥ 6. many patients and clinicians consider a gs of 6 indicative of an intermediate prognosis and seek immediate treatment;(3,4) however, there is a lack of consensus concerning the cancerous pattern of pca with a gs of 6(5). due to deficiencies, the international society of urological pathology (isup) has updated the gleason grading system from time to time; the latest update was 1clinic of urology, turkiye yuksek ihtisas training and research hospital, ankara. turkey. 2clinic of pathology, turkiye yuksek ihtisas training and research hospital, ankara. turkey. *correspondence: turkiye yuksek ihtisas training and research hospital clinic of urology, 06230 altindag ankara, turkey tel: +90 312 3061829. e-mail: dr.senoltonyali@gmail.com. received may 2018& accepted july 2018 in 2014. the newly proposed system stratifies patients into 5 distinct prognostic groups, which enables more accurate and simplified classification of tumors. moreover, the lowest grade in the newly proposed system is 1 not 6, as in the gleason system, which might result in reducing the incidence of overtreatment of indolent cancer(3). there are several preand post-treatment assessment tools used to predict prognosis after definitive treatment of pca, including the kattan nomogram, d’amico classification, and the cancer of the prostate risk assessment (capra) score(6-8). the capra score is a pre-treatment score based on patient age, preoperative prostate-specific antigen (psa), prostate biopsy gs, clinical stage, and the percentage of positive cores in a prostate biopsy specimen. although the capra score is an externally validated and easy to use tool; biopsy gs, clinical stage, and the percentage of positive biopsy cores are approximations by nature and, therefore, might overor underestimate the actual grade or extension of disease(8). as such, the present study aimed to determine the correlation between the newly proposed gleason grading system and the capra score. a possible correlation might help clinician in patient risk stratification and treatment planning. urological oncology 355 vol 15 no 06 november-december 2018 356 materials and methods after the approval of the study protocol by turkiye yuksek ihtisas training and research hospital review board, the records of all patients that underwent radical prostatectomy at our hospital between 2007 and 2013 were retrospectively reviewed. patients who had a biopsy confirmed localized pca were treated with radical prostatectomy. patients that received neoadjuvant treatment for pca were excluded from the study. the study parameters included patient demographics, the percentage of pre-operative prostate biopsies positive for pca, biopsy gs, and preand post-operative psa values. the capra score was calculated using the university of california, san francisco (ucsf), webbased calculator(9) by s.t.. needle biopsies and radical prostatectomy materials were examined by the same pathologist (g.a.). samples that could not be diagnosed via hematoxylin & eosin staining were studied using p63, hmwk, and amacr immunohistochemistry. mean ± sd was used to describe quantitative variables. quantitative measurements were compared using non-parametric spearman’s correlation analysis. data were analyzed using ibm spss statistics for windows v.21.0 (ibm corp., armonk, ny). the level of statistical significance was set at p < .05. results the study included 146 patients with complete medical records and follow-up data. mean age of the patients was 66.6 ± 6.08 years. the mean pre-operative psa value was 9.3 ± 9.6 mg dl˗1 and the mean number of pca-positive prostate biopsy cores was 3.1 ± 1.3 (range: 1-6). the distribution of prostate biopsy gss was as follows: gs 6: n = 115 (78.7%); gs 7: n = 18 (12.3%); gs 8: n = 13 (8.9%). an upstaging of gs was observed via final pathologic examination of some rp specimens, as shown in table 1. according to the newly proposed gleason grading system, 97 (66.4%) patients were grade 1, 20 (13.7%) were grade 2, 8 (5.5%) were grade 3, 11 (7.5%) were grade 4, and 10 (6.8%) were grade 5. the distribution of capra scores was as follows: 1: n = 43 (29.5%); 2: n = 53 (36.3%); 3: n = 22 (15.1%); 4: n = 14 (9.6%); 5: n = 8 (5.5%); 6: n = 4 (2.7%); 7: n = 1 (0.7%); 8: n = 1 (0.7%). according to capra risk categorization 96 patients (65.7%) had low risk, 44 patients (30.1%) had intermediate risk and 6 patients (4.4%) had high-risk disease. among the 146 patients, 25 (17.1%) patients developed biochemical recurrence; 18 within 2 years and 7 within 5 years of treatment. correlation analysis showed that the capra score was significantly correlated with gs based on the newly proposed gleason grading system (correlation coefficient=0.361, p < .001). on univariate regression analysis both capra score and newly proposed gleason grading system were found significantly predict biochemical recurrence after radical prostatectomy (p < .01 for both correlations) (table 3). discussion pca is the most common solid malignancy diagnosed in men in europe and the united states,(1,10) and is the second leading cause of death in the united states(10). most patients with pca die due to other causes; however, pca does cause mortality in some cases. due to the ambiguous behavior of the disease and the potential side effects of its treatment, risk stratification of pca patients has become an important facet of its management(11). the gleason grading system was developed in the 1960’s to categorize adenocarcinoma of the prostate according to 5 patterns, ranging from well differentiated (1) to poorly differentiated (5)(12). the gs is the sum of the most common (primary) and the second most common (secondary) grade patterns, ranging from 2 to 10; table 1. upstaging between prostate biopsy and final pathology results table 2. the newly proposed grading system groups for prostate cancer by isup gleason score prostate biopsy gs rp specimen gs gleason 6 (3+3) 115 (78.8 %) 97 (66.4 %) gleason 7 (3+4) 14 (9.6 %) 20 (13.6%) gleason 7 (4+3) 4 (2.7 %) 8 (5.4%) gleason 8 (3+5) 12 (8.2 %) 8 (5.4%) gleason 8 (4+4) 1 (0.7 %) 2 (1.3%) gleason 8 (5+3) 1 (0.6%) gleason 9 (4+5) 6 (4.1%) gleason 9 (5+4) 4 (2.7%) prognostic grade group definition grade group 1 gleason score ≤ 6 grade group 2 gleason score 3+4=7 grade group 3 gleason score 4+3=7 grade group 4 gleason score 8 (4+4, 3+5, 5+3) grade group 5 gleason score 9–10 (4+5,5+4,5+5) biochemical recurrence, n (%) p value international society of urological pathology (isup) grade group < 0,01 1 9/97 (9,3) 2 6/20 (30) 3 2/8 (25) 4 1/11 (9,1) 5 7/10 (70) cancer of the prostate risk assessment (capra) score < 0,01 1 2/43 (4,7) 2 6/53 (11,3) 3 7/22 (31,8) 4 4/14 (28,6) 5 3/8 (37,5) 6 1/4 (25) 7 1/1 (100) 8 1/1 (100) table 3. association between different grading systems and frequency of biochemical recurrence (br). new proposal for prostate cancer grading-isikay et al. however, nowadays the most commonly reported gs in clinical practice is ≥ 6. despite being the most popular grading system, the gleason grading system is not perfect(4). a rational patient could consider a gs of 6 (on a scale of 10) to indicate an intermediate prognosis or to indicate that immediate treatment is required, whereas, in fact, gs 3 + 3 = 6 is a good score indicating that treatment with active surveillance is sufficient. in addition, although both are gs 7, gs 3 + 4 = 7 has a better prognosis than gs 4 + 3 = 7(4). due to gleason grading system deficiencies, the need for a better grading system emerged and in 2014 isup proposed a new grading system, as shown in table 2(3). during the past 20 years several research groups have proposed various nomograms and statistical models for predicting recurrence-free survival following definitive treatment and for determining pre-treatment pathologic stage of pca; the most well-known being the kattan nomogram and d’amico classification,(6,13) and the capra score(14). cooperberg et al.(14) developed the capra score for preoperative prediction of biochemical recurrence-free survival after rp in patients with clinically localized pca, as appropriate preoperative risk assessment is an integral component of counseling such patients(15). the capra score is the sum of the weighted risk factors, including age and psa value at diagnosis, biopsy gs, clinical tumor stage, and the percentage of biopsy cores positive for pca(16). the external validation of the capra score was studied by multiple researchers,(17, 18) and was reported to accurately predict recurrence-free survival and stratify patients according to their risk. in the past, pca patients were stratified according to gs as low risk (gs < 7), intermediate risk (gs = 7), and high risk (gs = 8-10); however, now it is well known that all gs 7 and gs 8-10 pca cannot be grouped in the same categories and treated in that manner. in the present study the capra score was significantly correlated with the newly proposed isup grading system. based on this finding, we think that both the newly proposed isup grading system and the capra score can be considered reliable instruments for predicting the prognosis in pca patients. none of the patients in the present study had a gs of 9 or 10, which might have been due the widespread use of psa screening in turkey, which facilitates early detection of pca. also patients with high gs in prostate biopsy might have chosen or been directed to alternative treatment modalities. our study is also not without limitations. first of all, this is a retrospective study with a relatively small number of patients. and as mentioned above there are not many patients with high grade/high risk pca. conclusions the literature includes multiple studies on the validity of the capra score for predicting pca recurrence; however, to the best of our knowledge the present study is the first to determine the correlation between the newly proposed gleason grading system and the capra score. as a strong correlation was noted between these 2 independent grading systems, we think clinicians that seek to predict the prognosis in pca patients should take into consideration both the newly proposed isup grading system and the capra score. conflict of interest no potential conflict of interest relevant to this article was reported. references 1. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. eur urol. 2014;65:124-37. 2. johnson me, zaorsky ng, martin jm, et al. patient reported outcomes among treatment modalities for prostate cancer. can j urol. 2016;23:8535-45. 3. epstein ji, egevad l, amin mb, et al. the 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. am j surg pathol. 2016;40:244-52. 4. khochikar m. newly proposed prognostic grade group system for prostate cancer: genesis, utility and its implications in clinical practice. curr urol rep. 2016;17:80. 5. knuchel r. gleason score 6 prostate cancer or benign variant? oncol res treat. 2015;38:629-32. 6. kattan mw, eastham ja, stapleton am, wheeler tm, scardino pt. a preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. j natl cancer inst. 1998;90:766-71. 7. d'amico av, moul j, carroll pr, sun l, lubeck d, chen mh. cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. j clin oncol. 2003;21:2163-72. 8. cooperberg mr, hilton jf, carroll pr. the capra-s score: a straightforward tool for improved prediction of outcomes after radical prostatectomy. cancer. 2011;117:5039-46. 9. prostate cancer risk assessment and the ucsf-capra score [available from: https://urology.ucsf.edu/research/cancer/ prostate-cancer-risk-assessment-and-the-ucsfcapra-score. 10. cooperberg mr. implications of the new aua guidelines on prostate cancer detection in the u.s. curr urol rep. 2014;15:420. 11. cooperberg mr. prostate cancer risk assessment: choosing the sharpest tool in the shed. cancer. 2008;113:3062-6. 12. gleason df. histologic grading of prostate cancer: a perspective. hum pathol. 1992;23:273-9. 13. d'amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for new proposal for prostate cancer grading-isikay et al. urological oncology 357 vol 15 no 06 november-december 2018 358 clinically localized prostate cancer. jama. 1998;280:969-74. 14. cooperberg mr, pasta dj, elkin ep, et al. the university of california, san francisco cancer of the prostate risk assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. j urol. 2005;173:1938-42. 15. cooperberg mr, vickers aj, broering jm, carroll pr. comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. cancer. 2010;116:5226-34. 16. cooperberg mr, broering jm, carroll pr. risk assessment for prostate cancer metastasis and mortality at the time of diagnosis. j natl cancer inst. 2009;101:878-87. 17. may m, knoll n, siegsmund m, et al. validity of the capra score to predict biochemical recurrence-free survival after radical prostatectomy. results from a european multicenter survey of 1,296 patients. j urol. 2007;178:1957-62; discussion 62. 18. cooperberg mr, freedland sj, pasta dj, et al. multiinstitutional validation of the ucsf cancer of the prostate risk assessment for prediction of recurrence after radical prostatectomy. cancer. 2006;107:2384-91. new proposal for prostate cancer grading-isikay et al. urology in history 228 urology journal vol 6 no 3 summer 2009 avicenna’s canon of medicine and modern urology part iv: normal voiding, dysuria, and oliguria seyed mohammad ali madineh avicenna, the iranian scientist, describes the mechanisms of normal voiding in his famous book, the canon of medicine. then, he enumerates urinary symptoms. in this article, his discussion on dysuria, its causes, and its pathophysiology is compared with these concepts in modern urology. avicenna points to some etiologic theories of interstitial cystitis and chronic prostatitis. in the canon, we can distinguish bases of the theory of infection and mucosal theory, along with abnormalities of urine, psychological factors, and abnormalities in prostatic secretions. avicenna also indicates some differential diagnoses of and associated disorders with interstitial cystitis. his short but rather concise discussion on oliguria and its causes is an interesting point for urologists and nephrologists. urol j. 2009;6:228-33. www.uj.unrc.ir urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: seyed mohammad ali madineh, md mostafa khomeini hospital, italia st, tehran, iran tel: +98 21 6643 8140 fax: +98 21 6690 7895 e-mail: madinehurologist@yahoo.com introduction in the previous three parts of these articles, i reviewed chapters of the canon of medicine, written by avicenna—the iranian scientist in the 10th century—on the bladder and its diseases with modern urological findings.(1-3) in this part of this article series, i continue with the 2nd treatise of book iii, part 19, which is on urine, voiding, and urinary symptoms. materials and methods this study is the comparison of modern urology with the urological chapters of avicenna’s canon of medicine. i used the canon in its original language (arabic),(4) along with its persian translation.(5) the 2nd treatise of part 19 of book iii covers normal voiding and its mechanisms, as well as urinary symptoms. i compared the text with the current urological findings. selected topics from the canon are presented and a brief discussion follows each subject. i translated the original arabic version into persian and compared it with the available persian translation in order to present an accurate text. i skipped avicenna’s discussions on traditional and herbal medicine as these subjects were not comparable with the modern therapeutic methods, and thus, they were beyond the aim of this study. i was only engaged with the items that the current modern medicine obviously and clearly proceeds with them. discussion book iii, part 19, treatise 2 part 19 of book iii in the canon is entitled “on urinary bladder and urine.(1,4)” this part has 2 treatises: treatise 1 is on the urinary bladder avicenna’s canon of medicine—madineh urology journal vol 6 no 3 summer 2009 229 and treatise 2, on urine and its timing. in the three previous articles of this series, i analyzed in detail the 1st treatise which included filling or reservoir function of the urinary bladder and its abnormalities such as disability and laxity of the bladder and various inflammation disorders of the bladder.(1-3) in treatise 2, avicenna discusses the emptying or voiding function of the urinary bladder and its abnormalities.(4) book iii, part 19, treatise 2, chapter 1 when urine accumulates in the bladder and it needs to be emptied, the bladder contracts from every side, and at the same time, the muscle of the bladder outlet [famol masaneh in arabic] opens. and in this way, urine goes through the path of exit by the aid of the pressure of the muscles of the soft part of the belly [meragh in arabic].(4,5) discussion. in chapter 1, “on mechanism of normal voiding,” avicenna describes in brief the bladder emptying and voiding. of interest, he describes carefully the contraction phase of bladder function and inhibition of bladder neck guarding mechanism during voiding. he also explains carefully the synergism between bladder contraction and its neck’s inhibition during voiding. these are completely in line with the modern urophysiology.(6) book iii, part 19, treatise 2, chapter 2 the symptoms that originate from abnormal status of urine are: (1) dysuria, (2) difficult voiding, (3) urinary retention, (4) frequency, (5) dribbling, and (6) abnormally excess urine in disorders including diabetes [diabitos in arabic].(4,5) discussion. avicenna here enumerates some lower urinary tract symptoms that include symptoms of bladder outlet obsruction.(7) book iii, part 19, treatise 2, chapter 3 dysuria [hergatal bel in arabic] is induced by the following situations: (1) urinary matter is pungent and borax [alkaline; bouraghi in arabia] due to abnormal temperament; (2) there is a matter which is nessesary for regulation and preparation of the urinary substance. when it is absent, the result is dysuria. this necessary substance for regulation of urinary temperament is a moisturizing material in fleshy gland [prostate] that is nutritious and rich. this moisturizing material is flowing through the urethra and sticks to it and covers it. when this substance is removed, the urinary pathway is left without this sticky cover, and also, the lubricant material is urine is removed. thus, its regulatory and preparatory function is stopped. why is this moisturizing substance with its useful function removed? it has 2 causes. first, sexual intercourse is responsible. this moisturizing substance often exits in large amount along with seminal fluid. thus, it is not surprising that if a person has frequent sexual intercourses, he will have dysuria, too. second, the cause is body melting [cachectic] diseases that causes removing this moisturizing material. third, there is possibility of desquamation or pustules [jarab in arabic] or ulcer in the penile urethra that causes disuria. if urine is pungent and borax [alkaline], its only sign is urinary pungency [acuity], and there is no pus in urine. however, if dysuria is due to pustules or ulcer in the penile urethra, its sign is discharge of pus or dirt with urine. it is frequent that the pungent urine couses pustules or ulcer in the bladder. thus, pungent urine is a predisposing factor for developing pustules or ulcer in the penile urethra, so as biliary diarrhea is a predisposing factor for intestinal ulcer. if dysuria is associated with pus and blood, its management is the some as the management of bladder ulcer. however, if it is not due to ulcer and there is no pus in urine, its best manegement is cleansing the urine [by herbs] and that you make the urine to be drained. avoid pungent, salty, and very sweet diets. the patient must not make himself tired and must not have sexual intercourse. if the cause of dysuria is the dry state of the glands, you should do something for recovery of normal moistures of the body and you should aviod any thing that dries your body such as sexual intercourse.(4,5) discussion 1. the etiologic description of dysuria by avicenna in this part is compatible with 2 lower urinary tract syndromes: painful avicenna’s canon of medicine—madineh 230 urology journal vol 6 no 3 summer 2009 bladder syndrome/interstitial cystitis (pbs/ic) and prostatitis or prostatitis-like syndrome. painful bladder syndrome/interstitial cystitis is a condition diagnosed as a clinical basis today requiring a high index of suspicion by the clinician.(8) it is likely to have multifactorial etiology that may act predominationtely through one or more pathogens resulting in the typical symptom complex mostly in women (female-male ratio, 5:1).(8) in modern urology, the proposed of pbs/ic causes are infection autoimmunity and inflammation, mast cell involvement, bladder glycosaminoglycan and epithelial layers permeability, neurobiologic factors, anti proliferative factor, urine abnormalities, and other potential factors such as anxiety, psychological stresses, mood dysregulation, and pelvic floor dysfunction.(8) the counterpart entities in men is prostatitis and prostatitis-like syndromes that are very prevalent, being seen in 2% to 10% of men.(9) prostatitis is the most common urologic disease in men younger than 50 years old.(9) the etiologies of prostatitis and prostatitis-like syndromes is similar to those of pbs/ic. they include microbiologic causes (gram-negative uropathogens, gram-positive bacteria, anerobic bacteria, corynebacteria, chlamydia, ureaplasma, nonculturable microorganisms, and fungi), altered prostate health factors, dysfunctional voiding, intraprostatic ductal reflux, immunologic alterations, chemically induced inflammation, neural dysregulation/plevic floor muscular abnormalities, interstitial cystitis-like causes, and psychological factors.(9) discussion 2. avicenna refers in the canon to some modern theories (infection theory and mucosal theory). the first one is infection, especially sexually transmitted disease. in modern urology, it has been proven that sexually transmitted organisms and some sexual behaviors such as unprotected penetrative anal intercourse can induce prostatitis and dysuria.(9) at that time, avicenna was not aware of nonspecific and specific pathogens involved in urinary tract infections; consequently, he attributed the symptoms to loss of moisturizing substance of urothelium due to infection. today in modern urology, this attribution is not completely rejected because of 2 reasons: first, infection has a major role in bacterial prostatitis, but most of the cases are nonbacterial prostatitis and prostatodynia.(9) second, in interstitial cystitis, urinary tract infection may trigger its symptoms, but it is unlikely in some patients that active infection is involved in the ongoing pathologic process or unlikely that antibiotics have a role to play in treatment.(8) discussion 3. the mucosal theory or bladder glycosominolycan layer theory is one of the most acceptable theories in the pathogenesis of interstitial cystitis. it is based on the absence of “moisturizing substance in urine” theory of avicenna. he mentions that this moisturizing substance is necessary for regulation and preparation of the urinary matter, and it is nutritious. it is flowing through the urethra and sticks to it, and if removed, its function is stopped and thus dysuria ensues.(5) parsons and hurst hypothesized and popularized the concept of “defect in the epithelial permeability barrier of the bladder surface glycosominolycans” in inducing pbs/ic.(10) the major classes of glycosominolycans are hyaluronic acid, heparine sulfate, heparin sulfate, chondroitin, dermatan sulfate, and keratan sulfate. these carbohydrate chains coupled to protein cores produe diverse classes of macromolecules, the proteoglycans.(11) glycosominolycans exist as a continuous layer on bladder urothelium.(12,13) except heparine, all the other types of glycosominolycans have been found on the bladder surface.(14) the glycosominolycan layer functions as a permeability barrier and antiadherent. in the absence of this protective layer, the urinary bladder’s susceptibility to infeetion would increase.(8) parsons and hurst reported lower excretion levels of urinary uronic acid and glycosominolycans in patients with interstitial cystitis than in healthy volunteers.(10) support for epithelial abnormality from a different perspective (genetic studies) has come from bushman and colleagues,(15) and further information on an abnormal surface came from moskowits and colleagues.(16) the glycosominolycan concept for interstitial cystitis of course has some opponents, and it is still at theoretical level.(12,17-20) discussion 4. another theory of interstitial avicenna’s canon of medicine—madineh urology journal vol 6 no 3 summer 2009 231 cystitis to which avicenna points is urine abnormalites. he describes it as “pungent and borax” urine without indicating pus in urine.(4,5) current theories of pathogenesis generally involve access of a component of urine to the interstices of the bladder wall, resulting in an inflammatory response induced by toxic, allergic, or immunologic means.(8) this substance acts as initiator only in particularly susceptible individuals or may act like a true toxin, gaining access to the urine by a variety of mechanisms or metabolic pathways.(21) in clemmensen and coworker’s study,(22) the histology suggested a toxic rather than allergic reaction. circumstantial evidence for the toxicity of urine in interstitial cystitis is suggested by the failures of substitute cystoplasty and continuous diversion in some of these patients because of the development of pain or contraction of bowel segments over time.(23-26) also in prostatitis, there is an etiologic theory named “chemically induced inflammation.” accordingly, urine and its metabolites (eg, urate) are present in prostatic secretion of patients with chronic prostatitis. discussion 5. concerning psychological factors in the management of dysuria, avicenna recommends these patients not make themselves tired and avoid sexual intercourse.(4) among the etiologic factors of interstitial cystitis, anxiety, psychological stresses, and mood dysregudation have their own roles,(8) and psychological factors always have considered to play an important role in exacerbation of chronic prostatitis symptoms.(9) discussion 6. prostatic secretion is scrutinized by avicenna. he points to the role of a fleshy gland with its nutritious moisturizing substance, the lack of whose secretions induces dysuria.(4) in part i of this article series, i showed that the gland avicenna describes is the prostate.(1) the nutritious secretion that avicenna described 10 centuries ago are—according to the modern urophysiology—nonpeptide components such as citric acid; polyamines including spermine; phosphorylcholine; cholesterol; lipids; zinc; and secretory proteins such as prostatespecific antigen, human kallikreins, prostatespecific transglutaminase, semenogelin, betamicroseminoprotein, beta-inhibin, leucine aminopeptidase, lactate dehydrogenase, immunoglobulins, complement 3, and transferrin.(27) first, the relation between prostatitis and citric acid has been investigated.(28) second, it is possible that polyamines and their aldehyde products, which produce the characteristic odor of semen, protect the urogenital tract from infectious agents.(27) third, high levels of zinc in human seminal plasma appear to originate principally from secretions of the prostate.(29) an important role of zinc in prestotic secretion has been postulated in a study of fair and coworkers,(30) which suggested the dominate role of zinc as a prostatic antibacterial factor. in the study of 36 men free from bacterial prostatic infection, the mean value of zinc in prostatic secretions was 350 mg/ml (range, 150 mg/ml to 1000 mg/ml), while in patients with documented chronic bacterial prostatitis, a reduction of more than 80% to an average of 50 mg/ml (range, 0 to 139 mg/ml) in zinc concentrations. in vitro studies of free zinc ions at concentrations normally found in prostatic fluid have confirmed the bactericidal activity of zinc against a variety of gram-positive and gramnegative bacteria; however, a considerable part of zinc in the prostate appears to be bound to unique proteins such as metallothionein, and this might alter the biologic properties of zinc.(31) fourth, there are immunoglubulins in human seminal plasma and they are found in expressed prostatic fluids, which may be related to infections.(32,33) and fifth, chronic prostatitis also has been shown to be related to complement 3 concentration.(34) discussion 7. avicenna mentions some conditions in the bladder that today are included in the differential diagnosis of interstitial cystitis, such as bladder tumors or desquamation and “body melting” disease.(4) diagnosis of interstitial cystitis is made after ruling out the other causes of lower urinary tract symptoms such as urinary tract infection, bladder tumors (especially carcinoma in situ), bladder calculi, tuberculosis cystitis, and radiation cystitis.(8) disability and voiding problems in cachechtic states (called “body melting” in the canon) lead to chronic urinary infection, urinary retention, hospitalization, and catheterization which induces dysuria. avicenna’s canon of medicine—madineh 232 urology journal vol 6 no 3 summer 2009 discussion 8. an interesting point is this part of the canon is attention of avicenna to the similarity between some bowel disorders and dysuria induced by interstitial cystitis that is on the agenda today in modern urology, too. avicenna studies the relaton of biliary diarrhea with intestinal ulcer. the associated disorders of interstitial cystitis, according to modern texts, are allergies, irritable bowel syndrome, fibromyalgia, systemic lupus erythematosus, inflammatory bowel disorders, vulvitis, and sjogren syndrome.(8) thirty percent of patients are diagnosed with irritable bowel syndrome.(35) in these patients, intestinal pain is induced with gas accumulation volumes lower than that which causes pain in healthy persons, similar to the pain of bladder distention in patients with interstitial cystitis.(36) this has been confirmed by koziol, too.(37) also, inflammatory bowel disease was found in more than 7% of a population with interstitial cystitis.(36) alagiri and colleagues found that in comparison with the general population, patients with interstitial cystitis are 100 times more likely to have inflammatory bowel disease and 30 times more likely to have systemic lupus erythematosus.(38) abnormal leukocyte activity has been implicated in both interstitial cystitis and systemic lupus erythematosus.(8,39,40) the similarity of these to what avicenna cited 10 centuries age about differential diagnosis of dysuria, especially his emphasis on the presence or absence of pus in urine, is noteworthy. book iii, part 19, treatise 2, chapter 4 oliguria can be due to the below causes: (1) drinking inadequate liquids, (2) body porosity, (3) effect of diarrhea on the body, (4) disability of the kidneys, resulting in impaired absorption of fluids, and (5) disability of the liver in separation of the fluid and sending it to the kidneys, so as in hepatic cirrhosis [sou of gonieh in arabic] and dropsy state [estesgha in arabic]. you should know that sour diets are harmful to the patient, and sexual intercouse aggravates the disease.(4,5) discussion. in this chapter, avicenna enumerates the causes of oliguria. in modern urology and nephrology, this sign it the cardinal sign of acute renal failure, with the following causes: (1) prerenal renal failure due to dehydration, sepsis, and reduced cordiac output; (2) hepatorenal syndrome; (3) iatrogenic causes including drugs’ side effects; (4) vascular disorders; (5) intrarenal (parenchymal) diseases such as nephritis and acute tubular and cortical necrosis; and (6) postrenal causes.(41) avicenna points to most of these causes. he also recommends avoiding astringent and “sour” (acidic) diets, which reminds us that renal failure causes metabolic acidosis. references 1. madineh sma. avicenna’s canon of medicine and modern urology. part i: bladder and its diseases. urol j. 2008;5:284-93. 2. madineh sma. avicenna’s canon of medicine and modern urology. part ii: bladder calculi. urol j. 2009;6:63-8. 3. madineh sma. avicenna’s canon of medicine and modern urology. part iii: other bladder diseases. urol j. 2009;6:138-44. 4. ibn sina. al-qanun fi al-tibb. rome: typgraphia mediciea; 1593. p. 543-4. 5. abu ali sina. qanun [translated into persian by sharafkandi ar]. tehran: soroush; 2004. book iii, p. 175-80. 6. andersson ke, arner a. urinary bladder contraction and relaxation: physiology and pathophysiology. physiol rev. 2004;84:935-86. 7. mcaninch jw. symptoms of disorders of the genitourinary tract. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 17th ed. new york: lange medical books/mcgraw-hill; 2008. p. 30-8. 8. hanno pm. painful bladder syndrome/interstitial cystitis and related disorders. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 330-48. 9. nickel jc. inflammatory conditions of the male genitourinary tract: prostatitis and related conditions, orchitis, and epididymitis. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbellwalsh urology. 9th ed. philadelphia: saunders; 2007. p. 304-10. 10. parsons cl, hurst re. decreased urinary uronic acid levels in individuals with interstitial cystitis. j urol. 1990;143:690-3. 11. trelstad rl. glycosaminoglycans: mortar, matrix, mentor. lab invest. 1985;53:1-4. 12. dixon js, holm-bentzen m, gilpin cj, et al. electron microscopic investigation of the bladder urothelium and glycocalyx in patients with interstitial cystitis. j urol. 1986;135:621-5. 13. cornish j, nickel jc, vanderwee m, costerton jw. ultrastructural visualization of human bladder mucous. urol res. 1990;18:263-6. avicenna’s canon of medicine—madineh urology journal vol 6 no 3 summer 2009 233 14. ruoslahti e. structure and biology of proteoglycans. annu rev cell biol. 1988;4:229-55. 15. bushman w, goolsby c, grayhack jt, schaeffer aj. abnormal flow cytometry profiles in patients with interstitial cystitis. j urol. 1994;152:2262-6. 16. moskowitz mo, byrne ds, callahan hj, parsons cl, valderrama e, moldwin rm. decreased expression of a glycoprotein component of bladder surface mucin (gp1) in interstitial cystitis. j urol. 1994;151:343-5. 17. collan y, alfthan o, kivilaakso e, oravisto kj. electron microscopic and histological findings on urinary bladder epithelium in interstitial cystitis. eur urol. 1976;2:242-7. 18. johansson sl, fall m. clinical features and spectrum of light microscopic changes in interstitial cystitis. j urol. 1990;143:1118-24. 19. ruggieri mr, steinhardt gf, hanno pm. comparison of antiadherence activity of bladder extracts from interstitial cystitis patients with recurrent urinary tract infections. semin urol. 1991;9:136-42. 20. nickel jc, emerson l, cornish j. the bladder mucus (glycosaminoglycan) layer in interstitial cystitis. j urol. 1993;149:716-8. 21. wein aj, broderick ga. interstitial cystitis. current and future approaches to diagnosis and treatment. urol clin north am. 1994;21:153-61. 22. clemmensen oj, lose g, holm-bentzen m, colstrup h. skin reactions to urine in patients with interstitial cystitis. urology. 1988;32:17-20. 23. nielsen kk, kromann-andersen b, steven k, hald t. failure of combined supratrigonal cystectomy and mainz ileocecocystoplasty in intractable interstitial cystitis: is histology and mast cell count a reliable predictor for the outcome of surgery? j urol. 1990;144:255-8. 24. trinka pj, stanley bk, noble mj, et al. mast-cell syndrome: a relative contraindication for continent urinary diversion. j urol. 1993;149:506a. 25. lotenfoe rr, christie j, parsons a, burkett p, helal m, lockhart jl. absence of neuropathic pelvic pain and favorable psychological profile in the surgical selection of patients with disabling interstitial cystitis. j urol. 1995;154:2039-42. 26. baskin ls, tanagho ea. pelvic pain without pelvic organs. j urol. 1992;147:683-6. 27. fair wr, parrish rf. antibacterial substances in prostatic fluid. prog clin biol res. 1981;75a:247-64. 28. wolff h, bezold g, zebhauser m, meurer m. impact of clinically silent inflammation on male genital tract organs as reflected by biochemical markers in semen. j androl. 1991;12:331-4. 29. bedwal rs, bahuguna a. zinc, copper and selenium in reproduction. experientia. 1994;50:626-40. 30. fair wr, couch j, wehner n. prostatic antibacterial factor. identity and significance. urology. 1976;7:16977. 31. suzuki t, suzuki k, nakajima k, otaki n, yamanaka h. metallothionein in human seminal plasma. int j urol. 1994;1:345-8. 32. grayhack jt, wendel ef, oliver l, lee c. analysis of specific proteins in prostatic fluid for detecting prostatic malignancy. j urol. 1979;121:295-9. 33. fowler je, jr., kaiser dl, mariano m. immunologic response of the prostate to bacteriuria and bacterial prostatitis. i. immunoglobulin concentrations in prostatic fluid. j urol. 1982;128:158-64. 34. blenk h, hofstetter a. complement c3, coeruloplasmin and pmn-elastase in the ejaculate in chronic prostato-adnexitis and their diagnostic value. infection. 1991;19 suppl 3:s138-40. 35. hand jr. interstitial cystitis; report of 223 cases (204 women and 19 men). j urol. 1949;61:291-310. 36. lynn rb, friedman ls. irritable bowel syndrome. n engl j med. 1993;329:1940-5. 37. koziol ja. epidemiology of interstitial cystitis. urol clin north am. 1994;21:7-20. 38. alagiri m, chottiner s, ratner v, slade d, hanno pm. interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. urology. 1997;49:52-7. 39. bohne aw, hodson jm, rebuck jw, reinhard re. an abnormal leukocyte response in interstitial cystitis. j urol. 1962;88:387-91. 40. kontras sb, bodenbender jg, mcclave cr, smith jp. interstitial cystitis in chronic granulomatous disease. j urol. 1971;105:575-8. 41. amend wjc, vincenti fg. oliguria; acute renal failure. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 17th ed. new york: lange medical books/mcgraw-hill; 2008. p. 531-4. a modıfıed partın table to better predıct extracapsular extensıon in clınıcally localızed prostate cancer erkan merder,¹* ahmet arıman,¹ fatih altunrende¹ purpose: prediction of extracapsular extension (ece) before radical prostatectomy in clinically localized prostate cancer (pca) is very important for clinical practice. ece affects our decision on treatment strategy. the aim of this study is to identify the predictors of ece, determine cut-off values, and compare them with the accuracy of partin table parameters to improve tumor staging in clinical practice. materials and methods: 374 patients with clinically localized pca who underwent open radical retropubic prostatectomy (rrp) were included in this study. gleason score (gs), age, digital rectal examination (dre), prostate specific antigen (psa), prostate specific antigen density (psad), free psa, free/total psa, prostate volume (pv), number of cores involved, tumor length, and tumor percentage in maximum involved core in biopsy were investigated. results: psad, tumor percentage, and tumor length are predictive factors of ece. the cut-off values of psa, psad, maximum tumor length, and maximum tumor percentages in predicting ece are: > 8.90 ng/ml, > 0.26 ng/ml2, >5mm, and >50%, respectively. the cut-off values for partin extraprostatic extension (epe) and organ confined (oc) disease are >29% and ≤ 64%, respectively. conclusion: partin tables could better predict extracapsular extension in clinically localized pca if they include psad, tumor percentage, and tumor length. the cut-off values of these predictive factors can be beneficial in treatment strategies and in the decisions of lymphadenectomy and nerve-sparing surgery at radical prostatectomy. keywords: extracapsular extension; localized prostate cancer; partin table; psa; psad; radical prostatectomy introduction prostate cancer (pca) takes second place among all cancers seen in men(1). the epidemiology of pca differs between geographic regions, countries, and ethnicities. the incidence rate of pca in turkish ethnicity was found to be 7.9 per 100.000 by basiri, a et al.(2). treatment strategy varies according to the clinical stage of pca. excellent results of radical prostatectomy (rp) are obtained when pca is organ confined(3). exceeding tumor cells beyond the prostatic capsule, presence of tumor cells in the periprostatic tissue and/ or neurovascular plexus, and ≥ pt3 with or without lymph positivity is defined as ece. clinically distinguishing organ confined (t stage 1-2 and n0) from locally advanced prostate cancer (lapc) is very important. locally advanced disease changes the treatment plan and the prognosis of pca(4,5). in the presence of locally advanced disease, lymphadenectomy is needed, nerve-sparing surgery cannot be done on the affected side, and rate of positive surgical margin increases (4,6). if we can predict preoperative ece, we can modify the treatment method and surgical technique in rrp. lymphadenectomy and nerve-sparing surgery are related to the ece status of the patient. we can inform the patient about the course of the disease, prognosis, and additional postoperative treatments. all these factors affect the oncologic outcomes, morbidity, and the risk of recurrence in patients. university of health sciences, prof dr. cemil taşçıoğlu city hospital, department of urology, istanbul, turkey. *correspondence: department of urology, university of health sciences, prof dr. cemil taşçıoğlu city hospital, istanbul, turkey. tel: +90 532 6161065, email: drerkanmerder@gmail.com. received september 2020 & accepted december 2020 ece or lymph node involvement have been seen after rp in some patients diagnosed with localized pca(7,8). there are many studies in the literature dealing with ece, upstaging, and upgrading between prostate biopsy and rp specimens(9). several clinical parameters, such as digital rectal examination (dre), multiparametric magnetic resonance imaging (mpmri), and preoperative nomograms (partin, memorial sloan kettering cancer center, kattan) are used in the prediction of disease extension in the literature. we use partin table frequently in our clinical practice in the prediction of final pathologic stage before rp. partin uses dre, biopsy psa, and biopsy gleason score (gs) in the nomogram to predict extraprostatic extension (epe), organ confined (oc) disease, seminal vesicle involvement (sv+), and lymph involvement (ln+) before rp. partin table has a 95 % confidence interval for predicting the probabilities of each pathologic stage. partin showed that using psa, dre, and biopsy gs together gives more accurate results than using these factors separately(7,8). in recent years there have been various studies on adding mpmri and some other predictive factors to the preoperative nomograms to improve tumor staging. materials and methods this study was carried out in the urology department urology journal/vol 18 no. 1/ january-february 2021/ pp. 74-80. [doi: 10.22037/uj.v16i7.6477] urological oncology vol 18 no 1 january-february 2021 20 of the university of health sciences, prof. dr. cemil taşçıoğlu city hospital, istanbul, turkey. 374 patients who had open rrp for clinical localized pca (≤ct2c) between january 2015 and september 2020 were analyzed retrospectively. prof. dr. cemil taşçıoğlu city hospital ethics committee approval was obtained and all patients provided informed consent (date 14.07.2020 and no:304). patients with localized pca (clinical stage ≤ct2) before rrp were included. patients who were treated previously (radiation therapy or androgen deprivation), those with ≥ct3 or lymph positive preoperatively, those who had an active surveillance program before, and those with missing data were excluded. all 374 patients in our study group were evaluated as localized pca (≤ ct2) and n0 before rrp. pca was diagnosed by transrectal ultrasoundguided prostate biopsy of minimum 12 cores based on elevated serum psa, and mpmri findings or palpable nodule at dre. the clinical stage was evaluated using dre, bone scan, computed tomography (ct), or mpmri before rrp. table 1. demographic, clinical and histopathological parameters in organ confined (group 1) and ece group (group 2). group 1 (n=248) (organ confined) group 2 (n=126)(ece) p value age (years) min-max (median) 53-82 (69) 54-82 (68) a0,866 meann ± sd 68,48 ± 6,63 68,3 ± 6,76 prostate volume (cc) min-max (median) 12-125 (41,5) 15-90 (40) b0,101 mean±sd 49,14±25,0 41,63 ± 18,14 biopsy psa ng/ml min-max (median) 3,4-28 (7) 3,3-42 (10) b0,001* mean ± sd 8 ± 3,9 12,13 ± 7,59 <6,1 88 (35,5) 22 (17,5) c0,001* 6,1-10 116 (46,8) 42 (33,3) >10 44 (17,7) 62 (49,2) free psa ng/ml min-max (median) 0-2,3 (0) 0-2,4 (0) b0,608 mean ± sd 0,19 ± 0,48 0,19 ± 0,53 psad ng/ml2 min-mak (median) 0,1-1,2 (0,2) 0,1-1 (0,3) 0,001* mean ± sd 0,20±0,13 0,32 ± 0,19 f psa/t psa % min-max (median) 0-0,7 (0,2) 0,1-0,2 (0,1) b0,481 mean ± sd 0,20 ± 0,18 0,14 ± 0,03 number of positive cores min-max (median) 1-12 (3) 1-12 (5) b0,001* mean ± sd 3,17 ± 2,09 5,38 ± 2,59 ≤2 114 (46,0) 16 (12,7) c0,001* ≥3 134 (54,0) 110 (87,3) tumor length in maximum min-max (median) 1-12 (4) 2-18 (8) b0,001* involved core (mm) mean ± sd 4,15 ± 1,99 8,72 ± 3,38 percentage of tumor in min-max (median) 7-90 (30) 12,5-100 (67) b0,001* maximum involved core % mean ± sd 33,64 ± 17,74 70,55 ± 23,45 < %25 106 (42,7) 4 (3,2) c0,001* %26-50 104 (41,9) 20 (15,9) > %51 38 (15,3) 102 (81,0) astudent t test bmann whitney u test cpearson chi square test *p < 0,05 figure 1. roc curve of psa,psad, tumor length and tumor percentage a modified partin table-merder et al. vol 18 no 1 january-february 2021 75 findings of dre, age, gs of biopsy, psa, free psa, pv, psad, free/total psa, partin table parameters (epe, oc, svi, ln+), tumor positive core numbers, tumor length, and tumor percentage in maximum involved core in prostate biopsy were investigated preoperatively and data were recorded retrospectively. extracapsular extension, apical, bladder neck and seminal vesicle involvement, positive surgical margin, vascular and perineural invasion, histology of tumor surrounding tissue, lymph node dissection, and positivity after rrp were recorded. biopsy gleason scores were graded according to the international society of urological pathology (isup) by two uropathology experts in our hospital. these uropathologists also evaluated the presence of extraprostatic disease and other criteria in the final pathologic analysis of surgical specimens. invasion of adipose tissue and/or of the periprostatic neurovascular plexus and ≥pt3 with or without lymph-positivity were accepted as extraprostatic extension (ece) of disease. 248 of the patients were evaluated as the organ confined group (group 1). they had clinical and pathological stage ≤ct2 before and after rrp. 126 of the patients had clinical and pathological stage ≤ct2 before but pathologic stage ≥pt3 (n0 or n1) after rrp and were evaluated as the ece group (group 2). we investigated clinical and histopathological parameters, psad, and partin nomogram parameters in predicting ece in both groups and these values were compared to each other in terms of improving the accuracy of tumor staging. statıstıcal analysıs we used the number cruncher statistical system (ncss) statistical software (ncss, llc, kaysville, utah, usa) in all statistical analysis. student’s ttest, mann-whitney u test, pearson’s chisquared test, and roc curve analysis were used. logistic regression analysis was also performed. p values were considered statistically significant if p ˂ 0.05. results demographic, clinical and histopathological parameters in the organ confined (group 1) and ece (group 2) groups are shown in table 1. nodule on dre, psa, psad, number of positive cores, tumor length, and tumor percentage on maximum involved core showed a statistically significant difference between the two groups. age, prostate volume, free psa, and free psa/total psa values were not statistically different between the groups. regarding pca risk groups, distribution of patients with low, moderate, and high-risk groups were 52.4%, 38.5%, and 9.1%, respectively. overall, dre positivity, ece, and upgrading rates were 17.6%, 33.7%, and 37.5%, respectively. biopsy and postoperative gs, preoperative clinical and postoperative pathologic stages of the patients are shown in table 2. we detected ece in 126 of 374 (33.7%) patients (group 2). 82 of these 126 patients (65.1%) upstaged to pt3a, 26 (20.6%) upstaged to pt3b, 10 (7.9%) upstaged to t3a n1, and 8 (6.3%) upstaged to t3b n1. upgrading rates in the ece group in gleason score 3+3, 3+4, 4+3, and 4+4 patients were 24.2%, 7.3%, 3.5%, and 2.5%, respectively. downgrading rates in gleason score 3+4, 4+3, and 4+5 patients were 2.4%, 2.6%, and 0.8%, respectively. determination of cut-off values for psa, psad, tumor length, and tumor percentage in maximum involved core related to ece is shown in table 3. table 4 shows the logistic regression analysis of risk factors that affect upstaging. the cut-off values for psa, psad, tumor length, and tumor percentage were: >8.90ng/ml, >0.26ng/ml2, >5mm, and >50%, respectively. the accuracy rates of psad, tumor length, and tumor percentage were 73.8%, 79.7%, and 83.4% respectively. the odds ratios (95% ci) for tumor percentage, tumor length, and psad were 9.898, 4.259, and 3.361, respectively. roc curves for psa, psad, tumor length, and tumor percentage are shown in figure 1. the auroc (95% ci) of psad was higher than psa, and the auroc of tumor length and tumor percentage table 2. biopsy and postoperative gs, preoperative clinical and postoperative pathologic stages of the patients. biopsy gs 3+3 196 52.4 3+4 120 32.1 4+3 46 12.3 4+4 8 2.1 4+5 4 1.1 postoperative gs 3+3 116 31.0 3+4 126 33.7 4+3 110 29.5 4+4 14 3.7 4+5 8 2.1 preoperative clinical stage t1c 305 81.6 t2a 61 16.3 t2b t2c 8 2.1 postoperative pathologic stage pt2a 32 8.5 pt2b 46 12.3 pt2c 170 45.5 pt3a 82 21.9 pt3a n1 10 2.7 pt3b 26 7 pt3b n1 8 2.1 table 3. determination of cut off values of psa, psad, maximum tumor length and tumor percentage related to ece. biopsy psa ng/ml psad ng/ml2 max tumor length (mm) tumor percentage (%95 ci 0.628-0.764) (%95 ci 0.661-0.793) (%95 ci 0.832-0.928) (%95 ci 0.831-0.927) area under the roc 0.700 (0.628 0.764) 0.731 (0.661. 0.793) 0.886 (0.832. 0.928) 0.886 (0.831. 0.927) curve auroc (95%ci) cut-off >8.90 >0.26 >5 >50 sensitivity 61.90 (48.8-73.9) 52.38 (39.4-65.1) 84.13 (72.7-92.1) 80.95 (69.1-89.8) specificity 70.97 (62.1-78.8) 84.68 (77.1-90.5) 77.42 (69.0-84.4) 84.68(77.1-90.5) positive predictive value (ppv) 52.00 (43.6-60.3) 63.50 (51.9-73.7) 65.40 (57.3-72.7) 72.90 (63.6-80.5) negative predictive value (npv) 78.60 (72.4-83.7) 77.80 (72.8-82.1) 90.60 (84.4-94.5) 89.7 (83.9-93.6) accuracy 67.9 (58.4-81.0) 73.8 (62.9-84.7) 79.7 (69.8-89.6) 83.4 (74.2-92.6) a modified partin table-merder et al. andrology 106urological oncology 76 were higher than psa and psad. the cut-off values for partin table parameters are shown in table 5. the lowest accuracy rate was found in the partin ln-positive parameter. the highest accuracy rate was in partin oc. the roc curves of partin table parameters are shown in figure 2. the auroc of psad, max tumor length, and tumor percentage were 0.731, 0.886, and 0.886, respectively, all being higher than psa (0.700), which is one of the partin table criteria. the auroc of partin table epe was 0.785, lower than max tumor length and tumor percentage. 192 of the 374 patients (51.3 %) had lymph node dissection. 122 of the 248 patients in the organ confined group (49.2 %) and 70 of the 126 patients in the ece group (55.5%) had lymph node dissection. we found the rate of apical involvement after rp as 60.2%, perineural invasion as 72.6%, ece as 33.7%, bladder neck involvement as 8.1%, vascular invasion as 8.0 %, capsular invasion as 33.9%, sv+ as 9.1%, positive surgical margin as 14.3 %, ln+ as 4.8%, and high pin as 60.7%. histopathological characteristics in tumor surrounding tissues after surgery were nodular hyperplasia (89.3%), chronic prostatitis and nodular hyperplasia (5.9%), and chronic prostatitis (4.8%). discussion some patients with prostate cancer have pathologic upstaging (ece) and gs upgrading after rp(9). the rate of upstaging varies between 29%-34% and upgrading varies between 24%-41% in the literature(9,10,11,12). upstaging and upgrading results may be associated with diagnostic problems in prostate biopsy like insufficient biopsy material and histopathologic evaluation of the gleason grade of the tumor in biopsy(13). this is related to the experience of the histopathologist who examines the tissue, and the urologist or radiologist who makes the biopsy. number of biopsy cores and involved cores may also cause this difference. although our physicians who performed the prostate biopsy and the histopathologists who examined the tissue were very experienced, our ece and upgrade rates were found very close to those in the literature.extraprostatic extension (ece) and positive surgical margins in pca affect prognosis and survival(14,15,16). in our study, 71.4% of overall upstaging occurred in ct1c patients, and 66.1% of overall upgrading occurred in biopsy gleason score 3+3 patients. this shows that upstaging and upgrading occurs mostly in organ confined patients where ece was not suspected according to preoperative findings. therefore, predictive factors are very important in detecting upstaging, upgrading, ece, and oc disease in clinical practice. in our study, the rates of upstaging (ece) was 33.7% and upgrading was 37.5%. several studies in the literature have investigated the clinical and pathological predictors in the diagnosis of ece. age has been reported as one of the significant predictors of ece in some studies(17,18). however, we could not find age to be a significant predictor of ece in our cohort (p = 0.866). valette et al., showed that tumor percentage is a predictor of epe and adding it to the preoperative nomograms increases the accuracy of the nomogram(19). we found the same result in our study. the highest accuracy rate for predicting ece was found in tumor percentage (83.4%). x. gao et al. included t1c-2b patients with gleason scores ≤ 7 and psa ≤ 10 ng/ml and found that the maximum percentage of tumor on the most involved core was predictive for epe in both univariate and multivariate analysis(20) similar to our findings. horiguchi et al. found prostate volume to be a significant predictor for ece in localized pca(21). however, sayyid et al. did not find prostate volume to be a significant factor, similar to findings(18). on the other hand, both horiguchi et al. and sayyid et al. found that psa was a significant predictor of ece, in parallel with our findings. horiguchi et al. also determined, psad and gleason score to be significant predictors (18,21). their ece rate was 33.4% (21). we found psad to be a significant predictor with an auroc of 0.731 at 95% ci. horiguchi et al. reported that psad showed the largest area under the roc curve among other parameters p odds 95% c.i.odds lower upper tumor length in max. involved core (mm) (>5) 0.030* 4.259 1.155 15.704 tumor percentage % (>50) 0.000** 9.898 3.725 26.296 number of positive cores (≥3) 0.096 2.480 0.851 7.224 psad ng/ml2 (>0.26) 0.005** 3.361 1.445 7.815 *p < 0.05 table 4. logistic regression analysis of factors that affect upstaging. partin epe (%95 ci) partin oc (%95 ci) partin sv+ (%95 ci) partin ln+ (%95 ci) auroc (95%ci) 0.785 (0.716. 0.885) 0.791 (0.725. 0.847) 0.759 (0.684. 0.835) 0.773 (0.698. 0.848) cut-off >29 ≤64 >4 >1 sensitivity 49.20 (36.9-61.5) 52.38 (40.0-64.7) 49.21 (36.9-61.6) 84.12 (75.1-93.1) specificity 91.13 (84.1-98.2) 90.32 (83.0-97.9) 91.94 (85.2-98.7) 50.81 (75.1-93.1) ppv 73.81 (63.0-84.7) 73.33 (62.4-84.3) 75.61 (65.0-86.2) 46.49 (34.2-58.8) npv 77.93 (67.7-88.2) 78.87 (68.8-89.0) 78.08 (67.9-88.3) 86.30 (77.8-94.8) accuracy 77.01 (66.6-87.4) 77.54 (67.2-87.8) 77.54 (67.2-87.8) 62.03 (50.0-74.0) abbreviations: auroc: area under the roc curve; ppv: positive predictive value; npv: negative predictive value; ci: confidence interval a modified partin table-merder et al. vol 18 no 1 january-february 2021 77 table 5. cut-off values for partin table parameters in our study (auc=0.732). they found that using psad, mri findings, and biopsy gleason scores all together could give more information on staging(21). number of involved cores was found to be statistically different in our univariate analysis, but not in the multivariate analysis (p = 0.096). we found dre to be a predictive factor (p = 0.005). 82.4% of our patients had no positive finding in dre. dre is an easy, low-cost, and practical method, although with low sensitivity and a tendency to understage the disease(22). it is difficult to find or feel small, centrally or anteriorly located tumors in dre. obesity is another problem for dre. in our opinion, dre is the weakest of the 3 criteria used in partin table to predict ece, oc, svi, and ln+. biopsy and clinical parameters are the findings at our disposal, that do not require anything else, are practical, useable, easily accessible, and cheaper; hence, we use them routinely in our clinical practice. tumor percentage, tumor length, and psad can be added to the partin table to predict tumor staging more accurately or these predictive factors can be used instead of dre to predict ece, oc, svi, and ln+ in localized pca. in the coming years, depending on the advancements in technology, mpmri criteria can may be added to partin tables (instead of dre) to increase the accuracy of preoperative staging. so, we can make treatment plans more preicisely and make decisions of lymphadenectomy and nerve-sparing surgery more accurately. partin tables have low sensitivity (28.1%) and ppv (42.9%), but high specificity (88.1%) and npv (79.5%) for the diagnosis of epe(23). here, we found partin tables to have a sensitivity, specificity, ppv, and nnp of 49.20%, 91.13%, 73.81%, and 77.93%, respectively for epe. de rooij et al. found the sensitivity and specificity of mpmri in the detection of ece as 57% and 91%, respectively(24). there are different studies in the literature about adding mpmri and some other predictive factors to preoperative nomograms to improve the accuracy of tumor staging. jansen et al. showed that combining mpmri with partin and memorial sloan kettering cancer center nomograms did not increase the accuracy rate of staging(25). gupta et al. compared the accuracy of mpmri and partin tables and showed that the diagnosis of organ confined disease was superior in mpmri compared to partin tables. they found the auroc of mpmri and partin tables to be 0.88 and 0.70, respectively(26). we found the auroc of partin table 0.791 and the auroc of both tumor percentage and tumor length as 0.886, higher than the findings of gupta et al. the retrospective, and single-center nature of our research, along with the relatively small number of patients and the lack of mpmri and targeted biopsies were the limitations in this study. the indication and role of lymph node dissection in localized pca has not been standardized yet. we use the value of partin ln+ as >5% for lymphadenectomy in our clinical practice. in this study, we found that partin ln+ had a cut-off value of >1%. if partin ln+ is >1%, we must perform lymphadenectomy without nerve-sparing surgery on the affected side in these patients due to the high possibility of ece. we found partin sv+ to have a cut-off value of >4%. we should consider lymphadenectomy in these patients as well. figure 2. roc curves of partin table parameters a modified partin table-merder et al. urological oncology 78 conclusions psa, psad, tumor percentage, and tumor length are predictive of ece. if these factors are included in the content of the partin table, the accuracy rate of the partin table in tumor staging will increase significantly. the cut-off values of these predictive factors will be very useful in treatment strategies and the decisions for performing lymphadenectomy and nerve-sparing surgery. references 1. fitzmaurice c, abate d, abbasi n, et al. global, regional and national cancer incıdence, mortality,years of life lost, years lived with disability and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. jama oncol. 2019;5:1749-68. 2. basiri a, eshrati b, zarehoroki a, et al. incidence, gleason score and ethnicity pattern of prostate cancer in the multi-ethnicity country of iran during 2008-2010. urol j. 2020 may 4. doi:10.22037/uj.v0i0.5618. 3. hull gw, rabbani f, abbas f, et al. cancer control with radical prostatectomy alone in 1.000 consecutive patients. j urol. 2002;167:528-34. 4. conford p, bellmunt j, bolla m, et al. eauestro-siog guidelines on prostate cancer. part 2: 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biopsy-derived nomogram to predict risk of ipsilateral extraprostatic extension. bju int 2017;120:76-82. 19. thiago n. valette, alberto a. antunes, katia moreira leite, miguel s. probability of extraprostatic disease according to the percentage of positive biopsy cores in clinically localized prostate cancer. int braz j urol 2015;41:449-54. 20. x. gao, n. mohideen, r c. flanigan, w b. waters, eva m. wojcık, c r. leman, the extent of biopsy involvement as an independent predictor of extraprostatic extension and surgical margin status in low risk prostate cancer. implıcations for treatment selection. j urol. 2000;164:1982-86 21. akio horiguchi, j. nakashima, y. horiguchi, k. nakagawa et al. prediction of extraprostatic cancer by prostate spesific antigen density, endorectal mri and biopsy gleason score in clinically localized prostate cancer. prostate 2003;56:23-29. 22. philip j, dutta roy s, ballal m, foster c.s, javie p. is a digital rectal exemination necessary in the diagnosis and clinical staging of early prostate cancer. bju int 2005;95:96971. 23. davis r, salmasi a, koprowski c, et al. accuracy of multiparametric magnetic vol 18 no 1 january-february 2021 79 resonance imaging for extracapsular extension of prostate cancer in community practice. clin genitourin cancer. 2016;14:61722. 24. de rooij m, hamoen ehj, witjes j.a, barentsz j.o, rovers m.m, accuracy of magnetic resonance imaging for local staging of prostate cancer. a diagnostic metaanalysis eur-urol. 2016;70:233-45. 25. bernard h e. jansen, j a. nieuwenhuijzen, daniela e. oprea, et al. adding multiparametric mri to the mskcc and partin nomograms for primary prostate cancer: improving local tumor staging? urologic oncology: seminars and original investigations 2018; 1-6. urol oncol. 2019;37:181.e1-e6. 26. gupta r.t, brown a.f, silverman r.k, et al. can radiologic staging with multiparametric mri enhance the accuracy of the partin tables in predicting organ-confired prostate cancer? genitourinary imaging. ajr. 2016;207:87-95. a modified partin table-merder et al. urological oncology 80 urological oncology prognostic significance of body mass index and other tumor and patient characteristics in nonmetastatic renal cell carcinoma vusal ahmedov, fuat kızılay*, i̇brahim cüreklibatır purpose: in this retrospective study, we aimed to investigate the prognostic effect of body mass index (bmi) in localized renal cell carcinoma (rcc) cases who underwent surgical treatment. furthermore, the assessment of various patient and tumor characteristics and surgical methods on survival has been identified as additional targets. materials and methods: three hundred and eighty patients with localised, non-metastatic, unilateral rcc who underwent radical or partial nephrectomy in our clinic between january 2007 and december 2016 were enrolled in this study. age, gender, height, weight, bmi, operation type and method, pathology results and tumor stage of the patients were recorded. patients were divided into 3 groups according to body mass index (bmi): normal weight (< 25 kg/m2), overweight (25-30 kg/m2) and obese (> 30 kg/m2) as groups 1, 2 and 3, respectively. we analyzed the relation between the bmi, gender, smoking, hypertension, type and method of surgical treatment, histologic subtype, tumor stage, estimated glomerular filtration rate (egfr) and cancer-specific (css) and recurrence free survival (rfs). all data analysis was performed using spss® statistical software for windows (version 13.0) and a p value less than 0.05 was considered to be significant. results: the effect of bmi on both css and rfs was statistically significant (p < .001). there was also a significant relation between smoking, operation type (partial/radical), egfr and tumor stage and css and rfs. conclusion: our findings show that overweight and obese rcc patients according to the bmi have a more favorable prognosis. multicenter, prospective studies with more cases and longer oncological follow-up period are needed to support these findings. keywords: body mass index; prognosis; renal cell carcinoma; recurrence; survival. introduction renal cell carcinoma (rcc) accounts for 2-3 % of all cancers(1). the incidence of rcc increases around the world in the last decades and it has been reported that 20-40 % of patients will develop local recurrence or distant metastases after localized rcc treatment with partial or radical nephrectomy(2). rcc is a very heterogeneous and complex disease with a widely varying prognosis. in cases of kidney cancer, it is very important to be able to predict the prognosis and the response to selected treatments prior to disease management. however, some problems are anticipated in predicting the prognosis of rcc. the main causes of these are as follows; natural course of kidney cancer is highly complicated and significantly differs between the patients, many defined prognostic variables are present and these variables interact with each other. factors affecting prognosis of rcc are tumor-related (anatomical and histological features) and patient-related factors (clinical findings, symptoms, general health status, laboratory findings, and molecular factors). at present, the pathologic stage (pt), lymph node status (pn) and histologic grade of the tumor represent the most important prognostic variables. however, some other characteristics of the patient and the tumor have been shown to be associated with renal cancer outcomes. recently, several systems have been designed ege university school of medicine, urology department, izmir, turkey. *correspondence: department of urology, ege university school of medicine, izmir, turkey. tel: +90 532 5800685. fax: +90 232 3746552. e-mail: fuatkizilay@gmail.com. received july 2017 & accepted december 2017 by combining various prognostic factors to obtain a powerful and important prognostic model for rcc(3-5). many epidemiological studies have shown that obesity and family history are important risk factors for rcc(68). although obesity is a well-known risk factor for rcc, there are articles reporting that obesity improves or at least does not worsen the disease prognosis(9,10). in this study, we aimed to analyze the prognostic effect of body mass index (bmi) in our localized rcc cohort managed with surgical treatment. we also evaluated the effect of gender, smoking, hypertension, surgical treatment type and method, histologic tumor subtype, estimated glomerular filtration rate (egfr) and tumor stage on cancer-specific (css) and recurrence free survival (rfs). patients and methods patient selection the study was initiated after the local ethics committee approval. three hundred and eighty patients with localised, non-metastatic, unilateral renal cell carcinoma who underwent radical or partial nephrectomy in our clinic between january 2007 and december 2016 were enrolled in this retrospective study. these were consecutive cases and all of them were operated in the same clinic. patients with metastatic renal tumor who underwent radical nephrectomy (n = 14) and patients with biurological oncology 96 vol 15 no 03 may-june 2018 97 lateral renal tumor who underwent partial nephrectomy (n = 4) were excluded from the study. seventy-seven patients with papillary histology were excluded from the study since it may be hereditary. also, patients whose pathologic report revealed end-stage angiomyolipoma, oncocytoma and unclassified carcinoma were not included in the study (n = 8), 6 patients had missing data and 7 patients were lost to follow-up (figure 1). database and patient groups age, gender, height, weight, bmi, operation type and method, pathology results and tumor stage of the patients were recorded. tumor staging was established according to 2010 tumor, node, metastasis classification (11). the results of preoperative and postoperative laboratory examinations such as chest x-ray, abdominal ultrasonography, thorax and abdominal tomography, magnetic resonance imaging, brain tomography and bone scintigraphy were reviewed from patient files. the weight and height of the patients were recorded at the first visit. patients were divided into 3 groups according to bmi: normal weight (< 25 kg/m2), overweight (25-30 kg/m2) and obese (> 30 kg/m2) as groups 1, 2 and 3, respectively. the abbreviated modified diet and renal disease equation was used to measure egfr using the last serum creatinine before surgery(12). patients were classified as having a baseline egfr of above 60, between 45-60 and less than 45 ml/min per 1.73 m2. recurrences detected at the site of the surgery in patients who underwent radical nephrectomy and recurrences detected in the residue kidney in patients who underwent partial nephrectomy were accepted as local. in cases of partial nephrectomy, recurrences at different locations in the same kidney were also accepted as local. elsewhere in the body, masses that are associated with kidney tumors were considered as distant recurrences. all recurrences were detected by cross-sectional imaging in the postoperative follow-up period. patients were stratified according to the american society of anesthesiologists (asa) score. preoperative preparation before surgery, all patients underwent physical examination, routine blood and urine examinations, two-dimensional chest radiography, abdominal ultrasonography and tomography. preoperative imaging of the patients did not reveal any regional (retroperitoneal adenopathy) or distant metastasis. where necessary, diagnostic tests such as doppler ultrasonography, magnetic resonance imaging and bone scintigraphy were added. written, informed consent of the patients was obtained before surgery. all patients underwent detailed anesthesia examination before the operation. surgical treatment and follow-up patients underwent radical or partial nephrectomy with open or laparoscopic methods under general anesthesia. tumor size (4 cm) was typically the determining factor in the selection of partial or radical nephrectomy. however, this criterion was not strictly determinative, table 1. proposed surveillance schedule following treatment for rcc, taking into account patient risk profile and treatment efficacy. risk profile follow-upa 6 12 24 36 48 60 > 60 low us ct us ct us ct discharge intermediate ct ct ct us ct ct ct once every 2 years high ct ct ct ct ct ct ct once every 2 years a numbers indicate the month. ct: computed tomography of chest and abdomen, alternatively use mri; us: ultrasound of abdomen, kidneys and renal bed. figure 1. study flow chart arenal cell carcinoma, bbody mass index prognostic factors in rcc-ahmedov et al. and surgical decision was made according to factors such as surgeon preference and experience, tumor location, size and patient comorbidities. patients were divided into groups according to type and method of surgery, and the difference between survival rates was examined. the protocol recommended by the guidelines of the european urological association(13) was used to follow-up the patients (table 1). outcome measures our primary outcome measurement was the relation between the bmi and survival rates and our secondary outcome measurement was the relation between gender, smoking, hypertension, type and method of surgical treatment, histologic subtype, tumor stage and survival rates. we calculated the css ratios by calculating the percentage of patients who did not die from the rcc in the follow-up period. patients who died from causes other than the disease being studied are not counted in this measurement. the length of time after primary treatment for rcc ends that the patient survives without any signs or symptoms of cancer was calculated as rfs. statistical analysis the kolmogorov-smirnov test was used to determine whether the variables met the normal distribution. normal distribution-matching data were shown by mean and standard deviation while the non-matching data were shown by median and between the quarters. the student test was used to compare the variables and survival analysis was performed by univariate and multivariate cox proportional hazards model and kaplan-meier method. all data analysis was performed using spss® statistical software for windows (version 13.0). p value less than 0.05 was considered to be significant. results two hundred and forty-one (63.4 %) of the 380 patients were male and 139 (36.6 %) were female. the vast majority of patients (306, 80.5%) were in the asa i-ii group. sixty-two patients (16.3%) were in asa iii group and 12 patients (3.1%) were in asa iv group. the mean follow-up period of the patients was 62.28 ± 1.16 months (0-98). according to the follow-up protocol proposed in table 1, 72 patients were followed up at 6 months, 68 at 12 months, 62 at 24 months, 58 at 36 months, 51 at 48 months, 42 at 60 months and 27 at > 60 months. seven patients who did not comply with the protocol were excluded from the follow-up. when bmi table 2. patient and operation characteristics variables number (n) ratio (%) mean(±sd) sex male 241 63.4 female 139 36.6 age (year) male 61.6 ± 10.8 female 39.2 ± 12.3 bmia (kg / m2) 25.6 ± 2.9 height (cm) 162.8 body weight (kg) 75.4 smoking yes 191 50.2 amount (cigarettes/day) 1-10 55 10-20 61 > 20 75 duration (years) 1-10 60 11-20 92 no 189 49.8 hypertension yes 27 7.1 no 353 92.9 operation type partial nephrectomy 85 22.3 radical nephrectomy 295 77.7 operation method laparoscopy 74 19.4 open 306 80.6 egfrb < 45 88 23.1 45-60 143 37.6 > 60 149 39.3 tumor characteristics stage t1a 138 36.3 t1b 128 33.6 t2a 38 10.0 t2b 6 1.57 t3a 70 18.4 localization upper pole 115 30.2 middle pole 128 33.6 lower pole 122 32.1 hilar 15 3.94 side right 194 51.1 left 186 48.9 histological subtypes clear cell 316 83.1 chromophobe 59 15.5 mucinous tubular spindle cell 4 1.05 multilocular cystic 1 0.26 abody mass index bestimated glomerular filtration rate (ml/min per 1.73 m2) prognostic factors in rcc-ahmedov et al. urological oncology 98 vol 15 no 03 may-june 2018 99 and histologic subtype relation were examined, clear cell pathology was higher in the first group compared to the other two groups, but it was not statistically significant (p = .0822). the mean tumor size was 5.3 cm (iqr = 3.92). the mean follow-up period of the patients was 50.8 ± 18.1 months. surgical margin positivity was confirmed in 33 patients (8.68%). local or distant recurrence was observed in 82 of 380 patients (21.57%). the mean time to recurrence was 30.2 ± 21.4 months. eighty-two of the patients (21.57%) died in follow-up. the mean time to exitus was 29.6 ± 12.4 months. demographic and operation data and tumor characteristics are shown in table 2. cancer-specific survival the mean cancer-specific survival time of the patients after diagnosis was 73.5 ± 1.2 months. when the relation between bmi and survival time was analyzed, the mean survival time in group 1 was 58.6 ± 2.8 months, 82.5 ± 1.5 months in group 2 and 84.6 ± 1.4 months in group 3 (p < .001) (figure 2). the mean survival time was 64.6±2.4 months in smokers and 84.2 ± 1.2 months in non-smokers (p < .001). the number of cigarettes smoked per day and the duration of smoking also significantly affected survival rates (p < .001). mean survival time was 88.6 ± 1.1 months in patients undergoing partial nephrectomy and 73.7 ± 1.8 months in patients undergoing radical nephrectomy (p = .001). multilocular cystic and mucinous tubular spindle cell carcinoma tumors were excluded from the analysis due to low number of cases. mean survival time was 75.6 ± 2.0 months in patients with clear cell pathology and 82.2 ± 3.6 months in patients with chromophobe pathology (p = .442). a statistically significant difference was also observed between tumor stage and survival time (p < .001). we found that preoperative egfr significantly affected the css (p < .001). because tumor stage is a very important determinant of cancer-specific survival, css analysis according to the stage is shown in figure 3. recurrence-free survival the mean recurrence-free survival time of the patients was 74.8 ± 1.8 months. when the relation between bmi and recurrence-free survival was examined, the mean recurrence-free survival time was 58.2 ± 3.4 months in group 1, 77.3 ± 2.5 months in group 2 and 82.8±1.9 months in group 3 (p < .001) (figure 4). mean recurrence-free survival time was 69.8 ± 2.6 months in smokers and 89.6 ± 1.8 months in non-smokers (p = .001). the number of cigarettes smoked and the smoking duration significantly affected rfs (p < .001). the mean recurrence-free survival time was 88.4 ± 1.3 months in patients undergoing partial nephrectomy and 68.4 ± 2.2 months in patients undergoing radical nephrectomy (p table 3. effects of patient and tumor characteristics on survival. variables number (n) number of number of mean cancer-specific mean recurrence-free 95% cia 95% cib p valuea p valueb deaths (n) recurrences (n) survival (month) survival (month) local distant bmic groups 1 126 48 32 10 58.6 58.2 51.8–66.9 51.6–67.8 < 001 < 001 2 135 11 11 6 82.5 77.3 80.1–88.2 72.3–83.6 3 119 7 7 2 84.6 82.8 82.1–89.7 79.6–89.7 sex male 241 41 22 16 74.7 72.9 71.8–81.4 68.6–78.8 0.540 0.648 female 139 25 22 8 74.2 73.8 70.2–81.3 67.8–80.4 smoking yes 191 49 31 13 64.6 69.8 62.1-74.0 61.2-73.4 amount (cigarettes/ day) 1-10 72 8 5 2 78.3 74.3 68.2-78.5 10-20 61 13 7 4 62.8 64.2 71.5-80.5 60.4-68.9 > 20 58 28 20 6 44.6 52.2 57.8-64.1 48.4-56.8 < 001 < 001 duration (years) 121 15 8 5 67.5 70.2 65.2-70.6 65.5-74.1 1-10 70 34 22 9 42.2 62.1 39.2-46.4 58.2-65.4 11-20 no 189 17 17 7 84.2 89.6 80.1–88.2 78.7–91.8 hypertension yes 27 12 23 8 62.6 56.2 56.7–71.6 49.6–64.4 0.488 0.089 no 353 54 22 15 74.4 74.6 72.7–81.4 70.8–79.2 operation type partial 85 8 6 3 88.6 88.4 83.1–91.6 82.8–91.6 < 001 < 001 radical 295 58 44 15 73.7 68.4 67.2–77.1 63.5–72.2 operation method open 306 38 24 9 76.7 75.2 72.1–81.3 70.7–79.5 0.720 0.680 laparoscopic 74 28 23 12 76.1 76.8 69.2–81.9 68.3–82.8 histological clear cell 316 42 24 7 75.6 74.7 71.1–79.8 69.8–78.8 0.442 0.584 subtypes chromophobe 59 24 23 14 82.2 79.6 76.7–92.6 73.8–92.1 stage t1a 138 3 5 2 88.1 87.9 82.2–90.2 83.4–90.6 < 001 < 001 t1b 128 8 6 3 77.8 76.4 71.8–82.5 71.8–82.2 t2a 38 12 8 3 71.3 71.6 66.5–80.1 69.1–81.3 t2b 6 16 10 5 58.5 56.4 48.9–66.6 46.1–62.8 t3a 70 27 18 8 48.9 46.1 42.8–63.6 38.4–54.3 egfrd < 45 88 37 25 7 45.8 52.9 38.8-48.1 50.8-54.3 < 001 < 001 45-60 143 23 17 5 59.6 61.8 52.2-61.4 59.7-63.3 > 60 149 6 11 3 82.1 84.3 78.3-86.8 82.8-86.5 aconfidence interval and p values for cancer-specific survival bconfidence interval and p values for recurrence-free survival cbody mass index destimated glomerular filtration rate (ml/min per 1.73 m2) prognostic factors in rcc-ahmedov et al. < .001). there was a statistically significant negative association between tumor stage and recurrence free survival (p < .001). preoperative egfr significantly affects rfs similarly to css (p < .001). the relation between patient and tumor characteristics and css and rfs is shown in table 3. univariate and multivariate analyzes indicating the relationship of variables with survival are presented in table 4. discussion nowadays, obesity is a very important public health problem and it is reported that in the united states more than one-third of adults and 17 % of youth are obese (14). obesity is indicated to be an important risk factor for sporadic rcc in the european urological association (eau) guideline and the risk of rcc is reported to be 3.6 times more in obese patients compared with the general population(15). as already mentioned, the incidence of rcc is increasing every year worldwide. it is quite significant that this incidence shows parallelism with the increase in the incidence of obesity. several community-based case-controlled epidemiological and clinical, prospective studies have been conducted to establish the relationship between obesity and renal cancer. many epidemiological studies have addressed the relationship between obesity and renal cancer. the upregulation of leptin and downregulation of adiponectin pathways has largely explained the pathogenesis of rcc(16). obese people have more health problems than normal weight people, so they are subjected to more frequent health controls and this may be the reason of more frequent occurrence of incidental masses. however, in our study, such information is not available. also, filling the questionnaires by the patients and in case of patients’ tending to report lower body weighs in some studies and some methodological differences such as the use of waist circumference or hip circumference parameters instead of body mass index in some other studies have resulted in different outcomes reporting different risk ratios and suggesting that obesity is only a risk factor for women and even that obesity is not a risk factor for kidney cancer. however, outcomes of the studies conducted by the european prospective investigation into cancer and nutrition research group (epic) on about 350.000 europeans have shown that obesity is an important risk factor for rcc (6). in this study, it was reported that while all of the parameters used for obesity evaluation in women (such as bmi, body weight, waist circumference, waist circumference) increased the risk of kidney cancer, only the hip circumference as a risk factor in men was reported to have a predictive value. many hypotheses have been proposed to explain why obesity is a risk factor for rcc cases. scacchi et al showed high serum concentrations of free insulin-like growth factor-i in obese patients(17). this factor affects cell cycle and is an important mutagenic factor associated with many cancers, including breast, prostate, lung and colorectal. it is stated that obesity may increase figure 2. kaplan-meier analysis of the cancer-specific survival of individuals in terms of body mass index. figure 3. kaplan-meier analysis of the cancer-specific survival of individuals in terms of tumor stage. figure 4. kaplan-meier analysis of the recurence-free survival of individuals in terms of body mass index. prognostic factors in rcc-ahmedov et al. urological oncology 100 vol 15 no 03 may-june 2018 101 rcc risk by raising serum concentrations of free estrogens in animal studies(18). recently, it has been suggested that lipid peroxidation is a partially responsible mechanism for increased rcc risk in obese and hypertensive patients(19). these data suggest that increased bmi may also cause poor prognosis in rcc cases. but the results of the studies are far from supporting this assumption. donat et al. retrospectively reviewed the data of 1137 rcc patients and reported that although an increased bmi was associated with a greater proportion of clear cell histology, comorbidity, and surgical morbidity, bmi did not adversely impact overall or progression-free survival(9). reeves et al.(20) followed up 1.2 million women on avarage for 5.4 years for cancer incidence and 7.0 years for cancer mortality. they found that increasing body mass index was associated with an increased incidence of kidney cancer in addition to many other cancers (trend in relative risk per 10 units=1.53, 95% confidence interval 1.27 to 1.84) and concluded that increasing body mass index is associated with a significant increase in the risk of cancer for 10 out of 17 specific types examined. kamat et al.(10) reviewed the records of 400 patients who underwent nephrectomy for localized rcc. their findings revealed that overweight and obese patients with renal cell carcinoma have a more favorable prognosis than patients with a normal bmi and they concluded that if others confirm their finding that a high bmi confers a survival advantage to patients undergoing nephrectomy, bmi may prove to be an important prognostic factor in renal cell carcinoma. we also found that a high bmi score leads to better prognosis in rcc patients in our study, similar to the results of kamat et al. in a large cohort study conducted in korea, the data of 1017 patients were retrospectively reviewed. after a mean follow-up of 76.9 months, the authors found that overweight and obese patients had less aggressive tumors, such as less lymph node and/or distant metastases, low pathological t stage and low fuhrman grade vs normal weight patients. in terms of cancer specific survival and overall survival multivariate analysis showed that overweight and obese patients had good survival rates compared to those with a body mass index in the normal range in the cohort (t1-4nallmall) groups. in addition, overweight and obese status was significantly associated with cancer specific and overall survival in the t14n0m0 groups. they concluded that overweight and obese korean patients with rcc have more favorable pathological features and a better prognosis than those with a normal bmi(21). similar results were obtained with the above studies in our study. we found that cancer-specific survival and recurrence-free survival were better in the overweight and obese patient group than prognostic factors in rcc-ahmedov et al. table 4. univariate and multivariate analysis model for overall survival. variables univariate multivariatec hra 95% cib p value hra 95% cib bmid group 1 1.28 (0.88-1.32) 0.004 1.34 (1.02-1.42) group 2 1.09 (0.92-1.22) 0.028 1.21 (0.96-1.39) group 3 0.92 (0.82-1.14) 0.036 1.22 (1.06-1.38) sex male 1.06 (0.89-1.21) 0.584 female 1.02 (0.91-1.21) 0.480 smoking yes 1.36 (1.21-1.58) 0.043 1.44 (1.22-1.56) amount (cigarettes/day) 1-10 1.17 (0.88-1.21) 0.038 1.28 (1.19-1.32) 10-20 1.23 (1.15-1.32) 0.026 1.33 (1.26-1.42) > 20 1.38 (1.24-1.43) 0.018 1.45 (1.39-1.56) duration (years) 1-10 1.19 (1.11-1.25) 0.021 1.24 (1.18-1.31) 11-20 1.24 (1.17-1.41) 0.017 1.35 (1.22-1.43) no 1.08 (1.03-1.22) 0.022 1.19 (1.09-1.24) hypertension yes 1.02 (0.89-1.14) 0.086 no 1 operation type partial 1.68 (1.56-1.72) 0.004 1.72 (1.62-1.79) radical 2.13 (1.99-2.24) 0.023 2.34 (2.18-2.44) operation method open 1.04 (0.96-1.12) 0.880 laparoscopic 1.08 (0.99-1.19) 0.420 histological subtypes clear cell 1.14 (0.99-1.21) 0.560 chromophobe 1.09 (1.03-1.14) 0.226 stage t1a 1.17 (1.08-1.22) 0.004 1.22 (1.18-1.33) t1b 1.39 (1.15-1.48) 0.021 1.49 (1.36-1.55) t2a 1.69 (1.58-1.79) 0.019 1.75 (1.68-1.84) t2b 1.98 (1.84-2.21) 0.024 2.28 (2.12-2.88) t3a 2.23 (2.12-2.46) 0.038 2.49 (2.31-2.65) egfr < 45 2.16 (1.89-2.32) 0.012 2.38 (2.21-2.49) 45-60 1.86 (1.74-1.99) 0.005 2.04 (1.92-2.32) > 60 1.62 (1.54-1.78) 0.049 1.92 (1.82-2.18) a hazard ratio b confidence interval c multivariate analysis included variables that were significant (p < 0.05) in univariate analysis in the normal group, but we did not find any significant difference between the genders. however this study allows us to obtain important information on the impact of bmi on the prognosis of rcc, it has several limitations. first of all, this study is a retrospective analysis of data collected from a single center; hence the number of cases is relatively small and limited to calculate the general population. in addition, the loss of body weight and preoperative nutritional status are also reported to be significant prognostic factors for rcc(22), but our study did not include these. smoking is also considered as an important risk factor for rcc. several cancerous substances found in cigarettes cause cancers with different relative risk ratios in many other organs and increase the risk of developing rcc by 1.4-2.3 times(23). the risk of developing kidney cancer is directly related to the number of cigarettes consumed per day and the duration of use. smoking cessation decreases the risk of developing cancer and then this reduction rate reaches 30% in 10 years. in our study, we also found that the survival of smokers was lower than non-smokers. the mean age of women in our study was significantly lower than that of men (38.3 vs 60.7). the birth rate in our country is quite high (2.3 4.2%)(24). accordingly, women are frequently exposed to physician control at a young age and are consulted to urologists with renal masses that the obstetricians identify incidentally at the ultrasound. we consider that the age difference mainly depends on this. we stratified the patients according to asa groups as it could affect survival rates. we consider that the asa score did not affect the survival rates because the vast majority of the patients (80.5%) were in low-risk group (asa i-ii). although preliminary reports of hypertension and diuretic use indicate different risk factors for kidney cancer, recent studies have shown that only hypertension is a risk factor and diuretics are not a risk factor(25). in our study, there was no statistically significant difference between the two groups, although hypertensive patients had less mean survival time than those without hypertension. as for surgical treatment, death and recurrence were observed in 5 patients after partial nephrectomy in our study. we found that survival rate was better in cases underwent partial nephrectomy than those underwent radical nephrectomy. we think that this is due to the larger tumor size of patients who underwent radical nephrectomy. for this reason, the number of deaths and recurrences was higher in radical nephrectomy group. decreased renal function in rcc patients is a common finding. it has been shown that low egfr affects overall survival in patients undergoing surgery for rcc and nephron sparing surgery is recommended in these patients(26). similarly, we found that the low egfr level significantly reduced css and rfs in our study. lymph node involvement may be predicted by preoperative radiologic imaging and some predictive models(27). in our clinic, we perform lymph node dissection (lnd) in rcc patients who have lymph node enlargement in preoperative imaging and peroperative suspicious lymph node involvement. however, we did not include the lnd effect in this analysis because the data of these patients are incomplete and we do not have a standard protocol. nowadays, in the treatment of renal tumors, laparoprognostic factors in rcc-ahmedov et al. scopic radical nephrectomy and partial nephrectomy operations can be successfully performed with both transperitoneal and retroperitoneal approaches. when the eau guidelines were analyzed, it has been stated that the laparoscopic approach resulted in lower morbidity, equivalent oncologic outcomes in t1-2 tumors in experienced hands, and possibly equivalent oncologic outcomes in t3a tumors (grade of evidence: 3). laparoscopic radical nephrectomy is recommended as a treatment option in experienced centers (recommendation level: b). there was no significant difference in survival rates after open and laparoscopic surgery in our study. based on this result, we concluded that laparoscopic method can be utilized as a standard approach in the treatment of kidney tumors. rcc is known as a heterogeneous malignancy with different clinical and pathological subgroups. papillary and chromophobe rccs constitute approximately 1525 % of total renal cancers and have a better prognosis than the clear cell rcc group(28,29). in our study, no statistically significant difference was found between histologic subtypes in terms of survival. tumor stage is the most important factor determining rcc prognosis(30). tumor stage was also an important prognostic factor in our study. css and rfs decreased as tumor stage increased. conclusions bmi was significantly associated with prognosis in patients with rcc. our findings indicate that overweight and obese rcc cases, which are determined by bmi, have a more favorable prognosis. however, our findings need to be supported by multicentre, prospective studies including more number of patient groups and longer oncologic follow-up period. acknowledgement this study was approved by ege university local ethics committee. conflict of interest the 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11. sobin l, gospodarowicz m. wittekind ch. eds. tnm classification of malignant tumors: wiley-blackwell, oxford; 2009. 12. levey as, bosch jp, lewis jb, greene t, rogers n, roth d. a more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. ann intern med. 1999; 130: 461-70. 13. ljungberg b, bensalah k, canfield s, et al. eau guidelines on renal cell carcinoma: 2014 update. eur urol. 2015; 67: 913-24. 14. ogden cl, carroll md, kit bk, flegal km. prevalence of childhood and adult obesity in the united states, 2011-2012. jama. 2014; 311: 806-14. 15. bergström a, hsieh c, lindblad p, lu c, cook n, wolk a. obesity and renal cell cancer–a quantitative review. br j cancer. 2001; 85: 984. 16. drabkin ha, gemmill rm. obesity, cholesterol, and clear-cell renal cell carcinoma (rcc). adv cancer res. 2010; 107: 39-56. 17. scacchi m, pincelli a, cavagnini f. growth hormone in obesity. int j obes. 1999; 23: 26071. 18. hodgson av, ayala-torres s, 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radiotherapy: springer; 2014: 241-9. 24. sahin h, sahin h. reasons for not using family planning methods in eastern turkey. the european journal of contraception & reproductive health care. 2003; 8: 11-6. 25. shapiro ja, williams ma, weiss ns, stergachis a, lacroix az, barlow we. hypertension, antihypertensive medication use, and risk of renal cell carcinoma. am j epidemiol. 1999; 149: 521-30. 26. pettus ja, jang tl, thompson rh, yossepowitch o, kagiwada m, russo p. effect of baseline glomerular filtration rate on survival in patients undergoing partial or radical nephrectomy for renal cortical tumors. paper presented at: mayo clinic proceedings, 2008. 27. thompson rh, raj gv, leibovich bc, russo p, blute ml, kattan mw. preoperative nomogram to predict positive lymph nodes during nephrectomy for renal cell carcinoma. j. urol. 2008; 179:212. 28. moch h, gasser t, amin mb, torhorst j, sauter g, mihatsch mj. prognostic utility of the recently recommended histologic classification and revised tnm staging system of renal cell carcinoma. cancer. 2000; 89: 604-14. 29. beck sd, patel mi, snyder me, et al. effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. ann surg oncol. 2004; 11: 71-7. 30. brierley jd. tnm classification of malignant tumours: john wiley & sons; 2017. miscellaneous effect of unilateral iatrogenic testicular torsion on the contralateral testis in rats: prepubertal and postpubertal hassan ahmadnia1, mahmoud dolati1, alireza ghanadi1, mehdi younesirostami2, alirezaakhavan rezayat3* purpose: the present study was conducted to investigate the influence of hemicastration and age at hemicastration on the contralateral testis weight and function/testosterone production. materials and methods: 64 wistar-derived male rats were divided randomly into 4 groups. group 1 was named immature intervention, group 2 immaturecontrol, group 3 mature intervention, and group 4mature control. in group 1, rats were hemicastrated at 30 days of age (prepubertal). in group 2, sham surgery (midscrotal incision) was performed atthe same age. in group 3, rats were hemicastrated at 70 days of age (postpubertal) and in group 4,sham surgery was done at the same age. twenty days after the first surgery, contralateral orchiectomy wasperformed in intervention groups and controls underwent random orchiectomy (left or right). blood sampling for evaluation of serum testosterone was performed just before second surgery. results:the mean testis weight (1692 ± 26.7 in group 1 versus 1375 ± 39.7 in group 2; p < .001 and 1760 ± 26.6 in group 3 versus 1425 ± 44.9 in group 4; p < .001) and the mean testicular weight (mg) per 100 g of body weight (735.8 ± 82.3 in group 1 versus 634.8 ± 84.8 in group 2; p = .005 and 652.4 ± 61.4 in group 3 versus 572.6 ± 97.7 in group 4; p = .03) were significantly greater in hemicastrated rats as to their controls. also, these parameters was greater in prepubertal group than postpubertalhemicastrated rats. there was no appreciable difference in serum testosterone levels across the 4 groups (p = .77). conclusion: our research demonstrated that hemicastration results in compensatory hypertrophy of the remaining testis and it decreases as the animals age. hemicastration does not lead to reduction in serum testosterone levels and the remaining testis can retrieve a normal serum testosterone level. keywords: compensatory hypertrophy; iatrogenic testicular torsion; rat; testis; unilateral orchiectomy introduction in paired organs, the removal of or injury to one organ may result in compensatory hypertrophy of the remaining organ. this phenomenon has previously been proved in the kidneys, thyroid glands, and ovaries(1-3). the time of unilateral testis removal (prior to and following puberty) due to undescended testis (udt), trauma, and testicular abscess affects the amount of compensatory hypertrophy. that is, compensatory hypertrophy of the testis occurs more frequently before puberty. torsion of the spermatic cord is associated with restriction and interruption of testicular blood flow. anatomical abnormalities (the bell-clapper deformity caused by lack of normal attachment of the epididymis to the tunica vaginalis which leads to incomplete fixation of the testis and the epididymis to the scrotum or abnormally high attachment of the testis to the epididymis), cold weather, sudden movements or trauma which activate the cremasteric reflex, and rapid growth of the testis throughout puberty make individuals prone to this medical condition. the symptoms of testicular torsion include a sudden and intense scrotal 1mashhad university of medical sciences, mashhad,iran. 2department of urology, , mazandaran university of medical sciences, sari,iran. 3kidney transplantation complications research center, mashhad university of medical sciences, mashhad,iran. *correspondence: kidney transplantation complications research center, mashhad university of medical sciences, mashhad,iran. tel: +98 9153148223. fax : +98 5138436199. e-mail: alirezaakhavan30@yahoo.com. received november 2017 & accepted june 2018 pain which has started within the last six hours, vomiting, nausea, scrotal edema and erythema, fever as well as dysuria. on physical examination, tenderness of the scrotum, absence of cremasteric reflex, a higher testicular position, abnormal position of the epididymis on the anterior, thickening of the spermatic cord, testicular induration, loss of the grooves between the testis and the epididymis along with scrotal edema and erythema might also be observed(4,5). in order to diagnose testis torsion, radionuclide scanning, color doppler ultrasound (cdus), and high resolution ultrasound (hrus) can be used(6-8). the presence of sexual findings is an indication for surgical exploration with detorsion and fixation as the treatment of choice(9-11). the prognosis and long-term outcomes of torsion are unknown. nevertheless, considering the recent studies it is indicated that ischemic injury is likely to occur quickly, even if the testis appears viable during detorsion(11,12). as testicular development in humans is akin to rats, it is assumed that the use of an experimental model in rats provides beneficial evidence for further research on the morphology and histology of the testis(13). in the present study, comurology journal/vol 16 no. 5/ september-october 2019/ pp. 501-505. [doi: 10.22037/uj.v0i0.4289] pensatory hypertrophy caused by iatrogenic torsion of the testis on the contralateral side is investigated in an experimental rat model prior to and following puberty and then compared with the control group. materials and methods study population in this investigation, the effect of iatrogenic torsion (in order to do a unilateral functional orchiectomy, but not surgical orchiectomy) was explored in the contralateral testis of either mature or immature rats. a total of 64 male wistar rats with 20 days of age and an average weight of 60 ± 8 gr were purchased from an animal library in mashhad university of medical sciences. the experimental room was automatically air-conditioned once each 3 minutes and maintained in the standard temperature of 20-22 °c (sd: ± 2 °c),a humidity of 55%, and an 12 hour day-night cycle. the rats spent one week for quarantine and acclimation in the room before the start of the experiment. they were subsequently assigned into four groups (n = 16) at random. study design and procedures group 1: after weighing, the immature rats in the first group underwent a unilateral iatrogenic torsion in 30 days of age. either a right or left iatrogenic torsion was conducted randomly. after 20 days (at 50 days of age), their testis and body weight was measured again and general anesthesia was induced before collecting a supraorbital blood sample from the cavernous sinus to determine the plasma testosterone. thereafter, the remaining testis was also removed and weighed(14)using a high-precision balance (readable to the nearest 0.0001 g). group 2: this group served as control immature rats. they were weighed on the 30th day and underwent sham surgery with scrotal incision on their skin after general anesthesia. blood samples were obtained from the same vein and unilateral orchiectomy were carried out randomly before the second weight measurement of the testes. group 3: akin to group 1, all mature rats in this group underwent a unilateral iatrogenic torsion on the 10th week. on the 90th day, they were weighed and underwent general anesthesia, blood sampling, as well as contralateral orchiectomy. in the long run, the weight of the testis was evaluated. group 4: at the same time as group 3, mature rats in this group were treated with sham operation. a right (n = 8) or left (n = 6) orchiectomy was randomly performed after 20 days of sham surgery and weight of the testes was measured thereafter. an elisa assay was used to determine the plasma level of testosterone by a commercially available testosterone rat/mouse elisa kit. this study was approved by mashhad university of medical sciences ethics committee and investigators had been certified to study on laboratory animals. surgical technique all rats underwent general anesthesia before surgery. after making a unilateral incision on the scrotum, iatrogenic torsion was performed and the testis was subsequently fixed by 4-0 nylon thread sutures in order to prevent detorsion. incisions were sutured finally. we performed unilateral iatrogenic torsion to induce unilateral functional orchiectomy without any surgical orchiectomy intervention in the first step. surgical orchiectomies were only carried out in the last step in order to weigh the testes. both of the control groups underwent sham surgery with scrotal incision on their skin after general anesthesia and then incisions were closed by sutures. statistical analysis the data was collected and entered into spss (version 11.5, ibm, chicago, il, usa). the concentration of serum testosterone was compared among groups by analysis of variance (anova) and independent sample t-test. a p-value of less than .05 was considered significant. results in this study, rats were randomly divided into four groups, mature and immature ones underwent unilateral iatrogenic torsion in addition to their corresponding controls. during the study period, two rats from group combined of thulium laser and bipolar in prostatectomy-huang et al. table 1. comparison of body weights across groups before the intervention. group mean weight (sd), g minimum weight, g maximum weight, g p-value g1 (n = 15) 151 (7.3) 140 165 .94a g2 (n = 16) 149 (13.1) 117 165 g3 (n = 16) 231 (12.3) 208 259 .34b g4 (n = 15) 224 (13.1) 195 241 abbreviations: g: group; m: mean; sd: standard deviation, g: gram. a: presents the comparison of body weights before the intervention between group1 and group 2 b: presents the comparison of body weights before the intervention between group3 and group 4 group mean weight (sd), g minimum weight, g maximum weight, g p-value g1 (n = 15) 231 (19.4) 194 263 .17a g2 (n = 16) 217 (15.2) 191 248 g3 (n = 16) 271 (17.5) 248 310 .02b g4 (n = 15) 250 (22.2) 203 285 abbreviations: g: group; m: mean; sd: standard deviation, g: gram. a: presents the comparison of body weights after the intervention between group1 and group 2 b: presents the comparison of body weights after the intervention between group3 and group 4 table 2. comparison of body weights a across groups after the intervention. miscellaneus 502 vol 16 no 04 september-october 2019 503 1 and 4 died, thus 62 were included in the final analysis. table 1 and table 2 show the mean body weight of the study groups prior to and following intervention. there was no remarkable difference across the groups before intervention (p > .05)(table 1). it was revealed that a unilateral iatrogenic torsion did not have any impact on body growth and rats’ weight at prepubertal age (p = .17). on the contrary, performing this surgery following puberty was found to significantly accelerate body growth and increase rats’ weight from 250 ± 22.2 g in group 4 to 271 ± 17.5 g in group 3 (p =.02). moreover, the weight of the contralateral testis was remarkably higher in group 3 compared with group 1 (1760 (26.6)mg vs.1692( 26.7) mg; p < .001), and group 4 was also higher than group 2 (1425 (44.9) mg vs.1375 (39.7) mg; p < .001). therefore, it could be concluded that unilateral iatrogenic torsion possibly causes hypertrophy in the contralateral testis and is associated with a higher degree of compensatory hypertrophy at postpubertal age (table 2& table 3). a significant difference was observed in the mean weight of the remaining testis in group 1when compared to group 2 (1692 ± 26.7 vs. 1375 ± 39.7; p < .001). a similar increase was evident in groups 3 and 4 (from 1425 ± 44.9 mg to 1760 ± 26.6 mg; p < .001). pairwise comparisons between groups 1 and 3, as well as groups 2 and 4 indicated no statistically significant difference (p = 0.52 and p = 0.75, respectively). as the weight of the testis is contingent on the body weight of the animal, the ratio of testis weight (mg) to total body weight was measured in each rat in order to minimize any possible errors in estimating compensatory hypertrophy of the remaining testis. this ratio was defined as the mean testis weight (mg) per 100 gram of body weight. table 4 summarizes the results of this analysis. as shown, groups 1 and 3 presented with a notably higher ratio than their corresponding controls (p < .05). furthermore, this ratio was significantly higher in group 1 compared to group 3; p =.02), however, the other two groups demonstrated comparable ratios (p = .15). additionally, the plasma testosterone levels were statistically shown to be alike across the study groups (p =.77) (table 5). thus, unilateral iatrogenic torsion and the time of which it is induced does not seem to have an effect on the level of testosterone as evident by the remaining testis being able to compensate for desirable testosterone levels. discussion the removal of or injury to one pair of a paired organ may result in compensatory hypertrophy of the remaining organ. this phenomenon has been previously proved in the kidneys, thyroid glands, and ovaries(2,3,15). removal of unilateral testis due to undescended testis (udt), trauma, and testicular abscess causes great difficulties in future. it is hypothesized that the unilateral testis removal ends up in compensatory hypertrophy of the contralateral testis. however, this occurs under normal circumstances when the testis is palpable in the usual position(3). on the other hand, testicular removal prior to and following puberty is influential on the degree of compensatory hypertrophy. if the testis is removed at prepubertal age, more compensatory hypertrophy occurs than after puberty(16).orchiectomy is recommended for prepubertal patients who are afflicted with udt, torsion, and testicular trauma and whose probability of testicular loss is high. nowadays, some surgeons, in spite of testicular loss, still insist on retaining the appearance of the testes. the removal of an injured testis which has lost its viability and spermatogenesis is more likely to increase fsh and then cause compensatory hypertrophy of the contralateral testis(17,18). furthermore, contralateral testicular injury on affinity of anti-sperm antibody may induce damage to the healthy testis and cause hypofertility in future(12,17). as testicular development in humans is akin to rats, it is assumed that the use of an experimental rat model provides beneficial evidence for further research on the morphology and histology of the testis. considering the results of the present study it is concluded that a unilateral functional orchiectomy at postpubertal age leads to an increase in body growth, which is corroborated by putra et al.(19) also, a unilateral functional orchiectomy came up with compensatory hypertrophy of the combined of thulium laser and bipolar in prostatectomy-huang et al. table 3. comparison of the contralateral testis weight ofthe rats after the intervention. group mean weight ( sd), mg minimum weight, mg maximum weight, mg p-value g1 (n = 15) 1692( 26.7) 1540 1860 < .001a g2 (n = 16) 1375 (39.7) 1060 1650 g3 (n = 16) 1760 (26.6) 1540 1900 < .001b g4 (n = 15) 1425 (44.9) 980 1680 abbreviations: g: group; m: dean; sd: standard deviation, mg: milligram. a: presents the comparison of the remaining testis weightafter the intervention between group1 and group 2 b: presents the comparison of the remaining testis weightafter the intervention between group3 and group 4 group mean testis weight minimum testis weight (mg) / maximum testis weight (mg) / p-value (mg)/100g ofbody weight (sd) 100g of body weight 100g of body weight g1 (n = 15) 735.8(82.3) 618.5 853.7 .005a g2 (n = 16) 634.8(84.8) 495.3 774.5 g3 (n = 16) 652.4(61.4) 496.8 746.0 .03b g4 (n = 15) 572.6(97.7) 343.9 704.4 abbreviations: g: group; m: mean; sd: standard deviation a: presents the comparison of the ratio of the remaining testis weight (mg) per 100g of body weight between group 1 and group 2 b: presents the comparison of the ratio of the remaining testis weight (mg) per 100g of body weight between group 3 and group 4 table 4. comparison of the contralateraltestis weight (mg)per 100g ofbody weight after the intervention. contralateral testis, which is in agreement with putra, lin, simorangkir, and sanefuji’s findings yet contradicts romero’s findings(3,17,19,20,21.22,23).having a unilateral functional orchiectomy prior to puberty is associated with more compensatory hypertrophy in the contralateral testis. this is supported by putra, furuya, cunningham, and tusti where as some researchers have reported the opposite effect(19,24,25-28). besides, in this study, a unilateral functional orchiectomy was not correlated to the plasma level of testosterone, with the remaining testis being able to compensate for diminished testosterone concentrations. in spite of ahmadi’s results, this is confirmed by furuye et al.(25,29) it has been reported that the size of the testis is directly related to the amount of spermatogenesis. given the occurrence of compensatory hypertrophy in the contralateral testis, it would be expected that normal spermatogenesis and fertility can be preserved(21). there were some limitations to our study including absence of histopathologic study, and fertility status assessment. also there was no evaluation of testis weight before the intervention. compensatory hypertrophy could be the consequence of multiple factors including unilateral torsion and we did not assess the role of other possible factors. conclusions our research demonstrated that hemicastration results in compensatory hypertrophy of the remaining testis and the degree of compensation is inversely associated with the age of rats (prepubertal or postpubertal). hemicastration did not lead to reduction in serum testosterone levels and the remaining testis retrieved a normal serum testosterone level. it is recommended that future studies investigate histopathologic changes, fertility status and also other possible factors which could lead to compensatory hypertrophy of the contralateral testis. this study paved the way for further research on larger animals such as dogs, cats, rabbits, and goats. acknowledgment we are thankful of the research council of mashhad university of medical science for their financial support. conflict of interest the authors report no conflict of interest. references 1. gibadulin r. compensatory hypertrophy of the thyroid gland. bullexper biolmed. 1963;54:790-3. 2. khan z, gada rp, tabbaa zm, et al. unilateral oophorectomy results in compensatory follicular recruitment in the remaining ovary at time of ovarian stimulation for in vitro fertilization. fertilsteril. 2014;101:722-7. 3. grinspon rp, habib c, bedecarrás p, et al. compensatory function of the remaining testis is dissociated in boys and adolescents with monorchidism. eurj endocrinol. 2016;174:399-407. 4. howe as, palmer ls. testis torsion: recent lessons. canj urol. 2016;23:8602. 5. boettcher m, bergholz r, krebs tf, et al. differentiation of epididymitis and appendix testis torsion by clinical and ultrasound signs in children. urology. 2013;82:899-904. 6. hartman c, samson p, palmerola r, et al. mp43-13 heterogeneity on testicular ultrasound differs between normal and torsed testes in pediatric patients. j urol. 2016;195:e583-4. 7. güneş m, umul m, çelik ao, et al. a novel approach for manual de-torsion of an atypical (outward) testicular torsion with bedside doppler ultrasonography guidance. can urol assoc j. 2015;9:e676. 8. lubner mg, simard ml, peterson cm, et al. emergent and nonemergent nonbowel torsion: spectrum of imaging and clinical findings. radiographics. 2013;33:155-73. 9. bermejo ce, lucas jj. surgical management of testicular torsion. advanced surgical techniques for rural surgeons. new york: springer; 2015. p. 247-9. 10. gajbhiye as, shamkuwar a, surana k, et al. surgical management of testicular torsion. int surg j. 2016;3:195-200. 11. chauhan k, bown g, davies bw, et al. successful outcome in perinatal intravaginal torsion of testis in neonate: long-term outcome. int jclin pediatr. 2016;5:38-40. 12. lin ww, kim ed, quesada et,et al. unilateral testicular injury from external trauma: evaluation of semen quality and endocrine parameters. jurol. 1998;159:841-3. 13. picut ca, remick ak, de rijk ep, et al. postnatal development of the testis in the rat i. morphologic study and ii. correlation of morphology to neuroendocrine parameters. toxicolpathol. 2015;43(3):326-420. 14. shadpour p, kashi a, arvin a. scrotal testis size in unilateral non-palpable cryptorchidism, combined of thulium laser and bipolar in prostatectomy-huang et al. table 5. comparison of the serum level of testosterone (ng/ml)across groups after the intervention. group mean serum level (sd) minimum serum level maximum serum level p-value g1 (n = 15) 3.5 (1.9) 1.0 7.2 .77 g2 (n = 16) 3.4 (2.4) 0.8 9.5 g3 (n = 16) 3.1(1.9) 0.7 7.2 g4 (n = 15) 3.9 (2.4) 0.6 9.5 abbreviations: g: group; m: mean; sd: standard deviation miscellaneus 504 vol 16 no 04 september-october 2019 505 what it can and cannot tell: study of a middle eastern population. jpediatr urol. 2017;13:268.e1-6. 15. shellabarger cj. compensatory hypertrophy of the thyroid gland, adrenal gland and the gonad studied singly or in combination. endocrinology. 1963;73:124-6. 16. yao q, ye z, wang x, et al. experimental study of contralateral testicular changes after unilateral testicular torsion in rats. zhonghua nan ke xue. 2003;9:586-8. 17. simorangkir d, de kretser d, wreford n. increased numbers of sertoli and germ cells in adult rat testes induced by synergistic action of transient neonatal hypothyroidism and neonatal hemicastration. jreprodfertil. 1995;104:207-13. 18. simorangkir dr, wreford ns, kretser dm. impaired germ cell development in the testes of immature rats with neonatal hypothyroidism. jandrol. 1997;18:186-93. 19. putra d, blackshaw a. morphometric studies of compensatory testicular hypertrophy in the rat after hemicastration. austj biol sci. 1982;35:287-94. 20. lin t, li x, wei g, et al. hemodynamic and histological effects of unilateral testicular torsion on the contralateral testis in immature rats. zhonghua nan ke xue. 2008;14:815-8. 21. sulaiman i, mabrouk m, adamu l, et al. sexual behavior and fertility of male rats following subacute hemi-orchidectomy. int j biosci. 2015;6:1-8. 22. romero gg, fernandez p, gimeno e, et al. effects of the gnrh antagonist acyline on the testis of the domestic cat (felis catus). vet j. 2012;193:279-82. 23. sanefuji t. tissue culture studies on compensatory testicular hypertrophy of the young rabbit after hemicastration. hinyokika kiyo. 1988;34:585-91. 24. rombaut c, faes k, goossens e. the effect of a unilateral orchiectomy before gonadotoxic treatment on the contralateral testis in adult and prepubertal rats. plos one. 2016;11:e0164922. 25. furuya t. onset of compensatory hypertrophy of interstitial tissue and leydig cells in rats hemicastrated around the time of puberty. biolreprod. 1990;42:491-8. 26. romero g, barbeito c, fernandez p, et al. unilateral orchidectomy in mature cats is not followed by compensatory hypertrophy. reprod domest anim. 2012;47:226-8. 27. thompson tl, berndtson we. testicular weight, sertoli cell number, daily sperm production, and sperm output of sexually mature rabbits after neonatal or prepubertal hemicastration. biolreprod. 1993;48:952-7. 28. cunningham gr, tindall dj, huckins c, et al. mechanisms for the testicular hypertrophy which follows hemicastr ation. endocrinology. 1978;102:16-23. 29. ahmadi r, sattarils, khakpour b, et al. effects of unilateral and bilateral orchidectomy on serum levels of carcinogenic embryonic antigen in male rats. bull env pharmacol life sci. 2014;3:164-7. combined of thulium laser and bipolar in prostatectomy-huang et al. case report 138 urology journal vol 7 no 2 spring 2010 mucinous adenocarcinoma of the urachal remnant with pseudomyxoma peritonei benjamin w lamb, ram vaidyanathan, marc laniado, omer karim, hanif motiwala urol j. 2010;7:138-9. www.uj.unrc.ir keywords: urachus, adenocarcinoma, pseudomyxoma peritonei department of urology, wexham park hospital, uk corresponding author: benjamin lamb, md 54 cyprus avenue, london, n3 1sr, uk tel: +44 783 011 9301 fax: +44 207 281 0446 e-mail: benwlamb@googlemail.com received march 2009 accepted october 2009 introduction we report a rare case of urachal carcinoma causing pseudomyxoma peritonei (pmp) in a patient who presented with symptoms of chronic urinary retention. it is very unusual for urachal carcinoma to present in this way. case report a 63-year-old man presented with suprapubic pain, terminal dribbling, a suprapubic mass, and microscopic hematuria. flexible cystoscopy showed a mass in the dome of the bladder (figure 1). magnetic resonance imaging revealed a cystic mass in the dome of the bladder, but separated from the bladder with fluid, debris, and nodularity within the abdomen and the pelvis. the patient underwent laparotomy, where extensive pmp was discovered. thereafter, he underwent partial cystectomy, omentectomy with excision of the tumor. histological examination revealed mucinous adenocarcinoma of the urachal remnant with metastases to the omentum (figures 2 and 3). the patient underwent further debulking of the tumor with limited peritonectomy. at 18 months follow-up, recurrence occurred in the liver and the patient underwent further resection. discussion urachal carcinoma is a rare neoplasm, accounting for 0.01% of all malignancies and 0.34% of the bladder carcinomas.(1,2) urachal carcinoma is usually seen in male figure 1. cystoscopy showing tumor bulging into dome of the bladder. figure 2. low power view of section of the bladder showing the interface between the normal bladder wall on the left and urachal carcinoma on the right. pseudomyxoma peritonei in urachal carcinoma—lamb et al 139urology journal vol 7 no 2 spring 2010 patients between 40 and 70 years of age. (3) the prognosis is poor; the tumor produces few symptoms until it is advanced. about 95% of patients have muscle invasion or metastatic cancer at the time of diagnosis.(4) typically, the cancer spreads locally to the abdominal wall, and the peritoneum.(1,2) although histological analysis reveals mucin production in about 75% of cases, mucinuria occurs in about 25% of patients.(5) the radiographic finding of supravesical calcification associated with a bladder lesion is pathognomonic for urachal adenocarcinoma.(3) pseudomyxoma peritonei is characterized by dissecting gelatinous ascites and peritoneal implants secreting copious amounts of extracellular mucin. pseudomyxoma peritonei causes scalloping of the margins of the abdominal viscera, with septation of fluid collection with or without calcification. progressive disease of the peritoneal cavity and compression of abdominal viscera are common, leading to wasting and repeated bowel obstruction. urachal carcinoma is almost uniformly resistant to chemotherapy or radiotherapy. treatment for urachal carcinoma is surgical, usually en bloc radical cystoprostatectomy with wide excision of the urachus and umbilicus. partial cystectomy with urachectomy can be as effective as more radical excision and causes less morbidity (5-year overall survival rate of 43%).(3,5) this case highlights a rare presentation of urachal carcinoma with pmp in a patient with bladder outflow obstruction. it is a difficult tumor to treat and generally has a poor prognosis. although there is little literature on the subject, some reports of less radical surgery suggest reduced morbidity with effective oncological results. acknowledgements the authors would like to thank dr hatyam sheriff, consultant pathologist, wexham park hospital, slough. conflict of interest none declared. references 1. ravi r, shrivastava br, chandrasekhar gm, prahlad s, balasubramanian kv, mallikarjuna vs. adenocarcinoma of the urachus. j surg oncol. 1992;50:201-3. 2. chow yc, lin wc, tzen cy, chow yk, lo ky. squamous cell carcinoma of the urachus. j urol. 2000;163:903-4. 3. yu js, kim kw, lee hj, lee yj, yoon cs, kim mj. urachal remnant diseases: spectrum of ct and us findings. radiographics. 2001;21:451-61. 4. cooperman lr. carcinoma of urachus with extensive abdominal calcification. urology. 1978;12:614-6. 5. sheldon ca, clayman rv, gonzalez r, williams rd, fraley ee. malignant urachal lesions. j urol. 1984;131:1-8. figure 3. high power view of a slide showing nests of mucinous adenocarcinoma cells. note the large quantities of extracellular mucin. endourology and stone disease 87urology journal vol 7 no 2 spring 2010 risk of radiation exposure during pcnl heshmatollah soufi majidpour purpose: fluoroscopic guidance is a routine practice in endourology; both the physician and the assistances are exposed to some radiation via radiation scatter. measurement of radiation doses in staff is important, but often these data are not reported. materials and methods: we measured radiation exposure during 100 cases of percutaneous nephrolithotomy using lithium fluoride thermoluminescent dosimeters placed at the head, eye glasses, the fingers, and the legs of the operating surgeon, the assistant, and the circulating nurse. results: the mean screening time was 4.5 minutes (range, 1 to 8 minutes) with mean fluoroscopy tube potential of 73 kvp, and mean tube current of 2.8 ma. the estimated scatter exposure rate at 40 cm from the x-ray beam was 0.47, 0.04, 0.21, and 4.1 µgy to the head, eye glasses, the fingers, and the legs of the operating surgeon, respectively. the estimated scatter exposure rate at different points from the x-ray beam was 0.05, 0.01, 0.025, and 0.1 µgy to the head, eye glasses, the fingers, and the legs of the assistant, respectively and the estimated scatter exposure rate at all different points from the x-ray beam for circulating nurse was 0 µgy. conclusion: fluoroscopic screening results in radiation exposure of the medical staff. the surgeon received the maximum radiation exposure, mostly to the legs and very least to the eyes. the assistant received less radiation exposure than the surgeon and the nurse did not receive significant amount of radiation. urol j. 2010;7:87-9. www.uj.unrc.ir keywords: operating rooms, radiation, percutaneous nephrolithotomy department of urology, touhid hospital, kurdistan university of medical sciences, sanandaj, kurdistan, iran corresponding author: heshmatollah soufi majidpour, md department of urology, touhid hospital, kurdistan university of medical sciences, sanandaj, kurdistan, iran tel: +98 918 1710 360 fax: +98 871 3561 814 e-mail: hmajidpour@yahoo.com received june 2009 accepted january 2010 introduction percutaneous nephrolithotomy (pcnl) is a common urologic practice for treatment of upper urinary tract calculi, tumors, and stricture. the practice of pcnl, having been refined over time, continues to evolve and has largely replaced open stone surgery for the treatment of complex upper tract calculi unsuitable for extracorporeal shockwave lithotripsy or ureteroscopy, resulting in stone removal with less morbidity, shorter convalescence, and reduced cost compared with open surgery. (1,2) fluoroscopic guidance is the preferred technique for most of the stone therapies with pcnl. as endourology has become an important practice of urology, the use of fluoroscopic guidance has increased the exposure of urologists to the possibly deleterious effects of radiation.(3) the radiation exposure of staff increases due to scattered radiation produced from interaction of the primary radiation beam with the patient and the operating table. the medical staff standing next to the c-arm fluoroscopy unit are subjected to receive scatter radiation from all directions. the lower and radiation exposure in pcnl—soufi majidpour 88 urology journal vol 7 no 2 spring 2010 upper extremities are in radiation risk. standard radiation protection protocol requires the use of 0.35 mm lead aprons and thyroid shields for the operating surgeon and 0.25 mm lead aprons for other operating room staff.(4) the aprons and shields reduce transmission by 100-fold or more and hence gonadal and thyroid doses are minimal. (5,6) in this study, we attempted to evaluate the doses of radiation received by the operating room personnel during pcnl at endourology centers to assess the radiation risk and the radiation exposure rate at different parts of the body. materials and methods one hundred patients underwent pcnl. the patients were placed initially in a lithotomy position for retrograde ureteral catheter placement in the renal pelvis/superior calyx on the stone bearing side under fluoroscopic guidance. thereafter, the patient was placed in a prone position and the location of the stones in the kidney was confirmed using air contrast instilled via the ureteral catheter. the operating urologist established the tracts by puncturing the desired calyces and dilating the tracts under fluoroscopic guidance. stone fragmentation was performed using pneumatic lithotripsy and the fragments were removed with stone grasping forceps. at the end of the procedure, fluoroscopic screening of the renal area was performed to ensure stone clearance using a mobile multidirectional c-arm fluoroscopy unit with an under the couch x-ray tube and an over the couch image intensifier (shimadzu opescope 50 n, japan). the fluoroscopy unit has a combined energy/current (kvp/mamp) selector, which controls the radiation output at the tube and an automatic brightness control (abc) mode, which selects the optimal tube voltage and current, automatically. the urologist wore lead aprons, thyroid shields (0.5 mm equivalent lead thickness) (meditronics, iran), and lead glasses during the entire procedure. other operating room staff wore lead aprons and thyroid shields (0.5 mm equivalent lead thickness) (meditronics, iran). to measure the radiation exposure, lithium fluoride thermoluminescent dosimeter chips (tlds) have been placed at the head, eyeglasses, the fingers, and the legs of the operating surgeon, the assistant, and the circulating nurse. thermo luminescentdosimeter chips were later read in a tld reader. an estimation of radiation exposure to the operating surgeon was made based on average screening exposure time and surgeon’s position. results the mean time of performing pcnl procedure was 116 minutes (range, 42 to 160 minutes). the mean fluoroscopy screening time during the procedure was 4.5 minutes (range, 1 to 8 minutes). fluoroscopy screening time during the procedure decreased with increasing experience of surgeon, resulting in radiation exposure decrease. the mean fluoroscopy tube potential was 73 kvp and tube current mean was 2.8 ma. the additional radiation exposure was not monitored. the estimated scatter exposure rate at 40 cm from the x-ray beam of the operating surgeon for each procedure was: 0.47 µgy to the head, 0.04 µgy to the eye glasses, 0.21 µgy to the fingers, and 4.1 µgy to the legs. the estimated scatter exposure rate at different points from the x-ray beam for the assistant was: 0.05 µgy to the head, 0.01 µgy to the eye glasses, 0.025 µgy to the fingers, and 0.1 µgy to the legs. the estimated scatter exposure rate at all different points from the x-ray beam for circulating nurse was: zero (0). discussion fluoroscopic imaging is widely practiced in various interventional procedures. although collimation of the x-ray beam prevents direct radiation exposure to the urologist and assisting personnel, the patient becomes a secondary source of exposure through radiation scatter by absorbing radiation during the procedure.(7) therefore, it is imperative to measure radiation exposure to patients and the staff to maintain safe levels of cumulative radiation. the international commission on radiation protection recommends an effective dose of 20 msv per year over a defined period of 5 years on average as the occupational dose limit.(8) according to our findings, radiation exposure dose to the radiation exposure in pcnl—soufi majidpour 89urology journal vol 7 no 2 spring 2010 operating room staff is less than 1% of permissible annual limits; however, radiation exposure dose to the urologist was greater in comparison to the assistant and the nurse, which is due to his/her closer proximity to the x-ray tube. our results clearly place the intensive care environment well below the hazardous level of radiation exposure, even in the case of pregnant staff. in our study, the highest radiation exposure dose was to the legs for the operating surgeon and assistant with 4.1 µgy and 0.1 µgy, respectively. hellawell and colleagues have shown that the surgeon received the highest radiation exposure with the lower leg (11.6 ± 2.7 µgy) and the foot (6.4 ± 1.8 µgy) receiving more radiation than the eyes (1.9 ± 0.5 µgy) and the hands (2.7 ± 0.7 µgy).(9) the radiation exposure to the fingers of urologists reported in previous studies are as below: 360 µgy (kumari), 145 µgy (bowshar), 340 µgy (law), 5800 µgy (rao), and 280 µgy (kumar), while it was 0.2 µgy in our study. probably, it is due to advances in technology, the urologist experience, fluoroscopy time, and intensive care from radiation exposure.(10) rao and associates documented a mean total radiation dose of 5.2 msv to the hands, 7.5 msv to the fingers, and 1.6 msv to the eyes, with the mean fluoroscopy time of 21.9 minutes, which was very high in comparison to that cited in literature.(11) in a study by kumari and coworkers, the mean radiation exposure dose to the patient was 0.56 ± 0.35 msv, while the mean incident radiation exposure to the finger of the urologist was 0.28 ± 0.13 msv.(12) conclusion our results demonstrated that the operating room staff are within the safe radiation dose limits during pcnl; however, following proper precautions as well as efficient fluoroscopy and avoiding useless exposure during the procedure can further reduce the dose, especially the scattered radiation. care must be taken by all the staff operating in the field to achieve as low as reasonably achievable dose by adhering to good practices. acknowledgement i would like to thank the director and members of atomic energy organization of iran for their cooperation. this work was supported by grant from kurdistan university of medical sciences. conflict of interest none declared. references 1. brannen ge, bush wh, correa rj, gibbons rp, elder js. kidney stone removal: percutaneous versus surgical lithotomy. j urol. 1985;133:6-12. 2. lam hs, lingeman je, mosbaugh pg, et al. evolution of the technique of combination therapy for staghorn calculi: a decreasing role for extracorporeal shock wave lithotripsy. j urol. 1992;148:1058-62. 3. kumari g, kumar p, wadhwa p, aron m, gupta np, dogra pn. radiation exposure to the patient and operating room personnel during percutaneous nephrolithotomy. int urol nephrol. 2006;38:207-10. 4. links a. medical and dental guidance notes. a good practice guide on all aspects of ionising radiation protection in the clinical environment. j radiol prot. 2002;22:334. 5. kicken pj, bos aj. effectiveness of lead aprons in vascular radiology: results of clinical measurements. radiology. 1995;197:473-8. 6. christodoulou eg, goodsitt mm, larson sc, darner kl, satti j, chan hp. evaluation of the transmitted exposure through lead equivalent aprons used in a radiology department, including the contribution from backscatter. med phys. 2003;30:1033-8. 7. giblin jg, rubenstein j, taylor a, pahira j. radiation risk to the urologist during endourologic procedures, and a new shield that reduces exposure. urology. 1996;48:624-7. 8. [no author listed]. international commission on radiological protection [homepage on the internet]. summary recommendation [cited 2008 feb 1]. available from: http://www.icrp.org/docs/summary_bscan_icrp_60_ ann_icrp_1990_recs.pdf. 9. hellawell go, mutch sj, thevendran g, wells e, morgan rj. radiation exposure and the urologist: what are the risks? j urol. 2005;174:948-52; discussion 52. 10. kumar p. radiation safety issues in fluoroscopy during percutaneous nephrolithotomy. urol j. 2008;5:15-23. 11. rao pn, faulkner k, sweeney jk, asbury dl, sambrook p, blacklock nj. radiation dose to patient and staff during percutaneous nephrostolithotomy. br j urol. 1987;59:508-12. 12. bush wh, jones d, brannen ge. radiation dose to personnel during percutaneous renal calculus removal. ajr am j roentgenol. 1985;145:1261-4. vol 15 no 03 may-june 2018 65 editorial comments re: the tolerability of potassium citrate tablet in patients with intolerance to potassium citrate powder form the authors have presented an interesting publication on the tolerability of tablet formulated potassium citrate in patients who were intolerant to the powder form of potassium citrate. they enrolled patients with calcium stones with hypocitraturia who were intolerant to the powder formulation of potassium citrate after one month of therapy into taking the tablet formulated form of potassium citrate for 2 weeks and concluded that the verbal taste scale of using tablets was significantly less than when they used the powder form. this is an important finding as one of the main problems with administration of potassium citrate is patients’ low compliance with long term use of the medication as described earlier(1,2). in one study, the long term compliance with only one evening dose of potassium citrate has been as low as 40%. nevertheless, the following points needs to be addressed: the authors failed to provide a synchronous control sample. ideally, they are expected to study the tolerance of the tablet and powder forms in two groups of patients with calcium stones with hypocitraturia and allocate them to treatment groups of tablet and powder preparations. instead the intolerant patients to a medication were offered to a second medication. this trial design is famous in epidemiology and has previously been used for criticizing the studies on the influence of praise versus punishment on performance. the conclusion of these studies revealed that punishment influences more favorably than praising because participants after punishment acted better but participant who were gifted acted less favorably. the known error of these designs is “regression toward the mean” that is extreme tail of patients will naturally shift toward the mean value in the next measurements(3). then participant in the best performance tail who were gifted will naturally perform less favorably in their net measurement and participants in the least performance tail will naturally perform better in their next measurement. a similar problem has occurred with the study design of the authors as only intolerant patients to the powder form were enrolled, they are expected to report less intolerance if they were continued on the powder form for a longer duration. a second point is tolerance to medication after continued use. intolerance to some medications will mitigate after continual use. for example the side effects of tadalafil on muscle pain mitigates after continual use(4). therefore, less intolerance after continual use could be the influence of adaptation or not cannot be answered with the current trial design of the study. and a last point is that the authors failed to report the adequacy of treatment on the powder formulation nor the tablet formulation based on urinary ph. normally the amount of powder used daily is calibrated with urinary ph measurement. improved responses were reported with urinary ph > 6.5(5). the average ph reported by the authors during trial is 6.1 with the standard deviation of .08 which indicates that a substantial number of participant could have urinary ph below 6. in brief, in order to draw reliable conclusions, we need to wait for publication of randomized parallel group comparison of the tolerability of the powder and tablet formulations of potassium citrate as the authors have promised. references 1. jendle-bengten c, tiselius hg. long-term follow-up of stone formers treated with a low dose of sodium potassium citrate. scand j urol nephrol. 2000 ;34:36-41. 2. pak cy, fuller c, sakhaee k, preminger gm, britton f. long-term treatment of calcium nephrolithiasis with potassium citrate. j urol. 1985 ;134:11-9. 3. barnett ag, van der pols jc, dobson aj. regression to the mean: what it is and how to deal with it. int j epidemiol. 2005; 34:215-20. 4. hellstrom wj. current safety and tolerability issues in men with erectile dysfunction receiving pde5 inhibitors. int j clin pract. 2007 sep;61(9):1547-54. 5. robinson mr, leitao va, haleblian ge, scales cd jr, chandrashekar a, pierre sa, preminger gm. impact of long-term potassium citrate therapy on urinary profiles and recurrent stone formation. j urol. 2009 ;181:1145-50. dr. amir h kashi assistant prof of urology hasheminejad kidney center (hkc) iran university of medical sciences, tehran, iran reply by authors the tolerability of potassium citrate tablet in patients with intolerance to potassium citrate powder form i appreciate the editor’s interest and comments on present article. the first point that the editor poses as the weak-ness of our study is a lack of a synchronous control group of calcium stones on powder form of potassium citrate. i disagree with this opinion, since the study design was according to quasi controlled trial, so the control group of our patients were themselves (before and after the taking drug). the other point is mentioned about the short time of the study (two weeks) that how we could conclude the better tolerance to potassium citrate tablet versus powder form? previous studies by gonzalez et al.(1), mechlin et al.(2) have demonstrated the assessment of tolerance or the adverse effects of the potassium citrate preparations on upper gastro-intestinal mucosa can be even after three days of taking the medication. of course it is acceptable that intolerance to some medications will mitigate after long term consumption. therefore, in confirmation with your opinion, another study with two parallel groups of calcium stone patients (potassium citrate tablet and powder) is in processing, that the duration of treatment is longer and, the long term tolerance to potassium citrate preparations will be assessed. finally, the last point is regarding to the failure of potassium citrate tablet on urine ph correction. although the changing of spot urine ph (5.7 ± 0.6 to 6.1 ± 0.8, p = 0.006) and 24-hour urine citrate (235.8 ± 190.2 to 482.5 ± 323.2, p = 0.0002) were significantly high after the treatment in our study(3), it is noteworthy that the correction of these urine metabolites are of our main goals in another study with longer treatment duration which above mentioned. references 1. gonzalez gb, pak cy, adams-huet b, taylor r, bilhartz le. effect of potassium-magnesium citrate on upper gastrointestinal mucosa. alimentary pharmacology & therapeutics. 1998;12(1):105-10. 2. mechlin c, kalorin c, asplin j, white m. splenda(r) improves tolerance of oral potassium citrate supplementation for prevention of stone formation: results of a randomized double-blind trial. journal of endourology / endourological society. 2011;25(9):1541-5. 3. basiri a, taheri f, taheri m. the tolerability of potassium citrate tablet in patients with intolerance to potassium citrate powder form. urology journal. 2018;15(1):16-20. maryam taheri, md urology nephrology research center, no. 103, 9th boostan street, pasdaran avenue, tehran, iran. editorial comment 66 availability and patterns of intravesical bcg instillations sławomir poletajew*, aleksandra majek, piotr magusiak, katarzyna śledzikowska, bartosz dybowski, piotr radziszewski purpose: intravesical bcg instillations improve recurrence free survival in patients with non-muscle-invasive bladder cancer (nmibc). methods: this is a national survey study, covering 223 urological centres, aimed at reliable identification of bcg availability and implemented treatment patterns. results: response rate was 93.7%. bcg was used in 56.5% of urological departments. another 22.7% referred patients to other hospitals for instillations, while 20.8% did not recommend bcg at all. the most common indications for bcg instillations were as follows: t1 tumours (88.5%), carcinoma in situ (83.6%) and high grade tumours (73.8%). maintenance therapy was routinely abandoned in 16.4% of centres or was scheduled for <1 year, 1 year, 3 years and 1-3 years in 6.6%, 19.7%, 21.3% and 31.2% of centres, respectively. continuation of bcg despite treatment failure in carcinoma in situ cases was considered in 21.3% of departments. conclusion: our findings indicate that bcg is underused, while patterns of maintenance and follow-up are suboptimal. keywords: bacillus calmette-guerin; bladder cancer; intravesical instillation; physician survey; recurrence. department of urology, medical university of warsaw, warsaw, poland. *correspondence: department of urology, medical university of warsaw 4 lindleya st., 02005 warsaw, poland. tel: +48225021702. fax: +48225022148. e-mail: slawomir.poletajew@wum.edu.pl. received november 2016 & accepted may 2017 introduction intravesical bacillus calmette-guerin therapy (bcg) improves recurrence-free, as well as may prolong progression-free survival in patients with highand intermediate-risk non-muscle-invasive bladder cancer (nmibc) after transurethral resection of bladder tumour (turbt). however, bcg is associated with important limitations. first, half of patients does not complete full bcg course due to toxicity, discomfort, deterioration in quality of social life or disease recurrence.(1) second, urological community has to face reduced availability of bcg strains. finally, adherence to eau guidelines on bcg therapy and monitoring of nmibc patients vary between institutions and countries in europe.(2) these factors can lead to underuse of intravesical immunotherapy. despite clear clinical significance, reliable real-life data on usage of bcg in europe is limited. this data would be of special attention in the region of central europe, where survival of patients with bladder cancer was reported to be significantly lower than in western europe(3,4) and where the incidence of high-risk nmibc is relatively high.(5) in this context, we decided to perform a national analysis of availability and patterns of bcg therapy in poland. methods based on national health fund registry, we identified 223 urological centres in poland. afterwards, we contacted these departments electronically and/or by telephone in the period from december 2015 to march 2016. urologists working in these centres were asked to complete a unified survey. it consisted of 23 questions in five blocks, concerning availability of bcg, indications for therapy, technique of instillations, duration and scheme of treatment, and follow-up protocols. questions applied to hospital policy regarding bcg instillations and did not incorporate any patient clinical data. before answering the questions, all responders were informed about the character of the study and were ensured about anonymous publication of data. results response rate was 93.7% (n=209/223). among the responders, there were 55 highly specialized or one-day surgery centres, which did not take care of patients with bladder cancer. they were excluded from further analysis, limiting the study group to 154 urological departments routinely performing turbts. bcg was available in 56.5% of these departments (n=87/154). in 22.7% of cases urologists declared to routinely refer patients to other centres for bcg (n=35/154). in 20.8% of departments bcg was not recommended irrespectively of oncological characteristics of individual patient (n=32/154) (figure 1). full data regarding indications, preparation of patient, bcg strains and follow-up was available for 70.1% of centres (n=61/87; table 1). in patients with high-risk nmibc, follow-up cystoscopy was scheduled 3 and 6 months after turbt in 95.1% and 78.7% of cases, brief communication vol 14 no 06 november-december 2017 5068 therapy was continued in 59.0% and 21.3% of departments, respectively. urinary cytology complemented endoscopic assessment only in 32.8% of departments. discussion this is a unique national survey study, presenting real pattern of bcg treatment in poland. as the study covered 94% of urological centres in the country, it presents fully reliable data. the importance of our findings are highlighted by the fact that mortality rate from bladder cancer in europe is the highest among latvian and polish patients.(4) our survey study indicated significant shortcomings in the adjuvant treatment of patients with nmibc. the most important findings can be summarized as a “triple one-fifth rule”. one fifth of patients has no access to bcg therapy, thus it is advocated to state this therapy is underused. one fifth of patients are not considered for maintenance therapy or its duration is inadequate, thus bcg therapy is suboptimal. finally, in patients with cis, in one fifth of cases the therapy is continued despite bcg failure. our data allowed us to formulate several possible reasons for unsatisfactory survival of bladder cancer patients in poland. it can be assumed that both limited use of bcg and suboptimal follow-up, as well as delaying the decision for radical treatment could be the contributing factors. however, it is of utmost importance to establish whether these findings are a kind of regional phenomenon or they rather present global trend. this question is particularly relevant if one considers high toxicity related to the treatment, bcg shortage, data on decreased effectiveness in elderly and limited compliance of bladder cancer patients.(1,6,7) however, none of these facts eventually advocate intentional underuse of bcg therapy. the use of bcg in patients with high-risk nmibc varies between institutions. recent study by witjes et respectively. in patients with history of carcinoma in situ (cis), 19.7% of departments routinely performed random bladder biopsy during follow-up. in case of presence of cis at 3 and 6 months after turbt, bcg patterns of intravesical bcg instillations-poletajew et al. table 1. adopted indications, patient preparation and bcg strains in polish departments applying bcg treatment. indications t1 tumours 88.5% high grade or g3 tumours 73.8% carcinoma in situ 83.6% intermediate-risk nmibc 44.3% patient preparation urine alkalisation before instillation 4.9% changing position after instillation 73.8% limitation of fluid intake before instillation none 29.5% for 2-3 hours 50.8% for > 3 hours 14.8% unspecified time 4.9% limitation of fluid intake after instillation none 59.0% for 1-2 hours 26.2% for 2-3 hours 14.8% bcg strain used rivm 60.7% moreau 26.2% tice 3.3% different / unspecified 9.8% duration of maintenance therapy none (only induction course) 16.4% < 1 year 6.6% 1 year 19.7% 1-2 years 4.9% 3 years 21.3% 1-3 years, depending on patient individual risk 31.2% abbreviations: nmibc – non muscle-invasive bladder cancer. figure 1. flowchart presenting constitution of study group and availability of bcg in polish urological centres. nmibc – non muscle-invasive bladder cancer; turbt – transurethral resection of the bladder tumour. brief communication 5069 al. demonstrated significant non-adherence to clinical guideline recommendations for bcg use in north america and europe. in their study only 29% of intermediate-risk patients received intravesical therapy, while in the group of high-risk patients bcg induction and maintenance was offered to 50% of patients. (8) in contrast, based on survey study among american urologists, nielsen et al. reported routine use of bcg induction and maintenance therapy in over 80% of patients with high-grade nmibc. however, despite high number of responders included, the response rate in the study was only 6.9%.(9) gontero et al. showed that 22% of high-risk nmibc patients receive no further treatment after turbt in referral italian centres, while bcg maintenance is implemented in 57% of cases.(10) historical analysis of seer database by chamie et al. presented the rate of implementation of maintenance bcg therapy in 26% of high-risk patients.(11) all papers cited above analysed individual patient data from selected urological centres or presented clinical practice of individual urologists. none of them present fully reliable regional schemes of bcg treatment. our study presents strategies of bladder cancer treatment adopted in all polish centres. it avoids individual preferences of urologists, as majority of centres usually have unified policy of bcg therapy. the most important limitation of our survey is the lack of questions on further treatment in departments that routinely do not recommend bcg therapy. conclusions to conclude, bcg therapy in poland is underused and treatment schemes are frequently suboptimal. there are significant differences in the policy of intravesical treatment of nmibc patients between institutions. improvement of adherence to guideline recommendations should become a priority for urologists treating patients with bladder cancer. references 1. serretta v, scalici gesolfo c, alonge v, cicero g, moschini m, colombo r. does the compliance to intravesical bcg differ between common clinical practice and international multicentric trials? urol int. 2016;96:20-4. 2. aziz a. bp, chun fk, dobruch j, et al. discrepancy between guidelines and daily practice in the management of non-muscleinvasive bladder cancer (nmibc): results of a european survey. eur urol suppl. 2016;15:e216. 3. dybowski b, ossolinski k, ossolinska a, peller m, bres-niewada e, radziszewski p. impact of stage and comorbidities on five-year survival after radical cystectomy in poland: single centre experience. cent european j urol. 2015;68:278-83. 4. torre la, bray f, siegel rl, ferlay j, lortettieulent j, jemal a. global cancer statistics, 2012. ca cancer j clin. 2015;65:87-108. 5. poletajew s, biernacki r, buraczynski p, et al. stage of bladder cancer in central europe polish perspective. neoplasma. 2016;63:6427 6. brausi m, oddens j, sylvester r, et al. side effects of bacillus calmette-guerin (bcg) in the treatment of intermediateand high-risk ta, t1 papillary carcinoma of the bladder: results of the eortc genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance bcg. eur urol. 2014;65:69-76. 7. oddens jr, sylvester rj, brausi ma, et al. the effect of age on the efficacy of maintenance bacillus calmette-guerin relative to maintenance epirubicin in patients with stage ta t1 urothelial bladder cancer: results from eortc genito-urinary group study 30911. eur urol. 2014;66:694-701. 8. witjes ja, palou j, soloway m, et al. current clinical practice gaps in the treatment of intermediateand high-risk non-muscleinvasive bladder cancer (nmibc) with emphasis on the use of bacillus calmetteguerin (bcg): results of an international individual patient data survey (ipds). bju int. 2013;112:742-50. 9. nielsen me, smith ab, pruthi rs, et al. reported use of intravesical therapy for non-muscle-invasive bladder cancer (nmibc): results from the bladder cancer advocacy network (bcan) survey. bju int. 2012;110:967-72. 10. gontero p, oderda m, altieri v, et al. are referral centers for non-muscle-invasive bladder cancer compliant to eau guidelines? a report from the vesical antiblastic therapy italian study. urol int. 2011;86:19-24. 11. chamie k, saigal cs, lai j, et al. compliance with guidelines for patients with bladder cancer: variation in the delivery of care. cancer. 2011;117:5392-401. patterns of intravesical bcg instillations-poletajew et al. vol 14 no 06 november-december 2017 5070 pediatric urology the effect of pre-incision urethral plate width and glanular width on the outcome of tubularized incised urethral plate repair surgery in distal penile hypospadias, a prospective study mohamed galal1, diaa-eldin taha1*, khaled zein elabden1, hossam nabeeh1, tarek abdelbaky1 purpose: to determine hypospadias repair's cosmetic and functional outcome concerning the urethral plate width and glanular width. materials and methods: a prospective study including 38 patients. the urethral plate width (upw) was measured preoperatively. the cosmetic outcome was evaluated by hypospadias objective penile evaluation [hope] score, and the urinary stream evaluated functional outcome. we included boys with distal penile hypospadias and excluded recurrent cases with severe chordee. all patients were operated on by snodgrass tubularized incised plate repair (tip); they were followed up for one year. success was defined as slit-shaped meatus at the tip of the glans without fistula. results: the mean age of surgery was 4.5 ± 2.1 years. upw was < 8 mm in 24 patients (63.2 %) (group a), while 14 patients (36.8 % ) (group b) had a upw ≥ 8 mm. overall, the mean ± sd of upw was 4.84 ± 1.29 mm. the mean ± sd of gw was 9.52 ± 1.56 mm. overall success was documented in 35/38 patients (92.1 %). no significant relation was founded between the complications and upw of the patients (p-value = 0.7). overall, the mean ± sd hope score was 39.1 ± 8.83. a significant relation was found between the cosmetic outcome of the two groups and the hope score (p-value = 0.02). conclusion: the pre-incision urethral plate width and glanular width were not correlated with the tip outcome. a better hope score is associated with a wide urethral plate. keywords: glans width (gw); hypospadias; hypospadias objective penile evaluation [hope]; tubularized incised plate (tip) repair; urethral plate width (upw) introduction for the last two decades, tubularized incised urethral plate procedure (tip) for repairing distal penile hypospadias has been the foremost common method at numerous institutions. in any case, a few downsides counting meatal and/or neourethral stenosis and the requirement for standard urethral dilatation have been recorded(1). the preservation of the urethral plate and the increase in the surface area with healthy epithelium give better outcomes(2). tip is a procedure that is more dependent on urethral plate quality in comparison with other surgical procedures. the plate quality is generally regarded as one of the intrinsic risk factors influencing the outcome of hypospadias repairs. however, there is currently no clear agreement on the evaluation of the urethral plate(3) the urethral plate width was classified based on an arbitrary 8-mm cut-off value, while groove depth was graded as deep, moderate, and shallow. however, is the arbitrary value of 8 mm suitable for all penis sizes?(4). generally, urethral plate width increases with penis size as the patient grows. it might be more appropriate to evaluate urethral plate quality with a parameter scaled with penis size. in recent years, glans–urethral meatus–shaft score was proposed to classify the severity of hypospadias, providing a concise method for evaluating 1urology department, kafer elsheikh university, egypt. *correspondence: lecturer of urology, department of urology, faculty of medicine, 4 elgesh street kafrelsheikh university, kafrelsheikh, egypt. tel: +0201008531384 – 0201205222323. e-mail: drdiaaeldin@gmail.com. drdiaaeldin@med.kfs.edu.eg received december 2020 & accepted september 2021 urethral plate quality(3,5). there is a debate regarding the effect of upw and gw on post-operative complications post tip surgery. some reports have found that urethral plate (up) widths < 8 mm before tip incision increase urethroplasty complications(6), while, bush, n.c. and w. snodgrass found that the up width before incision did not increase urethroplasty complications. surgeons do not need to measure or categorize the up to determine suitability for tip repair, as long as the plate incision was made deeply to the corpora.(7,8) glans size didn't correlate with age in patients with hypospadias between 3 and 24 months old, supporting the decision to operate as early as three months in some centers. small glans size, defined as width < 14 mm, is an independent risk factor for urethrocutanous fistula (9). to address this void, we aimed to answer a question, are the upw and gw controlling factors for hypospadias outcome regarding the functional and cosmetic outcome? materials and methods study population after approval from institutional review board, we conducted a prospective study that was carried out by urology journal/vol 19 no. 1/ january-february 2022/ pp. 50-55. [doi: 10.22037/uj.v18i.6618] vol 19 no 1 january-february 2022 138 the urology department in kafr elsheikh university between november 2018 and november 2019. a total of 38 children diagnosed with distal penile hypospadias were included. inclusion criteria were distal penile hypospadias, primary, uncircumcised, no or mild chordee (less than 30°), aged < 10 years, no associated syndromes, and boys able and willing to comply with follow up schedule. we table 1. patients’ demographic and clinical characteristics variable distal hypospadias ( n= 38) age “years” (mean ± sd) 4.5 ± 2.1 weight “kg” (mean ± sd) 17.45 ± 3.94 bmi (kg/m2) 16.06 ± 1.64 presentation abnormal eum 38 (100%) asa score 1 38 (100%) un-circumcised yes 38 (100 %) congenital anomalies absent 38 (100%) testis palpable 38 (100%) meatal location glanular 8 (21.1 %) coronal 15 (39.5 %) distal penile 15 (39.5 %) urethral plate width (upw) 4.84 ± 1.29 urethral plate width <8mm 24 (63.2%) ≥8mm 14 (36.8%) urethral plate adequacy adequate 30 (78.9 %) deficient 8 (21.1%) glans length (mean ± sd) 7.29 ± 1.64 glanular width (mean ± sd) 9.55 ± 1.54 gw <14 mm 36 (94.7%) ≥14 mm 2 (5.3%) chordae (ventral curvature ) present 10-30 3 (7.9 %) ≤ 10 5 (13.2 %) absent 30 (78.9%) figure 1. (a) a traction suture using a 5–0 silk is placed in the glans just beyond the anticipated dorsal lip of the neomeatus (b) separate the urethral plate from the glans wings (c) a circumferential subcoronal incision was made proximal to the hypospadiac urethral meatus, then degloving of the penile skin to the penoscrotal junction. (d) the urethral plate is incised longitudinally after complete penile degloving the upw effect on tip repair of distal penile hypospadias-galal et al. data are presented as mean ± sd or number (percent) sd: standard deviation vol 19 no 1 january-february 2022 51 excluded boys who were recurrent, circumcised, with severe chordee. a detailed description of the operation and expected complications were explained, and the parents signed written consents. informed consent was obtained from a parent and/or legal guardian. procedures a single pediatric urologist performed all operations. preoperative intravenous antibiotic prophylaxis was given. a circumferential subcoronal incision was made proximal to the hypospadiac urethral meatus (figure 1 a,b). the penis was degloved. a bilateral longitudinal incision was made along the urethral plate to prepare the glanular wings(figure 1c,d). the flap was obtained from the inner dartos muscle and sutured overlying the incision line with 6/0 vicryl. the flap width and length were different in every case according to the location of the meatus, urethral plate characteristics, and depth of the midline incision. urethroplasty was performed using 6/0 vicryl continuous subcuticular then interrupt variable distal hypospadias ( n= 38) type of operation tip 38 (100%) operation time “min” (mean ± sd) 133.82 ± 20.84 new urethral tube yes 38 (100%) covering flap dartos flap 38 (100%) torniquite time “min” (mean ± sd) 79.61 ± 10.03 nerve block no 38 (100%) diathermy no 7 (18.4%) yes (bipolar) 31 (81.6%) hospital stay “days” (mean ± sd) 11.79 ± 1.73 urine cath yes 38 (100%) type nelton 6f 6 (15.8%) nelton 8f 25 (65.8%) nelton 10f 7 (18.4%) urine ph acidic 38 (100 %) uti(pre-operative) no 26 (68.4 %) yes 12 (31.6 %) e coli 7 (18.4 %) proteus 2 (5.3 %) klebseilla 1 (2.6 %) other 2 (5.3 %) creatinine “mg / dl” (mean ± sd) 0.38 ± 0.17 hb pre “gm / dl ” (mean ± sd) 11.73 ± 0.79 hb post “gm / dl ” (mean ± sd) 11.22 ± 0.70 p < 0.001** hct pre “%” (mean ± sd) 32.99 ± 0.55 hct post “%” (mean ± sd) 32.89 ± 0.49 p 0.34 ns table 2. operative data. pediatric urology 52 sd: standard deviation p: paired t test ns: non-significant (p > 0.05) **: highly significant (p < 0.001) upw ≤ 8 mm ( n= 24) upw ≥ 8 mm ( n= 14) χ2/t m success failure 2 (8.3%) 1 (7.1%) 1.9 0.17 ns succeed 22 (91.7%) 13 (92.9%) complications early no comp 23 (95.8%) 12 (85.7%) 0.02 0.90 ns infection(glanular dehiscence) 1 (4.2%) 2 (14.3%) late no comp 22 (91.8%) 13 (92.9%) 0.01 0.99 ns meatal stenosis 2 (8.3%) 1 (7.1%) uc fistula 2 (8.3%) 1 (7.1%) slit like urethra 20 (83.3%) 12 (85.7%) 0.04 0.85 ns straight penis 20 (83.3%) 12 (85.7%) 0.04 0.85 ns skin shape normal 20 (83.3%) 12 (85.7%) 0.04 0.85 ns slightly abnormal 4 (16.7%) 2 (14.3%) glans shape normal 20 (83.3%) 12 (85.7%) 0.04 0.85 ns slightly abnormal 4 (16.7%) 2 (14.3%) meatal shape vertical slit 20 (83.3%) 12 (85.7%) 2.33 0.31ns circular 4 (16.7%) 1 (7.1%) abnormal 0 (0%) 1 (7.1%) meatus position distal glanular 20 (83.3%) 12 (85.7%) 5.77 0.06 ns proximal glanular 4 (16.7%) 0 (0%) coronal 0 (0%) 2 (14.3) urinary stream single stream 20 (83.3%) 12 (85.7%) 0.04 0.85 ns spray 4 (16.7%) 2 (14.3%) cosmetic out come good 20 (83.3%) 12 (85.7%) 0.04 0.85 ns bad 4 (16.7%) 2 (14.3 %) q max (mean ± sd) 8.4 ± 2.4 10.4 ± 3.1 1.98 0.61 ns hope 37.2 ± 6.4 42.4 ± 6.1 2.46 0.02 * sd: standard deviation t: independent t test χ2: chi square test ns: non-significant (p > 0.05) *: significant (p < 0.05) table 3. outcome in relation to upw: the upw effect on tip repair of distal penile hypospadias-galal et al. vol 19 no 1 january-february 2022 138 ed sutures and 2nd layer cover using dartos fascia flap (figure 2a,b). glanular approximation was done with 6/0 vicryl (figure 2c). a stent was kept for 7-10 days (figure 2d). evaluation all 38 patients were routinely followed up for cosmetic and functional results at three months intervals for one year. by routine examination of the external genitalia, evaluation of the voiding symptoms, uroflowmetery study was performed if possible, and it was repeated when the voided volume was insufficient or when the result was inconsistent with the physical examination and history. the overall acceptable cosmetic appearance of the penis was decided according to the slit-like appearance of the neo-meatus; an independent blinded observer judged the straight position of the penis and this cosmetic aspect (figure 3 a,b). hypospadias objective penile evaluation (hope) is a valuable tool for assessing the outcome(10). we used two medical interobserver, and the mean was taken. the glans width and upw were measured using a ruler in mm, flow rate using a uroflowmetry device connected to the electronic sensor was measured in ml/sec. ethical committee: the article has been accepted by kafr el sheikh faculty of medicine ethical committee in compliance with ethical standards ethical approval: all procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research editorial boards and with the 1964 helsinki declaration and figure 2. (a) neourethral tubularization (b) dartos flap is transposed ventrally and fixed to cover the entire neourethra after the creation of the neourethra (c) glanular wings approximation (d) closure of penile skin its later amendments and comparable ethical standards. consent to participate: both written and verbal consent for participation in the study that involves an education and information exchange that takes place between the patients' parents and us. consent for publication: formal consent was signed by the patients' parents to share and to publish their data in this research. statistical analysis statistical analysis was performed with ibm statistical package for social sciences (spss) for windows version 25.0 (armonk, ny). quantitative data were expressed as mean & sd, and qualitative data were expressed as numbers and percentages. the chi-square test was used to compare qualitative data, and the independent t-test and paired t-test were used for quantitative data. pearson's correlation coefficient was used to find the correlation between quantitative data. the significance level was set to p-value < 0.05. results all 38 patients were followed up for one year. the mean age at surgery was 4.5 ± 2.1 years. of the 38 patients who had their distal hypospadias repaired using tip, eight patients (21.1 %) had glanular hypospadias, 15 patients (39.5 %) had coronal hypospadias, and 15 patients (39.5 %) had distal penile hypospadias (table 1). overall, the mean ± sd of upw was 4.84 ± 1.29 mm. 24 patients (63.2 %) (group a) had a urethral plate width of less than 8 mm while 14 patients (36.8 %) (group b) had a urethral plate width greater or equal to 8 mm. the mean ± sd of gw was 9.55 ± 1.54 mm. functional outcome the average urine flow rate (q-max) of 38 patients was 7 ml/sec (5.3-10.3). 20 (83.3 %) patients in group a had good urinary stream (single stream), which improved after six months and became 23 patients (95.8 %), while 12 patients (85.7 %) in (group b) had good urinary stream after 3 and 6 months post-operative. there was no significant relationship between the good urinary stream and the mean upw of the studied groups (p-value = 0.61). cosmetic outcome the cosmetic outcome was assessed using hypospadias objective penile evaluation (hope), as shown in table 3. overall, the mean ± sd hypospadias objective penile evaluation (hope) score was 39.1 ± 8.83. group a patients had a mean hope score of 37.2 ± 6.4 sd, while group b patients had a mean hope score of 42.4 ± 6.1 sd. a significant relation was found between the cosmetic outcome of the two groups (hope score), and upw of the patients with an increase in scores among cases had upw ≥ 8mm (p-value = 0.02). post-operative complications early post-operative complication (infection & glanular dehiscence) occurred in 3 (7.9 %) patients; 1 (4.2 %) cases in group a developed early post-operative complications while 2 (14.3 %) cases in group b developed these complications. meatal stenosis was developed in 6 (15.8%) patients (spray urinary stream and straining with urination); 4 (16.7 %) patients in group a, while 2 (14.3 %) cases in group b and they underwent serial urethral dilatation by a medical thermometer which improved after six months and became 3 (7.9 %) patients; the upw effect on tip repair of distal penile hypospadias-galal et al. vol 19 no 1 january-february 2022 53 2 (8.3 %) in group a and 1 (7.14 %) in group b. late post-operative complications that required redo operation occurred in 3 (7.9 %) patients who developed small urethrocutanous fistula; 2 (8.3 %) cases in group a developed late post-operative complications while 1 (7.14 %) case in group b developed these complications. no statistical significance relation was found between the complications and the mean upw of the patients (p-value = 0.7). discussion hypospadias is an extremely common anomaly. different procedures have been described for the adjustment of hypospadias since the presence of various hypospadias presentations. be that as it may, no single technique had a 100 % satisfactory result. hypospadias surgery goals include developing a urethra of sufficient caliber and length, orthotopic meatus at the tip of the glans permitting the patient to void in a straight stream without maddening spreading(11). moreover, obtaining a conical glans and rearrangement of the dorsal skin provide a uniform ventral skin cover and correction of penile curvature to achieve proper sexual intercourse and effectively inseminate(12). despite the recognition of the urethral plate as the tissue distinct from the glans and penile skin that would have formed the urethra and as having a well-vascularized connective tissue and its incorporation in hypospadias repair, an objective way of assessing the impact of the urethral plate on the outcome is yet to be established. snodgrass, in 1994, reported his own technique of tubularized incised plate urethroplasty (tip) repair for distal hypospadias that gained widespread use for its perceived simplicity and good cosmetic outcomes in the majority of cases(10). besides, 53.5% of 170 surgeons participating in an internet international-based survey done with a multiple-choice questionnaire on google forms comparing the outcomes of different surgical procedures prefer tubularized incised plate hypospadias repair (tip) as the best method of surgery for simple distal hypospadias(13). in the current study, we evaluated the effect of the width of the urethral plate and glanular width on the outcome of hypospadias repair. most of our patients had coronal and distal penile hypospadias (30 patients 78.9 %), the same findings by prat et al.; the reason for this is not clear but might be explained by the geographical location(14). we used 8 mm in the present study because urethral plate width 8 mm or greater is essential for the creation of adequate neourethra and successful hypospadias repair(16), nguyen et al.(9) and aboutaleb et al. (6) in their studies also used 8 mm as the dividing line. while da silva et al.(15) in their study used 10 mm as the dividing line between narrow and wide urethral plates. the urethral plate of more than 8 mm is associated with good cosmetic outcomes(16,17). on the assessment of the functional outcome, there was no statistically significant difference between the two groups (p-value = 0.61). our findings followed nguyen et al., 2004 & da silva ea et al., 2014, who reported that the width of the urethral plate does not affect the functional outcome of hypospadias repair(9,15). however, other studies concluded that a narrow urethral plate is associated with a poor functional outcome such as poor urinary stream and complications such as meatal stenosis and urethrocutanous fistula(17-19). this is related to the fact that there were confounding variables in their studies, such as penile size, glans shape, and vascularity of the prepuce, which were not separately analyzed. we did not assess the penile size, glans shape, and vascularity of the prepuce in the current study. there was a statistical significance increase in hope score among cases which `had upw ≥ 8mm compared to cases < 8 (p-value = 0.02) [there was a statistical positive correlation between hope score and upw (r = 0.41, p-value = 0.02)]. these findings are in accordance with krull, rissmann et al. 2018 who reported a significant correlation between the hope-score and the outcome after hypospadias repair was observed.(15). however, k e chukwubuike et al.; in their study, found that the hope-score after hypospadias repair may not be determined by upw(16) there was a diversity in the complications following hypospadias repair. it ranges from 6-30%(17,18). the most common complication we recorded was the urethrocutanous fistula. the difference in surgical experpediatric urology 54 figure 3: (a) dressings were applied, and the stent drips into the diaper; the 1st dressing was done after five days (b) post-operative follow up of snodgrass patient after 12 months the upw effect on tip repair of distal penile hypospadias-galal et al. vol 19 no 1 january-february 2022 55 tise may explain these differences in complication rates due to our department's low volume of hypospadias repairs per year. in our study, on the assessment of the post-operative complications, there was no statistically significant difference between the two groups (p-value = 0.7). this finding agrees with the result from da silva, e.a. et al.2014 as they found that up width does not significantly affect the complication rate of tip repair in distal hypospadias;(19)while, aboutaleb et al.; reported a higher incidence in fistula in patients with narrow urethral plates when compared to those with wide urethral plate (6,18) meatal stenosis could be blamed for distal obstruction predisposing to fistula formation, which could be resolved with urethral dilation. in our study, the meatal stenosis of 3 cases (2 cases in group a & 1 case in group b) resolved with urethral dilation that agrees with the result from a elbakry, 1999 and radojicic zi et al., 2006 as they found that regular urethral dilatation is important in preventing adhesions between both sides of the incised plate, which could result in meatal stenosis and fistula(20,21). though this study was a prospective study, it was limited by a small sample size that hindered the significant statistical difference detection in complications. moreover, the outcome of repair, including complications done by a single surgeon, cannot be generalized as it depends on the surgeon's skills, among other factors. conclusions the pre-incision urethral plate width and glanular width were not correlated with tip outcome. a better hope score was associated with a wide urethral plate. however, the width of the urethral plate and glanular width may predict the functional outcome (urinary stream). references 1. silay ms, sirin h, tepeler a, et al. "snodgraft" technique for the treatment of primary distal hypospadias: pushing the envelope. j urol. 2012;188:938-42. 2. wilkinson dj, farrelly p, kenny se. outcomes in distal hypospadias: a systematic review of the mathieu and tubularized incised plate repairs. j pediatr urol. 2012;8:307-12. 3. arlen am, kirsch aj, leong t, broecker bh, smith ea, elmore jm. further analysis of the glans-urethral meatus-shaft (gms) hypospadias score: correlation with postoperative complications. j pediatr urol. 2015;11:71.e1-5. 4. holland aj, smith gh. effect of the depth and width of the urethral plate on tubularized incised plate urethroplasty. j urol. 2000;164:489-91. 5. merriman ls, arlen am, broecker bh, smith ea, kirsch aj, elmore jm. the gms hypospadias score: assessment of interobserver reliability and correlation with post-operative complications. j pediatr urol. 2013;9(6 pt a):707-12. 6. aboutaleb h. role of the urethral plate characters in the success of tubularized incised plate urethroplasty. indian j plast surg. 2014;47:227-31. 7. bush nc, snodgrass w. pre-incision urethral plate width does not impact shortterm tubularized incised plate urethroplasty outcomes. j pediatr urol. 2017;13:625.e1-.e6. 8. nguyen mt, snodgrass wt, zaontz mr. effect of urethral plate characteristics on tubularized incised plate urethroplasty. j urol. 2004;171:1260-2; discussion 2. 9. bush nc, dajusta d, snodgrass wt. glans penis width in patients with hypospadias compared to healthy controls. j j pediatr urol. 2013;9(6 pt b):1188-91. 10. van der toorn f, de jong tp, de gier rp, et al. introducing the hope (hypospadias objective penile evaluation)-score: a validation study of an objective scoring system for evaluating cosmetic appearance in hypospadias patients. j pediatr urol. 2013;9(6 pt b):1006-16. 11. stein dm, thum dj, barbagli g, et al. a geographic analysis of male urethral stricture aetiology and location. bju int. 2013;112:8304. 12. moriya k, kakizaki h, tanaka h, et al. long-term cosmetic and sexual outcome of hypospadias surgery: norm related study in adolescence. j urol. 2006;176(4 pt 2):188992; discussion 92-3. 13. saeedi sharifabad p, poudineh v, hiradfar m, mohammadipour a, shojaeian r. current trends in hypospadias repair. where are we standing? j urol. 2020. 14. eassa w, he x, el-sherbiny m. how much does the midline incision add to urethral diameter after tubularized incised plate urethroplasty? an experimental animal study. j urol. 2011;186(4 suppl):1625-9. 15. krull s, rissmann a, krause h, et al. outcome after hypospadias repair: evaluation using the hypospadias objective penile evaluation score. eur j pediatr surg. 2018;28:268-72. 16. chukwubuike ke, obianyo nen, ekenze so, ezomike uo. assessment of the effect of urethral plate width on outcome of hypospadias repair. j pediatr urol. 2019;15:627.e1-.e6. 17. bhat a, mandal ak. acute post-operative complications of hypospadias repair. indian j urol. 2008;24:241-8. 18. shapiro sr. complications of hypospadias repair. j urol. 1984;131:518-22. 19. da silva ea, lobountchenko t, marun mn, rondon a, damião r. role of penile biometric characteristics on surgical outcome of hypospadias repair. pediatr surg int. 2014;30:339-44. 20. elbakry a. tubularized-incised urethral plate urethroplasty: is regular dilatation necessary for success? bju int. 1999;84:683-8. 21. radojicic zi, perovic sv, stojanoski kd. calibration and dilatation with topical corticosteroid in the treatment of stenosis of neourethral meatus after hypospadias repair. bju int. 2006;97:166-8. the upw effect on tip repair of distal penile hypospadias-galal et al. endourology and stone disease ureteroscope-aided reinsertion of dislodged pigtail nephrostomy tube through collapsed tract shun-kai chang1#, bo-jung chen1#, yeong-chin jou1*, min-chun li1, pei-yi chen1 purpose: to introduce an alternative method for the reinsertion of pigtail catheter for collapsed nephrostomy tract. materials and methods: between january 2013 and october 2016, a total of ten patients with collapsed nephrostomy tract underwent ureteroscope-aided reinsertion of the pigtail catheter after the failure of manual reinsertion by guidewire. under local anesthesia, the ureteroscope was inserted through a percutaneous nephrostomy (pcn) opening. the access path was obtained by careful tracing for prior placement of pigtail catheter. the clinical features of these ten patients, including operation time, success rate and complications, were evaluated by retrospective chart review. the clavien classification was applied to define the grade of complications after one-month follow-up. results: among the ten cases of difficult pcn revision, eight underwent the procedure within 24 hours of the dislodgement. the remaining two patients underwent the procedure within 2 days and 8 days. the period of pigtail tube dwelling ranged from 2 weeks to 10.5 months. the procedure was successful in nine cases and the operation time ranged from 10 to 30 minutes. no fluoroscope was used in any patient. all of the nine patients had a good drainage function after tube reinsertion. complications occurred only in one patient who had postoperative fever classified as clavien grade 2. conclusion: reinserting the dislodged pigtail nephrostomy tube with the aid of an ureteroscope is an alternative method that may decrease the necessity of new tract creation. key words: dislodgement; kidney; nephrostomy; percutaneous; ureteroscopy introduction since 1955, when goodwin and colleagues pub-lished the first therapeutic percutaneous nephrostomy (pcn), there has been a worldwide application of pcn in either relief of urinary obstruction, urinary diversion, access for endourologic procedures, or diagnostic tests(1). approximately 10% of the combined major and minor complication rates of pcn insertion with 0.05%–0.3% mortality rate were reported in most publications(2,3). the incidence of tube dislodgement ranges from 11%– 30% in the months after the procedure(4,5). pigtail catheters are the smallest nephrostomy tubes available for urinary drainage or diversion. if a pigtail tube dislodges, it is sometimes too difficult to pass the guidewire through the collapsed tract. these cases are addressed by either performing a radiology-guided nephrostomy tractogram to pass a guidewire or a renal puncture for new pcn creation. in order to reinsert the dislodged nephrostomy tube through the original tract, a novel method was used at our hospital. ureteroscopy was performed to identify the missing tract for replacement of the pigtail catheter. this procedure may significantly decrease the necessity of new pcn creation and hence could diminish the complications of pcn. the aim of this study is to evaluate the efficacy and 1 department of urology, ditmanson medical foundation chia-yi christian hospital, chia-yi, taiwan. *correspondence: department of urology, ditmanson medical foundation chia-yi christian hospital, chia-yi, taiwan. tel: +886-5-2765041. fax: +886-5-2774511. e-mail: b729@cych.org.tw. # shun-kai chang and bo-jung chen contributed equally to this manuscript received november 2017 & accepted february 2018 outcome of performing ureteroscope-aided reinsertion through the collapsed tract in patients with pcn tube dislodgement. to our knowledge, this method has never been reported in the literature before. materials and methods study population between january 2013 and october 2016, 10 patients underwent ureteroscope-aided pigtail catheter reinsertion after the manual reinsertion of a new catheter into the collapsed tract failed. the study procedures were well explained to each patient and informed consent was obtained. the institutional review board of chia-yi christian hospital approved this study. inclusion and exclusion criteria patients with pcn tube dislodgement underwent tract re-establishment by a straight tipped guidewire and dilating sheath. patients with failed pcn tube reinsertion subsequently received ureteroscope-aided reinsertion and were enrolled in this study. procedures the patients lay in a prone or decubitus position initially without any anesthesia. lidocaine (2%) instillation into the pcn tract was given to patients who indicated feeling pain during the procedure. all ten patients had endourology and stones diseases 251 vol 16 no 03 may-june 2019 252 received ultrasound guided pcn drainage with an 8 or 10 f catheter for the relief of urinary tract obstruction. at the beginning of the procedure, we introduced a 6.5 f (richard wolf, germany) semi-rigid ureteroscope into the pcn cutaneous orifice. the access tract was dilated with the infusion of irrigation fluid, and this allowed us to advance the ureteroscope. we approached the renal pelvis with the ureteroscope by careful tracing or in some cases, with the aid of the soft end of a straight guidewire (angiotech, denmark) for the tortuous tract (figure 1). after reaching the renal pelvis, we inserted the guidewire in preparation for the subsequent insertion of a new pigtail catheter. no fluoroscope or ultrasound was used as access guidance throughout the whole course of the procedure. after completing the procedure, we checked the drainage patency by irrigation with normal saline. subsequent kub was done to confirm the position of the catheter. cephalexin was prescribed as a prophylactic antibiotic for 3 days following the procedure. evaluations patient demographics, the cause of pcn, time from pcn creation to dislodgment and dislodgment to procedure, operation time, and postoperative complications were analyzed by a retrospective chart review. the operation time was measured as the time from the completion of surgical site draping to the end of the pigtail tube reinsertion. postoperative complications were defined as the incidence of any complication within the first month after the procedure. complications were classified into five grades using clavien–dindo classification. statistical analyses continuous variables are presented as numbers, whereas the categorical data are presented as means ± standard deviations (sd). spss 21.0 was used to perform all statistical analyses. results the mean age of the ten enrolled patients was 76.1 ± 10.73 years (56–85 years); three were male and seven were female. the demographic and clinical characteristics of the enrolled patients are shown in table 1. all the dislodgement events were attributed to accidental pulling. the reasons for pcn catheter insertion included ureteral stones in three patients, ureteral strictures in two patients, and cancer in five patients. the average period elapsed since pcn catheter placement was 5.05 ± 3.73 months (2 weeks–10.5 months). eight patients received the ureteroscope-aided reinsertion procedure within 24 h after the pigtail nephrostomy tube had been dislodged. the others received the procedure 2 days and 8 days post dislodgement. the time to procedure, operation time, and procedure results are presented in table 2. upon ureteroscopy inspection, an epithelized access tract was found in most patients. the access tract was usually obscured at the level of the external oblique muscle. gentle probing with guidewire was used to discover the lost tract. the diameter of the ureteroscope is smaller than that of the access tract; therefore, the excess irrigation fluid usually leaks outside the access tract without significant increase in the pressure of the collecting system. the mean operative time was 21.5 ± 7.09 min with a range of 10–30 min. in nine of the ten patients (90%), pigtail nephrostomy tube was successfully reinserted with the aid of a ureteroscope. the one failed case was because of the inability to identify the concealed tract in the midway of fascia level. subsequently, a renal puncture with new pcn creation under ultrasound guide was performed for this patient. during the 1-month postoperative follow-up, the new inserted pigtail functioned well in all patients table 1. patients’ demographics and clinical characteristics case gender (female/male) age (years) etiology of pcn pcn size (french) 1 female 64 retroperitoneal leiomyosarcoma invasion to kidney 8 2 female 81 ureteral stone 8 3 female 63 ureteral stricture 8 4 male 85 bladder cancer invasion to uvj* 8 5 male 83 ureteral cancer 10 6 male 85 bladder cancer invasion to uvj 8 7 female 81 ureteral stone 8 8 female 81 post-radiotherapy ureteral fibrosis 8 9 female 56 cervical cancer related 8 10 female 82 ureteral stone 8 abbreviations: pcn, percutaneous nephrostomy; uvj, ureterovesical junction case pcn creation to dislodgment (months) dislodgment to procedure (h) operation time (min) result complication 1 0.5 < 24 25 success nil 2 9.5 48 30 success nil 3 1 < 24 20 failure nil 4 5 < 24 20 success nil 5 5 < 24 20 success nil 6 2 < 24 15 success fever 7 10 192 10 success nil 8 4 < 24 30 success nil 9 3 < 24 30 success nil 10 10.5 < 24 15 success nil abbreviations: pcn, percutaneous nephrostomy table 2. results of ureteroscope-aided reinsertion reinsertion of pigtail renal tube by ureteroscope-chang et al. and only one patient developed postoperative fever 1 day after the procedure. this patient received intravenous antibiotic treatment and recovered well without any sequelae. the postoperative complication was fit with clavien grade 2, defined as requiring pharmacological treatment with drugs other than such allowed for grade 1 complications(6). there were no procedure-related complications among the rest of nine patients. discussion pcn is an interventional procedure that is widely used for the drainage of the obstructive upper urinary tract. catheter-related complications, such as obstruction, infection, and dislodgement, are common(7,8). in cases of dislodged nephrostomy catheters where passing the guidewire into the collecting system fails, revision may involve having the radiologist perform nephrostomy tractogram to access tract restoration or to create a new access tract. however, an emergency radiologist consultant is not always available to perform catheter reinsertion immediately after catheter dislodgement. delays in pcn reinsertion may increase the risk of urinary tract infection because of urine retention in the collecting system and decrease the success rate for catheter reinsertion because of tract distortion or healing. the recreation of a new access tract is a more invasive procedure and will carry the risk of major complications. the major complications of pcn placement include hemorrhage, vascular injury, sepsis, bowel transgression, and pleural complications(2). the rate of major complications was 1.6%–6% in the literature(5,9), whereas that of minor complications was 11%–25 %(5,9). ureteroscope-aided catheter reinsertion is a simple modification that the endourologist can perform without the necessity of x-ray exposure. it can also be done promptly after the patient’s visit. in this study, we used 6.5 f ureteroscopes to reinstate the access tract with a high success rate (90%) equivalent to that of tract revision by tractogram performed by the radiologist felipe et al(10). they reported 25 cases of reinsertion of pcn tubes with a success rate of 88% when performed within the first 48 h after dislodgement. the procedure in our study is also timesaving and the mean procedure time was only 21.5 min. longer pcn catheter indwelling time implies a mature access tract, which will theoretically increase the success rate for the reinsertion of the dislodged catheter. the catheter indwelling time of the patient whose ureteroscope-aided catheter reinsertion failed in the present study was only one month. the access tract heals after the dislodgement of the catheter; a shorter interval between dislodgement and reinsertion increases the success rates of catheter reinsertion. most patients in our study received the procedure within 24 h after the pigtail nephrostomy tube dislodged. one patient successfully underwent the procedure 2 days after dislodgement; another one had a successful procedure more than one week after dislodgement. on account of the limited number of cases, whether the catheter indwelling time after pcn creation and dislodgement interval may influence the successful rate of replacement needs to be further studied. the morbidity in this case series was very low. only one patient experienced transient fever after the procedure. long-term catheter indwelling tends to harbor bacteria cloning(11,12) in the collecting system and irrigating infusion during ureteroscope manipulation carries a high risk of urinary tract infection. the low infection rate in this report is possibly because of the caliber of the scope being rather smaller than the diameter of pre-existed tract and the infused fluid spilling toward the opening of the access tract. such an open irrigation system does not increase the hydrostatic pressure in the collecting system, and this might increase the risk of bacteria backflow. the advantages of the ureteroscope-aided reinsertion technique include its relative simplicity such that it can be performed easily by the endourologist. it is a highly effective procedure that can be done under local or no anesthesia, and it can be done on an outpatient basis. nonetheless, there are some limitations and constraints in our study. first, our study had a retrospective nature and was based on a relatively small sample size. second, in the era of mini-perc for percutaneous renal surgery, many percutaneous procedures can be done by mini nephroscopy with safety and efficacy(13,14). whether mini nephroscopy affects the outcomes of the procedures for the restoration of collapsed tract is undetermined in the present study because the mini nephroscope system is not available at our hospital. conclusions ureteroscope-aided reinsertion of dislodged pcn through a collapsed tract has a similar success rate compared with that of tractogram-aided catheter reinsertion without an increase in the morbidity. the potential advantages of this modification include that it may be performed by the endourologist soon after the patient’s visit, and this would allow an increase in the success rate and preventing the sequels of urinary tract obstruction. it may also decrease the requirement of a new pcn creation, which carries a high risk of major complications. it may be an alternative method for the urologists to manage patients with collapsed tract after the dislodgement of the pigtail pcn catheter. acknowledgment we would like to acknowledge dr. ian-seng cheong for assistance with statistical analyses. figure 1. a well-epithelized tract can usually be identified during ureteroscope inspection. (arrow: epithelialized tract, arrowhead: renal pelvis) reinsertion of pigtail renal tube by ureteroscope-chang et al. endourology and stones diseases 253 vol 16 no 03 may-june 2019 254 conflict of interest the authors report no conflict of interest. references 1. dagli m, ramchandani p. percutaneous nephrostomy: technical aspects and indications. semin intervent radiol. 2011; 28:424-37. 2. ramchandani p, cardella jf, grassi cj, et al. quality improvement guidelines for percutaneous nephrostomy. j vasc interv radiol. 2003; 14:s277-81. 3. zagoria rj, dyer rb. do’s and don’t’s of percutaneous nephrostomy. acad radiol. 1999; 6:370-77. 4. farrell ta, hicks me. a review of radiologically guided percutaneous nephrostomies in 303 patients. j vasc interv radiol. 1997; 8:769-74. 5. lee wj, patel u, patel s, pillari gp. emergency percutaneous nephrostomy: results and complications. j vasc interv radiol. 1994; 5:135-9. 6. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 7. lewis s, patel u. major complications after percutaneous nephrostomy—lessons from a department audit. clin radiol. 2004; 59:1719. 8. radecka e, magnusson a. complications associated with percutaneous nephrostomies: a retrospective study. acta radiol. 2004; 45:184-8. 9. karim r, sengupta s, samanta s, aich rk, das u, deb p. percutaneous nephrostomy by direct puncture technique: an observational study. indian j nephrol. 2010; 20:84-8. 10. collares fb, faintuch s, kim sk, rabkin dj. reinsertion of accidentally dislodged catheters through the original track: what is the likelihood of success? j vasc interv radiol. 2010; 21:861-4. 11. tenke p, riedl cr, jones gl, williams gj, stickler d, nagy e. bacterial biofilm formation on urologic devices and heparin coating as preventive strategy. int j antimicrob agents. 2004; 23:67-74. 12. jones sr, smith jw, sanford jp. localization of urinary-tract infections by detection of antibody-coated bacteria in urine sediment. n engl j med. 1974; 290:591-3. 13. jackman sv, docimo sg, cadeddu ja, bishoff jt, kavoussi lr, jarrett tw. the “mini-perc” technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol. 1998; 16:371-4. 14. kirac m, bozkurt öf, tunc l, guneri c, unsal a, biri h. comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in management of lowerpole renal stones with a diameter of smaller than 15 mm. urolithiasis. 2013; 41:241-6. reinsertion of pigtail renal tube by ureteroscope-chang et al. letter living donor kidney transplantation: global and regional trend mohammad nadjafi-semnani1*, nasser simforoosh2, ali nadjafi-semnani3 request for kidney transplantation (k.t.) is increasing rapidly because of the worldwide pandemic of end-stage renal disease, and the most critical issue is organ shortage. the available deceased donors will not resolve the continuing scarcity of organs. it is now professionally and ethically acknowledged and is vital to pay money to the donors for excluding disincentives of living organ donation. living organ donation should be a vital part of the k.t. program of any country. 1associate professor of urology, birjand university of medical sciences, birjand, iran. 2distinguished professor of urology, urology-nephrology research center, shahid labafinejad medical center, the center of excellence in urology and kidney transplantation, shahid beheshti university of medical sciences, tehran, iran. 3resident of general surgery, zahedan university of medical sciences, zahedan, iran. *correspondence: associate professor of urology, birjand university of medical sciences, birjand, iran. e mail: monadjafi@gmail.com received may 2021 & accepted may 2021 the worldwide pandemic of end-stage renal disease results from an aging population, increased heart and vascular diseases, and inadequate preventive medical care(1). kidney transplantation (k.t.) is the treatment of choice for escalating chronic kidney disease. request for k.t. is increasing rapidly(2,3), and the most critical issue is the organ shortage. obviously, the available deceased donors will not resolve the continuing scarcity of organs(1). at the end of 2017, 192,307 patients were on k.t. waiting lists globally. however, only 34% received k.t. k.t.'s mean waiting time is 3 to 5 years, and yearly mortality is 15% to 30%(2). due to the deficiency of deceased donor kidneys (ddk), living kidney donation (lkd) has become a crucial necessity for the increasing number of patients with end-stage renal disease in need of transplantation(2). the superiority of lkd over ddk is diverse: lkd helps patients avoid the waitlist and alleviate the hardships of dialysis. the kidney survival rates for lkd are significantly better; 50% still functioning after 20 years; for ddk, this is only ten years(2); kidney survival halflife of 17–18 years for ldk vs. 10–11 years for ddk(4). in 2016, the graft failure rates for ldk and ddk were 1.3% and 4.8%; 34.2% and 51.6% at six months and ten years, respectively(5). also, ldk is more cost-effective than ddk. smith and colleagues figured out that ldk's mean payment to be 37.7% less than ddk(6). in most cases, living donation enables patients to circumvent years of dialysis waiting for ddk. longer time on dialysis is consistent with inferior results after a kidney transplant(6). five and ten year event free graft survival is two times better for k.t. recipient on dialysis less than 6 months vs. more than two years (78% vs. 58% at 5 years; 63% vs. 29% at 10 years, respectively)(7). many patients prefer ldk to ddk(2). for these reasons, this is evident that adequate medical and ethical rationals exist to encourage the many possibilities of lkd(2). in the u.k., living donor kidney transplantation (ldkt) is one of the most forward-looking and growing areas of donation and transplantation(8). from 2000 to 2010, living donation transplantation activity in the u.k. trebled, most of which was in ldkt because: • state of the art donor care is a prime concern • patient and graft survival are better than for deceased donor kidney transplantation (ddkt) • it is the treatment of choice for pre-emptive transplantation • it is the treatment of choice for clinically complex patients • it is a cost-effective alternative to dialysis also, more patients and their families will benefit from k.t., and it will be feasible to provide transplants to those that might not else get a transplant(9). the u.k. national health service (nhs) claims benefit as more people get k.t. before entering the kidney dialysis treatment, thus reducing costs(9). the strategy's effective operation will be reliant on all members of the broader transplant community(9). to better promote the plan, nottingham city hospital in an innovative manner sent a silver pin to every organ donor in recognition of the gift of donation. now sending the gift is adopted by nhs to every donor in the uk.(9). in the u.k., the rate of ldkt was 16 per million population (pmp) in 2016, and the proposed plan by the ldkt strategy implementation group was to reach 26 pmp by march 2020(9). from 2004 to 20017 the lkd rate decreased in the u.s. due to the substantial economic disincentives that exist, including out-of-pocket expenses, loss or increased costs of insurability, and possible loss of career(7). stale in 2014 wrote: “our current transplant regime is a qualified failure. in 2013, in one year about 4300 patiets in the waiting list died, and over 3000 were removed from the list due to medical conditions that prohibited k.t.(10). about 27 years ago, the typical waiting time for a ddkt about one year; now, it is almost five years(10). in many parts in the u.s. it has reached 10 years—if one can live for these years(10).the u.s. transplant community has recognized the need to lessen barriers and increase oppurtiunities was posed by the the national organ transplant act (nota) of 1984 which expressly has forbidden the offer of ‘valuable urology journal/vol 18 no. 3/ may-june 2021/ pp. 359-361. [doi: 10.22037/uj.v18i.6820] consideration’ for lkd(7). in 2007, the u.s. congress funded the national living donor assistance center (nldac) to assist low-income organ donors and recipients by paying travel and lodging expenses(11). once more, on july 10, 2019, president of the united states issued an executive order to reimburse living donors for extra costs associated with organ donation, such as lost wages and childcare(11). hhs secretary alex azar states that “decades of paying for sickness and procedures in kidney care, rather than paying for health and outcomes, has produced less-than-satisfactory outcomes at tremendous cost. through new payment models and many other actions under this initiative, the u.s. administration will transform this situation and deliver americans better kidney health, more kidney treatment options, and more transplants(12).” in the united states there has been a energetic argument on the wisdom of paid donation, indirectly referred to as “compensation” or “financial incentives(7). matas states: “organ sale just does not sense proper; but letting patients die on the waiting list (when this could be prevented) also does not feel correct.”(13) are doctors “failing their patients “as long as the ban on payments is maintained?(13) working group on incentives for living donation claim that incentives for donation could—and should—be explored in other countries to increase the number of donations(2). this may not be appropriate in all countries(2). in some authoritiy, such as the netherlands, the number of lkds is now so high that the waitlist has decreased significantly(2). models of ‘rewarded gifting’ may not be needed in countries with high lkd rates(2). supporters of financial rewards or incentives for live kidney donors(3) say that the prohibition of payment is “sanctimonious.”(2) in current transplant medicine, everybody is earning, but the donor: society benefits, the hospital gets reimbursements, the surgeon and the medical team are salaried, the transplant coordinator gets waged, and the recipient receives a vast profit(2). some authors say that an effective and proper response is regulation or a monopsonistic market(2,14). they also submit the most crucial and proper standards or conditions(2) for such a marketplace(2). in contrast to the concept of “transplant commercialism”, there is no doubt that organ trafficking should be forbidden totally(2). it is projected that about 5–10% of all kidney transplants globally in 2005 were through transplant tourism(7). the idea of “rewarded gifting” was developed during the 1990s. according to this standards, organs are not sailed, rather donors have a “reward” for the gifted organ(14). reward given to the donors is not the same as obtaining a good with a price tag on it, but rather a acknowledgement that somebody who volunteer to donate an organ should have gratitude and some level of compensation for time taken from work, travel, and loss of wages incurred, and even perhaps to be suffered in future, with the intention of supply the organ(14). obviously it is not ethically suitable to offer a tempting “inducement” that may drive miserable people to offer their organs. defining whether an offer meet the requirements as fair compensation or a coercively persuasive inducement is a serious subject and an important mission of the ethics committees that would develop and manage any procurement policy involving donor compensation(14). regarding ldk, who has changed its principle of transplantation during the last three decades. in 1991 the who issued its guiding principles on human organ transplantation(2). principle 3 stated that organs for transplantation “should be removed preferably from the bodies of deceased persons.” adult living persons “may donate organs, but in general, should be genetically related to the recipient.” for years ldk was generally limited to genetically related donors(2). in 2008 the who updated its guiding principles. principle 3 now states, “living donors should be genetically, legally or emotionally related to their recipients.”(2) a working group of the european platform on ethical, legal, and psychosocial aspects of organ transplantation fig 1. ldkt pmp in 2019. https://www.irodat.org/ letter 360 vol 18 no 3 may-june 2021 361 (elpat) developed a new classification for lod(2). at present, the donor pool has extended from genetically related donors to partners, supports, friends, and even anonymous donors(2). by 2010, genetically unrelated donors accounted for 48% of lkd in the united states(2), 45% in the eurotransplant area, and 52% in the netherlands(2). the development of new technologies and innovations, and changes under the human tissue acts (h.t. acts) has made more living donor organs available for transplant in the u.k.(8). instances of successful other living donation programs are national kidney-exchange programs, domino-paired anonymous donation, abo-incompatible programs, and desensitization in hla incompatible recipients(2). under the rule and regulation of the parliament’s law, iran runs a regulated ngo compensation system called the iranian model of kidney transplantation, a rewarded gifting model, and an active cadaveric transplantation program(14). figure one shows the rate of ldk transplantation in 2019. figure two compares the rate of ldk of iran and turkey. the iranian model has a crucial role in minimizing transplantation costs as the model views this challenging surgery as a humanitarian act rather than a source of revenue(14). references 1. delmonico f-l, dew m-a. living donor kidney transplantation in a global environment. kidney international. 2007;71:608-14. 2. ambagtsheer f, weimar w. ethical and legal aspects of kidney donation. in: knechtle sj, marson pl, morris pj, eds. kidney transplantation principles and practice. 8th ed. china: elsevier; 2020:724-36. 3. simforoosh n. an updated iranian model in kidney transplantation: rewarded gifting a practical solution to kidney shortage crisis. urol j. 2016;13:2803. 4. bastani b. the iranian model as a potential solution for the current kidney shortage crisis. int braz j urol. 2019;45:194-6. 5. lee l-y, pham ta, melcher ml. living kidney donation: strategies to increase the donor pool. surgical clinics. 2019;99:37-47. 6. smith cr, woodward rs, cohen ds, et al. cadaveric versus living donor kidney transplantation: a medicare payment analysis 1. transplantation. 2000;69:311. 7. bastani b. the present and future of transplant organ shortage: some potential remedies. j nephrol. 2020;33:277-88. 8. blood n, site tw. living donor kidney transplantation 2020: a uk strategy. 2014. 9. transplant ne-nba. living donor kidney transplantation: position paper august 2017. pdf] https://nhsbtdbe.blob.core.windows.net/ umbraco-assets-corp/7887/august-2017living-donor-kidney-transplantation-positionpaper.pdf. accessed august 7. 2020, 2020. 10. satel s, morrison jc, jones rk. state organdonation incentives under the national organ transplant act. law & contemp. probs. 2014;77:217. 11. mccormick f, held pj, chertow gm, peters tg, roberts jp. removing disincentives to kidney donation: a quantitative analysis. journal of the american society of nephrology. 2019;30:1349-57. 12. [no authorlisted]. hhs launches president trump's ‘advancing american kidney health' initiative | hhs.gov. https://www.hhs. gov/about/news/2019/07/10/hhs-launchespresident-trump-advancing-american-kidneyhealth-initiative.html. 13. matas aj. the case for living kidney sales: rationale, objections and concerns. american journal of transplantation. 2004;4:2007-17. 14. simforoosh n. kidney donation and rewarded gifting: an iranian model. nat clin pract urol. 2007;4:292-3. urological oncology urine biomarkers for the diagnosis of bladder cancer: a network meta-analysis ying dong1, ting zhang2, xining li2, feng yu2, hongwei yu 2, shenwen shao2* purpose: to identify effective urine biomarkers for bladder cancer diagnosis. materials and methods: this meta-analysis was conducted following the guidelines of the meta-analyses (prisma) statement. relevant studies were searched from the pubmed, embase, and cochrane library databases. heterogeneity tests were performed using q statistics and i2 tests to determine the use of the random or fixed effects model. a direct comparison meta-analysis and network meta-analysis were conducted. the effect values are presented as odds ratios and 95% confidence intervals. sensitivity analysis and consistency tests were performed. results: fifty-eight studies with 12,038 participants were included. direct comparison meta-analysis showed statistically significant differences in bladder cancer antigen (bta) trak vs. nuclear matrix protein 22 (nmp22), bta stat vs. urine cytology (uc), and fluorescence in situ hybridization (fish) vs. uc, among the sensitivity indicators. among the specificity indicators, there were statistically significant differences in bta trak vs. uc, immunocyt (immunocyte) vs. nmp22, and bta stat vs. fish. among the positive predictive indicators, nmp22 vs. uc, bta stat vs. uc, and fish vs. nmp22 showed statistically significant differences. among the negative predictive indicators, the differences in fish vs. uc, fish vs. nmp22, and hyaluronidase 1 (hyal-1) vs. uc were statistically significant. among the accuracy indicators, fish vs. nmp22, fish vs. uc, and hyal-1 vs. uc showed statistically significant differences. network meta-analysis showed that hyal-1, urothelial carcinoma associated 1 (uca1) and survivin had the highest sensitivity, while uc had the lowest sensitivity. the specificity of uc, fish, and hyal-1 was the highest, while that of uca1 was the lowest. in terms of positive predictive indicators, uc, fish, and hyal-1 had the highest positive predictive value, while the bta group had the lowest positive predictive value. in terms of negative predictive indicators, hyal-1, uca1, and survivin had the highest negative predictive value, while uc had the lowest negative predictive value. in terms of accuracy indicators, hyal-1, uca1, and survivin had the highest accuracy, while uc had the lowest accuracy. conclusion: hyal-1 and survivin are suitable urine biomarkers for bladder cancer diagnosis. keywords: bladder cancer; urine biomarker; network meta-analysis; diagnostic value introduction bladder cancer (bc) is a common malignancy of the genitourinary system, which is characterized by urine occult blood, lower back pain, and painful urination(1). bc is generally induced by family history, bladder infection, smoking, radiotherapy, and chemical exposure (2,3). the main bc types include transitional cell carcinoma, adenocarcinoma, and squamous cell carcinoma (4). bc patients in different stages may be treated with surgery, immunotherapy, chemotherapy, or radiotherapy, with five-year survival rates of 77% in the united states(5). bc is more likely to occur in males than in females, and often occurs in people between the ages of 65–85 years(6). in 2015, bc affected approximately 3.4 million people and was responsible for 188,000 deaths globally(7). therefore, bc should be further studied to improve its diagnosis and treatment. with the development of molecular biology techniques, 1schools of medicine and nursing sciences, huzhou university, huzhou central hospital, huzhou, zhejiang, 313000, china. 2schools of medicine and nursing sciences, huzhou university, huzhou, zhejiang, 313000, china. *correspondence: schools of medicine and nursing sciences, huzhou university, no.1 xueshi road, wuxing district, huzhou, 313000, china. tel: +86-15857277362. email: jiajitouwen6@163.com received may 2020 & accepted september 2021 new bc detection methods have arisen in recent years. bladder tumor antigen (bta) and fluorescence in situ hybridization (fish) are the primary urine biomarkers for noninvasive screening and monitoring of bc in clinical research(8), however, the sensitivity and specificity of urine biomarkers for bc diagnosis vary widely among different studies. for example, nuclear matrix protein-22 (nmp22) and fibronectin have greater sensitivity than voided urine cytology (uc) and urinary bta, while voided uc and nmp22 have superior specificities(9). urinary bta has higher sensitivity and specificity for screening lowgrade and low-stage bc, and thus, may be more valuable for bc diagnosis than the bta stat test and nmp22(10). uc is highly specific but poorly sensitive for detecting bc, and fish combined with uc has good sensitivity and specificity in evaluating bc(11). moreover, direct comparison meta-analyses have explored the diagnostic value of urine biomarkers urology journal/vol 18 no. 6/ november-december 2021/ pp. 623-632. [doi: 10.22037/uj.v18i.6254] in bc(12,13). chou et al. found that urine biomarkers miss a considerable fraction of bc patients, and their accuracies are low for low-grade and low-stage tumors(12). guo et al. revealed that the uc test may have a higher q index, specificity, negative likelihood ratio (lr), positive lr, area under the curve, and diagnostic odds ratio in comparison to the bta stat test, while the sensitivity of the bta stat test is superior to that of the uc test(13). however, no relevant network meta-analyses have been published to date. therefore, it is necessary to carry out urine biomarkers for diagnosing bc-dong et al. figure 2. the network diagram. uc: urine cytology; fish: fluorescence in situ hybridization; nmp-22: nuclear matrix protein 22; uca1:urothelial carcinoma associated-1; hyal-1: hyaluronidase 1; uc: urine cytology; immunocyt: immunocyte; bta: bladder cancer antigen. figure 1. the literature screening processes. urological oncology 624 a network meta-analysis of the literature related to the accuracy of urine biomarkers in bc diagnosis using cystoscopy or pathological examination as the gold standards. this study may clarify the diagnostic values of several urine biomarkers for bc and provide a scientific basis for future clinical treatment, including hyaluronidase 1 (hyal-1), urothelial carcinoma associated 1 (uca1), survivin, immunocyte (immunocyt), bta stat, nmp22, bta trak, uc, and fish.. materials and methods this meta-analysis was conducted following the guidelines of the meta-analyses (prisma) statement (14). search strategy from pubmed (http://www.ncbi.nlm.nih.gov/pubmed), embase (http://www.embase.com), and cochrane library (http://www.cochranelibrary.com) electronic literature databases, the english literature on urine biomarkers in bc diagnosis (published before september 30, 2020) were systematically retrieved. the searching words were "bladder urothelial cell carcinoma" or "carcinoma of urinary bladder" or "bladder cancer” or “carcinoma of bladder" or "bladder carcinoma" or "bladder tumor" and "bladder cancer antigen" or “bta” or "bta stat" or "bta trak", “fish” or "fluorescence in situ hybridization", “cytology” or “cytological”, “immunocyt” or “immunocyte”, "nuclear matrix protein 22" or “nmp22”, “hyal1”, or “hyaluronidase”, “survivin”, “urothelial carcinoma associated 1” or “uca1” and “diagnostic” or “diagnosis” or “sensitiveness” or “susceptibility” or “sensitivity” or “specificity” or “roc”. furthermore, the reference lists of reviews and retrieved articles were manually searched for additional records. inclusion and exclusion criteria strict inclusion criteria were established, and the included literature were selected based on the following criteria: (1) the study was a published english literature on the diagnostic value of urinary biomarkers in patients with suspected bladder cancer (including primary bladder cancer, and recurrent or metastatic bladder cancer); (2) the cases were pathologically confirmed by cystoscopy or surgically proven bladder cancer patients; (3) the control group included healthy controls and other benign tumor participants; (4) the study involved at least two bta, fish, uc, immunocyt, nmp22, hyal-1, survivin, and uca1, and the true positive (tp) number, false positive (fp) number, false negative (fn) number, and true negative (tn) number of diagnostic tests could be provided or obtained according to the relevant known indicators. the exclusion criteria were as follows: (1) the study contained incomplete data and could not be used for statistical analysis; (2) the study was comment, review, letter, etc.; (3) for repeatly published studies or studies involving the same population data, only the most recent study or the study with the most complete information would be included; (4) studies with fewer than 10 patients were excluded in order to reduce the bias caused by chance. data extraction two investigators independently extracted relevant data from the included literature, and the extracted contents included: the first author of the literature, publication year, study year, study country, total number of included people, age of the subjects, number of men, diagnostic methods of bladder cancer, and number of tp, fp, fn, and tn. the quality assessment of diagnostic accuracy studies (quadas) tool was used to evaluate literature quality, and 14 items were evaluated according to three criteria: "yes" (meeting this standard), "no" (not meeting or not mentioned), and "unclear" (partially meeting or not getting information obtained from the literature) (15). in case of any dispute in the data extraction and quality evaluation processes, a group discussion would be held, and a consistent result would be obtained after communicating with the third investigator. statistical analysis the meta package (version 3.4.3, http://cran.r-project. org/webpackages/meta/index.html) in r(16) was used for direct comparison. sensitivity (se), specificity (sp), positive predictive value (ppv), negative predictive value (npv), and accuracy were used to evaluate the efficacies of the two diagnostic methods, and the odds ratio (or) and 95% confidence interval (ci) were used as the effect values of the results. before data consolidation, the research data were tested for heterogeneity, and the i2 statistic was used for the heterogeneity test. if the heterogeneity test showed a statistical difference (i2 > 50%), the random effects model was used to calculate the combined effect value. alternatively, the fixed effects model was selected to merge data (i2 ≤ 50%) (17). egger’s test was used to evaluate whether there was publication bias among the included studies. network meta-analysis was conducted using the netmeta package (version 3.4.3, https://cran.r-project.org/ web/packages/netmeta/index.html) in r(18). the heterogeneity of the whole network meta-analysis was table 1. the comprehensive comparison of sensitivity bta stat 0.84[0.30;2.38] bta trak 1.08[0.67;1.74] 1.28[0.44;3.73] fish . 0.23[0.07;0.71] 0.27[0.06;1.19] 0.21[0.07;0.66] hyal-1 . 0.80[0.38;1.69] 0.95[0.28;3.22] 0.74[0.35;1.57] 3.54[0.97;12.92] immunocyt . 1.10[0.75;1.62] 1.31[0.47;3.60] 1.02[0.65;1.61] 4.84[1.56;15.02] 1.37[0.66;2.83] nmp22 . 0.60[0.31;1.14] 0.71[0.22;2.26] 0.55[0.28;1.09] 2.62[0.88;7.81] 0.74[0.30;1.83] 0.54[0.28;1.04] survivin . 2.69[1.90;3.81] 3.19[1.16;8.79] 2.49[1.72;3.59] 11.82[3.98;35.14] 3.34[1.65;6.77] 2.44[1.76;3.39] 4.52[2.52;8.10] uc ] 0.47[0.13;1.72] 0.55[0.11;2.78] 0.43[0.12;1.60] 2.05[0.39;10.82] 0.58[0.14;2.45] 0.42[0.12;1.55] 0.78[0.20;3.13] 0.17[0.05;0.61] uca1 abbreviations: uc, urine cytology; fish, fluorescence in situ hybridization; nmp-22, nuclear matrix protein 22; uca1:urothelial carcinoma associated-1; hyal-1, hyaluronidase 1; uc, urine cytology; immunocyt, immunocyte; bta, bladder cancer antigen. urine biomarkers for diagnosing bc-dong et al. vol 18 no 6 november-december 2021 625 urological oncology 626 calculated using cochran’s q statistic, and the model was selected based on the degree of heterogeneity (fixed effect model was used for the combination if the p-values of the q statistic were all > 0.05. otherwise, a random-effect model was used for the combination) (19). the mantel-haenszel method was used for the fixed effect model, and the dersimonian-laird method was utilized for the random effect model. the good and bad order of each intervention was ranked according to the p-score(20). the higher the p-score, the better the diagnostic effect. sensitivity analysis of the p-score was performed using random effect and fixed effect models. in the test of consistency, all the p-values of the node-splitting analysis were used to judge the results of indirect and direct comparisons. if p > 0.05, it was considered consistent with the consistency hypothesis. results eligible studies the literature retrieval results and literature screening processes are presented in figure 1. a total of 5,001 english articles were retrieved from pubmed (2103), embase (2209), and cochrane library (689) databases using previously developed retrieval strategies. after 1812 duplicates were removed, 3189 studies remained. then, 2960 articles were filtered out by browsing the title and abstract. from the remaining 229 studies, 171 studies (26 case series/reports, 28 letters/comments, 31 article reviews/meta-analysis, 9 repeated articles, and 77 researches with only a diagnostic method) were screened out after reading the full text. finally, 58 studies were included in this meta-analysis(21-78). study characteristics the 58 literatures were published from 1998 to 2020. the research locations include the united states, china, germany, spain, italy, and others. a total of 12,038 participants were enrolled in this study. in terms of the age index, the participants were predominantly middle-aged and elderly. in terms of gender, there were more male participants than female participants. biomarkers mainly included bta, fish, uc, immunocyt, nmp22, hyal-1, survivin, and uca1. in the bta trak group, the tp, fp, fn, and tn numbers were 98, 68, 53, and 188, respectively. in the bta stat group, the tp, fp, fn, and tn numbers were 1177, 573, 571, and 1631, respectively. in the immunocyt group, the tp, fp, fn, and tn numbers were 226, 69, 90, and 171, respectively. in the fish group, the tp, fp, fn, and tn numbers were 964, 368, 421, and 2878, respectively. in the nmp 22 group, the tp, fp, fn, and tn numbers were 1551, 731, 616, and 3612, respectively. in the uc group, the tp, fp, fn, and tn numbers were 2034, 935, 1592, and 6412, respectively. in the hyal1 group, the tp, fp, fn, and tn numbers were 205, 21, 13, and 1239, respectively. in the survivin group, the tp, fp, fn, and tn numbers were 616, 152, 48, and 509, respectively. in the uca1 group, the tp, fp, fn, and tn numbers were 153, 16, 20, and 110, respectively. (supplementary table 1). quality evaluation of the results showed that the overall quality of the literature was relatively high (supplementary table 2). however, part of the literatures did not mention “did the spectrum of patients represent the patients who will receive the test in practice,” and all the literatures did not mention “were uninterruptable/ intermediate test results reported.” in other projects, most studies showed a low risk of bias. direct comparison meta-analysis first, the heterogeneity test of sensitivity, specificity, positive predictive indicators, negative predictive indicators, and accuracy were performed, and suitable effect models were utilized (supplementary table 3 and supplementary figures 1–5). for instance, in the direct comparison meta-analysis, the sensitivity of bta bta stat 1.16[0.44;3.03] bta trak 0.34[0.20;0.58] 0.30[0.11;0.82] fish 0.26[0.02;2.81] 0.22[0.02;2.85] 0.76[0.07;8.37] hyal-1 0.59[0.27;1.30] 0.51[0.16;1.66] 1.73[0.80;3.75] 2.29[0.19;27.17] immunocyt 0.84[0.57;1.23] 0.72[0.28;1.84] 2.44[1.49;4.01] 3.23[0.30;34.91] 1.41[0.66;3.02] nmp22 1.29[0.53;3.14] 1.11[0.32;3.92] 3.76[1.45;9.73] 4.96[0.52;47.49] 2.17[0.71;6.67] 1.54[0.63;3.75] survivin 0.21[0.14;0.31] 0.18[0.07;0.47] 0.62[0.40;0.94] 0.81[0.08;8.69] 0.36[0.17;0.75] 0.25[0.18;0.36] 0.16[0.07;0.39]uc 2.01[0.31;13.20] 1.74[0.22;13.76] 5.87[0.89;38.75] 7.75[0.39;155.69] 3.39[0.47;24.64] 2.40[0.37;15.63] 1.56[0.20;11.94] 9.54 uca1 [1.52;60.04] table 2. comprehensive comparison of specificity. uc, urine cytology; fish, fluorescence in situ hybridization; nmp-22, nuclear matrix protein 22; uca1:urothelial carcinoma associated-1; hyal-1, hyaluronidase 1; uc, urine cytology; immunocyt, immunocyte; bta, bladder cancer antigen. uc, urine cytology; fish, fluorescence in situ hybridization; nmp-22, nuclear matrix protein 22; uca1: urothelial carcinoma associated-1; hyal-1, hyaluronidase 1; uc, urine cytology; immunocyt, immunocyte; bta, bladder cancer antigen. bta stat 1.28[0.59;2.77] bta trak 0.48[0.31;0.73] 0.37[0.16;0.85] fish . 0.26[0.03;2.13] 0.20[0.02;1.88] 0.55[0.07;4.52] hyal-1 0.58[0.31;1.05] 0.45[0.18;1.14] 1.20[0.66;2.20] 2.20[0.25;19.13] immunocyt 0.94[0.70;1.26] 0.74[0.35;1.55] 1.96[1.32;2.92] 3.60[0.44;29.31] 1.63[0.91;2.93] nmp22 1.30[0.64;2.62] 1.02[0.37;2.78] 2.71[1.27;5.79] 4.97[0.67;36.75] 2.26[0.94;5.43] 1.38[0.68;2.79] survivin 0.45[0.33;0.62] 0.36[0.17;0.76] 0.95[0.68;1.33] 1.74[0.22;14.11] 0.79[0.45;1.40] 0.48[0.37;0.64] 0.35[0.18;0.70] uc 2.36[0.43;13.07] 1.85[0.29;11.71] 4.93[0.89;27.42] 9.04[0.62;132.43] 4.10[0.69;24.26] 2.51[0.46;13.82] 1.82[0.29;11.22] 5.19 uca1 [0.96;27.92] table 3. the comprehensive comparison of positive predictive. urine biomarkers for diagnosing bc-dong et al. vol 18 no 6 november-december 2021 627 stat vs. fish, bta stat vs. nmp22, bta trak vs. uc, bta stat vs. uc, and fish vs. immunocyt showed significant heterogeneity (i2 > 50%); thus, the random effect model was adopted. there were no significant differences in the sensitivity of bta stat vs. immunocyt, bta trak vs. nmp22 (i2 < 50%); therefore, a fixed-effect model was used. the results of the meta-analysis showed that there were statistically significant differences between bta training and nmp22 (nmp22 was superior to bta trak), bta stat vs. uc (bta stat was superior to uc), fish vs. uc (fish was superior to uc), nmp22 vs. uc (nmp22 was superior to uc), hyal-1 vs. uc (hyal1 was superior to uc), survivin vs. hyal-1 (hyal1 was superior to survivin), survivin vs. uc (survivin was superior to uc), and uca1 vs. uc (uca1 was superior to uc) among the sensitivity indicators (p < 0.05). among the specificity indicators, there were statistically significant differences in bta training vs. uc (uc was superior to bta trak), immunocyt vs. nmp22 (immunocyt was superior to nmp22), bta stat vs. fish (fish was superior to bta stat), bta stat vs. bta trak (bta group was superior to bta stat), bta stat vs. uc (uc was superior to bta stat), nmp22 vs. uc (uc was superior to nmp22), hyal-1 vs. uc (uc was superior to hyal-1), survivin vs. uc (uc was superior to survivin), and uca1 vs. uc (uc was superior to uca1) (p < 0.05). among the positive predictive indicators, nmp22 vs. uc (uc was superior to nmp22), bta stat vs. uc (uc was superior to bta stat), fish vs. nmp22 (fish was superior to nmp22), immunocyt vs. nmp22 (immunocyt was superior to nmp22), bta trak vs. uc (uc was superior to bta track), uca1 vs. uc (uc was superior to uca1), and survivin vs. uc (uc was superior to survivin) showed statistically significant differences (p < 0.05). among the negative predictive indicators, fish vs. uc (fish was superior to uc), fish vs. nmp22 (fish was superior to nmp22), hyal-1 vs. uc (hyal-1 was superior to uc), survivin vs. hyal-1 (hyal-1 was superior to survivin), and survivin vs. uc (survivin was superior to uc) were statistically significant (p < 0.05). among the accuracy indicators, fish vs. nmp22 (fish was superior to nmp22), fish vs. uc (fish was superior to uc), hyal-1 vs. uc (hyal-1 was superior to uc), survivin vs. hyal-1 (hyal-1 was superior to survivin), and survivin vs. uc (survivin was superior to uc) showed statistically significant differences (p < 0.05). there are no significant differences between the other groups (supplementary table 3). egger’s test showed that there was no significant publication bias among the groups. network meta-analysis network meta-analysis was performed using the netmeta package, and a network diagram was constructed (figure 2); a total of nine biomarkers are included in this network meta-analysis: hyal-1, uca1, survivin, immunocyt, bta stat, nmp22, bta trak, uc, and fish. among all the indicators, the heterogeneity of the network meta-analysis was calculated using q statistics. based on the results, a random effects model was used for meta-analysis consolidation. the results of the network meta-analysis are listed in tables 1–6. in terms of sensitivity, hyal-1, uca1, and survivin were the most sensitive groups in terms of p-score, and uc was the least sensitive group. moreover, hyal-1, uca1, survivin, immunocyt, bta stat, nmp22, and fish were statistically different from uc, and bta stat was statistically different from hyal-1. in terms of specificity, uc, fish, and hyal-1 were the highest, and that of uca1 was the lowest. uc and fish were statistically different from bta stat. bta, immunocyt , nmp22, and fish were statistically difbta stat 0.95[0.46;1.95] bta trak 0.85[0.62;1.18] 0.90[0.43;1.88] fish 0.25[0.11;0.54] 0.26[0.09;0.73] 0.29[0.13;0.64] hyal-1 0.81[0.48;1.35] 0.85[0.36;1.98] 0.95[0.57;1.58] 3.27[1.32;8.10] immunocyt 1.00[0.77;1.29] 1.05[0.52;2.12] 1.17[0.86;1.59] 4.05[1.84;8.93] 1.24[0.75;2.05] nmp22 0.62[0.39;0.97] 0.65[0.29;1.46] 0.72[0.45;1.17] 2.51[1.16;5.44] 0.77[0.41;1.44] 0.62[0.39;0.97] survivin 1.31[1.04;1.66] 1.39[0.69;2.80] 1.54[1.20;1.98] 5.34[2.49;11.45] 1.63[1.00;2.66] 1.32[1.06;1.64] 2.13[1.42;3.20] uc 0.39[0.15;0.99] 0.41[0.13;1.28] 0.46[0.18;1.16] 1.58[0.49;5.15] 0.48[0.17;1.35] 0.39[0.15;0.99] 0.63[0.24;1.69] 0.30 uca1 [0.12;0.73] table 4. comprehensive comparison of negative predictive. uc, urine cytology; fish, fluorescence in situ hybridization; nmp-22, nuclear matrix protein 22; uca1: urothelial carcinoma associated-1; hyal-1, hyaluronidase 1; uc, urine cytology; immunocyt, immunocyte; bta, bladder cancer antigen. bta stat 0.91[0.45;1.82] bta trak 0.74[0.52;1.06] 0.82[0.40;1.69] fish 0.22[0.09;0.53] 0.24[0.08;0.72] 0.30[0.12;0.72] hyal-1 0.77[0.44;1.35] 0.85[0.37;1.98] 1.04[0.60;1.80] 3.49[1.29;9.43] immunocyt 1.01[0.76;1.35] 1.12[0.57;2.21] 1.36[0.97;1.90] 4.57[1.91;10.96] 1.31[0.76;2.26] nmp22 0.46[0.28;0.76] 0.51[0.23;1.15] 0.62[0.37;1.05] 2.09[0.90;4.89] 0.60[0.30;1.20] 0.46[0.28;0.75] survivin 1.03[0.79;1.34] 1.14[0.58;2.23] 1.38[1.05;1.81] 4.65[2.00;10.82] 1.33[0.79;2.26] 1.02[0.80;1.29] 2.22[1.41;3.50] uc 0.56[0.21;1.50] 0.62[0.19;1.98] 0.75[0.28;2.02] 2.53[0.71;9.02] 0.73[0.24;2.15] 0.55[0.21;1.47] 1.21[0.42;3.47] 0.54 uca1 [0.21;1.41] uc, urine cytology; fish, fluorescence in situ hybridization; nmp-22, nuclear matrix protein 22; uca1: urothelial carcinoma associated-1; hyal-1, hyaluronidase 1; uc, urine cytology; immunocyt, immunocyte; bta, bladder cancer antigen. table 5. comprehensive comparison of accuracy. urine biomarkers for diagnosing bc-dong et al. urological oncology 628 bta stat 0.95[0.46;1.95] bta trak 0.85[0.62;1.18] 0.90[0.43;1.88] fish 0.25[0.11;0.54] 0.26[0.09;0.73] 0.29[0.13;0.64] hyal-1 0.81[0.48;1.35] 0.85[0.36;1.98] 0.95[0.57;1.58] 3.27[1.32;8.10] immunocyt 1.00[0.77;1.29] 1.05[0.52;2.12] 1.17[0.86;1.59] 4.05[1.84;8.93] 1.24[0.75;2.05] nmp22 0.62[0.39;0.97] 0.65[0.29;1.46] 0.72[0.45;1.17] 2.51[1.16;5.44] 0.77[0.41;1.44] 0.62[0.39;0.97] survivin 1.31[1.04;1.66] 1.39[0.69;2.80] 1.54[1.20;1.98] 5.34[2.49;11.45] 1.63[1.00;2.66] 1.32[1.06;1.64] 2.13[1.42;3.20] uc 0.39[0.15;0.99] 0.41[0.13;1.28] 0.46[0.18;1.16] 1.58[0.49;5.15] 0.48[0.17;1.35] 0.39[0.15;0.99] 0.63[0.24;1.69] 0.30 uca1 [0.12;0.73] ferent from uc. in terms of positive predictive indicators, uc, fish, and hyal-1 had the highest positive predictive value, while the bta group had the lowest positive predictive value. hyal-1 and uc were statistically different from fish results. furthermore, the differences in bta stat/fish and uc, fish and nmp22, nmp22 and uc comparison groups were statistically significant. in terms of negative predictive indicators, hyal-1, uca1, and survivin had the highest negative predictive value, while uc had the lowest negative predictive value. there was a significant difference between fish and uc groups. in terms of accuracy indicators, hyal-1, uca1, and survivin had the highest accuracy, while uc had the lowest accuracy. the differences between fish and bta stat were statistically significant. additionally, the differences between fish/nmp22 and uc were statistically significant. there were no statistically significant differences among the groups for the other indicators. sensitivity analysis in the sensitivity analysis, the random effect model and fixed effect model of the p-score were calculated. the results show that the order is basically identical, proving that the results are relatively stable (table 6). consistency test combined with the p-values of the node-splitting analysis, the results of indirect and direct comparisons were determined. the results showed that most results were > 0.05. these findings suggest that the results are relatively stable (supplementary tables 4–8). discussion in this meta-analysis, 58 eligible studies were selected. quality evaluation showed that the overall quality of the included studies was relatively high. network meta-analysis revealed that hyal-1, uca1, and survivin were the most sensitive groups, and uc was the least sensitive group. in terms of specificity, the specificity of uc, fish, and hyal-1 was the highest, and that of uca1 was the lowest. uc, fish, and immunocyt had the highest positive predictive value, while the bta trak had the lowest positive predictive value. moreover, hyal-1, uca1, and survivin had the highest negative predictive value, whereas uc had the lowest negative predictive value. additionally, hyal-1, uca1, and survivin had the highest accuracy, while uc had the lowest accuracy. sensitivity analysis and consistency tests suggest that the results are relatively stable. hyal-1 has been reported to play an important role in tumor growth and progression. kramer et al. found that hyal-1 expression predicted bc metastasis disease-specific survival(79). hyal-1 and -2 are presumed to constitute the major hyaluronidases involved in the catabolism of hyaluronic acid (ha) in somatic tissues. a previous study indicated that haase mrna exhibited superior sensitivity (86.67%) over uc (38.33%) with specificities of 97.5% and 100%, respectively, in bc detection(68). moreover, survival had a slightly lower sensitivity of survivin (78.33%) than haase (86.67%) for bc detection(68). these results indicate that hyal-1 is useful for bc diagnosis. however, inconsistent findings have been reported in other studies. for example, eissa et al. showed that uca1 (91.5% and 96.5%) had a greater sensitivity and specificity than hyal-1 (89.4 and 91.2%) for distinguishing bc patients from nonbc patients(80). these controversial results of the above studies might be due to different study countries and different total numbers of included people. therefore, this network meta-analysis was important for providing a quantitative evaluation of the differences in the 58 included studies. survivin is expressed in urine, and its expression is associated with several adverse prognostic signs. survivin can be reliably and quantitatively measured in the urine of bc patients, improving the sensitivity and specificity of urine cytology for bc diagnosis(68). a previous study showed that uc had lower sensitivity, accuracy, and negative predictive values than survivin for bc diagnosis(70), which is consistent with our results. moreover, chang et al. found that 73% of low-grade bc cases were diagnosed by positive survivin, while only 57.5% were diagnosed with positive uc(81). the survivin level is a more accurate test than the nmp22 test and the uc for the detection of lower grade and superficial bc (81), which further illustrates that survivin is suitable for bc diagnosis. hyal-1 using real-time polymerase chain reaction (rt-pcr) is considered the best individual test, while enzyme-linked immunosorbent assay (elisa) is the best test for survivin(68). despite the lower sensitivity, specificity, and positive predictive value of survivin compared to hyal-1, survivin detection has the advantage of being a quantitative test measured through elisa, which is lower cost and more easily performed than rt-pcr. in this study, the diagnostic results of urine biomarkers (including bta, fish, uc, immunocyt, nmp22, sensitivity specificity positive negative predictive accuracy predictive group fixed random group fixed random group fixed random group fixed random group fixed random hyal-1 0.9775 0.9596 uc 0.9230 0.9431 hyal-1 0.8882 0.8452 hyal-1 0.9712 0.9694 hyal-1 0.9930 0.9829 uca1 0.8960 0.7546 fish 0.7687 0.7867 uc 0.7763 0.8345 uca1 0.9011 0.8496 survivin 0.7678 0.8146 survivin 0.7410 0.7170 hyal-1 0.8543 0.7709 fish 0.8247 0.7929 survivin 0.7329 0.7136 uca1 0.8624 0.6642 immunocyt 0.5176 0.5429 immunocyt 0.6575 0.5907 immunocyt 0.7222 0.6872 immunocyt 0.5630 0.5105 fish 0.5032 0.5607 btatrak 0.2217 0.5019 nmp22 0.4001 0.4462 nmp22 0.4461 0.4107 fish 0.5034 0.4800 immunocyt 0.5868 0.4957 btastat 0.4666 0.3948 btastat 0.2559 0.3137 btastat 0.3413 0.3524 btatrak 0.2268 0.3612 btatrak 0.2430 0.3499 fish 0.2716 0.3252 btatrak 0.4230 0.2703 btatrak 0.1931 0.2338 nmp22 0.2986 0.2945 btastat 0.1389 0.2332 nmp22 0.4078 0.3020 survivin 0.1699 0.2168 survivin 0.2236 0.2182 btastat 0.2754 0.2926 nmp22 0.1496 0.2145 uc 0.0002 0.0020 uca1 0.0477 0.1615 uca1 0.0846 0.1251 uc 0.0276 0.0286 uc 0.2554 0.1843 table 6. ranking results of network meta-analysis (p-score). uc, urine cytology; fish, fluorescence in situ hybridization; nmp-22, nuclear matrix protein 22; uca1: urothelial carcinoma associated-1; hyal-1, hyaluronidase 1; uc, urine cytology; immunocyt, immunocyte; bta, bladder cancer antigen. urine biomarkers for diagnosing bc-dong et al. vol 18 no 6 november-december 2021 629 hyal-1, uca1, and survivin) for bc were analyzed for the first time using network meta-analysis, providing certain clues and basis for further clinical diagnosis of bc. however, this study also had certain non-negligible shortcomings. first, heterogeneity test showed that heterogeneity was statistically significant, which might be due to different study subjects (primary, recurrent, and metastatic) and different control groups (healthy and benign controls). as a potential confounding factor, heterogeneity might affect the results of the meta-analysis. second, sponsorship bias may exist in this study. third, sensitivity analysis of the p-score was performed using the random effect and fixed effect models, while the ranking results were not completely consistent. furthermore, the consistency test showed that the p-values of sensitivity and negative predictive value in bta trak and nmp22 were < 0.05, which was inconsistent with the consistency test and proved unstable results. the inconsistency might be caused by insufficient literature and other biases (e.g., sponsor bias, selection bias, etc.). finally, this study only focused on studies on subjects with suspected bc; thus, we will pay attention to this research direction of noninvasive detection tests for bc patients with hematuria in the future, and continue to conduct a meta-analysis. conclusions in conclusion, hyal-1 and survivin were found to be the two most suitable urine biomarkers for bc diagnosis. however, 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self-management among kidney transplant recipients is a key factor in long-term survival. the present study aims to determine the predictors of self-management among kidney transplant recipients in iran. materials & methods: this cross-sectional analytical study was conducted on 360 kidney transplant recipients who were selected from six transplantation clinics affiliated to six major universities of medical sciences in iran. the data were collected using a demographic and clinical characteristics questionnaire and the persian version of the 24-item self-management scale for kidney transplant recipients. result: the mean score of the participants’ self-management was 62.39±8.04. multiple regression analysis revealed that the significant predictors of self-management among kidney transplant recipients were age (b = -0.319), gender (b = -1.70), pre-transplantation dialysis duration (b = 0.256), dialysis type (b = 3.060), duration after transplantation (b = 0.08), and marital status (b = 4.44) (model r2 = 0.444). conclusion: this study showed that kidney transplant recipients in iran have a moderate self-management status. the significant predictors of their self-management were age, gender, marital status, pre-transplantation dialysis type and duration, and the length of time passed after transplantation. the findings of this study provide a basis for developing interventions to improve self-management among kidney transplant recipients. keywords: self-management; transplantation; kidney introduction kidney transplantation is the best treatment for end-stage renal disease.(1) in 2014, 17107 kidney transplantations were performed and more than 100000 patients were still on the waiting list in the united states. the number of candidates for kidney transplantation increases by 3000 annually.(2) in iran, 2700 kidney transplantations are performed each year. in other words, 48% of the patients with end-stage renal disease in iran receive kidney transplant, while the global rate is 20%. these statistics denote the good status of kidney transplantation in iran.(3) self-management is among the most important factors behind transplant survival and outcomes.(4) by definition, self-management is the ability to manage symptoms, treatments, physical and mental complications, and lifestyle behaviors in relation to a chronic condition.(5) currently, self-management is considered as a main aspect of successful healthcare delivery. it significantly improves patients’ health status and quality of life and reduces the rate of re-hospitalization.(6,7) self-management has three main components, namely medical management, emotional management, and new 1ph.d. ph.d. student of nursing, baqiyatallah university of medical sciences, faculty of nursing, tehran, iran. e-mail: khezerloos@yahoo.com 2associate professor, trauma research center and faculty of nursing, baqiyatallah university of medical sciences, tehran, ir iran. 3ph.d. assistant professor, amol faculty of nursing and midwifery, mazandaran university of medical sciences, sari, iran. 4assistant professor, health management research center, medical-surgical group. nursing faculty, baqiyatallah university of medical sciences, tehran, iran. zohrehvafadar@gmail.com. *correspondence: assistant professor, health management research center, medical-surgical group. nursing faculty, baqiyatallah university of medical sciences, tehran, iran. mobile: +98 917 3117 227. e mail: zohrehvafadar@gmail.com. received february 2019 & accepted july 2019 life roles management.(8) accordingly, self-management behaviors among kidney recipients may include adherence to the following: medications, regular monitoring of transplant rejection symptoms, regular medical visits, adequate fluid intake, adequate sun exposure protection, undergoing cancer screening tests, and a low-salt low-fat diet.(9) limited self-management may result in transplant rejection.(10) unhealthy lifestyle behaviors predispose transplant recipients to infection and other complications. these complications may result in psychological problems and thereby, undermine self-management ability.(11) on the other hand, transplant recipients need immunosuppression in order to prevent transplant rejection.(12) the success of immunosuppression largely depends on adherence to immunosuppressive regimens. (13) poor treatment adherence among transplant recipients increases the risks of renal failure and transplant rejection by seven times and increases the likelihood of hospitalization mostly due to infections.(14) yet, estimates show that 30% of transplant recipients have poor treatment adherence(5–7). in addition, another study conducted in iran has shown that the rate of poor treatment adherence is as high as 57.8%.(15) urology journal/vol 16 no. 4/ july-august 2019/ pp. 366-370. [doi: http://dx.doi.org/10.22037/uj.v0i0.5061] a key prerequisite to self-management improvement is to determine its contributing factors. these factors (include donor factors, recipient factors, and immunological factors), which greatly influence the outcome of kidney transplantation. of these three factors, the factors associated with the recipient are related to the patients' self-management. in order to design a plan for improving of these patients' self-management, in the first step, it is necessary to understand the current status of self-management behaviors and the predictor variables among kidney transplant recipients. however, in iran, few studies have been done on these factors so far. therefore self-management improvement interventions usually face different challenges and difficulties. thus, the present study has been conducted to determine the predictors of self-management among kidney transplant recipients in iran. materials & methods this cross-sectional analytical study was conducted from 2016 to 2017. the study population consisted of the transplant recipients referring to the kidney transplantation clinics affiliated to six major universities of medical sciences in iran situated in tehran, tabriz, urmia, mashhad, kerman, and hamadan. a random sample of 360 kidney transplant recipients were selected through cluster random sampling. the inclusion criteria were: age above eighteen, ability to answer the study questionnaires, and having stable physical and mental conditions. data collection the data collection instruments were a demographic and clinical characteristics questionnaire and the self-management scale for kidney transplant recipients. the items included in the first questionnaire (predictors) were related to age, gender, educational level, marital status, employment status, financial status, dialysis type (hemodialysis or peritoneal dialysis), daily fluid intake, comorbid conditions, organ source (live or cadaver), the amount of sleep per day, the pre-transplantation dialysis history, and the length of time after transplantation. in this study no potential confounders were detected. the self-management scale for kidney transplant recipients was developed in 2013 by kosaka et al.(16) khezerloo et al. translated this scale into persian, evaluated its psychometric properties, and reported that it had the four subscales of self-monitoring (eight items), self-care behaviors (six items), early detecting and coping with abnormalities (six items), and drug management (four items). they also reported a cronbach’s alpha of 0.73 and an intraclass correlation coefficient of 0.9 for the scale.(17) the items of this scale are scored from 1 to 4, resulting in a possible total score of 24 to 96—the higher the score, the greater the patient self-management. ethical considerations this study was part of a phd dissertation in nursing approved by the ethics committee of baqiyatallah university of medical sciences, tehran, iran (code: ir.bmsu.rec.1395.304). the aim of the study was explained to the participants and written informed consents were received from them. all the participants had the freedom to voluntarily withdraw from the study. the study data are kept confidentially. statistical analysis the spss software (v. 25.0) was used for data analysis. initially, the distribution of the self-management variable was evaluated through the kolmogorov-smirnov test. then, the simple and the linear regression analyses were used to predict the participants’ self-management based on their demographic and clinical characteristics. independent variables were entered into the regression predictors of self-management -khezerloo et al. table 1. participants’ demographic and clinical characteristics. characteristics n (%) or mean ± sd gender male 205 (56.9) female 155 (43.1) age (years) 47.11±11.84 marital status single 122 (33.9) married 283 (66.1) educational status below diploma 91 (25.3) diploma 82 (22.8) associate degree 10 (2.8) bachelor’s degree 137 (38.1) master’s degree and higher 40 (11.1) employment status unemployed 39 (10.8) housewife 105 (29.5) employee 138 (38.3) self-employed 78 (21.7) financial status poor 114 (31.7) moderate 191 (53.1) good 55 (15.3) dialysis type peritoneal 139 (36.6) hemodialysis 221 (61.4) history of dialysis (month) 51.48±19.98 duration after transplantation (month) 43.76±23.27 organ source live donor 234 (65.0) cadaver 126 (35.0) number of sleeping hours a day less than 7 108 (30) 7–9 169 (46.9) more than 9 83 (23.1) daily fluid intake (liter) less than 1 91 (25.3) 1–2 204 (56.7) more than 2 65 (18.1) kidney transplantation 367 model using the hierarchical method (backward model). multicollinearity was evaluated through variance inflation factor and tolerance value. the variance inflation factor values greater than 10 and the tolerance values of .1 or less were considered problematic.(18) the level of significance was set at less than.05. results the participants were mostly male (56.9%) and married (66.1%), had received hemodialysis (61.4%), had received kidney transplant from live donors (65%), and aged 47.11±11.84 years on average. the mean age among the male and the female participants were 46.41±10.54 and 48.1±13.35 years, respectively (table1). the mean score of the participants’ self-management was 62.39 ± 8.04 (in the range of 24 to 96). the mean scores of the male and the female participants’ self-management were 61.45 ± 9.09 and 63.63 ± 6.19, respectively. table 2 shows the mean scores of self-management and its four subscales. multiple linear regression showed that the significant predictors of self-management among kidney transplant recipients were age (b = -.319), gender (b = -1.70), pre-transplantation dialysis duration (b =.256), dialysis type (b = 3.060), the length of time after transplantation (b =.08), and marital status (b = 4.44) (model r2 = .444). accordingly, older age, masculinity, shorter pre-transplantation dialysis duration, receiving dialysis through the peritoneal route, shorter post-transplantation time, and singularity were associated with poorer self-management (all p <.05) (table 3). discussion this study aimed to determine the predictors of self-management among kidney transplant recipients. the findings revealed that the mean score of the participants’ self-management was 62.39 ± 8.04 (ranging from of 24 to 96), which indicates moderate self-management. similarly, an earlier study had found that only a few kidney transplant recipients had good self-management status in areas such as fluid intake, physical exercise, and adherence to treatment and dietary regimens.(19) however, another study reported that kidney transplant recipients had great self-management.(6) this contradiction may be due to the differences in the settings, samples, and the contexts of the studies. the study also shows that age is one of the significant predictors of self-management among kidney transplant recipients; older age was associated with poorer self-management. greater self-management among the younger participants may be due to their unfamiliarity with serious health conditions, fear of the unknown, fear of the long-term effects of not adhering to the treatments and the greater support they receive from their table 2. the mean scores of self-management and its subscales. subscales min-max mean ± sd number of items subscale mean self-monitoring 8-25 17.22 ± 5.43 8 2.15 self-care behavior 12-24 18.34 ± 3.31 6 3.056 early detecting and coping with abnormalities 7-22 12.55 ± 4.12 6 2.091 drug management 9-16 14.27 ± 1.68 4 3.56 total 44-74 62.39 ± 8.04 24 —— predictor unadjusted model* adjusted model* tolerance vif b [95% ci] p b [95% ci] p age (years) .10 [0.03 ,.17] .005 –.31 [–.39, –.24] <.001 .488 2.051 sex male –2.18 [–3.85 , –.51] .01 –1.70 [–3.07, –.32] .016 .845 1.184 female 1 marital status single 1 married 6.23 [4.62, 7.90] <.001 4.44 [2.96, 5.92] <.001 .797 1.255 educational status below 0.46 [–0.16, 0.99] 0.16 diploma diploma 1 associate 1 degree bachelor’s 1 degree master’s 1 degree and higher dialysis type peritoneal 1 hemodialysis –1.92 [–3.62, –.22] .02 3.06 [1.40, 4.71] <.001 .604 1.656 history of dialysis (month) .202 [.16 , 0.23] <.001 0.256 [0.19, 0.31] <.001 .282 3.542 duration after .14 [.11,.17] <.001 .087 [.05,.12] <.001 .604 1.654 transplantation (month) organ source live donor 1 cadaver –5.83 [–7.74, –4.19] .88 *univariate linear regression and multiple linear regression were used to analyze the association between multiple determinants of self-management. table 3. predictors for effective factors on the self-management among kidney transplant recipients. predictors of self-management -khezerloo et al. vol 16 no 04 july-august 2019 368 families and peers. however, contrary to the findings of the present study, the previous studies have reported greater self-management among older kidney transplant recipients.(20, 21) this contradiction may be due to the differences among different societies regarding cultural characteristics and health literacy. culture and health literacy are among the significant factors affecting self-management among the patients with chronic conditions.(22) gender was another significant predictor of self-management in the present study; the female participants had greater self-management than their male counterparts. earlier studies reported that female organ recipients had better infection prevention and sun exposure protection behaviors(4,23), while male organ recipients were better at drug management.(23,24) women seem to have poorer adherence to their medications due to their fear of the side effects of immunosuppressive agents on their appearance. moreover, they are more adherent to sun protection due to the effects of sun exposure on their beauty and appearance. however, a study reported that women usually have better health-related knowledge; therefor, they have better self-monitoring and greater self-protection against health risk factors.(25) this contradiction may be due to the fact that the present study has assessed all the aspects of self-management, while the other one has only considered some of its aspects. marital status was another significant predictor of self-management in the present study. the findings show that married participants have better self-management than their single counterparts. previous studies reported the same finding, too.(25) spousal and emotional support may be significant factors behind married participants’ greater self-management. a previous study reported a positive relationship between social support and self-management among transplant recipients.(26) moreover, spouses usually share their health-related knowledge with each other and help each other select appropriate health-related behaviors. in addition, the findings of the present study revealed that pre-transplantation dialysis type and duration were significant predictors of self-management among kidney transplant recipients. the participants with a longer dialysis period and a history of hemodialysis had significantly greater self-management compared to those with a shorter dialysis period and a history of peritoneal dialysis. the patients with a longer dialysis period and a history of hemodialysis might have experienced more difficulties. therefore, they might as well have attempted to more closely adhere to self-management behaviors in order to avoid returning to their difficult pre-transplantation conditions. similarly, a previous study indicated that due to the significant effects of hemodialysis on the patients’ lives and autonomy, the patients who were receiving hemodialysis had poorer quality of life compared to those who were receiving peritoneal dialysis.(27) the other predictor of self-management in the present study was length of time passed after transplantation— the longer the duration, the greater self-management. this factors lead to self-management improvement due to the acquisition of better coping and self-management abilities over time.(23) contrarily, several earlier studies reported reduction in drug self-management over time. (20,28,29) this contradiction may be due to the difference in the side effects of immunosuppressive agents experienced by the participants in these studies. the side effects of immunosuppression are a significant factor affecting self-management among kidney transplant recipients—the more the side effects, the poorer medication adherence and self-management.(20) another justification regarding self-management variation over time, may be the fact that the present study assessed all the components of self-management, while the other ones have only evaluated some. to the best of our knowledge, this was the first study conducted in iran on the prediction of self-management among kidney transplant recipients. one limitation of the study was that sampling was done among kidney transplant recipients who were over eighteen. therefore, the study provides little information, if any, on self-management predictors among children and adolescents. conclusions this study showed that kidney transplant recipients in iran have moderate self-management status. the significant predictors of their self-management are age, gender, marital status, pre-transplantation dialysis type and duration, and the length of time passed after transplantation. the findings of this study provide a basis for developing interventions to improve self-management among kidney transplant recipients. acknowledgement hereby, the authors appreciate all the kidney transplant recipients who participated in this study, as well as the whole staffs of the kidney transplant centers who contributed to data collection. conflict of interest the authors declare that they had no conflict of interest. references 1. schmid-mohler g, schäfer-keller p, frei a, fehr t, spirig r. a mixed-method study to explore patients' perspective of selfmanagement tasks in the early phase after kidney transplant. prog transplant. 2014;24:818. 2. nkf. organ donation and transplantation statistics. available at https://wwwkidneyorg/ news/newsroom/factsheets/organ-donationand-transplantation-stats.march 28, 2017. 3. farhangnews. available at http:// w w w f a r h a n g n e w s i r / c o n t e n t / 1 8 5 0 5 2 . september 27, 2016. 4. hedayati p, shahgholian n, ghadami a. nonadherence behaviors and some related factors in kidney transplant recipients. iran j nurs midwifery res. 2017 ;22:97-101. 5. yusoff ssm, ishak nh, rahman ra, kadir aa. diabetes self-care and its associated factors among elderly diabetes in primary care. j t u med sc. 2017. 6. weng lc, dai yt, huang hl, chiang yj. self‐efficacy, self‐care behaviours and quality of life of kidney transplant recipients. j adv nurs. 2010;66:828-38. 7. dawkes s. self-management of coronary predictors of self-management -khezerloo et al. kidney transplantation 369 heart disease in angina patients after elective percutaneous coronary intervention: a mixed methods study: doctoral dessertation, edinburgh napier university; 2014. 8. novak m, costantini l, schneider s, beanlands h, editors. approaches to self‐ management in chronic illness. seminars in dialysis; 2013: wiley online library. 9. jamieson nj, hanson cs, josephson ma, gordon ej, craig jc, halleck f, et al. motivations, challenges, and attitudes to selfmanagement in kidney transplant recipients: a systematic review of qualitative studies. am j kidney dis. 2016;67:461-78. 10. meier‐kriesche hu, schold jd, kaplan b. long‐term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? am j transplant. 2004;4:1289-95. 11. weng lc, dai yt, wang yw, huang hl, chiang yj. effects of self‐efficacy, self‐ care behaviours on depressive symptom of taiwanese kidney transplant recipients. j clin nurs. 2008;17:1786-94. 12. lamb k, lodhi s, meier‐kriesche hu. long‐term renal allograft survival in the united states: a critical reappraisal. am j transplant. 2011;11:450-62. 13. group kdigotw. kdigo clinical practice guideline for the care of kidney transplant recipients. am j transplant. 2009;9(suppl 3):s1-s157. 14. medscape. kidney transplantation patients have high readmission rates. october 3, 2016:available at http://www.medscape.com/ viewarticle/772950. 15. shabany-hamedan m, mohmmad-aliha j, shekarabi r, hosseini a. the relationship between medication adherence and quality of life in renal transplant patients. ijn. 2010;23:29-34. 16. kosaka s, tanaka m, sakai t, tomikawa s, yoshida k, chikaraishi t, et al. development of self-management scale for kidney transplant recipients, including management of post-transplantation chronic kidney disease. isrn transplantation. 2013;2013. 17. khezerloo s, mahmoudi h, vafadar z. evaluating the psychometric properties of the persian self-management scale for kidney transplant recipients. urol j. 2019;16: 72-78. 18. orme jg, combs-orme t. multiple regression with discrete dependent variables: oxford university press; 2009. 19. gordon ej, prohaska tr, gallant m, siminoff la. self-care strategies and barriers among kidney transplant recipients: a qualitative study. chronic illn. 2009;5:75-91. 20. prendergast mb, gaston rs. optimizing medication adherence: an ongoing opportunity to improve outcomes after kidney transplantation. clin j am soc nephrol. 2010;5:1305-11. 21. estabrooks pa, nelson cc, xu s, king d, bayliss ea, gaglio b, et al. the frequency and behavioral outcomes of goal choices in the self-management of diabetes. diabetes educ. 2005;31:391-400. 22. shaw sj, huebner c, armin j, orzech k, vivian j. the role of culture in health literacy and chronic disease screening and management. j immigr minor health. 2009;11:460-7. 23. germani g, lazzaro s, gnoato f, senzolo m, borella v, rupolo g, et al., editors. nonadherent behaviors after solid organ transplantation. transplant proc; 2011: elsevier. 24. gheith o, el-saadany s, abuo ds, salem y. compliance with recommended life style behaviors in kidney transplant recipients: does it matter in living donor kidney transplant? iran j kidney dis. 2008;2:218-26. 25. august kj, sorkin dh. marital status and gender differences in managing a chronic illness: the function of health-related social control. soc sci med. 2010;71:1831-8. 26. chen yc, chang lc, liu cy, ho yf, weng sc, tsai ti. the roles of social support and health literacy in self‐management among patients with chronic kidney disease. j nurs scholarsh. 2018;50:265-75. 27. theofilou p. quality of life in patients undergoing hemodialysis or peritoneal dialysis treatment. j clin med res. 2011;3:132. 28. shimaya m, watanabe m, azumi m, shichiri k, tomiyama c, tanabe m, et al. a questionnaire survey in kidney transplant outpatients: factors associated with good self-management. health j. 2015;7:589. 29. massey ek, tielen m, laging m, beck dk, khemai r, van gelder t, et al. the role of goal cognitions, illness perceptions and treatment beliefs in self-reported adherence after kidney transplantation: a cohort study. j psychosom res. 2013;75:229-34. predictors of self-management -khezerloo et al. vol 16 no 04 july-august 2019 370 case report retrocaval ureter manifested after ureteral reimplantation for ipsilateral vesicoureteral reflux: a case report masahiro katsui, hiroshi asanuma*, keishiro fukumoto, ryuichi mizuno, mototsugu oya keywords: cohen cross-trigonal technique; hydronephrosis; retrocaval ureter; ureteral reimplantation; vesicoureteral reflux we report a female patient diagnosed with retrocaval ureter (rcu) after ureteral reimplantation for vesicoureteral reflux (vur). she was diagnosed as right grade iv vur with breakthrough urinary tract infections, and underwent ureteral reimplantation with cohen cross-trigonal technique. thereafter, she developed severe right hydronephrosis associated with rcu, which was presumably due to caudal traction of right ureter at ureteral reimplantation. she underwent uretero-ureterostomy anterior to the inferior vena cava, and recovered well. detailed evaluation for upper urinary tract is mandatory for high grade vur, and cohen technique should be avoided for vur associated with rcu. department of urology, keio university school of medicine, tokyo, japan. *correspondence: department of urology, keio university school of medicine, tokyo, japan. tel: +81-3-5363-3825. fax: +81-3-3225-1985. e-mail: asataro@qc5.so-net.ne.jp. received august 2017 & accepted january 2018 introduction retrocaval ureter (rcu) is congenital abnormal looping of the proximal ureter behind the inferior vena cava (ivc), resulting in progressive hydronephrosis.(1) there are few reports regarding vesicoureteral reflux (vur) associated with rcu.(2) we report a female patient who was diagnosed as right rcu after ureteral reimplantation for ipsilateral vur. figure 1. voiding cystourethrography at 11 y-o it shows right grade iv vur with tortuous upper ureter. case report 397 vol 15 no 06 november-december 2018 398 case report a 10-year-old girl presented with multiple febrile urinary tract infections (uti), and was finally diagnosed as right grade iv primary vur with multiple renal scarring (figure 1). she underwent ureteral reimplantation with cohen cross-trigonal technique at the age of 11. postoperative study revealed reflux resolution, however, she had one recurrent uti at the age of 12 and several right flank pain episodes within several years after surgery. at the age of 25, severe right hydronephrosis was detected incidentally on the gynecological work-up. she subsequently underwent retrograde pyeloureterography which showed s-shaped tortuous upper ureter and its obstruction without ureterovesical junction stricture, and was referred to our institution for further treatment. computerized tomography revealed right rcu (figure 2a), and renography showed deteriorated right split renal function (32.2%). she underwent uretero-ureterostomy with open retroperitoneal approach (figure 2b). right ureter was transected at the obstructive level behind the ivc, and was anastomosed over 6fr double-pigtail stent with interrupted 6-0 absorbable sutures anterior to the ivc. the patient recovered well and the stent was removed after 2 months of surgery. the follow-up is now of 3 years without any complications including recurrent uti and obstruction. discussion rcu is a comparatively rare sequelae to the mal development of the ivc, not of the ureter.(1) it occurs as a consequence of the persistence of the posterior cardinal veins during embryologic development. rcu is termed circumcaval ureter or preureteral vena cava as well. rcu causes ureteral obstruction considerably slowly, therefore it usually does not show symptoms such as flank pain, hematuria or uti until 3rd or 4th decades of life.(1) its presence used to be suspected with the finding of a characteristic s-shaped deformity on intravenous pyeloureterography which is not routinely performed anymore now in children. our patient did not lead to a diagnosis of rcu before ureteral reimplantation in childhood, because uti and upper ureteral tortuosity without marked hydronephrosis were supposed to result from high grade reflux. rcu is associated with several abnormalities of various systems and organs. genitourinary anomalies are reported in half of those patients, however, there is only one case report associated with vur. tazaki et al. reported a 4-month-old boy who presented uti, and was diagnosed as bilateral vur associated with right rcu. (2) there are potentially more patients with this association, because the prevalence of rcu or vur has been estimated at 0.06-0.17% or 0.4-1.8%, respectively.(3,4) in our case, the patient had recurrent uti and right flank pain episodes after vur resolution, even though rcu rarely shows any symptoms in childhood. severe hydronephrosis presumably developed due to ureteral figure 2. abdominal computerized tomography (a) and operative finding (b) a: it shows the right ureter with double-pigtail stent (arrow) located posterior to the ivc. b: it shows the right ureter (taping) located behind the ivc (arrow). figure 3. schema of deteriorated right hydronephrosis associated with rcu after ureteral reimplantation severe right hydronephrosis presumably developed due to ureteral obstruction with its caudal traction (arrow) at the time of ureteral reimplantation with cohen technique. retrocaval ureter manifested after ureteral reimplantation katsui et al. retrocaval ureter manifested after ureteral reimplantation katsui et al. obstruction with its caudal traction at the time of ureteral reimplantation with cohen technique (figure 3). cohen’s procedure has become the most commonly used technique for intravesical reimplantation, in which the ureter is disconnected from bladder wall once and advanced across the trigone toward the contralateral wall, resulting in ureteral caudal traction. meanwhile, extravesical lich-gregoir technique preserves ureterovesical junction continuity and its blood supply without risk of ureteral caudal traction. ureteral blood supply should be preserved as much as possible to prevent postoperative its stricture when ureteral reconstruction is needed for rcu. therefore, if our patient had been diagnosed as rcu as well as vur preoperatively, lich-gregoir procedure could have been adopted for vur correction because of prevention of ureteral obstruction and possible future ureteral reconstruction. furthermore, if it had been now, deflux injection therapy could have been also an alternative choice. in conclusion, detailed evaluation for upper urinary tract is mandatory in children with high grade vur before and after ureteral reimplantation, especially with some symptoms. our patient suggests cohen technique should be avoided for vur correction in children associated with rcu. conflict of interest the authors report no conflict of interest. references 1. peters ca, mendelsohn c. ectopic ureter, ureterocele, and ureteral anomalies in wein aj, kavoussi lr, partin aw, peters ca (eds): campbell-walsh urology 11th ed, saunders elsevier, philadelphia, pp3075-3101, 2016. 2. tazaki t, ichikawa t, yamaoka h, kanehiro t, tsumura h, hino h. a case of retrocaval ureter associated with vesicoureteral reflux. jap j pediatr surg. 2010; 46: 1130-5. 3. utnappa mc, anthony d, allen c. retrocaval ureter: mr appearances. brit j radiol. 2002; 75: 177-9. 4. sargent ma. what is the normal prevalence of vesicoureteral reflux? pediatr radiol. 2000; 30: 587-93. case report 399 editorial comments re: the evaluation of the result of warm normal saline irrigation in ureteral endoscopic surgeries: a randomized clinical trial the authors have presented an interesting study on the results and complications of transureteral lithotripsy with ambient air temperature and with 40 °c irrigation fluid(1). interestingly the success rate has been higher with a lower profile of complications in the 40 °c irrigation fluid group. they have concluded that using 40 °c irrigation fluid would lessen ureteral spasm and ensue in easier ureteroscopy and less complications. i was very happy to read this article as failure to progress in semi-rigid ureteroscopy is a relatively common problem. this report may provide first evidence based basis to illuminate strategies to tackle with problems of ureteroscope impaction and ureteral spasm during ureteroscopy. nevertheless, the following points should be clarified by the authors. the success rate reported by the authors in the 40 °c irrigation fluid group is 96% versus 76% for patients in the ambient air temperature group. their success rate in the control group is lower than most contemporary series for upper ureteral stones with success rates over 80%(2) while 65% of stones in the control group were in lower ureter in which success rates over 90% are expectable. median success rate for lower ureteral stones were 90% in 1990’s(3) and has been improving since. the authors compared their success with other reported studies, but the studies they used for comparison were focused on treating ureteral stones with basketing(4) that is different from their method or were impacted ureteral stones(5) with naturally lower success rates in comparison with non-impacted stones. the authors ascribed the reason for improved performance in the 40 °c irrigation fluid group to less ureteral spasm in this group but provided no solid evidence to back their hypothesis in their study or in review of the literature. references 1. mohammadzadeh rezaei ma, akhavan rezayat a, tavakoli m, jarahi l. evaluation the result of warm normal saline irrigation in ureteral endoscopic surgeries. urol j. 2018;15:83-6. 2. drake t, grivas n, dabestani s, knoll t, lam t, maclennan s, petrik a, skolarikos a, straub m, tuerk c, yuan cy, sarica k. what are the benefits and harms of ureteroscopy compared with shock-wave lithotripsy in the treatment of upper ureteral stones? a systematic review. eur urol. 2017;72:772-86. 3. segura jw, preminger gm, assimos dg, dretler sp, kahn ri, lingeman je, macaluso jn jr. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. the american urological association. j urol. 1997;158:1915-21. 4. basiri a, simforoosh n. trans ureteral lithotripsy. medical journal of the islamic republic of iran (mjiri). 1990;4:247-52. 5. yagisawa t, kobayashi c, ishikawa n, et al. benefits of ureteroscopic pneumatic lithotripsy for the treatment of impacted ureteral stones. j endourol. 2001;15:697-9. dr. amir h kashi assistant prof of urology hasheminejad kidney center (hkc), iran university of medical sciences, tehran, iran. email: ahkashi@gmail.com editorial comments 222 reply by authors re: the evaluation of the result of warm normal saline irrigation in ureteral endoscopic surgeries: a randomized clinical trial success rate in ureteroscopic lithotripsy depends on many different variables, such as available instruments, type and size of ureteroscope, type of energy source, number of intervention sessions, auxiliary procedures and experience of surgical team.(1) in our study we used semirigid ureteroscope and pneumatic lithotripsy for all patients. flexible ureteroscope, laser lithotripter and stone retrieval devices such as n-trap or stone cone were not available. some studies have reported their success rate with flexible ureteroscopy and laser lithotripter(2). we also reported our results after only one session of tulp however some other studies have reported their results after more than one session(3). another important variable is time point in which stone free rate (sfr) is measured. we used two weeks and some other studies used four weeks, six weeks or even 3 months(3-5). heterogeneity in many of these variables in different studies can affect the success rate and metanalysis of the results is not possible(1). in our study the only available instrument for comparison was basket. although we didn’t use basketing in our study but we used similar studies for comparison(6). our hypothesis is that warmed 40 c normal saline results in lower ureteral spasm, ease of access to stone, lower ureteroscope impaction and easier tulp. however in our knowledge there was no similar study for citation. finally we think this study can provide a strategy to solve some problems during tulp such as ureteral spasm and ureteroscope impaction. however more studies with higher sample size are needed. references 1. drake t, grivas n, dabestani s, knoll t, lam t, maclennan s, et al. what are the benefits and harms of ureteroscopy compared with shock-wave lithotripsy in the treatment of upper ureteral stones? a systematic review. eur ,rol. 2017;72:772-86. 2. binbay m, tepeler a, singh a, akman t, tekinaslan e, sarilar o, et al. evaluation of pneumatic versus holmium:yag laser lithotripsy for impacted ureteral stones. int urol nephrol. 2011;43:989-95. 3. lee jh, woo sh, kim et, kim dk, park j. comparison of patient satisfaction with treatment outcomes between ureteroscopy and shock wave lithotripsy for proximal ureteral stones. k j urol. 2010;51:78893. 4. izamin i, aniza i, rizal am, aljunid sm. comparing extracorporeal shock wave lithotripsy and ureteroscopy for treatment of proximal ureteric calculi: a cost-effectiveness study. the medical journal of malaysia. 2009;64:12-21. 5. stewart gd, bariol sv, moussa sa, smith g, tolley da. matched pair analysis of ureteroscopy vs. shock wave lithotripsy for the treatment of upper ureteric calculi. inte j clin practice. 2007;61:784-8. 6. basiri a, simforoosh n. trans ureteral lithotripsy. medical journal of the islamic republic of iran. 1990;4:247-52. mahmoud tavakkoli1, alireza akhavanrezayat1* assistant prof. of urology, mashhad university of medical sciences, mashhad iran correspondence: assistant prof. of urology, mashhad university of medical sciences, mashhad iran. tel: 09153148223. e-mail: akhavanra@mums.ac.ir vol 15 no 04 july-august 2018 223 urological oncology comparison of classic and inguinal obturator nerve blocks applied for preventing adductor muscle contractions in bladder tumor surgeries: a prospective randomized trial recai dagli1*, mumtaz dadali2, levent emir2, sahin bagbanci2, hakan ates3 purpose: obturator nerve block (onb) has been performed in surgeries of transurethral resection of bladder tumors (tur-bt) for the prevention of the development of obturator muscle contraction. currently, classic and inguinal approaches are frequently being used. in the present study, we aimed to compare the success rate, performance speed, and complication risks of both approaches. materials and methods: sixty-six patients who underwent tur-bt under spinal anesthesia were randomly selected, and onb was performed on the tumor location side using classic (n = 33) or inguinal (n = 33) approaches. ten milliliters of 0.25% bupivacaine were administered using a peripheral nerve stimulator in both approaches. two endpoints were defined in the study: primary endpoint; the duration of the determination of the obturator nerve and number of interventions when each participant is assessed in at the end of the onb procedure. secondary endpoint; development of contractions, and complications each participant is assessed during the tur-bt and 24 hours after onb. (clinical trial registration number: actrn12617001050347) result: general anesthesia was applied to the five patients in the classic onb group who detected diffuse or bilateral tumors. these patients were excluded from the study. contractions developed in 4 patients in each group, no statistically significant difference was detected between the groups (14.3%, n = 4 versus 12.1%, n = 4) (p = 1.00). no complications were detected in both groups during the tur-bt and 24 hours after onb. we found that the inguinal approach provided a statistically significant advantage regarding the number of punctures (1.9 ± 0.9 versus 1.5 ± 0.7) (p = .036), and duration of the procedure (99.1 ± 48.4 seconds versus 76.0 ± 31.9 seconds) (p=.029) compared with the classic approach. conclusion: although complications and success rates were similar in both groups, the inguinal method may be a better approach because it is faster and requires fewer punctures. keywords: obturator nerve block; transurethral resection of bladder tumor; bladder tumor; adductor spasm; nerve stimulator introduction transurethral resection of bladder tumors (tur-bt) are frequently performed under spinal anesthesia, and contractions may develop in adductor muscles due to electrical stimuli applied during side wall localized tumor resection. as a consequence, bladder wall perforations and pelvic organ injuries may develop. general anesthesia or obturator nerve block (onb) may be required so as to perform the required resection(1,2). some studies showed that a safer surgical area could be provided with onb applied during tur-bt, and tumor recurrence decreased because the required resection was performed(3). different methods have been tested for preventing adductor muscle contractions during tur-bt surgeries(4-6). some studies suggested that onb could be performed through blind attempts using anatomic land marks and that it was a safe procedure(7,8). however, 1department of anesthesiology and reanimation, ahi evran university faculty of medicine, kirsehir, turkey. 2department of urology, ahi evran university faculty of medicine, kirsehir, turkey. 3department of anesthesiology and reanimation, ahi evran university training and research hospital, kirsehir, turkey. *correspondence: department of anesthesiology and reanimation, ahi evran university faculty of medicine, kirsehir 40200, turkey. tel: +905426536975. e-mail: drresel@gmail.com. received september 2017 & accepted april 2018 some studies reported complications due to block during the proceedings(9). therefore, new approaches or nerve stimulator and ultrasonography have been used to provide a safer and effective block(10,11). at present, classic and inguinal approaches are used for onb(10). the obturator nerve stems from the anterior division of the ventral rami of l2-l3-l4 nerves in the lumbar plexus, contains motor and sensory nerve fibers. the nerve descends through the psoas major muscle. it runs close the inferolateral bladder, bladder neck, and prostatic urethra, along with the inner lateral wall of the pelvis. and then it enters the upper part of the obturator foramen and the thigh. the obturator nerve divides into anterior and posterior branches in the pelvic cavity, the obturator canal, or the thigh. the branches of obturator nerve emerges from the obturator foramen and runs among the pectineus and obturator externus muscles. the anterior branch urological oncology 62 vol 16 no 01 january-february 2019 63 runs between the pectineus and adductor brevis muscles, as the posterior branch runs between the adductor brevis and adductor magnus muscles(12,13). the obturator nerve is blocked from the obturator foramen in the classic method, and between the adductor brevis and adductor magnus muscles in the inguinal method(10). in literature, there are a numerous studies have been used with different methods, drugs, and devices for onb. however, during the literature reviews, we have found that there are only a small number of studies on onb application during tur-bt with the current consort guidelines. for this reason, we planned this parallel-group randomized clinical trial with current guidelines. in the present study, we aimed to compare the success rate, performance speed, and complication risks of both classic and inguinal onb performance. materials and methods study population the patients who underwent tur-bt due to bladder tumor in the urology clinic of ahi evran university education and training hospital, and required onb due to obturator muscle spasm were included in the study. the patients were informed about the study and written informed consents were obtained after the approval of the clinical research ethics committee of turgut ozal university faculty of medicine (decision no: 99950669/104) was given. (clinical trial registration number: actrn12617001050347) inclusion and exclusion criteria patients who were american society of anesthesiologists (asa) risk grade i-iii and aged between 18-80 years were included in the study. patients who had undergone previous surgery in the study region and had anatomic disorders, neurologic problems such as parestesia, muscle disease such as the motor neuron disorders and muscular atrophy, and coagulation disorders were excluded. study design this study was a prospective, double blind, parallel group, randomize clinical trial. the patients who underwent cystoscopy under local anesthesia and had tumors on the side wall of the bladder were examined preoperatively. sixty-six patients who matching inclusion criteria and allowed onb to practice were included in the study within the research period allowed by the ethics committee(01.02. 201601.08.2017). patients were randomized for classic (n = 33) and inguinal (n = 33) onbs by the principal investigator of the study (figure 1). simple randomization was done before study commencement by the excel (microsoft, redmond, wa, usa) random number generation function. sixty-six patients included in the study were enumerated as classical(1) and inguinal(2) and assigned to onb 'groups and the procedures was carried out. two endpoints were defined in the study: primary endpoint; the duration of the determination of the obturator nerve and number of interventions when each participant is assessed in at the end of the onb procedure. secondary endpoint; development of contractions, and complications each participant is assessed during the tur-bt and 24 hours after onb. procedures age, sex, body mass index (bmi), and asa scores were recorded. before surgery, 500 ml intravenous 0.9% nacl was administered to the patients. heart rate, spo2, blood pressure, and electrocardiography were monitored in the operating room. spinal anesthesia was performed using 12.5 mg hyperbaric bupivacaine after insertion of a 25-gauge quincke spinal needle from l3-4 or l4-5 in the sitting position. patients were laid in the supine position. development of sensory block was examined at the t10 level. required anatomic markings were made on the wall where the tumor was located by the approach to be applied (figure 2): in the classic method, the puncture point was marked 1.5 cm lateral of tuberculum pubis and 1.5 cm caudal. in the inguinal method, the tuberculum pubis, spina iliaca anterior superior, inguinal ligament, and femoral artery were marked. the puncture entry point was determined as the middle of the tuberculum pubis and figure 1. consort flow diagram of study figure 2. obturator nerve block ((1) spina iliaca anterior superior (2) nervus obturatorius (3) inguinal ligament (4) tuberculum pubicus (5) arteria femoralis (6) classical approach onb point (7) inguinal approach onb point) obturator nerve blocks for adductor muscle contractions -dagli et al. femoral artery, and 5-8 cm below the inguinal ligament. the required sterilization was applied on the surgical area. the patients were considered blind because of not seeing the surgical site during onb administration and tur-mt. the peripheral nerve stimulator (pajunk, melsungen, germany) was adjusted to 1.5 ma 1 hz. insertion was applied from the determined points using an isolated 22-gauge, 100-mm nerve stimulator needle (pajunk, melsungen, germany). the needle was directed cephalad in the inguinal approach. in the classic method, the needle was perpendicularly inserted and slightly withdrawn after reaching the bone; the needle was manipulated 2-4 cm towards the medial. first, suction was performed, and then 10 ml 0.25% bupivacaine were administered when an adductor muscle contraction area was detected with the peripheral nerve stimulator between the range of 0.4-0.7 ma. withdrawal and remanipulation of the needle was counted as one puncture. the period between the first puncture insertion and local anesthesia injection was recorded as the practice period. the duration of the determination of the obturator nerve of classic or inguinal onb approaches were compared by stopwatch timing of procedure by the research assistant. onb was administered by the same anesthesiologists while the urologist was not in the operating room. adductor muscle contractions and complications such as bladder perforation that occurred during the resection were recorded by a urologist who was blinded to the onb technique. transurethral resection of bladder tumor (tur-bt) was performed using a 26-french bipolar resectoscope, and a 30-degree optic. we used 0.9% naci for irrigation. surgery was initiated 10 minutes after the onb. all onb and tur-bt procedures were performed by the same anesthesiologists and urologists. no other additional technique was performed for the prevention of adductor muscle contractions. the onb applied zone was evaluated by the phisical examination 24 hours after the surgery. the complications such as vein injuries, hematoma, paresthesia and motor neuronal deficit recorded by a urologist who was blinded to the onb technique. age, sex, bmi, asa classification, success rates, puncture periods, complications, and switch rates to general anesthesia were compared between the two groups. statistical analysis the statistical package for the social sciences (spss) 23.0 (ibm spss inc., chicago, il, usa) was used in data analysis. the chi-square test was used in the comparison of qualitative data in addition to descriptive statistical methods (frequency, percentage, mean, standard deviation). the kolmogorov-smirnov and shapiro-wilk tests were used in the evaluation of normally distributed data. the independent samples t-test was used to evaluate normally distributed quantitative data, and the mann-whitney u test was used in the evaluation of data with no normal distribution. correlations of variables were evaluated using pearson’s correlation tests. probability values less than (p) α=.05 were regarded as significant and indicating a difference between the groups. power analysis was performed the g*power 3.1.9.2 statistical package program; and power (1-β) was found as 0.86 considering n1 = 28, n2 = 33, α = .05, and effect size as d = .8. results general anesthesia was applied to the five patients in the classic onb group who detected diffuse or bilateral tumors. these patients were excluded from the study. the demographic data are shown in table 1. no statistically significant difference was detected between the groups regarding sex, age, weight, height, bmi, and asa scores (p = .091, p = .519, p = .907, p = .191, p = .494, p = .087). although no statistically significant differences were detected regarding the development of adductor muscle contraction (p = 1.00), a statistically significant difference was detected between the number of punctures (p = .036), and duration of the procedure (p = .029). the number of punctures was higher and duration of the table 1. comparison of the demographic characteristics between the groups classic (n=28) inguinal (n=33) p-value sex male 25 (89.3%) 33 (100.0%) .091* female 3 (10.7%) 0 (0.0%) age (year) 61.0 ± 14.0 58.6 ± 15.1 .519** weight(kg) 80.9 ± 13.8 81.3 ± 13.8 .907** height (cm) 173.1 ± 8.5 170.7 ± 4.4 .191** bmi(kg/m2) 27.1 ± 5.0 28.0 ± 5.2 .494** asa i 6 (21.4%) 9 (27.3%) .087*** ii 16 (57.1%) 24 (72.7%) iii 6 (21.4%) 0 (0.0%) * chi-square test, ** independent samples t test, *** mann-whitney u classic (n=28) inguinal (n=33) pvalue number of punctures 1.9 ± 0.9 1.5 ± 0.7 .036* duration of the procedure (seconds) 99.1 ± 48.4 76.0 ± 31.9 .029* contraction no 24 (85.7%) 29 (87.9%) 1.000** yes 4 (14.3%) 4 (12.1%) * independent samples t test, ** chi-square test table 2. comparison of the groups regarding puncture-duration and procedure-development of adductor muscle contractions obturator nerve blocks for adductor muscle contractions -dagli et al. urological oncology 64 vol 16 no 01 january-february 2019 65 procedure was longer in the classic onb group (table 2). no complications such as vein injuries, hematoma, paresthesia and motor neuronal deficit were detected in both groups during the tur-bt and 24 hours after onb. discussion obturator nerve block has been used for anesthesia or postoperative analgesia in knee surgeries, in the treatment of adductor spasticity, and in the prevention of adductor muscle contractions during tur-bt surgeries as a part of “3-in-1” blocks(14). the obturator nerve can be blocked from different anatomic regions during its navigation in the body(15). block success rates vary depending on anatomic variations in the coursing of the obturator nerve(13). therefore, different approaches or different equipment such as nerve stimulators and ultrasonography have been tested to enable safer and more effective blocks(15). in their comparison study with 30 patients, moningi et al. reported that inguinal approach was a good alternative for the classic approach. although vascular trauma was detected in 4 patients in the classic group, the researchers concluded that both approaches were similar regarding the convenience of the practice(16). even though no complications and no statistical differences were detected regarding success rates in our study, we found that the inguinal approach could be performed faster and with fewer punctures. another study compared the classic and inguinal pubic approaches in 102 patients. the success rate (96.1% vs. 84%) was found higher, and fewer punctures were required in the inguinal group, and the authors reported that the inguinal technique was anatomically easier to perform. two failed blocks in the inguinal group, and eight failed blocks in the classic group were detected, with no complications in either group (17). in our study, although the success rate was higher in the inguinal group, no statistical significance was detected between the groups. we found that onb could be performed faster with fewer punctures in the inguinal approach. minimal contractions developed in four patients in each group, but they were not so intense as to prevent the surgical procedure or require switching to general anesthesia. in another study, researchers found an 86% success rate and fewer complications with the classic approach using a nerve stimulator for onb(18). we also found similar success rates in the classic approach. the success rate was reported as 90.5% using a nerve stimulator in the inguinal group in a study by hızlı et al. in their study, the block could not be provided in 2 patients out of 21 in the inguinal group under ultrasonography. bladder perforation developed in two patients (19). different to that study, we used a nerve stimulator only, and the success rate was found as 87.9%. despite the fact that complete block could not be accomplished in four patients, no complications were detected. sharma et al. conducted a study using a nerve stimulator on 20 patients in the classic approach. a minimal contraction was observed in one patient, and complete block was accomplished in the other patients(20). however, a mixture of 15 ml lignocaine and bupivacaine was used in that study. we used 10ml 0.25% bupivacaine in our study. a higher success rate was detected in that study compared with ours. the high success rate could be due to the use of high-volume, high-concentration drugs. different methods, different drugs, and different drug concentrations were used in onb studies, and very different success rates were obtained(2,21,22). higher success rates were obtained in some blind attempt onb studies (7). on the other hand, less local anesthetic drugs were used in studies where both nerve stimulator and ultrasonography were used to avoid systemic local anesthetic drug toxicity compared with blind attempt blocks (11,22). bolat et al. used 0.25% levobupivacaine in their study and found the success rate as 88.6%, which was similar to ours(18). limitations: only sixty-six patients who matching inclusion criteria could be included in the study within the research period allowed by the ethics committee, and thus the power analysis of study was performed. the drug was administered into the first detected region using a nerve stimulator between 0.4-0.7 ma in both approaches in our study. no other intervention was performed to identify other branches of the obturator nerve. we suggest that this was one of the reasons we had more contractions in our study. the depth of the stimulator needle at the injection site may affect the administration speed. we did not investigate the depth in our study because the needles were manipulated at different angles after penetration into the skin in both methods. some studies found a higher depth in the inguinal approach, but they did not compare the block performance speed(17). we suggest that more punctures were required in classic approach onb because the obturator nerve was located deeper during the navigation from the obturator foramen; therefore, it was more difficult to determine the location. conclusions in conclusion, although the complication and success rates were similar in both methods, it seems that the inguinal method with a nerve stimulator is a better approach because it enables faster onb with fewer punctures. conflict of interest the authors report no conflict of interest. references 1. kitamura t, mori y, ohno n, suzuki y, yamada y. [case of bladder perforation due to the obturator nerve reflex during transurethral resection (tur) of bladder tumor using the tur in saline (turis) system under spinal anesthesia]. masui. 2010;59:386-9. 2. hradec e, soukup f, novak j, bures e. the obturator nerve block. preventing damage of the bladder wall during transurethral surgery. int urol nephrol. 1983;15:149-53. 3. erbay g, akyol f, karabakan m, celebi b, keskin e, hirik e. effect of obturator nerve block during transurethral resection of lateral bladder wall tumors on the presence of detrusor muscle in tumor specimens and recurrence of the disease. kaohsiung j med sci. 2017;33:86-90. 4. augspurger rr, donohue re. prevention obturator nerve blocks for adductor muscle contractions -dagli et al. of obturator nerve stimulation during transurethral surgery. j urol. 1980;123:170-2. 5. ong el, chan st. transurethral surgery and the adductor spasm. ann acad med singapore. 2000;29:259-62. 6. ozer k, horsanali mo, gorgel sn, ozbek e. bladder injury secondary to obturator reflex is more common with plasmakinetic transurethral resection than monopolar transurethral resection of bladder cancer. cent european j urol. 2015;68:284-8. 7. khorrami m, hadi m, javid a, et al. a comparison between blind and nerve stimulation guided obturator nerve block in transurethral resection of bladder tumor. j endourol. 2012;26:1319-22. 8. tatlisen a, sofikerim m. obturator nerve block and transurethral surgery for bladder cancer. minerva urol nefrol. 2007;59:137-41. 9. akata t, murakami j, yoshinaga a. lifethreatening haemorrhage following obturator artery injury during transurethral bladder surgery: a sequel of an unsuccessful obturator nerve block. acta anaesthesiol scand. 1999;43:784-8. 10. choquet o, capdevila x, bennourine k, feugeas jl, bringuier-branchereau s, manelli jc. a new inguinal approach for the obturator nerve block: anatomical and randomized clinical studies. anesthesiology. 2005;103:1238-45. 11. manassero a, bossolasco m, ugues s, palmisano s, de bonis u, coletta g. ultrasound-guided obturator nerve block: interfascial injection versus a neurostimulationassisted technique. reg anesth pain med. 2012;37:67-71. 12. jo sy, chang jc, bae hg, oh js, heo j, hwang jc. a morphometric study of the obturator nerve around the obturator foramen. j korean neurosurg soc. 2016;59:282-6. 13. selmi nh, sahin s, gurbet a, et al. obturator nerve block in adductor spasticity: comparison of peripheral nerve stimulator and ultrasonography techniques. turk j anaesth reanim. 2013;41:121. 14. yoshida t, nakamoto t, kamibayashi t. ultrasound-guided obturator nerve block: a focused review on anatomy and updated techniques. biomed res int. 2017;2017:7023750. 15. anagnostopoulou s, kostopanagiotou g, paraskeuopoulos t, chantzi c, lolis e, saranteas t. anatomic variations of the obturator nerve in the inguinal region: implications in conventional and ultrasound regional anesthesia techniques. reg anesth pain med. 2009;34:33-9. 16. moningi s, durga p, ramachandran g, murthy pv, chilumala rr. comparison of inguinal versus classic approach for obturator nerve block in patients undergoing transurethral obturator nerve blocks for adductor muscle contractions -dagli et al. resection of bladder tumors under spinal anesthesia. j anaesthesiol clin pharmacol. 2014;30:41-5. 17. jo yy, choi e, kil hk. comparison of the success rate of inguinal approach with classical pubic approach for obturator nerve block in patients undergoing turb. korean j anesthesiol. 2011;61:143-7. 18. bolat d, aydogdu o, tekgul zt, et al. impact of nerve stimulator-guided obturator nerve block on the short-term outcomes and complications of transurethral resection of bladder tumour: a prospective randomized controlled study. can urol assoc j. 2015;9:e780-4. 19. hizli f, argun g, guney i, et al. obturator nerve block transurethral surgery for bladder cancer: comparison of inguinal and intravesical approaches: prospective randomized trial. ir j med sci. 2016;185:555-60. 20. sharma d, singh vp, agarwal n, malhotra mk. obturator nerve block in transurethral resection of bladder tumor: a comparative study by two techniques. anesth essays res. 2017;11:101-4. 21. kakinohana m, taira y, saitoh t, hasegawa a, gakiya m, sugahara k. interadductor approach to obturator nerve block for transurethral resection procedure: comparison with traditional approach. j anesth. 2002;16:123-6. 22. pladzyk k, jureczko l, lazowski t. over 500 obturator nerve blocks in the lithotomy position during transurethral resection of bladder tumor. cent european j urol. 2012;65:67-70. urological oncology 66 kidney transplantation 105urology journal vol 7 no 2 spring 2010 changes of left ventricular mass index among end-stage renal disease patients after renal transplantation mohammad hassan namazi,1 saeed alipour parsa,2 banafshe hosseini,1 habibollah saadat,1 morteza safi,1 mohammad reza motamedi,1 hossein vakili1 purpose: the aim of this study was to determine left ventricular (lv) mass index via echocardiography in end-stage renal disease patients (esrd) before and after renal transplantation, and its association with one-year survival. materials and methods: forty-seven patients with esrd who were candidate for renal transplantation were evaluated with echocardiography before and 4 months after the operation. left ventricular ejection fraction (ef), lv mass, and lv mass index were determined. all of the patients were followed up for 1 year. results: mean lvef was 51.6% which increased to 53.7% after renal transplantation (p = .001). mean lv mass was 209 gr before the operation which decreased to 189 gr after the operation (p = .001). mean lv mass index before the operation was 120 gr/m2 which decreased to 110 gr/m2 following the operation (p = .002). all of the patients survived during 1-year follow-up, and no death was reported. conclusion: renal transplantation had beneficial effects in terms of lv function in young patients with esrd. urol j. 2010;7:105-9. www.uj.unrc.ir keywords: end-stage renal disease, left ventricular hypertrophy, kidney transplantation, echocardiography 1cardiovascular research center, modarres hospital, shahid beheshti university, mc, tehran, iran 2department of cardiology, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran corresponding author: saeed alipour parsa, md, department of cardiology, labbafinejad medical center, 9th boustan st, pasdaran ave. tehran, iran tel: +98 21 2258 0333 fax: +98 21 2258 0333 e-mail: s_alipour@sbmu.ac.ir received may 2009 accepted march 2010 introduction end-stage renal disease (esrd) is considered as one of the most important diseases with a great burden on health care systems. complications of esrd on various organs, especially cardiovascular system, are noticeable. cardiovascular diseases are the major cause of morbidity and mortality in all stages of esrd, in both adults and children. (1,2) coronary artery disease and left ventricular hypertrophy (lvh) are the two most common cardiac complications in patients with esrd. (3,4) left ventricular hypertrophy is a risk factor for cardiovascular morbidity, including sudden death, congestive heart failure, etc among patients with esrd. (1,5) some of the variables which contribute to progression of lvh in patients with esrd include hypertension, volume overload, an increase in left ventricular afterload, uremia, and anemia.(6) renal transplant is the most acceptable treatment modality for the patients with esrd, which improves some complications of renal failure such as chronic uremia and volume overload.(7) in previous studies, the effect of successful renal transplantation on the carotid left ventricular mass index and renal transplantation—namazi et al 106 urology journal vol 7 no 2 spring 2010 artery indices and ventricular hypertrophy has been showed.(8,9) correction of the uremic state by renal transplantation has lead to regression of lvh during a 12-month follow-up.(7) on the contrary, other studies did not show a significant impact of renal transplantation on cardiovascular status. in a study by de lima and colleagues(8) on patients without obvious cardiovascular diseases who underwent renal transplantation due to esrd, it was noted that renal transplantation improved the esrd-induced cardiovascular morbidities, especially ventricular distensibility and lv mass index (lvmi), but did not cause complete regression. the aim of this study was to determine echocardiography parameters such as lvmi in esrd patients who underwent renal transplantation. materials and methods this cross-sectional study lasted for one year in 2 university hospitals, and 47 patients with diagnosis of esrd who were candidates for renal transplantation and were older than 18 years were included using convenient sampling method. patients with history of cardiovascular diseases, cardiac valvular diseases, congenital cardiovascular diseases, or usage of cardiotoxic medications were excluded. data collected by a questionnaire consisted of demographic information, risk factors of a cardiovascular disease (including diabetes mellitus, hypertension, hyperlipidemia, and cigarette smoking), etiology of esrd, systolic blood pressure (sbp), diastolic blood pressure (dbp), need to dialysis and its type, and laboratory parameters such as hemoglobin, creatinine, sodium, and potassium. all of the patients underwent echocardiography prior to operation by a cardiologist and lv mass (lvm), lv mass index (lvmi), and lv ejection fraction (ef) were determined. for determination of lvm, the devereux formula was used:(10) lv mass (gr): 1.04 [(lvid + pwt + ivst)3 – lvid3] – 14 lvid = lv internal dimension pwt = posterior wall thickness ivst = interventricular septal thickness left ventricular mass was divided by body surface area to measure lvmi. four months after the operation, echocardiography was performed again. all of the patients were followed up for one year in outpatient clinics. descriptive indices, including frequency (percentage) and mean were calculated. for comparison of hemoglobin and hematocrit levels as well as echocardiography variables and blood pressure before and 4 months after the operation, the paired student t test was used. p values less than .05 were considered statistically significant. all statistical analysis was performed using spss (statistical package for the social science, version 13.0, spss inc, chicago, illinois, usa) software. informed consents were obtained from all participants prior to enrollment. the study protocol was in accordance with declaration of helsinki. results the patients population consisted of 27 men (57.4%) and 20 women (42.6%) with age range of 23 to 56 years. of patients, 14(29.8%) were ≥ 46 years old (figure). twenty patients received dialysis (42.6%), of whom 4 patients underwent peritoneal dialysis (20%) and the remaining 16 subjects (80%) underwent hemodialysis. five frequency of 47 patients who underwent renal transplantation in different age groups. left ventricular mass index and renal transplantation—namazi et al 107urology journal vol 7 no 2 spring 2010 patients (25%) received dialysis 3 times a week while 15 patients (75%) received dialysis 2 times per week. table 1 demonstrates the etiologies of esrd in the study participants. forty-five patients had only one diagnosed etiology for esrd, whereas 2 patients (4.3%) had two diagnosed etiologies for esrd. diabetes mellitus was the most common cause of esrd with the prevalence of 21.3% (10 patients). table 2 presents the frequency of cardiovascular disease risk factors in the studied patients. twenty-three patients (48.9%) had sbp more than 140 mmhg and 15 subjects (31.9%) had dbp greater than 90 mmhg. mean (± sd) serum hemoglobin level before renal transplantation was 10.14 (± 2.87) mg/ dl which increased to 12.5 (± 2.18) mg/dl (p = .001, 95% confidence interval (ci), – 3.63 to – 1.07) afterward. mean (± sd) serum hematocrit level before the operation was 30.86% (± 8.68) which significantly increased to 37.57% (± 7.56) (p = 0.003, 95% ci, – 10.94 to – 2.46) after the operation. mean (± sd) systolic blood pressure was 136.09 (± 17.7) mmhg before the surgery, which decreased to 127.39 (± 12.95) mmhg (p = .07, 95% ci, – 1.11 to 18.5). there was no significant decrease in diastolic blood pressure before and after transplantation; 79.22 (± 9.6) mmhg vs. 76.09 (± 7.68) mmhg, p = .25, 95% ci, – 2.45 to 8.71). comparison of blood pressure and laboratory findings before and after the operation are summarized in table 3. mean lvef of patients before renal transplantation was 51.6%, which increased to 53.7% after the operation (p = .001). mean lvm before the operation was 209 gr, which decreased to 189 gr after the operation (p = .001). mean lvmi was 120 gr/m2 before the operation which decreased to 110 gr/m2 following operation (p = .002). all of the patients survived during 1-year followup, and no death was observed. discussion according to previous studies, the most prevalent echocardiographic abnormalities seen in esrd patients are lvh and systolic dysfunction. left ventricular hypertrophy is a strong predictor of poor prognosis and determinant of survival in esrd patients.(8,9) it has been shown that lvh initiates along with renal failure, increases with renal failure progression, and it will not be even improved by renal transplantation.(11,12) the high rate of cardiovascular diseases following renal transplantation is mainly due to a high incidence of conventional risk factors both before and after the operation.(13) number of risk factor* frequency percentage, % one 11 23.4 two 11 23.4 three 9 19.1 four 2 4.3 no risk factor 14 29.8 total 47 100 *risk factors evaluated were diabetes mellitus, hypertension, hyperlipidemia, and cigarette smoking. table 2. frequency of cardiovascular risk factors in 47 esrd patients who underwent renal transplantation. etiology frequency percentage (%) diabetes mellitus 10 21.3 hypertension 6 12.8 glomerulonephritis 9 19.1 urologic diseases 7 14.9 others 7 14.9 unknown 10 21.3 table 1. etiologies of esrd in 47 patients who underwent renal transplantation. before after sig. systolic blood pressure, mmhg 136.09 (±17.77) 127.39 (±12.95) 0.07 diastolic blood pressure, mmhg 79.22 (±9.6) 76.09 (±7.68) 0.25 hemoglobin, mg/dl 10.14 (±2.87) 12.5 (±2.18) 0.001 hematocrit, % 30.86 (±8.68) 37.57 (±7.56) 0.003 table 3. frequency distribution of systolic blood pressure, diastolic blood pressure, and laboratory results in 47 esrd patients before renal transplantation. left ventricular mass index and renal transplantation—namazi et al 108 urology journal vol 7 no 2 spring 2010 factors, which contribute to decreased lvmi after the operation, are treatment of hypertension and reduction in intravascular volume. on the other hand, there are some variables that result in increased lvm such as treatment with immunosuppressive agents.(11,12) based on our findings, renal transplantation significantly improved lvef, and decreased both lvm and lvmi. in most studies on renal transplant recipients, lvm and lvmi have decreased significantly. in the study by montanaro and colleagues(9) on 23 adult renal transplant recipients, a significant reduction in the mean lvm (246.2 to 202.7 gr) and mean lvmi (161.4 to 122.1 gr/m2) was observed at 2-year follow-up. the incidence of lv hypertrophy also decreased from 76 to 35 subjects. however, the underlying cause has not been understood well.(14) in another study performed on 22 esrd patients who underwent renal transplantation, it was shown that after 40 months, the survival rate was 100% without any major cardiovascular complication. in spite of a significant reduction in lv end-diastolic diameter, the mean lvmi remained above normal limits, and only one-third of subjects had normal lvmi. (8) in a recent study, echocardiography performed within 1 year after renal transplantation revealed a decrease of lvh from 67% to 37%.(15) the survival rate of our subjects was 100%, therefore, we were not able to determine any statistical correlations between lvmi changes and survival. the reported survival rate in another study was 95%.(16) the high survival in this study may be due to the younger age; 42.6% were younger than 35 years old. based on previous studies, patients who did not receive dialysis before renal transplantation had less mortality than those who underwent dialysis. (17) only 57% of the patients had undergone dialysis before operation, and this could be another reason for a better survival rate. it has been reported that persistent lvh may be associated with a high rate of infection and chronic rejection, which in turn worsens the prognosis of renal transplant recipients.(18) contrary to the literature indicating beneficial impact of renal transplantation on lvmi, a recent study performed cardiac magnetic resonance imaging, which showed no significant change in lvmi in subjects who received renal transplantation (2.75%/yr, ± 9.1) compared to patients who remained on dialysis (-3.6%/ yr ± 16.7). the authors concluded that renal transplantation is not associated with significant regression of lvmi, which may be due to overestimation of lvmi by echocardiography.(19) conclusion in conclusion, renal transplantation had a beneficial effect on lv function, improved lvef, and decreased both lvm and lvmi in young patients with esrd. concomitant treatment of risk factors with renal transplantation is recommended. further studies with long-term follow-ups as well as larger sample sizes are required to better clarify the impact of renal transplantation on echocardiographic variables. conflict of interest none declared. references 1. skorecki k, green j, brenner b. chronic renal failure. in: kasper dl, braunwald e, fauci as, hauser sl, longo dl, jameson al, eds. harrison‘s principles of internal medicine. 16 ed: new york: mcgrow-hill; 2005:1653-60. 2. becker-cohen r, nir a, ben-shalom e, et al. improved left ventricular mass index in children after renal transplantation. pediatr nephrol. 2008;23: 1545-50. 3. berl t, henrich w. kidney-heart interactions: epidemiology, pathogenesis, and treatment. clin j am soc nephrol. 2006;1:8-18. 4. osorio moratalla jm, ferreyra lanatta c, baca morilla y, et al. left ventricular structure and function in longterm kidney transplantation: the influence of glucose metabolism and oxidative stress. transplant proc. 2008;40:2912-5. 5. foley rn, parfrey ps, kent gm, harnett jd, murray dc, barre pe. long-term evolution of cardiomyopathy in dialysis patients. kidney int. 1998;54:1720-5. 6. malik j, tuka v, mokrejsova m, holaj r, tesar v. mechanisms of chronic heart failure development in end-stage renal disease patients on chronic hemodialysis. physiol res. 2009;58:613-21. 7. ferreira sr, moises va, tavares a, pachecoleft ventricular mass index and renal transplantation—namazi et al 109urology journal vol 7 no 2 spring 2010 silva a. cardiovascular effects of successful renal transplantation: a 1-year sequential study of left ventricular morphology and function, and 24-hour blood pressure profile. transplantation. 2002;74: 1580-7. 8. de lima jj, vieira ml, viviani lf, et al. long-term impact of renal transplantation on carotid artery properties and on ventricular hypertrophy in endstage renal failure patients. nephrol dial transplant. 2002;17:645-51. 9. montanaro d, gropuzzo m, tulissi p, et al. effects of successful renal transplantation on left ventricular mass. transplant proc. 2005;37:2485-7. 10. devereux rb, reichek n. echocardiographic determination of left ventricular mass in man. anatomic validation of the method. circulation. 1977;55:613-8. 11. mcgregor e, jardine ag, murray ls, et al. preoperative echocardiographic abnormalities and adverse outcome following renal transplantation. nephrol dial transplant. 1998;13:1499-505. 12. levin a, thompson cr, ethier j, et al. left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. am j kidney dis. 1999;34: 125-34. 13. fazelzadeh a, mehdizadeh a, ostovan ma, raissjalali ga. incidence of cardiovascular risk factors and complications before and after kidney transplantation. transplant proc. 2006;38:506-8. 14. parfrey ps, harnett jd, foley rn, et al. impact of renal transplantation on uremic cardiomyopathy. transplantation. 1995;60:908-14. 15. dzemidzic j, rasic s, saracevic a. the influence of renal alograft function on cardiovscular status and left ventricular remodelling. bosn j basic med sci. 2009;9:102-6. 16. kasiske bl, guijarro c, massy za, wiederkehr mr, ma jz. cardiovascular disease after renal transplantation. j am soc nephrol. 1996;7:158-65. 17. silberberg js, barre pe, prichard ss, sniderman ad. impact of left ventricular hypertrophy on survival in end-stage renal disease. kidney int. 1989;36:286-90. 18. sheashaa ha, abbas tm, hassan na, et al. association and prognostic impact of persistent left ventricular hypertrophy after live-donor kidney transplantation: a prospective study. clin exp nephrol. 2009;14:68-74. 19. patel rk, mark pb, johnston n, mcgregor e, dargie hj, jardine ag. renal transplantation is not associated with regression of left ventricular hypertrophy: a magnetic resonance study. clin j am soc nephrol 2008;3:1807. january-february 2018 reviewer of the issue matthew roberts matthew roberts march 2018 matthew roberts mb bs, phd is a medical graduate of the university of queensland and current urology specialty trainee based in queensland, australia as well as being a lecturer in the department of surgery, the university of queensland. he completed his phd under the supervision of professor “frank” gardiner investigating new biomarkers for the early detection and characterization of prostate cancer. he has authored over 50 peer reviewed papers in international journals and presented his research at international urology and clinical cancer meetings. his clinically related research interests involve a diverse range of collaborations and extend into urological infectious diseases, evidence-based medicine using meta-analysis and early detection and imaging of localized prostate cancer, for which he has received numerous research scholarships and awards. he has provided peer review for manuscripts submitted to bju international, journal of clinical urology, international urology and nephrology, asian journal of andrology, plos one, journal of pain research, journal of antimicrobial chemotherapy, qjm: an international journal of medicine, urology journal, open forum infectious diseases, british journal of research, biomed research international and metabolomics. he holds active membership in the urological society of australia and new zealand with reciprocal membership of the american urologic association and european association of urology, as well as the royal australasian college of surgeons and the australian medical association. “peer review is a central element to optimizing scientific method and reporting of findings to further the field and ultimately improve outcomes for our patients. i enjoyed reviewing for urology journal, who made the process simple and time effective.” dr. roberts, was chosen by editorial board of the urology journal for his valuable and timely men with high prostate specific antigen have higher risk of gleason upgrading after prostatectomy: a systematic review and meta-analysis xiaochuan wang, yu zhang, zhengguo ji, peiqian yang, ye tian* purpose: to examine the correlation between prostate specific antigen (psa) and the risk of gleason sum upgrading (gsu) from biopsy gleason sum (bgs) to prostatectomy gleason sum (pgs). materials and methods: five electronic databases (web of science, ovid medline, ovid embase, scopus and the cochrane library) were searched from inception until march 2020. studies were included if they focused on the relationship between psa and gsu analyzed in multivariable analysis. preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines were utilized. quality of included studies was appraised utilizing the newcastle-ottawa quality assessment scale (nos) for case-control studies. the publication bias was evaluated by funnel plot and egger’s test. results: our search yielded 19 studies with high quality including 42193 patients. gsu was found in 28.2% of patients. higher psa level was associated with a significant increased risk of gsu (pooled or = 1.14, 95% ci: 1.10–1.18; p < .05; i2 = 92%). for the definition of upgrading from bgs ≤ 6 to pgs ≥ 7, the odds of upgrading with higher psa level as opposed to lower psa level was 1.12 (95% ci: 1.11–1.14; p < .05; i2 = 13%), while the odds of upgrading with other definitions were 1.11 (95% ci: 1.05–1.18; p < .05; i2 = 89%). conclusion: patients with high level of serum psa are at high risk of undergoing pathologic upgrading at prostatectomy. combined with other risk factors, psa prompts risk reclassification and improve confidence of urologists in management decisions for optimal therapy. nevertheless, further robust studies are necessitated to confirm these results. keywords: gleason score; meta-analysis; needle biopsy; prostate cancer; prostate specific antigen; systematic review introduction prostate cancer (pca) is the second most common cancer in males in the world(1). gleason score (gs) is a critical prognostic factor for risk stratification and disease management of pca. even if gleason grading system has been modified over time(2), the accuracy of biopsy gleason sum (bgs) for predicting prostatectomy gleason sum (pgs) was reported to be barely satisfactory. a systematic review of 14839 patients reported that concordance rate between bgs and pgs was 63%, while overall upgrading from bgs to pgs was found in 30%(3). active surveillance (as) is recommended for patients with gs 6 or 3+4 and not appropriate for ones with gs 4+3 or greater(4). patients with gs 8 or greater reap the benefit of undergoing rp followed by lymph node dissection and/ or other ancillary therapy against unfavorable outcomes(5). in these scenarios, unpredictable gleason sum upgrading (gsu) bring urologists into a dilemma that how to assess the true risk for patients with pca and select optimal treatment modalities for them. it has been demonstrated in large-scale studies department of urology, capital medical university affiliated beijing friendship hospital, no. 95, yongan road, xicheng district 100050, beijing, people’s republic of china. *correspondence: department of urology, capital medical university affiliated beijing friendship hospital, no. 95, yongan road, xicheng district, beijing, people’s republic of china tel: +8618611509977. email: tianye166@126.com. received april 2020 & accepted october 2020 that patients with gsu were significantly associated with biochemical recurrence and other unfavourable surgical outcomes(6-8). prostate specific antigen (psa) is another critical factor not only for early detection of pca but also for risk classification. psa has appeared in view of urologists with its predictive performance on gsu. in recent years, robust multivariable models with nomograms consisting of psa were built for predicting gsu(9). however, previous literatures were mostly based on single-center studies with limited population and psa was marginally significant in a few studies. in this systematic review and meta-analysis, we aimed to investigate the correlation between psa and the risk of gsu in the current literature. materials and methods our study was performed according to the preferred reporting items for systematic reviews and meta-analysis (prisma) guidelines(10). methods of this analysis and inclusion criteria were specified in advance and documented in a protocol as a reference for our investigators. urology journal/vol 18 no. 5/ september-october 2021/ pp. 477-484. [doi: 10.22037/uj.v16i7.6127] review psa’s impact on gleason upgrading-wang et al. endourology and stones diseases 130 vol 18 no 4 july-august 2021 396 table 1. summary data for included studies with definitions of upgrading from bgs ≤ 6 to pgs ≥ 7 for this review. study characteristic a patient characteristic author (year ) study study size, no. selection criteria of variables adjusted in age, yr psa, ct no. cores region n upgrading, as for eligible patients multiple regression ng/ml obtained, (interval) n (%) who turned to pv, ml n immediate prostatectomy epstein 2012 (18) usa 5071 1841(36.3) na age; pw; mean 57.6, mean 5.4, na t1-3 ≥ 10 (2002-2010) gpc range range 34.0-79.0 0.2-97.2 fu 2012 usa 1632 723(44.3) d’amico criteria b age; race; median median 5, na t1c-2a nr (1993-2009) pw; ct; 61.0, range tpc; cancer range 0.2-9.9 laterality; pt; 34.0-79.0 ece; svi; psm gofrit 2007 (24) usa 448 91(20.3) na age; pv; mean 59.1, mean 6.0 mean 52.7 t1c-2 8-12 (2003-2006) psad; ct; sd 6.5 gpc; ppc; cancer laterality gokce 2016 (29) turkey 210 69(32.9) psa < 10 ng/ml; neutrophil mean 59.2, mean 5.4, nr t1c-2a nr (2005-2015) gs ≤ 6; ≤ t2a; ≤ 2 tosd 8.1 sd 1.1 positive cores; ≤ 50% lymphocyte cancer involvement ratio jalloh 2015 (21) usa 4231 1123(26.5) d’amico criteria b age; race; mean 59.9 na na t1-2 mean 9.15 (1990-2012) no. cores obtained; gpc; prostatectomy approach; year of diagnosis lee 2015 (22) korea 339 102(30.1) d’amico criteria b age; bmi; mean 65.4, mean 5.4, mean 38.0, t1c-2a mean 12.4, (2007-2012) pv; ct; no. sd 6.8 sd 2.0 sd 14.3 sd 0.8 cores obtained; gpc; ppc; tpc; core length lyon 2016 (13) usa 1256 647(51.5) na age; race; nr nr nr t1-4 ≥ 6 (1999-2015) bmi; pw; ct; no. cores obtained; gpc; ppc; tpc; year of surgery; statin use; charlson comorbidity index; ibp; biopsy pathology reviewed pietzak 2014 (33) usa 400 86(21.5) msk criteria c age; ct; nr nr nr t1c-2a ≥ 10 (1998-2008) no. cores obtained; no. positive cores; asap; hgpin; biopsy history porcaro 2017 (14) italy 170 111(65.3) d’amico criteria b pv; ppc mean 73.8, median 5.7, median t1c-2a ≥ 12 (2013-2014) sd 6.0, range 40.0, median 0.8-9.9, range 64.0, mean 5.9, 15.0-120.0, range sd 1.9 mean 41.3, 46.0-75.0 sd 15.8 quintana 2016 (20) usa 375 76(20.3) na age; race; na na na t1-2 12-33 (2003-2013) pv; ct; no. cores obtained; no. positive santok 2017 (15) korea 359 145(40.4) na cores; age; mean mean 39.2, t1-4 12 (2005-2010) race; psad; 6.8, sd 20.9, pv; ct; iqr iqr ppc 5.0–10.0 10.5-164.0 mean 63.0, sd 7.5 sooriakumaran usa 750 297(39.6) psa ≤ 10 ng/ml; age; pv; mean 59.0, mean 4.6, mean 54.0, t1-2a nr 2012 (16) (2005-2010) gs ≤ 6; ≤ t2a; ≤ ct; no. sd 6.9 sd 1.9 sd 23.2 2 positive cores; ≤ cores. 50% cancer involvement obtained; no positive cores; gpc; hgpin tosoian 2013 usa 7486 1620(21.6) d’amico criteria b age; race; mean 57.3, mean 5.2, nr t1c-2a mean \ (1975-2013) bmi; no. sd 6.4 sd 2.2 12.2, sd 3.6 cores obtained; gpc; risk stratification; year of surgery abbreviations: as, active surveillance ct, clinical t-stage; pt, pathologic t-stage; psa, prostate specific antigen; psad, psa density; pv, prostate volume; pw, prostate weight; bmi, body mass index; bgs, biopsy gleason sum; pgs, prostatectomy gleason sum; gsu, gleason sum upgrading; ppc, percentage of positive cores; gpc, greatest percentage of cancer in any core; tpc, total percentage of cancer in all cores; asap, atypical small acinar proliferation; hgpin, high-grade prostatic intraepithelial neoplasia; ece, extra-capsular extension; svi, seminal vesical invasion; psm, positive surgical margin; nr, not reported; na, not available; sd, standard deviation; iqr, interquartile range. a all studies were case-control designs; b psa ≤ 10 ng/ml; gs ≤ 6; ≤ t2a; c psa ≤ 10 ng/ml; gs ≤ 6; ≤ t2a; ≤ 3 positive cores; ≤ 50% cancer involvement review 478 vol 18 no 5 september-october 2021 479 search strategy a comprehensive search for eligible records was conducted using the following databases from inception until march 10th, 2020: web of science, ovid medline, ovid embase, scopus and the cochrane library. besides, we managed to find relevant records from electronic website of grey literatures including grey literature report, open grey and greynet international. no restriction of language was included in the search. the search used search terms included mesh and emtree terms combined with free-words. the major terms consist of ‘prostatic neoplasms’, ‘multivariate analysis’, ‘neoplasm grading’, ‘odds ratio’ and ‘upgrad*’. the full ovid medline search strategy was shown in supplementary figure 1. additional records were identified through reviewing reference lists of relevant articles. eligibility criteria and study selection eligible studies had to meet the following inclusion criteria: (1) original studies with experimental design; (2) peer-reviewed studies; (3) studies with a sample size more than 50 patients. exclusion criteria included as follows: (1) case reports, reviews, meta-analyses, and commentaries; (2) studies not in the field of gleason upgrading of prostate cancer; (3) full-text was not available; (4) studies in which psa was not included in multivariable analysis (mva); (5) studies in which adjusted odds ratios (aors), confidence intervals (cis) or p value were not available for pooled analysis. records retrieved from electronic databases and reference lists were deduplicated and the remaining were screened via title and abstract for eligibility of full-text review. if studies reported the overlapping results (same author or institution), we selected the one with the latest year of publication. the final included articles were evaluated in both qualitative synthesis and quantitative synthesis (meta-analysis). see figure 1 for the prisma flow diagram detailing the study criteria and the selection process. this whole selection process was conducted by two investigators (xw, yz) independently and disagreement was resolved by consensus and approved by a third investigator (zj). data extraction, data synthesis, and quality evaluation included studies were categorized into subgroups by definition of upgrading. subgroup a consisted of studies with the upgrading definition (from bgs ≤ 6 to pgs ≥ 7). patients in studies of subgroup a might be eligible for active surveillance but finally turned to immediate prostatectomy. subgroup b consisted of studies with other definitions of gleason upgrading. data from included studies were independently extracted by two investigators (xw, yz) and any discrepancies were resolved by consensus and approved by a third investigator (zj). procedures of extraction were performed using table 2. summary data for included studies with other definitions of gleason sum upgrading for this review. study characteristic a patient characteristic author (year ) study study no. definition of variables age, yr psa, pv, ml gs ct no. cores region size, n upgrading, upgrading adjusted in ng/ml obtained, n (interval) n (%) multiple regression bullock 2019 (27) uk 17598 4489(25.5) any gsu age; ct; mean 63.2, median 7.9, nr > 7: 14% t1-4 nr (2011-2016) bgg; year median 64.0, range of surgery; range 0-181.0, geographical 35.0-92.0 mean 10.1 region freedland 2007 (32) usa 1113 299(26.9) any gsu bmi; bgs; mean 60.6, median 6.4, nr > 3+4: 13% t1-3 median 10, (1996-2007) no. cores sd 6.5 mean 8.3, range 6-40 obtained; no. sd 7.4 positive cores; year of surgery kassouf 2007 (19) canada 247 80(32.4) any gsu age; pv; median median median > 7: 10% t1c-3 10-11 (1997-2004) ct; bgs 61.0, 5.5, 37.0, range range range 56.0-65.0 4.3-8.7 28.5-48.0 martin 2017 (30) usa 136 19(14.0) from bgs ≤ 7 to age; ct; median median nr ≤ 7 t1c-2 ≥ 10 (2005-2008) pgs ≥ 8 bgs; gpc; 60.5, 5.8, ppc iqr iqr 56.1-64.3 4.7-8.1 porcaro(2) 2017 (23) italy 135 12(8.9) from bgs = total median median median ≤ 3+4 t1c-2b ≥ 12 (2014-2015) 6/3+4 to pgs ≥ 8 testosterone; 65.0, 6.4, 40.0, psad range range range 51.0-75.0 1.2–17.9 14.0-105.0 xu 2017 china 237 62(26.2) any gsu age; bmi; mean 67.8, mean 19.2, na > 7: 19% t1-3 10 (2011-2015) ct; bgs; median median dre; 67.0, 13.4, range range 47.0-86.0 1.0-293. abbreviations: ct, clinical t-stage; psa, prostate specific antigen; psad, psa density; pv, prostate volume; bmi, body mass index; gs, gleason sum; bgs, biopsy gleason sum; pgs, prostatectomy gleason sum; gsu, gleason sum upgrading; bgg, biopsy grade group; ppc, percentage of positive cores; gpc, greatest percentage of cancer in any core; dre, digital rectal examination; nr, not reported; na, not available; sd, standard deviation; iqr, interquartile range. a all studies were case-control designs psa’s impact on gleason upgrading-wang et al. a standardized form (table 1 and table 2). two investigators (zj and qp) independently evaluated each included study utilizing the newcastle-ottawa quality assessment scale (nos) for case-control studies. discrepancies in score assignment were later resolved by consensus. statistical analysis the conversion to means of variables was roughly calculated using medians combined with range or infigure 1. preferred reporting items for systematic reviews and meta-analysis (prisma) flow diagram. figure 2. newcastle-ottawa quality assessment scale (nos) of 19 included studies. psa’s impact on gleason upgrading-wang et al. review 480 vol 18 no 5 september-october 2021 481 terquartile range (iqr) according to luo’s methods (11). the meta-analysis was conducted by computing log-transformed aors (logaors) and their standard errors (ses). fixed effect model was used for analysis of subgroup a and random effect models were used for analysis of subgroup b and total group in order to assess the predictive performance of psa on gsu. further subgroup analysis was carried out utilizing subgroup a and b. forest plot was performed to provide the pooled results in total and subgroups. the forest plot also provided the overall effect measure (z) and heterogeneity among studies. heterogeneity was appraised using i2 statistic, which represented whether the variation was attributed to heterogeneity or chance. the publication bias was evaluated by visually inspecting the asymmetry of funnel plot and subsequently quantifying the asymmetry by egger’s test. tests were 2 sided and p = .05 was the threshold for statistical significance. mefigure 3. forest plot of prostate specific antigen (psa) predicting gleason sum upgrading in total and subgroups. an odds ratio of > 1 indicates relative chance of upgrading for higher level of psa versus lower level of psa. figure 4. funnel plot of studies focused on gleason sum upgrading. a: all 19 included studies; b: studies defining upgrading from bgs ≤ 6 to pgs ≥ 7. psa’s impact on gleason upgrading-wang et al. ta-analysis and statistical tests were performed using computer software of revman version 5.3 and stata version 12.0. results 4878 records were retrieved from electronic databases (53 records from electronic websites of grey literatures) and 31 were from pertinent references. total 2375 results were deduplicated and the remaining 2534 records were screened via title and abstract for eligibility of full-text review. 189 articles were selected after screening and 19 of them published between 2007 and 2019 met the criteria for this review. all were studies of case-control series with total sample size of 42193 patients and with a study interval of 41 years (19752016). 7 studies were large series (sample size greater than 1000) from the usa and the uk. there were 11 articles from the usa, 2 from korea and another 2 from italy and the remaining 4 were from the china, uk, canada and turkey respectively. 13 series applied the definition of upgrading from bgs ≤ 6 to pgs ≥ 7, while 4 focused on any gsu and 2 consisted of patients upgraded from bgs ≤ 3+4 or 7 to pgs ≥ 8. (table 1 and table 2) of 42193 patients, the gsu was found in 11892 (28.2%) with higher-grade rp specimens. the rate of gsu in subgroup a (25.5%) was lower than that in subgroup b (30.5%). the pooled mean age of 40537 patients was 60.8 years (95%ci: 46.3-75.3) from 17 articles with extractable data. the pooled mean age of 21071 patients in subgroup a was 58.7 years (95%ci: 44.9-72.5), whilst the 19466 patients in subgroup b were older with pooled mean age of 63.1 years (95%ci: 49.1-77.0). patients in 8 subgroup a studies were eligible for as criteria but turned to prostatectomy instead. even if patients in other 5 subgroup a studies were not all eligible for as criteria, they all had opportunities to undergo surgeries for curative treatment. patients in subgroup a were likely to have lower psa level (mean or median 4.6-6.8 ng/ml) than ones in subgroup b (mean or median 5.5-19.2 ng/ml). most patients (at least 77.7%) had organ confined disease ( ≤ t2) in subgroup b. (table 1 and table 2) all included studies had high quality according to nos scale with attained scores greater than 6. 11 articles were rated as a total score of 7, while other studies were rated 8. (figure 2) as shown in the forest plot (figure 3), psa level was found to be an independent predictor of gsu regardless of definitions of upgrading. higher psa level was associated with a significant increased risk of gsu with high heterogeneity observed (pooled aor = 1.14, 95% ci: 1.10–1.18; p < .05; i2 = 92%). for the definition of upgrading from bgs ≤ 6 to pgs ≥ 7 (subgroup a), the odds of upgrading with higher psa level as opposed to lower psa level was 1.12 (95% ci: 1.11–1.14, p < .05; i2 = 13%), while the odds of upgrading in subgroup b was 1.11 (95% ci: 1.05–1.18, p < .05; i2 = 89%). as shown in funnel plots (figure 4), publication bias was pronounced with apparent asymmetry in the analysis of 19 included studies. egger’s test also demonstrated that the publication bias existed with pegger < .05. after 6 studies of subgroup b removed, asymmetry of funnel plot improved significantly with pegger = .239 which indicated that no evidence of publication bias was observed in the 13 studies for psa predicting upgrading from bgs ≤ 6 to pgs ≥ 7. discussion in this systematic review and meta-analysis of 19 studies with high ranking of quality, we identified psa as a predictor for gsu regardless of the definition of upgrading in patients eligible for curative treatment or as. the most convincing finding was observed within the subgroup of upgrading from bgs ≤ 6 to pgs ≥ 7 in which all studies consistently verified the predictive performance of psa on gsu with small heterogeneity (or = 1.12; 95% ci: 1.11–1.14; p < .05; i2 = 13%; pegger = .239). this review also demonstrated the inaccuracy of bgs to predict pgs with upgrading occurring in 28.2% of 42193 patients. gleason upgrading has always been a prolonged invariable topic over time. even if agreement between bgs and pgs has improved over decades(12), due to the nature of diagnostic method, the phenomena of gleason upgrading cannot be eliminated. a systematic review (3) including 14839 patients from 1982–2007 reported upgrading from bgs to pgs was found in 30% (range from 6% to 36%), which had no overlapping population with our review and was comparable with what we had found (28.9%, range from 8.9% to 65.3%). lyon et.al (13), porcaro et.al(14), santok et.al(15) and sooriakumaran et.al(16) identified 51.5%, 65.3%, 40.4% and 39.6% of patients with gsu partly due to the upgrading from the ‘bottom’ (bgs = 6). although psa is typically elevated in high-grade disease, some patients present with the discordant scenario of high-grade disease and low psa. for gleason 8–10 disease, these patients with low psa have a higher risk for pca death and are more likely to be associated with neuroendocrine genomic features than ones with high psa(17). high-grade disease could be harboured in these patients which may result in upgrading. however, our pooled results showed that there is a positive linear relationship between psa and gsu. the following two reasons might explain. the proportion of these patients in the population is small which may not influence the linearity of multivariable analysis. the diagnoses of these patients are difficult via psa screening and these patients might be ineligible for prostatectomy when they are diagnosed. hence, most of these patients may not be incorporated in the included studies of this review. psa is organ but not cancer specific and hence it may be elevated in patients with large prostate gland or other clinical scenarios such as prostatitis. counterintuitively, small rather than large prostate volume (pv) was strongly associated with pathologic outcomes including gsu(18), which was also determined by 2 included studies(19,20) in our review. in 9 articles included(14-16, 2025), pv was also incorporated into mva to adjust for confounders or collinearity. however, psa was still an independent predictor for gsu. psa density (psad) is the level of psa divided by the trus-determined pv, which is another predictor for risk stratification and prognosis and more likely to be associated with clinically significant pca(26). due to psad as a better indicator adjusting for pv, it has been reported that psad other than psa was an independent predictor of upgrading (27). controversially, 3 articles(15,24,25) included in this review demonstrated that psa was still strongly assopsa’s impact on gleason upgrading-wang et al. review 482 vol 18 no 5 september-october 2021 483 ciated with gsu even when psad was incorporated into mva. however, no matter what we will find from further studies addressing this issue, psa is a critical factor which urologists or oncologists should be fully considerate to in terms of risk reclassification. all the articles except one(28) incorporated at least one pathologic variable into mva. including variables such as the number of positive cores and/or tumor extent in cores improved the predictive performance for a comprehensive risk assessment of gsu. individual differences including racial variation(13,20-22,26), body mass index(13,14, 22-24,26) and comorbidity(13,22) which might potentially affect gsu were also adjusted. multifarious variables being included in different articles verified psa as the independent risk factor, but would do so at the cost of inducing the heterogeneity between studies. heterogeneity among studies focused on upgrading from bgs ≤ 6 to pgs ≥ 7 was acceptable, whilst the variation within subgroup b was significant. the combination of different definitions in subgroup b was a major source of heterogeneity. the number of biopsy cores obtained was a vital factor influencing the accuracy of predicting pgs(29). most studies adjusted for it or it was an invariant part of study design, however, there were 6 studies(14,19,24,28,30,31) did not do so or report the details, which might contribute to significant variation in outcomes. given the nature of case-control studies, the limitation of study design was also an inevitable reason of heterogeneity. further prospective, large-scale and well-designed research is needed to determine psa’s impact on gsu. experience in gs assignment varies across pathologists especially in different hospitals and regions. interobserver variability was found to correlate with the accuracy between bgs and pgs(32). in view of pooled analysis of studies, this interobserver variability cannot be eliminated but reflect the true contemporary clinical practice. except the heterogeneity discussed above, our review still has several limitations. first of all, the quality of the studies varied. moreover, incomplete retrieval of all research due to inevitable reasons such as no access to full-text, non-extractable data or inappropriate data type. last but not least, only patients who had undergone rp were selected for analysis which might not represent the reality. according to our pooled analysis, there are several clinical implications of psa predicting gsu in current clinical practice. patients who are reevaluated to have high probabilities of gsu during as could adhere to more active follow-up policies in case of delay of treatment. on the contrary, patients with low probabilities of gsu who are unwilling to or could not receive interventions are more inclined to undergo the watchful waiting or as. these clinical recommendations might give urologists more confidence in clinical decision-making and provide more precise and comprehensive assessment of the risk and more personalized and optimal treatment options for pca patients. conclusions psa is an independent predictor for gleason sum upgrading regardless of the definition of upgrading. patients with high level of serum psa are at high risk of undergoing pathologic upgrading at prostatectomy. combined with other risk factors, psa prompts more accurate risk stratification and helps providers to select optimal therapies for pca patients. nevertheless, further robust studies are necessitated to confirm these results. conflicts of interest: none of the authors have any 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groups for one day applications of sham control, torsion, melatonin, pulsed magnetic field (pmf) and melatonin plus pmf. similarly, the other 30 rats were divided into the same five groups (n = 6) for one week treatment, but the animals were sacrificed after one week. rats were exposed to 50 hz, 1 mt pmf for two hours. pet/ct with 37 mbq 18f-fdg and testicular scintigraphy with and 37 mbq 99mtc pertechnetate examinations were carried out, and testicular tissue was examined using histopathological methods. results: in one day treatment, melatonin administration significantly increased perfusion and glucose metabolism compared to torsion group (p < 0.01). perfusion and glucose metabolism was also higher in the pmf and melatonin plus pmf groups than torsion group (p < 0.01). in one week treatment, melatonin administration resulted in a significantly higher perfusion and glucose metabolism rates compared to torsion group (p < 0.01 and p < 0.001, respectively). in addition, perfusion and glucose metabolism significantly increased in pmf and melatonin plus pmf groups compared to torsion group (p < 0.01 and p < 0.001, respectively). furthermore, caspase-3 immunoreactivity and pathological changes increased in the torsion group (p < 0.05). melatonin and melatonin plus pmf treatment reduced the rate of immunoreactivity and pathological findings compared to the torsion group (p < 0.05). conclusion: according to these results it can be concluded that pmf application has a therapeutic benefit as effective as melatonin administering. in addition, it was indicated that pet/ct with 18f-fdg and testicular scintigraphy with 99mtc pertechnetate could be efficiently used in determining the treatment efficiency in testicular torsion. keywords: positron emission tomography/computed tomography; pulsed magnetic field; scintigraphy; testis torsion introduction testis torsion is a surgical condition with acute on-set especially in childhood and young adolescent men, and it needs to be diagnosed and treated. it refers to inhibition of blood flow into testis and associated structures depending upon twisting of spermatic cord around its axis. it has an incidence rate of 1/4,000 in men younger than 25 years of age.(1) the main treatment in testis torsion is manual or surgical detorsion of testis. even with successful intervention, testis atrophy and infertility develops in 40-60% of these patients.(2) the major pathology after testis torsion is testis ischemia. in testis where developed torsion was detorsioned, injury continues after reperfusion. at start, ischemic damage occurs in testis, and during restoration of blood flow reperfusion damage may also occur.(3) free oxygen radicals that formed during reperfusion 1gaziosmanpasa university, faculty of medicine, department of nuclear medicine, tokat 60100, turkey. 2gaziantep university, faculty of medicine, department of biophysics, gaziantep 27000, turkey. 3gaziosmanpasa university, faculty of medicine, department anatomy, tokat 60100, turkey. 4gaziosmanpasa university, faculty of medicine, department of urology, tokat 60100, turkey. *correspondence: gaziosmanpaşa university, faculty of medicine, department of nuclear medicine, tokat 60100, turkey. tel: +90 356 2120045, fax: +90 356 2120045, e-mail: gopnukleertip@gmail.com. received february 2018 & accepted may 2018 id: 4404 causes testis injury.(4) the main damage of free oxygen radicals to testis is in the form of cell viability loss through lipid peroxidation and break of membrane integrity.(5) since sperms have high levels of unsaturated fatty acids in their plasma membranes, they are highly sensitive to oxidative stress and especially to lipid peroxidation. accordingly, loss of sperm motility due to negative effect of free oxygen radicals on sperms via this mechanism, especially adenosine triphosphate loss within cell and axoneme damage, loss of sperm viability and morphological changes impairs sperm capacity and acrosome reaction.(6,7) many studies in literature established torsion models and investigated histological changes in serum and tissue levels. antioxidants were also extensively studied for treatment purposes. it is known that antioxidants act in a way to counterbalance the effect of free oxygen radicals and block their negative effects. many antioxidant agents, mainly melatonin, have been used to treat the oxidative damage from free oxygen radicals.(8-10) despite these classical studies, magnetic field application was not investigated in testis torsion and, except for diagnostic purposes, nuclear medicine imaging methods were not commonly used to determine the changes and efficiency of treatments using the same parameters. the aim of the present study was to evaluate the protective effect of pulsed magnetic field (pmf) and melatonin applications on damage during and after one sided testis torsion using positron emission tomography/computed tomography (pet/ct) with (18) flour fluoro-2-deoxyd-glucose (18f-fdg) examination, testicular scintigraphy with (99m) technesium (99mtc) pertechnetate and histopathological methods. materials and metods this study was conducted with permission of the local ethics committee (2014 hadyek-50). all experiments and protocols described in the present study were performed in accordance with the guide for the care and use of laboratory animals, as adopted by national institutes of health (u.s.). all procedures were approved by the medical faculty experimentation ethics committee of gaziosmanpaşa university. study population sixty male wistar-albino rats, 90 days of age and weighing 200–250 g each, were used in this study. the rats were raised under a 12h light/12h dark cycle (light from 07:00 to 19:00) in quiet rooms with 22–24°c ambient temperature and they had free access to standard rat nutrients and purified drinking water ad libitum. for one day treatment groups, 30 rats were divided into five groups; sham control, torsion, melatonin, pmf and melatonin plus pmf. similarly, for one week group, other 30 rats were divided into the same five groups (n = 6). in sham control group, testes were taken out via scrotal cutting, put back without any other procedure, and the skin was appropriately closed. in torsion group, no treatment was carried out after torsion procedure. after the experiment, rats were sacrificed using intraperitoneal administration of high dose pentobarbital (100 mg/ kg). procedures testis torsion and detorsion in the day of experiment, rats were taken to operation room. after anesthesia using intraperitoneal administering of 50 mg/kg ketamine (ketalar®, parkedavis) and 10 mg/kg xylazine (alfazyne®, alfasan), rats were stabilized in operation table. for rats which would be subjected to torsion, detorsion and sham operations, standard scrotal incision was realized after local anesthesia application to left side ilioinguinal area carried out using (2% citanest®, astra zeneca). in all groups, left testis was taken out after scrotal incision. in testis torsion groups, torsion was carried out via twisting left table 1. statistical data to left/right testis ratio from one day treatment groups (abbreviations: pmf, pulsed magnetic field). one-way anova test was used for comparing groups. ‡p < 0.01, *p < 0.001 and €p < 0.01 compared with torsion. one day groups n mean std. deviation std. error 18f fdg glucose metabolism sham 6 0.998‡ 0.024 0.010 torsion 6 0.754 0.075 0.030 melatonin 6 1.088‡ 0.085 0.034 pmf 6 1.065‡ 0.107 0.044 melatonin plus pmf 6 1.142‡ 0.153 0.062 total 30 1.009 0.165 0.030 99mtc pertechnetate testicular perfusion sham 6 1.001* 0.051 0.020 torsion 6 0.750 0.054 0.022 melatonin 6 1.171€ 0.116 0.047 pmf 6 1.311€ 0.317 0.129 melatonin plus pmf 6 1.175€ 0.159 0.065 total 30 1.082 0.252 0.046 figure 1. schematic representation of work plan (abbreviations: pmf, pulsed magnetic field; 99mtc, (99m)technesium; 18f fdg, (18)flour fluoro-2-deoxy-d-glucose). figure 2. testis torsion and detorsion model images. effects of magnetic field and melatonin on torsion and detorsion-gül et al. testis 720° clockwise. in order to maintain the torsion, testis was fixed to scrotum at tunica albuginea via silk suture after twisting. after the operation, incision was closed. after two hours of torsion, left testis was detorsioned. then, tissues were closed appropriately. all details about the study were shown in figure 1. testis torsion and detorsion model was shown in figure 2. melatonin treatment in one day melatonin group, a single dose of 40 mg/kg melatonin was administered intravenously, while in one week melatonin group a daily 40 mg/kg of melatonin was administered intravenously. pmf application protocol before pmf application, rats were acclimated to their environment for a week. habituation to the treatment conditions was accomplished by placing the rats in a restrainer at least three times for 30 min. pmf was conditioned using helmholtz coil apparatus in a earthed shielded faraday cage (90x90x55 cm3) (figure 3a). coils of 60 cm diameter and 30 cm clearance were constructed by electrically and thermally insulated copper wire of 2.5 mm diameter with 50 turns. resistance was 0.78 ω and inductance was 8.8 mh. coils were connected to a signal generator (ilfa electronic ltd., adana, turkey) to produce magnetic field with a peak amplitude of 1 mt. the peak value of the magnetic field was measured using a gaussmeter equipped with a hall-effect probe (fw bell 5180, pacific scientific oeco, milwaukie, or) (figure 3b). the time-varying magnetic field consisted of quasi-triangular waveform, a rise time of 0.3 ms and a fall time of 9.7 ms. the maximum induced electrical field between the coils was 0.25 v/m calculated based on faraday’s law. after twohour testis torsion and detorsion, rats were placed in a 26x17x13 cm restrainer and housed in the center of the helmholtz coils. the horizontal, uniform, and homogenous pmf (1 mt; 15 hz) was applied. rats (f-mf;mmf) were then exposed to a horizontal and sinusoidal mf (50hz,1mt) for two hours, while the control rats (fc; mc) were kept at the same laboratory conditions as intact groups. the ambient geomagnetic field was recorded as 50 μt. no significant temperature change was detected during the experiments between two activated helmholtz coils. the temperature (20–22 °c) and humidity (40–60%) were monitored continuously throughout the experiment. all pmf applications were carried out at the same hours of the day (9:00–11:00 a.m.). sham treatment was performed under the same environmental conditions using another apparatus including only helmholtz coils in a faraday cage. the polycarbonate cages were cleaned after every test session to avoid any biochemical effects. after two hours of pmf exposure, scintigraphic evaluation was made on rats. pmf application was carried out by two investigators (sg and mu) who were unaware of the study groups. nuclear medicine imaging all groups had testicular perfusion imaging using 99mtc pertechnetate testicular scintigraphy and glucose metabfigure 3. a) schematic drawing of pmf exposure system. b) magnetic field amplitude with hall-effect probe. figure 4. testicular scintigraphy using 99mtc pertechnetate; one day sham control (1a), torsion (1b), melatonin (1c), pmf (1d), melatonin plus pmf (1e), and one week sham control (2a), torsion (2b), melatonin (2c), pmf (2d), melatonin plus pmf(2e). figure 5. examination of glucose metabolism using pet/ct with 18f-fdg; one day sham control (1a), torsion (1b), melatonin (1c), pmf (1d), melatonin plus pmf (1e), and one week sham control (2a), torsion (2b), melatonin (2c), pmf (2d), melatonin plus pmf (2e). effects of magnetic field and melatonin on torsion and detorsion-gül et al. olism imaging using pet/ct with 18f-fdg. 18f-fdg pet/ct was performed to assess glucose metabolism in bilateral testes. rats received intravenous injections of 1 mci (37 mbq) of fdg 1 hour before the acquisition of the pet/ct image. pet imaging was performed using a combined pet/ct scanner (siemens biograph 2 pet/ct, new jersey, usa). attenuation correction of pet images with the ct data was performed. right after ct data acquisition, a standard pet imaging protocol was taken from the cranium to the mid-thigh with an acquisition time of 3 min/bed in 3-dimensional mode. ct and pet images were matched and fused into transaxial, coronal and sagittal images. the testicular scintigraphy was performed with intravenous injection of 1 mci (37 mbq) of 99mtc pertechnetate. the perfusion phase (5 second/frame, for 2 minutes) and static imaging (5 minute anterior view, immediately after dynamic imaging) using a dual head variable angle nuclear gamma camera (symbia siemens, hoffman estates, usa) equipped with a low energy high resolution collimator and 140 kev 99mtc photopeak) demonstrated arterial flow in the bilateral testes. images obtained were evaluated. region of interest (roi) were drawn in both testis regions after imaging and left/right testis activity rates were determined using semi-quantitative method. image analysis was carried out by a researcher (ssg) who was not informed about the source of the images. histopathological examination during the torsion period, color changes due to edema and venous stasis which were macroscopic results of ischemia were observed in all testes to which surgical procedure was applied. histopathological evaluations carried on tissue samples were recorded in forms prepared to this aim. there were normal distributions among all groups. left and right testis tissues in all groups were studied for glucose metabolism and perfusion. in addition, histopathological evaluations were carried out. testis tissue samples were taken and submersed in 10% formaldehyde solution. these tissues underwent routine histological procedures and were embedded in paraffin. five and twenty-five micron dissections were taken from these paraffin embedded tissues using rotary microtome. histopathological evaluations were carried out after hematoxylin eosin staining of testis tissue samples. numbers of spermatogonium and spermatocyte, and volume and diameter of seminiferous tubules were determined. in addition, the johnsen score was used to evaluate the morphological damage of testis tissue as a result of testis torsion. johnsen score was determined and damage in seminiferous tubules was assessed for the purpose of evaluation of spermatogenesis. the johnsen scoring system is principally based on the progressive degeneration of germinal epithelium and a successive loss of the most mature cell types during testicular damage evaluated using the following categories: 1 (no cells at all within the tubules), 2 (no germinal cells, only sertoli cells), 3 (only spermatogonia), 4 (no spermatozoa and spermatids, less than 5 spermatocytes, but numerous spermatogonia per cross-section), 5 (no spermatozoa and spermatids, numerous spermatocytes and spermatogonia), 6 (no spermatozoa, 5 ± 20 spermatids, numerous spermatocytes and spermatogonia per cross-section), 7 (no spermatozoa, numerous spermatids, spermatocytes and spermatogonia), 8 (less than 5 ± 10 spermatozoa per tubular cross-section), 9 (numerous spermatozoa, germinal epithelium disorganized with sequestration of germinal cells, tubular lumen was obturated) and 10 (complete spermatogenesis, numerous spermatozoa, germinal epithelium of regular height, tubular lumen of normal diameter).(11) finally, h-score of caspase-3, an enzyme active in apoptosis, was carried out immunohistochemically to determine the level of this enzyme.(12) evaluation of the immunohistochemical labeling was performed using h-score analyses as previously described. caspase3 immunoreactivities were semi-quantitatively evaluated using the following categories: 0 (no staining), 1+ (weak but detectable staining), 2+ (moderate or distinct staining), figure 6. microscope images of hematoxylin eosin stained tissues in one day sham control (a), torsion (b), melatonin (c) and pulsed magnetic field (d) groups figure 7. microscope images of caspase-3 stained tissues in one day sham control (a) and torsion (b) groups. effects of magnetic field and melatonin on torsion and detorsion-gül et al. and 3+ (intense staining). for each tissue, an h-score value was derived as follows: first, the sum of the percentages of cells that stained at each intensity category was calculated, which was then multiplied by the weighted intensity of the staining using the formula as follows: h-score = ∑pi (i+ l). in this formula, ‘i’ represents the intensity scores, and ‘pi’ is the corresponding percentage of the cells. five randomly selected areas were evaluated under a light microscope on each slide (40x objective). two investigators (mu and ssg), who were not informed about the type and source of the tissues, determined the percentage of cells at each intensity within these areas at different times. the combined average score of both observers was used. statistical analysis all data were analyzed by ibm spss statistical software version 18.0. the normal distribution of data and the homogeneity of variance were evaluated using the kolmogorov smirnov test and the levene test, respectively. because of the normal distribution in the study groups, one-way anova test was used for comparing groups in terms of glucose metabolism, testicular perfusion, johnsen score and h-score values, and tukey test was used as post-hoc test. results of the experiments were given as mean ± standard deviation and p < 0.05 was considered statistically significant. results a. one-day groups evaluation of “left testis/right testis” perfusion with testicular scintigraphy using 99mtc pertechnetate findings of testicular scintigraphy in different groups were shown in table 1 and graphic 1. there was a significant decrease in perfusion based on scintigraphy between torsion and sham groups (p < 0.001). perfusion of left testis was significantly impaired compared with the right one. melatonin, pmf and melatonin plus pmf application significantly increased the perfusion compared with that in the torsion group (p < 0.01), but this increase was more prominent in the pmf group. when compared with the sham group, it was apparent that melatonin, pmf and melatonin plus pmf groups had an increase in perfusion, but these differences were not statistically significant (p = .08, p = .09 and p = .09, respectively). images from one day treatment were given in figure 4. evaluation of “left testis/right testis” glucose metabolism with pet/ct using 18f-fdg results of pet/ct in different groups were shown in table 1 and graphic 1. a significant decrease was graphic 1. comparison of the results from one day treatment groups (abbreviations: pmf, pulsed magnetic field). one-way anova test was used for comparing groups. ‡p < 0.01, *p < 0.001 and €p < 0.01 compared with torsion. graphic 2. comparison of the results from one week treatment groups (abbreviations: pmf, pulsed magnetic field). one-way anova test was used for comparing groups. §p < 0.05, ‡p < 0.01, ɸp < 0.01 and *p < 0.001 compared with torsion; #p < 0.01, ¥p < 0.05 and £p < 0.01 compared with sham; ⸸p < 0.01compared with melatonin plus pmf. graphic 3. comparison of one day treatment groups using johnsen score after histopathological examination (abbreviations: pmf, pulsed magnetic field). one-way anova test was used for comparing groups. graphic 4. comparison of one day treatment groups using h-score after histopathological examination (abbreviations: pmf, pulsed magnetic field). one-way anova test was used for comparing groups. effects of magnetic field and melatonin on torsion and detorsion-gül et al. detected between torsion and sham groups in glucose metabolism assay using 18f-fdg pet/ct (p < 0.01). it was revealed there was a decrease in glucose metabolism of left testis compared with the right one after one day treatment period and the difference was significant (p < 0.01). glucose metabolism was significantly higher in melatonin, pmf and melatonin plus pmf groups than in torsion group (p < 0.01), but this increase was more prominent in the melatonin plus pmf group. there was no significant difference among melatonin, pmf, melatonin plus pmf and sham groups for glucose metabolism. pet/ct images from one day treatment were given in figure 5. b. one week treatment groups evaluation of “left testis/right testis” perfusion with testicular scintigraphy using 99mtc pertechnetate findings of testicular scintigraphy in different groups were shown in table 2 and graphic 2. a significant decrease was observed in perfusion based on scintigraphic method between torsion and sham groups (p < 0.01). perfusion rates in melatonin, pmf and melatonin plus pmf groups, on the other hand, were significantly higher than that in torsion group (p < 0.001). melatonin, pmf and melatonin plus pmf application eliminated the perfusion loss and led to a significant increase in perfusion (p <0.01). additionally, melatonin plus pmf group had perfusion increase compared with the melatonin and pmf groups (p < 0.01). evaluation of “left testis/right testis” glucose metabolism with pet/ct using 18f-fdg results of pet/ct in different groups were shown in table 2 and graphic 2. a significant decrease was determined in glucose metabolism via pet/ct using 18f-fdg between torsion and sham groups (p < 0.05). after one week of treatment period, left testis metabolism was shown to be significantly lower than right testis metabolism. glucose metabolism in melatonin, pmf and melatonin plus pmf groups was significantly higher than that in torsion group (p < 0.01), but this increase was more prominent in the melatonin and melatonin plus pmf groups. when compared with the sham group, it was apparent that melatonin and melatonin plus pmf groups had a significant increase in glucose metabolism (p < 0.01 and p < 0.05, respectively). histological and immunohistochemical results were presented in table 3. histopathological analyses using hematoxylin eosin staining of one day treatment group revealed that cell damage was more prominent in torsion group compared to sham group and melatonin plus pmf group (p < 0.05) (figure 6). caspase-3 staining showed a higher level of apoptosis in torsion group than in sham group (p < 0.05) (figure 7). johnsen score indicated the cell damage in testis tissue. johnsen score was 9.6 for sham group 2.2 for torsion group, 4.0 for melatonin group, 2.1 for pmf group and 3.9 for melatonin plus pmf group (graphic 3). h-score indicated the cell damage in testis tissue. h-score was 18 for sham group, 56 for torsion group, 24 for melatonin group, 49 for pmf group and 30 for melatonin plus pmf group (graphic 4). discussion table 2. statistical data to left/right testis ratio from one-week treatment groups (abbreviations: pmf, pulsed magnetic field). one-way anova test was used for comparing groups. §p < 0.05, ‡p < 0.01, ɸp < 0.01 and *p < 0.001 compared with torsion; #p < 0.01, ¥p < 0.05 and £p < 0.01 compared with sham; ⸸p < 0.01compared with melatonin plus pmf. one week groups n mean std. deviation std. error 18f fdg glucose metabolism sham 6 0.997§ 0.252 0.103 torsion 6 0.630 0.193 0.079 melatonin 6 1.442‡, # 0.144 0.059 pmf 6 1.199‡ 0.270 0.110 melatonin plus pmf 6 1.427‡, ¥ 0.228 0.093 total 30 1.139 0.355 0.640 99mtc pertechnetate testicular perfusion sham 6 0.994ɸ 0.059 0.024 torsion 6 0.724 0.143 0.058 melatonin 6 1.245*, £, ⸸ 0.135 0.055 pmf 6 1.254*, £, ⸸ 0.114 0.046 melatonin plus pmf 6 1.413*, £ 0.026 0.010 total 30 1.126 0.264 0.048 groups n mean std. deviation johnsen score sham 6 9.8 0.3 torsion 6 2.3*, # 0.6 melatonin 6 4.1* 0.9 pmf 6 2.2*, # 0.5 melatonin plus pmf 6 3.9* 0.7 total 30 4.5 0.6 h-score sham 6 18 3 torsion 6 56*, # 7 melatonin 6 26 6 pmf 6 48*, # 8 melatonin plus pmf 6 30* 5 total 30 36 6 table 3. statistical data to johnsen score and h-score from one day treatment groups (abbreviations: pmf, pulsed magnetic field). one-way anova test was used for comparing groups. *p < 0.05 compared with sham group; #p < 0.05 compared with melatonin and melatonin plus pmf group. effects of magnetic field and melatonin on torsion and detorsion-gül et al. testis torsion is known as ischemia-reperfusion damage in clinical practice. the diagnosis and treatment of testis torsion is critical for the maintaining of fertility since inappropriate treatments could lead to male infertility. experimental testis torsion lowers blood flow without causing a significant change in central blood pressure, and it results in impairment of apoptosis, testicular atrophy and spermatogenesis in germ cells.(13) following a torsion of more than four hours, blood flow in ipsilateral testis could not be completely restored even 24 hours after detorsion.(14) during ischemia, germ cell death takes place due to low level of oxygen to meet metabolic needs, cellular energy stores are depleted, and toxic metabolites accumulate.(15) experimental studies revealed that testis necrosis develop within two hours in arterial blocking and within six hours in venous blocking.(16) the testes which are not treated within 12 hours after the development of symptoms could be lost.(17) the aim in the present study was to create an acceptable ischemia in torsioned testes before a treatment. in addition, torsion and the experiment had to be ended before irreversible damage occurred in testes. therefore, duration of ischemia was two hours. experimental studies showed that ischemic damage occurred as a result of testis torsion and was associated with number and duration of torsion. in addition, it was also shown that blood flow ceased irreversibly in 720° torsion of testes and a complete ischemia developed. nevertheless, experimental studies generally use testis torsion angles between 360° and 720°. in addition, left testis torsion is more commonly encountered since left testis has a longer spermatic cord than that of right testis.(18) therefore, a 720° torsion-detorsion model of left testis was used in the present study. oxidant and antioxidant mechanisms are in a balance state in body, and break down of this balance in favor of oxidant mechanisms result in tissue damage. (19) in the case of a torsion, detorsion is classical way of treatment, but detorsion is known to cause a more comprehensive damage in testis through oxidative damage due to reperfusion. as a result of reperfusion of ischemic tissue, toxic free oxygen radicals such as nitric oxide, superoxide anions, hydrogen peroxide and hydroxyl radical form.(20) free oxygen radicals are short half-life chemical compounds and they consist of one or more uncoupled electrons, which render them to be unstable and quite reactive.(21) in order to be stable, free oxygen radicals attack lipids, amino acids and nucleic acids. although in normal conditions free oxygen radicals play roles in cell differentiation, sperm capacitation, acrosome reaction and maintaining the fertility, their high levels due to various stresses negatively affect cells. protein, carbohydrate, nucleic acid and lipid components of cells are potential targets of free oxygen radicals. as a result of their impact on abovementioned cell components, free oxygen radicals that increase as secondary to oxidative damage leads to negative consequences such as inflammation, apoptosis, breakdown of cell membrane integrity, fibrosis and proliferation. it has been reported in literature that oxidative damage play role in pathogenesis of arthritis, cancer, diabetes mellitus, carious infections, central nervous system diseases, cardiac diseases and testis torsion.(22-26) testis torsion model has shown that oxidative damage occurs within hours or even within minutes following the perfusion. it has also been revealed in these models that levels of antioxidant enzymes decreased while free oxygen radicals increased.(27) free oxygen radicals formed during testicular reperfusion activate leucocytes and cause them to adhere to vein endothelium, consequently impairing blood circulation. lack of restoration of perfusion in some of capillaries after ischemia/reperfusion is called no-reflow phenomenon.(28) similarly, we established ischemia/reperfusion in the present study and examined testis perfusion and glucose metabolism. testicular torsion–detorsion generates ros that cause apoptosis, resulting in lipid peroxidation and metabolic alterations. it is known that the formation of intracellular ros or the depletion of cellular antioxidants may result in apoptosis.(29) apoptosis is a form of programmed cell death characterized by dna fragmentation, cytoplasmic shrinkage, membrane changes, and cell death without damage to neighboring cells. caspase-3, also known as the primary executioner caspase, is responsible for morphological changes of apoptosis.(30) the ischemia/reperfusion (i/r) phenomenon occurs in testicular torsion–detorsion in which torsion comprises the ischemic period, whereas detorsion comprises reperfusion injury.(10) in particular, reperfusion injury results in anoxia, leading to the generation of large quantities of ros, pro-inflammatory cytokines and lipid peroxidation, followed by activation of the apoptosis pathway which causes even severe ischemic tissue damage. (31) in our study, it was observed that caspas-3 activities increased significantly in testis of rats subjected to testicular torsion–detorsion. it was found that this increase aggravated testicular damage. it was also noticed that melatonin, pmf and melatonin plus pmf application significantly increased the perfusion compared with that in the torsion group. therefore, reperfusion injury resulting in an increase in perfusion may be the main reason why melatonin and pmf treatments did not show a significant effect in terms of apoptosis. in addition, it supports our assumption that melatonin is more successful than pmf against apoptosis that occurs in the oxidative damage caused by reperfusion injury. as we have shown in this study, the antioxidant effect of melatonin may have demonstrated a better improvement in apoptosis, possibly by showing more protective efficacy than pmf against increased oxidative damage after reperfusion. it is well known that the general approach to decrease or eliminate the effects of free oxygen radicals occurring as secondary to oxidative damage is the use of antioxidants. in this context, effects of antioxidants on some pathologies in various tissues such as atherosclerosis, hypertension, diabetes mellitus, renal disease, ulcerative colitis, chronic obstructive pulmonary disease and testis torsion were investigated. for this purpose, vitamin e, melatonin, retinol, β-carotene, omega-3, resveratrol, allopurinol, n-acetylcystein, zinc, caffeic acid, vitamin c, coenzyme q10 and melatonin were used as antioxidant agents in various studies.(32-35) melatonin is known as the strongest antioxidant agent to reduce testicular damage after testis torsion. melatonin is produced in pituitary gland with a circadian rhythm. it has been shown to have an antioxidant effect both directly by eliminating free oxygen radicals and indirectly by elevating the level of antioxidant enzymes. in addition, melatonin has an inhibitory effect on nitric oxide synthesis. melatonin has been reported to prevent lipid peroxidation in many organs and tissues, not only in testes, and to protect against the effect of oxidative effects of magnetic field and melatonin on torsion and detorsion-gül et al. damage.(27) in this context, erdemir et al. studied the effect of melatonin on antioxidants in systemic circulation after one sided testis torsion in rats. they administered 50 mg/kg melatonin to a group rats after 720° of torsion for two hours and measured blood levels of malondialdehyde, superoxide dismutase, protein carbonyl and nitric oxide in rats. their results showed that melatonin significantly decreased the levels of antioxidant enzyme and lipid peroxidation products of torsion and brought them to levels of control group.(36) similarly, melatonin administration lowered the levels of reactive oxygen radicals and minimized oxidative stress in the present study. further, efficiency of early and late administration of melatonin was investigated. the pmf are electromagnetic stimulation which are in 30-300 hz interval and they are considered not to have any adverse or harmful effects because of their low energy levels. they are assumed to assist therapies through their ionic activities and accelerating blood flow. effects of electromagnetic fields on living organisms have been investigated since 1950s. very low level of electricity is conducted to tissues and there are studies reporting its therapeutic and regulatory effects. these effects basically involve cell division rate, mrna and protein synthesis levels, permeability of cell membranes, changes in transfers of ca+2, na+, k+ ions, and as a result, increases in micro blood circulation. these changes affect both electrical and metabolic behaviors of cell. in addition, they directly or indirectly influence melatonin production, and change daily metabolism and hormone production of organism. electromagnetic fields of certain frequencies and amplitudes change the behaviors of t-lymphocyte cells and affect cytotoxicity.(37,38) kumar et al. showed the therapeutic effect of pulsed magnetic field application on testicular function.(39) in the present study, whether pmf application would be beneficial in testis torsion was investigated. in addition, early and late period effects of pmf application were studied. testicular scintigraphy using 99mtc pertechnetate is a nuclear medicine imaging technique commonly used for especially acute testis torsion. it gives information on perfusion in torsioned testis.(40-42) pet/ct with 18f-fdg are used to evaluate glucose metabolism levels of cells. this technique is frequently used especially in oncology patients for diagnosis, staging, re-staging and evaluation of response to therapy.(43,44) testicular scintigraphy using 99mtc pertechnetate and pet/ct with 18f-fdg techniques were used together in the present study, and thus perfusion and glucose metabolism in testis tissue were evaluated simultaneously. numerous studies that have been conducted so far have shown that damage due to testis torsion cannot be completely resolved and there is not a routinely used therapeutic agent in clinical practice. in addition, although testis is the most easily torsioned organ in body, number of studies in the literature is not satisfactory on this issue. therefore, experimental and clinical studies about treatment of testis torsion have been going on. testis torsion-detorsion model was used in the present study. protective effects of melatonin whose anti-oxidizing therapeutic efficiency is well known and pmf application which, to our best knowledge, has not been so far used for this aim were investigated using testicular scintigraphy with 99mtc pertechnetate, pet/ct with 18f-fdg and histopathological methods. it was revealed that pmf application alone improved perfusion and glucose use as efficiently as melatonin in one day and in one week treatment groups. combined use of pmf and melatonin, on the other hand, increased perfusion only in one day treatment group, and increased glucose use only in one week treatment group compared to each of pmf and melatonin. in this study, we investigated the blood supply by testicular scintigraphy using 99mtc pertechnetate and the level of glucose use by 18f-fdg pet/ct in testicular tissue. glucose use of testicular tissue is an active process. simply, increasing blood supply in testis may not cause an increase in glucose use. therefore, the two methods must be evaluated together. limitations of the study: histopathological examinations were not made in one-week treatment groups due to the problems experienced during the fixation of tissue. there is a need for a one-month treatment group work in order to better understand the effectiveness of pmf. conclusions in conclusion, it was found that pmf application was as effective as melatonin administration both in early and late period after testis torsion. in addition, it was also shown that testicular scintigraphy with 99mtc pertechnetate and pet/ct with 18f-fdg methods could be effectively used both in diagnosis and in determining the efficiency of the therapy in testis torsion. however, randomized, prospective clinical studies are necessary to confirm our results. limitations of the study: histopathological examinations were not made in one-week treatment groups due to the problems experienced during the fixation of tissue. there is a need for a one-month treatment group work in order to better understand the effectiveness of pmf. conflict on interest the authors declare that they have no competing interests. references 1. gultekin a, tanrıverdi hi, inan s, yilmaz o, gunsar c, sencan a. the effect of tunica albuginea incision on testicular tissue after detorsion in the experimental model of testicular torsion. urol j. 2018;15(1):32-9. 2. barada jh, weingarten jl, cromie wj. testicular salvage and age related delay in the presentation of testicular torsion. j urol. 1989;142:746-8. 3. akgür fm, kılınç k, aktug t. reperfusion injury after detorsion of unilateral testicular torsion. urol res. 1993;21:395-9. 4. menger md, rücker m, vollmar b. capillary dysfunction in striated muscle ischemia/ reperfusion: on the mechanisms of capillary “no-reflow ”. shock. 1997;8:2-7. 5. tang d, kang r, zeh hj, lotze mt. oxidative stress, and disease. antioxid redox signal. 2011;14:1315-35. 6. aktan g, doğru-abbasoğlu s, küçükgergin effects of magnetic field and melatonin on torsion and detorsion-gül et al. c, kadıoğlu a, ozdemirler-erata g, koçaktoker n. mystery of idiopathic male infertility: is oxidative stress an actual risk? fertil steril. 2013;99:1211-5. 7. morielli t, o'flaherty c. oxidative stress impairs function and increases redox protein modifications in humanspermatozoa. reproduction. 2015;149:113-23. 8. karaguzel e, kadihasanoglu m, kutlu o. mechanisms of testicular torsion and potential protective agents. nat rev urol. 2014;11:3919. 9. payabvash s, salmasi ah, kiumehr 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status with oxidative tissue damage in patients with rheumatoid arthritis. clinrheumatol. 2014;33:1557-64. 23. glasauer a, chandel ns. targeting antioxidants for cancer therapy. biochem pharmacol. 2014;92(1):90-101. 24. udupa as, nahar ps, shah sh, kshirsagar mj, ghongane bb. study of comparative effects of antioxidants on insulin sensitivity in type 2 diabetes mellitus. j clin diagn res. 2012;6:1469-73. 25. ware lb, fessel jp, may ak, roberts lj. plasma biomarkers of oxidant stress and development of organ failure in severe sepsis. shock. 2011;36:12-7. 26. cvetkovic t, stankovic j, najman s, et al. oxidant and antioxidant status in experimental rat testis after testicular torsion/detorsion. int j fertil steril. 2015;9:121-8. 27. kanter m. protective effects of melatonin on testicular torsion/detorsion-induced ischemiareperfusion injury in rats. exp mol pathol. 2010;89:314-20. 28. orlinsky m, shoemaker w, reis ed, kerstein md. current controversies in shock and resuscitation. surg clin north am. 2001;81:1217-62. 29. ryter sw, kim hp, hoetzel a, et al. mechanisms of cell death in oxidative stress. antioxid redox signal. 2007;9:49–89. 30. tao w, kurschner c, morgan ji. modulation of cell death in yeast by the bcl-2 family of proteins. j biol chem. 1997;272:15547-52. 31. shimizu s, tsounapi p, dimitriadis f, et al. testicular torsion-detorsion and potential therapeutic treatments: a possible role for ischemic postconditioning. int j urol. 2016;23:454-63. 32. ribeiro ct, milhomem r, de souza db, costa ws, sampaio fj, pereira-sampaio ma. effect of antioxidants on outcome of testicular torsion in rats of different ages. j urol. 2014;191:1578-84. 33. tang f, wu x, wang t, et al. tanshinone ii a attenuates atherosclerotic calcification in rat model by inhibition of oxidative stress. vascul pharmacol. 2007;46:427-38. 34. soufi fg, sheervalilou r, vardiani m, khalili m, alipour mr. chronic resveratrol administration has beneficial effects in experimental model of type 2 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2.45-ghz microwave field. clinics. 2011;66:1237-45. 40. shayegani h, divband g, tavakkoli m, banihasan m, sadeghi r. torsion of the undescended testis detected by 99mtc testicular scintigraphy: a case report. nucl med rev cent east eur. 2016;19:24-5. 41. lavallee me, cash j. testicular torsion: evaluation and management. curr sports med rep. 2005;4:102-4. 42. wu hc, sun ss, kao a, chuang fj, lin cc, lee cc. comparison of radionuclide imaging and ultrasonography in the differentiation of acute testicular torsion and inflammatory testicular disease. clin nucl med. 2002;27:490-3. 43. börksüz mf, erselcan t, hasbek z, yücel b, turgut b. morphologic and metabolic comparison of treatment responsiveness with 18fludeoxyglucose-positron emission tomography/computed tomography according to lung cancer type. mol imaging radionucl ther. 2016;25:63-9. 44. hasbek z, yucel b, salk i, et al. potential impact of atelectasis and primary tumor glycolysis on f-18 fdg pet/ct on survival in lung cancer patients. asian pac j cancer prev. 2014;15:4085-9. effects of magnetic field and melatonin on torsion and detorsion-gül et al. kidney transplantation evaluating the psychometric properties of the persian self-management scale for kidney transplant recipients somayeh khezerloo1, hosein mahmoudi2*, zohreh vafadar3 purpose: there was no appropriate instrument for assessing the self-management of iranian kidney transplant recipients. this study was done to translate the self-management scale for kidney transplant recipients into persian and evaluate its psychometric properties. material and methods: this cross-sectional methodological study was done from october 2016 to march 2017. the psychometric properties of the scale were evaluated in the following four steps: forward-backward translation, face and content validity assessments, construct validity assessment via exploratory factor analysis, and reliability assessment via internal consistency and test-retest techniques. results: the means of item impact score, content validity ratio, and simplicity, clarity, and relevance content validity indices were 3.94, 0.73, 0.96, 0.93, and 0.98, respectively. exploratory factor analysis revealed a four-factor structure for the scale which explained 70.75% of the total self-management variance. the four factors of the scale were “self-monitoring”, “self-care behaviors”, “early detecting and coping with abnormalities”, and “drug management”. the cronbach’s alpha and the test-retest intraclass correlation coefficient of the scale were 0.73 and 0.90, respectively. conclusion: the persian self-management scale for kidney transplant recipients has acceptable validity and reliability. it can be used in educational and clinical environments and also in research studies for measuring kidney transplant recipients’ self-management. keywords: self-management; kidney transplant recipient; validity; reliability; instrument development introduction treatment modalities for esrd include hemodi-alysis, peritoneal dialysis, and kidney transplantation(1). the treatment of choice is kidney transplantation(2). despite great advances in the area of kidney transplantation and immunosuppressive therapies(3), the risk for transplant rejection is still high(4). moreover, transplant recipients are at risk for the side effects of immunosuppressive therapies, particularly infection. a study showed that during the first post-transplantation months, recipients are frequently hospitalized mainly due to different types of infection (5). moreover, compared with other chronically-ill patients, transplant recipients suffer from higher levels of stress, anxiety, depression, and emotional problems(6,7). a significant factor behind transplantation success or transplant rejection is self-management(8,9). by definition, self-management is the ability to personally manage the outcomes of chronic conditions (9,10). according to strauss and corbin, self-management has three main dimensions, namely medical, role, and emotional managements. medical management includes adherence to 1 ph.d. student of nursing, trauma research center and faculty of nursing, baqiyatallah university of medical sciences, tehran, ir iran. 2 associate professor, trauma research center and faculty of nursing, baqiyatallah university of medical sciences, tehran, ir iran. 3 assistant professor, faculty of nursing, baqiyatallah university of medical sciences, tehran, ir iran. *correspondence: associate professor, trauma research center and faculty of nursing, baqiyatallah university of medical sciences, tehran, ir iran. tel:+98 21 88620880. fax: +98 21 26127237. e-mail: h.mahmoudi@bmsu.ac.ir, aeceived december 2017 & accepted july 2018 treatment and dietary regimens as well as to the permitted level of physical activity. role management deals with managing the new post-transplantation roles. in other words, transplant recipients need to significantly change their behaviors, habits, and activities in order to cope with their new roles. emotional management refers to learning how to manage emotions, such as anger, fear, despair, and depression, which are usually experienced by chronically-ill patients (11). self-management significantly affects the effectiveness of healthcare services; promotes treatment adherence, engagement in physical activities, independence in doing activities (12,13), and general health; and helps prevent disease recurrence(14). post-transplantation self-management includes a wide range of activities such as engagement in adequate physical activity, adherence to dietary regimen and immunosuppressive therapies, infection prevention, self-supervision, medication side effect management, and regular medical visits(15-18). self-management is of greater importance during the first post-transplantation months. in this period, patients need to take greater kidney transplantation 186 vol 16 no 02 march-april 2019 187 responsibility for managing their treatment regimen, undergo different laboratory tests, and supervise the symptoms of transplant rejection and systemic infection (19). otherwise, they may experience severe problems such as infection and transplant rejection(20-23). an absolute requirement for self-management assessment is valid and reliable assessment tools. such tools help easily and quickly identify and overcome patients’ problems in the area of self-management. one of these tools is the self-management scale for kidney transplant recipients (ktr-sms). developed in 2013 by kosaka et al.(14), ktr-sms is a specific tool for the assessment of self-management among kidney transplant recipients. however, the psychometric properties of the scale have not yet been evaluated in many countries, including iran. given the lack of a specific valid and reliable tool for assessing the self-management of iranian kidney transplant recipients, this study was done to translate ktr-sms into persian, cross-culturally adapt it to the iranian culture, and evaluate its psychometric properties. material and methods study design this cross-sectional methodological study was done from october 2016 to march 2017 in the following four steps: forward-backward translation, face and content validity assessments, construct validity assessment via exploratory factor analysis, and reliability assessment via internal consistency and test-retest techniques. instrument ktr-sms is a specific tool for the assessment of self-management among kidney transplant recipients. it contains twenty items in four subscales in addition to four single items. ktr-sms subscales include “self-monitoring of vital signs” (six items), “self-care behaviors in daily living” (7 items), “early detecting and coping with abnormalities after kidney transplantation” (4 items), and “stress management” (three items). the remaining four single items deal with the management of treatment regimen and dehydration prevention and are called “items with high clinical importance”. ktr-sms items cover all aspects of kidney transplantation self-management including appropriate use of immunosuppressant agents, medication side effect assessment, self-supervision, self-care activities, infection prevention, stress and emotional management, adherence to prescribed dietary regimen, and regular medical visits(16,24). possible responses to each item include “not applied”, “barely applied”, “fairly applied”, and “strongly applied”, which are scored from 1 to 4, respectively.the scale has 24 items, so the total score of ktr-sms is 24–96. forward-backward translation of ktr-sms after obtaining necessary permissions from ktr-sms developers (shiho kosaka et al) to use the scale, the scale was translated from english into persian based on the four-step instrument translation method proposed by world health organization. the four steps of this method are forward translation, expert panel back-translation, pre-testing and cognitive interviewing, and final version(25). in the present study, forward english-persian translation was done by two independent translators. the first translator was a nursing doctorate with a clinical work experience of more than ten years while the second had no expertise in healthcare areas but was experienced in text translation. a nursing faculty member compared their translations with the original ktrsms and produced a single persian translation. then, the translation was back-translated into english by two bilingual translators who held nursing degrees and had lived in an english-speaking country for more than five years. thereafter, a panel of experts compared the generated english ktr-sms with its original version and confirmed their similarity. after that, the persian ktr-sms was provided to thirty transplant recipients and they were invited to read and evaluate the difficulty, clarity, and appropriateness of each item. their comments were sought through face-to-face personal interviews. finally, the scale was amended based on their comments and thereby, the final persian version of ktr-sms was generated. due to cross-cultural differences, translation of an instrument is usually associated with inevitable changes in the characteristics of its items(26). yet, we did our best to minimize discrepancies between the original and the persian ktr-sms and to produce a cross-culturally appropriate scale for the assessment of iranian kidney recipients’ self-management. face validity assessment face validity was assessed using qualitative and quantitative techniques. qualitative face validity assessment was done in the “pre-testing and cognitive interviewing” step of the translation (see the above paragraph). quantitative face validity was assessed through calculating item impact score. accordingly, thirty transplant recipients were asked to comment on the importance of ktr-sms items using the following five-point scale: “not important”, “slightly important”, “moderately important”, “important”, and “very important”. first the percent of patients who scored 4 or 5 to item importance (frequency) was calculated, and the mean importance score of item (importance) and then item impact score of instrument items was calculated by following formula: item impact score= frequency×importance. item impact scores 1.5 and greater are considered acceptable (which corresponds to a mean frequency of 50% and an importance mean of 3 on the 5-point likert scale)(27). content validity assessment content validity was also assessed using both qualitative and quantitative techniques. in qualitative content validity assessment, five instrument development specialists, five nephrologists, and twenty nurses with a work experience of more than fifteen years in the area of kidney transplantation (thirty in total) were invited to provide detailed written comments on the clarity, simplicity, wording, and grammar of the items. their comments were used to amend items. on the other hand, quantitative content validity was assessed via content validity ratio (cvr) and content validity index (cvi). for cvr, the experts were asked to assess the essentiality, while for cvi, they were asked to assess the relevance, clarity, and simplicity of each item on a fourpoint scale. lawshe determined that for a panel of thirty experts, the minimum acceptable cvr and cvi values are 0.33 and 0.79, respectively(28). construct validity assessment construct validity of ktr-sms was evaluated via exploratory factor analysis with varimax rotation(29). the kaiser-meyer-olkin (kmo) and the bartlett’s tests psychometric properties of persian ktr-smskhezerloo et al. kidney transplantation 188 were used to examine sampling adequacy and factor analysis appropriateness. eigenvalues greater than 1 and scree plot were used to determine the number of factors. the minimum factorial loading value was 0.4. participants and data collection for construct validity assessment, a convenient sample of 360 kidney transplant recipients were selected. this sample size was determined based on the 5–10 cases per item method(30) and an attrition rate of 20%. recipients were selected from different genders, ages, educational status, cities, and subcultures. primarily, several cities in iran were selected and then, study participants were selected from the kidney transplantation centers in those cities. eligibility criteria were an age of eighteen or more, stable physical and mental health conditions, and basic literacy skills. participants signed the informed consent form and then, completed ktrsms. a demographic questionnaire was also used to record their age, gender, educational status, history of undergoing hemodialysis, and time from kidney transplantation. reliability ktr-sms reliability was assessed through both internal consistency and test-retest techniques. for internal consistency assessment, the data obtained from 360 recipients in the construct validity assessment were used to calculate the cronbach’s alpha values of the scale and its subscales. moreover, for test-retest stability assessment, thirty recipients were asked to complete the scale twice with a two week interval. then, intraclass correlation coefficient (icc) was calculated. statistical analysis the spss software (v. 21.0) was employed for data analysis. the bartlett’s and the kmo tests were done for exploratory factor analysis. a kmo value of greater than 0.6 was considered acceptable. eigenvalues and maximum explained variance were calculated for each psychometric properties of persian ktr-smskhezerloo et al. table 1. self-management mean scores based on recipients’ demographic characteristics. variable n= 360 self-management scores p value mean ± standard deviation age groupa 20–40 140 60.85 ± 8.63 .000 41–60 144 65.63 ± 5.7 61–80 76 60.71 ± 8.4 genderb male 160 64.16 ±6.54 .002 female 200 61.58 ±8.70 educational degreea diploma and lower 171 51.94 ± 7.16 .000 bachelor’s 148 61.34 ± 8.2 master’s and higher 41 71.17 ± 2.8 history of undergoing < 2 years 25 46.80 ± 3.27 .000 dialysisa 2–4 years 156 63.14 ± 5.54 4–6 years 135 64.85 ± 7.73 > 6 years 44 63.84 ± 7.50 time from < 2 years 86 69.79 ± 3.90 .000 transplantationa 2–4 years 140 66.85 ± 8.27 4–6 years 105 61.83 ± 7.59 > 6 years 29 58.72 ± 5.56 a one-way anova b independent samples test ktr-sms items factor 1 factor 2 factor 3 factor 4 1.daily measurement and recording of blood pressure 0.76 2. daily measurement and recording of body temperature 0.88 3. daily measurement and recording of body weight 0.70 4. daily measurement and recording of physical status 0.81 5. daily measurement and recording of frequency of urination 0.8 6. i contact my doctor when the dada are deviated from the desirable values 0.66 7. i eat balanced meals 0.59 8. i keep my house clean 0.74 9. i reduce sodium (salt) consumption 0.46 10. i avoid high calories foods 0.68 11. i eat fresh food 0.70 12. i avoid compacting and compression of the abdomen 0.69 13. i wash my mouth (gurgle) and hands 0.84 14. i monitor the signs of kidney function decrease 0.6 15. i touch transplant region and check for pain and hardness signs 0.61 16. i check for adverse effects of immunosuppressive drugs 0.75 17. i act precisely if forget to take immunosuppressive drugs 0.78 18. i receive sufficient emotional support 0.73 19. i consult with a psychiatrist when i feeling depressed 0.42 20. i have enough rest and sleep 0.42 21. i take the dosage of immunosuppressive drugs as prescribed doses 0.48 22. i take immunosuppressive drugs on prescribed time 0.62 23. i check the remaining amounts of immunosuppressive drugs 0.77 24. i drink enough liquids to prevent dehydration 0.56 table 2. factor loading values of ktr-sms items vol 16 no 02 march-april 2019 189 factor. varimax rotation was used for the simpler interpretation of the factors(31). icc was calculated for the two-week test-retest stability. icc values 0.75–0.9 and greater than 0.9 show moderate and strong test-retest correlations, respectively. moreover, cronbach’s alpha was calculated for the purpose of internal consistency assessment. alpha values greater than 0.7 indicate acceptable internal consistency(32). the level of significance was below 0.05. ethical considerations this study was part of a phd dissertation in nursing in baqiyatallah university of medical sciences, tehran, iran. the dissertation was approved by the ethics committee of the university with the code of ir.bmsu. rec.1395.304. study aim was explained for participants and they filled out the informed consent form of the study. participants retained the right to voluntarily withdraw from the study. all data were managed confidentially. results descriptive statistics participants aged 47.01±11.79, on average. the mean of self-management score was 62.73±7.91. the independent samples test showed a significantly difference in self-management mean scores between male and female groups. table 1 shows self-management mean scores based on demographic characteristics. face and content validity assessments qualitative face validity assessment revealed that recipients had difficulties in understanding the ktrsms item 12, i.e. “i avoid abdominal compression”. in other words, they wrongly perceived it as “avoidance from overeating” instead of “avoidance from applying pressure to the abdomen”. therefore, based on the comments of the experts and with the approval of ktrsms developers, this item was reworded as, “i avoid the compacting and the compression of the abdomen”. besides, item 18, i.e. “i receive sufficient support”, was ambiguous for recipients in that they interpreted “support” as “financial support”. thus, it was also reworded as, “i receive sufficient emotional support”. quantitative face validity assessment also indicated that the item impact scores of all items were greater than 1.5 and the mean item impact score was 3.94. during qualitative content validity assessment, the experts confirmed that all items were appropriate. moreover, quantitative content validity assessment showed that cvr and cvi values of all items were greater than 0.33 and 0.79, respectively. moreover, the mean values of cvr, simplicity cvi, clarity cvi, and relevance cvi were 0.73, 0.96, 0.93, and 0.98, respectively. construct validity assessment construct validity was assessed via exploratory factor analysis. kmo value was 0.72 and the bartlett’s test was significant (χ2 = 5737.807; p <.001), confirming sampling adequacy. four factors with factor loadings of greater than 0.4 were extracted. scree plot (figure 1) also confirmed the four-factor structure. the factor loadings of each item as well as the items of each factor are shown in table 2. based on their items and the names of the original ktr-sms subscales, the four factors were nominated as “self-monitoring”, “self-care behaviors”, “early detecting and coping with abnormalities”, and “medication management” (table 3). the four extracted factors explained 70.75% of the total variance of self-management. reliability assessment the cronbach’s alpha of the persian ktr-sms scale and its four subscales were 0.73, 0.87, 0.77, 0.72, and 0.6, respectively. moreover, test-retest icc values for ktr-sms and its subscales were 0.90–0.96 (table 4). discussion the aim of this study was to translate ktr-sms into persian and evaluate its psychometric properties. findings revealed that the persian ktr-sms has acceptable validity and reliability and therefore can be used to assess the self-management of iranian kidney transplant recipients. to the best of our knowledge, the persian ktr-sms is the first valid and reliable instrument for self-management assessment after kidney transplantation in the iranian context. face-to-face personal interviews with recipients for the purpose of face validity assessment revealed that they had difficulties in understanding items 12 and 18. thus, these two items were amended based on experts’ comments. cultural discrepancies among different cultures can result in different understandings about healthcare issues(33). quantitative face validity assessment also revealed that item impact scores of all items were greater than 1.5, denoting that all items are important for psychometric properties of persian ktr-smskhezerloo et al. the self-management factors factor 1 factor 2 factor 3 factor 4 eigenvalue 6.31 3.79 3.52 3.35 explained variance (%) 26.32 15.79 14.67 13.96 total explained variance (%) 70.75 table 3. the eigenvalue and the amount of explained variance of ktr-sms factors sms-ktr icc (n=30) ci=0.95 p value cronbach’s alpha n=360 lower limit upper limit factor 1 (self-monitoring) 0.93 0.87 0.96 .000 0.87 factor 2 (self-care behavior) 0.96 0.93 0.98 .000 0.77 factor3 (stress management, early 0.96 0.92 0.98 .000 0.72 detecting and coping with abnormalities) factor 4 (drug management) 0.96 0.92 0.98 .000 0.6 total 0.90 0.81 0.95 .000 0.73 table 4. reliability and stability of sms-ktr in kidney transplant recipients kidney transplantation 190 self-management assessment. besides, qualitative and quantitative content validity assessments indicated that all items had been worded appropriately and were essential, clear, simple, and relevant to self-management. the original ktr-sms includes four subscales (with twenty items) and four single items. however, during exploratory factor analysis in the present study, the first twenty items were loaded on three factors and the four single items were loaded on the independent factor of “medication management”, resulting in a four-factor structure for the scale. this discrepancy between the factor structures of the original and the persian ktrsms can be attributed to the differences in the populations and the sample sizes in the original and the present studies. findings also indicated that the cronbach’s alpha values of ktr-sms and all its subscales were 0.6–0.87. these values are almost the same as those of the original(14). the lowest cronbach’s alpha value in the present study was related to the four-item “medication management” subscale. similarly, the lowest cronbach’s alpha value of the original ktr-sms subscales has been related to the subscale with the lowest number of items (i.e. stress management with just three items). moreover, in line with the findings reported by kosaka et al. for the original ktr-sms(14), icc values in the present study were 0.90–0.96. these values denote that the persian ktrsms has acceptable stability over time. findings also showed that the mean of ktr-sms score was 62.73 ± 7.91, which implies moderate self-management among iranian kidney transplant recipients. this finding highlights the necessity of educational interventions for improving the self-management of this patient population. moreover, findings revealed that male participants had higher self-management compared with their female counterparts. recipients with higher educational status and longer history of undergoing hemodialysis had also higher self-management. however, the amount of time passed from transplantation was negatively correlated with self-management. similarly, lee et al. found that male recipients as well as those with higher educational status had closer adherence. moreover, their findings showed that adherence reduced over time(34). hedayati et al. also found that treatment adherence was higher among male recipients and those with higher educational status(35). a study reported that the side effects of post-transplantation treatments significantly reduce self-management among females(36). in line with our findings, shimaya et al. also reported significant decrease in post-transplantation treatment adherence over time(37). these findings may be due to the greater fear and anxiety over transplant rejection during the first post-transplantation months. limitations study sample was selected from recipients who aged eighteen or more. therefore, the persian ktr-sms is valid and reliable only for adult transplant recipients. further studies are needed to test the psychometric properties of the persian ktr-sms among random samples of recipients with different demographic characteristics. conclusions the findings of this study show that the persian ktrsms has acceptable psychometric properties and thus, can be used for the assessment of self-management among iranian kidney transplant recipients. the simple scoring system and the great validity and reliability of ktr-sms make it more applicable and easier to use. the persian ktr-sms can be used in different studies and settings in order to assess recipients’ self-management, their problems in self-management, and the effects of interventions on self-management. acknowledgement we must thank all kidney transplant recipients who participated in this study as well as all staffs of kidney transplant centers who contributed to data collection. the research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors. conflict of interest the authors declare that they have no conflict of interests. references 1. mehrotra r, marsh d, vonesh e, peters v, nissenson a. patient education and access of esrd patients to renal replacement therapies beyond in-center hemodialysis. kidney int rep. 2005; 68:378-90. 2. schmid-mohler g, schäfer-keller p, frei a, fehr t, spirig r. a mixed-method study to explore patients' perspective of selfmanagement tasks in the early phase after kidney transplant. prog transplant. 2014;24:818. 3. opelz g, döhler b. influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. j transplant. 2009;87795802. psychometric properties of persian ktr-smskhezerloo et al. figure 1. scree plot vol 16 no 02 march-april 2019 191 4. van dyke k. transplantation rejection*. reference module in biomedical sciences: elsevier; 2014. 5. medscape. kidney transplantation patients have high readmission rates. october 3, 2016:available at http://www.medscape.com/ viewarticle/772950. 6. pascazio l, nardone ib, clarici a, enzmann g, grignetti m, panzetta go, et al. anxiety, depression and emotional profile in renal transplant recipients and healthy subjects: a comparative study. transplant proc. 2010 ;42:3586-90. 7. san gregorio máp, rodríguez am, bernal jp. psychological differences of patients and relatives according to post-transplantation anxiety. span j psychol. 2008;11:250-8. 8. group kdigotw. kdigo clinical practice guideline for the care of kidney transplant recipients. american journal of transplantation: official journal of the american society of transplantation and the american society of transplant surgeons. 2009;9(suppl 3):s1s157. 9. grijpma j, tielen m, van staa a, maasdam l, van gelder t, berger s, et al. kidney transplant patients’ attitudes towards selfmanagement support: a q-methodological study. patient educ couns. 2016;99:836-43. 10. barlow j, wright c, sheasby j, turner a, hainsworth j. self-management approaches for people with chronic conditions: a review. patient educ couns. 2002;48:177-87. 11. novak m, costantini l, schneider s, beanlands h, editors. approaches to self‐ management in chronic illness. seminars in dialysis; 2013: wiley online library. 12. lorig kr, holman hr. self-management education: history, definition, outcomes, and mechanisms. ann behav med. 2003;26:1-7. 13. redman bk. the ethics of self-management preparation for chronic illness. j nurs ethics. 2005;12:360-9. 14. kosaka s, tanaka m, sakai t, tomikawa s, yoshida k, chikaraishi t, et al. development of self-management scale for kidney transplant recipients, including management of post-transplantation chronic kidney disease. isrn transplantation. 2013;2013. 15. bodenheimer t, lorig k, holman h, grumbach k. patient self-management of chronic disease in primary care. jama. 2002;288:2469-75. 16. akyolcu n. patient education in renal transplantation. edtna-erca j. 2002;28:176-9. 17. kobus g, małyszko j, małyszko j, puza e, bachorzewska-gajewska h, myśliwiec m, editors. compliance with lifestyle recommendations in kidney allograft recipients. transplant proc; 2011: elsevier. psychometric properties of persian ktr-smskhezerloo et al. 18. jeong kh, lee yj, park je, oh wt, lee yj, moon jy, et al. factors predicting long-term graft survival after kidney transplantation. korean j nephrol. 2006;25:613-20. 19. weng lc, dai yt, wang yw, huang hl, chiang yj. effects of self‐efficacy, self‐ care behaviours on depressive symptom of taiwanese kidney transplant recipients. j clin nurs. 2008;17:1786-94. 20. lamb k, lodhi s, meier‐kriesche hu. long‐term renal allograft survival in the united states: a critical reappraisal. am j transplant. 2011;11:450-62. 21. meier‐kriesche hu, schold jd, kaplan b. long‐term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? am j transplant. 2004;4:1289-95. 22. chisholm‐burns m, spivey c, graff zivin j, lee jk, sredzinski e, tolley e. improving outcomes of renal transplant recipients with behavioral adherence contracts: a randomized controlled trial. am j transplant. 2013;13:2364-73. 23. butler ja, roderick p, mullee m, mason jc, peveler rc. frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. j transplant. 2004;77:769-76. 24. gheith oa, el‐saadany sa, abuo donia sa, salem ym. compliance of kidney transplant patients to the recommended lifestyle behaviours: single centre experience. int j nurs pract. 2008;14:398-407. 25. organization wh. "process of translation and adaptation of instruments". available at . 26. mankan t, erci b, turan gb, aktürk ü. turkish validity and reliability of the diabetes self-efficacy scale. int j nurs sci. 2017. 27. ghanbari s, ramezankhani a, montazeri a, mehrabi y. health literacy measure for adolescents (helma): development and psychometric properties. plos one. 2016;11:e0149202. 28. lawshe ch. a quantitative approach to content validity. pers psychol. 1975;28:56375. 29. suhr dd. exploratory or confirmatory factor analysis?: sas institute cary; 2006. 30. gorsuch r. factor analysis. 2nd. hillsdale, nj: lea. 1983. 31. stevens jp. applied multivariate statistics for the social sciences: routledge; 2012. 32. devon ha, block me, moyle‐wright p, ernst dm, hayden sj, lazzara dj, et al. a psychometric toolbox for testing validity and reliability. j nurs scholarsh. 2007;39:155-64. 33. stone te, kang sj, cha c, turale s, kidney transplantation 192 murakami k, shimizu a. health beliefs and their sources in korean and japanese nurses: a q-methodology pilot study. nurse educ today. 2016 ;36:214-20. 34. lee sy, chu sh, oh eg, huh kh. low adherence to immunosuppressants is associated with symptom experience among kidney transplant recipients. transplant proc. 2015 ;47:2707-11. 35. hedayati p, shahgholian n, ghadami a. nonadherence behaviors and some related factors in kidney transplant recipients. iran j nurs midwifery res. 2017 marapr;22:97-101. 36. kugler c, geyer s, gottlieb j, simon a, haverich a, dracup k. symptom experience after solid organ transplantation. j psychosom res. 2009 feb;66:101-10. 37. shimaya m, watanabe m, azumi m, shichiri k, tomiyama c, tanabe m, et al. a questionnaire survey in kidney transplant outpatients: factors associated with good self-management. health j. 2015;7:589. psychometric properties of persian ktr-smskhezerloo et al. urological oncology an open radical prostatectomy approach that mimics the technique of robot-assisted prostatectomy: a comparison of perioperative outcomes. orkunt özkaptan1*, muhsin balaban2, cuneyd sevinc3, tahir karadeniz3 purpose: to report on an ascending radical retropubic prostatectomy (rrp) technique and determine whether this technique has better perioperative, oncological and functional outcomes than the standard rrp technique applied in our clinic. materials and methods: the perioperative and functional outcomes of the 246 patients that underwent standard rrp (n = 150) or modified rrp (n = 96) were evaluated, retrospectively. in the modified rrp technique the dorsal vascular complex (dvc) was controlled at first. thereafter, the bladder neck was incised at the prostate-vesical junction. after seminal vesicles and vasa were exposed, posterior dissection was continued until to the apex. finally, the urethra was divided. results: the mean volume of estimated blood loss (ebl) was significantly longer in the standard rrp group than in the modified rrp group (610 vs. 210 ml, respectively; p = .001). the mean operative time (ot) was significantly less in the modified rrp group (177 vs. 134 min, respectively; p = .003), as were the transfusion rate tr (p = .041). with regard to the rate of postoperative complications, a statistically significant difference was observed between the two groups (p = .014). continence rates after 3 and 12 months postoperatively were 98.95% and 98.95 % in the modified rrp group, and 97.33% and 98.66% in the standard rrp group, respectively ( p = .83). conclusion: we observed that the ebl, tr and ot were significantly lower when we applied the modified rrp technique to patients. this modified technique might be applicable for institutions as an alternative procedure for the standard rrp technique. keywords: perioperative outcome; prostate cancer; surgical technique; radical prostatectomy introduction radical prostatectomy is the current treatment of choice for clinically localised prostate cancer. open retropubic radical prostatectomy (rrp) has become a refined surgical procedure with excellent outcomes over the last decade. nevertheless, the narrowness of the pelvis and complexity of the pelvic anatomy makes this procedure still challenging for the surgeons. in recent years, there has been a significant trend towards the utilisation of minimally invasive approaches to radical prostatectomy for the treatment of prostate cancer.(1) binder was first to report on robot-assisted prostatectomy (rarp) in germany in 2001; this technique was then refined in the usa by menon et al.(2,3) rarp was introduced in an attempt to attain more precision during surgery, which enables urologist to preserve neurovascular bundles and to achieve better continence rates. although there is no large-scale randomised controlled trial demonstrating its superiority over rrp, observational cohort studies and meta-analyses reported the benefit of rarp over rrp with regards to blood transfusions, length of stay (los) and 1 department of urology, kartal training and research hospital, kartal, istanbul 34890, turkey. 2 department of urology, biruni university medical school, topkapı, istanbul 34010, turkey. 3 department of urology, medical faculty, i̇stinye university, bei̇iktai̇, istanbul 34450, turkey. *correspondence: department of urology, kartal training and research hospital, kartal, istanbul 34890, turkey tel: +905058296107, fax: +9002163520083, e-mail: ozkaptanorkunt@gmail.com. received august 2018 & accepted february 2019 lower rates of perioperative complications.(4-7) the aims of rarp and rrp are to obtain a favourable oncological and functional outcome; however, the two technical approaches towards prostate dissection and urethrovesical anastomosis are quite different. rarp is mostly performed in an antegrade fashion. on the other hand, rrp is conducted in a retrograde fashion. the advancements in rarp have also contributed to the advancement of rrp. after beginning to perform rarp at our institution, we attempted to adapt the operative techniques/manoeuvres of rarp to rrp; an antegrade approach during open rrp was conducted for prostate dissection instead of the standard retrograde technique. therefore, the primary objective of this study was to report on an ascending rrp technique and determine whether this technique has better perioperative, oncological and functional outcomes than the standard rrp technique applied in our clinic. materials and methods study population this study was conducted after the approval of the urological oncology 168 ethics committee of medicana international hospital (no. [2018] 1775). the data from 246 patients without history of suergery, radiotherapy and hormonotherapy, who underwent rrp for prostate cancer between 2013 and 2017 with two different open approaches and who had at least 12 months follow-up, was evaluated retrospectively from an electronic database. because of the retrospective nature of the study a written patient consent was not taken from the patients. the standard rrp technique was applied between 2013 and 2015, whereas the modified rrp technique was performed in 2015-2017. of the patients, the final 96 were operated on using an ascending rrp technique as described by patel et al.(8). these patients were the first patients who were operated with the ascending technique. all other patients prior to that time underwent the standard rrp technique described by walsh.(9) the last 150 patients of the standart rrp group who were eligible for the study were included. all patients were operated by the same senior surgeon who had performed over 900 rrp procedures. all patients had a minimum of one year follow-up. variables including patient characteristics, perioperative parameters, pathologic data, postoperative complications reported according to the clavien-dindo classification system and postoperative incontinence rates were evaluated between the two techniques.(10) the perioperative outcomes included the duration of surgery (defined as skin incision to skin closure time in both procedures), ebl volume (ml) during rrp, hospitalization time (ht, day), days of catheterization and intra/post-operative transfusion rate (tr, units). continence was defined as using no pads and having no urine leakages. to determine the anastomosis integrity, drain fluid was assessed for creatinine in all patients, postoperatively. routine cystography in the absence of suspicion was not performed. the recovery of continence was evaluated in routine controls at 3 and 12 months after the operation. the short term oncological outcome was assessed by surgical margins and biochemical recurrence at the 1 year follow-up. sexual function was defined as the ability to have complete sexual intercourse (with or without oral pharmacological therapy). postoperative complications that occurred within 90 days were recorded. surgical technique during surgery, the adipose tissue from the prostate was removed to expose the endopelvic fascia. once adequate exposure had been obtained, the endopelvic fascia was incised from near the pelvic sidewall anteriomedially, preserving the puboprostatic ligaments. proceeding from the base to the apex, the levator fibres were moved away from the prostate until the dorsal table 1. patient characteristics and operative parameters. variablesa,b modified rrp (n=96) standard rrp (n=150) p-value age, year; mean ± sd (range) 61.96 ± 5.2 (48-77) 61.34 ± 5.9 (45-77) .254 bmi, kg/m2; mean ± sd (range) 27.12 ± 2.5 (20.7-33.8) 26.98 ± 2.9 (20.3-34.4) .456 prostate volume, ml; mean ± sd (range) 49.1 ± 14.8 (17-109) 48.5 ± 15.9 (19-111) .344 preoperative psa, ng/dl; mean ± sd (range) 13.12 ± 7.0 (2.4-95) 9.98 ± 8.2 (1.8-59) .043 ot (minutes), mean ± sd (range) 134 ± 50.1 (106-188) 177 ± 64.3 (116-201) .003 ebl, ml; mean ± sd (range) 210 ± 90.1 (5-600) 610 ± 220.3 (190-1800) .001 plnd, (n%) 54 (51.8) 61 (40.7) .023 lymph positivity 9 7 pathological stage, n (%) .024 t2 70 (72.9 ) 119 (79.3) t3 26 (27.1) 31 (20.7) nerve sparing .98 bilateral, n(%) 44 (45.8) 69 (46) pathological gleason score, n(%) 6 22 39 7 48 85 8 14 17 9 7 9 10 1 0 asa, n (%) .95 1 62 (64.6) 98(65.4) 2 29 (27.8) 42 (28) 3 5 (4.8) 8 (4.6) readmission rates, n(%) 1 (1.04) 2 (1.33) 1 overall complication rate n(%) 14 (14.6) 42 (28) .014 gastrointestinal (constipation, subileus) 7 (7.3) 11 (7.3) transfusion rate 7 (7.3) 36 (24) < 0.001 urinary ]nfection 5 (5.2) 7 (4.7) wound infection 3 (3.12) 3 (2) cardiac 2(2.1) 4 (2.7) respiaratory 2 (2.1) 3 (2) anastomosis stricture 2 (2.1) 2 (1.3) deep venous thrombosis 1 (1.05) 1 (0.7) ureteral injury 1(0.7) lymphorrhoea 4 (4.2) 4 (2.7) abbreviations: bmi, body mass index; ot, operative time; ebl, estimated blood loss; plnd, pelvic lymph node dissection; asa, american society of anesthesiologists score. acontinuous variables were compared by independent sample t-test; bcategorical variables were compared by chi-square test or fisher’s exact test. radical retropubic prostatectomy with an ascending approach-ozkaptan et al. vol 16 no 02 march-april 2019 169 vein complex (dvc) and urethra could be visualized. titanium clips and hem-o-lock clips with a rectangular applicator in different sizes were used. magnification glasses with a 3.5-fold magnification and a xenon headlight were also used. extensive dissection of the apex was avoided at this time. a slip knot with a non-braided caprosyn suture using a large needle was performed for the dvc control. a second suture was placed to suspend the urethra to the pubic bone and secondarily ligate the dvc. the dvc was encircled and then stabilized against the pubic bone along with the urethra. thereafter the bladder neck was incised at the prostate-vesical junction. the bladder was dissected away from the prostate at the midline with monopolar energy and ligasure. after the midline of the bladder neck was opened, either side of it was dissected and the foley catheter was retracted out upwards. the posterior bladder neck was dissected in the cranial direction to locate the seminal vesicles. after the vasa and seminal vesicles were identified, the vasa was retracted upwards and followed posteriorly to find the base of the seminal vesicles. small vessels were controlled with ligasure or clipped with 5 mm clips. after dissection of seminal vesicles, they were retracted upwards and the denovillier’s fascia was stripped down from the prostatic capsule. the periprostatic fascia was not incised in the nerve sparing technique, only blunt dissection was performed. care was taken to avoid any injury to the neurovascular bundle (nvb), which runs in close proximity to the tips of the seminal vesicles. dissection was continued gradually towards the apex. the seminal vesicles were elevated to allow exposure of the prostatic pedicles, which were clipped and cut directly on the surface of prostatic capsule (dissection of the nvb was performed without coagulation in order to avoid thermal damage of the fibres. the posterior part of the prostate was dissected until the urethra. apical dissection and division of the urethral was carried out with cold scissors and sharp dissection. the urethra was then incised at the apex of the prostate under direct vision. bipolar energy was used for coagulation if necessary. the urethra was divided and detached from the prostate; the prostate was then mobilised from the remainder of the periprostatic fascia toward the apex and nvb’s. bladder-neck sparing was not attempted. the bladder outlet was narrowed (0.8 1 cm) with 2-0 vicryl continuous seromuscular sutures using a tennis racquet technique. five 3-0 vicryl sutures with a ur-6 needle were placed along a 22 fr urethral catheter without eversion of the bladder mucosa. the sutures were placed at 5, 7, 9, 2 and 12 o’clock. statistical analysis baseline characteristics and overall outcomes were summarized as the mean and standard deviation (sd) for continuous variables, and frequencies and percentages for categorical variables. to assess the differences between the two groups for patient characteristics and perioperative outcome, the independent sample t-test was used. differences between the two groups for complication, margin rates, continence, erectile function and biochemical recurrence were assessed using chisquare test or fisher’s exact test. spss version 17.0 (chicago, il, usa) was used for statistical analyses. a p value of <0.05 was considered statistically significant. results patient characteristics the average age at diagnosis was 64 (42-77 years). preoperative clinical characteristics such as mean age, preoperative prostate specific antigen (psa), prostate volume and histopathologic characteristics of the patients are presented in table 1. the mean follow-up for the standard rrp group and the modified rrp group was 14 ± 10.3 months and 12 ± 9 months, respectively. operative variables according to the variables of operative difficulty, some statistically significant differences were observed. table 2 presents the operative and postoperative results, as well as the complications in both groups. the mean volume of ebl was significantly longer in the standard rrp group than in the modified rrp group (610 vs. 210 ml, respectively; p = .001). the mean ot was significantly lower in the modified rrp group (177 vs 134 min, respectively; p = .003), as was the tr (p < .041). however, no significant difference was noted for the amount of time spent in recovery unit (3.2 (2.0-6.3) vs. 3.3 (2.2-7.4) hours, respectively; p = .87). postoperative variables patients who underwent the modified rrp operation had a shorter mean ht (3.0 (1-15) days) than those who underwent the standard rrp (4.3 (2-17 days; p = 0.03). regarding the time to the recovery of continence, the outcomes for both groups were similar (p = .83). incontinence after 12 months was observed in one (1.05 %) and two (1.34%) patients in the modified rrp and standard rrp groups, respectively. the positive surgical margin (sm) rates were similar between the two groups (7.3% in the modified rrp 3 months 12 months variables modified rrp (n=96) standart rrp (n=150) p-value modified rrp (n=96) standart rrp (n=150) p -value number of complication, n(%) 82 (86.6) 108 (72) .014 negative sm, n(%) 89 (92.7) 140 (93.33) .85 continence, n(%) 95 (98.95) 146 (97.33) .38 95 (98.95) 148 (98.66) .83 erectile function at months, n(%) 27 (28.12) 43 (28.66) .93 35 (36.5) 57 (38) .81 bcr, n (%) 2 (2.08) 1 (0.67) .56 3 (3.12) 3 (2.67) .57 pentafacta rates, n(%) 25 (25.9) 36 (24) .71 30 (31.3) 45 (30) .83 abbreviations: biochemical recurrence, bcr. acontinuous variables were compared by independent sample t-test; bcategorical variables were compared by chi-square test or fisher’s exact test. table 2. pentafacta rates between standard rrp and modified rrp at 3 and 12 months. radical retropubic prostatectomy with an ascending approach-ozkaptan et al. urological oncology 170 group vs. 6.7% in the standard rrp group) and no intergroup difference was observed (p = .85). biochemical recurrence after 12 months was observed in 3.12% vs. 2.67% of patients in the modified and standard rrp groups, respectively (p = .56). with regards to the rate of postoperative complications, a statistically significant difference was observed between the two groups (p = .014). complications classified as grade 1, grade 2 and grade 3a were observed in 6.7%, 16.3% and 1.9% of patients in the modified rrp group, and 4.7%, 32.7% and 1.4% patients in the standard rrp group, respectively. the overall complication rate was 22.8%. twenty-nine complications were encountered in 14 (14.6%) patients in the modified rrp group, whereas 56 complications were observed in 42 (28%) patients in the standard rrp group. the observed complications are listed in table 2. in addition, readmission rates were lower in the modified rrp group, although this was not statistically significant (1.04% vs. 1.33%; p = .97). pelvic lymph node dissection (plnd) was performed in 54 (51.8%) and 61 (40.7%) patients in the modified rrp group and standard rrp group, respectively. furthermore, a nerve sparing approach was applied in 44 (45.8%) and 69 (46%) patients in the modified rrp group and standard rrp group, respectively. both differences were not significant (p =.023 and p = .98, respectively). the percentage of patients who achieved a functional erection at 3 months postoperatively was similar in both groups (p = .93). this result did not change after 12 months. the overall potency rate after 12 months was 36.5 % in the standard rrp and 38% in the modified rrp group (p = .81). the pentafecta rate at 3 months postoperatively was 25.9% and 24% in the modified rrp and standard rrp groups, respectively (p = .71). the pentafecta rate at 12 months was 31.3% and 30% for each group, respectively (p = .83). the difference in the pentafecta rate did not reach statistical significance. discussion rrp is a well-established technique for the treatment of prostate cancer. it is performed through a small incision that is infrequently associated with significant pain, has relatively short ht and provides excellent oncological outcomes.(11,12) rarp is gaining popularity with the help of intensive marketing; however, patients with a lower socioeconomic status prefer to undergo open rrp due to the lower costs.(13,14) even though the majority of patients have an unaffected postoperative course, the overall rate of complications, ebl, tr and the functional and oncological outcome may vary between different techniques. rarp is reported to result in decreased ebl and tr, and quicker convalescence.(5-7,11,15,16) previous studies reporting on the complications associated with the standard rrp technique determined an ebl of 1100 (800-1600) ml and 540 ml.(17,18) another review regarding the two different approaches determined an ebl of 951 ml in rrp vs. 164.2 ml in rarp.(19) the ebl rate in the standard rrp group in our study was similar with that reported in recent studies for open rrp, whereas the ebl rate was significantly lower using the modified rrp technique (210 ml).(20) decreased intraoperative blood loss has been reported to be the main advantage of rarp. (19) this is explained by the pneumoperitoneum and the early identification and precise ligation of vessels, which facilitates the limitation of the ebl. however, the ebl rates in our study operated using an ascending technique were close to the rarp and laparoscopic radical prostatectomy ebl rates.(16,19,21,22) therefore, with an ascending approach, you overcome the disadvantage of working in the deep pelvis without optimal vision and a lack of optimal movement. this technique provides better visualization of the surgical field, better access to the surgical field and early identification and more precise ligation of vessels. consequently, the factors above mentioned may be the reason for the lower ebl rates in the modified technique. the use of ligasure loops and clips also contributes to the more precise control of vessel ligation. a 3.5-fold magnification lens and xenon head light were used to combine the advantages of rarp (magnification and optimal light) with the advantages of open surgery (tactile sensation and a 3-dimensional view). the complication rates for the standard technique group were similar to those reported in the studies by loppenberg et al. which fulfills the martin criteria.(17) the complication rates using the modified technique were lower compared to the standard technique (14.6% vs 28%). according to studies comparing rrp and rarp, lawrence et al. and hu et al. found a similar rate of overall postoperative complications, while other studies concluded that rarp was superior to rrp.(7,23,24) the rate of complication and the way of reporting the complication rates after rrp or rarp appears to vary between different institutions. therefore, it is not easy to compare the complication rates of rarp and rrp. the results of the current study indicate that the rate of complications were significantly lower in the modified rrp group than in the standard rrp group, even though most patients had an unaffected postoperative course. the reasons for the slightly higher complication rate using the standard rrp technique were mainly related to the tr, which is categorised as a complication in the clavien-dindo classification system.(10) the rate of other complications were similar between the two groups. the difference in the tr between the two groups was remarkable. the need for transfusion was lower in the modified rrp group, which was closer to that previously observed using rarp.(16) the tr for the standard rrp group was comparable with other reports; however, the transfusion criteria varies between different studies.(18) the ot was longer for patients in the standard rrp group than for those in the modified rrp group (177 vs 134 min, p = .003). ot of the modified technique was comparable with previous reported rarp series.(25) the ascending technique provides an improved vision of the operative field. in particular, the access to prostate pedicules after the prostate base and the seminal vesicles were dissected and freed was easier in the ascending technique. bleeding can also be controlled more easily with this approach. furthermore, dissection of the apical prostate can be performed more precisely and easily after the posterior part of the prostate is released. all of the above mentioned factors contribute to the shorter operative time achieved with the ascending technique. regarding the ht, the rarp procedure is often reported to result in a shorter ht compared to rrp (1.43 vs. 3.48 days, respectively).(6,15,19) according to our study, radical retropubic prostatectomy with an ascending approach-ozkaptan et al. vol 16 no 02 march-april 2019 171 the ht was shorter in the modified rrp group, which may be related to the lower rate of complications and reduced need for transfusion in the modified rrp group having an effect on the patient recovery time. in our study, the surgical approach made no difference in the rate of positive sms, a surrogate marker of oncological outcome. in both groups, the positive sm rates were relatively low, which could be explained by the experience of the surgeon. these rates were low in comparison to those reported in a large case series.(24,26) in agreement with another study, our results indicate that the surgical approach makes no difference to the positive sm rate; the experience level of the surgeon is the most important factor beside the cancer characteristics.(20) another important favourable surgical outcome is the recovery of continence. the same interrupted suturing technique for urethral anastomosis was performed in both groups. in our opinion, it is technically easier to perform this technique in rrp than to use a running suturing technique. in addition, the results of this study showed continence rates and urethral stricture to be, in our opinion, in a good range (1.62%). as we have much experience with this suturing technique, we did not see any reason to change our anastomosis technique. further, a previous study comparing rarp using continuous suturing and rrp performed with an interrupted anastomosis technique found no difference in continence rates between the two groups.(20) overall, it is difficult to compare our results with the outcomes of rarp; however, our study did demonstrate that the tr, ebl and complication rates were lower in the modified rrp group than in the standard rrp group. some potential limitations to this study are the retrospective design and the small sample size of the study. these facts precludes us to make any definitive conclusion from this study. another weakness of the study is the difference of the period when each study group underwent the surgeries. more reliable results would be obtained in a prospective randomised study design. further, the fairly short follow up time for biochemical recurrence is also a limitation. finally, we did not use questionnaires to define erectile function and continence. more reliable and objective findings regarding continence and erectile function could have been determined by the use of questionnaires. conclusions open rrp is a well-known and established procedure with excellent outcomes, and advancements in the rarp technique have contributed to the advancement of open rrp. we observed that the ebl, tr and operative time were significantly lower when we applied the modified ascending rrp technique to patients. in our opinion, rrp can be performed more easier with the ascending than in the standard rrp technique. as rarp is becoming a more preferential approach for the localised treatment of prostate cancer, we believe that this modified technique might be applicable for institutions performing rrp as an alternative procedure for the standard rrp technique. conflict of interest the authors report no conflict of interest. references 1. begg cb, riedel er, bach pb, et al. variations in morbidity after radical prostatectomy. n engl j med. 2002;346:1138–44. 2. binder j, kramer w. robotically-assisted laparoscopic radical prostatectomy. bju int 2001;87:408–410 . 3. menon m, shrivastava a, tewari, et al. laparoscopic and robot assisted radical prostatectomy:establishment of a structured program. j urol. 2002;168:945-9. 4. gardiner ra, coughlin gd, yaxley jw, et al. a progress report on a prospective randomised trial of open and robotic prostatectomy. eur urol. 2014;65:512–5. 5. novara g, ficarra v, rosen rc, et al. systematic review and metaanalysis of perioperative outcomes and complications after robotassisted radical prostatectomy. eur urol. 2012;62:431–52. 6. gandaglia g, sammon jd, chang sl, et al. comparative effectiveness of robotassisted and open radical prostatectomy in the postdissemination era. j clin oncol. 2014;32:1419–26. 7. trinh qd, sammon j, sun m, et al. perioperative outcomes of robotassisted radical prostatectomy compared with open radical prostatectomy: results from the nationwide inpatient sample. eur urol. 2012;61:679–85. 8. vr patel a, kk. shah, rk. thaly, et al. robotic-assisted laparoscopic radical prostatectomy: the ohio state university technique. j robotic surg. 2007; 1:51–59. 9. walsh p: anatomic radical prostatectomy. campbell’s urology. philadelphia, wb saunders, 2002:3107-28. 10. dindo d, demartines n, clavien pa. classification of surgical complications. a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240: 205–13. 11. menon m, tewari a, baize b, et al. prospective comparison of radical retropubic prostatectomy and robot-assisted anatomic prostatectomy: the vattikuti urology institute experience. urology. 2002;60:864-8. 12. nelson b, kaufman m, broughton g, et al. comparison of length of hospital stay between radical retropubic prostatectomy and robotic assisted laparoscopic prostatectomy. j urol. 2007;177:929-31. 13. menon m, bhandari m, gupta n, et al: biochemical recurrence following robotassisted radical prostatectomy: analysis of 1384 patients with a median 5-year follow-up. eur urol. 2010;58:838-46. 14. lowrance wt, eastham ja, yee ds, et al: costs of medical care after open or minimally invasive prostate cancer surgery: a populationbased analysis. cancer. 2012;118:3079-86. 15. mustafa m, davis jw, gorgel sn, et al. radical retropubic prostatectomy with an ascending approach-ozkaptan et al. urological oncology 172 robotic or open radical prostatectomy in men with previous transurethral resection of prostate. urol j. 2017 ;14:2955-60. 16. hamidi n, atmaca af, canda ae, et al. does presence of a median lobe affect perioperative complications, oncological outcomes and urinary continence following robotic-assisted radical prostatectomy? urol j. 2018;15:248-255. 17. löppenberg b, noldus j, holz a, palisaar rj. reporting complications after open radical retropubic prostatectomy using the martin criteria. j urol. 2010;184:944-8. 18. graefen m. the modified clavien system: a plea for a standardized reporting system for surgical complications. eur urol. 2010; 57(3):387-9. 19. coelho rf, rocco b, patel mb, et al. retropubic, laparoscopic, and robot-assisted radical prostatectomy: a critical review of outcomes reported by high-volume centers. j endourol. 2010;24:2003-15. 20. haglind e, carlsson s, stranne j, et al. urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: a prospective, controlled, nonrandomised trial. lappro steering committee. eur urol. 2015;68:216-25. 21. jiang dg, xiao ct, mao yh, et al.. impact and predictive value of prostate weight on the outcomes of nerve sparing laparoscopic radical prostatectomy in patients with low risk prostate cancer. urol j. 2018;.(article in press). 22. chen s, jiang g, liu n, et al. the association of shorter interval of biopsy-radical prostatectomy and surgical difficulty. urol j. 2018;15:344-347. 23. lowrance wt, elkin eb, scardino pt, eastham ja. re: comparative effectiveness of minimally invasive vs open radical prostatectomy. eur urol. 2010;57:538. 24. hu jc, gandaglia g, karakiewicz pi, et al. comparative effectiveness of robot-assisted versus open radical prostatectomy cancer control. eur urol. 2014; 66: 666–72. 25. islamoglu e, karamik k, ozsoy c, tokgoz h, ates m, savas m. the learning curve does not affect positive surgical margin status in robot-assisted laparoscopic prostatectomy. urol j. 2018;15:333-8. 26. suardi n, delloglio p, gallina a, et al. evaluation of positive surgical margins in patients undergoing robot-assisted and open radical prostatectomy according to preoperative risk groups. urol oncol. 2016; 34: 57. radical retropubic prostatectomy with an ascending approach-ozkaptan et al. vol 16 no 02 march-april 2019 173 may-june 2017 reviewer of the issue nikolaos grivas nikolaos grivas june 2017 dr nikolaos grivas graduated from medical school in university of ioannina and in 2013 he finished his phd study at the same university. he completed his urology training in g.hatzikosta general hospital of ioannina. very recently he finished his fellowship in the urology department of netherlands cancer institute, nki-avl in amsterdam. he stayed 1 year in this center of excellence where he was trained in the robotic urological surgery. the last 3 years he is an associate member of european association of urology (eau) guidelines panel of urolithiasis. he has received 5 awards in three european congresses and in 2016 he received the best young urologist award in greece. he has 30 publications in peer-reviewed journals while he is a reviewer in 16 urological journals. he belongs also in the editorial board of 8 urological journals. he has also received scholarships from greek urological association and european association of urology. finally he has 40 oral presentations and invited speeches in many international conferences. the peer review process is a fundamental process for improving the scientific literature and it also allows the reviewers to improve themselves and to have a critical view also on theirs way of scientific writing. in order to be a good reviewer a lot of time and extremely detailed work is needed which sometimes is difficult especially if the review topic is outside of your field of expertise. however it is a great honor and i always feel satisfaction when i see my comments to be included in a manuscript since you feel like a co-author in some way. this best reviewer awards gives me the strength to try to improve myself and continue doing a review in as high professional way as possible. endourology and stone disease safety and efficacy of rirs in geriatric patients: a comparative evaluation on an age based manner kaan gokcen1*, gokce dundar2, murat bagcioglu3, mehmet ali karagoz3, gokhan gokce1, kemal sarica3 purpose: in this retrospective study, we aimed to comparatively evaluate the efficacy and safety of rirs procedure on an age-based manner in patients younger and above 65 years. materials and methods: a total of 165 patients undergoing rirs procedure for renal stones were divided into two groups on an age-based manner namely; group 1 (n=122) patients aging < 65 years and group 2 (n=43) patients aging above 65 years. demographic and clinical data regarding the stone free rates, complication rates and need for secondary procedures were retrospectively evaluated. results: of all the patients undergoing rirs for kidney stones, 122 were below the age of 65 (73.9%) and 43 were above the age of 65 (26.1%). mean age value for the patients aging more than 65 years was 74.16 ± 5.03 years and in addition to higher percentage of comorbidities, serum creatinine levels as well as asa scores were also higher in this group when compared with younger counterparts. although there was no statistically significant difference with respect to the operative duration, stone-free rates (sfr) and hospitalization period between the two groups, both complication rates and the need for additional interventions were higher in the older patient group (p = 0.038; p = 0.032). all complications noted in the both groups were minor (grade i) complications according to the clavien classification system. conclusion: rirs procedure can be applied as an effective and safe treatment alternative for the minimal invasive management of renal stones in relatively older patients (> 65 years) with similar hospitalization as well as stone free rates noted in the younger patients. no procedure related severe complication was noted in these cases. keywords: geriatric patients; renal stones; rirs introduction published data clearly point out that the population above the age of 60 years will have surpassed 2 billion by the year 2050(1). as a result of the increase in this age group the prevalence of urolithiasis is also expected to increase to the levels of 10-12% in the near future(2). aging population will suffer from decreased functional reserves in different organ systems and associated comorbidities with aging will cause certain problems that could be encountered either in the perioperative and/or postoperative follow-up periods after certain treatment approaches(3). additionally, decreased cardiopulmonary and renal functional status in geriatric patients may also lead higher rate of complications associated with major surgeries making it difficult to cope with the perioperative problems when compared with the younger cases(4). as the least invasive method available so far, extracorporeal shock wave lithotripsy (swl) is a commonly performed treatment alternative for kidney stones compared to other endourological approaches. despite its well-known advantages, this technique requires repeated treatments which may commonly be associated with colic pain during the passing of fragmented stones 1cumhuriyet university, school of medicine, department of urology, sivas, turkey. 2kestel state hospital, department of urology, bursa, turkey. 3kafkas university, school of medicine, department of urology, kars, turkey. *correspondence: assistant professor, m.d. cumhuriyet university, school of medicine, department of urology , sivas, turkey. tel: +90 346 2580000 email: kaangokcen@hotmail.com. received october 2018 & accepted april 2019 causing discomfort to the patients. in light of these disadvantages and the advances in endoscopic technology, other minimally invasive endourologic methods with high stone-free and acceptable complication rates have been introduced into the clinical practice in the last two decades(5). of these procedures, despite its markedly higher stone-free rates particularly for stone sizing smaller than 2 cm, percutaneous nephrolithotomy (pcnl) procedure may be associated with certain severe complications such as bleeding requiring transfusion, visceral organ damage and hydrothorax in the perioperative/postoperative period(6). such complications may be associated pcnl method with a higher percentage particularly in geriatric patients presenting with higher comorbidities(7). retrograde intrarenal surgery (rirs) has become popular in the minimal invasive management of renal calculi in the last two decades due to its higher stonefree rates than swl, particularly for lower pole stones, and significantly lower morbidity than pcnl(8). due to the certain advantages of this approach such as similar success as well as lower complication rates along with the shorter hospitalization period currently rirs urology journal/vol 17 no. 2/ march-april 2020/ pp. 129-133. [doi: 10.22037/uj.v0i0.4921] is being recommended as the primary treatment modality particularly for kidney stones smaller than 20 mm(9). in the light these advantages and the accumulated experience so far, endourologists began to perform rirs procedure more commonly also in the older population as a minimal invasive method to limit the likelihood of complications associated with swl as well as pcnl approaches. although limited, rirs has been used in older cases with varying success rates as reported in the literature, there is really very limited data in the published literature comparing the safety and efficacy of this approach in older population on an age based manner. in this present retrospective study we aimed to evaluate the effectiveness and safety of the rirs technique in the minimal invasive management of renal stones in older patients (> 65 years) compared to their relatively younger counterparts. materials and methods a total of 165 cases with kidneys stones have been managed with rirs method between 2017 january 2018 may and the data obtained from departmental files at the department of urology at cumhuriyet university health sciences practice and research hospital were evaluated in a retrospective manner. depending on the age interval, patients undergoing this procedure were divided into two groups as follows; group 1 (n = 122) including the patients below the age of 65 years and group 2 (n = 43) patients above the age of 65 years. all patients were well evaluated well with respect to their demographic characteristic, medical comorbidities, american society of anesthesiologists (asa) scores, anticoagulant therapy use, number and stone size, presence of hydronephrosis, preoperative serum creatinine and hemoglobin levels, use of ureteral access sheath (uas), operative time, complication as well as stone-free rates (sfr) and lastly need for additional interventions. in our study, patients who underwent a stone surgery previously were excluded from the study. preoperative evaluation of the cases included urinalysis, full blood count, serum biochemical evaluation, coagulation tests, and urine culture antibiogram tests. in cases with culture proven urinary tract infections, antimicrobial therapy matching with the antibiogram sensitivity tests was initiated to eradicate the infection and bring the urine sterile prior to the procedure to limit the possible risk of infective complications. a non-contrast computed tomography (ncct) was performed in all patients to evaluate the stone characteristics and surface area (mm²) was calculated by the multiplication of the longest diameters in axial and coronal sections in millimeters. in patients with multiple stones however, data for each stone was calculated individually and the total value was recorded. last but not least an informed consent form explaining all details related with the application as well as possible complications of rirs was obtained from all patients and they were informed about the possible need for a multi-stage procedure to obtain satisfactory stone clearance if needed. prior to procedure, 1 gr cefazolin via intravenous route was applied for infection prophylaxis. all patients were operated in the lithotomy position under general anesthesia. based on the surgeon’s preference and experience, uas (11.5/9.5 fr 45/55 cm) was passed over the guidewire into the ureter before lithotripsy by using 200-µm holmium: yag laser (stonelight® holmium laser system; ams inc., minnetonka, mn, usa) accompanied by a 7.5 fr flexible ureterorenoscope (storz flex-x2, tuttlingen, germany). laser lithotripsy was applied using values between 1.0 1.5 joule and 8 10 hz. in the end of laser lithotripsy, stone fragments < 2 mm that could be passed spontaneously were left to remain in the collecting system while fragments > 2mm were extracted using a basket in the presence of a uas. in the end of the operation, 4.8 f double-j (dj) stents were routinely inserted to all patients which was planned to be removed after 3 weeks postoperatively. in both groups: patients dj stents’ were removed under local anesthesia. the operative time was calculated as the time between the introduction of the cystoscope into the urethra and the insertion of the dj stent into the ureter after the procedure. intraoperative and postoperative complications were evaluated and noted based on the modified clavien classification system(10). although patients were evaluated and followed by plain abdominal film as well as urinary sonography at regular safety and efficacy of rirs in geriatric patients – gokcen et al. table 1. demographic as well as stone related characteristics of patients undergoing rirs. group 1 (age<65) group 2 (age≥65) p age, mean ± std (min.-max.) 41.4 ± 15.97 (19-65) 74.16 ± 5.03 (65-86) < 0,001* sex, (male/female) 70/52 20/23 0.482 stone burden, (mm2) mean±std (min.-max.) 222.16 ± 101.9 (74-460) 227.88 ± 57.24 (132-378) 0.653 side, (right/left) 63/59 15/28 0.036* localization, 45 (36) 17(39.5) 0.673 • renal pelvis, n (%) 22 (18) 6 (13.9) • upper calyx, n (%) 29 (24) 6 (13.9) • middle calyx, n (%) 26 (22) 14(32.5) • lower calyx, n (%) number and rate of cases with multiple stones, n (%) 51/122 (41.8) 21/43 (55.8) 0.27 stones’ hounsfield units (hu), mean±std (min.-max.) 896,83±323,25 (260-2010) 834.35±292.16 (307-1530) 0.334 ≥3 asa score, n (%) 7 (5.7) 15 (34.8) < 0.001* presence of hyperlipidemia, n (%) 18 (14.7) 15 (34.8) 0.005* presence of coronary artery disease, n (%) 9(7.3) 14 (32.5) < 0.001* presence of diabetes, n (%) 27 (22.1) 19 (44.1) 0.038* presence of hypertension, n (%) 34 (27.8) 31 (72.1) < 0.001* presence of chronic kidney disease, n (%) 0 (0) 7 (16.2) 0.003* presence of anticoagulant use, n (%) 9 (10.6) 14 (32.5) 0.004* presence of hydronephrosis, n (%) 39 (31.9) 16 (37.2) 0.598 * p < 0.05: statistically significant endourology and stones diseases 130 follow-evaluations, final stone-free status was evaluated by performing a ncct for during post-operative 3-months follow-up evaluation in all cases. a stonefree state was considered as no remaining residual fragment or the presence of fragments sizing ≤3 mm. patients demonstrating residual fragments were planned to remove these fragments with a second rirs session. statistical methods statistical analysis was performed with ibm spss statistics for windows (version 22.0). data was given as mean±standard deviation (std), minimum and maximum values for continuous variables. the mann–whitney u test was used to evaluate numerical variables with a skewed distribution. categorical variables were compared using chi-square test, while continuous variables were compared using independent sample t-test. for the comparison of hemoglobin and serum creatinine perioperative values, percent changes were calculated according to perioperative measurement as: percent change=(postoperative-preoperative)/preoperative. statistical significance was considered at p ≤ 0.05 level. results while the mean age in group 1 was 41.4 ± 15.97 years (19-64), this value was 74.16 ± 5.03 (65-86) years in group 2 cases (p < 0.001). male ratio was 70/122 in group 1 and 20/43 in group 2. stone burden was 222.16 ± 101.9 (74-460) mm2 for group 1 and 227.88±57.24 (132-378) mm2 for group 2; with no statistically significant difference between the two groups (p = 0.653). patients demographics, stone characteristics as well as the presence and degree of hydronephrosis are summarized in table 1. as demonstrated in table 1 again comorbidity rates as well as the use anticoagulant medication were statistically higher in group 1 when compared with the younger group. regarding the procedure related parameters, while the mean operative time was 64.8 ± 15.6 (30-90) minutes in group 1, this value was 67.3 ± 16.2 (50-100) minutes in group 2. additionally, uas was used in 98 patients (80.3%) in group 1 and 34 patients (79.1%) in group 2 with no statistically significant difference on this aspect. there was also no significant difference with respect to the post-operative hospitalization period as demonstrated in table 2. comparative evaluation of preoperative and postoperative (day 1) serum creatinine levels with significantly higher mean values were found in group 2 and the type as well as percentage of complications are given in table 2. although being minor in nature, complications were observed more common in older patients when compared with the younger counterparts. evaluation of the final stone-free rates after 3 months did show that although not statistically significant lower success rates observed in group 1 cases compared to group 2 (91.8% vs 81.4%; p = 0.060). last but not least as demonstrated in table 2 again need for additional rirs procedures for remaining residual fragments was slightly higher in group 1 cases (p = 0.022). discussion the incidence of urolithiasis is gradually increasing with a prevalence rate of varying between 4-20%(11). parallel to this fact, the incidence of kidney stones in older patients is expected to rise as result of the increasing elderly population in developed countries among which struvite and uric acid stones are being the more common ones(12). taking the reported severe complications of pcnl and to a certain extent for swl approach, as a minimally invasive endourologic approach, rirs has become a preferred option in the treatment of kidney stones with its acceptable success and limited complication rates particularly in complex situations such as pregnancy, obesity, coagulopathy, skeletal deformities, large kidney stones, calyceal diverticula and kidney anomalies(13). in this present retrospective study we aimed to evaluate the efficacy of rirs in the older populations namely patients older than 65 years presenting with possible associated problems like asa scores ≥3, hyperlipidemia, coronary artery disease, diabetes, hypertension, chronic kidney disease, and common anticoagulant use as expected. our findings did clearly demonstrate that despite relatively lower stone free rates and higher incidence of minor (clavien grading i) complication rates encountered, rirs procedure can be applied in patients older than 65 years in a safe and effective manner when compared with younger counterparts. when compared with the other available endourologic stone management techniques (pcnl and swl) rirs with its minimal invasive nature enables us to remove the majority of moderate sized stones in one session in the majority of such cases. related with this issue, in a study comparing management of moderate sized stones with pcnl and rirs procedures in geriatric patients, overall sfr following a single-stage procedure were 82.1% and 92.8% respectively for the rirs and pcnl groups, indicating that table 2. procedure related (success and complication rates) findings and need for additional interventions in patiens underoing rirs. group 1 (age<65) group 2 (age ≥ 65) p preoperative hemoglobin value (mg/dl) mean ± std (min.-max.) 14.42 ± 1,62 (10.7-18.2) 13.76 ± 1,85 (8.8-17.5) 0.057 postoperative hemoglobin value (mg/dl) mean ± std (min.-max.) 13.98 ± 1.57 (10.9-17.4) 13.49 ± 1.73 (9.8-17.8) 0.082 percent change of hemoglobin value (mg/dl) mean ± std (min.-max.) -0.03 ± 0.03 (-0.13-0.4) -0.02 ± 0.05 (-0.10-0.23) 0.175 preoperative serum creatinine value (mg/dl) mean ± std (min.-max.) 0.98 ± 0.29 (0.23-1.82) 1.23 ± 0.64 (0.7-3.72) < 0.001* postoperative serum creatinine value (mg/dl) mean ± std (min.-max.) 0.86 ± 0.26 (0.22-1.65) 1.09 ± 0.46 (0.59-2.7) < 0.001* percent change of serum creatinine value (mg/dl) mean ± std (min.-max.) -0.10±0.19 (-0.56-0.76) -0.09±0.15 (-0.58-0.14) 0.197 operative time (min) mean±std (min.-max.) 64.8±15.6 (30-90) 67.3±16.2 (50-100) 0.248 complication rate 4 (3.2%) 5 (11.6%) fever: 4 fever: 2 hematuria: 3 0.038* uas use, n/total (%) 98/122 (%80.3) 34/43(%79.1) 0.487 hospitalization time (days), mean ± std (min.-max.) 1.4 ± 0.6 (1-3) 1.7 ± 0.8 (1-4) 0.162 sfr, n/total (%) 112/122 (91.8) 35/43 (81.4) 0.060 number and rate of repeated rirs, n (%) 8 (6.6) 8 (18.6) 0.022* * p < 0.05: statistically significant safety and efficacy of rirs in geriatric patients – gokcen et al. vol 17 no 02 march-april 2020 131 rirs could be performed in a safe and effective manner in the older patient group as well. in the same study 17.8% of the older patients treated required a second rirs procedure(7). in our study, the need for a second procedure was determined as 18.6% in the older group. related with this issue again data reported from experienced centers on flexible urs (furs) demonstrated similar final sfrs compared with pcnl and lower complication rates associated with shorter postoperative hospitalization period(3,8,14,15). although studies focusing on the success and safety of rirs in older patients compared to relatively younger populations are limited, beradinelli et al. showed that sfr, operative time, uas use, hospitalization period, and the need for additional procedures were not affected by the patient’s age(16). similarly our findings also did not show significant differences with regard to sfr and uas use where the sfrs were determined as 91.8% and 81.4% for group 1 and group 2, respectively. in the light of the data reported in meta-analysis studies including patients undergoing additional interventions; sfrs of 71.5-100% in moderate sized stones and the 91.5 % sfr after a mean of 1.4 rirs sessions in cases with large stones ( > 2 cm)(17,18), despite the need for additional sessions, rirs can be preferred as a primary treatment for larger stones with higher sfrs than swl(19–21). despite the similar operative duration values in two groups, a higher prevalence of minor (grade 1 according to clavien classification) complications such as fever managed with antipyretic agents and postoperative hematuria requiring no erythrocyte replacement have been observed in our cases as demonstrated also in other trials(22. the higher complication rates observed in group 2 in our study was thought to originate from the hemorrhagic diathesis and associated other comorbidities of the older patients treated. while the overall complication rate for furs was 3.2 % in younger (< 65 years) cases and this rate was determined as 11.6% for the older group in our study which were certainly were in accordance to the reported percentages in the literature(3,16,18). as mentioned above the number of studies focusing on the safety as well as efficacy of rirs in older patients is limited and demonstration of no severe complication in both groups is the difference of our data from the other reported ones with notable complications. regarding the pcnl procedure again, an age value of above 70 was stated to be an independent risk factor for the presence and severity of complications as well as prolonged hospitalization in the croes global study(23). published data show that while the overall rate of pcnl related complications is 12.5% in the general population and 8.3% of these are higher than grade 1 requiring intervention, the complication rate was reported to be 17.5% in older patients which is significantly higher than noted in our older patients(22,24). in our study, additional rirs was performed 18.6% in older patients for the residual fragments and the possible causes could be restricted fluid intake and immobilization and low renal function in this age group of cases compared to the relatively younger ones. a review of the literature in this regard reveals that, similar to our results, the need for additional interventions in older patients treated with furs was connected to prolonged operative times in the first session, large stones, and the decisions of the physician or the patient(7). our study has certain limitations where the retrospective design is the major one. additionally, the limited number of cases included, inability to evaluate the need for postoperative analgesia and pain scores and the lack of stone analysis are the additional limitations. however, taking the limited number of studies focusing on the safety and efficacy of rirs in older cases (particularly in a age based comparative manner as performed in our study) our results will be contributive enough to the existing limited data in the literature. we certainly think that further confirmed by prospective and multicenter studies with larger series of cases on this topic are certainly needed. conclusions the increased prevalence of stone disease in advanced age and the higher number of comorbidities encountered in these patients complicate the decision making of the urologist for the most appropriate procedure to achieve a successful outcome with limited complications. our results clearly demonstrated that rirs could be performed as a safe and effective treatment alternative in the minimal invasive management of moderate sized stones in older patients. despite the higher percentage of minor complications as well as relatively higher need for additional interventions rirs in older patients may offer shorter hospitalization duration comparable and acceptable sfrs in elderly patients when compared with other available modalities in this specific population particularly in experienced centers. conflict of interest the authors declare that they have no conflict of interest. references 1. chatterji s, byles j, cutler d, seeman t, verdes e. health, functioning, and disability in older adults--present status and future implications. lancet (london, england). 2015;385:563-75. 2. mccarthy j-p, skinner taa, norman rw. urolithiasis in the elderly. can j urol. 2011;18:5717-20. 3. hu h, lu y, he d, et al. comparison of minimally invasive percutaneous nephrolithotomy and flexible ureteroscopy for the treatment of intermediate proximal ureteral and renal stones in the elderly. urolithiasis. 2016;44:427-34. 4. tonner ph, kampen j, scholz j. pathophysiological changes in the elderly. best pract res clin anaesthesiol. 2003;17:163-77. 5. marchini gs, mello mf, levy r, et al. contemporary trends of inpatient surgical management of stone disease: national analysis in an economic growth scenario. j endourol. 2015;29:956-62. 6. de la rosette j, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol. 2011;25:11-7. 7. akman t, binbay m, ugurlu m, et al. outcomes safety and efficacy of rirs in geriatric patients – gokcen et al. endourology and stones diseases 132 vol 17 no 02 march-april 2020 133 of retrograde intrarenal surgery compared with percutaneous nephrolithotomy in elderly patients with moderate-size kidney stones: a matched-pair analysis. j endourol. 2012;26:625-9. 8. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015;67:125-37. 9. türk c, petřík a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016;69:468-74. 10. dindo d, demartines n, clavien p-a. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 11. trinchieri a. epidemiology of urolithiasis: an update. clin cases miner bone metab. 2008;5:101-6. 12. knoll t, schubert ab, fahlenkamp d, leusmann db, wendt-nordahl g, schubert g. urolithiasis through the ages: data on more than 200,000 urinary stone analyses. j urol. 2011;185:1304-11. 13. giusti g, proietti s, cindolo l, et al. is retrograde intrarenal surgery a viable treatment option for renal stones in patients with solitary kidney? world j urol. 2015;33:309-14. 14. javanmard b, kashi ah, mazloomfard mm, ansari jafari a, arefanian s. retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j. 2016;13:2823-8. 15. zheng c, xiong b, wang h, et al. retrograde intrarenal surgery versus percutaneous nephrolithotomy for treatment of renal stones >2 cm: a meta-analysis. urol int. 2014;93:417-24. 16. berardinelli f, de francesco p, marchioni m, et al. rirs in the elderly: is it feasible and safe? int j surg. 2017;42:147-51. 17. geraghty r, abourmarzouk o, rai b, biyani cs, rukin nj, somani bk. evidence for ureterorenoscopy and laser fragmentation (ursl) for large renal stones in the modern era. curr urol rep. 2015;16:54. 18. skolarikos a, gross aj, krebs a, et al. outcomes of flexible ureterorenoscopy for solitary renal stones in the croes urs global study. j urol. 2015;194:137-43. 19. donaldson jf, lardas m, scrimgeour d, et al. systematic review and meta-analysis of the clinical effectiveness of shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy for lowerpole renal stones. eur urol. 2015;67:612-6. 20. karakoyunlu n, goktug g, şener nc, et al. a comparison of standard pcnl and staged retrograde furs in pelvis stones over 2 cm in diameter: a prospective randomized study. urolithiasis. 2015;43:283-7. 21. sari s, ozok hu, topaloglu h, et al. the association of a number of anatomical factors with the success of retrograde intrarenal surgery in lower calyceal stones. urol j. 2017;14:4008-14. 22. de la rosette jjmch, opondo d, daels fpj, et al. categorisation of complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012;62:246-55. 23. kamphuis gm, baard j, westendarp m, de la rosette jjmch. lessons learned from the croes percutaneous nephrolithotomy global study. world j urol. 2015;33:223-33. 24. sahin a, atsü n, erdem e, et al. percutaneous nephrolithotomy in patients aged 60 years or older. j endourol. 2001;15:489-91. safety and efficacy of rirs in geriatric patients – gokcen et al. letter intermittent catheterization frequency and interval in children: are we clear enough? seyyed mohammad ghahestani1*, sara karimi2 since the introduction of clean intermittent catheterization (cic) it has been a mainstay in the treatment of neu-rogenic and non-neurogenic bladder dysfunction. proactive management with cic beginning in the first month of life is recommended and supposed to decrease the likelihood of bladder intestinal augmentation.(1). despite this inseparable integration of cic and the burden of frequency of doing this procedure for the patient, intervals of catheterization in children are not clarified. in adults, the frequency has been a recapitulation of normal voiding patterns and this has been reported to have a frequency of 4-6 times a day. generally, bladder volume must be kept below 500 cc(2) . normal voiding frequency in healthy children has been reported to vary between 2 to 10 times a day which is clearly a wider range.(3).obviously, bladder volume range is also considerably variable in a growing child. despite the facts, the literature is boldly reticent about the frequency of catheterization in children. catheterizing every three hours has been widely speculated as the shortest interval and the highest frequency of cic the patient can tolerate with an acceptable compromise in quality of life. it seems that this has been construed as an extrapolation of recommendations in the adult population of catheterizing 4 to 6 times during a day(2). in children, it is perceivable that there are cases in whom more frequent cicmay help the patient to sustain a low pressure and stable bladder without prompt rush to bowel cystoplasty. vice versa some children may suffer unnecessary high cic frequency and lose their quality of life even more. especially when you consider the fact that recommendations of proactive institution of intermittent catheterization during the neonatal period are increasingly advocated.(1) another aggravating factor, particularly attributable to children is decreased specific gravity of urine. this defect may be potentially correctable by more frequent cic to lower bladder pressure and push the patient out of a vicious cycle. the patient and parents have a right to know that a more than generally supposed frequency of cic (we improvised to call it hyper frequent cic e.g. every 2 hours during awake time) may procure them a window to hinder bowel cystoplasty. the question is what an interval or number of cic attempt per day are desirable for an individual patient. the goal is keeping the filling pressure below safe dlpp. we presume there is no component of bladder neck insufficiency. the safe dlpp has been widely touted as 35-40. observing a safety margin ,20 cmh 2 o has been recently proposed as safe dlpp while still 40 cmh20 is widely accepted as the most quoted upper tract deterioration redline(3). we can consider 35 the lower threshold to stay on the self-side securely. the patients specially those on the brink of cystoplasty are presumed to use free overnight drainage(4). the compliance number of bladder shows us how much a specific amount of urine volume raises the pressure. therefore, we estimate: the safe volume the bladder retains in each interval will be 35*compliance. if you want to know the number of catheterization in wake hours, it will simply be wake hours out put(wto)/35*comp. the wake hours’ output can be obtained by avoiding diary as an initial and essential assessment for any functional lower urinary tract disorder. knowing the number of hours, the child remains awake, the interval can be easily calculated: interval in hours=35*comp*whrs /wto as a simplification in the usual scenario of a toddler sleeping eight hours a day the wake hours will be 16 and calculation will be: interval in hours: 560*compliance/wto this easily understandable formula helps us be clearer. in some instances, this number may fall below 3 hours. some parents need time to adjust to the supposed cystoplasty procedure or get ready in life circumstances. a temporizing hyper frequent schedule may also help kidneys regain their concentrating ability. sometimes one can give a try to lengthen the intervals gradually and bladder may be apt to improve its functional capacity a little bit. patient compliance with the schedule decreases with intolerably short intervals and close observation is mandatory. intermediary interventions e.g. intradetrusor onabutilinium toxin injection or neurostimulation may increase bladder compliance and functional capacity if not done previously. this may recruit some marginal patients into hyper frequent schedule before intestinal cystoplasty. i think this should be proposed to parents especially in marginal cases with a calculated interval between 2 and 3. moreover, we must be plain and explicit with patients about intervals 1assistan professor,tehran university of medical sciences (tums), urology department. pediatric urology ward, children medical center hospital, gharib st, keshavarz blvd, tehran , iran. 2fellow of female and functional urology, shahid beheshti medical university, urology nephrology research center,boostan 9th,pasdaran ave,tehran,iran. *correspondence: assistan professor,tehran university of medical sciences (tums), urology department. pediatric urology ward, children medical center hospital, gharib st, keshavarz blvd, tehran , iran. phone:+989128491811. email:mgrosva@gmail.com. received may 2021 & accepted may 2021 urology journal/vol 18 no. 3/ may-june 2021/ pp. 362-363. [doi: 10.22037/uj.v18i.6827] vol 18 no 3 may-june 2021 363 in any case. data and trials are undoubtedly required. references 1. stein r, bogaert g, dogan hs, hoen l, kocvara r, nijman rj, et al. eau/espu guidelines on the management of neurogenic bladder in children and adolescent part i diagnostics and conservative treatment. neurourol urodyn. 2020;39(1):45-57. 2. blanker mh, bohnen am, groeneveld fp, bernsen rm, prins a, ruud bosch j. normal voiding patterns and determinants of increased diurnal and nocturnal voiding frequency in elderly men. j urol. 2000;164(4):1201-5. 3. mattsson sh. voiding frequency, volumes and intervals in healthy schoolchildren. scand j urol nephrol. 1994;28(1):1-11. 4. nguyen mt, pavlock cl, zderic sa, carr mc, canning da. overnight catheter drainage in children with poorly compliant bladders improves post-obstructive diuresis and urinary incontinence. j urol. 2005;174(4):1633-6. laparoscopic urology 254 urology journal vol 6 no 4 autumn 2009 laparoscopic management of adrenal lesions larger than 5 cm in diameter rajan sharma, arvind ganpule, muthu veeramani, ravindra b sabnis, mahesh desai introduction: laparoscopic adrenalectomy remains a controversial procedure for large tumors. the incidence of adrenocortical carcinoma increases and technical difficulty of adrenalectomy increases as the size increases. we examined the outcome and complications of laparoscopic adrenalectomy for such lesions. materials and methods: twenty-nine patients underwent laparoscopic adrenalectomy, of whom 19 had tumors larger than 5 cm in diameter, having a median tumor size of 7.0 cm. they were compared with patients whose adrenal tumors were smaller than 5 cm. results: patients with small tumors (< 5 cm) had a significantly shorter median operative time of 90 minutes as compared to 145 minutes in those with large tumors (> 5 cm). there was no significant difference in the median hemoglobin drop (1.05 g/dl versus 1.30 g/dl), time for starting oral intake (24 hours in both groups) or hospital stay (3.5 days versus 4.0 days) between patients with small and large tumors, respectively. there were no intra-operative complications except for 1 incidence of supraventricular tachycardia in a patient with a large pheochromocytoma. there were no major complications seen in any of the patients and no open conversions. histopathology of large tumors revealed 16 benign tumors (8 pheochromocytomas, 4 adenomas, 2 ganglioneuromas, 1 pseudocyst, and 1 myelolipoma) and 3 malignancies, of which 1 was primary adrenocortical carcinoma and 2 were metastatic renal cell carcinoma. conclusion: in experienced hands, laparoscopic adrenalectomy is safe and feasible for large functioning adrenal tumors. large adrenal tumors suspicious of harboring malignancy with no peri-adrenal involvement can be tackled laparoscopically. urol j. 2009;6:254-9. www.uj.unrc.ir keywords: laparoscopy, adrenal gland neoplasms, adrenalectomy methods muljibhai patel urological hospital, nadiad, gujarat, india corresponding author: mahesh desai, ms, frcs, frcs muljibhai patel urological hospital, nadiad, 387001, gujarat, india tel: +91 0268 252 0323 e-mail: mrdesai@mpuh.org received april 2009 accepted august 2009 introduction first laparoscopic adrenalectomy was performed in 1992 by michel gagner,(1) and since then, laparoscopic adrenalectomy has become the standard of care for managing small benign adrenal masses.(2) size threshold for offering laparoscopic adrenalectomy is controversial, as the prevalence of adrenocortical carcinoma (acc) increases with increasing tumor size, and there is increasing risk of peritoneal dissemination during surgery.(3) it has also been reported in the literature that the skill required for laparoscopic adrenalectomy is proportional to the tumor size.(4) we retrospectively reviewed our 6-year clinical experience in laparoscopic management of adrenal lesions laparoscopic management of large adrenal lesions—sharma et al urology journal vol 6 no 4 autumn 2009 255 sized greater than 5 cm and its feasibility and safety in such patients. materials and methods patients a total of 29 patients underwent laparoscopic adrenalectomy from march 2003 till february 2009. a prior approval from the institutional review board was taken before data accrual and analysis. all of the patients had a complete endocrinological workup done in order to know about the functional status of the tumor. radiological workup was done in the form of computed tomography or magnetic resonance imaging. all of the patients with suspected pheochromocytoma had alpha blockers instituted preoperatively. the indications for laparoscopic adrenalectomy were the presence of functioning or nonfunctioning adrenal lesions, a potentially malignant lesion with no radiological evidence of periadrenal spread or capsular disruption, and solitary adrenal metastases of a treated primary tumor elsewhere. surgical technique transperitoneal approach was used in 27 patients and retroperitoneal in 2 patients according to the standard procedures described.(2) for transperitoneal adrenalectomy, the patient was placed in the lateral decubitus position with 45to 60-degree flank position. four ports were employed on the right side (1 port for liver retraction) and 3 ports on the left side. pneumoperitoneum was created in all cases with veress needle, which was inserted in the midpoint of the spino-umbilical line at the upper border of the umbilicus. a 10-mm camera port was inserted at the lateral border of the rectus abdominis muscle at a point which was at the one-third distance from the costal margin and the iliac fossa port. a 5-mm working port was inserted at the costal margin, and on the right side, an extra port was inserted for liver retraction. pneumoperitoneum was maintained below 15 mm hg. on the right side, after mobilizing the liver and exposing the inferior vena cava, the adrenal vein was dissected; clipped, using hem-o-lok clips (teleflex medical, research triangle park, nc, usa), and divided. on the left side, after medially mobilizing the descending colon, spleen, and pancreas, the renal vein was dissected and the adrenal vein was identified arising from the renal vein. care was taken to do minimal handling of the adrenal gland till the adrenal vein was ligated, which was helpful in preventing a catecholamine surge in cases of pheochromocytoma. peri-adrenal tissue dissection was done using a harmonic scalpel (ethicon, johnson & johnson, research triangle park, nc, usa), and wherever necessary, the hem-o-lok clips were used. the specimen was retrieved by extending the iliac fossa incision and entrapping the tumor in an indigenously designed endocatch bag.(5) retroperitoneal approach was used in 2 patients according to the procedure described by kumar and albala.(6) statistical analyses a comparative analysis was done between adrenal lesions smaller and larger than 5 cm in diameter. group 1 consisted of tumors smaller than 5 cm and group 2 consisted of those larger than 5 cm. the parameters studied were the operative time, hematocrit drop, blood transfusion requirement, intra-operative complications, conversions to open surgery, analgesia requirement, postoperative hospital stay and start of oral intake, postoperative complications, and recurrences (including local and distant). the data is expressed as median and range of minimum to maximum values. comparison between groups was done by the mann-whitney u test and a p value less than .05 was considered significant. results the patients’ characteristics are tabulated in table 1. there were 10 patients in group 1 and 19 in group 2. the patients were well matched for age in both of the groups; however, patients in group 2 had a higher body mass index. all but 2 patients had transperitoneal adrenalectomy and none of them required conversion to open laparoscopic management of large adrenal lesions—sharma et al 256 urology journal vol 6 no 4 autumn 2009 surgery. sixty percent of tumors in group 1 and 57.8% in group 2 were detected incidentally. the median operative time was longer in group 2 (on average, 42 minutes longer; 103 minutes versus 145 minutes). there were no intra-operative complications in group 1, but the patients in group 2 had 1 instance of intraoperative supraventricular tachycardia in a patient with pheochromocytoma, which was successfully managed (table 2). the median tumor size was 4.0 cm in group 1 and 7.0 cm in group 2. tumors in group 2 were significantly heavier as compared to those in group 1 (59 g versus 17.5 g). there was no significant difference in hemoglobin drop, postoperative hospital stay, analgesic requirements, and time to starting oral intake between the two groups. none of the patients in either group required blood transfusion. there were no major postoperative complications except for a minor wound infection in 1 patient in group 2 (table 3). pheochromocytoma was the most common histopathological diagnosis in both groups. ten of 13 patients with pheochromocytoma (76.9%) did adrenal tumor size characteristic < 5 cm > 5 cm p number of patients 10 19 … age, y 27.5 (8 to 70) 38 (10 to 66) .23 sex male 2 (10.0) 13 (68.4) female 8 (80.0) 6 (31.6) … tumor side right 9 (90.0) 10 (52.6) left 1 (10.0) 9 (47.4) … body mass index, kg/m2 18.2 (9.2 to 30.6) 23.2 (13.4 to 30.8) .04 incidentally detected 6 11 … table 1. characteristics of patients who underwent laparoscopic adrenalectomy* *values in parentheses demonstrate range for age and body mass index and percents for the remaining. ellipses indicate not analyzed. adrenal tumor size characteristic < 5 cm > 5 cm p operative time, min 90 (60 to 210) 145 (60 to 240) .02 approach transperitoneal 10 (100) 17 (89.5) retroperitoneal 0 2 (10.5) … conversions 0 0 … complications 0 1 (5.3)† … *values in parentheses are range for the operative time and percents for the remaining. ellipses indicate not applicable. †intra-operative supraventricular tachycardia occurred in 1 patient with pheochromocytoma. table 2. intra-operative parameters in patients who underwent laparoscopic adrenalectomy* adrenal tumor size characteristic < 5 cm > 5 cm p hemoglobin drop, g/dl 1.0 (0.2 to 2.2) 1.3 (0.3 to 4.0) .37 packed cell volume drop 4.4 (0.2 to 6.4) 4.1 (0.3 to 13.8) .69 tumor size, cm 4 (1.3 to 5.0) 7 (5.3 to 10.6) < .001 weight of specimen, g 17.5 (7.0 to 156.0) 59 (8 to 280) .006 time to oral intake, h 24 (20 to 36) 24 (20 to 48) .47 tramadol requirement, mg 125 (25 to 500) 150 (50 to 550) .39 hospital stay, d 3.5 (1 to 7) 4.0 (1 to 7) .78 complications 0 1 … *values in parentheses are range. table 3. postoperative parameters in patients who underwent laparoscopic adrenalectomy* laparoscopic management of large adrenal lesions—sharma et al urology journal vol 6 no 4 autumn 2009 257 not require any antihypertensive drugs following surgery. histopathological diagnoses of both groups are tabulated in table 4. there were 3 cases of malignancy (15.7%), 1 primary acc (5.2 %), and 2 metastatic renal cell carcinomas (rccs) in group 2. one patient with rcc had developed synchronous ipsilateral adrenal involvement and contralateral adrenal metastases of size 7.5 cm; he underwent laparoscopic radical nephrectomy followed later by contralateral retroperitoneoscopic adrenalectomy. the second patient with metastases had synchronous contralateral metastases of an rcc, measuring 6.5 cm in the maximum dimension; he underwent simultaneous laparoscopic radical nephrectomy and contralateral adrenalectomy. the patient with primary acc had a 10.6-cm tumor, which had been the largest tumor treated by us laparoscopically. there was no capsular disruption during dissection of this tumor. surgical margins for tumor resection were negative in all the 3 cases. the patient with primary acc received postoperative adjuvant mitotane therapy. there was no recurrence at the last follow-up of 48 months. one patient with metastatic rcc (bilateral synchronous adrenal involvement) succumbed to distant relapse in the liver and lymph nodes 3 months following adrenalectomy, and the other patient with synchronous contralateral adrenal metastases was lost to follow-up at 6 months. discussion laparoscopic adrenalectomy has been proven to be the standard of care for managing small benign adrenal masses.(1) the absolute contraindication for laparoscopic adrenalectomy is acc with periadrenal invasion or venous thrombus, apart from other general contraindications for laparoscopy, which include uncorrected coagulopathy, abdominal sepsis, intestinal obstruction, and unacceptable cardiopulmonary risk.(2) although size alone is not a contraindication, there is considerable debate as to the size threshold for offering laparoscopic adrenalectomy, as it is well known that the incidence of carcinoma increases with increasing size.(3) the estimation of the risk of acc for lesions larger than 6 cm is 25%, for tumors between 4 cm and 6 cm is 6%, and for tumors smaller than 4 cm is 5%, as stated in the national institutes of health consensus statement.(7) our data revealed an incidence of 5.2% for accs among tumors larger than 5 cm. other potential problems associated with offering laparoscopic adrenalectomy for large adrenal masses, namely anatomical considerations, are handling of tumors, technical difficulty in dissecting large adrenal tumors, more likelihood of complications, and the risk of peritoneal dissemination of carcinoma. there is no welldefined arterial supply to the adrenal gland. the adrenal gland is supplied by branches from 3 arterial systems, namely the inferior phrenic artery, aorta, and renal artery, which divide into multiple small branches with a complex arcade around the medial and superior border before entering the adrenal parenchyma.(2) hence, there will be more technical difficulties in dissection of the large adrenal mass, leading to higher chances of intraoperative hemorrhage. direct handling of larger tumors is more likely to lead to fracture during handling, resulting in troublesome bleeding and inadequate removal and peritoneal dissemination.(2) it was recommended by godellas and colleagues that all tumors suspected of being malignant should not be removed by laparoscopic approach,(8) and winfield and coworkers also felt that tumors larger than 6 cm and highly suspected lesions of adrenal carcinoma should be managed by open surgery and lesions smaller than 6 cm which are suspected of having adrenal tumor size histopathology < 5 cm > 5 cm pheochromocytoma 5 (50.0) 8 (42.1) functioning cortical adenoma 1 (10.0) 0 nonfunctioning adenoma 3 (30.0) 4 (21.0) pseudocyst 0 1 (5.3) myelolipoma 1 (10.0) 1 (5.3) ganglioneuroma 0 2 (10.5) carcinoma 0 1 (5.3) metastases 0 2 (10.5) table 4. histopathology reports of patients who underwent laparoscopic adrenalectomy* *values in parentheses are percents. laparoscopic management of large adrenal lesions—sharma et al 258 urology journal vol 6 no 4 autumn 2009 metastases can be dealt with laparoscopically. (9) review of the literature reveals that as more and more experience is being gained, larger sized tumors are being tackled laparoscopically with minimal or no complications.(10) similar experience has also been reported recently by simforoosh and colleagues in managing large adrenal tumors laparoscopically. (11) the various contemporary series which have reported laparoscopic management of large adrenal tumors are summarized in table 5 for comparison with our series.(12-16) the results reveal that our series is comparable to almost all contemporary series reported in the world literature for managing large adrenal masses. the mean tumor size tackled is comparable, while the operative time is less as compared to other series. there is no conversion in our series, while in these series, the conversion rate varies from zero to 20%. similarly, complication rates reported are 10% to 30%, while we had a complication rate of 5.2%. adrenocortical carcinoma is associated with a 5-year survival of 16% to 60%, and recurrence is seen in almost two-thirds of patients, even in patients with localized disease and complete resections.(17) there have been few reports of local, intra-abdominal, and port site recurrences following laparoscopic adrenalectomy for cancer. (18,19) our results showed that the patient with primary acc was healthy and recurrence free 48 months following the surgery. while the patient with synchronous ipsilateral and contralateral adrenal involvement with metastatic rcc had a survival of 3 months, developing recurrences in the liver and lymph nodes.(20) the other patient with synchronous contralateral rcc was lost to follow-up at 6 months. it has been shown by various authors that laparoscopic approach as compared to open adrenalectomy has fewer complications, less operative blood loss, less postoperative pain, shorter postoperative hospital stay, and faster return to regular activity.(2,13) when size is considered as the sole criterion on which the operative approach has to be based, then many patients who have large benign adrenal tumors will have to undergo an unnecessary open adrenalectomy that might increase their morbidity.(15) our series also showed that laparoscopy allowed patients who had large adrenal tumors to experience the same benefits that laparoscopic resection has afforded to patients with small adrenal tumors. laparoscopy is feasible in larger tumors as it allows close manipulation with magnified field of vision, careful and precise dissection of the adrenal gland, and early control of the adrenal vein. the adrenal gland is not handled till the adrenal vein is controlled, reducing the risk of hemodynamic instability. however, the surgeon should be ready to convert to open adrenalectomy if there is evidence of local invasion, capsular disruption, or technical difficulties observed during the operation.(12,14,21) conclusion laparoscopic adrenalectomy is safe and feasible for large functioning adrenal masses as well as nonfunctioning adrenal masses. even large adrenal tumors suspected of harboring malignancy can be managed laparoscopically, provided there is no peri-adrenal involvement or capsular disruption. conflict of interest none declare. study year tumors > 5 cm approach mean tumor size, cm mean operative time, min conversions, % complications, % hobart et al(12) 2000 14 transperitoneal & retroperitoneal 8.0 205 14.3 21.4 macgillivray et al(13) 2002 12 transperitoneal 8.0 190 0 41.6 tsuru et al(14) 2005 29 transperitoneal 6.5 176 13.7 12.0 liao et al(15) 2006 39 transperitoneal 6.2 207 25.6 10.25 bhat et al(16) 2007 10 transperitoneal 8.0 142.7 20.0 30 simforoosh et al(11) 2008 17 transperitoneal 6.3 159 0 0 our study 2009 19 transperitoneal & retroperitoneal 7.2 145 0 5.2 table 5. comparision of studies on laparoscopic management of large adrenal lesions laparoscopic management of large adrenal lesions—sharma et al urology journal vol 6 no 4 autumn 2009 259 references 1. gagner m, lacroix a, bolte e. laparoscopic adrenalectomy in cushing’s syndrome and pheochromocytoma. n engl j med.1992;327:1033. 2. gill is. the case for laparoscopic adrenalectomy. j urol. 2001;166:429-36. 3. soon ps, yeh mw, delbridge lw, et al. laparoscopic surgery is safe for large adrenal lesions. eur j surg oncol. 2008;34:67-70. 4. chrousos george p. is laparoscopic surgery suitable for all adrenal masses? nat clin pract endocrinol metab. 2007;3:210-1. 5. mishra s, jain p, ganpule a, muthu v, manohar t, desai m. laparoscopic specimen retrieval: made cost effective with novel bag. j endourol. 2007;21:168. 6. kumar u, albala dm. laparoscopic approach to adrenal carcinoma. j endourol. 2001;15:339-43. 7. [no authors listed]. nih state-of –the-sciencestatement on management of clinically inapparent adrenal mass (incidentaloma). nih consens state sci statements. 2002;19:1–25. 8. godellas cv, prinz ra. surgical approaches to adrenal neoplasms: laparoscopic versus open adrenalectomy. surg oncol clin north am.1998;7: 807-17. 9. winfeild hn, hamilton bd, bravo el, novick ac. laparoscopic adrenalectomy: the preferred choice? a comparision to open adrenalectomy. j urol. 1998;160:325-9. 10. henry jf, defechereux t, gramatica l, raffaelli m. should laparoscopic approach be proposed for large and/or potentially malignant adrenal tumors? langenbecks arch surg.1999;384:366-9. 11. simforoosh n, majidpour hs, basiri a, et al. laparoscopic adrenalectomy: 10-year experience, 67 procedures. urol j. 2008;5:50-4. 12. hobart mg, gill is, schweizer d, sung gt, bravo el. laparoscopic adrenalectomy for large-volume (> 5 cm) adrenal masses. j endourol. 2000;14:149-54. 13. macgillivray dc, whalen gf, malchoff cd, oppenheim ds, shichman sj. laparoscopic resection of large adrenal tumors. ann surg oncol. 2002;9:480-5. 14. tsuru n, suzuki k, ushuyama t, ozono s. laparoscopic adrenalectomy for large adrenal tumors. j endourol. 2005;19:537-40. 15. liao ch, chueh sc, lai mk, hsiao pj, chen j. laparoscopic adrenalectomy for potentially malignant adrenal tumors greater than 5 centimeters. j clin endocrinol metab. 2006;91:3080-3. 16. bhat hs, nair tb, sukumar s, mohammed saheed cs, mathew g, kumar pg. laparoscopic adrenalectomy is feasible for large adrenal masses >6cm. asian j surg. 2007;30:53-6. 17. vassilopoulou-sellin r, schultz pn. adrenocortical carcinoma. clinical outcome at the end of the 20th century. cancer. 2001;92:1113–21. 18. suzuki k, ushiyama t, mugiya s, kageyama s, saisu k, fujita k. hazards of laparoscopic adrenalectomy in patients with adrenal malignancy. j urol.1997;158: 2227. 19. chen b, zhou m, cappelli mc, wolf js jr. port site, retroperitoneal and intra-abdominal recurrence after laparoscopic adrenalectomy for apparently isolated metastasis. j urol. 2002;168:2528-9. 20. sharma r, gupta r, manohar t, desai mr. renal cell carcinoma with ipsilateral adrenal involvement with synchronous contralateral adrenal metastases. indian j urol. 2006;22:368-9. 21. porpiglia f, fiori c, tarabuzzi r, et al. is laparoscopic adrenalectomy feasible for adrenocortical carcinoma or metastases? bju int. 2004;94:1026-9. miscellaneous comparison of alpha-blockers and antimuscarinics in improving ureteral stent-related symptoms: a meta-analysis yiyang gao1,3,#,hengrui liang1,2,3,#, luhao liu1,4, alberto gurioli5, wenqi wu1* purpose: a meta-analysiswas conducted to compare alpha-blocker (ab) and antimuscarinic (am) monotherapies in releasing us-related symptoms. methods: a comprehensive literature search was performed on online databases pubmed, web of science, medline, and cochrane library. ureteric symptom score questionnaire (ussq), international prostate symptom score (ipss), quality of life (qol) and visual analogue pain scale (vaps) were pooled and compared. results: nine full-text articles met the inclusion criteria and have been included. the studies were conducted in 9 different centers between 2009 and 2016. all articles were rct studies and a total of 654 patients were recorded totally, among which 323 were given alpha-blockers while others were given antimuscarinics. although patients using alpha-blockers presented lower ussq scores, no statistically significant difference was recorded in urinary symptom(smd 0.5, 95 % ci -0.2 to 1.20, p = 0.159), pain(smd 0.33, 95 % ci -0.26 to 0.92, p = 0.280),general health, work performance(smd-0.34, 95 % ci -0.08 to 0.76, p = 0.115) and sexual performance (all p > 0.05) (smd 0.12, 95 % ci -0.10 to 0.34, p = 0.280). meanwhile ipss (smd -0.10, 95 % ci -0.32 to 0.11, p = 0.358), qol(smd-0.03, 95 % ci -0.23 to 0.18, p = 0.802) and vaps(smd 0.08, 95 % ci -0.15 to 0.31, p = 0.447) were similar between the two groups (all p > 0.05). conclusion: the analysis suggests that ab showed a similar effect with am. it is necessary to conduct a larger and more detailed cohort study and find the population that potentially might benefit most by am. keywords: alpha-blockers; antimuscarinics; ureteral stent-related symptoms; meta-analysis introduction indwelling ureteral stent (us) is common during en-dourological practice since 1967[1]. however,it has been reported that 38% to 80% patients ever experienced stent related symptoms(2,3), which may be caused by the spasm of ureteric smooth musculature around the indwelling foreign object. alpha-blockers (ab) efficacy is already proven in releasing stent-related morbidity(4, 5). the potential mechanism may include the reduction of bladder irritation symptoms due to involuntary bladder contraction. meanwhile, antimuscarinics (am) have been used to overcome symptoms caused by the involuntary overactive contraction of the bladder due to the distal end of the stent in the urinary bladder, with encouraging results(6).a randomized clinical trial has proved that preoperative administration of oral toltero1 department of urology, minimally invasive surgery center, the first affiliated hospital of guangzhou medical university, guangdong key laboratory of urology, guangzhou, guangdong, china 2 nanshan school, the first affiliated hospital of guangzhou medical university, guangzhou medical university, guangzhou 511436, china 3 the first clinical academy, the first affiliated hospital of guangzhou medical university, guangzhou medical university, guangzhou 511436, china 4 department of organ transplantation, the second affiliated hospital of guangzhou medical university, guangzhou 511436, china 5 department of urology, turin university of studies, italy #these authors equally contributed to the paper *correspondence: department of urology, minimally invasivesurgery center, the first affiliated hospital of guangzhou medical university, guangdong key laboratory of urology. kangda road 1#, haizhu district, guangzhou, china, 510230. telephone: 86-020-34294145. email: wwqwml@163.com. received september 2017 & accepted april 2018 dine could reduce catheter related bladder discomfort after percutaneous nephrolithotomy(7). several cohort studies and meta-analysis have demonstrated the superiority of either ab or am to placebo on alleviating us-related symptoms(8,9,10). however, there are still limited studies to compare the therapeutic effect on us-related symptom between ab and am. to address this issue, we gathered the available prospective randomized controlled studies and conducted a meta-analysisto investigate if a statistically significant difference exist between ab and am monotherapies in releasing us-related symptoms. methods literature search and selection a systematic and comprehensive literature search of onmiscellaneus 307 vol 16 no 03 may-june 2019 308 line databases pubmed (national library of medicine, bethesda, md, us), web of science (thompson scientific, philadelphia, pa, us), embase, and cochrane library was performed to identify randomized controlled trials(rcts) before february 28th,2017. search strategy was as following:(alpha-blocker or α-blocker or tamsulosin) and (antimuscarinic or tolterodine or solifenacin) and (ureteral stent-related symptoms or ureteric stent-related discomfort or srs).meanwhile,references and related articles of clinical studies and reviews were also manually checked. language was limited to english. the therapeutic effects of ab and am on patients with us-related symptoms were examined. we evaluated all search results according to the prisma (preferred reporting items for systematic reviews and meta-analyses) statement(11). the selection of original studies was based on the process of viewing titles, abstracts and full papers. the inclusion criteria were as following:(1) studies focused on patients with us insertion;(2) comparative studies examining effect of ab versus am;(3) rcts studies;(4) comparative studies that reported at least one outcome of interest. non-comparative studies, review articles, abstracts, case reports, editorials, expert opinions, commentary articles, and letters were excluded. data extraction and quality assessment data were extracted independently by two investigators (y.y. gao and h.r. liang) and conflicts were adjudicated by a third investigator (w.q. wu). information about all available variables from selected studies was extracted. ureteric symptom score questionnaire (ussq)(12)including urinary symptom, pain, general health, work performance and sexual performance, international prostate symptom score (ipss), quality of life (qol)[13] and visual analogue pain scale (vaps) were used to evaluate the outcomes. quality assessment was assessed using the jadad scoring(14). statistical analysis standardized mean difference (smd) with 95% ci was calculated for outcomes. cochran’s x2 test and i2 were used to examine the heterogeneity among effect estimates. statistical heterogeneity among studies was defined as i2 statistic greater than 50%. fixed effects model was preferred to random effects model when there was no statistically significant heterogeneity and vice versa when there was significant heterogeneity(15). study bias was detected using the methods of funnel plots and the egger and begger’s test(16). statistical significance was taken as two-sided p < 0.05. the analysis was conducted with stata 12.0 (stata corporation college station, tx, usa) results study selection and quality assessment initially 146 records were screened and 38 additional relevant studies were identified after a hand searching inspection. 153 papers remained after excluding duplicates. after an in-depth review, 9 full-text articles met the inclusion criteria and were considered in the analysis(6,17-24) (figure 1). all of the articles were rct studies with a total of 654 patients. 323 patients were treated with ab monotherapy while 331 were treated with am monotherapy. all studies gained 6 or 7 score in study quality assessment (table 1). ureteric symptom score questionnaire (ussq) ussq was presented for evaluating the us-related symptoms including frequency, urgency, pain, dysuria, comprison of abs and ams in improving usss-yiyang gao et.al. table 1. characteristics of the included studies in the meta-analysis. year design treatment outcomes duration total n α-blocker n antimuscarinic n stent size jadad score 2016 rct tamsulosin 0.4mg qd oxybutynin 5mg qd ussq,qol day 7 34 17 17 24/26cm;6f 3 2016 rct tamsulosin 0.4mg qd solifenacin 5mg qd ussq day 14 87 44 43 24/26cm;6f 3 2016 rct tamsulosin 0.4mg qd solifenacin 5mg qd ussq day 21 117 59 58 24/26/28cm;4.7/6/7f 5 2015 rct tamsulosin 0.2mg qd solifenacin 5mg qd ussq day 14 40 20 20 20/22/24/26/28cm;6f 3 2013 rct terazosin 2mg bid tolterodine 2mg qd ipss,vaps,qol ng 46 23 23 28cm;4.8f 5 2013 rct tamsulosin 0.4mg qd solifenacin 10mg qd ipss,vaps,qol day 14 160 80 80 ng 5 2012 rct doksazosin 4 mgqd tolterodine 4 mg qd ipss,qol ng 42 21 21 26/28cm;4.7f 5 2011 rct tamsulosin 0.2mg qd solifenacin 5mg qd ipss,vaps,qol day 14 88 43 45 24/26cm;6f 3 2009 rct alfuzosin 10mg qd tolterodine 4mg qd ussq day 42 40 20 20 24-28cm;6f 5 table2. summaryswd of ureteric symptom score questionnaire of alpha-blockers versus antimuscarinic. outcomes study number heterogeneity i2(%) statistical method summary swd(%)(95%ci) urinary symptom 5 88.2 random 0.50 [ -0.2,1.20], p = 0.159 pain 5 83.9 random 0.33 [-0.26,0.92], p = 0.280 general health 5 68.9 random 0.34 [-0.08,0.76], p = 0.115 work performance 5 54.9 random 0.29 [-0.05,0.64], p = 0.098 sexual performance 5 20.8 random 0.12 [-0.10,0.34], p = 0.280 incomplete emptying and hematuria. random effects model was used in the five groups. although lower ussq score was noticed in patients using ab compared with am group in all items, urinary symptom (smd 0.5, 95 % ci -0.2 to 1.20, p = 0.159), pain (smd 0.33, 95 % ci -0.26 to 0.92, p = 0.280), general health (smd-0.34, 95 % ci -0.08 to 0.76, p = 0.115), work performance (smd 0.29, 95 % ci -0.05 to 0.64, p = 0.098) and sexual performance (smd 0.12, 95 % ci -0.10 to 0.34, p = 0.280) there is no significant difference (table 2). international prostate symptom score (ipss) the ipss was lower in patients treated with ab monotherapy than in patients treated with am monotherapy in fixed model, but no significantly (smd -0.10, 95 % ci -0.32 to 0.11, p = 0.358), with low heterogeneity (i2 = 9.8%, p = 0.344) (figure 2). quality of life (qol) 6 studies including 370 cases reported qol. fixed model was used. no significant difference was found between ab and am monotherapies (smd-0.03, 95 % ci -0.23 to 0.18, p = 0.802), with no heterogeneity (i2 = 0, p = 0.425) (figure 3). visual analog pain score (vaps) the present meta-analysis in fixed model indicated that the vaps was similar between ab or am (smd 0.08, 95 % ci -0.15 to 0.31, p = 0.447), with low heterogeneity (i2 = 21.8, p = 0.279) (figure 4). publication bias and sensitivity analysis visual inspection of funnel plots suggested there was no obviously asymmetric distribution of main outcomes. begger and egger’s test confirmed there was no significant publication bias (table 3). a sensitivity analysis was performed by excluding the studies with the lowest-quality score. this did not influence the results. discussion to our knowledge, this is the first meta-analysis aimed to evaluate the efficacy of ab and am monotherapies in relieving us-related symptoms. we did not observed statistically significant superiority of ab in overcoming stent-related symptoms compared to am. the analysis suggests that both drugs can effectively treat us-related symptoms. despite a growing number of studies on us-related symptoms, explicit pathophysiology is still matter of debate. lang et al.(25) proposed that us-related pain and urinary symptoms may be the result of ureteric spasm or trigonal irritation. pain and lower urinary tract symptoms (luts) caused by stent could be worsened by the increasing pressure transmitted to the renal pelvis during urination, bladder ischemia and lower ureteric and bladder spasm(26,27). a us may also exacerbate pre-excomprison of abs and ams in improving usss-yiyang gao et.al. outcomes number of estimates p value for begg's test p value for egger's test general health 5 0.806 0.908 urinary symptom 5 0.462 0.572 pain score 5 0.806 0.907 work performance 5 1 0.927 sexual performance 5 0.462 0.457 ipss 4 0.308 0.592 qol 5 0.806 0.588 vaps 3 0.296 0.297 table 3.assessment for publication bias. figure 1. flow diagram detailing the search strategy and identification of studies used in meta-analysis figure 2. . forest plot of international prostate symptom score (ipss) of alpha-blockers versus antimuscarinic miscellaneus 309 vol 16 no 03 may-june 2019 310 isting subclinical detrusor over-activity and induce overactive bladder symptoms(28). ab are the first-line treatment for luts, while am are widely used for the treatment of overactive bladder. both drugs have been applied to treat us-related symptoms in clinical practice. ab could reduce the us-induced pain during voiding probably determining a relaxation of bladder neck/prostatic smooth musculature and consequently reducing voiding pressure and urinary reflux(29). flank pain may be the result of ureter spasm in patients with indwelling us, ab may relieve it by decreasing ureteral spasm and vescico-ureteral reflux(30). ureteral stent symptom questionnaire(ussq), international prostate symptom score (ipps), visual analogue pain score (vaps) and quality of life (qol) are measuring tools used in the included studies about ureteral stent-related symptoms. ussq was designed to characterize urinary symptoms associated with stent including frequency, urgency, pain, dysuria, incomplete emptying and hematuria. ipss was used as frequently as ussq for assessing stent-related symptoms, which was divided into the total score, obstructive symptom score, and irritative symptom score. analogue pain scale graded from 1 (minimal or no symptoms) to 10 (symptoms of maximal severity). in endourological clinical practice, ab are much more commonly used than am to release us-related symptoms. however, our results suggest that am were not significantly inferior in improving us-related symptoms if compared to ab. thus, am can be a valid alternative to ab in this category of patients. this study has some limitations. first, many clinical factors and any underlying ureteral disease would have influenced the outcomes, and different patient characteristics also may have a negative influence on the overall results. second, different types of intra-corporeal lithotripsy and dose difference of medications to patients were not sub-analyzed in our study because of data limitation. third, since majority of included studies reported an insufficient follow-up period, consequently, we were unable to evaluate the outcomes varying from time. conclusions in conclusion, the analysis suggests that ab showed a similar effect with am. although lower ussq and ipss score were noticed in patients using ab compared with am group in all items, but without statistically significant difference, and equally no significant difference were found between ab and am monotherapies in the way of qol and vaps. it is necessary to conduct a larger and more detailed cohort study and find the population that potentially might benefit most by am. references 1. zimskind pd, fetter tr, wilkerson jl. clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically.j urol. 1967;97:840-844. 2. nabi g, cook j, n'dow j, et al. outcomes of stenting after uncomplicated ureteroscopy: systematic review and meta-analysis. bmj.2007;334:572. 3. byrne rr, auge bk, kourambas j, et al. routine ureteral stenting is not necessary after ureteroscopy and ureteropyeloscopy: a randomized trial. j endourol. 2002;16:9-13. 4. beddingfield r, pedro rn, hinck b, et al. alfuzosin to relieve ureteral stent discomfort: a prospective, randomized, placebo controlled study.j urol. 2009;181:170-176. 5. damiano r, autorino r, de sio m, et al. effect of tamsulosin in preventing ureteral stent-related morbidity: a prospective study. j endourol. 2008;22:651-656. 6. kuyumcuoglu u, eryildirim b, tuncer m, et al. effectiveness of medical treatment in overcoming the ureteral double-j stent related symptoms. can urol assoc.2012;6:e234-7. 7. maghsoudi r -, farhadi-niaki s, etemadian m,et al.comparing the efficacy of tolterodine comprison of abs and ams in improving usss-yiyang gao et.al. figure 3. forest plot of quality of life (qol) of alpha-blockers versus antimuscarinic figure 4. forest plot of visual analog pain score (vaps) of alphablockers versus antimuscarinic and gabapentin versus placebo in catheter related bladder discomfort after percutaneous nephrolithotomy: a randomized clinical trial.j endourol.2017 dec 26. doi: 10.1089/ end.2017.0563. [epub ahead of print]. 8. zhou l, cai x, li h, et al. effects of alphablockers, antimuscarinics, or combination therapy in relieving ureteral stent-related symptoms: a meta-analysis.j endourol. 2015;29:650-656. 9. yakoubi r, lemdani m, monga m, et al. is there a role for alpha-blockers in ureteral stent related symptoms? a systematic review and meta-analysis.j urol. 2011;186:928-934. 10. norris rd, sur rl, springhart wp, et al. a prospective, randomized, double-blinded placebo-controlled comparison of extended release oxybutynin versus phenazopyridine for the management of postoperative ureteral stent discomfort. urology. 2008;71:792-795. 11. knobloch k, yoon u, vogt pm. preferred reporting items for systematic reviews and meta-analyses (prisma) statement and publication bias. j cranio maxill surg. 2011;39:91-92. 12. joshi hb, newns n, stainthorpe a, et al. ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. j urol.2003;169:1060-1064. 13. joshi hb, stainthorpe a, keeley fx jr, et al.indwelling ureteral stents: evaluation of quality of life to aid outcome analysis. j endourol.2001;15:151-154. 14. jadad ar, moore ra, carroll d, et al. assessing the quality of reports of randomized clinical trials: is blinding necessary? control clin trials. 1996;17:1-12. 15. higgins jp, thompson sg, deeks jj, et al. measuring inconsistency in meta-analyses. bmj. 2003;327:557-560. 16. seagroatt v, stratton i. bias in meta-analysis detected by a simple, graphical test. test had 10% false positive rate. bmj. 1998;316:470; author reply 470-1. 17. park sc, jung sw, lee jw, et al. the effects of tolterodine extended release and alfuzosin for the treatment of double-j stent-related symptoms. j endourol. 2009;23:1913-1917. 18. lim kt, kim yt, lee ty, et al. effects of tamsulosin, solifenacin, and combination therapy for the treatment of ureteral stent related discomforts. korean j urol. 2011;52:485-488. 19. shalaby e, ahmed af, maarouf a, et al. randomized controlled trial to compare the safety and efficacy of tamsulosin, solifenacin, and combination of both in treatment of double-j stent-related lower urinary symptoms. adv urol. 2013;2013:752382. 20. tehranchi a, rezaei y, khalkhali h, et al. effects of terazosin and tolterodine on ureteral stent related symptoms: a double-blind placebo-controlled randomized clinical trial. int braz jurol. 2013;39:832-840. 21. park j, yoo c, han dh, et al. a critical assessment of the effects of tamsulosin and solifenacin as monotherapies and as a combination therapy for the treatment of ureteral stent-related symptoms: a 2 x 2 factorial randomized trial. world j urol. 2015;33:1833-1840. 22. abdelaal am, al-adl am, abdelbaki sa, et al. efficacy and safety of tamsulosin oralcontrolled absorption system, solifenacin, and combined therapy for the management of ureteric stent-related symptoms. arab j urol. 2016;14:115-122. 23. el-nahas ar, tharwat m, elsaadany m, et al. a randomized controlled trial comparing alpha blocker (tamsulosin) and anticholinergic (solifenacin) in treatment of ureteral stentrelated symptoms. world j urol. 2016;34:963968. 24. maldonado-avila m, garduno-arteaga l, jungfermann-guzman r, et al. efficacy of tamsulosin, oxybutynin, and their combination in the control of double-j stentrelated lower urinary tract symptoms. int braz jurol.2016;42:487-493. 25. lang rj, davidson me, exintaris b. pyeloureteral motility and ureteral peristalsis: essential role of sensory nerves and endogenous prostaglandins.exp physiol. 2002;87:129-146. 26. siggers jh, waters s, wattis j, et al. flow dynamics in a stented ureter. math med biol. 2009;26:1-24. 27. camoes j, coelho a, castro-diaz d, et al. lower urinary tract symptoms and aging: the impact of chronic bladder ischemia on overactive bladder syndrome. urol int. 2015;95:373-379. 28. joshi hb, okeke a, newns n, et al. characterization of urinary symptoms in patients with ureteral stents. urology. 2002;59:511-516. 29. wang cj, huang sw, chang ch. effects of specific alpha-1a/1d blocker on lower urinary tract symptoms due to double-j stent: a prospectively randomized study. urol res. 2009;37:147-152. 30. davenport k, timoney ag, keeley fx, jr. effect of smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study. urol res. 2007;35:207-213. comprison of abs and ams in improving usss-yiyang gao et.al. miscellaneus 311 may-june 2018 reviewer of the issue sherri m. donat sherri m. donat june 2018 sherri m. donat, md, facs is an urologic oncologist who specializes in medical and surgical treatment of genitourinary cancers. dr. donat completed her undergraduate studies and medical degree at the university of oklahoma health sciences center in oklahoma city, oklahoma. she completed her general surgery and urology residency at the university of oklahoma and then her fellowship training in urologic oncology at memorial sloan kettering cancer center in new york city. following completion of her fellowship training she was on staff at m. d. anderson cancer center in houston texas where she served as an assistant professor of urology for three years treating all types of genitourinary cancers. dr. donat then moved back to memorial sloan kettering cancer center in 1996 where she remains today as an attending surgeon in urology and as a professor of urology at new york hospital weill cornell medical college in new york city. dr. donat has focused both her research and institutional activities on the improvement of perioperative care and outcomes for patients undergoing major gu oncologic surgeries. the centerpiece of her career at mskcc has been the establishment of evidence based patient care pathways (eras) for the five major surgical procedures performed by the urology service at mskcc in 1996 including radical prostatectomy, radical and partial nephrectomy, radical cystectomy, and retroperitoneal node dissection, which are continually updated as new evidentiary data is published or if we determine changes need to be implemented based on automated quarterly morbidity/mortality reports. for the past several years, her academic research efforts have been centered on raising awareness of the need and benefits of accurate adverse event reporting to establish an international standard for reporting surgical morbidity in urologic oncology. in collaboration with our european colleagues her proposed reporting surgical complications methodology for urologic procedures has been accepted internationally and culminated in the establishment of surgical reporting guidelines by the european urologic association (eur urol. 2012 feb;61(2):341-9), for which she served as an external advisor, as well as the establishment of guidelines for authors reporting surgical experiences in the major urologic peer review journals including j urol, urology, british j urol and european urology for which she also serves as a reviewer. in addition, she served as an advisor to the the international minimally invasive society, for the creation of the international database for open and robotic radical cystectomy that has facilitated the comparison of surgical series and outcomes. she has written 97 peer reveiw publication, multiple chapters, as well as serving as a course director and session moderator at the aua national meeting, abstract reveiwer for the aua and eua meetings, as well as making multiple presentations at national and international forums. in addition, on a national level, she has been appointed to leadership roles in the american urological association (aua) serving as a member of the aua quality assurance and patient safety committee and the aua data committee, and as the chair of aua national guideline committee for follow-up of renal neoplasm’s, all of which are centered around establishing guidelines, quality measures, and methodologies for accurate data collection and measurement related to improving quality of patient care on a national level. she has also played an integral role in national and international activities, including the progress review group for bladder and renal cancer at the nci/nih, the society of international urology guidelines panel bladder preservation committee, and contributes time and expertise to the austrian american foundation/esu master class and eua in an effort to improve the quality of surgical care globally. careful and fair-minded evaluation of scientific articles is an important scholarly contribution and a gratifying duty in academics. peer review is a vital process for any journal and enables publication of innovative research that meets the highest standards of quality. dr. cheh was chosen by editorial board of the urology journal for his valuable and timely review of manuscript”. pediatric urology the prevalence of diurnal urinary incontinence and enuresis and quality of life: sample of school sevim savaser1, nezihe kizilkaya beji2, ergul aslan3*, duygu gozen4 purpose: enuresis can cause loss of self-esteem in children, change relations with family and friends, and decrease the school success. this study was conducted to determine the prevalence of urinary incontinence (ui) in school children aged between 11-14 years and identify the emotions and social problems of enuretic children. materials and methods: a mixed methods approach was used on a group of students who reported ui by combining quantitative data from school population-based cross-sectional design with qualitative data using in-depth interview techniques. the data of this descriptive and cross-sectional study were collected from 2750 primary school students aged between 11-14 years in istanbul. results: the overall prevalence of ui was 8.6% and decreased with age. prevalence of the diurnal enuresis in children was 67.9% and all of them had non-monosymptomatic enuresis. 83.3% of the children were identified with secondary enuresis for 1-3 years. ui was significantly more common in boys and those who had frequent urinary infections, whose first degree relatives had urinary incontinence problem in childhood, and who reported low socioeconomic level in the family. the emotional and social effects of urinary incontinence were given in the context of children's own expressions. conclusion: urinary incontinence is an important problem of school-age children. in this study the prevalence of ui was found to be 8.6%, diurnal ui and secondary enuresis were very common, and all of the children were non-monosymptomatic. enuresis has negative emotional and social effects on children. keywords: child; urinary incontinence; enuresis; epidemiology; quality of life; risk factors; schools. introduction urinary incontinence is the involuntary leakage of urine that may occur as “continuous” or “intermittent”. intermittent incontinence is the leakage of urine in discrete amounts. the subgroups of intermittent incontinence are diurnal incontinence and enuresis. diurnal incontinence occurring while the person is awake is identified as intermittent incontinence(1). enuresis is among the most common conditions in childhood(2). the international children’s continence society defines enuresis as bed-wetting while asleep/nocturnal incontinence after five years(1). the enuresis has two types. the non-monosymptomatic enuresis is characterized by symptoms of diurnal incontinence, sudden jamming, incontinence before catching up on the toilet, and intermittent voiding and straining during voiding and nocturnal enuresis. the nocturnal incontinence without other symptoms is defined as “monosymptomatic enuresis”. the primer enuresis is described as the fact that the child has never been able to control urine. the secondary enuresis signifies that the child had controlled urine for at least 6-month dry period after 5 years of age. it is important to identify enuresis type for management(1,3). primary enuresis accounts for 80-90% of all enuretic cases(4), toilet training is never achieved, and genetic 1department of child development, biruni university faculty of health sciences, istanbul, turkey. 2department of nursing, biruni university faculty of health sciences, istanbul, turkey. 3department of women health and diseases nursing, florence nightingale faculty of nursing, istanbul university, istanbul, turkey. 4department of pediatric nursing, florence nightingale faculty of nursing, istanbul university istanbul, turkey. *correspondence: department of women health and diseases nursing, florence nightingale faculty of nursing, istanbul university, istanbul, turkey. tel : +(90) 212 440 00 00 – 27030. fax : +(90) 212 224 49 90. e-mail : ergul34tr@hotmail.com / e.aslan@istanbul.edu.tr. received may 2017 & accepted november 2017 disposition and biological and developmental factors play a major role(3). in secondary enuresis, the child resumes wetting after at least six months of dryness. secondary enuresis is suggested to be often triggered by psychological factors(3,4). related studies have revealed that the prevalence of intermittent incontinence is 3.2-9.0 % and the prevalence of diurnal incontinence is 1.8-9.0 % among 7 year-old children. the prevalence of intermittent incontinence is 1.1-12.5 % and the prevalence of diurnal incontinence is 0.9% in 11-13 year old children(5). studies have showed that 5-7 million children aged 7 or over are affected by enuresis and its prevalence increases in boys and with family history of enuresis(6). it is reported that prevalence decreases with age(6,7) and decreases to 1-3% at the age of 15(8). while enuresis does not result in serious physical discomfort in childhood, it is a problem with adverse effects on the quality of life among many children and their parents due to its social and psychological results(9,10). the aim of this study was to determine the prevalence of diurnal ui and enuresis in children aged between 1114 years and evaluate the emotional and social effects of enuresis on a group of students, who reported enuresis, by using in-depth interview methods. vol 15 no 04 july-august 2018 173 materials and methods study design this is a mixed methods study. the data were collected using “descriptive questionnaire form” for the first stage of this descriptive and cross-sectional study. for the study, written approvals were obtained from the ethics committee of iu (irb approval number: 26211); the governorship of city; and the provincial national education authority (irb approval number: 120). in the second stage, the data were collected from primary enuresis cases who reported ui, were voluntary to participate in the study, and met dsm-v diagnosis criteria for enuresis, which is among qualitative research methods(11). the population of the study the population of the study consisted of the 5th, 6th, 7th and 8th-graders of public primary schools in istanbul. the sample size of the study was determined by using the calculation formula of the sample size (n = t2xp x q/d2). prevalence (p) was taken 13%(12) as a mean value, acceptable sampling error was d = .03, and minimum sample size was determined as n = 483 for each grade. it was determined that a total of 1932 students must be contacted for the sample group, as a minimum requirement. the cluster sampling method for simple randomization was used to determine the schools where the data would be collected. each school was considered a cluster and the mean number of students in each grade of primary schools located in istanbul was assumed to be 30. when taking any possible data loss into consideration, it was ascertained that it was required to include students from 73 classes (target number-2200 / 30-size of class) and those 73 classes must be selected from 18 primary schools. in the first stage, 18 districts were chosen out of 32 districts in istanbul by drawing lots. the data were collected from the students studying in branch a of 5th, 6th, 7th and 8th grades of 18 schools (figure 1). first stage: the questionnaire was distributed to the students in each of the designated schools within the same day and was completed in a classroom setting. all voluntary students were enrolled in the study. evaluation was made over 2750 forms. the forms were filled by voluntary students in the classroom except for the course. second stage: the effect of enuresis on the quality of life was evaluated using in-depth interview technique as a qualitative research method on a group of students who reported enuresis. the interviews were conducted by one of the researchers with 16 students reporting ui in a quiet room at the school by incorporating themes associated with enuresis-related emotional and social problems in children. among these 16 students who were interviewed, 11 were girls and 5 were boys. data collection after the questionnaire was prepared based on relevant literature and submitted to 6 faculty members for remarks to ensure the content validity, a pilot study was conducted with 20 students from 5th, 6th, 7th and 8th grades and the questionnaire was finalized. the questionnaire including a total of 37 questions was designed to obtain information about sociodemographic characteristics of the students. the questionnaire involves the students’ age, gender, class, parents’ educational level, income level of family, individuals with whom they lived together, number of siblings. in terms of general health; diseases, medications, smoking, constipation, fluid intake, the habit of going to the toilet, urinary complaints, and the presence of urinary incontinence are asked. the effect of urinary incontinence on daily life is evaluated by the visual analogue scale. during in-depth interviews, semi-structured questionnaire was used. the interviews were recorded on tape and then transcribed. this questionnaire involved 5 basic questions. these questions were as follows: what do you feel because of enuresis?, what do you when you recognize leakage of urine ?, what do you do to cope with ui?, does ui affect the daily life?, and how do the surroundings react to ui? statistical analysis the data were analyzed by using spss 22.0 packaged software. the value of p < .05 was considered as statistically significant. mean, sd, percentage, pearson's chisquare test, and logistic regression analysis were used for analysis. audio records of the in-depth interviews were transcribed and coded, and descriptive and content analyses were used. the collected data were divided into two thematic groups. results the data gathered through the questionnaire the mean age of 2750 children was 12.53 ± 1.12 (range: 11-14), 50.3% were boys and 26.3% were 14 years old. it was found that 43.1 % of the mothers of the children were primary school graduates and 76.9 % were unemployed. 33.8 % of their fathers were primatable 1. distribution of ui characteristics of children (n=2750). characteristics n % urinary incontinence no 2513 91.4 yes 237 8.6 time of ui day time 161 67.9 nighttime 40 16.9 day and night 36 15.2 primer enuresis 29 34.9 secondary enuresis 54 65.1 figure 1. flow diagram of the study urinary incontinence in school children-savaser et al. pediatric urology 174 ry school graduates and 51.5 % of the families stated that their income status was high. 92.7 % of the students were living together with their both parents. the most of the students had a high school performance in previous year (67.8 %). it was found that there was no statistically significant difference within the study group in terms of distribution of gender (p = .73) and age (p = .09). table 1 shows the incidence of urinary incontinence of the participants. it was determined that 8.6% of the children had ui based on their own personal statements. all participants in enuresis group were non-monosymptomatic. it was determined that 83.3% of the children with enuresis had secondary enuresis for 1-3 years. table 2 shows the comparison of urinary incontinence data within the sample group by demographic and other characteristics. as is seen from table 2, there was a statistically significant decrease in the prevalence of enuresis with age (p < .001), enuresis was more common among males (p = .01), and the number of enuretic children was statistically significantly higher than expected in children of mothers (p < .001) and fathers (p < .001) with low educational level, in children whose mother was employed (p < .001), whose school performance was low (p < .001), and whose family income status was low (p < .001). the number of enuretic children was lower in the group of children living with their both parents (p < .001). in addition, it was determined that the prevalence of childhood enuresis was significantly high (p < .001) in the immediate family of children who reported urinary incontinence. as is seen in table 3, it was determined that enuresis table 2. comparison of urinary incontinence data within the sample group by demographic and other characteristics (n = 2750). characteristics incontinent continent *p-value n % n % age 11 73 30.8 574 22.8 12 63 26.6 654 26 < .001 13 60 25.3 603 24 14 41 17.3 682 27.2 gender 99 41.8 1267 50.4 .01 female male 138 58.2 1246 49.6 mother’s educational level illiterate 26 11.2 128 5.1 literate 15 6.4 76 3.1 primary school 105 45.1 1079 43.4 < .001 secondary school 30 12.9 409 16.4 high school 45 19.2 574 23.1 college 12 5.2 221 8.9 father’s educational level illiterate 7 3 23 .9 literate 10 4.3 71 2.9 primary school 86 36.9 844 34.1 < .001 secondary school 58 24.9 473 19.1 high school 43 18.5 705 28.5 college 29 12.4 360 14.5 income status of family high 101 42.6 1314 52.4 middle 103 43.5 1113 44.4 < .001 low 33 13.9 79 3.2 previous year’s school performance high (certificate of merit/achievement) 135 57 1646 65.5 < .001 medium (pass) 77 32.5 727 29 low (conditional pass/repeat) 25 10.5 138 5.5 mother’s employment status employed 72 30.8 552 22 < .001 unemployed 162 69.2 1952 78 lives with both parents 207 87.3 2341 93.2 one of the parents 18 7.6 112 4.5 < .001 other family members 12 5.1 58 2.3 immediate family history yes 107 45.1 < .001* no 130 54.9 2513 100 p = pearson's chi-squared test * fisher’s exact test characteristics incontinent continent *p-values n % n % frequent urinary infection yes 24 10.1 60 2.4 < .001 no 213 89.9 2453 97.6 constipation yes 60 25.3 149 5.9 < .001 no 177 74.7 2364 94.1 the use of school toilet yes 131 55.3 1572 62.6 .03 no 106 44.7 941 37.4 p = pearson's chi-square test table 3. distribution and comparison of urinary incontinence by some characteristics (n = 2750). urinary incontinence in school children-savaser et al. vol 15 no 04 july-august 2018 175 was more common among children who reported frequent urinary infections (p < .001), constipation (p < .001) and school toilet avoidance (p = .03). in the study, a logistic regression model which contained risk factors associated with urinary incontinence in children aged between 11-14 years was prepared. table 4 shows the variables which posed a significant risk in the forward propagation multivariate logistic regression analysis compared to the reference. in the regression analysis, it was determined that enuresis risk was significant for younger children (3.05 times higher at the age of 11 compared to 14), children who reported lower maternal educational level (2.46 times higher compared to high school and college graduates), children of employed mothers (1.55 times higher compared to those of unemployed mothers), children with low school performance (2.19 times higher compared to those with high performance), children not living with their parents (1.92 times higher compared to those living with their parents), children from families with low income status (4.27 times higher compared to those from families with high economic status), children reporting frequent urinary infections (1.83 times higher compared to those not reporting frequent urinary infections), and children reporting constipation (4.66 times higher compared to those not reporting constipation). mean scores of the students, who reported urinary incontinence to the question “how much does urinary incontinence affect your daily life”, was 2.95 ± 2.73 (median = 3, mode = 0) in the visual analogue scale (vas: 0 to 10 0: doesn’t affect al all, 10: affects pretty much). children were grouped and evaluated as follows; those who marked 0 on the scale were not affected by urinary incontinence in daily life; those who marked 1, 2, and 3 were slightly affected; those who marked 4, 5, and 6 were moderately affected; and those who marked 7, 8, 9, and 10 were considerably affected. it was determined that two thirds of enuretic children stated that their daily life was slightly (36.1%) and moderately (25.8%) affected by enuresis. the data on emotional effects of urinary incontinence: during the interviews, almost all of the children answered the question “what do you feel when you have leakage of urine?” by using the expressions such as embarrassment, worry, downheartedness. the data on social effects of urinary incontinence: the majority of the children answered the question “does your problem of urinary incontinence have any effect on your daily life? how?” by stating that their daily life was affected by this problem and they took some measures including taking a change of clothes with them and avoiding drinking water or tea etc. discussion continence problems in children can persist into later childhood and have a serious effect on quality of life. number of studies on its causes and impact is scarce and useful resources are limited(13). the statistical results obtained due to large size of the sample were thought to be significant in terms of urinary incontinence and the associated factors in the study. the review of the literature showed that data in studies conducted to identify emotions and social problems of enuretic children were usually collected from mothers(10,14). the strength of this study is that it determined the effect of urinary incontinence on emotional and social life of children through in-depth interviews. limitation of the study is that the data on factors thought to be associated with urinary incontinence were collected only from children. it is thought that this study is significant and original since the data of the study were collected from epidemiologic studies obtained from children, the sample size can be regarded as sufficient and emotions of the children reporting urinary incontinence were tried to be determined through in-depth interviews. this study revealed that the prevalence of ui was 8.6%, significantly higher in boys, and decreased with age. in the study conducted by dirim et al., with school children, they identified urine problems at the rate of 7.2%(15). in the several studies, diurnal ui frequencies showed a difference between 1.8% and 49%(5). the wide range of frequencies is associated with difference in ui definition criteria and difference in data collection table 4. risk factors associated with urinary incontinence based on the logistic regression analysis (n = 2750). associated factors 95% cl (or) b s.e. df. sig. (p) exp. (b) lower upper age 14 (reference) 13 .72 .22 1 < .001 2 .06 1.33 3.19 12 .76 .23 1 < .001 2.13 1.36 3.35 11 1.12 .23 1 < .001 3 .05 1.96 4.75 mother’s educational level high school and ↑ (ref.) primary .25 .18 1 .16 1.29 .90 1.83 l or il* .90 .25 1 < .001 2.46 1.51 3.99 mother’s employment status unemployed (ref.) employed .44 .16 1 < .001 1.55 1.13 2.14 school performance high (ref.) medium .23 .17 1 .17 1.26 .91 1.75 low .78 .27 1 <.001 2.19 1.29 3.70 household parents together (ref.) either parent or other .65 .23 1 < .001 1.92 1.23 2.99 relatives income status of family high (ref.) medium .08 .16 1 .61 1.08 .80 1.47 low 1.45 .26 1 < .001 4.27 2.57 7.07 frequent urinary i no (ref.) nfections yes .61 .29 1 .04 1.83 1.03 3.25 constipation no (ref.) yes 1.54 .19 1 < .001 4.66 3.21 6.77 constant -.50 .19 1 < .001 .61 * l = literate, il = illiterate urinary incontinence in school children-savaser et al. pediatric urology 176 methods with different samples(16). studies indicate a wide range between 3.1-24.4% for the prevalence of enuresis. its prevalence usually seems to decrease with age and enuresis is more common among boys in early school years compared to girls (17,18). prevalence of enuresis was determined to be 10.517.5% in turkey(8,12). diurnal ui was more frequent in the present study, as well. enuresis is a clinical condition of multifactorial etiology that leads to difficulties in social interaction of the child(19). many studies report that enuretic children have a family history of enuresis at a high rate (ec)(6,20,21), and the rate of positive family history is between 40.7-76.5 in turkey(22). the enuresis rate was found to be 45.1% among immediate family members in this study, which is compatible with associated literature. in the study conducted by fagundes on treatment of 82 patients with enuresis, 91.1% had a family history of enuresis in first-/second-degree relatives, 89.3% had constipation and 40.7% had mild-to-moderate apnea(23). role of sleep disorders is controversial in enuresis(21, 23). wille et al.,(24) reported that 60% of ec experienced the problem of deep sleep and 75% of children with nocturnal enuresis had difficulty in waking up. akbaba(25) determined that the prevalence of enuresis was 1.8 times greater in sound sleepers than light and moderate sleepers. one thirds (32.9%) of children who reported ui in this study stated that they wetted their bed because they were sound sleepers. zaffanello et al., expressed that the symptoms of snoring, sleep apnea, and restless sleep were examined for the children with enuresis in their systematic review study. in the same systematic review, zaffanello et al., suggested immediate treatment for obstructive sleep and irregular breathing(26). it was determined that the prevalence of enuresis was 4.27 times greater in children with a low socioeconomic status than children with a higher socioeconomic status(12). in addition to trials showing a higher prevalence among children of families with lower maternal educational level, there are trials which confirm the inexistence of such relation(6,12). the incidence of enuresis was higher among mothers’ educational levels in this study. the studies in the literature have shown that environmental factors including poor living conditions to which the child is exposed, suffered traumas, etc. are among psychosocial risk factors(13) contributing to enuresis and enuresis is more common particularly among children of broken families(4,17). in the present study, the prevalence of enuresis is higher among ec living with either parent/relatives compared to ec living with both parents. it is reported that the presence of enuresis in a child creates a vicious circle of decreased self-confidence, social avoidance, and lower school performance(9). in their studies involving 2984 children aged between 6-18 years, gorur et al.,(21) determined that problems in friend relationships and low school performance were significantly common in the enuretic group. although it was reported that enuresis was accompanied by urinary tract infections and constipation(21), such accompaniment was not fully clear. one study revealed that the rate of coexistence of enuresis and constipation was 31% (27), and another study determined a relationship between enuresis and urinary tract infections(25). the present study revealed higher enuresis rates in children reporting constipation and in children reporting frequent urinary infections. it is stated that ec may experience lack of self-confidence and self-esteem if they are not treated until school age when social circle widens(23). in this study, the result indicating that low percentage of subjects seeking medical treatment for enuresis among those who reported ui is compatible with the literature. when taking high rate of family history into consideration, this result may be interpreted as parents’ being inured to and ignoring the problem. discussion of the data collected with in-depth interviews bower(28) revealed that children with ui symptoms experienced the feelings of inferiority, irritability and embarrassment more frequently, the quality of life impaired with failed treatment, and the aspects in which children are affected the most are self-confidence, independence, and mental health, respectively. in a previous study, it was showed that 65% of ec were unhappy(29). morison(30) identified that the majority of bedwetting children were embarrassed and worried because of their bedwetting problem, and especially those with perceived hopelessness were less engaged in treatment and lost heart in a short time. when associated studies are reviewed, it is seen that bedwetting children develop more negative feelings than those not bedwetting(20), level of self-esteem in bedwetting children are lower than the general population(9), and psychological problems slightly increase in the case of ec(17,29), whereas a study comparing ec with healthy children showed no psychological difference between the enuretic and non-enuretic groups(29). during in-depth interviews made in the present study, all of ec expressed embarrassment, sadness, inconvenience, fear of being exposed to peers; and almost all of them expressed dispiritedness/unhappiness and fear of being mocked and teased. in addition, there were children who expressed anger, guilt, fear of drawing peers away / being left alone, smelling of urine and staining their clothes, and negative feelings arising from this problem. children stated that they did not accept sleepover invitations because of enuresis, they experienced problems and fear of wetting themselves during school trips, vacations or travels, and, therefore, their participation in overnight activities was limited, and, if they participated, they would change underwear and clothes, they would not drink water, tea, etc. at night, they would visit the bathroom frequently, and they would not sleep well. it is reported that parents are concerned about the effect of enuresis on their child’s social and emotional development(7,14), however, most children are frustrated in response to attending to one’s hygiene and do more laundry(23,29). parents need to be reassured that bedwetting is not due to a child’s laziness but beyond his/her control(3,30). it is argued that a child’s management of bedwetting must be individually addressed(20,23,26). conclusions in the present study, it is suggested that urinary incontinence is very important health problem in school-age child. to reduce the complaints of this multi-factor problem, the first option can be description and well management of risk factors. in this study, the prevalence urinary incontinence in school children-savaser et al. vol 15 no 04 july-august 2018 177 of ui was found to be 8.6%, diurnal ui and secondary enuresis were very common and all children were non-monosymptomatic. ui became less common with age, and considerably high in boys and those who reported frequent urinary infections, history of childhood enuresis among their immediate family members and a low socio-economic status. enuresis have negative emotional and social effects in school children. school and field screening programs should be conducted with school-age children and information should be gathered from children and parents for diagnosing undisclosed ui in the society, and guidance should be provided about the optimal treatment of children with ui. acknowledgement this study was supported by the support program for scientific and technological research projects of tubitak (program code: 1001 project no: 107s062). conflicts of interest the authors declare no conflict of interest. references 1. austin pf, bauer sb, bower w, et al. the standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the international children's continence society. neurourol urodyn. 2016; 35: 471-1. 2. butler rj, heron j. the prevalence of infrequent bedwetting and nocturnal enuresis in childhood: a large british cohort. scand j urol nephrol. 2007; 42: 1-8. 3. ball jw, bindler rc. child health nursing: partnering with children and families. new jersey: upper saddle river; 2006. p.1189-2. 4. barroso u, dultra a, de bessa j, et al. comparative analysis of frequency of lower urinary tract dysfunction among institutionalized and non-institutionalized children. bju international. 2006; 97: 813-5. 5. milsom i, altman dr, cartwright mc, et al. committee 1. epidemiology of urinary incontinence (ui) and other lower urinary tract symptoms (luts), pelvic organ prolapse (pop) and anal incontinence (ai). in: abrams b, cardozo l, khoury s, et al. editors. incontinence consultation book. 5th ed. paris: eau; 2013, p.18-5. 6. hansakunachai t, ruangdaraganon n, udomsubpayakul u, sombuntham t, kotchabhakdi n. epidemiology of enuresis among school age children in thailand. j dev behav pediatr. 2005; 26: 356-0. 7. butler rj. childhood nocturnal enuresis: developing a conceptual framework. clin psychol rev. 2004; 24: 909-31. 8. ozden c, ozdal ol, altinova s, oguzulgen i, urgancioglu g, memis a. prevalence and associated factors of enuresis in turkish children. int braz j urol. 2007; 33: 216-2. 9. redsell sa, collier j. bedwetting, behaviour and self esteem: a review of the literature. child care health dev. 2001; 27: 149-62. 10. meydan ea, civilibal m, elevli m, duru ns, civilibal n. the quality of life of mothers of children with monosymptomatic enuresis nocturna. int urol nephrol. 2011; 44: 655-9. 11. american psychiatric association. diagnostic and statistical manual of mental disorders. 5th ed. arlington, va: american psychiatric publishing; 2013. 12. abali o, onur m, gurkan k, celik o, tuzun du. enuresis nocturna among school age children and its evaluation according to sociodemographic data. turkish journal of child and adolescent mental health. 2006; 13: 49-3. 13. joinson c. childhood incontinence: risk factors and impact. nurs times. 2016; 112: 15-6. 14. sarici h, telli o, ozgur bc, demirbas a, ozgur s, karagoz ma. prevalence of nocturnal enuresis and its influence on quality of life in school-aged children. j pediatr urol. 2016; 12: 1-6. 15. dirim a, aygün yc, bilgilisoy ut, durukan e. prevalence and associated factors of daytime lower urinary tract dysfunction in students of two primary schools of turkey with different socioeconomic status. turkiye klinikleri j urology. 2011; 2: 1-6. 16. yüksel s, yurdakul aç, zencir m, çördük n. evaluation of lower urinary tract dysfunction in turkish primary school children: an epidemiological study. j pediatr urol. 2014; 10: 1181-6. 17. lee sd, sohn dw, lee jz, park nc, chung mk. an epidemiological study of enuresis in korean children. bju int. 2000; 85: 869-3. 18. butler rj, golding j, northstone k, the alspac study team. nocturnal enuresis at 7.5 years old: prevalence and analysis of clinical signs. bju int. 2005; 96: 404-10. 19. fagundes sn, soster la, lebl as, et al. impact of a multidisciplinary evaluation in pediatric patients with nocturnal monosymptomatic enuresis. pediatr nephrol. 2016; 31: 1295303. 20. culbert tp, banez ga. wetting the bed: integrative approaches to nocturnal enuresis. the journal of science and healing. 2008; 4: 215-20. 21. gorur s, inandi t, turhan e, helli a, kiper an. the prevalence and risk factors of enuresis in children aged between 6 and 18 years in hatay. turkish journal of urology. 2008; 34: 42-50. 22. ozkan ku, garipardic m, toktamis a, karabiber h, sahinkanat t. enuresis prevalence and accompanying factors in school children: a questionnaire study from urinary incontinence in school children-savaser et al. pediatric urology 178 southeast anatolia. urol int. 2004; 73: 14955. 23. fagundes sn, lebl as, soster la, et al. monosymptomatic nocturnal enuresis in pediatric patients: multidisciplinary assessment and effects of therapeutic intervention. pediatr nephrol. 2017; 32: 843-51. 24. wille s. nocturnal enuresis: sleep disturbance and behavioral patterns. acta paediatr. 1994; 83: 772-6. 25. akbaba m, kis su, sutoluk z, demirhindi h, ozdener oe, kis c. the prevalence and causes of enuresis nocturna in a regional dormitory school. taf prev med bull. 2008; 7: 213-6. 26. zaffanello m, piacentini g, lippi g, fanos v, gasperi e, nosetti l. obstructive sleepdisordered breathing, enuresis and combined disorders in children: chance or related association? swiss med wkly. 2017; 147: w14400. 27. hellerstein s, linebarger js. voiding dysfunction in pediatric patients. clin pediatr. 2003; 42: 43-9. 28. bower wf. self-reported effect of childhood incontinence on quality of life. j wound ostomy continence nurs. 2008; 35: 617-21. 29. butler rj. impact of nocturnal enuresis on children and young people. scand j urol nephrol. 2001; 35: 169-76. 30. morison mj. parents’ and young people’s attitudes towards bedwetting and their insurance on behaviour, including readiness to engage in and persist with treatment. br j urol. 1998; 81 suppl 3: 56-66. urinary incontinence in school children-savaser et al. vol 15 no 04 july-august 2018 179 therapeutic and preventive effects of aqueous extract of date palm (phoenix dactylifera l.) pits on ethylene glycol-induced kidney calculi in rats pouria mohammadparast tabas1, hamed aramjoo1, ali yousefinia1, mahmoud zardast2, mohammad reza abedini3 & 4, mohammad malekaneh5* purpose: urinary tract stones are one of the most common diseases in the urinary tract. lack of kidney stone treatment causes irreparable damages to the kidneys, which has many harmful effects. date palm pits are recommended in traditional medicine as an effective drug in the treatment of kidney stones. the aim of this study was to investigate the effect of aqueous extract of date palm pits on kidney stones induced by ethylene glycol in male rats. methods: in this study, 40 rats were classified into five groups (n = 8), including the healthy group receiving normal water, the negative control group, the therapeutic groups with doses of 150 mg/kg and 300 mg/kg, and the prevention group with a dose of 300 mg/kg. in order to induce kidney stones, ethylene glycolated water (1%) was used as drinking water in the studied groups. blood and urine of rats were collected on days 14 and 28 of the study to assess urinary parameters of calcium, creatinine, uric acid and phosphorus, and serum parameters of blood urea nitrogen, creatinine, uric acid, calcium, and phosphorus. also, the kidneys of rats were removed from the body on day 28 of the study and were given to a pathologist for examination. results: results of serum parameters show that the use of date palm pits extract in the treatment and prevention groups with a dose of 300 mg/kg significantly (p < .05) has reduced the levels of blood urea nitrogen, uric acid, calcium, creatinine, and phosphorus. also, the results of urinary parameters show that the use of the extract caused a significant decrease (p < .05) in creatinine, uric acid, and calcium in the prevention group and a significant decrease (p < .05) in creatinine and uric acid in the therapeutic group with a dose of 300 mg/kg. pathological results show a decrease in the number and size of calcium oxalate crystals in renal tubules in the treatment and prevention groups in a dose-dependent manner. conclusion: the results of this study showed that the use of aqueous extract of date palm pits has been effective in the treatment and prevention of kidney stones induced by ethylene glycol in rats. keywords: calcium oxalate; date palm pits; ethylene glycol; kidney calculi; rat introduction kidney stone (ks) is the most common urinary tract disease due to urinary tract infections and prostate disorders. kss are formed from organic and inorganic crystals in combination with protein(1). about 80 percent of kidney stones are calcium stones, which are composed of a combination of calcium oxalate (caox) and calcium phosphate(2). the prevalence of ks has been increasing globally over the last three decades. as this prevalence has increased, we have also seen an increase in the expenses associated with this disease. by 2030, the united states is expected to spend more than $ 5 billion a year to treat patients with kss(3). ks formation is associated with a variety of factors including lifestyle, race, genetic background (heritability of ~45-60%), gender, and diet. underlying dis1student research committee, birjand university of medical sciences, birjand, iran. 2cardiovascular diseases research center, birjand university of medical sciences, birjand, iran. 3chronic disease program and regenerative medicine program, ottawa hospital research institute, ottawa, canada. 4cellular and molecular medicine research center, department of pharmacology, birjand university of medical sciences, birjand, iran. 5department of clinical biochemistry, birjand university of medical sciences, birjand, iran. *correspondence: associate professor of biochemistry, department of clinical biochemistry, school of medicine, birjand university of medical sciences, birjand, iran. email: drmalekaneh21@gmail.com. received october 2020 & accepted june 2021 eases such as diabetes, obesity and inactivity, gout, hyperparathyroidism, hyperoxaluria, increased calcium, and changes in urine ph play an important role in the formation of ks(4-6). people suffering from kss have severe colic pain, and on the other hand, obstruction caused by these stones reduces the urine output and, in some cases, hematuria, and if left untreated, can lead to kidney damage, kidney failure, and urinary tract infections(7). there are currently several methods to remove kss; supportive methods such as fluid intake and the use of analgesics to remove stones spontaneously and in the case of larger stones, methods such as chemically dissolving stones, removing stones from the urethra, breaking stones with ultrasonic waves and, if necessary, open surgery could be used. in addition to many side effects such as urinary tract infections, tissue damage and the possibility of stone re-formation can impose many urology journal/vol 18 no. 6/ november-december 2021/ pp. 612-617. [doi: 10.22037/uj.v18i.6530] endourology and stone disease costs on the patient(8,9). nowadays, considering the side effects and severe detrimental effects of chemical drugs, the use of herbal and natural medicines has been considered by contemporary researchers, and in several studies, the effects of various herbs in the treatment of kidney stone disease have been studied(10,11). monocotyledonous date palm tree belongs to the arecaceae or palmae family is from the phoenix genus with the scientific name phoenix dactylifera. date palms are grown in desert areas, especially in the middle east, and are native to iraq and western and southern regions of iran(12). date palm pits extract enriches from polyphenols(13), which exerts many biological properties, including antioxidant, anti-inflammatory, antiviral, and antibacterial activities(14) as well as anti-cancer effects, and could be used for the treatment of diabetes. moreover, it is useful to prevent neurological disorders and alzheimer's disease, enhance sexual potency and improve anemia(15-17). pits consist of 10 to 15 percent of the date palms weight and contain compounds that are chemically composed of saturated fatty acids such as palmitic acid and stearic acid, and unsaturated fatty acids such as oleic acid and linoleic acid, as well as elements such as zinc, cadmium, calcium, and potassium(18). it also contains antioxidants such as carotenoids, anthocyanins, glycosidic flavonoids from flavones, flavonols, and flavoxanthines classes, and due to the high percentage of antioxidant activity, they protect the body against oxidative damage (19,20). owing to the fact that the medicinal plants have fewer side effects, and patients show higher emotional compliance, date palm pits is recommended as a treatment for kidney and bladder stones in traditional medicine; however, and to our knowledge, no relevant scientific research has been reported so far in this regard. therefore, the present study was conducted to investigate the therapeutic and preventive effects of date palm (phoenix dactylifera) pits on kidney stones induced by ethylene glycol in rats. materials and methods preparation of date palm pits extract to prepare date palm pits extract, some dates known in the market as zahedi dates were purchased from the local market and after approval in the herbarium section of birjand university of medical sciences were used. the date palm pits were first removed from the fruit and then thoroughly washed to remove any fruit residue and surface contaminants. after the pits dried in the shade, they were grinded using a grinder. to prepare the aqueous extract, 5 g of dried and grinded date palm pits powder was poured into 100 ml of distilled water, twice distilled at 95 °c, and after stirring, brewed for 15 minutes. then, using filter paper (blue ribbon, grade 589, germany), the obtained solution was filtered in the specific containers of freeze-dryer (dena vacuum industry, model fd-5005-bt, iran) and placed in a -20° c freezer. after freezing, the solution was placed in a freeze-dryer and freeze-dried at a -50 °c and vacuum conditions. the dry powder obtained was stored in specific polyethylene containers at 4 °c until use. the extract solution was provided daily. animals and study design in this study, 40 male wistar rats (200 ± 25 g, 2 months) were kept in stable physical conditions at a temperature of 25 ± 2 °c and a 12-hour light and dark cycle on research center of experimental medicine birjand data palm pit effects on kidney calculi in rats-mohammadparast tabas et al. figure 1. effect of date palm pits on histopathology of kidney. histopathological sections of the kidney sample showed that there were no intratubular crystal deposition in the nc group and the tissue showed normal architecture of the renal epithelia and tubular structure (fig. 1a). the ethylene glycol treated group showed the presence of intratubular deposition of the crystals and necrotic degeneration of the renal epithelia leading to damage to nephron and collecting system (fig. 1b). sections from 150mg/kg date palm pits (fig. 1c) and 300mg/kg date palm pits (fig. 1d) treated rats also demonstrated less retention of crystals in tubules and prevented necrotic damage. the sections from the kidney of rats treated with 150mg/kg date palm pits (fig. 1c) exhibited the prevention of retention and tubular deposition of crystals and lesser degree of necrotic damage to renal epithelia (type of staining: hematoxylin and eosin; magnification ×400). vol 18 no 6 november-december 2021 613 endourology and stones diseases 614 university of medical sciences, birjand, iran. the study was approved by the deputy of research and technology and ethics committee of birjand university of medical sciences (ethics code: ir.bums.rec.1398.156). the rats had free access to standard food (javanneh-khorasan co, iran) and drinking water, and were grouped 72 hours before the study began and placed in relevant cages to adapt to the new conditions. the duration of the study was considered 28 days, according to previous studies(21-24). the rats were divided into 5 groups (n = 8): group 1: received regular drinking water and receive 1 ml of normal saline orally per day (gavage) during the study (nc). group 2: received 1 ml of normal saline per day orally and 1% ethylene glycol (merk, germany) is added to their drinking water (eg). group 3: received the date palm pits extract 150 mg/kg per day from the 14th day until the end of the study and 1% ethylene glycol was added to their drinking water (t150). group 4: received the date palm pits extract 300 mg/kg per day from the 14th day until the end of the study and 1% ethylene glycol was added to their drinking water (t300). group 5: received 300 mg/kg of date palm pits extract per day orally and 1% ethylene glycol was added to their drinking water (p300). collecting urine samples each rat was kept in a separate metabolic cage for 24 hours and their urine was collected on days 14 and 28 of the study. calcium, creatinine, uric acid, and phosphorus in the rats’ urine were measured and analyzed with an auto-analyzer (tokyo bokei prestige 24i, japan). collecting blood samples blood samples from rats were taken on day 14 of the study through the retro-orbital sinus, and on day 28 of the study through their heart following anesthesia, and the serum was separated by blood centrifugation at 2500 rpm for 10 minutes at 4 °c, and was kept at -80 °c until biochemical analyzes were performed. serum levels of blood urea nitrogen (bun), creatinine, uric acid, calcium, and phosphorus were measured by commercially available kits and analyzed. histopathological evaluation to study the kidney’s pathology, following anesthesia of the rats with ketamine and xylazine (65:10 mg/kg) on day 28, rats’ kidneys were removed, washed with normal saline (0.9%), and placed in 10% formalin solution. after dehydration and embedding in paraffin, 5 microns-thick sections were prepared. from the prepared sections, 4 sections from each kidney (2 sections from each kidney lobe) were selected and stained by hematoxylin and eosin method and were given to the blinded pathologist to examine the possible damage of kidney tissue and formation of calcium oxalate crystals. statistical analysis finally, all data were entered into spss software (version 19). after testing the normality of the data distribution using a kolmogorov-smirnov test, one-way analysis of variance (anova) was performed. tukey hsd multiple comparisons were performed as a posthoc test to see any significant differences between each group. non-parametric variables were compared using the kruskal-wallis test followed by mann-whitney test. the data were presented as mean ± sd and a p-value of .05 or less was considered statistically significant. results effects of date palm pits on plasma biochemical parameters groups bun (mg/dl) creatinine (mg/dl) uric acid (mg/dl) calcium (mg/dl) phosphorus (mg/dl) nc 27 ± 10.23 0.55 ± 0.12 2.12 ± 0.55 8.77 ± 0.3 8.07 ± 0.34 eg 32.5 ± 3.41 0.8 ± 0.08* 3.57 ± 0.26* 10.4 ± 0.75** 8.37 ± 1.34 t150 38.5 ± 2.51 0.72 ± 0.05 2.72 ± 0.48 9.55 ± 0.49 8.12 ± 1.72 t300 40.75 ± 17.32 0.85 ± 0.1 2.72 ± 0.74 9.5 ± 0.34 6.92 ± 1.35 p300 37 ± 5.47 0.82 ± 0.22 3.8 ± 0.75 8.77 ± 0.29## 7.8 ± 0.73 chi-square = 7.29 f = 3.45 f = 5.45 f = 8.18 f = 0.86 p = 0.12 p = 0.03 p = 0.006 p = 0.001 p = 0.5 table1. the pre-operative, baseline characteristics of the two groups abbreviations: bun, blood urea nitrogen. all data were expressed as mean ± sd (n = 8). # p < .05, ## p < 0.01, and ### p < .001 compared with nc group; * p < .05, ** p < .01, and *** p < .001 compared with eg group. groups bun (mg/dl) creatinine (mg/dl) uric acid (mg/dl) calcium (mg/dl) phosphorus (mg/dl) nc 26.85 ± 12.64 0.57 ± 0.32 2.28 ± 0.77 8.3 ± 1.48 8.14 ± 2.48 eg 66.5 ± 14.08*** 1.08 ± 0.41** 3.22 ± 0.79* 11.45 ± 2.36** 11.37 ± 1.97** t150 50.75 ± 8.87 0.87 ± 0.21 2.65 ± 0.36 10.63 ± 1.21 9.52 ± 2.1 t300 44.87 ± 18.61# 0.76 ± 0.35# 2.45 ± 0.57# 9.46 ± 1.69 9.48 ± 1.28# p300 43.87 ± 13.06## 0.7 ± 0.27# 2.05 ± 0.65## 8.9 ± 2.1# 8.1 ± 1.52## f = 7.42 chi-square = 10.84 chi-square = 12.85 f = 3.76 chi-square = 13.03 p < 0.0001 p = 0.01 p = 0.01 p = 0.01 p = 0.01 table2. the effect of date palm pits extract on plasma parameters on day 28. abbreviations: bun, blood urea nitrogen. all data were expressed as mean ± sd (n = 8). # p < .05, ## p < 0.01, and ### p < .001 compared with nc group; * p < .05, ** p < .01, and *** p < .001 compared with eg group. data palm pit effects on kidney calculi in rats-mohammadparast tabas et al. examination of bun and plasma phosphorus levels of rats on day 14 showed an increase in the groups that received ethylene glycol compared to the control group. bun and plasma phosphorus levels on day 28 in the eg group showed a significant increase compared to the control group (p < .05). consumption of date palm pits extract decreased the amount of bun and plasma phosphorus in the therapeutic and prevention groups, which was significant in the therapeutic group with a dose of 300 mg/kg (t300) and prevention (p300) (p < .05). examination of creatinine and uric acid levels in the plasma showed a significant increase in the eg group compared to the control group on days 14 and 28, and consumption of date palm pits extract caused a significant decrease in creatinine and uric acid levels of the therapeutic group with a dose of 300 mg/kg (t300) and prevention group with a dose of 300 mg/kg (p300) (p < .05). plasma calcium levels on days 14 and 28 had a significant increase in the eg group compared to the control group, which consumption of the extract caused a significant decrease in plasma calcium levels in the prevention group with a dose of 300 mg/kg (p300) compared to the eg group (p < .05). effects of date palm pits on urinary biochemical parameters the urinary levels of creatinine showed a significant decrease and levels of uric acid and calcium showed a significant increase in the eg group compared with the control group on day 28 of the study (p < .05). the urinary level of creatinine show significantly increased and uric acid and calcium showed a significant decrease in the prevention group with a dose of 300 mg/ kg (p300) in comparison to the eg group (p < .05). also, creatinine showed a significant increase and uric acid showed a significant decrease at the dose of 300 mg/kg (t300 group) compared with the eg group (p < .05) (table 2). pathological results while pathological results did not show any stones or tissue damage in the healthy group, a large number of calcium oxalate crystals were visible in the tubules from the rats in the negative control group. date palm pits extract decreased calcium oxalate crystals formation and also prevented stone formation in rats’ nephrons in a dose-dependent manner (figure 1). discussion in this study, the therapeutic and preventive effects of aqueous extract of date palm (phoenix dactylifera l.) pits on kidney stones induced by ethylene glycol in male rats were investigated. the results of the study demonstrated that oral treatment of date palm pits extract effectively reduced kidney damage and stone formation in a dose-dependent manner compared with the control group. the results also showed that date palm pits extract had a preventive effect on kidney stone formation. ethylene glycol is naturally converted to glycine in the body after being converted to glyoxylic acid by the enzyme alanine-glyoxylate aminotransferase; when the amount of glyoxylic acid reaches too high, it is converted by lactate dehydrogenase to oxalic acid, which in the presence of calcium is converted to insoluble calcium oxalate and deposited in body tissues, especially the kidneys(25). the study of chemical factors in urine could consider as a good indicator of stone formation rate and type of stone. urinary saturation with stone constituents is the most important factor in the formation of kidney stones. previous studies have shown that taking ethylene glycol for fourteen days causes the formation of kidney stones, mainly from calcium oxalate stones in rats, and this is due to the increased concentration of calcium and uric acid in the urine(26-28). uric acid plays an important role in calcium solubility. increasing uric acid prevents the formation of calcium-phosphate and calcium-citrate soluble stones and the production of calcium oxalate stones, thus increasing the production of urinary stones groups creatinine (mg/dl) uric acid (mg/dl) calcium (mg/dl) phosphorus (mg/dl) nc 34.75 ± 19.8 3.85 ± 2.38 2.52 ± 1.02 23.7 ± 2.04 eg 34.25 ± 10.71 5.82 ± 5.73 5.12 ± 2.03 20.65 ± 0.63 t150 34.75 ± 19.68 5.7 ± 2.48 8 ± 1.59 23.42 ± 0.68 t300 36.75 ± 18.44 4.97 ± 3.1 7.6 ± 2.05 22.52 ± 1.77 p300 28.75 ± 6.29 3.95 ± 0.42 5.9 ± 7.21 19.25 ± 2.67 chi-square = 0.47 f = 0.32 f = 1.5 f = 4.73 p = 0.97 p = 0.86 p = 0.25 p = 0.01 table 3. the pre-operative, baseline characteristics of the two groups for proximal all data were expressed as mean ± sd (n = 8). # p < .05, ## p < .01, and ### p < .001 compared with nc group; * p < .05, ** p < 0.01, and *** p < .001 compared with eg group. groups creatinine (mg/dl) uric acid (mg/dl) calcium (mg/dl) phosphorus (mg/dl) nc 33.75 ± 12.94 4.47 ± 4.02 2.94 ± 1.53 22.3 ± 3.04 eg 18.5 ± 9.05** 12.28 ± 3.23** 8.2 ± 3.12** 25.25 ± 7.78 t150 22.85 ± 8.6 7.55 ± 3.6# 7.1 ± 1.56 25.7 ± 7.2 t300 27.96 ± 7.78# 5.96 ± 3.13### 6.7 ± 3.7 24.63 ± 6.7 p300 32.2 ± 12.1## 5.51 ± 3.39## 3.02 ± 1.44## 24.15 ± 7.25 chi-square = 11.37 chi-square = 16.05 f = 7.43 chi-square = 1.78 p = 0.02 p = 0.003 p < 0.0001 p = 0.77 table4. the effect of date palm pits extract on urinary parameters on day 28. data was presented as n (%) and mean ± sd; *ureteral injury as in european association guideline including i: mucosal abrasion; ii: ureteral perforation; iii: intussusception / avulsion data palm pit effects on kidney calculi in rats-mohammadparast tabas et al. vol 18 no 6 november-december 2021 615 endourology and stones diseases 616 (29,30). consumption of date palm pits extract in the treatment of kidney stones significantly reduced uric acid and also prevented the increase in urinary uric acid and calcium in a dose-dependent manner thus reduced the risk of formation of kidney stones. glomerular filtration rate (gfr) in urolithic rats decreases due to the blockage of urinary tubules by stones formation inside them, and this reduction causes the accumulation of excretory substances such as uric acid, calcium, phosphate, creatinine, and urea in the blood and increases the serum level of these substances and also reduces the excretion substances such as creatinine into the urine and reduces its urinary amounts(27,31,32). previous studies have shown that the use of ethylene glycol increases lipid peroxidation and reduces the antioxidant potential of renal tissue, which is an important factor in damaging the tubules and decrease of renal filtration(33). treatment with date palm pits extract significantly reduces serum levels of urea, calcium, phosphate, creatinine, and uric acid and also dramatically prevents the increase in serum levels of urea, calcium, phosphate, creatinine, and uric acid and also treatment with date palm pits extract significantly increases urinary creatinine level and also dramatically prevents the reduces urinary creatinine. increased gfr in therapeutic groups, as well as prevention group, is attributed to antioxidant activity and anti-lipid properties (peroxidation reactions) of date palm pits extract(14,34). study of baghbani et al.(34) on the antioxidant and antimicrobial properties of date palm pits extract and its effects on physicochemical, microbial and sensory properties of cupcake have shown that date palm pits can be considered as an important source of natural antioxidants for medicinal and commercial purposes. catechins and rutin are found in abundance among the 7 active compounds in date palm pits, including gallic acid, catechin, chlorogenic acid, rutin, vanillin, p-coumaric acid, and sinapic acid. catechin is the most important polyphenolic compound extracted from date palm pits and flavonoids with significant antioxidant activity. the antioxidant activity of catechins is mostly related to the ortho dihydroxyl groups in the beta ring of the catechin structure, which has anti-free radical activity(35). it seems that the antioxidant properties of catechins and consequently dates have been one of the main factors in showing the protective properties of date seeds against damage to kidney tissue due to exposure to ethylene glycol. previous studies on date palm pits have proven its anti-inflammatory properties, so it could be stated that the aqueous extract of date palm pits may have reduced kidney inflammation. the microscopic study of kidneys of urolithic rats shows the presence of irregular shapeless crystals inside the tubules, which causes tubule inflammation. date palm pits extract reduced the number and size of calcium oxalate crystals in the tubules. the results show that the use of date palm pits extract reduces and prevents the formation of urinary stones. it seems that date palm pits extract is effective in preventing recurrent kidney stones. the precise mechanism of action of date palm pits extract may be due to its antioxidant properties or decrease of the main stone-former constituents in the urine. however, according to our studies knowledge, no study has been reported the effect of date palm pits on kidney stones and the resulting damages; therefore, it is not possible to comment on the exact effects of date palm pits on kidney stones and their possible mechanisms. conclusions the results of this study show that aqueous extract of date palm pits has been effective in the treatment and prevention of kidney stones induced by ethylene glycol in rats. its precise mechanism on kidney stones is not clear and requires further investigation. however, its effect may be attributed to the antioxidant and anti-inflammatory properties and the decrease of the main stone-former constituents in the urine. conflict of interest the authors declared that they have no conflict of interest. acknowledgments this article is the outcome of a research project approved by the research council of birjand university of medical sciences (ir.bums.rec.1398.153). we hereby would like to thank the deputy of research and technology of birjand university of medical sciences for financing the project (grant no. 5044), and the clinical research development unit (crdu) of valiasr hospital, birjand university of medical sciences, birjand, iran, for their support, cooperation and assistance throughout the period of study. references 1. winoker js, bamberger jn, chandhoke ra, atallah w, gupta m. what factors drive staghorn vs nonstaghorn pattern growth in patients with metabolic stones? j endourol. 2019;33:954-9. 2. evan ap. physiopathology and etiology of stone formation in the kidney and the urinary tract. pediatr nephrol. 2010;25:831-41. 3. howles sa, wiberg a, goldsworthy m, bayliss al, gluck ak, ng m, et al. genetic variants of calcium and vitamin d metabolism in kidney stone disease. nat. commun. 2019;10:1-0. 4. coe fl, worcester em, evan ap. idiopathic hypercalciuria and formation of calcium renal stones. nat. rev. nephrol. 2016;12:519. 5. khan sr. is oxidative stress, a link between nephrolithiasis and obesity, hypertension, diabetes, chronic kidney disease, metabolic syndrome? urol. res. 2012;40:95-112. 6. yoshioka i, tsujihata m, momohara c, akanae w, nonomura n, okuyama a. effect of sex hormones on crystal formation in a stone-forming rat model. urol. j. 2010;75:90713. 7. hiller n, berkovitz n, lubashevsky n, salaima s, simanovsky n. the relationship between ureteral stone characteristics and secondary signs in renal colic. clin. imaging. 2012;36:768-72. 8. cheungpasitporn w, rossetti s, friend k, erickson sb, lieske jc. treatment effect, adherence, and safety of high fluid intake for data palm pit effects on kidney calculi in rats-mohammadparast tabas et al. the prevention of incident and recurrent kidney stones: a systematic review and meta-analysis. j. nephrol. 2016;29:211-9. 9. labadie k, okhunov z, akhavein a, moreira dm, moreno-palacios j, del junco m, et al. evaluation and comparison of urolithiasis scoring systems used in percutaneous kidney stone surgery. j urol. 2015;193:154-9. 10. abdel-aal e, daosukho s, el-shall h. effect of supersaturation ratio and khella extract on nucleation and morphology of kidney stones. j. cryst. growth. 2009;311:2673-81. 11. atmani f, slimani y, mimouni m, aziz m, hacht b, ziyyat a. effect of aqueous extract from herniaria hirsuta l. on experimentally nephrolithiasic rats. j. ethnopharmacol. 2004;95:87-93. 12. hajian s, hamidi-esfahani z. date palm status and perspective in iran. date palm genetic resources and utilization: springer; 2015. p. 19-47. 13. hamada j, hashim i, sharif f. preliminary analysis and potential uses of date pits in foods. food chem. 2002;76:135-7. 14. ardekani mrs, khanavi m, hajimahmoodi m, jahangiri m, hadjiakhoondi a. comparison of antioxidant activity and total phenol contents of some date seed varieties from iran. ijpr. 2010;9:141. 15. dehghanian f, kalantaripour tp, esmaeilpour k, elyasi l, oloumi h, pour fm, et al. date seed extract ameliorates β-amyloid-induced impairments in hippocampus of male rats. biomed pharmacother. 2017;89:221-6. 16. hasan m, mohieldein a. in vivo evaluation of anti diabetic, hypolipidemic, antioxidative activities of saudi date seed extract on streptozotocin induced diabetic rats. jcdr. 2016;10:ff06. 17. orabi sh, shawky sm. effect of date palm (phoenix dactylifera) seeds extracts on hematological, biochemical parameters and some fertility indices in male rats. ijbas. 2014;17:137-47. 18. al‐shahib w, marshall rj. fatty acid content of the seeds from 14 varieties of date palm phoenix dactylifera l. int. j. food sci. technol. 2003;38(6):709-12. 19. adeosun am, oni so, ighodaro om, durosinlorun oh, oyedele om. phytochemical, minerals and free radical scavenging profiles of phoenix dactilyfera l. seed extract. jtusci. 2016;11:1-6. 20. habib hm, ibrahim wh. effect of date seeds on oxidative damage and antioxidant status in vivo. j sci food agric. 2011;91:1674-9. 21. christina a, packia lakshmi m, nagarajan m, kurian s. modulatory effect of cyclea peltata lam. on stone formation induced by ethylene glycol treatment in rats. methods find exp clin pharmacol. 2002;24:77-80. 22. safari h, esmaeili s, naghizadeh ms, falahpour m, malekaneh m, sarab ga. the effects of aqueous extract of eryngium campestre on ethylene glycol-induced calcium oxalate kidney stone in rats. urol. j. 2019 dec 24;16:519-24. 23. mohammadian n, rahmani z, rassouli fb. effect of thymoquinone on ethylene glycol-induced kidney calculi in rats. j. urol. 2008;5:149-55. 24. sakly r, chaouch a, el hani a, najjar mf. effects of intraperitoneally administered vitamin e and selenium on calcium oxalate renal stone formation: experimental study in rat. ann urol. 2003;37:47-50. 25. guo c, cenac ta, li y, mcmartin ke. calcium oxalate, and not other metabolites, is responsible for the renal toxicity of ethylene glycol. toxicol. lett. 2007;16:173-8. 26. azaryan e, malekaneh m, nejad ms, haghighi f. therapeutic effects of aqueous extracts of cerasus avium stem on ethylene glycol-induced kidney calculi in rats. j. urol. 2017;14:4024-9. 27. karadi rv, gadge nb, alagawadi k, savadi rv. effect of moringa oleifera lam. rootwood on ethylene glycol induced urolithiasis in rats. j. ethnopharmacol. 2006;105:306-11. 28. sikarwar i, dey yn, wanjari mm, sharma a, gaidhani sn, jadhav ad. chenopodium album linn. leaves prevent ethylene glycolinduced urolithiasis in rats. j. ethnopharmacol. 2017 jan 4;195:275-82. 29. shekarriz b, stoller ml. uric acid nephrolithiasis: current concepts and controversies. j urol. 2002 oct 1;168:130714. 30. makasana a, ranpariya v, desai d, mendpara j, parekh v. evaluation for the antiurolithiatic activity of launaea procumbens against ethylene glycol-induced renal calculi in rats. toxicol. rep. 2014 jan 1;1:46-52. 31. manjula k, rajendran k, eevera t, kumaran s. effect of costus igneus stem extract on calcium oxalate urolithiasis in albino rats. urol. res. 2012;40:499-510. 32. el menyiy n, al waili n, bakour m, al-waili h, lyoussi b. protective effect of propolis in proteinuria, crystaluria, nephrotoxicity and hepatotoxicity induced by ethylene glycol ingestion. arch med res. 2016;47:526-34. 33. shah jg, patel bg, patel sb, patel rk. antiurolithiatic and antioxidant activity of hordeum vulgare seeds on ethylene glycolinduced urolithiasis in rats. indian j pharmacol. 2012 nov;44:672. 34. baghbani f, shirazinejad a. study of antioxidant and antimicrobial activity of date seed extract and its effects on physicochemical, microbial and sensory properties of cupcake. food sci. technol. 2019;16:327-42. 35. higdon jv, frei b. tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. crit rev food sci nutr. 2003;43:89-143. data palm pit effects on kidney calculi in rats-mohammadparast tabas et al. vol 18 no 6 november-december 2021 617 january-february 2018 reviewer of the issue siavash falahatkar siavash falahatkar march 2018 siavash falahatkar is professor of urology at guilan university of medical science. he graduated from the university of mashhad in the field of urology. he spent the general fellowship period of minimally invasive surgery in laparoscopy hospital in india. he also spent the course on endourology in the labafinezhad hospital in iran. he works in razi research & educational hospital, rasht, iran. he is director of urology research center, guilan university of medical science since 2005. he has published more than 70 scientific papers in international peer reviewed journals. he is also the author of 1 chapter for iranian text book of urology and his 3 articles are cited in campbell-walsh urology. he had written three books on urology in persian: practical urology, urology questions and answers, uroradiology. he set up the pnl surgeries and advanced laparoscopy for the first time in guilan province, in iran. in 2007, he performed the complete supine pcnl (cspcnl) for the first time in the world and in 2008, published a paper about this new method of pcnl surgery in endourology journal. since then, he routinely performs the cspcnl for all his patients. falahatkar: “it is a great honor and privilege to cooperate and work with urology journal as a reviewer”. dr. falahatkarbv was chosen by editorial board of the urology journal for his valuable and timely review of manuscript”. case report unroofing of lower pole native kidney cysts in patients with autosomal dominant polycystic kidneys at the time of kidney transplantation abbas basiri1, nasser simforoosh1, amirhossein nayebzade1, hamed marufi2, amir h kashi1* to report our experience with unroofing of ipsilateral lower pole kidney cysts in five patients with adult-type polycystic kidneys [adpkd] when free implantation of kidney allograft interfered with lower pole native kidney cysts. in all of these patients, the native kidneys extended to the ipsilateral pelvis and bilateral adpkd caused enlargement of the abdomen on gross examination. unroofing of lower pole kidney cysts was performed during the same session of allograft transplantation. the decision to unroof lower pole cysts of the ipsilateral kidney was made after observing interference of lower pole cysts with free implantation of the allograft. in patient a, bilateral native nephrectomy was performed 6 weeks after kidney transplantation after consultation with the patient, when there was evidence of the good function of the allograft and the recipient was on a low dose of immunosuppressive medications. in other patients, no need for native nephrectomy observed. this experience suggests the possibility that when large ipsilateral kidney cysts interfere with safe implantation of the allograft, there is an option of performing cyst unroofing at the same session and proceeding with allograft implantation. in many patients, there would be no need for native nephrectomy and of deemed necessary, it will be performed later, when there is evidence of the good function of the allograft and the patient is on good kidney function with a low dose of immunosuppressive medications and a less risk profile for the operation. to our best knowledge, there is no prior such report in the literature.. keywords: transplantation; adult type polycystic kidneys; native nephrectomy 1urology and nephrology research center (unrc), shahid labbafinejad hospital, shahid beheshti university of medical sciences (sbmu), tehran, iran. 2kurdistan university of medical sciences, sanandaj , iran. *correspondence: urology and nephrology research center (unrc), shahid labbafinajad hospital, shahid beheshti university of medical sciences (sbmu), tehran, iran. email: ahkashi@gmail.com. received october 2021 & accepted march 2023 introduction transplantation is the optimal choice for renal replacement therapy in patients with autosomal dominant pol-ycystic kidney disease (adpkd)(1). the size of the polycystic kidney should be assessed before transplant surgery, preferably by a surgeon who will implant a new kidney(2). if the size of the kidneys is so large that a transplant is not possible, native nephrectomy can be performed before or at the same time of transplantation(3). polycystic nephrectomy is best performed laparoscopically or through an open operation(4). native polycystic kidney nephrectomy is still under discussion and the right time is not well defined, especially for patients undergoing peritoneal dialysis as an alternative treatment due to the risk of peritoneal injury(3). most studies recommend that native nephrectomy be performed just before or during transplantation. nephrectomy in peritoneal dialysis patients increases peritoneal damage and decreases diuresis volume, both leading to an unnecessary switch to hemodialysis(2). another option is cyst removal before transplantation which is usually done laparoscopically. benefits of this approach include no need for erythropoietin and reduced risk of cyst infection(5). we report our experience with unroofing of ipsilateral lower pole kidney cysts at the time of allograft implantation and follow-up of these patients. case presentation the patient a was a 50-year-old man with a history of adpkd for 25 years. he suffered from end stage renal disease (esrd) for several years and had been on hemodialysis for 2 months before transplantation. the patient was candidate to receive kidney from a deceased donor. on ultrasound and computed tomography (ct) scan, the patient had very large polycystic kidneys that filled the entire abdominal space and bilateral iliac fossa. the patient was scheduled for kidney transplant from a deceased donor in february 2021. our surgical method for transplantation is through para-rectal incision and extra peritoneal approach, as previously described(6). after exposing the implantation site, it was found that without removing lower pole cysts; it is not possible to create the necessary space for allograft implantation due to the pressure of the native kidney on the allograft. we decided to unroof ipsilateral lower pole cysts after ensuring provision of enough space for the allograft. the allograft renal vein was anastomosed end-to-side to the recipient external iliac vein by 6-0 polypropylene suture. allograft renal artery was anastomosed end-to-side to the common iliac artery by 6-0 polypropylene sutures. the allograft ureter was anastomosed by extravesical modified lich leaving a double-pigtail (double-j) catheter in place. a dtpa scan on the fifth postoperative day revealed normal perfusion and function of allograft with no leakage from native kidurology journal/vol 20 no. 4/ july-august 2023/ pp. 269-273. [doi:10.22037/uj.v20i.7047] figure 1. patient a: a: unroofing of lower pole ipsilateral kidney cysts to create necessary space for kidney implantation. b: necessary space created for kidney implantation. c: dtpa scan performed 5 days after kidney implantation documenting proper function of the allograft neys (figure 1). a non-contrast ct scan also revealed the normal location of kidney allograft in the pelvis. foley catheter was removed on the fifth postoperative day and double-pigtail ureteral catheter after 4 weeks. serum creatinine was 1.4mg/dl one month after transplantation. bilateral native nephrectomy was performed through an open midline transperitoneal operation 6 weeks after transplantation, when serum creatinine was normal and the patient was on a low dose of immunosuppressive medications. the weights of bilaterally removed native kidneys were 15kg. the follow up of this patient is 24 months. native nephrectomy was done based on consultation with the patient and his desire for removed of native kidneys due to their very large size. the patient b was a 48-year-old woman with a history of adpkd for 20 years. she suffered from esrd for several years and had been on hemodialysis for 1 year. the patient was a candidate to receive a kidney from a familiar living donor. on ultrasound and computed tomography (ct) scan, the patient had very large polycystic kidneys that filled the entire abdominal space and bilateral iliac fossa. the patient was scheduled for a kidney transplant from a living donor in september 2021. similar to the condition of the previous patient, after exposing the implantation site, it was found that without removing lower pole cysts, it is not possible to create the necessary space for allograft implantation due to the pressure of the native kidney on the allograft. the allograft renal vein, artery, and ureter were anascyst unroofing of adpkd at transplantation-basiri et al. case report 270 tomosed to the places and with the same technique as patient a. foley catheter was removed on the fifth postoperative day and finally, the patient was discharged on the seventh day after surgery with serum creatinine equivalent of 1.3mg/dl. the patient was scheduled for double-j removal 4 weeks later. creatinine was 1.3mg/ dl two weeks after transplantation. the follow up of this patient is 17 months (figure 2). the patient c was a 61-year-old woman with a history of adpkd for 23 years. she had been on hemodialysis for 5 years. the patient was a candidate to receive a kidney from a familiar living donor. on ultrasound and computed tomography (ct) scan, the patient had very large polycystic kidneys that filled the entire abdominal space and bilateral iliac fossa. the patient was scheduled for a kidney transplant from a living donor in september 2022. after exposing the implantation site, it was found that due to the large space occupied by the kidney and its cysts, there is not enough space for an allograft kidney. so similar to previous patients, we decided to unroof ipsilateral lower pole cysts after ensuring the provision of enough space for the allograft. the allograft renal vein, artery, and ureter were anastomosed to the external iliac vein, internal iliac artery and bladder. the patient had no evidence of leak or more than usual discharge from the drain and had normal vascular flow of the transplanted kidney in color doppler ultrasound a foley catheter was attached to the double-pigtail ureteral catheter and both were removed on postoperative day 14 and after 2 days the patient was discharged with serum creatinine of 1.8 mg/dl. creatinine was 1.3mg/dl two weeks after transplantation. the patient was scheduled for double-j removal 4 weeks later. the follow up of this patient is 5 months. the patient d was a 42-year-old man with esrd in the context of adpkd for 10 years. she had been on hemodialysis for two years. the patient was a candidate to receive a kidney from a familiar living donor. on imaging before surgery, the patient had very large cysts in bilateral kidneys that filled the entire abdominal space and bilateral iliac fossa. the patient was scheduled for a kidney transplant from a living donor in may 2022. our surgical method for transplantation was similar to previous patients and due to not enough space in iliac fossa we decided to unroof ipsilateral right kidney lower pole cysts after ensuring the provision of enough space for the allograft kidney. the anastomosis of allograft renal vein, artery, and ureter were similar to previous patient. the patient had no evidence of leak or more than usual discharge from the drain and had normal vascular flow of the transplanted kidney in color doppler ultrasound. a foley catheter was attached to the double-pigtail ureteral catheter and both were removed on postoperative day 10 and after 2 days the patient was discharged with serum creatinine equivalent of 1.8 mg/dl. . creatinine was 1.6 mg/dl two weeks after transplantation. the patient was scheduled for double-j removal 4 weeks later. the follow up of this patient is 9 months the patient e was a 55-year-old man with esrd in the field of adpk for 20 years. he had been on hemodialysis for six years. this patient was similar to the previous patients and on imaging before surgery had very large cysts in bilateral kidneys that filled the entire abdominal space and bilateral iliac fossa. during transplantation surgery in october 2022 we decided to unroof ipsilateral right kidney lower pole cysts for provision of enough space for the allograft kidney. the anastomosis of allograft renal vein, artery, and ureter were similar to previous patient. post-operative conditions went well and we had no evidence of leakage or collection. the post-operative function of the transplanted kidney was also checked with color doppler ultrasound, which was normal. foley catheter was removed on the seventh postoperative day and finally, the patient was discharged on the ninth day after surgery with serum creatinine of 1.6mg/dl. creatinine was 1.5mg/dl two weeks after transplantation. the patient was scheduled for double-j 4 weeks later. the follow up of this patient is 4 months. in all cases, the unroofing technique was such that we opened the cysts with metz and immediately, suctioned the fluid inside the cysts. in case of bleeding from the edge of cyst, we sew the edges with 2-0 chromic or vicryl sutures. discussion these cases show a technique of performing renal transplantation in the presence of large ipsilateral polycystic kidneys. the benefits of such an approach are obviating the necessity of native nephrectomy which will remove native kidneys that are sources of erythropoietin secretion and to avoid imposing an operation to the patient figure 4. patient e: a: there is not enough space for an allograft kidney. b: unroofing ipsilateral lower pole cysts of kidney. c: provision of enough space for the allograft kidney. cyst unroofing of adpkd at transplantation-basiri et al. vol 20 no 4 july-august 2023 271 by our approach in some cases. furthermore, in case native nephrectomy is deemed necessary, it is postponed for weeks to months after transplantation when the condition of the recipient is stable and the risk of operation is lower and there is assurance of the proper function of the allograft. to our best knowledge, there is no prior report of such a procedure in the transplant literature. furthermore, in case the transplantation fails due to rejection, a major native nephrectomy operation has not been imposed on the recipient. as indicated previously, the timing of native nephrectomy is a matter of debate. many recent publications suggest that pretransplant nephrectomy may be associated with a higher rate of morbidity and mortality(7-11). sulikawski et al. reported 30 patients with a history of polycystic kidney disease. patients were divided into two groups. eleven procedures entailed laparoscopic cyst excisions. in the remaining 19 patients, nephrectomy was done. they found that laparoscopic cyst removal results were more favorable than nephrectomy results including a less operative time, less postoperative pain scores, shorter hospitalization stay, and less time for recovery. also, other benefits of laparoscopic cyst removal included maintaining urination and no need for erythropoietin substitution, as well as reduced risk of cyst contamination. when eligible for renal transplantation, patients after laparoscopic cyst removal have smaller kidneys that do not interfere with the graft and the risk of infection during immunosuppression seems lower (5). nevertheless, this approach incorporates a separate operation for cyst unroofing before transplantation. kanaan et al. limited native prophylactic nephrectomy to patients with a history of cyst infection or recurrent bleeding or those in whom a space must be created for the implant to be implanted(12). in a retrospective analysis of adpkd patients, patients who underwent nephrectomy before and after transplantation at a single center between january 2003 and december 2009 were compared. there were 35 individuals in the cohort. the authors concluded that pretransplant nephrectomy has many complications and suggested post-transplant nephrectomy as a safer approach with fewer complications (13). another larger retrospective study including 121 patients compared the timing of native nephrectomy in relation to transplantation considering outcomes of transplant and operation complications. these authors also observed that pretransplant nephrectomy was associated with a higher profile of complications however not statistically significant. native nephrectomy timing was not associated with the outcomes of transplantation (14). another alternative therapy for unilateral nephrectomy in adpkd patients is embolization. the experience with this technique is limited. in a recent report, pierre et al. compared the outcomes of unilateral nephrectomy versus embolization in 37 adpkd patients (unilateral nephrectomy in 16 and embolization in 21 patients) undergoing peritoneal dialysis. they reported fewer switches to permanent hemodialysis after embolization in comparison with unilateral nephrectomy. however, embolization failed in 6 patients (29%) in whom 4 patients needed nephrectomy(15). in this manuscript, we report the feasibility of lower pole ipsilateral kidney adpkd cysts reroofing creating necessary space when interference with allograft implantation was observed. follow up investigation revealed that remained native polycystic kidney had no adverse effect on the allograft including displacement or hydronephrosis. there is evidence that adpkd kidneys can shrink after transplantation. this evidence suggests that in case nephrectomy of adpkd kidneys can be obviated before transplantation, there could be a low need for native nephrectomy after transplantation. keeping native kidney is associated with the benefits of erythropoietin synthesis in case transplanted kidneys are rejected later in life and will remove the risk of a postoperative condition from the patient. in case needed, posttransplant elective native nephrectomy can be performed weeks to months later when serum creatinine is in the normal range and the risk of operation for the patient is decreased and the patient is on a low dose of medications. we could not find any report of this technique in the transplantation literature. references 1. perico n, cortinovis m, remuzzi g. [renal transplantation in autosomal dominant polycystic kidney disease (adpkd)]. giornale italiano di nefrologia : organo ufficiale della societa italiana di nefrologia. 2016;33(5). 2. tyson md, wisenbaugh es, andrews pe, castle ep, humphreys mr. simultaneous kidney transplantation and bilateral native nephrectomy for polycystic kidney disease. j urol. 2013;190:2170-4. 3. ietto g, raveglia v, zani e, iovino d, parise c, soldini g, et al. pretransplant nephrectomy for large polycystic kidneys in adpkd (autosomal dominant polycystic kidney disease) patients: is peritoneal dialysis recovery possible after surgery? biomed res int . 2019;:7343182. 4. hume dm, magee jh, kauffman hm, jr., rittenbury ms, prout gr, jr. renal homotransplantation in man in modified recipients. ann surg. 1963;158:608-44. 5. sulikowski t, kamiński m, rózański j, zietek z, domański l, majewski w, et al. laparoscopic removal of renal cysts in patients with adpkd as an alternative method of treatment and patient preparation for kidney transplantation: preliminary results. transplant proc. 2006;38:23-7. 6. simforoosh n, basiri a, tabibi a, javanmard b, kashi ah, soltani mh, et al. living unrelated versus related kidney transplantation: a 25-year experience with 3716 cases. urol j. 2016;13:2546-51. 7. akoh ja. current management of autosomal dominant polycystic kidney disease. world j nephrol. 2015;4:468-79. 8. drognitz o, kirste g, schramm i, assmann a, pohl m, gobel h, et al. kidney transplantation with concomitant unilateral nephrectomy: a matched-pair analysis on complications and outcome. transplantation. 2006;81:874-80. 9. fuller tf, brennan tv, feng s, kang sm, stock pg, freise ce. end stage polycystic kidney disease: indications and timing of native nephrectomy relative to kidney transplantation. j urol. 2005;174:2284-8. cyst unroofing of adpkd at transplantation-basiri et al. case report 272 10. rozanski j, kozlowska i, myslak m, domanski l, sienko j, ciechanowski k, et al. pretransplant nephrectomy in patients with autosomal dominant polycystic kidney disease. transplant proc. 2005;37:666-8. 11. skauby mh, øyen o, hartman a, leivestad t, wadström j. kidney transplantation with and without simultaneous bilateral native nephrectomy in patients with polycystic kidney disease: a comparative retrospective study. transplantation. 2012;94:383-8. 12. kanaan n, devuyst o, pirson y. renal transplantation in autosomal dominant polycystic kidney disease. nature rev nephrol. 2014;10:455-65. 13. kirkman ma, van dellen d, mehra s, campbell ba, tavakoli a, pararajasingam r, et al. native nephrectomy for autosomal dominant polycystic kidney disease: before or after kidney transplantation? bju int. 2011;108:590-4. 14. maxeiner a, bichmann a, oberländer n, el-bandar n, sugünes n, ralla b, et al. native nephrectomy before and after renal transplantation in patients with autosomal dominant polycystic kidney disease (adpkd). j clin med. 2019;8:1622. 15. pierre m, moreau k, braconnier a, kanagaratnam l, lessore de sainte foy c, sigogne m, et al. unilateral nephrectomy versus renal arterial embolization and technique survival in peritoneal dialysis patients with autosomal dominant polycystic kidney disease. nephrol dial transplant. 2020;35:320-7. cyst unroofing of adpkd at transplantation-basiri et al. vol 20 no 4 july-august 2023 273 endourology and stone disease effects of isothermic irrigation on core body temperature during endoscopic urethral stone treatment surgery under spinal anesthesia: a randomized controlled trial mehmet cantürk1* , meltem hakkı1, nazan kocaoglu1 purpose: isothermic irrigation decreases the reduction in core temperature and shivering in patients undergoing transurethral resection of prostate gland but this effect has not been studied in patients undergoing endoscopic urethral stone treatment surgery. the current study is designed to study the effect of isothermic hydration on core temperature in patients scheduled for endoscopic urethral stone treatment surgery under spinal anesthesia. materials and methods: sixty patients allocated randomly into two groups. in groupw (n = 30) irrigation fluid at 37°c was used whereas at room temperature in grouprt (n = 30). spinal anesthesia was performed at l3-l4 interspace with 15mg of hyperbaric bupivacaine. core temperature, shivering, and hemodynamic parameters were measured every minute until 10th minute and five minute intervals until the end of operation. shivering and surgeon comfort was also recorded. the primary outcome was the core temperature at the end of surgery. frequencies, means, standard deviations, percentages, chi-square tests, independent samples t-test, and mann whitney u tests were used where eligible for the statistical analysis. results: baseline core temperature was 36.6 ± 0.4°c in groupw and 36.6 ± 0.5°c in grouprt (p = .097) which decreased to 36.0 ± 0.5°c and 35.2 ± 0.7°c respectively (p = .018) at the end of operation. shivering was observed in 36.7% (n = 11) in grouprt and 6.7% (n = 2) in groupw (p = .012). hemodynamic parameter changes and demographic data were not significant between groups. conclusion: isothermic irrigation decreases both the reduction in core temperature and the incidence of shivering while increasing the surgeon comfort. keywords: core temperature; endoscopes; isothermic irrigation, shivering, spinal anesthesia, urethral stone treatment surgery introduction endoscopic urethral stone treatment surgery is usu-ally performed with spinal anesthesia in outpatient settings. spinal anesthesia affects the thermoregulatory homeostasis by decreasing the vasoconstriction and shivering thresholds by 0.5°c.(1,2) because the surgical procedure has a short duration, monitorization of the patient for hypothermia is generally neglected during endoscopic urethral stone treatment surgery. however, the duration of surgery may exceed an hour when it is a complicated case. in such a case the amount of irrigation fluid may be excessive and may accelerate the development of hypothermia. maintaining core temperature is an important phenomenon under spinal anesthesia. perioperative hypothermia defined as core body temperature ≤ 36.0°c is a common inadvertent result of both general and regional anesthesia due to heat redistribution from core to periphery affected by ambient temperature,(3) duration of exposure to cold,(4) temperature of the fluid administered via intravenous route(5) or as irrigation and antimicrobial solutions used for skin preparation. hypothermia 1department of anesthesiology and reanimation, ahi evran university training and research hospital, kırsehir, turkey. *correspondence: department of anesthesiology and reanimation, ahi evran university training and research hospital, kirsehir, turkey. tel: +90 505 3574372.fax: +90 386 2133398.e-mail: drmcanturk@gmail.com. received april 2018 & accepted december 2018 has well documented deleterious effects(6) as increased bleeding from the surgical site,(7) reversible dysfunction of platelets,(8) shivering,(9) increased oxygen consumption and cardiac morbidity,(10) increased risk of wound infection,(11) delayed recovery from anesthesia,(12) and increased length of hospital stay.(13) therefore perioperative hypothermia should be avoided whenever possible. several previous studies have defined different protocols to maintain core temperature during transurethral resection of prostate as well as arthroscopic surgeries up to date.(14-25) main goal of these previous studies was to determine the effect of irrigation fluid temperature on core body temperature. except for the studies reported by oh jh et al.(20) and jaffe et al.(16) almost all studies supported the use of warmed irrigation fluids to maintain core temperature in perioperative setting. the effects of irrigation fluid temperature on core body temperature during transurethral resection of prostate gland was studied in previous articles but this effect was not investigated for patients scheduled for endoscopic urethral stone treatment surgery. in this prospective urology journal/vol 17 no. 1/ january-february 2020/ pp. 1-7. [doi: 10.22037/uj.v0i0.4524] randomized controlled trial we decided to investigate the effect of irrigation fluid temperature on core body temperature during endoscopic urethral stone treatment surgery under spinal anesthesia. patients and methods ethics this prospective, randomized controlled trial was conducted at ahi evran university training and research hospital, kirsehir, turkey between august 2016 and december 2016 in line with the consort statement. after receiving approval from the ethical committee (turgut özal university clinical trials ethical committee, 99950669/115, approved at 23.05.2016) the study was registered at australian new zealand clinical trials registry (actrn12616000795493, registered at 17.06.2016). the study was designed and conducted in adherence to the consolidated standards of reporting trials (consort) statement, good clinical practice guidelines, and declaration of helsinki. written informed consent was obtained from all participants. study population sixty patients with american society of anesthesiologists (asa) physical status i or ii scheduled for elective endoscopic urethral stone treatment surgery under spinal anesthesia was included in the study (figure 1). patients that have a contraindication for spinal anesthesia (infection at puncture site, coagulopathy, anticoagulant medication or patient refusal to spinal anesthesia), patients with thyroid disease or any febrile condition, dysautonomia, asa physical status > ii, and pregnant patients were excluded from the study. study design the patients were allocated into two groups by sealed envelope technique at their preoperative visit. the envelope was brought in to the operation room with the patient and was opened by the anesthesiologist who will be in charge of the patient and the irrigation fluid temperature was adjusted according to patients’ group allocation by the same anesthesiologist. the irrigation fluid and the intravenous fluids were given at room temperature in group rt (n = 30). group w (n = 30) received irrigation fluid at body temperature (37°c) and the intravenous fluids at room temperature. the irrigation fluid in group w was warmed by an incubator (nuve fn500, ankara, turkey) set at 37°c and was protected in a non-transparent heat protection bag. the temperature of the irrigation solution was controlled with an infrared thermometer (riester ri-thermo®n, rudolf riester gmbh, germany) by the anesthesiologist in charge of the patient. the manufacturer of riester ri-thermo®n (rudolf riester gmbh, germany) states that the thermometer gives accurate measurements between 0 – 100°c and its use is appropriate for measuring body temperature, ambient temperature and fluid temperature. ambient temperature was recorded before spinal anesthesia. all core body temperature was measured from the same tympanic membrane by the same investigator. all measurements in the study were done by an investigator other than the anesthesiologist in charge of the patient care, who was blinded for the temperature of the irrigation fluid. the thermometer used for the study was same for all the participants that had a disposable sleeve for each patient. in the operating room, the anesthesiologist in charge of the patients monitored the patients with standard asa monitors (electrocardiogram, pulse oximeter, non-invasive blood pressure). baseline hemodynamic data (heart rate and non-invasive blood pressure were measured with the monitor of the anesthesia device, peripheral oxygen saturation was measured with pulse oxymeter), ambient temperature and core body temperature (both effect of isothermic irrigation on core temperature-cantürk et al. figure 1. consort flow-diagram endourology and stones diseases 02 vol 17 no 01 january-february 2020 03 measured with riester ri-thermo®n) were recorded before starting intravenous infusion. a 16g intravenous line was secured on the dorsum of left hand. all intravenous fluids were given at room temperature. temperature of the irrigation fluid was adjusted according to the group allocation of the patient by the anesthesiologist in charge of the patient. intrathecal space was introduced with a 26g atraumatic spinal needle (atraucan, bbraun, melsungen, germany) by the same anesthesiologist at l4-l5 interspace navigated by ultrasonography with 15mg 0.5% hyperbaric bupivacaine. intrathecal local anesthetic solution was opioid free. the level of spinal anesthesia was monitored with loss of sensation to pinprick test at midclavicular line and recorded at the same time points with core temperature measurements by another anesthesiologist blinded for the temperature of the irrigation fluid. all patients were covered with a single layer of sterile surgical cover at lithotomy position. none of the active warming modalities were used until the core temperature was below 34°c or patient had a shivering score > 3. surgery was commenced when spinal block reached ≥ t6 dermatome determined by loss of sensation to pain with pinprick test. core body temperature and hemodynamic data were collected every minute for the first ten minutes and with five minute intervals till 30 minutes after spinal anesthesia and at the end of surgery. patients were transferred from operation room to post anesthesia care unit (pacu) after measurements of 30th minute follow-up data were recorded even if the surgery is completed earlier. data for demographic variables, total duration of surgery, ambient temperature, amount of intravenous fluids and irrigation solution, spread of spinal anesthesia, amount of atropine and ephedrine used and shivering were recorded. shivering was graded according to the scale defined by wrench et al.(26): 0 = no shivering; 1 = one or more of the following: piloerection, peripheral vasoconstriction, peripheral cyanosis without other cause, but without visible muscular activity; 2 = visible muscular activity confined to one muscle group; 3 = visible muscular activity in more than one muscle group; and 4 = gross muscular activity involving the entire body. active warming was commenced when the shivering score of the patient was > 3 for ethical reasons. effect of irrigation fluid temperature on surgeon comfort was assessed by a questionnaire graded between one to three which was completed by the surgeon at the end of the surgery where 1= i finished my surgery conventionally, 2 = i was not comfortable during the surgery, 3 = i was comfortable during the surgery. the primary outcome of the current study is core body temperature at the end of surgery. the secondary outcomes were the incidence of shivering and the degree of surgeon comfort at the end of surgery. we hypothesized that isothermic irrigation will help us to maintain patients’ core temperature and decrease the incidence of shivering while increasing the surgeon comfort. statistical analysis power analysis was performed with g*power 3.1.9.2 software. according to a previous study(22), where patients in group i received isothermic irrigation and group ii received irrigation at room temperature. in this study, baseline body temperatures were not significantly different (p = .60) between groups but during surgery body temperature of the patients in group ii decreased nearly 1°c more than patients in group i (p < 0.001). with a significance of .05 and a power of .86; a sample size of 30 in each group was necessary for the current study. table 1. demographic data of the patients and surgery variables. acharacteristics group w (n = 30) group rt (n = 30) p age(y) 44.2 ± 11.1 44.3 ± 10.7 .972 height(cm) 168.4 ± 8.8 169.9 ± 10.2 .553 weight(kg) 84.7 ± 12.4 83.8 ± 13.9 .810 bmi(kg/m2) 29.4 ± 3.9 29.2 ± 5.2 .910 asa [n(%)] i 17 (56.7) 15 (50.0) .796 ii 13 (43.3) 15 (50.0) iv volume (ml) 930.0 ± 265.4 880.0 ± 392.1 .642 i̇rrigation fluid volume (ml) 2040.0 ± 1553.2 1866.7 ± 1568.0 .745 duration of surgery (min) 32.8 ± 13.8 30.4 ± 18.5 .576 ambient temperature (°c) 23.3±1.1 23.7±1.1 .876 abbreviations: group w, patients received irrigation fluid at 37°c; group rt, patients received irrigation fluid at room temperature; bmi, body mass index; asa, american society of anesthesiologists; p, statistical significance; adata are presented as mean ± sd, or number (percent). time (min) group w group rt ap (n=30) (n=30) t 0 (min) 36.6 ± 0.4 36.6 ± 0.5 .977 t 1 (min) 36.6 ± 0.5 36.6 ± 0.5 .610 t 2 (min) 36.6 ± 0.5 36.5 ± 0.5 .643 t 3 (min) 36.5 ± 0.5* 36.4 ± 0.6* .469 t 4 (min) 36.4 ± 0.6* 36.3 ± 0.5* .379 t 5 (min) 36.4 ± 0.5* 36.3 ± 0.5* .960 t 6 (min) 36.4 ± 0.5* 36.2 ± 0.4* .698 t 7 (min) 36.3 ± 0.5* 36.2 ± 0.5* .676 t 8 (min) 36.2 ± 0.5* 36.1 ± 0.4* .811 t 9 (min) 36.1 ± 0.5* 35.9 ± 0.5* .453 t 10 (min) 36.1 ± 0.5* 35.8 ± 0.4* .256 t 15 (min) 36.0 ± 0.6* 35.6 ± 0.5* .051 t 20 (min) 36.0 ± 0.6* 35.4 ± 0.5* .038 t 25 (min) 36.0 ± 0.6* 35.1 ± 0.5* .015 t 30 (min) 36.0 ± 0.5* 35.1 ± 0.7* .013 t op (min) 36.0 ± 0.5* 35.2 ± 0.7* .018 δt (°c) 0.6 ± 0.4 1.4 ± 0.7 .016 bp .000 .000 abbreviations: group w, patients received irrigation fluid at 37°c; group rt, patients received irrigation fluid at room temperature; t, core body temperature (numbers near t indicates the time after spinal anaesthesia); δt, the difference of temperature between and baseline value and at the end of surgery *, in-group statistically significant temperature change between actual temperature and baseline value; a, independent samples t test (mean ± sd); b, repeated measures anova; p, statistical significance. table 2. in-group and between groups comparison of temperature change with time effect of isothermic irrigation on core temperature-cantürk et al. data collected from the current study was analyzed with ibm spss version 23.0 (spss inc., chicago, il, usa). frequencies, percentages, mean, and standard deviation were used to analyze descriptive data. qualitative data was analyzed with pearson chi square (x2), yates (x2) or fisher’s (x2) tests. normal distribution of data was analyzed with kolmogorov-smirnow and shapiro-wilk tests. independent samples t-test, mann whitney-u test, repeated measures analysis of variance tests were used for the comparison of data between groups. lsd (post-hoc) test was used to analyze the difference between data sampling intervals. probability (p) of less than .05 was accepted as statistically significant. results there was no statistically significant difference in patient and surgical variables as age, height, weight, bmi, asa physical status, iv and irrigation fluid volume, duration of surgery, and ambient temperature (table 1). maximum spread of spinal anesthesia in both groups reached to t5 dermatome (p = .352) and all patients completed the surgery under spinal anesthesia. need for atropine (n = 1, 3.3% in group w; n = 4, 13.3% in group rt) and ephedrine (n = 2, 6.7% in group w; n = 2, 6.7% in group rt) was not significantly different between groups (p = .353 and .617 respectively). baseline core body temperature was 36.6 ± 0.4°c in group w and 36.6 ± 0.5°c in group rt which was not statistically significant (p = .977). there was a gradual decrease in core temperature compared to basal core temperatures in both groups and the change in temperature was significant after the third minute until the end of surgery (p = .000, in-group analysis). the decrease in core temperature was statistically significant between groups after 20th minute until the end of surgery (table 2, figure 2). the change in temperature at the end of surgery was 0.6 ± 0.4°c in group w and 1.4 ± 0.7°c in group rt which was statistically significant (p = .016). shivering was observed in 2 patients (6.7%) in group w and 11 patients (36.7%) in group rt, and the difference was statistically significant (p = .012). we observed shivering ≥ 20 minutes after induction of spinal anesthesia in both groups. this was the time point where the change in core temperature was statistically significant between groups. of the 11 patients in group rt, 2 had grade 1 shivering, 6 had grade 2 shivering, 2 had grade 3 shivering and 1 had grade 4 shivering and this patient was warmed with active warming. however, the two patients that shivered in group w had grade 1 shivering (table 3, figure 3). there was a statistically significant difference in surgeon comfort between groups (p = .000). in group w surgeons stated they were comfortable in 29 cases but in group rt they were only comfortable in 11 cases (table 4). no complications were reported during the operation and within the postoperative 24 hours. discussion our study has shown that use of isothermic irrigation in endoscopic urethral stone treatment surgery with spinal anesthesia is effective to decrease the incidence of intraoperative hypothermia and one of its perturbing results shivering as well as increasing surgeon comfort. hypothermia under spinal anesthesia is a common occurrence but it is not considered by most of the anesthesiologists(27) especially when the predicted duration of operation is short. hypothermia under spinal anesthesia is affected by the ambient temperature,(3) the magnitude and duration of surgery,(4) and the temperature of intravenous fluids given.(5) endoscopic urethral stone treatment surgery is a short lasting surgical procedure, when uncomplicated, and carried out in outpatient settings in our institution. up to date we were not monitoring this patient group for hypothermia as most of the anesthesiologists do worldwide. however the results of the current study have shown that there is a significant core temperature difference between basal values and the temperature measured at the end of operation if the patients are irrigated with fluids at room temperature rather than irrigated with isothermic fluids. in our study, the difference in core body temperature in isothermic irrigation group was 0.6 ± 0.4°c and 1.4 ± 0.7°c in patients receiving irrigation fluid at room temperature (p = .016). the amount of irrigation fluid, intravenous table 3. distribution of shivering ashivering data group w(n = 30) group rt (n = 30) p shivering [n(%)] 0 28 (93.3) 19 (63.3) .012 > 0 2 (6.7) 11 (36.7) 1 2 (6.7) 2 (6.7) 2 - 6 (20.0) 3 - 2 (6.7) 4 - 1 (3.3) abbreviations: group w, patients received irrigation fluid at 37°c; group rt, patients received irrigation fluid at room temperature. p = statistical significance. data are presented as numbers and frequencies. shivering is graded between 0 and 4. adata are presented as mean ± sd, or number (percent) abbreviations: group w, patients received irrigation fluid at 37°c; group rt, patients received irrigation fluid at room temperature; data is presented as means ± standard deviations and percentages. p = statistical significance. adata are presented as mean ± sd, or number (percent) asurgeon comfort group w (n = 30) group rt (n = 30) p surgeon comfort 3.0 ± 0.2 2.2 ± 0.7 .000 1 0 (0.0%) 5 (16.7%) .000 2 1 (3.3%) 14 (46.7%) 3 29 (96.7%) 11 (36.7%) table 4. surgeon comfort distribution. effect of isothermic irrigation on core temperature-cantürk et al. endourology and stones diseases 04 vol 17 no 01 january-february 2020 03vol 17 no 01 january-february 2020 05 fluid, the duration of surgery and ambient temperature were not significantly different between the groups in the current study (p > 0.05). the temperature of the irrigation fluid was the only different variable effecting the change in core temperature. our study results were in accordance with most of the previous studies performed to analyze the effect of irrigation fluid temperature on core body temperature(14,18,21-24) but jaffe et al. (16) have documented that length of stay in operation room, ambient temperature, and the amount of absorbed irrigation fluid might have a greater effect on core body temperature than the irrigation fluid temperature in patients undergoing transurethral resection of the prostate gland. however, in the current study the only parameter affecting the core body temperature at the end of operation was the temperature of the irrigation fluid and we found a significant difference between the groups. in our study, ambient temperature and length of stay in operating room were not significantly different between groups. unlike transurethral resection of prostate gland, there is not much fluid absorption in endoscopic urethral stone treatment surgery which is speculated to affect the change in core body temperature by jaffe et al.(16) we did not use active warming modalities until the core body temperature of the patient was below 34°c whereas jaffe et al.(16) used external warming for their patients which may have affected their results. in the current study the incidence of decrease in core body temperature was less with isothermic irrigation but could not be prevented in all participant patients. besides isothermic irrigation, active warming devices and warmed intravenous fluids should be used to prevent hypothermia when eligible to avoid well known perturbing effects of hypothermia. but we have to acknowledge the clinicians to strictly control the warmed irrigation fluid temperature to prevent thermal injury to the bladder and the urinary tract. okeke(21) have reported that although patients receiving isothermic irrigation and intravenous hydration at room temperature in their group2, some decrease in core temperature still occurred as in our study but when warmed intravenous and isothermic irrigation fluids were given no alterations in core body temperatures were observed. there are four reliable sites defined to measure core body temperature: pulmonary artery, nasopharynx, distal esophagus, and tympanic membrane.(2) the first three measurement sites are inappropriate to monitor core temperature in an awake patient under spinal anesthesia. therefore we used tympanic membrane temperatures measured with infrared tympanic thermometer (riester ri-thermo®n, rudolf riester gmbh, germany) which by its manufacturers is said to give accurate measurements between 0-100°c. in our study shivering was graded according to scale defined by wrench et al.(26) patients who had shivering started to shiver ≥ 20 minutes after administration of spinal anesthesia which was consistent with the observation of statistically significant difference in core body temperature between groups. shivering was observed in two patients (6.7%) in group w and eleven patients in group rt (36.7%). these results are in accordance with the results of okeke et al.(21) where in their study 13 of 40 patients in group1 and 3 of 40 patients in group2 had shivering. surgeon comfort during endoscopic urethral stone surgery is inversely proportional to the presence and degree of shivering. when patient starts to shiver, it becomes very difficult for the surgeon to manipulate the lithotripter (sphinx 30 litho, lisa laser products ohg, katlenburg-lindau, germany) therefore the surgeon asks the anesthesiologist in charge of the patient for decreasing the degree of shivering or preventing it. the results of surgeon comfort in the current study was significantly higher in group w (p < .001) compared to group rt. besides improvement in surgeon comfort with warmed irrigation during endoscopic surgeries, mohammadzadeh razaei et al.(28) have reported that they obtained better surgical outcomes when warmed irrigation is used hovewer in an editorial and the response letter to this editorial it was reported that these results needed validation with more studies with higher sample size.(28,29) limitations of our study includes the data collection time was limited with thirty minutes. although measurement of core temperature continued while patients were in pacu, these measurement results were not collected as study data according to study protocol. patients were warmed with active warming modalities if their core temperature was below 340c or shivering score was > 3 at pacu. the patients were hydrated with fluids at room temperature but it is recommended to infuse iv fluids at 37°c. another limitation of the study was patient comfort was not included in the study protocol. conclusions in conclusion, isothermic irrigation during endoscopic urethral stone treatment surgery decreases the incidence of postoperative hypothermia and shivering while increasing surgeon comfort. although the surgical procedure lasts shorter and the amount of irrigation fluid figure 2. temperature changes in groups with respect to time figure 3. distribution of shivering according to grade effect of isothermic irrigation on core temperature-cantürk et al. is less compared to transurethral resection of prostate gland, isothermic irrigation provides similar benefits against intraoperative hypothermia and its perturbing comorbidities during endoscopic urethral stone treatment surgery under spinal anesthesia. acknovledgement none to declare. conflict of interest the authors declare no conflict of interest. references 1. kurz a, sessler di, schroeder m, kurz m. thermoregulatory response thresholds during spinal anesthesia. anesth analg. 1993;77:7216. 2. sessler di. temperature monitoring and management during neuraxial anesthesia. anesth analg. 1999;88:243-5. 3. morris rh, wilkey br. the effects of ambient temperature on patient temperature during surgery not involving body cavities. anesthesiology. 1970;32:102-7. 4. vaughan ms, vaughan rw, cork rc. postoperative hypothermia in adults: relationship of age, anesthesia, and shivering to rewarming. anesth analg. 1981;60:746-51. 5. workhoven mn. intravenous fluid temperature, shivering, and the parturient. anesth analg. 1986;65:496-8. 6. connor el, wren kr. detrimental effects of hypothermia: a systems analysis. j perianesth nurs. 2000;15:151-5. 7. rajagopalan s, mascha e, na j, sessler di. the effects of mild perioperative hypothermia on blood loss and transfusion requirement. anesthesiology. 2008;108:71-7. 8. michelson ad, macgregor h, barnard mr, kestin as, rohrer mj, valeri cr. reversible inhibition of human platelet activation by hypothermia in vivo and in vitro. thromb haemost. 1994;71:633-40. 9. just b, delva e, camus y, lienhart a. oxygen uptake during recovery following naloxone. relationship with intraoperative heat loss. anesthesiology. 1992;76:60-4. 10. frank sm, fleisher la, breslow mj, et al. perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. a randomized clinical trial. jama. 1997;277:1127-34. 11. winfree ch, baker kz, connollly es. perioperative normothermia and surgicalwound infection. n engl j med. 1996;335:749; author reply -50. 12. lenhardt r, marker e, goll v, et al. mild intraoperative hypothermia prolongs postanesthetic recovery. anesthesiology. 1997;87:1318-23. 13. mahoney cb, odom j. maintaining intraoperative normothermia: a metaanalysis of outcomes with costs. aana j. 1999;67:155-63. 14. campbell g, alderson p, smith af, warttig s. warming of intravenous and irrigation fluids for preventing inadvertent perioperative hypothermia. cochrane database syst rev. 2015cd009891. 15. dyer pm, heathcote ps. reduction of heat loss during transurethral resection of the prostate. anaesth intensive care. 1986;14:126. 16. jaffe js, mccullough tc, harkaway rc, ginsberg pc. effects of irrigation fluid temperature on core body temperature during transurethral resection of the prostate. urology. 2001;57:1078-81. 17. jin y, tian j, sun m, yang k. a systematic review of randomised controlled trials of the effects of warmed irrigation fluid on core body temperature during endoscopic surgeries. j clin nurs. 2011;20:305-16. 18. kelly ja, doughty jk, hasselbeck an, vacchiano ca. the effect of arthroscopic irrigation fluid warming on body temperature. j perianesth nurs. 2000;15:245-52. 19. monga m, comeaux b, roberts ja. effect of irrigating fluid on perioperative temperature regulation during transurethral prostatectomy. eur urol. 1996;29:26-8. 20. oh jh, kim jy, chung sw, et al. warmed irrigation fluid does not decrease perioperative hypothermia during arthroscopic shoulder surgery. arthroscopy. 2014;30:159-64. 21. okeke li. effect of warm intravenous and irrigating fluids on body temperature during transurethral resection of the prostate gland. bmc urol. 2007;7:15. 22. pit mj, tegelaar rj, venema pl. isothermic irrigation during transurethral resection of the prostate: effects on peri-operative hypothermia, blood loss, resection time and patient satisfaction. br j urol. 1996;78:99103. 23. singh r, asthana v, sharma jp, lal s. effect of irrigation fluid temperature on core temperature and hemodynamic changes in transurethral resection of prostate under spinal anesthesia. anesth essays res. 2014;8:20915. 24. tekgul zt, pektas s, yildirim u, et al. a prospective randomized double-blind study on the effects of the temperature of irrigation solutions on thermoregulation and postoperative complications in percutaneous nephrolithotomy. j anesth. 2015;29:165-9. 25. winter m. effects of irrigation fluid warming on hypothermia during urologic surgery. urol nurs. 1994;14:6-8. 26. wrench ij, cavill g, ward je, crossley aw. effect of isothermic irrigation on core temperature-cantürk et al. endourology and stones diseases 06 vol 17 no 01 january-february 2020 03vol 17 no 01 january-february 2020 07 comparison between alfentanil, pethidine and placebo in the treatment of post-anaesthetic shivering. br j anaesth. 1997;79:541-2. 27. frank sm, nguyen jm, garcia cm, barnes ra. temperature monitoring practices during regional anesthesia. anesth analg. 1999;88:373-7. 28. mohammadzadeh rezaei ma, akhavan rezayat a, tavakoli m, jarahi l. evaluation the result of warm normal saline irrigation in ureteral endoscopic surgeries. urol j. 2018;15:83-6. 29. kashi ah. re: the evaluation of the result of warm normal saline irrigation in ureteral endoscopic surgeries: a randomized clinical trial. urol j. 2018;15:222-3. effect of isothermic irrigation on core temperature-cantürk et al. kidney transplantation medium-term outcomes of covid-19 infection after kidney transplantation for ongoing living and deceased kidney transplantations within the covid-19 pandemic nasser simforoosh1, atefe eslami1, yaghub mohammadian roshan1, majeed ali askari2, navid masoumi2, maryam vaezjalali3, pardis ziaeefar1, amir h kashi1* objectives: to present the early to midterm experience of two referral kidney transplantation centers with living and deceased kidney transplantations that were performed within the covid-19 pandemic. materials and methods: all cases performed in two referral centers in iran within the covid-19 pandemic were investigated. transplantations were performed from may 2020 to february 2021. the protocol for screening included nasopharyngeal rt-pcr with chest ct scan for living and deceased transplantations in center a and rtpcr for living transplantations and chest ct scan for deceased transplantations in center b. patients were followed for 14-26 months after transplantation regarding covid-19 infection and its outcomes in case of infection. results: 103 kidney transplantations were performed during the study period including 54 (52.4%) living and 49 (47.6%) deceased kidney transplantations. twenty-four recipients (23.3%) and a living donor (1%) were infected with covid-19. the severity of covid-19 infection was mild, moderate, severe, and critical in 16 (66.6%), 4 (16.6%), 2 (8.4%), and 2 patients (8.4%), respectively. two mortalities were observed within transplantation recipients with covid-19 infection (1.9%). 87.5% (7/8) covid-19 infections in center b were observed in recipients of deceased transplantations who were screened only by chest ct scan. conclusion: the results of this study indicate a low frequency of covid-19 mortality (1.9% for the whole cohort and 8.3% within covid-19 infected patients) for recipients of living and deceased kidney transplantation that were performed within the covid-19 pandemic. the above findings highlight for the first time in a large study the probability of living kidney transplantation during the covid-19 pandemic in case strict screening of donors and recipients and close supervision of operating rooms and wards are implemented. we further hypothesize the inadequacy of chest ct scan for screening of covid-19 in kidney transplantation surgery candidates. keywords: kidney transplantation; covid-19 pandemic; living donor; deceased donor; rt-pcr covid-19 test introduction with the emergence of coronavirus disease of 2019 (covid-19) in early 2020, the continuation of kidney transplantation activities was called into serious reconsideration. the adverse consequences of covid-19 in patients with immune suppression and early reports of high covid-19 fatality in patients who were previously transplanted(1,2) resulted in the closure of kidney transplantation programs from living donors in most centers. the statistics for deceased kidney transplantations also showed a decrease of 25-90 percent in many centers(3). as a result, the waiting list for kidney transplantation substantially increased in many countries. for example, the waiting list for kidney transplantation in new york has increased by 100%(1). later reports, confirmed the increased propensity for infection with covid-19 in end-stage renal disease (esrd) patients waitlisted for transplantation(1). frequent visits to dialysis centers which were mainly located in hospitals rendered esrd 1urology and nephrology research center (unrc), shahid labbafinejad hospital, shahid beheshti university of medical sciences (sbmu), tehran, iran. 2department of urology, shahid modarres hospital, shahid beheshti university of medical sciences, tehran, iran. 3department of microbiology, shahid beheshti university of medical sciences (sbmu), tehran, iran. *correspondence: urology and nephrology research center (unrc), shahid labbafinejad hospital, shahid beheshti university of medical sciences (sbmu), tehran, iran. email: ahkashi@gmail.com. received august 2021 & accepted november 2021 patients at a higher risk of infection with covid-19(1). high mortality of covid-19 has been reported in kidney transplantation waitlisted patients. craig-shapiro and colleagues reported a 34% mortality rate of covid-19 in waitlisted patients(1). also, it is noteworthy that most published literature on the outcomes of covid-19 infection in transplantations from living and deceased donors relate to the transplantations performed before the entrance of the covid-19 pandemic in any country and after that, transplantation activities have been suspended in most centers and up to our best knowledge, there is no large report of ongoing kidney transplantations from living donors within the covid-19 pandemic. in this report, we have included the ten-month experience of kidney transplantation from living and deceased donors within the covid-19 pandemic in two referral centers from iran. we followed kidney transplant recipients and investigated the frequency of early and mid-term covid-19 infection in these patients and the outcomes of such an infection in them. urology journal/vol 19 no. 2/ march-april 2022/ pp. 126-130. [doi: 10.22037/uj.v18i.6930] vol 19 no 2 march-april 2022 127 materials and methods after the start of the covid-19 pandemic in iran on the 20th of february 2020, the ministry of health ordered to suspend all kidney transplantations from living donors. then in may 2020, permissions for transplantations from living donors were granted on limited indications for donor or recipient. these indications included vascular access for dialysis in recipients and the unavailability of donors in the future due to a change of residential place or workplace for donors. then based on the review of kidney transplantations from living donors based on the above indications, the restriction on this kind of transplantation was lifted after november 2020. all cases of kidney transplantations from living and deceased donors performed in two referral transplantation centers in iran which were done within the covid-19 pandemic from may 2020 until february 2021 were included in this study. we have previously published our protocol of kidney transplantation(4) and the added details based on the covid-19 pandemic which was different in the 2 studied centers as explained below: in center a: all personnel of the transplantation ward and operation rooms were screened for covid-19 by nasopharyngeal specimens after the start of elective operations in may 2020. the urology ward protocol permitted elective operations for patients after a negative nasopharyngeal reverse transcription polymerase chain reaction (rt-pcr) which was performed within 1-3 days before surgery. all cases of emergent or urgent operations for patients who did not have a covid-19 test result were done in a dedicated operating room which was not used for elective operations. hospitalization of patients in urology and transplantation wards was permitted once a negative nasopharyngeal pcr was obtained. patients without a negative covid-19 test stayed in the emergency ward or in a transition ward until when the result of the covid-19 test was prepared. covid-19 patients with any disease were managed in the covid-19 ward. donors and recipients were first screened before hospitalization regarding clinical signs and symptoms and high-risk behaviors. in case of negative findings on the above screening, donors and recipients were referred for covid-19 rt-pcr and assessment of covid-19 serum immunoglobulin m (igm) and immunoglobulin g (igg). if the result of the above-mentioned tests were negative, the donor and recipients were referred for chest computed tomography ct scan and consultation by the infectious disease specialist who reviewed the results of pcr, serum igm and igg, and chest ct scan and gave permission for transplantation. recipients of deceased transplantations were also screened for covid-19 by nasopharyngeal rt-pcr and chest ct scan. donors and recipients were hospitalized in the transplantation ward 1-2 days before the scheduled operation. the transplantation ward only admitted recipients and donors just before and after transplantation or in the case of need for hospitalization shortly after the discharge. donor nephrectomy in center a was performed through a mini laparoscopic transperitoneal approach as previously explained(4). after completion of transplantation, donors and recipients were transferred to the transplantation ward. immunosuppressive agents included tacrolimus 0.1 mg/kg from 24 hours before transplantation, and the following medications after transplantation: mycophenolate mofetil every 8 hours; valganciclovir once daily. prednisolone was administered 200mg iv one hour before transplantation and then 50 mg on the 1st postoperative day, 40 mg on the 2nd day, 30 mg on the 3rd day, 20 mg on the 4th day, and 15 mg until discharge. patients were discharged on 10 mg of prednisolone and referred to a nephrologist one week after discharge for any required change in medications. in center b: the screening protocol included screening regarding clinical signs and symptoms and high-risk behaviors for the two weeks before admission. in case of negative findings on the above screening, nasopharyngeal rt-pcr was performed for living transplantation donors and recipients. if the result of rt-pcr was negative with negative clinical and history findings no further investigation was performed. recipients of deceased donors were screened by chest ct scan and clinical signs and symptoms. in case of suspicious findings on the aforementioned investigations, rt-pcr was requested. if no suspicious findings were observed in chest ct scan or clinical evaluation of a deceased transplant recipient in center b, no further investigation was performed. screening of ward personnel and operating theatres personnel as explained for center a was not performed in center b. donor nephrectomy in center b was performed through open nephrectomy in flank position. all patients were followed up after discharge in nephrology and urology clinics and also by phone call. results the first transplantation in center a was performed in the covid-19 pandemic on the 5th of may 2020 from a living donor and the first transplantation in center b was performed on the 8th of june 2020 from a deceased variable center a center b total number 53 50 103 gender; female, n(%) 21 (39.6) 13 (26.0) 35 (34.0) age (years), mean±sd (range) 37.4 ± 13.7 (9-65) 41.4 ± 13.1 (18-69) 40.5 (12-69) living donor, n(%) 39 (74) 14 (28) 54 (52) first transplantation, n(%) 50 (94) 47 (94) 98 (95) preemptive transplantation, n(%) 10 (19) 5 (10) 16 (15) dialysis duration (months), median (iqr) 12 (5-24) 20 (8-30) 18 (6-30) preoperative creatinine; mg/dl, mean ± sd 8.4 ± 3.2 9.9 ± 3.2 8.7 (6.6-10.9) 7th postop day creatinine; mg/dl, median (iqr) 1.5 (1.2-1.9) 1.5 (1.3-2.1) 1.5 (1.3-2.0) preoperative hemoglobin; mg/dl, mean ± sd 11.2 ± 1.6 11.1 ± 2.5 11.1 ± 2.1 7th postop day hemoglobin; mg/dl, mean ± sd 10.0 ± 1.5 9.8 ± 1.5 9.9 ± 1.5 follow up duration (months); median (iqr) 22 (20-24) 22 (20.7-23.7) 22 (20-24) table 1. demographic and operative characteristics of transplantations performed during the covid-19 pandemic in two referral centers. ongoing kidney transplantation within the covid-19 pandemic-simforoosh et al. kidney transplantation 128 donor. one hundred three transplantations were performed collectively in centers a and b from the start dates mentioned above till the end of the study including 53 transplantations in center a and 50 transplantations in center b. the demographics of transplantations performed in the two centers have been presented in table 1. the reasons for chronic kidney failure were: hypertension (37 patients, 35.9%), idiopathic (14 patients, 13.6%), alport syndrome (4 patients, 3.9%), diabetes mellitus (4 patients, 3.9%), polycystic kidney disease (7 patients, 6.8%), nephritis syndrome (5 patients, 4.9%), nephrotic syndrome (14 patients, 13.6%), reflux nephropathy (4 patients, 3.9%), and other miscellaneous causes (14 patients, 13.6%). patients’ follow-up duration ranged from 14 months to 26 months in center a and from 19.5 to 25 months in center b. twenty-four patients (23.3%) were diagnosed with covid-19 infection in the hospitalization period or posttransplantation period investigation including sixteen patients in center a and eight patients in center b. in center a out of sixteen covid-19 infections, 12 were from living donors, and 4 were from deceased donors. five of the cases were identified when one of the service personnel of the transplantation ward in center a was identified to be infected with covid-19. he had mild symptoms for some days before being diagnosed with covid-19 infection. after this observation, all personnel of the transplantation ward of center a were reinvestigated for covid-19 infection by nasopharyngeal rt-pct and also all hospitalized patients in this ward. furthermore, transplantation was suspended for 2 weeks in this center. during this investigation, 5 transplantation recipients (4 from living donors and one from a deceased donor) and one donor were diagnosed patients number center age gender donor type severity* hospitalization presentation medication duration of changes infection from transplantation 1 a 22 m l mild yes (one day) myalgia and mild fever symptomatic medication 3 weeks 2 a 53 f c mild no fatigue and myalgia, mild conservative management 4 months involvement in chest ct 3$ a 17 m l mild yes nil conservative management 3 weeks 4$ a 22 m l moderate yes presented with fever and remdesivir and 5 months dyspnea, patchy plasmapheresis infiltration in chest ct 5$ a 13 m c mild no non-symptomatic, transplant was rejected 1 week rt-pcr was performed as screening 6$ a 34 m l moderate yes fever and dyspnea, favipiravir, remdesivir 10 days patchy ground-glass in mycophenolate withheld chest ct 7$ a 65 m l moderate yes fever and dyspnea remdesivir and 1 month plasmapheresis 8 a 27 f l mild yes fever,cough,dyspnea, conservative management 1 week mild involvement in chest ct 9 a 37 m l mild no nil nil 1 month 10 a 36 f l mild no fatigue and myalgia nil 7 months 11 a 22 f l mild no myalgia, headache conservative management 1 year 12 a 47 m l critical yes severe respiratory remdesivir, bolus steroid 2 months symptoms,o 2 saturation drop, icu admitted (only 1 day), intubated, expired 13 a 29 m l mild no nil conservative management 11 months 14 a 32 m c mild no throat pain, fatigue sovodak, conservative 10 months management 15 a 36 m c mild no throat pain, fever conservative management 4 months 16 a 47 f l mild no coryza, headache conservative management 9 months 17 b 53 m c severe yes fever and dyspnea, 80% remdesivir, bolus steroid 2 months involvement in chest ct cellcept withhold 18 b 27 f c mild no nil nil 1 week 19 b 51 f c mild no fever and myalgia levofloxacin cellcept 9 months dose reduced 20 b 38 m c critical yes severe respiratory ramdesivir, plasma 2 weeks symptoms, o 2 saturation exchange, levofloxacin drop, icu admitted, intubated, transplant rejected, expired 21 b 42 m c moderate yes fever and dyspnea, 40% remdesivir, levofloxacin 1 month chest involvement in ct mycophenolate withhold 22 b 32 m c mild no fatigue, myalgia conservative management 6 months 23 b 68 f c severe yes dyspnea, fever remdesivir, steroid 6 months 24 b 50 m l mild no common cold conservative management 2 months table 2. details of recipients with covid-19 infection in the post-transplantation period. *based on the who-china joint mission classification (13) $patients in center a who were diagnosed with covid-19 after screening of all patients in consequence to the detection of covid-19 infection in one of the service personnel of transplantation ward. all these patients were transplanted within a time range of 10 day ongoing kidney transplantation within the covid-19 pandemic-simforoosh et al. vol 19 no 2 march-april 2022 129 with covid-19 infection. patients without symptoms or with mild symptoms were managed as outpatient and patients with moderate to severe symptoms were kept hospitalized. the donor with covid-19 infection was a mother who gave her kidney to her child. both mother and child were hospitalized when screening was performed. the child who was the transplant recipient was not infected and was kept hospitalized and her mother who has covid-19 infection without any symptoms was managed as an outpatient without any complications or need for readmission. eleven other covid-19 infections were detected in the whole transplantations that were performed in center a out of this short period mentioned above. in center a, one patient died due to the severity of pulmonary involvement. another patient from the center a cohort also died in the follow up period due to cardiac arrest at home. in center b, 7 posttransplantation covid-19 infections were observed in recipients of deceased donors (7/35, 20.0%) and only one covid-19 infection was observed in recipients of living donors (1/14, 7.1%). four patients were hospitalized due to the severity of their covid-19 infection of whom one patient died. another four patients in the center b cohort experienced mild flu-like symptoms and were assumed to be suffering from common cold according to their nephrologist and did not perform covid-19 pcr. all these four patients experienced a subtle course of disease and recovered with symptomatic medications. details on cases of posttransplantation covid-19 infection and their management are given in table 2. discussion the results of this study reveal a recipient covid-19 mortality rate of 1.9% (2/103) and no mortality for donors for the kidney transplantation activities that were performed under regulatory protocols in the covid-19 pandemic. to our best knowledge, this is the first report of experience with ongoing living kidney transplantations within the covid-19 pandemic including short and medium term frequency and outcomes of covid-19 infection in these recipients. the infection rate with covid-19 for donors and recipients was 23.3% (24/103) and the mortality rate for transplant patients who were infected with covid-19 was 8.3% (2/24) during 14-26 months of follow up after transplantation. the reported frequencies show that performing living and deceased kidney transplantations in the covid-19 pandemic can be permissible in case strict regulatory disciplines are followed to ensure safety in the operation room and hospitalization wards. the mortality percent of recipients with covid-19 is 3.86 times the average mortality rate of covid-19 in iran but is considerably lower than earlier high mortality rates for old-time transplanted patients infected with covid-19 from our center(2) or other centers around the world which were reported in a range of 6-46%(5). the mortality rate of transplanted patients with covid-19 in the current report is one of the lowest figures presented in the literature. also in donors, only one case of covid-19 infection was observed in a mother who gave her kidney to her child who experienced a mild covid-19 infection and recovered by outpatient management and did not require hospitalization. one of the interesting findings of this study is that most cases (7/8, 87.5%) of covid-19 infection in center b were observed in recipients of deceased donors. the protocol for screening of recipients in center b was different for recipients of living versus deceased donors. recipients of deceased donors were screened only by chest ct scan while recipients of living donors were screened by nasopharyngeal rt-pcr. this observation can challenge the adequacy of chest ct scan in the screening of transplantation recipients. covid-19 infection in transplant patients has mostly been reported in patients who received a transplant before the covid-19 pandemic or from patients who had received a transplant before the entrance of the pandemic to a country or region and then have been infected with covid-19. one of the main issues investigated in the outcome of covid-19 infection in transplant patients is the interval between transplantation and infection with covid-19. most studies have reported transplants with a long interval between transplantation and infection with covid-19. in these series, the mortality rate has been reported widely from 6% by montguad-marrahi and colleagues (6) to 46 % by clarke et al.(5). the relationship of the time since transplantation with the outcome of covid-19 infection was investigated in two studies(7). these studies failed to disclose any relationship between the time since transplantation and outcomes of covid-19 in transplant patients. besides, two studies that investigated the mortality of covid-19 in transplant patients who were infected within 60 days after transplantation reported a high mortality rate of up to 46% which is one of the highest mortality rates of covid-19 in transplant patients(8, 9). nevertheless, there is limited experience on the outcome of covid-19 in the early time after kidney transplantation and up to our best knowledge, we could not find studies that report the outcomes of ongoing transplantations in living donor transplantations that were performed within the established covid-19 pandemic. the importance of such investigation lies in the different behavior of people, medical personnel, and hospitals regarding the adoption of covid-19 safe practices(10, 11). any delay in the adoption of safety protocols in the advent of covid-19 in any region can result in higher infection and mortality rates in the primary surge of covid-19 and relative improvement after the primary surge in many countries due to better adoption and regulation of safety protocols and better access to personal protective equipment. furthermore, the highest dose of immunosuppressive regimens is in the first month after transplantation and the recovery study reported a favorable outcome of high dose of corticosteroids in some severe cases of covid-19(12). in iran, as indicated above, all living transplantation activities were prohibited after the entrance of covid-19 by the ministry of health. after two months, living kidney transplantations were possible for limited indications of donor and recipient. the deceased kidney transplantations also faced a dramatic drop down in the first two months after the covid-19 pandemic in iran. the investigation of the results of living kidney transplantations by limited indications lately by the ministry of health resulted in a lifting of the constrictions for living kidney transplantation during the covid-19 pandemic by the ministry of health. one of the reasons which cause to think of a different outcome of covid-19 infection during the early days after kidney transplantation is the high dose of immuongoing kidney transplantation within the covid-19 pandemic-simforoosh et al. kidney transplantation 130 nosuppressive regimen during the early days after transplantation. this high dose can theoretically predispose patients to a higher propensity for covid-19 infection. but on the other hand, another theory describes a smoother complication of covid-19 in early transplantation as the mechanism of tissue injury in covid-19 is immune-mediated tissue injury which will be smoother under high doses of immunosuppressive regimens(12). the mortality rate of transplanted patients infected with covid-19 in the current report is one of the lowest reports. the investigation of the reasons behind this observation is out of the scope of this report. one of the considerations in this report is the performance of donor nephrectomy by mini laparoscopy in one of the reported centers. the favorable outcomes of this report considering the low covid-19 infection rate in the first month after donation and transplantation is a clue to the relative safety of the described protocol for screening of donors and recipients despite performance of a laparoscopic donor nephrectomy. previous reports from our center during the early days of the covid-19 pandemic in iran revealed a very high mortality (8/12; 75%) of previously transplanted patients with covid-19 infection in the early advent of covid-19 in iran(2). however, despite sustaining a relatively high mortality among old transplantations with covid-19 infection, the results of covid-19 infection in the early days after transplantation in our experience have been more favorable. further studies are needed to replicate our findings. in consideration of the results of the current report, the following limitations should be taken into account: this report investigated the covid-19 infection and mortality of kidney transplantations during the early-midterm period after transplantation, the possibility of infection with covid-19 and its consequences in the longterm cannot be ruled out however if even such infections occur, it will not influence the early-midterm infection and mortality rate of covid-19 after transplantation which is the main focus of this study; the protocol for donor and recipient screening and also protocols for screening and personnel and restrictions in the wards and operating rooms were not the same for centers of the study however data regarding outcomes of each center and the details of safety protocols for each center has been explained in this report. conclusions the findings of our study disclose that provided strict criteria are implemented to screen donors and recipients for kidney transplantation including radiologic, and pcr investigation of covid-19 infection associated with isolation of transplantation wards and careful monitoring of patients flow in the operating rooms, the performance of ongoing living and also deceased kidney transplantation during the covid-19 pandemic can be associated with a low mortality profile. conflict of interest the authors declare no conflict of interest. references 1. craig-schapiro r, salinas t, lubetzky m, abel bt, sultan s. covid-19 outcomes in patients waitlisted for kidney transplantation ongoing kidney transplantation within the covid-19 pandemic-simforoosh et al. and kidney transplant recipients. am j transplant.2020. 2. abrishami a, samavat s, behnam b, arabahmadi m, nafar m, sanei taheri m. clinical course, imaging features, and outcomes of covid-19 in kidney transplant recipients. eur urol. 2020;78:281-6. 3. rodrigo e, miñambres e. covid-19related collapse of transplantation systems: a heterogeneous recovery? am j transplant. 2020;20:3265-6. 4. simforoosh n, basiri a, tabibi a, javanmard b, kashi ah, soltani mh, et al. living unrelated versus related kidney transplantation: a 25-year experience with 3716 cases. urol j. 2016;13:2546-51. 5. clarke c, lucisano g, prendecki m, gleeson s, martin p, ali m, et al. informing the risk of kidney transplantation versus remaining on the waitlist in the coronavirus disease 2019 era. kidney int rep. 2021;6:46-55. 6. montagud-marrahi e, cofan f, torregrosa jv, cucchiari d, ventura-aguiar p, revuelta i, et al. preliminary data on outcomes of sarscov-2 infection in a spanish single center cohort of kidney recipients. am j transplant. 2020;20:2958-9. 7. cravedi p, mothi ss, azzi y, haverly m, farouk ss. covid-19 and kidney transplantation: results from the tango international transplant consortium. am j transplant. 2020;20:3140-8. 8. pascual j, melilli e, jiménez-martín c, gonzález-monte e, zárraga s, gutiérrezdalmau a, et al. covid-19-related mortality during the first 60 days after kidney transplantation. eur urol. 2020;78:641-3. 9. mahalingasivam v, craik a, tomlinson la, ge l, hou l, wang q, et al. a systematic review of covid-19 and kidney transplantation. kidney int rep. 2021;6:2445. 10. basiri a, zafarghandi m, golshan s, eshrati b, fattahi a, kashi ah. covid-19 infection and mortality rates within medical specialists and general practitioners and its comparison with the general population: a longitudinal nationwide study. iran j public health. 2021;50:1421-7. 11. ghahestani sm, kashi ah. guidelines for urological surgeries in the covid-19 pandemic: is it time for revision? urol j. 2021;17:560-1. 12. horby p, lim ws, emberson jr, mafham m, bell jl, linsell l, et al. dexamethasone in hospitalized patients with covid-19. new eng j med. 2021;384:693-704. 13. kataria a, yakubu i, winstead r, gowda m, gupta g. covid-19 in kidney transplantation: epidemiology, management considerations, and the impact on kidney transplant practice. transplantation direct. 2020;6:e582. vol 16 no 01 january-february 2019 21 endourology and stone disease chinese one-shot dilation versus sequential fascial dilation for percutaneous nephrolithotomy: a feasibility study and comparison xiong jing1#, shi ying2#, zhang xiaoping2, xing yifei2, li wencheng m.d.2* purpose: nephrostomy tract creation is a key step to perform a successful percutaneous nephrolithotomy (pcnl). in an attempt to improve the conventional technique of the tract dilation, a chinese one-shot dilation was developed and compared with the sequential fascial dilation using a retrospective study. materials and methods: we retrospectively reviewed medical records of 116 patients who had undergone 116 pcnl in our department from january 2012 to december 2012. the nephrostomy tracts had been created by using chinese one-shot (one-shot group, 59 cases) or sequential fascial dilation technique (sequential group, 57 cases). tract creation time, hemorrhage loss, overall renal function, tract dilation failure and major complications were compared between the two groups. results: the one-shot group had a significantly shorter mean (sd) tract creation time (1.9 ± 0.5 vs 4.5 ± 0.8 min, p < 0.001) and lower mean (sd) decrease in hemoglobin concentration (0.60 ± 0.34 vs 0.69 ± 0.36 g/dl, p = 0.0008) compared to the sequential group, respectively. there were no significant differences in mean (sd) value changes of preoperative and postoperative serum creatinine concentrations (4.7 ± 11.5 vs 4.8 ± 14.8 μmol/l, p = 0.2611) and stone-free rate (86.4% vs 85.9%, p = 0.6145) between the one-shot and sequential group. no tract dilation failure or major complications occurred in both of the groups. conclusion: this retrospective study demonstrated that the chinese one-shot dilation technique is as safe and feasible as the conventional sequential fascial dilation. furthermore, a greater reduction in tract creation time and blood loss was achieved using this technique. key words: nephrolithotomy, percutaneous; dilation; kidney calculi; complications introduction percutaneous nephrolithotomy (pcnl) is an effec-tive treatment method for large and complex kidney stones (1,2) and increasingly applied to moderate stone burdens, particularly for stones in the lower pole calyces(3). the key step of pcnl is nephrostomy tract creation and the most common complications of pcnl, such as renal hemorrhage, tract dilation failure, and collecting system perforation, are all associated with this step(4). currently, nephrostomy tract creation is performed with three classical dilation techniques: alken metal telescopic dilation(5), amplatz serial fascial dilation(6,7), and high-pressure balloon dilation(8). alken metal telescopic dilation and amplatz serial fascial dilation are sequential dilation methods composed of repeated insertion and withdrawal of incremental dilators, and associated with prolonged tract dilation time, excessive radiation exposure and increased possibility of tract loss and collecting system perforation(9). high-pressure balloon dilation technique, though decreases the number of exchanges, still requires multiple exchanges and time consuming(10), and may cause disruption of dilated 1department of nephrology, union hospital, tongji medical college, huangzhong university of science & technology, wuhan, china. 2department of urology, union hospital, tongji medical college, huangzhong university of science & technology, wuhan, china. # these authors contributed equally to this work. *correspondence: jiefang avenue 1277, wuhan, china. postal code: 430022. phone: +8618108626569. email addresses: liwencheng@hust.edu.cn. received july 2018 & accepted december 2018 structures. moreover, the expensiveness of high-pressure balloon precludes it to be commonly used(9,11), and the effect of this technique on blood loss is still in controversy(2,12-14). a safe, efficient and easy-to-perform technique for nephrostomy tract creation of pcnl are always highly desired by endourologists. over a decade before, a “one-step” or “one-shot” dilation technique was developed by using a single 25-30 f amplatz dilator over alken guidance, which was safe and effective, as well as less time consuming, less blood loss, and less x-ray exposure as reported(15,16). however, this technique still required to exchange the dilator once. recently, we described a novel one-shot nephrostomy tract dilation technique (chinese one-shot) using a single fascial dilator, and the clinical outcome demonstrated that it was safe and highly efficient(17). in this retrospective study, we present our experiences by comparing the outcomes of chinese one-shot dilation group to those of a conventional sequential fascial dilation group. the parameters included tract creation time, hemorrhage loss, overall renal function, tract dilation failure and major complications. we aim to further evaluate the safety and efficacy of our chinese one-shot technique and discuss the possibility of popularizing it. patients and methods a retrospective review of 116 pcnl cases performed by a single surgeon from january 2012 to december 2012 in our department were performed. demographic and stone information was presented in table 1. stone burden was assessed by preoperative ct, where for each stone the cross-sectional area was calculated by multiplying length by width. the cross-sectional area of all stones was summed and reported as the total burden in case of multiple stones. fifty-seven consecutive patients who had undergone the sequential fascial dilation technique (the sequential group) were compared to fifty-nine patients who had undergone with the chinese one-shot technique (the one-shot group). all patients were in accordance with the routine indications of pcnl, and exclusion criteria were patients who required bilateral pcnl or second stage pcnl. nephrostomy tract creation time, puncture position, renal hemorrhage, blood transfusion rates, overall renal function (preoperative and postoperative serum creatinine concentrations), tract dilation failure, the incidence of complications and stone-free rate were compared between the two groups. the outcomes included tract creation time, hemorrhage, overall renal function, tract dilation failure, stone-free rate and major complications. the tract creation time was defined as the time from the chiba needle puncture to the direct observation of the collecting system under nephroscope. the hemorrhage loss was evaluated by comparing the last preoperative hemoglobin level with 24-hour postoperative counterpart. blood transfusion was conducted provided that the cardiopulmonary compensation mechanisms were insufficient due to anemia or the postoperative hemoglobin value was less than 80 g/dl. the number and volume of blood transfusion were recorded. the overall renal function assessed by comparing the last preoperative and the 24-hour postoperative serum creatinine concentration level. residual fragments <4 mm was considered to be stone-free. the incidence of complications such as tract dilation failure and collecting system perforation was noted. chinese one-shot dilation after adequate epidural anesthesia was induced, each patient received a single dose of antibiotic intravenously and positioned in the lithotomy position. a 6 f ureteral catheter was introduced to the ipsilateral renal pelvis using cystoscopy. after indwelling a foley catheter, the patient was then repositioned in a prone position. the puncture pathway of the 18 g chiba needle was strictly through the central point of the target fornix and along the axis of the infundibulum with the guidance of a grayscale ultrasound (us, b-k medical, herlev, denmark) (supplementary figure. 1). the aspiration of urine on removal of the stylet of the needle confirmed the entrance into the collecting system, a super-rigid guidewire (urovision gmbh, bad aibling, germany) was then introduced under us guidance (supplementary figure. 2). before the needle was removed, the skin and fascia were incised over the puncture site, and then a 22 f pencil-shaped fascial dilator (create, yokohama, japan, figure. 1) with matched sheath was advanced into collecting system over super-rigid guidewire directly. rotating the dilator with angular shearing force may facilitated the passage through the renal capsule into the renal collecting system. the appearance of break-through feeling or aspiration of urine from the dilator indicated the matched sheath was advanced smoothly into the collecting system, and then the dilator was removed while holding the sheath in position for the next operation (figure. 2). all steps including needle puncture, tract dilation and sheath placement were performed without fluoroscopic control in all patients. table 1. patient demographics and stone features one-shot group n: 59 sequential group n:57 p value age (y) mean ± sd 46.7±12.3 47.4 ± 10.6 0.6076 range 20-77 24-69 gender, n (%) male 36 (61.0) 37 (64.9) 0.6641 female 23 (39.0) 20 (35.1) stone side, n (%) left kidney 32 (54.2) 35 (61.4) 0.4347 right kidney 27 (45.8) 22 (38.6) stone location, n (%) 0.2312 pelvis 23 (39.0) 17 (29.8) upper segment of ureter 5 (8.5) 2 (3.5) middle calyceal group 1 (1.7) 4 (7.0) lower calyceal group 6 (10.2) 3 (5.3) pelvis and calyx 24 (40.7) 31 (54.4) stone burden (cm) 0.5169 mean ± sd 4.9 ± 3.2 4.8 ± 3.9 range 1.9-10.5 1.6-11.4 figure 1. the detail of the special design of creator dilator. as pointed out by the red square, creator dilator (the upper) has a sharper tip and longer tapered end compared to amplatz dilator (the lower) (2.5 cm vs. 1.5 cm). chinese one-shot dilation for percutaneous access-jing et al. endourology and stone diseases 22 vol 16 no 01 january-february 2019 23 stone treatment and removal were performed in a conventional manner. a 20.8 f nephroscope (wolf, mainburg, germany) was introduced through the 22 f sheath and stones were disintegrated using ultrasonic/ pneumatic lithotripters (swiss lithoclast, nyon, switzerland). at the end of the procedure, residual stones were detected by abdominal radiography (siemens, muenchen, germany) or ultrasound in case of radiolucent stones. after complete clearance was confirmed, a 6 f double-j stent was introduced antegradely, followed by a 20 f nephrostomy tube placement. after the clearance of hematuria (usually within 12 to 48 h), the urethral catheter was removed and the nephrostomy tube was clamped. if neither fever nor urine leakage occurred, the nephrostomy tube was removed 12-24 hours later after the clamping. conventional sequential fascial dilation using the conventional technique, the access tract was dilated with a series of pencil-shaped fascial dilators (create, yokohama, japan) from 8 f to 22 f in a multi-increment manner, overlapping at 2 f intervals, over the super-rigid guidewire. after the correct position of 22 f dilator (with matched sheath) was verified, the matched sheath was introduced and retained in the collecting system. statistical data were analyzed using sas 9.13 for windows (sas institute inc, cary, nc), whereby statistical significance was determined at the level of α = 0.05. univariate descriptive statistics included mean and standard deviation (mean ± sd) for quantitative variables and frequency and percentage for qualitative variables. student’s t test or mann-whitney u test was applied to compare one-shot dilation with sequential fascial dilation for quantitative variables, and chi-square test or fisher’s exact test for qualitative variables. results as shown in table 1, there were no significant differences between the one-shot and sequential group in demographic data such as age, gender, or clinical data such as stone location and burden. nine patients in the one-shot group and seven in the sequential group had a history of ipsilateral open nephrolithotomy. the intraoperative and postoperative variables of clinical data in both groups were summarized in table 2. successful access was established in all patients of both groups. the one-shot technique resulted in a significant reduction in mean tract creation time (1.9 ± 0.5 min vs 4.5 ± 0.8 min, p < 0.0001) compared to the conventional technique. of note, a statistically significant drop in mean postoperative hemoglobin value was observed in the sequential group (0.60 ± 0.34 g/dl vs 0.69 ± 0.36 g/dl, p = 0.0008). however, none of these patient was administered blood transfusion intraoperatively or postoperatively. there were no significant difference in serum creatine concentration between the two groups (4.7 ± 11.5μmol/l vs 4.8 ± 14.8 μmol/l, p = 0.2611) and stone-free rate (86.4% vs 85.9%, p = 0.6145). no tract dilation failure occurred in both of the groups. notably, there were three cases (two cases in one-shot group and one in the sequential group) whose kidney rotated even when the 18 g needle touched the renal capsule surface. for those patients, target calices were punctured successfully with prompt action, and then the nephrostomy tracts of all the 3 cases were dilated successfully. furthermore, there are no major complications such as adjacent organ injury, major vascular injury or hydrothorax occurred in all cases during or after the surgery. discussion the success and safety of pcnl are directly influenced by the quality of the access(18). great efforts have been made to improve the methods for establishing renal access over decades. in 1991, travis et al(10) first described a single-increment dilation method in a canine model, and the result demonstrated that this technique was as safe as conventional dilation techniques with minimal hemorrhage or parenchymal damage either immediately or at 6 weeks. fattini et al(15) later reported a novel “one-shot” method to dilate the nephrostomy access for percutaneous lithotripsy. they first introduced alken guide or 8 f amplatz dilator over the guidewire, and then a single 25 f or 30 f amplatz dilator was advanced, followed by a 34 f sheath. their results showed that this “one-shot” technique was feasible and effective and also significantly reduced x-ray exposure during table 2. comparison of two groups: the outcomes during and after surgery of 116 cases one-shot group n: 59 sequential group n:57 p value tract creation time (min) mean ± sd 1.9 ± 0.5 4.5 ± 0.8 < 0.0001 range 1.5-3 3.5-6 successful access, n (%) 59 (100%) 57 (100%) hemoglobin value (g/dl), mean ± sd preoperative 133.7 ± 16.3 131.6 ± 16.5 0.6405 postoperative 127.5 ± 15.7 123.5 ± 15.8 0.5917 decrease after operation 0.60 ± 0.34 0.69 ± 0.36 0.0008 serum creatine concentration (μmol/l), mean ± sd preoperative 85.4 ± 42.7 78.4 ± 21.6 0.6164 postoperative 80.6 ± 39.4 73.2 ± 18.4 0.4759 increase after operation 4.7 ± 11.5 4.8 ± 14.8 0.2611 stone-free rate 51 (86.4%) 49 (85.9%) 0.6145 adjacent organ injury 0 0 major vascular injury 0 0 collecting system perforation during tract dilation procedure 0 0 dilation failure 0 0 transfusion requirement 0 0 angiography requirement 0 0 chinese one-shot dilation for percutaneous access-jing et al. the dilation of the tract. the safety and efficacy of this method were subsequently verified by other urological centers in adult patients(9,11,16,19-23). as distinct from the one-shot dilation technique described by fattini(15) and falahatkar(16), we established the renal access with a single 22 f fascial dilator passing over the j-tip super-rigid guidewire into the collecting system directly(17). in this study, the retrospective data strongly demonstrated that our chinese one-shot dilation technique was as safe and feasible as the conventional sequential fascial dilation, and greater reductions in tract creation time and blood loss were achieved using this technique as well. on the basis of these results, we later innovated our chinese one-shot dilation technique by applying stimulated diuresis instead of retrograde ureteral catheter placement, which is more time-saving(17). dilation failure is one of the most frequent complications of pcnl, especially when more exchanges or passes were needed during dilation with sequential dilators(3). the cause could be ascribed to the presence of excessive fibrotic scarring from previous open surgery or displacement of guidewire. it was documented that the tract dilation failure rates were 6% (4/67) in amplatz group and 1.7% (2/121) in alken group, respectively(4). ozok et al(4) reported that excessive scarring, renal hypermobility and insufficient insertion of the j-tip rigid guidewire into the collecting system resulted in dilation failure when using amplatz serial dilation. the scarring and renal hypermobility also attributed to dilation failure of one-shot dilation technique and used to be regarded as real contraindications to one-shot dilation(15). however, falahatkar et al(16) reported that the successful access rate of one-shot dilation technique was 87.0% (20/23) in patients who had past history of ipsilateral open stone surgery. amjadi(19) and sofikerim (24) also confirmed that one-step dilation was feasible in patients with previous open nephrolithotomy as well as amplatz serial fascial dilation. in our study, we chose a special designed dilator with sharper tip and longer tapered end compared to amplatz dilator (figure.1), and applied it in both of the groups. the successful access rate was 100% in either group, including sixteen patients who had previous history of ipsilateral open nephrolithotomy (nine in oneshot group and seven in the sequential group). moreover, the data analysis revealed a significant reduction in mean tract creation time in one-shot group (1.9±0.5 min vs 4.5 ± 0.8 min, p < 0.0001) compared to the conventional technique, since the operating procedure was remarkably simplified in one-shot technique. the renal hypermobility often causes guidewire displacement. we encountered three cases (two in one-shot group and one in sequential group) whose kidney rotated along the long axis even when the 18 g chiba needle touched the renal capsule surface, and we managed to create the nephrostomy tract successfully in all of the cases. there are two key points that should be noticed under certain situations mentioned above. first, the super-rigid guidewire should be inserted as deep as possible, which ensures the super-rigid part of the guidewire is actually located in the collecting system. second, do remind that the super-rigid guidewire should be pushed gently by the assistant all the time, which allows the movement of the guidewire is synchronous with that of the kidney during the dilation procedure. renal hemorrhage is the most common complication of pcnl and related to sheath size, aggressive manipulation, stone burden and operating time(2,25,26). it was reported that nephrostomy tract dilation procedure accounted for half of the total blood loss in pcnl(27). the correct needle puncture route and proper dilation technique are critical factors that may affect, even decide, the bleeding and transfusion rates. practice indicates that renal hemorrhage can be best avoided when the puncture and dilation route strictly goes through the center point of the fornix of the target calyx and along the axis of the infundibulum(17,28). during the process of stone disintegration, a cautious and minimal angulation of the working sheath and nephroscope may minimize the risk of calyceal neck laceration and consequent renal bleeding. in the present study, the mean hemoglobin decline 24 h after surgery in one-shot and sequential group was 0.60 ± 0.34 g/dl and 0.69 ± 0.36 g/dl, respectively, which clearly indicated that the oneshot technique was associated with less blood loss (p = 0.0008). the fascial sequential dilators system comprised 8 semi-rigid dilators which increased at a 2 f interval from 8 f to 22 f. during the tract dilation, every exchange of serial dilators would cause hemorrhage due to disappearance of tamponade effect on the small vessels. on the contrary, there is no dilator exchange or increment happened during the tract creation process with one-shot dilation technique. employment of a single 22f fascial dilator tamponades the access tract, imposes consecutive pressure on the potential impaired small vessels throughout the entire dilation procedure, and therefore reduces blood loss. ozok et al(4) reported that mean hemoglobin decrease was 1.5 ± 1.2 g/dl in amplatz group with mean stone surface area 673.4 ± 466.9 mm2. the clinical research office of the endourological society percutaneous nephrolithotomy study group concluded that working sheath was associated with increased transfusion rates, with rates of 1.1% for the smallest sheath and 12.0% for the largest sheath(2). one of the reasons account for the different hemoglobin decrease values between our study and ozok’s might be the different size of working sheath used in the two studies (22 f vs 30 f). figure 2. the dilator is removed and the sheath kept in place for the next nephroscopic operation when the sheath is advanced smoothly into the collecting system. chinese one-shot dilation for percutaneous access-jing et al. endourology and stone diseases 24 vol 16 no 01 january-february 2019 25 conclusions we developed a novel, safer and more efficient chinese one-shot tract dilation technique for pcnl. in contrast to the conventional sequential dilation technique, the major advantages of this solution are simpler without any dilator exchanges, less time-consuming and less renal hemorrhage. references 1. miller nl, lingeman je. management of kidney stones. bmj 2007; 334:468-72. 2. yamaguchi a, skolarikos a, buchholz np, et al. operating times and bleeding complications in percutaneous nephrolithotomy: a comparison of tract dilation methods in 5,537 patients in the clinical research office of the endourological society percutaneous nephrolithotomy global study. j endourol 2011; 25:933-9. 3. antonelli ja, pearle ms. advances in percutaneous nephrolithotomy. urol clin north am 2013; 40:99-113. 4. ozok hu, sagnak l, senturk ab, karakoyunlu n, topaloglu h, ersoy h. a comparison of metal telescopic dilators and amplatz dilators for nephrostomy tract dilation in percutaneous nephrolithotomy. j endourol 2012; 26:630-4. 5. alken p, hutschenreiter g, gunther r, marberger m. percutaneous stone manipulation. j urol 1981; 125:463-6. 6. castaneda-zuniga wr, clayman r, smith a, rusnak b, herrera m, amplatz k. nephrostolithotomy: percutaneous techniques for urinary calculus removal. ajr am j roentgenol 1982; 139:721-6. 7. rusnak b, castaneda-zuniga w, kotula f, herrera m, amplatz k. an improved dilator system for percutaneous nephrostomies. radiology 1982; 144:174. 8. clayman rv, castaneda-zuniga wr, hunter dw, miller rp, lange ph, amplatz k. rapid balloon dilatation of the nephrostomy track for nephrostolithotomy. radiology 1983; 147:884-5. 9. aminsharifi a, alavi m, sadeghi g, shakeri s, afsar f. renal parenchymal damage after percutaneous nephrolithotomy with one-stage tract dilation technique: a randomized clinical trial. j endourol 2011; 25:927-31. 10. travis dg, tan hl, webb dr. singleincrement dilatation for percutaneous renal surgery: an experimental study. br j urol 1991; 68:144-7. 11. ziaee sa, karami h, aminsharifi a, mehrabi s, zand s, javaherforooshzadeh a. one-stage tract dilation for percutaneous nephrolithotomy: is it justified? j endourol 2007; 21:1415-20. 12. wezel f, mamoulakis c, rioja j, michel ms, de la rosette j, alken p. two contemporary series of percutaneous tract dilation for chinese one-shot dilation for percutaneous access-jing et al. percutaneous nephrolithotomy. j endourol 2009; 23:1655-61. 13. shen ch, cheng mc, lin ct, jou yc, chen pc. innovative metal dilators for percutaneous nephrostomy tract: report on 546 cases. urology 2007; 70:418-21; discussion 21-2. 14. de la rosette j, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol 2011; 25:11-7. 15. frattini a, barbieri a, salsi p, et al. one shot: a novel method to dilate the nephrostomy access for percutaneous lithotripsy. j endourol 2001; 15:919-23. 16. falahatkar s, neiroomand h, akbarpour m, emadi sa, khaki n. one-shot versus metal telescopic dilation technique for tract creation in percutaneous nephrolithotomy: comparison of safety and efficacy. j endourol 2009; 23:615-8. 17. shi y, liang hg, yang x, et al. ultrasonography-guided percutaneous nephrolithotomy with chinese one-shot tract dilation technique based on stimulated diuresis: a report of 67 cases. j huazhong univ sci technolog med sci 2016; 36:881-6. 18. de la rosette jj, laguna mp, rassweiler jj, conort p. training in percutaneous nephrolithotomy--a critical review. eur urol 2008; 54:994-1001. 19. amjadi m, zolfaghari a, elahian a, tavoosi a. percutaneous nephrolithotomy in patients with previous open nephrolithotomy: one-shot versus telescopic technique for tract dilatation. j endourol 2008; 22:423-5. 20. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j 2016; 13:2899-902. 21. basiri a, nouralizadeh a, kashi ah, et al. x-ray free minimally invasive surgery for urolithiasis in pregnancy. urol j 2016; 13:2496-501. 22. aghamir smk, salavati a, hamidi m, fallahnejad a. primary report of totally tubeless percutaneous nephrolithotomy despite pelvi-calyceal perforations. urol j 2017; 14:4020-3. 23. mousavi-bahar sh, amirhasani s, mohseni m, daneshdoost r. safety and efficacy of percutaneous nephrolithotomy in patients with severe skeletal deformities. urol j 2017; 14:3054-6058. 24. sofikerim m, demirci d, gulmez i, karacagil m. does previous open nephrolithotomy affect the outcome of percutaneous nephrolithotomy? j endourol 2007; 21:401-3. 25. kurtulus f, fazlioglu a, tandogdu z, karaca s, salman y, cek m. analysis of factors related with bleeding in percutaneous nephrolithotomy using balloon dilatation. can j urol 2010; 17:5483-9. 26. akman t, binbay m, sari e, et al. factors affecting bleeding during percutaneous nephrolithotomy: single surgeon experience. j endourol 2011; 25:327-33. 27. kessaris dn, bellman gc, pardalidis np, smith ag. management of hemorrhage after percutaneous renal surgery. j urol 1995; 153:604-8. 28. de lisa a, caddeo g. pcnl: tips and tricks in targeting, puncture and dilation. arch ital urol androl 2010; 82:32-3. chinese one-shot dilation for percutaneous access-jing et al. endourology and stone diseases 26 march-april reviewer of the issue – mahmood morshedi mahmood morshedi april 2017 mahmood morshedi, ph.d., hcld(abb), ctbs, is a professor and director of andrology and endocrine units at the department of obstetrics and gynecology at eastern virginia medical school in norfolk, virginia, usa. dr. morshedi earned his undergraduate degree in medical technology from the university of tehran and his graduate degrees from san francisco state university and eastern virginia medical school. dr. morshedi is an expert in the area of male infertility and has published extensively in peer-reviewed journals and is the author or co-author or 9 book chapters. he has directed one of the few centers in the united states established to assist hiv serodiscordant couples in whom the male partner is hiv+ with their efforts to have children. dr. morshedi has been extensively involved in research in the area of male infertility. he has also received a grant from the national institute of health (nih) for investigating the contraceptive/spermicidal effect of cellulose acetate phthalate, a common compound used for the enteric coating of some medications. dr. morshedi is a member of the american society for reproductive medicine, american andrology society and the american association of tissue banks. he is the peer reviewer for various scientific journals including american journal of obstetrics and gynecology, andologia, fertility and sterility, gynecological endocrinology, international journal of fertility and sterility, and urology journal. it is with pleasure to hear that i have been selected as the best reviewer of the month for the urology journal. undoubtedly, the peer review process plays a major role in streamlining the publication of high quality scientific work. a review of the recent high quality manuscripts published in urology journal, points to the vision of the editorial board in their review of the submitted works and for selecting studies worthy of publication. congratulations! review 5α-reductase inhibitors could prevent the clinical and pathological progression of prostate cancer: a meta-analysis yue yang1,2,3, haifeng hu1**, hanchao zhang1,2,3, zhengdao liu2,3, faliang zhao2, jin yang1, guobiao liang2,3* purpose: to explore the efficacy of 5-aris in pca (prostate cancer). methods: searching through the major medical databases such as pubmed, science citation index, embase, medline, web of science, cochrane library for all published studies in english until 2018. the following search terms were used: “finasteride”, “dutasteride”, “5α reductase inhibitors”, “5-aris”, “prostate cancer”, “prostate neoplasm” and the additional related studies were manually searched. newcastle-ottawa scale (nos) assessed the qualities of studies, and the outcome measures were observed by rr or or with 95% cis. results: we included 9 eligible studies for analyses from 2011 to 2017. we found that 5-aris group may have fewer progression (or = 0.48 95%ci: 0.37-0.61 p < 0.00001, i2=4% p = 0.39) and lower pathological progression (or = 0.46; 95%ci: 0.29-0.73; p = 0.001, i2=0% p = 0.45), compared with control groups. however, the os did not show significant difference between two groups (or=1.10; 95%ci:0.90-1.35; p = 0.35, i2 = 93% p < .00001 ). conclusion: the use of 5-aris could prevent progression in pca patients both clinical and pathological. keywords: 5α-reductase inhibitors, prostate cancer, clinical progression, pathological progression, meta-analysis introduction inhibitors of 5a-reductase(5-aris), such as finas-teride and dutasteride, are widely used in the medical treatment of benign prostatic hyperplasia (bph)(1), and these drugs inhibit the conversion of testosterone to dihydrotestosterone(dht) to reduce the prostate size and alleviate the lower urinary obstruction. blocking dht leads to a lower level of androgen, which is involved in the development of prostate cancer, thus we may wonder that 5-aris may have an effect on prostate cancer or not. the prostate cancer prevention trial (pcpt)(2), a large, phase iii and double-blind placebo-control trial, reported that finasteride may decrease the risk of new prostate cancer through changes in intraprostatic androgen. the data was impressive, however, some other studies(3) also pointed out that there were no strong pieces of evidence that showed the benefit of the finasteride and analogous 5-aris. therefore, researchers have a furious conflict about the efficacy of 5-aris in prostate cancer, and we did this meta-analysis to quantify the effect of 5-ari on pca patients. methods search strategy we searched pubmed, embase, and the cochrane library(until may 6, 2018). in addition, we searched 1urological department, the affiliated hospital and clinical medical college of chengdu university, chengdu, sichuan, china 2urological department, the affiliated hospital of zunyi medical university, zunyi, guizhou, china) 3medical college of soochow university, suzhou, jiangsu, china *correspondence: doctoral supervisor of medical college of soochow university, suzhou, jiangsu, china and the affiliated hospital of zunyi medical university, zunyi, guizhou, china. tel: 010-035-88623287 email: yyjakejerry@163.com. ** contributed equally to this work and should be considered a co-first author. received september 2018 & accepted january 2021 potentially relevant trials from the references of selected studies by hand. the search strategy was followed by using all possible combinations of medical subject headings(mesh) or non-mesh terms: “finasteride”, “dutasteride”, “5α reductase inhibitors”, “5-aris”, “prostate cancer”, “prostate neoplasm” and the additional related studies were manually searched. each search strategy met each database. (figure 1) selection criteria studies that were published in english were selected if they met the following criteria: (1) all patients should be diagnosed with prostate cancer(pca) in pathology. (2) all patients’ clinical and pathological parameters were covered (3) all studies should be controlled trials which compared 5-aris with placebo (4) the observations should report at least one of our outcomes: progression of cancer and overall survival(os). (5) the same trial that was reported by different articles should be excluded. (6) case reports, letters, systematic reviews, comments, and animals trial should be excluded. data extraction two reviewers independently assessed all eligible publications, and disagreements were resolved by discussion with a third reviewer. data from all full-text studies that accorded with selection criteria were independently extracted by each reviewer using a standardized exurology journal/vol 18 no. 3/may-june 2021/ pp. 247-251. [doi: 10.22037/uj.v18i.4831] traction form. all the data extracted from the studies included details on the first author name, publication year, country, study design, study period, number of patients, duration of follow-up (table 1). outcome measures the primary outcome measures were a progression of cancer, defined as the number of the patients who got disease progressing including clinical and pathological progression. secondary outcome measures in this meta-analysis were overall survival (os), defined as the time from observation to death during the research. statistical analysis differences were expressed as rr with 95% cis for the primary outcome and or for the secondary outcome. the rr below 1 meant an advantage of 5-aris better than the placebo such as none of the analogy. i2 statistics were used to quantify the heterogeneity across trials, which is a standardized measure of inconsistency and chi-square(cochrane q statistic) test. if i2 statistics < 50% and as a p-value > 0.05 for chi-square test, it indicted to have a low level of heterogeneity. a fix-effects model was used to pool estimates in a low level of heterogeneity. a random-effects model was used to pool estimates in a high level of heterogeneity. patient characteristics and other confounding factors in all the studies didn’t have significant heterogeneity. meanwhile, subgroup analyses were planned to assess the effect of different progression of the tumor. a p value <.05 was affirmed as statistically significant. quality assessment the methodological quality of each controlled trial was evaluated by using the newcastle-ottawa scale (nos) [4] which was recommended for assessing the qualities of studies and a study with >= 7 awarded stars was considered as a high-quality study. results after removing 122 duplicates, 209 potential studies were identified through reviewing abstracts and articles, 42 studies were excluded due to no combination therapy, incomplete outcome data, no comparison group, or not in english. the final set of eligible studies included 9 studies(5-13), published from 2011 to 2017. the selection strategy is shown in figure 1. the characteristics of 9 included studies are summarized in table 1. a to5-aris prevent progression of prostate cancer-yang et al. review 248 table 1. demographic and clinical data of dm and non-dm patients in different studies. reference country center design period sample age follow-up event quanity 5-ari placebo 5-ari placebo ( years) aners kjellman 2013 denmark m t 1989-2001 199 2806 73.9+8.3 73.6+8.5 3 1,2 ********* antonio finalli 2011 canada s t 1995-2010 70 218 65.6+6.4 63.8+7.8 4 3,4 ******* ashley e.ross 2011 usa m t 1994-2010 47 540 66 65 4 3,4 ****** charles dai 2017 egypt s t 2002-2015 70 301 66+7 64+7 3 1,3 ******* fritz schroder 2013 usa s r n 147 146 69.7 68.6 2 3 ****** laurent azoulay 2015 canada m t 1999-2009 574 13318 76.2+8.2 71.9+9.2 5 3,5 ******** neil e fleshner 2012 canada s r 2006-2007 147 155 n n 3 3,4 ***** rodolfo monotironi 2013 italy s r n 41 42 64+4 63+7 2 3,4 ****** teemu j.murtola 2013 finland s t 1995-2009 24 901 n n 4 1,3,4 ***** center: m: multiple centers, s: single center ;event: 1:overall survival,2:prostate-cancer specific surviva, 3:progression, 4:pathologic progression, 5:all cause mortality;t:retropective, r:rondomized;n: not mentioned figure 1. selecting flowchat for included studies in the meta-analysis tal of 19764 patients were included in this meta-analysis. 1319 patients were treated with 5-aris. effect of interventions on the primary outcome measure progression (both clinical and pathological progression) was the primary outcome measure in this meta-analysis. using a random-effects model, the pooled or was 0.48(95%ci: 0.37-0.61; p < 0.00001, figure 2). this represented significantly fewer progression in patients with 5-aris, and no heterogeneity was observed (i2=4%, p = 0.39). furthermore, the subgroup analyses were conducted and shown in figure 3. the pathological progression also decreased in 5-aris groups (or=0.46; 95%ci: 0.29-0.73; p = 0.001, heterogeneity p = 0.45, i2 = 0%), thus pca patients gained more benefit from 5-aris. the second outcome, overall survival(os) did not show significant difference between two groups (or=1.10; 95%ci, 0.90-1.35; p = 0.35, heterogeneity p < 0.00001, i2=93%, figure 4).no significant publication bias existed in the funnel plots. discussion we present this meta-analysis to assess the effect of 5-aris in treatment with pca, and the results showed an inspiring outcome that 5-aris may prevent the progression of pca. in our study, less progression was observed in the 5-aris groups ( 5-aris vs placebo or=0.48 95%ci:0.37-0.61; p < 0.00001). furthermore, the subgroup analysis was also undertaken and we identified a positive effect of 5-aris in pathological progression(5-aris vs placebo, or=0.46, 95%ci: 0.29-0.73, p = 0.001, i2=0%). moreover, the results were coincident with recent researches, and increasing evidence suggested that there may be a close affinity between pca and 5-aris. in the prostate cancer prevention trial(pcpt), a total of 18882 patients were assigned to finasteride or placebo for pca with 7 years follow-up, and the study showed that the finasteride could reduce the risk of prostate cancer by 25%(14). meanwhile, fritz schroder.et(10)also conducted a randomized, placebo-controlled avodart after radical therapy for prostate cancer study(arts), which included 294 subjects with dutasteride treatment over 2 years and they concluded that dutasteride could delay the progression of pca, even in patients with biochemical failure after radical therapy for clinically localized disease. in fact, the drugs, such as finasteride, dutasteride, and other 5-aris, inhibited testosterone to dht, which played an important role in the pca mechanism. the progression of pca could perform in a clinical or pathological way. the clinical progression may behave as tumor metastasis, a higher level of psa, or biochemical progression after therapies. studies demonstrated that pca was an androgen-relative tumor, thus impeding the original substrate of translation to androgen should prevent the progression of pca somehow. besides, pathological progression can be defined as an increased 5-aris prevent progression of prostate cancer-yang et al. vol 18 no 3 may-june 2021 249 grade, increased number of scores to more than three, or any core involvement over 50%. noticeably, the trial[13] reported that those taking 5-aris could bring an approximate 50% reduction in the rate of pathological progression. however, many conflicts(15) also pointed out that the finasteride contributed to the increase in high-grade cancers. long-term 5-aris treatment had been proposed to alter the histologic appearance of prostate cancer tissue, which would falsely lead to high gleason grades in a low-grade tumor(5), but larger prostates are more likely to be undergraded at initial diagnostic biopsy, thus patients who took 5-aris might theoretically be likely to be detected with a higher grade with subsequent biopsies(16) and it might not be ascribed the higher gleason score in a low-grade tumor to a pathologic progression. eventually, as the aspect of the amount of observation(12), 5-aris appeared to diminish the progression of pca patients. counting for the overall survivals, our study found there was no significant difference between 5-aris and placebo (or=1.10; 95%ci, 0.90-1.35; p = 0.35). a recent finnish prostate cancer screening trial[18] similarly implicated that 5-aris use didn’t have an impact on survival ( hr=1.51, p = 0.8). meanwhile, a larger study(18), which included over 3 million patients from denmark, reported that 5-aris were associated with an increased risk of pca-specific mortality( hr=2.1, 95%ci: 1.97-2.30). however, even more, studies should be needed to definitely prove this in the future. to our knowledge, this is the first meta-analysis to systemically assess the efficiency of 5-aris in the progression of the pca patients. the present meta-analysis carries few limitations that must be taken into account. the main limitation is that our meta-analysis contains few randomized data, most of the studies included were observational. although the heterogeneity of studies was not obvious, all the patients in different groups were not possible to match for age, bmi, preoperative therapy, and these biases may affect the primary outcome. all these factors may have contributed to a higher heterogeneity between studies. because of these limitations, larger and randomized control trials were needed to confirm these results. conclusions the use of 5-aris could prevent progression in pca patients both in clinical and pathological terms. achnowledgements funding: this study was funded by the education department fund project of guizhou province,grant no.ky (2017) 045 and science and technology fund project of guizhou province (grant no. (2015) 31). conflict of interest none of the authors have a conflict of interest to declare. references 1. taghavi a, mohammadi-torbati p, kashi a h, et al. polyomavirus hominis 1(bk virus) infection in prostatic tissues: cancer versus hyperplasia[j]. urol j, 2015,12(4):2240-2244. 2. hoque a, yao s, till c, et al. effect of finasteride on serum androstenedione and risk of prostate cancer within the prostate cancer prevention trial: differential effect on highand low-grade disease[j]. urology, 2015,85(3):616-620. 3. unger j m, hershman d l, till c, et al. using medicare claims to examine longterm prostate cancer risk of finasteride in the prostate cancer prevention trial[j]. j natl cancer inst, 2018. 4. irish m, ramanan s. a question of scale[j]. elife, 2019,8. 5. murtola t j, kujala p m, tammela t l. high-grade prostate cancer and biochemical recurrence after radical prostatectomy among men using 5alpha-reductase inhibitors and alpha-blockers[j]. prostate, 2013,73(9):923931. 6. montironi r, bartels p h, decensi a, et al. a randomized phase iib presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. efficacy monitored by karyometry[j]. urol oncol, 2013,31(5):557-565. 7. fleshner n e, lucia m s, egerdie b, et al. dutasteride in localised prostate cancer management: the redeem randomised, double-blind, placebo-controlled trial[j]. lancet, 2012,379(9821):1103-1111. 8. azoulay l, eberg m, benayoun s, et al. 5alphareductase inhibitors and the risk of cancerrelated mortality in men with prostate review 250 5-aris prevent progression of prostate cancer-yang et al. vol 18 no 3 may-june 2021 251 cancer[j]. jama oncol, 2015,1(3):314-320. 9. dai c, ganesan v, zabell j, et al. impact of 5alpha-reductase inhibitors on disease reclassification among men on active surveillance for localized prostate cancer with favorable features[j]. j urol, 2018,199(2):445-452. 10. schroder f, bangma c, angulo j c, et al. dutasteride treatment over 2 years delays prostate-specific antigen progression in patients with biochemical failure after radical therapy for prostate cancer: results from the randomised, placebo-controlled avodart after radical therapy for prostate cancer study (arts)[j]. eur urol, 2013,63(5):779-787. 11. ross a e, feng z, pierorazio p m, et al. effect of treatment with 5-alpha reductase inhibitors on progression in monitored men with favourable-risk prostate cancer[j]. bju int, 2012,110(5):651-657. 12. wong l m, fleshner n, finelli a. impact of 5-alpha reductase inhibitors on men followed by active surveillance for prostate cancer: a time-dependent covariate reanalysis[j]. eur urol, 2013,64(2):343. 13. kjellman a, friis s, granath f, et al. treatment with finasteride and prostate cancer survival[j]. scand j urol, 2013,47(4):265271. 14. unger j m, till c, thompson i j, et al. longterm consequences of finasteride vs placebo in the prostate cancer prevention trial[j]. j natl cancer inst, 2016,108(12). 15. lucia m s, epstein j i, goodman p j, et al. finasteride and high-grade prostate cancer in the prostate cancer prevention trial[j]. j natl cancer inst, 2007,99(18):1375-1383. 16. kulkarni g s, al-azab r, lockwood g, et al. evidence for a biopsy derived grade artifact among larger prostate glands[j]. j urol, 2006,175(2):505-509. 17. murtola t j, karppa e k, taari k, et al. 5-alpha reductase inhibitor use and prostate cancer survival in the finnish prostate cancer screening trial[j]. int j cancer, 2016,138(12):2820-2828. 18. orsted d d, bojesen s e, nielsen s f, et al. association of clinical benign prostate hyperplasia with prostate cancer incidence and mortality revisited: a nationwide cohort study of 3,009,258 men[j]. eur urol, 2011,60(4):691-698. 5-aris prevent progression of prostate cancer-yang et al. urological oncology decrease of preoperative serum albumin-to-globulin ratio as a prognostic indicator after radical cystectomy in patients with urothelial bladder cancer jeong seok oh1,2, dong jin park1,4, kyeong-hyeon byeon2, yun-sok ha2,3, tae-hwan kim2,3, eun sang yoo1,3, tae gyun kwon2,3, hyun tae kim1,3* purpose: this study aims to evaluate whether preoperative serum albumin-to-globulin ratio (agr) could predict the prognosis of patients with urothelial bladder cancer (ubc) after radical cystectomy (rc). materials and methods: a total of 176 patients with ubc who underwent rc in a tertiary hospital between 2008 and 2019 were retrospectively analyzed. the agr was calculated as albumin/(total protein − albumin). in addition, the agr was divided into two groups for the time-dependent receiver operating characteristic curve (roc) analysis. survival was estimated using the kaplan–meier analysis and compared using the log-rank test. cox proportional-hazards models were used for multivariate survival analysis. results: the best cutoff agr value for metastasis prediction was 1.32 based on the roc curve analysis. patients who had lower pretreatment agr (<1.32) values composed the low-agr group (n = 57; 32.4%). on the other hand, the remaining patients (n = 119; 67.6%) composed the high-agr group. the patients in the low-agr group had more advanced stage tumors compared with the patients in the high-agr group. the kaplan–meier curves revealed that the patients in the low-agr group had significantly lower rates of metastasis-free survival (mfs) and cancer-specific survival (css). the multivariate cox regression analysis showed that preoperative agr was an independent prognostic factor for mfs and css. conclusion: in this single-institution retrospective study, lower preoperative agr values demonstrated a poor prognostic effect on mfs and css in patients with ubc who underwent rc. keywords: cystectomy; prognosis; serum albumin; serum globulins; survival; urinary bladder neoplasms introduction bladder cancer (bc) is the tenth most frequent type of neoplasms globally, and europe and north america have higher age-standardized incidence rates for bc(1). in the usa, bc is the sixth most frequent cancer and the seventh most frequent cause of cancer mortality(2). in korea, the incidence rate of bc is lower than in the usa. however, the 5-year survival rates in the usa and korea are similar (77% vs. 76.8%, respectively)(2,3). nearly 90% of bc cases are urothelial bladder cancer (ubc)(4). radical cystectomy (rc) accompanied by extended pelvic lymph node dissection is the approved management for patients with muscle-invasive bc (mibc) and those at the highest risk for bacillus calmette–guérin unresponsive nonmuscle invasive bc(5,6). the 5-year relative survival rates of patients with regional and distant diseases are still lower than those with other genitourinary cancers despite the increase in the 5-year relative survival rate of bc from 70% to 76.8% over the past 20 years(3). recently, several prognostic markers have been studied in patients with mibc(7-10). however, no biological markers can be 1department of urology, kyungpook national university hospital, daegu, korea. 2department of urology, kyungpook national university chilgok hospital, daegu, korea. 3department of urology, school of medicine, kyungpook national university, daegu, korea. 4department of urology, dongguk university school of medicine, gyeongju, korea. *correspondence: department of urology, kyungpook national university hospital, college of medicine, kyungpook national university, 130 dongdeok-ro, jung-gu, daegu, republic of korea. tel: +82-53-420-5843. fax: +82-53-421-9618. e-mail: urologistk@knu.ac.kr. received july 2020 & accepted december 2020 recommended for routine clinical use to make clinical decisions for patients with mibc(6,7). factors, such as skeletal muscle index, require using a commercially available software by a subspecialty-trained urogenital radiologist to quantitatively calculate muscle areas(8). however, a preoperative routine laboratory blood test is one of the fastest, most convenient, and lowest-cost clinical investigations(9). to date, various preoperative laboratory tests have been studied to predict the prognosis of patients with ubc who have undergone rc. prognostic indicators, such as the de ritis ratio, platelet-to-lymphocyte ratio (plr), and neutrophil-to-lymphocyte ratio (nlr), have been reported to be able to predict the prognoses of patients with bc after rc(9,10). serum albumin is a biochemical marker for malnutrition and has been associated with systemic inflammation(11,12). in addition, serum globulin has been related to cancer-related inflammation(13). the albumin-to-globulin ratio (agr), which is computed by albumin/(total protein − albumin), is a good indicator of the nutritional and systemic inflammatory state of patients because it combines these two states in a single measurement(14). urology journal/vol 18 no. 1/ january-february 2021/ pp. 66-73. [doi: 10.22037/uj.v16i7.6350] to date, two retrospective studies conducted in china have evaluated the efficiency and efficacy of pretreatment agr as a prognostic factor in patients with bc after undergoing rc(15,16). these studies demonstrated in a multivariable analysis that agr, pathological tumor stage, and lymph nodes metastasis were independent prognostic predictors(15,16). however, only a few studies have exhibited the prognostic predictive value of preoperative agr in patients with bc in korea. thus, this retrospective study aims to evaluate the correlation between preoperative agr and prognosis of patients with bc who underwent rc in korea. materials and methods study population the medical records of 183 patients with nonmetastatic ubc who underwent cystectomy at the authors’ hospital (one institution) between august 2008 and may 2019 were reviewed retrospectively. patients who underwent partial cystectomy (three), has a history of radiation therapy of the pelvis (three), and has a history of combination surgery (one) were excluded. a total of 176 patients were enrolled in this retrospective study. of the patients, 146 (83.0%) underwent transurethral resections of the bladder tumors (turbts) before rc and 110 (62.5%) were diagnosed with mibc before rc (figure 1). the institutional review board (irb) of kyungpook national university chilgok hospital, daegu, republic of korea, approved the present trial (approval number: knumc 2020-04-037). the study was conducted in compliance with the relevant laws and regulations, albumin-to-globulin ratio and bladder cancer oh et al. table 1. patient demographics and preoperative characteristics. variablesa total (n = 176) low-agr group high-agr group p value agr < 1.32 (n = 57) agr ≥ 1.32 (n = 119) age, years 68.05 ± 8.96 69.32 ± 9.34 67.44 ± 8.75 .194 sex (male/female) 151/25 (85.8/14.2) 48/9 (84.2/15.8) 103/16 (86.6/13.4) .677 bmi, kg/m² 23.01 ± 2.99 23.57 ± 3.24 22.75 ± 2.83 .090 diversion type .408 conduit 119 (67.6) 38 (66.7) 81 (68.1) neobladder 31 (17.6) 8 (14.0) 23 (19.3) pcn, ureterostomy 26 (14.8) 11 (19.3) 15 (12.6) nac 35 (19.9) 12 (21.1) 23 (19.3) .788 ac 58 (33.0) 18 (31.6) 40 (33.6) .788 mibc 110 (62.5) 34 (59.6) 76 (63.9) .589 operation method .503 open 68 (38.6) 20 (35.1) 48 (40.3) robot 108 (61.4) 37 (64.9) 71 (59.7) total protein (g/l) 7.13 ± 0.60 7.39 ± 0.58 7.00 ± 0.57 < 0.001 serum albumin (g/l) 4.14 ± 0.32 4.04 ± 0.30 4.19 ± 0.33 .005 agr 1.41 ± 0.24 1.22 ± 0.11 1.50 ± 0.17 < 0.001 avalues are presented as mean ± standard deviation or number (%) unless otherwise indicated. abbreviations: agr, albumin-to-globulin ratio; bmi, body mass index; pcn, percutaneous nephrostomy; nac, neoadjuvant chemotherapy; ac, adjuvant chemotherapy; mibc, muscle-invasive bladder cancer. figure 1. flowchart of participants in the study. vol 18 no 1 january-february 2021 67 good clinical practices, and ethical principles described in the world medical association’s declaration of helsinki. requiring patients to provide informed consent was waived by the irb because of the retrospective feature of the present study. inclusion and exclusion criteria the current study included patients with mibc without distant metastases, recurred multifocal superficial refractory tumor, repeated turbts, and bacillus calmette–guérin-resistant carcinomas in situ. in addition, the patients with a history of radiation therapy to the pelvis, clinical-stage m1, and history of combination surgery were excluded from the study. the 7th edition of the american joint committee on cancer tnm staging system for bc was utilized in estimating the clinical tumor stage(17). histological grades were defined in accordance with the 2004 world health organization classification system(18). evaluations imaging investigation, histopathological analyses, and routine preoperative laboratory tests were performed before rc. the chest, abdominal, and pelvic computed tomography, and/or pelvic magnetic resonance imaging were performed to determine the clinical stage of the patients with bc. a bone scan was performed to evaluate bone metastasis. laboratory tests for agr were performed before neoadjuvant chemotherapy (nac) for patients who underwent cisplatin-based nac. otherwise, laboratory tests were performed within 1 month before rc. rc was performed after completing these preoperative workups. the patients with pathological tumor stage > 3 and node-positive diseases who have a good performance status underwent cisplatin-based adjuvant chemotherapy (ac) for at least four cycles. on the other hand, the patients with clinical tumor stage > 3 and node-positive diseases (based on the imaging investigation) who have a good performance status underwent cisplatin-based nac for at least three cycles. follow-up and management were performed for all the patients after rc according to published guidelines(19). statistical analysis the time-dependent receiver operating characteristic (roc) curve of the agr for tumor metastasis was utilized in computing the ideal cutoff level by using the r package survival roc, version 4.0.3 (r foundation for statistical computing, vienna, austria). areas under the curve were calculated for agr. the best cutoff value was calculated to be 1.32 in the roc curve at 12 months based on the highest youden index score. the decision curve analysis was utilized in evaluating the effectiveness of their marker in a decision-making process by using r package rmda, version 4.0.3 (r foundation for statistical computing, vienna, austria). consequently, the patients with agr values ≥ 1.32 composed the high-agr group, while patients with agr values < 1.32 composed the low-agr group. the normal distribution of the continuous variables was evaluated by histogram and analytical methods (kolmogorov–smirnov and shapiro–wilk tests). other continuous variables had normal distributions and were shown as mean ± standard deviation except for the folurological oncology 68 table 2. comparison of clinicopathological variables. variablesa total (n = 176) low-agr group high-agr group p value agr < 1.32 (n = 57) agr ≥ 1.32 (n = 119) pathological tumor stage .080 ≤t2 103 (58.5) 28 (49.1) 75 (63.0) ≥t3 73 (41.5) 29 (50.9) 44 (37.0) histological grade .470 low 8 (4.5) 6 (5.9) 2 (2.7) high 168 (95.5) 96 (94.1) 72 (97.3) lymph nodes involvement 40 (22.7) 15 (26.3) 25 (21.0) .432 lvi 35 (19.9) 12 (21.1) 23 (19.3) .788 follow-up periodb, months 32.4 (0.2–95.3) 32.6 (4.4–95.3) 32.2 (0.2–92.1) .794 metastasis 52 (29.5) 27 (47.4) 25 (21.0) < 0.001 cancer-related mortality 41 (23.3) 22 (38.6) 19 (16.0) .001 avalues are presented as mean ± standard deviation or number (%) unless otherwise indicated. bvalues are presented as median (range) abbreviations: agr, albumin-to-globulin ratio; lvi, lymphovascular invasion. variables hr 95% ci p value age 0.993 0.959–1.028 .680 sex (female vs. male) 0.978 0.413–2.325 .960 pathological tumor stage (≤ t2 vs. ≥ t3) 2.254 1.178–4.312 .014 lymph nodes involvement (no vs. yes) 1.899 0.966–3.734 .063 histological grade (low vs. high) 0.532 0.155–1.820 .314 lvi (no vs. yes) 1.950 1.002–3.792 .049 agr (< 1.32 vs. ≥ 1.32) 0.435 0.248–0.763 .004 abbreviations: agr, albumin-to-globulin ratio; ci, confidence interval; hr, hazard ratio; lvi, lymphovascular invasion. table 3. multivariable cox regression analysis for metastasis. albumin-to-globulin ratio and bladder cancer oh et al. low-up period with non-normal distribution. moreover, the follow-up period was shown as median (range). student’s t-test for the continuous variables with normal distribution, mann–whitney test for the continuous variable with non-normal distribution, and the chisquared test for the categorical variables were used to compare the clinicopathological features between the two groups. the kaplan–meier method was utilized to calculate the survival spreads including metastasis-free survival (mfs) and cancer-specific survival (css). a log-rank test was performed to compare survival distributions between the two groups. for mfs, the dependent and independent variables were metastasis and the mfs period, respectively. for css, the dependent and independent variables were cancer-related mortality and the css period, respectively. the factors independently related to mfs and css were estimated using a multivariate cox proportional-hazards regression model with hazard ratios (hr) and 95% confidence intervals (ci) calculated for each factor. the same statistical analyses aforementioned were done for the subgroup without nac. all statistical analyses except for time-dependent roc curves were performed using the statistical package for the social sciences, version 18.0 (ibm, chicago, il, usa). p values < .05 were considered statistically significant. results a time-dependent roc analysis for agr was conducted to evaluate the preoperative agr for metastasis prediction. the areas under the curves for agr at 12, 18, and 24 months were 0.632, 0.596, and 0.608, respectively (figure 2). the best cutoff agr value was determined to be 1.32 in the roc curve at 12 months (figure 3a). moreover, the best cutoff agr value was determined to be 1.32 in patients without nac (figure 3b). the standardized net benefit of agr was higher than that of albumin and globulin in the decision curve analysis for metastasis prediction (figure 4). the demographics and preoperative characteristics of the patients in the two groups are shown in table 1. the mean age of all the patients was 68.05 ± 8.96 years. the mean body mass index (bmi) was 23.01 ± 2.99 kg/m2. the mean age and bmi were not statistically different between the two groups. among the patients, 14.2% were females. of the patients, 62.5%, 19.9%, and 33.0% were diagnosed with mibc before rc, underwent nac, and patients underwent ac, respectively. the ratio of females, diversion type, operation methods, mibc, nac, and ac were not significantly different between the two groups. the mean total protein, mean serum albumin, and mean agr were 7.13 ± 0.60, 4.14 ± 0.32, and 1.41 ± 0.24 g/l, respectively. the mean total protein in the low-agr group was significantly higher than that in the high-agr group (7.39 ± 0.58 vs. 7.00 ± 0.57; p < .001). on the other hand, the mean serum albumin (4.04 ± 0.30 vs. 4.19 ± 0.33; p = .005) and mean agr (1.22 ± 0.11 vs. 1.50 ± 0.17; p < 0.001) were significantly lower in the low-agr group than those in the high-agr group. a comparison of the clinicopathological characteristics of the patients between the two groups is shown in table 4. multivariable cox regression analysis for cancer-specific mortality. variables hr 95% ci p value age 0.993 0.956–1.031 .705 gender (female vs. male) 0.988 0.380–2.569 .980 pathological tumor stage (≤ t2 vs. ≥ t3) 3.349 1.640–6.839 .001 lymph node involvement (no vs. yes) 1.060 0.503–2.232 .878 histological grade (low vs. high) 0.973 0.126–7.494 .920 lvi (no vs. yes) 2.660 1.297–5.457 .008 agr (< 1.32 vs. ≥ 1.32) 0.488 0.257–0.924 .028 abbreviations: agr, albumin-to-globulin ratio; ci, confidence interval; hr, hazard ratio; lvi, lymphovascular invasion. figure 2. time-dependent roc curves of preoperative agr according to times from rc for metastasis. albumin-to-globulin ratio and bladder cancer oh et al. vol 18 no 1 january-february 2021 69 table 2. the mean follow-up period in this study was 32.4 months (range, 0.2–95.3 months). the histological subtype (low vs. high grade), lymphovascular invasion (lvi), and pathological tumor stages between the two groups were not statistically different. metastasis rates were significantly higher in the low-agr group than in the high-agr group (47.4% vs. 21.0%; p < .001). in addition, cancer-related mortality rates were significantly higher in the low-agr group than in the highagr group (38.6% vs. 16.0%; p = .001). the kaplan–meier curve analysis demonstrated that the patients in the low-agr group had significantly lower rates of mfs than those in the high-agr group (52.6% vs. 79.0%; p = .001; figure 5a) and lower rates of css compared with the high-agr group (61.0% vs. 84.0%; p = .003; figure 5b). nmibc has a higher survival rate than mibc, so an additional analysis was done only for patients with mibc. for patients with mibc, urological oncology 70 the kaplan-meier curves were utilized to calculate mfs and css. mfs was significantly different between the two groups (44.7% vs. 70.1%; p = .015) (figure 6a). the css in the low-agr group was lower than that in the high-agr group, but not statistically significant (53.8% vs. 74.8%; p = .053) (figure 6b). the multivariate analysis for metastasis is shown in table 3. the pathological tumor stage ≥ t3 (hr = 2.254; 95% ci = 1.178–4.312; p = .014), lvi (hr = 1.950; 95% ci = 1.002–3.792; p = .049), and agr ≥ 1.32 (hr = 0.435; 95% ci = 0.248–0.763; p = .004) were shown to be independent predictive prognostic factors for metastasis. table 4 shows the multivariate analysis for cancer-related mortality. consequently, the pathological tumor stage ≥ t3 (hr = 3.349; 95% ci = 1.640–6.839; p = .001), lvi (hr = 2.600; 95% ci = 1.297–5.457; p = 0.008), and agr ≥ 1.32 (hr = 0.488; 95% ci = 0.257–0.924; p = .028) were shown figure 3. the best cutoff value of agr was calculated with time-dependent roc curves for metastasis at 12 months in the study population (a) and patients without nac (b). figure 4. decision curve analysis for agr, albumin, and globulin predicting metastasis. albumin-to-globulin ratio and bladder cancer oh et al. vol 18 no 1 january-february 2021 71 to be independent predictive factors for cancer-related mortality. discussion this retrospective study showed that preoperative agr can be valuable as a predictive factor in estimating css and mfs in patients with ubc who have undergone rc. this study is one of the first studies conducted in korea to assess the efficiency and accuracy of preoperative agr as a predictive prognostic factor in estimating mfs and css in patients with ubc who have undergone rc although some retrospective studies previously demonstrated that preoperative agr is related to the prognosis after rc of patients with ubc in china(15,16). it is generally accepted that inflammation is related to cancer(20). cancer-related inflammation, which consists of local immune and systemic inflammatory responses, is common in advanced cancer and is associated with shorter overall survival (os)(13,21,22). variable biomarkers from laboratory tests were studied (including c-reactive protein, albumin, glasgow prognostic score (gps), modified gps, plr, nlr, and lymphocyte-to-monocyte ratio) to estimate cancer-related systemic inflammation(23). serum albumin, a component of systemic inflammation, has several crucial physiological functions, including maintaining colloidal osmotic pressure, binding charged compounds, and doing antioxidant activities(13,24). decreased serum albumin and increased serum globulin level is associated with cancer-related systemic inflammation and tumor progression(12,13). agr is a factor that reflects both low albumin level and high globulin level in cancer-related systemic inflammation(14). several studies have examined the efficiency and accuracy of preoperative agr as a predictive prognostic factor for diverse human cancers in the past 10 years(25). in a healthy screening population, low agr is a risk factor for the occurrence of malignancies and malignancy-related mortality in the shortand long-term figure 5. the kaplan–meier curves showing mfs (a) and css (b) between lowand high-agr groups. figure 6. the kaplan–meier curves showing mfs (a) and css (b) between lowand high-agr groups in patients with mibc. albumin-to-globulin ratio and bladder cancer oh et al. periods(26). a meta-analysis of preoperative agr and human cancers reported that low preoperative agr values are related to poor os, progression-free survival (pfs), and disease-free survival in patients with malignancies(25). to date, two retrospective agr studies in china have been conducted involving patients with bc who underwent rc(15,16). liu et al.(15) carried out a retrospective study involving 296 patients with ubc who underwent rc. they determined the cutoff value of agr as 1.6 and reported that high-agr values are a strong independent predictive factor of long-term recurrence-free survival and css in patients with ubc undergoing rc. moreover, liu et al.(16) reported a retrospective cohort study involving 189 patients with primary high-grade ubc using a propensity score-matched analysis and determined that the cutoff value of agr was 1.55. their study demonstrated that preoperative agr, age (≥ 60 years), before and after propensity score-matched analysis, the pathological tumor stage, and lymph nodes metastasis were independent components in predicting pfs, css, and os in multivariate cox regression analyses. this study was a retrospective study involving 176 patients with ubc who underwent rc. in contrast to the previous two studies, this study included patients with clinical t3 or t4 who received nac. the cutoff value for agr in the current study was defined to be 1.32, which is lower than those in other studies. the ratio of pathologic tumor stage ≥ t3 (41.5% vs. 34.4%–36.5%) (15,16) and the ratio of the histological high-grade tumor (95.5% vs. 74.7%) were higher compared with other studies(15). considering that cancer progression is related to local and systemic inflammatory responses, these differences may be the reason why the cutoff value for agr in this study is lower than other studies(15,16,20). moreover, the study population included nac patients with clinical tumor stages 3–4 and node-positive disease. the downstaging effect of nac was not affected in these patients because preoperative laboratory tests were performed before nac(27). these points may also be the reason why the cutoff value for agr is lower than in other studies. the pathological tumor stage, lvi, and agr were independent predictive prognostic factors in the multivariate cox regression analyses for metastasis and cancer-specific mortality. moreover, a meta-analysis demonstrated that lvi is a significant component in predicting cancer recurrence and cancer-specific mortality in patients with bc(28). among the three studies that investigated the association between agr and ubc, one study(15) did not include lvi as a variable. in another study(16), lvi was not an independent factor for css, pfs, and os in multivariate cox regression analysis. in this study, the difference in lvi (in percent) between the low and high-agr groups was smaller than that of another study (18.1% vs. 19.8% and 36.4% vs. 20.3%, respectively)(16). in contrast to these two studies, the involvement of the lymph nodes was not an independent factor for metastasis and cancer-specific mortality in this study. the ratio of the involvement of the lymph nodes was higher in the low-agr group in these two studies (31.8% vs. 9.9% and 21.8% vs. 11.4%; respectively) (15,16). however, the difference in the involvement of the lymph nodes between the two groups in this study was smaller than that of the other studies (26.3% vs. 21.0%). patients with clinical tumor stages of 3 or 4 and lymph node-positive diseases in this study received neoadjuvant cisplatin-based chemotherapy. nac decreases residual cancer burden in patients with advanced ubc(29). nearly half of the patients with ubc treated with rc achieved pathological downstaging through nac(27). therefore, nac may be the cause of the lower differences in the involvement of the lymph nodes and lvi between the two groups in this study. this study evaluated agr as a prognostic factor for recurrence and survival in bc in korea and included patients who underwent nac (< 20%). however, this study had some limitations, including its retrospective study design and the shortest follow-up period (32 months) among the three studies investigating the association between ubc and agr. these limitations could affect subsequent results. furthermore, other prognostic factors from routine preoperative laboratory testing were not included. finally, the single-institutional database of this study did not contain data from other institutions. this could lead to imperfect reflections of the whole population of patients with ubc treated with rc in korea. therefore, a larger-scale, multi-institutional, and prospective study is required to provide a better conclusion. conclusions agr, which is an easily accessible and inexpensive marker, is an important predictive factor in patients with ubc treated with rc. the pathological tumor stage, metastasis, and cancer-specific mortality were significantly correlated with low agr values. low agr values showed a poor prognostic effect on css and mfs in patients who underwent rc for the treatment of ubc. preoperative agr is a readily accessible and inexpensive prognostic marker that can be utilized to predict outcomes in patients with ubc treated with rc. acknowledgment this research was supported by kyungpook national university research fund 2018. the authors would like to thank enago (www.enago. co.kr) for the english language review. conflict of interest none declared. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2018;68:394424. 2. siegel rl, miller kd, jemal a. cancer statistics, 2020. ca cancer j clin. 2020;70:730. 3. hong s, won yj, park yr, jung kw, kong hj, lee es. cancer statistics in korea: incidence, mortality, survival, and prevalence in 2017. cancer res treat. 2020;52:335-50. 4. reuter ve. the pathology of bladder cancer. urology. 2006;67:11-7. albumin-to-globulin ratio and bladder cancer oh et al. urological oncology 72 vol 18 no 1 january-february 2021 73 5. babjuk m, burger m, comperat em, et al. european association 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associated with cancer incidence and mortality in generally healthy adults. ann oncol. 2014;25:2260-6. 27. choueiri tk, jacobus s, bellmunt j, et al. neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. j clin oncol. 2014;32:1889-94. 28. mari a, kimura s, foerster b, et al. a systematic review and meta-analysis of lymphovascular invasion in patients treated with radical cystectomy for bladder cancer. urol oncol. 2018;36:293-305. 29. ha ys, kim th, kim th. chemotherapy in advanced urothelial carcinoma. korean j urol oncol. 2016;14:47-53. albumin-to-globulin ratio and bladder cancer oh et al. comparison of mini percutaneous nephrolithotomy (mini pcnl) and retrograde intrarenal surgery (rirs) for the minimal invasive management of lower caliceal stones alper coskun1*, bilal eryildirim2, kemal sarica3, emre çamur4, utku can5, erkin saglam6 purpose: to evaluate the stone-free rates, quality of life, complications, use of fluoroscopy, analgesic requirements, and hospital stay following the management of lower calyceal with two different techniques (mini percutaneous nephrolithotomy and retrograde intrarenal surgery) in a prospective manner. material and methods: 50 patients diagnosed with lower pole 1-2 cm stone were included in the study and randomized into two groups. (mini pcnl n: 25) ( rirs n: 25). the safety and efficacy of both methods, along with some other certain related factors, were comparatively evaluated in both groups. results: there was no significant difference between preoperative stone size, stone-to-skin distance, hemogram, creatinine values, need for the analgesic drug, patients' replies to visual analog scale (vas). the duration of both the hospital stay and the exposure to fluoroscopy, hematocrit decrease due to hemorrhage; complication rates were significantly higher in cases undergoing mini pcnl when compared to rirs. additionally, no significant difference was observed concerning the stone-free rates. despite an increase in quality of life following both types of operations, there was no significant difference in the quality of life between the patients in both groups. conclusion: our findings demonstrated that both surgical techniques are feasible alternatives in the minimally invasive treatment of lower pole stones. although there was no meaningful difference in stone-free rates between the two groups, complications, use of fluoroscopy, bleeding, and duration of hospital stay were noted to be significantly higher in cases treated with mini pcnl. keywords: fluoroscopy; hospital stay; mini percutaneous nephrolithotomy(mini pcnl); quality of life; retrograde intrarenal surgery(rirs); visual analog scale (vas) introduction as a pathology affecting 1-5% of the industrial coun-tries, urolithiasis is the third pathology influencing the urinary system after urinary tract infections and prostate pathologies. although the prevalence of stone disease throughout life varies between 1-20%, this rate has been reported to be up to 37% in some countries reported during the last two decades.(1) 25 % of patients with kidney stones have a family history. also, diseases transitioning by genetic such as renal tubular acidosis (rta), cystinuria, xanthinuria, dent disease have been identified in a certain percent of stone forming cases.(2) diagnostic evaluation requires a thorough physical examination, laboratory, and radiological imaging investigations to evaluate the stone and patient-related factors for a proper treatment plan. despite the developed medical therapies alternatives regarding the treatment, definitive treatment of stones is performed with extracorporeal shock wave lithotripsy (eswl) and minimally invasive surgery. eswl is the primary approach for stones smaller than 2 cm in the renal pelvis and calyx system.(3) although eswl has more excellent success rates in most of the stones mentioned above, in the event of a hard stone with a steep infundibulopelvic angle and narrow infundibular neck, the success rates of eswl could be decreased.(4) furthermore, for larger stones (> 2 cm) requiring possible additional interventions, other minimally invasive surgical alternatives like pcnl or rirs could be recommended as the first choice instead of eswl treatment.(3) according to eau guidelines, the surgical treatment of lower calyceal stones is the first choice for stones greater than 20 mm has been stated to be pcnl. for stones sizing between 10-20 mm, eswl or endourological methods are recommended as equally effective, and for stones smaller than 10 mm, the first approach was defined as eswl/rirs, and as second-choice is pcnl.(3) pcnl has replaced open surgery due to the short hospital stay, low cost, and morbidity. although standard 1department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul, turkey. 2department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul, turkey. 3medicana international istanbul hospital. urology department. istanbul turkey. 4department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul, turkey. 5department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul, turkey. 6department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul, turkey. *correspondence: department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul, turkey. phone: +90-0216 458 30 00. +90530 563 25 33. e-mail: dr.alper05@gmail.com received september 2020 & accepted february 2021 endourology and stone disease urology journal/vol 18 no. 5/ september-october 2021/ pp. 485-490. [doi: 10.22037/uj.v18i07.6443 pcnl has been used with 24-30 f nephroscope for an extended period, equipment sizes have started to be miniaturized subsequently due to the increased risk of complications due to the relatively higher invasiveness originating from large-sized access tracts. in 1998, jackman et al. described the mini-pcnl technique in the pediatric patient group where a nephroscope sizing 11-18 f has been favored.(5) among surgical methods for the minimally invasive removal of lower calyceal stones, rirs is one of the most frequently used methods due to its limited morbidity and the similar success rates obtained as an alternative to eswl as well as pcnl. in an original study performed by grasso et al., rirs was applied for the management of different sized lower pole stones (less than 10 mm, between 10-20 mm, and greater than 20 mm, respectively), and the obtained success rates were 82%, 71%, 65%.(6) in the light of this literature knowledges, we aimed to compare the rirs and mini pcnl in lower calyceal stones in all aspects. patients and methods between june 2016 and december 2016; patients referring to the urology department of dr. lutfi kirdar kartal city hospital ( aging between 18 and 65 years of age) with single or multiple stones ( sizing 1-2 cm) localized in the lower calyx systems were included into the study program and evaluated prospectively. following obtaining approval from the ethics committee of our hospital and informed consent forms filled by the patients. a total of 50 patients were included in the study in 2 groups of 25 people. group 1 (n = 25) operated with mini pcnl and group 2 ( n = 25) treated with rirs. groups were divided into two groups by patient preference. the exclusion criteria were assigned as the presence of bleeding diathesis, cognitive dysfunction, skeletal deformity preventing surgery, kidney collecting system anomaly, and the previous history of any renal surgery. to outline the stone-related factors (location, size, number) and kidney anatomy, a preoperative non-contrast spiral tomography was performed in all patients. the patients were evaluated with direct genitourinary system radiography (dusg) and/or urinary ultrasonography(usg) to outline the presence and size of residual stones during the postoperative first day, 1st week, 1st month, and 3 rd month. non-contrast tomography was joined to those tests if necessary. preoperative and postoperative quality of life evaluation was performed on all patients. a visual analog scale (vas) was used to outline the patients' pain both before the procedures and in postoperative follow-up. wewers and lowe had described vas in 1990.(7) this form represents the severity of pain, whether ‘no pain’ with a score of ‘0’ or ‘the worst pain i could imagine with a score of ’10’. (supplementary figure1) in addition to the evaluation of pain, euroqol 5d (eq 5d) general health scale form was filled out for the quality of life questionnaire both before and 3 months after the procedures. the eq5d common health scale was outlined in 1987 by the euroqol bunch of the western european quality of life examination community. (supplementary figure 2,3) it has been translated into more than 60 languages, and one of them is turkish in 1990.(8) at the first step of the mini pcnl to access to kidney collecting system, the combination of both ultrasound and fluoroscopy was used, after which the dilatation was performed with the amplatz dilation system (microvasive-boston scientific, usa). for stone fragmentation, our choice was a pneumatic lithotripter (elmed vibrolith, pck electronic p 1500 ankara-turkey) along with an ultrasonic lithotriptor used with this aim. we do not have a specific protocol regarding the use of these two techniques. the success of stone fragmentation of the two methods was found to be similar in the literature. a nephrostomy tube was placed in all patients routinely. in the rirs technique, the following semirigid ureteroscopy evaluation, the ureteral access sheath was placed into the ureter over the stiff guidewire under fluoroscopic guidance. after getting access into the collecting system, a 5,5 f flexible ureterorenoscope (f-urs) (karl storz, tuttlingen, germany) was used for the flexible ureteroscopy procedure. stones were fragmented with a holmium yag laser (sphinx 30 watt holmium laser usa). a single experienced urologist performed all these procedures. in addition to the demographic findings of the cases in both groups, surgical time, the extent of radiation in the course of operation, length of hospital stay(days), complications, blood transfusion rates, decrease in hematocrit levels, stone-free status, preoperative and postoperative analgesic requirements as well as the quality of life scores were compared in both groups. regarding the size of residual fragments, fragments smaller than 3mm or large were accepted as clinically significant. complications related to the procedures were classified table 1. demographics and baseline characteristics of the patients. mini pcnl rirs p value number of patients 25 25 age 44 ± 14 48 ± 13.9 0.4 (p > 0.05) gender m:% 60 (15 patients) m:%52 (13 patients) 0.569 f: % 40 (10 patients) f:%48 (12 patients) (p > 0.05) pre-operative stone size(mm) 15.7 ± 2.5 13.6 ± 2.2 0.09 (p > 0.05) stone-skin distance (mm) 95.6 ± 24.1 97.4 ± 15.2 0.294 (p > 0.05) preoperative creatinine 0.9 ± 0.3 0.9 ± 0.4 0.586 (p > 0.05) preoperative hematocrit 41 ± 5.6 40 ± 3.7 0.459 (p > 0.05) preoperative analgesic requirements. yes:% 44 (11 patients) yes:% 68 (17 patients) 0.87(p > 0.05) no: %56 (14 patients) no:% 32 (8 patients) *preoperative vas in pain 4 ± 0.4 4 ± 0.4 0.549 (p > 0.05) stones single:%44(11 patients ) single:%36(9 patients ) 0.564(p > 0.05) multiple: %56(14 patients) multiple: %64(16 patients) * vas: visual analog scale, m: male, f: female m-pcnl vs. rirs for lower pole stones-coskun et al. endourology and stones diseases 486 by using a modified clavien classification system.(9) in statistical analysis, spss for windows 22 program was utilized. numerical variables determined not to distribute in a normal manner were evaluated by using the kolmogorov smirnov test. , mann whitney u test and chi-square tests. p < 0.05 was considered statistically significant. results patients' demographic findings, preoperative values, and postoperative outcomes were recorded and evaluated comparatively in both groups. these findings are summarized in table 1. the preoperative size of stones measured with non-contrast computed tomography(ncct) in the mini pcnl and rirs groups were 15,7 ± 2,5 mm, 13,6 ± 2,2 mm, respectively. furthermore, values of the distance of stone from to skin based on preoperative non-contrast ct was detected as 95,6 (± 24,1) mm for mini pcnl and 97,4 (± 15,2) mm. for rirs. these results pointed out no statistically significant difference between groups. (p = 0.09, p = 0,294) while 44 % of patients in the mini pcnl group and 36 % in the rirs group demonstrated a single stone in the lower pole calyx, the remaining patients had multiple stones. there was no statistically significant difference in the preoperative routine biochemistry and serum hematocrit values (creatinine p = 0.586, hematocrit p = 0,459). regarding the comparison of vas scale values in both groups and the requirement of an analgesic drug, there was no significant difference with respect to both parameters between two groups (analgesia requirement p = 0.87, vas in pain p = 0.549) mean value of the pre-operative vas score assessment in the event of pain was noted to be as ''4'' for both groups. also, the highest pain value noted with vas scoring was ''8''. 11 patients of the mini pcnl group (%44) and 17 patients of the rirs group expressed use of oral analgesics due to severe pain. in the light of data obtained, the average operational duration for mini pcnl was 71.7 min(± 24.4) and rirs 72.8 min (± 24.2); there was again no statistical difference among both groups. (p = 0.696) another notable point is the time of fluoroscopy exposure, which is measured by seconds. while this duration was18,9 sec (± 13,8) in the mini pcnl group, it was noted to be 2.7 sec (± 2.8) in the rirs group, indicating that the need for fluoroscopy was less in rirs group than the mini pcnl with a significant statistical difference among both groups. (p < 0.05) similarly, bleeding and decrease in hematocrit values were less for the rirs group. (p < 0.05) however, as noted during the follow-up period, only two patients operated with mini pcnl required blood transfusion, and these findings have emphasized that the difference was not statistically significant between the two groups (p = 0.490). evaluation of the period in hospital demonstrated that the average value was 1,2 ±0.59 and 4,6 ± 3,5 days in rirs and mini pcnl groups, respectively, with a statistically significant difference among the two groups. (p < 0.05) during the postoperative 1st week, the analgesic requirement was needed in 12 patients in mini table 3. the questionnaire of pre-operative and post-operative quality of life (eq5d index, eq5d vas scale) mini pcnl rirs p preoperative eq-5dvas (%) % 61.4 ± 3.37 % 63.6 ± 2.2 0.239 (p > 0.05) preoperative eq-5d indeks 0.271 ± 0.750 0.177 ± 0.631 0.865 (p > 0.05) postoperative 3rd month eq-5d vas (%) % 83.1± 2.4 % 81 ± 2.6 0.604 (p > 0.05) postoperative 3rd month eq-5d indeks 0.570 ± 0.914 0.740 ± 0.852 0.264 (p > 0.05) m-pcnl vs. rirs for lower pole stones-coskun et al. mini pcnl rirs p operation time (min) 71.7 ± 24.4 72.8 ± 24.2 0.696 (p > 0.05) floroscopy time using (sec) 18.9 ± 13.8 2.7 ± 2.8 0.001 (p < 0.05) the length of hospital stay(days) 4.6 ± 3,5 1.2 ± 0.59 0.000 (p < 0.05) analgesic requirement post-operative at 1 st week yes:12 (% 48) yes:8 (% 32) 0.248 (p > 0.05) no:13 (% 52) no:17 (% 68) blood transfusion yes: 2 (% 8) yes: 0 (% 0) 0.490 (p > 0.05) no:23 (% 92) no:25 (% 100) hematocrit decrease (%) 4.8 ± 3.8 1.6 ± 2.6 0.000 (p < 0.05) *(sfs) postoperative first day 16 (% 64) 12 (% 48) 0.254 (p > 0.05) (sfs) postoperative 1 rd week 17 (% 68) 16 (% 64) 0.765(p > 0.05) (sf s) postoperative 1 rd day 17 (% 68) 17 (% 68) 1.000 (p > 0.05) (sf s) postoperative 1 rd day 18 (% 72) 17 (% 68) 0.758(p > 0.05) vas in pain postoperative 1 rd week 2 ± 0.2 2±0.38 0.346 (p > 0.05) **complications grade 1: 7 patients grade1: 22 patients 0.000 (p < 0.05) grade 2: 9 patients grade2: 3 patients grade 3:6 patients grade 4:3 patients grade 5:none dj stent placement yes:4 (%16) yes:20 (% 80) 0.000 (p < 0.05) no:21(% 84) no: 5 (% 20) table 2. results of operations. *stone-free status, ** clavien classification: 1.any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions, 2.requiring pharmacological treatment with drugs other than such allowed for grade i complications. 3. requiring surgical, endoscopic or radiological intervention, 4.life-threatening complications (including cns complications) requiring ic/icu-management, 5.death of a patient. vol 18 no 5 september-october 2021 487 endourology and stones diseases 488 pcnl and 8 patients in rirs group, and the equivalent of this type of pain in the vas score was found ''2''(very little), which did not make any significant statistical difference. (analgesia requirement((2x1 75 mg diclofenac daily)) p = 0.248, vas in pain p = 0.346) to evaluate and compare complications associated with between groups, findings obtained according to modified clavien calcification were considered. results with modified clavien classification of the complications showed that while grade 4 complications were observed in 3 patients, grade 3 in 6, and grade 2 in 9 patients in the mini pcnl, grade 2 complications were seen in 3 patients in the rirs group. these results have clearly demonstrated that the complication rates were higher in cases undergoing mini pcnl. (p < 0.05) while 20 of 25 patients in the rirs group required the double j catheter placement, only 4 of 25 patients in mini pcnl had this stent after the procedure. (p < 0.05) postoperative stone-free rates of the patients in both groups are being summarized in table 2. despite evidently increased rates within three months noted in both groups, there was no statistically significant difference between the two groups on this aspect. (table 2) the evaluation of the pre-operative and postoperative measurements of the eq5d index and eq5d vas values are being summarized in table 3. a significant improvement in the quality of life of the patients was noted in all cases without any statistically significant difference between the groups on this aspect. discussion as the success rates in terms of stone-free status for kidney stones have been increased as a result of the improvements in endourology, the hospitalization period has been shortened, surgical complications, as well as other morbidity conditions, have decreased significantly. the reported overall success rates of pcnl vary between 76-91% in the literature, with a rate of complications ranging from 20,5-29%.(10,11) although this approach has been performed for an extended period with great acceptance, rirs has started to play an important role in the surgical treatment of kidney stones with advancing laser technology.(12) during the rirs procedure, stones in almost all anatomical locations within the kidney can be easily reached without any risk of damage to the renal parenchyma. therefore, rirs increased its popularity with low complications as well as comparable success rates. rirs is also accepted as the most effective technique with minimal morbidity in patients with bleeding diathesis and the cases using anticoagulants.(13) concerning the stone location, pcnl and rirs are effective methods for the surgical treatment of lower calyceal stones. the comparative valuation of these surgical methods from different aspects has often been subjected to various studies. related to this issue, albala et al. reported in 2001 that stone-free rates after pcnl were 100%, 93%, and 86%, respectively, in lower calyceal stones sizing less than 1 between 1-2 cm and above 2 cm.(11) in another study published by preminger et al., the efficacy of eswl and pcnl were compared in lower calyceal stones, and while 100% and 92% stone-free rates have been obtained after pcnl in stones between 1 cm and 1-2 cm, these rates were noted to be 67% and 21% after eswl respectively.(14) other studies in the literature have also reported high stonefree rates after pcnl for lower calyceal stones.(15,16) mini pcnl technique with low complication rates compared to the standard pcnl approach has become the focus of interest in such studies. nagele et al. have used 12 f nephroscope during mini pnl procedure for lower calyceal stones ( sizing between 0,8-1,5 cm) and have reported a stone-free rate of 96,5% without any need for blood transfusion. (17) mishra et al. have compared standard pcnl with 12 f mini-pcnl in the treatment of kidney stones between 1 and 2 cm, a similar stonefree rate has been obtained in both methods, and bleeding was found to be significantly lower in mini-pcnl. (18) also, elsheemy et al. compared mini-pcnl with standard pcnl in 2019, and although the stone-free rate was lower in mini-pcnl, it was found to be advantageous in terms of complications and hospital stay.(19) reported data in the literature evaluating the success of rirs, which is a convenient method for the minimally invasive surgical treatment of lower calyx stones, have demonstrated high stone-free rates with low complication after this modality when compared with pcnl. for instance, a study carried about by grasso and ficazzola revealed stone-free rates of 82%, 71%, and 65%, respectively, when the lower pole stones were smaller than 1cm, 1-2 cm, and greater than 2 cm were treated with rirs.(20) other studies in the literature have clearly reported that the stone-free rate for rirs has gradually increased.(21,22,23) while high stone-free and low-complication rates were obtained with both rirs and mini pcnl approaches, the advantages and disadvantages of these techniques have been discussed in detail in a number of studies published in the literature. pan et al. have compared the results of rirs and mini pcnl in 2-3 cm kidney stones, and while the results showed higher stone-free rates for mini pcnl, complication rates were lower for rirs.(24) lee et al. have compared mini pcnl and rirs methods for kidney stones larger than 1 cm and have emphasized that both methods were comparable. although not statistically significant, cases in the rirs group had a higher stone-free rate than mini-pcnl, but there is a higher need for analgesics in rirs cases. (5) in their original study, kıraç et al. compared mini pcnl and rirs techniques in lower pole stones less than 15 mm, and it has been stated that no major complications were observed in any patient where the final stone-free rates were similar in both groups of cases.(26) in the same study, however, length of hospital stay and fluoroscopy exposure time were found to be higher in mini pcnl group when compared to rirs group. although there are enough studies in the literature comparing pcnl and rirs techniques for lower pole calculi, a limited number of randomized prospective studies comparing the efficacy of both techniques in the management of lower calyceal stones have been reported far in the literature. the basal criteria in many studies investigating the surgical treatment of lower pole stones include stone-free status, complication rates, length of hospitalization, fluoroscopy time, along with bleeding and transfusion rates. in the majority of such studies, while the stone-free rates following pcnl method were found to be higher, this approach was found to be relatively disadvantageous in the light of the other criteria evaluated. as shown in the review article focusing on the comparison of the results obtained with pcnl, m-pcnl vs. rirs for lower pole stones-coskun et al. rirs, and eswl in lower pole stones; all complication rates, bleeding, transfusion need, and length of hospitalization were found to be significantly higher in cases undergoing pcnl(27) in the light of the data obtained in our study, we were able to show that the duration of radiation exposure, length of hospitalization, the decrease rate in the percentage of hematocrit due to hemorrhage, and the rate of complications ( evaluated by clavien classification) were all higher in cases undergoing mini pcnl procedure for lower pole stones. these findings were found to be parallel with the data reported in the literature. considering the stone-free rates, we did not find any significant difference between the two groups during postoperative day 1, week 1, month 1, and month 3 evaluations. although reported higher stone-free rates in favor of pcnl and mini pcnl compared to rirs obtained in the literature.(24,28) however, the stone-free success of both techniques was found similar in our study. similarly, di mario et al. had reported stonefree for two similar operations in their study.(29) in this respect, our study showed that rirs is an effective treatment alternative for lower calyceal stones, considering the fact that stone-free success is similar to mini pcnl associated with lower complication rates, shorter length of stay, and shorter duration of fluoroscopy exposure time. nevertheless, in 20 out of 25 patients undergoing rirs, double-j catheter-related lower urinary tract symptoms, as well as additional pathologies such as catheter migration, catheter fall, or encrustation (calcification), have been observed as the disadvantages of this method. in addition, re-hospitalization of these patients for catheter withdrawal may cause the further quality of life changes in these patients. as an important parameter to be focused on, in addition to the limited number of studies comparing mini-pcnl and rirs techniques in lower calyceal stones, none of these studies have aimed to evaluate the quality of life changes in these cases after both interventions. in our study, by using the eq5d general health scale form filled by the cases during both the pre-operative and postoperative 3-month evaluation phases, changes in the quality of life ( qol) were well assessed, and our data did not show any significant difference in qol of the cases between the two groups during both pre-operative and postoperative evaluations regarding the possible changes in patients’ quality of life. regarding the limitations of our present study, the lower number of patients from a single center, the lack of data on the anatomy of the lower pole involved ( length, width, and angle of the infundibulum) are important parameters to be taken into account in such studies. also, criticism may be that there is no specific protocol regarding using these two stone-breaking techniques. but when review to literature, the success of stone fragmentation of the two methods was similar.(30) last but not least, the lack of statistical data regarding the possible unfavorable effects of double j catheter placement on lower urinary tract functions may constitute another limitation. however, due to the limited number of studies focusing on the success and complications of these two methods (especially when evaluated with patients' quality of life findings), we believe that our present findings will contribute sufficiently to the current literature data. conclusions there is an ongoing controversy regarding the optimal minimal invasive management of lower calyceal stones. our findings clearly indicate that rirs could be applied as a more favorable procedure with respect to the rate of complications, risk of bleeding, length of hospital stay, and the duration of radiation exposure when compared to mini-pcnl approach. however, in addition to the stone as well as anatomy-related factors, the patient's preference, surgeon's experience, technical possibilities need to be considered as a whole in selecting the most appropriate surgical technique for such stones. all patients should be informed in detail about the complications and possible success rates of these methods. we believe that further multicenter studies, including large patient series, are certainly needed to improve the scientific quality of the data obtained in our current trial. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/15 references 1. türk c, petřík a, sarica k et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016;69:468-474 2. pearle ms and lotan y. urinary lithiasis: etiology, epidemiology, and pathogenesis. campbell-walsh urology. 2007;2: 13631392. 3. türk c, petřík a, sarica k et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-482. 4. kijvikai k and de la rosette j. assessment of stone composition in the management of urinary stones. nat rev urol. 2011; 8:81-85. 5. jackman sv, hedican sp, peters ac, docimo sg. percutaneous nephrolithotomy in infants and preschool age children: experience with a new technique. urology. 1998;52: 697-701. 6. grasso m and m. ficazzola. retrograde ureteropyeloscopy for lower pole caliceal calculi. j urol. 1999;162:1904-1908. 7. wewers me and lowe nk. a critical review of visual analogue scales in the measurement of clinical phenomena. research in nursing & health. 1990;13:227-236. 8. the euroqol group. euroqola new facility for the measurement of health-related quality of life. health policy 1990;16:199-208. 9. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-213. 10. rosette jdl, assimos d, desai m et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol. 2011;25:11-17. 11. albala dm, assimos dg, clayman rv et al. lower pole i: a prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for lower pole nephrolithiasis-initial results. j urol. 2001;166:2072-2080. m-pcnl vs. rirs for lower pole stones-coskun et al. vol 18 no 5 september-october 2021 489 endourology and stones diseases 490 12. johnson gb, portela d, grasso m. advanced ureteroscopy: wireless and sheathless j endourol. 2006;20:552-555. 13. papatsoris a and sarica k. flexible ureterorenoscopic management of upper tract pathologies. urol res. 2012;40:639-646. 14. preminger gm. management of lower pole renal calculi: shock wave lithotripsy versus percutaneous nephrolithotomy versus flexible ureteroscopy. urol res. 2006;34:108-111. 15. lingeman j, siegel iy, steele b, nyhuis aw, woods jr. management of lower pole nephrolithiasis: a critical analysis. j urol. 1994;151:663-667. 16. resorlu b, kara c, senocak c, cicekbilek i, unsal a. effect of previous open renal surgery and failed extracorporeal shockwave lithotripsy on the performance and outcomes of percutaneous nephrolithotomy. j endourol. 2010;24:13-16. 17. nagele u, schilling d, sievert kd, stenzl a, kuczyk m. management of lower-pole stones of 0.8 to 1.5 cm maximal diameter by the minimally invasive percutaneous approach. j endourol. 2008;22:1851-1854. 18. mishra s, sharma r, garg c, kurien a, sabnis, r, desai m. prospective comparative study of miniperc and standard pnl for treatment of 1 to 2 cm size renal stone. bju int. 2011;108:896-900. 19. elsheemy sm, elmarakbi aa, hytham m, ibrahim h, khadgi s, al-kandari ma. mini vs standard percutaneous nephrolithotomy for renal stones: a comparative study. urolithiasis. 2019;47:207-214. 20. grasso m and ficazzola m. retrograde ureteropyeloscopy for lower pole caliceal calculi. the j urol. 1999;162:1904-1908. 21. galvin dj and pearle ms. the contemporary management of renal and ureteric calculi. bju int. 2006;98:1283-1288. 22. mariani aj. combined electrohydraulic and holmium: yag laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. j urol. 2007;177:168-173. 23. bozkurt of, resorlu b,yildiz y, can ec, unsal a. retrograde intrarenal surgery versus percutaneous nephrolithotomy in the management of lower-pole renal stones with a diameter of 15 to 20 mm. j endourol. 2011; 25: 1131-1135. 24. pan j, chen q, xue w et al. rirs versus mpcnl for single renal stone of 2-3 cm: clinical outcome and cost-effective analysis in chinese medical setting. urolithiasis. 2013;41:73-78. 25. lee wj, park j, lee bs, son h, cho ys, hyeon j. mini-percutaneous nephrolithotomy vs retrograde intrarenal surgery for renal stones larger than 10 mm: a prospective randomized controlled trial. urology. 2015;86:873-877. 26. kirac m, bozkurt öf, tunc l, guneri c, unsal a, biri h. comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in management of lowerpole renal stones with a diameter of smaller than 15 mm. urolithiasis. 2013;41:241-246. 27. donaldson jf, lardas m, scrimgeour d, stewart f, mclennan s, lam tb et al. systematic review and meta-analysis of the clinical effectiveness of shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy for lowerpole renal stones. eur urol. 2015;67:612616. 28. cabrera jd, manzo bo, torres je, vicentini fc, sánchez hm, rojas ea et al. mini percutaneous nephrolithotomy versus retrograde intrarenal surgery for the treatment of 10–20 mm lower pole renal stones: a systematic review and meta-analysis. world j urol. 2020;38:2621-2628. 29. di mauro d, la rosa vl, cimino s, di grazia e. clinical and psychological outcomes of patients undergoing retrograde intrarenal surgery and miniaturised percutaneous nephrolithotomy for kidney stones. a preliminary study. arch ital urol androl. 2020;91:256-260. 30. radfar mh, basiri a, nouralizadeh a, shemshaki h, sarhangnejad r, kashi ah et al. comparing the efficacy and safety of ultrasonic versus pneumatic lithotripsy in percutaneous nephrolithotomy: a randomized clinical trial. eur urol focus. 2017;3:82-88. m-pcnl vs. rirs for lower pole stones-coskun et al. vol 15 no 06 november-december 2018 370 sexual dysfunction and andrology relationship between erectile dysfunction, diabetes and dyslipidemia in hypertensive-treated men josé j. zamorano-león1,antonio segura2, vicente lahera3, josé m. rodriguez-pardo4, rafael prieto5, ana puigvert6, antonio j. lópez farré1* purpose: presiden study is a large study to analyze the erectile dysfunction (ed) incidence in spanish population. the present study is a pilot sub-analysis from presiden to determine if ed or plasma testosterone (tst) level in controlled hypertensive patients may be associated with comorbidities and/or plasma nitrite+nitrate and antioxidant capacity. materials and methods: forty-four hypertensive individuals were aleatory selected from presiden study, matching by age (28 showing ed and 16 without ed). result: diabetes was present in 28.57% of ed patients and in 18.75% of patients without ed. in patients with and without ed, increasing age showed tendency of higher frequency of an additional comorbidity (diabetes or dyslipemia) (p = .09). apparently, plasma tst levels were lower in older ed patients compared to younger patients with and without ed, although it did not reach statistical significance (p = .69). older ed patients also showed lower tst levels than older patients without ed, although it was not statistical significant (16.15 ± 2.84 vs 13.91 ± 2.77; p = .69). dyslipidemia was showed by 52.17% with lower tst (≤ nmol/l) while 23.80% of patients with plasma tst levels > 15 nmol/l had dyslipidemia. the percentage of ed patients was similar between patients with low and high tst levels. conclusion: more ed hypertensive patients seem to show two comorbidities (diabetes and dyslipidemia) than hypertensive patients without ed. younger patients with ed tended to show more commonly diabetes than older ed patients. plasma tst levels were not associated with more prevalence of ed but lower plasma tst levels showed tendency to higher prevalence of dyslipidemia. keywords: diabetes; dyslipidemia; erectile dysfunction; hypertension; oxidative stress; plasma testosterone. introduction erectile dysfunction (ed) has higher prevalence among hypertensive men than in general population.(1) indeed, hypertension is considered risk factor for ed and often precedes it.(2) in the hypertensive patients different factors have been associated with ed, including duration and severity of hypertension, non-controlled hypertension, older age, as well as some antihypertensive therapy among others.(3,4) in this regard, thiazides have negative effect on ed.(5) however, independently of these factors, ed and hypertension shared that endothelial dysfunction seems to be cause of their genesis. moreover, endothelial dysfunction is also common cause to promoting other vascular co-morbidites including diabetes mellitus.(6,7) in this regard, reduction of nitric oxide (no) generation 1departments of medicine. school of medicine. universidad complutense, madrid, spain. 2health science institute, talavera de la reina, toledo, spain. 3department of physiology. school of medicine. universidad complutense, madrid, spain. 4life and health unit. universidad carlos iii. madrid. spain. 5andrology, sexual and reproductive medicine unit. hospital regional universitario reina sofía, córdoba, spain. 6andrology and sexual medicine institute, barcelona, spain. *correspondence: department of medicine, school of medicine universidad complutense. plaza de ramón y cajal, s/n. madrid 28040, spain. tel: +34 91 394 15 91. e-mail: ajlf@telefonica.net. received july 2017 & accepted december 2017 and oxidative stress are key players in the pathogenesis of endothelial dysfunction, and therefore, in hypertension and ed.(8-10) the increased oxidative stress associated with hypertension was reported to result not only by increasing oxidative-related molecules but also by diminishing antioxidant capacity.(11) hypertension is often associated with metabolic abnormalities, such as diabetes and dyslipidemia.(12) however, although both dyslipidemia and diabetes have also a close relationship with ed, less has been analyzed if the presence of ed may increase the frequency of them in hypertensive men. indeed, ed was suggested as predictor of cardiovascular diseases and even some authors note that ed symptoms in hypertensive patients would represent more deterioration of endothelial functionality, alerting for a possible progression of the disease.(13,14) if this hypothetical major vascular deterioration can imply an additional worse on either the ability to generate no or the oxidative stress, remains to be established. hormonal abnormalities have been also identified as possible cause of ed, particularly associated in older age with low serum testosterone (tst) levels. indeed, at tst levels as high as 12-15 nmol/l patients may undergo low sexual potency and low libido.(15) although, it was suggested that tst levels are inversely correlated with severity of erectile dysfunction, controversial results exists about it. indeed, a recent meta-analysis concluded that tst had positive effects on male sexual function in hypogonadal subjects but its effects on hypogonadal men is uncertain.(16) however, in our knowledge it is not well established the possible relationship between low total plasma tst levels and cardiovascular comorbidities, including ed, in hypertensive patients. taken together, the aims of the present study were to analyze if the presence of ed modify the frequency of dyslipidemia and diabetes mellitus in hypertensive treated patients and if there is any relation with modifications in the plasma levels of either nitric oxide or total antioxidant capacity. moreover, it was analyzed whether low tst levels may be associated with either the frequency of comorbidities in pharmacologically controlled hypertensive patients and/or with the circulating levels of the above-mentioned biochemical parameters. material and methods population included in 2011 the spanish andrology society (asesa) started the campaign “men change”, where men were invited to participate in a cross-sectional national epidemiologic prevalence study called as presiden study. subjects who agreed to participate completed a series of specific questionnaires and blood samples were also taken for determining biochemical parameters. the present work is a retrospective pilot sub-analysis from the presiden study carried out in pharmacologically controlled arterial hypertensive men who were only recruited in the province of malaga, spain. men recruited in the present work were aleatory selected and matching by age. inclusion criteria were age ≥ 18 years with arterial hypertension that was defined as previously diagnosed by a physician. all the included hypertensive patients were receiving optimal antihypertensive therapy. patients with the following conditions were excluded: non-controlled hypertension, malignant hypertension, secondary forms of hypertension, evidence of myocardial infarction, angina pectoris or heart failure. patients who had plasma creatinine levels greater than 2.0 mg/ dl (176.8 µmol/l) or missing covariates were excluded. patients with a history of neoplasia, infections or autoimmune disease, or any surgical procedure in the preceding 6 months were excluded. the abridged five-item version of the 15-item international index of erectile function (iief-5)(17) was used to determine presence of ed. on this scale, a score < 21 is indicative of ed. for the analysis of the cardiovascular co-morbidities, dyslipidemia was defined as previously diagnosed by a physician, receiving lipid lowering drugs, or either total cholesterol > 200 mg/dl, ldl-cholesterol >100 mg/dl or serum triglyceride > 150 mg/dl. diabetes mellitus as previously diagnosed by a physician and was defined according to the clinical guidelines task force from the international diabetes federation.(18). plasma for total tst, nitrite+nitrate and total antioxidant capacity determinations were obtained from overnight fasting blood samples recollected in tubes containing edta. blood samples were immediately centrifuged and plasma aliquots was made and stored at -80ºc until the biomarker determinations. the study was blinded for the researches that performed the molecular analysis, was approved by the ethical committee of hospital clínico san carlos and informed consent was obtained from all individual participants included in the study. determination of nitrite+nitrate, total antioxidant capacity and testosterone plasma levels. plasma nitrite/nitrate and total antioxidant capacity were determined using commercial elisa kits (cayman chemical company, ann arbor, mi, usa) plasma total tst levels were also determined by using an elisa commercial kit (ab 108666 abcam, uk). statistical analysis kolmorov-smirnov test was used to assess plasma parameters distribution. in this regard, both plasma nitrite+nitrate levels and antioxidant capacity did not follow normal distribution. therefore, the values of these parameters were represented as medians and 25th and 75th percentiles and their comparison between groups was performed with the non-parametric mann-whitney´s test. age and plasma tst values were normally distributed and were represented as mean ± sem. comparisons of age and tst levels were performed using table 1. erectile dysfunction(ed) in the hypertensive hypertensive patients (n=44) without ed (n=16) with ed (n=28) age 59.43 ± 2.31 60.85 ± 1.65 comorbidities +0 8/16 13/28 +1 7/16 10/28 +2 1/16 5/28 diabetes 3/16 8/28 dyslipidemia 6/16 12/28 nitrites+nitrates (µmol/l) 4.54 (3.21-7.76) 3.53 (2.41-6.85) antioxidant capacity (µmol/l) 1.68 (1.29-1.87) 1.61 (1.33-1.83) tst (nmol/l) 15.78 ± 1.11 15.44 ±1.05 the results of continuous variables (age and plasma testosterone (tst) levels) are represented as mean ± sem. the variables without normal distribution (plasma nitrate +nitrite levels and plasma antioxidant capacity) were represented as medians and 25th-75th percentiles (numbers into brackets). the results of categorical variables are represented as number of cases with respect to the total included patients within each experimental group. erectile dysfunction and frequency of comorbidity-zamorano-león et al. sexual dysfunction and andrology 371 vol 15 no 06 november-december 2018 372 unpaired two-sided student´s t test. categorical variables were compared by the fisher’s exact test. for statistical significance were assuming a type i error probability of <.05. spss statistical software (version 17.0, spss inc., chicago, il, usa) was used for all analyses. results comparison between hypertensive patients with and without ed forty-four pharmacologically controlled arterial hypertensive men were included in the study. twenty eight of them showed iief-5 score < 21, indicative of ed, and 16 had iief-5 score ≤ 21 suggesting erectile functionality (table 1). mean age was similar between ed patients and patients without ed (table 1). similar number of patients with and without ed had no comorbidities 46.42% and 50% respectively. as shown in table 1 in absolute number, 43.75% of patients without ed and 35.71% of ed patients had additional comorbidity (p = .70). however, the percentage of patients with ed showing two comorbidities tended to be higher than in the patients without ed (17.85% and 6.26% respectively), although the sample size was probably small enough to achieve statistical significance. there were not differences in the percentage of patients showing dyslipemia or diabetes between the two groups of patients (table 1).in this regard, dyslipemia was present in 37.5% of patients without ed and 42.85% of the ed patients. diabetes was more common in patients with ed 28.57% than in patients without ed 18.75%, although it was far of reaching statistical significance (p = .70). plasma levels of nitrite+nitrate (as measured of nitric oxide levels), seem to be lower in ed patients as compared with those in patients without ed, although statistically were not different (p = .31, table 1). the plasma antioxidant capacity and tst levels were similar between hypertensive patients with and without ed (table 1). in the hypertensive patients with and without ed, increased age was associated with tendency to present higher frequency of additional comorbidity, although it did not reach statistical significance (p = .09, table 2). as table 2 shows, diabetes appeared to be more common in the younger (< 65 years) patients with ed than in ed patients with age > 65 years old, (with ed < 65 years: 31.57%; > 65 years: 11.11%), although it was not did not reach statistical significant (p = .37). no statistical differences were observed in the nitrite+nitrate plasma levels when younger and older patients with and without ed were compared (p = .69 and p = .23 respectively, table 2). however, it should be of interest that older patients without ed and ed patients of any age slightly showed lower nitrite+nitrate plasma levels than younger patients without ed (table 2). however, it did not achieve statistical significance in any case (p = .69). total plasma antioxidant capacity was similar in younger and older patients with and without ed (table 2). total tst plasma levels were also similar between patients with and without ed, although the mean value was lower in older patients with ed as compared with the remaining patients (table 2). relationship between total plasma testosterone levels and comorbidities in hypertensive patients to identify patients with tst deficiency, and due to the small sample size, the statistical analysis was performed considering the cut-off point of total plasma tst levels > 15 nmol/l, since the mean value found in the included individuals was 15.57. as table 3 shows, age was not different between hypertensive patients with low and normal total plasma tst levels. in addition, there were no statistical differences in the comorbidities number between patients with low total tst level (≤ 15 nmol/l) and those with higher plasma tst levels (> 15 nmol/l) (table 3) (p = .29). however, apparently more patients having two and three comorbidities were present in the patients with lower tst levels (≤ 15 nmol/l) as compared with patients with tst levels higher than 15 nmol/l (table 3). indeed, nine of the patients with lower tst levels 39.13% showed two or three comorbidities while in the group of patients with tst levels over 15 nmol/l only five patients showed two or three comorbidities 23.80%. dyslipidemia was present in 52.17% of patients with lower plasma tst levels while 23.80% of patients with total plasma tst levels >15 nmol/l showed dyslipidemia as comorbidity (p = .04, table 3). similar percentage of patients with low and high tst levels showed diabetes as comorbidity (21.73% vs 23.80%, table 2. influence of aging without ed (n=16) with ed (n=28) < 65 years old ≥ 65 years old < 65 years old ≥ 65 years old patient´s number 11 5 19 9 comorbidities +0 6/11 2/5 9/19 4/9 +1 4/11 3/5 6/19 5/9 +2 1/11 0/5 4/19 0/9 diabetes 2/11 1/5 6/19 1/9 dyslipidemia 4/11 2/5 7/19 4/9 nitrites+nitrates (µmol/l) 4.85 3.92 3.83 3.34 (3.29-10.45) (3.12-4.67) (2.54-7.34) (2.27-4.40) antioxidant capacity (µmol/l) 1.71 1.65 1.61 1.59 (1.29-1.87) (1.50-1.84) (1.31-1.92) (1.43-1.87) tst (nmol/l) 15.61 ± 1.21 16.15 ± 2.84 16.09 ± 0.98 13.91 ± 2.77 the results of continuous variables (age and plasma testosterone (tst) levels) are represented as mean ≤ sem. the variables without normal distribution (plasma nitrate +nitrite levels and plasma antioxidant capacity) were represented as medians and 25th-75th percentiles (numbers into brackets). the results of categorical variables are represented as number of cases with respect to the total included patients within each experimental group. ed: erectile dysfunction. erectile dysfunction and frequency of comorbidity-zamorano-león et al. table 3). moreover, the percentage of patients showing erectile dysfunction (iief-5 <21) was similar between patients with low and high tst levels (65.21% vs 61.90%; p = .82). patients showing lower tst levels (≤15 nmol/l) had no statistical differences in plasma nitrite+nitrate, although it tended to be diminished in patients with tst values above 15 nmol/l (p = .15). total plasma antioxidant capacity levels were similar between patients with total plasma tst levels > 15 nmol/l and those with tst levels ≤ 15 nmol/l (table 3). discussion in the present study was evaluated if the presence of ed may modify the frequency of dyslipidemia and diabetes as comorbidities in patients under hypotensive treatment. the results showed that ed was associated with tendency to show more commonly two comorbidities (dyslipidemia and diabetes). moreover, more patients with ed showed diabetes, as comorbidity, although probably the small sample size made that the differences did not achieve statistical significance when it was compared with patients without ed. in this regard, an apparent paradoxical observation was that in older patients with ed (≥ 65 years old) only 1 from 9 patients showed diabetes as comorbidity suggesting lesser frequency of diabetes as comorbidity than in younger hypertensive patients with ed. it may suggest that hypertension and diabetes may be independent risk factors for ed. indeed, it was reported that diabetic patients have ed at early age and with higher prevalence that non-diabetic patients.(19) moreover, it could be plausible that patients with ed and diabetes has worse outcome than those without ed, promoting higher mortality. indeed, in the ed group only 9 patients with age older than 65 years old were recruited while 19 patients with age younger than 65 years old were recruited in the study. in this regard, ed was reported as additional risk factor for 10-years coronary risk.(20) although it is commonly assumed that hypertension predisposes somehow men to impotence, precise consequences associated with the presence of ed in hypertensive patients has not been sufficiently established. in this regard, vascular disease is commonly implicated in the pathogenesis of ed. therefore, ed in hypertensive men could be indicative of higher vascular damage, which may favour an increased frequency of cardiovascular comorbidities. in the present study, the percentage of patients with ed showing two comorbidities tended to be higher than in the patients without ed although it did not reach statistical significance probably due to the small sample size. endothelial dysfunction has been identified as one of the major pathophysiological mechanisms for ed.(21) patients with ed of any age and older patients (> 65 years) without ed also tended to show reduction of circulating nitrite+nitrate levels (as measured of no) when they were compared with younger hypertensive patients without ed. in this regard, reduction of the ability of the vascular cells to produce no has been linked to both ed and aging.(21,22) plasma testosterone levels and comorbidities in hypertensive patients total plasma tst levels in ed patients older than 65 years tended to be reduced as compared with younger ed patients and patients without ed. therefore, it was analysed whether total plasma tst levels may influence cardiovascular comorbidities in the hypertensive patients. in this regard, exogenous tst therapy has been associated with improvement of cardiac risk factors, especially in those patients with hypertension.(23) probably, the more relevant observation of this analysis was that in the patients with higher plasma tst levels (> 15 nmol/l) dyslipidemia was less common than in the patients with lower plasma tst levels (≤ 15 nmol/l). however, diabetes was equally frequent between patients with high and low plasma tst levels. accordingly, it was reported that in hypertensive patients low tst levels was associated with impaired lipids management and pro-atherogenic lipid profile.(24) there are several evidences that men with marked hypogonadism have ed. however, the level of hypogonadism required to induce this ed is questionable.(25) indeed, in the present study hypertensive patients with total plasma tst levels below 15 nmol/l showed similar prevalence of ed than those with total plasma tst levels higher than 15 nmol/l. however, as above mentioned in older patients with ed was where circulating total tst levels tended to be reduced. in this regard, it was suggested that reduction of tst could contribute to enhance the severity of atherosclerosis contributing to increase arterial stiffness and, therefore, ed.(26) paradoxically, in the present study, plasma nitrite+nitrate levels tended to be diminished in patients with the higher tst levels. indeed, initially we may expect table 3. influence of plasma testosterone (tst) levels . tst≤ 15 nmol/l (n=23) tst> 15 nmol/l (n=21) age 60.22 ± 1.82 60.48 ± 2.12 comorbidities +0 4/23 4/21 +1 10/23 12/21 +2 6/23 4/21 +3 3/23 1/21 dyslipidemia 12/23 5/21* diabetes 5/23 5/21 iief-5 (< 21) 15/23 13/21 nitrites+nitrates (µmol/l) 4.67 (3.07-7.43) 3.43 (2.54-6.36) antioxidant capacity (µmol/l) 1.51 (1.30-1.87) 1.65 (1.36-1.97) the results of continuous variables (plasma testosterone (tst) levels and age) are represented as mean ± sem. the variables without normal distribution (plasma nitrate +nitrite levels and plasma antioxidant capacity) were represented as medians and 25th-75th percentiles (numbers into brackets). the results of categorical variables are represented as number of cases with respect to the total included patients within each experimental group. * p < 0.05 with respect to tst ≤ 15 nmol/l. erectile dysfunction and frequency of comorbidity-zamorano-león et al. sexual dysfunction and andrology 373 vol 15 no 06 november-december 2018 374 that no levels should be positively associated with tst levels. however, in experimental animals it was reported inverse no-gonadal relationship and even it was postulated that modulation of no activity may affect gonadal activity.(27) in addition, intertesticular treatment with no-donors decreased serum and interstitial fluid tst concentration.(28) taken together, the fact that nitrite+nitrate plasma levels tended to be higher in patients with lower tst levels while dyslipidemia was more commonly found in them diminished the involvement of no in the possible relationship between tst levels and the frequency of this comorbidity. in this regard, other factors could be involved in the observed tendency to show higher dyslipidemia frequency by in the hypertensive patients with lower total tst levels. as example, there are evidences supporting a role of tst on inflammatory-related mechanisms. in this regard, tst increases the in vitro production of the anti-atherogenic cytokine il-10, and tst therapy reduced circulating levels of several pro-inflammatory cytokines in men with low tst levels, most of them with coronary disease.(29,30) study limitations there are several limitations in the study that deserve comment. the first of them is that the very small sample size probably limited the possibility to achieve statistical significance in the parameters in which were observed a tendency to be different. another limitation of the present study is that due to the transversal nature of the study it is not possible to determinate strictly dependence of variables but simply of association among variables. a longitudinal study (cohort or case-control) would have been necessary to establish the dependency relationship. another important limitation was that in the experimental design of the presiden study was not contemplated collecting the drugs that the patients were taking at inclusion. however, at inclusion physicians declared that the patients were taken optimal clinical medication by their morbidities. conslusions as conclusions, the percentage of hypertensive patients with ed showing two comorbidities (diabetes and dyslipidemia) tended to be higher than that in hypertensive patients without ed. moreover, the younger hypertensive patients with ed tended to show more commonly diabetes as additional comorbidity than older patients with ed. older hypertensive patients with ed tended to show lower levels of total plasma tst than the younger ed patients and that patients without ed of all age. however, tst levels were not associated with higher presence of ed but lower tst levels were associated with higher prevalence of dyslipidemia. it was accompanied of a tendency to show lower nitrite+nitrate plasma levels in patients with lower tst levels than in those hypertensive patients with higher tst levels. taken together, although clarification of the physiological and clinical significance of the relationship between hypertension, ed and tst require further investigations; these open the possibility that in hypertensive patients, ed and low total tst levels may be independently associated with cardiovascular comorbidities. acknowledgement the authors thank begoña larrea for secretarial assistance. this work was supported by an unrestricted research grant from bayer hispania and by redes temáticas de investigación cooperativa (retics) rd12/0042/0040 and rd12/0042/0033 fondo europeo de desarrollo regional (fondos feder). conflict of interest the authors declare that they have not conflict of interest. references 1. giuliano fa, leriche a, jaudinot eo, et al. prevalence of erectile dysfunction among 7689 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2013;26: 373-381. 24. haffner sm, mykkanen l, valdez ra, et al. relationship of sex hormones to lipids and lipoproteins in 380 nondiabetic men. j clin endocrinol metab 1993;77:1610-5. 25. buena f, swerdloff rs, steiner bs, et al. sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range. fertil steril 1993;59:1118–23. 26. hougaku h, fleg jl, najjar ss. relationship between androgenic hormone and arterial stiffness, based on longitudinal hormone measurements. am j physiol endocrinol metabolism 2006; 290:e234-42. 27. singh v, chaturvedi ch. correlation of nitric oxide and testicular activity in laboratory mouse, mus musculus. int j innov res science 2013; 2:721-9. 28. gaytán f, bellido c, aguilar r, et al. role of testis in response of the pituitary-testicular axis to nitric oxide related agents. eur endocrinology. 1997;137:301-8. 29. liva sm, voskuhl rr. testosterone acts directly on cd4+ t lymphocytes to increase il-10 production. j immunol 2001;167:20607. 30. malkin cj, pugh pj, jones, et al. the effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. j clin endocrinol metab 2004;89:3313-8. erectile dysfunction and frequency of comorbidity-zamorano-león et al. sexual dysfunction and andrology 375 an investigation into the effects of intravenous vitamin c on pulmonary ct findings and clinical outcomes of patients with covid19pneumonia a randomized clinical trial shabnam tehrani1 ,davood yadegarynia 2, alireza abrishami3 , hamideh moradi1, babak gharaei4, masoomeh raoufi5, fatemeh maghsudi nejad6, shahnaz sali2, neda khabiri1, sara abolghasemi2* urology journal/vol 19 no. 6/ november-december 2022/ pp. 460-465. [doi:10.22037/uj.v18i.6863] introduction human respiratory coronaviruses were first recognized in the 1960s and have been known to cause respiratory infections with rather mild symptoms. however, two infamous infectious coronaviruses in the beta coronavirus genus, the severe acute respiratory syndrome (sars) virus and middle east respiratory syndrome coronavirus (mers-cov), can cause severe respiratory tract infections with high mortality.(1) pathological tests of samples obtained from patients who had died of sars showed diffuse alveolar lesions, accompanied by prominent hyperplasia of pulmonary epithelial cells and presentation of activated alveolar and interstitial macrophages. considerably, these pulmonary manifestations were usually found after the release of a cytokines and in the absence of other opportunistic infections. therefore, local inflammatory responses could result in alveolar damage.(2) supernumerary macrophages produced high levels of 1labbafinejad clinical research center, shahid beheshti university of medical sciences, tehran, iran. 2infectious diseases and tropical medicine research center, shahid beheshti university of medical sciences, tehran, iran. 3department of radiology, shahid labbafinejad hospital,shahid beheshti university of medical sciences, tehran,iran. 4anesthesiology department, school of medicine, shahid beheshti university of medical sciences, tehran, iran. 5department of radiology, school of medicine, imam hossein hospital, shahid beheshti university of medical sciences, tehran, iran. 6school of medicine, shahid beheshti university of medical sciences, tehran, iran. *correspondience: infectious diseases and tropical medicine research center, shahid beheshti university of medical sciences, tehran, iran. e mail: saraabolghasemi1@gmail.com received june 2021 & accepted november 2021 unclassified purpose: in late december 2019, a series of unexplained cases of pneumonia were reported in wuhan, china. on january 12, 2020, the world health organization temporarily named the virus responsible for the emerging cases of pneumonia as the 2019 coronavirus. acute respiratory distress syndrome (ards) due to covid-19 has rapidly spread around the world, and while no specific treatment or vaccine has been reported, mortality rates remain high. one of the suggested treatments for cellular damage in the pathogenesis of ards caused by the coronavirus is the administration of high doses of intravenous vitamin c. considering the paucity of literature on the therapeutic effects of high doses of intravenous vitamin c in patients with ards resulting from the coronavirus, this study was conducted to assess this therapeutic supplement in these patients. materials and methods: this study was performed as a single-center clinical trial in patients with a documented diagnosis of covid-19 pneumonia. 54 eligible patients with moderate to severe covid-19 symptoms, based on specific inclusion and exclusion criteria, were included in the investigation and randomly divided into two groups. the control group consisted of 26 patients who received standard treatment, whereas the treatment group was comprised of 18 patients administered intravenous vitamin c at a dose of 2 g every 6 hours for 5 days in addition to standard treatment. demographic characteristics, underlying diseases, length of hospital stay, and mortality rates were reviewed and collected. oxygen saturation, respiratory rates, serum c reactive protein (crp) levels, lymphopenia and lung parenchymal involvement on ct were investigated at the time of admission and on the sixth day after hospitalization. results: of these variables, the amount of oxygen saturation in the vitamin c group increased significantly from 86 ± 5% on the first day of hospitalization to 90 ± 3% on the sixth day of hospitalization (p value = 0.02). also, the respiratory rate in the vitamin c group decreased significantly from 27 ± 3 on the first day of hospitalization to 24 ± 3 on the sixth day of hospitalization (p value = 0.03). lung ct scans of patients in the two groups reported by two radiologists were also compared. based on the report of the radiologists, the rate of lung involvement in the vitamin c group was significantly lower than in the control group at the end of treatment (p value = 0.02). conclusion: due to the effectiveness of high doses of intravenous vitamin c on reducing lung involvement and improving clinical symptoms, further studies with a larger sample size are recommended to demonstrate the effects of this drug supplement. keywords: vitaminc; covid-19; coronavirus; ards; treatment inflammatory mediators through type i ifn stimulation. moreover, type i ifn-induced immune dysregulation led to the apoptosis of t cells, which would normally promote virus clearance, resulting in reduced numbers of virus-specific cd8 and cd4 t cells. overall, massive repletion of pathogenic inflammatory macrophages increased the severity of sars. (3) numerous studies have shown that vitamin c plays an important role in various aspects of the immune system, especially the function of immune cells.(4,5) vitamin c (ascorbic acid) is a powerful antioxidant that helps the immune system and supports several intrinsic immune cell functions and adaptive immune systems. it forms an epithelial barrier against pathogens and eliminates oxidants in the skin, thus protecting them from environmental oxidative stress. vitamin c rapidly donates electrons, which disrupts the damage of oxidative biomolecules.(6) it is also a cofactor for various enzymes, such as the monooxygenase and the dioxygenase enzymes. individuals with vitamin c deficiency are more prone to fatal infections such as pneumonia. in turn, infections can affect vitamin c levels due to increased inflammation and metabolic needs. respiratory infection is particularly serious in individuals who are already malnourished.(7) letter 242 stage definition 1 (early) chest ct shows single or multiple scattered patchy or conglomerate ground-glass opacities, predominantly in the middle and lower lungs along with bronchovascular bundles. these ground glass lesions are often located in the peripheral and subpleural areas of the lung. intraand interlobular septal thickening, sometimes present in the areas of ground-glass opacity, can give a crazy-paving pattern. 2 (advanced) chest cts show new lesions that are similar to the earlier lesions described above. also, findings from the early stage of disease increase in density and extent, coexisting with the new areas of disease. as areas of consolidation grow, air bronchograms are often present in the areas of consolidation. 3 (severe) chest ct shows diffuse consolidation of the lungs of varying density secondary to the fibrous exudate into the alveolar cavity, air bronchograms and bronchial dilation. nonconsolidated areas of the lung appear as patchy ground-glass opacity. when most of the lungs are involved, the lungs appear as a “whited out a lung.” the pleura is thickened and there can be a small amount of pleural effusion. 4 (dissipation) the images show gradual resolution of the ground glass opacity and consolidation in the lungs with some residual curvilinear opacities compatible with fibrosis. table 1. stages of lung involvement in covid-19 vit c and covid-19 pneumonia-tehrani et al. figure 1. patients enrollment diagram unclassified 461 based on previous experiences with the use of intravenous vitamin c in critically ill patients and patients with respiratory infections, due to the high morbidity and mortality of covid-19 pneumonia, we decided to study the possible effect of high dose intravenous vitamin c in covid-19 pneumonia. materials and methods this study was performed as a single-center clinical trial for patients with a confirmed diagnosis of covid-19 pneumonia from march to may 2020 at the referral center of shahid labbafi nejad hospital in tehran. the present clinical trial protocol has been approved by the iranian registry of clinical trials (irct id: irct20211004052664n1). the inclusion criteria in our study were as follows: age ≥ 18y, hospitalized patients with: respiratory rate >30/ min or oxygen saturation <93% and pulmonary infiltration> 50%); pcr confirmation for the nuclide acid of sars-cov-2 in a nasopharyngeal swab specimen and chest lung ct scan compatible with covid-19 patterns. the exclusion criteria were the following: known allergic reaction to vitamin c, shortness of breath due to cardiogenic pulmonary edema, pregnancy or breastfeeding, chronic renal failure, diabetic ketoacidosis and a history of nephrolithiasis. sample size was based on a pilot study assuming the incidence of fibrosis to be around 50% in no vitamin c regimen while near 15% in vitamin c therapy group. considering a confidence interval of 95% with a power of 80%, 25 patients were required in each arm of this study. thinking of some drop offs 27 patients were enrolled in each group. fifty-four patients were enrolled in this study. they were randomized through a computerized random allocation of patients. one patient in the control group and nine in the study arm were excluded as depicted in the consort chart. finally, all variables were analysed using spss 23. normality test of kolmogorov-smirnov was done and after confirmation of non-skewed data and absence of any outlier, parametric statistics were applied. independent t-test was utilized for means while chitwo for frequencies. a p-value of 0.05 was considered as statistically significant and confidence intervals of 99% are mentioned as required treatment design study variables such as age and underlying diseases were selected similarly to minimize the distorting effects of these variables. the control group (group a) consisted of 26 patients who received standard treatment [hydroxicholoroquine (400 mg stat) and kaletra (400/100 mg q 12 h) and interferon beta-1a (44 micrograms three times)] and the treatment group (group b) included 18 patients receiving intravenous vitamin c at a dose of 2 g every 6 hours for 5 days in addition to standard treatment. demographic characteristics, underlying diseases, length of hospital stay and mortality rates were reviewed and collected. oxygen saturation, respiratory rates, serum crp levels, lymphopenia, lung parenchymal involvement on ct at the time of admission and on the sixth day after hospitalization were investigated. in three cases in the vitamin c treatment group, the control ct scan was not performed on the sixth day due to instability of vital signs. the patient's lung ct scans were examined by two experienced radiologists who had no knowledge of the patients' groups. both radiologists reported lung ct scans based on the pattern and extent of lung involvement. (tables 1, 2) this study was approved by the ethics committee of shahid beheshti university of medical sciences in tehran, iran. (ir.sbmu.retech.rec.1399.067) unclassified 408 lung involvement scoring definition 0 none 1 mild (involvement of 2 zone) 2 moderate (involvement of 4 zone) 3 severe (involvement of 6 zone) table 2. for classifying lung zone involvement, three-zone were defined as follows: upper zone: above the carina region, middle zone: the area between the carina and inferior pulmonary vein, and lower zone: below the inferior pulmonary vein vitamin c group n=18 control group n=26 p value age (year) 58 ± 19 61 ± 17 0.73 gender (m/f) 8/10 18/8 0.14 start of symptom to admission (day) 9 ± 6 7 ± 4 0.39 diabetes 33% 35% 1 hypertension 33% 46% 0.48 ischemic heart disease 27% 19% 0.67 chronic kidney disease 0 15% 0.23 chronic lung disease 7% 8% 1 immunocompromised 20% 8% 0.22 respiratory rate 27 ± 3 29 ± 2 0.61 o2 sat (%) 86 ± 5 87 ± 2 0.23 wbc 9380 ± 5113 7253 ± 3936 0.19 lymphocyte 2233 ± 1970 1044 ± 362 0.032 neutrophils 6820 ± 3840 5881 ± 3600 0.43 plt 257 ± 86 218 ± 75 0.13 crp 42 ± 17 35 ± 31 0.49 pre-treatment ct stage i 33% 23% 0.51 99%ci:0.49-0.52 ii 13% 27% iii 40% 46% iv 14% 4% table 3. demographic characteristics, admission-time clinical and laboratory findings in the two groups. vit c and covid-19 pneumonia-tehrani et al. vol 19 no 6 november-december 2022 462 results in this study, twenty-six patients were enrolled as a control group, while eighteen received vitamin c as a treatment group. the average age of the control group was 61 years, with 18 women and 8 men. in this group, 35% had diabetes, 46% had hypertension, 19% had ischemic heart disease, 15% had chronic kidney disease, 8% had chronic lung disease, and 8% had received immunosuppressive medication. in the intervention group, the mean age was 58 years, of which 10 were women and 8 were men. in this group, 33% had diabetes, 33% had hypertension, 27% had ischemic heart disease, 0% had chronic kidney disease, and 7% had chronic lung disease, and 20% had been administered immunosuppressive drugs. the oxygen saturation and respiratory rate, leukocyte, lymphocyte, neutrophil and platelet counts, crp levels on the first and sixth days of hospitalization, the length of hospital stay and mortality rates were compared between the two groups (tables 3 and 4). of these variables, the amount of oxygen saturation in the vitamin c group increased significantly from 86 ± 5% on the first day of hospitalization to 90 ± 3% on the sixth day of hospitalization (p-value = 0.02). also, the respiratory rate in the vitamin c group decreased significantly from 27 ± 3 on the first day of hospitalization to 24 ± 3 on the sixth day of hospitalization (p-value = 0.03). lung ct scans of patients in the two groups reported by two radiologists were also compared. based on the reports of the radiologists, the rate of improvement in lung involvement at the end of treatment was significantly higher in the vitamin c group in comparison to the control group. (p-value = 0.02). discussion this study was conducted to shed more light on the effects of vitamin c on the clinical symptoms, laboratory findings and pattern and extent of lung involvement on vitamin c group n=18 control group n=26 p value day-6 respiratory rate 24 ± 3 28 ± 4 0.028 day-6 o2 sat (%) 90 ± 3 87 ± 5 0.021 day-6 wbc 6900 ± 2484 7788 ± 5193 0.53 day-6 lymphocyte 1706 ± 1811 1186 ± 696 0.21 day-6 neutrophil 4878 ± 1652 6349 ± 4657 0.18 day-6 plt 272 ± 68 228 ± 86 0.092 day-6 crp 29 ± 15 29 ± 22 0.52 on recigen treatment 33% 42% 0.67 duration of hospitalization (day) 14 ± 8 17±8 0.23 needed intubation death (patients) 0 4 0.21 post treatment ct stage i 13% 4% 0.71 99%ci:0.70-0.72 ii 7% 4% iii 20% 31% iv 60% 61% post treatment fibrosis in ct 0 7% 35% 0.023 99%ci: 0.021-0.029 1 40% 8% 2 33% 23% 3 20% 35% table 4. day-6 clinical and laboratory findings, mortality and morbidity rates and length of stay in the two groups. figure 2. a 63-year-old patient who no history of underlying disease. he was recently hospitalized with complaints of cough and dyspnea and diagnosed with covid 19 pneumonia. left image: the first day of admission. consolidation and peribronchovascular thickening in the right upper lobe. right image: on the sixth day of treatment with vitamin c. mottled ground glass infiltration and fine reticulation is present in the right upper lobe. vit c and covid-19 pneumonia-tehrani et al. unclassified 463 ct in patients with covid-19. one hypothesis about the mechanisms by which covid-19 can cause severe forms of the disease is the occurrence of an uncontrolled inflammatory response in the course of the disease.(8). an important point in the pathophysiology of vitamin c (ascorbic acid) is the regulation of cytokine storms and the reduction of oxidative damage in the endothelium, which in some studies is valuable in controlling the severe form of covid 19 diseases.(9 ,10) various results have been reported in the clinical outcome of patients with severe sepsis and acute respiratory distress syndrome following high-dose intravenous vitamin c administration.(11–13). in a study conducted by hossaini zabet et al in 2016 in iran, 28 patients with septic shock and ards syndrome were injected with vitamin c at a dose of 25 mg /kg body weight daily for three days. the variables of this study included hemodynamic parameters, the oxygenation status, laboratory parameters, the need for vasopressors and the mortality rates of the patients. the need for vasopressors and mortality rates in this group were significantly reduced compared to the control group, but there was no significant difference in the length of stay in icu. also, there was no significant difference between the two groups in the other variables. (14) in our study no significant differences were observed between the two groups in terms of age, sex and underlying comorbidities. our results revealed that the group administered vitamin c demonstrated considerably lower respiratory rates on the sixth day compared to the control group (p value = 0.03). it is noteworthy that in our study, there was a clear improvement in blood oxygen levels and respiratory rate on the sixth day in the group receiving vitamin c, which was statistically significant. (p value = 0.02). in a 2019 study by zhi yong peng in china, 85% of the 252 patients with covid 19 who received vitamin c (at a dose of 1 gram per hour for six hours and then 3 grams daily) showed improvement of disease symptoms. however, in patients with sepsis and ards syndrome who were treated with high-dose vitamin c, there was no significant improvement in clinical symptoms and prognosis. all things considered, due to the different results, it was recommended to conduct more studies on the effects of vitamin c in the treatment of patients with covid 19. in this study, the effects of vitamin c on patients' lab tests and lung ct scans were not investigated.(15) at an rct in china, 56 patients with severe sarscov-2 pneumonia were studied with a high dose of intravenous vitamin c (12 g every 12 hours) for 7 days. finally, in the group receiving vitamin c, an increase in pao2 / fio2 and lower levels of il-6 were reported on day 7 compared to the control group.(16) in our study, we did not identify a statistically significant difference in terms of laboratory findings such as day-6 lymphocyte counts, neutrophil counts, serum crp levels, and mortality rates between the two groups. it is notable that, although the length of hospital stay between the two groups was not significantly different, the number of hospitalization days for patients with vitamin c was lower. it is possible to get better results by increasing the sample size. in the study of jamali moghadam et al., the effect of a high dose of intravenous vitamin c (6 g daily) on 30 patients with covid-19 pneumonia was investigated. the rate of fever and oxygen saturation on the third day of treatment and the duration of hospitalization was significantly better compared to the control group, but the period of hospitalization in the icu and the mortality rate were not significantly different from the control group, which is similar to the results of the present study.(17) in a study by hakamifard et al., a low dose of vitamin c (1000 mg daily) was evaluated in 38 patients with non-severe covid-19 pneumonia. there was no significant difference in response to treatment, length of hospital stay, and mortality compared with the control group.(18) according to the two experienced radiologists' reports, the stages of lung involvement did not change considerably in the two groups before and after treatment. (p value = 0.6) lung involvement scoring in the control group after treatment was: 35% none, 8% mild, 23% figure 3. a 42-year-old patient who had no history of underlying disease. he was hospitalized with complaints of cough and dyspnea and diagnosed with covid 19 pneumonia. left image: the first day of admission. mixed consolidation and ground glass with peripheral and peribronchovascular distribution. right image: one month after treatment with vitamin c. only mottled subpleural ground-glass infiltrations are observed. vit c and covid-19 pneumonia-tehrani et al. vol 19 no 6 november-december 2022 464 unclassified 410 moderate, and 35% severe. while lung involvement scoring in the vitamin c group after treatment was: 7% none, 40% mild, 33% moderate, and 20% severe. this difference between the two groups was significant. (p value = 0.02). this study had certain limitations. the interval between the onset of symptoms and the patients' time of hospitalization varied between patients and this factor might have affected all variables in the study. it is generally assumed that the earlier patients are admitted to hospital, the slower the progression of the disease and the better the response to treatment. due to limited access to intravenous vitamin c in iran, the sample size was relatively small, which could in turn have had an impact on the reliability of the study. to better evaluate the effects of vitamin c on lung fibrosis, a lung ct scan carried out 4 to 6 weeks after the onset of the disease would have been beneficial, but performing these scans was not possible due to lack of cooperation by patients. considering the high prevalence of pneumonia and acute respiratory distress syndrome caused by the coronavirus in iran and other countries and the mortality rate of this disease, it is necessary to identify effective treatment methods. also, bearing in mind the complications of this disease such as lung fibrosis, the use of treatments that prevent lung fibrosis and improve lung function in patients is of the utmost importance. due to the effectiveness of high doses of intravenous vitamin c in this study on reducing lung involvement and improving clinical symptoms, further studies with a larger sample size are recommended to demonstrate the effects of this drug supplement. conclusions this review aimed to evaluate the effect of vitamin c treatment in patients with covid-19 pneumonia. in this study, we found that there were improvements in peripheral oxygen saturation and the respiratory rate in the group who were treated with high-dose vitamin c. acknowledgments the authors would like to acknowledge their gratitude to participants in data collection in selected hospitals. conflict of interest the authors did not declare any conflict of interest. references 1. e. kindler, v. thiel. sars-cov and ifn: too little, too late cell host microbe, 19 (2016), pp. 139-141. 2. t. yoshikawa, t. hill, k. li, j. peters, c.t. tseng. severe acute respiratory syndrome (sars) coronavirus-induced lung epithelial cytokines exacerbate sars pathogenesis by modulating intrinsic functions of monocytederived macrophages and dendritic cells. j virol, 83 (2009), pp. 3039-3048 3. parkin, j.; cohen, b. an overview of the immune system. lancet 2001, 357, 1777–1789 4. maggini, s.; wintergerst, e.s.; beveridge, s.; hornig, d.h. selected vitamins and trace elements to support immune function by strengthening epithelial barriers and cellular and humoral immune responses. br. j. nutr. 2007, 98, s29–s35. 5. webb, a.l.; villamor, e. update: effects of antioxidant and non-antioxidant vitamin supplementation on immune function. nutr. rev. 2007, 65, 181. 6. carr ac, maggini s vitamin c, and immune function. nutrients, 2017, 9 (11). pii: e1211. https://doi.org/ 10.3390/nu9111211 pmid: 29099763. 7. mandl, j, szarka a, ba´nhegyi g. vitamin c: update on physiology and pharmacology. br j pharmacol, 2009,157 (7): 1097–110. 8. zabetakis i, lordan r, norton c, tsoupras a. covid-19: the inflammation link and the role of nutrition in potential mitigation. nutrients. 2020 may 19;12:1466 9. cheng rz. can early and high intravenous dose of vitamin c prevent and treat coronavirus disease 2019 (covid-19)?. med drug discov. 2020 mar;5:100028 10. hemilä, h. vitamin c and infections. nutrients 2017, 29, 339. 11. syed, a.a.; knowlson, s.; sculthorpe, r.; farthing, d.; dewilde, c.; farthing, c.a.; larus, t.l.; martin, e.; brophy, d.f.;gupta, s.; et al. phase i safety trial of intravenous ascorbic acid in patients with severe sepsis. j. transl. med. 2014, 12, 32. 12. fowler, a.a., iii; truwit, j.d.; hite, r.d.; morris, p.e.; dewilde, c.; priday, a.; fisher, b.; thacker, l.r., ii; natarajan, r.; brophy,d.f.; et al. effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial. jama 2019, 322, 1261–1270. 13. wei, x.-b.;wang, z.-h.; liao, x.-l.; guo,w.-x.;wen, j.-y.; qin, t.-h.;wang, s.-h. efficacy of vitamin c in patients with sepsis:an updated meta-analysis. eur. j. pharmacol. 2020, 868, 172889. 14. mohadeseh hosseini zabet, mostafa mohammadi, masoud ramezani, and hossein khalili. effect of high-dose ascorbic acid on vasopressor's requirement in septic shock. j res pharm pract. 2016 apr-jun; 5: 94–100. 15. englard s, seifter s. the biochemical functions of ascorbic acid. annu revnutr.,1986,6:365–406. 16. zhang, j.; rao, x.; li, y.; zhu, y.; liu, f.; guo, g.; luo, g.; meng, z.; de backer, d.; xiang, h.; et al. pilot trial of high-dose vitamin c in critically ill covid-19 patients. ann. intensive care 2021, 11, 3–14. 17. jamalimoghadamsiahkali, s.; zarezade, b.; koolaji, s.; seyedalinaghi, s.; zendehdel, a.; tabarestani, m.; sekhavati moghadam,e.; abbasian, l.; dehghan manshadi, s.a.; salehi, m.; et al. safety and effectiveness of high-dose vitamin c in patients with covid-19: a randomized open-label clinical trial. eur. j. med. res. 2021, 26, 20 18. hakamifard a, soltani r,maghsoudi a. the effect of vitamin e and vitamin c in patients with covid-19 pneumonia; a randomized controlled clinical trial. immunopathol persa. 2022;8:e08 .doi:10.34172 vit c and covid-19 pneumonia-tehrani et al. unclassified 465 letter implementation of telemedicine in indonesian urology practice during covid19pandemic: a national survey faridz albam wiseso1*, ahmad zulfan hendri2, sakti r. brodjonegoro2 urology journal/vol 19 no. 3/ may-june 2022/ pp. 241-245. [doi:10.22037/uj.v18i.6772] many aspects of living were affected by the pan-demic of coronavirus-19 (covid-19). medical care demand keeps going on, although the pandemic put many other activities to be restricted. the care of the patients should not be compromised, although many restrictions and locks down may limiting our patients or even our physical presence in the urological field. nevertheless, the ability to deliver the standard of care is precedence. like many other works that shifted to amplify online platforms, the medical field also faces a similar problem and needs changes to adapt to the new situation. in the urologic field, the treatment of our patients is reprioritized with specific safety measures. treatments should be regulated by considering the risk to benefit ratio. therefore, guidelines are issued to help urologists take the proper decision upon urologic treatment during the pandemic. one of the recommendations from the indonesian urological association is to improve the utilization of telemedicine. this study is aimed to understand the views of applying this method from urological practitioners throughout indonesia. an online survey created using www.typeform.com was conducted from october to november 2020. the indonesian urological association accompanied the survey. the survey was sent by email to all association members, urology specialists, and urology residents throughout the country. the online survey page was targeting a total of 485 urologists and 220 urology residents across indonesia. however, the survey was engaged by only 410 or 58% of the targeted respondents, and 43% were dropped off on the welcome screen. then, 270 participants continued, but only 232 participants finished the survey (85% completion rate). the average time to complete this survey was in 6 minutes. the survey was completed by 50 urologists (10,3%) of indonesian urological association members and 182 urology residents (82%) of total urology residents from 5 urology centers in indonesia. our respondents came from 15 provinces in indonesia, and the majority (70%) was from java, the most populated and developed island where the capital city of indonesia, jakarta, is located. the working experience period of participated urologist was mostly ≤ five years (49%) and followed by > 10 years (29,4%), and for the rest, 21,5% is for 6-10 years. they work mostly at the secondary-tier hospital (type b and c hospital in indonesia) for 90%, and the rest are working in a tertiary-tier hospital (type a hospital in indonesia). the urology resident participants come from urology centers in 5 universities in indonesia. the majority of respondents (64%) had provided informal medical consultation using social media, a messaging application, or a medical consultation website. the most used platform was messaging apps (62%), such as whatsapp or line, and secondly, the informal consultation was through social media (16%) like instagram or facebook. almost half of our respondents currently do not have facilities to held a telemedicine practice in their institution. the other respondents have a formal official telemedicine facility in their institutions, but the facility reported inadequate by 14%. a total of 28% of respondents reported formal telemedicine practice in their institution, and half of them used texting and picture sharing through the institution's official platform. video call and voice call are used by 28 % and 19%, respectively. most participants rated their telemedicine practice's effectiveness 4 to 5 from a maximum score of 5. we have positive responses regarding telemedicine appliances as a hospital service. over half of the respondents agree with telemedicine service, while 23 percent still neutral and 4 percent disagree with telemedicine. if they could encounter telemedicine, the majority will choose texting and picture sharing platforms (48%), followed by video call forms with picture sharing (34%). video call-only is preferred by ten percent, while both text-only or voice call-only are chosen by three percent. we proposed several possible service areas to use telemedicine, and we assessed how many respondents selected these areas. the most widely chosen area is the outpatient visit for a follow-up patient non-operative or preoperative case that accounted for 77%. outpatient for postoperative follow-up is chosen by 55%, followed by a new outpatient visit and inpatient ward rounding (online rounding) for 46% and 24%. to know the preferred case to be treated through telemedicine, we ask the possible cases to use telemedicine. all urology problems without emergency voted by 73% of the respondents, followed by benign prostate hyperplasia (46%), stone cases (40%), malignancy (20%), pediatric (14%), and kidney transplant cases (7,5%). as much as 39% of participants think that a possible obstacle to run this method was due to insufficient facility. other issues like insurance coverage and patient's inter1urology resident, division of urology, department of surgery, prof. dr. sardjito hospital faculty of medicine, public health and nursing, universitas gadjah mada, yogyakarta – indonesia. 2division of urology, department of surgery, prof. dr. sardjito hospital faculty of medicine, public health and nursing, universitas gadjah mada, yogyakarta – indonesia. *correspondence: division of urology, department of surgery, prof. dr. sardjito hospital faculty of medicine, public health and nursing, universitas gadjah mada, yogyakarta – indonesia. address: rsup dr. sardjito, jalan kesehatan no 1, yogyakarta, indonesia. email: albamwiseso@gmail.com. received may 2021 & accepted july 2021 est in telemedicine were both voted by 16%. the risk of patient data leak and the urologist's lack of interest in telemedicine accounted for 11% and 10%. participants also mentioned inadequate physical examination (2,5%) and the unsettled legal protection of telemedicine (1,5%) as a potential obstacle. despite some doubts about telemedicine, in sum, 36% of the respondents thought telemedicine would keep utilized although the pandemic is resolved, and even more, 17% highly agreed. however, 29% voted for neutral regarding this, and the rest is on the contrary. disagree and highly disagree for 11 and 5 percent, respectively. discussion looks back to 1997, according to the world health organization, telemedicine is the delivery of health care services by all health care professionals using information and communication technologies that intended not only for the diagnosis, treatment, and prevention of disease and injury but also for the research and evaluation, and the continuing education of health care providers1. telemedicine was described in 1950 by the lancet's article explaining the telephone's uses to reduce unnecessary patient visits. with more accessible communication technology, the modern infrastructure nowadays figure 1. current telemedicine situation figure 2. the form of institution-based official telemedicine performed letter 242 vol 19 no 3 may-june 2022 100 uplifted communication technology utilization in the medical field2. the covid-19 pandemic highlighted, even more, the critical role of telemedicine to reduce the risk of virus transmission caused by a person-to-person close contact at the medical care. the chance of the virus transmission is lowered by "social distancing", which lessens physical contact. telemedicine can help to mitigate the risk for the patients and also the physician. both physicians and patients can avoid crowds in the clinic or waiting rooms 3. while the current pandemic situation pushes us to adapt and implement telemedicine, telemedicine uses in urology are not very well defined. data to support the evidence-based practice of telemedicine is not robust 4. studies to evaluate the use of telemedicine in urology practice were obtained only from developed countries. a literature review paper about telemedicine in urology revealed that currently, telemedicine is used for several roles in delivering care and educational purposes, including outpatient teleconsultation, televisit, remote patient monitoring, and telementorship 2. another article reported its use for telerounding, teleimaging, and telesurgery 4,5. previous studies reported its impact on figure 3. possible areas to utilize telemedicine figure 4. urologic case to be treated with telemedicine vol 19 no 3 may-june 2022 243 figure 6. view of telemedicine in the future means of efficiency of time and cost spent for the travel expenses 6. a potential drawback when adopting this method is a lack of physical examination 7, which our responders also realized. however, a good and systematized anamnesis may be enough leading to the diagnosis. perhaps this matter will decide whether a patient may need a visit to the clinic or not. on the other hand, when the physical examination is not critical, such as a clear photo of the abnormal findings, and a laboratory test report may be sufficient to evaluate. another potential challenge is to provide the device to conduct telemedicine and excellent internet infrastructure on both of care provider and patient’s side, so the exchange of information runs smoothly. even so, the patients, nurses, and hospital management needs to adapt to the approach. moreover, the government or regulatory institution needs to solve the policy arranged for this new approach, and the national health insurance coverage needs to be provided for the telemedicine service. the engagement rate of the questionnaire by 58% of the target respondents which 43% of them were dropped off in the welcome screen, and the completion rate of figure 5. potential obstacle during the implementation of telemedicine letter 244 vol 19 no 3 may-june 2022 100 the online questionnaire accomplished by only 10,3% of urologists and 82% of urology residents across indonesia, these may represent that interest to voluntarily involved in this study field is low. besides that, the response regarding the possibility of continuity of telemedicine responded positively only by 53% may reflect the current overall disinterest in telemedicine practice. after all, the low interest in adopting this method has become the greatest barrier. the potency of telemedicine practice depends on the acceptance and willingness of the urologist to reshaping the traditional way of practice. in a developing country, we may find it hard and need more effort to adopt this approach as telemedicine may not be included in the medical training. nevertheless, if we all together can adapt to this opportunity, then it is expected that telemedicine will be more common, popular, and keep utilized after the pandemic, especially if it has proven to be beneficial and efficient 8. the covid-19 pandemic has presented health care systems with challenges. since the global situation is rapidly evolving, indonesian urologists are currently learning the novel telemedicine implementation that may disrupt the traditional urology practice. in indonesia, as a developing country, some challenges still need to be resolved. starting from the regulation and legal protection fundamentally, and the health insurance coverage needs to be determined. after all, the low interest in adopting this method has become the greatest barrier. this study was approved by the indonesian urological association through a recommendation letter no: 0162/ sr/pp.iaui/x/2020 the authors report no conflict of interest to disclose. references 1. world health organization. a health telematics policy in support of who’s health-for-all strategy for global health development. 1997:33. https://apps.who.int/ iris/handle/10665/63857. 2. castaneda p, ellimoottil c. current use of telehealth in urology: a review. world j urol. 2020;38(10):2377-2384. doi:10.1007/s00345019-02882-9 3. smith ac, thomas e, snoswell cl, et al. telehealth for global emergencies: implications for coronavirus disease 2019 (covid-19). j telemed telecare. 2020;26(5):309-313. doi:10.1177/1357633x20916567 4. ellimoottil c, skolarus t, gettman m, et al. telemedicine in urology: state of the art. urology. 2016;94:10-16. doi:10.1016/j. urology.2016.02.061 5. gettman m, rhee e, spitz a. telemedicine in urology. american urological association. h t t p s : / / w w w . a u a n e t . o r g / g u i d e l i n e s / telemedicine-in-urology. published 2016. 6. chu s, boxer r, madison p, et al. veterans affairs telemedicine: bringing urologic care to remote clinics. urology. 2019;86(2):255261. doi:10.1016/j.urology.2015.04.038 7. miller a, rhee e, gettman m, spitz a. the current state of telemedicine in urology. med clin north am. 2018;102(2):387-398. doi:10.1016/j.mcna.2017.10.014 8. desouky e. impact of covid-19 on urologists: learning on the go. eur urol focus. 2020. doi:10.1016/j.euf.2020.04.008 vol 19 no 3 may-june 2022 245 cellular and molecular urology 289urology journal vol 6 no 4 autumn 2009 inductive role of collagen type iv during nephrogenesis in mice mehdi jalali,1 mohammad reza nikravesh,1 abbas ali moeen,2 mohammad hassan karimfar,3 shahin saidinejat,1 shabnam mohammadi,1 houshang rafighdoost4 introduction: during nephrogenesis, transition of mesenchyme to the epithelium of tubules and glomeruli occurs via the interaction of ureteral bud and metanephric mesenchyme. the distribution pattern of collagen type iv suggests that a regulated balance of activities is required to facilitate migration of the ureteral bud branches into the mesenchyme and to control early extracellular matrix changes during tubulogenesis. we used a specific antibody for tracing collagen type iv basement membrane during renal tubules morphogenesis. materials and methods: twenty female balb/c mice were divided randomly into 10 groups and were kept until finding vaginal plug was as an indicator of day zero of pregnancy. twelve pregnant mice were sacrified by cervical dislocation in one of gestational days 13 to 18 and their fetuses were fixed, serially sectioned, and underwent immunohistochemical study for tracing of collagen type iv in basement membrane of glomeruli. the same processes were used for kidneys preparation on postnatal days 5, 10, 15, and 20 in newborns of 2 mothers for each day. results: collagen type iv showed weak reaction on day 14 of gestation in tubular basement membrane. the amount of collagen increased continuously until the following days of fetal life and of the first 5 postnatal days in basement membrane. after this period, collagen type iv reaction did not show significant change in newborns. conclusion: these results indicate that developmental changes in various nephron segments from most immature stages to most differentiated structures are dependent on the collagen type iv expression. urol j. 2009;6:289-94. www.uj.unrc.ir keywords: collagen type iv, basement membrane, kidneys 1department of anatomy, school of medicine, mashhad university of medical sciences, mashhad, iran 2department of anatomy, school of medicine, zabol university of medical sciences, zabol, iran 3department of anatomy, school of medicine, qazvin university of medical sciences, qazvin, iran 4department of anatomy, school of medicine, zahedan university of medical sciences, zahedan, iran corresponding author: houshang rafighdoost, phd department of anatomy, school of medicine, zahedan university of medical sciences, zahedan, iran tel: +98 915 143 1492 fax: +98 541 341 4574 e-mail: rafhighdoosth@yahoo.com received january 2009 accepted august 2009 introduction previous studies have shown that various types of collagen have been found in tissues so far, and different structures of polypeptides are responsible for varieties of collagens.(1) tropocollagen molecules hold together and form collagen fibers.(2) the ends of adjacent molecules overlap each other. these arrangement cause stretch and stability for collagen fibers. (3) in spite of the fact that other collagens have fibril or reticular structure, collagen type iv has an unpolymerized structure and it is the main component of basement membranes (bms).(4) although other proteins such as laminin and fibronectin play a crucial role, collagen type iv is the most inductive role of collagen during nephrogenesis—jalali et al 290 urology journal vol 6 no 4 autumn 2009 abundant composition of the bm and play a key role in formation of the bm.(5) during formation of metanephrose, the ureteral bud grows into the metanephric mesenchyme and division of it begins continually, and branches up to collecting tubule form during tubules morphogenesis.(6) this stage is about embryonic day 11 in mouse (equal to the 5th week in human).(7) the embryologic studies show that the distal end of collecting tubules causes induction effects on mesenchyme cells of metanephric blastoma and transit to metanephric tubules on the 13th embryonic day.(8) in this stage, the distal part of tubules forms when the proximal part evaginates by differentiated bowman capsule. during next days of development, different parts of a nephron, consisting of renal corpuscles, proximal convoluted tubule, loop of henle, and distal convoluted tubules, will develop and associate with collecting tubules.(9) some studies have shown that fibroblasts are responsible for producing amino acids that synthesize procollagen molecules.(10) these molecules alter to tropocollagens by procollagen peptidase enzyme. polymeric tropocollagens produce collagen and prevent from collagen distribution by hyaloronic acid and help to deposit in bm.(10) extracellular matrix and tubular bm contribute to form nephrons during kidney tubule morphogenesis. the present investigation was carried out to demonstrate collagen type iv expression and distribution pattern in nephron morphogenesis and its structural changes from immature nephron to differentiated nephron. materials and methods study subjects twenty virgin female balbc/c mice were divided randomly into 10 groups and finding vaginal plug was designated as day zero of pregnancy. two pregnant mice were anesthetized by chloroform and were sacrified by cervical dislocation during gestational day 13 to 18. the kidneys of the fetuses were collected and were processed for histological studies. the similar processes were used for newborns on postnatal days 5, 10, 15, and 20. finally, all samples of fetuses and new borns were placed in paraffin blocks and sectioned serially at a thickness of 7 μm. the study protocol complied with the national ethics regulations for studying on animal models, and was approved by the local ethics committee. methods after deparaffination and rehydration, sections of kidneys were washed twice for 5 minutes with tris buffer (containing 1.5% sodium chloride at a ph of 7). nonspecific antibodies were blocked with 3% triton x-100 and goat serum for 3 hours. for blocking endogenous peroxides activity, the sections were treated with 3% h2o2methanol for 1 hour and were incubated with the antibody collagen type iv (conjugated with horse radish peroxidase) at a dilution of 1:50 overnight. then, the sections were again placed in tris buffer solution containing 3% triton and 2% goat serum and were washed three times for 10 minutes with tris buffer. after this stage, the sections were placed for 15 minutes in di-aminobenzidine containing 0.03% h2o2, and after washing, the samples were counterstained with hematoxylin. the sections were mounted with glycerol gel. in this method, collagen would show positive reaction according to the amount of appearance and the rate of reaction, from light to dark brown. because collagen immunoreaction is a proper index for determination of its density, firth and reade’s method was used for grade staining. (11) this grading was scored ranging from zero to 4+ in conformity with the severity of reaction, corresponding to negative, weak, moderate, strong, and highly strong. images of different regions of the kidneys were captured by a camera microscope and the intensity of staining was graded by two separate individual according to the above method.(11) statistical analyses statistics analyses of the results were completed by using the spss (statistical package for the social sciences, version 11.5, spss inc, chicago, illinois, usa) and data analyses were done using the nonparametric kruskal-wallis test and inductive role of collagen during nephrogenesis—jalali et al urology journal vol 6 no 4 autumn 2009 291 mann-withney u test. p values less than .05 were considered significant. results although the mesenchyme cells were enclosed by the ureteral bud in embryonic day 13 and rudimentary tubules were observed, collagen type iv could not be found in any part of the developing nephron. in addition, there was no such reaction in different parts of metanephrose (figure 1, left). the first immunostaining was weakly detected around day 14 of gestation in distal tubular bm and vessels in kidney parenchyma, whereas the bmg did not show any reaction (figure 1, middle). the intensity of staining increased on day 15 of gestation in the distal tubular bm, proximal tubular bm, and cortical regions of the glomerulus (figure 1, right). the amount of collagen increased continuously on day 16 of gestation in different parts of the tubular bm (figure 2, left). the intensity of reaction increased gradually until day 18 of gestation not only in the bm of epithelial cells, but also in the tufts of the capillary (figure 2, middle). the amount of collagen increased continuously until 5 days postnatal in the bm (figure 2, right), but no remarkable change was recorded afterwards in the newborns (table). figure 2. sections through kidney tubules on 16, 18, and 5 postnatal days (left to right, respectively). the amount of collagen increased continuously with development of kidney tubules. the reaction changes from light to dark brown are represents the strong staining. day distal tubular basement membrane proximal tubular basement membrane cortical regions of glomerulus vessels embryonic 13 14 + + 15 ++ ++ +++ 18 ++ ++ ++ +++ postnatal 5 ++++ ++++ ++ ++++ lens components collagen type iv reaction during nephrogenesis* *this gradation was scored ranging from negative to 4+ in conformity with the severity of reaction from negative, weak, moderate, strong, and highly strong. inductive role of collagen during nephrogenesis—jalali et al 292 urology journal vol 6 no 4 autumn 2009 discussion the appearance and high density of collagen type iv during tubules morphogenesis represents that kidney formation is dependent on specific molecules, of which collagen type iv is the most important.(12-14) basement membrane is a specialized region of extracellular matrix that consists of different components, such as proteins and carbohydrates. this substance usually comprises from collagen types iv and v, laminin, fibronectin, and sulfated and nonsulfated glycosaminoglycans.(15-17) collagen is the most abundant composition of the bm and among its different types, type iv is the main structural component of the bm. studies have shown that different types of collagen had widespread distribution, whereas collagen type iv was specifically found in the bms of epithelial tissues such as the endothelium of vessels, gastrointestinal tract, kidney tubules, and glumerulus.(18-20) on the other hand, although collagen type iv is not distinguished with routine histological staining, immunohistochemistry technique showed that the immune reaction of collagen begins when nephrons structure forms. this confirms that interactions of tubular structures lead to induction of collagen synthesis and help to provide a bed of bm.(21) the appearance of collagen type iv in distal tubular and proximal tubular bm and bm of glomeruli indicates that in addition to serving structural role, collagen plays roles for exchange of substance and glumerular filtration in tubular bm and bm of glomeruli.(22) the composition of collagen type iv in different stages of development is required for proper function of the kidney in filtration and exchange of substances.(23) an intact bm contributes to selective absorption of molecules as a filter.(24) it seems damage to collagen type iv results in functional and structural defects in the kidney. for example, in diabetes mellitus, collagen changes cause thickening of the bm that can affect kidneys’ filtration rate seriously.(25,26) our results indicated the amount of collagen did not change after final development of tubules. these data may refer to this fact that if a high density of collagen increases continuously during postnatal days, it may cause thickening of the bm and kidney dysfunction.(27) for example, age-related changes in tissues and hyperglycemia in diabetes mellitus result in a high density of collagen type iv and other components of the bm.(28) hence, it figure 1. cross-sections through the kidney during days 13 to 15 of gestation (left to right, respectively). left, no reaction of collagen could be found in any part of the kidney; distal tubules (arrow heads) and collecting tubules (arrows). middle, the first reaction was observed on day 14 of gestation in tubular basement membrane (arrowheads) and increased in vessel sections (arrow). right, this labeling was detected identically in basement membrane as well as extracellular matrix. inductive role of collagen during nephrogenesis—jalali et al urology journal vol 6 no 4 autumn 2009 293 seems epithelium arrangement of kidney tubules and proper function of nephrons are dependent upon bm synthesis. conclusion collagen type iv, one of the most remarkable structures of the bm, is synthesized under induction mechanisms and it presents close to the primordial of rudimentary tubules. the first sign of collagen was detected on day 14 of gestation in the bm and increased in next day, which suggests that tubular development is dependent on components of bm formation such as collagen type iv. after birth, when nephrons are developed, collagen density did not show any changes in newborns. acknowledgements we thank both mashhad and zabol universities of medical sciences for their cooperation. also, we are grateful to ms motajadded from histology laboratory of the medical school for her technical assistance. financial support this study was a collaborative research project of mashhad university of medical sciences and zabol university of medical sciences. it was funded by zabol university research deputy. conflict of interest none declared. references 1. bergijk ec, van alderwegen ie, baelde hj, et al. differential expression of collagen iv isoforms in experimental glomerulosclerosis. j pathol. 1998;184:307-15. 2. poschl e, schlotzer-schrehardt u, brachvogel b, saito k, ninomiya y, mayer u. collagen iv is essential for basement membrane stability but dispensable for initiation of its assembly during early development. development. 2004;131:1619-28. 3. lauer-fields jl, minond d, brew k, fields gb. application of topologically constrained mini-proteins as ligands, substrates, and inhibitors. methods mol biol. 2007;386:125-66. 4. hasegawa h, naito i, nakano k, et al. the distributions of type iv collagen alpha chains in basement membranes of human epidermis and skin appendages. arch histol cytol. 2007;70:255-65. 5. sund m, maeshima y, kalluri r. bifunctional promoter of type iv collagen col4a5 and col4a6 genes regulates the expression of alpha5 and alpha6 chains in a distinct cell-specific fashion. biochem j. 2005;387:755-61. 6. bernstein j, cheng f, roszka j. glomerular differentiation in metanephric culture. lab invest. 1981;45:183-90. 7. unsw embryology [web site on the internet]. hill m. mouse development stages. university of south wales [cited 12 october 2009]. available from: http:// embryology.med.unsw.edu.au/otheremb/mouse1.htm 8. yamagata m, kimoto a, michigami t, nakayama m, ozono k. hydroxylases involved in vitamin d metabolism are differentially expressed in murine embryonic kidney: application of whole mount in situ hybridization. endocrinology. 2001;142:3223-30. 9. barasch j, yang j, ware cb, et al. mesenchymal to epithelial conversion in rat metanephros is induced by lif. cell. 1999;99:377-86. 10. favor j, gloeckner cj, janik d, et al. type iv procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, mus musculus: an extension of the col4a1 allelic series and the identification of the first two col4a2 mutant alleles. genetics. 2007;175:725-36. 11. firth na, reade pc. the prognosis of oral mucosal squamous cell carcinomas: a comparison of clinical and histopathological grading and of laminin and type iv collagen staining. aust dent j. 1996;41:83-6. 12. berkholtz cb, lai be, woodruff tk, shea ld. distribution of extracellular matrix proteins type i collagen, type iv collagen, fibronectin, and laminin in mouse folliculogenesis. histochem cell biol. 2006;126:583-92. 13. wu zz, li p, huang qp, qin j, xiao gh, cai sx. inhibition of adhesion of hepatocellular carcinoma cells to basement membrane components by receptor competition with rgdor yigsr-containing synthetic peptides. biorheology. 2003;40:489-502. 14. guinec n, dalet-fumeron v, pagano m. “in vitro” study of basement membrane degradation by the cysteine proteinases, cathepsins b, b-like and l. digestion of collagen iv, laminin, fibronectin, and release of gelatinase activities from basement membrane fibronectin. biol chem hoppe seyler. 1993;374: 1135-46. 15. david l, nesland jm, holm r, sobrinho-simoes m. expression of laminin, collagen iv, fibronectin, and type iv collagenase in gastric carcinoma. an immunohistochemical study of 87 patients. cancer. 1994;73:518-27. 16. de rosa g, barra e, guarino m, staibano s, donofrio v, boscaino a. fibronectin, laminin, type iv collagen distribution, and myofibroblastic stromal reaction in aggressive and nonaggressive basal cell carcinoma. am j dermatopathol. 1994;16:258-67. 17. nakano k, naito i, momota r, et al. the distribution of type iv collagen alpha chains in the mouse ovary and its correlation with follicular development. arch histol cytol. 2007;70:243-53. inductive role of collagen during nephrogenesis—jalali et al 294 urology journal vol 6 no 4 autumn 2009 18. merjava s, liskova p, jirsova k. [immunohistochemical characterization of collagen iv in control corneas and in corneas obtained from patients suffering from posterior polymorphous corneal dystrophy]. cesk slov oftalmol. 2008;64:115-9. czech. 19. sato h, naito i, momota r, et al. the differential distribution of type iv collagen alpha chains in the subepithelial basement membrane of the human alimentary canal. arch histol cytol. 2007;70:313-23. 20. khoshnoodi j, pedchenko v, hudson bg. mammalian collagen iv. microsc res tech. 2008;71:357-70. 21. hartman ha, lai hl, patterson lt. cessation of renal morphogenesis in mice. dev biol. 2007;310:379-87. 22. carone fa, butkowski rj, nakamura s, polenakovic m, kanwar ys. tubular basement membrane changes during induction and regression of drug-induced polycystic kidney disease. kidney int. 1994;46: 1368-74. 23. monaghan p, warburton mj, perusinghe n, rudland ps. topographical arrangement of basement membrane proteins in lactating rat mammary gland: comparison of the distribution of type iv collagen, laminin, fibronectin, and thy-1 at the ultrastructural level. proc natl acad sci u s a. 1983;80:3344-8. 24. sasaki h, kishiye t, fujioka a, shinoda k, nagano m. effects of extracellular matrix macromolecules on the differentiation of plasma membrane structure in cultured astrocytes. cell struct funct. 1996;21:133-41. 25. miner jh, sanes jr. molecular and functional defects in kidneys of mice lacking collagen alpha 3(iv): implications for alport syndrome. j cell biol. 1996;135:1403-13. 26. carlson ec, audette jl, veitenheimer nj, risan ja, laturnus di, epstein pn. ultrastructural morphometry of capillary basement membrane thickness in normal and transgenic diabetic mice. anat rec a discov mol cell evol biol. 2003;271:332-41. 27. schafer k, bader m, gretz n, oberbaumer i, bachmann s. focal overexpression of collagen iv characterizes the initiation of epithelial changes in polycystic kidney disease. exp nephrol. 1994;2:190-5. 28. abrass ck, spicer d, raugi gj. induction of nodular sclerosis by insulin in rat mesangial cells in vitro: studies of collagen. kidney int. 1995;47:25-37. 29. zent r, yan x, su y, et al. glomerular injury is exacerbated in diabetic integrin alpha1-null mice. kidney int. 2006;70:460-70. 30. nicoloff g, baydanoff s, petrova c, christova p. serum antibodies to collagen type iv and development of diabetic vascular complications in children with type 1 (insulin-dependent) diabetes mellitus. a longitudinal study. vascul pharmacol. 2002;38:143-7. vol 19 no 1 january-february 2022 138 female urology evaluation of the clinical effects of abobotolinum toxin a (dysport) injection in the treatment of neurogenic lower urinary tract dysfunction farzaneh sharifiaghdas1, maryam taheri2, nasrin boroumandnia2, zhila sheikhi3* purpose: neurogenic lower urinary tract dysfunction (nlutd) is one of the most challenging problems in urology. in recent years, onabotulinum toxin a (botox) is considered a second-line treatment in these patients. this study aimed to evaluate the clinical effects of abobotolinum toxin a (dysport) into the bladder and urethra. materials and methods: we classified our patients with nlutd into three groups: neurogenic detrusor overactivity (group 1), detrusor sphincter dyssynergia (group 2), and patients with both symptoms (group 3). the severity of the patient’s symptoms was assessed using the urinary distress inventoryshort form (udi-6), urodynamic study, and post-void residual urine (pvr) at baseline. after injection of dysport, the patients were evaluated by the change in udi-6 score, pvr, and the patient’s general satisfaction. in group 1, 500-900 u diluted dysport injected intra-vesical. if associated with detrusor sphincter dyssynergia (group 3), 100 u diluted dysport injected peri-urethral. in group 2, only 100 u diluted dysport injected peri-urethral. results: data from 52 women with nlutd were analyzed. the mean age was 51.3 ± 21.6 years. the prevalence of detrusor overactivity and the value of q max was more in group 1. however, the amount of pvr was more in groups 2 and 3. the overall success rate was acceptable in all three groups. in addition, there were significant improvements in udi-6 parameters. conclusion: peri-urethral injection of abobotolinum toxin a is effective and safe. however, the selection of the patients and the dose of toxin needs more studies. keywords: abobotolinum toxin a; neurogenic; urethra; voiding dysfunction introduction appropriate diagnosis and management of patients with neurogenic lower urinary tract dysfunction (nlutd) are among the most challenging problems in urology through significant medical and social aspects. various disorders or injuries of the central or peripheral nervous system (i.e., stroke, spinal cord injury, parkinson’s disease, multiple sclerosis, etc.) may cause nlutd. these events' consequences depend on the location and extent of the neurologic lesion leading to neurogenic dysfunction of the urinary bladder with or without adverse effects on the urethra(1). neurogenic detrusor overactivity (ndo), detrusor sphincter dyssynergia (dsd), incomplete voiding and high pressure often lead to structural bladder damage, upper urinary tract dilation, vesicoureteral reflux, and renal insufficiency. therefore, the main goals of nlutd treatment consist of preserving renal function, achieving urinary continence, prevention and control of urinary tract infection, with improved quality of life(1). the current methods to manage nlutd include medications, botulinum toxin a (btx-a) injection, neuro1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 3department of urology, mashhad university of medical sciences, mashhad, iran. *correspondence: assistant professor of urology, fellowship of female urology, department of urology, mashhad university of medical sciences, mashhad, iran email: sheikhizh@mums.ac.ir, dr.sheikhi@yahoo.com. received february 2021 & accepted october 2021 modulation, and surgical procedures. each of these has advantages and disadvantages(2). nowadays, the combination of anticholinergic drugs with clean contamination catheterization (cic) is the gold standard treatment for ndo(2). onabotulinumtoxin a (botox) has been approved to treat ndo in certain parts of the world, such as the usa(3), on the theoretical basis that injection into the detrusor muscle would temporarily block the presynaptic release of acetylcholine from parasympathetic innervation. therefore, botox injection can result in the paralysis of the detrusor smooth muscle that may last for an estimated nine months(2). one of the common problems in patients with nlutd is detrusor sphincter dyssynergia, which increases the post-void residual urine (pvr)(4) and results in urinary tract infection or upper urinary tract deterioration. urethral injections of botox were proposed by dykstra et al. in 1988(5). steinhardt et al. were the first to report botox’s injections into the urethral sphincter of children with neurogenic voiding dysfunction in 1997(6). after that, botox injection in the urethral sphincter has become popular in various neurogenic or non-neurogenic urology journal/vol 19 no. 1/ january-february 2022/ pp. 63-68. [doi: 10.22037/uj.v18i.6720] conditions, including voiding dysfunction, detrusor underactivity, or chronic urinary retention(7). according to the literature, this treatment's effectiveness is reported in 60–100% of patients with spinal cord injury, which can last up to six months without significant side effects (8). however, dosage, injection schedule, and period of efficacy vary from article to article(9). most of the existing studies have focused on injecting onabotulinum toxin a (botox) in patients with nlutd. in this study, we evaluate the clinical efficacy of abobotolinum toxin a (dysport) injection into the bladder, peri-urethra, or both. abobotolinum toxin a (dysport) is the only commercially available btx-a in our country, which there is very little evidence in this regard in the literature till now. materials and methods study population in this prospective study, patients with symptoms of nlutd who were referred to a tertiary urology clinic were recruited during 20182019, based on convenience sampling. the patient’s symptoms including urgency, frequency, urinary incontinence (urge or stress), incomplete voiding, and pain or discomfort during voiding. all patients were female, ≥18 years old with refractory to medical treatment (for at least three months), and no btx-a injection history. in those with active or recurrent urinary tract infection (uti), prompt medical therapy was prescribed, and in persistent utis, effective suppressive antibiotic treatment was registered. the exclusion criteria were the inability to complete the questionnaire, significant stress incontinence, interstitial cystitis, bladder carcinoma, urinary tract stones, intolerance or inability to perform clean self-intermittent catheterization, and pregnancy or lactation. in addition, we excluded any patients with moderate to high hydroureteronephrosis or serum creatinine ≥1.5 mg/dl. the patient’s symptoms were assessed by validated urinary distress inventoryshort form (udi-6)(10), urodynamic study (uds), and the amount of pvr at baseline. the patient’s outcome was assessed by change in the udi score, the amount of pvr, and patients’ general satisfaction.(11) udi-6 questionnaire is defined by six items with a total score ranging from 0 to 18, with higher scores indicating increasing symptom severity(10). the uds parameters including; detrusor overactivity (do), defined by involuntary detrusor contractions during the filling phase and, dsd, defined as a detrusor contraction concurrent with an involuntary contraction of the urethral or periurethral striated muscles(12). the patients’ general satisfaction was evaluated by the summation of improvement in urinary incontinence, difficult urination, and the need for cic. after treatment, the patient’s satisfaction scored 0–3, representing not, mild, moderate, and very satisfied. the final therapeutic result was categorized as a successful outcome, including moderate, and very satisfied and failed outcomes representing those without or low satisfaction. written informed consent was obtained from all patients before enrollment in the study. the ethics committee of the urology nephrology research center of shahid beheshti university of medical sciences approved this study (ethic code: ir. sbmu.unrc.1397.16). also, this is under the helsinki declaration of 1964 and its later amendments. patients were informed about the study objectives in their language. procedure all patients were assessed at baseline by routine history, physical examination, urine analysis, urine culture, and urinary tract ultrasound (to measure pvr). the patients were also assessed by the udi-6 questionnaire and urodynamic examination. before cysto-urethroscopy, 500-900 u abobotolinum toxin a (dysport, 500 u/vial, ispen, uk) was diluted in 6 ml of saline 0.9%. the amount of required dysport was calculated according to the patient’s weight, ten units per kilogram. in patients with ndo, diluted dysport was injected intra-vesical by a 27-g disposable needle into 30 sites in the bladder wall to distribute drugs better. if associated dsd, 100 u dysport (equal to 35 u of botox) was injected peri-urethral, at 3, 9, and 12 o’clock in presumed external urethral sphincter place. in patients who only had dsd symptoms, such as an intermittent urinary stream or low maximal flow rate, 100 u of dysport diluted in 1 cc normal saline injected peri-urethral using 31-gauge insulin syringe (figure 1). after the procedure, a 14 fr. foley catheter was placed and removed the next day, routinely. broad-spectrum antibiotics were given for 3 to 5 days after injection. at discharge note, patients were advised to come to the emergency department for any acute problems. patients visited one month then followed four months after the procedure in the outpatient clinic. during this time, anticholinergic drugs were discontinued after dysport injection. statistical analysis for data analysis, the first normal distribution of data was evaluated by the shapiro-wilks test. mean, standard deviation (sd), median, interquartile range (iqr), frequency, and percent were reported to describe variables. a fischer exact test was used to explore the association between categorical variables. anova (or kruskal-wallis test) and paired t-test (or wilcoxon test) dysport injection in bladder and urethrasharifiaghdas et al. female urology 64 table 1. determination and comparison of demographic variables in the two groups. ndo (n=36) dsd (n=8) ndo with dsd (n=8) p-value age: mean± sd 48 ± 20 57 ± 27 49 ± 18 0.583a bmi: mean± sd 26.52 ± 5.16 29.35 ± 8.11 30.10 ± 5.31 0.181a uds do: n (%) 22 (61.1) 1 (12.5) 6 (75.0) 0.028b capacity: mean± sd 288 ± 115 408 ± 230 330 ± 91 0.153a q max: median (iqr) 13 (10.4-15) 8.3 (6.5-15) 8 (5-8) 0.004c pvr: median (iqr) 15 (9.5-37.5) 100 (20-200) 80 (24-237) 0.053c *significant at level of 0.05, a. anova, b, fischer exact test, c. kruskal-wallis test abbreviations: ndo. neurogenic detrusor overactivity, dsd. detrusor sphincter dyssynergia, bmi. body mass index, uds. urodynamic study, do. detrusor overactivity, pvr. post void residual urine, sd. standard deviation, iqr. interquartile range. vol 19 no 1 january-february 2022 138 were used for between and within-group comparisons in terms of numeric variables. p < 0.05 is considered significant. statistical analysis was done using spss (statistical product and service solution) 21. results fifty-two consecutive adult women with symptoms of nlutd were included. the mean age was 51.3 ± 21.6 years. table 1 shows the characteristics of three groups of patients with nlutd; group 1: neurogenic detrusor overactivity (ndo), group 2: patients with detrusor sphincter dyssynergia (dsd), and group 3: patients with ndo accompanied with dsd. regarding comorbid diseases, four patients had a history of diabetes, 13 patients had high blood pressure and, the cause of nlutd in 17 patients was spinal canal diseases (intervertebral disc prolapse, trauma, or after disc surgery). the prevalence of detrusor overactivity and higher q max was more in group 1 of patients, as the pvr amount was lower than the other two groups (table 1). peri-operatively, there were no acute complications during the injection. post-injection adverse events, including hematuria, were found in 11 patients (21.15%), urinary tract infection in 8 patients (15.38%), and fever in 3 patients (5.76%) who responded to outpatient medical treatment. four months after dysport injection, the overall success rate in valid cases was 61.3% in group 1, 71.4% in group 2, and all of the patients in group 3 (according to the general patient’s satisfaction). there is no significant difference in success rate between the three groups of patients (table 2). table 3 shows the changes in udi-6 scores (each question) at baseline and four months after dysport injection in patient groups. significant improvements in frequency (question 1) and difficult voiding (question 5) were observed in all patients. however, pvr significantly decreased in group 2 (dsd), and group 3 (ndo associated with dsd). discussion onabotulinumtoxin a (botox) has been approved to treat neurogenic detrusor overactivity in certain parts of the world, such as the us and the uk(3). herein; we present our experience of abobotolinum toxin a (dysport) injection in patients with nlutd. there was a significant improvement in urinary symptoms and general patient satisfaction in three groups of our patients with ndo, dsd, and ndo with dsd. post void residual urine was significantly decreased in patients with dsd as ndo associated with dsd. btx-a is a potent neurotoxin, which can inhibit the release of neurotransmitters from efferent nerve terminals at neuromuscular junctions, thereby paralyzing the muscle(13). therefore, the use of botox in the bladder detrusor muscle and urethral muscles has been considered for many years. however, since central and peripheral nerve pathways are related to the bladder and urethra's function, injection of btx-a in one of them will affect another. according to the literature, when the bladder is filled, stimulation of some afferent nerves in the bladder influences external urethral sphincter activity by central neural mechanisms such as guarding reflex(14,15). in addition, shafik et al.(16) described that during bladder filling, when the vesical pressure increases, the pressure in the internal urethral meatus (urethral smooth muscle) rises. based on the literature referenced above, detrusor relaxation by btx-a injections in the bladder muscle induces fewer triggering of the mechanoreceptors in the female urology 672 failed success ndo: n (%) 12 (38.7%) 19 (61.3%) dsd: n (%) 2 (28.6% 5 (71.4%) ndo with dsd: n (%) 0 (28.6%) 6 (100.0%) total: n (%) 14 (28.6%) 30 (68.2%) table 2. the overall success rate of the three groups of patients according to the general patient’s satisfaction after four months of abobotolinum toxin a (dysport) injection. abbreviations: ndo. neurogenic detrusor overactivity, dsd. detrusor sphincter dyssynergia. udi-6 ndo median (iqr) dsd median (iqr) ndo with dsd median (iqr) question 1: bl 3 (3-3) 3 (3-3) 3 (3-3) question 1: 4m 1 (1-3) 1 (1-3) 1 (1-1) p-valueb <.001 .034 * .008 * question 2: bl 3 (3-3) 1 (0-3) 2 (1-3) question 2: 4m 0 (0-1) 1 (1-2) 1 (1-2) p-valueb <.001 .157 .038 * question 3: bl 1 (0-3) 1 (0-2) 1 (0-2) question 3: 4m 0 (0-2) 1 (0-2) 0 (0-1) p-valueb .010 * 0.998 .180 question 4: bl 3 (2-3) 2 (1-3) 2 (1-3) question 4: 4m 1 (0-3) 0 (0-2) 2 (1-3) p-valueb <.001 .028 * 0.998 question 5: bl 0 (0-1) 3 (3-3) 3 (2-3) question 5: 4m 0 (0-1) 1 (1-2) 1 (1-2) p-valueb .046 * .024 * .034 * question 6: bl 1 (0-3) 3 (3-3) 2 (1-3) question 6: 4m 0 (0-2) 0 (0-2) 2 (1-3) p-value b .038 * .018 * 0.998 pvr-bl 22.50 (10.00-50.00) 120.00 (50.00-350) 140.00 (39.00-225.50) pvr-4m 25.00 (15.00-45.00) 55.00 (32.50-150.00) 65.00 (15.00-125.00) p-value b .104 .027 .017 a.kruskal-wallis, b. wilcoxon abbreviations: udi-6. urinary distress inventoryshort form, ndo. neurogenic detrusor overactivity, dsd. detrusor sphincter dyssynergia, pvr. post void residual urine, bl. baseline, 4m. four months after injection. table 3. comparing the udi-6 score and post-void residual urine in three groups of patients with neurogenic lower urinary tract dysfunction at baseline and four months after abobotolinum toxin a (dysport) injection. dysport injection in bladder and urethrasharifiaghdas et al. vol 19 no 1 january-february 2022 65 bladder wall and consequently a decrease in urethral pressure(9). therefore, the use of intravesical btx-a in ndo could improve bladder outlet obstruction; since the patient experienced easier cic. on the other hand, urinary bladder emptying requires the relaxation of the bladder neck and urethral sphincter followed by the contraction of detrusor smooth muscles, and voluntary coordinated urethral sphincter relaxation completes the voiding process(17). coordination between the urethral sphincter and the urinary bladder is mediated by complex neural control and reflex pathways. so, during the voiding phase, when the urethral sphincter is poorly relaxed, a forceful detrusor contraction may be inhibited by inhibiting the detrusor contraction micturition center at the sacral spinal cord(18). whenever the urethral sphincter contraction during the voiding phase can also inhibit detrusor muscle contraction by activating the inhibiting afferent reflex(14). therefore, both a poorly relaxed urethral sphincter and a urethral sphincter with contraction during voiding not only interfere with urinary flow, causing a functional bladder outlet obstruction but also affect the detrusor contractions contributing to bladder dysfunctions, such as detrusor underactivity. conceptually, urethral sphincter injection with btx-a might facilitate voiding by reducing urethral resistance due to its paralyzing effect and enhancing detrusor contraction due to its potential neuromodulation effects(7). another mechanism that can explain btx-a injection on the neighboring structure might be the spread of toxins in contiguous structures. it means that besides the effect on bladder function, btx-a may affect the bladder neck. caremel et al. have discussed this idea of dispersion of detrusor-injected toxin towards the internal sphincter(19). in this retrospective study of 11 patients with spinal cord injury and repeated botox treatment, caremel et al. found a decreased ejaculated volume in 10 patients following botox treatment compared to pretreatment patients, concerning the increased incidence of retrograde ejaculation. with the same idea of passive distribution, some others described that fewer injection sites of toxin in detrusor were as useful as the established technique with more injection areas(20). despite the limited injection sites, it implies migration of btx-a throughout the whole detrusor, meaning a local and systemic diffusion(9). although btx-a injections into the bladder and urethra have been widely used in recent years, various studies have different success rates. the possible reasons for this discrepancy or failure of some studies are not fully understood. the difference in success rate is the dose and site of injection (bladder or urethra or both). in a study involving patients with low detrusor contractility, 48% (13 of 27) of patients who received an injection of 50–100 u botox into the urethral sphincter showed improvement in detrusor contractility, indicating the neuromodulation effects between the urethral sphincter and bladder(21). another study by kuo et al. revealed that in patients with dsd, urethral sphincter injection of 100 u botox reported to achieve an overall satisfactory result of 60.6% with significant improvement in the reduction of voiding detrusor pressure and post-void residual urine volume and an increase in maximal urinary flow rate(22). they showed that in spinal cord injured patients with dsd, de novo urge urinary incontinency (48.5%) was the main reason for patient dissatisfaction with urethral sphincter botox injection therapy(22). in adult patients, liao et al. reported that urethral sphincter injection with a usual dose of 50–100 u botox resulted in an overall success rate of 86.7% in patients with dysfunctional voiding and a success rate of 95.7% in patients with poor relaxation of the urethral sphincter(23). franco et al. reported that increasing the botox dose to 200–300 u resulted in increased efficacy without increasing the morbidity rate(24). botox's repeated injection in urethral sphincter with better therapeutic effects in both dysfunctional voiding and detrusor underactivity patients, indicating that a higher dose or repeated injection of botox is necessary for optimal pharmacologic effects in these patients. other reasons for the differences in the success rate of btx-a injection in patients with nlutd are the type and brand of toxin(25) and associated pathology such as detrusor underactivity or bladder neck dyssynergia(26). for example, in patients with detrusor underactivity, urethral sphincter botox injection might result in a reduction in urethral resistance, which allowed patients to void more easily with the aid of abdominal pressure. however, if the patient is weak and cannot generate adequate abdominal pressure to void, voiding difficulty and large post-void residual volume might persist. also, an open bladder neck is essential because abdominal pressure can passively overcome the urethral resistance. if patients with detrusor underactivity cannot open the bladder neck by abdominal straining, urethral sphincter botox injection might not be successful(7). a stricter definition of successful results in some studies is also mentioned. psychogenic factors can also affect sphincter relaxation. in a randomized, double-blind, placebo-controlled trial study by jiang et al., female urology 546 figure 1. injection of diluted dysport in peri-urethra at 12 o’clock using 31-gauge insulin syringe. dysport injection in bladder and urethrasharifiaghdas et al. female urology 66 vol 19 no 1 january-february 2022 138 comparing the efficacy of botox with placebo (normal saline) injections into the urethral sphincter in patients with dysfunctional voiding and detrusor underactivity had been shown. interestingly, the therapeutic effects of the placebo were similar to those of botox subgroups. it seems that the local injection of either substance into the urethral sphincter might result in reduced spasticity of the urethral sphincter in patients with dysfunctional voiding. stimulation of the urethral sphincter via solution injection might provide partial urethrolytic effects on a spastic, poorly relaxed, and non-relaxed urethral sphincter, ameliorating voiding symptoms and facilitating bladder emptying that increased relaxation of the urethral sphincter in patients with detrusor underactivity, regardless of the pharmacologic effects of btx-a. however, only toxin injection in the urethra resulted in increased maximum flow rate and voided volume, and reduced detrusor pressure, which demonstrates the paralytic effect of btx-a(7). our study's primary limitations are the small number of patients with a lack of control groups. also, the heterogeneous underlying pathogenesis of our patients with nlutd. the third limitation was the relatively short follow-up period. a longer follow-up might reveal better pharmacologic effects of btx-a on the urethral sphincter and eliminate the placebo effects. conclusions according to our findings and previous studies, the periurethral injection of btx-a (botox or dysport) is effective and safe in decreasing urethral resistance in dsd besides the routine use of botox in patients with ndo. therefore, the urethra is a potential therapeutic target in patients with nlutd. however, dosage, injection schedule, and patient selection should be standardized to facilitate bladder emptying, improve subjective symptoms, and life quality. our findings can help clinicians choose an alternative treatment in some patients, especially those unwilling or unable to perform clean intermittent catheterization. conflict on interest the authors have no conflicts of interest to declare. references 1. przydacz m, denys p, corcos j. what do we know about neurogenic bladder prevalence and management in developing countries and emerging regions of the world? ann phys rehabil med 2017; 60: 341-6. 2. liao l. evaluation and management of neurogenic bladder: what is new in china? int j mol sci 2015; 16: 18580-600. 3. seth jh, dowson c, khan ms, et al. botulinum toxin-a for the treatment of overactive bladder: uk contributions. j clin urol 2013; 6: 77-83. 4. schurch b, hauri d, rodic b, curt a, meyer m, rossier ab. botulinum-a toxin as a treatment of detrusor-sphincter dyssynergia: a prospective study in 24 spinal cord injury patients. j urol 1996; 155: 1023-9. 5. dykstra dd, sidi aa, scott ab, pagel jm, goldish gd. effects of botulinum a toxin on detrusor-sphincter dyssynergia in spinal cord injury patients. j urol 1988; 139: 919-22. 6. steinhardt gf, naseer s, cruz oa. botulinum toxin: novel treatment for dramatic urethral dilatation associated with dysfunctional voiding. j urol 1997; 158: 190-1. 7. jiang yh, wang cc, kuo hc. onabotulinumtoxina urethral sphincter injection as treatment for non-neurogenic voiding dysfunction a randomized, double-blind, placebo-controlled study. sci rep 2016; 6: 38905. 8. soler jm, previnaire jg, hadiji n. predictors of outcome for urethral injection of botulinum toxin to treat detrusor sphincter dyssynergia in men with spinal cord injury. spinal cord 2016; 54: 452-6. 9. hervé f, viaene a, everaert k. onabotulinumtoxin a injections in detrusor facilitate self-catheterisation in a patient with paraplegia and bladder outlet dyssynergia. bmj case rep 2017. 10. uebersax js, wyman jf, shumaker sa, mcclish dk. short forms to assess life quality and symptom distress for urinary incontinence in women: the incontinence impact questionnaire and the urogenital distress inventory. neurourol urodyn 1995; 14: 131-9. 11. kuo hc. therapeutic outcome and quality of life between urethral and detrusor botulinum toxin treatment for patients with spinal cord lesions and detrusor sphincter dyssynergia. int j clin pract 2013; 67: 1044-9. 12. schurch b, yasuda k, rossier ab. detrusor bladder neck dyssynergia revisited. j urol 1994; 152: 2066-70. 13. chancellor mb, fowler cj, apostolidis a, et al. drug insight: biological effects of botulinum toxin a in the lower urinary tract. nat clin pract urol 2008; 5: 319-28. 14. de groat wc, fraser mo, yoshiyama m., et al. neural control of the urethra. scand j urol nephrol 2001; 35: 35-43. 15. kakizaki h, fraser m, de groat w. reflex pathways controlling urethral striated and smooth muscle function in the male rat. am j physiol regul integr comp physiol 1997; 272: r1647-r56. 16. shafik a. study of the effect of vesical filling and voiding on ureterovesical junctions and internal urethral meatus: the filling and meato‐ vesico‐ureteral reflexes. int j urol 1998; 5: 449-53. 17. blaivas j. pathophysiology of lower urinary tract dysfunction. urol clin north am 1985; 12: 215-24. 18. elbadawi a, schenk ea. a new theory of the innervation of bladder musculature. part 4. innervation of the vesicourethral junction and external urethral sphincter. j urol 1974; 111: 613-5. 19. caremel r, courtois f, charvier k, ruffion a, journel nm. side effects of intradetrusor botulinum toxin injections on ejaculation and fertility in men with spinal cord injury: preliminary findings. bju int 2012; 109: female urology 674 dysport injection in bladder and urethrasharifiaghdas et al. vol 19 no 1 january-february 2022 67 1698-702. 20. siegel s, noblett k, mangel j, et al. results of a prospective, randomized, multicenter study evaluating sacral neuromodulation with interstim therapy compared to standard medical therapy at 6‐months in subjects with mild symptoms of overactive bladder. neurourol urodyn 2015; 34: 224-30. 21. kuo h-c. recovery of detrusor function after urethral botulinum a toxin injection in patients with idiopathic low detrusor contractility and voiding dysfunction. urology 2007; 69: 5761. 22. kuo hc. satisfaction with urethral injection of botulinum toxin a for detrusor sphincter dyssynergia in patients with spinal cord lesion. neurourol urodyn 2008; 27: 793-96. 23. liao y-m, kuo h-c. causes of failed urethral botulinum toxin a treatment for emptying failure. urology 2007; 70: 763-6. 24. franco i, landau-dyer l, isom-batz g, collett t, reda ef. the use of botulinum toxin a injection for the management of external sphincter dyssynergia in neurologically normal children. j urol 2007; 178: 1775-80. 25. emami m, shadpour p, kashi ah, choopani m, zeighami m. abobotulinum a toxin injection in patients with refractory idiopathic detrusor overactivity: injections in detrusor, trigone and bladder neck or prostatic urethra, versus detrusor only injections. int braz j urol 2017; 43: 1122-8. 26. liao ym, kuo hc. causes of failed urethral botulinum toxin a treatment for emptying failure. urology 2007; 70: 763-6. dysport injection in bladder and urethrasharifiaghdas et al. female urology 68 vol 19 no 2 march-april 2022 100 is 10/12 fr ureteral access sheath more suitable for flexible ureteroscopic lithotripsy? wenfeng li,1 yuanshen mao,1 yufei gu,1 chao lu,1 xin gu,1 bao hua,1 weixin pan,1 qinghong xi,1** zhong wang1* purpose: to choose the ideal ureteral access sheath (uas) size for an unstented ureter in flexible ureteroscopic lithotripsy (furl). materials and methods: a retrospective study was conducted in patients treated with furl for renal calculi from 2005 to 2020. the patients were divided into two groups: smaller (10/12 fr) vs. larger (12/14 fr) calibre uas. the outcomes were the insertion success rate, systemic inflammatory response syndrome (sirs) complication rate after the operation, ureteral wall injury, operative time, and stone-free rate. results: of the 1573 patients enrolled, 10/12 fr uas was used in 957 patients (group a), and 12/14 fr uas was used in the remaining patients (group b). the insertion success rate was significantly better in group a (91.2% vs. 86.9%, p = .006), with no significant difference between the groups regarding the stone-free rate, postoperative pain, operative time or hospital stay. the severity of visible ureteral lesions with 10/12 fr uas was significantly lower than that with larger uass (80.1% vs 85.2%, p < .001). despite the lack of a significant difference in the incidence of sirs between the two groups, the incidence of sirs in the 10/12 fr group showed a sharp increase with stones > 2 cm (17.0% vs. 8.5%, p = 0.037). conclusion: the use of 10/12 fr uas was beneficial with respect to insertion success rate, avoiding ureteral wall injury and not increasing postoperative infectious complications in furl. we recommend the use of a smaller calibre (10/12 fr) uas in patients with renal calculi < 2 cm. keywords: ureteroscopy; ureter; lithotripsy; ureteral access sheath; infectious complications introduction with the development of ureteroscopy (urs), including miniaturization of the ureteroscope, advanced fragmentation technology and improved extraction devices, urs is rapidly becoming the most common method for the treatment of urinary calculi in the world.(1) both eau and aua recommend flexible ureteroscopy lithotripsy (furl) as the first-line treatment for proximal ureteral and renal calculi < 2 cm. during routine furl, high levels of intrarenal pressure may be related to urinary system infection and bleeding complications as well as to renal function damage. (2, 3) several studies have shown that the placement of ureteral access sheath (uas) can improve the surgical efficiency, facilitate ureteroscopy, and reduce the intrarenal pressure and postoperative complications of furl.(4-6) however, in the case of non-prestent furl, the probability of uas failure to enter the ureter is 9.8% to 22.0%, and the larger the diameter is, the higher the failure rate.(7) additionally, the use of large uass increases the possibility of ureteral wall injury, which may lead 1department of urology, the ninth people's hospital affiliated to shanghai jiao tong university, shanghai 200011, china. *correspondence: department of urology, the ninth people's hospital affiliated to shanghai jiao tong university, 639 zhizhaoju road, shanghai 200011, china.tel: +862156691101, e-mail: kuangfeng0612@126.com. ** department of urology, the ninth people's hospital affiliated to shanghai jiao tong university, 639 zhizhaoju road, shanghai 200011, china.tel: +8613611829161, e-mail: 13611829161@163.com. received december 2020 & accepted july 2021 to the formation of ureteral strictures.(8) although prestenting can effectively improve the success rate of uas implantation, ureteral stents have a negative impact on the quality of life of the vast majority of patients. to adapt to different conditions of the ureter and equipment, surgeons can select various uas lengths (1355 cm) and diameters (10/12 fr-16/18 fr). currently, 10/12 fr and 12/14 fr uas are mainly used in flexible ureteroscopes in our department for the treatment of urolithiasis. we conducted a retrospective single-centre study to compare the efficacy and safety between these two different uas sizes to determine whether 10/12 fr uas is more suitable for furl. materials and methods study population after institutional review board approval, we identified 1573 furl procedures performed between may 2005 and february 2020 at our institution. all eligible patients were divided into two groups based on the use of the different sizes of uas: cook medical flexor 12/14 fr (wider) and 10/12 fr (narrower). the size of urology journal/vol 19 no. 2/ march-april 2022/ pp. 89-94. [doi: 10.22037/uj.v18i.6620] endourology and stone disease the uas was determined at the surgeons’ discretion during surgery. all operations were performed by two skilled surgeons. inclusion and exclusion criteria patients undergoing furl for kidney stones with the use of uas in an unstented ureter were included. patients with prior impacted ureteral stones, the presence of ureteral stones during surgery, prior ureteroscopies, prior ureteral drainage (ureteral stent or pcn), documented ureteral strictures, prior radiation treatment, the presence of renal or ureteral malignancy or other metabolic diseases, such as renal tubule acidosis or hyperparathyroidism, were excluded from the study. cases in which wider uass could not be inserted successfully followed by the use of a narrower uas, appropriate balloon dilatation or the direct use of flexible ureteroscopy without uas were also excluded from the study. procedures after admission, a kidney, ureter, and bladder radiograph (kub) x-ray and a noncontrast ct were performed at the same time. routine blood, urine and renal function tests as well as urine culture were performed to determine the presence of anaemia, urine infection, renal insufficiency, or any other condition that needed to be treated before surgery. patients with preoperative positive urine cultures were treated with a complete course of culture-specific antibiotics before the furl procedure. prophylactic antibiotics with ciprofloxacin supine versus prone position for uc-lu et al. variables 10/12 fr uas (n=957) 12/14 fr uas (n=616) p-value age, years; mean±sd 51.0 ± 13.5 52.1±14.1 .139a sex, n (%) .095b male 599 (62.6) 411 (66.7) female 358 (37.4) 205 (33.3) bmi , kg/m2; mean±sd 25.4 ± 2.9 25.2 ± 3.2 .109a asa ; mean±sd 2.1 ± 0.4 2.2 ± 0.4 .071a stone size, mm; mean±sd 16.2 ± 3.3 16.2 ± 3.7 .800a stone location, n (%) .453a upper calix 67 (7.0) 32 (5.2) medium calix 118 (12.3) 66 (10.7) lower calix 287 (30.0) 198 (32.1) pelvis 188 (19.6) 119 (19.3) multiple 297 (31.0) 201 (32.6) laterality, n (%) .091b left 551(57.6) 328 (53.2) right 406 (42.4) 288 (46.8) stone ct value, hu; mean±sd 834.1±170.5 828.6 ± 172.6 .542a table 1. patients’ demographics and baseline characteristics in the study abbreviations: bmi, body mass index; asa, american society of anesthesiologists; hu, hounsfield units; ct, computed tomography; a non-normal distribution variables were compared by mann-whitney u test b categorical variables were compared by chi-square test figure1. comparison of postoperative sirs and sfr rate between group a (10/12 fr uas) and group b (12/14 fr uas) in all patients with stones >2 cm and <2cm separately. endourology and stones diseases 90 vol 19 no 2 march-april 2022 100 (cephalosporin for patients with abnormal renal function) were administered to all patients before the operation. all furl procedures were performed in the lithotomy position under general anaesthesia. a size 3 or 4 laryngeal mask airway was inserted and fentanyl at doses of up to 2 μg/kg given intravenously was administered as required during surgery. the ureteroscopy was performed with an 8/9.8 fr semirigid ureteroscope (richard wolf, germany), and a 0.035-inch nickel-titanium guide wire (cook inc, usa) was inserted into the renal collection system. under the guidance of fluoroscopy, the uas with infiltrated inner and outer surfaces was inserted into the proximal ureter along the guide wire. a 7.5 fr flexible ureteroscope (storz flex x2, germany) was used to find calculi in the pelvis or each calyx of the kidney, and the technique of dusting, working tangentially from the edge of the stone with the laser fibre at a high frequency (hf) with low energy, was then used. irrigation (90 ml/minute) was performed to keep the visual field clear. after no obvious residual stones were found, the ureteroscope was withdrawn with the sheath, and ureteral wall injury was assessed. a 6 fr double-j stent (cook inc., usa) was placed after the procedure for approximately 2 weeks. if the ureter was narrow or twisted or uas entry was difficult, the operation was abandoned, and a 6 fr double-j stent was placed. evaluations a complete medical history along with anthropological parameters was routinely collected. body mass index (bmi) was calculated as weight in kilograms divided by height in metres squared (kg/m2). blood samples were taken and tested for blood count and serum creatinine level. urinalysis and urine culture were also performed before furl. stone number, size, location and hounsfield unit (hu) were assessed by means of a low-dose ncct scan, an accurate imaging modality for defining stone size and location. the outcomes were the insertion success rate, systemic inflammatory response syndrome (sirs) complication rate, ureteral wall injury, postoperative pain, operative time, hospital stay, and stone-free rate. there are four components of sirs (temperature < 36° or > 38 °c, heart rate > 90 bpm, respiratory rate > 20 per minute, wbc# < 4000 or > 12000 cells/mm3), and at least two of these criteria need to be met. ureteral wall injury was evaluated according to ureteral injury grading at the end of the operation by watching the surgical video and the description of some surgical records.(9) the operative time was defined as the time from the insertion of ureteroscope to the end of operation. the stone-free rate was defined as no more than a 2 mm residual stone detected by postoperative kub x-ray approximately 2 to 3 weeks after removing the double-j stent. the postoperative pain was defined as unbearable postoperative pain, which needs to be treated with intravenous or intramuscular analgesics. statistical analysis statistical analysis was performed using a t-test for continuous, normally distributed variables and a mann-whitney u test for non-normally distributed variables. for categorical variables, the chi-square test or fisher’s exact test was applied. a p < .05 was considered to indicate statistical significance. results demographic data, date on stone characteristics and preoperative evaluation are shown in table 1. of the 1573 patients enrolled, 10/12 fr uass were used in 957, and 12/14 fr uass were used in the remaining patients. the average age was 51.4 years, and 64.2% were male. there was no significant difference in baseline data between the two groups of patients. the clinical outcomes and safety of the two groups are presented in table 2. the insertion success rate was significantly better in the 10/12 fr uas group than in the 12/14 fr uas group (91.2% vs. 86.9%, p = .006), although postoperative pain, operative time and hospital stay were not significantly different. the multivariable logistic regression analysis identified uas size (95% ci: 1.157–2.231, or = 1.607, p = .005) as an independent risk factor for insertion success rate. in our study, we did not record any grade iv ureteral wall injury. the number of patients with grade iii ureteral wall injury was the same in both groups (2 cases). regarding mild ureteral wall injury, 80.1% of patients experienced ureteral wall injury during the operation, including 73.7% with a grade i injury and 6.3% with a grade ii injury in group a. the situation was significantly worse in group b, with 85.2% sustaining ureteral wall injury during the operation, including 71.8% with a grade i injury and 13.1% with a grade ii injury variables 10/12 fr uas (n=957) 12/14 fr uas (n=616) p-value clinical efficacy insertion success rate, n (%) 873 (91.2) 533 (86.9) .006b operative time, min; mean ± sd 24.8 ± 11.3 25.7 ± 9.9 .096a sfr, n (%) 865(90.4) 565 (91.7) .369b hospital stay, d; mean±sd 4.0 ± 0.8 3.9 ± 0.8 .174a safety pain requiring iv/im analgesics, n (%) 109 (11.4) 78 (12.7) .447b sirs, n (%) 91(9.5) 49 (8.0) .291b grades of ureteral injury, n (%) < .001b 0 190 (19.9) 91(14.8) 1 705 (73.7) 442 (71.8) 2 60 (6.3) 81(13.1) 3 2 (0.2) 2 (0.3) table 2. comparison of clinical efficacy and safety abbreviations: sfr, stone free rate; sirs, systemic inflammatory response syndrome. a non-normal distribution variables were compared by mann-whitney u test b categorical variables were compared by chi-square test supine versus prone position for uc-lu et al. vol 19 no 2 march-april 2022 91 (x2= 25.590, p = .000) (table 2). there was no significant difference in the incidence of sirs or sfr between the two groups. even when considering only patients whose calculi were > 2 cm, there was still no significant difference in sfr between the two groups (83.5% vs. 89.7%, p = .130). however, the incidence of sirs in the 10/12 fr group showed a sharp increase that was significantly higher than that in the 12/14 fr group (17.0% vs. 8.5%, p = .037) (figure 1). discussion since flexible ureteroscopy was introduced into modern medicine in the late 1980s, the use of uass has become widespread due to its many advantages, such as allowing for a clear surgical field, simplifying the surgical process, shortening the operative time, reducing the intraoperative renal pressure, and further reducing infection-related complications.(4-6) unfortunately, primary insertion of a uas is not always successful. in recent years, some studies have reported that the failure rate of uas insertion is 9.8% to 22.0%.(10) arguably, the reason is likely the discrepancy between the diameter of the ureter (6-9 fr) and the outer diameter of the uas (12-18 fr). abandoning the operation due to uas insertion failure will increase pain and cost. when furl was carried out in china, double-j stents were routinely placed to dilate the ureter for 2 weeks before surgery to avoid the difficulty of passing the uas through the ureter during the operation. although prestenting can greatly improve the success rate of uas insertion, its routine use remains controversial. the eau guidelines recommend that ureteral stents should not routinely involve prestenting for all patients undergoing furl. prestenting not only increases the cost and cycle of treatment but also increases the occurrence of complications such as infection, haematuria, bladder irritation and urine reflux, which will affect the daily life of patients and increase their psychological burden. furthermore, 58% of patients reported that stent symptoms had a negative economic impact due to work interruption. in fact, an increasing number of urologists are trying to avoid this incidence and are not routinely performing prestenting.(7) although active balloon dilatation is another option, potential risks, such as ureteral oedema, postoperative discomfort and secondary stenosis, should not be ignored.(11) our study showed that in the case of non-preoperative prestenting, the insertion success rate of narrower uass (10/12 fr) was significantly higher than that of wider uass (12/14 fr) (91.2% vs. 86.9%, p = .006). moreover, the vast majority of patients can undergo complete furl at one time to avoid pain and economic loss caused by reoperation. the results of our study indicated the same effect on sfr, operative time and hospital stay between the two different uas sizes. some studies have reported that a wider uas can reduce operative time, but these studies generally used active stone fragment retrieval with basket extraction.(4) the smaller diameter of the access sheaths (inner diameter 10 fr) allows only small stone fragments (< 3 mm) to be removed. fragments of this size may be difficult to capture in the basket and will inevitably prolong the operative time. in all of our furls, the ‘‘dusting’’ technique was used to treat kidney stones. a recent multicentre prospective study showed that there was no difference in the readmission rate, reintervention rate or symptoms due to residual fragments in the short term between dusting and fragmentation with stone retrieval for kidney stones < 15 mm.(12) another recent study in which calculi 10-40 mm were treated with ureteroscopy showed that active fragment retrieval using a nitinol basket was not associated with improvements in stone-free rates.(13) gamal and mamdouh performed furl on 46 patients with unilateral renal calculi less than 2 cm. the patients were randomly divided into two groups: group 1 was treated with dusting for stones using low power (0.2-0.4 j) and high frequency (20-30 hz), and group 2 was treated with fragmented stones using high power (1-2 j), low frequency (4-5 hz) and basket extraction of fragments. the sfrs of the two groups were similar (86% and 89%, respectively), and dusting was associated with a significantly shorter operative time (57 minutes vs 70 minutes, p = .001).(14) another argument for dusting involves the cost of surgery. regardless of whether the fragments need to be actively retrieved after laser lithotripsy, both operations require guide wires and laser fibres. dusting procedures can usually be performed with these devices alone. however, extraction requires the use of a grasper or basket further, and in some cases, having a tacit assistant during active fragment retrieval is also critical to shorten the operative duration. infectious complications are the most common and dangerous complications of furl, including sepsis or infectious shock. one of the main functions of uas is to control the pressure of the renal pelvis to reduce the incidence of infection. it is well known that stones located in different locations (especially in the lower calyces) can result in increased operative difficulty and duration, and a longer operative time can increase the incidence of sirs. in our study, there was no significant difference in the location of kidney stones between the two groups. when the size of the kidney stone was less than 2 cm, there was no significant disadvantage with respect to infectious postoperative complications of 10/12 fr uas compared with 12/14 fr uas (7.7% vs. 7.2%, p = .728). nonetheless, when the stone size was larger (> 2 cm), the incidence of sirs in the 10/12 fr uas group increased significantly and was twice that in the 12/14 fr uas group (17.0% vs. 8.5%, p = .032). in all ureteroscopies, the irrigation system is the key to visualization. pressurized saline irrigation is usually used in ureteroscopy, which can increase the pressure of the renal pelvis.(15) there is a large amount of endotoxin in renal calculi, which increases significantly with increasing stone burden.(16) it has been shown that high pelvic pressure can lead to regurgitation; in addition, systemic absorption of irrigation fluid containing bacteria or endotoxins can lead to postoperative fever and/or sirs. due to rapid outflow through uas, its use during ureteroscopy enhances the visibility of the upper urinary tract while maintaining low pelvic pressure (< 40 cmh 2 o).(17) in some studies, maximal intrapelvic pressure was similar between 12/14 fr and 14/16 fr uas, and it did not exceed 46 cmh 2 o even under manual pumping using the 10/12 fr uas.(18) when the instruments occupy the working channel of the ureteroscope, they decrease flow significantly (for a fixed driving pressure). thus, there is no obvious irrigation outflow with the increase in uas diameter.(19) one of the main problems with the use of large uass is the possibility of ureteral wall injury, which may supine versus prone position for uc-lu et al. endourology and stones diseases 92 vol 19 no 2 march-april 2022 100 lead to the formation of ureteral strictures.(20) traxer and thomas described ureteral injury after exposure to sheath-assisted urs and established the five-point scale for ureteral wall injury used in this study.(9) due to the lack of routine prestenting before furl in our study, the overall incidence of ureteral injury was higher than that in other studies. however, our study confirmed that reducing the size of the uas can avoid the risk of ureteral injury, as the risk associated with visible ureteral lesions with 10/12 fr uass was significantly lower than that with larger uass (80.1% vs 85.2%, p < .001). although severe ureteral injuries are rare during the operation, even the external diameter of the smallest uas exceeds the normal ureter, i.e., 3-4 mm, equivalent to the outer diameter of 9-12 fr. some studies have shown that the histopathological evaluation of ureteral wall lesions after uas placement revealed a significantly higher degree of severity than that observed endoscopically in a porcine model.(21) additionally, in a swine animal model, lallas et al. measured the blood flow of the ureter with a laser doppler blood flow metre. after insertion of the uas, a lower ureteral blood flow and slower recovery were obtained with a larger uas.(22) therefore, the incidence of uas-related complications of ureteral injury is expected to decrease significantly with the reduction in uas diameter. under the influence of a large uas, the proinflammatory mediators cox-2 and tnf-a become significantly upregulated in the ureteral wall, which may have an impact on postoperative pain.(23) however, oguz et al. prospectively investigated factors related to early postoperative pain after retrograde intrapelvic surgery in 250 patients. the only operation-related factor associated with severe pain was the total duration of uas placement: 46.57 minutes in those with severe pain versus 41.54 minutes in those without pain; the size of uas, operative time, ureteral injury and prestenting were not related to pain after urs.(24) our study also showed that even with the use of smaller uas, the proportion of postoperative analgesia did not improve due to the similar lithotripsy time. our study is the first to compare the efficacy and complications between two different sizes of uass (10/12 vs 12/14 fr) in previously unstented and unmanipulated ureters, although the study did have limitations. the study was retrospective in nature, which may lead to selection bias. we attempted to overcome this limitation by including all cases of furl for renal calculi that were dusted during the study period. unfortunately, we did not assess whether the results were influenced by basketing and digital scopes. the operation was also performed by two different surgeons, which may lead to technical differences. in addition, the choice of uas size was at the discretion of the surgeon and was not random. however, these limitations do not change the outcome, namely, that 10/12 fr uas has an advantage for unstented ureters. conclusions with the development of technology, the size of the ureteroscope is becoming increasingly smaller. the 10/12 fr uas showed an advantage in the insertion success rate and prevented ureteral wall injury in furl compared with the 12/14 fr uas. the 10/12 fr uas can provide proper irrigation flow, which does not significantly increase the possibility of postoperative infectious complications. we recommend the use of the 10/12 fr uas as a first-line choice in patients with kidney stones less than 2 cm. acknowledgment we are thankful for the financial supported by specialty alliance development fund (zklm010). conflict of interest the authors report no conflict of interest. references 1. reis sjm. ureteroscopy from the recent past to the near future. urolithiasis. 2018;46:31-7. 2. ozgor f, sahan m, cubuk a, ortac m, ayranci a, sarilar o. factors affecting infectious complications following flexible ureterorenoscopy. urolithiasis. 2019;47:4816. 3. tokas t, skolarikos a, trw h, nagele u. pressure matters 2: intrarenal pressure ranges during upper-tract endourological procedures. world j urol. 2019;37:133-42. 4. tracy cr, ghareeb gm, paul cj, brooks na. increasing the size of ureteral access sheath during retrograde intrarenal surgery improves surgical efficiency without increasing complications. world j urol. 2018;36:971-8. 5. shvero a, herzberg h, zilberman d, et al. is it safe to use a ureteral access sheath in an unstented ureter. bmc urol. 2019;19:80. 6. traxer o, wendt-nordahl g, sodha h, et al. differences in renal stone treatment and outcomes for patients treated either with or without the support of a ureteral access sheath: the clinical research office of the endourological society ureteroscopy global study. world j urol. 2015;33:2137-44. 7. fuller tw, rycyna kj, ayyash om, et al. defining the rate of primary ureteroscopic failure in unstented patients: a multiinstitutional study. j endourol. 2016;30:9704. 8. lildal sk, sørensen fb, andreassen kh, et al. histopathological correlations to ureteral lesions visualized during ureteroscopy. world j urol. 2017;35:1489-96. 9. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013;189:580-84. 10. lima a, reeves t, geraghty r, et al. impact of ureteral access sheath on renal stone treatment: prospective comparative non-randomised outcomes over a 7-year period. world j urol. 2020;38:1329-33. 11. kuntz nj, neisius a, tsivian m, et al. balloon dilation of the ureter: a contemporary review of outcomes and complications. j urol. 2015;194:413-7. 12. humphreys mr, shah od, monga m, et al. dusting versus basketing during ureteroscopy-which technique is more efficacious? a prospective multicenter trial from the edge research consortium. j urol. supine versus prone position for uc-lu et al. vol 19 no 2 march-april 2022 93 2018;199:1272-6. 13. matlaga br, chew b, eisner b, et al. ureteroscopic laser lithotripsy: a review of dusting vs fragmentation with extraction. j endourol. 2018;32:1-6. 14. santiago je, hollander ab, soni sd, et al. to dust or not to dust: a systematic review of ureteroscopic laser lithotripsy techniques. curr urol rep. 2017;18:32. 15. sener te, cloutier j, villa l, et al. can we provide low intrarenal pressures with good irrigation flow by decreasing the size of ureteral access sheaths. j endourol. 2016;30:49-55. 16. gao x, lu c, xie f, et al. risk factors for sepsis in patients with struvite stones following percutaneous nephrolithotomy. world j urol. 2020;38:219-29. 17. fang l, xie g, zheng z, et al. the effect of ratio of endoscope-sheath diameter on intrapelvic pressure during flexible ureteroscopic lasertripsy. j endourol. 2019;33:132-9. 18. noureldin ya, kallidonis p, ntasiotis p, et al. the effect of irrigation power and ureteral access sheath diameter on the maximal intrapelvic pressure during ureteroscopy: in vivo experimental study in a live anesthetized pig. j endourol. 2019;33:725-9. 19. williams jg, turney bw, rauniyar np, et al. the fluid mechanics of ureteroscope irrigation. j endourol. 2019;33:28-34. 20. loftus cj, ganesan v, traxer o, et al. ureteral wall injury with ureteral access sheaths: a randomized prospective trial. j endourol. 2020;34:932-6. 21. lildal sk, andreassen kh, jung h, et al. evaluation of ureteral lesions in ureterorenoscopy: impact of access sheath use. scand j urol. 2018;52:157-61. 22. lildal sk, nørregaard r, andreassen kh, et al. ureteral access sheath influence on the ureteral wall evaluated by cyclooxygenase-2 and tumor necrosis factor-α in a porcine model. j endourol. 2017;31:307-13. 23. huang j, zhao z, alsmadi jk, et al. use of the ureteral access sheath during ureteroscopy: a systematic review and meta-analysis. plos one. 2018;13:e0193600. 24. oğuz u, şahin t, şenocak ç, et al. factors associated with postoperative pain after retrograde intrarenal surgery for kidney stones. turk j urol. 2017;43:303-8. . supine versus prone position for uc-lu et al. endourology and stones diseases 94 july-august 2018 reviewer of the issue soroush t. bazargani soroush t. bazargani august 2018 soroush t. bazargani, md, is fellow of clinical urology, at the usc institute of urology. dr. bazargani went to medical school at tehran university of medical sciences in tehran, iran. he was among the top in his class and did urology residency between 2005-2009 in imam-khomeini hospital of urmia university, one of the well-known urology centers in iran, recognized for renal transplantation. before finishing his residency, dr. bazargani attended the 7th european urology residential education program (eurep) course as one of the topfive iranian urology residents. he then got the first score in european board of urology in sep 2009. after certification with iranian board of urology with a top score in sep 2009, he started his career in urology as a full certified urologist. from 2009 to 2013, he took part in multiple research and clinical training program while in urology practice. he also did a 6-month fellowship training in pediatric urology in tehran children medical center of excellence, one of the most prestigious centers pioneering modern pediatric urology in middle-east and has been granted for multiple prize-winning research projects and high-impact publications in both clinical, basic science and stem cell research. subsequently, dr. bazargani moved to the united states in 2013 and spent one year of research at nyu urology, and three years in clinical research in urologic oncology, endourology and minimally invasive surgery at usc institute of urology, usc/norris comprehensive cancer center. dr. bazargani has had more than 60 abstracts and presentations for which, he honored five international prizes. and has published more than 30 peer-reviewed articles and book chapters, some of them are the results of impressive multicenter clinical trials. he has also been selected as a reviewer to many urology journals. dr. bazargani has recently been licensed for practice urology in ca, united states, and started his endourology/ uro-laparoscopy fellowship at the keck school of medicine of usc in may 2017. peer review is a vital process for any journal and enables publication of innovative research that meets the highest standards of quality. dr. soroush t. bazargani was chosen by editorial board of the urology journal for his valuable and timely review of manuscript”. introduction prostate cancer is the second most reported malig-nancy (after lung cancer) in men worldwide, with 1,276,106 new cases in 2018. prostate cancer is responsible for 3.8% of all cancer deaths in men in men. 2018. (1) new cases of prostate cancer are estimated to emerge 2,293,818 cases by 2040, with projections of small variations in mortality in the form of a 1.05% increase.(2) about 40% of local prostate cancer patients decided to undergo radical prostatectomy.(3) urinary incontinence is a typical and predictable post-radical prostatectomy episode and is triggered by activities such as sneezing, coughing, lifting, changing positions, and exercising. after prostatectomy, persistent and disturbing urinary incontinence is a commonly reported side effect, with an incidence rate of 1% to 40% postoperatively.(4–6) however, this number might be much higher, depending on the definition used and the validity of the incontinence questionnaire used. post-radical prostatectomy urinary incontinence significantly affects most men's quality of life undergoing surgical management of prostate cancer.(7) in assessing the quality of life of patients undergoing radical prostatectomy, incontinence was significantly associated with increased confusion, depression, and anger, and inversely related to physical and psychological healthiness.(8) as many as 28 and 18% of patients in the surgical group from the spcg-4 study experienced moderate to severe discomfort due to urinary incontinence during the day or night.(9) although improvements in surgical techniques have helped reduce the incidence of post-prostatectomy incontinence,(10) the overall rate continues to increase due to an increase in the total number of prostatectomies performed throughout the world. several studies recommend delaying invasive urinary incontinence therapy at least one year postoperatively.(11,12) therefore, behavioral therapy was chosen in several cases as an alternative.(13) this noninvasive behavioral therapy consists of diet modification, bladder training, pelvic floor muscle training (pfmt ), biofeedback, and functional electrical stimulation. in addition to being inexpensive and practical, they do not involve side effects.(14) however, some randomized controlled trials have investigated pelvic floor muscle training (pfmt) on postoperative urinary incontinence, providing conflicting evidence. while some support pfmt exercise benefits,(15,16) a cochrane review in 2015 does not recommend pfm training as a first-line rehabilitation performed post-prostatectomy because there are no significant improvements in ui symptoms over time.(17) the protocol related to pfm training initiated preoperatively and continues postoperatively has not been established yet. the low level of evidence and the lack of systematic reviews that comprehensively review this technique's efficacy might be the contributing factor. on review the effect of preoperative pelvic floor muscle training on incontinence problems after radical prostatectomy: a meta-analysis ervandy rangganata1, harrina erlianti rahardjo1* purpose: to evaluate whether additional pelvic floow muscle training (pfmt), which began before radical prostatectomy and resumes immediately after catheter removal, will significantly improve urinary incontinence after rp. materials and methods: we reviewed articles obtained from medline, central, ebscohost, cinahl, and elsevier from july – august 2020, which compared preoperative pfmt with postoperative pmft or non-pfmt, with continence incidence parameters. there were no restrictions on the definition of incontinence, treatment regimens, and radical prostatectomy surgical approach. the risk of bias was assessed using the cochrane risk of bias assessment tool. a meta-analysis was also carried out to pool the effect estimates. results: we included 12 eligible studies in this review, 11 of which we included in the meta-analysis. the pfmt initiated preoperatively significantly reduced the incidence of persistent urinary incontinence at 1, 3, and 6 months postoperatively with an or of 0.58 (95% ci, 0.41–0.81), 0.57 (95% ci, 0.43–0.74), and 0.38 (95% ci, 0.17-0.83). there was no difference in improvement in patients' incontinence at 12 months postoperatively [or = 1.31 (95% ci, 0.65-2.63)]. conclusion: pfmt initiated before radical prostatectomy significantly reduced the incidence of urinary incontinence in the first, third, and sixth months postoperatively. at 12 months postoperatively, additional preoperative pfmt did not cause a significant difference in urinary incontinence incidence. keywords: pelvic floor muscle training; urinary incontinence; radical prostatectomy 1department of urology, cipto mangunkusumo hospital—faculty of medicine, universitas indonesia, jakarta, indonesia. *correspondence: department of urology, universitas indonesia, jakarta, indonesia. tel: +62 816 825226. e-mail: harrinaerlianti@gmail.com. received september 2020 & accepted april 2021 urology journal/vol 18 no. 4/ july-august 2021/ pp. 380-388. [doi: 10.22037/uj.v18i.6481] the other hand, several studies had shown a significant role for pfmt when it is initiated before surgery and/or early postoperatively (< 6 weeks postoperatively).(18,19) however, some studies also report controversial results. therefore, the authors would like to evaluate whether a pfmt which begins before radical prostatectomy and resumes immediately after catheter removal, will significantly improve urinary incontinence. patients and methods description of condition and intervention this study was compiled based on the preferred reporting items protocol for systematic reviews and meta-analysis (prisma) statements. this study attempted to explore the effectivity of pmft initiated preoperatively in improving urinary incontinence that occurs in patients after radical prostatectomy. radical prostatectomy techniques were not limited to one particular approach. the use of laparoscopic and robot-assisted technology was also not a criterion for exclusion, as several studies have found there was no significant difference between the type of prostatectomy technique to urinary incontinence.20,21 improvement of urinary incontinence was not restricted to one definition or parameter. besides, we also did not limit the types of interventions (pmft) given to patients, other than the timeline of intervention that must be initiated before radical prostatectomy. a follow-up duration of at least three months was a requirement that must be fulfilled by each study. database searching and literature screening we conducted literature searches using five search engines (pubmed, cochrane, ebscohost, proquest, and scopus) based on four electronic databases (medline, central, cinahl, and embase). the search was conducted from july 14 to august 1, 2020. we used picos in the literature screening process to assess the suitability of each study for this meta-analysis, as described on supp.table 1. we used specific keywords, which were tailored to each search engine specification. we also looked at a reference list of several reviews to broaden the scope of study searches. study selection each author selected the study independently according to inclusion and exclusion criteria. inclusion criteria in this study included: 1. rct or quasi-rct studies comparing pfmt (with or without biofeedback) before and after surgery with pmft only after radical prostatectomy; 2. english/indonesian written articles; 3. full-text articles available; 4. outcomes are the percentage of patients recovering from incontinence; and 5. were published in the last 20 years. we included all types of surgical techniques (open radical prostatectomy, robot-assisted radical prostatectomy, and laparoscopic radical prostatectomy). the definition of incontinence of each study was also not a criterion for study selection. exclusion criteria of this study included review articles, case reports, case series, editorial letters, studies on animals, and/or studies in the process of peer review (has not been published yet). the determination of study eligibility was determined by each author independently. after that, a full-text analysis was performed on the remaining article. any disagreement was resolved by discussion. data extraction and outcome of interest each author conducted data extraction. we extracted the study's primary characteristics, including the first author, location, sample size, year of publication, and figure 1. prisma flow chart describes the identification process of included articles. pfmt on incontinence after rp-rangganata et al. review 381 patient's demography. we also extracted patient baseline data, including the degree of prostate malignancy and incontinence scores before the intervention (if available). we also extracted patterns or regimens of intervention (pmft), but there were no restrictions on the pattern of pmft. any discrepancies have been resolved by discussion. this meta-analysis explored the effectiveness of pmft initiated before radical prostatectomy compared to pfmt initiated following radical prostatectomy or no pfmt at all, in improving the recovery rate of incontinence. the output of this study was the continence rate for each independent variable. we used 2x2 contingency tabs to obtain the ors for each study and pooled the overall or using the review manager 5 application. heterogeneity was measured by looking at the i2 value. the i2 value greater than 50% indicated a moderate to high heterogeneity. when the high heterogeneity was found between studies, an effect estimate analysis was performed with the dersimonian and laird random-effects model. if heterogeneity between studies was low, fixed effect model analysis was performed using the mantel-haenszel methods. assessment of methodologic quality this meta-analysis included only rcts and quasi-rcts. rct studies' quality assessment was carried out using the cochrane risk-of-bias tool for randomized trials (rob 2). studies with, at least, moderate quality were included in the overall effect estimate calculation (meta-analysis). red dot indicated a high risk of bias of each bias criterion, while yellow meant moderate and green meant low risk of bias. selection bias criterion was not applicable for quasi-rct study as no random sequence was generated in patient selection. blinding of participant was also impossible in these settings. results literature search a literature search on five electronic databases found 883 articles (first hit), and we found 285 similar articles. for 598 remaining articles, we screened and found that only 17 articles were eligible. we independently conducted a full-text analysis of the remaining 17 articles and found five articles that did not fit the picos that we specified in this meta-analysis. we included 12 articles in this review and 11 articles in quantitative synthesis (meta-analysis)—flowchart of this literature search described in figure 1. study characteristics we found 12 eligible studies based on the suitability of patient characteristics, types of interventions in the experimental and control groups, and outcomes measured in each study (table 1). eleven studies were randomized controlled trials and only 1 study with a quasi-rct design, which did not implement randomization and patient’s data was fully based on the patient's medical record. five studies lasted for six months, four studies lasted for 12 months, and only three studies lasted for three months. overall, the total number of patients involved in this study was 1348 patients. 3 of the 12 studies applied the same treatment regimen between the control and experimental groups,(22–24) two studies did not apply any treatment to the control group,(25,26) and the rest applied different treatment regimens. (18,19,27–31) risk of bias of included studies each author assessed each study's quality using the cochrane risk of bias assessment (rob) tool for rct independently. overall, studies had a high risk of performance bias caused by the impossibility of participants and personnel blinding (figure 2). therefore, we did not exclude studies just because of the high risk of figure 2. risk of bias assessment of rcts using cochrane risk of bias assessment pfmt on incontinence after rp-rangganata et al. vol 18 no 4 july-august 2021 382 performance bias. in general, the studies included in this meta-analysis were of good quality. the selection bias from the study of patel et al. 2013 could not be assessed because this study was a quasi-rct study. intervention regimen we found a large variety of interventions given to patients in each study, which was generally based on each health center's protocol, where the study was conducted. pfmt accompanied and guided by a physiotherapist, followed by a biofeedback session, was the most widely review 383 figure 3. forest plot shows odds ratio of getting incontinence after radical prostatectomy at several time points: (a) 1 month; (b) 3 months; (c) 6 months; and (d) 12 months. figure 4. funnel plot shows the distribution of studies based on the effect estimate and standard error: (a) 1 month; (b) 3 months; (c) 6 months; and (d) 12 months. pfmt on incontinence after rp-rangganata et al. used treatment regimen.(18,22,24,25) only the parekh et al. (2003) study did not include biofeedback in the treatment regimen.(29) most studies conducted training and biofeedback sessions at least once a week for 30–60 minutes per session, four weeks before radical prostatectomy. only the tienforti et al.(30) and sayilan et al.(26) studies conducted therapy less than two weeks before radical prostatectomy, and two studies did not report the specific time of the pfmt therapy initiation.(19,29) incontinence rate at several time points we compiled incontinence rates between studies in the form of or patients experience post-radical prostatectomy incontinence at several time points (table 2 and figure 3). in the first 1-month after radical prostatectomy, we found that the experimental group had a significantly lower risk for incontinence after radical prostatectomy. the significance of this risk difference is was marked by the low or and the width of the confidence interval that does did not exceed one unit [or = 0.58 (95% ci, 0.41–0.81)]. the heterogeneity between studies was also not significant (i2 = 44%, p = 0.09), so we performed calculations using the mantel-haenszel fixed-effect model. at three months postoperatively, the incontinence rate’s difference between the experimental and control groups also remained significant. the experimental group's odds ratio for incontinence compared to the control group at three months postoperatively was 0.57 (95% ci, 0.43–0.74), with no significant heterogeneity between studies (i2 = 48%, p = 0.05). only two studies reported that the control group reported a lower risk of persistent incontinence than the experimental group. (23,27) six months postoperatively, the incidence of urinary incontinence was still significantly lower in the experimental group. at this time point, the experimental group's odds ratio to the control group was 0.38 (95% ci, 0.17–0.83), with significant heterogeneity between studies (i2 = 57%, p = 0.03). only seven studies compared incontinence in the experimental and control groups in the 6th-month post radical prostatectomy, and only two studies reported a significantly higher incidence of persistent urinary incontinence six months postoperatively in the control group. the minimum number of studies involved in the meta-analysis for this six-month time point and the considerable variation in odds ratios between studies might become the cause of high heterogeneity between studies. there were only three studies comparing incontinence author intervention* timing control† n age (yr) duration bales et al. 2000.27 nurse guided graded pfmt 4 times/day oral and verbal advice 47/50 59.3/60.9 6 months with biofeedback 2–4 weeks to surgery to perform pfmt without biofeedback burgio et al. 2006.19 instruction of pfmt with single nr verbal advice to perform 57/55 60.7 ± 6.6/ 6 months session of biofeedback pfmt 60.7 ± 6.6 centemero et al. physiotherapist guided pfmt twice per week verbal instruction of 59/59 60.5 (48–68) 3 months 2010.18 with visual feedback (30 minutes), 2–4 pfmt with visual 57.5 (46–67) weeks preoperatively feedback / collado et al. written instruction of pfmt 3 weeks preoperatively verbal instruction of 87/92 nr 12 months 2013.28 with weekly assisted-biofeedback kegel exercise session and tva dijkstra-eshuis et al. physiotherapist guided pfmt with 30 minutes weekly, physiotherapist guided 65/56 63.7 ± 5.3 12 months 2015.22 biofeedback and es 4 weeks preoperatively pfmt with biofeedback and es geraerts et al. guided pfmt with digital/emg 30 minutes weekly, guided pfmt with 85/85 61.88 (44–73)/12 months 2013.23 biofeedback 3 weeks preoperatively digital/emg biofeedback 62.04 (41–76) lira et al. 2019.25 physiotherapist guided pfmt with 3 times/day 3 weeks postoperative care 16/15 63.53 ± 7.62/ 3 months emg biofeedback preoperatively without pfmt 67.3 ± 5.63 parekh et al. 2003.29 formal instruction with 2 sessions of 2 sessions preoperatively non-formal pfmt 19/19 55.5/61.6 12 months guided pfmt instruction patel et al. 2013.24 physiotherapist guided pfmt with 1–4 sessions (1 hour), physiotherapist guided 152/132 60 (41–76)/ 3 months visual feedback 4 weeks preoperatively pfmt with visual 62 (44–76) feedback sayilan et al. 2018.26 guided pfmt with visual feedback 1–4 sessions (1 hour), no exercise instruction 30/30 63.00 ± 8.61/ 6 months 1 week preoperatively 59.93 ± 6.98 tienforti et al. supervised pfmt with biofeedback 1 day preoperatively oral and written 16/16 67 (60–74)/ 6 months 2012.30 instructions of pfmt 64 (52–74) yoshida et al. physician guided pmft with single 1 month preoperatively verbal instruction of 36/80 66.5 ± 6.2/ 6 months 2018.31 session us-biofeedback pfmt 66.5 ± 5.8 table 1. characteristic of the study included in this systematic review. * interventions were given both before and after surgery; † interventions were given postoperatively only; nr: not reported; tva: transversus abdominis activation; es: electrical stimulation; pfmt: pelvic floor muscle training; emg: electromyographic; us: ultrasound pfmt on incontinence after rp-rangganata et al. vol 18 no 4 july-august 2021 384 events at 12 months post radical prostatectomy.(22,23,29) none of these studies reported significant differences between incontinence events in the experimental and control groups. therefore, we also found something similar in the meta-analysis at that time point. we found no significant difference between the control and experimental groups on experiencing incontinence 12-month after radical prostatectomy, with the experimental group's tendency to be more susceptible [or = 1.31 (95% ci, 0.65-2.63), i2 = 30%, p = 0.44]. we used a funnel plot to predict the probability of publication bias in this meta-analysis (figure 4). the risk of publication bias was relatively high in several outcomes: six months and 12 months after surgery. the low number of studies assessing these outcomes, especially 12 months postoperatively, variations in patient characteristics and outcome measurement, and the inclusion of studies with low quality were thought to cause the high risk of publication bias. subgroup analysis was not carried out as we did not find any relevant characteristic that might influence the outcome. the types of prostatectomy (orp, larp, rarp) did not significantly affect the incontinence rate after prostatectomy.(20,21) discussion persistent and disturbing urinary incontinence after prostatectomy is a commonly reported side effect postoperatively, with an incidence rate of 1% to 40%.(4–6) several studies recommend delaying invasive urinary incontinence therapy at least one year postoperatively. (11,12) therefore, behavioral therapy was chosen in some cases as an alternative.(13) this noninvasive behavioral therapy consists of diet modification, bladder training, pelvic floor muscle training (pfmt), biofeedback, and functional electrical stimulation. apart from being cheap and practical, these therapies have never been reported to cause any side effects.(14) urinary continence depends on the smooth and striated muscle fibers' complex interactions that work sinergically to form a continuity mechanism. some authors are still debating about whether incontinence after prostatectomy is due to effects on the detrusor muscle (bladder) or the sphincter. detrusor overactivity and intrinsic sphincter insufficiency due to sphincteric injury are the most important causes of persistent incontinence after radical prostatectomy. some reports mention that detrusor overactivity is a significant cause of postprostatectomy incontinence,(32,33) others strongly argue that even if other factors play a role, intrinsic sphincter deficiency is the main cause of ui after radical prostatectomy.(34–36) detrusor overactivity is an incontinence pathophysiology that is corrected by pfmt. this method includes exercising specific pelvic floor voluntary muscle contractions using biofeedback, as well as coordinating and determining the time of contraction for increased intraabdominal pressure. specific and repetitive contractions of the pelvic floor muscles can increase strength and efficiency when there is an increase in intraabdominal pressure; thus, this would suppress detrusor overactivity. berghmans and colleagues reported that pelvic floor muscle contractions effectively held the urethra by review 149review 385 author n continence definition types of prostatectomy incontinence (or) quality 1 mo 3 mo 6 mo 12 mo bales et al. 2000 47/50 the use of ≤ 1 pad per day nr 1.33 1.21 1.64 nr fair burgio et al. 2006 57/55 no leakage (3 consecutive nr 0.19 0,37 0.48 nr fair weekly 1-day diaries/7 day diary) centemero et al. 2010 59/59 no urinary leakage in orp 0.32 0.41 nr nr fair bladder diary and a negative stress test collado et al. 2013 87/92 not reported nr nr nr nr nr fair dijkstra-eshuis et al. 65/56 no leakage at all on a larp nr nr nr 2.11 fair 2015 24-hr pad test, pelfis, and khq geraerts et al. 2013 85/85 3 days of 0 g of urine rarp and orp 1.00 1.36 1.00 0.49 fair loss on the 24-h pad test lira et al. 2019 16/15 patient’s perception of orp nr 0.80 nr nr good loss of at least a few drops of urine parekh et al. 2003 19/19 the use of ≤ 1 pad per day nr 0.46 0.27 nr 0.79 fair patel et al. 2013 152/132 patient-reported one pad orp nr 0.61 nr nr poor usage/day sayilan et al. 2018 30/30 iciq-ui score of zero nr 0.29 0.11 0.03 nr good tienforti et al. 2012 16/16 iciq-ui score of zero orp 0.05 0.07 0.04 nr good yoshida et al. 2018 36/80 the number of days nr 0.49 0.48 0.40 nr good requiring a small pad (20 g)/day table 2. systematic review table of the experiment’s outcomes. nr: not reported, orp: open radical prostatectomy, rarp: robot-assisted laparoscopic radical prostatectomy, larp: laparoscopic radical prostatectomy pfmt on incontinence after rp-rangganata et al. providing structural support to the pelvic organs; and pfmt triggers hypertrophy of the urethral muscular muscles thereby increasing mechanical pressure on the urethra, which in turn can prevent detrusor overactivity and prevent urinary incontinence.(37) several clinical studies have proven that the strength of pfm correlates with incontinence and that pfmt increases the strength of pfm can effectively speed up the recovery of incontinence in patients post radical prostatectomy.(17,38) in this study, we found that pfmt carried out before radical prostatectomy significantly reduced the risk of persistent urinary incontinence one month after radical prostatectomy [or = 0.58 (95% ci, 0.41–0.81)], compared to patients who underwent pfmt only after surgery or did not undergo pfmt at all. this reduction in incontinence risk is consistent for up to 6 months postoperatively, in which most studies agree that the experimental group has a much higher rate of continence than the control group. at 12 months postoperatively, the control group could achieve the same continence rate as the experimental group, indicating that almost all patients in both groups had regained continence at 12 months postoperatively [or = 1.31 (95% ci, 0.65–2.63)]. this meta-analysis combined several radical prostatectomy approaches, such as open radical prostatectomy (orp), laparoscopic radical prostatectomy (larp), and robot-assisted (rarp). a combination of these approaches was undertaken to increase the heterogeneity of studies extrapolated in various clinical settings. moreover, several prospective comparative studies found no statistically significant difference in urinary incontinence between post-orp, lrp, or rarp patients.(20,21) our findings are in line with chang et al. (2016), who included six studies in their meta-analysis to determine the effect of pfmt in improving incontinence. the study found that the experimental group's odds were lower in 1, 3, and 6 months postoperatively and were significantly different in the three months postoperatively.(39) some previous meta-analyses reported the opposite of what we found. wang et al. (2014) reported no significant difference in the incidence of the relative risk of persistent incontinence at 1, 3, 6, and 12 months post radical prostatectomy.(40) however, this study included no more than four studies for meta-analysis, and there were only two studies that have good quality. a meta-analysis by wu et al. (2019) found that guided-pfmt effectively reduced the risk of persistent incontinence at all time points, and preoperative guide-pfmt did not provide any benefit to patients. however, this study only included two studies and two-time points (3 and 6 months), and had a high heterogeneity (79%).(41) the impact of incontinence on a patient's quality of life is clearly visible. geraerts et al. (2013) reported a smaller reduction in quality of life in the preoperative exercise group, and all patients in the experimental group expressed satisfaction in receiving pfmt before surgery.(23) research by centemero et al. (2010) showed that 75% of patients in the intervention group reported a high level of satisfaction by starting pfmt before surgery.(18) considering that urinary incontinence is a complication that significantly reduces the quality of life, any intervention that can shorten its duration is worth a try. moreover, patients who receive additional pfmt before surgery show a high level of satisfaction, so pmft can be a noninvasive therapy option that should be recommended to patients before radical prostatectomy. there are several limitations in this meta-analysis that may interfere with the interpretation of final results. we found considerable heterogeneity between studies. this heterogeneity arises due to the large variety of pfmt regimens in each study. for example, pfmt accompanied and guided by a physiotherapist, accompanied by a biofeedback session, is the most widely used treatment regimen, but only 4 of 12 studies used this treatment regimen. one included study did not even include biofeedback in the treatment regimen. the definition of the "intervention group" in each study also varies. three studies considered the intervention as an additional pfmt so that the treatment regimen between the control and experimental groups was the same, with the only difference being the time the therapy was started. moreover, the definition of incontinence and continence of each study was also diverse, and it was impossible to establish a single definition of incontinence as an inclusion criterion. some other things that cause high heterogeneity were surgery techniques, the frequency of pfmt intervention, and the time of initiation of preoperative and postoperative pfmt. our meta-analysis included quite a large number of studies, and most had a low risk of bias, considering that participant blinding was not possible in this study with pico. conclusions pfmt initiated before radical prostatectomy significantly reduced the incidence of urinary incontinence in the first, third, and sixth months postoperatively. at 12 months postoperatively, additional preoperative pfmt did not cause a significant difference in the incidence of urinary incontinence. conflict of interest the authors report no conflict of interest. acknowledgments the first author of the paper (e. rangganata) received a scholarship from indonesia endowment fund for education (lpdp scholarship) from the ministry of finance, republic of indonesia. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2018;68:394– 424. 2. rawla p. epidemiology of prostate cancer. world j oncol. 2019;10:63–89. 3. cooperberg mr, broering jm, litwin ms, lubeck dp, mehta ss, henning jm, et al. the contemporary management of prostate cancer in the united states: lessons from the cancer of the prostate strategic urologic research endeavor (capsure), a national disease registry. j urol. 2004;171:1393–401. 4. krupski tl, saigal cs, litwin ms. variation in continence and potency by definition. j urol. 2003;170:1291–4. pfmt on incontinence after rp-rangganata et al. vol 18 no 4 july-august 2021 386 5. olsson le, salomon l, nadu a, hoznek a, cicco a, saint f, et al. prospective patientreported continence after laparoscopic radical prostatectomy. urology. 2001;58:570–2. 6. rodriguez e, skarecky dw, ahlering te. post-robotic prostatectomy urinary continence: characterization of perfect continence versus occasional dribbling in pad-free men. urology. 2006;67:785–8. 7. talcott ja, rieker p, propert kj, clark ja, kantoff pw, wishnow ki, et al. patientreported impotence and incontinence after nerve-sparing radical prostatectomy. j natl cancer inst. 1997;89:1117–23. 8. braslis k g., santa-cruz c, brickman a l., soloway m s. quality of life 12 months after radical prostatectomy. british journal of urology. 1995;75:48–53. 9. johansson e, steineck g, holmberg l, johansson j-e, nyberg t, ruutu m, et al. long-term quality-of-life outcomes after radical prostatectomy or watchful waiting: the scandinavian prostate cancer group-4 randomised trial. the lancet oncology. 2011;12:891–9. 10. hu jc, elkin ep, pasta dj, lubeck dp, kattan mw, carroll pr, et al. predicting quality of life after radical prostatectomy: results from capsure. j urol. 2004;171:703–7; discussion 707-708. 11. ficarra v, borghesi m, suardi n, de naeyer g, novara g, schatteman p, et al. longterm evaluation of survival, continence and potency (scp) outcomes after robot-assisted radical prostatectomy (rarp). bju int. 2013;112:338–45. 12. frawley hc, dean sg, slade sc, haysmith ejc. is pelvic-floor muscle training a physical therapy or a behavioral therapy? a call to name and report the physical, cognitive, and behavioral elements. phys ther. 2017;97:425–37. 13. meyer p. 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intrinsic sphincteric deficiency in men. j urol. 1996;155:10–3. 35. chao r, mayo me. incontinence after radical prostatectomy: detrusor or sphincter causes. j urol. 1995;154:16–8. 36. majoros a, bach d, keszthelyi a, hamvas a, romics i. urinary incontinence and voiding dysfunction after radical retropubic prostatectomy (prospective urodynamic study). neurourol urodyn. 2006;25:2–7. 37. berghmans lc, hendriks hj, bo k, haysmith ej, de bie ra, van waalwijk van doorn es. conservative treatment of stress urinary incontinence in women: a systematic review of randomized clinical trials. br j urol. 1998;82:181–91. 38. manley l, gibson l, papa n, beharry bk, johnson l, lawrentschuk n, et al. evaluation of pelvic floor muscle strength before and after robotic-assisted radical prostatectomy and early outcomes on urinary continence. j robot surg. 2016;10:331–5. 39. chang ji, lam v, patel mi. preoperative pelvic floor muscle exercise and postprostatectomy incontinence: a systematic review and metaanalysis. eur urol. 2016;69:460–7. 40. wang w, huang qm, liu fp, mao qq. effectiveness of preoperative pelvic floor muscle training for urinary incontinence after radical prostatectomy: a meta-analysis. bmc urol [internet]. 2014 [cited 2020 aug 4];14. available from: https://www.ncbi.nlm.nih. gov/pmc/articles/pmc4274700/ 41. wu m-l-y, wang c-s, xiao q, peng c-h, zeng t-y. the therapeutic effect of pelvic floor muscle exercise on urinary incontinence after radical prostatectomy: a meta-analysis. asian j androl. 2019;21:170–6. pfmt on incontinence after rp-rangganata et al. vol 18 no 4 july-august 2021 388 vol 16 no 03 may-june 2019 246 endourology and stone disease comparison of two different anesthesia methods in patients undergoing percutaneous nephrolithotomy. mehmet solakhan1*, ersan bulut2, mehmet sakıp erturhan3 purpose: the study aims to compare the effectiveness, safety and costs of two different anesthesia methods in percutaneous nephrolithotomy (pcnl) operations. material and method: in our study, data was retrospectively examined of 1657 patients who underwent pcnl due to renal calculi between 2009 and 2017. patients were separated into two groups according to the type of anesthesia; as those who underwent pcnl by general anesthesia (ga) (n = 572) and those under spinal anesthesia(sa) (n = 1085). standard pcnl technique was used in both groups. gender, age, operation duration, period of hospitalization, stone-free ratio, post-operative narcotic analgesic need and complications were compared between these two groups. results: a total of 1657 patients consisting of 1064 (64.2%) male patients and 593 (35.8%) female patients were included in the study. the average age of the all patients was 33.2 ± 12.4 (range 16-74) years. the two groups were similar in terms of mean age, gender, stone size, stone location and body mass index. mean operation time was significantly shorter in the sa group than in the ga group (81.8 ± 33.9 minute vs. 118.2 ± -42.9 minute respectively, p < .001). mean period of hospitalization was remarkable shorter in the sa group than in the ga group (30.0 ± 9.9 hours vs. 38.4 ± 11.2 hours respectively, p < .001). post-operative narcotic analgesic need rate was significantly higher in the ga group than in the sa group (33.4% vs. 10.9%, respectively, p < .001). anesthesia cost was found significantly lower in the sa group than in the ga group (usd 21.3±2.8 vs. usd 83.6 ± 9.5, respectively, p < .001). significant difference was not observed between both groups in terms of stone-free ratio, amount of bleeding, fluoroscopy time, pre-operative and post-operative complications. conclusion: compared to those performed with ga, pcnl performed with sa is a safe, effective and low-cost method. keywords: cost; percutaneous nephrolithotomy; spinal anesthesia introduction percutaneous nephrolithotomy (pcnl) was defined in the treatment of renal calculi for the first time in 1976 by fernström and johansson.(1) a breakthrough in the surgical treatment of renal calculi, this development, together with the technological developments in endourology, became a method preferred against open surgery in the treatment of renal calculi as a minimal invasive method. in time, depending on the miniaturization of the equipment used, pcnl started being implemented on patients in almost all age groups by leading to less complication and less bleeding. pcnl is a treatment method preferred in renal calculi larger than 2 cm, in many renal calculi and staghorn renal calculi.(2) general anesthesia (ga) is the most widely used anesthesia method in pcnl operations.(3) however, there are risks of encountering pulmonary (atelectasia), vascular and neurological complications in ga. especially, under ga, there is the risk of brachial plexus and spinal trauma when giving operative position to the patient. 1urology departmant, gaziantep medicalpark hospital, school of medicine, bahcesehir university, istanbul, turkey. 2urology departmant, school of medicine, bulent ecevit university, zonguldak, turkey. 3urology departmant, school of medicine, gaziantep university, gaziantep, turkey. *correspondence: school of medicine, bahcesehir university, gaziantep medicalpark hospital, istanbul, turkey tel: +90 532 7785068. fax: +90 342 3248860-5026. e-mail: msolakhan@hotmail.com. received december 2017 & accepted february 2018 (4) it is obvious that this risk will increase especially in elder and obese patients. in addition, compared to those receiving spinal anesthesia (sa), patients receiving ga have the risk of staying immobile post-operatively and hence the risk of extended ileus and deep vein thrombosis. however, in pcnl operations performed with sa, as the patient is awake under the first access, risk is minimized for damage that may occur in extremities or nerves during positioning. morever, early mobilization can be achieved in the post-operative period.(4,5) in the examination we conducted on the large retrospective patient series, we evaluated different parameters such as effectiveness, safety, cost and complications in pcnl conducted with ga and sa. materials and methods study population and design a number of 1657 patients undergoing pcnl between march 2009 and april 2017 were included in our study. patients included in the study were those who were planned to undergo pnl due to stone disease and had no anesthetic concerns. the patients with the following characteristics were excluded from the study: patients younger than 16 years old, patients with renal anomaly, patients with solitary kidney, with irreversible coagulopathy, with vertebral and/or skeletal anomaly, with severe cardiac-pulmonary failure. the operations were performed by similar teams and by implementing the same procedure. parameters such as gender, age, body-mass index, operation duration, hospitalization period, pre-operative asa (american society of anesthesia) evaluation, post-operative narcotic analgesia need, stone burden, pre-operative and post-operative hemoglobin, post-operative complication, pre-operative tension tracking, anesthesia cost and fluoroscopy duration were compared between the two groups. (table1 & 2) all patients were administered intravenous prophylactic antibiotic (ceftriaxone 1 gram) treatment. calculi of size 4 mm and smaller were considered as insignificant residue. pre-operative 20mg/kg ringer lactate solution was given to each patient in the sa group in order to prevent hypotension. then, 20 mg 0.5% bupivacaine was given to the subarachnoid cavity in the decubitus position using 27-gauge injection, by entering intervertebral between l2-l3. midazolam (2 mg) was given as intravenous for sedation. midazolam (2 mg) was given as pre-medication to all the patients in the ga group. then 2mg/kg propofol, 1 mg/kg fentanyl and 0.5 mg/kg rocuronium bromide was given for induction. 1-2% isoflurane and 40% nitrous oxide was given with oxygen. then intubation was conducted. surgical technique 5f or 6f ureteral catheter was used for retrograde catheterization in both groups. after the catheter was mounted, the patient was taken to prone position. the kidney was entered with 19 gauge percutaneous injection accompanied with fluoroscopy. amplatz dilators were used for dilation. 30f sheat was placed and 26f nephroscope was used. standard pcnl procedures were implemented. intravenous tenoxicam 20 mg was used for post-operative pain. tramadol or morphine sulphate was used in severe pain cases. erythrocythe suspension was given to patients with hemoglobin values below 10g/dl and who were symptomatic. statistical analysis statistical analyses were performed using spss software version 15. the variables were investigated using visual (histograms, probability plots) and analytical methods (kolmogorov-simirnov/shapiro-wilk’s test) to determine whether or not they are normally distributed. as the patient numbers did not show normal distribution, analyses of the groups were compared using the wilcoxon test and mann-whitney u test. the chisquare test, where appropriate, was used to compare table 1. pre-operative attributes of the patients variables1 spinal anesthesia general anesthesia p gender (m/f) 723/362 341/231 .134 age, (median/y) 34.3 ± 11.1 32.7 ± 13.1 .645 average calculi size,mm2 635.2 ± 304.1 644.5 ± 301.8 .456 stone location 0.76 upper calyx 163 (15%) 98 (17.1%) pelvis and caliyx 507 (46.7%) 237 (41.5%) lower calyx 305 (28.2%) 171 (29.9%) proximal ureter 38 (3.5%) 23 (4%) staghorn 72 (6.6%) 43 (7.5%) stone laterality(left/right) 500/585 354/218 asa2 .92 i 514 (47%) 231 (40%) ii 443 (41%) 235 (41%) iii 128 (12%) 106 (19%) bmi3 kg/m2 25.1 ± 4.6 24.2 ± 3.5 .127 previous stone intervention 117 (10.7) 58 (10.1) .83 open 66 (%6) 31(%5.4) pcnl 51(%4.7) 27(%5) 1data are presented as mean ± sd or number (percent) abbreviations: asa, american society of anesthesia; bmi, body mass index variable1 general anesthesia spinal anesthesia p operation time (min) 118.2 ± -42.9 81.8 ± 33.9 < .001 hospitalization period (hours) 38.4 ± 11.2 30.0 ± 9.9 < .001 fluoroscopy duration (s) 61.2 ± 21.2 63.4 ± 23.4 .86 stone free rate 477(83.4%) 923(85.1%) .48 bleeding amount (ml) 179.2 ± 94.3 166.3 ± 83.4 .32 narcotic analgesia need 191(33.4%) 118(10.9%) < .001 blood transfusion(1 or 2 ü erythrocyte susp.) 24(4.2%) 45(4.1%) .92 drug and consumables cost usd2 83.6 ± 9.5 usd 21.3 ± 2.8 < .001 1 data are presented as mean ± sd or number (percent) abbreviations: usd: american dollar table 2. intra-operative and post-operative attributes in both groups. sa is a safe, effective and low-cost in pcnl-solakhan et al. endourology and stones diseases 247 vol 16 no 03 may-june 2019 248 proportions in different groups. a p-value of less than 0.05 was considered to show a statistically significant result. results a total of 1657 patients consisting of 1064 (64.2%) male patients and 593 (35.8%) female patients were included in the study. demographic attributes of the patients are provided in table 1. statistically significant differences were not observed between the two groups in age, gender, body-mass index, average calculi size, calculi localization, anesthesia risk assessment (asa), and previous stone intervention. (p = .645, p = .134, p = .127, p = .456, p = .76, p = .92, p = .83 respectively). operation results, intra-operative and post-operative situations are given in table 2. operation duration, hospitalization period, post-operative narcotic analgesic need and anesthesia drug-consumables cost was determined to be higher in the ga group (p < .001). post-operative complications were classified according to modified clevian and provided in table 3. complications of spinal anesthesia were observed in 265 (24%) patients during operation. hypotension, nausea and vomiting were the most frequently observed complications. they were taken under control with ephedrine and metoclopramide. serious hypotension developed in 2 patients. the patients were taken to supine position and the operation was continued after blood pressure was corrected with ephedrine and volume expander and colloid fluid. one unit of blood was given to 45 patients due to hypotension and bleeding. anesthesia related complications were observed in 136 (23%) patients in the ga group. hypertension, nausea and vomiting during extubation was observed most frequently. major vascular injury, neurological and visceral organ injury was not observed in both groups. intraoperative hypotension was determined to be higher in the sa group. atelectasia developed in 8 (1.4%) patients in the ga group. they were corrected with breathing exercises. the success of the operation was assessed with abdominal ultrasonography and radiography taken after the surgery in both groups. residual calculi burden was observed to be similar in both groups (p = .48). narcotic analgesia requirement was observed to be higher in the ga group. average drug and material cost used in spinal and general anesthesia was determined as usd 21.3±2.8 and usd 83.6 ± 9.5 respectively (p < .001). the operation duration and the hospitalization period were determined to be significantly lower in the sa group (p < .001). discussion in this large series study that we conducted, we showed that compared to ga, pcnl conducted with sa had many advantages such as short operation duration, short hospitalization period and low cost. pcnl is an effective method applied usually under ga on large, multiple and complex calculi in the upper urinary system.(2) the number of publications on pcnl performed with regional anesthesia is increasing. however, the number of patients has usually remained low in these publications.(4,6,7) the current study aimed to compare pcnl performed with sa and ga in terms of safety and effectiveness in the wide series patient group. although ga is the first preference in many centers, applying ga may be inconvenient in many cases such as chronic obstructive pulmonary disease and cardiovascular diseases.(4,6-10) moreover, ga has disadvantages such as, anaphylaxis development risk and probability of the endotracheal tube getting displaced when going from the lithotomy to prone position.(4) due to high probable complications in morbid obese patients, sa may be a better alternative for these patients.(4,5) stone-free ratios in different studies conducted with different methods were reported as 53.8% and 97%.(4,6,7,11) in our study, stone-free rate table 3. comparison of post-operative complications according to modified clavien classification. modified clavien classification group ga group sa (n=572) (n=1085) no complication 436(76.2%) 820(75.5%) grade 1 40(6.9%) 114(10.5%) fever 28(4.9%) 52(4.8%) hedache 12(2%) 62(5.7%) grade 2 55(9.6%) 89(8.2%) blood transfusion 24(4.2%) 45(4.2%) atelectasi 8(1.4%) 0(%) urinary tract infection 15(2.6%) 28(2.6%) hematuria> 48 h 8(1.4%) 16(1.4%) grade 3a 24(4.2%) 31(2.9%) pneumothrax 0(%) 0(%) hemothorax 0(%) 0(%) prolonged drainage 19(3.3%) 28(2.6%) urinoma 5(0.9%) 3(0.3%) grade 3b 14(2.4%) 26(2.4%) arteriovenous fistula 3(0.5%) 6(0.5%) perirenal haematoma 4(0.7%) 8(0.7%) calculi in the ureter or bladder 7(1.2%) 12(1.2%) perinephric abscess 0(%) 0(%) grade 4a 0(%) 0(%) heart attack 0(%) 0(%) pulmonary embolism 0(%) 0(%) grade 4b 3(0.5%) 5(0.5%) urosepsis 3(0.5%) 5(0.5%) grade 5 0(%) 0(%) death 0(%) 0(%) total 572(100%) 1085(100%) sa is a safe, effective and low-cost in pcnl-solakhan et al. was found as 83.4% in the ga group and 85.1% in the sa group and the difference between the two groups was found to be statistically insignificant. in the studies performed, hospitalization period and operation duration were determined to be different in pcnl performed with sa and ga. in some studies, the hospitalization period was found to be related to the anesthesia technique. shorter hospitalization period was reported in patients to whom regional anesthesia was applied. in these studies, no difference was detected in terms of the type of anesthesia applied and operation and fluoroscopy duration.(6,7,11) in our study, the operation duration and the hospitalization period was determined to be significantly shorter in the sa group. we determined that the operation time was longer in the ga group, specifically, for longer durations of the stages of process of preparation for ga, the period in intubation, giving supine position to the patient in a longer time, extubation time and post-operative waking. also, we observed that early mobilization of patients and starting to eat earlier shortened the hospitalization periods. conducted as prospective randomized, in the study with pcnl performed with spinal and general anesthesia, visual analog pain score and early post-operative analgesia need were found to be significantly lower in the sa group.(7,11,12) in our study, the post-operative narcotic analgesic need was determined as 33.4% in the ga group 10.9% in the sa group and was found to be statistically significant. in the systematic compilation and meta-analysis comparing regional anesthesia and ga in pcnl, it was shown that regional anesthesia offered many advantages such as surgery time, hospitalization period, fluoroscopy duration, blood transfusion, post-operative pain and analgesic requirements. however, it was reported that the anesthesia method implemented had no significant effect on the stone-free and complication ratios.(13) there is a different application for classifying the complications of pcnl. the most frequently used method is the modified clavien classification.(14,15) we used mcc (modified clavien classification) to evaluate the complications in both groups in our own study. headache was the most frequently observed post-operative complication in patients with sa.(16) headache incidence was between 0% and 25% in sa performed with 25-gauge injection.(17) 27–gauge injection was used for sa in our patients. according to mcc, headache was the most frequently observed group 1 complication in the sa group (5.7%). in the study by karakaş et al. it was shown that pre-operative complication risk was higher in patients with high asa score.(18) in our study, it was shown that potential pre-operative problems could be minimized with sa in such patients. basiri et al. stated that intraoperative pain was excessive in patients with sa. although the duration of operation is short in this study, the presence of pain may be related to the anesthesia block made.(19) because with spinal anesthesia you are doing a complete nerve block. we have not encountered such a situation in our own work. 54 (4,9%) patients were very uncomfortable with this position. but they did not feel pain. in our study, we observed that sa cost was lower compared to ga. comparing the costs of the drugs and consumables used for anesthesia, the mean cost in the sa group was determined as usd 21.3 while the mean cost in the ga group was determined as usd 83.6 (p < .001). this cost difference was determined to be even greater in patients with long operation times. adding to this cost the shorter hospitalization duration and the fact that post-operative drugs are less in amount, we can easily say that pcnl performed with sa is very effective in terms of cost. there is a certain operation duration in operations performed with sa. this duration is between 2-6 hours, depending on the drug dosage. therefore, if sa is to be performed in patients with extreme calculi burden or potential prolongation of the operation duration, then epidural catheter should be mounted concomitantly. therefore, patients to use this method should be assessed well and ga method should be preferred in unsuitable patients. of course, the experience of the surgeon and the anesthesia team performing the operation is very important.(20) this experience has great impact on the operation duration. hypotension and pre-operative medication are the issues to pay attention most during sa. conclusions in this study we found that the stone-free rates were similar in operations performed in both anesthesia groups. however, operation duration, hospitalization period, post-operative narcotic analgesic need and cost were found to be significantly lower in the sa group. in the light of this data, it was shown that pnl can be performed more effectively, safely and with lower cost using sa. conflict of interest the authors report no conflict of interest. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. ramakumar s, segura jw. renal calculi. percutaneous management. urol clin north am 2000;27:617-22. 3. lingeman je, matlaga br, evan ap. surgical management of upperurinary tract calculi. in: wein aj, kavoussi lr, novick ac, et al.,eds. campbell-walsh urology. ed. 9th vol. 2. philadelphia: saunders elsevier; 2007:14311507. 4. mehrabi s, shirazi kk. results and complications of spinal anesthesia in percutaneous nephrolithotomy. urol j. 2010;7:22-25. 5. aravantinos e, karatzas a, gravas s, tzortzis v, melekos m. feasibility of percutaneous nephrolithotomy under assisted local anaesthesia: a prospective study on selected patients with upper urinary tract obstruction. eur urol. 2007;51:224-7. 6. kuzgunbay b, turunc t, akin s, et al. percutaneous nephrolithotomy under general versus combined spinal-epidural anesthesia. j endourol. 2009;23:1-5. 7. singh v, sinha rj, sankhwar sn, et al. a prospective randomized study comparing sa is a safe, effective and low-cost in pcnl-solakhan et al. endourology and stones diseases 249 vol 16 no 03 may-june 2019 250 percutaneous nephrolithotomy under combinedspinal-epidural anesthesia with percutaneous nephrolithotomy under general anesthesia. urol int. 2011;87:1-6. 8. rozentsveig v, neulander ez, roussabrov e, et al. anesthetic considerations during percutaneous nephrolithotomy. j.clin anesth. 2007;19:351-5. 9. trivedi ns, robalino j, shevde k. interpleural block: a new technique for regional anaesthesia during percutaneousnephrostomy and nephrolithotomy. can j anaesth.1990;37:479-81. 10. el-husseiny t, moraitis k, maan z, et al. percutaneous endourologic procedures in high-risk patients in the lateral decubitus position under regional anesthesia. j endourol. 2009;23:1603-6. 11. tangpaitoon t, nisoog c, lojanapiwat b. efficacy and safety of percutaneous nephrolithotomy (pcnl): a prospective and randomized study comparing regional epidural anesthesia with general anesthesia. int braz j urol. 2012;38:504-11. 12. karacalar s, bilen cy, sarihasan b, et al. spinal-epidural anesthesia versus general anesthesia in the management of percutaneous nephrolithotripsy. j endourol. 2009;23:15917. 13. pu c, wang j, tang y, et al. the efficacy and safety of percutaneous nephrolithotomy under general versus regional anesthesia: a systematic review and meta-analysis. urolithiasis 2015 ;43:455-66. 14. de la rosette jj, zuazu jr, tsakiris p, et al. prognostic factors and percutaneous nephrolithotomy morbidity: a multivariate analysis of a contemporary series using the clavien classification. j urol. 2008;180:248993. 15. tefekli a, karadag ma, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008;53:184-90. 16. zencirci b. postdural puncture headache and pregabalin. j pain res. 2010;3:11-14. 17. turnbull dk, shepherd db. post-dural puncture headache: pathogenesis, prevention and treatment. br j anaesth. 2003;91:718-29. 18. karakaş hb, çiçekbilek i̇, tok a, alışkan t, akduman b. comparison of intraoperative and postoperative complications based on asa risks in patients who underwent percutaneous nephrolithotomy. turk j urol. 2016 ;42:162-7. 19. basiri a, kashi ah, zeinali m, nasiri mr, valipour r, sarhangnejad r. limitations of spinal anesthesia for patient and surgeon during percutaneous nephrolithotomy. 2018;15(4):164-7. 20. buldu i, tepeler a, kaynar m, karatag sa is a safe, effective and low-cost in pcnl-solakhan et al. t, tosun m, umutogluv t, tanriover h, istanbulluoglu o. comparison of anesthesia methods in treatment of staghorn kidney stones with percutaneous nephrolithotomy. urol j. 2016 ;13(1):2479-83. urological oncology human papilloma virus dna in tumor tissue and urine in different stage of bladder cancer babak javanmard1, mohammad reza barghi2, davar amani3, morteza fallah-karkan4*, mohammad mohsen mazloomfard5 purpose: there are some previous reports on the relationship between bladder cancer pathological grades and hpv detection. to determine the human papilloma virus(hpv) dna in tumor tissue and urine in different stage of bladder cancer conducted this study. materials and methods: polymerase chain reaction (pcr) was used to detect general hpv and hpv16 and 18 subtypes in 110 bladder tumor tissue and urine specimens of patients with tcc of bladder between january 2014 to may 2016 that underwent transurethral resection of bladder tumor. exclusion criteria were genital wart and cases with immunosupression. results: mean age of 110 patients was 61.6±10 years and fourteen (12.7%) of patients were female. pcr for general hpv primer in bladder tumor tissue was positive in 3 (9.4%), 22 (38.6%) and 15 (71.4%) of ta, t1 and t2 bladder tumors, respectively (p < 0.001). pcr for hpv16 in bladder tumor tissue was positive in 2(6.3%), 10 (17.5%) and 13 (61.9%) and pcr for hpv18 in bladder tumor tissue was positive in 1 (3.1%), 14 (24.6%) and 12 (57.1%) of ta, t1 and t2 bladder tumors, respectively (p < 0.001, p < 0.001). thirty seven (33.6%) of urine specimens were positive for general hpv using pcr and hpv16 and 18 subtypes were positive in 17 (15.5%) and 14 (12.7%) of urine specimens, respectively. conclusion: hpv infection may be associated with higher stages and grades of bladder carcinomas. urine sampling for hpv detection is as reliable as tumor tissue sample which could be considered for prognostic and follow up implications. keywords: human papilloma virus; bladder transitional cell carcinoma; cancer grade; cancer stage introduction one of the most common sexually transmitted vi-ruses worldwide are human papilloma viruses (hpvs)(1). many epidemiological studies described that the prevalence of hpv among healthy men, is as high as that among healthy women(2). it has been proposed that hpv is the most important risk factor for development of carcinoma in urogenital system(3). recent researches have shown that prevalence of hpv infection in subjects with bladder transitional cell carcinoma (tcc) varies between 2% to 81.3% (4,5). a study from iran by using polymerase chain reaction (pcr), has showed the presence of hpv in 35.6% of tcc tissue specimens(6). there are some previous re1assistant professor of urology. urology and nephrology research center (unrc), department of urology. shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 2associate professor of urology, urology and nephrology research center (unrc), shahid beheshti university of medical sciences, tehran, iran. 3professor of immunology department of immunology school of medicine, shahid beheshti university of medical sciences, tehran, iran. 4resident of urology. laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran. 5urologist. department of urology. shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. *correspondence: resident of urology. laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran. tel & fax: +98 2122736386, mobile +98 9111863352. e mail: mortezafallah.md@gmail.com. received september 2017 & accepted october 2018 ports on the relationship between pathological grades of bladder carcinoma and hpv detection. tenti et al. has described that hpv prevalence in 79 samples of bladder carcinoma was 32.9%, and hpv infection was frequently found in low-grade (grade 1) tumors compared with high-grade tumors(7). badawi et al. also mentioned that hpv was detected in 44.4% of bladder carcinoma cases, which tended to be frequent in low-grade tumors(8). our previous study showed that hpv was positive in 8 (38.1%) of grade 1, 10 (47.6%) in grade 2, and 3 (14.3%) in grade 3 carcinomas(6). conversely, another study investigated the prevalence of hpv among the bladder wash samples in the patients with bladder carcinoma, and found positive correlation between urology journal/vol 16 no. 4/ july-august 2019/ pp. 352-356. [doi: http://dx.doi.org/10.22037/uj.v0i0.4181] hpv-positive rate and the pathological grade(9). the prognostic implication of hpv infection in bladder cancer survival was suggested by some studies(10,11). the aim of this study was to assess the correlation between urine and bladder tumor tissue hpv infection in different stages(12) of bladder cancer. material and methods patients and samples a total number of 110 patients who underwent transurethral resection of bladder tumor (turbt) between january 2014 to may 2016 with the diagnosis of bladder tcc entered our study. exclusion criteria were genital wart (according to physical examination and medical history) and cases with immunosupression (history of chemotherapy and high dose corticosteroids medication in long time). after insertion of resectoscope sheath, 10 ml of urine was collected and transported to laboratory under sterile condition. bladder tumor tissue specimens after turbt were evaluated histopathologically for grading(12) ,and staging and analyzed by pcr. sample preparation and dna extraction formalin-fixed, paraffin-embedded bladder tumor tissue specimens and urine samples (urine was frozen in molecular biology research center) were collected and transported to molecular biology research center of shahid beheshti university of medical sciences under a well-controlled condition. tissues were finely chopped (5-10 µm) using sterile microtome blades and digested in lyses buffer (0.33 m sucrose, 10 mm tris bas, 5 mm mgcl2, 2% titon x-100) at 37°c for 4 hours. about one ml of each urine sample also centrifuged at 10000 g for 5 min and 100 ul of protease buffer was added to the sediment. phenol-chloroform extraction and ethanol precipitation were performed. the precipitated dna was suspended in distilled water and used for amplification. polymerase chain reaction in this reaction, pcr amplifications were carried out in 50 µl volumes of a reaction mixture containing 1.5 mm mgcl2, 0.1 mm of each dntp, 20 pico mol of each primer, 0.1 µg dna, 1.25 units of taq dan polymerase and 1× pcr buffer. the sequences of primers were; hpv pcr kit a101122 ,hpv-118 detection kit a101192 ,hpv-16 detection kit a101182. initial 4 min denaturation step at 94 °c was followed by 30 cycles of amplification with an automated thermal cycler machine. each cycle included a denaturation step at 94 °c for 30 s, an annealing step at 38 °c for 30 s, and an elongation step at 72 °c for 90 s, with a final elongation step was prolonged for further 4 min. each pcr experiment included samples with reference plasmids as positive control (figure 1) and several samples lacking template dna as negative controls(10,11). the reference plasmids were; hpv 450 bp, hpv-18 331 bp, hpv-16 246 bp and internal control 260 bp. electrophoresis pcr products were analyzed by electrophoresis on 2% agarose gels stained with ethidium bromide and visualized on an ultraviolet imager at 254 nm. statistical analysis statistical analysis was done with spss software (spss inc., chicago, il, version 18.0) using mann-whitney, t-test, kruskal-wallis and fisher's exact tests as appropriate. the level of significance was established at p < 0.05. informed consent was obtained from all patients, also benefits and complications were described for them before entering the study. this study was designed and approved by ethical committee of shahid beheshti university of medical sciences. results ninety six (87%) of patients were male, the mean (±sd) age was 61.6 ± 10 years (ranged between 32 to 85 years). forty four (40%) patients had previous history of bcg therapy. sixty eight (62%) patients were cigarette smoker. according to the pathologic pt stage, human papillomavirus dna in bladder tumor-javanmard et al. table 1. the association between patient characteristics and grade and stage of bladder tumor age ( ± sd) male (%) cigarette smoker (%) bcg therapy (%) total (%) stage pta 59.9 ± 8.8 26 (81.3) 16 (50) 10 (31.3) 32 (100) pt1 61.3 ± 11 50 (87.7) 40 (70.2) 22 (38.6) 57 (100) pt2 65 ± 9.2 20 (95.2) 12 (57.1) 12 (57.1) 21 (100) p value 0.2* 0.35** 0.17** 0.18** grade low grade 61.8 ± 11.1 50 (83.3) 38 (63.3) 18 (30) 60 (100) high grade 61.3 ± 8.9 46 (92) 30 (60) 26 (52) 50 (100) p value 0.79*** 0.25** 0.72** 0.019** *kruskal-wallis test,** fisher’s exact test, ***t-test figure 1. pcr experiment included samples with reference plasmids as positive controland several samples lacking template dna as contamination controls. urological oncology 353 cases were classified into: pta in 32 (29.2%), pt1 in 57 (51.8%) and pt2 in 21 (19.1%). regarding nuclear grading, 60 cases (54.5%) were low grade (low malignant potential and low grade) tcc. pcr for general hpv primer was positive in 40 (36.4%) of bladder tumor tissue specimens. twenty five (22.7%) and 27 (24.5%) of subjects had positive results for hpv 16 and 18 subtypes, respectively. thirty seven (33.6%) of urine specimens were positive for general hpv primer using pcr and hpv16 and 18 subtypes were positive in 17 (15.5%) and 14 (12.7%) of urine specimens, respectively. table 1 shows the association between patient characteristics and grade and stage of bladder tumor. our data showed no relation between age, sex, cigarette smoking and grade and stage of bladder tcc. although history of bcg therapy was associated with histological grade of bladder tcc (p = .019). there was not any association between history of bcg therapy and pcr for general hpv primer in bladder tumor tissue (p = .23). table 1. the association between patient characteristics and grade and stage of bladder tumor. association between stage and grade of bladder tcc and hpv, hpv 16 and 18 infections are shown in table 2. discussion bladder cancer is one of the most common cancer in the worldwide(13). therefore, management of predisposing factors, early detection and appropriate treatment of bladder cancer is crucial for improved patient prognosis and survival(14-17). correlation between bladder tumors and hpv infection first reported in 1988 by kitamura(18). afterward, many studies have been designed to evaluate the association between hpv infection and urinary tract neoplasms with controversial conclusions. it has been shown that detection of hpv dna is largely dependent on a series of technical factors such as tissue fixation, dna preparation and amplification conditions (19). in our study pcr for general hpv in bladder tumor tissue was positive in 3 (9.4%), 22 (38.6%) and 15 (71.4%) of ta, t1 and t2 bladder tumors, respectively (p < .001). pcr for hpv16 in bladder tumor tissue was positive in 2(6.3%), 10 (17.5%) and 13 (61.9%) and pcr for hpv18 in bladder tumor tissue was positive in 1 (3.1%), 14 (24.6%) and 12 (57.1%) of ta, t1 and t2 bladder tumors, respectively (p < .001, p < .001). tenti et al.(7) revealed overall rate of hpv dna of 32.9%, and the prevalence of hpv 16 and/or hpv 18 infection was significantly higher in low-grade than in high-grade tumors. lopez-beltran et al.(20) studied the samples of a small group of 76 consecutive patients with tcc and determined hpv infection by pcr using dna primers for hpv types 6, 11, 16, and 18 only. they found a correlation between higher grades of bladder cancer and hpv 16 dna. in another study, furihata et al.(11) studied 90 patients with tcc and determined the presence of hpv dna types 16, 18, and 33 by in situ hybridization. they showed a significantly worse tumor behavior and survival in patients with tumors positive for hpv dna and/or p53 protein. in year 2007, moonen and colageous(9) suggested a positive trend in the correlation between tumor grade/stage and high-risk type hpv infection. melchers and coworker demonstrate that hpv can be transported by the urine, probably in exfoliated hpv-infected cells. a similar mechanism may occur during ejaculation, allowing sexual transmission of hpv viruses harbored in the ceils of the male genital tract(21). forslund et al.(22) showed that the frequency of hpv dna-positive urine samples is lower than that of urethra or cervix samples collected in parallel. he also revealed fair to excellent agreement between hpv dna results for urine and urethra specimens and poor to fair agreement for parallel cervix specimens. in another study, the sensitivity of the urine pcr assay for detecting cervical hpv infection among inner city adolescents was 82%(23). as we found in our study, there was fair agreement between general hpv primer dna detection in urine and bladder tumor tissues of patients with tcc. however, the relationship between urine hpv 16 and 18 dna and bladder tumor tissues of these patients were not as good as general hpv. investigations show that hpv may have a prominant role in progression of tccs to higher stages and/or grades by inactivation of the tumor suppressor prb, abnormal p53 protein accumulation, centrosome amplification and lagging chromosomes during mitosis and other unknown mechanisms(24,25). the most important limitation of this research is the lack of examination of radical cystectomy specimens. another limitation is the inadequate follow-up of the patient and the evaluation of the tumor's behavior in response to various treatments. conclusions the prevalence of hpv dna in patients with bladder tcc is relatively high and associated with higher stage and grade of the disease; so, it can be used as a predictor table 2. association between stage and grade of bladder tcc and hpv, hpv 16 and 18 infections hpv 16 dna hpv 18 dna general hpv dna total stage pta 2 (6.3%) 1 (3.1%) 3 (9.4%) 32 (100%) pt1 10 (17.5%) 14 (24.6%) 22 (38.6%) 57 (100%) pt2 13 (61.9%) 12 (57.1%) 15 (71.4%) 21 (100%) p value* < 0.001 < 0.001 < 0.001 grade low grade 3 (5%) 3 (5%) 9 (15%) 60 (100%) high grade 22 (44%) 24 (48%) 31 (62%) 50 (100%) p value* < 0.001 < 0.001 < 0.001 * fisher’s exact test human papillomavirus dna in bladder tumor-javanmard et al. vol 16 no 04 july-august 2019 354 of bladder tumor behavior. urine sampling for hpv detection is noninvasive and simple approach and is as reliable as tumor tissue sample which could be considered for prognostic and follow up implications. acknowledgments the authors would like to thank all nursing of urology ward in shohada-e-tajrish hospital. conflict of interest the authors declare no conflict of interest. references 1. tolstov y, hadaschik b, pahernik s, hohenfellner m, duensing s, editors. human papillomaviruses in urological malignancies: a critical assessment. urologic oncology: seminars and original investigations; 2014: elsevier. 2. dunne ef, nielson cm, stone km, markowitz le, giuliano ar. prevalence of hpv infection among men: a systematic review of the literature. j infect dis. 2006;194:1044-57. 3. abdollahzadeh p, madani sh, khazaei s, sajadimajd s, izadi b, najafi f. association between human papillomavirus and transitional cell carcinoma of the bladder. urol j. 2017;14(6):5047-50. 4. barghi mr, rahjoo t, borghei m, hosseinimoghaddam sm, amani d, farrokhi b. association between the evidence of human papilloma virus infection in bladder transitional cell carcinoma in men and cervical dysplasia in their spouses. arch iran med. 2012;15(9):572. 5. shigehara k, sasagawa t, namiki m. human papillomavirus infection and pathogenesis in urothelial cells: a mini-review. j j infect chemother. 2014;20(12):741-7. 6. barghi m, hajimohammadmehdiarbab a, moghaddam sh, kazemi b. correlation between human papillomavirus infection and bladder transitional cell carcinoma. bmc infect dis. 2005;5(1):102. 7. tenti p, zappatore r, romagnoli s, civardi e, giunta p, scelsi r, et al. p53 overexpression and human papillomavirus infection in transitional cell carcinoma of the urinary bladder: correlation with histological parameters. j pathol. 1996;178(1):65-70. 8. badawi h, ahmed h, ismail a, diab m, moubarak m, badawy a, et al. role of human papillomavirus types 16, 18, and 52 in recurrent cystitis and urinary bladder cancer among egyptian patients. medscape j med. 2008;10(10):232. 9. moonen pm, bakkers jm, kiemeney la, schalken ja, melchers wj, witjes ja, et al. human papilloma virus dna and p53 mutation analysis on bladder washes in relation to clinical outcome of bladder cancer. eur urol. 2007;52(2):464-9. 10. anwar k, naiki h, nakakuki k, inuzuka m. high frequency of human papillomavirus infection in carcinoma of the urinary bladder. cancer. 1992;70(7):1967-73. 11. furihata m, inoue k, ohtsuki y, hashimoto h, terao n, fujita y. high-risk human papillomavirus infections and overexpression of p53 protein as prognostic indicators in transitional cell carcinoma of the urinary bladder. cancer res. 1993;53(20):4823-7. 12. humphrey pa, moch h, cubilla al, ulbright tm, reuter ve. the 2016 who classification of tumours of the urinary system and male genital organs—part b: prostate and bladder tumours. eur urol. 2016;70(1):106-19. 13. mohammadi m, hosseini j, karkan mf, hedayati m. serum resistin levels in bladder cancer. men's health journal.2(1):5. 14. pelucchi c, bosetti c, negri e, malvezzi m, la vecchia c. mechanisms of disease: the epidemiology of bladder cancer. nat clin pract urol. 2006;3(6):327. 15. razzaghi mr, karkan mf, ghiasy s, javanmard b. laser application in iran urology: a narrative review. j lasers med sci. 2018;9(1):1. 16. janković s, radosavljević v. risk factors for bladder cancer. tumori. 2007;93(1):4-12. 17. al-zalabani ah, stewart kf, wesselius a, schols am, zeegers mp. modifiable risk factors for the prevention of bladder cancer: a systematic review of meta-analyses. eur j epidemiol. 2016;31(9):811-51. 18. kitamura t, yogo y, ueki t, murakami s, aso y. presence of human papillomavirus type 16 genome in bladder carcinoma in situ of a patient with mild immunodeficiency. cancer res. 1988;48(24 pt 1):7207-11. 19. larue h, simoneau m, fradet y. human papillomavirus in transitional cell carcinoma of the urinary bladder. clin cancer res. 1995;1(4):435-40. 20. lopez-beltran a, escudero al, vicioso l, munoz e, carrasco jc. human papillomavirus dna as a factor determining the survival of bladder cancer patients. br j cancer. 1996;73(1):124-7. 21. melchers wj, schift r, stolz e, lindeman j, quint wg. human papillomavirus detection in urine samples from male patients by the polymerase chain reaction. j clin microbiol. 1989;27(8):1711-4. 22. forslund o, hansson bg, rymark p, bjerre b. human papillomavirus dna in urine samples compared with that in simultaneously collected urethra and cervix samples. j clin microbiol. 1993;31(8):1975-9. 23. jacobson dl, womack sd, peralta l, zenilman jm, feroli k, maehr j, et al. human papillomavirus dna in bladder tumor-javanmard et al. urological oncology 355 concordance of human papillomavirus in the cervix and urine among inner city adolescents. pediatr infect dis j. 2000;19(8):722-8. 24. fan x, liu y, chen jj. activation of c-myc contributes to bovine papillomavirus type 1 e7-induced cell proliferation. j biol chem. 2003. 25. patel d, incassati a, wang n, mccance dj. human papillomavirus type 16 e6 and e7 cause polyploidy in human keratinocytes and up-regulation of g2-m-phase proteins. cancer res. 2004;64(4):1299-306. human papillomavirus dna in bladder tumor-javanmard et al. vol 16 no 04 july-august 2019 356 march-april 2018 reviewer of the issue matjaž kopač matjaž kopač april 2018 dr. matjaž kopač is currently an assisstant professor in the department of nephrology in the university medical centre ljubljana. below is his career history in his own words: i graduated at faculty of medicine, ljubljana university, in 1999 and was awarded the student's prešeren award for a research on genetic susceptibillity for lung cancer in slovenian population in 1997. post-graduate education: i completed master of science degree, entitled induced sputum in asthma in 2002. i was pediatric nephrology research fellow and resident of pediatrics at university medical centre ljubljana between 2002 and 2007 and completed the doctor of science thesis, entitled indirect voiding urosonography for detecting vesicoureteral reflux in children during that time. i was appointed for assistant professor in pediatrics in 2013 (all at faculty of medicine, ljubljana university). special training: i completed international course in ultrasonography of the urinary tract at the university medical centre ljubljana, slovenia, under the auspices of jefferson ultrasound research and education institute in 2002 and internship in pediatric radiology with emphasis on ultrasonography of the urinary tract at the division of pediatric radiology at the medical university graz (austria) in 2007. i also attended several other regional courses on ultrasonography of the urinary tract recently since i regularly perform these investigations in children. i completed practical training in dialysis at the dialysis centre, university medical centre ljubljana in 2004, and attended several dialysis courses afterwards. i completed observership with training in pediatric nephrology (3 months) at the nephrology division, department of pediatrics, at the children's hospital of philadelphia (usa) in 2008. i actively participated at pediatric urology (in 2003), pediatric nephrology (in 2006) and pediatric nephrology and endocrinology (in 2011 and 2014) seminars in salzburg (austria) and received the certificate for academic excellence (in 2011 and 2014). i completed urodynamic course at bristol urological institute / warrell unit manchester (uk) in 2013 and have regularly performed urodynamic investigations in children since then. i have published more than thirty papers in slovenian and international peer reviewed journals. »being a reviewer for urology journal is an honor, as you are allowed to contribute to the scientific level of this journal. the urology journal has a unique approach with a review form that enables concise and systematic review process. careful evaluation of scientific articles is an important scholarly contribution and a gratifying duty in academics. peer review is a vital process for any journal and enables publication of innovative research that meets the highest standards of quality.« kopač, was chosen by editorial board of the urology journal for his valuable and timely review of manuscript”. vol 16 no 04 september-october 2019 417 endourology and stone disease the prevalence of urinary tract infection following flexible ureterenoscopy and the associated risk factors barbaros baseskioglu 1* purpose: to evaluate the risk factors for urinary tract infection (uti) after retrograde intrarenal surgery (rirs). materials and methods: a retrospective evaluation of the records of patients who underwent rirs from january 2013 to september 2016 was performed. all interventions were done by the same surgeon and by applying the same technique. result: 111 patients were included in the study with a mean age of 47.5 years (range: 14-84 years). postoperative infection rate was 12.6% (n= 14). swl, preoperative double j stent insertion, localization, gender, and the operation side had no impact on origination of infectious complications (p > .05 for all). preoperative infection history (p = .002, or=7.96, %95ci: 2.030.5), comorbidity score (p = .008, or=7.79, ci%95: 1.735.5), and residual fragments (p = .045, or=5.12, ci%95: 1.03 – 25.36) were found to be the significant risk parameters of postoperative infectious complications. conclusion: to reduce uti complications, it is necessary to pay attention to patients with comorbidities, prescribe appropriate prophylactic antibiotic therapy for those who have urinary tract infection history and help patients to achieve stone free status. keywords: infection; intrarenal surgery; kidney stone; retrograde intrarenal surgery introduction treatment of urinary tract stones changed from open surgery to endourological procedures in the last decade according to the strategy ‘to achieve maximum stone extraction with minimal morbidity’. minimal invasive procedural choices for ureteral stones were ureteroscopy (urs) and shock-wave lithotripsy (swl) and for kidney stones; percutaneous nephrolithotomy (pnl), retrograde intrarenal surgery (rirs) and swl. with the increase in technological developments, rirs has been accepted as an effective treatment option for stones smaller than 20mm and selected cases.(1) rirs has potential advantages; lower morbidity than percutaneous procedures and higher stone free rates than swl. (2) the rirs procedure is a safe treatment option for renal stones of ≤ 2cm with less pain and higher success rate at first session compared to swl.(3) however urinary tract infections and urosepsis are the main morbidity and mortality causes after rirs and pcnl. antibiotic prophylaxis is strongly recommended in clinical practice.(4) uti is one of the most common morbidities of pcnl, occurring in 21–39.8% of patients.(5) this wide and high percent of infectious complications occurs despite antibiotic prophylaxis. infectious com¬plication rates including fever and sepsis in patients undergoing rirs have been reported to vary 1acıbadem university fac of med; department of urology and osmangazi univ fac of med; department of urology. *correspondence: assistant professor, acıbadem university,faculty of medicine, department of urology eskisehir, turkey. tel: +90 505 497 62 86. email: barbaroza@gmail.com. received december 2017 & accepted may 2018 from 2% to 28% and from 3% to %5, respectively.(6) although there have been attemps to reduce uti after rirs in literature, still controversial issues exist and to lower the infection rates, determination of risk factors could be an important issue as much as preoperative negative urine culture. predicting the risk factor may change treatment policy. in this retrospective study our purpose was to evaluate the risk factors for infectious complications after rirs. materials and methods study population patients who underwent rirs for kidney stones from january 2013 to september 2016 in our clinic were retrospectively reviewed. demographic, pre and postoperative data were included in the study. patients’ data were reviewed in terms of age, sex, stone localization, stone diameter, stone-free status, preoperative infection history and post-operative residual stone. charlson comorbidity index was used to standardize the comorbidities. patients were grouped whether uti occurred or did not occur. the stones were evaluated with computerized tomography and the longest two axis of the stone measured (mm2) was recorded as the stone surface area. for multiple stones, total diameter was recorded. in all cases with obstruction due to uretropelvic junction or urology journal/vol 16 no. 5/ september-october 2019/ pp. 439-442. [doi: 10.22037/uj.v0i0.4340] upper urinary tract stone, a double j stent was inserted and procedure was postponed. stone-free status was defined as either no residue or residue smaller than 4 mm in postoperative evaluation. preoperative sterile urine was ‘a must’ before procedure. inclusion and exclusion criteria inclusion criteria was presence of renal stones ≤ 2 cm in diameter and patients with 2-3cm stones who preferred rirs. the exclusion criteria was immune compromised patients, kidney anomalies, history of previous renal surgery or swl, uncontrolled coagulopathies, pregnancy and renal failure (serum creati¬nine ≥ 1.5mg/dl), urinary tract infection (positive urine culture) and insufficient medical records. unsuccessful ureteral access sheath insertion was also an exclusion criteria due to the increased pressure effect on renal pelvis which may increase infection risk. procedures all procedures were done by same surgeon (bb) in a standard fashion. the procedure was performed under general anesthesia. patient was positioned from trendelenburg position to lithotomy position. orifices were checked using a 22fr. cystoscope. following insertion of a hydrophilic guideline catheter, a 9.5-11.5fr. (plasti-med, turkey) ureteral access sheath was inserted under fluoroscopic guidance. 7.5fr. flexible ureteroscope (karl storz,germany) was used to access the collecting system. different laser energy were used based on the stone characteristics during operation. a 200 µm laser probe was used. spontaneous irrigation (about 40 cm height) was the method and irrigation pump was not used in all cases. peroperative 400 mg ciprofloxacin intravenously was used as prophylaxis in all cases and was continued for 5 days orally. evaluations postoperative urine culture was performed in all cases with fever which was defined as >38c. according to the clavien grading system, all infectious complications were recorded. sepsis was defined as the criteria by sepsis definitions conference(7) all patients were discharged within 24 hours after surgery. prolonged hospital stay was related to ic. all patients were evaluated with urine analysis, kub graphy and ultrasound one month after operation. this retrospective study was approved by the local ethic committee (26.12.2016/02). statistical analysis all analysis was done by using ibm spss statistics 21.0. continuous and categorical variables were defined as mean ± standard deviation and percent (%), respectively. pearson chi-square, pearson exact chi-square, fisher’s exact chi-square and yates chi-square were used for significant differences of groups. mann-whitney u test was used when distribution between stone size and infection for normality test failed. binary logistic regression test was the choice to find the risk factors with stepwise method. p < 0.05 was defined as statistiinfectious complications after flexible ureterenoscopy-baseskioglu endourology and stones diseases 440 table 1. demographic data of patients (n= 111) postoperative infection p negative positive gender male 57 (% 58.8) 8 (% 57.1) .908* female 40 (% 41.2) 6 (% 42.9) symptom pain 71 (% 73.2) 7 (% 50.0) .301** hematuria 5 (% 5.2) 1 (% 7.1) infection 1 (% 1.0) 1 (% 7.1) incidenatal 17 (% 17.5) 4 (% 28.6) akd 2 (% 2.1) 1 (% 7.1) ckd 1 (% 1.0) 0 (% 0.0) opacity opaque 85 (% 87.6) 13 (% 92.9) 1.000** semi-opaque 3 (% 3.1) 0 (% 0.0) non-opaque 9 (% 9.3) 1 (% 7.1) side right 43 (% 44.3) 7 (% 50.0) .812** left 31 (% 32.0) 5 (% 35.7) bilateral 23 (% 23.7) 2 (% 14.3) uti history negative 86 (% 88.7) 7 (% 50.0) .002*** positive 11 (% 11.3) 7 (% 50.0) swl negative 56 (% 57.7) 8 (% 57.1) .967* positive 41 (% 42.3) 6 (% 42.9) location upper calyx 11 (% 11.3) 2 (% 14.3) .137** mid calyx 10 (% 10.3) 1 (% 7.1) lower calyx 23 (% 23.7) 3 (% 21.4) pelvis 27 (% 27.8) 6 (% 42.9) up 13 (% 13.4) 0 (% 0.0) proximalureter 13 (% 13.4) 1 (% 7.1) mid ureter 0 (% 0.0) 1 (% 7.1) peop djs negative 53 (% 54.6) 5 (% 35.7) .299**** positive 44 (% 45.4) 9 (% 64.3) residu negative 87 (% 89.7) 10 (% 71.4) .076*** positive 10 (% 10.3) 4 (% 28.6) comorbidity <= 3 86 (% 88.7) 9 (%64.3) .030*** >= 4 11 (%11.3) 5 (%35.7) mean ± sd. median (q1 – q3) p postoperative infection negative positive stone surface area 142.73 ± 109.23 224.28 ± 272.50 100.00 (90.00 – 160.00) 150.00 (92.50 – 237.50) .363***** *pearson chi-square test,** pearson exact chi-square test, *** fisher’s exact chi-square test, **** yates chisquare test cally significant. results one hundred eleven patients were enrolled in the study. the mean age of patients was 47.5 (range: 14-84 ). demographic data is summarized in table 1. infectious complications were reported in 14 ( 12.6% ) patients. 8 of 14 patients had only fever (clavien 1), 4 ( .03% ) patients had positive urine culture (clavien 2), and two patients ( .018% ) had sepsis (clavien 4a). early antibiotics and antipyretics were given immediately to these patients except two patients who had sepsis. these two patients were treated in intensive care unit with vasoconstrictor agents. one of those patients had acute tubular necrosis which revealed after treatment. mortality was not observed. swl, preoperative double j stent insertion, localization, gender, operation side and residual fragments had no impact on origination of infectious complications ( p > .05 for all). operation time for patients without infection and with infection were 49.12 ± 11.63 minutes and 52.85 ± 8.7 minutes, respectively (p = .252). pre-operative infection history, comorbidity score and residual fragments were found responsible for postoperative infectious complications (p =.001; p =.016; p = .04, respectively) (table 2). discussion the first rirs using a flexible ureterorenoscope was described in 1990 by fuchs et al.(8) after advances in technology especially in laser technology and scopes, rirs was accepted as an alternative treatment method to swl and pnl for kidney stone management in eau guidelines. the main advantage of rirs is minimal morbidity compared to pnl and a higher stone free rate than swl.(9) postoperative infections are the most common adverse event after rirs. sometimes prophylactic antibiotics are not enough to solve the problem. the rate of infectious complications in this study was 12.6%. in a study by croes, this rate was lower than our study ( 2.2% ). however rigid ureterorenoscopy series were also included in the croes study which might have lowered these rates(10). also groups were not homogenous such that only 16% of patients underwent rirs. berardinelli et al. confirmed our opinion with their study. uti rates were higher in the latter study compared to croes (7.7 %). this rate was also lower than our study but this was a multi-center study. operation techniques and antibiotic prophylaxis were not the same and also antibiotics were continued for five days. similarly, uti was 8.3% in a retrospective study by fan et al.(11) interestingly, systemic inflammatory response syndrome (sirs) rate was 8.1% in another study.(12) in our study, this rate was .018 %. early antibiotic administration and aggressive fluid therapy might explain why we had lower rates. preoperative infection history, comorbidity score and residual fragments were the risk factors of this study. although residual stone alone was not a risk factor; after binary logistic regression test it became a significant risk factor. this means especially in patients with preoperative infection history, and comorbidities you should give much more effort not to leave residual stones. similarly; comorbidities, history of recurrent uti were the examples of risk factors according to grabe et al.(13) in another study, fan et al. found that operation time, infection stone and pyuria were significant parameters for uti.(11) stone burden, infection stone, irrigation with a high flow rate and small caliber sheaths were found to be responsible to develop sirs after rirs.(12) unfortunately, we could not include stone types because of lack of data. in the aforementioned study about 20 % of stones was struvite stones. this may be the reason for increased sirs rate compared to our study (8.1% vs .018%). in our study we tried to analyze a homogenous group of patients. technique, sheaths and sheath calibers were all the same and standard. we tried to exclude the intrarenal pressure to find the risk factors. increased intra-renal pressures were associated with uti in the study above and also in literature(14). inversely to all these data above, berardinelli et al. could not identify any predictors of ic. lack of stone analysis and the retrospective design were the main limitations of this study. conclusions preoperative infection history, comorbidity score and residual fragments were found to predict postoperative uti risk in this study. antibiotic prophylaxis regimens can be determined according to previous microbial agent in patients with infection history. although active stone removal is controversial in literature; trying to remove all fragments in patients with comorbidities and infection history may lower uti risk. conflict on interest none declared. references 1. guisti g, proietti s, peschechara r et al. sky is no limit for ureteroscopy: extending the indications and special circumstances. world j urol 2015;33: 309-14 2. ising s, labenski h, baltes s et al. flexible ureterorenoscopy for treatment of kidney stones: establishment as primary standard therapy in a tertiary stone center. urol int. 2015;95:329-35 3. javanmard b, kashi ah, mazloomfard mm, ansari jafari a, arefanian s. retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j. 2016;13:2823-8 4. samplaski mk, irwin bh, desai m. lessinvasive ways to remove stones from the kidneys and ureters. cleve cain j med 2009; 76: 592-8 5. michel ms, trojan l, rassweiler table 2. binary logistic regression (stepwise method elimination) analysis output. p odds ratio 95% ci lower upper uti history .002 7.966 2.077 30.550 comorbidity .008 7.797 1.708 35.593 residue .045 5.125 1.036 25.368 constant <.001 0.037 infectious complications after flexible ureterenoscopy-baseskioglu vol 16 no 04 september-october 2019 441 jj. complications in percutaneous nephrolithotomy. eur urol 2007: 51:899 6. senocak c, ozcan c, sahin t et al. risk factors of infectious complications after flexible uretero-renoscopy with laser lithotripsy. urol j. 2018 jan 4. doi: 10.22037/ uj.v0i0.3967 7. levy mm, fink mp, marshall jc et al scm/ esicm/accp/ats/sis international sepsis definitons conference. crit. care med. 2003;31: 1250-6 8. fuchs gj, fuchs am. flexible endoscopy of the upper urinary tract. a newminimally invasive method for diagnosis and treatment. urologe a. 1990 ;29:313-20 9. türk c, petřík a, sarica k et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016; 69: 468-74 10. martov a, gravas s, etemadian m et al. postoperative infection rates in patients with a negative baseline urine culture undergoing ureteroscopic stone removal: a matched casecontrol analysis on antibiotic prophylaxis from the croes urs global study. j endourol. 2015 ;29 :171-80 11. fan s, gong b, hao z et al. risk factors of infectious complications following flexible ureteroscope with a holmium laser: a retrospective study. int j clin exp med. 2015;8:11252-9. 12. zhong w, leto g, wang l, zeng g. systemic inflammatory response syndrome after flexible ureteroscopic lithotripsy: a study of risk factors. j endourol. 2015;29:25-8 13. grabe m, botto h, cek m et al. preoperative assessment of the patient and risk factors for infectious complications and tentative classification of surgical field contamination of urological procedures. world j urol. 2012;30:39-50 14. zhong w, zeng g, wu k et al. does a smaller tract in percutaneous nephrolithotomy contribute to high renal pelvic pressure and postoperative fever? j endourol. 2008 ;22:2147-51 endourology and stones diseases 442 infectious complications after flexible ureterenoscopy-baseskioglu appendixes 314 urology journal vol 6 no 4 autumn 2009 a abdi h, see nouralizadeh a, 176 abdollahi a, ayati m. frequency and outcome of metaplasia in needle biopsies of prostate and its relation with clinical findings, 109 abdollahifard s, see bohlouli a, 194 abolbashari m, see shamsa a, 170 achakzai i, see ather mh, 14 adamopoulos vm, see papadimitriou vd, 223 afsar f, see nowroozi mr, 27 aghamir smk, alizadeh f, meysamie a, assefi rad s, edrisi l. sterile water versus isotonic saline solution as irrigation fluid in percutaneous nephrolithotomy, 249 aghamohammadi h, mehrabi s, mohammad ali beigi f. prevention of bradycardia by atropine sulfate during urological laparoscopic surgery: a randomized controlled trial, 92 agrawal s, see munjal k, 87 aherne n. re: conservative management of early bladder rupture after postoperative radiotherapy for prostate cancer, 145 ahmadieh a, see djaladat h, 9 ahuja a, aulakh bs, cheena dk, garg r, singla s, budhiraja s. aspergillus fungal balls causing ureteral obstruction, 127 akbarpour m, see salehi m, 301 alizadeh f, see aghamir smk, 249 aminsharifi a, see simforoosh n, 163 amoueian s, see tavakkoli tabassi k, 199 arrabal-martin m, see arrabal-polo ma, 50 arrabal-polo ma, arrabal-martin m, palaoyago f, jiménez-pacheco a, garcia-galvis of, zuluaga-gomez a. wunderlich syndrome from a malignant epithelioid angiomyolipoma, 50 arshadi h, dianat ss, ganjehei l. accuracy of radiological features for predicting extracorporeal shock wave lithotripsy success for treatment of kidney calculi, 88 asgari m, see ghafoori m, 182 assari s, see soroush mr, 114 assefi rad s, see aghamir smk, 249 author index to volume 6 ather mh, faizullah k, achakzai i, siwani r, irani f. alternate and incidental diagnoses on noncontrast-enhanced spiral computed tomography for acute flank pain, 14 ather mh, zaidi m. predicting recurrence and progression in non-muscle-invasive bladder cancer using european organization of research and treatment of cancer risk tables, 189 aulakh bs, see ahuja a, 127 ayati m, see nowroozi mr, 27 ayati m, see abdollahi a, 109 b babaei ar, safarinejad mr, kolahi aa. penile revascularization for erectile dysfunction: a systematic review and metaanalysis of effectiveness and complications, 1 baharvand h, see sharifiaghdas f, 283 baker la, see cost ng, 220 barkam m, see ketabchi aa, 214 basiri a, mohammadi sichani m. supine percutaneous nephrolithotomy, is it really effective? a systematic review of literature, 73 basiri a, see nouralizadeh a, 176 basiri a, see simforoosh n, 276 bohlouli a, tarzamni mk, zomorrodi a, abdollahifard s, hashemi b, nezami n. postnephrectomy changes in doppler indexes of remnant kidney in unrelated kidney donors, 194 budhiraja s, see ahuja a, 127 c cheena dk, see ahuja a, 127 christoulakis i, see efthimiou i, 60 cost ng, sanchez fs, weinberg ag, koral k, baker la. neurofibromatosis presenting as painless clitoromegaly, 220 d d’ancona ca, see prudente a, 96 dadkhah a, see mohammadi sichani m, 298 dahm p, see singh jc, 245 author index to volume 6 315urology journal vol 6 no 4 autumn 2009 dalela d, see goel a, 40 das p, see shaik ap, 78 denardi f, see matheus we, 260 desai m, see sharma r, 254 dianat ss, see arshadi h, 88 djaladat h, mahouri k, khalifeh shooshtary f, ahmadieh a. effect of rowatinex on calculus clearance after extracorporeal shock wave lithotripsy, 9 e edrisi l, see aghamir smk, 249 efthimiou i, mamoulakis c, papageorgiou g, kazoulis s, prevedorou d, kontogiorgos g, christoulakis i. unilateral malignant leydig cell tumor of testis in a patient with contralateral cryptorchidism, 60 eghbalian f, monsef a, mousavi-bahar sh. urinary tract and other associated anomalies in newborns with esophageal atresia, 123 f faizullah k, see ather mh, 14 falahatkar s, see salehi m, 260 ferreira u, see matheus we, 260 frança rd, see prudente a, 96 g ganjehei l, see arshadi h, 88 ganji mr, see naderi gh, 31 ganpule a, see sharma r, 254 garcia-galvis of, see arrabal-polo ma, 50 garg r, see ahuja a, 127 ghafoori m, varedi p, hosseini sj, asgari m, shakiba m. value of prostate-specific antigen and prostate-specific antigen density in detection of prostate cancer in an iranian population of men, 182 ghahestani sm, shakhssalim n. palliative treatment of intractable hematuria in context of advanced bladder cancer: a systematic review, 149 ghanei m, see soroush mr, 114 goel a, sinha rj, dalela d, sankhwar s, singh v. andropause in indian men: a preliminary crosssectional study, 40 gogus c, see ozden e, 208 golshan a, see razzaghi mr, 132 gonenc f, see ozgur bc, 267 gopalakrishnan g, see thomas aj, 57 goswami j, see rohan v, 217 gupta a, see singh v, 226 gupta m, sood d, singh a. adrenal lipoma complicated by perinephric abscess, 162 gupta r, rizvi sj, modi pr. bilateral spontaneous perinephric hematoma, 8 gupta r, see yadav ak, 303 h hanji a, see rohan v, 217 hariharan s, see naraynsingh v, 295 harnarayan p, see naraynsingh v, 295 hashemi b, see bohlouli a, 194 hatefi n, see nouraee n, 101 heidarpour m, see mohammadi sichani m, 298 heretis ie, see papadimitriou vd, 223 hosseini j, kaviani a, mohammadhosseini m, rezaei a, rezaei i, javanmard b. fistula repair after hypospadias surgery using buccal mucosal graft, 19 hosseini j, rezaei a, mohammadhosseini m, rezaei i, javanmard b. supracrural rerouting as a technique for resolution of posterior urethral disruption defects, 204 hosseini j, see kaviani a, 135 hosseini j, tavakkoli tabassi k, razi a. delayed retropubic urethroplasty of completely transected urethra associated with pelvic fracture in girls, 272 hosseini sj, see ghafoori m, 182 hosseini-moghaddam sm, see sharifiaghdas f, 283 i irani f, see ather mh, 14 j jalali m, nikravesh mr, moeen aa, karimfar mh, saidinejat s, mohammadi s, rafighdoost h. inductive role of collagen type iv during nephrogenesis in mice, 289 jamil k, see shaik ap, 78 jamshidian h, see nowroozi mr, 27 javaherforooshzadeh a, see simforoosh n, 163 author index to volume 6 316 urology journal vol 6 no 4 autumn 2009 javaherforooshzadeh a, see simforoosh n, 276 javanmard b, see razzaghi mr, 120 javanmard b, see razzaghi mr, 306 javanmard b, see hosseini j, 19 javanmard b, see hosseini j, 204 jiménez-pacheco a, see arrabal-polo ma, 50 k karimfar mh, see jalali m, 289 kashi ah, see nouralizadeh a, 176 kaviani a, hosseini j, vazirnia ar. a huge penile mass which turned out to be an epidermoid inclusion cyst, 135 kaviani a, see hosseini j, 19 kazemeyni sm, see naderi gh, 47 kazemeyni sm, see razi a, 23 kazoulis s, see efthimiou i, 60 ketabchi aa, ketabchi m, barkam m. percutaneous drainage of a late-onset giant posttraumatic urinoma, 214 ketabchi m, see ketabchi aa, 214 khalifeh shooshtary f, see djaladat h, 9 khoddami vishteh hr, see soroush mr, 114 kilic o, see ozden e, 208 kolahi aa, see babaei ar, 1 kontogiorgos g, see efthimiou i, 60 koral k, see cost ng, 220 kostakos e, see stamatiou k, 157 koutsonasios v, see stamatiou k, 157 kühn r, see labanaris ap, 54 l labanaris ap, zugor v, smiszek r, nützel r, kühn r. small cell carcinoma encountered in a urinary bladder diverticulum, 54 lardas m, see stamatiou k, 157 latif ah, see naderi gh, 31 latif ah, see naderi gh, 47 leitao va, see matheus we, 260 lepidas d, see stamatiou k, 157 lotfi b, see razzaghi mr, 120 m madineh sma. avicenna’s canon of medicine and modern urology: part ii: bladder calculi, 63 madineh sma. avicenna’s canon of medicine and modern urology: part iii: other bladder diseases, 138 madineh sma. avicenna’s canon of medicine and modern urology: part iv: normal voiding, dysuria, and oliguria, 228 mahmoudnejad n, see nouralizadeh a, 176 mahmoudnejad n, see sharifiaghdas f, 283 mahouri k, see djaladat h, 9 mamoulakis c, see efthimiou i, 60 matheus we, reis lo, ferreira u, mazzali m, denardi f, leitao va, pedro rn, netto jr nr. kidney transplant anastomosis: internal or external iliac artery?, 260 mazloomfard mm, see razzaghi mr, 306 mazzali m, see matheus we, 260 mehraban d, see naderi gh, 31 mehraban d, see naderi gh, 47 mehrabi s, see aghamohammadi h, 92 meysamie a, see aghamir smk, 249 miranda m, see prudente a, 96 mistry y, see thomas aj, 57 modi pr, see gupta r, 8 moeen aa, see jalali m, 289 moghadasali r, see sharifiaghdas f, 283 mohammad ali beigi f, see aghamohammadi h, 92 mohammadhosseini m, see hosseini j, 19 mohammadhosseini m, see hosseini j, 204 mohammadhosseini m, see razzaghi mr, 306 mohammadi l, see shamsa a, 170 mohammadi s, see jalali m, 289 mohammadi sichani m, heidarpour m, dadkhah a, rezvani m. persistent mullerian duct syndrome with an irreducible inguinal hernia, 298 mohammadi sichani m, see basiri a, 73 molaeian m, shojaei h. splenogonadal fusion presented with cryptorchidism, 130 monsef a, see eghbalian f, 123 moradi a, see nowroozi mr, 27 moudi ea, see simforoosh n, 276 mousavi-bahar sh, see eghbalian f, 123 mowla sj, see nouraee n, 101 munjal k, agrawal s, munjal s. leiomyomatous author index to volume 6 317urology journal vol 6 no 4 autumn 2009 angiomyolipoma of kidney, 87 munjal s, see munjal k, 878 mustafa m, wadie bs. in situ anterior vaginal wall sling for treatment of stress urinary incontinence: extended application and further experience, 35 n naderi gh, mehraban d, ganji mr, yahyazadeh sr, latif ah. tacrolimus rescue therapy for corticosteroid-resistant and polyclonal antibodyresistant kidney allograft rejections, 31 naderi gh, mehraban d, kazemeyni sm, yahyazadeh sr, latif ah. polytetrafluoroethylene vascular graft as a rescuer of short renal vessels during kidney transplantation, 47 naraynsingh v, harnarayan p, hariharan s. a safe surgical approach to a giant intrarenal arteriovenous fistula and aneurysm, 295 neiroomand h, see salehi m, 301 netto jr nr, see matheus we, 260 nezami n, see bohlouli a, 194 nikravesh mr, see jalali m, 289 nouraee n, mowla sj, ozhand a, parvin m, ziaee am, hatefi n. expression of survivin and its spliced variants in bladder tumors as a potential prognostic marker, 101 nouralizadeh a, ziaee sa, basiri a, simforoosh n, abdi h, mahmoudnejad n, kashi ah. transperitoneal laparoscopic partial nephrectomy using a new technique, 176 nowroozi mr, zeighami s, ayati m, jamshidian h, ranjbaran ar, moradi a, afsar f. prostatespecific antigen doubling time as a predictor of gleason grade in prostate cancer, 27 nützel r, see labanaris ap, 54 o ozden e, gogus c, kilic o, yaman o, ozdiler e. analysis of suprapubic and transrectal measurements in assessment of prostate dimensions and volume: is transrectal ultrasonography really necessary for prostate measurements?, 208 ozdiler e, see ozden e, 208 ozgur bc, gonenc f, yazicioglu ah. sildenafil or vardenafil nonresponders’ erectile response to tadalafil, 267 ozhand a, see nouraee n, 101 p palao-yago f, see arrabal-polo ma, 50 papadimitriou vd, stamatiou kn, takos dm, adamopoulos vm, heretis ie, sofras fa. angiosarcoma of kidney: a case report and review of literature, 223 papageorgiou g, see efthimiou i, 60 parvin m, see nouraee n, 101 patel j, see rohan v, 217 pedro rn, see matheus we, 260 prevedorou d, see efthimiou i, 60 prudente a, reis lo, frança rd, miranda m, d’ancona ca. vesicostomy as a protector of upper urinary tract in long-term follow-up, 96 r rafighdoost h, see jalali m, 289 rahjoo t, see razzaghi mr, 132 ranjbaran ar, see nowroozi mr, 27 razi a, see hosseini j, 272 razi a, yahyazadeh sr, sedighi gilani ma, kazemeyni sm. bladder neck preservation during radical retropubic prostatectomy and postoperative urinary continence, 23 razzaghi mr, rahjoo t, golshan a. endometriosis with pure urinary symptoms, 132 razzaghi mr, rezaei a, javanmard b, lotfi b. desmopressin as an alternative solution for urinary leakage after ureterocaliceal surgeries, 120 razzaghi mr, rezaei a, mazloomfard mm, javanmard b, mohammadhosseini m, rezaei i. successful macrosurgical reimplantation of an amputated penis, 306 reis lo, see matheus we, 260 reis lo, see prudente a, 96 rezaei a, see hosseini j, 19 rezaei a, see razzaghi mr, 120 rezaei a, see razzaghi mr, 306 rezaei a, see hosseini j, 204 rezaei i, see hosseini j, 19 rezaei i, see hosseini j, 204 rezaei i, see razzaghi mr, 306 rezvani m, see mohammadi sichani m, 298 rizvi sj, see gupta r, 8 rohan v, hanji a, patel j, goswami j, tankshali r. author index to volume 6 318 urology journal vol 6 no 4 autumn 2009 penile metastases from prostate cancer, 217 s sabnis rb, see sharma r, 254 safarinejd mr, see babaei ar, 1 saidinejat s, see jalali m, 289 salehi m, falahatkar s, neiroomand h, akbarpour m. fibroepithelial congenital polyp of prostatic urethra in an adult man, 301 sanchez fs, see cost ng, 220 sankhwar s, see goel a, 40 saremi e, see tavakkoli tabassi k, 199 sarhangnejad r, see simforoosh n, 276 sedighi gilani ma, see razi a, 23 shaik ap, jamil k, das p. cyp1a1 polymorphisms and risk of prostate cancer: a meta-analysis, 78 shakeri m, see shamsa a, 170 shakhssalim n, see ghahestani sm, 149 shakiba m, see ghafoori m, 182 shamsa a, mohammadi l, abolbashari m, shakeri m, shamsa s. comparison of open and laparoscopic varicocelectomies in terms of operative time, sperm parameters, and complications, 170 shamsa s, see shamsa a, 170 sharifiaghdas f, moghadasali r, baharvand h, hosseini-moghaddam sm, mahmoudnejad n. special characteristics of culturing mature human bladder smooth muscle cells on human amniotic membrane as a suitable matrix, 283 sharifiaghdas f, see simforoosh n, 276 sharma r, ganpule a, veeramani m, sabnis rb, desai m. laparoscopic management of adrenal lesions larger than 5 cm in diameter, 254 shojaei h, see molaeian m, 130 simforoosh n, basiri a, ziaee sam, sharifiaghdas f, tabibi a, javaherforooshzadeh a, sarhangnejad r, moudi ea, tajali f. the use of unaltered appendix transfer in ileal continent reservoir: 10 years experience, a novel technical modification, 276 simforoosh n, javaherforooshzadeh a, aminsharifi a, tabibi a. early continence after open and laparoscopic radical prostatectomy with sutureless vesicourethral alignment: an alternative technique, 8 years’ experience, 163 simforoosh n, see nouralizadeh a, 176 singh a, see gupta m, 162 singh jc, see dahm p. relevance of levels of evidence to the urologist, 245 singh ur, see yadav ak, 303 singh v, gupta a. stenturia: a rare complication of indwelling ureteral stent, 226 singh v, see goel a, 40 singla s, see ahuja a, 127 sinha rj, see goel a, 40 siwani r, see ather mh, 14 smiszek r, see labanaris ap, 54 sofras fa, see papadimitriou vd, 223 sood d, see gupta m, 162 soroush mr, ghanei m, assari s, khoddami vishteh hr. urogenital history in veterans exposed to high-dose sulfur mustard: a preliminary study of self-reported data, 114 stamatiou k, lardas m, kostakos e, koutsonasios v, lepidas d. prostate cancer screening in greece: current facts, 157 stamatiou k. management of benign prostatic hypertrophy-related urinary retention: current trends and perspectives, 237 stamatiou kn, see papadimitriou vd, 223 t tabibi a, see simforoosh n, 276 tabibi a, see simforoosh n, 163 tajali f, see simforoosh n, 276 takos dm, see papadimitriou vd, 223 tankshali r, see rohan v, 217 tarzamni mk, see bohlouli a, 194 tavakkoli tabassi k, amoueian s, saremi e. pattern of compensatory hypertrophy in contralateral testis after unilateral orchiectomy in immature rabbits, 199 tavakkoli tabassi k, see hosseini j, 272 thomas aj, mistry y, gopalakrishnan g. giant cystadenoma of prostate, 57 v varedi p, see ghafoori m, 182 vazirnia ar, see kaviani a, 135 veeramani m, see sharma r, 254 author index to volume 6 319urology journal vol 6 no 4 autumn 2009 w wadie bs, see mustafa m, 35 weinberg ag, see cost ng, 220 y yadav ak, gupta r, singh ur. extramammary paget’s disease in prostate, 303 yahyazadeh sr, see naderi gh, 31 yahyazadeh sr, see naderi gh, 47 yahyazadeh sr, see razi a, 23 yaman o, see ozden e, 208 yazicioglu ah, see ozgur bc, 267 z zaidi m, see ather mh, 189 zeighami s, see nowroozi mr, 27 ziaee am, see nouraee n, 101 ziaee sa, see nouralizadeh a, 176 ziaee sam, see simforoosh n, 276 zomorrodi a, see bohlouli a, 194 zugor v, see labanaris ap, 54 zuluaga-gomez a, see arrabal-polo ma, 50 editorial comments re: urethral meatus and glanular closure line: normal biometrics and clinical significance this article presents an assessment of ventral glans closure and meatal opening measurements which could serve as an objective measure for cosmetic reconstruction of the glans in boys during hypospadias surgery. although the idea was addressed previously, the article is interesting in that the evaluation was performed in a population of middle eastern boys, aged 0.6 to 13 years. in addition, the results were comparable to the previous studies held in western countries.(1) as indicated in the study, the measurements evolve during course of normal development in the patients. moreover, it would be particularly interesting to observe similar studies in circumcised boys and in those with specific conditions such as meatal stenosis addressing the possible alterations of the aforementioned measurements and ratio. we believe that glans size/circumference is correlated with meatal vertical opening and glanular closure line as well, therefore glans size/circumference is expected to be considered in further investigations. references 1. hutton ka, babu r. normal anatomy of the external urethral meatus in boys: implications for hypospadias repair. bju int. 2007;100:161-3. pediatric urology and regenerative medicine research center, children's medical center, tehran university of medical sciences, tehran, iran *correspondence: pediatric urology and regenerative medicine research center, children's medical center, tehran university of medical sciences, no.62, dr. gharib's street, keshavarz boulevard, tehran, iran. p.o. box: 1419733151 tel: + 98-21-66565400. fax: + 98-21-66565500. email: kajbafzd@tums.ac.ir. abdol-mohammad kajbafzadeh*, behnam nabavizadeh editorial comments 300 vol 15 no 05 september-october 2018 301 reply by authors re: urethral meatus and glanular closure line: normal biometrics and clinical significance thanks a lot for your comment and interest in this article. we do agree with you that studying the meatal length/glanular closure line ratio has a high potential to objectively assess the severity of meatal stenosis which so far does not have any consensus in its definition. moreover, we showed that the two components of this ratio do correlate with the age of the patients while finding another link with other penile anthropometric measurements like the glans size or penile shaft length might be of great significance. we believe that hypospadias surgery should keep the momentum towards perfection and every effort should be spent to reach the “normal” looking penis in an objectively, reproducible as well as easily applicable way. thanks tariq o abbas hamad general hospital, pediatric surgery department, pediatric surgery department, hamad general hospital, doha, qatar. tel: (+974) 55093651; email: tariq2c@hotmail.com. female urology evaluation of the clinical efficacy and complications of duloxetine in comparison to solifenacin in the treatment of overactive bladder disease in women: a randomized clinical trial mahboubeh mirzaei, azar daneshpajooh, seyed omidreza anvari*, salar dozchizadeh, mohamad teimourian purpose: snris (serotonin and norepinephrine reuptake inhibitors) like duloxetine are known to have a role in the treatment of anxiety disorder and stress urinary incontinence. according to the correlation of anxiety disorder and overactive bladder, this study aimed to evaluate the clinical efficacy and complications of duloxetine (snri) as a medication in the treatment of overactive bladder in female patients. we were interested to know the probable therapeutic effect and side effects of duloxetine in overactive bladder. materials and methods: in this single-blinded interventional randomized clinical trial, 60 female patients with idiopathic overactive bladder (hyperreflexia) referred to the urology clinic, were divided into two groups as pilots. the first group was treated by 10mg/daily solifenacin and the second group received 20mg/daily duloxetine. the patients were evaluated by the iciq-oab questionnaire before and after a one-month follow-up period. the intervention primary outcomes were evaluated by the patient’s presentation of the frequency, nocturia, urgency, urge urinary incontinence and the drugs side effects as secondary outcomes were checked. results: sixty women with confirmed overactive bladder disease were evaluated. solifenacin and duloxetine had the same effect on the treatment of overactive bladder (p value = 0.148). the clinical symptoms were obviously relieved in both groups after treatment. side effects were insignificantly more common in the solifenacin group (p value > 0.05). however, the different frequency of blurred vision in the two groups was statistically significant (p value = 0.04). the most common complication in the solifenacin and duloxetine groups was anxiety. conclusion: the results showed that solifenacin and duloxetine improved overactive bladder symptoms. according to this evaluation, duloxetine can be a suitable alternative option for overactive bladder treatment, due to the acceptable therapeutic effect and side effects. keywords: solifenacin; duloxetine; overactive bladder (oab); stress urinary incontinence (sui) introduction the international continence society (ics) defines the overactive bladder (oab) as a “symptom syndrome suggestive of lower urinary tract dysfunction.” the disease is defined as “urinary urgency, usually accompanied by increased daytime frequency and/or nocturia, with urinary incontinence (oab-wet) or without (oab-dry), in the absence of urinary tract infection or other detectable disease. ”(1) therefore, the patient usually suffers from the excess need to urinate frequently throughout the day. the disease presentations include the urinary urgency (sudden and severe urge to urinate), frequent urination (more than 8 times in 24 hours), and urge urinary incontinence(2). urge urinary incontinence (uui) is defined as sudden and involuntary urine leakage associated with urgency.(3) more than 40% of patients with oab have urinary incontinence. also, about 40-70% of urinary incontinence is caused by overactive bladder(4). the main cause of bladder overactivity disorder is not known(5). the disease can be idiopathic(6,7) or caused by involuntary contractions of the bladder wall muscles (hyperreflexia) or a major underlying disorder such as department of urology, shahid bahonar hospital, kerman university of medical sciences, kerman, iran. *correspondence: department of urology, shahid bahonar hospital, kerman university of medical sciences, kerman, iran. tel: +989396317557. email: omidr.anvari@gmail.com received may 2020 & accepted july 2021 supraspinal neurologic disorders, spinal cord injury, stroke, parkinson's disease, alzheimer's disease, multiple sclerosis, neurologic trauma, diabetes, prolonged recurrent bladder infections, etc. although, the loss of bladder wall muscles elasticity could be due to tuberculosis, bladder stones, bladder tumors, prior prostate surgery in men, and multiple pregnancies in women(8). the interactions of neurological and muscular causes result to bladder function impairment, and the number of urinations increases without any voluntary control. overactive bladder also can be associated with poor autonomic nervous system function. excess release of acetylcholine at the level of epithelial cells or parasympathetic fibers of the bladder muscle layer or detrusor muscles is one of the mechanisms.(9) prior researches showed that the disease has a high prevalence in the world and is more common among women and the elderly(5,10). prevalence of the disease varies between different populations and depends on age, sex, race, and ethnic group(11). although the disease can affect anyone of any age, its prevalence increases with age(12). people over the age of 65 are 39.9 percent more likely to get the disease. postmenopausal women are also more likely to develop the disease due to the urology journal/vol 18 no. 5/ september-october 2021/ pp. 543-548. [doi: 10.22037/uj.v18i.6274] decreased estrogen level(13). milsom et al. showed that the prevalence of overactive bladder was 1.8-30.5% in europe, 1.7-36.4% in the united states, and 1.5-15.2% in asia(10). wein et al. estimated that at least 17 million americans were affected by overactive bladder (2). about 49 million in europe and 33 million in the united states have symptoms of bladder overactivity. this ratio is higher than the prevalence of hypertension, asthma and diabetes(14). sometimes, the oab disease severity disrupts the patient's individual life(15). untreated and frequent urination can affect physical, social and emotional health(2). oab affects daily activities such as traveling, physical activity, relationships, sexual function, and also the normal sleep(16). studies have shown that patients with overactive bladder have a lower quality of life. urinary incontinence can lead to urinary tract infections, skin rashes, skin fragility, increased risk of hospitalization, embarrassment, mental distress, reduced social interactions, reduced quality of life, self-restriction, or avoidance of sexual activity(4). as an example, the quality of life of patients with overactive bladder was lower than that of patients with diabetes in the social and functional areas(17). the disease should not be mistaken for urinary tract infections due to the symptoms overlap(5,15). the volume of urine is relatively small each time urinating. pain during urination indicates that there is a problem other than overactive bladder(5). the predisposing factors are perineal muscle weakness in women and bph in men, along with other underlying and chronic disorders in the elderly(18). primary treatment options include medication, behavioral therapy, or a combination. in very rare cases, where patients do not respond to primary treatment, surgery such as detrusor myectomy, augmentation enterocystoplasty with continent urinary diversion is recommended(5). anticholinergic drugs, tricyclic antidepressants (tcas), and calcium channel blockers (ccbs) are among the main drugs used(19). unfortunately, many people do not seek medical treatment, because they mistakenly believe that bladder control problems are an inevitable part of old age and that there is no cure for it, or that they are embarrassed to talk to the doctors and other health care providers about their problems(2). due to the attribution of its symptoms to the other diseases, only a few will benefit from appropriate treatment. they experience a sense of embarrassment and fear of being in a social environment, that isolates them from the workplace and society, ultimately leading to depression. the correlation between obsessive-compulsive symptoms and the oab has been evidenced in the literature.(20) in our research, we proposed to try the drug, duloxetine to treat the oab, to compare it with the standard treatment, and to evaluate the side effects, according to the correlation of the oab and obsessive-compulsive disorder. since duloxetine is known to have a therapeutic role in the treatment of anxiety disorders and stress or mixed urinary incontinence in adults, we were interested to know the probable therapeutic effect and side effects in oab. if the drug proves to be effective, it could be used as a single medication in mixed urinary incontinence, instead of combination treatment with anticholinergics in these patients. there is no prior literature in this regard. patients and methods this research was a single-blinded randomized clinical trial study. this clinical trial was approved in the clinical ethics committee of kerman university of medical sciences. (code: ir.kmu.ah.rec.1398.099) iran clinical trial registration center approved the clinical trial. (code: irct20191010045047n1) the study population was the women referred to the urology clinic in kerman in 2018 who had bothersome urgency with or without other irritative urinary tract symptoms. we decided to evaluate 30 patients in each group as pilots. the patients under 18 years of age, the ones with known urinary tract infection, bladder stones, positive history table 1. determination and comparison of demographic variables in the two groups. duloxetine group. solifenacin group. p. value mean sd mean sd age 52.13 12.64 54.10 14.68 0.580 weight 72.46 12.85 70.20 9.55 0.441 0.921 number of pregnancy 3.73 2.61 3.80 2.56 prevalence % prevalence % p. value vaginal atrophy yes 11 36.7 11 36.7 1 no 19 63.3 19 63.3 side-effect duloxetine group. solifenacin group. p. value prevalence % prevalence % dry mouth yes 8 26.7 10 33.3 0.389 no 22 73.3 20 66.7 constipation yes 10 33.3 10 33.3 1 no 20 66.7 20 66.7 blurred vision yes 2 6.7 9 30 0.042 no 28 93.3 21 70 anorexia yes 5 16.7 6 20 1 no 25 83.3 24 80 sleep disturbances yea 5 16.7 11 36.7 0.143 no 25 83.3 19 63.3 anxiety yes 11 36.7 17 56.7 0.195 no 19 63.3 13 43.3 table 2. determination and comparison of the frequency of complications in the two groups. clinical efficacy of duloxetine in oab treatmentmirzaei et al. female urology 544 vol 18 no 5 september-october 2021 545 of urogynecological malignancy, obesity (bmi>40), high grade cystocele and rectocele (more than 2 according to the pelvic organ prolapse quantification system (pop-q)), residue of urine>100cc and or maximum flow rates of lower than 15ml/s, pregnant, suffering from underlying neurologic disorder such as spinal cord injury, stroke, parkinson's disease, alzheimer's disease, multiple sclerosis, neurologic trauma, and diabetes were excluded from the evaluation. after obtaining written ethical consent, patients were randomly divided into two groups using the random allocation software. patients were allowed to use other treatments through the follow-up period. the research was single blinded. as the 10 mg dosage for solifenacin had better clinical efficacy in prior researches, group 1 received the anticholinergic solifenacin 10mg/daily and group 2 received snri duloxetine 20mg/daily without knowing the drugs name and characteristics. these patients were followed up for one month and then the iciq-oab questionnaire was filled out to compare the drug’s effectiveness after the intervention. the intervention outcomes were evaluated by the patient’s presentation of the frequency, nocturia, urgency, urge urinary incontinence, and the drugs side effects. a clinical interview was conducted by a psychologist to assess the psychologic side effects, based on the criteria in the reference of diagnostic & statistical manual of mental disorders. after collecting the questionnaires, the data were statistically analyzed by spss statistical software version 20 using bivariate analysis between the two groups. to provide descriptive results, frequency index, relative frequency and central mean index, statistical chi-square test and statistical regression test were used. patients’ enrollment algorithm is shown in figure 1. (consort flow diagram) results 130 patients with urinary urgency were referred, in which, 60 patients met the criteria for evaluation after the exclusion criteria review, urine analysis, and uroflowmetry. two groups of thirty patients were evaluated in this study (figure 1). the mean age was insignificantly higher in the solifenacin group (54.10 years) compared to the duloxetine group (52.13 years) (p value=0.580). the two groups were completely identical in table 3. the average iciq-oab questionnaire in the two groups. duloxetine group. solifenacin group. p. value mean sd mean sd before treatment 13.90 3.19 14.86 2.89 0.225 after treatment 8.76 2.14 9.66 2.59 0.148 p. value < 0.001 < 0.001 figure 1. consort reporting diagram of the clinical trial. clinical efficacy of duloxetine in oab treatmentmirzaei et al. terms of demographic variables. eleven patients in the duloxetine group and eleven patients in the solifenacin group had concomitant atrophic vaginitis, who were treated with topical estrogen at the same time (table 1). the clinical disorders like frequency, nocturia, urgency and urge urinary incontinence were obviously relieved in both groups after treatment. the mean of questionnaire score in the solifenacin group was 14.86 before the intervention and 9.66 after the treatment, respectively. these scores were 13.90 and 8.76 in the duloxetine group. this difference was not statistically significant (p value = 0.148). the scores in both groups decreased after the intervention. this difference was statistically significant (p value < 0.01) (table 3). the prevalence of complications like dry mouth, blurred vision, anorexia, sleep disturbance, and anxiety was higher in the solifenacin group than in the duloxetine group. but, only the frequency of blurred vision was statistically significant (p value = 0.042). gastrointestinal side effects were equal in both groups (table 2). discussion our results showed that snri, duloxetine relieved the overactive bladder symptoms. according to this evaluation, duloxetine may be a suitable alternative option for overactive bladder treatment, due to the acceptable therapeutic effect and side effects. overactive bladder disease is one of the main causes of medical expenses for the patient and the health care systems in the world. early diagnosis and treatment of the disease will play a better and more effective role in the patient care and cost reduction. the exact disease diagnosis includes the patient history, physical examination, and laboratory tests to rule out the differential diagnoses. diagnostic cystoscopy, urine cytology, and diagnostic ultrasound of the kidneys and bladder are not recommended in the early stages of disease diagnosis(5). urodynamic test purpose is to distinguish between different types of incontinency; therefore, it is the most effective diagnostic method(21). many patients who suffer from bladder overactivity need long-term treatment to relieve the symptoms (12). different treatments can be used, depending on the patient’s condition and the physician’s decision, to improve the quality of life. but specific treatment for the disease is not always necessary(5). the pelvic floor muscle exercises, bladder training, and other behavioral therapies are sometimes recommended(5,15). the bladder training teaches the patient how to resist the urge to urinate. in some cases, the patient must have a plan to empty the bladder. weight loss for overweight patients, reducing caffeine consumption (tea and coffee), and balancing fluid intake can also be beneficial(5, 22). decreased sensitivity of the bladder nerve fibers by the use of capsaicin or the use of botox, potassium channel blockers, beta-adrenergic agonists, muscle relaxants, and neurotransmitter blockers are also used to treat overactive bladder(23,24). as said, primary treatment options include medication, behavioral therapy, or a combination(5). there are very effective medications for treating overactive bladder which can help the patient return to normal life. however, no drug is as beneficial to lifestyle changes as it is for elder patients(5,22). anticholinergic drugs are the mainstay and the first line treatment medications, including trospium, fesoterodine, solifenacin, darifenacin, oxybutynin, tolterodine, and hyoscyamine(25). these drugs reduce the range of bladder contractions and voluntary contractions. the common side effects include confusion, dry mouth, constipation, prolonged qt interval, hypotension in the elderly, and papillary dilatation. these drugs should not be used if the patient has closed-angle glaucoma and myasthenia gravis(26). solifenacin, a specific muscarinic receptor antagonist (m3) has a high selectivity for the urinary and bladder secretory glands. the drug reduces the elasticity of bladder smooth muscle and allows more urine to be retained in the bladder. solifenacin is administered orally at 5 and 10 mg. doses, and the full therapeutic effects will be seen 2-4 weeks after treatment. solifenacin is not recommended in people with severe renal or liver failure. dry mouth is one of the most common side effects of solifenacin(27). another class of drugs is snris (serotonin and norepinephrine reuptake inhibitors), including duloxetine (cymbalta)، desvenlafaxine (pristiq)، tofenacin (elamol, tofacine) ، milnacipran (ixel, savella) ، levomilnacipran (fetzima), and venlafaxine (effexor). the side effects are sexual dysfunction, generalized anxiety disorder, dyspepsia and panic attacks (28, 29). duloxetine has been used to treat severe depressive disorders and generalized anxiety disorder in adults and to control diabetic neuropathic pain. it significantly increases the capacity of the sphincter muscle in the phase of urinary filling and storage. therefore, it is known to have a therapeutic role in the treatment of anxiety disorders and stress or mixed urinary incontinence in adults. in a study of 306 women with oab, by steers. et al., it was found that the group receiving duloxetine had a significant improvement over the group receiving placebo. the most common adverse events with duloxetine (nausea, 31%; dry mouth, 16%; dizziness, 14%; constipation, 14%; insomnia, 13%; and fatigue, 11%) were the same as those reported by women with sui and were significantly more common with duloxetine than placebo.(30) wang et al. evaluated the condition of a 17-year-old female suffering from oab for 2 years. the results showed that duloxetine improved the bladder capacity and decreased urinary frequency(31). ghanbari et al. examined the efficacy and side effects of oxybutynin and tolterodine in the treatment of overactive bladder. the results showed that both oxybutynin and tolterodine improved the patient's quality of life. in that study, the effectiveness of these two drugs did not differ significantly(32). basu and duckett examined the condition of a 47-year-old patient with urinary incontinence. the results showed that treatment of this patient with duloxetine was successful(33). according to the prior researches, there are various treatments for oab. the 10 mg dosage for solifenacin had better clinical efficacy at 12 weeks. although the 5mg is starting dose.(34) as the results of our study showed, patients with oab treated with duloxetine had side effects including dry mouth (26.7%), blurred vision (7.6%), anorexia (16.7%), sleep disturbance (16.7%), anxiety (7.36%) and constipation (33.3%). these results showed the duloxetine same efficacy and adverse effects of the steers., et al. research with a little more incidence.(30) these side effects have also been reported in people treated with solifenacin. however, the clinical efficacy of duloxetine in oab treatmentmirzaei et al. female urology 546 10md/daily solifenacin may have more side effects than the 5mg/daily dosage. the most common complication in both groups was anxiety. this research compared the medication duloxetine with the standard treatment, solifenacin in oab. however, prior researches did not compare the two treatments and the efficacy was compared with the placebo. our follow-up period was one month, that was less than some prior researches. since the aim of this study was to replace duloxetine, alone as the first line of treatment, instead of combination therapy of duloxetine and anticholinergics in patients with mixed urinary incontinence, the follow-up time for the evaluation of the effects of duloxetine on oab was considered as one month. however, longer follow-up periods may present more drug’s efficacy and also side effects. the results of the study of solifenacin and duloxetine in the treatment of oab in women referring to urology clinic in kerman in 2018 showed that the clinical efficacy of these two drugs was the same and no preference was observed between the two drugs. since, both can be suitable options in the treatment of oab. future researches with larger populations are needed to confirm the clinical efficacy of duloxetine to be used. conclusions our results showed that solifenacin and duloxetine relieved the overactive bladder symptoms. according to this evaluation, duloxetine can be a suitable alternative option for overactive bladder treatment, due to the acceptable therapeutic effect and side effects. we recommend to try other snris for the oab treatment to figure out the efficacy and complications in the future research. acknowledgments the clinical trial was approved in the clinical research center of kerman university of medical sciences. we appreciate all the people who contribute in the preparation and fulfillment of this evaluation. conflict of interest none declared by the authors. references 1. haylen bt, de ridder d, freeman rm, swift se, berghmans b, lee j, et al. an international urogynecological association (iuga)/ international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. int urogynecol j. 2010;21:5-26. 2. wein aj, rovner es. the overactive bladder: an overview for primary care health providers. int j fertil womens med. 1999;44:56-66. 3. demaagd ga, davenport tc. management of urinary incontinence. p & t : a peerreviewed journal for formulary management. 2012;37:345-61h. 4. gibbs cf, johnson tm, 2nd, ouslander jg. office management of geriatric urinary incontinence. am j med. 2007;120:211-20. 5. gormley ea, lightner dj, burgio kl, chai tc, clemens jq, culkin dj, et al. diagnosis and treatment of overactive bladder (nonneurogenic) in adults: aua/sufu guideline. clinical efficacy of duloxetine in oab treatmentmirzaei et al. j urol. 2012;188:2455-63. 6. yarker ye, goa kl, fitton a. oxybutynin. a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. drugs aging. 1995;6:243-62. 7. hebjørn s, andersen jt, walter s, mouritzen dam a. detrusor hyperreflexia. scand j urol nephrol. 1976;10:103-9. 8. liu ht, jiang yh, kuo hc. increased serum adipokines implicate chronic inflammation in the pathogenesis of overactive bladder syndrome refractory to antimuscarinic therapy. plos one. 2013;8:e76706. 9. torimoto k, matsumoto y, gotoh d, morizawa y, miyake m, samma s, et al. overactive bladder induces transient hypertension. bmc res notes. 2018;11:196-. 10. milsom i, coyne ks, nicholson s, kvasz m, chen ci, wein aj. global prevalence and economic burden of urgency urinary incontinence: a systematic review. eur urol. 2014;65:79-95. 11. coyne ks, sexton cc, bell ja, thompson cl, dmochowski r, bavendam t, et al. the prevalence of lower urinary tract symptoms (luts) and overactive bladder (oab) by racial/ethnic group and age: results from oab-poll. neurourol urodyn. 2013;32:2307. 12. milsom i, stewart w, thüroff j. the prevalence of overactive bladder. am j manag care. 2000;6:s565-73. 13. robinson d, cardozo l, milsom i, pons me, kirby m, koelbl h, et al. oestrogens and overactive bladder. neurourol urodyn. 2014;33:1086-91. 14. stewart wf, van rooyen jb, cundiff gw, abrams p, herzog ar, corey r, et al. prevalence and burden of overactive bladder in the united states. world j urol. 2003;20:32736. 15. gormley ea, lightner dj, faraday m, vasavada sp. diagnosis and treatment of overactive bladder (non-neurogenic) in adults: aua/sufu guideline amendment. j urol. 2015;193:1572-80. 16. abrams p, kelleher cj, kerr la, rogers rg. overactive bladder significantly affects quality of life. am j manag care. 2000;6:s580-90. 17. komaroff al, fagioli lr, doolittle th, gandek b, gleit ma, guerriero rt, et al. health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. am j med. 1996;101:281-90. 18. bear m, dwyer jw, benveneste d, jett k, dougherty m. home-based management of urinary incontinence: a pilot study with both frail and independent elders. j wound ostomy continence nurs. 1997;24:163-71. 19. ouslander jg. management of overactive bladder. n engl j med. 2004;350:786-99. 20. ahn k-s, hong h-p, kweon h-j, ahn a-l, oh e-j, choi j-k, et al. correlation between overactive bladder syndrome and obsessive vol 18 no 5 september-october 2021 547 compulsive disorder in women. korean journal of family medicine. 2016;37:25-30. 21. arnold j, mcleod n, thani-gasalam r, rashid p. overactive bladder syndrome management and treatment options. aust fam physician. 2012;41:878-83. 22. ruxton k, woodman rj, mangoni aa. drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: a systematic review and metaanalysis. br j clin pharmacol. 2015;80:20920. 23. babu r, vaidyanathan s, sankaranarayan a, indudhara r. effect of intravesical instillation of varying doses of verapamil (20 mg, 40 mg, 80 mg) upon urinary bladder function in chronic traumatic paraplegics with overactive detrusor function. int j clin pharmacol ther toxicol. 1990;28:350-4. 24. liu h, liu p, mao g, chen g, wang b, qin x, et al. efficacy of combined amlodipine/ terazosin therapy in male hypertensive patients with lower urinary tract symptoms: a randomized, double-blind clinical trial. urology. 2009;74:130-6. 25. sussman do. overactive bladder: treatment options in primary care medicine. the journal of the american osteopathic association. 2007;107:379-85. 26. staskin dr. overactive bladder in the elderly: a guide to pharmacological management. drugs aging. 2005;22:1013-28. 27. luo d, liu l, han p, wei q, shen h. solifenacin for overactive bladder: a systematic review and meta-analysis. int urogynecol j. 2012;23:983-91. 28. medarov bi, chaudhry h, sun jh, rane n, judson ma. effect of ssris and snris on nocturnal urinary frequency. ann pharmacother. 2016;50:471-4. 29. stahl sm, grady mm, moret c, briley m. snris: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. cns spectr. 2005;10:732-47. 30. steers wd, herschorn s, kreder kj, moore k, strohbehn k, yalcin i, et al. duloxetine compared with placebo for treating women with symptoms of overactive bladder. bju int. 2007;100:337-45. 31. wang s-m, lee h-k, kweon y-s, lee ct, lee k-u. overactive bladder successfully treated with duloxetine in a female adolescent. clinical psychopharmacology and neuroscience : the official scientific journal of the korean college of neuropsychopharmacology. 2015;13:212-4. 32. ghanbari z, esmaeili m, eftekhar t, esmaeili m, miri e. comparison of efficacy and side-effects of oxybutynin and tolterodine in the treatment of overactive bladder. tehran university medical journal (tumj). 2011;69:302-8. 33. basu m, duckett jr. detrusor overactivity successfully treated with duloxetine. j obstet gynaecol. 2007;27:438-40. 34. madhuvrata p, cody jd, ellis g, herbison gp, hay-smith ej. which anticholinergic drug for overactive bladder symptoms in adults. cochrane database syst rev. 2012;1:cd005429. clinical efficacy of duloxetine in oab treatmentmirzaei et al. female urology 548 1 confusion in gonadal dysgenesis terminology persisting beyond chicago consensus statement on disorders of sexual development seyyed mohammad ghahestani (1) *, sara karimi (2) (1) *: assistant professor of pediatric urology, tehran university of medical sciences(tums), department of urology address: children medical center hospital, gharib st, keshavarz blvd, tehran, iran email: mgrosva@gmail.com , sm-ghahestani@sina.tums.ac.ir phone:+989128491811 sara karimi, fellow of female urology, urology nephrology research center(unrc), shahid beheshti medical university(sbmu) corresponding and first author: seyyed mohammad ghahestani address: labbafinejad hospital, urology nephrology research center, boostan 9th, pasdaran ave, tehran, iran phone: +9133004032 keywords: sexual development disorder, gonad, dysgenesis, consensus, terminology, sex abbreviations: dsd: disorder(difference) in sexual development so: streak ovary dt: dysgenetic testis gd: gonadal dysgenesis ot-dsd: ovotesticular disorder(difference) in sexual development mailto:sm-ghahestani@sina.tums.ac.ir 2 a consensus on dsd classification and terminology was published in 2006 under the auspices of the lawson wilkins pediatric endocrine society and the european society for paediatric endocrinology. terminology in this group of disorders has social, psychologic and even political and philosophical intricacies, and the medical community should be cautious about any trace of stigmatization or social unfairness. preceding literature has adopted a confusing approach toward the terminology of gonadal dysgenesis with inconsistent emphasis on either gonadal histology or karyotype. descriptive words “partial,” ”complete,” and “pure” have been used diversely and sometimes interchangeably. we try to show some inconsistencies below in enumeration: 1) the phrase “partial gonadal dysgenesis” is used as a discriminative term vs mixed gonadal dysgenesis. since mgd denotes a streak gonad on one side and a dysgenetic testis on the other, the term “partial gonadal dysgenesis” has been used to denote a condition of bearing dysgenetic testes on both sides. 2) a condition of two streak gonads with xx karyotype and without somatic features of turner syndrome is called 46xx pure gonadal dysgenesis. the word “pure” is presumed to convey a non-mosaic karyotype (46xx). this is somewhat obscure as there are cases of two streak gonads and 45x/46xy karyotype that are mosaic and evade the quoted applicability of the word “pure”. this condition is not covered by the 2006 chicago statement (1). 3) complete gonadal dysgenesis has been used to denote cases of bilateral streak ovaries and hypergonadotropic hypogonadism (2). specifically, swyer syndrome with 46xy and bilateral streak ovaries has been called 46xy-cgd in the 2006 consensus statement (3). confusingly, cases of pure gonadal dysgenesis have also been called cgd in some essays, sparing the dsd consensus statement (2, 4). there are cases of 45x/46xy bilateral so that have been proposed to be called cgd (4) and 46xy-pure gonadal dysgenesis in some dissertations (2). although the dsd statement attempted to solve the confusion by attributing any terminology to a specific situation, the words partial, complete, and pure are still nondescriptive and difficult to understand regarding the assigned condition. one does not find a clear explanation why the word “partial” is presumed to represent two dysgenetic testes and the word “complete”, two streak ovaries. it is clear that much confusion remained in the 2006 consensus about the terminology of gonadal dysgenesis conditions as an important subclass of dsd. confusion in terminology appears to be due to uncertainty in shifting emphasis between karyotype and gonadal histology in each disorder. any proceedings in terminology must be scientifically well sought and bear significant consequences. such decisions must be adopted and coined by multidisciplinary conventions. a terminology in any of gonadal dysgenesis conditions should convey these specifications: a) it is one of the gonadal dysgenesis subtypes of dsd. b) types of dysgenetic gonads: streak ovaries, dysgenetic testes, ovotestis, or undifferentiated c) karyotype: it must be mentioned if specifically addressed in the definition of the condition, e.g. swyer syndrome. if the condition is not specifically attributed to a non3 mosaic karyotype, it is adequate to declare it as a type of gonadal dysgenesis; this simply denotes that the karyotype may have any combination. we attempted to propose a more descriptive blueprint terminology in table 1. we aimed to demonstrate this study’s message in a clearer exemplary fashion. there is no doubt that a newer statement on dsd is necessary after fifteen years. . references: 1. bagci g, bisgin a, karauzum sb, trak b, luleci g. complete gonadal dysgenesis 46, xy (swyer syndrome) in two sisters and their mother's maternal aunt with a female phenotype. fertility and sterility. 2011;95(5):1786. e1-. e3. 2. rocha vbc, guerra-júnior g, marques-de-faria ap, de mello mp, maciel-guerra at. complete gonadal dysgenesis in clinical practice: the 46, xy karyotype accounts for more than one third of cases. fertility and sterility. 2011;96(6):1431-4. 3. hughes ia, houk c, ahmed sf, lee pa, society lwpe. consensus statement on management of intersex disorders. journal of pediatric urology. 2006;2(3):148-62. 4. öcal g, berberoğlu m, şıklar z, ruhi hi, tükün a, çamtosun e, et al. the clinical and genetic heterogeneity of mixed gonadal dysgenesis: does “disorders of sexual development (dsd)” classification based on new chicago consensus cover all sex chromosome dsd? european journal of pediatrics. 2012;171(10):1497-502. 4 table 1. confusion in current terminology and proposal of a blueprint condition proposed terminology traditional or frequently cited consensus 2006(1) 1 gd:so-dt asymmetrical gonadal dysgenesis mixed gonadal dysgenesis mgd 2 46 xxbilateral dt 46xxsymmetrical testicular gd 46 xx sex reversal de la chapelle 46-xx testicular dsd 3 46xx-bilateral so 46 xx symmetrical ovarian gd 46xx-pure gonadal dysgenesis (2) 46 xx complete gonadal dysgenesis (2, 4) 46xx-pure gonadal dysgenesis 4 xo/xybilateral so mosaic (xo/xy)symmetrical ovarian gonadal dysgenesis complete gonadal dysgenesis (2) not found 5 gd: bilateral dt symmetrical testicular gonadal dysgenesis partial gonadal dysgenesis dysgenetic male pseudohermaphroditism partial gonadal dysgenesis 6 46xy bilateral so 46 xy symmetrical ovarian gonadal dysgenesis 46xy-sex reversal or xx female swyer syndrome 46 xy complete gonadal dysgenesis 7 ot-dsd true hermaphrodite ot-dsd urological oncology responses to targeted therapy among organs affected by metastasis in patients with renal cell carcinoma are organ-specific weixing jiang1, hongzhe shi1*, lianyu zhang2, jin zhang2, xingang bi1, dong wang1, li wen1, changling li1, jianhui ma1, jianzhong shou1** purpose: previous reports showed that targeted therapy efficacy varied due to different metastatic organs in patients with metastatic renal cell carcinoma (mrcc). this study aimed to further evaluate the response and progression-free time (pft) of individual metastatic organs. materials and methods: data from mrcc patients, who were treated with sunitinib between january 2008 to december 2018, were retrospectively reviewed. individual metastatic organs were assessed separately by the response evaluation criteria in solid tumors criteria. results: we evaluated response heterogeneity and pft as characteristics of 281 individual organs affected by mrcc in 213 patients. the objective response rates in these organs were 72.7% in pancreas, 63.7% in spleen, 14.3% in adrenal glands, 13.5% in bone and soft tissue, 11.6% in lymph nodes, 11.6% in lungs, and 9.1% in liver. the median pft was 15.2 months (95% confidence interval [ci] 2.7–27.7 months) for adrenal glands, 13.2 months (95% ci 3.5–22.9 months) for bone and soft tissue, 9.0 months (95% ci 7.6–10.4 months) for lymph nodes, 8.6 months (95% ci 6.3–10.9 months) for lungs, and 5.2 months (95% ci 2.9–7.5 months) for liver. median pft was not reached in pancreas and spleen, but was > 22.8 months and > 20.6 months, respectively. conclusion: our results indicated that organs affected by metastasis may have individual responses to sunitinib treatment. the pancreas and spleen may have the best responses, and liver may have the worst response. further research is needed to verify these findings. keywords: metastasis; objective response rate; organ; renal cell carcinoma; targeted therapy introduction renal cell carcinoma (rcc) accounts for 3% of malignant tumors in adults; approximately 17% of patients with rcc harbor distant metastases at the time of the initial diagnosis(1-3). the organs most commonly affected by rcc metastasis are the lungs, lymph nodes, and bones(4). targeted therapy is the mainstay in the treatment of patients with metastatic rcc (mrcc), as it results in improvements in quality of life and survival (5,6). sunitinib, one of the multitarget receptor-tyrosine-kinase inhibitors (tkis), has been the gold-standard first-line treatment for mrcc for over 10 years(7,8). our clinical practice of sunitinib-based treatment revealed the possibility of organ-specific responses to metastatic lesions. to date, there is no published evidence relating to this potential response heterogeneity in patients with mrcc who receive targeted therapy. understanding any organ-specific variations in response and prognosis would be important for the per1department of urology, national cancer center/national clinical research center for cancer/cancer hospital, chinese academy of medical sciences and peking union medical college, 100021, beijing, china 2department of imaging, national cancer center/national clinical research center for cancer/cancer hospital, chinese academy of medical sciences and peking union medical college, 100021, beijing, china *correspondence: national cancer center/national clinical research center for cancer/cancer hospital, chinese academy of medical sciences and peking union medical college, beijing, china. tel: 86-10-87787171. fax: 86-10-87787363. e-mail: hongzhe_shi@163.com ** national cancer center/national clinical research center for cancer/cancer hospital, chinese academy of medical sciences and peking union medical college, beijing, china tel: 86-10-13601332989. fax: 86-10-87787170. e-mail: shoujzh@126.com. received april 2020 & accepted october 2020 sonalization of mrcc patient treatments. in this paper, we demonstrated organ-specific differences in objective response rates (orrs) and progression free time (pft) that were indicative of response heterogeneity. patients and methods ethics statement this retrospective study focused on the evaluation of the efficacy and clinical outcomes of first-line sunitinib treatment in patients with mrcc, and was reviewed and approved by the ethics committee of the domain-specific review board (id num: ncc2016xq-22). study population patients with mrcc who were treated in our institute between january 2008 and december 2018 were retrospectively identified. the medical records of all patients with mrcc who were treated with sunitinib were reviewed. among them, 213 patients with diagnoses of urology journal/vol 18 no. 5/ september-october 2021/ pp. 512-518. [doi: 10.22037/uj.v16i7.6129] clear-cell rcc (ccrcc) who had detailed imaging data collected every two cycles of sunitinib treatment, and had not received other systemic treatments or metastasectomy, were included in the study. sunitinib was administered at a dosage of 50 mg once daily, on a 4/2 (on/off) schedule. dosages were reduced or interrupted only in cases of treatment intolerance, in which case stepwise dose reductions occurred in 12.5 mg increments. all patients had complete imaging data and follow-up information. characteristics including age, sex, memorial sloan kettering cancer center (mskcc) criteria, and eastern cooperative oncology group (ecog) performance status(9). radiological assessment computed tomography (ct) or magnetic-resonance imaging (mri) scanning was performed every 4–8 weeks, and the response evaluation criteria in solid tumors (recist) 1.1 criteria were used for evaluation of the responses of the lesions in every organ affected by metastasis(10). patients with measurable disease at baseline were collected. the tumor burden was assessed in centimeters of the tumor diameter by the sum of five measurable diseases for each metastatic organ at baseline according to recist 1.1. the best response of each individual organ was determined (complete response [cr] was better than partial response [pr], which was better than stable disease [sd], which was better than progressive disease [pd]), with the proviso that the response had to have been maintained for ≥ 28 days. all ct and mri data were reviewed by two independent genitourinary radiologists. organs with metastases at the beginning of sunitinib treatment were evaluated throughout the treatment period, and the efficacy was recorded for each individual organ. metastatic lesions that appeared during sunitinib treatment were considered to be primary drug-resistant lesions, and were not included in the study. brain metastasis was not investigated, because in our institution nearly all brain metastases were treated with radiotherapy or surgical resection. evaluation continued until death, the end of follow-up, or the replacement of sunitinib with a second-line targeted therapy or another systemic therapy. statistical analysis the chi-square test was used to compare the difference of distribution data between the groups; non-normally distributed continuous data were compared using the mann-whitney u test. pft for each organ, progression-free survival (pfs) and overall survival (os) from the initiation of sunitinib were analyzed by the kaplan– characteristics n (%) total patients 213 gender male 139 (65.3) female 74 (34.7) median age (range), year 55 (17–76) ecog 0 148 (69.5) 1 53 (24.9) > 1 12 (5.6) mskcc good 102 (47.9) intermediate 72 (33.8) poor 39 (18.3) prior surgery yes 165 (77.5) no 48 (22.5) sites of disease (by organs) lung 95 (33.8) lymph node 69 (24.6) bone and soft tissue 52 (18.5) liver 22 (7.8) adrenal gland 21 (7.5) pancreas 11 (3.9) spleen 11 (3.9) table 1. patient characteristics at baseline. metastatic-organ-specific responses to targeted therapy-jiang et al. abbreviations: ecog, eastern cooperative oncology group; mskcc, memorial sloan-kettering cancer center figure 1. responses and maximal tumor shrinkage of lung metastasis (a) and lymph node metastasis (b) assessed by recist1.1. the green-shaded area corresponds to follow-up time (months). the positioning of the markers with different colors indicates the point of complete response (cr), partial response (pr), stable disease (sd), and progressive disease (pd). the arrow (on therapy) indicates continuing treatment with sunitinib. vol 18 no 5 september-october 2021 513 urological oncology 514 meier method and the log-rank test. the deadline for follow-up was october 2019. statistical analysis was performed using spss statistics for windows, version 23.0 (ibm corp. armonk, ny, usa), and differences were considered statistically significant if p < 0.05. results patient characteristics the patient characteristics are summarized in table 1. a total of 213 metastatic ccrcc patients, with a measurable response to sunitinib, were included in the study. this population consisted of 139 men (65.3%) and 74 women (34.7%), with a median age of 55 years (range 17–76 years). the numbers of patients with ecog scores of 0, 1, and > 1 were 148 (69.5%), 53 (24.9%), and 12 (5.6%), respectively. good, intermediate, and poor mskcc risk levels were assessed in 102 (47.9%), 72 (33.8%), and 39 (18.3%) patients, respectively. in 165 patients (77.5%), nephrectomy was performed prior to sunitinib treatment. we only statistically analyzed target organs that were identified in >10 participants, which meant that 281 individual organs were available for analysis. these organs were lung in 95 patients (33.8%), lymph node in 69 (24.6%), bone and soft tissue in 52 (18.5%), liver in 22 (7.8%), adrenal gland in 21 (7.5%), pancreas in 11 (3.9%), and spleen in 11 (3.9%). there was no difference in mskcc risk distribution between metastatic organs (p = 0.071) (table 2). the median tumor burden for lung, lymph node, bone and soft tissue, liver, adrenal gland, pancreas, and spleen was 4.3 cm (interquartile range [iqr]: 2.3-5.6), 4.0 cm (iqr: 2.4-5.1), 3.8 cm (iqr: 2.1-4.8), 4.1 cm (iqr: 2.6-5.5), 3.9 cm (iqr: 1.8-4.9), 3.8 cm (iqr: 1.4-5.0), and 3.6 cm (iqr:1.9-4.5), respectively. difference of tumor burden between metastatic organs was not statistically observed (p = 0.068) (table 2). organ-specific treatment efficacy for metastasis the treatment responses in each individual organs are shown in figure 1; the best responses and orrs for each organ type are summarized in table 3. for lung metastasis, the median times to cr, pr, and sd were 8.6 months, 7.4 months, and 4.3 months, respectively (figure 1a). for lymph-node metastasis, the median times to cr, pr, and sd were 5.6 months, 3.6 months, and 4.2 months, respectively (figure 1b). for bone and soft-tissue metastasis, the median times to cr, pr, and sd were 7.5 months, 8.6 months, and 4.6 months, respectively (figure 2a). for adrenal metastasis, the median time to cr was 6.4 months, only one patient achieved pr (in 4.3 months), and the median time to sd was 2.6 months (figure 2b). for liver metastasis, the median times to pr and sd were 6.9 months and 2.6 months, respectively (figure 3a). for pancreas metastasis, the median times to cr, pr, and sd were 6.9 months, 6.5 months, and 2.4 months, respectively (figure 3b). for spleen metastasis, the median times to cr, pr, and sd were 10.2 months, 3.0 months, and 2.8 months, respectively (figure 3c). clinical outcomes of metastases in different organs the final follow-up was in october 2019. the median overall follow-up period was 32.0 months (range, 2.6–125.8 months). median pfs was 10.7 months (95% confidence interval [ci] 9.9–11.4 months) and median os was 28.3 months (95% ci 26.5–30.1 months) (supplementary file). dose interruption and reduction due to adverse events were required in 30.5% (65/213) and 47.4% (101/213) of patients, respectively. the rate of dose reduction or treatment discontinuation for lung, lymph node, bone and soft tissue, liver, adrenal gland, pancreas, and spleen was 50.5% (48/95), 47.8% (33/69), 38.5% (20/52), 45.5% (10/22), 52.4% (11/21), 36.4% (4/11), and 27.3% (3/11), respectively. difference of the rates was not significant (p = 0.714) (table 2). kaplan–meier analysis revealed that median pft was 8.6 months (95% ci: 6.3-10.9) for lung metastasis, which was similar to lymph node metastasis with 9.0 months (95% ci: 7.6-10.4) (p = 0.762). median pft was 13.2 months (95% ci: 3.5-22.9) for bone and soft tissue metastasis, which was slightly shorter than adrenal metastasis with 15.2 months (95% ci: 2.7-27.7) (p = 0.501). median pft of liver metastasis was 5.2 months (95% ci: 2.9-7.5), which was shorter than other organs (p < 0.001). median pft was not reached in pancreas and spleen, but was > 22.8 months and > 20.6 months, respectively. an overall comparison of all the pft curves for each organ is shown in figure 4. discussion it is clear that different therapeutic effects of targeted therapy in the treatment of patients with mrcc are partly correlated with individual metastatic organs. in this study, we further evaluated the response and pft of each organ individually. we found that metastasis in different organs resulted in organ-specific pfts and responses to sunitinib. tumor burden has been shown to be a prognostic factor in mrcc(11-13). in this study, we evaluated the tumor burden separately based on the metastatic organs. the results showed that the median tumor burden between different organs was relatively consistent with 4.3 cm table 2. the distribution of mskcc scores, tumor burden, and dose changes based on different metastatic organs metastatic organs n (%) mskcc risk classification median tumor burden (iqr), cm dose reduction or interruption n (%) low intermediate poor lung 46 (48.4) 31 (32.6) 18 (19.0) 4.3 (2.3–5.6) 48 (50.5) lymph node 38 (55.1) 21 (30.4) 10 (14.5) 4.0 (2.4–5.1) 33 (47.8) bone and soft tissue 19 (36.5) 15 (28.9) 18 (34.6) 3.8 (2.1–4.8) 20 (38.5) liver 6 (27.3) 6 (27.3) 10 (45.4) 4.1 (2.6–5.5) 10 (45.5) adrenal gland 7 (33.3) 8 (38.1) 6 (28.6) 3.9 (1.8–4.9) 11 (52.4) pancreas 3 (27.3) 5 (45.4) 3 (27.3) 3.8 (1.4–5.0) 4 (36.4) spleen 3 (27.3) 3 (27.3) 5 (45.4) 3.6 (1.9–4.5) 3 (27.3) p value 0.071 0.068 0.714 abbreviations: mskcc, memorial sloan-kettering cancer center; iqr, interquartile range. metastatic-organ-specific responses to targeted therapy-jiang et al. vol 18 no 5 september-october 2021 515 in lung, 4.0 cm in lymph node, 3.8 cm in bone and soft tissue, 4.1 cm in liver, 3.9 cm in adrenal gland, 3.8 cm in pancreas, and 3.6 cm in spleen. however, the efficacy of sunitinib varied among organs. previous results have suggested that the biological behaviors of organs affected by metastasis and the corresponding microenvironments may be related to the efficacy of antiangiogenic therapy(14-16). in the present study, although all of the metastases originated from ccrcc, the therapeutic responses were organ specific. the orrs were from 72.7% in the pancreas to 9.1% in the liver. the wide range of orrs may reflect heterogeneity among the metastatic tumors or the relationship between the growth of metastatic tumors and neovascularization in the various organs. identification of organ-specific differences in the efficacy of targeted therapies may enafigure 2. responses and maximal tumor shrinkage of bone and soft tissue metastasis (a) and adrenal metastasis (b) assessed by recist1.1. cr, complete response; pd, progressive disease; pr, partial response; sd, stable disease. figure 3. response and maximal tumor shrinkage of liver metastasis (a), pancreas metastasis (b) and spleen metastasis (c) assessed by recist1.1. cr, complete response; pd, progressive disease; pr, partial response; sd, stable disease. metastatic-organ-specific responses to targeted therapy-jiang et al. urological oncology 516 ble a breakthrough in individualized therapy. the lung is the primary major target organ of metastasis in mrcc, as it is involved in ~45% of cases(4). in a previous study of patients with mrcc and metastases solely to the lung(17), targeted therapy was found to result in a relatively stable pfs (10.6 months), which is similar to that observed in our study (8.6 months). the lung is an organ with an abundant blood supply, and an anti-angiogenic probably could be more effective. however, we found that lung metastasis had a worse response and shorter pft than bone and soft tissue, adrenal gland, spleen, or pancreas metastasis. in addition, lymph-node metastasis had a similar pft to lung metastasis, with a median pft of 9.0 months. it has previously been suggested that surgical resection is beneficial for isolated lymph-node metastases(18). in our population, patients with lymph-node metastasis receiving sunitinib mostly had metastases to retroperitoneal lymph nodes that were accompanied by metastases to other organs. for these patients, metastatic lymph node excision may not benefit from surgery. from the above results, we considered that patients with lung and lymph node metastasis treated with sunitinib may have poor prognosis, and be more suitable for immunotherapy or immunotherapy combined with targeted therapy. however, clinical research validation with large cohorts is needed. previous studies reported that some selected patients with adrenal-gland metastasis underwent surgery as an alternative treatment option(19,20). differently, in our study we found that the organ-specific median pft for adrenal-gland metastasis was 15.2 months longer than lung, lymph node, and liver metastasis; this suggested that surgical treatment of adrenal-gland metastasis may be not a priority and can be postponed if other metastases are also well controlled. bone and soft-tissue metastasis had a similar response to adrenal-gland metastasis, with a median pft of 13.2 months. bone and soft tissue metastasis has previously been shown to have a negative effect on the outcome in patients with ccrcc who are treated with sunitinib, due to skeletal-related events, including pain, impending fractures, nerve compressions, hypercalcemia, and pathological fractures(21). considering the relatively long pft and stable response associated with bone metastasis in patients with mrcc, we suggest that local therapy may prevent the occurrence of skeletal-related events and may improve the therapeutic effects associated with targeted therapy. in this regard, radiotherapy has been shown to have promising effects on short-term pain control, prevention of fractures, and avoidance of the need for surgery in patients with rcc and multiple bone metastases(22). in our study population, the orr and pft for liver metastasis were only 9.1% and 5.2 months, respectively. the association of poor outcomes with liver metastasis in patients with mrcc who are undergoing targeted therapy is supported by previous findings(23,24). therefore, it may be beneficial for patients with liver metastasis to also receive adjuvant treatment, such as surgery, transarterial chemoembolization, or radioablation(25-27). in addition, immune checkpoint inhibitors may also be applicable. the pancreas and spleen are infrequently affected by metastasis in mrcc, and published reports relating to these types of metastasis involve cases of isolated and metachronous lesions, for which surgical resections have been recommended(28-32). however, we found that metastases in the pancreas and spleen had favorable responses to sunitinib, compared with other organs, suggesting that targeted therapy is a suitable treatment for these lesions, and that surgery or other systematic therapies may not be necessary. a limitation of our study was that it was a retrospective study involving a limited number of cases. a prospective, observational study with a larger population may be needed to confirm (or refute) our findings. in addition, further exploration of the possible mechanisms underlying the organ-specific responses of metastases is needed. conclusions the present study found organ-specific responses of figure 4. kaplan–meier analysis of organ-specific progression free time. metastatic-organ-specific responses to targeted therapy-jiang et al. vol 18 no 5 september-october 2021 517 metastases to sunitinib treatment. metastases in the pancreas and spleen may have the best responses, and liver metastasis may have the worst. we suggest that other therapies may be explored for the optimal treatment of liver, lung, and lymph-node metastasis. further prospective validation is needed to confirm these findings. acknowledgement funding this work was supported by the chinese academy of medical sciences (cams) initiative for innovative medicine [2016-i2m-1-007] and the beijing hope run special fund of the cancer foundation of china [lc2018l02]. availability of data and materials the datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request. conflict of interest the authors report no conflict of interest. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/31 references 1. siegel rl, miller kd, jemal a. cancer statistics, 2019. ca cancer j clin. 2019;69:734. 2. capitanio u, montorsi f. renal cancer. lancet. 2016;387:894-906. 3. capitanio u, bensalah k, bex a, et al. epidemiology of renal cell carcinoma. eur urol. 2019;75:74-84. 4. bianchi m, sun m, jeldres c, et al. distribution of metastatic sites in renal cell carcinoma: a population-based analysis. ann oncol. 2012;23:973-80. 5. albiges l, choueiri t, escudier b, et al. a systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer. eur urol. 2015;67:100-10. 6. choueiri tk, motzer rj. systemic therapy for metastatic renal-cell carcinoma. 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[two cases of pancreatectomy for pancreatic metastasis from renal cell carcinoma]. gan to kagaku ryoho. 2019;46:561-63. metastatic-organ-specific responses to targeted therapy-jiang et al. urological oncology 518 urology for people 140 urology journal vol 7 no 2 spring 2010 urinary stones and familial relations the prevalence of urinary stones varies significantly from country to country all over the world. current data on the occurrence of urinary stones ranges between 2% and 20%. the annual incidence of stone formation in the industrialized regions is generally considered to be 1500 to 2000 subjects per million. urinary stones prevalence may vary according to cultural, racial, and health variables among countries. accurate prevalence of a disease can only be determined if geographical region, socioeconomic status, race, age, gender, climate, nutrition, and other environmental and cultural factors are also considered. urinary stones were significantly associated with a positive family history of urinary stones. the positive family history of urinary stone has been reported in 16% to 37% of patients with the kidney stone compared with 4% to 22% in healthy population. in this study, it was also documented that family history is very common in iranian population and is a risk factor for recurrence. see page 81 for full-text article kidney transplantation and heart renal insufficiency is one of the most important diseases, if left untreated can compromise the patient’s life. renal insufficiency can affect adversely various organs, most importantly the heart. heart diseases are the major cause of death in patients with renal insufficiency. coronary artery disease and left ventricular hypertrophy (thickness of the left ventricle wall) are the two most common heart complications in patients with advanced renal insufficiency. left ventricular hypertrophy is a risk factor for various heart diseases such as sudden death. renal transplantation is the best method of treatment for the patients with advanced renal insufficiency. with renal transplantation, most complications of renal insufficiency in various organs will improve. the present study showed that renal transplantation had beneficial effects on function of the left ventricle in young patients with advanced renal insufficiency. indeed, renal transplantation significantly improves the left ventricle function. patients with renal insufficiency should proceed as early as possible for renal transplantation. see page 105 for full-text article kidney cancer kidney cancer accounts for 3% of all adult malignancies and is known as “great mimicker”. it means that kidney cancer can produce various signs and symptoms in affected patients. however, kidney cancer usually presents itself by three symptoms and signs: bloody urine, loin pain, and a palpable mass in the flank. bloody urine, especially at older ages, is a very important sign; if it is ignored, it can cause serious problems for the affected person. nowadays, with increased use of imaging, some kidney cancers are detected before causing classic presentation. every solid renal mass is important and should be addressed by physician. sometimes the renal mass spontaneously ruptures and causes emergency situation. therefore, timely dealing with every solid renal mass is mandatory. see page 99 for full-text article what’s up in urology journal, spring 2010? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. the persian translation of this article is available from www.uj.unrc.ir. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2010;7:140. www.uj.unrc.ir endourology and stone disease is screening of staghorn stones cost-effective? ali-muhammad kavosh1, ali-reza aminsharifi 2,vahid keshtkar1, abdosaleh jafari3, gholamreza abdollahifard1,4* background: staghorn stones can cause damage to the kidneys and are considered as the one of the main cause of renal failure. if they are identified during the initial stages of diagnosis, kidney damage can be prevented. screening can lead to a better diagnosis. before the screening, it is necessary to calculate the cost-effectiveness of screening. methods: using the possibility calculations of staghorn stones in the society and different age groups as well as a decision tree model, the screening costs and effectiveness were calculated against no screening. effectiveness was determined based on the number of prevented cases of renal failure. ultimately, the incremental cost-effectiveness ration (icer) was calculated and compared with the world health organization (who) method based on the gross domestic product (gdp) per capita and subgroup analysis was done for different age groups. in addition, the robustness of results was examined by sensitivity analysis. results: the results of decision tree showed that in the screening group, the expected cost was 8815997 usd and the expected effectiveness was 358 and in the no-screening group, the expected cost was 3954214 usd and the expected effectiveness was 258. based on the results of the study, screening compared with no screening would increase the cost by 4861783 usd and effectiveness would increase by 100 people. the incremental cost-effectiveness ratio (icer) showed that for each unit of increase in effectiveness of screening compared with no screening, would lead to an increase the cost by 48618 usd. the results also indicated that screening 30-70-year-old people compared with other age groups (20-70 and 25-70) if done every two years, could reduce the mean costs per preventing each case of renal failure. conclusion: if screening staghorn stones are done every two years for 30-70-year-old individuals, it would be cost effective considering who method and 3026 usd could be saved in the health care system per each person. keywords: staghorn stones; screening; cost effectiveness; kidney stone introduction urolithiasis is the third most common cause of uri-nary system disorders, after prostate pathological diseases, and urinary tract infections and is a common systemic disease, significantly associated with human health status and socio–economic consequences(13). renal involvement is unilateral in some patients and bilateral in others. patients who have kidney stones can have a wide range of symptoms; some patients have no symptoms and some present with episodes of symptoms, such as pain, hematuria, urinary obstruction, fever, nausea and vomiting(1). urolithiasis can cause complications, such as urinary tract infections, urinary obstruction, and even renal failure and some studies have attributed kidney, prostate, and bladder cancer to urolithiasis(3–7). one of the most important types of urinary stones are kidney staghorn stones that involve a large part of the renal collecting system, pelvis, and calyx. staghorn stones are usually made of struvite stones and are associated with high urine ph and urinary tract infections (8,9). these stones do not usually obstruct the kidney and 1department of community medicine, school of medicine, shiraz university of medical sciences, shiraz, iran. 2department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran. 3health management and economics research center, iran university of medical sciences, tehran, iran. 4drug abuse and mental health research center, shiraz university of medical sciences, shiraz, iran. *correspondence: department of community medicine, school of medicine, imam hussain square, zand st. shiraz, iran, po box: 7134845794. email: abdolahigh@sums.ac.ir. received february 2018 & accepted november 2018 hence the patients feel little pain, and the stones are usually found by radiological studies, and can cause renal infection, septicemia and damage renal tissue(8). the overall annual incidence of urolithiasis was estimated 136:100,000(11).the prevalence of staghorn kidney stones is various in different parts of the world. in one study, the prevalence of these stones was27.5% in patients with kidney stones(10). although urolithiasisis a rare cause of renal failure, some types of stones, including struvite and infectious types of stones, can cause renal failure(12). in one study 3.2% of all patients suffering from renal failure had urolithiasis as the cause of their renal failure, among which 42.2% were infectious and struvite stones(13). this type of stone can decay and destroy the kidney and the extent of kidney decay is calculated to be 28%, based on all relevant risk factors in staghorn kidney stones(5). the mean age of onset of kidney stones is 41.5 years (sd = 16. 3y) in patients and delay in diagnosis and treatment of these stones can lead to renal decay.(11) urolithiasis is usually diagnosed when a person has symptoms that are confirmed by methods, such as radiurology journal/vol 16 no. 4/ july-august 2019/ pp. 337-342. [doi: http://dx.doi.org/10.22037/uj.v0i0.4425] vol 16 no 04 july-august 2019 338 ography, ultrasound, and ct scan. the tests of choice for diagnosis of kidney stones are ct scan and ultrasonography; ct scan has a higher sensitivity, but has disadvantages of being expensive, exposing the patient to radiation, and limited access(14), while the sensitivity of ultrasound to diagnose urolithiasis is 81–96% with a specificity of 100% (11). in order to prevent the formation, diagnosis, and treatment of kidney stones, like other diseases, different levels of prevention can be applied. in the first level, in order to avoid the creation and formation of kidney stones, various steps can be taken, including dietary and medical prevention. in the second level, screening, early diagnosis, and appropriate treatment aimed at preventing further damage can be applied. since health care and methods of diagnosis and treatment are growing and expanding around the world, the costs are growing and the financial burden on the health system is increasing(15). one of these measures include screening for diseases that meet the ten criteria of wilson and jungner. certainly, one of the principles of screening programs is principal evaluation of the costs and benefits of screening and one of the important methods of economic evaluation is evaluation of cost–effectiveness that plays an important role in the assessment and evaluation of health systems(16). cost–effective analysis is the most common form of economic evaluation in health sector and if the consequences of various options are measured with natural units and have different effects, the cost–effective analysis would be the most appropriate method for economic evaluation that can be used(17).considering the high prevalence of urolithiasis and significant rise in its prevalence in both sexes, as well as the financial burden imposed on patients and health care system, investigating low–cost strategies for on–time diagnosis and treatment of stones, particularly staghorn stones that may require widespread and costly treatment interventions and even cause renal failure are essential. the present study aimed to calculate the cost–effectiveness of screening programs for staghorn kidney stones in adults living in shiraz, in order to implement the project in the community, in case of its cost–effectiveness. materials and methods this study was a cost-effectiveness analysis done as a cross-sectional study in shiraz, in the south of iran. in this study, sampling was not done and all the population of shiraz city, aged between 20 and 70 years (1,226,590 people) were included in the study. first, considering the incidence of kidney stones and staghorn stones, the number of patients with staghorn stones was estimated (appendix 1). in the present study, using a decision tree model the cost-effectiveness of screening staghorn stone was estimated versus no screening (figure 1). the decision tree demonstrates a graphical representation of the route of diagnosis and treatment of various diseases, the costs, consequences, and probabilities(18). the final indicator of effectiveness in this study was the number of prevented cases of renal failure. also, in this study the costs were identified and measured from patients’ viewpoint; according to the perspective of the study, only direct medical costs, including the cost of general practitioner’s visits, the cost of kidneys ultrasonography, the cost of laboratory tests, the cost of dialysis, and kidney transplant were considered. in order to calculate the total cost of screening, the population aged 20–70 years (1,226,590 people) was multiplied by the total cost of the doctor and the kidneys ultrasonography. in order to estimate the cost of no screening, taking into account the incidence of kidney stones, staghorn stones, and renal failure, the number of patients with renal failure as a result of staghorn stones was calculated and then, taking into account the cost of laboratory tests, the cost of dialysis, and kidney transplant surgery costs, the total cost for no screening was calculated for the population aged between 20 and 70. for demographic subgroups, including age groups 25–70 and 30–70 years, similar methods were used to estimate the costs of screening and no screening programs (calculations is screening of staghorn stones cost-effective?-kavosh et al. table 1.the costs of items in screening method and no screening method for staghorn stones. the costs of items the unit cost irr usd the costs of physician’s visit 92000 2.8 the costs of ultrasound 140800 4.34 the costs of laboratory tests 390500 12 the costs of dialysis 1496000 46.2 the costs of renal transplant surgery 88000000 2717 table 2. cost–effectiveness analysis of screening for staghorn stone, compared with no screening in 2015(usd). strategy cost (usd) incremental cost (∆c) effect incremental effect (∆ e) c / e icer screening 8815997 4861783 358 100 24626 48618 no screenings 3954214 258 figure 1. decision tree model of staghorn stone screening versus no screening. screening initially divides people into two groups, according to the result of the test (positive or negative). subsequent tests would divide the population into trueand false-positive cases. p= probability of have stone= 3.8% sensitivity= 96% specificity=100% (11) effectiveness= the number of prevented cases of renal failure source: research finding are given in appendix 2). data were analyzed using treeage pro2011 software (treeage software, inc., williamstown, ma, usa). using the decision tree, the expected costs and effectiveness were calculated and the incremental cost-effectiveness ratio (icer) was calculated according to the formula that included the change in the cost of two programs or interventions than change their consequences. in other words, this ratio shows how much the costs change by the one-unit increase in the effectiveness(17). after calculation of icer, for the decision, this ratio was compared with the threshold limit. in order to calculate the threshold, the method of the world health organization was used, in which, if icer index is lower than three times the gdp per capita, the program is cost-effective(19) and since each economic evaluation study has some uncertainty, in this study it was tried to test the generalizability of the results, using sensitivity analysis(20). as such, one– way sensitivity analysis was performed and the amount of each variable increased 20% and tornado graph was prepared accordingly (figure 2). results the results of the collected cost items are shown in table 1, which shows the costs of kidney transplant surgery as the highest and physician’s visit as the lowest. the results of the decision tree, according to different age groups are shown in table 2, which shows that screening method, compared with no screening, increases the cost at 157,473,174,510 irr (4,861,783 usd) and increases the effectiveness (prevented cases of renal failure) at 100 persons. in order to make a decision, icer should be calculated and then compared with the threshold. icer = the difference in cost of screening compared with no screening/ the difference in effectiveness of screening compared with no screening incremental cost–effectiveness ratio (icer) = ∆c/(∆ e) icer= (88159973954214)/(358-258) = 48618 cost of screening = 8815997 dollar cost of no screening= 3954214 dollar, effectiveness of screening =358 effectiveness of no screening= 258 the calculated incremental cost-effectiveness ratio indicates that for each unit increase in effectiveness, a screening method compared with no screening increases the costs at 1,574,731,745 irr (48618 usd). in order to calculate the threshold level, the world health organization method was used, based on which, the program is cost-effective if icer index is lower than three times the gdp per capita(19). according to the world bank's report, the gdp per capita of iran and based on purchasing power parity (ppp) that equals 16507 $(21) is 32,390 irr according to the central bank of iran and the exchange rate(22); the gdp per capita is 534,661,730 irr(16507 usd) and the threshold is three times this amount 1,603,985,190 irr (49521usd); considering the icer index at 1,574,731,745 irr (48618usd), which is lower than the threshold value 1,603,985,190 irr (49521usd), screening method is cost-effective in the age group 20 to 70 years, compared with no screening. subgroup analysis in order to determine the age and screening intervals, the cost-effective analysis was performed for the age groups 20 to 70 years, 25 to 70, and 30 to 70years with screening intervals of 1, 2, 3, and 5 years. the results of this analysis are shown in table 3, which shows that screening is more cost-effective for the age group 30–70 years, compared to other age groups and if screening is conducted group every two years for this age, the mean costs will drop to 398,094,522 irr (12290 usd) for each case of prevention of renal failure that would be 496,096,456 irr (15316usd) in case of no screening. so, it can be said that screening is cost-effective, when performed every two years in the age group 30–70 years old and saves costs at 98,001,934 irr (3025usd) per person. based on the results of table 3, for age groups 20 to 70 and 25 to 70 years, the mean cost per case of prevention of renal failure was 398,813,061irr (12313usd), and 398,203,619 irr, (12294usd) respectively, which are higher compared with mean cost of the age group 30 to 70 year (398,094,522 irr), (12290usd) so screening is not cost-effective for age program groups effect (prevention of renal failure) cost per prevention of renal failure interval 1 year 2 years 3 years 5 years screening 20-70 358 24626 12313 8208 4925 no screening 20-70 258 15326 screening 25-70 298 24588 12294 8196 4918 no screening 25-70 215 15272 screening 30-70 232 24581 12291 8194 4916 no screening 30-70 167 15316 table 3. cost–effectiveness analysis of screening for staghorn stone, compared with no screening in 2015 (usd), according to age and screening intervals. figure 2. results of one-way sensitivity analysis (tornado graph). source: research finding is screening of staghorn stones cost-effective?-kavosh et al. endourology and stones diseases 339 vol 16 no 04 july-august 2019 340 groups 20 to 70, and 25 to 70 years. sensitivity analysis since each type of economic evaluation study is associated with some uncertainty, in this study the generalizability of the results was tested using sensitivity analyses(20). therefore, one–way sensitivity analysis was performed and the amount of change by 20% increase in each of the variables was calculated and tornado diagram was prepared accordingly. the steps of the one–way sensitivity analysis were as follows: in the first step, icer was calculated. as previously explained, icer is calculated as the difference in the cost of screening compared with no screening to the differences in their effectiveness. icer, in the present study, was calculated using the data of table 2 as follows: icer= ( 285550152000 -128076977490)/(358-258) = 1574731745 irr icer= ( 8815997 -3954213)/(358-258) = 48618usd in the second step, we changed the amount of each of the model parameters (for example, by 20% increase). in the third step, icer values were computed for each parameter change. for example, the effectiveness of no screening increased from 4 to 310 by 20%, according to table 4. this increase in the effectiveness of no screening also changed icer as follows: icer= (285550152000 -128076977490)/(358-310) = 3253577986 irr icer= (8815997 -3954213)/(358-310) = 101287 usd for all other parameters, the amount of icer changed in the same way. the results for each of the parameters are listed in table 4. as the results of this table show, 20% increase in two parameters of the effectiveness of no screening and the costs of screening, increased the amount of initial icer and increased the two parameters of the effectiveness of screening and the costs of no screening reduced the amount of initial icer. in the next step, the initial icer (1574731745irr (48618usd) and the amount of each of the new icer, calculated in table 4, was plotted in a graph that is called tornado graph (figure 2). the numbers on the horizontal axis of the graph represent the new icer and the value 1574731745irr (48618usd) represents initial icer values. one-way sensitive analysis using tornado diagram indicated that changes in most of the input parameters had few effects on the outcome. moreover, icer had the highest and lowest sensitivities to the increases in the effectiveness and costs of no screening, respectively (figure 2) discussion a review of studies on the cost-effectiveness of screening and preventing kidney stones indicated the main focus of studies on economic evaluation of the first level prevention, ie comparison between diets, drinking proper water and fluids, and metabolic and metaphylaxis studies(22–24) or focus on the second level prevention of comparing different drug treatment and surgical treatment methods(25–27). there was no study focusing on the cost-effectiveness of screening and early diagnosis of kidney stones, by checking databases, including pubmed, science direct, and scopus. nevertheless, there are multiple studies on the cost-effectiveness of screening for early diagnosis of other diseases such as colon cancer, breast cancer, cervical cancer, addiction, and diabetes in adults(28–32) that all confirmed the cost-effectiveness of screening. since our study is the first study on the cost-effectiveness of the screening for staghorn stones, compared with no screening (the current situation) using a decision tree model, it was not possible to compare the results with other studies. the results revealed that the screening for staghorn stones was more cost-effective than no screening. the results of this study also showed that screening is more cost-effective every two years for the age group 30–70 years, compared to other age groups. one reason for this can be the higher incidence of kidney stones, as well as lower costs of prevention of each case of renal failure in this age group, compared with the age groups 20 to 70, and 25 to 70 years. in other words, it can be said that screening, every two years, for age group 30 to 70 years, saves the costs at 98001934 irr (3026usd) per person, compared to doing it on an annual basis. in addition, the results of the one-way sensitivity analysis powerfully confirmed the finding of the present study and increased the generalizability of the results. to generalize the findings of this study, we can generalize these results to other provinces of the country, but certainly, these results cannot be generalized to other countries, because of differences in the costs of insurance coverage, affordability of patients, the prevalence of the disease, payment system, and relative prices. also, the results of this study can be used in the development of clinical guidelines for prevention of staghorn stones in iran by the department of health, ministry of health and medical education, medical universities, department of health economics, and department of assessing health technology at ministry of health. as mentioned, a review of previous articles resulted in no similar articles on determining the effectiveness of screening staghorn kidney stones and perhaps this study is the first study focusing on this subject. also, compared with other screening methods on other diseases, it can be said that screening staghorn kidney stones with kidneys ultrasonography is cost–effective in the age group 30 to 70 years, when performed each two years and the mean costs (irr)(usd) for each case of prevenparameter’s name the main value 20% increase the new icer value the initial icer value effectiveness of no screening 258 310 100450 effectiveness of screening 358 430 28332 48618 the cost of screening 8815997 10579197 66250 the cost of no screening 3954213 4745056 40709 table 4. results of one–way sensitivity analysis. is screening of staghorn stones cost-effective?-kavosh et al. tion of renal failure was 398,094,522 irr (12291usd) that increased to 496,096,450 irr (15316usd) in case of no screening. therefore, as to the results of the present study, it can be said that screening is cost-effective every two years in the 30-70-year-old age group and saves the cost at 98001934 irr (3026usd) per person. in this study, in order to calculate the threshold level, the world health organization method was used. although this recommendation of who about threshold is mostly used for “cost per qaly gained” or “cost per daly averted” as the outcome, because there is not any threshold calculated or accepted for iran, we used it as our threshold. conclusions the world health organization defines the threshold of cost–effectiveness of various projects and interventions that is calculated based on gdp per capita and if, in any country, the health care interventions and programs are less than three times the gdp per capita, the cost will be cost–effective(25) and in this study, considering the save in the costs at 98001934 irr (3026usd) per person and according to the threshold of the world health organization, screening every two years will be cost–effective for patients aged 30 to 70 years by the conditions listed on this study. conflict of interest the authors report no conflict of interest. references 1. amend w, anderson k, barbour s, baskin l, berger t, carroll p, et al. smith’s general urology. 17th ed. mcgraw hill: lange medical; 2007. 2. lotan y. economics and cost of care of stone disease. advances in chronic kidney disease. 2009; 16:5-10. 3. b a s i r i a , s h a k h s s a l i m n , k h o s h d e l a r , ghahestanism, basiri h. the demographic profile of urolithiasis in iran: a nationwide epidemiologic study. int urol nephrol. 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journal of guilan university of medical sciences. 2008; 68: 63-68. 10. desai m, de lisa a, turna b, rioja j, walfridsson h, d'addessi a, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: staghorn versus nonstaghorn stones. j endourol. 2011; 25:1263-8. 11. safarinejad mr. adult urolithiasis in a population-based study in iran: prevalence, incidence, and associated risk factors. urol res. 2007; 35:73-82. 12. gambaro g, favaro s, d'angelo a. risk for renal failure in nephrolithiasis. am j kidney dis. 2001; 37:233-43. 13. jungers p, joly d, barbey f, choukroun g, daudon m. esrd caused by nephrolithiasis: prevalence, mechanisms, and prevention. am j kidney dis. 2004; 44:799-805. 14. ray aa, ghiculete d, pace kt, honey rj. limitations to ultrasound in the detection and measurement of urinary tract calculi. urology. 2010; 76:295-300. 15. khani m, hosseini h. expenses of health facilities in rural and urban health care centers in 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[cited]; available from: https://hyperlink "http://www. cbi. ir/exrates/rates_en.aspx"www.cbi.ir/exrates/ rates_en.aspx. 23. hyams es, matlaga br. economic impact of urinary stones. translandrol urol. 2014; 3: 278–283. 24. strohmaier wl. economics of stone disease/ treatment. arab j urol. 2012; 10:273-8. 25. saigal cs, joyce g, timilsina ar; urologic diseases in america project. direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? kidney int. 2005; 68:1808-14. 26. matlaga br, jansen jp, meckley lm, byrne tw, lingeman je. economic outcomes of treatment for ureteral and renal stones: a systematic literature review. j urol. 2012; 188:449-54. 27. siu j, chen h, liao p, chiang j, chang c, chen y, et al. the cost-effectiveness of treatment modalities for ureteral stones: a national comprehensive studyl. the journal of health care organization, provision, and financing. 2016; 28. chandhoke ps. economics of urolithiasis: cost-effectiveness of therapies. curr opin urol. 2001; 11:391-3. 29. sarasin fp, giostra e, hadengue a. costeffectiveness of screening for detection of small hepatocellular carcinoma in western patients with child-pugh class a cirrhosis. am j med. 1996; 101:422-34. 30. goldie sj, gaffikin l, goldhaber-fiebert jd, gordillo-tobar a, levin c, mahe c, et al. cost-effectiveness of cervical-cancer screening in five developing countries. new eng j med. 2005; 353:2158-68 31. frazier al, colditz ga, fuchs cs, kuntz km. cost-effectiveness of screening for colorectal cancer in the general population. jama. 2000; 284:1954-61. 32. sonnenberg a, delcò f, inadomi jm. costeffectiveness of colonoscopy in screening for colorectal cancer. ann intern med. 2000; 133:573-84. is screening of staghorn stones cost-effective?-kavosh et al. the efficacy of sexual intercourse or masturbation for the expulsion of distal ureteral stones in men: a systematic review and meta-analysis of randomized-controlled trials yi lu1, wanyu zhang2,3, hao su1, chengquan ma1, hongjun li1* purpose: several randomized-controlled trials (rcts) were performed to compare the efficacy of sexual intercourse or masturbation with no sexual activity in treating distal ureteral stones, indicating conflicting results. the meta-analysis was conducted to assess the role of sexual intercourse or masturbation in the treatment of distal ureteral calculi. materials and methods: pubmed, cochrane library, embase, scopus, clinicaltrail.gov, and web of science were searched by october 2021. men who were instructed of no sexual intercourse or masturbation, and those who only received standard symptomatic treatment are comparators. relative risk (rr), weighted mean difference (wmd), and their 95% confidence intervals (cis) were calculated using random or fixed effects models. results: five rcts including 500 subjects were analyzed in the study. compared with controls, subjects in experimental group had significantly higher expulsion rate at 2nd and 4th week (95%ci: 1.334 to 2.638, rr: 1.876, i2 = 73.6%, p < .001; 95%ci: 1.148 to 1.752, rr: 1.418, i2 = 55.9%, p < .001), significantly decreased requirement for analgesic injections (95%ci: -1.071 to -.126, wmd: -.598, i2 = 90.3%, p = .013), and significantly shorter expulsion time (95%ci: -6.941 to -.436, wmd: -3.689, i2 = 83.7%, p = .026). conclusion: performing sexual intercourse or masturbation 3 or 4 times a week can be an alternative treatment option of distal ureteral calculi (0-10 mm in size). however, more clinical evidence with better designs aiming to solve raised concerns is warranted. keywords: distal ureteral calculi; masturbation; meta-analysis; randomized-controlled trial; sexual intercourse introduction urolithiasis, a common and multifactorial disease affecting around 5-10% of people worldwide, is now increasing with an incidence of 1% per year.(1-3) ureteral stones account for approximately one in the fifth of all urinary calculi, 70% of which are distal ureteral calculi.(4) therapies for urolithiasis consists of invasive and non-invasive options including spontaneous passage, conservative therapy, medical expulsive therapy (met), extracorporeal shockwave lithotripsy (eswl), etc.(5) the rate of spontaneous passage of distal ureteral stones varies from 50% (5-10 mm in size) to 95% (2-4 mm in size), which depends on the size and location of the stone.(6-9) therefore, met is more preferred in the treatment of distal ureteral calculi with a size of 5-10 mm10. currently, tamsulosin is the most frequently used α-blockers in met.(11-13) the met is based on the wide distribution of α-receptors in the distal ureter. nitric oxygen (no) plays a crucial role in erection as well as ureteral peristalsis. 1department of urology, peking union medical college hospital, peking union medical college, chinese academy of medical sciences, beijing, china. 2national clinical research center for obstetric & gynecologic diseases, beijing, china. 3department of obstetrics and gynecology, peking union medical college hospital, chinese academy of medical sciences & peking union medical college, beijing, china. *correspondence: the department of urology, peking union medical college hospital, peking union medical college, chinese academy of medical sciences, no. 1 shuaifuyuan, beijing 100730, china. tel: +86 17731859375. e-mail: yplmailbox@126.com. received december 2021 & accepted may 2022 anatomical and pharmacologic studies had indicated the distribution and the role of nitrergic fibers in the human intravesical ureter.(14) during sexual intercourse or masturbation, no is abundantly released in these nerve endings, causing ureteral muscle relaxation, providing a possible alternative option for the management of ureteral stones.(15) studies have indicated the efficacy of sexual intercourse or masturbation in the treatment of distal ureteral calculi, while findings are controversial. (16-18) a previously published meta-analysis conducted by xu et al. only included 3 rcts and now new findings were available.(26) therefore, we conducted the meta-analysis to make a summary of evidence to date. patients and methods data sources we made detailed inclusive criteria according to the well-established report guidelines before we searched the literatures.(19,20) in october 2021, all available evidence in pubmed, web of science, cochrane library, scopus, clinicaltrail.gov website, and embase was urology journal/vol 19 no. 4/ july-august 2022/ pp. 246-252. [doi: 10.22037/uj.v19i.7119] review systematically searched. no restrictions on language were made when searching for evidence. no observational studies were found and only randomized controlled trials (rcts) were included. references and citations of related articles were also searched carefully. the search process was performed independently by 3 authors. the keywords for the search were “sexual behavior”, “masturbation”, “sexual intercourse”, and “distal ureteral stones”. details about search methods were summarized in supplementary table 1. the protocol of the study was registered in prospero (crd42021273390). inclusion and exclusion criteria studies that met the following criteria were included. (a) population: men with distal ureteral stones; (b) interventions: sexual intercourse or masturbation alone, or combined with standard symptomatic treatment; (c) comparators: men who were instructed of no sexual intercourse or masturbation, and only received standard symptomatic treatment; (d) outcomes: providing sufficient data for analysis, including at least the expulsion rate of stone, number of analgesic injections, or mean expulsion time of stone; (e) study design: only rcts; (f) article type: only original articles; (g) studies with a sample size of more than 50 and follow-up duration of at least 2 weeks. studies which failed to meet the inclusive criteria were excluded. data collection three authors screened retrieved literature independently. information including the first author, publication year, study design, regions, demographic and stone features, interventions and controls details, and outcomes were recorded from included studies. missing or unclear information was collected by contacting the article authors. when there is no reply from authors, corresponding information will be considered as “not available”. risk of bias (rob) assessment the cochrane collaboration’s tool for assessing the risk of bias in the trial was used to evaluate the rob by 3 authors independently.(21) disagreements in the assessment were solved by discussion among the 3 authors and communication with the article authors. statistical analysis weighted mean difference (wmd) and its 95% ci were used for continuous results by follow-up analysis and pooled relative risks (rrs) and their 95% confidence intervals (cis) for dichotomous data that complies with normality assumption. random effect model was applied when there was a significant heterogeneity (i2 > 50%), otherwise fixed effect model will be used.(22) sensitivity analyses were conducted by excluding one study at each time. all statistical analyses were performed by using stata 12.0 (stata-corp.) and r software (version 4.1.1). two-tailed p < .05 was considered as statistically significant. results literature selection under the established search strategy, we found 36 review 247 sexual intercourse and distal ureteral stones-lu et al. table 1. characteristic of included studies abbreviation: rct, randomized controlled trial. study study design country subjects stone features interventio ns in the experiment al group treatment in the control group sample size total follo w-up, week s main outcomes experi mental group control group doluoglu 2015 rct turkey men aged over 18 with active partners radiopaq ue distal ureteral stones ≤ 6 mm in size. sexual intercourse at least 3-4 times a week and essential symptomatic treatment standard symptomatic treatment alone and instruction of no sexual intercourse or masturbation 31 23 4 expulsion rate at 2nd and 4th week, expulsion time, and need for analgesics abdelkader 2017 rct egypt married males aged 2655 radiopaq ue distal ureteral stones 5– 10 mm in size. sexual intercourse 3-4 times/week and symptomatic treatment standard symptomatic treatment alone and instruction of no sexual intercourse or masturbation 28 28 4 expulsion rate at 2nd and 4th week, expulsion time, need for analgesics, and frequency of colicky attacks bayrakta r 2017 rct turkey married males aged 26 to 55 radiopaq ue distal ureteral stones or intramura l stones 5–10 mm in size. sexual intercourse at least 3 times/week standard symptomatic treatment alone 66 64 4 expulsion rate at 2nd and 4th week, expulsion time, need for analgesics, and need for ureterorenoscop ic lithotripsy li 2019 rct china men aged 21 to 50 who received shockwa ve lithotrips y for stones radiopaq ue distal ureteral stones 715 mm in size. sexual intercourse 3-4 times/week and symptomatic treatment standard symptomatic treatment alone 70 68 2 stone free rate, time to stone expulsion, pain score at admission, number of hospital visits for pain and steinstrasse turgut 2021 rct turkey men aged over 18 having distal ureteral stones ≥ 5 mm and < 10 mm in size. distal ureteral stones 5– 10 mm in size. masturbatio n at least 3– 4 times a week and instruction to avoid sexual intercourse standard symptomatic treatment alone and instruction to avoid sexual intercourse and masturbation 43 44 4 rates of expulsion, need for analgesic, and ureterorenoscop ic lithotripsy figure 1. prisma flow chart of the data search. vol 19 no 4 july-august 2022 248 figure 2. risk of bias analysis (a): percentage; (b): traffic light. sexual intercourse and distal ureteral stones-lu et al. non-repeated records. after the screening and eligibility evaluation, 5 rcts were included in the meta-analysis (shown in figure 1).(16-18,23-25) characteristics of included studies five double-blinded rcts published in recent 6 years were included in the analysis (shown in table 1). all the follow-up durations were longer than 2 weeks. among these studies, three were conducted in turkey, one was in egypt, and one in china. from the pooled results, no differences between experimental and control group were observed in terms of age and stone size (95%ci: -1.576 to 1.460, wmd: -.063, i2 = .0%, p = .674; 95%ci: -.291 to .164, wmd: -.052, i2 = 11.7%, p = .542). the rob analysis indicated that all studies had high qualities (shown in figure 2 a and b). expulsion rate and expulsion time of distal ureteral stones 500 individuals, including 238 in the sexual intercourse or masturbation group and 227 in the control group, were included. compared with controls, individuals in sexual intercourse or masturbation groups had significantly higher expulsion rate at both 2nd and 4th week (95%ci: 1.334 to 2.638, rr: 1.876, i2 = 73.6%, p < .001; 95%ci: 1.148 to 1.752, rr: 1.418, i2 = 55.9%, p < .001) (shown in figure 3 and figure 4). objects in the experimental group also had significantly shorter expulsion time than those in the control group (95%ci: review 249 figure 3. pooled results of expulsion rate at 2nd week. rr: relative risk; ci: confidence interval. figure 4. pooled results of expulsion rate at 4th week. rr: relative risk; ci: confidence interval. sexual intercourse and distal ureteral stones-lu et al. -6.941 to -.436, wmd: -3.689, i2 = 83.7%, p = .026) (shown in figure 5). requirement for analgesic injections (per day) the number of analgesic injections was considered as a measurement for stone related pain in four studies. (16-18,23,25) the research performed by li et al. was not included in the pooling because they used a quantified visual analog scale to evaluate pain.(24) the pooled results demonstrated that controls had statistically more injections than subjects in experimental group (95%ci: -1.071 to -.126, wmd: -.598, i2 = 90.3%, p = .013) (shown in figure 6). subgroup analysis details were summarized in supplementary table 2. sensitivity analysis studies were extracted subsequently in each analysis and no study could affect pooled results, indicating the results were reliable (supplementary figure 1 and supplementary figure 2). discussion a comprehensive meta-analysis containing 5 rcts with 500 individuals was conducted to evaluate the efficacy of sexual behavior, including sexual intercourse and masturbation in the expulsion of distal ureteral stones. results indicated that compared with controls, sexual intercourse and masturbation can increase expulsion rate, reduce expulsion time, and sexual intercourse can further lower the demand for analgesic injections. in the meta-regression analysis, no factors were found to significantly influence the pooled results. results were robust. this study builds on a previous meta-analysis that only investigated the role of sexual intercourse figure 5. pooled results of expulsion time. wmd: weighted mean difference; ci: confidence interval. figure 6. pooled results of requirement for analgesic injections. wmd: weighted mean difference; ci: confidence interval. sexual intercourse and distal ureteral stones-lu et al. vol 19 no 4 july-august 2022 250 in the expulsion of distal ureteral stones and includes all available high-quality evidence to date.(26) since 2015, a series of studies have reported the expulsion role of sexual intercourse. doluoglu et al. firstly demonstrated that men having at least 3 sexual intercourses a week had significantly shorter median expulsion time and higher expulsion rate than controls. (16) subsequent two rcts examined the efficacy of sexual intercourse in treating patients with larger ureteral stones in size (5-10 mm) and found consistent findings. (17,23) li and his colleagues extended it further by investigating the role of sexual intercourse after shockwave lithotripsy for men with 7-15 mm distal ureteral stones. (24) they indicated that having more than 3 sexual intercourse a week after shockwave lithotripsy can be a treatment choice for lower ureteral stones.(24) former studies have some limitations such as only male subjects are included and only sexual intercourse were examined. to fill the gap, turgut et al. conducted a rct investigating the role of masturbation in expulsion of distal ureteral stones in men.(18,25) however, the level of compliance in these studies is hard to measure and the loss to follow-up between groups is different in some studies. the underlying mechanisms lie in the role of nitric oxide (no). no is a non-adrenergic and non-cholinergic neurotransmitter which plays an inhibitory role in signal transmission.(27,28) previous studies had shown that both exogenous and endogenous no can cause relaxation of intravesical ureter in pigs.(29,30) the ureter is innervated by sympathetic nerves originating from t11-l1 and para-sympathetic nerves come from s2-4.(31) erection can be induced by the stimulation of cavernous nerves and pelvic plexus, whereas detumescence can be caused by sympathetic system excitation.(32) no is the main neurotransmitter that is helpful in erection, masturbation, and sexual intercourse.(32) when cavernous nerves were stimulated, they will activate nitrergic nerves which can release no from its end, leading to penile smooth muscle relaxation and erection. furthermore, the endothelium can also release no. the hypothesis that erection and sexual intercourse induced no release leads to ureteric muscle relaxation may be supported by the following two points. previous studies indicated that nitrergic nerve endings in the distal ureter can produce no.(33,34) moreover, many clinical trials reported that the stone expulsion rate of the sexual intercourse group is as high as the tamsulosin group.(16,23-25) therefore, sexual intercourse or masturbation can reduce analgesic demand and increase stones passing through no/ cgmp pathway during erection. our findings may have some clinical and research implications. firstly, performing sexual intercourse or masturbation 3 or 4 times a week can increase expulsion rate of distal ureteral stones (diameter less than 10 mm) at 2nd or 4th week and reduce stone-related pain in men. this may be used for patient counselling and lifestyle modification. secondly, more evidence is required for the role of masturbation in stone passage. thirdly, given the fact that healthy men usually have morning or nocturnal erection, the confounding factor should be considered in further studies. fourthly, how, when, and if the no/cgmp pathway can be effectively used in treatment need further exploration. moreover, a comparison of the efficacy of sexual intercourse and masturbation in the treatment of distal ureteral stones may help better understand the problem. the most notable strength of the meta-analysis is the origin of evidence. only high quality randomized double-blind, placebo-controlled trails were included in the meta-analysis, making the final conclusions relatively reliable and solid. however, some limitations also should be mentioned. firstly, the diverse stone sizes may influence the application of findings. while we pooled stone sizes data and found that the experimental group is comparable with the control group. we think that the findings in the study are applicable to distal ureteral stones 0-10 mm in size. secondly, there is still lack of long-term outcomes. thirdly, the compliance of subjects to perform or not to perform masturbation or sexual intercourse are difficult to ascertain. fourthly, due to the small number of included studies, the findings of the study should be treated tentatively until validated by more future studies. last but not the least, sleep-related erection is hard to control. further studies should address these concerns. conclusions conducting sexual intercourse or masturbation 3 or 4 times a week can achieve better efficacy in the treatment of distal ureteral calculi and better pain controls compared with placebo. however, given the concerns mentioned above, more studies with better study designs are expected. acknowledgement this work was supported by the grants from national natural science foundation of china (grant no. 81871152 and grant no.82171588) and the grant from national population health science data sharing service platform clinical medical science data center (ncmi-abd02-201906). conflict of interest the authors report no conflict of interest. references 1. türk c, petřík a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. mar 2016;69:468-74. 2. pearle ms, goldfarb ds, assimos dg, et al. medical management of kidney stones: aua guideline. j urol. 2014;192:316-24. 3. moe ow, pearle ms, sakhaee k. pharmacotherapy of urolithiasis: evidence from clinical trials. kidney int. 2011;79:38592. 4. tzortzis v, mamoulakis c, rioja j, gravas s, michel mc, de la rosette jj. medical expulsive therapy for distal ureteral stones. drugs. 2009;69:677-92. 5. türk c, petřík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 6. yallappa s, amer t, jones p, et al. natural history of conservatively managed ureteral stones: analysis of 6600 patients. j endourol. 2018;32:371-79. 7. loftus c, nyame y, hinck b, et al. medical expulsive therapy is underused for the review 251 sexual intercourse and distal ureteral stones-lu et al. management of renal colic in the emergency setting. j urol. 2016;195:987-91. 8. sarier m, duman i, callioglu m, et al. outcomes of conservative management of asymptomatic live donor kidney stones. urology. 2018;118:43-46. 9. preminger gm, tiselius h-g, assimos dg, et al. 2007 guideline for the management of ureteral calculi. eur urol. 2007;52:1610-31. 10. ordon m, andonian s, blew b, schuler t, chew b, pace kt. cua guideline: management of ureteral calculi. can urol assoc j. 2015;9:e837-51. 11. hollingsworth jm, rogers ma, kaufman sr, et al. medical therapy to facilitate urinary stone passage: a meta-analysis. lancet. 30 2006;368:1171-9. 12. lojanapiwat b, kochakarn w, suparatchatpan n, lertwuttichaikul k. effectiveness of low-dose and standard-dose tamsulosin in the treatment of distal ureteric stones: a randomized controlled study. the journal of international medical research. 2008;36:52936. 13. al-ansari a, al-naimi a, alobaidy a, assadiq k, azmi md, shokeir aa. efficacy of tamsulosin in the management of lower ureteral stones: a randomized double-blind placebo-controlled study of 100 patients. urology. 2010;75:4-7. 14. smet pj, edyvane ka, jonavicius j, marshall vr. colocalization of nitric oxide synthase with vasoactive intestinal peptide, neuropeptide y, and tyrosine hydroxylase in nerves supplying the human ureter. j urol. 1994;152:1292-6. 15. fernandes vs, hernández m. the role of nitric oxide and hydrogen sulfide in urinary tract function. basic clin pharmacol toxicol. 2016;119 suppl 3:34-41. 16. doluoglu og, demirbas a, kilinc mf, et al. can sexual intercourse be an alternative therapy for distal ureteral stones? a prospective, randomized, controlled study. urology. 2015;86:19-24. 17. abdel-kader ms. evaluation of the efficacy of sexual intercourse in expulsion of distal ureteric stones. int urol nephrol. 2017;49:2730. 18. turgut h. evaluation of the efficacy of sexual intercourse on distal ureteral stones in women: a prospective, randomized, controlled study. international urology and nephrology. 2021;53:409-13. 19. stroup df, berlin ja, morton sc, et al. meta-analysis of observational studies in epidemiology: a proposal for reporting. meta-analysis of observational studies in epidemiology (moose) group. jama. 19 2000;283:2008-12. 20. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021;372:n71. 21. higgins jpt, altman dg, gøtzsche pc, et al. the cochrane collaboration's tool for assessing risk of bias in randomised trials. bmj. 2011;343:d5928. 22. dersimonian r, kacker r. random-effects model for meta-analysis of clinical trials: an update. contemp clin trials. 2007;28:105-14. 23. bayraktar z, albayrak s. sexual intercourse as a new option in the medical expulsive therapy of distal ureteral stones in males: a prospective, randomized, controlled study. international urology and nephrology. 2017;49:1941-6. 24. li w, mao y, lu c, et al. role of sexual intercourse after shockwave lithotripsy for distal ureteral stones: a randomized controlled trial. urol j. 2020;17:134-8. 25. turgut h, sarıer m. evaluation of the efficacy of masturbation on distal ureteral stones: a prospective, randomized, controlled study. int urol nephrol. 2021;53:655-60. 26. xu b, yan h, zhang x, cui y. meta-analysis of the efficacy of sexual intercourse for distal ureteric stones. j int med res. 2019;47:497504. 27. bredt ds, hwang pm, snyder sh. localization of nitric oxide synthase indicating a neural role for nitric oxide. nature. 1990;347:768-70. 28. bredt ds, snyder sh. nitric oxide, a novel neuronal messenger. neuron. 1992;8:3-11. 29. hernández m, prieto d, orensanz lm, barahona mv, garcía-sacristán a, simonsen u. nitric oxide is involved in the nonadrenergic, non-cholinergic inhibitory neurotransmission of the pig intravesical ureter. neurosci lett. 1995;186:33-6. 30. stief c. a possible role of nitric oxide (no) in the relaxation of renal pelvis and ureter. j urol. 1993;149:492a. 31. gosling ja, dixon js, jen py. the distribution of noradrenergic nerves in the human lower urinary tract. a review. eur urol. 1999;36 suppl 1:23-30. 32. lue tf. erectile dysfunction. n engl j med. 2000;342:1802-13. 33. yucel s, baskin ls. neuroanatomy of the ureterovesical junction: clinical implications. j urol. 2003;170:945-8. 34. iselin ce, ny l, larsson b, et al. the nitric oxide synthase/nitric oxide and heme oxygenase/carbon monoxide pathways in the human ureter. eur urol. 1998;33:214-21. sexual intercourse and distal ureteral stones-lu et al. vol 19 no 4 july-august 2022 252 comparing the frequency of lymphoceles which needed intervention in recipients of living donor versus deceased donor kidney transplants nasser simforoosh, abbas basiri, ali tabibi, hamed marufi, amir h kashi* purpose: in this study, we aimed to compare the frequency of lymphoceles that needed intervention in recipients who received kidneys from living versus deceased donors. materials and methods: the records of all patients who underwent kidney transplantation at the labbafinejad hospital from 2012 to 2021 were retrospectively reviewed to determine the incidence of lymphoceles that needed intervention for management. results: from march 2012 to april 2021, 1752 patients received kidney transplantation in labbafinejad hospital including 975 transplantations from living donors and 777 transplantations from deceased donors. symptomatic lymphoceles were observed postoperatively in 23 patients. symptoms included compressive effect on the ureter, hydroureteronephrosis of the transplanted kidney, frequency, urinary retention, infection, abdominal discomfort, or rise in serum creatinine. out of 23 patients who needed intervention for symptomatic lymphocele, 15 patients were recipients of living donors and 8 patients were recipients of deceased donors [1.53% versus 1.03%, p = .40]. intervention consisted of open surgical drainage in 6 patients [4 recipients of living donors and 2 recipients of deceased donors], and nephrostomy insertion in 17 patients. open operation was necessary for 5 (47%) patients in whom arterial anastomosis was made to the internal iliac artery versus 1 (9%) patient in whom the anastomosis was not made to the internal iliac artery (p = 0.15). conclusion: symptomatic lymphoceles which needed intervention were observed at a low frequency (1.31%). most cases can be managed by endoscopic drainage without relapse. type of donation had no relationship with the need for open or endoscopic intervention in lymphoceles. a higher proportion of open surgeries to control lymphocele were observed in recipients in whom the internal iliac artery was used for arterial anastomosis however the difference was not statistically significant. keywords: lymphocele; kidney transplantation; living donor; deceased donor; postoperative complications introduction the prevalence of clinical lymphoceles after kidney transplantation varies from 0.6 to 18%. the cause of lymphocele is the disruption of lymphatic vessels without ligation when releasing the recipient’s iliac vessels. also, secretions from transplanted kidney lymphatic vessels, especially during rejection, can cause lymphocele. a normal kidney has well-developed lymphatic drainage that is generally left unligated when transplanted. however, studies of injected radiopaque dyes and radiolabeled substances showed that most lymphoceles originate from the iliac lymphatics of the recipient.(1) it is estimated that 300 ml of lymph per day passes through the external iliac lymph channels. why the transplant kidney lymphatics contribute so little, if any, to the presence of a lymphocele remains unexplained(1). traditional teaching suggests that meticulous ligation of even the smallest lymphatic trunk with nonabsorbable or slowly absorbed ligature material during mobilization of the iliac vessels is crucial in the prevention of lymphoceles. however, the utilization of newer energy delivery devices such as the harmonic scalpel and ligasure, and even judicious use of diathermy, may urology and nephrology research center (unrc), shahid labbafinajad hospital, shahid beheshti university of medical sciences (sbmu), tehran, iran. *correspondence: urology and nephrology research center (unrc), shahid labbafinajad hospital, shahid beheshti university of medical sciences (sbmu), tehran, iran. email: ahkashi@gmail.com. received november 2021 & accepted april 2022 be as effective and less time consuming.(2,3) the use of bipolar cautery to occlude lymphatic vessels and prevent lymphocele formation in kidney transplantation is feasible, safe, and easy to perform. therefore, bipolar cautery could be a valuable tool instead of the use of silk suture ligature.(4) another less important source of lymphatic leakage after kidney transplantation is the graft itself as indicated above and occasionally this may be the case.(2,3) on the contrary, surgical dissection technique was not a factor in the development of post-renal transplant lymphocele in one study while young age, living donor transplantation, and repeat transplantation were found to be predictive variables for symptomatic lymphoceles requiring drainage.(5) based on their own experience, sansalone et al. proposed that lymphoceles could be preventable if the vascular anastomoses were to the common iliac vessels, where fewer lymphatics and lymph nodes are encountered during dissection.(6) this recommendation has not been adopted by many authors. symptomatic lymphoceles especially the smaller ones are first approached by endoscopic drainage. open or laparoscopic surgical drainage is indicated in cases of large lymphoceles or when endoscopic drainage fails.(7) kidney transplantation urology journal/vol 19 no. 3/ may-june 2022/ pp. 228-231. [doi:10.22037/uj.v19i.7050] vol 19 no 3 may-june 2022 100 we aimed to study the frequency of lymphoceles which need intervention after kidney transplantation and to explore the factors which will necessitate the adoption of open or laparoscopic drainage for lymphoceles. materials and methods the records of all patients who underwent kidney transplantation at the labbafinejad hospital from march 2012 to april 2021 were retrospectively reviewed to determine the incidence of lymphocele that needed intervention. lymphoceles were diagnosed primarily by sonographic imaging which was ordered 2 weeks and 6 months after transplantation or when needed based on patients' symptoms or signs. intervention consisted of nephrostomy insertion, drainage of lymphocele through an open operation, or drainage into the abdominal cavity by connecting the lymphocele cavity to the intraperitoneal space through an open or laparoscopic operation. our study also included donor kidneys with multiple arteries. donor nephrectomy was performed by the laparoscopic method as explained previously.(8) in the recipients, a standard right or left lower pararectal incision was made and the renal bed was prepared extraperitoneally. external or common iliac vein and common, external, or internal iliac arteries were selected for allograft anastomosis. lymphatic vessels were tied by silk sutures or cauterized by bipolar cautery. lymphatics of the donor kidneys were also ligated by silk sutures and by the use of bipolar electrocautery. immunosuppressive medications were administered in accordance with lymphocele in kidney transplantation-simforoosh et al. table 1. characteristics of studied patients abbreviatoins: dd=deceased-donor; f=female; m=male; ld=living-donor; vur=vesicoureter reflux; rif=right iliac fossa; osd= open surgical drainage; lif=left iliac fossa; pcn= percutanous nephrostomy; ivc=inferior vena cava; dm=diabetes mellitus; adpkd=autosomal dominant polycystic kidney disease vol 19 no 3 may-june 2022 229 kidney transplantation 230 the standard kidney transplant method in our center as described earlier(9). apart from programmed ultrasound exams in follow-up that was explained above, further ultrasound examinations were performed only in symptomatic patients or if serum creatinine levels increased. other radiological procedures such as ct scan and isotope scan were performed if necessary. we treated symptomatic patients first with nephrostomy insertion. if recurrence occurred, open extraperitoneal drainage of fluid or intraperitoneal drainage of lymphocele through open surgery or laparoscopy was performed. statistical methods data were entered into the statistical package for social sciences (spss) ver. 21. comparison of categorical variables over two groups of different treatments for lymphocele was performed using fisher exact test. results from march 2012 until april 2021, 1752 patients received a kidney transplantation in the labbafinejad hospital including 975 transplantations from living donors and 777 transplantations from deceased donors. postoperatively, symptomatic lymphoceles were observed in 23 patients (1.31%; ci95%:0.88-1.96). symptoms included compressive effect on the ureter and hydroureteronephrosis of the transplanted kidney, frequency, urinary retention, infection, abdominal discomfort, or rise in serum creatinine. out of 23 patients who needed intervention for symptomatic lymphocele, 15 patients were recipients of living donors and 8 patients were recipients of deceased donors ([1.54%; ci95%: 0.93-2.52] versus [1.03%; ci95%: 0.53-2.02], p = .40). details of patients in whom intervention for lymphocele was necessary are presented in table1. open surgical drainage was performed in 6 patients, and nephrostomy insertion in 17 patients. opens surgery was necessitated in 4 patients (27%) from living donors versus 2 patients (25%) from deceased donors (p = 1.0). 21 cases of lymphoceles were observed on the right side and 2 cases on the left side. left side lymphoceles were managed by nephrostomy insertion. open surgery was necessary in 2 cases (25%) in whom bipolar cautery was used to control recipient lymphatics versus 4 patients (27%) in whom silk sutures were used to control recipient lymphatics (p = 1.0). open surgery to control postoperative lymphocele was necessary for 5 patients (42%) in whom arterial anastomosis was made to the recipient's internal iliac artery. however, open surgery was necessary only in one patient (9%) in whom arterial anastomosis was made to arteries other than internal iliac including aorta, common and external iliac arteries (p = 0.15). discussion the findings of the current study reveal a low frequency of need for intervention due to lymphocele after both living and deceased kidney transplantation without any statistically significant difference between the two groups. the mode of intervention (open surgery versus nephrostomy insertion was not statistically different in recipients of living versus deceased donors. the failure of nephrostomy insertion and need for treatment was not related to donor type (living versus deceased), side of donation, method of lymphatic control in the recipient, and type of arterial or venous anastomosis. open surgery for lymphocele was necessary for 5 patients (47%) in whom the arterial anastomosis was made to the internal iliac artery versus 1 patient (9%) in whom the arterial anastomosis was not made to the internal iliac artery, however, this large difference was not statistically significant due to the low cumulative number of lymphoceles (n = 23). there has been an increase in the frequency of lymphocele detection after kidney transplantation due to more frequent use of ultrasound examinations and the use of mtor inhibitors.(10) lymphoceles are usually innocuous and asymptomatic but can occasionally cause complications as a result of external pressure on the transplant and its adjacent structures, when complicated by infection, or causing edema or thrombosis by pressure on the lymph nodes and veins of the lower extremities. in some cases, large lymphocytes cause frequent urination or urinary retention. macrophage function is adversely affected by steroids, and there is some evidence that the incidence of lymphoceles has decreased since the introduction of low-dose steroid regimens. the more recent strong association of mtor inhibitors with problematic lymphoceles is attributed to their powerful antifibroblastic activity, particularly in obese patients being treated for rejection.(3-6,10,11) in the study of golriz et al., various factors contributed to lymphocele formation, such as surgical technique, recipient co-morbidities, immunosuppression, and delayed graft function.(7) lymphoceles were reported more frequently among grafts with multiple arteries.(12) saeedi et al. reported more lymphatic leakage in recipients of living donor kidneys that were operated through laparoscopic donor nephrectomy compared with recipients of deceased donor kidneys.(13) likewise, fakhryasseri et al. reported a higher frequency of lymphoceles in recipients of living donor kidneys that were removed through open donor nephrectomy versus deceased donors.(14) on the contrary, lima et al. reported a higher frequency of lymphocele in recipients of deceased donors.(15) based on their own experience, sansalone et al. proposed that lymphoceles could be preventable if the vascular anastomoses were to the common iliac vessels, where fewer lymphatics and lymph nodes are encountered during dissection.(6) in the study of lucewice et al., the majority of lymphoceles were asymptomatic and self-limiting. the rate of symptomatic lymphoceles requiring interventions has been reported to be around 5.6% of the total cases.(16) the limitations of this study include the low number of lymphoceles that needed intervention during the study period which makes statistical analysis relatively weak and the retrospective nature of the study. conclusions in this study, we observed that postoperative lymphocele that needed intervention for treatment is not common. most cases of lymphocele (74%) were treated by nephrostomy insertion without a further need for another intervention. open surgery was necessary in a limited number of patients and there was no difference in the need for open surgery between recipients of living versus deceased donor kidneys. a higher proportion of open surgeries to control lymphocele were observed in recipients in whom the internal iliac artery was used for arterial anastomosis however the difference was not statistically significant. lymphocele in kidney transplantation-simforoosh et al. vol 19 no 3 may-june 2022 100 references 1. allen srkrd. vascular and lymphatic complications after kidney transplantation. in: morris sjklpmpj, ed. kidney transplantation principles and practice. philadelphia: elsevier; 2020:481. 2. lucan cv, jurchis i, suciu m, selicean se, buttice s. modern lymphatic dissection techniques for preventing post renal transplant lymphocele. clujul med. 2017;90:416-9. 3. morris pj, yadav rv, kincaid-smith p, et al. renal artey stenosis in renal transplantation. med j aust. 1971;1:1255-7. 4. simforoosh n, tabibi a, rad hm, gholamrezaie hr. comparison between bipolar lymphatic vessels cautery and suture ligature in prevention of postrenal transplant lymphocele formation: a randomized controlled trial. exp clin transplant. 2019;17:26-30. 5. nelson ew, gross me, mone mc, et al. does ultrasonic energy for surgical dissection reduce the incidence of renal transplant lymphocele? transplant proc. 2011;43:3755-9. 6. sansalone cv, aseni p, minetti e, et al. is lymphocele in renal transplantation an avoidable complication? am j surg. 2000;179:182-5. 7. golriz m, klauss m, zeier m, mehrabi a. prevention and management of lymphocele formation following kidney transplantation. transplant rev (orlando). 2017;31:100-5. 8. simforoosh n, basiri a, tabibi a, et al. living unrelated versus related kidney transplantation: a 25-year experience with 3716 cases. urol j. 2016;13:2546-51. 9. simforoosh n, eslami a, mohammadian roshan y, et al. outcomes of ongoing living and cadaveric kidney transplantations within the covid-19 pandemic in two referral centers. urol j. 2022. 10. pengel lh, liu lq, morris pj. do wound complications or lymphoceles occur more often in solid organ transplant recipients on mtor inhibitors? a systematic review of randomized controlled trials. transpl int. 2011;24:1216-30. 11. vítko s, margreiter r, weimar w, et al. three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. am j transplant. 2005;5:2521-30. 12. mazzucchi e, souza aa, nahas wc, antonopoulos im, piovesan ac, arap s. surgical complications after renal transplantation in grafts with multiple arteries. int braz j urol. 2005;31:125-30. 13. saidi rf, wertheim ja, ko ds, et al. impact of donor kidney recovery method on lymphatic complications in kidney transplantation. transplant proc. 2008;40:1054-5. 14. fakhr yasseri am, namdari f, gooran s, et al. living versus deceased kidney transplantation: comparison of complications. urologia. 2021;88:185-9. 15. lima ml, cotrim ca, moro jc, miyaoka r, d'ancona ca. laparoscopic treatment of lymphoceles after renal transplantation. int braz j urol. 2012;38:215-21; discussion 21. 16. lucewicz a, wong g, lam vw, et al. management of primary symptomatic lymphocele after kidney transplantation: a systematic review. transplantation. 2011;92:663-73. lymphocele in kidney transplantation-simforoosh et al. vol 19 no 3 may-june 2022 231 letter a survey on current procedural terminology by iranian urological association farzad allameh1, abbas basiri2, amir reza abedi3, seyyed mohammad ghahestani4, saeed montazeri5*, vahid fakhar6 surgical conditions represent 28% to 32% of the global burden of disease(1). access to timely, safe, and cost-ef-fective surgical care has been considered as an “indivisible andindispensable part of health care” worldwide(2). current procedural terminology (cpt) attempts to offer a universal language for describing diagnostic, medical, and surgical services and therefore, considered to be an effective tool of communication between physicians and other health care providers, patients, and third parties(3). american medical association first developed cpt in 1966, which mostly included surgical procedures. the code book of cpt is being updated every few years and expanded to include therapeutic and diagnostic and also internal medicine procedures. cpt was accepted as a part of centers for medicare & medicaid services in 1983. today, cpt is the primary way of communication between providers and payers for reimbursement. many developed countries have developed their own unique systems for classification of procedures(4), including the united states (cpt and international classification of diseases, 9th revision, clinical modification), united kingdom (office of population censuses and surveys classification of surgical operations and procedures, 4th revision), and canada (canadian classification of health interventions). the elaborate systems designed by high-income countries are not fully applicable in ones with limited resources, where minimally invasive surgical procedures are rarely performed. even if applicable, these systems would be expensive and hard to implement. hence, physicians seek a revised or even new cpt code system in iran especially due to recent inflation experienced in this country which consequently caused the loss in iranian currency's value. in the course of two months (from december of 2019 to january of 2020) under the supervision of the research committee of the iranian urological association, a selected group of urologists including general urologists, endo-urologists, pediatric urologists, onco-urologists as well as a urology residents' representative started evaluating different appraisal approaches to determine cpt. they decided to choose an essentially simple and common surgical procedure without any significant side effects to serve as a standard procedure: varicocelectomy (code: 18) appointed for this purpose. in the next step, 15 urological procedures were chosen in february 2020, and urologists around the country were asked to fill out an online questionnaire comparing these procedures with standard one based on the differences in four categories, including difficulty, duration, adverse events, and legal issues. data collection lasted almost three weeks during which announcements were made particularly from the iranian urological association through various methods to encourage urologists to partake in the poll. the 15 selected procedures were as follows: open prostatectomy, transurethral resection of the prostate, percutaneous nephrolithotomy, transureteral lithotripsy, radical nephrectomy, radical prostatectomy, hypospadias repair, female incontinence sling surgery, pyeloplasty, inguinal herniorrhaphy, ureteroneocystostomy, urethroplasty, orchiopexy for undescended testis, urodynamic study and extracorporeal shock wave lithotripsy. the rationale for selecting these procedures was that they were amongst the most common surgeries and interventions serving as exemplar urological procedures. 273 urologists completed the questionnaire. simple mean scores of the four categories were determined separately for each of the 15 procedures. subsequently, simple mean score for each surgery was measured using the calculated mean scores of the four aforementioned categories. even though calculating the weighted mean of these four categories by considering some categories to have more weight in final mean were feasible, however, it was ignored due to lack of consensus. 60% of participants were general urologists and others included endo-urologists, onco-urologists kidney transplant fellowships, pediatric urologists, female urologists, reconstructive urologists, and andrologists. active urologists both in public and private medical practice participated in the polling. urology residents were also amongst the participants. also, urologists from almost all provinces partook in the poll. all of the calculated codes were higher compared with current codes. urethroplasty showed the least increment with 25.22 equivalent to 51.69%, whilst extracorporeal shock wave lithotripsy showed the most increment of 63.59 equivalent to 114.37%. table 1 shows the current codes, calculated codes, and their differences and percentage of these differences in each 15 procedures. 1men’s health and reproductive health research center, shahid beheshti university of medical sciences, tehran, iran. 2iranian urological association (president), urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 3laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran. 4iranian urological association (board of directors), tehran university of medical sciences, tehran, iran. 5department of urology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 6hasheminejad kidney center (hkc), iran university of medical sceiences (iums), tehran, iran. *correspondence : email: department of urology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. fax: +982122736386. saeed.montazeri89@gmail.com. received september 2020 & accepted november 2020 urology journal/vol 18 no. 3/ may-june 2021/ pp. 347-348. [doi: 10.22037/uj.v16i7.6445 ] table 1. comparison of current and calculated procedures codes. various administrations around the world have developed different coding systems to address clinical terminologies and nomenclatures(5). in the united states, for example, the cpt editorial panel consisting of an independent group of experts appointed by the american medical association board of trustees is responsible for cpt code set maintaining and updating. they represent various parts of the health care industry and their task is to guarantee the evidence-based review of the code changes(6). in iran, medical and healthcare procedures have been described as relative value units (rvu) based on cpt coding system(7), which is currently in its third edition. early investigations by the national institute of health research showed some degrees of satisfaction regarding rvus amongst the patients whereas some researchers reported less satisfaction amongst healthcare professionals based on their technical and methodological concerns about the new rvus(8). in the current study, we aimed to compare the calculated codes based on urologists' point of view. 15 urological procedures were appointed as exemplar urological procedures for investigating their values. all of the calculated codes were higher compared with current codes. in the united states, cpt editorial panel meets three times each year in which hospitals, medical specialty societies, individual physicians, and third-party payers can submit their request for changes in cpt to be considered by the editorial panel(9). to make changes in cpt in low-to-middle-income countries such as islamic republic of iran seem even more necessary, specially due to economic turbulences. there is also evidence suggesting that such discrepancies between the current codes and so-called "should be codes" can lead to more informal payments even in more developed countries (10). even though the results of this study focused solely on urologists and other involved parties' opinions are not investigated but still, it can be considered as urologists' standpoint in future changes of cpt codes. therefore, appropriate evaluation and monitoring programs should exist to adapt the rvus to any policy circumstances as well as environmental and systemic changes, with the aim of generating sustainable solutions for the whole health system survival. references 1. meara jg, leather aj, hagander l, alkire bc, alonso n, ameh ea, bickler sw, conteh l, dare aj, davies j, mérisier ed. global surgery 2030: evidence and solutions for achieving health, welfare, and economic development. the lancet. 2015 aug 8;386(9993):569-624. 2. bath m, bashford t, fitzgerald je. what is ‘global surgery’? defining the multidisciplinary interface between surgery, anaesthesia and public health. bmj global health. 2019 oct 1;4(5). 3. ducatman bs. cytology-diagnostic principles and clinical correlates. elsevier-health sciences division; 2014. 4. mathauer i, wittenbecher f. hospital payment systems based on diagnosis-related groups: experiences in low-and middle-income countries. bulletin of the world health organization. 2013 aug 6;91:746-56a. 5. peden ah. an overview of coding and its relationship to standardized clinical terminology. topics in health information management. 2000 nov 1;21(2):1-9. 6. ama: american medical association; 2019 available from: https://www.ama-assn.org/ practice-management/cpt/cpt-overview-andcode-approval [access date: 2020] 7. olyaeemanesh a, manavi a, monazzam k. documentation and studies conducted at the department of health economics. department of health, ministry of health and medical education, iran. 2004. 8. moradi-lakeh m, vosoogh-moghaddam a. health sector evolution plan in iran; equity and sustainability concerns. international journal of health policy and management. 2015 oct;4(10):637. 9. ama: american medical association; 2019 available from: https://www.ama-assn.org/ about/cpt-editorial-panel/cpt-code-process [access date: 2020] 10. johnson se, newton wp. resource-based relative value units: a primer for academic family physicians. family medicinekansas city-. 2002 mar 1;34(3):172-6. table 1. comparison of current and calculated procedures codes. procedure current code calculated code difference percent open prostatectomy 42.00 97.38 55.38 131.86 turp 55.00 101.41 46.41 84.38 pcnl 68.00 116.02 48.02 70.62 tul 45.00 90.00 45.00 100.00 radical nephrectomy 62.50 113.83 51.33 82.13 radical prostatectomy 84.00 139.96 55.96 66.62 hypospadias 49.00 112.59 63.59 129.78 female incontinence sling 40.00 90.32 50.32 125.80 pyeloplasty 57.00 103.46 46.46 81.51 inguianl herniorrhaphy 28.50 67.87 39.37 138.14 reimplantation 61.00 108.00 47.00 77.05 urethroplasty 80.00 121.35 41.35 51.69 orchiopexy for udt 35.00 81.10 46.10 131.71 uds 25.00 50.22 25.22 100.88 eswl 15.00 66.51 51.51 343.40 turp: tranurethral resection of the prostate, pcnl: percutaneous nephrolithotomy, tul: tranurethral lithotripsy, udt: undescended testis, uds: urodynamic study, eswl: extracorporial shockwave lithotripsy letter 348 point of technique 295urology journal vol 6 no 4 autumn 2009 a safe surgical approach to a giant intrarenal arteriovenous fistula and aneurysm vijay naraynsingh, patrick harnarayan, seetharaman hariharan urol j. 2009;6:295-7. www.uj.unrc.ir keywords: renal artery, arteriovenous aneurysm, urologic surgical procedures department of clinical surgical sciences, university of the west indies, eric williams medical sciences complex, mount hope, trinidad, west indies corresponding author: seetharaman hariharan, md department of clinical surgical sciences, university of the west indies, eric williams medical sciences complex, trinidad, west indies tel: +868 662 4030 fax: +868 662 4030 e-mail: uwi.hariharan@gmail.com received november 2008 accepted april 2009 introduction giant arteriovenous fistulas (avf) pose a challenging management problem with respect to open surgery versus endovascular interventional techniques. endovascular techniques may not be ideal for larger fistulas and may be associated with potential risks of embolism, whilst open surgery poses the risk of uncontrollable hemorrhage.(1,2) we describe a safe surgical technique for this challenging problem. case report a 43-year-old woman presented with worsening hypertension that required increasing doses of antihypertensive drugs for control. she had no past history of surgery, kidney biopsy, or trauma. on clinical examination, an expansile pulsatile mass and an overlying thrill were palpated in her left loin. angiography showed a normal right renal artery, vein, and kidney. on the left, the renal vein was as wide as the inferior vena cava and the tortuous renal artery was almost as large as the abdominal aorta. the high flow avf showed simultaneous arterial and venous opacification (figure 1). renal scintigraphy showed 43% function on the right side and 57% function on the left. cardiovascular assessment revealed neither cardiomegaly nor high-output cardiac failure. nephrectomy was recommended since facilities for advanced interventional radiology were not available at that time. moreover, the risks of these options are considerable if the avf is large, as in this case. figure 1. angiography showed simultaneous arterial and venous opacification. ivc indicates inferior vena cava; lrv, left renal vein; ao, aorta; and avm, arteriovenous malformation. intrarenal arteriovenous fistula and aneurysm—naraynsingh et al 296 urology journal vol 6 no 4 autumn 2009 technique through a flank incision, the pulsatile left kidney was mobilized anteriorly by dissecting outside gerota’s fascia posteriorly, thus avoiding the enlarged veins. the aorta was approached posteriorly (well posterior to the left kidney), leaving only the fascia over the quadratus lumborum and psoas major behind. the tortuous huge renal artery was exposed without difficulty and ligated, prior to any attempt at dissecting the kidney or the veins. the renal pulsation immediately disappeared; it was then quite easy to dissect anterior to the kidney to expose and ligate the renal, suprarenal, and gonadal veins to complete the nephrectomy. the patient recovered uneventfully and her antihypertensive regimen decreased to single-drug therapy at a reduced dose. results grossly, a 2.5-cm intrarenal aneurysm with atheroma was identified with a 4-mm communication with the renal vein (figure 2). histology revealed cystic dilatation of vascular malformation within the kidney including artherosclerotic degenerative changes of the vascular wall. sections of renal parenchyma showed cortical atrophy, interstitial infiltrates of mononuclear cells, and medial hypertrophy of medium-sized arteries. the renal artery showed early myxoid degenerative changes of the media. features were consistent with hypertensive changes in the kidney. discussion aneurysmal intrarenal avfs are very uncommon. they are usually classified into 3 groups by etiology—congenital, acquired, and idiopathic.(1) congenital malformations account for almost 20% of the presentations. patients with acquired avf may have a history of trauma, neoplasm, previous renal surgery, or biopsy done many years ago.(3) according to this classification, our patient could be categorized as idiopathic avf. although usually asymptomatic, some patients may present with painless hematuria due to erosion of the avf into the collecting system. other common presentations include flank pain, worsening hypertension, and a palpable thrill in the lumbar region. the risk of spontaneous rupture is small; however, it may be sudden and dramatic, presenting as massive retroperitoneal hemorrhage requiring emergency intervention. (4) cardiomegaly on the chest radiography is a corroborative finding which improves following treatment.(5) our patient presented with refractory hypertension and palpable thrill, but did not have cardiomegaly. diagnosis of intrarenal avfs can be made by magnetic resonance angiography or duplex scan with color flow augmentation. computerized tomographyangiography using 2.5-mm cuts through the collecting system with delayed imaging, gives good visualization of the feeding and draining vessels.(6) however, routine digital subtraction angiography is regarded as the gold standard. our patient had a digital subtraction angiography and renal scintigraphy as preoperative imaging studies. currently, there are a number of treatment options available for avfs. endovascular techniques have been well documented, using staged methods such as metallic coils and various sutures which reduce flow and cause thrombosis of the fistula.(1) releasable balloons mounted on a coaxial microcatheter can also be utilized to produce complete fistula occlusion, thus providing a relatively safe method of closure.(7) although transcatheter embolization techniques have been reported for large renal avfs, there is a significant risk of renal parenchymal infarction, postembolization fever and flank pain.(2,8,9) figure 2. gross appearance of the intrarenal aneurysm shows the communication. c indicates communication between aneurysm and renal vein. intrarenal arteriovenous fistula and aneurysm—naraynsingh et al urology journal vol 6 no 4 autumn 2009 297 the presence of a high-flow fistula with a large diameter increases the chance of coil migration, pulmonary embolism, incomplete occlusion, and outright failure to close the fistula. these may lead to unnecessary delay in recovery, prolonged hospital stay, excessive cost overruns, and probably, emergency salvage surgery.(10) for high-flow intrarenal avfs, surgery has been found to be a reliable method of treatment. however, during the surgery, it may be difficult to gain proximal and distal aortic control due to the tortuous nature of the renal artery, and injury may occur to the abnormally large renal veins.(10) gralino and colleagues considered their case to be at excessive risk for nephrectomy because of anticipated technical difficulties in controlling inflow and hemorrhage.(1) we believe that this risk can be virtually eliminated if the initial dissection is carried out posterior to the gerota’s fascia and directed towards exposing the aorta from its left posterolateral aspect at the level of the renal artery. this plane, even with huge intrarenal avf, is almost avascular; the only dilated vein that may be encountered in this plane is the lumbar vein, which communicates with the left renal vein. however, because the lumbar vein is closely apposed to the aorta, the tortuous, dilated renal artery will be encountered first and ligated far lateral to the aorta, thus minimizing or eliminating the risk of hemorrhage from this vein. in summary, the surgical approach to the renal artery, as described, from the posterolateral aspect of the aorta behind the gerota’s fascia and retroperitoneal fat, leaving only the quadratus lumborum and the psoas muscles posteriorly, provides a safe and almost bloodless access in an otherwise highly vascular field. conflict of interest none declared. references 1. gralino bj jr, bricker dl. staged endovascular occlusion of giant idiopathic renal arteriovenous fistula with platinum microcoils and silk suture threads. j vasc interv radiol. 2002;13:747-52. 2. kearse ws jr, joseph ae, sabanegh es jr. transcatheter embolisation of large idiopathic renal arteriovenous fistula. j urol 1994;151:967-9. 3. okamura t, tatsura h, kohri k. asymptomatic intrarenal arteriovenous fistula accompanying severe renal vein dilatation detected 30 years after percutaneous renal biopsy. urol int. 1998;61:261-2. 4. hagikura m, okamoto n, tanaka k, tomita h, mizutani m. spontaneous rupture of an aneurysmal arteriovenous fistula of the kidney causing massive retroperitoneal hemorrhage: a case report. hinyokika kiyo. 2008;54:273-5. 5. osawa t, watarai y, morita k, kakizaki h, nonomura k. surgery for giant high-flow renal arteriovenous fistula: experience in one institution. bju int. 2006;97:794-8. 6. dönmez fy, coşkun m, uyuşur a, et al. noninvasive imaging findings of idiopathic renal arteriovenous fistula. diagn interv radiol. 2008;14:103-5. 7. djellouli n, boyer l, ravel a, et al. cure of renovascular hypertension by percutaneous occlusion of a large idiopathic renal arteriovenous fistula. case report int angiol. 1997;16:255-7. 8. lupattelli t, garaci fg, manenti g, belli am, simonetti g. giant high-flow renal arteriovenous fistula treated by percutaneous embolization. urology. 2003;61:837. 9. giavroglou ce, farmakis tm, kiskinis d. idiopathic renal arteriovenous fistula treated by transcatheter embolisation. acta radiol. 2005;46:368-70. 10. smaldone mc, stein rj, cho js, leng ww. giant idiopathic renal arteriovenous fistula requiring urgent nephrectomy. urology. 2007;69:576.e1-3. september-october 2018 reviewer of the issue farhad pishgar farhad pishgar october 2018 farhad pishgar, md mph, is currently a senior research assistant at non-communicable diseases research center at tehran university of medical sciences, tehran, iran. farhad went to medical school there back in 2010, and in 2013, he was among the 40 scholars who were selected to study mph in a dual degree program at the school. completing these degrees, farhad was provided with foundational knowledge and skills in clinical medicine as well as the science and practice of the public health. he was equipped with the necessary tools and knowledge to address the health challenges and complex health issues both on individual and population levels. farhad joined the scientific teams of noncommunicable diseases and uro-oncology research centers at tehran university of medical sciences back in 2015. his aspiration for public health and his knowledge in urological sciences led him to collaborate in several projects on estimating the burden of diseases, including the urological malignancies, at national and subnational levels at these centers. his works resulted in the publication of more than 25 peer-reviewed scientific papers, most of which are multicenter projects through collaboration with international institutes, including the university of washington, the university of southern california, the university of british columbia, and the johns hopkins university. through his academic career, farhad won several honors and awards; gold medal of national and silver medal of international student biology olympiads, the prestigious avecinna award for the best medical researcher, and the farin kamangar award for the outstanding medical research, to name some. “i view peer-review, not only as the basic tool to optimize scientific methods of articles and reporting of findings but also as an educational opportunity to authors and the reviewers themselves. i would like to appreciate the policies of the urology journal to engage early-career researchers in the journal’s peer-review practice.” farhad was chosen as the best reviewer of the issue by the editorial board of the urology journal for his valuable and timely review of manuscripts. high resolution melting analysis for rapid detection of pik3ca gene mutations in bladder cancer: a mutated target for cancer therapy zahra ousati ashtiani1, 2, abdol rasoul mehrsai1, mohammad reza pourmand3, gholamreza pourmand1* purpose: pik3ca gene mutations have clinical importance and their presence is associated with therapy response. they are also considered as a molecule for targeted therapy. as regards to their importance, genetic variation within a population as well as among different populations, this study was conducted to detect common mutations of exons 9 and 20 and other probable mutations in pik3ca gene as well as their frequencies in iranian bladder cancer patients. materials and methods: paired tumor and adjacent normal tissues samples were obtained from 50 bladder cancer patients. mutations of pik3ca gene were detected using high resolution melting (hrm) analysis which is a highly sensitive, repeatable, rapid, and cost-effective technique. to determine the precision of the hrm analysis, sanger sequencing analysis was used. results: the result showed that mutations were present in 10% (5/50) of the subjects. the majority of these cases (4/5) had the mutation(s) in exon 9, spanning over five different mutations, among which three of them were actually novel mutations. further analysis showed that 2 cases had simultaneous mutations for exon 9. in addition to novel mutations, the pik3ca mutation rate observed in iranian bladder patients was not as frequent as previous reports and cosmic. conclusion: hrm can be used as a rapid and sensitive method for mutation screening. dysregulation of pik3ca gene in bladder cancer reveals its potentials as a mechanistic link for cancer development, which in turn suggests its special use in interventional studies for targeted therapy. keywords: bladder cancer; high resolution melting; mutation; pik3ca gene; targeted therapy. 1urology research center, sina hospital, tehran university of medical sciences, tehran, 113746911, iran. 2department of medical genetics, school of medicine, tehran university of medical sciences, tehran, 1417613151, iran. 3division of microbiology, department of pathobiology, school of public health, tehran university of medical sciences, tehran, 1417613151, iran. *correspondence: urology research center, sina hospital, tehran university of medical sciences, tehran, iran. received may 2017 & accepted october 2017 introduction bladder cancer is one of the most frequent non-cu-taneous solid malignancies next to prostate cancer among the most common genitourinary cancers worldwide(1). it is caused by both genetic and environmental factors. according to iranian cancer registry report, it represents the fourth most common cancer and even the second most common in some regions in men with less frequency in women. although, the occurrence of bladder cancer is increasing, but this increase rate is up to six times higher in developed countries(2,3). since close continuous surveillance by cystoscopy and other monitoring interventions are highly popular, i.e. for earlier detection of its recurrence, bladder cancer is considered to be one of the most costly cancers in health care systems. urothelial carcinoma is the most common type of bladder tumors that originate from epithelial cells. it consists of two major types: non-muscle-invasive (nmibc) which accounts for approximately 75% of the cases and muscle invasive (mibc)(4,5). remarkable inter-individual variations make it difficult to provide efficient therapeutic cares for a given patient, because of the significant heterogeneity of urothelial carcinomas in terms of its clinical and genetic backgrounds. such heterogeneity partly originates from different changes in different genes that affect signal transduction cascades, most notably pi3k/mtor/akt pathways. these dysregulations are potentially accountable for the initiation and progression of both nmibc and mibc(6,7). advances in our understanding of molecular pathogenesis of cancer have led to new approach of targeted therapies for many cancers. one of the most deregulated pathways in cancer is phosphatidylinositol 3-kinase signaling pathway (pi3k). this signaling pathway is involved in regulation of a number of normal processes such as cell growth, apoptosis, proliferation, and survival and will be activated by interacting with tyrosine kinase receptors(8-10). based on subunit structure, function and substrate selectivity, the phosphoinositol-3-kinase family is divided into three different classes. class ia pi3k, which is heterodimers, consists of a regulatory (p85) and catalytic (p110) subunits and is the one most clearly implicated in tumorigenesis and cancer progression. catalytic subunit p110 is encoded by pik3ca gene located on 3q26.3. p110α is important in the induction of the signaling cascade called pten/akt pathway. the genetic aberration of this gene has been associated with different cancer development. mutaurological oncology urological oncology 26 tions in the pik3cagene have been reported in head and neck squamous cell carcinomas (hnscc), breast, colorectal, gastric, endometrial and many other cancers with various frequencies(11-16). most of the pik3ca gene mutations are located at 3 hot spot codons in exon 9 (e542k, e545k) and exon 20 (h1047l). these exons are responsible for coding helical and kinase domains. pik3ca has been proposed as an oncogene, due to its high mutation frequency, being heterozygous missense changes and clustering mutations in 2 hot spot exons. these characteristics may be related to kinase activity. oncogenic mutation of pik3ca in human cancers with its clinical importance makes it a target for cancer therapy studies on urothelial carcinoma confirmed that the pik3ca gene changes are present in 13 to 35% of the cases and this rate decreases when the tumor’s stage and grade are increasing. also, it has been reported that other genes such as fgfr3 are involved in superficial lowgrade bladder cancer that is more frequently associated with pik3ca gene mutations(5,17-21). in addition to mutations, gene amplification or increased copy gains have been reported. it has been reported in recent studies that pik3ca mutations can independently hamper the therapeutic response to anti-egfr biological therapies(22). among the mutation detection methods, high resolution melting (hrm) is a powerful technique in molecular biology. it is a simple polymerase chain reaction (pcr)-based method used for the discovery of dna sequence variations by measuring changes in the melting curve of a dna without the need for any post-pcr handling. in other words, hrm analysis is the quantitative analysis of the melt curve of a dna fragment. unlike other methods, hrm has many advantages, such as high sensitivity, repeatabiliy, rapid turn-around time that greatly diminishes contamination risk, and low cost (23). considering the importance of molecular targeted therapy, conflicting responses of bladder cancer cells owing to mutations in some genes in signaling pathways and some inhibitors were assessed in clinical trials in bladder cancer patients. more importantly, since there are considerable genetic variation within a population and also among different populations, this study was conducted to detect common mutations of exons 9 and 20 and other probable mutations in pik3ca gene as well as their frequencies in iranian bladder cancer patients by using hrm analysis which is a useful method for mutation screening with high analytical sensitivity. material and methods patients and tissue samples bladder tumor and adjacent normal tissue samples were obtained from 50 iranian individuals who underwent transurethral bladder tumor resection or radical cystectomy at the sina and imam khomeini hospitals. cancerous and their adjacent non-cancerous samples as normal control both from the bladder were rapidly frozen in liquid nitrogen following collection and were stored at -80 until subsequent rna and dna extraction. two experienced pathologists appraised the grade, stage, and nodal status. of the 50 patients, 45 were males and 5 were females with the mean age of 67.3 ± 10 years. none of the patients received previous treatment such as bcg therapy, radiotherapy or chemothertable 1. list of primer sets for hrm, sanger sequencing primers sequence amplicon size pik3ca ex9fhrm aattaagggaaaatgacaaagaacagc 114 pik3ca-ex9rhrm attttagcacttacctgtgactcc pik3ca-ex20f-hrm aagaggctttggagtatttcatg 99 pik3ca-ex20r-hrm catgctgtttaattgtgtggaag pik3caex9f-sequencing ccagaggggaaaaatatgaca 196 pik3ca-ex9-sequencing cattttagcacttacctgtgac pik3ca -ex20-sequencing catttgctccaaactgacca 387 pik3ca-ex20r-sequencing ggtctttgcctgctgagagt figure 1. examples of melting curves of wild and mutant samples. shoulders on curves demonstrate nucleotide changes in pik3ca gene. figure 2. normalized (a) and differenc (b) graphs of wild and mutant samples. hrm analysis of pik3ca mutations in bc-ousati ashtiani et al. vol 15 no 01 january-february 2017 27 urological oncology 28 apy prior to surgery and sample collection. all participants in this research signed written informed consent. this study was approved by research review board and also the ethics committee of tehran university of medical sciences (tums) (ethic code: ir.tums. rec.1395.2895). dna extraction genomic dna from cancerous and normal frozen tissue samples were extracted by high pure pcr template preparation kit (roche) according to manufacturer instructions. the quality and quantity of dna were assessed by spectrophotometry with nanodrop -2000 (thermo, usa). dna template samples were diluted to 20-30 ng /μl for using in hrm analysis. primer design specific set of primers for each of the pik3ca exons 9 and 20 that embrace hotspot regions were designed for hrm analysis with pre-amplification. for sanger sequencing, other sets of primers for exons 9 and 20 were used to have a suitable length of amplicons. primers sets were checked by primer-blast and oligoanalyzer software. table 1 shows the primers sequences and amplicon lengths. high resolution melting analysis hrm analysis with pre-amplification was performed on rotor-gene q 5-plex hrm (qiagen, germany) using 0.1 ml strip tubes (qiagen, gmbh) in the presence of evagreen, the fluorescent dna intercalating dye. the reaction was conducted in a 20 μl final volume containing 4 μl 5x hot firepol evagreen qpcr mix (solis biodyne), 0.5 μl of 10 pmol/μl primers (forward and reverse) and 20-30 ng⁄μl dna sample. for each exon, one mixture was prepared. two verified samples with and without mutation were used as a positive and negative control, respectively. hrm was performed in duplicate on all samples. cycling for pre-amplification and melting conditions were as follows: an initial denaturation at 95°c for 10 minutes, followed by 40 cycles of 15 seconds at 95°c, 20 seconds at 60°c, and 20 seconds at 72°c, followed by melting from 75°c to 85°c. the temperature was increased by 0.1°c/sec. all data and melting curves from different samples were analyzed using rotor-gene q series software version 2.0.2. to confirm the findings resulted by hrm analysis, the samples were subjected to sequencing. for pcr reaction, primers for exons 9 and 20 were added to pcr master mix (takara) separately, and dna was added. pcr was performed on sensoquest lab cycler. finally, pcr products were applied for sequencing. statistical analysis using fisher´s exact test or pearson chi-square, the results were statistically analyzed by spss version 21 and clinicopathologic parameters total wild type muted p-value number percent number percent number percent age (year) 0.353 ≤67 4 8 3 6.7 1 20 >67 46 92 42 93.3 4 80 stage 0.616 i 21 42.9 18 40.9 3 60 ii 20 40.8 19 43.2 1 20 iii 6 12.2 5 11.4 1 20 iv 2 4.1 2 4.5 0 0 grade 0.584 low 12 24.5 10 22.7 2 40 high 37 75.5 34 77.3 3 60 tumor type 0.638 non-invasive muscle 21 42 18 40.0 3 60 invasive muscle 29 58 27 60.0 2 40 family history of bladder cancer 0.566 no 44 78 40 88.9 4 80 yes 6 12 5 11.1 1 20 family history of other cancer 0.736 no 49 98 44 97.8 5 100 yes 1 2 1 2.2 0 0 smoker 0.690 no smoker 23 46 20 44.4 3 60 ≤10 years 1 2 1 2.2 0 0 >10 years 26 52 24 53.3 2 40 occupational exposure 0.004 yes 18 36 13 28.9 5 100 no 32 64 32 71.1 0 0 table 2. demographics and clinical characteristics of participants pik3ca nucleotide change protein (codon,amino acid) mutation type exon 9 c.1571g>a r524k missense c.1578t>a n526k missense c.1624g>a e542k missense c.1633g>a e545k missense c.1638g>a e547r missense exon20 c.3140 a>t h1047l missense table 3. mutations in exon 9 and 20 of pik3ca gene hrm analysis of pik3ca mutations in bc-ousati ashtiani et al. p value was set at 0.05 or less to indicate statistically significant difference. kolmogorovsmirnov test was performed to assess the normality of quantitative data. results a total of 50 bladder cancer patients including 45 (90%) men and 5 (10%) women participated in this study. pik3ca hot spot mutations and pik3ca gene expression at mrna level were examined. table 2 shows the demographic and clinicopathological characteristics of all the patients. their median age was 67 years (33 to 87 years). there were 26 patients (54.5%) with smoking habit and 98% of them were cigarette smoker for more than 10 years and 13.6% were opium-addict. among these patients, 14% were suffering from diabetes and 54% had cardiovascular and respiratory diseases. the rate of occupational exposure was about 38%. pik3ca mutations hot spot mutations in exons 9 and 20 of pik3ca gene were screened in tumors and adjacent non-tumor tissues of all the subjects using hrm analysis. mutation 10% (5/50) was detected in pik3ca gene in tumor tissues. melting curve and normalized graph for hrm are as shown in figures 1and 2. direct sanger sequencing confirmed and documented the exact mutational parameters (figure 3). in addition to hot spot mutations, e542k and e545k in exon 9, three novel mutations in the helical domain of pik3ca gene that lead to amino acid substitution in r524k and n526k, and e547r were also evident. it was notable that two samples harbored two and three mutations simultaneously. no mutation was found in non-tumor tissues. most of the mutations were clustered in helical domain of pik3ca, whereas only one mutation (h1047l) was located in the kinase domain. nucleotide changes in exons 9 and 20 pik3ca gene are shown in table 3. the relationships between tumors characteristics and the mutations were analyzed. there was no statistically significant correlation between age, grade, stage, and other indices concerning the mutations. while occupational exposures showed a significant relationship (p = .005), no relationship was found when smoking habit was compared with the mutations’ status. discussion in the present study, hrm being a sensitive, rapid and cost-effective and simple approach was used to screen pik3ca gene mutation, which is a key component of the pi3k pathway. hrm with sanger sequencing showed new mutations in addition to hot spot mutations in pik3ca gene. the pi3k signaling pathway is associated with a number of oncogenes and multiple receptor classes for several basic cellular functions. it has been proposed to be the most commonly activated signaling pathway in human cancers(24-25). there are several lines of evidence that show different mutations at pik3ca gene to be one of the main mechanisms responsible for pi3k pathway activation in cancer cells (5,9,26). therefore, it has been considered that cancer accompanied by pik3ca mutations could be the potential candidate for targeted therapeutic intervention with catalytic subunit (p110α) specific-inhibitor. moreover, pik3ca mutations can independently hinder the therapeutic response to anti-receptor tyrosine kinase therapy(27). common hot spot mutations were examined in pik3ca gene in our patients since the pattern of genetic makeup from health to disease states is highly dependent on the population racial background and as such more information are also needed for targeted therapy. to the best of our knowledge, this is the first study that examined the pik3ca mutations in iranian bladder cancer patients. out of the patients, almost 10% (5/50) cases harbored pik3ca mutations in relation to the prevalence of 13 to 35% reported in previous studies(5,9,10,17,18). in the present study, nearly 75% of subjects had high-grade tumor that explains the lower frequency of mutation in the study. this frequency has been observed to decrease in the case of advanced stage and grade tumors. however, a much higher frequency of 18% for these mutations has also been reported for high-grade tumor of the bladder cancer(18). however, considering the fact that the high frequency (35%) of pik3ca gene mutations is present in superficial bladder tumors (low grade, low stage) and the low frequency is present in bladder cancer cases with muscle invasive tumors and advanced stage and grade(5,10), pik3ca gene mutations were postulated to be early event in bladder carcinogenesis process. on the other hand, the disagreement in pik3ca mutations rate among different reports can be partly explained by ethnic variation, population base diversity, and methodological parameters including preferences in mutation detection techniques and histopathological heterogeneity within individual tumor type. the majority of the pik3ca mutations in the present research were clustered in helical domain (exon 9) of pik3ca gene which is in agreement with previous findings of bladder cancer(5,9,28). besides, hot spot codons e542k and e545k mutations are available at catalogue of somatic mutations in cancer (cosmic) (http://cancer.sanger.ac.uk/cosmic), hence, three novel mutations: r524k, 526k, and e547r were reported. figure 3. mutations in exon 9 and 20 of pik3ca gene. first and second rows show normal and mutant sequences, respectively. hrm analysis of pik3ca mutations in bc-ousati ashtiani et al. vol 15 no 01 january-february 2017 29 urological oncology 30 remarkably, in one sample, three mutations were present at the same time. although, occupational exposures have shown statistically significant correlation with mutation presence (p = .005), there was no significant relationship between mutations and other clinicopathological parameters. the habit of tobacco smoking has been reported to be the most well-known risk factor for bladder cancer development, but no significant relationship was observed between this habit and mutations, whereas more than half of the cases in the present study were smoker. the lack of significant correlation may be as a result of the relatively small number of samples in this study. according to some reports, it seems that pik3ca gene mutations’ specific location in association with, or development of, different cancers have a particular implication that may partly translate their heterogeneity at the molecular level. for example, in contrast to bladder cancer, breast cancer mutations in the kinase domain (exon 20) are more common than in the helical domain as the mutation rate sharply rises to 25-40% (12,16,24,25,28,29). also, in colon cancer, heterogeneity may depend on different histological aspects of the lesion(30). conclusions to the best of our knowledge, this is the first study on pik3ca mutations in iranian bladder cancer patients. pik3ca hot spot mutations and three new variants were detected in 10% of the cases. also, hrm analysis was confirmed to be a rapid and low-cost method for mutation screening. since pik3ca gene is considered as a target for cancer therapy and the mutations of this gene can resist some anti-tumor agents for individualized medicine in our patients, a better understanding of both general and specific events that took place at the cellular and molecular level in bladder cancer is needed. this comprehensive study would make it possible to design new targeted and tailored interventions by considering both the subject who has the disease and the disease itself. acknowledgments this study was financially supported by a grant from tehran university of medical sciences (tums) (grant no. 23368). we would like to thank mrs fariba heidari for her contribution in administrative issues. conflict of interest the authors declare that there is no conflict of interest in this study. references 1. jemal a, bray f, center mm, ferlay j, ward e, forman d. global cancer statistics. ca cancer j clin. 2011; 61:69-90. 2. salehi a, khezri a, malekmakan l, aminsharifi a. epidemiologic status of bladder cancer in shiraz, 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alterations in cancer: variations on a theme. oncogene 2008; 27:5497-510. 9. platt fm, hurst cd, taylor cf, gregory wm, harnden p, knowles ma. spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. clin can res. 2009; 15:6008-17. 10. knowles ma, platt fm, ross rl, hurst cd. phosphatidylinositol 3-kinase (pi3k) pathway activation in bladder cancer. can metas rev. 2009; 28:305-16. 11. kommineni n, jamil k, pingali u, addala l, naidu m. association of pik3ca gene mutations with head and neck squamous cell carcinomas. neoplasma. 2014; 62: 72-80. 12. kandula m, chennaboina kk, ammi r, raju s. phosphatidylinositol 3-kinase (pi3kca) oncogene mutation analysis and gene expression profiling in primary breast cancer patients. asian pac j cancer prev. 2013; 14:5067-72. 13. dirican e, akkiprik m, özer a. mutation distributions and clinical correlations of pik3ca gene mutations in breast cancer. tumor biol. 2016; 37: 7033-7045. 14. guedes j g, veiga i, rocha p, et al. high resolution melting analysis of kras, braf and pik3ca in kras exon 2 wild-type metastatic colorectal cancer. bmc cancer. 2013; 13: 169. 15. konopka b, janiec–jankowska a, kwiatkowska e, et al. pik3ca mutations and amplification in endometrioid endometrial carcinomas: relation to other genetic defects and clinicopathologic status of the tumors. hum pathol. 2011; 42: 1710-19. 16. tserga a, chatziandreou i, michalopoulos nv, patsouris e, saetta aa. mutation of genes of the pi3k/akt pathway in breast cancer supports their potential importance as biomarker for breast cancer aggressiveness. virchows arch. 2016; 469: 35-43. 17. lópez-knowles e, hernández s, malats n, et al. pik3ca mutations are an early genetic alteration associated with fgfr3 mutations in superficial papillary bladder tumors. cancer res. 2006; 66: 7401-4. 18. serizawa rr, ralfkiær u, steven k, et al. integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of fgfr3 mutations and hypermethylation events. int j cancer. 2011; 129: 78-87. 19. kompier lc, lurkin i, van der aa mn, van rhijn bw, van der kwast th, zwarthoff ec. fgfr3, hras, kras, nras and pik3ca mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. plos one. 2010; 5: e13821. 20. juanpere n, agell l, lorenzo m, et al. mutations in fgfr3 and pik3ca, singly or combined with ras and akt1, are associated with akt but not with mapk pathway activation in urothelial bladder cancer. hum pathol. 2012; 43: 1573-82. 21. agell l, hernández s, salido m, et al. pi3k signaling pathway is activated by pik3ca mrna overexpression and copy gain in prostate tumors, but pik3ca, braf, kras and akt1 mutations are infrequent events. mod path. 2011; 24: 443-52. 22. vorkas pa, poumpouridou n, agelaki s, kroupis c, georgoulias v, lianidou es. pik3ca hotspot mutation scanning by a novel and highly sensitive high resolution small amplicon melting analysis method. j mol diagn. 2010; 12: 697-704. 23. montgomery jl, sanford ln, wittwer ct. high-resolution dna melting analysis in clinical research and diagnostics. expert rev mol diagn. 2010; 10: 219-40. 24. nosho k, kawasaki t, longtine ja, et al. pik3ca mutation in colorectal cancer: relationship with genetic and epigenetic alterations. neoplasia. 2008; 10: 534-41. 25. xing jc, tufano rp, murugan ak, et al. single nucleotide polymorphism rs17849071 g/t in the pik3ca gene is inversely associated with follicular thyroid cancer and pik3ca amplification. plos one. 2012; 7: e49192. 26. wong k k, engelman j a, cantley l c. targeting the pi3k signaling pathway in cancer. currt opin genet dev. 2010; 20: 8790. 27. nisa l, häfliger p, poliaková m, et al. pik3ca hotspot mutations differentially impact responses to met targeting in metdriven and non-driven preclinical cancer models. mol cancer. 2017; 16: 93-106. 28. millis sz, bryant d, basu g, et al. molecular profiling of infiltrating urothelial carcinoma of bladder and nonbladder origin. clin genitourin cancer 2015; 13:e37-e49 29. azizi tabesh g, izadi p, fereidooni f, emami razavi an, tavakkoly bazzaz j. the high hrm analysis of pik3ca mutations in bc-ousati ashtiani et al. frequency of pik3ca mutations in iranian breast cancer patients. cancer inves. 2017; 35:36-42 30. bonetti l r, barresi v, bettelli s, caprera c, manfredini s, maiorana a. analysis of kras, nras, pik3ca and braf mutational profile in poorly differentiated clusters (pdc) of kras mutated colon cancer. hum pathol. 2017; 62: 91-98 vol 15 no 01 january-february 2017 31 1 an update on biochemical and genomic markers for prostate cancer authors: reza falahatkar (m.d.) student research committee, school of medicine, guilan university of medical sciences, rasht, iran email: rfalahatkar76@gmail.com gholamreza mokhtari (m.d.) urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran email: gh.mokhtari@yahoo.com madjid momeni-moghaddam (m.d.) department of biology, hakim sabzevari university, sabzavar, iran email: urc1384@yahoo.com mojtaba teimoori (m.d.) (corresponding author) urology department, sabzevar university of medical sciences, sabzavar, iran email: mojtaba_teimoori@yahoo.com address: urology research center, razi hospital, rasht, iran telfax: 00981333525259 hamidreza baghani aal (m.d.) urology department, sabzevar university of medical sciences, sabzavar, iran email: hamidreza_baghani@yahoo.com ardalan akhavan (m.d.) urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran email: ardalan.akhavan@gmail.com siavash falahatkar (m.d.) urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran email: falahatkar_s@yahoo.com samaneh esmaeili (m.s.) urology research center, razi hospital, school of medicine, guilan university of medical sciences, rasht, iran email: samaneh_815@yahoo.com running title: biochemical and genomic markers for prostate cancer keywords: prostate cancer, biomarkers, genetic test, diagnosis, prognosis mailto:rfalahatkar76@gmail.com mailto:gh.mokhtari@yahoo.com mailto:urc1384@yahoo.com mailto:mojtaba_teimoori@yahoo.com mailto:hamidreza_baghani@yahoo.com mailto:ardalan.akhavan@gmail.com mailto:falahatkar_s@yahoo.com mailto:samaneh_815@yahoo.com 2 abstract: purpose: detecting prostate cancer, developing therapeutic plans after negative biopsies, and prognosisbased patient counseling can be challenging for many urologists dealing with prostate cancer-specific antigens. new biomarkers advances made improvement for prediction of responses to therapeutic option and can tell us about survival and recurrence. in this review, we have assessed current and upcoming biomarkers that are opening a new era in diagnosing the disease. materials and methods: we conducted a comprehensive literature review of studies describing prostate cancer biomarkers. two independent investigators searched pubmed, embase, web of science, and cochrane databases to identify biomarkers in prostate cancer conducted a literature review. results: recently, combining prostate cancer-specific biomarkers into a single test has gained increasing attention, especially since the introduction of genomic and molecular tools. the development of the prostate health index (phi), selectmdx, and confirm mdx have shown promising results for prostate cancer detection, in addition to risk stratification and biopsy avoidance. conclusion: despite major improvements and innovations in prostate cancer biomarkers, application in current clinical practice is limited. however, these biomarkers have an important role in determining risk, preventing unnecessary prostate biopsies, and predicting prognoses. additional confirmatory studies will be needed to fully understand the impact of prostate cancer-specific biomarkers. keywords: prostate cancer, biomarkers, genetic test, diagnosis, prognosis. 3 introduction prostate cancer is one of the most common cancer and the fifths leading cause of cancer-related mortality in men.(1) this is compounded by the fact that prostate cancer incidence is increasing, especially in countries with higher socioeconomic development. however, global mortality rates have only marginally improved.(2) there is a considerable debate concerning the role that current prostate-specific cancer biomarkers have in decreasing mortality rates. issues include over-diagnosis and biopsies with negative results or indolent cancers that can cause complications. this has led many to suspect that biomarkers have only a small effect on patient survival.(3) finding new and better genomic and biochemical markers to detect those at high risk of prostate adenocarcinoma is therefore essential. it is also important to differentiate benign and aggressive tumors and biomarkers that contribute to decision making after biopsy are required. finally, more biomarkers that are accurate will allow a better discussion with patients concerning prognosis, enabling medical practitioners to develop the most effective therapeutic plans as showed in image 1 and 2. therefore, the purpose of this review is to provide an up-to-date assessment of new and upcoming prostate-specific cancer biomarkers to help clinicians and patients come to the best possible treatment decisions. biomarkers that aid in reducing unnecessary biopsies prostate-specific antigen (psa) is a conventional biomarker commonly used for the detection of prostate cancer, although it has limited specificity. psa is a member of the kallikreins, a regulatory family of 15 serine proteases that are involved in the development of many malignant, inflammatory, and degenerative diseases. they all are expressed by prostatic tissue but psa (hklk3) is solely secreted by prostate epithelial cells.(4) both complexed and free psa are found circulating in the blood of patients. psa starts as a zymogen (prepropsa or [−7] propsa) that is cleaved by hk2 to make a propsa. subtraction of the propsa leads to the active form of psa. partial cleavage of propsa can produce other propsas that are particularly elevated in prostate cancer, such as [−2] propsa, [−4] propsa, and [−5] propsa. among the different psa isoforms 4 that have shown a role in prostate cancer detection, [-2] propsa (p2psa) has received the most attention as it has been found to be possess greater precision than other isoforms. (5) for applications in clinical settings, several studies have shown that a set of four serum kallikrein biomarkers used together can increase prostate cancer diagnostic accuracy in comparison to using only psa. (4) this test is known as the 4kscore test and includes tpsa, fpsa, ipsa, and hk2. image 1 provides an overview of the biomarkers recommended for prostate cancer diagnosis and determining therapeutic approaches. mixed biomarkers the 4kscore panel (opko lab, nashville, tn, usa) in combination with an assessment of clinical features, such as age and digital rectal examination (dre), and total psa levels, has been reported to be more accurate for diagnosing gleason 7 or more severe prostate cancers.(6) recent studies have also shown that the 4kscore panel helps physicians reclassify severity after an initial biopsy, although it did not add any predictive value for men diagnosed with prostate cancer during later surveillance biopsies.(7) recently, a report showed that combination of 4kscore panel and mri may decrease redundant prostate biopsies furthermore.(8) prostate health index (phi) the prostate health index (phi) is an encouraging new test based on prostate-specific antigen (psa) that aims to mathematically estimate the risk of prostate cancer using the formula (p2psa/free psa) × √psa. (9)the phi test has been used to prevent more than one third of avoidable biopsies and its failure rate for detecting prostate cancer is below 2%.(10) a recent meta-analysis of the diagnostic accuracy of the phi and 4kscore tests for detecting and predicting high-grade prostate cancer rates found phi more sensitive but 4kscore more specific. specifically, pooled sensitivity was 0.93 for phi and 0.87 for the 4kscore panel, whereas the diagnostic accuracy of phi was 0.82 and 0.81 for 4kscore. both the phi and the 4kscore tests had acceptable diagnostic accuracy rates for identifying overall and high-grade prostate cancer.(11) a recent 5 meta-analysis showed that combination of these 4kscore and prostate cancer antigen 3 may be more predictive together than any of these test lonely.(12) prostate-specific membrane antigen (psma) prostate-specific membrane antigen (psma) is a glycoprotein found in the serum, urine, and tissues of patients with prostate cancer and is a well-established biomarker. psma is expressed by the epithelium of prostate tissues, although it is also secreted by the central nervous system and intestine. recently, three splice variants of psma (psm′) have been defined as a possible new biomarker for prostate cancer, although data are limited.(13) psma is also a promising molecular probe for positron emission tomography (pet) that offers better detection compared to conventional imaging methods, particularly at the very low psa levels found during biochemical recurrence. the current imaging modalities used for detecting prostate cancer metastases have only modest accuracy. in addition to the possible diagnostic applications of psma, it may also have a therapeutic role involving the immune system that can delay disease progression.(14) for instance, a controlled in vivo study using a mouse model found that anti-psma monoclonal antibodies led to a decrease in tumor growth and prolonged survival rates.(15) prostate cancer antigen 3 (pca3) prostate cancer antigen 3 (pca3) is non-coding rna (ncrna) that can be measured by quantitative amplification using reverse transcription polymerase chaining reaction (rt-pcr]. the detection of pca3 in urine by rt-pcr can improve prostate cancer diagnoses. (16)more recently, a newer technique has been developed for pca3 detection that has improved sensitivity and quantitation. (16)the technique has been approved by the fda for informing therapeutics decisions and is typically used after a negative prostate biopsy. however, appropriate thresholds have become a matter of concern as different cutoff levels result in variable sensitivity and specificity rates.(17) a meta-analysis by cui et al. indicated that pca3 levels in the urine have high sensitivity and specificity,(18) although a more recent report has questioned the use of pca3 6 and suggested it may not be useful for determining intermediateor high-risk prostate cancers.(19) zhikui jiang et al report that score cutoff value of 20 as a best diagnostic efficacy.(20) tmprss2:erg gene fusions in normal prostate tissue, the erg proto-oncogene is inactive, although limited expression has been reported in other tissue types. during prostate cancer, erg is activated by gene fusion events, most frequently with tmprss2 to create tmprss2:erg.(21) the fusion of the tmprss2 promoter region to the erg oncogene is reported in half of all cases of prostate cancer and is a highly specific biomarker.(22) however, an important consideration is that the prevalence of tmprss2:erg fusions is lower in men of african descent, indicating that alternate genomic biomarkers may be more suitable for this population.(23) exo106 score exosomes are small lipid membrane vesicles produced by most cells of the body that often contain nucleic acids.(24) both exosomal pca3 and tmprss2:erg transcript levels are higher in the first voided urine after prostate massage and may be useful for diagnosis.(25) however, a combination of pca3 and erg transcript levels can also assessed without prostate massage by rt-pcr, termed the exo106 score.(26) although measuring exosomes remains challenging, it may become a standard method to assess the levels of important biomarkers, such as pca3 and erg . exodx prostate (intelliscore) the exodx prostateurine-based test (intelliscore; exosome diagnostics, inc., waltham, ma, usa) is an application of exo106 that aims to identify the presence of high-grade prostate cancer in men over 50 years of age and psa levels between 2-20 mg/ml. the test detects rna from three specific genes (erg, pca3, and spdef) in the urine and combines analysis with clinical findings (psa levels, age, race, and family history) to diagnose the disease.(27) decipher https://pubmed.ncbi.nlm.nih.gov/?term=jiang+z&cauthor_id=30203935 https://pubmed.ncbi.nlm.nih.gov/?term=jiang+z&cauthor_id=30203935 7 decipher, developed by genome dx biosciences (vancouver, canada) and the mayo clinic (rochester, mn, usa), is a genomic panel of rna biomarkers that assays the expression of 22 different genes. it is a validated genomic classifier used to predict metastasis after radical prostatectomy. decipher can be used to predict metastasis and prostate cancer-specific mortality using an initial diagnostic biopsy in intermediate and high-risk patients after radiotherapy or radical prostatectomies.(28) a systematic review proposed that decipher genomic classifier is best for intermediate-risk pca and after radical prostatectomy therapeutic plans.(29) selectmdx the mrna levels of dlx1, hoxc6, and klk3 have also been shown to be promising candidates for the detection of prostate cancer. by assessing the levels of these transcripts post-dre using first-void urine, unnecessary biopsies can often be avoided. higher levels of these mrnas after biopsy can also have a predictive role in significant prostate cancer. the selectmdx algorithm (mdxhealth, irvine, ca, usa) combines rt-pcr of hoxc6 and dlx1 with clinical and para-clinical findings (psa levels, psad, dre, age, and family history).(30) dijkstra et al. propose that applying selectmdx in patients with psa levels greater than 3 ng/ml can result in a reduction in therapeutic costs and an increase in quality-adjusted life years (qalys).(31) quintana discussed that selectmdx is a vaoluable diagnostic tools in patients with a very low risk or patient with negative biopsy and patient withdoubtful mpmri.(32) michigan prostate score (mips) prostate cancer antigen 3 (pca3) assessment has also been recommended by the national comprehensive cancer network (nccn) and approved by the fda to assess men at high risk of prostate cancer but with negative needle biopsy results.(33) this test, in combination with tmprss2:erg fusion-gene transcript assays, has emerged as a potentially valuable novel biomarker. the michigan prostate score (mips) is an https://www.ncbi.nlm.nih.gov/pubmed/?term=dijkstra%20s%5bauthor%5d&cauthor=true&cauthor_uid=28370948 https://pubmed.ncbi.nlm.nih.gov/?term=quintana+lm&cauthor_id=32475689 8 application of this methodology to diagnose prostate cancer that combines serum psa levels with tmprss2:erg and pca3 genes levels in the urine.(34) oncotype dx and prolaris the oncotype dx multi-gene rt-pcr (genomic health, redwood city, ca, usa) has also shown promising results. the test uses quantitative rt-pcr to measure 12 specific cancer-related rnas using prostate biopsy specimens.(35) prolaris (myriad genetics, salt lake city, ut, usa) is a similar molecularbased test that assays 31 genes and is valuable for risk assessment in patients with prostate cancer.(36) however, a recent meta-analysis found insufficient evidence to show the effectiveness of the prolaris test when determining prostate cancer clinical outcomes.(37) moschovas and colleagues showed that oncotype dx higher scores is related to high pathologic grade of the tumor after surgery.(38) other genes and single nucleotide polymorphisms (snps) several other genetic markers have been identified as mutated in prostate cancer, particularly in hereditary cancers, that may serve as biomarkers. these include the tumor suppressor genes breast cancer type 1 and 2 (brca1 and brca2), the mdm2 promoter p1 region, the development gene hoxb13, and multiple mismatch repair genes, including several from the melanocyte-stimulating hormone (msh) family.(39-41) however, the full roles of these genes in prostate cancer and whether they could be applied to diagnosis require further study.while single nucleotide polymorphisms (snps) have been identified in many genes and loci related to prostate cancer, the relationships are often weak. therefore assessing effects multiplicatively may be a more valuable approach.(42) epigenetic alterations while changes that lead to cancer are often due to genetic effects, epigenetic alterations that do not affect dna sequence can also influence gene activity and expression. hypermethylation, hypomethylation, and histone post-translational modifications have all been associated with prostate cancer and may serve as https://pubmed.ncbi.nlm.nih.gov/?term=covas+moschovas+m&cauthor_id=33757735 https://en.wikipedia.org/wiki/dna_sequence https://en.wikipedia.org/wiki/gene_expression 9 potential biomarkers. for example, methylation of the glutathione s-transferase pi 1 promoter region, the ras association domain family protein 1 isoform a promoter region, retinoic acid receptor beta 2, adenomatous polyposis coli, and several other loci (including aox1 and rarb), has been linked to prostate cancer.(43, 44) confirmmdx one potential application of epigenetics to diagnose prostate cancer is confirmmdx, developed by mdxhealth. this test uses post biopsy specimen analysis of hypermethylation in cpg islands of the promoter regions of gstp1, apc, and rassf genes.(45) however, there is still little evidence to support the effectiveness of the test. biomarkers for predicting prognosis in addition to detecting prostate cancer, understanding severity and developing therapeutic plans are key issues for medical practitioners and are especially important for recently diagnosed patients. several biomarkers have been proposed for predicting prostate cancer prognosis [image 1]. recently, immunohistochemical analysis of the fork-head box protein a1 (foxa1 or hnf-3a) transcription factor using post-prostatectomy tissue from erg negative patients has found that high foxa1 expression may be a useful prognostic.(46) in addition, aberrant androgen biosynthesis is often associated with prostate cancer and may have prognostic implications, although the underlying mechanisms are not well established.(47) for example, the synthesis of androgens in the prostate of patients with castration-resistant prostate cancer (crpc) depends on the enzymatic activity of hsd3b1. polymorphisms in this protein have shown some prognostic roles during crpc.(48) recent studies have also shown that estrogen receptors α/β and aromatase in the androgen synthesis and catalysis cascade can predict the outcome of prostate cancer.(49) current evidence suggests that only the minority of prostate stem cells are androgen-independent and can cause crpc, although many genes have been found to be more highly expressed in such cases, including ccnb2, 10 dlgap5, cenpf, cenpe, mki67, pttg1, cdc20, plk1, hmmr, and ccnb1. these likely have a prognostic role in the heterogeneous response to androgen-deprivation therapies used for prostate cancer.(50) several other genes have been implicated in the variation inherent to prostate cancer prognoses. for example, valla et al. showed that the rna component of telomerase (terc) is overexpressed in prostatic cancer and regulated by myc. terc therefore may serve as a potential new biomarker.(51) the phase ii swog s0925 androgen deprivation combination study also suggested that circulating micro-rnas (mirnas) may have a prognostic role, including mir-141, mir-200a, mir-19a, and mir-375.(52, 53) the involvement of mirnas is supported by a further study that found a high combined mirna score in the mir-17-92 cluster was prognostic for shorter biochemical recurrence in patients with prostate cancer.(54) additionally, the differential expression of several genes has been linked to metastasis occurrence, including cd4, pcna, and baculoviral iap repeats.(55) finally, mutations in many dna repair genes have also emerged as potential prognostics and patients with metastatic crpc have a greater frequency of mutations in brca2, brca1, palb2, chek2, and atm.(56, 57) although based on racial variation, some of these genes role are matter of concern.(58) portos a recent analysis of the 24 gene post-operative radiation therapy outcomes score (portos) has shown that it is valuable in predicting metastases in patients with prostate cancer. the authors of the study suggest that adjuvant radiotherapy should be routinely practiced for men with high portos scores.(59) promark promark (metamark, waltham, ma, usa) is a protein-based test that quantitatively examines multiplexed proteomics from prostate tissue. the panel utilizes 12 protein markers that can serve to predict prostate cancer aggressiveness.(60) dna-ploidy 11 aberrant dna has also been shown to be a prognostic factor in patients with prostate cancer. this includes the presence of deletions that amplify the risk of biochemical recurrence in diploid, tetraploid, and aneuploid tissues. this has led to the development of a diagnostic nomogram that uses an assessment of ploidy and deletions to determine prostate cancer prognosis.(61) ersvaer et all suggested that the dna ploidy beside automatically estimated stroma fraction is a useful test for prognosis assessment.(62) tumor circulating cells the biomarker potential of circulating tumor cells (ctcs) has expanded significantly over recent years, especially since the development of tests that detect psa mrna during prostate cancer. however, cellsearch (menarini-silicon biosystems, castel maggiore, italy) is currently the only fda-approved test for identifying circulating tumor cells. the system uses antibodies specific to epcam and cytokeratins 8, 18, and 19 (positive) with cd45 (negative) to detect tumor cells.(63) however, a recent study has developed a new system that applies analysis of 14 genes, including epithelial markers, stem cell markers, and epithelial-tomesenchymal-transition markers, to perform in vivo ctc isolation. this allows downstream rna analysis and may be of use for molecular diagnostics.(64) there has also been developments in improving crpc survival, including better detection and therapeutic approaches.(65) the ctcs found in crpc feature alternate active androgen receptors, a consequence of differential splicing that can occur in the human androgen receptor gene. these unique variants may offer a promising biomarker for predicting prognosis during crpc. for example, ar-v7 mrna expression is higher in ctcs isolated from patients with metastatic crpc that have aggressive tumors. these patients also have poor treatment outcome after androgen deprivation therapy.(66, 67) however, tests based on ctcs are limited in clinical practice due to methodological limitations. such as separation methods and purify that. summary 12 despite major developments in biomarkers, it is clear that additional work and more focused clinical trial design is required to develop effective diagnostic tests for prostate cancer that have prognostic capacity. it is therefore additional large, multi-center clinical studies are needed to provide more vigorous evidence that will aid the development of prostate cancer biomarkers and to further validate these findings abbreviations pc: prostate cancer psa: prostate-specific antigen phi: prostate health index 4k: four-kallikrein pca3: prostate cancer antigen 3 as: active surveillance mrna: messenger rnas mips: mi prostate score mpmri: multiparametric magnetic resonance imaging of the prostate mirnas: micro rnas references: 1. rawla p. epidemiology of prostate cancer. world j oncol. 2019;10(2):63-89. 2. wong mc, goggins wb, wang hh, et al. global incidence and mortality for prostate cancer: analysis of temporal patterns and trends in 36 countries. eur urol. 2016;70(5):862-74. 3. hayes jh, barry mj. screening for prostate cancer with the 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prostate int. 2016 dec;4(4):130-5. 31. dijkstra s, govers tm, hendriks rj, et al. cost-effectiveness of a new urinary biomarkerbased risk score compared to standard of care in prostate cancer diagnostics a decision analytical model. bju int. 2017;120(5):659-65. 32. quintana lm, fernández pascual e, linares espinós e, et al. initial experience with selectmdx(r) in the diagnosis of prostate cancer in a real-world evidence clinical practice setting. actas urol esp (engl ed). 2020;44(6):400-407. english, spanish. 33. mohler jl, armstrong aj, bahnson rr, et al. prostate cancer, version 1.2016. j natl compr canc netw. 2016;14(1):19-30. 34. gaudreau po, stagg j, soulieres d, saad f. the present and future of biomarkers in prostate cancer: proteomics, genomics, and immunology advancements. biomark cancer. 2016;8(suppl 2):15-33. 16 35. knezevic d, goddard ad, natraj n, et al. analytical validation of the oncotype dx prostate cancer assay a clinical rt-pcr assay optimized for prostate needle biopsies. bmc genomics. 2013;14:690. 36. crawford ed, scholz mc, kar aj, et al. cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry. curr med res opin. 2014;30(6):1025-31. 37. health quality ontario. prolaris cell cycle progression test for localized prostate cancer: a health technology assessment. ont health technol assess ser. 2017;17(6):1-75. 38. covas moschovas m, chew c, bhat s, et al. association between oncotype dx genomic prostate score and adverse tumor pathology after radical prostatectomy. eur urol focus. 2021:s2405-4569(21)00094-8. 39. ozdemir bc, siefker-radtke ao, campbell mt, subudhi sk. current and future applications of novel immunotherapies in urological oncology: a critical review of the literature. eur urol focus. 2018;4(3):442-54. 40. morgan r, el-tanani m, hunter kd, et al. targeting hox/pbx dimers in cancer. oncotarget. 2017;8(19):32322-31. 41. gansmo lb, vatten l, romundstad p, et al. associations between the mdm2 promoter p1 polymorphism del1518 (rs3730485) and incidence of cancer of the breast, lung, colon and prostate. oncotarget. 2016;7(19):28637-46. 42. benafif s, eeles r. genetic predisposition to prostate cancer. br med bull. 2016;120(1):75-89. 43. ferro m, ungaro p, cimmino a, et al. epigenetic signature: a new player as predictor of clinically significant prostate cancer (pca) in patients on active surveillance (as). int j mol sci. 2017 may 27;18(6):1146. 44. steiner i, jung k, schatz p, et al. gene promoter methylation and its potential relevance in early prostate cancer diagnosis. pathobiology. 2010;77(5):260-6. 17 45. wojno kj, costa fj, cornell rj, et al. reduced rate of repeated prostate biopsies observed in confirmmdx clinical utility field study. am health drug benefits. 2014;7(3):12934. 46. tsourlakis mc, eleftheriadou a, stender a, et al. foxa1 expression is a strong independent predictor of early psa recurrence in erg negative prostate cancers treated by radical 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58. creed jh, berglund ae, rounbehler rj, et al. commercial gene expression tests for prostate cancer prognosis provide paradoxical estimates of race-specific risk. cancer epidemiol biomarkers prev. 2020;29(1):246-53. 59. zhao sg, chang sl, spratt de, et al. development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. lancet oncol. 2016;17(11):1612-20. 60. shipitsin m, small c, choudhury s, et al. identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error. br j cancer. 2014;111(6):1201-12. 61. lennartz m, minner s, brasch s, et al. the combination of dna ploidy status and pten/6q15 deletions provides strong and independent prognostic information in prostate cancer. clin cancer res. 2016;22(11):2802-11. 62. ersvaer e, hveem ts, vlatkovic l, et al. prognostic value of dna ploidy and automated assessment of stroma fraction in prostate cancer. int j cancer. 2020;147(4):1228-1234. 63. parimi s, ko jj. recent advances in circulating tumor cells and cell-free dna in metastatic prostate cancer: a review. expert rev anticancer ther. 2017;17(10):939-49. 64. markou a, lazaridou m, paraskevopoulos p, et al. multiplex gene expression profiling of in vivo isolated circulating tumor cells in high-risk prostate cancer patients. clin chem. 2018;64(2):297-306. 65. djavan b, nelson k, kazzazi a, bruhn a, sadri h, gomez-pinillos a, et al. immunotherapy in the treatment of advanced prostate cancer. can j urol. 2011;18(5):5865-74. 66. garcia jl, lozano r, misiewicz-krzeminska i, et al. a novel capillary nano-immunoassay for assessing androgen receptor splice variant 7 in plasma. correlation with cd133 antigen 19 expression in circulating tumor cells. a pilot study in prostate cancer patients. clin transl oncol. 2017;19(11):1350-7. 67. seitz ak, thoene s, bietenbeck a, et al. ar-v7 in peripheral whole blood of patients with castration-resistant prostate cancer: association with treatment-specific outcome under abiraterone and enzalutamide. eur urol. 2017;72(5):828-34. image 1: different biomarkers and their roles in prostate cancer prognosis agressivness asessment • promark,fox1 , mir-141,mi-r200a,mi-r375 androgen ablation response • ccnb2,dlgap,cenpf,mki67,ptig1,cdc20,plk1 ,hmmr,ccnb1 biochemical response • dna ploidy,mir-1792 cluster crpc prognosis • hsd3b1 polymorphism ,ar-v7 , abberation in brca 1 and 2 , palb3,atm 20 image 2: new emerging prostate biomarkers and their roles in screening, treatment, and establishing prognoses. point of technique 194 urology journal vol 7 no 3 summer 2010 laparoscopically assisted percutaneous pyelolithotomy in pelvic kidneys a different approach pejman shadpour, robab maghsoudi, masoud etemadian, kaveh mehravaran urol j. 2010;7:194-8. www.uj.unrc.ir keywords: laparoscopy, percutaneous nephrolithotomy, kidney calculi, kidney pelvis, nephrostomy, combined modality therapy hasheminejad kidney center, iran university of medical sciences, tehran, iran corresponding author: pejman shadpour, md hasheminejad kidney center, vanak sq, tehran, 19697, iran tel: +98 21 8864 4444 fax: + 98 21 8864 4447 e-mail: pshad@iums.ac.ir received october 2009 accepted february 2010 introduction pelvic kidney stones pose a unique challenge to the urologists. treatment options published in the literature to date include extracorporeal shockwave lithotripsy (swl), percutaneous nephrolithotomy (pcnl), retrograde intrarenal surgery, laparoscopically assisted pcnl, laparoscopic pyelolithotomy, and open surgery. although ectopic location of the kidney can cause positioning problems during swl, many have suggested that calculi in these kidneys should be approached with swl initially if feasible. (1) however, when reviewing the national institutes of health consensus conference recommendation for stones greater than 20 mm in size, pcnl was favored as the initial treatment option.(2) laparoscopically assisted percutaneous transperitoneal nephrolithotomy has been described to decrease the risk for the bowel injury.(3) there are serious limitations to pcnl. the amplatz sheath is inserted dorsally near the iliac crest, which restricts free movement of the nephroscope and may damage retroperitoneal nerves. alternatively, laparoscopic transperitoneal and retroperitoneal pyelolithotomy in the pelvic kidney have been reported. (1,4) this approach is time consuming and adequate skill is needed to suture the pelvis. in addition, intrarenal visibility during laparoscopic surgery is severely limited. we describe our experience with an alternative approach, laparoscopically assisted percutaneous pyelolithotomy, to treat these patients. case report three patients (two men and one woman) presented to our clinic with dull abdominal pain. the initial workup revealed a pelvic kidney largely loaded with stones. the mean age of the patients was 39.6 years (range, 24 to 54 years). the patients’ mean weight and body mass index were 81.7 kg (range, 60 to 93 kg) and 33 kg/m2 (range, 29 to 37 kg/m2), respectively. the mean stone size was 3 cm (range, 2 to 4 cm). two patients had a single stone and one had two stones. these calculi were located in the pelvis, the middle calyx, or infundibulum of the lower calyx. two pelvic kidneys were located percutaneous pyelolithotomy in pelvic kidneys—shadpour et al 195urology journal vol 7 no 3 summer 2010 on the left and one on the right side (figures 1 and 2). in addition to obvious obesity and short stature, one patient had history of previous open extraperitoneal pyelolithotomy of the affected kidney and another one had undergone abdominoplasty with tubal ligation. all had previous failed swl of the pelvic kidney stone. intervening bowel and/or extremely thick fat figure 2. pre-operative plain film and intravenous urographic image of one of the patients show left pelvic renal stones. figure 1. plain film and retrograde pyelography show right pelvic kidney stone in one patient. percutaneous pyelolithotomy in pelvic kidneys—shadpour et al 196 urology journal vol 7 no 3 summer 2010 layer precluded access to the kidney through the lumbodorsal approach in all three patients. given these limitations, all patients consented to undergo laparoscopically assisted percutaneous pyelolithotomy. technique pre-operative laboratory examination was within the normal limits. intravenous urography and non contrast spiral computed tomography scan of the abdomen and the pelvis were performed preoperatively for all three patients. on the day of surgery, after induction of general anesthesia and placing a ureteral catheter by cystoscopy, patients were prepped and draped in supine position. laparoscopy was performed using two to three 5-mm ports in the midline. after exploration of the peritoneal cavity, the pelvic kidney was found and posterior peritoneum was incised to swiftly expose the renal pelvis by blunt dissection. the third trocar was needed only where dissection of previous adhesions became necessary. with adequate visualization of the typically abnormal renal vasculature, the safest path to enter the congenitally anterior renal pelvis was readily determined. an 18-gauge needle was inserted from the anterior abdominal wall into the renal pelvis. after full distention of the pelvis via the ureteral catheter, the tract was dilated in single pass by an amplatz clad cone dilator. a 24-f rigid nephroscope was used to perform pyeloscopy. the stones were either removed intact or fragmented by swiss lithoclast master lithotripter (ems, bern, switzerland). a 14-f closed tube drain was inserted through the lowermost laparoscopic port. the renal pelvis was not repaired after removal of the scope, but the ureteral catheter was left in place attached to a 14-f foley catheter. complete blood count, blood urea nitrogen, creatinine, and plain radiography were repeated the day after surgery. both catheters were removed 24 hours postoperatively and the drain was removed on the second postoperative day. all patients were discharged from hospital 48 hours after the procedure. kidney, ureter, bladder x-ray and renal ultrasonography were also carried out at weeks 2 and 12 postoperatively. results mean operative time was 71 minutes (range, 48 to 113 minutes). estimated blood loss was 26 ml (range, 8 to 50 ml). no patient received blood transfusion during or after the procedure. all three patients were rendered stone-free based on final intra-operative nephroscopic and fluoroscopic inspection of the pyelocalyceal system, which was confirmed by postoperative plain film and ultrasonography. patients were discharged from the hospital after urine leakage discontinuation and documentation of stone-free state. the postoperative period remained uneventful with no clinically detectable leakage. discussion although ectopic location of the kidney can cause problems during swl due to intervening bowel anteriorly and bones posteriorly, calculi in these kidneys should be approached by this method initially if at all possible.(1) in the case of swl failure, alternative modalities may be used. our patients were not appropriate candidates for classic prone dorsal pcnl because of their obesity, short stature, and intervening bowels. eshghi and colleagues described laparoscopically assisted pcnl in 1985 to deal with the frequent problems encountered by retrorenal intestines. (3) holman and toth reported good results and no major complications in 15 patients treated by laparoscopically assisted pcnl.(5) el-kappany and associates presented the combination of laparoscopy and nephroscopy for treatment of ectopic pelvic kidney stones in 11 patients and concluded that this combination is feasible, safe, and effective for treatment of such stones.(6) aron and coworkers reported laparoscopically assisted percutaneous nephrolithotomy in a patient with history of previous open pyelolithotomy.(7) in pcnl, the tract traverses renal parenchyma, and obtaining a suboptimal non trans-papillary route is common. the latter plus exaggerated angulation required to access middle and lower calyces in percutaneous pyelolithotomy in pelvic kidneys—shadpour et al 197urology journal vol 7 no 3 summer 2010 many pelvic kidneys can be associated with high probability of bleeding from infundibular or more extensive parenchymal laceration. this explains the frequent occurrence of bleeding that sometimes requires blood transfusion. kramer and colleagues performed laparoscopic pyelolithotomy in three patients with a horseshoe kidney. there were no minor or major complications, and the estimated blood loss was <50 ml. the pelvis was incised and required suturing leading to mean operative time of 123 minutes (range, 74 to 150 minutes). they concluded that laparoscopic pyelolithotomy can be done safely, effectively, and efficiently with proper patient selection and adherence to standard laparoscopic surgical principles.(8) alternatively, laparoscopic retroperitoneal pyelolithotomy was performed in a pelvic kidney by harmon and associates.(1) collins and coworkers reported the combination of laparoscopic pyelolithotomy and ultrasonic lithotripsy.(9) their patient underwent uncomplicated laparoscopic pyelolithotomy. the stone has been located into an entrapment sack. the open end of the endocatch sack was brought through a trocar site and a nephroscope and ultrasonic lithotripter were deployed. the stone was fragmented and aspirated in the standard manner, thereby, avoiding the need to extend the 12-mm trocar incision for stone extraction. the patient was stone-free and discharged in the morning of the first postoperative day without any complication.(9) in this study, we presented an entirely different approach for percutaneous pyelolithotomy. we used laparoscopic view to guide our nephroscope directly into the renal pelvis through a dilated needle puncture. by logical deduction based on the common feature of the anteriorly placed pelvis and posteriorly located renal parenchyma peculiar to this patient group, it is easy to see why accessing the renal parenchyma to perform laparoscopically assisted pcnl is conceivably more difficult than the method hereby described from the anatomical standpoint. our patients were not amenable to the dorsal approach to the renal cortex even with laparoscopic dissection, for reasons mentioned above. another well-known characteristic of pelvic kidneys is the presence of vascular variations, in which direct visualization afforded by laparoscopy can result in reduced associated risks. at the same time, percutaneous radially dilated access to the pelvis brings a novel minimally invasive method for access to the kidney without requiring incision and/or subsequent reclosure by suturing the urinary tract, thereby, saving time without causing any clinically significant leakage or risking vascular injury. also of note is the much more adequate visualization of the pyelocalyceal interior in the submerged irrigant medium of the closed pyelocalyceal system through a nephroscope, instead of the encumbered tangential air or water view through a pyelotomy incision during classic laparoscopic pyelolithotomy of a pelvic kidney. it is also more efficient than putting the nephroscope into a gaping wide gas filled pyelotomy incision as described earlier.(8) there is a case report by figge which although claimed to represent percutaneous transperitoneal nephrolithotomy, had actually involved a transpelvic route as described in our series. that case report, however, did not include any attempt at intracorporeal stone fragmentation, and did not require exploration of the entire calyceal system. (10) the fact that our patients had no postoperative leakage is particularly concerting. we believe this owes, at least in part, to deliberately leaving the ureter without an indwelling stent once stonefree state was ascertained postoperatively. in addition to allowing unimpeded reflux to exert high physiologic voiding pressures directly onto the pyelotomy site, a double j stent could often be blocked by clots and debris. interestingly, the only instance of prolonged urinary drainage in a study by holman and toth was reported in a stented patient due to instrument malfunction. (5) unstented subjects in kramer and colleagues’ report had uneventful recovery.(8) similarly, totally tubeless pcnl is now widely perceived to lessen urinary leakage significantly. percutaneous pyelolithotomy in pelvic kidneys—shadpour et al 198 urology journal vol 7 no 3 summer 2010 conflict of interest none declared. references 1. harmon wj, kleer e, segura jw. laparoscopic pyelolithotomy for calculus removal in a pelvic kidney. j urol. 1996;155:2019-20. 2. segura jw, preminger gm, assimos dg, et al. nephrolithiasis clinical guidelines panel summary report on the management of staghorn calculi. the american urological association nephrolithiasis clinical guidelines panel. j urol. 1994;151:1648-51. 3. eshghi am, roth js, smith ad. percutaneous transperitoneal approach to a pelvic kidney for endourological removal of staghorn calculus. j urol. 1985;134:525-7. 4. meria p, milcent s, desgrandchamps f, mongiat-artus p, duclos jm, teillac p. management of pelvic stones larger than 20 mm: laparoscopic transperitoneal pyelolithotomy or percutaneous nephrolithotomy? urol int. 2005;75:322-6. 5. holman e, toth c. laparoscopically assisted percutaneous transperitoneal nephrolithotomy in pelvic dystopic kidneys: experience in 15 successful cases. j laparoendosc adv surg tech a. 1998;8:431-5. 6. el-kappany ha, el-nahas ar, shoma am, eltabey na, eraky i, el-kenawy mr. combination of laparoscopy and nephroscopy for treatment of stones in pelvic ectopic kidneys. j endourol. 2007;21:1131-6. 7. aron m, gupta np, goel r, ansari ms. laparoscopyassisted percutaneous nephrolithotomy (pcnl) in previously operated ectopic pelvic kidney. surg laparosc endosc percutan tech. 2005;15:41-3. 8. kramer ba, hammond l, schwartz bf. laparoscopic pyelolithotomy: indications and technique. j endourol. 2007;21:860-1. 9. collins s, marruffo f, durak e, et al. laparoscopic pyelolithotomy with intraperitoneal ultrasonic lithotripsy: report of a novel minimally invasive technique for intracorporeal stone ablation. surg laparosc endosc percutan tech. 2006;16:435-6. 10. figge m. percutaneous transperitoneal nephrolithotomy. eur urol. 1988;14:414-6. case report a large number of metastatic subcutaneous nodules: a complication of percutaneous biopsy for atypical renal cell carcinoma hao liu1, weiyun pan2, xiaocao shen1, nan zhang1* a -68year-old man underwent ultrasound-guided needle biopsy of a suspicious renal mass. just two weeks later, a large number of subcutaneous nodules was found in patient's chest-back, neck and axilla. pathology analysis was found to be metastatic subcutaneous nodules. these features suggest that tumor seeding have occurred during needle biopsy. despite needle tract seeding is a rare event, this rare complication should be taken into consideration before contemplating its use in a patient. keywords: renal biopsy; renal cell carcinoma; tumor seeding introduction improved imaging technology has led to an increase in the diagnosis of renal masses and allow urologists to propose a management plan without biopsy in many cases. however, we still need biopsy if imaging cannot determine the nature of the tumor. in this case report, we describe the complication of tumour seeding in a patient with atypical renal cell carcinoma who underwent percutaneous biopsy. despite needle tract seeding is a rare event (the risk is reported to be less than 1:10000), clinicians should inform patients of this rare complication especially those who are candidates for alternative treatment modalities. case report a 68-year-old male was admitted due to hematuria and left back pain for 2 weeks. clinical imaging revealed a renal tumor in the left kidney. in order to better treatment, he was referred to our hospital. an abdominal computed tomography scan was then performed to further characterise this lesion, which showed a 7.7*6.2mm solid mass in the left kidney and heterogeneous density in enhanced scan. fortunately, lymphadenopathy (swollen lymph nodes) were not found in abdominal cavity and retroperitoneum (figure1a). beyond that, chest x-ray showed suspicious area in the right side of hilus pulmonis. the patient’s case was discussed at the urology weekly meeting. treatment options discussed were surgical removal and renal biopsy. considering the patient had an atypical re1department of urology. the second affiliated hospital of zhejiang university school of medicine. china. 2department of ultrasonic. zhejiang cancer hospital, china. *correspondence: department of urology. the second affiliated hospital of zhejiang university school of medicine, hangzhou, zhejiang 310000, china, e-mail: nanzhang@zju.edu.cn. received february 2018 & accepted october 2018 figure 1. ct scan showed a 6.2*77 mm solid mass in the left kidney and heterogenous density in enhanced scan (a). pathology analysis of the biopsy specimen was clear cell type of renal cell carcinoma (b). subcutaneous nodule in the chest (c) and right axilla (d). urology journal/vol 16 no. 4/ july-august 2019/ pp. 415-416. [doi: http://dx.doi.org/10.22037/uj.v0i0.4355] vol 16 no 04 july-august 2019 416 nal mass and most likely was a renal lymphoma which were sensitive to chemotherapy, we finally opted for ultrasound-guided biopsy of the lesion after communicating with patient and family members. first, the contrast agent (sonovue, 2ml) was injected intravenously. the left renal mass was heterogeneous density enhanced. an 18g biopsy needle (hs hospital service s. p. a. specifications: top cut m 18g×200mm) was used to take two samples of the lesion, and the sample length was 2cm. unfortunately, we did not use a coaxial needle technique. there were no immediate complications. pathology analysis of the biopsy specimens was clear cell type of renal cell carcinoma (figure1b). after that, the patient readmitted for surgical removal two weeks later. to our astonishment, there were a large number of subcutaneous nodules in the chest-back, neck and axilla (figure1c, d). renal cell carcinoma seeding along a percutaneous biopsy tract was the first diagnosis. given this finding, the patient underwent a subsequent subcutaneous nodules resection and pathology analysis was found to be metastatic subcutaneous nodules, thereby confirming tumour tract seeding. we recommend that patients use targeted drugs (sunitinib or sorafenib). however, in china, targeted drugs are so expensive that patients can't afford them. finally we took immunotherapy. interleukin-2(il-2) , 200miu, hypodermic injection, three time a week(monday, wednesday, friday). the patient gave up after 2 weeks of treatment. because the patient was in poor condition, the metastatic lesion was not treated. unfortunately, despite additional treatment, the patient died from this disease two months after initial diagnosis. discussion theoretically, preoperative biopsy could saving patients from the unnecessary surgery and reducing burden on surgical services. but now, many clinicians are still reluctant to use renal biopsy in the diagnostic investigation of renal masses, and almost 55.9% of urologists never obtain a preoperative biopsy(1). this was due to the risk of false-negative results and tumor seeding. in this case, we opted for renal biopsy was based on the considering of the patient most likely with a renal lymphoma which were sensitive to chemotherapy. the discovery that tumour cells had seeded into the subcutaneous during the biopsy procedure was unfortunate. renal cell carcinoma seeding associated with diagnostic biopsies to be a very rare event(< 0.01%) with only a few reported cases on this(2). to minimise the risk of seeding, several factors should take into consideration such as needle calibre, number of punctures, tumour grade and the use of specialised techniques. first of all, along with the enlargement of needle circumference, the area of defect on the surface of the tumor was also increased. therefore, in theory, a larger-size needle would increase the risk of seeding. but in previous study, tumor seeding has been reported using needles size from 14-gauge to 25-gauge, and it is difficult to determine the relationship between needle size and the risk of tumor seeding(2). second, along the same lines, as the number of punctures increased, the risk of seeding increased. in our case, two passes were made with the biopsy needle which could have contributed to the increased risk of tumor seeding. but there are too few cases to establish a firm relationship between seeding and the number of punctures. thirdly, many urologists think that the grade of tumour may also play an important role in seeding. in our case, pathology analysis was clear cell type of renal cell carcinoma with poor differentiation. instead, same clinicians have reported seeding in rcc have been low-grade type. they speculated that the possible explanation is that lower grade tumour cells can survive longer in the blood or clot tract induced by the needle, due to its lower metabolic requirements. but this standpoint has not been tested so far in clinical trials. finally, several techniques, such as coaxial catheter system, have been advocated to minimise the risk of seeding. this technology allow multiple passes through the mass with only one pass through the surrounding normal tissue, which reduces the risk of bleeding as well as tumour seeding(3). besides, ct-guided biopsy could be advocated when visualisation is difficult with ultrasound. although tumour seeding to be a very rare event, but some studies indicated that tumour tract seeding is underreported. one version hold that most pathologists don't actually go through the overlying fat of the renal mass as well as most surgeon do not mark the puncture site for the pathologists. this caused difficulty to find seeding of tumour along a needle tract(2). beyond that, the tumor could theoretically seed into skin, subcutaneous tissue and muscle which can not be found soon after surgery. this delayed presentation may lead to poorer prognosis(4). conclusions tumor seeding following renal tumor biopsy is a rare event but may be under-reported. appropriate patient selection and suitable biopsy technique should be made to minimise the risk of this complication. acknowledgements this research was supported by zhejiang provincial nature science foundation of china under grant no.y18h050009 conflict of interest the authors have no conflicts of interest. references 1. alexander laird, catriona h couper, stephen glancy, et al. renal cell carcinoma needle biopsy: sowing the seed for later complications? bmj case rep. 2014: bcr2014203691. 2. deanne soares, nariman ahmadi, oana crainic. papillary renal cell carcinoma seeding along a percutaneous biopsy tract. case rep urol. 2015: 925254. 3. arash akhavein, molly m neuberger, philip dahm. tumour-seeding: a rare complication of ablative therapy for clinically localised renal cell carcinoma. bmj case rep. 2012: bcr2012006948. 4. dwayne t.s. chang, hariom sur, mikhail lozinskiy, et al. needle tract seeding folloring percutaneous biopsy of renal cell carcinoma. korean j urol. 2015; 56:666-9 biopsy and tumor seeding-hao liu et al. 1 running head: 3d reconstruction method in pcnl-hosseini et al. three-dimensional virtual reconstruction method versus standard fluoroscopy as a guiding tool for an optimal puncture rout in patients undergoing percutaneous nephrolithotomy: a randomized trial study seyed reza hosseini,1 elham tehranipour,1 aliakbar khadem,2 sayed mohammed jawad alwedaie3 1 department of urology, sina hospital,tehran university of medical sciences ,tehran, iran. 2 islamic azad university,central department,tehran, iran. 3 department of internal medicine,royal college of surgeons in irland and medical university of bahrain. abstract purpose three-dimensional (3d) could help for planning and creating an optimal access route in percutaneous nephrolithotomy (pcnl) procedure by achieving a more accurate approach to the renal collecting system and stone treatment while decreasing the risk of complications. the aim of our study is to compare the efficacy of 3d imaging technique with standard fluoroscopy method as guiding tools for renal stone location, while striving to reduce intra-operative x-ray exposure in the former method. materials and methods this randomised clinical trial enrolled 48 pcnl candidates who were referred to sina hospital (tehran, iran). participants were divided to two equal groups of intervention (3d virtual reconstruction) and control, using block randomization method. age, sex, stone type and location, x-ray exposure during the procedure, stone access accuracy rate and the necessity of blood transfusion during surgery were taken into account. results the mean age of participants (n=48) was 46.4 ± 4.8 years, 34 (70.8%) were male, 27 (56.3%) had partial staghorn stones and all participants had stones within the lower calyx. the radiation exposure time, stone access time and stone size were 2.99 ± 1.81 seconds, 272.3 ± 108.9 seconds and 23.06 ± 2.28 mm, respectively. in the intervention group, the accuracy rate for lower calyceal stone 2 access was 91.5%. also, x-ray exposure and time to stone access were significantly lower in the intervention group compared to the controls (p<0.001). conclusion we concluded that the utilization of 3d technology in the pre-operative location of renal calculi in pcnl candidates may result in a significant improvement in the accuracy and time to access the renal calculi, as well as reduction in x-ray exposure. keywords: 3-dimensional (3d) technology, percutaneous nephrolithotomy, renal stone,x ray, lithotripsy introduction urolithiasis is a frequently occurring condition, observed in 5-50% of the adult population depending on anthropometric and clinical values such as gender, race and region.(1)with regards to composition, the majority (70-80%) of the renal calculi are comprised of calcium oxalate, followed by calcium phosphate, uric acid and cysteine stones.(2) although supportive care is the primary method of approach in treating urolithiasis and acute renal colic, the size and location of the calculi may require more invasive methods of intervention, such as surgery.(3) the more primary methods of surgical intervention included open surgery which have been replaced by extracorporeal shock wave lithotripsy, ureteroscopy and percutaneous nephrolithotomy (pcnl) in recent decades.(4) pcnl is a minimally invasive procedure which involves the location of renal calculi with the aid of a fluoroscopy x-ray-guided needle and subsequent extraction of the stone using a nephroscope. the usual indications for pcnl include stones larger than 20mm, staghorn or partial staghorn calculi and stones situated in the lower poles. high levels of exposure to ionizing radiation is a major disadvantage to conventional pcnl and has prompted the search for more accurate and less harmful methods. (5) a novel approach involves the utilization of reconstructive 3-dimensional (3d) technology to accurately locate renal calculi and their relation to other anatomical structures and landmarks. this is in part indebted to the advances in fluoroscopy imaging techniques, such as rapid spiral acquisition and reconstructive software. (6,7) establishing the percutaneous tract is the initial most important step in pcnl surgery. choosing the perfect tract, position, and direction is highly dependent on surgical experience, and the ability to 3 understand the renal and peri-renal anatomy. in general, a good ct scan of the abdomen and pelvis, and a well-experienced surgeon in enough, but we appreciate any system that can add information. in this study, we evaluated if the 3d technology can help the surgeon in doing the optimal tract, compared to preoperative regular x-ray fluoroscopy, while striving to reduce intra-operative x-ray exposure in the former method. materials and methods study population in this randomized clinical trial, 48patients undergoing pcnl in sina university hospital were enrolled. participants were comprehensively informed of the goals and procedure of the study and were required to provide a written informed consent prior to entry. participants reserved the right to withdraw at any stage of the study. this study adhered to the guidelines of the helsinki declaration, was approved by the ethics committee of tehran university of medical sciences and registered in the iranian registry of clinical trials (irct20200905048625n1). the inclusion criteria consisted of patients aged between 18 to 80 who had the indications for pcnl procedure. in our department, pcnl is performed in patients with kidney stones more than 2 cm in diameter, stones refractory to extracorporeal shock wave lithotripsy, proximal ureteral stones larger than 1.5 cm in diameter, diverticular stones, and stones producing distal obstruction. the exclusion criteria were medium to high cardiovascular risk, coagulation disorder, renal failure, hepatic failure, diabetes mellitus, and hypothyroidism. patients’ enrolment algorithm is illustrated in figure 1. study design for the purpose of randomization, all pcnl candidates were randomly divided into two group using block randomization method. the randomization process was performed using the random function in excel software. for randomization, the balanced block randomization method is used to generate four blocks. intervention group a and control group b have been determined. quadruple blocks (a or b) were placed in envelopes. after the arrival of the first patient with the inclusion criteria, the envelopes were randomly selected and the type of patient group was informed to the research team 4 through a trained technician. patient were placed in pcnl surgery using 3d technology or in x-ray fluoroscopy group based on the randomly selected envelope. all the collected data for statistical analysis were coded and the statistician was not aware of the allocated interventions. surgical technique in both groups ct-scan were performed in prone position. the scan was performed before and after contrast administration. non contrast ct-scan (ncct) was used for stone location, the contrast phase was used to visualize collecting system. in the intervention group, the following anatomical sites were marked using a ct-scan appropriate marker: second lumbar vertebra, the costovertebral angle (cva), posterior axillary line and the iliac crest (figure 2a). prior to imaging, patients were positioned in prone position and were asked to fully inhale and hold their breath for duration of ten seconds. this position was later replicated at the time of surgery with the help of an artificial inspiration to minimise movement and possible relocation of the calculi. obtained images were reconstructed using the materialise mimics 3d reconstruction software (leuven, belgium) (figure 2b). based on this reconstruction, the solid works software (premium 2019 x64 edition sp.1) was then employed to reconstruct the exact shape of the stone based on the measurements and distances between the calculi and the pre-marked landmarks on the sagittal, coronal and axial plains (figure 3). the resulting images were provided to the operators for an accurate location of the calculi and operative planning (figure 4a, b, c, d). all images were obtained with the aid and supervision of a single radiology technician, 12-24 hours prior to the surgical procedure. the resulting images were provided to the operators for an accurate location of the calculi and pre-operative planning. the durations of radiation exposure were measured by a single person via stopwatch. pcnl was performed under general anaesthesia in the prone position. in both groups, a dye was injected through the lower urinary tract, in order to visualize the anatomy of renal collecting system with the help of fluoroscopy. in intervention group puncture was rechecked under pulsed fluoroscopy control. all the procedures were performed by using a 26 fr nephroscope. whenever clear withdrawal of urine was observed, stone access was confirmed and tract was dilated up to 30 fr amplatz sheath. the entire procedures were performed by two highly experienced (more than 18 years) operators in pcnl. 5 statistical analysis statistical analyses were performed using spss version 20 (spss inc., chicago, illinois, usa). quantitative variables are expressed as mean ± standard deviation (sd), while qualitative data are presented as frequencies and regarded percentages. the relationships between qualitative data were investigated using the chi-square and fishers’ exact test, while the comparison of quantitative data was performed using the student t-test or mann-whitney test for non-parametric conditions. the p-value <0.05 is considered as statistically significant. results in this study, 48 patients (n=24, each group) were evaluated. the mean age of the participants was 46.4 ± 4.8 (ranging 38-57) years and 34 (70.8%) were male (table 1). the two groups were similar with regards to the distribution of age and sex (p=1). the mean kidney stone access time was 272 ± 109 seconds and a significantly shorter access time was observed in the intervention group in comparison to control group (168.9 ± 26.3 and 375.6 ± 35.3 seconds respectively, p=.0001). the mean radiation exposure time in patients assessed 2.99 ± 1.81 seconds and the mean time was significantly lower in the intervention group rather than those in control group (1.25 ± 0.37 and 4.73 ± 0.5 seconds, respectively, p=.0001). the mean size of the kidney stone was 23.06 mm with no observable difference between the two groups (p=.21). the majority (56.3%) of the extracted stones were found to be partial staghorn calculi and, although statistically insignificant, these calculi were more frequently observed in the intervention group compared to those in controls. lower calyceal calculi were observed in all the participants. in overall, the mean duration of surgery was 44.2 ± 5.6 minutes. however, this duration was lower in the intervention group compared to the control group but was not statistically significant (41.9 ± 4.1 and 46.5 ± 6 minutes respectively, (p=.09). among the intervention group, in 22 (91.5%) patients the lower calyceal stone access was obtained in the first try. on the other side, the same parameter in the control group was obtained in 21 (87.5%) patients. the complications such as fever, bleeding, urinary leakage, changes in hemoglobin and creatinine were not statistically significant. 6 discussion when considering a pcnl procedure, surgeons are very cautious regarding one crucial step which is the exact point in which the intended renal calyx should be punctured. up to the present time, the radiological methods of ultrasound and fluoroscopy guidance have been combined to assist the surgeon for this purpose. the introduction of 3d virtual reconstructive imaging technology is able to resolve such issues through providing a better understanding of the location and position of renal calculi in relation with the adjunct anatomical structures. the use of such techniques has been associated with higher accuracy in the location of renal calculi, as well as a significant reduction in operational adverse effects. (8) porpiglia et al. reviewed the application of 3d reconstructive technologies in the field of urology. they concluded that despites its sporadic use and lack of comprehensive data in meantime, such methods could prove to be of great aid in accurate surgical planning. in another report, they evaluated the use of 3d reconstructive imaging technology in robot-assisted radical prostatectomy and minimally invasive partial nephrectomy in a subjective manner. they reported a significant utility of 3d reconstructed printed models in surgical planning, anatomical representation and the role of technology in surgical training, as well as favourable feedbacks by the patients regarding the use of this technology in the process of their surgery. (7) in another study by porpiglia et al., the use of three-dimensional technique for partial nephrectomy in 21 patients, achieved successful results in 90% of the cases, in whom pre-operation expectations closely matched those of post-operation outcomes .(9) according to their findings, the use of such technique could potentially decrease the risk of post-operative renal ischemia. toshitaka et al. reported excellent post-operative results in a study of four high-risk prostate cancer patients with a 1mm surgical margin, as determined under the guide of 3d reconstructive technology and evidenced by negative involvement of margins in the final pathology reports.(10) zhang et al. also reported that the use of 3d reconstructive techniques may be of practical use in the setting of t1n0m0 renal tumours in the hands of experienced surgeons.(11) one recent study introduced i-pad assisted navigation as a technique that uses pre-operation ct-scan in conjunction with augmented reality (ar) feature in order to visualize the desired structures 7 such as kidneys, ureters and prostate, in addition to their surrounding boundaries .(8) an experimental study on animal models demonstrated a minute superiority of ultrasound guided renal puncture over ipad assisted and fluoroscopic-guided puncture in term of timing, as it was shown to be faster than its rival techniques .(12) although our study was unique in a global scale in terms of methodology and objectives, some of its aspects are comparable to several similar studies. in a study conducted by linda ce lee et al., the sample size and the mean age of participants were found to be higher than our study .(13) the percentage of patients who needed blood transfusion in the mentioned study was 0.6%, in contrast to the present study where no patient required any form of transfusions. in a study of 118 pcnl candidates, xu et al. compared the surgical measures of outcome between conventional ultrasound with fused 3d virtual reconstruction and ultrasound guided location of calculi. in line to our findings, they reported a significant improvement in accuracy, time to puncture, overall duration of surgery and haemoglobin loss in the fused us and 3d reconstruction group (pvalues<0.001). in another study by christiansen et al., evaluated the effectiveness of five different advanced imaging modalities during a complex renal surgical procedure. they reported that the 3d print model was helpful in providing a tangible model of the complex kidney with its insight into the location of the kidney stones and renal vasculature. (14) in a recent similar study conducted by tan et al, (15) the authors investigated the feasibility of 3d reconstruction method in pcnl for complex renal calculi treatment. the findings mirrored the results of our study in terms of shorter duration of surgery and higher first-time puncture success rate with significantly lower radiation exposure time among the intervention group compared to the controls. the study’s limitation is the small sample size. however, it could be viewed as a pilot study, and more study could be done to better understand this technique. conclusions we conclude that the use of 3d reconstructive technology is an effective method in improving accuracy and time to access. more importantly, the application of this technique resulted in a significant reduction 8 in the exposure to ionizing radiation during surgery. larger sample sizes and in-depth analysis of clinical and demographic characteristics are necessary to further consolidate the finds of this study. references 1. khan a. prevalence, pathophysiological mechanisms and factors affecting urolithiasis. int urol nephrol.2018; 50:799-806. 2. lieske jc, rule ad, krambeck ae, et al. stone composition as a function of age and sex. clin j am soc nephrol. 2014; 9:2141-6. 3. bahmani m, baharvand-ahmadi b, et al. identification of medicinal plants for the treatment of kidney and urinary stones. j renal inj prev. 2016; 5:129-33. 4. miller nl, lingeman je.management of kidney stones. bmj.2007;334:468-72. 5. de la rosette jj, opondo d, daels fp, et al. categorisation of complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246-55. 6. autorino r, porpiglia f, dasgupta p. precision surgery and genitourinary cancers. eur j surg oncol. 2017; 43:893-908. 7. porpiglia f, amparore d, checcucci e, et al.current use of three-dimensional model technology in urology: a road map for personalised surgical planning. eur urol focus. 2018;4:652-6. 8. rassweiler-seyfried mc, rassweiler jj, weiss c, et al. ipad-assisted percutaneous nephrolithotomy (pcnl): a matched pair analysis compared to standard pcnl. world j urol. 2020;38:447-53. 9. porpiglia f, bertolo r, checcucci e, et al. development and validation of 3d printed virtual models for robot-assisted radical prostatectomy and partial nephrectomy: urologists' and patients' perception. world j urol.2018; 36:201-7. 10. shin t, ukimura o, gill is. three-dimensional printed model of prostate anatomy and targeted biopsy-proven index tumor to facilitate nerve-sparing prostatectomy. eur urol.2016; 69:377-9. 9 11. zhang y, ge hw, li nc, et al.evaluation of three-dimensional printing for laparoscopic partial nephrectomy of renal tumors: a preliminary report. world j urol.2016; 34:533-7. 12. klein jt, rassweiler j, rassweiler-seyfried mc. validation of a novel cost effective easy to produce and durable in vitro model for kidney-puncture and percutaneous nephrolitholapaxysimulation. j endourol.2018; 32:871-6. 13. lee lc, violette pd, tailly t, et al. a comparison of outcomes after percutaneous nephrolithotomy in children and adults: a matched cohort study. j pediatr urol.2015; 11:250.1-6. 14. christiansen ar, shorti rm, smith cd, prows wc, bishoff jt. intraoperative utilization of advanced imaging modalities in a complex kidney stone case: a pilot case study. world j urol.2018; 36:733–43. 15. tan h, xie y, zhang x, et al. assessment of three-dimensional reconstruction in percutaneous nephrolithotomy for complex renal calculi treatment. front surg. 2021;8:701207. corresponding author: seyed reza hosseini,md; professor of urology, sina hospital,tehran university of medical sciences ,tehran, iran. email: srhosseini@tums.ac.ir or srhoseini@tums.ac.ir tel:0098-21-6312000 10 figure 1: all participants' enrolment summary is represented based on the consort (consolidated standards of reporting trials) 2010 checklist assessed for eligibility (n= 57) excluded (n=9) not meeting inclusion criteria (n=6) declined to participate (n=2) other reasons (n= 1) analysed (n=24) excluded from analysis (give reasons) (n=0) lost to follow-up (give reasons) (n=0) discontinued intervention (give reasons) (n=0) allocated to intervention (n=24) received allocated intervention (n=24 ) did not receive allocated intervention (give reasons) (n= 0 ) lost to follow-up (give reasons) (n=0) discontinued intervention (give reasons) (n=0) allocated to intervention (n= 24) received allocated intervention (n= 24 ) did not receive allocated intervention (give reasons) (n= 0 ) analysed (n=24) excluded from analysis (give reasons) (n=0) allocation analysis randomized (n=48) enrolment follow-up 11 figure 2: a. anatomical sites which marked; second lumbar vertebra, pcnl access point of entry and the costovertebral angle (cva) and the iliac crest. b. marked point in 3d reconstructed image figure 3: sagittal, coronal and axial plains in solid works software 12 figure4: a. measuring the access angles according to preoperative data from solidworks software by surgeon. b. fluoroscopy checking after entry according calculated angles. c. checked fluoroscopy image after trying one’s hand at accessing to stone. d. access sheet on accurate point after using reconstructive 3-dimensional (3d) technology. sexual dysfunction and andrology neutrophil-lymphocyte ratio could be a marker for erectile dysfunction ali aslan1*, yasemin kaya2, abdullah çırakoglu3, erdal benli3, esra yancar demir4, mustafa kerem çalgın5 purpose: the literature reveals lots of information about the relationship between inflammatory markers and many diseases. in this study, we aimed to determine the relationship between erectile dysfunction and the neutrophil-lymphocyte ratio (nlr), which is a simple and nonspecific inflammatory marker. materials and methods: ninety patients with erectile dysfunction (ed) and ninety-four healthy subjects were included in this study from our internal medicine and urology clinics. as diagnosis criteria, we used the first 5 questions of international index for erectile function. the duration of erectile dysfunction was asked and recorded. height, weight and waist circumference of patients were measured. we performed total blood count, sedimentation, c-reactive protein, and blood chemistry. results: there were statistically significant differences between the control [1,038 (0,507-1,92)] and ed [59,5 (52,0-68,0)] groups in terms of nlr (p < .001). according to the multivariate logistic regression analysis, duration of ed (cut off: 7,5 month) predicted ed with 78,8% sensitivity and 63,1% specificity (auc: < ,001, 95% ci 1,030 (1,010-1,050), p = .003). moreover, nlr (cut off: 1,574) predicted ed with 81,8% sensitivity and 67,0% specificity (auc: < 0,001, 95% ci 1,994 (1,139-3,490), p = .016) according to the multivariate logistic regression analysis. conclusion: it was found that the neutrophil-lymphocyte ratio was higher in patient group than the control group. also, the neutrophil-lymphocyte ratio (nlr) predicted ed and it might be helpful in diagnosing erectile dysfunction. keywords: erectile dysfunction; neutrophil-lymphocyte ratio; inflammation; diabetes mellitus; coronary artery disease introduction erectile dysfunction (ed) is described as the impo-tency to obtain or sustain an erection sufficiently in order to enable convincing sexual intercourse.(1) erectile dysfunction develops from inadequate penile tissue response to a sexual indication. the reaction can be interrupted at several points. for instance, impairing of vascular smooth muscle cells (obesity, age) and endothelial cells (diabetes, smoking), and compression of the vascular lumen (hypertension, cad) have all led to congestion of the corpus cavernosum.(2) furthermore, denervation from spinal trauma or prostatic surgery and psychological issues should be considered in discussions with patients. erectile dysfunction (ed) is estimated to affect about 75% of men over the age of 75 and 20% of men over the age of 20.(3) in age-adjusted models, erectile dysfunction has been indicated to be related with: high cholesterol, diabetes, cardiovascular disease history, hypertension, hormone problems, alcohol consumption, stress, anxiety, smoking, bmi greater than 30 kg/ m2 and less than 25 kg/m2.(4) 1 department of physiology, school of medicine, ordu university, ordu/turkey. 2 department of internal medicine, school of medicine, ordu university, ordu/turkey. 3 department of urology, school of medicine, ordu university, ordu/turkey. 4 department of psychiatry, school of medicine, ordu university, ordu/turkey. 5 department of microbiology, school of medicine, ordu university, ordu/turkey. *correspondence: department of physiology, school of medicine, ordu university, ordu/turkey tel: +90 505 4868214, e-mail: draslan@yahoo.com . received december 2018 & accepted march 2019 although guidelines such as the international index of erectile function (iief-5) have been developed to assess erectile dysfunction, it is most often diagnosed on the basis of the clinical notion, while validated evaluation procedures are reserved for clinical trials.(5) the association among many diseases, inflammatory markers and also their roles in the disease etiopathogenesis are important. the literature reveals that emerge and severity of ed are related with markers and mediators of inflammation and endothelial dysfunction.(6) routinely available markers and mediators (interleukin (il)-1β, tnf-β, il-6, crp, il-10,) and endothelial/prothrombotic factors of the systemic inflammatory response is the neutrophil-lymphocyte ratio (nlr), a ratio of the neutrophil to lymphocyte count, and it has been reported to have prognostic value in a variety of diseases.(7-11) this study was aimed to identify the relationship between ed and the nlr, which is a simple and non-specific inflammatory marker. sexual disfunction & andrology 216 vol 16 no 02 march-april 2019 217 material and methods ethics standards this planned research complies with the helsinki declaration rules including ethical guidelines and patient’s rights were confirmed by the ordu university, ethics committee (date: may 2014, number: 2014/05). patient selection patients evaluated in urology and internal medicine outpatient clinics of ordu university between september 2016 and july 2017 were enrolled in this study. 90 patients with erectile dysfunction and 94 healthy subjects were included in this study. inclusion and exclusion criteria as diagnosis criteria, we used the first 5 questions of international index for ed. the exclusion criteria used for both ed and control group. the exclusion criterias were as follows: current treatment (cialis, levitra, staxyn, stendra, viagra etc.) for ed, aged older than 70 years and younger than 40 years, psychiatric disease, being of an endocrine disturbance (except for type 2 dm), diabetic complications (neuropathy, ketoacidosis) concomitant malignancies, background of prior penile, pelvic surgery-trauma, neurological disease, penile bending disease and chronic diseases (hepatic, renal). measurements comprehensive anamnesis and a thorough medical examination were applied to all participants. drug usage and prior operation history were asked, and cigarette habits (at least 10 years) were also noted. body mass index (bmi), waist circumference, weight, and height were measured for each individual. total blood count, sedimentation, c-reactive protein, bun (blood urea nitrogen), creatine, cholesterol, ldl-c (low-density lipoprotein cholesterol) and hdl-c (high-density lipoprotein cholesterol) measurements of the patients were recorded. the nlr was computed as the total neutrophil count separated by the total lymphocyte count. statistical analysis spss 25.0 statistics package software was used for statistical analysis. the normality of the distribution of variables was analyzed by the kolmogorov–smirnov normality test. for normally distributed data, comparisons between the two groups were made using a t-test. comparisons between the two groups were made using a mann–whitney u test for not normally distributed data. all values were reported as mean ± sem or median (min-max). statistical significance was considered as p < 0.05. the categorical data analysis was realized using the fisher’s exact, pearson chi-square test and fisher–freeman–haltin test. variables having unadjusted p-value lower than 0.10 in univariate analysis were considered as possible risk markers for ed and included in the multivariate model. multivariate logistic regression analysis with backward elimination was applied to define independent predictors of ed. a stepwise linear regression model was established with variables related to the dependent variables. results the comparisons of the demographic characteristics and biochemical parameters in groups are shown in table 1. the mean age of the patients with ed was 61.0 (53.0-66.25) and the mean age of control group was 59.5 (52.0–68.0) (p = .69). the ratio of smokers was 20% in patient group and 15.2% in control group (p = .41). there weren’t statistical differences between the groups in terms of bmi and weight. the nlr was 2.38 (1.67-3.90) in patient group and 1.038 (0.507-1.92) in table 1. comparison of the demographic characteristics and biochemical parameters in groups. variables control (n=94) ed (n=90) p value mean±sem or median (min-max) age (year) 59.5 (52.0 68.0) 61.0 (53.0 66.25) 0.690 smoking (%) 15.1 20 0.413 chf (%) 2.7 1.1 0.449 copd (%) 4.1 1.1 0.224 cad (%) 5.5 16.7* 0.05(or:2.457%95ci:0.951-6.348) ht (%) 29.7 42.2 0.195 dm (%) 14.9 28.9 0.05 (or:1.980 %95 ci:0.979-.008) goiter (%) 1.9 1.4 0.852 size (m) 1.70 ± 0.060 1.70 ± 0.058 0.907 weight (kg) 81.04 ± 15.094 83.86 ± 12.055 0.183 bmi (kg/m²) 27.048 (25.102 30.44) 28.871 (26.72 30.85) 0.053 waist circumference 101 (95 108) 102 (94 108) 0.903 hemoglobin (g/dl) 14.43 ± 1.196 14.57 ± 1.41 0.375 lymphocytes 2.28 (1.64-3.03) 1.86 (1.0 2.39) 0.194 rdw 14.30 ± 1.132 14.0 ± 1.31 0.111 neutrophil 2.67 (1-3.94) 4.49 (3.62-5.35)*** < 0.001 nlr 1.038 (0.507 1.92) 2.38 (1.67 3.90)*** < 0.001 esr 12.50 (9.0-19.5) 11 (4.75 17.25) 0.251 crp (mg/l) 0.681 (0.14-0.59) 0.42 (0.12 1.0) 0.626 bun (mg/dl) 15.0 (13.0 – 17.0) 15.8 (13.0 18.6) 0.099 creatine (mg/dl) 0.90 (0.82-0.95) 0.92 (0.80 1.06) 0.229 cholesterol (mg/dl) 205.75 ± 35.22 196.902 ± 48.75 0.321 triglyceride (mg/dl) 159 (88 211) 143 (92 213) 0.686 ldl-c (mg/dl) 132.10 (104.90 153.20) 128 (110.0 -156.0) 0.949 hdl-c (mg/dl) 42.0 (38.0-51.25) 42.0 (35.0 48.0) 0.222 abbreviations: ed: erectile dysfunction, copd: chronic obstructive pulmonary disease, cad: coronary artery disease, ht: hypertension, dm: diabetes mellitus, chf: chronic heart failure, bmi: body mass index, rdw: red cell distribution width, nlr: neutrophil-lymphocyte ratio, esr: sedimentation, crp: c-reactive protein, bun: blood urea nitrogen, ldl-c: low-density lipoprotein cholesterol; hdl-c: high-density lipoprotein cholesterol. *: p < 0.05; **: p < 0.01; ***: p < 0.001 nlr associated with erectile dysfunction-aslan et al. sexual disfunction & andrology 218 control group (p < .001) (figure 1). nlr over 1.574 (cut-off value) is predictive for ed with 81.8% sensitivity and 67.0% specificity (auc: <.001, 95% ci: 1.994 (1.139-3.490), p = .016) according to the multivariate logistic regression analysis (figure 2). in univariate analysis, increased neutrophil and the nlr values and the presence of dm and cad were seen to be related with increased ed possibility. however, the bmi was not related with increased ed possibility. consequently, multivariate logistic regression analysis pointed that the nlr could be an independent predictor of ed (table 2). discussion ed is a well-known disease with increasing frequency that affects both the individual and his/her partner. in a recent study, aytac et al. predicted that there were over 152 million men who experienced ed in the world in 1995, and the projections for 2025 show a prevalence of around 322 million patients with ed, an increase of nearly 170 million.(12) therefore, the reliable and fast diagnosis and treatment of ed is important. in general population ed prevalence ranges between 18 and 51%. (13) ed incidence raises with age; its frequency between men aged 60-69 is 20 40%, whereas along the eighth and ninth decades this ratio raises up to 50–100%.(14) several ratios declared by multiple researches are possibly owing to variations in the research methodology and the age distribution and socio-economic status of the research groups. ed decreases the general health and life quality of both the patient and partner. it is a multifactorial disease with hormonal, psychogenic, iatrogenic and anatomical factors supporting to its pathophysiology.(15) the most important reason of ed among aged men is organic disease owing to atherosclerosis mediated vascular disturbance.(16) in our study, we investigated psychogenic ed, which is the principle reason of ed in men aged 40–70, and we accepted other reasons of ed (e.g., hormonal disturbance, psychogenic disorders, history of pelvic surgery or previous trauma and neurological disease). the relation between dm and ed was reported by corona et al.(17) in our study, there are significant differences between the control groups and ed in terms of diabetes. furthermore, in univariate regression analysis dm was showed to be related with increased possibility of ed. besides that aging, cardiovascular risks (diabetes, hypertension, dyslipidemia, obesity and smoking status) are given to be firmly associated with the ed pathophysiology.(18) thus, it is reputed that ed is an early trail of a systemic disorder that could arise in cvd. exposed to atherogenic risk factors lead to endothelial injury and finally result in atherosclerosis. atherosclerosis affects all vascular beds at a comparable rate, however the time of symptom initiation diverge relying on the affected artery diameter.(19) in our study, there are significant differences between the control and ed groups in terms of coronary artery disease (cad). furthermore, in univariate regression analysis, cad was found to be associated with increased probability of ed. endothelial injury plays a considerable role in the ed and coronary artery diseases pathogenesis.(20-22) subclinical inflammation with low-degree may affect endothelial function and result in prothrombotic cases. some researches have represented that the onset and ed severity are weakly related with increased levels of table 2. univariate and multivariate logistic regression analysis for the independent predictors of ed. variables univariate p value multivariate or and 95% ci multivariate p value neutrophil < 0.001 1.541 (0.987 2.406) 0.057 nlr < 0.001 1.994 (1.139 3.490) 0.016 dm 0.05 2.528 (0.814 7.852) 0.109 cad 0.05 0.058 0.096 abbreviations: ci: confidence interval, or: odds ratio, nlr: neutrophil-lymphocyte ratio, dm: diabetes mellitus, cad: coronary artery disease figure 1. comparison of nlr in patient group and in control group. figure 2. nlr over 1.574 (cut-off value) is predictive for ed with %81.8 sensitivity and %67.0 specificity. nlr associated with erectile dysfunction-aslan et al. vol 16 no 02 march-april 2019 219 inflammatory markers.(21,23-25) researches have reported that ed patients showed increased formation of inflammatory mediators (interleukin (il)-1β, tnf-α, il-6, crp, il-10), markers, and endothelial/prothrombotic factors. as reported in these research, ed is related with many inflammatory mediators and markers.(21,23,25) based on these knowledge, we aimed to investigate the relation of ed with the nlr, which is the marker of inflammation and has been extensively studied in several recent studies.(26-28) there are numerous research that studied the nlr in cad progression. the nlr is related with prognosis in cardiac failure and cad.(29) demirkol et al. sighted significantly increased levels of the nlr among patients with cardiac syndrome x and cad. also, they showed a correlation between the nlr and the carotid intima thickness.(30) kalay et al. reported that nlr was significantly elevated in the patients with atherosclerosis and showed that nlr is a biomarker for atherosclerosis development.(31) sambel et al. showed that the neutrophil-to-lymphocyte ratios are associated with a ed diagnosis, and they could assist as applied parameters that will not expense additional charge.(32) ventimiglia et al. and seftel made two separate studies showed that increased nlr (greater than 3) the risk of having severe ed, enhancing the already existing evidence linking systemic inflammation to ed.(33,34) some studies have linked ed with enhanced inflammatory state in men with obesity or metabolic syndrome. (35,36) although, eaton et al did not find any association between the level of inflammatory activation and ed.(37) in our study, it was found that the nlr, which is the marker of the systemic inflammatory response, was higher in patient group than control group. also, nlr over 1.574 (cut-off value) is predictive for ed and could be helpful in diagnosing ed. according to our findings, neutrophil, nlr, dm and cad were found to be related to increased possibility of ed. conclusions this study showed that nlr value could be a potential parameter for diagnosing ed. in addition, increased neutrophil, and the presence of dm and cad should be considered in diagnosis of ed. conflict of interest the authors declare that they have no conflict of interest. references 1. jama. nih consensus conference. impotence. nih consensus development panel on impotence. 1993;270:83-90. 2. heaton jp, adams ma. causes of erectile dysfunction. endocrine. 2004;23:119-23. doi:10.1385/endo:23:2-3:119. 3. selvin e, burnett al, platz ea. prevalence and risk factors for erectile dysfunction in the us. am j med. 2007;120:151-7. 4. rew kt, heidelbaugh jj. erectile dysfunction. am fam physician. 2016;94:820-7. 5. rosen rc, cappelleri jc, gendrano n 3rd. the international index of erectile function (iief): a state-of-the-science review. int j impot res. 2002;14:226-44. 6. vlachopoulos c, rokkas k, ioakeimidis n, stefanadis c. inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. eur urol. 2007;52:1590-600. 7. cetinkaya m, buldu i, kurt o, inan r. platelet-to-lymphocyte ratio: a new factor for predicting systemic inflammatory response syndrome after percutaneous nephrolithotomy. urol j. 2017;14:4089-93. 8. zhang xk, yang p, zhang zl, hu wm, cao y. preoperative low lymphocyte-to-monocyte ratio predicts poor clinical outcomes for patients with urothelial carcinoma of the upper urinary tract. urol j. 2018;15:348-54. 9. eren ae, ersay ar, demirci e, alan c, basturk g. diagnostic value of plasma pentraxin3level for diagnosis of erectile dysfunction. urol j. 2018;15:199-03. 10. otunctemur a, bozkurt m, besiroglu h, polat ec, ozcan l, ozbek e. erectile dysfunction is positively correlated with mean platelet volume and platelet count, but not with eosinophil count in peripheral blood. urol j. 2015;12:2347-52. 11. zamorano-leon jj, segura a, lahera v, et al. relationship between erectile dysfunction, diabetes and dyslipidemia in hypertensivetreated men. urol j. 2018;15:370-5. 12. ayta ia, mckinlay jb, krane rj. the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999;84:50-6. 13. martin-morales a, sanchez-cruz jj, de tejada is, rodriguez-vela l, jimenez-cruz jf, burgos-rodriguez r. prevalence and independent risk factors for erectile dysfunction in spain: results of the epidemiologia de la disfuncion erectil masculina study. the journal of urology. 2001;166:569-75. 14. lewis rw, fugl-meyer ks, corona g, et al. definitions/epidemiology/risk factors for sexual dysfunction. j sex med. 2010;7:1598607. 15. chew k-k, bremner a, stuckey b, earle c, jamrozik k. is the relationship between cigarette smoking and male erectile dysfunction independent of cardiovascular disease? findings from a population-based cross-sectional study. j sex med. 2009;6:22231. 16. solomon h, man jw, jackson g. erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. heart. 2003;89:251-3. 17. corona g, giorda cb, cucinotta d, guida p, nada e, subito‐de gds. sexual dysfunction at the onset of type 2 diabetes: the interplay of depression, hormonal and cardiovascular factors. j sex med. 2014;11:2065-73. 18. fung mm, bettencourt r, barrett-connor nlr associated with erectile dysfunction-aslan et al. sexual disfunction & andrology 220 e. heart disease risk factors predict erectile dysfunction 25 years later: the rancho bernardo study. j am coll cardiol. 2004;43:1405-11. 19. montorsi p, ravagnani pm, galli s, et al. association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient. eur urol. 2006;50:721-31. 20. montorsi p, ravagnani pm, galli s, et al. association between erectile dysfunction and coronary artery disease. role of coronary clinical presentation and extent of coronary vessels involvement: the cobra trial. eur heart j. 2006;27:2632-39. 21. vlachopoulos c, aznaouridis k, ioakeimidis n, et al. unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease. eur heart j. 2006;27:2640-48. 22. yao f, huang y, zhang y, et al. subclinical endothelial dysfunction and low‐grade inflammation play roles in the development of erectile dysfunction in young men with low risk of coronary heart disease. int j androl. 2012;35:653-9. 23. chiurlia e, d’amico r, ratti c, granata ar, romagnoli r, modena mg. subclinical coronary artery atherosclerosis in patients with erectile dysfunction. j am coll cardiol. 2005;46:1503-6. 24. bocchio m, desideri g, scarpelli p, et al. endothelial cell activation in men with erectile dysfunction without cardiovascular risk factors and overt vascular damage. j urol. 2004;171:1601-4. 25. araña rosaínz mdj, ojeda mo, acosta jr, et al. imbalanced low‐grade inflammation and endothelial activation in patients with type 2 diabetes mellitus and erectile dysfunction. j sex med. 2011;8:2017-30. 26. yüksel m, yıldız a, oylumlu m, et al. the association between platelet/lymphocyte ratio and coronary artery disease severity. anatol j cardiol. 2016;15:640-7. 27. sunbul m, gerin f, durmus e, et al. neutrophil to lymphocyte and platelet to lymphocyte ratio in patients with dipper versus nondipper hypertension. clin exp hypertens. 2014;36:217-21. 28. azab b, shah n, akerman m, mcginn jt. value of platelet/lymphocyte ratio as a predictor of all-cause mortality after non-stelevation myocardial infarction. j thromb thrombolysis. 2012;34:326-34. 29. uthamalingam s, patvardhan ea, subramanian s, et al. utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure. am j cardiol. 2011;10:433-8. 30. demirkol s, balta s, unlu m, et al. neutrophils/lymphocytes ratio in patients with cardiac syndrome x and its association with carotid intima–media thickness. clin appl thromb hemost. 2014;20:250-5. 31. kalay n, dogdu o, koc f, et al. hematologic parameters and angiographic progression of coronary atherosclerosis. angiology. 2012;63:213-7. 32. sambel m, kilic m, demirbas m, et al. relationship between erectile dysfunction and the neutrophil to lymphocyte and platelet to lymphocyte ratios. int j impot res. 2018;30:27-35. 33. ventimiglia e, cazzaniga w, pederzoli f, et al. the role of neutrophil-to-lymphocyte ratio in men with erectile dysfunction-preliminary findings of a real-life cross-sectional study. andrology. 2018;6:559-563. 34. seftel ad. re: the role of neutrophil-tolymphocyte ratio in men with erectile dysfunction-preliminary findings of a real-life cross-sectional study. j urol. 2018;200:480-2. 35. esposito k, giugliano f, martedì e, et al. high proportions of erectile dysfunction in men with the metabolic syndrome. diabetes care. 2005;28:1201-3. 36. giugliano f, esposito k, di palo c, et al. erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men. j endocrinol invest. 2004;27:665-9. 37. eaton c, liu y, mittleman m, miner m, glasser d, rimm e. a retrospective study of the relationship between biomarkers of atherosclerosis and erectile dysfunction in 988 men. int j impot res. 2007;19:218. nlr associated with erectile dysfunction-aslan et al. vol 16 no 03 may-june 2019 300 evaluation of oxidative stress in testis and sperm of rat following induced varicocele naeem erfani majd1, 5*, niloofar sadeghi2, marziyeh tavalaee3, mohammad reza tabandeh4, 5, mohammad hossein nasresfahani3 purpose: oxidative stress (os) plays a central role in the pathophysiology of varicocele (vc), however, comprehensive studies concomitantly assessing semen parameter along with chromatin status, oxidative stress, and enzymatic antioxidants in both testis and sperm are limited. therefore, this study aims to assess these parameters in varicocelized rats. materials and methods: for this study, 30 wistar rats were randomly divided into three groups: control group (i); sham-operated group (ii) and left varicocele group (iii). left varicocele was induced and two months after surgery, we evaluated sperm parameters, persistent histone, dna integrity and lipid peroxidation in sperm and also oxidant/antioxidant markers in testis. results: the results showed that sperm concentration, motility, and normal morphology significantly decreased in varicocele group compared to other groups (p < 0.001). also, we observed a significant increase in persistent histone and dna damage of sperm cells in varicocele rats (p < 0.05). in addition, oxidant assessment analysis showed that ros level was higher in testis tissue and sperm cells from the left varicocele rats compared to the control group (p < 0.05). conclusion: this results show that varicocele has a negative effect on spermatogenesis and increased oxidative stress and reduce in antioxidant capacity hand in hand lead to the production of sperm with damaged chromatin which reduces the fertility potential and may jeopardize the future health of the progeny. keywords: dna damage; oxidative stress; rat; varicocele introduction varicocele is one of the most common causes of male infertility which occurs in 4.4% to 22% of the male population and is described as the dilation and tortuosity of plexus pampiniformis (especially in the left testis) and leads to some pathological problems in the testis tissue. (1-3) the pathogenesis of varicocelerelated infertility is not completely defined, although there are numerous hypothesis such as scrotal hyperthermia, oxidative stress, hypoxia, hormonal disturbances, testicular hypo-perfusion, testicular hypoxia, and backflow of toxic metabolites to explain the correlation of varicocele and infertility. but the most confirmed mechanism is the testicular hyperthermia.(4,5) indeed, the male scrotum temperature is kept 1–2℃ lower than core body temperature. reduced scrotal temperature compared to body temperature is necessary for proper testicular function. but it is still obscure why most of the mam1department of histology, faculty of veterinary medicine, shahid chamran university of ahvaz, ahvaz, iran. 2phd student in histology, faculty of veterinary medicine, shahid chamran university of ahvaz, ahvaz, iran. 3department of reproductive biotechnology, reproductive biomedicine research center, royan institute for biotechnology, acecr, isfahan, iran. 4department of biochemistry and molecular biology, faculty of veterinary medicine, shahid chamran university of ahvaz, ahvaz, iran. 5stem cells and transgenic technology research center, shahid chamran university of ahvaz, ahvaz, iran. *correspondence: department of histology, faculty of veterinary medicine, shahid chamran university, ahvaz, iran. tel: +989161184875, e-mail: naeemalbo@yahoo.com. received august 2018 & accepted october 2018 mals have evolved to maintain their testes at low temperatures.(6) in varicocele, dilation of the pampiniform plexus leads to backflow of warm blood into the internal spermatic vein which impairs testicular temperature exchange system. so, failure to adjust scrotal temperature and increased testicular temperature of around 2.5℃, result in testicular heat stress which affects spermatogenesis, and subsequently increase of oxidative stress (os), accumulation of reactive oxygen spices (ros), induction of germ cell apoptosis and dna fragmentation (both germ cell and epididymal sperm) as well as hormonal imbalance.(7-9) generally, os is due to an imbalance of ros and protective antioxidant system. interestingly, testis tissue is extremely vulnerable to oxidative stress because of two main reasons: (i) the existence of abundant unsaturated fatty acids in the plasma membrane of cells (ii) the presence of potential reactive oxygen species (ros)-generating systems with low enzymatic antisexual dysfunction and andrology oxidant capacity due to low cytoplasm of sperm.(10) indeed, a physiological level of ros usually produces by some of the cells like somatic cells and spermatozoa as a byproduct of the electron transfer chain in mitochondria. the main types of ros are h 2 o 2 and o 2 and antioxidants like glutathione peroxidase (gpx), catalase (cat), and superoxide dismutase (sod) present in mitochondria help to balance ros. both oxidants and antioxidants are also present within the reproductive tract. (11) although the normal physiological level of ros is essential for a successful fertilization such as regulation of sperm hyperactivation, capacitation, acrosome reaction and sperm-oocyte fusion, numerous studies have demonstrated the harmful effects of excess ros on sperm function.(4,12) leukocytes and abnormal spermatozoa are considered as important sources of ros generation. in addition, oxidative stress is able to disrupt the steroidogenic ability of leydig cells and also impairing the germinal epithelium to differentiate into normal spermatozoa.(10) in view of the fact that oxidative stress is known as the main factor in the pathophysiology of varicocele and in the most cases, increase of ros level and decrease antioxidant capacity have been observed.(4,13-15) to the best of our knowledge, this is the first study to evaluate sperm parameters, chromatin status and also ros level in both testis and sperm of rats with experimentally induced varicocele. material and methods study population and study design 30 mature, male wistar rats, aged 4 weeks and weighing 150200 gram were used in this study. the rats were obtained from the institute for biotechnology (isfahan, iran). this study received approval of the institutional review board from the royan institute (no: 97000110), and all the experiments conducted on the animals were in accordance with royan institute guidance from the ethical committee for research on laboratory animals. rats were maintained and housed in a controlled environment (12 hours light, 12 hours dark at 24℃) with free access to the standard food and water. rats were randomly divided into 3 groups of 10. in the first group, according to ko, left-side varicocele was induced surgically (varicocele group).(16) rats in group 1 underwent a sham laparotomy (sham group). and the third group consists of untreated rats (control group). surgical technique and outcome assessment each rat was anesthetized by an intraperitoneal injection of ketamine and xylazine mixture. after induction of standardized anesthesia, the left renal vein was exposed and identified through a midline abdominal incision. in order to reduce the renal vein diameter to 1 mm, a 4.0 silk suture was tied around the left renal vein medial to the adrenal and spermatic veins. this occlusion led to increased intravenous pressure lateral and then the pressure is transmitted to the left spermatic vein. this causes a varicocele to develop. at the end of the second month, all rats in the control, sham, and varicocele groups were sacrificed, and their genital systems were collected. at first, the length, width, thickness, and weight of the left testes were assessed using caliper. then, the dissected testes were used for oxidant/antioxidant assessment. samples were weighed and placed phosphate-buffered saline (pbs; gibco-europe, uxbridge, middlesex, uk) and homogenized by a homogenizer. subsequently, homogenized tissues were centrifuged (three-time 10 min at 12000 rpm) and the supernatant was collected and stored at -70°c until assay. in addition, the left epididymitis was separated from the testis and after removing the blood vessels, the epididymis was divided into three distinct segments: caput, corpus, and caudal.(17) the caudal segment was isolated and placed in a petri dish that contained 5 ml of sperm washing media (vitasperm, inoclon, tehran, iran). the sperm retrieved from the caudal epididymis were evaluated for sperm concentration, morphology, motility, dna damage, and protamine deficiency. oxidant/antioxidant assessment in testis for evaluation of enzymatic oxidants, total protein was determined in tissue samples by biuret method (parsazmoon kit, iran) and using bt-1500 autoanalyzer. the activity of catalase (cat) was measured at 37℃ by following the rate of disappearance of h 2 o 2 at 240 nm. (18) the activity of glutathione peroxidase (gpx) was measured using a commercial kit (zellbio gmbh, germany). superoxide dismutase (sod) activity was determined using a commercial kit (ransod-randox lab, antrim, uk). in addition, malondialdehyde (mda) which is an important indicator of oxidative damage was calculated in homogenized tissue by detecting the absorbance of thiobarbituric acid reactive substances at 532 nm as an index of lipid peroxidation.(19) sperm parameters assessment sperm concentration and motility was determined with the aid of a sperm counting chamber (sperm meter; sperm processor, aurangabad, india) and light microscopy using prewarmed slides and also eosin/nigrosin staining was used for morphology assessment. in brief, sperm samples were washed in pbs afterward 30 μl of the sperm suspension was mixed with 60 μl of eosin (merck, darmstadt, germany) for 3 min. then, 90 μl of nigrosin (merck) was added to this mixture and used to prepare the smears. we observed 200 sperm under a light microscope and the percentage of abnormalities visualized in the head, neck, and tail were determined for each sample.(20) evaluation of sperm chromatin condensation and dna damage using aniline blue and acridine orange staining histones during the spermatogenesis are replaced by protamines. defected spermatozoa with poor protamination are rich in lysine and stained by aniline blue (ab) while normal spermatozoa with protaminerich nuclei are contained arginine and cysteine and cannot be stained by this staining.(21) so, for assessment of sperm maturation, a drop of sperm sample was smeared, airdried and fixed for 120 min in 3% glutaraldehyde in 0.2 m phosphate buffer (ph = 7.2). when the smear was dried, each sample was stained with 5% aqueous aniline blue mixed with 4% acetic acid (ph 3.5) for 90 minutes (ph = 3.5). subsequently, for each sample, at least 200 sperm were counted per slide by light microscopy and the rate of sperm with persistent histones was determined.(20) for evaluation of sperm dna damage, sperm samples were washed with pbs buffer and fixed with 4% methanol-free formaldehyde. afterward, slides were stained with acridine orange stain (merck) according to afiyani(20). consequently, microscopic analyses of oxidative stress in testis and sperm of varicocelized rats-majd et al. sexual dysfunction and andrology 301 vol 16 no 03 may-june 2019 302 each slide were done using an olympus fluorescent microscope (bx51, tokyo, japan) by the appropriate filters (460–470 nm). the percentage of green (normal double-stranded dna) and orange/red (abnormal/denatured dna) fluorescence sperm per sample was counted.(20) oxidant assessment in sperm assessment of sperm lipid peroxidation was done according to aitken protocol.(21) bodipy c11 loading bodipy w 581/591 c11 (d3861, molecular probes) was added to 2 ×106 spermatozoa at a final concentration of 5 mm and allowed to incubate for 30 min at 37°c. then, samples were washed twice with pbs buffer at 650g for 5 min an evaluated by a facscalibur flow cytometer (becton dickinson, san jose, ca, usa). positive controls were obtained after the addition of h2o2 to sperm suspensions. statistical analysis data analysis was done using the statistical package for the social sciences for windows, version 18.0. the shapiro-wilk test was performed to evaluate the normal distribution and levene’s test for equality of variances. all results are presented as mean ± sd. differences among groups were analyzed by one-way analysis of variance (anova) followed by tukey hsd test to identify significant differences among the three groups. means were considered statistically significant when p < .05. results comparison of morphometric parameters of testis measurement of testis length, width, thickness, weight, and volume of each group are presented in table 1. these parameters significantly reduced in varicocele group compared to control and sham groups (p < .05) except testis weight. comparison of the aforementioned parameters showed no significant difference between sham and control groups. comparison of sperm parameters mean of sperm concentration were 115.2 ± 8.28, 99.3 ± 9.49 and 62.8 ± 12.84 in control, sham and varicocele groups, respectively and a significant reduction was observed between the varicocele compared to the control (p < 0.001) and sham (p = 0.005) groups (table 2). mean percentage of sperm motility were 85.2 ± 3.7, 78.8 ± 5.51 and 42.0 ± 7.03 in control, sham and varicocele groups, respectively and a significant reduction was observed in varicocele group compared to the control (p < .001) and sham (p = .04) groups (table 2). mean percentage of abnormal sperm morphology were 6.0 ± 1.82 , 8.0 ± 1.33 and 9.6 ± 1.07 in control, sham and varicocele groups, respectively and a significant reduction was observed between the varicocele compared to the control (p < .001) and sham (p = .012) groups (table 2). for the aforementioned parameters, no significant difference was observed between the control and sham groups. comparison of sperm chromatin condensation, dna damage, and lipid peroxidation the result of aniline blue staining in table 3 showed that the percentage of sperm with persistent histone was significantly (p < .05) higher in varicocele group (9.1 ± 4.69) compared to control (4.2 ± 1.27) and sham (5.8 ± 2.37) groups while no difference was observed between the control and sham groups (p > .05). table 1. comparison of mean weight, volume, length, width, and thickness of left testis between control, sham and varicocele groups. variable c control sham varicocele p-value testis weight, gr; mean ± sd 1.66 ± 0.08 1.63 ± 0.13 1.5 ± 0.16 > 0.05 testis volume, ml; mean ± sd 1.59 ± 0.15a 1.66 ± 0.23a 1.12 ± 0.30b < 0.001 * .04 ** testis length, mm; mean ± sd 1.71 ± 0.07a 1.78 ± 0.07a 1.54 ± 0.12b < 0.001 * .012 ** testis width ,mm; mean ± sd 0.89 ± 0.08a 0.89 ± 0.05a 0.72 ± 0.07b < 0.001 * < 0.001** testis thickness, mm; mean ± sd 0.70 ± 0.08a 0.68 ± 0.07a 0.48 ± 0.06b < 0.001 * < 0.001** different letters indicate significant differences between groups at p < 0.05. c continuous variables were compared by one-way analysis of variance (anova) *varicocele to control **varicocele to sham c continuous variables were compared by one-way analysis of variance (anova) variable c control sham varicocele p-value concentration, 106/ml; mean ± sd 115.2 ± 8.28a 99.3 ± 9.49a 62.8 ± 12.84b < 0.001 * .005 ** motility, %; mean ± sd 85.2 ± 3.70a 78.8 ± 5.51a 42.0 ± 7.03b < 0.001 * .04 ** abnormal morphology, %; mean ± sd 6.0 ± 1.82a 8.0 ± 1.33a 9.6 ± 1.07b < 0.001 * .012 ** different letters indicate significant differences between groups at p < 0.05. c continuous variables were compared by one-way analysis of variance (anova) *varicocele to control **varicocele to sham table 2. comparison of sperm parameters between control, sham and varicocele groups. oxidative stress in testis and sperm of varicocelized rats-majd et al. assessment of dna damage by acridine orange staining in table 3 showed that percentage of sperm dna damage was significantly (p < .05) higher in varicocele induction (52.7 ± 18.77) group compared to control (40.4 ± 22.55) and sham (39.4 ± 12.45) while no difference was observed between the control and sham groups. assessment of lipid peroxidation level by bodipy c11 in table 3 showed that the percentage of bodipy c11 positive spermatozoa for lipid peroxidation was significantly (p <0.05) increased in varicocele group (39.7 ± 4.78) compared to control (6.7 ± 4.62) and sham (7.9 ± 5.3) groups while no difference was observed between the control and sham groups. comparison of antioxidant status the results of testicular antioxidants assessment in this study are shown in table 4. the level of cat was significantly (p < .05) lower in varicocele group (7.24 ± 1.23) compared to control (15.67 ± 3.36) and sham (15.64 ± 3.61) groups while such difference was not observed between the control and sham groups. in addition, the level of sod was significantly (p < .05) lower in varicocele group (0.22 ± 0.03) compared to control (0.5 ± 0.11) and sham (0.55 ± 0.05) groups while such difference was not observed between the control and sham groups. similar to cat and sod, the level of gpx was significantly (p < .05) lower in varicocele group (1.89 ± 0.72) compared to control (4.86 ± 0.64) and sham (5.8 ± 0.05) groups while such difference was not observed between the control and sham groups. furthermore, the level of mda as a marker of lipid peroxidation was significantly (p < .05) higher in varicocele group (0.83 ± 0.15) compared to control (0.26 ± 0.08) and sham (0.23 ± 0.04) groups while such difference was not observed between the control and sham groups. discussion in accordance with the results of the current study and previous studies, increased testicular temperature due to varicocele results in reduction of testis weight and testicular volume and these reductions can be related to loss of germ cells by apoptosis with the high mitotic activity which is highly sensitive to hyperthermia.(23, 24) germ cells can incur damage by main mediators such as apoptosis, autophagy and, oxidative stress. in view of the fact that heat stress is involved in the induction of oxidative stress within the testis and the close relationship between heat exposure and ros generation has been confirmed in various studies.(15, 25) therefore, increased lipid peroxidation observed by bodipy staining and malondialdehyde formation is consistent with the result of this and previous studies.(9,26,27) over production or under production of these ros, termed “oxidative” or “reductive” stress, respectively, are both considered to negatively influence normal sperm physiological functions.(28,29) however, cells to contest with overproduction of ros has become highly equipped with different forms of antioxidants.(30) sod, catalase and, gpx are three enzymatic antioxidants which protect cells from oxidative stress. sod is present both in mitochondria and cytoplasm and its main role is to reduce superoxide, the main ros produced through cellular oxygen metabolisms to hydrogen peroxide which in turn is reduced to o 2 and water by either catalase or gpx to protect cells from damaging effects of these oxygen species. therefore, a balance between the oxidant-antioxidant system permits the beneficial oxidants to perform their normal cellular functions and concurrently limits the detrimental effects of excess oxidative stress.(31) however, the condition gets aggravated in presence of traces of metals (such as iron, copper or zinc), superoxide and hydrogen peroxide which work hand in hand to form hydroxyl radicals (oh-) in a reaction called habertable3. comparison of mean percentage sperm with persistent histone, dna damage, and lipid peroxidation between groups. variable c control sham varicocele p-value persistent histone, %; mean ± sd 4.2 ± 1.27a 5.8 ± 2.37a 9.1 ± 4.69b .02 * .04 ** dna damage, %; mean ± sd 40.4 ± 22.55a 39.4 ± 12.45a 52.7 ± 18.77b .02 * .03 ** lipid peroxidation, %; mean ± sd 6.7 ± 4.62a 7.9 ± 5.3a 39.7 ± 4.78b < 0.001 * < 0.001 ** different letters indicate significant differences between groups at p < 0.05. c continuous variables were compared by one-way analysis of variance (anova) *varicocele to control **varicocele to sham variable c control sham varicocele p-value catalase, μ/mg protein; mean ± sd 15.67 ± 3.36a 15.64±3.61a 7.24±1.23b .004 * .002** sod , μ/mg protein; mean ± sd 0.5 ± 0.11a 0.55±0.05a 0.22±0.03b .019 * .015 ** gpx, iu/mg protein; mean ± sd 4.86 ± 0.64a 5.8 ± 0.05a 1.89±0.72b .004 * .002 ** mda, nmol/mg protein; mean ± sd 0.26 ± 0.08a 0.23 ± 0.04a 0.83±0.15b .004 * .005 ** different letters indicate significant differences between groups at p < 0.05. c continuous variables were compared by one-way analysis of variance (anova) *varicocele to control **varicocele to sham table 4. comparison mean of cat, sod, and gpx activity, and also mda level between groups oxidative stress in testis and sperm of varicocelized rats-majd et al. sexual dysfunction and andrology 303 vol 16 no 03 may-june 2019 304 weiss. these radicals are considered to be highly toxic and damaging to cellular functions. an imbalance in the chain of reduction of superoxide, to hydrogen peroxide and consequently to oxygen and water may prone cells to oxidative stress which as stated, the damage becomes intensified in presence of traces of metals.(32) to observed the status of these enzymes in testis of a rat with varicocele, the content or activities of sod, catalase, and gpx enzymes were assessed in the left testis of these rats and the results were compared with corresponding controls. the results revealed that the antioxidant activity or the content of the three antioxidant enzymes significantly reduced in the varicocele group compared to sham or control groups. taken together the results of this study concomitant with other studies in the literature(33,34) demonstrate that the content or the activity of these enzymes (sod, catalase, and gpx) are reduced in state of varicocele which may account for increased rate of lipid peroxidation assessed by bodipy and malondialdehyde formation and increased dna damage assessed by acridine orange staining. in addition, oxidative stress and elevated temperature hinder the rate of histone/protamine exchange which makes sperm nuclear dna more sensitivity to ros damages.(35-37) indeed, observed increase in the percentage of aniline blue-positive spermatozoa, indicating the excessive presence of histones, and increased rate of dna damage strengthens the association between hinder histone/protamine exchange and dna damage in the state of varicocele which is in line with previous reports.(38-40) to reduce the chance of fertilization by dna damaged sperm, epididymis has become equipped by a system called “ubiquitin-proteasome system” that remove damaged sperm. miss-folded or damaged structures and proteins present on the sperm surface are recognized and become ubiquitinated which prone the labeled sperm to phagocytosis by epididymis. (41) the process by which damaged sperm bypass these barriers is called abortive apoptosis and this process appear to be active in the state of varicocele.(42) the main reason for ros associated sperm dna damage might be the activation of mitochondria in caudal epididymis which derives both atp and ros production. production of the excessive amount of superoxide by mitochondria become converted to hydrogen peroxide by both mitochondrial and cytoplasmic sod, h 2 o 2 can freely leave these structure and become entangled with lipids within and between spermatozoa to induce lipid peroxidation and the formation of lipid adducts such as 4 hydroxynonenal, acrolein, and malondialdehyde. these adducts interact with nucleophilic sensitive proteins especially succinic acid dehydrogenase within the mitochondria which further aggravate ros production and subsequently induce a vicious cycle for production ros.(36) the vicious cycle of ros production become detrimental in presence of traces of metal elements and reduce the enzymatic antioxidant capacity of sperm which is intensified in state varicocele, and eventually lead to the execution of apoptosis and cell death. therefore, increase rate of malondialdehyde formation and lipid peroxidation, reduced enzymatic antioxidant capacity in the state of varicocele in our model, intensifies the possible activity of this vicious cycle of ros production in the state of varicocele. lipids, in the form of polyunsaturated fatty acids (pufas), are considered as a central part of the fluidity of membrane layers, especially in sperm as a highly motile cell.(36) approximately 60% of the fatty acid is lost from the membrane while the lipid peroxidation cascade occurs in the sperm and affects sperm function by reduction of its fluidity, mobility, increasing non-specific permeability to ions, and inactivating membrane-bound receptors and enzymes.(12) therefore, increased in lpo assessment by bodipy and mda formation (table 3) may account for the notable decrease in motility due to alterations in the membrane and also increases of sperm dna fragmentation. so judging by the recent studies and our results, the relationship between varicocele and os are proven by detecting the higher ros and lipid peroxidation product like mda in varicocele status.(15, 26) moreover, the negative effects of lipid peroxidation in membrane structure can influence the ability of spermatozoa to take place in the membrane fusion events relevant to fertilization. overall, there is evidence in the literature that defective sperm function is commonly induced by oxidative stress, affect sperm motility by lipid peroxidation, dna integrity by base oxidation and capability for sperm-oocyte to fuse by the formation of adducts.(36, 43) in conclusion based on literature background study, varicocele through different route including testicular hypoxia, increase of scrotal temperature and reflex of metabolites can lead to elevated levels of ros which through lipid peroxidation, dna fragmentation and induction of apoptosis can as well as reduced antioxidant capacity impair sperm functional characteristics, seminal parameters and consequently decrease of male reproductive potential. therefore, concomitant assessment of these parameters may provide more insight in mechanism involved in varicocele male infertility and may help the specialist in this filed to provide therapeutic approach based on molecular mechanism defined in these models. acknowledgement this study was supported by the royan institute, iran. we would like to express our gratitude to the staff of the biotechnology department of royan institute for their full support. conflict on interest the authors have no conflict of interest or financial disclosures to declare. references 1. miyaoka r, esteves sc. a critical appraisal on the role of varicocele in male infertility. adv urol. 2012; 2012:597495. 2. jin g, liu j, qin q, et al. increased level of c-kit in semen of infertile patients with varicocele. urol j. 2017; 14:3023-7. 3. karami h, hadad ah, fallahkarkan m. six years’ experience of laparoscopic varicocelectomy using bipolar electrosurgery and its effect on semen parameters. urology journal. 2016; 13:2788-93. 4. cho cl, esteves sc, agarwal a. novel insights into the pathophysiology of varicocele and its association with reactive oxygen oxidative stress in testis and sperm of varicocelized rats-majd et al. species and sperm dna fragmentation. asian j androl. 2016;18:186. 5. ghandehari-alavijeh r, tavalaee m, zohrabi d, foroozan-broojeni sh, abbasi h, nasresfahani m.h. hypoxia pathway has more impact than inflammation pathway on etiology of infertile men with varicocele. andrologia. 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azadi l, abbasi h, deemeh mr, et al. zaditen (ketotifen), as mast cell blocker, improves sperm quality, chromatin integrity and pregnancy rate after varicocelectomy. int j androl. 2011;34:446-52. 39. tavalaee m, abbasi h, deemeh mr, fotohi f, sadoughi gilani ma, nasr esfahani mh. semen parameters and chromatin packaging in microsurgical varicocelectomy patients. int j fertil steril. 2012;6:165-74. 40. dieamant f, petersen cg, mauri al, et al. semen parameters in men with varicocele: dna fragmentation, chromatin packaging, mitochondrial membrane potential, and apoptosis. jbra assist reprod. 2017 1;21:295-301. 41. sutovsky p, moreno r, ramalho-santos j, dominko t, thompson we, schatten g. a putative, ubiquitin-dependent mechanism for the recognition and elimination of defective spermatozoa in the mammalian epididymis. j cell sci. 2001;114:1665-75. 42. greco e, scarselli f, iacobelli m, et al. efficient treatment of infertility due to sperm dna damage by icsi with testicular spermatozoa. hum reprod. 2005;20:226-30. 43. aitken rj. reactive oxygen species as mediators of sperm capacitation and pathological damage. mol reprod dev. 2017;84:1039-52. oxidative stress in testis and sperm of varicocelized rats-majd et al. letter urology practice in the time of covid-19 ali nowroozi, erfan amini* uro-oncology research center, tehran university of medical sciences, tehran, iran. correspondence: uro-oncology research center, tehran university of medical sciences, tehran, iran. email: e-amini@sina.tums.ac.ir. covid-19 has been suggested to behave like a “once-in-a-century pathogen we’ve been worried about”.(1) it has led to profound negative consequences in healthcare systems especially in countries with rapid spread of disease including iran. according to world bank data, iran had 1.5 hospital beds per 1000 population in 2014. this is much lower than italy (3.4 as of 2012) and china 4.2 (4.2 as of 2012), which both are experiencing major infection rates of covid-19, alongside iran.(2) this shortage of hospital resources will cause excess burden on iranian health care providers and is expected to result in even higher infection and mortality rates over time. healthcare workers are especially prone to burnout due to overstress as the hospitals are overwhelmed by patients. in addition to complete closure of schools and universities the government cancelled several political, social and religious events to tackle the rapid spread of the disease. despite all measures, rapid escalation of covid-19 happened partly due to delay in disease prevention and control. therefore, almost all hospitals were dedicated to these patients and modified their activities to ensure adequate number of beds for covid-19 patients. many surgical departments including urology departments suspended surgeries to accommodate covid-19 patients. this has the potential to postpone many time-sensitive surgeries. currently surgeries are limited to urological emergencies and almost all high volume centers have suspended timesensitive surgeries including turbt or radical cystectomy for high risk bladder cancer, rplnd and nephroureterectomy as well as radical prostatectomy/radiation therapy for poorly differentiated prostate cancer. moreover, fear and anxiety of covid-19 can cause patients to avoid presenting in outpatient clinics and this may result in inappropriate follow up after treatment and poor outcomes in certain patients with urological malignancies. it is crucial that government take steps to slow the disease spread as further escalation results in shortage in available staff and hospital beds. delay in disease control not only limits resources available and increases covid-19 mortality rate but also causes further delay in treating patients with malignant disorders including urological malignancies. the potential of communication technologies and cancer helplines should also be used for counselling these patients. healthcare workers including physicians irrespective of specialty have voluntarily participated in disease control and treatment and this commitment and solidarity is tremendous; however, covid-19 medical frontliners should be protected as they are the most vulnerable populations. it also should be considered that measures to control this pandemic impose a significant financial burden on healthcare and many lowand middle-income countries need economic support. sanctions have further complicated the situation in iran, and a joint effort from the global community is required to lift the extra burden from iranian healthcare providers.(3) references 1. gates b. responding to covid-19 a once-in-a-century pandemic? the new england journal of medicine, 2020. 2. https://data.worldbank.org/indicator/sh.med.beds.zs. 3. takian a, raoofi a, kazempour-ardebili s. covid-19 battle during the toughest sanctions against iran. lancet (london, england). 2020. urology journal/vol 17 no. 3/ may-june2020/ pp. 326-326. [doi: 10.22037/uj.v0i0.6065] 1 running title: vaginal cyst mimicking high stage pelvic organ prolapse title: huge vaginal wall mullerian cyst mimicking high stage pelvic organ prolapse farzaneh sharifiaghdas1 , nastaran mahmoudnejad2, maede mohseni3 1.professor of urology, shahid labbafnejad medical center, urology nephrology research center, shahid beheshti university of medical sciences 2.assistant professor of urology, fellowship of female urology, shahid labbafnejad medical center, urology nephrology research center, shahid beheshti university of medical sciences 3.assistant professor of urology, urology and nephrology research center, hamadan university of medical sciences, hamadan, iran *corresponding author: maede mohseni ,urology and nephrology research center, hamadan university of medical sciences, hamadan, iran mao.mohseni@gmail.com tel: +98 81 38380704 dear editor: the prevalence of vaginal cysts (vc) is estimated to be 0.5 %. however, the exact prevalence is unknown because most of the vcs are small and asymptomatic 1. the most common differential diagnoses of vaginal cystic lesions include: mullerian cyst, gartner’s duct cyst and epidermal inclusion cyst. lesions originating from the urethra and surrounding tissues, such as skene’s duct cyst, urethral diverticulum and ectopic ureterocele may occasionally mimic vc. pelvic organ prolapse, may also present as vc 1-3. mullerian cysts are the most prevalent vcs which are lined predominately by benign mucinous epithelium 1. these cyst are usually small and symptom free and require no treatment. however 2 sometimes they can become large as in the present case and may cause symptoms such as sensation of pressure or fullness in the vagina, palpable mass, dyspareunia, pain or lower urinary tract symptoms 1, 3. since the vcs are relatively rare and due to the wide differential diagnosis and variable clinical manifestations, sometimes it is difficult to reach to exact diagnosis. herein we report an uncommon case of a huge mullerian cyst, mimicking grade four pelvic organ prolapse and its management. a 37-year-old woman presenting with stage four anterior vaginal wall prolapse (cystocele), was referred to our hospital for further evaluation. she had a history of two normal vaginal deliveries. she did not mention any history of pelvic surgeries. routine laboratory tests were all within normal limits. during pelvic examination a huge non-tender cystic mass measuring about 15 × 10 cm was protruded from the introitus (figure 1a). the cyst remained unchanged after voiding. perineal ultrasonography showed the cystic nature of mass and no evidence of bowel components at the region. cysto urethroscopy and dynamic pelvic mri (magnetic resonance imaging) showed no communication between the cyst wall and adjacent pelvic organs (figure 1b). imaging also ruled out concomitant renal or internal genital anomalies. under spinal anesthesia and in lithotomy position, a foley catheter was passed through the urethra into the bladder. the anterior vaginal wall epithelium and cystic wall was incised longitudinally, and a massive amount of mucoid fluid about 400 ml was drained. during dissection, the inner cavity of the cyst was carefully inspected for probable communication with bladder or intestinal elements (figure 1c).in order to reduce recurrence rate, we removed the whole germinal layer of cyst by sharp and blunt dissection with minimal damage to surrounding tissues. there was not any 3 intra or post-operative complications. the patient was discharged the following day after operation. she had no problem at the second week follow-up visit. histopathology report revealed a vaginal mullerian cyst lined by benign mucinous epithelium. vaginal wall mullerian cysts are the most prevalent type of vc (about 40%) which are usually located on the anterior or lateral vaginal wall. however, these lesions may exist at any location in the vaginal cavity. mullerian cysts are often benign which are divided into the following types: mucinous endocervical (the most common), ciliated fallopian tubal and endometrial ones 1. they are usually small and asymptomatic and do not require any intervention. if the vcs grow in size, they can be easily misdiagnosed with other inter labial lesions such as anterior vaginal wall prolapse, enterocele or even a urethral diverticulum. thus in these situations, before planning for any intervention, it is recommended to obtain as much information about the vc and the adjacent organs as possible. in the majority of cases, a definitive diagnosis is made by history and pelvic examination. however sometimes imaging modalities such as perineal or vaginal ultra sonography and pelvic mri are required for accurate diagnosis, exact location, number of cysts, and communication with adjacent organs. 3-5 in fact, most of the time a definitive diagnosis is only made after surgical exploration and pathology report. our patient was an unusual case with a very large vaginal cyst, thus assessment by ultrasonography, mri and cysto urethroscopy was essential to ensure diagnosis. vaginal cysts are treated via surgical excision. the cyst wall shoud be removed completely to reduce recurrence rate. if a portion of the cyst remains unresected, it should be vaporized to diminish the risk of recurrence. 4 in conclusion, when evaluating an anterior vaginal wall pathology, especially atypical ones, it is necessary to consider three points: 1. accurate assessment by history and pelvic physical examination is necessary to confirm cyst location and size. in this regard perineal or vaginal ultrasonography and dynamic mri are helpful modalities useful to differentiate between the vcs and other diagnoses. 2. in vc surgery, complete removal of the cyst wall is necessary to reduce the recurrence rate . 3. in case of huge vcs, the surgeon should be careful to prevent vaginal shortening during vaginal mucosal reduction and repair. conflict of interest statement: the authors declare that there is no conflict of interest. informed consent statement: patient provided written informed consent for publication of the photographs in medical journals. disclosure statement: no competing financial interests exists. references: 1. eilber ks, raz s. benign cystic lesions of the vagina: a literature review. j urol 2003; 170:717 – 22. 2. liaci al, boesmueller h, huebner m, brucker sy, reisenauer c. perivaginal benign masses: diagnosis and therapy in a series of 66 women. arch gynecol obstet 2017; 295:367–374. 3.toz e,sanci m, cumurcu s, ozcan a. müllerian cyst of the vagina masquerading as a cystocele. case rep obstet gynecol 2015:376834. 5 4. gaizo ad, silva ac, lam-himlin dm, allen bc, leyendecker j, kawashima a. magnetic resonance imaging of solid urethral and peri-urethral lesions. insights imaging 2013; 4:461–469. 5. chaudhari vv, patel mk, douek m, raman ss. mr imaging and us of female urethral and periurethral disease. radiographics 2010; 30:1857–1874. 6 figure 1a: anterior virginal wall cyst measuring about 15 cm in diameter, mimicking a high grade pelvic organ prolapse. figure 1b: dynamic pelvic mri of the large vaginal cyst. 7 figure 1c: intra-operative view of longitudinal incision for vaginal cyst removal. the prevalence of renal stones and outcomes of conservative treatment in kidney transplantation: a systematic review and meta-analysis alimohammad fakhr yasseri1, mohammad saatchi2, 1, fatemeh khatami1, hossein dialameh1, hormat rahimzadeh1,3**, seyed mohammad kazem aghamir1* background: nephrolithiasis is a rare complication in the transplanted kidneys, and limited information is available regarding its therapeutic options. this study aimed to review the conservative management of nephrolithiasis and its outcomes in kidney transplanted recipients. methods: a systematic review and meta-analysis of the scientific literature were performed in medline, scopus, and embase databases between january 1st, 1980, and may 19th, 2020. inclusion criteria were deemed as studies encompassing patients with renal stones in the transplanted kidney, either de-novo or donated stones, and used conservative treatment for all or part of their patients. exclusion criteria were considered as studies reporting bladder or ureteral stones, conference abstracts, and full-text unavailability. results of the included studies were combined using a random-effect model, and the prevalence of renal stones and conservative treatment with their corresponding 95% confidence intervals (cis) were reported. results: a total of eight studies (consisting of 14,988 transplanted patients) were included. among these, 195 patients suffered from renal stones, and the prevalence of renal stones was 1.3% (95%ci 0.89%-1.7%). conservative management was utilized in 35% (95%ci 19%-51%) of these patients. the mean stone size ranged from 0.29 cm to 1 cm. three studies reported a stone-free rate (sfr) of %100. except for two studies that did not report complications, other studies reported zero percent. conclusion: more than one-third of nephrolithiasis cases were conservatively managed in transplanted patients. despite limited data, conservative treatment can be adopted in less than 4 mm stones with high sfr and few complications. keywords: conservative treatment; kidney calculi; kidney transplantation; nephrolithiasis introduction as the most effective treatment of advanced renal failure, renal transplantation has attracted increasing attention. by applying effective immunosuppressive regimens, recent advances in the diagnosis and treatment of short-term complications have prolonged graft survival(1) and have increased the risk of rare and longterm complications (2, 3). urinary stone in transplanted kidneys is an uncommon complication occurring over an average time of 1.6 to 3.5 years after transplantation, with the prevalence ranging from 0.2% to 6.3% (1,4). despite its rare incidence, allograft stone formation can lead to significant morbidity, increased risk of infection, and deterioration of renal function through obstruction development(1,3,5). some factors such as the immunosuppressive status of the patient, the extra-anatomic site, and denervation of the transplanted kidney can cause 1urology research center, tehran university of medical sciences, tehran, iran 2department of epidemiology and biostatistics, school of public health, tehran university of medical sciences, tehran, iran. 3department of internal medicine, nephrology, sina hospital, tehran university of medical sciences, tehran, iran. *correspondence: professor;urology research center (urc), sina hospital, hassan abad sq., tehran – iran. tel: (+9821) 6634 8560, fax: (+9821) 6634 8561, email: mkaghamir@tums.ac.ir. **associate professor; urology research center (urc), sina hospital, hassan abad sq., tehran – iran. tel: (+9821) 6634 8560, fax: (+9821) 6634 8561, email: h-rahimzadeh@sina.tums.ac.ir. received september 2019 & accepted may 2020 challenges for the accurate diagnosis and treatment of renal stones in kidney transplant patients(1,3,6). overall, allograft stones' formation could be due to the following conditions. first, allograft stones could exist in the transplanted kidney, which is called "donor-gifted renal stones". second, de-novo stones could develop after transplantation, which might be originated from metabolic, anatomic, or physiological factors. some of these factors are urinary stasis or reflux, nonabsorbable suture material, recurrent urinary tract infections (uti), hyperparathyroidism, hypercalcemia, hypercalciuria, hypocitraturia, and immunosuppressive drugs(3,5). nephrolithiasis in the transplanted kidney is often asymptomatic, although, in those with clinical symptoms, the most common ones include unexplained fever, increased creatinine, decreased urinary output, hematuria, and pain(6,7). therapeutic strategies for transplanted renal stones include extracorporeal shock wave urology journal/vol 18 no. 3/ may-june 2021/ pp. 252-258. [doi: 10.22037/uj.v18i02.6531] review vol 18 no 3 may-june 2021 253 lithotripsy (eswl), flexible ureteroscopy (f-urs), percutaneous nephrolithotomy (pcnl), open surgery, and conservative medical treatment. endourological management is generally challenging, needs high-volume experience, and sometimes is associated with important complications. however, conservative treatment is recommended when stones are asymptomatic and small, which are often passed spontaneously(1,4). excessive fluid intake, urinary alkalization, and dietary changes are considered conservative therapies in these patients(8). ascertaining the overall view of conservative management and its outcomes in kidney transplant recipients is of utmost importance given that limited information exists on the treatment of nephrolithiasis in these patients due to its low prevalence. in addition, no prior study has systematically reviewed the topic. hence, in this study, we aimed to investigate the prevalence of renal stones and outcomes of conservative treatment in kidney transplanted patients. materials and methods study population and outcomes the target population was deemed as kidney transplant recipients with renal stones. the intervention was considered conservative treatment, defined as expectant management, dietary manipulation, or urinary alkalization without invasive endourological interventions. the outcomes were regarded as the prevalence of renal stones in the transplanted patients, the proportion of patients managed conservatively, stone-free rate (sfr), defined as the absence of stone fragments and passage of stones during the follow-up period, and any complications following conservative management. inclusion and exclusion criteria this systematic review was conducted in adherence to the prisma (preferred reporting items for systematic reviews and meta-analyses) guidelines. inclusion criteria were considered as studies encompassing patients with renal stones in the transplanted kidney, either de-novo or donated stones, and used conservative treatment for all or part of their patients. exclusion criteria were considered as studies reporting bladder or ureteral stones, conference abstracts, and studies without available full-texts. according to the predefined inclusion and exclusion criteria, articles were assessed, and relevant observational studies (case-series, cross-sectional, and cohort studies) were carefully chosen. search strategy and study selection a systematic search of three main target databases, medline (pubmed), scopus, and embase, were performed from january 1st, 1980, to the may 19th, 2020, with mesh search syntax grouping of "renal transplantation", "kidney grafting", "kidney stones", "ureterolithiasis", "litholapaxy", "percutaneous nephrolithotomy", "percutaneous ultrasonic lithotripsies", "extracorporeal shockwave lithotripsy", "eswl", "noninvasive litholapaxy", "laparoscopic surgical procedure", "minimally invasive surgery", and "ureteroscopies" (provided in supplementary file 1). an expert urologist (smka) designed the search strategy and found all relevant documents from three targeted databases. to minimize the selection bias, two investigators (amfy and hd) selected articles independently by scanning titles and abstracts. disagreements were solved by a discussion with a third investigator (fkh). in order to find additional documents, the list of references of each candidate article was reviewed as well. the full texts of relevant articles were evaluated carefully against the inclusion and exclusion criteria. data extraction and quality assessment the following data were extracted from the included studies: the name of the first author, publication year, study design, country where the study was performed, total transplant patients and their demographics, the total number of patients with nephrolithiasis, donated or de-novo stones, the number of patients managed conservatively, sfr, and complications after conservative management. the quality of the included studies was assessed based on the newcastle–ottawa scale (nos) table 1. summary of results recruited from the included studies. first year study country total nephroprevalence of donated de-novo mean conservative mean stone sfr complications nos score author design patients (n) lithiasis (n) enal stones (%) (n) (n) age (years) management (n) size (cm) (%) lancia 1997 retrospain 794 16 2.01 3 13 na 12 na na na 5 martin (11) spective devasia 2004 case series india 5 5 5 0 na 3 0.33 100 0 (9) strav2012 case series greece 1525 7 0.46 0 7 na 1 na 100 0 odimos (3) verrier 2012 retrofrance 3000 31 1.03 0 31 40.5 12 na 16 0 5 (12) spective xing 2012 retrochina 974 19 1.95 0 19 47 11 na na na 5 (13) spective yuan 2015 retrochina 1615 19 1.17 0 19 38.7 2 0.42 100 0 5 (1) spective haraz 2017 cross egypt 1208 16 2.02 0 16 41 2 1 66 0 (10) sectional emiliani 2018 retrospain 2115 51 2.41 0 51 48.9 14 na 35 0 7 (4) spective abbreviations: na, not available; nos, the newcastle-ottawa scale; sfr, stone-free rate renal stones and outcomes of conservative treatment in kidney transplantation-fakhr yasseri et al. assessment tool. each study that reached six points or above (from a maximum of nine scores) was considered "high-quality". statistical analysis the results of included studies, in the final analysis, were combined using a random-effect model with "metaprop" command, a routine for pooling proportions, and the prevalence of renal stones and conservative treatment with their corresponding 95% confidence intervals (cis) were reported. the cochrane's q-test of heterogeneity at a rank of 5% was considered to assess statistical heterogeneity of the studies, and i2 was applied for quantitative estimation of heterogeneity among outcomes according to the higgins classification, in which i2 value ≥75% can be indicative of high heterogeneity. egger's test was employed to assess publication bias. all relevant extracted data were recorded in an excel spreadsheet, and analyses were conducted using stata v.14.0 se (college station, tx, usa) and revman 5. results a total of eight studies(1,3,4, 6,9-13) (consisting of 14,988 transplant patients) met the inclusion criteria for the final review (figure 1). of the included studies, two were from spain(4,11), two from china(1,13), and one from france(12), turkey(6), greece(3), egypt(10), and india (9). regarding the study design, five articles were retrospective cohorts(1,3,4,6,11-13), one cross-sectional(10), and two case series(9)(table 1). according to egger's test, there was no publication bias in the included study (p = 0.224). the mean age of the patients was 43 years, and the range of male to female ratio was from 0.19 in the sarier and et al.(6) study to 19.5 in the emiliani and et al. (4) study.(4,14) prevalence of renal stone in order to estimate the prevalence of renal stones, the study by devasia et al.(9) was excluded due to the impossibility of calculating the prevalence. a total of 195 patients suffered from renal stones, and the prevalence of renal stones was 1.3% (95% ci 0.89 % 1.7%) (figure 2). the lowest and highest prevalence of renal stones was 0.4% (3) and 2.4% (4), respectively. prevalence of conservative treatment the prevalence of conservative treatment in 195 patients with nephrolithiasis was 35% (95% ci 19% 51%). this measure ranged from 11% in the study of yuan et al. to 58% in the study of xing and et al. (figure 3)(1,13). stone-free rate (sfr) and complications two studies did not report the sfr (11,13). three studies reported %100 (1,3,9), and the lowest rates were reported by verrier et al.(12), only 16%. except for two studies that did not report complications(9,13), other studies reported zero percent. risk factors for renal stone in transplant patients were not reported in most studies. hyperparathyroidism and gout (hyperuricosuria) were the only risk factors reported in the three studies(3,4, 13). figure 1. flowchart of study selection according to prisma guidelines. renal stones and outcomes of conservative treatment in kidney transplantation-fakhr yasseri et al. review 254 vol 18 no 3 may-june 2021 255 the mean stone size in patients treated conservatively was not reported in five studies(3,4,11-13). in the other study, this size was ranged from 0.29 cm to 1 cm(1,6, 9,10). discussion although many physicians use conservative treatment for urinary stones in kidney transplant recipients, a systematic review on various aspects of this method has not been performed yet. based on our meta-analysis, of each three transplanted recipients with nephrolithiasis, one underwent conservative management. generally, these stones were sized from 0.29 cm to 1 cm. the sfr was 100% in the majority of the studies, and no complications were reported after this management strategy. the prevalence of nephrolithiasis in the renal graft was 1.3% in our analysis. although this prevalence is based on studies concentrating on conservative treatment, it could be worthful due to its large sample size. recently, cheungpasitporn et al. performed a systematic review on 64,416 kidney transplant recipients and estimated the incidence of 1.0% for kidney stones(15). the management of renal stones in transplanted kidneys varied from expectant management to less invasive therapies and open surgery. as a rule, in living donors, the surgeon is committed by the principle that "first no harm" to the graft(16). since transplanted patients are considered single-kidney and receive many immunosuppressive medications, any unnecessary intervention could cause complications. on the other hand, due to the rarity of nephrolithiasis in kidney transplantation, the evidence is not robust, and there is no clear approach protocol in this group of patients. treatment options include expectant management, eswl, f-urs, and pcnl. european urology (eau) guidelines on urolithiasis recommended shock wave lithotripsy for small caliceal stones as an option with minimal risk of complication. however, localization of the stone can be challenging, and sfrs are poor(17). traditionally, urology texts considered a 1.5 cm cut-off for pcnl in nephrolithiasis of renal graft(18), although recent guidelines have recommended the algorithm of stone management in native kidneys for transplanted kidneys. in non-obstructing asymptomatic stones with a size below 4 mm, observation with serial ultrasonography and serum creatinine level check is helpful. other invasive methods are suggested when stone grows or becomes symptomatic(19). generally, conservative management could be divided into medical treatment and expectant management. expectant management for small graft calculus could be done in stones less than 4 mm(20). yuan et al. have reported successful conservative treatment for allograft stones in 2 out of 19 patients and emphasized the central role of close follow-up to prevent complications(1). medical treatment for large stone burden seems potentially feasible. there are a few reports on medical therapy of graft stones due to their low prevalence. for instance, complete resolution of a staghorn stone with adequate drainage of the pyelocaliceal system using a ureteral stent and medical treatment had been demonstrated previously(20). in another one, 19 patients with uric acid nephrolithiasis after renal transplantation treated with medical therapy, including the daily water intake above 3000 ml to maintain the urine volume in the range of 2000-3000 ml/d, urine alkalization with sodium bicarbonate, oral allopurinol, analgesic, and antispasmodic. in this study, oliguria, anuria, stone obstruction, stone length greater than 7 mm, or severe hyfigure 2. forest plot for the prevalence of nephrolithiasis in kidney transplant patients. renal stones and outcomes of conservative treatment in kidney transplantation-fakhr yasseri et al. dronephrosis were indications of surgery(13). many factors could affect a physician's decision during expectant management in graft stone. it could be divided into stone-related and renal anatomic factors. stone-related factors are size, number, location, and composition. renal anatomic factors are circumstances such as obstruction or stasis, hydronephrosis, and caliceal diverticulum(18). most kidney transplanted recipients are considered single-kidney, and the primary recommendation for patients with single kidney and stone is an intervention. however, some researchers tried to use conservative treatment in transplanted patients. of note, there exist several conditions, including the presence of fever, uremia, shortage of urinary output, and refractory pain, in which conservative treatment is contraindicated. these situations usually require emergent decompression of the urinary system. additionally, another crucial factor is the stone size or stone burden. many studies utilized a 4 mm cut-off to manage graft stones conservatively; nevertheless, some larger stones have been successfully managed by surveillance. emiliani et al. used active surveillance in 13 patients and urine alkalization in one. except for two, all of these stones were smaller than 1 cm. they reported four spontaneous expulsions of stones in the active surveillance group(4). one of the drawbacks of the study is the lack of details about the composition, location, and mean size of these stones. in another series with conservative treatment in 31 donated transplanted patients, the spontaneous passage rate of above 4 mm stones was 0% vs. 92.8% in the less than 4 mm group. it should be mention that no pretreatment was performed for donated stones(14). yuan et al. reported two spontaneous passages in ureteropelvic stones, with the size of 0.4 * 0.5 cm and 0.3 * 0.5 cm(1). harraz et al. used a watchful waiting policy with hemolysis for a 10 mm radiolucent stone with no change in size. in their series, conservative treatment was successful in two patients with the stones in kidney and ureter, and the stones passed spontaneously(10). nevertheless, they did not mention the size of these two stones. devasia et al. performed expectant management in three gift-donated stones, with a mean size of 3.3 mm. during two years of follow-up, graft function remained stable, and stones were invisible in ultrasonography or x-ray. one of these cases experienced spontaneous passage(9). regarding other factors such as multiple stones and their composition, there is not sufficient evidence with respect to the conservative treatment. concerning the stone location, there is no difference between upper and lower pole stones in spontaneous passage rates. in one report, 83% and 84% of lower and mid-upper pole stones passed spontaneously (p-value = 0.9). this insignificant difference may be due to changing the position of calyces in transplanted kidneys (14). for calculating sfr among studies, clinically insignificant residual fragments (crif) could be used, which may be a misnomer as some small residual particles eventually become symptomatic and clinically important as they can move and cause obstruction, act as niduses for stone growth, or become sources for persistent infections(18). unfortunately, sfr was not reported accurately in these studies. data were extracted based on the stone passage during the follow-up period. two studies did not report sfrs. three studies reported 100% sfr, and the lowest rates were reported by varrier et al., who performed active surveillance in seven post-transplant kidney stones. they reported two figure 3. forest plot for the prevalence of conservative treatment in kidney transplant patients with nephrolithiasis. renal stones and outcomes of conservative treatment in kidney transplantation-fakhr yasseri et al. review 256 vol 18 no 3 may-june 2021 257 spontaneous passages, and other stones were stable(12). in case the patient selection for expectant management is performed well, and close follow-up is achieved, minimal complications would be expected. the major complication in this management is the requirement of invasive intervention. verrier et al. performed surveillance in 12 cases, in which two of the patients passed stones spontaneously, and ten were stable during the follow-up(12). in another study with 31 transplanted recipients, only three patients (9.6%) with a stone size of ≥ 4 mm required further intervention. during this time, none of the patients with stones smaller than 4 mm became symptomatic or required any intervention(14). the duration of follow-up and its intervals were not precise in the studies, and there was no similar strategy. in these studies, the follow-up duration ranged from 24 to 96 months. in one study, patients were followed up every three months with serum creatinine levels and ultrasonography. at their last follow-up within the study period, all patients underwent non-contrast computed tomography (ct) for stone evaluation, and they were followed up for a minimum of 12 months(14). in another one, serum concentrations of urea, creatinine and uric acid, and cyclosporine a or tacrolimus were tested every 2–3 months. the patients underwent ultrasonography every three months in the first year after the transplantation and every six months thereafter(1). emiliani et al. used only ultrasonography every 3–4 months in active surveillance cases(4). for gifted stones, devasia et al. repeated imaging every six months after transplantation over a follow‐up period of two years and annually afterward(9). overall, there is no consensus on the follow-up protocol of kidney transplant patients with nephrolithiasis, while, in our center, we perform ultrasonography every three months. this review revealed that our knowledge of conservative treatment of nephrolithiasis in renal transplantation is insufficient. during the last 40 years, few studies have been dedicated to this entity, and this topic was usually addressed as a part of a study, besides other modalities. authors reported neither stone characteristics nor outcomes in this group separately. the stone size has not been mentioned in most studies, so the exact cut-off for stone-size for conservative treatment could not be advised. there were heterogeneous data of immunosuppressive regimens in the reviewed studies, and most of them did not specialize the regimen in the conservative group. we suggest further multi-central studies on conservative treatment modality in transplanted patients to assess stone characteristics, sfr, and outcomes. conclusions approximately 35% of nephrolithiasis was conservatively managed in transplanted patients. there are few articles regarding this treatment option in kidney transplant patients with incomplete data in the literature. conservative treatment could be utilized in stones less than 4 mm in size with high sfr and low rate of complications. further studies are required to explore the sfr, complications, and follow-up of conservative management in kidney transplant recipients with nephrolithiasis. conflict of interest all authors declare there is no conflict of interest. references 1. yuan h-j, yang d-d, cui y-s, et al. minimally invasive treatment of renal transplant nephrolithiasis. world j urol . 2015;33:207985. 2. challacombe b, dasgupta p, tiptaft r, et al. multimodal management of urolithiasis in renal transplantation. bju int. 2005;96:385-9. 3. stravodimos kg, adamis s, tyritzis s, georgios z, constantinides ca. renal transplant lithiasis: analysis of our series and review of the literature. j. endourol. 2012;26:38-44. 4. emiliani e, subiela jd, regis f, angerri o, palou j. over 30-yr experience on the management of graft stones after renal transplantation. eur urol focus. 2018;4:16974. 5. palazzo s, colamonico o, forte s, et al. experience of percutaneous access under ultrasound guidance in renal transplant patients with allograft lithiasis. arch ital urol nefrol androl . 2016;88:337-40. 6. sarier m, duman i, yuksel y, et al. results of minimally invasive surgical treatment of allograft lithiasis in live-donor renal transplant recipients: a single-center experience of 3758 renal transplantations. urolithiasis. 2019;47:273-8. 7. cicerello e, merlo f, mangano m, cova g, maccatrozzo l. urolithiasis in renal transplantation: diagnosis and management. arch ital urol nefrol androl . 2014;86:25760. 8. sha-dan l, qing-tang w, wei-guo c. treatment of urinary lithiasis following kidney transplantation with extracorporeal shockwave lithotripsy. chin med j. 2011;124:14314. 9. devasia a, chacko n, gnanaraj l, cherian r, gopalakrishnan g. stone-bearing livedonor kidneys for transplantation. bju int. 2005;95:394-7. 10. harraz am, zahran mh, kamal ai, et al. contemporary management of renal transplant recipients with de novo urolithiasis: a single institution experience and review of the literature. exp clin transplant. 2017;15:277-81. 11. lancina martín ja, garcía buitrón jm, díaz bermúdez j, et al. [urinary lithiasis in transplanted kidney]. arch esp urol. 1997;50:141-50. 12. verrier c, bessede t, hajj p, aoubid l, eschwege p, benoit g. decrease in and management of urolithiasis after kidney transplantation. j urol. 2012;187:1651-5. 13. xing l, jiang x, wang zp, miao sz, qu qs. uric acid nephrolithiasis after renal transplantation. chinese j. tissue eng. res. 2012;16:7433-7. 14. sarier m, duman i, callioglu m, et al. outcomes of conservative management of asymptomatic live donor kidney stones. urology. 2018;118:43-6. 15. cheungpasitporn w, thongprayoon c, mao renal stones and outcomes of conservative treatment in kidney transplantation-fakhr yasseri et al. ma, et al. incidence of kidney stones in kidney transplant recipients: a systematic review and meta-analysis. world j transplant. 2016;6:790-7. 16. ganpule a, vyas jb, sheladia c, et al. management of urolithiasis in live-related kidney donors. j endourol. 2013;27:245-50. 17. c. türk an, a. petrik, c. seitz, a. skolarikos , k. thomas, n.f. davis, j.f. donaldson, r. lombardo, n. grivas, y. ruhayel. eau guidelines urolithiasis2019. available from: https://uroweb.org/guideline/urolithiasis/. 18. alan w. partin cap, louis r. kavoussi, roger r. dmochowski, alan j. wein. campbell walsh urology. 11 ed2016. 4906 p. 19. alan w. partin cap, louis r. kavoussi, roger r. dmochowski, alan j. wein. campbell walsh wein urology. 12 ed2020. 4096 p. 20. harraz am, kamal ai, shokeir aa. urolithiasis in renal transplant donors and recipients: an update. int. j. surg.2016;36:6937. renal stones and outcomes of conservative treatment in kidney transplantation-fakhr yasseri et al. review 258 endourology and stone disease 81urology journal vol 7 no 2 spring 2010 familial relations and recurrence pattern in nephrolithiasis new words about old subjects abbas basiri1, nasser shakhssalim,1 ali reza khoshdel,2 ahmad javaherforooshzadeh,3 hossein basiri,4 mohammad hadi radfar,3 negar dorraj4 purpose: while medical and surgical approaches to urolithiasis are different for single and recurrent stone former (rsf), the rsf definition itself is commonly overlooked. moreover, despite consensus on association between family history (fh) and urolithiasis, more epidemiologic evidence is required to clarify the nature of this relationship. our purpose was to propose a more precise definition of rsf, and also to investigate how family history may affect urolithiasis. materials and methods: using a multistage stratified sampling in 4 seasonal phases, 6127 subjects with imaging-proven urolithiasis were detected in 12 iranian regions. the fh of urolithiasis and the average interval between episodes (cycles) were determined by an informed interview. results: of 6127 patients with the mean age of 41.8 ± 15.1 years, 42% had fh, and 22.2% were rsf of whom 61% were men. the patients with fh had a greater chance of recurrence (or = 1.2, 95% confidence interval (ci), 1.1 to 1.4). furthermore, patients with positive fh had more episodes (p = .0001), comparable cycles and younger ages at the onset (p = .02) than those patients without a fh. in the rsf group, the 90th percentiles of the cycle were 60 months and the estimated mean stone cycle for the population was 25.34 months (99% ci, 23.0 to 27.7). conclusion: family history seems very common in iranian population and is a risk factor for recurrence. moreover, rsf could be identified by the estimated average cycle in the population (25.3 months) or by the percentiles. urol j. 2010;7:81-6. www.uj.unrc.ir keywords: epidemiology, genetics, recurrence, urolithiasis 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran 2aja university of medical sciences, tehran, iran 3urology and nephrology research center, shahid labbafinejad medical center, tehran, iran 4urology and nephrology research center, tehran, iran corresponding author: nasser shakhssalim, md no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: slim456@yahoo.com received may 2009 accepted february 2010 introduction urolithiasis is a common worldwide disease and its lifetime incidence is approximately 10% to 15% .(1-4) furthermore, 20% to 75% of the patients experience the recurrence of the disease within ten years of the first episode. (4-6) consequently, urolithiasis causes a burden on the society and significantly influences patients’ life quality. therefore, various approaches, including several metabolic workup protocols have been suggested in order to reduce the recurrence rate of the disease.(2,4,7,8) due to economic considerations and limited resources, however, metabolic evaluation of the disease is not usually recommended for the firsttimers or occasional recurrent stone formers (rsfs);(8) thus, medical treatment is considered costeffective only in rsfs.(9,10) urinary recurrent stone and family history—basiri et al 82 urology journal vol 7 no 2 spring 2010 nevertheless, the definition of rsf is still vague and mainly based on arbitrary cut-points, personal opinions, or even economic and insurance standards, whereas epidemiologic evidence has rarely been referred to classify the patients. although there is consensus on the association of family history (fh) and the urolithiasis, more epidemiologic information regarding the nature and the impact of fh are required to enable us to recognize the high risk groups for community interventions. this population-based study aimed to identify the magnitude of the stone episode interval as a marker of rsf definition in iranian population, particularly in patients with fh of the disease. such definition not only could help in the related risk assessments in those patients, but also provides the health system with the opportunity to have a forecast for the related services. materials and methods this study was conducted as part of a nationwide epidemiologic research in 787 imaging centers in 12 ecologic regions (composed of 30 provinces) across iran. a stratified “epsem scheme” (equal probability selection method) sampling method was used and radiologically documented 6 127 positive subjects for urinary stone were determined out of 117 956 referrals (for various causes) to the imaging centers. based on a detailed interview, the history of stone disease in close family members, including father, mother, siblings, and the descendants was asked from the patients as well as the history of the disease in their spouses, and the relative frequency of each was recorded. in addition, the number of the family members with the disease was considered as a separate variable. to minimize any potential confounding effect of the gender on the results, the familial profile was also evaluated in genders, separately. the relationships between the familial profile (either as a dichotomous or as a string variable) and the other variables such as the number of stone episodes, age of onset, and recurrence intervals were evaluated by non-parametric spearman correlation and chi-square, and the difference in subgroups was analyzed by kruskalwallis and median tests. patients with one or more previous episodes of the stone disease were recognized as rsf. the duration of the disease from the time of the diagnosis to the date of the interview was recorded, and patients with duration of less than 240 months were selected for study purposes, since data beyond this point were scant and unreliable. thereafter, the stone episode interval (cycle) was obtained for each patient that was the duration divided by the episode number. subsequently, the mean and the standard error (se) for the point estimate were calculated and 99% confidence interval (ci) of the episode cycle was determined using the following formula: 99% confidence interval = mean ± (2.58×se) the demographic reports for the population were tabulated, and the “cycle” and the mean episode number were compared in different sexes by mann-whitney u test, and multivariate analysis was applied using the spss (statistical package for the social science, version 12.0, spss inc, chicago, illinois, usa) software. a p value less than .05 was considered statistically significant. results general characteristics: forty-two percent of the stone positive subjects had fh of urinary stone disease in their close families and 22.2% had at least one episode of recurrence (labeled as rsf). around 61% of the samples were men and more than 75% were from urban areas. the mean age was 41.8 ± 15.1 years and 82.5% were married. in the studied population, there were 13.7% smokers, and 22.2% uneducated participants. approximately, 34% had received some forms of medications in their lifetime for urolithiasis, 31% experienced extracorporeal shock wave lithotripsy, and 17.4% had a history of a surgical intervention for urinary stones (either endoscopic, or open). reducing the salt consumption, dairy products, and protein were considered by 49%, 39%, and 35% of the patients, whereas increasing water intake was taken seriously in about 70% of the patients. urinary recurrent stone and family history—basiri et al 83urology journal vol 7 no 2 spring 2010 familial pattern: of 6127 subjects, over 22% had a parental history of the disease, while 1.7% had a dual parental history (both parents). the fh in the siblings and descendents was 27.9% and 9.8%, respectively, ie, 14.2% in sisters and 20.7% in brothers. when gender was separately analyzed, 40.8% of men and 46% of women had a positive fh of the urinary stone disease (p = .0001). women were dominant with respect to the fh in their sisters and children (p = .001 and p = .0001, respectively). however, men and women groups were comparable regarding the frequency of the disease in their parents and their brothers (p = .88 and p = .67, respectively). in other words, the fh in brothers was the most frequent relationship in both genders. interestingly, the frequency of the stone disease history in the spouse was 54% in women, whereas it was 46% in men (p < .0001); ie, the concurrence of the disease in spouse is more likely in women. nonetheless, this might be due to the male predominance in the disease. family history in the younger group (≤ 40 y, n = 3056) was more frequent than the older group (> 40 y, n = 2946) (44.5% vs. 41.5%, p = .03). mann-whitney u test demonstrated that the number of stone episodes was significantly higher in the group with a positive first degree fh (p = 00.1) (figure 1). nevertheless, the cycle was not significantly different between the groups (p > .05) (figure 2). instead, the age of onset of the disease was younger in patients with a fh [medians: 34 interquartile range (iqr) = 19) vs. 36 (iqr = 22), p = .02]. as a categorical scale, the stone episodes raised with increase in number of family members with urolithiasis (pearson chi2 = 28.3, p = .03). consequently, when both variables were considered as dichotomous variables, patients with a positive fh had 1.2 times more chance of recurrence (fisher exact test, p = .002, or = 1.2, 95% ci, 1.1 to 1.4). to compare the median age at the onset based on the number of the affected family members, since only 28 and 1 patients remained with 4 or 5 positive fh, respectively, they were discarded for the next analysis. kruskal-wallis test demonstrated a trend of younger age at onset for stronger fh (p = .02) (figure 3), which was also confirmed by the median test (median = 35.3, p = .004). there was a weak but significant positive relationship between the number of family members with the stone disease and the number of stone episodes (spearman’s rho = 5%, p = .001). in contrast, there was a weak but significant inverse correlation between the number of the affected family members and the age of the onset of the disease (spearman’s rho = 6%, p = .006). recurrence pattern: the mean duration of the disease was 53.3 months (sd = 58.0, se = 1.6), figure 1. mean episodes for urolithiasis in patients with and without first degree family history of the disease (p = .001). figure 2. mean stone episodes in urolithiasis patients, males and females (p = .001). urinary recurrent stone and family history—basiri et al 84 urology journal vol 7 no 2 spring 2010 and over 41% had 3 or more episodes (mean = 3.3, sd = 5.3, se = 0.1) of the disease. the median cycle was 12 months, and 75th and 90th percentiles were 32.4 and 60 months in our sample, respectively. more importantly, the estimated mean stone episode interval (cycle) was 25.34 months (se = 0.91) (99% ci, 23.0 to 27.7) for the population. while men and women in this group had a comparable mean age (p > .05), men had more stone episodes than women on average (p = .001). nevertheless, the cycle was not significantly different in men if compared to women (p > .05). the age of onset was significantly younger in men than the women (mann whitney u test, mean difference = 1.4 y, p = .01). the age of the disease onset was inversely (though weakly) associated with the number of episodes (spearman’s rho = -0.1, p = .001). multivariate analysis demonstrated that in a model containing potential influential factors on the cycle (episode interval), some factors such as night-time sleeping, smoking, and family history were associated with shorter cycles, and some others, including medical treatment, increasing fluid intake, and reducing salt intake were correlated with longer interval between episodes (p = .001 for model). however, among these factors, only age remained significantly correlated after the adjustments (p = .001). discussion several studies have examined the impact of fh on the incidence and prevalence of nephrolithiasis. (11-13) comparing these studies demonstrates a large variation in different geographic regions and various types of stones. polito and colleagues reported the probability of positive fh to be 69% in patients with hypercalciuia, 75% in patients with hyperuricusuria, 78% in patients with both of the diseases, and 22% in the control group.(14) the positive fh of stone has been reported in 16% to 37% of patients with the kidney stone compared with 4% to 22% in healthy control subjects.(11) the prevalence of fh in our study was 42%. this high rate might be due to intra-familial marriage in iranian culture. safarinejad reported a 2-fold increase in urolithiasis prevalence in the first degree relatives of the patients compared to the general iranian population.(15) in agreement with the previous reports,(11,16) our study showed that fh also increases recurrence by 20% compared to 25% in the study by indridason and associates (17) and 15% in the study by stamatiou and coworkers. (18) also men experienced more recurrence in our study. moreover, the results showed that the more family members with urinary stone are, the more the chances for recurrence. however, the episode interval (cycle) was relatively constant. instead, the disease started earlier in rsfs than those patients without recurrence. to our best knowledge, this is the first study reporting that despite the relationship between the number of the affected family members and the male gender with the disease incidence at a younger age, recurrence intervals (cycles) are not related with the family history. recurrence is now a well-known characteristic of urolithiasis with a great impact on the community as well as the patients’ quality of lives.(1,5,8,19) however, there is a marked variety of the recurrence rate in different parts of the world and the treatment approach is considerably influenced by the burden of disease, economic condition, access to the medical services, and patients’ attitude and compliance. while identifying rsf has a pivotal role in the selection of the appropriate treatment protocol, epidemiologic figure 3. non-parametric comparison of the age of onset according to the number of the affected individuals in the close family members. urinary recurrent stone and family history—basiri et al 85urology journal vol 7 no 2 spring 2010 studies about rsf definition and recurrence cycle (episode interval) is sparse. in this study, we evaluated the urinary stone recurrence according to a population-based study and the presented epidemiologic evidence to facilitate rsf definition in our population. the reported recurrence rate of urolithiasis widely varied from 20% to 75% in different studies due to the diversities in the populations, sampling, study settings, designs, follow-up periods, response rates, etc. (1,3,5,6,8,19,20) while retrospective studies are prone to cause bias and usually overestimates the rate because of using the referral clinic data, prospective researches may be influenced by extrapolation limitations, follow-up completions, loss, and symptomless episodes when no radiologic screening is used for recurrence determination. in our populationbased study, 22% of the patients with a current imaging-proven stone had at least one previous episode of the disease. however, we may underestimate the recurrence rate in the community in this cross-sectional study and miss some asymptomatic rfss who did not attend the imaging centers at the time of study. a major focus of this study was on the interval between the episodes (cycle) in order to facilitate rsf definition because of its important impact on the treatment approach. in a recent review article, chandhoke noted that metabolic workup and medical therapy are not recommended for the first-time or occasional rsf who forms new stones less frequently than once every 5 years.(8) in a study, strohmaier reviewed 31 references, and reported 30% to 40% recurrence rates, and 0.10 to 0.15 stone per year (equivalent to 79.2 to 120 months as interval) and that the first 4 years was claimed to have the highest recurrence probability.(3) however, the study was neither systematic nor homogenous with respect to the included studies. chandhoke evaluated the frequency of the stone recurrence in 10 academic centers and concluded that a recurrent calcium stone former should have a recurrence at least once in 2 years in the usa for medical prophylaxis to be cost-effective,(9) but the cost of suffering and time lost from work was unaccounted for. daudon and colleagues labeled their patients from france as “nonrecurrent” only if they had no evidence of new stone formation for at least 3 years.(21) although they referred to the average interval recurrence reported in 2 other studies from the usa as the rationale for such a classification,(7,20) the original studies did not clearly describe their findings. furthermore, geographic variations were overlooked in this extrapolation. all in all, although considering the average recurrence time as an index for rsf definition is justified, the spectrum of the reported recurrence time is very wide, ranging from 13(2) to 81 months,(1) and there could not be a model suitable for all. in other words, the recurrence time must be individually estimated in each population. more importantly, the evidence should be obtained from population-based studies, not the referrals to the tertiary clinics. we tried to overcome these potential biases by a representative sampling and precisely estimated that the mean cycle between the episodes was 25.34 months that could be from 23 to 27.7 months with 99% ci in our “general population”. we also reported 75th and 90th percentiles of the samples (32.4 and 60 months) to facilitate proper classification of the patients based on the practical applications including clinical, laboratory, economic, legal, and social purposes. defining rsf based on the above indexes, not only improves recurrence risk stratification of the patients, but also points to the patients with higher probability of co-existing diseases. furthermore, it helps to select the metabolic evaluation of the candidates and improves disease prevention. male gender was associated with greater number stone episodes in our study; however, the cycle was comparable between various genders. in fact, it seems that the higher rate of episodes is mainly caused by an earlier onset of the disease in men. this finding is in parallel with the majority of the studies about urolithiasis recurrence demonstrating a higher tendency of men for recurrence and potential inhibitory role of female hormones on urolithiasis;(6,22,23) but it contradicts studies by trinchieri and colleagues as well as hess and associates, who reported similar recurrence rates and episodes in genders. (2,5) nevertheless, the former reported a tertiary clinic urinary recurrent stone and family history—basiri et al 86 urology journal vol 7 no 2 spring 2010 data, and the latter result may be influenced by greater response rate from women than men in their study. conclusion in this large epidemiologic study, a high frequency of fh in imaging-proven urolithiasis was observed. while recurrence was more frequent among patients with fh and in men, cycle was relatively constant and in fact, more number of episodes was due to younger age at the first onset of the disease. since average cycle has been traditionally considered for rsf definition, we may define rsf as any patient with a recurrence of the urinary stone earlier than 23 months (lower limit of the estimated mean episode interval) in our population. furthermore, the presented 75th and 90th percentiles could also been applied for the rsf risk classification, while including a certain proportion of the patients. this approach promises to improve patients’ care and prevention strategies. acknowledgements this study was supported by iranian ministry of health. conflict of interest none declared. references 1. coe fl, keck j, norton er. the natural history of calcium urolithiasis. jama. 1977;238:1519-23. 2. hess b, hasler-strub u, ackermann d, jaeger p. metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasis. nephrol dial transplant. 1997;12:1362-8. 3. strohmaier wl. course of calcium stone disease without treatment. what can we expect? eur urol. 2000;37:339-44. 4. krepinsky j, ingram aj, churchill dn. metabolic investigation of recurrent nephrolithiasis: compliance with recommendations. urology. 2000;56:915-20. 5. trinchieri a, ostini f, nespoli r, rovera f, montanari e, zanetti g. a prospective study of recurrence rate and risk factors for recurrence after a first renal stone. j urol. 1999;162:27-30. 6. unal d, yeni e, verit a, karatas of. prognostic factors effecting on recurrence of urinary stone disease: a multivariate analysis of everyday patient parameters. int urol nephrol. 2005;37:447-52. 7. parks jh, asplin jr, coe fl. patient adherence to long-term medical treatment of kidney stones. j urol. 2001;166:2057-60. 8. chandhoke ps. evaluation of the recurrent stone former. urol clin north am. 2007;34:315-22. 9. chandhoke ps. when is medical prophylaxis cost-effective for recurrent calcium stones? j urol. 2002;168:937-40. 10. pak cy. should patients with single renal stone occurrence undergo diagnostic evaluation? j urol. 1982;127:855-8. 11. curhan gc, willett wc, rimm eb, stampfer mj. family history and risk of kidney stones. j am soc nephrol. 1997;8:1568-73. 12. ahmadi asr badr y, hazhir s, hasanzadeh k. family history and age at the onset of upper urinary tract calculi. urol j. 2007;4:142-5; discussion 5-6. 13. amato m, lusini ml, nelli f. epidemiology of nephrolithiasis today. urol int. 2004;72 suppl 1:1-5. 14. polito c, la manna a, nappi b, villani j, di toro r. idiopathic hypercalciuria and hyperuricosuria: family prevalence of nephrolithiasis. pediatr nephrol. 2000;14:1102-4. 15. safarinejad mr. adult urolithiasis in a populationbased study in iran: prevalence, incidence, and associated risk factors. urol res. 2007;35:73-82. 16. ljunghall s, hedstrand h. epidemiology of renal stones in a middle-aged male population. acta med scand. 1975;197:439-45. 17. indridason os, birgisson s, edvardsson vo, sigvaldason h, sigfusson n, palsson r. epidemiology of kidney stones in iceland: a population-based study. scand j urol nephrol. 2006;40:215-20. 18. stamatiou kn, karanasiou vi, lacroix re, et al. prevalence of urolithiasis in rural thebes, greece. rural remote health. 2006;6:610. 19. sutherland jw, parks jh, coe fl. recurrence after a single renal stone in a community practice. miner electrolyte metab. 1985;11:267-9. 20. ulmann a, clavel j, destree d, dubois c, mombet a, brisset jm. [natural history of renal calcium lithiasis. data obtained from a cohort of 667 patients]. presse med. 1991;20:499-502. 21. daudon m, hennequin c, boujelben g, lacour b, jungers p. serial crystalluria determination and the risk of recurrence in calcium stone formers. kidney int. 2005;67:1934-43. 22. iguchi m, takamura c, umekawa t, kurita t, kohri k. inhibitory effects of female sex hormones on urinary stone formation in rats. kidney int. 1999;56:479-85. 23. curhan gc, willett wc, speizer fe, stampfer mj. twenty-four-hour urine chemistries and the risk of kidney stones among women and men. kidney int. 2001;59:2290-8. assessment of sperm pawp expression in infertile men somayeh tanhaei1,2, solmaz abdali-mashhadi1, marziyeh tavalaee1, soudabeh javadian-elyaderani1, kamran ghaedi2,3, seyed morteza seifati 4, mohammad h. nasr-esfahani1,2,5* purpose: the aim of this study was to evaluate expression of post-acrosomal ww binding protein (pawp) in infertile men with low and high fertilization post icsi and also globozoospermic men. materials and methods: semen samples were collected from 18 infertile men with previously failed or low fertilization (< 25%) post icsi, 10 men with high fertilization (>50%) post icsi, 15 globozoospermic men, and 21 fertile individuals. then, expression of pawp was assessed at rna with quantitative real time pcr. results: relative expression of pawp in sperm was significantly (p < .05) lower in infertile men with globozoospermia (41.5 ± 5.7) or low fertilization rate (43.3±10.4) compared to fertile (138.8 ± 17.3)or men with high fertilization (211.6 ± 75.6). in addition, a significant positive correlation (r = 0.628; p = .001) was observed between percentage of fertilization with the relative expression of pawp. conclusion: considering solid recent evidences regarding plcζ as the main sperm factor involved in oocyte activation, therefore co-localization of plcζ with pawp in perinuclear theca may account for the above observation and it is likely that pawp may have other functions and/or it may assist plcζ. keywords: pawp; fertilization; oocyte activation; globozoospermia. introduction intracytoplasmic sperm injection (icsi) is recom-mended to ameliorate fertilization in couples with male factor infertility(1,2). the average fertilization rate is reported to range from 40% to 70% and total failed fertilization rate is around 2-3%(3). the etiology of failed fertilization has been ascribed to three main factors;(4,5) defects in oocytes, sperm(6,7,8), or the icsi procedure(9). oocyte and sperm defects are mainly attributed to defects in the process of gametogenesis and gamete maturation. cytologic analysis of failed fertilized human oocytes after icsi indicates that lack of oocyte activation accounts for over half of failed fertilized oocytes(3). it is well documented that upon fusion of sperm with oocyte, unknown component(s) release(s) from sperm head, possibly localized in the perinuclear theca (pt) region, into the oocyte, inducing oocyte activation. these components are collectively termed “sperm-associated oocyte activating factors (saoafs)” (10,11). saoaf should be (11);1) synthesized during spermiogenesis and localized in sperm head, so that during sperm oocyte fusion, it can diffuse into the oocytes, 2) detectable during the early stages of fertilization(12), 3) elicited oocyte activation events such as calcium os1department of reproductive biotechnology, reproductive biomedicine research center, royan institute for biotechnology, acecr, isfahan, iran. 2 department of cellular biotechnology, cell science research center, royan institute for biotechnology, acecr, isfahan, iran. 3department of biology, faculty of sciences, university of isfahan, isfahan, iran. 4 department of medical biotechnology research center, ashkezar branch, islamic azad university, ashkezar, yazd, iran. 5 isfahan fertility and infertility center, isfahan, iran. *correspondence: department of reproductive biotechnology, reproductive biomedicine research center, royan institute for biotechnology, acecr, isfahan, iran. tel: 03195015682. fax: 03195015687. e-mail: mh.nasr-esfahani@royaninstitute.org. received may 2018 & accepted february 2019 cillations, secondary polar body formation and pronucleus formation(13) and, 4) blocked by use of competitive peptides or antibodies (14,15). a number of proteins have been proposed as saoaf candidates, including phospholipase c zeta (plcζ)(16,17), post-acrosomal ww binding protein (pawp)(18,19), truncated form of kit tyrosine kinase (tr-kit)(20) and citrate synthase(21). in this regard, muciaccia et al (2010) showed that tr-kit was mainly localized in the sub-acrosomal and equatorial regions of human sperm(20). citrate synthase is a 45 kda protein and microinjection of recombinant citrate synthase into the newt eggs can cause ca2 release, but the exact mechanism of this factor in human and other species remains to be studied (21). plcζ, a sperm-specific 70 kda protein, is predominantly located in sperm head (22). previous studies have shown that injection of plcζ crna into mouse oocytes induces calcium oscillation (17). study of literature reveal that low expression of plcζ , mutation in plcζ, and a variance in distribution and amount of plcζ are related with male infertility (23-27). post-acrosomal ww binding protein (pawp) is also located in sperm head and is mainly localized in perinuclear theca(18,28). despite numerous reports that have proposed plcζ to be the main saoaf candidate, aaraandrology urology journal/vol 16 no. 5/ september-october 2019/ pp. 488-494. [doi: 10.22037/uj.v0i0.4621] bi et al.(15) proposed that pawp could be considered as one of the diagnosis factors for treatment of infertility. they demonstrated that induction of calcium oscillations with pawp in human and mouse mii oocytes (29). in addition, a significant correlation was observed between pawp expression with fertilization rate and embryonic development after icsi(29). concomitantly, a paper published by nomikos group reported that pawp cannot hydrolyze phosphatidylinositol 4, 5-bisphosphate (pip2) in vitro and induce calcium oscillations in mouse mii oocytes(30). therefore, the ability of pawp to induce calcium oscillations in mammals need to be further studied. we have also shown that reduced expression of plcζ in sperm from infertile men with previous failed fertilization and globozoospermia, and a strong correlation between sperm plcζ and fertilization rate(31-33). therefore, we suggested that plcζ expression at the mrna level, could be a suitable marker for predication of semen potency to induce oocyte activation post-icsi. in the current study, for the first time, sperm pawp expression was compared between different groups of infertile men with fertile individuals. in addition, the association of this protein with the fertilization rate was reported. materials and methods this study received approval from the institutional review board of royan institute and isfahan fertility and infertility center and the all individual whom provided semen samples signed the consent form. inclusion and exclusion criteria inclusion criteria: infertile couples with male factor infertility, lower 45 years, and candidate for icsi were included for this study. exclusion criteria: semen samples with higher than one million per ml somatic cell, men with varicocele, azoospermia, and cryptorchidism were excluded from study. semen samples semen samples were obtained from males who referred to the isfahan fertility and infertility center from 2009 to 2013. these samples were collected in sterile containers by masturbation after 3–4 days of sexual abstinence. in this study, we subdivided the individuals into four groups: 1) low percentage of fertilization post-icsi (lf-icsi) consisted of 18 individuals who had previous experience of failed or low fertilization (< 25%) post-icsi; 2) high percentage of fertilization post-icsi (hf-icsi) consisted of 10 individuals who had a fertilization rate equal or greater than 50% post icsi; 3) globozoospermic group consisted of 15 individuals; and 4) fertile or control group consisted of 21 individuals who participated in the embryo donation program and had at least one live child. percentage of fertilization rate was only reported for hf-icsi and lf-icsi groups. in addition, 20 semen samples from fertile (n=10) and infertile (n=10) men referring to the isfahan fertility and infertility center were only collected and correlation of rna expression with protein expression for pawp were assessed. evaluation of semen parameters of all participants were performed by light microscopy according to the world health organization (34). a portion of each sample was used for clinical assessment of semen parameters; the remainder was used for icsi. the retained portion was washed twice in pbs (ph 7.4). the relative expression level of pawp mrna was assessed by real-time pcr. intracytoplasmic sperm injection (icsi) outcomes sperm processing, superovulation, oocyte recovery, icsi procedure and embryo culture were carried out in accordance with our previous study(35). we assessed the fertilization rate at approximately 16–18 hours post-icsi, as determined by the presence of two pronuclei. the percent of fertilization for each case was calculated by considering the ratio of fertilized oocytes to the total number of surviving, injected metaphase ii (mii) oocytes, multiplied by 100. if percentage of fertilization was between 0 to 25%, these couples were considered for lf-icsi groups, while percentage of fertilization in the hf-icsi were between 50 to 100%. isolation of total rna, cdna synthesis and quantitative real-time pcr we extracted total rna from fresh semen samples using the rnx-plus method (cinnagen) according to the manufacturer's protocol. the concentration of rna was assessed by measuring absorbance at 260 nm. in order to eliminate possible contamination from genomic dna, we treated the samples with rnase-free dnase i (fermentas). then, 1 μg rna was subjected to a reverse transcription (rt) reaction using the revert aid h minus first strand cdna synthesis kit (fermentas) and oligo-dt primer (fermentas) (table 1). rt-pcr for confirmation of cdna synthesis and quantitative real-time pcr were performed according to the method by aghajanpour et al (2011) in a thermal cycler rotor gene 6000 (corbett) using sybr green as described in the manufacturer's protocol (takara). the levels of expression of pawp were normalized to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (gapdh) expression. calculation of relative expression was assessed by the ct method (36), and results were expressed as 2-(∆∆ct) (33). protein isolation, western blot analysis and quantification of protein protein was extracted using tri reagent (sigma) and protein concentration of each sample was estimated by bradford assay (biorad) to determine total protein load per each lane. equal amounts of each sample containing 30 μg of protein was subjected to 12% sdspolyacrylamide gel electrophoresis (page) and then transferred to pvdf membrane (bio-rad). blocking was achieved with 10% non-fat dry milk overnight incubation followed by incubating with polyclonal anti-pawp antibody (1:200 dilution; sc-86781; santa cruz) in 2% skimmed milk for 90 min at 25°c and washed in tbs–t, three times each for 15 min. finally, the membranes were incubated with horseradish peroxidase-conjugated polyclonal rabbit antigoat igg (1:100000; a5420, sigma) for 1 h at room temperature. the immune reactivity on western blots was detected pawp in infertility-tanhaei et al. table 1. primers used for gene expression analysis of pawp. gene symbol primer sequences (5´-3´) pawp f:cagatgccttgttcagttattgtc r:gccttcatttcctacgggttg gapdh f: ccactcctccacctttgacg r: ccaccaccctgttgctgtag abbreivations: f: forward primer; r: reverse primer. vol 16 no 04 september-october 2019 489 by ge amersham ecl plus western blotting detection reagent (amersham) by exposure to x-ray films. the protein bands obtained from western blot were analyzed by image j (version 1.240) software to determine the band density. statistical analysis we used microsoft excel and spss (version 17, usa) for data analyses. data were expressed as mean ± standard error of mean (sem). differences in gene expressions between the four groups were determined with one-way anova. correlation analysis was carried out using pearson’s correlation analysis. result of pawp at rna and protein were expressed as 2-(∆∆ct) [δct=ct of pawp -ct of gapdh; δδct= δct of each infertile – mean of ζct fertile; and lastly data was expressed as 2-(∆∆ct)], and band density [density of pawp bands were divided by the density of their respective gapdh band, as housekeeping protein, which represented the expression level of this protein], respectively. p < .05 was considered significant. results the mean ages of fertile (n = 21) and infertile individuals (n = 43) were 35.6±1.1 and 36.1 ± 0.9 years, respectively; their partners mean ages were 29.9 ± 0.8 years and 30.2 ± 0.9 years, respectively. the descriptive analysis of sperm parameters in the fertile, hf-icsi (> 50%), failed or low fertilization post-icsi (lf-icsi; < 25%), and globozoospermic groups were shown in table 2. sperm concentration and percentage of sperm motility were significantly higher in fertile, hf-icsi (> 50%) groups compared to lf-icsi (< 25%), and globozoospermic groups (p < .05). in addition, percentage of abnormal sperm morphology was significantly lower in fertile, hf-icsi (> 50%) groups compared to lf-icsi (< 25%), and globozoospermic groups (p < .05). in this study, the mean ct for the house keeping genes in the fertile, hf-icsi, lf-icsi, and globozoospermic groups were 19.95 ± 2.4, 19.71 ± 2.05, 19.13 ± 1.97 and 20.06±1.76, respectively. these results show that the quality of rna between samples were similar. we assessed the relative expressions of pawp by quantitative real-time pcr between study groups. there were significantly higher expressions of pawp in the fertile group compared to the lf-icsi (138.8 ± 17.3 vs. 43.3 ± 10.4; p ≤ 0.035) and globozoospermic groups (138.8 ± 17.3 vs. 41.5 ± 5.7; p ≤ .043). in addition, mean relative expression of pawp was significantly higher in the hf-icsi group compared to lf-icsi (211.6 ± 75.6 vs. 43.3 ± 10.4; p ≤ 0.001) and globozoospermic (211.6 ± 75.6 vs. 41.5 ± 5.7; p ≤ 0.001) groups. furthermore, a significant positive correlation (r = 0.628; p = .001) was observed between percentage of fertilization with the relative expression of pawp (figure 1a-b). table 2. description of semen parameters in the fertile, high fertilization post-icsi (hf-icsi), low fertilization post-icsi (lf-icsi), and globozoospermic groups (n = 64). group parameter maximum minimum mean ± se concentration ×10⁶ 93.25 ± 10.83 42.00 234.00 fertile (n=21) % sperm motility 58.81 ± 2.23 30.00 70.00 % abnormal morphology 96.32 ± 0.61 90 100.00 volume(ml) 3.74 ± 0.34 1.00 6.00 concentration ×10⁶ 90.80 ± 23.25 27.00 284.00 high fertilization % sperm motility 59.50 ± 2.83 40.00 70.00 (hf-icsi; n=10) % abnormal morphology 96.50 ± 1.50 87.00 100.00 volume(ml) 2.95 ± 0.53 1.50 7.00 concentration ×10⁶ 60.65 ± 22.21 0.25 328.00 low fertilization % sperm motility 34.35 ± 4.64 2.00 65.00 (lf-icsi; n=18) % abnormal morphology 99.78 ± 0.15 99.00 100.00 volume(ml) 3.29 ± 0.42 1 7.00 concentration ×10⁶ 73.20 ± 7.85 7.00 110.00 globozoospermic % sperm motility 38.00 ± 3.99 20.00 70.00 (n=15) % abnormal morphology 100.00 ± 0.00 100.00 100.00 volume (ml) 2.57 ± 0.26 1.00 4.00 figure 1 a) quantitative real-time analysis of pawp in fertile, high fertilization post-icsi (hf-icsi), low fertilization post-icsi (lf-icsi), and globozoospermic individuals. (n = 64) b) scatter plot shows significant correlation (r = 0.628; p = 0.001) between percent of fertilization and relative expressions of pawp (n = 25). pawp in infertility-tanhaei et al. andrology 490 western blot analysis of different semen samples from fertile and infertile couples showing that in some of the infertile individuals has low expression level of pawp (figure 2a). furthermore, the mean relative expression at both rna and protein level was significantly lower in infertile compared to fertile couples (figure 2b). in addition, correlation analysis between rna with protein expression showed a strong significant positive correlation (r = 0.8; p ≤ .0001) (figure 2c). discussion understanding the etiology of failed fertilization is essential for counseling and improving the treatment outcome of in infertile individuals. one main reason for failed fertilization is impaired oocyte activation, the mechanism of which is debated within the literature. it is generally accepted that a sperm-associated factor is responsible for initiation of oocyte activation(10). in this regard, numerous studies have focused on a sperm-specific protein called plcζ that induces calcium oscillations and, thereby, oocyte activation through the insp3 pathway(17,37). it is believed that plcζ is inactive inside spermatozoa and upon entry into the oocyte; it becomes activated(38). however, wu et al. have introduced pawp as a new candidate of saoaf that has the ability to induce oocyte activation(18,28). it has been suggested that both pawp and plcζ possess dual roles in oocyte activation mechanism and pawp-mediated signaling pathway may act upstream or downstream of ca2+ signaling(18). our previous studies have shown decreased expressions of plcζ in lf-icsi and globozoospermic men(33,39,40). in the current study, we also showed that the expression of pawp was significantly lower in lf-icsi and globozoospermic men compared to fertile or individuals with high fertilization. therefore, low expression of pawp, as in globozoospermic individuals, might account for impaired spermiogenesis in these individuals. this conclusion is consistent with previous reports which showed, sperm from individuals with low fertilization rates had a high degree of protamine deficiency as a sign of impaired spermiogenesis(33). the general consensus in the literature states that the chance for fertilization by injection of round sperm is very low(41), despite very rare report of fertilization and pregnancy following icsi in globozoospermia(42). in this study, we observed a low expression of pawp in globozoospermia cases at rna level and also protein level. pawp might be related to acrosomal biogenesis, considering the fact that globozoospermia have different genetic causes and this reason may lead to low expression of pawp in these individuals(43,44). furthermore, localization of pawp is dependent on microtubule-manchette protein transport, manchette descent and is independent of sub-acrosomal pt formation. considering the absence of manchette(28) and acrosomes in globozoospermia, this may suggest another reason for low expression of pawp in globozoospermic individuals. sperm, a transcriptionally inactive cell, contains rna transcripts the role of which remains to be identified.(45) considering pawp mrna could be translated during fertilization and possibly sustain a ‘long-lived’ ca2+ response, therefore, significant low expression of pawp in the lf-icsi and globozoospermic groups is consistent with the inability of these sperm to induce ca2+ oscillations and fertilization following their insemination. in this study, we showed a significant correlation between expression of pawp (r = 0.6) with the percentage of fertilization which is in accordance with others reports in this filed(29) and contrary to two previous studies(46,47). this is likely to be due to different cohort of patients recruited in these studies. in our study, the patients were infertile men with failed or low fertilization. despite these observations, pawp null mice show that pawp is not the main candidate for saoaf(46). therefore, observation and associations observed in this study may be related to co-localization of two proteins in the same region of sperm and correctly emphasizes previous study(11) working on tr-kit, as they state: “it cannot be excluded that factors present in the perinufigure 2 a) western blot analysis of pawp in fertile (f) and infertile (if) individuals. b) comparison of mean relative expression of pawp rna and protein level in fertile and infertile individuals and c) correlation analysis between rna and protein for pawp (r = 0.8; p ≤ 0.0001). aster indicates significant difference at p < 0.001 between fertile and infertile individuals (b). pawp in infertility-tanhaei et al. vol 16 no 04 september-october 2019 491 clear theca (pt) and/or in the equatorial region might equally be absent in spermatozoa that are unable to trigger egg activation”. considering that pawp null mice do not jeopardized the fertilizing ability of sperm and in human absence of plcζ alone is adequate to prevent fertilization regardless of presence of pawp(47), therefore, it is likely that pawp may have other functional roles and/or it may assist plcζ. in this study, we also showed that there is a significant correlation between pawp expressions at rna level with pawp protein. we further showed that rna and protein of pawp, are lower in infertile compared to fertile individuals and this is likely to be due to their associative expression and co-localized in pt. the causes of spermatogenic defects in infertile men are multifactorial and other factors such as level of oxidative stress, genetic and epigenetic alterations, and environmental factors can affect spermatogenesis and fertility potential(48). therefore, one limitation of this study was assessment of only sperm pawp in low number of infertile men. more researches are needed to confirm these results and factors involved in men infertility. acknowledgmnt this study was support by royan institute and we would like to express our gratitude to staff of isfahan fertility and infertility for their full support. conflict of interest none of the authors has any conflicts of interest to disclose and all authors support submission to this journal. references 1. bonduelle m, camus m, de vos a, staessen c, tournaye h, van assche e, verheyen g, devroey p, liebaers i, van steirteghem a. seven years of intracytoplasmic sperm injection and follow-up of 1987 subsequent children. hum reprod. 1999; 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27: 222-31. 26. yoon sy, jellerette t, salicioni am, lee hc, yoo ms, coward k, parrington j, grow d, cibelli jb, visconti pe, mager j, fissore ra. human sperm devoid of plc, zeta 1 fail to induce ca(2+) release and are unable to initiate the first step of embryo development. j clin invest. 2008; 118: 3671-81. 27. kashir j, jones c, mounce g, ramadan wm, lemmon b, heindryckx b et al. variance in total levels of phospholipase c zeta (plc-ζ) in human sperm may limit the applicability of quantitative immunofluorescent analysis as a diagnostic indicator of oocyte activation capability. fertil steril. 2013; 99: 107-17. 28. wu, a. t., sutovsky, p., xu, w., van der spoel, a. c., platt, f. m., oko, r. the postacrosomal assembly of sperm head protein, pawp, is independent of acrosome formation and dependent on microtubular manchette transport. dev. biol. 2007; 312: 471–83. 29. aarabi m, balakier h, bashar s, moskovtsev si, sutovsky p, librach cl, oko r. sperm content of postacrosomal ww binding protein is related to fertilization outcomes in patients undergoing assisted reproductive technology. fertil steril. 2014; 102: 440-7. 30. nomikos m, sanders jr, theodoridou m, kashir j, matthews e, nounesis g, lai fa, swann k. sperm-specific post-acrosomal ww-domain binding protein (pawp) does not cause ca2+ release in mouse oocytes. mol hum reprod. 2014; 20:938-47. 31. tavalaee m, nomikos m, lai fa, nasresfahani mh. expression of sperm plcζ and clinical outcomes of icsi-aoa in men affected by globozoospermia due to dpy19l2 deletion. reprod biomed online. 2018; 36:348-55. 32. tavalaee m, kiani-esfahani a, nasr-esfahani mh. relationship between potential sperm factors involved in oocyte activation and sperm dna fragmentation with intracytoplasmic sperm injection clinical outcomes. cell j. 2017; 18: 588-96. 33. aghajanpour s, ghaedi k, salamian a, deemeh mr, tavalaee m, moshtaghian j, parrington j, nasr-esfahani mh. quantitative expression of phospholipase c zeta, as an index to assess fertilization potential of a semen sample. hum reprod. 2011; 26: 29506. 34. world health organization. who laboratory manual for the examination and processing of human semen 5th edn. cambridge, uk: cambridge university press. 2010. 35. nasr-esfahani m h, tavalaee m, deemeh m r, arbabian m, parrington j. can assessment of total acrosin activity help predict failed or low fertilization rate icsi for implementation of artificial oocyte activation? open androl j. 2010; 2:19–26. 36. vaerman j l, saussoy p, ingargiola i. evaluation of real-time pcr data. j. biol. regul homeost. agents. 2004 ;18: 212–14. 37. berridge m j. inositol trisphosphate and calcium signalling mechanisms. biochim. biophys acta. 2009;1793: 933-40. 38. swann k, larman m g, saunders c m, lai f a. the cytosolic sperm factor that triggers ca2+ oscillations and egg activation in mammals is a novel phospholipase c: plczeta. reproduction. 2004; 127: 431-9. 39. javadian-elyaderani s, ghaedi k, tavalaee m, rabiee f, deemeh mr, nasr-esfahani mh. diagnosis of genetic defects through parallel assessment of plcζ and capza3 in infertile men with history of failed oocyte activation. iran j basic med sci. 2016; 19: 281-9. pawp in infertility-tanhaei et al. 40. kamali-dolat abadi m, tavalaee m, shahverdi a, nasr-esfahani mh. evaluation of plcζ and pawp expression in globozoospermic individuals. cell j. 2016;18:438-45. 41. bechoua s, chiron a, delcleve-paulhac s, sagot p, jimenez c. fertilisation and pregnancy outcome after icsi in globozoospermic patients without assisted oocyte activation. andrologia. 2009 ;41: 55-8. 42. elinati e, kuentz p, redin c, jaber s, vanden meerschaut f, makarian j, koscinski i, nasresfahani m h, demirol a, gurgan t, louanjli n, iqbal n, bisharah m, pigeon f c, gourabi h, de briel d, brugnon f, gitlin s a, grillo j m, ghaedi k, deemeh m r, tanhaei s, modarres p, heindryckx b, benkhalifa m, nikiforaki d, oehninger s c, de sutter p, muller j, viville s. globozoospermia is mainly due to dpy19l2 deletion via nonallelic homologous recombination involving two recombination hotspots. hum mol genet. 2012; 21: 3695-702. 43. stone s, o'mahony f, khalaf y, taylor a, braude p. a normal livebirth after intracytoplasmic sperm injection for globozoospermia without assisted oocyte activation: case report. hum reprod. 2000;15:139-41. 44. kuentz p, vanden meerschaut f, elinati e, nasr-esfahani m h, gurgan t, iqbal n, carré-pigeon f, brugnon f, gitlin s a, velez de la calle j, kilani z, de sutter p, viville s. assisted oocyte activation overcomes fertilization failure in globozoospermic patients regardless of the dpy19l2 status. hum reprod. 2013; 28: 1054-61. 45. hecht n, cavalcanti m c, nayudu p, behr r, reichenbach m, weidner w, steger k. protamine-1 represents a sperm specific gene transcript: a study in callithrix jacchus and bos taurus. andrologia. 2011;43: 167-73. 46. satouh y, nozawa k, ikawa m. sperm postacrosomal ww domain-binding protein is not required for mouse egg activation. biol reprod. 2015; 93: 94. 47. freour t, barragan m, ferrer-vaquer a, rodríguez a, vassena r. wbp2nl/pawp mrna and protein expression in sperm cells are not related to semen parameters, fertilization rate, or reproductive outcome. j assist reprod genet. 2017;34: 803-810. 48. tavalaee m, razavi s, nasr-esfahani mh. influence of sperm chromatin anomalies on assisted reproductive technology outcome. fertil steril. 2009 apr;91:1119-26. pawp in infertility-tanhaei et al. andrology 494 prospective investigation on the paternity intention and affecting factors in 84 post-treatment testicular cancer patients serkan yenigurbuz1, caner ediz1, yunus emre kizilkan1, serkan akan2, mehmet pehlivanoglu1, muhammed cihan temel3, hasan huseyin tavukcu1, tuna erturk4, omer yilmaz1 introduction testicular cancer is the most prevalent type of cancer in men aged 15–44 years in developed countries. (1) low birth weight and a history of undescended testis are established etiological factors of testicular cancer along with sociocultural factors, including ethnicity, environmental exposure, family history, and inguinal hernia.(2,3) testicular cancer is often detected at a young age, and there is a high treatment success rate, thanks to early diagnosis.(4) in patients with testicular cancer, fertility remains an important problem.(3,5-7) the post-treatment infertility rate is as high as 30%.(8) factors that affect semen parameters include patient's age, tumor type, treatment regimen, chemotherapy, radiotherapy, and retroperitoneal lymph node dissection.(9-13) sperm cryopreservation is routinely recommended to patients prior to the surgery due to the risk of organic-induced infertility.(14) diagnosis and treatment of testicular cancer may impair the quality of life (qol) of patients and create psychological stress along with infertility.(15) however, the paternity intention, which is considered secondary to cancer, is not adequately questioned, and thus, patients cannot be provided with routine psychosocial support in this regard. a study found that 51% of patients diagnosed with testicular cancer had paternity intentions for the future, while 49% did not.(16) there are insufficient studies on paternity intention in patients with testicular cancer although many studies in the relevant literature have focused on organic-induced infertility based on semen analysis.(17-20) the present study intended to investigate the factors affecting post-treatment paternity intention in patients followed up after the diagnosis of testicular cancer and to make recommendations for the early postoperative period based on the identified factors. 1department of urology, sultan 2. abdulhamid han education and research hospital, istanbul, turkey. 2department of urology, fatih sultan mehmet education and research hospital, istanbul, turkey. 3department of urology, nevsehir state hospital, nevsehir, turkey. 4department of anesthesiology and reanimation, sultan 2. abdulhamid han education and research hospital, istanbul, turkey. *correspondence: sultan abdulhamid han education and research hospital, istanbul, turkey. tibbiye cad. selimiye mah. uskudar/istanbul tel: +90 553 453 34 27. fax: +90 216 542 20 20 . e-mail: yunusemrekizilkan@gmail.com. received june 2022 & accepted january 2023 purpose: to investigate the factors affecting post-treatment paternity intention in patients followed up after the diagnosis of testicular cancer and to make recommendations for the early postoperative period based on the identified factors. materials and methods: this prospective descriptive study included a total of 185 patients who presented to our outpatient clinic between february 2000 and july 2020 who had radical orchiectomy due to suspected testicular cancer based on physical examination and other assessments. contact information was found for 88 of 185 patients, and accordingly, the patients were reached by one-to-one phone calls. upon literature review, a questionnaire consisting of 10 previously validated items was developed by the researchers. the patients were compared by separating them into two groups composed of patients with (group 1) and without (group 2) paternity intention. results: a total of 84 patients participated in the study, and the participation rate was 95.5%. it was found that 19 of 32 (38%) patients with paternity intention already had children. only 21 (40%) of 52 patients without paternity intention were married. the mean age was 26.65 (18–39) years in group 1, while it was 28.73 (19–45) years in group 2. tumor volume and serum tumor markers were higher in group 2 than in group 1. parameters such as testicular side in which the tumor was located, smoking status, undescended testis history, and postsurgical chemotherapy history were not statistically significant difference between the two groups. conclusion: the major findings included that the young aged, unmarried, and serious testicular cancer (tumor volume and serum tumor markers were higher) can be affecting factors for testicular cancer patients’ paternity intention. early psychological counseling about paternity may be useful for testicular cancer patients. keywords: cancer; fatherhood; infertility; testis; testicular cancer urology journal/vol 20 no. 3/ may-june 2023/ pp. 181-186. [doi:10.22037/uj.v20i.7337] andrology materials and methods study design this prospective descriptive study was approved by the local ethics committee and was conducted pursuant to the principles of the world medical association declaration of helsinki's ethical principles for medical research involving human subjects (hbaek:20/415). participants the study included patients who presented to our outpatient clinic between february 2000 and july 2020 with complaints of testicular swelling or mass and for whom a radical orchiectomy decision was made due to suspected testicular cancer based on physical examination and other assessments. patients who were not diagnosed with testicular cancer upon the pathology results were excluded from the study. a total of 185 patients meeting the criteria were included in the study. contact information was found for 88 of 185 patients, and accordingly, the patients were reached by one-to-one phone calls. all the patients confirmed that their partner was not infertile. only one patient declined to participate in the study. the interview could not be realized with one of the patients, because of death. in addition, two patients were excluded due to bilateral orchiectomy. the remaining 84 patients with testicular cancer were included in the study. data collection upon literature review, a questionnaire consisting of 10 previously validated items was developed by the researchers. study data were collected over the phone based on the patients’ responses for the questionnaire items, including the education status, comorbid diseases, smoking status, additional treatment status after the surgery, number of children, follow-up periods, paternity status, treatment choices for infertility, and if any of their male children were diagnosed with undescended testis. upon collection of the data, the participants were classified into two groups composed of patients with (group 1) and without (group 2) paternity intention. patients with paternity intention were further divided into two subgroups based on having (group 1a) and not having (group 1b) children. patients without paternity intention were also divided into two subgroups as married (group 2a) and not married (group 2b). letter 242 paternity intention in post-treatment testicular canver patients-yenigurbuz et al. table 1. baseline characteristics of enrolled patients variable group 1 group 2 p-value age (year)(iqr) 26.65 (9,25) 28.73 (10,5) .199 education status under high school 18.8% 26.9% .006* high school and above 81.2% 73.1% smoking status smoker 12 15 .410 non smoker 20 37 tumour volume (cc) 37.5 (26,25) 43.1 (31,5) .478 afp (ng/ml) 221 (215,7) 1455 (312,75) .418 β-hcg (mlu/ml) 99 (25,23) 3144 (44,05) .677 ldh (u/l) 371(198,5) 541(278) .078 abbreviations: iqr, interquartile range; cc, cubic centimeter; ng/ml, nanogram / milliliter; mlu/ml, mililiter unit/mililiter; u/l, unit/ liter. figure 1. flow chart for patients' enrollment vol 20 no 3 may-june 2023 182 andrology 183 statistical analysis spss for windows version 22.00 was used for the statistical analyses. shapiro–wilk test and q-q plot were used to determine normal data distribution. all the variables were non-normally distributed. quantitative variables were expressed as median (interquartile range). qualitative variables were expressed as frequency and percentage, and a chi-square test was applied and no expected cell count was less than 1 and at most 20% of expected cell counts were less than 5. mann–whitney's u-test was used to evaluate all the non-normally distributed variables. a p value of <.05 was considered statistically significant in all analyses. results in this study, 88 patients were contacted over phone. a total of 84 patients participated in the study, and the participation rate was 95.5%. it was found that 19 of 32 (38%) patients with paternity intention already had children. only 21 (40%) of 52 patients without paternity intention were married. the data are presented in the flowchart (figure 1). the patients were compared by separating them into two groups composed of patients with (group 1) and without (group 2) paternity intention. the mean age was 26.65 (18–39) years in group 1, while it was 28.73 (19–45) years in group 2. in groups 1 and 2, the rates of high school and higher education were 81.2% and 73.1%, respectively, and it was higher in the group with paternity intention than in the group without such an intention (p = .006). while 37.5% of the patients in group 1 were smokers, this rate was 28.8% in group 2. an investigation of history of undescended testis and smoking data indicated that there was no statistically significant difference between the two groups (p = .409 and p = .41, respectively). tumor volume and serum tumor markers were higher in group 2 than in group 1, but the difference was not statistically significant (table 1). parameters such as testicular side in which the tumor was located, smoking status, undescended testis history, and postsurgical chemotherapy history were not statistically significant difference between the two groups. in addition, there was no effect of lymph node positivity in retroperitoneal, thorax, or both regions on the paternity intention in terms of the presence of lymph nodes (table 2). a comparison of the subgroups with and without children in group 1 indicated that the use of food supplements was similar in both subgroups. however, the patients not having children applied to assisted reproductive techniques significantly more often than the other subgroup (p = .006) (table 3). while the mean time from treatment to paternity intention was 23 months (iqr:36) in the subgroup with children, this duration was 29 months (iqr:48) in the subgroup without children. furthermore, pregnancy was achieved after an average of 7.6 months of unprotected sexual intercourse. the postoperative follow-up periods of the patients were 65.4 (iqr:64,4) and 72.6 (iqr:67,6) months in groups 1 and 2, respectively, and there was no significant difference between the two groups (p = .467). an investigation of the patients’ pathology specimens showed that 7 patients out of 32 with paternity intention were diagnosed with seminoma and 25 with non-seminoma testicular cancer. on the other hand, 18 patients out of 52 without paternity intention were diagnosed with seminoma and 34 with non-seminoma testicular cancer. the pathology results did not have any effect on the paternity intention upon comparative analysis between the two groups (p = .215). discussion testicular cancer generally occurs during the peak reproductive years of men, which coincides with career and family planning. the paternity intention and the success of fertilization in disease management vary depending on the administered treatments and the psychosocial effects of the disease. in the present study, 38.09% (n = 32) of the patients who were followed up after testicular cancer diagnosis stated their paternity intention following the diagnosis. similarly, in a study by spermon et al., paternity intention was stated by 43% of the subjects(13), whereas uçar et al. reported the rate as 30%.(12) it is noteworthy that although the rates of paternity intention are at comparable levels, they tend to be below 50%. the young age of the population and the possible low level of marriage may account for these rates.(21) however, a study conducted in norway published results inconsistent with the aforementioned reasoning. the likelihood of marriage among men diagnosed with cancer was 5% higher than that in men without cancer diagnosis (or = 1.05, %95 ci: 1.01–1.11). according to the above study, the rates were significantly higher, especially after testicular cancer (or = 1.11). marriage after cancer diagnosis is more common today than it used to be, and there are minor general differences in the marriage rates of cured individuals compared to the population not diagnosed with cancer. nevertheless, testicular cancer in men is associated with increased marriage rates.(22) according to a study conducted in turkey, 82.5% of patients diagnosed with cancer obtain information about their disease from a doctor. moreover, 45.8% of the patients stated that communication with healthcare professionals was partially sufficient, 35.0% as insufficient, and 19.2% as sufficient. additionally, 63.3% of the patients requested better communication with their variable group 1 group 2 p-value testicular side right 16 29 .607 left 16 23 smoking status (-) 20 37 .410 (+) 12 15 undescended testis (-) 27 47 .495 (+) 5 5 chemotherapy (-) 10 12 .408 (+) 22 40 retroperitoneal ln (-) 15 26 .781 (+) 17 26 thorax ln (-) 27 45 .761 (+) 5 7 retro + torax ln (-) 27 45 .761 (+) 5 7 abbreviations: ln, lymph node. chi-square test was used. p < .05 was accepted as the degree of significance. (n = 84) table 2. statistical comparison of the factors in the questionnaire that affect paternity desire in both groups. paternity intention in post-treatment testicular canver patients-yenigurbuz et al. doctor. while 65.8% of the patients expected emotional support, 75% wanted to learn about the effects of the disease on their psychological state.(23) another study found a high level of psychological morbidity in both patients and their relatives, even 5 years after diagnosis, despite an excellent prognosis in patients with testicular cancer.(24) it is advisable to start educational activities about the disease immediately after the diagnosis of testicular cancer, especially in case of patients with low educational status. at this point, patient associations can play an active role as regards psychosocial support for the disease. recently, the web-based kanker nazorg wijzer (guidelines for post-cancer care) was developed in the netherlands to provide cancer survivors with psychosocial and lifestyle support. although such a support is not available for patients with testicular cancer, it can be used to that end in the future.(25) although there is no clear correlation between testicular cancer treatment and biochemical hypogonadism, it may be suggested that sexual aversion and dysfunction may be substantially associated with psychological factors, including testicular cosmetic deficiency due to orchiectomy, chronic pain, or anxiety, fear, and mood disorders caused by cancer diagnosis.(26,27) in addition, major surgical interventions such as retroperitoneal lymph node dissection, which can lead to ejaculation and/or orgasm disorders in patients with testicular cancer, may give rise to such problems.(28) physical and psychological changes in these patients also adversely affect their perspectives on business and general life and career decisions.(25) although not addressed during the telephonic interviews with the patients, these unexpected changes may be effective in paternity intention. education is another possible factor that decides the paternity intention in patients with testicular cancer.(30) the intention to have a child was higher in patients with testicular cancer with a higher educational status. the higher values of both tumor volume and tumor markers in group 2 patients with a lower high school or higher education level may be associated with presenting late to a physician. the high success rate in testicular cancer is associated with early diagnosis. as the diagnosis period is delayed, the requirement for additional treatments increases. gonadotoxic treatments lead to an overall reduction in male fertility by 30%, and there is currently no method available to predict which patients would become azoospermic following the treatment. the possible size difference in the palpable mass as a result of late diagnosis may also explain the lower paternity intention compared to the other group because of the fact that the patients are psychosocially more affected. along with paternity intention, patients with larger, more invasive tumors are at risk for infertility due to local tumor effects.(29) the effects of late diagnosis in this patient group should be evaluated in further detail as regards both the paternity intention and infertility. chemotherapeutic agents constitute another aspect in the treatment of testicular tumor, which should be considered carefully in terms of both their effects and side effects. in the present study, there was no effect of adjuvant chemotherapy following orchiectomy on paternity intention, which was consistent with the relevant literature.(30) the patients became fathers after an average of 30 months after treatment in the present study, while the european society of medical oncology recommends postponing pregnancy for at least 12 months after chemotherapy to avoid teratogenic effects. (31,32) uçak et al. suggested in their study that this period was 3 years(30), whereas spermon et al. reported that the patients became fathers within 1 year after the treatment.(33) although the results are heterogeneous, it is noteworthy that the patients complied with the recommendations. it is important to know how sociocultural differences in sexuality, masculinity, and fertility affect the survivors to better understand the impact of testicular cancer on the qol. although qol distinctively deteriorates at diagnosis and throughout the treatment, it later returns to normal levels defined by matched controls. nevertheless, there are several chronic conditions associated with the diagnosis and treatment of testicular cancer that plague the survivors and affect their qol, including anxiety, sexuality, and fertility. even if these issues have no impact on qol measurements, they have an impact on qol.(21) as expected, the rate of use of supplemental food and assisted reproductive techniques was higher in patients with testicular cancer who had paternity intention but did not have a child when compared with the other group. this information reflects the desire of patients with testicular cancer who have fertility problems to access supportive treatments in case of a paternity intention. therefore, the first problem to be addressed is the elimination of negative thoughts that psychosocially lead to paternity desire. early introduction of supportive treatments against misconceptions should be discussed frequently by urologic oncologists and andrologists. a review published in 2019 reported that clear guidelines on fertility counseling for patients with cancer in the context of fertility preservation, which removes ambiguity as regards who conducts the counseling, what the counseling covers, and what level of psychosocial support can be most effective, might be helpful.(21) early assessment of this patient group by psychiatrists and/ or clinical psychologists through a multidisciplinary approach might be the “next step” in the management of patients with testicular cancer. this study suffers from the following limitations. although more patients could have been included in our retrospective archive-based study, the number of particvariable group 1a group 1b p-value supplementary food (-) 18 10 .135 (+) 1 3 assisted reproductive techniques (-) 15 4 .006* (+) 4 9 table 3. the effect of using assisted reproductive techniques and supplementary food on having a child in those with a desire for paternity crosstab analysis was used. p < .05 was accepted as the degree of significance. (n = 32) paternity intention in post-treatment testicular canver patients-yenigurbuz et al. vol 20 no 3 may-june 2023 184 andrology 185 ipants was lower than anticipated because of the fact that there were patients whose data could not be accessed. furthermore, the contact information of certain patients had changed. owing to the covid-19 pandemic, faceto-face interviews aimed to inform patients about paternity in psychosocial terms could not be conducted during the diagnosis and treatment. another important point is that collecting patients' answers through phone call might be interfered by subjective thoughts of the authors. in addition, the lack of an age-matched control group can be considered as one of the limitations of the present study. conclusions while studies in the relevant literature on testicular cancer and fertility have often focused on semen parameters, low educational status was found to be a factor that might negatively affect the paternity intentions in our study. psychosocial counseling, which can be commenced immediately after the diagnosis, can play an important role in this regard and cover many factors that may negatively affect the qol and the paternity intention. early diagnosis should be reinforced by early psychological counseling. acknowledgement the authors would like to thank urology and pathology department of hospital for the preparing of this manuscript. conflict of interest the authors report no conflict of interest. this research received no specific grant from any funding agency in the public, commercial, or not for profit sectors. references 1. znaor a, lortet-tieulent j, jemal a, bray f. international variations and trends in testicular cancer incidence and mortality. eur urol 2014; 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48: 425-30. 29. moody ja, ahmed k, yap t et al. fertility managment in testicular cancer: the need to establish a standardized and evidence-based patient-centric pathway. bju int 2019; 123: 160-72. 30. ucar ma, arikan f, coskun hs et al. fertility in testicular cancer patients: a single-centre study in turkey. int j clin oncol 2020; 25: 495-500. 31. pentheroudakis g, orecchia r, hoekstra hj et al. cancer, fertility and pregnancy: esmo clinical practice guidelines for diagnosis, treatment and follow-up. ann oncol 2010; 21 suppl 5: v266-73. 32. peccatori fa, azim ha, jr., orecchia r et al. cancer, pregnancy and fertility: esmo clinical practice guidelines for diagnosis, treatment and follow-up. ann oncol 2013; 24 suppl 6: vi160-70. 33. spermon jr, kiemeney la, meuleman ej et al. fertility in men with testicular germ cell tumors. fertil steril 2003; 79 suppl 3: 1543-9. paternity intention in post-treatment testicular canver patients-yenigurbuz et al. vol 20 no 3 may-june 2023 186 urological oncology potential prognostic role for spop, daxx, rarres1, and lamp2 as an autophagy related genes in prostate cancer leila jamali1, afshin moradi2,3 , maziar ganji1, mohsen ayati4, behrang kazeminezhad5, zahra fazeli attar1, hamid ghaedi1, seyyed mohammad hossein ghaderian6,1*, morteza fallah-karkan7,8, arash ranjbar 7 purpose: autophagy plays a critical role in pca development. daxx has a potent pro-survival effect by enhancing cell growth in pca via suppression of autophagy. here, we depicted a network governed by daxx and spop by which the autophagy pathway is suppressed through the ubiquitination and modulation of key cellular signaling pathways mediators including lamp2 and rarres1. materials and methods: through network-based bioinformatics approaches, the expression levels of daxx, rarres1, lamp2, and spop genes was assessed in 50 pca tissues and 50 normal adjacent from the same sample as well as 50 benign prostatic hyperplasia (bph) tissues by quantitative rt-pcr. the normal adjacent tissues were taken from regions more than 5mm away from the bulk of those tumor tissues with clearly distinct margins. rna extraction, cdna synthesis and real-time quantitative rt-pcr were done for assessment of gene expression. to evaluate the primary gene network centered on autophagy pathway, according to the query-dependent weighting algorithm, these two networks were integrated with cytoscape 3.4 software. results: we found that in pca tissues the daxx expression level was significantly increased (p < 0.001) and the expressions of spop, rarres1, and lamp2 were significantly down-regulated, when compared to both control groups including normal adjacent and bph tissues. moreover, significant correlations were observed between expression levels of all four genes. additionally, roc curve analysis revealed that lamp2 had the most sensitivity and specificity. conclusion: these findings suggest that the contribution of spop, daxx, rarres1, and lamp2 together could be a putative regulatory element acting as a prognostic signature and therapeutic target in pca. keywords: prostate cancer; autophagy; gene regulatory network; spop; daxx; rarres1; lamp2 introduction prostate cancer (pca) is the most common malig-nancy in men(1-5). currently, clinicopathological features including gleason score (gs), staging, and prostate-specific antigen (psa) are conventional prognostic markers(6,7) and utilized for clinical decision making. nonetheless, they are insufficiently accurate to discriminate the indolent tumors from aggressive ones due to heterogeneous genetic background of pca(8-10), which emphasizes the inevitable necessity of identifying novel molecular biomarkers and high-risk individuals(11-13). autophagy is a survival-promoting pathway that plays the key role of eliminating damaged cellular compartments and aggregated proteins in lysosomes(14). autophagy also can serve as a tumor suppressor via prevent1department of medical genetics, school of medicine, shahid beheshti university of medical sciences, tehran, iran. 2cancer research center, shohada-e-tajrish hospital, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. 3infertility and reproductive health research center, shohada-e-tajrish hospital, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. 4uro-oncology research center, tehran university of medical sciences, tehran, iran. 5department of pathology, shahid beheshti university of medical sciences, tehran, iran. 6cellular and molecular biology research center shahid beheshti university of medical sciences, tehran, iran 7 urology resident, shohada-e-tajrish hospital, shahid beheshti medical university, tehran, iran. 8 laser application in medical science research center, shohada-e-tajrish hospital, faculty of medicine, shahid beheshti university of medical sciences, tehran, iran. *correspondence: department of medical genetics, shahid beheshti university of medical sciences. velenjak blvd. kodakyar close, tehran, iran. post code: 1985717443; tele fax: + 98 21 23872572. sghaderian@sbmu.ac.ir received november 2018 & accepted february 2019 ing the damaged proteins accumulation. despite various attempts, role of autophagy and its precise function in pca, remains unclear(15). various studies have indicated the crucial roles of speckle-type poz protein (spop) and death-domain associated protein (daxx) in cell apoptosis, proliferation and that their dysregulated expression may contribute to autophagy pathways in tumorigenesis(16,17). extensive genomic documents have considered spop as a tumor suppressive role via degradation of oncogenic substrates in malignant prostate cells(18). daxx, as a transcriptional repressor, in co-operation with other transcription elements participates in regulating dapk1/3 tumor suppressor protein kinases(19), which are associated with autophagy(20,21). as another element relevant to autophagy, retinoic acid urology journal/vol 17 no. 2/ march-april 2020/ pp. 156-163. [doi: 10.22037/uj.v0i0.4935] receptor responder 1 (rarres1) is a new retinoic inducible gene. expression of rarres1 is known to activate the autophagy pathways. furthermore, dysregulation in rarres1 was indicated to associate with malignant transformations and tumor progression (1,22). retinoic acid receptors (rars) signaling controls the activation of lysosome-associated membrane glycoprotein 2 (lamp2)(23). lamp2 encodes a single-span lysosomal membrane protein that is involved in the lysosomal stability. nonetheless, apart from preserving the structural integrity of lysosomal membranes, a critical role has been proposed for lamp2 in lysosomal function and autophagy in the context of cancer(24). in this study, first we aimed to construct a network for candidate genes participating in autophagy pathway based on literatures to clarify the role of these candidate genes in relation with diverse interactions in cellular networks. we hypothesized these interactions may potentially affect the individual behavioral of each target gene in a context-dependent manner. altogether, here we aim to develop network enrichment for spop, daxx, rarres1, and lamp2 genes and to examine their expression levels in pca tissues in comparison to normal adjacent and bph tissues. materials and methods patients and tissue samples after institutional ethical committee approval (ethics code:ir.sbmu.msp.rec.1396.286), this case-control study was conducted on a series of 189 paraffin-embedded prostate tissue samples. the exclusion criteria included the blocks with poor histopathological quality, patients who had history of chemoradiotherapy before surgery, presence of other malignancies in patients, and samples with technical problems in tissue processing. subjects aged from 55 to 79 years in pca and 59 to 79 years in benign prostatic hyperplasia (bph) were included in study. finally leaving a total of 150 samples for the final analysis. our collection included 50 pca and 50 normal adjacent tissues from the same sample in addition to 50 bph tissues. considering the fact table 1. the sequences of primers used in this study. gene primer sequences primer length product length b2m f: agatgagtatgcctgccgtg 20 105 r: gcggcatcttcaaacctcca 20 rarres1 f: ctagtgtgaggcagtggaaaac 22 110 r: gaccaagtgaatgcgacagg 20 lamp2 f: atggctccgttttcagcattg 21 106 r: gctccagacactgaaacagtc 21 spop f: taccctcttctgcgaggtga 20 129 r: cgggaattctcccacagtcc 20 daxx f: gactataggccaggcgttga 20 144 r: ctcgccctcctcacttttgt 20 a: kruskal-wallis test, b: anova. c: independent sample t test, d: mann-whitney u. note: normality was checked using shapiro-wilk test. table 2. the association of four candidate genes with clinicopathological characteristics gathered from pca patients. a: kruskal-wallis test, b: anova. c: independent sample t test, d: mann-whitney u. note: normality was checked using shapiro-wilk test. clinicopathological features daxx pvalue rarres1 pvalue lamp2 pvalue spop pvalue n mea n sd media n iqr 25 iqr 75 n mean sd media n iqr 25 iqr 75 n mea n sd media n iqr 25 iqr 75 n mea n sd media n iqr 25 iqr 75 age -1.2675 4.458 6 .3736 -3.1850 5.142 6 -.9699 -5.2275 6.685 5 1.978 3 -4.0925 6.293 9 2.689 8 -1.9525 3.280 7 -.7380 -4.0200 5.014 1 3.258 5 -3.4775 4.321 7 2.726 3 -4.5075 5.177 3 3.357 7 -4.6050 7.275 5 2.030 5 -3.4800 5.918 8 1.725 2 -1.4800 6.246 3 .9703 -2.1150 -.4071 -3.98 gs -1.16 -1.99 1.02 -3.39 -5.25 -3.18 -3.43 -4.76 -1.50 -3.89 -5.93 -2.46 -3.73 -4.27 -1.75 -3.13 -5.00 -1.24 -3.41 -4.61 -1.12 -2.91 -6.08 -2.12 -1.92 -4.61 -1.14 -4.69 -5.73 -2.81 -4.01 -6.23 -1.76 -3.98 -6.97 -1.69 stage -2.71 -4.29 -1.28 -3.39 -5.00 -2.76 -3.43 -4.76 -1.76 -2.91 -5.93 -2.12 -1.56 -1.75 -.14 -3.48 -6.85 -.52 -2.11 -3.53 -1.36 -2.46 -3.70 -2.12 -1.74 -2.96 -.47 -3.91 -5.38 -2.64 -5.75 -6.42 -4.79 -6.94 -7.79 -3.71 -3.28 -7.58 1.02 -.44 -3.66 2.78 -1.31 -1.50 -1.12 -2.76 -6.13 .61 -3.09 -5.92 -1.14 -5.32 -5.90 -2.81 -3.24 -5.06 -1.48 -3.70 -6.47 -1.69 -1.91 -2.62 -1.53 -3.99 -5.42 -2.43 -6.47 -7.20 -4.06 -5.95 -7.35 -4.51 perineurial invasion -2.11 -4.17 -1.46 -4.30 -5.00 -3.13 -3.22 -3.53 -1.50 -3.18 -6.08 -2.12 -1.83 -5.10 -1.06 -3.43 -5.73 -2.29 -4.39 -6.23 -1.89 -3.93 -6.47 -2.11 pin -1.62 -4.29 .42 -3.66 -4.69 -3.13 -1.76 -4.95 -1.36 -3.70 -5.80 -1.41 -1.95 -4.39 -1.15 -3.95 -5.56 -2.50 -3.53 -5.41 -1.91 -3.79 -6.61 -2.12 circumferenti al margins & capsule -2.11 -4.61 -1.14 -3.66 -5.32 -2.31 -3.53 -5.40 -1.74 -3.98 -6.47 -2.12 -1.83 -2.31 -.65 -4.20 -6.24 -3.37 -2.74 -4.88 -1.12 -3.08 -4.51 -1.90 vol 17 no 02 march-april 2020 157 spop, daxx, rarres1, and lamp2 genes in prostate cancer-jamali et al. that although normal adjacent tissue is normal based on pathological feature, it is abnormal pertaining to molecular changes and there is a potential of tumor progression to adjacent tissue cells over time, so we utilized bph as secondary external controls. the adjacent normal tissues were taken from regions more than 5 mm away from the bulk of those tumor tissues with clearly distinct margins. one-mm tissue cores were obtained from all samples after processing and were transferred to the rnase-free microtubes for rna extraction. all samples were diagnosed by an expert pathologist to determine and confirm the differentiation status of adenocarcinoma tissue and dysplasia degree of the adenoma tissues. evaluation of tumor differentiation was based on the architectural and glandular differentiation as well as tumor nuclear features. tumor grade was figured out based on gs system according to the 2014 international society of urological pathology (isup) consensus on gleason scoring of prostatic carcinoma(25). other parameters such as pt category, prostatic intraepithelial neoplasia (pin), perineural invasion, and serum psa levels were included too. all these samples were gathered from february 2014 to october 2016 from mehr and shohada-e-tajrish hospitals, tehran, iran. the study protocol was approved by the institutional review board of shahid beheshti university of medical sciences. bioinformatic analysis we designed a network for candidate genes, gathered from literature review, and their cellular interactions with other genes in various signaling pathways were created. the gene regulatory network drawing was accomplished by string 1.1 software with confidence cutoff value of 0.1 for the interactions. as the next step, another gene network was plotted with genemania prediction server by applying unregularized algorithm. to evaluate the primary gene network centered on autophagy pathway, according to the query-dependent weighting algorithm, these two networks were integrated with cytoscape 3.4 software, validated regulatory interactions network analysis software(26-28). we applied the reactome fi 5.2 package to analyze and enrich the gene network and interactions. rna extraction and cdna synthesis total rna extraction was carried out from all samples using formalin-fixed, paraffin-embedded (ffpe) rna purification kit (cat. 25300; norgene, canada) according to the manufacture’s protocol. the standard de-crosslinking and column purification as well as dnase i treatment were performed to remove proteins and other cellular components in addition to genomic dna prior to cdna synthesis. the rna quality and quantity were measured using agarose gel electrophoresis and nanodrop 2000 (thermo fisher scientific, wilmington, de, usa), respectively. samples with sufficient yield (>100 ng) and a260/a280 ratio between 1.8–2 were used for single-strand cdna synthesis. briefly, 500 ng of total rna from each sample was subjected to reverse transcription for target gene. cdna was synthesized utilizing prime script ii reverse transcriptase (takara, japan) by the following method: at 37 °c for 15 minutes (reverse transcription) followed by 85 °c 5 second (inactivation of reverse transcriptase with heat treatment). real-time quantitative rt-pcr (qrt-pcr) the cdna was diluted 1:10 in nuclease-free water. real-time pcr was performed in duplicate in a lightcycler96 instrument (roche diagnostics). sybr premix ex taq ii (takara, japan) was used for detection of gene expressions. the sybr qrt-pcr was: 30 sec incubation at 95 °c followed by 40, two step cycles of amplifications consists of 95 °c for 15 sec and 60°c for one min. the formation of pcr products was confirmed through melting curves. primer sequences were designed by allele id software version 7.0 for windows (premier biosoft international, palo alto, ca, usa). exon-exon junction method and ncbi primer blast were applied (table 1). table 1. the sequences of primers used in this study. each run had a negative control (without cdna temurological oncology 158 spop, daxx, rarres1, and lamp2 genes in prostate cancer-jamali et al. table 3. the correlations between expression levels of candidate genes in pca tissues. correlations daxx rarres1 lamp2 spop daxx correlation coefficient (r) 1.000 0.320 0.338 0.220 sig. (2-tailed) . 0.003 ** 0.001 ** 0.029 * rarres1 correlation coefficient (r) 1.000 0.373 0.351 sig. (2-tailed) . > 0.0001 ** 0.001 ** lamp2 correlation coefficient (r) 1.000 0.535 sig. (2-tailed) . > 0.0001 ** spop correlation coefficient (r) 1.000 sig. (2-tailed) . * correlation is significant at the 0.05 level (2-tailed). ** correlation is significant at the 0.01 level (2-tailed). gene age psa gs stage r p-value r p-value r p-value r p-value daxx -0.18 0.22 0.033 0.84 -0.14 0.36 -0.026 0.86 rarres1 -0.07 0.61 0.17 0.3 -0.08 0.57 -0.12 0.42 lamp2 0.22 0.14 -0.31 0.05 -0.07 0.61 -0.14 0.37 spop 0.25 0.09 -0.23 0.14 -0.01 0.92 -0.13 0.38 table 4. the correlations between gene expression levels and clinicopathological characteristics plate) to check any possible contamination. the relative quantification of expression changes was calculated after normalization to beta 2microglobuline (b2m) expression according to previous study (29). data were evaluated using the comparative cycle threshold (ct). statistical analysis relative quantification of mrna expression was evaluated using the comparative cycle threshold (ct) method. the expression of samples was normalized to the expression of b2m and fold change was calculated, using the 2−∆∆ct method. all statistical analyses were conducted on spss statistical software version 20 (spss inc., chicago il, usa). p values < 0.05 were considered statistically significant. mean normalized gene expression ± sd was calculated from independent experiments. for comparisons between pca and normal adjacent tissues the normality of the response variables was checked using shapiro-wilk statistical test. if normality is accepted, the t test is used; otherwise the mann-whitney test or wilcoxon was utilized for independent non-parametric and dependent variables, respectively. furthermore, to investigate the correlations, given the normality test of the data the pearson correlation coefficient for parametric values and spearman's rank for nonparametric data utilized. also, to evaluate statistically significant differences between two or more groups of an independent variable one-way anova and kruskal-wallis test was used respectively, for parametric and nonparametric data. in addition, authors represented the receiver operating characteristic (roc) curve to determine the sensitivity and specificity of gene expression levels as diagnostic markers for pca. roc was calculated to determine the potential of genes to discriminate between malignant and non-malignant samples. ethics the ethical committee of shohada-e-tajrish hospital approved this study and permitted us to review patients’ medical data. the personal data of the subjects were not disclosed and the principles of patient secrecy were observed. results clinicopathological characteristics the mean age and psa level were 65.49 ± 6.28 years and 10.34 ± 11.10 ng/ml in cancerous sample. the subjects with bph also had the mean age of 66.35 ± 4.55 with 4.34 ± 1.09 ng/ml psa level. table 2 illustrates the associations between gene expression levels and clinicopathological characteristics, no significant association was found. table 2. the association of four candidate genes with clinicopathological characteristics gathered from pca patients. bioinformatic network analysis the results from network enrichment of string and genemania softwares in terms of statistical significance (false discovery rate < 0.25) revealed the interfigure 1. four network clustering modules based on bioinformatics analysis, shown with different colors. figure 2. receiver operating characteristic (roc) curve showing the area under the curves for discriminating between malignant, bph tissues by daxx, rarres1, lamp2, and spop genes. vol 17 no 02 march-april 2020 159 spop, daxx, rarres1, and lamp2 genes in prostate cancer-jamali et al. action of candidate genes with other genes in relation to biological and molecular pathways. during functional categorization analysis, four main modules were identified in gene network, each with up to 11 genes (figure 1). first module included “co-regulation of androgen receptor (ar) activity” [p = 1.27e-05] and “pathways in cancer” [p = 3.20e-03] (comprising spop, ar, gli3, rnf4, pdx1, gli2, she, tmf1, snurf, atrx, cul3 genes). the module of “class i pi3k signaling” [p = 4.33e-04] and “apoptosis” [p = 6.53e-03] (including daxx, map3k5, hipk1, ube21, ets1, slc2a4, kdm1a, hspb1, rassf1, kif5b genes) was also demonstrated in this network. moreover, the modules of “lysosome” [p = 5.92e-03] and “phagosome” [p = 3.87e-03] (including rarres1, lamp2, impdh1, lxn) as well as “retinoic acid receptors-mediated signaling” [p = 1.18e-07] and “rna polymerase ii transcription” [p = 1.40e-08] (comprising genes such as of esr1, pparg, nr3c1, klk3, ncoa2, ncoa1, rxra, ppara, rara) were implicated in this network. the genes in the modules were mainly located in the nucleus, cytoplasm, and lysosome. figure 1. the network clustering modules found in this study. four modules, shown with different colors, are displayed based on bioinformatics analysis. relative expression levels of spop, daxx, rarres1, and lamp2 by the 2−∆∆ct method a statistically significant decrease in spop mrna expression level of malignant prostate tissues was observed in both normal adjacent and bph tissues (both at p < 0.001). as well as, daxx expression level in pca tissues was significantly up-regulated in comparison with both controls (both at p < 0.001). the expression of rarres1 gene was significantly down-regulated in pca group in comparison to groups of normal adjacent and bph samples (p < 0.001, p < 0.011, respectively). finally expression of lamp2 in pca samples showed a total significant decreased level compared with normal adjacent and bph groups (both at p < 0.001). correlation analysis the assessment of correlations between expression levels of our four candidate genes in pca tissues was accomplished (table 3). in this regards, there were significant correlations between daxx and expression levels of rarres1 (r = 0.320, p = 0.003), lamp2 (r = 0.001, p = 0.338), and spop (r = 0.220, p = 0.029). the expression of rarres1 demonstrated significant correlations with lamp2 (r = 0.373, p < 0.0001) and spop (r = 0.351, p = 0.001). in addition, the correlation of lamp2 and spop (r = 0.535, p < 0.0001) statistically significant. table 3. the correlations between expression levels of candidate genes in pca tissues. the analysis of correlations between gene expression levels and clinicopathological characteristics such as age, psa, gs, and stage of disease in pca tissues was carried out. lamp2 expression was significantly correlated with psa (r = -0.31, p = 0.05). however, the other correlation related to four candidate genes did not reach a significance level (table 4). table 4. the correlations between gene expression levels and clinicopathological characteristics roc curve analysis the predictive value of gene expressions for discriminating between malignant and non-malignant tissues was investigated by constructing an roc curve (figure 2). critical cut-off values of significantly different rarres1, lamp2, spop, and daxx levels were determined. the area under the curve (auc), sensitivity, and specificity for rarres1 were 0.659, 72.1%, and 53.5%, respectively. auc for lamp2 expression showed the most predictive power, 0.884 (with sensitivity of 90.7% and specificity of 62.8%). as well, the auc for expression levels of spop (sensitivity of 86.0% and specificity of 60.5%) and daxx (sensitivity of 86.0% and specificity of 60.5%) as predictors of malignancy in prostate tissue was 0.809 and 0.837, respectively (table 5). figure 2. receiver operating characteristic (roc) curve showing the area under the curves (auc) for discriminating between malignant and non-malignant prostate tissues by daxx, rarres1, lamp2, and spop genes. discussion gene-module level analysis has emerged as a novel design principle in biological systems. this type of evaluations aims to explain biological network design and system behavior in development of diseases, via highlighting the modules of genes instead of individual genes(30,31). in the current study, first we enriched the candidate genes and directed biological pathways, by bioinformatics approaches, and their gene network as well as interactions with other genes was designed. then, expression analysis of spop, daxx, rarres1, and lamp2 was assessed by qrt-pcr in 50 pca tissues, compared with 50 bph and 50 normal adjacent prostatic tissues. puto et al. described daxx as a transcription factor that serves its suppressive role by recruiting dna methyl transferases and histone deacetylases in pca cell lines(16). here, by developing a network we depicted that daxx mediates its key role in cellular process by interactions with spop and other factors in pathways related to lysosome, rars-mediated signaling, pi3k signaling, and ar activity. spop encodes an e3 ubiquitin ligase component acting through degradation of several regulators of cell proliferation and apoptosis including daxx in a cancer context(32). our findings confirms these concepts by showing the inverse relationship between expression levels of daxx (up-regulated) and spop (down-regulated) and further points to their connection and vital roles as autophagy-related urological oncology 160 table 5. the results obtained from roc curve analysis of four candidate genes. gene cut-off point auc 95% confidence interval %sensitivity %specificity p-value daxx -6.302 0.837 [0.751-0.924] 86 60.5 < 0.0001 rarres1 -2.557 0.659 [0.542-0.776] 72 53.5 0.011 lamp2 -3.065 0.884 [0.815-0.953] 90.7 62.8 < 0.0001 spop -2.437 0.809 [0.715-0.904] 86 60.5 < 0.0001 spop, daxx, rarres1, and lamp2 genes in prostate cancer-jamali et al. genes in pca. these results are consistent with those of ju et al. speculating that spop selectively suppresses the pca through stability regulation of cyclin e1 in pca cell lines. substantially, expression of cyclin e1 rescues the tumor formation, proliferation, and migration of pca cells(33). the results from exome sequencing of 112 pca and normal tissue pairs revealed that spop gene had the most frequently recurrent mutations influencing its expression level(34). noticeably, dysregulated levels of spop may accordingly serve as a specific hallmark in early detection of pca carcinogenesis(35), which can bring us to precise understanding of molecular mechanism and its clinical applications for targeted pca therapies(36). evidence also suggests that strong expression of daxx correlates with high gs and elevated cell proliferation index, exhibiting its potential prognosticator role in pca outcomes(37). by considering the network enrichment and correlation outcomes, our study represents for the first the interactions of rarres1 and lamp2 between themselves and in network of spop and daxx genes, altogether emphasizing a network developed from different modules (figure 1). literature introduces rarres1 as a putative tumor suppressor gene that negatively regulates the cell proliferation, while less is known about responsible mechanisms(38). particularly, it has been emphasized that rarres1 is involved in autophagy induction(1). our network enrichment and qrt-pcr findings supported this hypothesis by revealing the significant reduction of rarres1 in tumor samples relative to both controls including adjacent and bph tissues. based on the obtained gene network, this reduced level might be indirectly related to the increased levels of daxx, offering their inverse relationship in pca in our study. we found a total reduction in lamp2 expression level in tumor tissues. evidence exist that this decreased level can trigger lysosomal membrane permeabilization and subsequently sensitize cells to the lysosomal pathway of cell death(39). noteworthy, we found that inosine monophosphate dehydrogenase 1 (impdh1), as a mediator, interacts with lamp2 in autophagy module of our network. this suggests that daxx may be able to down-regulate the lamp2 expression through impdh1 in the depicted gene network. on the other hand, daxx can adjust the expression of autophagy-related genes such as rarres1 and lamp2 by interactions with ar and retinoic acid receptor alpha (rara) (figure 1). importantly, the roc curve analysis showed the good predictive value (auc above 0.8) for daxx, spop, and lamp2 gene expressions in discrimination of malignant and non-malignant tissues in pca, among which lamp2 had the most sensitivity and specificity. again, the integrated picture of roc curve for all four candidate genes, in addition to the significant correlations observed between their expression levels, potentially suggests the putative clinical application of this network. in this kind of study, which different molecular techniques can yield different results, it is recommended to study greater sample size with the same methods to increase the accuracy of the results. as the next step forward, we suggest the study of a more extended gene network from each module to enrich our knowledge of reciprocal interactions between these genes. in line, investigation of their expression alterations in protein level, as well as considering a larger sample size of pca and bph tissues, could be of great value for future. conclusions in conclusion, given the importance of autophagy in pca tumorigenesis, these findings not only indicate the complicated cellular networks and context-dependent manner of autophagy induction, also suggest that the contribution of spop, daxx, rarres1, and lamp2 together could be a putative regulatory element acting as a prognostic signature and therapeutic target in pca. acknowledgments we would like to thank all staff of urology and pathology department staff in shohada-e-tajrish hospital. we would like to show our appreciation towards dr. naser rakhshani and dr. arman morakabatif, for them invaluable help throughout this study. conflict of interest none declared by the authors. references 1. roy a, ramalinga m, kim oj, et al. multiple roles of rarres1 in prostate cancer: autophagy induction and angiogenesis inhibition. plos one. 2017;12:e0180344. 2. taeb 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abdullah gul1, ozgur ekici2*, salim zengin1, caglar boyaci1 purpose: to evaluate whether there were any changes in the rates of urinary tract infection (uti) and antibiotic resistance in pediatric patients during the pandemic period. materials and methods: urine culture samples collected due to suspected uti were searched retrospectively from our hospital database, and the patients with growth in urine culture were identified. they were divided into 2 groups as group a (before covid-19, march 11, 2019march 11, 2020) and group b (covid-19 period, march 11, 2020march 11, 2021). also, covid-19 period was divided into 3 subgroups (march 2020– june 2020: first epidemic peak, july 2020 – november 2020: normalization process, december 2020– march 2021: second epidemic peak). we adjusted the patient age as <1, 1-6 and 7-18 years. age, gender, microorganism strain types, and their antibiotic resistance patterns were compared between the 2 groups results: this cross-sectional study included 250 eligible patients (group a, n=182 and group b, n=68) with a mean age of 10.91 ± 5.58 years. the male/female ratio was higher in group b than in group a (p = .004). incidence of utis was lower in the curfew and restriction periods due to epidemic peaks than normalization process (p = .001). the proportion of e.coli decreased from 80.2% to 61.8% during the pandemic period when compared to pre-pandemic period (p = .001). group b had lower rates of resistance to ampicillin, fosfomycin and nitrofurantoin for e.coli than group a (p = .001, p = .012 and p = .001, respectively). also, group b had higher rate of uncommon microorganisms and lower rate of resistance to nitrofurantoin for e.coli than group a in patients aged 7-18 years (p = .003 and p = .023, respectively). conclusion: our study demonstrates that the ongoing covid-19 pandemic process has caused alterations in community-acquired utis in children. more hygienic lifestyle may be considered as the main factor in this change. keywords: coronavirus; covid-19; pediatrics; urinary tract infection introduction the urinary tract infection (uti) is the most com-mon bacterial infection in children(1). escherichia coli (e. coli) is the most common type of the produced species(1). early diagnosis and treatment of utis in children is essential to prevent the development of renal scarring. severe acute respiratory syndrome coronavirus 2 (sars cov-2), a single-stranded rna virus with positive polarity that caused coronavirus disease (covid), was discovered for the first time in november 2019 in wuhan, china. it has influenced all of humanity since that day and has resulted in a complete change in our daily routine. the first coronavirus case in turkey was reported on march 11, 2020. following this date, the schools were closed and quarantine practices began. curfews was also declared for the entire society, lasting several days or weeks on specific dates, including weekends and holidays. during the pandemic, hospital admissions for non-covid reasons decreased in the pediatric age group, as well as in all age groups(2). postponing elective procedures in hospitals, closing the polyclinics or reducing the number of those, and patients' avoidance of coming to the 1department of urology, university of health sciences, bursa yuksek ihtisas education and research hospital, bursa, 16000, turkey. 2department of urology, nusaybin state hospital, mardin, 47200, turkey. *correspondence: department of urology, nusaybin state hospital, nusaybin, mardin, 47200, turkey. tel: +90 531 917 45 90, fax: +90 (482) 415 33 63, e-mail: ekici_1990@hotmail.com. received february 2022 & accepted june 2022 hospital are several factors that contribute to a lower rate of hospital admission. along with a decrease in hospital admissions, there was a decrease in the rate of some diseases transmitted through contact as a result of protective measures such as mask use, social distance considerations, and adherence to hygiene rules. although this decrease has been observed in diseases such as viral upper respiratory tract infections and asthma(3, 4), studies on urinary tract infections have revealed contradictory results(5-7). the purpose of this study was to evaluate whether the covid-19 period affects the rates of community-acquired uti in children, the distribution of causative bacteria, and the resistance of these bacteria. materials and methods study design ethical approval was granted by the university of health sciences, bursa yuksek ihtisas training and research hospital ethics committee with reference number 2011/kaek-25 2021/11-19. one year period prior to march 11, 2020, the date of the first covid-19 case in turkey, was defined as the pre-covid-19 period, and the one year period following this date was defined as the post-covid-19 period. also, we divided the urology journal/vol 19 no. 5/ september-october 2022/ pp. 386-391. [doi:10.22037/uj.v19i.7227] pediatric urology post-covid-19 era into 3 periods based on the intervals when the restrictions began (march-june 2020), the restrictions partially decreased (july-november 2020) and the second epidemic peak (december 2020-march 2021). similarly, the pre-covid-19 period was divided into 3 intervals for comparative analysis. inclusion and exclusion criteria this cross-sectional study included the patients under the age of 18 who presented to the urology polyclinic with suspected uti symptoms and had bacterial growth in their urine cultures for the first time within one-year intervals (march 11, 2019 march 11, 2020, and march 11, 2020 march 11, 2021). we divided the patients into 3 groups according to their age: <1, 1-6, and 7-18. the study excluded the patients with vesicoureteral reflux, posterior urethral valves, urolithiasis, bladder bowel dysfunction, urogenital tract abnormalities, immune system disorders and uncircumcised boys. also, all of the cohort evaluated in our study were sexually naive. evaluation of urine samples after anamnesis and a thorough physical examination, microscopic findings of centrifuged urine samples from suspicious patients were recorded, in order to make a diagnosis. urine samples were obtained by transurethral bladder catheter in children who had not been toilet trained. midstream urine samples were collected from older children. these samples were incubated overnight at 37°c with a standard loop of blood agar and macconkey agar media. in catheterization and midstream urine samples, 103-104 cfu/ml growth was considered significant, while leukocytes in spot urine tests with >5 leukocytes in each field in centrifuged urine were considered significant. antimicrobial susceptibility testing was performed using a panel of antimicrobial agents based on the causative organism in cultures with significant bacteriuria using the disc diffusion method. until the antibiogram results were available, prophylactic empirical antibiotics based on the local susceptibility patterns were prescribed to the patients. following that, the treatment was scheduled in accordance with the antibiogram results. the patients were divided into 2 groups as group a (before covid-19, march 11, 2019march 11, 2020) and group b (covid-19 period, march 11, 2020march 11, 2021). the difference in uti rates, distribution of bacteria grown in culture, and antibiotic resistance between two groups were analyzed. statistical analysis the normal distribution of data was evaluated using the kolmogorov-smirnov test and graphical method via q-q plot. the data were presented as median, interquartile range, number and percentage. groups were analyzed using the mann whitney u test for quantitative data and the chi-square test or fisher's exact test for categorical data as appropriate. also, we used logistic regression model to identify possible confounding factors. p < 0.05 was considered as statistically significant. spss 21.0 program was used. results after 49 patients met exclusion criteria were removed from the study, a total of 250 patients (182 in group a and 68 in group b) were evaluated. during the covid-19 period, there was a huge decrease in the number of patients when compared to pre-pandemic period (variation: -62.64%). the mean age of the patients was 10.91 ± 5.58 (range: 6 months 18 years). the initial characteristics of the patients are presented in table 1. of the patients, 225 had cystitis and 25 had pyelonephritis. seven patients (5 in group a and 2 in group b) with a clinical pyelonephritis and impaired oral intake were hospitalized. it was comparable between the groups in terms of hospitalization (p = .967). while e.coli (75.2%), klebsiella pneumoniae (10%), and proteus mirabilis (4%) were the most commonly isolated bacteria, bacteria such as p. aeroginosa, enterococcus and streptococcus spp. were observed at a rate of 10.8%. the distribution patterns of the bacteria by gender are shown in table 2. while no significantly difference in median age was observed between the two groups, there was a significantly increase in the male/female ratio in group b (p= .004). the hospital admission rates for uti in the first and second epidemic peak periods were higher than in group a (p = .001). despite the fact that e.coli was the most commonly isolated microorganism in both groups, it was significantly less isolated in group b than in group a (61.8% vs 80.2%) (p = .001). ampicillin resistance for e.coli was also found to be statistically lower in group b than in group a (27.9% vs 58.2%) (p = .001). furthermore, there was significantly less resistance to fosfomycin and nitrofurantoin for e.coli in group b (p = .012 and p = .001, respectively) (table 3). there was no difference in uti rates between the two groups according to age groups and infection type (p= .515 and p = .925, respectively) (table 3). in the subgroup analysis of the patients according to age groups in terms of microorganism strain types and antibiotic resistance patterns, there was no difference in the periods including the patients aged <1 and 1-6 years, while a significant increase was observed at the uncommon microorganisms rate in the group aged 7-18 years during the covid-19 period (table 4). in addition, only the rate of nitrofurantoin resistance for e.coli decreased significantly during the covid period in the same group (p = .023). patient’ age did not influence the uti rate according to the regression analysis (95%ci: 0.8421.146, or: 0.988, p = .874) discussion covid-19 has increasingly led to radical lifestyle changes all over the world since its breakthrough. people have begun to avoid crowded places in order to prevent transmission. furthermore, as a result of social regulations in which governments play a role, patients' table 1. demographic data of the cohorts data n=250 age, years 10.91 ± 5.58 gender, n (%) female 199 (79.6) male 51 urine microscopy, n (%) < 5 hpf 85 (34) >5 hpf 165 isolatedmicroorganisms, n (%) escherichia coli 188 (75.2) klebsiella pneumonia 25 (10) proteus mirabilis 10 (4) others 27 (10.8) the effect of covid-19 on uti in childrengul et al vol 19 no 4 july-august 2022 308 hpf: high power field vol 19 no 5 september-october 2022 387 non-emergency hospital admissions have been reduced, and home health services have begun to be used more effectively. both the reduction in hospital admissions and the emphasis on social distance have resulted in a reduction in some diseases for which crowded environments are risk factors(4). in our study, hospital admissions due to utis in children decreased during this period, and the gender predominance along with antibiotic resistance patterns changed. there are some studies in the literature evaluating the changes in uti rates in children during the pandemic. pines et al. reported in their study that the number of patients admitted to the hospital with uti diagnosis decreased by 47% during the pandemic period compared to the pre-covid-19 period(6). similarly, according to the results of a study reported from scotland, the rate of admission to hospital due to uti in children decreased by 55.3% in 2020 when compared to 2018 and 2019(8). in the study by wilder et al., a decrease in hospitalizations due to asthma, bronchiolitis, and pneumonia, which are more clearly related to social distance and viruses, was observed in the pediatric patient group during the covid-19 period compared to the pre-covid-19 period, while hospitalizations rates for cellulite, gastroesophageal reflux, and uti did not change(7). similarly, according to the results of a multicenter study conducted in japan, the number of children who required hospitalization due to uti during the covid-19 period did not differ significantly from the pre-covid-19 period(5). kuitunen et al. found a significant decrease in the incidence of cystitis and pyelonephritis, especially in patients aged 1-6 years during the pandemic period(9). in their national study, similar to our study, a significantly decrease was found in the incidence of utis during the periods of restriction-due to epidemic peak intervals. in our study, while there was no difference in the incidence of uti according to age subgroups between the groups, patients aged 7-18 years in covid-19 period had higher rate of uncommon microorganisms than those in pre-pandemic period. the reason for this difference may be that day-care centers where have worse hygienic condition than homes are kept open for day-care aged children whose caregiver parents have to work during the period of restriction in our country, and elementa e.coli k. pneumoniae p. mirabilis others before covid-19, n (%) male 16 (6.4) 8 (3.2) 4 (1.6) 1 (0.4) female 130 (52) 10 (4) 4 (1.6) 9 (3.6) covid-19 period, n (%) male 8 (3.2) 1 (0.4) 1 (0.4) 12 (4.8) female 34 (13.6) 6 (2.4) 1 (0.4) 5 (2) p value 0.166 0.158 0.990 0.002 table 2. distribution of the bacteria by gender between the groups pediatric urology 309 variables group a (n=182) group b (n=68) p value age (years) 11 (iqr: 7-16) 12.5 (iqr: 5.25-16.75) 0.558 age groups, n (%) 0.515 <1 year 3 (1.6) 1 (1.4) 1-6 years 41 (22.6) 20 (29.4) 7-18 years 138 (75.8) 47 (69.2) infection type, n (%) 0.925 cystitis 164 (90.1) 61 (89.7) pyelonephritis 18 7 infection period, n (%) 0.01 march-june 46 (25.3) 11 (16.1) julynovember 79 (43.4) 44 (64.7) decemberfebruary 57 (31.3) 13 (19.2) gender, n (%) 0.004 male 29 (15.89) 22 (32.35) female 153 46 microorganism, n (%) 0.001 e. coli 146 (80.2) 42 (61.8) k. pneumoniae 18 (9.9) 7 (10.3) p. mirabilis 8 (4.4) 2 (2.9) others 10 (5.5) 17 (25) antibiotic resistance for e. coli, % ampicillin 58.2 27.9 0.001 piperacillin-tazobactam 18.1 22 0.483 gentamicin 8.8 7.3 0.715 amikacin 7.1 1.5 0.083 ceftriaxone 37.3 35.3 0.763 cefuroxime 42.8 38.2 0.509 ceftazidime 39.5 38.2 0.849 ciprofloxacin 17.5 23.5 0.288 meropenem 1.6 1.4 0.921 ertapenem 2.7 1.4 0.557 fosfomycin 11.5 1.4 0.012 nitrofurantoin 19.7 2.9 0.001 trimethoprim-sulfamethoxazole 34.1 29.4 0.485 table 3. comparison of pre-covid-19 (group a) and covid-19 period (group b) data the effect of covid-19 on uti in childrengul et al pediatric urology 388 ry, middle and high schools interrupt their education. kruizinga et al. compared the pediatric emergency department admissions between 2016-2019 and 2020(10). a significant decrease in admissions was observed in february 2020 along with the highest decrease in april 2020. however, in the group of non-communicable diseases including uti in their study, no significant change was observed between the periods. similar to the results of study mentioned above, we observed significantly decrease in the incidence of uti during the first and second epidemic peak periods in our study. several hypotheses can explain the decrease in the number of pediatric patients diagnosed with uti. the first reason could be that schools were closed during this period(11). it is a well-known fact that schools and common areas have usually worse hygienic conditions than homes in our country. the second reason might be that more attention was paid to personal hygiene during this period and interpersonal contact was minimized. although uti is not classified as a communicable disease, societal outbreaks have been reported(12). since e.coli is found in normal intestinal flora, hand and food hygiene appear to play a role in contamination. it is known to be transferred between sexual partners and people living in the same household(13). third, during the pandemic, parents may have preferred to take their children to branch hospitals where only children can be treated, rather than general hospitals where adults are more numerous. according to the study of goldmann et al., the decrease in the rate of pediatric admissions to the general hospital emergency department during the pandemic period was 70%, while the fall in the rate of admissions to the pediatric hospital emergency department was determined as 57%(2). public health measures against covid-19 are also known to cause a decrease in other infectious diseases. according to a study conducted in taiwan, the incidence of kawasaki disease reduced by 30% in 2020 when compared to 2018(14). however, it was mentioned that this decline, according to the study's authors, may be a result of both the precautions taken and the decrease in patients' admission to the hospital. during the pandemic period, a new type of phobia, known as "covid phobia," emerged(15). lin et al. reported in their study that as a result of this "covid phobia," the incidence of emergency department admissions due to respiratory tract infections dropped by nearly 50% in taiwan(16). however, no similar decrease in rates of uti table 4. analysis of microorganism strain types and their antibiotic resistance patterns according to age groups variables group a group b p value the patients aged < 1 year microorganism, n 0.500 e. coli 2 0 k. pneumoniae 1 0 p. mirabilis 0 0 others 0 1 the patients aged 1-6 years microorganism, n 0.175 e. coli 30 10 k. pneumoniae 6 4 p. mirabilis 3 2 others 2 4 antibiotic resistance for e. coli, % ampicillin 63.3 50 0.482 piperacillin-tazobactam 23.3 40 0.418 gentamicin 13.3 20 0.629 amikacin 3.3 10 0.442 ceftriaxone 53.3 70 0.471 cefuroxime 53.3 60 0.734 ceftazidime 50 60 0.721 ciprofloxacin 20 30 0.665 meropenem 6.6 0 0.615 ertapenem 10 0 0.560 fosfomycin 16.6 0 0.306 nitrofurantoin 16.6 0 0.306 trimethoprim-sulfamethoxazole 43.3 30 0.485 the patients aged 7-18 years microorganism, n 0.003 e. coli 114 32 k. pneumoniae 11 3 p. mirabilis 5 0 others 8 12 antibiotic resistance for e. coli, % ampicillin 50.8 34.4 0.098 piperacillin-tazobactam 14.9 15.6 0.921 gentamicin 3.5 6.2 0.612 amikacin 0.8 0 0.781 ceftriaxone 31.5 25 0.474 cefuroxime 39.4 34.4 0.600 ceftazidime 34.2 31.2 0.754 ciprofloxacin 18.4 18.7 0.573 meropenem 0.8 0 0.781 ertapenem 0.8 0 0.781 fosfomycin 8.7 3.1 0.457 nitrofurantoin 14.1 0 0.023 trimethoprim-sulfamethoxazole 28.9 28.1 0.559 the effect of covid-19 on uti in childrengul et al vol 19 no 5 september-october 2022 389 was seen. according to the findings of roongpisuthipong et al., there was a change in the pattern of skin diseases during the covid-19 period(17). another result of our research was that the male/female ratio in uti increased throughout the pandemic period. while female patients used public toilets in schools and playgrounds prior to the pandemic, they met these needs at home since schools were closed and social areas were restricted during the pandemic. considering that anatomical factors are one of the leading causes of uti in girls, since houses has better hygienic conditions, it is reasonable to predict that the reduction rate of uti in girls would be more compared to boys. this relative decrease might account for the rise in the male/ female ratio for bacterial growth. another finding was that the rate of e. coli decreased during the pandemic period when compared to other uncommon causative microorganisms. this might be attributed to a rise in the male/female ratio. in the covid-19 period, male predomination was observed in the other causative microorganism species in our study. edlin et al. reported in their research, which involved 24,815 pediatric patients, that microorganisms without e. coli were seen at a higher rate in men than in women(18). in our study, the highest antibiotic resistance for e. coli was observed in ampicillin (50%). it was followed by cephalosporins[cefuroxime (41.6%), ceftazidime (39.2%), ceftriaxone (36.8%)] and trimethoprim-sulfamethoxazole (32.8%). according to edlin et al., the highest resistance rates were seen in ampicillin (45%) and trimethoprim-sulfamethoxazole (24%) in their investigation(18). another finding of our study is the change in antibiotic resistance patterns during the covid-19 period. resistance for e.coli has declined dramatically, particularly to ampicillin, fosfomycin and nitrofurantoin. there may be several reasons for this change. in general, lockdown, restriction or less personal interaction with the peers might be the main reasons for this situation. as it is known, pathogen resistance in uti varies according to time as well as geographical and regional location. for example, in their 6-year study on the change of antibiotic resistance, erol et al. discovered that resistance to ampicillin, trimethoprim-sulfamethoxazole and nitrofurantoin increased whereas cephalosporin resistance remained steady(19). saperston et al. discovered that e.coli resistance to trimethoprim-sulfamethoxazole, ampicillin, cephalosporins, and ciprofloxacin differed significantly between inpatients and outpatients(20). another reason could be that antibiotic use has dropped throughout the pandemic. unless a bacterial agent superinfected, the ministry of health did not recommend routinely antibiotic treatment for covid-19 patients in turkey during the covid-19 period, but only favipiravir was utilized. antibiotic use in other countries has fallen dramatically in both inpatient and outpatient groups(21,22). travel limitations abroad might have reduced the transfer of regional antibiotic resistance genes during this period(23). according to a study conducted in belgium, the use of amoxicillin, which is commonly used to treat respiratory tract infections, declined dramatically during the pandemic period, while the use of nitrofurantoin did not change(24). based on this information, the decrease in ampicillin resistance may be related to a reduction in the use of this antibiotic group in upper respiratory tract infections during the pandemic. it is believed that the drop in other antibiotic resistances is related to a general decrease in antibiotic use(21,22). although our study reveals that the proportion of uti in children has decreased and antibiotic resistance patterns have changed during the covid-19 period, but it also has some limitations. first, our study population consisted of relatively small number of patient groups, and the data were analyzed retrospectively. second, our study population was limited to our region only and consisted of patients who applied to the general urology polyclinic. as the measures taken during the pandemic period differ between countries, results of our study cannot be generalized and cannot represent to the all regions of the world. conclusions as a result, hospital admission rate for community-acquired uti in the patients aged ≤18 years has decreased substantially during the pandemic period. furthermore, male predominance and uncommon microorganism species have increased, and antibiotic resistance patterns have changed. therefore, we think that it would be more appropriate for clinicians to manage the disease by taking into account the changes in the distribution of microorganism agents under pandemic conditions. further studies with larger sample size are needed to support the findings of our study. summary the covid 19 pandemic has led to lifestyle changes all over the world. all these changes have led to changes in the incidence of microorganisms. in our study, we showed that there was a decrease in urinary tract infection rates in children, changes in gender predominance and antibiotic resistance during the pandemic period. conflict of interest the authors declared no conflict of interest. references 1. jacobson sh, eklof o, eriksson cg, lins le, tidgren b, winberg j. development of hypertension and uraemia after pyelonephritis in childhood: 27 years follow up. bmj 1989; 299: 703-6. 2. shaikh n, craig jc, rovers mm, et al. identification of children and adolescents at risk for renal scarring after a first urinary tract infection: a meta-analysis with individual patient data. jama pediatr 2014; 168: 893900. 3. conway ph, cnaan a, zaoutis t, henry bv, grundmeier rw, keren r. recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. jama 2007; 298: 179-86. 4. hoberman a, wald er, hickey rw, et al. oral versus initial intravenous therapy for urinary tract infection in young febrile children. pediatrics 1999; 104: 79-86. 5. martinell j, hansson s, claesson i, jocobsson b, lidin-janson g, jodal u. detection of urographic scars in girls with pyelonephritis followed for 13-38 years. pediatr nephrol 2000; 14: 1006-10. 6. wennerstrom m, hansson s, jodal u, stokland e. primary and acquired renal scarring in boys the effect of covid-19 on uti in childrengul et al pediatric urology 390 and girls with urinary tract infection. j pediatr 2000; 136: 30-4. 7. panaretto ks, craig jc, knight jf, howmangiles r, sureshkumar p, roy lp. risk factors for recurrent urinary tract infection in preschool children. j. pediatr child health 1999; 35: 454-9. 8. shaikh n, haralam ma, kurs-lasky m, hoberman a. association of renal scarring with number of febrile urinary tract infections in children. jama pediatr 2019; 173: 949-52. 9. matoo tk, chesney rw, greenfield sp, et al. renal scarring in the randomized intervention for children with vesicoureteral reflux (rivur) trial. clin j am soc nephrol 2016; 11: 54-61. 10. shaikh n, ewing al, bhatnagar s, hoberman a. risk of renal scarring in children with a first urinary tract infection: a systematic review. pediatrics 2010; 126: 1084-91. 11. johansson b, berg u, svensson l. renal damage after acute pyelonephritis. arch dis child 1994; 70: 111-5. 12. rushton hg. the evaluation of acute pyelonephritis and renal damage with technetium99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions. pediatr nephrol 1997; 11: 108-20. 13. karen r, shaikh n, pohl h, et al. risk factors for recurrent urinary tract infection and renal scarring. pediatrics 2015; 136: e13-21. 14. subcommittee on urinary tract infection, steering committee on quality improvement and management, roberts kb. urinary tract infection: clinical practice guideline for the diagnosis and management of the initial uti in febrile infants and children 2 to 24 months. pediatrics 2011; 128: 595-610. 15. avner ed, harmon we, niaudet p, yoshikawa n. pediatric nephrology, 6th edn. springer, berlin heidelberg, new york, 2009. 299-310. 16. pickworth fe, carlin jb, ditchfield mr, et al. sonographic measurement of renal enlargement in children with acute pyelonephritis and time needed for resolution: implications for renal growth assessment. ajr 1995; 165: 405-8. 17. dinkel e, orth s, dittrich m, schultewisermann h. renal sonography in the differentiation of upper from urinary tract infection. ajr 1986; 146: 755-80. 18. peratoner l, pennesi m, bordugo a, et al. kidney length and scarring in children with urinary tract infection: importance of ultrasound scans. abdom imaging 2005; 30: 780-5. 19. bouissou f, munzer c, decramer s, et al. prospective randomized trial comparing short and long intravenous antibiotic treatment of acute pyelonephritis in children: dimercaptosuccinic acid scintigraphic evaluation at 9 months. pediatrics 2008; 121: e553-60. 20. muller l, preda i, jocobsson b, et al. ultrasonography as predictor of permanent renal damage in infants with urinary tract infection. acta pediatr 2009; 98: 1156-61. 21. nguyen ht, benson cb, bromley, et al. multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (utd classification system). j pediatr urol. 2014; 10: 982-98. 22. rosembaum dm, korngold e, teele rl. sonographic assessment of renal length in normal children. ajr 1984; 142: 467-9. 23. lebowitz rl, olbing h, parkkulainen kv, smellie jm, tamminen-mobius te. international reflux study in children. international system of radiographic grading of vesicoureteric reflux. pediatr radiol 1985; 15: 105-9. 24. shaikh n, morone ne, bost je, farrell mh. prevalence of urinary tract infection in childhood: a meta-analysis. pediatr infect dis j 2008; 27: 302-8. 25. singh-grewal d, macdessi j, craig j. circumcision for the prevention of urinary tract infection in boys: a systematic review of randomized trial and observational studies. arch dis child 2005; 90: 853-8. 26. jodal u. the natural history of bacteriuria in childhood. infect dis clin north am 1987; 1: 713-29. 27. carpenter ma, hoberman a, mattoo tk, et al. the rivur trial: profile and baseline clinical associations of children with vesicoureteral reflux. pediatrics 2013; 132: e34-45. 28. hoberman a, charron m, hickey rw, baskin m, kearney dh, wald er. imaging study after a first febrile urinary tract infection in young children. n engl j med 2003; 348: 195202. 29. simicic ma, arapovic a, saraga-babic m, et al. intrarenal reflux in the light of contrastenhanced voiding urosonography. front pediatr 2021; mar 2; 9: 642077. doi: 10.3389/ fped.2021.642077. ecollection 2021. 30. colleran gc, barnewolt ce, chow js, paltiel hj. intrarenal reflux: diagnosis and contrast-enhanced voiding urosonography. j ultrasound med 2016; 35: 1811-9. 31. montini g, zucchetta p, tomasi l, et al. value of imaging studies after a first febrile urinary tract infection in young children: data from italian infection study 1. pediatrics 2009; 123: e239-43. 32. marks sd, gordon i, tullus k. imaging in childhood urinary tract infections: ime to reduce investigations. pediatr nephrol 2008; 23: 9-17. 33. craig jc, simpson jm, williams gj, et al. antibiotic prophylaxis and recurrent urinary tract infection in children. n engl j med 2009; 361: 1748-59. 34. johansson b, troell s, berg u. renal parenchymal volume during and after acute pyelonephritis measured by ultrasonography. arch dis child 1988; 63: 1309-14. the effect of covid-19 on uti in childrengul et al vol 19 no 5 september-october 2022 391 vol 19 no 1 january-february 2022 138 review suctioning versus traditional access sheath in mini-percutaneous nephrolithotomy: a systematic review and meta-analysis di chen2, changsheng chen3, yurun xie3, zhihua luo3, gang liu1* purpose: the suctioning access sheath (sas) is a novel access sheath connected to a negative pressure suction device and absorbs fragments. some comparative studies have reported sas with a higher stone-free rate and lower operative time. however, no higher-level evidence was published to support sas. hence, this systematic review and meta-analysis aimed to assess the clinical safety and efficacy of sas versus traditional access sheath (tas) for the treatment of renal stones in mini-percutaneous nephrolithotomy (mpcnl). materials and methods: a systematic review of the literature was conducted using pubmed, embase (ovid), medline (ebsco), cochrane central register of controlled trials, and sinomed to search comparative studies as recent as december 2020 that assessed the safety and effectiveness of sas in pcnl. the quality of retrospective case-control studies (rccs) and randomized controlled trials (rcts) were evaluated by the newcastle-ottawa scale (nos) and the cochrane risk of bias tool, respectively. the oxford center set up evidence-based medicine was used to assess the level of evidence (le). statistical analyses were performed by the comprehensive meta-analysis program. results: seven studies, with a total of 1655 patients, were included. compared with the tas group, the sas group had a shorter operative time (md = -17.30; 95%ci:-23.09,-11.51; p < .00001), higher stone-free rate (or = 2.37;95%ci:1.56,3.61;p < .0001), fewer total complication rate (or=0.50;95%ci:0.35,0.70; p < .0001), lower auxiliary procedures rate (or=0.48;95%ci:0.36,0.64; p<.00001), and lower postoperative fever rate (or = 0.46;95%ci:0.34,0.62; p < .00001). conclusion: the sas can significantly improve mpcnl in the stone-free rate, operative time, and total complication rate, especially for auxiliary procedures and postoperative fever rates. keywords: suctioning access sheath; mini-percutaneous nephrolithotomy; systematic review; meta-analysis; efficacy; safety introduction urolithiasis is a common urinary disease. with a 10% recurrence rate in one year and 1.7%-14.8% prevalence rates(1,2), the disease brings a severe burden to patients and society. minimally invasive surgery, such as pcnl, extracorporeal shock wave lithotripsy (eswl), and retrograde intrarenal stone surgery (rirs), are used to remove stones and relieve obstruction in the clinic. due to better safety and effectiveness, pcnl is the first-line treatment for larger than 2 cm or complex renal stones(3). however, high renal pelvic pressure and damage still can be a tricky question to pcnl. many approaches are developed to decrease the complications, including the use of minimally access sheath. according to the access sheath size, pcnl is divided into minimally invasive percutaneous nephrolithotomy (mpcnl) and standard percutaneous nephrolithotomy (spcnl). with a smaller access sheath, mpcnl has the advantage of lower bleeding, fewer transfusion rate, and shorter hospitalization(4). however, minimally ac1the reproductive hospital of guangxi zhuang autonomous region, nanning, 530021, guangxi, china. 2the nanxishan hospital of guangxi zhuang autonomous region, guilin, 541000, guangxi, china. 3department of urology, people’s hospital of guangxi zhuang autonomous region, nanning, 530021, guangxi, china. *correspondence: the reproductive hospital of guangxi zhuang autonomous region, nanning, 530021, guangxi, china. email: urology.dr_liu@foxmail.com received march 2021 & accepted october 2021 cess sheath is reported with higher renal pelvic pressure and longer operative time, causing a high risk of postoperative urinary infection(5,6). recently, the application of continuous suctioning systems, such as sas(7), swiss lithoclast@(8), cyberwand(9), reported a lower renal pelvic pressure and less operative time than the standard perfusion system. sas, retrofitted from a traditional minimally access sheath or a patented sheath, is inexpensive and cost-effective(10). keeping the advantage of minimally access sheath, the sas can connect with a negative pressure aspirator. with the help of negative pressure, fragments and perfusate would be sucked out from patients immediately. several rcts have investigated the safety and effectiveness of sas in pcnl. in 2017, a study conducted by huang et al. reported the sas group's stone-free rate is 96.7%, while that of the tas group is 73.6%(p < 0.05) in the treatment of nonstaghorn calculi(11). xu et al. designed a study that included staghorn calculi cases to determine the operative time between tas and sas(12). the result indicated that sas could significantly improve complication, stonefree rate, and operative time in pcnl. urology journal/vol 19 no. 1/ january-february 2022/ pp. 1-8. [doi: 10.22037/uj.v18i.6773] meta-analysis has a high level in evidence-based medicine and the advantage of overcoming samples' limitations from different studies. however, to date, the effectiveness and safety of sas have not still been evaluated by systematic review or meta-analysis. therefore, our systematic review and meta-analysis was performed to assess the safety and effectiveness between sas and tas in mpcnl. materials and methods the meta-analysis was registered on the international prospective register of systematic reviews(13) (prospero, https://www.crd.york.ac.uk/prospero/, id: crd42021228513). according to the prisma guidelines(14), our perspective protocol included an objective, study search strategy, selection criteria, level of evidence, assessment of quality, data extraction, meta-analysis, sensitivity analysis, and publication assessment bias. study search strategy a systematic review of studies, from published studies until december 2020, was performed from the following databases: pubmed, embase (ovid), medline (ebsco), cochrane central register of controlled trials, sinomed. besides, the references of all related studies were screened. two authors independently performed the search of studies (yu-run xie and zhi-hua luo). when there were any disagreements, two previous authors cross-checked and then discussed with a third author (chang-sheng chen). mesh terms were used in each database, and retrieval strategy used sequentially as follows: table1. characteristics of the included studies author year period study type le quality of study sheath size(f) sample (n) sas tas du et al. (20) 2018 2009-2014 rct 1b 3a 16-18 311 304 zhu et al. (10) 2019 2018-2019 rcc 3b 6b 20 256 256 huang et al. (11) 2016 2011-2013 rct 1b 4a 16 91 91 xu et al. (12) 2020 2018 rct 1b 4a 20 30 30 lai et al. (18) 2019 2017-2018 rcc 3b 6b 18 75 75 song et al.(19) 2011 2008-2009 rct 1b 3a 16 30 30 lai et al. (7) 2020 2017-2018 rct 1b 4a 20 38 38 sas versus tas in mini-percutaneous nephrolithotomy-chen et al. review 2 figure 1. study retrieval flow chart sas suction access sheath, tas traditional access sheath, rct randomized controlled trial, rcc retrospective case control study, le level of evidence, a using the cochrane risk of bias tools (score from 0 to 7), b using the newcastle-ottawa scale (score from 0 to 9) vol 19 no 1 january-february 2022 138 (1): (((((((((suctions) or (suctioning)) or (aspiration, mechanical)) or (aspirations, mechanical)) or (mechanical aspiration)) or (mechanical aspirations)) or (drainage, suction)) or (drainages, suction)) or (suction drainage)) or (suction drainages) (2): (((percutaneous nephroscope) or (nephrolithotomies, percutaneous)) or (percutaneous nephrolithotomies)) or (percutaneous nephrolithotomy) (3): (1) and (2) selection criteria searched studies were eligible if the following selection criteria were met. inclusion criteria: (1) english language; (2) full text available; (3) comparative study including rct or rcc; (4) included renal calculus patients needed the treatment of mpcnl; (5) sas and tas used in two groups, respectively. exclusion criteria: (1) included patients with anatomical malformation or coagulation function abnormalities; (2) repeated publication. quality assessment of eligible studies the oxford center set up evidence-based medicine was used to assess the le(15). furthermore, the nos(16) and the cochrane risk of bias tool(17) were applied to assess the quality of rccs and rcts, respectively. two authors independently performed this step and compared consistencies (yu-run xie and zhi-hua luo). any disagreements were resolved by a third author (changsheng chen). data extraction two authors browsed the full text of eligible studies and recorded related data (di chen and chang-sheng chen). main outcome indicators were defined as follows:(1) at least three studies reported; (2) measurement or definition was similar. finally, we extracted selected data as following: name of the first author, year of publication, the period of study, study type, stone burden, sheath size, lithotripter, sample, and main outcome indicators. meta-analysis the meta-analysis was performed by review manager software (revman v.5.2, cochrane collaboration, oxauthor lithotripter stone burden staghorn calculi outcome indicators sas tas du et al. (20) hl 13.6 ± 5.2b 13.9 ± 4.7b yes sfr, pfr, apr zhu et al. (10) hl 15.23 ± 6.67b 14.87 ± 6.32b yes sfr, pfr, apr, tcr, ot huang et al. (11) hl 1.67 ± 0.58a 1.51 ± 0.63a no sfr, pfr, apr, ot xu et al. (12) hl 4.2 ± 1.0a 3.8 ± 1.4a yes sfr, pfr, apr, tcr, ot lai et al. (18) hl 6.76 ± 0.22b 6.29 ± 0.34b no sfr, pfr, apr, tcr, ot song et al. (19) hl 8.57 ± 2.25b 8.65 ± 2.03b no sfr, pfr, apr lai et al. (7) hl 2.34 ± 0.73a 2.02 ± 0.65a no sfr, pfr, tcr, ot table 2. details of stone burden and outcome indicators hl holmium laser, sas suction access sheath, tas traditional access sheath, a stone maximal diameter(cm), b stone surface area (cm2), sfr stone-free rate, pfr postoperative fever rate, apr auxiliary procedures rate, tcr total complication rate, ot operative time figure 2. forest plot of the operative time of the suctioning access sheath (sas) group and the traditional access sheath (tas) group sas versus tas in mini-percutaneous nephrolithotomy-chen et al. vol 19 no 1 january-february 2022 3 ford, uk). two categorical variables of main outcome indicators, sfr and complication, were calculated as the summary statistic using the pooled odds ratios with 95% confidence intervals (cis). due to continuous variables, mean differences (mds) with 95%ci were performed for statistical analysis of operative time. with p < .05 considered statistically significant, the z test was used to determine all the pooled effects. the pooled heterogeneity of statistics was assessed by the cochrane chi-squared test and inconsistency(i2). the random-effects model was adopted when the heterogeneity was significant (p < .05 or i2 > 50%). otherwise, a fixed-effects model was used for the pooled. subgroup analyses and sensitivity analysis was performed to assess the cause of significant heterogeneity. furthermore, a funnel plot was used to examine publication bias when eligible studies less than ten. results characteristics of studies according to the previous search strategy, 206 studies were identified. then, 113 duplicate studies were excluded. finally, a total of seven studies(7,10-12,18-20), with 1655 cases, were included in the meta-analysis (figure 1). the characteristics, level of evidence, and quality assessment of eligible studies are reported in table 1. five rcts and two rccs were 1b and 3b levels of evidence, respectively. simultaneously, the quality assessment of rccs was high (nos: 6 of 9 points). table2 exhibits lithotripter, stone burden, and main outcome indicators. only three eligible studies reporting staghorn calculi cases included. operative time five eligible studies(7,10-12,18), three of which were rcts and two were rccs, reported operative time (from the insertion of the ureteroscope to the placement of nephrostomy tube). with 490 cases in the sas group and the same cases in the tas group, the result indicated operative time in the sas group was shorter than that of the tas group (md=-17.3;95%ci: -23.09, -11.51; p < .00001; figure 2). the result had significant heterogeneity (p < .0001; i2 = 85%). stone burden was an important factor affecting operative time. duo to large size and complex morphology, staghorn stones require more time to remove. therefore, a subgroup analysis based on stone burden was performed. in the subgroup analysis, two studies were assigned in a staghorn calculi group and the other three studies in a non-staghorn calculi group. as shown in figure 2, the sas group of staghorn calculi was shorter than that of the tas group in operative time (md = -22.21;95%ci: -32.39, -12.03; p < .0001). the non-staghorn calculi subgroup had a similar result (md = -14.60;95%ci: -17.03, -12.16; p < .0001). test for subgroup differences was significant (p = .15; i2 = 50.8%). stone-free rate all eligible studies reported stone-free rate after one session, and the stone-free state was defined as no residual stones > 4 mm evaluated by no-contrast ct or kub. five studies informed that the evaluation was performed on postoperative one week. as presented in figure 3, the sas group was higher than the tas group in stone-free rate. (or=2.37;95%ci:1.56,3.61; p < .0001). however, a subgroup analysis was performed due to heterogeneity (p = .06; i2 = 51%). stone burden was a factor affecting stone-free rate, suggesting may affects heterogeneity in our meta-analysis. in subgroup analysis, three studies in the staghorn calculi group and four in the non-staghorn calculi group. with low heterogeneity (p = .39; i2 = 0%) in the staghorn calculi subgroup, the sas group had a higher stonefree rate (or=1.63;95%ci:1.25,2.13; p = .0003). the non-staghorn calculi subgroup also had a similar result (or=3.75;95%ci:2.00,7.06; p < .0001). test for subgroup differences was significant (p = .02; i2 = 82.3%). figure 3. forest plot of the stone-free rate of the suctioning access sheath (sas) group and the traditional access sheath (tas) group sas versus tas in mini-percutaneous nephrolithotomy-chen et al. review 4 vol 19 no 1 january-february 2022 138 total complications rate four eligible studies reported total complications rate(7,10,12,18). modified clavien classification was used to evaluate total complications in three studies. one study assessed total complication by the clavien grade classification. the total complication rate between the sas group and the tas group is presented in figure 4. compared with the tas group, the sas group had a lower total complication rate (or=0.50;95%ci:0.35,0.70; p < .0001). furthermore, the heterogeneity was low (p = .75; i2 = 0%). in subgroup analysis, two studies in the staghorn calculi group and two in the non-staghorn calculi group. with low heterogeneity (p > .05; i2 > 50%) and subgroup differences ( p = .97; i2 = 0%), two subgroup results reported that the sas group had a lower total complication rate (p < .001). auxiliary procedures rate auxiliary procedures, such as shockwave lithotripsy, 2nd pcnl, and retrograde intrarenal stone surgery, were reported in six eligible studies(10-12,18-20). in the meta-analysis, the auxiliary procedures rate was significantly lower in the sas group than the tas group (or = 0.48;95%ci :0.36,0.64; p < .00001; fig.5). the result exhibited a low heterogeneity (p = .15; i2 = 39%). in figure 5. forest plot of the auxiliary procedures rate of the suctioning access sheath (sas) group and the traditional access sheath (tas) group figure 4. forest plot of the total complication rate of the suctioning access sheath (sas) group and the traditional access sheath (tas) group sas versus tas in mini-percutaneous nephrolithotomy-chen et al. vol 19 no 1 january-february 2022 5 subgroup analysis, three studies in the staghorn calculi group and three in the non-staghorn calculi group. with low heterogeneity (p > .05; i2 < 50%) and significant subgroup differences ( p = .03; i2=79%), two subgroup results reported that the sas group had a lower auxiliary procedures rate (p < .001). postoperative fever rate all eligible studies reported postoperative fever. six studies defined postoperative fever as postoperative temperature > 37.5℃. as presented in figure 6, the postoperative fever rate was found to be significantly lower in the sas group than the tas group(or = 0.46; 95%ci:0.34,0.62 ;p < .00001).the result exhibited a low heterogeneity (p = .76; i2 = 0%). notably, subgroup analysis also exhibited similar results. sensitivity analysis and bias of publication to test the stability of the result, we performed a sensitivity analysis with an article-by-article culling method. after the research by zhu et al. was excluded in operative time, the i2 value changed from 85% to 0%. simultaneously, the i2 value of stone-free rate changed from 51% to 0% by huang et al. was excluded. while the result of operative time and stone-free rate was still stable. therefore, the analysis suggested that both studies were the major cause of the heterogeneity, and our result is convincing. however, the funnel plot, used to assess publication bias, was unbalanced and indicated some publication bias. discussion higher safety and effectiveness are still the goals for urologists to improve pcnl. although mpcnl has the advantage of being minimally invasive, the increased operative time and renal pelvic pressure > 30mmhg are high-risk postoperative infection factors(21,22). therefore, accelerated suctional speed of perfusate and fragments may be a rational approach to reduce complications. in 2011, song et al.’s rct firstly reported a patented sas, which can connect to a negative aspirator and keep a 16 f size(19). the result indicated that patients in the sas group had a higher stone-free rate than the tas group (stone-free rate: 90% vs. 73.3%; p < .05). however, the sas was not further investigated and used in clinical practice widely. recently, sas has gradually been concerned and used in clinics since other simplified or purchasable sas reported(23), such as clearpetra(7) and homemade sas(10). many scholars have conducted related clinical studies. in 2019, lai et al. performed a feasibility study that reported the clearpetra with the function of suction and store fragments(18). next year, xu et al. conducted an rct that included staghorn stones to assess the safety and effectiveness of clearpetra(12). the result suggested that compared with tas, clearpetra can significantly improve renal pelvic pressure, stone-free rate, and complications in mpcnl. similarly, zhu et al. reported a simplified and homemade sas in a case-matched comparative study, which had a lower operative time and lower complication rate(10). however, to date, the sas has not been evaluated by a systematic review or meta-analysis. stone-free rate and operative time are valid indicators to assess the effectiveness of pcnl. because of the high recurrence rate in fragments > 4mm(24), fragments < 4mm are regarded as clinically insignificant residual fragments (cirfs) and the symbol of stone-free(25). however, the removal of renal stone fragments still remains a tricky problem. clinically, graspers or baskets were commonly used to remove fragments, but repetitive mechanical operation will cause mucosa damage and is time consuming. in order to improve fragments removal, several modalities have been proposed. panah et al. reported a technique to flush out renal stone fragments by refluxed infusion(26). subsequently, kati figure 6. forest plot of the postoperative fever rate of the suctioning access sheath (sas) group and the traditional access sheath (tas) group sas versus tas in mini-percutaneous nephrolithotomy-chen et al. review 6 vol 19 no 1 january-february 2022 138 et al. performed a comparative study between aspiration method and irrigation method(27). they found that stonefree rate was higher in aspiration method, containing the advantage of high efficiency and convenience. in our study, the stone-free rate and operative time were better in the sas group. the result may relate with the characteristic of sas. with the advantage of continuous negative pressure suction, sas can gather around fragments and then suck out, avoiding escape to other renal calyces. due to the gravity, the lower pole calyx is a common and tricky position for deposited fragments. sas, with continuous suction, may improve the treatment of fragments deposited in the lower pole calyx. du et al. performed a multicenter rct and reported a similar opinion that sas could immobilize stone and limit the movement of fragments, causing a higher stonefree rate and less operative time(20). furthermore, sas may reduce the necessity of powder fragments. several studies revealed that fragments < 5mm could be sucked out(19). lai et al. reported that fragments with a maximum diameter of 6.3mm can be aspirate by a 20f sas, which decreases operative time in shattering stone(7). moreover, when the holmium laser smashes stone, sas can accelerate perfusate mobile speed and keep a clear visual field, which is an important cause of operative time shorted. although our result had significant heterogeneity, subgroup analysis and sensitivity analysis were performed and found the cause of heterogeneity. after reducing the heterogeneity, our result still indicated that the sas group had a higher stone-free rate and less operative time than the tas group. when evaluating the safety of pcnl, the postoperative complication rate is a credible indicator. currently, the modified clavien-dindo system is a rational and validated complication classification system widely used to assess urology surgery complications(28). postoperative fever is a grade i complication in the modified clavien-dindo system. although only four eligible studies reported total complications assessed by the clavien-dindo system, all seven included studies reported postoperative fever risk. the present result suggested that the sas group showed much less total complication rate than the tas group, especially in postoperative fever and auxiliary procedures. these results may be the following causes: (1) a lower interoperative renal pelvis pressure in the sas group. high renal pelvis pressure contributes to absorbed bacterial endotoxin and damages the collecting system, causing high operative fever and even urinary tract infection. zhong et al. informed that high rpp (> 30mmhg) and accumulated time of high rpp (> 50 s) are risk factors of postoperative fever(29). xu et al.’s rct assessed the renal pelvis pressure of different puncture poles and period reported that sas can significantly decrease renal pelvis pressure and pressure-related complications(12). several studies reported operative time is a dependent risk factor of postoperative fever or urosepsis(22,29). with a continuous negative pressure state, sas accelerated the speed of fragments removal, decreased operative time. additionally, because the heterogeneity of total complication rate, postoperative fever rate, and auxiliary procedures rate is low, we achieved a convincing result that the sas can improve complications compared with tas. our study also had some limitations:(1) even if we had found the cause of heterogeneity in our result, the definition of some outcomes among included studies was not completely consistent or clear, causing the increase of heterogeneity.(2) although two rccs included in the study were of high quality, more related rcts are needed to be included.(3) because all included studies were independent studies and came from the same country, included high-quality rct from different countries may improve credibility further.(4) all included studies in our research used holmium laser lithotripsy. different lithotripsy techniques may impact the effectiveness and safety of pcnl due to crushing mechanisms differences(30), and thus our conclusions may not apply to other types of lithotripsy. conclusions above all, our study results found that compared with the tas group, patients in the sas group had higher stone-free rate, less operative time, lower total complication rate, lower postoperative fever rate, and lower auxiliary procedure rate. therefore, sas is a safe and effective method in mpcnl. competing interests the authors declare that they have no competing interests references 1. wilkinson h. clinical investigation and management of patients with renal stones. ann clin biochem. 2001;38:180-7. 2. viljoen a, chaudhry r, bycroft j. renal stones. ann clin biochem. 2019;56:15-27. 3. yang yh, wen yc, chen kc, chen c. ultrasound-guided versus fluoroscopy-guided percutaneous nephrolithotomy: a systematic review and meta-analysis. world j urol. 2019;37:777-88. 4. zhu w, liu y, liu l, et al. minimally invasive versus standard percutaneous nephrolithotomy: a meta-analysis. urolithiasis. 2015;43:563-70. 5. wu c, hua lx, zhang jz, zhou xr, zhong w, ni hd. comparison of renal pelvic pressure and postoperative fever incidence between standardand mini-tract percutaneous nephrolithotomy. kaohsiung j med sci. 2017;33:36-43. 6. feng d, zeng x, han p, wei x. comparison of intrarenal pelvic pressure and postoperative fever between standardand mini-tract percutaneous nephrolithotomy: a systematic review and meta-analysis of randomized controlled trials. transl androl urol. 2020;9:1159-66. 7. lai d, xu w, chen m, et al. minimally invasive percutaneous nephrolithotomy with a novel vacuum-assisted access sheath for obstructive calculous pyonephrosis. a randomized study. urol j. 2020;17:474-9. 8. nottingham cu, large t, cobb k, et al. initial clinical experience with swiss lithoclast trilogy during percutaneous nephrolithotomy. j endourol. 2020;34:151-5. 9. york ne, borofsky ms, chew bh, et al. randomized controlled trial comparing three different modalities of lithotrites for intracorporeal lithotripsy in percutaneous sas versus tas in mini-percutaneous nephrolithotomy-chen et al. vol 19 no 1 january-february 2022 7 nephrolithotomy. j endourol. 2017;31:114551. 10. zhu z, cui y, zeng h, et al. suctioning versus traditional minimally invasive percutaneous nephrolithotomy to treat renal staghorn calculi: a case-matched comparative study. int j surg. 2019;72:85-90. 11. huang j, song l, xie d, et al. a randomized study of minimally invasive percutaneous nephrolithotomy (mpcnl) with the aid of a patented suctioning sheath in the treatment of renal calculus complicated by pyonephrosis by one surgery. bmc urol. 2016;16:71. 12. xu g, liang j, he y, et al. comparison of two different minimally invasive percutaneous nephrostomy sheaths for the treatment of staghorn stones. bju int. 2020;125:898-904. 13. harris jd, quatman ce, manring mm, siston ra, flanigan dc. how to write a systematic review. am j sports med. 2014;42:2761-8. 14. liberati a, altman dg, tetzlaff j, et al. the prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. bmj. 2009;339:b2700. 15. kaefer m, castagnetti m, herbst k, et al. evidence-based medicine iii: level of evidence. j pediatr urol. 2019;15:407-8. 16. norris jm, simpson bs, ball r, et al. a modified newcastle-ottawa scale for assessment of study quality in genetic urological research. eur urol. 2020. 17. higgins jp, altman dg, gøtzsche pc, et al. the cochrane collaboration's tool for assessing risk of bias in randomised trials. bmj. 2011;343:d5928. 18. lai d, chen m, sheng m, et al. use of a novel vacuum-assisted access sheath in minimally invasive percutaneous nephrolithotomy: a feasibility study. j endourol. 2020;34:33944. 19. song l, chen z, liu t, et al. the application of a patented system to minimally invasive percutaneous nephrolithotomy. j endourol. 2011;25:1281-6. 20. du c, song l, wu x, et al. suctioning minimally invasive percutaneous nephrolithotomy with a patented system is effective to treat renal staghorn calculi: a prospective multicenter study. urol int. 2018;101:143-9. 21. omar m, noble m, sivalingam s, et al. systemic inflammatory response syndrome after percutaneous nephrolithotomy: a randomized single-blind clinical trial evaluating the impact of irrigation pressure. j urol. 2016;196:109-14. 22. zhu l, jiang r, pei l, li x, kong x, wang x. risk factors for the fever after percutaneous nephrolithotomy: a retrospective analysis. transl androl urol. 2020;9:1262-9. 23. gökce m, karaburun mc, babayiğit m, et al. effect of active aspiration and sheath location on intrapelvic pressure during miniaturized percutaneous nephrolithotomy. urology. 2021. 24. chew bh, brotherhood hl, sur rl, et al. natural history, complications and reintervention rates of asymptomatic residual stone fragments after ureteroscopy: a report from the edge research consortium. j urol. 2016;195:982-6. 25. türk c, petřík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 26. panah a, masood j, zaman f, papatsoris ag, el-husseiny t, buchholz n. a technique to flush out renal stone fragments during percutaneous nephrolithotomy. j endourol. 2009;23:5-6. 27. kati b, pelit es, yagmur i, akin y, ciftci h, yeni e. which way is best for stone fragments and dust extraction during percutaneous nephrolithotomy. urolithiasis. 2018;46:297302. 28. singh ak, shukla pk, khan sw, rathee vs, dwivedi us, trivedi s. using the modified clavien grading system to classify complications of percutaneous nephrolithotomy. curr urol. 2018;11:79-84. 29. zhong w, zeng g, wu k, li x, chen w, yang h. does a smaller tract in percutaneous nephrolithotomy contribute to high renal pelvic pressure and postoperative fever? j endourol. 2008;22:2147-51. 30. radfar mh, basiri a, nouralizadeh a, et al. comparing the efficacy and safety of ultrasonic versus pneumatic lithotripsy in percutaneous nephrolithotomy: a randomized clinical trial. eur urol focus. 2017;3:82-8. sas versus tas in mini-percutaneous nephrolithotomy-chen et al. review 8 the role of pentraxin-3, fetuin-a and sirtuin-7 in the diagnosis of prostate cancer özer güzel1* ,arzu kösem2,yılmaz aslan1,ahmet asfuroglu1,melih balcı1,cagdas senel1,altuğ tuncel1 purpose: prostate cancer is the most commonly diagnosed type of cancer and one of the leading causes of cancer-related death in men. numerous efforts have been made to improve existing diagnostic methods and develop a new biomarker to identify patients with prostate cancer. in line with current literature, we preferred new serum-based biochemical markers as pentraxin-3, fetuin-a and sirtuin-7 in the present study. materials and methods: a total of 174 patients aged 42-76 years were included in the study. patients with prostate cancer (n = 38) were enrolled as group 1 and patients with benign prostatic hyperplasia (n = 136) as group 2. the serum levels of pentraxin-3, fetuin-a and sirtuin-7 levels were compared between the groups. results: the mean age of the patients was 61.9 ± 7.6 years (p = .001). the mean serum prostate specific antigen levels 32.0 ± 59.6 (2.6-336) ng/ml and 10.0 ± 11.3 (2.5-77.4) ng/ml in group 1 and 2, respectively (p = .029). the mean serum levels of pentraxin-3 and fetuin-ain group 1 were statistically significantlydifferent from group 2(3.3 ± 4.4 ng/ml vs 1.8 ± 2.4 ng/ml, p = .002 and 466.8 ± 11.0 µg/ml vs 513.3 ± 11.0 µg/ml, p = .041,respectively). there was no significant difference between group 1 and 2 according to serum levels of sirtuin-7 (12.7 ± 8.2 ng/ml vs 12.7 ± 12.4 ng/ml respectively, p = .145). conclusion: pentraxin-3, fetuin-a and sirtuin-7 may be effective in the diagnosis of prostate cancer in light of the current literature. in this study, it was found that pentraxin-3 and fetuin-a were significantly different in the diagnosis of prostate cancer. larger-scale prospective studies are needed to determine the importance of pentraxin-3 and fetuin-a in the diagnosis of prostate cancer. keywords: pentraxin-3; fetuin-a; sirtuin-7; prostate cancer; biochemical marker introduction prostate cancer (pca) is among the most commonly seen cancers in men and comprises 15% of newly-diagnosed cases.(1) in spite of developments in diagnosis and treatment, many people die due to this disease. intense research continues around the world to prevent this disease. while some risk factors like age and family history have been defined, the definite cause is still unknown.(2) however, people with certain behavior or living in certain regions are known to have increased pca incidence. additionally, when people living in regions with low risk of pca move to riskier regions, the pca development risk of these people displays similarities to people living in this region.(3,4) when all this information is assessed together, it brings to mind that there are some preventable risk factors contributing to development of pca. the most notable among these risk factors is sexual behavior. sexual behavior without control, especially, is an important public health problem around the world. it is considered to be a risk factor for development of pca. studies associated pca with many sexual behaviors like age of first sexual relations, number of partners 1university of health sciences, ankara numune research and training hospital, department of urology, ankara, turkey. 2university of health sciences, ankara numune research and training hospital, department of medical biochemistry, ankara, turkey. *correspondence: university of health sciences, ankara numune research and training hospital, department of urology, 06100, ankara, turkey tel : +90 5324301496. fax: +90 312 310 34 60. e-mail: drozerguzel@gmail.com. received december 2020 & accepted september 2021 and ejaculation frequency. however, the underlying cause has not been fully revealed. among the causes given most focus is the accumulation of a variety of toxic matter in prostate tissue or the inflammatory process caused by microbial agents.(5,6) however, it is difficult to reach a definite conclusion from studies on this topic because there is no standardization of topics like patient selection, information gathering method and time. most were performed retrospectively. to our knowledge, to date there is no study comparing the sexual behavior and inflammatory parameters of prostate cancer patients with healthy people. this study was prospectively planned to resolve this deficiency about the topic. the aim of the study was to compare sexual behavior and inflammatory markers measured in serum among people with prostate cancer diagnosis with healthy peers. additionally, to identify whether there are precautions which can be recommended to protect healthy people from cancer. materials and methods study population from april 2013 to april 2020, information from male urological oncology urology journal/vol 19 no. 3/ may-june 2022/ pp. 196-201. [doi: 10.22037/uj.v18i.6626 ] vol 19 no 3 may-june 2022 100 patients aged over 40 years attending hospital was recorded prospectively by a single expert. all patient data, diagnosis, and follow-up duration were prospectively recorded by a doctor specialized in the topic. patients were persuaded to provide accurate information during their first interview. they were told that this was important for treatment. if they did not remember the answer to questions or did not want to answer, it was not recorded in the study. patients had sexual behavior like age of first sexual relations, number of sexual partners and monthly ejaculation numbers and laboratory values recorded in detail. patients gave permission for information to be used in research. blood samples were taken in the morning after overnight fasting. blood samples of patients were taken after underlying pathologies like uti were excluded during the first visit. patients were assessed for prostate cancer with psa and digital rectal examination (dre). causes such as constipation, urinary tract infection (uti) and urethral interventions which may cause benign psa elevation were excluded. high values were checked 2 weeks later. psa value > 4 ng/ml or suspect dre findings were accepted as biopsy criteria and the study included patients positive for pca as a result of prostate biopsy. patients attending check-ups with no complaints with psa value ≤ 3 ng/ml and without suspect dre were included in the control group. the control group was randomly selected from among people with similar basic features to the control group. the study was performed in a single tertiary hospital serving a region with population of nearly 800,000, very homogeneous structure and receiving very little immigration. the two groups were similar in terms of risk factors like nutrition, genetic and environmental factors. procedures patients were divided into 2 groups of the control group and prostate cancer (pca) group. the study recorded a total of 654 patients abiding by the criteria including 263 pca patients and 392 control patients. parameters like age, comorbid diseases, sexual behavior (like age of marriage, number of partners, mean ejaculation frequency), psa value, sedimentation, c-reactive protein (crp), neutrophil lymphocyte ratio (nlr, neutrophil count/lymphocyte count), and systemic inflammatory index (sii, neutrophil count x platelet count/lymphocyte count) were compared between the groups. inclusion and exclusion criteria the study included circumcised male patients over the age of 40 years, who granted consent, could remember sexual behavior and did not avoid talking about these topics. patients who could not remember or did not want to talk about sexual behavior, who spoke inconsistently during examinations, with cognitive disorders, using psychiatric medication or with psychiatric disease, with previous pca diagnosis, uti or history of pelvic radiotherapy and, for the control group patients with elevated psa values, were excluded from the study. the study received permission from the local ethics committee (number: 025/2020). statistical analysis data obtained in the research was analyzed with the statistical package for the social sciences (spss) version 21 program. descriptive statistics are number and percentage for categoric variables and mean, standard deviation, median, minimum and maximum values with interquartile range (iqr) for numerical variables. normal distribution of numerical variables was assessed with the kolmogorov-smirnov test. for comparison of numerical variables, the student t test was used for variables abiding by parametric conditions, while the mann whitney u test was used for variables not abiding by parametric conditions. analysis of categoric variables used the chi-square test. in situations with type 1 error level below 5%, p < .05 was accepted as statistically significant. results the study used data collected from a total of 654 patients, with 262 (40.1%) in the pca and 392 (59.9%) in the control group. mean age was identified as 61.81 ± 8.49 (41-85) years in the control group and 67.65 ± 9.08 (43-97) years in the pca group (p < .001). the comorbid diseases and habits of groups are given in table 1. laboratory parameters (median ± iqr) were compared table 1. prostate volume and serum biochemistry analysis of both groups parameters group 1 (n=38) (median±sd)(range) group 2 (n=136) (median±sd) (range) p age (year) 65.5 ± 8.3 (43-76) 62.0 ± 8.4 (42-75) 0.101 prostat volume (cm3) 51.5 ± 28.7 (23-140) 55.0 ± 35.8 (16-241) 0.288 total psa (ng/ml) 9.2 ± 59.6 (2.6-336) 6.5 ± 11.3 (2.5-77.4) 0.029* psa density (ng/ml2) 0.24 ± 0.96 (0.02-4.80) 0.12 ± 0.24 (0.03-1.77) 0.006* serum albumin (g/dl) 4.5 ± 0.3 (3.6-4.8) 4.3 ± 0.3 (3.4-4.8) 0.077 serum crp (mg/l) 1.1 ± 0.7 (0.1-2.4) 1.2 ± 0.7 (0.1-2.5) 0.645 *:statistically significant difference parameters group 1 (n=38) (median ± sd) (range) group 2 (n=136) (median ± sd) (range) p* serum pentraxin-3 levels (ng/ml) 1.6 ± 4.5 (0.2–17.6) 1.1 ± 2.4 (0.1–15.2) 0.002** serum fetuin-a levels (µg/ml) 469.9 ± 110.5 (250.0–657.1) 523.9 ± 119.3 (290.6–913.6) 0.041** serum sirtuin-7 levels (ng/ml) 10.7 ± 12.4 (2.9– 91.4) 9.3 ± 8.2 (4.1– 48.7) 0.145 table 2. serum ptx3, fetua, sirt7 levels compared between groups with mann whitney u test * mann-whitney u test **:statistically significant difference efficacy of new biomarkers in prostate cancer diagnosis -guzel et al. vol 19 no 3 may-june 2022 197 in the control and pca patients. median psa values were 1.03 ± 1.15 (0.10 3) ng/ml in the control group and 8.29 ± 13.28 (4.10 1381) ng/ml in the pca group (p = .001). testosterone levels were 5.87 ± 2.97 (1.3213.90) ng/dl and 5.34 ± 2.7 (2.31-16.14) ng/dl, respectively (p = .024). when groups were compared in terms of crp, fibrinogen, nlr and sii score, inflammatory markers were identified to increase in the cancer group. this increase was statistically significant (table 2). the groups were compared in terms of marital age, lifelong number of sexual partners and monthly ejaculation frequency. as data were non-parametric, results are given as median (mean rank) ± iqr. when groups were compared in terms of sexual behavior, median age of marriage was 18 (261.63) ± 6 years in the control group and 20 (323.23) ± 5 years in the pca group (p = .001). the lifelong median number of partners was 1 (299.87) ± 1 in the control group and 1 (367.75) ± 9 in the pca group (p = .001) and this difference was significant. additionally, the lifelong median ejaculation frequency (monthly) was determined as 12 (382.53) ± 5 for controls and 10 (230.02) ± 4 for the pca group (p = .001) (table 3). discussion though some risk factors have been defined like aging, family history and genetic features, the definite cause is still unknown. like many cancers, it is considered that multifactorial risk factors are effective. the aim of this study was to investigate whether there was a correlation between sexual behavior, inflammatory parameters in serum and pca. in this study, the most important finding is that there was a correlation between pca with sexual behavior and inflammatory parameters compared to the control group. it is known that the incidence of pca increases in people living in certain regions or with certain forms of behavior. a study in our neighboring country of iran reported the 3-year cancer frequency per 100,000 people was 11.2%.(7) studies on this topic have reported that asian males have 10-15 times increased pca risk compared to males living in western countries, while african-american males have 1.6 times increased pca risk compared to caucasians.(8) the difference in this disease between geographies is implied to be possibly due to some risky personal behaviors related to this disease. there is increasing evidence showing sexual behavior, a significant health problem around the world, is an important risk factor for pca development. this topic + attracted attention to sexual behavior like partner numbers, especially, but also age of first sexual relations and ejaculation frequency.(9) efficacy of new biomarkers in prostate cancer diagnosis -guzel et al. parameters* isup isup isup isup isup p** grade group1 (n=18) grade group 2 (n=4) grade group3 (n=4) grade group4 (n=6) grade group5(n=6) serumpentraxin-3 1.4 ± 5.3 (0.2–17.5) 1.6 ± 0.9 (0.9–3.1) 2.9 ± 2.2 (1.6–6.6) 1.1 ± 4.7 (0.9–12.9) 1.6 ± 1.9 (1.0–11.4) 0.281 levels (ng/ml) serum fetuin-a 448.9 ± 107.4 491.6 ± 147.0 539.4 ± 108.2 531.1 ± 98.6 371.2 ± 135.5 0.787 levels (µg/ml) (250.0–621.9) (345.0– 620.4) (373.7–613.2) (331.3–570.7) (322.2–657.1) serum sirtuin-7 11.0 ± 5.2(4.1–25.5) 11.8 ± 4.9(9.5–19.9) 10.1 ± 4.8(4.4–14.5) 8.0 ± 4.9(5.3–16.8) 15.9 ± 16.2(7.9–48.7) 0.614 levels (ng/ml) * values are expressed as median ± sd (range) **kruskal-wallis test table 3. ptx3, fetua, sirt7 levels in group 1 patients according to isup grade urological oncology 198 figure 1. roc analysis compared serum ptx3 levels between group 1 and group 2 (p = 0.002). (aucserumpentraxin-3=0.667, 95%ci: 0.574-0.760) figure 2. roc analysis compared serum fetua levels between group 1 and group 2(p = 0.041). (aucserumfetuin-a=0.608, 95%ci: 0.504-0.713, or:2.190) vol 19 no 3 may-june 2022 100 some studies have investigated the correlation between ejaculation frequency and pca. rider et al. reported that in the absence of risky sexual behavior, increased ejaculation frequency has protective effects against pca. (10) another study by jian et al. reported that there was a significant correlation between sexual behavior like reduced sexual partner numbers, advanced age for first sexual relations and moderate levels of ejaculation frequency with reduced pca risk.(11) some authors reported the protective ejaculation frequency is 1-4 times per week.(12) in our study, the cancer group was identified to have reduced ejaculation frequency compared to the control group. the protective number is not known in our study. in spite of broad investigation of the literature about ejaculation, the protective effect is not fully understood. according to the most accepted view, increased ejaculation frequency is effective by preventing accumulation of some carcinogenic material within prostate fluid.(13,14) we think ejaculation may be effective through a different route. like the mechanical cleaning effect of urine, frequent ejaculation may prevent access to or colonization of prostatic tissue by a variety of microorganisms. additionally, sexual activity means a certain level of physical activity, mental calmness and better communication with partners. in conclusion, continuing active sexual life may have beneficial contributions by making the person feel good about themselves, and have positive effect on the vascular system by better perfusion and oxygenation of tissues leading to benefits for immune system cells. this is very important for the battle with cancer cells. we think there is a need for more comprehensive studies to say anything definite about this topic. increased partner numbers is an important public health problem increasing the risk of many sexually-transmitted diseases. many studies have proposed that sexual activities without control and with many people is an important risk factor for pca development.(15) a meta-analysis by jian et al. investigated the correlation between partner numbers and pca. the authors reported that each increase in partner numbers by 10 increased cancer risk by 1.1 times.(11) these results were supported by other researchers. in our study, the partner number was significantly increased in the pca group compared to the control group. the reason for the correlation between partner numbers and pca has not been fully explained. one of the views proposed about this topic associates increased sexual activity with high androgen levels and proposed that high hormone levels may trigger cancer development. (16) however, many studies have shown no relation between pca and androgens. in our study, contrarily, the cancer group had reduced androgen levels compared to the control group. this is not surprising to us; we know the androgen levels reduce in elderly patients. another view which is a focus in the correlation between partner numbers and cancer is the inflammatory process caused by sexually transmitted infections (sti).(17-19) independent of vector, there are studies in the literature reporting sti experienced in any period of life increases cancer risk by 50%.(20,21) we know the correlation between cancer and the inflammatory process from many cancers in the gastrointestinal system, thyroid, pancreas, bladder and pleura. (22,23) chronic inflammation results in collection of many immune system cells and increases in a variety of mediators and cytokines. increasing reactive oxygen species (ros) in this process affect the physiological conditions required by normal cells. if this toxic material is not removed from tissues, lipid peroxidation and dna injury may develop.(24,25) in prostate tissue, chronic infection beginning for a variety of reasons may begin the cancer development process with the same mechanism. (26,27) a study by taghavi et al. supports this view. the authors investigated the correlation between polyomavirus hominis 1 (bk virus, bkv), known to cause latent infection, with prostate specimens. the results of the study reported the bkv infection was more prevalent compared to bph in pca specimens. in our study, inflammatory parameters were investigated differently to many studies. inflammatory parameters examined in serum from pca patients were identified to be increased compared to the control group. according to our knowledge, this study is the first to compare prostate cancer patients in terms of partner numbers and inflammatory parameters to date. in spite of not knowing std history, we think agents transmitted through the sexual route with increased partner numbers may have caused a chronic inflammatory process triggering cancer development in patients included in the study. we do not fully know why these patients married at younger ages and how partner numbers and ejaculation frequency changes in which periods of life. sexual relations with many partners at younger ages may cause marriage at later ages and less sexual relations after marriage. the results of our study identified that the number of partners was increased and the ejaculation frequency was reduced in the pca group compared to the control group. additionally, compared to the control group, the pca group had increased inflammatory parameters like crp, sedimentation, fibrinogen, nlr in serum and sii. people included in the study were statistically similar in terms of geography, genetics and nutritional characteristics, which is very important in terms of homogenization. this allows the opportunity to compare people with similar features (control and pca group) in terms of sexual behavior and inflammatory parameters. these results show that in addition to unchangeable risk factors like aging, genetics and family history, there are risk factors which are preventable with simple precautions. when the literature and our study results are interpreted together, sexual behavior appears to be a changeable risk factor for prevention of cancer. there are some limitations to our study. the first is that information related to sexual life was based on patient statements. it is not possible to know if there were situations involving forgetting or purposely providing misleading information. however, information was not obtained from patients with any survey or by telephone. all diagnosis and treatment processes were completed by the same person. this situation is important in terms of receiving accurate information from patients and for standardization of the study. it is not known if the group used as control in the study included undiagnosed cancer cases (due to silent progression of many cancer cases, lack of reliable psa value). additionally, in the cancer group, there was no evidence for diseases related to stis available, like serologic tests. however, this situation is valid for the control group. efficacy of new biomarkers in prostate cancer diagnosis -guzel et al. vol 19 no 3 may-june 2022 199 conclusions in conclusion, this prospective study obtained important results. it was identified that the partner number was increased and ejaculation frequency reduced in the pca group compared to the control group and that these patients married at later ages. additionally, an increase in systemic inflammatory markers was observed in the cancer group. these results show the presence of increased inflammatory processes in the pca group with increased partner numbers. these results, when assessed with the literature, lead to consideration that increased partner numbers and reduced ejaculation frequency may begin or ease the inflammatory background for cancer development. these results indicate there are some precautions that may be taken for this disease. providing necessary sexual information from a young age, taking protective precautions against sexually transmitted diseases and increasing the frequency of ejaculation were identified as changeable behaviors for pca. conflict of interest the authors report no conflict of interest. references 1. feng s, qian x, li h, zhang x. combinations of elevated tissue mirna-17-92 cluster expression and serum prostate-specific antigen as potential diagnostic biomarkers for prostate cancer. oncol lett. 2017; 14: 6943-9. 2. center mm, jemal a, lortet-tieulent j, et al. international variation in prostate cancer incidence and mortality rates. eur urol. 2012; 61: 1079-92. 3. taghavi a, mohammadi-torbati p, kashi ah, rezaee h, vaezjalali m. polyomavirus hominis 1(bk virus) infection in prostatic tissues: cancer versus hyperplasia. urol j. 2015; 12: 2240-4. 4. basiri a, eshrati b, zarehoroki a, et al. incidence, gleason score and ethnicity pattern of prostate cancer in the multiethnicity country of iran during 2008-2010. urol j. 2020; 17: 602-6. 5. matthes kl, limam m, dehler s, korol d, rohrmann s. primary treatment choice over time and relative survival of prostate cancer patients: influence of age, grade, and stage. oncol res treat. 2017; 40: 484-9. 6. fredsoe j, koetsenruyter j, vedsted p, et al. the effect of assessing genetic risk of prostate cancer on the use of psa tests in primary care: a cluster randomized controlled trial. plos med. 2020;17: e1003033. 7. stallone g, cormio l, netti gs, et al. pentraxin 3: a novel biomarker for predicting progression from prostatic inflammation to prostate cancer. cancer res. 2014; 74: 4230-8. 8. garlanda c, bottazzi b, bastone a, mantovani a. pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. annu rev immunol. 2005; 23: 337-66. 9. stallone g, netti gs, cormio l, et al. modulation of complement activation by pentraxin-3 in prostate cancer. sci rep. 2020; 10: 18400. 10. ochieng j, nangami g, sakwe a, et al. impact of fetuin-a (ahsg) on tumor progression and type 2 diabetes. int j mol sci. 2018;19: 2211. 11. dabrowska am, tarach js, wojtysiakduma b, duma d. fetuin-a (ahsg) and its usefulness in clinical practice. review of the literature. biomed pap med fac univ palacky olomouc czech repub. 2015; 159 : 352-9. 12. he l, shi x, liu z, et al. roles of eaat1, dhfr, and fetuin-a in the pathogenesis, progression and prognosis of chondrosarcoma. onco targets ther. 2019; 12: 8411-20. 13. ding m, jiang cy, zhang y, zhao j, han bm, xia sj. sirt7 depletion inhibits cell proliferation and androgen-induced autophagy by suppressing the ar signaling in prostate cancer. j exp clin cancer res. 2020; 39: 28. 14. romain haider fm, lisa kaminski, stephan clavel, et al. sirtuin 7: a new marker of aggressiveness in prostate cancer. oncotarget. 2017; 8: 77309-16. 15. becerra mf, atluri vs, bhattu as, punnen s. serum and urine biomarkers for detecting clinically significant prostate cancer. urol oncol. 2020; s1078-1439(20)30059-4. 16. kohaar i, petrovics g, srivastava s. a rich array of prostate cancer molecular biomarkers: opportunities and challenges. int j mol sci. 2019; 20: 1813. 17. koseoglu e, tuncel a, balci m, et al. netrin 1 and alpha-methyl acylcoenzim-a racemase in diagnosis of prostate cancer. colomb med (cali). 2018; 49 :164-8. 18. hendriks rj, van oort im, schalken ja. blood-based and urinary prostate cancer biomarkers: a review and comparison of novel biomarkers for detection and treatment decisions. prostate cancer prostatic dis. 2017; 20: 12-9. 19. giacomini a, ghedini gc, presta m, ronca r. long pentraxin 3: a novel multifaceted player in cancer. biochim biophys acta rev cancer. 2018; 1869: 53-63. 20. matarazzo s, melocchi l, rezzola s, et al. long pentraxin-3 follows and modulates bladder cancer progression. cancers (basel). 2019; 11: 1277. 21. ronca r, alessi p, coltrini d, et al. long pentraxin-3 as an epithelial-stromal fibroblast growth factor-targeting inhibitor in prostate cancer. j pathol. 2013; 230: 228-38. 22. scimeca m, bonfiglio r, urbano n, et al. programmed death ligand 1 expression in prostate cancer cells is associated with deep changes of the tumor inflammatory infiltrate composition. urol oncol. 2019; 37: 297 e19 e31. 23. nangami gn, sakwe am, izban mg, et al. fetuin-a (alpha 2hs glycoprotein) modulates growth, motility, invasion, and senescence in high-grade astrocytomas. cancer med. 2016; 5: 3532-43. 24. icer ma, yıldıran h. effects of fetuin-a with diverse functions and multiple mechanisms on effect of sexual behavior on prostate cancer-benli et al. urological oncology 200 vol 19 no 3 may-june 2022 100 human health. clinical biochemistry. 2020; 88: 1-10. 25. guillory b, sakwe am, saria m, et al. lack of fetuin-a (alpha2-hs-glycoprotein) reduces mammary tumor incidence and prolongs tumor latency via the transforming growth factorbeta signaling pathway in a mouse model of breast cancer. am j pathol. 2010; 177: 263544. 26. mintz pj, rietz ac, cardo-vila m, et al. discovery and horizontal follow-up of an autoantibody signature in human prostate cancer. proc natl acad sci u s a. 2015; 112: 2515-20. 27. zhan k, liu r, tong h, et al. fetuin b overexpression suppresses proliferation, migration, and invasion in prostate cancer by inhibiting the pi3k/akt signaling pathway. biomed pharmacother. 2020; 131: 110689. 28. haigis mc, sinclair da. mammalian sirtuins: biological insights and disease relevance. annu rev pathol. 2010; 5: 253-95. 29. kiran s, anwar t, kiran m, ramakrishna g. sirtuin 7 in cell proliferation, stress and disease: rise of the seventh sirtuin! cell signal. 2015; 27: 673-82. efficacy of new biomarkers in prostate cancer diagnosis -guzel et al. vol 19 no 3 may-june 2022 201 urology journal/vol 20 no. 4/ july-august 2023/ pp. 222-228. [doi: 10.22037/uj.v20i.7402] upfront androgen receptor-axis-targeted therapies in men with de novo high-volume metastatic hormone-sensitive prostate cancer natsuo kimura1,6*, yuki kaneko2, takahiko tetsuka3, akinori takei4, takato uchida5, hirokazu abe6, yoshiyasu amiya1, takayuki shima1, noriyuki suzuki1, satoru hayashi2, hiroomi nakatsu1 purpose: the extent of effectiveness of upfront androgen receptor-axis-targeted therapies (arat) versus total androgen blockade (tab) in improving prostate cancer-specific survival (css) and progression-free survival (pfs) in a real-world sample of japanese patients with high-volume mhspc remains unclear. we, therefore, investigated the efficacy and safety of upfront arat versus bicalutamide for de novo high-volume mhspc in japanese patients. material and methods: this was a multicenter retrospective study that analyzed css, clinical pfs, and adverse events (aes) in 170 patients with newly diagnosed high-volume mhspc. fifty-six patients were treated with upfront arat, and 114 of them were prescribed bicalutamide in addition to adt between january 2018 and march 2021. the primary and secondary endpoints were css and pfs, respectively. a 1:1 nearest neighbor propensity score matching (psm) with a caliper of 0.2 was performed to match the arat group to tab patients. results: during the follow-up for a median of 21.5 months, the median css was not reached and 37 months in the upfront arat and total androgen blockade (tab) groups, respectively (log-rank test: p = 0.006) by propensity score matching (psm). moreover, while the pfs of arat was unreached, the median pfs of tab was 9 months (log-rank test: p < 0.001). nine patients discontinued arat owing to grade ≥ 3 aes; one patient who was treated with tab had a grade 3 ae. conclusion: upfront arat significantly prolonged the css and pfs of patients with high-volume mhspc better than tab, although arat was associated with a higher rate of grade ≥ 3 aes. upfront arat can be more beneficial for patients with de novo high-volume mhspc than tab. keywords: upfront arat; bicalutamide; metastatic; hormone-sensitive; prostate cancer introduction prostate cancer has the highest incidence among male individuals in japan and globally. the number of patients with this cancer was 1.44 million in 2016 worldwide and 78,400 in japan in 2018.(1,2) although the incidence of prostate cancer is relatively lower in the middle east and asia compared to europe and the united states, prostate cancer caused 12,250 deaths in japanese male individuals, and it ranks sixth among all male cancers in 2018.(3) total androgen blockade (tab) therapy, also known as combined androgen blockade (cab) therapy, mainly androgen deprivation therapy (adt) plus non-steroidal antiandrogens, such as bicalutamide, has been frequently used for the initial care of patients with metastatic hormone-sensitive prostate cancer (mhspc) in japan. 1department of urology, asahi general hospital 1326 i, asahi city 289-2511, chiba prefecture, japan. 2department of urology, gyoda general hospital 376 mochida, gyoda city 361-0056, saitama prefecture, japan. 3department of urology, shizuoka saiseikai general hospital.1-1-1 oshika suruga ward, shizuoka city 422-8527, shizuoka prefecture, japan. 4department of urology, funabashi municipal medical center 1-21-1 kanasugi, funabashi city 273-8588, chiba prefecture, japan. 5department of urology, shizuoka city shimizu hospital1231 miyakami shimizu ward, shizuoka city 424-8636, shizuoka prefecture, japan. 6department of urology, kameda general hospital 929 higashi-cho, kamogawa city 296-8602, chiba prefecture, japan. *correspondence: department of urology, asahi general hospital 1326 i, asahi city 289-2511, chiba prefecture, japan tel: +81 80-5895-9707, fax: +81 479-63-8580, email: rusikamusic@gmail.com. received august 2022 & accepted march 2023 in recent years, docetaxel, abiraterone, enzalutamide, and apalutamide have been used in standard care for initial treatments for mhspc instead of tab or adt alone, owing to the results of the chaarted, latitude, enzamet/arches, and titan trials. (4–8) the latitude trial showed that abiraterone, a cyp17 inhibitor, with prednisone plus adt substantially favored overall survival (os) and radiographic progression-free survival (pfs) in newly diagnosed high-risk mhspc patients when compared with adt plus placebo treatment. high risk was defined as matching at least two of the following three criteria: gleason score of ≥ 8, three or more bone metastatic lesions, and visceral metastasis. by contrast, high volume was defined as the presence of visceral metastases or at least four bone lesions, with one or more lesions present beyond the vertebral bodies and pelvis, based on the urological oncology chaarted trial results.(9) one of the main differences between high-risk and high-volume criteria is that high-risk criteria require a gleason score. in this study, we adopted high-volume because some patients with mhspc needed immediate therapies skipping prostate biopsies; current rcts use high-volume criteria more commonly. the reports of the efficacy and safety of upfront androgen receptor-axis-targeted therapy (arat) in real-world japanese high-volume mhspc patients over the tab group were few and remain unclear.(10,11) upfront arat in men with mhspc-kimura et al. variablesa arat (n = 56) tab (n = 114) p-value median (range) age (years) 72 (52-85) 77 (58-96) < .001 median (range) initial psa (ng/ml) 286 (0.94-15,450) 473 (2.79-12,802) .027 median (range) pretreatment alp (iu/l) 408.5 (67-21,104) 584 (56-11,600) .419 median (range) pretreatment hb (iu/l) 13.3 (6.2-16.3) 12.1 (5.4-17.2) .020 median (range) pretreatment ldh (iu/l) 201 (125-503) 215 (106-864) .073 median (range) pretreatment bsi 3.77 (0-24) 3.35 (0-13.22) .297 median (range) pretreatment ecog ps 0 (0-3) 1 (0-3) .099 median (range) pretreatment cci 3 (1-6) 4 (1-7) .005 gleason score (n, %) 6 0 (0%) 1 (0.9%) .066 7 2 (3.6%) 1 (0.9%) 8 5 (8.9%) 28 (24.6%) 9 35 (62.5%) 25 (21.9%) 10 9 (16.1%) 16 (14.0%) missing data 5 (8.9%) 43 (37.7%) visceral metastasis (n, %) 18 (32.1%) 17 (14.9%) .009 nadir psa ≤ 0.2ng/ml in 3 months (n,%) 20 (35.7%) 14 (12.3%) < .001 table 1. patient demographics investigations were from multiple municipal or private hospitals in japan between january 2018 and march 2021. abbreviations: arat, androgen receptor-axis–targeted therapy; cci, charlson comorbidity index; psa, prostate-specific antigen; tab, total androgen blockade a continuous variables were compared by independent samples t-test figure 1. kaplan-meier estimates of cancer-specific survival in the arat and tab groups. arat includes abiratetone, enzalutamide, and apalutamide. the median css was not achieved and was 37 months in the arat and tab groups, respectively. there were two and 13 deaths in the arat and tab groups, respectively. after psm, the log-rank test was set at p = .006 abbreviations: arat, androgen receptor-axis-targeted therapy (including abiraterone, enzalutamide, and apalutamide); tab, total androgen blockade; css, cancer-specific survival; tab, total androgen blockade vol 20 no 4 july-august 2023 223 therefore, we aimed to determine the efficacy and safety of upfront arat versus tab in japanese patients with de novo high-volume mhspc. propensity score matching (psm) was addressed if biases exist between those two groups. materials and methods trial design this study retrospectively investigated the prostate cancer-specific survival (css) and pfs of patients with high-volume mhspc treated with upfront arat or tab in multiple municipal or private hospitals in japan. eligible patients were required to be at least 20 years old with newly diagnosed with high-volume mhspc with 3 months or less adt between january 2018 and march 2021. the definition of high-volume is the presence of visceral metastases or ≥ 4 bone lesions with ≥ 1 beyond the vertebral bodies and pelvis. the amount (%) of bone metastasis on bone scintigraphy is calculated as a bone scan index (bsi). patients with small cell prostate cancers were excluded. patients were also excluded if they received any previous chemotherapy, radiation therapy, or surgery for metastatic prostate cancer. the primary and secondary endpoints were css and pfs, respectively. the css in this study was defined as the duration from the initial treatment to death from prostate cancer. pfs was defined as the duration from the initial treatment to the diagnosis of castration-resistant prostate cancer (crpc). crpc diagnosis was made based on european association of urology guidelines for prostate cancer. the guideline defines crpc if one of the two criteria are met: (i) biochemical progression, which means that three consecutive increases in prostate-specific antigen (psa) levels at least one week apart, resulting in two 50% increases over nadir, and a psa level of >2 ng/ml, with a castrate serum testosterone level of less than 50 ng/dl or 1.7 nmol/l, or (ii) radiological progression, i.e., the appearance of two or more new bone lesions on bone scintigraphy or a soft tissue lesion according to the response evaluation criteria in solid tumors criteria.(12) this study also assessed whether css in both groups was affected by nadir psa, which achieved ≤ 0.2 ng/ml in 3 months since the start of initial treatment. the css in the study was defined as the duration from the initial treatment to death from prostate cancer. the ethics committee of all the facilities approved this study, which was conducted in compliance with the declaration of helsinki. the ethics committees waived individual written informed consent because of the retrospective nature of this study, and opt-out information was provided to patients on the website of asahi general hospital. variablesa arat (n = 36) tab (n = 36) p-value median (range) age (years) 73 (64-85) 71.5 (60-89) .498 median (range) initial psa (ng/ml) 359 (5.41-15,450) 324 (2.79-5,656) .928 median (range) pretreatment alp (iu/l) 463 (105-21,104) 372 (100-4,455) .692 median (range) pretreatment hb (iu/l) 13.2 (6.2-16.1) 13.0 (8.5-16.3) .848 median (range) pretreatment ldh (iu/l) 197 (125-503) 200 (106-605) .710 median (range) pretreatment bsi 5.35 (0-24) 1.98 (0-12.15) .126 median (range) pretreatment ecog ps 0 (0-3) 0 (0-3) .746 median (range) pretreatment cci 3 (2-6) 3 (2-5) .328 gleason score (n, %) 6 0 (0%) 0 (0%) .354 7 1 (2.8%) 1 (2.8%) 8 4 (11.1%) 12 (33.3%) 9 26 (72.2%) 15 (41.7%) 10 5 (13.9%) 8 (22.2%) visceral metastasis (n, %) 8 (22.2%) 6 (16.7%) .554 table 2. patient demographics after psm abbreviations: psm, propensity score matching; arat, androgen receptor-axis–targeted therapy; cci, charlson comorbidity index; psa, prostate-specific antigen; tab, total androgen blockade a continuous variables were compared by independent samples t-test variablesa nadir psa > 0.2 ng/ml (n = 100) nadir psa ≤ 0.2 ng/ml (n = 14) p-value median (range) age (years) 77 (58-96) 75 (63-89) .959 median (range) initial psa (ng/ml) 592.5 (2.79-12,802) 277.0 (6.1-12,045) .049 median (range) pretreatment alp (iu/l) 639.5 (56-11,600) 248 (75-4,349) .072 median (range) pretreatment hb (iu/l) 11.8 (5.4-17.2) 14.0 (8.4-15.4) .014 median (range) pretreatment ldh (iu/l) 226.5 (106-864) 197 (139-279) .182 median (range) pretreatment bsi 4.41 (0-13.22) 0.56 (0-7.02) .018 median (range) pretreatment ecog ps 1 (0-3) 0 (0-2) .139 median (range) pretreatment cci 4 (0-7) 4 (2-6) .407 gleasen score (n, %) 6 1 (1.1%) 0 (0%) .019 7 0 (0%) 0 (0%) 8 17 (18.1%) 11 (55.0%) 9 24 (25.5%) 1 (5.0%) 10 14 (14.9%) 2 (10.0%) missing data 38 (40.4%) 6 (30.0%) visceral metastasis (n, %) 12 (12.0%) 5 (35.7%) .020 table 3. patient demographics in the tab group abbreviations: arat, androgen receptor-axis–targeted therapy; cci, charlson comorbidity index; psa, prostate-specific antigen; tab, total androgen blockade a continuous variables were compared by independent samples t-test upfront arat in men with mhspc-kimura et al. urological oncology 224 patients and treatments men who were newly diagnosed with high-volume mhspc between january 2018 and march 2021 in our hospital and other facilities participated in this study. the clinical cutoff date was march 2022. the median follow-up duration was 21.5 months. in this study, the arat group included patients newly diagnosed with high-volume mhspc who were treated with abiraterone, enzalutamide, and apalutamide. bone and visceral metastases were assessed using bone scintigraphy and computed tomography, respectively. treatment was discontinued due to the occurrence of grade ≥ 3 adverse events (aes) or due to the diagnosis of crpc. statistical analysis ezr statistical software (jichi medical university saitama medical center, saitama, japan) was used for all statistical analyses. the two groups were compared using the chi-square test. css and pfs were analyzed using the kaplan-meier method and log-rank test, and the statistical significance was set at p < .05. the cox proportional hazards model was used for multivariate analysis, and hazard ratios (hrs) and 95% confidence intervals (cis) were calculated. the covariates included in the cox model were treated as continuous values as shown in every relevant table. the safety profile of these drugs was assessed in patients who received at least one dose. a 1:1 nearest neighbor propensity score matching (psm) with a caliper of 0.2 was performed to match the initial psa and gleason scores of the arat group to tab patients. the ethics committee of all the facilities approved this study, which was conducted in compliance with the declaration of helsinki. the ethical irb number is 2022011801. results patient characteristics a total of 170 men were newly diagnosed with high-volume mhspc at multiple facilities between january 2018 and march 2021. fifty-six of the 170 patients were treated with arat (39 with abiraterone [1000 mg/day] plus prednisolone [5 mg/day], 14 patients treated with enzalutamide [160 mg/day], 3 patients treated with apalutamide [240 mg/day]), and 114 patients were treated with bicalutamide (80 mg/day). the baseline demographics of patients and disease characteristics in both groups are shown in table 1 and were well balanced except for the significant differences in age, baseline hb level, cci, and presence or absence of visceral metastases. prostate css during a median follow-up of 21.5 months, 5 of 56 patients in the arat group and 44 of 114 patients in the tab group died of prostate cancer. one-to-one psm figure 2. kaplan-meier estimates of pfs in the arat and tab groups. the median pfs was not achieved in the arat group but was 9 months in the bicalutamide group. eleven and 86 men developed crpc in the arat and tab groups, respectively. after psm, the log-rank test was set at p < .001. abbreviations: arat, androgen receptor-axis–targeted therapy (including abiraterone, enzalutamide, and apalutamide); tab, total androgen blockade; crpc, castration-resistant prostate cancer; pfs, progression-free survival upfront arat in men with mhspc-kimura et al. vol 20 no 4 july-august 2023 225 was applied to the data, and psm resulted in 2 equally sized groups of 36 arat vs 36 tab groups, with no residual statistically significant differences (table 2), and 2 of 36 patients in the arat group and 13 of 36 patients in the tab group died by prostate cancer. based on kaplan-meier estimation, the median css was not reached in the arat group and 37 months in the bicalutamide group, and the 2-year css was 94.2% in the arat group and 68.8% in the tab group, with a significant difference (log-rank test, p = .006; figure 1). univariate analysis revealed that pretreatment ldh level and tab therapy were independent risk factors for css, and the hrs were 1.005 (95% ci: 1.0011.010) and 6.138 (95% ci: 1.379-27.33). multivariate analysis also revealed that ldh and tab therapy were independent risk factors for css, and the hrs was 1.009 (95% ci: 1.002-1.016) and 11.09 (95% ci: 1.640-74.94) in this study (table s1). progression-free survival disease progression was assessed by radiologic, clinical, or psa progression or death. there were 11 of 56 in the arat group and 86 of 114 treatment failure events in the tab group. after 1:1 psm was applied, there were 7 of 36 and 25 of 36 treatment failure events, and the 2-year pfs rates were 77.5% and 25.7% in the arat and tab groups, respectively. the median time to crpc was na in the arat group and 9 months in the tab group, with a significant difference (log-rank test, p < .001; figure 2). adverse events seven patients in the arar group and two patients in the tab group reported aes of grade ≥ 3 based on common terminology criteria for adverse events version 5.0 (table s2 in the supplementary appendix). among them, one (2.6%) died due to hepatic failure induced by abiraterone during the follow-up period. we also encountered one case (2.6%) of grade 3 rhabdomyolysis, an extremely rare ae of abiraterone. four cases (10.3%) were grade 3 aspartate aminotransferase (ast) increased with abiraterone. one (7.1%) grade 3 ast increase was reported in patients treated with enzalutamide. in the tab group, two (1.8%) grade 3 ast increases were reported as ae. treatment after progression in the arat group, 11 patients experienced disease progression. 10 patients were treated with docetaxel, and 1 patient received enzalutamide after progression. eighty-six men received secondary treatment after disease progression in the tab group, and the post-treatment details are shown in table s3. fifty-five patients in the bicalutamide group underwent arat after acquiring crpc. subgroup analysis we compared whether the achievement of psa, which became ≤ 0.2 ng/ml, in 3 months could affect the css in both groups. the achievement of psa ≤ 0.2 at 3 months after initiation of systemic therapy was assofigure 3. prostate css comparison of nadir psa > 0.2ng/ml or nadir psa ≤ 0.2ng/ml in 3 months in the tab group. the median css was not achieved in the nadir psa ≤ 0.2 ng/ml group and was 33 months in the nadir psa > 0.2 ng/ml group. there were no deaths in the nadir psa ≤ 0.2 ng/ml group and 42 deaths in the psa > 0.2 ng/ ml group. log-rank test was set at p = .011. upfront arat in men with mhspc-kimura et al. urological oncology 226 ciated with better css in the tab group(log-rank test, p = .011; figure 3) but the values were statistically insignificant in the arat group (log-rank test, p = .42; figure s1). the demographic characteristics of both patients in the arat group showed statistically significant differences in bsi (table s4), and the demographic characteristics of both patients in the tab group were statistically different in initial psa, bsi, baseline hb level, and presence of visceral metastasis (table 3). discussion this is a retrospective real-world study comparing the efficacy and safety of upfront arat in addition to adt and those of bicalutamide with adt in patients with high-volume mhspc in multiple centers in japan. this is the first study to reveal that upfront arat for patients with high-volume mhspc significantly prolongs css and pfs when compared with tab, and the number of psa level reductions significantly prolongs css in both groups. in japan, tab treatment for high-volume mhspcs is often performed in daily clinical practice. there are several possible explanations for this finding. one of the reasons for the use of bicalutamide in men with high-volume mhspc is that there was no significant difference in os between the arat and adt groups in the japanese subgroup in the latitude, arches, or titan trials, even though the hrs of os were similar to those of the entire group.(13–15) in addition, although the enzamet trials showed that the enzalutamide group had significantly prolonged os when compared with the standard care group, the study did not include japanese facilities.(5) some studies have compared the efficacy and safety of up-front abiraterone and bicalutamide for de novo high-volume mhspc in japanese patients.(10,11) all these studies reveal that abiraterone significantly prolongs pfs or time to crpc compared to bicalutamide, consistent with the results of this study. however, previous studies do not show the differences in css or os between abiraterone and bicalutamide groups due to the short period of observation. this is the first study to also reveal a significant difference in the css and pfs of patients in the arat group, a treatment that included abiraterone, enzalutamide, and apalutamide compared to the tab group in a real-world sample from multiple centers in japan. our study also implied that the grade ≥ 3 aes of arat were more frequent than those of tab; therefore, more attention should be paid to monitoring aes in arat in daily clinical practice. especially when using arat, ast and alt levels have to be monitored by blood tests to assess hepatic damage to the patients. other studies showed significant differences in os when the psa reaches a certain level after initial treatment.(16,17) we assessed how the css was affected when nadir psa of ≤ 0.2 ng/ml was reached in 3 months. the kaplan-meier estimation of both groups showed that there are significant differences in css between patients with nadir psa of ≤ 0.2 ng/ml and patients with nadir psa of > 0.2 ng/ml in the tab group but there were no significant differences in arat group. the demographic characteristics showed that initial psa, bsi, initial hb level, and presence of visceral metastases were potential indicators for achieving nadir figure 4. prostate cancer specific survival comparison of nadir psa > 0.2 ng/ml or nadir psa ≤ 0.2 ng/ml in 12 months in tab group. abbreviations: css, cancer-specific survival; psa, prostate-specific antigen upfront arat in men with mhspc-kimura et al. vol 20 no 4 july-august 2023 227 psa of ≤ 0.2 ng/ml in 3 months in the tab group. if patients with high-volume mhspc who are undergoing treatment with tab change to arat when the nadir psa ≤ 0.2 ng/ml in 3 months is not achieved, more benefits may be achieved. this study has some limitations. first, this was not a randomized retrospective study. although we applied psm analysis to adjust for possible confounders, this approach does not account for randomization. second, the number of patients and follow-up period were limited. in particular, there were only seven participants who had crpc in the arat group. hence, it remains unclear whether the css of the bicalutamide group cases receiving arat after crpc could match that of the arat group. conclusions upfront arat with adt significantly prolonged css and pfs compared to tab in de novo high-volume mhspc patients in japan; however, careful attention should be paid to aes. further investigation with a longer follow-up period is still needed on css after crpc in both groups. these data suggest that upfront arat can be more beneficial for patients with de novo high-volume mhspc than tab. conflict on interest the authors declare that they have no conflicts of interest. references 1. fitzmaurice c, akinyemiju tf, al lami fh, et al. global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990-2016: a systematic analysis for the global burden of disease study. jama oncol. 2018;4:1553-68. 2. center for cancer control and information services. cancer. stat interface japan 2018;2019. cited 29 mar 2021 available from url: https://ganjoho.jp/public/qa_links/ report/statistics/pdf/cancer_statistics_2019_fi g_e.pdf 3. basiri a, eshrati b, zarehoroki a, golshan s, et al. incidence, gleason score and ethnicity pattern of prostate cancer in the multiethnicity country of iran during 2008-2010. urol j. 2020 ;17:602-6. 4. kyriakopoulos ce, chen yh, carducci ma, et al. chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase iii e3805 chaarted trial. j. clin. oncol. 2018 ;36:1080-7. 5. fizazi k, tran n, fein l, et al. abiraterone plus prednisone in metastatic, castrationsensitive prostate cancer. n. engl. j. med. 2017;377:352-60. 6. davis id, martin aj, stockler mr, et al. enzamet trial investigators and the australian and new zealand urogenital and prostate cancer trials group. enzalutamide with standard first-line therapy in metastatic prostate cancer. n. engl. j. med. 2019;381:121-31. 7. armstrong aj, szmulewitz rz, petrylak dp, et al. arches: a randomized, phase iii study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. j. clin. oncol. 2019;37:2974-86. 8. chi kn, agarwal n, bjartell a, et al. titan investigators. apalutamide for metastatic, castration-sensitive prostate cancer. n. engl. j. med. 2019;381:13-24. 9. sweeney cj, chen yh, carducci m, et al. chemohormonal therapy in metastatic hormone-sensitive prostate cancer. n. engl. j. med. 20;373:737-46. 10. naiki t, takahara k, ito t, et al. comparison of clinical outcomes between androgen deprivation therapy with up-front abiraterone and bicalutamide for japanese patients with latitude high-risk prostate cancer in a real-world retrospective analysis. int j clin oncol. 2022;27:592-601. 11. yanagisawa t, kimura t, mori k, et al. abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormonesensitive prostate cancer. prostate 2022;82:312. 12. mottet n, cornford p, briers e, et al. european association of urology prostate cancer guidelines (2020) available from url:https:// uroweb.org/guideline/prostate-cancer/#5_2 13. fukasawa s, suzuki h, kawaguchi k, et al. efficacy and safety of abiraterone acetate plus prednisone in japanese patients with newly diagnosed, metastatic hormone-naïve prostate cancer: a subgroup analysis of latitude, a randomized, double-blind, placebocontrolled, phase 3 study. jpn. j. clin. oncol. 2018;48:1012-21. 14. iguchi t, kimura g, fukasawa s, suzuki h, et al. enzalutamide with androgen deprivation therapy in japanese men with metastatic hormone-sensitive prostate cancer: a subgroup analysis of the phase iii arches study. int. j. urol. 2021 jul;28:765-73. 15. uemura h, arai g, uemura h, et al. apalutamide for metastatic, castrationsensitive prostate cancer in the japanese population: a subgroup analysis of the randomized, double-blind, placebo-controlled phase 3 titan study. int. j. urol. 2021;28:2807. 16. hussain m, tangen cm, higano c, et al. southwest oncology group trial 9346 (int-0162). absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from southwest oncology group trial 9346 (int0162). j clin oncol 2006;24:3984-90. 17. zhang lm, jiang hw, tong sj, et al. prostatespecific antigen kinetics under androgen deprivation therapy and prostate cancer prognosis. urol int 2013;91:38-48. upfront arat in men with mhspc-kimura et al. urological oncology 228 brief communication urinary stone location with ureteral stents in place: always on the move, and not where you would expect manolis pratsinis2*, ahmet c. tekin1, valentin zumstein1, sabine güsewell2, hans-peter schmid1, dominik abt1, patrick betschart1, purpose: to assess migration of urinary stones with ureteral stents in place. materials and methods: we performed a retrospective analysis of stone characteristics and locations in patients treated with secondary retrograde intrarenal surgery for symptomatic urinary stones at our institution. we analyzed 393 patients with a median age of 53 years and a median stone size of 7 mm. stone location was assessed at ureteral stent insertion and four weeks later prior to stent removal and retrograde intrarenal surgery (rirs). results: migration of urinary stones was seen in 33.1% of the patients with an indwelling ureteral stent. stones with caudal migration were smaller for any given initial position. 7.1% of the stones were located at one of the three sites of narrowing at initial presentation, this percentage increased to 18.8% at the time of stone extraction. stone composition did not affect stone migration. conclusion: radiographic imaging prior to retrograde intrarenal surgery is recommended due to the migration of urinary stones with indwelling ureteral stents. the most appropriate surgical approach can be devised depending on stone localization. keywords: nephrolithiasis; retrograde intrarenal surgery; stone composition; stone migration; ureteral stents; ureterolithiasis; urolithiasis; introduction spontaneous expulsion of urinary stones requires passage of the three anatomic sites of narrowing: the ureteropelvic junction (upj), the crossing of iliac vessels and the ureterovesical junction (uvj)(1). ureteral stents can be inserted to offer symptomatic relief and prepare the ureter for secondary interventions. whilst it is well established that small stones can pass with a ureteral stent in place(2,3), there is still very little scientific understanding of the migration process of urinary stones with indwelling ureteral stents. the specific objective of this study was to assess the migration of urinary stones with indwelling ureteral stents, and assess the role of stone size, location and composition. methods we performed a retrospective analysis of stone characteristics and positions in patients treated with secondary retrograde intrarenal surgery (rirs) for symptomatic urinary stones between january 2015 and 2019 at our institution. stone location was assessed at the time of ureteral stent insertion and three to four weeks later before the planned stent removal and rirs. inclusion criteria were the availability of a computed tomography prior to ureteral stent insertion and an abdominal x-ray prior to stent removal. the latter is routinely performed at our institution in order to identify stone location and aid rirs planning, as well as identifying patients in which spontaneous stone passage has occurred. patients with radiolucent stones in the abdominal x-ray 1department of urology, rorschacherstrasse 95, cantonal hospital st. gallen, 9007 st. gallen, switzerland. 2department of urology, rorschacherstrasse 95, cantonal hospital st. gallen, 9007 st. gallen, switzerland. * correspondence: department of urology, rorschacherstrasse 95, cantonal hospital st. gallen, 9007 st. gallen, switzerland. tel: +41 (0) 71 494 14 16, e mail: manolis.pratsinis@kssg.ch. received april 2020 & accepted october 2020 were excluded from the analysis. patients requiring initial ureteral stenting due to persistent pain, associated urinary tract infections, as well as progressive kidney failure were all included. ureteral stent insertion was performed at the discretion of the surgeon (percuflex, boston scientific, usa; charr. 6; stent length 26 or 30 cm). for each of the two time points, stone position was classified as one of six positions on the pathway from the kidney to the bladder (figure 1), and the proportion of stones found at each position was determined. for the analysis of stone migration, the positions were pooled to distinguish three main parts (kidney: only stones in the kidney, proximal: ureteropelvic junction and proximal ureter and vessel intersection, distal: distal ureter and ureterovesical junction) (figure 1). the proportion of stones staying in place (no migration), and of stones with cranial or caudal migration was determined. wilcoxon's signed-rank test, based on the positions ranked from kidney to distal, was used to test whether one sense of migration predominated. in addition, the proportion of stones found at a site of anatomic narrowing (ureteropelvic junction, vessel intersection or ureterovesical junction) was determined for the two time points and compared between time points with mcnemar’s test. to assess whether stone migration was related to stone size, we needed to consider that opportunities for stone migration depended on initial position, which could itself depend on stone size. we therefore compared mean stone size between the three types of migration after adjusting for initial stone position with a two-way analyurology journal/vol 17 no. 6/ november-december 2020/ pp. 667-670. [doi: 10.22037/uj.v16i7.6140] vol 17 no 06 november-december 2020 668 sis of variance. stone composition was analyzed for the presence or absence of certain minerals using infrared spectroscopy and classified into six types, according to the predominant stone composition (table 1). the associations of these six composition types with stone position and with stone migration were assessed using chi-squared tests with continuity correction. the study was conducted according to the declaration of helsinki and good clinical practice and was approved by the local ethics committee (ekos 2019-00923). results a total of 393 patients were included (284 males, 109 females), the median age was 53.0 years (range 17-89) and the median stone size (largest diameter on axial images) was 7 mm (range 2–30). at initial presentation, 39.7% of stones were located in the kidney, 30.5% in the proximal ureter, 22.6% in the distal ureter (figure 1), while 7.1% of the stones were located at one of the three sites of narrowing. in regard to stone migration, prior to rirs (pooled position in three main parts), 14.3% of the stones were located in the kidney, 58.0% in the proximal part (ureteropelvic junction, proximal ureter and vessel intersection) and 27.7% in the distal part (distal ureter and ureterovesical junction) (table 2). when considering individual transitions between the three main parts, 66.9% of the stones stayed in place, 29% moved caudally (mostly from the kidney) and 4.1% moved cranially (table 2), with a significant predominance of caudal migration (wilcoxon signed-rank test, p < 0.001). the proportion of stones located at a site of anatomic narrowing increased significantly from 7.1% (28/393) at initial presentation to 18.8% (74/393) at the time of stone extraction (mcnemar’s test, x2 = 27.4, p < .001). the mean size of stones was significantly (p < .001) related to their initial position and to the type of migration: the largest stones were initially seen in the kidney, and for any given initial position, stones with caudal migration were smallest (figure 2). patient age had no effect on stone migration. in a two-way analysis of variance analogous to that carried out for stone size, patient age was not significantly related to initial stone position (p = .46) nor to the presence and direction of stone migration (p = .39). patient sex was also unrelated to initial stone position (p = .30) and to the presence and direction of stone migration (p = .86) in a logistic regression model. stone composition classified into six types (table 1) was not associated with the stone's tendency towards migration (chi-squared test, x2 = 0.9, p = .97) or probability of being found at a site of anatomic narrowing prior to rirs (x2 = 2.42, p = .79). however, stone composition appeared to be associated with different locations of stones prior to rirs (x2 = 20.1, p = .03): calculi containing carbonate apatite without calcium oxalate were more commonly seen in the kidney than calculi containing calcium oxalate or uric acid. stones table 1. categorized stone composition based on the presence or absence of certain minerals with the frequency of each category (total n = 376). with calcium oxalate monohydrate / whewelit (no dihydrate) 206 (54.8%) with calcium oxalate dihydrate / weddellit (no monohydrate) 40 (10.7%) with calcium oxalate monohydrate and dihydrate 99 (26.3%) with uric acid, no calcium oxalate 14 (3.7%) with carbonate apatite / dahllit, no calcium oxalate 12 (3.2%) no calcium oxalate, no uric acid, no carbonate apatite 5 (1.3%) table 2. frequency of stone positions at the time of ureteral stent insertion (initial) and prior to rirs (final), and frequency of stone migration between these two time points. in order to assess migration, stone position was pooled in three main parts, ranked from 1 to 3: kidney (1), proximal (2, combining ureteropelvic junction, proximal ureter and vessel intersection) and distal (3, combining distal ureter and ureterovesical junction). the number of stones with each combination of initial and final positions is given, as well as the total number and percentage of stones at each position per time point. cell colors indicate the combinations of initial and final positions corresponding to caudal, cranial and no migration, respectively. the number and percentage of stones with each migration type is given at the bottom of the table. the lower part of the table gives the number of stones found either at a site of anatomic narrowing or at another position; again for each combination of initial and final positions and in total per time point. initial position position prior to rirs total n (%) kidney (1) proximal (2) distal (3) kidney (1) 50 87 19 156 (39.7%) proximal (2) 4 131 8 143 (36.4%) distal (3) 2 10 82 94 (23.9%) total n (%) 56 (14.3%) 228 (58.0%) 109 (27.7%) narrowing other total n (%) narrowing 14 14 28 (7.1%) other 60 305 365 (92.9%) total n (%) 74 (18.8%) 319 (81.2%) types of migration n (%) caudal 114 (29.0%) none 263 (66.9%) cranial 16 (4.1%) abbreviations: rirs, retrograde intrarenal surgery. location of urinary stones with ureteral stents in place – pratsinis et al. containing calcium oxalate monohydrate alone or in combination with calcium oxalate dihydrate were more often seen in a distal position (30.2%) than stones without this mineral (15.5%). discussion in line with previous studies describing the spontaneous passage of stones with an indwelling ureteral stent(2,3), a caudal migration of urinary stones was seen in 29% of the patients with indwelling ureteral stents. contrary to popular belief, symptomatic urinary stones were rarely seen at a site of anatomic narrowing, as this was the case in only 7.1% of the patients at initial presentation. this increased to 18.8% with an indwelling ureteral stent in place. compared to previous studies, more ureteral stones were seen in the proximal ureter and less at the distal ureter or uvj, while the mean stone size in our study was also slightly larger(4,5). both of these findings may in-part be due to the fact that patients with figure 1. six classified and possible ureteral stone positions on the pathway from the kidney to the. the percentage on the left denotes the frequency at initial presentation, the frequency on the right the frequency prior to rirs. the positional pooling performed for the analysis of stone migration is given on the right: kidney (only stones in the kidney), proximal (ureteropelvic junction and proximal ureter and vessel intersection) and distal (distal ureter and ureterovesical junction). figure 2. stone size in relation to initial position and direction of migration from stent insertion to time of retrograde intrarenal surgery. location of urinary stones with ureteral stents in place – pratsinis et al. breif communication 669 vol 17 no 06 november-december 2020 670 a spontaneous passage of stones were not included in this analysis, as all data were collected from patients who underwent rirs. a recent analysis by stojkova gafner et al. assessed the migration of urinary stones with an indwelling ureteral stent in place and within 24 hours after stent removal for patients with symptomatic ureterolithiasis (6). in their retrospective analysis of 216 patients, they demonstrated that 34% of the patients had spontaneous stone expulsion with a stent in place. in a multivariate analysis, they showed that spontaneous stone expulsion was significantly associated with smaller stone size and distal stone location. in line with these findings, we were able to demonstrate an increased rate of stone migration associated with smaller stone size. the study by stojkova gafner et al. was limited to the spontaneous expulsion rate of ureterolithiasis, and the overall stone size was significantly smaller than in our study (median stone size 5 mm vs. 7 mm). furthermore, we were able to demonstrate that kidney stones also tend to migrate with a urinary stent in place. considering the findings of both studies, it appears that the overall rate of urinary stone migration with a urinary stent is higher than previously assumed(7). stone composition was available for 376 patients. interestingly, the stone composition appeared to influence the location of the calculi prior to rirs, with carbonate apatite containing stones often found in the kidney, and calculi composed of calcium oxalate monohydrate often seen in more distal positions. a possible explanation for this finding may be the smooth surface of calcium oxalate monohydrate calculi(8), which may help facilitate caudal migration with an indwelling ureteral stent. in clinical practice, the knowledge of stone composition is of great use when planning stone treatment, e.g. deciding which stones may be treated by urinary alkalinisation, and which stones may be amendable to extracorporal shock wave lithotripsy(9). while the stone composition did not appear to affect the rate of stone migration in our study, it is worth noting the differing stone location with a ureteral stent in place in dependency of stone composition. this may aid decision-making in cases where population-specific studies regarding stone composition are available, as stone composition can vary regionally and across climates zones(10). our study has limitations that need to be addressed. the position of stones was assessed by two different methods, namely with a computed tomography at initial presentation and with less sensitive abdominal x-ray imaging prior to stent removal. we used a more granular classification of stone location (e.g. omitting middle third of ureter), in order to minimize potential discrepancies between the different imaging modalities. nonetheless, the determination of definitive stone location is challenging with plain films, in particular the distinction between distal ureter and uvj does not always appear to be clear(1). however, in clinical practice it is not common to perform several ct scans on a regular base due to the radiation exposure. furthermore, possible positional changes of the urinary stones through the insertion of the ureteric stents were not factored in this analysis (push-back). this is a potential limitation, though cranial migration was only noted in 4.1% of cases. as the population studied was exclusively patients treated with secondary rirs, patients with spontaneous stone expulsion were omitted from the analysis, which leads to an underestimation of the rate of caudal migration. a further potential limitation lies in the retrospective analysis which may have potentially introduced an unknown bias. our study further supports the notion of urinary stone migration with a ureteral stent in place. in line with other studies, we were able to demonstrate that smaller stones are more likely to migrate caudally. furthermore, we showed that urinary stones are more than twice as likely to be found at a site of anatomic narrowing, when a ureteral stent is in place. these findings further support the use of radiographic imaging prior to retrograde intrarenal surgery. depending on the stone localization, the most appropriate surgical approach can be devised. conflict of interest none of the contributing authors have any conflict of interest, including specific financial interest or relationships and affiliations relevant to the subject matter or materials discussed in the manuscript. references 1. wein aj, kavoussi lr, partin aw, et al. campbell-walsh urology, 11th edition. elsevier ltd, oxford; 2017. 2. baumgarten l, desai a, shipman s, et al. spontaneous passage of ureteral stones in patients with indwelling ureteral stents. can j urol 2017;24:9024-9. 3. kuebker jm, robles j, kramer jj, miller nl, herrell sd, hsi rs. predictors of spontaneous ureteral stone passage in the presence of an indwelling ureteral stent. urolithiasis 2019;47:395-400. 4. eisner bh, reese a, sheth s, stoller ml. ureteral stone location at emergency room presentation with colic. j urol 2009;182:1658. 5. ordon m, schuler td, ghiculete d, pace kt, honey rj. stones lodge at three sites of anatomic narrowing in the ureter: clinical fact or fiction? j endourol 2013;27:270-6. 6. stojkova gafner e, grüter t, furrer ma, et al. a treatment strategy to help select patients who may not need secondary intervention to remove symptomatic ureteral stones after previous stenting. world j urol 2020 doi: 10.1007/s00345-020-03087-1. 7. lennon gm, thornhill ja, grainger r, mcdermott te, butler mr. double pigtail ureteric stent versus percutaneous nephrostomy: effects on stone transit and ureteric motility. eur urol 1997;31:24–9. 8. khan sr, pearle ms, robertson wg, et al. kidney stones. nat. rev. dis. primers, 2, 16008. https://doi.org/10.1038/nrdp.2016.8 9. türk c, neisius a, petrik a, seitz c, skolarikos a, knoll t. european association of urology. non-oncology guidelines. urolithiasis: http://uroweb.org/guideline/ urolithiasis/. accessed april 2020. 10. hadian b, zafar-mohtashami a, ghorbani f. study of urine composition of patients with recurrent nephrolithiasis in lorestan, iran. iran j kidney dis. 2018;12(1):22-6. location of urinary stones with ureteral stents in place – pratsinis et al. vol 15 no 03 may-june 2018 31 pediatric urology pudendal nerve block versus penile nerve block in children undergoing circumcision a cigdem tutuncu,1* pinar kendigelen,1 gulruh ashyyeralyeva,1 fatiş altıntas,1 senol emre,2 rahsan ozcan,2 guner kaya1 purpose: penile nerve block is the most popular nerve block for the circumcision in pediatric patients. this study aimed to compare the analgesic efficiency of penile nerve block and the pudendal nerve block on postoperative pain and additional analgesic requirements in children undergoing circumcision. material and methods: this prospective randomized double-blind study enrolled 85 children, aged 1 to10 years, undergoing circumcision. the patients were randomly divided into two groups either receiving dorsal penile block group (pnb-group) or pudendal nerve block (pdb-group). in the pnb-group, 0.3 ml/kg 0.25 % bupivacaine was used; and, in the pdb-group, 0.3 ml/kg bupivacaine was applied with nerve stimulator at a concentration of 0.25 %. in the postoperative period, the modified cheops pain scale scoring and additional analgesic demand were evaluated at the 5th and 30th minutes and at the 1st and 2nd hours. the subsequent pain evaluations were made by the parents at home, at the postoperative 6th, 12th, 18th and 24th hours. results: seven patients were excluded from the study, and seventy eight patients were evaluated for analysis. patients in pdb-group had significantly lower postoperative pain intensity and lower mcheops scores (3.83 ± 0.98) when compared to the pnb-group (6.47 ± 0.91) (p < .01) at all measurement times and none of patients in pdb-group had additional analgesic requirements up to 24 hours. patients in the pnb-group had significantly more analgesic requirements at all measurements times except at the 1st, 2nd, 24th hours. 3.8%, 30.8%, 46.2% and 59% of the patients in the pnb group needed additional analgesia respectively at 5th, 6th, 12th and 18th hours. conclusion: pudendal nerve block provided additional analgesic free period and had better analgesic efficiency compared to the penile nerve block lasting until 24 hours after operation. keywords: analgesia; circumcision; nerve block; pain; pediatric. introduction circumcision is one of the most frequently per-formed penile surgeries, necessitated by cultural, religious and medical reasons. although a minor same day surgery, circumcision is painful with postoperative pain being one of the significant problems. topically or intravenously administered agents and caudal or penile nerve blocks constitute the routine modes of analgesia used. the analgesic method employed has to be reliable, effective and compatible with fast recovery and low incidence of complication in patients sent home shortly after the intervention. for postoperative analgesia the penile nerve block and caudal block have been using as common techniques.(1) while providing effective postoperative analgesia, the caudal block method can have adverse side effects such as subarachnoid, intraosseous and intravascular puncture, motor block and delayed postoperative micturition.(2). pudendal nerve block may be an alternative block to other blocks in circumcision. the pudendal nerve is a peripheral nerve with both motor and sensorial innervation of penis.(3) some recent studies have reported that pudendal block provided better analgesia than caudal block in hypospadias surgery and also had shorter hospital discharge time which is an important topic for circumcision surgery.(4,5) in this prospective, randomized double blind study, we 1cerrahpasa medical faculty, department of anesthesiology and reanimation, istanbul, turkey. 2cerrahpasa medical faculty, department of pediatric surgery, istanbul turkey. *correspondence: cerrahpasa medical faculty, department of anesthesiology and reanimation cerrahpasa medical faculty, kocamustafapasa, istanbul, 34280, turkiye. tel: +90 212 414300-2187 gsm: + 90 532 592 0584. fax: +90 212 41422766. e-mail: actutuncu@gmail.com. received november 2017 & accepted december 2017 aimed to compare the postoperative pain intensity and additional analgesic use after the application of dorsal penile nerve block and nerve stimulator guided pudendal nerve block in children undergoing circumcision. materials and methods study population and inclusion criteria the study enrolled 85 children with asa (american society of anesthesiologist physical status) i-ii and in the age range of 1-10 years, planned to undergo circumcision, after obtaining the hospital ethical committee approval and the informed written consent of the parents. (ethical approval no: 242893, clinical trial no: nct03258255) exclusion criteria children with neurological or neuromuscular disorders, a history of hemorrhage or coagulation disorders were not included in the study. after premedication with midazolam, the patients were taken into the operating room, for application of the appropriate monitoring and anesthesia induction achieved with propofol (2-3mg/kg), fentanyl (0.5 mcg/kg) and 2% sevoflurane. laryngeal mask airway of the appropriate number was inserted without neuromuscular blocker administration and maintenance of anesthesia was provided with 2% sevoflurane. the patients’ randomization was performed with sealed enveloped techniques (based on computer-generated random numbers), and they were randomly divided into two groups, as the penile nerve block group (pnbgroup) or the nerve stimulator guided pudendal nerve block group (pdb-group). procedure in penile nerve block group (pnb group), dorsal penile block was achieved by two surgeons in the supine position, after skin sterilization, by palpating the symphysis pubis and perforating the scarpa’s fascia with a pop feeling by 25 g needle and injecting 0.25 % bupivacaine mixture of 0.3 ml/kg volume on the midline into the dorsal base of penis, between the pubis and the penis under scarpa’s fascia. in pudendal nerve block group (pdb group ) pudendal nerve block was performed by same two anesthesiologists a in the lithotomy position, after the appropriate skin sterilization. the nerve stimulator was adjusted to 3ma and 2hz, and the stimulator needle (22-24 g stimuplex a, 50-100mm, b. braun, melsungen, germany) was inserted from the inferomedial of ischial tuberosities while palpating the tuberosities located at position of 3 and 9 o’clock of the anus (figure 1). bupivacaine administered as a 0.25 % mixture at 0.3 ml/ kg volume. injection was performed bilaterally after the perineal muscle contraction and the up-down penile movements. dorsal penile nerve blocks were performed by two experienced pediatric surgeons and the pudendal nerve blocks were performed by two experienced anesthetists. pain evaluation the primary outcome was the assessment of postoperative pain intensity and analgesic usage in the postoperative period. all patients were evaluated in the pediatric recovery room by two different anesthesiologists who did not know which technique was performed for analgesia during the surgery. the secondary outcome was to evaluate the hemodynamic response of the blocks during surgery. surgical incision was made minimally 15 minutes after the block. before and after the block, the heart rate and the noninvasive arterial blood pressure were recorded first 5th minutes then every ten minutes during the surgery by anesthetists who performed the block and cared the patient during surgery. if any increase over 20% was seen, remifentanil infusion (0.1 mcg/kg/min) was started and the dose was increased if necessitated. in the postoperative period, after the patient was transferred to the recovery unit, the modified children hospital of eastern ontario pain scale (m cheops) was used. the modified cheops is an observational scale including five parameters of pain behavior which is scaling crying, facial expression, verbal response and body posture to assess the pain intensity of children aged between 15-year-old, (mcheops: 0 = no pain; 10 = severe pain) in this study the pain score which needs treatment was described as mcheops 5 or higher score (figure 2). the pain evaluation was performed at the postoperative 5th and the 30th minutes and the first and second hours. when mcheops score was above 5, tramadol (1 mg/kg) was used. the postoperative pain evaluation and the analgesic applications were carried out by the recovery unit anaesthetists who were blinded to the type of nerve block technique. all patients were sent home after an average of 2 hours after the operation, when the control of pain, consciousness, nausea, vomiting and surgical complications were completed and the first nourishment had been provided. at home, pain evaluations were made at the postoperative 6th, 12th, 18th and the 24th hours by the patients’ families using the faces pain scale. the families, blind to the type of nerve block performed on the patient, were previously instructed on the postoperative pain evaluation which was made easy by the selective use of the faces pain scale forms illustrated with faces expressing different degrees of pain. use of ibuprofen (10mg/kg-orally) was recommended when the pain score of the patient was above 4. sample size the sample size was estimated on the basis of the number of patients per group. it has been suggested to be 35 with at least 40 % difference in pain scores between two groups with a power of 95 % at the 5 % significance level. statistical analysis the statistical analyses were carried out using the spss 15.0 package program for windows. for the numerical data, descriptive analyses with the mean, the standard deviation and the median were employed. percentages were used for the categorical data. the student t-test was used for the normally distributed numerical variables in two independent groups. when normal distritable 1. demographic data. pudendal block (n=39) penile block (n=39) mean ± sd min-max mean ± sd min-max p-value age (month) 44.1 ± 23.9 6-96 46.2 ± 32.7 9-120 .714 weight (kg) 17.0 ± 7.6 6.5-39 17.7 ± 7.5 8-35 .779 pudendal block (n=39) penile block (n=39) mean ± sd median mean ± sd median mean difference p-value mcheops 5.min 3.79 ± 0.80 4 (3-4) 8.95 ± 2.24 10 (6-11) -5.16 < 0.001 30.min 3.69 ± 0.77 4 (3-4) 5.74 ± 1.02 6 (5-6) -2.05 < 0.001 1.h 3.62 ± 0.92 4 (3-4) 5.23 ± 0.43 5 (5-5) -1.61 < 0.001 2.h 3.84 ± 1.12 4 (3-5) 5.21 ± 0.41 5 (5-5) -1.37 < 0.001 6.h 3.65 ± 1.01 4 (3-4) 5.85 ± 1.16 6 (5-6) -2.20 < 0.001 12.h 3.81 ± 1.05 4 (3,5-4) 6.59 ± 0.99 6 (6-8) -2.78 < 0.001 18.h 3.81 ± 0.97 4 (4-4) 7.13 ± 0.73 7 (7-8) -3.32 < 0.001 24.h 4.46 ± 1.24 5 (4-5) 7.10 ± 0.31 7 (7-7) -2.64 < 0.001 table 2. comparison of mcheops scores between pudendal block and penile block. pudendal vs penile nerve block in circumcisiontutuncu et al. pediatric urology 32 vol 15 no 03 may-june 2018 33 bution was not observed, the mann-whitney u test was employed. ratio comparisons between the data on the two groups of patients were carried out by the chi-square analysis, the alpha significance level was rated by the p < .05 value. results although 85 children were included the study, seventy-eight children were eligible for analysis, thirty-nine patients were evaluated for each group; accurately seven patients had to be excluded from the study; at beginning of the study, one of them had a neurological disorder, two of patients had hematological disease, and four of patients had incomplete pain evaluation expected to be made at home (figure 3). there were not significant differences between groups with respect to age and body weight (table 1). for the primary outcome, the postoperative pain evaluation by mcheops scores were significantly higher in the pnb-group than in the pdb-group at each measurement time (table 2). statistically significant differences in the mcheops levels of the patient groups were determined in follow up (p < .001, for both groups). in the pdb-group, significant change did not occur in the mcheops level until the postoperative 18th hour. the increase at the 24th hour was significant as compared to the levels at the postoperative 5th minute and the 18th hour (p < .001 and p = .001, respectively). in the pnb-group significant falls were observed at the postoperative 30th minute vs the 5th minute and at the postoperative 1st hour vs the level at the 30th minute; with a significant elevation at the postoperative 6th hour vs the 2nd hour (p = .003). at the postoperative 24th hour the mean mcheops score was significantly lower than that at the postoperative 5th minute (p < .001) (table 3). at the postoperative 5th minute a 38.4% additional analgesia requirement was observed in the pnb-group. at follow up, the needs for additional analgesia were 0%, 7.7%, 30.8%, 46.2%, 59% and 59% at, respectively, the postoperative 30th minute, 1st, 2nd, 6th,12th, 18th and 24th hours. in the pdb-group none of the patients needed additional analgesia until the postoperative 24th hour, when 75.7% of the patients had to receive additional analgesia. the requirement for extra analgesia at the postoperative 24th hour of the two groups did not differ significantly (p = .121) (table 4). in the perioperative period only two patients of the pdb-group required remifentanil use during the first 10 minutes, while 18 patients in the pnb-group required remifentanil use (table 5). the initial mean systolic blood pressure (sbp) of the two groups did not differ significantly (p = .871). the mean sbp levels of the pdb-group were significantly lower as compared to those of the pnb-group between the 5th minute and the 20th minute after the incision (respectively, p < .001, p = .037, p = .018, p < .001, p = .001, and p < .001). however, the mean sbp of the groups did not differ significantly at the 20th minute (p = .058). intragroup sbp levels of both groups did not differ significantly (p < .001, for both groups) (table 6). the initial mean diastolic blood pressure (dbp) of the two groups did not differ significantly (p = .308). the 5th minute mean dpb of the pdb-group was significantly lower as compared to that of the pnb-group (p = .006). the mean dbp of the two groups did not differ significantly at the 10th minute and before the incision (p = .100 and p = .308). after the incision, the mean dbp of the pdb-group was statistically lower than those of the pnb-group. while significant fall in the dbp as compared to the initial levels was observed in the pdb-group (p < .001), in the pnb-group significant fall was observed at all timings except at the perioperative 20th minute (p < .001). the initial mean heart rate (hr) of the two groups did not differ significantly (p =.197). at the 5th minute after incision, the mean hr of the pdb-group was significantly lower than that of the pnb-group (p < .001). however, statistically significant intergroup differences were not observed in the mean hr at other timings. no surgical complications were detected in the studied patients. discussion circumcision is one the most painful surgical procetable 3. comparison of mcheops scores within groups pudendal block penile block p value p value cheops 30.min cheops 5.min .285 < 0.001 cheops 1.h cheops 30.min .564 .002 cheops 2.h cheops 1.h .088 .564 cheops 6.h cheops 2.h .200 .003 cheops 12.h cheops 6.h .201 .009 cheops 18.h cheops 12.h 1.000 .026 cheops 24.h cheops 18.h < .001 .835 cheops 24 h cheops 5.min .001 < 0.001 pudendal block penile block n % n % p additional analgesic 5.min 0 0.0 15 38.4 < 0.001 30.min 0 0.0 0 0.0 1.h 0 0.0 3 7.7 .241 2.h 0 0.0 3 7.7 .241 6.h 0 0.0 12 30.8 < 0.001 12.h 0 0.0 18 46.2 < 0.001 18.h 0 0.0 23 59.0 < 0.001 24.h 28 75.7 23 59.0 .121 table 4. comparison of additional analgesic requirements pudendal vs penile nerve block in circumcisiontutuncu et al. dures performed on the pediatric patient. it is obligatory to reduce postoperative pain of this outpatient surgery. application of different anaesthetic and analgesic methods have been reported in the literature.(6) the most frequently reported methods are topical analgesia, and caudal and penile nerve blocks with each method resulting in different requirements of analgesia and incidences of side effects. in caudal nerve block, complications specific to central block can be seen. penile nerve block is simpler to perform than the caudal block and does not involve complications such as delayed mobilization and urinary retention which delay discharge from hospital. (7) however, complications including hematoma and edema development and anesthetic toxicity have been reported with penile nerve block which can be applied by differing approaches such as the dorsal penile nerve block or subcutaneous ring infiltration.(8) in this study, we have used the dorsal penile nerve block method. the dorsal penile nerve is a branch of the pudendal nerve and innervates the penile shaft, the urethra and the glans penis.(9) the results of this study have indicated an achievement of better analgesic effect with pudendal nerve block as compared to the dorsal penile nerve block which also resulted in reduced postoperative analgesic use. less effective analgesia was observed after dorsal penile nerve block. faraoini et al. performed penile nerve block guided by ultrasonography (usg) or by using anatomical landmarks for circumcision of 40 children. although there were no differences in the block failure in the two approaches, the usg-guided approach was observed to provide more effective analgesia and less use of analgesics. they reported that visualization of the dorsal penile nerve and the spread of the local anaesthetic during the application of the block increased the effectiveness of the penile nerve block.(10) sademan et al., using a similar approach with the assistance of usg or by use of anatomical indicators for penile nerve block, also reported that the use of perioperative opioids were reduced and better analgesia was provided by the usg-guided procedure. they reported that the one sided spread of the local anaesthic visualized by the usg aided nerve block, reduced the effectiveness of the nerve block.(11) it has been reported in the literature that the mean failure incidence of penile nerve block is 3-10% and that 30% of the patients require perioperative and postoperative additional analgesia.(11,12) in our study, as high as 38.4% of the patients operated with dorsal penile nerve block have required extra analgesic administration, and the possibility of not having blocked the scrotal branch of the pudendal nerve as well as the penile nerve may be considered to have contributed to this result. studies on circumcisions performed by blocking the scrotal nerve and the dorsal penile nerve, which is not the routine method of penile block for circumcision, have reported increased analgesic effectiveness. in this respect, the routine pudendal nerve block is a better choice of analgesia as compared to the routine approach of penile nerve block.(13,14) pudendal nerve originates from the sacral nerve roots 2, 3 and 4; passes between the sacrospinous and sacrotuberous ligaments in the pelvis, passes through the pudendal canal and supplies the dorsal penile nerve, the inferior anal nerve and the scrotal skin innervation. (15) the ischial tuberosity, that the sacrotuberous ligament is attached to, is used as an anatomical indicator for determining the location of the pudendal nerve in our study.(3) this involves a more lateral entry point as compared to the method of naja(14) comparing the putable 5. comparison of remifentanil (rf) usage percentage and dosage in perioperative period pudendal block penile block n % n % p rf (%) beginning 0 0.0 1 2.6 1.000 1.min 0 0.0 0 0.0 5.min 0 0.0 0 0.0 10.min 0 0.0 0 0.0 before incision 0 0.0 1 2.6 1.000 incision 1. min 0 0.0 26 66.7 <0.001 ncision 5. min 2 5.1 23 84.6 <0.001 ncision 10.min 2 5.1 23 84.6 < 0.001 ncision 20.min 0 0.0 33 84.6 < 0.001 pudendal block penile block mean ± sd median mean± sd median p* rf mcg/kg/min before incision 0.05 incision 1. min 0.13 ± 0.06 0.1 incision 5. min 0.05 ± 0.00 0.05 0.16 ± 0.05 0.2 incision 10. min 0.05 ± 0.00 0.05 0.17 ± 0.05 0.2 incision 20. min 0.14 ± 0.05 0.1 *sample size was not sufficient enough to create a p value figure 1. pudendal block application area. pudendal vs penile nerve block in circumcisiontutuncu et al. pediatric urology 34 vol 15 no 03 may-june 2018 35 dendal and penile nerve block methods in circumcision. schmidt, on the other hand, has argued for the use of the ischial tuberosity for determining the ischial spine as the most suitable point for perineal approach to pudendal innervation.(16) in our study, 0.3 ml/kg, 0.25% bupivacaine was used for both the penile and the pudendal nerve blocks. sfez et al. used 0.25 and 0.5 mg/ kg bupivacaine for penile nerve block, achieving equivalent analgesic effectiveness with both doses, without differences in the time for peaking although the serum bupivacaine concentration was higher with the 0.5 mg/ kg dosage but remained below the 4 mcg/ml limit of toxicity. in our study 0.75 mg/kg bupivacaine was used but the serum concentration was not determined. however, indications of local anaesthetic toxicity were not observed.(17) in another study on comparison of penile nerve and pudendal nerve block for circumcision,(14) lidocaine, fentanyl and clonidine were used. in this study, the time of discharge from hospital was given to vary between 2 and 6 hours. there were no differences in the arterial blood pressure and heart rate data in the two procedures. the better analgesia and less analgesic use achieved by this study in comparison to the outcomes in our pnb-group is attributed to the additional use of opioids and clonidine. in our routine surgery procedure, the mean time of discharge is 2 hours in the absence of complications which was achieved with all patients of our study. also, in our study the mean systolic blood pressure of the pdb-group of patients was significantly lower in comparison to the pnb-group of patients and this was attributed to the effective and profound analgesia provided by the pudendal nerve block method. one of the limitations of ours study is not recording the exact time of the initial use of rescue analgesics. another limitation is having relied on parents to evaluate the postoperative pain severity. the single disadvantage of the pudendal nerve block is placing the patient in the lithotomy position and the prolonging of the preoperative procedures by the preparative and application procedures of the pudendal nerve block. these details, however, have been overlooked in penile block pudendal block mean ±sd median mean ± sd median p value systolic bp beginning 96.3 ± 22.3 98 96.9 ± 10.1 96 .871 5.min 81.3 ± 9.1 79 91.7 ± 13.5 92 <0 .001 10.min 84.5 ± 9.5 85 89.7 ± 12.2 90 .037 before incision 82.8 ± 10.1 83 88.9 ± 11.9 90 .018 incision 5.min 83.4 ± 8.3 82 93.0 ± 16.8 89 .001 incision 10.min 80.5 ± 8.4 79 91.7 ± 15.1 88 < 0.001 incision 20.min 80.7 ± 9.6 79 86.3 ± 14.9 84 .058 penile block pudendal block mean.±sd median mean.±sd median p value diastolic kb beginning 61.2 ± 16.1 60 57.3 ± 8.7 56 .308 5.min 48.9 ± 9.0 45 53.9 ± 10.9 52 .006 10.min 47.8 ± 8.8 46 52.3 ± 9.0 52 .100 before incision 48.8 ± 9.2 46 51.2 ± 8.6 52 .308 incision 5.min 48.1 ± 8.6 45 55.3 ± 10.8 53 < 0.001 incision 10.min 46.9 ± 6.7 45 55.7 ± 14.8 52 < 0.001 incision 20.min 46.5 ± 7.4 45 57.6 ± 18.1 52 < 0.001 penile block pudendal block mean ±sd median mean ± sd median p value hr beginning 112.4±30.3 114 121.6±20.9 122 .197 5.min 109.2±15.5 104 115.3±20.5 120 .086 10.min 104.8±16.0 98 111.8±19.6 114 .057 before incision 104.6±15.1 104 110.3±18.4 110 .068 incision 5. min 103.9±14.2 102 117.4±18.0 121 < 0.001 incision 10. min 100.7±13.2 99 107.9±15.0 110 .060 incision 20. min 98.0±9.9 96 96.7±15.0 96 .657 table 6. comparison of hemodynamic parameters between groups figure 2. modified cheops score. pudendal vs penile nerve block in circumcisiontutuncu et al. view of the better analgesic effectiveness and patient comfort achieved by pudendal nerve block approach. conclusions in conclusion, we observed that the pudendal nerve block has provided a better analgesic effect and less use of postoperative analgesics as compared the dorsal penile nerve block. pudendal block provided very comfortable and painless postoperative period in circumcision surgery, and seems to be a more favorable option relative to penile block. conflict of interest authors declare that they have no conflict of interest. references 1. cyna am, middleton p. caudal epidural block versus other methods of postoperative pain relief for circumcision in boys. cochrane database syst rev. 2008; 8: 2-6. 2. dalens b, vanneuville g, dechelotte p penile block via the subpubic space in 100 children. anesth analg. 1989; 1: 41-5. 3. reitz a, gobeaux n, mozer p, delmas v, richard f, chartier-kastler e. topographic anatomy of a new posterior approach to the pudendal nerve for stimulation. eur urol. 2007; 5 : 1350-5. 4. kendigelen p, tutuncu ac emre s, altindas f, kaya g. pudendal versus caudal block in children undergoing hypospadias surgery: a randomized controlled study reg anesth pain med. 2016; 5: 610-5. 5. hecht s, piñeda j, bayne a. ultrasoundguided pudendal block is a viable alternative to caudal block for hypospadias surgery: a single surgeon pilot study. urology 2017; s0090-4295: 31197-4. 6. bellieni cv, alagna mg, buonocore g. analgesia for infants' circumcision ital j pediatr. 2013; 39: 1-7. 7. allan cy, jacqueline pa, shubhda jh. caudal epidural block versus other methods of postoperative pain relief for circumcision in boys. cochrane database syst rev. 2003; 2: 2-8. 8. soh cr1, ng sb, lim sl. dorsal penile nerve block. paediatr anaesth. 2003; 4: 329-33. 9. yang cc, bradley we. neuroanatomy of the penile portion of the human dorsal nerve of the penis. b j urol. 1998; 82: 109-113. 10. faraoni d, gilbeau a, lingier p, barvais l, engelman e, hennart d. does ultrasound guidance improve the efficacy of dorsal penile nerve block in children? paediatr anaesth. 2010; 10: 931-6. 11. sandeman dj1, dilley av. ultrasound guided dorsal penile nerve block in children. anaesth intensive care. 2007; 2: 266-9. 12. brown tck, weidner nj, bouwmeester j. dorsal nerve of the penis block-anatomical and radiological studies. anaesth intensive care. 1989; 17: 34-8. 13. serour f, mori j, barr j. optimal regional anesthesia for circumcision. anesth analg. 1994; 79: 129-31. 14. naja z, al-tannir ma, faysal w, daoud n, ziade f, el-rajab m. a comparison of pudendal block vs dorsal penile nerve block for circumcision in children: a randomized controlled trial. anesthesia. 2011; 9: 802-7. figure 3. flowchart of consort diagram of patients’ selection pudendal vs penile nerve block in circumcisiontutuncu et al. pediatric urology 36 vol 15 no 03 may-june 2018 37 15. hruby s, ebmer j, dellon al, aszmann oc. anatomy of pudendal nerve at urogenital diaphragm--new critical site for nerve entrapment. urology. 2005; 5: 949-52. 16. schmidt ra. technique of pudendal nerve localization for block or stimulation. j urol. 1989; 6: 1528-31. 17. sfez m, le mapihan y, mazoit x, dreuxboucard h. local anesthetic serum concentrations after penile nerve block in children. anesth analg. 1990; 4: 423-6. pudendal vs penile nerve block in circumcisiontutuncu et al. unclassified post-operative acute urinary retention after greenlight laser. analysis of risk factors from a multicentric database davide campobasso1, anna acampora2, cosimo de nunzio3, francesco greco4, michele marchioni5, paolo destefanis6, vincenzo altieri4, franco bergamaschi7, giuseppe fasolis8, francesco varvello8, salvatore voce9, fabiano palmieri9, claudio divan10, gianni malossini10, rino oriti11, lorenzo ruggera12, agostino tuccio13, andrea tubaro3, giampaolo delicato14, antonino laganà14, claudio dadone15, lugi pucci16, maurizio carrino16, franco montefiore17, stefano germani18, roberto miano18, salvatore rabito19, gaetano de rienzo20, antonio frattini1, giovanni ferrari19, luca cindolo21. purpose: greenlight laser is a mini-invasive technique used to treat benign prostatic obstruction (bpo). some of the advantages of greenlight photoselective vaporization (pvp) are shorter catheterization time and hospital stay compared to turp. post-operative acute urinary retention (paur) leads to patients' discomfort, prolonged hospital stay and increased health care costs. we analyzed risk factors for urinary retention after greenlight laser pvp. materials and methods: in a multicenter experience, we retrospectively analyzed the onset of early and late post-operative acute urinary retention in patients undergoing standard or anatomical pvp. the pre-, intraand post-operative characteristics were compared betweene patients who started to void and the patients who developed post-operative urinary retention. results: the study included 434 patients suitable for the study. post-operative acute urinary retention occurred in 39 (9%). patients with a lower prostate volume (p < .001), an adenoma volume lower than 40 ml (p < .001), and lower lasing time (p = .013) had a higher probability to develop paur at the univariate analysis. the multivariate logistic regression confirmed that lower lasing time (95% ci: 0.86-0.99, or = 0.93, p = .046) and adenoma volume (95% ci: 0.89–0.98, or = 0.94, p = .006) are correlated to paur. furthermore ipss ≥ 19 (95% ci: 1.1910.75, or = 2.27, p = .023) and treatment with 5-ari (95% ci: 1.05-15.03, or = 3.98, p = .042) are risk factors for paur. conclusion: in our series, post-operative acute urinary retention was related to low adenoma volume and lasing time, pre-operative ipss ≥ 19 and 5-ari intake. these data should be considered in deciding the best timing for urethral catheters removal. keywords: laser; prostatectomy; retention introduction greenlight laser is one of the most versatile and saf-est procedures to treat benign prostatic obstruction (bpo), with the possibility to perform standard 1dept. of urology, ospedale civile di guastalla ed ospedale ercole franchini di montecchio emilia, azienda usl-irccs di reggio emilia, italy. 2department of public health, università cattolica del sacro cuore, rome, italy. 3dept of urology, "sant'andrea" hospital, sapienza university, roma, italy. 4department of urology, humanitas gavazzeni, bergamo, italy. 5dept. of medical, oral and biotechnological sciences,“g. d'annunzio” university of chieti, chieti, italy 6dept. of urology, azienda ospedaliera città della salute e della scienza di torino – sede molinette, torino, italy. 7dept. of urology, “arcispedale santa maria nuova”, reggio emilia, italy. 8dept. of urology, “s. lazzaro” hospital, alba, italy. 9dept. of urology, “santa maria delle croci hospital”, ravenna, italy. 10dept. of urology, “rovereto hospital”, rovereto, italy. 11dept. of urology, “ulivella e glicini clinic”, florence, italy. 12dept. of urology, clinica urologica azienda ospedaliera university of padova, padova, italy. 13department of urology, university of florence, unit of oncologic minimally-invasive urology and andrology, careggi hospital, florence, italy. 14dept. of urology, “s. giovanni evangelista” hospital, tivoli, italy. 15dept. of urology, “santa croce e carle” hospital, cuneo, italy. 16dept. of urology, aorn “antonio cardarelli”, naples, italy. 17dept. of urology, “san giacomo” hospital, novi ligure, italy. 18uosd urologia, fondazione policlinico tor vergata, rome, italy. 19dept. of urology, “hesperia hospital”, modena, italy. 20dept. of emergency and organ transplantation, urology and andrology unit ii, university of bari, bari, italy. 21dept. of urology, “villa stuart” private hospital, rome, italy.. *correspondence: urology unit civil hospital of guastalla, azienda usl-irccs di reggio emilia, via donatori di sangue 1, guastalla 42016 (re), italy. phone: +39 0522 837364. fax: +39 0522 837365.e-mail: d.campobasso@virgilio.it received september 2020 & accepted august 2021 vaporization (spvp), anatomical vaporization (apvp) or pure enucleation (greenlep) (1-3). which technique should be preferred in terms of outcomes and adverse events is still a matter of debate. in a previurology journal/vol 18 no. 6/november-december 2021/ pp. 693-698. [doi: 10.22037/uj.v18i.6489] ous paper, we showed similar functional results and complication rates after apvp and spvp(4). some of the advantages of greenlight photoselective vaporization (pvp) are shorter catheterization time and hospital stay compared to transurethral resection of the prostate (turp)(5). post-operative acute urinary retention leads to patients' discomfort, prolonged hospital stay and increased health care costs(6). in a recent review, post-operative acute urinary retention (paur) and clot retention in patients undergoing monopolar o bipolar turp, greenlight pvp and holmium laser enucleation of the prostate (holep) were reported between 0-6% and 0-15.5%, 1-5% and 0-5% and 2-50% and 0-12%, respectively(7). different hypotheses have been postulated to explain this phenomenon, but no clear conclusions or indications have been reached(7-10). understanding risk factors of post-operative acute urinary retention would allow better tailoring of the procedures and of post-operative care. based on these considerations, we decided to analyze a large multicenter cohort of patients in order to evaluate the characteristics of patients developing paur and to identify independent risk factors possibly influencing this event in patients with bpo treated by 180w lbo laser. materials and methods we retrospectively analyzed the onset of early post-operative acute urinary retention in patients undergoing standard or anatomical pvp for lower urinary tract symptoms (luts) secondary to bpo, in a multi-institutional prospectively collected database, including 20 centers, with one or two experienced surgeons per center, between september 2011 and october 2018 using the 180-w xps gl system. post-operative urinary retention was considered as the inability to urinate after the removal of bladder catheter. expert surgeons performed all the procedures. informed consent was obtained from all individual participants included in the study. after the approval of our local ethical committee (protocol number: 1550/2017 ss annunziata hospital, "g. d'annunzio" university of chieti, chieti, italy) a retrospective analysis of the institutional prospectively maintained database of all patients who underwent greenlight laser pvp was performed. indications to greenlight pvp was indwelling urinary retention and failure of medical therapies for luts. data were collected from patients’ charts and outpatient clinical consultations. inclusion criteria were: availability of data about prostate volume evaluated with trans-rectal ultrasound (trus), lower urinary tract symptoms therapy, pre-operative international prostate symptom score (ipss), history of catheterization or urinary retention, type of anesthesia (spinal or general), surgical technique (anatomical versus standard pvp), operative time, lasing time, energy used, energy density, catheterization time and post-operative acute urinary retention. exclusion criteria were: history of prostate cancer, neurogenic bladder disease, previous prostate surgery as well as those who underwent greenlep or contemporary urethrotomy, treatment of bladder stones or bladder tumors and conversion to turp. antibiotic prophylaxis was administered to all patients according to local protocols. surgical procedures were performed according to surgeon’s preferences, as previously described(1,11). in all procedures a cystoscopy to exclude bladder tumors was performed, then ureteral orifices and striated sphincter were visualized. in spvp after the creation of variables a overall (n = 434) no paur (n = 395) paur (n = 39) p age (years) mean ± sd 68.9 ± 8.3 68.7 ± 8.3 70.0 ± 8.3 .359 prostate volume (trus) (ml) < .001 median [iqr] 55 [43-70] 58.5 [45-74] 45 [35-55] < .001 adenoma volume (trus) (ml) median [iqr] n (%) 36 [25-50] 38 [25-50] 25 [20-35] < 40 ml 238 (54.8%) 206 (52.2%) 32 (82.1%) < .001 > 40 ml 196 (45.2%) 189 (47.8%) 7 (17.9%) bpo/luts therapy n (%) none 81 (18.7%) 71 (18.0%) 10 (25.6%) .037 alpha-blockers 227 (52.3%) 213 (53.9%) 14 (35.9%) 5-ari 16 (3.7%) 12 (3.0%) 4 ( 10.3%) combination 110 (25.3%) 99 (25.1%) 11 (28.2%) phytotherapy n (%) yes 59 (13.6%) 56 (14.2%) 3 (7.7%) .260 no 375 (86.4%) 339 (85.8%) 36 (92.3%) pre-operative ipss median [iqr] n (%) 23 [19-28] 22 [19-28] 24 [21-28] .132 < 19 93 (21.4%) 89 (22.5%) 4 (10.3%) .075 ≥ 19 341 (78.6%) 306 (77.5%) 35 (89.7%) indwelling catheter history n (%) yes 62 (14.3%) 59 (14.9%) 3 (7.7%) .217 no 372 (85.7%) 336 (85.1%) 36 (92.3%) post-operative catheterization time (days) median [iqr] 2 [1-3] 2 [1-3] 1 [1-3] .248 anesthesia n (%) spinal 402 (92.6%) 365 (92.4%) 37 (94.9%) .574 general 32 (7.4%) 30 (7.6%) 2 (5.1%) surgical technique n (%) standard pvp 243 (56.0%) 219 (55.4%) 24 (61.5%) .464 anatomic pvp 191 (44.0%) 175 (44.6%) 15 (38.5%) energy used (kj) median [iqr] 210[152.178-304.594] 214.45[153.11-315] 190[149.64-246.04] .148 energy density (kj/ml) median [iqr] 4.1 [2.6-5.3] 4.1 [2.5-5.4] 4.1 [3.2-5.2] .573 operative time (min) median [iqr] 52 [40-70] 52 [40-70] 52 [35-60] .314 lasing time (min) median [iqr] 24.6 [18-35] 25 [18-35.1] 20 [16-26] .013 table 1. patients’s pre-, intraand post-operative characteristics stratified according acute urinary retention incidence. atable values are n (%), mean ± sd or median [iqr]. abbreviations: trus, trans-rectal ultrasound; bpo, benign prostatic obstruction; luts, lower urinary tract symptoms; ipss, international prostate symptom score; paur, post-operative acute urinary retention. predicting factors of post-operative acute urinary retention after greenlight laser-campobasso et al. unclassified 694 vol 18 no 6 november-december 2021 695 a working space at 5 and 7 o’clock, the prostate was vaporized in circumferential manner from the prostatic urethra towards the prostatic capsule (inside out). differently, in apvp after vaporization of the adenoma at the apex up to the localization of the capsule, the surgeon carried out a bilateral incision lateral to verumontanum and using the tip of resectoscope performes a mechanical dissection of the tissue. the dissection plane is followed towards the bladder neck at 6 o’clock and during the dissection the tissue is vaporized, which is obtained by firing the laser towards prostatic urethra (outside in). depending on the center, a 24.5-ch (richard wolf, germany) or 26-ch (karl storz, germany) resectoscope with a laser bridge were used. in both techniques, all the tissues were vaporized and morcellation was not necessary. considered pre-operative variables were: prostate volume, drugs treatment for luts, ipss, the presence of indwelling bladder catheter. intra-operative variables were: type of anesthesia, operative time, lasing time, energy used, energy density and surgical technique. the post-operative variable was catheterization time and the incidence of early and late (at 90 post-operative days) urinary retention. statistical analysis descriptive analyses were performed for total sample and according to the reporting of post-operative aur, calculating means and standard deviations (sd) of normally distributed continuous variables, such as age, based on their distribution (assessed using shapiro– wilk test) and median and interquartile range (iqr) for non-normal variable (e.g. adenoma volume, energy and irradiation time). frequencies and related percentages were reported to synthesize categorical variables. univariate analyses, aimed at identifying factors potentially associated with the development of post-operative aur, were carried-out using chi square test for comparing categorical variables and using t student test or mann-whitney test for numeric continuous variables as appropriate. the normality of these variables was tested using the shapiro wilk test. factors showing a p < .200 at univariate analysis were, therefore, included in the multivariate analysis and a logistic regression was performed. results the multicenter database included 434 patients suitable for the study. post-operative acute urinary retention occurred in 39 patients (9%). all the cases of paur occurred due to the inability to void after bladder catheter removal, in the absence of bleeding or retention due to clots or hemorrhage. patients who developed paur were treated with application of bladder catheter for 5 days (± 4.5). no further episode of aur occurred, the patients did not require reintervention or ancillary procedures/exams (urodynamic evaluation) at 90 post-operative days. the characteristics of the study population are shown in table 1. history of preoperative urinary retention in the paur and no paur groups was 7.7% and 14.9%, respectively (p = .217). referring to pre-operative variables, a lower prostate volume was present in patients who developed paur (45 ml, iqr 35-55 versus 58.5 ml, iqr 45-74, p < .001). patients with an adenoma volume less than 40 ml had a higher probability to develop paur at univariate analysis (82.1%, p < .001) and the type of the pre-operative medical treatment for bpo was linked to the risk of failure of early catheter removal after surgery. on the contrary, the incidence of paur was not affected by age, ipss score and indwelling catheter history (table 1). however, in patients with an ipss score ≥ 19 the p was equal to .075, suggesting an increased occurrence of paur. the multivariate logistic regression showed that an ipss ≥ 19 was associated with higher probability to develop postoperative aur (95% ci: 1.1910.75, or = 2.27, p = .023). analyzing intra-operative findings at the univariate analysis, surgical techniques (standard or anatomical pvp), operative time, energy used and density and type of anesthesia (general or spinal) did not differ between the two groups (table 1). interestingly, at the univariate analysis lower lasing time correlated to the incidence of paur (p = .013). this datum received a borderline confirmation at the multivariate logistic regression analysis with an or of 0.94 (0.88–1.00). age-adjusted logistic regression showed that the higher was the adenoma volume the lower was the probability to develop a post-operative aur. furthermore, an increase in adenoma volume of 1 ml was associated with a decrease of the probability of post-operative aur of 6% (95% ci: 0.89-0.98, or = 0.94, p = .006). on the contrary prostate volume was not statistically significant at the multivariate analysis (p = .184), despite its statistical significance at the univariate analysis. moreover, the multivariate logistic regression confirmed that energy used during surgery did not influence the incidence of paur. in addition, the difference between the two groups in terms of medical treatments have preserved their significance. patients treated with 5 alpha-reductase inhibitors (5-ari) reported a higher probability of paur than those treated with alpha-blockers or no treatments with an or equal to 3.98 (95% ci: 1.05-15.03, p = .041). the complete multivariate logistic regression analysis of the probability to develop post-operative aur are reported in table 2. instead, the two groups did not have a significant difference in term of post-operative catheterization time (p = .248). discussion turp is still considered the gold standard for bpo surgical treatment. nevertheless, in the last decade, guidelines have started to include greenlight and holmium laser among bpo treatment options. a recent survey reported how most urologists follow the eau guidepredicting factors of post-operative acute urinary retention after greenlight laser-campobasso et al. table 2. multivariate logistic regression analysis of the probability to develop post-operative aur. paur adj or* 95% ci p pre-operative ipss < 19 1 ≥ 19 2.27 1.19 10.75 .023 bpo/luts therapy none 1.78 0.72 4.41 .212 alpha-blockers 1 5-ari 3.98 1.05 -15.03 .042 combination 1.74 0.72 4.21 .216 adenoma volume 0.94 0.89 0.98 .006 prostate volume 1.03 0.99 1.07 .184 energy used (kj) 1.00 1.00 1.00 .138 lasing time (min) 0.93 0.86 0.99 .046 unclassified 696 lines for luts in men with a growing interest in laser procedures(12). one of the advantages of these technological improvements is to perform mini-invasive procedures and the possibility to perform tailored surgery based on patients' characteristics. laser treatments in bpo ensure the same surgical outcomes of traditional ones with different laser prostatectomy techniques and minor invasiveness(3,5,13-16). hematuria, post-operative acute urinary retention and urinary tract infections are the three common peri-operative and early complications in prostate surgery for bpo(7,17). urinary retention after removal of bladder catheter is a cause of patient's dissatisfaction and delay the return to normal activity. in the literature, data on prediction of re-catheterization after endoscopic prostate surgery for bpo are sparse, retrospective and heterogeneous. in patients undergoing turp, catheterization for clot retention is variable between different series (0-15.5%) and is one of the most common causes. other potential elements for persistent obstruction are residual chips of prostatic tissue obstructing the urethra, or underactive bladder(7,8,18). further factors investigated with discordant results in patients undergoing turp, holep or greenlight laser pvp were bladder over-distension during surgery, history of diabetes mellitus, age, and several comorbidities such as coronary heart disease, renal insufficiency, and alzheimer’s disease(7,9,10). in the literature greenlight laser has been reported to have shorter catheterization time compared to turp (19,20). in this study, we retrospectively analyzed our multicenter experience in order to understand if there are pre-, intraor post-operative factors that could determine a higher risk of paur. several papers demonstrated that chronic urinary retention and age did not have a negative impact on the possibility to resume normal voiding function after catheter removal in patients having greenlight vaporization(20). in agreement with a previously published articles(21,22), we did not find a statistically significant difference in patients with a history of indwelling catheter and a correlation with age between the two groups (p = .217 and p = .359, respectively). multivariate analysis also confirmed these data. as previously reported, even different surgical techniques (standard versus anatomical pvp) did not influence failure of catheter removal(4). in one of our recent papers, where we compared the results of patients undergoing spvp or apvp, the median catheterization time was 1 day for both groups with a post-operative acute urinary retention of 8.9 and 9.2% in spvp and apvp (p = .872), respectively(4). these data were confirmed as well in this specific analysis of our series. the type of surgical technique and the post-operative catheterization time did not reach statistical significance between the two groups (p = .464 and p = .248, respectively). at univariate analysis of our multicenter database, smaller prostate, adenoma volume less than 40 ml and lower lasing time correlate with an increased risk of post-operative catheter removal failure. the importance of adenoma volume and lasing time were confirmed at the logistic regression, while prostate volume was not significant. the presence of smaller adenoma volume in patients with paur did not influence further intra-operative aspects except the lasing time. in fact, we did not find any difference at the univariate and multivariate analyses between the two groups in terms of operative time, energy delivered and density even though the patients who developed paur had lower prostate and adenoma volumes (table 1). these data might be explained by inefficacious vaporization related to inadequate adenoma removal with excessive energy absorption by the prostatic tissue, which might have an inflammatory and irritating effect. ineffective tissue removal together with an inflammatory effect might be two factors affecting de novo urinary retention after surgery. in our series, men with a history of severe luts may be at risk of paur compared to patients with moderate luts. this aspect has been never investigated in other reports(9,10,20). our consideration is due to the correlation between treatment with 5-ari at the univariate and multivariate analysis and an ipss score ≥ 19 at the multivariate analysis, with the occurrence of paur. in addition, we hypothesize that a pre-existing inflammatory component might influence the rate of paur. the paur group was composed by men with a lower prostate and adenoma volume, but with a higher rate of 5-ari assumption in combination or monotherapy (28.2 versus 25.1% and 10.3 versus 3%, respectively) than the no paur group. as we know, treatment with 5-ari should be considered in patients affected by moderate to severe luts(23-25). this drug acts by inhibiting cells proliferation and inducing apoptosis of prostatic epithelial cells. furthermore, the reduction of expression of cox-2 and rhoa in the prostatic tissue probably attenuate the inflammation process (26). for these reasons, the presence in the paur group of a higher rate of assumption of 5ari in patients with low prostate volume and high ipss value might be explained by an inflammatory component responsible of the post-operative urinary retention. obviously, this is a hypothesis needing further investigations. concerning the operative time, bae et al(9) previously reported that operative time is a risk factors for paur. the authors presumed that the longer operative time caused a prolonged bladder distension. this over-distension may result in temporary bladder dysfunction. in our series, as well as in the series reported by kim et al(10), we did not find a correlation between operative time and failure of catheter removal (p = .314). some limitations are present in this study. first of all it is a retrospective analysis, with a small sample size. the lack of details about the comorbidity profile, preoperative urodynamic parameters and post void residual urine of our study population may be misleading. another confounding factor might be the multi-center nature of this study involving several surgeons with not clustered data analyses. in the future, larger prospective studies are needed to better investigate these issues. however, the major strength of our work, in spite of these limitations, is that it is the first study in the literature trying to analyze the risk factors for post-operative catheter removal failure in patients undergoing greenlight laser pvp. conclusions in our series, we analyzed pre-, intraand post-operative factors affecting urinary retention after greenlight pvp. low adenoma volume and lasing time, pre-operative ipss ≥ 19 and 5-ari intake resulted as risk factors for paur. these variables might be analyzed with prospective studies to confirm our data and for the timing of catheter removal in this subgroup of patients in order predicting factors of post-operative acute urinary retention after greenlight laser-campobasso et al. vol 18 no 6 november-december 2021 697 to better organize hospitalization and recovery. conflict of interest the authors declares that there is no conflict of interest references 1. cindolo l, ruggera l, destefanis p, dadone c, ferrari g. vaporize, anatomically vaporize or enucleate the prostate? the flexible use of the greenlight laser. int urol nephrol 2017; 49:405-11. 2. mordasini l, moschini m, mattei a, iselin c. greenlight laser for benign prostatic hyperplasia. curr opin urol 2018; 28:322-8. 3. barco-castillo c, plata m, zuluaga l, et al. functional outcomes and safety of greenlight photovaporization of the prostate in the highrisk patient with lower urinary tract symptoms due to benign prostatic enlargement. neurourol urodyn 2020;39:303-9. 4. cindolo l, de nunzio c, greco f, et al. standard vs. anatomical 180-w greenlight laser photoselective vaporization of the prostate: a 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acute urinary retention after greenlight laser-campobasso et al. unclassified hydatid cyst treatment and management in retroperitoneal organs; is percutaneous drainage an option? yunus emre göger1, mehmet serkan özkent2*, mehmet aykut yıldırım3, suleyman bakdık4, mehmet giray sönmez1, cengiz kadıyoran4, mehmet balasar1, murat çakır3 purpose: to evaluate patients who had hydatid cyst (ch) in their retroperitoneal space and organs in order to determine a standard treatment option for ch. materials and methods: the files of 56 patients who were treated for ch in our clinic were evaluated retrospectively. all patients underwent either percutaneous drainage (pd) or surgery. patients were divided into two groups as pd (group one) and surgery groups (group two). preoperative and postoperative results were compared statistically. results: 31 of 56 patients were male. mean age of the patient was 39.7 (10–85). 16 patients had been treated with pd and 40 with different surgical interventions such as total cystectomy, partial cystectomy, partial nephrectomy, total nephrectomy, surrenalectomy, and laparoscopic partial surrenalectomy. patients’ followed up was 18 months (6-38m). relapse was seen in 1 patient who underwent pd. on comparing the results, hospitalization period was prolonged in the surgical group with enlarged cyst presence. conclusion: ch presence in the retroperitoneal area is rare. pd, a minimally invasive method, has the potential to be the standard treatment option as it can be performed safely in selected patients. however, currently surgical treatment is considered as the first treatment option after ch diagnosis. keywords: hydatid cyst; percutaneous drainage; retroperitoneal-placed cyst hydatid; treatment of hydatid cyst disease; minimally invasive surgery introduction hydatid cyst (ch) disease is a worldwide zoonosis caused by infection with a small tapeworm parasite called echinococcus granulosus. sheep and cattle are intermediate hosts for the pastoral form and humans are an accidental intermediate host(1). patients with hydatidosis usually present with liver (75%), lung (15%) and other organ involvements (10%)(1-3). ch of kidneys is rare and just 1-5% of all ch diseases in humans involve the kidneys(2-4). it is scarce in the retroperitoneal area(2). patients who refer to clinics with renal ch usually have flank pain, hydraturia, and renal colic(2,4,5). while pelvic placed small cysts are asymptomatic, bigger pelvic cysts can show symptoms due to the compressions of surrounding organs like bladder and rectum(6,7). however, cysts placed in retroperitoneal area can be both asymptomatic and can have symptoms such as flank pain(8,9). likewise, renal ch also can either be asymptomatic or have symptoms such as hypertension and flank pain(5). in treatment of ch disease, treatment options vary according to cyst location, size, and interrelation with surrounding organs. percutaneous drainage (pd) has an important place in the treatment of liver ch(10). there are small-sized series that show its use in kidneys and the other organs(10-12). in cysts of the retroperitoneal area and its organs, despite treatment modalities such as cyst excision, or1department of urology, meram medical faculty, necmettin erbakan university, konya, turkey. 2department of urology, konya education and research hospital, health sciences university, konya, turkey. 3department of general surgery, meram medical faculty, necmettin erbakan university, konya, turkey. 4department of radiology, meram medical faculty, necmettin erbakan university, konya, turkey. *correspondence: department of urology, konya education and research hospital, health sciences university, 42090, konya, turkey. tel: +90 505 9364155. fax: +90 332 2236416. e-mail: msozkent@gmail.com received july 2020 & accepted november 2020 gan-preserving surgery, total excision according to place of the lesions, the first treatment option considered is surgical excision. the present study evaluates ch patients with retroperitoneal area and its organs involvement according to their symptoms, diagnoses, and treatment modalities. percutaneous drainage in selected patients are compared with surgery. patients and methods retrospective analyses of the patients referring necmettin erbakan university, meram medicine faculty, urology, general surgery and radiology departments diagnosed with ch with in the past two decades were made. hereby, cases with unusual cyst location and hepatic involvement were accepted as secondary ch cases and with no hepatic and pulmonary cysts or no history of ch treatment were accepted as a primary cases. imaging methods such as ultrasonography and computed tomography (ct) were routinely performed in cyst diagnosis. magnetic resonance imaging (mri) was performed if considered as necessary. subsequent to the intervention, computed tomography was performed in the first postoperative month in order to distinguish remaining cyst cavity from recurrent new cysts. serologic tests were not conducted routinely. the tests were utilized in cases where imaging methods proved to be insufficient in differential diagnosis. patients were divided into two groups as pd and surgery groups. urology journal/vol 17 no. 6/ november-december 2020/ pp. 657-663. [doi: 10.22037/uj.v16i7.6353] vol 17 no 06 november-december 2020 658 percutaneous drainage procedure the cyst was entered using a 14f (bioteq, taipei, taiwan) trocar with usg or ct-guided trocar method. the contents of the cyst were evacuated as much as possible and irrigated with 0.09% nacl then aspirated. the vesicles were crushed with negative pressure and aspirated out of the catheter. 20-30% of the aspirated amount was filled with contrast material. the integrity of the cyst and its relationship with the surrounding structure were evaluated by fluoroscopy or ct. the cyst was aspirated again. the cyst was refilled with a mixture of alcohol (98% ethanol, approximately 30-50% aspirated volume) and contrast agent (10% cyst volume). after waiting 20 minutes, the cyst was aspirated again. in large cysts and multiple cysts, the cyst cavity was irrigated with 500 cc saline (0.09% nacl) in order to prevent the risk of ethanol intoxication in case of not completely draining the given ethanol. it was then left to free drainage. in order not to develop ethanol intoxication, the amount of alcohol was not exceeded 500 cc in any patient during the procedure. patients treated with pd were hospitalized for 1 day and controlled by usg the next day. if the cyst was completely emptied, the catheter was removed. surgical procedure hydatid cyst in solid organs such as kidney, adrenal gland, endophytic; if large, multiple and associated with the collecting system, was completely removed by surgery. for exophytic and single cysts, primary organ-sparing surgery was performed (partial nephrectomy and adrenolectomy). total cystectomy was performed in all surgically removable cysts. partial cyst excision was performed if the cyst was adhered to surrounding structures and the total excision could not be performed due to morbidity. during partial cyst excision, serum (20% nacl) was given into the cyst and it was waited for 10 minutes. afterwards, the cyst was opened partially, all the contents were aspirated, the cyst wall was removed as far as possible and the procedure was terminated. preoperative and postoperative results were compared statistically. the local human research ethics committee approved the protocol 2020/2772 (necmettin erbakan university, meram medical faculty ethics committee). the analysis and data collection were performed according to the declaration of helsinki after written informed consent was obtained from all patients. statistical analysis spss package program was used for statistical analyses of the data obtained from patients’ files. descriptive statistics were used for patient demographic findings. independent samples t-test was used for parametric data and mann-whitney u test was used for non-parametric data with p values considered significant at < 0.05. results a total of 56 patients were divided into two groups. table 1. clinical characteristic with hydatid cysts. age (mean) 39.7±12.3 (10-85) gender female 25 (35.5%) male 31 (54.5%) contact with animals no 36 (65.4%) yes 20 (34.6%) cyst localization adrenal 3 (9.1%) kidney 31 (50.9%) retroperitoneal 11 (20%) retrovesical 11 (20%) clinical symptoms back pain 26 (47.2%) upper abdominal pain 19 (34.5%) hematuria 2 (3.6%) hydraturia 4 (7.2%) luts 5 (10.8%) asymptomatic 8 (14.5%) hypertension 1 (1.4%) surgery adrenalectomy 1 partial adrenalectomy 1 partial nephrectomy 5 nephrectomy 12 total cystectomy 14 partial cystectomy 8 percutaneous drainage 16 characteristics pd group (n:16) surgical group (n:40) p value female 6 15 0.18 male 12 25 age 38.8±12.6 (18-55) 40.1±10.3 (10-80) 0.09 diameter of the cyst 8.6±1.8 (4-16) 15.4±2.3 (4-25) 0.002 hospital time 1.1±0.9 (1-3) 4.7±1.6 (3-10 days) 0.003 table 2. evaluations of patient groups minimally invasive treatment of cyst hydatid -göger et al. 16 patients (group 1) had been treated with pd and 40 with different surgical interventions (group 2). out of the 56 patients, 31 were male and 25 female. patients’ mean age was 39.7 ± 12.3 years (10–85 years). of the 56 patients, 51.9% (31 patients) had renal ch, 9.1% (3 patients) surrenal ch, 20% (11 patients) retroperitoneal-placed ch, and another 20% (11 patients) retrovesical-placed ch. retroperitoneal organs hydatid cyst (ch) are shown in figure 1. renal hydatid cyst different imaging methods, and surgery specimen are shown in figure 2. out of the renal ch cases, in 17 patients, cyst location was on the left kidney and in 14 on the right. simultaneous cyst presence on both kidneys could not be determined in any of the patients. whereas 9 patients with kidney ch, 1 with retroperitoneal-placed ch, 1 with retrovesical-placed ch, 2 with surrenal ch were considered as primary ch, all the others as secondary cyst. amongst the renal ch patients, simultaneous hepatic ch was determined in 16 patients, ch in liver and lungs in 4 patients. in retroperitoneal ch patients, simultaneous ch in the liver in 8 patients and in the spleen of 1 patient was determined. in retrovesical ch patients’ simultaneous spleen and peritoneum placed ch was determined in 1 patient, spleen and liver ch in 1 patient, and ch in the liver of 7 patients. simultaneous ch in the liver of 2 patients with surrenal ch was also determined. among the symptoms present was the most common one back pain with 26 (47.2%) ratio, followed by upper abdominal pain 19 (34.5%), hematuria 2 (3.6 %), hydraturia 4 (7.2%), lower urinary tract symptoms 5 (10.8%), palpable mass 8 (14.5%), and hypertension 1 (1.4%) (table 1). 41 patients’ indirect hemagglutination (iha) values were preoperatively controlled and the results were found to be significant in 31 of these patients. 7 patients with renal ch, 4 patients with retrovesical-placed ch, 4 patients with retroperitoneal-placed ch, 1 patient with adrenal ch underwent pd. pd in retroperitoneal hydatid cyst is shown in figure 3. also, pd in retrovesical hydatid cyst is shown in figure 4. among the patients who underwent a surgical intervention, total cystectomy was performed in14 patients, partial cystectomy in 8 patients, partial nephrectomy in 5 patients, nephrectomy in 10 patients, surrenalectomy in 1 patient, and laparoscopic partial surrenalectomy in 1 patient (table 2). all patients who underwent pd had secondary ch. medical treatment was administered 1 month before pd and completed to 3 months in total after pd. 7 patients who were operated due to kidney ch and 2 patients who were performed surrenalectomy had primary ch and surgical intervention was decided subsequent to pathology results. in these patients, a 3 month postoperative medical treatment in total was administered. mean hospitalization period in group 2 was 4.7 ± 1.6 days (3-10 days), prolonged ileus emerged in 2 patients who had undergone nephrectomy and in 2 patients who had undergone total cystectomy, and fewer in 6 patients. these patients were discharged after they were followed-up with medical treatment. patients of group 1 drainage were followed-up for only 1 day for control purposes discharged. drainage cathefigure 1. retroperitoneal organs hydatid cyst (ch). a: adrenal hydatid cyst; b: renal hydatid cyst; c: retrovesical hydatid cyst (mri image of the cyst from the back wall of the bladder and seminal vesicles); d: retrovesical hydatid cyst (ct image of the cyst from compressing bladder anterior wall and the patient had hydraturia) minimally invasive treatment of cyst hydatid -göger et al. unclassified 659 vol 17 no 06 november-december 2020 660 ter was removed when the drainage stopped after 2nd or 3rd day. out of group 1, 1 patient had fever and was discharged with medical treatment after 3 days. a mean follow up period of 19 months (10-38 months) was determined. total nephrectomy was performed in renal ch patient subsequent to pd due to relapse detected in 6thpost op month. comparing group 1 (pd group) and group 2 (surgery group), cyst diameter was longer in the group that underwent group 2 with a statistically significant difference. group 1 had a shorter hospitalization period. there was no statistically difference the other parameters. discussion ch is endemic in places where cattle and pig breeding are widely practiced such as south africa, australia, new zealand, south america and a number of mediterranean countries including turkey. location of ch is in the liver with 60-70% ratio, in the lungs 20-25%, in the serosal surfaces 6%, in the kidneys 2.9%, in the spleen and other organs 0.5%, according to the literature (1-4). adult echinococcus granulosus worm lives in the proximal small intestine of the definitive host, attaching by their hooks to the mucosa. eggs are released into intestine of host and are excreted in the feces. humans may become intermediate host through contact with a definitive host (usually a domestic dog) or ingestion of contaminated water or vegetables. when embryo passed through the intestinal wall to reach the portal venous system or lymphatic system, the liver acts as the first line of defense and is therefore the most frequently involved organ. it is not clear how hydatid embryo reaches the kidney, retroperitoneum and pelvis in cases of primary hydatid disease but it was postulated that it must pass through the portal system into the liver and retroperitoneal lymphatics(13). etiopathogenic mechanism in ch of pelvis is possible with the primitive blood-graft of oncosphere or hexacanth and a graft in the pelvic pouch of douglas of protoscolices which come from the cracking of abdominal hydatid cysts(6, 14). the oncospheres in blood pass through the liver and lungs without seeding and develop an implant in retroperitoneum. other hypothesis including disseminating through intestinal lymph vessel and thoracic duct(15). renal and adrenal hydatid cysts usually remain asymptomatic for many years. patients usually present with complaints of dull flank pain, hematuria, palpable flank mass, hypertension, and renal colic(5). our cases applied to our clinic with similar symptoms. even, there was complaint of hydraturia in 4 patients. göğüş c.et al reported 20 patients with renal hydatids in14 cases on the left and in 6 cases on the right side(16). rexiati et al noted cyst presence in the left kidneys of 22 patients and in the right kidneys of 9 patients, in their study(17). likewise, the present study also determined higher cyst sequence in the left kidney. retroperitoneal masses are considered secondary to previous rupture of hepatic cysts or spillage of cystic fluid during surgery or puncture, most of the abdominal or pelvic cystic hydatid disease(8). primary retroperitoneal hydatid cyst means cysts presented in retroperitoneum independent from any peritoneal viscera, and no simultaneous or previous hydatid disease of other organs(9). the occurrence of primary retroperitoneal hydatid cyst is extremely rare. retroperitoneal hydatid cysts can present as abdominal or back pain (31%), palpable mass (65.1%) or urinary tract symptoms (13.9%) depending on the size(9,18). 8 of 11 patients who had retroperitoneal ch referred to hospital with complaints of back pain and palpable mass. there was no symptom in 3 patients. incidence of hydatid disease in surrenal is about 0.5%. figure 2. renal hydatid cyst different imaging methods and surgery material. a: huge renal hydatid follicle cyst image ct image; b: huge renal hydatid follicle cyst image mri image; c-d: nephrectomy material and macroscopic follicle image minimally invasive treatment of cyst hydatid -göger et al. although they are usually asymptomatic, they can show symptoms such as hypertension, flank pain due to compression of the mass(19). in the present study, one of the 3 patients had hypertension, the other 2 patients had pain. the retrovesical location of hydatid cyst is very rare(6, 20). it represents 1-2% of tunisian series and less than 1% of the european series(6). patients can apply to hospital with palpable mass in abdomen and dysfunction due to compression on pelvic organs such as the bladder and rectum(7,14,18). 5 of the 11 patients in the present study applied with lower urinary tract symptoms (luts), 3 with abdominal pain, and one of them with vesical fistula. serological tests can be utilized in the follow-up of operated cases. kuru et al. stated that the iha test had less sensitivity in the pulmonary hydatid cysts and might show false negativities in inactive or calcified cysts and therefore should be supported by another serological method(21). some researchers consider iha sensitivity and specificity of above 90%(22). the iha values of the 41 patients in the present study were determined and were positive in 31 (75.6%) cases. imaging modalities enable differential diagnosis in most of cases. sonography and ct show a uniloculated or a multiloculated cyst that may have some heterogeneous echoes on sonography or have rim enhancement on ct. daughter vesicles (brood capsules) are small spheres that are formed from rests of the germinal layer and appear as cysts within a cyst. it was stated that mri in cyst hydatid diagnosis can be helpful for suspected cases because of it shows soft tissue better in solid organ invasions especially(23). therefore, tomography was widely used for the diagnosis of secondary cases. ct and mri failed in the differential diagnosis of 12 cyst hydatid patients diagnosed as primary and hence differential diagnosis was verified with pathological results in 5 patients of the present study. previous to pd, albendazole treatment is recommended in ch of the liver and lungs, peritoneal ch, and presence of multiple cysts in 1 or more organs, as it reduces cyst tension, contributes to dying and decreasing activity of echinococcus larvae and in needle aspiration it reduces the risk of planting(24). there are studies reporting albendazole treatment efficient success in combined treatments and combined treatment even as more efficient than surgery(25,26). likewise albendazole treatment was initiated to 18 patients10 days before pd performance. a total of 3 months treatment was administered in total continuing after pd. no recurrence, except in 1 case, was seen. figure 3. pd in retroperitoneal hydatid cyst. a: after the operation, the placement of the catheter into the cyst; b: retroperitoneal hydatid cyst accessing needle ct image; c: after the pd operation, the placement of the catheter into the cyst figure 4. pd in retrovesical hydatid cyst. a: retrovesical hydatid cyst ct image; b: retrovesical hydatid cyst accessing needle ct image; c: after the pd operation, the placement of the catheter into the cyst minimally invasive treatment of cyst hydatid -göger et al. unclassified 661 vol 17 no 06 november-december 2020 662 surgical intervention is more on the fore in the treatment of renal cyst hydatids according to the review of the current literature(16,17,27). however, recent publications show that renal cyst hydatid follow-up with pd is on the increase. göğüş et al. performed nephrectomy to 13 out of 20 renal cyst hydatid patients and cystectomy to the rest(16). in the study with a patient series of 30, rexiati at al. performed nephrectomy for renal ch treatment in 1, partial nephrectomy in 1, external capsule excision in 5, internal capsule excision in the remaining 23 cases(17). ödev et al. performed nephrectomy in 8, partial nephrectomy in 4, cystectomy in 3 of their patients in their seventeen-case study(27). in the present study, nephrectomy was performed in 9 out of 30 patients, partial nephrectomy in 5, and total cyst excision in 6 of cases. there were renal cyst hydatid patients who were performed elective pd. pd was performed by akhan et al to 5 cases, el kady et al to 4 cases, goel et al to 4 patients, baijal et al to 2 cases and they did not report any complications neither during the intervention nor during the follow-up(11,28-30). zerem et al. performed pd to 7 renal ch patients in their 72 patient series. 29 patients have developed short-term complications such as urticaria, hypotension, and fever in the aftermath of the intervention; however, no long term complications emerged(12). in the present study, nephrectomy was performed in 1 case due to relapse during the follow-up of 8 cases who had undergone pd. although adrenal gland ch was represented generally in the relevant literature as case reports, with surgical excision and within surrenalectomy, but only in 1 case it was followed-up subsequent to draining with puncture (19,31,32). in the present study, surrenalectomy was preferred in 1 of ch patients, partial surrenalectomy in another 1, and pd treatment to patient with accompanying liver ch. pd drained cyst of patient was 6 cm as it was unilocular and easily differentiated from surrounding tissues. partial adrenalectomy was decided subsequent to pathological evaluation. total cystectomy was performed in 14 patients who have had retroperitoneal, pelvic and kidney cysts that weren’t related with surrounding tissue and without neighboring pancreas, duodenum, ureter, bladder and major vessels. partial cystectomy was performed in the remaining 8 patients. for pd process, into the cyst an injection of a scolicidal solution (hypertonic saline) for 10 minutes is made and the cyst than drained. saadi et al mentioned difficulties of extravesical dissection stemming from relation with surrounding organs (ureter, bladder, and gastrointestinal system), and from the relation of cyst with the peritoneum, in their 4-case study(7). they performed partial cystectomy in 3 of their cases. khouaja et al performed total cystectomy in 5 and partial cystectomy in 3 cases in their 8-case series(14). akbulut et al performed total excision to 55.8% of the patients with retroperitoneal ch, partial cystectomy to 44.2%(9). ben abdullah et al performed partial cystectomy in their 9-case retroperitoneal and retrovesical hydatid cyst series and reported no complications(18). unlike the current literature in the present study pd was applied to 8 cases with retroperitoneal and retrovesical ch. the patients we had undergone pd were all secondary cases. no complications emerged during or after the intervention. in the present retrospective study, the clinical approach to ch at various sites in the human body except the liver is evaluated. in ch endemic geographies, turkey included, ch is to be considered as a differential diagnosis in patients referring to hospitals with c, abdominal pain, and cystic mass in the retroperitoneal area. moreover, in locations where ch is widespread, organs unlikely to be affected are also to be considered. cyst hydatid is not a common widespread phenomenon in our clinic; therefore, the first preference is surgery. while organ-preserving surgery (partial nephrectomy, total cystectomy etc.) is commonly preferred, in cases where this is beyond possibility, total excision is performed. another fact to be considered is that ch can be confused with mass, tumor or cysts during the radiological examination of the cases. the most important underlying reason is the lack of experience because ch presence in retroperitoneal organs is not as common as ch in the liver or lungs. pd is a minimal invasive method for patients and has advantages such as shorter hospitalization period and decreased postoperative complications emergence (bleedings, fever, ileus etc.). therefore, pd has the potential to be an efficient treatment modality that can be employed with frequent patient control. the retrospective analyses of patient files revealed shorter hospitalization in pd compared to surgery. moreover, it can be assumed that first pd and if still necessary subsequently surgery can be practiced in urological ch treatments as currently conducted in liver ch treatment in time with the increase in patient series as the routine treatment modality. conclusions in spite of rare ch presence in the retroperitoneal area and organs, these can lead to important symptoms and severe disorders in patients.ch should be considered in a differential diagnosis in endemic regions. although currently surgical treatment is the first line treatment option considered, pd as a minimal invasive method can be performed in suitable cases. pd comes to the fore due to advantages such as shorter hospitalization and diminished possibility of surgery related complications. the present study is a retrospective study favoring pd to become a standard treatment modality; however, studies with larger patient series are required to determine the first choice treatment modality. acknowledgement the authors thank all staff members and colleagues in department of urology, department of general surgery and department of radiology, necmettin erbakan university, meram medical hospital for their helpful and for their support. conflict of interest the authors report no conflict of interest. references 1. mcmanus dp, zhang w, li j, bartley pb. echinococcosis. lancet 2003; 362:1295-1304. 2. horchani a, nouira y, kbaier i, attyaoui f, zribi as. hydatid cyst of the kidney. eur urol 2000; 38:461-7. 3. göǧüş o, bedük y, topukcu z. renal hydatid disease. br j urol 1991; 68:466-469. 4. zmerli s, ayed m, horchani a, chami i, el ouakdi m, ben slama mr. hydatid cyst of minimally invasive treatment of cyst hydatid -göger et al. the kidney: diagnosis and treatment. world j surg 2001; 25:68–74. 5. volders wk, gelin g, stessens rc. best cases from the afip: hydatid cyst of the kidney: radiologic-pathologic correlation. radiographics 2001; 21:255-260. 6. hafsa c, golli m, kriaa s, et al. retrovesical hydatid cyst in children: report of 3 cases. j radiol 2007; 88:968-71. 7. saadi a, bouzouita a, cherif m, et al. retrovesical hydatic cyst: about 4 cases. can urol assoc j 2015; 9:374-378. 8. erdem mr, akbaş a, onol f, tanidir y, onol s. an unusual retroperitoneal sero-negative hydatid cyst presenting with lower urinary tract symptoms. turkiye parazitol derg 2009; 33:82-84. 9. akbulut s, senol a, ekin a, bakir s, bayan k, dursun m. primary retroperitoneal hydatid cyst: report of 2 cases and review of 41 published cases. int surg 2010; 95:189-196. 10. smego jr ra, bhatti s, khaliq aa, beg ma. percutaneous aspiration-injection-reaspiration drainage plus albendazole or mebendazole for hepatic cystic echinococcosis: a metaanalysis. clin infect dis 2003; 37:1073-1083. 11. el kady n, ramzy i, hanan h, haleem a, elbahnasawy mm. echoguided pair technique in diagnosis and treatment of abdominal hydatid cystic disease in egyptian patients: clnical and ultrasonographic follow up. j egypt soc parasitol 2011; 41:527-542. 12. zerem e, sabanović z, smajić m. percutaneous treatment of abdominal and retroperitoneal echinococcal cysts using ultrasonography. med arh 2003; 57:71-73. 13. pedrosa i, saíz a, arrazola j, ferreirós j, pedrosa cs. hydatid disease: radiologic and pathologic features and complications 1: (cme available in print version and on rsna link). radiographics 2000; 20:795-817. 14. khouaja m, ben ns, haddad n, mosbah a. retrovesical hydatid cyst: diagnosis and treatment in 8 cases. prog urol 2004; 14:489492. 15. khan ra, wahab s, chana rs, fareed r. isolated retroperitoneal hydatid cyst in a child: a rare cause of acute scrotal swelling? j pediatr surg 2010; 45:1717-1719. 16. göğüş ç, şafak m, baltaci s, türkölmez k. isolated renal hydatidosis: experience with 20 cases. j urol 2003; 169:186-189. 17. rexiati m, mutalifu a, azhati b, et al. diagnosis and surgical treatment of renal hydatid disease: a retrospective analysis of 30 cases. plos one 2014; 9:e9660. 18. ben ra, hajri m, aoun k, ayed m. retrovesical and retroperitoneal extrarenal hydatid cyst: descriptive study of 9 cases. prog urol 2000; 10:424-431. 19. akhan o, canyigit m, kaya d, et al. longterm follow-up of the percutaneous treatment of hydatid cyst in the adrenal gland: a case report and review of the literature. cardiovasc intervent radiol 2011; 34:256-259. 20. ben ahmed y, khemekhem r, nouira f, et al. retrovesical hydatic cyst in children: about four cases. jpp. 2012; 25:131-135. 21. kuru c. uniloküler kistik ekinokokkozis’in bb. tanısında indirekt hemaglütinasyon yönteminin değeri. turkiye parazitol derg 1999; 23:251-254. 22. delibaş sb, ozkoç s, sahin s, aksoy u, akisü c. evaluation of patients presenting with a suspicion of cystic echinococcosis to the serology laboratory of the parasitology department of dokuz eylül university medical faculty. turkiye parazit derg 2006; 30:279-281. 23. stojkovic m, rosenberger k, kauczor h-u, junghanss t, hosch w. diagnosing and staging of cystic echinococcosis: how do ct and mri perform in comparison to ultrasound? plos negl trop dis 2012; 6:e1880. 24. vuitton d, meslin f, eckert j, et al. guidelines for treatment of cystic and alveolar echinococcosis in humans. bull world health organ 1996; 74:231-242. 25. yasawy mi, mohammed ae, bassam s, karawi ma, shariq s. percutaneous aspiration and drainage with adjuvant medical therapy for treatment of hepatic hydatid cysts. world journal of gastroenterology: world j gastroenterol. 2011; 17:646-650. 26. cretu c, codreanu r, mastalier b, et al. albendazole associated to surgery or minimally invasive procedures for hydatid disease–how much and how long. chirurgia (bucur) 2012; 107:15-21. 27. ödev k, kilinç m, arslan a, et al. renal hydatid cysts and the evaluation of their radiologic images. eur urol. 1996; 30:40-49. 28. akhan o, üstünsöz b, somuncu i, et al. percutaneous renal hydatid cyst treatment: long-term results. abdominal imaging 1998; 23:209-213. 29. goel m, agarwal m, misra a. percutaneous drainage of renal hydatid cyst: early results and follow‐up. br j urol 1995; 75:724-728. 30. baijal s, basarge n, srinadh e, mittal b, kumar a. percutaneous management of renal hydatidosis: a minimally invasive therapeutic option. j urol 1995; 153:1199-1201. 31. gurbuz r, guven s, kilinc m, abasiyanik f, gokce g, piskin mm. primary hydatid cyst in adrenal gland: a case report. int urol nephrol 2005; 37:21-23. 32. mohammadi a, ghasemi-rad m, oklu r. primary hydatid cyst in the adrenal gland. bmj case rep 2014; 2014:bcr2014207003. minimally invasive treatment of cyst hydatid -göger et al. unclassified 663 case report 298 urology journal vol 6 no 4 autumn 2009 persistent mullerian duct syndrome with an irreducible inguinal hernia mehrdad mohammadi sichani, mitra heidarpour, asghar dadkhah, mehran rezvani urol j. 2009;6:298-300. www.uj.unrc.ir keywords: mullerian ducts, inguinal hernia, congenital abnormalities azahra hospital, isfahan university of medical sciences, isfahan, iran corresponding author: mehrdad mohammadi sichani, md department of urology, azahra hospital, isfahan university of medical sciences, isfahan, iran tel: +98 311 261 4561 e-mail: m_mohammadi@med.mui.ac.ir received january 2008 accepted october 2008 introduction persistent mullerian duct syndrome (pmds), or hernia uteri inguinale, describes a group of patients with a 46,xy karyotype and normal male external genitalia, but internal mullerian duct structures. typically, these phenotypic males have unilateral or bilateral undescended testes, bilateral fallopian tubes, a uterus, and an upper vaginal draining into a prostatic utricle. the condition is commonly diagnosed after mullerian tissue is encountered during inguinal herniorrhaphy or orchidopexy.(1) pmds is a form of male pseudohermaphroditism. when it presents through an inguinal hernia, it is referred as hernia uteri inguinale.(2) persistent mullerian duct syndrome results from either a deficiency of antimullerian hormone (amh) activity or by an abnormality in its receptor. antimullerian hormone, produced by fetal testicular sertoli cells, is responsible for the involution of embryonic mullerian structures in normal males.(2) approximately, 150 cases of pmds have been reported, whereas hernia uteri inguinale is even scarcer.(3) familial association has been found in some cases.(4) the condition may occur sporadically or be inherited as an x-linked, autosomal dominant, or autosomal recessive pattern.(5) in transverse testicular ectopia, both testes descend through the same inguinal canal into the same scrotal sac. persistent mullerian duct syndrome associated with transverse testicular ectopia is much rarer.(6) we report a case of pmds with liomyoma incidentally found during surgery for irreducible inguinal hernia. case report a 55-year-old man was admitted with the diagnosis of irreducible right inguinal hernia. the patient had got married 20 years earlier. he had no sexual dysfunction and was fertile. he had 3 daughters and 1 son. his son had hypospadiasis. on examination, the secondary sex characters were found to be well developed. the patient had normal masculine features, moustache, beard, pubic and axillary hair, and penis. the right testis was well developed, with hernia descending to the external ring. the left scrotum was normal. the hernia was irreducible, tense, and nontender. after general anesthesia, an inguinal incision was made. the spermatic cord was delivered. the peritoneal sac was recognized and dissected off from the cord. a standard herniorrhaphy was performed. in addition, we encountered a solid persistent mullerian duct with an inguinal hernia—sichani et al urology journal vol 6 no 4 autumn 2009 299 mass parallel to the cord, approximately 6 × 3 cm in diameter. this structure was tapered in both sides to a fibrotic band; in one side, it had been adhered to the scrotum and had been fixed to the epididymis and in the other side, it had been adhered to the pelvic cavity. after dissection, the typical figure of a uterus and 2 mullerian ducts were found (figure 1). the mass comprised of mullerian duct derivatives with rudimentary uterus in the center (figure 2). postoperative period was uneventful. histologic examination revealed uterus (with a small liomyoma) and normal fallopian tubes. karyotyping was 46,xy. discussion mullerian duct derivatives are present in male fetuses until the 8th week of gestation. thereafter, it regresses by amh, a glycoprotein produced by fetal sertoli cells. the human gene for amh has been mapped to chromosome 19.(3) absent of amh or abnormal amh, as well as defects in its receptor, causes persistence of mullerian duct derivatives in male fetuses. persistent mullerian duct syndrome is characterized by a normal 46,xy karyotype and normal masculinization of the external genitalia.(1,3) antimullerian hormone does not have a direct role in the descent of the testes. serum levels of amh remain fairly high until 2 years of age; measurable levels persist until puberty and then become undetectable.(5) in this case, its level could not be assessed as the patient was 55 years old. in pmds, the testes are usually histologically normal, apart from lesions, due to longstanding cryptorchidism. the overall incidence of malignant transformation in these testes is 18%, similar to the rate in abdominal testes in otherwise healthy men.(5) there have been reports of embryonal carcinoma, seminoma, yolk sac tumor, and teratoma in patients who have pmds.(4) malignancy arising from the mullerian remnants is also reported (2 cases of adenocarcinoma arising from the remnant uterus in english language literature).(7) there are three anatomic variants: (1) in the most common male type, one testis is usually found within the scrotum; the uterus and ipsilateral fallopian tube are either in the inguinal canal or can be brought into it by gentle traction on the presenting testis.(3) (2) in some cases, the contralateral testis and tube are also in the hernia sac; transverse testicular ectopia can also occur. (6) (3) the least common form, or female type, is characterized by bilateral cryptorchidism with testes embedded in the broad ligaments in an ovarian position with respect to the uterus, which is fixed in the pelvis.(1) correct management of pmds requires recognition of the condition by the surgeon and confirmation with testicular biopsies and chromosomal studies. distinguishing pmds from other intersex disorders is critical. a karyotyping and assessment of testicular response to chorionic gonadotropin stimulation are essential to verify both genetic sex and the existence of functional testicular tissue.(8) as in this case, the diagnosis figure 2. resected uterus and mullerian ducts. histopathology examination confirmed the clinical diagnosis. figure 1. a typical picture of the uterus and mullerian ducts in contact with the testis in persistent mullerian duct syndrome. u indicates uterus; t, testis; and m, mullerian duct. persistent mullerian duct with an inguinal hernia—sichani et al 300 urology journal vol 6 no 4 autumn 2009 is often made incidentally during surgery for an inguinal hernia or during exploration for cryptorchidism.(2) transverse testicular ectopia should be suspected preoperatively in patients who have unilateral inguinal hernia associated with a contralateral nonpalpable testis.(9) in suspected cases, ultrasonography, computerized tomography, magnetic resonance imaging, and laparoscopy may be helpful in diagnosis. (1,10) before puberty in patients with bilateral cryptorchidism, serum amh levels also helps in diagnosis. the initial procedure consists of testicular biopsies, herniorraphy, and replacement of the gonads and mullerian remnants within the pelvis.(3) after confirmation of the diagnosis, definitive surgery consists of removal of the mullerian remnants with orchiopexy or orchiectomy.(3) in cases with transverse testicular ectopia, crossed orchiopexy gives good results, particularly if it is performed with minimal delay.(4) every effort should be made to preserve fertility and hormonal function, in patients less than 2 years of age.(11) although orchiopexy, even if performed early in life, does not reduce the risk of malignancy, it provides a palpable location for the early detection of malignancy. preservation of the mullerian derivatives is incompatible with successful orchiopexies because with sexual maturation, the uterus may become hypertrophic and cause discomfort, or may present as a mass whose origin is unknown.(3) in this case, the characteristic macroscopic appearance gives sufficient evidence of the pmds .we found 123 case reports on pmds. the most common presenting symptoms were inguinal hernia, undescended testis, testis tumor, and abdominal mass. surgeons dealing with hernia should consider the possibility of pmds, especially when it is associated with cryptorchidism. conflict of interest none declared. references 1. david ad. sexual differentiation: normal and abnormal. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 3826-7. 2. turaga kk, st peter sd, calkins cm, holcomb gw 3rd, ostlie dj, snyder cl. hernia uterus inguinale: a proposed algorithm using the laparoscopic approach. surg laparosc endosc percutan tech. 2006;16:366-7. 3. di clemente n, belville c. anti-müllerian hormone receptor defect. best pract res clin endocrinol metab. 2006;20:599-610. 4. berkmen f. persistent mullerian duct syndrome with or without transverse testicular ectopia and testis tumours. br j urol. 1997;79:122-6. 5. shamim m. persistent mullerian duct syndrome with transverse testicular ectopia presenting in an irreducible recurrent inguinal hernia. j pak med assoc. 2007;57:421-3. 6. boleken me, kaya m, guran s, memetoglu me, kanmaz t, yucesan s. persistent mullerian duct syndrome with transverse testicular ectopia. int urol nephrol. 2007;39:1173-5. 7. romero fr, fucs m, castro mg, garcia cr, fernandes rde c, perez md. adenocarcinoma of persistent mullerian duct remnants: case report and differential diagnosis. urology. 2005;66:194-5. 8. dekker hm, de jong ij, sanders j, wolf rf. persistent mullerian duct syndrome. radiographics. 2003;23:309-13. 9. chandrasekera sk, barber nj, sheriffdeen ah. persistent mullerian duct syndrome with transverse testicular ectopia. urology. 2003;62:1120. 10. otsuka t, nakazono t, matsuo y, kanou t, masaki z, kudo s. persistent mullerian duct syndrome suggested by magnetic resonance imaging. radiat med. 2003;21:277-9. 11. brandli dw, akbal c, eugsster e, hadad n, havlik rj, kaefer m. persistent mullerian duct syndrome with bilateral abdominal testis: surgical approach and review of the literature. j pediatr urol. 2005;1:423-7. reconstructive surgery long-term effect of colchicine treatment in preventing urethral stricture recurrence after internal urethrotomy orhun sinanoglu,1* fatih osman kurtulus,2 feride sinem akgun3 purpose: urethral stricture, known as a scar formation leading to urethral lumen stricture in sub-epithelial tissue, is the most common late complication of transurethral prostate resection (turp). the aim of study is to evaluate efficacy of colchicine treatment in preventing urethral stricture recurrence in patients after internal urethrotomy, and to determine whether colchicine treatment had a sustained effect in decreasing stricture recurrences in patients with concomitant diseases. methods: patient data with weak urine stream and/or voiding difficulty, and who had internal urethrotomy in urology department of maltepe university hospital between dates 01 january 2011 and december 2016 were collected. they were randomized to colchicine receiving, and non-receiving arms. colchicine was given 1 g/day orally for two months, and primary efficacy point was defined as urethral stricture development in 3, 6, and 12 months after internal urethrotomy. results: the study was conducted on 84 males with the mean age of 67.7 ± 7.5 years. the mean ages of colchicine receivers and non-receivers were 68.2 ± 7.6 and 67.1 ± 7.6 years, respectively. recurrence rate of urethral stricture was significantly lower in colchicine receivers (p = .044) than non-receivers. in overall evaluation, recurrence rate of urethral stricture was significantly low, if there was only one comorbidity (p = .006), but rates were significantly higher in presence of three (p = .010) and four (p = .040) comorbidities. no significant difference in recurrence rates was determined in patients without comorbidities or with two comorbidities (p > .05). conclusion: combination of oral colchicine with internal urethrotomy reduces recurrence rates of urethral stricture significantly. keywords: urethral stricture; colchicine; peyronie’s disease; male; fibrosis; recurrence. introduction urethral stricture, the oldest and most difficult dis-ease to treat in urology, is known to be caused by scar formation leading to urethral lumen stenosis in sub-epithelial tissue. it is observed with the incidence of 2.7% in late phase of endourological interventions such as transurethral prostate resection.(1,2) it was first reported in 1974, and direct visual internal urethrotomy (dviu) was performed more commonly than blinded urethrotomy methods such as periodic urethral dilation in urethral stricture treatment, because it was easy to perform and had a short recovery duration. the curative rate of internal urethrotomy was reported as 20% with the most common complication high recurrence rate. during the procedure, scarred tissue could not be taken, and thus internal urethrotomy might be curative in strictures shorter than 1 cm, and with minimal spongiofibrosis.(1) pansadoro and heyns reported recurrence rates as 61%, 100% and 100% in their 4-year patient follow-up studies reciprocally.(3) on the other hand, studies indicated that mean recurrence rates of 68% after a single urethrotomy intervention, 58% after a bulbar stricture, and 89% after a penile urethral stricture.(3) in general, the usual disease initiation occurs after urethral mucosal 1urology department, maltepe university faculty of medicine, istanbul turkey. 2urology clinic kolan hospital, istanbul turkey. 3emergency department, maltepe university faculty of medicine, istanbul turkey. *correspondence: maltepe universitesi, uroloji ad, feyzullah cadesi no: 39 maltepe istanbul turkey. tel: +90 216 444 06 20. e-mail: orhundr@hotmail.com. received october 2017 & accepted january 2018 lesion and infection which is followed by a scar tissue. today, most urethral strictures are resulted from trauma such as endoscopic urological interventions. although peyronie’s disease is an uncommon condition in middle aged men, inflammation is observed in the tunica causing ultimately scarring and penile curvature. it is believed that fibrin intravasation occurs from blood circulation into tunica albuginea after a trauma. fibrin reaching tunica albuginea stimulates profibrotic tgf-1 compound release, then induces formation of reactive oxygen species (ros). thus, irregular collagen accumulation is observed, and destruction of newly formed collagen mass is hindered, which leads eventually to plaque calcification.(4) it is assumed that etiopathogenesis of urethral stricture and peyronie’s disease may have the common background as trauma and fibrosis as well. patients at early stages of peyronie’s disease are candidates for medical treatment. in the literature, there are studies conducted with various biological agents for the disease such as calcium channel blockers, corticosteroids, vitamin e, and colchicine.(5) although the most effective treatment has not been determined for peyronie’s disease yet, combination of verapamil with vitamin e and colid: 4198 chicine has shown better pain control while reducing penile curvature, dimensions of calcification and the degree of erectile dysfunction, thus improving the quality of life.(5) considering the similar etiological and pathophysiological backgrounds for both diseases, the present study was conducted to evaluate efficacy of colchicine treatment in preventing urethral stricture in patients after internal urethrotomy, and to determine whether colchicine treatment had a sustained effect in decreasing recurrence of urethral strictures in patients with multiple comorbidities. to our knowledge, colchicine treatment in the prevention of urethral stricture has not been investigated yet, this is the first study evaluating the effect of oral colchicine against this common long-term complication of turp. patients and methods study population medical data of patients who applied to urology department of maltepe university hospital with complaints of weak urine stream or difficulty on urination following a past turp operation between dates 01 january 2011 and december 2016 were collected, and after internal urethrotomy patients were randomized either to colchicine receiver or non-receiver study arms. random numbers were obtained from computer software. the treatment modality for each patient was inserted in envelopes. when the eligible patient agreed to participation, the envelopes were opened by one of the researchers and allocated treatment started as described below. the outcomes were evaluated by investigators who were blind to treatment assignments. colchicine receivers (n=41) colchicine non-receivers (n=43) p age (year) min-max (median) 55-82 (66) 54-84 (66) a0.488 mean±sd 68.2 ± 7.6 67.1 ± 7.6 etiology; n (%) turp 31 (75.6) 38 (88.4) c0.127 open prostatectomy 10 (24.4) 5 (11.6) residual urine amount (cc) min-max (median) 0-800 (160) 0-800 (160) b0.939 mean ± sd 224.88 ± 212.85 207.44 ± 179.60 mean urine flow rate (ml/sec) min-max (median) 0-8 (4) 1-8 (4) a0.754 mean ± sd 4.24 ± 1.93 4.12 ± 1.79 maximum urine flow rate (ml/sec) min-max (median) 0-14 (8) 3-13 (8) a0.729 mean ± sd 8.20 ± 3.33 7.95 ± 3.03 table 1. evaluation of descriptive characteristics according to groups astudent-t test bmann whitney u test cpearson chi-square test sd; standard deviation figure 1. study flow diagram colchicine effect against urethral stricture-sinanoglu et al. procedures urethrography-uroflowmetry was performed to assess the presence and extent of urethral stricture. colchicine was given 1 g/day orally (2x0.5 mg) for two months, and primary efficacy point was defined as whether urethral stricture recurrence was developed or not in 3, 6, and 12 months after internal urethrotomy in both study arms. inclusion and exclusion criteria patients undergoing tur-p having urethral stricture complication which is shorter than 1.5 cm, treated with internal urethrotomy were included in the study. patients who had urethral stricture longer than 1.5 cm and/or multiple urethral strictures, and developed urethral stricture after external trauma were excluded from the study. patients who have previous history of hypersensitivity to colchicine, twice as high ast or alt as the hospital's reference value, creatinine level of 2.0 mg/dl or higher, past history of malignant tumor, peptic ulcer, serious hematological disorder, serious cardiac disorder, aspirin induced asthma and patients who are ineligible for the study as judged by the investigator were exluded. flow diagram of the study are summarized in figure 1 . evaluations hospital information management systems (medipro software and pusula) determined medical information of eligible patients, such as demographic and investigation results, comorbidities, etiologies, preoperative ipss scores, results of uroflowmetry, and stricture recurrences. hospital information management systems (medipro software and pusula) determined medical information of eligible patients, such as radiological and laboratory results, comorbidities, etiologies, preoperative ipss scores, results of uroflowmetry, and stricture recurrences. the comorbidities were also confirmed by combining history taking, previous consultations. the study was initiated after obtaining approval of local ethics committee (maltepe university medical faculty ethics committee number 2017/900/08). statistical analysis the external statistician remained blind to outcomes variables. ncss (number cruncher statistical system) 2007 (kaysville, utah, usa) program was used for statistical analysis. the continuous variables; the urinary flow rate, residual urine and ipps scores were measured to assess urethral stricture and were expressed as means and standard deviations. variables in terms of comorbidities between colchicine receiver and non-receiver groups were compared using pearson chi-square test and fisher’s exact test. comparisons of groups with normally distributed quantitative data were performed by using student t test. if the distribution was abnormal, comparisons were performed by using mann whitney u test. the level of significance was determined as p < 0.05. results the study was conducted on 84 males with the mean age of 67.7 ± 7.5 (range = 54-84) years. the mean ages of colchicine receivers and non-receivers were 68.2 ± 7.6 and 67.1 ± 7.6 years, respectively (table 1). groups were age matched (p > .05). the average diameter of male urethra without stricture was 9-10 mm. in colchicine receiver group, turp was performed in 75.6% (n = 31), and open prostatectomy was performed in 24.4% (n = 10) patients. in colchicine non-receiver group, turp was performed in 88.4% (n = 38) patients, whereas open prostatectomy was performed in 11.6% (n = 5) patients. residual urine amount, mean urine flow rate, and maximum urine flow rate were compared between the groups, and no significant difference was determined (p > .05) (table 1). recurrence rate of urethral stricture was significantly lower in colchicine receivers (14.6%) than non-receivers (32.6%) (p = .044) (table 2). the recurrence rates were significantly different according to number of comorbidities (p = .001). according to paired comparisons to determine number of table 2. evaluation of urethral stricture recurrence according to groups colchicine receivers (n=41) colchicine non-receivers (n=43) cp recurrence of urethral recurrence (+) 6 (14.6) 14 (32.6) 0.044* stricture; n (%) recurrence (-) 35 (85.4) 29 (67.4) cpearsonchi-square test *p < 0.05 colchicine receivers (n = 41) colchicine non-receivers (n = 43) us recurrence p us recurrence p (+) (-) (+) (-) comorbidity positive 3 (50.0) 24 (68.6) d0.393 14 (100) 18 (62.1) d0.008** negative 3 (50.0) 11 (31.4) 0 (0) 11 (37.9) dm positive 1 (16.7) 13 (37.1) d0.645 12 (85.7) 8 (27.6) c0.001** negative 5 (83.3) 22 (62.9) 2 (14.3) 21 (72.4) copd positive 2 (33.3) 3 (8.6) d0.148 6 (42.9) 2 (6.9) d0.009** negative 4 (66.7) 32 (91.4) 8 (57.1) 27 (93.1) ht positive 3 (50.0) 20 (57.1) d1.000 12 (85.7) 12 (41.4) c0.006** negative 3 (50.0) 15 (42.9) 2 (14.3) 17 (58.6) cad positive 2 (33.3) 6 (17.1) d0.578 7 (50.0) 2 (6.9) d0.003** negative 4 (66.7) 29 (82.9) 7 (50.0) 27 (93.1) cpearsonchi-square test dfisher’sexact test **p < 0.01 abbreviations: us, urinary stricture; dm, diabetes mellitus; copd, chronic obstructive pulmonary disease; ht, hypertension; cad, coronary arterial disease. table 3. evaluation of relationship between comorbidity and urethra stricture recurrence rates according to groups colchicine effect against urethral stricture-sinanoglu et al. comorbidity which caused difference, recurrence rate of urethra stricture was significantly low if there was only one comorbidity (p = .006), but the rates were significantly higher if there were three (p = .010) and four (p = .040) comorbidities. there was no significant difference in the rates in patients without comorbidities and with two comorbidities (p > .05) (table 3). discussion the average lifespan in elderly men has been extended with advances in diagnostic and treat-ment modalities in the past decades therefore, in recent years, the number of elderly patients having benign prostate hyperplasia (bph) with several comorbidities who meet the criteria for recommended sur¬gery has increased.(2) however, surgical procedures including the widely used turp have complications such as hemorrhage, electrolyte disturbances and long-term urethral strictures particularly in elderly patients with concomitant cardiovascular, pulmonary, and another organ diseases. (6) in the present study, we evaluated patients suffering from urethral stricture following prostatectomy procedures, and determined that colchicine may be an effective option to decrease stricture recurrence rate after internal urethrotomy during 1-year follow-up. to the best of our knowledge this study is the first one, where combination of internal urethrotomy and oral colchicine treatment was employed to prevent recurrence of urethral stricture. the underlying conditions are still not clearly known how the process follows after internal urethrotomy, but it is assumed by some authors that if epithelialization progresses completely before wound contraction, urethrotomy may be successful.(2,6) therefore, if wound contraction is delayed by any drug or procedure, then the recurrence rate of urethral stricture will decrease. mazdak et al.(1) conducted a prospective study on 50 patients with anterior urethral stricture, who underwent internal urethrotomy, and randomized to 40 mg submucosal triamcinolone injection receivers and non-receivers. after a mean follow-up of 13.7 ± 5.5 months, they reported that recurrence rate was significantly decreased in triamcinolone receiving arm. the urethral stricture was (21.7 %) in the triamcinolone group and in 11 patients (50 %) in the control group. in our study recurrence rate of urethral stricture was significantly lower in colchicine receivers (14.6 %) compared to the studies combining urethrotomy with local medication. corticosteroid injections are a well-established pharmacological treatment for skin scars, mucosal strictures, and in a few cases of urethral strictures to decrease collagen production.(1,7) however, the reported success rates were not very promising especially for urethral stricture recurrence rates. korhonen et al. indicated that total success rate was only 11 % at the end of the first year in patient group that received internal urethrotomy plus methylprednisolone.(8) tavakkoli tabassi k et al. performed a double-blind, randomized, placebo-controlled study in which experimental group (34 patients) received triamcinolone acetonide injection and the control group (36 patients) received an injection of sterile water after internal urethrotomy. complication and recurrence rates in experimental group were lower than the control group, but the difference was not statistically significant. however, time to recurrence colchicine effect against urethral stricture-sinanoglu et al. decreased significantly in triamcinolone group suggesting that intralesional corticosteroid injection may delay the recurrence.(10) these lower success rates with corticosteroids may be explained with the fact that routine urethral instrumentation destroys the wound and simultaneous subepithelial or intralesional medication with short duration of action may not reverse the fibrotic process. moreover, ye tian et al. report that active surveillance is a better option for preventing stricture recurrence as compared with routine invasive manipulations as shearing force caused by them splits the epithelium. urine extravasates through these fissures or ulcers leading to subepithelial fibrosis.(10) therapeutic potential of colchicine was recently recognized in peyronie's disease. its mechanism of action was described by blocking the path of arachidonic acid lipoxygenase, thus preventing leukotriene formation by reducing inflammation and chemotaxis and interferes with procollagen transcellular migration. therefore, procollagen formation was decreased, and collagenase production was increased. its mechanism of action would lead to antifibrotic, antimitotic and anti-inflammatory effects.(4,5) in the present study, we inspired from promising results of colchicine in peyronie’s disease treatment. data of patients with anterior urethral stricture who underwent internal urethrotomy and received oral colchicine treatment in the subsequent 2 months were collected. it was most probable that significant decrease in recurrence rate of stricture in the colchicine receivers was related to antifibrotic and anti-inflammatory effects of colchicine. when demographic characteristics of our study group was considered, presence of multiple comorbidities were expectable.(6) they could decrease the success rate of urethrotomy, and thus recurrent interventions would be required. comorbidities in the study cohort were mainly diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and coronary arterial disease. combined treatment of internal urethrotomy with oral colchicine had positive influences in decreasing recurrence rates of urethral stricture in patients with three or four comorbidities. there are some limitations in our study. firstly, the sample size was small and could not be increased. however, it could be accepted as a pilot study, which would help to design new prospective randomized studies about the same issue. secondly, we presented here 1-year follow-up results of the study. five-year follow-up results would be more helpful in interpreting efficacy of this combination treatment, as it was frequently reported in the literature. thirdly, data about cost-effectiveness and patient’s quality of life would show whether this treatment modality could reach secondary endpoints. conclusions combination of oral colchicine with internal urethrotomy reduced the stricture recurrence rate significantly. further prospective randomized studies with larger sample sizes are required to determine efficacy and safety of this new treatment approach in more detail. acknowledgement none conflict of interest the authors report no conflict of interest. references 1. mazdak h, izadpanahi mh, ghalamkari a, et al. internal urethrotomy and intraurethral submucosal injection of triamcinolone in short bulbar urethral strictures. int urol nephrol 2010;42:565-8. 2. jordan gh, schlossberg sm. surgery of penis and urethra. in: wein aj, kavoussi lr, novick ac (eds) campbell-walshurology, 9th edn. saunders, philadelphia, 2007. pp 1055–75. 3. pansadoro v, emiliozzi p. internal urethrotomy in the management of anterior urethral strictures: long-term follow up j urol. 1996;156:73-5. 4. tunuguntla hs. management of peyronie's disease: a review. world j urol 2001;19:24450. 5. halal aa, geavlete p, ceban e. pharmacological therapy in patients diagnosed with peyronie's disease. j medlife 2012;5:192-5. 6. sinanoglu o, ekici s, balci m.b.c, ahazar a i, nuhoglu b. comparison of plasmakinetic transurethral resection of the prostate with monopolar transurethral resection of the prostate in terms of urethral stricture rates in patients with comorbidities prostate int 2014;2:1-6 7. geovannini um. treatment of scars by steroid injections. wound repair regen 2002;10:116–7. 8. korhonen p, talja m, ruutu m, alfthan o. intralesional corticosteroid injections in combination with internal urethrotomy in the treatment of urethral strictures. int urol nephrol. 1990;22:263-9. 9. tavakkoli tabassi k, yarmohamadi a, mohammadi s. triamcinolone injection following internal urethrotomy for treatment of urethral stricture. urol j. 2011 ;8:132-6. 10. tian y, wazir r, wang j, wang k, li. prevention of stricture recurrence following urethral internal urethrotomy: routine repeated dilations or active surveillance? h.urol j. 2016 25;13:2794-6. colchicine effect against urethral stricture-sinanoglu et al. reconstructive surgery the whitaker test in the follow-up of complex upper urinary tract reconstruction: is it clinically useful or not xinfei li1, kunlin yang1, weijie zhu1, yuke chen1, yang yang1*, peng zhang2, juan wu3, pengjie wu4, shiliang wu1, xuesong li1*, liqun zhou1 purpose: to evaluate the feasibility and guiding significance in postoperative management of the whitaker test after complex reconstruction of the upper urinary tract. materials and methods: patients who underwent complex ureteral reconstruction and received the whitaker test after surgery between december 2018 and december 2019 were included. we judged it abnormal that the renal pelvis pressure was higher than 22 cmh 2 o or the pressure difference was greater than 15 cmh 2 o. the results were used as a reference for removing the nephrostomy tube. based on whether the renal pelvic pressure was higher than 22 cmh 2 o, the patients were divided into the elevated pelvis pressure group and the normal group. follow ups at 1 month and every 3 months were collected. results: a total of 19 patients were included. fifteen patients did not present obvious abnormalities. one patient suffered from contrast infiltrating into the renal parenchyma, and the pressure was higher than 15 cmh2o. ureteral stent implantation was performed. the other 3 patients had either elevated pelvis pressure or insufficient image, 2 of which prolonged the duration of nephrostomy tubes. the median follow-up time was 12.6 months. ctu/mru after removing nephrostomy tubes indicated improved/stable hydronephrosis in all patients. the creatinine in the elevated pelvis pressure group was higher than that in the normal group (91.4 ± 27.6 vs 86.7 ± 16.5 μmol/l, p = .782), and the egfr was lower (76.0 ± 14.0 vs 81.8 ± 24.1 ml/min/1.73m2, p = .695), but without significant difference. the change in creatinine during follow-up in the elevated renal pelvic pressure group was significantly different from that in the normal group (-13.6 ± 1.0 vs -0.2 ± 10.6 umol/l, p = .047). conclusion: postoperative whitaker test can help judge whether nephrostomy could be removed. elevated pressure in upper urinary tract after reconstruction suggests the need to prolong the time of the nephrostomy tube or even re-intervene. proper management for patients with elevated renal pelvis pressure can help restore the renal function. keywords: dilation; ureteral reconstruction; diagnostic techniques; urodynamic study; renal function; the whitaker test introduction complex ureteral stricture can lead to severe dila-tion and hydrops of the urinary tract. upper urinary tract reconstructive surgery aims to restore the continuity of the urinary tract and protect renal function.(1) the main reconstructive strategies included boari flap, appendix, oral mucosa, ileal ureter replacement and autotransplantation,(2-4) however, patients often receive ureteral stent or retain nephrostomy tube for the protection of the reconstructive upper urinary tract, and the majority need a relatively long time to recovery. routinely, patients are suggested to undergo ultrasound, intravenous urography, diuretic renography, 1department of urology, peking university first hospital. institute of urology, peking university. national urological cancer center, beijing, p.r. china. 2department of urology, emergency general hospital, beijing, p.r. china. 3china rehabilitation research center, beijing boai hospital, beijing, p.r. china. 4department of urology, beijing hospital, national center of gerontology; institute of geriatric medicine, chinese academy of medical sciences, beijing, p.r. china. *correspondence: department of urology, peking university first hospital. institute of urology, peking university. national urological cancer center, beijing, china. tel:+86-10-83575101, fax:+86-10-66551726, e-mail: goldflamingo@126.com; pineneedle@126.com xinfei li, kunlin yang and weijie zhu contributed equally to this article received may 2020 & accepted january 2021 computed tomography urography (ctu) and magnetic resonance urography (mru) at follow-up. the interpretation relies on the degree of hydrops and urinary tract lumen dilation to determine whether the urinary tract is unobstructed. whereas, dilatation or hydrops does not always equate with obstruction.(5,6) more difficult to interpret is the dilatation that remains after relief of obstruction. different from imaging examination, renogram utilized radioisotopes to assess the excretory function through radioisotopes and has been widely used since it was proposed. however, in a kidney with impaired function or associated with an extremely large system the test may be invalid, and the response to a diuretic is in doubt and different according to whether urology journal/vol 19 no. 1/ january-february 2022/ pp. 56-62. [doi: 10.22037/uj.v18i.6277] vol 19 no 1 january-february 2022 57 the damage mainly is glomerular or tubular. moreover, with a renogram no information is achieved about compliance.(7) since radionuclide imaging presents a blurred image of anatomical structure, the result of diuresis renogram cannot reflect the changes in the shape of the upper urinary tract and the degree of difficulty of deformation during urine transportation. more importantly, all the present examinations are affected by a ureteral stent and a nephrostomy tube. the uncertain outcome after removing protective ureteral stents or nephrostomy tubes is a concern. in 1973, whitaker advocated the use of a constant perfusion flow study to distinguish whether urinary tract dilatation is caused by obstruction.(8) currently, there are seldom articles discussing the role of the whitaker test in the postoperative evaluation of complex upper urinary tract reconstruction. in addition, previous studies investigating the relationship between the whitaker test and renal function focused almost on the pelvis-bladder pressure difference, and the result is still controversial. this study presents the postoperative results of the whitaker test in reconstructive upper urinary tract. we also explore the renal function after the whitaker test guided management, aiming to evaluate the instructional significance of the whitaker test in complex reconstructive upper urinary tract. materials and methods study population a retrospective study of complex upper urinary tract reconstruction in 19 patients was conducted from december 2018 to december 2019. all patients were indicated to a surgical management by severe hydronephrosis, flank pain, and/or poor renal function. complex reconstruction was defined as (1) long ureter defects longer table 1. clinical characteristics and surgical information variables n (%) gender male 7 (36.8%) female 12 (63.2%) age, years, mean ± sd 41.6±9.8 bmi, kg/m2, mean ± sd 24.2±3.2 side left 6 (31.6%) right 10 (52.6%) bilateral 3 (15.8%) lesion upper 5 (26.3%) middle 3 (15.8%) lower 11 (57.9%) etiology ureteroscopic holmium laser lithotripsy 9 (47.4%) radiotherapy 4 (21.1%) cervical cancer surgery 4 (21.1%) idiopathy 2 (10.5%) surgery ileal ureter 11 (57.9%) boari flap 3 (15.8%) ureteroneocystostomy 2 (10.5%) appendiceal onlay flap 2 (10.5%) lingual mucosal 1 (5.3%) mean preoperative serum creatinine (μmol/l) 92.9 ± 27.0 mean preoperative egfr (ml/min/1.73m2) 79.2 ± 23.7 figure1: normal postoperative result of the whitaker test (lingual mucosal graft). figure 1a &1b. imaging of renal pelvis, upper urinary tract and bladder. figure 1c. the record of pressure during perfusion. co: cough, fi: first time feeling of urination, uu: urgency of urination; p: point of imaging time. the whitaker test after complex reconstruction-xinfei li et al. abbreviations: egfr, estimated glomerular filtration rate. reconstructive surgery 58 than 5 cm that cannot be managed with simple resection and anastomosis, (2) secondary reconstruction and (3) severe ureteral injuries such as avulsion or rupture. data on patient characteristics, etiology, laboratory data, imaging studies, surgery information and perioperative data were collected from our reconstruction of urinary tract: technology, epidemiology and result (recutter) database. the present study was approved by the institutional ethics committee of our hospital. informed consent was obtained from all individual participants included in the study. whitaker test all patients had a nephrostomy tube before surgery. in order to protect the reconstructed upper urinary tract, the nephrostomy tube was intermittently clipped after surgery instead of being removed immediately. patients were followed up at 1 and 3 months after surgery to determine whether to remove the nephrostomy tube. the process of perfusion was the same as the method whitaker described in 1973. patients took a prone position. a urinary catheter was placed before the examination. nephrostomy tubes and urinary catheters were connected to the pressure transducer respectively. the contrast medium was diluted at 50 % with saline. the initial perfusion rate was 10 ml/min (decreasing to 5 ml/min in 3 equivocal cases). the perfusion was continued until a steady state was reached at which the pressure did not change. the pressure was recorded simultaneously from the renal pelvis and the bladder. if the patient had a bladder distention or the elevated pressure did not ease, the perfusion should be suspended or terminated. we judged it abnormal when the renal pelvis pressure was higher than 22 cmh 2 o or the pressure difference was greater than 15 cmh 2 o.(8-10) at the same time, x-ray was used to evaluate the morphology of the upper urinary tract. hold-up of contrast medium at anywhere in the ureter may be suspected. a significant rise in the pressure difference across the suspected obstruction allows the diagnosis, whereas free drainage of contrast at low pressure excludes obstruction. based on whether the renal pelvic pressure was higher than 22 cmh 2 o, the patients were divided into 2 groups for further comparison. namely the elevated pelvis pressure group and the normal group. follow-up after removing the nephrostomy tubes, patients came to the clinic every three months. physical examination, blood serum creatinine tests, urine routine tests and urinary ultrasound were performed at each visit. ctu/ mru was performed to evaluate the morphology of the reconstructive urinary tract. based on the anteroposterior diameter of the pelvis in b-ultrasound, hydronephrosis is defined as normal (<5 mm), mild (5-9 mm), moderate (10-14 mm) and severe (≥15 mm). the estimated glomerular filtration rate (egfr) is calculated by the chronic kidney disease epidemiology collaboration (ckd-epi) equation. successful nephrostomy removal was defined as no symptoms and improved or stable hydronephrosis. data analysis all analyses were performed with spss® statistics (version 20.0). the kolmogorov-smirnov test was used to check whether the data (age, bmi, preand postoperative creatinine, preand postoperative egfr, changes in the creatinine and egfr, pressure difference, follow-up time) were normally distributed. independent-sample t-test was used to compare the difference of average value (creatinine and egfr) between the elevated renal pelvic pressure group and the normal pressure group. pearson’s analysis was used to test the correlation of perfusion volume and pressure difference with the creatinine and egfr. a two-sided p < .05 was taken to indicate statistical significance. results the clinical characteristic and surgical information table 2. the detailed information of the whitaker test in patients with abnormal results patients surgery perfusion speed perfusion volume pelvis pressure final perfusion pressure difference imaging (ml/min) (ml) (cmh 2 o) volume (ml) (cmh 2 o) 1 ileal ureter 20 113 54 211 -6 clear 2 ileal ureter 10 71 46 205 -5 (1) poor imaging at ureterovesical junction; (2) no contrast in the bladder until 86 ml; (3) lower ureter was not visualized. 3 uretero neocystostomy 5 21 155 24 49 (1) contrast penetrated into the renal parenchyma; (2) lower ureter was not visualized. 4 ureteroneocystostomy 5→10 / stable 366 0 lower ureter and ureterovesical junction was visualized insufficiently the whitaker test / ultrasound no mild moderate severe total p normal 5 5 2 4 16 .225 abnormal 0 1 2 0 3 total 5 6 4 4 19 table 3. comparative analysis between whitaker test and ultrasound the whitaker test after complex reconstruction-xinfei li et al. vol 19 no 1 january-february 2022 59 were shown in table 1. all patients received a nephrostomy preoperatively. all patients completed the whitaker test successfully. no one experienced perfusion-related symptoms. the median perfusion volume at the end of the test was 227 ml (range 24 to 366 ml). 15 patients did not present obvious abnormalities (figure 1). among them, 4 patients showed a negative pressure difference that was lower than 0 cmh 2 o. one patient had only insufficient image at the lower ureter. one patient showed elevated pelvis pressure without abnormal pressure difference or poor imaging. an unusual rise in renal pelvis pressure during perfusion together with poor imaging at the ureterovesical junction was observed in 1 patient. in detail, perfusion fluid did not appear in the bladder until perfusion to 86 ml. particularly, one patient showed obvious elevated pelvis pressure and suffered from contrast penetrating into the renal parenchyma (figure 2). consequently, the perfusion was temporarily suspended. after the pressure dropped, the perfusion was continued, and the pelvis-bladder pressure was higher than 15 cmh2o (table 2). the results of b-ultrasound and perfusion test were consistent negative in 5 patients. in contrast, 14 patients had remained different degree of dilation in ultrasound after surgery, but the whitaker test showed a velocity of 10 ml/min perfusion could be tolerated in 11 of 14 patients (table 3). 16 patients removed the nephrostomy tube after the confirmation of the whitaker test. two patients with elevated pressure prolonged the duration of the nephrostomy tube. one patient with obvious abnormality during perfusion underwent ureteral stent implantation, and the tube was removed after 3 months. the median follow-up time was 12.6 months (range 8.6 to 17.3 months). all the patients were free of symptoms. the mean postoperative serum creatinine was 90.6 ± 25.3 μmol/l, and the mean egfr was 80.9 ± 22.6 ml/ min/1.73m. urine routine tests showed positive white variables elevated pelvis pressure group normal pressure group p serum creatinine, μmol/l 91.4 ± 27.6 86.7 ± 16.5 .782 egfr, ml/min 1.73m2 76.0 ± 14.0 81.8 ± 24.1 .695 δcreatinine, μmol/l -13.6 ± 1.0 -0.2 ± 10.6 .047 δegfr, ml/min 1.73m2 12.7 ± 4.2 -0.4 ± 12.7 .101 table 4. the comparative results of creatinine and egfr between the elevated pelvic pressure group and the normal pressure group figure 2. obstructive result of the whitaker test. a. contrast penetrating into renal parenchyma. b. lower ureter was not visualized. c. the record of pressure during perfusion, the elevated renal pelvis pressure decreased when the perfusion was suspended, but it was still higher than the initial basic pressure. the final pressure difference was 49 cmh 2 o. sp: supine position, s: suspension, lp: lithotomy position. abbreviations: δ, change; egfr, estimated glomerular filtration rate. the whitaker test after complex reconstruction-xinfei li et al. reconstructive surgery 60 blood cells in 8 patients. there were no obvious abnormalities in the urine routine of the other patients. ultrasound showed that hydrops was improved in 5 patients, meanwhile, the degree of dilation remained stable in the other 14 patients. ctu/mru confirmed no dilation or mild dilation of the collecting system that was improved than before. for 3 patients with abnormal imaging urodynamic results, ultrasound found that hydrops disappeared in one patient and remained stable in the other 2 cases. ctu/mru showed only mild dilation in these 3 patients (figure 3). the creatinine in the elevated pelvis pressure group was higher than that in the normal group (86.7 ± 16.5 vs 91.4 ± 27.6 μmol/l, p = .782), and the egfr was lower (76.0 ± 14.0 vs 81.8 ± 24.1 ml/min/1.73m2, p = .695), but without significant difference. figure 4 presented the changing trend of the creatinine and egfr in the normal and elevated renal pelvis pressure group, respectively. the change in creatinine during follow-up in the elevated renal pelvic pressure group was significantly different from that in the normal group (-13.6 ± 1.0 vs -0.2 ± 10.6 umol/l, p = .047), but there was no difference in the change in egfr (12.7 ± 4.2 vs -0.4 ± 12.7, p = .101). neither the pressure difference show correlation with creatinine (r = -.056, p = .819) or egfr (r = -.109, p = .657), nor did the perfusion volume showed correlation with creatinine (r = .205, p = .401)) or egfr (r = -.040, p = .870). discussion ureters are slender ducts that drainage urine from the kidney to the bladder. urine transport relies on two major mechanisms: the active contraction of the smooth muscles, and passive flow driven by hydrostatic pressure. an obstruction that results in a decrease in urine output can cause dilation. relaxed smooth muscle of the collecting system owing to long term hydronephrosis can also lead to dilation. therefore, it is not enough to observe the dilation of the urinary tract, which is the shortcoming of the existing imaging examinations. the reasons behind the dilation also need to be brought to the forefront. while investigating the dilation of upper urinary tract after reconstruction, whether the obstruction still exists is the focus of attention. the renogram not only judges how well the isotope can pass through the urinary system but also gives information on split renal function. however, dilated renal pelvic and ureter, particularly if associated with a poorly functioning kidney, can cause stasis to give a false impression of obstruction. (7) in addition, protective ureteral stent or nephrostomy tube may lead to better imaging results than it is. the whitaker test uses a constant perfusion flow study to evaluate the function of the upper urinary tract.(8) the whitaker test provides a quantitative assessment of outflow resistance, and it has the advantage that it does not rely on renal function or a diuretic response. during the past decade, researchers have passed different judgments on the whitaker test. djurhuus et al. figure 3. preand postoperative ctu of the patient with elevated renal pelvis pressure and abnormal pressure difference. a. preoperative cross section ctu; b. preoperative coronary section ctu; c. cross section ctu after removing the percutaneous nephrostomy tube; d. coronary section ctu after removing the percutaneous nephrostomy tube. the whitaker test after complex reconstruction-xinfei li et al. vol 19 no 1 january-february 2022 61 have shown that the resting pelvis pressure may show considerable overlap in a hydronephrotic or in a normal one.(11) wahlin et al. also agreed the specificity of the method was limited.(12) however, proponents of the whitaker test have approved its values for the diagnosis of obstruction and exclusion of unobstructed dilatation. johnston proposed the whitaker test was useful in evaluating patients with skeptical ureteropelvic or ureterovesical junction obstruction.(13) lupton and george concluded that the whitaker test contributed to the clinical management in 84% of the suspected upper urinary tract obstruction.(9) except for these arguments, there are seldom articles reporting the use of the whitaker test for postoperative evaluation of complex urinary tract reconstruction. the whitaker test can help clarify whether the urinary tract is still obstructed and determine when percutaneous nephrostomy tubes could be safely removed, especially for those patients who showed no improvement in radiographic appearances. previous studies underlined that about 60% of the patients showed no clear improvement in ultrasound after reconstruction.(14) in the present study, we found 14 patients retained urinary tract dilation in ultrasound, while the negative whitaker test in 11 of 14 patients provided evidence for nephrostomy removal. ctu or mru prompted satisfactory imaging results of the reconstructive upper urinary tract after removing the nephrostomy tube. no patients suffered from renal function deterioration. therefore, with normal results of the whitaker test, no need to worry too much that ultrasound changes recovered slowly.(15) the obstructive results often indicated a prolonged time of nephrostomy and even the possibility of reintervention. in our study, 3 cases with abnormal results were treated accordingly. in detail, 1 case who underwent ureteroneocystostomy had high pelvis pressure, high pressure difference and poor imaging, which together indicated the existence of obstruction. marshall et al. reported a similar patient with left megaureter that was reimplanted into the bladder showed a pressure of 19 cmh2o in the whitaker test. a transureteroureterostomy and temporary left nephrostomy ensued. the pressure again was less than 8 cmh 2 o, and the patient was free of symptoms and deterioration.(16) for our patient, the renal pelvis pressure increased with the progress of perfusion, and the perfusion was temporarily suspended twice. after a brief stop and position change, the renal pelvis pressure decreased to a stable level. but the pressure was still higher than the initial basic pressure, and the final pressure difference was greater than 15 cmh 2 o. this patient subsequently underwent ureteral stent implantation. the other 2 patients showed high renal pelvis pressure with or without poor imaging. the pressure gradually decreased and remained stable as the perfusion went on. the reason may be the poor pelvic compliance. the whitaker test simulates a high urine flow actually to evaluate the ability of the reconstructive upper urinary tract to convey urine. under physiological conditions, the urine production rate is 1-3 ml/min,(17) but it can increase up to 20 ml/min after diuresis.(9) accompanied by moderate dilation in ultrasound, these 2 patients were treated by prolonging the time of nephrostomy. the ctu/mru during follow-up showed improved dilation in the collecting system. negative pressure difference reminds urologists to be vigilant against reflux, but for patients undergoing ileal ureter replacement, it may be a normal phenomenon. the ureter is contracted to close when transporting urine downward without reflux.(6) in this study, 4 patients had negative pressure difference, and 3 of them underwent ileal ureter replacement. the wide intestine was difficult to be completely closed during peristalsis, allowing reflux confined to the bowel segment. these 3 patients were not given special treatment, and there were no recurrent urinary tract infections, aggravated hydronephrosis, or deterioration of renal function during the follow-up. another patient underwent boari flap surgery. the negative pressure difference was due to the displacement of the transducer, and the measured bladder pressure was lower than the actual pressure. renal pelvis pressure was an informative factor. we found the creatinine in the elevated pelvis pressure group was higher than that in the normal group, and the egfr was lower, but without significant difference. figure 4. the changing trend of the renal function during follow-up. a. the trend of the creatinine in the normal and elevated renal pelvis pressure group. b. the trend of the egfr in the normal and elevated renal pelvis pressure group. black arrow: the time of the whitaker test and corresponding management. the whitaker test after complex reconstruction-xinfei li et al. the changes of the creatinine and egfr during follow-up were related to whether the renal pelvis pressure was elevated. the reason was that increased renal pelvic pressure indicated that the upper urinary tract had poor tolerance to hydrops, and the renal function could be impaired easily. however, the consequences were still reversible, so timely treatment helped restore the renal function. in the past, most researchers considered that abnormal results of the whitaker test did not predict worse renal function. djurhuus et al. pointed out the renal function in the high pressure group was the same as those in the low pressure group.(11,18) identical with previous literature reports, pressure difference had no predictive value for postoperative renal function in our patients. however, few articles involved the pressure of the renal pelvis, which indicated the compliance of the upper urinary tract. koff et al. thought renal pelvis pressure was an indicator determinant to progression.(19) in general, it was necessary to deal with when the renal pelvis pressure was abnormal, and the outcome was not different from the normal group after timely treatment. there are still some limitations in our study. firstly, contrast media have a greater viscosity than urine or saline and will produce higher pressure at a given flow rate. moreover, with the high infusion rates used that are not physiological, the urinary tract may be overstretched. thus, follow-up needs to perfect 1-3 ml/min physiological velocity perfusion or even individualize the infusion rates, so that some of the measurement bias could be avoided. secondly, we didn’t perform a diuresis renogram for reference because the nephrostomy tube would affect the result of diuretic renogram. at last, large samples and long term follow-up result are necessary. conclusions despite the concerns and debates over its relative value, the whitaker test can help judge whether nephrostomy tube could be removed. abnormal results during perfusion prompt reintervention or longer duration of nephrostomy tube. proper management for patients with elevated renal pelvis pressure can help restore renal function. conflict of interest the authors have no conflicts of interest to declare. references 1. jayanthi vr. reconstructive surgery of the upper urinary tract. curr opin urol. 1998;8:215-20. 2. wang j, xiong s, fan s, et al. appendiceal onlay flap ureteroplasty for the treatment of complex ureteral strictures: initial experience of nine patients. j endourol. 2020;34:874-81. 3. fan s, yin l, yang k, et al. posteriorly augmented anastomotic ureteroplasty with lingual mucosal onlay grafts for long proximal ureteral strictures: ten cases of experience. j endourol. epub ahead of print. doi: 10.1089/ end.2020.0686. 4. gu h, chen s, wu y, et al. improved long ureteral reconstruction with ileum by longitudinal clipping and mucosal stripping: an animal study. urol j. 2020;17:198-203. 5. vignoli g. urodynamics of the upper urinary tract. in: vignoli g, editor. urodynamics. switzerland: springer cham; 2017. p. 175-84. 6. farrugia mk, whitaker rh. the search for the definition, etiology, and effective diagnosis of upper urinary tract obstruction: the whitaker test then and now. j pediatr urol. 2019;15:1826. 7. whitaker rh, buxtonthomas ms. a comparison of pressure flow studies and renography in equivocal upper urinary tract obstruction. j urol. 1984;132:1209-10. 8. whitaker rh. methods of assessing obstruction in dilated ureters. br j urol. 1973;45:15-22. 9. lupton ew, george nj. the whitaker test: 35 years on. bju int. 2010;105:94-100. 10. george nj, o'reilly ph, barnard rj, blacklock nj. high pressure chronic retention. br med j. 1983;286:1780-3. 11. djurhuus jc, jorgensen tm, norgaard jp, nerstrom b, hvid-hansen h. constant perfusion provocation in idiopathic hydronephrosis. urology. 1982;19: 611-6. 12. wahlin n, magnusson a, persson ae, lackgren g, stenberg a. pressure flow measurement of hydronephrosis in children: a new approach to definition and quantification of obstruction. j urol. 2001;166:1842-7. 13. johnston rb, porter c. the whitaker test. urol j. 2014;11:1727-30. 14. amling cl, o'hara sm, wiener js, et al. renal ultrasound changes after pyeloplasty in children with ureteropelvic junction obstruction: long-term outcome in 47 renal units. j urol. 1996;156:2020-4. 15. fernandez-ibieta m, nortes-cano l, guiraopinera mj, et al. radiation-free monitoring in the long-term follow-up of pyeloplasty: are ultrasound new parameters good enough to evaluate a successful procedure? j pediatr urol. 2016;12:230-1. 16. marshall v, whitaker rh. ureteral pressure flow studies in difficult diagnostic problems. j urol. 1975;114:204-7. 17. weiss rm. clinical implications of ureteral physiology. j urol. 1979;121:401-13. 18. djurhuus jc, sorensen ss, jorgensen tm, et al. predictive value of pressure flow studies for the functional outcome of reconstructive surgery for hydronephrosis. br j urol. 1985;57:6-9. 19. koff sa. determinants of progression and equilibrium in hydronephrosis. urology. 1983;21:496-500. the whitaker test after complex reconstruction-xinfei li et al. reconstructive surgery 62 letter indirect factors affecting fertility in the era of covid-19 amirali karimi, ali nowroozi, sanam alilou, erfan amini* dear editor, a portion of the patients might experience spermatogenic failure and impairment of follicular and luteal processes after sars‐cov‐2 infection. although the exact pathophysiology is poorly understood, these effects are hypothetically mediated through an alteration in the ace2 cascade(1). in addition to the adverse effects of sars‐cov‐2 infection on gametogenesis, several other factors may also indirectly affect the fertility in men and women during covid-19 pandemic. patients with other causes of infertility are not willing to seek medical care due to fear and anxiety associated with the pandemic(2). in addition, several institutions suspended elective surgeries and interventions related to infertility. overall, this situation would result in irreversible consequences and higher rates of infertility. therefore, researchers and health policy makers should assess factors that indirectly increase the rate of infertility in the era of covid-19. these factors may also have a greater impact and should be addressed through multiple pathways, including: 1) ensuring safe access to health care for those who are suffering from infertility, 2) reassuring patients through media to decrease the anxiety related to the pandemic, 3) focusing on treatments that are effective and has the potential to reduce the harmful effects of the sars‐cov‐2 infection. references 1. singh b, gornet m, sims h, kisanga e, knight z, segars j. severe acute respiratory syndrome-corona virus-2 (sars-cov-2) and its effect on gametogenesis and early pregnancy. american journal of reproductive immunology (new york, ny : 1989). 2020:e13351. 2. campi r, tellini r, grosso aa, amparore d, mari a, viola l, et al. deferring elective urologic surgery during the covid-19 pandemic: the patients' perspective. urology. 2021;147:21-6. uro-oncology research center, tehran university of medical sciences, tehran, iran. *correspondence: uro-oncology research center, tehran university of medical sciences, tehran, iran. e-mail: amini.erfan@gmail.com received february 2021 & accepted april 2021 urology journal/vol 18 no. 3/ may-june 2021/ pp. 358-358. [doi: 10.22037/uj.v18i.6737] case report non functioning paraganglioma in the urinary bladder: a case report shangren wang1, aiqiao zhang1, shiqiao huang2, yong ma2,*, yongjiao yang1, xiaoqiang liu1 , ludong zhang2 1department of urology, tianjin medical university general hospital, tianjin, 300052, china. 2department of urology, shanxian central hospital, heze 274300, china. *correspondence: department of urology, tianjin medical university general hospital, tianjin, 300052, china. e-mail: xiaoqiangliu1920@126.com received august 2018 & accepted january 2019 paragangliomas are tumors that arise from autonomic nervous system. non-functioning bladder paraganglioma is rare and usually misdiagnosed. here we describe a case of a 45-year-old man with primary urinary bladder paraganglioma. the patient had no active signs and symptoms, and histological and immunohistological examinations of a transurethral resection specimen confirmed correct diagnosis. after successful transurethral resection of the tumors, the patient showed no signs of recurrence at one-year follow-up. keywords: pheochromocytoma; non-functioning paraganglioma; urinary bladder introduction primary urinary bladder paraganglioma is a rare neoplasm that develops from the chromaffin tissue of the sym-pathetic nervous system in urinary bladder wall. the diagnosis and prognosis of bladder paraganglioma has not been well established. in addition, non-functioning paragangliomas of the urinary bladder have rarely been reported (1-4). here we present a rare case of an asymptomatic patient with non-functioning paraganglioma of the urinary bladder. case report a tumor of the urinary bladder was found during a routine physical examination of a 45-year-old man. the patient had been in a good health without abdominal and urinary tract symptoms. routine hematological and biochemical examinations showed no evidence of hypertension. ultrasound revealed a mass (1.4*1.1 cm) on the left wall of the bladder. color doppler sonography showed the mass with abundant blood supply (figure 1 a, b). non-contrast and contrast ct of the abdomen showed a solitary tumor protruding into the bladder (figure 1 c, d). metastatic disease was not found in other abdominal organs. the patient was diagnosed with synchronous nonfunctional paraganglioma in retroperitoneum and urinary bladder, and underwent a transurethral resection of bladder tumor. the mass was well circumscribed (figure 2a), and tumor cells were arranged in a nested pattern (figure 2b). figure 1. ultrasound and computed tomography images. ultrasound revealed a mass on the left wall of the bladder (a, arrow), color doppler sonography showed that the mass had abundant blood supply (b, arrow), non-contrast ct (c) and contrast-enhanced ct (d) showed a solitary tumor protruding into the bladder (arrow). urology journal/vol 17 no. 4/ july-august 2020/ pp. 426-428. [doi: 10.22037/uj.v0i0.4741] vol 17 no 04 july-august 2020 112 histopathological examination showed positive staining for nse, syn and cga, and ki-67 staining revealed a proliferation index of < 1%. on a recent follow-up after one year, ultrasound examination and cystoscopy examination showed no signs of recurrence. discussion paraganglioma of the urinary bladder is extremely rare, accounting for less than 0.05% of all bladder neoplasm. in particular, 10-15% of such tumors are non-functioning and the patients had no history of hypertension, headache or flushing that would suggest a diagnosis of paraganglioma(5). thus non-functioning paragangliomas are more difficult to diagnose. imaging examinations are essential for preoperative localization of paragangliomas. ultrasound showed the tumor as a submucosal homogeneous mass with continuous mucosa and abundant blood supply. scintigraphy with i-123 labelled mibg offered superior specificity than ct and mri(6). pet has an increased accuracy compared with mibg scans for the localization of paragangliomas due to the higher spatial resolution of pet scanning(7). the tumors in cystoscopy appeared as globular submucosal masses protruding into the bladder. however, the significance of diagnostic cystoscopy and biopsy is limited since it has a low positive rate, risk of bleeding and may provoke a hypertensive crisis if the tumor is functional. therefore, histological and immunohistochemical diagnosis is important. the tumors show histological features similar to adrenal pheochromocytomas and the cells usually grow in a characteristic nested zellballen pattern. chromogranin, synaptophysin and nse may aid the identification of neural tissue and neuroendocrine cells. a positive staining with synaptophysin, nse, cga and s-100 was observed in present case, which was compatible with paraganglioma(8). therefore, differential diagnosis of paraganglioma depends on histological and immunohistochemical aspects. the most effective treatment of paraganglioma is surgery, including transurethral resection, partial or csytectomy and laparoscopy partial cystectomy. however, the optimal management mode is still uncertain. for patients with paroxysmal hypertension it is necessary to stabilize hypertension before the operation by using alpha-blocking drugs, similar to treatment for other pheochromocytomas(9). in this case, although the patient was asymptomatic, we successfully performed a transurethral resection of the tumor to prevent its progression and metastasis, and blood pressure was stable during the operation. we chose conventional loop resection because the tumor was relatively small and this resection has little impact on the patient’s quality of life. in addition, this technique has very low risk of bladder perforation. primary non-functioning bladder paraganglioma is easily misdiagnosed(10). this case is unique because of two rare synchronous nonfunctional paraganglioma in retroperitoneum and urinary bladder without any clinical symptoms. if ct or cystoscopy reveals a mass well-defined that is located in the submucosa with an intact surface and there is no symptom of hematuria, a diagnosis of bladder paraganglionma must be considered. a definitive diagnosis may be reached by histological analysis. conflict of interest the authors report no conflict of interest. references 1. verma a, pandey d, akhtar a, arsia a, singh n. non-function paraganglima of retroperitoneum mimicking pancreatic mass with concurrent urinary bladder paragan glioma: an extremely rare entity. j clin diagn res. 2015;2:xd09-xd11. 2. liang j, li h, gao l, yin l, yin l, zhang j. bladder paraganglioma: clinicopathology and magnetic resonance imaging study of five patients. urol j. 2016;13:2605-2611. 3. dhawan dr, ganpule a, muthu v, desai mr. laparoscopic management of calcified paraganglioma of bladder. urol j. 2008;5:126128. 4. heinrich e, gattenloehner s, muellerhermelink hk, michel ms, schoen g. paraganglioma of urinary bladder. urol j. 2008;5:57-59. 5. mhanna t, pianta e, bernard p, hervieu v, partensky c. preaorticparaganglioma mimicking a hypervascular tumor of the pancreas. hepato-gastroenterology. 2004; case report 413 non functioning paraganglioma-wang et al. figure 2. cystoscopy and histological analysis. bladder mass on left vesical wall with spherical shape and well circumscribed (a, arrow). the tumor cells were arranged in a nested pattern (he staining ×200) (b). vol 17 no 04 july-august 2020 427 51:1198-1201. 6. rha se, byun jy, jung se, chun hj, lee hg, lee jm. neurogenic tumors in the abdomen: tumor types and imaging characteristics. radiographics. 2003; 23:29-43. 7. bagchi a, dushai k, shrestha a, leytin al, bhuiyan sa, radparvar f, topchik s, tuli ss, kim p, bakshi s. urinary bladder paragangloma presenting as micturitioninduced palpitations, dyspnea, and angina. am j case rep. 2015;16:283-286. 8. zhou m, epstein ji, young rh. paraganglioma of the urinary bladder: a lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens. am j surg pathol. 2004;28: 94-100. 9. onishi t, sakata y, yonemura s, sugimura y. pheochromocytoma of the urinary bladder without typical symptoms. int j urol. 2003;10:398-400. 10. limani k, velthoven rv, aoun f. bi-focal retroperitoneal paraganglioma in a young patient: a case report and review of the literature. med surg urol. 2014; 3:127. case report 212 non functioning paraganglioma-wang et al. case report 428 andrology evaluation of sperm parameters and dna integrity following different incubation times in pvp medium ali nabi1,2 ,farahnaz entezari2,3, seyed mohsen miresmaeili3, serajoddin vahidi2*, keivan lorian2, fatemeh anbari2 , leila motamedzadeh2 purpose: polyvinylpyrrolidone (pvp) is a chemical material used in intracytoplasmic sperm injection (icsi) program. the aim of this study was to investigate the ideal time that sperm can be safely incubated in pvp with less structure and dna damage. method: thirty-one oligoasthenoteratospermia (oat) samples were used. sperm samples were prepared by discontinuous density-gradients method and incubated in 10% pvp at different time intervals (0, 5, 10, 15, 20, and 30 min). the effect of pvp was assessed on sperm dna fragmentation and viability via scd assay and eosin–nigrosin staining respectively. results: data showed there was a significant increase in sperm dna fragmentation at 10 min compared to 0 min. the viability rate also significantly reduced at 10 min compared to 0 min. conclusion: as a result, sperm samples could be incubated with pvp for less than 10 min. while prolonged incubation may significantly damage the sperm dna integrity and viability. keywords: dna fragmentation; intracytoplasmic sperm injections; polyvinylpyrrolidone (pvp); semen analyses; spermatozoa. 1abortion research center, yazd reproductive sciences institute, shahid sadoughi university of medical sciences, yazd, iran. 2andrology research center, yazd reproductive sciences institute, shahid sadoughi university of medical sciences, yazd, iran. 3department of biology, science and arts university, yazd, iran. *correspondence: andrology research center, yazd reproductive sciences institute, safayeh, bou-ali ave., yazd, iran. postal code: 8916877391. tel.: +983538247085; fax: +983538247087; e-mail: vahidi.seraj@gmail.com. received august 2021 & accepted october 2021 introduction intracytoplasmic sperm injection (icsi) is one of the methods of assistant reproductive technology (art) used for the treatment of male infertility(1). during this method, sperm with motility and normal morphology is selected, and then they are immobilized under an inverted microscope. sperm immobilization is a necessary procedure that must be performed before sperm injection. reducing the speed of sperm movement and stopping it are two processes used to immobilize sperm (2). polyvinylpyrrolidone (pvp) is a water-soluble polymer of n-vinyl-2-pyrrolidone(3). it is used for icsi because increases the viscosity of sperm solution and reduces the sperm movement speed; therefore, sperm immobilization becomes facilitated. pvp is also used to control and manage sperm movement inside the injection needle(4). performing icsi in oligoasthenoteratozoospermia (oat) patients is often a challenge because it is not possible to find enough spermatozoa with acceptable morphology. pasqualotto and borges reported that the rate of fertilization was lower when icsi is performed with sperm from men with oat and non-obstructive azoospermia(5). low sperm concentration with bad quality in these samples causes the time of sperm selection to be increased by the embryologist. moreover, pvp has been shown to damage sperm membranes, mitochondrial membrane, and destroy axonal tubules and fibrous sheaths(6). injected pvp with sperm remains in the oocyte for a long time and cannot be digested by lysozyme enzymes(7). the existence of pvp in oocyte delays the onset of calcium oscillation; therefore, the chromosomal abnormalities in embryos is increased(8,9). dna integrity of sperm chromosomes is essential for natural fertilization and transmission of parental genetic information. sperm dna integrity plays an important role in reproductive outcomes. studies showed that high dna fragmentation in sperm cells causes a lower development rate in embryos(10). genetic damages to gametes during the icsi technique may affect the result of this process(11). gomez and co-workers in 2007 showed that pvp can increase sperm dna fragmentation. it was also shown that sperm immobilization before icsi technique is one of the causes of ultra-structural sperm damage(12). these side effects of pvp are major concerns for infertility centers. therefore, it is required to search for methods to reduce pvp side effects in the art laboratory. the main aim of the present study was to investigate the appropriate and maximum time that sperm could stay in the pvp media without possible damage such as dna fragmentation and viability. materials and methods study participants in this study, the semen samples were obtained from patients referring to yazd reproductive sciences institute. the age range of the male participants was 20-45 years. male partners with diseases such as varicocele, cancer, urinary tract infection, diabetes, or orchitis were urology journal/vol 19 no. 3/ may-june 2022/ pp. 232-237. [doi:10.22037/uj.v18i.6936] vol 19 no 3 may-june 2022 100 excluded. samples were prepared by masturbation in sterile specimen container after 2-5 days of sexual abstinence. then, thirty -one moderate oat samples were incubated in 37 ˚c for 20 min for liquefaction. the routine seminal parameters were performed according to the world health organization criteria(13). this study was approved by the ethics committee of yazd reproductive sciences institute (ir.ssu.rsi. rec.1398.030). sperm preparation semen samples were prepared by the discontinuous density – gradients method. a 40/80 gradient (perception, sage, usa) was prepared in a 15ml conical tube and then a layer of 1 ml semen is placed on top of the density media. the first centrifuge (eppendorf, north america) was performed with 300×g for 20 min. then the supernatant was removed and the sediment was kept. the sediment was washed with 5ml ham’s f10 (biochrome, berlin, germany) media for two times at 300×g for 5 min and then sediment resuspend to assess for sperm concentration, motility, viability, normal morphology and dna integrity(14). pvp preparation in this study, 10% pvp solution (10% pvp solution with has (5mg/ml), irvine scientific, usa) according to the laboratory routine was used. the pre-warmed pvp was placed in a petri dish (falcon, usa) as 20 µl droplets. after that, sterile mineral oil (life global, belgium) was poured on drops to cover the surface of all drops. study design each sample was divided into 6 equal parts after washing by a discontinuous density-gradients method. then, 20 µl of samples were placed in 10% pvp droplets on a hot plate with a temperature of 37◦c at 0, 5, 10, 15, 20 and 30 min and, each part was evaluated at specific times for sperm viability and dna integrity. sperm parameters 10 µl of sample was placed on the makler chamber slide for sperm motility and concentration assessment. the number of sperm in 10 vertical squares and 10 horizontal squares was counted and the average of the two was taken. for motility assessment according to who sperm parameters before preparation (n=31) after preparation (n=31) p-value sperm count (×106) 10.14 ± 3.29 18.00 ± 7.40 .0001* progressive motile sperm (%) 17.68 ± 7.26 29.14 ± 8.72 .0001* non-progressive motile sperm (%) 8.18 ± 3.09 11.73 ± 4.10 .0001* immotile sperm (%) 74.05 ± 9.33 58.95 ± 10.79 .0001* sperm morphology (%) 1.95 ± 0.78 5.77 ± 2.67 .0001* sperm viability (%) 41.59 ± 7.33 58.91 ± 10.68 .0001* table 1. sperm parameters before and after discontinuous density – gradients method the data were presented as mean ± sd. data were calculated using paired t-test. * p-value <0.05 was significant. figure 1. different halo patterns were appeared around sperm cells. a: large and b: medium-sized halos were considered as sperm cells with no dna fragmentation. c: small halo or d: no halos were considered as sperm cells with dna fragmentation. effect of pvp on sperm dna integrity-nabi et al. vol 19 no 3 may-june 2022 233 andrology 234 2010 recommendation, the percentages of progressive motile, non-progressive motile and non-motile spermatozoa were recorded(13). for sperm morphology, papanicolaou staining, og-6 (merck, germany) was used. in this staining, the head becomes blue and the midpiece and tail of the sperm becomes red(13). this parameter was assessed by 1000× magnification light microscope. eosin–nigrosin staining was used to assess sperm viability. the sperm viability was assessed by light microscopy at ×1000 magnification. viable spermatozoa remained colorless; while, dead spermatozoa stained pink or red(13). the results were recorded before and after the discontinuous density-gradients method and also at different times that sperm was incubated with pvp media. sperm chromatin dispersion (scd) test scd test was used to assess dna integrity. this test was performed according to fernandez et al(15). in brief, the slides were covered by 0.65% standard agarose (merck, germany). 30 µl of sperm suspension was mixed with 70 µl low melting agarose (roche, germany). 50 µl of the prepared mixture was placed on precoated slides and then allowed to become solid. they were put at 4 °c for 4 min. then, denaturation solution (0.08 n hcl) (merck, germany) was used to immerse slides for 7 min at rt in dark. the slides were placed into lysing solution 1 (0.4 m tris, 2-mercaptoethanol, 1% sds, and 50 mm edta, ph 7.5) for 20 min at rt. after that, the slides were transferred in the lysing solution 2 (0.4 m tris, 2 m nacl, and 1% sds, ph 7.5) for 15 min at rt and washed in trisborateedta buffer (0.09 m tris-borate and 0.002 m edta, ph 7.5 and 12 min at rt. to dehydrate samples, 70%, 90% and 100% ethanol were used (2 min each) and then they became dry at rt. the wright stain solution (sigmaaldrich, usa) which was mixed with phosphate buffer solution (pbs) (1: 1) was used to stain samples. after staining for 10 min, samples were evaluated for size of the halos by light microscope. different halo patterns appeared around sperm cells. large or medium-sized halos appeared around sperm cells with no dna fragmentation (16). small halo or no halo, sign that dna fragmentation occurred in sperm cells (figure 1). two hundred spermatozoa were evaluated for dna fragmentation and the percentage of spermatozoa was recorded. statistical analysis we used spss 20 (spss, inc., il, usa) for statistical analysis. normalization of data was determined with the kolmogorov-smirnov normality test. paired t-test was used to compare sperm parameters before and after the discontinuous density-gradients method. repeated measure one-way anova was done between groups and multiple comparison was followed by paired t-test. significance level was corrected using bonferroni correction and it was considered as 0.0125. results sperm parameters before and after discontinuous density gradients method are summarized in table 1. all parameters except count were significantly different before and after preparation by this method. the dna fragmentation rate after the preparation of sperm by discontinuous density-gradients method (0 min) was not significantly increased compared to the 5 min after incubation with pvp (p = .296). in 10 min (p<.001), 15 min, 20 min and 30 min (p < .0001) after figure 2. effect of different incubation times in pvp on the sperm dna damage. p values were significant between all of the groups except between 0 and 5. ***= p < 0.001, **** = p < 0.0001. data were calculated using repeated measure anova. effect of pvp on sperm dna integrity-nabi et al. vol 19 no 3 may-june 2022 100 incubation with pvp, the dna fragmentation was significantly increased compared to the 0 min (figure 2). the sperm viability rate in 0 min compared to 5 min after pvp incubation was not significantly decreased (p = 0.42). however, the percentage of sperm viability decreased significantly in 10 (p = .041), 15, 20 and 30 min (p < .0001) after pvp incubation compared to the 0 min after processing (figure 3). moreover, the dna fragmentation rate in 5 min compared to 10 min was not significantly increased after incubation with pvp (p = .169). according to table 2, the dna fragmentation and the rate of viability were significantly increased between other times after incubation with pvp (table 2). discussion 10% pvp is conventionally applied in icsi process to reduce the speed of sperm movement. although, pvp facilities the icsi process, it can inhibit the decondensation of the sperm head and also increase dna damage, which can affect the outcomes of fertilization and embryonic development(15). in the present study, the best time that sperm could be incubated with pvp with less damage was 5min, while the exposure times higher than ten minutes had negative effects on dna and viability of sperm. performing of icsi procedure with spermatozoa from oat patients is still a challenge. enough spermatozoa is not available and subsequently lower fertilization and pregnancy rates is observed after icsi(17). in these cases, time frame for the search of spermatozoa is long due to morphological defects and low concentration of sperm. a cohort study showed that the extended sperm search for both ejaculated and tese decreased the fertilization and pregnancy rates from 44% to 23%(18). the study of the effects of sperm incubation in pvp is one of the topics that have been considered by researchers in the last decade. previous studies have been conducted on the effects of sperm incubation in pvp drops by evaluating sperm parameters such as motility, viability, and morphology. by understanding the important role of sperm dna health and quality infertility, many research groups have made great efforts to find a relationship between sperm cell health and sperm dna integrity(19). sperm dna integrity is an important parameter of sperm quality that plays a fundamental role in art outcomes. it is proved that increasing dna damage is associated with poor embryo development and decreased implantation and pregnancy outcomes(20). some assays have been developed to evaluate sperm dna status. scd is an assay that evaluates the property of fragmentation dna with denaturation solution under certain conditions. however, the scd assay is less complex, cost effective, and not time-consuming which presents similar sensitivity for the assessment of dna fragmentation compared to other assays(21,22). in this study, the effect of different time intervals on dna fragmentation and viability of sperm cells, which were incubated in pvp, was investigated. the results demonstrated that after ten min of sperm incubation in pvp, dna fragmentation increased and sperm viability reduced significantly. sterler et al. showed that pvp had negative effects on plasma membrane, acrosomal membrane, and sperm mitochondrial membrane on the samples which were exposed to 10% pvp solution for 30 min(23). in an animal study conducted by kato and nagao in 2009, the effect of pvp at different times, 0, 15, 30 and 60 min on the capacity and acrosomal reacfigure 3. the effect of pvp on sperm viability in different times. p values were significant between all of the groups except between 0 and 5. ** = p < 0.05, ****= p < 0.0001. data were calculated using repeated measure anova. effect of pvp on sperm dna integrity-nabi et al. vol 19 no 3 may-june 2022 235 andrology 236 tion of cow spermatozoa was assessed. they found that the highest rate of fertilization and embryo growth occurred in the first 15 min and by passing time most destructive effects of pvp on sperm were observed(24). another study showed that nuclear and chromatin damage was noticed in sperms exposed to pvp(25). although, the best way is to avoid the use of exogenous substances in art procedures, selecting sperm without a reduction in the speed of their movements is not practical. however, a physiological alternative to pvp is suggested. for instance, materials such as sodium hyaluronate slow sperm movements and prevent sperm from sticking to the dish or pipette. however, sperm motility in a media containing hyaluronate is faster than in a media containing pvp, since no difference was observed in post-icsi zygote growth in both of these media(26). this study suggested that sperm addition to pvp in art procedure for more than 10 min caused possible damages, such as dna fragmentation and sperm viability reduction, that ultimately affect fertility outcomes. therefore, pvp could be potentially dangerous for the sperm nucleus during icsi treatments, and it may be better to reduce the length of the treatment period of pvp solution. conclusions taken together, following sperm incubation in pvp at different times (0, 5, 10, 15, 20, and 30 min), we presented incubation times in pvp medium for >10 min, causes significantly increased fragmentation of sperm dna. therefore, icsi should be performed within 10 min of sperm incubation in pvp. conflict of interest there is no conflict of interest in this study. references 1. esteves sc, roque m, bradley ck, garrido n. reproductive outcomes of testicular versus ejaculated sperm for intracytoplasmic sperm injection among men with high levels of dna fragmentation in semen: systematic review and meta-analysis. fertil steril. 2017;108:45667. e1. 2. hussain t, ranjha nm, shahzad y. swelling and controlled release of tramadol hydrochloride from a ph-sensitive hydrogel. des monomers polym. 2011;14:233-49. 3. ding d, wang q, li x, et al. effects of different polyvinylpyrrolidone concentrations on intracytoplasmic sperm injection. zygote. 2020;28:148-53. 4. kato y, nagao y. effect of polyvinylpyrrolidone on sperm function and early embryonic development following intracytoplasmic sperm injection in human assisted reproduction. reprod med biol. 2012;11:165-76. 5. pasqualotto ff, borges e, jr. re: sperm defect severity rather than sperm source is associated with lower fertilization rates after intracytoplasmic sperm injection. int braz j urol. 2008;34:231-2. 6. strehler e, baccetti b, sterzik k, et al. detrimental effects of polyvinylpyrrolidone on the ultrastructure of spermatozoa (notulae seminologicae 13). hum reprod. 1998;13:120-3. 7. jean m, mirallié s, boudineau m, tatin c, barrière p. intracytoplasmic sperm injection with polyvinylpyrrolidone: a potential risk. fertil steril. 2001;76:419-20. 8. nyboe andersen a, goossens v, ferraretti a, et al. assisted reproductive technology in europe, 2004: results generated from european registers by eshre. hum reprod. 2008;23:756-71. 9. ding d, wang q, li x, et al. effects of different polyvinylpyrrolidone concentrations on intracytoplasmic sperm injection. zygote. 20201-6. 10. mohammad hn-e, mohammad s, shahnaz r, et al. effect of sperm dna damage and sperm protamine deficiency on fertilization and embryo development post-icsi. reprod biomed online. 2005;11:198-205. 11. matsuura r, takeuchi t, yoshida a. preparation and incubation conditions affect the dna integrity of ejaculated human spermatozoa. asian j androl. 2010;12:753. 12. gomez-torres mj, ten j, girela jl, romero j, bernabeu r, de juan j. sperm immobilized before intracytoplasmic sperm injection undergo ultrastructural damage and acrosomal disruption. fertil steri. 2007;88:702-4. 13. organization wh. who laboratory manual for the examination and processing of human semen. fifth ed: world health organization; 2010. 14. jayaraman v, upadhya d, narayan pk, adiga sk. sperm processing by swim-up and density gradient is effective in elimination of sperm with dna damage. j assist reprod genet. 2012;29:557-63. 15. fernández jl, muriel l, rivero mt, goyanes v, vazquez r, alvarez jg. the sperm chromatin dispersion test: a simple method for the determination of sperm dna fragmentation. j androl. 2003;24:59-66. 16. anbari f, khalili ma, agha-rahimi a, maleki b, nabi a, esfandiari n. does sperm dna fragmentation have negative impact on embryo morphology and morphokinetics in ivf programme? andrologia. 2020e13798. 17. nordhoff v, fricke rk, schüring an, zitzmann m, kliesch s. treatment strategies for severe oligoasthenoteratozoospermia (oat) (<0.1 million/ml) patients. andrology. 2015;3:856-63. 18. palermo gd, neri qv, schlegel pn, rosenwaks z. intracytoplasmic sperm injection (icsi) in extreme cases of male infertility. plos one. 2014;9:e113671. 19. zhang x-d, chen m-y, gao y, han w, liu d-y, huang g-n. the effects of different sperm preparation methods and incubation time on the sperm dna fragmentation. hum fertil. 2011;14:187-91. 20. liffner s, pehrson i, garcia-calvo l, et al. diagnostics of dna fragmentation in human spermatozoa: are sperm chromatin structure analysis and sperm chromatin dispersion tests (scd-halospermg2((r)) ) comparable? effect of pvp on sperm dna integrity-nabi et al. vol 19 no 3 may-june 2022 100 andrologia. 2019;51:e13316. 21. anbari f, halvaei i, nabi a, ghazali s, khalili ma, johansson l. the quality of sperm preparation medium affects the motility, viability, and dna integrity of human spermatozoa. j hum reprod sci. 2016;9:2548. 22. nabi a, khalili ma, halvaei i, roodbari f. prolonged incubation of processed human spermatozoa will increase dna fragmentation. andrologia. 2014;46:374-9. 23. strehler e, capitani s, collodel g, et al. submicroscopic mathematical evaluation of spermatozoa in assisted reproduction. i. intracytoplasmic sperm injection. (notulae seminologicae 6). j submicrosc cytol pathol. 1995;27:573-86. 24. kato y, nagao y. effect of pvp on sperm capacitation status and embryonic development in cattle. theriogenology. 2009;72:624-35. 25. tarozzi n, nadalini m, borini a. effect on sperm dna quality following sperm selection for art: new insights. genetic damage in human spermatozoa: springer; 2019:169-87. 26. bm a, ma a, kg a, as o, sa b. efficiency of hyaluronic acid binding ability to improve sperm selection in intracytoplasmic sperm injection (icsi). egypt j hosp med. 2016;65:536-46. effect of pvp on sperm dna integrity-nabi et al. vol 19 no 3 may-june 2022 237 laparoscopic and robotic urology the learning curve does not affect positive surgical margin status in robot-assisted laparoscopic prostatectomy ekrem islamoglu1*, kaan karamık1, cagatay ozsoy1, husnu tokgoz1, mutlu ates1, murat savas1 purpose: to assess the oncologic results of our robot-assisted laparoscopic prostatectomy (ralp) cases and investigate whether the learning curve (lc) affects the oncological outcomes. materials and methods: between march 2015 and september 2017, 111 patients underwent ralp by a single surgeon in our clinic. the learning curve was analyzed using the moving average method. we compared the rate of positive surgical margins(psm) and oncological outcomes, operation times, hematocrit changes and duration of hospitalization among the patients during and after the lc. complications were also noted according to clavien system. result: lc analysis using the moving average method showed that the lc stabilized between cases 51–60. so, patients were classified into two groups; 1-50 cases (group 1) and 51-111 cases (group 2). psm rates were 36% for group 1 and 18% for group 2, and statistically different (p = 0,032). extracapsular invasion (eci) was significantly higher in group 1 (56,5%) than in group 2 (29,5%) (p = 0.005). multiple logistic regression analysis revealed that presence of eci was an independent factor for psm associated with the groups (or: 2.512; 95% ci: 1.055-5.979). both operation time and duration of postoperative hospitalization were significantly reduced from group 1 to group 2. a total of 11 patients (10%) had complications and one of them (0.9%) required surgical intervention. conclusion: we can conclude that at least 50 ralp cases are needed to gain proficiency even for an experienced surgeon in laparoscopic radical prostatectomy. our study demonstrates that surgeons experience can affect the perioperative variables but the lc does not affect psm status in ralp. keywords: learning curve; positive surgical margin; robot-assisted prostatectomy introduction prostate cancer (pca) is the most commonly diag-nosed cancer in men and it's also second-ranked cancer that results in death in the united states.(1) according to the cancer statistics collected in turkey, it is the second most common type of cancer in 11.8% of men, in all age groups.(2) currently, radical prostatectomy is the only surgical treatment of localized pca. in 1980, walsh et al. described retropubic radical prostatectomy (rrp) and this procedure remained the gold standard for a long time.(3) in 1992, schuessler et al. performed the first laparoscopic radical prostatectomy (lrp) as an alternative to rrp.(4) despite the development of laparoscopic technique in the following years, the lrp continued to be a long and complex surgery with a steep learning curve and even surgeons with high laparoscopy skills required a series of 40-100 cases to gain mastery.(5) the difficulties of the lrp brought along different quests and after the introduction of the da vinci robotic surgery system, binder et al. performed the first robot-assisted laparoscopic radical prostatectomy (ralp) in may 2000.(6) with its three-dimensional magnified vision, enhanced ergonomics, computer filtration of tremors and scaled-down movement with the use of an endo-wrist instrument with seven degrees of freedom of range in motion, robotic surgery has initi1university of health sciences, antalya training and research hospital, antalya, turkey. *correspondence: university of health sciences, antalya training and research hospital, antalya, turkey. orcid id: 0000-0003-0693-0666. phone: (+90)05327115759. fax: +90 242 2494487. e-mail: meislamoglu@gmail.com. received february 2018 & accepted september 2018 ated a new era of radical prostatectomy. as a matter of fact, 85% of radical prostatectomies in the us have become robot-assisted, less than a decade after its introduction.(7) of course, robotic surgery has some disadvantages; high costs, inability to understand the tissue or suture tension due to lack of tactile sensation and collision of robotic arms with each other or assistant port are the major ones.(8) we assessed the results of our ralp cases performed by a single surgeon in our clinic and investigated whether the learning curve affects the oncological outcomes. patients and methods our robotic team consists of a console surgeon, one assistant surgeon, one surgical nurse, one surgical technician and one circulating nurse. before the robotic prostate surgery, the console surgeon and the assistant surgeon had gained experience in open rrp and lrp cases. between march 2015 and september 2017, 111 patients who underwent ralp by a single surgeon in our clinic, were enrolled in the study. preoperative clinical data; including age, serum prostate-specific antigen (psa), biopsy gleason score and number of cores positive, were collected. the preoperative risk was determined by d'amico risk stratification and patients were classified as low, intermediate and high risk.(9) we performed laparoscopic and robotic urology 333 vol 15 no 06 november-december 2018 334 all ralp procedures via transperitoneal approach, using 6 trocar ports of a conventional 4-arm da vinci xi robotic system, beginning with initial dissection of the seminal vesicles and the prostate in a posterior fashion as described by zorn et al.(10) subsequently, returning to the anterior aspect of the prostate and separating the dorsal vein complex. the neurovascular bundle (nvb) was completely released and the prostate is dissected from the bladder neck. urethrovesical anastomosis was done continuously, using two 15 cm 3-0 v-lock sutures and 18 french foley catheter with 10 ml balloon was inserted. bilateral pelvic lymphadenectomy (bplnd) was performed in all high risk and selected intermediate-risk patients according to briganti nomogram.(11) none of the patients received neoadjuvant hormonal therapy. perioperative parameters were recorded such as operation time, intraoperative complications and whether bplnd or nvb preservation was done. operation time was defined as skin to skin time in minutes and includes the docking and undocking time. postoperative parameters including hematocrit change, duration of hospitalization and catheter removal date were noted. pathological outcomes included pathological gleason score; positive surgical margin (psm) status; extracapsular, lymphovascular, perineural and seminal vesicle invasion; as well as lymph node positivity. in order to classify the complications after surgery, the clavien system, which provides standardization in the literature, was used.(12) patient data were prospectively registered in a specific database that was accessible only to authorized people. the patients who provided a written informed consent document were assured regarding the confidentiality of their data. the data were analyzed in a retrospective way to evaluate the clinical and pathological outcomes. our study was in accordance with the helsinki declaration and did not gain ethics committee permission as it included retrospective data. statistical analysis the learning curve evaluation parameter was operation time. the learning curve was analyzed using the moving average method.(13) we decided to use the 10-case moving average as the moving averages for less than 10 cases that exhibited excessive variation. trends in the operation time can be unclear because of differences between individual cases. with the moving average method, using the mean operation times, the individual changes are removed, and trends are clarified. the patients were divided into two groups, one inside and one after the learning curve. between two groups; statistical analysis was made using ibm spss statistics for windows, version 22.0 (ibm corp., armonk, ny). fisher’s exact test and pearson chi-square analysis performed for categorical variables. the normality assumptions were controlled by the shapiro-wilk test. the differences between two groups were evaluated with student’s t-test for normally distributed data or mann-whitney u test for non-normally distributed data. data are expressed as n(%), table 1. comparison of demographic and clinical characteristics of both groups group 1(1-50) group 2 (51-111) p-value age, mean±sd 63.5 ± 6.4 64.7 ± 6.9 0.331 psa, median(min-max) 7.8 (3.1-53.4) 6.5 (0.3-40) 0.406 number of cores positive, median(min-max) 3 (1-10) 3 (1-11) 0.144 biopsy gleason score, n(%) 4-6 32 (64) 38 (62.3) 0.981 7 15 (30) 19(31.1) 8-10 3(6) 4 (6.6) risk group, n(%) low 18 (45) 28 (45.9) 0.932 intermediate 15 (37.5) 24 (39.3) high 7 (17.5) 9 (14.8) group 1(1-50) group 2(51-111) p-value surgical margin status, n(%) negative 32 (64) 50 (82) 0.032 positive 18 (36) 11(18) extracapsular invasion, n(%) yes 28 (56) 18 (29.5) 0.005 no 22 (44) 43 (70.5) lymphovascular invasion, n(%) yes 15 (30) 11(18) 0.139 no 35 (70) 50 (82) perineural invasion, n(%) yes 39 (78) 45 (73.8) 0.605 no 11(22) 16 (26.2) seminal vesicle invasion, n(%) yes 10 (20) 11(18) 0.792 no 40 (80) 50 (82) pathological gleason score, n(%) 4-6 19 (38) 22 (36.1) 0.922 7 27 (54) 35 (57.4) 8-10 4 (8) 4 (6.6) lymph node positive, n(%) yes 5 (25) 2 (13) 0.240 no 15 (75) 13 (87) pathological stage, n(%) pt2 27 (54) 39 (64) 0.262 pt3 23 (46) 22 (36) pt3 13/23(56%) 6/22 (27%) biochemical recurrence, n(%) yes 6 (12) 4 (6.6) 0.999 no 44 (88) 57 (93.4) duration of follow-up, months 15 (12-33) 6 (3-12) < 0.001 additional treatment, n(%) 11(22) 6 (9.8) 0.153 table 2.comparison of clinical and pathological outcomes of both groups lc does not affect psm status in ralp-islamoglu et al. mean ± standard deviation(sd) or median (min-max), as appropriate. p values < 0.05 were considered statistically significant. multivariate analysis was performed using logistic regression. results as shown in figure 1, learning curve analysis using the moving average method showed that the learning curve stabilized between cases 51–60. so, we divided the patients into two groups, group 1 (cases 1-50) and group 2 (cases 51-111). preoperative clinical characteristics of both groups are shown in table 1 and two groups were similar to each other as seen. the entire cohort aged 64 years on median (range 44-75), with a median psa of 7.1 ng/ml. according to d'amico risk classification and biopsy gleason scores, there was no difference between the two groups before surgery (p > 0.05). pathological outcomes and clinical follow-up are shown in table 2. psm rates were 36% for group1 and 18% for group 2, and statistically different (p = 0.032). additionally, extracapsular invasion (eci) was significantly higher in group 1 (56.5%) than in group 2 (29.5%) (p = 0.005). there was no difference between the two groups in terms of pathologic gleason score; lymphovascular, perineural, seminal vesicle invasion and pathologic t stage (p > .05). multivariate analysis was performed to define whether eci affected psm, using logistic regression. as seen in table 3, multiple logistic regression analysis revealed that presence of eci was an independent factor for psm associated with the groups (or: 2.512; 95% ci: 1.055-5.979). a total of 35 patients underwent extended bplnd during ralp, 20 patients in group 1 (40%) and 15 patients in group 2 (24%). although lymph node positivity was higher in group 1(25% and 13%, respectively), there was no statistically significant difference between two groups (p = 0.24). the median follow-up of entire patients was 11 months and biochemical recurrence (bcr) rates were 12% and 6,6% in group 1 and 2, respectively (p = 0.99). a total of 7 patients with positive lymph nodes received early hormone therapy and 10 patients with bcr directed to radiotherapy. although patients in group 1 needed more additional treatment (22% and 9,8%, respectively), there was no statistically significant difference between two groups (p = 0.153). patients with psm are analyzed in subgroups and relationship between psm and pt stage, lymphovascular, perineural, extracapsular invasion are shown in table 4. operative parameters are shown in table 5. both operation time (skin to skin time, as defined) and duration of postoperative hospitalization were significantly reduced from group 1 to group 2 (p < 0.001). a factor that could affect the operation time is whether bplnd is performed or not. since the bplnd performed patients were equally distributed in two groups, the effects on the operation time were evaluated as being equal. hematocrit decrease on the first postoperative day did not show a significant difference between two groups (p = 0.587). the complications were classified using the clavien system (from 1 to 4) and shown in table 6.(14) a total of 11 patients (10%) (each one suffering single event) had complications and one of them (0.9%) required surgical intervention. this patient had adhesions due to previous peritonitis surgery, and ileal perforation was detected when he was explored due to the acute abdomen on the 2nd postoperative day. the ileum was repaired as primary and patient was discharged on the postoperative 9th day. two patients with urethra-vesical anastomosis stenosis and one patient with urethral stricture were treated with endoscopic intervention. discussion radical prostatectomy is a complex surgery combined of extraction and reconstruction of tissues. robotic surgery has the advantage to simplify this complex procedure with its excellent three-dimensional vision and high motion range endo-wrist instruments. after the introduction of ralp, there has been a rapid increase in daily practice and interest in robotic surgery. but it should be kept in mind that, as with any new surgical technique ralp also have a learning curve. there is no consensus regarding the optimal way of detecting the learning curve of a surgical procedure but traditionally, the operative time has been widely used to assess this. zorn et al. suggested that 120 ralp cases are needed to achieve a skin-to-skin operation time under 4 hours. (15) ou et al. reported that the console time becomes gradually shorter with every 50 cases experience in their study.(16) in our study; operation time, described as table 3. multiple logistic regression analysis for the effect of eci on surgical margin status wald p-value odds ratio (95%ci) surgical margin status 0.972 0.324 1.635(0.615-4.344 extracapsular invasion 4.331 0.037 2.512(1.055-5.979) psm (n:29) group 1(1-50) group 2 (51-111) p-value lymphovascular invasion, n(%) no 10(55.6) 9(81.8) 0.234 yes 8(44.4) 2(18.2) perineural invasion, n(%) no 2(11.1) 3(27.3) 0.339 yes 16(88.9) 8(72.7) extracapsular invasion, n(%) yes 0(0) 6(54.5) 0.001 no 18(100) 5(45.5) pathological stage n(%) t2 5(27.8) 5(45.5) * t3a 6(33.3) 4(36.4) t3b 7(38.9) 2(18.2) table 4. comparison of pathological parameters in patients with psm between two groups lc does not affect psm status in ralp-islamoglu et al. laparoscopic and robotic urology 335 vol 15 no 06 november-december 2018 336 skin-to-skin time, was used to detect the learning curve. we used the moving average method to find the cut-off point for a learning curve in ralp, as used in the literature before.(17,18) we found that at least 50 ralp cases are needed to gain proficiency even for an experienced surgeon in laparoscopic radical prostatectomy. to our understanding, reducing docking time with the more rapid determination of trocar positions and placement affected the operation time as well as improvements in surgical technique. the independent risk factors for disease recurrence and progression after radical prostatectomy are the presence of psm, preoperative psa, pathologic gleason score and seminal vesicle involvement.(19) among these, psm is the only factor dependant on surgical experience. the main purpose of any urologist performing radical prostatectomy should be to reduce psm rate and prevent disease recurrence. in the most extensive literature review, novara et al. reported a 15% mean rate of psms in ralrp series published between 2008 and 2011 (each including >100 cases), with a range of 6.5–32% and concluded that psm rate is higher in men with a more advanced pathologic stage.(20) our study included a single surgeon with open and laparoscopic surgical background in radical prostatectomy and yielded that psm rate has decreased dramatically from 36% to 18% after first 50 patients. but the higher rate of eci in group 1 directed us to make a multivariate analysis to find out the effect of eci on psm. in this analysis, we found that the presence of extracapsular invasion was an independent factor for psm and affected the psm rates in both groups. from this point of view, we feel that the learning curve does not play a significant role in pathologic outcomes of ralp. we performed video documentation in all ralps and reviewed our records in correlation with pathological reports to improve our technique. according to discussions with pathologists we made minor modifications in our technique after 40 patients. after dissecting seminal vesicles from a posterior approach we continued dissection until neurovascular bundle and apex appear, then turned in anterior approach and completed nvb dissection, dorsal venous complex ligation, and urethral incision in a traditional way. in tewari's series, this retroapical technique decreased the authors' rate of psms from 4.4% to 1.4% and we believe that this modification had an effect in our lower psm rate in the second group.(21) although positive margins in prostate cancer are considered an adverse oncologic outcome, their long-term impact on survival is highly variable and largely influenced by other risk modifiers.(22) bcr rates for ralp differs with follow-up time in different series. propiglia et al. and asimakopoulos et al. reported their bcr rates as 2,0% and 4,4% respectively, with a 12 months follow-up.(23,24) park et al. and ploussard et al. found bcr rates as 13,1% within 19 months and 10,3% within 15 months follow-up, respectively.(25,26) in our study, we had a bcr rate as 12% in group 1 with 15 months of follow-up and 6,6% in group 2 with a 6 months follow-up. the rates of need for additional therapy were 22% and 6,6% (p = 0,153) in group 1-2, respectively. although follow-up period was short these findings were consistent with the literature. we classified our complications using clavien system and our 10% complication rate is within average when compared with newer series ranging from 5,08% to 19,6%.(16,27) in patel's series with 2500 cases, a single surgeon had low complication rates of 5,08% in a large volume center and demonstrated a tendency to decrease with increasing experience of the surgeon.(28) this study has some limitations. although it was based on a prospective database the study was retrospective. also, the follow-up period is relatively short and oncological outcomes such as bcr require further observation. lastly, the cohort was small with 111 cases and a study with larger sample size could demonstrate the effect of learning curve on psm better. table 5. comparison of operative parameters of both groups group 1(1-50) group 2 (51-111) p-value operation time, (mean ± sd) min 257.1 ± 32.7 174.4 ± 41.3 < 0.001 duration of hospitization (min-max) 4 (2-9) 3 (2-8) < 0.001 hematocrit decrease median (min-max) 4.5 (0.7-10.9) 3.3 (0.5-14.5) 0.587 bplnd, n(%) 20 (40) 15 (24) 0.376 nvb preservation, n(%) 18 (36) 29 (47) 0.403 number (by event) detail clavien 1 5 lymphocele(2), urine leakage(1), intraoperative tachycardia(1), umblical wound infection(1), clavien 2 2 blood transfusion(2) clavien 3 3 urethral stricture(1), urethra-vesical anastomosis stenosis (2) clavien 4 1 ileum perforation(1) table 6. classification of complications occurred in entire patients using clavien system figure 1.time taken to perform ralp in each case. moving average curve of ralp. lc does not affect psm status in ralp-islamoglu et al. conclusions we can conclude that at least 50 ralp cases are needed to gain proficiency even for an experienced surgeon in laparoscopic radical prostatectomy. our study demonstrates that surgeons experience can affect the perioperative variables but the learning curve does not affect psm status in ralp. acknowledgement the authors would like to thank dr.basak oguz and appreciate her support for the statistical analysis of this study. conflict of interest no competing financial interests exist. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2018. ca cancer j clin. 68, 7-30. 2. gültekin m, boztaş g. türkiye kanser istatistikleri. in: saglık bakanlıgı, türkiye halk saglıgı kurumu, 2014; 43. 3. walsh pc, partin aw, epstein ji. cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. j urol. 1994;152(5 pt 2), 1831-6. 4. schuessler ww, schulam pg, clayman rv, kavoussi lr. laparoscopic radical prostatectomy: initial short-term experience. urology. 1997;50, 854-7. 5. ahlering te, skarecky d, lee d, clayman rv. successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. j urology. 2003;170(5), 1738-41. 6. binder j, kramer w. robotically‐assisted laparoscopic radical prostatectomy. bju int. 2001;87, 408-10. 7. lepor h. status of radical prostatectomy in 2009: is there medical evidence to justify the robotic approach? rev urol. 2009;11, 61. 8. kural ar, atug f. the applications of robotic surgery in urology. turk j urol. 2010; 36, 248-58. 9. d'amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998; 280, 969-74. 10. zorn kc, gofrit on, orvieto ma, et al. robotic-assisted laparoscopic prostatectomy: functional and pathologic outcomes with interfascial nerve preservation. eur urol. 2007; 51(3), 755-63. 11. briganti a, larcher a, abdollah f, et al. updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. eur urol. 2012; 61, 480-7. 12. gandaglia g, bravi ca, dell’oglio p, et al. the impact of implementation of the european association of urology guidelines panel recommendations on reporting and grading complications on perioperative outcomes after robot-assisted radical prostatectomy. eur urol. 2018; https://doi.org/10.1016/j. eururo.2018.02.025 13. diggle pj. time series: a biostatistical introduction. in: clarendon press, oxford. 1990: p 257 14. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009; 250, 187-96. 15. zorn kc, orvieto ma, gong em, et al. robotic radical prostatectomy learning curve of a fellowship-trained laparoscopic surgeon. j endourol. 2007; 21, 441-7. 16. ou yc, yang cr, wang j, et al. the learning curve for reducing complications of robotic‐ assisted laparoscopic radical prostatectomy by a single surgeon. bju int. 2011; 108, 420-5. 17. fukumoto k, miyajima a, hattori s, et al. the learning curve of laparoendoscopic single-site adrenalectomy: an analysis of over 100 cases. surg endosc. 2017; 31, 170-7. 18. kayano h, okuda j, tanaka k, kondo k, tanigawa n. evaluation of the learning curve in laparoscopic low anterior resection for rectal cancer. surg endosc. 2011; 25, 2972-9. 19. wieder ja, soloway ms. incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer. j urology. 1998; 160, 299315. 20. novara g, ficarra v, mocellin s, et al. systematic review and meta-analysis of studies reporting oncologic outcome after robot-assisted radical prostatectomy. eur urol. 2012; 62:382–404. 21. tewari ak, srivastava a, mudaliar k, et al. anatomical retroapical technique of synchronous (posterior and anterior) urethral transection: a novel approach for ameliorating apical margin positivity during robotic radical prostatectomy. bju int. 2010;106: 1364–73. 22. yossepowitch o, briganti a, eastham ja, et al. positive surgical margins after radical prostatectomy: a systematic review and contemporary update. eur urol. 2014; 65, 303-13. 23. porpiglia f, morra i, chiarissi ml, et al. randomised controlled trial comparing laparoscopic and robot-assisted radical prostatectomy. eur urol. 2013; 63, 606-14. 24. asimakopoulos ad, miano r, di lorenzo n, spera e, vespasiani g, mugnier c. laparoscopic versus robot-assisted bilateral lc does not affect psm status in ralp-islamoglu et al. laparoscopic and robotic urology 337 vol 15 no 06 november-december 2018 338 nerve-sparing radical prostatectomy: comparison of pentafecta rates for a single surgeon. surg endosc. 2013; 27, 4297-304. 25. park b, kim w, jeong bc, et al. comparison of oncological and functional outcomes of pure versus robotic-assisted laparoscopic radical prostatectomy performed by a single surgeon. scand j urol. 2013; 47, 10-18. 26. ploussard g, de la taille a, moulin m, et al. comparisons of the perioperative, functional, and oncologic outcomes after robot-assisted versus pure extraperitoneal laparoscopic radical prostatectomy. eur urol. 2014; 65, 610-19. 27. lasser ms, renzulli j, turini ga, haleblian g, sax hc, pareek g. an unbiased prospective report of perioperative complications of robotassisted laparoscopic radical prostatectomy. urology. 2010; 75, 1083-9. 28. coelho rf, palmer kj, rocco b, et al. early complication rates in a single-surgeon series of 2500 robotic-assisted radical prostatectomies: report applying a standardized grading system. eur urol. 2010; 57, 945-52. lc does not affect psm status in ralp-islamoglu et al. 1 running head: can cadaveric transplant alone eradicate the kidney wl? can deceased donor transplantation alone eradicate the kidney waiting list? mohsen khakzad kelarijani1,2* 1 shahid labbafinejad medical center, the center of excellence in urology and kidney transplantation, shahid beheshti university of medical sciences, tehran, iran 2 deputy for public health, mazandaran university of medical sciences, sari, iran corresponding author: mohsen khakzad kelarijani, m.d. department of kidney transplantation and urology, shahid labbafinejad hospital, 9th boostan street, pasdaran ave, tehran, iran. tel: +98 21 22588016 e-mail: mohsenkh1010@yahoo.com orcid id: https://orcid.org/0009-0009-0439-1700 keywords: rewarded gifting; paid donation; living donation; unrelated paid transplantation; kidney donation; renal transplantation; living donor; living unrelated donor. 2 the prevalence of end-stage kidney disease (eskd) could greatly increase in the upcoming decades, caused by population aging and rising diabetes and hypertension cases. an estimation of 3.9 million individuals globally undergoing renal replacement therapy for eskd in 2017 is expected to climb to 5.4 million by 2030. chronic kidney disease was the 13th most common cause of death all around the world in 2016, and it is predicted to be the 5th leading cause of years of life lost by 2040(1). kidney transplantation is the gold standard treatment for eskd patients. however, the shortage of transplant kidneys is a global crisis. it is well understood that post-transplant outcomes of living donor kidney transplants are better than those of deceased donor transplants. living donor kidney transplants from unrelated donors resulted in longer graft survival compared to related donors, according to a large cohort study on more than 70,000 kidney transplants in the us(2). nevertheless, some authors believe that living unrelated donor kidney transplantation should be stopped(3); the experience of shiraz transplant center (stc) with the exclusively deceased organ donation program may apply to the city or province, but it cannot be extended to larger regions like iran or the middle east. some patients on the waiting list of the stc, especially those requiring second or third re-transplantation, have gone to other centers in the country to have a living unrelated kidney transplant, as they could not wait any longer for a deceased donor in shiraz. even in developed countries with the most successful deceased organ procurement and transplantation networks, the entire demand for kidney transplants cannot be met (figure 1), resulting in many deaths for patients on long waiting lists. for example, in the united states, over 90,000 patients are currently wait-listed for a kidney transplant with an average waiting time of five years. tragically, 4-5 thousand of these patients lose their lives each year before 3 receiving the kidney they need. spain, which has approximately 90% of kidney transplants coming from deceased donors, had the most deceased-donor kidney transplants per population in the world from 2017 to 2019 and was ranked second after the united states in 2020 and 2021, but the waiting list did not decrease significantly. at the end of 2017 and 2021, the number of people awaiting a kidney transplant in spain was 3942 and 3945, respectively(4). in iran and the middle east, even if the number of kidney transplants from deceased donors reaches the highest possible level, it will still not be enough to meet the needs of those on the waiting list. health systems officials should therefore consider supporting all types of kidney transplants, including living related and unrelated donors, as they are directly responsible for the lives and well-being of patients. more than twenty countries have implemented some types of reimbursement programs to remove disincentives for living kidney donors(5). anyone who donates a kidney, even if they receive a financial reward, should be celebrated as a hero since they are saving a human life. the iranian model of government regulated paid living-unrelated kidney donation (rewarded gifting) started in the 1980s has proven its usefulness and success in shortening the waitlist(6) and now requires more support from the government and the public. in this direction, in november 2022, the iranian government substantially increased the financial compensation by forty times. with this cost-effective approach, compared to dialysis, more lives can be saved, patients can experience a higher quality of life, and the burden on taxpayers can be reduced(7). rewarded or paid living kidney donation has been endorsed by islamic religious-ethical leaders. nonetheless, some opponents find this practice unethical. they do not feel accountable for the lives of dialysis patients, and they strive to propagate their critical views in society, but this will only lead to more deaths. deceased and living kidney donations must be used together, like two 4 wings of a bird (upgraded iranian model of kidney transplantation), and weakening either will cause irreparable damage. once the waiting list is eliminated, living-donor kidney transplantation can be reconsidered. until that time, which does not appear to be soon, the transplant community should unite in the pursuit of saving human lives. 5 references 1. foreman kj, marquez n, dolgert a, et al. forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories. lancet. 2018;392:2052-2090. 2. husain sa, king kl, sanichar n, crew rj, schold jd, mohan s. association between donor-recipient biological relationship and allograft outcomes after living donor kidney transplant. jama netw open. 2021;4(4):e215718. 3. malek hosseini sa, arasteh p, shamsaeefar a, roozbeh j, gholami s, nikeghbalian s. the beginning of the end for living unrelated donation kidney transplantations in the middle east: the shiraz transplant center experience. transplantation. 2022;106(9s):s411. 4. global observatory on donation and transplantation. https://www.transplantobservatory.org/. accessed march 20, 2023. 5. siddique ab, apte v, fry-revere s, jin y, koizumi n. the impact of country reimbursement programmes on living kidney donations. bmj glob health. 2020;5(8):e002596. 6. simforoosh n. kidney donation and rewarded gifting: an iranian model. nat clin pract urol. 2007;4(6):292-3. 7. held pj, mccormick f, ojo a, roberts jp. a cost-benefit analysis of government compensation of kidney donors. am j transplant. 2016;16(3):877-85. https://www.transplant-observatory.org/ https://www.transplant-observatory.org/ 6 figure 1. despite the growth in kidney transplants, the gap between demand and supply has expanded. prof abbas basiri, md editor in chief urology journal dear professor basiri, letter to the editor re: evaluation of the clinical effects of abobotolinum toxin a (dysport) injection in the treatment of neurogenic lower urinary tract dysfunction we read with interest the recent publication by sharifiaghdas et al evaluation of the clinical effects of abobotolinum toxin a (dysport) injection in the treatment of neurogenic lower urinary tract dysfunction 1. a small study involving 52 female patients with neurogenic voiding dysfunction who were treated with dysport following a trial of medical therapy for 3 months is presented. it is noted that 36 patients had neurogenic detrusor activity, 8 had sphincter dyssynergia and 8 had both. the authors only mention the cause of neurogenic voiding dysfunction in 17 patients and it is unclear how many had multiple sclerosis or a traumatic spinal cord injury. additionally, is not stated whether any patient underwent video urodynamic assessment and preoperative pad usage, and patient weight are not documented. the authors proceed to discuss the preoperative assessment and exclusion criteria. although the urogenital distress inventory questionnaire was used in this study2 specific neurogenic bladder questionnaires which have been validated in both traumatic spinal cord injury and multiple sclerosis exist3, 4 and are not referenced. in our unit all neurogenic bladder patients undergo pre and post operative assessment with the sf qualiveen questionnaire to document baseline status and treatment response following intravesical botox 5. it should also be acknowledged by the authors that the pivotal dignity trial involving intravesical botox therapy which investigated improved continence as an end point and improved urodynamic parameters as end points is also not referenced 6, 7. the authors allude to the small sample size and limit follow up period. however, the failure to fully elucidate the exact cause of neurogenic voiding dysfunction and reliance on one questionnaire only are also drawbacks of this study. yours sincerely, mr mahmoud s gadelrab, registrar in urology, st. helens & knowsley hospital nhs trust, whiston hospital, merseyside, l35 5dr mr alaa chamsin, associate specialist in urology. st. helens & knowsley hospital nhs trust, whiston hospital, merseyside, l35 5dr. mr rauf n khadr, consultant urological surgeon, department of urology 1 & north west spinal cord injury unit 2, southport & ormskirk nhs foundation trust, southport, merseyside, uk mr ahmad m omar, consultant urological surgeon, department of reconstructive urology, st. helens & knowsley hospital nhs trust, whiston hospital, merseyside, l35 5dr mr michael s floyd jr, consultant urological surgeon, department of reconstructive urology, st. helens & knowsley hospital nhs trust, whiston hospital, merseyside, l35 5dr & north west spinal cord injury unit 2, southport & ormskirk nhs foundation trust, southport, merseyside, uk the authors declare that there are no conflicts of interest. level of evidence: n/a references sharifiaghdas f, taheri m, borumandnia n et al. evaluation of the clinical effects of abobotolinum toxin a (dysport) injection in the treatment of neurogenic lower urinary tract dysfunction. urology journal 2022; 1: 63-68 uebersax j, wyman j, shumaker s, et al. short forms to assess life quality and symptom distress for urinary incontinence in women: the incontinence impact questionnaire and the urogenital distress inventory. neurourol urodyn 1995; 14: 131-9 costa p, costa p, perrouin-verbe b, et al. quality of life in spinal cord injury patients with urinary difficulties. european urology 2001; 39: 107-113 bonniaud v, bryant d, parratte b, et al. development and validation of the short form of a urinary quality of life questionnaire: sf-qualiveen. the journal of urology 2008; 180: 2592-2598 floyd ms, jr. and khadr rn. role of gentamicin in reducing urinary tract infections in patients with neurogenic bladder. canadian urological association journal journal de l'association des urologues du canada 2017; 11: 427-428. 2017/11/01 cruz f, herschorn s, aliotta p, at al. efficacy and safety of onabotulinumtoxin a in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial, eur urol, 2011; 60: 742-75 ginsberg d, gousse a, keppenne v, et al. phase 3 efficacy and tolerability study of onabotulinumtoxin a for urinary incontinence from neurogenic detrusor overactivity. j urol, 2012; 187: 2131-2139 reply by author in response to the above letter to the editor, a wide variety of potential neurologic etiologies can lead to neurogenic lower urinary tract dysfunction (nlutd) which is categorized by the neuroanatomic location [1,2]. in this study, we only mentioned the reason for nlutd in patients who had known neurologic disorders in the spinal canal (17 participants; intervertebral disc prolapses:8, trauma:5 and, after disc surgery:4). the other patients had potential risk factors for neurologic diseases such as long-time diabetes mellitus, iatrogenic injuries during pelvic or bladder surgeries, pelvic radiation, etc. who’s maybe categorized as the probable peripheral neuropathy that cannot be proved by imaging (mri of the brain or spinal cord). we thank the authors for their attention, the mean weight of our patients (kg) was 69.46 ± 14.33. regarding the evaluation of nlutd patients, according to the latest version of aua/sufu guidelines on nlutd [2], in addition to the detailed history, physical examination and, urine analysis, there are a variety of tools such as voiding diaries, questionnaires (e.g., nbss, qualiveen), uroflow, urodynamics, renal ultrasound, and cystoscopy which do not recommend all of those in each patient. video urodynamic is performed only in one center in our country, which is not easily available for our patients who came from a significant distance and is used for very limited referral patients. we agree that the use of validated questionnaires would significantly have improved the initial evaluation and follow-up of nlutd patients. we will plan to employ these specific questionnaires in future studies. the main outcome of our study was a subjective improvement in patient continence which was evaluated by patients’ general satisfaction questionnaire including; improvement in urinary incontinence, difficult urination, and the need for clean intermittent catheterization [3]. existing evidence regarding the improved urodynamic parameters as endpoints reveals that a patient’s follow-up based on uds may improve treatment satisfaction [4], however, urodynamic parameters do not guarantee improvement in bothersome lower urinary tract symptoms [5]. along with these results, in the last meta-analysis by guang-ping et al. [6] outcome treatment after botulinum injection in patients with neurogenic detrusor overactivity caused by spinal cord injury were uroflow, postvoid residual volume, urge incontinency episode, or just adverse events in some studies. again, we thank the authors for their interest and comments in our work. yours sincerely, farzaneh sharifiaghdas, md, maryam taheri, md, zhila seikhi, md. references 1. gajewski jb, schurch b. an international continence society (ics) report on the terminology for adult neurogenic lower urinary tract dysfunction (anlutd). 2018;37:1152-61. 2. ginsberg da, boone tb, cameron ap, gousse a, kaufman mr, keays e, et al. the aua/sufu guideline on adult neurogenic lower urinary tract dysfunction: diagnosis and evaluation. j urol 2021;206:1097-105. 3. kuo hc. therapeutic outcome and quality of life between urethral and detrusor botulinum toxin treatment for patients with spinal cord lesions and detrusor sphincter dyssynergia. int j clin pract 2013;67:1044-9. 4. verghese ts, middleton lj, daniels jp, deeks jj, latthe pm. the impact of urodynamics on treatment and outcomes in women with an overactive bladder: a longitudinal prospective follow-up study. int urogynecol j 2018;29:513-9. 5. goldman hb, lloyd jc. international continence society best practice statement for use of sacral neuromodulation. 2018;37:1823-48. 6. li gp, wang xy, zhang y. efficacy and safety of onabotulinumtoxina in patients with neurogenic detrusor overactivity caused by spinal cord injury: a systematic review and meta-analysis. int neurourol j 2018;22:275-86. case report 129urology journal vol 7 no 2 spring 2010 wunderlich syndrome as the first manifestation of renal cell carcinoma sheng f oon, michael murphy, stephen s connolly urol j. 2010;7:129-32. www.uj.unrc.ir keywords: renal cell carcinoma, spontaneous rupture, therapeutic embolization department of urology, st. vincent’s university hospital, elm park, dublin, ireland corresponding author: sheng f oon, md 5 alexander court, fenian street, dublin 2, republic of ireland tel: +353 874187467 e-mail: shengfeioon@rcsi.ie received january 2010 accepted february 2010 introduction renal cell carcinoma (rcc) classically presents as a triad of hematuria, loin pain, and a palpable mass. however, rccs are increasingly found as incidental findings on the radiological imaging ordered for other reasons.(1) the spontaneous rupture of the kidney, or wunderlich syndrome, is very rarely the first presentation of rcc. we describe a clinical case of spontaneous renal hemorrhage as the first manifestation of rcc that was treated with therapeutic embolization and early radical nephrectomy. case report a 63-year-old woman presented to the emergency department with severe generalized abdominal pain. she had marked pallor and was triaged to the resuscitation area. she described a history of 12-hour severe, constant pain with sudden onset and no associated radiation, which became progressively worse. there had been no precipitating factors or history of trauma. she did not have a previous medical disorder and did not take any medications. she was a non-smoker. on examination, her vital signs were normal. examination elicited generalized guarding and tenderness over the left flank. her bowel sounds were present and a poorly defined mass was palpable over the left side of her abdomen. when she was asked for a urine specimen, a gross hematuria was noted. serial blood tests showed a drop in serum hemoglobin from 12.5 g/dl to 10.1 g/dl after just one hour, with a concomitant decrease in hematocrit level (from 37% to 29%). she was immediately resuscitated with intravenous fluids and cross matched with 4 units of blood. then, a computed tomography (ct) scan was performed, which revealed a 14-cm mass involving the left kidney consistent with bleeding complicating a probable rcc at the lower pole of the kidney (figures 1 and 2). the patient’s hemoglobin levels continued to decrease, and she was transfused with 4 units of blood. her creatinine level was normal. the patient underwent emergency embolization (figures 3 and 4). then, she was admitted to the intensive care unit for close observation and strict bed-rest. moreover, a broad-spectrum antibiotic was commenced. she also had a central line inserted for access. her hemoglobin level stabilized. five days after presentation, the patient underwent nephrectomy. surgical excision was difficult, but wunderlich syndrome—oon et al 130 urology journal vol 7 no 2 spring 2010 figure 2. axial ct image showing extensive retroperitoneal hemorrhage. mixed attenuation within the hemorrhage reflects the temporal heterogeneity of the bleeding. the epicenter of the hemorrhage appears to be a calcified soft tissue density mass consistent with a renal cell carcinoma. figure 3. selected image from digital subtraction angiography demonstrating paucity of vessels at the lower pole with contrast blush (as shown by arrow) indicating intraparenchymal hemorrhage. figure 4. selected post-embolization image demonstrating absence of contrast blush with no flow of contrast to the lower pole of the kidney. figure 1. coronal ct reconstruction demonstrating irregularity of the renal contour with extensive hemorrhage into the perirenal fat. areas of calcification are demonstrated within a lower pole mass consistent with a renal cell carcinoma. wunderlich syndrome—oon et al 131urology journal vol 7 no 2 spring 2010 with careful dissection, the kidney and associated hematoma were removed, and the specimen was delivered. later, the patient made a remarkable recovery and was discharged after 2 weeks. histological examination revealed an extensively necrotic and disrupted rcc that could not be nuclear graded. the adrenal gland and the renal vein margin were free of tumor consistent with a pt2 stage (figures 5 and 6). within the 6-month follow-up, there was no sign of recurrence on repeated ct and her creatinine levels remained normal. discussion with increasingly sophisticated imaging techniques, the classic presentation of loin pain, palpable mass, and frank hematuria are less commonly seen. instead, rccs are now more commonly discovered as ‘incidentalomas’ on the radiological imaging for alternative abdominal pathologies.(1) the spontaneous rupture of the kidney, however, is rarely the first clinical presentation of rcc. in 1856, carl reinhold august wunderlich described the spontaneous bleeding of the kidney with dissection of blood into the subcapsular and/ or perinephric spaces.(2) wunderlich syndrome is uncommon and is usually caused by a benign disease.(3) the most recent meta-analysis by zhang and colleagues in 2002 reviewed 165 patients with spontaneous perirenal hemorrhage due to various causes between 1985 and 1999.(4) seventy percent of subjects with hemorrhage were due to benign causes, including vascular disease, infection, and neoplasia. overall, neoplastic causes accounted for 61.2% of these cases, with benign and malignant causes approximately divided equally (table). in treating wunderlich syndrome, some urologists favor an early or immediate exploratory surgery.(5) others prefer interventional radiology to stop an acutely hemorrhaging vessel.(6) there are logical reasons to avoid surgery in the acute scenario when the patient’s general condition are not fully stabilized, but embolization with the intention of delayed surgery also results in a more difficult resection due to adherence. there are currently no guidelines favoring either approach. the efficiency of ct to diagnose renal tumors at the time of bleeding is a further area of concern. computed tomography remains one of the most etiology percentage (%) tumor 61.2 benign 31.5 malignant 29.7 vascular disease 17.0 infection 2.42 miscellaneous 12.7 idiopathic hemorrhage 6.7 *adapted from zhang and colleagues(4) with their permission. etiology of spontaneous renal hemorrhage* figure 5. resected kidney specimen image showing rupture of the lower pole and features of infarction and necrosis consistent with hemorrhage and embolization. figure 6. high power view of specimen showing conventional clear cell carcinoma. wunderlich syndrome—oon et al 132 urology journal vol 7 no 2 spring 2010 reliable modalities in diagnosing retroperitoneal hemorrhage and rccs.(7) kendall and colleagues, however, found that 60% of subjects showed a rcc undiagnosed at the time of initial ct(8), which is in agreement with zhang’s meta-analysis where ct performed at the time of hemorrhage was only partially efficient at identifying renal tumors (sensitivity 0.57).(4) for malignant tumors diagnosed on initial ct, radical nephrectomy is eventually required. however, in the renal hemorrhages thought to be benign, embolization may be the sole modality used. if these patients were later found to have a malignancy on the follow-up ct, delayed surgery would not only affect the overall resectability of the tumor, but also the clinical staging of the disease.(9,10) wunderlich syndrome is a rare phenomenon that usually occurs due to a benign renal pathology, but a significant proportion, as in this case, are associated with malignancy. underlying malignancy may be missed on initial ct scan. one must, therefore, be suspicious when confronted with any spontaneous perirenal hemorrhage. the cornerstones of management include resuscitation, embolization, and nephrectomy, but timing, as well as the treatment modality, is important. where rcc is diagnosed on initial ct, immediate embolization and early resection, when the patient is stable, is a safe and reasonable approach to the timely management of this difficult condition. acknowledgements the authors are highly thankful to dr. simon walsh, department of radiology, st. vincent’s university hospital, for interpretation of the images. conflict of interest none declared. references 1. rousseau t, peyret c, zerbib m, thiounn n, flam t, debre b. circumstances of the detection of kidney cancer. current part of accidental discoveries. j urol (paris). 1994;100:189-95. 2. wunderlich cra. handbuch der pathologie und therapie. 2nd ed: stuttgart: ebner & seubert; 1856. 3. daskalopoulos g, karyotis i, heretis i, anezinis p, mavromanolakis e, delakas d. spontaneous perirenal hemorrhage: a 10-year experience at our institution. int urol nephrol. 2004;36:15-9. 4. zhang jq, fielding jr, zou kh. etiology of spontaneous perirenal hemorrhage: a meta-analysis. j urol. 2002;167:1593-6. 5. hao lw, lin cm, tsai sh. spontaneous hemorrhagic angiomyolipoma present with massive hematuria leading to urgent nephrectomy. am j emerg med. 2008;26:249 e3-5. 6. pummer k, lammer j, wandschneider g, primus g. renal cell carcinoma presenting as spontaneous retroperitoneal haemorrhage. int urol nephrol. 1990;22:307-11. 7. sebastia mc, perez-molina mo, alvarez-castells a, quiroga s, pallisa e. ct evaluation of underlying cause in spontaneous subcapsular and perirenal hemorrhage. eur radiol. 1997;7:686-90. 8. kendall ar, senay ba, coll me. spontaneous subcapsular renal hematoma: diagnosis and management. j urol. 1988;139:246-50. 9. hashimoto t, yamamoto s, togo y, et al. spontaneous rupture of renal cell carcinoma: a case report. hinyokika kiyo. 2007;53:49-52. 10. nakai m, nakamura n. a case report of spontaneous rupture of renal cell carcinoma difficult to be distinguished from angiomyolipoma. hinyokika kiyo. 2003;49:99-101. robot assisted radical cystectomy outcomes in micropapillary and plasmacytoid variants erdem koç1*, bahri gök1, berrak gümüşkaya2, ali fuat atmaca3, abdullah erdem canda4, mevlana derya balbay4,5 purpose: to compare the patients who underwent robot assisted radical cystectomy (rarc) and extended pelvic lymph node dissection (eplnd) and whose pathology result was reported as micropapillary variant (mv), plasmacytoid variant (pv) and pure urothelial carcinoma (puc). materials and methods: the data of 133 patients who underwent rarc and eplnd with the postoperative pathology results reported as mv, pv and puc were analyzed. according to the postoperative pathology results, patients were divided into two groups in initial analyses as variant pathologies group (n=14) and puc group (n=119). in secondary analyses, patients were divided into three groups as mv group (n=7), pv group (n=7) and puc group (n=119). the operative data, oncologic outcomes and complications were compared between the groups. results: median operation time and estimated blood loss were significantly increased in variant pathologies group (p <0.001 and p = .001, respectively). the postoperative pathological t stage, positive surgical margin rate and lymph node involvement were also significantly increased in variant pathologies (p = .001, p = 0.004, p <0.001, respectively). kaplan-meier analysis revealed significant decrease in os and css times in pv group compared to puc group (p = .048 and p = .016, respectively). conclusion: mv and pv are rarely seen variant pathologies with higher pathological t stages. rarc is a minimally invasive surgical technique that can be performed successfully by an experienced surgical team with low morbidity rates and similar oncological results, even in challenging cases. keywords: cystectomy; micropapillary urothelial carcinoma; plasmacytoid; robotic surgical procedures; urinary bladder neoplasms introduction urothelial carcinoma is the most common malig-nancy of the bladder, accounting for approximately 90% of bladder neoplasms(1). approximately 75 % of bladder cancers are classified as pure urothelial carcinoma (puc), while 25% consist of other histological variants (2,3). plasmacytoid variant (pv) and micropapillary variant (mv) are histologically rarely seen subtypes of urothelial cancer of the bladder. they exhibit lymphovascular invasion, high pathological stage and aggressive behavior compared to other urothelial cancers (4). through the all types of bladder cancer, the prevalence of pv and mv was reported as 1% and 0.62 %, respectively(5-8). due to the rareness of these two variant pathologies, their optimal treatment is controversial(9). on the other hand, gold standard treatment for muscle-invasive and high-risk bladder cancer is open radical cystectomy (rc) and urinary diversion. robot-assisted radical cystectomy (rarc) has been used 1department of urology, school of medicine, ankara yıldırım beyazıt university, ankara state hospital, ankara, turkey. 2department of pathology, school of medicine, ankara yıldırım beyazıt university, ankara state hospital, ankara, turkey. 3department of urology, memorial hospital, ankara, turkey. 4department of urology, school of medicine, koç university, istanbul, turkey. 5department of urology, vkf american hospital, istanbul, turkey. *correspondence: ankara yıldırım beyazıt university, school of medicine, department of urology, ankara state hospital. adress: bilkent street 3, ankara 06800, çankaya/ankara. turkey. tel: +90 506 661 43 66; e-mail: drerdemkoc@gmail.com. received september 2020 & accepted november 2020 increasingly worldwide in recent years(10). robotic surgery has some advantages compared to open surgery as lesser estimated blood loss (ebl), decreased flatus time, decreased need for analgesics and lesser mean hospital stay time with similar oncologic outcomes(11-13). to date, there have been reports on micropapillary and plasmacytoid variants, however, all of the reported rc series were open surgeries and the data regarding to the operation have not been presented. in this current study, we aimed to compare the perioperative, clinical and oncological outcomes of patients who underwent rarc and extended pelvic lymph node dissection (eplnd) and whose pathology result was reported as mv, pv and puc. materials and methods a quality assurance database of our institution was reviewed and the data of 224 patients who underwent rarc between may 2009 and february 2020 was anaurological oncology urology journal/vol 17 no. 6/ november-december 2020/ pp. 607-613. [doi: 10.22037/uj.v16i7.6446] lyzed. patients whom we performed rarc and eplnd with the postoperative pathology results reported as mv, pv and puc were included in statistical analysis. all pathologic specimens were re-reviewed by a single genitourinary pathologist (bo). the study was approved by ankara yıldırım beyazıt university ethics committee (11.12.2019 #114). there were 7 patients with mv, 7 patients with pv and 119 patients with puc. patients were divided into groups according to the postoperative pathology rerarc in variant pathology-koc et al. table 1. demographic features, clinical characteristics and perioperative data of the patients. variables variant pathologies (n=14) puc (n=119) p-value mv (n=7) pv (n=7) puc (n=119) p-value age at radical 60.5 (55.25-67) 63 (56-70) .292 67 (59-67) 60 (49-61) 63 (56-70) .299 cystectomy (years) median (iqr) gender n (%) .317 .606 male 14 (100) 111 (93.3) 7 (100) 7 (100) 111 (93.3) female 0 (0) 8 (6.7) 0 (0) 0 (0) 8 (6.7) bmi (kg/m2) 26.5 (25.87-27.25) 26 (25.61-26.3) .212 27 (26-28) 26 (25.48-27) 26 (25.61-26.3) .417 median (iqr) asa score n (%) .125 .13 i 10 (71.4) 55 (46.2) 6 (85.7) 4 (51.7) 55 (46.2) ii 2 (14.3) 50 (42) 1 (14.3) 1 (14.3) 50 (42) iii 2 (14.3) 4 (11.8) 0 (0) 2 (28.6) 4 (11.8) iv 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) smoking history smoking 14 (100) 87 (73.1%) .022* 7 (100%) 7 (100%) 87 (73.1%) .89 status n (%) package 30 (20-36) 40 (25-40) .769 30 (20-30) 30 (20-45) 40 (25-40) .73 /years median (iqr) creatinine level 1 (0.88-1.12) 1 (0.86-1.2) .971 1 (0.95-1,2) 1 (0.7-1.1) 1 (0.86-1.2) .999 (mg/dl) median (iqr) previous 2 (14.3) 21 (17.6) .753 2 (28.6) 0 (0) 21 (17.6) .351 intravesical bcg therapy n (%) diversion type n (%) .001* .001* i̇leal loop 11 (78.6) 40 (38.3) 7 (100) 4 (57.1) 40 (38.3) studer pouch 3 (21.4) 79 (61.7) 0 (0) 3 (42.9) 79 (61.7) diversion technique n (%) .064 .132 intracorporea l10 (71.4) 107 (89.9) 5 (71.4) 5 (71.4) 107 (89.9) . extracorporeal 4 (28.6) 12 (10.1) 2 (28.6) 5 (71.4) 12 (10.1) neoadjuvant 2 (14.3) 21 (17.6) .753 0 (0) 2 (27.6) 21 (17.6) .351 chemotherapy n (%) adjuvant 12 (85.7) 31 (26.1) < 0.001* 7 (100) 5 (71.4) 31 (26.1) < 0.001* chemotherapy n (%) median operation 360 (335-440) 280 (240-330) < 0.001* 340 (320-360) 440 (350-440) 280 (240-330) < 0.001* time (minute) median (iqr) ebl (ml) 480 (287-562) 200 (100-300) .001* 500 (400-540) 300 (200-700) 200 (100-300) .002* median (iqr) blood transfusion 3 (21.4) 14 (11.8) .306 1 (14.3) 2 (28.6) 14 (11.8) .403 n (%) flatus time (days) 3 (3-3) 3 (3-3) .355 3 (3-3) 3 (3-3) 3 (3-3) .520 median (iqr) lodge drain 8 (6-11) 9 (7-11) .618 7 (6-10) 11 (7-12) 9 (7-11) .250 removal time(days) median (iqr) length of hospital 12 (10-14) 13 (10-15) .974 12 (10-14) 13 (9-15) 13 (10-15) .997 stays (days) median (iqr) * p < 0.05 is considered as statistically significant. abbreviations: bmi: body mass index, asa: american society of anesthesiologists, puc: pure urothelial carcinoma, mv: micropapillary variant, pv: plasmacytoid variant, ebl: estimated blood loss, iqr: interquartile range. vol 17 no 06 november-december 2020 608 urological oncology 609 sults. in initial analyses, patients were divided into two groups in terms of "variant pathologies" including mv, and pv (n=14) and "puc" (n=119). in secondary analyses, patients were divided into three groups as "mv" (n=7), "pv" (n=7) and "puc" (n=119). demographic features and perioperative data of the patients including age, gender, smoking history, body mass index (bmi), american society of anesthesiologists (asa) score, diversion type, ebl, flatus time and length of hospital stay were recorded. the oncologic results were presented including pathologic stages, overall survival (os) time and cancer specific survival (css) time. preoperative abdominal computed tomography (ct) or magnetic resonance imaging (mri) was performed in all patients for local clinical staging. in addition, non-contrast thorax ct, and when necessary, bone scintigraphy and positron emission tomography-ct were performed in all patients to detect distant organ metastasis. the complications were classified according to clavien-dindo classification and complications at 0-90 days were presented. since the ileal loop or studer pouch was formed either extracorporeally or intracorporeally, the operation time was defined as the time period during the course of cystectomy and eplnd. patients who had previous abdominal surgery and radiotherapy (rt) were excluded from the study, since they may adversely affect the operation time due to the intra-abdominal adhesions. abdomen ct or mri and thorax ct were performed at the postoperative 3rd month follow-up. the following controls were performed twice a year through clinical and radiological evaluation. statistical analysis statistical analysis was carried out by using the spss for windows 17.0 (spss inc. il, usa) software package. normality of the data was tested via shapiro-wilk test. mann-whitney u test and kruskal-wallis test were used for not normally distributed continuous variables and the data were presented as median (iqr). fisher's exact test was used for categorical variables and the data were presented as n (%). bonferroni correction was performed in post hoc analyses. correlation between the cumulative survival times and histopathological subtypes were studied with kaplan-meier analysis (log rank test). with the confidence interval (ci) of 95%, a p-value of less than .05 was considered as statistically significant. results among a total of 224 patients, 91 patients were excluded from the study. of those 91 patients; 18 patients had previous abdominal surgery, 3 patients received rt due to prostate carcinoma, 64 patients had other variant pathologies and 7 patients had both previous abdominal surgery history, and other variant pathologies. in final analyses, the data of the remaining 133 patients with the diagnosis of mv (n=7), pv (n=7) and puc (n=119) were analyzed. demographic features, clinical characteristics and perioperative data of the patients were presented at table 1. all of the patients with mv and pv were male. ileal loop formation was significantly increased in variant pathologies compared to puc group (p = .001). diversion type was significantly different also in three group comparisons (p = .001) which was found to be due to the increased ileal loop formation in mv group compared to puc (p = .001), in subgroup analyses. ebl was significantly increased in variant pathologies (p = .002). there was also significant difference in terms of ebl in three group comparisons (p = .001) and subgroup analyses revealed that the difference was due to the significant increase in mv group compared to puc (p = .002). there was a significant increase in median operation time in variant pathologies (p < .001). the difference was also significant in three group comparisons (p < .001) which was related with the significant increase in median operation time both in mv group (p = .009) and pv group (p = .001), compared to puc. smoking history was found as significantly higher in table 2. preoperative and postoperative pathologic outcomes of the patients. variables variant pathologies (n=14) puc (n=119) p-value mv (n=7) pv (n=7) puc (n=119) p-value pre-cystectomy pathology n (%) .592 .807 pta 0 (0) 1.7 0 (0) 0 (0) 1.7 pt1 1 (7.1) 19 (16) 0 (0) 1 (14.3) 19 (16) pt2 13 (92.9) 98 (82.4) 7 (100) 6 (85.7) 98 (82.4) pathological t stage n (%) .001* .004* < pt3 2 (14.3) 72 (60.5) 1 (14.3) 1 (14.3) 72 (60.5) ≥ pt3 12 (85.7) 47 (39.5) 6 (85.7) 6 (85.7) 47 (39.5) ln involvement n (%) < 0.001* <0.001* pn 0 3 (21.4) 94 (79) 0 (0) 3 (42.9) 94 (79) pn (+) 11 (78.6) 25 (21) 7 (100) 4 (57.1) 25 (21) total lns yield 23 (18-33) 26 (19-33) .982 30 (21-34) 19 (18-33) 26 (19-33) .603 (n) median (iqr) psm n (%) 4 (28.6) 7 (5.9) .004* 2 (28.6) 2 (28.6) 7 (5.9) < 0.001* incidental 3 (21.4) 33 (27.9) .616 2 (28.6) 1 (14.3) 33 (27.9) .897 prostate carcinoma n (%) * p < 0.05 is considered as statistically significant. abbreviations: puc: pure urothelial carcinoma, mv: micropapillary variant, pv: plasmacytoid variant, ln: lymph node, psm: positive surgical margin, iqr: interquartile range. rarc in variant pathology-koc et al. variant pathologies compared to puc (p = .022). two patients (27.6 %) in pv group and 21 patients (17.6 %) in puc group received neoadjuvant chemotherapy. adjuvant chemotherapy was given to all patients in mv group (100 %), 5 patients in pv group (71.4 %) and 31 patients in puc group (26.1 %). there was significant difference between the variant pathologies and puc groups in terms of receiving adjuvant chemotherapy (p < .001). post hoc analyses revealed that the difference was found to be due to the significant increase in mv subgroup (p < .001). preoperative and postoperative pathologic outcomes were presented in table 2. the postoperative pathological t stage was presented as < pt3 stage and ≥ pt3 stage. a significant increase in ≥ pt3 stage was observed in variant pathologies compared to puc group (p = .001). the three group comparison was also revealed significant difference (p = .004) which arised from the higher ≥ pt3 rate both in mv and pv compared to puc (p = .014). ln involvement was significantly increased in variant pathologies compared to puc (p < .001). the difference was also significant in three group analyses (p < .001) and was found to be due to the increased ln involvement in mv group (p < .001). psm rate was significantly increased in variant pathologies (p = .004). the three group comparison was also revealed significant difference in psm (p < .001), which was due to the increase both in mv and pv compared to puc (p < .001). the data regarding to intraoperative and postoperative 0-90 day complications were presented in table 3. a patient with puc necessitated blood transfusion intraoperatively (grade 2) that was the only intraoperative complication in our series. none of the cases required conversion to open surgery. the median follow-up time was 47 months. in kaplan-meier analysis, median os time for variant pathologies and puc was 42.2 and 70.2, respectively, table 3. intraoperative and postoperative complication data of the patients according to clavien-dindo classification. variables variant pathologies (n=14) puc (n=119) p-value mv (n=7) pv(n=7) puc (n=119) p-value complications (n) a. intraoperative 0 1 0 0 1(3b) b. postoperative grade 1 1 8 1 0 8 2 2 8 0 2 8 3a 0 3 0 0 3 3b 1 1 1 0 1 4 1 0 0 1 0 5 minor complications 3 (21.4) 46 (38) .253 1 (14) 2 (28) 46 (38) .386 (grade 1-2) n (%) major complications 2 (14) 30 (25) .517 1 (14) 1 (14) 30 (25) .664 (grade 3-5) n (%) readmission rate due to 3 (21.4) 13 (11) .376 1 (14) 2 (28) 13 (11) .371 minor complication n (%) readmission rate due to 2 (14) 14 (12) .784 1 (14) 1 (14) 14 (12) .963 major complication n (%) * p < 0.05 is considered as statistically significant. abbreviations: puc: pure urothelial carcinoma, mv: micropapillary variant, pv: plasmacytoid variant. figure 1. a. overall survival time for puc (upper curve) (70.2 months, iqr: 63.8-76.5, n=119) and variant pathologies (lower curve) (44.7 months, iqr: 33.6-55.6, n=14), b. overall survival time for puc (upper curve) (70.2 months, iqr: 63.8-76.5, n=119), mv (middle curve) (50.1 months, iqr: 36.2-61.7, n=7) and pv (lower curve) (33.2 months, iqr: 18.2-48.3, n=7). rarc in variant pathology-koc et al. vol 17 no 06 november-december 2020 610 urological oncology 611 and similar between the two groups (p = .064). the median os time for mv and pv was 50.1 and 33.2 months, respectively, and significant difference was found in three group comparisons (p = .048) which was observed as related with the decreased os time in pv group compared to puc, in subgroup analyses (p = .014, log rank) (figure 1). median css time for puc and variant pathologies was 77.1 and 44.7 months, respectively. in subgroup analyses, median css time was observed as 51.1 and 37.8 months in mv and pv, respectively. the css time was not significantly different between the variant pathologies and puc group (p = .054). however, the subgroup analyses in three group comparisons revealed a significantly decreased median css time in pv group compared to puc (p = .016, log rank) (figure 2). discussion mv and pv are rarely seen urothelial carcinoma subtypes which are clinically important due to their poorer prognosis, aggressive course and inexplicit optimal treatment approach. previous studies on these two variant pathologies were all conducted on open surgical series. in addition, the operative data and complication results have not been reported yet in any of the studies conducted to date. to the best of our knowledge, our current study is the first one to present the variant pathology results of a robotic cystectomy series. our study is also important to provide the operative and complication data of these two rarely seen variant pathologies. in a study including 205 patients, keck et al. compared 9 mv, 18 pv and 178 puc cases. all patients received adjuvant chemotherapy and their os times were reported as 64.2 months in puc, 27.4 months in pv, and 62.6 months in mv. there is no difference between the three groups in terms of cancer stage(14). however, their results conflict with the current study, as well as the literature, since they found no difference between the groups in terms of lymph node metastasis and pathological t stage(15-19). sui et al. compared 869 mv and 389,603 puc cases in a study including patients in all preoperative pathological stages in terms of transurethral resection pathology results. they reported the os time as 44.7 months for mv. consistent with the curfigure 2.a. cancer specific survival time for puc (upper curve) (77.1 months, iqr: 70.3-81, n=119) and variant pathologies (lower curve) (months, iqr: 31.1-53.1, n=14), b. cancer specific survival time for puc (upper curve) (77.1 months, iqr: 70.3-81, n=119), mv (middle curve) (51.1 months, iqr: 36.2-61.7, n=7) and pv (lower curve) (37.8 months, iqr: 21.8-53.8, n=7). figure 3. bulky and adherent lymph nodes which were visualized in variant pathology cases during rarc and eplnd. rarc in variant pathology-koc et al. rent study they found higher pathological t stage and ln stage in mv. however, they did not present any operative data and they did not specify the os times through the patients to whom they performed rc (380 mv patients and 40,151 puc patients)(15). fairey et al. reported higher pathological stage but similar ln involvement rate in mv cases in their study including totally 1,380 patients who underwent open rc and whose pathology results were reported as puc in 1,347, and mv in 33 patients the os time was not significantly different between mv and puc cases(16). the current study also revealed similar median os times through the mv and puv patients besides a significant increased ln stage in mv compared to puc. in a study conducted by li et al., 1,312 puc and 98 pv patients were compared. this study was also conspicuous to include the highest number of pv patients, in the literature. they reported higher pathological stage, psm rate and ln involvement in pv patients. they found median os time as 3.8 years in pv and 8 years in puc patients(17). kaimakliotis et al. reported decreased median os time and css time in pv cases (19 and 22 months, respectively) in a study involving 30 pv and 278 puc patients. they reported higher ln involvement, ln stage, pathological t stage and psm rate in pv patients(18). cockerill et al. compared 46 pv cases with 972 puc cases and found higher pathological t stage, psm rate and decreased os time in pv patients(19). the current study has also consistent results in terms of significantly decreased os time, as well as css time, higher pathological t stage and increased psm rate in pv patients. in current study, the mean operation time was longer in both pv and mv cases, compared to puc. this may be considered as a result of the higher ln involvement and the prolonged ln dissection time due to the technique difficulties related with the bulky and adherent lymph nodes in patients with variant pathologies (figure 3). the increased pathological t stage in variant pathologies which means extravesical dissemination of the tumor may also be considered as another difficulty that may lead to prolonged mean operation time. the significant difference in mean ebl has been interpreted as the consequence of similar mechanisms. however, the increased ebl not absolutely states a significant increase in need for blood transfusion as observed in the current study. the current study revealed that the major, and the minor complication rates and readmission rates due to the major, and the minor complications were similar between the variant pathologies and puc, both in initial and secondary analyses. none of the cases necessitated conversion to open surgery. this can be explained by the situation that the operations are performed in a high volume center by an experienced surgical team on robotic procedures. the current study had some limitations regarding to the single centered design and retrospective nature. diversion type was significantly different between the three groups related with the increased ileal loop formation in mv group compared to puc. however, the literature on this specific subject exploring the safety and efficacy of rarc with intracorporeal urinary diversion is very limited. as this was a retrospective study and the number of patients in the variant histology group is limited, it is not easy to draw strict conclusions about the diversion type. robotic surgery is a novel procedure compared to open surgery. therefore, patient series underwent robotic surgery has been covered in a narrower time interval than open surgery. the single centered design and novelty of the technique lead to limitation in number of patients included in this current study in terms of variant pathologies. the long term oncologic results were not presented in the current study, however, our short-term oncological results were found to be compatible with the literature. conclusions this study has significant results to reveal the operative data, complications and oncologic outcomes of the rarely seen and clinically significant variant pathologies of bladder cancer which underwent rarc. robotic cystectomy is a minimally invasive surgical technique that can be performed by an experienced surgical team with low morbidity rates and similar oncological results even in challenging cases. conflict of interest all authors declare that, there is no conflict of interest in connection with this paper. references 1. black pc, brown ga, dinney cp. the impact of variant histology on the outcome of bladder cancer treated with curative intent. urol oncol 2009;27:3-7. 2. wasco mj, daignault s, zhang y, et al. urothelial carcinoma with divergent histologic differentiation (mixed histologic features) predicts the presence of locally advanced bladder cancer when detected at transurethral resection. urology. 2007;70:69-74. 3. cai t, tiscione d, verze p, et al. concordance and clinical significance of uncommon variants of bladder urothelial carcinoma in transurethral resection and radical cystectomy specimens. urology. 2014;84:1141-6. 4. moschini m, d'andrea d, korn s, et al. characteristics and clinical significance of histological variants of bladder cancer. nat rev urol. 2017;14:651-668. 5. amin mb, ro jy, el-sharkawy t, et al. micropapillary variant of transitional cell carcinoma of the urinary bladder. histologic pattern resembling ovarian papillary serous carcinoma. am j surg pathol. 1994;18:122432. 6. guo cc, dadhania v, zhang l, et al. gene expression profile of the clinically aggressive micropapillary variant of bladder cancer. eur urol. 2016;70:611-20. 7. watts ke, hansel de. emerging concepts in micropapillary urothelial carcinoma. adv anat pathol. 2010;17:182-6. 8. moschini m, dell'oglio p, luciano' r, et al. incidence and effect of variant histology on oncological outcomes in patients with bladder cancer treated with radical cystectomy. urol oncol. 2017;35:335-41. 9. willis dl, porten sp, kamat am. should histologic variants alter definitive treatment of rarc in variant pathology-koc et al. vol 17 no 06 november-december 2020 612 bladder cancer?. curr opin urol. 2013;23:43543. 10. gill i, cacciamani g. lba3 the changing face of urologic oncologic surgery from 2000-2018 (63141 patients) impact of robotics. j urol. 2018;199:577–8. 11. raza sj, wilson t, peabody jo, et al. long-term oncologic outcomes following robot-assisted radical cystectomy: results from the international robotic cystectomy consortium. eur urol. 2015;68:721-8. 12. leow jj, reese sw, jiang w, et al. propensitymatched comparison of morbidity and costs of open and robot-assisted radical cystectomies: a contemporary population-based analysis in the united states. eur urol. 2014;66:569-76. 13. collins jw, sooriakumaran p, sanchez-salas r, et al. robot-assisted radical cystectomy with intracorporeal neobladder diversion: the karolinska experience. indian j urol. 2014;30:307-13. 14. keck b, wach s, stoehr r, et al. plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy. bmc cancer. 2013;13:71. 15. sui w, matulay jt, james mb, et al. micropapillary bladder cancer: insights from the national cancer database. bladder cancer. 2016;2:415-23. 16. fairey as, daneshmand s, wang l, et al. impact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy. urol oncol. 2014;32:110-6. 17. li q, assel m, benfante ne, et al. the impact of plasmacytoid variant histology on the survival of patients with urothelial carcinoma of bladder after radical cystectomy. eur urol focus. 2019;5:104-8. 18. kaimakliotis hz, monn mf, cary kc, et al. plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm?. urol oncol. 2014;32:833-8. 19. cockerill pa, cheville jc, boorjian sa, et al. outcomes following radical cystectomy for plasmacytoid urothelial carcinoma: defining the need for improved local cancer control. urology. 2017;102:143-7. rarc in variant pathology-koc et al. urological oncology 613 brief communication urinary human kidney injury molecule1(hkim1-) is not increased in patients with renal cell carcinoma łukasz białek1, sławomir poletajew2*, michał niemczyk3, katarzyna czerwińska4, mateusz nowak5, anna sadowska4, tomasz borkowski3, piotr radziszewski3, jakub dobruch1, piotr kryst2 purpose: human kidney injury molecule-1 (hkim-1) was proposed as urinary biomarker of renal cell carcinoma (rcc). the aim of the study was to validate urinary hkim-1 as a biomarker of rcc. material and methods: forty-six participants were enrolled into the study, including 30 patients with clear-cell or papillary rcc and 16 matched patients in the comparison group. preoperative urinary hkim-1 levels were measured using commercially available elisa kit and normalized to urinary creatinine levels. results: the concentrations of urinary hkim-1 normalized to urinary creatinine in patients with rcc and comparison group did not differ significantly (1.35 vs. 1.32 ng/mg creatinine, p = .25). there was also no difference in urinary hkim-1 concentration regarding stage or grade of renal cancer. additional analysis of patients without chronic kidney disease (defined as egfr ≥ 60ml/min/1.73m²) also did not reveal significant difference in urinary hkim-1 concentrations between the groups (1.54 vs. 1.37; p = .47). conclusion: results of our study do not confirm recent suggestions that urinary hkim-1 may be a biomarker of rcc. keywords: hkim-1; biomarker; kidney cancer; diagnosis; urine 1first department of urology, centre of postgraduate medical education, warsaw, poland. 2second department of urology, centre of postgraduate medical education, warsaw, poland. 3department of general, oncological and functional urology, medical university of warsaw, warsaw, poland first department of urology, centre of postgraduate medical education, warsaw, poland. 4department of transplantation medicine, nephrology and internal diseases, medical university of warsaw, warsaw, poland. 5department of urology, tarnów, poland. *correspondence: second department of urology; centre of postgraduate medical education, warsaw, poland. slawomir.poletajew@cmkp.edu.pl received march 2020 & accepted august 2020 introduction renal cell carcinoma (rcc) is the 13th most com-mon malignancy worldwide(1). incidence rates of rcc continue to increase steadily with age, with a peak of incidence at the age of 75 years(2). despite intensive technological development in imaging diagnostics and the increasing availability of various imaging techniques, biomarkers that could indicate the presence of kidney cancer are still awaited. recently, human kidney injury molecule-1 (hkim-1) also known as tim-1 (t cell immunoglobulin domain and mucin domain protein 1) or havcr1 (hepatitis a virus cellular receptor 1) was identified as a sensitive and specific biomarker for renal proximal tubules injury(3). moreover, several studies confirmed that hkim1 may be a useful immunohistochemical marker for clear cell and papillary rcc diagnosis(4-6). furthermore hkim-1 has been introduced as a promising urinary biomarker of rcc(5-8). for example, mijuskovic et al.(5) performed a study in which they noticed that expression of tissue hkim-1 was documented in all cases of patients who underwent radical nephrectomy. moreover, preoperative urinary hkim-1 was significantly higher in patients with kidney cancer than in controls, and its values decreased after the surgery. similar results has been previously published by han et al.(6). however, it is worth to notice that control groups in all of those studies consisted mainly of healthy participants. recently published study by kushlinskii et al.(9) shows that hkim-1 concentration is also increased in blood plasma in patients with kidney cancer with sensitivity of 81% for stage i kidney cancer and 97% for stage ii-iv. the aim of our study was to assess diagnostic performance of urinary hkim-1 as a biomarker of rcc in patients with clear cell or papillary rcc and patients suffering from benign urological conditions. materials and methods participants the study was designed as a prospective cohort study and was approved by the local ethic committee. recruited patients were divided into two study groups. one group consisted of 32 consecutive patients qualified for partial or radical nephrectomy due to primary renal tumor. out of them 30 patients had histologically confirmed clear-cell or papillary rcc and were included in further analyses (rcc group). the second group consisted of 16 patients with benign urological conditions and no suspicion of cancer (7 patients with benign prostate hyperplasia, 4 with uretero-pelvic junction stricture, 3 with overactive bladder, 1 with detrusor underactivity, 1 with interstitial cystitis). they were urology journal/vol 17 no. 6/ november-december 2020/ pp. 664-666. [doi: 10.22037/uj.v16i7.6077] matched according to gender, age and smoking history. urolithiasis and urinary tract infection were the exclusion criteria. basic patient characteristics are summarized in table 1. all participants voluntarily gave written informed consent to participate in the study and were asked to void first morning urine before the surgery for hkim-1 and creatinine levels assessment. urine analysis both serum and urine creatinine levels, as well as urinalysis were performed as clinical samples. egfr was calculated using mdrd equation (egfr = 186 x serum cr-1.154 x age-0.203 (x 0.742 if female)). urine hkim-1 concentration was measured using human urinary tim-1/kim-1/havcr quantikine elisa kit (r&d systems biotechne) for direct elisa in accordance to manufacturer protocol. measured concentrations (ng/ml) were normalized to urinary creatinine to compensate for the differences in relative amounts of water removed along the nephrons. urinary kim-1 was expressed as ng/mg creatinine. statistical analysis to test the normality of variables the shapiro–wilk test was used. chi-square test was used to examine the association between the groups and genders, t-test was used to assess the difference between age and egfrs among the groups, mann-whitney u test was used to evaluate the difference in serum creatinine and urinary hkim-1 concentrations between the groups, kruskal-wallis test was used to evaluate the difference in urinary hkim-1 concentrations regarding stage and grade. the results are presented as means ± sd or medians (1st,3rd quartiles). statistical analysis was performed using statistica 13.1 software, statsoft, usa. results the concentrations of urinary hkim-1 normalized to urinary creatinine in patients with rcc and comparison group did not differ significantly (1.35 (1.08; 2.1) vs. 1.32 (0.72; 1.59) ng/mg creatinine (median, 1st; 3rd quartile), p=.25). there was also no difference in the urinary hkim-1 concentration with respect to renal cancer stage (p = .92) or grade (p = .54) (table 2). as increased levels of hkim-1 may reflect different types of kidney injuries (10), we have also performed a secondary analysis including only patients with or without chronic kidney disease (egfr of less or more than 60 ml/min/1.73m²). however, this again showed no difference in hkim-1 concentration between study groups (1.54 ± 0.71 vs. 1.37 ± 0.36; p = .47 for patients without kidney injury and 1.39 (0.86; 2.83) ± vs. 0.48 (0.35; 2.31); p = .76 for patients with kidney injury). discussion the incidence of rcc in the uk increased by 3.1% annually from 1993 and achieved 21 newly diagnosed cases per 100000 in 2014(11). however population screening is not recommended, because of the risk of overdiagnosis, costs and radiation exposure(11). major barriers to population screening include also the relatively low prevalence of the disease and a substantial risk of detecting benign renal tumor or slow-growing rcc, which does not need specific management(11, 12). usage of urinary biomarker may be an interesting alternative but so far no test has been clinically validated with proper sensitivity and specificity. in the previous studies matrix metalloproteinases (mmps), aquaporin-1 (aqp1), perilipin-2 (plin2) and neutrophil gelatinase-associated lipocalin (ngal) concentrations were tested as potential biomarkers for rcc but did not achieve satisfactory results(13,14). recently hkim-1 was discovered as not only the early biomarker for renal proximal tubule injury but also as a potential renal cancer biomarker(6,15). contrary to the previously published data(5-8), the results of our study showed no effect of renal cancer on urinary urinary hkim-1 in rcc – białek et al. table 1. patient characteristics. rcc group comparison group p-value number 30 16 age 64.1 ± 11.4 67.8 ± 9.4 .28* sex 10f / 20m 5f / 11m .85** serum creatinine (mg/dl) 0.97 (0.77; 1.29) 1.08 (0.76; 1.26) .97*** egfr (ml/min/1.73m²) 77.2 ± 33.5 74.1 ± 21.9 .74* stage of renal cancer pt1a – 21 (70%) pt0 – 16 (100%) pt1b – 5 (16.7%) pt2 – 2 (6.7%) pt3 2 (6.7%) * t-test ** chi-square test *** mann-whitney u test number of patients in the group urinary hkim-1 concentration (ng/mg creatinine) rcc 30 1.35 (1.08 ; 2.10) pt1a 21 1.32 (0.93 ; 2.10) pt1b 5 1.40 (1.34 ; 1.66) pt2 2 2.16 (1.11 ; 3.22) pt3 2 1.46 (1.26 ; 1.66) g1 9 1,36 (1.07 ; 2.44) g2 17 1,40 (1.11 ; 2.10) g3 4 1,16 (1.02 ; 1.44) comparison group 16 1.32 (0.72 ; 1.59) table 2. urinary hkim-1 concentrations in groups. breif communication 665 vol 17 no 06 november-december 2020 666 hkim-1 concentration. partially this can be explained by the construction of a comparison group. in previous studies, it consisted of orthopedic patients(7) or healthy participants(5). only in the study by han et al. the control group consisted partially of patients with urological disorders, namely prostate cancer(6). the fact that the comparison group in our study consisted of patients with urogenital disorders may be, at least in part, the answer why our results differ from the data available in the literature. however, this does not limit the significance of our results. the main limitation of our study is small number of recruited patients. comparison group patients suffered from various urological disorders, what also suggests heterogeneity of the group. however, it is worth to notice that none of the patients in the comparison group suffered nor had the suspicion of malignancy or urolithiasis. another limitation is the fact that the urinary creatinine levels were not measured as scientific but clinical samples, which may partially be a source of a bias. despite previous studies showing higher hkim-1 concentrations in acute kidney diseases compared to rcc (4,5), in our study we noticed that hkim-1 not only cannot differentiate rcc patients from controls, but also hkim-1 values in both groups were similar to those previously reported for acute kidney diseases(9,10). this brings into question the real clinical role of hkim-1, while the reason for these phenomena remains unclear. conclusions results of our study did not confirm recent suggestions that urinary hkim-1 may be a urinary biomarker of rcc. the reason for high urinary hkim-1 concentration among patients with benign urological conditions is unclear and needs further assessment. conflict of interest the authors declare no conflict of interest references 1. scelo g, larose tl. epidemiology and risk factors for kidney cancer. j clin oncol. 2018:jco2018791905. 2. znaor a, lortet-tieulent j, laversanne m, jemal a, bray f. international variations and trends in renal cell carcinoma incidence and mortality. eur urol. 2015;67:519-30. 3. bailly v, zhang z, meier w, cate r, sanicola m, bonventre jv. shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. j biol chem. 2002;277:39739-48. 4. lin f, zhang pl, yang xj, shi j, blasick t, han wk, et al. human kidney injury 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for patients with renal cell carcinoma. int urol nephrol. 2014;46:379-88. 9. kushlinskii ne, gershtein es, naberezhnov ds, taipov ma, bezhanova sd, pushkar dy, et al. kidney injury molecule-1 (kim-1) in blood plasma of patients with clear-cell carcinoma. bull exp biol med. 2019;167:38892. 10. han wk, bailly v, abichandani r, thadhani r, bonventre jv. kidney injury molecule-1 (kim-1): a novel biomarker for human renal proximal tubule injury. kidney int. 2002;62:237-44. 11. rossi sh, klatte t, usher-smith j, stewart gd. epidemiology and screening for renal cancer. world j urol. 2018;36:1341-53. 12. richard po, lavallée lt, pouliot f, komisarenko m, martin l, lattouf j-b, et al. is routine renal tumor biopsy associated with lower rates of benign histology following nephrectomy for small renal masses? j urol. 2018;200:731-6. 13. pastore al, palleschi g, silvestri l, moschese d, ricci s, petrozza v, et al. serum and urine biomarkers for human renal cell carcinoma. dis markers. 2015;2015:251403. 14. morrissey jj, mobley j, figenshau rs, vetter j, bhayani s, kharasch ed. urine aquaporin 1 and perilipin 2 differentiate renal carcinomas from other imaged renal masses and bladder and prostate cancer. mayo clin proc. 2015;90:35-42. 15. ichimura t, bonventre jv, bailly v, wei h, hession ca, cate rl, et al. kidney injury molecule-1 (kim-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. j biol chem. 1998;273:4135-42. unclassified urology journal/vol 20 no. 4/ july-august 2023/ pp. 255-260. [doi:10.22037/uj.v20i.7593] sildenafil vs. tadalafil for the treatment of benign prostatic hyperplasia: a single-arm self-controlled clinical trial mazyar zahir1,2 *, mohammad samzadeh2, amirhossein poopak3, ali reza khoshdel4, arash armin2 purpose: to compare the efficacy and adverse events of sildenafil monotherapy for benign prostatic hyperplasia (bph) with its fda-approved counterpart, tadalafil. materials and methods: in this single-arm self-controlled clinical trial, 33 patients were enrolled. all patients underwent a 6-week treatment with sildenafil, followed by a 4-week washout period and finally a 6-week treatment with tadalafil. patients were examined on each appointment and post-void residual (pvr) urine, international prostate symptom score (ipss) and quality of life index (ipss-qol index) were recorded subsequently. efficacy of each drug regimen was then evaluated by comparing these outcome parameters. results: both sildenafil and tadalafil were shown to improve pvr (both p < .001), ipss (both p < .001) and ipss-qol index (both p < .001) significantly. sildenafil was more effective than tadalafil in reducing pvr (mean difference (95%ci) = 9.91% (4.11, 15.72), p < .001) and ameliorating ipss-qol index (mean difference (95%ci) = 19.3% (4.47, 34.41), p = .027). moreover, although not significant, sildenafil reduced ipss more than tadalafil (mean difference (95%ci) = 3.33% (-0.22, 6.87), p = .065). concurrent erectile dysfunction did not affect responsiveness to therapy with either sildenafil or tadalafil but age was inversely related to post-treatment ipss in both sildenafil (b = 0.21 (0.04, 0.37), p = .015) and tadalafil (b = 0.14 (0.02, 0.26), p = .021) regimens with a more prominent role in responsiveness to sildenafil (β = 0.31) compared to tadalafil (β = 0.19). conclusion: considering the significantly better improvement of pvr and ipss-qol index with sildenafil, this drug can be nominated as a suitable alternative for tadalafil as a bph treatment, especially in younger patients who don’t have any contraindications. keywords: lower urinary tract symptoms; phosphodiesterase 5 inhibitors; prostatic hyperplasia; sildenafil citrate; tadalafil introduction with an estimated lifelong cumulative prevalence of 26%, benign prostatic hyperplasia (bph) is the most prevalent urological disease in male individuals(1,2). the substantial burden of this disease necessitates proper treatment in order to decrease morbidity, complications and subsequent costs. historically, various treatments (i.e., medications, surgeries and alternative medicine) have been developed for bph(3). during the last three decades, medical treatment has overtaken surgical techniques to become the mainstay of treatment. alpha-1a adrenergic receptor blockers (abs) and 5-alpha reductase inhibitors (5aris) are the most commonly prescribed medications for bph(4). despite their high efficacy, both medications are associated with fairly prevalent sexual, sympathetic, anxiogenic, and deppresogenic side effects; ultimately leading to remarkably low adherence to these treatments(5-7). in the last two decades, phosphodiesterase inhibitors (pde5is) have been nominated as effective alternative treatments for bph(8). the main rationale behind this 1urology and nephrology research center, shahid beheshti university of medical sciences , tehran, iran. 2department of urology, islamic azad university of tehran medical sciences, tehran, iran. 3tehran university of medical sciences, tehran, iran. 4islamic azad university of tehran medical sciences, tehran, iran. *correspondence: urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. email: m.zahir@unrc.ir. received december 2022 & accepted may 2023 proposition is the shared pathological pathways between bph and erectile dysfunction (ed) and the ample presence of phosphodiesterase (pde) isoenzyme 5 in enlarged prostate tissue (9-11). to date only tadalafil has been approved by the u.s. food and drug administration (fda) for bph/lower urinary tract symptoms (luts), and despite the abundant body of evidence in favor of sildenafil’s efficacy in combination therapies and its lower price and easier accessibility compared to tadalafil(12-15); it has not yet been approved for bph/ luts. this appears to be mainly due to a paucity of evidence on sildenafil’s efficacy and possible side effects as a monotherapy regimen in bph and also due to a lack of direct comparative studies between sildenafil and tadalafil. to our best knowledge, this is the first study to directly compare the effectiveness of sildenafil and its fda-approved counterpart, tadalafil, for bph treatment. patients and methods this non-blinded, single-arm clinical trial was conducted at three university-affiliated medical centers, from december 2020 to september 2021, according to the declarations of helsinki and istanbul. respective laws and regulations and principles of good clinical practice were closely followed. all patients were thoroughly informed of the study procedure and written consent was obtained prior to any interventions. the study protocol was approved by the institutional review board (accreditation id: ir.iau.tmu.rec.1399.339). this study has been registered in the iranian registry of clinical trials (irct) (accreditation code: irctid: irct20210925052576n1). subjects the inclusion criteria of our study were: men aged ≥ 50 years old, clinically diagnosed with bph through medical history (mainly secondary luts) and physical exam (including digital rectal exam) for at least 6 months, initial international prostate symptoms score (ipss) ≥ 10, total serum prostatic specific antigen (psa) < 4.0 ng/ml, willing to take part and grant written informed consent and act in accordance with study protocols. the exclusion criteria were: previous treatment with bph medications during the past month, total psa ≥ 4 ng/ml, evidence of concurrent prostate pathology (e.g., malignancy, acute or chronic bacterial prostatitis, prostatodynia), history of prior prostatic surgery, extensive pelvic or perineal surgeries, bladder diseases(e.g., bladder malignancy, neurogenic bladder or bladder neck contracture), cardiovascular pathologies(e.g., unstable angina, myocardial infarction, poorly controlled hypertension and idiopathic orthostatic hypotension), lumbar degenerative disc disease or associated lumbar spinal surgery, simultaneous treatment with shortor long-acting nitrates, current upper or lower urinary tract infection and unwillingness to participate in the study. included patients agreed to avoid all bph medications other than our treatment regimen during the study. efficacy measures efficacy outcomes were evaluated through both subjective (ipss, ipss-qol index) and objective (post-void residual volume/pvr) measurements. therefore, all patients filled out the ipss questionnaire (questions 1 to 7) and answered the ipss-qol index (question 8, “if you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?”) on every appointment. similarly, an abdominal ultrasonography (aus) was performed on age (range) 59.8 ± 5.5 (50 – 71) ipss (range) 19.3 ± 4.0 (12 26) ipss-qol 2.0 (2.0, 3.0) pvr (ml) 43.0 (30.0, 57.5) number of patients with concurrent ed (%) 10 (30.3%) table 1. characteristics of study patients at the first appointment ed = erectile dysfunction; ipss = international prostate symptom score; ipss-qol = ipss quality of life question; pvr = post-void residual volume. all data are reported as mean ± sd or median (interquartile range). figure 1. flow diagram illustrating the study design sildenafil vs. tadalafil for bph treatment – zahir et al. unclassified 256 every appointment, immediately after micturition in order to determine the pvr. safety measures medical history, drug history and physical examination were performed on all patients during the initial appointment. cardiology consultation was requested for all patients older than 60 years of age to rule out any possibly neglected cardiac comorbidity prior to initiation of medications. safety was evaluated by assessing the incidence rate of patient-reported side effects in course of the study. study design as shown in figure1 our study was uniquely designed as a single arm study with two consecutive drug regimens, separated by a washout period. firstly, each patient was treated with sildenafil (viagra) 50mg/day for 6 weeks, then went through a 4 week washout period to abolish the effect of sildenafil(16); and lastly, was treated with tadalafil (cialis) 5mg/day – fda-approved dose for bph for 6 weeks. the main rationale behind this study design was to eliminate the confounding effect of initial prostate size on responsiveness to treatment and clinical outcome(17,18). subjects were instructed to take the medications at the approximately similar time every night, regardless of the timing of sexual activity or food consumption. all patients filled in the ipss questionnaire, answered the ipss-qol index and underwent an aus before and after each intervention (weeks 0, 6, 10 and 16). the recorded ipss, ipss-qol and pvr figures were then used to evaluate the efficacy of each treatment regimen and determine the superior treatment choice. statistical analysis to calculate the required sample size for the primary outcome – ipss – the correlation induced by the paired study design was taken into account. a previous clinical trial suggested a corresponding standard deviation (sd) of 2.5 for ipss scores in pde5is treatments(19). assuming an equal sd and a correlation coefficient of 0.6 between the ipss scores in the two consecutive treatments for the same patient, a superiority margin of 4 ipss points and a significance level of 0.05, a minimum of 30 patients would be required to guarantee a 80% power to detect a least true difference of 3 ipss points in the tadalafil and sildenafil treatment groups (20,21). statistical analyses of all data were performed using spss software version 23 (ibm, armonk, ny, united states). data were described as mean ± standard deviation and frequency (percentage) for quantitative and qualitative variables, respectively. shapiro-wilk test was used to assess the normality of data distribution. based on normality test results and symmetry of differences; a paired t-test, wilcoxon signed ranks test or sign test was used to compare pvr, ipss and ipss-qol before and after each treatment. similarly, the percentages of pvr, ipss and ipss-qol change with either of the drugs were compared with paired t-test or sign test in order to compare the efficacy of the drugs. finally, considering the results from previous studies which suggested a possible confounding effect for age and ed in responsiveness to pde5is(11,22), multivariable linear regressions were utilized to evaluate the possible effects of these two variables on treatment outcome. the latest standards for reporting research results were followed(23). p < .05 was considered statistically significant. results study population of the 55 patients screened for this experiment, 40 were assigned to treatment. 33 patients (83%) completed the study and 7 patients (17%) were either lost during follow-up (n=5) or discontinued their treatment due to adverse events (n=2). baseline clinical characteristics of patients who completed the study are shown in table 1. the baseline characteristics of excluded cases were not significantly different from the patients who completed the study. regarding adverse events, 2 patients had severe headache with sildenafil which led to withdrawal from the study while no patient reported any serious side effect with tadalafil. efficacy on luts and pvr volume as illustrated in table 2, ipss improved significantly after 6 weeks of treatment with both sildenafil (mean difference (95%ci) = 7.67 (6.57, 8.77), p < .001) and tadalafil (mean difference (95%ci) = 5.15 (4.48, 5.82), p < .001). this improvement was slightly higher with sildenafil compared to tadalafil but this difference was not statistically meaningful (mean difference (95%ci) = 3.33% (-0.22, 6.87), p = .065) (table 3). likewise, ipss-qol significantly improved with both sildenafil (mean difference (95%ci) = 1.70 (1.42, 1.97), p < .001) and tadalafil (mean difference (95%ci) = 1.06 (0.78, 1.34), p < .001). however, contrary to ipss, the reduction observed in ipss-qol was meaningfully more in sildenafil treatment compared to tadalafil (mean difference (95%ci) = 19.3% (4.47, 34.41), p = .027). similarly, there was a significant amelioration of pvr with both sildenafil (mean difference (95%ci) = 32.82 (21.32, 44.31), p < .001) and tadalafil (mean difference (95%ci) = 15.67 (12.47, 18.87), p < .001). furthermore, sildenafil was shown to be more efficient than tadalafil in this regard (mean difference (95%ci) = 9.91% (4.11, 15.72), p < .001). finally, 25 patients (75.7%) stated that they personally preferred sildenafil. evaluating the possible effect of age and concurrent ed on responsiveness to treatment as illustrated in table 4, considering post-treatment ipss, ipss-qol and pvr as outcome measures; concurrent ed was shown to be unrelated to the degree of responsiveness to therapy with either sildenafil or sildenafil tadalafil before after p-value before after p-value ipss 19.3 ± 4.1‡ 11.6 ± 3.7‡ < .001† 14.0 (11.5, 18.0) 10.0 (6.0, 13.0) < .001* ipss-qol 2.0 (2.0, 3.0) 1.0 (0.0, 2.0) < .001# 2.0 (1.0, 3.0) 1.0 (0.0, 1.5) < .001# pvr (ml) 43.0 (30.0, 57.5) 15.0 (10.0, 27.5) < .001* 30.0 (20.0, 45.0) 15.0 (10.0, 26.5) < .001# ipss = international prostate symptom score; ipss-qol = ipss quality of life question; pvr = post-void residual volume. all values are expressed as medians (interquartile ranges) except for ‡ which are expressed as means ± sd. † paired t-test; # wilcoxon signed ranks test; * sign test. table 2. comparison of ipss, ipss-qol index, and pvr before and after each treatment regimen sildenafil vs. tadalafil for bph treatment – zahir et al. vol 20 no 4 july-august 2023 257 tadalafil (table 4). similarly, age didn’t show any significant effect on post-treatment ipss-qol or pvr in either sildenafil or tadalafil regimen. however, age was shown to contribute significantly to post-treatment ipss with both sildenafil (b = 0.21 (0.04, 0.37), p = .015) and tadalafil (b = 0.14 (0.02, 0.26), p = .021). additionally, it was shown that this contribution is relatively larger with sildenafil (β = 0.31) in comparison with tadalafil (β = 0.19). discussion in spite of the very long history of surgical management of bph and its staggering improvements during the last century(24), medical treatment has become the fundamental part of treatment since mid-90s(4). according to the latest version of american urological association (aua) guideline for bph management, abs are still the first-line treatment; usually followed by 5aris (25). adherence to treatment with abs and 5aris remains a major challenge in bph treatment with previous studies reporting 12-month adherence rates as low as 35% and 9% respectively(6). this unwillingness towards long-term therapy with these agents seems to be mainly due to the perceived lack of efficacy among patients and the relatively high rates of medical (i.e., orthostatic hypotension, syncope, depression, anxiety, and impaired cognition) and sexual (i.e., ed, anejaculation, decreased libido and loss of penis sensitivity) side effects(5,7,25). these adverse events seriously hamper effective treatment and obligate the investigation for suitable alternatives; especially in younger sexually active patients. pde5is are a plausible substitute, especially in relatively younger sexually active patients with prostate size < 30 cc(25). pde5is were initially proposed for the treatment of bph/luts after observing common pathologic pathways and clinical association between ed and bph. for instance, an abundant body of evidence supports the fundamental role of nitric oxide / cyclic guanosine monophosphate (no – cgmp) disruption in the etiopathology of both diseases(26,27). similarly, a large meta-analysis of 24 clinical studies underscored the association between bph/luts and ed(28). moreover, pde isoenzyme 5 is known to be abundantly expressed in the hypertrophied prostate, further supporting the possible role of pde5is(9,11). previous clinical studies have shown that pde5is can effectively relaxate prostate, bladder, and urethral tissues; thus alleviating the irritative symptoms of bph(11). however, only tadalafil has been approved by fda for bph/luts and sildenafil has not yet been granted approval. previous studies have confirmed sildenafil’s efficacy in combination therapies for bph/luts. for instance, a combination of sildenafil (50mg/daily) and doxazosin (2mg/daily) was shown to improve pvr and ipss more than monotherapy with either of the drugs(14). moreover, a lower dose of sildenafil (25mg/daily) was shown to further improve nocturia, frequency, pvr, and ipss when added to alfuzosin (10mg/daily) or tamsulosin (0.4mg/daily)(10,13). nevertheless, tuncel et al.(29) argued that dosages lower than 25mg/daily cannot effectively improve clinical outcomes when added to combination regimens. they evaluated a combination of sildenafil (25mg/four doses per week) and tamsulosin (0.4mg/ sildenafil tadalafil p-value % of ipss change (after vs. before treatment ) 39.9 ± 14.1 36.6 ± 15.2 .065† % of ipss-qol change (after vs. before treatment) 66.6 (50 , 100)‡ 50 (12.5 , 100)‡ .027* % of pvr change (after vs. before treatment ) 59.3 ± 21.0 49.4 ± 21.4 < .001† ipss = international prostate symptom score; ipss-qol = ipss quality of life question; pvr = post-void residual volume. all values are expressed as means ± sd except for ‡ which are expressed as medians (interquartile ranges). † paired t-test; * sign test. table 3. comparison of the efficacy of sildenafil and tadalafil according to the percentage of change of ipss, ipss-qol index, and pvr before and after each treatment regimen sildenafil tadalafil model dependent variable : post-treatment ipss dependent variable : post-treatment ipss r2 = 0.57 , adj r2 = 0.53 < .001 r2 = 0.82 , adj r2 = 0.80 < .001 b (95% ci) p-value b (95% ci) p-value pre-treatment ipss 0.63 (0.40, 0.85) < .001 0.94 (0.76, 1.12) < .001 age 0.21 (0.04, 0.37) .015 0.14 (0.02, 0.26) .021 concurrent ed 0.36 (-2.33, 1.62) .714 0.10 (-1.42, 1.42) .989 model dependent variable : post-treatment ipss-qol dependent variable : post-treatment ipss-qol r2 = 0.64 , adj r2 = 0.60 < .001 r2 = 0.59 , adj r2 = 0.55 < .001 b (95% ci) p-value b (95% ci) p-value pre-treatment ipss-qol 0.55 (0.39, 0.71) < .001 0.52 (0.35, 0.70) < .001 age 0.02 (-0.01, 0.06) .162 0.00 (-0.03, 0.04) .845 concurrent ed 0.09 (-0.51, 0.34) .658 0.17 (-0.30, 0.64) .459 model dependent variable : post-treatment pvr dependent variable : post-treatment pvr r2 = 0.51 , adj r2= 0.46 < .001 r2 = 0.75 , adj r2 =0.72 < .001 b (95% ci) p-value b (95% ci) p-value pre-treatment pvr 0.22 (0.14, 0.30) < .001 0.62 ( 0.48, 0.75) < .001 age 0.26 ( -0.85, 0.33) .374 0.09 (-0.33, 0.51) .659 concurrent ed 0.18 (-7.17, 6.81) .959 2.47 (-2.52, 7.45) .321 ed = erectile dysfunction; ipss = international prostate symptom score; ipss-qol = ipss quality of life question; pvr = post-void residual volume. adj r2 = adjusted r2; b = regression coefficient; ci= confidence interval. table 4. evaluation of the possible effect of age and concurrent ed on responsiveness to treatment. sildenafil vs. tadalafil for bph treatment – zahir et al. unclassified 258 daily) and showed that this combination is not superior to either of the medications alone in improving objective or subjective outcomes(29). despite the aforementioned, only a few reports have been published on bph/luts single-drug therapy with sildenafil. in two distinct studies, mcvary et al. showed that sildenafil (50 and 100 mg/daily) can significantly improve ipss and erectile function, irrespective of demographic and anthropometric indices(30,31). likewise, ko et al. stated that sildenafil (50 or 100mg/daily) can lower ipss significantly but didn’t have any effect on pvr(12). parallel to these studies, our results confimed the significant improvement of ipss and ipss-qol with sildenafil 50mg/daily. however, contrary to ko et al.(12), our results demonstrated a significant decrease of pvr with sildenafil treatment. this discrepancy can be partly due to different dose frequency and timing between the two studies. our results also confirmed the established efficacy of tadalafil (5mg/daily) in improving ipss, ipss-qol and pvr. interestingly, the improvement of pvr and ipss-qol score were shown to be significantly higher with sildenafil in comparison with tadalafil. besides, although not statistically significant, ipss reduction was also more prominent with sildenafil compared to tadalafil. we also evaluated the possible contribution of age and concurrent ed on responsiveness to either therapy. while concurrent ed did not affect any of the outcome parameters, age was shown to directly influence post-treatment ipss in both regimens and its impact was more prominent in treatment with sildenafil. considering the higher post-treatment ipss in older patients, it can be postulated that older age is inversely related to responsiveness to treatment, especially with sildenafil. this finding is in accordance with a previous study by lee et al., which showed a significantly better response to sildenafil in younger patients(22). a notable point to ponder is that 5 (12.5%) patients from the original 40 patients who were recruited for our study were lost to follow-up, either due to retrieval of their consent form (n = 2) or not returning for follow-up appointments (n = 3). consequently, the reason for treatment discontinuation in neither of these patients is available. the most reasonable explanation is discontinuation of the treatments due to perceived inefficiency or side effects(32). this finding is of value since it suggests that a number of patients may not benefit from treatment with pde5is and these treatments must be reserved for patients who are willing to try them and especially those who suffer from concurrent ed. finally, it is also worth mentioning that a recent study has shown that sildenafil is significantly more cost-effective in treating ed in comparison with other pde5is (15). this can be mainly due to a loss of exclusivity and generic entry of sildenafil. consequently, it can be deduced that a relatively cheaper price and more accessibility makes sildenafil a more convenient choice than tadalafil, especially in developing countries. our study was subject to some limitations. the most important shortcomings of our study were those inherent to the single-arm design (e.g., reduced internal validity due to selection bias, regression to the mean, social interaction, attrition and etc.). moreover, although sample size was calculated accurately as described before, the relatively small sample size limits the strength of our findings and calls for future double arm randomized clinical trials with larger sample sizes to further evaluate these findings. finally, we were unable to measure and compare maximum urinary flow rate because of limited access to uroflowmetry diagnostic test in our medical centers. nevertheless, the novelty of our study and accurate control of confounding factors can compensate for these shortcomings to a large degree. conclusions in conclusion, our results revealed the amelioration of all outcome parameters with both treatments. sildenafil was shown to be significantly superior to tadalafil in improving pvr and ipss-qol. although not significant, sildenafil was also shown to reduce ipss more than tadalafil. however, sildenafil was associated with two cases of severe headache leading to termination of treatment. considering the abovementioned evidence, lower price and easier accessibility; sildenafil can be nominated as a suitable alternative for tadalafil in treating bph/luts, especially in younger patients who don’t have any contraindications. summary in this study we compared the efficacy of sildenafil (viagra) with tadalafil (cialis) in improving the symptoms and signs related to benign prostatic hyperplasia. although only tadalafil is fda-approved for bph, our study showed that sildenafil is even more efficient in resolving symptoms and improving medical outcomes. moreover, sildenafil is more affordable and easily accessible and can be thus considered as a possible alternative for tadalafil. conflict of interest the authors of this manuscript have no conflicts of interest to disclose. references 1. lim kb. epidemiology of clinical benign prostatic hyperplasia. asian j urol. 2017;4:148-51. 2. awedew af, han h, abbasi b, et al. the global, regional, and national burden of benign prostatic hyperplasia in 204 countries and territories from 2000 to 2019: a systematic analysis for the global burden of disease study 2019. the lancet healthy longevity. 2022;3:e754-e76. 3. lokeshwar sd, harper bt, webb e, et al. epidemiology and treatment modalities for the management of benign prostatic hyperplasia. transl androl urol. 2019;8:529-39. 4. lepor h. medical treatment of benign prostatic hyperplasia. rev urol. 2011;13:20-33. 5. ahn st, lee dh, jeong hg, et al. treatment persistence with a fixed-dose combination of tadalafil (5 mg) and tamsulosin (0.4 mg) and reasons for early discontinuation in patients with benign prostatic hyperplasia and erectile dysfunction. investig clin urol. 2020;61:81-7. 6. cindolo l, pirozzi l, fanizza c, et al. drug adherence and clinical outcomes for patients under pharmacological therapy for lower urinary tract symptoms related to benign prostatic hyperplasia: population-based cohort sildenafil vs. tadalafil for bph treatment – zahir et al. vol 20 no 4 july-august 2023 259 sildenafil vs. tadalafil for bph treatment – zahir et al. study. eur urol. 2015;68:418-25. 7. diviccaro s, melcangi rc, giatti s. postfinasteride syndrome: an emerging clinical problem. neurobiol stress. 2020;12:100209. 8. cantrell ma, baye j, vouri sm. tadalafil: a phosphodiesterase-5 inhibitor for benign prostatic hyperplasia. pharmacotherapy. 2013;33:639-49. 9. mcvary k. lower urinary tract symptoms and sexual dysfunction: epidemiology and pathophysiology. bju int. 2006;97 suppl 2:23-8; discussion 44-5. 10. kaplan sa, gonzalez rr, te ae. combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. eur urol. 2007;51:1717-23. 11. tinel h, stelte-ludwig b, hütter j, sandner p. pre-clinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms. bju int. 2006;98:1259-63. 12. ko wj, han hh, ham ws, lee hw. daily use of sildenafil 50mg at night effectively ameliorates nocturia in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia: an exploratory multicenter, double-blind, randomized, placebo-controlled study. aging male. 2017;20:81-8. 13. fawzi a, kamel m, salem e, et al. sildenafil citrate in combination with tamsulosin versus tamsulosin monotherapy for management of male lower urinary tract symptoms due to benign prostatic hyperplasia: a randomised, double-blind, placebo-controlled trial. arab j urol. 2017;15:53-9. 14. abolyosr a, elsagheer ga, abdel-kader ms, hassan am, abou-zeid am. evaluation of the effect of sildenafil and/or doxazosin on benign prostatic hyperplasia-related lower urinary tract symptoms and erectile dysfunction. urol ann. 2013;5:237-40. 15. hansen sa, aas e, solli o. a cost-utility analysis of phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction. eur j health econ. 2020;21:73-84. 16. debruyne f, barkin j, van erps p, reis m, tammela tl, roehrborn c. efficacy and safety of long-term treatment with the dual 5 alphareductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. eur urol. 2004;46:488-94; discussion 95. 17. ho elm, tong sf, tan hm. prostate size: is size all that matters? (when does size matter?). journal of men's health. 2011;8:s22-s4. 18. nickel jc. benign prostatic hyperplasia: does prostate size matter? rev urol. 2003;5 suppl 4:s12-7. 19. amano t, earle c, imao t, matsumoto y, kishikage t. administration of daily 5 mg tadalafil improves endothelial function in patients with benign prostatic hyperplasia. aging male. 2018;21:77-82. 20. pandis n, chung b, scherer rw, elbourne d, altman dg. consort 2010 statement: extension checklist for reporting within person randomised trials. bmj. 2017;357:j2835. 21. balk em, earley a, patel k, trikalinos ta, dahabreh ij. ahrq methods for effective health care. empirical assessment of within-arm correlation imputation in trials of continuous outcomes. rockville (md): agency for healthcare research and quality (us); 2012. 22. lee sn, chakrabarty b, wittmer b, et al. age related differences in responsiveness to sildenafil and tamsulosin are due to myogenic smooth muscle tone in the human prostate. sci rep. 2017;7:10150. 23. greenland s, mansournia ma, joffe m. to curb research misreporting, replace significance and confidence by compatibility: a preventive medicine golden jubilee article. prev med. 2022;164:107127. 24. herr hw. the enlarged prostate: a brief history of its surgical treatment. bju int. 2006;98:947-52. 25. lerner lb, mcvary kt, barry mj, et al. management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: aua guideline part i-initial work-up and medical management. j urol. 2021;206:806-17. 26. calogero ae, burgio g, condorelli ra, cannarella r, la vignera s. lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction: from physiology to clinical aspects. aging male. 2018;21:261-71. 27. kirby m, chapple c, jackson g, et al. erectile dysfunction and lower urinary tract symptoms: a consensus on the importance of co-diagnosis. int j clin pract. 2013;67:606-18. 28. song g, wang m, chen b, et al. lower urinary tract symptoms and sexual dysfunction in male: a systematic review and meta-analysis. front med (lausanne). 2021;8:653510. 29. tuncel a, nalcacioglu v, ener k, aslan y, aydin o, atan a. sildenafil citrate and tamsulosin combination is not superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. world j urol. 2010;28:17-22. 30. mcvary kt, monnig w, camps jl, jr., young jm, tseng lj, van den ende g. sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. j urol. 2007;177:1071-7. 31. mcvary kt, siegel rl, carlsson m. sildenafil citrate improves erectile function and lower urinary tract symptoms independent of baseline body mass index or luts severity. urology. 2008;72:575-9. 32. evans jd, hill sr. a comparison of the available phosphodiesterase-5 inhibitors in the treatment of erectile dysfunction: a focus on avanafil. patient prefer adherence. 2015;9:1159-64. unclassified 260 care report a -16year remained urolume stent without any complication; a case report lumen diameter reduction which is called urethral stricture has several causative agents including iatrogenic, inflammatory, traumatic, and idiopathic factors. the main treatment options are transurethral or open surgical interventions. the urolume which was introduced around 33 years ago is an intraurethral stent and as a temporary treatment approach has a maximum 9-month durability, but here we present the first ever reported forgotten 16year remained urolume without any complication. men’s health and reproductive health research center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: men’s health and reproductive health research center, shahid beheshti university of medical sciences, tehran, iran. telephone: +98(021) 22712234. email: aliaskari56@yahoo.com received june 2021 & accepted december 2021 introduction urethral stricture can be defined as lumen diameter reduction in virtue of ischemic spongiofibrosis(1). the caus-es are categorized into 4 groups: iatrogenic (like transurethral resections, prolonged catheterization, cystoscopy, hypospadias repairs, and prostatectomy), inflammatory (such as infection and post-infectious inflammation and lichen sclerosis), idiopathic and traumatic(2). urethral stricture is a relatively common disease in men with an associated prevalence of 2-6 per 1000 males, or 0.6% of the at-risk population, who are typically older(3). current treatment mainly are classified into transurethral (stent or balloon dilation, internal urethrotomy) and open surgical (stricture resection and anastomosis, urethroplasty, and perineal urethrostomy)(4). the urolume urethral stent (american medical systems) has been introduced commercially since 1988 for the treatment of urethral stricfigure 1. voiding cystogram and retrograde urethrogram of the patient. seyed jalil hoseini, shideh moftakhari hajimirzaei, rayka sharifian, ehsan shojaeefar, ali mohammad mirjalili* urology journal/vol 19 no. 2/ march-april 2022/ pp. 157-158. [doi: 10.22037/uj.v18i.6874] ture in men with benign prostatic hyperplasia. recent studies have identified long-term complications such as urethral restenosis, urethral pain, recurrent urinary tract infections, and stent migration(5). we present a case who underwent urolume stent therapy for urethral stricture 16 years ago and the applied urolume has been thoroughly wrapped with mucosa. this case is the first ever reported forgotten long-term stayed urolume according to our electronic search at time of submission. case presentation a 53-year old man presented in the urology clinic with the chief complaint of mild obstructive symptoms. he wasn’t on any long-term preventive medication such as vitamin c to stop stone or incrustation formation. he had omitted the regular follow-up himself due to no urinary symptoms to urge him for stent removal. on further investigation, the international prostatic symptom score (ipss) was calculated and the result was 19. the patient had experienced urethral trauma 29 years ago and underwent urolume stent insertion 16 years ago. recent cystoscopy revealed that the stent in bulbar urethra has completely covered by urothelium and there were some mucosal erosions throughout the urethra. he hadn't uroflowmetry evaluation before and there wasn’t a significant post voiding residual (pvr) in sonography. voiding cystourethrography (vcug) had a normal pattern without diverticula and a neurogenic bladder was not found. retrograde urethrography (rug) showed the urolume pattern. in the preinjection scout film of the urethra and after contrast injection, the urethra was completely open and no stricture, kink, or other abnormality was seen (figure 1). finally, he was diagnosed with benign prostatic hyperplasia and underwent therapy by tamsulosin 0.4 mg daily and we informed him about our intention for reporting his unusual case, unanimously. he was re-evaluated two weeks later and the ipss had not changed significantly. so, he was a candidate for stent removal but at that time we didn’t remove the stent because the patient didn’t come back for further work up. discussion the patient presented with urethral stricture and had gone through stent dilation therapy but stent epithelization was discovered and cystoscopy revealed that the urethra has been open since then. the urolume endoprosthesis is a non-magnetic, self-expanding urethral stent employed to maintain the urethral lumen in cases of subvesical obstruction(6). it can be adopted for recurrent bulbar urethral strictures, benign prostatic hyperplasia (bph), and detrusor-external sphincter dyssynergia(7). it is thought to be a good choice in old patients with bph and urinary retention and simultaneous high surgical risk(6). north american multicenter trial has announced complications of this stent as migration, encrustation, epithelialization, pain, and irritative voiding symptoms that require removal of the stent(7). a retrospective study of forty-five men who underwent placement of the urolume stent with an average follow-up of 55.8 months evaluated urinary continence, ingrowth of the urolume stent, need for repeat operations, and complications related to this treatment including artificial urinary sphincter (aus) erosion. 78% of patients had simultaneous or subsequent placement of an aus. ingrowth was seen in 36% and aus erosion in 19.5%. of the 16 patients treated for ingrowth, the average number of treatments was 2.7 per patient. there was no association between treatment for ingrowth and the rate of aus erosion(8). conclusions despite the average 9-month competency of urolume stents reported in previous articles, we have observed a 16-year efficacy and no complication in this patient. we suggest performing a further thorough investigation to find out the background factors and features in this case responsible for stent protection. our limitations in this report were no uroflowmetry available and also, we couldn’t take the cystoscopy photograph. conflict of interest the authors report no conflict of interest. references 1. mangir n, chapple c. recent advances in treatment of urethral stricture disease in men. f1000research. 2020;9. 2. abdeen bm, badreldin am. urethral strictures. statpearls [internet]. 2020. 3. alwaal a, blaschko s, mcaninch j, breyer b. epidemiology of urethral strictures. transl androl urol 2014; 3: 209–13. 4. tritschler s, roosen a, füllhase c, stief cg, rübben h. urethral stricture: etiology, investigation and treatments. deutsches ärzteblatt international. 2013;110:220. 5. frankiewicz m, karolina m, marcin m. diagnosis and management of urolume urethral stent complications using ultrasonography and magnetic resonance imaging. urology. 2020;144:e4-e5. 6. botelho f, thomas aa, miocinovic r, angermeier kw. endoscopic removal of a proximal urethral stent using a holmium laser: case report and literature review. urology annals. 2012;4:191. 7. corujo m, badlani gh. uncommon complications of permanent stents. journal of endourology. 1998;12:385-8. 8. mcnamara er, webster gd, peterson ac. the urolume stent revisited: the duke experience. urology. 2013;82:933-6. a case of long-lasting urolume stent-hoseini et al. unclassified 158 endourology and stone disease postoperative progress after stone removal following treatment for obstructive acute pyelonephritis associated with urinary tract calculi: a retrospective study shimpei yamashita1*, yasuo kohjimoto1, masatoshi higuchi1, yuko ueda1, takashi iguchi1 isao hara1 purpose: we aimed to identify the prevalence and risk factors of three outcomes after stone removal following treatment for obstructive acute pyelonephritis (apn) associated with urinary tract calculi: immediate postoperative febrile urinary tract infection (uti), stone recurrence, and apn recurrence during the follow-up period. materials and methods: we retrospectively reviewed the charts of 107 patients who underwent stone removal following treatment for obstructive apn associated with urinary tract calculi. logistic regression analysis was used to identify the factors that contributed to postoperative febrile uti after stone removal. cox proportional hazard analyses were used to identify the factors contributing to stone recurrence and apn recurrence during the follow-up period. results: postoperative febrile uti was observed in 23 out of 107 patients (21.5%). multivariate logistic regression analysis revealed that female sex (p = .02) and having multiple stones (p < .01) were independently significant predictors of postoperative febrile uti. one-year recurrence-free survival rates of stone disease and apn were 76.1% and 82.5%, respectively. multivariable cox proportional hazard analyses revealed that presence of residual fragments was the only significant risk factor for stone recurrence (p < .01) and marginally significant for apn recurrence (p = .05). conclusion: patients presenting with obstructive apn frequently develop postoperative febrile uti after active stone removal with the risk factors being female sex and having multiple stones. residual fragments after stone removal in patients with obstructive apn can cause urolithiasis and apn recurrence, indicating that complete removal of stone fragments ≥ 4 mm is imperative to the disease management. keywords: lithotripsy; postoperative complications; pyelonephritis; retrospective studies; risk factors; urolithiasis introduction obstructive acute pyelonephritis (apn) associat-ed with upper urinary tract calculi is one of the main emergency diseases in the urological field. it may progress to severe sepsis and become life-threatening. despite intensive care and emergency urinary drainage, the mortality rate is reported to be around 2% (1). several studies of the predictors of progression of sepsis have therefore been reported and clinicians have attempted to effectively treat this disease by risk stratification(2,3). eau guidelines on interventional treatment for urolithiasis (2016) specify that obstruction and infection caused by stones are indications for active stone removal(4) and stone removal is considered to be necessary for most of these patients. treatment for patients presenting with obstructive apn secondary to upper urinary tract calculi should comprise of not only amelioration of the infection, but also stone removal. stone removal surgery has become effective and safe, but there are sometimes severe postoperative complications(5). there are concerns about immediate postoperative pyelonephritis, especially when active stone removal is performed for patients after treatment of obstructive apn. in addition, there are also concerns about recurrence of 1department of urology, wakayama medical university, kimiidera 811-1, wakayama, japan. *correspondence: department of urology, wakayama medical university, 811-1 kimiidera, wakayama 641-8509, japan. tel: +81-73-441-0637. fax: +81-73-444-8085. e-mail: keito608@wakayama-med.ac.jp. received september 2018 & accepted may 2019 stones and apn recurrence during the follow-up period after active stone removal. however, few studies have reported these problems. the current study aims to examine postoperative progress after active stone removal and to identify the predictors of three outcomes: immediate postoperative febrile urinary tract infection (uti), stone recurrence, and apn recurrence during the follow-up period. materials and methods patients between may 2006 and august 2013, 166 patients were treated for obstructive apn associated with urinary tract calculi at the wakayama medical university hospital, wakayama rosai hospital and kinan hospital. of these patients, five were transferred to other medical facilities after acute-phase treatment, 34 experienced spontaneous stone expulsion, five underwent nephrectomy and 15 underwent conservative treatment without active stone removal. enrolled in this study, therefore, were the 107 patients who underwent stone removal following treatment for apn (figure 1). in accordance with our treatment policy, patients continued to have antibiotic treatment by cephem-based antibiotics or carbapenem-based antibiotics for at least two weeks and urology journal/vol 17 no. 2/ march-april 2020/ pp. 118-123. [doi: 10.22037/uj.v0i0.4847] vol 17 no 02 march-april 2020 119 they underwent active stone removal after improvement of their infection was confirmed. placement of drainage tubes was left to the judgment of attending physicians. after stone removal, we performed regular follow-up of patients by using kidney-ureter-bladder (kub) film and ultrasonography every six months and non-contrast computed tomography (ncct) every few years. this study was approved by the institutional review board of wakayama medical university (approval number 1953). while since this study was a retrospective observational study for ordinary medical practice and information about this clinical study was disclosed on institutional web pages and displayed in each hospital’s visitor consultation rooms, written informed consent to participate in this study was not obtained from patients also patient’s data would be excluded if any patient objected to participate. surgical techniques ureteroscopy (urs) the procedure was performed with the patient in the dorsal lithotomy position under general anesthesia. in distal ureteral stones cases, 7.5 fr semi-rigid ureteroscope (karl storz, germany) was used. in cases with stones in another location, flexible ureteroscope (urf-p5/urf-v, olympus, japan) was used for the main procedure. the stones were fragmented using a 200 µm versa pulse ho:yag laser (lumenis, israel). stone fragments were extracted by stone basket. at the end of each procedure, a double-j ureteric catheter was stone removal after obstructive pyelonephritis-yamashita et al. endourology and stones diseases 02 table 1. patient demographic and clinical data. no. of patients 107 age*, years 69 (24-94) gender, n (%) male 35 (32.7) female 72 (67.3) compromised host, n (%) 24 (22.4) karnofsky performance scale ≤70%, n (%) 34 (31.8) previous history of urinary tract calculi, n (%) 38 (35.5) stone side, n (%) right 52 (48.6) left 55 (51.4) location, n (%) renal calyx 3 (2.8) ureteropelvic junction 17 (15.9) upper ureter 54 (50.5) middle ureter 24 (22.4) lower ureter 9 (8.4) size*, mm 9.0 (3.0-35.0) multiple stones, n (%) 40 (37.4) laboratory data at the consultation wbc count* (/µl) 12400 (1900-37200) crp* (mg/dl) 12.19 (0.07-42.14) sirs, n (%) 70 (65.4) drainage, n (%) 93 (86.9) ureteral stent 75 (70.1) percutaneous nephrostomy 18 (16.8) abbreviations: wbc: white blood cell, crp: c-reactive protein, sirs: systemic inflammatory response syndrome *continuous variables are shown as median (range figure 1. study cohort flow diagram. apn: acute pyelonephritis. figure 2. comparison of (a) stone recurrence-free survival rate and (b) pyelonephritis recurrence-free survival rate between patients with and without residual fragments . routinely placed. percutaneous nephrolithotomy (pcnl) the procedure was performed with the patient in the prone split-leg position under general anesthesia. flexible cystoscopy was performed first to cannulate the ureteral orifice with a 0.035 mm guidewire that was passed into the upper urinary tract under fluoroscopic guidance. next, a 12/14 fr flexor® ureteral access sheath (cook medical, usa) was inserted to allow frequent passage of the ureteroscope (urf-p5/urf-v, olympus, japan) to the site of the calculi. calyceal puncture was performed under ultrasonographic and fluoroscopic guidance. antegrade access was established by one-step dilation and placement of the 16.5/19.5 fr operating sheath. lithotripsy was performed by using a 12 fr miniature nephroscope (karl storz, germany) and lithoclast® (boston scientific, usa). stones were broken into small fragments and washed out through the sheath by retrograde irrigation. at the end of each procedure, a double-j ureteric stent and a 16 fr nephrostomy tube were routinely placed. predictors patients’ demographic data (including age, sex, performance status based on karnofsky performance scale, and previous history of urinary tract calculi) and clinical data (stone location, stone size, number of stones, and laboratory data at the time of consultation) were collected, retrospectively. clinical records were also reviewed and information about urinary drainage, method of stone removal, and presence of residual stones after stone removal was collected. patients who had diabetes mellitus or were being administered anti-cancer agents or immunosuppressive agents were included in the compromised host group. stone size was defined as the maximum diameter in millimeters and determined by kub film or ncct. the presence of residual stones was determined using kub film or ncct within three months of stone retable 2. logistic regression analyses of associations between various parameters and postoperative febrile uti after stone removal (n=107). variable univariate analysis multivariate analysis n number of uti or 95% ci p value or 95% ci p value age, years 0.99 0.96 1.03 .64 gender female 72 20 4.10 1.28 18.39 .01 5.02 1.21 20.66 .02 male 35 3 compromised host + 24 7 1.72 0.59 4.76 .31 83 16 karnofsky performance scale ≤ 70% 34 5 0.53 0.16 1.48 .23 ≥ 80% 73 18 stone location ureteral stone 87 22 6.43 1.22 118.81 .02 6.27 0.70 55.57 .09 renal stone 20 1 stone size, mm 1/03 0.96 1.10 .43 stone number multiple 40 17 7.51 2.76 23.05 < 0.01 9.71 3.01 31.29 < 0.01 single 67 6 crp, mg/dl 0/98 0.93 1.03 .37 sirs + 70 6 1.65 0.62 4.99 .32 37 17 drainage + 93 19 0.64 0.19 2.54 .50 14 4 method of stone removal urs/pcnl 55 16 2.64 1.01 7.48 .04 3.03 0.93 9.82 .06 eswl 52 7 abbreviations: crp: c-reactive protein, sirs: systemic inflammatory response syndrome, urs: ureteroscopy, pcnl: percutaneous nephrolithotomy, eswl: extracorporeal shock wave lithotripsy variable univariate analysis multivariate analysis n number of events hr 95% ci p value hr 95% ci p value age, years 0.96 0.93 0.99 .02 0.98 0.95 1.01 .30 gender male 30 5 0.50 0.17 1.28 .15 female 60 17 karnofsky performance scale ≤ 70% 20 7 1.53 0.59 3.65 .36 ≥ 80% 70 15 compromised host + 17 5 1.76 0.58 4.48 .26 73 17 stone history recurrent stone former 34 11 1.05 0.43 2.52 .90 non-recurrent stone former 56 11 stone number multiple 34 15 3.26 1.36 8.60 < 0.01 2.13 0.78 5.82 0.13 single 56 7 method of stone removal urs/pcnl 44 11 0.97 0.41 2.26 .93 eswl 46 11 residual fragments + 18 10 5.18 2.12 12.64 < 0.01 3.72 1.44 9.57 < 0.01 72 12 table 3. cox proportional hazard analyses of associations between various parameters and stone recurrence during follow-up period (n=90) abbreviations: urs: ureteroscopy, pcnl: percutaneous nephrolithotripsy, eswl: extracorporeal shock wave lithotripsy stone removal after obstructive pyelonephritis-yamashita et al. endourology and stones diseases 120 vol 17 no 02 march-april 2020 121 moval and residual stones were defined as residual fragments ≥ 4 mm. outcomes and statistical analyses we investigated immediate postoperative febrile uti after stone removal, stone recurrence, and apn recurrence during the follow-up period, and analyzed the factors contributing to these three outcomes. postoperative febrile uti was defined as body temperature > 38˚c which required additional antibiotic treatment. stone recurrence was defined as the appearance of symptoms caused by urinary tract calculi, intervention for urinary tract calculi, and the appearance or growth of stones on imaging tests. logistic regression analysis was performed to identify the factors contributing to immediate postoperative febrile uti after stone removal. univariate and multivariate analyses were performed to identify the factors contributing to stone recurrence and apn recurrence during the follow-up period using the cox proportional hazard model. for all statistical tests, p < .05 was considered significant. recurrence rates of stone disease and apn were calculated by the kaplan-meier method. all statistical analyses were performed using jmp pro 12 software (sas institute, usa). results patients’ demographic and clinical data are shown in table 1. the median age was 69 years old (range: 2494 years) and 72 patients (67.3%) were female. the median stone size was 9.0 mm (range: 3.0-35.0 mm). seventy patients (65.4%) developed systemic inflammatory response syndrome (sirs) and 93 patients (86.9%) received urinary drainage by either ureteral stenting (n = 75, 70.1%) or percutaneous nephrostomy (n = 18, 16.8 %). of the 107 patients, 52 patients (48.6%) underwent extracorporeal shock wave lithotripsy (eswl), 49 patients (45.8%) underwent urs and six patients (5.6%) underwent pcnl. overall, residual stones were observed in 22 patients (20.6%). ninety patients (84.1%) had regular follow-up after stone removal in their respective institutions. immediate postoperative febrile urinary tract infection postoperative febrile uti (clavien-dindo classification grade 2) was observed in 23 out of the 107 patients (21.5%). among the potential variables, female sex (p = .01), ureteral stones (p = .02), multiple stones (p < .01), and endoscopic therapies (p = .04) were statistically significant predictors of febrile uti based on univariate analysis. after performing multivariate analysis, female sex (p = .02) and multiple stones (p < .01) were significant predictors of postoperative febrile uti, independently. table 2 shows the results of univariate and multivariate logistic regression analyses of factors predictive of postoperative febrile uti. stone recurrence during the follow-up period stone recurrence was observed in 22 out of 90 patients who had regular follow-up (mean follow-up period: 17.7 months) and the one-year stone recurrence-free survival rate was 76.1%. among the investigated variables, univariate analysis revealed the significant predictors of stone recurrence during the follow-up period as younger age (p = .02), multiple stones (p < .01) and residual fragments (p < .01). one-year stone recurrence-free survival rates in patients with or without residual fragments was 39.7% and 86.1%, respectively (p < .01, figure 2a). in multivariate analysis, presence of residual fragments was the only independent significant predictor of stone recurrence (p < 0.01). table 3 shows the results of univariate and multivariate cox proportional hazard analysis of factors predicting stone recurrence during the follow-up period. apn recurrence during follow-up period apn recurrence was observed in 20 out of the 90 patients who were followed (mean follow-up period: 17.5 months) and the one-year apn recurrence-free survival rate was 82.5%. among the potential variables, statistically significant predictors of apn recurrence were younger age (p < .01), poor performance status (p = .03), multiple stones (p = .04,) and residual fragments (p < 0.01) during the follow-up period. one-year apn recurrence-free survival rates in patients with or without residual fragments was 48.5% and 92.6%, respectively (p < .01, figure 2b). in multivariate analysis, residual fragments were not significant, but were considered a possible predictor of apn recurrence (p = .05). table 4 shows the results of univariate and multivariate cox proportional hazard analyses of factors which predict apn recurrence during the follow-up period discussion we examined the postoperative status of patients after table 4. cox proportional hazard analyses of associations between various parameters and recurrence of apn during follow-up period (n=90) variable univariate analysis multivariate analysis n number of events hr 95% ci p value hr 95% ci p value age, years 0.96 0.93 0.99 < 0.01 0.97 0.94 1.00 .14 gender male 30 8 1.42 0.55 3.44 .45 female 60 12 karnofsky performance scale ≤ 70% 20 9 2.70 1.09 6.55 .03 2.26 0.91 5.60 .07 ≥ 80% 70 11 compromised host + 17 5 1.89 0.61 4.92 .24 73 15 stone history recurrent stone former 34 10 1.15 0.46 2.86 .75 non-recurrent stone 56 10 former stone number multiple 34 12 2.48 1.01 6.43 .04 1.20 0.39 3.61 .74 single 56 8 method of stone removal urs/pcnl 44 8 1.03 0.67 1.58 .89 eswl 46 12 residual fragments + 18 9 3.67 1.46 9.11 < 0.01 2.65 0.96 7.25 .05 72 11 abbreviations: urs: ureteroscopy, pcnl: percutaneous nephrolithotripsy, eswl: extracorporeal shock wave lithotripsy stone removal after obstructive pyelonephritis-yamashita et al. active stone removal in cases presenting with obstructive apn secondary to upper urinary tract calculi, and identified the predictors of immediate postoperative febrile uti, stone recurrence, and apn recurrence during the follow-up period. in this study, we made two important clinical observations: first was that patients presenting with obstructive apn frequently develop postoperative febrile uti after active stone removal. the most important risk factors of this outcome were female sex and presence of multiple stones. most of the patients in the present study underwent urs or eswl. previous studies reported that the rate of developing postoperative fever or sepsis after treatment with these approaches is between 1.1 and 12.6% (6-8). on the other hand, lingeman et al. (1986) reported that 15.5% of their 1,416 patients undergoing eswl treatment developed febrile uti(9). the incidence of postoperative febrile uti in our study was 21.5%, which was much higher than previous studies. this might suggest that a history of obstructive pyelonephritis is the main risk factor for postoperative febrile uti. in previous studies, presence of multiple stones has been reported to be a predictor of infectious complications in urs cases(10,11). this factor was significantly associated with postoperative febrile uti in our patients too. therefore, stone removal for patients with obstructive pyelonephritis caused by multiple stones requires extra caution. few studies have reported that the incidence of postoperative febrile uti is different depending on sex. consistent with their findings, female sex was also a risk factor in our study. this might be because the proportion of magnesium ammonium phosphate stones in females is generally higher than in males. however, much of the data about stone composition was unavailable in the current study. our second main finding was that the presence of residual fragments after stone removal in patients with obstructive apn increases the chance of apn recurrence and stone recurrence. several studies on the natural history of residual stones after urs, eswl and pcnl have been reported. chew et al. (2016) and atis et al. (2011) examined the natural history of fragments after ureteroscopy and reported that fragments > 4 mm were associated with more complications(12,13). rebuck et al. (2011) reported that 19.6% of patients experienced stone-related events even if their residual fragments were ≤ 4 mm(14). in eswl treatment, residual fragments of > 5 mm have generally been considered a failure of eswl. buchholz et al. (1997) examined the natural history of residual fragments < 5 mm after eswl and did not recommend more invasive attempts to clear all minor fragments since all of the residual fragments were asymptomatic and only 2% showed stone regrowth(15). on the other hand, in recent studies, close follow-up or positive therapeutic intervention has been recommended, even if residual fragments after eswl are ≤ 5 mm, because they can later become symptomatic (16-18). as for the natural history of residual stones after pcnl, raman et al. (2009) analyzed 527 patients who underwent pcnl and reported that 42 patients (8%) had residual fragments and that 18 of these 42 patients (43%) experienced a stone-related event(19). in their study, maximum residual fragment size > 2 mm and stone location in the renal pelvis or ureter were independent significant predictors of stone events. to the best of our knowledge, no study has reported the natural history of residual stones after stone removal following the treatment of obstructive apn. the results of the present study show that the presence of residual stones ≥ 4 mm after stone removal following obstructive apn is an independent risk factor for stone recurrence and marginally significant for pyelonephritis recurrence during the follow-up period. notably, residual fragments can cause acute pyelonephritis recurrence as well as stone recurrence in patients with obstructive acute pyelonephritis with urinary tract calculi. as shown in figure 2, more than half of the patients with residual fragments experienced stone recurrence or pyelonephritis recurrence within one year. even when compared with the previous studies described above, these recurrence rates seemed to be higher. therefore, our results suggest that complete removal of stone fragments ≥ 4 mm is essential for patients with obstructive pyelonephritis associated with urinary tract calculi. there are several limitations to the present study. first, it is a retrospective study with relatively small number of patients undertaken across several centers. second, the evaluation method of residual fragments differed between the patients (i.e. ct and kub). third, the definition of residual stones ≥ 4 mm might be criticized as inappropriate since even residual stones < 4 mm can cause symptomatic stone events and stone recurrence. however, no significant differences were noted in stone recurrence and apn recurrence between patients without any residual stones (completely stone-free) and those with residual stones of 1 mm (hr, 1.82; 95% ci, 0.43-6.99 and hr, 0.28; 95% ci, 0.04-1.41, respectively) or 2-3 mm (hr, 1.11; 95% ci, 0.15-5.41 and hr, 0.54; 95% ci, 0.07-2.71, respectively). it is therefore reasonable to use the definition of residual stones ≥ 4 mm in this study. in addition, several factors that might influence postoperative complications, such as preoperative urine culture, stone composition and operation time, were not included in our analysis because the data was unavailable. nonetheless, this study showed that remaining residual fragments can frequently cause apn recurrence as well as stone recurrence. a multicenter prospective analysis is required to overcome these limitations. conclusions patients presenting with obstructive apn frequently develop postoperative febrile uti after active stone removal. the risk factors are female sex and presence of multiple stones. also, residual fragments after stone removal in patients with obstructive apn can often cause apn recurrence as well as stone recurrence . therefore, stone removal without leaving residual fragments is of outmost importance for these patients. acknowledgements we acknowledge proofreading and editing of this article by benjamin phillis at wakayama medical university. conflicts of interest none declared. stone removal after obstructive pyelonephritis-yamashita et al. endourology and stones diseases 122 vol 17 no 02 march-april 2020 123 references 1. yoshimura k, utsunomiya n, ichioka k, ueda n, matsui y, terai a. emergency drainage for urosepsis associated with upper urinary tract calculi. j urol. 2005;173:458-62. 2. kamei j, nishimatsu h, nakagawa t, et al. risk factors for septic shock in acute obstructive pyelonephritis requiring emergency drainage of the upper urinary tract. int urol nephrol. 2014;46:493-7. 3. yamamoto y, fujita k, nakazawa s, et al. clinical characteristics and risk factors for septic shock in patients receiving emergency drainage for acute pyelonephritis with upper urinary tract calculi. bmc urol. 2012;12:4. 4. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 5. cindolo l, castellan p, primiceri g, et al. life-threatening complications after ureteroscopy for urinary stones: survey and systematic literature review. minerva urol nefrol. 2017;69:421-31. 6. geavlete p, georgescu d, nita g, mirciulescu v, cauni v. complications of 2735 retrograde semirigid ureteroscopy procedures: a singlecenter experience. j endourol. 2006;20:17985. 7. sohn dw, kim sw, hong cg, yoon bi, ha us, cho yh. risk factors of infectious complication after ureteroscopic procedures of the upper urinary tract. j infect chemother. 2013;19:1102-8. 8. baseskioglu b. the prevalence of urinary tract infection following flexible ureterenoscopy and the associated risk factors. urol j. 2018. 9. lingeman je, newman d, mertz jh, et al. extracorporeal shock wave lithotripsy: the methodist hospital of indiana experience. j urol. 1986;135:1134-7. 10. shields jm, bird vg, graves r, gomez-marin o. impact of preoperative ureteral stenting on outcome of ureteroscopic treatment for urinary lithiasis. j urol. 2009;182:2768-74. 11. el-nahas ar, el-tabey na, eraky i, et al. semirigid ureteroscopy for ureteral stones: a multivariate analysis of unfavorable results. j urol. 2009;181:1158-62. 12. chew bh, brotherhood hl, sur rl, et al. natural history, complications and reintervention rates of asymptomatic residual stone fragments after ureteroscopy: a report from the edge research consortium. j urol. 2016;195:982-6. 13. atis g, pelit es, culpan m, et al. the fate of residual fragments after retrograde intrarenal surgery in long-term follow-up. urol j. 2018;0:1-5. 14. rebuck da, macejko a, bhalani v, ramos p, nadler rb. the natural history of renal stone fragments following ureteroscopy. urology. 2011;77:564-8. 15. buchholz np, meier-padel s, rutishauser g. minor residual fragments after extracorporeal shockwave lithotripsy: spontaneous clearance or risk factor for recurrent stone formation? j endourol. 1997;11:227-32. 16. candau c, saussine c, lang h, roy c, faure f, jacqmin d. natural history of residual renal stone fragments after eswl. eur urol. 2000;37:18-22. 17. khaitan a, gupta np, hemal ak, dogra pn, seth a, aron m. post-eswl, clinically insignificant residual stones: reality or myth? urology. 2002;59:20-4. 18. el-nahas ar, el-assmy am, madbouly k, sheir kz. predictors of clinical significance of residual fragments after extracorporeal shockwave lithotripsy for renal stones. j endourol. 2006;20:870-4. 19. raman jd, bagrodia a, gupta a, et al. natural history of residual fragments following percutaneous nephrostolithotomy. j urol. 2009;181:1163-8. stone removal after obstructive pyelonephritis-yamashita et al. sequential chemotherapy followed by radiotherapy versus concurrent chemoradiation in muscle invasive bladder cancer mohammad hasan larizadeh1, fateme arabnejad2*, mohammad reza ebadzadeh3 1. associate professor of radiation oncology, kerman medical university of iran 2. assistant professor of radiation oncology, kerman medical university of iran 3. associate professor of urology, kerman medical university of iran *corresponding author abstract: bladder cancer is diagnosed at older age compared to all other known cancer types. radical cystectomy after neoadjuvant chemotherapy or tri-modality treatment (consist of turb, concurrent chemo-radiation) are the standard treatments. many of the patients cannot receive trimodality treatment (concurrent chemo-radiation) because of medical comorbidities. the present study assessed the results of sequential use of chemotherapy and radiotherapy versus concurrent use of them in 266 muscle invasive bladder cancer patients. the results showed similar overall survival but lower disease-free survival in the sequential group. recurrence rate was higher in the concurrent group. the results showed that sequential use of chemotherapy and radiotherapy provides comparable results to concurrent use of them and provides better results than less than tri-modality treatments. introduction: the globocan estimated 573,278 new bladder cancer cases and 212,536 bladder cancer deaths in 2020 worldwide in the latest report on the global cancer burden(1). evidence has shown that bladder cancer, the ninth most common type of cancer worldwide, and the most common urinary tract cancer is diagnosed at older age compared with all other known cancer types (2). nearly 25% of new cases are muscle-invasive bladder cancer (mibc) (t2-t4 disease), which has a 5-year survival of 15% without treatment(3). radical cystectomy (rc) after neo-adjuvant cisplatin-based combination chemotherapy is the gold standard of treatment for muscle invasive bladder cancer, but some patients have medically inoperable disease or refuse cystectomy to preserve their bladder function. a representative bladder preservation therapy (bpt) that uses concurrent chemo-radiotherapy (ccrt) following maximal transurethral resection of the bladder tumor (turbt) is named tri-modal therapy (tmt). it is considered as an alternative curative treatment to rc for carefully selected mibc patients who desire bladder preservation (elective cases) and for those medically unfit for rc (imperative cases). tmt is ranked conditionally as category 1 in the treatment of locally advanced mibc according to the national comprehensive cancer network (nccn) guideline published in 2022 which resulted in comparable outcomes to rc for properly selected patients (4). chemotherapy is an important component of tmt, as the randomized bc2001 trial showed that chemo-radiation provides superior loco-regional disease free survival compared to radiation alone (5). a large proportion of patients with mibc are elderly and with renal dysfunction; therefore, many could not receive a complete course of chemotherapy with cisplatin during bladder preservation therapy (6). studies show that older adults with mibc tend to have poorer cancer-specific survival compared with younger patients, probably due to a lower rate of standard-of-care ( rc and tri-modality therapy) (7). in the recent uptodate guideline, radiation with or without chemotherapy is preferred in the frail patients who are not surgical candidates or who elect bladder sparing treatment approach and for the patients who are ineligible for or decline radiotherapy, systemic therapy is a reasonable alternative (8). to date, data on the survival and local control outcomes for mibc patients undergoing sequential chemotherapy and radiotherapy in the setting of unsuitability for concurrent therapy are still limited, and the findings are inconsistent(5,9,10). the absence of evidence from randomized clinical trials makes the results from observational studies valuable. so, the study was designed to retrospectively evaluate the feasibility and outcome of sequential chemotherapy/radiotherapy in comparison to concurrent chemo-radiation in mibc patients after turbt. materials and methods the present retrospective case series study was conducted at the shafa radiotherapy center of kerman. it has been approved in kerman medical university ethics committee by the code: ir.kmu.rec.1401.949 medical records of the patients with bladder cancer were collected from april 22, 1994, to april 12, 2021. patients co-diagnosed with any other cancers, a history of prior malignancy, non-urothelial cell carcinoma (non-transitional cell carcinoma, or variant histology), multiple/unknown primary, node positive, metastasis present, short rt schedule on request for fragile patients or received palliative intent therapy, presence of extensive carcinoma in-situ (cis) and missing clinical stage and treatment information were excluded. clinical staging for all cases has been assessed, by abdomino-pelvic ct scan, cystoscopy and turb. one turb was considered as standard, but there was some exceptions such as suboptimal turb, any t1 ang absence of muscle in the specimen. suboptimal turb was considered as incomplete resection of the mass in the sonography. muscle-invasive cancer was defined as localized non-metastatic bladder cancer (clinical stage t2-4n0m0). from mibc patients, concurrent chemo-radiation treated and sequential chemotherapy/radiotherapy treated patients were collected. there was no randomization between the groups. selection of the sequential use of chemo-radiation has been based on the patient condition, comorbidities and the physician’s choice. medical comorbidities, age, gender, recurrence time and turb type (optimal/suboptimal), hematologic and gastrointestinal toxicities were recorded by the nci version 4 grading system. suboptimal turb was defined as reside in the post cystoscopy turb. the survival data was collected by calling the patient registered phone number. radiotherapy dose and chemotherapy regimen were recorded. local recurrence was defined as a histologically proven urothelial carcinoma of the bladder or a papillary bladder tumor on cystoscopy or urine cytology that showed a suspicion of high-grade urothelial carcinoma. follow-up time was calculated from the first visit to the last visit by the physician. the patients were visited regularly during the follow up time. the first documented recurrence was noted as the recurrence time. radiotherapy total doses was 60 gy (2 gy/fraction) delivered to the bladder and pelvic lymph nodes, in two phases (first 44 gy to whole pelvis and then up to 60 gy as a boost to the bladder), using a four-field box three-dimensional conformal radiotherapy technique. in the concurrent group the chemotherapy regimen was 5-fluorouracil alone or cisplatin alone (40 mg/m2 cisplatin every week during radiotherapy). in the sequential group, the chemotherapy regimen was gemcitabine and cisplatin (1000 mg/m2 gemcitabine on day 1, 8 and 75 mg/m2 cisplatin on day 1 repeated every three weeks) or gemcitabine and carboplatin (1000 mg/m2 gemcitabine on day 1, 8 and 5 auc carboplatin on day 1 repeated every three weeks). incomplete response to concurrent or sequential chemo-radiotherapy in the follow up was referred for radical cystectomy. data was analyzed by spss 22 software. descriptive statistics presented the baseline characteristics in the sequential and concurrent groups. categorical variables were evaluated via chi-square tests and continuous variables by anova. the 2-year, 3-year and 5-year overall survival and disease-free survival rates were estimated using the kaplan-meier method. log-rank test was used to compare survival outcomes according to various factors. to define independent prognostic factors cox regression analysis was used. significance level for all tests was set at p-value< 0.05. results: in the present study, 275 patients were enrolled. 9 of them were excluded because of incomplete recordings. the mean follow-up time was 28 months (range: 1-890 months, sd: 61.7). the patient’s characteristics and treatment details have been shown in table 1. median age in all the patients was 66.4±10.58 years and there was no significant difference between the age of concomitant (65.18 years) and sequential (67.18 years) group, (p-value: 0.216). there was no significant difference in the t-stage between the treatment groups (p-value: 0.629). hematologic toxicities was seen in 42.9% of the concurrent group (grade i, ii: 40.18%(n=43), grade iii, iv: 2.8%(n=3)) and 20.7% of the sequential group (grade i, ii: 20.1%(n=32), grade iii, iv: 0.6%(n=1)) . gastro-intestinal toxicities was seen in 22.42% of the concurrent group (grade i, ii: 21.49%(n=23), grade iii, iv: 0.9%(n=1)) and 15.7% of the sequential group (grade i, ii: 15.7%(n=25), grade iii, iv: 0%(n=0)) . median survival time was 56±17.68 (ci: 21.34-90.65) months. the 2year, 3year and 5year overall survival rates for all the patients were estimated to be 76%, 64% and 48%, respectively (figure 1). the survival curves according to t stage, treatment type and tur type has been shown in figure 2. log-rank test showed no significant difference in survival rates according to t-stage (p=0.5), treatment modality (p=0.09) and tur type (p=0.46). however, multivariate analysis showed that t stage had a statically significant relation with survival (p=0.01). treatment modality (p=0.054) and tur type (p=0.7) had no significant correlation. median survival time according t stage for t2, t3 and t4 was 61.22, 41.91 and 17.6 months respectively (p-valve: 0.463). two-year overall survival was 77% in t2, 77% in t3 and 36% in t4. five-year overall survival was 50% in t2 and 49% in t3, (figure 2). median survival time was 65 months in concurrent crt group and 54.47 months in sequential group (p-valve: 0.93). two-year overall survival was 80% in concurrent group and 74% in sequential group. five-year overall survival was 57% in concurrent group and 43% in sequential group (figure 2). median survival time was 56.49 month in optimal and 61.31% in suboptimal cases (p-valve: 0.463) (figure 2). two-year overall survival was 77% and 74% in optimal and suboptimal turb cases, respectively. five-year overall survival was 48% and 56% in optimal and suboptimal turb cases, respectively. recurrence was experienced in 71 cases of all the patients within 5 years that 41 of them had received concurrent and 30 of them received sequential treatment. from 71 recurrences, 13 had metastasis, 26 were muscle invasive and 32 were non-muscle invasive. mibc and nmibc were treated by chemotherapy, turb, intravesical ctx or intravesical bcg. no salvage cystectomy was done possibly because of comorbidities. median disease-free survival was 15 (10.01-19.98, sd: 2.5) months in all the patients, 26 (10-91.9, sd: 8.1) months in the concurrent group and 12(8.2-15.7, sd: 1.9) in the sequential group. the 2year, 3year and 5year disease free survival rates for the concurrent group were 50%, 42% and 27% and was 37%, 33% and 20% for the sequential group respectively. disease free survival was more in the concurrent group in the logrank test (p-value: 0.024). on the cox regression analysis treatment modality was the only variable that had significant relation with disease free survival (p-value: 0.04). other variables did not have a significant relationship, t-stage (p-value: 0.9), tur type (p-value: 0.2), gender (p-value: 0.9) and age (p-value: 0.1). recurrence rate was significantly lower in the sequential group (p-value<0.0001), (figure 6). median time to recurrence was 29.04±34.26 months, 34.16±42.26 months in concurrent group and 25±26.31 months in sequential group and there was no significant difference in the time to recurrence in concurrent and sequential group (pvalue=0.299). there was no difference in recurrence time according the gender (p-value=0.51). table1. patient characteristics & treatment information characteristics results age: mean (range, sd) 66.4 (31-90,10.58) gender: number (%) male female 221(83.1) 45(16.9) t stage: number (%) t2 t3 t4 234(88) 27(10.2) 5(1.9 treatment modality concomitant sequential 107(40.2) 159(59.8) tur type optimal suboptimal 250(94) 16(6) figure1. overall survival (a) & recurrence free survival (b) curves for all the patients (a) (b) figure2. overall survival curves according to t stage (a), treatment type (b) & tur type(c) discussion: to our best knowledge, this is one of the largest retrospective studies reporting outcomes of bladder-sparing concurrent and sequential chemotherapy/radiotherapy in mibc patients. radical cystectomy after neo-adjuvant cisplatin-based combination chemotherapy is the gold standard of treatment for muscle invasive bladder cancer and concurrent chemo-radiotherapy following maximal transurethral resection of the bladder tumor named tri-modal therapy is considered as an alternative curative treatment. sequential versus concurrent chemo-radiation in a tri-modality manner: chemotherapy is an important part of tri-modality therapy, as the randomized bc2001 trial showed that chemo-radiation provides superior loco-regional disease free survival compared to radiation alone.(5) chemotherapy can potentially improve loco-regional control, as up to 50% of patients with mibc may have occult metastasis. omitting the chemotherapy from chemoradiation therapy in fragile patients will compromise the oncologic outcomes (11). in the circumstances that the patient cannot receive sufficient concurrent chemotherapy because of comorbidity or poor medical condition, the patient will be deprived of these clinical benefits, and we aimed to assess the feasibility and results of the sequential use of chemotherapy and radiotherapy (to reduce the toxicity and treatment interruptions) as compared to the concurrent use. in terms of median survival, the present study showed comparable results between concurrent crt and sequential crt. median survival time was 65 months and five-year overall survival was 57% in concurrent group, which is comparable to the literature that shows localized muscle invasive bladder cancer (mibc, stage ≥t2) has a 5-year overall survival of 40–60% with concurrent chemo-radiation(12,13). two-year survival was 74% and five-year survival was 43% in the sequential group. there are just few articles that report the results of sequential use of chemotherapy and radiotherapy, in which the estimated 5 year overall survival is to be 52% (10), but comparing our results for sequential chemo-radiotherapy with the data for definitive radiotherapy in the literature shows superiority of sequential therapy in terms of overall survival and local control (27.6% five year survival and 67% two year local control for radiotherapy alone)(9-14). (c) median disease-free survival was 15±2.54 months in our study. the 3year and 5year disease free survival rates for the concurrent group were estimated to be 50% and 42% respectively, which are comparable and even better that the reported disease free survival (dfs) for trimodality therapy in some other studies, in which 3 year and 5 year dfs has been 44% and 29.1% respectively (15) . disease free survival was more in the concurrent group. recurrence rate was significantly lower in the sequential group in our study that might be due to lower interruptions during the treatment. sequential chemo-radiation versus less than tri-modality therapy: for patients with mibc who are ineligible radical cystectomy or tri-modality therapy, radical turbt alone, partial cystectomy with or without lymphadenectomy, chemotherapy alone or maximum turbt + radiotherapy alone can be potential alternatives (15). evidence has shown that such palliative treatments showed inferior os than tri-modality therapy. therefore, aggressive treatment should be provided as much as possible (16,17). however recently some studies have investigated the role of radiotherapy alone in the patients who are not suitable for chemotherapy and have reported that ebrt without chemotherapy could still be a feasible alternative treatment to maintain quality of life and achieve acceptable local control rates, but still lower than combined modality treatments(14, 18-21). also, accelerated hypo-fractionated radiotherapy alone has shown good local control in elderly patients unfit for chemo-radiotherapy (22,23). on the other hand neo-adjuvant chemotherapy was shown to lead to down-staging in some patients, in a way that 30% to 40% of patients having no residual disease at time of radical cystectomy which shows the inevitable and significant role of chemotherapy alone (24). the addition of neo-adjuvant chemotherapy to definitive radiation-alone provides a 6% overall survival benefit (10) , even in the elderly patients (11). a study on 976 bladder cancer patients showed that three cycles of cmv (cisplatin, methotrexate, vinblastine) chemotherapy before radiotherapy or cystectomy results in a 16% reduction in the risk of death, corresponding to an increase in 3-year survival from 50% to 56%, 10-year survival from 30% to 36%, and median survival time of 7 months (from 37 to 44 months). the reductions in the risk of death with cmv were 20% for the radiotherapy alone groups, and for loco-regional disease-free survival, chemotherapy given before radiotherapy caused a 9% reduction in risk (10). although, this study shows a significant effect of chemotherapy before local therapy but the results could not be compared to ours because of the inclusion of radical cystectomy in the local therapy group in the final analysis. in a cohort of 63 patients who refused rc after complete response following neoadjuvant chemotherapy. the 5-year os was 64%; however, the relapse rate was relatively high at 64%, with 38% (24 patients) of recurrence being muscle-invasive. the median time to recurrence was 16 months, which is much shorter than the results of our study for median time to recurrence in the sequential group that was 29 months which shows the inadequacy of single modality treatment even in the presence of pathologic complete response (25). external beam radiotherapy (ebrt) has been shown to lead to complete regression of mibc in up to 70% of patients, however, more than 50% of individuals will develop metastatic disease and 5-year os is only 20–30% which is significantly lower than 5 year survival in the sequential group of our study that was 43%(26). comparing recurrence in concurrent and sequential chemotherapy radiotherapy groups, our data showed equal time to recurrence but lower recurrence rate in the sequential group which might be due to more comorbidity in the sequential group and lack of adequate referral for follow-up. on the uni-variant analysis, there was no significant difference in the survival according t-stage but in the multi-variant analysis t-stage was a predictive factor for survival that could be due to small number of cases in the t4 group. by considering the significant but inadequate response to chemotherapy alone or radiotherapy alone after turbt, it seems that combining these modalities in a sequential order would be a reasonable offer for the fragile patients, a hypothesis which is powered by the results of the present study that shows comparable outcomes between sequential and concurrent use of chemotherapy and radiotherapy. conclusion: the results of our study showed that sequential use of chemotherapy and radiotherapy provides comparable results to concurrent use of them and provides better results than less than trimodality treatments. these results are important because they fill an existing gap in the literature regarding whether the sequential use of chemotherapy and radiotherapy can be a suitable substitute to concurrent chemo-radiation in special circumstances that the concurrent use is not possible. limitations: there are several limitations to our study. first, frail patients were often only seen in case of complaints and did not always undergo follow-up cystoscopy. this may have impacted the reported local control rates in this group. second, by considering the retrospective design of the study, the cases could not be wellmatched and there was no randomization between the groups, so the sequential group probably had more medical complications and had been more frail. references: 1. sung h, ferlay j, siegel rl, laversanne m, soerjomataram i, jemal a, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021;71:209-49. 2. siegel rl, miller kd, fuchs he, jemal a. cancer statistics, 2022. ca cancer j clin. 2022;72:7-33. 3. lobo n, mount c, omar k, nair r, thurairaja r, khan ms. landmarks in the treatment of muscle-invasive bladder cancer. nature reviews urology. 2017;14:565-74. 4. www.nccn.org 5. james nd, hussain sa, hall e, jenkins p, tremlett j, rawlings c, et al. radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. new england journal of medicine. 2012;366:1477-88. 6. kimura t, ishikawa h, kojima t, kandori s, kawahara t, sekino y, et al. bladder preservation therapy for muscle invasive bladder cancer: the past, present and future. japanese journal of clinical oncology. 2020;50:1097-107. 7. verschoor n, heemsbergen wd, boormans jl, franckena m. bladder-sparing (chemo) radiotherapy in elderly patients with muscle-invasive bladder cancer: a retrospective cohort study. acta oncologica. 2022;61:1019-25. 8. www.uptodate.com 9. izumi k, iwamoto h, yaegashi h, shigehara k, nohara t, kadono y, et al. gemcitabine plus cisplatin split versus gemcitabine plus carboplatin for advanced urothelial cancer with cisplatin-unfit renal function. in vivo. 2019;33:167-72. 10. international collaboration of t, medical research council advanced bladder cancer working p, european organisation for r, treatment of cancer genito-urinary tract cancer g, australian bladder cancer study g, national cancer institute of canada clinical trials g, et al. international phase iii trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the ba06 30894 trial. j clin oncol. 2011;29:2171-7. 11. korpics mc, block am, martin b, hentz c, gaynor er, henry e, et al. concurrent chemotherapy is associated with improved survival in elderly patients with bladder cancer undergoing radiotherapy. cancer. 2017;123(18):3524-31. 12. jiang dm, chung p, kulkarni gs, sridhar ss. trimodality therapy for muscle-invasive bladder cancer: recent advances and unanswered questions. curr oncol rep. 2020;22:14. 13. mottet n, ribal mj, boyle h, de santis m, caillet p, choudhury a, et al. management of bladder cancer in older patients: position paper of a siog task force. journal of geriatric oncology. 2020;11:1043-53. 14. verschoor n, heemsbergen wd, boormans jl, franckena m. bladder-sparing (chemo)radiotherapy in elderly patients with muscle-invasive bladder cancer: a retrospective cohort study. acta oncol. 2022;61:1019-25. 15. huang s, tseng w-h, liu c-l, kuo j-r, hun s-h, chen c-h, et al. comparison of trimodal therapy versus radical cystectomy for each stage of muscle-invasive bladder cancer. urological science. 2021;32. 16. tholomier c, souhami l, kassouf w. bladder-sparing protocols in the treatment of muscle-invasive bladder cancer. translational andrology and urology. 2020;9:2920. 17. nishihara k, ueda k, kurose h, ogasawara n, hiroshige t, chikui k, et al. survival outcomes of non-definitive therapy for muscle-invasive bladder cancer. oncol lett. 2022;23:126. 18. majewski w, nieckula j, dworzecki t, miszczyk l. bladder-conserving approach in radical treatment of patients with bladder cancer–a single-institution experience. anticancer research. 2020;40:5861-8. 19. mottet n, ribal mj, boyle h, de santis m, caillet p, choudhury a, et al. management of bladder cancer in older patients: position paper of a siog task force. journal of geriatric oncology. 2020;11:1043-53. 20. d’andrea d, soria f, zehetmayer s, stangl-kremser j, grubmüller b, abufaraj m, et al. comparative effectiveness of radical cystectomy and radiotherapy without chemotherapy in frail patients with bladder cancer. scandinavian journal of urology. 2020;54:52-7. 21. gergelis kr, kreofsky cr, choo cs, viehman j, harmsen ws, lester sc, et al. outcomes and profiles of older patients receiving definitive radiation therapy for muscleinvasive bladder cancer at a tertiary medical center. practical radiation oncology. 2020;10:e378-e87. 22. hammer l, laufer m, dotan z, leibowitz-amit r, berger r, felder s, et al. accelerated hypofractionated radiation therapy for elderly frail bladder cancer patients unfit for surgery or chemotherapy. american journal of clinical oncology. 2019;42:179-83. 23. symon n, mattout j, lewin r, hammer l, laufer m, berger r, et al. is ultra hypofractionated radiation therapy a safe and effective treatment for invasive bladder cancer in the elderly?: a retrospective single institution review. american journal of clinical oncology. 2021;44:369-73. 24. lavery hj, stensland kd, niegisch g, albers p, droller mj. pathological t0 following radical cystectomy with or without neoadjuvant chemotherapy: a useful surrogate. the journal of urology. 2014;191:898-906. 25. robins d, matulay j, lipsky m, meyer a, ghandour r, decastro g, et al. outcomes following clinical complete response to neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder in patients refusing radical cystectomy. urology. 2018;111:116-21. 26. milosevic m, gospodarowicz m, zietman a, abbas f, haustermans k, moonen l, et al. radiotherapy for bladder cancer. urology. 2007;69:80-92. kidney transplantation 260 urology journal vol 6 no 4 autumn 2009 kidney transplant anastomosis internal or external iliac artery? wagner e matheus, leonardo oliveira reis, ubirajara ferreira, marilda mazzali, fernandes denardi, victor a leitao, renato n pedro, nelson r netto jr introduction: we compared the best technique for arterial anastomosis in kidney transplantation, end-to-side anastomosis to the external iliac artery or end-to-end anastomosis to the internal iliac artery. materials and methods: a total of 38 patients with end-stage renal disease who received a kidney transplant from a deceased donor were randomized into two groups in order to undergo either end-to-end anastomosis to the internal iliac artery or end-to-side anastomosis to the external iliac artery. length of arterial anastomosis, cold ischemia time, hospital stay, serum creatinine level, recovery of urinary output, and surgical and clinical complications during hospitalization were evaluated. after 3 years, in the patients with a functioning allograft, creatinine clearance measure, doppler ultrasonographic study, survival, graft loss, and erectile function were compared between the two groups. results: postoperative analyses showed similar recovery of urinary output (p = .39) and creatinine (p = .95) between the two groups. no differences in clinical (p = .55) and surgical (p = .80) complications or in hospital stay (p = .90) were noted. the 3-year follow-up demonstrated no differences in doppler ultrasonography results, creatinine clearance (p = .80), patient survival (p = .22), and graft loss (p = .72). erectile dysfunction was similar, being related only to pre-operative medical history and age. conclusion: both techniques showed similar results in shortand long-term follow-ups. larger prospective studies are warranted to clarify the risk of renal artery stenosis and development of erectile dysfunction. urol j. 2009;6:260-6. www.uj.unrc.ir keywords: kidney transplantation, surgical anastomosis, renal artery, survival, erectile dysfunction division of urology, state university of campinas, são paulo, brazil corresponding author: leonardo oliveira reis, md rua votorantim, 51, ap 43 – vila nova, campinas, sao paulo, brazil – 13073-090 tel: + 55 19 3521 7481 e-mail: reisleo@unicamp.br received july 2008 accepted july 2009 introduction results of kidney transplantation have dramatically improved during the past 3 decades due to refinements in surgical instruments, new immunosuppressive regimens, improved kidney preservation, and advances in antimicrobial therapy. (1-4) however, the principles of the vascular anastomosis technique proposed by carrel in 1902 and the accomplishment of the implantation in the iliac vessels by kuss in 1951 are still in use.(5-7) there are scarce data comparing vascular anastomosis techniques, and while there is no difference in the incidence of transplant renal artery stenosis following end-to-end (hypogastric artery) or end-to-side (common or external iliac artery) arterial anastomosis, most of data come from retrospective studies.(8) although some doubts persist about what the best technique for kidney transplant anastomosis techniques—matheus et al urology journal vol 6 no 4 autumn 2009 261 arterial anastomosis is, end-to-side anastomosis to the external iliac artery is the preferred technique in deceased donors, because of the large carrel patch obtained from the aorta.(9) on the other hand, in the absence of this advantage, when a kidney from a living donor is transplanted, the usual option is the end-to-end anastomosis to the internal iliac artery (hypogastric) at many centers. (9) however, no well-designed prospective studies comparing the results of these two techniques are available with long-term follow-up. the purpose of this prospective study was to compare long-term outcomes of kidney transplants using two different techniques of arterial anastomosis to the internal or the external iliac artery. materials and methods patients from may 2000 to february 2001, a total of 62 patients with end-stage renal disease received a kidney from a deceased donor, of whom 38 fulfilled the inclusion criteria and were divided into 2 groups; group 1 received end-to-end anastomosis to the internal iliac artery and group 2 underwent end-to-side anastomosis to the external iliac artery. the study protocol was approved by the research ethics board and all of the patients consented to participate in the study. patients who received a primary kidney transplant and were older than 18 years of age at surgery were included. the exclusion criteria for donors were sepsis or cancer as death causes, as well as positive serology for human immunodeficiency virus and hepatitis b or c viruses. the exclusion criteria were atherosclerotic plaques in the iliac vessels, kidneys with multiple arteries, internal or external iliac artery stenosis, pancreas/kidney transplantation, diabetes mellitus, uncontrolled hypertension, and taking phosphodiesterase 5 inhibitors. all the surgical procedures were performed by the same surgeon and by unilateral retroperitoneal approach to the iliac vessels. anastomosis was performed using 5-0 prolene running stitches in the end-to-side fashion and separated stitches in the end-to-end fashion. the patients were previously evaluated through anamnesis, physical examination, and pelvic computed tomography. centralized computed generated randomization was utilized to define anastomosis technique in each pair of the kidneys from the same deceased donor to distribute equally the same donor between groups. erectile dysfunction (ed) was evaluated before and 3 years after the transplantation. all of the patients were asked to fill out the previously validated self-administered abridged 5-item version of the international index of erectile function questionnaire (iief-5), also described as sexual health inventory for men, items 2, 4, 5, 7, and 15 from the full-scale iief.(10) the maximal score is 25; lower domain scores indicate impaired sexual function. the respondents were asked to report their experience over the past 60 days. the abbreviated score was used for its simplicity and immediacy.(11) evaluation of engraftment duration of arterial anastomosis, cold ischemia time, hospital stay, serum creatinine levels, recovery of urinary output, and surgical and clinical complications during postoperative period of hospitalization were evaluated. after discharge, the patients were evaluated every month until clinical and laboratory stabilization. afterwards, the patients were followed every 2 to 3 months, depending on graft function and clinical outcome. during 3 years of follow-up, patients with a functioning graft were compared using biannual creatinine clearance (cockroft-gault) and clinical complications. all these patients underwent doppler ultrasonography with measurement of peak systolic velocity and resistive indexes in the main and segmental arteries, in order to exclude renal artery stenosis.(12) statistical analyses statistical evaluation between the 2 groups was performed using the mann-whitney test (for numerical variables without normal distribution) and the chi-square test (for categorical measures). comparison of data variations between the groups over time was performed by the analysis of variance test. the wilcoxon test was performed kidney transplant anastomosis techniques—matheus et al 262 urology journal vol 6 no 4 autumn 2009 to compare survival between the two groups. in all statistical analyses, the level of significance adopted was 5% (p < .05). results the mean age of the kidney transplant recipients was 46.5 ± 2.3 years and 51.9 ± 1.5 years in groups 1 and 2, respectively (p = .05). regarding gender, the two groups were similar (7 women and 12 men in group 1 versus 8 women and 11 men in group 2, p = .74). the groups were also comparable in arterial anastomosis duration, cold ischemia interval, hospital stay, and follow-up (table 1). no statistical difference between the curves of urinary flow recovery (p = .39), and decrease in serum creatinine level (p = .95) were encountered (figures 1 and 2). surgical and clinical complications related to kidney transplantation occurred in both groups with a comparable overall incidence (p = .80 and p = .55, respectively). surgical complications occurred in 4 patients (21.0%) in each group and clinical complications occurred in 4 patients in group 1 (21.0%) and 5 in group 2 (26.3%). arterial thrombosis developed in 2 patients in group 1 (internal iliac artery anastomosis) and 1 in group 2 (external iliac artery anastomosis; table 2). in the functioning grafts, renal flow measured by doppler ultrasonography was also comparable between the two groups. the transplanted kidneys were evaluated for peak systolic velocity and resistive indexes in the main renal artery and the upper, middle, and lower segmental branches. no differences between groups were encountered when data was corrected by age (table 3). during the 3-year follow-up, there were 6 deaths kidney transplant recipients variable end-to-end anastomosis to internal iliac artery end-to-side anastomosis to external iliac artery p number of patients 19 19 age, y 46.5 ± 2.3 51.9 ± 1.5 .05 arterial anastomosis time, min 21.6 ± 5.5 25.6 ± 6.8 .07 venous anastomosis time, min 11.5 ± 2.2 11.4 ± 3.1 .89 cold ischemia time, min 1085 ± 246 1034 ± 206 .62 hospital stay, d 24.0 ± 14.0 23.5 ± 13.1 .90 follow-up, mo 25.4 ± 14.1 21.4 ± 15.4 .44 table 1. data on demographic criteria, vascular anastomosis, and hospitalization in two groups of kidney transplant recipients with different anastomosis techniques* *data are presented as mean ± standard deviation. figure 1. recovery of urinary volume over time in the short-term follow-up of kidney recipients with end-to-end anastomosis to the internal iliac artery (group 1) and end-to-side anastomosis to the external iliac artery (group 2; p = .39). figure 2. decrease of serum creatinine level over time in the short-period analysis of kidney recipients with end-to-end anastomosis to the internal iliac artery (group 1) and end-to-side anastomosis to the external iliac artery (group 2; p = .95). kidney transplant anastomosis techniques—matheus et al urology journal vol 6 no 4 autumn 2009 263 (15.8%): 3 in group 1 (1 due to sepsis and 2 secondary to cardiologic complications) and 3 in group 2 (2 due to acute myocardial infarction and 1 due to secondary to peritonitis). five graft losses (13%) including 3 in group 1 and 2 in group 2 were seen. in group 1, there were 2 patients who lost their kidneys shortly after the surgery due to arterial thrombosis (on the 1st and the 4th days after transplantation) and 1 due to chronic rejection, after 1 year. one patient in group 2 lost his kidney on the 1st day after transplantation due to arterial thrombosis and the other due to chronic rejection, after 2 years. in these patients, only 1 from group 1 was re-transplanted. after 3 years of follow-up, 13 and 14 patients in groups 1 and 2 remained with a functioning allograft. analysis of kidney function by means of biannual creatinine clearance measurement showed no differences with repeated measures corrected by age (p = .80; figure 3). the 3-year graft and patient survival rates were 68.4% and 84.2 % in group 1 and 73.7% and 84.2 % in group 2, respectively (p = .22 and p = .72, respectively). kidney transplant recipients ultrasonography parameter end-to-end anastomosis to internal iliac artery end-to-side anastomosis to external iliac artery p ps of renal artery 137.8 ± 57.5 106.6 ± 48.1 .21 ri of main renal artery 0.72 ± 0.07 0.76 ± 0.11 .38 ri of upper sb 0.66 ± 0.08 0.66 ± 0.09 .99 ri of middle sb 0.68 ± 0.08 0.69 ± 0.10 .72 ri of lower sb 0.67 ± 0.06 0.70 ± 0.13 .47 table 3. comparison of doppler ultrasonography results in two groups of kidney transplant recipients with different anastomosis techniques* *data are presented as mean ± standard deviation. ps indicates peak systolic velocity; ri, resistive indexes; and sb, segmental branches. kidney transplant recipients complications end-to-end anastomosis to internal iliac artery end-to-side anastomosis to external iliac artery surgical arterial thrombosis† 2 (10.5) 1 (5.3) urine leak 1 (5.3) 0 lymphocele 1 (5.3) 0 bleeding 0 1 (5.3) wound infection 0 1 (5.3) peritonitis‡ 0 1 (5.3) clinical rejection† 1 (5.3) 1 (5.3) sepsis‡ 1 (5.3) 0 cariac disease‡ 2 (10.5) 2 (10.5) benign prostatic hyperplasia 0 1 (5.3) genital herpes 0 1 (5.3) table 2. surgical and clinical complications following kidney transplantation in two groups with different anastomosis techniques* *numbers in parentheses are percents. †these complications resulted in 5 graft losses. ‡these complications resulted in 6 deaths. figure 3. evolution of creatinine clearance every 6 months in kidney recipients with end-to-end anastomosis to the internal iliac artery (group 1) and end-to-side anastomosis to the external iliac artery (group 2; p = .80). kidney transplant anastomosis techniques—matheus et al 264 urology journal vol 6 no 4 autumn 2009 among patients who were followed for 3 years, 13 were men (8 in group 1 and 5 in group 2). erectile dysfunction (ed) persisted after transplantation in all of the 7 patients who had pre-operative complaints (2 in group 1 and 5 in group 2). only 1 patient (group 1) of 6 with previous normal erectile function initiated ed after transplantation. all patients older than 52 years had ed and all those younger than 52 years of age did not have ed, except for 1 patient in group 1 with de novo ed that was 50 years old. discussion since the first surgical reports of kidney transplantation procedures from carrel in the beginning of the 20th century and küss in the 1950s, few modifications in surgical technique have been described.(6,7,13) while great advances have achieved in immunosuppressive drug regimens, transplant immunology, infection prophylaxis, and development of better surgical instruments, the best arterial anastomosis technique remains controversial. the classical kidney transplantation surgery was described using end-to-side anastomosis to the external iliac vein and end-to-end anastomosis to the internal iliac artery. this technique is performed in many transplant centers until today.(14) however, some authors described the possibility of the occurrence of ed and renal artery stenosis with this type of anastomosis.(15,16) arterial stenosis is a challenging issue, with a high incidence of complications during arterial stenosis correction, either by surgery or by stent insertion using percutaneous methods, due to the angle of the arterial anastomosis point.(8) these authors suggested that arterial anastomosis to the external iliac artery could reduce the incidence of ed, mainly in cases of a second transplant, in which the first kidney graft had been anastomosed to the contralateral internal iliac artery.(13-17) nevertheless, the defenders of end-to-end internal iliac artery anastomosis worry about external iliac artery anastomosis complications, such as early obstruction, late stenosis, and the steal phenomenon, which could cause ischemia of the transplanted kidney during ambulation or intense physical effort, which are not frequent. (18-20) in our study of end-to-end anastomosis to the internal iliac artery and end-to-side anastomosis to the external iliac artery, the two groups were comparable regarding age, sex, arterial anastomosis duration, cold ischemia time, hospital stay, and follow-up. in order to reduce possible differences between groups, we equalized some factors, such as donor characteristics (same donor source for both groups), cold ischemia time (reversed randomization for sequential deceased donors), immunosuppressive regimen (calcineurin inhibitor and purine synthesis inhibitor in all recipients), and the same surgeon utilizing a similar surgery technique in all transplants. in early postoperative period, both groups showed similarities in the recovery of kidney function measured by reduction of serum creatinine levels and recovery of urinary output. these parameters are frequently used to evaluate grafts function during the postoperative period of hospitalization.(21) we detected no significant differences in clinical and surgical complications or hospital stay. some authors declared that the most common cause of death following kidney transplantation has been heart disease, and the most common cause of transplant failure has been rejection.(4) in our patients, we found heart disease as the most common cause of death. the 3-year follow-up revealed comparable kidney function between the groups and doppler ultrasonography also demonstrated similar results and confirmed appropriate renal flow in both groups. furthermore, patient and graft survival rates were comparable. the 3-year patient survival rate in this study was 84.2% and graft survival rate was 71%, comparable with the review by barry and colleagues; 82% and 63%, respectively.(4) after 3 years of follow-up, there were no cases of renal artery stenosis, suspected or diagnosed. the frequency of this complication after kidney transplantation surgery is less than 2%.(19,22) in the present study, an appropriate evaluation of ed was not possible due to the small number of patients in the 3-year follow-up (13 men). however, ed was more related to age and ed prior to surgery than to the kind of arterial kidney transplant anastomosis techniques—matheus et al urology journal vol 6 no 4 autumn 2009 265 anastomosis technique. in this regard, current literature is controversial. kidney transplantation has varying effects on erectile function, and in the majority of cases, it has no negative impact on the quality of erection. in the absence of associated vascular risk factors, unilateral interruption of the internal iliac artery decreases arterial penile blood flow, but not to a degree that compromise erectile function.(23) by the other side, peng and coworkers recently described that 16 patients who received end-to-side revascularization to the external iliac artery experienced better erectile function recovery than 39 patients who underwent end-to-end revascularization to the internal iliac artery.(24) due to similar postoperative results in both arterial anastomosis groups in our study, the choice of anastomosis technique in cadaver grafts still depends on surgical circumstances such as arteriosclerosis involving internal or external iliac arteries, multiple renal arteries, kidney position, and surgery team preferences.(25-27) however, some considerations should be observed; first, living donor transplantation surgery is still performed using internal iliac artery due to the absence of the “carrel patch”; second, men who have already had a kidney transplantation should undergo external iliac anastomosis in order to reduce the risk of erectile dysfunction.(16) conclusion in summary, to our knowledge, this is the first prospective study comparing internal and external iliac artery anastomosis techniques in kidney transplant recipients from the same deceased donor and our data suggests that both technical procedures, end-to-end anastomosis to the internal iliac artery and end-to-side anastomosis to the external iliac artery are safe for recipients of kidneys from deceased donors. they have a similar rate of surgical and clinical complications, as well as comparable kidney function in longterm follow-up. larger prospective studies are warranted to better clarify the risk of renal artery stenosis and development of ed. conflict of interest none declared. references 1. ali-el-dein b, osman y, shokeir aa, shehab el-dein ab, sheashaa h, ghoneim ma. multiple arteries in live donor renal transplantation: surgical aspects and outcomes. j urol. 2003;169:2013-7. 2. schnuelle p, lorenz d, trede m, van der woude fj. impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. j am soc nephrol. 1998;9:2135-41. 3. simmons rg, abress l. quality-of-life issues for end-stage renal disease patients. am j kidney dis. 1990;15:201-8. 4. barry jm. current status of renal transplantation. patient evaluations and outcomes. urol clin north am. 2001;28:677-86. 5. moore fd. transplantation--a perspective. transplant proc. 1980;12:539-50. 6. carrel a, guthrie cc. anastomosis of blood vessels by the patching method and transplantation of the kidney. 1906 [classical article]. yale j biol med. 2001;7:243-7. 7. cinqualbre j, kahan bd. rené küss: fifty years of retroperitoneal placement of renal transplants. transplant proc. 2002;34:3019-25. 8. sutherland rs, spees ek, jones jw, fink dw. renal artery stenosis after renal transplantation: the impact of the hypogastric artery anastomosis. j urol. 1993;149:980-5. 9. ersöz s, anadol e, aydintuğ s, bumin c, erkek b, ateş k. anastomotic artery stenosis in living related kidney transplantation: the impact of anastomotic technique. transplant proc. 1996;28:2331-2. 10. rosen rc, riley a, wagner g, osterloh ih, kirkpatrick j, mishra a. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997;49:822-30. 11. rosen rc, cappelleri jc, smith md, lipsky j, peña bm. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 2000;12:342-3. 12. goel mc, laperna l, whitelaw s, modlin cs, flechner sm, goldfarb da. current management of transplant renal artery stenosis: clinical utility of duplex doppler ultrasonography. urology. 2005;66:59-64. 13. bitker mo, benoit g. surgical aspects of kidney transplantation in france in 1997. eur urol. 1998;34:15. 14. moon i, kim y, park j, kim s, koh y. various vascular procedures in kidney transplantations. transplant proc. 1998;30:3006. 15. abdel-hamid ia, eraky i, fouda ma, mansour oe. role of penile vascular insufficiency in erectile dysfunction in renal transplant recipients. int j impot res. 2002;14:32-7. 16. prieto castro rm, anglada curado fj, regueiro lópez jc, et al.treatment with sildenafil citrate in renal transplant patients with erectile dysfunction. bju int. 2001;88:241-3. kidney transplant anastomosis techniques—matheus et al 266 urology journal vol 6 no 4 autumn 2009 17. moray g, bilgin n, karakayali h, haberal m. comparison of outcome in renal transplant recipients with respect to arterial anastomosis: the internal versus the external iliac artery. transplant proc. 1999;31:2839-40. 18. fanti s, mirelli m, curti t, et al. exercise renal scintigraphy shows renal ischemia in a transplanted kidney. clin nucl med. 2002;27:483-5. 19. humar a, johnson em, payne wd, et al. the acutely ischemic extremity after kidney transplant: an approach to management. surgery. 1998;123:344-50. 20. teh wl, king cm, dacie je. the significance of ipsilateral leg ischaemia after renal transplantation. clin radiol. 1995;50:111-4. 21. davison jm, uldall pr, taylor rm. relation of immediate post-transplant renal function to long-term function in cadaver kidney recipients. transplantation. 1977;23:310-5. 22. lopes ja, de almeida cj, hachul m, srougi m. frequency of stenosis of renal the artery in 676 renal transplantations. rev assoc med bras. 1998;44:210-3. 23. el-bahnasawy ms, el-assmy a, dawood a, et al. effect of the use of internal iliac artery for renal transplantation on penile vascularity and erectile function: a prospective study. j urol. 2004;172:2335-9. 24. peng t, zhang gt, chen m, chen sq, sun zy. [erectile function in male kidney transplant recipients and effects of different methods of renal arterial anastomosis]. zhonghua nan ke xue. 2007;13:396-9. chinese. 25. gałazka z, szmidt j, nazarewski s, et al. kidney transplantation in recipients with atherosclerotic iliac vessels. ann transplant. 1999;4:43-4. 26. makiyama k, tanabe k, ishida h, et al. successful renovascular reconstruction for renal allografts with multiple renal arteries. transplantation. 2003;75:82832. 27. benedetti e, troppmann c, gillingham k, et al. short and long-term outcomes of kidney transplants with multiple renal arteries. ann surg. 1995;221:406-14. v07_no_4.pdf sexual dysfunction and infertility 249urology journal vol 7 no 4 autumn 2010 improvement of urodynamic indices by single dose oral tadalafil in men with supra sacral spinal cord injury karim taie,1 hayat moombeini,2 dinyar khazaeli,2 mohammad salari panah firouzabadi3 purpose: to investigate the changes in urodynamic indices following a single dose of oral tadalafil in patients with supra sacral spinal cord injury (sci). materials and methods: urodynamic study was accomplished on 20 patients with supra sacral sci before and one hour after administration of 20 mg oral tadalafil as a single dose. changes in the bladder capacity and compliance, maximum voiding detrusor pressure, and maximum detrusor filling pressure before and after tadalafil administration were recorded. results: following administration of 20 mg oral tadalafil, there was a significant increase in the bladder compliance (from 12.7 to 18.5 ml/cmh20, p < .001), bladder capacity (from 169.8 to 198.5 ml, p < .001), maximum voiding detrusor pressure (from 64.8 to 48.6 cmh2o, p < .001), and maximum detrusor filling pressure (from 24.3 to 14.0 cmh2o, p < .001). conclusion: single dose of oral tadalafil has significant positive effects on urodynamic indices in patients with supra sacral sci. urol j. 2010;7: -53. www.uj.unrc.ir keywords: urodynamic, spinal cord injury, phosphodiesterase inhibitors, drug therapy 1department of urology, imam jondishapour university of medical 2department of urology, golestan university of medical sciences, 3department of urology, fatemeh corresponding author: department of urology, golestan grand hospital, jondishapour university of medical sciences, tel: +98 611 391 3228 received june 2009 accepted august 2010 introduction spinal cord injury (sci) occurs most often in young population and results in negative psychosocial and physical consequences.(1,2) one of the most bothersome complaints of these patients is chronic and lifelong lower urinary tract symptoms (luts). it has been postulated that overactive bladder maybe the underlying cause for luts in these patients.(3) tadalafil is a potent phosphodiesterase-5 (pde5) inhibitor that has been shown to be effective and safe for treatment of erectile dysfunction.(4) phosphodiesterase-5 inhibitors are the first choice treatment for erectile dysfunction that can also significantly improve luts compared with placebo.(5) therefore, it has been recommended for patients with concomitant erectile dysfunction and luts.(3,6) the probable mechanism by which these drugs decrease luts is that nitric oxide enters the smooth muscles and stimulates guanosine cyclase which converts cyclic guanosine three phosphates to cyclic guanosine mono phosphate. cyclic guanosine mono phosphate decreases intracellular calcium concentration and consequently causes muscle relaxation.(7) it has been shown that receptors for pde5 are also present in the detrusor muscle and with less frequency in the gastrointestinal, pulmonary, and vascular systems.(8) it can be postulated that by tadalafil in sci—taie et al 250 urology journal vol 7 no 4 autumn 2010 inhibiting pde5 in the bladder, we would be able to decrease overactivity of the detrusor muscle and increase the bladder capacity and compliance. it has been shown that 20mg tadalafil per day leads to clinically meaningful and statistically significant efficacy and is well tolerated in men with benign prostatic hyperplasia (bph) and luts. urodynamic study is an extremely important part of the evaluation of patients with sci.(9,10) it is “gold standard” for evaluation of the bladder and sphincter function as well as effectiveness of new drugs.(11) our aim was to evaluate changes in urodynamic indices following administration of a single dose of oral tadalafil. materials and methods this pilot study was carried out on 70 men with documented supra sacral sci who referred to our clinic from february 2007 to february 2008. suffering from endocrinopathies (the thyroid, the pancreas, and the liver diseases) that interfere with the bladder function, renal failure, a history of previous bladder surgery, brain vascular disorders, recurrent urinary tract infection, and usage of drugs that have contraindication for pde5 inhibitors administration were considered as exclusion criteria. thus, 5 patients with diabetes mellitus, 3 with hypothyroidism, 4 with hyperthyroidism, 5 with renal failure, 7 with cardiac failure, 6 with cerebral vascular accident, 8 with previous bladder injury, and 4 patients with recurrent urinary tract infection were excluded from the study. eight patients refused to participate in the study. finally, 20 subjects fulfilled our criteria and were evaluated. at baseline, all of the patients underwent urodynamic study. thereafter, the patients were asked to take 20 mg tadalafil (cialis; lily icos. llc, indianapolis, in, usa) as a single dose. after one hour, another urodynamic test was performed. urodynamic indices before and after administration of tadalafil were compared. normal bladder compliance of 20 ml/cmh2o, normal bladder capacity of 200 ml, maximum detrusor voiding pressure of 50 cmh2o, and maximum detrusor filling pressure of 5 to 10 cmh2o were based on gacci and colleagues’ study.(12) urodynamic studies were performed in urodynamic center of golestan grand hospital. after intramuscular injection of 80 mg of gentamicin as an antimicrobial prophylaxis, the patients were placed in the lithotomy position. first, the bladder was emptied by a 14f urethral catheter; then, a double lumen 9f catheter was inserted in the bladder. abdominal pressure was checked with rectal catheter. selfadhesive skin electrodes were placed to perform electromyography. after calibrating cystometry transducers to zero atmosphere, the bladder was filled with normal saline 10ml/min. the bladder pressure, detrusor pressure, abdominal pressure, filling rate, volume of infused normal saline, and electromyography data were recorded. when the patients were unable to retain the urine, they were asked to void, and voiding phase urodynamic study was done. we used mms (medication measurement system, gladbeck, germany) for urodynamic study. data were analyzed by spss software (statistical package for the social science, version 16.0, spss inc, chicago, illinois, usa) using paired sample t test. results the bladder compliance and capacity before the intervention were 12.7 ml/cmh2o and 169.8 ml which increased to 18.5 ml/cmh2o and 198.5 ml after a single dose of tadalafil, respectively (p < .001 and p < .001). improvement in the bladder capacity with regard to normal bladder capacity in neurogenic bladders (200 ml) was statistically significant (p < .001) (table 1 and figure 1). maximum voiding detrusor pressure was 64.8 cmh2o before the intervention which decreased to 48.6 cmh2o after one dose of oral tadalafil (p < .001). the improvement of maximum voiding detrusor pressure based on normal maximum voiding detrusor pressure (50 cmh2o) was also statistically significant (p < .001) (table 2 and figure 2). maximum detrusor filling pressure before the intervention was 24.3 cmh2o which decreased tadalafil in sci—taie et al 251urology journal vol 7 no 4 autumn 2010 urodynamic indices after 20mg oral tadalafilbaseline urodynamic indices bladder compliance bladder capacity maximum detrusor voiding pressure maximum detrusor filling pressure bladder compliance bladder capacity maximum detrusor voiding pressure maximum detrusor filling pressure 1715047171015065291 171855314814570222 1619048131215566183 2021058161517075214 2321545101617552235 162203817920052306 1818535141116048327 2122556141318070278 2017045161617060199 22175371318145541710 21195331514140492511 17189491710175682612 16200581613165772913 20195481516160663114 17200621311165792115 18210421012170542016 17220451413210632717 16210561810200793218 2121557917185761919 172106089175721820 table 1. urodynamic indices before and after oral 20mg tadalafil outcome before tadalafilmean (± sd) p * † after tadalafil mean (± sd) p * † mean difference (95% confidence interval) p ‡ bladder compliance, ml/ cmh2o 12.7 (± 2.9) <.001 18.5 (± 2.3) .008 5.9 (2.0 to 6.7) <.001 bladder capacity, ml 169.8 (± 19.0) <.001 198.5 (±19.2) .721 28.7 (21.6 to 35.8) <.001 maximum detrusor voiding pressure, cmh2o 64.8 (± 10.3) <.001 48.6 (± 8.7) .482 16.2 (14.5 to 17.8) <.001 maximum detrusor filling pressure, cmh2o 24.3 (± 5.1) <.001 14.0 (± 2.8) <.001 10.4 (8.5 to 12.2) <.001 *compared to normal value. †one sample t test. ‡paired sample t test. table 2. urodynamic indices before and after a single dose of tadalafil in men with spinal cord injury figure 1. bladder compliance before and after a single dose of tadalafil. figure 2. maximum detrusor voiding pressure before and after a single dose of tadalafil. tadalafil in sci—taie et al 252 urology journal vol 7 no 4 autumn 2010 statistically significantly to 14.0 cmh2o after a single dose of oral tadalafil (p < .001). discussion efficacy of pde5 inhibitors in amelioration of luts has gained attention in recent years. the mrna expression of pde5 has been demonstrated in lower urinary tract of rats and the highest expression is in the detrusor muscle followed by the urethra and the prostate. phosphodiesterase-5 inhibitors can produce significant relaxation of the aforementioned tissues.(13) sildenafil can prevent the bladder overactivity secondary to the bladder outlet obstruction in rats by preventing detrusor muscle hypertrophy and collagen deposition, which seems more effective than its effect on relaxation of the bladder outlet.(14) recent published randomized controlled trials of tadalafil versus placebo show significant clinical efficacy of tadalafil for treatment of luts in patients with bph. the ability of tadalafil in treating both erectile dysfunction and bphinduced luts is impressive.(15,16) however, in a recent study from mayo clinic, broderick and colleagues compared the safety and efficacy of tadalafil on bph-induced luts in men with and without erectile dysfunction. they concluded that changes in bph-induced luts after 12 weeks of treatment with placebo or various doses of once daily administered tadalafil were similar in men with and without erectile dysfunction.(17) since receptors of pde5 are expressed in the detrusor muscle and the underlying pathophysiology of luts in supra sacral sci patients is bladder overactivity, the impact of pde5 inhibitors on amelioration of sciinduced luts seems logical. to the best of our knowledge, gacci and associates were the first ones who reported positive effects of vardenafil on improvement of urodynamic parameters in men with sci.(12) based on their randomized, double-blind, placebo controlled trial on 25 patients with supra sacral sci, administration of a single dose of 20 mg vardenafil resulted in a 12% decrease in maximum detrusor pressure, a 17% improvement in maximum cystometric capacity, and a mean 25% increase in detrusor overactivity volume. our results are consistent with gacci and colleagues’ investigation; however, we used single dose of oral tadalafil, as the state-of-the-art pde5 inhibitor, and we found it beneficial in improvement of urodynamic parameters. conclusion we conclude that tadalafil has beneficial effects on improvement of urodynamic parameters in patients with supra sacral sci. however, larger studies with special attentions to clinical outcomes of tadalafil are needed before drawing final conclusion conflict of interst none declared. financial support this study was financially supported by research affair, jondishapour university of medical sciences. references 1. wyndaele m, wyndaele jj. incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? spinal cord. 2006;44:523-9. 2. giuliano f, sanchez-ramos a, lochner-ernst d, et al. efficacy and safety of tadalafil in men with erectile dysfunction following spinal cord injury. arch neurol. 2007;64:1584-92. 3. giuliano f. phosphodiesterase type 5 inhibitors improve male lower urinary tract symptoms. eur urol. 2008;53:1121-3; discussion 3-4. 4. del popolo g, marzi v, mondaini n, lombardi g. time/ duration effectiveness of sildenafil versus tadalafil in the treatment of erectile dysfunction in male spinal cord-injured patients. spinal cord. 2004;42:643-8. 5. palea s, rekik m, rischmann p, botto h, lluel p. tadalafil exerts an additive effect on alfuzosin-induced relaxation in pre-contracted human isolated prostatic adenoma. journal of urology. 2008;179:454. 6. kohler ts, mcvary kt. the relationship between erectile dysfunction and lower urinary tract symptoms and the role of phosphodiesterase type 5 inhibitors. eur urol. 2009;55:38-48. 7. oger s, behr-roussel d, gorny d, lebret t, validire p, giuliano f. sildenafil relaxes human detrusor by cyclic gmp-independent signalling pathways. european urology supplements. 2008;7:263. 8. behr-roussel d, oger s, tinel h, sandner p, giuliano f. 768 pde5 gene expression and relaxant effects of vardenafil in male and female human and rat detrusor tadalafil in sci—taie et al 253urology journal vol 7 no 4 autumn 2010 muscle. european urology-supplements. 2008;7:263. 9. linsenmeyer ta, culkin d. aps recommendations for the urological evaluation of patients with spinal cord injury. j spinal cord med. 1999;22:139-42. 10. butler mr. patterns of bladder recovery in spinal injury evaluated by serial urodynamic observations. urology. 1978;11:308-14. 11. chou fh, ho ch, chir mb, linsenmeyer ta. normal ranges of variability for urodynamic studies of neurogenic bladders in spinal cord injury. j spinal cord med. 2006;29:26-31. 12. gacci m, del popolo g, macchiarella a, et al. vardenafil improves urodynamic parameters in men with spinal cord injury: results from a single dose, pilot study. j urol. 2007;178:2040-3; discussion 4. 13. tinel h, stelte-ludwig b, hutter j, sandner p. preclinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms. bju int. 2006;98: 1259-63. 14. beamon cr, mazar c, salkini mw, phull hs, comiter cv. the effect of sildenafil citrate on bladder outlet obstruction: a mouse model. bju int. 2009;104:252-6. 15. gonzalez rr, kaplan sa. tadalafil for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. expert opin drug metab toxicol. 2006;2:609-17. 16. roehrborn c. lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction, and phosphodiesterase-5 inhibitors. reviews in urology. 2004;6:121. 17. broderick ga, brock gb, roehrborn cg, watts sd, elion-mboussa a, viktrup l. effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. urology. 2010;75:1452-8. case report primary prostate lymphoma managed with combined modality treatment: a case report anya jafari¹*, bahram mofid ¹, ali tabibi ², farid kowsari ³ keywords: prostate lymphoma; r-chop regimen; diffuse large b cell lymphoma 1department of radiation oncology, shohada-e-tajrish hospital, faculty of medicine, shahid beheshti university of medical sciences, tehran, ir iran 2 shahid labbafinejad medical center, urology and nephrology research center, shahid beheshti university of medical sciences (sbmu), tehran, iran. 3department of pathology, tehran university of medical sciences. tehran, iran. *correspondence: department of radiation oncology, shahid beheshti university of medical sciences, tehran, iran. tel.: 00989125491074. fax: 009822719200. e-mail: anyajafari@yahoo.com. received december 2017& accepted june 2018 prostate cancer is one of the most common malignancies in men; the main reported pathology is adenocarcinoma while there are few published cases of prostate lymphoma. there is not enough data regarding the natural history and best management of prostate lymphoma. in this paper, we have described a case of prostate lymphoma that managed with combined modality treatment and have survived for three years. introduction one of the rare pathologic entities in prostate cancers is lymphoma (1). diffuse large b cell lymphoma (dlb-cl) is the most common reported primary lymphoma in prostate (2, 3, 4), with no proved standard management. case report we describe a man at the age of 71, who was complaining of hematuria and dysuria for three months. familial figure1. immunohistochemical staining of the tumor cells showing positive cd20. urology journal/vol 16 no. 4/ july-august 2019/ pp. 412-414. [doi: http://dx.doi.org/10.22037/uj.v0i0.4294] history was unremarkable. in his past medical history, diabetes mellitus was mentioned. he had no fever, night sweet or weight loss (b symptoms). physical examination didn’t reveal any abnormal finding except of diffusely enlarged prostate during digital rectal examination. his serum psa, ldh and esr were 2.1 ng/ml, 263u/l and 24 (mm/hr) respectively. other laboratory tests were normal. thoracic and abdominopelvic ctscan showed a huge mass at the bottom of the bladder and an enlarged prostate with some nonspecific lymph nodes on external iliac veins. with a clinical diagnosis of bladder or prostate malignancies, he underwent cystoscopy, that showed inflamed, obstructive prostatic urethra with active bleeding and normal bladder, some biopsies were taken. microscopic and immunohistochemical (ihc) features confirmed the diagnosis of dlbcl with positive ihc staining for lca, cd20, bcl6 and negative staining for cd3, cd34, cytokeratin and nse (figure 1). pathologic examination of bone marrow specimen was normal. the patient was treated by r-chop chemotherapy regimen at radiation oncology ward. hematuria and dysuria were diminished at the end of second cycle. then, he underwent whole pelvic radiotherapy (50 gy) after eight cycle chemotherapy and was followed up for three years until now. according to a recent thoracic and abdominopelvic imaging that showed only abnormality in prostate (figure 2), biopsy was preformed again, and any local recurrence has been ruled out. discussion dlbcl was the most common type and then small cell lymphocytic lymphoma(2,3). in the study of terris et al., of the 1092 radical prostatectomy specimens, they found 13 cases with hematolymphoid pathologies (1.2%).(4) dlbcl is the most frequent type of prostate lymphomas that have been reported in case reports, until now.(4,5,6,7) the mean age at presentation was in the seventh decade.(2,4) the most reported presentations of prostate lymphoma are frequency, urgency and obstructive symptoms. there are usually no systemic or b symptoms.(2,5,8) there have been only two reported patients with elevated psa that were returned to the normal range after therapy.(9,10) it should be mentioned that lymphoma should be considered as a differential diagnosis of poorly differentiated carcinomas or neoplasms in prostate and ihc would be helpful in these cases. sometimes we can see non hodgkins lymphoma concurrent with adenocarcinoma.(2,11) we have some data about treatment outcomes in reported cases. terris et al. reported more cure rates with aggressive combination chemotherapy followed by radiotherapy to bulky or extra nodal sites.(4) in france, three cases of primary prostate lymphoma underwent doxorubicin-based combination chemotherapy, and they experienced complete response that last over three years.(12) there are at least 25 cases of prostate lymphoma with a complete response after chemotherapy with chop regimen.(8,13, 14) combination of chemotherapy with external-beam radiation provided long term local control on a case reported in 2008. (15) the use of anticd 2 0 antibody has been employed for the treatment of cd 2 0 positive lymphomas and is considered in combination with chop regimen.(8,16,17) in a series of 22 patients who were treated in japan, three of five cases experienced progression after surgery or radiotherapy alone, 11 of 16 cases whom received chemotherapy had a complete response. (18) there isn’t any standard indication for radiotherapy or surgery but radiotherapy has been used in localized cases after chemotherapy.(19) finally, it should always be noticed that prostate lymphoma should be in deferential diagnosis of prostate neoplasms and combination of chemotherapy and radiotherapy after biopsy could provide long-term survival. refrences 1. rakhsha a, kashi as, mofid b, houshyari m. biochemical progression-free survival in localized prostate cancer patients treated with definitive external beam radiotherapy. electron physician. 2015; 7:1330-5. 2. bostwick dg, iczkowski ka, amin mb, discigil g, osborne b. malignant lymphoma involving the prostate: report of 62 cases. cancer. 1998;83:732–8. 3. chu pg, huang q, weiss lm. incidental and concurrent malignant lymphomas discovered at the time of prostatectomy and prostate biopsy: a study of 29 cases. am j surg pathol. 2005;29:693–9. 4. terris mk, hausdorff j, freiha fs. hematolymphoid malignancies diagnosed at the time of radical prostatectomy. j urol. 1997;158:1457-9. 5. petrakis g, koletsa t, karavasilis v, et al. primary prostatic lymphoma with components of both diffuse large b-cell lymphoma (dlbcl) and malt lymphoma. hippokratia. 2012;16:86-9. 6. judith af, robert hy. malignant lymphoma of the genitourinary tract. curr diagn pathol. 1997; 4:145–69. 7. alvarez ca, rodriguez bi, perez la. primary diffuse large b-cell lymphoma of the prostate in a young patient. int braz j urol. 2006; 32:64–5. 8. rao rn, bansal m, raghuvanshi s, ansari ms, neyaz z. diffuse large b-cell nonprostate lymphoma treatment-jafari et al. case report 413 figure 2. recent t-2weighted mri hodgkin lymphoma of the prostate presenting with urinary outlet obstruction: a case report. urol ann. 2015;7:100-3. 9. tomaru u, ishikura h, kon s, kanda m, harada h, yoshiki t. primary lymphoma of the prostate with features of low grade b-cell lymphoma of mucosa associated lymphoid tissue: a rare of urinary obstructions. j urol. 1999;162:496–97. 10. oosterheert jj, budel lm, vos p, wittebol s. high levels of serum prostate-specific antigen due to psa producing follicular nonhodgkin's lymphoma. eur j haematol. 2007; 79:155–8. 11. wang c, jiang p, li j. primary lymphomas of the prostate: two case reports and a review of the literature. contemp oncol (pozn). 2012;16:456-9. 12. sarris a, dimopoulos m, pugh w, cabanillas f. primary lymphoma of the prostate: good outcome with doxorubicin-based combination chemotherapy. j urol. 1995; 153:1852–4. 13. fukutani k, koyama y, fujimori m, ishida t. primary malignant lymphoma of the prostate: report of a case achieving complete response to combination chemotherapy and review of 22 japanese cases. nippon hinyokika gakkai zasshi. 2003; 94:621–5. 14. mounedji-boudiaf l, culine s, et al. primary, highly malignant b-cell lymphoma of the prostate. apropos of a case and review of the literature. bull cancer. 1994;81:334–7. 15. chargari c, gillion n, ghalibafian m, ribrag v, girinsky t, magné n. [a rare case of primitive prostatic large b-cell lymphoma and review of literature]. cancer radiother. 2009;13:69-71. 16. csomor j, kaszás i, kollár b, et al. prolonged survival using anti-cd20 combined chemotherapy in primary prostatic intravascular large b-cell lymphoma. pathol oncol res. 2008;14:281-4. 17. essadi i, ismaili n, tazi e, et al. primary lymphoma of the head and neck: two case reports and review of the literature. cases j. 2008; 1:426. 18. fukutani k, koyama y, fujimori m, ishida t. [primary malignant lymphoma of the prostate: report of a case achieving complete response to combination chemotherapy and review of 22 japanese cases]. nihon hinyokika gakkai zasshi. 2003 sep;94(6):621-5. 19. ghose a, baxter-smith dc, eeles h, udeshi u, priestman tj. lymphoma of the prostate treated with radiotherapy. clin oncol (r coll radiol) 1995; 7:134. prostate lymphoma treatment-jafari et al. vol 16 no 04 july-august 2019 414 development and psychometric properties of the sexual health scale for middle-aged married women (shima): a mixed methods study sedigheh moghasemi1, masoumeh simbar2, fazlollah ahmadi3, ali montazeri4,5, hamid sharif nia6, giti ozgoli2* purpose: this study aimed to develop and psychometrically validate the sexual health scale for middle-aged sexually active women (shima). methods: this study was a sequential exploratory study consisting of two phases. in phase one, we interviewed 19 middle-aged women and reviewed the existing instruments to generate an item pool. then, a panel of experts (n = 16) examined the items. in the second phase, the psychometric properties of the scale were assessed. for content and face validity, a panel of experts (n = 8) and a group of middle-aged women (n = 10) reviewed the items. for construct validity, a cross-sectional study was carried out on a sample of 427 married women. finally, shima’s reliability was assessed. results: in the first phase, the sexual health concept was explored, and a provisional scale including 60 items was generated. next, 21 items were removed based on content and face validity. accordingly, the results obtained from the exploratory factor analysis (efa) indicated acceptable loading for 34 items tapping into six factors that jointly explained 48.67% of the total variance observed. the internal consistency evaluation revealed that cronbach’s alpha and mcdonald’s omega were greater than 0.7, and the average inter-item correlation was greater than 0.4, except for one factor that showed borderline results. test-retest reliability over a 2-weeks interval was 0.90, indicating its high stability. conclusion: the shima is a reliable and valid scale for measuring sexual health in middle-aged married women. it can be used as a sexual health screening scale by healthcare professionals and for research purposes. keywords: surveys and questionnaires; middle aged; sexual health; psychometrics introduction according to the world health organization (who), “sexual health is a state of physical, emotional, mental and social well-being in relation to sexuality” that is important not only during reproductive years but also during lifetime(1). however, sexual health is an issue beyond the absence of disease or dysfunction(2) such that a holistic approach to sexual health is recommended by international societies such as who and the international society for the study of women’s sexual health (isswsh)(3). female sexual problems and dysfunctions are usually due to the interaction of best identified and resolved factors using the biopsychosocial model. female sexual function is influenced by some psychosocial, relational, and contextual factors. therefore, addressing these variables in therapy can help improve sexual functioning 1counseling and reproductive health research centre, school of nursing and midwifery, golestan university of medical sciences, gorgan, iran. 2midwifery and reproductive health research center, department of midwifery and reproductive health, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. 3department of nursing, faculty of medical sciences, tarbiat modares university, tehran, iran. 4health metrics research center, iranian institutes for health sciences research, acecr, tehran, iran. 5faculty of humanity sciences, university of science & culture, tehran, iran. 6psychiatry and behavioral sciences research center, addiction institute, mazandaran university of medical sciences, sari, iran. *correspondence: midwifery and reproductive health research center, department of midwifery and reproductive health, school of nursing and midwifery, shahid beheshti university of medical sciences , tehran, iran. mobile: (98)9123223453 . email: g.ozgoli@gmail.com. received december 2021 & accepted june 2022 in women. ultimately, a comprehensive biopsychosocial assessment and treatment plan will provide women with the most holistic method to ameliorate their sexual health difficulties(3). in this respect, the result of a survey showed that biopsychosocial management of female sexual dysfunction (fsd) was associated with patient-perceived benefits, satisfaction, and value(4). the sexual health of women beyond reproductive years has long been considered taboo. this attitude has resulted in the sexual life of middle-aged women do not receive enough attention and have to conceal their sexual desire(5). the mentioned issues make it difficult for middle-aged women to receive their desired health services, despite their particular sexual health needs. for instance, health workers in sexual health do not have the required competencies to meet the care needs of middle-aged women such that they concentrate on meeting their biomedical urology journal/vol 19 no. 5/ sep[tember-october 2022/ pp. 398-405. [doi:10.22037/uj.v19i.7154] andrology needs(6). hence, this important health component is ignored by middle-aged women and health care providers, and issues such as sexual health are not prioritized in preventive health care(7). by increasing the life expectancy(8), women spend at least a third of their lives in middle age and beyond. therefore, it is necessary to reform the concept of sexual health as a part of public health and women’s health in middle age and beyond. on another side, using questionnaires is one element of the basic structured approach to screen and diagnosing a sexual problem(3). recently, a more holistic approach has been developed to measure sexual health. the female sexual well-being scale (fswb scale) assessing sexual well-being rather than sexual dysfunction in women without medical/ psychosocial conditions is an example(9). collected data from such tools play an essential role in determining individual sexual health, health service planning, and policy-making(10). as sexual health have different meaning based on the socio-cultural context(11), its definition varies in different age groups(7). hence, it is necessary to assess female sexual health based on their understanding of sexual health from a more holistic viewpoint. the present study aimed to investigate the sexual health of iranian married middle-aged women (shima) through the development and psychometric validation of a sexual health scale in sexually functional women in their midlife. materials and methods the present exploratory sequential mixed method study was conducted in gorgan, iran. it is a joint research between shahid beheshti university of medical sciences and golestan university of medical sciences with the ethical codes of ir.sbmu.pharmacy. rec.1399.175 and ir.goums.rec.1397.146, respectively. following the descriptions of the waltz model(12), the present study included two phases: a) scale development and b) psychometric evaluation. a summary of the two phases is presented in fig. 1. phase one: scale development i: qualitative study: using a conceptual framework to systematically guide the measurement process increases the likelihood of identifying and illustrating the concepts and variables universally salient to health care practice(12). thus, the conceptual model of sexual health was explored using qualitative content analysis. to this end, between may and november 2015, 19 middle-aged women aged 40-65 years were interviewed. the main research question was “how do middle-aged women perceive the notion and dimensions of sexual health?” purposive sampling with maximum diversity in terms of age, education, and economic status was performed on women under the coverage of comprehensive health centers affiliated with golestan university of medical sciences (table 1). data were collected through semi-structured in-depth interviews conducted by the main researcher (s. m). women interested in talking about their marital and sexual experiences were invited with the assistance of trusted health professionals to participate in the study. each interview lasted about 60 minutes on average. all interviews were audio-recorded. before each interview, the participants were informed about their rights in the study and signed written consent. the interviews were carried out in a private and calm place. because talking about sexuality in iranian culture is very hard and embarrassing, especially with middle-aged and elderly people, after warm-up, interviews began with the open-end, general, and the well-known question of “please talk about your marital relationship”. then, the interview continued by considering the points mentioned by the interviewee, which were related to their sexuality. the principal questions raised through the interviews included “when do you feel healthy sexually?” and “when have you felt healthy/ unhealthy sexually? explain it”. moreover, we verified the trustworthiness and accuracy of data and promoted the validity of results by rewording or summarizing the participants’ responses. except in one case, one interview session was held for all participants. data collection and data analysis were conducted simultaneously. data were collected until data saturation was achieved. next, data analysis was performed based on the systematic approach proposed by graneheim and lundman(13). ii: then, concept maps and primary items for each theme were provided to generate an item pool. simultaneously, similar tools and related documents were variable n = 19 age (years) 40-49 11 50-59 5 60-65 3 educational level lower than diploma 5 diploma 8 bachelor degree or higher 6 occupation housewife 12 working 7 religion (islam) shia’ 16 sunni 3 menopausal state premenopausal 12 postmenopausal 7 marital status divorced 3 married 16 table 1. demographic characteristics of participants in the qualitative study construct number of the generated items number of the items extracted from the literature review sexual health care 19 1 holistic/multi-dimensional sexual preparation 22 quality of sexual relationship 42 4* partner sexual incompetency 11 compatibility and resolving sexual problems conflicts 22 conservative socio-cultural norms 42 total 159 table 2. the number of items in each construct of sexual health in the item pool of shima andrology 321 the sexual health scale for middle-aged married women (shima)-moghasemi et al. vol 19 no 5 september-october 2022 399 unclassified 238 searched using a literature review via electronic databases in persian (scientific information database (sid), iranmedex) and english (proquest, pubmed, science direct, and scopus) languages. finally, the initial item pool included 158 items generated by the research team and 1 item extracted from the study conducted by lotfi et al.(14). in addition, 4 items were modified according to the fswb scale proposed by rosen(9); see table 2. the provisional 159 items scale was reviewed by an expert panel (n = 16), including scholars in sexual reproductive health, nurses and sex therapists. the output of this revision was the initial item reduction, and as a result, 99 items were removed. the items were removed mostly because of the similarity and repetition of the items. for example, we merged the following three questions “i feel like i am a means to satisfy my husband’s sexual needs”, “i am worth sexually to my husband”, and “i am satisfied as being a woman in sex” into the following question: “i feel valuable during sex with my wife”. phase two: psychometric evaluation i. content validity the content validity of the study scale was performed both qualitatively and quantitatively. eight experts (psychology, sexual and reproductive health, nurse, and community medicine) were invited to evaluate the scale. for qualitative content validity, experts commented on vol 19 no 2 march-april 2022 153 characteristics n = 407 age, years mean (±sd) 46.38 (± 5.46) range 40-63 education, n (%) college 14 (± 3.4) missing 1 (± 0.2) job status, n (%) employee 154 (± 27.8) unemployed 253 (± 62.2) duration of marriage, years mean (sd) 22.6 (±8.6) range 1-47 menstrual status, n (%) premenopause 296 (±72.7) postmenopaus 106 (±26.0) missing 5 (±1.2) table 3. demographic characteristics of participants in the cross-sectional study the sexual health scale for middle-aged married women (shima)-moghasemi et al. table 4. the results obtained from the exploratory factor analysis for the shima andrology 400 items factor loading h2 variance λ q12: my partner can satisfy my sexual expectations. 0.831 0.646 14.08 4.928 q5: in general, i have a good sexual relationship with my partner. 0.820 0.738 q9: after the intercourse is over, my partner kisses or hugs me 0.762 0.513 q6: before having sex, i am mentally ready 0.757 0.647 q11: i can satisfy my partner’s sexual desires. 0.698 0.566 q8: in a sexual relationship, my partner does enough touch and foreplay. 0.680 0.504 q10: my partner and i talk about our sexual desires and reach an agreement. 0.635 0.575 q7: we have sex in a safe and private place. 0.633 0.361 q28: my partner cares about my sexual satisfaction. 0.568 0.605 q29: my partner is satisfied with the quality of our sex. 0.466 0.617 q27: i get relaxed after sex. 0.345 0.582 q20: my partner and i respect each other. 0.960 0.720 12.31 4.311 q19: my partner and i are close to each other. 0.878 0.700 q18: i am satisfied with my marriage. 0.876 0.744 q21: my partner has accepted me and he pays attention to me. 0.831 0.667 q22: i have good memories of sexual relationships with my partner in the past. 0.675 0.545 q23; i feel valued during the sexual relationship with my spouse. 0.600 0.627 q24; i have the willingness to have sex with my partner. 0.588 0.534 q34: i am satisfied with my breasts’ appearance. 0.855 0.670 7.42 2.599 q35: i am satisfied with the appearance and function of my genitals 0.844 0.728 . q31: i am satisfied with my partner’s penis erection (penile stiffness) during the sex. 0.619 0.603 q33: i am satisfied with my face and appearance. 0.589 0.505 q30: i am satisfied with my partner’s ejaculation time (releasing the semen from the penis) 0.504 0.563 during the sex. q25: i am satisfied with the degree of moisture and wetness of my genitalia during the sex. 0.330 0.424 q4: if needed, i would easily ask my sexual questions from experts in counseling and/or 0.935 0.837 6.23 2.185 health centers. q3: if needed, i would go to a counseling or health center to solve my sexual problem. 0.804 0.714 q2: if needed, i have access to counseling and/or health centers to solve my sexual problem. 0.685 0.484 q1: if i have any sexual problem, i will try to solve it. 0.437 0.536 q17: i take the initiative to have sex with my spouse 0.646 0.443 3.15 1.103 q14: i feel very sexual, like when i was younger. 0.594 0.471 q16: i try to have a romantic relationship with my partner. 0.577 0.540 q37: i worry about urinary control (urinary incontinence) during sex. 0.833 0.690 4.766 1.668 q36: i am worried that my partner does not find me sexually attractive. 0.705 0.602 q38: i am worried that having sex too often damages my health. 0.691 0.456 couple sexual interaction factors couple relationship quality satisfaction w ith sex organs’appearance and function a ccess to sexual health services sexual agency sexual concerns h2: item communality, λ: eigenvalue whether appropriate words and structure for each item were used, whether items were placed in a fair domain, and whether appropriate scoring was assigned. eight experts calculated the content validity index (cvi) and content validity ratio (cvr) for content validity analysis. items with cvi > 0.75 were retained. as the number of experts was less than 10, cvi for each item (i-cvi) was calculated by modified kappa (k*). i-cvi > 0.74 and summative cvi (s-cvi) average ≥ 0.9 were considered appropriate(15). ii. face validity face validity was evaluated both qualitatively and quantitatively. first, 10 married middle-aged women stated their viewpoints about the difficulty, relevance, and ambiguity of each item. second, items’ impact score was calculated, and items with an impact score higher than 1.5 were retained. iii. construct validity the construct validity of the scale was determined using factor analysis. since the scale has 39 items, an average of 6 samples per item (360 people) was considered appropriate(18). finally, the sample size was calculated to be 424 people, considering the dropout rate of 15%. the samples were selected through stratified random sampling with appropriate allocation from the electronic files available in the centers for integrated healthcare services of gorgan (nab system). for this purpose, in the order of the list, the eligible individuals were invited to complete the scale. inclusion criteria in this study were marriage, age 40-65 years, fluency in persian, and at least high school education. on the other hand, the exclusion criteria were having diseases such as uncontrolled diabetes or hypertension, psychiatry (e.g., depression and anxiety under treatment) problems, based on self-reporting, incomplete filling of the questionnaire by not answering more than 5% of the questions. data collection tools included: 1) a written consent form, 2) a demographic characteristics form, and 3) the 39-item shima. data was analyzed to estimate scale validity and reliability. the procedure for construct validity analysis is as follows: a. structural validity was evaluated using estimation of maximum likelihood exploratory factor analysis (efa) with promax rotation. items with a factor loading equal to or greater than 0.4 were included in the scale. next, we conducted maximum likelihood cfa to validate the factorial structure extracted from efa. the model fit was assessed through a number of fit indices, such as chi-square (χ2) test, chi-square(χ2) /degree of freedom(df) ratio < 4, goodness-of-fit index (gfi)> .9, factors ave msv cr maxr (h) alpha (95% ci) aic omega couple sexual interaction 0.504 0.676 0.917 0.922 0.918 (0.906 to 0.930) 0.508 0.920 couple relationship quality 0.586 0.527 0.909 0.918 0.910 (0.896 to 0.923) 0.592 0.912 couple sexual function 0.492 0.676 0.853 0.857 0.857 (0.835 to 0.878) 0.510 0.864 access to sexual health services 0.570 0.332 0.840 0.857 0.827 (0.798 to 0.853) 0.540 0.832 sexual agency 0.426 0.537 0.688 0.699 0.690 (0.633 to 0.738) 0.427 0.692 sexual concerns 0.581 0.012 0.804 0.834 0.799 (0.762 to 0.830) 0.571 0.804 table 5. the indices of the convergent, divergent validity, and internal consistency of shima ave: average variance extracted; msv: maximum shared squared variance; cr: composite reliability; maxr (h): maximum reliability, alpha: cronbach’s alpha; aic; average inter-item correlation; omega: mcdonald’s omega coefficient. comparative fit index (cfi)> .9, normed fit index (nfi) > .9, relative fit index (rfi) >.9, incremental fit index (ifi) > .9, and tuckerlewis index (tli) > .9, standardized root mean square residual (srmr) < .09, and root mean square error of approximation (rmsea) < .08(16). b. convergent and divergent validity: the convergent and divergent validity was estimated using fornell and larcker approach (1981) by measuring average variance extracted (ave), maximum shared squared variance (msv), and composite reliability (cr). an ave < 0.5 and cr > ave reflects suitable convergent validity and msv > ave confirms divergent validity. c. reliability: the internal consistency was assessed via calculating cronbach’s alpha, mcdonald’s omega, and average inter-item correlation (aic). cronbach’s alpha and mcdonald’s omega values of more than 0.7 and the minimum aic values of 0.2-0.4 were considered satisfactory. ten middle-aged women completed shima twice for two weeks, and stability was assessed using test-retest analysis (intraclass correlation coefficient-icc)(16). in addition, absolute reliability was examined by the standard error of measurement (sem), which was calculated according to the following formula: sem = sd pooled√(1-icc). results findings from phase one table 1 shows the demographic characteristic of the participants. qualitative data analysis resulted in 1624 condensed codes, 166 codes, 46 sub-categories, 15 categories, and 6 themes. the emerged themes were ‘quality of sexual relationship’, ‘sexual health care’, ‘holistic/multi-dimensional sexual preparation’, ‘partner sexual incompetency’, ‘conservative socio-cultural norms’, and ‘compatibility and resolving sexual problems conflicts’. finally, based on the themes extracted from the experiences of middle-aged women participating in the present study, the conceptual framework of middle-aged women’s sexual health was extracted as follows: “sexual health is a dynamic and multi-dimensional concept perceived through general health, sexual rights, and a satisfactory sexual response. the realization of this concept is affected by how to take care of sexual health, the cohabitation context, the sexual satisfaction of the spouse, and how to adapt and resolve conflicts in sexual matters. conservative socio-cultural patterns are the contextual factors shaping the sexual attitudes and behaviors of middle-aged women. the product of women’s sexual health is family stability”. accordingly, the provisional 60-items scale was developed, and its psychometrics was assessed in phase two. the sexual health scale for middle-aged married women (shima)-moghasemi et al. vol 19 no 5 september-october 2022 401 findings from phase two i. content validity cvr and cvi were calculated for quantitative content validity assessment. in this step, 21 items were eliminated. finally, the scvi/ave for the remaining 39 items was 0.95. ii. face validity: in the qualitative face validity, some minor wording changes were made according to the women’s suggestions. the results revealed that all the items had an impact score ≥ 1.5. these items were important in the target group. iii. construct validity a. exploratory factor analysis (efa): all 424 middle-aged women completed the questionnaire. of these participants, 17 women were excluded due to incomplete responses to the questionnaire. thus, the data obtained from 407 participants were analyzed for construct validity. the characteristics of the study participants are presented in table 3. in efa, the kmo test value the sexual health scale for middle-aged married women (shima)-moghasemi et al. andrology 402 figure 1. the flowchart of shima scale development process was 0.943 and bartlett’s test value was 7843.55 (p < 0.001). thirty-four items and six factors were extracted and named as couple sexual interaction (11 items), couple relationship quality (7 items), satisfaction with sex organs appearance and function (6 items), access to sexual health service (4 items), sexual agency (3 items), and sexual concerns (3 items). the six factors explained 48.67% of the total variance (table 4). figure 2 presents the final factor analysis model for shima. b. the results (table 5) revealed that all factors had acceptable convergent and divergent validity. c. reliability: for five factors, internal consistency evaluation revealed that cronbach’s alpha and mcdonald’s omega were greater than 0.7, and the average inter-item correlation was greater than 0.4. finally, the composite and maximum reliability (h) were acceptable except for one factor (table 5). test-retest reliability over a 2-week period was 0.90. discussion this study showed that sexual health is a multi-dimensional concept for middle-aged married women, and the shima had acceptable psychometric properties to measure sexual health in this population. the shima represents the multidimensionality of the sexual health concept and assesses it in the dimensions beyond sexual satisfaction or sexual function. according to the definition of sexual health(1), in addition to the physical aspect, shima encompasses psycho-socio-emotional dimensions. in other words, it indicates sexual health in a bio-psycho-social model. as the quality of a relationship affects women’s sexual health in different ways(17,18), “couple sexual interaction” and “couple relationship quality” are the most powerful predictive factors of this concept. these two factors encompass 26.39% from 48.67% of the total variance of shima, respectively. in this regard, based on the theory of systems, an individual’s situation in a couple affects the whole system (both members of a couple). therefore, partners’ competency and life skills can help a couple have a happier relationship(19). however, there is not any similar domain in female sexual function index (fsfi)(20), which is a widely-used measure in women’s sexuality studies. “interpersonal domain” and “cognitive-emotional” domains in fswb imply the importance of couple interactions in women’s sexual health in a similar way(9). therefore, these items should be considered in sexual health promotion intervention programs. the third factor is “satisfaction with sex organs appearance and function”. normal sexual function is assessed based on the sexual response cycle, which is a combination of mind and body responses(21). as body image affects all aspects of female sexual function(22), the items of the third facto are related to the body and sexual self-image. in recent years, several studies have reported the association between body image and female sexual function(22-24). a multi-center study in iran showed that sexual dysfunction is more prevalent in married women who feel they are not attractive to their partners (or: 1.9)(25). the scale used in this study had an item about the satisfaction about lubrication during sex. this question assessed the most objective part of female sexual response. limited lubrication is related to vaginal dryness and dyspareunia especially after cessation of the menfigure 2. the final factor analysis model for shima the sexual health scale for middle-aged married women (shima)-moghasemi et al. vol 19 no 5 september-october 2022 403 strual cycles in menopausal women. also, kennedy et al. in a systematic review found that lubricants can be an important part of improving sexual health and well-being(26). in the third factor, not only female sexual function but also a spouse’s sexual function is assessed from the women’s viewpoint. in sexual dysfunction assessment, it is strongly recommended to evaluate sex partner-related factors regularly(18,21). it is worthy to mention that as sex and sexual desire are considered undesirable for women in the most conservative cultures and communities, such as iran, especially in the post-reproductive years, thus questioning straight about sexuality may be seemed unfair or accompanied by feelings of shame. so some items which are related to sexual desire such as q 17 (i have the willingness to have sex with my partner) and q 24 (i take the initiative for having sex with my spouse) were loaded in the “sexual agency” and “couple relationship quality” domain, respectively. the fourth factor is “access to sexual health service”, which encompasses three factors, namely physical, financial, and information(27). in this respect, the provision of free-of-charge primary health care (phc) in most countries, such as iran, facilitates access to health care services physically and financially. nevertheless, there are some limitations in providing health information, especially on a difficult topic such as sexuality(28). sexual health care services are restricted to providing contraception methods and reproductive cancer screening for reproductive-aged and married women and prevention of stds in high-risk groups (6, 29). therefore, sexual health generally is neglected for men and women beyond reproductive age or marriage. this approach can result in unmet sexual health needs in different groups and communities. access to sexual health services, as an important factor in an individual’s sexual health, can help both individuals and hcps plan appropriate interventions based on a need assessment or situation analysis. the fifth factor is “sexual agency”. it refers to people’s ability to act on their sexual needs, desires, and wishes. starting sex and attempting to make love imply women’s tendency to break common limiting beliefs and norms to meet their sexual needs and wishes. women with a high negotiation ability about the sexual agency have more sexual desire and better sexual well-being(30). the sixth factor is sexual concerns. this dimension, which has three items, is very important because, despite various changes in sexual life in midlife and beyond, there are substantial barriers to seeking help for sexual health problems and concerns. hence, only a few middle-aged people with sexual problems seek care(31). in this regard, pakgohar et al. showed that 27.2% of menopausal women with urinary incontinence seek medical attention(32). it is assumed that the “sexual concern” dimension can be an appropriate trigger for women to speak about their sexual health problems with healthcare providers (hcps). sexual health is a multi-dimensional and dynamic issue(22). therefore, researchers and hcps should focus on women’s sexual health from a multi-dimensional or bio-psycho-social perspective instead of focusing solely on sexual function as a physical problem. this approach could result in an individual’s well-being and quality of life. in other words, considering genitalia the sexual health scale for middle-aged married women (shima)-moghasemi et al. response to sexual function, sexual health cannot be outlined without incorporating individuals’ satisfaction with physical, emotional, and social experiences(33). the shima is a multi-dimensional and context-based scale developed using a more holistic approach to women’s sexual health. thus, it assesses not only physical but also intrapersonal (sexual concerns and sexual agency), interpersonal (couple relationship quality, couple sexual interaction, and couple sexual function), and the social/community (access to sexual health service) measures of sexual health from a bio-psycho-social perspective. overall, it is assumed that shima can provide a better sexual health profile of women in research and clinic than the female sexual function questionnaires. this study had some limitations. although this scale was designed specifically for middle-aged married women, there are few specific items for this age group. this pattern may indicate that being in midlife solely is not an important factor in women’s sexual health. in other words, psychosocial factors are more important than physical and age-related changes, including hormonal alteration. therefore, it is recommended to apply this scale to other populations such as reproductive-age women, women with special conditions (e.g., chronic diseases), and intervention studies to confirm its validity and reliability in other populations. moreover, conducting the same study on unmarried women could give insight into the meaning and importance of sexual health in these women. conclusions the sexual health scale for middle-aged women (shima) is a validated and reliable scale for measuring sexual health in this population that can be used as a sexual health-screening tool. also, the data acquired by the scale could be useful for designing appropriate interventions to improve women’s sexual health, especially in their midlife. conflict of interest the authors report no conflict of interest. references 1. world health organization. sexual and reproductive health. availabe at: http://www. who.int/reproductivehealth/topics/sexual_ health/conceptual_elements/en/ acess date: 27/4/2016. 2. world health organization. measuring sexual health: conceptual and practical considerations and related indicators. 2010. 3. goldstein i, clayton ah, goldstein at, kim nn, kingsberg sa. textbook of female sexual function and dysfunction: diagnosis and treatment: john wiley & sons; 2018. 4. rullo j, faubion ss, hartzell r, goldstein s, cohen d, frohmader k, et al. biopsychosocial management of female sexual dysfunction: a pilot study of patient perceptions from 2 multi-disciplinary clinics. sex med. 2018;6:217-23. 5. lusti-narasimhan m, beard jr. sexual health in older women. bull world health organ. 2013;91(9):707-9. 6. binfa l, pantoja l, gonzalez h, ransjoandrology 404 arvidson ab, robertson e. chilean midwives and midwifery students' views of women's midlife health-care needs. midwifery. 2011;27:417-23. 7. world health organisation. defining sexual health report of a technical consultation on sexual health.geneva. 2006. 8. world health organisation. the estimates confirm the trend for longevity: lifespans are getting longer. [cited 2022 4/11/2022]. available from: https://www.who.int/data/ gho/data/themes/mortality-and-global-healthestimates/ghe-life-expectancy-and-healthylife-expectancy. 9. rosen rc, bachmann ga, reese jb, gentner l, leiblum s, wajszczuk c, et al. female sexual well-being scale (fswb scale): development and psychometric validation in sexually functional women. the j sex med. 2009;6:1297-305. 10. hensel dj, fortenberry jd. a multidimensional model of sexual health and sexual and prevention behavior among adolescent women. j adolesc health. 2013;52:219-27. 11. beatricebean'e r, bockting wo, rosser bs, miner m, coleman e. the sexual health model: application of a sexological approach to hiv prevention. health educ res. 2002;17:43-57. 12. waltz cf, strickland ol, lenz er. measurement in nursing and health research: springer publishing company; 2010. 13. graneheim uh, lundman b. qualitative content analysis in nursing research: concepts, procedures and measures to achieve trustworthiness. nurse educ today. 2004;24:105-12. 14. lotfi r, tehrani fr, yaghmaei f, hajizadeh e. developing a valid and reliable instrument to predict the protective sexual behaviors in women at risk of human immunodeficiency virus. iran red crescent med j. 2014;16(9). 15. polit df, beck ct, owen sv. focus on research methods; is the cvi an acceptable indicator of content validity? appraisal and recommendation. res nurs health. 2007;30:459-67. 16. esposito vinzi v, chin ww, henseler j, wang h. handbook of partial least squares: concepts, methods and applications. computational statistics handbook series. 2010;2. 17. nazarpour s, simbar m, tehrani fr. factors affecting sexual function in menopause: a review article. taiwan j obstet gynecol. 2016;55:480-7. 18. brotto l, atallah s, johnson-agbakwu c, rosenbaum t, abdo c, byers es, et al. psychological and interpersonal dimensions of sexual function and dysfunction. j sex med. 2016;13:538-71. 19. larson jh, blick rw, jackson jb, holman tb. partner traits that predict relationship satisfaction for neurotic individuals in premarital relationships. j sex marital ther. 2010;36(5):430-44. 20. rosen cb, j. heiman, s. leiblum, c. meston, r. shabsigh, d. ferguson, r. d'agostino, r. the female sexual function index (fsfi): a multidimensional self-report instrument for the assessment of female sexual function. j sex marital ther. 2000;26:191-208. 21. basson r. women's sexual dysfunction: revised and expanded definitions. cmaj. 2005;172:1327-33. 22. woertman l, van den brink f. body image and female sexual functioning and behavior: a review. j sex res. 2012;49:184-211. 23. pandya aa, corkill ha, goutos i. sexual function following burn injuries: literature review. j burn care res. 2015;36:e283-93. 24. male da, fergus kd, cullen k. sexual identity after breast cancer: sexuality, body image, and relationship repercussions. curr opin support palliat care. 2016;10:66-74. 25. ramezani tehrani f, farahmand m, mehrabi y, malek afzali h, abedini m. prevalence of female sexual dysfunction and its correlated factors: a population based study. payesh. 2012;11:869-78. 26. kennedy ce, yeh pt. lubricants for the promotion of sexual health and well-being: a systematic review. sex reprod health matters. 2021;29:2044198. 27. world health organisation. gender, equity and human rights. [cited 2020]. available from: https://www.who.int/gender-equityrights/understanding/accessibility-definition/ en/ 28. gott m, galena e, hinchliff s, elford h. “opening a can of worms”: gp and practice nurse barriers to talking about sexual health in primary care. fam pract. 2004;21:528-36. 29. damari b, tabrizchi n, riazi-isfahani s. designing a national plan for improving sexual health in iran: an experience of an islamic country. mjiri. 2016;30:407. 30. wood jm, mansfield pk, koch pb. negotiating sexual agency: postmenopausal women's meaning and experience of sexual desire. qual health res. 2007;17:189-200. 31. moreira jr ed, brock g, glasser db, nicolosi a, laumann eo, paik a, et al. help‐seeking behaviour for sexual problems: the global study of sexual attitudes and behaviors. int j clin pract. 2005;59:6-16. 32. pakgohar m, sabetghadam s, vasegh rahimparvar sf, kazemnejad a. quality of life (qol) and help-seeking in postmenopausal women with urinary incontinence (ui): a population based study. arch gerontol geriatr. 2014;59:403-7. 33. thomas hn, thurston rc. a biopsychosocial approach to women's sexual function and dysfunction at midlife: a narrative review. maturitas. 2016;87:49-60. the sexual health scale for middle-aged married women (shima)-moghasemi et al. vol 19 no 5 september-october 2022 405 urol_montage.pdf kidney transplantation 31urology journal vol 6 no 1 winter 2009 tacrolimus rescue therapy for corticosteroidresistant and polyclonal antibody-resistant kidney allograft rejections gholam hossein naderi,1 darab mehraban,2 mohammad reza ganji,3 seyed reza yahyazadeh,2 amir hossein latif4 introduction: the conventional treatment of acute kidney allograft rejection consists of high-dose corticosteroids and polyclonal antibodies. we report our experience of tacrolimus rescue therapy in patients with acute rejections refractory to corticosteroids and polyclonal antibodies. materials and methods: a total of 34 patients with a mean age of 42.3 years and clinical diagnosis of acute kidney allograft rejection underwent tacrolimus rescue therapy when treatment with corticosteroids and polyclonal antibodies failed. kidney allograft biopsy results were available in 21 patients. all of the patients received tacrolimus, 0.1 mg twice daily, and in those who responded to the therapy after 4 to 6 months, tacrolimus was replaced with cyclosporine. results: pathologic examination of 21 biopsy specimens of the kidney allografts showed acute vascular rejection in 7 patients (33.3%), acute humoral rejection in 6 (28.6%), acute cellular rejection in 3 (14.3%), and accelerated acute rejection in 3 (14.3%). twenty-six patients (76.5%) responded to rescue therapy with tacrolimus and discharged with a mean serum creatinine level of 1.4 mg/dl (range, 1.1 mg/dl to 1.7 mg/dl). allograft nephrectomy was done in 8 patients (23.5%) because of no response to treatment of rejection, the pathology reports of which consisted of acute vascular rejection in 5 patients and extensive necrosis in 3. conclusion: tacrolimus therapy is able to salvage kidney allografts with acute refractory rejection. we recommend that tacrolimus be used as an alternative to the conventional drugs used for antirejection therapy. however, severe infectious complications as a result of overt immunosuppression must be considered. urol j. 2009;6:31-4. www.uj.unrc.ir keywords: kidney transplantation, tacrolimus, graft rejection, graft survival 1department of kidney transplantation, shariati hospital, tehran university of medical sciences, tehran, iran 2department of urology, shariati hospital, tehran university of medical sciences, tehran, iran 3department of nephrology, shariati hospital, tehran university of medical sciences, tehran, iran 4students’ scientific research center, school of medicine, tehran university of medical sciences, tehran, iran corresponding author: gholam hossein naderi, md department of kidney transplantation, shariati hospital, jalal-e-al-e-ahmad ave, tehran, iran tel: +98 21 8490 2406 fax: +98 21 8863 3039 e-mail: gh_naderi2000@yahoo.com received april 2008 accepted january 2009 introduction refractory kidney allograft rejection is still a major cause of graft loss and poor graft survival despite the use of newer immunosuppressive drugs. until now, there are no effective and reliable therapeutic approaches for accelerated acute rejection (aar) or acute vascular rejection (avr).(1) in addition, the gold standard treatment of acute humoral rejection has remained undefined.(2) therefore, the graft loss rates are still high. tacrolimus is a new immunosuppressive agent that has undergone clinical trials for efficacy as a primary treatment in kidney transplantation tacrolimus for kidney allograft rejection—naderi et al 32 urology journal vol 6 no 1 winter 2009 and as an agent for salvage in kidney allograft rejection.(1) several studies have suggested tacrolimus as an effective rescue therapy to reverse ongoing acute rejection or aar refractory to conventional immunosuppressive agents.(3-7) however, some recent studies have disputed its efficacy.(8) the aim of this study was to report the experience of tacrolimus rescue therapy in patients with acute allograft rejection refractory to conventional immunosuppressive agents. most of the kidney recipients had received their kidneys from living donors and were not anuric after transplantation. materials and methods during a 5-year period between march 2001 and november 2006, we had 34 patients with a clinical diagnosis of acute allograft rejection who had undergone tacrolimus rescue therapy at shariati hospital in tehran, iran. in all of them, treatment with corticosteroids and polyclonal antibodies, consisting of antithymocyte or antilymphocyte globulin, had failed. the crossmatch and panel reactive antigens tests had been negative between each donor and his/her recipient. diagnosis of rejection had been made by clinical and laboratory findings, doppler ultrasonography, renal scintigraphy, and kidney allograft biopsy (in 21 patients). rejections had occurred in the third posttransplant day or thereafter. they had received an induction therapy including prednisolone, 1.5 mg/kg, and mycophenolate mofetil, 1 g twice daily. the maintenance therapy regimen included prednisolone, 1.5 mg/kg, plus mycophenolate mofetil, 1 g twice daily, and cyclosporine, 8 mg/kg. the antirejection therapy consisted of methylprednisolone, 1 g daily for 3 days and then 500 mg daily for 2 further days, and antithymocyte globulin, 1.5 mg/kg for 10 to 14 days, or antilymphocyte globulin, 15 mg/ kg for 10 to 14 days. plasmapheresis was used in 1 patient. allograft rejections did not respond to methylprednisolone in all of the patients. therefore, other treatment options were discussed with the patients and they consented to start tacrolimus rescue therapy. all of the patients received tacrolimus, 0.1 mg twice daily, after prior unsuccessful conventional therapies. the expenses of tacrolimus rescue therapy were high and serum level of tacrolimus was not measured. thus, tacrolimus was changed to cyclosporine in patients who responded to the therapy after 4 to 6 months. results the mean age of the patients was 42.3 years (range, 22 to 62 years), and they were 18 men (52.9%) and 16 women (47.1%). a living donor was the source of kidney allograft in 27 patients (79.4%) and a deceased donor in 7 (20.6%). three patients (8.8%) had their second transplantation. the mean follow-up period was 31.7 months (range, 6 to 67 months). pathologic examination of 21 biopsy specimens of the kidney allografts showed avr in 7 patients (33.3%), acute humoral rejection in 6 (28.6%), acute cellular rejection in 3 (14.3%), and aar in 3 (14.3%). pathologic examination of 2 biopsy specimens was not possible. after treatment with tacrolimus, 26 patients (76.5%) responded to the therapy and discharged with a mean serum creatinine level of 1.4 mg/ dl (range, 1.1 mg/dl to 1.7 mg/dl). one of the patients died due to herpetic encephalitis 6 months after discharge. allograft nephrectomy was done in 8 patients (23.5%) because of no response to treatment of rejection, the pathology reports of which consisted of avr in 5 patients and extensive necrosis in 3. discussion accelerated acute rejection and acute vascular rejection are uncommon aggressive forms of kidney allograft rejection. to date, effective and reliable therapeutic approaches to the treatment of aar or avr do not exist, and graft loss rates remain high.(1) conventional treatment of acute kidney allograft rejection is high-dose pulses of corticosteroids, and treatment of corticosteroidresistant rejection is done with polyclonal antibody preparations such as muromonabcd3, equine antithymocyte globulin, and rabbit antithymocyte globulin. in some cases of recalcitrant rejection, graft salvage can be achieved by conversion of one baseline immunosuppressive tacrolimus for kidney allograft rejection—naderi et al urology journal vol 6 no 1 winter 2009 33 regimen to another, even in the presence of corticosteroid-resistant rejection.(9) in recent years, several studies have shown that tacrolimus can effectively reverse the ongoing accelerated or acute rejection refractory to conventional immunosuppressive agents including corticosteroids and antithymocyte globulin.(3-7) tacrolimus, formerly known as fk506, selectively inhibits transcription of interleukin-2 and several other cytokines and is also a macrolide antibiotic.(10) although most of its effects may be attributed to an inhibitory effect on t-cell function, tacrolimus has also a direct inhibitory effect on calciumdependent b-cell activation. additionally, it inhibits human b-cell proliferation in response to certain calcium-independent stimuli.(11) the introduction of tacrolimus in 1990s significantly improved the survival of transplanted organs. this immunosuppressive drug is also becoming popular in the therapy for various immunemediated diseases.(10) jang and associates reported that with a mean follow-up of 8.1 months (range, 1 to 15 months), all of their 11 kidney allografts were successfully salvaged by tacrolimus therapy. overall graft survival was 59%. they concluded that tacrolimus therapy is able to salvage kidneys with acute refractory rejection and that it is an alternative in patients with cyclosporine toxicity. moreover, their study confirmed that tacrolimus therapy has a beneficial effect on patients with aar or avr who had been considered to have a poor prognosis.(1) pascual and colleagues demonstrated that a therapeutic approach of combining plasma exchange and tacrolimus/mycophenolate mofetil rescue therapy has the potential to improve the outcome of acute humoral rejection.(2) jordan and colleagues attempted graft salvage with tacrolimus conversion in a total of 169 patients with ongoing rejection on baseline cyclosporine immunosuppression after failure of highdose corticosteroids and/or antilymphocyte preparations to reverse rejection. with a mean follow-up of 30 months, 74% were successfully rescued. of the 144 patients previously treated with antilymphocyte preparations, 81% were salvaged. they recommended that tacrolimus could be used as an alternative to the conventional drugs used for antirejection therapy.(11) however, schwarz and coworkers showed that the efficacy of tacrolimus/mycophenolate mofetil rescue therapy in established c4d-positive chronic allograft dysfunction is not satisfactory.(8) all the patients of the current study had decreased urine volume or had become anuric in their third posttransplantation day or thereafter. in all of the patients, doppler ultrasonography showed a resisting index of 100% and open functional arteries and veins. renal scintigraphy showed impaired perfusion in all of the kidneys which was in contrast to acute tubular necrosis. hence, the diagnosis of rejection was made by the clinical, laboratory, and radiological evidences in these patients who had a refractory rejection to corticosteroids and polyclonal antibodies. biopsy was taken in some of the patients and not all of them. in this cohort of patients, 76.5% were successfully rescued by tacrolimus when used after unsuccessful conventional immunosuppressive therapy. these 26 successfully rescued kidney allografts were followed-up for a mean duration of 31.7 months (range, 6 to 67 months). their serum creatinine levels were below 1.7 mg/dl at discharge that demonstrates the success of tacrolimus rescue therapy. although the technique of measuring the trough level of tacrolimus was not available in our hospital during the study, it seems that the dosage of tacrolimus used in our patients (0.1 mg twice daily) was enough, especially when the serum level of tacrolimus was in normal ranges in the following studies. death of one of the kidney allograft recipients 6 months after discharge due to herpetic encephalitis could be possibly an adverse effect of overt immunosuppression related to tacrolimus therapy. therefore, it is important to consider the possible complications of this treatment including opportunistic infections. conclusion our findings are compatible with the previous reports that tacrolimus provided potent suppression of antibody-mediated rejection episodes in the liver and kidney allografts. we recommend tacrolimus be used as an alternative tacrolimus for kidney allograft rejection—naderi et al 34 urology journal vol 6 no 1 winter 2009 to the conventional drugs used for antirejection therapy in kidney transplantation. however, determination of the optimal dosing scheme for tacrolimus rescue therapy is important, so as to avoid life-threatening risks of excessive immunosuppression. conflict of interest none declared. references 1. jang hj, kim sc, han dj. tacrolimus for rescue therapy in refractory renal allograft rejection. transplant proc. 2000;32:1765-6. 2. pascual m, saidman s, tolkoff-rubin n, et al. plasma exchange and tacrolimus-mycophenolate rescue for acute humoral rejection in kidney transplantation. transplantation. 1998;66:1460-4. 3. kliem v, petersen r, ehlerding g, et al. tacrolimus for steroidand okt3-resistant rejection in kidney recipients. transplant proc. 1998;30:1251-3. 4. goh bl, tan sy. fk506 “rescue” therapy complicated by renal tubular acidosis in renal allograft recipients. transplant proc. 1998;30:3594-5. 5. ji sm, liu zh, chen js, sha gz, ji dx, li ls. rescue therapy by immunoadsorption in combination with tacrolimus and mycophenolate mofetil for c4d-positive acute humoral renal allograft rejection. transplant proc. 2006;38:3459-63. 6. boratynska m, banasik m, patrzalek d, klinger m. conversion from cyclosporine-based immunosuppression to tacrolimus/mycophenolate mofetil in patients with refractory and ongoing acute renal allograft rejection. ann transplant. 2006;11:51-6. 7. sun q, liu zh, yin g, et al. tacrolimus combined with mycophenolate mofetil can effectively reverse c4dpositive steroid-resistant acute rejection in chinese renal allograft recipients. nephrol dial transplant. 2006;21:510-7. 8. schwarz c, regele h, huttary n, et al. rescue therapy with tacrolimus and mycophenolate mofetil does not prevent deterioration of graft function in c4d-positive chronic allograft nephropathy. wien klin wochenschr. 2006;118:397-404. 9. jordan ml, naraghi r, shapiro r, et al. tacrolimus rescue therapy for renal allograft rejection--five-year experience. transplantation. 1997;63:223-8. 10. eberhard ok, kliem v, oldhafer k, et al. how best to use tacrolimus (fk506) for treatment of steroidand okt3-resistant rejection after renal transplantation. transplantation. 1996;61:1345-9. 11. woodle es, perdrizet ga, so sk, white hm, marsh jw. fk 506 rescue therapy for hepatic allograft rejection: experience with an aggressive approach. clin transplant. 1995;9:45-52. urological oncology 168 urology journal vol 7 no 3 summer 2010 genetic aberrations of the k-ras proto-oncogene in bladder cancer in kashmiri population mahoor s. nanda,1,2 a. syed sameer,2 nidda syeed,2 zaffar a. shah,2 imtiyaz murtaza,1 mushtaq a siddiqi,2 arif ali1 purpose: to assess the frequency of specific point mutations in the k-ras gene in a group of kashmiri patients with bladder cancer. materials and methods: we analyzed the incidence of k-ras exon 1 gene mutations in tumors and surgical margins in 60 patients with transitional cell carcinoma of varied clinical stages and histological grades using the polymerase chain reaction-single strand conformation polymorphism and dna sequencing. results: a significant correlation was found between the k-ras, the lymph node status, and tumor recurrence (p < 0.05). also, smokers and patients with higher tumor grade showed a significantly higher relative risk of developing k-ras mutations than the normal ones. conclusion: k-ras exon 1 gene mutations were found with low frequency in the bladder cancer tumors from kashmir valley, which suggests that k-ras gene might be involved in a sub-set of bladder tumors, but it needs further investigation on a larger cohort sample to authenticate the current findings. urol j. 2010;7:168-73. www.uj.unrc.ir keywords: proto-oncogene protein, urinary bladder neoplasm, ras genes, genetics 1department of biosciences, jamia millia islamia, jamia nagar, new delhi. india 2department of immunology and molecular medicine, sher-i-kashmir institute of medical sciences, soura, srinagar, kashmir, india corresponding author: arif ali, phd department of biosciences, jamia millia islamia, jamia nagar, new delhi, 110011 tel: +91 194 2401 013 fax: +91 194 240 3470 e-mail: mousavi786@gmail.com received august 2009 accepted february 2010 introduction bladder cancer, which is the fourth most incident cancer in the usa and affects more than 350 000 subjects worldwide, is one of the leading causes of mortality.(1,2) in kashmir, the northern region of india, bladder cancer is considered as the 9th most common cancer.(3) the ras gene family consisting of 4 functional genes, harvey ras (h-ras), kristen ras (k-ras) a and b, and neuroblastoma ras (n-ras), encode highly similar and conserved proteins with a molecular weight of 21 kda.(4) these closely related proteins are localized in the internal part of the cell membrane and have intrinsic gtpase activity, which regulates their cellular activity. (5) the main function of the ras proteins is to induce activation of downstream kinases belonging to mitogen-activated protein kinase pathway, which in turn results in continuous mitogenic signaling and transformation of immortalized cells.(6) because of their active involvement in proliferative and/ or differentiative signals within the growing cell, ras genes are the most common targets for somatic gainof-function mutations in almost all human cancers that lead to the formation of constitutively active proteins due to altered intrinsic gtpase activity.(7) mutated ras genes are associated with 15% to 30% of all human cancers, with highest frequencies genetic aberrations of k-ras in bladder cancer in kashmir—nanda et al 169urology journal vol 7 no 3 summer 2010 associated with pancreatic, lung, and colon carcinomas.(8,9) these mutated ras genes encode constitutively active proteins, most commonly with single amino acid substitutions at residues 12, 13, or 61 causing usually the loss of intrinsic gtpase activity of the proteins.(10) the first report of the activating ras mutations in bladder tumors was made by bos in t24 cell line.(11) since then, many studies have been carried out on human bladder tumors across the globe, and reports of different types of activating ras mutations involved in the tumorigenesis are well documented in the available literature.(12-19) because of these observations and the possibility of activating ras mutations to be involved in the tumorigenesis of bladder cancer as well as various suspected etiological factors, the present study was carried out in ethnic kashmiri population to investigate the frequency of specific point mutations in the k-ras gene and to correlate them with the various etiological parameters to which our population is exposed. materials and methods sample collection surgically resected specimens of 60 patients were collected from department of urology, sher-ikashmir institute of medical sciences, kashmir, india. the study protocol was approved by the research ethics committee of sher-i-kashmir institute of medical sciences. informed consent was obtained from each patient and/or guardian on pre-designed questionnaire (available on request). data regarding age, sex, and smoking history of the patients were obtained. patients who had received previous chemotherapy for a metastatic disease were excluded. in order to avoid evaluator variability, resected tissue specimens were brought fresh from the theater to department of pathology, where they were meticulously examined by two independent and experienced pathologists. the excision of the tumor was histologically proven by examination of the resected margins. all tumors were histologically confirmed to be transitional cell carcinoma. the specimens (both tumor and adjacent normal tissues) were snap-frozen at -70oc immediately until further analysis. patients were followed up for 1 year after the surgical resection of the tumor. dna extraction we extracted dna from primary tumors and adjacent noncancerous tissues, using the dna extraction kit ii (zymo research), for examining mutations in the k-ras exon 1 gene. polymerase chain reaction-single strand conformation polymorphism (pcr-sscp) exon 1 of the k-ras (containing hot spot codons 12 and 13) was amplified using the previously described specific primers.(20) polymerase chain reaction was performed in a 25 μl volume containing 50 ng of genomic dna, 1 × pcr buffer containing 15 mm mgcl2, 100 μm each of datp, dgtp, dttp, dctp, 1.5 unit of taq dna polymerase (biotools, spain), and 10 μm of forward and reverse primers. the amplification program was as initial denaturation at 95°c for 5 minutes, 35 cycles of denaturation at 94°c for 30 seconds, annealing at 48°c for 30 seconds, extension at 72°c for 30 seconds, and final extension at 72°c for 7 minutes. in every instance, positive human genomic dna (genei, india) was also amplified as internal control. polymerase chain reaction products were run on 2% agarose gel and analyzed under a ultra violet illuminator (figure 1). the single strand conformation polymorphism analysis of the amplicons of exon 1 of k-ras was performed on 6% non-denaturing polyacrylamide gel electrophoresis utilizing either non-radioactive silver staining or radioactive procedures.(20) the purified pcr amplicons of the tumor samples showing mobility shift on sscp analysis (figure 2) and randomly chosen normal samples were used for direct dna sequencing (figure 3), using the automated dna sequencer abi prism 310. statistics fisher’s exact test (one-tailed) was used to evaluate the association between clinicopathological variables in case of k-ras. p values less than .05 were considered statistically significant. genetic aberrations of k-ras in bladder cancer in kashmir—nanda et al 170 urology journal vol 7 no 3 summer 2010 results the mean age of the patients was 61 years and 63.3% of the patients were older than 50 years. about 83.4% were men, 80% were rural, and 75% were smoker (table 1). the mutational examination of exon 1 of k-ras gene revealed an overall k-ras mutation in 7 subjects aggregating to about 11.67% of the studied sample, which included 6 transitions and 1 transversion. transition mutation was of only one type g→a, and sole transversion was g→c. further more, of a total of 7 mutations, 4 affected codon 12 and 3 affected codon 13 (table 2). two cases were g12d (ggt > gat), 2 cases were g13d (ggc > gac), 2 cases were g12s (ggt > agt), and 1 case was g13r (ggc > cgc). the mutations in exon 1 of k-ras gene were found relatively more at codon 12 (57.1%) than codon 13 (table 2), which is consistent with the already available data.(21) no germ line mutations were found, indicating that in every case the change was somatic. statistical analysis of the mutants with respect to various clinicopathological variables revealed a significant association (p < .05) between the k-ras mutation, the lymph node status, and tumor recurrence. furthermore, smokers and patients with higher tumor grade showed a significantly higher relative risk of developing a bladder cancer than the normal ones (or > 2) (table 1). discussion a number of different studies carried out on various different cancers have demonstrated some hot spot regions in ras gene family that are susceptible to point mutations, the frequent among them are changes of glycine to valine/ aspartate/serine at codon 12, glycine to arginine/ cysteine at codon 13, and glutamine to arginine/ lysine/leucine at codon 61.(21,22) figure 1. amplified dna fragments of exon 1 of k-ras (162 bp amplicon) gene; first lane represents 100 bp molecular ladder and rest represent amplicons from different tumor tissues. figure 3. partial nucleotide sequences (reverse) of the normal and mutants – t3, t46 in exon 1 of kirsten ras oncogene. figure 2. a radioactive sscp analysis of k-ras exon 1 showing mobility shifts in tumor sample. genetic aberrations of k-ras in bladder cancer in kashmir—nanda et al 171urology journal vol 7 no 3 summer 2010 the incidence of ras mutation varies and is greatly dependent on the tissue or cell type from which the cancer cells are derived. although ras mutations occur in 75% to 95% of pancreatic carcinomas and 50% of colon carcinomas, they are rare in several other neoplasms.(23-25) mutations at codon 12 of k-ras are infrequent in the bladder cancer.(26,27) in a recent study, jebar and colleagues have found k-ras mutations in 3 of 98 patients with the bladder cancer.(16) interestingly, experimental studies on transgenic mice have shown that tissue-specific expression of a k-ras transgene in the urothelium leads to urothelial hyperplasia and superficial papillary tumors.(28) these observations suggest that activation of ras may contribute to early steps of carcinogenesis in the bladder.(16,26-28) results of the present investigation confirmed the role of k-ras mutations in the development of urinary bladder carcinoma, as we found 11.67% tumors (7/60 tumors) having mutations in this gene in kashmiri population, which is in consistent with many of the previous studies on bladder cancer.(12,16,27) furthermore, in this study, we also found a significant correlation between the k-ras mutant status and the lymph node involvement and tumor recurrence, suggesting a possible role of k-ras proteins in the metastasis of the cancer. the activating mutations of ras proteins have been previously implicated in all aspects of the malignant tumor, especially cellular proliferation, transformation, invasion as well as metastasis.(29) furthermore, campbell and der(30) demonstrated that activation of ras proteins causes an increase in the transformative, invasive, and metastatic properties of the murine fibroblast cells.(31) other studies also showed the same concomitant results.(32,33) since the transformation to a metastatic phenotype requires many changes in cell-cell adhesion, yan and associates have variable total (n = 60) (%) mutants (m = 7) (%) p; or; ci (95%) sex males: 50 (83.4) females: 10 (16.6) males: 6/50 (12.0) females: 1/10 (10.0) .67, 1.2273; 0.1313 11.4727 age ≤50: 22 (36.7) >50: 38 (63.3) ≤50: 3/22 (13.6) >50: 4/38 (10.5) .50, 1.3421, 0.2713 6.6394 dwelling rural: 48 (80) urban: 12 (20) rural: 5/48 (10.4) urban: 2/12 (16.7) .42, 0.5814; 0.0982 3.442 smoking status smokers: 45 (75) nonsmokers: 15 (25) smokers: 6/45 (13.3) nonsmokers: 1/15 (6.7) .43; 2.1538; 0.2379 19.5038 differentiation grade ii: 21 (35) iii +iv: 39 (65) ii: 4/21 (19.1) iii + iv: 3/39 (7.7) .18; 2.8235; 0.5676 14.0446 histological type s: 35 (58.3) mi: 25 (41.7) s: 3/35 (8.5) mi: 4/25 (16.0) .31; 0.4922; 0.0999 2.4256 lymph node status no: 55 (91.7) yes: 5 (8.3) no: 4/55 (7.3) yes: 3/5 (60.0) .009; 0.0523; 0.0067 0.4096 tumor recurrence nr: 47 (78.3) r: 13 (21.7) nr: 2/47 (4.3) r: 5/13 (38.5) .003; 0.0711; 0.0117 0.432 stage pt1: 39 (65) pt2: 21 (35) pt1: 4/39 (10.3) pt2: 3/21 (14.3) .46; 0.6857; 0.1383 3.4007 table 1. clinico-epidemiological variables of the patients with bladder cancer versus the mutant phenotypes of the k-ras exon 1 gene patient id age / sex rural/ urban histopathological stage histopathological grade smoking status type codon number base change amino acid change t3 80/m r pt1 ii ever mi 12 ggt>gat gly>asp t11 45/m r pt2 iii ever s 12 ggt>agt gly>ser t17 60/m r pt1 ii ever mi 12 ggt>gat gly>asp t22 81/f u pt1 iv ever mi 13 ggc>cgc gly>arg t42 65/m r pt2 ii ever mi 13 ggc>gac gly > asp t46 41/m r pt1 ii never s 12 ggt>agt gly>ser t55 38/m u pt2 iv ever s 13 ggc>gac gly > asp table 2. details and nature of k-ras exon 1 gene mutations in patients with bladder cancer from kashmir valley m, indicates male; f, female; r, rural; u, urban; mi, muscle invasive; s, superficial; and base change, mutated or inserted nucleotide underlined. genetic aberrations of k-ras in bladder cancer in kashmir—nanda et al 172 urology journal vol 7 no 3 summer 2010 reported that mutant k-ras, but not h-ras, causes disruption of the adhesive qualities of the mutant cell due to oncogene’s ability to interfere with the maturation of cell surface integrins.(34) furthermore, in our study, a significantly higher relative risk of k-ras mutant status was observed in patients with history of smoking and/or having higher tumor grade than the normal ones (or > 2) (table 1). this observation is in harmony with the other studies, where smoking has been implicated as one of the risk factors of the bladder cancer.(35) in our study, almost 75% of the patients with the bladder cancer were smoker and they were almost two times more prone to k-ras mutations than the normal ones (or = 2.15). the k-ras activating mutations that were identified in this study were missense in nature, 57.15% were found at codon 12 and 42.85% at codon 13; these results were consistent with other reported studies.(12,20) the mutations of codons 12 and 13 are the most common genetic aberration in k-ras, involving the substitution of the active site of glycine residue, which in turn changes the functionality of k-ras protein.(20) the substitution at codons 12 and 13 can either alter intrinsic gtpase activity of k-ras protein or change its ability to interact with wide variety of regulators.(33) the effectiveness of the substitution depends on the amino acid that replaces the original glycine (at 12/13). in this study, we also found that all k-ras mutants were g>r or g>s or g>d variants. it has been reported that replacement of glycine residues with valine or arginine has the aggressive transforming capability followed closely by serine and glutamine variants. (7,21,36,37) all of the above variants have the diminished gtpase activity due to which they remain activated under basal conditions, too, as there is no switching back to inactive gdp-bound form.(7) substitution by proline makes k-ras protein resistant to gap activity and hence is less aggressive in phenotypic expression.(37) of a total of 7 missense mutations, 6 (85.7%) were transitions and only 1 (14.3%) was transversion. all transistions were a>g type, 4 affecting codon 12 and 3 affecting codon 13. the sole transversion of g>c occurred at codon 13 causing replacement of glycine to arginine. the g>a transitions have been already reported to be the most common genetic change in k-ras and incidentally these aberration also score second in the human gene mutation database after c>t conversion.(38) conclusion to sum up, we can say that k-ras exon 1 gene mutations were found with low frequency in bladder cancer tumors from kashmir valley, which suggests that k-ras gene is involved in a sub-set of bladder tumors. nevertheless, these observations need further investigations in a bigger cross section of the patients with bladder cancer and relevant controls. conflict of interest none declared. references 1. jemal a, siegel r, ward e, hao y, xu j, thun mj. cancer statistics, 2009. ca cancer j clin. 2009;59:225-49. 2. ferlay j, randi g, bosetti c, et al. declining mortality from bladder cancer in europe. bju int. 2008;101: 11-9. 3. dhar gm, shah gn, naheed b, hafiza. epidemiological trend in the distribution of cancer in kashmir valley. j epidemiol community health. 1993;47:290-2. 4. varras mn, koffa m, koumantakis e, et al. ras gene mutations in human endometrial carcinoma. oncology. 1996;53:505-10. 5. watzinger f, lion t. ras family atlas genet cytogenet oncol haematol. 1999;http://atlasgeneticsoncology. org/deep/ras.html. 6. capon dj, chen ey, levinson ad, seeburg ph, goeddel dv. complete nucleotide sequences of the t24 human bladder carcinoma oncogene and its normal homologue. nature. 1983;302:33-7. 7. schubbert s, shannon k, bollag g. hyperactive ras in developmental disorders and cancer. nat rev cancer. 2007;7:295-308. 8. shields jm, pruitt k, mcfall a, shaub a, der cj. understanding ras: ‘it ain’t over ‘til it’s over’. trends cell biol. 2000;10:147-54. 9. ulku as, der cj. ras signaling, deregulation, of gene expression and oncogenesis. in: frank da, ed. in signal transduction in cancer. 1 ed. new york: kluwer academic publishers; 2004:189-209. 10. shinohara n, koyanagi t. ras signal transduction in carcinogenesis and progression of bladder cancer: molecular target for treatment? urol res. 2002;30:273-81. genetic aberrations of k-ras in bladder cancer in kashmir—nanda et al 173urology journal vol 7 no 3 summer 2010 11. bos jl. ras oncogenes in human cancer: a review. cancer res. 1989;49:4682-9. 12. karimianpour n, mousavi-shafaei p, ziaee aa, et al. mutations of ras gene family in specimens of bladder cancer. urol j. 2008;5:237-42. 13. oxford g, 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viola mv, fromowitz f, oravez s, deb s, schlom j. ras oncogene p21 expression is increased in premalignant lesions and high grade bladder carcinoma. j exp med. 1985;161:1213-8. 20. sameer as, ul rehman s, pandith aa, et al. molecular gate keepers succumb to gene aberrations in colorectal cancer in kashmiri population, revealing a high incidence area. saudi j gastroenterol. 2009;15:244-52. 21. levesque p, ramchurren n, saini k, joyce a, libertino j, summerhayes ic. screening of human bladder tumors and urine sediments for the presence of h-ras mutations. int j cancer. 1993;55:785-90. 22. sameer as, chowdhri na, abdullah s, shah za, siddiqi ma. mutation pattern of k-ras gene in colorectal cancer patients of kashmir: a report. indian j cancer. 2009;46:219-25. 23. almoguera c, shibata d, forrester k, martin j, arnheim n, perucho m. most human carcinomas of the exocrine pancreas contain mutant c-k-ras genes. cell. 1988;53:549-54. 24. smit vt, boot aj, smits am, fleuren gj, cornelisse cj, bos jl. kras codon 12 mutations occur very frequently in pancreatic adenocarcinomas. nucleic acids res. 1988;16:7773-82. 25. vogelstein b, fearon er, hamilton sr, et al. genetic alterations during colorectal-tumor development. n engl j med. 1988;319:525-32. 26. olderoy g, daehlin l, ogreid d. low-frequency mutation of ha-ras and ki-ras oncogenes in transitional cell carcinoma of the bladder. anticancer res. 1998;18:2675-8. 27. uchida t, wada c, ishida h, et al. infrequent involvement of mutations on neurofibromatosis type 1, h-ras, k-ras and n-ras in urothelial tumors. urol int. 1995;55:63-7. 28. zhang zt, pak j, huang hy, et al. role of ha-ras activation in superficial papillary pathway of urothelial tumor formation. oncogene. 2001;20:1973-80. 29. malumbres m, barbacid m. to cycle or not to cycle: a critical decision in cancer. nat rev cancer. 2001;1:222-31. 30. campbell pm, der cj. oncogenic ras and its role in tumor cell invasion and metastasis. semin cancer biol. 2004;14:105-14. 31. giehl k. oncogenic ras in tumour progression and metastasis. biol chem. 2005;386:193-205. 32. pozzatti r, muschel r, williams j, et al. primary rat embryo cells transformed by one or two oncogenes show different metastatic potentials. science. 1986;232:223-7. 33. al-mulla f, mackenzie em. differences in in vitro invasive capacity induced by differences in ki-ras protein mutations. j pathol. 2001;195:549-56. 34. yan z, chen m, perucho m, friedman e. oncogenic ki-ras but not oncogenic ha-ras blocks integrin beta1chain maturation in colon epithelial cells. j biol chem. 1997;272:30928-36. 35. dolin pj. an epidemiological review of tobacco use and bladder cancer. j smoking related dis. 1991;2:129-43. 36. seeburg ph, colby ww, capon dj, goeddel dv, levinson ad. biological properties of human c-ha-ras1 genes mutated at codon 12. nature. 1984;312:71-5. 37. stenson pd, ball ev, mort m, et al. human gene mutation database (hgmd): 2003 update. hum mutat. 2003;21:577-81. 38. lijinsky w. n-nitroso compounds in the diet. mutat res. 1999;443:129-38. urological oncology expression of endocan in tissue samples from prostate adenocarcinoma and prostate hyperplasia: a comparative retrospective study mumtaz dadali1*, murat tad 2, muhammed sahin bagbanci1 purpose: in this study, we aimed to determine whether there is a significant difference in endocan expression levels between prostate adenocarcinoma and prostate hyperplasia tissues by using an immunohistochemical method. materials and methods: all 51 patients, who were getting treatment for the last 5 years, participated in the study. 31 of 51 patients underwent transrectal sonography (trusg) -assisted prostate biopsy because of prostate adenocarcinoma as diagnosed with elevated psa levels and histopathological examination. the remaining 20 patients comprised the control group. the control group included patients with benign prostate hyperplasia based on pathological examination. results: it was found that there was strong positive epithelial staining in 74.2% of patients with prostate cancer while in 5% of controls, indicating a statistically significant difference (p < .001). it was also found that the rate of strong positive endothelial staining was 77.4% in the patient group whereas 5% in the control group (p < .001). also, the rate of strong positive stromal staining was 64.5% in the patient group while 5% in the control group (p < .001). conclusion: we found that tissue endocan expression level was statistically significantly higher in patients with prostate cancer compared to those with benign prostate hyperplasia by using an immunohistochemical method. keywords: benign prostate hyperplasia; endocan; expression; immunohistochemistry; prostate adenocarcinoma introduction prostate cancer (pca) is the second most common-ly diagnosed cancer and the sixth leading cause of cancer death among men worldwide, with an estimated 1 276 000 new cancer cases and 359 000 deaths in 2018(1) the worldwide prostate cancer burden is expected to grow to almost 2.3 million new cases and 740 000 deaths by 2040 simply due to the growth and aging of the population.(2) in a study conducted in iran in 20082010 that investigates the geographical frequency and degree of prostate cancer and evaluates its relationship with ethnicity, the average 3-year pca incidence rate standardized for age was found to be 11.52 per 100,000 men.(3) given biological heterogeneity and clinical variability in localized pca, an individualized approach is required for risk stratification and management.(4) to date, prostate-specific antigen (psa) is the only biomarker approved for detection and prognostication of prostate cancer by the us food and drug administration (fda). (5) initially, psa allowed identifying more patients with pca at early stages. however, psa screening also causes overdiagnosis and overtreatment.(6) psa showed severe limitations and inconsistencies as a diagnostic and prognostic marker for prostate cancer.(7) in recent years, proteoglycans (pgs) have emerged as critical modulators of key cellular processes such as cell proliferation, adhesion, and migration, which are 1department of urology, medical faculty, kırsehir ahi evran university, kırsehir 40100, turkey. 2department of pathology, medical faculty, kırsehir ahi evran university, kırsehir 40100, turkey. *correspondence: department of urology, medical faculty, kırsehir ahi evran university, kırsehir 40100, turkey. tel:+90 505 3344603, fax:+90 386 2803917, e-mail: mumtazdadali@gmail.com received february 2020 & accepted october 2020 linked to several pathological conditions including inflammation, cancer, or infection.(8) endocan (esm-1 = endothelial cell-specific molecule 1) is one of the novel and promising biomarkers. endocan is produced by many distinct types of the cell including prostatic epithelium. endocan is a soluble dermatan sulfate (50 kda in length) proteoglycan and it was first cloned from complementary dna library of human umbilical vein endothelium by lasalle et al. in 1996.(9) endocan secreted by active vascular endothelial cells including tumor endothelium.(10) also, endocan is present in the cell surface, extracellular matrix, and body fluids.(9) endocan can be involved in molecular interaction in biologically active conditions such as cell adhesion, migration, proliferation, or neovascularization.(11) the excessive levels of endocan in sepsis, cancers, and inflammatory disorders suggest that it may play a role in the pathogenesis of these disorders.(12-18) some studies investigated endocan in bladder cancer, renal cell cancer, prostate cancer, and erectile dysfunction in the literature.(19-22) it was reported that serum endocan levels were significantly higher in patients who developed biochemical recurrence after radical prostatectomy in early prostate cancers.(21) there is a limited number of studies that investigated endocan expression in tissues from prostate cancer or benign prostate hyperplasia by using immunohistochemical techniques. in this study, we aimed to investigate whether there is urology journal/vol 18 no. 5/ september-october 2021/ pp. 530-536. [doi: 10.22037/uj.v18i.6544] a statistically significant difference in endocan expression level between pca cancer and benign prostate hyperplasia (bph) tissues by using an immunohistochemical method. materials and methods this retrospective study was conducted in the research and training hospital of kırsehir ahi evran university. the study was approved by the local ethics committee (approval#2017-17/201). it was conducted by following the helsinki declaration. between 2012 and 2017, 51 patients were included in this study. of the 51 patients, 31 underwent transrectal ultrasonography (trusg)-assisted prostate biopsy because of prostate adenocarcinoma as diagnosed with elevated psa level and a histopathological examination (table 1). the remaining 20 patients comprised the control group. the patients in the control group were selected based on the benign surgical pathological results (table 2). study design individuals in the patient group had undergone 12-core biopsy and were diagnosed with prostate adenocarcinoma by examination of the first biopsy. a prostate needle biopsy was performed under local anesthesia for all patients. under lateral decubitus position, the perianal region was cleaned with povidone-iodine. a local anesthetic gel with lidocaine was squeezed into the rectum. a trusg probe was inserted, and the measurements of the prostate gland were done. a periprostatic nerve block was done with lidocaine for all patients. a systematic 12 core biopsy from parasagittal and peripheral basal, middle and apical regions was performed. gleason score was recorded in these cases. the patients who were diagnosed in the biopsy other than the first attempt and/or those who underwent biopsy by different core numbers other than 12, and those considered to have locally advanced or metastatic cancer were excluded. the remaining 20 patients comprised the control group. the patients in the control group were selected based on the benign surgical pathological results. patients with chronic prostatitis were also excluded. besides, patients with systemic comorbidity were excluded. 4 patients of the control group underwent transvesical prostatectomy due to recurrent urinary retention and a mean prostate size of 130 g . we performed transurethral prostatectomy due to recurrent retention and unresponsiveness to medical therapy in the remaining 16 individuals in the control group. we determined endocan expression in prostate tissue by using paraffin-embedded blocks from 51 patients in an immunohistochemical manner. the psa levels of the cases (pre-biopsy and preoperative) included in the study in both groups were reached and recorded. immunohistochemistry tissue sections (4 µm in thickness) were cut from paraffin blocks, which were then deparaffinized and labeled by benchmark xt automated ihc/isd slide staining system (ventana, medical systems, tucson, az) using recommended kits (ultra view universal dab detection kit; ventana medical systems inc., tucson, az). immunohistochemical evaluations were performed by using an anti-endocan mouse monoclonal antibody (3 mg/ml; ab56914: endocan antibody (anti-esm1 antibody); 100 µg at 0.5 mg/ml; mouse monoclonal suitable for ihc-p, wb reacts with: human) in formalin-fixed, paraffin-embedded tissues. renal tissue was used as a positive control as recommended in the protocol (figure 1. a-b). immunostaining was assessed independently by a pathologist who was blinded to clinical findings and sample characteristics. endothelial, epithelial, and stromal cells with brownish cytoplasm were considered as positive staining for enexpression of endocan in prostate cancerdadali et al. table 1. data of patients with prostate cancer patient number age (year) psa(ng/dl) gleason score number of tumors monitored foci prostate size (ml) 1 63 6.06 6 (3+3) 5 48 2 61 11.49 6 (3+3) 8 86 3 69 17.96 6 (3+3) 4 78 4 56 8.75 6 (3+3) 2 110 5 47 7.84 6 (3+3) 4 56 6 72 9.29 6 (3+3) 5 86 7 70 6.51 6 (3+3) 3 94 8 59 4.59 6 (3+3) 3 105 9 61 9.64 6 (3+3) 5 65 10 65 11.84 6 (3+3) 3 65 11 70 4.78 5 (3+2) 3 82 12 68 8.52 6 (3+3) 8 92 13 65 10.91 6 (3+3) 4 54 14 61 4.89 6 (3+3) 6 120 15 64 6.08 6 (3+3) 5 88 16 77 40.79 7 (3+4) 3 64 17 60 5.40 7 (3+4) 11 75 18 79 100 7 (3+4) 11 50 19 62 100 7 (3+4) 9 45 20 71 14.63 7 (3+4) 6 78 21 77 100 7 (4+3) 10 44 22 77 90.32 8 (4+4) 5 86 23 56 30.47 8 (4+4) 6 54 24 61 9.07 8 (4+4) 3 74 25 60 8.23 8 (4+4) 5 56 26 75 43.28 8 (4+4) 12 130 27 65 41.00 8 (4+4) 8 56 28 76 100 9 (4+5) 12 44 29 59 50.59 9 (4+5) 11 78 30 83 27.42 9 (4+5) 12 120 31 82 100 9 (5+4) 10 88 vol 18 no 5 september-october 2021 531 urological oncology 532 docan. endocan expression was assessed in epithelial, endothelial, and stromal cells in the tissue samples from patient and control groups. sections with spotted staining were classified into 4 groups by using a semi-quantitative scoring system based on the intensity of spotted staining. 0, negative; 1, weak cytoplasmic staining in more than 50% of tumor cells; 2, moderate staining in more than 50% of tumor cells and 3, strong staining in more than 50% of tumor cells.(23) given better visualization, endocan expression in epithelial cells was rated according to staining intensity: 0; negative, 1; weak, 2; moderate, and 3; strong.(16) endocan expression in endothelial and stromal cells was also rated according to staining intensity: 0; negative, 1; weak, 2; moderate, and 3; strong. statistical analysis data were analyzed using spss version 20.0 (armonk, new york, usa). chi-square test was used for categorical variables. for group comparisons, t-test or mann-whitney u test was used in independent groups, depending on whether the assumptions were met or not. p values under 0.05 were considered statistically significant. g-power 3.1 (department of psychology, university of düsseldorf, germany) was used for post power analysis. results mean age was 66.9 ± 1.6 years as a mean ± standard error of the mean (m ± sem) in the patient group whereas 68.3 ± 2.2 years in the control group. study and control groups were found to be similar in terms of age (p = .355). we found that there was strong positive epithelial staining in 74.2% of patients with pca while in 5% of controls (bph patients), indicating a statistically significant difference (p < .001) (figure 2a, 2b, 2c, 2d blue arrow). also, we found that the rate of strong positive endothelial staining was 77.4% in the patient group whereas 5% in the control group (p < .001) (figure 2a, 2b, 2c, 2d red arrow). besides, the rate of strong positive stromal staining was 64.5% table 2. data of the patients with benign prostatic hyperplasia patient number diagnostic method age (year) psa (ng/dl) prostate size (ml) 1 tur-p 55 1.78 44 2 tur-p 61 3.41 56 3 tur-p 60 4.39 74 4 tur-p 77 2.66 66 5 tvp 82 8.66 166 6 tvp 71 8.82 185 7 tvp 76 1.97 136 8 tur-p 73 1.70 78 9 tur-p 61 3.90 74 10 tur-p 54 3.13 62 11 tur-p 83 1.09 50 12 tur-p 69 1.58 76 13 tvp 75 5.17 140 14 tur-p 78 4.27 63 15 tur-p 72 0.44 44 16 tur-p 55 4.06 56 17 tur-p 64 5.61 86 18 tur-p 84 1.67 48 19 tur-p 55 26.52 96 20 tur-p 81 10.85 78 abbreviations: tur-p, transurethral resection of the prostate; tvp, transvesical prostatectomy figure 1. immunostaining with endocan in kidney tissue (positive control) [ax50, bx200] expression of endocan in prostate cancerdadali et al. in the patient group whereas 5% in the control group (p < .001) (figure 2a, 2b, 2c, 2d green arrow). endocan expression levels in epithelial, endothelial, and stromal cells were presented in figure 3. mean psa levels were 5.5 ± 1.3 ng/ml in the control group while 31.8 ± 6.6 ng/ml in the pca group (p < .05). study and control groups were compared in terms of psa and prostate size values; the mean psa in the biopsy group was found to be statistically significantly higher than the control group (p < .001). in terms of prostate size values, there was no significant difference between the study and control groups (p = .469). pca patients were divided into 3 groups according to their psa values as psa ≤ 10, 11 < psa < 20 and psa > 20 ng / dl. no statistically significant difference was found between psa groups and stroma (p = .308), endothelial (p = .966), and epithelial (p = .747) groups in terms of density and prevalence. pca patients were divided into 3 groups as gleason score < 7, = 7 and > 7. no statistically significant difference was found between gleason score groups and stroma (p = .131), endothelial (p = .782), and epithelial (p = .454) groups in terms of density and prevalence. post-power analysis was performed using the g-powfigure 2. weak staining with endocan (the blue arrow shows epithelium, the red arrow shows endothelium and the green arrow shows stroma) in benign prostate hyperplastic tissue samples (a-b) [ax100, bx200]. strong staining with endocan (the blue arrow shows epithelium, the red arrow shows endothelium and, the green arrow shows stroma) in prostate adenocarcinoma tissue samples (c-d) [ax200, bx400]. figure 3. endocan staining intensity levels of epithelial, endothelial, stromal tissues among groups. the number of tissues in each subgroup (n) was presented inside the column. expression of endocan in prostate cancerdadali et al. vol 18 no 5 september-october 2021 533 urological oncology 534 er 3.1 to determine the power of the study. according to the results of the study in which a large effect size was achieved between the endothelial, epithelial, and stroma groups and the study groups, the power of the study was found to be 98% at the end of the study with a sample size of 31 people with an error margin of 5%. discussion considering the strong evidence in the literature regarding the association between endocan and malignant disorders, we hypothesized that endocan may have a role in the pathogenesis of pca. our study showed higher strong staining of endocan in tissues from pca patients which supports our hypothesis. we could not measure tissue or plasma endocan concentrations which could contribute to our study. nevertheless, our results have the potential to contribute to the existing literature on the topic of using endocan as a biomarker for pca and distinguishing pca from bph. previous studies have shown that endocan is associated with the regulation of major processes such as cell adhesion, inflammatory disorders, or tumor progression. (24) although regulatory mechanisms for endocan production haven't been fully understood, recent studies indicated that numerous signaling pathways and bioactive mediators play a role. inflammatory cytokines such as vascular endothelial growth factor-a (vegf-a), vegf-c, interleukin-1 (il-1), tumor necrosis factor-α (tnf-α), transforming growth factor-ß1, fibroblast growth factor-2 (fgf-2) increase while phosphatidylinositol-3-kinases (pi3k) and interferon-γ decrease during endocan production and secretion.(9,10) in a study investigating the prognostic value of endocan, serum endocan levels were studied.(21) the study included 86 patients who underwent radical prostatectomy (rp) due to localized prostate cancer and 80 control patient with the normal digital rectal examination and psa levels. serum endocan and psa levels were measured before the procedure. biochemical recurrence was defined as serum psa level > 0.2 ng/ml at the end of year one. the mean serum endocan level was 3.14 ng/ ml in the rp group whereas 2.98 ng/ml in the control group. the rp group was stratified into two groups according to serum endocan levels: ≥ 1.8 ng/ml and < 1.8 ng/ml. gleason score and biochemical failure rate were found to be significantly higher in patients with endocan level ≥1.8 ng/ml. the time of biochemical recurrence was 38 months (31-42 months) and 56 months (46-65 months) in patients with endocan levels ≥ 1.8 ng/ml and < 1.8 ng/ml, respectively (p = .041). this study revealed that elevated serum endocan level ( ≥ 1.8 ng/ml) is an important marker for biochemical progression-free survival. elevated serum levels may be due to systemic disorders and/or inflammation from an unknown source. thus, endocan studies at target tissue may provide more accurate results compared to serum endocan studies. there is a need for prospective studies which will evaluate serum and target tissue endocan levels simultaneously. in another study, expressions of vegf (vegf-a and vegf-c) and their receptors were measured in neoplastic tissues and corresponding stroma from rp specimens by using tissue micro-array assays and immunohistochemical methods from 535 norwegian patients. (25) high vgefr-2 expression in stroma and epithelium was associated with a high incidence of pca recurrence (p = .038). high expression of vgef-a, vgefr-2, or both in the stroma was independently associated with high biochemical failure incidence (p = .011). this study emphasizes the prognostic value of stromal vegf-a and vggfr-2 expressions. since endocan is stimulated by these factors, the results of this study support our findings. asgari m et al. studied endothelin-1 expression for the determination of prognosis in patients with prostate adenocarcinoma.(23) the authors assigned 83 patients who underwent rp into 2 groups: 43 patients without extra-prostatic extension (epe) and 40 patients with epe. endothelin-1 staining was performed on paraffin-embedded blocks obtained from preoperative core biopsies. endothelin-1 expression was increased in 72% of patients in the epe group (p < .001). serum psa levels were found to be higher in the group with endothelin-1 positivity (p = .039). also, endothelin-1 expression was positive in 67% of patients with perineural invasion (p < .001). according to this study, endothelin-1 positivity can effectively predict epe in patients with pca (or = 5.46, p = .010). the authors recommend using the endothelin-1 expression as a complementary factor in the assessment of core biopsies in prostate adenocarcinoma. chung-yu lai et al. investigated the relationship between endocan and androgen receptor (ar) expressions.(26) they measured the gleason score of human pca tissues. also, they evaluated endocan and ar expressions in prostate tissues from healthy individuals and patients with pca using immunohistochemistry. this study found that endocan expressions were higher in tissues from prostate tumors than normal prostate tissues (p < .01). besides, they found that endocan expressions in tumor tissues were associated with gleason score (p < .016) and gleason grade (p < .013). it was found that endocan expressions were higher in tumor tissues with higher gleason score and grade (p < .001 for each) and endocan expressions were correlated to ar expressions (r = 0.727, p < .001). the authors proposed considering endocan as a marker for the diagnosis of pca which supports our study’s results. in a study by taghavi a et al., the frequency of the polyomavirus hominis 1, better known as bk virus (bkv) infection was found to be higher in pca patients compared to bph patients.(27) it has been stated that bkv may be a predisposing factor for pca. the retrospective design and the low sample size are the limitations of this study. conclusions our study showed strong epithelial staining of endocan in pca tissues compared to bph tissues. to our knowledge, the present study is the first study that showed elevated endocan expression levels in pca tissues compared to bph tissues. this finding may help to distinguish pca from bph. this finding also suggests that endocan may have a role in the pathogenesis of prostate adenocarcinoma. many studies in the literature showed that endocan is closely related to the recurrence of pca. we found that endocan expression was statistically significantly higher in patients with prostate cancer than those with benign prostate hyperplasia by using an immunohistochemical method. the interactions between endocan and other cytokines and growth factors in prostate adenocarcinoma development are still unclear, and expression of endocan in prostate cancerdadali et al. their clarification requires further studies. conflict of interest the authors report no conflict of interest. acknowledgement data presented previously at 4th national urological surgery congress. 31 october 04 november 2018. antalya / turkey (oral presentation) ss – 046. references 1. culp mbb, soerjomataram i, efstathiou ja, freddie bray f, jemal a. recent global patterns in prostate cancer incidence and mortality rates. eur urol. 2020;77:38-52. 2. rawla p. epidemiology of prostate cancer. world j oncol. 2019;10:63-89. 3. basiri a, eshrati b, zarehoroki a, golshan s, shakhssalim n, khoshdel a, et al. incidence, gleason score and ethnicity pattern of prostate cancer in the multi-ethnicity country of iran during 2008-2010. urol j. 2020;17:602-606. 4. hodges kb, bachert e, cheng l. prostate cancer biomarkers: current status. crit rev oncol. 2017;22:253-269. 5. rittenhouse hg, finlay ja, mikolajczyk sd, partin aw. human kallikrein 2 (hk2) and prostate-specific antigen (psa): two closely related, but distinct, kallikreins in the prostate. crit. rev. clin. lab. sci. 1998;35:275-368. 6. schroder fh, hugosson j, roobol mj, tammela tl, zappa m, nelen v, et al. screening and prostate cancer mortality: results of the european randomised study of screening for prostate cancer (erspc) at 13 years of follow-up. lancet. 2014;384:202735. 7. catalona wj, richie jp, ahmann fr, hudson ma, scardıno pt, flanıgan rc, et al. comparison of digital rectal examination and serum prostate-specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. j. urol. 2017; 197:200-207. 8. delehedde m, devenyns l, maurage ca, vivès rr. endocan in cancers: a lesson from a circulating dermatan sulfate proteoglycan. int j cell biol. 2013;2013:705027. 9. lassalle p, molet s, janin a, heyden jv, tavernier j, fiers w, et al. esm-1 is a novel human endothelial cell-specific molecule expressed in the lung and regulated by cytokines. j biol chem. 1996;271:20458-64. 10. sarrazin s, adam e, lyon m, depontieu f, motte v, landolfi c, et al. endocan or endothelial cell-specific molecule-1 (esm1): a potential novel endothelial cell marker and a new target for cancer therapy. biochim biophys acta. 2006;1765:25-37. 11. kali a and rathan shetty ks. endocan: a novel circulating proteoglycan. indian j pharmacol. 2014;46:579-583. 12. roudnicky f, poyet c, wild p, krampitz s, negrini f, huggenberger r, et al. endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates vegfa-induced angiogenesis. cancer res. 2013;73:1097-106. 13. scherpereel a, gentina t, grigoriu b, sénéchal s, janin a, tsicopoulos a, et al. “overexpression of endocan induces tumor formation. cancer res. 2003;63:6084-9. 14. huang g-w, tao y-m, and ding x. endocan expression correlated with poor survival in human hepatocellular carcinoma. dig. dis. sci. 2009;54:389-394. 15. maurage c-a, adam e, min´eo j-f, sarrazin s, debunne m, siminski r-m, et al. endocan expression and localization in human glioblastomas. j neuropathol exp neurol. 2009; 68: 633-641. 16. matano f, yoshida d, ishii y, tahara s, teramoto a and morita a. endocan, a new invasion and angiogenesis marker of pituitary adenomas. j neurooncol. 2014;117:485-491. 17. scherpereel a, depontieu f, grigoriu b, cavestri b, tsicopoulos a, gentina t, et al. endocan, a new endothelial marker in human sepsis. crit care med. 2006;34:532-37. 18. kiliç r, kurt a, tad m, taşdemir s. endocan overexpression in pterygium. cornea. 2017;36:696-99. 19. laloglu e, aksoy h, aksoy y, ozkaya f, akcay f. the determination of serum and urinary endocan concentrations in patients with bladder cancer. ann clin biochem. 2016;53: 647-653. 20. leroy x, aubert s, zini l, franquet h, kervoaze g, villers a, et al. vascular endocan (esm-1) is markedly overexpressed in clear cell renal cell carcinoma. histopathology. 2010; 56:180-7. 21. arslan b, onuk ö, hazar i̇, aydın m, çilesiz nc, eroglu a, et al. prognostic value of endocan in prostate cancer: clinicopathologic association between serum endocan levels and biochemical recurrence after radical prostatectomy. tumori. 2017;103:204-208. 22. akarsu m, atalay ha, canat l, ozcan m, arman y, aydın s, et al. endocan is markedly overexpressed in severe erectile dysfunction. andrologia. 2018;50: e12912. 23. asgari m, eftekhar e, abolhasani m, shahrokh h. endothelin-1 expression in prostate needle biopsy specimens correlated with aggressiveness of prostatic cancer. iran j pathol. 2017;12:171-176. 24. cox la, van eijk lt, ramakers bp, dorresteijn mj, gerretsen j, kox m, et al. inflammation-induced increases in plasma endocan levels are associated with endothelial dysfunction in humans in vivo. shock. 2015; 43:322-326. 25. nordby y, andersen s, richardsen e, ness n, al-saad s, melbø-jørgensen c, et al. stromal expression of vegf-a and vegfr-2 in prostate tissue is associated with biochemical and clinical recurrence after radical prostatectomy. the prostate. 2015;75:16821693. 26. lai cy, chen cm, hsu wh, hsieh yh, expression of endocan in prostate cancerdadali et al. vol 18 no 5 september-october 2021 535 liu cj. overexpression of endothelial cellspecific molecule 1 correlates with gleason score and expression of androgen receptor in prostate carcinoma. int. j. med. sci. 2017;14:1263-1267. 27. taghavi a, mohammadi-torbati p, kashi ah, rezaee h, vaezjalali m. polyomavirus hominis 1(bk virus) infection in prostatic tissues: cancer versus hyperplasia. urol j. 2015 sep 4;12(4):2240-4. expression of endocan in prostate cancerdadali et al. urological oncology 536 case report 132 urology journal vol 5 no 2 spring 2008 relapse of acute myeloid leukemia as isolated bilateral testicular granulocytic sarcoma in an adult mojtaba ghadiany,1 hamid attarian,1 abbas hajifathali,1 adnan khosravi,1 saatat molanaee2 urol j. 2008;5:132-5. www.uj.unrc.ir keywords: acute myeloid leukemia, bone marrow, myeloid sarcoma, recurrence 1department of medical oncology and hematology, taleghani hospital, shahid beheshti university (mc), tehran, iran 2department of pathology, milad hospital, tehran, iran correspondence author: mojtaba ghadiany, md taleghani teaching hospital, velenjak, tehran, iran tel: +98 21 8804 7999 e-mail: mghadiany@taleghanihospital.ir received april 2007 accepted september 2007 introduction acute myeloid leukemia (aml) is a malignant hematologic disease characterized by bone marrow infiltration with leukemic (blast) cells. infiltration of extramedullary organs by these cells is called granulocytic sarcoma (gs). relapsed aml with isolated testicular gs without bone marrow involvement is very rare and only a few cases have been reported.(1,2) we report a case of aml that relapsed as isolated bilateral testicular gs, 6.5 years after initial remission was induced by chemotherapy. case report the patient was a 45-year-old man who presented with weakness in 1997. initial laboratory examination showed a leukocyte count of 9.2 ×109/l; hemoglobin, 6.2 g/dl; and platelet count, less than 10 ×109/l. bone marrow examination was indicative of more than 50% blasts of myeloid lineage and few auer rods. flow cytometry analysis confirmed aml by the following findings: cd45, 79.6%; cd3=19.2%; cd20, 3%; cd13, 22%; cd33, 1.2%; human leukocyte antigendr, 64.7%; and cd34, 65.2%. cytogenetic study was not available. the patient received induction chemotherapy (daunorubicin for 3 days plus cytarabine for 7 days), and complete remission was achieved. then, he received 2 courses of chemotherapy as consolidation. he was in complete remission for 6.5 years, but in 2003, he noticed enlargement of his left testis. therefore, he was referred to our hematology clinic. physical examination was unremarkable except for bilateral testicular enlargement. the left testis was about 6 cm large, firm, and with a smooth surface. the right testis was a little smaller. ultrasonography, done a month earlier, had shown that the left testis sized 4.5 × 3.5 cm and diffusely hypoechoic, and the right testis sized 4.0 × 2.7 cm with a hypoechoic mass inside. the complete blood count, betahuman chorionic gonadotropin, alpha-fitoprotein, and lactate dehydrogenase were all within normal limits. bone marrow aspiration and biopsy showed no evidence of systemic relapse. we did not have the facility to do immunohistochemistry examination on fine-needle relapse of leukemia as testicular sarcoma—ghadiany et al urology journal vol 5 no 2 spring 2008 133 aspiration samples. therefore, left radical orchiectomy was done. gross pathologic evaluation of the testis showed that it was 7.5 × 5.5 × 3.0 cm, about 120 g, creamy in appearance, firm, and hemorrhagic and necrotic in some regions. on microscopic examination, the testicular tissue was infiltrated by mononuclear cells with vesicular and prominent nucleoli, some of which showed myelocytic differentiation compatible with gs (figure 1). two other pathologists reviewed the specimens and confirmed the diagnosis of gs. immunohistochemistry (positive for leukocyte common antigen, cd34, cd43, c-kit, and myeloperoxidase, but negative for cd3) confirmed the above diagnosis (figure 2). myeloperoxidase was repeated in another center and was positive. cerebrospinal fluid was intact. for editorial comment see p 134 radiotherapy consultation was done and the right testis was radiated. at the end of radiotherapy, because of abdominal pain, computed tomography (ct) was ordered which showed massive multiple para-aortic lymphadenopathy plus left-side hydronephrosis. induction chemotherapy with idarubicin plus cytarabine was started and followed by 4 cycles of high-dose cytarabine. abdominal ct which was repeated after chemotherapy showed normal pattern without any residue. hepatitis b surface antigen was positive; hence, bone marrow transplantation was not considered. during a 3.5-year followup after relapse, the patient was still in complete remission. discussion in 1975, schiffer and colleagues reported a case of aml relapsed with isolated gs of the testis 4 months after complete remission by radiotherapy plus systemic chemotherapy with dounorobicine. the patient died 7 months after relapse.(3) litam and colleagues reported a 63year-old man who had completed induction and intensification chemotherapy whose cancer relapsed as isolated unilateral testicular enlargement. biopsy confirmed infiltration of acute monocytic leukemia.(2) this case relapsed 1 month after complete remission, which was treated by radiotherapy without chemotherapy. however, the patient died 10 days after diagnosis of relapse.(2) according to shaffer and coworkers, testicular relapse in the absence of systemic relapse has been reported only in 2 adults and 12 children until 1992.(1) they reported a case that relapsed 2 months after hematologic remission. the patient denied chemotherapy and received only radiation to his testis. he died after 3 months with systemic relapse.(1) testicular granulocytic sarcoma in a patient with acute figure1. diffuse infiltration of the testis with intermediate-sized cells and small nucleoli with a high-mitotic rate (hematoxylineosin, × 40). figure 2. expression of myeloperoxidase in most of the cells (histochemistry, × 100). relapse of leukemia as testicular sarcoma—ghadiany et al 134 urology journal vol 5 no 2 spring 2008 megakaryoblastic leukemia has also been reported.(4) the patient in this case was in complete remission for 4 months before his relapse in left testis. relapse of aml as isolated testicular gs after initial full hematologic remission induced by chemotherapy is very rare. in the previous cases, the time between remission and testicular relapse (relapse-free time) was only few months, and testicular relapse was usually followed by bone marrow relapse. in our case, however, the relapse-free time was 6.5 years, and to our knowledge, this is the longest interval so far reported. our case presented by bilateral testicular enlargement without any other symptom, but abdominal pain that appeared just after radiation suggests disease progression during radiotherapy. therefore, we think chemotherapy should be started as soon as possible during or even before radiotherapy for prevention of disease progression. detection of para-aortic lymphadenopathy tells us computed tomography should have been done before starting treatment. although most reported had a short survival, our patient, being alive after 3.5 years without any evidence of relapse, is the evidence of long-term survival by chemoradiation therapy. conflict of interest none declared. references 1. shaffer dw, burris ha, o’rourke tj. testicular relapse in adult acute myelogenous leukemia. cancer. 1992;70:1541-4. 2. litam pp, koller ca, mccredie kb. relapse of adult acute myelogenous leukemia isolated in testicle. tex med. 1989;85:36-8. 3. schiffer ca, sanel ft, stechmiller bk, wiernik ph. functional and morphologic characteristics of the leukemic cells of a patient with acute monocytic leukemia: correlation with clinical features. blood. 1975;46:17-26. 4. sastre jl, ulibarrena c, armesto a, et al. [testicular granulocytic sarcoma as a form of relapse in a patient with acute megakaryoblastic leukemia]. sangre (barc). 1998;43:248-50. spanish editorial comment granulocytic sarcoma (gs) is a localized extramedullary tumor composed of immature myeloid cells. the common sites of involvement are the bone, orbit, periosteum, soft tissue, lymph nodes, and skin. it is a rare primary manifestation of acute myeloid leukemia (aml), blastic transformation of chronic myeloid leukemia, and myelodysplastic syndromes.(1) granulocytic sarcoma of the testis is rare and has a poor prognosis. it develops in 2% to 8% of patients with aml.(2) granulocytic sarcoma may present independently of, precede, or develop concurrently with aml. although some patients present with localized disease (such as the presented case by ghadiany and colleagues), gs should be considered a systemic process because recurrence and progression are common. cytogenetic study has an important prognostic role in gs complicating adult aml. unfortunately, in the presented case, this study has not been done. the most common cytogenetic findings in gs complicating adult aml have been t(8;21)(q22;q22) and inv(16) (p13q22).(1) patients with tetraploid karyotype have a very poor prognosis, compatible with the very aggressive course of the disease. that patient presented with unilateral testicular enlargement, but physical examination revealed bilateral testicular enlargement. although it is an extremely rare entity, extramedullary myeloid cell tumors must be considered in the differential diagnosis of unilateral testicular masses in patients with myelodysplastic/myeloproliferative disease. testicular relapse often heralds subsequent bone marrow relapse or other extramedullary relapse, as this occurred in this case. diagnosis of testicular gs is difficult. biopsy, but not necessarily complete excision, is appropriate for diagnosis. granulocytic sarcoma is easily confused with non-hodgkin lymphoma because of the morphologic similarities of the blasts to large cell lymphoma, the presence of lymphoglandular bodies, and the rarity of auer rods and eosinophilic myelocytes.(3) immunohistochemical examination can be diagnostic, as it has been done in the presented case. immunophenotyping of bone marrow relapse of leukemia as testicular sarcoma—ghadiany et al urology journal vol 5 no 2 spring 2008 135 mononuclear cells by flow cytometry reveals positive cd45, cd34, human leukocyte antigendr, and cd7 blast cells expressing the myeloid markers cd13, cd33, and myeloperoxidase. the treatment of gs with or without associated aml should involve intensive systemic chemotherapy with radiation. mohammad reza safarinejad associate editor, urology journal references 1. byrd jc, edenfield wj, shields dj, dawson na. extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. j clin oncol. 1995;13:1800-16. 2. economopoulos t, alexopoulos c, anagnostou d, et al. primary granulocytic sarcoma of the testis. leukemia. 1994;8:199-200. 3. suh yk, shin hj. fine needle aspiration biopsy of granulocytic sarcoma: a clinicopathologic study of 27 cases. cancer. 2000;90:364-72. urology for people 214 urology journal vol 7 no 3 summer 2010 persistent erection can be dangerous priapism is a painful and persistent erection that is not associated with sexual activity or desire, and does not subside after sexual intercourse or masturbation. this disorder usually mandates prompt medical attention. if priapism lasts more than 4 hours, it can result in erectile dysfunction or impotence. it is quite prevalent in certain conditions. for example, in ethnic groups (south of iran) with sickle cell disease, it has been reported to affect approximately 40% of men. idiopathic (the cause is unknown) priapism accounts for as many as half of all documented cases. priapism can occur with some medications. with the introduction of intracavernously (intrapenile) administered drugs for impotence, priapism resulting from the use of these agents is being increasingly diagnosed. the rate of priapism with the above mentioned agents in young men without significant erectile dysfunction is higher. despite the risk of aphrodisiacs (erectile function enhancer), their prescription and use are increasing markedly. self administration of any medication that may affect erectile function should be avoided. see page 174 for full-text article renal colic or flank pain kidney stone affects 13% of men and 7% of women during their lifetime. renal colic is an acute and severe pain related to the migration of calculus along the urinary tract. pain associated with renal colic is often reported as the more intense that patients can experience. it should be mentioned that more than one third of patients presenting to the emergency department with flank pain have significant findings other than renal stone. twenty-four percent of these patients have findings that require immediate attention, such as appendicitis and cholecystitis. therefore, in patients with a history of kidney stone, recurrent flank pain should not be attributed absolutely to kidney stone. it is worthwhile to know that patients with acute renal colic could be especially vulnerable to receiving different care depending on the timing of their presentation. generally, weekend presentation is associated with lower rates of intervention and with treatment delays. because the decision for acute intervention is made by clinical judgment, the decisions to intervene could vary by whether the patient presents in the weekend and could be vulnerable to a range of external pressures. see page 148 for full-text article inborn kidney abnormalities kidney abnormalities (anomalies) are frequently detected on the routine second trimester ultrasonography offered to pregnant women. congenital genitourinary tract anomalies occur commonly in the general population. unilateral renal absence is a relatively common kidney anomaly that is noted in 1:1,000. the absence of a kidney is usually without symptoms. knowledge of these conditions is essential for adequate management of the pregnancy and effective parental counseling. pregnancies complicated by fetal renal anomalies are at risk for newborn baby respiratory and renal insufficiency. detailed obstetric ultrasound scans in the second trimester of pregnancy can detect genitourinary abnormalities. some of the kidney anomalies are incompatible with life, and some may require intrauterine or early neonatal intervention. therefore, in some instances prior to childbirth, diagnosis of renal anomalies can save the life of newborn baby. if an anomaly is detected prior to childbirth, necessary interventions can significantly lessen maternal and child complications. all pregnant women should undergo ultrasonography in the second trimester. see page 161 for full-text article what’s up in urology journal, summer 2010? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2010;7:214. www.uj.unrc.ir introduction according to the european association of urology (eau) guidelines, treatment options for stage i non-seminomatous germ cell tumors (nsgcts) include active surveillance after orchiectomy, platinum-based chemotherapy, or primary retroperitoneal lymphnode dissection (rplnd)(1). risk of relapse is a major concern for active surveillance, with five year relapsing rate up to 30.6%(2). despite the good response of platinum-based chemotherapy in nsgct, its usage is limited by complications, such as adverse cardiac events, deterioration of renal function, and the risk of secondary malignancies(3). in spite of controversies, primary rplnd play a role in the management of patients with stage i nsgcts in term of retroperitoneal local control, accurate clinical staging, removal of chemo-resistant tumor elements, and avoiding overtreatment of chemotherapy(3). traditionally, the rplnd was performed via open surgery through transperitoneal or retroperitoneal approach. despite excellent oncologic outcomes, open-rplnd (o-rplnd) was associated with great operative trauma, significant morbidity, and prolonged hospitalization(4,5). the first laparoscopic rplnd (l-rplnd) was described by rukstalis et al. in 1992 for diagnostic purpose(6). with the development and advancement of the technique, l-rplnd has been applied to testicular cancer for treatment purposes with less operative trauma and perioperative complications, more favorable cosmetic results, similar oncologic outcomes, and shorter hospitalization as compared with o-rplnd(7-9). with the popularization of robotic technology in recent years, robotic surgery has replaced laparoscopy in many challenging urologic procedures. robotic technology has demonstrated significant advantages in term of excellent 3-dimension vision, shorter learning curve, stability, and dexterity. r-rplnd was first described laparoscopic and robotic urology robotic versus laparoscopic retroperitoneal lymph node dissection for clinical stage i non-seminomatous germ cell tumor of testis: a comparative analysis yansheng xu1,*, hongzhao li1,*, baojun wang1,*, liangyou gu1, yu gao1, yang fan1, yuanxin yao1, xenginn fam2, xin ma1, #, xu zhang1# purpose: to compare the treatment outcomes of robotic retroperitoneal lymph node dissection (r-rplnd) versus laparoscopic rplnd (l-rplnd) for clinical stage i non-seminomatous germ cell testicular tumors (nsgcts). materials and methods: we retrospectively reviewed the data of patients with stage i nsgcts who underwent robotic or laparoscopic rplnd between 2008 and 2017. perioperative data and oncologic outcomes were reviewed and compared between the two groups. progression-free survival was analyzed using kaplan-meier survival curves and compared between two groups. results: a total of 31 and 28 patients underwent r-rplnd and l-rplnd respectively. the preoperative characteristics of the patients were comparable in the two groups. patients in r-rplnd group had significantly shorter median operative time (140 vs. 175 minutes, p < .001), a shorter median duration to surgical drain removal (2 vs. 4 days, p = .002) and a shorter median postoperative hospital stay (5 vs. 6 days, p = .001). there were no statistical differences in intraand post-operative complication rate between the groups and the oncologic outcomes were similar in the two groups. conclusion: in expert hands, r-rplnd and l-rplnd were comparable in oncological parameter and morbidity rate; r-rplnd showed superiority in operation duration, median days to surgical drain removal and postoperative hospital stay for stage i nsgcts. multicenter and randomized studies with good power of study and sufficient follow-up duration are required to validate our result. keywords: lapraroscopy; nonseminomatous germ cell tumor; retroperitoneal lymph node dissection; robotic surgical procedures; treatment outcomes 1department of urology, the third medical center, chinese pla general hospital, beijing, china 2urology unit, surgery department, ukm medical centre, kuala lumpur malaysia *these authors equally contributed to this article. # these authors are joint corresponding authors of this paper. department of urology, the third medical center, chinese pla general hospital, beijing, china. tel.: +86 010 66938008; fax: +86 010 6822 3575. email: urologist@foxmail.com xu zhang, m.d, ph.d. department of urology, the third medical center, chinese pla general hospital, beijing, china. tel.: +86 010 66938008; fax: +86 010 6822 3575. email: xzhang@tjh.tjmu.edu.cn received december 2020 & accepted october 2021 urology journal/vol 18 no. 6/ november-december 2021/ pp. 618-622. [doi: 10.22037/uj.v18i.6629] by davol p et al in 2006(10,11). since then, the feasibility of r-rplnd has been fully demonstrated in several series reports(12-14). up to date, there is only one comparative analysis comparing r-rplnd with l-rplnd, and it remains to be demonstrated that r-rplnd offers a specific benefit over l-rplnd(15). in this study, we compare the perioperative results and oncologic outcomes between r-rplnd and l-rplnd for clinical stage i nsgcts. materials and methods study population after the approval was obtained from the medical ethics committee of our institute, data of patients with clinical stage i nsgct who had undergone l-rplnd or r-rplnd in our institute were retrospectively reviewed. patients who had received chemotherapy prior to rplnd, patients with primary diagnosis other than nsgct and patients with nsgct higher than clinical stage i were excluded from this study. clinical staging was performed according to the recommendation of eau guideline on testicular cancer, including computed tomography of the chest or x-ray, computed tomography or magnetic resonance imaging of the abdomen and pelvis, and serum tumor markers consisting of α-fetoprotein (afp), beta human chorionic gonadotropin (β-hcg), and lactate dehydrogenase (ldh). the patients were provided counseling on the advantages and disadvantages of treatment options including close surveillance, platinum-based chemotherapy and rplnd, and rplnd was their final choice. surgical technique all the procedures were performed transperitoneally by a single surgeon (xu zhang) with advanced laparoscopic and robotic experience. all the patients in both groups were positioned in 70° lateral and 15° trendelenburg position. the time between the placement of the first trocar and removal of the last trocars was recorded as the duration of the operation. for the patients with left testicular cancer, the template of lymph node dissection included left common iliac, preaortic above inferior mesenteric artery, paraaortic, retroaortic, interaortocaval and precaval lymph nodes. for the right-sided disease, the template included right common iliac, paracaval, precaval, retrocaval, interaortocaval, and preaortic above inferior mesenteric artery lymph nodes. the cranial border of dissection was the level of renal hilum and the lateral border was the ipsilateral ureter. sympathetic nerves were meticulously recognized and spared during the operation. postoperative surveillance patients with positive lymph node disease were recommended to adjuvant chemotherapy postoperatively. all the patients were regularly followed up postoperatively. physical examination, ultrasound on scrotum and abdomen, serum tumor markers examination and thoracic x-ray were performed every 3 months for the first two years, every 6 months between year 3 and 5 and annually thereafter. computerized tomography on abdomen and chest is done every 6 months for 5 years postoperatively and annually thereafter. statistical analysis the demographic and clinical data were collected and compared between l-rplnd and r-rplnd groups. ibm spss statistics 19.0 for windows (spss, ibm, al monk, ny) was utilized for the data analysis, and the significance level was set at two-tailed p < .05. continuous variables were presented as the median and iqr r-rplnd vs l-rplnd for stage i nsgcts-xu et al. figure 1. progression-free survival vol 18 no 6 november-december 2021 619 laparoscopic and robotic urology 620 and compared with the wilcoxon rank sum test. the χ2 and fisher’s exact test were used for comparisons of categorical variables. the kaplan-meier method was used to estimate survival probabilities, which were compared by the log rank test. results from september 2009 to march 2018, 31 and 28 patients underwent r-rplnd and l-rplnd respectively for stage i nscgt in our institute. the preoperative clinical characteristics of the patients were displayed in table 1. variables including age, bmi, primary laterality of the disease, pathological tumor-stage and histopathological result of orchidectomy were similar with p value > .05 between the groups. the perioperative clinical data of the patients was displayed in table 2. the estimated blood loss (ebl), ln yield, and median duration of ryle’s tube insertion were similar (p > .05) between the two groups. intraoperative complications, including open conversion, major blood loss and major blood vessels injury, were not encountered in both groups. the robotic cohorts had significantly shorter operative duration (140 vs. 175 minutes p < .05), median duration to surgical drainage removal (removed when the drainage less than 100 ml 2 vs. 4 days p =.002) and median postoperative hospital stay (5 vs. 6 days p = .001). one patient from the r-rplnd cohort and 2 patients from the l-rplnd cohort were complicated with chylous ascites. they were treated conservatively. one patient in the l-rplnd cohort presented with hypertension as sequelae of right renal artery stenosis, and he was treated with percutaneous dilatation of stenotic renal artery. two patients in the r-rplnd cohort and 1 patient in the l-rplnd cohort experienced retrograde ejaculation. the overall postoperative complication rate was similar between the two groups (9.7% vs. 14.3% p = .609). eight patients in the r-rplnd cohort and 5 patients in the l-rplnd cohort had retroperitoneal metastasis. the distribution of r-rplnd vs l-rplnd for stage i nsgcts-xu et al. variables r-rplnd l-rplnd p value number of cases 31 28 median (iqr) age (yrs) 27 (16-52) 29 (18-56) 0.429 bmi (kg/m2) 23.7 (18.7-29.4) 24.5 (17.3-29.3) 0.539 primary laterality, n (%) left 11(35.5) 12 (42.9) 0.602 right 20(64.5) 16 (57.1) pt stage, n (%) pt1 21 (67.8) 22 (78.6) 0.478 pt2 9 (29.0) 6(21.4) pt3 1(3.2) 0 primary pathological type, n (%) mixed 14 (45.2) 15 (53.6) 0.630 embryona 14 (45.2) 11 (39.3) teratoma 0 1(3.6) yolk sac 1(3.2) 0 leydig cell tumor 2(6.4) 1(3.6) elevation of tumor markers, n (%) afp 2(6.54) 2(7.2) 1.000 β-hcg 0 1(3.6) 0.475 ldh 1(3.2) 1(3.6) 1.000 table 1. patient demographics and tumor characteristics variables r-rplnd l-rplnd p value number of cases 31 28 median (iqr) operative time, mins 140(100-210) 175(120-300) 0.000 median (iqr) estimated blood loss, ml 50(20-200) 50(10-350) 0.847 median (iqr) ln yield 23(14-33) 21(9-30) 0.150 intraoperative complication, n (%) open conversion 0 0 ns transfusion 0 0 major vessel injury 0 0 median (iqr) days to surgical drain removal 2(0-9) 4(1-25) 0.002 to ryle’s tube removal 1(1-2) 1(1-3) 0.288 median (iqr) hospital stay, days 5(3-9) 6(3-25) 0.001 postoperative complication, n (%) 3(9.7) 4(14.3) chylous ascites 1 2 0.609 renal artery stenosis 0 1 retrograde ejaculation 2 1 pn stage, n (%) pn0 23(74.1) 23(82.1) 0.654 pn1 6(19.4) 3(10.7) pn2 2(6.5) 2(7.2) median (iqr) follow-up, months 24(12-51) 68.5(42-116) < 0.001 table 2. intraand post-operative information the pn stage was similar between the two groups (p = .654). median follow-up of the patients in the r-rplnd and l-rplnd group was 24 and 68.5 months respectively (p < .05). no patients with pn0 stage showed retroperitoneal recurrence in either groups but pulmonary replase was detected in 2 patients in the r-rplnd cohort and 1 patient in the l-rplnd cohort. all the patients with pn1 and pn2 disease in both groups selected chemotherapy, there was no retroperitoneal recurrence and systemic relapse detected in either group. there was no significant difference in pfs between the 2 groups (p = .384, figure 1). discussion testicular cancer is a common malignancy for males between 15 to 35 years old. it represents nearly 1% of male neoplasms and 5% of urological tumors(16,17). the majority of the cases are germ cell tumors which can be further classified as seminoma or nonseminoma (1). as compared to seminoma, nonseminoma is more aggressive in nature(1). up to 25-30% of patients with nsgcts have retroperitoneal lymph nodal metastatic disease with negative imaging evidence(18). according to eau guideline 2017, options for clinical stage i nsgcts include close surveillance, chemotherapy, and rplnd. despite controversies, rplnd remains its role in treatment options for some selected patients with stage i nsgct(1). traditionally, the rplnd was performed via open surgery through a transperitoneal or retroperitoneal approach. while o-rplnd has shown excellent oncologic outcomes, these procedures were associated with great operative trauma, significant morbidity, and prolonged hospitalization(4,5). with the advancement of minimally invasive techniques, l-rplnd and r-rplnd have become alternatives to open surgery and demonstrated the advantages of minimally invasive surgery such as less operative trauma and perioperative complications, favorable cosmetic results and shorter hospitalization time(7,8,12-14). robotic-assisted surgery has demonstrated advantages over laparoscopic surgery in many challenging urologic procedures(19-21). in consideration of superior advantages of robotic technology, it is logical to suppose that r-rplnd offers a specific benefit over l-rplnd. however, the available published data are limited and there is only one direct comparative analysis of r-rplnd and l-rplnd for nsgcts(15). unfortunately, according to the results of this study, it cannot be proved that r-rplnd offers any tangible benefits over conventional laparoscopy(15). in our study, as compared to l-rplnd, r-rplnd demonstrated better results in a few parameters, which were, operative duration, median duration to the surgical drain removal, and hospitalization time. this finding is different from the study reported by harris at el (15). the mean operative duration was significantly shorter in r-rlpnd group than that in l-rlpnd group (140 vs. 175 minutes p < .05). this result could be attributed to the characteristics of robotic surgery, such as the enhanced three-dimensional magnification view, the stability and dexterity of the robotic equipment, and the assistance of third arm that allow a good operative field, a controlled and precise dissection as compared with laparoscopy surgery. according to our experience, robotic surgery offered significant advantages for dissection posterior to the great vessels or at the bifurcation of the major vessels. the flexibility of the wristed instruments offered good retraction of blood vessels to assess lymphatic tissue posterior to the great vessels (13). such retraction is difficult to achieve with straight and rigid laparoscopic instruments. a shorter median time to the surgical drain removal was also noted in robotic group as compared to the laparoscopy group (2 vs. 4 days p = .002). this may also be attributed to the previously mentioned characteristics of robotic surgery. in our department, a surgical drain is routinely inserted for rplnd, which is removed when the drainage is less than 100 ml. patients were discharged from the hospital after the removal of surgical drain. thus postoperative hospitalization stay of the robotic group was shorter than the laparoscopic group. the postoperative hospitalization time in our study was significantly longer than studies from the western countries(8,9,12,14,22). this finding might be due to differences in health-care system and culture background between china and western countries. patients in china intend for longer hospital stay until full recovery even though they are fit to be discharged. regarding the overall complications, there was no statistically significant difference between the two groups (9.7% vs. 14.3%, p = .609). the overall complication rate of our cohort is similar to complication rates in other published studies(12,15,22). in terms of safety, the result is comparable between the two groups. at oncological aspect, no significant differences were observed in ln yield, frequency of ln positivity, and pn stage between the two groups. kaplan-meier curve showed no significant differences in pfs between the groups. oncological control is comparable between the two study cohorts. since this surgery involves dissection of major vessel, it is a real challenge when major vessels injury failed to be repaired intracorporeally. surgeon need to scrub and return to the operation table that may endanger patient life. in laparoscopic approach, the bleeding can be temporally controlled using a laparoscopy satinsky clamp while converting to open surgery(15). even so, it cannot be denied that robotic approach really benefits the surgeons in term of shorter learning curve, more comfortability and less fatigue as compared with traditional laparoscopic approach(11,21). there were some limitations of this study. first, it is a retrospective and nonrandomized controlled study with a small sample size, so that the power of study was not strong. second, our targeted subjects were patients with nsgct stage i disease, where rplnd was expected to be simpler as compared with patients with higher clinical stage or residual masses post-chemotherapy. in addition, the surgeon for this study is a very skillful and has extensive experience in robotic and laparoscopic surgeries. conclusions r-rplnd and l-rplnd were comparable in oncological parameter and morbidity rate; r-rplnd showed superiority in operation duration, median days to surgical drain removal, and postoperative hospital stay for stage i nsgcts. laparoscopic and robotic urology 506 r-rplnd vs l-rplnd for stage i nsgcts-xu et al. vol 18 no 6 november-december 2021 621 conflict on interest the authors have no conflicts of interest to declare. references 1. m.p. laguna (chair), p. albers, f. algaba,et al. members of the eau–estro–esur – siog testicular cancer guidelines panel. eau–estro–esur–siog guidelines on testicular cancer. retrieved from:http:// uroweb.org/guideline/testicular-cancer/ access date [december 16, 2020]. 2. de wit r. optimal management of clinical stage i nonseminoma: new data for patients to consider. j clin oncol. 2014;32:3792-3. 3. heidenreich a, paffenholz p, nestler t, pfister d, daneshmand s. role of primary retroperitoneal lymph node dissection in stage i and low-volume metastatic germ cell tumors. curr opin urol. 2020;30:251-7. 4. baniel j, foster rs, rowland rg, et al. complications of primary retroperitoneal lymph node dissection. j urol. 1994;152:4247. 5. baniel j, sella a. complications of retroperitoneal lymph node dissection in testicular cancer: primary and postchemotherapy. semin surg oncol. 1999;17:263-7. 6. rukstalis db, chodak gw. laparoscopic retroperitoneal lymph node dissection in a patient with stage 1 testicular carcinoma. j urol. 1992;148:1907-9; discussion 1909-10. 7. nicolai n, tarabelloni n, gasperoni f, et al. laparoscopic retroperitoneal lymph node dissection for clinical stage i nonseminomatous germ cell tumors of the testis: safety and efficacy analyses at a high volume center. j urol. 2018;199:741-7 8. öztürk ç, been lb, van ginkel rj, gietema ja, hoekstra hj. laparoscopic resection of residual retroperitoneal tumor mass in advanced nonseminomatous testicular germ cell tumors; a feasible and safe oncological procedure. sci rep. 2019;9:15837. 9. porter jr. a laparoscopic approach is best for retroperitoneal lymph node dissection: yes. j urol. 2017;197:1384-6. 10. davol p, sumfest j, rukstalis d. roboticassisted laparoscopic retroperitoneal lymph node dissection. urology. 2006;67:199. 11. jain s, gautam g. robotics in urologic oncology. j minim access surg. 2015;11:404. 12. pearce sm, golan s, gorin ma, et al. safety and early oncologic effectiveness of primary robotic retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer. eur urol. 2017;71:476-82. 13. stepanian s, patel m, porter j. robot-assisted laparoscopic retroperitoneal lymph node dissection for testicular cancer: evolution of the technique. eur urol. 2016;70:661-7. 14. cheney sm, andrews pe, leibovich bc, et al. robot-assisted retroperitoneal lymph node dissection: technique and initial case series of 18 patients. bju int. 2015;115:114-20. 15. harris kt, gorin ma, ball mw, et al. a comparative analysis of robotic vs laparoscopic retroperitoneal lymph node dissection for testicular cancer. bju int. 2015;116:920-3. 16. filippou p, ferguson je, 3rd, nielsen me. epidemiology of prostate and testicular cancer. semin intervent radiol. 2016;33:1825. 17. park js, kim j, elghiaty a, ham ws. recent global trends in testicular cancer incidence and mortality. medicine (baltimore). 2018;97:e12390 18. fernandez eb, moul jw, foley jp, et al. retroperitoneal imaging with third and fourth generation computed axial tomography in clinical stage i nonseminomatous germ cell tumors. urology. 1994;44:548-52. 19. roh hf, nam sh, kim jm. robot-assisted laparoscopic surgery versus conventional laparoscopic surgery in randomized controlled trials: a systematic review and meta-analysis. plos one. 2018 13:e0191628. 20. bhattu as, ganpule a, sabnis rb, et al. robotassisted laparoscopic donor nephrectomy vs standard laparoscopic donor nephrectomy: a prospective randomized comparative study. journal of endourology. 2015;29:133440. 21. tang b, gao gm, zou z, et al. efficacy comparison between robot-assisted and laparoscopic surgery for mid-low rectal cancer: a prospective randomized controlled trial. zhonghua wei chang wai ke za zhi. 2020;23:377-83. 22. nicolai n, tarabelloni n, gasperoni f, et al. laparoscopic retroperitoneal lymph node dissection for clinical stage i nonseminomatous germ cell tumors of the testis: safety and efficacy analyses at a high volume center. j urol. 2018; 199:741-7. r-rplnd vs l-rplnd for stage i nsgcts-xu et al. laparoscopic and robotic urology 622 sexual dysfunction and infertility 110 urology journal vol 7 no 2 spring 2010 pre-operative serum level of inhibin b as a predictor of spermatogenesis improvement after varicocelectomy mohammadreza dadfar,1 akram ahangarpour,2 aliakbar habiby,1 dinyar khazaely1 purpose: due to various reasons, spermatogenesis might not improve after varicocelectomy. inhibin b, a sertoli cell glycoprotein, has proved itself as a marker of spermatogenesis. in this study, we measured serum level of inhibin b in patients with varicocele and through comparing pre and post operative semen analysis data, we tried to use serum level of inhibin b as a predictor of spermatogenetic improvement. materials and methods: this prospective clinical trial was carried out between september 2007 and september 2008 on 36 infertile men with high grade unilateral or bilateral varicocele. scrotal ultrasonography and measurement of seminal parameters and serum level of inhibin b were performed for the patients and after confirmation of impaired spermatogenesis, they underwent a subinguinal nonmicroscopic varicocelectomy by a single surgeon. physical examination, scrotal ultrasonography, and semen analysis were repeated at postoperative months of 3 and 6. statistical data analysis was done by independent and paired sample t test and spearman’s rho test. results: mean size of the testis remained the same (p = .5), but mean sperm density, normal morphology, and motility all increased statistically significant after the operation (p < .05, p = .042, p = .023). a significant relationship was found between serum levels of inhibin b and the testis sperm count and morphology (p < .05), but not sperm motility (p > 0.05). conclusion: it seems that serum level of inhibin b can be used as a reliable pre-operative marker of testicular potential activity and can also predict chance of spermatogenesis after varicocelectomy and save patients from useless surgical procedures. urol j. 2010;7:110-4. www.uj.unrc.ir keywords: varicocele, spermatogenesis, sertoli cells, inhibin b 1department of urology, imam khomeini hospital, school of medicine, jundishapoor university of medical sciences, ahwaz, iran 2physiology and diabetes research center, school of medicine, jundishapoor university of medical sciences, ahwaz, iran corresponding author: mohammadreza dadfar, md department of urology, imam khomeini hospital, school of medicine, jundishapoor university of medical sciences, ahwaz, iran tel: +98 916 311 0530 fax: +98 611 222 5763 e-mail: mdadfar@yahoo.com received january 2009 accepted july 2009 introduction varicocele is identified by the presence of dilated and tortuous veins in the spermatic cord. about 15% of the normal men population and up to 40% of infertile men experience varicocele(1) and it seems to be the underling disease in 70% of men with secondary infertility.(2) varicocele is recognized as the most surgically correctable cause of male infertility, and a varicocele repair is the most commonly performed surgical procedure in treatment of male infertility.(3) inhibin b is a 32-kd glycoprotein which consists of two chains (α, β).(4) based on the β chain, inhibin b is classified to two subgroups (a, b) and is detectable by radioimmunoassay and enzymeserum level of inhibin b and spermatogenesis improvement—dadfar et al 111urology journal vol 7 no 2 spring 2010 linked immunosorbent assay.(5) inhibin b is secreted by the sertoli cells in response to folliclestimulating hormone (fsh)(5) and regulates gametogenesis by negative feedback effect on fsh secretion.(6) it selectively inhibits fsh synthesis and has local paracrine functions on the testis. (7) inhibin b has been reported as an endocrine marker to monitor normal gonadal function in both sexes(6) and is identified as an effective predictor of improvement of spermatogenesis after varicocelectomy.(8) recently, inhibin b has been reported to be a more sensitive factor in study of azoospermic men than the testis size, fsh, and even the testis biopsy.(9) a correlation has been found between serum level of inhibin b, total sperm count, and the testis volume(10) while in a study by fugisawa and colleagues, no significant correlation was seen between serum level of inhibin b and post varicocelectomy fsh, testosterone, the testis volume, and sperm count, but it was concluded that differences in serum level of inhibin b after varicocelectomy may be a predictor of improvement in the testis function.(11) turkyilmaz and associates in 2006 also confirmed that increase in serum level of inhibin b is correlated with improvement of testis function after varicocelectomy.(12) in this study, we evaluated the efficacy of serum level of inhibin b as a predictor of improvement in the seminal indices after varicocelectomy. materials and methods from september 2007 to september 2008, 65 infertile men with varicocele presented to the urology clinic. our study inclusion criterion was diagnosis of grade ii-iii uni or bilateral varicocele on physical examination by an experienced urologist. patients with a past history of cryptorchidism, scrotal surgery, and solitary testis or who had a history of medical therapy for infertility were excluded. of 65 patients, 35 subjects were enrolled in the present study. after a 3-day abstinent period, semen specimens were collected for computer aided seminal analysis, and serum specimens were obtained for measurement of inhibin b at 8 a.m. all these measurements were done in a single reference andrology laboratory. ultrasonographic evaluation was performed to assess the testis volume by empirical formula of lambert (length × width × eight × 0.71) and to rule out testicular abnormalities. blood specimens were centrifuged in the room temperature for 15 minutes by 2000 rounds per minute, and collected serum were kept in a refrigerator in -25°c. serum level of inhibin b was measured by double antibody immunoenzyme metric assay, using solid phase sandwich enzymelinked immunosorbent assay test (dsl-10-84100i, diagnostic systems laboratories, webster, texas, usa) by specific monoclonal antibody against βb chain for inhibin b, with detection limits between 7 and 1000 pg/ml. subinguinal varicocelectomy was performed for all of the patients by a single urologist. four weeks after the operation, a doppler ultrasonography examination was performed to confirm the improvement of varicocele by demonstrating lack of venous back flow in all of the subjects. we followed up the patients for 3 and 6 months, and seminal analysis and scrotal ultrasonography were performed to evaluate changes in the seminal indices and the testis volume. eventually, data were analyzed using spss (statistical package for the social science, version 16.0, ssps inc, chicago, illinois, usa) software. for independent variables we used independent sample t test and for dependent variables, paired sample t test was utilized. p values less than .05 were considered statistically significant. results three subjects refused to continue the follow-up after 3 months and were excluded from our study. the mean age of the patients was 25.32 ± 4.13 years. all the patients had left side varicocele with a 15% prevalence of bilateral varicocele. mean serum level of inhibin b was 110 ± 38 pg/ml. patients were classified into 2 groups based on serum inhibin level: group a (inhibin b < 110 pg/ml, 16 subjects) and group b (inhibin b > 110 pg/ ml, 17 subjects). the mean serum levels of inhibin b for groups a and b were 70.78 (sd = 10.32) and 211.47 (sd = 16), respectively. the mean age for groups a and b were 26.26 ± 1.3 and 24.71 ± 2.2 years, respectively, which showed no significant difference between two groups (p = .36) serum level of inhibin b and spermatogenesis improvement—dadfar et al 112 urology journal vol 7 no 2 spring 2010 the mean testis volume was 16.58 ± 23 ml, 16.86 ± 14 ml, and 16.94 ± 22 ml before the varicocelectomy and at 3 and 6 months postoperation, respectively, which showed no significant changes in the testis volume before the operation and during the follow-up periods (p = .5). the mean sperm count was 11.62 ± 0.22 × 106 /ml before the operation which increased to 13.36 ± 0.15 × 106 /ml and 19.5 ± 0.33 × 106 /ml at 3 and 6 months after the operation, respectively, which showed a significant correlation between varicocelectomy and improvement in sperm count at 3 and 6 months (p = .032). there was also a significant improvement in sperm count from 3 to 6 months (p = .036). the mean sperm motility was 14.27 ± 9% which increased to 16.97 ± 11% at 3 months and 23.82 ± 6% at 6 months, which showed a significant improvement in sperm motility after varicocelectomy (p = .023). the mean normal sperm morphology was 8.317 ± 0.54% which increased to 11.09 ± 0.87% and 16.36 ± 0.22% at 3 and 6 months after the operation, respectively, and showed a significant improvement in sperm morphology (p = .042). the mean volume of the testis was 15.3 ± 2.5 ml, 15 ± 1.22 ml, and 34 ± 1.1 ml for group a and 17.8 ± 2.32 ml, 17.97 ± 2.11 ml, and 18.26 ± 3.21 ml for group b before and at 3 and 6 months after varicocelectomy, respectively, which showed a significant difference between two groups, and we detected a significant correlation between the testis size and serum level of inhibin b. the mean sperm count for group a was 11.6 ± 3.32, 13.21 ± 4.32, and 14.76 ± 2.22 × 106 sperm/ml and for group b was 11.64 ± 4.41, 13.5 ± 2.22, and 23.96 ± 3.44 × 106 sperm/ ml before the operation, and at 3 and 6 months after the procedure, which showed no significant difference at 3 month, while it was significant at month 6 for each group and there was also a significant correlation between serum inhibin b level and improvement in sperm count at month 6 (spearman’s rho = 0.567) (figure 1). analysis showed that we may be able to calculate postoperative sperm count by having pre-operative serum inhibin b level using the following formula: y = 13.452 + 0.042 x (y = sperm count at 6 months after varicocelectomy, x = pre-operative serum inhibin b level). the mean sperm motility and density before the operation and at 3 and 6 months after varicocelectomy was 14.188 ± 3.3%, 16.25 ± 4.32%, and 21.81 ± 3.12% for group a and 14.353 ± 2.11%, 17.647 ± 3.11%, and 25.71 ± 4.32% for group b. t test showed no significant difference between the two groups, but we detected moderate improvement in sperm motility for each group after varicocelectomy. the mean normal sperm morphology was 9.5 ± 2.11, 11.31 ± 3.22, and 13.38 ± 4.11 for group a and 7.133 ± 7.11, 10.2 ± 3.21, and 18.52 ± 3.43 for group b before the procedure and at 3 and 6 months after varicocelectomy, which showed no significant difference in normal sperm morphology for two groups, but showed significant improvement at months 6 (p = .021). it seems that with increase in serum level of inhibin b before varicocelectomy, there will be more improvement in sperm morphology at 6 months after the operation (figure 2). following formula was designed to predict changes in sperm morphology after the operation; y = 12.039 + 0.03 x (y = normal sperm morphology after varicocelectomy, x = serum level of inhibin b before procedure). figure 1. regression analysis of pre-operative serum level of inhibin b against 6 months postoperative sperm counts. serum level of inhibin b and spermatogenesis improvement—dadfar et al 113urology journal vol 7 no 2 spring 2010 discussion deleterious effects of varicocele can cause reduction in function and number of the testicular cells,(13) and subsequently leads to decreased testis volume, spermatogenesis, inhibin b production,(2) and lowered serum level of inhibin b.(14) in patients with a higher pre-operative serum level of inhibin b, it can be assumed that varicocele has had less destroying effects on the testicular parenchyma. (15) thus, more improvement in spermatogenesis may be anticipated after varicocelectomy. in this study, a significant correlation was found between serum level of inhibin b and the testis volume as well as improvement in spermatogenesis indices (sperm count and morphology) post varicocelectomy. in accordance with our findings, nowroozi and coworkers concluded that higher pre-operative serum inhibin b level was correlated with a better testicular histology and more chance of positive testicular biopsy in azoospermic patients.(16) bohring and krause also reported that inhibin b can be used as a serum marker of sertoli cells function and patients with normal serum level of this marker will have better spermatogenesis and testicular functions.(17) romeo and colleagues reported decreased serum level of inhibin b in adolescents with varicocele and a significant statistical correlation between serum level of inhibin b and the testis volume.(18) in another study, fujisawa and associates reported that pre-operative serum inhibin b concentration could not reliably predict a response to varicocelectomy. however, a change in serum inhibin b concentration after varicocelectomy might be helpful to evaluate the improvement of testicular function after varicocelectomy.(11) conclusion it may be concluded that pre-operative serum level of inhibin b can be used to predict postoperative improvement in spermatogenesis indices. however, further detailed and comprehensive studies are required in this regard. evaluation of predictive efficacy of serum inhibin b level on smaller subclinical varicoceles also may be a good research area for further studies. conflict of interest none declared. references 1. nagler hm, luntz rk, martinis fg, lipshultz li, howars ss. infertility in the male. 3 ed: mosbi year book; 1997. 2. witt ma, lipshultz li. varicocele: a progressive or static lesion? urology. 1993;42:541-3. 3. abdel-maguid af, othman i. microsurgical and nonmagnified subinguinal varicocelectomy for infertile men: a comparative study. fertil steril. 2010. 4. knight pg, beard aj, wrathall jh, castillo rj. evidence that the bovine ovary secretes large amounts of monomeric inhibin alpha subunit and its isolation from bovine follicular fluid. j mol endocrinol. 1989;2:189-200. 5. anderson ra, wallace em, groome np, bellis aj, wu fc. physiological relationships between inhibin b, follicle stimulating hormone secretion and spermatogenesis in normal men and response to gonadotrophin suppression by exogenous testosterone. 1997;12:746. 6. ramaswamy s, marshall gr, pohl cr, friedman rl, plant tm. inhibitory and stimulatory regulation of testicular inhibin b secretion by luteinizing hormone and follicle-stimulating hormone, respectively, in the rhesus monkey (macaca mulatta). endocrinology. 2003;144:1175-85. 7. luisi s, florio p, reis fm, petraglia f. inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy. hum reprod update. 2005;11:123-35. 8. pierik fh, vreeburg jt, stijnen t, de jong fh, weber rf. serum inhibin b as a marker of spermatogenesis. j clin endocrinol metab. 1998;83:3110-4. figure 2. regression analysis of pre-operative serum level of inhibin b against 6 months postoperative normal sperm morphology. serum level of inhibin b and spermatogenesis improvement—dadfar et al 114 urology journal vol 7 no 2 spring 2010 9. van beek rd, smit m, van den heuvel-eibrink mm, et al. inhibin b is superior to fsh as a serum marker for spermatogenesis in men treated for hodgkin’s lymphoma with chemotherapy during childhood. hum reprod. 2007;22:3215-22. 10. welt c, sidis y, keutmann h, schneyer a. activins, inhibins, and follistatins: from endocrinology to signaling. a paradigm for the new millennium. exp biol med (maywood). 2002;227:724-52. 11. fujisawa m, dobashi m, yamasaki t, et al. significance of serum inhibin b concentration for evaluating improvement in spermatogenesis after varicocelectomy. hum reprod. 2001;16:1945-9. 12. turkyilmaz z, karabulut r, sonmez k, et al. inhibin b levels in peripheral vein do not correlate with inhibin b levels in the spermatic vein in adolescents with varicocele. arch androl. 2006;52:325-8. 13. paduch da, niedzielski j. repair versus observation in adolescent varicocele: a prospective study. j urol. 1997;158:1128-32. 14. yamamoto m, hibi h, hirata y, miyake k, ishigaki t. effect of varicocelectomy on sperm parameters and pregnancy rate in patients with subclinical varicocele: a randomized prospective controlled study. j urol. 1996;155:1636-8. 15. [no author listed]. mesterolone and idiopathic male infertility: a double-blind study. world health organization task force on the diagnosis and treatment of infertility. int j androl. 1989;12:254-64. 16. nowroozi mr, radkhah k, ayati m, jamshidian h, ranjbaran a, jabalameli p. serum inhibin b concentration as a prognostic factor for prediction of sperm retrieval in testis biopsy of patients with azoospermia. arch iran med. 2008;11:54-6. 17. bohring c, krause w. serum levels of inhibin b in men with different causes of spermatogenic failure. andrologia. 1999;31:137-41. 18. romeo c, arrigo t, impellizzeri p, et al. altered serum inhibin b levels in adolescents with varicocele. j pediatr surg. 2007;42:390-4. clinical pathology case 199urology journal vol 7 no 3 summer 2010 a complication after percutaneous nephrolithotomy farzaneh sharifiaghdas, nasser simforoosh, ardalan ozhand urol j. 2010;7:199-200. www.uj.unrc.ir urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, m.c., tehran, iran case presentation a 24-year-old woman with left renal pelvis and lower calyceal stones was admitted for percutaneous nephrolithotomy (pcnl) (figure 1). the surgery was uneventful. nephrostomy tube and ureteral stent were removed on the 2nd postoperative day. soon after, urine leakage from the site of the nephrostomy tube and fever developed. temperature was as high as 39˚c and leukocytosis up to 20 000/mm3, with neutrophils as the dominant part (80%), was reported. double j stent was inserted through ureteroscope. on the 3rd postoperative day, the patient showed signs and symptoms of obstipation, vomiting, abdominal tenderness and rebound tenderness, and high fever. plain abdominal x-ray at supine and upright position revealed air fluid level and no evidence of gas pattern in the pelvis (rectum) and sentinel loop in the left upper quadrant (figure 2). chest x-ray revealed pleural effusion in both sides (figure 3). figure 1. intravenous urography demonstrates a 3-cm stone in the left kidney. a b clinical pathology case 200 urology journal vol 7 no 3 summer 2010 quiz what could be the possible cause of the abdominal pain and obstipation? what is your suggestion as the next step of diagnosis and treatment? the answers will be discussed in the next issue of urology journal. figure 2. plain abdominal radiography shows multiple air fluid level patterns and empty pelvic cavity. figure 3. chest x-ray reveals bilateral pleural effusion. case report 62 urology journal vol 5 no 1 winter 2008 inflammatory pseudotumor of bladder report of 2 cases and review of literature ali razi,1 ali radmehr2 keywords: bladder, pseudosarcoma, inflammatory pseudotumor 1department of urology, dr shariati hospital, tehran university of medical sciences, tehran, iran 2department of radiology, dr shariati hospital, tehran university of medical sciences, tehran, iran corresponding author: ali razi, md department of urology, dr shariati hospital, north kargar st, tehran, iran tel: +98 21 8800 5895 fax: +98 21 8800 5895 e-mail: arazi@sina.tums.ac.ir received may 2006 accepted february 2007 introduction inflammatory pseudotumor of the bladder is a rare benign proliferative lesion that resembles a neoplastic tumor.(1-5) most of the tumors of the bladder are malignant, and transitional cell carcinoma is the most common malignant tumor; however, other tumors such as adenocarcinoma, squamous cell carcinoma, sarcoma, and teratoma have to be included in the differential diagnosis. in fact, their clinical manifestations are similar and patients usually present with hematuria (painless and microscopic or gross). pelvic pain and urinary bladder irritation may be seen uncommonly. these symptoms may also be caused by nonmalignant conditions such as clustering polypoid cystitis or granulomatous cystitis. these lesions may mimic malignant tumor.(5,6) we report 2 cases of inflammatory pseudotumors of the bladder presented with gross hematuria and urinary symptoms. we reviewed the literature and found few cases of pseudotumor, and our cases were unique in terms of their etiologies.(7-9) case report case 1 a 58-year-old woman was referred to our hospital with long-standing dysuria (more than 2 years) and painless hematuria. at the time of admission the patient was anemic. she had no prior history of trauma, instrumentation, or surgical operation on the pelvis or abdomen. she seemed mentally normal with no history of spurious self-trust. on physical examination, tenderness on deep palpation of the suprapubic area was found. urinalysis showed persistent microscopic hematuria, whereas urine culture remained negative for microorganisms for past 2 years. cystoscopy revealed blister edema in the bladder. evaluation for tuberculosis and other organisms were negative. intravenous urography revealed a normal pyelocaliceal system and a filling defect within the urinary bladder. contrast-enhanced computed tomography (ct) showed an oval polypoid mass in the left side of the urinary bladder with a linear shape high-density foreign body within the mass (figure 1). the lesion also exhibited an infiltrative feature and extension to the perivesicular fat and the lower abdominal and pelvic walls (figure 1). the patient underwent transurethral resection of the lesion. it was a 60 × 65-mm pinktan rubbery tissue. microscopic examination of lesion revealed severe lymphoplasmocytic urol j. 2008;5:62-5. www.uj.unrc.ir inflammatory pseudotumors of bladder—razi and radmehr urology journal vol 5 no 1 winter 2008 63 infiltration with lymphoid follicles in a fibrotic foreign-body type granulomatous inflammatory background. two irregular pieces of foreign bodies (wood) were also seen. the patient denied any possible cause of the appearance of a foreign body in the bladder. no malignancy or recurrent lesions were detected 1 year after the surgery. case 2 a 23-year-old woman was admitted to the rheumatology clinic for acute pelvic pain and painful gross hematuria following 2 months of oral cyclophosphamide intake (100 mg/d) for treatment of lupus erythematous which was resistant to corticosteroid therapy. physical examination was unremarkable. urinalysis confirmed gross hematuria and a urine culture was negative for microorganisms. ultrasonography revealed a round-shape hypoechoic mass in the right side of the bladder and irregularity and thickness of its anterior wall. contrast-enhanced ct showed a filling defect in the wall of the bladder (figure 2). on cystoscopy, the floor and the lateral lower third of the bladder were normal, but a papillary-type lesion had occupied the remaining portion of the walls and entire dome of the bladder, which was more prominent on right side. the patient underwent transurethral resection. the surgical specimen was a firm polypoid mass with surface figure 2. left, contrast-enhanced pelvic ct scan shows filling defects with an exophytic growth pattern of the lesion in the right side of the bladder (black arrow). air bubbles in the bladder are related to previous catheterization (white arrows). right, spiral ct intravenous urography shows an irregularly outlined mass within the right side of bladder (black arrow). note mild dilatation of the right distal ureter. figure 1. left, contrast-enhanced pelvic ct scan shows an oval shape polypoid mass protruded into the bladder in the left anterior aspect (white arrow). note a linear high-density foreign body within the mass. middle, a slightly upper slide of the pelvic ct scan demonstrates an infiltrative feature as extension of the lesion out of the bladder with involvement of the perivesicular fat (long white arrow) and the pelvic wall (short white arrow). some low-attenuation area (necrotic) within the lesion is noted (black arrows). right, the lesion shows extension to the abdominal wall adjacent to the pelvic cavity with subcutaneous edema (white arrow). inflammatory pseudotumors of bladder—razi and radmehr 64 urology journal vol 5 no 1 winter 2008 irregularity and hemorrhage. on physical examination, transitional mucosa with subjacent muscle layer was seen. the mucosa showed edema, infiltration of mononuclear leukocytes, and formation lymphoid follicles. no evidence of malignancy was noted. the final diagnosis was polypoid cluster-type cystitis. during the followup, cyclophosphamide was discontinued and the patient was free of symptom. discussion inflammatory pseudotumor of the urinary bladder was first reported in 1980 by roth.(10) this lesion has been referred to by various terms including nodular fasciitis, pseudosarcomatous fasciitis, inflammatory pseudotumor, and reactive pseudotumor.(7,8) there is no sex or age predilection.(4) although some of these lesions are considered to represent an unusual inflammatory response to infection, trauma, or surgery, most patients show no predisposing factors.(4) it is assumed that multiple etiologic factors may play a role in the pathogenesis. in our patients, we assumed these factors may be related to cyclophosphamide administration and foreign body (wood). diagnosis of the lesion may remain as a dilemma for the urologist, radiologist and pathologist. because of an aggressive appearance of lesion, inflammatory pseudotumor may be confused with transitional cell carcinoma, adenocarcinoma, or other malignant tumors. in children, this lesion may clinically mimic and may even pathologically resemble rhabdomyosarcoma.(2,7,9) immunohistochemical study can be misleading since pseudotumor of the bladder shares in common with those malignant conditions, positivity with some markers, such as desmin with rhabdomyosarcoma and cytokeratin with sarcomatoid carcinoma(11); however, immunohistochemistry and electron microscopy can be confirmatory when diagnosis by routine light microscopy is deficient. the radiological appearance of inflammatory pseudotumor is nonspecific and cannot be differentiated from a malignant neoplasm.(2,7,12) a broad-based enhancing centrally necrotic mass may be seen on ct scan involving the bladder wall with extension to the perivesical soft tissues and the rectus abdominus muscle. our case 1 showed an oval polypoid mass on the ct scan. the lesion protruded into the left and anterior walls of the bladder and contained cystic area with a linear-shape density which was proved a foreign body (wood). the perivesical soft tissue and abdominal muscles were also involved. in the case 2, the patient showed a slightly irregularly outlined defect on ct scan. the lesion showed enhancement with an exophytic growth pattern. in the recent studies, magnetic resonance imaging of inflammatory pseudotumor of the bladder and polypoid and papillary cystitis showed a large intraluminal mass with a narrow stalk, mimicking a welldifferentiated papillary tumor that was accompanied by massive hematuria.(4,6) kim and colleagues reported an isosignal intensity with the bladder wall on t1-weighted images with central necrosis. on t2-weighted image, the lesion had a low-signal intensity with central necrosis and mild enhancement after contrast media administration.(6) there is no consensus on the best treatment method due to the rarity of the disease. partial or total cystectomy has been performed, and no recurrence has been reported after mass excision or transurethral resection.(3) our patients showed no evidence of recurrent lesion, either. conflict of interest none declared. acknowledgment we would like to thank dr m kashi for his invaluable assistance. references 1. ricchiuti dj, ricchiuti vs, ricchiuti rr, qadri am, resnick mi. fibrous inflammatory pseudotumor of the bladder. rev urol. 2000;2:232-5. 2. schneider g, ahlhelm f, altmeyer k, et al. rare pseudotumors of the urinary bladder in childhood. eur radiol. 2001;11:1024-9. 3. choi sk, choi yd, cheon sh, byun y, cho sw. inflammatory pseudotumor of the urinary bladder in a child. yonsei med j. 2000;41:401-3. inflammatory pseudotumors of bladder—razi and radmehr urology journal vol 5 no 1 winter 2008 65 4. sugita r, saito m, miura m, yuda f. inflammatory pseudotumour of the bladder: ct and mri findings. br j radiol. 1999;72:809-11. 5. fujiwara t, sugimura k, imaoka i, igawa m. inflammatory pseudotumor of the bladder: mr findings. j comput assist tomogr. 1999;23:558-61. 6. kim sh, yang dm, kim nr. polypoid and papillary cystitis mimicking a large transitional carcinoma in a patient without a history of catheterization: computed tomography and magnetic resonance findings. j comput assist tomogr. 2004;28:485-7. 7. miki sc, kwatra a, kawashima a, milam jd, goldman sm, sandler cm. pseudosarcomatous fibromyxoid tumor of the bladder: biphasic contrast-enhanced helical ct findings. j comput assist tomogr. 1997;21:271-3. 8. stark gl, feddersen r, lowe ba, benson ct, black w, borden ta. inflammatory pseudotumor (pseudosarcoma) of the bladder. j urol. 1989;141:610-2. 9. proppe kh, scully re, rosai j. postoperative spindle cell nodules of genitourinary tract resembling sarcomas. a report of eight cases. am j surg pathol. 1984;8:101-8. 10. roth ja. reactive pseudosarcomatous response in urinary bladder. urology. 1980;16:635-7. 11. foschini mp, scarpellini f, rinaldi p, mancini af, accinelli g, eusebi v. [inflammatory pseudotumor of the urinary bladder. study of 4 cases and review of the literature]. pathologica. 1995;87:653-8. italian. 12. gugliada k, nardi pm, borenstein ms, torno rb. inflammatory pseudosarcoma (pseudotumor) of the bladder. radiology. 1991;179:66-8. robotic and laparoscopic urology the effect of single-port transvesical laparoscopic radical prostatectomy on erectile function and urinary continence compared to intrafascial endoscopic extraperitoneal radical prostatectomy yi yang1*, guoliang hou2*, hongbing mei1, xintao zhang1, xiaohong han1, jun pang3, xin gao4 purpose: to compare the erectile function and urinary continence of patients after single-port transvesical laparoscopic radical prostatectomy (stlrp) with intrafascial endoscopic extraperitoneal radical prostatectomy (ieerp). materials and methods: patients treated with stlrp (35) or ieerp (52) were recruited from september 2013 to june 2017. at baseline preoperatively and 2-year follow-up postoperatively, sex and continence assessments were performed by international index of erectile function-6 (iief-6) and daily pads, respectively. results: the sexual function at 3 months after rp declined obviously. 71.4% (stlrp) and 38.5% (ieerp) patients recovered potency at 6 months postoperatively (p < .01). 82.9% (stlrp) and 59.6% (ieerp) patients recovered potency at 2 years postoperatively (p < .05). 97.1% (stlrp) and 75.0% (ieerp) patients recovered continence (0 pad/day) at 3 months postoperatively (p < .01). continence achieved 100.0% at 2 years after rp in both groups. conclusion: patients receiving stlrp may obtain better and faster postoperative functional recovery than the ones receiving ieerp. as an exploratory research, stlrp may be another effective treatment for organ-confined prostate cancer. keywords: radical prostatectomy; transvesical; single-port; erectile; continence introduction worldwide, prostate cancer (pca) is the second most common malignancy among men. in america, the incidence of prostate was 105.1 per 100000. in middle east/iran, the rate was 11.52 per 100000. in china, the rate was 20.7 per 100000 males. for early pca, surgical treatment can achieve the goal of radical cure, and the five-year survival rate can reach 100%.(1) in recent years, laparoscopic radical prostatectomy (lrp) is recommended in low-risk organ-confined prostate cancer (pca) patients who present with significant obstructive symptoms, which can not only resolve the obstruction but also control the pca development. because lrp do not significantly reduce pca mortality for low-risk patients,(2) the operation effect on health-related quality of life for pca patients with long term survival becomes pretty important. postoperative sexual and urinary function, playing important roles in quality of life (qol), is quite important to the success of lrp.(3-5) intrafascial endoscopic extraperitoneal radical prostatectomy (ieerp) has been widely accepted for its limiting trauma to the surrounding fascia of prostate, which can protect the enclosed neurovascular bundles and bring a better sexual and urinary functional recovery than the previous operations.(6) still, modifications 1department of urology, shenzhen second people's hospital, the first affiliated hospital of shenzhen university, shenzhen, 518039, china. 2department of urology, foshan first municipal people's hospital, foshan, china. 3department of urology, the seventh affiliated hospital, sun yat-sen university, shenzhen, china. 4department of urology, the third affiliated hospital, sun yat-sen university, guangzhou, china. * these authors contributed equally to this work. *correspondence: department of urology, the third affiliated hospital, sun yat-sen university, tianhe road 600, guangzhou, 510630, china. telephone: +86-20-85252990; fax: +86-20-85252678, email: urologygx20@163.com. received july 2020 & accepted september 2020 have been in progress to improve the functional recovery in operation. we first launched single-port transvesical laparoscopic radical prostatectomy (stlrp) for patients with lowrisk organ-confined pca (psa ≤ 10 ng/ml, gleason score < 7, and clinical stage t1~t2an0m0) in 2010. compared with ieerp, stlrp can utilize the natural space of bladder lumen, avoid the bladder and perivesical space, not only to minimize the dissection of the tissue around the bladder neck, prostate and urethra but also to completely preserve the surrounding tissue of bladder, which may bring better erectile function and urinary continence postoperatively.(4) however, a longterm follow-up study is still required. in order to better assess the superiority of this novel way (stlrp), we surveyed 87 patients treated with stlrp or ieerp at 2-year follow-up postoperatively, compared the sexual and urinary functional recovery. materials and methods patients’ selection this retrospective study was conducted in accordance with the guidelines of the ethics committee of the third affiliated hospital of sun yat-sen university. from september 2013 to june 2017, a total of 87 urology journal/vol 17 no. 6/ november-december 2020/ pp. 592-596. [doi: 10.22037/uj.v16i7.6355] patients diagnosed with low-risk organ-confined pca (psa ≤ 10 ng/ml, gleason score < 7, and clinical stage t1~t2an0m0) combined with significant obstructive symptoms (ipss score > 20, qol > 3) who received stlrp (35) or ieerp (52) with bilateral nerve preservation were included in this study. the postoperative follow-up of each patient was at least 24 months. incidence of complications was graded according to the modified clavien system. biochemical recurrence was defined as at least 2 consecutive detectable psa levels > 0.2ng/ml.(7-9) we offered patients two operations (stlrp and ieerp) and informed them of the pros and cons of each. the patient chose the plan and signed the informed consent. all operations were performed by a stationary surgeon and two non-stationary assistants. stlrp the equipment, device, methodology, etc. used for stlrp in more detail were introduced in our previous studies.(4) the main operational procedure included the following: 1. port (similar to the single-port approach) which extended into the bladder was established between the umbilicus and pubic symphysis. 2. a posterior incision was created along the bladder neck distal to the ureteric orifices. 3. dissection of vas deferens and functional recovery after radical prostatectomy-ynag et al. table 1. preoperative, intraoperative and postoperative data. stlrp (35 cases) ieerp (52 cases) p-value preoperative mean (range) age, years 60 (45-69) 61 (42-68) .772 mean (range) bmi, kg/m2 23.2 (21-25.8) 23.1 (20.5-25.6) .825 asa score, n .830 1 21 30 2 14 22 mean (range) psa, ng/ml 7.54 (6.15-9.25) 7.15 (5.28-9.16) .729 mean prostate volume (range), ml 31.5 (12.8-65.5) 33.5 (12.6-75.2) .350 biopsy gleason score, n 1.000 3+3 35 52 clinical stage, n .721 t1c 26 39 t2a 9 13 ipss score, n .663 21~25 22 30 26~30 13 21 31~35 0 1 qol score, n .540 4 20 25 5 15 26 6 0 1 iief score, n .646 18~21 2 3 21~25 33 49 intraoperative mean (range) operative time, min 105.0 (75-185) 102.5 (72-180) .786 mean (range) ebl, ml 130 (65-500) 135 (60-550) .702 mean btr, % 0 0 1.000 nerve sparing, n (%) bilateral 35 (100) 52 (100) 1.000 intraoperative complications (clavien), n 0 0 1.000 postoperative positive margins, n 0 0 1.000 pathological gleason score, n .984 3+3 20 29 3+4 12 18 4+3 3 5 pathological stage, n .623 pt2a 24 33 pt2b 11 19 clavien system .525 postoperative complications, grade i, n 1 3 biochemical recurrence (n) 0 0 1.000 abbreviations: ebl, estimated blood loss; btr, blood transfusion rate; qol, quality of life. table 2a. the recovery of erectile function at different intervals (stlrp vs ieerp) erectile function (timing) iief-6 score stlrp ieerp p-value baseline ≥ 18 35 (100%) 52 (100%) 1.000 < 18 0 0 3 months ≥ 18 4 (11.4%) 3 (5.8%) .341 < 18 31 49 6 months ≥ 18 25 (71.4%) 20 (38.5%) .003 < 18 10 32 12 months ≥ 18 28 (80.0%) 26 (50.0%) .005 < 18 7 26 24 months ≥ 18 29 (82.9%) 31 (59.6%) .022 < 18 6 21 robotic and laparoscopic urology 593 vol 17 no 06 november-december 2020 594 seminal vesicles, and anterograde separation of denonvillier’s fascia. 4. lateral separation of the prostate and intrafascial nerve sparing. 5. remove of the puboprostatic ligaments and dorsal vein complex. 6. dissection of the urethra and prostate apex. 7. vesico-urethral tension-reduced anastomosis. ieerp the main operational procedure of ieerp included the following: 1. port (establish the preperitoneal space) which carried down to the posterior rectus sheath where trocars were inserted. 2. expose the anterior surfaces of both bladder and prostate as well as the endopelvic fascia. 3. dissection of bladder-neck, vas deferens and seminal vesicles, and stripping down denonvillier’s fascia. 4. lateral separation of the prostate and intrafascial nerve sparing. 5. remove of the puboprostatic ligaments and dorsal vein complex. 6. dissection of the urethra and prostate apex. 7. vesico-urethral tension-reduced anastomosis.(6) functional assessment sexual and urinary function at baseline and various time points (3, 6, 12, 24 months) after surgery were evaluated using the iief-6 and ics (international continence society) questionnaires, respectively. these questionnaires were relatively effective and universal measurement methods at present and they had been cited and used in many studies. potency was defined as an iief-6 score ≥ 18 with or without phosphodiesterase 5 inhibitors (pde5-is) support. continence was defined as no need for pads. mild incontinence was defined as 1-2 pads requirement daily by patients for normal physical activity and incontinence was defined as > 2 pads daily.(8,10) statistical analysis we compared the two groups (stlrp vs ieerp) by student t test for numeric values, and chi-square test for non-numeric values. generalized linear mixed models were used for comparison of postoperative functional recovery between the two groups. significance was defined by p < .05. results there were 87 patients (stlrp 35, ieerp 52) in accordance with the inclusive criteria. there was no significant difference between the two groups (stlrp vs ieerp) on clinical and pathological parameters preoperatively (table 1). there were 10 cases in stlrp group received pde5-is after surgery, while 15 patients in ieerp. table 2 lists show the erectile function of patients preoperatively (baseline) and postoperatively (3, 6, 12, 24 months). potency (iief-6 score ≥ 18) preoperatively achieved 100% (both stlrp and ieerp), while declined obviously at 3 months postoperatively. after rp, sexual function recovered over time, and finally, 82.9% (stlrp) and 59.6% (ieerp) patients recovered potency at 2 years postoperatively. besides, patients (stlrp: 71.4%) obtained better potency than others (ieerp: 38.5%) at 6 months postoperatively, and generalized linear mixed models showed the erectile function of patients after stlrp recovered better than ones after ieerp on the whole (figure 1). table 3 lists show the urinary continence of patients preoperatively (baseline) and postoperatively (3,6,12, 24 months). the rate of continence (0 pad/day) preoperatively in all patients was 100%. at 3 months postoperatively, the rate of continence (0 pad/day) in patients receiving stlrp achieved 97.1%, and only one patient showed mild incontinence (1-2 pads/day). patients (stlrp: 97.1%) obtained better continence than others (ieerp: 75.0%) at 3 months. the rate of continence returned to 100% (stlrp) and 96.2% (ieerp) at 6 months postoperatively, and continence achieved 100.0% at 12 months after rp in both groups. on the whole, the continence of patients after stlrp recovered better than ones after ieerp by generalized variable estimate std error t p intercept -.878 .495 -1.770 .077 time -.077 .042 -1.840 .066 groups .374 .294 1.280 .203 time*group .057 .025 2.310 .021 table 2b. potency (stlrp vs ieerp) by generalized linear mixed models. table 3a. the recovery of urinary continence at different intervals (stlrp vs ieerp) urinary continence (timing) daily pads stlrp ieerp p-value baseline 0 35 (100%) 52 (100%) 1.000 1-2 0 0 3 months 0 34 (97.1%) 39 (75.0%) .001 1-2 1 13 6 months 0 35 (100%) 50 (96.2%) .240 1-2 0 2 12 months 0 35 (100%) 52 (100%) 1.000 1-2 0 0 24 months 0 35 (100%) 52 (100%) 1.000 1-2 0 0 figure 1. potency recovery after rp. functional recovery after radical prostatectomy-ynag et al. linear mixed models (figure 2). discussion radical prostatectomy (rp) is always used aiming for prostate cancer cure, but usually, it adversely affects health-related quality of life. cancer-specific survival approaches 96.3% at 10 years, and 95% at 15 years after surgery for early localized prostate cancer.(11) when low risk disease is common, the heavy focus will be the functional recovery. sexual and urinary function, often being considered as part of the important quality of life, will be more significant for patients receiving rp.(12) nerve sparing in rp may always play a critical role in functional recovery postoperatively.(13) prostatectomy itself is a definitely traumatic operation. preserving the external striated urethral sphincter and its innervation may facilitate the recovery of sexual and urinary function postoperatively.(14) with the intrafascial nerve-sparing, endoscopic extraperitoneal radical prostatectomy was reported to minimize the operational trauma of fascia and the related neurovascular bundle.(6) much evidence has shown that the preservation of dorsolateral neurovascular bundles during operation may not be the only key factor in functional rehabilitation, and the unknown and complicated neural tissue distributing around bladder, prostate and urethra or in fascia may also participate in sex and continence.(15,16) single-port transvesical enucleation of the prostate was reported as an effective treatment for large-volume obstructive bph and all patients (34 cases) receiving this operation got no incontinence.(17) recent studies also showed that sex and continence-relevant nerves may largely exist in the periprostatic and perivesical space, and careful separation of prostate from its surroundings (periprostatic fascia) could improve functional outcome.(18) stlrp can utilize the natural entry point and space of bladder, avoid the bladder, perivesical space and fascia, minimize the dissection of tissue and the injury of operation, and maximize the preservation of nerve plexus around the bladder neck, prostate and urethra, from which better recovery of erectile function and continence may benefit. our research showed that patients receiving stlrp can obtain better functional recovery than the ones receiving ieerp in early time following rp. besides, patients receiving stlrp obtained better functional recovery during 2 years of follow-up, which evaluated by generalized linear mixed models. it showed that patients after stlrp got distinct advantages throughout the postoperative recovery process, which were closely related to a better quality of life. sexual and urinary recovery after rp is complicated and multifactorial, influenced by age, smoking status, comorbidities such as obesity and diabetes, baseline potency and continence, operation, complications and so on.(19,20) besides, previous research has found that there is also mutual influence between sexual and urinary recovery.(21) previous studies suggested that sexual function of patients recovered significantly within 1-2 year after surgery, and then declined slowly.(22) our research also showed that potency recovered over time after rp (figure 1), including stlrp and ieerp. stlrp, as an exploratory research, may have some advantage in potency recovery postoperatively. besides, active adjuvant therapy, like biofeedback, phosphodiesterase-5 inhibitors, intracavernous injection, vacuum and biofeedback postoperatively, may also promote the potency recovery. however, the potency recovery will still be a long-term process, and often 1-2 year or even longer time may be supposed for improving time.(23) there were also limitations in our study for the relatively small sample size and limited follow-up years. conclusions stlrp can minimize the nerve injury and obtain better and faster postoperative functional recovery than ieerp. stlrp may be another effective treatment for low-risk organ-confined prostate cancer. acknowledgement the authors acknowledge financial support received from the chinese national natural science foundation of china (81902557, 81572503) and the shenzhen key medical discipline construction fund (no. szxk020). references 1. basiri a, eshrati b, zarehoroki a, et al. incidence, gleason score and ethnicity pattern of prostate cancer in the multiethnicity country of iran during 2008-2010. urol j. 2020. 2. wilt tj, jones km, barry mj, et al. follow-up of prostatectomy versus observation for early prostate cancer. n engl j med. 2017;377: 132-42. 3. bianco fj, scardino pt, eastham ja. radical prostatectomy: long-term cancer control and recovery of sexual and urinary function ("trifecta"). urology. 2005;66: 83-94. 4. gao x, pang j, si-tu j, et al. singleport transvesical laparoscopic radical prostatectomy for organ-confined prostate cancer: technique and outcomes. bju int. 2013;112: 944-52. 5. ellison js, he c, wood dp. stratification of postprostatectomy urinary function using expanded prostate cancer index composite. table 3b. continence (stlrp vs ieerp) by generalized linear mixed models. variable estimate std error t p intercept -31.367 632.190 -.050 .961 time .142 .061 2.340 .020 groups 14.694 316.090 .050 .963 time*group -.142 .000 ∞ <.0001 figure 2. continence recovery after rp. functional recovery after radical prostatectomy-ynag et al. robotic and laparoscopic urology 595 vol 17 no 06 november-december 2020 596 urology. 2013;81: 56-60. 6. stolzenburg ju, rabenalt r, do m, et al. intrafascial nerve-sparing endoscopic extraperitoneal radical prostatectomy. eur urol. 2008;53: 931-40. 7. yang y, luo y, hou gl et al. laparoscopic radical prostatectomy after previous transurethral resection of the prostate in clinical t1a and t1b prostate cancer: a matched-pair analysis. urol j. 2015;12: 2154-9. 8. yang y, luo y, hou gl, huang qx, pang j, gao x. laparoscopic radical prostatectomy plus extended lymph node dissection in combination with immediate androgen deprivation therapy for cases of pt3-4n01m0 prostate cancer: a multimodal study of 8 years' follow-up. clin genitourin cancer. 2016;14: e321-7. 9. xu aj, taksler gb, llukani e, lepor h. long-term continence outcomes in men undergoing radical prostatectomy: a prospective 15-year longitudinal study. j urol. 2018;200: 626-32. 10. limoncin e, gravina gl, lotti f, et al. the masturbation erection index (mei): validation of a new psychometric tool, derived from the six-item version of the international index of erectile function (iief-6) and from the erection hardness score (ehs), for measuring erectile function during masturbation. bju int. 2019;123: 530-7. 11. tsurumaki sy, fukuhara h, suzuki m, et al. long-term results of radical prostatectomy with immediate adjuvant androgen deprivation therapy for pt3n0 prostate cancer. bmc urol. 2014;14: 13. 12. ko yh. functional recovery after radical prostatectomy for prostate cancer. yeungnam univ j med. 2018;35: 141-9. 13. harris cr, punnen s, carroll pr. men with low preoperative sexual function may benefit from nerve sparing radical prostatectomy. j urol. 2013;190: 981-6. 14. steiner ms. continence-preserving anatomic radical retropubic prostatectomy: the "notouch" technique. curr urol rep. 2000;1: 20-7. 15. martinez-pineiro l. prostatic fascial anatomy and positive surgical margins in laparoscopic radical prostatectomy. eur urol. 2007;51: 598-600. 16. ganzer r, blana a, gaumann a, et al. topographical anatomy of periprostatic and capsular nerves: quantification and computerised planimetry. eur urol. 2008;54: 353-60. 17. desai mm, fareed k, berger ak, et al. single-port transvesical enucleation of the prostate: a clinical report of 34 cases. bju int. 2010;105: 1296-300. 18. alsaid b, bessede t, diallo d, et al. division of autonomic nerves within the neurovascular bundles distally into corpora cavernosa and corpus spongiosum components: immunohistochemical confirmation with three-dimensional reconstruction. eur urol. 2011;59: 902-9. 19. ficarra v, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012;62: 405-17. 20. gacci m, simonato a, masieri l, et al. urinary and sexual outcomes in long-term (5+ years) prostate cancer disease free survivors after radical prostatectomy. health qual life outcomes. 2009;7: 94. 21. gandaglia g, suardi n, gallina a, et al. preoperative erectile function represents a significant predictor of postoperative urinary continence recovery in patients treated with bilateral nerve sparing radical prostatectomy. j urol. 2012;187: 569-74. 22. neumaier mf, segall cj, hisano m, rocha f, arap s, arap ma. factors affecting urinary continence and sexual potency recovery after robotic-assisted radical prostatectomy. int braz j urol. 2019;45: 703-12. 23. litwin ms, melmed gy, nakazon t. life after radical prostatectomy: a longitudinal study. j urol. 2001;166: 587-92. functional recovery after radical prostatectomy-ynag et al. laparoscopic urology 90 urology journal vol 7 no 2 spring 2010 finger asisted laparoscopic renal cyst excision a simple technique mete kilciler, mustafa okan istanbulluoğlu, şeref basal, selahattin bedir, ali avci, yaşar özgök purpose: simple renal cysts are asymptomatic incidental findings; however, for a small subset of benign renal cysts, patients may present with pain, hematuria, recurrent infection, pyelocaliceal obstruction, or hypertension. laparoscopic cyst ablation is an effective minimally invasive modality for the treatment of symptomatic benign renal cysts. we describe a simple laparoscopic cyst excision technique. materials and methods: between june 2003 and may 2008, 28 patients underwent laparoscopic renal cyst excision via retroperitoneal approach. in our technique, retroperitoneum and gerota’s fascia were dissected with finger blindly before insertion of the trocars to the retroperitoneal space. following finger dissection, 3 trocars were placed and the cyst walls were excised at the level of renal cyst and base of the cysts were cauterized with electrocautery scissors. results: mean patients’ age was 59.3 years (range, 31 to 72 years). mean operation duration time was 46 minutes (range, 27 to 102 minutes). symptomatic and radiological success were achieved in 26 (92.8%) and 27 (96.4%) patients, respectively, with a median follow-up of 28 months (range, 6 to 56 months). no serious complications were encountered. conclusion: laparoscopy is a versatile minimally invasive modality ideal for treating benign symptomatic renal cysts. according to our experience, we think that the finger assisted laparoscopic cyst excision is an easy and noninvasive procedure. urol j. 2010;7:90-4. www.uj.unrc.ir keywords: dissection, laparoscopy, cystic renal disease, retroperitoneal space gulhane faculty of medicine, department of urology, ankara, turkey corresponding author: mustafa okan i̇stanbulluoğlu, md gulhane askeri tıp akademisi, uroloji bölümü 06018 etlik, ankara, turkey tel: +90 312 304 5610 fax: +90 332 257 0637 e-mail: drokanist@yahoo.com received august 2009 accepted february 2010 introduction simple renal cysts are the most common benign lesions of the kidney. in recent years, with the increasing use of diagnostic tools such as ultrasonography and computed tomography, the number of renal cysts diagnosed increased dramatically although most of them do not require treatment. the treatment indications for renal cysts are abdominal and/or flank pain, hematuria, hypertension, recurrent urinary infection, and obstruction in the collecting system due to compression.(1-11) open surgery had been successfully performed for the treatment of symptomatic renal cysts, but in this case morbidity increased while patient satisfaction decreased. (1-11) percutaneous cyst aspiration is one of the most common treatment modalities.(1,2,5,6,10,11) there had been some modifications regarding cyst aspiration such as injecting sclerosing material into laparoscopic renal cyst excision—kilciler et al 91urology journal vol 7 no 2 spring 2010 the cysts,(2,6,8) but high treatment failure and recurrence rates have been reported.(4,8-11) on the other hand, laparoscopic renal cyst excision, which was first described by hulbert in 1992, is an effective and minimally invasive treatment method that is commonly used.(1,3,4,9-11). finger assisted laparoscopic cyst excision method that we describe below, decreases the operation time and morbidity. materials and methods finger assisted retroperitoneal laparoscopic approach was performed on 28 patients with symptomatic renal cysts who referred to our clinic between june 2003 and may 2008. preoperatively, all patients were evaluated with urine analysis, urine culture, renal ultrasonography, and abdominal computed tomography. bosniak class 3-4 renal cysts, cysts located at the parapelvic regions, multiple cysts, and patients with history of previous renal surgery were excluded from the study. since obesity was an obstacle to performing the procedure, obese patients were also excluded from the study. patients were placed in the lateral decubitus position under general anesthesia. three trocars were used. a 1.5 to 2 cm incision was performed on the midaxillary line, and the muscles and the transversalis fascia were dissected blindly with finger. the peritoneum was swept medially. the gerota’s fascia over the cyst was dissected carefully, avoiding rupture of the cyst and the adipose tissue was visualized as much as possible. then, a second incision was performed on the anterior axillary line under digital guidance. the muscles and the transversalis fascia were dissected blindly with finger once more, and a second finger was used for this procedure (figures 1 and 2). the third trocar was placed at the junction of the lateral border of the erector spinae muscle underside the 12th rib (posterior axillary line). the retroperitoneal dissection was performed with balloon dissectors, which was inflated 600 cc maximally. following co2 insufflation, a 10-mm trocar was inserted in the first incision and 30° telescope was placed through this trocar. the other trocars used in the operation were 5-mm trocars. it was observed through the telescope whether sufficient dissection of the perirenal tissue was performed. the pressure was kept at 12 to 14 mmhg during the operation. the cyst wall was excised at the level of renal capsule and the base of renal cyst was fulgarised after excision to destroy the secretory activity of the residual cyst wall and to avoid recurrence. the excised cyst wall was pathologically evaluated. results twenty-two men and 6 women with the mean age of 59.3 years (range, 31 to 72 years) were operated on. twelve cysts were located on the right side and 16 were on the left side. nineteen cysts were located in the lower pole and 9 were figure 1. operative image of the bilateral finger assisted laparoscopic renal cyst excision. figure 2. illustration of bilateral finger dissection of gerota’s fascia and perirenal fat tissue. laparoscopic renal cyst excision—kilciler et al 92 urology journal vol 7 no 2 spring 2010 located in the middle portion of the kidney. the cysts were laterally and posteriorly localized in 15 and 13 patients, respectively. twenty-two cysts were bosniak class 1, while 6 cysts were bosniak class 2. the mean diameter of cysts measured with computed tomography was 7.6 cm (range, 6 to 14 cm). the treatment indications were obstruction in the collecting system in 12 patients and pain that was unresponsive to analgesics in 16 patients. thirteen patients had history of previous unsuccessful cyst aspiration at other institutions (table). in all of the patients, the operation was performed with 3 ports. the mean operation duration was 46 minutes (range, 27 to 102 minutes). any major bleeding requiring transfusion did not occur. blunt dissection of the renal fat tissues caused minor bleeding, but it did not lead to any significant sight impairment during the procedure. the mean hospitalization was 1.7 days (range, 1 to 4 days). all the drains were removed on the first postoperative day. two patients had pain that was unresponsive to nonsteroidal analgesics during the postoperative period. thus, they were treated with narcotic analgesics. two patients had prolonged fever that was treated with parenteral antibiotics for 3 days. pathological evaluation of all cysts was reported as benign. no other serious complications were encountered. the mean follow-up was 28 months (range, 6 to 56 months). follow-up was performed with renal ultrasonography on postoperative 3-, 6-, and 12-month in the first year, then annually. symptomatic improvement was achieved in 26 patients (92.8%) while radiological recurrence was reported only in 1 patient (96.4% radiological success). discussion simple renal cyst is common in adults and the incidence increases with age. till the age of 40, simple renal cyst has been reported in 20% of adults, while at the age of 60, the incidence increases to 30 to 35%.(1,7) the cysts are mostly asymptomatic. bleeding, pain refractory to analgesics, hypertension, unresolved infection, and compression to the collecting system are the indications for the treatment. a very small subset of patients with renal cyst need intervention.(1-11) the percutaneous cyst aspiration is non-invasive and there is no need for hospitalization; thus, percutaneous cyst aspiration is the first choice of treatment, but recurrence rates were reported to be up to 78%.(11) many sclerosing agents were used as a combination to increase the effectiveness of the percutaneous treatment such as ethanol, tetracycline, glucose phenol, povidone–iodine, bismuth-phosphate, urea cholohydrolactate, polidocanol, and pantopaque.(2,5,6,8) there have been some successful reports in the literature upon the usage of sclerosing agents, but on the other hand, the recurrence rates still range from 32% to 100%.(4,9,11) sclerosing agents had been used in repeated sessions to increase the effectiveness although they had potential side effects such as migration to the collecting system, allergy, and anaphylaxis.(4,9) chung and colleagues compared 40 patients that had been treated with multiple 99% ethanol injections via a pigtail catheter inserted into the cyst, with 42 patients who were treated with single session injections. the multiple session treatment was reported to be more effective.(12) okeke and associates also revealed that the multiple session treatment was superior to single session. but 2 to 3 days hospitalization and discomfort caused by the catheter are disadvantages of multiple treatments. (13) the only study in the literature that compares the percutanous treatment with male/female 22/6 mean age 59.3 years (31 to 72 years) side right 12 (42.8%) left 16 (57.2%) cyst size (mean) 7.6 cm (6 to 14 cm) localization middle 9 (2.1%) lower 19 (67.9%) previous surgery percutaneous aspiration 13 (46.4%) none 15 (53.6%) indication for operation pain 16 (57.2%) obstruction in the collecting system 12 (42.8%) procedure retroperitoneal patients characteristics laparoscopic renal cyst excision—kilciler et al 93urology journal vol 7 no 2 spring 2010 laparoscopic excision was reported by okeke and coworkers in which they concluded that laparoscopic treatment is a better option.(5) open surgery is the most effective treatment for the renal cysts and has been performed since the beginning of the 20th century.(1) laparoscopic procedures have replaced open surgery due to its high morbidity. laparoscopy is now being performed in many centers. in the literature, symptomatic progression of the patients with laparoscopic surgery is 78% to 100%, and the radiological treatment rates are 80% to 100%. the mean operation duration differ from 75 to 194 minutes.(1,9-11) in our series, the symptomatic and the radiological success rates were 92.8% and 96.4%, respectively, which are compatible with the literature, but the mean operation duration is shorter than those previously reported. with laparoscopy, we performed minimal retroperitoneal dissection to reach the renal cyst that resulted in minimum postoperative pain. “short operation period” term describes decreased anesthetic gas usage and decreased systemic toxicity. hulbert performed the first laparoscopic cyst excision 16 years ago.(3) thwaini and colleagues reported that of a total of 22 patients with renal cysts, 17 (77%) fully recovered, with a radiological success rate of 100% (mean follow-up of 60 months).(9) shiraishi and coworkers also showed that in 36 patients treated with laparoscopic cyst excision, symptomatic and radiologic success rates were 92% and 81%, respectively, after a mean follow-up of 69 months (range, 13 to 128 months).(10) in the series of 45 patients, atug and associates reported 91.1% symptomatic and 95.5% success rates (mean follow-up of 39 months, ranging from 3 to 96 months).(11) the long-term follow-up studies demonstrate that laparoscopic cyst excision is an effective treatment. another important issue in laparoscopic surgery is the approach route which can be transperitoneal or retroperitoneal. the transperitoneal approach is the most preferred one in the published literature. transperitoneal approach has advantages especially for the anteriorly located exophytic and parapelvic cysts. in addition, anatomical landmarks help us to reach the kidney easily. however, retroperitoneal way is beneficial especially for the posteriorly located cysts. the organ injury is less compared to transperitoneal approach and there is no risk of peritonitis, as the intracystic fluid does not interact with the peritoneum.(1) in our study, we preferred the retroperitoneal approach. if the location of the cysts is favorable, we recommend retroperitoneal approach, which has lower morbidity. conclusion laparoscopy is a versatile minimally invasive modality ideal for treating benign symptomatic renal cysts. according to our experience, we think that the finger assisted laparoscopic cyst excision is an easy, non-invasive, and not time consuming procedure. however, it is better to evaluate this technique with further prospective studies that are matched with control group. conflict of interest none declared. references 1. su lm. laparoscopic renal cyst ablation: technique and results. in: gill is, ed. textbook of laparoscopic urology. new york: taylor & francis ltd; 2006:259-78. 2. demir e, alan c, kilciler m, bedir s. comparison of ethanol and sodium tetradecyl sulfate in the sclerotherapy of renal cyst. j endourol. 2007;21:9035. 3. hulbert jc. laparoscopic management of renal cystic disease. semin urol. 1992;10:239-41. 4. gupta np, goel r, hemal ak, kumar r, ansari ms. retroperitoneoscopic decortication of symptomatic renal cysts. j endourol. 2005;19:831-3. 5. okeke aa, mitchelmore ae, keeley fx, timoney ag. a comparison of aspiration and sclerotherapy with laparoscopic de-roofing in the management of symptomatic simple renal cysts. bju int. 2003;92:6103. 6. kilinc m, tufan o, guven s, odev k, gurbuz r. percutaneous injection sclerotherapy with tetracycline hydrochloride in simple renal cysts. int urol nephrol. 2008;40:609-13. 7. laucks sp, jr., mclachlan ms. aging and simple cysts of the kidney. br j radiol. 1981;54:12-4. 8. madeb r, feldman pa, knopf j, rub r, erturk e, yachia d. povidone-iodine sclerotherapy is ineffective in the treatment of symptomatic renal cysts. j endourol. 2006;20:402-4. laparoscopic renal cyst excision—kilciler et al 94 urology journal vol 7 no 2 spring 2010 9. thwaini a, shergill is, arya m, budair z. longterm follow-up after retroperitoneal laparoscopic decortication of symptomatic renal cysts. urol int. 2007;79:352-5. 10. shiraishi k, eguchi s, mohri j, kamiryo y. laparoscopic decortication of symptomatic simple renal cysts: 10-year experience from one institution. bju int. 2006;98:405-8. 11. atug f, burgess sv, ruiz-deya g, mendes-torres f, castle ep, thomas r. long-term durability of laparoscopic decortication of symptomatic renal cysts. urology. 2006;68:272-5. 12. chung bh, kim jh, hong ch, yang sc, lee ms. comparison of single and multiple sessions of percutaneous sclerotherapy for simple renal cyst. bju int. 2000;85:626-7. 13. okeke aa, mitchelmorre ae, timoney ag. comparison of single and multiple sessions of percutaneous sclerotherapy of simple renal cysts. bju int. 2001;87:280. editorial comment renal cyst is a common finding among old age population; however, few cases require intervention. percutaneous aspiration and sclerosing agents injection are the first option for treatment.(1) laparoscopic cyst decortication is an appropriate alternative for management of parapelvic cysts and recurrent symptomatic cysts after percutaneous aspiration.(2) however, based on my experience, there is a large amount of fibrosis and adhesion surrounding the cyst in patients with the previous history of aspiration. as mentioned in this paper, laparoscopic cyst ablation needs general anesthesia and hospitalization, while percutaneous aspiration is an outpatient less invasive procedure. authors selected posterior and lateral renal cysts that are easily accessible by percutaneous aspiration; however, success rate in laparoscopic cyst ablation is higher than percutaneous procedure. in most cases, although cysts were not completely disappeared after percutaneous aspiration and sclerosing agents injection, but their size reduced and patients’ problems resolved.(3) i think that their technique is simple and minimally invasive with short operation time, but i recommend comparing this technique with classic laparoscopic cyst ablation in a prospective controlled study with long-term follow-up. akbar nouralizadeh urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran e-mail: nouralizadeh@yahoo.com references 1. demir e, alan c, kilciler m, bedir s. comparison of ethanol and sodium tetradecyl sulfate in the sclerotherapy of renal cyst. j endourol. 2007;21: 903-5. 2. abbaszadeh s, taheri s, nourbala mh. laparoscopic decortication of symptomatic renal cysts: experience from a referral center in iran. int j urol. 2008;15:486-9. 3. chung bh, kim jh, hong ch, yang sc, lee ms. comparison of single and multiple sessions of percutaneous sclerotherapy for simple renal cyst. bju int. 2000;85:626-7. reply by author editorial comment includes valuable personal experience leading to comparisons between alternative procedures, together with positive suggestions. we will take these recommendations into consideration in our future studies. mete kilciler gulhane faculty of medicine, department of urology, ankara, turkey outcomes of artificial urinary sphincter implantation in patients with detrusor underactivity and postprostatectomy incontinence kyu hun han1, joon chul kim1, woong jin bae2, jin bong choi1, jun sung koh1, kang jun cho1* purpose: there is insufficient evidence for postoperative outcomes of artificial urinary sphincter (aus) implantation for postprostatectomy incontinence (ppi) with detrusor underactivity (du). thus, we assessed the impact of preoperative du on the outcomes of aus implantation for ppi. materials and methods: medical records of men who underwent aus implantation for ppi were reviewed. patients who had bladder outlet obstruction surgery before radical prostatectomy or aus-related complications that required revision of aus within three months were excluded. patients were divided into two groups based on the preoperative urodynamic study including pressure flow study, a du group, and a non-du group. du was defined as a bladder contractility index less than 100. the primary outcome was postoperative postvoid residual urine volume (pvr). the secondary outcomes included maximum flow rate (qmax), postoperative satisfaction, and international prostate symptom score (ipss). results: a total of 78 patients with ppi were assessed. the du group consisted of 55 patients (70.5%) and the nondu group comprised 23 patients (29.5%). qmax was lower in the du group than in the non-du group and pvr was higher in the du group as per a urodynamic study before aus implantation. there was no significant difference in postoperative pvr between the two groups, although the qmax after aus implantation was significantly lower in the du group. while the du group showed significant improvements in qmax, pvr, ipss total score, ipss storage subscore, and ipss quality of life (qol) score after aus implantation, the non-du group showed postoperative improvement in ipss qol score. conclusion: there was no clinically significant impact of preoperative du on the outcome of aus implantation for ppi; thus, surgery can be safely performed in patients with ppi and du. keywords: artificial urinary sphincter; underactive bladder; urinary stress incontinence introduction radical prostatectomy may improve bladder func-tion by resolving bladder outlet obstruction (boo), which is one of the main pathophysiologies of male lower urinary tract dysfunction. however, radical prostatectomy may worsen lower urinary tract symptoms (luts) owing to changes in the neural circuit of the lower urinary tract, including the urethral sphincter. (1) radical prostatectomy can cause urethral sphincter deficiency and detrusor function changes such as detrusor underactivity (du) or detrusor overactivity (do).(2) postprostatectomy incontinence (ppi) is known to have a significant impact on patients’ quality of life (qol). it is most severe in the first two months post-surgery, but improves over time.(3) unfortunately, some patients only recover partially, which influences their qol and self-esteem. surgical management of ppi can be offered to patients who still have incontinence after one year of conservative treatment. one retrospective analysis showed that approximately 3.3% of ppi cases received 1department of urology, bucheon st. mary's hospital, college of medicine, the catholic university of korea, seoul, republic of korea 2department of urology, seoul st. mary's hospital, college of medicine, the catholic university of korea, seoul, republic of korea. *correspondence: department of urology, bucheon st. mary's hospital, college of medicine, the catholic university of korea, 327 sosa-ro, bucheon-si, gyeonggi-do 14647, republic of korea. telephone: +82-32-340-7730; e-mail: gift99@catholic.ac.kr. received august 2022 & accepted march 2023 anti-incontinence surgery within two years after prostatectomy.(4) a variety of methods and devices are available for patients undergoing anti-incontinence surgery, including bulking agents, male slings, and artificial urinary sphincters (aus). aus has been the gold standard for surgical intervention in ppi, as the literature shows high satisfaction and success rates.(5-7) the prevalence of du after radical prostatectomy has been reported in 14%-51% of patients, and ppi with du was observed in 44% of patients after radical prostatectomy.(8-10) one important concern that may arise after bladder outlet procedures for ppi in patients with du is the possible aggravation of voiding problems, such as urinary retention. a previous study reported that a male sling for ppi did not affect residual urine volume and can be safely used in men who have du but void normally.(11) however, a single report is not sufficient to represent the results of all bladder outlet procedures for ppi with du, and male slings are sometimes considered a contraindication for patients with du because of possible urinary retention.(12) aus implantation has reconstructive surgery urology journal/vol 20 no. 4/ july-august 2023/ pp.234-239. [doi:10.22037/uj.v20i.7403] generally been performed for such patients in clinical practice, but there is a lack of sufficient evidence on postoperative outcomes. as urethral catheterization for urinary retention after aus implantation is associated with device survival and urethral erosion, it is important to ensure that aus can be safely used in patients with du.(13) here, we compared the outcomes of aus for ppi between patients with and without du patients. this study aimed to determine whether aus can be applied in patients with and without du without postoperative complications related to voiding function. materials and methods a retrospective review was conducted in patients with ppi who underwent aus implantation from january 2010 to december 2019 and were followed up for longer than three months post-surgery. the patients’ preoperative urodynamic study (uds) results, including a pressure-flow study, were reviewed. exclusion criteria included patients who had bladder outlet obstruction surgery before radical prostatectomy or aus-related complications that required revision of the device within three months of implantation. aus implantation was performed by one of the two experienced urologists (jck and wjb). the ams800tm (american medical system, inc., minnetonka, mn, usa) urinary control system was implanted through a perineal or penoscrotal incision. all patients received single bulbar urethral cuffs (3.5-4.5 cm), had a balloon reservoir placed in the right lower quadrant of the preperitoneal space through a separate lower abdominal incision and had a pump in the scrotum. the cuff size was determined by measuring the periurethral circumference with a cuff sizer enclosed in the ams800 kit after careful dissection of the urethra. the implanted cuff was tested under urethroscopy before closing the wound to ensure that the urethra was open and closed with adequate pressure from the cuff. the device was activated six weeks after implantation. this study was approved by the ethics committee and the institutional review board of our center. (hirb20211221-016) preoperative evaluation included age, body mass index, international prostate symptom score (ipss), and uds results. uds was performed in accordance with the good urodynamic practice standards recommended by the international continence society (ics).(14) investigated postoperative results were maximum flow rate (qmax), postvoid residual urine volume (pvr), ipss, stress urinary incontinence (sui) status, and patient satisfaction. these factors were evaluated three months after aus implantation. the enrolled patients were divided into two groups, du and non-du groups, based on preoperative urodynamics. du was defined as a bladder contractility index (bci) less than 100.(15) surgical method of aus implantation was the same for every patient, regardless of which group the patient was allocated. preoperative factors and postoperative results were compared between the two groups. the primary outcome was postoperative pvr. secondary outcomes included postoperative treatment satisfaction, sui status, changes in qmax, changes in ipss, and complications. subjective patient outcomes were defined as follows: ‘cured’ was defined as one or less pad per day for use in social situations, ‘improved’ was defined as more than a 50% decrease in frequency and amount of urine leakage, and all other outcomes were regarded as ‘failed’. treatment satisfaction was analyzed according to patient responses as ‘satisfied’, ‘neutral’, and ‘dissatisfied’. numerical variables are reported as means with standard errors of the mean. nominal variables are expressed as counts and percentages. the variables were statistivariables total (n = 78) du group (n = 55) non-du group (n = 23) p-value age, year 70.2 ± 0.8 69.6 ± 0.9 71.7 ± 1.3 .212 bmi, kg/m2 24.4 ± 0.3 24.1 ± 0.3 24.7 ± 0.5 .298 history of radiation 24 (30.8) 19 (34.5) 5 (21.7) .297 diabetes 15 (19.2) 12 (21.8) 3 (13.0) .532 hypertension 44 (56.4) 32 (58.2) 12 (52.2) .803 medication on anticholinergics 41 (52.6) 29 (52.7) 12 (52.2) .964 ipss total 16.9 ± 1.8 17.5 ± 2.2 15.8 ± 2.9 .658 ipss storage subscore 8.5 ± 0.8 8.8 ± 0.9 7.8 ± 1.3 .539 ipss voiding subscore 8.5 ± 1.1 8.7 ± 1.4 8.0 ± 1.9 .782 ipss qol score 4.6 ± 0.2 4.7 ± 0.3 4.2 ± 0.4 .335 urodynamic parameters qmax, ml/s 12.2 ± 0.9 8.6 ± 0.5 20.8 ± 1.6 < .001* voided volume, ml 242.1 ± 12.9 224.5 ± 16.3 283.7 ± 18.1 .036* pvr, ml 49.8 ± 10.6 66.9 ± 14.4 9.9 ± 4.2 < .001* maximum cystometric capacity, ml 293.4 ± 11.7 295.4 ± 14.9 288.7 ± 18.1 .798 vlpp, cmh2o 83.4 ± 3.5 81.5 ± 4.4 87.9 ± 5.7 .412 compliance 1.000 < 20 ml/cmh2o 8 (10.3) 6 (10.9) 2 (8.7) ≥ 20 ml/cmh2o 70 (89.7) 49 (89.1) 21 (91.3) pdetqmax, cmh 2 o 18.5 ± 2.1 17.7 ± 1.9 20.4 ± 5.4 .637 bci 79.5 ± 4.1 60.7 ± 2.7 124.2 ± 5.1 < .001* mucp, cmh2o 38.4 ± 2.9 39.0 ± 3.4 37.1 ± 5.9 .765 boo index 7.8 ± 1.8 7.4 ± 1.5 8.6 ± 4.9 .277 detrusor overactivity 8 (10.2) 7 (12.7) 1 (4.3) .097 table 1. baseline clinical characteristics and urodynamic parameters of enrolled patients data are presented as mean ± standard error of mean or number (%) abbreviations: du, detrusor underactivity; bmi, body mass index; ipss, international prostate symptom score; qol, quality of life; qmax, maximal flow rate; pvr, post-void residual; mucp, maximal urethral closure pressure; pdetqmax, detrusor pressure at maximal flow; boo, bladder outlet obstruction; bci, bladder contractility index; vlpp, valsalva leak point pressure * statistically significant. outcomes of aus in detrusor underactivity and postprostatectomy incontinence-han et al. vol 20 no 4 july-august 2023 235 recunstructive surgery 236 cally compared using the student’s t-test, paired t-test, mann-whitney u test, or wilcoxon's signed-rank test for continuous variables and the chi-square or fisher's exact tests for categorical variables. statistical analyses were performed using ibm spss statistics for windows (version 20.0; ibm corp., armonk, ny, usa). a p-value of < .05 was considered significant. the authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. this study was performed in accordance with the declaration of helsinki (as revised in 2013) and the ethical guidelines for clinical studies. the study protocol was reviewed and approved by the institutional review board of the catholic university of korea bucheon st. mary’s hospital (approval no. hirb-20211221-016), and individual consent for this retrospective analysis was waived. results of the 93 patients who underwent aus for ppi in our center, 78 were included in the analysis. the du and non-du groups consisted of 55 (70.5%) and 23 (29.5%) patients, respectively. the mean follow-up period was 41.2 months. table 1 shows the baseline clinical characteristics and preoperative urodynamic results of the two groups. qmax was lower in the du group than in the non-du group (p < .001), while pvr was higher in the du group than in the non-du group (p < .001) in the urodynamic study before aus implantation. the preoperative bci was significantly lower in the du group than in the non-du group (p < .001). there was no significant difference in postoperative pvr between the du group and non-du group (18.7 ± 3.8 versus 18.9 ± 3.4, p = .986). although qmax after aus implantation was significantly lower in the du group (18.2 ± 1.5 versus 27.6 ± 2.6, p = .002), the subjective cure rates were 58.2% in the du group and 52.2% in the non-du group (p = .887) and the satisfaction rates were 60% in the du group and 56.5% in the non-du group (p = .662) (table 2). in total patients, the ipss total score (16.9 ± 1.8 to 12.2 ± 1.3, p = .022) and qol score (4.6 ± 0.2 to 2.6 ± 0.2, p < .001) were significantly lower postoperatively than the baseline scores. however, postoperative ipss scores did not differ between the two groups (figure 1). while the du group showed significant improvements in qmax, pvr, ipss total score, ipss storage subscore, and ipss total (n = 78) du group (n = 55) non-du group (n = 23) p-value postoperative sui status .887 cured 44 (56.4) 32 (58.2) 12 (52.2) improved 31 (39.7) 21 (38.2) 10 (43.5) failed 3 (3.8) 2 (3.6) 1 (4.3) satisfaction .662 satisfied 46 (58.9) 33 (60.0) 13 (56.5) neutral 28 (35.9) 19 (34.5) 9 (39.1) dissatisfied 4 (5.1) 3 (5.5) 1 (4.4) table 2. treatment outcomes between du group and non-du group data are presented as number (%) abbreviations: du, detrusor underactivity; sui, stress urinary incontinence. figure 1. comparison of postoperative ipss between du and non-du group. ipss, international prostate symptom score; du, detrusor underactivity; qol, quality of life. outcomes of aus in detrusor underactivity and postprostatectomy incontinence-han et al. qol score after aus implantation, the non-du group showed postoperative improvement in ipss qol score (figure 2). one patient in the du group required clean intermittent catheterization for temporary poor post-obstructive voiding. none of the patients in the non-du group required catheterization. urethral stricture or erosion occurred in five patients: four in the du group and one in the non-du group (p = 1.000). mechanical dysfunction occurred in a total of two patients, one in each group (p = .505). discussion our study showed that voiding function after aus implantation did not differ significantly regardless of the presence of du before surgery. postoperative qmax was significantly lower in patients with du than in those without non-du; however, this did not lead to significant differences in postoperative pvr and satisfaction rates between the two groups. voiding or storage function outcomes of aus implantation for urinary incontinence with concomitant lower urinary tract dysfunction after prostatectomy have been reported since aus has been used for the management of ppi. mild bladder dysfunctions, such as small bladder capacity, low compliance, and non-neurogenic bladder overactivity, can sometimes be improved after aus implantation, and they are not considered contraindications to aus implantation for ppi.(16) there have been reported to depend on whether a patient voided by straining with minimal detrusor contraction, which can reflect decreased detrusor contractility during the voiding phase after prostatectomy. those reports showed that about 30%-50% of ppi patients voided by straining, and this voiding pattern did not negatively affect the results of aus implantation. there were no differences in pvr and pad usage compared with those in patients with normal detrusor voiding patterns.(17,18) at present, there have been only a few studies on the influence of the cuff on urethral closure pressure in the deactivation or open state of the device. bentellis et al. reported no significant difference between the preoperative maximum urethral closure pressure (mucp) and postoperative mucp in the open-state cuff.(19) we can infer that aus implantation itself does not negatively influence voiding function, which is well supported by our results showing improved and no difference in postoperative pvr in the du and non-du groups, respectively. queissert et al. suggested that small cuff size (3.5 cm) is a risk factor for urethral erosion.(20) this would make surgeons consider complications related to the cuff itself if patients have lower urinary tract dysfunction before the insertion of an aus. further studies are needed to elucidate the influence of the cuff on the urethra and associated voiding function. one of the main mechanisms of du after radical prostatectomy is detrusor denervation due to pelvic nerve injury during dissection of structures around the seminal vesicles.(21,22) severe neurological changes or accumulation of neurological damage during radical prostatectomy can cause urinary retention; however, in our study, the average pvr in the du group before aus implantation was approximately 67 ml. this was not to the extent that urethral catheterization was required, although the average pvr in the du group was higher than that of the non-du group. previous studies also showed that pvr before aus implantation was less figure 2. changes in urodynamic parameters and ipss after aus implantation in du and non-du group. qmax, maximum flow rate; pvr, postvoid residual; ipss, international prostate symptom score; qol, quality of life ; du, detrusor underactivity. * statistically significant. outcomes of aus in detrusor underactivity and postprostatectomy incontinence-han et al. vol 20 no 4 july-august 2023 237 than 150 ml, even when voiding functions were impaired in patients with ppi.(11,17) in the case of ppi, even if bladder function is significantly degraded, a considerable amount of urine can leak out through a weakened urethral sphincter before voiding. voiding efficiency appears to be preserved by valsalva voiding or abdominal straining. therefore, pvr measured before aus implantation may not be used to evaluate the severity of du. in all patients, the subjective cure and satisfaction rates were 56% and 60%, respectively, with significant improvement in the postoperative ipss total score and qol score in this study. the presence of du did not affect postoperative outcomes. lai et al. also demonstrated that preoperative voiding dysfunction did not negatively affect incontinence outcomes after aus implantation.(23) a possible reason why du did not affect the subjective cure rate is that the cuff was selected and applied according to consistent criteria during aus surgery, regardless of the presence of du. additionally, there was no negative effect on storage symptoms such as increased do after surgery. we believe that du did not affect satisfaction after surgery because there was no significant difference in pvr between the two groups. the qmax in each group improved after aus implantation, although there was a difference in qmax between the groups. sphincteric incompetence has been suggested to be an important cause of ppi, and constant incontinence may lead to bladder dysfunction.(16,21,24) aus not only prevents urine leakage but also stabilizes the urethra and bladder. functional recovery of the bladder may have led to improvements in qmax and pvr in patients with du. this study has several limitations. first, the retrospective and nonrandomized nature of our study should be noted. second, there is currently no consensus on a standardized urodynamic methodology to diagnose du with sui. the main concept underlying du is voiding dysfunction of the bladder due to low detrusor pressure. urologists have used surrogate measurements from uds to quantitatively evaluate detrusor functions, such as qmax, detrusor pressure at the time of qmax (pdetqmax), and bci.(25) jura and comiter suggested using isometric detrusor contraction pressure (piso) as a more appropriate measurement of detrusor contractility in patients with ppi due to intrinsic sphincter deficiency, since conventional pdetqmax can be underestimated in such patients.(26) however, as there is insufficient data on piso, it seems too understudied to be used in practice. bci has been devised to assess the bladder function of males in ‘standard’ situations, i.e., males with prostate cancer. unfortunately, we do not have urodynamic data of patients before prostatectomy, therefore we do not know whether the patients had du or not in the ‘standard’ situation. however, vesicourethral anastomosis after prostatectomy involves surgical techniques to reduce incontinence. comparing bci among postprostatectomy patients may have a role in assessing bladder function and predicting the outcomes of aus implantation. moreover, because we did not perform uds after aus implantation, we could not accurately evaluate the change in du after aus. in reality, it is not easy to recommend invasive uds to patients unless there is a serious change in the luts after aus implantation. in addition, objective evaluations, such as postoperative voiding diaries or pad tests for incontinence, were also insufficient. however, the purpose of this study was to evaluate whether du negatively affects voiding symptoms after aus implantation by investigating the representative parameters: qmax, pvr, and patients’ voiding symptom questionnaire. conclusions du is relatively common in post-radical prostatectomy patients, and preoperative urodynamic data show differences in some parameters, such as qmax and pvr, between du and non-du patients. however, the postoperative results suggest that aus implantation could be safely recommended for ppi patients with du without concerns about urinary retention or voiding dysfunction. conflict of interests the authors have no conflicts of interest to declare. data availability statement the data that support the findings of this study are available on request from the corresponding author. the data are not publicly available due to privacy or ethical restrictions. references 1. 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after radical prostatectomy: a urodynamic study including risk factors. can urol assoc j. 2013;7:e33-7. 10. giannantoni a, mearini e, zucchi a, et al. bladder and urethral sphincter function after radical retropubic prostatectomy: a prospective long-term study. eur urol. 2008;54:657-64. 11. han js, brucker bm, demirtas a, fong e, nitti vw. treatment of post-prostatectomy incontinence with male slings in patients with impaired detrusor contractility on urodynamics and/or who perform valsalva voiding. j urol. 2011;186:1370-5. 12. hennessey db, hoag n, gani j. impact of bladder dysfunction in the management of post radical prostatectomy stress urinary incontinence-a review. transl androl urol. 2017;6:s103-s11. 13. linder bj, piotrowski jt, ziegelmann mj, rivera me, rangel lj, elliott ds. perioperative complications following artificial urinary sphincter placement. j urol. 2015;194:716-20. 14. drake mj, doumouchtsis sk, hashim h, gammie a. fundamentals of urodynamic practice, based on international continence society good urodynamic practices recommendations. neurourol urodyn. 2018;37:s50-s60. 15. abrams p. bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: three simple indices to define bladder voiding function. bju int. 1999;84:14-5. 16. afraa ta, campeau l, mahfouz w, corcos j. urodynamic parameters evolution after artificial urinary sphincter implantation for post-radical prostatectomy incontinence with concomitant bladder dysfunction. can j urol. 2011;18:5695-8. 17. gomha ma, boone tb. voiding patterns in patients with post-prostatectomy incontinence: urodynamic and demographic analysis. j urol. 2003;169:1766-9. 18. lai hh, hsu ei, teh bs, butler eb, boone tb. 13 years of experience with artificial urinary sphincter implantation at baylor college of medicine. j urol. 2007;177:10215. 19. bentellis i, el-akri m, hascoet j, et al. determinants and prognostic value of postoperative maximum urethral closure pressure after artificial urinary sphincter in men. world j urol. 2020;38:1303-9. 20. queissert f, huesch t, kretschmer a, et al. artificial urinary sphincter cuff size predicts outcome in male patients treated for stress incontinence: results of a large central european multicenter cohort study. int neurourol j. 2019;23:219-25. 21. chao r, mayo me. incontinence after radical prostatectomy: detrusor or sphincter causes. j urol. 1995;154:16-8. 22. hollabaugh rs, jr., dmochowski rr, kneib tg, steiner ms. preservation of putative continence nerves during radical retropubic prostatectomy leads to more rapid return of urinary continence. urology. 1998;51:960-7. 23. lai hh, hsu ei, boone tb. urodynamic testing in evaluation of postradical prostatectomy incontinence before artificial urinary sphincter implantation. urology. 2009;73:1264-9. 24. winters jc, appell ra, rackley rr. urodynamic findings in postprostatectomy incontinence. neurourol urodyn. 1998;17:493-8. 25. osman ni, chapple cr, abrams p, et al. detrusor underactivity and the underactive bladder: a new clinical entity? a review of current terminology, definitions, epidemiology, aetiology, and diagnosis. eur urol. 2014;65:389-98. 26. jura yh, comiter cv. urodynamics for postprostatectomy incontinence: when are they helpful and how do we use them? urol clin north am. 2014;41:419-27, viii. outcomes of aus in detrusor underactivity and postprostatectomy incontinence-han et al. vol 20 no 4 july-august 2023 239 21-fold higher covid-19 mortality rate in patients with severe renal dysfunction on admission authors: 1hamidreza ghorbani (md), affiliation: kidney transplantation complications research center, mashhad university of medical sciences, mashhad, iran 2alireza golshan affiliation: kidney transplantation complications research center, mashhad university of medical sciences, mashhad, iran 3atena aghaee (md) affiliation: nuclear medicine research center, mashhad university of medical sciences, mashhad, iran 4mahdi mottaghi (md) affiliation: kidney transplantation complications research center, mashhad university of medical sciences, mashhad, iran 5salman soltani * (md) affiliation: kidney transplantation complications research center, mashhad university of medical sciences, mashhad, iran * correspondence since december 2019, coronavirus disease (covid-19) has quickly become a pandemic. the associated mortality rate is higher in patients with hypertension, diabetes, cardiovascular diseases, cancer, and acute kidney injury (1,2). chronic renal failure (ckd) is one of the comorbidities that can affect the disease severity, the treatment process, and the mortality rate; clark a et al. reported that ckd, after age, is among the strongest risk factors for severe covid-19 disease (3). previous studies showed an association between severity of renal function impairment (rfi) and disease aggravation, icu admission, and mortality rate (4). it seems that evaluation of renal function is important as one of the predictors of covid-19 severity. to enhance patients’ outcomes and decrease mortality, prompt risk stratification of disease severity is important; thus, we observed the potential relation of estimated glomerular filtration rate (egfr) and covid-19 patients’ outcomes. we enrolled 186 patients of our covid-19 center from march to april 2020. we included patients with confirmed covid-19 (based on pcr or ct scan). patients less than 18 years or those with a history of ckd or dialysis were excluded. we categorized patients into four groups according to their egfr on admission: normal (≥ 90 ml/ min), mild impairment (60–90 ml/min), moderate impairment (≥ 30–60 ml/min), and severe impairment (< 30 ml/min) (5). egfr of patients was calculated using the cockcroftgault formula. the mean age of the participants was 60.74 ± 16.88 years. of 186, 113 (60.8%) were female. according to egfr, individuals were divided into four groups; 43 (23.1%) were normal, 67 (36%) were mild, 58 (31.2%) were moderate, and 18 (9.7%) had severe rfi. subjects with severe renal dysfunction were older than normal subjects (43.11 ± 13.22 vs. 79.55± 10.99; p < 0.001). the most common comorbidity among patients was hypertension (86.5%). there was no significant difference between the four groups regarding sex and severity of pulmonary infection and admission to the intensive care unit (icu). there was a significant difference between the four groups in length of hospital stay (p = 0.011) and death (p = 0.01). the demographic characteristics of patients are shown in table 1. there was a significant difference between the four groups in heart rate (p = 0.027) and respiration rate (p = 0.001) on admission. comparison of egfr levels with radiological and laboratory parameters showed that severe rfi was associated with higher plural effusion on ct scan (2.3% vs 22.2, p=0.048) and lower levels of red blood cells (4.83×109/l vs 4×109/l, p=0.005). pearson correlation between renal function indicators including egfr, blood nitrogen urea (bun), serum creatinine (scr), and various laboratory parameters showed a significant negative correlation between egfr and white blood cells (wbc) (r = -0.158, p=0.032), scr (r =-0.472, p<0.001), bun (r =-0.507, p<0.001), and potassium (r = -0.282, p<0.001). bun was significantly and positively correlated with neutrophil percentage (r =0.106, p=0.025), wbc (r =0.131, p=0.004), as well as a significant negative correlation with hemoglobin (r = 0.181, p<0.001), and platelets (r = -0.120, p=0.009). we detected a significant negative correlation between scr and hemoglobin (r = 0.184; p <0.001), platelets (r = -0.149, p=0.001) and erythrocyte sedimentation rate (esr) (r = -0.222, p=0.01), but a significant positive correlation existed with potassium (r = 0.373; p <0.001) and total bilirubin (r = 0.378 p <0.001). similar to previous studies (5), 40.8% of our covid-19 patients had moderate to severe kidney disease, and patients with severe rfi were older than those with normal egfr levels. our study indicated that hypertension and ischemic heart disease were the most common underlying comorbidities in patients with moderate-severe rfi among covid-19 patients, like in previous studies (6). we found a significant association between length of hospital stay and mortality rate with severe rfi; this finding is expected as lower egrf increases the risk of infection (7). we found that severe renal dysfunction is associated with a 21.2-fold excess risk of mortalities in patients with covid-19 (or,21.2;95%ci, 2.29-191.82, p=0.007); whereas adjustment for age and gender in this group was not statistically significant (or,10.35;95%ci, 0.71-135.52, p=0.075). these findings suggest that renal failure may be an independent prognostic factor in hospitalized patients with covid-19 infection. the low sample size limited our findings. our study is also a retrospective, single-center study; thus, our laboratory data (such as proteinuria, another renal function index) was missing. finally, we did not assess long-term renal function outcomes in survivors, and further research is needed to extend our results to a larger population. final point the present survey of covid-19 patients demonstrated that age and degree of rfi were associated with increased length of hospital stay and in-hospital mortality. our findings highlight the importance of evaluating the renal function indicators as predictors of disease severity and outcomes. table1: demographics characteristics, the laboratory features, and their association with egfr of covid-19 patients normal n=43(23.1%) mild n=67(36%) moderate n=58(31.2%) severe n=18(9.7%) p-value mean age 43.11±13.22 59.86±12.34 68.96±12.95 79.55±10.99 <0.001 male female 31(72.1) 12(27.9) 43(64.2) 46(15.5) 30(51.7) 25(84.5) 9(50) 9(50) 0.138 icu admission 5(11.6) 8(11.9) 2(3.4) 2(11.1) 0.348 hospital stay: (mean± sd) 8.37±9.43 5.56±4.57 6.25±5.05 10.83±9.81 0.011* expired 1(2.3) 8(11.9) 9(15.5) 6(33.3) 0.01* hemoglobin (g/l) 14(12.8,15.1) 13.4(12.6,14.2) 13.8(12.6,14.2) 12.35(10.77,15.37) 0.095 rbc 4.83(4.55,5.2) 4.6(4.28,4.9) 4.3(4.58,4.89) 4(3.69,4.83) 0.005 lymphocyte % 15(19,26.25) 17(10.75,24.25) 16(11,24) 20(11.5,26.25) 0.310 wbc 6.20(4.20,7.30) 6.20(4.80,8.50) 7.20(5.10,9.10) 6.60(5.02,12.62) 0.170 neutrophils % 75.5(69,82) 77(70,84.25) 79(72,85) 75(69.75,84.25) 0.318 monocyte % 2.2(2,3) 3(2,3) 3(2,3) 3(2,3) 0.982 platelet count (×10⁹) 177(145,230) 187(147,241) 160(144,210) 158.5(137.75,211) 0.436 fasting blood suger 105(97,150) 124.5(104,176.5) 131(106,158) 113(86.85,127) 0.04* serum creatinine (μmol/l) 1(0.8,1.1) 1.1(1,1.3) 1.4(1.17,1.6) 2.2(1.67,3.62) <0.001* bun 12.7(10,15) 16(11.20) 24(18.75,36) 41.8(31.2,63.5) <0.001* na 135(133,137) 134(132,137) 135(133,137) 135.5(131.75,137) 0.519 k 3.9(3.5,4.1) 4(3.67,4.32) 4.2(3.85,4.8) 4.35(4.07,5) <0.001* cpr 34(23,44.5) 48(23.5,48) 31(19.25,43.5) 33.5(23.75,49) 0.380 esr 50(27,87) 69(46,93) 51(40.5,77.5) 37.5(13.5,101.25) 0.612 references 1. sobhani s, aryan r, kalantari e, et al. association between clinical characteristics and laboratory findings with outcome of hospitalized covid-19 patients: a report from northeast iran. interdisciplinary perspectives on infectious diseases. 2021;2021. 2. sobhani s, kazemi a, kalantari f, et al. hematological and biochemical parameters associated with mortality in covid-19 infection and their correlation with smoking. journal of patient safety & quality improvement. 2021;9:41-6. 3. clark a, jit m, warren-gash c, et al. global, regional, and national estimates of the population at increased risk of severe covid-19 due to underlying health conditions in 2020: a modelling study. the lancet global health. 2020;8:e1003-e17. 4. flythe je, assimon mm, tugman mj, et al. characteristics and outcomes of individuals with preexisting kidney disease and covid-19 admitted to intensive care units in the united states. american journal of kidney diseases. 2021;77:190-203. e1. 5. hachim iy, hachim my, naeem kb, et al. kidney dysfunction among covid-19 patients in the united arab emirates. oman medical journal. 2021;36:e221. 6. wu z, mcgoogan jm. characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention. jama. 2020;323:1239-42. 7. ishigami j, matsushita k. clinical epidemiology of infectious disease among patients with chronic kidney disease. clinical and experimental nephrology. 2019;23:437-47. comparison of incision types used for kidney extraction in laparoscopic donor nephrectomy: a retrospective study selçuk şahin1, osman özdemir1, mithat ekşi2, i̇smail evren1, serdar karadağ1, deniz noyan özlü1*, ali i̇hsan taşçı1 purpose: laparoscopic donor nephrectomy (ldn) is the most commonly used method for kidney removal in kidney transplantation and, various incisions are used for kidney extraction. in this study, we aimed to compare the results of ldn operations using iliac fossa incision and pfannenstiel incision. material and method: ldn cases performed in our institute between june 2016 and february 2020 were retrospectively analyzed. patients with previous abdominal surgery, bleeding coagulation disorders, ectopic kidneys, and patients who were converted to perioperative open surgery were excluded. demographic data of the patients, operation times, warm ischemia times, complications were recorded and the patients were divided into two groups according to incision types. results: after the inclusion and exclusion criteria, 203 patients were included in the study. iliac fossa incision was used in 65% of the patients and the pfannenstiel incision was used in 35% of the patients to remove the donor’s kidney. there were no difference in age, body mass index, gender, and charlson comorbidity index (cci) scores between the two groups. operation time and warm ischemia time were significantly longer in the pfannenstiel group (p = 0.001 and p = 0.016 respectively). there was no significant difference between the two groups in terms of bleeding amount, length of hospital stay, need for narcotic analgesic, visual analog scale scores, and postoperative complications. conclusion: both types of incisions can be used successfully and safely for the extraction of the kidney in ldn. although wit and operation time has been observed to be longer when a pfannenstiel incision is made, complications and analgesic use are not different between pfannenstiel incisions and iliac fossa incisions. keywords: laparoscopic donor nephrectomy; kidney transplantation; pfannenstiel incision; iliac fossa incision introduction the gold standard treatment for end-stage renal dis-ease (esrd) is renal transplantation(1). in this procedure, donor nephrectomy can be performed through open, laparoscopic, or robot-assisted surgery. as minimally invasive surgical approaches have gained widespread use, laparoscopic donor nephrectomy (ldn) has become the standard approach in many transplantation centers because of its advantages including a short recovery time and minimal postoperative pain(1,2). in ldn, time from clamping of the aorta or renal artery to cold perfusion is defined as the warm ischemia time (wit) and is reported to be associated with postoperative early graft function(3,4). therefore, it is important to extract the kidney through a healthful and fast approach. to perform ldn; the pfannenstiel incision, vertical midline incisions, and iliac fossa incisions are frequently used for the extraction of the harvested kidney(5-9). in the literature, there are studies comparing different incision types in kidney extraction in laparoscopic donor nephrectomy(10-13). in this study, we have aimed to 1bakirkoy dr. sadi konuk training and research hospital, department of urology, istanbul, turkey. 2arnavutköy state hospital, department of urology. istanbul, turkey. *correspondence: university of health sciences bakirkoy dr. sadi konuk training and research hospital, department of urology, istanbul, turkey . zuhuratbaba mah, dr. tevfik sağlam cd no:11, 34147 bakırköy/i̇stanbul phone: +90 535 233 6440 fax: +90 212 414 7280. noyanozlu@hotmail.com. received march 2022 & accepted october 2022 compare the results of two routinely performed incisions for ldn in our clinic, namely iliac fossa incisions and the pfannenstiel incision. to the best of our knowledge, our study is one of the largest series of single surgeons comparing these two incisions. material and methods study design and patient selection ldn cases, performed in the period between june 2016 and may 2021 in bakırköy dr. sadi konuk research and training hospital, were reviewed retrospectively. to eliminate learning curve effects, the first 35 cases for both techniques were excluded from the study(14). other exclusion criteria were patients with severe intraperitoneal adhesions due to previous abdominal surgery, conversion of the laparoscopic procedure to open surgery perioperatively, presence of bleeding-clotting disorders, and presence of an ectopic kidney. patients undergoing iliac fossa incisions were assigned to group 1 and patients undergoing a pfannenstiel incision were urology journal/vol 20 no. 1/ january-february 2023/ pp. 11-16. [doi:10.22037/uj.v19i.7233] robotic and laparoscopic urolgy assigned to group 2. approval for this retrospective study was obtained from the same hospital (approval no: 2020-352). preoperative evaluation standard laboratory tests, immunological tests, urinary ultrasound examinations, and doppler ultrasound tests to assess the condition of the iliac artery of the transplant candidate were performed. computed tomography angiography (cta) was performed to evaluate the vascular structure of the candidate donor. renal scintigraphy was performed to evaluate the function of separate donor kidneys. all donor nephrectomy operations were performed laparoscopically by a single surgeon (s.ş). after the nephrectomy was completed, the kidney was extracted through an iliac fossa incision or a pfannenstiel incision. the length of incisions, the number of ports, the number of arteries, operative times, wit, bleeding volume, and perioperative complications were recorded in order to analyze perioperative data by the incision type. wit was defined as the period from the time of clamping the artery of the graft until the time of immersion of the graft into ice water. in order to evaluate postoperative data; the length of hospital stay, the need for narcotic analgesics, wound site infections, and the development of incisional hernia were recorded. the visual analog scale (vas) was used for assessing postoperative 24th hour pain. on this scale, the score of 10 described severe pain, while the score of 0 described benign completely painless. postoperative complications were recorded according to the clavien-dindo classification(15). surgical technique iliac fossa incision in the lateral decubitus position, a 5-6 cm oblique incision was made in the transverse line parallel to the inguinal ligament, starting from a distance of 5 cm to the superior iliac spine and after the dissection of the fascia and the peritoneum and opening of the surgical site, the gelport (applied medical, rancho santa margarita, ca, usa) was placed into this area (figure 1). using the gelport system, co 2 insufflation was performed and the intra-abdominal pressure was increased to 15 mmhg. a 5-mm-port was placed approximately 4 cm lateral to the umbilicus and another 5-mm-port was placed approximately 3 cm inferior to the intersection point of the costal margin and the lateral rectus muscle. then, the intra-abdominal pressure was adjusted to 12 mmhg. the colon was dissected along the line of toldt and medialized. then, the ureter was found on the psoas muscle. the ureter and the surrounding tissues were retracted. to retract the ureter, another 5-mm-port was inserted through the intersection point of the anterior axillary line and a transverse line at the level of the umbilicus. tracing the ureter, the hilus of the kidney was reached. the renal artery and the renal vein were dissected and completely liberated from the surrounding tissue. after processing the renal pedicle, the kidney was liberated from the surrounding tissue and mobilized. the ureter was clamped and transected. a multifire endo-ta stapler (covidien, walpole, massachusetts, abd) was used to ligate and transect the renal artery. a hem-o-lock® clip (teleflex medical, research triangle park, north carolina, usa) was used to ligate and transect the renal vein. the kidney was extracted through the gelport under direct vision manually. the purpose of gelport in our procedures is not a hand-assisted laparoscopy technique, but to be used for kidney extraction at this stage. a draining catheter was placed and the operation was terminated. pfannenstiel incision in the supine position, a pfannenstiel incision of approximately 6 cm was made in the suprapubic region. tissue layers were passed through to reach the peritoneum. robotic & laparoscopic urology 12 table 1: *indepent t test “chi-squire test ! fisher exact test & mann-whitney u test + presented as median (iqr) bmi: body mass index ebl: estimated blood loss incision types for kidney extraction-şahin et al. parameters (mean ± sd) total (n=203) group 1 n=132 (65) group 2 n=71 (35) p age (years) 48.6 ± 12.4 49 ± 12.3 47.2 ± 12.9 0.437* gender (n ; %) male 95 (46.7) 60 (45.4) 35 (49.2) 0.709” bmi (kg/m2) 25.2 ± 2.1 25.3 ± 3.9 26 ± 3.2 0.450* side (n ; %) left 196 (96.6) 127 (96.2) 69 (97.2) 0.593! incision length (cm) 5.4 ± 0.6 5.2 ± 0.5 6 ± 0.6 0.0001* no. of ports 3.2 ± 0.4 3 ± 0.1 4 ± 0.1 0.0001* no. of renal arteries 1.1 ± 0.4 1.1 ± 0.4 1.2 ± 0.4 0.571* operation time (mn)+ 90 (12.5) 90 (15) 95 (15) 0.000& warm ischemia time (sc) 92.4 ± 5.4 91.9 ± 5.4 94.2 ± 5 0.016* ebl (cc) + 50 (20) 50 (20) 50 (15) 0.568& length of stay (days) 2.2 ± 0.6 2.2 ± 0.6 2.2 ± 0.5 0.787* table 1. comparison of parameters according to incision types. narcotic analgesic requirement (n; %) 8 (4.6) 8 (6) 2 (2.8) 0.201! vas 3.7 ± 0.9 3.9 ± 1.1 3.4 ± 0.8 0.611” perioperative complication (n ; %) 1 8 (3.5) 5 (3.7) 3 (4.2) 0.569! 2 9 (3.9) 7 (5.3) 2 (2.8) 3 5 (2.5) 3 (2.2) 2 (2.8) wound site infection (n ; %) 6 (3) 4 (3) 2 (2.8) 0.844” incisional hernia 0 (0) 0 (0) 0 (0) table 2. perioperative complications and visual analog scale scores. “chi-squire test ! fisher exact test + presented as median (iqr) vas: visual analog scale urological oncology 291 the peritoneum was not dissected. subsequently, only the skin layer of the incision was sutured continuously with a 3/0 polypropylene suture, leaving the most lateral 1.5 cm of the donor kidney side open. (figure 2a) then, the site was closed with a sterile bandage. then, the patient was placed in the lateral decubitus position (figure 2b). to perform a right donor nephrectomy, an incision was made at the level of the umbilicus along with the line corresponding to the margin of the lateral rectus muscle. passing through the skin and subcutaneous tissue, the fascia was reached. co 2 insufflation was initiated after entering the intraperitoneal area with the verres needle. for the left side, a veress needle was introduced through palmer's point. the intra-abdominal pressure was increased to 15 mmhg. through the same point, a 10-mm-port was placed. subsequently, a 5-mm-port was placed approximately 3 cm inferior to the intersection point of the costal margin and the lateral rectus muscle and a 10-mm-port were placed approximately at a distance of 6 cm inferiorly and laterally to the camera port. from this stage until clipping the renal pedicle, the procedures were performed in the same way using the same technique as we described in the iliac fossa incision. then, another port was inserted under direct vision through the abovementioned 1.5-cm-opening at the most lateral part of the pfannenstiel incision. through this port, a multifire endo-ta stapler (covidien, walpole, massachusetts, abd) was placed on the renal artery and a hem-o-lock® clip (teleflex medical, research triangle park, north carolina, usa) clip was applied to the renal vein. subsequently, the renal artery and the renal vein were ligated and transected. the sutures at the pfannenstiel incision were removed and the kidney was extracted manually. a draining catheter was placed and the operation was terminated. the study was approved by the university of health sciences, dr. sadi konuk training and research hospital ethical committee, bakirkoy, istanbul, turkey (decision no: 2020-352). informed consent was obtained from all the patients. statistical analysis for statistical analyses, the ncss (number cruncher statistical system) 2007 (kaysville, utah, usa) software was used. the continuous variables were given as means ± standard deviations. the nonnormally distributed variables were presented as medians and interquartile ranges. categorical data were presented as numbers and percentages. the normality of quantitative data was tested by the shapiro-wilk test and graphical plots such as q-q plot. the student's t-test was used to compare two groups conforming to a normal distribution. the levene’s test used to assess the equality of the variances. the mann-whitney u test was used to compare two groups that did not conform to a normal distribution. to compare qualitative data, the pearson's chi-square test were used if ≤ 20% of expected cell counts are less than 5, the fisher’s exact test were used if >20% of expected cell counts are less than 5. statistical significance was assessed according to a p-value of < 0,05. results of the 203 patients included in the study, an iliac fossa incision was used in 65% (n = 132; group 1) and a pfannenstiel incision was used in 35% (n = 71; group 2) to extract the donor’s kidney. between two groups, age, body mass index (bmi), gender, and charlson comorbidity index (cci) scores were similar. a comparison of parameters according to incision types can be seen in table 1. the median operative time was 90(15) minutes in group 1 and 95(15) minutes in group 2. the operative time was statistically longer in group 2 (p = 0.001). wit was 91.9 ± 5.4 seconds in group 1 and 94.2 ± 5 seconds in group 2, which was statistically significantly longer in figure 1: port placement in the iliac fossa incision group incision types for kidney extraction-şahin et al. vol 20 no 1 january-february 2023 13 urological oncology 435 group 2 (p = 0.016). the mean length of hospital stay of the patients was found to be 2.2 ± 0.6 days. the length of hospital stays and the bleeding volumes was not significantly different between the groups (p = 0.787, p = 0.568, respectively). perioperative complications and vas scores are observed in table 2. in the postoperative period, 8 (6%) patients in group 1 and 2 (2.8%) patients in group 2 required narcotic analgesics. when evaluated in terms of vas scores at the postoperative 24th hour, the mean vas score was 3.9 ± 1.1 in group 1, while it was 3.4 ± 0.8 in group 2. there was no significant difference between the two groups in terms of narcotic analgesic need and vas scores. (p = 0.201 and 0.611, respectively). complications developed in a total of 22 (10.8%) patients (table 2). of these patients; 8 had grade i, 9 had grade ii, and 5 had grade iii complications according to the clavien-dindo system. wound site infections developed in 6 patients (3%) in the postoperative period. there was no significant difference between the two groups in terms of complications and wound site infections. an incisional hernia was not observed in any of the patients in the long term after the operation. discussion ldn is used as the gold standard approach in many transplantation centers(2). several types of incisions including midline incisions, pfannenstiel incisions, or iliac fossa incisions are used to perform graft extraction in ldn. each of them has advantages and disadvantages compared to other types of incisions(16,10). in the studies by gupta et al, adiyat et al, and iemsupakkul et al; no differences in operative times were reported between operations using a pfannenstiel incision or an iliac fossa incision(10-12). however, a prospective randomized study has recently reported a shorter operative time in operations where a pfannenstiel incision was used(13). in contrast to similar studies in the literature, we have found the operative time longer in the pfannenstiel incision group compared to the iliac fossa incision group in our study, and the difference between the two groups was found to be significant (p < 0.05). this finding can be explained by the fact that; in contrast to the start of the operation after positioning the patient in the iliac fossa incision group, the operation started with the patient in the supine position in the pfannenstiel incision group and the position of the patient was later changed to the lateral decubitus position after making the incision. as for wit; no differences in wit were reported in the study performed by gupta et al. but the study by iemsupakkul et al. reported a longer wit in operations, where a pfannenstiel incision was used(11,12). contrary to those studies, another study comparing midline incisions with iliac fossa incisions have reported a statistically significantly shorter wit in the group undergoing a pfannenstiel incision(10). in our study, wit was longer in the pfannenstiel incision group (p = 0.016). the common point of iemsupakkul et al.'s study and our study are not only the significant prolongation of the wit in the pfannenstiel group but also the preference for a completely laparoscopic technique, not using the hand-assisted technique(12). they attributed the lengthening of the wit to the length of the distance between the position of the incision and the kidney. as can be seen, the results of studies related to wit are controversial in the literature. we suggest that such different results may be associated with the experience levels of teams. surgeons may be achieving better results when they use the technique with which they are more experienced. moreover, we think that the use of the gelport in the iliac fossa incision group but not in the pfannenstiel incision group in our study played a role in obtaining different wit values between the groups. on the other hand, statistically significant differences in wit values should be investigated further by examining graft functioning in recipients in order to be able to evaluate potential clinical implications. it is reported that bleeding volumes were not significantly different by the incision type across the groups(10–12). urological oncology 374 figure 2. a: pfannenstiel incision made in the supine position and the opening left for port insertion at the most lateral of the incision. b: providing the lateral decubitus position after the pfannenstiel incision is made and covered. incision types for kidney extraction-şahin et al. robotic & laparoscopic urology 14 similarly, in our study, there was no statistically significant difference in bleeding volumes between the two groups. results of comparisons of incision lengths are variable in the literature. incisions were reported to be significantly longer in the pfannenstiel incision group in the study by gupta et al.; however, adiyat et al. reported that lengths of midline incisions were shorter compared to the lengths of iliac fossa incisions and pfannenstiel incisions(10,11). in a meta-analysis; which included both of those studies, it was reported that the groups were significantly heterogeneous but there were no significant differences in incision lengths(16). in our study, we have found that incision lengths were significantly longer in the pfannenstiel group (p = 0.0001). there was an extra incision because of the use of an extra port in patients in the pfannenstiel incision group. studies in the literature reported a similar length of hospital stays according to incision type,(10,11,13) and there was no statistical difference between the groups in our study. in the literature, it has been reported that the need for analgesic use is less in the patient group who underwent pfannenstiel incision compared to the iliac fossa group(11). also, in the same study, vas scores were compared between the two groups. while no significant difference was observed in both groups in the first 4 hours postoperatively, the pfannenstiel incision group reported less pain at the postoperative 24th hour. in our study, it was observed that the patients in the pfannenstiel incision group required less narcotic analgesics in the postoperative period and reported a lower vas score, but no significant difference was found. we think that retracting the muscles instead of making the incision in patients with pfannenstiel incision may lead to less analgesic requirement in the postoperative period. a meta-analysis study in the literature reported that wound site complications were not significantly different across groups(16). gupta et al. reported that two patients developed wound site infections in the iliac fossa incision group, whereas, two patients developed wound dehiscence and 6 patients developed wound site infections in the pfannenstiel incision group. on the contrary; in the study by adiyat et al., no wound site infections were reported in the pfannenstiel incision group, but wound site complications occurred in 7 patients in the iliac fossa incision group(10,11). in our study, we observed a wound site infection in only two patients in the pfannenstiel incision group but wound site infections developed in four patients in the iliac fossa incision group. it has been reported that bladder and bowel injuries may occur during the extraction of the kidney through a pfannenstiel incision. performing a pfannenstiel incision in the lateral decubitus position might be more difficult and lead to small intestine injuries in patients(11). in our study, no bladder or bowel injury was observed in the pfannenstiel group. we think that our surgical technique did not lead to any bladder and bowel injuries in the pfannenstiel incision group because the incision was made with the patient in the supine position and, then the position of the patient was changed to the lateral decubitus position after the preparation of the incision site. at the last stage of the operation, while placing the trocar and other working tools through the incision, the procedures should be performed under direct vision and incisions should be made attentively to prevent bowel injuries during the extraction of the kidney. the gelport was used to perform ldn with an iliac fossa incision. after making the incision just enough to extract the kidney and entering into the peritoneal cavity, placing the gelport prevents gas leakage and allows extracting the kidney in a short time. another advantage of the gelport is that it allows hand-assisted surgery in case of the development of any perioperative complications. however, as we mentioned before, we do not routinely use the hand-assisted laparoscopy technique in standard donor nephrectomy procedures. therefore, we think that the gelport should be used especially at the beginning of the learning curve. the major disadvantage of the gelport can be the high cost. in our clinic, we have used the gelport and performed iliac fossa incisions in ldn cases since 2019 but, since then, we have started performing pfannenstiel incisions to reduce costs. in the study of iemsupakkul et al., cosmetic results were worse in the pfannenstiel group, but statistical significance could not be obtained(12). however, on the contrary, there are studies in the literature in which pfannenstiel incision gives more satisfactory cosmetic results(11,13). in a randomized study comparing standard laparoscopic live donor nephrectomy and mini-laparoscopic donor nephrectomy(17), better cosmetic results were observed in the mini-laparoscopic donor nephrectomy group, although peri and postoperative findings were the same. the authors explained this situation as pubic hair covering the wound site(17,18). we did not examine the cosmetic results between both incisions in our study, and this can be considered as one of the limitations of our study. the strengths of our study are that the procedures were performed by a single surgeon experienced in laparoscopy, the cases with both techniques performed at the time of the learning curve were not included in the study, and the two commonly preferred methods were compared. the limitations of our study are the retrospective design, the unequal distribution of the number of patients between the two groups, and the use of the gelport in only one arm of the study. when the pfannenstiel incision is used, we think that the staples are placed at a steeper angle to the renal vessels during the closure of the renal pedicle, thus, the safety of the procedure will be promoted and longer segments of renal vessels can be harvested. however, our study design was not suitable to evaluate this suggestion and this may be another limitation. conclusions both types of incisions can be used successfully and safely for the extraction of the kidney in ldn. although wit and operation time have been observed to be longer when a pfannenstiel incision is made, complications and analgesic use are not different between pfannenstiel incisions and iliac fossa incisions. conflict of interest the authors declare that they have no conflict of interest references 1. ratner le, ciseck lj, moore rg, cigarroa fg, kaufman hs, kavoussi lr. laparoscopic live donor nephrectomy. transplantation. incision types for kidney extraction-şahin et al. vol 20 no 1 january-february 2023 15 1995;60:1047-9 2. ng zq, he b. a proposed classification system and therapeutic strategy for chyle leak after laparoscopic living-donor nephrectomy: a single-center experience and review of the literature. exp clin transplant. 2018;16:143-9 3. hellegering j, visser j, kloke hj, d'ancona fc, hoitsma aj, van der vliet ja, et al. deleterious influence of prolonged warm ischemia in living donor kidney transplantation. transplant proc. 2012;44:1222–6. 4. marzouk k, lawen j, alwayn i, kiberd ba. the impact of vascular anastomosis time on early kidney transplant outcomes. transplant res. 2013;2:8–12 5. su lm, ratner le, montgomery ra, jarrett tw, trock bj, sinkov v, et al. laparoscopic live donor nephrectomy: trends in donor and recipient morbidity following 381 consecutive cases. ann surg. 2004;240:358–63. 6. øyen o, andersen m, mathisen l, kvarstein g, edwin b, line pd, et al. laparoscopic versus open living donor nephrectomy: experiences from a prospective, randomized, single center study focusing on donor safety. transplantation 2005;79:1236– 40. 7. dubey d, shrinivas rp, srikanth g. transumbilical laparoendoscopic singlesite donor nephrectomy: without the use of a single port access device. indian j urol. 2011;27:180-4. 8. allaf me, singer a, shen w, green i, womer k, segev dl, et al. laparoscopic live donor nephrectomy with vaginal extraction: initial report. am j transplant 2010;10:1473-7 9. silva ans, georgiades f, bath mf, hosgood sa, nicholson ml. iliac fossa muscle splitting incision in laparoscopic donor nephrectomy: a comparison with the suprapubic approach. urology. 2020;143:142-6. 10. adiyat kt, tharun bk, shetty a, samavedi s. comparison of three different techniques of extraction in laparoscopic donor nephrectomy. indian j urol. 2013;29:184-7. 11. gupta m, singh p, dubey d, srivastava a, kapoor r, kumar a. a comparison of kidney retrieval incisions in laparoscopic transperitoneal donor nephrectomy. urol int. 2008;81:296-300 12. iemsupakkul p, kongchareonsombat w, kijvikai k. comparison of pfannenstiel or extended iliac port site kidney extraction in laparoscopic donor nephrectomy: do we have consensus? exp clin transplant. 2017;15:138‐42. 13. deshmukh cs, ganpule ap, sudharsan sb, singh ag, sabnis rb, desai mr. iliac fossa vs pfannenstiel retrieval incision in laparoscopic donor nephrectomy: a critical analysis. arab j urol. 2019;17:318‐25. 14. serrano ok, bangdiwala as, vock dm, berglund d, dunn tb, finger eb, et al. defining the tipping point in surgical performance for laparoscopic donor nephrectomy among transplant surgery fellows: a risk-adjusted cumulative summation learning curve analysis. am j transplant. 2017;17:1868-78. 15. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205–13 16. amer t, biju rd, hutton r, alsawi m, aboumarzouk o, hasan r, et al. laparoscopic nephrectomy – pfannenstiel or expanded port site specimen extraction: a systematic review and meta-analysis. cent european j urol. 2015;68:322-9 17. simforoosh n, hosseini sharifi sh, valipour r, narouie b, kamranmanesh mr, soltani mh. minilaparoscopy vs. standard laparoscopic donor nephrectomy: comparison of safety, efficacy and cosmetic outcomes in a randomized clinical trial. urol j. 2015;12:2223-7. 18. simforoosh n, basiri a, tabibi a, javanmard b, kashi ah, soltani mh, obeid k. living unrelated versus related kidney transplantation: a 25-year experience with 3716 cases. urol j. 2016;13:2546-51. incision types for kidney extraction-şahin et al. robotic & laparoscopic urology 16 female urology postoperative outcomes following tension-free vaginal mesh surgery for pelvic organ prolapse: a retrospective study aki oride*, haruhiko kanasaki, tomomi hara, satoru kyo purpose: we retrospectively reviewed the postoperative outcomes of patients who underwent tension-free vaginal mesh (tvm) surgery in our institution. methods: in total, 195 tvm surgeries were performed at the shimane university school of medicine from january 2010 to may 2016 in patients with pelvic organ prolapse–quantification (pop-q) stage ii or higher. perioperative complications and problems arising following surgery were assessed from medical charts. results: among the 195 patients, only 1 patient required blood transfusion due to massive intraoperative blood loss. none of the patients experienced intraoperative complications, such as injury to the bladder or rectum during surgery. mesh exposure was observed in 10 patients (5.1%). overall, 6 of these 10 patients were asymptomatic, and surgical treatment was required in only 1 patient. mesh exposure occurred at significantly higher frequencies in patients aged less than 60 years. postoperative recurrence of pop, which was defined as recurrence over pop-q stage 2, was noted in 13 of the 195 patients (6.6%). re-operation was performed in 1 patient in whom recurrence was observed within 3 months postoperatively. recurrence of pop was likely to occur in patients with higher pop-q stages. overall, 31 of the 195 patients (15.9%) required medication for postoperative stress urinary incontinence (sui) after surgery. among these, 2 patients underwent surgical treatment for sui. conclusion: outcomes following the tvm procedure were satisfactory. however, caution should be exercised against mesh exposure in younger patients and recurrence of pop in patients with advanced pop-q stage. keywords: tvm; mesh surgery; pelvic organ prolapse; mesh exposure; stress urinary incontinence introduction in the super-aging society of japan, pelvic organ prolapse (pop) is a major healthcare problem, and the number of patients with this disorder has increased in recent years. although japanese gynecologists have traditionally performed vaginal hysterectomy (vh), anterior and posterior colpoplasty, and circumferential suturing of the levator ani muscles as curative surgery for pop, a gold standard operation for pop is yet be established worldwide. thus, the surgical treatment of pop continues to be a clinical challenge for gynecologists. after the development of tension-free vaginal mesh (tvm) surgery for the repair of pop in france, this new transvaginal technique has been adopted in many countries(1). tvm surgery, which does not require hysterectomy, is associated with favorable cure rates and a low frequency of complications(1), and many gynecologists in japan have now switched to using this new technique as the first-line surgical option for pop. the procedure of tvm surgery is simple and easy to learn. however, there exist certain tvm surgery-specific periand postoperative complications, such as mesh exposure, wound granulation, infection, dyspareunia, and stress urinary incontinence (sui)(2,3). for example, in a recent review, the overall mesh exposure rate has been reported to be 10.3% (2), and the recurrence department of obstetrics and gynecology, shimane university school of medicine, izumo, japan. *correspondence: department of obstetrics and gynecology, shimane university school of medicine89-1 enya cho, izumo city, shimane 693-8501, japan. tel.: +81-853-20-2268; fax: +81-853-20-2264. email: oride@med.shimane-u.ac.jp. received june 2018 & accepted august 2019 rate following tvm operation has been reported to be low but significant at 7.0% (1). indeed, the us food and drug administration (fda) expressed concerns about the safety and effectiveness of tvm surgery in 2008 and 2011(4). we have employed tvm surgery as the first-line surgical treatment for pop in our institution since 2010. to evaluate the postoperative outcomes and complications of this transvaginal surgery, we retrospectively reviewed cases of pop treated with tvm surgery in our institution. materials and methods between january 2010 and march 2016, 195 women with pop underwent tvm surgery in shimane university hospital. women with asymptomatic prolapse designated pelvic organ prolapse quantification system (pop-q) stage ii (leading edge of the prolapse > -1 cm) or higher were candidates for tvm surgery. exclusion criteria were premenopausal women, diabetes mellitus, and very low activities of daily living. patients were provided preoperative counseling regarding uterine preservation procedures, safety, efficacy, and potential complications. moreover, we also provided explanations about alternative measures such as the use of pessary ring, native tissue repair, and sacrocolpopexy. urology journal/vol 16 no. 6/ november-december2019/ pp. 581-585. [doi: 10.22037/uj.v0i0.4631] patients who had provided written informed consent were scheduled for tvm surgery. data were collected retrospectively from the patients’ medical records, and ethical approval for this study was obtained from the ethical committee of shimane university hospital. all procedures were performed by two experienced gynecologists in our hospital. the surgery was performed under general or lumbar spinal anesthesia in the lithotomy position. the conventional tvm technique has been described previously(5). we used monofilament polypropylene mesh (polyform™; boston scientific, natick, ma) cut into a shape similar to that used with the prolift system (ethicon, somerville, nj) before each operation, because mesh kits for tvm surgery are not available in japan. the anterior tvm (a-tvm) procedure starts with anterior colpotomy after local infiltration. repair of a cystocele requires two arms of transobturator mesh to be passed on both sides in order to suspend the cystocele. on either side, both arms of the mesh are passed into the paravesical region using a modified emmet needle. the anterior subvesical strap is inserted into the tendinous arch of the pelvic fascia. the posterior subvesical strap is inserted in the tendinous arch 1 cm from the ischial spine using a gently curved needle. in the posterior tvm (p-tvm) procedure, posterior colpotomy is performed longitudinally and the mesh is placed under the vaginal wall. on each side, one strap of the mesh is passed into the pararectal space through the sacrospinous ligament and exteriorized via incisions located outside and below the anus. after cystoscopy and digital examination of the rectum, the colpotomy is closed with a 2-0 pds running suture without additional colpectomy. in our institution, patients with anterior vaginal wall prolapse underwent a-tvm, patients with both anterior and posterior vaginal wall prolapse underwent a combined a-tvm and p-tvm (ap-tvm) procedure, and patients without a uterus underwent total tvm (t-tvm). for t‐tvm, we connected the a-tvm mesh and p-tvm mesh, and created a one-piece mesh with six arms. we then created a tunnel under the mucous membranes of the vaginal stump through which the mesh was passed and inserted in the anterior and posterior walls. perioperative and postoperative complications, including mesh extrusion, dyspareunia, sui, and recurrence of pop were evaluated according to patient age and preoperative stage of pop-q. recurrence of pop was defined as pop-q stage ii or higher after the initial operation. patients were discharged 3 days after surgery and monitored for postoperative complications in the outpatient clinic at 1, 3, 6, and 12 months and then annually after the surgery. pop recurrence and mesh exposure were diagnosed based on gynecological examination. de novo sui was determined based on the presence of both the patient’s complaints and a positive stress test. statistical analysis was performed to determine significant differences between the groups using the chisquared test and the fisher exact test with p < 0.05 indicating statistical significance. the data were finalized in december 2016. results the characteristics of the 195 patients who underwent tvm surgery between january 2010 and march 2016 are shown in table 1. the mean follow-up duration was 12 ±15 (range 3 to 60) months. regarding tvm surgery, the combined ap-tvm was the most commonly performed surgery in patients with pop, and this was performed in 128 women. the number of a-tvm, p-tvm, and t-tvm surgeries were 34, 29, and 4, respectively. stage iii was the most commonly diagnosed pop-q stage (n = 135), followed by stage ii (n = 32) and stage iv (n = 28). also, the age distribution is shown in table 2. about 77% of women who underwent tvm surgery were aged between 61 and 80 years; 13 wompostoperative outcomes of tvm surgery-oride et al. table 1. baseline characteristics of the 195 patients. age (at the time of surgery) 69.0 ± 8.5 surgery a-tvm, n (%) 34 (17.4) ap-tvm, n (%) 128 (65.6) p-tvm, n (%) 29 (14.9) t-tvm, n (%) 4 (2) pop-q stage ii, n (%) 32 (16.4) iii, n (%) 135 (69.2) iv, n (%) 28 (14.4) abbreviations: tvm: anterior tvm, p-tvm: posterior tvm, ap-tvm: anterior and posterior tvm, t-tvm: total tvm 41-60 y 61-70 y 71-80 y 81-90 y total (%) mean of age (± sd) tvm-a 11 10 9 5 34 (17.4) 67.9 (± 10.8) tvm-ap 17 59 44 7 128 (65.6) 68.7 (± 8.0) tvm-p 3 6 19 1 29 (14.9) 71.4 (± 8.0) t-tvm 1 1 2 0 4 (2) 68.3 (± 6.0) 32 76 74 13 195 69 (± 8.6) table 2. age distribution of patients. figure 1. shape of mesh and a intraoperative picture of t-tvm. (a)a-tvm mesh, (b) p-tvm mesh, (c) t-tvm mesh, (d) insertion of t-tvm mesh into a tunnel of vaginal stump female urology 582 vol 16 no 06 november-december2019 583 en were aged over 81 years, and 32 women were aged below 60 years. only 2 of the 195 patients had vaginal hysterectomy due to uterine fibroid. no other patients had undergone previous vaginal surgery. among 195 cases, only 1 intraoperative complication occurred, wherein over 1800 ml of intraoperative bleeding required transfusion in a patient. there were no cases of bladder injury, rectal injury, or injury to the ureters. during postoperative routine follow-up examinations, we found mesh exposure in 10 of the 195 patients (5.1%). furthermore, 6 of these 10 patients were asymptomatic, and 4 patients complained of abnormal vaginal bleeding during follow-up hospital visits. mesh exposure was identified at various intervals following surgery, between 6 months and 2 years and among patients whose age ranged from 49 to 79 (average age, 73.8 ± 11.0) years. the age distribution of patients with mesh exposure demonstrated that younger patients who underwent tvm surgery were more likely to have mesh exposure postoperatively. when patients were divided into two groups by age ≤ 60 years and > 60 years, we noted that the occurrence of mesh exposure was significantly higher in those aged ≤ 60 years of age (p < 0.007) (table 3). among the 10 patients with mesh exposure, only 1 patient underwent additional surgical treatment, which included removal of the exposed mesh and re-suturing of the vaginal wall to control abnormal bleeding. among the 195 patients who underwent tvm surgery, 13 patients were diagnosed with recurrent prolapse (6.6%). recurrence was diagnosed based on physical indications, not patient’s complaints. the time points at which recurrence of pop was diagnosed varied from 3 months to 3 years postoperatively, and the average time was 13.6 ± 10.3 months after the initial tvm surgery. pop-q stages at the time of initial operation were compared among the recurrent cases. overall, 8 patients with recurrence were initially diagnosed as pop-q stage iii (8/135, 5.90%), while the remaining 5 patients had pop-q stage iv (5/24, 17.90%). the recurrence rate of pop was thus significantly higher in patients with pop-q stage iv than those with pop-q stage iii at initial diagnosis. there was no significant difference between age groups and pop-q stage. among these 13 table 3. age and pop-q stage distribution of 10 patients with mesh exposure. age (years) mesh exposure p value yes n (%) no n (%) 41-50 1 (50) 1 (50) 51-60 4 (13.3) 26 (86.7) 61-70 1 (1.3) 75 (98.7) p = 0.0071 71-80 4 (5.4) 70 (94.6) 81-90 0 (0) 13 (100) pop-q stage ii 3 (9.4) 29 (90.6) iii 6 (4.4) 129 (95.6) iv 1 (3.6) 27 (96.4) the percentage is the proportion of patients of the same age or at the same disease stage who developed mesh exposure following tvm surgery. the chi-squared test was performed to compare two groups divided by age ≤ 60 years and > 60 years. the incidence of mesh exposure was significantly higher in patients over 60 years. the percentage of mesh exposure did not differ between pop-q stages. age (years) recurrent pop p value yes n (%) no n (%) 41-50 0 (0) 2 (100) 0.06 51-60 1 (3.3) 29 (96.7) 61-70 7 (9.2) 69(90.8) 71-80 5 (6.8) 69 (93.2) 81-90 0 (0) 13 (100) pop-q stage 0.66 ii 0 (0) 32 (100) iii 8 (5.9) 127 ((94.1) iv 5 (17.9) 23 (82.1) the percentage is the proportion of patients of the same age or at the same disease stage whose pop recurred following tvm surgery. the fisher’s exact test was performed to make comparisons within each group. the recurrence rate was not related to the patient’s age and pop-q stage. table 4. age and pop-q stage distribution of 13 patients with recurrent pop. patients with sui after tvm yes n (%) no n (%) 31 (15.9) 164 (84.1%) age (years) p value 41-50 0 (0) 2 (100) 0.200 51-60 1 (3.3) 29 (96.7) 61-70 14 (18.4) 62 (81.6) 71-80 15 (20.3) 59 (79.7) 81-90 1 (7.7) 12 (92.3) pop-q stage ii 7 (21.9) 25 (78.1) 0.29 iii 22 (16.3) 113 (83.7) iv 2 (7.1) 26 (92.9) yes n (%) no n (%) consultation to urologists 7 (3.6) 188 (96.4) tvt surgery 2 (1.0) 193 (99.0) abbreviations: sui: stress urinary incontinence; tvt: tension-free vaginal tape the percentage is the proportion of patients of the same age or at the same disease stage who developed sui following tvm surgery. the chi-squared test was performed to make comparisons within each group. the occurrence of sui was not related to the patient’s age and pop-q stage. table 5. occurrence of sui after tvm surgery. postoperative outcomes of tvm surgery-oride et al. patients who presented with recurrent pop, only 1 patient underwent a second surgery at her request (table 4). finally, we analyzed the occurrence of postoperative sui in the 195 patients who underwent tvm surgery; 15 of 31 patients who developed postoperative sui had preoperative sui. during postoperative follow-up, 31 patients (15.9%) received medication for complaints of onset or worsening of sui; these included transient or continuous medication. the majority of patients who complained of sui following tvm surgery recovered or did not consider the problem serious enough to warrant further treatment. however, 7 of the 31 patients (22.5%) consulted a urologist to request further examination and treatment. of these, 2 patients underwent tension-free vaginal tape surgery for sui (table 5). patients’ symptoms associated with de novo sui improved after surgery. no patients complained of postoperative recurrent urinary tract infection or deterioration of sexual function including dyspareunia and vaginismus. there was no evidence of wound granulation or infection at the postoperative examination. discussion in this study, we reviewed the records of patients who underwent tvm surgery for pop and analyzed the postoperative outcomes. as previously reported, we concurred that tvm surgery can be performed safely and that it is associated with a relatively low rate of complications(6). we have not encountered severe complications during the tvm surgeries that we have performed so far, except in 1 case where blood transfusion was required following heavy bleeding. this was our 24th case after starting tvm surgery in our institution, and the unexpected blood loss probably occurred due to poor surgical technique when opening the paravesical space by blunt dissection. as expected, this study revealed that mesh exposure was one of the major postoperative complications of tvm surgery. our mesh exposure rate was 5.1%. the occurrence of mesh exposure has varied significantly among different studies. in 2007, falagas et al. reported that the incidence of mesh exposure ranged from 0% to 33% (7). in 2016, niu et al. reported a series of 195 patients in which the incidence of mesh exposure was 16.4% (8); they assumed that the number of concomitant procedures and the operation times were risk factors for mesh exposure. indeed, a report by heinonen et al. in 2016 demonstrated a mesh exposure rate of 23% and noted that the complications in the first half and second half of patients sampled revealed a reduction in mesh exposure from 14% to 5%. luo et al. reported that the mesh exposure rate will be close to zero if tvm surgery is performed using the anatomical implant technique (9). we did not evaluate the cases of mesh exposure in detail because our study had only 10 such cases; however, mesh exposure was more likely to occur in patients younger than 60 years of age. sexual activity may also be a risk factor for mesh exposure as previously suggested(10,11). however, several studies have shown no significant difference in patient age between mesh exposure and non-exposure groups(8,12). considering that more than half of the patients with mesh exposure were asymptomatic and only 1 patient (0.5%) required reoperation due to repeated abnormal bleeding, which implied that most cases with mesh exposure and abnormal bleeding were easily cured by medical intervention with local vaginal estrogen tablets), tvm surgery should not be excluded based on patient age. nevertheless, since mesh exposure was noted as late as 2 years postoperatively, longer follow-up durations may increase the incidence rate of mesh exposure in the future. recurrence of pop after tvm surgery occurred in 13 patients (13/195, 6.6%) in our evaluation. of the 13 patients, only 1 patient underwent reoperation, while the remaining 12 patients either did not notice pop recurrence or did not find it inconvenient. in 2008, caquant et al. reported a recurrence rate at 6-18 months of 6.9% after tvm surgery(13). sho et al. retrospectively reviewed 526 tvm operations in 2014 and indicated a recurrence rate of 7.0%(14). similar to our results, these reports also described low rates of reoperation among cases of recurrent pop. since the recurrence rate of pop was higher in patients with advanced stages of preoperative pop, such patients should be followed up carefully. although children might also develop sui , sui and pop are common diseases in postmenopausal women. some reports state that sui is observed in approximately 40% of women aged 51 or over. changes in certain neuropeptides such as vasoactive intestinal peptide and neuropeptide y, and neuronal nitric oxide in the vaginal wall have been observed in sui and pop patients . postoperative sui is a well-known complication of tvm surgery. we have previously reported that 47.3% of patients without preoperative sui experienced de novo postoperative sui after tvm surgery(3). in the present study, not all women who complained of postoperative sui wished to receive medication, because their sui symptoms were not severe. treatment was prescribed to 31 of 195 patients for sui using clenbuterol hydrochloride and/or propiverine hydrochloride after tvm surgery. in most patients, the symptoms resolved or subsided over time, and only 7 of 31 patients were referred to the urologist for further expert examination and treatment. ultimately, only 2 patients who underwent tvm surgery underwent surgical treatment for sui by the urologist. sui can result from resolution of urethral obstruction by anatomical reconstruction. interestingly, tvm surgery can improve sui in some cases(3). thus, even when postoperative sui occurred, most cases were transient. however, a small number of serious cases may require surgery. limitations of our study are its retrospective and single-center design. additionally, although the study duration was 3 years at the longest, the follow-up period for some patients was too short for any complications to have been observed. overall, we were satisfied with the outcomes of tvm surgery performed in our institution in the past 6 years. however, the us fda has described increasing concerns regarding complications after tvm surgery(15). furthermore, two recent studies from scotland and the uk took a stand against mesh surgery for pop because their investigations revealed that vaginal repair with mesh material did not improve outcomes for women (16,17). therefore, this surgical technique needs further consideration, and patients undergoing tvm surgery should be followed up carefully. conflict of interest the authors declare that they have no conflicts of interpostoperative outcomes of tvm surgery-oride et al. female urology 584 vol 16 no 06 november-december2019 585 est. no funding was received for this study. references 1. debodinance p, berrocal j, clave h, et al. [changing attitudes on the surgical treatment of urogenital prolapse: birth of the tension-free vaginal mesh]. j gynecol obstet biol reprod (paris). 2004;33:577-88. 2. abed h, rahn dd, lowenstein l, et al. incidence and management of graft erosion, wound granulation, and dyspareunia following vaginal prolapse repair with graft materials: a systematic review. int urogynecol j. 2011;22:789-98. 3. kanasaki h, oride a, mitsuo t, miyazaki k. occurrence of preand postoperative stress urinary incontinence in 105 patients who underwent tension-free vaginal mesh surgery for pelvic organ prolapse: a retrospective study. isrn obstet gynecol. 2014;2014:643495. 4. costantini e, lazzeri m. what part does mesh play in urogenital prolapse management today? curr opin urol. 2015;25:300-4. 5. collinet p, belot f, debodinance p, ha duc e, lucot jp, cosson m. transvaginal mesh technique for pelvic organ prolapse repair: mesh exposure management and risk factors. int urogynecol j pelvic floor dysfunct. 2006;17:315-20. 6. takahashi s, obinata d, sakuma t, et al. tension-free vaginal mesh procedure for pelvic organ prolapse: a single-center experience of 310 cases with 1-year follow up. int j urol. 2010;17:353-8. 7. falagas me, velakoulis s, iavazzo c, athanasiou s. mesh-related infections after pelvic organ prolapse repair surgery. eur j obstet gynecol reprod biol. 2007;134:14756. 8. niu k, lu yx, shen wj, zhang yh, wang wy. risk factors for mesh exposure after transvaginal mesh surgery. chin med j (engl). 2016;129:1795-9. 9. luo dy, yang tx, shen h. long term follow-up of transvaginal anatomical implant of mesh in pelvic organ prolapse. sci rep. 2018;8:2829. 10. achtari c, hiscock r, o'reilly ba, schierlitz l, dwyer pl. risk factors for mesh erosion after transvaginal surgery using polypropylene (atrium) or composite polypropylene/polyglactin 910 (vypro ii) mesh. int urogynecol j pelvic floor dysfunct. 2005;16:389-94. 11. kaufman y, singh ss, alturki h, lam a. age and sexual activity are risk factors for mesh exposure following transvaginal mesh repair. int urogynecol j. 2011;22:307-13. 12. kim j, lucioni a, govier f, kobashi k. worse long-term surgical outcomes in elderly patients undergoing sparc retropubic midurethral sling placement. bju int. 2011;108:708-12. 13. caquant f, collinet p, debodinance p, et al. safety of trans vaginal mesh procedure: retrospective study of 684 patients. j obstet gynaecol res. 2008;34:449-56. 14. sho t, yoshimura k, hachisuga t. retrospective study of tension-free vaginal mesh operation outcomes for prognosis improvement. j obstet gynaecol res. 2014;40:1759-63. 15. stanford e, moen m. patient safety communication from the food and drug administration regarding transvaginal mesh for pelvic organ prolapse surgery. j minim invasive gynecol. 2011;18:689-91. 16. morling jr, mcallister da, agur w, et al. adverse events after first, single, mesh and non-mesh surgical procedures for stress urinary incontinence and pelvic organ prolapse in scotland, 1997-2016: a population-based cohort study. lancet. 2017;389:629-40. 17. glazener cm, breeman s, elders a, et al. mesh, graft, or standard repair for women having primary transvaginal anterior or posterior compartment prolapse surgery: two parallel-group, multicentre, randomised, controlled trials (prospect). lancet. 2017;389:381-92. postoperative outcomes of tvm surgery-oride et al. reconstructive surgery persian version of patient-reported outcome measure for urethral stricture surgery (uss-prom) questionnaire, validation and adaptation study ali tayyebi azar1,2, morteza fallah-karkan3,4, mohammad ali hosseini5, babak kazemzadeh azad1, abtin heidarzadeh6, jalil hosseini7* purpose: the aim of the present study was translation, cross cultural adaptation and face validity evaluation of the persian version of patient-reported outcome measure for urethral stricture surgery (uss-prom) questionnaire. materials and methods: this study was assessed: translation, translation quality, reverse translation and comparison of the english version, content validity, internal consistency and stability. content validity presents by index of content validity (cvi) and the content validity ratio (cvr). internal consistency reliability was tested by cronbach’s α, and test-retest reliability was evaluated by intraclass correlation coefficient (icc) assessed by guttman two way mixed absolute agreements. result: forty males with history of urethroplasty and mean age of 41.4 ± 9.08 (range of 19 to 52) years old were enrolled. in the case of mean scores of difficulty from the 16 translated items, 80% had easy translation. in terms of translation quality, 92% were the satisfactorily clear. in terms of similar concept, 92% were satisfactory. the overall quality of the translation was satisfactory at 88%. the translated questionnaire has a good internal consistency (cronbach's alpha as 0.84). cvi and the cvr, test-retest icc evaluation were appropriate/acceptable in all questions. the questionnaire icc was .791(ci 95%, .678-.876). two main different aspects of the questionnaire consisted of urinary symptoms (question 1-10) and quality of life (question 11-15). cronbach's alpha were .800 and .671 respectively. conclusion: the persian version of the questionnaire has acceptable cultural adaptation and face validity. further studies should be done using this translated tool to determine its applicability in the urethroplasty patients. keywords: adaptation; patient-reported outcomes measures; uss-prom questionnaire; face validity; urethroplasty; urethral stricture introduction urethral stricture disease (usd) is a common and challenging problem for urologists(1-3). it has an estimated prevalence rate of 0.6%(4-6). many valid option modalities are accessible for the management of usd(7,8). the success criteria for urethroplasty are based on clinical and objective examinations, such as uroflowmetry parameters, retrograde-voiding cyst urethrogram (rug-vcug), urethroscopy and post void residue (9-11). recent studies emphasize the need for using a questionnaire that presents surgical outcomes based on subjective perspective(12,13). thus, the british scientist jackson et al. for the first time, developed and validated a questionnaire with mental characteristics for patients undergoing urethroplasty named patient-reported outcome measure for urethral stricture surgery (uss-prom)(14). 1fellowship of reconstructive urology, infertility and reproductive health research center shahid beheshti university of medical sciences, tehran, iran. 2urology department, urmia university of medical sciences, urmia, iran. 3laser application in medical science research center, shahid beheshti university of medical sciences, tehran, iran. 4urology resident, shohada-e-tajrish hospital, shahid beheshti medical university, tehran, iran. 5student research committee qazvin university of medical sciences, qazvin, iran. 6associated professor of community medicine, guilan university of medical sciences, iran. 7professor of reconstructive urology, infertility and reproductive health research center shahid beheshti university of medical sciences, tehran, iran. *correspondence: professor of reconstructive urology, infertility and reproductive health research center shahid beheshti university of medical sciences, tehran, iran. telfax: +98 22716383. mobile: +98 9123289944. email: jhosseinee@gmail.com. this is a questionnaire developed for early identification of the patients at risk of developing symptoms and complications of urethral stricture, and also a good instrument for assessing need to intervention. the ussprom consists of four main constructs: lower urinary tract symptoms (luts) and luts-related quality-of-life (qol) domain, peeling's voiding picture, euroqol dimensional scale (eq-5d), and post-operative overall patient satisfaction questions (14,15). due to the ethnic, linguistic, cultural and geographical differences in the countries, the questionnaire should be developed in accordance with the social norms of target community. this study aims to translate and validate the persian version of uss-prom questionnaire to investigate psychometric properties and determine its appropriateness for use in clinics in persian-speaking countries. urology journal/vol 17 no. 1/ january-february2020/ pp. 61-67. [doi: 10.22037/uj.v0i0.4937] materials and methods first step: translating the original version into persian language in the first stage, two native persian translators who were unfamiliar with uss-prom questionnaire (supplementary table 1) translated it independently from english into persian and then, one translation was selected for the questionnaire in a meeting with the presence of scholars and translators. one of the translators had a history of translating medical texts and was familiar with medical terms. furthermore, each translator scored the items in terms of difficulty using a 100-point visual scale (0 = completely easy; 100 = completely difficult). during a meeting with the presence of translators and authors of the present study, the first translated copy of the questionnaire was discussed and, finally, with regard to the items with difficult translation and their equivalences, a common persian translation version was selected. in order to assess the quality of translation in terms of four concepts of clarity (using plain and intelligible words), usage in common language (avoiding the use of technical, specialized, and artificial words), conceptual equivalence (having the conceptual content of the main version of questionnaire) and the overall quality of translation, the third translator whose mother tongue was persian and fluent in english, rated the quality of translation forward. so, this translator scored four points for each item of the uss-prom questionnaire based on a 100-point visual scale (0 = completely bad/ unsatisfactory quality; 100 = completely good/ satisfactory quality). the criterion for deciding on the satisfactory quality of translations was the average quality scores more than 90. for phrases and sentences with unsatisfactory translations, the proper equivalences suggested by translators one and two were used and the translation quality score was again calculated. this process continued to gain a desirable level. at the end of this stage, a persian version was obtained that was satisfactory in terms of quality according to translators of one to three. second step: translating the persian version into english language at this stage, the original version translated into persian was reverse-translated into english by the fourth native english translator with sufficient knowledge and experience of texts from persian into english. the new english version was compared with the original version of the questionnaire in terms of identical concepts and was discussed during two sessions with the presence of the translator and the authors to confirm the identical translation. eventually, a persian version of good translation quality was available. for verifying the face validity, the obtained version was distributed to 40 patients with urethral stricture and, with the presence of one of the researchers in the form of an interview, the subjects completed the questionnaire. the face validity of each item of the persian version of the uss-prom questionnaire was determined by a survey of 40 people with urethral stricture and urethroplasty in terms of clarity of the items, ability to answer questions, from and arrangement of items in the questionnaire. participants completed the questionnaire based on a four-point likert scale (4 = completely disagree; 3 = disagree; 2 = agree; 1 = completely agree). third step: face validity with the lot quality assurance sampling model with an upper limit of .95 and lower limit of .90 with a sample size of 40 patients, up to 5 people could announce that questions, which is not understandable. this was not the case with the current questionnaires. forth step: content validity content validity was assessed by two ways: first, in rounds of expert consensus meetings (six reconstructive urologists, four general urologists, one epidemiologist, one methodologist, one psychologist, one sociologist and one spiritualist), document circulation, and patient interviews. the result of these meetings was no need to add or omit a question to the questionnaire. second, index of content validity (cvi/averages the item-level; the sum of cvis is divided by the total number of items)(16) and the content validity ratio (cvr) was evaluated. the numeric value of cvr is determined by lawshe (supplementary table 1). in our investigation that is number of panelists 15, if cvr is > 0.49, the item with an acceptable level of significance will be accepted(17). fifth step: internal consistency (reliability) internal consistency characterizes the extent to which question items within the same construct measure the same conceptual domain and demonstrates whether it is valid to sum those item scores. this was statistically evaluated using cronbach’s alpha coefficient. a cronbach’s value of ≥0.70 was considered acceptable for internal consistency. internal consistency for each question (cronbach's alpha if item deleted) value assessed for all item. sixth step: stability (test-retest reliability) a test–retest analysis indicates the extent to which a questionnaire, test, or measuring procedure will yield the same results over a period of time. it is assessed after an interval of four weeks. the intraclass correlation coefficient (icc) assessed by guttman two way mixed absolute agreements. an icc > 0.70 was the predefined threshold for inclusion. statistical analysis the final statistical analysis was performed using spss 19 (spss inc, chicago, illinois, usa) using suitable methods for assessment of multi-steps. the level of significance was set at p<0.05. internal consistency reliability was tested by cronbach’s α, and test-retest reliability was evaluated by icc test. content validity present by cvi and the cvr. ethics after shohada-e-tajrish hospital review board approval was obtained the study conducted in reconstructive urology clinics (referral center of reconstructive urology in iran), shahid beheshti medical university, tehran, iran, between may 2017 to september 2018. written informed consent was taken for all participation in the study. results forty patients with history of bulbar (32 cases), oneor two-stage (six and two respectively) penile urethroplasty, with mean age of 41.4 ± 9.08 (range of 19 to 52) years; preoperatively, six and seven month following urethroplasty, without history of neurologic, psychic and mental disease, educational status higher than dipersian version of uss-prom questionnaire-tayyebiazar et al. reconstructive suegery 62 vol 17 no 01 january-february 2020 63 ploma without communications barrier (hearing/speaking, accent) were enrolled in the study. usd etiology was traumatic, idiopathic and iatrogenic in 29, seven and four patients, respectively. twenty-four subjects had undergone at least one endoscopic intervention before the urethroplasty. objective success of urethroplasty was defined as demonstration of urethral patency on post-operative ru/vcug at 6th month. furthermore, patients with diabetes mellitus, pelvic radiation history and previous history of any kind of urethroplasty were excluded from our study as well. the localization process was followed by translation steps, translation quality measurement and reverse translation. in the case of mean scores in terms of difficulty from the 16 translated items, 80% had easy translation, 16% had relatively easy translation, and 4% had difficult translation. in terms of translation quality, the results also showed that 92% were the satisfactorily clear and 8% were relatively clear. also, in terms of common language usage, 100% had a good translation. in terms of similar concept, 92% were satisfactory and 4% were unsatisfactory. in other cases, (4%), the similarity was relatively favorable. finally, the overall quality of the translation was also satisfactory at 88% and relatively satisfactory at 12%. so, overall, the satisfactory quality of translation was provided. the results showed that the translation and equivalence process of the uss-prom questionnaire was of a satisfactory and desirable quality. the internal consistency of the translated instrument was calculated using cronbach's alpha as 0.84. cronbach's alpha if “item deleted” for any item is presented in (supplementary table 1). two main different aspects of the questionnaire consisted of urinary symptoms (question 1-10) and quality of life (question 11-15) cronbach's alpha were .800 and .671 respectively. this results indicating that the translation of the questionnaire has a good internal consistency and supported the content validity of the persian version of uss-prom questionnaire according to iranian socio-cultural and religious features by contemporary literature review, expert opinion, consensus meetings of the study coworker and subject interviews. the translated persian form of the tool, cvi and cvr content validity and stability icc evaluation is provided in the (supplementary table 1). the questionnaire icc was .791(ci 95%, .678-.876). (supplementary table 1). english questions, translation into persian, test-retest reliability and internal consistency results discussion one of the most important features that should always be considered when choosing an instrument is the easy translation and optimal quality of the translated version into a second language. this issue is primarily addressed by the original designers of such instruments. it means that these designers always seek to avoid obscure, intangible, non-transparent, and polysomic terms when using words, phrases and sentences, thereby facilitating the process of translating and finding the equivalence for the text from one language into another(18). the present study, such a score is clearly seen. in other words, three translators in this project confirmed the easiness and satisfactory quality of translation in a quantitative, measurable and reportable manner. the available texts on the second versions of the uss-prom questionnaire also confirm this. as mentioned before, the original version of the uss-prom questionnaire has been translated into several languages, including german, italian, spanish, turkish and dutch(19-23). according to our results, in the case of mean scores in terms of difficulty from the 16 translated items, 80% had easy translation. in terms of translation quality, the results also showed that 92% were the satisfactorily clear. also, in terms of common language usage, 100% had a good translation. in terms of similar concept, 92% were satisfactory. finally, the overall quality of the translation was also satisfactory at 88%. the translated questionnaire has a good internal consistency (cronbach's alpha as 0.84). cvi and the cvr evaluation were appropriate/acceptable in all questions (supplementary table 1). two main different aspects of the questionnaire consisted of urinary symptoms (question 1-10) and quality of life (question 11-15) cronbach's alpha were .800 and .671 respectively. intraclass correlation coefficient was .791. guido barbagli and coworkers(19) in 2011 published italian validation of the uss-prome questionnaire in patients undergoing anterior urethroplasty. test-retest reliability and internal consistency statistics demonstrating criterion validity; intra-class correlation coefficients ranged from 0.81 to 0.90 for the individual voiding questions. cronbach's alpha was 0.79 for the overall score and ranged between 0.74 and 0.81. psychometric validation of a german language version of a prom was conducted on ninety-three men before and 3 months after surgery, with 40 (43 %) also completing the uss-prom 6 months after surgery to assess reliability. internal consistency: cronbach’s α was 0.83 for the luts. the test–retest icc was 0.94(20). for internal consistency in spanish version of ussprom(22), the cronbach's alpha was 0.701. for the test–retest reliability, the overall icc was 0.974, and the icc for each item separately ranged from 0.799 to 0.980. in turkish research(21) 42 men had complete pre and postoperative 6th month data for analysis. the test-retest icc was 0.79. cronbach's α for internal consistency of the luts construct was 0.79. according to present study the persian language ussprom adaption and validation shows similar properties to the original english, italian, german, spanish and turkish language version. therefore, the easy and high quality persian translation of this scale as well as the relatively large number of international translations can be considered as one of the advantages of this validation. a further study is recommended with greater sample size cohorts to increase the accuracy of the results in urethroplasty patients. conclusions during the translation process and cultural adaptation, the questionnaire was changed. it seems that the persian version of the uss-prom questionnaire with these changes is ready for evaluating its validity and reliability in subsequent studies and is comparable in psychometric properties with the original version. moreover, further studies should be done using this translated tool to determine its applicability in the urethroplasty patients. acknowledgments persian version of uss-prom questionnaire-tayyebiazar et al. the authors would like to thank all staff of reconstructive urology clinic in shohada-e-tajrish hospital. we would like to show our appreciation towards dr. saeed montazeri and nasrin borumandnia for invaluable help throughout this study. conflict of interest the authors declare no conflict of interest. references 1. cotta bh, buckley jc. endoscopic treatment of urethral stenosis. urol clin north am. 2017;44:19-25. 2. hosseini j, tabassi kt. surgical repair of posterior urethral defects: review of literature and presentation of experiences. urol j. 2008;5:215-22. 3. fallahkarkan m, razzaghi mr, karami h, ghiasy s, tayyebiazar a, javanmard b. experience of 138 transurethral urethrotomy with holmium: yag laser. j lasers med sci. 2019;10:104-7. 4. osterberg ec, murphy g, harris cr, breyer bn. cost-effective strategies for the management and treatment of urethral stricture disease. urol clin north am. 2017;44:11-7. 5. mirzazadeh m, fallahkarkan m, hosseini j. penile fracture epidemiology, diagnosis and management in iran: a narrative review. transl androl urol. 2017;6:158. 6. erickson ba, ghareeb gm. definition of successful treatment and optimal followup after urethral reconstruction for urethral stricture disease. urol clin north am. 2017;44:1-9. 7. razzaghi mr, karkan mf, ghiasy s, javanmard b. laser application in iran urology: a narrative review. j lasers med sci. 2018;9:1. 8. hosseini j, azad bk, aliakbari f, hosseini ma. familial urethral stricture, five adult patients overview. urol j. 2019. 9. kessler tm, fisch m, heitz m, olianas r, schreiter f. patient satisfaction with the outcome of surgery for urethral stricture. j urol. 2002;167:2507-11. 10. barbagli g, de angelis m, romano g, lazzeri m. long-term followup of bulbar end-to-end anastomosis: a retrospective analysis of 153 patients in a single center experience. j urol. 2007;178:2470-3. 11. hosseini j, tayebi-azar a, rahavian ah, ghiasy s. end to end urethroplasty post urethral uventa stent stricture, the first case report. urol j. 2019. 12. use cfmpfh. reflection paper on the regulatory guidance for the use of healthrelated quality of life (hrql) measures in the evaluation of medicinal products. london, e ma. 2005. 13. bottomley a, jones d, claassens l. patientreported outcomes: assessment and current perspectives of the guidelines of the food and drug administration and the reflection paper of the european medicines agency. eur j cancer. 2009;45:347-53. 14. jackson mj, sciberras j, mangera a, et al. defining a patient-reported outcome measure for urethral stricture surgery. eur urol. 2011;60:60-8. 15. jackson mj, chaudhury i, mangera a, et al. a prospective patient-centred evaluation of urethroplasty for anterior urethral stricture using a validated patient-reported outcome measure. eur urol. 2013;64:777-82. 16. polit df, beck ct, owen sv. is the cvi an acceptable indicator of content validity? appraisal and recommendations. res nurs health. 2007;30:459-67. 17. lawshe ch. a quantitative approach to content validity. personnel psychology. 1975;28:563-75. 18. salavati m, mazaheri m, khosrozadeh f, mousavi sm, negahban h, shojaei h. the persian version of locomotor capabilities index: translation, reliability and validity in individuals with lower limb amputation. qual life res. 2011;20:1-7. 19. barbagli g, romano g, sansalone s, lazzeri m. [italian validation of the english promuss-q questionnaire in patients undergoing anterior urethroplasty]. urologia. 2011;78:98107. 20. kluth la, dahlem r, becker a, et al. psychometric validation of a german language version of a prom for urethral stricture surgery and preliminary testing of supplementary ed and ui constructs. world j urol. 2016;34:369-75. 21. onol ff, bindayi a, tahra a, basibuyuk i, onol sy. turkish validation of the urethral stricture surgery specific patient-reported outcome measure (uss-prom) with supplemental assessment of erectile function and morbidity due to oral graft harvesting. neurourol urodyn. 2017;36:2089-95. 22. puche-sanz i, martin-way d, flores-martin j, et al. psychometric validation of the spanish version of the uss-prom questionnaire for patients who undergo anterior urethral surgery. actas urol esp. 2016;40:322-7. 23. verla w, waterloos m, lumen n. urethroplasty and quality of life: psychometric validation of a dutch version of the urethral stricture surgery patient reported outcome measures. urol int. 2017;99:460-6. persian version of uss-prom questionnaire-tayyebiazar et al. reconstructive suegery 64 vol 17 no 01 january-february 2020 65 persian version of uss-prom questionnaire-tayyebiazar et al. supplementary table. english questions, translation into persian, test-retest reliability and internal consistency results 2 no. eng q eng a per q per a cvr cvi icc cronbach's alpha if item deleted cronbach's alpha 1 is there a delay before urinating? never sometimes occasionally often always آیا پیش از شروع به ادرار کردن شما تاخیری وجود دارد ؟ هرگز برخی اوقات گه گاهی اغلب اوقات همیشه .56 1 .889 .825 .800 2 the power of your urine output is normal sometimes it is decreased occasionally it is decreased often it is decreased always it is decreased قدرت جریان خروج ادرار شما عادی است برخی اوقات کاهش می یابد گه گاهی کاهش می یابد اغلب اوقات کاهش می یابد همیشه کاهش می یابد .73 1 .708 .825 3 do you have to push to continue your urine? never sometimes occasionally often always آیا برای ادامه خروج ادرارتان باید زور بزنید ؟ هرگز برخی اوقات گه گاهی اغلب اوقات همیشه .6 1 .695 .826 4 is your urine interrupted more than once during urination? never sometimes occasionally often always آیا در هنگام ادرار کردن بیش از یکبار ادرارتان قطع و وصل می شود ؟ هرگز برخی اوقات گه گاهی اغلب اوقات همیشه .53 1 .787 .827 5 how often do you feel after your urination that your urine is not completely drained? never sometimes occasionally often always چقدر پیش می اید که پس از ادرار کردن احساس کنید که ادرارتان کامل تخلیه نشده است ؟ هرگز برخی اوقات گه گاهی اغلب اوقات همیشه .6 1 .937 .837 6 how often do you feel that your pants are soaked after you urinate and wear clothes? never sometimes occasionally often always چقدر پیش می آید که پس از ادرار کردن و پوشیدن لباس احساس کنید که شلوارتان خیس شده است ؟ هرگز برخی اوقات گه گاهی اغلب اوقات همیشه .61 1 .931 .832 7 in general, how much does your urination issues affect your everyday life? never little somewhat so much در مجموع، مسائل مربوط به ادرار کردن شما چقدر روی زندگی روزمره شما تاثیرگذار است ؟ هیچ وقت کمی تا حدودی خیلی .73 1 .688 .826 8 please mark the number that shows your urine flow capacity in the last month. لطفاً روی شماره ای که قدرت جریان ادراری شما را در یک ماه گذشته نشان می دهد عالمت بزنید. 1 1 1 .818 9 are you satisfied with the outcome of your surgery? i’m completely satisfied. i’m satisfied. آیا از نتیجه عمل جراحی خود رضایت دارید ؟ بله ، کامالً راضی هستم بله ، راضی هستم نه ، ناراضی هستم نه ، کامالً ناراضی هستم .86 .974 .835 persian version of uss-prom questionnaire-tayyebiazar et al. reconstructive suegery 66 3 i’m dissatisfied. i’m completely dissatisfied. 10 i am dissatisfied or completely dissatisfied because my urination is not good. my urination is good, but there are other problems. my urination is not good and there are other problems ناراضی و یا کامالً ناراضی هستم به دلیل اینکه وضعیت ادرار کردنم خوب نشده است وضعیت ادرار کردنم خوب شده است ولی مشکالت دیگری پیش آمده است. وضعیت ادرار کردنم خوب نشده است و مشکالت دیگری هم پیش آمده است. .5 1 ß which following options is the best description of your health situation today? 11 mobility i have no trouble in walking there are a few problems in walking i got stuck تحرک مشکلی در راه رفتن ندارم در راه رفتن کمی مشکل دارم زمین گیر شده ام . 5 .93 1 .835 .671 12 self-care i have no problem in self-care i have trouble in washing myself and wearing clothes i cannot wash myself and wear clothes خود مراقبتی مشکلی در مراقبت از خود ندارم با شستشو خود و پوشیدن لباس مشکل دارم قادر به شستشوی خود و پوشیدن لباس نیستم .5 1 ß .845 13 daily activities (such as work, study, home, family or leisure) i have no problems doing my daily activities i have a problem doing my daily activities i cannot do my daily activities فعالیت های روزانه ) مانند کار ، تحصیل ، امور خانواده یا منزل ، اوقات فراغت ( هیچ مشکلی در انجام فعالیت های روزانه ام ندارم کمی با انجام فعالیت های روزانه ام مشکل دارم قادر به انجام فعالیت های روزانه ام نیستم 1 1 1 .838 14 pain / discomfort i have no pain and discomfort i have some pain and discomfort i strongly feel pain and discomfort درد/ناراحتی هیچگونه احساس درد و ناراحتی ندارم تا حدودی درد و ناراحتی دارم شدیداً احساس درد و ناراحتی دارم .06 1 .976 .820 15 anxiety / depression i'm not anxious or depressed i'm somewhat anxious or depressed i'm very anxious or depressed اضطراب/افسردگی مضطرب یا افسرده نیستم تا حدودی مضطرب یا افسرده هستم شدیداً مضطرب یا افسرده هستم .06 .86 .972 .821 16 in order to help people to know what good or bad health conditions is, we designed a scale (similar to a thermometer) in which the best imaginary health conditions are represented by 100 and the worst imaginary health conditions are the best imaginary health conditions برای کمک به مردم که بگوییم شرایط سالمتی خوب و بد چگونه است، مقیاسی طراحی کردیم )که به یک دماسنج شبیه است( که در آن بهترین شرایط قابل تصور با عدد و بدترین 100 شرایط قابل تصور نشان داده 0با عدد ما می شده است. خواهیم که شما ی این مقیاس رو مشخص کنید که شرایط سالمتی امروز شما خوب یا لطفا این بد است. کار را با کشیدن یک خط از پایین تا هر نقطه ای روی بهترین تصور از وضعیت سالمت بدترین تصور از وضعیت سالمت .76 1 .951 vol 17 no 01 january-february 2020 67 persian version of uss-prom questionnaire-tayyebiazar et al. 4 question 10 has no answers; ß question10 and 12 scale has zero variance items. represented by zero. we ask you to determine on this scale that your health conditions are good or bad today. please show this by dragging a line from below to any point on the scale that indicates your good or bad health status. the worst imaginary health conditions این مقیاس که وضعیت خوب یا بد بودن سالمت شما را نشان می دهد، نشان دهید. relationship between oxidative stress and detrussor overactivity: a case control study murat keske1*, bahri gök2, kemal ener3, muhammet fuat özcan4, asım özayar4, emrah okulu4, salim neşelioğlu5, serdar çakmak6, erem asil4, mustafa aldemir4, özcan erel7 purpose: we analyzed the role of oxidative stress in detrusor overactivity (do) by measuring serum total antioxidant capacity (tac), total oxidant status (tos), binding capacity of exogenous cobalt to human albumin (ima), serum advanced oxidation protein products (aopp), paraoxonase (pon), and arylesterase. materials and methods: the study included 38 female patients diagnosed with do and 29 healthy female subjects forming the control group. serum total antioxidant capacity (tac), total oxidant status (tos), binding capacity of exogenous cobalt to human albumin (ima), serum advanced oxidation protein products (aopp), paraoxonase (pon), and arylesterase were analyzed. the results of serum tac, tos, ima, aopp, pon, and arylesterase of the subjects in both groups were compared. results: there was no difference between the groups in terms of age. when compared to the control group, serum tac and ima levels were statisticaly lower (p < 0.001) and higher (p = 0.003), respectively. however, tos, aopp, pon, arylesterase levels were similar in both groups ( p > 0.05 ). conclusion: there seems to be an association between do and oxidative damage according our results, this can be measured by analyzing tac and ima in this patient group. keywords: detrusor overactivity; hypoxia; ischemia; oxidative stress; total antioxidant capacity introduction detrusor overactivity (do) is a common distressing condition with an unknown etiology that affects both genders.(1,2) many pathophysiological mechanisms that could cause this condition have been investigated, including oxidative damage and free radicals originating from decreased blood flow, ischemia, and hypoxia. (3–5) it has been proposed that free oxygen radicals are involved in this pathophysiological process. oxidative stress damages the muscarinic receptor-linked signaling system and affects detrusor muscle contractions.(6,7) the resulting hypoxia and pelvic ischemia increases the frequency of spontaneous bladder contractions.(8,9) since separate measurements of different antioxidant and oxidant molecules are not efficient in terms of cost and time, total antioxidant capacity and total oxidant status (tac and tos, respectively)(10,11) can be evaluated in order to demonstrate the individual effects of these molecules. the binding capacity of exogenous cobalt to human albumin (ima), serum advanced oxidation protein products (aopp), paraoxonase (pon), 1kayseri city hospital, department of urology, kayseri, turkey. 2yildirim beyazit university, school of medicine, ankara ataturk training and research hospital, department of urology, ankara, turkey. 3umraniye training and research hospital, department of urology, istanbul, turkey. 4ankara ataturk training and research hospital, department of urology, ankara, turkey. 5ankara ataturk training and research hospital, department of biochemistry, ankara, turkey. 6ordu university training and research hospital, department of urology, ordu, turkey. 7yildirim beyazit university, school of medicine, ankara ataturk training and research hospital, department of biochemistry, ankara, turkey. *correspondence: department of urology, kayseri city hospital, kayseri, 38080, turkey. tel: +90 5426620882, e-mail: muratkeske@yahoo.co.uk. received february 2019 & accepted july 2019 and arylesterase are the best known and most frequently studied antioxidant molecules.(12–18) to the best of our knowledge, there are no studies in the literature focusing on the association of these biomarkers with do. in the current study, the levels of serum tac, tos, pon, arylesterase, aopp, and ima of do patients and healthy controls were investigated and compared. based on these results, this study presents the characteristics of a preliminary report analyzing the role of ischemia-related oxidative stress in do. materials and methods this study was approved by the institutional review board, and patients’ consent for the use of their information was taken in writing. the study group consisted of 38 female patients admitted to the ankara ataturk training and research hospital urology outpatient clinic between march 2017 and october 2018 and diagnosed for the first time with do and 29 healthy female subjects forming the control group. in the do group, the patients had complaints regarding an increase in female urology urology journal/vol 16 no. 4/ july-august 2019/ pp. 371-374. [doi: http://dx.doi.org/10.22037/uj.v0i0.5090] daytime ( >9 times/day ) and nighttime urinary frequency, urgency, and urge incontinence. in order to eliminate other diseases presenting with idiopathic overactive bladder in the differential diagnosis of do, an overall physical examination, urinalysis, routine biochemical analysis, and detailed laboratory tests, including a urine culture, were performed. additionally, blood samples were obtained after overnight fasting in order to evaluate oxidative stress status and antioxidant parameters. samples were drawn from the median cubital vein into blood tubes and immediately stored on ice at 4°c. serum was separated from the cells by centrifugation at 1000 g for 10 min and then analyzed. in patients with an increase in urinary frequency, urgency, or urge incontinence, urodynamic analyses were done, and those that were diagnosed with do were included in the study. patients were excluded from the study if they were using alcohol, tobacco, taking any medication(s), or had systemic diseases since these factors can affect oxidative status. for patients in the do group , oral solifenacin succinate treatment was started at a daily dose of 10 mg. measurement methods of pon, arylesterase, tos, tac, aopp, and ima were performed in the same manner that was described in our previous study.(19) statistical analysis the sample size of this study was determined using a power analysis. g-power software was used in this analysis. the power of the study was calculated as 86% when groups 1 and 2 consisted of 38 and 29 participants, respectively. the normal distribution of the oxidative stress biomarkers was evaluated by the kolmogorov-smirnov test. mean ± standard deviations and median (25%–75% quartile) were used for descriptive statistics. student’s tand mann whitney u tests were used for statistical analyses. the data were analyzed by using spss for windows (version 25.00). results table 1 summarizes the comparison of oxidative parameters between patients with detrusor overactivity and healthy controls. there was no difference between the do and control groups in terms of age. no statistically significant differences were observed between the two groups in terms of the pon (p = 0.934), tos (p = 0.109), ares (p = 0.662), and aopp (p = 0.641) levels. when compared to the control group, tac was significantly lower (p < 0.001), and ima was significantly higher (p = 0.003) in the do group. discussion reactive oxygen radicals are produced during the final stages of metabolic and physiological processes. during these processes, harmful oxidative reactions, which are counteracted or detoxified by enzymatic and non-enzymatic oxidative mechanisms, can develop. when an increase in oxidant agents and decrease in antioxidants cannot be prevented, an imbalance occurs between the oxidants and antioxidants, resulting in oxidative stress, which has been shown to be responsible for more than a hundred of diseases.(19) current evidence suggests that oxidative stress plays an important role in the pathogenesis of urinary dysfunction.(20) the prevalence of lower urinary tract symptoms (luts) in both genders increases with age. it has been suggested that the arterial occlusive disease, which can lead to chronic bladder ischemia and oxidative damage, has a role in the pathogenesis of lower urinary tract dysfunction, including do.(21,22) using a rabbit model, azadzoi et al. investigated the association between luts and atherosclerotic vascular risk factors and showed that pelvic ischemia caused smooth muscle alterations and denervation in the prostate, penis, and urinary bladder.(23) these smooth muscle alterations and denervation induces the frequency of spontaneous bladder contractions and results in do. similarly, nomiya et al.(22) investigated the effects of chronic bladder ischemia on voiding behavior and bladder function in rats and reported a significant increase in the rats’ urination frequency via cystometric evaluations. the authors concluded that atherosclerosis-induced chronic bladder ischemia could facilitate the voiding reflex, which is defined as do. in our study, we tried to find an association between do and oxidative stress by analyzing biomarkers rather than doing histological evaluations. malona et al.(3) reported that oxidative stress was hightable 1. the comparison of oxidative parameters between patients with detrusor overactivity and healthy controls. group n mean ± s.d p-value ( student t test) age c 29 42.7 ± 10.6 0.531 do 38 44.6 ± 14.8 tac c 29 2.1 ± 0.216 < 0.001 do 38 1.8 ± 0.199 tos c 29 4.1 ± 1.46 0.109 do 38 4.7 ± 1.77 ares c 29 189.7 ± 55.7 0.662 do 38 184.6 ± 39.2 aopp c 29 138.9 ± 46.0 0.641 do 38 134.4 ± 32.6 ima c 29 0.530 ± 0.117 0.003 do 38 0.614 ± 0.106 median(25%-75% quartel) p values ( mann whitney u test) pon c 29 158.6(91.1-280.8) 0.934 do 38 144.1(91.6-249.5) abbreviations: c, control group; do, detrusor overactivity group; tac, total antioxidant capacity; tos, total oxidant status; ares, arylesterase; aopp, serum advanced oxidation protein products; ima, binding capacity of exogenous cobalt to human albumin; pon, paraoxonase; oxidative stress and detrussor overactivity-keske et al. vol 16 no 04 july-august 2019 372 er in the bladder strips of the rats in which in vitro ischemia/reperfusion had been applied and that bladder dysfunction occurred due to oxidative damage. in another study, serum ima levels were found to have increased in ischemia-induced oxidative stress. the authors also suggested that the ima levels increase as a result of endothelial and extracellular hypoxia, acidosis, free radical damage, and free iron and copper ions. (17) therefore, ima was proposed as a marker indicating ischemia.(17) similarly, in the current study, serum ima levels were found to be higher in the do group compared to healthy subjects, which support the conclusions of previous studies in which serum ima levels were used as a marker of ischemia. these studies also support the hypothesis that ischemia is an important factor in the etiology of do. to date, there are no studies attempting to find an answer to the association between do and oxidative stress in humans. the studies were performed in animal models, including rabbits and rats. in 2011, lin et. al. reported that there was a significant decrease in plasma tac levels in rabbits having partial bladder outlet obstruction. however, our study included patients with do, such as the aforementioned group, and we found that tac levels were statistically lower in patients having do when compared to healthy subjects.(24) the concentrations of many antioxidants can be measured separately using complicated laboratory techniques, which are time-consuming, labor-intensive, and not cost-effective. since this is not practical in routine practice, and the antioxidant effects of these molecules are additive, a commonly used alternative is the tac measurement. using a serum tac analysis, the imbalance between oxidants and antioxidants in diseases and the overall oxidative status of the subjects can be clearly demonstrated. in the current study, tac levels were found to be reduced in the do group compared to the healthy subject group. this supports the association between oxidative stress and do. despite the considerable amount of research in this area, the etiology of do has not yet been clearly identified. however, in this study, the mechanism of hypoxia-induced oxidative damage seems to be prominent. currently, the most effective therapy for do consists of anticholinergic drugs.(25) identifying the role of ischemia-induced oxidative stress in the etiopathogenesis of do can contribute to development of alternative treatment options for the disease, such as eliminating the need for lifetime use of medication. there are several limitations to this study. first of all, our study was a case control study and based on a small sample size. we think that the level of evidence in the study increased since it was designed in a randomized prospective manner, and the finding of oxidative stress was supported by histopathological evaluation. another limitation could be the lack of biomarker evaluation in the urine samples. conclusions the results showed that there was an association between oxidative stress and do. thus, oxidative stress biomarkers can be easily evaluated in patients with do. we found that serum tac and ima levels were statistically lower and higher, respectively, when compared with healthy subjects. acknowledgements we would like to thanks to mert ali karadag md for his support during analysis of the results of this study. conflict of interest the authors declare that they have no conflict of interest. references 1. yamaguchi o, aikawa k, shishido k, nomiya m. place of overactive bladder in male lower urinary tract symptoms. world j urol. 2009;27:723-8. 2. emami m, shadpour p , kashi ah , choopani m , zeighami m. abobotulinum a toxin injection in patients with refractory idiopathic detrusor overactivity: injections in detrusor, trigone and bladder neck or prostatic urethra, versus detrusor only injections. int braz j urol. 2017 ;43:1122-8. 3. malone l, schuler c, leggett re, levin rm. effect of estrogen and ovariectomy on response of the female rabbit urinary bladder to two forms of in vitro oxidative stress. int urogynecol j 2014;25:791-8. 4. liang cc, shaw ss, lin yh, lee th. amniotic fluid stem cells ameliorate bladder dysfunction induced by chronic bladder ischemia in rat. neurourol urodyn. 2018 jan;37:123-31. 5. andersson ke, boedtkjer db, forman a. the link between vascular dysfunction, bladder ischemia, and aging bladder dysfunction. ther adv urol. 2017 ;9:11-27. 6. de jongh r, haenen gr, van koeveringe ga, dambros m, de mey jg, van kerrebroeck pe. oxidative stress reduces the muscarinic receptor function in the urinary bladder. neurourol urodyn. 2007;26:302-8. 7. bykoviene l, kubilius r, aniuliene r, bartuseviciene e, bartusevicius a. pelvic floor muscle training with or without tibial nerve stimulation and lifestyle changes have comparable effects on the overactive bladder. a randomized clinical trial. urol j. 2018 ;15:186-192. 8. matsui t, oka m, fukui t, et al. suppression of bladder overactivity and oxidative stress by the phytotherapeutic agent, eviprostat, in a rat model of atherosclerosis-induced chronic bladder ischemia. int j urol. 2012;19:669-75. 9. zhang j, cao m, chen y, liang w, liang y. hypersensitive or detrusor overactivity: which is associated with filling symptoms in female bladder outlet obstructed patients? urol j. 2019 mar 18. doi: 10.22037/ uj.v0i0.4362. [epub ahead of print] 10. erel o. a novel automated direct measurement method for total antioxidant capacity using a new generation, more stable abts radical cation. clin biochem. 2004;37:277-85. oxidative stress and detrussor overactivity-keske et al. female urology 373 11. erel o. a new automated colorimetric method for measuring total oxidant status. clin biochem. 2005;38:1103-11. 12. camps j, marsillach j, joven j. the paraoxonase: role in human diseases and methodological difficulties in measurement. crit rev clin lab sci. 2009;46:83-106. 13. furlong ce, suzuki sm, stevens rc, et al. human pon1, a biomarker of risk of disease and exposure. chem biol interact 2010;187:355-61. 14. novak f, vavrova l, kodydkova j, et al. decreased paraoxonase activity in critically ill patients with sepsis. clin exp med. 2010;10:21-25. 15. bar-or d, lau e, winkler jv. a novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminaryreport. j emerg med. 2000;19:31115. 16. bar-or d, lau e, winkler jv. a novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. j emerg med. 2000;19:311-15. 17. berenshtein e, mayer b, goldberg c, kitrossky n, chevion m. patterns of mobilization of copper and iron following myocardial ischemia: possible predictive criteria for tissue injury. j mol cell cardiol. 1997;29:3025-34. 18. gryszczyńska b, formanowicz d, budzyń m, et. al. advanced oxidation protein products and carbonylated proteins as biomarkers of oxidative stress in selected atherosclerosismediated diseases. biomed res int. 2017;2017:4975264. 19. ener k, keske m, aldemir m, et al. evaluation of oxidative stress status and antioxidant capacity in patients with painful bladder syndrome/interstitial cystitis: preliminary results of a randomised study. int urol nephrol. 2015;47:1297-1302. 20. andersson ke. oxidative stress and its possible relation to lower urinary tract functional pathology. bju int. 2018 ;121:52733. 21. yamaguchi o, nomiya m, andersson ke. functional consequences of chronic bladder ischemia. neurourol urodyn. 2014;33:54-58. 22. nomiya m, yamaguchi o, andersson ke, et al the effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat. neurourol urodyn. 2012;31:195200. 23. azadzoi km, tarcan t, siroky mb, krane rj. atherosclerosis-induced chronic ischemia causes bladder fibrosis and non-compliance in the rabbit. j urol. 1999;161:1626-35. 24. lin wy, chen cs, wu sb, lin yp, levin rm, wei yh. oxidative stress biomarkers in urine and plasma of rabbits with partial bladder outlet obstruction. bju int. 2011 ;107:1839-43. 25. choi jb, cho kj, park wh, et. al. treatment satisfaction with flexible-dose fesoterodine in patients with overactive bladder who were dissatisfied with previous anticholinergic therapy: a multicenter single-arm clinical study. urol j. 2019 mar 18. doi: 10.22037/ uj.v0i0.4650. [epub ahead of print] oxidative stress and detrussor overactivity-keske et al. vol 16 no 04 july-august 2019 374 extra-peritoneal versus trans-peritoneal open radical cystectomy comparison of two techniques in early post-operative complications mohammad soleimani1, ehsan moradkhani 2, navid masoumi1*, jafar gholivandan1 purpose: the conventional trans-peritoneal radical cystectomy (tprc) harbors numerous postoperative complications, the most prevalent of which are gastrointestinal (gi) problems. to reduce these morbidities we introduced our own version of extra-peritoneal approach and compared it with the conventional method. materials and methods: in a cross-sectional observational retrospective design, eligible bladder cancer patients whom underwent extra-peritoneal radical cystectomy (eprc) or tprc in our center, were considered for this study and were compared for early post-operative complications. results: ninety-nine patients in tprc and 81 in eprc were compared. the two techniques differed in their mean operation time (298.2 ± 37.8 min tprc vs. 262.8 ± 37.2 min eprc , p : 0.001). early gi complications were lower in eprc groups, including oral intake intolerance ( 21 vs. 8, p: 0.04), ileus (19 vs. 8, p : 0.04), intestinal obstruction (3 vs. 0, p : 0.04), and anastomosis leakage (8 vs. 1, p : 0.01). urine leak (14 vs.7 , p : 0.02) and wound related complications (19 vs. 6 , p: 0.02) also favored eprc group. conclusion: the extra-peritoneal technique is beneficial in reducing postoperative morbidity, especially the more prevalent gi complications. this approach is functionally safe and allows preservation of the peritoneal integrity. keywords: bladder cancer; cystectomy; urinary diversion; postoperative complications introduction although trans-peritoneal radical cystectomy (tprc) with pelvic lymphadenectomy is the standard technique in muscle invasive and high risk non-muscle invasive bladder cancer, its postoperative complications, ranging from pain to metabolic disturbances, makes it a difficult choice for the patient and even the surgeon(1). given this, revising the traditional technique to lower postoperative morbidity is imperative. in this regard, the extra-peritoneal (ep) approach was first introduced by kulkarni in 1999(2) and further along, slightly various modifications were introduced in other patient series(3-5). this approach resulted in decreased postoperative complications. nevertheless, the best patients suitable for this technique are still a matter of debate and this is mostly due to paucity of studies, small number of included patients, and limited number of randomized trials. additionally, the issue of oncologic efficacy and the danger of residual tumor cells is still not completely reinstated. with these issues in mind, we designed this study to implement our technique with small modifications, to compare tp and ep approaches with regard to early postoperative (< 30 days) complications and patients' characteristics. 1department of urology, shahid modarres hospital, shahid beheshti university of medical sciences; tehran/ iran. 2urology-nephrology research center, shahid beheshti university of medical sciences; tehran/ iran. *correspondence: address: saadat abad st., shahid modarres hospital, tehran/iran. tel: +982122074087. fax: +982122074101. email: nmasoumig@gmail.com received april 2020 & accepted august 2020 materials and method patients in a cross-sectional observational retrospective design, all bladder cancer patients of a single clinician whom underwent radical cystectomy in our center, from april 2015 till january 2019, were considered for this study. all surgeries were done by the senior author. before may 2017, cystectomies were performed with trans-peritoneal approach and after that it was changed to extra-peritoneal method and the results of these two methods were compared. both ileal orthotopic and conduit diversions were included. altogether, our study population was 200 patients, 100 in each group, and their data were collected from their admission records, using a questionnaire. our objective was to compare the complications in the early postoperative period ( first 30 days) between the two groups. length of surgery and hospital stay, amount of intraoperative bleeding and pack cell (pc) transfusion, perioperative complications (including pain, ileus, oral intake intolerance, urinary leak, anastomosis leak, intestinal obstruction, and wound related problems), oncological parameters (including surgical margin, histo-pathological stage and resected lymph nodes) and 30 day mortality rate were the study variables applied for comparison. any patient with a previous history of extensive abdominal surgery, abdominal or pelvic radiotherapy, urological oncology urology journal/vol 18 no. 5/ september-october 2021/ pp. 519-524. [doi: 10.22037/uj.v16i7.6147] or inflammatory bowel disease was excluded as it may impede peritoneal release. none of the patients had neo-adjuvant or systemic chemotherapy. our ethics committee approved the design and all persons gave us their informed consent prior to inclusion in the study. pain was measured by the mean amount of times patients ordered on demand morphine on postoperative days. ileus was defined as oral intolerance with nausea, vomiting and abdominal distention which required holding oral intake and starting intravenous support. oral intake intolerance was milder form of nausea after meal without distention which usually resolved with a brief period of food abstinence and gradual restart afterwards. anastomosis leak was defined as bile-colored secretion from abdominal drain ± abdominal distention. preoperative preparation all patients underwent mechanical bowel preparation with 2-3 li of poly ethylene glycol (peg) the day before surgery. they also received 1 dose of intravenous ceftriaxon (1 gr) and metronidazole (500 mg) and had only a liquid diet the day before surgery. spiral pelvic computed tomography and abdominal ultrasonography were used for preoperative staging. all worn antithrombotic stockings before transferring to the operation room. surgical technique the technique for tprc was the same as described by hautmann(6) and we followed the steps described by kulkarni(2) for the eprc. in brief, for extra-peritoneal approach, after a median infra-umbilical incision and entering the space of retzius, standard bilateral pelvic lymphadenectomy was performed; the boundaries were: genitofemoral nerve laterally, the internal iliac artery medially, cooper ligament caudally, and the crossing of the ureter at the common iliac artery cranially. the release of the prostate was accomplished as retro-pubic radical prostatectomy with care to preserve the neurovascular bundle in eligible patients and releasing the attachments of the denonvilliers' fascia off the rectum. the dissection is continued cephalad , dividing the inferior and middle vesical vessels on either side until releasing the ureters 1 cm proximal to the uretero-vesical junction which was then ligated and cut alongside the vasa and ureteral tip was sent for frozen section. the remainder of the surgery for either dissecting the peritoneum off the bladder or removing the bladder with the overlying peritoneum was dependent on the location of the tumor inside the bladder and the feasibility of dissecting the peritoneum off the bladder dome. in case of dome or posterior bladder wall tumor or suspicious adherence of peritoneum to bladder, a circular window was made in the peritoneum at the level of the bladder dome and then cystectomy was completed by the cutting the urachus at the level of the umbilicus. the extremes of the peritoneal window were controlled by 2 vicryl sutures, for preventing the over tearing and keeping the flaps available for later closing the peritoneal cavity. in the remainder of the patients, the peritoneum was dissected off the dome and urachus was cut at the level of umbilicus, superficial to the peritoneum, completing the cystectomy totally extra-peritoneally and only a small slit in peritoneum was opened to access the small intestine. with this technique, distal ureters needed limited dissection and they were implanted extra-peritoneally and in a refluxing manner to conduit or neobladder (figure 1). at the end, peritoneal window was closed by stitching the peritoneum to the mesenteric pedicle( figure 2). in female patients the genital organs were resected in all cases. post operation management post operation management was the same for the 2 groups. antithrombotic medication was started the morning after surgery. all patients were monitored in icu on the first postoperative day and then transferred to the ward for the remainder of the post op period. all mobilized the day after surgery and nasogastric (ng) tube was removed. pain was controlled by iv acetaminophen (apotel ®) 1 gr every 6 hours ± on demand 2.5 mg of intramuscular morphine. liquid diet was comurological oncology 520 tprc† group (n=99) eprc‡ group (n=81) p value conduit orthotopic conduit orthotopic number (%) 69 (70) 30 (30) 56 (69) 25(31) 1.00 mean age (years) 73.01 ± 9.7 63.4±7.4 68.89±10 64.52±8 0.00 sex male : 90 male: 74 0.9 female: 9 female: 7 mean bmi~ (kg/m2) ± sd 25.4 ± 3.36 25.15 ± 2.71 0.21 mean asa* score 1.6 1.5 0.27 prior abdominal surgery (%) 1 (1) 5 (6) 0.18 pathological tumor category t0n0 1 0 2 2 0.31 t1n0 24 10 18 9 t1n1 0 2 7 3 t2n0 26 11 16 8 t2n1 11 2 8 2 t3an0 0 2 1 0 t3an1 6 2 1 1 t3b n1 2 0 0 0 t3an2 0 0 1 0 t4a n0 1 0 0 0 t4a n1 0 1 0 0 positive surgical margin 2 0 0 0 0.19 peritoneal involvement (stage) 1 (t4n0) 2 (t4n1-t3an1) 1(t3an2) 1(t3an1) 0.2 table 1. patients' clinical and pathological characteristics. †trans-peritoneal radical cystectomy ‡extra-peritoneal radical cystectomy ~ body mass index * american society of anesthesiologists' classification of physical health extra versus trans-peritoneal radical cystectomy-soleimani et al. menced on day 3 with gradual addition of solid food on day 5. statistical analysis we used spss v.25 program for statistical calculations. t and chi square tests were used for difference analysis between 2 groups. mann-whitney u test were utilized for non-normal distributions. p value < 0.05 was considered significant. results of a total of 200 patient records, 20 were excluded (six previous abdominal surgeries and 14 uretero-cutaneous diversions) and 180 patients were considered for analysis. hundred and sixty-four (91.1%) of our participants were male and 16 (8.9%) were female. the mean age of our study population was 68.95 ± 9.93 (range: 37-88 years). the characteristics of enrolled patients are presented and compared in table 1. the mean operation time was shorter in ep method (262.8 ± 37.2 in eprc vs. 298.2 ± 37.8 in tprc, p = 0.001). however, there were no statistically significant difference in the mean post operation hospital stay, intra-operative bleeding and pain medication (table 2). detailed assessment of gastrointestinal complications disclosed differences in oral intake intolerance (p: 0.04), ileus (p : 0.04), intestinal obstruction (p : 0.04) and anastomosis leak (0.01) in favor of ep group. redo surgery was required in two patients, due to intestinal obstruction and anastomosis leak, both of them in tp group. urine leak was diagnosed in 14 (14%) tp and 7 (9%) ep patients, none of which required re-exploration. wound related complications favored eprc group with significant difference (p: 0.02). however, the type of diversion (conduit or orthotopic) did not affect wound complication rate. the post-operative complications using clavien dindo classification is presented in table 3. the most prevalent pathologic stage of the rc specimen was t2n0. the histologic subtype was tcc in all our patients and we didn't have any pure non-urothelial histologic group. detailed descriptions of pathological stages are illustrated in table 1. the most number of lymph nodes resected was 17 which was reported in 36 patients. the average number of resected lymph nodes per patient was 15.59 (range: 7-25) which disclosed no difference between the two groups (p : 0.07). only 2 patients were margin positive and both were in tprc group. no relation was observed between surgical mar†trans-peritoneal radical cystectomy ‡extra-peritoneal radical cystectomy ~ number of patients received pack cell transfusion * number of patients which requested doses of morphine †trans-peritoneal radical cystectomy ‡extra-peritoneal radical cystectomy tprc† group (n=99) eprc‡ group (n=81) p value length of surgery (min) (mean ± sd) 298.2 ± 37.8 262.8 ± 37.2 0.001 postoperative hospital stay (days) (mean ± sd) 10.11 ± 5.78 8.72 ± 4.02 0.07 intra-operative bleeding (li) (mean) 1.31 1.63 0.1 pack cell transfusion~ (%) conduit: 13(13) conduit: 15(18) 0.14 orthotopic: 11(11) orthotopic: 6(7) pain medication 0.42 no morphin* 2 1 1 dose of on-demand morphin* 2 2 2 doses of on-demand morphin* 45 35 3 doses of on-demand morphin* 49 43 4 doses of on-demand morphin * 1 0 oral intake intolerance (%) conduit: 9(9) conduit: 3(4) 0.04 orthotopic: 12(12) orthotpoic: 5(6) ileus after surgery (%) conduit: 9(9) conduit: 4(5) 0.04 orthotopic: 10(10) orthotopic: 4(5) anastomosis leak (%) conduit: 3(3) conduit: 1(1) 0.01 orthotopic: 5(5) orthotopic: 0(0) urine leak (%) conduit: 6(6) conduit: 3(4) 0.02 orthotopic: 8(8) orthotopic: 4(5) obstruction (%) conduit: 1(1) conduit: 0(0) 0.04 orthotopic: 2(2) orthotopic: 0(0) wound infection(%) 19 (19) 6 (7) 0.02 death (%) 2 (2) 1 (1) 0.1 table 2. surgery related data in trans-peritoneal and extra-peritoneal cystectomy patients. tprc† group (n=99) eprc‡ group (n=81) total p value conduit orthotopic conduit orthotopic grade 1 9 10 4 4 27 0.03 grade 2 6 8 3 4 21 0.02 grade 3 1 2 0 0 3 0.04 grade 4 0 0 0 0 0 grade 5 1 1 0 1 3 0.7 extra versus trans-peritoneal radical cystectomy-soleimani et al. table 3. surgery related complications in trans-peritoneal and extra-peritoneal cystectomy patients based on clavien dindo classification. vol 18 no 5 september-october 2021 521 gin and method of surgery (p : 0.19). five patients had peritoneal involvement in pathology report ( 3 in tprc and 2 in eprc group, table 1) all of which were >t2 stage (p : 0.2). three mortalities were reported in the 30 postoperative day which was due to massive pulmonary emboli (tp orthotopic), acute myocardial infarction (ep conduit), and septicemia due to intestinal leak ( tp conduit). discussion radical cystectomy with trans-peritoneal approach and antegrade bladder resection has a major drawback in violating the anatomical compartmentalization of peritoneal and retroperitoneal space(1). this translates into increased morbidity (16-66%) in the early 30 postoperative days(7,8). amongst which, the most frequent complication is gastrointestinal problems with nearly 29% of cystectomy patients affected(4). a possible reason for this high rate is the contact of intestinal serosa with the de-peritonealized pelvic wall. this induces an inflammatory reaction that alongside postoperative adhesion bands, reduces bowel peristalsis, causes ileus, obstruction, distention, and increases pain(4). increased exposure of the intestines to atmosphere and upward packing of bowel loops for clearing the operative field during the surgery are other reasons mentioned in the literature(5). hence, keeping the peritoneal continuity in this surgery has been reported as an important milestone in reducing postoperative complications(2,5,9-12). to this end, 2 main techniques were introduced over the years. the first technique was by kulkarni(2) which indicated an extra-peritoneal approach with small infra-umbilical incision and retrograde cystectomy. in their long time follow up results of 180 patients published in 2018 (13), there was a considerable decrease in gastrointestinal complications, ( 5% vs. 15.8%, p < 0.001) and intestinal obstruction rate ( 1.7% vs. 7.8%, p = 0.002) in comparison with transperitoneal technique. the other technique introduced by roth et al(4) in 2011 indicated a conventional transperitoneal approach with bilateral readaptation of the dorsolateral peritoneal layer with flaps that they created at the start of the surgery in order to omit the contact of intestines with the denuded surface of the pelvic wall and iliac vessels. although with this style, the amount of time that the intestines are exposed to atmosphere is not decreased, they reported a significant decrease in pain and fewer bowel complications in the early postoperative days. this group performed a randomized trial based on this method(9) and in their medial follow up of 59 months, the effects of readaptation was again resurfaced with less pain and better gastrointestinal function. concurrent with previous studies, our results indicated a considerable decrease in early postoperative gastrointestinal complications (ileus , obstruction, anastomosis leak and urine leak) and wound infection. moreover, the lower operation time in ep group meant faster surgery with limited time of bowel exposure to air which had an important role in reducing postoperative ileus(5). in addition to decreased gastrointestinal problems, this technique is very advantageous in performing the most delicate part of the surgery, which is preserving the striated sphincter, at the beginning where the surgeon is the sharpest. this will allow for better urethral preservation urological oncology 522 figure 1. extra-peritoneal implant of the right ureter to ileal conduit. extra versus trans-peritoneal radical cystectomy-soleimani et al. and sutures and better continence in orthotopic surgeries. although in theory this idea seems reasonable but none of the studies so far could not demonstrate any difference between the 2 procedures in this regard(3,5,12,13). this could be explained by the low number of orthotopic surgeries and no randomized trials, since difficult cases will mostly end up in conduit diversion. wound infection were lower in ep group (19% vs. 7%, p = 0.02) . all were superficial infections which were resolved by bed side opening of stitches and irrigation. no dehiscence was encountered in the early post op period. although for better quantifying the effect of small infra-umbilical incision in preventing dehiscence or hernia formation, longer follow-up would be needed. a concern with this technique is the increased chance of pelvic lymphocele formation. because the peritoneum is closed, the lymph will no longer be absorbed and most probably create collections in the pelvic cavity, which concomitantly increase the chance of infection or deep vein thrombosis. in our series, we didn't have lymphocele formation. this could be due to our technique of meticulous ligation of all lymph vessels with silk tie stitches during the lymphadenectomy. however, in other reports which did have lymphocele formation, the difference was either not significant(4,13) or it did not cause any other major problems and all were resolved by less invasive measures(12). one of the major critics for extra-peritoneal procedure was its oncologic efficacy and the chance of residual tumor cells over peritoneum(2,3,5,12-14). considering that, some of the series only included ct1-t2 tumors and lesions away from the dome and posterior wall as their inclusion criteria(2,3). in an interesting study by zhu et al.(14) the characteristics of patients suitable for extra-peritoneal approach were evaluated. they performed ex vivo biopsies of the peritoneum overlying the bladder in 136 cystectomy specimens (either random or from gross suspicious lesions). in their report, patients with t2-t4 stage, positive lymph nodes or non-urothelial histologies, were not good candidates for peritoneum preservation. albeit, in two other studies which included >t2 patients and had mean follow up of 37(12) and 70(13) months, the rate of local recurrence and distant metastasis were similar, indicating that ep approach is applicable even in higher stages. the readaptation technique of roth(4) and vartolomei(9) also did not show any oncologic inferiority which was not surprising, since their procedure was essentially the extra versus trans-peritoneal radical cystectomy-soleimani et al. figure 2. readaptation of the peritoneal integrity by stitching the peritoneum to the mesenteric pedicle (*). vol 18 no 5 september-october 2021 523 transperitoneal approach with an additional step of readaptation of peritoneum at the end of the surgery. given the lack of confirmed oncologic inferiority of ep technique for higher stages, we did include all clinical stages in this study. although, due to short follow up, no comment can be made on the oncologic safety as it requires longer surveillance. missing intra abdominal metastases is another oncologic concern in ep approach. nevertheless, the chance of its occurrence is very slim because of comprehensive pre-operative evaluation and in none of the series, including ours, no metastases was encountered during the surgery. a few limitations of this study should be regarded. the patients' information were retrospectively collected which is susceptible to information bias in data insertion and collection. the number of included patients was limited and the follow up was short for deciding about longer term complications and oncologic efficacy and since this is not a randomized trial, bias in patient selection is pertinent to this study. conclusions eprc is a feasible option with tangible effects in reducing the post operative morbidity, especially the more prevalent gastrointestinal complications. our technique while benefits from this approach by starting extra-peritoneally and releasing the urethra and sphincter meticulously at the beginning, it also permits the examination of the overlying peritoneum at the end of the cystectomy for its appearance and decision for its preservation or removal. conflict of interest none declared by the authors. references 1. hollenbeck bk, miller dc, taub d, et al. identifying risk factors for potentially avoidable complications following radical cystectomy. j urol. 2005;174:1231-7; discussion 7. 2. kulkarni jn, gulla ri, tongaonkar hb, kashyapi bd, rajyaguru kb. radical cystoprostatectomy: an extraperitoneal retrograde approach. j urol. 1999;161:545-8. 3. park ds, gong ih, choi dk, hwang jh, kang mh, oh jj. a feasibility study of peritoneum preservation in radical cystectomy with extraperitonealization of orthotopic neobladder for invasive high-grade bladder cancer: a preliminary analysis. int urol nephrol. 2014;46:1107-13. 4. roth b, birkhauser fd, zehnder p, burkhard fc, thalmann gn, studer ue. readaptation of the peritoneum following extended pelvic lymphadenectomy and cystectomy has a significant beneficial impact on early postoperative recovery and complications: results of a prospective randomized trial. eur urol. 2011;59:204-10. 5. serel ta, sevin g, perk h, kosar a, soyupek s. antegrade extraperitoneal approach to radical cystectomy and ileal neobladder. int j urol. 2003;10:25-8; discussion 9. 6. hautmann re, egghart g, frohneberg d, miller k. the ileal neobladder. j urol. 1988;139:39-42. 7. nieuwenhuijzen ja, de vries rr, bex a, et al. urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions. eur urol. 2008;53:834-42; discussion 42-4. 8. novotny v, hakenberg ow, wiessner d, et al. perioperative complications of radical cystectomy in a contemporary series. eur urol. 2007;51:397-401; discussion -2. 9. vartolomei md, kiss b, vidal a, burkhard f, thalmann gn, roth b. long-term results of a prospective randomized trial assessing the impact of re-adaptation of the dorsolateral peritoneal layer after extended pelvic lymph node dissection and cystectomy. bju int. 2016;117:618-28. 10. gillitzer r, farasaty-ghazwiny m, fritsch j, schede j, hampel c. extraperitoneal ileal conduit. bju int. 2011;108:298-301. 11. de nunzio c, cicione a, leonardo f, et al. extraperitoneal radical cystectomy and ureterocutaneostomy in octogenarians. int urol nephrol. 2011;43:663-7. 12. jentzmik f, schostak m, stephan c, et al. extraperitoneal radical cystectomy with extraperitonealization of the ileal neobladder: a comparison to the transperitoneal technique. world j urol. 2010;28:457-63. 13. kulkarni j.n. ah. transperitoneal vs. extraperitoneal radical cystectomy for bladder cancer: a retrospective study. int braz j urol. 2018;44:296-303. 14. zhu yp yd, yao x, zhang sl, dai b, shen yj, wang cf. defining good candidates for extraperitoneal cystectomy: results from random peritoneum biopsies of 136 cases. urology. 2013;81:820-5. urological oncology 524 extra versus trans-peritoneal radical cystectomy-soleimani et al. comparison of single monthly instillations of intra-vesical bacillus calmette-guerin maintenance therapy with southwest oncology group regimen in non-muscle invasive bladder cancer patientsa retrospective analysis in a single institute alireza lashay1, saeed taleghani2, navid masoumi1* purpose: to compare the efficacy and complication rate of monthly instillations of bacillus calmette-guerin (bcg) as maintenance therapy in intermediate and high risk non-muscle invasive bladder cancer (nmibc) patients with the current standard southwest oncology group (swog) protocol. materials and methods: in this observational retrospective study, 40 intermediate and high risk nmibc patients, receiving standard bcg maintenance regimen, were compared with another 40 nmibc patients, undergoing monthly intra-vesical instillations of bcg with regard to recurrence, progression and major and minor adverse effects. results: the two groups were similar in their basic characteristics except for the older age in the monthly instillation group ( 70.95 ± 9.66 years vs. 64 ± 8.8, p = 0.001). study objectives between the monthly instillation group and the standard group, including recurrence ( 17.5 % vs. 25%, p = 0.34) and progression rate ( 7.5% vs. 10%, p = 0.54) did not show statistically significant difference. major and minor complication rate also did not show any difference between the two groups. conclusion: in addition to the currently recommended standard protocol of bcg maintenance therapy, our study shows that the monthly regimen can be recommended in intermediate and high risk nmibc patients without compromising the efficacy of the treatment. keywords: adverse effects; bcg immunotherapy; maintenance schedule; progression; recurrence introduction one to 3 years of intra-vesical bacillus cal-mette-guerin (bcg) maintenance therapy is the recommended regimen in intermediate and high risk non-muscle invasive bladder cancer (nmibc) patients after resection of visible tumors and induction course of bcg(1,2). however, the optimal dose and the frequency of its instillation are not clearly defined(1). the most applied protocol for maintenance bcg is based on the southwest oncology group (swog) trial by lamm et al.(3) in which maintenance bcg is administered in 3 weekly doses at the 3rd and 6th months following transurethral resection of bladder tumor (turbt) and 3 weekly repetitions every 6 months up to 3 years. although this regimen is considered as the gold standard, it is only an empirical program based on weak clinical evidence and other alternative protocols have also been suggested; i.e. monthly instillations(4-6), 3 monthly instillations for 1 year(7), 6 doses of bcg every 6 months for 2 years(8), or single instillation every 6 months for 3 years(9), but the studies that compare these regimens in an head-to-head manner is rather scarce. with this state in mind, we designed the current retrospective study to compare the swog regimen with our method of monthly instillations in efficacy and complications rate. 1department of urology, shahid modarres hospital, shahid beheshti university of medical sciences, tehran/iran. 2urology nephrology research center, shahid beheshti university of medical sciences, tehran/iran. *correspondence: saadat abad st., shahid modarres hospital, tehran/iran cell phone: +989123084965. tel: +982122074087. fax: +982122074101. email: nmasoumig@gmail.com. received september 2020 & accepted may 2021 materials and methods patients selection all nmibc patients who underwent tumor resection from april 2015 to study commencement at our institution were considered for this retrospective observational institutional review board approved study. they were chosen from the patients of the two attending urologists in one university hospital whom met our study's criteria. the inclusion criteria were patients in whom, after tumor resection and induction course of bcg, there was no residual cancer at 3 months follow up cystoscopy and were candidate to commence maintenance therapy. patients who had serious side effects to the induction course which dissuaded commencing maintenance therapy were not included in the analysis. lost to follow up patients or participants with missed records were also excluded. in the end, a total of 80 patients who had complete and valid follow up records were selected for comparison (figure 1). all persons gave us their informed consent. each of the attending urologists practices different regimens of bcg maintenance (classic swog or monthly instillation) as their accepted approach and based on that, we had two groups of patients' records; group 1, from patients' records of the 1st attending which received classic swog protocol, and group 2 from patients' records of the 2nd attending which received urology journal/vol 19 no. 2/ march-april 2022/ pp. 106-110. [doi: 10.22037/uj.v18i.6491] urological oncology vol 19 no 2 march-april 2022 100 monthly bcg instillations (40 patients in each group). each patient had been briefed about the regimen and after consent, had been commenced with the maintenance protocol. maintenance schedule four weeks after tumor resection, all patients received 120 mg of intra-vesical bcg (mycobacterium bovis, pastor 1173p2 strain, 5-30 ×106 cfu/vial, pastocis®, pastor institute, iran, tehran) for 6 consecutive weeks as induction phase. a check cystoscopy was done 6 weeks after induction phase, and patients with no tumor were considered for maintenance therapy. the length of therapy (1 or 3 years) had been chosen based on the nmibc risk group (intermediate or high risk). risk stratification was based on the model outlined by 2016 aua/suo guideline and european organization for research and treatment of cancer trials (eortc) risk tables of recurrence and progression, presented by sylvester et al(10). as mentioned, the patients had been assigned into two groups based on the treating physician's policy. no tumor or patient characteristics had been considered in group assignments of the participants. in both groups the follow up protocol for cancer recurrence was the same, including urine cytology and cystoscopy every 3 months for 1 year, every 6 months for the next 2 years, and annually afterwards, with inclusion of upper urinary tract imaging in case of new onset hematuria. in case of severe irritative voiding symptoms, hematuria or symptoms lasting more than 48 hours, the dose was reduced to half in the next instillations. our primary outcome variable was to compare the effigure1: flow diagram of patient selection in accordance to our study criteria. group 1: group receiving swog protocol, group 2: group receiving monthly bcg monthly bcg as maintenance therapy-lashay et al. table 1. baseline characteristics of the patients in the two groups characteristics group 1 †(n=40) group 2 ‡(n=40) p value age (years) 64 ± 8.84 70.95 ± 9.66 0.001 gender (%) male 35 (87.5) 33 (82.5) 0.5 female 5 (12.5) 7 (17.5) smoking history (%) yes 38 (95) 36 (90) 0.6 no 2 (50) 4 (10) cancer stage(%) carcinoma in situ 0 (0) 2 (5) 0.3 t1 26 (65) 21(52.5) ta 14 (35) 17 (42.5) cancer grade(%) high grade 28 (70) 27 (67.5) 0.8 low grade 12 (30) 13 (32.5) †group 1: standard swog protocol ‡ group 2: monthly bcg instillation group vol 19 no 2 march-april 2022 107 urological oncology 108 ficacy, i.e. reduction of recurrence and progression of nmibc lesions, of monthly bcg in relation to swog regimen. the secondary outcome variable was the difference of adverse events between the two groups. recurrence was defined as the appearance of bladder lesions of the same characteristics to the primary lesion during follow up. this also included any lesions of lower stage or grade. progression was defined as the appearance of bladder lesions of higher stage or grade than primary lesions during follow up. bcg side effects entailed minor (dysuria, frequency, hematuria and urgency) and major symptoms (high grade fever, systemic symptoms, generalized weakness and pulmonary or hepatic complications). in case of recurrence or bcg side effects which forces discontinuation of treatment, the duration of follow up was defined until the time of recurrence or occurrence of side effects. in those who completed the maintenance regimen, the time of the last cystoscopy was defined as the end of follow up. statistical analysis we used spss v.22 program for statistical calculations. mean value was used for description of qualitative parameters. chi square test and fisher's exact test were used for difference analysis of quantitative variables between the two groups. p value < 0.05 was considered significant. results the participants’ characteristics are summarized in table 1. other than mean age which was higher in group 2 (70.95 ± 9.66 years vs. 64 ± 8.86, p = 0.00), the two groups were comparable in other properties. group 1 received 7.5± 2.72 and group 2 received 7.28 ± 3.46 doses of maintenance bcg (p= 0.74). with inclusion of induction course, group 1 and group 2 received a total sum of 13.5 ± 2.72 and 13.27 ± 3.46 doses, p = 0.74, respectively. the average time of follow up was 36.68 ± 17.37 months in group 1 and 33.45 ± 17.35 months in group 2 (p = 0.4). table 2 demonstrates the bcg complication rate. despite the prevalence of minor complications in the two groups (80% in group 1 and 75% in group 2, p = 0.2), patients in group 2 did not experience any major complications. in two patients in group 1, bcg maintenance was discontinued due to fever, weakness and severe anhedonia. no difference was observed between the two groups in regard to minor or major complication rate. table 3 summarizes the recurrence and progression rate. there was no statistically significant difference in the rate of recurrence [group1: 10 out of 40 (25%)), group 2:(7 out of 40 (17.5%)), p = 0.34] and progression [group1: 4 out of 40 (10%), group2: 3 out of 40 (7.5%), p = 0.54)] between the two groups. discussion there is a general consensus in prescribing bcg maintenance therapy in patients responsive to induction course(1,2), however the issue of proper dose and timing continues to remain an area of contention due to the dearth of studies in this area. meanwhile, reducing adverse effects and improving patients' compliance by incorporating feasible schedules have always been a concern which have been addressed in several studies (4,5,9). the pivotal study by lamm et. al. demonstrated that the maintenance regimen of 3 weekly instillations at 3 and 6 months after induction course with 6 monthly repetitions for 3 years, not only decreased the recurrence rate, but also decreased progression and metastases rate which ended up in improved overall survival(3). with the scope of maintaining efficacy while decreasing bcg complications by the way of reducing the number of maintenance instillations, the spanish urology association for oncological treatment (cueto) group(9), conducted an experiment with 3 monthly instillations of single dose of bcg for 3 years, for a total sum of 12 instillations and compared them with another group which did not receive maintenance regimen. their trial demonstrated no difference between the 2 groups in regard to recurrence rate. they concluded that 3 monthly instillations are not enough to boost immunity against cancer cells and postpone recurrence and recommended designing a study with 2 doses of 3 monthly instillations for 3 years with the end of reaching swog regimen’s efficacy as well as dose reduction. with the above mentioned goal in mind, multiple bcg instillation regimens was proposed in other trials(4,5,7,8,11). akaza et.al. study(4) on 107 bladder cancer patients, showed that monthly bcg instillations did not decrease the recurrence and progression rate in compartable 2. number of patients having bcg complications in the two groups variable group 1†(n=40) group 2‡(n=40) p value minor complications (%) 32(80) 30(75) 0.2 major complications (%) 2(5) 0(0) †group 1: standard swog protocol ‡ group 2: monthly bcg instillation group variable group 1† (n=40) group 2‡ (n=40) p value recurrence (%) 5(12.5) 7(17.5) 0.5 progression (%) 4(10) 3(7.5) 1.0 table 3. number of patients having recurrence and progression in the two groups †group 1: standard swog protocol ‡ group 2: monthly bcg instillation group monthly bcg as maintenance therapy-lashay et al. vol 19 no 2 march-april 2022 100 ison to the classic method. however, their result cannot be generalized because of two reasons. first, they used 40 mg (half dose) of tokyo 172 variant and second, this study was the phase 2 of another study in which the patients received bcg in lieu of tumor resection and in those whom no response were observed, maintenance bcg was started. this treatment plan is not the standard approach nowadays and complete tumor resection of visible lesions is a must before considering bcg treatment. other trial by badaloment et. al.(5) on 93 patients for comparison of monthly instillations of bcg with no instillations, also did not reveal any advantage of monthly instillations on reducing recurrence or progression. yoo et. al.(11) studied the role of monthly bcg in 92 patients with nmibc and compared them with 34 patients on no maintenance regimen with regard to recurrence free survival (rfs) , progression free survival (pfs) , disease specific survival (dss) and side effects. the median follow up time was 43 months. they reported that the monthly regimen resulted in improved rfs. the estimated median rfs was 87 months (95% ci 53.0-120.9) in the maintenance group and 48 months (95% ci 0-96.8) in the no maintenance group (p = 0.002). they also reported that the toxicity and side effects were higher in the no maintenance group by 4% which was not statistically significant. again, this study did not compare the monthly regimen with the classic swog regimen, but only compared them with no maintenance regimen which obviously result in better recurrence results. furthermore, although the side effects were higher in the no maintenance group, all of their symptoms were minor irritative symptoms. while in the maintenance group, major side effects including gross hematuria, high grade fever and pulmonary tuberculosis were occurred. single instillation of bcg every 3 months for 1-year (4 doses total) which was adopted in another trial(7) did not show any results either which was no surprise considering the results of cueto(9) study which had already showed 3 monthly single injections will not suffice to harness efficacy. six instillations every 6 months for 2 years adopted by palou(8) as maintenance protocol also did not result in any difference in recurrence or progression rate, in comparison to control group (no maintenance instillations). in our retrospective study, we demonstrated that monthly bcg maintenance instillations can provide similar efficacy to swog regimen with no additional complication rate. also the advanced age in group 2 did not cause any difference in efficacy or complication rate in comparison to group 1. the only study which had compared monthly bcg with swog protocol in an head-to-head manner is the prospective trial conducted by gupta n.k. et al,(6) in 2020. in their trial, 78 intermediate and high risk bcg naive nmibc patients were randomized into 2 groups of monthly bcg or swog protocol. monthly group received 12 monthly doses of 80 mg moscow strain bcg and the other group received bcg in accordance with the swog regimen of 80 mg bcg for 3 consecutive weeks at 3 and 6 months and 6 monthly thereafter for a period of 3 years. their mean follow-up was 24 months (range: 15-31). the rate of recurrence, progression and bcg toxicity were statistically insignificant between the two groups and they concluded that swog protocol can be replaced by monthly regimen in nmibc. our results are in line with gupta's trial(6). in the swog maintenance group (group 1) 12.5 % of patients had recurrence at the end of follow up (15% in gupta's trial (6) at the end of 2 years) and in the monthly group (group 2) 17.5 % of patients had recurrence at the end of follow up (16.1 % in gupta's trial(6) at the end of 2 years). our follow up time was longer (36.68 ± 17.37 months in group 1 and 33.45 ± 17.35 months in group 2) and still monthly regimen proved to be effective. another difference was that in gupta's trial(6) all patients in swog group received bcg for 3 years and in monthly group for 12 months, irrespective of their risk group (intermediate or high), however in our study, intermediate risk patients received bcg for 1 year and high risk patients received bcg for 3 years. regarding bcg major complications, the reason for its absence in our study, could be due to the fact that any major complications commonly do occur in the induction course(12). since we excluded these patients from study, there is no surprise that we had low major complication rate, and we can deduct that patients who do not show serious complications for induction course, will tolerate maintenance dose as well. this finding is also in line with gupta's trial(6) in which both groups only demonstrated grade 1 level of bcg toxicity (i.e. minor) and grade 2 and 3 (i.e. major) were absent. our monthly regimen did not decrease the total number of instilled bcg ( 36 versus 21 in swog regimen, if 3 years of maintenance is completed), however since it disperses the instillation times, it is probably a more convenient schedule for patients which could increase their compliance. the issue of compliance has always been a concern in long term bcg maintenance therapy, as in the swog trial(3), only 16% of patients had completed the treatment. in gupta's study(6) the dropout rate was 7.3% for monthly group while it was 18.4% for the swog group. although the difference was not statistically significant, they hypothesized from their patients' given reasons that adopting treatment at short orderly intervals was easier to follow. there is a theory regarding monthly bcg instillation that with monthly boost, there is the possibility of keeping the immunity more on edge(13,14). this raises the question of "if monthly bcg instillation keeps the immunity more alert, is it possible to decrease the amount of prescribed dosage or even the total maintenance time to derive the same efficacy?". obviously, this statement is just theoretical and needs a larger trial for verification. this was a retrospective study with its inherent limitations. furthermore, the number of patients was limited and it requires a larger population to derive extensible results. the reason for our results could be due to patient selection bias. all our patients had good response to induction course, were free of tumor in their follow up cystoscopy, had good compliance and had no serious complications with instillation. good response to induction course could translate into bcg sensitivity of these patients(15,16). still, this will not compromise the validity of our study because our objective was to compare two different regimens and this can be done in primary bcg responsive patients. conclusions in the aggregate, after induction course, our regimen of monthly bcg as maintenance therapy-lashay et al. vol 19 no 2 march-april 2022 109 urological oncology 110 monthly instillations of bcg as maintenance therapy, shows no difference in the complication rate in comparison to swog protocol and it has comparable efficacy regarding recurrence and progression rate. conflict of interest none was declared by the authors. references 1. babjuk m, burger m, compérat em, et al. european association of urology guidelines on non-muscle-invasive bladder cancer (tat1 and carcinoma in situ) 2019 update. eur urol. 2019;76:639-57. 2. chang ss, boorjian sa, chou r, et al. diagnosis and treatment of non-muscle invasive bladder cancer: aua/suo guideline. j urol. 2016;196:1021-9. 3. lamm dl, blumenstein ba, crissman jd, et al. maintenance bacillus calmette-guerin immunotherapy for recurrent ta, t1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized southwest oncology group study. j urol. 2000;163:1124-9. 4. akaza h, hinotsu s, aso y, kakizoe t, koiso k. bacillus calmette-guérin treatment of existing papillary bladder cancer and carcinoma in situ of the bladder. four-year results. the bladder cancer bcg study group. cancer. 1995;75:552-9. 5. badalament ra, herr hw, wong gy, et al. a prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus calmette-guérin therapy of superficial bladder cancer. j clin oncol. 1987;5:441-9. 6. gupta n, sarkar d, pal d. monthly maintenance protocol bacillus calmette–guerin as a viable alternative to southwest oncology group maintenance protocol in nonmuscleinvasive bladder cancer: a prospective randomized study. urology annals. 2020;12:116-21. 7. koga h, ozono s, tsushima t, et al. maintenance intravesical bacillus calmetteguérin instillation for ta, t1 cancer and carcinoma in situ of the bladder: randomized controlled trial by the bcg tokyo strain study group. int j urol. 2010;17:759-66. 8. palou j, laguna p, millán-rodríguez f, hall rr, salvador-bayarri j, vicente-rodríguez j. control group and maintenance treatment with bacillus calmette-guerin for carcinoma in situ and/or high grade bladder tumors. j urol. 2001;165:1488-91. 9. martínez-piñeiro l, portillo ja, fernández jm, et al. maintenance therapy with 3-monthly bacillus calmette-guérin for 3 years is not superior to standard induction therapy in high-risk non-muscle-invasive urothelial bladder carcinoma: final results of randomised cueto study 98013. eur urol. 2015;68:256-62. 10. sylvester rj, van der meijden ap, oosterlinck w, et al. predicting recurrence and progression in individual patients with stage ta t1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials. eur urol. 2006;49:466-5; discussion 757. 11. yoo kh, lim tj, chang sg. monthly intravesical bacillus calmette-guérin maintenance therapy for non-muscle-invasive bladder cancer: 10-year experience in a single institute. exp ther med. 2012;3:221-5. 12. oddens j, brausi m, sylvester r, et al. final results of an eortc-gu cancers group randomized study of maintenance bacillus calmette-guérin in intermediateand highrisk ta, t1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. eur urol. 2013;63:462-72. 13. de reijke tm, de boer ec, kurth kh, schamhart dh. urinary cytokines during intravesical bacillus calmette-guerin therapy for superficial bladder cancer: processing, stability and prognostic value. j urol. 1996;155:477-82. 14. ratliff t, catalona w. depressed proliferative responses in patients treated with 12 weeks of intravesical bcg. j. urol. 1989;141:230a. 15. chen s, zhang n, shao j, wang x. maintenance versus non-maintenance intravesical bacillus calmette-guerin instillation for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized clinical trials. int j surg. 2018;52:248-57. 16. woldu sl, bagrodia a, lotan y. guideline of guidelines: non-muscle-invasive bladder cancer. bju int. 2017;119:371-80. monthly bcg as maintenance therapy-lashay et al. 1 current trends in hypospadias repair. where are we standing? parisa saeedi sharifabad1, vahid poudineh2, mehran hiradfar3, ahmad mohammadipour4, reza shojaeian5 1associate professor of pediatric urology, mashhad university of medical sciences iran, islamic republic of 2general physician, mashhad university of medical sciences iran, islamic republic of 3associate professor of pediatric surgery, mashhad university of medical sciences iran, islamic republic of 4assistant professor of pediatric surgery, golestan university of medical sciences iran, islamic republic of 5assistant professor of pediatric, mashhad university of medical sciences iran, islamic republic of head of pediatric surgery department – akbar children hospital akbar children’s hospital; 14 kaveh blv; mashhad; iran phone: +989155150923 email: drshojaeian@ymail.com hypospadias is a common congenital anomaly of male urogenital tract. the incidence of hypospadias is estimated as one affected boy in every 250 male live birth(1) while several reports and evidences indicate increasing rate of hypospadias.(2) 2 the history of hypospadias is backing to roman emperor (3, 4) different aspects of hypospadias such as it’s etiology, classification and treatment have been a place of discussion.(5) the choice of surgical technique depends on the surgeon’s personal experience and training.(6) different specialties are involved in hypospadias surgical reconstruction including pediatric surgeons, pediatric urologists, general urologist and plastic surgeons and each group has their own principals and favorite techniques. (7) several studies and reviews have been published to report the advantages and success rate of each method.(2, 8, 9) in this study we surveyed different groups of surgeons who are involved in hypospadias reconstruction about their preferences in treatment of various types of hypospadias. method and materials: we designed a multiple choice questionnaire on google forms in english, including general questions such as name, age, email address, academic rank, duration of practice, estimated hypospadias reconstructive surgeries per month and finally their preferred method of treatment for three hypospadias cases that were introduced providing a brief history and some pictures, which is still available on line using the link: https://goo.gl/forms/jvrqrjleqyt0uqa93 to determine the validity and reliability of the survey we distributed the printed version of questionnaire among some of audiences during hypospadias and disorders of sexual development congress (hdsd) 2017 twice at the opening ceremony and gala dinner of congress and also take the expert opinion. iranian pediatric surgeons, iranian pediatric urologists and iranian urologists were invited to participate in this survey. email address list was provided by iranian society of pediatric surgeons and iranian urological association contains 97 email address of surgeons in practice at the time of this study. https://goo.gl/forms/jvrqrjleqyt0uqa93 3 a comprehensive search was performed in in pubmed central, medline, scopus, embase, scielo, cochrane database and google scholar from 2010 up to 2018 using combination of mesh words of ‘hypospadias ‘and ‘surgery” and “pediatrics” total of 374 articles focusing on hypospadias reconstruction in pediatrics were identified. email address of corresponding author were available in 313 published articles. 291 invitation e mails were sent after excluding duplicated addresses. all personal data of participants remained confidential and the study protocol was approved in ethical committee of mashhad university of medical sciences with the confirmation code of ir.mums.medical.rec.1397.364. results: mean age of 170 surgeons who took part in this survey was 47.5±16.34 years. 42 professors (24.7%), 43 associate professors (25.3%) and 57 assistant professors (33.5%) participated in this study while the academic rank was not mentioned in 28 feedbacks (16.5%). 51 general urologists (30%), 61 pediatric surgeon (35.9%), 16 plastic surgeons (9.4%) and 42 pediatric urologists (24.7%) enrolled in this study. a high volume surgeon was defined as a surgeon with more than 50 hypospadias surgery per year (almost 5 cases or more every month)(6) 61 low volume surgeons (35.9%) and 109 high volume surgeons (64.1%) were participated in our survey. regarding the years of practice, 22 surgeons (12.9%) had less than 5 years surgical experience, 30 surgeons (17.7%) declared 5-10 years of experience and 118 surgeons (69.4%) were in practice for more than 10 years. 36 iranian surgeons were participated in this survey and we received 18 emails from north america, 8 emails from south america, 48 emails from europe 41 emails from asia (apart from iran), 16 emails from africa and 3 emails from australia. 4 preferred method of surgery for a simple distal hypospadias was tubularized incised plate hypospadias repair (tip) in 53.5%, thiersch-duplay in 18.8%, meatal advancement and glanduloplasty (magpi) in 14.1% and mathieu procedure in 4.7%. 8.8% of participants suggested not to operate this case until adulthood and waiting for the patient to decide by himself. surgical procedure of choice for the proximal hypospadias without cordee was tubularized incised plate hypospadias repair (tip) in 39.4%, two stage urethroplasty in 24.7%, island onlay flap in 21.2%, tubuluraized prepupital island flap in 10%, sleeve advanced urethroplasty in 3.5% and asopa procedure 1.2%. suggested technique of reconstruction in proximal hypospadias surgery with severe cordee was two-stage bracka in 59.4%, two-stage durham smith in 24.7%, modified asopa (hodson) procedure in 8.8%, one-stage ducket procedure in 5.9% and koyanagi nonomura one-stage repair in 1.2%. comparing the technique of choice regarding the specialty of surgeons, operation load and geographic patterns was done and summarized in table 1. surgical approach to distal hypospadias and proximal hypospadias without cordee were significantly different between high volume and low volume surgeons. the most popular technique in distal hypospadias was tip in both groups but magpi was more popular among low volume surgeons. proximal hypospadias without cordee was mostly corrected by tip in low volume surgeons while tip, onley island flap and two stage urethroplasty were suggested with almost the same rate in high volume surgeons. onley island flap had popularity among high volume surgeons but it was not suggested commonly with low volume surgeons. trends in proximal hypospadias with severe cordee repair was almost the same in both low and high volume surgeons and two stage bracka or durham smith were more accepted techniques. 5 comparison of surgical approach to hypospadias among different is summarized in table 3. mathieu procedure was suggested by 13.9% iranian surgeons for distal hypospadias repair while it was uncommon in other countries. magpi procedure was also more common among iranian compare to other countries. american surgeons were more interested in two stage repair to reconstruct different type of proximal hypospadias. european surgeons suggested koyanagi repair and were not interested in durham smith for severe proximal hypospadias repair while other surgeons suggested two stage bracka or durham mainly. discussion: in this international internet base survey on hypospadias reconstruction we assessed and compare recent trends among surgeons who are involved in hypospadias repair in different specialties and countries to inspect any consensus on hypospadias surgery to date. previous surveys revealed growing trends to tip for distal hypospadias and two stage repair for proximal hypospadias reconstruction(6, 8) tip was also the most common reconstructive method for distal hypospadias among all specialties. surgical approaches were quiet the same in pediatric surgeons and pediatric urologists while adult surgeons recommended watchful waiting and mathieu technique. different specialties had almost similar approach to proximal hypospadias although island flap was not popular among urologists and plastic surgeons. growing tendency to tip in treatment of proximal hypospadias without cordee was notable compare to previous reports.(6, 8) tendency to postpone hypospadias reconstruction to preschool age in plastic surgeons was also reported in other surveys(6) while several published literatures recommended the second 6months of life as the ideal timing of hypospadias repair.(7) experts believed that complications increase above this optimal age of operation.(2) 6 the most common approach to distal hypospadias among both high and low volume surgeons was tip but low volume surgeons were more interested to minimal interventions while high volume surgeons were mostly believed on optimal correction of distal hypospadias. both high and low volume surgeons suggested tip for proximal hypospadias without cordee. low volume surgeons that may represented by the new generation of surgeons were not interested in onley island flap compare to their high volume colleagues. other previous international surveys were also reported a growing trend toward two stage repair for reconstruction of proximal hypospadias. (6, 10) a uniform surgical approach was seen in proximal hypospadias with severe cordee and both low and high volume surgeons suggested two stage repair. (bracka or durham smith) we studied the geographic pattern of surgical options in hypospadias repair. the results showed notable popularity of tip and thiersch-duplay procedure in distal hypospadias repair while magpi and mathieu techniques are less commonly used but iranian surgeons were still interested in these methods. literature reported favorable outcome of tip repair in distal hypospadias(9) although there is some concerns about meatal stenosis and abnormal uroflowmetry pattern after tip repair(11) but a consensus is evolving on the approach to distal hypospadias worldwide and recent recommendations are in favor of correction of distal hypospadias versus watchful waiting.(12) tip is commonly used for correction of proximal hypospadias without cordee in asia while various techniques were suggested in our survey from europe. two stage repair was the method of choice for severe proximal hypospadias with cordee in most of the feedbacks. there is technical variations among different surgeons and more challenges and complications should be expected in this field.(13) 7 this study was based on self-declaration and this was a limitation because some variables such as case load could be over-estimated by participants. conclusion: • some adult surgeons are still in favor of delayed or no intervention. • tip is the most popular option for and distal proximal hypospadias without cordee hypospadias reconstruction • most of surgeons suggested two stage repair for proximal hypospadias with severe cordee. 8 references: 1. horowitz m, salzhauer e. the ‘learning curve’in hypospadias surgery. bju international. 2006;97(3):593-6. 2. macedo jr a, rondon a, ortiz v. hypospadias. current opinion in urology. 2012;22(6):447-52. 3. lambert sm, snyder hm, canning da. the history of hypospadias and hypospadias repairs. urology. 2011;77(6):1277-83. 4. hadidi at. history of hypospadias: lost in translation. journal of pediatric surgery. 2017;52(2):211-7. 5. snodgrass w, macedo a, hoebeke p, mouriquand pd. hypospadias dilemmas: a round table. journal of pediatric urology. 2011;7(2):145-57. 6. springer a, krois w, horcher e. trends in hypospadias surgery: results of a worldwide survey. european urology. 2011;60(6):1184-9. 7. manzoni g, bracka a, palminteri e, marrocco g. hypospadias surgery: when, what and by whom? bju international. 2004;94(8):1188-95. 8. timmons m. the uk primary hypospadias surgery audit 2006–2007. journal of plastic, reconstructive & aesthetic surgery. 2010;63(8):1349-52. 9. snodgrass wt, bush n, cost n. tubularized incised plate hypospadias repair for distal hypospadias. journal of pediatric urology. 2010;6(4):408-13. 10. cook a, khoury ae, neville c, bagli dj, farhat wa, salle jlp. a multicenter evaluation of technical preferences for primary hypospadias repair. the journal of urology. 2005;174(6):2354-7. 11. barbagli g, perovic s, djinovic r, sansalone s, lazzeri m. retrospective descriptive analysis of 1,176 patients with failed hypospadias repair. the journal of urology. 2010;183(1):207-11. 12. bhandarkar k, garriboli m. repair of distal hypospadias: cosmetic or reconstructive? urology. 2019. 13. misra d, elbourne c, vareli a, banerjee d, joshi a, friedmacher f, et al. challenges in managing proximal hypospadias: a 17-year single-center experience. journal of pediatric surgery. 2019;54(10):2125-9. 9 table 1: procedure of choice for various hypospadias scenarios regarding surgeons’ specialty and work load and geographic pattern proximai hypospadias with cordee (%) proximal hypospadias without cordee (%) distal hypospadias (%) m o d ifie d a so p a (h o d so n ) o n e sta g e k o y a n a g i t w o -sta g e d u rh a m s m ith t w o -sta g e b ra c k a o n e -sta g e d u c k e t t w o -s ta g e u re th ro p la sty a so p a p ro c e d u re s le e v e a d v a n c e d t u b u la riz e d p re p u tia l f la p isla n d o n la y fla p t ip t ip t h ie rsc h -d u p la y m a th ie u m a g p i w a tc h a n d w a it s u r g e o n ’ s sp e c ia lty general urologist 1 5 .7 1 1 .8 7 .8 1 3 .7 5 1 3 7 .3 1 9 .6 1 3 .7 2 2 2 5 .5 5 .9 6 2 .7 2 5 .5 3 .9 2 pediatric surgeon 3 .3 1 3 .1 1 .6 2 1 .3 6 0 .7 4 7 .5 2 4 .6 8 .2 3 .3 0 1 6 .4 6 .6 5 9 1 8 1 4 .8 1 .6 pediatric urologist 4 .8 1 6 .7 2 .4 2 3 .8 5 2 .4 3 5 .7 2 1 .4 4 .8 4 .8 2 .4 3 1 4 .8 5 7 .1 3 1 7 .1 0 plastic surgeon 1 8 .8 1 8 .8 1 2 .2 1 2 .5 3 7 .5 2 5 1 2 .5 1 8 .8 6 .3 0 3 7 .5 6 .3 5 6 .3 3 1 .3 7 .1 0 p value 0.184 0.653 0.824 p a tie n t v o lu m e low volume 1 6 .4 2 3 8 .2 8 .2 4 4 .3 5 9 1 1 .5 9 .8 1 .6 1 .6 1 6 .4 3 .3 6 0 .7 2 7 .9 6 .6 1 .6 high volume 4 .6 9 .2 2 .8 2 4 .8 5 8 .7 2 8 .4 2 6 .6 1 0 .1 4 .6 0 .9 2 9 .4 7 .3 5 8 .7 2 2 .9 1 0 .1 0 .9 p value 0.001 0.04 0.693 g e o g r a p h ic p a tte r n america 3 .8 7 .7 0 3 8 .5 5 0 3 4 .6 1 9 .2 0 0 0 4 6 .2 0 5 3 .8 4 2 .3 0 3 .8 europe 1 0 .4 1 4 .6 4 .2 2 5 4 5 .8 2 9 .2 3 3 .3 6 .3 8 .3 2 .1 2 0 .8 1 2 .5 6 6 .7 2 .1 asia 9 .1 9 .1 2 .3 9 .1 7 0 .5 2 9 .2 3 3 .3 6 .3 8 .3 2 .1 2 0 .8 1 2 .5 6 6 .7 2 .1 1 8 .8 0 africa 9 .1 9 .1 2 .3 9 .1 7 0 .5 5 6 .8 9 .1 6 .8 0 0 2 7 .3 2 .3 6 5 .9 2 2 .7 6 .8 2 .3 iran 1 3 .9 2 5 1 3 .9 2 .8 4 4 .4 4 4 .4 1 9 .4 1 6 .7 0 0 1 6 .7 5 .6 5 2 .8 3 8 .9 2 .8 0 p value 0.004 0.001 0.002 laparoscopic and robotic urology evaluation of the results and complications of transabdominal preperitoneal laparoscopic inguinal hernia repair in patients with a history of radical prostatectomy mohammad hossein izadpanahi1, rana milasi2* purpose: radical prostatectomy is one of the most common urological surgeries. inguinal hernia is a well-known complication of radical prostatectomy. there are many controversies about selection of surgical techniques for repair of inguinal hernia. traditionally laparoscopic approach was contraindicated for patients with history of lower abdominal surgery, but recent studies showed that it could be safe and successful and even has some advantages over open repair. in this prospective study we evaluated outcomes of laparoscopic hernia repair in patients who previously underwent radical prostatectomy. materials and methods: in this prospective study, 34 consecutive patients diagnosed with inguinal hernia after radical retropubic prostatectomy underwent laparoscopic transabdominal inguinal repair and followed up for outcomes and complications. results: the surgery duration was 167.44 ± 52.85 min (75-230 min). no intraoperative complications occurred. patients were discharged within 20.79 ± 4.76 hours (12-34 hours). 69.8% of cases (30 patients) needed analgesic administration. no conversion to open surgery occurred. there were 9.3% (4 hernias) hernia recurrences. we followed patients for 9.9 ± 5.33 months (2-19 months). conclusion: it is concluded that tapp for inguinal hernia repair after radical prostatectomy has good results and is effective. but according to rate of recurrence, its safeness is conflicting. we notice no major complication in our patients during the time of follow up. this may be due to safety of the operation in the proposed patients. keywords: inguinal hernia repair; laparoscopy; radical prostatectomy; recurrence; tapp introduction prostate cancer (pc) is a major worldwide health problem especially among old men. the incidence of pc is increasing by age. radical prostatectomy (rp) is the gold standard treatment for localized pc(1-4). the 10-year cancer-specific survival rate for patients underwent radical retropubic prostatectomy (rrp) is reported to be 96%(5). however, some complications have been reported for rrp such as urinary incontinence, anastomotic stricture, erectile dysfunction, and impotence, and developing a recto urethral fistula(6-8). moreover, studies have reported that rrp increases the risk of postoperative inguinal hernia with reported incidence from 12.4% to 23.9%, depending on the institute’s experience (9, 10) which occur between 6 months and 24 months after operation(11-13). several laparoscopic techniques have been described to manage inguinal hernia(14-17) such as transabdominal preperitoneal repair (tapp)(18) and totally extra peritoneal (tep)(19). different indications have been described for both procedures, however the tapp technique has also been advocated in cases with recurrent and complicated inguinal hernia (such as sliding or incarcerated inguinal hernias)(20). moreover, several 1isfahan kidney transplantation research center, department of urology, alzahra research centers, isfahan university of medical sciences, isfahan, iran. 2isfahan university of medical sciences, isfahan, iran. *correspondence: isfahan university of medical sciences,isfahan, iran. tel: +98 913 4814267. email: ranamilasi@yahoo.com. received autgust 2018 & accepted september 2018 advantages have been reported for tapp such as simpler procedure, larger working space and finally better intraoperative anatomical landmarks(21). furthermore, the learning curve of tapp repair is shorter(20). given that inguinal hernia seen frequently following rrp, few studies evaluated the results of tapp repair in patients with history of rp compared to those without previous rp(22). as to best of our knowledge, there isn't enough prospective study about this issue, therefore, this study was designed to evaluate the results and complications of laparoscopic inguinal herniorrhaphy in patients with a history of radical prostatectomy. patients and methods study design and patients this prospective study was conducted in urology department of isfahanalzahra hospital, in period april 2015 to april 2018. the recurrence rate and other outcomes in patients who underwent tapp repair with history of rp were evaluated. the study received ethics approval from the ethics committee of isfahan university of medical sciences (395657). 40 consecutive patients diagnosed with inguinal hernia after rrp were enrolled in the study. (figure 1) urology journal/vol 17 no. 1/ january-february 2020/ pp. 24-29. [doi: 10.22037/uj.v0i0.4751] vol 17 no 01 january-february 2020 25 inclusion and exclusion criteria inclusion criteria consisted of patients with indication for inguinal herniorrhaphy referred to alzahra hospital, age between 50-80 years-old, history of rp, operated by same experienced surgeon and in the same method, and exclusion criteria consisted of subjects with age below 50 years or more than 85 years, not available for further postoperative follow up, or patients with incomplete medical data. the criteria for diagnosis of inguinal hernia after radical retro-pubic prostatectomy in this study was in line with the european hernia society guidelines, described previously(23). procedures the procedure was performed under general anesthesia in all patients. first of all urinary catheter was inserted and patients were placed in trendelenburg position. then a 10-mm trocar was inserted exactly above the umbilicus, so that the 0-degree scope was inserted. afterwards, two other 5-mm trocars were inserted from the left and right side on the midclavicular line. the surgical procedure started with examining the anatomical conditions inside the abdomen and the defect side, the peritoneum opening position was from the anterior superior iliac spine to the medial umbilical fold. after that, peritoneal flap developed by sharp and blunt dissection to reach the psoas muscle and after complete reduction of the hernia sac, dissection continued inferomedially to pubic symphysis. thereafter, a mesh size of 12 * 15 cm was reconfigured and placed in a way that overlaps around the inguinal ring with at least 3 cm distance and fixed with 2-3 non absorbable or absorbable tackers. at the end, the peritoneal flap was closed by running 2-0 prolene sutures. all patients received antibiotic (ceftriaxone 1gr intravenous) and analgesic agents (pethidine and apotel) were prescribed on demand after surgery. evaluations different variables were evaluated in patients including age, previous history of smoking, history of previous inguinal hernia, hernia side and classification based on nyhus criteria, described previously(24) and variables during surgery such as damage to the bladder and viscera, respiratory failure, stroke, damage to the bowel, damage to the lower epigastric vessels, duration of surgery, conversion to open approach. the severity of postoperative pain was measured by the visual analogue scale (vas) (0 = painless and = 10 worst pain during life), which was measured 6 and 24 hours and 2 weeks after surgery. hematuria, seroma and hematoma, hospital discharge time, orchitis, testis atrophy, urinary tract infection, surgical site infection, examination of hernia complications of inguinal hernia repair in prostatectomy-izadpanahi et al. table 1. studied variables before and after surgery variables no. (%) minimum maximum mean sd. age (year) 51 80 65.97 8.16 smoking 13 (30.2%) duration between rp and lh (month) 6 60 22.41 12.42 side right 15 (44.1%) left 10 (29.4%) bilateral 9 (26.5%) nyhus criteria ii 11 (25.6%) iiia 11 (25.6%) iiib 13 (30.2%) iv 8 (18.6%) surgery duration (min) 75 230 167.44 52.85 hospitalization duration (hour) 12 34 20.79 4.76 vas score after 6 hours 2 6 4.41 1.11 after 24 hours 0 4 1.48 0.93 after 2 weeks 0 2 0.2 0.46 analgesic administration 30 (69.8%) follow up (month) 2 19 9.9 5.33 post-operative complication seroma 1 (2.3%) infection 1 (2.3%) hematuria 1 (2.3%) hernia recurrence 4 (9.3%) duration between lh and hernia recurrence (month) 0 7 0.55 1.84 abbreviations: rp, radical prostatectomy; lh, laparoscopic herniorrhaphy figure 1. patients’ enrollment algorithm. recurrence based on physical examination, hernia type and location in cases of recurrence, time to detect hernia recurrence and other complications after surgery. all outcomes were measured at baseline, 2 weeks, 3 months, 6 months, and 1 year postoperatively and at the end of study or when they were clinically symptomatic or reported by patients. as several studies demonstrated, most ihs develop during the first 3–4 years after radical retro pubic prostatectomy (rrp)(31), therefore all hernias were considered due to prostatectomy in our follow up. two weeks after operation, patients were allowed to have their routine occupational activity. statistical analysis statistical analysis of data was performed using spss version 24 software. kolmogorov-smirnov test was used in order to evaluate the normal distribution quantitative variables. independent t-test was used for variables with normal distribution and mann-whitney test for non-normal distribution variables. chi-square test was used to compare qualitative variables between groups. two tailed p-value less than .05 were considered significant. results thirty-four patients with mean age of 65.97 ± 8.16 years (51-80 years) prospectively entered the study. the duration between rp and laparoscopic herniorrhaphy (lh) was 22.41 ± 12.42 months (6-60 months). fifteen cases (15/43, 44.1%) were on the right side. moreover, 30.2 % of subjects were type iiib inguinal hernia (13/43), 25.6 % (11/43) type ii and iiia respectively and 18.6% (8/43) were type iv inguinal hernia bases on nyhus criteria. we found that 30.2% of cases had history of smoking. the mean operative time was 167.44 ± 52.85 min (75230 min) and hospitalization time was 20.79 ± 4.76 hours (12-34 hours). there was no conversion to open surgery. moreover, the mean pain score based on vas in 6, 24 hours and 2 weeks after surgery were 4.41, 1.48, and 0.2, respectively. thirty cases (69.8 %) (based on hernia) needed analgesic administration. no intraoperative complications occurred. we followed patients for 9.9 ± 5.33 months (2-19 months) and found that 3 cases (6.97%) showed post-operative complications including seroma, hematuria due to difficult and traumatic urethral catheterization and superficial surgical site infection. moreover, 4 cases (9.3%) had hernia recurrence. the duration between lh and hernia recurrence was 0.55 ± 1.84 months (0-7 months). (table 1). we evaluated different factors affecting the hernia recurrence rate. we found that history of smoking was significantly higher in cases with hernia recurrence (75% vs. 25.6%, p = .041). on the other hand, we found that hospitalization time was significantly higher in cases with later hernia recurrence (26.5 ±5 vs. 20.2 ± 4.39 hours, p = .024). (table 2) we evaluated pain score based on vas and we did not observed significant differences in vas score during follow up (p > .05). but by evaluating pain changes during 2 weeks follow up, we found that reduction in pain score in cases with hernia recurrence was lower as compared to other patients especially in first 6 and 24 hours after surgery. (p < .001). history of lymphadenectomy in previous radical prostatectomy and pathological evaluation of the specimens was not available. discussion we evaluated 43 hernias from 34 cases and we followed patients for mean of 9.9 ± 5.33 months (2-19 months) and found that 6.97% of cases showed post-operative complication and 9.3% had hernia recurrence. recurrences were seen more in cases with history of smoking, higher hospitalization duration and lower pain reduction during first 24 hours. in a study performed by claus et al., mean operative time was reported 67.5 min and 5% of cases had intraoperative minor complication, without major postoperative complications. moreover, after 24 hours and on the seventh day after surgery, 85% and 90% of patients had no pain, respectively. forty five percent of subjects did not need any analgesics postoperatively. there was no conversion to open surgery. after a mean follow-up of 14 months, no recurrence was observed(25). laparoscopic urology 26 table 2. studied variables before and after surgery based on recurrence recurrence variables negative (n=39) positive (n=4) p-value age (year) ; mean ± sd (range) 65.51 ±8.27 70.5 ±5.97 .249 smoking 10 (25.6%) 3 (75%) .041 duration between rp and lh (month) 8.5±3.69 23.84 ±12.12 < 0.001 side right 14 (45.2%) 1 (33.3%) .922 left 9 (29%) 1 (33.3%) bilateral 8 (25.8%) 1 (33.3%) nyhus criteria ii 10 (25.6%) 1 (25%) .616 iiia 11 (28.2%) 0 iiib 11 (28.2%) 2 (50%) iv 7 (17.9%) 1 (25%) surgery duration (min) 164.61 ± 54.07 195 ± 30.82 .299 hospitalization duration (hour) 20.2 ± 4.39 26.5 ± 5 .024 vas score ; mean ± sd (range) after 6 hours 4.53 ± 1.02 3.25 ± 1.5 .091 after 24 hours 1.43 ± 0.88 2 ± 1.41 .557 after 2 weeks 0.15 ± 0.36 0.75 ± 0.95 .227 vas differences ; between 24 and 6 hours -3.1 ± 0.64 -1.25 ± 0.5 < 0.001 mean ± sd (range) between 2 weeks and 6 hours -4.38 ± 0.98 -2.5 ± 0.57 .001 between 24 hours and 2 weeks -1.28 ± 0.85 -1.25 ± 0.5 .888 analgesic administration 26 (66.7%) 4 (100%) .167 follow up (month) ; mean ± sd (range) 9.66 ±5.31 12.25 ± 5.67 .479 post-operative complication 2 (5.1%) 1 (25%) .259 abbreviations: tul, transurethral lithotripsy; rp, radical prostatectomy; lh, laparoscopic herniorrhaphy complications of inguinal hernia repair in prostatectomy-izadpanahi et al. vol 17 no 01 january-february 2020 27 the results of this study were not similar to the results of our study. we did not observed intraoperative complication, while 6.97% of cases showed post-operative complication. moreover, we found that 9.3% had hernia recurrence. these differences may due to different sample size, different types and sizes of hernia, different inclusion and exclusion criteria, and surgeon experience. also, two patients which had hernia recurrence in our study had history of previous surgeries including appendectomy and herniorrhaphy. in another study, performed by hawn et al., rate of recurrence after inguinal herniorrhaphy was 6.5% and 21.3% of patients had complications at 2 years. the authors stated that most of recurrences occur in first year (32). the laparoscopic inguinal herniorrhaphy after pelvic or abdominal surgeries is a time consuming procedure because releasing lateral adhesions of bladder to pelvic wall and dissecting free the peritoneal flap is technically challenging compared to those patients without history of surgery. our study showed higher rate of recurrence and longer operative time. our patients underwent herniorrhaphy with a mean time of 22 months after radical prostatectomy with a range between 6-60 months. postponing the treatment of inguinal hernia after radical prostatectomy may result in increasing the size of defect or sac and also more adhesions which make subsequent dissection more difficult with higher rates of recurrences. as shown in table 2 patients with subsequent recurrences have significant delay in diagnosis and or treatment of inguinal hernia (23 versus 8 months). so it seems that patients with radical prostatectomy diagnosed with inguinal hernias should be treated as soon as possible in follow-up moreover, dulucq et al. reported that laparoscopic tep for inguinal hernia repair in patients with previous low abdominal surgery (such as radical prostatectomy) has good results, similar to those without previous surgery (such as major intraoperative complications, hospital stay, and recurrence rate). however, a longer operative time was observed in patients with previous low abdominal surgery. finally they concluded that tep repairs can be performed efficiently and safely in patients after radical prostatectomy by skilled and experienced laparoscopic surgeons(26). although the design of the study was not the same as our study, but the results of this study were similar to the results of our study, however, we found that 9.3% of cases had hernia recurrence. it seems history of smoking increases intra-abdominal pressure and higher duration between radical prostatectomy and tapp cause more adhesive bands and make operation more difficult. in follow up patients were allowed to have activity about 2 weeks after surgery but all recurrences occurred in patient with back to activity less than one week. in the procedure of operation, the peritoneum opening position was from the anterior superior iliac spine to the medial umbilical fold, as described in dorga et al. (27) sakon et al. in 2017 showed that the mean operation time in patients who had previously undergone robot-assisted laparoscopic radical prostatectomy was 99.5 ± 38.0 min. the volume of blood loss was small intraoperatively, and the hospitalization duration was 2.0 ± 0.5 days. no major intraoperative or postoperative complications occurred. during the average 11.2-month follow-up period, no recurrence was observed(28). wauschkuhn et al. reported that patients with history of prostatectomy were older, had higher duration of operation and higher morbidity (5.7 vs. 2.8%), but recurrence rate was similar (0.8 vs. 0.7%) as compared to group without history of prostatectomy. finally, they concluded that, even if tapp after prostatectomy is a difficult operation it can be done efficiently and safely(29). in another study, atmaca et al. showed mean operation time in patient with concurrent repair of inguinal hernia with mesh application during transperitoneal robotic assisted radical prostatectomy was 139 ± 21 minutes. the mean time of hospitalization was 4 ± 0.9 days (range: 2-7). no intra-operative complication was seen. mean follow up time was 13 months and they did not observe hernia recurrence or mesh infection(33). in the present study, patients experienced inguinal hernia repair (imhr) with mesh placement. in a similar study performed by hocaoglu et al., patients with previous imhr were compared with patients without previous mesh implantation (nmi) who underwent open radical prostatectomy. results showed that there was no significant difference between functional outcomes of open radical prostatectomy in study groups(30). one of the limitations of the study was the small size of study population and therefore the limited power to reflect statistical differences. conclusions it is concluded that tapp for inguinal hernia repair after radical prostatectomy has good results and is effective. but according to rate of recurrence, its safeness is conflicting. we noticed no major complication in our patients during the time of follow up. this may be due to safety of the operation in the proposed patients. moreover, we found that 9.3% of cases had hernia recurrence which depends on different factors such as history of smoking, higher duration between radical prostatectomy and tapp, higher hospitalization stay and with lower pain reduction during first 24 hours. therefore, according to the risk factors related to higher incidence of hernia recurrence, we can predict high risk patients to provide preventive conselling and preparations such as performing by skilled and experienced laparoscopic surgeons. this may decrease the rate of hernia recurrence. however, for a definite conclusion regarding recurrence rate or late post-operative complications, longer-term follow up is necessary. acknowledgement this study was funded and supported by deputy of research, isfahan university of medical sciences, and grant number 395657. we gratefully acknowledge the dedicated efforts of the investigators, and the coordinators who participated in this study. conflict of interest the authors have indicated that they have no conflicts of interests regarding the content of this article. references 1. j. hugosson, j. stranne and s. v. carlsson, “radical retropubic prostatectomy: a review of outcomes and sideeffects,” acta oncologica. 2011;50:9297. 2. e. xylinas, a. daché and m. rouprêt, “is complications of inguinal hernia repair in prostatectomy-izadpanahi et al. radical prostatectomy a viable therapeutic option in clinically locally advanced (ct3) prostate cancer?” bju international. 2010;106:1596-1600. 3. p. c. walsh, “anatomic radical prostatectomy: evolu-tion of the surgical technique,” journal of urology, 1998;160:2418-24. 4. m. wirth, “radical prostatectomy—the gold standard in the treatment of localised and locally advanced prostate cancer,” european journal of cancer. 2011;47:134-7. 5. m. han, a. w. partin, c. r. pound, et al., “long-term 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outcomes after inguinal herniorrhaphy. surgery 2006;140:1-8. 33. atmaca af, hamidi n, canda ae, keske m, ardicoglu a. concurrent repair of inguinal hernias with mesh application during transperitoneal robotic-assisted radical prostatectomy: is it safe?. urol j. 2018: 23:4158. complications of inguinal hernia repair in prostatectomy-izadpanahi et al. v07_no_4.pdf reconstructive surgery 254 urology journal vol 7 no 4 autumn 2010 tunica vaginalis flap as a second layer for tubularized incised plate urethroplasty kamyar tavakkoli tabassi,1 shabnam mohammadi2 purpose: to investigate the success rate of snodgrass method in combination with tunica vaginalis flap as the second layer for hypospadias repair. materials and methods: in a prospective study, 33 patients with penile hypospadias who were treated using a tubularized incised plate urethroplasty (snodgrass method) and vascularized tunica vaginalis flap as a second layer, were evaluated. wound infections, meatal stenosis, and urethrocutaneous fistula were considered as treatment complications. success rates of surgery were recorded. failure was defined as need for re-operation. results: the mean age of the patients was 9.93 ± 4.4 years (range, 1.5 to 18 years). the mean follow-up was 8.79 ± 5.43 months (range, 6 months to 5 years). four patients were lost to follow-up and excluded from the study. the location of hypospadias was distal penile in 17 patients (59%) and midpenile in 12 (41%). of studied patients, 3, 2, and, 1 developed fistula, wound infection, and meatal stenosis, respectively. two subjects with meatal stenosis and one with wound infection were managed conservatively. conclusion: snodgrass technique in combination with tunica vaginalis flap as a second layer is a reasonable procedure for hypospadias repair because of good cosmetic appearance and acceptable complication rates. currently, fistula formation remains the most common complication of this technique, which often needs surgical repair. urol j. 2010;7: -7. www.uj.unrc.ir keywords: urethra, urethral stricture, hypospadias, surgical flaps, graft survival, reconstructive surgical procedure 1mashhad center for reconstructive urology, mashhad university of medical sciences, mashhad, iran 2department of anatomy and cell biology, school of medicine, mashhad university of medical sciences, mashhad, iran corresponding author: kamyar tavakkoli tabassi, md fax: +98 511 859 1057 e-mail: kamiartt@yahoo.com received september 2009 accepted february 2010 introduction hypospadias, with prevalence of 1 per 300 live births, is a congenital malformation(1) caused by incomplete fusion of urethral folds, in which the meatal orifice opens on the inferior surface of the penis.(2) tubularized incised plate method was first described by snodgrass in 1994(3) and has rapidly become a procedure for various types of hypospadias. the principal advantage of this technique is the excellent cosmetic appearance with the minimum scarring in the urethra.(4) in any reconstructive surgeries like hypospadias repair, vascularity of the repaired site is a major concern.(5) hence, to obtain better outcome of hypospadias repair, some vascularized flaps like dartos fascia and tunica vaginalis flap were introduced. these vascularized flaps are placed on the neourethra as the second layer. it seems that use of a vascularized tunica vaginalis flap as a second layer combined with snodgrass procedure results in better outcome. the aim of this study was to evaluate the efficacy of snodgrass method in combination with vascularized tunica vaginalis flap. materials and methods patient selection this pilot case series study was tunica vaginalis flap in urethroplasty—tavakkoli tabassi and mohammadi 255urology journal vol 7 no 4 autumn 2010 performed on 33 patients with penile hypospadias without chordee, who referred to a single urologist from december 2003 to june 2008. all the patients underwent tubularized incised plate supported by tunica vaginalis flap. five patients received pre-operative androgen therapy, which was administered as testosterone enanthate injection (2 mg/kg) for 2 to 5 weeks before the operation. we followed up the patients every 3 months for the first year, every 6 months thereafter, and whenever a patient experienced a problem. we called the patients if they did not show up for the follow-up. a need for repeat surgical intervention during the follow-up was considered as a failure. wound infections, development of meatal stenosis, scrotal disorders, and urethrocutaneous fistula were regarded as surgical complications. surgical technique under general anesthesia, after placing stay sutures, according to the traditional snodgrass technique, one midline deep incision was carried out in the urethral plate from hypospadic meatus to the glans penis. then, by another 2 parallel incisions, tubularized urethroplasty was completed over a silicon urethral catheter (8-12 f according to the penile size and patient’s age). thereafter, the testis was delivered via a separate scrotal incision and a vascularized tunica vaginalis flap was harvested and transferred to the site of surgery through a subcutaneous tunnel. care was taken to make a wide tunnel to avoid compression of flap pedicle. scrotal dissection was done gently with paying attention to complete hemostasis. ventral side of the urethra was covered by serosal layer of tunica vaginalis flap. the penile skin was then sutured with 5-0 or 6-0 vicryl sutures. urethral catheter was removed 5 to 7 days after the surgery (figure). statistical analysis data were analyzed using spss software (statistical package for the social science, version 13.0, spss inc, chicago, illinois, usa) and chi-square test. p values less than .05 were considered statistically significant. we assessed the relationship between age and complication rate by old and > 6 years of age. results the mean age of the patients was 9.93 ± 4.4 years (range, 1.5 to 18 years). the mean followup was 8.79 ± 5.43 months (range, 6 months to 5 years). four patients were lost to followup and excluded from the study. location of hypospadias was distal penile in 17 patients (59%) and mid-penile in 12 (41%). eight patients (27.5%) had a history of circumcision. the following complications occurred in 10 patients (34.48%): fistula formation in 3 (10.34%), wound infections in 4 (13.79%), and meatal stenosis in 3 (10.34%). there were no cases of hematoma and scrotal complications. in 6 patients (21.69%), the surgery failed because of fistula formation in 3 (10.34%), wound infection in 2 (6.89%), and meatal stenosis in 1 (3.44%). two subjects with meatal stenosis and 2 patients with wound infections were treated conservatively, and hence, were not considered as failures, but were included in complication rates. there were not any statistically significant differences in the terms of age (p = .49), meatus location on the penis (p = 1.000) (mid or distal penile), history of circumcision (p = 1.000), and history of androgen therapy (p = 1.000) between two patients with and without complications. discussion several different surgical methods have been proposed to achieve normal appearing penis with low complications rates in the treatment of hypospadias. some of these techniques use the penile skin while some other methods use extra penile tissues, including the buccal mucosa,(6) the skin graft,(7) and the tunica vaginalis as a flap or graft.(8) snodgrass procedure or incised plate urethroplasty is a method with high success rate;(3) however, urethrocutaneus fistula is a common complication following this technique. (9) to decrease the rate of this complication, a tunica vaginalis flap in urethroplasty—tavakkoli tabassi and mohammadi 256 urology journal vol 7 no 4 autumn 2010 vascularized tissue is applied as a second layer between the neourethra and the skin coverage.(5) dorsal flap is a tissue that has been used for the neourethra coverage to improve the outcome; however, this technique sometimes results in penile torsion or chordee.(3) an alternative technique is the use of tissues such as dartos fascia of ventral side of the penis. furness and hutcheson reported a success rate of 98% for this method and of 109 patients, only 2 developed fistulas.(10) a study in turkey demonstrated better cosmetic results using mucosal collars. in that study, fistula and meatal stenosis rates were 8.3% and 14%, respectively.(11) it should be noted that fascia is not always available to be used as a second layer. in our a, b: a vascularized tunica vaginalis flap (arrow) is harvested through a scrotal incision. c, d: tunica vaginalis flap (arrow) covers the neourethra. tunica vaginalis flap in urethroplasty—tavakkoli tabassi and mohammadi 257urology journal vol 7 no 4 autumn 2010 series, 28% of the subjects were circumcised, which made preparation of dorsal based dartos flap difficult. tunica vaginalis is another tissue that can be used as a second layer in hypospadias repair. advantages of this flap are its availability and excellent vascularity. furthermore, because this tissue is far from the penis, it is not affected by the penis disorders. besides, acceptable outcomes have been achieved from the use of tunica vaginalis flap for repair of urethrocutaneus fistula. in another study, the success rate with tunica vaginalis flap was 100% without a significant complication.(8) in a study by snow and colleagues, most of the post tunica vaginalis flap complications were related to scrotal hematoma and abscess, while the rate of 5% was reported for urethrocutaneus fistula.(12) therefore, snow and associates has recommended tunica vaginalis flap as a second layer for primary hypospadias repair. in our study, the rate of fistula was higher compared to their study. this could be due to the use of microscope by snow and colleagues. by performing complete hemostasis, anatomical dissection, and well dressing of the scrotal region, we did not encounter scrotal complications. in an indian study, snodgrass method alongside dartos fascia was used in 20 patients and tunica vaginalis flap in 29 patients as a second layer for hypospadias repair.(13) after urethral catheter removal, 20% and 10% urinary leakage was observed in dartos fascia and tunica vaginalis groups, respectively. the rate of urinary leakage was similar to urinary fistula rate in our study. interestingly, in the above-mentioned study, placement of a urethral catheter (urethral recatheterization) for another 7 to 10 days resulted in urinary leakage improvement as well as prevention of permanent fistula formation. in contrast, those subjects in whom a dartos fascia has been used as the second layer, urethral re-catheterization could not prevent permanent fistula formation. since we did not use urethral re-catheterization, we could not comment on this subject. conclusion our results showed that snodgrass technique in combination with tunica vaginalis flap, as the second layer, is a reasonable method for hypospadias repair, resulting in good cosmetic appearance and acceptable complication rates. however, further refinement of this technique could lower the complication rate. careful dissection of the scrotum and attention to hemostasis can reduce scrotal complications as well. currently, fistula formation remains the most common complication of this technique, which often necessitates re-operation. conflict of interest none declared. references 1. baskin ls. hypospadias and urethral development. j urol. 2000;163:951-6. 2. retik ab, borer jg. hypospadias. in: walsh pc, retik ab, vaughan ed, et al., eds. campbell’s urology. vol 3. 8 ed. philadelphia: wb saunders; 2002:2284-333. 3. snodgrass w. tubularized, incised plate urethroplasty for distal hypospadias. j urol. 1994;151:464-5. 4. cheng ey, vemulapalli sn, kropp bp, et al. snodgrass hypospadias repair with vascularized dartos flap: the perfect repair for virgin cases of hypospadias? j urol. 2002;168:1723-6; discussion 6. 5. yang ss, chen sc, hsieh ch, chen yt. reoperative snodgrass procedure. j urol. 2001;166:2342-5. 6. ahmed s, gough dc. buccal mucosal graft for secondary hypospadias repair and urethral replacement. br j urol. 1997;80:328-30. 7. ehrlich rm, alter g. split-thickness skin graft urethroplasty and tunica vaginalis flaps for failed hypospadias repairs. j urol. 1996;155:131-4. 8. snow bw. use of tunica vaginalis to prevent fistulas in hypospadias surgery. j urol. 1986;136:861-3. 9. duckett jw, jr., kaplan gw, woodard jr, devine cj, jr. panel: complications of hypospadias repair. urol clin north am. 1980;7:443-54. 10. furness pd, 3rd, hutcheson j. successful hypospadias repair with ventral based vascular dartos pedicle for urethral coverage. j urol. 2003;169:1825-7; discussion 7. 11. firlit cf. the mucosal collar in hypospadias surgery. j urol. 1987;137:80-2. 12. snow bw, cartwright pc, unger k. tunica vaginalis blanket wrap to prevent urethrocutaneous fistula: an 8-year experience. j urol. 1995;153:472-3. 13. chatterjee us, mandal mk, basu s, das r, majhi t. comparative study of dartos fascia and tunica vaginalis pedicle wrap for the tubularized incised plate in primary hypospadias repair. bju int. 2004;94: 1102-4. transperitoneal laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for treating the patients with staghorn kidney stones: a randomized clinical trial mohammad hossein soltani1, amir hossein kashi1, saman farshid2*, seyyed javad mantegy1, rohollah valizadeh3 purpose: to compare the performance and outcomes of laparoscopic pyelolithotomy (lpl) versus percutaneous nephrolithotomy (pcnl) in the management of staghorn kidney stones. materials and methods: this study was a parallel-group randomized clinical trial study carried out on 68 patients with staghorn stones (one single piece or maximally two-piece stones with large extra renal part) over 18 years referred to labbafinejhad hospital. patients were randomly divided on a ratio of 1:1 into two groups of lpl and pcnl using random allocation software. the primary outcome was the stone free rate, which was evaluated with kub, and ultrasonography. secondary outcomes were duration of surgery, bleeding, fever, post-operative pain, length of hospital stay, and postoperative complications. results: the mean±sd age of patients in pcnl and lpl groups were 48.50 ± 13.33 years and 52.17 ± 15.74 years, respectively (p = .303). lpl was associated with a higher duration of surgery (196.55 ± 26.58 minutes versus 110.88 ± 34.82; p = .001). hemoglobin drop in the pcnl group was higher than the lpl group (2.67 ± 2.61 g/dl versus -0.7912 ± 1.06 g/dl; p=.001). stone free status was observed in 29 (85.3%) patients in the lpl group, which was significantly higher than the pcnl group (22 patients, 64.7%; p =.050). conclusion: the results of this study indicate that lpl offers a higher stone free rate with less bleeding in patients with single particle or limited particles staghorn stones with extrarenal pelvis but is associated with a higher duration of operation. the application of lpl in patients with multiple stones carries a lower achievement and is not encouraged. keywords: calculi; laparoscopy; percutaneous nephrolithotomy; pyelolithotomy; staghorn stone introduction it is estimated that about 2% to 5% of people in the community have urinary tract stones and iran is one of the countries located on the kidney stone belt with a prevalence of 2-3%. (1,2) staghorn stones consist of 4% of all urinary stones in developed countries. regarding severe morbidities associated with this type of stones (10-year mortality of 28% and 36% renal impairment), the treatment should be commenced as soon as possible.(3,4) staghorn stones were reported to be struvite in 49–68% of the cases which has close relation with urease-producing organisms.(5) however, according to more recent studies, staghorn stones composed of calcium phosphate (55%), calcium oxalate (14%), uric acid (21%), and cysteine are increasing in number, which reveals the association between staghorn stones and metabolic disorders.(6) there are several treatment modalities for the management of staghorn stones. percutaneous nephrolithotomy (pcnl) offers stone free rates of 98% for partial 1urology and nephrology research center (unrc), shahid labbafinejad hospital, shahid beheshti university of medical sciences (sbmu), tehran, iran. 2clinical research development unit of imam khomeini hospital, urmia university of medical sciences, urmia, iran. 3student research committee, department of epidemiology, school of public health, iran university of medical sciences, tehran, iran. *correspondence: clinical research development unit of imam khomeini hospital, urmia university of medical sciences, urmia, iran. e mail: farshid.s@umsu.ac.ir received may 2021 & accepted december 2021 staghorn stones and 71% for complete staghorn stones and a complication rate of 4% and has supplanted open surgery for treatment of staghorn stones.(7-10) laparoscopic pyelolithotomy (lpl) is also a suitable option for kidneys with extrarenal pelvis and a single pelvic stone.(11,12) some studies have reported convincing results of lpl for the management of multiple renal stones(13), and stones in kidneys with intrarenal pelvis. (14) however, evidence on the use of lpl for the management of staghorn stones is poor and mostly in the format of limited case series. therefore, this study was designed to investigate the performance of pcnl and lpl in the treatment of partial and complete staghorn stones in a randomized clinical trial. materials and methods study population this study was a parallel-group randomized clinical trial with 1:1 allocation ratio carried out on 68 patients laparoscopic and robotic urology urology journal/vol 19 no. 1/ january-february 2022/ pp. 28-33. [doi: 10.22037/uj.v18i.6831] vol 19 no 1 january-february 2022 138 with staghorn stones with extrarenal pelvis over 18 years who were referred to labbafinejad hospital for treatment modalities. sample size was determined using a presumed stone free rate of 91% for lpl and 64% for pcnl based on the outcomes reported by lee and colleagues. considering a type i error rate of 0.05 and type ii error rate of 0.2, the needed sample size for each group was determined to be 34 patients. random allocation software was used to divide the patients into two groups of laparoscopic pyelolithotomy and pcnl (figure 1). patients were randomized by permuted block randomization in block sizes of four to either of the treatment modalities by pregenerated allocation sequence of the software that was kept in concealed envelopes. inclusion and exclusion criteria inclusion criteria were: american society of anesthesia class i or ii, willingness to participate, complete staghorn stone in imaging, age between 18-65 years, absence of coagulopathy, preoperative hemoglobin equal to or above 10 mg/dl, and absence of urinary tract infection. exclusion criteria were: a need for urgent surgery, sepsis, active bleeding, patient decision to leave the study before the operation, patients with solitary kidneys, anatomical abnormalities of the urinary tract, and history of previous surgery on the same kidney (open surgery or pcnl). patients underwent general anesthesia based on the diagnosis of the anesthesiologist after an initial examination. one hour before surgery, 1 gram intravenous cefazolin was administered to all patients. in the preoperative room, patients were assessed regarding the criteria for inclusion after discussing with them and receiving their acceptance to enroll in the study. patients were then investigated for exclusion criteria and relevant information was recorded. then patients were allocated to either of the interventions by the opening of the concealed envelopes containing the allocation treatment as explained above. the surgeons were blind to the allocation of every next patient and after fulfillment of eligibility criteria, the envelopes were opened. pncl procedure pcnl was done in the standard prone position under fluoroscopic guidance as described previously(7). patients were placed in lithotomy position and a 5f ureteral catheter was inserted by cystoscopy or ureteroscopy. then, the patient was turned into the prone position with careful padding of the pressure points. access was made under fluoroscopy guidance and a 24f wolf nephroscope was used for nephroscopy. stones were disintegrated with a pneumatic lithoclast (ems, switzerland) and fragments were removed by grasper. a second access was established if deemed necessary for better stone clearance. a double pigtail catheter and a nephrostomy tube were inserted at the termination of the operation for all pcnl patients. laparoscopic pyelolithotomy lpl was done in lateral decubitus position using one camera port and three 5mm working trocars in triangular orientation. after medialising colon, the ureter was identified and was pursued to release renal pelvis from surrounding tissues. a horizontal incision was made by cautery on renal pelvis. after releasing the attachments of stone to pelvis and calices, the stone was grasped with forceps and extracted. as the pyelocalyceal system was dilated in most cases, the laparoscopy camera was figure 1. consort flow chart showing the flow of patients through the trial. pcnl vs. lpl for staghorn kidney stonessoltani et al. vol 19 no 1 january-february 2022 29 introduced inside the pyelocalyceal system, and residual stones were searched and extracted. a double pigtail catheter was inserted and pelvis incision was repaired in a separate or running manner using 4-0 vicryl sutures. stones were extracted by endobag through the lower 5 mm trocar site under laparoscopic vision. stone free rate was evaluated by the 1st postoperative day kub. remnants larger than 4 mm were considered clinically significant residual fragments. haemorrhage was defined as postoperative hemoglobin drop more than 2.5gr/dl. postoperative pain severity was evaluated by visual analogue pain score. the primary outcome of interest was the stone free rate. secondary outcomes were duration of surgery (recorded from anesthesia induction up to end of the surgery), bleeding, fever, post-operative pain (quantifying by frequency of narcotic administration in the first postoperative day), length of hospital stay, postoperative hemoglobin drop, prolonged urinary leakage (lasting more than 4 days), and other complications. the ethics of this study was approved by the ethics committee of the urology and nephrology research center of the shahid beheshti university of medical sciences on 20th july 2019 with the following code: ir.sbmu. unrc.rec.1399.003. patients were explained about the study objectives in their own language and their informed consent was obtained. this study is registered in the iranian registry of clinical trials (irct) with the following code: irct20180625040232n5 (https:// en.irct.ir/trial/48258). statistical analysis data were entered into spss and the statistician who analyzed data was not aware of the patient's group allocation. frequency and percentage were used to describe the qualitative variables. the mean and standard deviation for the quantitative variables was reported. student t-test or mann-whitney test were used to compare quantitative variables between the two groups, and chisquare was used to compare qualitative variables. results as indicated previously the study aimed to enroll 68 participants in the two study groups. enrollment began from april the 3rd 2020 and ended on december the 3rd 2020. eighty participants with staghorn stones who were candidates for stone operation were screened to enroll the required number of patients. twelve patients were excluded after primary screening due to the following causes: 5 patients did not accept the probability of open surgery in the laparoscopy group, 4 patients had previous history of surgery in the same side (2 percutaneous nephrolithotomy, 1 open surgery, and 1 laparoscopic pyeloplasty), and surgery was postponed in 3 patients because of failure in preoperative preparation. the comparison of demographic and operative paramepcnl vs. lpl for staghorn kidney stonessoltani et al. figure 2. laparoscopic stag-horn stone extraction. laparoscopic and robotic urology 30 vol 19 no 1 january-february 2022 138 ters in the two studied groups has been provided in table 1. there was no statistically significant difference in the age of patients, their weight, preoperative hemoglobin and creatinine between the studied groups. the mean ± sd age of patients in pcnl and lpl groups was 48.50 ± 13.33 and 52.17 ± 15.74 years, respectively (p = .303). the comparison of demographic and perioperative data of patients in the two study groups has been presented in table 1. the staghorn stone in the lpl group was a single staghorn stone and in a few patients, the stone consisted of two pieces including a main stone bulk and a separate stone apart from the main bulk. we did not include patients with staghorn stones consisting of more than one separate stone in calices. stone free status was observed in 29 (85.3%) patients in the lpl group, which was significantly higher than the pcnl group (22 patients, 64.7%; p =.050). in the pcnl group, 11 patients (32.35%) needed more than one access to achieve stone free status, 4 (36.36%) of these accesses were supracostal. eight (23.52%) patients in the pyelolithotomy group had urinary leakage that lasted more than 4 days after surgery. seven (87.5%) of these patients were managed conservatively by maintaining foley catheter and keeping the abdominal drain for a longer time, however, a patient required salvage pcnl because of an obstructive stone in the ureteropelvic junction. in the pcnl group, 1 (2.94%) patient developed prolonged urinary leakage for more than 4 days that was managed conservatively, 2 (5.88%) patients needed salvage tul after ureteral stent extraction. the drop in the 1st postoperative day hemoglobin relative to preoperative hemoglobin for the pcnl group was 2.67 ± 2.61 g/dl compared to 0.79 ± 1.06 g/dl for the lpl group (p = .001). the mean (iqr) of drop in postoperative creatinine relative to preoperative creatinine for the pcnl group was .03 (-.1/.15) mg/dl versus 0.17 (0/.23) mg/dl for the lpl group (p = .014). residual stone equal to or more than 5 mm according to postoperative kub was noticed in 12 patients in the pcnl group, and 5 patients in the lpl group. in figure 2, a sample of stag-horn stone can be seen. discussion the results of this study indicate a higher stone free rate as the primary outcome of study in patients with complete staghorn stones who underwent lpl. lpl was also associated with less bleeding and need for transfusion but at the cost of a longer operating time and a higher frequency of urinary leakage. despite being the first option for the treatment of large renal stones, pcnl is still associated with complications like massive bleeding and infectious complications including fever and sepsis, and infrequent but serious complications like colon injury.(15) severe bleeding necessitating transfusion has been reported in 16% of pcnl operations for staghorn stones and angioembolization has been resorted to control bleeding in 2% of these cases in one report.(16) besides, postoperative fever was observed in 27% and septic shock in 1.8% of pcnls for staghorn stones in another report.(17) parenchymal laceration and vascular injury in the access tract and torque during nephroscopy are the causes of bleeding in pcnl. the absorption of irrigation fluid bacteria through veins and lymphatics especially in high pressure situations is the main cause of infectious complications and sepsis.(18) lpl is not associated with parenchymal injury or with irrigation and absorption of irrigation fluid. furthermore, the stone is not broken into small parts as with pcnl so that bacteria embedded within stone are released during the operation and hence will theoretically be associated with less infectious complications. this theory has been substantiated in a meta-analysis comparing lpl with pcnl.(19) the comparison of pcnl with lpl in case of nonstaghorn stones has been investigated in a few reports. most such comparative studies performed lpl for pavariable groups p-value pcnl lpl age, years; mean±sd 4 8.5 ± 13.3 52.2 ± 15.7 .03 preoperative hemoglobin, mg/dl; mean±sd 13.7 ± 2.0 13.4 ± 1.7 .65 preoperative creatinine, mg/dl; mean(iqr) 1.36 (1.15-1.47) 1.64 (1.30-1.80) .018 weight, kg; mean±sd 80.6 (67.7-90.0) 74.9 (66.7-82.5) 0.11 surgery duration, minutes; mean (iqr) 110 (90-131) 197 (183-210) < .001 1st postop day hemoglobin, mg/dl; mean±sd 11.0 ± 1.8 12.7 ± 1.9 < .001 1st postop day creatinine, mg/dl; mean±sd 1.33 (1.09-1.47) 1.47 (1.10-1.80) .16 hospitalization days; mean±sd 2.3 ± 1.1 2.4 ± 0.9 .62 postoperative fever; n(%) 9 (27) 8 (23) .78 postoperative pain severe/moderate/mild 24 (70.6) / 10 (29.4) / 0 14 (41.2) / 20 (58.8) / 0 .015 stone free status; n(%) 22 (65) 29 (85) .05 transfusion; n(%) 6 (18) 1 (3) .046 hemorrhage; n(%) 15 (44) 5 (15) .008 prolonged urinary leakage; n(%) 1 (2.94) 8 (23.52) .012 gender; n(%) female 21 (61.8) 18 (52.9) .462 male 13 (38.2) 16 (47.1) clavien-dindo grade of complications; n(%) pcnl group lpl group grade 1 grade 2 grade 3a grade 1 grade 2 grade 3a fever 9 (26.5) 8 (23.5) prolonged extravasation 1(2.9) 8 (23.5) transfusion 6 (17.6) 1(2.9) tul for residual ureteral stones 2 (5.9) salvage pcnl for residual upper ureteral stone 1 (2.9) total 10 6 (17.6) 2 (5.9) 16 (47) 1(2.9) 1(2.9) table 1. comparison of the demographic and perioperative variables between the two study groups. pcnl vs. lpl for staghorn kidney stonessoltani et al. vol 19 no 1 january-february 2022 31 laparoscopic and robotic urology 32 tients with a single pelvic stone or with limited number of stones.(20,21) these studies mainly reported a higher stone free rate in lpl with less bleeding at a cost of higher operation duration and/or hospitalization. the application of lpl for patients with multiple renal stones is more challenging. lee and colleagues reported a higher sfr with less bleeding and postoperative pain but longer operation duration for lpl compared with pcnl for multiple renal stones.(13) we have previously presented the experience of our center with lpl for patients with staghorn stones, patients with intrarenal pelvis, and patients with prior extensive abdominal operations.(14,22,23) up to our best knowledge, only one recent randomized clinical trial has compared pcnl with retoroperitoneal lpl in the case of staghorn stones. in this study, 54 patients in the pcnl group were compared with 51 patients in the lpl group. the results revealed that lpl was associated with higher sfr, less hemoglobin drop, less postoperative fever, less need for ancillary procedures, and better kidney function one year after surgery. however, the surgery duration and its cost were higher in the lpl group.(24) laparoscopic operation for pyelolithotomy can be performed through a transperitoneal or a retroperitoneal approach. the aforementioned randomized clinical trial included performance of lpl through a retroperitoneal route. the comparison of transperitoneal and retroperitoneal routes for pyelolithotomy has only been presented in a small study on 20 patients who underwent robotic pyelolithototmy.(25) the authors reported a higher operation duration and bleeding in case of retroperitoneal operation for robotic pyelolithotomy compared with a transperitoneal route with similar sfrs. in the transperitoneal route, the kidney pelvis is incised on its anterior surface so that when the pelvis is incised, the pelvis area and calices are in front of the surgeon and incision line so that insertion of rigid nephroscope, or laparoscopic camera, or even semi-rigid ureteroscope through the working trocars will allow inspection of the kidney calices for removal of residual fragments as we have commented on earlier.(14) in comparison, in the retroperitoneal route, the incision is made on the posterior surface of kidney and the trocars look to the kidney from its posterior side. therefore, inspection of kidney calices is more difficult considering the angle of entry to kidney pelvis from the posterior surface of body and will usually be possible with use of flexible instruments.(24) perhaps the longer duration of operation and higher amount of bleeding in retroperitoneal pyelolithotomy as reported by d’agostino and colleagues can be explained by the above elaborations. up to our best knowledge, no prior study has compared transperitoneal lpl with pcnl in case of staghorn stones. the results of the current study also confirm a higher sfr with less bleeding and need for transfusion at the expense of a higher likelihood for urinary leakage and a considerably longer operation duration as the operation duration in the lpl group was on average 80% longer than the pcnl group. it is also noteworthy to consider that lpl in the current study was implemented for staghorn stones in kidneys with extrarenal pelvis with a maximum of one separate stone from the main bulk. it is highly likely that the application of lpl for staghorn stones with intrarenal pelvis or in case of multiple separate stone particles will result in a different success or complication profile. at last, it should be noted that this study suffers from the following limitations. this study reports short term follow up for the investigated operations, long term outcomes regarding stone recurrence or the long term effect of this operation in kidney function were not evaluated in this study. this study is a single center study, multicenter studies can provide more convincing results. conclusions the results of the current study disclose that transperitoneal laparoscopic pyelolithotomy compared with pcnl offers a higher stone free rate, with less bleeding and need for transfusion at the expense of a higher likelihood of urinary leakage and longer operation duration. conflicts of interest the authors report no conflicts of interest. references 1. erbagci a, erbagci ab, yilmaz m, et al. pediatric urolithiasis. scand j urol nephrol. 2003;37:129-33. 2. pearle ms, lotan y. urinary lithiasis: etiology, epidemiology, and pathogenesis. campbell-walsh urology. 2007;2:1363-92. 3. koga s, arakaki y, matsuoka m, ohyama c. staghorn calculi—long‐term results of management. bju int. 1991;68:122-4. 4. blandy jp, singh m. the case for a more aggressive approach to staghorn stones. j urol. 1976;115:505-6. 5. heimbach d, jacobs d, müller s, hesse a. chemolitholysis and lithotripsy of infectious urinary stones–an in vitro study. urol int. 2002;69:212-8. 6. parks jh, worcester em, coe fl, evan ap, lingeman je. clinical implications of abundant calcium phosphatein routinely analyzed kidney stones. kidney int. 2004;66:777-85. 7. basiri a, kashi ah, zeinali m, nasiri mr, valipour r, sarhangnejad r. limitations of spinal anesthesia for patient and surgeon during percutaneous nephrolithotomy. urol j. 2018;15:164-7. 8. al-kohlany km, shokeir aa, mosbah a, et al. treatment of complete staghorn stones: a prospective randomized comparison of open surgery versus percutaneous nephrolithotomy. j urol. 2005;173:469-73. 9. chibber pj. percutaneous nephrolithotomy for large and staghorn calculi. j endourol. 1993;7:293-5. 10. basiri a, nouralizadeh a, kashi ah, et al. x-ray free minimally invasive surgery for urolithiasis in pregnancy. urol j. 2016;13:2496-501. 11. chang dt, dretler sp. laparoscopic pyelolithotomy in an ectopic kidney. the journal of urology. 1996;156:1753-. 12. hoenig dm, shalhav al, elbahnasy am, mcdougall em, clayman rv. laparoscopic pyelolithotomy in a pelvic kidney: a case report and review of the literature. jsls: journal of the society of laparoendoscopic pcnl vs. lpl for staghorn kidney stonessoltani et al. vol 19 no 1 january-february 2022 138 surgeons. 1997;1:163. 13. lee jw, cho sy, jeong cw, et al. comparison of surgical outcomes between laparoscopic pyelolithotomy and percutaneous nephrolithotomy in patients with multiple renal stones in various parts of the pelvocalyceal system. j laparoendosc adv surg tech a. 2014;24:634-9. 14. simforoosh n, radfar mh, valipour r, dadpour m, kashi ah. laparoscopic pyelolithotomy for the management of large renal stones with intrarenal pelvis anatomy. urol j. 2020;18:40-4. 15. maghsoudi r, etemadian m, kashi ah, mehravaran k. management of colon perforation during percutaneous nephrolithotomy: 12 years of experience in a referral center. j endourol. 2017;31:1032-6. 16. el-nahas ar, eraky i, shokeir aa, et al. factors affecting stone-free rate and complications of percutaneous nephrolithotomy for treatment of staghorn stone. urology. 2012;79:1236-41. 17. kyriazis i, panagopoulos v, kallidonis p, özsoy m, vasilas m, liatsikos e. complications in percutaneous nephrolithotomy. world j urol. 2015;33:1069-77. 18. kreydin ei, eisner bh. risk factors for sepsis after percutaneous renal stone surgery. nat rev urol. 2013;10:598-605. 19. wang x, li s, liu t, guo y, yang z. laparoscopic pyelolithotomy compared to percutaneous nephrolithotomy as surgical management for large renal pelvic calculi: a meta-analysis. j urol. 2013;190:888-93. 20. al-hunayan a, khalil m, hassabo m, hanafi a, abdul-halim h. management of solitary renal pelvic stone: laparoscopic retroperitoneal pyelolithotomy versus percutaneous nephrolithotomy. j endourol. 2011;25:975-8. 21. li s, liu tz, wang xh, et al. randomized controlled trial comparing retroperitoneal laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for the treatment of large renal pelvic calculi: a pilot study. j endourol. 2014;28:946-50. 22. nouralizadeh a, simforoosh n, soltani mh, et al. laparoscopic transperitoneal pyelolithotomy for management of staghorn renal calculi. j laparoendosc adv surg tech a. 2012;22:61-5. 23. radfar mh, kashi ah. laparoscopic pyelolithotomy for a staghorn stone in a patient with history of cystectomy and ileal conduit. urol j. 2020;17:522-4. 24. xiao y, li q, huang c, wang p, zhang j, fu w. perioperative and long-term results of retroperitoneal laparoscopic pyelolithotomy versus percutaneous nephrolithotomy for staghorn calculi: a single-center randomized controlled trial. world j urol. 2019;37:14417. 25. d'agostino d, corsi p, giampaoli m, et al. mini-invasive robotic assisted pyelolithotomy: comparison between the transperitoneal and retroperitoneal approach. arch ital urol androl. 2019;91. pcnl vs. lpl for staghorn kidney stonessoltani et al. vol 19 no 1 january-february 2022 33 case report 57urology journal vol 5 no 1 winter 2008 paraganglioma of urinary bladder elmar heinrich,1,2 stefan gattenloehner,3 hans konrad mueller-hermelink,3 maurice stephan michel,2 georg schoen1 keywords: paraganglioma, pheochromocytoma, bladder neoplasms, urinary bladder 1department of urology, missionsaerztliche klinik wuerzburg, wuerzburg, germany 2department of urology, university clinic mannheim, mannheim, germany 3department of pathology, university clinic wuerzburg, wuerzburg, germany corresponding author: elmar heinrich, md theodor-kutzer-ufer 1-3, 68135 mannheim, germany tel: +49 621 383 2229 fax: +49 621 383 2184 e-mail: elmar.heinrich@gmx.de received june 2007 accepted september 2007 introduction paraganglioma of the urinary bladder is rarely encountered and its biological behavior is uncertain. it represents less than 1% of the bladder tumors and is usually benign. the tumor usually develops in young adult women.(1) the most prevalent involved sites are discussed controversially in the literature. in a recently published work, lateral and posterior walls of the bladder are described as the most prevalent sites, while in the latest edition of the campbellwalsh urology, the trigones and the posterior wall have been stated as the most common tumor sites for paraganglioma.(2,3) common symptoms and signs are dysuria, hematuria, and hypertension, caused by local irritation of the tumor, and increased catecholamine levels. as many as 50% of the paragangliomas are hereditary and may be associated with familial paraganglioma, neurofibromatosis type 1, von hippellindau disease, and the carney triad.(4) we report a single case of paraganglioma in the urinary bladder primarily diagnosed as myoma. case report a 37-year-old woman presented with frequency and dysuria. physical examination showed no abnormalities. no constitutional symptoms suggesting an endocrine active paraganglioma, such as hypertension, were detected. transabdominal ultrasonography showed a low-echoic mass at the bottom of the bladder. to prove the ultrasonographic diagnosis, conventional cystoscopy was performed and led to the diagnosis of a 2-cm myoma. since infiltration of the muscle layer was ruled out by computed tomography, we decided to perform transurethral resection of the tumor (figure 1). however, during the first transurethral resection, infiltration of the muscle layer was seen and confirmed by urol j. 2008;5:57-9. www.uj.unrc.ir figure 1. computed tomography of the pelvis showed the tumor mass on the right side of the urinary bladder. paraganglioma of urinary bladder—heinrich et al 58 urology journal vol 5 no 1 winter 2008 pathologic examination. the preliminary histological diagnosis of a granular cell tumor led to the decision for a second transurethral resection.(5) despite the high risk of bladder perforation, it was possible to resect the tumor in 2 surgical operations without any residual tumor tissue. endocrinologic examination showed physiologic levels of serum catecholamines. the histopathologic examination showed positive staining for cd56 (figure 2a), synaptophysin (figure 2b), and weekly positive but specific for chromogranin (figure 2c). sustentacular cells stained positive for s100 (figure 2d). the ki67 staining revealed a proliferation index lower than 2%. the patient was discharged without any complaints. computed tomography of the pelvis and the abdomen in the 3-month followup visit did not show any suspected lymph nodes or local recurrence. figure 3. the picture shows the superficial urothelium (right) and the tumor (left; hematoxylin-eosin, × 100). figure 2. immunohistochemical study of the tumor specimen for different stains shows the tumor cells (× 400). brown staining is indicative of a positive result for tumor. a, positive staining for cd56. b, positive staining for synaptophysin c, positive staining for chromogranin. d, typically, between the tumor cells are located the sustentacular cells which are stained positive for s100 protein. paraganglioma of urinary bladder—heinrich et al urology journal vol 5 no 1 winter 2008 59 discussion paragangliomas are extra-adrenal neoplasms of the neural crest derivation, and if hormonally active, they are termed pheochomocytoma. there are at least 20 reported cases of the malignant paraganglioma in the english literature.(6) histologically, they are characterized by cells arranged in discrete nests separated by a prominent sinusoidal network. no defined histological features have been identified to safely distinguish benign from malignant paragangliomas. if the paraganglioma of the bladder is suspected, cystoscopy should only be performed following adrenergic blockade in a controlled environment such as an operating room. biopsy should be avoided.(6) options for treatment include transurethral resection and laparoscopic or open cystectomy (partial or radical) with the aim of complete local excision of the tumor. surgery is planned in a similar fashion as in adrenal pheochromocytomas and includes volume expansion and adrenergic blockade.(7) regarding the disposition of malignant paragangliomas to recur locally and develop metachronous metastasis, lifelong follow-up is indicated. conflict of interest none declared. references 1. yadav r, das ak, kumar r. malignant non-functional paraganglioma of the bladder presenting with azotemia. int urol nephrol. 2007;39:449-51. 2. cheng l, leibovich bc, cheville jc, et al. paraganglioma of the urinary bladder: can biologic potential be predicted? cancer. 2000;88:844-52. 3. messing em. urothelial tumors of the bladder. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2407. 4. young wf jr. paragangliomas: clinical overview. ann n y acad sci. 2006;1073:21-9. 5. kontani k, okaneya t, takezaki t. recurrent granular cell tumour of the bladder in a patient with von recklinghausen’s disease. bju int. 1999;84:871-2. 6. dahm p, gschwend je. malignant non-urothelial neoplasms of the urinary bladder: a review. eur urol. 2003;44:672-81. 7. klingler hc, klingler pj, martin jk jr, smallridge rc, smith sl, hinder ra. pheochromocytoma. urology. 2001;57:1025-32. vol 19 no 1 january-february 2022 138 supine is superior to prone position in treating the distal ureteral calculi during extracorporeal shockwave lithotripsy: an updated meta-analysis haiyan lu,1 jun wang,1* peixuan han,2 weizhen xu3 purpose: although extracorporeal shockwave lithotripsy (swl) has been confirmed to be effective in treating ureteral stone, a definitive conclusion on which patient’s position is the optimal option during swl treatment remains unclear. we, therefore, performed this updated meta-analysis to further clarify it. materials and methods: pubmed, embase, and cochrane library were performed to capture all potentially eligible studies from their inception to october 2020. after screening eligible studies, extracting essential data, and assessing the risk of bias, we used stata 14.0 to complete all statistical analyses. results: we included 7 studies involving 8 cohorts in the final analysis. our meta-analysis suggested that the prone position was inferior to the supine position in terms of stone fragmentation and stone clearance rate after completing the first treatment (95% ci: 0.30-0.63; or = 0.44;), however, subgroup analysis indicated that the difference between supine and prone positions for stone fragmentation and the stone clearance rate was only getting statistical significance for distal ureteral stone (95% ci: 0.23-0.53; or = 0.35). moreover, subgroup analysis of two eligible randomized controlled trials suggested that the mean number of sessions per patient in the supine group was less than that in the prone group (95% ci: 0.11-0.48; wmd = 0.294). no major and severe complication was detected to be done with the association with positions. conclusion: swl of the supine position may be the preferred option because this strategy can increase the distal ureteral stone-free rate compared to the prone position. keywords: lithotripsy; meta-analysis; prone position; shockwave lithotripsy; supine position; ureteral stone introduction there is no optimal strategy for the management of ureteral stone, especially distal ureteral stone so far.(1) although extracorporeal shockwave lithotripsy (swl) and ureteroscopy are all considered as acceptable treatments for ureteral stones, swl is considered the first-line therapeutic option and has been extensively used to treat ureteral stones, especially distal ureteral stones(2,3) because it has several advantages, compared to ureteroscopy, such as characteristics of noninvasive management, ambulatory procedure, and lack of severe undesirable side effects.(4) however, the clinical value of swl is associated with several aspects such as basic characteristics of stones including size, location and specified composition and the type of the lithotripter used.(1) for the purpose of improving the treatment effects of swl, several regimes including sedation, a slow shock wave firing rate, ramping up the voltage, sufficient transmission media for optimal coupling, a wider focal zone, the application of a belt, and adequate pain relief have been developed and introduced.(5) unfortunately, the optimal strategy of ureteral stone especially distal location has not yet been obtained. 1department of urology, the first people's hospital of lanzhou city, lanzhou city, gansu province, china. 2winona state university, winona city, minnsota state, the united states. 3maternal and child health care hospital, lanzhou city, gansu province, china. *correspondence: department of urology, the first people's hospital of lanzhou city, lanzhou city, gansu province, china. tel: 86-13993169748. e-mail: wyr3514828@163.com. #these authors contributed equally to this work. received august 2021 & accepted december 2021 evidence suggested that the position of patients during swl will directly affect the treatment effects of swl because the bony structure of the pelvis will interfere with the effective transmission of the shock waves to the target stone.(6,7) although the pronee position has been widely used for the treatment of distal ureteral stone in order to reduce the negative effect of the pelvis,(8) several drawbacks such as large skin-to-stone distance limits the application of prone position.(9) therefore, modifications to patient positioning during swl have been proposed in order to improve the efficacy of the treatment.(10) as an alternative option, supine position has been introduced previously into clinical practice to address the issues faced by conventional prone position during swl because it can effectively avoid the negative impact of pelvic bone through passing the greater sciatic foramen along the gluteus maximus muscle to deliver the shock waves.(11) to date, several clinical trials have been performed to investigate the comparative efficacy and safety of conventional prone position and modified supine position during swl for the treatment of ureteral calculi and found that swl via the supine position is more effective and safer than that via the prone position. moreover, a review urology journal/vol 19 no. 1/ january-february 2022/ pp. 9-16. [doi: 10.22037/uj.v19i.6946] previous meta-analysis(12) also suggested that supine swl is more effective than prone swl for achieving a stone-free status. however, there are limited studies providing a high level of evidence. so, a definitive conclusion about the optimal position during swl remains conflicting. moreover, previous meta-analysis simultaneously incorporated studies with different designs into individual analysis which will cause to estimate biased results because of bias resulting from studies with different designs can not be eliminated, supine versus prone position for uc-lu et al. study, year country design location of stone sizea, mm; sample size age, year; ureteral stone mean ± sd (range) mean ± sd (range) prone supine prone supine prone supine choo, 2018 korea rct distal 6.73 ± 1.67 6.40 ± 1.54 75 73 44.95 ± 11.5 44.5 ± 12.2 göktaş, 2000 turkey rct proximal 7.85 ± 0.94 8.10 ± 0.83 48 48 na na kamel, 2015 egypt rct distal 8.4 ± 0.65 8.6 ± 0.5 49 49 47.6 ± 3.5 44.3 ± 4.3 hara, 2006a japan rsc both 7.3 (3-11) 9.1 (3-28) 110 248 na na hara, 2006b japan rsc both 7.7 (3-18) 9.1 (3-24) 98 156 na na istanbulluoglu, 2011 turkey rsc distal 61.32 (16-204)a 59.04 (10-238)a 194 148 41.12 (2-81) 50.16 (10-84) phipps, 2013 uk rsc distal 7.9 ± 0.4 7.6 ± 0.3 38 72 48.3 ± 2.2 51.3 ± 1.8 zomorrodi, 2007 iran rsc proximal 13.6 12.8 35 33 43.6 46 table 1. basic characteristics of 7 included studies abbreviations: rct, randomized controlled trial; rsc, retrospective cohort; athe unit of number is mm2; na, not available. figure 1. flow diagram of identification and screening of eligible studies. other sources are defined as reference lists of included studies. review 10 vol 19 no 1 january-february 2022 138 which greatly comprises the robustness and reliability of findings. we, therefore, performed this updated systematic review and meta-analysis to further determine the comparative efficacy of swl for treating ureteral stone including distal and proximal location performed in the supine related to the prone position. materials and methods we developed the framework of the current systematic review and meta-analysis according to the recommendations issued by the cochrane collaboration(13) for the purpose of ensuring the methodological quality because we did not register formal protocol. moreover, all results were reported based on the framework recommended by the preferred reporting items for systematic reviews and meta-analyses (prisma) statement.(14) we did not impose ethical approval and patients’ informed consent because all essential data in the current systematic review and meta-analysis was extracted from published studies. eligibility criteria we mainly designed our selection criteria according to the previous meta-analysis.(12) the inclusion criteria were as follows: (a) adult patients who underwent lithotripsy for ureteral stone; (b) trials investigating the comparative efficacy and safety of supine swl with prone swl for treating ureteral stone; and (c) studies that discuss at least one of the following outcomes including stone-free rate after the first and the final swl session and the mean number of swl sessions per patient. studies were excluded if they met the following criteria: (a) a preliminary study group and another updated study with comprehensive information has been reported by the same study, (b) studies without sufficient information, and (c) reviews, editorials, letters, case reports, conference abstracts, and cell and animal studies. no ethical consent was required because this study was prepared on the basis of previous data. information sources and search strategy according to the recommendation proposed by the study, year type of sedation rate of shocks mean no. of shock wavesa mean powera, % prone supine prone supine choo, 2018 general or regional anesthesia 90 pulses/min, with a maximum na na na na of 4000 shock waves/session göktaş, 2000 no analgesics or anesthetics na 4863.54 ± 2114.85 3704.16 ± 1726.75 na na kamel, 2015 sedoanalgesia maximum of 4000 shocks/session 3667±187 3634 ± 156 78.7 ± 3.1 75.6 ± 2.9 hara, 2006a diclofenac sodium or intramuscular pentazocine 3000 waves shocks/session na na na na hara, 2006b na na na na istanbulluoglu, 2011 midazolam and fentanyl na 3960 (1940-7000) 2953 (1250-5500) na na phipps, 2013 oral/rectal diclofenac na 3997.9 ± 225 5043.2 ± 154.7 71.4 ± 1.9 70.7 ± 1.6 zomorrodi, 2007 na na 3148.5 ± 621.0 3066.1 ± 346.3 na na table 2. parameters of eswl adata are presented as mean ± sd (range). eswl, extracorporeal shock wave lithotripsy; na, not applicable. figure 2. forest plot of stone-free rate after the first session. or, odds ratio. the black horizontal line and diamond presents 95% confidence interval (ci) of individual study respectively, and grey square represents weight of each study. moreover, the blue diamond refers to pooled estimate. supine versus prone position for uc-lu et al. vol 19 no 1 january-february 2022 11 cochrane handbook, a systematic search was conducted in three electronic databases including pubmed, embase and the cochrane library in order to identify relevant studies. the time of search was limited from their inception until to october 2020. we used medical subject heading (mesh) of ‘lithotripsy’, ‘ureteral’, ‘prone position’ and ‘supine position’ as well as relevant keywords to develop the search strategy, and modification was made according to the unique requirements of each database. we only considered studies figure 3. subgroup analysis of stone-free rate after the first session. or, odds ratio; rct, randomized controlled trial. the black horizontal line and diamond presents 95% confidence interval (ci) of individual study respectively, and grey square represents weight of each study. moreover, the blue diamond refers to pooled estimate. figure 4. forest plot of the number of sessions. or, odds ratio. the black horizontal line and diamond presents 95% confidence interval (ci) of individual study respectively, and grey square represents weight of each study. moreover, the blue diamond refers to pooled estimate. supine versus prone position for uc-lu et al. review 12 vol 19 no 1 january-february 2022 138 published in the english language for inclusion because no translator who has expertise in other languages was enrolled. meanwhile, we also manually the references list of all included studies and topic-related reviews to help identify any potential studies. any disagreements about identification of studies were resolved by discussion or consulting a third senior reviewer. study selection two independent investigators selected eligible studies according to our selection criteria. we firstly removed duplicate studies based on literature management software. then, we excluded ineligible studies through screening titles and abstracts of unique studies. finally, we retrieved the full-texts of the remaining studies to check their eligibility for inclusion. data collection two investigators independently extracted the following items using the pre-designed data extraction sheet: basic characteristics of the study including first author, publication year, and country, patients’ characteristics including sample size, the number and age of the patients, location of the ureteral stone, and stone size, and clinical characteristics of study including outcomes, and sources of risk of bias. stone-free rate after the first swl treatment session was included as the primary outcome, and the mean number of swl sessions per patient was regarded as the secondary outcome. stonefree status was defined as having either no or only clinically insignificant residual stone fragments (< 3 mm), evaluated by kidney-ureter-bladder radiography or ultrasonography performed at the third month or longer after the last swl session.(12) if an included study was designed to have more than two groups, then the methods recommended by the cochrane handbook for systematic reviews of interventions were used to divide the individual study into two unique rcts or combine groups to create a single pair-wise comparison.(15) if essential information was missed from the original study, then the leading author was contacted for additional information. any inconsistencies in data extraction were solved based on the consensus principle. quality of the evidence at the end of our research, a total of 8 cohorts of patients from 7 studies entered our analysis. level of evidence of all articles was assessed independently by two authors according to the cochrane handbook(16) and modified the newcastle-ottawa quality assessment scale. (17) in cochrane risk of bias assessment tool, the quality of all eligible studies was assessed from the following six domains: random sequence, allocation concealment, blinding, incomplete data, selective reporting, and other sources. in the modified newcastle-ottawa scale, a score of 1-9 stars were assigned to all controlled studies. discrepancy in the assessment were resolved through discussion until a consensus was achieved. statistical analysis all of the analyses were performed using stata se 14.0 software (statacorp, college station, texas, usa). the number of stone-free patients after the first session and the average number of treatment sessions under each position was extracted. dichotomous data and continuous data were expressed as odds ratio (or) and weighted mean difference (wmd) with 95% confidence interval (ci), respectively. statistical heterogeneity among these studies was qualitatively assessed using cochran’s q and estimated quantitatively using i2 statistic (> 50%, and p < .1, high heterogeneity).(18) considered the potential heterogeneity from variabilities of study region and patients, we adopted random-effect model in all of the combined effects to avoid the overestimation of the pooled results.(19) moreover, we also performed subgroup analysis of stone-free after figure 5. subgroup analysis of the number of sessions. or, odds ratio; rct, randomized controlled trial. the black horizontal line and diamond presents 95% confidence interval (ci) of individual study respectively, and grey square represents weight of each study. moreover, the blue diamond refers to pooled estimate. supine versus prone position for uc-lu et al. vol 19 no 1 january-february 2022 13 the first session and number of sessions based on location of ureteral stone and type of study design. we didn’t assess possible publication bias by funnel plots and egger’s test due to the number of studies included in each quantitative analysis was less than 10, in which case the funnel plots and egger’s test could yield misleading results.(20,21) results search results a total of 114 studies were identified at the initial search stage for pubmed, embase, and cochrane library. we excluded 13 duplicate studies with the endnote software. a total of 32 studies were retained after excluding 69 ineligible studies through verifying the title and abstract. we included 7 eligible studies for the final analysis after excluding 25 ineligible studies as the following reasons through full-text check: ineligible aim or study design (n = 4), ineligible participants (n = 2), ineligible intervention regime (n = 8), not accessible (n = 2), and ineligible language (n = 9). the process of searching and screening literature was shown in figure 1. basic characteristics of all included studies a total of 7 eligible studies involving 8 cohorts were enrolled finally. of 7 studies, three were randomized controlled trial(9,22,23) and four were retrospective cohort.(6,8,24,25) these studies were undertaken in korea,(22) turkey,(23,24) egypt,(9) japan,(6) uk,(8) and iran,(25) respectively. the publication year of all included studies were between 2006 and 2018. the sample size of individual eligible study was between 68 and 358, with the total sample size of 1474. of these 7 eligible studies, one study(6) was divided into two unique cohorts. four studies(8,9,22,24) focused on distal ureteral stone, two(23,25) focused on proximal ureteral stone, and one(6) focused on both ureteral stone. we documented the basic characteristics of all 7 studies were in table 1. meanwhile, parameters of eswl and characteristics of stone were summarized in table 2. quality of all included studies among the three randomized controlled trials, only one study(22) was grated as low risk of bias in random sequence generation and allocation concealment, all were high risk of bias in blinding of participants and personnel and low risk of bias in incomplete outcome data, selective reporting, and other bias. among four retrospective cohorts,(6,8,24,25) the total quality score of individual study was all more than 7. we summarized the results of appraising quality of all included studies in table s1. stone-free rate after the first session seven studies(6,8,9,22-25) involving 8 cohorts reported stone-free rate for swl in the supine and prone positions after the first swl session. heterogeneity in pooled analysis was not significant (p = .21; i2 = 27%). based on a meta-analysis of data from these 8 cohorts, the stone-free rate in the prone group was significantly lower than that in the supine group (95% ci: 0.300.63; or = 0.44; figure 2), and the sensitivity analysis through omitting individual study with one by one further confirmed the robustness of pooled result (figure s1). subgroup analysis based on location of stone indicated that the difference between supine and prone positions was only statistical significance in distal ureteral stone (95% ci: 0.23-0.53; or = 0.35; figure 3a). subgroup analysis based on study design including randomized controlled trial (95% ci: 0.25-0.71; or = 0.42; figure 3b) and retrospective cohort (95% ci: 0.26-0.81; or = 0.46; figure 3b) further confirmed the difference between supine and prone positions. number of sessions per patient among 7 eligible studies, four(22-25) reported the number of sessions per patient. meta-analysis suggested no statistical difference (95% ci: -0.03-0.31; wmd = 0.14; figure 4) between prone and supine positions during swl, which was further confirmed by sensitivity analysis through omitting individual study with one by one (figure s2). subgroup analysis depending on the location of the stone (figure 5a) obtained consistent pooled results with overall pooled result. however, subgroup analysis based on study design found that the mean number of sessions per patient in the supine group was lower than that in the prone group when calculated pooled estimates bwas ased on two eligible randomized controlled trials (95% ci: 0.11-0.48; wmd = 0.294; figure 5b). complications during treatment of seven included studies, five studies reported complications during swl treatment. istanbulluoglu and colleagues reported that patients experienced petechiae with various degrees and early hematuria.(24) göktas and colleagues reported that patients in the prone position experienced discomfort on inspiration and expiration and pain localized to the lumbar vertebrae.(23) however, no serious complications were reported by phipps et al.,(8) kamel et al. ,(9) and choo et al.(22) we could not quantitatively estimate the pooled effects about complications because data were not suitable for meta-analysis. however, most importantly, available evidence suggested that no major or severe complications were observed in any of these trials. discussion to date, the optimal strategy of ureteral stone is not still unclear, especially for distal ureteral stone.(26) whereas, swl and ureteroscopy were considered as the acceptable therapeutic methods for distal ureteral stones by both the american urological association (aua) and european association of urology (eau) guidelines. (27,28) however, compared to ureteroscopy, extracorporeal shockwave lithotripsy has been extensively used to treat distal ureteral stones as first-line treatment due to several advantages such as minimal invasion and lack of major or severe undesirable side effects.(4) to date, however, the optimal strategy of swl has not yet been obtained despite several advances in technology.(29) considering the fact that the efficiency of transmission of shockwave during swl is deeply associated with bony structure of pelvis, modifications of patient’s position during swl treatment was introduced, and then several studies have also investigated the impact of various patient’s positions on the efficiency of swl.(6,8,2325) meanwhile, one meta-analysis has also further investigated the comparative efficacy and safety between supine and prone positions during swl, and initially suggested that supine swl is more effective than prone swl for achieving a stone-free status.(12) nevertheless, a definitive conclusion has not yet been generated. after completing the current updated systematic review and meta-analysis, we found that the supine position was made in association with increased the stone-free distal ureter in nu-morriss et al.supine versus prone position for uc-lu et al. review 14 vol 19 no 1 january-february 2022 15 rate compared to prone position, which was also confirmed by sensitivity analysis and subgroup analysis based on study design. moreover, subgroup analysis based on location of ureteral stone further suggested that supine position during swl significantly increased the distal ureteral stone-free rate. although we did not find significant difference between supine and prone positions in terms of the number of sessions per patient when we incorporated all studies with various designs into individual analysis, subgroup results based on two randomized controlled trials indicated that supine position may be associated with decreased number of sessions compared to prone position during swl treatment. however, urologists must firstly identify whether swl should be adopted through comprehensively evaluating several factors such as stone size, stone location, patient medical status, patient age, and body mass index. to date, only one meta-analysis(12) focused on comparative efficacy and safety between supine and prone positions during swl has been published, and concluded a superior comparison of supine position compared to prone position from the stone-free rate after treatment. it must be pointed out that, however, the conclusion was generated from pooled estimate based on 4 clinical studies, of which 3 studies were retrospective design. moreover, the previous meta-analysis only focused on patients with distal ureteral stone although our present study found that the supine position only associated with increased distal ureteral stone-free rate after performing subgroup analysis. compared to the previous meta-analysis, our meta-analysis obtained more reliable and robust pooled results because our study has major two advantages including more eligible studies and detailed clarification of ureteral stone. we also must acknowledge some limitations in our systematic review and meta-analysis. firstly, we included the observational study in our analysis simultaneously owing to the paucity number of rcts in the specific topic. however, we performed subgroup analysis being dependent on the study design to further test the robustness of all pooled results. secondly, we failed to quantitatively obtain the pooled estimate of the safety profile of each position since only one study has reported numerical data.(22) thirdly, the stone free rate in the included studies was evaluated by the plain x-ray of kidney, ureter, and bladder (kub) and/or ultrasonography (us), however those both are inefficient for detection of ureteral stones. fourthly, we did not perform subgroup analysis to further explore the impact of several important features including stone composition and density and radiographic characteristics on pooled results due to limited data. fifthly, another one limitation with the present systematic review was the language restriction and that only three major databases were searched and therefore, relevant studies may have been missed. conclusions our study further confirmed the supine approach is superior in stone fragmentation and clearance than prone approach. stone-free rate of the supine position after the first treatment session is significantly higher compared to prone position for patients who underwent swl. however, research that compared the safety profile of each position is still destitute. future research can focus on the long-term benefit and patients report outcomes regarding the safety of supine and prone position. conflict of interest the authors declare that the submitted work was conducted with no conflict of interest. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/35 references 1. tiselius hg, chaussy cg. aspects on how extracorporeal shockwave lithotripsy should be carried out in order to be maximally effective. urol res. 2012;40:433-46. 2. assimos d, krambeck a, miller nl, et al. surgical management of stones: american urological association/endourological society guideline, part i. j urol. 2016;196:1153-60. 3. tzelves l, türk c, skolarikos a. european association of urology urolithiasis guidelines: where are we going? eur urol focus. 2020. 4. segura jw, preminger gm, assimos dg, et al. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. the american urological association. j urol. 1997;158:1915-21. 5. semins mj, matlaga br. strategies to optimize shock wave lithotripsy outcome: patient selection and treatment parameters. world j nephrol. 2015;4:230-4. 6. hara n, koike h, bilim v, takahashi k, nishiyama t. efficacy of extracorporeal shockwave lithotripsy with patients rotated supine or rotated prone for treating ureteral stones: a case-control study. j endourol. 2006;20:170-4. 7. jenkins ad, gillenwater jy. extracorporeal shock wave lithotripsy in the prone position: treatment of stones in the distal ureter or anomalous kidney. j urol. 1988;139:911-5. 8. phipps s, stephenson c, tolley d. extracorporeal shockwave lithotripsy to distal ureteric stones: the transgluteal approach significantly increases stone-free rates. bju int. 2013;112:e129-33. 9. kamel m, salem ea, maarouf a, abdalla m, ragab a, shahin am. supine transgluteal vs prone position in extracorporeal shock wave lithotripsy of distal ureteric stones. urology. 2015;85:51-4. 10. köse ac, demirbas m. the 'modified prone position': a new approach for treating prevesical stones with extracorporeal shock wave lithotripsy. bju int. 2004;93:369-73. 11. galli r, sighinolfi mc, micali s, et al. advantages of the supine transgluteal approach for distal ureteral stone extracorporeal shock wave lithotripsy: outcomes based on ct characteristics. minerva urol nefrol. 2017;69:189-94. 12. li t, gao l, chen p, et al. supine versus prone position during extracorporeal shockwave lithotripsy for treating distal ureteral calculi: a systematic review and supine versus prone position for uc-lu et al. meta-analysis. urol int. 2016;97:1-7. 13. higgins jpt, thomas j, chandler j, et al. cochrane handbook for systematic reviews of interventions version 6.0 (updated july 2019). cochrane, 2019. available from www. training.cochrane.org/handbook. 14. moher d, liberati a, tetzlaff j, altman dg. preferred reporting items for systematic reviews and meta-analyses: the prisma statement. j clin epidemiol. 2009;62:100612. 15. higgins jpt, green s. cochrane handbook for systematic reviews of interventions version 5.1.0 [updated march 2011]. the cochrane collaboration, 2011. available from www. handbook.cochrane.org. 16. higgins jp, altman dg, gotzsche pc, 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to treat distal ureter stones: a prospective, randomized, and multicenter study. world j urol. 2018;36:1299-306. 23. göktaş s, peşkircioğlu l, tahmaz l, kibar y, erduran d, harmankaya c. is there significance of the choice of prone versus supine position in the treatment of proximal ureter stones with extracorporeal shock wave lithotripsy? eur urol. 2000;38:618-20. 24. istanbulluoglu mo, hoscan mb, tekin mi, cicek t, ozturk b, ozkardes h. shock wave lithotripsy for distal ureteric stones: supine or prone. urol res. 2011;39:177-80. 25. zomorrodi a, elahian a, ghorbani n, tavoosi a. comparison of the effect of body position, prone or supine, on the result of extracorpreal shock wave lithotripsy in patients with stones in the proximal ureter. saudi j kidney dis transpl. 2007;18:200-5. 26. tiselius hg, ackermann d, alken p, buck c, conort p, gallucci m. guidelines on urolithiasis. eur urol. 2001;40:362-71. 27. rose vl. american urological association recommends observation for the majority of cases of ureteral calculi. am fam physician. 1998;57:862, 7-8. 28. ng cf, tolley d. lithotripsy for ureteric stones: throw away the ureteroscope. bju int. 2003;92:1045-6. 29. lu j, sun x, he l. sciaticum majus foramen and sciaticum minus foramen as the path of swl in the supine position to treat distal ureteral stone. urol res. 2010;38:417-20. . supine versus prone position for uc-lu et al. review 16 laparoscopic and robotic urology modified mini-laparoscopic surgery optimized the laparoscopic decortication of renal cyst wei chen*, zhi-bing xu, lei xu, chen cang, jian-ming guo* purpose: this study was to introduce the modified mini-laparoscopic surgery for renal cyst and investigate its advantages on operative time, cosmetic effect and pain reduction by comparison with laparo-endoscopic single site surgery (less) and conventional laparoscopic surgery. methods and patients: between may 2015 and october 2018, 140 consecutive patients with benign renal cyst underwent laparoscopic decortication of renal cyst. of which, 48 cases were in mini-laparoscopic surgery group (m group), 56 cases in less group and 36 cases in conventional laparoscopic surgery group (c group). the operative time, blood loss, visual analog scale (vas) and scar cosmesis assessment and rating (scar) scale was recorded. results: the mean operative time in m group (26.08±7.70 min) and c group (28.56 ± 7.99 min). was significantly less than that in less group (47.32 ±10.53 min) (p < 0.01). mean blood loss did not differ between the 3 groups (p > 0.05). mean vas pain scores in m group were significantly lower than that of less group and c group on postoperative day (pod) 1 and 3 (p < 0.01). the scar scale of pod 30 in c group (6.25 ± 1.0) was significantly higher than that in m group (0.77 ± 0.59) and less group (0.98 ± 0.70). the postoperative course was uneventful with no morbidity within 1to 6 months of follow-up. conclusion: modified mini-laparoscopic decortication of renal cyst have more comprehensive advantages comparing with less and conventional laparoscopic surgery. it is convenient and offered significant cosmetic benefit and reduced incisional pain. keywords: laparo-endoscopic single site surgery; decortication of renal cyst; mini-laparoscopic surgery; laparoscopic surgery; renal cyst; cosmesis introduction renal cysts prevalence varies in the adult population between 20% and 50%, the vast majority of them being asymptomatic and undergoing regular surveillance (1). treatment of simple renal cysts is recommended when they are associated with flank pain, infection, obstruction of the pyelocaliceal system and hydronephrosis. the surgical decortication was the recommended strategy(2). conventional laparoscopic decortication with three-port incisions tend to make three permanent scars. to resolve this problem, some doctors perform decortication of renal cyst with less. the introduction of less has offered cosmetic benefit to patients. it is a scar-free procedure with reduced surgical wound complications(3-6). but in the same time, surgeons must manipulate multiple instruments through one small incision. it is time consuming and difficult for the operators(7,8). it is an important question how to quickly and easily perform a scar-free operation. here, we describe modified mini-laparoscopic decortication for renal cyst. this technique is a modification of mini-laparoscopic surgery in order to overcome the disadvantages of the urology department of zhongshan hospital, fudan university. *correspondence: department of urology, zhongshan hospital, fudan university, shanghai, 200032, china. tel: (86) 2164041990-2906 e-mail: chen.wei3@zs-hospital.sh.cn *department of urology, zhongshan hospital, fudan university, shanghai, 200032, china. tel: (86) 2164041990-2906 e-mail: guo.jianming@zs-hospital.sh.cn. received january 2019 & accepted april 2019 less and previous mini-laparoscopic surgery. patients and methods to simplify the scar free operation for renal cyst, we describe modified mini-laparoscopic decortication for renal cyst. this technique can conveniently perform decortication by using 2 very fine (3-mm) mini-laparoscopic instruments through abdominal wall and a 5 mm ultrasonic dissector through umbilicus. it was expected to promote the cutting speed and hemostatic effect and simplify the extraction of specimen without any visible scar. in the study, we demonstrated the advantages of the modified mini-laparoscopic decortication on operative time, cosmetic satisfaction and the postoperative pain reduction by comparing the surgical results of mini-laparoscopic decortication with those of less and conventional laparoscopic decortication. we performed a retrospective analysis of data from consecutive patients who underwent decortication of renal cyst with modified mini-laparoscopic surgery, less or conventional laparoscopic surgery in zhongshan hospital, fudan university, between may 2015 and august 2018. the patients underwent a contrast-enhanced abdominal and pelvic computer tomography (ct) to diagnose simurology journal/vol 16 no. 6/ november-december2019/ pp. 547-551. [doi: 10.22037/uj.v0i0.5029] ple cyst and exclude the parapelvic cysts, calyceal diverticula and bilateral or multiple cyst. all of the case were diagnosed with bosniak category i large renal cyst with backache. the difference between the mini-laparoscopic surgery, less and conventional laparoscopic surgery were clearly explained to all the patients. all the decision of surgery type was made by patients and operations were performed by same surgeon group. the ethics committee approved the study. a total 140 consecutive cases of decortication were performed during the study period. 48 cases were in mini-laparoscopic surgery group (m group), 56 cases in less group and 36 cases in conventional laparoscopic decortication group (c group). demographic and operative data in the three groups were assessed (table 1 and table 2). the anesthesiologist recorded the operative time. it was the time frame between the skin incision and the entirely closure of the last incision. on pod 1, 3 and 5, the visual analog scale (vas) was used to evaluate incisional pain objectively. the scar cosmesis assessment and rating (scar) scale (9,10) was used to evaluate incisional cosmesis on pod 30. surgical technique all of the cases were successfully treated through transperitoneal approach without conversion to open surgery. after the induction of general anesthesia, the patient was rotated in 75o lateral decubitus, without the surgical table angle. the video cart was placed in back of the patient. in m group, a small transverse skin incision at the umbilicus was first made for a 5mm trocar. through a needle hole that made by a 14g syringe needle, a 3-mm trocar (storz, germany) for the mini-laparoscope (camera) (storz, germany)on the affected side of the abdomen were placed at the level of umbilicus on the midclavicular line (figure 1.a). another 3-mm trocar for mini-laparoscopic grasper (storz, germany) were placed on the abdomen near the surface projections of renal cyst (figure 1.b). the mini-laparoscopic grasper in left hand lifted up the posterior peritoneum and gerota fascia. an ultrasonic dissector in right hand was then placed into the 5-mm trocar at the umbilicus to incise the posterior peritoneum and gerota fascia. so, the surrounding tissue could be dissected and the cyst was easily incised (figure 1.c). for the cysts on the very top of right kidney, the operative area may be covered by liver margin. the fourth 3 mm trocar near the surface projections of renal cyst would be necessary. we inserted another mini-laparoscopic grasper through the fourth trocar to hold the gerota fascia on surface of the cyst and then the liver margin and gerota fascia can be lifted. specimen was extracted through 5-mm trocar and no drainage was placed. the small incision and the two needle holes require no stitch. in the less group, 20 mm of the skin incision at the umbilicus was also first made. single-port-access device (tri-port, olympus, japan) was placed through the umbilicus. a 5-mm flexible laparoscope (olympus, japan), a grasper and an ultrasonically activated scalpel were then positioned in this single-port-access device (figure 1.d). the remaining procedure was the same as that of the m group. but, the incision should be closed after the specimen extraction. in c group, a 10 mm trocar for laparoscope on the affected side of the abdomen were placed at the level of umbilicus on the midclavicular line. a 5-mm trocar for grasper was placed under rib arch on the midclavicular line. another 5-mm trocar for ultrasonic dissector was placed near mc burney’s point on the right side and the mirror position on the left side. the other procedure was the same as m group. the three incision should also be closed after the specimen extraction. for the cysts at the very top of the kidney, another 5 mm trocar modified mini-laparoscopic decortication of renal cyst-chen et al. table 1. patient demographics. needlescopic decortication less decortication conventional laparoscopic decortication age(years) 49.2 ± 15.7 43.6 ± 12.6 52.3 ± 17.2 sex(male/female) 21/27 31/25 19/17 cyst location(left/right) 19/29 34/22 15/21 cyst location (upper pole) 11 13 8 cyst location (middle) 21 20 18 cyst location( lower pole) 16 23 10 cyst diameter (mm) 65.6 ± 12.0 61± 16.4 67.7± 8.7 bmi 23.2 ± 4.2 24.5± 3.7 22.0± 5.5 patient characteristics in the three groups were comparable at baseline abbreviations: bmi, body mass index mini-laparoscopic less conventional laparoscopic p value mean operative time (min) 26.08 ± 7.70 47.32 ± 10.53* 28.56±7.99 .000 mean estimated blood loss (ml) 4.06 ± 3.49 5.45 ± 3.72 5.67 ± 4.40 .099 mean vas scores pod 1 1.79 ± 0.82* 2.41 ± 0.80* 3.03 ± 1.06* .000 pod 3 1.02 ± 0.51* 2.1 ± 0.86 2.17 ± 0.81 .000 pod 5 0.56 ± 0.50 0.71 ± 0.6 0.78 ± 0.54 .188 scar scores pod 30 0.77 ± 0.59 0.98 ± 0.70 6.25 ± 1* .000 the number that labeled with " * " means the parameter in the group was significantly different with that in other 2 groups. abbreviations: pod, postoperative day table 2. postoperative outcome of 3 groups. laparoscopic and robotic urology 548 was used to lift the liver. statistical analysis spss 19.0 for windows was used for statistical analysis. comparisons between the 3 operative approaches were performed with the one way analysis of variance（anova) and post hoc analysis (s-n-k). all statistical tests were 2-sided, with p < 0.05 indicating statistical significance. results patient characteristics in the three groups were comparable at baseline (table 1). there were no intraoperative complications or technique conversions at the time of surgery. all of the cases were successfully treated through transperitoneal approach without conversion to open surgery. for 2 cases in c group and 3 cases in m group a 4th trocar was used to lift the liver because of the very top location on upper pole of right kidneys. the postoperative outcomes of the 3 groups were indicated in table 2. the results show that the mini-laparoscopic procedure and conventional laparoscopic surgery required significantly less operating time than the less (26.08 ± 7.70 min vs. 28.56 ± 7.99 min vs.47.32 ±10.53 min, p < 0 .01). the blood lost was similar in the 3 groups (m group :4.06 ± 3.49 ml, less group: 5.45 ± 3.72 ml, c group 5.67 ± 4.40 ml, p > 0.05) (figure 2.b). the vas pain score in m group (1.79 ± 0.82) was significantly lower than that in less group (2.41 ± 0.80) and c group (3.03±1.06) on pod 1 ( p < 0.01) (figure 2.c). on pod 3, the difference was still significant (1.02±0.51 vs. 2.1 ± 0.86 vs. 2.17 ± 0.81, p < 0.01). on pod 5, the vas pain score have no difference in the 3 groups (0.56 ± 0.50 vs. 0.71 ± 0.6 vs. 0.78 ± 0.54, p > 0.05). five patients in c group used analgesics for one time. the scar scale in m group (0.77 ± 0.59) and less group (0.98 ± 0.70) was significantly better than that of c group (6.25 ± 1.0, p < 0.01) on pod 30 (figure 2.d). both of the two groups got satisfactory cosmetic results. but the scar scale in c group was still higher than m group and less group on that time. immediately after operation, only minimal wounds appeared on the patients' skin in m group and the small wounds in umbilicus was hidden. (figure 3.a). but the wounds were obvious in less group (figure 3.b) and c group (figure 3.c). the postoperative course was uneventful figure 1. the surgical technique of minilaparoscopic surgery and less. (a) through a needle hole that made by a 14g syringe needle, a 3-mm trocar for the mini-laparoscope on the affected side of the abdomen were placed at the level of umbilicus on the midclavicular line. (b) another 3-mm trocar for mini-laparoscopic grasper were placed on the abdomen near the surface projections of renal cyst. (c) with the help by 3mm grasper in left hand, an ultrasonic scalpel in right hand was then placed into the 5-mm trocar at the umbilicus to incise the posterior peritoneum and gerota fascia. (d) in less, a single-port-access device was placed through the umbilicus. a 5-mm flexible laparoscope, a grasper and an ultrasonic scalpel were then positioned in this single-port-access device. figure 2. postoperative outcome in m group, less group and c group. (a, top left) the results shown that the mini-laparoscopic procedure and conventional surgery required significantly less operating time than the less. (b, top right) the blood lost was similar in the 3 groups. (c, bottom left) on pod 1, the vas pain score in m group was significantly lower than that in less group and c group. (d, bottom right) the scar scale in m group and less group was significantly better than that of c group on pod 30. there was no significant difference between m group and less group in scar scale. figure 3. immediately after operation, wounds (arrow mark) appeared on the patients' skin in the 3 groups. (a, left) minimal wounds on the patients' skin in m group. the small wounds in umbilicus was hidden. (b, middle) wound on the patients' skin in less group. (c, right) obvious wounds on the patients' skin in c group. modified mini-laparoscopic decortication of renal cyst-chen et al. vol 16 no 06 november-december2019 549 with no morbidity within 1to 6 months of follow-up. discussion renal cyst is a common and frequently-occurring disease in adult. the percutaneous approach for renal cyst has shown lower success rates in comparison with the laparoscopic approach and currently it is not widely used. laparoscopic decortication of renal cyst has been considered the gold standard for the treatment of renal cyst. though it is easy to operate, conventional laparoscopic decortication always leads to scars. compared with conventional laparoscopic surgery, both of less and mini-laparoscopic surgery can perform the scar-less operations and each of them has its own advantages and disadvantages. less uses only single incision in the umbilicus that promotes cosmetic satisfaction. after operation, the incision hides in umbilicus without observed scar.(11) but, less surgery has both the cosmetic advantage and the technically disadvantage. through a small single incision, the incomplete triangulation and interference of the multiple instruments make less surgery very difficult and challenging(12). to date, less technique is still not widespreadly used. the insufficient instrument triangulation is one of the main causes. mini-laparoscopic surgery resolved the limitation(13,14). it was used in the same way as the conventional laparoscopic surgery. but in the past reports(15,16), mini-laparoscopic decortication of renal cyst also had some problems. the low efficiency of dissection and hemostasis with the fine instruments made the operation difficult and time consuming. after operation, the specimens have to be dissected into pieces and then extracted. so, it is necessary to promote the operating efficiency by modification of mini-laparoscopic decortication. in this study, we used 2 fine trocars (3 mm) for mini-laparoscope (camera) and mini-grasper. it only required 2 needle holes for insertion without any incision. after operation, puncture site heals without any scar. to facilitate hemostasis, dissection and specimen extraction, we modified the mini-laparoscopic decortication by addition of 5 mm trocar in umbilicus. through this trocar, the ultrasonic scalpel and hem-o-lok clip applier can be used. the addition of the 5 mm trocar in umbilicus simplified the procedures and it didn’t affect the cosmetic outcome. the small incision and puncture points did not need to be stitched. the results show that the operating time was similar between the mini-laparoscopic group and conventional laparoscopic group. compared with the other two groups, less was relatively time-consuming. the modified mini-laparoscopic surgery has only a very small incision in umbilicus and two puncture point. so the pain was very slight. according to the results, the vas pain score was significantly lower in mini-laparoscopic surgery group compared with less and conventional laparoscopic surgery on pod 1 and pod 3. the cosmetic results are visible on pod 30. both of the mini-laparoscopic group and less group got very satisfactory cosmetic results without obvious scar. but in conventional laparoscopic surgery group, the incisions leave three conspicuous scars. the only drawback to this approach is the small view field because of the very fine laparoscope (camera). however, renal cysts tend to poke out of the surface of kidney and are very easy to be focused. the drawback does not affect the results of operation. the limitations of this study was the small sample size. only 140 cases in the 3 groups were included. however, the operations were performed by a same surgeon group. all the data was collected prospectively although the study was a retrospective analysis. the possible bias may be minimized. conclusions modified mini-laparoscopic decortication of renal cyst is an easy and safe technique for decortication of benign renal cyst. it has both the convenience of conventional laparoscopic surgery and the cosmetic benefit of less surgery. in addition, it caused just a little pain that was significantly better than conventional laparoscopic surgery and less surgery. acknowledgments the study was supported by the shanghai committee of science and technology (18zr1407100). the authors thank dan-qing ren md for reviewing the article. conflict of interest none of the authors has any commercial associations that might be a conflict of interest in relation to this article. references 1. rané a. laparoscopic management of symptomatic simple renal cysts. int urol nephrol. 2004; 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28:71-83. modified mini-laparoscopic decortication of renal cyst-chen et al. urology journal peer review running head: extract of ziziphus jujuba leaf on kidney stones hydroalcoholic extract of ziziphus jujuba leaf to prevent ethylene glycol and ammonium chloride-induced kidney stones in male rat: is it effective? mohammad pourahmadi1, 2, mehran fathi1,3, marzieh rahimipour1, 2, negar shaterian3, hossein kargar jahromi1, 2* 1 research center for non-communicable disease, jahrom university of medical sciences, jahrom, iran. 2 zoonoses research center, jahrom university of medical sciences, jahrom, iran. 3 student research committee, jahrom university of medical sciences, jahrom, iran. corresponding author: hossein kargar jahromi, phd: research center for non communicable disease, jahrom university of medical sciences, jahrom, iran. telephone number: +987154336085, fax number: 07154340405, email: hossein.kargarjahromy@gmail.com, orcid: 0000-0002-2614-8885 the results described in this manuscript showed that: • z. jujuba extract could decrease serum bun, uric acid and creatinine levels • z. jujuba extract has an effect on the prevention and treatment of kidney stones, which can be due to phenolic compounds, flavonoids, fatty acids, and antioxidants and diuretic properties of this plan. these results will be very informative for your journals audience to focus on herbal benefits in protecting kidney from various damage and harmful metabolites. key words: ammonium chloride; calcium oxalate; ethylene glycol; nephrolithiasis; ziziphus jujuba; rat. mailto:hossein.kargarjahromy@gmail.com abstract purpose: this study aimed to evaluate the effect of ziziphus jujuba (z. jujuba) leaf hydroalcoholic extract on the prevention/treatment of kidney stones. materials and methods: thirty-six male wistar rats were randomly divided into six groups: control, sham (kidney stone induction (ksi) by ethylene glycol 1% + ammonium chloride 0.25% through drinking water for 28 days), prevention groups 1, 2 (ksi and z. jujuba leaf (250 and 500 mg/kg, respectively) through gavage for 28 days), and treatment groups 1, 2 (ksi and z. jujuba leaf (250 and 500 mg/kg, respectively) from the 15th day). on the 29th day, the rats’ 24-hour urine was assessed, the animals were weighed, and blood samples were taken. finally, after nephrectomy and weighing the kidneys, tissue sections were prepared to examine the number of calcium oxalate crystals and tissue changes. results: the results indicated a significant increase in kidney weight and index, tissue changes, and the number of calcium oxalate crystals in the sham group compared to the control; using z. jujuba leaf considerably reduced them in experimental groups compared to the sham. body weight decreased in the sham and experimental groups (except the prevention 2 group) compared to the control, while this observed reduction was lower in all experimental groups compared to the sham. the mean urinary calcium, uric acid, creatinine, and serum creatinine in sham and experimental groups (except the prevention 2 group) indicated a substantial increase compared to the control and decreased significantly in all experimental groups compared to the sham. conclusion: hydroalcoholic extract of z. jujuba leaf is effective in the reduction of calcium oxalate crystals forming, and its most effective dose was 500mg/kg. keywords: calcium oxalate; ziziphus jujuba; ethylene glycol; ammonium chloride; rat introduction kidney stone (urolithiasis, renal calculi, or nephrolithiasis) affects 5-15% of the world’s population, with a recurrence rate of 50% and a high cost of treatment.(1) despite the diffrentetypes of crystals, the most prevalent type are calcium oxalate stones, located in the pelvis, ureter, bladder, and urethra.(2, 3) the cause of this disease is not completely clear, but a diet rich in calcium, sodium, and protein,(1, 4) as well as immobility in people with hypercalciuria type ii and gastrointestinal diseases such as inflammatory bowel disease, involved in the developing of these stones.(5, 6) also, it is known that several gene polymorphisms are involved in the formation of kidney stones. ( 7 ) kidney stone symptoms include nausea, vomiting, hematuria, painful urination, urinary tract obstruction, hydronephrosis, and severe urinary tract bleeding, making surgery and stone breaking up an urgent need.( 2 , 8 ) high costs and numerous side effects such as severe kidney tissue damage and general infection have caused patients to seek alternative treatments;( 2 , 9 ) herbal products gained popularity today;( 1 0 , 1 1 ) despite the benefits of these herbs, it is believed that more investigation is needed to evaluate the effects of herbs on kidney stones.( 1 0 ) in traditional medicine, ziziphus genus is used in the treatment of kidney stones, but very few academic studies have been done so far. z.jujuba is one of the thorny shrubs of the rhamnaceae family.(11) glycosides and alkaloids are distributed in all parts of plant. the saponin, ziziphin and the alkaloids coclaurine, isoboldine, norisoboldine, asimilobine, iusiphine and iusirine were isolated from z. jujuba leaves. (12) moreover, z. jujuba leaf extract is rich in linolenic, palmitic, oleic, and linoleic acids, and in sitosterol, stigmasterol and flavonoid compounds (especially rutin and apigenin). previous studies show that the fatty acids and flavonoids in the z. jujuba leaves is responsible for their therapeutic and pharmaceutical effects. (12-14) since z. jujuba is rich in antioxidants and based on previous studies (12, 13), this study was conducted to evaluate the effect of oral consumption of hydroalcoholic extract of z. jujuba leaf on the prevention/treatment of oxalate kidney stones caused by ethylene glycol and ammonium chloride. materials and methods experimental animals and study design this experimental laboratory research has been registered in the ethics committee of jahrom university of medical sciences-iran )ir.jums.rec.1397.110(. only one of the authors was aware of the group allocation at different stages of the experiment during the experiment. in this study, 36 healthy adult male wistar rats (weight: 190-210 grams, 8-10 weeks) within their cages under 12:12 light: dark cycles with 24±1°c room temperature, 50-55% humidity, and ad libitum access to food and water. according to previous research, the animals were randomly divided into six groups (each group containing six rats): control group (without receiving any treatment), sham group (kidney stones induction (ksi) by ethylene glycol 1% + ammonium chloride 0.25% through drinking water for 28 days), prevention groups 1 and 2 (ksi and hydroalcoholic extract of z. jujuba leaf concentrations of 250 and 500 mg/kg (1 ml) respectively through gavage all these 28 days), and the treatment groups 1 and 2 (ksi and z. jujube leaf xetract with concentrations of 250 and 500 mg/kg respectively through gavage (1 ml) from the day 15 for two weeks). all treatments were performed daily at 8-10 am. preparation of z. jujuba leaf extraction to prepare z. jujuba, leaves were collected from jahrom city trees, registered with herbarium code 1151 in the islamic azad university of jahrom. the leaves were dried and powdered; 100 grams of the powder were poured into a one-liter beaker with 40cc ethanol (96%). then, the beaker was positioned on the shaker for 24 hours. after filtering the solution, ethanol (75%) was added to the remained waste and shacked for more than 12 hours. the filtered solution was concentrated by rotavapor at 50 c and at 90-rpm speed, up to 1/3 of the primitive volume. finally, the filtered solution was positioned in an incubator (50 c). after a few days, the powder was ready to be prepared at different concentrations.(15) evaluation of biochemical parameters on the 28th day, the rats were placed in metabolic cages for 24 hours to assess urine volume, uric acid, calcium, and creatinine. then, the animals were weighed and anesthetized with ketamine (90 mg/kg) and xylazine (10 mg/kg), and blood samples were taken from the hearts. analysis of urine and blood samples following assessing urine and blood, samples were centrifuged (1,500×g for 10 minutes), and the supernatants were stored at −20 °c. urine (uric acid, calcium, and creatinine) and serum (creatinine) parameters were evaluated using the pars-azmoon kits. kidney weight and histopathological analysis the next step was nephrectomy and washed kidneys with cold 0.9% nacl to calculate kidney index (the ratio of both kidneys weight to body weight), histological examination, and counting the number of calcium oxalate crystals. the kidneys were weighed and placed in formalin (10%). for tissue staining, after performing the usual steps of tissue passage, 5 microns of paraffin sections were serially prepared. five sections from each kidney were randomly selected, stained with h&e, and studied under a light microscope (olympus bx31, tokyo, japan). from each section, ten fields were randomly chosen with a magnification of ×100 and ×400. eventually, the average number of calcium oxalate crystals was counted, and tubulointerstitial changes such as tubular cell necrosis, atrophy, dilation, interstitial inflammation, hyaline cast, and tubular atrophy were evaluated using a semi-quantitative method:(16) 0 = none, 1 = trace (< 10%), 2 = mild (10-25%), 3 = moderate (26-50%) and 4 = marked (> 50%). statistical analysis statistical analysis was performed using spss version 21 software. after assessing the normality of the data by kolmogorov-smirnov test, we used one-way analysis of variance (oneway anova) followed by tukey’s test and duncan’s test to analyze them. results examination of left, right, and both kidneys weight and kidney index indicated weight rise in sham, treatment, and prevention groups in comparison with the control one. using z. jujuba leaf extract considerably decreased weight scores compared to the sham, which was significantly higher in the prevention groups. however, among the treatment groups, the higher dose showed better effects (table 1). evaluating the first-days body weight in all groups indicated no difference, while after 29 days, the weight alteration in the sham and experimental groups was significant. it should be noticed that using z. jujuba leaf extract increased animals’ weight in comparison with the sham group (p ≤ 0.05); in prevention groups, this increase was substantial (table 1). assessing body weight and its changes in different groups indicated decrease in sham and experimental groups (exception prevention group 1) compared to the control group. there was a significant increase in the experimental groups’ body weight and its changes compared to the sham; the prevention groups’ weight change was even higher than the treatment groups )p ≤ 0.05( (table 1). assessing 24-hour urine uric acid changes in different groups demonstrated substantial increase in the sham and the treatment groups compared to the control. in contrast, the prevention groups did not indicate any significant differences compared to the control group. a reduction in urine uric acid was shown between treatment group 2 and the other treatment group )p ≤ 0.05(. 24hour urine calcium and creatinine changes in different groups indicated increase in sham and experimental groups )p ≤ .05( except the prevention group 2, compared to the control. the experimental groups showed a significantly higher growth compared to the sham group )p ≤ 0.05(. urine 24-hour volume in different groups indicated a substantial increase in the sham and experimental groups compared to the control. in addition, substantial increase was observed in the z. jujuba groups in comparison with the sham )p ≤ 0.05(. experimental groups did not show any significant difference (table 1). assessing serum showed that only the prevention group2 brought serum creatinine to the control )p ≤ 0.05(. treating animals with a lower dose of z. jujuba showed the highest serum creatinine level among the experimental groups (table 1). calculation of stone numbers in different groups indicated a substantial increase in the sham and experimental groups compared to the control, but the z. jujuba groups had lower stones than with the sham group. higher doses in both prevention and treatment groups showed less stone count )p ≤ 0.05(. evaluating tissue changes in different groups indicated increase in the sham and experimental groups compared to the control. this reduction was significant in the experimental groups compared to the sham. higher doses in both prevention and treatment groups were considerably more effective )p ≤ 0.05 (. the prevention group had the least changes (table 1). results of histopathological changes in this study, the normal glomerular structure, renal tubule and regular interstitial area in the medulla and cortex of the control group were observed. we observed that the tubular damage with hyperemia, infiltration of inflammatory cells, tubular destruction, pyknoses nucleus and kidney stones (calcium oxalate crystals) are revealed in the eg-treated (sham) group. in the treatment and preventive groups tubular damage, hyperemia, infiltration of inflammatory cells, tubular destruction, pyknoses nucleus and calcium oxalate crystals were reduced (figure 1). discussion numerous individuals around the world endure from issues related to urinary tract stones. calcium stones are the foremost common and account for about 75% of the entire stones. these days, numerous researchers have based their investigations on therapeutic plants. (17, 18) what this study showed is the beneficial role of z. jujuba in kidney stone even by affecting the formation of calcium oxalate crystals, while the higher dose is associated with better effects. our results showed an increase in urine volume, which probably indicates the diuretic role of the extract. it is widely known that diuretic products can reduce the amount of calcium released into the urine and help prevent kidney stones. on this basis, z. jujuba leaf significantly increased the 24-hour urine calcium changes in such a way that the prevention group (500 mg/kg z. jujuba leaf) reduced calcium level to the control. comparison among groups demonstrated that the most effective dose of z. jujuba is 500 mg/kg in prevention (p = .003, p = .001, p = .047, p = .015) and treatment (p = .005, p = .001, p = .035, p = .011) group compare with control, sham, prevention group 1, and treatment group 1. z.spina-christi is another species of ziziphus genus. the benefits of z.spina-christi and z. jujuba extracts (seed, leaf, and so on) on renal function was shown previously.(13, 19-22) reducing the formation of kidney stones can be explained by a decrease in urinary calcium output within 24 hours in rats. saponins prevent kidney stone formation in animal studies by stimulating kidney atpases. therefore, this steroid forms an intracellular reservoir of na+ -k -atpase, which increases atpase activity in the renal tubule, and changes in sodium pumps of the cortex may lead to a change in urine composition.(17, 18) the renin-angiotensin-aldosterone system (raas) controls salt and water balance, blood volume, and blood pressure.(23) this system plays a fundamental physiological role in maintaining the body's homeostasis.(24) mohebbati et al. found that z.jujuba extract, another member of the ziziphus family with similar components, reduced the function of the raas and this may be due to the effect of the ingredients of z.jujuba on aldosterone compounds.(25) therefore, based on the similarity of these two plants (z.jujuba and z.spina-christi), this hypothesis can be expressed that the role of z.jujuba as a diuretic is another confirmation of its effect on raas system and renal diseases. in the kidney stone groups, tissue damage and the deposition of calcium oxalate crystals were increased significantly, in addition to the reduction of the bowman’s capsule diameter and renal glomerulus.(26) in an interesting way, tissue sampling showed no calcium oxalate crystal, tissue damage, or a significant change in the diameter of different parts of the nephron in groups receiving z. jujuba extract. in the z. jujuba groups (both treatment and prevention), the rate of tissue damage and deposition of calcium oxalate crystals decreased, and the best was the highest dose. the effects of z. jujuba can be attributed to its antioxidant properties. experimental studies have shown that antioxidant-rich substances reduce the risk of calcium oxalate stones developing.(27, 28) oxidants and free radicals can create a suitable environment for the growth of calcium oxalate crystals in kidney cells. at low concentrations of free radicals, crystals develop in calcium-rich areas, while at higher concentrations, crystals form in areas with a single layer of superficial damaged cells.(29-31) elevated oxalate secretion may also induce oxidative stress and an increase in free radicals of renal epithelial cells.(32) these conditions create an interaction between the crystals and renal tubular cells, which leads to the formation and growth of calcium oxalate crystals.(32, 33) as the study conducted by almeer et al., z.spinachristi has beneficial effects against mercury-induced renal toxicity and reversed kidney alterations to near normal values. the authors believe that these effects resulted from z.spinachristis’ chelation and antioxidant, which minimize the pathological changes induced by mercury.(20) or in another study by abdel-wahhab and colleagues, in animals treated with zizyphus spina-christi l. extract alone or plus aflatoxin (af), to induce oxidative stress, a significant improvement in all biochemical parameters and histological picture of the liver, kidney, and the testis was detected. this study proved that zizyphus extract has a powerful protective role against aflatoxicosis due to its antioxidative properties.(19) in addition, studies agreed that herbs with flavonoids and antioxidants could reduce creatinine levels and control tissue damage in the kidney.(34, 35) according to the results of the present study and other studies, z. jujuba extract is effective in the reduction of calcium oxalate crystals forming, which can be due to the phenolic compounds, flavonoids, fatty acids, antioxidants, and especially the diuretic properties of this plant. however, there is a need for further studies on their antioxidants role. acknowledgements the authors are grateful to deputy of research of jahrom university of medical sciences for their financial support. the authors have no conflicts of interest relevant to this article. limitations since, this research derived from a thesis, financial resources were limited. conflict-of-interest statement the authors have no conflicts of interest relevant to this article. references 1. khan sr, pearle ms, robertson wg, gambaro g, canales bk, doizi s, et al. kidney stones. nature reviews disease primers. 2016;2(1):1-23. 2. coe f, worcester em, lingeman je, evan ap. kidney stones: medical and surgical management: jaypee brothers medical publishers; 2019. 3. rule ad, lieske jc, pais vm. management of kidney stones in 2020. jama. 2020;323(19):1961-2. 4. qaseem a, dallas p, forciea ma, starkey m, denberg td, physicians* cgcotaco. dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults: a clinical practice guideline from the american college of physicians. annals of internal medicine. 2014;161(9):659-67. 5. spivacow fr, del valle ee, lores e, rey pg. kidney 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of inflammatory cells cross: tubular destruction. f) prevention group 1/medulla; cross: tubular destruction arrow: pyknoses nucleus. g) prevention group 2/cortex; cross: tubular destruction. h) prevention group 2/medulla; cross: tubular destruction arrow: pyknoses nucleus. i) treatment group 1/cortex; star: hyperemia plus sign: infiltration of inflammatory cells cross: tubular destruction arrow: pyknoses nucleus. j) treatment group 1/medulla; cross: tubular destruction arrow: pyknoses nucleus. k) treatment group 2/cortex; star: hyperemia plus sign; infiltration of inflammatory cells cross: tubular destruction arrow: pyknoses nucleus. l) treatment group 2/medulla; star: hyperemia arrow: pyknoses nucleus (type of staining: hematoxylin and eosin; magnification ×100). table 1: results in the different groups. groups parameters control sham prevention group 1 prevention group 2 treatment group 1 treatment group 2 left kidney weight (g) .86 ± .09 2.15 ± .19* 1.12 ± .07*+ 1.08 ± .09*+ 1.80 ± .14*+ψ! 1.47 ± .16*+ψ!# right kidney weight (g) .85 ± .08 2.13 ± .21* 1.10 ± .04*+ 1.06 ± .13*+ 1.68 ± .25*+ψ! 1.40 ± .17 *+ψ!# kidney weight (g) 1.70 ± .17 4.28 ± .37* 2.23 ± .09*+ 2.15 ± .21*+ 3.48 ± .39*+ψ! 2.87 ± .25*+ψ!# kidney index (×10-3) 0.72 ± .08 2.27 ± .26* 1.03 ± .08*+ 0.95 ± .09*+ 1.69 ± .22*+ψ! 1.38 ± .16*+ψ!# weight of first day (g) 210.83 ± 6.64 209.66 ± 5.60 208.33 ± 6.68 212.33 ± 6.12 210.83 ± 5.49 210.16 ± 5.91 weight of day 29 (g) 236.66 ± 9.04 188.83 ± 6.11* 216.66 ± 12.37*+ 226.83 ± 4.70 +ψp 206.66 ± 8.52*+! 209.16 ± 8.58*+! body weight change (g) 25.83 ± 7.67 -20.83 ± 6.82* 8.33 ± 8.18*+ 14.50 ± 6.31+ -4.16 ± 7.41*+ψ! -1 ± 7.77*+ψ! ua urine (mg/24 h) .65 ± .13 4.85 ± .90* 1.17 ± .10+ .73 ± .13+ 3.18 ± .76*+ψ! 2.47 ± .68*+ψ!# ca urine (mg/24 h) 4.63 ± .48 7.73 ± .72* 5.7 ± .63*+ 5.07 ± .77+ 6.93 ± .70*+ψ! 5.95 ± .38*+!# cr urine (mg/24 h) 39.20 ± 4.60 126.53 ± 22.30*+ 61.13 ± 7.34*+ 44.28 ± 9.70+ ψ 106.17 ± 9.43*+ ψ! 92.62 ± 7.16*+ψ! volume of urine (ml/24 h) 8.93 ± .99 18.27 ± 1.98*+ 21.83 ± 3.09*+ 22.37 ± 2.24*+ 22.70 ± 2.40*+ 23.36 ± 1.89*+ cr serum (mg/dl) .62 ± .20 2.95 ± .27* .87 ± .12*+ .72 ± .08+ 1.12 ± .16*+ ψ! .92 ± .07*+# calcium oxalate crystal count (n) .00 ± .03 28.50 ± 10.17* 19.50 ± 6.53*+ 11.83 ± 5.91*+ψ 21.33 ± 5.27*+ 11.33 ± 6.15*+ψ tubulointerstit ial changes .00 ± .00 2.96 ± .75* .93 ± .40*+ .66 ± .47*+ ψ 1.24 ± .45*+ψ! .85 ± .44*+!# *significant different with control group (p ≤ .05) + significant different with sham group (p ≤ .05) ψ significant different with prevention group 1 (p ≤ .05) ! significant different with prevention group 2 (p ≤ .05) # significant different with treatment group 1 (p ≤ .05) abbreviations: mg, milligram; kg, kilogram; ml, milliliter; dl, deciliter; h, hour; ua, uric acid; ca, calcium; cr, creatinine; n, number. **all data represent mean ± sd. according to duncan test, means that have at least one letter in common in each row, have no significant difference. p < .05 is considered statistically significant. unclassified first report of magnetic resonance imaging in patients with implanted interstim twin (model 7427t) sacral nerve stimulator stefan heidler1*, lukas lusuardib, franz dietersdorfer1 purpose: to detect possible effects of magnetic resonance imaging (mri) scans on the function of an interstim twin sacral nerve stimulation (sns) device and on patient’s health. there is currently no authorization for mri scans in interstim twin sns at all. material and methods: 10 patients with interstim twin sacral nerve stimulator implants underwent a singular mri scan. before the mri was performed, the sns device function was evaluated and the device was deactivated by the implanting urologist. continuous monitoring took place during the mri procedure. micturition-time chart preand post mri procedures were conducted. after the mri session was completed, the implanted device was examined once more and reactivated, function was then re-evaluated. results: a total of 10 patients required mri examinations in 8 different body regions. no patient reported pain or discomfort during and after the mri scan. after reactivation of the interstim twin device following the mri, impedances and stimulation amplitude, micturition frequency, urgency, and incontinence episodes remained stable. no significant differences between preand post mri were found (p > 0.05). conclusion: this is the first report of patients successfully undergoing a mri scan despite a previously implanted interstim twin sacral nerve stimulator. no negative effect of sns function or negative side effects for the patients were observed. keywords: magnetic resonance imaging, sacral nerve stimulator, interstim twin introduction although mri-safe devices have been introduced recently(1,2) the vast majority of the 300,000 interstim systems worldwide are not approved for full-body mri, resulting in the frequent question for off-label mri examinations in patients with legacy interstim devices. according to the neuromodulation mri safety status, mri scans in patients with sacral nerve stimulation (sns) are only feasible under strict regulations. so far, there is no authorization for mri scans in interstim twin (model 7427t, medtronic, inc) at all(1). this is due to concerns about dislodgement of the device, unintended stimulations, and, especially, heating of the leads and the device(2,3). however, increasing numbers of indications for mri scans require new regulations. it has been estimated that more than 50% of patients with a cardiac pacemaker or neurostimulator will have an mri indication over their lifetime(4,5). there have been no reports of mri scans with interstim twin implants so far. an aging population with an increasing number of comorbidities will lead to a growing number of mri scans in this patient group. the aim of this study was to assess possible impacts of mri scans on the function of interstim twin devices and on patient’s safety. 1department of urology, krankenhaus mistelbach, austria. 2department of urology, paracelsus medical university salzburg, austria. *correspondence: department of urology, landesklinikum mistelbach, liechtensteinstrasse 67, 2130 mistelbach, austria. phone: +43 2572 9004 21904. fax: +43 2572 9004 49251. e-mail: stefanheidler@gmx.at. received & accepted material and methods the data of this retrospective analysis originates in the necessity for mri diagnostic assessment of various disorders despite implanted sns devices. wherever possible, alternative methods other than mri for diagnosis were utilized. a written informed consent to perform the mri scan with explicit notice regarding possible risks due to the sns device was obtained from all patients. mri was performed as a standard with 1.5 tesla. implanted pulse generators were examined before and after mri procedures. all patients had impedances, battery life, stimulation amplitude and a micturition-time chart including micturition frequency, urgency, and incontinence episodes recorded prior to the mri scan; then the amplitude of the implanted impulse generator (ipg) was reduced to zero and the ipg was switched off. patients were monitored continuously during and after the procedure. the implanting urologist was present before, during, and after the mri scan. he specifically informed and monitored each and every patient himself. a list of questions was utilized, which included unspecific questions such as: “how are you feeling?”, as well as specific questions such as: “do you or did you at any point experience heat or pain in your pelvic region?” after the mri session, the site of the implanted device was examined to detect potential changes. urology journal/vol 18 no. 5/september-october 2021/ pp. 561-563. [doi: 10.22037/uj.v16i7.6307] impedances, battery life, and stimulation amplitude were checked once again, devices were then reactivated with their previous setting with the use of the physician programmer (n´vision, model 8840). micturition-time chart was asked via phone approximately one week after the mri. differences in stimulation settings and micturition-time chart were calculated with the paired t-test. results between 2005 and 2016, our department implanted the interstim twin neurostimulator (interstim® neurostimulator; medtronic, inc, minneapolis, mn, usa). in the course of those 11 years, 10 patients (8 women, 2 men; age: 56 years – 87 years, mean 73.4 years) with interstim twin implants required magnetic resonance imaging in the subsequent years. mri investigations were conducted with 1.5 tesla in 8 different regions of the body. as some of the mri scans were carried out in more than one body region, 10 mri scan sessions resulted in a total of 12 radiological results. 9 mri investigations were necessary due to orthopaedic causes, 1 was due to neurological problems and 2 were due to vascular causes. on average, patients were exposed to the magnetic field 19.9 ± 2.5 min. the longest mri scan was performed on the brain and took 27 minutes (table 1). during and after the mri scan, no patient reported any symptoms. all patients negated sensations of heat or discomfort at the implantation site of the electrodes and the ipg. after the implanted sacral nerve stimulator was reactivated following the mri, impedances pre (1010.1 ± 0.34) and post mri (1010.3 ± 0.29) showed no significant change (p = 0.09), as well as the stimulation amplitude (pre mri 1.28 ± 0.048, post mri 1.29 ± 0.047, p = 0.121). micturition frequency (pre mri 5.31 ± 0.98, post mri 5.61 ± 1.01, p = 0.68), urgency (pre mri 2.8±0.79, post mri 2.8±0.85, p = 0.36), and incontinence episodes (pre mri 1.77 ± 0.73, post mri 1.76 ± 0.41, p = 0.85) remained stable. in all tested parameters, no significant differences between preand post mri were found (table 2). discussion up to now, there is no authorization for mri scans in patients carrying an interstim twin implant, resulting in recommendations to avoid all off-label mri scans in patients with sns or explanting and reimplanting the device in patients with the need for an mri. the basis for this policy is that potential hazards such as heating of the leads and damage to the ipg might occur, resulting in painful stimulation(2,3). however, mri is an important diagnostic tool for a variety of diseases, and surgery to remove an important device cannot be justified due to potential complications. so far, studies conducted on patients with other implantable devices, such as pacemakers, have found the examination with mri at 1,5 tesla to be safe(5,6). nazarian et al. reported on 1509 patients with cardiac devices having off-label mri scans. no significant adverse events have been reported with 1.5 tesla(7). previous studies have demonstrated no serious adverse outcomes during and after mri in patients with the medtronic sns interstim and interstim ii of several regions of the body(8,9,10). this study reports the first series of successful mri examinations in 10 patients with an interstim twin device with no negative effects, neither on the patients nor on the sns device. however, several limitations of our study should be noted. first, the small patient cohort, this relatively small number is due to the fact that interstim twin implants are not very common and that the indications for mri scans without an alternative method of diagnostic tools are limited also. second, the data were acquired at a single centre and may not be generalizable to other clinical settings and mri facilities. third, in this study cohort only two mri of the pelvic region were included due to the non-selectivity of patients. therefore, a study with a larger number of patients, including more patients with pelvic region mris should be performed. conclusions this is the first report of patients successfully undergoing mri scans despite a legacy, non-full-body mri compatible interstim twin sns implant. 10 patients underwent mri with no negative effect on the functional outcome of the sns device or negative side effects for the patients. table 1. number of mri scans each patient received body site number of mri mri (mean minutes) knee 3 17.7 ± 1.2 carotisangiography 1 20 femoralisangiography 1 20 schoulder 1 18 cervical cord 2 20.5 ± 0.5 throracical cord 1 20 lumbal cord 2 20 ± 0 central nervous system 1 27 total 8 regions total 12 mri total min 19.9 ± 2.5 mri and interstim twin-heidler et al. unclassified 562 table 2. comparison of preand post mri settings amplitude (ma) impedance (ω) micturition frequency urgency episodes incontinence episodes pre-mri 1. 28 ± 0.048 1010.1 ± 0.34 5.31 ± 0.98 2.8 ± 0.79 1.77 ± 0.73 post-mri 1.29 ± 0.047 1010.3 ± 0.29 5.61 ± 1.01 2.8 ± 0.85 1.76 ± 0.41 p value p = 0.12 p = 0.09 p = 0.68 p = 0.36 p = 0.85 references 1. coolen rl, groen j, blok b: electrical stimulation in the treatment of bladder dysfunction: technology update. med devices. 2019;12:337-345. 2. thornton js: technical challenges and safety of magnetic resonance imaging with in situ neuromodulation from spine to brain. eur j paediatr neurol. 2017;21: 232–41. 3. quirouet a, bhattacharyya pk, dielubanza ej, gill bc, jones se, goldman hb: sacral neuromodulation device heating during lumbar and pelvic magnetic resonance imaging—a phantom study. urology. 2017;107: 61. 4. de wachter s, knowels ch, elterman ds, et al: new technologies and applications in sacral neuromodulation: an update. adv ther 2020;37(2):637-643. 5. kalin r, stanton ms: current clinical issues for mri scanning of pacemaker and defibrillator patients. pacing clin electrophysiol. 2005;28:326–8. 6. muehling om, wakili r, greif m, von ziegler f, morhard d, brueckmann h, et al: immediate and 12 months follow up of function and lead integrity after cranial mri in 356 patients with conventional cardiac pacemakers. j cardiovasc magn reson. 2014;16: 39. 7. nazarian s, hansford r, rahsepar aa, weltin v, mcveigh d, gucuk ipek e, et al: safety of magnetic resonance imaging in patients with cardiac devices. n engl j med. 2018;377: 2555. 8. chermansky cj, krlin rm, holley td, woo hh, winters jc: magnetic resonance imaging following interstim®: an institutional experience with imaging safety and patient satisfaction. neurourol urodyn. 2011; 30:1486–8. 9. elkelini ms, hassouna mm: safety of mri at 1.5tesla in patients with implanted sacral nerve neurostimulator. eur urol. 2006; 50:311–6. 10. alsyouf m, keheila m, marinone m, blackburn a, staack a: magnetic resonance imaging of the ankle performed on an interstim patient. can j urol. 2016; 23: 8168–70. mri and interstim twin-heidler et al. vol 18 no 5 september-october 2021 563 urol_montage.pdf female urology 35urology journal vol 6 no 1 winter 2009 in situ anterior vaginal wall sling for treatment of stress urinary incontinence extended application and further experience mahmoud mustafa,1 bassam s wadie2 introduction: our aim was to evaluate the efficacy of utilizing in situ anterior vaginal wall sling in the treatment of stress urinary incontinence (sui). materials and methods: the study included 11 women with a median age of 50 years (range, 36 to 60 years) who were operated on during the period of november 2005 to august 2006. they were diagnosed with sui and were operated on using placard-shaped in situ anterior vaginal wall sling technique. nine patients underwent surgical treatment for the first time, while 2 patients had postoperative recurrent sui. in all of the patients, urethral hypermobility with or without cystocele was observed. the mean follow-up period was 22.5 months (range, 17 to 28 months). results: ten patients (90.9%) were considered cured and 1 (9.1%) started leakage of urine after 1 month during the postoperative period. one patient (9.1%) had urinary retention. three patients (27.3%) had evidence of wound infection which was treated by appropriate oral medical therapy. conclusion: in situ anterior vaginal wall sling technique is accredited with a good success rate and low incidence of complications. it is easy to learn and cost-effective, making it a suitable technique for sui. longer follow-up and larger number of patients are needed before final conclusion could be drawn. urol j. 2009;6:35-9. www.uj.unrc.ir keywords: stress urinary incontinence, suburethral slings, urologic surgical procedures, female 1osmaniye state hospital, urology department, osmaniye, turkey 2female urology and voiding dysfunction, urology and nephrology center, mansoura university, mansoura, egypt corresponding author: mahmoud mustafa, md department of urology, izmir ataturk teaching hospital, izmir, turkey tel: +90 232 245 4545 fax: +90 232 243 1530 e-mail: dr_mahmoud68@yahoo.com received may 2008 accepted december 2008 introduction in women with stress urinary incontinence (sui) secondary to urethral hypermobility, the aim of surgery is to restore the proper position of the urethra and the bladder neck through a transvaginal or abdominal procedure. many published studies in the past 5 years have promoted the results of recently introduced minimally invasive techniques adopted for treating sui.(1-5) tension-free vaginal tape (tvt) represents a well-established surgical procedure for the treatment of sui. the technique, described in 1996 by ulmsten and colleagues,(6) is based on a midurethral prolene tape support, which is accepted worldwide as an easy-to-learn, effective, and safe surgical technique with low incidence of complications.(6-10) however, a 5% to 15% failure rate after tvt was reported and many techniques were offered as alternatives,(7,8,10,11) the results of some of which have remained far from optimum. furthermore, tvt was reportedly associated with serious perioperative complications, despite its high efficacy.(1) as an attempt in a recent study to modify the in situ anterior vaginal wall sling—mustafa and wadie 36 urology journal vol 6 no 1 winter 2009 technique to reach better outcomes, we reported encouraging results using placard technique, where we utilized in situ sling of the anterior vaginal wall for the treatment of sui, especially in selective patients with an average body mass index.(12) in the current study, we report our experience adopting the same technique as a first choice anti-incontinence procedure in all of our patients with sui. materials and methods eleven women were scheduled for surgical treatment of sui by placard-shaped anterior in situ vaginal wall sling between november 2005 and august 2006 at our center. clinical examination revealed urethral hypermobility with or without cystocele. the diagnosis of sui was based on a positive stress test and the presence of urethral hypermobility confirmed by cotton swab test. stress urinary incontinence was defined as involuntary leakage on effort, exertion, sneezing, or coughing, and urge incontinence was defined as the complaint of involuntary leakage accompanied by or immediately preceded by urgency.(13) urethral hypermobility was assessed with q-tip test. the degree of cystocele was assessed according to the baden-walker prolapse classification.(14) cystocele was observed in 10 patients with various grades; 3 patients had grade 3, 4 patients had grade 2, and 1 patient had grade 1 cystocele. urodynamic tests were performed in patients who were not diagnosed with pure stress incontinence. any patient suffered from urodynamically documented urge incontinence was excluded from the study. of the study group, 2 patients had had prior anti-incontinence surgeries, both of whom had tvts and were found to have bladder erosion and vaginal erosion, respectively. in the patient with bladder erosion of the tape, endoscopic excision of the tape was accomplished first, and when control cystoscopy revealed complete healing of the bladder mucosa, the patient was operated upon.(15) the operation was performed under spinal or general anesthesia. in the lithotomy position, an 18-f foley catheter was inserted and the bladder was evacuated. then, a placard-shaped incision was made in the anterior vaginal wall (figure 1), and dissection of the vaginal flap was carried out to prepare in situ anterior vaginal wall sling (figure 2). the length of midline incision at the anterior vaginal wall was determined according to the degree of cystocele. then, the dissection at the lateral side of the in situ sling was done until the surgeon’s index finger could be easily felt from the suprapubic area. a small transverse incision of 4 cm to 5 cm was made over the symphysis pubis without cutting the rectus fascia, and 2 suspension sutures of 1 polypropylene were inserted in figure 1. schematic illustration of placard-shaped incision (black line) at the anterior vaginal wall. figure 2. in situ vaginal sling prepared from the anterior vaginal wall after dissection of the vaginal flap was carried out. in situ anterior vaginal wall sling—mustafa and wadie urology journal vol 6 no 1 winter 2009 37 the flap (figure 3) and passed lateral to urethra. before fixation of the suspension sutures to the periosteum of symphysis pubis, the bladder was filled with 250-ml to 300-ml isotonic solution. manual pressure was applied to the suprapubic area to test for leakage, thus adjusting the tension of the sutures. closure of the placard incision then followed over the in situ sling. intraoperative cystoscopy was done to rule out bladder or urethral injury. all of the patients were hospitalized for 1 to 2 days. the foley catheter was left for 5 postoperative days. a vaginal sponge was placed at the end of the operation and removed 24 hours later. the operative time varied from 45 to 90 minutes (mean, 60 minutes). during the postoperative period, sexual intercourse and carrying heavy weights was discouraged for 2 months. all of the patients were followed at 1, 3, 6 postoperative months, and every 4 months thereafter. the mean follow-up period was 22.5 months (range, 17 to 28 months). postvoid residual urine of 50 ml or less was considered as insignificant. follow-up evaluation included self-made questionnaire assessment, physical examination with stress test, and postvoid residual measurement. cure of sui after the procedure was defined as the absence of any complaint of leakage and the absence of leakage on stress testing. improvement was defined as no urine loss on stress plus patients’ report of some leakage but overall satisfaction. therapeutic failure was considered in cases of sustained urinary stress incontinence. results eleven patients with a median age of 50 years (range, 36 to 60 years) underwent in situ anterior vaginal wall sling surgical operation. one patient had retention (9.1%) after removal of the catheter which was resolved by extra 5 days of catheterization. ten patients became totally continent (cure rate, 90.9%). one patient (9.1%) resumed incontinence after carrying heavy weight in the 1st month postoperatively. three patients (27.3%) had evidence of wound sepsis in the form of suprapubic tenderness and redness, which was treated by oral antibiotics and nonsteroidal antiinflammatory drugs. three patients (27.3%) had temporary urgency without urge incontinence, starting at the 3rd postoperative week, which were improved by anti-muscarinic drugs for 3 weeks. there was no significant postvoid residual urine detected by real-time abdominal ultrasonography after catheter removal. discussion the current view in incontinence surgery is in favor of pubovaginal fascial sling over traditional abdominal colposuspension techniques, as the results of the former is much better at long-term as regards efficacy, morbidity, hospital stay, and costs to public healthcare.(2,16,17) since its introduction, tvt has been found to be as effective as fascial sling.(18) however, many publications reported no significant differences between various midurethral sling procedures.(19,20) the success rate of midurethral sling in short-term and longterm follow-up varied from 85% to 95%.(7,8,10,11,18) although tvt is simple and minimally invasive, there were reportedly serious complications such as bowel perforation, retropubic hematoma, and venous injury.(21-25) urinary retention, bladder perforation, urethral erosion and wound infection were reported in 2.3%, 3.8%, 0.07%, and 0.8% of the operated patients, respectively.(8) in our figure 3. two suspension sutures are placed at the lateral sides of the sling. in situ anterior vaginal wall sling—mustafa and wadie 38 urology journal vol 6 no 1 winter 2009 technique, the success rate (90.9%) did not differ from the reported success rates of other techniques. cost effectiveness and low incidence of urethral or bladder erosion are the most important potential advantages of this technique. it also adjoins reasonable success as regards cure of incontinence to good feasibility of cystocele correction. the hospitalization period was short with no clinically significant morbidity in the postoperative period. however, the rates of complications in terms of urinary retention and wound infection were found to be higher than the rates reported in literature, which might be due to low number of patients included in the early experience. lo and coworkers reported that the immobilization of the urethra, as a result of fibrosis around the mesh, which is seen in about 26.8% of secondary cases of tvt, seems to be a risk factor for failure of reconstruction in the re-operated cases.(26) however, in our technique, the degree of fibrosis around the urethra was expected to be less than that of tvt as there was no exogenous material used. the use of this procedure in secondary cases of sui seems to be acceptable. of 2 patients who had in situ flap as a re-do, both were cured. however, performing this technique for secondary cases may carry some difficulties in preparing the in situ sling due to fibrosis because of the previously done surgeries. the place of urodynamic study in patients with pure urodynamic sui is not universally accepted. while some studies emphasize its importance,(27,28) others are not in support of routine urodynamic study in such patients.(29,30) in our study, patients who were diagnosed with pure sui were not urodynamically tested, because we believe that urodynamic study is not necessary in such cases. backing vaginal sponge with povidone iodine and antibiotics cream decreases vaginal infection and supports the sling in the early postoperative period. moreover, advising sexual abstinence and avoiding heavy lifting for a sufficient postoperative period helps in improving the outcome of the surgery. in general, we would like to underline that the learning curve of the surgeon is in such kinds of operation as a crucial issue in determining the success rate. conclusion in situ anterior vaginal wall sling technique for treatment of sui is simple and cost effective, while it has a low incidence of complications in the postoperative period. the mid-term success rate seems to be satisfactory; therefore, this procedure can be a reasonable option for sui. longer follow-up and a larger sample size are needed before final conclusion could be drawn. conflict of interest none declared. references 1. lebret t, lugagne pm, herve jm, et al. evaluation of tension-free vaginal tape procedure. its safety and efficacy in the treatment of female stress urinary incontinence during the learning phase. eur urol. 2001;40:543-7. 2. appell ra. the use of bone anchoring in the surgical management of female stress urinary incontinence. world j urol. 1997;15:300-5. 3. chaikin dc, rosenthal j, blaivas jg. pubovaginal fascial sling for all types of stress urinary incontinence: long-term analysis. j urol. 1998;160:1312-6. 4. cross ca, cespedes rd, mcguire ej. our experience with pubovaginal slings in patients with stress urinary incontinence. j urol. 1998;159:1195-8. 5. chaikin dc, blaivas jg, rosenthal je, weiss jp. results of pubovaginal sling for stress incontinence: a prospective comparison of 4 instruments for outcome analysis. j urol. 1999;162:1670-3. 6. ulmsten u, henriksson l, johnson p, varhos g. an ambulatory surgical procedure under local anesthesia for treatment of female urinary incontinence. int urogynecol j pelvic floor dysfunct. 1996;7:81-5. 7. olsson i, kroon u. a three-year postoperative evaluation of tension-free vaginal tape. gynecol obstet invest. 1999;48:267-9. 8. kuuva n, nilsson cg. a nationwide analysis of complications associated with the tension-free vaginal tape (tvt) procedure. acta obstet gynecol scand. 2002;81:72-7. 9. paraiso mf, muir tw, sokol ai. are midurethral slings the gold standard surgical treatment for primary genuine stress incontinence? j am assoc gynecol laparosc. 2002;9:405-7. 10. waetjen le, subak ll, shen h, et al. stress urinary incontinence surgery in the united states. obstet gynecol. 2003;101:671-6. 11. neuman m. tension-free vaginal tape bladder penetration and long-lasting transvesical prolene material. j pelvic med surg. 2004;10:307-9. 12. mustafa m, wadie bs. placard-shaped in situ vaginal wall sling for the treatment of stress urinary in situ anterior vaginal wall sling—mustafa and wadie urology journal vol 6 no 1 winter 2009 39 incontinence. int j urol. 2006;13:132-4. 13. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation subcommittee of the international continence society. neurourol urodyn. 2002;21:167-78. 14. baden wf, walker ta. surgical repair of vaginal defects. philadelphia: jb lippincott; 1992. 15. mustafa m, wadie bs. bladder erosion of tensionfree vaginal tape presented as vesical stone; management and review of literature. int urol nephrol. 2007;39:453-5. 16. coucke k, kesteloot k. a comparison of health care financing policies for incontinence products in european countries. eur urol. 2000;37:36-42. 17. albo me, richter he, brubaker l, et al. burch colposuspension versus fascial sling to reduce urinary stress incontinence. n engl j med. 2007;356:2143-55. 18. wadie bs, edwan a, nabeeh am. autologous fascial sling vs polypropylene tape at short-term followup: a prospective randomized study. j urol. 2005;174:990-3. 19. abdel-fattah m, barrington jw, arunkalaivanan as. pelvicol pubovaginal sling versus tension-free vaginal tape for treatment of urodynamic stress incontinence: a prospective randomized three-year follow-up study. eur urol. 2004;46:629-35. 20. tseng lh, wang ac, lin yh, li sj, ko yj. randomized comparison of the suprapubic arc sling procedure vs tension-free vaginal taping for stress incontinent women. int urogynecol j pelvic floor dysfunct. 2005;16:230-5. 21. volkmer bg, nesslauer t, rinnab l, schradin t, hautmann re, gottfried hw. surgical intervention for complications of tension-free vaginal tape procedure. j urol. 2003;169:570-4. 22. wyczolkowski m, klima w, piasecki z. reoperation after complicated tension-free vaginal tape procedures. j urol. 2001;166:1004-5. 23. sweat sd, itano nb, clemens jq, et al. polypropylene mesh tape for stress urinary incontinence: complications of urethral erosion and outlet obstruction. j urol. 2002;168:144-6. 24. jorion jl. endoscopic treatment of bladder perforation after tension-free vaginal tape procedure. j urol. 2002;168:197. 25. tsivian a, kessler o, mogutin b, et al. tape related complications of the tension-free vaginal tape procedure. j urol. 2004;171:762-4. 26. lo ts, horng sg, chang cl, huang hj, tseng lh, liang cc. tension-free vaginal tape procedure after previous failure in incontinence surgery. urology. 2002;60:57-61. 27. summitt rl, jr., stovall tg, bent ae, ostergard dr. urinary incontinence: correlation of history and brief office evaluation with multichannel urodynamic testing. am j obstet gynecol. 1992;166:1835-40. 28. weidner ac, myers er, visco ag, cundiff gw, bump rc. which women with stress incontinence require urodynamic evaluation? am j obstet gynecol. 2001;184:20-7. 29. hastie kj, moisey cu. are urodynamics necessary in female patients presenting with stress incontinence? br j urol. 1989;63:155-6. 30. lagro-janssen al, debruyne fm, van weel c. value of the patient’s case history in diagnosing urinary incontinence in general practice. br j urol. 1991;67:569-72. v08_no_1_print_3.pdf laparoscopic urology 31urology journal vol 8 no 1 winter 2011 laparoscopic redo pyeloplasty after failed open surgery pejman shadpour, ramin haghighi, robab maghsoudi, masoud etemedian purpose: to report our experience in treating patients with failed previous open pyeloplasty by transperitoneal laparoscopic pyeloplasty. materials and methods: eleven patients with previous failed open pyeloplasty were reviewed, all of whom had undergone transperitoneal laparascopic pyeloplasty. all procedures were performed by a single team. depending on the anatomic situation, either dismembered or a flap technique was utilized. subsequent follow-up was by ultrasonography initially, and diuretic renal scintigraphy and/or intravenous urography at least 12 months after the re-operation. data were collected from the medical records. results: the study group consisted of 7 men and 4 women with the mean age of 41.4 years (range, 27 to 55 years). mean operation time was 208 minutes (range, 165 to 250 minutes) and mean hospital stay was 3.6 days (range, 3 to 5 days). mean follow-up was 24.1 months (range, 12 to 42 months). the overall success rate for these salvage laparoscopic pyeloplasties was 90.9%. only one female patient developed dull flank pain 3 months after stent removal. there was no conversion to open surgery. none experienced major complications or required blood transfusion. conclusion: laparoscopic pyeloplasty can be a valid and feasible option in treating patients with failed prior open pyeloplasty. urol j. 2011;8:31-7. www.uj.unrc.ir keywords: laparoscopy, ureteral obstruction, reoperation, salvage therapy, treatment failure hasheminejad kidney center, tehran university of medical sciences, tehran, iran corresponding author: pejman shadpour, md hasheminejad kidney center, valiasr ave, vanak sq, 19697, tehran, iran tel: +98 21 8864 4444 fax: +98 21 8864 4447 e-mail: pshadpour@tums.ac.ir received april 2010 accepted september 2010 introduction ureteropelvic junction obstruction (upjo) may lead to hydronephrosis and progressive renal function impairment if left untreated. open pyeloplasty has become the gold standard for treatment of primary upjo, with success rates exceeding 90%.(1) although failure of pyeloplasty is uncommon; however, it can occur even years after the initial open procedure.(2) management options for secondary upjo continue to evolve.(3) until recently, endopyelotomy and open surgery were the only appropriate modalities for management of recurrent upjo. secondary open pyeloplasty is associated with significant difficulty and increased morbidity with variable success rates of 37.5% to 71.4%, which are uniformly lower than primary surgery.(4,5) endopyelotomy, once recommended as the initial salvage method of choice for failed upjo repair,(6) was later shown to be even inferior to open re-operation in outcome. laparoscopy has recently been adopted as another alternative.(2,5,7) therefore, we have continued our research for a sufficiently effective, laparoscopic redo pyeloplasty—shadpour et al 32 urology journal vol 8 no 1 winter 2011 yet less morbid option. we hereby report the midterm results of our experience with laparoscopic secondary pyeloplasty. materials and methods this retrospective study was carried out on 11 patients who had undergone transperitoneal laparoscopic pyeloplasty as salvage for prior failed open retroperitoneal pyeloplasty between february 2005 and january 2008. the patients presented to our center with lateralized flank symptoms or routine radiologic follow-up pointing to recurrent or unresolved upjo following open pyeloplasty. ureteropelvic junction obstruction was individually confirmed by diuretic renal scan, using diethylene triamine penta acetic acid (dtpa) and further clarified anatomically by an intravenous urography. patients with urinary obstruction, defined as evacuation t1/2 on diuretic renogram exceeding 20 minutes after 1mg/kg lasix infusion, were offered to choose between a second open procedure or laparoscopy (table 1). in all the patients consenting to laparoscopic salvage pyeloplasty, the procedure was performed by transperitoneal approach. as with any reoperative procedure, extra attention was paid to avoid inadvertent organ injury during entry, including c as e a ge g en de r ti m e si nc e op en py el op la st y, m on th te ch ni qu e of fa ile d pr oc ed ur e p re -o p d tp a sc an r ed o te ch ni qu e o pe ra tio n tim e, m in h os pi ta l st ay , d p os to p d tp a t1 /2 , m in fo llo w up , m on th c om pl ic at io n in ci de nt al fin di ng s t 1/ 2 % r en al fu nc tio n 1 27 f 40 d is m em be re d py el op la st y 90 40 h yn es py el op la st y 24 5 3 10 30 lo w er p ol e ve ss el 2 32 f 24 d is m em be re d py el op la st y 50 28 f la p pl as ty 24 1 4 65 18 in iti al p er si st en t ob st ru ct io n re lie ve d by ur et er os co pi c ba llo on di la ta tio n f ib ro si s 3 52 m 55 d is m em be re d py el op la st y 12 0 35 f la p pl as ty 17 0 3 10 12 a dh es io ns & f ib ro si s 4 45 m 40 d is m em be re d py el op la st y 60 44 h yn es py el op la st y 25 0 5 7 42 4da y dr ai na ge c ro ss in g ve ss el 5 47 m 40 d is m em be re d py el op la st y 60 49 f la p pl as ty 16 5 3 11 32 a dh es io ns & f ib ro si s 6 45 f 39 d is m em be re d py el op la st y 12 0 38 f la p pl as ty 18 0 4 14 18 f ib ro si s 7 29 m 48 d is m em be re d py el op la st y 40 36 f la p pl as ty 19 5 3 14 24 a dh es io ns & f ib ro si s 8 42 f 52 d is m em be re d py el op la st y 50 41 h yn es py el op la st y 23 0 5 13 28 5da y dr ai na ge a dh es io n ba nd 9 48 m 74 d is m em be re d py el op la st y 60 32 f la p pl as ty 17 0 3 15 34 a dh es io ns & f ib ro si s 10 33 m 46 d is m em be re d py el op la st y 90 43 f la p pl as ty 19 0 3 12 15 f ib ro si s 11 55 m 85 d is m em be re d py el op la st y 90 45 f la p pl as ty 25 0 4 12 12 a dh es io ns & f ib ro si s ta bl e 1. s um m ar y of fi nd in gs in 1 1 la pa ro sc op ic r ed o py el op la st ie s *d t pa in di ca te s di et hy le ne tr ia m in e pe nt a ac et ic a ci d; f , f em al e; a nd m , m al e. t 1/ 2 = 50 % e xc re tio n tim e. laparoscopic redo pyeloplasty—shadpour et al 33urology journal vol 8 no 1 winter 2011 anticipatory mechanical bowel prep on the night before the surgery. port placement was tailored to the patient’s habitus, but typically involved 4 trocars, with the camera at the umbilicus and two working trocars at the midline or pararectus position. the fourth port, used for retraction by the assistant and subsequent drain placement, was placed on the anterior axillary line. to gain adequate exposure of the right renal hilum, we suspended the liver edge by placing the fourth trocar just below the xyphoid. through it, a blunt tipped grasping instrument was introduced to support the inferior aspect of the liver, while attached to the parietal peritoneum overlying the costal margin. as a rule, we created sufficient exposure to visualize the first few centimeters of the proximal ureter down to the lower pole of the respective kidney. this was crucial to rule out de novo extrinsic obstructing structures, such as an adhesion band, and indeed overlook primary ones at the outset. we then chose between anderson-hynes dismembered pyeloplasty and flap pyeloplasty, based on individual anatomic circumstances on a case by case basis. we preferred dismemberment when the strictured and presumably ischemic segment was short (figure 1). as a rule, we avoided pelvic trimming whenever possible, and kept it to a necessary minimum otherwise. however, the extent of pelvic reduction at the initial open procedure was not known, because the patients had been referred to our center and procedural details of their first operation were not available. the use of heat and cautery was deliberately avoided by utilizing cold shears only during all dissections close to the pelvis and the ureter, as far as technically possible. suturing was done free-hand with absorbable 5-0 polyglactin suture over a single 4.8-f double j stent. a closed gravity drain was placed in proximity of the repair, and foley drainage maintained for at least 48 hours. the drain was removed 24 hours after the urethral catheter, provided there was no leak. preoperative parameters, including operation time, hospital stay, success rate, and complications if encountered were recorded. success was defined as both symptomatic relief and resolution of obstruction on scintiscan. patients were followed up by dtpa renal scan +/intravenous urography in addition to subjective symptoms. initial imaging follow-up began 6 weeks after stent removal and every 6 months with ultrasonography and dtpa +/ intravenous urography at 12 months and yearly thereafter unless dictated otherwise by symptoms or ultrasonographic findings (figure 2). results the participants consisted of 7 men and 4 women with the mean age of 41.4 years (range, 27 to 55 figure 1. a) freeing secondary adhesions at a redo right transperitoneal laparoscopic pyeloplasty case, b) antegrade stent placement through the freed ureter prior to completing the dismembering. laparoscopic redo pyeloplasty—shadpour et al 34 urology journal vol 8 no 1 winter 2011 years). seven patients had presented with chronic dull flank pain after primary surgery while 3, including one with coexisting flank pain, had complained of lower urinary tract symptoms. two remaining asymptomatic patients had been diagnosed on routine follow-up imaging. these patients had presented with recurrent obstruction at an average of 49.3 months (range, 24 to 85 months) after their initial open pyeloplasty. the failed initial technique had involved dismemberment in all 11 subjects. mean operation time was 208 minutes (range, 165 to 250 minutes) and mean hospital stay was 3.6 days (range, 3 to 5 days). technically, the obstruction was amenable to treatment by dismembering alone in 3 patients. the other 8 had longer stenotic segments and required flap pyeloplasty to procure a dependable caliber throughout the involved portion. two subjects were found to have an impinging crossing vessel, and were treated by dismemberment. fibrosis and/or periureteric adhesions seemed to be the cause in the remaining two-thirds of patients. no subject required conversion to open surgery or blood transfusion. no major complication, including persistent leak (beyond the first week), visceral or vascular injury, or symptomatic infection was encountered in the subjects. laparoscopic redo was considered as a failure in 1 female patient, who presented with persistent dull pain 3 months after removing her stent. diethylene triamine penta acetic acid renography revealed significant obstruction at the ureteropelvic junction once more. on ureteroscopic evaluation using an 8-f semi-rigid scope, a thin translucent epithelial diaphragm was found to be the cause for continued obstruction. this was probably resulted from early superficial adhesion of an otherwise healthy suture line. balloon dilation over a guidewire and re-stenting with two 4-f indwelling catheters side by side for four weeks solved the clinical problem. her flank pain resolved and did not recur. subsequent imaging was also consistent with effective resolution of upjo. the mean follow-up of the patients was 24.1 months (range, 12 to 42 months). considering the single incident of initial failure, the overall success rate for these salvage laparoscopic pyeloplasties was 90.9%. discussion ureteropelvic junction obstruction has enjoyed excellent surgical treatment outcomes consistently above 90%(4,8) since anderson and hynes first described dismembered pyeloplasty more than 50 years ago.(8) open surgical pyeloplasty by their technique remains the gold standard to which newer techniques must be compared.(1) despite observed success in relieving obstruction, functional improvement after upjo repair is less certain.(9) one study looking at renal function before and after pyeloplasty showed no improvement in patients with pre-operative renal function of less than 20%.(10) in another figure 2. a) pre-operative intravenous urogram displaying anatomical impression at the proximal ureteral segment corresponding to the bands in figure 1, b) postoperative image at one-year follow-up confirming funneling and relieved pressure effect. a b laparoscopic redo pyeloplasty—shadpour et al 35urology journal vol 8 no 1 winter 2011 study, only 2 of 10 patients with pre-operative renal function less than 30% improved after the repair.(11) the flank incision is inherently painful; thus, the search for decreasing morbidity and hospital care costs associated with this invasive approach has persuaded innovations directed toward developing less invasive techniques, while preserving the already excellent success rate.(12) application of endourologic techniques to the management of upjo has proved to be beneficial toward decreasing the length of hospital stay and time to return to pretreatment activities. however, success rates have not been comparable to classic open surgical intervention.(12-14) therefore, along with the growing application of various techniques for treatment of upjo; there has been a steadily growing number of patients who have “failed primary intervention”.(5) additionally, despite its high success rate, primary open pyeloplasty may also fail.(2) regardless of the initial technique, options for addressing recurrent upjo include surgical pyeloplasty and retrograde or antegrade endourologic intervention.(2,4,5,10,15) there are also a limited number of reports on the application of laparoscopy. laparoscopic pyeloplasty introduced by schuessler in 1993,(16) has been shown to reduce hospital stay while offering success rates equivalent to open surgery in primary subjects. excellent outcomes have been reported for both transperitoneal and retroperitoneal laparoscopic pyeloplasty.(17,18) we have also achieved excellent results with the transperitoneal approach over the past 9 years, and continue to use it as the standard approach at our institution. although most studies regarding laparoscopic pyeloplasty are in the context of primary repair, laparoscopic pyeloplasty has recently been shown to have excellent success rates for persistent upjo after a previously failed procedure.(7,17,18) sundaram and colleagues studied 3 laparoscopic redo pyeloplasties with history of initial open pyeloplasty.(7) they achieved 83% overall objective success for all 36 laparoscopic pyeloplasties, not differentiating between those failing open surgery and endopyelotomy. the authors concluded that salvage laparoscopic pyeloplasty can be performed safely with success comparable to primary open surgery (table 2). we must keep in mind, however, that only three patients in that series had failed prior open pyeloplasty. the overall number of patients with persistent upjo who have undergone salvage laparoscopic pyeloplasty and their follow-up are too limited to draw any firm conclusions. inagaki and associates reported that of a total of 147 patients who underwent laparoscopic pyeloplasty, 25 had failed prior upjo treatment. they stated a success rate of 84% in the salvage pyeloplasty cohort; however, technical characteristics of previously failed upjo treatment were not specified.(18) basiri and coworkers reported 18 patients that underwent laparoscopic pyeloplasty after a failed open procedure. this report is, nevertheless, limited by short-term follow-up (14 months).(15) shapiro and colleagues reported 89% success in their experience with a small group of 9 salvage laparoscopic pyeloplasties. all patients had open pyeloplasty with a mean of 67.7 months elapsing from the failed primary procedure. five of their patients underwent laparoscopic anderson-hynes, 3 foley y-v, and 1 z-plasty. but as the authors explained, their study was affected by referral bias, retrospective nature, study number of patients approach dismembered / total mean operation time, min mean hospital stay, d follow-up, month success rate, % basiri et al(15) 18 transperitoneal 6/18 254 (150 to 450) 7.2 14.1 (4 to 25.5) 77.8 sundaram et al(7) 36 transperitoneal na 372 (162 to 200) 2.9 10 (3 to 40) 83 shapiro et al(2) 9 transperitoneal 5/9 204 (80 to 264) 2.1 66 (12 to 119) 89 piaggio et al(19) 6 transperitoneal 5/6 290 (206 to 280) 2.5 7 (1 to 24) 80 shadpour et al (present series) 11 transperitoneal 3/11 208 (165 to 250) 3.6 24.1 (12 to 42) 90.9 table 2. comparison of representative laparoscopic repeat pyeloplasty reports with the present series *na indicates not applicable. laparoscopic redo pyeloplasty—shadpour et al 36 urology journal vol 8 no 1 winter 2011 and small sample size.(2) piaggio and gonzalez performed a retrospective chart review of 10 consecutive patients undergoing re-operative pyeloplasty. they confirmed the feasibility of redo laparoscopic pyeloplasty in the pediatric population, and concluded that in experienced hands, pediatric redo laparoscopic pyeloplasty can be performed safely with a success rate similar to the open procedure.(19) it may also provide faster recovery with decreased narcotic requirement and morbidity.(20) other options in patients with prior failed open pyeloplasty are repeated open pyeloplasty and endourologic procedures. lim and walker reported the results of repeated surgery for persistent upjo in 10 patients. satisfactory resolution was achieved by open redo with salvage rate of 75%, but as the authors mentioned, the overall number of patients is again too small to draw any firm conclusions.(3) ng and coworkers reported their experience with failed open surgery and antegrade or retrograde intervention for primary upjo.(5) open operative salvage pyeloplasty achieved significantly better results, with overall success rate of 95% in contrast with 59.1% for endourologic salvage. furthermore, the high success rate achieved by open salvage pyeloplasty was independent of whether the failed primary procedure was endourologic or open (94.1% and 100%, respectively). in contrast, endourologic salvage proved to be significantly more successful in the setting of failed open intervention compared to failed endourologic intervention, with success rate of 71.4% versus 37.5%, respectively (p = .026). although some entertain the opinion that endourologic intervention is generally the most attractive procedure for patients with failed open pyeloplasty, it has become clear that endourologic failure portends further endourologic failure. in our study, the overall success rate for redo laparoscopic pyeloplasty was 90.9%, which is compatible with literature. the only failure in our subjects occurred in a 32-year-old woman with flank pain, who was confirmed to have persistent stenosis 3 months after the secondary intervention. rigid ureteroscpy easily confirmed and relieved a thin epithelial adhesion at the anastomotic site. subsequently, there has been no recurrence of symptoms and this cure was confirmed by dynamic imaging one year onward. interestingly, she was our only patient who had less than 30% selective renal function on the affected side to begin with. this superficially agrees with ortapamuk and colleagues’ suggestion, that renal units with overall glomerular function of less than 30% frequently carry less desirable functional outcome.(20) the type of mechanical obstruction, ie, epithelial adhesion, encountered in our patient could have been facilitated by a poor functioning and possibly low flow (constantly coapted) anastomosis during the early phase of healing. this hypothesis must be further investigated. as mentioned earlier, we intentionally avoided the use of cautery and other types of heat injury to tissues during the complex dissection. this may have contributed to the favorable outcome. the theoretic drawback of such an effort would be delayed bleeding and hematoma formation; neither of which was detected in these 11 patients. the relatively longer stenotic segment in patients undergoing reoperation significantly limits the proportion of cases amenable to dismembered (as opposed to flap) repair. as seen in table 1, two of these 11 patients had failed due to oversight during the previous open retroperitoneal pyeloplasty, manifesting in a missed extrinsic vascular obstruction. these two subjects and another patient with a short thick adhesion band were the only three subjects correctable by anderson-hynes pyeloplasty. the possible implication of crossing vessels in refractory upjo should not be taken lightly, as suggested by our present report, in which 18% displayed such an element. this observation is likely to be repeated at similar tertiary referral settings. failure of a very effective procedure, such as hynes pyeloplasty, is exceedingly rare in experienced hands. therefore, this series of failed pyeloplasty subjects sent-in from other hospitals where the procedure may be too infrequent to give the added benefit of accumulating experience, must encourage extra diligence. this should include scrutiny of the entire diagnostic and treatment process leading to that suboptimal result. laparoscopic redo pyeloplasty—shadpour et al 37urology journal vol 8 no 1 winter 2011 our study may be limited by its retrospective nature and modest sample size, but is enhanced by comparing the surgical technique of initial and redo procedures, and more than two-year follow-up. the very promising response to a trivial intervention in our only failed subject may be copied in larger series making laparoscopic redo pyeloplasty an even more dependable and attractive alternative. conclusion clearly, for those with failed prior open pyeloplasty, the laparoscopic approach provides an attractive alternative. it brings minimal additional cosmetic detriment; with success rates comparable to open redo pyeloplasty, and by far surpassing the previous choice, ie, endopyelotomy. however, further large scale comparative studies are needed to draw final conclusion. conflict of interest none declared. references 1. persky l, krause jr, boltuch rl. initial complications and late results in dismembered pyeloplasty. j urol. 1977;118:162-5. 2. shapiro ey, rais-bahrami s, morgenstern c, napolitano b, richstone l, potters l. long-term outcomes in younger men following permanent prostate brachytherapy. j urol. 2009;181:1665-71; discussion 71. 3. lim dj, walker rd, 3rd. management of the failed pyeloplasty. j urol. 1996;156:738-40. 4. anderson jc, hynes w. retrocaval ureter; a case diagnosed pre-operatively and treated successfully by a plastic operation. br j urol. 1949;21:209-14. 5. ng cs, yost aj, streem sb. management of failed primary intervention for ureteropelvic junction obstruction: 12-year, single-center experience. urology. 2003;61:291-6. 6. jabbour me, goldfischer er, klima wj, stravodimos kg, smith ad. endopyelotomy after failed pyeloplasty: the long-term results. j urol. 1998;160:690-2; discussion 2-3. 7. sundaram cp, grubb rl, 3rd, rehman j, et al. laparoscopic pyeloplasty for secondary ureteropelvic junction obstruction. j urol. 2003;169:2037-40. 8. o’reilly ph, brooman pj, mak s, et al. the longterm results of anderson-hynes pyeloplasty. bju int. 2001;87:287-9. 9. khan m, khan wy, ahmad r, ghani f. diuretic radionuclide renography in assessing andersonhynes pyeloplasty in unilateral pelvi-ureteric junction obstruction. j postgrad med inst. 2007;21:296-300. 10. gupta m, tuncay ol, smith ad. open surgical exploration after failed endopyelotomy: a 12-year perspective. j urol. 1997;157:1613-8; discussion 8-9. 11. dimarco ds, gettman mt, mcgee sm, et al. longterm success of antegrade endopyelotomy compared with pyeloplasty at a single institution. j endourol. 2006;20:707-12. 12. preminger gm, clayman rv, nakada sy, et al. a multicenter clinical trial investigating the use of a fluoroscopically controlled cutting balloon catheter for the management of ureteral and ureteropelvic junction obstruction. j urol. 1997;157:1625-9. 13. badlani g, eshghi m, smith ad. percutaneous surgery for ureteropelvic junction obstruction (endopyelotomy): technique and early results. j urol. 1986;135:26-8. 14. tawfiek er, liu jb, bagley dh. ureteroscopic treatment of ureteropelvic junction obstruction. j urol. 1998;160:1643-6; discussion 6-7. 15. basiri a, behjati s, zand s, moghaddam sm. laparoscopic pyeloplasty in secondary ureteropelvic junction obstruction after failed open surgery. j endourol. 2007;21:1045-51; discussion 51. 16. schuessler w, grune m, tecuanhuey l, preminger g. laparoscopic dismembered pyeloplasty. j urol. 1993;150:1795. 17. zhang x, li hz, ma x, et al. retrospective comparison of retroperitoneal laparoscopic versus open dismembered pyeloplasty for ureteropelvic junction obstruction. j urol. 2006;176:1077-80. 18. inagaki t, rha kh, ong am, kavoussi lr, jarrett tw. laparoscopic pyeloplasty: current status. bju int. 2005;95 suppl 2:102-5. 19. piaggio la, gonzalez r. laparoscopic transureteroureterostomy: a novel approach. j urol. 2007;177:2311-4. 20. ortapamuk h, naldoken s, tekdogan uy, aslan y, atan a. differential renal function in the prediction of recovery in adult obstructed kidneys after pyeloplasty. ann nucl med. 2003;17:663-8. 1099vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l evidence based practice: perspectives of iranian urologists sakineh hajebrahimi,1 fatemeh sadeghi-ghyassi,2 nahid olfati,2 saeed dastgiri,3 leili maghbouli2 corresponding author: fatemeh sadeghi-ghyassi, msc iranian evidence based medicine center of excellence, faculty of medicine, tabriz university of medical sciences, tabriz, iran tel: +98 411 3342219 fax: +98 411 3342219 e-mail: ghyassif@tbzmed.ac.ir received march 2011 accepted july 2013 1 urology department, drug applied research center, tabriz university of medical sciences, tabriz, iran 2 iranian evidence based medicine center of excellence, tabriz university of medical sciences, tabriz, iran 3 community medicine department, iranian evidence based medicine center of excellence, tabriz university of medical sciences, tabriz, iran miscellaneous purpose: to determine the attitudes and beliefs of iranian urologists toward evidence based medicine (ebm) and investigation of the barriers of evidence based practice (ebp). materials and methods: a selfadministrated, likert scale questionnaire designed in persian and filled up by censuses selected urologist from iranian urology association (iua). data were entered to predictive analytics soft ware version 18.0 and descriptive statistics were obtained for all parts of the questionnaire. results: a total of 111 out of 500 iranian urologists who attended in iua annual meeting, responded to the questionnaires. mean attitude score of respondents was 30.4 (sd: 5.7, range 16-40). attitude score showed statistically significant association to previous participation in ebm workshops (p = .01). of participants 96% believed ebp will improve patient care and 76.2% of them appreciated the impact of use of research utilization and application of evidence based guidelines on clinical decision making and the outcome of surgery. the main barriers to ebp stated as lack of time (64.8%), facilities (53.4%), and training in ebm (29.4%). conclusion: the urologists have positive attitudes towards ebp. however, regarding lack of time, pre-appraised databases or ebp guidelines can be helpful. evidence based workshops and familiarity with evidence databases is recommended for iranian urologists. in addition, health care system and policy makers could play a major role to provide a culture of ebp. keywords: evidence based medicine; decision making; urology; attitude of health personnel; practice guidelines as topic. 1100 | miscellaneous introduction the birth of term “evidence-based medicine” was in 90’s of the twentieth century,(1) although it was introduced by rhazes and avicenna,(2) two iranian scientists, in very early ages. more than twenty years have passed and during this time evidence-based practice (ebp) concepts are coming more popular and acceptable by experts. it has entered in some medical schools’ curriculum, and consequently, in practice and patient care.(3,4) alongside these developments, pre-appraised evidence databases such as turning research into practice (trip), cochrane established, developed and grew progressively. now, after two decades, it seems that most of practitioners including surgeons have heard about ebm. but it doesn’t seem that attitudes toward and knowledge of ebm is growing so fast in surgical fields such as urology.(5,6) this might be due to some barriers such as lack of time or very busy clinics. some studies showed that most of urologists in the survey population have not enough knowledge about ebm concepts;(5,7) nevertheless, there is raising tendency among urologists toward learning of evidence-based practice.(7,8) beside lack of time, there are some known barriers for implementing ebp by practicing physicians and clinical staff. in many clinical disciplines, studies have been conducted to find these barriers as well as in urology.(5,6,9,10) factors such as lack of high quality evidence in the surgical practice field,(11) lack of formal educational curricula of ebm for residents(12) and surgical cultures have been reported as barriers of ebp by surgeons. limited studies have evaluated attitude and knowledge of ebm among urologist in developed countries.(5,6,9,10) although various studies have evaluated iranian practitioners’ implementation of ebm and the barriers as a developing country;(13-19) but iranian urologists’ perspectives have not evaluated and presented in a structured study. the aim of this study is to assess iranian urology association (iua) members’ attitudes and beliefs toward ebp using a standard questionnaire, and thereby, to form appropriate evidence based educational and training basis of iranian urologists in the future. materials and methods the study was a cross-sectional, questionnaire based survey performed during the annual congress of iranian urology association (april 2009). the questionnaire was designed based on a literature review in persian language including 34 likert scale items.(18) in most sections respondents were asked to select an option among a 5-point likert scale. a “no opinion” option was also offered. the questionnaire consisted of 8 sections including attributes, attitude/beliefs, research utilization, terminology, research utilization skills. descriptions of these sections and the related questionnaire item(s) are demonstrated in table 1. expert validation of the questionnaire was performed by experts in the iranian center for ebm and a number of urologists. results of the reliability analysis are shown in table 1. distributers took a stand in the congress and invited participants to fill in the questionnaire. study subjects were selected and invited by censuses from almost 500 participants. accepting to participation was counted as consent. one hundred eleven of participants filled in the questionnaire by censuses selection and all included in the analysis. data were analyzed using predictive analytics soft ware (pasw) version 18.0 and descriptive statistics were obtained for all parts of the questionnaire (percent for data on nominal or ordinal scale and means and sds for interval scale data). inferential statistics were used where applicable. results mean age of respondents was 43.62 (sd, 9.77; range, 2668). most participants were male (82.7%). mean years of clinical practice were 13.03 (sd, 8.26) (table 2). almost all urologists acknowledged the current information overload (98.1%) and the need to be familiar with evidence (92.3%). they as well appreciated the impact of research utilization and use of practice guidelines on clinical decision making and quality of health services and the outcome of surgery (76.2%). on the other hand, urologists 1101vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l almost believed that, clinical expertise is a major source of knowledge; they acknowledged that urology journals are the most informative sources of evidence. more than half of participants believed that research utilization is costly and time consuming (62.8% and 64.3%, respectively) but they stated that it won’t violate physicians’ autonomy or clinical expertise (69.1% and 61.6%, respectively). less than 40% of urologists stated that they don’t use research in practice because they hardly understand statistics whereas about 50% of them mentioned “unfamiliarity with information sources” as a reason. beside, 53.4% agreed that there are not enough facilities to practice evidence based. however about half (56.0%) expressed the idea that all their urologist colleagues use ebm in practice (table 3). in the attitudes section, scores calculated for each participant by adding up scores on each question. score 1 assigned to “somehow” and “strongly disagree” points of positively worded statements; score 2 to “somehow” and “strongly agree” points of positively worded statements, and 0 for “neutral”. reverse scores were assigned to negatively worded questions (i.e. score 2 to “somehow” and “strongly disagree” points of negatively worded statements; score 1 to “somehow” and “strongly agree” points of negatively worded statements, and 0 for “neutral). mean attitude score of respondents was 30.4 (sd, 5.7; range, 16-40). attitude score showed no statistical association to sex (p = .2), workplace (p = .5) and years of clinical experience (p = .09); whereas association to previous participation in ebm workshops was significant (p = .01). although 96% believed that ebp will improve patient care, 70.6% stated evidence based practice in urology | hajebrahimi et al table 1. questionnaire items and reliability analysis. section description cronbach α attributes including age, gender, years of clinical practice as an urologist, university of post-graduate study, work situation. n/a attitude/beliefs 21 questions (table 3), for example: there is information overload in the field of medicine: strongly disagree, somewhat disagree, neutral, somewhat agree, strongly agree 0.77 research utilization four questions assessing the overall, direct and indirect research use. for example: overall, in the past year, how often have you used research in the non-direct way in some aspect of your clinical practice? (1 = never to 5 = very often) n/a terminology eleven questions: how much do you understand the following terms? (1 = i don’t understand, 2 = don’t understand but would like to learn, 3 = it would not be helpful to me to understand, 4 = some understanding, 5 = understand and could explain to others): … sensitivity …relative risk …number needed to treat …level of evidence …confidence interval 0.76 organizational support eight questions: what percentage of your clinical practice do you feel is currently evidence-based? 1 ≤ 25% to 5 ≥ 75% 0.74 table 2. demographic characteristics of study subjects. numbers percent* mean (sd) gender female 18 17.3 male 86 82.7 missing 7 age (year) ≤ 30 5 5.3 43.62 (9.77) 31-40 39 53.2 > 40 50 8.8 missing 17 years of practice < 5 12 12.8 13.03 (8.26) 5-10 34 36.2 11-15 16 17.0 > 15 32 34.0 missing 17 place of practice only hospital 33 32.4 only private office 21 20.6 private office and hospital 47 46.1 missing 10 key: sd, standard deviation. * valid percent. 1102 | that they avoid using evidence in their practice because they think they don’t have authority to do so. although 52% reported that they have used evidence in at least half of their practice in the past year, this number dropped to 48.5% when we asked for the number of times they used research finding to answer their clinical questions and raised to 55.8% when we asked for indirect use of evidence. urologists were asked to say how much they are familiar with common terms used in clinical research papers. findings are presented in figure 1. for confirming the self-rated knowledge of related terms, we asked them to sort study designs in order of their level of evidence (figure 2). about half (43.4%) rated randomized controlled trials as the highest level and 30.3% gave case-controls the forth position. urologists were asked to rate their level of familiarity with evidence databases, including pubmed, ovid, trip database, cochrane library and also google. forty two (49.4%) have used google in their practice, and 37 (41.6%) have used pubmed. the similar numbers were 19 (23.8%), 4 (5.5%) and 13 (15.9%) for ovid, trip database and cochrane library, respectively. thirty five (39.3%) have heard about or read something about pubmed but didn’t use that in practice. the same data were 30.1%, 28%, 37.8% and 44.7% for ovid, trip database, cochrane library and google, respectively (figure 3). using likert scale questions, participants were asked to rate their skills regarding the use of evidence. about half (45.9%) reported that they are more than 50% positive in estimating their own research utilization skills and 54.5% table 3. urologists attitudes toward use of research evidence. strongly disagree somehow disagree don’t know somehow agree strongly agree there is information overload in the field of medicine. 0 0 1.3 12.8 85.3 urologists should be able to differentiate erroneous methodologies. 1.9 1 4.8 26 66.3 use of research will facilitate decision making. 1.0 4.9 5.8 42.7 45.6 using guidelines is the best exercise for health quality improvement. 1.0 1.0 10.5 41 46.7 clinical expertise could make a major source of knowledge for urologists. 1.9 11.1 3.7 48.1 35.2 medical practice is not based on research. 63.3 17.4 3.7 11.9 3.7 evidence based practice will improve the surgery outcome. 1.0 3.8 19.0 36.2 40 urology journals are the most informative sources of knowledge for urologists. 0.0 10.7 15.5 53.4 20.4 ebm is in contrast with autonomy. 29.9 39.2 16.5 10.3 4.1 use of research causes spending more time per visit. 5.1 19.4 11.2 43.9 20.4 use of research is costly 3.8 17.1 16.2 43.8 19.0 it’s difficult to understand statistics so i can’t use evidence. 26.5 35.3 13.7 16.7 7.8 ebm is in contrast with clinical expertise. 23.2 38.4 19.2 14.1 5.1 there are many socioeconomic factors that hinder research use. 2.9 15.5 25.2 36.9 19.4 all my urologist colleagues are using ebm in the management of patients. 7.5 14 22.4 33.6 22.4 i can’t use information resources so i can’t use evidence. 19.8 34.7 15.8 26.7 3.0 there are not enough facilities and resources to practice evidence based. 15.5 19.4 11.7 37.9 15.5 i don’t have knowledge to use evidence. 20.6 30.4 19.6 25.5 3.9 use of research is not practicable in the real world 23.5 25.5 27.5 18.6 4.9 i don’t have authority to change practice. 9.9 23.8 21.8 29.7 14.9 ebm is supported by non-clinicians. 13.6 14.6 34 24.3 13.6 numbers are in percent. key: ebm, evidence based medicine. miscellaneous 1103vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l evidence based practice in urology | hajebrahimi et al noted that more than half of their practice is based on evidence results. considering use of research by other surgeons, 54.9% had somehow or strongly positive attitudes towards use of research by their colleagues. nearly all (91.1%) urologists said that they want to learn and practice ebm. discussion in this study, the most common barriers in ebp mentioned by iranian urologists were time consuming, high costs, socioeconomic factors and lack of facilities and resources. although participants stated that ebp can improve patient care, but they believed that they were not allowed to apply the best evidence in their practice. whereas more than half of iranian urologists found socioeconomic factors, costs and lack of authority as barriers in ebp; in contrast to this finding, scales and colleagues showed that less than 10% of american urologists had same beliefs.(6) it might be related to some legal issues which lead the urologists to be more conservative. it seems that medical councilors and policy makers’ role is crucial in ebp in developing countries. similar to the results of this study, lack of time has been mentioned in some of the related studies as a main barrier. (20,21) it seems insufficient referral system in iran, has resulted in busy urology clinics. on the other hand, 53% of the american urologists concerned about lack of high quality evidences as an important barrier.(6) cabana and colleagues categorized barriers to implementation of clinical practice guidelines into three: knowledge, attitudes and behavior. they also argued that there are other “external factors” (i.e. environmental/guideline/patient factors) that may affect these three categories.(22) among external factors, lack of time, high costs and lack of facilities were the major barriers which we found in current study. all of these barriers are categorized in the environmental factors which can affect all three categories of knowledge, attitudes and behavior.(22) there was a significant relevancy among urologists’ attitude and their previous attendance in ebm workshops (p = .01). it means that education and knowledge may have a direct correlation with attitude. this issue has been configure 1. understanding of research-related terms. figure 2. rating of study types based on validity by urologists key: rct, randomized clinical trial. figure 3. use of different sources of knowledge. 1104 | firmed by other studies.(16,23) meanwhile, regarding that almost all of the urologists (91.1%) expressed their interest in learning and practicing ebm, it seems that iranian urology association should plan to hold ebm workshops in general and specific aspects. as well, medical schools’ role in ebm education for medical students can be defined in the long term. the authors had provided a practical guideline for ebp in urology departments, in their previous review.(24) at this study, according to the results, it seems there is a contrast between attitudes toward use of evidences to answer the clinical questions and familiarity with evidence databases. almost all of the urologists were aware of current information overloads and the need for appropriate search skills in order to find relevant evidence. in addition, they believed that relevant evidence could able them to facilitate decision making in routine clinical practice. nevertheless unfortunately only less than 16% of urologists were familiar with and used pre appraised recourses of high quality evidences like trip database and cochrane library. it should be noted that other studies reported an average of 4.3%-16% for above mentioned two databases. (25-28) we also conducted another survey for all health care professionals in iranian center for ebm which indicated 18.7% usage of cochrane and 10.8% usage of trip database which is rather same as this study.(29) however the gap between the rate of familiarity with these two databases and using them was high in these two studies (trip, 28% vs. 16.4%; cochrane, 37.8% vs. 18.2%). regarding that these two studies conducted in approximately same time, urologists need to be familiar with evidence databases and search strategies to improve their ebp. most of urologists in this study believed that ebp can improve their surgical outcomes but it is time consuming and costly. it can be solved by developing and using clinical guidelines. there is no debt that it takes often more time implementing of research findings in clinical practice as balas estimated approximately 17 years for fully integration of clinical research into everyday practice.(30) given that urologists appreciated the impact of guidelines and level of evidences, health policy makers can play a crucial role by supporting national practice guidelines and other high quality evidences. evidence based clinical guidelines should be adopted in persian and distributed among all iranian urologists. iranian urologists showed fractional understanding of the ebm terminology which is similar to another studies.(5,9,20) however the validation of self-rating skills is not explicit, but the good point is the interest of iranian urologists for implementation of the practice guidelines, which makes the understanding of ebm terminology much easier. conclusion in summery the urologists have a positive attitude towards ebp. however, this study identified a need for spend adequate time to ebm in daily urology practice. in addition the health system should provide an easy access to evidence databases. meanwhile evidence based workshops and preapprised recourses may play an important role. acknowledgements this study conducted by grant of iranian center for evidence-based medicine and research vice chancellor of the tabriz university of medical sciences. their great help is appreciated. also we would like to thank dr. jalil hosseini the secretary general of iranian urology association for his support. conflict of interest none declared. references 1. evidence-based medicine working group. evidence-based medicine. a new approach to teaching the practice of medicine. jama. 1992;268:2420-5. 2. shoja mm, rashidi mr, tubbs rs, etemadi j, abbasnejad f, agutter ps. legacy of avicenna and evidence-based medicine. int j cardiol. 2011;150:243-6. 3. widyahening is, van der heijden gj, moy fm, van der graaf y, sastroasmoro s, bulgiba a. from west to east; experience with adapting a curriculum in evidence-based medicine. perspect med educ. 2012;1:249-261. miscellaneous 1105vol. 10 | no. 4 | autumn 2013 |u r o lo g y j o u r n a l 4. kotur pf. introduction of evidence-based medicine in undergraduate medical curriculum for development of professional competencies in medical students. curr opin anaesthesiol. 2012;25:719-23. 5. dahm p, poolman rw, bhandari m, et al. american urological association membership. perceptions and competence in evidence-based medicine: a survey of the american urological association membership. j urol. 2009;181:767-77. 6. scales cd jr, voils ci, fesperman sf, et al. barriers to the practice of evidence-based urology. j urol. 2008;179:2345-50. 7. roth k, siemens dr. the status of evidence-based medicine education in urology residency. can urol assoc j. 2010;4:114-20. 8. dahm p, preminger gm, scales cd jr, fesperman sf, yeung ll, cohen ms. evidence-based medicine training in residency: a survey of urology programme directors. bju int. 2009;103:290-3. 9. sur rl, scales cd jr, preminger gm, dahm p. evidence-based medicine: a survey of american urological association members. j urol. 2006;176:1127-34. 10. stapleton am, cuncins-hearn a, pinnock c. attitudes to evidence-based practice in urology: results of a survey. anz j surg. 2001;71:297-300. 11. antes g, sauerland s, seiler cm. evidence-based medicine from best research evidence to a better surgical practice and health care. langenbecks arch surg. 2006;391:61-7. 12. bhandari m, montori v, devereaux pj, dosanjh s, sprague s, guyatt gh. challenges to the practice of evidence-based medicine during residents' surgical training: a qualitative study using grounded theory. acad med. 2003;78:1183-90. 13. mittal r, perakath b. evidence-based surgery: knowledge, attitudes, and perceived barriers among surgical trainees. j surg educ. 2010;67:278-82. 14. mozafarpour s, sadeghizadeh a, kabiri p, taheri h, attaei m, khalighinezhad n. evidence-based medical practice in developing countries: the case study of iran. j eval clin pract. 2011;17:651-6. 15. ahmadi-abhari s, soltani a, hosseinpanah f. knowledge and attitudes of trainee physicians regarding evidencebased medicine: a questionnaire survey in tehran, iran. j eval clin pract. 2008;14:775-9. 16. kouhpayehzadeh j, baradaran h, arabshahi ks, knill-jones r. clinical teachers' attitudes toward the efficacy of evidence-based medicine workshop and self-reported ability in evidence-based practice in iran. j contin educ health prof. 2006;26:210-4. 17. hatmi zn, tahvildari s, dabiran s, soheili s, sabouri kashani a, raznahan m. teaching evidence-based medicine more effectively. acta med iran. 2010;48:332-6. 18. olfati n, dastgiri s, hajebrahimi s, jahanbin h. factors influencing evidence-based practice by iranian general practitioners. int j health care qual assur. 2013;26:360-74. 19. ghanizadeh a, imaniyeh m, kadivar m. knowledge and attitude of medical students and lecturers toward evidence-based medicine: evidence from shiraz. j med educ. 2009;9:65-69. 20. mccoll a, smith h, white p, field j. general practitioners’ perceptions of the route to evidence based medicine: a questionnaire survey. bmj. 1998;316:361-5. 21. barghouti f, halaseh l, said t, halim-mousa a, dabdoub a. evidence-based medicine among jordanian family physicians-awareness, attitude, and knowledge. can fam physician. 2009;55:e6-13. 22. cabana md, rand cs, powe nr, et al. why don't physicians follow clinical practice guidelines? a framework for improvement. jama. 1999;282:1458-65. 23. khader ys, batayha w, al-omari m. the effect of evidencebased medicine (ebm) training seminars on the knowledge and attitudes of medical students towards ebm. j eval clin pract. 2011;17:640-3. 24. hajebrahimi s, mostafaie a. how to teach evidence-based medicine to urologists. indian j urol. 2011;27:490-3. 25. hider pn, griffin g, walker m, coughlan e. the informationseeking behavior of clinical staff in a large health care organization. j med libr assoc. 2009;97:47-50. 26. lai nm, nalliah s. information-seeking practices of senior medical students: the impact of an evidence-based medicine training programme. educ health (abingdon). 2010;23:151. 27. young jm, ward je. general practitioners' use of evidence databases. med j aust. 1999;170:56-8. 28. cullen rj. in search of evidence: family practitioners' use of the internet for clinical information. j med libr assoc. 2002;90:370-9. 29. sadeghi-ghyassi f, nosraty l, gojazadeh m, mostafaie a. evidence databases application: comparison of university faculties versus clinical residents in a developing country. j eval clin pract. 2013;19:292-97. 30. balas e. information systems can prevent errors and improve quality. j am med inform assoc. 2001;8:398-99. evidence based practice in urology | hajebrahimi et al assessment of the prognostic effect of blood urea nitrogen to serum albumin ratio in patients with fournier’s gangrene in a referral center farzad allameh1, saeed montazeri2, vahid shahabi2*, seyyed ali hojjati2, amir alinejad khorram2, zahra razzaghi4, sahar dadkhahfar3 urology journal/vol 19 no. 4/ july-august 2022/ pp. 325-328. [doi:10.22037/uj.v18i.6556] introduction fournier’s gangrene disease (fg), caused by a com-bination of aerobic and anaerobic organisms, is a life-threatening disease in which perineal and scrotal infections, followed by proliferation in the fascia, lead to soft tissue necrosis. the mortality risk is usually 20 to 40 %, but in some studies, it has been reported even at 88 %(1). fg mainly affects men through the third and sixth decade of their life though it may occur in all age groups, even women and infants(2). the average age of involvement is 50.9 years, and the disease ratio in men to women is 10 to 1(3). the mortality rate is higher in patients with delayed hospitalization, patients with diabetes mellitus, and those initially presented with sepsis(4). risk factors for fg include diabetes, alcoholism, medications, immunodeficiency, malignancies, kidney failure, and liver failure(5). female gender is also a risk factor for death in patients with fg, which is due to the increased prevalence of inflammation in the retroperitoneal space and the abdominal cavity on account of anatomical causes(6). the optimal outcome of fg treatment is based on rapid diagnosis, debridement of all necrotic tissues, and extensive antimicrobial experimental treatment, usually combined with antibiotics affecting aerobic and anaerobic bacteria. prevention of uroseptic shock is mandatory with the treatment of local infections(7). the prognostic role of the ratio of blood urea nitrogen (bun) to albumin in diseases such as hospital-acquired pneumonia and community-acquired pneumonia and non-small lung cancer has been proven. in this way, with increasing the ratio of bun to albumin, the risk of mortality and the need for icu, and the length of hospital stay will increase as well(8-11). given that no study has been performed on patients with fg, the current study could play a potentially beneficial role in reducing the mortality of fg patients. materials and methods patients with fg were consecutively admitted and enrolled to shohada-e-tajrish hospital (tehran, iran) from march 2008 to april 2020 in the study. the ethics committee of the hospital permitted us to review the patients' medical data. the patients' health records were de-identified. the research terms included fournier's gangrene (fg), soft tissue infection, and necrotizing fasciitis. patients’ gender, age, comorbidities (diabetes mellitus, cerebrovascular accidents, malignancies, urinary incontinence, and so on), laboratory data, duration of hospital stay, and final disease outcomes were included in 1urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 2department of urology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. 3skin research center, shahid beheshti university of medical sciences, tehran, iran. 4laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: epartment of urology, shohada-e-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. e mail: khafash88@gmail.com. iranreceived november 2020 & accepted may 2021 unclassified purpose: to assess the prognostic effect of blood urea nitrogen to serum albumin ratio in patients with fournier’s gangrene (fg) in a referral center. materials and methods: patients with fg were admitted and enrolled consecutively in this study from march 2008 to april 2020. statistical analysis was done to evaluate the differences between the two groups and to identify the best cutoff value to predict mortality and the need for intensive care. results: of all 114 patients, 46 patients (40.35%) died in the course of hospitalization and 40 entered the study. no variable manifested a notable difference except for the bun to albumin ratio, which was significantly different (p-value = 0.045). the ratio of bun to albumin was not associated with any other variables and was independently a predictor of death in fg patients. conclusion: the ratio of bun to albumin was significantly different among deceased and survived patients with fg. therefore, more studies with a larger sample size are still needed to access this parameter properly. keywords: blood urea nitrogen; fournier’s gangrene; intensive care unit; mortality; prognosis the medical data. disease diagnosis was based on the symptoms of pain, erythema, ulcers, swelling, crepitus, necrosis, purulent discharge, and later confirmations with the tissue inspection in the operating room. patients were excluded from the study if they had been hospitalized 90 days prior to the study. they were also excluded if they were chronically immunosuppressed (such as chemotherapy, human immunodeficiency virus infection, therapy with more than 20 mg prednisone or equivalent, and other immunosuppressive therapies) or if they had advanced liver disease or end-stage renal disease. the study was approved by the ethics committee of shahid beheshti university of medical sciences (ir. sbmu.src.rec.1399.005), and informed consent was obtained from all patients according to the hospital’s guidelines. some patients had missing data, so they were excluded. as mentioned, among 114 patients, 40 patients were enrolled in the study. results were expressed as mean ± sd frequency and confidence interval (ci). the normality of data was determined with the shapiro-wilk test. the nonparametric mann-whitney u test was applied for continuous variables and the chi-square test for categorical variables. variables significantly associated with mortal¬ity or need for intensive care at the 0.20 level in univariate analysis were considered in a multivariate backward analysis. analysis of a receiver-operating characteristic (roc) curve was performed to identify the best cutoff value to predict mortality and the need for intensive care. a probability value less than 0.05 was considered to be statistically significant. results during the study period, a total of 114 fg patients were admitted; of these, 40 patients entered the study and 74 patients were excluded. the average age of the patients was 62.58 ± 14.36 years, and the mean value of hospitalization days was 16.95 ± 12.14. among 114 patients, 46 (40.35%) died in the course of hospitalization. patient charac¬teristics are shown in table 1. the subjects were divided into two groups (deceased and surviving), and the variables were studied in both. none of the variables showed a significant difference, except for the ratio of bun to albumin. the comparison of variables in the two groups is given in table 2. according to the data, the ratio of bun to albumin was not correlated with any of the other variables and was independently a predictor of death in fg patients. roc curve was used to determine the optimal cut-off value of the bun to albumin ratio. the value of 12.71 was determined with 79% sensitivity and 62% specificity. the roc curve for predicting mortality by the bun to albumin ratio is depicted in figure 1. [the odds ratio is 6.13 ( 1.17 – 32.10 ) and the relative risk is 2.86 (1.08 – 7.58); auc = 0.690 (0.522 – 0.858 ) ( p-value = 0.040 )] no significant relationship was observed between the ratio of bun to albumin and the number of hospitalization days (p = 0.48) by the spearman correlation test. although patients who needed hospitalization in the icu had a higher bun to albumin ratio (18.90 ± 11.04 letter 242 minimum maximum mean std. deviation age 25 87 62.58 14.360 days of admission 3 62 16.95 12.140 hemoglobin 7.1 15.6 10.6 2.07 platelet (×1000) 28 461 216.6 107.3 white blood cells (×1000) 0.32 57 17.2 11.6 albumin 1 .50 4.07 2.57 0.56 bun 8 110 42.8 25.8 estimated sedimentation rate 2 92 43.5 26.3 c-reactive protein 4 181 70.25 46.3 ast 6 75 31.37 17.45 alt 4 146 24.74 27.12 alkaline phosphatase 90 2364 338.96 455.41 bun to albumin ratio 2.86 51.49 17.16 10.34 table 1. baseline characteristics of enrolled patients bun:blood urea nitrogen; ast:aspartate aminotransferase; alt:alanine aminotransferase bun, blood urea nitrogen; ast, aspartate aminotransferase; alt, alanine aminotransferase deceased (n = 20) surviving (n = 20) p value age 66.45 ± 10.097 58.70 ± 17.02 0.88 days of admission 18.45 ± 14.136 15.45 ± 9.897 0.44 hemoglobin 10.12 ± 2.209 11.2 ± 1.836 0.1 platelet (×1000) 206.1 ± 108.1 226.5 ± 108.3 0.55 white blood cells (×1000) 16.9 ± 13.5 17.5 ± 9.6 0.87 estimated sedimentation rate 42.8 ± 29.2 44.3 ± 24.9 0.91 c-reactive protein 75.7 ± 54.3 64.7 ± 39.7 0.65 ast 35.3 ± 17.9 26.5 ± 16.3 0.2 alt 30.2 ± 33.9 17.9 ± 13.5 0.25 alkaline phosphatase 382 ± 577.4 288.7 ± 268.8 0.61 bun to albumin ratio 20.4 ± 10.5 13.9 ± 9.3 0.045 table 2. comparison of characteristics between deceased and surviving patients blood urea nitrogen to albumin in fournier’s gangrene-allameh et al.. vol 19 no 4 july-august 2022 326 vs. 15.23 ± 9.42), this difference was not significant (p = 0.26). discussion fg is an uncommon disease; 110 cases of fg or necrotizing fasciitis admitted to our hospital for 10 years were reviewed, and finally, 40 patients were enrolled in the current study. due to its progressive nature, the disease mortality rate remains high (43–53%) despite intensive care treatment and advances in medical therapy(8,9). the overall mortality rate in the present study was 40.35% (46 of 114 patients). the mean age of survivors was 58.70 ± 17 years old, and deceased patients had a mean age of 66.45 ± 10 years old which was not statistically significant. some studies showed similar findings(4,12,13), whilst others showed contradictory results(2,7,8,14). many factors have been reported that predispose patients to the development of fg, with diabetes mellitus (dm), chronic renal failure (crf), and malignancy as the main ones. for example, tuncel et al.(13) found an association between dm and poor prognosis; however, corcoran et al. reported no similar relationship in their study(15). in the present study, 24 (60%) patients had a positive past medical history of dm, which was not significant between survivors and deceased patients. no consensus is available on clinical variables for predicting poor outcomes in fg(13). fgsi was developed to facilitate the prediction of the outcomes in fg patients. laor et al. found an fgsi score of > 9 that consisted of 75% death probability, while a score of ≤ 9 was associated with 78% survival probability(16). this threshold for predicting mortality in patients has been confirmed in other studies(3,11). recent studies have evaluated the ratio of bun to albumin in predicting the prognosis of diseases. feng et al.(8) studied its role on hospital-acquired pneumonia, while in three studies(9-11), community-acquired pneumonia was the main disease to be evaluated. moreover, kos(17) and gundpatil(18) assessed the bun/albumin on non-small lung cancer and non-chronic kidney diseases, respectively. in this way, the risk of mortality, the need for icu admission, and the length of hospital stay will increase with increasing the bun to albumin ratio. in the current study, the ratio of bun to albumin was significantly higher among deceased patients in comparison to the survived ones. despite the variations seen in the need for icu admission and the length of hospital stay, the differences were not significant. there are several indexes used for fournier gangrene prognosis like fournier’s gangrene severity index (fgsi), uludag fournier gangrene severity index (ufgsi), age-adjusted charlson comorbidity index (acci), laboratory risk indicator for necrotizing fasciitis (lrinec) score, the combined urology and plastics index (cupi) and neutrophil–lymphocyte ratio (nlr) and surgical apgar (sapgar). according to the studies, the ufgsi does not seem to be more powerful than fgsi. in daily routine, we suggest applying acci because it is more easily calculated, generally applicable, and well-validated. ufgsi has the most sensitivity rate (85%) and sapgar has the lowest sensitivity rate (55%). however, sapgar has the most specificity rate (91%) and ufgsi has the lowest specificity rate (67%).(19) in prediction for skin reconstruction in fg patients, fgsi, ufgsi, and nlr are more reliable.(20) overall, ufgsi is the most common index for assessing fg patients. according to our results, the sensitivity of bun/alb is not as high as ufgsi, but it is acceptable and very useful due to the simplicity of performing tests. according to the findings, the ratio of bun to albumin was significantly different among the deceased and survived patients with fg. further studies with a larger sample size are recommended to properly assess this parameter. figure 1. analysis of roc curve for predicting mortality blood urea nitrogen to albumin in fournier’s gangrene-allameh et al.. unclassified 327 conclusions the ratio of bun to albumin was significantly different among deceased and survived patients with fg. therefore, more studies with a larger sample size are needed to access this parameter properly. 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ls, tolia bm, reid re, winter hi. outcome prediction in patients with fournier’s gangrene. j urol. 1995; 154:89-92. 17. kos m, hocazade, c, kos f, et al. association between blood urea nitrogen/albumin ratio and prognosis in non-small cell lung cancer. acta med mediterr. 2015; 31:219-223. 18. gundpatil db, somani bl, saha tk, banerjee m. serum urea:albumin ratio as a prognostic marker in critical patients with non-chronic kidney disease. indian j clin biochem: ijcb, 2014;29(1):97–100. 19. roghmann f, von bodman c, löppenberg b, hinkel a, palisaar j, noldus j. is there a need for the fournier's gangrene severity index? comparison of scoring systems for outcome prediction in patients with fournier's gangrene. bju int. 2012 nov;110(9):1359-65. 20. selvi i, aykac a, baran o, burlukkara s, ozok u, sunay mm. a different perspective for morbidity related to fournier’s gangrene: which scoring system is more reliable to predict requirement of skin graft and flaps in survivors of fournier’s gangrene?. int urol nephrol. 2019 aug;51(8):1303-11. blood urea nitrogen to albumin in fournier’s gangrene-allameh et al.. vol 19 no 4 july-august 2022 328 kidney transplantation long-term results of posterolateral extravesical ureteroneocystostomy and its comparison with the conventional anterior extravesical ureteroneocystostomy method in the management of urologic complications in kidney transplant patients farid dadkhah1, hooshmand sofimajidpour2, majid aliaskari1, amirhesam alirezaei2, saed taleghani1, mohammad aziz rasouli3, heshmatollah sofimajidpour4* purpose: urological complications are common and serious in kidney transplant patients. correct diagnosis of urological complications and rapid intervention are very important to maintain the transplanted organ. using endoscopic methods and rapid access to ureteral orifice can be effective in treatment and management of urological complications in transplant patients. materials and methods: in this retrospective cohort study, 934 medical records of kidney transplant patients who underwent surgery through posterolateral extravesical ureteroneocystostomy (plevunc) and anterior extravesical ureteroneocystostomy (aevunc) techniques from 2011 to 2018 were evaluated. the outcomes of plevunc and aevunc techniques were evaluated in 461 and 473 transplant patients, respectively. the patients were followed up for 60 months. immediate and delayed complications, urological complications requiring endoscopic intervention, duration of access to ureteral orifice, as well as ureteroscopic and endoscopic outcomes were evaluated. results: the mean and ± sd (standard deviation) age of patients in plevunc and aevunc groups were 46.2 7± 2.7 years and 47.3 ± 3.6 years, respectively. urinary leakage and uti were the most common immediate (7% and 6.2%) and delayed (5.5% and 5.5%) complications in both groups, respectively. the time to find ureteral orifice in patients requiring endoscopic intervention was significantly shorter in plevunc group 3.5±1.2 compared with the aevunc group 10 ± 4.5 (p <.001). in 100% of plevunc group and 62.6% of aevunc group, ureteral orifice of transplanted kidney was observed (p <.001). ureteroscopy was reported successful in 94.5% and 37.4% of patients in plevunc and aevunc groups, respectively. conclusion: easy and safe access to the ureteral orifice and to the upper urinary tract in transplant recipients can be achieved with the plevunc technique. in case of urological complications this method facilitates endoscopy. keywords: kidney transplantation; ureteroneocystostomy; urological complications; urologic surgical procedures introduction the number of chronic renal failure patients need-ing alternative treatment is increasing annually. the treatments put a great economic and social burden on the health system.(1) there are three treatment methods for patients with end-stage renal disease (esrd): hemodialysis, peritoneal dialysis and kidney transplantation.(2) the most appropriate and effective treatment for patients with esrd is kidney transplantation.(3,4) in fact the goal of kidney replacement therapy is to increase the patients’ survival rate and quality of life.(1) the incidence of urological renal complications after transplantation has been reported in 3.8% of all recipients.(5,6) although there has been a significant improvement in the incidence of such complications in the last decade, urological complications are still common. anterior extravesical ureteroneocystostomy in kidney transplantation has become popular because it is an easy technique to perform(7-10). modern endoscopic in1department of urology, shahid modarres hospital, shahid beheshti university of medical sciences, tehran, iran. 2department of nephrology, shahid modarres hospital, shahid beheshti university of medical sciences, tehran, iran. 3clinical research development unit, kowsar hospital, kurdistan university of medical sciences, sanandaj, iran. 4department of urology, faculty of medicine, kurdistan university of medical sciences, sanandaj, iran. *correspondence: department of urology, faculty of medicine, kurdistan university of medical sciences, sanandaj, pasdaran ave, tel: +98-8733611250, e-mail: hsmajidpour@gmail.com received september 2020 & accepted january 2022 struments have made it possible to use endoscopic procedures in kidney and urinary tract.(11,12) anterior extravesical ureteroneocystostomy (lichgregoire) is usually an easy and fast method for ureteral reimplantation. however, this procedure has been severely criticized due to difficult endoscopic access to the reimplanted ureter and the transplanted kidney. in the aevunc method, reimplantation is usually performed on bladder dome in a filled bladder, and the angle between the orifice of the reimplanted ureter and the ureteroscopic device is about 90 degrees. in the last two decades, endourology interventions have been introduced as acceptable methods for the management of urological complications following kidney transplantation.(13,14) previously and traditionally, ureteral obstruction was managed by open surgery, which was associated with significant morbidity and mortality. nowadays, endourological techniques such as intra-luminal ureteral urology journal/vol 19 no. 2/ march-april 2022/ pp. 120-125. [doi: 10.22037/uj.v18i.6449] vol 19 no 2 march-april 2022 100 balloon dilatation and ureterotomy are associated with a high success rate.(1) catheterization and passage of endourological equipment as well as subsequent endourological procedures in aevunc technique are difficult, time consuming, and sometimes impossible.(4) inability to manage complications with endoscopic procedures can lead to open surgery.(4,6) the need for an alternative method of ureteroneocystostomy has become apparent because it results in better access to ureter and facilitates endourological interventions.(1,5,6) based on this, therefore, it is claimed that by performing the alternative method of ureteroneocystostomy, the ureter orifice is more accessible and endoscopic interventions are more possible. this study was an attempt to compare and evaluate the long-term outcomes of plevunc and aevnuc ureteral reimplantation techniques to facilitate the endoscopic management of urologic complications in kidney transplant patients. also we compared the abovementioned reimplantation techniques in terms of access to orifice of reimplanted ureter. materials and methods study population in this retrospective cohort study, medical records of 934 kidney transplant patients who underwent ureteral reimplantation with avunc and plvunc techniques were evaluated. all the patients were referred to shahid modarres hospital, affiliated to shahid beheshti university of medical sciences, from 2011 to 2018. according to clinical conditions, the patients were assigned to one of the avunc and plvunc surgical techniques groups by the surgeon. the number of patients in plevunc and aevunc groups were 461 and 473, respectively. demographic characteristics of all 934 patients were recorded in a checklist. all donors were live unrelated. immunosuppressive treatment protocols included induction with globulin antithymocytes and maintenance therapy with prednisolone, tacrolimus or cyclosporine, and mycophenolate mofetil. procedures the basic technical principles of the plevunc that we have utilized are described briefly: the bladder was filled with saline solution and a 1-cm full-thickness incision was done in the posterolateral wall of the bladder to expose bladder mucosa while applying medial retraction on anterior bladder wall. an ellipse of mucosa was excised from the distal apex. at the distal segment of the ureter, a 1cm lateral ureteral spatulation is performed and the edges were trimmed. stent (7-fr silastic urologic j-j stent) was left in the ureter and apical stitch was placed in spatulated ureter and passed inside out through most caudal portion of mucosal opening. the anastomosis of the mucosa of the bladder to the spatulated lower ureter was made using interrupted 4-0 vicryl sutures. detrusor muscle was subsequently closed over the anastomosis using 4-0 vicryl in interrupted fashion to create the antireflux mechanism. a distal fullthickness anchoring suture was used to keep the ureter from sliding cephalad in a submucosal tunnel.(13) after surgery, all patients were visited every month in the first year and then every 6 months for 5 years (60 months). they underwent physical and biochemical examination. at each visit, patients were evaluated by careful ultrasound and tests for urinary tract infections or signs of transplant rejection attacks and obstructive complications. evaluations when a urological complication was suspected, various interventions such as ivp, dtpatc99m and ct scan were used. for all patients with persistent leakage in the surgical field, fluid analysis was performed. hydronephrosis on ultrasound, obstructive uropathy on dtpa scanning, and increased creatinine were considered as ureteral obstruction. a month after the surgery, all paposterolateral extravesical ureteroneocystostomy versus conventional–dadkhah et al. table 1. determination and comparison of demographic variables in the two groups. variable a plevunc (n= 461) aevunc (n=473) p-value gender, n male 316 (68.5) 319 (67.4) .71 female 145 (31.5) 154 (32.6) age (year); mean ± sd, (range) 47.3 ± 3.6 (17-62) 46.2 ± 2.7 (19-59) .12 duration of dialysis before transplantation (year) 3.5 ± 0.8 (1-9) 2.5 ± 0.6 (1-8) < 0.001 duration of transplant surgery (minutes) 125 ± 21 (110-140) 120 ± 17 (107-139) < 0.001 preoperative creatinine 8.2 ± 1.2 (6.5-11) 8.3 ± 1.1 (7-11) .18 preoperative bun 90.4 ± 14.1 (80-115) 95.7 ± 16.2 (80-120) < 0.001 abbreviations: plevunc, posterolateral extravesical ureteroneocystostomy; aevunc, anterior extravesical ureteroneocystostomy; sd, standard deviation a continuous variables were compared by independent samples t-test variables plevunc (n= 461) aevunc (n=473) p-value nephrotic syndrome 10 (2.17) 9 (1.90) .95 pyelonephritis 27 (5.86) 33 (6.98) v.u.r 6 (1.30) 3 (1.06) glomerulonephritis 45 (9.76) 41 (8.67) hypertension 133 (25.88) 136 (28.76) diabetes mellitus 100 (21.70) 108 (22.83) polycystic kidney 37 (8.03) 32 (6.77) kidney stone 29 (6.29) 31 (6.55) amyloidosis 1 (0.22) 0 (0) lupus 3 (0.65) 2 (0.42) unknown 70 (15.18) 78 (16.4) abbreviations: plevunc, posterolateral extravesical ureteroneocystostomy; aevunc, anterior extravesical ureteroneocystostomy table 2. causes of renal failure in the two study groups. vol 19 no 2 march-april 2022 121 kidney transplantation 122 tients underwent cystoscopy and the ureteral orifice was observed. in patients who needed endourological surgery intervention due to complications, we initially attempted to access to the urinary system with endoscopic devices. transplant results in the two groups were compared in terms of ureteral and non-ureteral urological complications. in both groups, a total of 145 patients required endoscopic intervention. patients in the two groups were also compared based on successful ureteroscopy and manipulation normal ureteroscopy was defined as success in reaching the pelvis of transplanted kidney. main outcomes of this study were time to find ureteral orifice, ureteral orifice of transplanted kidney, and rate of successful ureteroscopy. moreover, immediate and delayed complications and urological complications were primary and secondary outcomes. in order to comply with research ethics, all patients participating in the study were informed of the study. ethical considerations this study was approved by the ethics committee of shahid beheshti university of medical sciences and registered with the code ir.sbmu.msp.rec.1399.221. statistical analysis categorical variables are expressed as frequency (percentage) and continuous variables are reported as mean ± sd. t-test was used for comparison of continuous data. categorical data was compared by using chisquare test and fisher exact test. all statistical analysis was performed by stata software version 16. p < .05 was considered as statistically significant. results the results of this study showed that in plevunc group, 316 patients were male (68.5%) and 145 were female (31.5%) while in aevunc group, 319 patients were male (67.4%) and 154 were female (32.6%). the mean ± sd age in duration plevunc group was 47.3 ± 3.6 and in aevunc group was 46.2 ± 2.7. there was no significant difference between the two groups of the patients in terms of sex and preoperative creatinine (p > .05) (table 1). the mean ± sd of transplant surgery in plevunc group was 125 ± 21 minutes and in aevunc group was 120 ± 17 minutes. there was no significant difference between the two groups in terms of causes of renal failure (p = .95). the most common causes of renal failure in two groups were hypertension (25.88% and 28.76%) and diabetes mellitus (21.70% and 22.83%) (table 2). in more than 88.9% of patients in plevunc group and 87.2% patients in aevunc groups, no immediate and delayed complications were reported. there was no significant difference between the two groups in terms of immediate and delayed complications (p >.05). the most common delayed complication was uti (5.5% in both groups). vesicourerteral reflux as a urinary complication in aevunc method was four times more than plevunc (1.7% vs 0.4 %,). in both plevunc and aevunc groups, urinary leakage was the most common immediate complication (7% and 6.2%, respectively) (table 3). the most common urological complication requiring endoscopic intervention in the two study groups was urinary leakage. the plevunc group had a urological complication variables plevunc (n= 461) aevunc (n=473) p-value immediate complications urinary leakage 32 (7) 29 (6.2) .92 urosepsis 0 (0) 1 (0.2) significant hematuria 2 (0.4) 2 (0.4) ureteral necrosis 0 (0) 0 (0) hydronephrosis after stent removal 17 (3.7) 19 (4) hematoma around the transplanted kidney 4 (0.8) 5 (1) no complication 406 (88) 417 (88.2) delayed complications lymphocele 4 (0.8) 5 (1) .61 vesicoureteral reflux 2 (0.4) 8 (1.7) urinary fistula 0 (0) 0 (0) uvj obstraction 9 (2) 11 (2.3) urinary system stones 9 (2) 8 (1.7) uti 25 (5.5) 26 (5.5) miss jj stent 2 (0.4) 3 (0.6) no complication 410 (88.9) 412 (87.2) table 3. immediate and delayed complications in the two study groups. abbreviations: plevunc, posterolateral extravesical ureteroneocystostomy; aevunc, anterior extravesical ureteroneocystostomy variables plevunc (n=461) aevunc (n= 473) p-value urinary leakage 32 (6.9) 29 (6.1) .99 hydronephrosis after stent removal 17 (3.7) 19 (4) lymphocele 4 (0.8) 5 (1) delayed uvj obstraction 9 (1.9) 11 (2.3) urinary system stones 9 (1.9) 8 (1.7) miss jj stent 2 (0.4) 3 (0.6) no urologic complications 388 (84.2) 398 (84.1) abbreviations: plevunc, posterolateral extravesical ureteroneocystostomy; aevunc, anterior extravesical ureteroneocystostomy table 4. urological complications requiring endoscopic intervention in the two study groups posterolateral extravesical ureteroneocystostomy versus conventional–dadkhah et al. vol 19 no 2 march-april 2022 100 requiring endoscopic intervention rate of 15.8%, which did not significantly differ from those in aevunc group (15.9%) (p = .99). urinary leakage was encountered in 32 (6.9%) patients in plevunc group and 29 (6.1%) in aevunc group (table 4). the results showed that the time to find ureteral orifice in patients requiring endoscopic intervention was significantly shorter in plevunc group compared with that of the aevunc group (3.5 ± 1.2 minutes vs. 10 ± 4.5 minutes) (p < .001) (table 5). in 73 (100%) of plevunc group and 47 (62.6%) of aevunc group, ureteral orifice of transplanted kidney was observed (p < .001). the results showed that the success rate of ureteroscopy in plevunc group was significantly higher than that of the aevunc group. the success rate of ureteroscopy in plevanc and aevunc groups were 69 (94.5%) and 28 (37.4%), respectively (p < .001) (table 5). the results of this study showed that 407 patients (88.2%) in plevunc group and 420 patients (88.8%) in aevunc group did not have chronic graft nephropathy. the mean creatinine one year after the surgery was 1.34 in the plevunc group and 1.37 in the aevunc group, there was no significant difference between the two groups (p = .19). discussion one of the major concerns in ureteroneocystostomy is endurological access to the ureter after transplantation. in this study, the success rate and ease of access to the ureter and endoscopic interventions in two methods plevunc and aevunc were evaluated. the most common causes of renal failure in two groups were hypertension (25.88% and 28.76%) and diabetes mellitus (21.70% and 22.83%), respectively. in more than 88% of the patients, no immediate and delayed complications were reported. in both plevunc and aevunc groups, urinary leakage was the most common immediate complication (7% and 6.2%, respectively). there was no significant difference between the two groups in terms of immediate and delayed complications (p > .05). the most common delayed complication was uti (5.5% in both groups). vesicourerteral reflux as a urinary complication in aevunc method was four times more than that of plevunc (1.7% vs 0.4 %,). in the plevunc method, the angle created by the spatula helps to prevent vesicourerteral reflux. the inner part of the ureter is surrounded by the muscles of the posterior bladder wall, which inverts the uretera mucosa inside the bladder lumen.(13) in a study by sanei et al., which evaluated urological complications in two full-thickness single layer anastomosis and lichgregoir methods, vesicouvertral reflux was reported as 7.4% in the lich-gregoir group(14) which was higher than the results of our study. in a study by balaban et al. they concluded that endoscopic treatment of symptomatic vur in transplanted kidney is a safe and feasible procedure.(15) there were no urological complications, requiring endoscopic intervention, in 84% of the patients in both groups. there was also no significant difference between the two groups in terms of urological complications requiring endoscopic intervention (p > .05). in our study urinary leakage was the most common urological complication. in the previous studies, urinary leakage has been reported as one of the most common urological complication after transplantation.(12,14,18) in endoscopy procedure, easy and safe access to reimplanted ureter and renal pelvis is important. the results of our study showed that the time to find ureteral orifice in patients requiring endoscopic intervention was significantly shorter in plevunc group compared with that of aevunc group (3.5 minutes vs. 10 minutes), (p < .001). plevunc provides approximate anatomical location for the ureteral orifice, as well as approximate normal anatomical alignment for the ureter. in this method, ureteral reimplantation is performed in the posterior side of the bladder, which is closer to the anatomical location of the ureteral orifice, as a result endoscopic procedures and finding the new ureteral orifice is easier.(13) reoperation on transplanted kidneys is associated with a significant increase in morbidity and mortality. the mortality rate for patients who underwent open correction of ureteral stenosis has been reported as 8%.(19) currently, the first treatment for ureteral obstruction in a transplanted kidney is endoscopy. (20) the first option for treatment of ureteral obstruction, which occurs in 2% to 10% of renal transplant patients postoperatively is interventional radiological methods. if all of these methods are unsuccessful, surgical treatment should be applied.(21) in our study in 100% (73 patients) of plevunc group and 37.4% (28 patients) of aevunc group, ureteral orifice of transplanted kidney was observed during the procedure (p < .001). ureteroscopy success rate was 94.5% (69 patients) in plevunc group and 37.4% (28 patients) in aevunc group and the difference between two groups was statistically significant (p < .001). there are limited studies related to our study topic. in the previous study by dadkhah et al, done with a fewer patients, conducted with the aim of easier access to the upper urinary tract in transplanted kidney with the help of endoscopic devices, the results of renal transplantation comparing two techniques of aevunc and plevunc were evaluated. they also compared ureteral and nonureteral complications at 36to 51-month follow-up. the results showed that access to ureteral orifice and endoscopic interventions were easier in plevunc than aevunc methods and the general complications of plevunc technique were not significantly different from that of the aevunc, which is the usual method.(13) krajewski et al. concluded in variables a plevunc (n= 461) aevunc (n=473) p-value mean time to find ureteral orifice (min) 3.5 ± 1.2 (2.5-6) 10 ± 4.5 (7-11) < 0.001 finding of ureteral orifice of transplanted kidney 73 (100) 47 (62.5) < 0.001 successful ureteroscopy 69 (94.5) 28 (37.5) < 0.001 table 5. data regarding ureteroscopy. abbreviations: plevunc, posterolateral extravesical ureteroneocystostomy; aevunc, anterior extravesical ureteroneocystostomy a continuous variables were compared by independent samples t-test posterolateral extravesical ureteroneocystostomy versus conventional–dadkhah et al. vol 19 no 2 march-april 2022 123 kidney transplantation 124 their study that most urological complications could be successfully treated with endourological procedures and kidney function improved in most patients.(16) in the study by ooms et al., 50 patients who had ureter stricture following kidney transplantation were treated with antegrade balloon dilatation which was technically successful in 86%.(17) endoscopic treatment of ureteral stenosis after kidney transplantation is recommended to prevent complications of open surgical treatment.(18) the present study was performed with a higher statistical population and longer follow-up of patients. it confirmed the success and ease of access of endourology interventions in reimplanted patients with plevunc technique. limitation of this study is, the study was performed as a retrospective group and it could have been done as a clinical trial. the study was also conducted at a center. conclusions the study showed that ureteroneocystostomy by plevunc method provides easy and safe access to the ureteral orifice and upper urinary tract in kidney transplant recipients. this method facilitates endoscopic intervention in case of urological complications. therefore, it is recommended to use plevunc method instead of aevunc method in kidney transplantation. acknowledgement the study was sponsored by the deputy of research and technology of shahid beheshti university of medical scienc¬es, tehran, iran. conflict on interest the authors declare that there is no conflict of interest. references 1. veale jl, yew j, gjertson dw, smith cv, singer js, rosenthal jt, gritsch ha. longterm comparative outcomes between 2 common ureteroneocystostomy techniques for renal transplantation. j urol. 2007 feb;177:632-6. 2. wong g, howard k, chapman jr, chadban s, cross n, tong a, webster ac, craig jc. comparative survival and economic benefits of deceased donor kidney transplantation and dialysis in people with varying ages and comorbidities. plos one. 2012 jan 18;7:e29591. 3. salehipour m, salahi h, jalaeian h, bahador a, nikeghbalian s, barzideh e, ariafar a, malek-hosseini sa. vascular complications following 1500 consecutive living and cadaveric donor renal transplantations: a single center study. saudi j kidney dis transp. 2009 jul 1;20:570. 4. el‐mekresh m, osman y, ali‐el‐dein b, el‐diasty t, ghoneim ma. urological complications after living‐donor renal transplantation. bju international. 2001 mar;87:295-306. 5. slagt ik, ijzermans jn, visser lj, weimar w, roodnat ji, terkivatan t. independent risk factors for urological complications after deceased donor kidney transplantation. plos one. 2014; 9:e91211. 6. streem sb. endourological management of urological complications following renal transplantation. seminars urol. 1994:12 : 123133 7. shah s, nath v, gopalkrishnan g, pandey ap, shastri jc. evaluation of extravesical and leadbetter‐politano ureteroneocystostomy in renal transplantation. br. j. urol. 1988 nov;62:412-3. 8. wasnick rj, butt km, laungani g, shirani k, hong jh, adamsons rj, waterhouse k. evaluation of anterior extra vesical ureteroneocystostomy in kidney transplantation. urol. j. 1981 sep;126:306-7. 9. hefty tr. experience with parallel incision extravesical ureteroneocystostomy in renal transplantation. j urol. 1985 sep;134:455-6. 10. mohammadi fallah mr, taghizadeh afshari a, asadi m, sharafi ah. comparision of barry and barry-taguchi ureterovesical reimplantation techniques in kidney transplantations: a randomized clinical trial. int j organ transplant med. 2010;1:77-83.. 11. krambeck ae, gettman mt, banihani ah, husmann da, kramer sa, segura jw. management of nephrolithiasis after cohen cross-trigonal and glenn-anderson advancement ureteroneocystostomy. j urol. 2007 jan 1;177:174-79. 12. buttigieg j, agius-anastasi a, sharma a, halawa a. early urological complications after kidney transplantation: an overview. world j transplant. 2018 sep 10;8:142-149. 13. dadkhah f, asgari ma, tara a, safarinejad mr. modified ureteroneocystostomy in kidney transplantation to facilitate endoscopic management of subsequent urological complications. int urol nephrol. 2010; 42:285-93. 14. sanei b, hashemi m, tabataei a, et al. a comparison between two kidney transplant ureteroneocystostomy techniques: fullthickness single layer anastomosis and lich-gregoir. j univer surg. 2016, 4:56-59. 15. balaban m, ozkaptan o, cubuk a, sahan a, duzenli m, tuncer m. endoscopic treatment of symptomatic vur disease after the renal transplantation: analysis of 49 cases. clin exp nephrol. 2020 may;24:483-88. 16. krajewski w, dembowski j, kołodziej a, małkiewicz b, tupikowski k, matuszewski m, et al. urological complications after renal transplantation a single centre experience. cent european j urol. 2016;69:306-311. 17. ooms lss, moelker a, roodnat ji, ijzermans jnm, idu mm, terkivatan t. antegrade balloon dilatation as a treatment option for posttransplant ureteral strictures: case series of 50 patients. exp clin transplant. 2018; 16:150-155. 18. frattini a, capocasale e, granelli p, mazzoni mp, maestroni mp, dalla valle r, et al. endourological management of ureteral stenosis and vesicoureteral reflux after renal transplantation. urologia. 2007;74:212-6. posterolateral extravesical ureteroneocystostomy versus conventional–dadkhah et al. vol 19 no 2 march-april 2022 125 19. kinnaert p, hall m, janssen f, vereerstraeten p, toussaint c, van geertruyden j. ureteral stenosis after kidney transplantation: true incidence and long-term followup after surgical correction. urol. j. 1985 jan; 133:1720. 20. he z, li x, chen l, zeng g, yuan j, chen w, zhang c. endoscopic incision for obstruction of vesico‐ureteric anastomosis in transplanted kidneys. bju international. 2008 jul;102:1026. 21. haberal m, boyvat f, akdur a, kirnap m, ozcelik u, karakayali f. surgical treatment for ureteral obstruction after kidney transplantation. transplantation. 2018; 102:s630. posterolateral extravesical ureteroneocystostomy versus conventional–dadkhah et al. editorial comment covid-19 and semen: an unanswered area of research amir h kashi *correspondence: urology and nephrology research center (unrc); shahid labbafinejad medical center; shahid beheshti university of medical sciences (sbmu), tehran, iran. email: ahkashi@gmail.com. the covid-19 has infected more than 2 million patients in the world including more than 200 countries and killing more than 180000 patients according to who’s situation report number 95 released on april 24th, 2020(1). this outstanding global pandemic has occurred in less than 4 months since its announcement by the chinese government in december 2019. the vast number of infections and the spreading pattern of infection has caused concerns over many health aspects of covid-19 which were overlooked for the earlier outbreaks of its family namely sars and mers. the latest researches report that the most infectious bodily fluids are nasopharyngeal, nasal, and lower respiratory tract secretions(2). the virus has also been detected in feces and a lower infection percentage has been reported in blood. there are reports on the presence of covid-19 in the urine of infected patients(3); however the percentages reported are much lower in comparison with sars and mers and have been reported only in limited studies, with most studies failing to report the presence of virus in urine. there is another potential area of concern which has not been addressed for the covid-19 infection: “the presence of covid-19 in semen”. the presence of viral particles in semen has neither been investigated earlier for the previously reported outbreaks of sars and mers(4). the importance of such investigation lies in the low reported rate of viremia in blood for covid-19(2) which makes the possibility of viral spreading to body organs including genital organs and its later secretion into genital secretions. the presence of ace2 receptors which function as binding sites for covid-19 has been reported in testis tissue and genitourinary organs(5,6). the earlier reports of sars and mers reported persistence of virus in urine and feces after patients convalescence and clearance of virus in nasopharyngeal secretions(7) raising concerns for viral spreading through these routes after patient improvement and his/her return to social activities. apart from the concern of viral shedding in semen, there are other concerns in infertility clinics on the possibility of the presence of covid-19 in semen. the potential for viral transmission in assisted reproductive techniques including sperm donation should be clarified as this pandemic seems to be staying for long. in iran, infertility clinics has been suspended from providing service to new patients. besides, we need to know about the presence of virus in semen to set standards of protective equipment needed in infertility clinics and laboratories working on semen samples. the importance of such investigation lies in the vast majority of patients who show little or no symptoms and recover from covid-19 infection who constitute 80% of infected patients. the symptomless patients are a potential reservoir of infection transmission. in order to have hard evidence for answering the above concerns we need studies exploring the presence or absence of covid-19 in semen samples of patients within different periods of their infection. the only published study on this respect has included semen samples from day 14 of the illness afterwards(6). no study has reported semen evaluation in the first 2 weeks of infection. we look forward to such studies. references 1. world health organization. coronavirus disease 2019 (covid-19) situation report – 95. world health organization; 2020. 2. wang w, xu y, gao r, lu r, han k, wu g, et al. detection of sars-cov-2 in different types of clinical specimens. jama. 2020. 3. ling y, xu s-b, lin y-x, tian d, zhu z-q, dai f-h, et al. persistence and clearance of viral rna in 2019 novel coronavirus disease rehabilitation patients. chinese medical journal. 2020. 4. niedrig m, patel p, abd el wahed a, schädler r, yactayo s. find the right sample: a study on the versatility of saliva and urine samples for the diagnosis of emerging viruses. bmc infect dis. 2018;18:1 14. 5. puliatti s, eissa a. covid-19 and urology: a comprehensive review of the literature. 2020. 6. song c, wang y, li w, et al. absence of 2019 novel coronavirus in semen and testes of covid-19 patients. biol reprod. 2020. 7. xu d, zhang z, jin l, chu f, mao y, wang h, et al. persistent shedding of viable sarscov in urine and stool of sars patients during the convalescent phase. european journal of clinical microbiology and infectious diseases. 2005;24:165-71. urology journal/vol 17 no. 3/ may-june 2020/ pp. 328-328. [doi: 10.22037/uj.v0i0.6160] case report 301urology journal vol 6 no 4 autumn 2009 fibroepithelial congenital polyp of prostatic urethra in an adult man mohammad salehi, siavash falahatkar, hassan neiroomand, marzieh akbarpour urol j. 2009;6:301-2. www.uj.unrc.ir keywords: fibroepithelial neoplasms, urethra, male, congenital polyps urology research center, razi hospital, rasht, iran corresponding author: mohammad salehi, md urology research center, razi hospital, rasht, iran tel: +98 911 181 1395 e-mail: salehi@gums.ac.ir received october 2008 accepted february 2009 introduction fibroepithelial polyps (feps) of the urethra are rare lesions in adults and are most frequently seen in men during the first decade of life.(1) these lesions are benign and congenital, usually discovered in infants and children, and have rarely been reported in adults.(2,3) solitary polyps are called different names, such as prostatic urethral polyps, feps of the urethra, or benign urethral polyps.(4) because of their location, as they achieve larger size, they can produce a variety of urinary symptoms including dysuria, hematuria, urinary tract infections, and obstructive symptoms, which may progress to urinary retention.(5) we report a case of benign fep of the prostatic urethra in a 20-year-old man who presented with obstructive urinary symptoms and urinary retention. case report a 20-year-old man presented with urinary retention. he had a 9-month history of voiding difficulties including dysuria, obstructive urinary symptoms, and suprapubic pain. grayscale ultrasonography revealed a round mass rose from the prostatic urethra, protruded to the bladder base. increased bladder wall thickness was also seen. urinalysis showed 18 to 20 erythrocytes and 4 to 5 leukocytes per high-power field, and urine culture was negative for growth of microorganisms. cystoscopy detected a 1.5-cm to 2-cm polypoid mass at the bladder neck, which had been attached to the verumontanum by a long stalk (figure). the mass had completely obstructed the urethral outflow. the lesion was completely removed by transurethral resection and cauterization of the stalk. the specimen consisted of a piece of polypoid creamy tissue with soft consistency, measured 2.0 × 0.9 × 0.9 cm. the cut surface contained small cysts 0.4 cm in greatest diameter. microscopically, the sections showed polypoid tissue lined by transitional epithelium with foci of squamous metaplasia, composed of proliferated and dilated endoscopic view of a pedanculated polyp in prostatic urethra. fibroepithelial congenital polyp of urethra—salehi et al 302 urology journal vol 6 no 4 autumn 2009 prostatic type glands. the stroma was congested and nonspecifically inflamed and consisted of benign fibrous connective tissue. neither cytologic atypia nor mitosis was seen. there was no evidence of malignancy. the diagnosis of a fibroepithelial congenital polyp of the prostatic urethra was made by pathologic examination. discussion urinary polyps have been described to be present from the middle calyxes of the kidney to the anterior urethra. the fep located in the lower part of the urinary tract usually develops in the posterior urethra and more often seen in children than in adults.(4) the etiology is controversial; however, congenital, irritative, infectious, obstructive, and traumatic causes have been proposed.(6) the presence of a large polyp in healthy newborns and infants is strongly in favor of a congenital origin. the histological findings of the fibroepithelial congenital polyps of the prostatic urethra are those of benign polypoid lesions lined by transitional urothelium. associated inflammation, erosion, ulceration, and reactive metaplastic changes may be present.(5) findings due to intermittent or acute obstruction of the bladder outlet, such as hesitancy, diminished urinary stream, incomplete emptying, and urinary retention are the main symptoms.(7) with a reported incidence of 30% to 60%, hematuria is another common symptom.(8) the differential diagnoses in these cases are extensive and include posterior urethral valves, inverted papilloma of the urinary bladder, acquired reactive polyps, ectopic prostatic tissue, villous polyps, prostatic adenocarcinoma, transitional cell carcinoma, and also malignant mesenchymal neoplasms of the urinary bladder such as rhabdomyosarcoma.(5) voiding cystourethrography and ultrasonography examinations aid to diagnose the polyps, but endoscopic examination is necessary to confirm and to excise the lesion.(9) when similar radiologic and endoscopic lesions are identified in adult population, the possibilities of a prostatic polyp or a villous polyp should be ruled out. prostatic polyps are considered reactive lesions, and fibrovascular stroma in these cases is lined by benign prostatic ducts and glands rather than by urothelium.(10) villous polyps, on the contrary, exhibit varying degrees of dysplasia and are known to recur and sometimes progress to malignant adenocarcinoma.(11) transurethral resection of a urethral polyp has become the treatment of choice. endoscopic resection using electrocautery or laser energy is usually successful and open cystomy is rarely required.(3) we reported a case of a fibroepithelial polyp of the prostatic urethra in an adult male who presented with obstructive urinary symptoms and urinary retention. the clinical, radiographic, and endoscopic findings are consistent with an obstructing mass at the bladder neck and prostatic urethra. the lesion was completely removed by transurethral resection. pathologic examination confirmed the diagnosis of an fep of the prostatic urethra. conflict of interest none declared. references 1. aita ga, begliomini h, mattos d, jr. fibroepithelial polyp of the urethra. int braz j urol. 2005;31:155-6. 2. madden np, turnock rr, rickwood a. congenital polyps of the posterior urethra in neonates. j pediatr surg. 1986. 3. yamashita t, masuda h, yano m, kobayashi t, kawano k, kihara k. female urethral fibroepithelial polyp with stricture. j urol. 2004;171:357. 4. demircan m, ceran c, karaman a, uguralp s, mizrak b. urethral polyps in children: a review of the literature and report of two cases. int j urol. 2006;13:841-3. 5. isaac j, snow b, lowichik a. fibroepithelial polyp of the prostatic urethra in an adolescent. j pediatr surg. 2006;41:e29-31. 6. downs ra. congenital polyps of the prostatic urethra. a review of the literature and report of two cases. br j urol. 1970;42:76-85. 7. williams tr, wagner bj, corse wr, vestevich jc. fibroepithelial polyps of the urinary tract. abdom imaging. 2002;27:217-21. 8. gleason pe, kramer sa. genitourinary polyps in children. urology. 1994;44:106-9. 9. walsh pj, wiener js. urethral polyp presenting in a male infant with hematuria and urinary retention. urology. 1999;54:921-2. 10. baroudy ac, o’connell jp. papillary adenoma of the prostatic urethra. j urol. 1984;132:120-2. 11. murphy wm. disease of the urinary bladder, urethra, ureter, and renal pelvis. in: murphy wm, editor. urological pathology. 2nd ed. saunders philadelphia; 1997:35-147. introduction 1 urologists and the novel coronavirus disease 2019 (covid-19): a urologist’s perspective from china yi lu1, 2, xiaoqiang liu1,* 1department of urology, tianjin medical university general hospital, tianjin, 300052, china 2tianjin medical university, tianjin, 300070, china *corresponding author: xiaoqiang liu, department of urology, tianjin medical university general hospital, 154 anshan road, heping district, tianjin 300052, china. e-mail: luis_will@126.com. tel: +86 17731859376 word count: 467 running title: urologists and the novel coronavirus disease 2019 acknowledgments none. competing interests no conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. funding this work was supported by the zhao yi-cheng medical science foundation, china [grant no.zyyfy2018031]. mailto:xiaoqiangliu1@163.com 2 text the novel coronavirus disease 2019 (covid-19), first reported in wuhan, china, in december 2019, has rapidly spread all over the world1. up till now, the epidemic situation in china is relatively stable and remains contained. however, the global spread of the epidemic seems to be unstoppable, especially in italy, iran, south korea and, the usa2. hence, we shared some of china’s experiences on what urologists could do to cope with the covid-19. in the epidemic area, urologists may receive suspected or confirmed covid-19 patients in hospitals. it is recommended by wang et al. that the key role of maintaining the emergency management plans and quick responses to national and local emergencies. in the clinical practice, suspected or confirmed patients should be strictly handled following the rules of nosocomial infection. yang et al. identified 15 (29%) patients with acute kidney injury in 52 severe covid-19 cases3. teleconsultation and if needed, bedside consultation can be provided by urologists. in outpatient and emergency rooms, urologists should differentiate patients with fever appropriately. patients with fever and other symptoms of covid-19, including cough, dyspnea, with or without epidemiological contact should be referred to the fever clinic. urologists should participant in the initial evaluation of patients presenting with fever without other symptoms of covid-19, such as urosepsis caused by the presence of urological devices. great self-protection to prevent cross-infection should be adopted. due to the overwhelming workload, frontline medical providers suffer from an increased risk of developing urinary tract infection and urolithiasis. therefore, prevention measures, such as skin cleansing, drinking water, diet guidance, and timely urination can be provided by urologists to health-care workers. although infectious diseases are far removed from urology specialty, we, urologists should keep the responsibilities as doctors in mind and participate in the fight against the epidemic worldwide. it is necessary to convey and diffuse prevent knowledge to the general public, 3 such as wearing masks and goggles, the possible urology-related transmission sources of covid-19 and the necessity of strict home quarantine. on the other hand, urologists should inform patients which urology conditions are not necessary to treat immediately, and when they should ask for medical help and urologists should reschedule patients timely to keep positive doctor-patient relationships. online teleconsultation sponsored by hospitals or governments through the internet or cellphone is strongly recommended to meet the patients’ medical needs. in conclusion, urologists can participant actively in the process of pre-examination, triage and management of outpatient, inpatient, and emergency patients. urologists can also convey urological knowledge to medical workers at the front, urological patients and the general public, provide teleconsultation, and keep positive doctor-patient relationships. now is the crucial time to work together to defeat the covid-19 outbreak. even though we have devoted ourselves to genitourinary career, urologists can also play a role in fighting against the epidemic. references 1. guan w, ni z, hu y et al. clinical characteristics of coronavirus disease 2019 in china. new engl j med. 2020; 2. bedford j, enria d, giesecke j et al. covid-19: towards controlling of a pandemic. the lancet. 2020; 3. yang x, yu y, xu j et al. clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study. the lancet respiratory medicine. 2020; a novel computed tomography-ultrasound image fusion technique for guiding the percutaneous kidney access xiaobo shen1,2,3*, kaiwen li1,2,3*, zhenyu wu1,2,3, cheng liu1,2,3, hao yu1,2,3, cong lai1,2,3, zhuang tang1,2,3, kuiqing li1,2,3, kewei xu1,2,3 purpose: to describe the feasibility of computed tomography (ct)-ultrasound image fusion technique on guiding percutaneous kidney access in vitro and vivo. materials and methods: we compare ct-ultrasound image fusion technique and ultrasound for percutaneous kidney puncture guidance by using an in vitro pig kidney model. the fusion method, fusion time, ultrasound screening time, and success rate of puncture were compared between the groups. next, patients with kidney stones in our hospital were randomized in the study of simulated puncture guidance. the general condition of patients, fusion method, fusion time, and ultrasound screening time were compared between the groups. results: a total of 45 pig models were established, including 23 in the ct-ultrasound group and 22 in the ultrasound group. the ultrasound screening time in the ct-ultrasound group was significantly shorter than that in the ultrasound group (p < .001). in addition, the success rate of puncture in the ct-ultrasound group was significantly higher than that in the ultrasound group (p =.015). furthermore, in the simulated pcnl puncture study, baseline data including age, bmi, and s.t.o.n.e score between the two groups showed no statistical difference. the ultrasound screening time of the two groups was (2.60 ± 0.33) min and (3.37 ± 0.51) min respectively, and the difference was statistically significant (p < .001). conclusion: our research revealed that the ct-ultrasound image fusion technique was a feasible and safe method to guide pcnl puncture. compared with traditional ultrasound guidance, the ct-ultrasound image fusion technique can shorten the learning curve of pcnl puncture, improve the success rate of puncture, and shorten the ultrasound screening time. keywords: kidney stone; percutaneous nephrolithotomy; computed tomography; ultrasound; puncture introduction kidney stone is one of the most common urolog-ical diseases around the world. due to the high stone free rate (sfr), percutaneous nephrolithotomy (pcnl) has been introduced for the treatment of patients with large kidney stones (> 20 mm)(1). the outcomes of pcnl are highly related to the accuracy of percutaneous kidney puncture in the targeted calyx(2,3). appropriate percutaneous renal access can guarantee the effectiveness and safety of pcnl and reduce the risk of complications (4). this challenging step can be accomplished by ultrasound and fluoroscopy, both of which have their shortcomings that may increase the risk of complications (5,6). it is well known that computed tomography (ct) scan is the gold-standard modality for the diagnosis of kidney stones and preoperative planning of pcnl due to its high sensitivity and specificity, precise stone sizing, and the feasibility of evaluating non-stone pathologies (7). therefore, we proposed to integrate the preoperative ct images into intraoperative ultrasound images to im1department of urology, sun yat-sen memorial hospital, sun yat-sen university, guangzhou, guangdong, p. r. china. 2guangdong provincial key laboratory of malignant tumor epigenetics and gene regulation, sun yat-sen memorial hospital, sun yat-sen university, guangzhou, guangdong, p. r. china. 3guangdong provincial clinical research center for urological diseases. *equal contribution *correspondence: ? department of urology, sun yat-sen memorial hospital, sun yat-sen university, guangzhou, guangdong, p. r. china. received october 2022 & accepted february 2023 prove the accuracy of percutaneous kidney puncture. ct-ultrasound image fusion technique has shown advantages in the treatment of other diseases. xu et al.(8) have reported that 92 patients with malignant liver tumors underwent radiofrequency ablation (rfa) under the guidance of ct-ultrasound fusion image, proving that fusion technique assisted rfa was a safe and effective option. as a result, our research aimed to apply the ct-ultrasound image fusion method to guide percutaneous kidney puncture and expected to increase the efficiency of stone removal and reduce the risk of complications. therefore, the research explored the feasibility of ct-ultrasound image fusion method in establishing an appropriate renal channel. first, we utilized an in vitro pig kidney model to study the feasibility of ct-ultrasound fusion in establishing a percutaneous kidney access. next, we performed the simulated ct-ultrasound image fusion on patients with kidney stones, further exploring the feasibility of ct-ultrasound fusion method in guiding pcnl puncture. urology journal/vol 20 no. 4/ july-august 2023/ pp. 208-214. [doi:10.22037/uj.v20i.7465] endourology and stone diseases materials and methods in vitro pig kidney model for the in vitro study, a well-established model was applied to modulate the percutaneous kidney puncture(9). the porcine kidneys and chicken carcasses were bought from commercial slaughterhouse. we incised the renal pelvis and inserted 2-3 artificial stones (10-20 mm) into the calyces through the incision. the prepared pig kidney was placed inside the eviscerated chicken carcass, and filled the remaining space with agar. after the agar was fixed, all the openings of the chicken carcass were closed with sutures to simulate a confined space (figure 1). a total of 45 models were established, including 23 in the ct-ultrasound group and 22 in the ultrasound group. patient selection patients in our hospital from december 2019 to february 2021 were enrolled in the simulated pcnl puncture study, who were randomly divided into ct-ultrasound group and ultrasound group with the help of sas software. the inclusion criteria were as follows: (1) renal pelvis and upper or middle calyx stones with a diameter of more than 2 cm; lower renal calyx stones with a diameter of more than 1.5 cm; (2) available urinary ct data; (3) patients were voluntarily participated and signed an informed consent. exclusion criteria were patients with anatomical structure or location of the kidney, such as horseshoe kidney, polycystic kidney, pelvic heterotopic kidney, etc. informed consent was taken from all eligible patients. this study was approved by the ethics committee of our hospital, whose ethical number was 2020-ky-021, and has been registered in clinicaltrials. gov (nct04645472). equipment and techniques the urinary ct image data were acquired using the optima 64-multidetecto helical ct scanner (ge healthcare, waukesha, wi) 1 month or less before the procedure. all images were obtained with 1.25-mm-thick sections and a 1:1 pitch. the ct-ultrasound image fusion was achieved by the real-time virtual sonography (rvs) method using the arietta 70 ultrasound system (hitachi aloka medical ltd., tokyo, japan, (figure 2). prior to the ct-ultrasound image fusion, the dicom volume data of the kidney were loaded onto the arietta 70 ultrasound system, and the magnetic generator was placed next to the working area. the image fusion of ultrasound and ct was executed sequentially by the rvs method by the professional ultrasound technician. in this step, we need to find out an image fusion region, which can be well visualized on both ct and ultrasound images, we can adjust the corresponding ultrasound image to match the ct plane through the image fusion region. establishment of percutaneous kidney access in the pig kidney model pig kidney models were randomly divided into the ct-ultrasound group and ultrasound group. we found that ct and ultrasound image can be fused using the long axis of the kidney and stones in the ct-ultrasound group. after the fusion was completed, the ultrasound probe was used to investigate the sonographic characteristics of hydronephrosis, stones, renal cortex, and medulla of the porcine kidney so to determine the targeted calyx. we punctured the targeted calyx from the fornix of the calyx. it was defined as a successful puncture when the puncture needle passed through the fornix to reach the targeted calyx after the kidney was opened (figure 3). in the ultrasound group, we used traditional ultrasound for screening and puncture. finally, the puncture results of the ct-ultrasound group and the ultrasound group were compared. simulated pcnl puncture in patients we randomly divided the selected patients into the ct-ultrasound group and ultrasound group. in the ct-ultrasound group, according to the previous study (8) and our existing experience, we using the long axis of the kidney and stones as the image fusion region to match the corresponding ultrasound image and the ct plane, since right kidney is adjacent to liver, the liver portal system can also be the image fusion region in right kidney (figure 4). the targeted renal calyx and simulated puncture site were determined based on the stone location, hydronephrosis and adjacent organs. notably in the ct-ultrasound group, we first determined the learning curve of the ct-ultrasound fusion technique. after the fusion time and ultrasound screening time reached the plateau, the ct-ultrasound group and ultrasound group were compared. statistical analysis spss 20.0 software was utilized for statistical analysis. the data were expressed as the mean ± standard deviation or median ± range, and qualitative variables were expressed as the rate. the independent t test was applied to compare quantitative variables between the two groups. normality and homogeneity of variance were also checked. the qualitative variables were compared using the chi-square test, when no expected cell count less than 1 and at most 20% of expected cell counts less ct-ultrasound versus ultrasound for percutaneous kidney access-shen et al. variables a ct-ultrasound group ultrasound group p-value sample size, n 22 23 chicken weight, kg; mean ± sd 3.44 ± 0.23 3.52 ± 0.28 .326 length of pig kidney, cm; mean ± sd 12.44 ± 0.75 12.45 ± 0.94 .951 width of pig kidney, cm; mean ± sd 4.75 ± 0.38 4.72 ± 0.43 .846 number of artificial stones, n 2 (2~3) 2(2~3) .661 image fusion method, n long axis of kidney and kidney stones 23 fusion time, min; mean ± sd 4.02 ± 0.54 ultrasound screening time, min; mean ± sd 2.52 ± 0.31 3.38 ± 0.50 < .001 puncture depth, cm; mean ± sd 5.99 ± 0.71 5.76 ± 0.80 .306 puncture success rate, n; (%) 19(86.4) 11(47.8) .015 table 1. characteristics of ct-ultrasound and ultrasound group in pig kidney model abbreviations: ct, computed tomography a continuous variables were compared by independent samples t-test vol 20 no 4 july-august 2023 209 than 5. a value of p < .05 was considered statistically significant. results the detailed results of the in vitro study were shown in table 1. a total of 45 models were established, including 23 in the ct-ultrasound group and 22 in the ultrasound group. there were no statistically significant differences in chicken weight, the length and width of kidney between the two groups. the ultrasound screening time in the ct-ultrasound group was significantly shorter than that in the ultrasound group (p < .001). in variables a ct-ultrasound group ultrasound group p-value sample size, n 52 53 gender, n; (%) .359 male 34 (65.4) 29 (54.7) female 18 (34.6) 24 (45.3) laterality, n; (%) 1 right 28 (53.8) 29 (54.7) left 24 (46.2) 24 (45.3) age, year; mean ± sd (range) 54.15 ± 11.65 (24-81) 52.74 ± 11.49 (43-82) .532 bmi, kg/m²; mean ± sd (range) 23.69 ± 3.98 (16.89-41.32) 23.37 ± 3.33 (18.07-32.47) .653 previous ipsilateral surgery history, n; (%) 10 (19.2%) 10(18.9%) 1 stone size, mm; median (iqr) 19.2 (22) 21.1 (17.6) .354 tract length, mm; mean ± sd 82.79 ± 15.24 80.15 ± 13.73 .354 obstruction or hydronephrosis, n; (%) .828 none or mild hydronephrosis 37 (71.2) 37 (69.8) moderate hydronephrosis 10 (19.2) 9 (17.0) heavy hydronephrosis 5 (9.6) 7 (13.2) number of involved calyces, n 2.40 ± 1.16 2.33 ± 0.91 .385 stone density, hu; mean ± sd 1122.71 ± 371.29 1022.32 ± 323.91 .143 s.t.o.n.e score (range) 7 (5-10) 7 (5-10) .356 table 2. demographic characteristics of ct-ultrasound and ultrasound group in simulated puncture guidance abbreviations: bmi, body mass index; iqr, interquartile range a continuous variables were compared by independent samples t-test figure 1. irregular tumor edge of renal cell carcinoma in contrast-enhanced ct (a) a mass with smooth margin and prominent nodules from part of it; (b) a mass with blurred margin; (c) a mass with completely irregular and non-elliptical shape; (d) renal sinus compression in contrast-enhanced ct ct-ultrasound versus ultrasound for percutaneous kidney access-shen et al. endourology & stone diseases 210 addition, the success rate of puncture in the ct-ultrasound group was significantly higher than that in the ultrasound group (p = .015). a total of 150 patients were included in the simulated pcnl puncture study, of which 97 cases in the ct ultrasound group and 53 cases in the ultrasound group. we first determined the learning curve of the ct-ultrasound image fusion method, indicating that the screening time of the ct-ultrasound group reached a plateau after 31-45 cases. therefore, the last 52 patients in the ct-ultrasound group and 53 patients in the ultrasound group were included in the comparison. there was no statistical difference in baseline data between the two groups (table 2). the fusion time in the ct-ultrasound group was (4.27 ± 0.56) min. eighteen cases of the right kidney were fused with the portal venous system; 10 cases were fused with the long axis of the kidney and stones; and all cases of the left kidney were fused with the long axis of the kidney and stones. the ultrasound screening time of the two groups was (2.60 ± 0.33) min and (3.37 ± 0.51) min, respectively, and the difference was statistically significant (p < .001, table 3). discussion in 1976, fernstrom et al.(10) first reported the experience of removing kidney stones through percutaneous nephrostomy, which had been widely used since the early 1980s. currently, pcnl is recommended for the treatment of upper urinary tract stones with a diameter > 2cm and complex kidney stones owing to its high efficiency and minimal invasiveness. establishing percutaneous renal access is the most critical step in pcnl. incorrect puncture can easily damage the blood vessels, thereby increasing the risk of complications such as bleeding and renal function damage(11). therefore, how to accurately puncture the targeted calyx has become the biggest problem for pcnl. rassweiler et al.(12) has reported an ipad-assisted technique with a three-dimensional reconstruction and marker tracking method for kidney puncture. before the surgery, patients underwent a preoperative ct in the prone position with 5 colored metal markers around the puncture site. the ct images were segmented and analyzed to establish a three-dimensional construction and adjacent organ anatomy on an ipad. during variablesa ct-ultrasound group ultrasound group p-value sample size, n 52 53 image fusion region, n; (%) portal vein 18 (34.6) long kidney axis and stones (right kidney) 10 (19.2) long kidney axis and stones (left kidney) 24 (46.2) fusion time, min; mean ± sd 4.27 ± 0.56 ultrasound screening time, min; mean ± sd (range) 2.60 ± 0.33 (2.0-3.2) 3.37 ± 0.51 (2.2-4.3) < .001 simulated puncture site, n; (%) .331 above the 12th rib 15 (28.8) 10 (18.9) below the 12th rib 37 (71.2) 43 (81.1) target calyx, n; (%) .818 upper calyx 3 (5.8) 2 (3.8) lower calyx 2 (3.8) 3 (5.6) middle calyx 47 (90.4) 48 (90.6) table 3. outcomes of ct-ultrasound and ultrasound group in simulated puncture guidance acontinuous variables were compared by independent samples t-test figure 1. establishment of percutaneous kidney access with the in vitro pig kidney model. (a) preparation of in vitro pig kidney model. (b) establishment of in vitro pig kidney model. (c) suture of the openings. (d) ct scan of the model. (e) ultrasound screening before puncture. (f) percutaneous kidney puncture with the model. ct-ultrasound versus ultrasound for percutaneous kidney access-shen et al. vol 20 no 4 july-august 2023 211 the operation, the integrated image was matched with the real-time puncture guidance through the ipad, and the simulated image of the puncture pathway was displayed on the screen. the limitations of this method were the additional ct examination and operation time. the sonix-gps system was another technology designed to track needle positioning under ultrasound guidance(13). this technology applied electromagnetic tracking to identify the needle location and display the planned puncture access. a prospective comparative study reported that the sonix-gps system can improve the success rate of a single puncture without increasing the risk of complications(14). however, the ultrasound image was greatly affected in obese patients. in addition, the uro-dyna-ct system reported by ritter et al. (15) was a modified angiography device that allowed 3d reconstruction of ct images and showed the exact pathway chosen for puncture. this device offered a 3d anatomical image with the characteristics of safe, fast, and accurate. the disadvantages included high radiation exposure, high costs, and difficulty in learning. in the research, we demonstrated an innovative technique for kidney puncture. the rvs technology combined the images of ultrasound and ct, allowing the surgeon to puncture with both ultrasound and ct images simultaneously. ct images can provide the information including the diameter and location of kidney stones, the anatomy of the renal pelvis and calyxes, and the refined construction of surrounding organs. during the puncture process, the surgeon can refer to the ultrasound and ct images at the same time, thereby increasing the accuracy of the percutaneous kidney access. the image fusion technology can improve the effectiveness of stone removal of the percutaneous access and reduce the damage to adjacent organs without increasing the risk of radiation exposure and complications. the image fusion technology can be of great help to beginners because of the high success rate of the ct-ultrasound group, which was operated by a urological intern in the whole study. in addition, our results verified the effectiveness of this technology through an in vitro pig kidney model and simulated ct-ultrasound fusion study. however, there are some limitations in our research. first, our study lacked a description of the intraoperative application of this technique. at present, our center has tested this technique during surgery, whose results will be published in another manuscript. second, after the fusion is completed, slight movements of the patient's body, such as breathing activity, can easily reduce the accuracy of the fusion image. during the puncture process, the anesthesiologist can decrease the patient's tidal volume to reduce the impact of breathing activity on the fusion image. finally, the fusion image cannot be used for the second puncture, as the first puncture changes the structure of the kidney and stones. conclusions our research demonstrated an innovative ct-ultrafigure 2. the overview of the arietta 70 ultrasound system. (a) arietta 70 ultrasound system. (b) probe ct-ultrasound versus ultrasound for percutaneous kidney access-shen et al. endourology & stone diseases 212 sound image fusion technique for percutaneous kidney puncture. the in vitro study revealed that compared with the traditional ultrasound guidance, the ct-ultrasound fusion imaging technique can shorten the ultrasound screening time, and improve the success rate of puncture. the simulated ct-ultrasound fusion research suggested that this technology can shorten the learning curve and ultrasound screening time. in summary, the image fusion assisted percutaneous kidney puncture appeared to be safe and effective for pcnl. conflict of interest the authors declare that they have no competing interests. this work was funded by grants from the national natural science foundation of china (grant numbers: 81572511, 81702525, 81702528), guangzhou science figure 3. the ct-ultrasound fusion images and puncture outcomes with the in vitro pig kidney model figure 4. simulated ct-ultrasound image fusion. (a) simulated ct-ultrasound fusion on the right kidney; (b) simulated ct-ultrasound fusion on the left kidney; (c) ct-ultrasound fusion image on the right kidney; (d) ct-ultrasound fusion image on the left kidney ct-ultrasound versus ultrasound for percutaneous kidney access-shen et al. vol 20 no 4 july-august 2023 213 and technology program key projects (grant numbers: 201803010029), natural science foundation of guangdong province (grant numbers: 2016a030313317), medical scientific research foundation of guangdong province (grant numbers: c2018060), and yixian clinical research project of sun yat-sen memorial hospital (grant numbers: sys-c-201802). references 1. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 2. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899-906; discussion 3. patel rm, okhunov z, clayman rv, landman j. prone versus supine percutaneous nephrolithotomy: what is your position? curr urol rep. 2017;18:26. 4. de la rosette jj, laguna mp, rassweiler jj, conort p. training in percutaneous nephrolithotomy--a critical review. eur urol. 2008;54:994-1001. 5. rodrigues pl, rodrigues nf, fonseca j, lima e, vilaça jl. kidney targeting and puncturing during percutaneous nephrolithotomy: recent advances and future perspectives. j endourol. 2013;27:826-34. 6. de la rosette j, kashi ah, farshid s. newer advances in access. in: agrawal ms, mishra dk, somani b, eds. minimally invasive percutaneous nephrolithotomy. singapore: springer singapore; 2022:145-55. 7. brisbane w, bailey mr, sorensen md. an overview of kidney stone imaging techniques. nat rev urol. 2016;13:654-62. 8. xu zf, xie xy, kuang m, et al. percutaneous radiofrequency ablation of malignant liver tumors with ultrasound and ct fusion imaging guidance. j clin ultrasound. 2014;42:321-30. 9. hacker a, wendt-nordahl g, honeck p, michel ms, alken p, knoll t. a biological model to teach percutaneous nephrolithotomy technique with ultrasoundand fluoroscopyguided access. j endourol. 2007;21:545-50. 10. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 11. hajiha m, baldwin dd. new technologies to aid in percutaneous access. urol clin north am. 2019;46:225-43. 12. rassweiler jj, müller m, fangerau m, et al. ipad-assisted percutaneous access to the kidney using marker-based navigation: initial clinical experience. eur urol. 2012;61:62831. 13. li r, li t, qian x, qi j, wu d, liu j. realtime ultrasonography-guided percutaneous nephrolithotomy using sonixgps navigation: clinical experience and practice in a single center in china. j endourol. 2015;29:158-61. 14. li x, long q, chen x, he d, he h. realtime ultrasound-guided pcnl using a novel sonixgps needle tracking system. urolithiasis. 2014;42:341-6. 15. ritter m, rassweiler mc, michel ms. the uro dyna-ct enables three-dimensional planned laser-guided complex punctures. eur urol. 2015;68:880-4. ct-ultrasound versus ultrasound for percutaneous kidney access-shen et al. endourology & stone diseases 214 urology journal peer review running title: (short form of the main title presented on the top of pages): early onset clean intermittent catheterization may avert voluminous dilute urine early onset clean intermittent catheterization may decrease prevalence and severity of urinary concentration defects in myelomeningocele patients with neurogenic bladder: a retrospective cohort study mohsen ebrahimnezhad, seyed mohammad ghahestani* 1fellow of pediatric urology, department of pediatric urology, tehran university of medical sciences, children medical center hospital, tehran, iran. address: urology ward,children medical center hospital,gharib st,keshavarz blvd,tehran,iran postal code:141973351 ,phone:+982161479000 cellphone number: +989131914581 email: mohsen.ebrahimnejad1359@gmail.com 2assistant professor of pediatric urology, fellow of pediatric urology, director board of iranian urology association , director of research committee iranian urology association , international affair deputy of tums (tehran university of medical sciences) urology department, deputy delegate of iran in siu(societe internationale d' urologie)e mail: mgrosva @gmail.com * corresponding author: seyed mohammad ghahestani, md postal address: no. 62, dr. qarib’s street, keshavarz boulevard, tehran, iran postal code/ p.o. box: 1419433151 telephone number: +98-21-66565400 fax number: +98-21-66565400 email address: mgrosva @gmail.com mobile phone number: +98-9128491811 abstract http://gmail.com/ http://gmail.com/ purpose: myelomeningocele is the most severe form of spina bifida. management of urologic consequences of spina bifida is life long, demanding and costly for both patient and public health system. there is a paucity of data in literature regarding concentration defect and its consequences on this disease. this paper aims to describe retrospectively early onset clean intermittent catheterization (cic) in the severity of urinary concentration defects in myelomeningocele patients with neurogenic bladder. materials and methods: in this 10-year retrospective cohort study, children with myelomeningocele were selected with the convenience sampling method. demographic characteristics, polyuria index ratio (pir) defined as 24 hour urine output of each patient divided by maximum normal urine output of the same patient in a healthy state , and nocturnal polyuria index (npi) were compared between early starters (< 2 years old) or late starters (≥ 2 years old) groups. results: seven patients who underwent cystoplasty were excluded and 130 patients (63.8% male, 5.4 ± 3.2 years old, 14.3 ± 2.83 kg, 28.5% early onset cic) were investigated. pir > 1 in inset (1.7 ± 0.2 vs. 2.2 ± 0.5, p = 0.021) and outset (1.5 ± 0.32 vs. 2.5 ± 0.7, p = 0.004) were lower in early starters group than in late starters group. npi in inset (0.2 ± 0.007 vs. 0.32 ± 0.10, p = 0.018) and outset (0.25 ± 0.15 vs. 0.42 ± 0.095, p = 0.007) were also lower in early starters group. no further adverse events were reported during -the injection or follow-up period. conclusions: early onset cic is more effective than late-onset cic in improving the urinary concentration defects preserving urinary ability of kidneys in myelomeningocele patients. keywords: myelomeningocele, neurogenic bladder, clean intermittent catheterization, urinary concentration introduction myelomeningocele is the most dangerous and severe form of spina bifida, characterized by nerve roots, spinal cord, and meninges protrusion through vertebrae defects [1, 2]. this condition brings chemical and mechanical damage to the intrauterine environment before birth [3, 4]. deficiency in urine concentration in this disease is associated with a high prevalence and in the long run, it can lead to functional kidney damage [2-4]. the standard treatment for these patients is surgical closure. the patients may also need a shunt for hydrocephalus or require urinary catheterization [5, 6]. myelomeningocele is associated with various sequelae such as lower limb paraplegia, muscle weakness, musculoskeletal deformities, and bowel and bladder dysfunction [2, 3]. neurogenic bladder is a common urological disease caused by neurological pathologies [9, 10]. about 98% of patients with myelomeningocele have a neurogenic bladder. important goals of treatment in these patients are ensuring safe storage pressures, adequate bladder emptying, and preventing kidney damage, to improve the quality of life [11]. although effect of partial urinary tract obstruction on concentrating ability of kidneys is clarified there is a paucity of data in literature regarding concentration defect and its consequences on specific situation of mmc patients with neurogenic bladder [12-14]. there were remarkably few complications associated with clean intermittent catheterization (cic) in myelomeningocele [15]. role of concentration defect and increasing amount of dilute urine on an already neurologically un-healthy bladder has not been addressed. effect of pre-emptive ic on this problem would give us a hint about role and mechanism of concentration defects as this has been shown to significantly reduce the rate of enterocystoplasty [13]. the authors performed a preliminary observational study to support the idea that cic might affect urine concentration. therefore, the present study was conducted to describe the prevalence and severity of urinary concentration defects in myelomeningocele patients pre-emptively treated by ic at an earlier age vs late starters. materials and methods in this retrospective cohort study, patients with myelomeningocele referred to our center in 10 years (september 2011 to september 2020) were selected using the convenience sampling method. including criteria were: a) age ≤ 14 years, b) access to clinical records, and b) both male and female. defects in the necessary information required for this study and using of nephrotoxic drugs (such as diuretics or aminoglycosides) in a period of two weeks leading to the measurements in archived documents, were the exclusion criteria. the information required for this study was extracted in the form of a checklist containing questions related to demographic information as well as information related to the disease, voiding diaries and laboratory findings already obtained in the center database. more precisely, this information included: demographic characteristics (age, sex, and weight), polyuria index ratio (pir), and nocturnal polyuria index (npi). nocturnal polyuria index (npi) was defined as the fraction of 24-hour urine output produced during the intended sleep period (nocturnal urine volume/24-hour urine volume) polyuria index ratio was calculated dividing the patient urine output by maximal 24 hour urine output of the same healthy index patient regarding definition of polyuria i.e. more than 4 ml/kg.hr in infants and children excluding neonatal period [16]) these indices were improvised as quantitative indices which can consider weight, age and body surface area regarding the adopted definition. in our case the definition by weight was picked up due to ease of use. patients were divided into two groups based on whether they began clean intermittent catheterization (cic) at early age (before two years old) as early starters or late starters (after two years old), and the information (pir and npi) was compared between these two groups. patients were cared for according to routine standards. finally, the data were analyzed with the kolmogorov smirnov, independent t test, mann-whitney, and chi-square tests, using statistical package for the social sciences 25.0 software (spss 25.0) and stata software version 2.9 (stata corp., college station, tx, usa). the primary assumption underlying the chi-square test, were no expected cell count less than 1 and at most 20% of the expected cell counts less than 5. the normality of the data was checked with the shapiro-wilk test. in all tests, the confidence level was 95% and the significance level was less than 0.05. results seven who underwent cystoplasty during the course of study were excluded, and 130 patients (63.8% male) aged 5.4 ± 3.2 years and weighing 14.3 ± 2.83 kg were investigated (table 1).age of early starters tended to be lower than late starters though not achieving statistical significance (19.1 ± 1.2 vs. 54.2 ± 2.3 and p = 0.453, respectively). the reason for the limitation of the volume of statistical samples is the small number of available patients. in this study, 130 performed cic (37 patients (28.5%) had presented before two years old and 93 patients (71.5%) after two years of age). according to the table and figure 1, the mean and standard deviation of pir > 1 in inset (p = 0.021) and outset (p = 0.004) were lower in the early starters group than in the late starters group, and this difference was significant. the mean and standard deviation of npi in inset (p = 0.018) and outset (p = 0.007) were lower in the early starters group than in the late starters group, and this difference was significant (table 2, figure 1). discussion clean intermittent catheterization (cic) is an effective, reliable long-term, and safe bladder management option for patients with myelomeningocele [16]. this 10-year cohort is the first study assessing the effect of early onset cic on renal concentration defects of children with neurogenic bladder. the concept rose when we noticed in the literature concentration defects induced by transient episodes of obstruction tend to persist beyond relief of obstruction [12]. the scenario may go on with a vicious cycle of obstruction leading to voluminous dilute urine over burdening of the bladder and leading to further functional obstruction (fig 2). early institution of ic which has been shown to be beneficial in several studies [13] may actually decrease these episodes of transient obstruction .this leads us to the core concept of this study. analysis of data showed early onset cic therapy played a major role in decreasing of polyuria index ratio (pir) and nocturnal polyuria index (npi) in children with myelomeningocele. according to the searches, few studies were found in this regard. elzeneini et al (2019) instituted early cic for all infants with spina bifida. based on renal protective functional data, they recommend indwelling and then early cic from birth in all patients with spina bifida [17]. in the other study, li et al (2018) demonstrated that early cic plays an important role in preserving bladder function in infants with neurogenic bladder, especially in the first year of life [18]. proponents of early onset of cic suggest that the benefits of improved conservation of renal function, bladder compliance, and bladder emptying outweigh the risk and potential discomfort and parental anxiety of early cic [19]. none of these studies specifically highlighted the role of concentration defect. contrary to these findings, freeman et al (2022) could not demonstrate that younger age at cic initiation increased the likelihood of achieving urinary continence in children with myelomeningocele. limitations include a lack of urodynamic data, data on the reason for starting cic and type of incontinence, and the observational nature of data collection [20]. we also found that no other adverse events were reported during observation period in early onset cic. https://www.sciencedirect.com/topics/medicine-and-dentistry/spinal-dysraphism https://www.sciencedirect.com/topics/medicine-and-dentistry/spinal-dysraphism this method is believed to decrease the need for future bladder augmentation and is well tolerated by families [21]. currently, many providers initiate early onset cic for mmc patients with the potential for neurogenic bladder, assuring the bladder can adequately empty and the urinary tract and kidneys do not appear to be exposed to high pressure [20, 21]. altogether, this study suggests that early onset cic therapy decreases number of pir > 1 cases and abnormal npi in children with myelomeningocele. presumably this may have a role in decreasing number of aggravating cases requiring complex bladder augmentation procedures, reduce severity of upper tract deterioration, and protect upper tract function among myelomeningocele patients with neurogenic bladder and imminent urinary concentration defects. this study has several limitations that may have influenced the results. first, we did not obtain data in a healthy control group. the small sample size decreases statistical power, and the relatively short observation duration of this study may have been insufficient to assess differences between the groups. obviously a large clinical trial is required to confirm our findings. conclusions in conclusion, early onset cic is more effective than late-onset cic in improving the urinary concentration defects preserving or impeding deterioration of urinary concentrating ability of kidneys in myelomeningocele patients . further studies may be necessary are absolutely necessary to evaluate the long-term safety and clinical effect of early onset cic on urinary concentration defects and presumably final outcome of neurogenic bladder of mmc1 patients. acknowledgement this study was supported by the tehran university of medical sciences, tehran, iran. conflict on interest the authors declare that they have no conflict of interests. references 1. coelho g, trigo l, faig f, vieira ev, da silva hp, acácio g, zagatto g, teles s, gasparetto tp, freitas lf, zanon n. the potential applications of augmented reality in fetoscopic surgery for antenatal treatment of myelomeningocele. world neurosurgery 2022; 159: 27-32. 2. macedo jr a, ottoni sl, moron a, cavalheiro s, cruz ml. in utero myelomeningocele repair and high-risk bladder pattern. a prospective study. international braz j urol 2022; 48: 672-8. 3. theodorou cm, jackson je, stokes sc, pivetti cd, kumar p, paxton zj, matsukuma ke, yamashiro kj, reynaga l, hyllen aa, de lorimier aj. early investigations into improving bowel and bladder function in fetal ovine myelomeningocele repair. journal of pediatric surgery 2022; 57(5): 941-8. 4. takoutsing bd, touzet ay, park jj, lee sh, bligh er, egiz a, gillespie cs, figaji aa. management and outcomes of myelomeningocele-associated hydrocephalus in low-and middleincome countries: a systematic review and meta-analysis protocol. medrxiv 2022. 5. marquart jp, foy ab, wagner aj. controversies in fetal surgery: prenatal repair of myelomeningocele in the modern era. clinics in perinatology 2022; 49(1): 267-77. 1 myelomeningocele 6. kukora sk, fry jt. resuscitation decisions in fetal myelomeningocele repair should center on parents’ values: a counter analysis. journal of perinatology 2022: 1-5. 7. reynolds ra, bhebhe a, garcia rm, chen h, bonfield cm, lam s, sichizya k, shannon c. surgical outcomes after myelomeningocele repair in lusaka, zambia. world neurosurgery 2021; 145: e332-9. 8. yu wr, kuo hc. usefulness of videourodynamic study in the decision-making of surgical intervention and bladder management for neurogenic lower urinary tract dysfunction among patients with myelomeningocele. international urology and nephrology 2022: 1-0. 9. copp aj, adzick ns, chitty ls, fletcher jm, holmbeck gn, shaw gm. spina bifida. nat rev dis prim 2015; 1: 1-45. 10. saadai p, nout ys, encinas j, et al. prenatal repair of myelomeningocele with aligned nanofibrous scaffolds—a pilot study in sheep. j pediatr surg 2011; 46(12): 2279-2283. 11. sager c, barroso jr u, netto mb, retamal g, ormaechea e. management of neurogenic bladder dysfunction in children update and recommendations on medical treatment. international braz j urol 2022; 48: 31-51. 12. shi y, li c, thomsen k, jørgensen tm, knepper ma, nielsen s, djurhuus jc, frøkiær j. neonatal ureteral obstruction alters expression of renal sodium transporters and aquaporin water channels. kidney international 2004; 66(1): 203-15. 13. geraniotis e, koff sa, enrile b. the prophylactic use of clean intermittent catheterization in the treatment of infants and young children with myelomeningocele and neurogenic bladder dysfunction. the journal of urology 1988; 139(1): 85-6. 14. geraniotis e, koff sa, enrile b. the prophylactic use of clean intermittent catheterization in the treatment of infants and young children with myelomeningocele and neurogenic bladder dysfunction. the journal of urology 1988; 139(1): 85-6. 15. lindehall b, abrahamsson k, jodal u, olsson i, sillén u. complications of clean intermittent catheterization in young females with myelomeningocele: 10 to 19 years of followup. the journal of urology 2007; 178(3): 1053-1055. 16. mishra g, chandrashekhar sr. management of diabetes insipidus in children. indian journal of endocrinology and metabolism 2011; 15(3): 180. 17. elzeneini w, waly r, marshall d, bailie a. early start of clean intermittent catheterization versus expectant management in children with spina bifida. journal of pediatric surgery 2019; 54(2): 322-5. 18. li y, wen y, he x, li y, wu j, feng j, wang q, wen j. application of clean intermittent catheterization for neurogenic bladder in infants less than 1 year old. neurorehabilitation 2018; 42(4): 377-82. 19. hobbs kt, krischak m, tejwani r, purves jt, wiener js, routh jc. the importance of early diagnosis and management of pediatric neurogenic bladder dysfunction. research and reports in urology 2021; 13: 647. 20. freeman ka, liu t, smith k, castillo h, castillo j, joseph d, wang y, tanaka s. association between age of starting clean intermittent catheterization and current urinary continence in individuals with myelomeningocele. journal of pediatric urology 2022. 21. edwards ab, jacobs m. early vs. expectant management of spina bifida patients-are we all talking about a risk stratified approach? curr urol rep 2019; 20(11): 76. tables and legends to figures table 1. demographic characteristics of myelomeningocele patients at early or late clean intermittent catheterization variables cis, mean (s.d)/ n (%) p-value early starters (n = 37) late starters (n = 93) age (year) 1.01 (0.21) 5.7 (1.12) < 0.001 * sex male 24 (64.8) 59 (63.4) 0.624 ** female 13 (35.2) 34 (36.6) weight (kg) 7.42 (1.01) 15.06 (2.42) < 0.001 * notes: cic, clean intermittent catheterization; sd, standard deviation; *student t test, **chi-square test table 2. mean (sd) for pir above one in early starters and late starters of cic variables cis, mean (s.d) p-value* early starters (n = 37) late starters (n = 93) pir > 1 inset 1.7 (0.2) 2.2 (0.5) 0.021 outset 1.5 (0.32) 2.5 (0.7) 0.004 notes: cic, clean intermittent catheterization, pir, polyuria index ratio; sd, standard deviation; * mannwhitney test table 3. mean (sd) for npi in early starters and late starters of cic variables cis, mean (s.d) p-value* early starters (n = 37) late starters (n = 93) npi inset 0.2 (0.007) 0.32 (0.10) 0.018 outset 0.25 (0.15) 0.42 (0.095) 0.007 notes: cic, clean intermittent catheterization, npi, nocturnal polyuria index; sd, standard deviation; * mannwhitney test figure 1: distribution of pir and npi in early starters and late starters of cic 0 0.5 1 1.5 2 2.5 pir npi pir npi inset outset early starters late starters figure 2: urinary concentration defects in myelomeningocele patients with neurogenic bladder may lead to a vicious cycle of functional urinary tract obstruction and further concentration defect. concentration defect high volume dilute urine already neuropathic bladder overburdened transient functional obstruction effect of vitamin e on semen quality parameters: a meta-analysis of a randomized controlled trial rui wang1#, shangren wang1#, yuxuan song2#, hang zhou1, yang pan1, li liu1, shuai niu1, xiaoqiang liu1* purpose: to explore the effectiveness of vitamin e in male infertility, a systematic review and meta-analysis was conducted. materials and methods: the retrieval time was from january 1947 to may 2021, without language restriction. stata 12.0 was used for the meta-analysis. results: a total of 8 randomized controlled trials involving 459 patients were included. the results showed that after vitamin e treatment, semen volume was reduced (95% ci: 0.55 to 0.06, smd = 0.30, p = 0.015), total sperm count was increased (95% ci: 0.02-0.45, smd = 0.23, p = 0.035), and the differences were statistically significant. there were no statistically significant differences in increasing sperm concentration (95% ci: -0.21-0.29, smd = 0.04, p = 0.769), total sperm motility (95% ci: -0.01-0.42, smd = 0.20, p = 0.061) or sperm forward motility rate (95% ci: -0.06-0.65, smd = 0.29, p = 0.106). subgroup analysis showed that vitamin e treatment for six months could improve sperm forward motility (95% ci: 0.46-1.14, smd = 0.80, p <0.001). conclusion: vitamin e could increase the total sperm count and reduce the volume of semen in male infertility patients, and long-term treatment could improve the forward motility rate of sperm. the decrease of semen volume may be the result of different abstinence time before and after the test. keywords: vitamin e; sperm quality; male infertility; sperm ; meta-analysis. introduction worldwide, infertility is becoming increasingly serious. at present, male infertility has received widespread attention. as a common clinical disease of the male reproductive system, the incidence of male infertility is increasing year by year.(1,2)infertility is defined clinically as having a normal sexual life without contraception and failing to achieve clinical pregnancy for 12 months or more.(3) the incidence of infertility is approximately 15%, and male factors account for at least 50% of all infertility cases.(4) the mechanism of male infertility is complex. one of the important causes of male infertility is the decline in semen quality, which leads to oligozoospermia or asthenospermia. these patients are prone to infertility. (5)there are many factors that can affect the quality of male semen, such as radiation, smoking, varicocele, urinary tract infection, oxidative stress, and other factors. (6) in recent years, people have gradually paid attention to the influence of oxidative stress on male infertility and how it affects the quality of semen. when oxidative stress occurs, reactive oxygen species (ros) produced by organisms exceed the body's natural antioxidant defense. when the production of ros is too high, it will exert toxic effects on many kinds of cells and tissues. among them, male germ cell sperm are very sensitive 1department of urology, tianjin medical university general hospital, tianjin, 300052, china. 2department of urology, peking university people's hospital, no. 11 xizhimen south street xicheng district, beijing, 100044, china. #contributed equally to this work. xiaoqiang liu, phd; department of urology, tianjin medical university general hospital, 154 anshan road, heping district, tianjin 300052, china. tel:+60361614 , e-mail: xiaoqiangliu1@163.com. received january 2022 & accepted july 2022 to ros. excessive ros can cause changes in sperm structure and function and affect sperm motility. evidence shows that the semen antioxidant capacity of infertile men is lower than that of fertile men, and the level of ros in the body is higher.(7,8) the most common treatment for oxidative stress is antioxidants. quite a few studies have started to explore whether the use of antioxidants improves semen quality, and antioxidants mainly include vitamin c, vitamin e, vitamin b12. among them, the most commonly used is vitamin e, which is a fat-soluble antioxidant that can neutralize free radicals, prevent lipid peroxidation, and inhibit the production of ros in infertile men. previous studies have shown that vitamin e deficiency might lead to impaired human fertility.(9) however, the therapeutic effect of vitamin e on male infertility is controversial. some studies have suggested that vitamin e is ineffective in the treatment of male infertility.(10,11) therefore, in order to resolve these disputes, we conducted a meta-analysis to evaluate the effectiveness of oral vitamin e in improving semen quality . materials and methods search strategy to formulate search strategies according to the requirements of the cochrane collaboration, we retrieved puurology journal/vol 19 no. 5/ september-october 2022/ pp. 343-351. [doi: 10.22037/uj.v19i.7160] review bmed, the cochrane library, web of science , scopus , the vip database, the wanfang database, and the china national knowledge infrastructure (cnki). the used search strategy included the following :(((((((((((male fertility) or (sterility, male)) or (male sterility)) or (subfertility, male)) or (male subfertility)) or (subfertility, male)) or (male subfertility)) or (subfertility, male)) or (infertility)) and (semen quality)) or (sperm)) and (vitamin e) .the time of retrieval was from database building to may 2021, without language restriction. in addition, a manual search of relevant citations of the included studies was performed. literature selection criteria we used pico/peco statement (population—intervention/exposure—comparator—outcomes statement) to set the inclusion criteria and exclusion criteria forfurther selecting eligible studies. the detailed criteria for selecting studies in the systematic review and meta-analysis are outlined in table 1. data extraction general information was extracted by two reviewers independently, including basic information of participants, interventions, the period of outcomes observed, the results and other information. disagreements between the two authors were resolved by a third senior person. quality assessment all included literature was evaluated for quality by 2 investigators independently referencing the modified jadad scoring criteria and resolved after discussion with a third party if a disagreement arose. the scoring criteria included (1) random sequence generation; (2) allocation hiding; (3) blinding; and (4) follow-up. the total score is 1 to 7, of which 1 to 3 are low-quality research and 4 to 7 are high-quality research.(12) statistical analysis stata software (version 12.0) was used for statistical analysis. standard statistical tables and charts were used to describe the characteristics of the respondents. the standardized mean difference (smd) and 95% confidence interval (ci) were used to analyze the continuous data. the q test and i2 statistics were used to test the heterogeneity of the included results. when i2 > 50% or p < 0.05, there was significant heterogeneity. if the heterogeneity between studies was obvious, the reasons for heterogeneity were analyzed, and subgroup analysis and sensitivity analysis were used. a p value of less than 0.05 for the difference was statistically significant. when i2 < 50% or p > 0.05, the fixed effects model was used for meta-analysis. in this study, begg’s test and egger’s test were used to evaluate publication bias. if the p value of the above test was less than 0.05, it indicated that there was significant publication bias.(13) results literature search results a total of 545 studies were identified, including 265 from pubmed, 67 from web of science, 32 from scopus, 26 from the cochrane library, 27 from cnki, 118 from the wanfang database, and 23 from vip. after reading titles and abstracts, 491 articles were excluded for animal experimentation, review, duplicate articles, and those that clearly did not meet the inclusion criteria. then, the remaining 54 articles were searched for fulltext reading, 46 articles were excluded that did not meet the inclusion criteria, and 8 articles(10,11,14-19) were finally included, with a total of 459 patients, including 238 cases in the experimental group and 221 cases in the control group. the literature screening flow is shown in figure 1, and the basic information of the included studies is shown in table 2. methodological quality assessment results the modified jadad score was used to evaluate the methodological quality of the included studies. four articles(10,11,14,17) were high-quality literature, and four (15,16,18,19) were low-quality literature, as detailed in table 3. meta-analysis results 1 ejaculate volume five studies(10,14,16,17,19) reported the relationship between vitamin e treatment of male infertility and semen volume, for a total of 263 patients. there was no statistical heterogeneity among studies (p = 0.697, i2 = 0%), and the pooled effect size of the fixed-effect model was used for analysis. the results of the meta-analysis showed that patients in the test group had less semen volume than those in the control group, and the difference was statistically significant (95% ci: -0.55 to -0.06, smd = -0.30, p = 0.015), as detailed in figure 2. the sensitivity analysis showed that the results of the meta-analysis were robust, and the results of the funnel plot and egger's test (p = 0.422) indicated the absence of publication bias, as shown in figure s1. 2 sperm concentration four studies(10,11,14,16) reported the relationship between vitamin e treatment of male infertility and sperm concentration in a total of 247 patients, as shown in figure 3. after testing, there was no significant heterogeneity between the studies (p = 0.604, i2 = 0%). the fixed-effect model analysis showed that the difference between the treatment group and the control group was not stareview 344 vitamin e and male infertility-wang et al. table 1. criteria for selecting studies based on pico/peco statement. inclusion criteria exclusion criteria population patients with male infertility who were diagnosed according to the who and other diagnostic criteria studies performed on cells or animals intervention/exposure the test group received vitamin e as the main treatment the test group was mainly supplemented with other supplements, such as coenzyme q10, folic acid, etc comparator/comparison placebo antioxidants or drugs outcomes sperm parameters and pregnancy rates serum vitamin e levels in initial study design randomized controlled trial no-control studies including single arm studies, case reports, meta-analyses, reviews, and comments. study was not a randomized controlled trial. abbreviations: pico/peco,population-intervention/exposure-comparator-outcomes statement. tistically significant (95% ci: -0.21-0.29, smd = 0.04, p = 0.769). 3 total sperm count five studies(10,14,15,17,19) reported the association between male infertility treated with vitamin e and total sperm count in 246 patients, as shown in figure 4. after testing, there was no significant heterogeneity among the studies (i2 = 39.0%, p = 0.132), and the fixed-effects model was used to combine the effect size. the results vol 19 no 5 september-october 2022 345 figure 1. flow chart of included studies abbreviations: iu,international unit; t/c, treatment group/control group; rct, randomized controlled trial. table2. characteristics of included studies. author country age patients case of intervention duration of outcomes (year) (mean ± sd) recruited infertility male study (t/c) (t/c) c.rolf (1999) germany 36.1±5.0/35.2 ± 4.8 15/16 asthenospermia 800 mg vitamin e+1000 56 days sperm parameters mg vitamin c daily/placebo hussein ghanem egypt 31.8±8.1 30/30 oligoasthenozo-ospermia 400 mg vitamin e+25 6 months sperm parameters (2010) mg clomiphene daily/ pregnancy rates placebo ermanno greco european unclear 32/32 men consulting for 500 mg vitamin e+500 mg 2 months sperm parameters (2005) infertility vitamin c twice daily/placebo sperm dna fragmentation suleiman sa saudi arabia unclear 52/35 asthenozoospe-rmia 100 mg vitamin e three 6 months sperm parameters pregnancy rates (1996) times a day/placebo ghazaleh eslamian iran 32.80±4.13/33.04±4.08 45/45 idiopathic 600iu vitamin e+ placebo/ 12 weeks sperm parameters (2020) asthenozoosper-mia placebo+ placebo k. ener turkey 25.8±4.6 22/23 varicocele vitamin e capsules 12months sperm parameters (2016) (300 mg×2)daily/nothing pregnancy rates rezvan bahmyari iran 37.23±7.09/36.65±6.41 30/32 oligo, astheno, vitamin e capsule 3 months sperm parameters (2021) teratozoospermia or (400 iu/day) + oligoasthenozo-ospermia selenium tablet (200 µg/day) + folic acid tablet (5 mg/day) l. keskestunisie unclear 12/8 unclear 400 mg vitamin e daily 3months sperm parameters ammar (2003) (ephynal 100 mg, 2 tablets, twice daily) or 225 mg selenium (bioselenium 35 mg, 2 capsules×3/day)/vitamin b vitamin e and male infertility-wang et al. showed that the total sperm count was significantly improved in the treatment group compared with the control group (95% ci: 0.02-0.45, smd = 0.23, p = 0.035), as shown in figure 4. sensitivity analysis showed that the results of the meta-analysis were relatively robust, and no obvious publication bias was detected (egger test: p = 0.553), as shown in figure s2. funnel plot found no significant publication bias in figure s6. 4 total sperm motility four studies with a total of 257 patients(14-17) reported the association between male infertility and total sperm motility with vitamin e treatment, as shown in figure 5. after testing, there was no significant heterogeneity among the studies (i2=49.9%, p = 0.076), and a fixed-effects model was used to combine the effect sizes. we identified a trend toward better total activity of sperm in treatment group than in control group. 5 forward motility six studies(11,14,16-19) reported the association between male infertility treated with vitamin e and sperm forward motility rate in a total of 383 patients. after testing the heterogeneity between the studies (i2 = 64.8%, p = 0.014), the random-effects model was used to combine the effect size. there was no statistically significant difference between the treatment group and the control group in terms of the sperm forward motility rate (95% ci: -0.06-0.65, smd=0.29, p = 0.106), as shown in figure 6. subgroup analysis was performed according to the duration of vitamin e administration in the treatment group, as shown in figure s3. the results showed that there was no statistical significance in terms of treatment duration of three months (95% ci: -0.31-0.29), smd = -0.01, p = 0.925). the treatment duration was statistically significant at six months (95% ci: 0.46-1.14, smd = 0.80, p = <0.001). sensitivity analysis and publication bias compared with the results after excluding one by one and rerunning the meta-analysis, the statistical results did not change significantly, as shown in figure s4 and s5. these results confirmed that the results of the meta-analysis of vitamin e treatment for male infertility were reliable, as shown in figure s4 and figure s5. results of sensitivity analyses and publication bias begg’s test and egger's test illustrated that no evidence of bias existed in this meta-analysis and the outcomes proved to be firm. discussion the aim of this meta-analysis was to assess whether oral vitamin e is effective in improving male infertility. our meta-analysis found that oral vitamin e treatment could review 346 figure 2. forest plot of meta-analysis of semen volume. table 3. results of methodological quality evaluations of included studies (score). author (year) design random sequence generation concealment of randomization blinding sign out score ghazaleh eslamian (2020) rcta 2 2 2 0 6 k. ener (2016) rct 1 1 0 0 2 rezvan bahmyari (2021) rct 2 0 2 0 4 c.rolf (1999) rct 2 2 2 1 7 hussein ghanem (2010) rct 1 2 2 0 5 ermanno greco (2015) rct 1 2 2 0 5 suleiman sa (1996) rct 0 0 1 0 1 l. keskes-ammar (2003) rct 2 1 0 0 3 abbreviations: rct:,randomized controlled trial. vitamin e and male infertility-wang et al. significantly increase the total sperm count and reduce the volume of semen. it was further found that oral vitamin e treatment for up to 6 months could improve the forward motility of sperm but not for 3 months. eslamian et al. explored the separate effects of docosahexaenoic acid and vitamin e and showed that the effect of vitamin e alone on sperm concentration, total motility, and forward motility was significant, and the association was stronger than that of docosahexaenoic acid alone.(14)the study by suleiman et al. reported that a 6-month vitamin e treatment can improve sperm motility.(18) a randomized double-blind controlled trial showed that oral administration of vitamin e could increase the levels of vitamin e in seminal plasma, and the levels of vitamin e in seminal plasma in the treatment group were significantly different from those in the control group.(20) treatment with vitamin e was based on the fact that it could increase body vitamin e levels and decrease sperm ros levels, thus protecting the function of sperm. figure 3. forest plot of meta-analysis of sperm concentration figure 4. forest plot of meta-analysis of total sperm count vitamin e and male infertility-wang et al. vol 19 no 5 september-october 2022 347 furthermore, it was found in many preclinical studies that vitamin e supplementation could indeed improve semen quality. as an antioxidant, vitamin e has a special affinity for membrane phospholipids, and it can prevent lipid peroxidation and protect the integrity of the sperm membrane. the in vivo study showed that vitamin e can increase the total sperm count and sperm concentration of boars; the in vitro study was carried out with a nonenzymatic method for lipid peroxidation of boar seminal plasma using a vitamin e analog that could inhibit seminal plasma lipid peroxidation to control levels.(21) another animal trial showed that oral administration of vitamin e improved sperm concentration, total sperm count, and percentage of normal sperm in infertile sires, and the plasma levels of vitamin e were also significantly increased.(22) another animal experiment showed that vitamin e and vitamin c treatments can significantly improve the sperm quality of rabbits. after treatment with vitamins, rabbits significantly reduced the number of abnormally dead sperm, especially in the vitamin e supplement group.(23) the results also indicated that vitamin e was more effecreview 348 figure 5. forest plot of meta-analysis of total sperm motility. figure 6. forest plot of meta-analysis of sperm forward motility vitamin e and male infertility-wang et al. tive than vitamin c in inhibiting lipid peroxidation, and the results of massaeli et al. supported this conclusion. (24) in contrast, rolf et al.'s study found that no changes in any of the conventional ejaculatory parameters were observed during shortor long-term vitamin treatment when compared with the parameters before treatment and with the placebo group.(10) several trials reported similar results to those of rolf et al .(20,25,26) the duration of treatment in the study by rolf et al. was 8 weeks, which is relatively short, perhaps explaining why it is in contrast to the results of suleiman et al. the same finding was reported by ermanno greco et al. after 2 months of treatment, there was no significant change in concentration, vitality and morphology in either the treatment group or the placebo group(11). however, the percentage of sperm with dna fragmentation was significantly lower in patients treated for 2 months than in those treated with placebo. only one of the studies we included reported that after vitamin e treatment, the proportion of sperm dna fragments was significantly lower than that of the control group. due to the lack of research data, no meta-analysis of sperm dna fragments was performed. vitamin e can inhibit the formation of free radicals and prevent their induced membrane lipid peroxidation, thereby maintaining the integrity of the sperm acrosomal membrane and reducing the rate of sperm malformation. high levels of reactive oxygen species reduced the activity of acrosin(27) and impaired the binding of sperm and oocytes.(28) a prospective study showed that men with high levels of reactive oxygen species production had a sevenfold lower chance of conception than men with low levels of production.(7) trials have shown that fertility is significantly improved by antioxidant treatment.(29) vitamin e had a positive effect on testicular and sperm fertility, and the prescription of a supplement containing vitamin e could improve sperm function in vivo and in vitro by reducing oxidative stress damage.(23) the issue of pregnancy rate was addressed in two of our included articles. suleiman et al. mentioned in a placebo-controlled double-blind study that vitamin e produced good effects in reducing the concentration of malondialdehyde and improving sperm motility; eleven of the 52 spouses in the treatment group became pregnant during the 6-month treatment period, and none became pregnant in the placebo group.(18) however, reasons for withdrawal or loss to follow-up were not described in this study, causing some degree of bias. hussein ghanem et al. showed four pregnancies in the placebo group and 11 pregnancies in the treatment group, with a significant increase in the cumulative number of pregnancies after treatment.(17) kessopoulou et al. designed a double-blind randomized controlled crossover trial to treat male infertility caused by ros using antioxidant vitamin e. the findings were not significant for semen parameters, but there was an improvement in sperm performance in the zona binding assay. thirty patients completed the 2-year trial. as a result, 108 of the 120 semen samples recovered vitality, and there were 3 successful pregnancies.(25) it was concluded that oral administration of vitamin e had beneficial effects on sperm fecundity and improved ivf rates.(25,30) because the study by kessopoulou et al. was not an rct trial, this article was not included in our review. therefore, only two studies in the included literature mentioned pregnancy rates, with fewer data, so we did not perform a meta-analysis of pregnancy rates. we also included a study of vitamin e supplementation after varicocele surgery. the reason is that varicocele cause reflux of blood and other impaired microcirculation, and an increase in ros levels will reduce the quality of semen and sperm function.(31) k. ener et al. reported that vitamin e supplementation after varicocele surgery resulted in an improvement in sperm concentration and motility in both groups after varicocele resection compared to preoperative parameters, and the factor contributing to this improvement was merely varicocele surgery.(15) the findings from the data obtained above were controversial. this may be explained by the fact that antioxidant treatment may have been ineffective in some studies in which infertility was not a result of oxidative stress. the effects of vitamin e treatment depended strictly on its dosage. in the studies we included, the doses of vitamin e were different, but they were less than 1000 mg/d. the food and nutrition committee of the institute of medicine has determined that the tolerable upper intake of vitamin e for adults is 1000 mg.(32) common side effects of vitamin e supplementation include nausea, headache, visual changes, gastrointestinal discomfort, risk of hemorrhagic stroke, slightly elevated urinary creatinine, and necrotizing enterocolitis. there is a potential risk of increased bleeding during surgery because vitamin e is known to inhibit platelet aggregation and may increase the risk of anterior adenocarcinoma.(33,34)the dose of vitamin e used in several studies we included is within the safe range, which can show that our results are reliable. however, further research is needed to determine the optimal dose of oral vitamin e for infertile men. the treatment duration of these studies was 2 to 6 months. the data of our study showed that semen volume decreased after oral vitamin e treatment. this may be attributed to the difference in the number of days of abstinence before and after treatment and between groups. long periods of abstinence can lead to increased semen volume. similarly, prolonged abstinence resulted in a higher total sperm count, so we need more trials to confirm the above results. the advantages of our meta-analysis included: 1) five of the included studies used the double-blind method, the results were robust, and 2) the subgroup analysis found more accurate and meaningful results. despite these advantages, we acknowledged that this meta-analysis also had several limitations. we included only 8 articles, half of which were low-quality articles, and the number of patients was small. due to the paucity of the included literature, there are certain limitations to the evaluation of publication bias. in several studies we included, vitamin e was combined with other drugs, which may confuse the results. the combined use of some antioxidants and vitamin e may increase or mask its own effects. the combination of drugs and vitamin e is used to treat semen quality. drugs will interfere with the results of vitamin e treatment. it is impossible to determine whether the improvement of semen quality comes from the effect of vitamin e. therefore, our conclusion needs to be verified by larger rcts with strict designs and long-term follow-up to further evaluate the effectiveness of oral vitamin e treatment for male infertility. vol 19 no 4 july-august 2022 252 vitamin e and male infertility-wang et al. vol 19 no 5 september-october 2022 349 conclusions vitamin e could increase the total sperm count and reduce the volume of semen in male infertility patients. the decrease of semen volume may be the result of different abstinence time before and after the test. and long-term treatment could improve the forward motility rate of sperm. summary this article show that oral vitamin e can increase the total number of sperm in male infertility patients, reduce semen volume, and long-term treatment can improve the positive motility of sperm. in other word long-term oral vitamin e and dosage within a safe range can improve men's semen quality. acknowledgement this study was financially supported by national natural science funds of china (no. 82171594) and zhao yi-cheng medical science foundation (no. zyyfy2018031). conflicts of interest all authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with, the subject matter or materials discussed in the 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reactive oxygen species associated male infertility. fertil sterilurnal.1995;64:825. 26. giovenco p, amodei m, barbieri c ,et al.effects of kallikrein on the male reproductive system and its use in the treatment of idiopathic oligozoospermia with impaired motility. andrologiaurnal.1987;19 spec no:238. 27. zalata a a, ahmed a h, allamaneni s s, comhaire f h, agarwal a.relationship between acrosin activity of human spermatozoa and oxidative stress. asian j androlurnal.2004;6:313. 28. jedrzejczak p, fraczek m, szumała-kakol a ,et al.consequences of semen inflammation and lipid peroxidation on fertilization capacity of spermatozoa in in vitro conditions. int j androlurnal.2005;28:275. 29. tremellen k.oxidative stress and male infertility--a clinical perspective. hum reprod updateurnal.2008;14:243. 30. geva e, bartoov b, zabludovsky n ,et al.the effect of antioxidant treatment on human spermatozoa and fertilization rate in an in vitro fertilization program. fertil sterilurnal.1996;66:430. 31. zini a, dohle g.are varicoceles associated with increased deoxyribonucleic acid fragmentation? fertil sterilurnal.2011;96:1283. 32. hathcock j n, azzi a, blumberg j ,et al.vitamins e and c are safe across a broad range of intakes. am j clin nutrurnal.2005;81:736. 33. brigelius-flohé r, kelly f j, salonen j t ,et al.the european perspective on vitamin e: current knowledge and future research. am j clin nutrurnal.2002;76:703. 34. chan j m, darke a k, penney k l ,et al.seleniumor vitamin e-related gene variants, interaction with supplementation, and risk of high-grade prostate cancer in select. cancer epidemiol biomarkers prevurnal.2016;25:1050. vitamin e and male infertility-wang et al. vol 19 no 5 september-october 2022 351 case report successful penile replantation with cavernoglandular shunt procedure in urban setting: a case series exsa hadibrata1*, awang dyan purnomo1, mars dwi tjahjo1, andrian rivanda2, ahmad farishal2 1urology department, faculty of medicine lampung university / abdul moeloek general hospital, lampung, indonesia. 2medical doctor, faculty of medicine lampung university, lampung, indonesia. *correspondence: urology department, faculty of medicine lampung university / abdul moeloek general hospital, lampung, indonesia. tel: +62 821 8326 6655. email: exsa.hadibrata@gmail.com. received october 2020 & accepted february 2021 purpose: traumatic penile amputation is a rare case with various etiologies. penile reconstruction using replantation technique should be performed to prevent the decline of patients quality of life even in areas with limited facilites. material and methods: we report three cases of total penile amputation in children after circumcision, who were successfully replanted by macro-surgical technique and cavernoglandular shunt procedure. results: postoperative follow-up showed promising results with good micturition, erectile function, cosmetic, and minimal complications. conclusion: matters affecting the successful penile replantation in macro-surgical techniques have been discussed. in addition, we also highlight the potential of cavernoglandular shunt procedure that can be used as an alternative treatment for penile replantation in limited facilities. keywords: amputation; cavernoglandular shunt; penis; replantation introduction traumatic penile amputation is a rare medical emergency case worldwide. penile amputation can be caused by self-inflicting amputation, felonious assault, or accidental trauma(1). since it is a rare case, there were only a few pieces of literatures reporting penile amputation incidences worldwide(2), and up until now, there is no literature reporting the prevalence of penile amputation in indonesia. penile amputation can cause psychological effects urology journal/vol 18 no. 5/ september-october 2021/ pp. 573-576. [doi: 10.22037/uj.v18i.6495] figure 1: case 1, the cut located above corona glands (a) and (b), anastomosis of his urethra and the cavernosal bodies (c), cavernoglandular shunt procedure (d), after replantation (e), 2-months follow up after replantation (f) such as loss of self-esteem and depression. besides that penile amputation can also cause dysfunction of sexual function and micturition which affect the patients quality of life(3). penile amputation is a medical emergency case that needs prompt treatment to prevent complications such as bleeding, infection, urethra stricture, and sexual dysfunction(4). one of the techniques developed to treat penile amputation is penile replantation. in early 1978, there was two successful replantation of penile amputation by using micro-replantation reported(5). micro replantation is the gold standard for the treatment of penile amputation. unfortunately, this technique must be done in a hospital that is completed with microsurgery equipment. in 1929 ehrich et al. reported a case of penile amputation treated with macro surgery. he reported that the patient had a good outcome following the surgery. the outcomes were normalized of micturition and sexual function within 2 years following the surgery(6). based on this report, macro surgery can be used as an alternative approach to treating patients with penile amputation in limited resource hospitals. in this case series, we reported a series of penile amputation treated with macro surgery procedure by using cavernoglandular shunt, we elaborate on the outcome of our patients. patients and methods in the last two years, we had three patients, age range from 7 to 10 years. the patients came to our emergency room with total penile amputation 6 hours post circumcision with a penile specimen amputated using a 0.9% saline solution bag in an icebox. all cases were carried out at a mass circumcision event performed by an inexperienced person under local anesthesia with the guillotine technique. on physical examination, the penis was completely amputated from the glans penis. in the first case, the cut was located above the corona glands (figure 1), and in the other two cases, the cut was located in the midshaft of the penile (figure 2b and 3b). the patient was taken immediately to the operating room under general anesthesia. the cut surfaces were cleaned with sterile saline, an 8-fr nasogastric tube or 8-fr foley catheter was inserted through the urethra of the amputated part, distal urethral into bulbar part [figure 2c]. the same technique of replantation was applied in all cases with macrosurgical repair of corpus cavernosum and urethra without arterial-venous anastomoses. anastomose corpus cavernosum was performed using synthetic monofilament non-absorbable suture 6/0 with continuous without locking suture technique (figure 1c). anastomose urethra uses 6/0 synthetic case report 413 penile replantation with cavernoglandular shunt-hadibrata et al. figure 3. case 3, the cut located in the midshaft of the penile (a) and (b), after replantation (c), 2-months follow up after replantation (d) case report 574 figure 2: case 2, the cut located in the midshaft of the penile (a) and (b), 8-fr foley catheter was inserted transurethrally through the distal amputated part (c), after replantation (d), cavernoglandular shunt procedure (e), case 2 had meatal stenosis and already done meatotomy (f) monofilament absorbable suture with a simple suture technique. after an anastomose, a cavernoglandular shunt procedure was performed using a 16g needle contained with heparin at a dose of 50 – 70 iu/kgbw was injected into the glans penis to the corpus cavernosum (figure 1d). a cavernoglandular shunt procedure improves venous circulation and arterial feeding from cavernosal imbibition. after replantation surgery, intravenous antibiotics and analgetics were given. the nasogastric tube or foley catheter was maintained and then the wound dressing was performed using a petroleum gauze combined with sterile gauze around the glans to keep the penis immobilized. wound care was carried out every day using 0.9% nacl solution to clean the wound, after that, use tulle and moist nacl gauze to dress the wound. the cavernoglandular shunt and heparin injection of 50-70 iu/kgbw dose was done through the glands to the corpus cavernosum during wound care by using sterile needle sized 16g once a day for 7 days (figure 2e). prior to this procedure, a topical spray of lidocaine was performed to reduce pain. after the 14th day of treatment, the catheter or nasogastric tube was removed then the patient was allowed to be outpatient on the 15th day. results in follow up 2 months after replantation, one case had meatal stenosis and had already done meatotomy [figure 2f], the other cases did not show any surgical complications [figure 1f and 3d]. overall cases showed normal urinary flow, normal sensation in the glans penis and good erectile function which was rated by early morning erection. discussion the successful rate of penile replantation is influenced by the blood flow of sinusoidal-corporal to the distal of the penis (glans penis)(7). cavernoglandular shunt is a technique commonly used to treat patients with priapism(8). the technique was done by insertion of 16g needle through glands penis to corpus cavernous. the purpose of the technique is to create an iatrogenic fistula to make an outflow for the blood from the corpus cavernous(9). heparin injection during this technique was done to prevent blood clots which can blockade the drainage of the vein and imbibition of the cavernosal artery. the outcome of those three cases was as good as the technique used by the microsurgery technique. due to the limitation of resources in our hospital and the small size of the cavernous artery, we did not manipulate the dorsal artery of the penis and the cavernous artery. the previous study by landstorm et al (2004) showed that the healing of the cavernous artery will increase the viability of penile replantation(10). in this case series, we did not do anastomose of the cavernous artery and it did not affect the treatment outcome, so we concluded that anastomoses of the cavernous artery are not always needed in penile replantation procedure. of the three cases above, the follow-up and wound care were done every day during hospitalization. we used normal saline to create a moist environment that has been proven to facilitate the healing process of the wound by preventing dehydration and enhancing angiogenesis and collagen synthesis together with increased breakdown of dead tissue. the puncture through the glans penis to the corpus cavernous with an injection of heparin was done daily during hospitalization to make sure good vein drainage and imbibition of the cavernous artery. post-surgery monitoring was done by visual analysis. the outcome of the procedure was good, although the second case suffered from meatal stenosis. this was a common complication following the penile replantation procedure(11). the other minor complications that can happen following micro and macro surgery are delayed wound healing or loss of sensation on the distal part of the penis(2,4). fortunately, we did not find any of that complication in our patients. this case series showed that there are no differences in outcome and complications after the procedure between macro surgery and microsurgery replantation. for this reason, macro surgery replantation with a cavernoglandular shunt can be used as an alternative in replantation procedures especially in hospitals with limited facilities. conclusions based on our literature searching, this is the first case series reporting the use of cavernoglandular shunt technique as a combination of vascularization repair technique without arterial anastomosis in penile replantation procedure with promising visual and functional results. this method can be used as an alternative procedure to replantation in a hospital with limited facilities. for more objective evaluation, doppler is advisable to use as a measure of the success of the revascularization procedure. conflict of interest the authors declare no conflict of interest references 1. tanagho ea, lue tf. anatomy of the genitourinary tract. in mcaninch jw, lue tf (editor) smith & tanagho’s general urology 19th ed. california: mcgraw-hill edication. 2020;1-15. 2. babaei ar, safarinejad mr. penile replantation, science or myth? a systematic review. urol j spring. 2007;4:62–5. 3. wihono f, sigumonrong y. surgical management (mcrosurgery) of traumatic penile amputation: a case report. open acces maced j med sci. 2019;7:1350-2. 4. jezior jr, brady jd, schlossberg sm. management of penile amputation injuries. world j surg. 2001; 25:1602-9. 5. garg s, date sv, gupta a, baliarsing as. successful microsurgical replantation of an amputated penis. indian j plast surg. 2016;49:99-105. 6. jordan gh. management of penile amputation. in hohenfeller m, santucci ra (editor) emergencies in urology. berlin: springer. 2007;270-4. 7. jordan gh, gilbert da. management of amputation injuries of the male genitalia. uro clin north am. 1989;16:359-67. 8. tay yk, spernat d, rzetelski-west k, appu s, love c. acute management of priapism in men. bju international. 2012;109:15-21. case report 212case report 428 penile replantation with cavernoglandular shunt-hadibrata et al. vol 18 no 5 september-october 2021 575 9. burnett al, bivalacqua tj. priapism: new concepts in medical and surgical management. urol clin north am. 2011;38:185-94. 10. landstrom jt, schuyler rw, macris gp. microsurgical penile replantation facilitated by postoperative hbo treatment. microsurgery. 2004;24:49–55. 11. biswas g. technical considerations and outcomes in penile replantation. seminars in plastic surgery. 2013;27:205–210 penile replantation with cavernoglandular shunt-hadibrata et al. case report 576 protective effect of gallic acid on testicular tissue, sperm parameters, and dna fragmentation against toxicity induced by cyclophosphamide in adult nmri mice zahra mehraban1, marefat ghaffari novin1, mohammadghasem golmohammadi2, mohsen sagha2, seyed ali ziai 3, mohammad amin abdollahifar1, hamid nazarian1* purpose: this study aimed to investigate the protective effect of gallic acid (ga) on the cyclophosphamide (cp) toxicity induced in the reproductive system. materials and methods: after a pilot study for dose responses of gallic acid, forty adult male nmri mice were divided into 5 groups (n=8): control, sham (nacl serum: 0.2ml per day), cp (15 mg kg1per week; ip), ga (12.5 mg kg1per day ; ip) and ga (12.5 mg kg1per day ; ip) +cp(15 mg kg1per week; ip). after treatment, the left testis was detached and used for histological examination and right testis used for malondialdehyde (mda) measures. left caudal epididymis was placed in the ham’s f10 medium and released spermatozoa were used in order to analyze sperm parameters. sperm dna fragmentation was assessed by sperm chromatin dispersion (scd) method. results: in the cp group, there was a significant increase in the sperm dna fragmentation (% 23.91 ± 57.89) compared with control group (% 10.27 ± 24.52). that was significantly improved by ga (12.5 mg kg1per day ; ip) in ga+cp group (% 8.85 ± 28.4) compared to cp group (p< .001). a significant increase was reported about mda levels in cp group (2.59 ± 6.26) in compared with the control group (2.05 ± 4.30), but ga (1.33 ± 3.24) decreased it in ga+ cp group (p< .01). the histopathological investigation revealed marked testicular atrophy in cp group, whereas ga diminished these deviations (p< .05). conclusion: gallic acid can modify the reproductive toxicity of cyclophosphamide in nmri mice and increase the antioxidant capacity of testis tissue. keywords: cyclophosphamide; gallic acid; sperm; dna fragmentation; toxicity introduction infertility is the most important reproductive problem affecting about 10-15% of young couples(1). several reasons may cause infertility, 35 % of them occur because of male factors(2). in a review of the causes of male infertility, documented evidence suggests that injuries to sperm by reactive oxygen species (ros) play an essential role on sperms motility(1). this can be caused by the use of antibiotics, toxic substances, pesticides, radiations, stress, air pollution, special medications used in the chemotherapy, and inadequate intake of vitamins(1). cyclophosphamide (cp) is one of chemotherapy drugs, which is widely used for treating various cancers and autoimmune diseases. with increasing the number of young people who have recovered from cancer, the risk of infertility has caused major concerns in these patients (1-3). despite various clinical applications of this drug, it has an adverse influence on the reproductive system in humans and in the experimental animals(2,3). administration of cp is associated with oligospermia, 1department of biology and anatomical sciences, school of medicine, shahid beheshti university of medical sciences, tehran, iran. 2research laboratory for embryology and stem cells, department of anatomical sciences and pathology, school of medicine, ardabil university of medical sciences, ardabil, iran. 3department of pharmacology, school of medicine, shahid beheshti university of medical sciences, tehran, iran. *correspondence: department of biology and anatomical sciences, school of medicine, shahid beheshti university of medical sciences, tehran, iran. tel:+982123872555. telefax:+982122439976. email: h.nazarian@sbmu.ac.ir. received october 2018 & accepted february 2019 azoospermia, and histological and biochemical changes in the testis and epididymis(4). additionally, altering gonadotrophin secretion, testicular damage, and decreased plasma testosterone levels are observed in patients treated with cp, therefore fertility recovery is unpredictable in such patients and in some cases may last for years(4). although, the defined mechanism by which cp causes testicular toxicity is unclear, in general it is known that cp interrupts with the balance of free radicals in the tissue and interferes with the antioxidant defense system(5). the structure of dna is very sensitive to oxidative damage(6). oxidative damage to the dna causes mutagenic changes, which in severe forms, disturb the quality of the germ cells and prevent fertilization. oxidative stresses play a significant role in the germ cells’ apoptosis and dna damage(6). in general, damages caused by oxidative stress in human sperm is associated with reduced motility, morphological defects, increased sperm abnormality, dna andrology urology journal/vol 17 no. 1/ january-february 2020/ pp. 78-85. [doi: 10.22037/uj.v0i0.4858] vol 17 no 01 january-february 2020 79 damage, lipid peroxidation and reduces the sperm acrosome reaction, capacitation, and fertility rates after assisted reproductive technology (art)(5,7-10). oxidative stress can be destructive for testicular tissues, which have a high metabolism, so the antioxidant capacity of the tissue is very important(9). thus, these studies indicate that administration of safe antioxidants might decrease cp-induced reproductive toxicity(4,11). gallic acid (also known as 3,4,5-trihydroxybenzoic acid), is a polyphenolic acid found in various plants such as ceratonia siliqua, green tea, sumac, grape seed, and apple. gallic acid has antioxidant, anti-fungal, anti-viral, and anti-allergic activities. it also plays an important role in traditional medicine in some countries (13,14). as mentioned before, gallic acid has antioxidant properties, which can protect the cells against oxidative damage by savaging free radicals(12-14). consequently, the present study was done to define whether gallic acid has protective effects against cp-induced toxicity on sperm parameters, dna fragmentation, and testicular tissue changes. materials and methods in this experimental study, adult male nmri mice (6-8 weeks old), weighing 20-25 g, were kept in wire mesh cages, under standard conditions with humidity of 3060%, temperature of 20-25°c, and light/dark cycles of 12 hours and fed with commercial mice chow and water ad libitum and received humane care. all procedure on the animals were studied carefully and the protocol of the ethics committee of the shahid beheshti university of medical sciences was considered (ir.sbmu.msp > rec > 1395.132). cyclophosphamide (cp) dose responses testicular and epididymal impairment was reached by single intraperitoneal administration of cyclophosphamide according to the report of bakhtiari et al.(4). gallic acid dose responses in various studies, the optimal amount of gallic acid affecting the testes of the mice was variable and different(13,15,16); therefore, a pilot study was done for determining the optimal concentration of gallic acid. to do this, 54 mice (6 mice per groups) were divided in 9 groups and were treated with different doses of gallic acid (12.5, 25, and 50 mg kg-1 per day ;ip), cp (15 mg kg-1 per week ;ip), cp+ gallic acid co treatment (12.5, 25, and 50 mg kg-1 per day ;ip), sham (nacl serum: 0.2 ml per day :ip), and then compared with the control protection of gallic acid on testis damage-mehraban et al. table 1. the effects of gallic acid on the testis weights and estimated testis volume of mices was treated with cp group left testis weight(mg) testis volume( mm3) control 141.75 ± 21.87 4.62 ± 0.37 sham 153.25 ± 19.99 4.66 ± 0.35 cp 93.62 ± 26.77ab 3.96 ± 0.43ab ga 143.50 ± 24.48 4.74 ± 0.70 ga+cp 153.38 ± 21.70 4.42 ± 0.17 abbreviations: ga, gallic acid: cp, cyclophosphamide statistical analyses were carried out through one way anova/ kruskal wallis. data are presented as means ± sd a: p < .05 compared with control group. b: p < .05 compared with cp+ga group. table2. the effect of gallic acid on the volume of testis intestinal layer and cells of seminiferous tubules of mice’s treated with cyclophosphamide group spermatogonia count primary spermatocyte count spermatid count sertoli cell count leydig cell count intestinal layer volume (mm3) control 1523.37 ± 115.26 961.75 ± 170.16 2515.07 ± 453.57 238.37 ± 44.05 725.12 ± 270.22 1.02 ± 0.22 sham 1399.52 ± 121.92 1015.87 ± 151.28 2257.90 ± 621.01 168.45 ± 28.28 681.37 ± 102.81 1.17 ± 0.15 cp 1116 ± 122.17 ab 784.12 ± 133.36 ab 1694 ± 416.27ab 234.25 ± 42.67 502.87 ± 97.98ab 0.65 ± 0.09ab ga 1403.21 ± 142.22 955.87 ± 124.56 2358.23 ± 700.32 187.50 ± 41.05 620.75 ± 94.88 1.00 ± 0.31 ga+cp 1402.25 ± 140.96 967 ± 194.26 2529.53 ± 442.85 245.37 ± 14.85 766.37 ± 174.73 0.98 ± 0.24 statistical analyses were carried out through one way anova/ kruskal wallis. data are presented as means ± sd a: p < .05 compared with control group. b: p < .05 compared with cp+ga group. figure1. photomicrograph of testis from treated mice, (a) control (b) sham (c) cyclophosphamide, (d) gallic acid and (e) gallic acid + cyclophosphomide. the control, sham, gallic acid group presented normal architecture with normal germ cells layer × 400and x100. the cp group (c) displayed atresia cells in the seminiferous tubules. ×100, reduced germ cells and point leydig cells, interstitial spaces, type of cells in seminiferous tubules. (c) ×400. ga+cp group presented nearly normal architecture (d) ×100 and ×400. the tissues were stained with h&e. represents hypoplasia of germ cell layer group by analyzing sperm parameters (count, morphology, motility). the optimal concentration of gallic acid, which had the better results in evaluating the sperm parameters, was determined 12.5 mg kg-1 per day. samples size was estimated based on previous works on the testis and sperm parameters(4,13,15,16). after the pilot study, 40 male mice were allocated to five groups randomly and treated for 35-day: 1. the control group without any administration 2. the sham group that received nacl solution (0.2 ml per day) intraperitoneally. 3. the cp group that received cp (15 mg kg-1 per week) intraperitoneally. 4. the gallic acid group that received only 12.5 mg kg-1 per day of gallic acid intraperitoneally. 5. the gallic acid + cp group that received gallic acid (12.5 mg kg-1 per day) plus cp (15 mg kg-1 per week) concurrent intraperitoneally. preparation of drugs 500 mg cp (baxter, germany) was prepared and dissolved in 50 ml of sterile 0.9 sodium chloride. gallic acid powder was purchased from the sigma (usaaldrich-g7384) and then dissolved in sterile phosphate buffered saline (pbs). histopathology left testis was fixed with 10% formalin solution. dehydration of tissues was done in a graded series of ethanol and fixed in paraffin. thin sections (4–5 μm) were made by microtome, after staining with hematoxylin and eosin, all slides were evaluated by light microscope. lipid peroxidation level malondialdehyde (mda) levels of testis were measured by using the thiobarbituric acid (tba) method at 532 nm, as explained by ohkawa and colleagues in 1979(17). the level of mda was defined as nmol / mg protein. evaluation of sperm parameters at the end of the treatment period, the caudal epididymis was removed and sliced in 2 ml of ham’s f10 medium with 1% bsa (bovine albumin serum). to swim sperm into the medium, the dishes were put in the co 2 incubator of 37°c for 30 min. a smear of sperm suspension was made on a microscope slide then sperm counts and motility were assessed by the method defined in the who manual, 2010(18). for the sperm morphology, 10 μm sperm was smeared then the slides were dried and stained by diff quick kit (avicenna, iran). percentage of spermatozoa with abnormal morphology was calculated. sperm vitality was tested using eosin-nigrosin staining method and the percentage of dead and live sperms was determined. dna fragmentation assessment sperm dna fragmentation was assessed by a sperm dna fragmentation kit (avicenna, iran) using the sperm chromatin dispersion (scd) method according to the manufacturer’s manual. briefly, the sperm specimens were washed twice with the pbs buffer, and a suspension of 15-20 million sperms was prepared. then, spermatozoa were immersed in agarose micro gel and smeared on the slide. in the order, denaturation by acid and lysis solution, dehydration and staining with diff-quick were done. sperms with large halos (that were similar or larger than the diameter of sperm’s head) and sperms with medium sized halos (halo greater than 1:3 of the smallest diameter of the sperm's head and less than the smallest diameter) were defined as spermatozoa having no fragmentation. stereological study interstitial tissue volumes were evaluated by the cavalieri method. the cavalieri method(19) was applied as a testis volume estimator. thus, eight sections were chosen using a systematic sampling method and stereological estimations were started randomly. each section of the samples was studied with a video-microscopy system (nikon, e-200, japan) which was linked to a video camera (sony, ssc dc 18p, japan) a p4 pc computer, and a lg monitor (795 ft plus). the stereological probe (points) was placed over the images of the tissue sections and was observed through the monitor. the following formula was used to estimate the testis volume: table3. the effect of gallic acid on the sperm parameters in the mice's treated with cp group sperm count(106/ml) rapid progressive sperm slow progressive sperm no motile sperm vitality normal morphology (%) (%) (%) (%) (%) control 31.23 ± 7.55 48.72 ± 7.26 23.22 ± 8.21 28.03 ± 5.87 72.04 ± 5.69 62.02 ± 6.65 sham 33.37 ± 6.46 48.85 ± 10.05 24.56 ±7.31 26.55 ± 4.40 b 74.94 ± 7.06 68.20 ± 8.74 cp 19.71 ± 6.37ab 20.67 ± 5.74ab 30.51 ± 18.32 48.79 ± 14.73ab 12.07±34.71abcd 47.68 ± 5.59ab ga 36.09 ± 5.31 58.91 ± 6.50a 17.89 ± 3.04 23.17 ± 5.09 73.92 ± 5.33 63.37 ± 8.74 ga+cp 39.84 ± 4.61a 53.76 ± 13.41 29.91 ± 8.63 16.30 ± 10.99a 77.19 ± 6.44 59.77 ± 9.93 statistical analyses were carried out through one way anova/ kruskal wallis. data are presented as means ± sd a: p < .01 compared with control group. b: p < .001 compared with cp+ga group. c: p < .01 compared with ga group. d: p < .01 compared with sham group. group abnormal head (%) abnormal mid-piece (%) abnormal tail (%) control 13.43 ± 4.01 22.03 ± 5.91 1.99 ± 1.78 sham 10.12 ± 5.87 19.97 ± 7.73 1.55 ± 1.09 cp 14.15 ± 3.39 35.94 ± 6.60 ab 2.39 ± 0.98 ga 13.17 ± 5.13 21.79 ± 8.82 1.66 ± 1.68 ga+cp 12.82 ± 6.75 25.10 ± 9.19 1.62 ± 1.55 statistical analyses were carried out through one way anova/ kruskal wallis. data are presented as means ± sd a: p < .05 compared with control group. b: p < .05 compared with cp+ga group. table4. the effect of gallic acid on the forms of sperm morphological abnormalities in the cp-treated mice protection of gallic acid on testis damage-mehraban et al. andrology 80 vol 17 no 01 january-february 2020 81 v (total) = ∑ p. (a/p0.d) where the “v (total)” was the testis volume, “σp” was the sum of the points on the section profile, “a/p” was the zone linked with each point at the level of tissue, and “d” was the space between the samples’ sections. each cell type was evaluated by this formula (n=number of cells counted/area of frame × number of frames × depth). the number of cells per testis was counted based upon nv (nv × testis weight). the germ cells were grouped into spermatogonia, primary spermatocytes, round spermatids (rs), sertoli cells, and leydig cells. data analysis methods all the data were analyzed using spss software. all the values were reported as mean ± sem. all values were computed with the one way anova/ kruskal wallis followed by post hoc tukey test. p < .05 was considered as statistically significance. results as shown in table 1, there was a significant difference between the mice's testis weight (mg), total testis volume, and testis interstitial layer volume after 35 days treatment with cp and control group. gallic acid administration with cp could significantly improved this reduction (p < .05). the total count of germ cells and leydig cells was reduced by cp administration, whereas gallic acid co-treatment restored all these changes (p < .05) (table 2). figure 1, shows the testes in the control, sham, and gallic acid groups with normal architecture and normal germinal epithelium (spermatogonia, primary spermatocyte, spermatids). moreover, there were focal areas of atresia in the cells of seminiferous tubules of the cp-treated group with hypoplasia in the germinal layer. interestingly, the testes of mice co-treated with cp and gallic acid seems normal. the effects of gallic acid on sperm parameters are shown in table 3. the mean percent of progressively motile sperm was significantly reduced in cp group (20.67 ± 5.74) versus the control group (48.72± 7.26 %) (p < .001). in addition, it was noticed that it was significantly higher in gallic acid +cp group (53.76 ± 13.41 %) (p < .001). there was no significant difference in sperms with non-progressive motility between the groups (p = .17) but the immotile sperm was significantly increased in cp group (48.79 ± 14.73 %) (p < .001) and decreased in the cp+gallic acid group (16.30 ± 10.79 %) compared with the control group (28.03 ± 5.78 %) (p = .015) (table 3). a significant decrease was observed when comparing the sperms count in the cp group (19.71 ± 6.37) and the control group (31.23 ± 7.55) (p = .001). the count of sperms increased significantly in the cp and gallic acid group (39.84 ± 4.61) compared with the control (p = .008) and the cp group (p < .001) (table 3). the mean percentage of alive sperms (i.e. the viability of the sperm) decreased significantly in the cp group (34.71 ± 12.07 %) in comparison with all the other groups (p = .01). on the other hand, the vitality of sperm in the cp + gallic acid (77.19 ± 6.44 %) group was recovered (table 3). considering the variety of sperm abnormalities (figure 2), it can be seen that the mean percentage of sperms with normal morphologies decreased significantly in cp group (47.68 ± 5.59 %) compared with the control group (62.02 ± 6.65 %) (p = .001). in addition, the percentage of sperms with normal morphology revived in the cp plus gallic acid group (59.77 ± 9.93 %) (p = figure3. the effect of gallic acid on testis malondialdehyde: mda (μmol/mg protein) level in mice treated with cp. data are mean ± se. a: p < .05 compared with control group. b: p < .01 compared with cp+ga group. figure 2. morphology of epididymal sperm from mice staining with diff quick method. (n) sperm with normal morphology, (h) sperm with abnormal head, (m) sperm with abnormal mid-piece , (t) sperm with twisted flagella. protection of gallic acid on testis damage-mehraban et al. .005) (table 3). on the other hand, it was shown that treatment with cyclophosphamide led to abnormality in the mid-piece of sperm and in this regard, the cp group had a significant difference with control group (p = .001) (table 4). the cp-treated group (6.26 ± 2.59 μmol/mg protein) showed a significant rise in the mda concentration (figure 3) in compared with the control group (4.30 ± 2.05) (p < .05). on the other hand, administration of gallic acid with cp (3.24 ± 1.33) decreased the mda concentration significantly in comparison with the cp group (p = .002). as demonstrated in figure 4, the percentage of dna fragmentation was high in the cp group ( % 57.89 ± 23.91 ) in comparison with control group ( % 24.52 ± 10.27 ) (p < .05). the concurrent administration of gallic acid and cp (% 28.4 ± 8.85) significantly decreased the percentage of sperms with dna fragmentation compared with the cp group (p < .001). picture from dfi (dna fragmentation index) was illustrated in figure 5. discussion according to data obtained in this study, cp may cause reproductive toxicity through oxidative stress, which can be reduced by concurrent administration of gallic acid as an antioxidant. in some studies, cp has the ability to produce free radicals, lipid peroxidation, and oxidative stress induction (20,21). long-term use of cp in low doses may cause fertility system impairments in male mice(13,15,22) and the level of intracellular thiol has an important role in determining cell susceptibility to cp-induced damages(20). 4-hydroxycyclophosphamide can react with cellular thiols and produce a thioalkyl derivative which can induce oxidative stress(20,23). our results presented that the weight of the mice's testicles decreases significantly during the treatment in the cp group, which is in line with some other studies (24,25). the decrease in the number of seminiferous germ cells, leydig cell lysis, and reduction in sperm production can be the possible reasons for the testicles weight loss. the testosterone level decrease along with leydig cells lysis(25,26). in addition to disrupting spermatogenesis, low concentration of testosterone associated with negative effects on epididymal tissue function can be associated with impairments in maturity and quality of the sperms(23). in addition, this weight loss can be attributed to a decrease in testicle size, the diameter of the seminiferous tubules, epithelial thickness, or increased interstitial space, which ultimately leads to the destruction of the testicle (20,24). our results suggest that the cp can cause reproductive toxicity on germinal layer through creating oxidative stress, although this toxicity effect could be reduced by concurrent administration of gallic acid as an antioxidant(13,16). various studies have reported possible mechanisms of cp and its toxic metabolite, acrolein, in producing ros, lipid peroxidation, and oxidative stress (20,26,27). in addition, testicles are suitable places for the side effect of chemotherapeutic drugs, such as cp, that targeting highly proliferative cells as germ cells(20) since it has been confirmed the role of cp in oligospermia and azoospermia(29), as well as the destruction of spermatogenetic cycles in adult men treated with this drug (30). in present investigation, gallic acid was used as an figure 5. sperm dna fragmentation test using the sperm chromatin dispersion (scd) technique. when sperm classification is performed using the images provided by the scd-halosperm® method, normal sperm containing nonfragmented dna are scored as the sperm population showing large or medium halos of dispersed chromatin surrounding a compact and well-defined core (1 n). spermatozoa either containing small halos or no halos, i.e., leaving only the chromatin core visible, are considered as those containing fragmented dna(1 s). spermatozoa exhibiting highly degraded chromatin are characterized by the presence of small nucleoids presenting nonuniform or faintly stained chromatin core in association with the absence of a halo of dispersed chromatin after direct staining (1 d). figure 4. the effect of gallic acid on dna fragmentation of sperm in mice's treated with cp. data are mean ± se. a: p < .05 compared with control group. b: p < .001compared with cp+ga group. protection of gallic acid on testis damage-mehraban et al. andrology 82 vol 17 no 01 january-february 2020 83 antioxidant to modify the side effects of oxidative stress induced by cp and we found it could prevent this destructive effects beside antioxidant capacity. gallic acid indicated an anti-lipid peroxidation effects through decreasing malondialdehyde (mda) level(31) which was higher in the cp group. previous reports have revealed that increased mda concentration is due to lipid peroxidation and reduced antioxidant enzymes levels resulted from oxidative damages(31,32). sperms mobility and viability are considered as the most important sperm parameters to measure the sperm membrane integrity and the fertilization ability. spermatozoa are so sensitive to oxidative damage(31-33). oxidative stress can lead to lipid peroxidation, atp depletion, and disturbance in the axonemal protein phosphorylation process, decrease the function of the membrane and ion channel enzymes, and membrane fluidity, and consequently, loss of sperm motility(33). cell death may occur following the atp depletion, which can be the reason for reduced sperm viability in the present study(33). various studies have reported the reduction of sperm motility during in vivo and in vitro studies(13,15,34,35) and the sperm viability(25,35) after treatment with cp. to support this idea, we have shown that gallic acid significantly modified the effects of cp on motility and viability of sperms. a significant reduction in epididymal sperms in cp-treated mice was observed that may be related to increase in the free radicals and oxidative stress (13,15,36) , reduction in antioxidant defense system of testicle and sperms(37,38), testicular germ cells and sertoli cells apoptosis caused by oxidative stress(39), changes in the concentration of sex hormones and disorders in the endocrine system(25,35), and destruction of the connections between sertoli cells in testicles(20). gallic acid could modify the destructive effects of cp on the sperm count and morphology and triggered the survived germ cells to proliferate,(13,15,20,40) by its antioxidant and anti-lipid peroxidation capacity (39,41-44). surprisingly, there were two statistically significant differences between ga+cp and control groups in sperm count and no motile sperm parameters without significant difference between ga and control. our hypothesis is that each of the substances (ga or cp) alone can have a good or bad effects on the reproductive system, but it is may be due to the synergistic effects of the two substances in condition of co treatment that result in a greater improvement, but no study was found to determine the mechanisms and effects of the two substances. as shown in previous studies, there is a positive correlation between increased ros production and degenerative changes in the single and double strand of dna helix, including the un-coupling of complementary bases, alternations, and deformations in cross-linking of dna, and chromosome structure reconstruction. consequently, a severe dna damage occurs because of such destructions (8,20,45-48). in support of previous reports, our data showed that cp increases sperm dna fragmentation and gallic acid significantly decreases the percentage of sperm dna fragmentation induced by cp. however, it is noteworthy that sperm chromatin condensation has a protective role against free radicals. therefore, most of the dna damages occur during the intermediate stages of spermatogenesis during protamine-histone transition process(49). in addition, cp can interrupt the protamine-dna binding process and thus lead to alkylation of protamine(20). based on this report, the cp-treated mice had a drastic reduction in the percentage of sperm with dense chromatin, according to which it can be assumed that gallic acid has the ability to protect the sperm dna content by protamination stimulation. conclusions cp showed severe toxicity to the male reproductive system by elevating oxidative stress in the testicular and epididymal tissue, decreased spermatogenesis and morphologically mis-shaped sperm probably via stimulation of apoptosis and increased fragmentation of sperm dna structure. this study suggests that using ga as antioxidant therapy with cp might has a protective effect against toxicity of cp on the reproductive system. acknowledgement this manuscript has been derived from a phd thesis of zahra mehraraban carried out in the department of biology and anatomical sciences, school of medicine, shahid beheshti university of medical sciences. conflict of interest the authors report no conflict of interest. references 1. khaki a, nouri m, fathizad f, khaki a. evaluation of zingiber officinalis and allium cepa on spermatogenesis in rat. medical journal of tabriz university of medical sciences & health services. 2008; 30 : 53-8. 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50:1-7. 24. hosseini a, zare s, ghaderi pakdel f, ahmadi a. effects of vitamin e and ginseng extract on fertility changes induced by cyclophosphamide in rats. medical journal of reproduction & infertility 2011; 11 : 227-37[persian] 25. elangovan n, chiou tj, tzeng wf, chu st. cyclophosphamide treatment causes impairment of sperm and its fertilizing ability in mice. toxicology. 2006; 222:60-70. 26. maremanda kp, khan s, jena g. zinc protects cyclophosphamide-induced testicular damage in the rat: involvement of metallothionein, tesmin, and nrf2. biochem biophys res commun. 2014; 445:591-96. 27. cao y, wang x, li s, wang h, yu l, wang p. the effects of l-carnitine against cyclophosphamide-induced injuries in mouse testis.basic clin pharmacol toxicol. 2017; 120:152-58. 28. olayinka et, ore a, ola os, adeyemo oa. ameliorative effect of gallic acid on cyclophosphamide-induced oxidative injury and hepatic dysfunction in rats. med sci (basel). 2015; 3:78-92. 29. shabanian s, farahbod f, rafieian m, ganji protection of gallic acid on testis damage-mehraban et al. andrology 84 vol 17 no 01 january-february 2020 85 f, adib a. the effects of vitamin c on sperm quality parameters in laboratory rats following long-term exposure to cyclophosphamide. j adv pharm technol res. 2017; 8:73-9. 30. qian l, yu s. protective effect of polysaccharides from lycium barbarum on spermatogenesis of mice with impaired reproduction system induced by cyclophosphamide. am j reprod immunol. 2016; 76:383-85. 31. shalaby ka, saleh em. ameliorative effect of honey bee propolis on the nonylphenol induced-reproductive toxicity in male albino rats. aus j basic appl sci 2011; 5: 918-27. 32. karafakioglu ys, aslan r. taurine prevents nonylphenol-induced oxidative stress in rats. j anim vet adv 2010; 9: 37-43. 33. tremellen k. oxidative stress and male infertility-a clinical perspective. hum reprod update 2008; 14: 243-58. 34. bakhtiary z, shahrooz r, ahmadi a, zare l. evaluation of antioxidant effects of crocin on sperm quality in cyclophosphamide-treated adult mice. veterinary research forum. 2014; 5 : 213 –18 35. lu wp, mei xt, wang y, zheng yp, xue yf, xu dh. zn (ii)-curcumin protects against oxidative stress, deleterious changes in sperm parameters and histological alterations in a male mouse model of cyclophosphamideinduced reproductive damage. environ toxicol pharmacol. 2015; 39:515-24. 36. aghaie s, nikzad h, mahabadi ja, taghizadeh m, taherian a, sajjadian sm, kamani m. protective effect of combined pumpkin seed and ginger extracts on sperm characteristics, biochemical parameters and epididymal histology in adult male rats treated with cyclophosphamide. anat sci int. 2016; 91:382-90. 37. potnuri ag, allakonda l, lahkar m. crocin attenuates cyclophosphamide induced testicular toxicity by preserving glutathione redox system. biomed pharmacother. 2018; 101:174-80. 38. erfani majd n, sadeghi n, tavalaee m, tabandeh mr, nasr-esfahani mh. evaluation of oxidative stress in testis and sperm of rat following induced varicocele. urol j. 2018 nov 21. [epub ahead of print] 39. li j, hu y, zhang q, ma b, wu z, wang y et al . strontium fructose 1, 6-diphosphate alleviate cyclophosphamide-induced oligozoospermia by improving antioxidant and inhibiting testicular apoptosis via fas/fasl pathway. andrologia. 2015; 47:995-1003. 40. rajan vk, muraleedharan k. a computational investigation on the structure, global parameters and antioxidant capacity of a polyphenol, gallic acid. food chem. 2017 apr 1; 220:93-9. 41. v. vijaya padma, p. sowmya, t. arun felix, r. baskaran, p. poornima.protective effect of gallic acid against lindane induced toxicity in experimental rats. food chem toxicol. 2011; 49:991-98. 42. delashoub m, ziaee m, khorrami a, banankhojasteh sm. comparison of the effects of clofibrate and silafibrate on sperm parameters quality and sex hormones in male rats. urol j. 2018; 15: 38-43. 43. irani m, amirian m, sadeghi r, lez jl, latifnejad roudsari r. the effect of folate and folate plus zinc supplementation on endocrine parameters and sperm characteristics in sub-fertile men: a systematic review and meta-analysis. urol j. 2017; 14 :4069-78. 44. ferk f, chakraborty a, jäger w, kundi m, bichler j, mišík m et al . potent protection of gallic acid against dna oxidation: results of human and animal experiments. mutat res. 2011; 715:61-71. 45. kanno t. y. n., sensiate l. a. , paula n. a. , salles m. j. s. toxic effects of different doses of cyclophosphamide on the reproductive parameters of male mice. braz. j. pharm. sci . 2009; 45:313-19. 46. asci h, ozmen o, ellidag hy, aydin b, bas e, yilmaz n. the impact of gallic acid on the methotrexate-induced kidney damage in rats. j food drug anal. 2017:25: 890-97. 47. karimi-khouzani o, heidarian e, amini sa. anti-inflammatory and ameliorative effects of gallic acid on fluoxetine-induced oxidative stress and liver damage in rats. pharmacol rep. 2017; 69: 830-35. 48. bakhtiari z, shahrooz r, ahmadi a, soltani f. protective effect of crocin on dna damage of sperm and in vitro fertilization (ivf) in adult male mice treated with cyclophosphamide. j mazandaran univ med sci. 2014; 24 :45-59 49. codrington am, hales bf, robaire b. spermiogenic germ cell phase-specific dna damage following cyclophosphamide exposure. j androl 2004; 25: 354-36 protection of gallic acid on testis damage-mehraban et al. best reviewer of the march-april 2020 issuemurat akand murat akand my 2020 dr. murat akand is a full-time associate professor at selcuk university, school of medicine, department of urology, konya, turkiye since 2016. he has worked as assistant professor at the same institution between july 2011 and april 2016. he has been certified both by the european board of urology and turkish board of urology. his main interests are urological oncology (especially bladder cancer) and urolithiasis. he has worked as principal investigator in two nationally funded projects in which a novel technique has been developed for renal access during percutaneous nephrolithotomy. currently he is the principal investigator of a nationally funded project for development of a robotic arm to be used in percutaneous nephrolithotomy. he is also working as a co-investigator in a prospective project leaded by university hospitals leuven, department of urology, leuven, belgium for identification of novel biomarkers for better stratification of intermediate and high-risk non-muscle-invasive bladder cancer patients. he has published more than fifty papers in international peer-reviewed journals. he has been performing peer reviews for more than fifteen journals, including european urology, european urology focus, european urology oncology, world journal of urology, journal of endourology, urology, and urology journal. “i was very honored when i was first invited to review a manuscript that has been submitted to urology journal. after this first invitation, i have reviewed several papers in which i did my best as a reviewer during evaluating the articles for publishing in urology journal in order to maintain the high quality of this journal. sound peer-review is one of the most important processes for assuring publication of high-quality scientific research. the editorial team and the electronic portal for reviewing of urology journal were very helpful during this important process.” v07_no_4.pdf reconstructive surgery 258 urology journal vol 7 no 4 autumn 2010 dorsal versus ventral anterior urethral spatulation in posterior urethroplasty jalil hosseini, mohammad jabbari, ali kaviani, mohammad mohsen mazloomfard, hooman mokhtarpour purpose: to compare dorsal versus ventral anterior urethral spatulation in posterior urethroplasty. materials and methods: in a retrospective study, we evaluated the records of 320 posterior urethroplasties which have been done in our center over a 7-year period from january 2000 to december 2006. the results of dorsal and ventral anterior urethral spatulations were compared. results: the studied subjects consisted of 264 men and 54 prepubescent mean follow-up was 52 months (range, 27 to 107 months). six o’clock (group a) and 12 o’clock (group b) anterior urethral spatulations were performed in 101 (32%) and 219 (68%) of the patients, respectively. the success rates were 96% and 87.6% in groups a and b, respectively (p = .025). there were no urethro-rectal fistula and perineal wound infection during the follow-up period. conclusion: our data suggest that the dorsal anterior urethral spatulation in urethroplasty is more efficient than ventral anterior urethral spatulation in terms of treatment success outcome. urol j. 2010;7:258-61. www.uj.unrc.ir keywords: urethra, urethral stricture, pelvic bones, retrospective study, complications research center, department of reconstructive urology, shohadauniversity, mc, tehran, iran corresponding author: research center, shohada-ereconstructive urology, shahid beheshti university, mc, tehran, iran e-mail: jhosseinee@gmail.com received june 2009 accepted may 2010 introduction posterior urethral injury occurs in 10% of pelvic fractures.(1) the surgical management of pelvic fracture urethral distraction defects (pfudd) has evolved significantly in the last 50 years. during 1970’s, turner-warwick popularized a delayed one-stage perineal urethroplasty with urethral mobilization and anastomosis.(2) the site of the injury is approached transperineally. repair is affected by a series of steps starting with a full mobilization of the bulbar urethra (to capitalize on its elasticity) and progressing to corporal separation and inferior pubectomy. this would entail rerouting of the urethra around the cruras of the penis when it is necessary to straighten out the natural curve of the bulbar urethra. it results in bridging the gap between the two ends of the urethra to allow an overlapping spatulated end-to-end anastomosis without tension.(3-4) to achieve better mucus-to-mucus anastomosis with at least 32f lumen, the proximal and distal parts of the urethra should be spatulated in opposite directions. some urologists believe that spatulation of the distal urethra at 6 o’clock provides more blood supply to the surrounding spatulation in urethroplasy—hosseini et al 259urology journal vol 7 no 4 autumn 2010 tissues;(5-8) however, many spatulate the distal urethra in opposite directions.(9) although both techniques have been reported to be successful, no published paper has yet compared their efficiency and outcomes. the aim of this study was to compare the efficacy and safety of dorsal and ventral anterior urethral spatulation in posterior urethroplasty. materials and methods we retrospectively evaluated the records of 320 posterior urethroplasties over a 7-year period from january 2000 to december 2006. the data of 101 patients who underwent dorsal spatulation (group a) were compared with 219 patients treated by ventral spatulation technique (group b). all of the patients had exactly the same history of pfudd. pre-operative evaluations included taking medical and surgical history, physical examination as well as simultaneous retrograde urethrography and voiding cystourethrography. thereafter, urethroscopy and flexible suprapubic cystoscopy were performed to assess the anterior and posterior urethral anatomy and determine the length of the defects.(10) posterior urethroplasty was scheduled at least 3 to 6 months after the pelvic fracture. surgical technique the patient was placed in the lithotomy position and under general anesthesia, an incision was made on the median raphe. anterior urethra was dissected from the surrounding tissue, and the continuity of the urethra through obliterated scar tissue was cut. after removal of the scar and fibrotic tissue from posterior urethra, the end point of the urethra was opened by using flexible cystoscope. for spatulation of the urethral end, two protocols have been followed: protocol ‘a’ (dorsal spatulation): spatulating of anterior and proximal end of the urethra at 6 o’clock position (figure 1). protocol ‘b’ (ventral spatulation): spatulating of anterior and proximal end of the urethra at 12 o’clock position (figure 2). mucus-to-mucus anastomosis of the two urethral ends was performed using 6 absorbable 3-0 vicryl sutures. urethral catheter was removed 3 weeks after the operation if there was no contrast extravasation in pericatheter urethrography. all the patients were followed up at 2, 3, 5, 7, 9, 15, 21, and 27 months postoperatively. they also underwent retrograde urethrography and urethrocystoscopy at 6 and 12 months after urethroplasty. if patients had new voiding problems or abnormal retrograde urethrography, figure 1. spatulating anterior urethra at 6 o’clock position (dorsal spatulation). black arrow shows counter clockwise rotation of the urethra. figure 2. spatulating anterior urethra at 12 o’clock position (ventral spatulation). spatulation in urethroplasy—hosseini et al 260 urology journal vol 7 no 4 autumn 2010 they were evaluated by urethrocystoscopy. successful operation was defined as the lack of stricture recurrence or defect after one internal urethrotomy. demographic characteristics, stricture length, mechanism of pfudd (cause of pelvic fracture), past surgical history (previous urethrotomy or urethroplasty), type of procedure done (bulbomembranous or bulboprostatic anastomosis), maneuvers during urethroplasty (crural separation and inferior pubectomy), and success rate were compared between two groups. the ethical aspect of this study was approved by the ethics committee of infertility and reproductive health research center. statistical analysis was performed using chisquare and fisher’s exact tests as appropriate with significance considered at p values less than .05. results the studied subjects consisted of 264 men and mean age of 23 years (range, 5 to 84 years). the mean follow-up was 52 months (range, 27 to 107 months). total success rate of posterior urethroplasty was 90%. there were no urethrorectal fistula and perineal wound infection during the follow-up period. six o’clock (group a) and 12 o’clock (group b) anterior urethral spatulations were performed in 101 (32%) and 219 (68%) of the patients, respectively. baseline demographic and clinical characteristics did not differ significantly between two groups (table). posterior urethroplasty success rates were 96% and 87.6% in groups a and b, respectively (p = .025). discussion the most common etiologies of strictures or defects of the posterior urethra in iran are motor vehicle crashes (63%) and falling (10%).(11) in pelvic fracture urethral injury, the site of the injury is dependent on the mechanism of fracture, but generally it is at the bulbo-membranous junction.(12) the gold standard for treatment of pelvic fracture urethral injuries is a bulboprostatic anastomotic urethroplasty.(3) in our series, flexible cystoscopy was performed to open the true end point of the urethra and for better guidance of scar tissue removal.(10) the principal complication of urethroplasty is recurrence of stricture. in mundy’s study, the rate of recurrence during the first postoperative year was 7% which increased to 12% after 5-year follow-up and remained constant during 10 years. (5) spatulation of both ends of the urethra is a procedure to achieve a tension-free mucus-tomucus anastomosis of at least 32 f lumen and a better successful result. in classic urethroplasty, spatulation site of the distal urethra is located at 6 o’clock position. this technique is generally used by many reconstructive urologists;(5-7) however, others spatulate the distal urethra at 12 spatulated at 6 o’clock spatulated at 12 o’clock p mean age (years) 29.3 ± 14.8 27.9 ± 14 .413 stricture length (cm) 3.3 ± 1 3.4 ± 1.3 .488 cause of pelvic fracture, n (%) car accident 83 (82.2) 159 (72.6) .087 falling down 12 (11.9) 39 (17.8) .237 crush injury 6 (5.9) 21 (9.5) .382 past surgical history (%) previous urethrotomy 22 (21.8) 42 (19.2) .696 previous urethroplasty 27 (26.7) 48 (21.9) .422 intra-operative procedure, n (%) bulbomembranous anastomosis 17 (16.8) 59 (26.9) .067 bulboprostatic anastomosis 84 (83.2) 163 (74.4) .112 crural separation 34 (33.6) 60 (27.4) .312 inferior pubectomy 33 (32.7) 51 (23.3) .102 success rate, n (%) 97 (96) 192 (87.6) .025* demographic and operative data of both 6 o’clock and 12 o’clock urethral spatulations *statically significant spatulation in urethroplasy—hosseini et al 261urology journal vol 7 no 4 autumn 2010 o’clock. both techniques are used for posterior urethroplasty in our reconstructive urology section. in our study, the success rates for 6 o’clock and 12 o’clock spatulations were 96% and 87.6%, respectively (p = .025). morey and mcaninch(13) and cooperberg and colleagues(8) have reported the success rates of 93% to 97% by using 6 o’clock spatulation, while flynn and associates had success rate of 97% by using 12 o’clock spatulation.(9) the observed difference could be due to that the bulbar urethra is located more posteriorly than corpus spongiosum. therefore, 6 o’clock spatulation causes less damage to the corpus spongiosum and urethral blood supply. furthermore, 6 o’clock spatulation decreases the gap between two ends of the urethra, resulting in less tension at the site of end-to-end anastomosis. conclusion our data suggest that the dorsal anterior urethral spatulation in urethroplasty is more efficient than ventral anterior urethral spatulation in terms of treatment success outcome. acknowledgement the authors are thankful to infertility and reproductive health research center, shahid beheshti university, mc, for supporting this study. conflict of interest none declared. references 1. jordan gh, schlossberg sm. surgery of the penis and urethra. in: walsh pc, retik ab, vaughan edj, et al., eds. campbell’s urology. vol 4. 8 ed. philadelphia wb saunders; 2002:3886-954. 2. turner-warwick r. a personal view of the management of traumatic posterior urethral strictures. urol clin north am. 1977;4:111-24. 3. andrich de, mundy ar. what is the best technique for urethroplasty? eur urol. 2008;54:1031-41. 4. hosseini sj, rezaei a, mohammadhosseini m, rezaei i, javanmard b. supracrural rerouting as a technique for resolution of posterior urethral disruption defects. urol j. 2009;6:204-7. 5. mundy ar. urethroplasty for posterior urethral strictures. br j urol. 1996;78:243-7. 6. koraitim mm. the lessons of 145 posttraumatic posterior urethral strictures treated in 17 years. j urol. 1995;153:63-6. 7. koraitim mm. on the art of anastomotic posterior urethroplasty: a 27-year experience. j urol. 2005;173:135-9. 8. cooperberg mr, mcaninch jw, alsikafi nf, elliott sp. urethral reconstruction for traumatic posterior urethral disruption: outcomes of a 25-year experience. j urol. 2007;178:2006-10; discussion 10. 9. flynn bj, delvecchio fc, webster gd. perineal repair of pelvic fracture urethral distraction defects: experience in 120 patients during the last 10 years. j urol. 2003;170:1877-80. 10. hosseini sj, kaviani a, jabbari m, hosseini mm, hajimohammadmehdi-arbab a, simaei nr. diagnostic application of flexible cystoscope in pelvic fracture urethral distraction defects. urol j. 2006;3:204-7. 11. hosseini j, tavakkoli tabassi k. surgical repair of posterior urethral defects: review of literature and presentation of experiences. urol j. 2008;5:215-22. 12. andrich de, day ac, mundy ar. proposed mechanisms of lower urinary tract injury in fractures of the pelvic ring. bju int. 2007;100:567-73. 13. morey af, mcaninch jw. reconstruction of posterior urethral disruption injuries: outcome analysis in 82 patients. j urol. 1997;157:506-10. review ramadan fasting and kidney stones: a systematic review mohsen amjadi1, farzin soleimanzadeh1*, hamidreza ghamatzadeh2, sakineh hajebrahimi3, hossein hosseinifard4, hanieh salehi pourmehr3, fateme tahmasbi2 purpose: ramadan fasting in muslims may contain several hours of abstaining from food and drinking in any kind. this can potentially increase the risk of urinary stone disease. current literature on possible effects of ramadan fasting on urolithiasis is rather limited. having the gap in scientific background, we decided to evaluate the available comparative information in this systematic review. materials and methods: we included all studies comparing fasting and non-fasting conditions, studies evaluating stone formation and clinical manifestations of kidney stone disease. all the english studies published from january 1980 to the end of 2019 were included. the exclusion criteria were as followed: fasting out of ramadan, non-comparative studies, animal studies, patients with bladder stones, and studies evaluating conditions that are only indirectly related to the stone formation or clinical manifestations of it. applying the joanna briggs institute (jbi) methodology for systematic review showed the quality of included studies was not high. results: only five studies remained after exclusion. meta-analysis was not applicable due to the diversity in methods and evaluated population. conclusion: main trend of the included studies is toward showing no difference between fasting and non-fasting conditions in terms of renal stone formation. however, generalization of the findings to greater populations should be applied carefully considering the heterogeneity of results and quality of studies. keywords: fasting; kidney calculi; kidney diseases; systematic review introduction ramadan is the ninth month of the islamic lunar calendar, during which muslims fast for a whole month. fasting in ramadan means abstaining from eating, drinking, and smoking from dawn to dusk. some conditions, either physiological or pathophysiological, can exempt one from fasting, including pregnancy, breastfeeding, and some disabilities (at their own discretion or the doctor's)(1,2). muslims eat two meals a day during this month. one meal before dawn, known as sahar, and the other after sunset, called iftar.(3) complete restriction of food and fluids intake from sunrise to sunset can lead to different levels of dehydration in fasting people. due to the low intake of fluids, the body responds to these changes by reducing urine output and increasing urine concentration as an attempt to reach normal homeostasis.(4) if proper care is not taken to ensure a hydrating diet during non-fasting hours, dehydration can be a serious complication and can even lead to death.(5) due to the increased urine concentration resulting from low fluid intake, changes in the renal system are expect1faculty of medicine, tabriz university of medical sciences, tabriz, iran. 2student research committee, faculty of medicine, tabriz university of medical sciences, tabriz, iran. 3research center for evidence based medicine, iranian ebm centre, a joanna briggs institute affiliated center, tabriz university of medical sciences, tabriz, iran. 4department of biostatistics, faculty of paramedical sciences, shahid beheshti university of medical sciences, tehran, iran. *correspondence: assistant professor of urology, faculty of medicine, tabriz university of medical sciences, tabriz, iran. tel: +989143511353. email: farzinsoleimanzade@gmail.com. received july 2020 & accepted september 2020 ed to occur in order to adapt the body to the dehydrated state. nevertheless, some studies show that in spite of these changes, there is no deterioration in renal function in healthy individuals and even in some patients with chronic kidney disease.(6) however, there are still concerns about fluid restriction in people with chronic kidney disease. some data, although not conclusive, suggest that fasting can alter the renal tubular system in people with chronic kidney disease.(7,8) another issue is the direct effects of ramadan fasting on urinary stone formation. in the available literature, controversial findings have been reported in this regard. several studies have shown that fluid restriction and dehydration increase the risk of urolithiasis.(9) most studies failed to find such a relationship.(10-14) in addition, the role of metabolic status has been suggested as a possible factor in the evaluation of lithogenic factors. for instance, the collection of some etiologic factors of stone formation may play a pathogenic role more than it was previously assumed.(15) several studies have tried to declare the effect of ramadan fasting on urinary stone formation. however, most urology journal/vol 18 no. 4/july-august 2021/ pp. 364-370. [doi: 10.22037/uj.v16i7.6373] of them are methodologically weak with different study designs, various outcome measures, and conclusions. considering the high incidence of fasting among muslims and the fact that the characteristics of this matter have not been dealt with in depth, we decided to run a systematic review evaluating the effect of ramadan fasting on urolithiasis. methods and materials this systematic review was conducted in accordance with the jbi methodology for systematic review of prevalence evidence(16) and preferred reporting items for systematic reviews and meta-analyses (prisma) (17) to make sure the methods and reporting of data is comprehensive and transparent. the question of this review was as followed: "does ramadan fasting affect urinary stone formation or clinical manifestation in people who fast continuously during ramadan?" inclusion and exclusion criteria we included any study which evaluated people who fast uninterruptedly and compared them with non-fasting people or with themselves while they were not fasting. all observational studies including prospective and retrospective cohort, case-control, and cross-sectional studies were included in this review. studies published in english from 1980 till the end of 2019 were considered for inclusion in the current review. exclusion criteria were as follows: 1) fasting out of ramadan conditions, 2. non-comparative studies (reviews, case series, reports…) 3. animal studies, 4. patients with bladder stones (due to different nature of pathogenesis) and 5. studies evaluating conditions that are only indirectly related to the stone formation or clinical manifestations of it (acid-base balance, changes in specific gravity…). the target population consists of people who fast continuously during the month of ramadan. outcome measures included both clinically symptomatic presentation of stone disease (renal colic, obstructive uropathy, urinary retention…) and asymptomatic finding of evidence in favor of urolithiasis (imaging or laboratory findings). search strategy we searched pubmed, embase, scopus, proquest, web of science, and the cochrane library pubmed database was searched using the following keywords: "fasting", "ramadan fasting", "ramazan fasting", "islamic fasting", "food abstinence", "fasting in islam", the term ramadan was added to different terms used for urinary stones disease (urolithiasis/ urinary lithiasis, urine calculi/ calculus, kidney stone / stones and many other phrases offered via mesh). for embase a specific keyword set was used. we first included all of the studies form january 1980 until the end of 2019. we screened reference lists of included studies and review articles. the full search strategy for pubmed and embase is provided in appendix i. study selection following the search, all identified citations were imported into endnote x9.1 and duplicates were removed. two independent reviewers (fs & hg) screened titles and abstracts for eligibility criteria of the review. the full text of potentially eligible studies was retrieved and assessed in detail against the inclusion criteria by the mentioned reviewers. studies that did not meet the inclusion criteria were excluded. any disagreements between the reviewers were resolved through discussion, or by referring to a third reviewer (ma). assessment of methodological quality two independent reviewers (fs & hs) critically appraised eligible studies at the study level using standardized critical appraisal instruments from the joanna briggs institute jbi critical appraisal checklist for analytical cross sectional and/ or case control studies. (figure 2, 3) any disagreements between the reviewers were resolved through discussion. the details of the study qualities are presented in table 1. data extraction two independent reviewers extracted data from included studies using modified standardized jbi data extraction tool.(16) the data extracted included populations, sample size, study methods, publication year, and region of study, mean age, gender, and outcome measurement. the reviewers resolved disagreements through discussion. extracted data from included studies are presented in table 2. results study inclusion comprehensive electronic searching identified 181 studies. in the screening steps of title, abstract and fulltext, two reviewers selected 106 studies, and finally 5 observational studies remained for critical appraising process. the prisma flowchart of this process is represented figure 1. meta-analysis could not be performed because of heterogeneity in terms of methods, objectives, and findings. among the included five studies, four of them evaluated the occurrence rate of renal colic in ramadan-fasting people, although in different methods. characteristics of the included studies the characteristics of the included studies are summarized in table 2. norouzy, et al(18) in 2011 evaluated the number of pafasting and kidney stone-amjadi et al. review 365 no. authors q1 q2 q3 q4 q5 q6 q7 q8 q9 q10 1 norouzy, et al (2011) ☺ ☹ 😐 ☹ 😐 😐 ☹ ☺ 2 al mahayni, et al (2018) ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ 3 basiri, et al (2004) ☹ ☹ 😐 😐 😐 😐 😐 ☺ 4 cevik, et al (2016) ☺ ☺ ☺ ☺ 😐 😐 ☺ ☺ 5 miladipour, et al (2012) ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ 😐 ☹ table 1. quality scoring results using jbi appraisal checklist for urolithiasis related studies* ☺: low risk ☹: high risk 😐: unclear risk *description of questions in jbi critical appraisal checklist for analytical cross sectional studies and case-control are listed in figures 2 and 3. tients admitted with renal colic during various stages of peri-ramadan month this was a prospective observational study. they defined four stages of two-week periods starting two weeks before ramadan (stage 1) and finishing two weeks after ramadan (stage 4). the authors found that the occurrences of renal colic among all 610 patients in two major hospitals were increased significantly during the first two weeks of ramadan (stage 2). however, the number of admissions decreased during the last two weeks of ramadan and two weeks after ramadan (stage 3 and 4). they also noticed the mean room temperature for each group (27.7°c, 24.8°c, 23.5°c, and 21.2°c for stages 1 to 4 respectively). this is important especially when we face the results of other studies. al mahayni, et al(19) retrospectively evaluated 237 patients admitted through the emergency room (er) with a diagnosis of renal colic secondary to urinary stones over a 10-year period and compared ramadan versus non-ramadan months, as well as ramadan in the summer (between 41-45 degrees celsius) versus in the winter (21-24 degrees celsius) among these patients. they concluded that ramadan fasting did not increase the risk for developing urinary stones compared to non-fasting vol 18 no 4 july-august 2021 366 table 2. characteristics of included studies. no. author year study country population sample subject study methods for results ``` design size characteristics duration (months) outcome measurement male females age (mean) 2 weeks prior symptoms of renal a significant 1 norouzy a, 2011 prospective mashad/ renal colic. 610 441 169 37.6 (range ramadan till colic based on increase in et al, 2011 observational iran due to urinary 15–85 years) 2 weeks after physician's clinical the incidence study tract stones ramadan judgment. of ureteric colic during ramadan. 2 al mahayni 2018 retroriyadh/ renal colic 237 178 59 45.8 1 confirmed clinically fasting in a, et al, 2018 spective kingdom due to urinary and radiologically ramadan of saudi tract stones. (non-contrast ct scan) does not arabia increase the risk for developing urinary stones compared to non-fasting months. ramadan in summer may increase the risk of developing ureter stones compared to fasting in ramadan during the winter. 3 basiri, 2004 retro varamin renal colic 574 398 176 36.4 1 acute attack higher et al, 2004 spective /iran due to urinary of renal colic temperature tract stones. rather than fasting is a cause for ureteric colic. 4 cevik y, 2016 prospective turkey renal colic 176 112 64 40.47 2 physician’s clinical no change et al, 2016 observational due to (range judgment according in visits study urinary tract 18-81 years) to classical clinical related to stones. features, history, renal colic and physical examination during ct in no definite ramadan. diagnoses. . 5 miladipour a, 2012 casetehran 37 recurrent 57 57 41.66 1 urine metabolite fasting et al, 2012 control /iran calcium concentrations and during calculus supersaturations during ramadan formers and fasting and non-fasting had different 20 with no periods in recurrent effects on history of calcium calculus total kidney calculi formers and healthy excretion and controls concentrtions of urinary precipitate and inhibitory factors contributing to calculus formation. fasting and kidney stone-amjadi et al. months. however, fasting in ramadan during the summer may increase the risk of developing ureteral stones compared to fasting in winter. they also mentioned that the possibility of finding a urinary stone in ureter during ramadan is more likely than other locations of urinary system. basiri, et al(11) evaluated monthly variations of renal colic in 574 patients in a 12-month period, 43 of which presented during ramadan. they found that high temperature rather than fasting can leads to increased colreview 367 figure 1. prisma flow diagram of selectio figure 2. jbi critical appraisal checklist for analytical cross sectional studies. fasting and kidney stone-amjadi et al. icky pain episodes. there were seven lunar months with more than 43 presented patients. cevik, et al(20), evaluated 176 patients with ureteric colic (89 before ramadan, 87 in ramadan) also showed that fasting did not change the number of ureteric colic visits. they also showed that despite some changes in urinary metabolites by fasting, there is not enough evidence that these changes increase urinary calculus formation. miladpour, et al(12) evaluated biochemical laboratory findings of urine and blood samples as well as renal ultrasonography in 57 patients (37 recurrent calcium stone formers and 20 people without history of urolithiasis) in fasting and non-fasting conditions. we should be cautious about the findings since changes in many of these tests cannot necessarily result in stone formation. however, some of the parameters like ultrasonography studies were objective means, directly addressing the stone. the authors found a number of effects on total excretion and concentrations of urinary precipitate and inhibitory elements but they concluded that enough evidence in favor of increased risk of calculus formation could not be found. discussion the studies evaluated for this systematic review are not sufficiently informative about the effects of ramadan fasting on urinary stone disease. this lack of conclusiveness was the result of different factors, some of which are discussed below: 1. methodological diversity: the studies were quite different in their methods. some are retrospective and others prospective, with various focus points, which can affect the overall results. 2. quality: no randomized clinical trials were available, which makes sense considering it is hardly feasible to randomize people in fasting and non-fasting groups none of our included studies met the good quality characteristics of jbi checklist except in rare aspects (table 1). 3. study objectives: four out of five studies used the frequency or monthly trend of acute renal colic, comparing non fasting condition with fasting as their main outcome. although this can be one aspect of clinical manifestations, it is an oversimplification of a complex multifactorial process, considering the fact that stone formation does not necessarily result in renal colfigure 3. jbi critical appraisal checklist for case-control studies. fasting and kidney stone-amjadi et al. vol 18 no 4 july-august 2021 368 ic in a given time frame. in other words, a small nidus of stone can be first formed in kidneys during the fasting period, turning to a visible, clinically important stone later, when it may not seem to be related to fasting. one other important aspect of choosing symptomatic stone passage as a means for evaluation of stone formation is the possibility of missing “asymptomatic stone passages". d’costa el al,(21) showed that among a group of patients with asymptomatic small kidney stones, at 5 years there was a ct scan-detected stone passage rate of 51 percent, only about half of which were accompanied by symptoms. this finding means that small stones may pass without obvious clinical symptoms and the stone formation rate can be underestimated using ureteric colic as the outcome of interest. 4. seasonal changes in ramadan: since the lunar year is ten days shorter than solar year, month of ramadan lies in different seasons during a long time frame. when it lies in summer, especially in hot climate, longer day hours and higher temperature may be related to a higher risk of dehydration and resultant stone formation rate. this is a possibility not appropriately addressed in all of the studies included. 5. heterogeneous results: even among these rare studies, the results are not homogenous. norouzy et al,(18) showed a significant difference in clinical presentation of renal colic during the first two weeks of ramadan compared to the other stages before and after this period. this increase-decrease pattern was the same in two different hospitals evaluated in this study, showing that possibly this is not a random finding. others however, could not find such relationship. instead, they found that the hot climate is much more likely than ramadan fasting itself to affect urolithiasis. 5. ignoring other possible factors: in the meantime, the effect of combining two or more risk-producing conditions on urinary stone disease has not been properly identified in the literature. as an instance, it is not clear whether ramadan fasting in summer and hot climate areas, would add an additional risk of stone formation to the risk attributed to the climate only? does coincidence of polycystic kidney disease, severe hypertension, diabetic nephropathy or different levels of chronic kidney disease plus fasting in ramadan, apply an additional risk of calculus formation to the kidneys? conclusions the effect of combining two or more risk-producing conditions on urinary stone disease has not been properly identified in the studies. due to the poor quality of the current literature as discussed, it is impossible to form a generalized opinion on whether fasting in ramadan affect the stone formation. for instance, it is not clear whether ramadan fasting in summer and hot climate areas, would add an additional risk of stone formation to the risk attributed to the climate only? does coincidence of polycystic kidney disease, severe hypertension, diabetic nephropathy or different levels of chronic kidney disease in addition to fasting in ramadan, apply an additional risk of calculus formation to the kidneys? this issues can be addresses in future studies. acknowledgement we hereby express our thankfulness to zahra golmarzi asl for her kind help. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/10 references 1. bernieh b, mohamed a, wafa a. ramadan fasting and renal transplant recipients: clinical and biochemical effects. saudi j kidney dis transpl. 1994;5:470-3. 2. kadri n, tilane a, el batal m, taltit y, tahiri sm, moussaoui d. irritability during the month of ramadan. psychosom med. 2000;62:280-5. 3. al-hourani hm, atoum mf. body composition, nutrient intake and physical activity patterns in young women during ramadan. singapore med j. 2007;48:906-10. 4. roky r, houti i, moussamih s, qotbi s, aadil n. physiological and chronobiological changes during ramadan intermittent fasting. ann nutr metab. 2004;48:296-303. 5. whitney e, rolfes s. planning a healthy diet. understanding nutrition, 11th ed.; thomson wadsworth: belmont, ca, usa. 200837-63. 6. imtiaz s, salman b, dhrolia mf, nasir k, abbas hn, ahmad a. clinical and biochemical parameters of hemodialysis patients before and during islamic month of ramadan. iran j kidney dis. 2016;10:75-8. 7. emami-naini a, roomizadeh p, baradaran a, abedini a, abtahi m. ramadan fasting and patients with renal diseases: a mini review of the literature. journal of research in medical sciences: the official journal of isfahan university of medical sciences. 2013;18:711. 8. el-wakil hs, desoky i, lotfy n, adam ag. fasting the month of ramadan by muslims: could it be injurious to their kidneys? saudi j kidney dis transpl. 2007;18:349. 9. siener r, hesse a. fluid intake and epidemiology of urolithiasis. eur j clin nutr. 2003;57:s47-s51. 10. al-hadramy ms. seasonal variations of urinary stone colic in arabia. j pak med assoc. 1997;47:281-3. 11. basiri a, moghaddam s, khoddam r, nejad s, hakimi a. monthly variations of urinary stone colic in iran and its relationship to the fasting month of ramadan. j pak med assoc. 2004;54:6-7. 12. miladipour ah, shakhssalim n, parvin m, azadvari m. effect of ramadan fasting on urinary risk factors for calculus formation. 2012. 13. emami-naini a, eshraghi a, shahidi s, et al. metabolic evaluation in patients with nephrolithiasis: a report from isfahan, iran. adv biomed res. 2012;1. 14. taha i. renal diseases and ramadan: a review of the literature. life science journal. 2013;10. 15. arrabal-polo ma, cano-garcia mdc, arrabal-martin m. lithogenic activity as a factor to consider in the metabolic evaluation of patients with calcium lithiasis. ijkd. 2015;9:469-71. 16. munn z, moola s, lisy k, riitano d, fasting and kidney stone-amjadi et al. review 369 vol 18 no 4 july-august 2021 370 tufanaru c. chapter 5: systematic reviews of prevalence and incidence. joanna briggs institute reviewer's manual. the joanna briggs institute. 201737. 17. moher d, liberati a, tetzlaff j, altman dg, group p. preferred reporting items for systematic reviews and meta-analyses: the prisma statement. plos med. 2009;6:e1000097. 18. abdolreza n, omalbanin a, mahdieh ts, et al. comparison of the number of patients admitted with renal colic during various stages of peri-ramadan month. saudi j kidney dis transpl. 2011;22:1199. 19. al mahayni ao, alkhateeb ss, abusaq ih, al mufarrih aa, jaafari mi, bawazir aa. does fasting in ramadan increase the risk of developing urinary stones? saudi med j. 2018;39:481. 20. cevik y, corbacioglu sk, cikrikci g, oncul v, emektar e. the effects of ramadan fasting on the number of renal colic visits to the emergency department. pak j med sci. 2016;32:18. 21. d’costa mr, haley we, mara kc, et al. symptomatic and radiographic manifestations of kidney stone recurrence and their prediction by risk factors: a prospective cohort study. j am soc nephrol. 2019;30:1251-60. fasting and kidney stone-amjadi et al. endourology and stone disease is rirs safe and efficient in patients with kidney stones who had previous open, endoscopic, or percutaneous kidney stone surgery? one center retrospective study burhan baylan1, sercan sarı2*, mehmet caglar cakıcı3, volkan selmi2, harun özdemir4, hakkı ugur ozok5, ahmet nihat karakoyunlu1, hikmet topaloglu1, azmi levent sagnak1,hamit ersoy1 purpose: in our study, we assessed the efficiency and reliability of retrograde intrarenal surgery secondary to open surgery for kidney stone treatment. moreover, we compared the efficiency and safety of retrograde intrarenal surgery for the patients with previous history of open surgery, percutaneous nephrolithotomy, secondary retrograde intrarenal surgery (rirs) and primary rirs. materials and methods: data was retrospectively reviewed. patients who had kidney anomalies, who had been stented due to ureteral stricture in the operation and who were < 18 years old, were excluded. there were 30 patients who underwent rirs secondary to open surgery. the demographic and stone characteristic as well as intraoperative and postoperative data of the patients were recorded. 30 patients with similar demographic and stone characteristics to those patients were selected by match pairing method from patients who had previous pnl, rirs history and had undergone primary rirs. a total of 120 patients, in total 4 groups, were included in the study. results: statistically significant difference was detected among the groups with regards to shock wave lithotripsy history and preoperative jj stent rate. there was no statistically significant difference in terms of stone characteristics, intraoperative and postoperative data. conclusion: rirs is an efficient and safe method for kidney stone treatment of the patients with previous history of open surgery, percutaneous nephrolithotomy and retrograde intrarenal surgery. it has a similar efficiency and safety for the patients who have undergone retrograde intrarenal surgery. this is the first study that compares the patients especially with different previous surgery methods. keywords: efficiency; kidney stone; previous surgery; retrograde intrarenal surgery; safety introduction urinary stone disease is a significant health problem affecting human health. kidney stone prevalence is 1-5% in general(1). shock wave lithotripsy (swl), percutaneous nephrolithotomy (pnl), open surgery and recently retrograde intra-renal surgery (rirs) are used for the treatment of kidney stones. by recently developing technology, certain improvements have been ensured for kidney stone treatment. non-invasive methods have replaced the invasive ones. despite significant decrease in preference for open surgery, it is still preferred for selected cases(2,3). usage of rirs has increased thanks to developing technology and increasing experience in recent times. efficiency of rirs for kidney stone treatment has been indicated in the studies(4). kidney stone may require repetitive surgical intervention subsequent to surgical treatment. fibrosis arising after open surgery and changing anatomy may decrease success(5). there are studies regarding percutaneous 1department of urology, university of health sciences, diskapi yildirim beyazit training and reserch hospital , ankara,turkey. 2department of urology, bozok university faculty of medicine,yozgat,turkey 3department of urology, medeniyet university, göztepe training and research hospital, istanbul,turkey. 4department of urology, avcılar state hospital, istanbul,turkey. 5department of urology, karabük university, faculty of medicine,karabük,turkey. *correspondence: bozok university, department of urology,yozgat, turkey. phone: +90 5356608838 fax: + 90 354 2127060. e-mail: sercansari92@hotmail.com. received november 2018 & accepted april 2019 nephrolithotomy after open surgery procedures for kidney stone treatment(6-8). although percutaneous nephrolithotomy is an efficient treatment method, life-threatening complications may be observed(9). there are a limited number of studies regarding usage of rirs following open surgery(10,11). there are studies regarding the factors affecting rirs success(12). its usage widened with the advanced technology(13). we planned the first study especially evaluating the effect of previous stone surgery on rirs safety and efficacy. in our study, we aimed to assess the efficiency and reliability of rirs secondary to open surgery for kidney stone treatment. moreover, we planned to compar the efficacy of rirs after previous open surgery, previous pnl and rirs and primary patients. materials and methods the data of the patients who had underwent rirs in our urology journal/vol 17 no. 3/ may-june 2020/ pp. 228-231. [doi: 10.22037/uj.v0i0.4950] clinic between 2012-2018 was reviewed retrospectively. to determine the effect of previous surgery history on rirs safety and efficacy, the records of the patients who had underwent rirs secondary to open surgery were evaluated. patients who had kidney anomalies, who had been stented due to ureteral stricture in the operation and who were < 18 years old, were excluded. there were 30 patients who had underwent rirs secondary to open surgery. the demographic and stone characteristics as well as intraoperative and postoperative data of the patients were recorded. 30 patients with similar demographic and stone characteristics to those patients were selected by match pairing from patients who had previous pnl, rirs history and had underwent primary rirs. the previous open surgery group was divided into groups according to stone size 5-10 mm, 11-15 mm, 16-20 mm, 21-25 mm, 26-30 mm, 3135 mm, 36-40 mm, 41-45 mm, 46-50mm, 51-55 mm. the same number of procedures were selected randomly from the other groups. the randomization was made similarly for the criterias such as stone laterality, stone number and stone localization. total 120 patients, in total 4 groups, were included in the study. all patients gave their informed consent for inclusion before they participated in the study. the study was conducted in accordance with the declaration of helsinki. preoperative routine blood biochemistry tests , complete blood count, coagulation profile and hepatic markers of the patients were analysed. preoperative urinary cultures of all patients were sterile. kidney ureter bladder graphy(kubg) , urinary system ultrasonography (us) and unenhanced computerized tomography (ct) were performed preoperatively. the longest stone diameter in imaging was defined as the stone size. in case of multiple stones, total of the longest diameters of each stone was defined as the stone size. all operations were performed under general anesthesia. preoperative single dose prophylactic antibiotic treatment was applied for the patients. the ureter was penetrated by placing a hydrophilic glidewire of 0.035/0.038 inch under fluoroscopy guidance by using semi-rigid ureteroscope at modified dorsal lithotomy position. ureteral access sheath(uas) (9.5/11.5 f or 11/13 f) (elite flex, ankara, turkey) was placed into the ureter down to the ureteropelvic junction via guidewire under fluoroscopy guidance. then, flexible ureteroscope (flex-x2, karl storz, tuttlingen, germany ) was moved through the uas. in case uas could not be placed, flexible ureteroscope was moved via hydrophilic guidewire and thus access to kidney was ensured. after finding the stone, lithotripsy was applied with 200μm holmium laser (ho yag laser; dornier medtech; munich, germany / dornier med-tech gmbh, medilas h20 and hsolvo, wessling, germany) thanks to a flexible ureteroscope. the methods of dusting and fragmentation were utilized. all calyxes were controlled at the end of the operation. subsequent to this operation, a jj stent was placed according to intraoperative conditions. the procedure was completed by placing a 16f foley catheter. in the postoperative first day, the urethral catheter was removed. following 3 weeks, jj stent was taken out under daily anaesthesia. time between starting to endoscopy and jj stent placing was defined as operation time. postoperative control was evaluated by kubg and us performed on the first postoperative day and unenhanced computerized tomography (ct) performed in the third postoperative month. the patients were followed-up for 3 months. after the controls carried out, patients who were stone free and who had residues <3 mm were accepted as successful. the intraoperative and postoperative data was recorded. the complications were recorded as per clavien dindo classification. the groups were compared in terms of efficiency and safety. statistical analysis analyse of data was performed with spss for windows 16.0 package program(spss,chicago). one sample kolmogorov smirnov test was performed to determine whether the distributions of the variables that have numerical values were normal. the distributions of the variables were not normal (p < .05) except age and body mass index (bmi). the comparisons between the groups were performed with one way anova test for the parameters with normal distribution. for the variables with non normal distribution such as stone number, stone size,operation time,scopy time and hospitalisation time, analyse between the groups were performed with kruskal wallis test. the analyse of the nominal varrirs safe and efficient in previous kidney stone surgery-baylan et al. table 1. demographics and stone characteristics of the studies patients group previous open surgery group previous pnl group previous rirs group primary p age(years)(±sd) 52.16 ± 12.31 49.9 ± 9.84 51.57 ± 11.29 50.5 ± 8.99 .843 gender(m/f)(n) 19/11 20/10 19/11 18/12 .962 bmi(kg/m2)(±sd) 29.2 ± 4.6 26.62 ± 3.77 29.76 ± 4.98 27.23 ± 2.54 .056 swl history (n, %) 9(30) 12 (40) 4 (13.32) 15(50) < .001 anticoagulant usage ( n,%) 0 1 (3.33) 0 0 .412 preoperative jj stent (n,%) 2(6.66) 7 (23.33) 18 (60) 0 < .001 stone laterality(r/l)(n) 14/16 15/13 15/13 11/18 .652 stone number(n)(±sd) 1.93 ± 0.26 1.96 ± 0.21 1.87 ± 0.15 1.80 ± 0.13 .887 stone size(mm) (±sd) 19.1 ± 11.94 19.2 ± 9.15 18.97 ± 5.81 19.67 ± 7.99 .579 stone localization (n,%) .917 upper calyx (n,%) 0 0 1 (3.33) 1 (3.33) lower calyx (n,%) 12 (40) 11 (36.67) 12 (40) 12 (40) mid calyx (n,%) 3 (9.99) 1 (3.33) 3 (9.99) 3 (9.99) pelvis (n,%) 7 (23.33) 4 (13.32) 7 (23.33) 7 (23.33) multicaliceal (n,%) 6 (20) 10 (33.33) 5 (16.65) 5 (16.65) proximal ureter(n,%) 2 (6.66) 4 (13.32) 2 (6.66) 2 (6.66) sd:standart deviation, m:male, f:female, bmi:body mass index, swl:shock wave lithotripsy mm:milimeter, r:right, l: left , pnl: percutaneous nephrolithotomy, rirs: retrograde intrarenal surgery vol 17 no 03 may-june 2020 229 iables such as gender, stone laterality, stone localization, uas usage, postoperative jj stent, success, swl history, preoperative jj stent, anticoagulant usage and complications was performed with pearson chi square test. p < .05 value was accepted as statistically significant for the results. results total 120 patients were included in our study. those who had underwent open surgery, pnl, rirs and primary treatment were divided into group 1, group 2, group 3 and group 4 respectively. in terms of demographic data, no statistically significant difference was found out among the groups with regards to the age, sex, bmi and anticoagulant usage. statistically significant difference was detected among the groups with regards to swl history and preoperative jj stent rate. (p < .001) (table 1) in terms of stone data, no statistically significant difference was revealed among the groups with reference to stone laterality, number, size and localization. (table 1) in terms of intraoperative data, no statistically significant difference was observed among the groups with regards to average operation and scopy time, use of jj stent postoperatively and uas. (table 2) in terms of postoperative data, no statistically significant difference was established among the groups with reference to success, hospitalization and complications (table 2) discussion significant changes have occurred in surgical treatment of kidney stone diseases(14). open surgery has been displaced to the methods such as rirs and pnl. stone disease is a morbidity that may show recurrence. it was found out via literature review that previous kidney stone surgery did not affect success of rirs(15). there are a limited number of studies regarding success of rirs after open surgery in the literature. in our study, we aimed to assess the efficiency and safety of rirs after open surgery that was performed for kidney stone treatment. moreover, we aimed to compare similar patients who had previous pnl and rirs histories and those for whom rirs was applied firstly. this is the first such study in the literature. in the literature, there are 2 studies which assess rirs success after open surgery performed for kidney stone treatment. in one of these studies, 53 patients who had underwent rirs and had an open surgery history for kidney stone were evaluated. in the other study, 38 primary patients with the same characteristics were compared to 32 patients who had underwent rirs and had an open surgery history for kidney stone. the average operation times were reported to be 79.5 ± 37.8 minutes and 82 minutes(10,11), respectively. in our study, the average operation time was 47.33 ± 19.33 minutes. in our study, average stone number and stone size of the patients who had underwent open surgery were 1.93 ± 0.26 and 19.1 ± 11.94 mm, respectively. while average stone number was respectively 3 and 2.7±1.5 in the studies in the literature, average stone size was 14.3mm and 25.4 ± 14.7mm , respectively. while the rate of uas usage was 86.67% in the group that underwent open surgery, the rate of postoperative jj stent usage was 93.33%. on the other hand, the rate of uas usage was 77% and 95% and the rate of postoperative jj stent usage was 100% and 71% respectively in the reviewed studies(10,11). in terms of success rate, it was 76.67% for the group that had underwent open surgery in our study. in the other studies, it was reported as 79.2% and 82%. complications were observed in 20.7% and 17% of the patients in the aforementioned studies in the literature(10,11). in our study, complication was observed in 1 patient in the group that underwent open surgery. in our study, the patients who had previous open surgery, pnl and rirs were compared to those who had underwent rirs firstly. the demographic and stone characteristics of the patients were similar. no statistically significant difference was observed between sucendourology and stones diseases 126 table 2. intraoperative and postoperative data of the groups group previous group previous group previous group primary p open surgery pnl rirs average operation time(min.) (±sd) 47.33 ± 19.33 56.67 ± 28.81 61.67 ± 27 52.53 ± 14.84 .157 average scopy time (sc.) (±sd) 26.17 ± 18.08 56.40 ± 18.25 32.2 ± 26.73 39.4 ± 29.19 .170 postoperative jj stent, n (%) 28 (93.33) 28(93.33) 30(100) 25(83.33) .106 ureteral access sheath usage , n (%) 26 (86.67) 24(80) 27(90) 29(96.67) .240 average hospitalisation time(±sd) (day) 1 1 2,55 ± 1.47 1 .392 success , (n) (%) 23 (76.67) 19(63.33) 19(63.33) 24(80) .341 stone-free , (n) (%) 23 (76.67) 18(60) 18(60) 21(70) residuel fragment (<3mm) , (n) (%) 0 1(3.33) 1(3.33) 3(10) residuel fragment (≥3mm), (n) (%) 7(23.33) 11(36.67) 11(36.67) 6(20) complication rate , n (%) 1(3.33) 7(23.33) 3(10) 4(13.32) .126 intraoperative complication, (n) (%) 1(3.33) 2(6.66) 1(3.33) 3(10) mucosal injury, n (%) 1(3.33) 1(3.33) 1(3.33) 3(10) bleeding , n (%) 0 1(3.33) 0 0 postoperative complication , n (%) 0 7(23.33) 2(6.66) 1(3.33) fever (clavien i) , n (%) 0 7(23.33) 0 0 bleeding (clavien i) , n (%) 0 4(13.32) 0 0 urinary tract infection (clavien ii) , n (%) 0 0 1(3.33) perirenal hematom(clavien 3a), n(%) 0 1(3.33) 0 0 steinstrasse(clavien iiib), n (%) 0 2(6.66) 2(6.66) 0 abbreviations: min:minute, sc: second, sd:standart deviation, mm:milimeter, , pnl: percutaneous nephrolithotomy, rirs: retrograde intrarenal surger rirs safe and efficient in previous kidney stone surgery-baylan et al. endourology and stones diseases 230 cess and complication rates of the patients. the developments in laser and flexible renoscopes and increasing experience may explain these findings. similar results were revealed in the studies researching rirs success and complications, too(16-17). our study is the first one in the literature that compares the patients with similar demographic and kidney stone characteristics who had previous different surgical methods and had underwent rirs first time. the limiting factors of our study are its retrospective design and limited number of patients. we need studies designed with larger number of patients and in a prospective design. conclusions rirs is an efficient and safe method for kidney stone treatment of the patients with previous history of open surgery, pnl and rirs. it has a similar efficiency and safety for the patients who had underwent rirs firstly. conflict of interest there is no conflict of declared by the authors. references 1. menon m, resnick mi. urinary lithiasis: etiology, diagnosis, and medical management. campbell’s urology, editor-in-chief: patrick c. walsh. sounders, 2002, 8. edition, part 96. 2. honeck p, wendt ng, krombach p et al., “does open stone surgery still play a role in the treatment of urolithiasis?data of a primary urolithiasis center,” j endourol,2009, 23:1209–1212. 3. paik ml, resnick mi.is there a role for open stone surgery?urol clin north am 2000, 27:323–331 4. wendt ng, mut t, krombach p, michel ms, knoll t. do new generation flexible ureterorenoscopes offer a higher treatment success than their predecessors? urol res. 2011;39:185–8. 5. margel d, lifshitz da,kugel v,dorfmann d, lask d, and livne pm, “percutaneous nephrolithotomy in patients who previously underwent open nephrolithotomy,” j endourol, 2005,19: 1161–1164. 6. sofikerim m , demirci d, gulmez i, karacagil m, “does previous open nephrolithotomy affect the outcome of percutaneous nephrolithotomy?” j endourol, 2007,21: 401– 403. 7. lojanapiwat b, “previous open nephrolithotomy: does it affect percutaneous nephrolithotomy techniques and outcome?” j endourol, 2006,20:17–20. 8. gupta r, gupta a, singh g,suri a,mohan sk, gupta cl, “pcnl a comparative study in nonoperated and in previously operated (open nephrolithotomy/pyelolithotomy) patients—a single surgeon experience,” int braz j uro, 2011,37:739–744. 9. kim sc, kuo rl, lingeman je, “percutaneous nephrolithotomy: an update,” cur opp in uro,2003, 13:235–241. 10. osman, m.m., gamal, w.m., gadelmoula, m.m. et al. urol res ,2012, 40: 403. 11. alkan e, saribacak a, ozkanli ao, baιar mm, acar o, balbay md. retrograde intrarenal surgery in patients who previously underwent open renal stone surgery. min inv sur. 2015;2015:198765. 12. sari s, ozok hu, topaloglu h, et al. the association of a number of anatomical factors with the success of retrograde intrarenal surgery in lower calyceal stones. urol j. 2017 jul 2;14:4008-4014. 14. javanmard b, kashi ah, mazloomfard mm, ansari jafari a, arefanian s . retrograde intrarenal surgery versus shock wave lithotripsy for renal stones smaller than 2 cm: a randomized clinical trial. urol j. 2016 ;13:2823-2828. 16. kerbl k, rehman j, landman j, lee d, sundaram c, clayman rv. current management of urolithiasis: progress or regress? j endourol 2002,16:281–288 17. resorlu b, unsal a, gulec h, oztuna d .a new scoring system for predicting stone-free rate after retrograde intrarenal surgery: the “resorlu-unsal stone score” urology ,2012, 80 : 512 518 18. tonyalı s, yılmaz m, karaaslan m, ceylan c, işıkay l. prediction of stone-free status after single-session retrograde intrarenal surgery for renal stones. turk j urol 2018; 44: 473-7. 19. baş, o., tuygun, c., dede, o. et al. world j urol ,2017, 35: 819. rirs safe and efficient in previous kidney stone surgery-baylan et al. vol 17 no 03 may-june 2020 231 urol_montage.pdf review 1urology journal vol 6 no 1 winter 2009 penile revascularization for erectile dysfunction a systematic review and meta-analysis of effectiveness and complications ali reza babaei,1 mohammad reza safarinejad,2 ali asghar kolahi3 introduction: patients with arteriogenic erectile dysfunction (ed) caused by traumatic localized arterial lesions can be treated successfully by penile revascularization (pr) surgery. we aimed to determine the subjective and objective outcomes of pr surgery in patients with arteriogenic ed. materials and methods: we searched for relevant publications released up to may 2008 in the cochrane central register of controlled trials, medline, embase, and biological abstracts. the citation lists of review articles and included trials were also searched. studies on different operative techniques of pr for men with ed due to traumatic penile arterial lesions were selected. data on participants’ characteristics, study quality, population, intervention, cure, and adverse effects were collected and analyzed. results: there were 25 studies on comparison of the pr operative techniques. concerning subjective cure, men younger than 30 years old had better results than older ones (odds ratio, 3.7; 95% confidence interval, 2.2 to 6.4; p = .001). venous leak (odds ratio, 1.8; 95% confidence interval, 1.2 to 2.6) and history of smoking (odds ratio, 3.4; 95% confidence interval, 2.2 to 5.6) influenced success rate. inconsistent measurements of outcomes limited the findings, and none of the studies were randomized controlled trials. conclusion: traumatic patients with arteriogenic ed might benefit from pr. patient selection is vital for a successful outcome. variations in penile vascular anatomy are also likely to be important when individualizing penile revascularization. in a limited number of highly selected individuals, pr can be successful for the long-term. randomized controlled trials examining pr techniques are warranted. urol j. 2009;6:1-7. www.uj.unrc.ir keywords: penis surgery, erectile dysfunction, vasculogenic impotence, penis blood supply, treatment outcome, meta-analysis 1department of plastic surgery, aja university of medical sciences, tehran, iran 2urology and nephrology research center, shahid beheshti university (mc), tehran, iran 3department of community medicine, shahid beheshti university (mc), tehran, iran corresponding author: mohammad reza safarinejad, md po box 19395-1849, tehran, iran tel: +98 21 2245 4499 fax: +98 21 2245 6845 e-mail: safarinejad@unrc.ir introduction background the first penile revascularization (pr) surgery was reported in 1972 by michal and colleagues.(1) one decade later, crespo and colleagues reported a 76% subjective success rate after arterio-arterial anastomosis in a large series of 257 patients,(2) and virag reported that 74.9% of their patients were content after deep dorsal vein arterialization.(3) thereafter, the indication criteria and surgical mode had largely been established by late 1990s. penile blood flow depends on the internal pudendal arteries, which are branches of the internal iliac arteries. the internal pudendal artery courses within the pudendal canal and is at risk of injury with fracture of the inferior pubic ramus.(4) the internal penile revascularization for erectile dysfunction—babaei et al 2 urology journal vol 6 no 1 winter 2009 pudendal arteries are often likely to be injured when the patient falls astride an object. any other arterial diseases reducing blood supply to the penis, both in flow and pressure, can lead to disturbances of erection. this is true for lesions of the hypogastric as well as smaller vessels such as the penile arteries.(5,6) erection is a complex physiological process in which vascular factors play a pre-eminent role. therapeutic options for men with arteriogenic erectile dysfunction (ed) are mainly administration of phosphodiesterase type 5 inhibitors, intracavernous injections of vasoactive agents (for example, prostaglandin el, papaverine/phentolamine, or triple drug), intraurethral administration of prostaglandin el, and administration of centrally acting drugs.(7,8) however, all of these methods circumvent the patient’s problem temporarily, and patients are not cured of impotence, remained dependent on these treatments for the remainder of their sexually active lives. we need an effective treatment that cures the problem permanently. penile revascularization is a treatment option for such patients. the preliminary results of pr surgeries seemed promising, and these treatment options have gained popularity. however, the long-term outcome has not been as good as expected. many techniques of pr have been used for the treatment of arteriogenic ed.(9,10) most of these vascular reconstructions use the inferior epigastric artery (iea). surgical techniques for pr are divided into 3 groups: venous arterialization, arteriovenous shunting, and arterio-arterial shunting.(11-16) information concerning the relative effectiveness, safety, acceptability, and costs of these different pr techniques is vital for decision making by both physicians and patients. however, the majority of studies to date are retrospective case series. these studies are problematic as they may underestimate failure rates for a number of reasons, including lower failure rates observed by experienced surgeons and short-term followup periods. we conducted a systematic review of the medical literature to evaluate the efficacy and safety of pr in the treatment of arteriogenic ed, and summed the influencing factors on the outcomes up by meta-analysis. objectives this review aimed to look at the short-term and long-term benefits of pr surgery. we also examined factors responsible for failure, including diabetes mellitus, smoking, alcoholism, general arteriosclerosis, obesity, coronary heart disease, hyperlipidemia, arterial hypertension, patient age at the time of surgery, and the surgical technique. finally, we attempted to provide the selection criteria for better patient selection. the outcomes identified were primarily related to subjective and objective improvements in ed and the duration of improvement. the following hypotheses were to be addressed: (1) pr surgery cures arteriogenic ed; (2) different surgical techniques have different long term results; (3) pr surgery is better than pharmacological interventions; (4) highly selected patients benefit more from pr surgery; and (5) intracavernosal injection of vasoactive drugs combined with pr surgery is better than pr alone. materials and methods criteria for selecting articles type of study. due to the lack of randomized controlled trials on this topic, nonrandomized comparative studies (where participants were their own controls) were selected for review. participants. men with arteriogenic ed due to trauma were considered. intervention. the primary intervention that this review was concerned with was pr surgery. outcome measures. the main outcome measure was satisfactory intercourse without additional therapy. secondary outcomes included duration of favorable response, overall satisfaction rate, quality-of-life outcome measures, and intervention-related complications. nonresponders to pharmacotherapy showing response after surgery were classified as having a partial success. search methods the following mesh terms and text words penile revascularization for erectile dysfunction—babaei et al urology journal vol 6 no 1 winter 2009 3 were used: impotence, erectile dysfunction, penile, revascularization, treatment, arteriogenic, and vasculogenic. our search strategy included an electronic search of the medline, confined to a period from 1966 to may 2008, to identify all relevant published studies on pr. we also searched the cochrane central register of controlled trials (the cochrane library 2007, issue 4), the embase (1980 to may 2008), and the biological abstracts (1980 to may 2008). the reference lists of the identified studies was checked for additional citations. in addition, information on the ongoing clinical trials was sought by searching the clinical trials registry web site of the national institute of health (http:// www.clinicaltrials.gov). no language restriction was considered in our search strategy. review methods the literature search results were screened, and by consensus among the authors, relevant articles were retrieved. data was extracted from each identified paper and included information on study design, participants, type of pr, and outcome measures. as there were no randomized trials identified, when the study fulfilled the inclusion criteria, data concerning methods of the trial, participant characteristics, intervention details, and outcome measures were independently extracted using a standard extraction form. the identified articles were selected for inclusion in the review on the basis of appropriateness as determined by at least 2 of the authors without prior consideration of the results. as no quantitative synthesis could be done, it was not possible to carry out any sensitivity analyses to assess the effects of differences in methodological quality. some studies had multiple publications; these were treated as a single source of data. the data were analyzed in the review manager 4.2.8 software (revman 4.2.8, cochrane library, oxford, uk). description of studies search results. the search criteria identified 64 studies. a total of 18 studies did not meet our inclusion criteria and were excluded. all the remaining 46 studies involved patients who had undergone some form of pr. in 4 studies, laparoscopy had been used for pr.(17-20) none of these studies described the experience level of the surgeons. types of interventions. an extensive workup is done for each patient prior to pr. the extent and types of workup varied in different studies. however, the mainstay of the workup included full examination and a series of laboratory tests. the examination included medical and sexual history and psychiatric examination. laboratory testing consisted of hormonal evaluation (folliclestimulating hormone, luteinizing hormone, thyroid hormones, testosterone, prolactin), nocturnal penile tumescence with or without the erectometry test, duplex ultrasonography with periodic measurement of hemodynamic parameters, color doppler ultrasonography, duplex doppler ultrasonography, dynamic infusion pharmacologic cavernosometry and cavernosography, and selective internal pudendal arteriography or digital subtraction angiography. penile revascularization surgery is usually done in patients younger than 50 years. various techniques are used. the iea is used to establish new arterial blood flow for most penile revascularization techniques.(21,22) the following techniques were reported in the selected articles: (1) end-to-end anastomosis of the iea to the dorsal artery in various modifications(23,24); (2) anastomosis of the iea to the deep dorsal vein at the base of the penis (virag procedures),(25) with a few modifications without (virag i-iii, furlow-fisher, lewis) or with creation of a surgical direct anastomosis to the cavernous bodies (virag iv-vi)(26); (3) direct anastomosis of the iea to the cavernosal artery(15); (4) hauri triple anastomosis, consisting of a triple anastomosis between the dorsal penile vein and dorsal penile artery (side-to-side) with the iea (end-to-side)(27); (5) modified version of the original hauri technique in which the dorsal penile artery is cut completely and 3 separate end-to-side anastomoses are constructed(23); and (6) furlowfisher modification of the virag v procedure.(28) results the studies explicitly excluded men with other penile revascularization for erectile dysfunction—babaei et al 4 urology journal vol 6 no 1 winter 2009 types of ed; therefore, the effects of the pr could be applied to men with arteriogenic ed. the definitions of improvement in ed varied across studies from perception of self-reported improvement to objective assessment of penile erection. none of the studies had the same design, making head-to-head comparisons difficult. although the era of microsurgical techniques has greatly expanded the number of possible solutions for pr, techniques selected (type of anastomosis) for pr and the experience of the surgeon who will do this are essential for successful pr. there was clinical heterogeneity regarding the patients’ demographics at baseline, type of recruitment and surgical technique, definition of success, and ancillary treatments. the wide range of success definitions and high failure rates also mean that the groups of the studied people differed. the success rate of penile revascularization was associated with various risk factors, including patient’s age, diabetes mellitus, smoking, alcoholism, obesity, hyperlipidemia, hypertension, preoperative arteriographic findings, surgical technique, and surgeon’s experience. the main risk factors of failure in pr were smoking, diabetes mellitus, hypertension, hyperlipidemia, radiation, coronary heart disease, alcoholism, obesity, cavernosal fibrosis, and distal arteriogenic disease. penile vascular architecture is a predominant factor in decision making. patients who do not respond to intracavernous injection therapy have irreversible degenerative changes in the cavernous smooth muscle.(29) the overall success rate of pr was about 50% after a mean follow-up period of 50 months,(12) of whom 30% had experiened spontaneous erections and 20% had pharmacologically induced erections (partial response). long-term failure had been reported in about 50% of the men. surgical complication rate was approximately 30%. thrombosis, hyperemia of the glans, and priapism were the common complications of pr. there was a strong correlation between success and the elapsed time from the operation (odds ratio [or], 3.6; 95% confidence interval [ci], 2.8 to 5.6). the success rate in all series tended to diminish as follow-up period increased. the success rate in the nonsmokers was twice as high as that in the smokers (or, 3.4; 95% ci, 2.2 to 5.6). the presence of venous leak (or, 1.8; 95% ci, 1.2 to 2.6) and type of procedure (or, 2.8; 95% ci, 1.6 to 4.6) had a significant impact on success rate (p = .03 and p = .01, respectively). the impact of age was greatest; patients younger than 30 years old showed better success rates than the older ones (or, 3.7; 95% ci, 2.2 to 6.4; p = .001). anticoagulants, usually aspirin, are recommended for 6 months after the operation. a patent microvascular anastomosis can be documented postoperatively by selective internal iliac arteriography. the surgical procedure for pr should be determined according to the anatomical variation of the penile artery and the pattern of arterial obstruction. discussion to the best of our knowledge, this systematic review with the data that were used summarizes all the studies that exist on this topic. there were several strengths and limitations in this review. the search was thorough and systematic without language restrictions. two reviewers independently performed the study selection and data extraction to minimize errors. no trials were identified examining various surgical techniques in various patients groups. no controlled clinical trials examining various surgical techniques have been conducted to date. variations in populations, interventions, and outcome measures, rather than study quality, resulted in heterogeneity between studies. selection criteria varied for the same interventions. pooling analysis was questionable because of clinical and methodological differences across the studies included in the present report. future research is required to determine predictors of the long-term curative effects of pr in men from different age and etiologic groups. despite extensive efforts to standardize outcome assessment for ed, the included studies measured a variety of outcomes, including self-reported symptoms and improvement and severity of ed. the measurement of outcomes was inconsistent within and across the studies. since the first report of pr by michal and coworkers in 1973,(1) several modifications have been made and the outcome of this surgery penile revascularization for erectile dysfunction—babaei et al urology journal vol 6 no 1 winter 2009 5 has been improved significantly and reached a level sufficient for general consideration.(23) currently, the only feasible cure of arteriogenic ed is pr.(15,23-25) success rates are difficult to compare because of varying definitions of success, different patients’ demographics, and different risk factors. some physicians perform pr only in patients who respond to intracavernous injection of vasoactive drugs, and others do so only in nonresponders.(30,31) there are multiple reasons for failure of pr. the most common causes of failed pr are inappropriate patient selection and misdiagnosis. selective angiography of the hypogastric arteries and their branches is essential to evaluate potential candidates for pr. patient history, physical examination, and even selective angiography of the hypogastric arteries are not always accurate indicators of a vasculogenic etiology.(32) after pelvic fracture, it is impossible to be certain whether a patient with vasculogenic impotence does not have a concomitant cavernosal nerve injury. color and power doppler ultrasound technology have greatly enhanced the capacity to study hemodynamics and penile vascular anatomy.(33-36) the patency of the whole length of cavernous artery and individual anatomical variations should also be examined. the traditional assessment without a detailed study of cavernous arterial anatomy can result in unsuccessful pr. variations in penile vascular anatomy should also be considered when individualizing pr procedures. the anatomical variations of the penile artery are common.(37) deep dorsal vein arterialization surgery for arteriogenic ed was introduced by virag and colleagues,(38) and then, it was modified by furlow and associates.(28) in the technique of end-to-end anastomosis of the iea to the dorsal artery, the major obstacle is discrepancy of the lumina between the iea and the dorsal artery. this can result in low flow rates, which is susceptible to stasis and thrombosis. later in 1986, creation of an anastomosis between the iea and the deep dorsal vein and the dorsal artery of the penis was introduced by hauri.(39) patient selection is vital for a successful outcome in pr. patients with the following criteria have had better outcomes: an age less than 30 years; fewer than 2 risk factors; and no history of smoking, diabetes mellitus, hypertension, or hyperlipidaemia. in highly selected patients, pr can be successful for more than 10 years.(40) in a population-based study, after adjusting for the strong effect of age on the incident of ed, men with diabetes mellitus, hypertension, peripheral vascular disorders, hypercholesterolemia, and coronary artery disease had a significant increase in the risk of ed.(41) ideal candidates for pr are young patients (younger than 30 years) with discrete arterial insufficiency (pudendal, common penile, or cavernous arteries) resulting from trauma-induced arterial occlusive disease and without significant concomitants risk factors. patients with significant risk factors are poor candidates for pr and they should be encouraged to consider other options for treatment of impotence.(42) in diabetic men, the response rate to sildenafil is lower.(43) in the workup of patients with vasculogenic ed, both functional and anatomic evaluation of penile arterial blood flow is essential. duplex ultrasonography is an excellent screening modality to evaluate intrapenile anatomy and the functional parameters of the cavernous and dorsal arteries. the operative risk of patients being evaluated for pr procedures should be carefully assessed and the concomitant risk factors should be minimized. when there are communicating branches between the dorsal and cavernosal arteries, hauri procedure is a better option. the technique should be individualized depending on the pathological findings in each case. where possible, physiological revascularization procedures are preferred. to prevent priapism, the inflow should be connected to the dorsal vein rather than implanted into the corpus cavernosum.(23,44) hyperemia of the glans is due to dorsal vein arterialization that can cause pain, skin ulceration, and urethral compression.(23,45) to harvest the iea, a long pararectal incision is necessary. this can cause some problems, such as cosmetic issues, postoperative pain, long hospitalization, and hernia formation.(9,46) to resolve these problems, laparoscopic-assisted mobilization of the iea and microsurgical pr can be used.(19,20) laparoscopy penile revascularization for erectile dysfunction—babaei et al 6 urology journal vol 6 no 1 winter 2009 provides many benefits, including decreased postoperative pain, reduced hospitalization and recovery time, and better cosmetic outcomes. meticulous microsurgical techniques are essential for completing patent microanastomoses. with the exception of direct anastomosis of the iea to the corpus cavernosum, other surgical techniques are currently used for surgical treatment of vasculogenic ed. extensive vascular evaluation is necessary to define fully the exact nature of the injury. as standardized criteria for patient selection, follow-up protocol and success definition have yet to be identified. conclusion implications for practice penile revascularization can successfully treat ed in selected patients with vasculogenic ed. high-quality trials regarding pr are unavailable. practitioners should bear in mind that greater experience in a revascularization technique is associated with higher rates of pr success. implications for research since these results are based on small studies, the evidence would be stronger if confirmed by large trials. effectiveness data were limited; however, the effectiveness of pr is largely determined by the patient selection criteria rather than the surgical technique. in addition, work is needed in the standardization of follow-up protocols, evaluation of pr success and failure, patient selection, and statistical analysis. randomized trials comparing various surgical techniques are warranted. these studies should evaluate efficacy, complications, quality of life, cost implications, and long-term outcomes of pr surgeries. acknowledgment we wish to thank dr farhat farrokhi, who assisted in preparing the manuscript. conflict of interest none declared. references 1. michal v, kramar r, pospichal j. femoro-pudendal by-pass, internal iliac thromboendarterectomy and direct arterial anastomosis to the cavernous body in the treatment of erectile impotence. bull soc int chir. 1974;33:343-50. 2. crespo e, soltanik e, bove d, farrell g. treatment of vasculogenic sexual impotence by revascularizing cavernous and/or dorsal arteries using microvascular techniques. urology. 1982;20:271-5. 3. virag r. revascularization of the penis. in: bennett ah, editor. management of male impotence. baltimore: williams & wilkins; 1982. p. 219-33. 4. goldstein i, hartzichristou dg, pescatori es. pelvic, perineal, and penile trauma-associated arteriogenic impotence: pathophysiologic mechanisms and the role of microvascular arterial bypass surgery. in: bennett ah, editor. impotence: diagnosis and management of erectile dysfunction. philadelphia: wb saunders; 1994. p. 213-28. 5. newman hf, northup jd, devlin j. mechanism of human penile erection. invest urol. 1964;1:350-3. 6. vial y, magrini g, ruedi b. [multidisciplinary approach to male impotence due to erectile dysfunction]. rev med suisse romande. 1986;106:1013-9. french. 7. safarinejad mr, hosseini sy. salvage of sildenafil failures with bremelanotide: a randomized, doubleblind, placebo controlled study. j urol. 2008;179:106671. 8. safarinejad mr. salvage of sildenafil failures with cabergoline: a randomized, double-blind, placebocontrolled study. int j impot res. 2006;18:550-8. 9. cookson ms, phillips dl, huff me, fitch wp, 3rd. analysis of microsurgical penile revascularization results by etiology of impotence. j urol. 1993;149:1308-12. 10. goldstein i. arterial revascularization procedures. semin urol. 1986;4:252-8. 11. virag r, zwang g, dermange h, legman m. vasculogenic impotence: a review of 92 cases with 54 surgical operations. vasc surg. 1981;15:9-11. 12. virag r, bennett ah. arterial and venous surgery for vasculogenic impotence: a combined french and american experience. arch ital urol nefrol androl. 1991;63:95-100. 13. michal v, kramar r, pospichal j, hejhal l. arterial epigastricocavernous anastomosis for the treatment of sexual impotence. world j surg. 1977;1:515-9. 14. crespo el, bove d, farrell c. microvascular surgery technique and follow-up. vasc surg. 1987;21:277-31. 15. konnak jw, ohl da. microsurgical penile revascularization using the central corporeal penile artery. j urol. 1989;142:305-8. 16. austoni e, colombo f, mantovani f. arteriogenic impotence:long-term follow-up in 68 patients treated by end-to-end epigastro-dorsal ortho and antiflow double anastomosis. in: giuliani l, puppo p, editors. urology. bologna (italy): monduzzi editore; 1992. p. 805. 17. hatzinger m, seemann o, grenacher l, rassweiler j. laparoscopy-assisted penile revascularization: a new method. j endourol. 1997;11:269-72. penile revascularization for erectile dysfunction—babaei et al urology journal vol 6 no 1 winter 2009 7 18. moon yt, kim sc. laparoscopic mobilization of the inferior epigastric artery for penile revascularization in vasculogenic impotence. j korean med sci. 1997;12:240-3. 19. trombetta c, liguori g, siracusano s, savoca g, belgrano e. laparoscopically assisted penile revascularization for vasculogenic impotence: 2 additional cases. j urol. 1997;158:1783-6. 20. lund go, winfield hn, donovan jf. laparoscopically assisted penile revascularization for vasculogenic impotence. j urol. 1995;153:1923-6. 21. lizza ef, zorgniotti aw. experience with the long-term effect of microsurgical penile revascularization. int j impot res. 1994;6:145-52. 22. munarriz rm, yan qr, a zn, udelson d, goldstein i. blunt trauma: the pathophysiology of hemodynamic injury leading to erectile dysfunction. j urol. 1995;153:1831-40. 23. manning m, junemann kp, scheepe jr, braun p, krautschick a, alken p. long-term followup and selection criteria for penile revascularization in erectile failure. j urol. 1998;160:1680-4. 24. zumbe j, drawz g, wiedemann a, grozinger k, engelmann u. indications for penile revascularization and long-term results. andrologia. 1999;31 suppl 1:83-7. 25. virag r, bennett ah. arterial and venous surgery for vasculogenic impotence: a combined french and american experience. arch ital urol nefrol androl. 1991;63:95-100. 26. sohn mh. current status of penile revascularization for the treatment of male erectile dysfunction. j androl. 1994;15:183-6. 27. hauri d. therapiemoglichkeitem bei der vascular bedingten erectilein impotenz. akt urol. 1984;15:350. 28. furlow wl, fisher j, knoll ld. penile revascularization: experience with deep dorsal vein arterialization: the furlow-fisher modification with 27 patients. in: proceedings of the third biennial world meeting on impotence. boston: international society of impotence research, 1988. 29. persson c, diederichs w, lue tf, et al. correlation of altered penile ultrastructure with clinical arterial evaluation. j urol. 1989;142:1462-8. 30. sohn m, sikora r, deutz fj, bohndorf k, gunther r. [selective microsurgical therapy in vascular-induced erectile impotence]. urologe a. 1988;27:164-72. german. 31. hauri d. [surgical possibilities in treatment of vascular-induced erectile impotence]. urologe a. 1989;28:260-5. german. 32. cormio l, nisen h, selvaggi fp, ruutu m. a positive pharmacological erection test does not rule out arteriogenic erectile dysfunction. j urol. 1996;156:1628-30. 33. chiou rk, pomeroy bd, chen ws, anderson jc, wobig rk, taylor rj. hemodynamic patterns of pharmacologically induced erection: evaluation by color doppler sonography. j urol. 1998;159:109-12. 34. sarteschi lm, montorsi f, fabris fm, guazzoni g, lencioni r, rigatti p. cavernous arterial and arteriolar circulation in patients with erectile dysfunction: a power doppler study. j urol. 1998;159:428-32. 35. chiou rk, pomeroy bd. erectile dysfunction: using color doppler ultrasound hemodynamic studies for evaluation. contemp urol. 1998;10:87-101. 36. mukherji sk. the american society of head and neck radiology. head and neck imaging: the next 10 years. radiology. 1998;209:8-14. 37. martinez-pineiro l, julve e, martinez-pineiro ja. topographical anatomy of the penile arteries. br j urol. 1997;80:463-7. 38. virag r, zwang g, dermange h, legman m, penven jp. [investigation and surgical treatment of vasculogenic impotency (author‘s transl)]. j mal vasc. 1980;5:205-9. french. 39. hauri d. a new operative technique in vasculogenic impotence. world j urol. 1986;4:237-49. 40. vardi y, gruenwald i, gedalia u, nassar s, engel a, har-shai y. evaluation of penile revascularization for erectile dysfunction: a 10-year follow-up. int j impot res. 2004;16:181-6. 41. safarinejad mr. prevalence and risk factors for erectile dysfunction in a population-based study in iran. int j impot res. 2003;15:246-52. 42. hatzichristou dg, goldstein, i. arterial by-pass surgery for impotence. curr opin urol. 1991;1:114-8. 43. safarinejad mr. oral sildenafil in the treatment of erectile dysfunction in diabetic men: a randomized double-blind and placebo-controlled study. j diabetes complications. 2004;18:205-10. 44. michal v, kramar r, pospichal j, hejhal l. [direct arterial anastomosis on corpora cavernosa penis in the therapy of erective impotence]. rozhl chir. 1973;52:587-90. czech. 45. wolf js, jr., lue tf. high-flow priapism and glans hypervascularization following deep dorsal vein arterialization for vasculogenic impotence. urol int. 1992;49:227-9. 46. sarramon jp, janssen t, rischmann p, bennis s, malavaud b. deep dorsal vein arterialization in vascular impotence. eur urol. 1994;25:29-33. review 141urology journal vol 7 no 3 summer 2010 mixed epithelial and stromal tumor of the kidney or adult mesoblastic nephroma an update mohammad kazem moslemi purpose: our aim was to review the spectrum of usual and unusual clinical and morphologic findings observed in mixed epithelial and stromal tumor of the kidney (mest). materials and methods: on the basis of medline database searches, we assessed all aspects of mest or adult mesoblastic nephroma since the first report in 1997 till the end of 2009. results: mixed epithelial and stromal tumor is a relatively rare and distinct neoplasm of the kidney that should be distinguished from other renal neoplasms. although the overall prognosis is favorable, recurrence and malignant transformation of mest can occur conclusion: it is difficult to distinguish benign or malignant nature on imaging studies. urol j. 2010;7:141-7. www.uj.unrc.ir keywords: mesoblastic nephroma, renal cell carcinoma, diagnosis, pathology department of urology, kamkar hospital, qom university of medical sciences, qom, iran corresponding author: mohammad kazem moslemi, md department of urology, kamkar hospital, qom university of medical sciences, qom, iran tel: +98 912 252 1646 fax: +98 251 771 3473 e-mail: moslemi@muq.ac.ir received april 2010 accepted may 2010 introduction background classification of kidney tumors in adults expands rapidly with new categories recently being incorporated. a number of recently described and unusual entities such as familial renal cell carcinoma (rcc), translocation rcc, rcc after neuroblastoma, tubular mucinous and spindle cell carcinoma, and mixed epithelial and stromal tumors (mests) have been presented.(1) the term of “renal epithelial and stromal tumor” has been proposed to encompass cystic nephroma and mixed epithelial and stromal tumor of the kidney.(2) mixed epithelial and stromal tumor is a rare complex renal neoplasm composed of a mixture of cystic and solid components. it was originally described in 1993 by pawade and colleagues as cystic hamartoma of the renal pelvis. (3) the term of “mixed epithelial and stromal tumor of the kidney” was proposed by michal and syrucek. (4) other names such as adult mesoblastic nephroma (mn), leiomyomatous renal hamartoma, solid and cystic biphasic tumor, and cystic hamartoma of the renal pelvis have also been used. mesoblastic nephroma is an uncommon, distinctive renal tumor reported in infants. it is a special type of nephroblastoma that rarely occurs in adults. mesoblastic nephroma was first described by block and colleagues in adults in 1973,(5) but it is the most frequent renal tumor during the first year of life and the most frequent benign renal tumor in the mesoblastic nephroma—moslemi 142 urology journal vol 7 no 3 summer 2010 childhood. in children, mn is non-metastatic, well differentiated, amenable to surgical removal, and carries a good prognosis, but its origin is under debate. wigger regarded mn as a hamartoma,(6) while bolande believed it originated from the renal blastema.(7) more recently, it was regarded as a tumor of the collecting ducts, but this has been shown to be untrue in a study by daniel and associates.(8) mesoblastic nephroma consists of classic and cellular (atypical) variants. there is no unanimous opinion on the biological behavior of mn because the tumor behaves differently. until 1999, only 22 cases of adult mn of the kidney were reported.(9) therefore, mn is poorly characterized in adults. objectives the primary aim of this review was to assess morphologic features, including macroscopy, microscopy, immunoprophile, epidemiology, and clinical findings of mest. materials and methods search strategy on the basis of medline database searches, we assessed all aspects of mixed epithelial and stromal tumor of the kidney or adult mesoblastic nephroma since the first report in 1997 till the end of 2009. totally, the reports of 90 cases of mest were found. results morphologic features macroscopy mixed epithelial and stromal tumors often arise centrally in the kidney and grow as expansile masses, frequently herniating into the renal pelvic cavity. the tumors are typically composed of multiple cysts and solid components and are 2 to 24 cm in size.(10,11) the largest tumor was reported by moslemi; 25 cm in size and 5400 grams in weight with malignant behavior and fatal recurrence.(12) it was well circumscribed and partially encapsulated, and displayed a solid/ cystic cut surface, with a predominantly solid component in most of them. one tumor was almost purely cystic. most tumors extended to the renal sinus, and some appeared entirely intrapelvic on imaging studies; however, gross and microscopic evaluation did not show destructive invasion of the pelvic wall.(13) microscopy mixed epithelial and stromal tumors are complex tumors composed of large cysts, microcysts, and tubules. the largest cysts are lined by columnar and cuboidal epitheliums that sometimes form small papillary tufts. urothelium, which may be hyperplastic, may also line some portions of the cysts. mixed epithelial and stromal tumor’s cytoplasm ranges from clear to pale, eosinophilic, or vacuolated.(14) the architecture of the microcysts varies from simple microcysts to densely packed clusters of microcysts, or complex branching channels that may be dilated. the stroma consists of a variably cellular population of spindle cells with plump nuclei and abundant cytoplasm. densely collagenous stroma is common and fat is occasionally present.(15-17) extension of the tumor beyond the renal capsule has not been described. each tumor is composed of both epithelial and stromal components. the epithelial component, which displays no difference between the classic and cellular variants, is composed of isolated or clustered tubules and cysts, lined by a benign epithelium with a wide range of cytologic differentiation. the stromal cells are composed of fibroblasts, myofibroblasts, and smooth muscle cells in various combinations. stromal cellularity is low for the classic variant, but high for the cellular variant. hemorrhage, necrosis, and high mitotic index are noted in the stroma of the cellular, but not in the classic variant.(13) microscopic characteristics of mests are eosinophilic spindle cells with ovoid nuclei, which proliferate tightly and arrange in a bundle or wholly. among tumor cells, tubuleforming columnar epithelial cells are scattered. cartilaginous tissue and extramedullary hematopoiesis are sometimes recognized. usually, the capsule of the tumor does not exist and tumor mesoblastic nephroma—moslemi 143urology journal vol 7 no 3 summer 2010 cells proliferate to infiltrate the normal renal tissue.(13) the proposed histogenesis of this tumor is controversial. bolande suggested that maturation and differentiation of wilms tumor and collagenization of the matrix leads to mest. (7) wigger proposed, from the observation with electron microscopy, that epithelial tissues are involved with tumor cells and the origin of epithelial elements and tumor cells are completely different.(6) electron microscopic study shows tubules with various sizes surrounded by bands of smooth muscle cells. the cytoplasm of the epithelial cells contains numerous intermediate filaments. the genetic make-up of mest differs from infantile mn by lacking etv6-ntrk3 gene fusion or polypoid chromosomes 8, 11, and 17.(8,11,18) immunoprophile mixed epithelial and stromal tumors show immunoreactivity of the epithelial components with antibodies to cytokeratin, especially cytokeratin 7. the stromal component expresses vimentin, smooth muscle actin, caldesmon, and desmin. in general, cd10, calretinin, inhibin, and estrogen receptor (er) and progesterone receptor (pr) expressions are seen in mests. the expression of pr is more extensive and is present in more cells in comparison with er.(19) the uninvolved kidney does not express sex steroid receptors. immunohistochemically, mn is consistently positive for myofibroblastic markers (vimentin, smooth muscle actin, and desmin) and negative for epithelial markers. (19) immunohistochemical studies usually show strong positivity for cytokeratin in epithelial elements as well as desmin and smooth muscle actin in stromal elements. both epithelial and stromal components are uniquely positive for vimentin, er, and pr. malignant transformation mixed epithelial and stromal tumors behave as benign lesions.(20) malignant transformation or behavior, including sarcomatous or carcinomatous transformation, has been reported in few subjects.(21) recently, 4 patients with local recurrence of mest and dismal clinical course have been reported.(15,22) a patient with mest displaying malignant transformation to a sarcomatoid carcinoma with heterogonous components was reported by shen and colleagues.(22) epidemiology and clinical features in a study by montironi and colleagues, the mean age of the patients with mest was reported to be 46 years, with the female to male ratio of 6 to 1.(14) mixed epithelial and stromal tumors were found incidentally in 25% of the subjects with the prevalence of 0.20% to 0.28% of all the renal tumors.(23) according to a study by shiraishi and coworkers, the mean age for diagnosis of adult mn (more than 15 years old) was 38.2 years (range, 19 to 66 years), and the tumor tended to occur more commonly in women with a male to female ratio of 7 to 15.(9) in 2000, nakano and colleagues reviewed a total of 38 adult subjects with mn.(24) another study on 22 patients with adult mn showed that the patients were predominantly women (20 subjects), with the age range of 19 to 78 years, who were asymptomatic (5 subjects) or had nonspecific signs and symptoms referable to a renal mass. twenty tumors were classified as classic and 2 as cellular. (13) we searched medline and collected reported cases of mest since 1997 (table 1). of 90 patients with mest, 7 subjects were men and 83 were women, with the mean age of 56 years (range, 17 to 84 years). eighty-one patients (90%) had benign mest, whereas in 9 subjects (10%) it was malignant. mixed epithelial and stromal tumors do not show distinctive clinical features; therefore, they can not be diagnosed before operation. there are no reports showing that mests can be diagnosed from other renal cystic and partially cystic lesions, such as rcc, with imaging modalities. presenting signs and symptoms of mest include flank mass, flank pain, hematuria, or symptoms of urinary tract infection. the most common presenting symptoms are flank mass (31.8%) and gross hematuria (27.3%). flank pain (22.7%) mesoblastic nephroma—moslemi 144 urology journal vol 7 no 3 summer 2010 is recognized frequently. the diameter of the tumor was comparatively large and more than 5 cm (mean, 12.3 cm) in all except 5 reported cases. most mn tumors occur around the upper pole of the kidney.(6) until 1998, only 22 cases of adult mn were reported in the english literature. after that, 7 cases have been added.(13,25) adult mn displays a distinctive morphologic spectrum similar to its pediatric counterpart. the collecting duct differentiation expressed by most tubules and cysts of adult mn implies the ureteric bud, which is the exclusive embryologic origin of the collecting duct, as an important element in the histogenesis of this rare, but fascinating type of tumor. differentiation is necessary from atypical mn, which shows aggressive behavior.(13,26) interestingly, mn almost exclusively affects adult women, with the mean age of 56 years (range, 20 to 71 years). patients can be asymptomatic, or they can present with abdominal pain or discomfort. differential diagnosis the main differential diagnosis of adult mn is rcc. the latter carries a significantly poorer prognosis and may need more radical treatment. the rcc is variable in appearance and far more abundant. a complete list of differential diagnosis is presented in table 2. diagnosis mesoblastic nephroma may present as a large (range, 4 to 8 cm), unilateral renal mass with nodular density, or as diffuse renal enlargement on ultrasonography. these tumors are predominantly solid, but cystic areas are occasionally seen.(27) although there is little documentation of the imaging appearances of adult mn, there has been a brief review of computed tomography features. most of these tumors appear as solid masses with homogenous attenuation on unenhanced sequences. the tumors tend to enhance heterogeneously after injection of intravenous contrast medium. there has been no evidence of associated venous abnormalities or lymphadenopathy in all the cases, demonstrating benign nature of these neoplasms.(9) cystic partially differentiated nephroblastoma multilocular cystic renal cell carcinoma angiomyolipoma with epithelial cysts synovial sarcoma of the kidney metanephric adenofibroma renal cell carcinoma surrounded by angiomyolipoma renal cell carcinoma associated with prominent angioleiomyoma-like proliferation sarcomatoid carcinoma with heterologous elements teratoma table 2. differential diagnoses(14) first author number of cases year of report gemechu t(25) 1 1997 truong ld(13) 22 1998 matias garcia jj(30) 1 1998 shiraishi k(9) 1 1999 yani h(31) 1 2000 nakano m(24) 1 2000 kumar n(32) 1 2000 tejido sanchez a(33) 1 2001 roy pg(34) 1 2002 bisceglia m(35) 2 2003 michal m(11) 22 2004 nakagawa t(36) 2 2004 groves am(37) 1 2004 yap ys(38) 1 2004 battisti s(39) 1 2004 moch h(40) 1 2004 alatassi h(41) 1 2005 comperat e(42) 1 2005 seike k(43) 1 2006 rauf f(44) 1 2006 ekici al(15) 1 2006 chou hp(45) 1 2006 kwon je(16) 1 2007 torres gomez fj(46) 1 2007 sharma jb(47) 1 2007 agarwal r(48) 1 2007 sukov wr(49) 1 2007 buritica c(50) 1 2007 gupta g(51) 1 2007 moslemi mk(12) 1 2008 jung sj(52) 2 2008 sireci an(53) 1 2008 colombo p(54) 1 2008 sangoi ar(55) 1 2008 mohd zam na(56) 3 2009 large mc(57) 1 2009 tsuchiyama k(58) 1 2009 xiang h(59) 5 2009 terao h(23) 1 2009 total of cases 90 table 1. reported cases of adult mesoblastic nephroma in the literature (from 1997 to 2009) mesoblastic nephroma—moslemi 145urology journal vol 7 no 3 summer 2010 according to the study by sahni and colleagues,(28) all mests of the kidney appeared as well-marginated, multi-septate cystic masses with a nodular component. all lesions were classified as bosniak category iii or iv. the presence of calcification or a capsule was variable. although the possibility of mn due to its rareness is never considered in adults, but the radiologist should be aware of its occurrence, especially in asymptomatic patients with no associated venous abnormality or lymphadenopathy. mixed epithelial and stromal tumor of the kidney has a diverse radiographic appearance, indistinguishable from multilocular cystic nephroma and cystic rcc. fine needle aspiration may have a role in the diagnosis of mn pre-operatively.(26) treatment mixed epithelial and stromal tumor of the kidney is probably a benign tumor that can be treated successfully by complete excision.(13) at the time of nephrectomy, the safety margin is necessary because mn shows fingerlike spread into the surrounding tissues.(29) mixed epithelial and stromal tumor of the kidney has been treated successfully by radical or partial nephrectomy or by tumorectomy alone.(13) none of the reported patients was put on any adjuvant chemotherapy or radiotherapy. prognosis rare and unusual morphologic features of mests have been reported. although an aggressive behavior has been reported in very few cases, but in general, mests are benign and surgical excision is curative. after total or partial nephrectomy without adjuvant chemotherapy or radiotherapy, 19 patients, including the 2 subjects with cellular mn, were alive and well at 8-month to 48-year follow-up. one case had recurrence at the surgical site 24 years after nephrectomy. (13) only one patient of a total of 22 reported subjects by truong and associates(13) and also the reported case by moslemi (12) have recurred. local recurrence is due to extensions into the adjacent tissues, making a complete surgical removal impossible.(13) although adult mn appears to be a benign tumor, documentation of more cases will contribute to an understanding of its clinical behavior. conclusion until the past decade, mixed epithelial and stromal tumors were called as adult mesoblastic nephroma, but this term is still used inadvertently that should be discarded.(12,34,43,46) the most important aspect is the occasional cases reported with malignant transformation to sarcoma(12) or carcinoma,(60) which pose the dilemma of their being actual malignant transformations. (14) therefore, in every patient with mest, malignant transformation should be borne in mind. it is important to consider the possibility of this tumor when encountering cases of cystic tumor in middle-aged and older women and men with a previous history of estrogen administration. conflict of interest none declared. references 1. lopez-beltran a, carrasco jc, cheng l, scarpelli m, kirkali z, montironi r. 2009 update on the classification of renal epithelial tumors in adults. int j urol. 2009;16:432-43. 2. turbiner j, amin mb, humphrey pa, et al. cystic nephroma and mixed epithelial and stromal tumor of kidney: a detailed clinicopathologic analysis of 34 cases and proposal for renal epithelial and stromal tumor (rest) as a unifying term. am j surg pathol. 2007;31:489-500. 3. pawade j, soosay gn, delprado w, parkinson mc, rode j. cystic hamartoma of the renal pelvis. am j surg pathol. 1993;17:1169-75. 4. michal m, syrucek m. benign mixed epithelial and stromal tumor of the kidney. pathol res pract. 1998;194:445-8. 5. block nl, grabstald hg, melamed mr. congenital mesoblastic nephroma (leiomyomatous hamartoma): first adult case. j urol. 1973;110:380-3. 6. wigger hj. fetal mesenchymal hamartoma of kidney. a tumor of secondary mesenchyme. cancer. 1975;36:1002-8. 7. bolande rp. congenital mesoblastic nephroma of infancy. perspect pediatr pathol. 1973;1:227-50. 8. daniel l, lechevallier e, bouvier c, coulange c, pellissier jf. adult mesoblastic nephroma. pathol res pract. 2000;196:135-9. 9. shiraishi k, yamamoto m, gondo t, shirataki s, naito k. mesoblastic nephroma in adulthood: a case report. mesoblastic nephroma—moslemi 146 urology journal vol 7 no 3 summer 2010 int j urol. 1999;6:414-8. 10. michal m. benign mixed epithelial and stromal tumor of the kidney. pathol res pract. 2000;196:275-6. 11. michal m, hes o, bisceglia m, et al. mixed epithelial and stromal tumors of the kidney. a report of 22 cases. virchows arch. 2004;445:359-67. 12. moslemi mk. adult mesoblastic nephroma: a case with fatal recurrence. urol j. 2008;5:136-7. 13. truong ld, williams r, ngo t, et al. adult mesoblastic nephroma: expansion of the morphologic spectrum and review of literature. am j surg pathol. 1998;22:827-39. 14. montironi r, mazzucchelli r, lopez-beltran a, et al. cystic nephroma and mixed epithelial and stromal tumour of the kidney: opposite ends of the spectrum of the same entity? eur urol. 2008;54:1237-46. 15. ekici ai, ekici s, gurel b, altinok g, erkan i, gungen y. benign mixed epithelial and stromal tumor of the kidney. scientificworldjournal. 2006;6:615-8. 16. kwon je, kang jh, kwon gy. mixed epithelial and stromal tumor of the kidney: a case report. j korean med sci. 2007;22:159-62. 17. maclennan gt, bostwick dg. tubulocystic carcinoma, mucinous tubular and spindle cell carcinoma, and other recently described rare renal tumors. clin lab med. 2005;25. 18. pierson cr, schober ms, wallis t, et al. mixed epithelial and stromal tumor of the kidney lacks the genetic alterations of cellular congenital mesoblastic nephroma. hum pathol. 2001;32:513-20. 19. portugal r, barroca h. clear cell sarcoma, cellular mesoblastic nephroma and metanephric adenoma: cytological features and differential diagnosis with wilms tumour. cytopathology. 2008;19:80-5. 20. gupta r, mathur sr, singh p, agarwala s, gupta sd. cellular mesoblastic nephroma in an infant: report of the cytologic diagnosis of a rare paediatric renal tumor. diagn cytopathol. 2009;37:377-80. 21. patel y, mitchell cd, hitchcock rj. use of sarcomabased chemotherapy in a case of congenital mesoblastic nephroma with liver metastases. urology. 2003;61:1260. 22. shen ss, truong ld, ayala ag, ro jy. recently described and emphasized entities of renal neoplasms. arch pathol lab med. 2007;131:1234-43. 23. terao h, makiyama k, yanagisawa m, et al. [mixed epithelial and stromal tumor of kidney: a case report]. hinyokika kiyo. 2009;55:495-8. 24. nakano m, kawamoto s, kanimoto y, et al. [a case of mesoblastic nephroma in an adult patient]. hinyokika kiyo. 2000;46:623-6. 25. gemechu t, bezabeh k. classical congenital mesoblastic nephroma in an adult: a case report on an ethiopian. ethiop med j. 1997;35:257-62. 26. dey p, radhika s, rajwanshi a, ray r. fine-needle aspiration cytology of leishmania lymphadenitis. diagn cytopathol. 1992;8:551-2. 27. ehman rl, nicholson sf, machin ga. prenatal sonographic detection of congenital mesoblastic nephroma in a monozygotic twin pregnancy. j ultrasound med. 1983;2:555-7. 28. sahni va, mortele kj, glickman j, silverman sg. mixed epithelial and stromal tumour of the kidney: imaging features. bju int.105:932-9. 29. kleist b, lorenz g, dietrich h, klebingat kj. [mesoblastic nephroma in adulthood]. pathologe. 1998;19:226-9. 30. matias garcia jj, riera canals l, serrano pinol t, franco miranda e, serrallach mila n. [mesoblastic nephroma in the adult. report of a case]. actas urol esp. 1998;22:707-11. 31. yanai h, ikeda a, kadena h, mizutani m, kurihara m, matsuki s. adult mesoblastic nephroma with ciliated epithelium. a case report. pathol res pract. 2000;196:265-8. 32. kumar n, jain s. aspiration cytology of mesoblastic nephroma in an adult: diagnostic dilemma. diagn cytopathol. 2000;23:124-6. 33. tejido sanchez a, de la morena gallego jm, garcia de la torre jp, et al. [mesoblastic nephroma in the adult: report of a new case]. arch esp urol. 2001;54:265-8. 34. roy pg, roy d, agarwal sb, singh t. mesoblastic nephroma in an adult: a case report. ir j med sci. 2002;171:236-7. 35. bisceglia m, bacchi ce. mixed epithelial-stromal tumor of the kidney in adults: two cases from the arkadi m. rywlin slide seminars. adv anat pathol. 2003;10: 223-33. 36. nakagawa t, kanai y, fujimoto h, et al. malignant mixed epithelial and stromal tumours of the kidney: a report of the first two cases with a fatal clinical outcome. histopathology. 2004;44:302-4. 37. groves am, hegarty pk, moxon r, doble a. adult mesoblastic nephroma: appearances on magnetic resonance imaging. magn reson imaging. 2004;22:1043-5. 38. yap ys, coleman m, olver i. aggressive mixed epithelial-stromal tumour of the kidney treated with chemotherapy and radiotherapy. lancet oncol. 2004;5:747-9. 39. battisti s, renaudin k, rigaud j, et al. [mixed epithelial and stromal tumour of the kidney]. prog urol. 2004;14:210-2. 40. moch h, schurch lv, sulser t, terracciano l. [mixed epithelial and stromal tumor of the kidney]. pathologe. 2004;25:356-61. 41. alatassi h, bell b, murphree s, zhao w. a 27-year-old woman with an incidental renal mass. arch pathol lab med. 2005;129:e185-6. 42. comperat e, couturier j, peyromaure m, cornud f, vieillefond a. benign mixed epithelial and stromal tumor of the kidney (mest) with cytogenetic alteration. pathol res pract. 2005;200:865-7. 43. seike k, saito a, mori y. [a case of mesoblastic nephroma in adulthood]. hinyokika kiyo. 2006;52: 863-5. 44. rauf f, yaqoob n, husain a. mixed epithelial mesoblastic nephroma—moslemi 147urology journal vol 7 no 3 summer 2010 and stromal tumour of kidney. j pak med assoc. 2006;56:340-1. 45. chou hp, ou yc, cheng cl, yang cr. mixed epithelial and stromal tumor of the kidney. j chin med assoc. 2006;69:140-2. 46. torres gomez fj, silva abad a, galan p. [adult’s mesoblastic nephroma. report of a case with aggressive course]. arch esp urol. 2007;60:72-5. 47. sharma jb, aruna j, mittal s, sharma mc. mixed epithelial and stromal tumor of the kidney in a puerperal woman. j obstet gynaecol res. 2007;33:574-7. 48. agarwal r, levinson aw, schowinsky j, su lm. large mixed epithelial and stromal tumor of the kidney masquerading as metastatic renal cell carcinoma. urology. 2007;70:1008 e17-9. 49. sukov wr, cheville jc, lager dj, lewin jr, sebo tj, lewin m. malignant mixed epithelial and stromal tumor of the kidney with rhabdoid features: report of a case including immunohistochemical, molecular genetic studies and comparison to morphologically similar renal tumors. hum pathol. 2007;38:1432-7. 50. buritica c, serrano m, zuluaga a, arrabal m, regauer s, nogales ff. mixed epithelial and stromal tumour of the kidney with luteinised ovarian stroma. j clin pathol. 2007;60:98-100. 51. gupta g, kumar s, panicker j, korula a. the mixed epithelial stromal tumor of the kidney: a recently recognized entity. indian j urol. 2007;23:326-7. 52. jung sj, shen ss, tran t, et al. mixed epithelial and stromal tumor of kidney with malignant transformation: report of two cases and review of literature. hum pathol. 2008;39:463-8. 53. sireci an, rodriguez r, swierczynski sl, netto gj, argani p. fat-predominant mixed epithelial stromal tumor (mest): report of a unique case mimicking angiomyolipoma. int j surg pathol. 2008;16:73-7. 54. colombo p, naspro r, vallieri l, et al. non-hormoneinduced mixed epithelial and stromal tumor of kidney in a man: description of a rare case. urology. 2008;71:168 e7-9. 55. sangoi ar, higgins jp. bilateral mixed epithelial stromal tumor in an end-stage renal disease patient: the first case report. hum pathol. 2008;39:142-6. 56. mohd zam na, lau wk, yip sk, cheng cw, tan ph. mixed epithelial and stromal tumour (mest) of the kidney: a clinicopathological report of three cases. pathology. 2009;41:403-6. 57. large mc, al-ahmadie h, shalhav al, zorn kc. mixed epithelial stromal renal tumor with dystrophic ossification: a case report and literature review. can j urol. 2009;16:4690-3. 58. tsuchiyama k, ueki o, minami h, kawaguchi k, sato k, katsuda s. [mixed epithelial and stromal tumor of the kidney: a case report]. hinyokika kiyo. 2009;55:219-21. 59. xiang h, ding w, liu f, ren gp, wang zm, zhu xz. [clinicopathologic analysis of mixed epithelial and stromal tumor of kidney and adult cystic nephroma]. zhonghua bing li xue za zhi. 2009;38:436-40. 60. raj gv, yowell c, madden jf, nosnik i, mouraviev v, polascik tj. malignant cystic nephroma. can j urol. 2006;13:3348-50. best reviewer of issue january-february 2020 hooman djaladat hooman djaladat february 2020 hooman djaladat, m.d., m.s., is an associate professor of clinical urology at the usc institute of urology since 2012. he earned his medical degree from tehran university of medical sciences and graduated from medical school as top 1%. he completed his residency training in sina hospital, tehran, iran. before finishing his residency, he participated in an endourology and oncology course in medway maritime nhs trust center affiliated to the university college of london. being among the top scorers of the iranian urology board exam (2004), he was appointed as an assistant professor of urology at hormozgan university of medical sciences from 2004 to 2007. to continue his scientific endeavor, he took part in an endourology and laparoscopy clinical fellowship program at labbafinejad medical center which is one of the most prestigious centers pioneering modern urology in the middle east. subsequently he moved to the usa were he performed research in the field of urologic oncology at the norris cancer center. he then pursued a suo-accredited urologic oncology fellowship at the keck school of medicine of usc in 2012 and a complimentary course in robotic surgery, and then immediately joined the usc institute of urology as faculty member. dr. djalalat also accomplished a master degree in clinical, biomedical, and translational investigation at the preventive medicine department of usc in 2014. he specializes in complex endourology and oncology cases (caval thrombus, retroperitoneal sarcoma, salvage cystectomy) and also minimally invasive/robotic techniques with more than 18 years of experience in this field. he is a member of many scientific societies such as the european association of urology, society of urologic oncology, western section american urologic association, and american urologic association. dr. djaladat is very passionate about research, mainly focusing on clinical and translational studies in bladder, testis, and kidney cancer. he has presented over 160 abstracts at scientific meetings, published more than 90 peer-reviewed articles and book chapters, and has invented a new foley catheter for prostatectomy patients, which has been filed with the us patent and trade organization. he is currently the pi of a novel rct studying “biologic mesh in preventing hernia in patients with bladder cancer undergoing radical cystectomy with ileal conduit diversion”. dr. djaladat is a reviewer for many journals in the field of urology. he has been selected by the editorial board of the “urology journal” as the best reviewer of january-february 2020 issue. sexual dysfunction and infertility 174 urology journal vol 7 no 3 summer 2010 erectile function and dysfunction following low flow priapism a comparison of distal and proximal shunts ali tabibi, hamidreza abdi, nastaran mahmoudnejad purpose: to compare erectile function following low flow priapism in patients undergoing distal and proximal shunts. materials and methods: from january 1995 to december 2005, we retrospectively studied 16 patients who presented to our medical center with refractory priapism. of 16 patients, 5 underwent winter shunt, while el-ghorab procedure was performed for 7 patients and the remaining 4 underwent grayhack shunt. erectile function was assessed in a minimum follow-up of 2 years (range, 2 to 10 years) using erectile dysfunction (ed) intensity scale [total score: 5 to 10 (severe ed); 11 to 15 (moderate ed); 16 to 20 (mild ed); and 21 to 25 (no ed)]. results: the mean patients’ age was 40.62 ± 15.27 years. mean duration of priapism was 51.12 ± 37.99 hours. of 4 patients (25%) who underwent proximal shunt (grayhack procedure), 2 (50%) were impotent, 1 had potency, and the other one achieved some penile erection with administration of oral sildenafil. of 5 patients (31.25%) who underwent winter procedure, 1 died because of metastatic bladder cancer and of 4 remainders, 2 (50%) had normal erectile function, but 1 patient suffered from recurrent priapism. of 7 patients (43.75%) who underwent el-ghorab procedure, 1 was lost for follow-up and of remaining 6 patients, 2 (33.3%) had normal erectile function and 4 (66.6%) were impotent. no surgical complication was seen. median lag time from priapism till surgery for patients with and without ed was 48 and 26 hours, respectively (p = .22). conclusion: grayhack shunt is a safe surgical procedure without any major complications and with lower ed rate. grayhack shunt might be considered as treatment of choice for refractory low flow priapism. urol j. 2010;7:174-7. www.uj.unrc.ir keywords: priapism, erectile dysfunction, impotency, surgery urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran corresponding author: ali tabibi, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2277 0954 e-mail: tabibiali@yahoo.com received may 2009 accepted october 2009 introduction priapism is a painful and persistent erection that is not associated with sexual excitement or desire, and does not subside after sexual intercourse or masturbation.(1) priapism can be categorized as low flow (ischemic) and high flow (non-ischemic) types. low flow priapism is a urological emergency, similar to compartment syndrome. if left untreated, low flow priapism can cause necrosis and fibrosis of the cavernous tissue and lead to impotence. incidence of impotence is directly related to the duration of priapism and aggressiveness of treatment. however, between 50% to 90% of patients will develop erectile dysfunction if the priapism surgical shunt in low flow priapism—tabibi et al 175urology journal vol 7 no 3 summer 2010 lasts more than 24 hours.(2) adequate evaluation to identify the cause and type of priapism is essential before initiation of therapy. the therapeutic goals are to avert the unwanted erection, relieve pain, and preserve potency.(1) it is stated that low flow priapism of particularly extended durations, such as 48 to 72 hours, is unlikely to be resolved with intracavernous treatment, and surgical shunting should be rapidly performed.(3) for distal shunting, creating a corporoglanular shunt using scalpel or needle core biopsy technique of ebbehøj or winter is the first reasonable approach.(3) el-ghorab procedure is considered as the most effective distal shunt, but it is a more invasive open surgical modification of this type of shunting maneuver.(3) proximal shunting by making a window between the corpus cavernosum and corpus spongiosum or by anastomosis of the saphenous vein to one of the corpora cavernosa (grayhack shunt) may be warranted if distal shunting fails.(4,5) the purpose of this study was to evaluate erectile function following distal and proximal shunts in long-lasting priapism management. materials and methods we retrospectively studied 16 patients who referred to our medical center complaining of priapism during the past 10 years (from january 1995 to december 2005), all of whom underwent shunting procedure. the etiologies of priapism are demonstrated in table. in 10 patients (62.5%), priapism had occurred during nocturnal penile tumescence. all of the 16 patients had had low flow priapism documented by gasometric estimation of the intracavernosal blood and had been refractory to conservative management, including evacuation of the blood and irrigation of the corpora cavernosa with intracavernous injection of an alpha adrenergic sympathomimetic agent. of 16 patients, 5 underwent winter shunt, while el-ghorab procedure was performed for 7 patients and the remaining 4 underwent grayhack shunt, based on surgeon’s decision (figures 1-3). relevant data were gathered from clinical records. all of the patients were followed up for a minimum period of 2 years (range, 2 to 10 years). erectile function was assessed by erectile dysfunction intensity scale [total score: 5 to 10 (severe ed); 11 to 15 (moderate ed); 16 to 20 (mild ed); and 21 to 25 (no ed)].(6) etiologic factor no percentage opium addiction 2 12.5% history of recurrent priapism 5 31.25% smoking 4 25% intracavernosal injection of vasoactive agents 4 25% psychologic problems 2 12.5% alcohol consumption 6 37.5% metastatic cancer 1 6.25% etiologic factors of priapism figure 1. identification of the saphenous vein in the medial aspect of the thigh. figure 2. creating a submucosal tunnel from the thigh to the lateral aspect of the corpus cavernosum. surgical shunt in low flow priapism—tabibi et al 176 urology journal vol 7 no 3 summer 2010 results the mean patients’ age was 40.62 ± 15.27 years (range, 19 to 65 years). mean duration of priapism was 51.12 ± 37.99 hours (range, 4 to 120 hours). of 16 patients, 4 (25%) underwent proximal shunt (grayhack procedure), of whom 2 (50%) had severe ed, 1 was potent (normal erectile function), and the other one had some penile erection with administration of oral sildenafil (mild ed). five patients (31.25%) underwent winter procedure, of whom 1 died because of metastatic bladder cancer. of 4 remainders, 2 (50%) had normal erectile function, but 1 experienced recurrent priapism. remainders in this group had severe ed. of seven patients (43.75%) who underwent el-ghorab shunt, 1 left the follow-up and of remaining 6 patients, 2 (33.3%) had normal erectile function and 4 (66.6%) suffered from severe ed. no surgical complication was observed in our series. median time to surgery in subjects with and without ed was 48 and 26 hours, respectively (p = .22 with mann-whitney u test). median time to surgery for patients with proximal shunt, el-ghorab, and winter procedure was 51, 26, and 34 hours, respectively. discussion one of the main goals in treatment of priapism is to maintain potency. the purpose of our study was to evaluate the relationship between the type of surgical shunts and postoperative erectile function. in a study on 26 patients undergoing proximal shunt (grayhack), only 7 patients (26.92%) were potent postoperatively.(7) moncada treated 5 patients with low flow priapism using grayhack procedure. he concluded that when erectile capacity does not restore within 3 months postoperatively, then the shunt should be ligated. (8) in another study, chen and colleagues reported 1 patient who underwent winter procedure and was potent in a 1-year follow-up.(9) in a study by nixon and associates, 28 patients were evaluated retrospectively. thirteen patients (46.4%) required more than one operation for failed detumescence, of whom 12 (92.3%) initially had undergone a winter shunt. of 20 men who completed the follow-up period, only 2 patients (10%) reported preservation of preoperative erectile function. three patients (15%) achieved some erection without the prescription of vasoactive agents. approximately, 50% of the subjects required re-operation for failed detumescence following a cavernoso-spongiosum shunt in their experience. winter shunt was the least successful operation whereas re-operation was uncommon following el-ghorab or quackles shunt.(10) about 90% of patients in the above mentioned study had ed during follow-up period. they concluded that ed after shunting procedure may be a direct consequence of the prolonged priapism itself.(10) in our study, 2 (50%), 2 (50%), and 2 (33.3%) of the patients who underwent proximal shunt (grayhack), winter procedure, and elghorab shunt had satisfactory erectile function, respectively. overall potent patients with proximal shunt were 50% in comparison to 40% for distal shunts (winter and el-ghorab). complications such as urethral fistulas, purulent cavernositis, and pulmonary embolism have been reported after various shunt procedures. since most shunts appear to close over time, figure 3. end to side anastomosis of the saphenous vein to the corpus cavernosum. surgical shunt in low flow priapism—tabibi et al 177urology journal vol 7 no 3 summer 2010 it is thought that shunting does not produce permanent ed. however, persistence of a shunt resulting in ed has been reported.(11) erectile dysfunction following shunting procedure might be due to adverse effects of prolonged priapism and type of shunting (distal or proximal), and the procedure itself does not seem to play an important role in postoperative erectile function. our findings suggest superiority of proximal shunt in management of low flow priapism. it has lower or at least equal impotence rate compared to distal shunts. this is especially true in patients who had undergone distal shunt or those with prolonged and refractory priapism. previous concerns about complications and higher rate of ed following proximal shunts should be re-evaluated. our study has some limitations. patients with different age groups, etiology, and priapism duration were enrolled in this study. therefore, drawing final conclusion about a special surgical method cannot be made based on our study. there is no doubt that a well-designed prospective study will find out the correlation between shunting procedures, duration of priapism, and following ed. conclusion grayhack shunt is a safe surgical procedure without any major complications and with lower ed rate compared to distal shunts. grayhack shunt might be considered as an appropriate and effective technique in the first line management of refractory low flow priapism. conflict of interest none declared. references 1. sadeghi-nejad h, seftel ad. the etiology, diagnosis, and treatment of priapism: review of the american foundation for urologic disease consensus panel report. curr urol rep. 2002;3:492-8. 2. ralph dj, garaffa g, muneer a, et al. the immediate insertion of a penile prosthesis for acute ischaemic priapism. eur urol. 2008. 3. montague dk, jarow j, broderick ga, et al. american urological association guideline on the management of priapism. j urol. 2003;170:1318-24. 4. grayhack jt, mccullough w, o’conor vj, jr., trippel o. venous bypass to control priapism. invest urol. 1964;1:509-13. 5. sacher ec, sayegh e, frensilli f, crum p, akers r. cavernospongiosum shunt in the treatment of priapism. j urol. 1972;108:97-100. 6. broderick ga, lue tf. evaluation and non surgical management of erectile dysfunction and priapism. in: walsh pc, retik ab, vaughan ed, wein aj, eds. campbell’s urology. vol 2. philadelphia wb saunders; 2002:1625. 7. kihl b, bratt cg, knutsson u, seeman t. priapsim: evaluation of treatment with special reference to saphenocavernous shunting in 26 patients. scand j urol nephrol. 1980;14:1-5. 8. moncada j. [potency disturbances following saphenocavernous bypass in priapism (grayhack procedure) (author’s transl)]. urologe a. 1979;18: 199-202. 9. chen cc, wang cj, chen cw, lee yc, chou yh, huang ch. management of low-flow priapism using the winter procedure: a case report. kaohsiung j med sci. 2003;19:88-92. 10. nixon rg, o’connor jl, milam df. efficacy of shunt surgery for refractory low flow priapism: a report on the incidence of failed detumescence and erectile dysfunction. j urol. 2003;170:883-6. 11. kulmala rv, lehtonen ta, tammela tl. priapism, its incidence and seasonal distribution in finland. scand j urol nephrol. 1995;29:93-6. vol 19 no 3 may-june 2022 100 record and appraisal of endophytic tumor localization techniques in minimally invasive kidney-sparing procedures. a systematic review spyridon paparidis1,2*, eleftherios spartalis1,3, eleftheria mavrigiannaki4, nikolaos ferakis2, konstantinos stravodimos1,5, gerasimos tsourouflis1,3, dimitrios dimitroulis1,3, nikolaos i. nikiteas1,3 purpose: review and efficacy assessment of techniques used for intraprocedural endophytic renal mass localization. materials and methods: advanced search was carried out on pubmed, cochrane library, web of science and google scholar databases up to august 2020. eligibility criteria were set, according to prisma statement. or (95 % ci) for identification or technical success, positive margins and recurrence, were calculated for completely endophytic tumors. risk of bias was evaluated using robvis tool. results: 77 studies were used for result synthesis, including 1,317 endophytic tumors, with 758 of them completely endophytic. 356 endophytic tumors were treated laparoscopically and 598 robotically, using ultrasound-based methods, transarterial embolization, dual-source ct, invasive signage, 3d printing, and augmented reality variations. identification success was 97.8-100%, positive margins 0-12.5 % (completely endophytic: 95 % ci; 0.2551.971, or 0.709 in laparoscopic, 95 % ci ; 0.379-3.109, or 0.086 in robotic partial nephrectomy), recurrences 0-3.9 % (completely endophytic: 0 recurrences in laparoscopic, 95 % ci ; 0.0917-2.25, or 0.454, in robotic partial nephrectomy), and complications 0-60 % . 363 were treated with ablation techniques using ct-based methods, thermal monitoring, transarterial embolization, ultrasound guidance and invasive signage. technical success was 33.4-100 % (completely endophytic: 95 % ci ; 0.00157-2.060, or 0.0569 for invasive and 95 % ci ; 0.598-13.152, or 2.804 for non-invasive localization techniques) and recurrences were 0-20%. conclusion: ultrasound-based techniques showed acceptable identification success and oncologic outcomes in the laparoscopic or robotic setting. augmented reality, showed no superiority over conventional techniques. near infrared fluoroscopy with intravenous indocyanine green, was incapable of endophytic tumor tracking, although when administered angiographic, results were promising, along with other embolization techniques. percutaneous hook-wire or embolization coil signage, aided in safe and successful tracking of parenchymal isoechoic masses, but data are inadequate to assess efficacy. ct-guidance, combined with ultrasound or thermal monitoring, showed increased technical success during thermal ablation, unlike ultrasound guidance that showed poor outcomes. keywords: endophytic, kidney, laparoscopy, neoplasms, robotic surgical procedures, systematic review introduction kidney-sparing procedures overrun radical nephrec-tomy for treating small renal masses. european association of urology guidelines 2019, recommend partial nephrectomy for t1 renal cell tumors(1). not only kidney preservation is important but also maintenance of maximum parenchyma for better functional outcomes, especially in patients with impaired renal function, comorbidities or bilateral tumors(2), indicating 1hellenic minimally invasive and robotic surgery (mirs) study group, national and kapodistrian university of athens, medical school, agiou thoma 15b, goudi, 11527athens, greece. 2department of urology, “korgialenio-benakio” hellenic red cross hospital, athanasaki 2, 11526, athens, greece. 3second department of propaedeutic surgery, national and kapodistrian university of athens, medical school, mikras asias75, 11527, athens, greece. 4second pediatric surgery department, general children’s hospital “agia sofia”, thivon 1, 11527, athens, greece. 5first department of urology, national and kapodistrian university of athens, medical school, mikras asias75, 11527, athens, greece. *correspondence: hellenic minimally invasive and robotic surgery (mirs) study group, national and kapodistrian university of athens, medical school, agiou thoma 15b, 11527, athens, greece, tel: 00306974971280, e-mail: sppap1986@gmail.com. received november 2021 & accepted april 2022 a shift from kidney to nephron-sparing procedures. minimally invasive nephron-sparing procedures were stratified by gill 2003(3) into three categories: excision, probe ablation, and non-invasive ablation. excision methods include surgeries such as laparoscopic or robotic-assisted partial nephrectomy(4). probe ablation methods include rfa, cryoablation, mwa and ire (5,6). finally, non-invasive ablation procedures include hifu and stereotactic body radiation ablation(5). urology journal/vol 19 no. 3/ may-june 2022/ pp. 161-178. [doi: 10.22037/uj.v19i.7056] review identification of endophytic renal masses, especially completely endophytic that acquire 3 points in the “(e)-endophytic/exophytic” parameter of r.e.n.al nephrometry score(7), can be challenging. lack of haptic feedback in minimally invasive procedures and visual feedback when treating intraparenchymal masses, are obstacles in tumor localization. our rationale is to concisely present and evaluate endophytic tumor identification techniques described during minimally invasive nephron-sparing procedures. we aim to comprise a decision-making guide for the clinician when treating endophytic and especially non-visible completely endophytic renal tumors. materials and methods clinical question and eligibility criteria this review is based on a focused clinical question using p.i.c.o (population, intervention, comparison, and outcome) worksheet and search strategy protocol (8) .(p) endophytic renal masses, (i) minimally invasive kidney-sparing procedures, (c) tumor localization techniques, (o) presentation of recorded techniques and evaluation of efficacy and oncologic outcomes. inclusion criteria were: 1) english language 2) population: renal masses characterized as endophytic, completely endophytic, intrarenal, totally intrarenal, intraparenchymal and parenchymal, 3) study design: randomized controlled trials and observational studies, as well as systematic reviews/meta-analyses, reviews and case reports 3) intervention: minimally invasive kidney-sparing treatments (laparoscopic or robotic partial nephrectomy, ablative methods and hybrid techniques). 4) outcomes: report, assessment or comparison of different invasive or non-invasive localization techniques used for signage of the aforementioned masses. exclusion criteria were: 1) animal, phantom, ex-vivo or cadaveric studies 2) abstracts or conference announcements and electronic book publications. 3) studies on upper tract urothelial masses. information sources and search strategy an advanced search was carried out on pubmed, cochrane library, web of science and google scholar databases up to august 2020, with the terms: kidney/renal/nephron sparing or kidney/renal/nephron preserving or laparoscopic/3d laparoscopic/robotic/ robotic assisted partial nephrectomy or ablation or minimal invasive and endophytic or intraparenchymal or intrarenal or parenchymal and renal tumor/ mass/lesion/cancer or kidney tumor/mass/lesion/cancer. keyword search with the terms: “tumor marking” table 1. summary of results from studies regarding laparoscopic-assisted partial nephrectomy (lpn) for endophytic tumors. review 162 a=endophytic refers to totally intrarenal tumors with no exophytic component, b=not included 4 radical nephrectomy conversions and 1 open conversion, c=all endophytic tumors were hilar, d= endophytic tumors were totally intraparenchymal not visualized in the kidney surface, e=endophytic defined as >66% of tumor volume embedded in parenchyma, f=5 conversions to open surgery are included with 14 intraoperative and postoperative complications, g=endophytic defined as <40% of the lesion extending off the kidney surface, h=endophytic defined as <40% mass protruding, i= clavien ≥ii, j=postoperative only, k= lesion extending <40% from the kidney surface,l=the exact number of endophytic were not described, all the masses were characterized as endophytic and complex, m=no complications directly related to dye injection, 9 overall complications overall mean follow-up months. 39.2 na 34 6.32 3 26 na na 16 27 na na na 6 12 17 na 18 na 16 na 1 recurrence n.(%) 0 0 0 0 na 0 na na 0 0 na na na na 0 0 na 0 na 0 0 0 complications n.(%) 10(19.6) 7(15.2)b 2(18) na 2(25) 68(18.7) 13(23.6)d 19(60)f 9(47.4) na na na 0i na 2(13,3)j 0 0 na na 0 0 0m positive margins n.(%) 1(1.96) 0 1(9) 0 1(12.5) 2(5.4) 0 na 2(10.5) 0 0 0 0 0 0 0 0 0 na 0 0 0 mean endophytic tumor size mm. 25 24.2 16 na 37 26 23 na 23.1 na na na 27.8 na 27 na 38 na na 33 16 na identification success n.(%) 51(100) 46(100) 11(100) 2(100) 8(100) 41(100) 55(100) na na 3(100) 6(100) 15(100) 5(100) 8(100) 15(100) 10(100) 10(100) 25(100) 1(100) 1(100) 1(100) na identification method ious ious ious ious and hydro-jet excision ious ious ious ious ious ious and perc needle delineation ar: 3d reconstruc tion manual registratio n ar: 3d reconstruc tion manual registratio n 3d printing physical kidney model navigation ar: 3d reconstruction manual registration ar: 3d reconstructio n manual registration combined with ilus aid ar: manual registration with cbct and fiducials ar: manual registration with cb imaging no fiducials dsct angiograp hy roll perc hookwire perc hookwire blue dye emboliz ation laparoscopic technique lpn retrolpn retrolp n lpn unclampe d handassisted lpn translp n retrolpn and translpn translpn translpn and retrolpn lpn translpn or retrolpn lpn translpn or retrolpn 3d-retrolpn retrolpn translpn retrolpn retrolpn translpn translp n translp n lpn study arms rapn vs lpn for complet ely endophy tic tumors tit vs exophytic single arm single arm single arm tit vs any exophyti compon ent intraparen chymal vs any other tumor single arm exophytic vs mesophytic vs endophytic vs hilar lpn vs lrn vs lap cryoablation 3d reconstruc tion vs no 3d reconstruc tion single arm single arm 3d-mirgs vs no 3d mirgs single arm single arm single arm single arm single arm single arm single arm single arm multivariate regression: statistically significant covariates/outc ome r.e.n.a l. score/ pentafec ta. na na na na na no covariates significant / complicati ons, surgical margins, warm ischemia and excision times, and blood loss na na na parenchy mal mass preserved/ renal function na na na na na na tumor location and number of clamped branches/ glomerula r filtration rate and blood loss na na na na endophytic tumors n./total tumors n. 61/112 46/583a 11/11c 2/35 8/8 41/402n 55/8000 32/184e 19/123g 3/50 6/49 15/91h 5/5 8/35 15/15 na/10l 10/10 25/125k 1/3 1/1 1/1 7/50 study type retrospe ctive compara tive retrospec tive casecontrol retrospe ctive caseseries prospective case-series retrospec tive caseseries retrospe ctive casecontrol retrospec tive comparati ve prospectiv e caseseries retrospecti ve comparativ e retrospective comparative retrospec tive casecontrol retrospec tive caseseries retrospective case-series retrospective case-control retrospective case-series retrospecti ve caseseries retrospective case-series retrospect ive caseseries case report case report case report prospect ive case -series study gu et al.2020 (12) qin et al.2018(13) di pierro et al.2014 (16) gao et al.2014 (17) engel et al.2013 (18) nadu et al.2013 (14) chung et al.2011 (15) shikanov et al.2009(21) venkatesh et al.2006 (19) fazio et al.2006 (20) wang et al.2019 (42) zhang et al.2018(43) fan.et al 2018 (31) wang et al.2015(44) chen et al.2014 (17) simpfendor fer et al .2016 (37) teber et al.2009 (38) shao et al.2012 (30) hernande z et al.2017 (45) kouriefs et al. 2019 (33) mandoo rah et al 2018 (32) bouvier et al 2020 (34) endophytic renal mass localization techniques-paparidis et al. vol 19 no 3 may-june 2022 100 “endophytic renal tumor” “minimal invasive” “kidney sparing” was performed synchronously in google scholar database. this study was conducted according to preferred reporting items for systematic reviews and meta-analyses (prisma) statement 2009(9). pubmed and cochrane library search resulted in 429, web of science in 29 and google scholar search in 977 studies. 97 originated from references manual cross-searching in relevant articles. 1,498 studies were screened for eligibility after duplicate extraction. 1,234 studies were initially excluded by title and abstract, 153 studies were secondarily excluded, after full reading, due to eligibility criteria mismatch. finally, 111 studies were included in our systematic review for evaluation. 77 studies, 1 multi-institutional prospective single arm, 6 prospective case-series, 5 prospective comparative and 59 retrospective and 6 case-reports, were included for narrative results presentation or subgroup analysis. search results are summarized in prisma flow-diagram(figure 1). data extraction and risk of bias assessment data extraction was performed in duplicate and included study type and design, minimally invasive approach, identification method, identification and technical success for ablative techniques, number and size of tumors, marginal status, perioperative complications, recurrence and follow-up. risk of bias was assessed using robvis tool(10) based on robins-i tool for assessing non-randomized studies of interventions(11). observational studies with inconclusive information, case reports and reviews were evaluated, although a priori considered critically biased. risk of bias was evaluated throughout seven domains: confounding, selection of participants, classification of interventions, deviations of intended interventions, missing data, measurement of outcomes, selection of the reported results. for each domain we used a judgment from low to serious. results are presented in a traffic-light plot (figure 2). result synthesis and statistical analysis results presentation is mainly narrative. a meta-analysis was not performed due to heterogeneity of overall study population. therefore, percentages of the outcome values for each variable instead of effect measures were calculated. table 2. summary of results from studies regarding robotic assisted partial nephrectomy (rapn) for endophytic tumors. a=5 intraoperative complications (3 conversions, 1 ureteric injury, 1 transfusion), 12 postoperative complications (2 ≥iii), b=1 local recurrence, 1 metastasis, c=1 intraoperative, 18 postoperative complications (4 iii-iv), d=1 tumor positive frozen biopsy, 97,8% technical success, e= 1 tumor positive frozen biopsies, conversion, f=3 intraoperative (2 conversion, 1 ureteric injury) and 9 postoperative (4 i, 3 ii, 2 iii), g=2 intraoperative and 6 postoperative (1 iii-iv), h=20 tumors >50% endophytic in the laparoscopic ious and 29 in robotic ious, i= 75 underwent rapn with robotic ious and 75 with laparoscopic ious, j=25,7 months in the laparoscopic ious and 10,3 months in the robotic ious, k=endophytic: ≥50% endophytic component, l=32mm in ldu, 34mm in non ldu, m,n= detection with ious, no fluorescence of icg, o=ha3d identified all endophytic masses before fat detachment allowing no kidney rotation. ov era ll me an fo llo wup 27, 3 12 59 na na 15, 2 10, 6 33 na 48 12, 6 18j 13 14 8 na 3 15 12 18, 5 12 na 5 3 na 4 na re cur r enc e n.( %) 0 0 2(3 ,9) b na na 0 0 0 na 1(2 ,2) 1(1 ,6) 0 0 0 0 na 0 0 0 na 0 na na 0 na na na co mp li cat ion s n.( %) 50( 82) 0 17( 32, 7 ) 14( 21, 9 ) 0 19( 21, 8 )c 2(6 ,67 ) na 0 12( 26, 7 )f 8(1 2,3 )g na na na na 0 0 0 0 na 0 na na na na 0 0 po siti ve ma rgi n s n .(% ) 2(3 ,27 ) 0 5(9 ,6) 0 0 4(5 ,4) 0 na 0 1(2 ,2) e 3(4 ,6) 3(6 ,1) 0 na na na 0 0 0 na 0 0 na na 0 0 0 me an end op h yti c tum or siz e mm . 23 24 28 26 na 28 23 na na 26 26 na na na na 33l 32, 5 na na na 30 na na na na na 25 ide nti fi cat ion suc ces s n.( %) 61( 100 ) 1(1 00) na 64( 100 ) 22( 100 ) na na na na 44( 97, 8 )d 65( 100 ) na 21( 100 ) 9(1 00) 3(1 00) na 4(1 00) na 6(1 00) 5(1 00) 10( 100 ) 0m 0n 28( 100 ) 0 12( 100 ) 2(1 00) 1(1 00) ide nti fi cat ion me tho d io us io us wit h do ppl er io us and fro zen bio psi es io us and fro zen bio psi es ro bio us io us ilu s o r rob io us io us io us ilu s and fro zen bio psi es io us ro bio us a nd llu si ro bio us ro bio us ilu s ilu s wit h do ppl er ilu s lil us lil us rob io u s and ce us ta e ni rf icg iv ni rf icg and lap io u s iv ni rf icg and ilu s/r o bio us ar : ha 3d nav iga ti on or io us ar : ha 3d nav iga ti on and ni rf tra cki ng ar : rea ltim e io us and vs p 3 d rec ons tr uct ion per cut a neo us em bol iz atio n coi ls and io us su rgi ca l ap pro a ch ra pn tra nsr a pn tra nsr a pn tra nsr a pn ro bot ic enu cle at ion ra pn 3 o r 4 arm tra nsr a pn tra nsr a pn tra ns or ret ror a pn tra nsr a pn tra nsr a pn tra ns and ret ro ra pn 3 -ar m tra nsr a pn of fcla mp tra ns and ret ror a pn tra nsr a pn ra pn tra nsr a pn 4 -ar m tra nsr a pn 3-a rm tra nsr a pn 4-a rm tra nsr a pn of fcla mp tra nsr a pn tra nsr a pn 4-a rm ra pn tra nsr a pn tra nsr a pn ra pn ret ror a pn stu dy arm s ra pn vs lp n for com ple t ely end oph yti c tum ors ra pn vs op n for com ple t ely end oph yti c tum ors ra pn vs op n for com ple t ely end oph yti c tum ors sin gle arm ra pn vs op n for com ple t ely end oph yti c tum ors int rar en al vs exo phy t ic tum ors ra pn ra pn vs op n out com es lon g wi t vs sh ort wi t en dop h yti c v s me sop h yti c v s ex oph y tic ra pn en dop h yti c v s me sop h yti c v s ex oph y tic ra pn ro bot ic vs lap aro sc opi c u s pro be in ra pn sin gle arm co mp le x vs not com ple x tum ors in ra pn sin gle arm ld u vs no ld u in ra pn sin gle arm sin gle arm sin gle arm glo bal vs sel ect iv e v s n o isc hem i a r ap n sin gle arm sin gle arm ni rf icg v s no ni rf icg ra pn 3d a r vs u s gui dan c e ha 3d vs no ha 3d gui dan c e for sel ect iv e cla mp in g sin gle arm mu ltiv a ria te reg res si on : sta tist i cal ly sig nif ic an t cov ari a tes /ou tc om e r.e .n. al . sco re/ pen taf e cta . na na pa du a s cor e/ tr ife ct a ach iev e me nt and tum or dia me te r for exc iso n al vol um e los s na na na na tu mo ratta che d sur fac e are a/ wi t ag e a nd r.e .n. a.l sco re/ pos top e rat ive ren al fun ctio n na na na na na na na na na na na na na na na na na en do p hy tic tum ors n./ tot al tum ors n. 61/ 112 1/1 52/ 89 64/ 140 na /22 87/ 143 30/ 297 8/6 6 4/4 8 45/ 225 65/ 389 49/ 150 h 21/ 22k 9/6 5 3/6 7 12/ 53 4/1 4 12/ 32 6/2 0 5/6 1 10/ 10 2/7 9 5/4 7 28/ 91 12/ 52 2/1 0 1/1 stu dy typ e re tro sp ect ive com par ativ e ca se rep ort re tro sp ect ive com par ativ e re tro sp ect ive com par ativ e re tro sp ect ive cas eser ies re tro sp ect ive com par ativ e re tro sp ect ive com par ativ e re tro sp ect ive com par ativ e re tro sp ect ive com par ativ e re tro sp ect ive com par ativ e pro spe c tiv e com par ativ e re tro sp ect ive com par ativ e re tro sp ect ive cas eser ies re tro ps ect ive cas econ tro l re tro sp ect ive cas eser ies pro spe c tiv e com par ativ e re tro sp ect ive cas eser ies re tro sp ect ive cas eser ies re tro sp ect ive cas eser ies re tro sp ect ive com par ativ e pro spe c tiv e cas eser ies re tro sp ect ive cas eser ies pro spe c tiv e com par ativ e re tro sp ect ice com par ativ e pro spe c tiv e com par ativ e re tro sp ect ive cas eser ies ca se rep ort stu dy gu et al.2 020 (12 ) tir yak i et al.2 018 (66 ) ab del ra hee m et al.2 018 (63 ) ha rke et al.2 018 (65 ) gu nel li et al.2 016 (49 ) ka ra et al.2 016 (50 ) cu rtis s et al.2 015 (51 ) bo ylu et al.2 015 ( 52) sh iro ki et al.2 015 (62 ) ko mn in os et al.2 014 (64 ) au tor in o et al.2 014 (53 ) ka czm a rek et al.2 013 (54 ) ka czm a rek et al.2 012 (56 ) kim e t al.2 012 ( 55) wh ite et al.2 011 (57 ) hy am s et al.2 011 (61 ) ro ger s et al.2 008 ( 60) go ng et al.2 009 (58 ) ho et al.2 009 (59 ) ale nez i et al.2 016 (68 ) sim one et al.2 018 (70 ) an gel l et al.2 013 (81 ) kr ane et al.2 012 (80 ) po rpi gli a et al.2 019 (74 ) po rpi gli a et al.2 018 (73 ) la sse r et al.2 012 ( 77) re eve s et al.2 015 (79 ) endophytic renal mass localization techniques-paparidis et al. vol 19 no 3 may-june 2022 163 statistical analysis, was performed for the distinctive subgroup of completely endophytic tumors (intraparenchymal, parenchymal, totally intrarenal, endophytic non-visible during surgery), which showed low clinical and methodological heterogeneity. pooled odds ratios (or) under random effects, using cochran-mantelhaenszel test, were calculated with medcalc-version 19.7.1 software, and forest-plots were used for presentation (figures 3-7). measured outcomes were, positive margins and recurrences for laparoscopic and robotic or technical success for ablation procedures, due to adequacy of data. we have not used adjusted ors, since they were not provided in all relevant studies and if applied, covariates were not the same in each study. all tumor localization techniques in laparoscopic and robotic procedures were non-invasive ultrasound-based, whereas in ablation procedures such techniques were heterogeneous (invasive and non-invasive) therefore separate analysis was performed respectively. publication bias was assessed using egger’s linear regression test and begg’s rank test, and presented in funnel-plots (figures 3-7). statistical heterogeneity was quantified, using cochran’s q test and i2 statistic index (p < .05 as statistically significant, i2 ≤ 50% for low heterogeneity). the latter was used to assess if the amount of variance across studies was likely to be real and not due to sampling errors. results were presented along with forest-plots(figures 3-7). “r package meta” in r (programming language) was used to perform subgroup meta–regression analysis and determine sources of heterogeneity. only confounding covariates present in all studies, either defined from authors of each study or determined according to our experience, were used for meta-regression. results showed that positive margins in robotic approach were negatively related to patient b.m.i. successful ablation was also negatively related to the number of thermal ablation needles used, as concluded from the negative meta-regression slope(table 4). results laparoscopic assisted partial nephrectomy data from 22 studies regarding 363 endophytic masses that underwent laparoscopic partial nephrectomy (lpn), were collected (table 1). described techniques were, intraoperative ultrasound (ious) (n = 265), intraoperative dual-source ct (dsct) (n = 25), three dimensional printing physical kidney model technique (3dp k.m) (n = 5), intraoperative ultrasound guidance combined with 22 gauge needles for tumor delineation (needle-ious) (n = 3), intratumoral ct-guided percutaneous hook-wire insertion for tumor signage (hook-wire) (n = 2), selective intra-arterial blue dye embolization (blue dye tae) (n = table 3.endophytic tumor localization techniques during ablation procedures. endophytic renal mass localization techniques-paparidis et al. review 164 vol 19 no 3 may-june 2022 100 7), augmented reality (a.r.) (n = 54), radio-guided occult lesion localization (roll) (n = 1). results on ious were extracted from retrospective comparative studies(12-15), retrospective single arm studies(16-20) and a prospective case-series study(21). identification success rate was 100%, mean tumor size was 16-37 mm, positive margin rate was 1.96 % -12.5 % , recurrence rate was 0 % in a mean 3-39.2 months follow-up and complication rate was 15.2 % -60 % . various observational studies(22-25) and reviews(26-29) highlighted the importance of ious for the identification of intrarenal masses, precise delineation of size and depth, and presence of satellite renal masses or collecting system infiltration. dsct was used in a retrospective study(30) for retroperitoneal lpn. overall accuracy of feeding artery orientation was 93.6 %, tumor identification success was 100 %, no positive margins or recurrences occurred in a mean 18-month follow-up. 3dp k.m(31) used markers orientated by anatomical landmarks, labeled on a kidney-model surface. navigation intraoperatively was performed using kidney-model’s distance measurements. mean tumor size was 27.8 mm, treated with trans or retro peritoneal lpn. identification rate was 100 % . no complications or positive margins were reported. needle ious assisted de novo identification of an unidentified intraparenchymal lesion with ious-only guidance. neither positive surgical margins nor recurrences were reported in 27-month follow-up. hook-wire was applied in 2 intraparenchymal tumors (32,33). identification success was 100 % , no complications or positive surgical margins were reported, and a 16-month follow-up in one case showed no recurrence. blue dye tae, followed by super selective tumor embolization with glue or micro coils was presented in a prospective study(34). no complications related to dye injection occurred nor positive surgical margins were present. all tumors were successfully embolized. data regarding identification success were inconclusive. early follow-up imaging showed no recurrences. a.r. summarizes a spectrum of techniques, all based on superimposing pre/intraoperative images, onto endoscopic scene. intraoperative imaging or preoperative 3d-reconstructions can be registered within surgical view in three ways: 1) surface-based registration using a stylus or a range scanner tool, 2) manual registration using fiducials and markers, 3) 3d to 3d registration using stereoscopic robotic camera ability(35,36). 10 masses were identified with real-time imaging like conebeam ct (cbct) combined with fiducial aid technique (37-39). cbct helps to resolve the tissue deformation issue, due to natural organ movement, that can cause imprecise image fusion(40). 44 tumors were identified with 3d reconstructed preoperative image fused with 2d or 3d laparoscopic view(41-44). identification rate was 100% and no positive surgical margins were reported table 4. results of meta-regression subgroup analysis for the five individual meta-analysis scopes. the model slope is presented in separate columns for the binary variables depending on their value (yes or no). statistically significant p values are presented in bold. tables’s abbreviationsce-ct=contrast enhanced ct, na= not assessed, data absent or inconclusive, n. =number, opn= open partial nephrectomy, perc=percutaneous, rfa= radiofrequency ablation rf-rcpn= radiofrequency ablation –assisted robotic clampless partial nephrectomy, retro= retroperitoneal, tit= totally intraparenchymal tumors, trans= trans peritoneal, vsp= virtual surgical planning, vs= versus, wit= warm ischemia time endophytic renal mass localization techniques-paparidis et al. vol 19 no 3 may-june 2022 165 for both techniques. cbct showed no complications while 3d reconstruction technique had 0-13.3 % complication rate. roll successfully used gamma camera for one intraparenchymal tumor in an experimental setting(45), this was the only case reported in english literature(46). completely endophytic subgroup analysis for lpn data were extracted from 12 studies (6 retrospective comparative, 3 retrospective single arm, 3 case-reports) (12,42,13,31,41,18,14,15,20,32,33,45). from 239 tumors, 17 were identified with a.r., 5 with 3dp k.m, 211 with ious, 3 with needle ious, 2 with hook-wire and 1 with roll. intraparenchymal growth showed no correlation to identification success among methods. all techniques had 100 % successful identification rates both for intervention and control groups. odds ratio was 95 % ci ; 0.255-1.971, or 0.709, p = .510, with low heterogeneity (q = 1.355, 95 % ci ; 0.00-41.36, i2 0.00 % , p = .8553) for positive margins with ious guidance or a.r. navigation in lpn(figure 3). positive margins with ious guidance had 95%ci; 0.0519-6.701, or 0.590 in lpn compared to rapn. consecutive studies showed 95 % ci; 0.0201-5.756, or 0.340 ; 95 % ci ; 0.179-3.589, or 0.790 and 95 % ci ; 0.0251-7.191, or 0.425 for an exophytic compared to an intrarenal mass to have positive margins. positive margins for 3d reconstruction a.r. techniques, such as 3d-medical image reconstructing and guiding system (mirgs), over control group had 95 % ci ; 0.116-115.805, or 3.667 for totally intraparenchymal tumors. local recurrence rate using ious, was 0 % in 5 comparative studies(12-14,20,41) with a mean 12-39.2 months follow-up, but data were insufficient for statistical analysis. robotic assisted laparoscopic partial nephrectomy data from 27 studies regarding 598 endophytic masses that underwent robotic assisted laparoscopic partial nephrectomy (rapn), were collected(table 2). ious was the cornerstone of identification methods during rapn(47,48). 365 masses were identified with ious. other sonography-based methods were, ious combined with frozen sample biopsies from tumor bed (frozen-sample ious) (n = 161), intraoperative laparoscopic ultrasound enhanced with color doppler modality (ldu) (n = 7) and intraoperative contrast enhanced ultrasound (ceus) (n = 5). apart from ultrasonography, embolization techniques such as iodized oil trans arterial embolization in tumor feeding-artery (iodized oil tae), tae with near infrared fluoroscopy imaging using indocyanine green (tae nirf-icg) (n = 10), figure 1. search strategy presented with prisma flow-chart endophytic renal mass localization techniques-paparidis et al. review 166 vol 19 no 3 may-june 2022 167 a.r. (n = 42) and percutaneous placement of embolization coils inside the mass for tumor signage (embolization coils) (n = 1) were used. endophytic tumor size in ious techniques(12,49-62) was 23-32,5mm. identification success rate was 100%, complication rate varied 0-21.8% and positive margin rate ranged 0 -6.1 % . recurrence rate varied among studies 0-1.6 % , in 8-48 months follow-up. frozen sample ious studies(63-65) included masses sized 26-28mm. identification success rate was 97.8 % 100 % . positive margin rate was 0-9.6 % . complication rate was 21.9 % -32.7 % , and distal or local recurrence rate was 2.2 % -3.9 % in a mean 48-59 months follow-up. ldu(61,66), was used, not only to locate tumor but to identify the resection margin, and tumor distance from collecting system(67) and to track adjacent vessels(60). identification success was 100 % , without complications. ceus was an alternative sonographic method to drop-in robotic ultrasound for in situ renal blood flow mapping after contrast agent injection(68). it allowed occlusion angiography after mapping vasculature and scanning the tumor along with its position and intraparenchymal depth assessment. tumor identification rate was 100 %(69). efficacy of embolization techniques, such as iodized oil tae and tae nirf-icg, in localizing endophytic tumors was specified in one study(70-72). mean tumor size was 30mm, identification success rate was 100 % , with no positive margins or recurrences at 12-month follow-up and no need for ultrasonography assistance. a.r. techniques with real-time 3d to 3d registration were: hyperaccuracy 3-dimensional reconstruction (ha3d)(73,74) and inverse realism technique using nvidia quadro dvp hardware(75). comparing ha3d to 2d ious techniques, both showed 100 % identification success rates, but with improved maneuverability, enhanced surgical movement and visualization of other hidden structures such as vessels or calyces for the ha3d arm. ha3d aided in 90% successful selective clamping versus 39 % successful pedicle management in non-ha3d group without positive margins in both arms. 3d to 2d image fusion utilizing vascular pulsation cues for guiding preoperative to intraoperative registration(76) was used for occluded structures tracking such as endophytic tumors or vessels occluded by fat during rapn. ious 2d images and 3d reconstructed images integrated in surgical console, but not overimposed to endoscopic view were also described without further numerical data provided. vsp, used reconstructions created preoperatively, and ious real-time imaging both projected simultaneously within surgical view (77). tumor identification rate was 100 % , showing no positive margins or complications. this technique could be helpful in cases with intraparenchymal or hilar tumors accompanying complicated renal vessels(78). ious-tracked embolization coils, were used in an enfigure 2. risk of bias traffic-light plot created with robvis tool. assessment of bias for each non-randomized study throughout seven domains of bias (d1-d7). domains are stratified with a judgment from low to serious. endophytic renal mass localization techniques-paparidis et al. dophytic isoechoic tumor during retroperitoneal rapn (79). identification success 100 % , and negative marginal status or complications, might suggest this as a method of choice when dealing with isoechoic intraparenchymal lesions. completely endophytic subgroup analysis for rapn data were extracted from 13 studies (7 retrospective comparative, 3 retrospective single arm, 3 prospective studies)(51,63,65,12,50,62,64,57,70,80,77,73,81). in 366 tumors, identification success rates were 100 % for a.r. (n = 1), 100 % for ious (n = 158), 99.08 % for frozen sample ious (n = 109), 100 % for tae nirf-icg (n = 10), and 0 % for intravenous (i.v.) nirf-icg (n = 7), (t-test, p = .9730). intraparenchymal growth showed no significant correlation to warm ischemia time(62). analysis for positive margins in ious guided rapn and a.r. navigation for completely endophytic tumors with or without frozen biopsies had total 95 % ci ; 0.379-3.109, or 1.086, p = .878, with moderate heterogeneity (i2 = 46.39 % , p = .0826) (figure 4). positive margins using ious rapn for intrarenal versus exophytic tumors had 95%ci; 0.00336-1.221, or 0.0641. positive margins with frozen sample ious had 95%ci; 1.209-15.835, or 4.375, for completely endophytic versus mesophytic or exophytic masses in lpn compared to rapn. positive margins for a.r. techniques such as ha3d compared to ious control group, had 95 % ci ; 0.186-247.067, or 6.778. total 95 % ci ; 0.0917-2.251, or 0.454, p = .0334 with low heterogeneity (i2 = 0.00 % , p = .07645) was estimated for recurrence in frozen sample ious rapn for intrarenal tumors, as other identification techniques showed insufficient data for further analysis. frozen sample ious had 95 % ci ; 0.0299-3.932, or 0.343 for recurrence after rapn compared to opn and 95 % ci ; 0.0673-4.686, or 0.562 for recurrence after rapn when comparing intrarenal to mesophytic or exophytic tumors(figure 5). radiofrequency ablation data from 14 studies, with 225 endophytic renal masses that underwent radiofrequency ablation (rfa), were collected(table 3). 127 neoplasms underwent percutaneous rfa (prfa), 55 underwent laparoscopic rfa (lrfa), and 26 underwent rfa assisted rapn. hybrid laparoscopic and robotic rfa assisted partial nephrectomy was described in literature without specific data recorded. localization methods described during prfa were: ct guidance alone or combined with ct guidance under general anesthesia (g.a-ct) and fiber optic thermal monitoring (fotm)(82-85), fluoroscopy ct (f-ct) guidance with embolization coil markers (n = 8)(86), ultrasound (us)-only guidance (n = 9)(87) and iodized oil tae(88). rfa with ga-ct and fotm (n = 43) was the only method with 93.48 % technical success rate and 8.7 % recurrence rate compared to 100 % success rate and 0 % recurrence rate of other modalities. tumor size data were only provided for us rfa, showing mean figure 3. odds ratio forest-plot for positive surgical margins after laparoscopic partial nephrectomy for completely endophytic tumors. or calculated overall and separately for positive margins using different localization techniques. i2 shows low heterogeneity of data. funnel-plot, egger’s test and begg’s test were used for publication bias evaluation. endophytic renal mass localization techniques-paparidis et al. review 168 vol 19 no 3 may-june 2022 169 size 26.9mm. complication rate 0% was announced for us and f-ct embolization coil methods. tae was used for difficult-to-detect endophytic tumors, but concise numerical data regarding success rate and surgical outcomes were not provided. lrfa was facilitated either by ious-alone(85,89-91) or combined with visual guidance and fotm(92-93) or ceus (94) for tumor localization. ious-alone technical success rate was 80 % -100 % and recurrence rate was 0 % overall. rfa assisted robotic clamp-less partial nephrectomy for 26 endophytic tumors had 100 % technical success rate and 0 % recurrence rate using ious alone(95). results were inconclusive for iousfotm and ceus. cryoablation data from 10 studies including 187 endophytic tumors treated with cryoablation were collected (table 3). 159 masses underwent with percutaneous cryoablation (pca) and 28 were treated with cryoablation during laparoscopy (lca). 88 were completely endophytic. identification techniques used in pca were: f-ct only or combined with us (n = 112)(96-99) and tae (n = 29) combined with ct guidance such as iodized oil and absolute ethanol tae (100) , iodized oil and gelatin particles tae(101), or polyvinyl alcohol particles in iodinated contrast agent tae(102). combined us and intermittent ct imaging during ablation for 76 masses showed 100% technical success rate, complication rates were 10 % -32 % . recurrence rate was 13 % in one retrospective single arm study with long term follow-up. f-ct only method, had 75 % technical success rate and 12.5 % recurrence rate in a retrospective study including 8 endophytic tumors with mean size 27mm. iodized oil and absolute ethanol tae showed inferior results compared to other tae techniques, with technical success rate 94.12 % , and 29.4 % recurrence rate, versus 100 % technical success rate and 0 % recurrence rate respectively. outcomes were comparable despite small study samples. ious was the only identification method described during lca. a retrospective single arm study(103) showed 33.4 % technical success rate, 0 % complication and recurrence rate in mid-term follow-up during lca for 3 completely endophytic non-visible tumors. limited data, indicated ultrasonography signage inexpediency for treating intrarenal tumors. retrospective comparative studies analysis on ct guided pca and ious guided lca(104-105) showed 100 % technical success and 20 % recurrence rates for both arms, while limitations such as small sample size and restrictions in definitions of technical success, persistent enhancement and recurrence, obscured safe statistical conclusions. microwave ablation data regarding microwave ablation (mwa) were collected (table 3). yu et al. 2012(106) reviewed intermediate-term outcomes after mwa with us and fotm sensors for 44 endophytic masses, mean size 18mm. 26 had parenchymal and 18 had endophytic growth patterns with 17.9-19.8 months median-follow up. parenchymal nodules showed 100 % technique efficacy and no recurrences. endophytic masses showed 94.4 % technique efficacy, and 15 % showed recurrence. retrospective comparative studies(107-109) on ct percutaneous thermal ablation for 165 endophytic masses figure 4. odds ratio forest-plot for positive surgical margins after robotic partial nephrectomy for completely endophytic tumors. or calculated overall and separately for positive margins using different localization techniques. i2 shows moderate heterogeneity of data. funnel-plot, egger’s test and begg’s test were used for publication bias evaluation. endophytic renal mass localization techniques-paparidis et al. showed overall 100 % technical success rate for all intervention types. in mwa group, no urothelial injury or clavien-dindo ii-iv complications occurred. irreversible electroporation one study from diehl et al. (110) reported the use of irreversible electroporation (ire) in endophytic tumors, but data were inconclusive (table 3). completely endophytic subgroup analysis for thermal ablation data were extracted from 11 studies (9 retrospective single arm, 1 retrospective comparative, 1 prospective) (83,84,87,86,93,96,100,101,99,103,106) including 153 completely endophytic tumors. localization methods during prfa were: ct guidance alone or combined with us (n = 18), us-alone (n = 9), and f-ct with embolization coil markers (n = 8). deep endophytic tumors during lrfa were identified with fotm ious. identification techniques during pca were: ct guidance alone or combined with us (n = 77) and iodized oil tae (n = 12), while ious was the only localization modality used during lca (n = 3). us with fotm was used for 26 tumors during percutaneous mwa. total or for technical success after thermal ablation procedures was 95 % ci ; 0.137-5.167, or 0.842, p = .853. we applied separate pooled or reporting for invasive (figure 6.) and non-invasive (figure 7) localization techniques regarding technical success in ablation procedures, in order to avoid heterogeneous data analysis. invasive techniques: iodized tae in pca, 95 % ci ; 0.0118-9.39), or 0.333 and laparoscopic ious guidance in pca, 95 % ci ; 0.000293-0.291, or 0.00923 both showed less likelihood for technical success, total random effect 95 % ci ; 0.0157-2.060, or 0.05690, fixed effect 95 % ci ; 0.00799-0.907, or 0.0851, p = .041, with significant heterogeneity of data 95 % ci ; 0.00-89.13, i2 55.26 % . non-invasive techniques: all non-invasive imaging techniques showed increased likelihood for success with total random effects 95 % ci ; 0.598-13.152, or 2.804 and low heterogeneity of data 95 % ci ; 0.0025.11, i2 0.00 % . us guidance in percutaneous rfa, 95 % ci ; 0.262152.872, or 6.333 and combined ct and us guidance, especially when performed under fotm, in mwa : 95 % ci ; 0.137 -91.090, or 3.533, in pca: 95 % ci ; 0.11847.114, or 2.361 and prfa: 95 % ci ; 0.069626.205, or 1.35, showed increased likelihood for success. comparison between thermal ablation methods showed that endophytic growth pattern attributed to hematoma formation with mean relative risk (rr) 95 % ci ; 0.90-1.51, rr 1.15 and to residual disease with mean 95 % ci ; 1.10-1.87, rr 1.30(107-109). overall estimated cumulative incidence of recurrence was 95 % ci ; 1-19, 5 % , at 3 years and 95 % ci ; 4-27, 10 % at 5 years for pca using combined ct and us guidance for completely endophytic tumors(96). wingo et. al.2008 (93), contrariwise, failed to predict increased risk for recurrence due to endophytic location (chi-square = .81 < 5.99) for ct-fotm prfa or ious lrfa. high intensity focused ultrasound ritchie et al.(111) evaluated 5 entirely endophytic tumors, mean size 20,4mm treated with high intensity focused ultrasound (hifu). us was used for tumor localization, surgical planning and real time evaluation. all were successfully identified. technical success rate was figure 5. odds ratio forest-plot depicting likelihood for tumour recurrence using intraoperative ultrasound guidance with frozen samples from tumor bed in robotic partial nephrectomy for completely endophytic tumours. i2 shows low heterogeneity of data. funnel-plot, egger’s test and begg’s test were used for publication bias evaluation. endophytic renal mass localization techniques-paparidis et al. review 170 vol 19 no 3 may-june 2022 100 20 %. no major complications occurred. recurrence rate was 25 % in a mean 36-month follow-up. discussion evidence on excision techniques showed that ious was widely applied identification method, with high identification rates, and recurrence rates up to 1.6 % in follow up period up to 60 months. positive margin rates were 1.96-12.5 % in lpn and 0-6.1 % in rapn, while complication rates varied from 0 % in lpn to 0-21.8 % in rapn. kaczmarek et al.2013(54) showed similar efficacy between laparoscopic and robotic ious probes, robotic group though, excelled in autonomy, maneuverability, cost effectiveness and practicality when depicting challenging tumor angles. frozen sample ious during rapn, showed increased complications, without improving positive margin or recurrence rates; making it questionable whether it should be performed. ldu or ceus showed insufficient data regarding tumor tracking but aided in identifying hidden vasculature, defining safe excisional margins or contact with the collecting system. dsct combined high identification success rate with efficient tumor feeding artery orientation. a.r. was useful in identification, especially within a robotic setting. overlapped 3d onto realtime endoscopic image, enhanced anatomical structures(112). despite high identification success rates, data were inconclusive to support superiority over conventional techniques. findings are compatible with international literature (113,114). only ha3d showed superiority compared to ious during rapn regarding surgical autonomy, and selective artery clamping. isoechoic intraparenchymal mass tracking was achieved using embolization coils during rapn. further studies are needed to confirm whether embolization coil or hook wire techniques could be the gold standard for such tumors. unlike tae nirf-icg, i.v. nirf-icg was contraindicated for endophytic tumors(115,40). studies(80,81) showed no identification success. the only utility for intraparenchymal lesions, was tumor delineation once surrounding normal parenchyma was first incised(116-119). regarding excision methods for completely endophytic tumors, identification success rates were high, regardless of identification technique, both for lpn and rapn. positive margins showed 40% less likelihood in ious guided lpn compared to rapn and significantly decreased odds for ious guided lpn or rapn for totally intraparenchymal tumors compared to masses with exophytic component. odds for positive margins were increased in a.r. techniques compared to ious during laparoscopic or robotic procedures for intrarenal masses. chances for recurrence were in favor of ious lpn compared to rapn, lca or laparoscopic radical nephrectomy and increased odds for recurrence were found during laparoscopy for intraparenchymal versus exophytic masses. frozen sample ious showed increased likelihood for positive margins in intrarenal compared to exophytic tumors and 45% less likelihood for recurrence of parenchymal masses compared to mesophytic or other exophytic lesions. evidence on ablation procedures suggest that, ct was preferred to us during all thermal ablation procedures figure 6. invasive techniques in ablation procedures. forest-plot depicting odds ratios for technical success during thermal ablation procedures for completely endophytic tumors. cochran’s q test and i2 statistic are calculated for heterogeneity. funnel-plot, egger’s test and begg’s test show publication bias. endophytic renal mass localization techniques-paparidis et al. vol 19 no 3 may-june 2022 171 due to improved anatomic resolution, ancillary maneuver permeability and periprocedural complication evaluation(109). ct guided prfa had technical success rate 93.48 % -100 % and recurrence rate 0-8.7 % in 2-year follow-up. g.a aided in better targeting and minimizing complications risk. wingo et al.2008(93) showed that fotm rfa, improved success rate. gupta et al.2009 (82) showed that or, an endophytic lesion compared to non-endophytic to be incompletely treated, was 95 % ci ; 0.65-24.8, or 4.0. rr of developing any recurrence for endophytic lesions compared to non-endophytic was 95 % ci ; 0.6-11.7, rr 2.6, p = .20. endophytic tumors were more resistant to ablation because of the “heat sink” effect caused by blood vessels surrounding the tumor. endophytic central masses had the highest risk for recurrence (hazard ratio hr, 6.3; p = .016). matsumoto et al.2005.(120) stated that, endophytic lesions, hardly localized during open partial nephrectomy and technically challenging for lpn, were easily targeted and ablated with ct-guided rfa. pietryga et al.2012(86) showed that use of marker coils in poorly visualized tumors, such as intraparenchymal and isoechoic lesions, facilitated ct prfa, by 58 % reduction in ct fluoroscopy time, showing equivalent technical outcomes with noncoil group. tae as add-on to prfa for difficult-to-detect endophytic tumors, reviewed by sommer et al.2017 (88), showed that residual post ablation positive margins were more common for endophytic tumors. ious lrfa, showed technical success 80-100%. yang et al.2014(94) showed that ceus, improved tumor outline visibility prior to ablation, allowed enhancement status evaluation after ablation, required no warm ischemia and allowed increased parenchymal preservation. ct pca showed technical success 75 % , reaching 100 % when combined with us. recurrence rate was approximately 13 % in short-term follow-up, and complication rate was 10-32 %. tae pca, technical success rate was comparable (94.12 % to 100 % ) but with higher percentage for recurrences (29.4 % ). harmon et al.2018(102) showed that pre ablation adjuvant embolization allowed better tumor demarcation, reduced cryoneedles needed and minimized procedural cost and complications. the “poor visualization phenomenon" concerning intraparenchymal or partly endophytic renal masses in unenhanced ct was a factor compromising pca success. therefore, kajiwara et al.2020(101) proposed a five-tier visualization score based on hounsfield units. mean visualization score, solely for endophytic and parenchymal tumors, after tae pca was 4, representing a tumor margin visibility 75-90 % . data on ious lca, showed technical success 33.4 % , probably due to ultrasonography signage inexpediency(103). multivariate analysis revealed that only endophytic status is a predictor of failure. derweesh et al.2008(105) compared lca to pca for endophytic tumors and showed that they had significant association with tumor persistence. nisbet et al. 2009(121) proposed a decision tree on whether to perform ious lca or lpn for small renal masses. endophytic tumors were predicted to have better results when treated with lca. results on completely endophytic subgroup for abfigure 7. non-invasive techniques in ablation procedures. forest-plot depicting odds ratios for technical success during thermal ablation procedures for completely endophytic tumors. cochran’s q test and i2 statistic are calculated for heterogeneity. funnel-plot, egger’s test and begg’s test show publication bias. endophytic renal mass localization techniques-paparidis et al. review 172 vol 19 no 3 may-june 2022 173 lation procedures, showed that non-invasive imaging techniques had increased likelihood of success. ct prfa had slightly increased odds for technical success between totally intrarenal and endophytic tumors (95 % ci ; 0.069626.205, or 1.351). technical success during us prfa was also in favor of intraparenchymal masses. combined ct and us pca, favored success over completely endophytic lesions compared to other endophytic tumors. us mwa with fotm, increased likelihood of success when applied to intrarenal masses compared to endophytic. contrariwise, invasive techniques showed less likelihood for success. tae pca showed 33 % less likelihood of success for intrarenal masses compared to masses with exophytic components. chances of success for completely endophytic tumors were significantly lower compared to masses with exophytic component during ious lca (95 % ci ; 0.000293-0.291, or 0.00923). data on recurrence after ablation were contradictive and therefore inconclusive. our limitations were 1) study selection bias from english language restriction: additional database search resulted in 6 studies eligible for further evaluation according to abstract, written in russian, spanish, french and hebrew. as authors were incapable of translating, we avoided including non-english literature due to bias of misinterpretation. 2) further databases could have been searched, such as scopus, which was not searched due to limited access. 3) serious uncontrolled confounding bias due to unmeasured confounders. 4) sparse data bias: unrealistic huge pooled or estimates and confidence limits, observed in subgroup analysis, suggest that sparse data is an important source of bias. 5) bias deriving from study design: no randomized controlled studies and limited number of prospective studies were included (6 comparative, 5 single arm studies and 1 multi-institutional), the majority were retrospective, making data extraction strenuous due to ambiguous reporting quality. 6) missing data within studies: data were partially missing or inconclusive in 58 studies, while 19 had complete data for extraction. 7) heterogeneity in terminology: variance in definitions of terms was a major drawback. the term endophytic described a variety of masses, ranging from totally intraparenchymal to masses protruding up to 50% from capsule. other definitions such as technical success rate, tumor response rate and recurrence, were diverse among studies resulting in bias during the interpretation of outcomes, although goldberg et al.2003(122) proposed a protocol for standardization of terms and reporting criteria for image guided ablation. 8) small study samples. low level of evidence, inconsistent reporting of data, bias in study design or subgroup analysis, small samples and heterogeneity of definitions led us to perform a narrative systematic review instead of meta-analysis. conclusions ious in lpn and rapn was an adequately evaluated method for tumor localization with high identification rates and acceptable oncologic outcomes. a.r., although showing increased surgical maneuverability and autonomy, showed no superiority regarding identification success, positive margins and recurrences. i.v nirf-icg, was not an appropriate option for successful endophytic tumor tracking. ct alone or combined with fotm and us, showed increased technical success for endophytic and intraparenchymal tumors during thermal ablation. us alone during lca, had discouraging results regarding technical success. limited evidence on isoechoic endophytic masses, suggest that more invasive localization methods such as hook-wire or embolization coil techniques, might rise as method of choice for such tumors. conflict of interest the authors report no conflict of interest. references 1. ljungberg b, albiges l, abu-ghanem y, et al. european association of urology guidelines on renal cell carcinoma: the 2019 update. eur. urol. 2019; 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however, data regarding a possible association with sex cordstromal testicular tumors are scarce. (2) hereby, we present a rare case of unilateral malignant lct in a patient with a history of contralateral cryptorchidism. case report a 72-year -old man presented with a 2-month history of painless left testicular enlargement. in the past, he had undergone orchidopexy of the contralateral testis for cryptorchidism. physical examination revealed an irregular hard swollen left testis and a small right one. he had no gynecomastia. tumor markers ( -fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase) were negative for malignancy. ultrasonography revealed an 11 × 6-cm nonhomogeneous testicular mass with multiple hypoechoic nodules. metastases were not evident in the staging investigations. figure 1. malignant leydig cell tumor: pronounced nuclear and cellular polymorphism and abnormal mitosis (× 400). figure 2. tumor cells stained for inhibin a (× 400). cryptorchidism and leydig cell tumor—efthimiou et al urology journal vol 6 no 1 winter 2009 61 a left radical orchidectomy was performed. histopathology of the specimen revealed malignant lct (figure 1). immunohistochemistry was positive for inhibin a (figure 2) and ki-67 (figure 3), and it was negative for pancytokeratin, cytokeratins ae1/ae3, cytokeratins 8/18, epithelial membrane antigen, carcinoembryonic antigen, alpha-fetoprotein, human chorionic gonadotropin, vimentin, cd30, and actin. postoperative hormone profile revealed hypergonadotropic hypogonadism. the patient was placed on testosterone substitution and retroperitoneal lymph node dissection was suggested, but he declined further surgery. discussion around 41.7% of the lcts in adults are diagnosed incidentally on ultrasonography, 29.2% present with a palpable testicular mass, 16.6% with scrotal pain, and 12.5% with gynecomastia.(3) gynecomastia is an unusual manifestation of a malignant lct and deserves special attention as it may progress to a palpable testicular mass over a 10-year period. leydig cell tumors in an undescended testis may exhibit only manifestations of endocrinological disorders (gynecomastia, impotence, and loss of libido). ultrasonographic findings vary, and hypoechoic nodules with a nonhomogeneous echoic pattern is the most prevalent feature.(3) contrast-enhanced magnetic resonance imaging seems to be superior to ultrasonography.(4) histopathological criteria are useful in predicting malignant potential.(5) in our patient, microscopic features included marked nuclear atypia and increased mitotic activity without vascular invasion or infiltrating margins. furthermore, additional value may be gained by dna aneuploidy and increased expression of ki67/mib-1 and p53,(5) as in our case in which ki-67 was expressed in 10% of the malignant cells. a thorough review of the literature revealed 480 reported lcts in adults.(2) however, only 20 cases were associated with cryptorchidism, indicating a minimal incidence in these patients. fifteen and 3 unilateral lcts have been reported in terms of homolateral cryptorchidism (3 intraabdominal testes) and bilateral cryptorchidism (1 intra-abdominal testis), respectively. a case with bilateral lcts was reported in a patient with unilateral cryptorchidism.(6) finally, a case of unilateral lct with contralateral undescended testis was reported; however, the malignant potential of the tumor was unclear.(7) our case presents the second report of such a rarity. molecular studies have shown specific mutations to have a causative role.(8-10) there is no evidence that undescended testes are prone to develop lcts. although testicular dysgenesis syndrome has been associated with testicular germ cell tumors,(11) it is unclear whether the same link can be proposed for lcts. further studies are needed to clarify this field. conflict of interest none declared. references 1. cheville jc. classification and pathology of testicular germ cell and sex cord-stromal tumors. urol clin north am. 1999;26:595-609. 2. albers p, albrecht w, algaba f, et al. guidelines on testicular cancer. european association of urology; 2008. p. 23-5. 3. carmignani l, salvioni r, gadda f, et al. long-term followup and clinical characteristics of testicular leydig cell tumor: experience with 24 cases. j urol. 2006;176:2040-3. 4. fernandez gc, tardaguila f, rivas c, et al. case report: mri in the diagnosis of testicular leydig cell tumour. br j radiol. 2004;77:521-4. 5. cheville jc, sebo tj, lager dj, bostwick dg, farrow gm. leydig cell tumor of the testis: a clinicopathologic, dna content, and mib-1 comparison of nonmetastasizing and metastasizing tumors. am j surg pathol. 1998;22:1361-7. figure 3. immunohistochemical nuclear expression of ki-67 (× 400). cryptorchidism and leydig cell tumor—efthimiou et al 62 urology journal vol 6 no 1 winter 2009 6. safak m, adsan o, baltaci s, bedük y. bilateral leydig cell tumors with unilateral cryptorchidism. case report. scand j urol nephrol. 1994;28:433-4. 7. calleja rk, rice a, bullock kn. unilateral leydig cell tumour associated with a contralateral undescended testis. bju int. 1999;83:152. 8. liu g, duranteau l, carel jc, monroe j, doyle da, shenker a. leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. n engl j med. 1999;341:1731-6. 9. fragoso mc, latronico ac, carvalho fm, et al. activating mutation of the stimulatory g protein (gsp) as a putative cause of ovarian and testicular human stromal leydig cell tumors. j clin endocrinol metab. 1998;83:2074-8. 10. carvajal-carmona lg, alam na, pollard pj, et al. adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations. j clin endocrinol metab. 2006;91:3071-5. 11. skakkebaek ne, holm m, hoei-hansen c, jorgensen n, rajpert-de meyts e. association between testicular dysgenesis syndrome (tds) and testicular neoplasia: evidence from 20 adult patients with signs of maldevelopment of the testis. apmis. 2003;111:1-9. case report hourglass urinary bladder in a male patient with paraplegia subramanian vaidyanathan,1* bakul m soni,1 peter l hughes,2 gurpreet singh,3 tun oo1 keywords: urinary bladder; diseases; pathology; spinal cord injuries; paraplegia; etiology; complications. introduction hourglass deformity of urinary bladder may occur as a result of congenital malformations (the commonest cause), herniated calculous bladder with an incarcerated incisional hernia, hypertonic neurogenic bladders, an improperly constructed augmentation cystoplasty or tuberculous cystitis.(1) we describe a spinal cord injury patient with paraplegia, who had undergone suprapubic cystostomy. hourglass bladder was detected by computed tomography, which was performed to investigate infected pressure sore in left hip. case report a british, caucasian male, born in 1938, sustained complete paraplegia at t8 level in march 1978 due to fall from a ladder while working on a drain pipe. he had indwelling urethral catheter during the acute stage and then condom drainage. in 1989, he underwent implantation of medtronic synchromed pump for intrathecal delivery of baclofen. in 1997, this patient developed a pressure sore in perineum involving the urethra, which was repaired by posterior thigh flap. the flap broke down. therefore, suprapubic cystostomy was performed on 12 december 1997. he was not prescribed any antimuscarinic drugs. the bulbar urethra got closed completely. in april 2008, this patient developed urinary tract infection. computed tomography (ct) scan of urinary tract revealed right renal calculi. the right kidney was hydronephrotic with dilatation of the pelvis and hydroureter extending all the way up to the vesico-ureteric junction with calcification/calculi noted within the right lower ureter. there were also calculi within the right renal pelvis and right lower pelvicalyceal system. right nephrostomy was performed followed by percutaneous lithotripsy of renal calculi. regional spinal injuries centre1, departments of radiology2 and department of urology3, district general hospital, southport, merseyside pr8 6pn, united kingdom. * correspondence: regional spinal injuries centre, district general hospital, town lane, southport, merseyside pr8 6pn, united kingdom. tel: +44 1704 547471; fax: +44 1704 543156. e-mail: subramanian.vaidyanathan@nhs.net. received april 2011 & accepted january 2012 figure 1. axial section of computed tomography of pelvis showed inflammatory granulation tissue in right hip; there was old dislocation and resorption of right femoral head. in the left hip, there was an abscess. again there was resorption and lysis of the femoral head. . an incidental finding was hourglass deformity of urinary bladder. suprapubic catheter was located in the anterosuperior compartment of the hourglass bladder. figure 2. axial section of computed tomography of pelvis clearly showed hourglass deformity of urinary bladder. suprapubic catheter was located in the anterosuperior compartment of the hourglass bladder. case report 1908 in 2008, this patient underwent ct scan of pelvis to investigate infected pressure sore in left hip. ct scan revealed inflammatory granulation tissue in right hip, old dislocation and resorption of the femoral head. an incidental finding was hourglass deformity of urinary bladder (figures 1, 2 and 3). the balloon of foley catheter was located in the anterosuperior compartment of hourglass bladder. discussion possible reasons for development of hourglass bladder in spinal cord injury patients are: traction applied to dome of urinary bladder by foley balloon when suprapubic catheter is taped tightly to anterior abdominal wall for several months; uncoordinated contractions of detrusor muscle; and chronic cystitis leading to hypertrophy of bladder wall.(2) ogawa and colleagues(3) found high-grade (greater than grade ii) bladder deformity more frequently in persons with complete spinal cord injury than in patients with incomplete injury. all patients with low compliance bladder had a high-grade bladder deformity. there was a significant relationship between severity of urinary tract infection and severity of bladder deformity. our patient had complete paraplegia and was getting urine infections. probably, the balloon of foley catheter, which was taped to anterior abdominal wall, had caused continuous, slow traction upon the bladder over a long period. these factors contributed to development of hourglass deformity of urinary bladder in our patient. intermittent catheterization program has been shown to be effective in preventing bladder deformity;(4) unfortunately, this patient could not manage his bladder by intermittent catheterization soon after spinal cord injury. kim and colleagues(5) studied 109 male spinal cord injured patients at the houston veterans affairs medical centre, who had been treated with chronic indwelling catheters (80 transurethral and 29 suprapubic). thirty-eight patients (35%) were identified as using oxybutynin on a regular basis. these patients were compared to those not using oxybutynin with regard to urodynamic parameters and upper tract deterioration. regular use of oxybutynin was found to be beneficial in spinal cord injured patients figure 3. sagittal reformat of computed tomography of pelvis showed thick walled urinary bladder. suprapubic catheter was located in the anterosuperior compartment of the hourglass bladder. who required chronic indwelling catheters. hydronephrosis was present in 15 of 66 patients (23%) without oxybutynin versus 1 of 36 (3%) patients, who were taking oxybutynin (p = .009). only recently, we started prescribing oxybutynin or propiverine hydrochloride as a routine to spinal cord injury patients with indwelling urinary catheters in order to reduce complications such as low vesical compliance, high-grade bladder deformity, and hydronephrosis. hourglass deformity of urinary bladder is a risk factor for upper urinary tract complications in patients with spinal cord injury.(3,4) this patient with hourglass urinary bladder also developed upper urinary tract complications; he had stones in right kidney with right hydronephrosis. in order to prevent occurrence of hourglass deformity of urinary bladder in spinal cord injury patients, we have been trying to implement the following measures: •intermittent catheterization along with antimuscarinic drug therapy should be recommended as the preferred method of bladder management in spinal cord injury patients •if a patient requires chronic indwelling urinary catheter, antimuscarinic drugs should be prescribed routinely to reduce uncoordinated contractions of detrusor muscle. •all possible measures including improved personal hygiene should be undertaken to prevent chronic urinary infection, as chronic bladder infection leads to hypertrophy of bladder wall. •traction should not be applied to suprapubic foley catheter while fixing the catheter to anterior abdominal wall. we routinely use cathgrip (bioderm inc. largo, florida 33773, usa) to anchor suprapubic catheters in spinal cord injury patients. conclusion patients with hourglass deformity of urinary bladder can develop problems with drainage of suprapubic catheter, especially if the tip of foley catheter is located in the superior compartment of hourglass bladder. but in this patient, suprapubic catheter continued to drain satisfactorily, as the bulbous urethra had closed completely. conflict of interest none declared. references 1. singh i, goel r, doddamani d, ansari ms, dogra pn. hourglass bladder – an unusual com plication of tubercular cystitis. bju int. 2002;90:e20-e21. 2. vaidyanathan s, hughes pl, soni bm, singh g, mansour p. hourglass urinary bladder in a spinal cord injury patient unusual late compli cation of suprapubic cystostomy: a case report. cases j. 2009;2:6866. 3. ogawa t, yoshida t, fujinaga t. bladder de formity in traumatic spinal cord injury patients. hinyokika kiyo. 1988;34:1173-8. 4. ogawa t. bladder deformities in patients with neurogenic bladder dysfunction. urol int. 1991;47 suppl 1:59-62. hourglass urinary bladder in patient with spinal cord injury-vaidyanathan et al vol 11. no 05 sept-oct 2014 1909 hourglass urinary bladder in patient with spinal cord injury -vaidyanathan et al 5. kim yh, bird et, priebe m, boone tb. the role of oxybutynin in spinal cord injured patie nts with indwelling catheters. j urol. 1997;158:2083-6. case report 1910 pediatric urology extravesical common sheath ureteral reimplantation versus intravesical techniques for refluxing duplex systems in children hamdy a. aboutaleb1,2*, tamer a. ali3,4, moamen m. amin3, mohamed f. sultan1 purpose: retrospective comparative study of the efficacy of extravesical non-dismembered common sheath ureteral reimplantation (ecsr) versus intravesical common sheath ureteral reimplantation (icsr) techniques for the correction of vesicoureteral reflux (vur) in complete duplex systems. material and methods: between 2010 and 2019, ecsr was performed in 38 children (8 bilaterally), and the mean ages at presentation and at surgery were 31 and 57 months, respectively. the icsr technique was performed in 25 units (25 patients). voiding cystography and ultrasound of the kidney and bladder were performed 3 and 12 months postoperatively. we analyzed the surgical outcomes for both groups. results: the mean follow-up times for the ecsr and icsr groups were 15 and 18 months, respectively. the success rate of the ecsr group was 93.5% at 3 months, improving to 95.7% at an average of one year; the rate of the icsr group was 96% at 3 months and was the same after one year, with no significant difference between the two groups (p = .66). postoperative complications were compared in the ecsr and icsr groups: transient contralateral vur was seen in 5 renal units versus 4, de novo hydronephrosis was seen in 3 units versus 2, and utis were observed in 3 patients versus 4. conclusion: both (ecsr) and (icsr) surgeries are highly successful for the correction of vur in uncomplicated complete duplex systems. the results of the extravesical approach are comparable with those of the intravesical technique with less morbidity and a shorter hospital stay. thus, ecsr is our preferred technique when open surgical repair is indicated. icsr should be reserved for complicated duplex systems necessitating concomitant reconstructive surgery. keywords: vesicoureteral reflux; duplex systems; ureteral reimplantation. introduction despite their rarity, with an incidence of 0.75% in the general population, renal duplex system anomalies are associated with vesicoureteral reflux (vur) in 95% of cases.(1-3) duplicated collecting systems are more common in females. spontaneous resolution of vur in duplex systems is assumed to be lower than that in single systems because of the anatomical configuration that prevents the development of an adequate submucosal tunnel.(2) some early studies suggested a high success rate of up to 58% for the nonsurgical management of refluxing duplicated systems, including high-grade vur. (4) on the other hand, lee et al.(2) reported higher resolution rates for grade i and ii reflux in duplex systems (85%), which decreased to 36% in grade iii and then decreased to nil (0%) in grade iv and v reflux. again, due to the nature of the anomaly, endoscopic sub-ureteral injections have shown poor results for the correction of reflux in complete duplex systems. (5-7) to date, the presence of vur in duplex systems, especially high-grade vur, has been considered an indication for open surgical correction.(8) in most studies in the published literature, laparoscopic and robotic ureter1urology department, menoufia university hospitals, menoufia, egypt. 2burjeel hospital, abu dhabi, uae. 3urology department, al-azhar university hospitals, cairo, egypt. 4gulf medical university, ajman, uae. *correspondence: professor of urology, menoufia university, egypt & burjeel hospital, abu dhabi, uae. p.o 7400 tel: +971 (50) 5323804. email: hamdyabotaleb@yahoo.com. received march 2021 & accepted september 2021 al reimplantation techniques have been reported to have equivalent success rates to open surgery.(9,10) however, because of the lack of randomized controlled trials and the insufficient long-term outcome data, open ureteral reimplantation is still accepted as the gold standard.(11) our objective is to compare retrospectively; (ecsr) versus (icsr) techniques for the correction of vesicoureteral reflux (vur) in complete duplex systems. material and methods in this retrospective comparative study, we reviewed all patients who underwent surgery for vur in complete duplex systems between 2010 and 2019. the criteria for selection for the type of technique either icsr or ecsr were based on the degree of reflux, surgeon preference and experience with technique as it is retrospective study. data were collected for all patients who underwent ecsr and icsr. the persistence of vur for more than 48 months, two breakthrough urinary tract infections (utis), upper tract deterioration (grade of reflux, renal functions) and noncompliance with medical management were considered indications for surgery. patients with incomplete ureteral duplications and other urology journal/vol 18 no. 6/ november-december 2021/ pp. 658-662. [doi: 10.22037/uj.v18i.6740] vol 18 no 6 november-december 2021 659 pathological conditions (for example, ureterocele) were excluded from our study. ecsr technique: if an extravesical procedure (lichgregoir technique) is planned, cystoscopy should be performed preoperatively to assess the bladder mucosa and the position and configuration of the ureteral orifices. the ecsr technique was performed as described by zaontz et al.,(12) briefly, through a pfannenstiel incision, the bladder was exposed and rotated to expose the involved ureters. ureters were gently mobilized together with attention to blood supply. the detrusor muscle was incised to expose the bladder mucosa to create the muscular defect that will form the tunnel, which should have a 5:1 ratio, based on the side-to side combined diameters of the two ureters. the edges of the detrusor muscle were dissected from the mucosa to form two detrusor flaps and trough sufficient to accommodate the common sheath. two advancing sutures were made, and the detrusor defect was closed over the ureters to form the submucosal tunnel (figures 1-3). icsr technique: the cohen cross-trigonal technique and modified leadbetter technique were performed in patients who underwent icsr. all patients were assessed postoperatively by kidney-bladder ultrasound (u/s kub) and voiding cystourethrography (vcug) at three months and at one year. all children were maintained on prophylactic antibiotics until the resolution of reflux was documented by vcug. we analyzed the outcomes in these two surgical groups in terms of success rates, contralateral reflux, de novo hydronephrosis, (utis) and the incidence of complications. data were collected, tabulated, and entered the statistical package for social science (ibm spss) version 20 for statistical analysis. results ecsr was performed in 38 children (8 males and 30 females), of whom 8 underwent bilateral reimplantation. their mean ages at presentation and at surgery were 31 months (range from birth-100) and 57 (11 –120) months, respectively. urinary tract infections represented the mode of presentation in 24 patients, antenatal hydronephrosis in 12 patients and incidental discovered reflux during investigations in 2 patients. one child had family history of reflux with past history of febrile uti. the second had voiding dysfunction and did not respond to anticholinergic medications. we found no statistically significant difference between the degree of reflux in either groups (p = .6). icsr was performed in 25 patients (20 females & 5 males) who underwent surgery. the mean ages at presentation and at surgery were 21 months (range from birth 90) and 40 (range from 13-122) months, respectively. the mode of presentation was uti in 22 patients and antenatal hydronephrosis in 3 patients. overall, the indications for surgery were breakthrough utis in 25 patients, persistence of reflux (follow-up > 48 months) in 31 patients, and deterioration in the grade of reflux in 7 patients. the table 1. demographics and success rates for duplex systems in all anti-reflux procedures. ecsr group icsr group statistics no of patients (% of total) 38 (60.3%) 25(39.7%) na no. of units 46 (60.5%) 25 (50%) .289 grade of reflux ii 8 (17.4%) 6 (24%) .601 iii 22 (47.8%) 8 (32%) iv 10 (21.7%) 6 (24%) v 6 (13.1%) 5 (20%) success rates at 3 months 43/46 (93.5%) 24/25 (96%) .659 last follow up 44/46 (95.7%) 24/25 (96%) .943 figure 1. dissection of the lower part of the duplex ureter. figure 2. creation of a tunnel with undermining the edges to cre-ate flaps for duplex ureters. common sheath ureteral reimplantation-aboutaleb et al. distribution of reflux grade is described in (table1). mean operative time was 125 minutes (range 105-140) for ecsr group compared to 160 minutes (range 115220) in icsr group (table 2). the mean postoperative follow-up in the ecsr and icsr groups were 15 (range 3-28) and 18 (range 3–32) months, respectively. the success rate of ecsr was 93.5% at 3 months, which improved to 95.7% at an average of 15 months (range 6-28). there was no statistically significant difference in the success rate of the ecsr group and that of the icsr group (p = .66). mean hospital stay was 3.8 days in ecsr group compared to 6.7 days in icsr group. urethral catheterization postoperatively was 3 days for ecsr versus 5 for icsr. all postoperative complications are described in the (table 3). persistent lowgrade reflux was noted after ecsr in 2 units (5%), one of which was resolved after 6 months with continuous prophylactic antibiotic. new contralateral reflux was detected in five renal units (13%) after ecsr. reflux was mild and resolved spontaneously with follow-up. de novo hydronephrosis was noted after ecsr in three units (8%), and it was mild and resolved after one year of follow-up. two patients (5%) had postoperative urinary retention after bilateral ecsr. for these two patients, they are managed conservatively with re-catheterization for more few days and removed safely with good urine flow. no patients had hematuria or bladder spasms postoperatively for ecsr group. three patients (8%) had postoperative utis. these post-ecsr complications were not correlated with the grade of vur. all the patients who underwent icsr were cured from reflux without significant complications, except two (8%) patients who had de novo hydronephrosis as an impact of the surgery, which is resolved spontaneously with conservative management, four (6%) who had utis and six (24%) who had postoperative hematuria. bladder spasms was reported in the form of leakage of urine around the catheter, pulling the catheter, crying and pain in 4 patients (16%) required anticholinergic medications. all the patients who underwent icsr had urethral catheterization for 5 days (range 3 – 10), while the patients who underwent ecsr had a catheter for 3 days (range 2-7). no statistically significant difference was found between the two groups regarding the postoperative persistence of reflux, contralateral reflux, or de novo hydronephrosis or the incidence of utis. discussion a duplex collecting system is one of the most reported urinary tract anomalies in the pediatric population. (13) the management of vesicoureteral reflux in duplicated collecting systems has evolved with time. in duplicated ureters with vur, without obstruction, and with preserved function of both renal moieties, the gold-standard surgical intervention is ureteral reimplantation. therefore, surgery remains the primary mode of management.(14,15) controversies regarding the management of reflux in duplex systems are still present because of the complexity of these anomalies and the availability of many nonand/or minimally invasive alternative treatments. some have advised medical management(16), but the low-resolution rate with long-term follow-up has prompted some surgeons to recommend early surgical intervention, especially for higher grades of vur. (17-19) the toronto team tried to inject low-grade refluxing duplex systems with macroplastique between 1997 and 2000 in 22 reflux moieties. they selected patients with low-grade reflux only. they had a success rate of 68% at the three-month follow-up, which improved to 81.8% at one year. they considered high-grade reflux in duplex systems to be an indication for early ureteral reimplantation. they compared these results with the results of ecsr performed in 34 children (10 bilaterally). the results showed that the success rate of ecsr was 95.5% at 3 months, which improved to 97.7% at an average of 15 months (p = .04).(20) our patients required surgical intervention due to the persistence of reflux after 48 months of follow-up or due to recurrent breakthrough infections during follow-up. various surgical interventions are available for repairing refluxing duplicated systems, including common sheath ureteral reimplantation techniques, such as icsr and ecsr. various ecsr and icsr techniques have been described for the surgical correction of vur. among these techniques, the cohen (intravesical) and lich-gregoir (extravesical) techniques are most used. however, there are a limited number of studies in the literature that have compared these two surgical techniques. in our study, common sheath reimplantation was performed via an extravesical approach in 38 patients and an intravesical approach in 25 patients. various techniques were used as dictated by surgeon preferences. our success rate with the extravesical technique was similar to that reported for reimplantation in single systems (92% to operative data ecsr group icsr group statistics no of patients (% of total) 38 (60.3%) 25 (39.7%) na hospital stays range (2-7) days (mean 3.8 + 2.2 days) range (3-10) days (mean 6.7 + 2.9 days) p < .05 period of urethral catheterization range (2-7) days (mean 3 3.5+ 1.7 days) range (3-10) days (mean 5.9 + 2.7 days) p < .05 operative time range (105-140 minutes) mean 123 + 21 minutes range (115-220 minutes) mean 151 + 17 minutes p < .05 table 2. operative data. postoperative complications ecsr group icsr group statistics no of patients (% of total) 38 (60.3%) 25 (39.7%) na persistence of reflux 2 (5.3%) 1 (4%) .817 contralateral reflux 5 (13.2%) 4 (16%) .753 de novo hydronephrosis 3 (7.9%) 2 (8%) 1.0 postoperative urine retention 2 (5.3%) 0 na postoperative hematuria 0 6 (24%) na utis 3 (7.9%) 4 (16%) .316 bladder spasms 0 4 (16%) na common sheath ureteral reimplantation-aboutaleb et al. pediatric urology 660 vol 18 no 6 november-december 2021 661 100%).(21-22) mesrur et al.(21) reported that both the intravesical and extravesical techniques had advantages and disadvantages, with high success rates reaching more than 90%. on the other hand, the evidence comparing these techniques is not yet sufficient, and there is a need for optimization of open surgical techniques. their results confirmed that both the cohen and the lich-gregoir procedures had equivalent success and complication rates in the treatment of unilateral primary vur. in addition, the lich-gregoir technique was superior to the cohen technique in terms of the hospital stay and operative time. moreover, it avoided the need for urethral and ureteral stenting, which may increase the comfort of patients postoperatively. ellsworth et al.(23) reported on common sheath ureteral reimplantation in refluxing systems. they reimplanted 48 units intravesically, and only 6 units were reimplanted extravesically. the overall success rate was 96%. they concluded that even though the presence of a duplicated collecting system increased the risk for surgical treatment, it did not adversely affect the surgical outcome. modifications of procedures commonly performed in the surgical treatment of single system reflux to accommodate common sheath reimplantation have excellent surgical results with minimal morbidity.(23) minevich et al.(24) reported a success rate of 98% without complications in 62 units (43 children). the follow-up time was 86 months. these results are supportive of our results in considering ecsr as the initial approach for the correction of vur in complete duplex systems.(24) further supporting the efficacy of ecsr, minimal short-term complications were noted in our patients except for one patient who had transient contralateral reflux. despite the higher success rate of icsr surgery, the morbidity was higher in terms of de novo hydronephrosis and contralateral vur. after icsr surgery, patients required a longer hospital stay with urethral catheterization and pain management. in contrast, the ecsr procedure offered a shorter hospital stay with less morbidity.(23,24) although excellent results with icsr have been reported in refluxing duplex systems, ecsr has comparable success rates for the treatment of uncomplicated cases figure 3. closure of the tunnel over the duplex ureters without tension. of vur with less morbidity.(24) however, the disadvantage of unnecessary reimplantation of the normal ureter with the refluxing ureter cannot be avoided in the common sheath reimplantation procedure. conversely, reimplantation of the refluxing ureter alone may compromise the blood supply of the normal ureter. conclusions both (ecsr) and (icsr) surgeries are highly successful for the correction of vur in uncomplicated complete duplex systems. the results of the extravesical approach are comparable with those of the intravesical technique with less morbidity and a shorter hospital stay. thus, ecsr is our preferred technique when open surgical repair is indicated. icsr should be reserved for complicated duplex systems necessitating concomitant reconstructive surgery. conflicting interests the authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. references 1. heidenreich a, enver o, zgur, becker t, haupt g. surgical management of vesicoureteral reflux.in pediatric patients. world j urol. 2004;22:96–106. 2. lee ph, diamond da, duffy pg., ransley pg. duplex reflux: a study of 105 children. j urol. 1991;146:657-9. 3. austin jc, cooper cs. vesicoureteral reflux: who benefits from correction? urol clin north am 2010;37:243–52. 4. peppas ds, skoog sj, canning da, belman ab. nonsurgical management of primary vesicoureteral reflux in complete ureteral duplication: is it justified? j urol. 1991;146:1594-5. 5. steinbrecher ha., edwards b., malone ps. the sting in the refluxing duplex system. br j urol. 1995;76:165-8. 6. reunanen m. endoscopic collagen injection: its limits in correcting vesico-ureteral reflux in duplicated ureters. eur urol. 1997;31:243-5. 7. miyakita h., ninan, gk., puri p. endoscopic correction of vesico-ureteric reflux in duplex systems. eur urol. 1993;24:111-5. 8. fehrenbaker lg., kelalis pp., stickler gb. vesicoureteral reflux and ureteral duplication in children. j urol. 1972;107:862-4. 9. weiss da, shukla ar. the robotic-assisted ureteral reimplantation: the evolution to a new standard. urol clin north am. 2015;42:99109. 10. bustangi n, kallas chemaly a, scalabre a, khelif k, luyckx s, et al. extravesical ureteral reimplantation following lich-gregoir technique for the correction of vesicoureteral reflux retrospective comparative study open vs. laparoscopy. front. pediatr. 2018;18;6(388):1-6. 11. gundeti ms, boysen wr, shah a. robotassisted laparoscopic extravesical ureteral reimplantation: technique modifications contribute to optimized outcomes. eur urol. common sheath ureteral reimplantation-aboutaleb et al. 2016;70:818-23. 12. zaontz mr, maizels m., sugar ec., firlit cf. detrusorrhaphy: extravesical ureteral advancement to correct vesicoureteral reflux in children. j urol. 1987;86:947-9. 13. rodriguez mv, boysen wr, gundeti ms. robot-assisted laparoscopic common sheath ureteral reimplantation in duplex ureters: luaa technique tips for optimal outcomes. j pediatr urol. 2018;14:353-5. 14. 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105: 44551. 19. canon sj, jayanthi vr, patel as. vesicoscopic cross-trigonal ureteral reimplantation: a minimally invasive option for repair of vesicoureteral reflux. j urol 2007;178:269–73 . 20. aboutaleb h, bolduc s, khoury ae, upadhyay j, bägli dj, farhat. polydimethylsiloxane injection versus open surgery for the treatment of vesicoureteral reflux in complete duplex systems. j urol. 2003;170:1563-5. 21. silay ms, turan t, kayalı y, bas‚i, gunaydi b, caskurlu t et al. comparison of intravesical (cohen) and extravesical (liche gregoir) ureteroneocystostomy in the treatment of unilateral primary vesicoureteric reflux in children. j pediatr urol 2018;14(65):1-4. 22. aboutaleb h, el-mahdy a, bolduc s, upadhyay j, shoukr r, khoury a. extravesical ureteral re-implantation versus intravesical techniques for vesicoureteral reflux in children. afr j urol. 2004;10:257–63 23. ellsworth pi, lim dj, walker p. s, stevens ma, barraza and mesrobian gj. common sheath reimplantation yields excellent results in the treatment of vesicoureteral reflux in duplicated collecting systems. j urol. 1996;155:1407-9. 24. minevich e, tackett l, wacksman j, sheldon ca. extravesical common sheath detrusorrrhaphy (ureteroneocystotomy) and reflux in duplicated collecting systems. j urol. 2002;167:88-90. common sheath ureteral reimplantation-aboutaleb et al. pediatric urology 662 the association of length of the resected membranous urethra with urinary incontinence after radical prostatectomy yasuo kohjimoto, shimpei yamashita, kazuro kikkawa, akinori iba, nagahide matsumura, isao hara* purpose: to retrospectively determine whether recovery of urinary continence after radical prostatectomy is associated with the preoperative length of membranous urethra (mu), the amount of rhabdosphincter and the length of mu removed with the prostate. materials and methods: the study cohort comprised 179 consecutive patients who underwent laparoscopic radical prostatectomy (lrp: n = 98) and robot-assisted radical prostatectomy (rarp: n = 81) at wakayama medical university between july 2010 and may 2014. the length of mu was measured by preoperative mri. the amount of resected rhabdosphincter and the length of resected mu were assessed in hematoxylin and eosin sections at the apical margin of prostate specimens. patient-reported urinary continence status was determined at 3, 6, 12 and 24 months postoperatively, with urinary continence considered as 0-1 pads/day. kaplan-meier analysis and the logrank test were used to compare time to urinary continence recovery. multivariate cox regression analyses were performed to determine the predictors of urinary continence. results: rarp vs lrp (p = 0.02) and shorter length of resected mu (p = 0.01) showed significantly better postoperative continence recovery by log-rank test. nerve-sparing, preoperative length of mu, and amount of resected rhabdosphincter did not significantly correlate with continence recovery. only the length of resected mu was the independent factor for predicting postoperative urinary continence by multivariate cox regression analysis (hazard ratio 0.84, p = 0.01). conclusion: these results demonstrated that the length of resected mu measured by specimen was an independent predictor of urinary incontinence after radical prostatectomy. care should be taken to preserve maximal length of mu for optimal continence outcomes. keywords: membranous urethral length; radical prostatectomy; urinary incontinence introduction radical prostatectomy is a standard treatment option for localized prostate cancer. although oncological outcome of radical prostatectomy is fairly satisfactory, postoperative complications including urinary incontinence and erectile dysfunction still remain problems to be solved(1). among them, urinary incontinence is a nuisance which affects patient’s daily life and quality of life (qol) directly. numerous factors are involved in postoperative urinary continence recovery. firstly, patient’s background including age, comorbidity, body mass index, history of prostate surgery and prostate size should be considered(2-4). second, surgical techniques of radical prostatectomy are other considerably important factors. techniques for improving postoperative urinary incontinence are classified into 2 categories(5,6). one is a preservation of the anatomical structure related to urinary continence including bladder neck, neurovascular bundle, puboprostatic ligament, rhabdosphincter and membranous urethra, and the other is a reconstrcution of the destroyed structure such as posterior reconstruction of department of urology, wakayama medical university, wakayama, japan. *correspondence: department of urology, wakayama medical university 811-1 kimiidera, wakayama 641-0012, japan. tel: +81-73-441-0637; fax: +81-73-444-8085. e-mail: hara@wakayama-med.ac.jp. received august 2018 & accepted january 2019 rhabdosphincter (rocco’s stitch) and periurethral suspension stitch. types of surgery are another concern, i.e. open radical prostatectomy (orp), laparoscopic radical prostatectomy (lrp) or robot-assisted radical prostatectomy (rarp). although recent systematic review and meta-analysis showed significantly better urinary continence rate at 12 month in rarp compared to rrp and lrp(7), clear conclusion has not been drawn yet. in this study, we investigate whether factors concerning membranous urethra (mu) and rhabdosphincter might influence postoperative urinary incontinence using preoperative magnetic resonance imaging (mri) and resected prostate specimens. patients and methods patients the cohort of this retrospective study comprised 179 consecutive patients who underwent lrp (n = 98) and rarp (n = 81) at wakayama medical university between july 2010 and may 2014. indications for radical prostatectomy were as follows; (1) age under 75, urological oncology urology journal/vol 17 no. 2/ march-april 2020/ pp. 146-151. [doi: 10.22037/uj.v0i0.4753] (2) psa less than 20ng/ml and (3) ct1-2 or ct3a only when the extracapsular invasion was minimum. demographic data were collected from medical chart. this study was approved by the institutional review board of wakayama medical university (no. 1670). surgical technique lrp and rarp were performed using a transperitoneal approach according to the standard techniques, which were previously described (8). briefly after cutting endopelvic fascia, we transected bladder neck followed by the dissection of seminal vesicle and prostate in an antegrade fashion. cavernous nerve-sparing was chosen according to the extent of cancer judged by mri and digital rectal examination. posterior rhabdosphincter reconstruction and periurethral suspension stich was performed in rarp but not in lrp. vesicourethral anastomosis was performed with a running suture. while limited lypmphadenectomy was performed in all patients in lrp, extended lymphadenectomy was performed only in high-risk patients in rarp. patient reported outcome to evaluate the status of urinary continence, we used expanded prostate cancer index composite (epic) questionnaire as patient reported outcome. the japanese version of epic was purchased from ihope international (kyoto, japan) and validation study of japanese version was reported previously(9). epic questionnaire was mailed to each patient periodically (3, 6, 12 and 24 months after operation). response rates of the questionnaire at 3, 6, 12 and 24 months were 95%, 93%, 87% and 82%, respectively. urinary continence status was judged from the response to one of the questions in urinary domain of epic and patients who wear 0 1 pad/day were considered continent. measurement of the length of membranous urethra (mu) all patients had mri examination before operation. length of mu was measured on coronal t2-weighted image of preoperative mri and determined as the distance from prostatic apex to the entry of urethra into penile bulb (figure 1, red arrow). measurement of the amount of resected rhabdosphincter and the length of resected mu a 3-4mm cone of tissue around the urethra at the apex of resected prostate was amputated and divided into left and right halves. each half was serially sectioned perpendicularly, typically resulting in 3 wedges of tissue from each half. these wedges were embedded in paraffin blocks and standard hematoxylin and eosin sections were made. the length of resected mu was measured in the cross section including urethra (figure 2, red arrow). the amount of resected rhabdosphincter was expressed as the percentage of total apical margin surface area occupied by rhabdosphincter (figure 2, blue arrow), and the overall percentage of resected rhabdosphincter was calculated as average of typically 6 wedges. these measurements were assessed by two independent uropathologists. when the inter-rater reliability was examined by pearson correlation coefficient, it showed high agreement (r = 0.867, p < 0.0001). statistical analyses clinical data, including age at surgery, preoperative psa, biopsy gleason score, ct stage, nerve preservation, length of mu, amount of resected rhabdosphincter, and length of resected mu were compared between lrp and rarp groups by wilcoxon signed-rank test for continuous variables and chi square test for categorical variables. kaplan-meier analysis and the log-rank test were used to compare time to urinary continence recovery and the cumulative incidence of urinary continence at follow-up. the first response to epic reporturinary incontinence after radical prostatectomy-kohjimoto et al. table 1. patient characteristics stratified by surgery (lrp vs rarp) total lrp rarp p = (lrp vs. rarp) no. patients (%) 179 98 (54.7) 81 (45.3) age, year 67(63 – 71) 68 (63 – 72) 67 (64 – 71) 0.94 psa, ng/ml 8.0 (5.9 – 11.0) 8.1 (5.9 – 12.3) 7.7 (5.9 – 10.1) 0.42 biopsy gleason score, n (%) 0.13 ≤ 6 50 (27.9) 28 (28.6) 22 (27.2) 7 74 (41.3) 41 (41.8) 33 (40.7) ≥ 8 55 (30.7) 29 (29.6) 26 (32.1) ct stage, n (%) 0.22 t1c 82 (45.8) 49 (50.0) 33 (40.7) t2 90 (50.3) 47 (48.0) 43 (53.1) t3a 7 (3.9) 2 (2.0) 5 (6.2) nerve preservation, n (%) 80 (44.7) 18 (18.4) 62 (76.5) < 0.01 length of mu 17.3 (14.6 – 19.7) 17.5 (14.9 – 19.3) 17.1 (14.5 – 19.8) 0.63 – preoperative mri, mm amount of resected rhabdosphincter 31.7 (25.0 – 40.0) 30.0 (25.0 – 40.0) 34.2 (25.8 – 42.1) 0.13 – pathology specimen, % length of resected mu 1.2 (0.5 – 2.0) 1.1 (0 – 2.1) 1.2 (0.6 – 2.0) 0.42 – pathology specimen, mm table2. cox regression analysis of factors predictive of urinary continence recovery hr 95% ci p age (year) 1.00 0.97 – 1.03 0.85 type of surgery, rarp/lrp 1.37 0.92 – 2.03 0.11 nerve preservation , yes/no 1.01 0.67 – 1.51 0.95 length of mu – preoperative mri (mm) 1.04 0.99 – 1.09 0.06 amount of resected rhabdosphincter – pathology (%) 0.99 0.98 – 1.00 0.57 length of resected mu pathology (mm) 0.84 0.73 – 0.97 0.01 vol 17 no 02 march-april 2020 147 ing urinary continence recovery (0 – 1 pad/day) was considered the event at that time. patients incontinent at their last response were censored at that time. multivariate cox regression analyses were performed to determine the predictors of urinary continence recovery time. clinically important or previously reported variables (age, type of surgery, nerve preservation, length of mu, amount of resected rhabdosphincter and length of resected mu) were included in the model. proportional hazards assumption was confirmed by plotting schoenfeld residuals and the fitness of the model was estimated by likelihood ratio test. in addition, multicollinearity of the model was assessed using variance inflation factor. data analyses were conducted by using the statistical software jmp pro 12 (sas institute, cary, usa). all p-values were 2 tailed, and p < 0.05 was defined as statistically significant. results patients’ characteristics baseline characteristics for all 179 patients are shown in table 1. although nerve preservation rate in rarp group (76.5%) was significantly higher than that in lrp group (18.4%), no significant differences were observed between lrp and rarp groups in other variables. length of mu, amount of resected rhabdosphinter and length of resected mu table 1 shows length of mu, amount of resected rhabdosphinter and length of resected mu. median length of mu measured by preoperative mri was 17.3mm (iqr, 14.6 – 19.7). median amount of resected rhabdosphinter and length of resected mu measured by pathology specimen was 31.7% and 1.2mm, respectively. no significant differences were found between lrp and rarp group in these variables. status of urinary continence according to various variables figure 3 shows kaplan-meier curve representing the percentage of patients achieving urinary continence recovery. the percentage of patients achieving urinary continence recovery after 3, 6, 12 and 24 months was 43.2%, 75.4%, 84.4% and 92.2%, respectively. figure 4 (a) shows the same kaplan-meier curve according to the type of surgery. continence rates after 12 months from surgery were 87.8% (rarp) and 81.6% (lrp). rarp showed significantly better continence recovery comparing to lrp (log-rank test, p = 0.02). urological oncology 148 figure 1. measurement of the length of membranous urethra (mu). length of mu was measured on coronal t2-weighted image of preoperative mri and determined as the distance from prostatic apex to the entry of urethra into penile bulb (red arrow). figure 2. measurement of the amount of resected rhabdosphincter and the length of resected membranous urethra (mu). the amount of resected rhabdosphincter was expressed as the percentage of total apical margin surface area occupied by rhabdosphincter (blue arrow, 50% in this section) and the overall percentage of resected rhabdosphincter was calculated as average of typically 6 wedges. the length of resected mu was measured in the cross section including urethra (red arrow). figure 3. overall cumulative incidence of urinary continence, defined as 0-1 pad/day, following radical prostatectomy. urinary incontinence after radical prostatectomy-kohjimoto et al. figure 4 (b) shows the same kaplan-meier curve according to nerve-sparing. continence rates after 12 months from surgery were 83.7% (nerve-sparing (+)) and 84.9% (nerve-sparing (-)). no significant difference was observed between nerve-sparing (+) and nerve-sparing (-) groups (log-rank test, p = 0.15). figure5 (a) shows the same kaplan-meier curve according to the length of mu measured by preoperative mri. continence rates after 12 months from surgery were 86.5% (length of mu ≥ 17.3mm) and 81.7% (length of mu < 17.3mm). no significant difference was observed between longer (≥17.3mm) and shorter (< 17.3mm) mu groups (log-rank test, p = 0.20). figure 5 (b) shows the same kaplan-meier curve according to the amount of resected rhabdosphincter. continence rates after 12 months from surgery were 90.5% (resected rhabdosphincter < 31.7%) and 78.3% (resected rhabdosphincter ≥31.7%). no significant difference was observed according to the amount of resected rhabdosphincter by pathology (log-rank test, p = 0.14). we also compared the apical positive surgical margin (psm) rates according to the amount of resected rhabdosphincter. apical psm rates were 10.3% and 16.3% in the resected rhabdosphincter < 31.7% group and ≥31.7% group, respectively. no statistical significance was observed (chi square test, p = 0.24). fig. 5 (c) shows the same kaplan-meier curve according to the length of resected mu measured by resected specimen. continence rates after 12 months from surgery were 88.5% (resected mu < 1.2mm) and 80.2% (resected mu ≥1.2mm). longer resected mu group (≥ 1.2 mm) showed significantly worse continence recovery comparing to shorter resected mu group (< 1.2 mm) (log-rank test, p = 0.01). we also compared apical psm rates according to the length of resected mu. apical psm rates was 16.9% and 10.0% in the resected mu < 1.2 mm group and ≥1.2mm group, respectively. no statistical significance was observed (chi square test, p = 0.18). multivariate analysis determining the factors influencing urinary continence recovery table 2 showed cox regression analysis of factors predicting urinary continence recovery. only the length of resected mu measured by specimen was independent predictive factor for urinary continence recovery (hazard ratio 0.84, p = 0.01). the length of mu measured by preoperative mu seems to be marginal predictive factor for urinary continence recovery, however the difference did not reach statistically significant (p = 0.06). discussion postoperative urinary incontinence is most annoying figure 4. cumulative incidence of urinary continence following radical prostatectomy stratified by (a) type of surgery (rarp vs lrp) and (b) nerve-sparing status. figure 5. cumulative incidence of urinary continence following radical prostatectomy stratified by (a) length of membranous urethra (mu) measured by preoperative mri, (b) amount of resected rhabdoshpincter measured by pathology specimen, and (c) length of resected mu measured by pathology specimen. urinary incontinence after radical prostatectomy-kohjimoto et al. vol 17 no 02 march-april 2020 149 complication after radical prostatectomy. recently, the anatomical mechanism regarding urinary continence in male has been gradually revealed by many vigorous studies(10-13). basically, the anatomical mechanism for urinary continence consists of 2 systems; a sphincteric system and a supportive system(5). the sphincteric system is composed of inner smooth muscle layer (longitudinal and circular smooth muscle) and striated urogenital sphincter muscle (rhabdosphincter). rhabdosphincter extends from the prostatic apex to the proximal bulbar urethra and considered the most important structure for urinary continence after radical prostatectomy. strasser et al. showed that the contractility of the remaining rhabdosphincter after transurethral resection of prostate or radical prostatectomy was associated with postoperative urinary incontinence by 3-dimensional ultrasound(14). the other system is supportive system of pelvic floor surrounding mu and bladder neck. in males, denonvilliers’ fascia, puboprostatic ligament, endopelvic fascia, levator ani muscle and arcus tendinous fascia pelvis correspond to this system. radical prostatectomy impairs this supportive system inevitably. in this study, we focused on the sphincteric system in urinary incontinence after lrp and rarp since the sphincteric system is more directly controlling urinary continence than the supportive system is. we selected several measurements concerning the sphincteric system. first one was preoperative length of mu measured by mri. paparel et al. demonstrated that both preoperative and postoperative membranous urethral length measured by preoperative and postoperative mri were correlated with urinary continence status after radical prostatectomy(15). unfortunately, we evaluated only preoperative membranous urethral length since we did not examine postoperative mri. second, we measured the amount of resected rhabdosphincter histologically using resected prostate specimens. such evaluation was conducted by skeldon et al. first(16). they measured the amount of striated muscle observed in apex of resected prostate specimen and expressed semiquantitatively as percentage of total apex tissue. they showed that the odds of a patient whose resected striated muscle occupied more than 11% of total apex tissue being incontinent was 11.7 times that of a patient whose resected striated muscle occupied less than 10%. we followed their methods exactly in this study. third, we measured the length of resected mu histologically using resected prostate specimen. to our knowledge, such measurement is firstly tried in this study. other variables we analyzed for postoperative urinary incontinence were age(17), type of surgery (rarp/lrp) (7), nerve preservation(18). all these variables were reported to be significant factors for postoperative incontinence, although negative reports were also observed. we performed cox regression analysis to identify the most relevant factor for postoperative urinary continence using the above-mentioned variables (age, type of surgery, nerve preservation, length of mu by preoperative mri, amount of resected rhabdosphincter by pathology, and length of resected mu by pathology). as a result, length of resected mu by pathology was the only independent factor for predicting postoperative urinary continence (table 2). although it did not reach statistically significant (p = 0.06), length of mu by preoperative mri also showed tendency to predict postoperative urinary continence. our results are consistent with paparel’s repot(15). they showed that both preoperative and postoperative membranous urethral length measured by preoperative and postoperative mri were correlated with urinary continence status after radical prostatectomy. the only difference is that our resected urethral length is an absolute length, whereas paparel et al. showed the resected urethral length in proportion to the original length of mu. another concern is the psm at the apex of prostate. we wondered if the psm rate would increase in cases where rhabdosphincter or mu at the apical region of prostate was preserved as much as possible to obtain good urinary continence. however, no significant differences were found in psm rates according to the amount of resected rhabodsphincter or the length of resected mu. limitations of this study were retrospective fashion and the relatively small number of patients. another limitation is that we could only evaluated the amount of resected rhabdosphincter semi-quantitatively. in conclusion, length of resected mu was the most important factor to predict urinary incontinence after lrp or rarp. in lrp or rarp, sophisticated manipulation is possible in a magnified field of view with less bleeding. to the extent that we do not sacrifice complete resection of the tumor, we should preserve maximal length of mu to prevent postoperative urinary incontinence. references 1. ficarra v, novara g, artibani w, et al. retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. eur urol. 2009;55:1037-63. 2. hamidi n, atmaca af, canda ae, et al. does presence of a median lobe affect perioperative complications, oncological outcomes and urinary continence following robotic-assisted radical prostatectomy? urol j. 2018;15:248-55. 3. jiang dg, xiao ct, mao yh, et al. impact and predictive value of prostate weight on the outcomes of nerve sparing laparoscopic radical prostatectomy in patients with low risk prostate cancer. urol j. 2018. 4. mustafa m, davis jw, gorgel sn, pisters l. robotic or open radical prostatectomy in men with previous transurethral resection of prostate. urol j. 2017;14:2955-60. 5. kojima y, takahashi n, haga n, et al. urinary incontinence after robot-assisted radical prostatectomy: pathophysiology and intraoperative techniques to improve surgical outcome. int j urol. 2013;20:1052-63. 6. vora aa, dajani d, lynch jh, kowalczyk kj. anatomic and technical considerations for optimizing recovery of urinary function during robotic-assisted radical prostatectomy. curr opin urol. 2013;23:78-87. 7. ficarra v, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012;62:405-17. urological oncology 150 urinary incontinence after radical prostatectomy-kohjimoto et al. 8. koike h, kohjimoto y, iba a, et al. healthrelated quality of life after robot-assisted radical prostatectomy compared with laparoscopic radical prostatectomy. j robot surg. 2017. 9. takegami m, suzukamo y, sanda mg, et al. [the japanese translation and cultural adaptation of expanded prostate cancer index composite (epic)]. nihon hinyokika gakkai zasshi. 2005;96:657-69. 10. burnett al, mostwin jl. in situ anatomical study of the male urethral sphincteric complex: relevance to continence preservation following major pelvic surgery. j urol. 1998;160:13016. 11. ganzer r, blana a, gaumann a, et al. topographical anatomy of periprostatic and capsular nerves: quantification and computerised planimetry. eur urol. 2008;54:353-60. 12. rocco f, carmignani l, acquati p, et al. early continence recovery after open radical prostatectomy with restoration of the posterior aspect of the rhabdosphincter. eur urol. 2007;52:376-83. 13. walz j, burnett al, costello aj, et al. a critical analysis of the current knowledge of surgical anatomy related to optimization of cancer control and preservation of continence and erection in candidates for radical prostatectomy. eur urol. 2010;57:179-92. 14. strasser h, pinggera gm, gozzi c, et al. three-dimensional transrectal ultrasound of the male urethral rhabdosphincter. world j urol. 2004;22:335-8. 15. paparel p, akin o, sandhu js, et al. recovery of urinary continence after radical prostatectomy: association with urethral length and urethral fibrosis measured by preoperative and postoperative endorectal magnetic resonance imaging. eur urol. 2009;55:62937. 16. skeldon sc, gani j, evans a, van der kwast t, radomski sb. striated muscle in the prostatic apex: does the amount in radical prostatectomy specimens predict postprostatectomy urinary incontinence? urology. 2014;83:888-92. 17. hou gl, luo y, di jm, et al. predictors of urinary continence recovery after modified radical prostatectomy for clinically high-risk prostate cancer. urol j. 2015;12:2021-7. 18. choi ww, freire mp, soukup jr, et al. nervesparing technique and urinary control after robot-assisted laparoscopic prostatectomy. world j urol. 2011;29:21-7. 19. lee se, byun ss, lee hj, et al. impact of variations in prostatic apex shape on early recovery of urinary continence after radical retropubic prostatectomy. urology. 2006;68:137-41. urinary incontinence after radical prostatectomy-kohjimoto et al. vol 17 no 02 march-april 2020 151 female urology 144 andrology comparison of dapoxetine /tadalafil and paroxetine/tadalafil combination therapies for the treatment of the premature ejaculation: a randomized clinical trial hamed mohseni rad1, telma zahirian moghadam2, ali hosseinkhani3,* nima soluki4, firouz amani5 purpose: the purpose of this study was to compare the effectiveness of dapoxetine, and paroxetine as well as dapoxetine/tadalafil and paroxetine/tadalafil combinational therapies, for the treatment of patients with premature ejaculation. materials and methods: in this clinical trial study, 120 patients with premature ejaculation were randomly divided into 4 groups: the first group was treated with paroxetine (pa), while the second group received dapoxetine(da). the third group received paroxetine combined with tadalafil(pt) whereas the fourth group's treatment involved the use of dapoxetine and tadalafil(dt) for one month. in the next 2 and 4 weeks, the cases were evaluated in terms of ejaculation duration, frequency of intercourse per week, and drug side effects. results: the mean age of the da, pa, pt, dt groups was 32 ± 6.9, 32.4 ± 7.2, 31.6 ± 1.9, and 32.9 ± 7.7 years, respectively. there was a significant difference between the da and dt groups (p = .029) in the ejaculation latency in the 4-week follow-up. in the two weeks follow-up, a significant difference was observed between da and dt (p = 0.043), pa and pt (p = 0.006), and pa and dt groups (p = 0.004) in terms of ejaculation latency. four weeks after the intervention, a significant difference was detected in the intercourse frequency of da and pt groups (p =0.033), pa and pt groups (p = 0.043), pa and dt groups (p = 0.02), and da and dt groups (p = 0.016). conclusion: combination therapy (tadalafil plus paroxetine or dapoxetine) was more effective in ielt (intra ejaculation latency time) than mono-therapy especially in younger patients despite its slightly more side effects. keywords: dapoxetine; paroxetine; premature ejaculation; tadalafil; treatment 1department of surgery, school of medicine, imam reza hospital, ardabil university of medical sciences, iran. 2social determinants of health research center, ardabil university of medical sciences, iran. 3department of surgery, school of medicine, imam reza hospital, ardabil university of medical sciences, iran 4department of surgery, school of medicine, imam reza hospital, ardabil university of medical sciences, iran. 5school of medicine, ardabil university of medical sciences, iran. *correspondence: department of surgery, school of medicine and allied medical sciences, imam reza hospital, ardabil university of medical sciences, ardabil, iran. e-mail: sirhamed2@gmail.com. received january 2021 & accepted november 2021 introduction the average time to reach orgasm in men is 4 min-utes (1,2). in most sources, premature ejaculation refers to cases in which ejaculation occurs in less than one minute from the onset of intercourse. some others consider ejaculation sooner than two minutes as abnormal and premature ejaculation. it should be noted that this definition is limited to intercourses through the vagina (3,4). according to the statistics, premature ejaculation affects more than one-third of men. the rate of premature ejaculation is 31% in the united states and 66% in germany(3). extensive studies on the anatomy of animal nerves and neuropharmacology have concluded that different regions control ejaculation rate through neurotransmitters such as serotonin and dopamine(5,6). dapoxetine is one of the specific serotonin reuptake inhibitors (ssris) on the market that has no place in the treatment of depression. thanks to its unique formulation and kinetics with rapid effect and short halflife, it could be applied in the treatment of premature ejaculation on-demand. paroxetine has been also used in various studies to treat premature ejaculation(7,8). the duration of erection seems to be one of the main concerns of patients with premature ejaculation(9,10). pde5 inhibitor (tadalafil) is the gold standard first-line treatment for erectile dysfunction capable of prolonging the ejaculation duration(11,12). however, some studies prefer single-drug therapy due to the high side effects of combination drugs(6,13). materials and methods study population in this parallel clinical trial study, 120 patients with premature ejaculation referring to the urology clinic in imam reza hospital, ardabil, iran were selected. these patients were selected from those with the complaint of premature ejaculation. the subjects were married with the age range of 20-50. all the selected patients had ielt (intra ejaculation latency time) of less than 2 minutes. they had sexual intercourse at least once a week. the sample size was calculated to be equal to 120 items using g * power 3.1.9.2 software considering the alpha and study power values of 0.05 and 0.8 for each group and with an effect size of 0.7, respectively. urology journal/vol 19 no. 2/ march-april 2022/ pp. 138-143. [doi: 10.22037/uj.v18i.6644] vol 19 no 2 march-april 2022 100 patients were selected by simple sampling and entered into study groups by distributing cards in four colors each assigned to one drug group. the study addressed 4 groups and each group consisted of 30 people. these four colors were written on four separate papers and the papers were placed inside a black bag. the participants were asked to pick up one piece of paper. inclusion and exclusion criteria exclusion criteria were having an underlying disease including diabetes, heart disease, high blood pressure, thyroid disease, sexually transmitted diseases, psychiatric illnesses treated with any psychiatric medication, and erectile dysfunction. patients who did not tolerate the side effects of drugs were also excluded from the study procedures data were collected using a designed checklist. no placebo was used in this study and all treatment groups were according to the guidelines for premature ejaculation treatment, thus no blinding was performed in this study. patients were randomly divided into 4 groups: all groups followed a one-month treatment period. the first group (control) received dapoxetine 30 mg tablets (shafa pharmaceutical company) orally one hour before sexual intercourse. the second group received paroxetine 20 mg tablets (tehran shimi company) orally once a day. the third group received paroxetine 20 mg tablets (tehran shimi company) orally once a day combined with tadalafil 10 mg tablets (rozdaro pharmaceutical company) orally one hour before sexual intercourse. the fourth group used dapoxetine 30 mg tablets (shafa pharmaceutical company) and 10 mg tadalafil tablets (rosedaro pharmaceutical company) orally one hour prior to sexual intercourse. patients' information including their age, ielt, and intercourses frequency in a week were recorded in researcher-made checklists before treatment. patients were contacted by the researcher for follow-up in the second and fourth weeks after treatment. the checklists including ielt, drug side effects (headache, hot flashes, sleep disturbance, nausea, vomiting, dizziness, and fatigue), and the number of intercourses per week were studied. evaluations the conditions of the study were fully explained to the patients and they consciously signed a written consent form to participate in the study. patients completely voluntarily took part in the study and they were assured that could leave the study at any time. their information was strictly kept confidential and recorded without their name or address. the study procedure was approved by the ethics committee of ardabil university of medical sciences (no: ir.arums.rec.1398.315) with irct no (20190528043747n1) and adhered to the tenets of the declaration of helsinki. statistical analysis the collected data were encoded in spss software version 21 using descriptive-analytical statistical methods as number, percentage, and mean values. various statistical tests such as anova and tukey’s post hoc test were applied to compare the two groups while the chisquare test was employed to examine their relationship. concerning the side effects, different drugs were separately analyzed at different times. results in this study, patients in the four groups did not significantly differ in terms of age (p > .05). the mean age of members of the dapoxetine, paroxetine, paroxetine/ tadalafil, and dapoxetine/tadalafil groups was 32 ± 6.9, 32.4 ± 7.2, 31.1 ± 6.9, and 32.9 ± 7.7 years, respectively. the four treatment regimes caused a significantly different effect on the ejaculation latency. the latency time for first, second, third, and fourth groups after 4-week treatment were 204.4 ± 82, 208.8 ± 65.1, 269.9 ± 100.4, and 259.3 ± 83.4 s, respectively. table 1. comparison of ejaculation time (ielt) and number of sexual intercourses per week based on table 1, two and four weeks after the intervention, the latency time increased in all groups, however, the longest ejaculation latency was observed in the third group (dapoxetine combined with tadalafil). using the tukey test for the dual study of the groups four weeks after the intervention, a significant difference was found between da and dt groups (p = .029), while the other groups did not show a significant difference. even two-week treatment by tadalafil in these groups significantly prolonged the latency time (comparing da with dt (p = .043), pa with pt (p = .006), and pa with dt (p = .004)). the effects of dapoxetine, paroxetine, dapoxetine/tadalafil, and paroxetine/tadalafilon on premature ejaculation were different in terms of the weekly frequency of intercourse. regarding the weekly frequency of intercourse, there was a significant difference between the groups in the two-week and four-week follow-ups. two weeks after the intervention, the mean frequency of intercourse per week was slightly higher in the pt group compared to treatment of premature ejaculationmohseni rad et al. time groups ejaculation time p-value number of relationships p-value per week (sex frequency) before the intervention dapoxetine 57.8 ± 34.2 0.9 2.04 ± 0.85 0.9 paroxetine 59.4 ± 32 2.08 ± 1 dapoxetine + tadalafil 56.1 ± 31 2 ± 0.8 paroxetine + tadalafil 54.6 ± 30.9 1.93 ± 0.8 two weeks after the intervention dapoxetine 166.7 ± 67.3 0.001 2.1 ± 0.8 0.036 paroxetine 146.4 ± 69.5 2.1 ± 1 dapoxetine + tadalafil 230 ± 112.6 2.63 ± 0.8 paroxetine + tadalafil 227.1 ± 90 2.64 ± 0.9 four weeks after the intervention dapoxetine 204.4 ± 82 0.007 2.2 ± 0.8 0.002 paroxetine 208.8 ± 65.1 2.2 ± 0.7 dapoxetine + tadalafil 269.9 ± 100.4 2.9 ± 0.9 paroxetine + tadalafil 259.3 ± 83.4 2.8 ± 0.9 table 1. comparison of ejaculation time and number of relationships per week (sex frequency in the studied groups at different times vol 19 no 2 march-april 2022 139 andrology 140 the others. four weeks after the intervention, groups treated with tadalafil plus arms exhibited statistically significant more intercourse frequencies, although the mean frequency of intercourses in the dt and pt groups was almost the same. using the tukey test, the results of binary comparison of the groups in the fourweek follow-ups showed significant differences among the groups regarding intercourse frequency (da and pt (p =.033), pa and pt (p = .043), pa and dt (p = .022), da and dt (p = .016)). table 2. comparison of the drugs in terms of complications two and four weeks post-intervention. the mentioned treatments caused significantly different side effects. according to table 2, two weeks after the intervention, there was a significant difference in complications such as headache and hot flashes, but no significant difference was detected between the groups in terms of other side effects. pt and dt groups with 10 cases of headache and 5 cases of hot flashes had the most complications. the groups were significantly different in terms of hot flashes and sleep problems after four weeks of intervention. regarding hot flashes, 5 people in each of the pt and dt groups had the most complications. concerning sleep disorders, the most complications were in the pt and dt groups with 12 people in each group. the effects of dapoxetine, paroxetine, dapoxetine/tadalafil, and paroxetine/tadalafil in the treatment of patients with early ejaculation are significantly different based on the patients’ age. table 3. comparison of ielt medicinal based on the age group according to table 3, after two and four weeks of the medical intervention in the age groups of 20-30, there was a significant difference between the drug groups in terms of ejaculation latency. two and four weeks post-intervention, the combined dt group had a longer ielt duration with average values of 240.5 ± 117 and 286.112 ± 2.7 s, which was significantly different from the other groups. no significant difference was observed between the groups in the age group of 31-40 and 41-50 in terms of (ielt) two and four weeks after the intervention as compared to the condition before the intervention. discussion our study showed that adding tadalafil to paroxetine or dapoxetine fortifies ejaculation latency time. zhang x et al. compared the combination therapy of sildenafil and sertraline versus sertraline monotherapy for the treatment of premature ejaculation. they showed that combination therapy was more efficient than mono-therapy with fewer side effects(14). however, in our study combination therapy exhibited a mild increment of headache and hot flashes. premature ejaculation has a prevalence of 20-30 % in the male population. tadalafil may be efficient in improving (ielt) even in combination with the pause-squeeze technique or glandular local anesthesia. dell'atti l et al. compared tadalafil with local anesthetics and reported the efficacy and tolerability of tadalafil in premature ejaculation(15). our study did not show a considerable difference in efficacy or side effects of dapoxetine and paroxetine. however, jern p. et al. reported a higher rate of discontinuation for dapoxetine compared to paroxetine. paroxetine was more effective and tolerable than dapoxetine(16). moudi e et al. compared tadalafil plus paroxetine with paroxetine only in the treatment of premature ejaculation. they showed that tadalafil could moderately increase intravaginal ejaculation latency time (ielt) and might be used to treat premature ejaculation in combination with paroxetine(1). this confirms our results that a combination of ssri and pde5 inhibitors could outperform monotherapy for the treatment of premature ejaculation. in the study of muhammad abu al-hamd, the combination of sildenafil plus dapoxetine led to the best response(17). in a meta-analysis, martyn-st james m et al. reported that although monotherapy by ssri and pde-5 inhibitors did not cause much difference in latency time, their combination therapy can make a significant difference (18). anova test was applied to compare the ielt of the four groups. the results showed that before the intervention, the groups were the same in terms of ejaculation time. two and four weeks later, dapoxetine/tadalafil and paroxetine/tadalafil groups exhibited significantly longer ejaculation latency time than the two groups of dapoxetine and paroxetine groups with the longest belonging to the dapoxetine/tadalafil group. these results indicate that combination therapies of dapoxetine/ tadalafilor and paroxetine/tadalafil had more effect on increasing ejaculation latency time in patients with premature ejaculation rather than single dapoxetine or paroxetine. in a clinical trial by mcmahon et al., the use of dapoxetine 1 to 2 hours before intercourse at doses of 30 mg and 60 mg enhanced the ejaculation latency by 2.5 and 3 times, respectively(19). pryor et al. also reported that table 2. the testis weight of mice in different treated groups and control after treatment complications first group second group third group fourth group dapoxetine paroxetine dapoxetine+tadalafil paroxetine+tadalafil two weeks after four weeks after two weeks after four weeks two weeks four weeks two weeks four weeks treatment treatment treatment after treatment after treatment after treatment after treatment after treatment headache 11.1 11.1 12 16 38 37 35.7 35.7 flushing 0 0 0 0 18.5 18.5 17.9 17.9 sleep disorder 7.4 11.1 12 16 14.8 44.4 17.9 42.9 nausea 11.1 11.1 16 12 22.2 25.9 28.6 32.1 vomit 0 0 0 8 3.7 3.7 3.6 0 vertigo 7.4 7.4 0 0 3.7 3.7 14.3 10.7 fatigue 7.4 7.4 0 0 0 0 0 3.6 treatment of premature ejaculationmohseni rad et al. vol 19 no 2 march-april 2022 100 receiving dapoxetine 1 to 2 hours before intercourse caused more control over ejaculation, reduced stress, and increased satisfaction(20). dapoxetine was effective in both sustained and acquired premature ejaculation(21-23). in 2018, li et al. conducted a meta-analysis study addressing the effects of dapoxetine on the treatment of premature ejaculation, they concluded that doses of 30 mg and 60 mg were more effective than placebo for ejaculation latency time(24). in some studies, paroxetine incremented mean ielt from 0-1 minute to an average of 4.5 minutes after 4-week treatment which was raised to 5.5 minutes after another 4-week therapy(25-27). on the contrary, some studies reported no difference between the combined treatment of paroxetine-tadalafil compared with paroxetine. they showed that the mean ielt after 3 months and even 6-month of treatment were not significantly different(28-30). so it seems that combination therapy has not been regarded as a standard treatment for premature ejaculation yet. however, polat ec et al. showed that the use of combination therapy with serotonin re-uptake inhibitors (ssri) and phosphodiesterase type 5 inhibitors (pde5-inhibitors) (combination therapy of paroxetine + tadalafil) can lead to a significantly better effect on increasing ielt than the single use of these drugs(31). in the present study, the combined groups exhibited a greater increase in ejaculation latency time than the single therapy groups. concerning the frequency of intercourse per week, there was no difference between the groups. two and four weeks after the intervention, however, the frequency of intercourses significantly increased. the dapoxetine/tadalafil and paroxetine/ tadalafil groups sowed almost at the same conditions in terms of the average frequency of intercourses per week; they exhibited, however, significantly higher intercourse frequency compared to dapoxetine and paroxetine groups. the combination therapy groups had longer ejaculation times, leading to more sexual satisfaction and desire compared to single drug groups which raised the intercourse frequency(32,33). side effects of dapoxetine include nausea and vomiting, diarrhea, dizziness, headache, and insomnia. side effects of paroxetine have been reported as the inability to ejaculate, and a decreased libido(31,34). in this study, common side effects were headaches and hot flashes that were more common in tadalafil plus groups. other side effects were sleep disorders, nausea, vomiting, dizziness, and fatigue. the results indicated that two weeks after the intervention, there was a significant difference between the groups in terms of headache and hot flashes. however, no significant difference was found between the groups concerning other complications. these side effects were greater in the dapoxetine/tadalafil and paroxetine/tadalafil groups than the dapoxetine and paroxetine groups. after 4 weeks, hot flashes and sleep problems were significantly more common. younger patients showed better responses to premature ejaculation treatment. in the age group of 20-30, dapoxetine/tadalafil had the greatest effect on the (ielt), but there was no significant difference in the (ielt) after the intervention compared to the start of the intervention the age groups of 31-40 and 41-50. according to the results of this study, more studies are recommended on the treatment of premature ejaculation with the combination therapy of dapoxetine/tadalafil and paroxetine/ tadalafil with a larger sample size and longer follow-up period. the sample size of this study was about 26 people in each group. it seems that more sample size could raise the accuracy of the results. another limitation of the present study was the lack of control over the correct use of prescribed drugs during treatment, which may disturb the results. satisfaction of individuals who can determine the outcome of drug tolerance and the effect of treatment was not examined in this study, which is another limitation of this study. conclusions combination therapy (tadalafilpl us paroxetine or dapoxetine) is more effective in ielt than monotherapy especially in younger patients although it may cause slightly more side effects. acknowledgement the authors trully appreciate managers and staffs of the imam reza hospital in ardabil, for their contribution in the research. conflict of 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lee wk, lee sh, cho st, et al. comparison between on‐demand dosing of dapoxetine alone and dapoxetine plus mirodenafil in patients with lifelong premature ejaculation: prospective, randomized, double‐blind, placebo‐controlled, multicenter study. j sex med. 2013;10:2832-41. 34. f lasker g, halis f, gokce a. selective serotonin reuptake inhibitors for premature ejaculation: review of erectile and ejaculatory side effects. curr. drug saf. 2014;9:118-26. treatment of premature ejaculationmohseni rad et al. vol 19 no 2 march-april 2022 143 1 running head: double-gloving vs. single-gloving for preventing infection-nagai et al. a multicenter, prospective, non-randomized study evaluating surgical hand preparation between double-gloving and single-gloving for preventing postoperative infection in robotic and laparoscopic minimally invasive surgeries takashi nagai1, kazumi taguchi1*, teruki isobe1, nayuka matsuyama1, tatsuya hattori1, rei unno1,2, taiki kato1, toshiki etani1, takashi hamakawa3, yasuhiro fujii4, yosuke ikegami3, hiroyuki kamiya4, shuzo hamamoto1, akihiro nakane1,2,5, ryosuke ando1,5, tetsuji maruyama1,3,6, atsushi okada1, noriyasu kawai1, and takahiro yasui1 1 department of nephro-urology, nagoya city university graduate school of medical sciences, nagoya, japan 2 department of urology, gamagori city hospital, gamagori, japan 3 department of urology, nagoya city east medical center, nagoya, japan 4 department of urology, daido clinic and hospital, nagoya, japan 5 education and research center for community medicine, nagoya city university graduate school of medical sciences, nagoya, japan 6 education and research center for advanced medicine, nagoya city university graduate school of medical sciences, nagoya, japan 2 key words: assistive devices; hand washing; laparoscopy; surgical site infection endoscopes abstract purpose: this study aimed to analyze a feasible and suitable surgical precautionary preparatory technique. the techniques of doublegloving with hygienic hand wash (dh) and single-gloving with surgical hand wash (ss) were compared for their ability to prevent postoperative infection in robotic and laparoscopic minimally invasive surgeries. materials and methods: a prospective, non-randomized, multicenter study was conducted between january 2016 and june 2020. we divided the robotic and laparoscopic cases into two groups: dh and ss. data on infectious outcomes were collected. propensity score matching was performed to control for operative characteristics between the two groups. the primary endpoint was the presence of fever and surgical site infections (ssis) indicating postoperative infection. results: among four medical centers, seven surgeons were allocated to either the dh or the ss group. a total of 221 and 251 patients underwent dh and ss, respectively. propensity score matching, which included 171 cases from each group, showed that the incidence of fever during hospitalization was significantly lower in the dh group than that in the ss group (11.7% vs. 23.4%, p=0.007). 3 multivariable analysis revealed that dh was associated with a reduced odds ratio for developing postoperative fever during hospitalization (risk ratio: 0.49, p=0.043). no differences were found in ssi before and after hospitalization between the two groups. conclusion: dh resulted in less postoperative fever and had a comparable effect in preventing ssis. this procedure could be an alternative to the ss protocol in some minimally invasive surgeries. 4 introduction several urological surgeries have shifted from open to robotic or laparoscopic surgeries. therefore, while we face fewer challenges, such as postoperative infections, the practices to mitigate these postoperative complications remain largely unchanged. surgical site infections (ssis) are crucial problems known to be associated with prolonged hospital stay, increased mortality, and disfiguring scars (1). appropriate hand washing and surgical gloving as part of the presurgical preparation have been researched. however, the duration wherein surgeons are in contact with the patients is reducing. therefore, modification of this protocol may benefit the current surgical trends. prevention of postoperative infection is essential and is at par with other desirable surgical outcomes. using an appropriate antiseptic agent to perform preoperative surgical scrub is recommended by the society for healthcare epidemiology of america (2). semmelweis et al. first reported on the utility of preoperative hand washing in 1847. although the conventional surgical scrub has been performed for decades, it has disadvantages; it is time-consuming and may cause skin damage or allergic reactions (3). in the 2000s, some studies supported hand rubs using alcohol components (4,5). regarding antiseptics, oriel bs et al. have reported that chlorhexidine gluconate aqueous scrubs and alcohol-based rubs were preferred over povidone-iodine (6). however, the most appropriate antiseptic remains a controversial topic owing to contradictory results and the impossibility of randomized trials due to ethical reasons. 5 double-gloving reportedly has lower incidence of pinhole micropunctures during surgery than single-gloving (7). moreover, double-gloving has been reported as a useful method for preventing surgical cross-infection (7). however, the world health organization has stated that double-gloving is not formally recommended because of the lack of evidence on its role in reducing the risk of ssi (8). the effectiveness of double-gloving over single-gloving remains undetermined; overall, the ideal methods of handwashing and the number of glove pairs surgeons should wear remain unclear. we focused on the necessity and efficiency of handwashing and gloving for urologic robotic or laparoscopic surgeries as most of these procedures are clean or clean-contaminated operations. in this study, we compared the effectiveness of double-gloving with hygienic hand wash (dh) and single-gloving with surgical hand wash (ss) in preventing postoperative infection in robotic and laparoscopic minimally invasive surgeries. patients and methods study design and patient population this was a multicenter, prospective cohort study that included patients who underwent urologic robotic or laparoscopic minimally invasive surgery at the nagoya city university hospital, nagoya city east medical center, daido clinic and hospital, and gamagori city hospital between january 2017 and june 2020. figure 1 elaborates the study protocol. the following procedures were selected as minimally invasive surgeries with only small incisions, defined as <4 cm for ports involving extraction of removed organs: 6 laparoscopic radical prostatectomy (lrp), robotic-assisted lrp (rarp), laparoscopic partial nephrectomy (lpn), robot-assisted lpn, laparoscopic radical adrenalectomy, laparoscopic radical nephrectomy, laparoscopic sacral colpopexy, laparoscopic peritoneal dialysis catheter placement, and laparoscopic urachal cyst excision. we excluded any robotic or laparoscopic surgery requiring additional incisions for an open procedure, such as nephroureterectomy and total cystectomy. all urologists who participated in this study were allocated to the dh and the ss groups (n=7 each) based on their preference and capability for double-gloving. the allocation was determined owing to their flexibility for altering their surgical hand antiseptic protocol. the two groups had similar proportions of residents, fellows, and attending physicians. at the time of surgery, all presurgical preparation was standardized among surgeons according to their assigned group. the patients were allocated to two groups (the dh group and the ss group) according to the surgery they would be underwent. randomization of the patients was not conducted because the allocation of the patients depended on the surgeries. the protocol of antibiotic prophylaxis was based on the japanese guidelines for the prevention of perioperative infections in the urological field (9). surgical procedures were classified according to the center for disease control and prevention wound classification (10). as antibiotic prophylaxis, the patients who underwent lpn, rapn, lra, lrn, lsc, lpdcp, and luce defined as clean (class i) were administrated 1st cephalosporins/ penicillins with beta(ß)-lactamase inhibitor (bli) and the patients who underwent lrp and rarp defined as clean-contaminated (class ii) 1st or 2nd cephalosporins/ penicillins with bli. 7 this study was conducted with the approval of the institutional review board of the nagoya city university hospital (#6020-0090) and followed the tenets set by the declaration of helsinki. all patients provided their verbal and opt-out informed consent for study participation. endpoints, data collection, and adjustment the primary endpoint was the presence of fever and ssi, indicating postoperative infection. the secondary endpoints included influence on shorter operation time, less blood loss, shorter duration of antibiotics after the surgeries, presence of pyuria, shorter duration of hospital stay, and changes in serum inflammatory markers. we obtained clinical data for each patient, including age, sex, body mass index (bmi), infection risk, use of preoperative antibiotics, presence of preoperative pyuria, and presence of bacteriuria. infection risk was defined as meeting at least one of the following conditions: obesity (bmi >30), diabetes mellitus, use of steroids, and receiving dialysis. furthermore, we collected intraoperative data, including operation time and estimated blood loss, as well as postoperative data during hospitalization, including duration of antibiotic use, use of additional antibiotics, number of antipyretics/analgesics use, fever (defined as temperature ≥ 38°c) during hospitalization, serum examination data at postoperative day (pod) 1, presence of ssi, and duration of hospital stay. the southampton wound scoring system was used to evaluate ssi (supplementary table 1) (11). grade ii or higher in the southampton 8 wound scoring system was defined as ssi. postoperative data after hospital discharge, presence of fever, ssi, pyuria, and serum examination data were collected at the clinical visit 1 month after the surgeries. all clinical data were collected prospectively. to mitigate case-collection bias due to the different surgeon groups, propensity score matching was performed to adjust for the differences in the patients who were assigned specific method for washing hands and wearing gloves. we matched age, sex, bmi, rate of infection risks, rate of preoperative pyuria, duration of antibiotics use, types of operations, and operation time using a logistic regression model. interventions: hand wash technique in the dh group, hand washing and gloving were performed according to the following protocol: (1) one pump of a non-medicated soap was applied followed by gentle rubbing of the fingertips to the arms for at least 1 min without using brushes, sponges, or nail tips and then rinsed with non-sterile water; (2) the hands and arms were dried with non-medicated towels/paper; and (3) double-gloving was performed after drying. in the ss group, hand washing was performed by the hand rubbing technique. hand rubbing was performed according to the following protocol: (1) the hands were washed using non-medicated soap and warm water for at least 1 min without using brushes, 9 sponges, or nail tips; (2) the hands and arms were wiped with non-medicated towels/paper; (3) alcohol-based hand rubs were used for both the hands and arms; (4) the hands were air-dried; and (5) single gloves were worn. for both groups, we utilized similar latex gloves for each institution, and no obligation for using gloves for either inner or outer set was implemented. sample size calculation the overall rate of postoperative infection in robotic or laparoscopic urological surgeries was estimated to be 3% according to a previous report (12). these surgeries were conducted using ss. we set the rate of ssis with dh as 5.5% because it seemed higher than single-gloving with surgical hand antisepsis due to the increased risk of infection with normal hand wash procedures. we calculated the sample size for a non-inferiority test using a statistical power of 80%, double-sided analysis, alpha value of 5%, and a noninferiority limit of 3%. based on these settings, the minimum required number of samples for each group was calculated as 211 using the ezr software (r project, vienna, austria) (13). statistical analysis 10 continuous normally distributed variables are presented as mean ± standard deviation, whereas non-normally distributed variables are presented as median (25% and 75% interquartile range). categorical variables are presented as numbers in each group (percentage within each group). for continuous variables, the normality and homogeneity of each variable were assessed and student's or welch's t-test was performed according to the homoscedasticity. for non-parametric variables, mann–whitney u test was used. categorical variables were compared using fisher’s exact test. propensity score matching was used to achieve a balance between the two groups. a minimally sufficient set of confounders were selected by literature research and using a causal directed acyclic graph (supplemental figure 1). propensity scores were calculated using a logistic regression model including age, sex, bmi, rate of infection risk, rate of preoperative pyuria, duration of antibiotics use, types of operations, and operation time. patients were matched by a matching ratio of 1:1 based on the propensity score with a standard caliper width of 0.02. a standardized differences (sd) between groups for all covariates were analyzed. sd value less than 0.2 refers to not statistically significant difference. multivariable modified poisson regression analysis was performed to estimate the risk ratio (rr) and confidence interval (ci) for postoperative fever and ssi. the covariates were selected based on previous reports which were associated with postoperative fever and ssi. (2, 3, 12). differences were considered statistically significant at alpha value of <0.05. all statistical analyses were performed using the ezr software. results patient characteristics 11 among the 472 patients included in this prospective cohort, 221 and 251 patients underwent dh and ss, respectively. table 1 summarizes the patient characteristics of the two groups. no significant differences were noted in age, bmi, infection risk, preoperative antibiotic use, and preoperative pyuria. the proportion of male patients and the rate of preoperative bacteriuria were higher in the ss group than in the dh group. in propensity score matching, age, sex, bmi, rate of infection risk, rate of preoperative pyuria, duration of antibiotics use, types of operations, and operation time were matched (table 1, 2). the data of a total of 342 patients were analyzed, and each group included 171 patients. intraand postoperative factors related to postoperative infection during hospitalization intraand postoperative outcomes during hospitalization are shown in table 2. in the entire cohort population, the dh group had significantly shorter operation time, less estimated blood loss, lower percentage of additional antibiotic use, less fever during hospitalization, and shorter hospital stay than the ss group. the duration of antibiotic use was longer and number of antipyretics/analgesics used increased in the dh group than those in the ss group. after propensity score matching, univariate analysis revealed that the incidence of fever during hospitalization was significantly lower in the dh group than in the ss group (11.7% vs 23.4%, p=0.007). other postoperative outcomes, including white 12 blood cell (wbc) count and c-reactive protein (crp) level at pod 1 and the ssi rate during hospitalization, were not significantly different between the two groups. postoperative factors related to postoperative infection after hospital discharge postoperative outcomes after discharge from the hospital in all cases and the propensity score-matched cases are also shown in table 2. in both settings, the rates of fever, ssi, pyuria, wbc count, and crp level 1 month postoperatively after discharge were not significantly different between the two groups. multivariable analyses for the factors associated with infectious surgical outcomes table 3 shows multivariable modified poisson regression analysis revealing that dh decreased the rr for developing fever during hospitalization (rr=0.49, p=0.043). no preor intraoperative factors were found to be associated with fever at 1 month and ssi during hospitalization or 1 month after the surgeries. discussion 13 our study demonstrated that infectious outcomes in dh were equivalent to or better than those in ss in urologic robotic/laparoscopic surgeries. moreover, dh was associated with lower incidence of postoperative fever. these findings were obtained for all patients as well as propensity score-matched patients. there are reports regarding infectious outcomes in urology, which mainly concern postoperative ssi. ssi is a postoperative complication that occurs in 0.1%–50.4% of cases, and its occurrence rate varies based on the type of surgery and risk factors, such as reduced fitness, patient frailty, increased surgery duration, and surgical complexity (14). in urologic cases, patients who underwent rarp showed a lower incidence of ssi and postoperative infections than patients who underwent radical retropubic prostatectomy (15,16). the incidence of ssis in minimally invasive urological surgery, including nephrectomy, nephrouretectomy, prostatectomy, and cystectomy, was reported to be less than that in open surgery (17). in our study, partially because procedures were limited to minimally invasive urological surgeries, there were few cases of ssi. postoperative fever is also a concern in clinical situations and is caused by various infectious and non-infectious etiologies. it is a common complication with incidence of 20%–90% in the postoperative period and may include serious infection resulting in sepsis if not correctly diagnosed (18). postoperative fever can prolong hospitalization and increase the mortality rate (18). in our study, dh reduced the rate of postoperative fever. reducing the incidence of fever after dh seemed to be beneficial for the patients. the present study resulted in a difference in terms of postoperative fever and there was not in terms of ssi. nowadays, the cause of postoperative fever is considered as biological response to surgical invasion if the obvious source of infection was not pointed out. but antibiotic prophylaxis might mask the small infection leads to postoperative fever but does not lead to ssi. 14 conflicting reports exist regarding ideal presurgical preparation, such as various methods of hand rubs. according to previous reports, alcohol-based rubbing yields better outcomes in terms of skin damage, microbial counts, and cost than traditional surgical scrubs (19). however, the bacterial colony counts of the hands increased during an operation even though alcohol-based rubbing was performed (20). it must be considered that changing methods of washing hand improves certain aspects of infection prevention; however, it is impossible to avoid bacterial colonization completely. in addition, the number of gloves worn during presurgical preparation is important; according to previous studies, doublegloving tends to prevent blood-skin exposure and glove perforation (21,22). in endourologic surgery, regular hand hygiene with doublegloving and surgical hand hygiene were reported to be effective in preventing endourological febrile urinary tract infections (23). in our study, the effectiveness of dh in preventing the indications of infection was comparable to or even exceeded that of ss, particularly regarding postoperative fever. this suggests that double-gloving helps prevent infections regardless of the hand wash technique used. regarding the cost, the preventive effect of double-gloving for healthcare workers in terms of perforation and bloodstains on the skin was reported as beneficial (24). moreover, a randomized trial conducted in non-sterile settings indicated that double-gloving could reduce contamination in an intraoperative environment (25). furthermore, double-gloving is effective in preventing hand contamination of healthcare workers when removing personal protective equipment (26). double-gloving was further reported to not influence tactile sensibility (27). in summary, double-gloving seems to have several benefits in infection prevention for both patients and healthcare workers. however, its effect on surgical performance remains unknown. 15 our study has some limitations. this was a non-randomized study, which might have resulted in a selection bias due to each surgeon’s preference in gloving. additionally, the operation time was statistically different between the two groups because of the study design. consequently, the duration of surgery may influence the risk of postoperative infections. the overall results were highly generalized because various surgical procedures were simultaneously analyzed. moreover, this multicenter study may have included unequal heterogeneity and diversity of cases among the sites. thus, the different settings of the study design may have resulted in baseline differences. we conducted propensity score matching to minimize these biases; however, there were some differences, such as operative methods, surgical instruments, and operating room conditions, which were not controllable. only measurable potential confounders were included in the model for estimating propensity scores, so we were not able to directly adjust for the effects of nonmeasurable potential confounders. the present study resulted in significantly shorter operation time and less estimated blood loss in the dh group than those in the ss group. they were also uncontrollable factors because we were unable to adjust them before surgery. these factors were considered to affect infectious outcomes as confounding biases but we attempted to adjust these factors by propensity score matching. finally, the type of gloves and the method of surgical hand wash differed between surgeons and cases. however, we believe that these different preoperative aspects might cause only small differences. conclusion 16 we found that double-gloving may result in reduced postoperative fever during hospitalization in robotic or laparoscopic urologic surgery regardless of omitting surgical hand hygiene. given that other infectious outcomes were comparable between the dh and ss groups, dh is effective in preventing complications and could be an alternative to the current protocols in microincisional laparoscopic and robotic surgeries. acknowledgement we thank the urology and operating room staff of each hospital who supported this study. conflict of interest the authors report no conflict of interest. appendix: 17 references 1. kolasiński w. surgical site infections review of current knowledge, methods of prevention. pol przegl chir. 2018; 91:41-47. 2. anderson dj, podgorny k, berríos-torres si et al. strategies to prevent surgical site infections in acute care hospitals: 2014 update. infect control hosp epidemiol 2014; 35:605-627. 3. shen nj, pan sc, sheng wh, tien kl, chen ml, chang sc, chen yc. comparative antimicrobial efficacy of alcohol-based hand rub and conventional surgical scrub in a medical center. j microbiol immunol infect. 2015; 48:322-328. 4. rotter ml. arguments for alcoholic hand disinfection. j hosp infect. 2001; 48:s4-s8. 5. parienti jj, thibon p, heller r et al. hand-rubbing with an aqueous alcoholic solution vs traditional surgical hand-scrubbing and 30-day surgical site infection rates: a randomized equivalence study. 2002; jama 288:722-727. 6. oriel bs, itani km. surgical hand antisepsis and surgical site infections. surg infect (larchmt) 2006; 17:632-644. 7. tanner j, parkinson h. double gloving to reduce surgical cross-infection. cochrane database syst rev 2006:cd003087. 8. world health organization (updated 2018) global guidelines for the prevention of surgical site infection. https://apps.who.int/iris/bitstream/handle/10665/250680/9789241549882-eng.pdf?sequence=8. accessed 11 mar 2022 9. yamamoto s, shigemura k, kiyota h et al. essential japanese guidelines for the prevention of perioperative infections in the urological field: 2015 edition. 2016; int j urol 23:814-824. 18 10. mangram aj, horan tc, pearson ml, silver lc, jarvis wr (1999) guideline for prevention of surgical site infection. centers for disease control and prevention (cdc) hospital infection control practices advisory committee. 1999; am j infect control 27:97132; quiz 133. 11. bailey is, karran se, toyn k, brough p, ranaboldo c, karran sj. community surveillance of complications after hernia surgery. 1992; bmj 304:469-471. 12. george ak, srinivasan ak, cho j, sadek ma, kavoussi lr. surgical site infection rates following laparoscopic urological procedures. 2011; j urol 185:1289-1293. 13. kanda y. investigation of the freely available easy-to-use software ‘ezr’ for medical statistics. 2013; bone marrow transplant 48:452-458. 14. korol e, johnston k, waser n, sifakis f, jafri hs, lo m, kyaw mh. a systematic review of risk factors associated with surgical site infections among surgical patients. 2013; plos one 8:e83743. 15. tollefson mk, frank i, gettman mt. robotic-assisted radical prostatectomy decreases the incidence and morbidity of surgical site infections. 2011; urology 78:827-831. 16. shigemura k, tanaka k, yamamichi f, muramaki m, arakawa s, miyake h, fujisawa m. comparison of postoperative infection between robotic-assisted laparoscopic prostatectomy and open radical prostatectomy. 2014; urol int 92:15-19. 17. de vermandois jar, cochetti g, zingaro md et al. evaluation of surgical site infection in mini-invasive urological surgery. 2019; open med (wars) 14:711-718. 19 18. gross k. postoperative fever. in: saclarides tj, myers ja, millikan kw (eds). common surgical diseases: an algorithmic approach to problem solving, 3rd edn. 2015; springer, new york, pp 341-342 19. larson el, aiello ae, heilman jm, lyle ct, cronquist a, stahl jb, della-latta p. comparison of different regimens for surgical hand preparation. 2001; aorn j 73:412-324, 417. 20. pietsch h. hand antiseptics: rubs versus scrubs, alcoholic solutions versus alcoholic gels. 2001; j hosp infect 48:s33–s36. 21. thomas s, agarwal m, mehta g. intraoperative glove perforation single versus double gloving in protection against skin contamination. 2001; postgrad med j 77:458-460. 22. lancaster c, duff p. single versus double-gloving for obstetric and gynecologic procedures. 2007; am j obstet gynecol 196:e36– e37. 23. unno r, taguchi k, fujii y et al. surgical hand hygiene and febrile urinary tract infections in endourological surgery: a singlecentre prospective cohort study. 2020, sci rep 10:14520. 24. mischke c, verbeek jh, saarto a, lavoie mc, pahwa m, ijaz s. gloves, extra gloves or special types of gloves for preventing percutaneous exposure injuries in healthcare personnel. 2014, cochrane database syst rev (3):cd009573. 25. birnbach dj, rosen lf, fitzpatrick m, carling p, arheart kl, munoz-price ls. double gloves: a randomized trial to evaluate a simple strategy to reduce contamination in the operating room. 2015, anesth analg 120:848-852. 26. casanova lm, rutala wa, weber dj, sobsey md. effect of singleversus double-gloving on virus transfer to health care workers’ skin and clothing during removal of personal protective equipment. 2012, am j infect control 40:369-374. 20 27. moog p, schulz m, betzl j et al. do your surgical glove characteristics and wearing habits affect your tactile sensibility? 2020, ann med surg (lond) 57:281-286. corresponding author: kazumi taguchi, m.d. ph.d department of nephro-urology, nagoya city university graduate school of medical sciences, nagoya, japan tel: +81 52 8538266 fax: +81 52 8523179 e-mail: ktaguchi@med.nagoya-cu.ac.jp mailto:ktaguchi@med.nagoya-cu.ac.jp 21 figure legends figure 1. protocol of this study supplemental figure 1. directed acyclic graph 22 table 1. preoperative characteristics of cases underwent robotic-assisted and/or laparoscopic urological surgeries all cases matched cases by propensity score factor dh group (n=221) ss group (n=251) p value dh group (n=171) ss group (n=171) p value sd age y.o 67.4 66.6 0.43 70.0 69.0 0.520 0.001 male sex (%) 138 ( 62.4) 183 ( 72.9) 0.018 119 ( 69.6) 111 ( 64.9) 0.420 0.074 bmi kg/m2 23.7 23.8 0.81 24.1 23.3 0.493 0.026 infection risk (%) 45 ( 20.4) 45 ( 18.0) 0.56 31 ( 18.1) 32 ( 18.7) 1 0.015 preop abx use (%) 6 ( 2.7) 3 ( 1.2) 0.32 5 ( 2.9) 2 ( 1.2) 0.448 0.12 preop pyuria (%) 34 ( 15.4) 51 ( 20.3) 0.19 31 ( 18.1) 27 ( 15.8) 0.666 0.062 bacteriuria (%) 10 ( 4.5) 13 ( 5.1) 0.50 10 ( 5.8) 7 ( 4.1) 0.208 0.20 type of procedure (%) lrp, rarp 61 (27.6), 36 (16.3) 55 (21.9), 57 (22.7) na 48 (28.1), 34 (19.9) 44 (25.7), 30 (17.5) 0.995 0.13 lpn, rapn 5 (2.3), 3 (1.4) 6 (2.4), 2 (0.8) 4 (2.3), 1 (0.6) 4 (2.3), 2 (1.2) lra, lrn 9 (4.1), 16 (6.4), 6 (3.5), 9 (5.3), 23 dh, double-gloving with hygienic hand wash; ss, single-gloving with surgical hand wash; sd, standardized difference; bmi, body mass index; preop, preoperative; abx, antibiotics; y.o, years old; lrp, laparoscopic radical prostatectomy; rarp, robotic-assisted laparoscopic radical prostatectomy; lpn, laparoscopic partial nephrectomy; rapn, robotic-assisted laparoscopic partial nephrectomy; lra, laparoscopic radical adrenalectomy; lrn, laparoscopic radical nephrectomy; lsc, laparoscopic sacral colpopexy; lpdcp, laparoscopic peritoneal dialysis catheter placement; luce, laparoscopic urachal cyst excision; na, not applicable. 45 (20.4) 67 (26.7) 37 (21.6) 39 (22.8) lsc 52 ( 23.5) 40 ( 15.9) 34 ( 19.9) 36 ( 21.1) lpdcp, luce 5 ( 2.3), 5 ( 2.3) 4 (1.6), 4 (1.6) 4 ( 2.3), 3 (1.8) 4 (2.3), 3 (1.8) 24 table 2. comparison of perioperative factors related to postoperative infection between the two antisepsis protocols. all cases matched cases by propensity score factor units dh group (n=221) ss group (n=251) p value dh group (n=171) ss group (n=171) p value sd intraand postoperative factors during hospitalization operation time min 164 [135, 199] 197 [156, 246] <0.001 174 [146, 216] 174 [149, 210] 0.946 0.009 estimate blood loss ml 50 [10, 250] 100 [10, 284] 0.045 51 [10, 250] 99 [10, 245] 0.725 0.082 duration of abx use days 3.0 [2.0, 3.0] 2.0 [2.0, 3.0] 0.031 3.0 [2.0, 3.0] 2.0 [2.0, 3.0] 0.064 0.077 additional abx use (%) 20 ( 9.1) 43 ( 17.1) 0.014 19 ( 11.1) 32 ( 18.7) 0.068 0.20 fever during hospitalization (%) 27 ( 12.2) 64 ( 25.5) <0.001 20 ( 11.7) 40 ( 23.4) 0.007 wbc at pod1 /μl 8300 [6900, 10180] 8600 [7063, 10400] 0.467 8280 [6935, 10500] 8450 [7078, 10200] 0.923 crp at pod1 mg/l 2.40 [1.62, 3.75] 2.88 [1.60, 4.22] 0.154 2.47 [1.62, 3.90] 2.51 [1.52, 3.90] 0.873 ssi during hospitalization (%) 1 ( 0.5) 2 ( 0.8) 1 1 ( 0.6) 2 ( 1.0) 1 hospital stay days 7.0 [4.0, 9.3] 8.0 [6.0, 10.0] 0.043 8.00 [5.0, 10.0] 7.00 [5.0, 10.0] 0.633 postoperative factors after discharge from hospital fever at 1 month (%) 1 ( 0.5) 2 ( 0.8) 1 1 ( 0.6) 1 ( 0.6) 1 25 ssi at 1 month (%) 4 ( 1.8) 1 ( 0.4) 0.191 3 ( 1.8) 1 ( 0.6) 0.371 pyuria at 1month (%) 33 ( 14.9) 36 ( 14.3) 0.418 26 ( 21.8) 27 ( 21.3) 1 wbc at 1 month /μl 5920 [4900, 6928] 5800 [4800, 6800] 0.275 5950 [4863, 7003] 5700[4800, 6730] 0.113 crp at 1 month mg/l 0.10 [0.05, 0.38] 0.10 [0.04, 0.30] 0.535 0.10 [0.05, 0.31] 0.08 [0.04, 0.20] 0.270 dh, double-gloving with hygienic hand wash; ss, single-gloving with surgical hand wash; sd, standardized difference; abx, antibiotics; #, number; wbc, white blood cell; pod; postoperative day; crp, c-reactive protein; ssi, surgical site infection. table 3. multivariable analysis for surgical outcomes related to postoperative infection among various parameters. modified poisson regression model fever during hospitalization fever at 1 month ssi during hospitalization ssi at 1 month rr (95% ci) p value rr (95% ci) p value rr (95% ci) p value rr (95% ci) p value bacteriuria 1.66 (0.65-4.24) 0.29 1.30 x10-8 (0.00-inf) 1.00 6.11 x10-8 (0.00-inf) 1.00 1.32x10-8 (0.00-inf) 1.00 estimate blood loss 1.00 (1.00-1.00) 0.93 1.00 (1.00-1.00) 0.99 1.00 (0.99-1.01) 0.88 1.00 (0.99-1.01) 0.76 preop abx use 1.46 x10-7 (0-inf) 0.99 2.68 x10-8 (0.00-inf) 1.00 1.11x10-7 (0.00-inf) 1.00 3.52x10-8 (0.00-inf) 1.00 26 dh group 0.49 (0.24-0.98) 0.043 1.78x108 (0.00-inf) 1.00 2.47x10-8 (0.00-inf) 1.00 1.77x108 (0.00-inf) 1.00 dh, double-gloving with hygienic hand wash; abx, antibiotics; ssi, surgical site infection; rr, risk ratio; ci, confidence interval. temporary renal enlargement in children with a first episode of febrile urinary tract infection is a significant risk of recurrent infection shingo ishimori1*, junya fujimura2, shohei oyama2, tadashi shinomoto3, satoshi onishi3, kengo hattori4, yo okizuka3, atsushi nishiyama2, hirotaka minami1 purpose: although morphological renal abnormalities in children with febrile urinary tract infection (futi) have shown a predictive factor for recurrent infection, there are no available data on recurrence regarding sonographic renal enlargement at the first futi episode, especially focusing on whether renal enlargement is temporary or not. materials and methods: this cohort study reviewed the medical records of children who underwent renal ultrasound during their first futi during 2005–2013 and who aged < 15 years at diagnosis. we defined a kidney as temporary enlarged when the kidney length was ≥ 2 standard deviation above normal renal length for that age on sonography or a difference of ≥ 1 cm in sonographic length between the right and left kidneys, following normal renal length after antibiotic treatment. results: a total of 132 children were enrolled, of whom 11 had sonographic temporary renal enlargement during their first futi. after completing antibiotic therapy for a first futi episode, 20 (15%) children had futi recurrence. the clinical characteristics at the first episode of futi were not significantly different between renal enlargement and nonrenal enlargement groups. children with temporary renal enlargement at a first futi episode had significantly lower futi recurrence-free survival proportion than those with nonrenal enlargement according to the kaplan–meier method (p = 0.003). conclusion: identification of temporary renal enlargement as a predictor of recurrent futi may help identify children with the first episode of futi who will be warned of close monitoring. keywords: children; febrile urinary tract infection; recurrence; renal sonography, temporary renal enlargement introduction in the long-term follow-up, the clinical sequela of fe-brile urinary tract infection (futi) in children is renal dysfunction, which is associated with recurrent futi, hypertension, and renal scarring(1). approximately 10% of children with the first experience of futi are known to have at least one episode of recurrent infection(2-4). recurrent episodes of futi are also associated with progression of renal scarring, which is a critical factor for long-term renal prognosis(5-10). it has been reported to identify the risk of recurrence of futi. one of the prognostic factors is morphological abnormality of the kidney and urological systems(5). vesicoureteral reflux (vur) has been reported to be the most common congenital anomaly of the kidney and urinary tract (cakut) that causes the risk for recurrence(7,11-13). however, it is important to evaluate the voiding cystourethrography (vcug) using contrast medium for making a definitive diagnosis of vur. although guidelines recommend the use of diagnostic imaging in only a limited group of children with an initial futi (12,14,15), it is essential to prioritize the avoidance of invasive procedures. sonographic examination is a noninvasive procedure and can be used even for younger children. the amer1department of pediatrics, takatsuki general hospital, 1-3-13 kosobecho, takatsuki city, osaka 569-1192 japan. 2department of pediatrics, kakogawa central city hospital, 439 kakogawa-honmachi, kakogawa city, hyogo 675-8611 japan. 3department of pediatric intensive care unit, takatsuki general hospital, 1-3-13 kosobecho, takatsuki city, osaka 569-1192 japan. 4department of pediatric surgery, takatsuki general hospital, 1-3-13 kosobecho, takatsuki city, osaka 569-1192 japan. *correspondence: department of pediatrics, takatsuki general hospital, osaka, japan tel: +81-72-681-3801. fax: +81-79-682-3834. e-mail: shingo-i0324os@live.jp received july 2021 & accepted february 2022 ican academy of pediatrics suggests that infants aged between 2 and 24 months with futi should undergo renal and bladder ultrasonography (rbus)(14). the most commonly identified findings of rbus in infants are cakut, such as hydronephrosis, solitary kidneys, and ectopic kidneys. although few in number, some children with futi have temporary renal enlargement, which is manifested as increased renal length on their renal ultrasound during the acute phase of futi following a normal renal length after antibiotic treatment(16). most of them showed a reduction to normal range within 2 weeks in the follow-up renal sonographic examination(17). temporary renal enlargement during the occurrence of futi can be a consequence of interstitial edema attributable to direct bacterial infection or local swelling reaction(18). although studies have reported that increased renal length is associated with renal scarring(18-20), no data are available on the recurrence of futi related to temporary renal enlargement. identifying whether renal enlargement is relatively associated with the recurrence of futi, focusing on temporary or permanent increased renal length on renal ultrasound not only at the acute period of futi but also after the antibiotic treatment, is considered to be useful in managing children with a first episode of futi. in the present urology journal/vol 19 no. 4/ july-august 2022/ pp. 307-314. [doi:10.22037/uj.v19i.6892] pediatric urology study, we conducted a retrospective cohort analysis of the data of children with an initial futi who underwent rbus during the acute phase, with a focus on recurrent futi concerning temporary renal enlargement at a first episode of futi. materials and methods patients and study design we retrospectively reviewed all files of pediatric patients with futi who were diagnosed at kakogawa central city hospital and takatsuki general hospital during 2005–2013. the inclusion criteria were patients who underwent prompt rbus within 72 hours after the commencement of antibiotic therapy for a first episode of futi and were aged <15 years at the time of futi diagnosis. the exclusion criteria were patients who were not subjected to rbus during a first episode of futi and those who have been managed with less than 2 months of follow-up at the hospital after the diagnosis of futi. we considered that 2 months follow-up was too short to evaluate whether children with a first episode of futi experience recurrent futi after antibiotic treatment. the other exclusion criteria were patients with bladder and bowel dysfunction, hypoplastic kidney, cystic kidney, ectopic kidney, solitary kidney, horseshoe kidney, duplex kidney, obstructed kidney, or severe hydronephrosis of urinary tract dilation (utd) p3 according to the new classification(21). we also excluded children with permanent enlarged kidney, because they might have cystic kidney, renal lymphoma, and renal involvement of acute lymphoblastic leukemia, if they are not diagnosed with any kidney disease at the time of detection of the enlargement. there were no male infants with circumcision. children with sonographic enlarged kidney at a first episode of futi were also excluded, unless they underwent a repeat rbus after the termination of antibiotic treatment. moreover, patients who were known to have vur before the development of a first futi episode and those who had a genetic abnormality, epilepsy, or abnormality of the central nervous system were excluded. this study was conducted according to the declaration of helsinki and the ethical guidelines for medical and health research involving human subjects formulated by the ministry of health, labor and welfare in japan. study approval was obtained from the institutional ethics review board of kakogawa central city hospital (approval number: 30-49). according to institutional ethics, no informed consent was obtained from the patients or their parents. in compliance with the guidelines and the institutional ethics review board for the patients’ benefit, the study protocol was displayed publicly in a poster at both institutions, so that each patient could have opportunities to refuse to participate in this study. definitions and imaging examinations in this study, futi was defined as fever of ≥ 38°c, with the urine culture yielding a growth of only one microorganism at 10,000 colony-forming units/ml or two microorganisms at 100,000 colony-forming units/ ml from a catheter specimen or midstream urine. if children have futi within 14 days after the termination of antibiotic treatment for the first episode of futi, this futi was defined as not a new episode of futi but a relapse of futi. therefore, we defined the second episode of futi as that occurring more than 14 days after the termination of antibiotic treatment for the first episode of futi. in addition, the timing of the first futi recovery was defined as the termination day of antibiotic treatment for futi without a relapse of futi. the initiation timing of follow-up was the termination day of antibiotic treatment for the first episode of futi, and the end of follow-up was the last day visited to our hospital. all sonographic examinations were performed within 72 hours after the commencement of antibiotic therapy. mild hydronephrosis was defined as utd p1 or p2 according to the new classification(21). renal length measurements were the longest length measurements recorded at any location. we considered a kidney as enlarged when the kidney length was ≥ 2 standard deviation above normal renal length for that age on rbus according to a previous report(22) or a difference of ≥ 1 cm in sonographic length between the right and left kidneys. permanent enlargement was defined as enlarged kidney that was observed not only during the acute phase of futi but also after the completion of treatment for acute futi. temporary enlargement was defined as enlarged kidney observed only at the acute phase and with normal length (between −2 and 2 standard deviations) or a difference of <1 cm in sonographic length between the right and left kidneys after the termination of antibiotic treatment. hypoplastic kidney was defined as <−2 standard deviation of the kidney length on rbus. the proportion of children table 1. characteristics of studied patients all (n=132) renal enlargement (n=11) nonrenal enlargement (n=121) p value male : female 88:44 7:4 81:40 1 age at onset of a first futi (months) 3 (2-9) 3 (2-56) 3 (2-9) 0.98 observation period (months) 16 (9-34) 27 (8-69) 16 (9-34) 0.58 characteristics at first futi bacteremia 5 (4 %) 0 (0 %) 5 (4 %) 1 microorganisms in the urine culture e. coli 107 (81 %) 9 (82 %) 98 (81 %) 1 other than e. coli 78 (59 %) 7 (64 %) 71 (59 %) 1 blood examination wbc counts (/μl) 16500 20600 16300 0.13 (12560-19950) (14400-23300) (12530-19235) crp (mg/dl) 4.3 (1.4-9.5) 8.0 (2.2-11.5) 3.8 (1.3-9.3) 0.17 urine examination pyuria 109 (83 %) 9 (82 %) 100 (83 %) 1 hydronephrosis 41 (32 %) 5 (45 %) 36 (30 %) 0.32 bilateral 6 (5 %) 0 (0 %) 6 (5 %) 1 unilateral 35 (27 %) 5 (45 %) 30 (25 %) 0.16 enlarged kidney and recurrent infection ishimori et al. vol 19 no 4 july-august 2022 308 with renal enlargement was defined as the percentage of those with enlarged kidney of either the right or left side. the operator was not aware of the results of other clinical examinations. we adopted the traditional radiography for vcug and classified to five degrees of vur according to the international reflux study(23) in a proportion of children who were not known to have vur before the development of a first futi episode. in our centers, we have the policies of administering vcug to children with first futi episode depending on the presence of bacteremia and their microorganism in the urine culture. if they have the bacteremia during the acute phase of futi or the microorganism other than escherichia coli in the urine culture, vcug is administered. renal scarring was defined as decreased uptake with distortion of the contours or cortical thinning with loss of parenchymal volume on 99 mtc-dimercaptosuccinic acid (dmsa) scintigraphy. we administer dmsa scintigraphy 6 to 12 months after acute futi to detect the formation of renal scarring(24,25). none of the children underwent continuous antibiotic prophylaxis after the first episode of futi. statistical analysis the calculated sample size was 150 children. we needed approximately 15 events (recurrent futi) in our analysis, because approximately 10% of children with a first episode of futi have at least one episode of recurrent infection. the number of inpatients with futi aged <15 years in each of our institutions is 30 per year. if the proportion of children with futi who were administered rbus at an acute episode and have been managed for more than 2 months was approximately 40%, the estimated number during a year is 24 in two institutions (40 %: 24 divided by 60). we assumed that 30-40 children would be subtracted from 192 (24 children times 8 years equals 192), because it would be very difficult to determine the correct data for some children managed more than 10 years earlier. hence, the sample size was set as 150 children, which was calculated to satisfy these assumptions. statistical analysis was conducted using the jmp 9.0 software (sas institute japan ltd., tokyo, japan). all data were expressed as median (interquartile range) or number (percentage). we expressed age at onset of a first futi, observation period, blood examination (white blood cell count, c-reactive protein), and clinical course during treatment (duration of fever, total duration of intravenous combined oral antibiotics, duration of intravenous antibiotics and duration of oral antibiotics) as median (interquartile range) and rate of bacteremia, microorganisms in the urine culture, rate of pyuria, rate of hydronephrosis, initial antibiotic therapy at first futi, and prognosis as number (percentage). the wilcoxon rank sum test was used for the association between categorical values and continuous values, and fisher’s exact test was used for two categorical values. time to recurrence of futi (the period between the time of the first episode of futi and the second episode of futi) based on the presence or absence of temporary renal enlargement at a first episode of futi was estimated using the kaplan–meier method and wilcoxon test. the hazard ratio for recurrent futi was calculated with 95% confidence intervals using cox proportional hazard regression adjusted for the factors that showed significance in the univariate analysis. a p value of < 0.05 was considered to be statistically significant. results characteristics during the first episode of futi a total of 227 children with a first episode of futi were treated at our hospital (figure 1). 26 children who did not undergo rbus examination during the episode of first futi and 69 who met any other exclusion criteria were excluded. therefore, a total of 132 children number escherichia coli 107 enterococcus faecalis 35 extended-spectrum β-lactamase escherichia coli 5 streptococcus agalactiae 5 klebsiella pneumoniae 3 citrobacter amalonaticus 3 staphylococcus epidermitis 2 staphylococcus haemolyticus 1 staphylococcus aureus 1 methicillin-resistant staphylococcus aureus 1 klebsiella oxytoca 1 pseudomonas aeruginosa 1 enterobacter aerogenes 1 yersinia enterocolitica 1 streptococcus lugdunensis 1 serratia marcescens 1 table 2. detailed microorganism in the urine culture all (n=132) renal enlargement (n=11) nonrenal enlargement (n=121) p value initial antibiotic therapy of first futi cefotaxime 83 (63 %) 4 (36 %) 79 (65 %) 0.1 ampicillin combined cefotaxime 3 (2 %) 1 (9 %) 2 (2 %) 0.23 cefotiam 8 (6 %) 2 (18 %) 6 (5 %) 0.13 ceftriaxone 2 (2 %) 1 (9 %) 1 (1 %) 0.16 sulbactam ampicillin 17 (13 %) 1 (9 %) 16 (13 %) 1 oral antibiotics 1 (1 %) 0 (0 %) 1 (1 %) 1 clinical course during treatment duration of fever (day) 2 (2-4) 2 (2-4) 2 (1-2) 0.51 total duration of intravenous combined oral antibiotics (day) 11 (8-14) 13 (8-14) 11 (8-14) 0.35 duration of intravenous antibiotics (day) 6 (4-7) 6 (6-7) 6 (4-7) 0.28 duration of oral antibiotics (day) 5 (3-7) 7 (3-9) 5 (3-7) 0.19 prognosis recurrent futi 20 (15 %) 5 (45 %) 15 (12 %) 0.01 vesicoureteral reflux † 8/53 (15 %) 0/8 (0 %) 8/45 (18 %) 0.33 futi; febrile urinary tract infection, †; evaluated 53 children who were performed voiding cystourethrography table 3. comparison of therapy, clinical course, and prognosis between the renal enlargement group and the nonrenal enlargement group. enlarged kidney and recurrent infection ishimori et al. pediatric urology 309 (88 boys and 44 girls) were included in this study. as shown in table 1, we divided the children into those who had temporary renal enlargement at a first episode of futi (renal enlargement group: 11 children) and those who did not have enlarged kidney (nonrenal enlargement group: 121 children). in comparison with the renal enlargement and nonrenal enlargement groups, the observation period showed no significant differences. the duration of the observation period in more than half of children was less than 1 year. the most common microorganism in the urine culture was escherichia coli (table 2). the results of blood and urine examinations showed no significant differences in both the renal enlargement and nonrenal enlargement groups. similar proportions of children in both groups had mild hydronephrosis at a first futi episode. therapy, clinical course, and prognosis except for a child who was treated orally without intravenous antibiotics, the majority of all children received intravenous antibiotics as initial therapy for a first futi episode following oral antibiotics (table 3). after the completion of antibiotic therapy for a first episode of futi, 20 (15%) children had recurrence of futi. comparison between the renal enlargement and nonrenal enlargement groups indicated a significantly higher proportion of children with recurrent futi in the renal enlargement group. no significant differences were observed among children who had vur between the two groups, although only a part of the patients were examined by vcug. table 4 shows the detailed characteristics of children with temporary renal enlargement. among five patients with recurrent futi, four progressed to recurrence within a year from a first episode of futi. four of the five children who had recurrence underwent vcug, and no child was found to have vur. of three children who underwent 99 mtc-dmsa scintigraphy, one had renal scarring. outcome the futi recurrence-free survival time based on temporary renal enlargement at a first episode of futi assessed using the kaplan–meier method is shown in figure 2. the futi recurrence-free survival proportion in children with nonrenal enlargement was 89.2% at 12 months from a first episode of futi. the futi recurrence-free survival proportion in children with temporary renal enlargement was 47.7% at 12 months from a first episode of futi. a significant difference was observed between the renal enlargement and nonrenal enlargement groups (p = 0.003). a significant difference was observed between the renal enlargement and nonrenal enlargement groups (p = 0.003). moreover, we divided the children into those who had recurrent futi (recurrent group: 20 children) and those who did not have recurrent futi (nonrecurrent group: 111 children). compared with the nonrecurrent group, the level of serum crp at the first episode of futi was higher, and the duration of intravenous antibiotics was longer in the nonrecurrent group with statistical significance. the proportion of children with renal enlargement at the first episode of futi and vur was significantly higher than that of children without renal enlargement or vur (data not shown). we calculated the hazard ratio for recurrent futi using cox proportional hazard regression adjusted for renal enlargement or nonrenal enlargement, the level of serum crp at the first episode of futi, and the duration of intravenous antibiotics with or without vur, because not all 132 children received the vcug management. the results of our recalculated analysis showed that there was no significant independent factor for recurrent futi using the multivariate cox regression analysis. table 4. detailed characteristics of 11 children with temporary renal enlargement futi; febrile urinary tract infection, e. coli; escherichia coli, iv; intravenous, dmsa; dimercaptosuccinic acid, vcug; voiding cystourethrography, vur; vesicoureteral reflux, utd; urinary tract dilatation, e. faecalis; enterococcus faecalis, na; not available enlarged kidney and recurrent infection ishimori et al. vol 19 no 4 july-august 2022 310 discussion our study results showed that children with temporary renal enlargement at a first episode of futi had a significantly high risk for recurrent infection, and approximately 12% of children required antibiotics for recurrent futi among our patients comparable with previous reports(3,4), wherein approximately half of the children with temporary renal enlargement progressed to a second episode of futi. in our cohort, we evaluated the relationship between temporary renal enlargement and clinical characteristics during the acute phase of futi and after the completion of treatment for futi. compared with children without renal enlargement at an initial futi episode, the proportion of patients with recurrent infection was significantly higher among those with renal enlargement. in recent studies, enlarged kidney during an initial episode of futi has been believed to be associated with permanent renal damage. muller et al. reported that the maximum renal longitudinal diameter on rbus correlated with the degree of 99 mtc-dmsa scintigraphic uptake (20). bouissou et al. demonstrated that increased renal diameter at initial futi significantly correlated with the risk of renal scarring(19). two hypotheses can be used for interpreting these analyses wherein renal enlargement was significantly associated with permanent renal damage. first, children with increased renal diameter at an futi episode could already have irreversible renal damage at the time of first futi episode, which would appear as the finding of permanent renal enlargement on rbus. second, these children could carry multiple risks for renal scarring, although increased renal length during the acute phase of futi indicates a temporary renal swelling reaction of interstitial edema and following normal renal length after antibiotic treatment(18). our present result show that temporary renal enlargement during an episode of futi is a predictor of recurrent futi as a risk of renal scarring and might match with the latter hypothesis. although more than half of children with an initial futi have never had recurrence, an increase in the number of recurrences increases the risk for renal scarring(26). following several studies focusing on a first episode of pediatric futi have been concerned with protecting the kidney function from further damage to avoid recurrence of futi and manage dilating reflux. the american academy of pediatrics recommends that children should receive medical evaluation to confirm futi and to intervene promptly if they have high fever or urinary symptoms(14). for children with initial futi, it is essential to identify valuable clinical and radiological indicators of recurrences and vur. panaretto et al. found that an age of <6 months, dilating reflux, and abnormality on 99 mtc-dmsa scintigraphy at the initial futi were the risk factors for recurrent infection(7). carpenter et al. demonstrated that nondetection of escherichia coli in urine culture during futi correlated with a high grade of vur(27). although our study results showed no significant relationship between temporary renal enlargement and vur, identification of temporary enlargement as a predictor of recurrent futi may flow chart of our retrospective cohort study. enlarged kidney and recurrent infection ishimori et al. pediatric urology 311 help identify patients for whom closer monitoring may be warranted or early intervention considered as previous study recommended(14,28). children with recurrent episode of futi, not detecting vur, may have some other triggers of recurrence. while we did not evaluate further investigation, patients with temporary renal enlargement without vur in our cohort have intrarenal reflux which plays an important role in the pathogenesis of reflux associated futi(29,30). in addition, male infants without circumcision have an increased risk of futi than circumcised boys(31,32). there were no male infants with circumcision in our cohort study, and three among seven boys with temporary renal enlargement had recurrence of futi. their recurrence of futi may relate to non-circumcision. moreover, children without vur who have recurrent futi are recommended antimicrobial prophylaxis(33). with further details, evaluating the effect of antimicrobial prophylaxis for children with temporary renal enlargement at an initial episode of futi, we might be able to conclude that detecting of temporary enlargement could prevent recurrence in terms of management of children without vur. in general, rbus is a sensitive and noninvasive procedure for detecting morphological renal anomalies, but it is insensitive for diagnosing acute pyelonephritis. some children with acute futi were reported to have focal or diffuse renal sonographic enlargement(10). previous studies have estimated the degree and radiological change of renal enlargement based on sonographic imaging measurements of renal length in patients with futi. one cohort study indicated that kidneys with scintigraphic defects such as acute pyelonephritis were longer than kidneys without defects, but they returned to normal size range within 11 days of starting treatment(16). johansson et al. showed that children with acute pyelonephritis had an average increase of 150% of the normal renal volume in control subjects(34). in the first 2 weeks, the most prominent decrease in renal length was detected in the follow-up ultrasound. dinkel et al. reported an average increase in renal volume of 176% in 51 children with acute pyelonephritis(17). they showed a reduction in renal volume of 50–60% within 2 weeks in the follow-up renal sonographic examination. in the present cohort analysis, rbus at a first episode of futi could be suggested as an important procedure for detecting enlarged kidney as a risk factor for recurrent futi. there were several limitations in our study. first, the duration of the observation period in more than half of children was less than 1 year. this duration may be too short to appropriately analyze the rate of recurrence in children with initial futi. some children may experience episodes of recurrent futi within a time range beyond our observation period. second, we excluded patients who did not undergo sonographic evaluation at an initial futi episode. moreover, unless children underwent a repeat renal ultrasound after the antibiotic treatment for futi, they were excluded even if they had figure 2. the febrile urinary tract infection (futi) recurrence-free survival time based on temporary renal enlargement. the solid line indicates children with nonrenal enlargement at a first episode of futi; the futi recurrence-free survival proportion was 89.2% at 12 months from a first episode of futi. the dashed line indicates children with temporary renal enlargement at a first episode of futi; the futi recurrence-free survival proportion was 47.7% at 12 months from a first episode of futi. a significant difference was observed between the renal enlargement and nonrenal enlargement groups (p = 0.003). enlarged kidney and recurrent infection ishimori et al. vol 19 no 4 july-august 2022 312 sonographic increased renal length at an initial futi episode. third, our study had sparse data bias because the sample size was too small. finally, as our study was a retrospective cohort analysis, imaging examinations for the evaluation of cakut and renal scarring after the completion of treatment for an initial futi were performed in some but not all children. although recurrent futi was significantly associated with the increase of kidney size in the acute phase of infection, no significant relationships were detected between renal enlargement and morphological abnormality of the kidneys, including vur. the strategy for contrast imaging in children with futi in our center was to evaluate cakut according to the protocol of a published guidelines(14). if we were to evaluate follow-up imaging examinations for all patients with futi with an interval of several months after an acute infection, we might obtain different results on the risk factors for recurrence. conclusions in conclusion, temporary renal enlargement on ultrasonography at a first episode of futi in pediatric patients was significantly associated with the recurrence of futi in a limited study with small sample size and no confounding adjustment. identification of temporary temporal renal enlargement as a predictor of recurrent futi may help identify children with a first episode of futi who will be warned of close monitoring. acknowledgment the authors would like to thank enago (www.enago.jp) for the english language review. conflict of interest the authors report no conflicts of interest relevant to this article. references 1. jacobson sh, eklof o, eriksson cg, lins le, tidgren b, winberg j. development of hypertension and uraemia after pyelonephritis in childhood: 27 years follow up. bmj 1989; 299: 703-6. 2. shaikh n, craig jc, rovers mm, et al. identification of children and adolescents at risk for renal scarring after a first urinary tract infection: a meta-analysis with individual patient data. jama pediatr 2014; 168: 893900. 3. conway ph, cnaan a, zaoutis t, henry bv, grundmeier rw, keren r. recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. jama 2007; 298: 179-86. 4. hoberman a, wald er, hickey rw, et al. oral versus initial intravenous therapy for urinary tract infection in young febrile children. pediatrics 1999; 104: 79-86. 5. martinell j, hansson s, claesson i, jocobsson b, lidin-janson g, jodal u. detection of urographic scars in girls with pyelonephritis followed for 13-38 years. pediatr nephrol 2000; 14: 1006-10. 6. wennerstrom m, hansson s, jodal u, stokland e. primary and acquired renal scarring in boys and girls with urinary tract infection. j pediatr 2000; 136: 30-4. 7. panaretto ks, craig jc, knight jf, howmangiles r, sureshkumar p, roy lp. risk factors for recurrent urinary tract infection in preschool children. j. pediatr child health 1999; 35: 454-9. 8. shaikh n, haralam ma, kurs-lasky m, hoberman a. association of renal scarring with number of febrile urinary tract infections in children. jama pediatr 2019; 173: 949-52. 9. matoo tk, chesney rw, greenfield sp, et al. renal scarring in the randomized intervention for children with vesicoureteral reflux (rivur) trial. clin j am soc nephrol 2016; 11: 54-61. 10. shaikh n, ewing al, bhatnagar s, hoberman a. risk of renal scarring in children with a first urinary tract infection: a systematic review. pediatrics 2010; 126: 1084-91. 11. johansson b, berg u, svensson l. renal damage after acute pyelonephritis. arch dis child 1994; 70: 111-5. 12. rushton hg. the evaluation of acute pyelonephritis and renal damage with technetium99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions. pediatr nephrol 1997; 11: 108-20. 13. karen r, shaikh n, pohl h, et al. risk factors for recurrent urinary tract infection and renal scarring. pediatrics 2015; 136: e13-21. 14. subcommittee on urinary tract infection, steering committee on quality improvement and management, roberts kb. urinary tract infection: clinical practice guideline for the diagnosis and management of the initial uti in febrile infants and children 2 to 24 months. pediatrics 2011; 128: 595-610. 15. avner ed, harmon we, niaudet p, yoshikawa n. pediatric nephrology, 6th edn. springer, berlin heidelberg, new york, 2009. 299-310. 16. pickworth fe, carlin jb, ditchfield mr, et al. sonographic measurement of renal enlargement in children with acute pyelonephritis and time needed for resolution: implications for renal growth assessment. ajr 1995; 165: 405-8. 17. dinkel e, orth s, dittrich m, schultewisermann h. renal sonography in the differentiation of upper from urinary tract infection. ajr 1986; 146: 755-80. 18. peratoner l, pennesi m, bordugo a, et al. kidney length and scarring in children with urinary tract infection: importance of ultrasound scans. abdom imaging 2005; 30: 780-5. 19. bouissou f, munzer c, decramer s, et al. prospective randomized trial comparing short and long intravenous antibiotic treatment of acute pyelonephritis in children: dimercaptosuccinic acid scintigraphic evaluation at 9 months. pediatrics 2008; 121: e553-60. 20. muller l, preda i, jocobsson b, et al. ultrasonography as predictor of permanent enlarged kidney and recurrent infection ishimori et al. pediatric urology 313 renal damage in infants with urinary tract infection. acta pediatr 2009; 98: 1156-61. 21. nguyen ht, benson cb, bromley, et al. multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (utd classification system). j pediatr urol. 2014; 10: 982-98. 22. rosembaum dm, korngold e, teele rl. sonographic assessment of renal length in normal children. ajr 1984; 142: 467-9. 23. lebowitz rl, olbing h, parkkulainen kv, smellie jm, tamminen-mobius te. international reflux study in children. international system of radiographic grading of vesicoureteric reflux. pediatr radiol 1985; 15: 105-9. 24. shaikh n, morone ne, bost je, farrell mh. prevalence of urinary tract infection in childhood: a meta-analysis. pediatr infect dis j 2008; 27: 302-8. 25. singh-grewal d, macdessi j, craig j. circumcision for the prevention of urinary tract infection in boys: a systematic review of randomized trial and observational studies. arch dis child 2005; 90: 853-8. 26. jodal u. the natural history of bacteriuria in childhood. infect dis clin north am 1987; 1: 713-29. 27. carpenter ma, hoberman a, mattoo tk, et al. the rivur trial: profile and baseline clinical associations of children with vesicoureteral reflux. pediatrics 2013; 132: e34-45. 28. hoberman a, charron m, hickey rw, baskin m, kearney dh, wald er. imaging study after a first febrile urinary tract infection in young children. n engl j med 2003; 348: 195202. 29. simicic ma, arapovic a, saraga-babic m, et al. intrarenal reflux in the light of contrastenhanced voiding urosonography. front pediatr 2021; mar 2; 9: 642077. doi: 10.3389/ fped.2021.642077. ecollection 2021. 30. colleran gc, barnewolt ce, chow js, paltiel hj. intrarenal reflux: diagnosis and contrast-enhanced voiding urosonography. j ultrasound med 2016; 35: 1811-9. 31. montini g, zucchetta p, tomasi l, et al. value of imaging studies after a first febrile urinary tract infection in young children: data from italian infection study 1. pediatrics 2009; 123: e239-43. 32. marks sd, gordon i, tullus k. imaging in childhood urinary tract infections: ime to reduce investigations. pediatr nephrol 2008; 23: 9-17. 33. craig jc, simpson jm, williams gj, et al. antibiotic prophylaxis and recurrent urinary tract infection in children. n engl j med 2009; 361: 1748-59. 34. johansson b, troell s, berg u. renal parenchymal volume during and after acute pyelonephritis measured by ultrasonography. arch dis child 1988; 63: 1309-14. enlarged kidney and recurrent infection ishimori et al. vol 19 no 4 july-august 2022 314 editorial 1urology journal vol 5 no 1 winter 2008 urology journal in 2008 a new look urol j. 2008;5:1-2. www.uj.unrc.ir happy new year to all our readers, contributors, reviewers, consultants, and editorial advisors. we welcome the new year—a time for reflection, transition, and looking ahead. the urology journal editorial team wishes all our readers an enjoyable, healthy, and successful new year. as 2008 has arrived, we at the urology journal are very pleased to enthusiastically unveil our new look. a major goal of the editorial board and staff of the journal is to meet our readers’ informational needs and respond to readers’ requests and suggestions for future content development. a transition can be thought of as a turning point or a passage from one contextual pattern to another. after several years of enormous activity and transitions, we are beginning a period where we are focused on improving our communications, processes, and procedures. what is down the path for the urology journal over the next months? one very exciting outcome in 2007 will be our indexing in medline/pubmed, a benchmark on the road to becoming a prestigious journal in the field of urology. we owe our improved position to the quality of our authors’ contributions, the quality of our reviewers and their comments, and the hard work of our industrious editorial and production teams. we also thank our executive editor dr farhat farrokhi, whose sharp critical eye has done so much to improve many manuscripts. the urology journal grew in many ways in 2007, and with the help of you all will continue to grow in 2008. we strive to publish information that is evidence based and useful. we recognize that our readers are busy clinicians; therefore, every issue of the urology journal offers a variety of concise articles. we were able to focus more on subjects of interest falling within the scope of our journal. processing, editing and reviewing more submissions, publishing more papers, and publishing those papers more quickly, all are among our goals in 2008. it would be hard to find anyone to dispute the idea that free access to the research literature is a laudable aim. the urology journal already provides entirely free access to the journal. our journal can be accessed directly through its web site (www.uj.unrc.ir). in 2008, readers and authors across the world will be able to continue to participate in the urology journal at no cost and without the bias that can come from commercial sponsorship. we are pleased to announce that as from january 2007 the journal’s manuscript submission and peer review process have all occurred on-line. this should speed up our processes significantly and we hope authors will be pleased with the new technology. in keeping with the recommendations of the international committee of medical journal editors, the urology journal editorial team adopted the definition of editorial freedom endorsed by the world association of medical editors. we were able to maintain our high standards of quality peer review. we would like to thank our large team of national and international reviewers, who provided us with invaluable advice on manuscripts submitted. consider joining our team as a urology journal reviewer. reviewers critique 4 to 6 manuscripts per year and may decline a review because of time constraints. in relation to the urology journal, in 2007, a sum of 145 manuscripts were submitted. the 4 issues published during the year consisted of a total of 58 articles (5 reviews, 32 original articles, 15 case reports, 3 editorials, and 2 letters) adding up to 262 pages. the geographical origins of the articles other than iran were as follows: 3 from usa and 1 from greece, turkey, india, pakistan, australia, urology journal in 2008—safarinejad 2 urology journal vol 5 no 1 winter 2008 and saudi arabia, each. the submissions last year were increased by 72%. we hope that 2008 will also be a fruitful year for the journal, and that we can increase the interest of our readers and authors. one indisputable role of the urology journal is to educate. we are making a concerted effort to focus our publications on 3 major areas: education, public health issues, and leadership issues. as we continue to evolve, we have solidified how we view our focus. such reflection is the genesis of our decision to concentrate more on our ongoing purposes. the journal’s primary focus is on publishing credible peer-reviewed researches that provide the evidence-based rationale needed for making clinical decisions. in 2008, we as editorial board, shall be happy to continue serving you as authors and readers of our open-access journal devoted to all aspects of urology. in the forthcoming years, we envisage continuing growth in the urology journal—a growth in readers, activities, and financial resources, and further expansion of our coverage. in 2008, we shall continue to work for the further advancement of the urology journal, among other things, by stepping up our efforts to solicit reviews on subjects of topical interest from active members of the research community. we look forward to a productive and successful 2008! mohammad reza safarinejad associate editor, urology journal vol 19 no 3 may-june 2022 100 effect of a probiotic supplement containing lactobacillus acidophilus and bifidobacterium animalis lactis on urine oxalate in calcium stone formers with hyperoxaluria: a randomized, placebo-controlled, double-blind and in-vitro trial sanaz tavasoli1, saba jalali1, mohammad naji1, nasrin borumandnia1, ghazaleh shakiba majd1, abbas basiri1, kianaoush khosravi darani2, dina karamad2, maryam tajabadi-ebrahimi3, maryam taheri1*. purpose: to determine the effect of a probiotic supplement containing native lactobacillus acidophilus (l. acidophilus) and bifidobacterium animalis lactis (b. lactis) on 24-hour urine oxalate in recurrent calcium stone formers with hyperoxaluria. moreover, the in-vitro oxalate degradation capacity and the intestinal colonization of consumed probiotics were evaluated. materials and methods: the oxalate degrading activity of l. acidophilus and b. lactis were evaluated in-vitro. the presence of oxalyl-coa decarboxylase (oxc) gene in the probiotic species was assessed. one hundred patients were randomized to receive the probiotic supplement or placebo for four weeks. the 24-hour urine oxalate and the colonization of consumed probiotics were assessed after weeks four and eight. results: although the oxc gene was present in both species, only l. acidophilus had a good oxalate degrading activity, in-vitro. thirty-four patients from the probiotic and thirty patients from the placebo group finished the study. the urine oxalate changes were not significantly different between groups (57.21 ± 11.71 to 49.44 ± 18.14 mg/day for probiotic, and 56.43 ± 9.89 to 50.47 ± 18.04 mg/day for placebo) (p = .776). the probiotic consumption had no significant effect on urine oxalate, both in univariable (p = .771) and multivariable analyses (p = .490). the consumed probiotics were not detected in the stool samples of most participants. conclusion: our results showed that the consumption of a probiotic supplement containing l. acidophilus and b. lactis did not affect urine oxalate. the results may be due to a lack of bacterial colonization in the intestine. keywords: lactobacillus acidophilus; bifidobacterium animalis subsp. lactis; hyperoxaluria; probiotics; urolithiasis; calcium oxalate. introduction hyperoxaluria is a common urinary metabolic risk factor in calcium stone formers(1). although it is more prevalent among iranians and some other asian countries, the global prevalence of hyperoxaluria in stone-forming patients has increased over the last two decades(1). despite its prevalence and significance, the level of evidence for hyperoxaluria management is low in current kidney stone guidelines(2). moreover, the most common approach for hyperoxaluria management is based on dietary limitation, which may not be applicable or accepted by all patients(3). the oxalate in the human body originates from dietary intake and liver metabolism(4). the liver is the primary source of oxalate generation in the human body, which metabolizes several precursors, such as glycine, glyoxylate, and ascorbic acid, to oxalate(4,5). since the human body could not degrade oxalate, controlling the intestinal absorption of dietary oxalate could be a treatment modality for hyperoxaluria management(4,6). the intestinal microbiota has a known contribution to kidney stone pathophysiology(7,8). studies demonstrated that intestinal microbiota could metabolize oxalate and reduce its absorption from the intestine(9). the well-known oxalate degrading bacterium in the gut microbiota is oxalobacter formigenes (o. formigenes) (7). o. formigenes exclusively depends on oxalate as its obligatory energy source. oxalyl-coa decarboxylase (oxc) is one of the critical bacterial enzymes for oxalate degradation that catalyze oxalyl-coa to co2 and formyl-coa(7). lactobacillus and bifidobacterium sp. occur in high numbers in the human gut and have been used extensively as probiotics for health improvement(5). few studies evaluated their effect on hyperoxaluria. however, most of these studies could not find an oxalate-lowering effect of evaluated probiotics(9). since there is a controversy in the effect of probiotics on hyperoxaluria, the selection of species with the most significant oxalate degrading activity may elicit a more favorable response(10). some in-vitro studies suggested that the oxc gene, encoding oxc, is not present in all the lacto1urology and nephrology research center, shahid beheshti university of medical sciences, tehran, i.r. iran. 2research department of food technology research, national nutrition and food technology research institute, shahid beheshti university of medical sciences, tehran, i.r. iran. 3department of biology, central tehran branch, islamic azad university, tehran, i.r. iran. *correspondence: urology and nephrology research center, shahid beheshti university of medical sciences, tehran, i.r. iran. tel: +982122567222 -fax: +982122567282. e-mail: taheri233@yahoo.com, received april 2021 & accepted may 2021 endourology and stone disease urology journal/vol 19 no. 3/ may-june 2022/ pp. 179-188. [doi: 10.22037/uj.v18i.6789] bacillus and bifidobacterium sp.; therefore, these species showed highly variable oxalate degrading capacity (11,12). lactobacillus acidophilus (l. acidophilus) and bifidobacterium animalis lactis (b. lactis) showed the highest oxalate degrading activity in in-vitro(11-13) and animal studies(14,15). however, the effect of the simultaneous use of both species on urine oxalate was not assessed in clinical trials. the current study aimed to determine the effect of a probiotic supplement containing native l. acidophilus and b. lactis on 24-hour urine oxalate in recurrent calcium stone formers with hyperoxaluria in a randomized, placebo-controlled, double-blind trial. these species were selected according to the results of previous studies(11-15). besides the clinical trial, the in-vitro oxalate degradation capacity of native l. acidophilus and b. lactis, and the presence of oxc gene in these species were evaluated. we also assessed the colonization of consumed probiotics in the intestine by real-time pcr of the mentioned species in the stool(16,17). materials and methods in-vitro study bacterial species, chemicals, and media two probiotic species, l. acidophilus (ptcc no: 1643) and b. lactis (ptcc no: 1736), were provided by tak gen zist pharmaceutical company, tehran, iran. both strains were isolated from iranian native foods and used for the production of the probiotic supplements. both bacteria were verified for genus and species by 16s rrna gene sequence typing. o. formigenes (dsm 4420) was purchased from the dsmz-german collection of microorganisms and cell cultures (braunschweig, germany). proteose peptone, yeast extract, tween® 80, potassium dihydrogen phosphate (kh 2 po 4 ), sodium acetate, di-ammonium hydrogen citrate, magnesium sulfate heptahydrate (mgso 4 .7h 2 o), manganese sulfate monohydrate (mnso4.h2o), di-ammonium oxalate monohydrate, d (+)-glucose anhydrous, l-cysteine, and anaerocult® a gas pack were purchased from merck (darmstadt, germany). the de man-rogosa and sharpe (mrs) broth was purchased from liofilchem® (roseto degli abruzzi (te), italy). d (+)-sucrose and sodium oxalate were purchased from carlo erba reagents (val de reuil, france). pre-adaptation to high oxalate contents the in-vitro study was conducted in the microbiology laboratory of the national nutrition and food technology research institute, shahid beheshti university of medical sciences, tehran, iran. all the bacteria were pre-adapted to non-inhibitory concentrations of oxalate before the oxalate degradation assay(12). anaerobic conditions were achieved in all experiments in anaerobic jars supplemented with a pad of anaerocult® a. after anaerobic growth of the bacteria in mrs broth for 16 hours, l. acidophilus was pre-adapted to high oxalate contents: first, l. acidophilus was grown in mrs broth containing 0.35 mmol/l sodium oxalate (ph 5.5) and incubated at 37°c for 16 hours. at the next step, growing microorganisms were transferred to mrs broth containing 35 mmol/l of sodium oxalate (ph 5.5) and incubated at 37 °c for 16 hours. as the method mentioned above, the b. lactis was pre-adapted to high oxalate contents after anaerobic growth of the bacteria in mrs broth + l-cysteine (0.5 g/l) for 16 hours. the pre-adaptation steps were growth within two incubation cycles at 37 °c for 16 hours, first in mrs broth + l-cysteine containing 0.35 mmol/l sodium oxalate (ph 5.5), and then mrs broth + l-cysteine, containing 35 mmol/l of sodium oxalate (ph 5.5). o. formigenes was pre-adapted to high oxalate contents, as we previously published, using 0.35 mmol/l and 35 mmol/l ammonium oxalate(18). oxalate degradation estimation the base culture medium used for oxalate degradation assay was prepared as the method used by campieri et al.(19). this enriched media contained proteose peptone (10 g), yeast extract (5 g), tween® 80 (1 ml), kh2 po 4 (2 g), sodium acetate (5 g), di-ammonium hydrogen citrate (2 g), mgso4.7h2o (0.05 g), and mnso4. h 2 o (0.05 g). all these materials were dissolved in distilled water, with a final volume of 500 ml. after sterilization, sodium oxalate (25 mmol/l), d (+)-glucose anhydrous (10 ml), and d (+)-sucrose (10 ml) (all sterilized using 0.46-µ filters) were added to the medium. the final ph of the medium was 5.5. the media were inoculated with study species (2*10^8 cfu/ml) and incubated for four days. o. formigenes has been employed as a positive reference to validate oxalate degradations assay, and an un-inoculated medium was used as a negative control. all the cultivations were performed in a bioscreen c system (growth curves ltd, finland), which also measured the population of bacteria by a turbidometric method. the oxalate contents of culture broth samples, positive control, and negative control were measured at the beginning and every day until the fourth day of the study. after pasteurization of media at 90 ºc for 15 min, the endourology and stones diseases 180 table 1. the sequence and amplicon size of the primers bacteria/gene sequence (5′-3′) amplicon size (bp) reference oxc gene in lactobacillus sp. f: agcctcgtcaccgtcttg 125 (21) r: accaaatgctgagtcaccttc oxc gene in bifidobacterium sp. f: accttcgtcgtgctcaac 107 (21) f: accttcgtcgtgctcaac probiotic l. acidophilus f: aaccaacagattcacttcg 250 this study r: ctctcaactcggctatgc probiotic b. lactis f: agcgaacaggattagatacc 254 this study r: gaagggaaaccgtgtctc universal primer for total bacteria f: ag(a/c)gtt(t/c)gat(t/c)(a/c)tggctcag 314-373 (25) r: gctgcctcccgtaggagt abbreviations: oxc: oxalyl-coa decarboxylase; l. acidophilus: lactobacillus acidophilus; b. lactis: bifidobacterium animalis lactis probiotic in calcium stone formers-tavasoli et al. vol 19 no 3 may-june 2022 100 media were centrifuged at 5000 × g for 10 min, and the supernatants were used to assess concentrations of residual oxalate. the oxalate content was assessed using a colorimetric enzymatic method (darman faraz kave kit, tehran, iran), as we previously reported(20). the oxalate degradation was reported as the percentage of oxalate utilized versus the initial values. all experiments were performed in triplicates. assessment of oxc gene in the probiotic species the presence of oxc gene in the genomic dna of probiotic species, i.e., l. acidophilus and b. lactis, was assessed by polymerase chain reaction (pcr). the genomic dna was extracted by boiling lysis and quantified using a wpa spectrophotometer (biochrom, cambridge, uk)(21). the used primers(table 1) and positive controls were adapted from our previous study(21). each pcr reaction was composed of 5 ng of genomic dna, 20 pmol of each forward and reverse primers, 10 mmol of each dntp, 1.5 mmol/l of mgcl2, 0.5 units of taq polymerase, and double distilled water to reach a final volume of 25 µl. the reactions were performed in a thermocycler (mastercycler, eppendorf). pcr products were electrophoresed on agarose gel (3%) and stained with ethidium bromide to visualize the amplicons. a gel documentation system (syngene, cambridge, uk) was used to capture the gel images. randomized clinical trial study design and participants the second step of the study was a randomized, placebo-controlled, double-blind clinical trial. the study had a parallel-group design, with an allocation ratio of 1:1. the clinical trial aimed to evaluate the effect of a probiotic supplement containing the same l. acidophilus and b. lactis species as in-vitro study, on the urine oxalate of recurrent calcium stone formers with hyperoxaluria. figure 1. the oxalate depredating behavior of study l. acidophilus and b. lactis, compared with o. formigenes. each point represents mean and error bars represent the standard deviation values. abbreviations: sd: standard deviation; bmi: body mass index; iqr: interquartile range. aindependent t test bchi square test cmann-whitney test. dfisher exact test table 2. baseline demographic and clinical characteristics of the studied participants probiotic (n = 34) placebo (n = 30) p-value age, years, mean (sd) 46.1 (12.7) 50.4 (9.3) .130a gender, number (percentage) .325b female 13 (38.2%) 8 (26.7%) male 21 (61.8%) 22 (73.3%) bmi, kg/m2, mean (sd) 28.85 (4.75) 30.45 (4.66) .281a positive family history, number (percentage) 17 (50%) 16 (53.3%) .790b disease duration, years, median (iqr)] 7.00 (4.00-15.00) 19.00 (5.00-29.00) .055c cigarette smoking, number (percentage) .314d yes 1 (2.9%) 2 (6.7%) no 33 (97.1%) 26 (86.7%) past smoking 0 (0.0%) 2 (6.7%) probiotic in calcium stone formers-tavasoli et al. vol 19 no 3 may-june 2022 181 endourology and stones diseases 182 patients with a history of at least two radiopaque stone episodes(22) and hyperoxaluria (24-hour urine oxalate ≥ 40 mg/24h) were recruited from the stone prevention clinic of shahid labbafinejad medical hospital, tehran, iran. all patients aged 18-70 who were capable of giving informed consent and had no history of surgical interventions or stone expulsion in the last twenty days(2). patients were not included if they had a history of primary or enteric hyperoxaluria (urine oxalate > 80 mg/24h), chronic kidney disease, current urinary tract infection, chronic diarrhea, thyroid or parathyroid diseases, diabetes mellitus, hepatic failure, cancers or immunologic diseases and in case of pregnancy or lactation. patients were also excluded from the study if they used antibiotics, any medication influencing urine oxalate homeostasis, including calcium and magnesium supplements and pyridoxine, or if they had a new prescription or changed the dose of thiazides and potassium citrate during the study. patients using antibiotics two weeks before the start and during the study were also excluded. all patients gave written informed consent, and the study was performed in accordance with the 1964 declaration of helsinki. the study was approved by the national institute for medical research development (nimad) (grant number: 940329) and urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. the ethics committee of nimad approved the study (reference number: ir.nimad.rec.1394.014). the trial was registered on the iranian registry of clinical trials (irct) (irct registration number: irct2016020626406n1). interventions the used probiotic supplement was a commercial product, containing assessed l. acidophilus and b. lactis species, produced by tak gen zist pharmaceutical company, tehran, iran. the supplement was approved by the food and drug organization of iran. each captable 3. 24-hour urine metabolites of the study groups at baseline, at the end of the intervention (post-treatment) and 4 weeks after the end of the intervention (post-follow-up). all values stand for mean (standard deviation) variable probiotic group placebo group p-valuea time effect group effect 24-hour urine oxalate, mg/day (n = 64) .017* .776 baseline 57.21 (11.71) 56.43 (9.89) post-treatment 53.82 (16.13) 51.17 (18.32) post-follow up 49.44 (18.14) 50.47 (18.04) calcium oxalate supersaturation (n = 64) .618 .804 baseline 7.44 (2.83) 6.96 (3.41) post-treatment 6.91 (3.88) 6.78 (4.31) post-follow up 6.61 (3.30) 6.74 (3.80) 24-hour urine volume, ml/day (n = 64) .557 .615 baseline 2398.5 (747.0) 2233.3 (624.8) post-treatment 2359.9 (658.7) 2311.7 (696.8) post-follow up 2257.4 (717.4) 2240.0 (740.5) 24-hour urine calcium, mg/day (n = 64) .596 .241 baseline 237.76 (113.00) 183.60 (77.04) post-treatment 230.88 (125.89) 222.47 (125.26) post-follow up 229.44 (120.48) 212.97 (107.30) 24-hour urine phosphor, gr/day (n = 62) .979 .640 baseline 0.81 (0.27) 0.76 (0.22) post-treatment 0.73 (0.25) 0.83 (0.26) post-follow up 0.78 (0.27) 0.80 (0.28) 24-hour urine magnesium, mg/day (n = 64) .524 .824 baseline 99.68 (39.67) 103.63 (50.98) post-treatment 97.82 (38.06) 98.93 (40.56) post-follow up 102.85 (46.83) 104.40 (52.68) 24-hour urine sodium, meq/day (n = 64) .362 .305 baseline 181.29 (64.60) 149.93 (50.84) post-treatment 181.06 (57.62) 178.47 (80.83) post-follow up 174.03 (69.50) 172.60 (69.52) 24-hour urine potassium, meq/day (n = 64) .445 .315 baseline 87.48 (134.81) 58.83 (21.59) post-treatment 61.42 (23.23) 64.57 (29.30) post-follow up 65.73 (22.68) 62.10 (25.01) 24-hour urine citrate, mg/day (n = 64) .448 .317 baseline 823.24 (343.95) 640.47 (338.34) post-treatment 736.38 (340.89) 719.67 (401.90) post-follow up 713.79 (320.76) 664.30 (398.75) 24-hour urine uric acid, mg/day (n = 64) .246 .982 baseline 545.88 (196.80) 476.83 (152.03) post-treatment 507.32 (162.32) 468.00 (160.41) post-follow up 409.59 (161.76) 520.00 (217.89) 24-hour urine urea, gr/day (n=61) .134 .704 baseline 37.48 (10.34) 34.04 (8.72) post-treatment 32.41 (9.66) 34.5 (9.97) post-follow up 34.15 (9.49) 34.90 (8.85) 24-hour urine creatinine, gr/day (n = 64) .751 .759 baseline 1.18 (0.41) 1.19 (0.38) post-treatment 1.23 (0.38) 1.21 (0.39) post-follow up 1.21 (0.45) 1.26 (0.39) arepeated measures anova analyses. * p < .05. bold values emphasize statistical significance. probiotic in calcium stone formers-tavasoli et al. vol 19 no 3 may-june 2022 100 sule of the supplement contained 1.8*10^9 cfu of the following species with the ratio of 1:1:1:1 l. acidophilus, b. lactis, bifidobacterium bifidum, and bifidobacterium longum. the placebo capsules had the same color, shape, size, and package. all study patients received two capsules of either probiotic or placebo every day for four weeks. both groups had the usual nutritional consult and suggestions of the stone prevention clinic according to the european association of urology (eau) guidelines, including normal calcium and restricted oxalate intake(2). drug compliance was defined as the ratio of consumed to total pills (23). sample size, randomization, and blinding the sample size was calculated to have the power to detect five units decrease in urine oxalate with a sensitivity of 80%. considering a 40% loss to follow up in nephrolithiasis prevention clinic (unpublished data), the study sample size was 50 patients in each group. we used permuted-block randomization, with the allocation ratio of 1:1, to divide patients into blocks with the size of four. in each block two patients were allocated to probiotic group and other two were allocated to placebo group. a random sequence was generated before the patient allocation by one of the study investigators. the same investigator sequentially coded the drug and platable 4. the effect of probiotic consumption on urinary oxalate using multi-variable general linear model (glm) with generalized estimating equation (gee) approach. variables univariable analysis multivariable analysis b (ci) p-value b (ci) p-value group probiotic 0.80 (-4.58, 6.19) .771 -2.13 (-8.18, 3.91) .490 placebo reference reference time post-follow-up -6.92 (-11.66, -2.18) .004** -6.31 (-12.48, -0.14) .045* post-treatment -4.26 (-9.00, 0.47) .078 -3.07 (-9.05, 2.91) .314 baseline reference reference gender male 6.88 (1.63, 12.13) .010** 6.12 (0.20, 12.03) .043* female reference reference 24-hour urine magnesium -0.05 (-0.10, -0.007) .025* -0.04 (-0.11, 0.02) .182 24-hour urine urea 0.05 (-0.18, 0.29) .649 0.07 (-0.19, 0.34) .602 24-hour urine sodium 0.03 (0.00, 0.07) .045* 0.06 (0.01, 0.10) .009** age 0.13 (-0.07, 0.34) .207 0.27 (-0.005, 0.54) .054 bmi 0.50 (-0.28, 1.28) .214 0.17 (-0.36, 0.71) .518 duration of disease 0.01 (-0.007, 0.02) .245 -0.02 (-0.04, 0.002) .075 abbreviations: ci: confidence interval; bmi: body mass index. * p < .05. ** p < .01. bold values emphasize statistical significance. figure 2. agarose gel electrophoresis of pcr amplification products in l. acidophilus (lane 2), and b. lactis (lane 6). lane 3 and 4: positive control for oxc gene in lactobacillus sp. and corresponding negative control, respectively. lane 7 and 5: positive control for oxc gene in bifidobacterium sp. and corresponding negative control, respectively. positive controls were adapted from(21). probiotic in calcium stone formers-tavasoli et al. vol 19 no 3 may-june 2022 183 cebo containers and kept the code secret until the end of data analysis. other researchers and study participants were unaware of study allocation. para-clinic assessments all study participants were assessed in three timepoints: before the interventions (baseline), at the end of the interventions (post-treatment), and four weeks after the end of the interventions (post-follow up). the colendourology and stones diseases 184 lected samples in assessment visits were one 24-hour urine sample (to evaluate the urine oxalate and other metabolites and calcium oxalate relative supersaturation (caoxss) values) and one fresh stool sample (to evaluate the colonization of the study probiotic bacteria). the 24-hour urine sample collection and urine metabolite analyses were performed as previously published(24). the caoxss values were calculated using lithorisk software (biohealth, italy). figure 3. flow diagram for participants included in the study. figure 4. number of positive stool samples for probiotic species at each group and time point, investigated by real-time pcr. a: l. acidophilus, b: b. lactis. time 0: baseline, time 1: post-treatment, time 2: post-follow-up probiotic in calcium stone formers-tavasoli et al. vol 19 no 3 may-june 2022 185 microbial assessment of stool samples the colonization of consumed probiotics in the intestine was assessed by fecal microbial analyses(16,17) at three time-points: baseline stool samples (s1), post-treatment stool sample (s2), and post-follow up stool samples (s3). the stool sample bacterial dna was extracted by the qiaamp® fast dna stool mini kit (qiagen, dusseldorf, germany) per the manufacturer’s guidelines. the extracted dna was quantified using a wpa spectrophotometer (biochrom, cambridge, uk)(21). we used quantitative real-time pcr to assess the relative amount of study species, i.e., l. acidophilus and b. lactis. the primers for the detection of l. acidophilus and b. lactis were designed by alleleid 6 software (table 1). these primers were designed to detect specific conserved sequences of 16s rrna of bacterial species. besides, a universal primer for bacterial 16s rrna gene (table 1) was used to quantify the total number of the eubacteria(25), as we reported previously(21). the presence of l. acidophilus and b. lactis were normalized to the total eubacteria to calculate the relative abundance of each specie. quantitative real-time pcr reactions were composed of realq plus 2x master mix green (ampliqon, denmark), specific primers (0.4 micromoles of each primer), and extracted bacterial dna (50 ng). using the rotor-gene instrument (qiagen), pcr reactions were conducted by the following parameters: 95°c for 15 min to activate the enzyme, 40 cycles of 95°c for 20 seconds, followed by 60 °c for 60 seconds. all reactions were performed in duplicates. amplification of specific sequences was monitored by melt curve analysis and electrophoresis of pcr products. the evaluated probiotic l. acidophilus and b. lactis genomic dnas were used as positive controls. statistical analysis statistical analyses were performed using ibm spss statistics for windows, version 26.0 (armonk, ny: ibm corp.). the final oxalate degrading activity of the bacteria on the fourth day of the study were compared with the kruskal-wallis test. post-hoc bonferroni correction was performed to compare the activity of o. formigenes with l. acidophilus and b. lactis. the chi-square and fisher exact tests were used to compare the groups in case of categorical data. the normality of numeric variables was checked using the shapiro-wilk test. the differences in continuous data between study groups were assessed using the independent t-test tests or mann-whitney u test in the case of non-normal variables. the effect of probiotic consumption on 24-hour urine metabolites during the study at baseline, post-treatment, and post-follow up were explored using repeated measures anova. general linear model (glm) with generalized estimating equation (gee) approach was applied to investigate the univariable and multivariable effect of the consumed probiotic on the 24-hour urine oxalate changes over time. the significance level was considered as p ˂ 0.05. results in-vitro study oxalate degrading activity figure 1 shows the degradation of oxalate salt by study species. as shown in figure 1, l. acidophilus degraded 49.08 ± 6.05 percent, b. lactis degraded 5.75 ± 0.50 percent, and o. formigenes degraded 62.88 ± 4.26 percent of the media oxalate at the end (fourth day) of the study, which was significantly different (p = .007). pairwise comparisons showed that there was no significant difference between l. acidophilus and o. formigenes (p = .226). however, b. lactis showed a low oxalate degrading activity that was significantly lower than o. formigenes (p = .004). the population of bacteria in all cultures were 106-108 cfu/ml in all measurements. assessment of oxc gene in the probiotic species the presence of oxc gene in the genomic dna of probiotic species, i.e., l. acidophilus and b. lactis, was assessed by pcr. the results are presented in figure 2. as shown in the figure, the oxc gene was present in the genomic dna of both species. randomized clinical trial effect of probiotic consumption on 24-hour urine oxalate five-hundred and ninety-seven patients with hyperoxaluria were screened, and from them, 100 patients were randomized to the probiotic (n = 50) and placebo (n = 50) groups, from september 2017 to march 2019. thirty-four patients from the probiotic group and thirty patients from the placebo group finished the study. all the participants consumed more than 80% of the probiotic or placebo and reported no severe side effects. the consort participant flow diagram is presented in figure 3. the baseline characteristics of the probiotic and placebo groups are presented in table 2. the study groups were not different in the case of baseline characteristics. table 3 shows the 24-hour urine metabolites and caoxss of the probiotic and placebo groups at baseline, post-treatment, and post-follow-up time points. the results of repeated measures anova analyses showed that although there was a significant decrease in the mean of 24-h urine oxalate in both groups (p = .017), the changes were not significantly different between groups (p = .776). the consumption of the probiotic supplement did not significantly affect other urinary metabolites and caoxss. moreover, none of these variables changed significantly over time (table 3). the effect of probiotic consumption on urinary oxalate was analyzed using both univariable and multivariable glm with gee approach (table 4). in agreement with the previous results, the univariable analysis revealed that the urinary oxalate decreased significantly at the end of the study in both groups (p = .004). however, the decrease was not different between the probiotic and placebo groups (p = .771). these results were confirmed in the multivariable analysis, which showed that probiotic consumption had no significant effect on urinary oxalate after adjusting for confounders (p = .490) (table 4). colonization of consumed probiotics in the stool samples the extracted dna from stool samples were analyzed for the presence of studied l. acidophilus and b. lactis species (figure 4). l. acidophilus was detected in 9 (26.5%) s1 samples of the probiotic group and in 8 (26.7%) s1 samples of the placebo group. regarding s2 samples, l. acidophilus was detected in 7 (20.6%) and 13 (43.3%) cases from the probiotic and the placeprobiotic in calcium stone formers-tavasoli et al. bo groups, respectively. five (14.7%) cases in probiotic group and 5 (16.7%) in placebo group showed positive signals (proper amplification) for the presence of l. acidophilus in s3 samples (figure 4). regarding b. lactis probiotic, a positive signal was observed in 3 (8.8%) patients of the probiotic group and 0 (0%) patients of the placebo group in s1 samples. in s2 samples, 7 (20.6%) in the probiotic group and 3 (10%) in the placebo group were positive for b. lactis. finally, b. lactis was detected in 3 (8.8%) probiotic and 4 (13.3%) placebo s3 samples (figure 4). since the studied bacteria were not detected in most participants, we could not compare the relative abundance of bacteria between groups. discussion hyperoxaluria is a known urinary metabolic risk factor in calcium stone formation. alteration in intestinal microflora is suggested as an important cause of secondary hyperoxaluria; therefore, modification of intestinal microbiome with oxalate degrading bacteria could be a treatment modality in this situation(26,27). since lactobacillus and bifidobacterium sp. are safe for human consumption as probiotics, they may be a good option for managing hyperoxaluria. however, most of previous studies could not show the oxalate-lowering effect of lactobacillus and bifidobacterium sp.(3,28-30). the main reason for such these findings may be that lactobacillus and bifidobacterium sp. have various oxalate degrading activity in-vitro(11,12,19,31,32) and most of the previous studies did not select species that efficiently degrade oxalate in-vitro(3). our results showed that the oxc gene was detected in both l. acidophilus and b. lactis. however, only l. acidophilus showed an efficient oxalate degrading activity in culture media, and b. lactis did not efficiently degrade oxalate. most previous studies showed that both species efficiently degrade oxalate in-vitro(11,12,19,31,32). however, mogna et al. reported that l. acidophilus is more efficient than b. lactis in oxalate degradation(13). the differences in the methods and conditions used to treat the bacteria in these studies are the reason for these controversies(5,13). the growth and oxalate degrading activity of l. acidophilus and b. lactis depend on various variables. one of these variables is the oxalate concentration in the culture media. some studies found that high oxalate levels might inhibit bacterial growth and reduce oxalate degrading activity, consequently(19). although we used a high oxalate concentration in the culture media to resemble the condition after eating a high oxalate diet, the study species were pre-adapted to high oxalate, and we did not have growth inhibition. another variable that affects oxalate degrading activity both in-vitro and in vivo is ph. as reported by turroni et al.(12), ph is a fundamental variable for expressing genes involved in oxalate catabolism. the best ph for the oxc gene expression is 5.5 for l. acidophilus(31) and 4.5 for b. lactis(12). we used a ph of 5.5 in our experiments to simulate a condition near the gut area. however, it is not an optimum ph for the oxc gene expression in b. lactis and may cause low oxalate degrading activity of the bacteria in our in-vitro study. our randomized clinical trial's results showed that probiotic consumption could not decrease urine oxalate. this finding may also be due to the effect of ph on gene expression. the normal colon ph, where lactobacillus and bifidobacterium sp. are colonized, is 5.5-7.5 (33), not the optimum ph for the oxalate degrading activity of l. acidophilus and b. lactis. we suggest that although previous studies reported that both l. acidophilus and b. lactis have a good oxalate degrading activity in-vitro (11,12,31,32), these probiotic bacteria are not necessarily efficient in vivo. this hypothesis needs further investigation. another reason for our finding may be the lack of bacterial colonization in the intestine. stool microbial assessment is suggested for the detection of probiotic colonization in the gastrointestinal tract(16). we assessed the stool microbiome, and the results showed that the consumed probiotic bacteria were not detected in stool samples. our study participants consumed 1.8*10^9 cfu of probiotic bacteria. using higher concentrations of bacteria (as high as 10^11 cfu) may improve bacterial colonization in the gut(19). however, it should be mentioned that investigating stool samples for bacterial colonization patterns have some potential limitations. the microbial analysis of stool samples does not necessarily demonstrate the gastrointestinal microbial composition and may underestimate the colonization of probiotic species. assessment of colonic biopsy samples may be more sensitive than stool samples for detecting bacterial colonization(34). other points that deserve attention in this context are the recent findings of studies using next-generation-sequencing methods to investigate the association between the gut microbiome composition and kidney stone formation(8,35-37). some of these studies showed that the abundance of o. formigenes was not different between stone formers and healthy people(8,36), suggesting that this bacterium is not necessarily the link between the gut microbiome and urinary stone formation. although their results had some controversies, these studies demonstrated that kidney stone formers might have a different gut microbiota profile compared to healthy controls at the phylum, genera, and specie levels(8,35,36,38). the study by liu et al showed that the presence of o. formigenes in the colon might be an indicator for the presence of a network of other bacteria(39). miller et al. showed that whole-community microbial transplants significantly increased oxalate degradation and decreased urine oxalate in a rat model, which persisted nine months after the transplants(40). according to these findings and vast differences between the microbiome of stone formers and healthy controls, ticinesi et al suggested that a complex microbial network is responsible for the oxalate-degradation. therefore, consuming a probiotic containing limited oxalate-degrading species may not be sufficient to influence oxalate catabolism (8). it seems that any treatment strategies (such as fecal transplant(41)) that could preserve the microbial network needed to maintain o. formigenes and other oxalate degrading bacteria would be a more successful treatment strategy for hyperoxaluria. our current knowledge in this field is limited, and future studies are needed to confirm the efficacy of these treatments. this study is one of the few randomized clinical trials that evaluated the effect of an oxalate degrading probiotic on urine oxalate. another strength of our study was that we only recruited the calcium stone formers with hyperoxaluria, and patients with other types of stones and normal urine oxalate were not included. the main limitation that should be considered for this study is probiotic in calcium stone formers-tavasoli et al. endourology and stones diseases 186 vol 19 no 3 may-june 2022 187 the lack of patients’ dietary intake data. however, both groups were asked to follow the same dietary guidelines for urolithiasis prevention, including low oxalate and normal calcium intake. another major limitation of the study was that we could not produce a supplement that contained only the species with the highest oxalate degrading activity. the daily dose of probiotics may be one more limitation of our study. higher concentrations of bacteria may be needed for colonization in the intestine. conclusions our results showed that the consumption of a probiotic supplement containing l. acidophilus and b. lactis did not affect 24-hour urine oxalate. these negative results may be due to a lack of bacterial colonization in the intestine or the effect of colon ph on gene expression of oxalate degrading enzymes. similar to previous studies' results, our findings could not confirm probiotics' efficacy as a treatment strategy for hyperoxaluria. further studies in this field are warranted. acknowledgement this study was funded by the national institute for medical research development (grant number: 940329), tehran, iran. conflict on interest 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intestinal luminal ph in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. gut. 2001;48:571. 34. tang q, jin g, wang g, et al. current sampling methods for gut microbiota: a call for more precise devices. front cell infect microbiol. 2020;10:151. 35. suryavanshi mv, bhute ss, jadhav sd, bhatia ms, gune rp, shouche ys. hyperoxaluria leads to dysbiosis and drives selective enrichment of oxalate metabolizing bacterial species in recurrent kidney stone endures. sci rep. 2016;6:34712. 36. tang r, jiang y, tan a, et al. 16s rrna gene sequencing reveals altered composition of gut microbiota in individuals with kidney stones. urolithiasis. 2018;46:503-14. 37. ticinesi a, nouvenne a, meschi t. gut microbiome and kidney stone disease: not just an oxalobacter story. kidney int. 2019;96:257. 38. stern jm, moazami s, qiu y, et al. evidence for a distinct gut microbiome in kidney stone formers compared to non-stone formers. urolithiasis. 2016;44:399-407. 39. liu m, koh h, kurtz zd, et al. oxalobacter formigenes-associated host features and microbial community structures examined using the american gut project. microbiome. 2017;5:108. 40. miller aw, oakeson kf, dale c, dearing md. microbial community transplant results in increased and long-term oxalate degradation. microb ecol. 2016;72:470-8. 41. assimos dg. re: microbial community transplant results in increased and long-term oxalate degradation. j urol. 2016;196:1586-7. probiotic in calcium stone formers-tavasoli et al. endourology and stones diseases 188 vol 19 no 1 january-february 2022 138 a prospective study to investigate the effect of fesoterodine treatment on quality of life, anxiety, and depression in urge-type urinary incontinence arif aksak1, güzin çakmak1*, zeynel abidin öztürk1 purpose: urinary incontinence (ui) is a fundamental health problem, can occur at any age but is especially common in older women. depression and anxiety are also considerable problems for the elderly. ui is one of the geriatric syndromes that are thought to be related to depression and quality of life (qol). materials and methods: this prospective study was conducted for a period of 2 months from february 2020 to april 2020. women who applied to the outpatient clinic of geriatrics with ui symptoms were taken into the study. the type of ui was determined by using the 3 incontinence questions (3iq). only patients with urge incontinence were included in the study. patients were evaluated for qol, anxiety, depression, disability, and geriatric syndromes before and after treatment. data analysis was done by using spss version 22. results: the study population was 42 women; the mean age was 69.7 +/4.3 years. qol, anxiety, and depression symptoms, and adl were revealed to be improved after treatment. iciq-sf, i-qol, and hads scores were associated with ui treatment when evaluated with one-way manova (f [4, 79] =3.25, p = 0.00, wilk's p = 0.859, partial η2=0.14). conclusion: ui is a common problem in the elderly. patients usually hesitate to tell this complaint to even doctors. that situation affects their physical and psychological condition negatively. in this study, we reached that anticholinergic treatment (fesoterodine) improved adl, qol, and psychological symptoms. those findings represented us that proper treatment of ui is critical for healthy aging. keywords: anxiety, depression, quality-of-life, urinary incontinence, urge-type introduction urinary incontinence (ui) is defined as “the com-plaint of involuntary loss (leakage) of urine” by the international continence society(1). it is a prevalent problem in the elderly, as it increases with age and affects about 35% and 22% of older women and men, respectively (2). ui in women is typically related to dysfunction of the bladder or pelvic floor muscles, with such dysfunction usually begin to occur during pregnancy or childbirth, or at the time of menopause(3). there are two main subtypes of ui: stress incontinence and urgency incontinence. according to the international urogynecological association (iuga) and the international continence society (ics) definitions, stress incontinence is the urinary leakage associated with coughing, sneezing, or physical exertion. in contrast, urgency incontinence is the urinary leakage associated with a sudden compelling desire to void that is difficult to defer(1). the most commonly seen subtype of ui in elderly patients is mixed incontinence, which is characterized by the combination of symptoms of these two subtypes(4). the diagnosis of ui is missed in 80% of cases due to patients' difficulties in expressing the complaint(5). continence is one of the most critical factors that can contribute to physical and mental health, quality of life, and people's well-being in all life stages, especially in old age(6). it has been widely documented that ui is more prevalent in an older woman and cause a low quality of 1gaziantep university, faculty of medicine, department of internal medicine, 27100 sahinbey, gaziantep, turkey. *correspondence: gaziantep university, faculty of medicine, department of internal medicine, division of geriatric medicine, 27100 sahinbey, gaziantep, turkey. phone : 0090 342 341 66 89. received may 2021 & accepted october 2021 life (qol) and severe complications(1). dermatological problems fall, psychological problems, impaired sexual performance, and social isolation are complications that cause decreased qol in patients with ui(2,7). in this study, we aimed to evaluate qol, depression, and anxiety levels of patients diagnosed with ui. we also compared the pre-treatment and post-treatment status of the ui patients in terms of these parameters. materials and methods participants this prospective study was carried out for a period of three months from february 2020 to april 2020. patients consulted at the outpatient clinic of geriatrics with urge ui symptoms were included in the study. all of the patients were women and ≥ 65 years old. the study was approved by the gaziantep university local research ethics committee. all participants gave informed consent. exclusion criteria patients below 65 are diagnosed with ui other than urge type, diabetes mellitus, urinary infection, urinary prolapsus, atrophic urethritis and vaginitis, mental retardation, and mobility restriction were excluded from the study. patients who were using diuretics or on dialysis programs were excluded too. evaluation of participants patients who were diagnosed with urge ui were evalfemale urology urology journal/vol 19 no. 1/ january-february 2022/ pp. 69-74. [doi: 10.22037/uj.v18i.6834] uated. their chronic diseases, drugs, fall history, and complaints about ui were recorded. comprehensive geriatric assessment (cga), frailty, and sarcopenia assessment were done on all patients. validated scales were used for evaluation of the quality of life (qol), depression, and anxiety. the same evaluation was done after three months of ui treatment. evaluation of patients took approximately 30 minutes. ui treatment patients were treated with 4 mg fesoterodine. fesoterodine is a competitive muscarinic cholinergic receptor antagonist with muscle relaxant and urinary antispasmodic properties. fesoterodine binds and inhibits muscarinic receptors on the bladder detrusor muscle, thereby preventing bladder contractions or spasms caused by acetylcholine. this resulted in the relaxation of bladder smooth muscle and increased bladder capacity, in addition to a reduction in involuntary muscle contractions and involuntary loss of urine. evaluation of urinary incontinence patients were evaluated for urinary incontinence by international consultation on incontinence questionnaire-short form (iciq-sf)(8) and 3 incontinence questions (3iq)(9). the iciq-sf questionnaire questioned the frequency, amount, type, and effects of urinary incontinence on daily life are and scoring between 0-21 values is made. the turkish validity and reliability study of the iciq-sf test was performed by çetinel et al(10). evaluation of quality of life (qol) patients were evaluated for quality of life by the incontinence quality of life scale. (i-qol). the i-qol contains three subscales. these are avoidance and limiting behaviors, psychosocial impact, social embarrassment. this scale consists of 22 items; all items are evaluated in a five-category likert-type scale with values ranging from 1(extremely) to 5 (not at all). a mean score for each subscale is calculated as well as a total score for all 22 items. the scores are then transformed into a 'scale score' ranging from 100 points for ease of interpretation(11). the turkish validity and reliability study of the i-qol test was performed by eyigor et al(12). evaluation of anxiety and depression patients were evaluated for anxiety and depression by the hospital anxiety and depression scale (hads). the hads questionnaire consists of 14 questions, 7 for depression, and 7 for anxiety. each question has four possible answers. furthermore, it is calculated between 0-3 points according to the likert scale. cut-off values for anxiety and depression are considered 8-10 mild, 11-14 moderate, and 15-21 severe(13). the validity and reliability study of the hads test was performed by aydemir et al(14). comprehensive geriatric assessment: the cognitive evaluation was done by the standardized form of mini-mental state examination (mmse) (15), assessment of daily living abilities (adl) by katz index(16), instrumental activities of daily living (iadl) by lawton brody, and nutritional assessment by mini nutritional assessment test-short form(17). in mmse, patients were evaluated for six different areas: orientation, registration, attention, calculation, language, and recall. patients whose scores were ≤ 24 were accepted for the presence of dementia(15). katz index of adl evaluated patients for personal hygiene, continence, dressing, feeding, and ambulating. scores were between intervals of 0 and 6; higher scores mean higher independence(16). lawton brody index was used for evaluating iadl like house cleaning, doing the laundry, marketing, managing medications, cooking, communicating with others, using transportation, and doing financial management; higher scores mean higher independence(18). mna-sf scores ≤ 7 indicate malfesoterodine treatment in urge-type urinary incontinence-aksak et al. scales and tests n mean (±se) (ci:95% ) adl* 42 4.86 0.07 iadl* 42 5.6 0.32 smmt* 42 25.57 0.76 mna-sf* 42 11.52 0.32 frail* 42 2.67 0.19 sarc-f* 42 3.12 0.29 handgrip strength (kg) 42 22.86 0.45 smm* (kg) 42 44.87 1 smmi* (kg/m2) 42 19.57 0.5 gait speed (m/s) 42 0.69 0.03 iciq-sf* 42 13.14 0.63 i-qol* 42 65.4 3.02 hads-a* 42 10.17 0.63 hads-d* 42 8.93 0.62 table 1. scores of scales and tests used in the study. adl*: activities of daily living smmt*: standardized mini mental test mna-sf*: mini nutritional assessment test short-form frail*: fatigue, resistance, ambulation, illness, and loss of weight sarc-f*: strength, assistance walking, rise from a chair, climb stairs, and falls smm*: skeletal muscle mass smmi*: skeletal muscle mass index iciq-sf*: international consultation on incontinence questionnaire-short form i-qol*: incontinence quality of life scale hads-a*: the hospital anxiety and depression scaleanxiety hads-d*: the hospital anxiety and depression scaledepression se: standard error female urology 70 vol 19 no 1 january-february 2022 138 nutrition(17). assessment for sarcopenia for defining sarcopenia, muscle strength, mass, and physical performances were assessed. sarc-f (strength, assistance walking, rising from a chair, climb stairs, and falls) test was used to select cases to evaluate muscle strength(19). the handgrip test was performed if the patient had point ≥ 4 from sarc-f to diagnose probable sarcopenia. the handgrip test was performed by using a hand dynamometer with the dominant hand(20). for females < 16 kg (kilograms), for males < 27 kg was accepted as probable sarcopenic. a bioimpedance test was carried out on probable sarcopenic patients to assess skeletal muscle mass. sarcopenia was diagnosed by skeletal muscle mass index. in this study, we used skeletal muscle mass index (smmi) adjusted to height. smmi was calculated by dividing skeletal muscle mass by the square of height(21). we evaluated gait speed with a four-meter gait speed test to diagnose severe sarcopenia(22) assessment of frailty we performed a frailty assessment by the frail scale. the frail scale includes five parameters: fatigue, resistance, ambulation, illness, and loss of weight. frail scale scores range from 0–5 (best to worst). scores 3-5 were considered frail (3–5), 1-2 pre-frail, and 0 robust(23). statistical analysis the variables were analyzed for their distribution normality using the kolmogorov–smirnov and shapiro wilk test. iciq, oab v8, and hads a variables were disturbed normally (p > 0,05), and other variables were not disturbed normally. the independent sample t-test was used for the comparison of two groups for normally distributed data. wilcoxon tests were used for the comparison of two groups for not normally disturbed data. numerical variables were denoted as mean ± standard error. the ibm spss for windows, version 22.0 (ibm corp., armonk, ny, usa) was used for statistical analysis. results forty-two female patients who were followed up and treated in the geriatric outpatient clinic due to the diagnosis of urge ui were included in the study. the mean age of them was 69.7 ± 4.3 (minimum 65 years old, maximum 74 years old). the average body mass index (bmi) of the patients was 33.50 ± 1. seven-point-one percent of them were normal weight (n = 3), 26.1% were overweight (n = 11), 52.6% were obese(22), and 14.2% were morbid obese (n = 6). all our participants had at least one chronic disease. the average number of medicine that patients used was 3.6 ± 0.6. polypharmacy was present in 23.8% of the patients educational status, marital status, social status, place of residence, smoking and/or alcohol consumption, driving and physical exercise status of the patients were not associated with ici q-sf, iqol, hads-a and hads-d scores(p > 0.05). number of pregnancies, number of normal vaginal deliveries, history of cesarean section, history of abortion and history of induced abortion were also not associated with iciq-sf, iqol, hads-a and hads-d scores (p > 0.05). the mean iciq-sf scores of the patients were 10.12 ± 0.63, the mean iqol score was 75.95 ± 3.02, the mean hads-a score was 7.83 ± 0.63, and the hads-d score was 6.14 ± 0.63. the first scores of scales and tests used in the study were summarized in table 1. all these measurements were repeated after three months of treatment and pre-post treatment values were compared. there was a significant improvement in the adl score after treatment (p = 0.049). there was also a significant upturn in the i-qol score (p = 0.02). the katz and i-qol scores were positively related to ui treatment. the frequency of incontinence and its effects pre-treatment (n=42) post-treatment (n=42) p= sarc-f* 3.12 ± 0.29 3.07 ± 0.17 0.91 handgrip strength (kg) 22.86 ± 0.45 25.52 ± 0.6 0.82 smm* (kg) 44.87 ± 1 44.68 ± 1.3 0.89 smmi* (kg/m²) 19.57 ±0.5 19.28 ± 0.65 0.64 gait speed (m/s) 0.69 ± 0.03 0.70 ± 0.04 0.76 adl* 4.86 ± 0.07 5.12 ± 0.09 0.049* smmt 25.57 ± 0.76 27.07 ± 0.8 0.1 mna-sf* 11.52 ± 0.31 12.17 ± 0.27 0.12 iciq-sf* 13.14 ± 0.63 10.12 ± 0.57 0.005* i-qol* 65.40 ± 3.02 75.95 ± 3.5 0.02* hadsa* 10.17 ± 0.63 7.83 ± 0.68 0.022* hadsd* 8.93 ± 0.62 6.14 ± 0.72 0.013* frail* 2.67 ± 0.19 2.24 ± 0.24 0.09 table 2. comparison of pre-post treatment scores of scales and tests. adl*: activities of daily living smmt*: standardized mini mental test mna-sf*: mini nutritional assessment test short-form frail*: fatigue, resistance, ambulation, illness, and loss of weight sarc-f*: strength, assistance walking, rise from a chair, climb stairs, and falls smm*: skeletal muscle mass smmi*: skeletal muscle mass index iciq-sf*: international consultation on incontinence questionnaire-short form i-qol*: incontinence quality of life scale hads-a*: the hospital anxiety and depression scaleanxiety hads-d*: the hospital anxiety and depression scaledepression fesoterodine treatment in urge-type urinary incontinence-aksak et al. vol 19 no 1 january-february 2022 71 on daily life significantly improved with urinary incontinence treatment (p = 0.005). improvement in anxiety (p = 0.022) and depression (p = 0.013) after treatment was revealed too. hads-a and hads-d scores were significantly decreased after treatment. iciq-sf and hads scores were negatively related to ui treatment. iciq-sf, i-qol and hads scores were correlated with ui treatment when evaluated with one-way manova (f [4, 79] = 3.25, p = 0.00, wilk's λ = 0.859, partial η2 = 0.14). a comparison of pre-post treatment values was summarized in table 2. adl and i-qol scores were positively correlated with treatment status (r=0.292, p = 0.007; r = 0.232, p = 0.02). iciq-sf, hads-a and hads-d scores were negatively correlated with treatment status (r = -0.304, p = 0.006; r = -0.279, p = 0.022; r = -0.349, p = 0.002). patients were also evaluated for anticholinergic-related side effects. anticholinergic side effects were not observed in 25 (59.5%) of the patients. dry mouth was observed in 10 patients (23.8%), constipation in 4 patients (9.5%), and tachycardia in 3 patients (7.1%). there was no significant correlation between the development of anticholinergic-related dry mouth, constipation and tachycardia and i-qol scores (p = 0.746, 0.072, 0.146). discussion urinary incontinence is one of the most common geriatric syndromes in the elderly. patients generally hesitate to tell this complaint even to doctors. this situation could negatively affect the physical and psychological status of the patients. in this study, we revealed improvements in patients' activities of daily life, frequency of incontinence and its effects on daily life, quality of life, and psychological status after 3 months of ui treatment. after the treatment, an increase in katz score and i-qol score and a decrease in iciq-sf score were found. regarding i-qol, a significantly good result was found in all scales (limitation of behavior, psychosocial influence, social isolation) after treatment. the relationship between ui and depression was investigated in several studies. felde et al. revealed that ui was a risk factor for both depression and anxiety with a dose-dependent trend (felde et al. 2015). in that study, 16263 women over 20 years of age were followed for 10 years. mild anxiety was detected in one of ten patients with urinary incontinence, and moderate or severe anxiety was detected in one of twenty patients. a significant relationship between ui and mild depression development was also found. lai et al. showed that 27.5 % of overactive bladder (oab) patients had depression in their study. they also reported oab patients with depression had more severe incontinence symptoms (iciq-ui) and more impact on quality of life compared to oab patients without depression(24). the relationship between ui, psychological problems, and quality of life could be explained by the patient's necessity to plan every detail in life due to ui and their fear to perform physical activities. this, in turn, can lead to feelings of loss of control and distress and can reduce the quality of life. the causal relationship between ui and anxiety/depression can be explained by serotonergic and sympathetic pathways. serotonergic pathways play a role in the regulation of both depression and continence functions. serotonin inhibits the voiding reflex pathway and increases the tonus of the urethral sphincter. serotonin levels are low in clinically depressed individuals. therefore, serotonin reuptake inhibitors may have positive effects in the treatment of stress-type urinary incontinence(25). in many studies investigating the relationship between iu and depression, the distinction between incontinence types has not been made(26). however, there are also studies analyzing the subject by distinguishing the types of urinary incontinence from each other, such as our study. walters and colleagues found no differences in psychological tests between women with detrusor instability and genuine stress incontinence(27). conversely, lee et al. concluded that women with urinary incontinence have more depression and stress than those who do not. the situation is similar for those women with both stress ui and urge ui as well as those with mixt ui(28). the relationship between ui and quality of life (qol) was also investigated in several studies. saboia et al. concluded that mixed urinary incontinence decreased the quality of life more than stress urinary incontinence and urinary incontinence(29). in the study of nygaard et al., it was shown that urinary incontinence negatively affects the quality of life and is more common in obese women(30). pizzol et al. concluded that the presence of urinary incontinence negatively affects the quality of life in their meta-analysis. it was also observed that studies supporting this result were mostly performed using the sf-36 and incontinence impact questionnaire (iiq-7)(31). different from them, in our study, quality of life was evaluated with i-qol. in the study of ptak et al., it was revealed that pelvic floor muscle exercises positively affect the life quality of women with stress ui(32). another study analyzing the effect of urge urinary incontinence treatment on quality of life has not been found in the literature. in this study, we evaluated the change in the quality of life, anxiety, and depression in patients who had received three months of fesoterodine treatment for urge ui. our study is the first study that evaluated the change in the quality of life, anxiety, and depression status of patients before and after treatment for urge urinary incontinence by an anticholinergic drug. the major strengths of our study are that it is a prospective study and similar studies showing the effects of urge ui treatment on quality of life, anxiety, and depression were not present. in our study, an improvement was also observed in the sarc-f, mna-sf, smmt, and frail scores after treatment. however, these were not statistically significant. large-scale studies with more patients are needed to explain these relationships. some limitations of the study should be mentioned. the number of patients included in the study is small and the degree of urinary incontinence has not been fully investigated (eg by ped test). another limitation is that the study was conducted three months after the ui treatment. improvements in other parameters could be seen with longer follow-up. the absence of an untreated control group is major limitation of the study. the reason we designed the study in this way was our ethical reservations about depriving some patients of treatment. therefore, we preferred to make the comparison between the preand post-treatment conditions of the patients, not with a control group that did not receive treatment. fesoterodine treatment in urge-type urinary incontinence-aksak et al. female urology 72 vol 19 no 1 january-february 2022 138 conclusions urinary incontinence is a geriatric syndrome that is common in the elderly. this situation can be skipped in many patients because patients generally hesitate to tell healthcare professionals about this complaint. the negative effects of urinary incontinence on quality of life and the increase in anxiety and depression can be attributed to many reasons. the first of these is social isolation that occurs with urinary incontinence. the quality of life of the individual, who moves away from his daily activities and social environment, decreases significantly. anxiety and depression are inevitable. in addition, we often come across elderly individuals avoiding fluid intake in order to prevent urinary incontinence. this situation and its consequences negatively affect the quality of life. in addition, urinary incontinence leads to urinary system infections and dermatological problems, thus negatively affecting the general health status and quality of life of the person. therefore, early diagnosis and treatment of urinary incontinence is very important. in this study, we showed that urge ui treatment with fesoterodine has a positive effect on the quality of life and psychological symptoms of patients. conflict on interest none declared by the authors. references 1. aoki y, brown hw, brubaker l, cornu jn, daly jo, cartwright r. urinary incontinence in women. nat rev dis prim. 2017;3. 2. thomas tm, plymat kr, blannin j, meade tw. prevalence of urinary incontinence. br med j. 1980;281:1243–5. 3. delancey jol, ashton-miller ja. pathophysiology of adult urinary incontinence. gastroenterology. 2004;126:23– 32. 4. minassian va, devore e, hagan k, grodstein f. severity of urinary incontinence and effect on quality of life in women by incontinence type. obstet gynecol. 2013;121:1083–90. 5. goode ps, 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zi̇nci̇r h, göri̇ş s cö. yaşlibi̇reylerde u y k u y u e t k i̇ l e y e n ö n e m l i̇ b i̇ r problemi ̇nkonti ̇nans an. 2014;23:29–35. 11. chen g, tan jt, ng k, iezzi a, richardson j. mapping of incontinence quality of life (i-qol) scores to assessment of quality of life 8d (aqol-8d) utilities in patients with idiopathic overactive bladder. health qual life outcomes. 2014;12:1–8. 12. eyigor s, karapolat h, akkoc y, yesil h, ekmekci o. quality of life in patients with multiple sclerosis and urinary disorders: reliability and validity of turkish-language version of incontinence quality of life scale. j rehabil res dev. 2010;47:67–71. 13. ding t, wang x, fu a, xu l, lin j. anxiety and depression predict unfavorable survival in acute myeloid leukemia patients. med (united states). 2019;98:1–7. 14. aydemir o¨ , gu¨ venir t, ku¨ ey l k ltu¨ r s. the validity and reliability of the turkish version of hospital anxiety and depression scale. turkish psychiatry. 1977;8:280–287. 15. mitchell aj. a meta-analysis of the accuracy of the mini-mental state examination in the detection of dementia and mild cognitive impairment. j psychiatr res. 2009; 16. shelkey m, wallace m. katz index of independence in activities of daily living (adl). director. 2000; 17. bauer jm, kaiser mj, anthony p, guigoz y, sieber cc. the mini nutritional assessment®its history, today’s practice, and future perspectives. nutr clin pract. 2008;23:388– 96. 18. oort q, taphoorn mjb, sikkes sam, uitdehaag bmj, reijneveld jc, dirven l. evaluation of the content coverage of questionnaires containing basic and instrumental activities of daily living (adl) used in adult patients with brain tumors. j neurooncol [internet]. 2019;143:1–13. 19. çakmak g, öztürk za. comparison of malnutrition assessment tools in terms of revealing the relationship between polypharmacy and inappropriate drug use and malnutrition. prog nutr. 2021;23(2). 20. cao l, chen s, zou c, ding x, gao l, liao z, et al. a pilot study of the sarc-f scale on screening sarcopenia and physical disability in the chinese older people. j nutr heal aging. 2014;18:277–83. 21. gąsior js, pawłowski m, williams ca, dąbrowski mj, rameckers ea. assessment of maximal isometric hand grip strength in school-aged children. open med. 2018;13:22– 8. 22. bahat g, tufan a, kilic c, öztürk s, akpinar ts, kose m, et al. cut-off points for weight and body mass index adjusted bioimpedance analysis measurements of muscle mass. aging clin exp res [internet]. 2019;31:935–42. 23. bohannon rw, wang yc. four-meter gait fesoterodine treatment in urge-type urinary incontinence-aksak et al. vol 19 no 1 january-february 2022 73 speed: normative values and reliability determined for adults participating in the nih toolbox study. arch phys med rehabil [internet]. 2019;100:509–13. 24. walston j, buta b, xue ql. frailty screening and interventions: considerations for clinical practice. clin geriatr med [internet]. 2018;34:25–38. 25. lai hh, shen b, rawal a, vetter j. the relationship between depression and overactive bladder/urinary incontinence symptoms in the clinical oab population. bmc urol [internet]. 2016;16:1–8. 26. felde g, engeland a, hunskaar s. urinary incontinence associated with anxiety and depression: the impact of psychotropic drugs in a cross-sectional study from the norwegian hunt study. bmc psychiatry. 2020;20:1–10. 27. smith ap. female urinary incontinence and wellbeing: results from a multi-national survey. bmc urol [internet]. 2016;16:4–9. 28. legendre g, ringa v, panjo h, zins m, fritel x. incidence and remission of urinary incontinence at midlife: a cohort study. bjog an int j obstet gynaecol. 2015;122:816–23. 29. lee h, rhee y, choi ks. urinary incontinence and the association with depression , stress , and self esteem in older korean women. sci rep [internet]. 2021;1–7. 30. saboia dm, firmiano mlv, bezerra k de c, neto jav, oriá mob, vasconcelos ctm. impact of urinary incontinence types on women’s quality of life. rev da esc enferm. 2017;51:1–8. 31. nygaard cc, schreiner l, morsch tp, saadi rp, figueiredo mf, padoin av. urinary incontinence and quality of life in female patients with obesity. rev bras ginecol e obstet. 2018;40:534–9. 32. pizzol d, demurtas j, celotto s, maggi s, smith l, angiolelli g, et al. urinary incontinence and quality of life: a systematic review and meta-analysis. aging clin exp res [internet]. 2021;33:25–35. 33. kiros t, damtie s, eyayu t, tiruneh t. review article bacterial pathogens and their antimicrobial resistance patterns of inanimate surfaces and equipment in ethiopia : a systematic review and metaanalysis. 2021;2021. fesoterodine treatment in urge-type urinary incontinence-aksak et al. female urology 74 pictorial urology 201urology journal vol 7 no 3 summer 2010 fungating anorectal carcinoma causing urinary retention urol j. 2010;7:201. www.uj.unrc.ir a 55-year-old woman had undergone diversion colostomy and chemo radiation for locally advanced rectal adenocarcinoma. however, her disease progressed in spite of 10 cycles of leucovorin, 5-fluorouracil, and oxaliplatinum. she presented to the urology department with urinary retention for 1 week. clinical examination revealed an exophytic, proliferative growth emerging from the anal canal, extending to the labia and onto the introitus. the urethral meatus was not visible due to the mass. the bladder was palpable till the umbilicus. bilateral, tender inguinal lymphadenopathy was present. she underwent an abdominal ultrasonography, which showed no lesion within the bladder. there was no hydroureteronephrosis or ascites. the liver and other viscera were normal, with no obvious metastasis. she underwent suprapubic catheter placement, and 1200 ml of urine was drained. she, subsequently, was referred to the medical oncology and radiotherapy unit for further management. large fungating tumors of the anorectum are rare and most reported series are of primary anal carcinoma with squamous cell histology. these are more common in homosexuals and may be related to the human papilloma virus.(1) the extensive nature of the disease causing urethral obstruction has never been reported to the best of our knowledge. aggressive surgical resection with local myocutaneous flaps may provide effective palliation in such locally advanced malignant perineal disease.(2) john s banerji*, ramya nagarajan department of urology, christian medical college, vellore, india *e-mail: johnsbanerji2002@yahoo.co.in references 1. cobb jp, schecter wp, russell t. giant malignant tumors of the anus. diseases of the colon & rectum. vol 33: springer; 1990:135-8. 2. temple wj, ketcham as. surgical palliation for recurrent rectal cancers ulcerating in the perineum. cancer. 1990;65:1111-4. urol_montage.pdf pictorial urology 8 urology journal vol 6 no 1 winter 2009 bilateral spontaneous perinephric hematoma urol j. 2009;6:8. www.uj.unrc.ir a 55-year-old man presented with a history of generalized swelling all over the body and uremic symptoms. physical examination revealed pallor, anasarca, and hypertension. a gradual elevation of serum creatinine level from 1.6 mg/dl to 6.49 mg/dl was documented within 3 weeks. urinalysis did not show any abnormal sign. ultrasonography revealed the right kidney sized 9.5 × 3 cm and the left kidney, 10 × 4.9 cm, with large bilateral perinephric collections. doppler ultrasonography revealed a 1.3-cm midpole aneurysm in the right kidney and multiple left renal aneurysms. computed tomography revealed heterogeneous bilateral collections with fascial thickening in the perirenal spaces suggestive of bilateral perirenal hematomas with bilateral renal artery aneurysms. he was subjected to bilateral renal angiography and coiling of the aneurysms. perinephric collection was evacuated by flank incision. subcapsular renal hematomas occur secondary to variable etiologies and page kidney phenomenon can lead to kidney failure.(1) when occurs unilaterally, it can be managed expectantly, but page kidney in a solitary unit or bilateral page kidney can lead to acute kidney failure, necessitating intervention to avoid the irreversible kidney damage.(2) rahul gupta, syed jamal rizvi, pranjal r modi department of urology, institute of kidney diseases and research centre, ahmedabad, gujarat, india e-mail: rajaguptadr@rediffmail.com references 1. haydar a, bakri rs, prime m, goldsmith dj. page kidney--a review of the literature. j nephrol. 2003;16:329-33. 2. matin sf, hsu th, klein ea, streem sb. acute renal failure due to subcapsular renal hematoma in a solitary kidney: improvement after decompression. j urol. 2002;168:2526-7. endourology and stone disease 79urology journal vol 5 no 2 spring 2008 percutaneous nephrostomy for treatment of posttransplant ureteral obstructions seyed abulghasem mostafa, shahin abbaszadeh, saeed taheri, mohammad hossein nourbala introduction: we report our experience with percutaneous management of urologic complications following kidney transplantation. materials and methods: of 1402 consecutive kidney transplant recipients from living donors at our hospital, 21 required percutaneous nephrostomy (pcn) for the treatment of obstructive lymphocele (n = 11), urinary calculus (n = 8), and stricture of the ureterovesical junction anastomosis (n = 2). we had also 11 kidney recipients with urine leakage from the ureter who were treated only by indwelling ureteral catheter. urinary complications were diagnosed based on the clinical symptoms, elevated serum creatinine levels, ultrasonography and renal scintigraphy. patients with ureteral obstruction or urine leakage were compared with kidney recipients without urologic complications. results: a mean decline of 3.1 ± 3.0 mg/dl (range, 0.1 to 10.7 mg/dl) in serum creatinine level was detected (p < .001) after pcn. all of the patients remained symptom free for a mean follow-up period of 34.2 ± 20.1 months (range, 3 to 81 months). patient and graft survival rates were not different between the patients undergoing pcn and other kidney recipients. the only difference was the history of using antilymphocyte globulin which was significantly more frequent in the patients of the pcn group (p = .01). conclusion: in our experience, pcn is a safe and effective method for the treatment of ureteral obstructions in kidney allograft recipients. this method provided long-term success with few recurrences and low morbidity and mortality rates. urol j. 2008;5:79-83. www.uj.unrc.ir keywords: kidney transplantation, obstruction, percutaneous nephrostomy nephrology research center, baqiyatallah university of medical sciences, tehran, iran corresponding author: mohammad hossein nourbala, md nephrology research center department of kidney transplantation, baqiyatallah hospital, mullasadra st, vanak sq, tehran, iran tel: +98 21 8126 4154 fax: +98 21 8126 4157 e-mail: nourbala@gmail.com received september 2007 accepted december 2007 introduction stricture of the ureterovesical junction (uvj) anastomosis, with reported incidence rates of 2% to 10%, is the most frequent urologic complication in kidney allograft recipients.(1-3) significant stricture is a serious complication which can result in kidney failure and permanent damage to the allograft. open surgery has traditionally been used for correction of the obstruction; however, open procedures are associated with morbidity and delayed convalescence. development of percutaneous modalities of treatment such as percutaneous nephrostomy (pcn) with low complication rates has altered the approach to ureteral stricture. percutaneous nephrostomy was first described by goodwin and colleagues for temporary drainage percutaneous nephrostomy for posttransplant ureteral obstructions—mostafa et al 80 urology journal vol 5 no 2 spring 2008 in cases of hydronephrosis.(4) nowadays, this procedure is widely used for the treatment of uvj obstruction in individuals without renal replacement therapy. however, small series have reported the safety and feasibility of this treatment method in ureteral complications after transplantation.(5) this paper is a report on the experience of an iranian major transplant center in correcting ureteral obstruction using pcn. materials and methods a total of 1402 kidney transplantation procedures from living donors were performed at our center between 1992 and 2002. of the allografts, 1305 (93.1%) were provided from living unrelated donors and the remaining 97 (6.9%), from living related donors. in a retrospective review of the clinical and radiological records, we identified 21 recipients (1.5%) who had undergone pcn for the management of obstructive complications of the ureter using the extravesical technique of ureteroneocystostomy (lich-gregoir method) with stent placement. eleven patients with urine leakage were treated by indwelling ureteral catheter for 21 to 60 days without the need for pcn or surgery. clinical suspicion of urinary complications was based on elevated serum creatinine levels. in all cases, ultrasonography was used to assess the status of the transplanted kidney and the collecting system. evidence suggestive of ureteral obstruction and urine leakage included ultrasonography findings of hydronephrosis and presence of peritransplant fluid collections, respectively. renal scintigraphy was also performed in 10 patients. findings suggestive of an obstruction included hydronephrosis and delayed visualization of the bladder and those suggestive of leakage were detection of radionuclide activity outside the collecting system. in order to perform pcn, the puncture site was chosen on the basis of the findings of ultrasonography. antegrade pyelography and ureterography were performed with fluoroscopic guidance. the pcn tube was removed when patency of the ureteral stent was confirmed by antegrade nephrostography and prior clamping. the ureteral stents were removed with cytoscopic guidance and the use of topical anesthesia about 3 months thereafter. we defined and compared 2 groups of kidney recipients who underwent pcn and those without ureteral complications (control group). statistical comparisons were performed using the chi-square and the fisher exact tests for the proportions and the t test and paired t test for the continuous data. survival analysis was done by kaplan-meier method (death-censored analysis) and differences were assessed using the log-rank test. data analyses for continuous data were also repeated with the mann-whitney test to confirm the results. a p value less than .05 was considered significant. results twenty-one patients underwent pcn, of whom 15 (71.4%) were men and 6 (28.6%) were women. their mean age at the time of the transplantation was 40.0 ± 12.7 years (range, 18 to 70 years). the mean interval between transplantation and nephrostomy was 74.5 ± 94.0 days (range, 1 to 382 days). the mean serum creatinine values before and after pcn were 5.8 ± 4.2 mg/dl (range, 1.7 to 17.0 mg/dl) and 2.7 ± 1.9 mg/ dl (range, 1.0 to 7.5 mg/dl), respectively. the patients experienced a mean decline of 3.1 ± 3.0 mg/dl (range, 0.1 to 10.7 mg/dl) in their serum creatinine values (p < .001). in the pcn group, 11 patients (52.4%) had obstructive lymphocele with hydronephrosis. percutaneous catheter drainage of the lymphocele for a period of 21 to 70 days relieved hydronephrosis and lymphocele without the need for further procedures. two patients (9.5%) had ultrasonographic features of uvj obstruction. percutaneous nephrostomy relieved the obstruction and serum creatinine values reduced to the stable levels. balloon dilation of the uvj obstruction and insertion of a stent in the ureter for 3 months were performed in these 2 patients. eight patients (38.1%) had calculi and underwent extracorporeal shock wave lithotripsy after pcn, of whom 6 experienced complete clearance of the calculus and 2 needed further interventions. percutaneous nephrostomy for posttransplant ureteral obstructions—mostafa et al urology journal vol 5 no 2 spring 2008 81 percutaneous nephrolithotomy was performed for these 2 patients through the pcn tract using a 12-f amplatz sheath and a 10-f ureteroscope, which made them stone free. all of the patients in the pcn group remained symptom free for a mean period of 34.2 ± 20.1 months (range, 3 to 81 months). one patient died 111 months after pcn and 2 experienced kidney failure 6 and 36 months thereafter. the table outlines demographic and clinical characteristics of the patients in the two groups. the mean follow-up period was 53.1 ± 27.5 months for the kidney recipients in the pcn group and 56.2 ± 38.1 months for the recipients of the control group (p = .70). kaplan-meier analysis showed no difference between the two groups in 10-year patient and allograft survivals (p = .40 and p = .90, respectively; figures 1 and 2). the only difference was the history of using antilymphocyte globulin which was significantly more frequent in the patients of the pcn group (p = .01) 120100806040200 posttransplant months 100 80 60 40 20 0 p at ie nt s ur vi va l controls pcn transplant recipients figure 1. patient survival curve of kidney allograft recipients with and without percutaneous nephrostomy. characteristics group 1(pcn) group 2 (no pcn) p age at transplantation, y 40.0 ± 12.7 42.9 ± 13.6 .56 sex, % male 71 68.1 female 29 31.9 .58 transplant time, % 1 100 94 2 0 5 3 0 0.3 .77 transplantation side (right iliac fossa), % 90 89 .88 warm ischemia time, min 17.2 ± 0.5 17.2 ± 2.7 .89 cold ischemia time, min 19.1 ± 1.7 20.6 ± 10.5 .46 ureteral anastomosis technique (lich-gregoir), % 95 99 .80 positive panel reactive antibodies, % 7 7 .90 positive cytomegalovirus, % igg 40 35 .72 igm 5 2.5 .53 positive epstein-barr virus, % igg 25 24 .92 igm 0 1.6 .64 drugs, % ganciclovir 30 14.5 .10 antilymphocyte globulin 30 10 .01 mycophenolate mofetil-based triple therapy 65 55 .70 living unrelated donor, % 75 81 .65 donor sex, % male 90 88 female 10 12 .84 donor age 28.1 ± 5.2 27.8 ± 5.2 .54 characteristics of kidney allograft recipients with and without percutaneous nephrostomy (pcn) percutaneous nephrostomy for posttransplant ureteral obstructions—mostafa et al 82 urology journal vol 5 no 2 spring 2008 discussion a number of studies have evaluated pcn in the treatment of ureteral obstruction and urine leakage in kidney transplant patients.(6-8) ureteral obstruction and leakage are the most common urologic complications encountered in kidney transplant recipients.(9-11) most series indicate that about 70% of the ureteral obstructions occur within 3 months of transplantation and 80% occur at the uvj site.(2,12,13) prompt diagnosis and early treatment are critical for preventing loss of the allograft and decreasing morbidity and mortality. ultrasonography and renal scintigraphy can be used as initial diagnostic techniques for assessing the patency and integrity of the renal collecting system. diagnosis of the obstruction or leakage can be definitively confirmed using percutaneous antegrade pyelography. percutaneous approach should be considered as a method of therapy for ureteral stricture regardless of the severity of obstruction.(6) obstructions that occur soon after transplantation are thought to be due to mechanical causes including blood clots, calculi, edema, and ischemic necrosis, whereas late obstructions are usually the result of local or generalized fibrosis due to ischemia or rejection.(4,11-15) fibrosis detected in late obstructions is less likely to resolve with insertion of an intraluminal ureteral stent. we had 2 patients with late uvj anastomosis obstruction and ureteral stent insertion for 3 months, in whom obstruction did not occur after stent removal during the follow-up period. as mentioned, pcn is a well-established technique for rapid relief of ureteral obstruction and improvement of the kidney function. however, if this method fails, open surgery will be considered which is associated with higher mortality and morbidity rates. repeated surgery in the kidney transplant patient can be extremely difficult and may result in graft loss and/or significant blood loss if not performed by an experienced surgeon. none of our patients needed open surgery. leakage is usually the result of ureteral necrosis as a consequence of rejection or vascular insufficiency.(14-16) aside from the 21 patients who underwent pcn in our study population, there were also 11 patients with leakage, all of whom were treated by insertion of an indwelling ureteral catheter for 21 to 60 days without the need for pcn or surgery. the overall incidence of posttransplant leakage and obstruction was 2.3% at our center. in the present study, we observed that most of the cases with atypical transplant ureteral strictures presented after more than 4 months posttransplant. no case of death or nephrectomy attributable to pcn occurred and the outcomes were comparable to those of the kidney recipients without urologic complications. one patient died after about 9 years and 2 experienced allograft rejection within 6 and 36 months after pcn. all of the patients remained symptom free for a mean duration of 34 months which represents excellent results. conclusion in our experience, pcn seems to be a safe and effective method for treatment of ureteral obstruction and leakage in kidney allograft recipients. it provides long-term success with few recurrences and low morbidity and mortality rates. indwelling stents may also be of use as a measure to control urinary leakage and allow stabilization of the immunocompromised patients who are too ill to undergo the surgery. 6000500040003000200010000 posttransplant days 100 80 60 40 20 0 k id ne y a llo gr af t s ur vi va l pcn controls transplant recipients figure 2. death-censored graft survival curve of kidney allograft recipients with and without percutaneous nephrostomy. percutaneous nephrostomy for posttransplant ureteral obstructions—mostafa et al urology journal vol 5 no 2 spring 2008 83 conflict of interest none declared. references 1. shoskes da, hanbury d, cranston d, morris pj. urological complications in 1,000 consecutive renal transplant recipients. j urol. 1995;153:18-21. 2. jones jw, hunter dw, matas aj. percutaneous treatment of ureteral strictures after renal transplantation. transplantation. 1993;55:1193-5. 3. lieberman sf, keller fs, barry jm, rösch j. percutaneous antegrade transluminal ureteroplasty for renal allograft ureteral stenosis. j urol. 1982;128:122-4. 4. goodwin we, casey wc, woolf w. percutaneous trocar (needle) nephrostomy in hydronephrosis. j am med assoc. 1955;157:891-4. 5. reek c, noster m, burmeister d, wolff jm, seiter h. urological complications of renal transplantation: a series of 900 cases. transplant proc. 2003;35:2106-7. 6. bhagat vj, gordon rl, osorio rw, et al. ureteral obstructions and leaks after renal transplantation: outcome of percutaneous antegrade ureteral stent placement in 44 patients. radiology. 1998;209:159-67. 7. swierzewski sj 3rd, konnak jw, ellis jh. treatment of renal transplant ureteral complications by percutaneous techniques. j urol. 1993;149:986-7. 8. alcaraz a, bujons a, pascual x, et al. percutaneous management of transplant ureteral fistulae is feasible in selected cases. transplant proc. 2005;37:2111-4. 9. loughlin kr, tilney nl, richie jp. urologic complications in 718 renal transplant patients. surgery. 1984;95:297-302. 10. kinnaert p, hall m, janssen f, vereerstraeten p, toussaint c, van geertruyden j. ureteral stenosis after kidney transplantation: true incidence and long-term follow up after surgical correction. j urol. 1985;133:17-20. 11. oosterhof go, hoitsma aj, witjes ja, debruyne fm. diagnosis and treatment of urological complications in kidney transplantation. urol int. 1992;49:99-103. 12. schwartz bf, chatham jr, bretan p, goharderakhshan r, stoller ml. treatment of refractory kidney transplant ureteral strictures using balloon cautery endoureterotomy. urology. 2001;58:536-9. 13. streem sb, novick ac, steinmuller dr, zelch mg, risius b, geisinger ma. long-term efficacy of ureteral dilation for transplant ureteral stenosis. j urol. 1988;140:32-5. 14. lojanapiwat b, mital d, fallon l, et al. management of ureteral stenosis after renal transplantation. j am coll surg. 1994;179:21-4. 15. thomalla jv, lingeman je, leapman sb, filo rs. the manifestation and management of late urological complications in renal transplant recipients: use of the urological armamentarium. j urol. 1985;134:944-8. 16. kashi sh, lodge jp, giles gr, irving hc. ureteric complications of renal transplantation. br j urol. 1992;70:139-43. effects of sertraline on spermatogenesis of male rats and its reversibility after terminating the drug hamidreza ghorbani1, alireza akhavanrezayat1, lida jarahi2, bahram memar3, sakineh amouian3, armin attaranzadeh4, sadegh ebrahimi5* purpose: the purpose of this research was to study the effects of sertraline on spermatogenesis of male rats and whether these probable effects are constant or provisional after terminating the drug. materials and methods: in this study, 32 two-month old male wistar albino rats were equally divided into the sertraline-treated and the control groups. the drug group was gavaged with sertraline daily while the control group was gavaged with water at the same volume. after 80 days, half of the rats in each group were selected randomly for hormonal evaluations and bilateral orchiectomy. histological and hormonal evaluations were performed. the remaining half of rats were kept alive for 90 more days without intervention and then underwent hormonal evaluation and bilateral orchiectomy in a similar fashion. results: there was no difference between the testes histology and pathology of the sertraline-treated and the control groups. there was a significant decrease in serum fsh in the sertraline-treated group compared to the control group (p <0.05). however, this decline appeared to be reversible following termination of exposure to sertraline. fsh returned to pretreatment levels in the remaining treated rats following 90 days of treatment cessation. conclusion: within the time-frame studied, sertraline can induce transitory changes in serum fsh of male rats without concomitant spermatogenic changes within the testes. this hormonal change appears to be reversible following withholding of sertraline. the long-term effect of sertraline usage on hormonal status and spermatogenesis in rats needs further investigation. keywords: sertraline; spermatogenesis; lh; fsh; testosterone; infertility introduction infertility is a common problem in the world and in one study conducted by who the global rate of primary infertility in 2010 had been reported to be 1.9% and that of secondary infertility as 10.5% (1). infertility has many socio-economic consequences for infertile couples. about 27% of the causes of infertility have been reported to be attributable to men(2). side effects of drugs have an important role in infertility. selective serotonin reuptake inhibitors (ssris) are the first line for the treatment of many psychological and some non-psychological disorders. therefore, the use of these drugs is relatively common(3). there have been published studies about the negative effect of ssris, including sertraline, on spermatogenesis(3,4). however, these studies have failed to investigate the reversibility of spermatogenesis following discontinuation of sertraline. we conducted this study to evaluate the effect of sertraline on male rats' spermatogenesis and its reversibility after discontinuing the administration of the drug. materials and methods this study was conducted in the animal facility of the 1kidney transplantation complications research center, mashhad university of medical sciences, mashhad, iran. 2department of community medicine, mashhad university of medical sciences, faculty of medicine, mashhad, iran. 3department of pathology, imam reza hospital, mashhad university of medical sciences, mashhad, iran. 4fellowship, department of molecular pathology and cytogenetics, mashhad university of medical sciences, faculty of medicine, mashhad, iran. 5resident, department of emergency medicine, faculty of medicine, mashhad university of medical sciences, mashhad, iran. *correspondence: resident, department of emergency medicine, faculty of medicine, mashhad university of medical sciences, mashhad, iran. tel: +99 9224153565, e-mail: ebrahimis981@mums.ac.ir. received august 2020 & accepted january 2021 mashhad faculty of medicine from december 2017 to june 2018. thirty two adult male wistar albino rats at approximately 2 months age and 180 to 220 grams weight were selected. the exclusion criteria of our study were any sign of sickness in the rats midst the studding or obvious anomaly in external genital organs of the rats. these rats at first were kept in 8 cages, 4 per cage. randomly, 4 cages were labeled as the drug group and 4 as the control group. each rat in the treatment group received (lavage) 0.5cc (2 mg) of sertraline solution every day for 80 days. each rat in the control group was lavaged for 80 days with 0.5 cc of water. the period of drug treatment and cessation was considered to double or triple the reported duration of rats spermatogenesis(5) and the treatment phase was 10 days lower than the cessation phase due to practical limitations. all rats were fed regularly with the regimen in a similar fashion. following 80 days of exposure, half of the rats were randomly selected and evaluated for hormone levels and the histology/pathology of the testes. briefly, rats in each cage were numbered from 1 to 4 and 2 were randomly selected for the first phase of the study. selected andrology urology journal/vol 18 no. 4/ july-august 2021/ pp. 434-438. [doi: 10.22037/uj.v16i7.6458] rats were removed one by one and exposed to ether to induce deep anesthesia. each rat's chest was then split by scissors and blood sample was aspirated from the ventricle and poured gently into the test tubes already labeled with the information related to the sacrificed rat. sampling of blood for all but one sertraline-treated rat was uneventful. as a result, the number of drug rats evaluated for this phase of the study was less than the control group by one. following the collection of blood samples, both testes were removed by pulling the spermatic cord, both were placed in a pre-labeled tube and filled with 10% formalin. following a waiting period for the formation of a clot and serum, clot from each tube was removed and the sample was centrifuged at 1000 rpm equal to 123 g for 10 minutes. the serum was then carefully aspirated and transferred into a properly labeled microfuge tube. the tubes were then stored in a freezer at a temperature of -19 degrees of centigrade until the contents were thawed for the measurement of lh (luteinizing hormone), fsh (follicular stimulating factor), and testosterone. containers of testes were kept until they were delivered to a pathology laboratory for histological and pathological evaluations of the testes as soon as possible. the remaining 16 rats were maintained safely in cages in an animal house and fed similarly for 90 more days without any intervention until they underwent the same process for similar hormonal and testicular histology/ pathology evaluations. data analysis was done by using spss version 20, with mann–whitney and wilcoxon test. a p-value of less than 0.05 was considered as significant. it is worth to say the sample size is calculated based on the formula of comparing means in two independent samples and results of the article by atli o, et al9. results as seen in table 1, comparison of hormonal levels in sertraline and control group does not show any significant difference on the 80th day after beginning the study except for the fsh that was significantly lower in the sertraline group compared to the control group (p = 0.004). also, there was not any significant difference in hormone levels between the drug and control groups on the 170th day. (p > 0.05, table 1). also when comparing each hormone level in each group at two times (80th day and 170th day), we found an increase in fsh level in the treatment group from 80th day to 170th day which was returned to the baseline level. results of testis pathology gross pathological information about each testis, including size, weight, color, consistency, cutting surface, infertility and urology-ghorbani et al. figure 1. microscopy of testis in a drug-treated rat in 80th day in two magnifications of 100 and 400. timing hormones sertraline group control group p-valuea median (iqr)b median (iqr) 80th day lh (mg/dl) 3/30 (3/10-5/20) 3.40 (2/12-4/17) 0.64 fsh (iu/l) 2/20 (2/00-3/40) 3/70 (2/95-4/45) 0.004 testosterone (iu/l) 5/30 (2/70-7/54) 4/99 (3/62-7/43) 0.18 170th day lh (mg/dl) 3/70 (2.35-5/00) 2/85 (1/90-4/30) 0.34 fsh (iu/l) 2/90 (2/20-4/07) 3/75 (3/05-4/25) 0.26 testosterone (iu/l) 5/40 (2/72-5/67) 3/80 (2/97-5/47) 0.83 table 1. comparison of the levels of lh, fsh and testosterone between sertraline-exposed rats and the control group in different periods of time. abbreviations: fsh, follicular stimulating factor; lh, luteinizing factor; iu, international unit; l, liter; iqr, interquartile range a mann-whitney test b inter quartile range (percentile 25, percentile 75) by comparing the hormonal levels in sertraline and control group we founded that fsh, lh and testosterone levels all increased in the sertraline group, but this increase was only significant for fsh (p < 0.05). there was no significant difference in lh, fsh and testosterone levels between the 80th day and 170th day in the control group (p > 0.05) andrology 335 vol 18 no 4 july-august 2021 138 and any changes in the physical characteristics were recorded. the testes were then processed for, the preparation of suitable parts, tissue processing, preparation of paraffin blocks, performing thin cuts (about 4 microns), and staining with hematoxylin and eosin. in the microscopic study of the testicular samples, examination of seminiferous tubules, interstitium, and tunica albuginea were carried out. in tubules, qualitative and semi-quantitative examinations of germ cells, including spermatogonia, primary spermatocytes, spermatids, permatozoa, and other cells, especially sertoli cells, were performed. in addition, the thickness of the basement membrane and probable sediments were observed. in interstitium, the status of leydig cells and the examination for abnormal inflammation or sediment were studied. spermatogenesis appeared to be normal in both sertralinetreated and control groups and no significant reduction in any of the germ cell types. in addition, no thickening of the basement membrane, atrophy or hyalinization of tubules were observed. the numbers of leydig cells in the interstitium were in normal range and no specific pathological findings were noticed (figures 1-4). discussion the main mechanism of ssris effects is primarily through the increase of serotonin activity in the brain and other organs(3). sertraline elevates serotonin levels in the brain through inhibition of serotonin reuptake in synaptic clefts playing an essential role in modulating nervous activity. for interpretation of the impact of each drug on organs, 2 approaches are taken. one approach is the determination of the direct effect of the drug on that organ and the other is the indirect effect of the drug on that organ through changes on the central cns that control the peripheral organs. the complexity of the serotoninergic system is evidenced by the great variety of subtypes of receptors for the regulation of the neurotransmitter functions(3). one of the most common and available methods for examining the functional status of reproductive system in laboratory animals is the examination of serum levels of sex hormones (including lh, fsh, and testosterone), as well as the examination of testicular pathology. in our study, no significant differences were observed between the sertraline-treated and the control groups of rats in regard to the testicular gross anatomy, histology, and pathology. erdemir and his colleague also found no significant reduction in johnson scoring on the sertraline group compared with the control group in the results of testicular tissue pathology(6). however, atli, et al. reported a higher number of sperm with abnormal morphology in the treatment group and noted that changes were more significant with higher doses. he used male wistar albino rats and categorized them into 4 groups: one control group (which was gavaged with water) and 3 treatment groups (which were gavaged figure 2. microscopy of testis in a control group rat in 80th day in two magnifications of 100 and 400 group hormones 80th day 170th day p-valuea median (iqr)b median (iqr) control lh (mg/dl) 3.40 (2/12-4/17) 2/85 (1/90-4/30) 0/34 fsh (iu/l) 3/70 (2/95-4/45) 3/75 (3/05-4/25) 0/27 testosterone (iu/l) 4/99 (3/62-7/43) 3/80 (2/97-5/47 0/83 sertraline lh (mg/dl) 3/30 (3/10-5/20) 3/70 (2.35-5/00) 0/86 fsh (iu/l) 2/20 (2/00-3/40) 2/90 (2/20-4/07) 0/002 testosterone (iu/l) 5/30 (2/70-7/54) 5/40 (2/72-5/67) 0/08 table 2. comparison of the levels of lh, fsh and testosterone between 80th and 170th day in sertraline and control group. abbreviations: fsh, follicular stimulating factor; lh, luteinizing factor; iu, international unit; l, liter; iqr, interquartile range awilcoxon test binter quartile range (percentile 25, percentile 75) infertility and urology-ghorbani et al. vol 18 no 4 july-august 2021 436 with 3 different sertraline doses of 5m/kg.day, 10mg/ kg.day and 20mg/kg.day) for 4 weeks. madlool, et al. injected sertraline intraperitoneally in male rats and found a significant decrease in the number of sperm and an increase in the number of deformed sperms(7). our study revealed a significant decrease in fsh in the drug group on the 80th day compared to the control group (p = 0.004). this significant decrease was resolved on the 170th day as there was no significant difference between the drug and control groups at that time (p = 0.26). it is recognized that fsh leads the production and maturation of sperms. perhaps the reason for the lack of significant changes in the spermatogenesis of the sertraline-treated rats is the short duration of exposure for an apparent effect of reduced fsh on spermatogenesis. in other words, if the administration of sertraline continued for a longer period of time, its negative effect on spermatogenesis may have been different. there was no significant difference between lh and testosterone in drug and control group in 80th day and 170th day after intervention. in male rats, lh and testosterone hormones are secreted episodically, so that lh has incremental episodes of 5 to 10 minutes, then gradually decreases over 50 to 70 minutes, and testosterone levels are within the range of 3-6 hours rise and then gradually fall(8). this finding can be justified by the possible central effects of medication by the pituitary, hypothalamus, or even the cerebral cortex in the first 80 days which is returned to the basal state after the gavage has been stopped in the second 90 days. in one study conducted by erdemir and his colleagues, there was no significant difference in the lh level similar to our study, but unlike to our study, there was a significant increase in fsh and a significant reduction in testosterone levels in the sertraline group compared to the control group(6). in another study conducted by atli ozlem and colleagues, contrary to the findings of our study and that of erdemir, there were increased levels of lh, increased levels of testosterone, and no change in fsh levels in the sertraline group compared with the control group(9). in the study of hadipour and colleagues on the mice of balb/c race, there was no significant change in lh, but in contrast to our study, there was a significant figure 3. microscopy of testis in a rat of drug group in 170th day in two magnifications of 100 and 400 figure 4. microscopy of testis in a rat of the control group in 170th day in two magnifications of 100 and 400 infertility and urology-ghorbani et al. andrology 337 vol 18 no 4 july-august 2021 138vol 18 no 4 july-august 2021 438 increase in fsh and a decrease in testosterone levels(10). in the study of madlood, only a significant decrease in serum testosterone level was detected(7). the possible reasons of differences we see in the findings of studies can be study design, episodic pattern of lh and testosterone secretion in male rats(8), operator mistakes in extracting the samples, preparing the samples, way of storing the serums, period of storing, and laboratory mistakes as using expired kits or changing the samples with each other. conclusions sertraline can induce changes on sexual hormones and these changes are probably due to a central effect on the hypothalamic-pituitary-gonadal axis. these changes are reversible after drug withholding. under the experimental conditions of our study, it appears that sertraline does not induce spermatogenic changes in wistar albino rats following 80 days of exposure to sertraline. whether or not the prolonged usage of sertraline can negatively impact spermatogenesis in rats and if this impact is reversible needs further investigation. acknowledgement this study was conducted in the animal facility of the mashhad faculty of medicine from december 2017 to june 2018. conflict on interest there was no conflict of interest in this study. references 1. mascarenhas mn, flaxman sr, boerma t, vanderpoel s, stevens ga. national, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. plos med. 2012;18:9-12. 2. hull mg, glazener cm, kelly nj, conway di, foster pa, hinton ra, coulson c, lambert pa, watt em, desai km. population study of causes, treatment, and outcome of infertility. br med j (clin res ed). 1985;14:1693-7. 3. el-mazoudy r, el-abd k, mekkawy d, kamel k. developmental effects on hypothalamic, hypophyseal, testicular and steroidogenic patterns of sertraline-exposed male rats by accumulated doses from juvenile to puberty. ecotoxicology and environmental safety. 2020;30:188-93. 4. riggin l, koren g. effects of selective serotonin reuptake inhibitors on sperm and male fertility. canadian family physician. 2015;6:529-30. 5. lara nl, santos ic, costa gm, cordeirojunior da, almeida ac, madureira ap, zanini ms, frança lr. duration of spermatogenesis and daily sperm production in the rodent proechimys guyannensis. zygote. 2016 oct 1;16:1-1. 6. erdemir f, atilgan d, firat f, markoc f, parlaktas bs, sogut e. the effect of sertraline, paroxetine, fluoxetine and escitalopram on testicular tissue and oxidative stress parameters in rats. international braz j urol. 2014;40:100-8. 7. madlool zs, faris sa, hussein am. effect of sertraline and fluoxetine on the reproductive abilities of male rats rattusnorvegicus. university of thi-qar journal of science. 2019;19:26-32. 8. ellis gb, desjardins c. male rats secrete luteinizing hormone and testosterone episodically. endocrinology. 1982;110:161827. 9. atli o, baysal m, aydogan-kilic g, kilic v, ucarcan s, karaduman b, ilgin s. sertralineinduced reproductive toxicity in male rats: evaluation of possible underlying mechanisms. asian journal of andrology. 2017;19:672. 10. jahromy mh, moghadam aa. effects of sertraline on sperm motility, number and viability and its relation to blood levels of testosterone, fsh and lh in adult male mice. advances in sexual medicine. 2014;4:2014. infertility and urology-ghorbani et al. letter reply letter to: gorgotsky i, shkarupa d, shkarupa a et al. a feasibility of percutaneous nephrolithotomy in positive urine culture: a single center retrospective study elisa de lorenzis1,2*, andrea gallioli1, emanuele montanari1,2 we read with interest the study by gorgotsky et al(1) regarding the outcomes of percutaneous nephrolithotomy (pcnl) performed in patients with preoperative positive urine culture. the authors concluded that infected urine is not an independent risk factor of post-operative infectious complications after pcnl in low risk patients with (non-obstructive) kidney stones. they also suggested that a 24-hours antibiotic administration before the surgery can be considered as alternative to 1-week treatment and allow to perform pcnl with sufficient safety in selected patients. these considerations, especially in low infectious risk population with sterile urine culture, can be also borrowed from the randomized control trial from the edge consortium(2) that demonstrated no advantage to providing 1 week of preoperative oral antibiotics in pcnl candidates. these results are in line with antimicrobial stewardship recommendations orientated in reducing antibiotic treatment duration in the antibiotic resistance era. as underlined by gorgotsky et al1, eau guidelines states that an obstructed kidney with all signs of urinary tract infection (uti) is a urological emergency(3) and instrumentation in the setting of an active infection can lead to an increased risk of post-procedural uti. however, a positive urine culture does not imply necessarily an active uti. the fundamental point is to distinguish between symptomatic uti and asymptomatic bacteriuria (asb) and, in patients with indwelling ureteral stent or nephrostomy tube, a bacterial colonization. this difference can be figured out by the integration of urine microscopy, complete blood count and c-reactive protein results. as recently stated by the best practice statement on urologic procedures and antimicrobial prophylaxis(4), asb does not need to be managed any differently prior to high-risk procedures (like pcnl) as single-dose antibiotic prophylaxis (ap). in the current study, the ap was continued in both groups for 3 days, in contrast with the intrinsic concept of prophylaxis and with the current urological guidelines that recommended single dose or 24hours duration. we know from the literature that bacteria can be cultured from the stones themselves in a variable rate (ranging from 15 to 70%)(5) and these results may be underestimated because stone culture is not routinely performed. in our experience, even when preoperative positive urine cultures were treated appropriately, the stone cultures revealed the same pathogen with similar resistance in the 63,6% of cases (article in press), implying that the pathogen is harbored inside the stone. in this study, the infectious complications, especially in group 2, are not correlated with intra-operative (i.e. stone culture) or post-operative blood and urine culture results, neglecting the possibility to evaluate the effect of antibiotic therapy on peri-operative cultures. moreover, it would have been useful to report the biochemical analysis of the fragments to evaluate the rate of struvite stones in the group 2 of this low risk population for infectious complications. the authors excluded from the cohort all patients with potential pre-operative risk factors for infectious complications, except the presence of a urinary diversion like nephrostomy or ureteric stent and history of recurrent uti, potential factors for bacterial colonization. some intraoperative potential risk factors for infectious complications were not investigated as multiple percutaneous tracts, drainage of purulent urine during the puncture and the intrarenal pressures. a prolonged use of antibiotics can be associated with an increased risk of acquiring antibiotic-resistance and, in the setting of kidney stones, can be useless because any calcified or non-calcified stone may be colonized by infectious organisms creating a persistent bacterial niche. in this view, the results by gorgotsky et al1 may help to reduce the rise of antibiotic resistance, avoiding pre-operative unnecessary treatments. the unsolved question remains how to efficiently treat the patients with risk factors for infectious complications, as they represent a considerable part of the population (34.5% in the series by gorgotsky et al1). future large prospective studies are needed to comprehensively investigate the impact of ap on patients that are candidate to stone removal with and without risk factors for infectious complications, both with asb and negative urine culture. 1 urology unit, fondazione irccs ca’ granda ospedale maggiore policlinico, milan, italy. 2 department of clinical sciences and community health, university of milan, milan, italy. *correspondence: department of urology, foundation irccs ca’ granda ospedale maggiore policlinico department of clinical sciences and community health, university of milan via della commenda 15, 20122 milan, italy. tel: +39 02 55034546. fax +39 02 50320584. email: elisa.delorenzis@gmail.com. received july 2020 & accepted august 2020 urology journal/vol 17 no. 5/ september-october 2020/ pp. 540-542. [doi: 10.22037/uj.v16i7.6383] vol 17 no 05 september-october 2020 541 refrences 1. gorgotsky i, shkarupa d, shkarupa a, et al. a feasibility of percutaneous nephrolithotomy in positive urineculture: a single center retrospective study. urol j. 2020 apr 19. doi: 10.22037/uj.v0i0.5561 2. chew bh, miller nl, abbott je, et al. a randomized controlled trial of preoperative prophylactic antibiotics prior to percutaneous nephrolithotomy in a low infectious risk population: a report from the edge consortium. j urol 2018 oct;200(4):801-808. 3. c. türk, a. neisius, a. petrik, et al. eau guidelines on urolithiasis (2020). https:// u r o w e b . o r g / w p c o n t e n t / u p l o a d s / e a u guidelines-on-urolithiasis-2020.pdf accessed 11th march 2020. 4. lightner dj, wymer k, sanchez j, et al. best practice statement on urologic procedures and antimicrobial prophylaxis j urol. 2020 feb;203(2):351-356. 5. schwaderer al, wolfe aj. the association between bacteria and urinary stones. ann transl med 2017;5(2):32 reply by author in fact, our study identified a group of patients with certain specific indications and minimally complicated conditions to assess the impact of positive urine as an independent factor. majority of such patients typically have a “simple” pelvis or calyx stone, which can be removed through single access without leaving significant residual fragments. thus, our study estimates the effect of only plankton forms of bacteria contained in urine. stone culture may play a role in further therapy in complicated patients, but under current conditions, this analysis with assessment of antibiotic resistance takes about 48-72 hours and has questionable feasibility, which limits its routine widespread use1. all patients participated in our study had no signs of acute obstruction or had previously established drainage (stent or nephrostomy tube) in this regard. of course, it is necessary to take into account the bacterial biofilms on the drainage surface, but it is difficult to assess the degree of colonization and the correlation of this factor on intra and postoperative results using existing routine methods of analysis. with the development of new experimental methods for rapid assessment of bacterial drainage contamination, this problem is likely to have some solution2. it is quite difficult to distinguish objectively between asymptomatic bacteriuria (asb) and latent manifestations of urinary tract infection. it may be worth excluding from the further study the category of patients who may have other reasons for asb (postmenopausal women, elder patients, etc.) if you look carefully at the section on a single dose of antibiotic prophylaxis for pcnl in eau guidelines, it refer to an article on ureteroscopy, not percutaneous interventions. struvite stone formers tend to have known additional risk factors, so we tried not to include such cases in the study. we absolutely agree that further research on antibiotic prophylaxis and treatment duration in complicated stone patients is needed. the major difficulty in organizing such studies is the impossibility to structure research in a modern, relevant fashion (e.g. double-blind randomized, etc.) primarily for ethical reasons. taking into account the presence of different local recommendations on antibiotic prophylaxis in each country and institution, detection of heterogenic types of bacteria in different countries, as well as private opinions of high-volume experts, no consensus has yet been reached on this problem3. despite the global tendency to decrease the duration of antibiotic use, some specialists still justify the tactics of long-term pre-operative therapy 2 weeks or more4. thus, it is difficult to perform meta-analyses and determine reliable conclusions. there is still hope for the development of bacteriological analysis technologies (modified gene sequencing, advanced polymerase chain reaction, etc.), that will enable fast and accurate determination of both plankton and biofilm pathogens for correlations with other clinical factors. references: 1. singh i, shah s, gupta s et al. efficacy of intraoperative renal stone culture in predicting postpercutaneous nephrolithotomy urosepsis/systemic inflammatory response syndrome: a prospective analytical study with review of literature j endourol. 2019 feb;33(2):84-92. doi: 10.1089/end.2018.0842. 2. dixon m., sha s., mcdonald m. is it time to say goodbye to culture and sensitivity? the case for culture-independent urology. urology. 2020 feb; 136:112-118. doi: 10.1016/j.urology.2019.11.030. 3. carlos ec, youssef rf, kaplan ag et al. antibiotic utilization before endourological surgery for urolithiasis: endourological society survey results. j endourol. 2018 oct;32(10):978-985. doi: 10.1089/end.2018.0494. 4. rivera m., viers b., cockerill p. et al. preand postoperative predictors of infection-related complications in patients undergoing percutaneous nephrolithotomy. j endourol. 2016 sep;30(9):9826. doi: 10.1089/end.2016.0191. letter 542 efficacy of obturator nerve block during transurethral resection on non-muscle invasive intermediate and high risk lateral wall bladder tumours: a prospective randomized controlled study omer gokhan doluoglu1*, ali kaan yildiz1, turgay kacan1, veysel bayburtluoglu1, meltem bektas2, berat cem ozgur1 purpose: we aimed to investigate the effects of obturator nerve block (onb) on obturator reflex, incomplete resection, perforation, progression and recurrence of tumor, presence of muscle tissue in the specimen, need for a second transurethral resection (turbt) of bladder tumors, and postoperative complications in patients who underwent turbt for intermediate-high risk lateral wall non-muscle invasive bladder cancers (nmibc). material and methods: patients were assigned to one of two groups by drawing lots: onb or no onb. early and late recurrence, tumor progression, obturator reflex beat, incomplete resection, perforation, presence of muscle layer in pathology, second turbt application, operation time, postoperative hospital stay, and complications were compared between the two groups. results: the median follow-up time of study was 32 (23-41) months. interquartile range (iqr) was 9. tumor recurrence at the 3rd month cystoscopy was observed in 5 (9.8%) patients in the onb group, while it was observed in 11 (20.8%) patients in the nonb group (p = 0.01). late tumor recurrence was observed in 10 patients (19.6%) in the onb group, and in 20 patients (37.7%) in the nonb group (p = 0.041). the rfs rate at 12th month was 84% in the onb group, 69% in the nonb group, 79% in the onb group at 36th month, and 58% in the nonb group at 36 months, the pfs rate was 94% in the onb group, while it was 85% in the nonb group (p = 0.041). conclusion: our study showed that onb decreases the early and late recurrence and increases recurrence free survival in patients with intermediate-high risk lateral wall bladder cancer. keywords: bladder cancer; obturator nerve; progression; recurrence; transurethral resection introduction non-muscle invasive bladder cancers (nmibc) are divided into three groups according to eortc (european organization for research and treatment of cancer) as low, intermediate, and high risk. in intermediate and high-risk nmibc, early recurrence was reported as 15%, late recurrence was 25%, and progression was 9% with bcg therapy.(1) transurethral resection (turbt) of bladder tumors is the main approach in diagnosis and treatment. while performing turbt of lateral wall-located bladder tumors, electrical current and adjacent obturator nerve stimulation may occur during surgical resection, resulting in adductor contraction and leg jerk. this condition, called the obturator reflex, occurs in 55,3% to 100% of lateral bladder tumors.(2) in case of obturator reflex, serious complications may occur in turbt, one of which is bladder perforation that may require laparotomy and open repair. perforation is also associated with poor patient outcomes due to tumor invasion into the abdominal cavity and failure to administer early single-dose intravesical chemotherapy. (3) various methods such as application of muscle relaxants under general anesthesia, less filling of the bladder, reduction of electric current, use of 90 degree classical loop, use of bipolar plasma kinetic energy and tumor resection with small pieces have been proposed to prevent 1university of medical sciences, department of urology clinic of ankara training and research hospital, ankara, turkey. 2university of medical sciences, department of anesthesiology, clinic of ankara training and research hospital, ankara, turkey. *correspondence: department of urology clinic of ankara training and research hospital sukriye mahallesi, ulucanlar caddesi. no:89 postal code: 06340 mobile: +90 533 215 78 09. fax: +90 312 362 49 33. e-mail: drdoluoglu@yahoo.com.tr. received august 2021 & accepted november 2021 failure and complications related to the obturator reflex. (4) however, these methods did not show the expected success and their effectiveness has not been proven. there are studies in the literature showing that obturator nerve block (onb) successfully reduces the obturator reflex, resulting in less incomplete resection and early tumor recurrence.(5,6) however, to our knowledge, there is no study investigating its effect on oncological outcomes with a mid-term follow-up period, especially in patients with intermediate-high risk nmibc, where the risk of tumor recurrence and progression is higher. in this study, we investigated the effects of onb on obturator reflex, incomplete resection, perforation, progression with tumor recurrence, presence of muscle tissue in the specimen, need for a second turbt, and postoperative complications in patients who underwent turbt for intermediate-high risk lateral wall nmibc. material and methods study population after the local ethics committee approval (e-20/495), it was planned to include patients who underwent turbt operation as of january 2018 in ankara training and research hospital urology clinic and diagnosed with eortc intermediate and high risk lateral wall primary nmibc. clinical trials registration number urology journal/vol 19 no. 6/ november-december 2022/ pp. 445-451. [doi:10.22037/uj.v18i.6953] urological oncology of the present study was nct04885309. our study was conducted in accordance with the principles of the declaration of helsinki, the planned study was explained to the patients in detail, and then written informed consent was obtained from each patient. lateral bladder tumors were defined as tumors reported in the lateral wall of the bladder on preoperative cystoscopy, ultrasonography (usg), or computed tomography (ct). incomplete resection was defined as the remaining visible tumor after the tur-bt. exclusion criteria in the study were defined as contraindications for spinal anesthesia, history of allergy to local anesthetic substances, coagulopathy, neuromuscular diseases affecting the central nervous system, and obturator nerve damage. patients who were found to have muscle-invasive bladder tumor (mibc) and low-risk nmibc during the study, who refused to participate in the study, and who did not come for postoperative follow-up were excluded. patients were assigned to one of two groups by drawing lots: onb (turbt with spinal anesthesia and obturator block) or nonb (turbt with spinal anesthesia). our analysis in the current study was per-protocol. there is a 90% chance of correctly rejecting the null hypothesis of no difference between expected and observed proportions with 29 participants (effect size 0.61 according to previous studies).(2,5) after confirming the spinal anesthesia level while in the lithotomy position, onb was applied unilaterally or bilaterally according to the tumor position to the patients in the onb group. the high-frequency usg probe was placed proximal to the adductor longus muscle, and immediately after the obturator nerve was embedded in the pectineus, the adductor longus and adductor brevis muscles were observed, and the location of the nerve was confirmed by setting the stimulator current to 1.52 ma and its duration to 0.1 milliseconds. under the vol 19 no 4 july-august 2022 308 table 1. demographic and surgical data results onb group (n=51) nonbgroup (n=53) p value age (year) 64.6 ± 11.7 64.3 ± 16.2 0.90 bmi (kg/m²) 27.3 ± 2.1 27.0 ± 2.2 0.57 tumor size (cm) 2.9 ± 1.56 2.9 ± 1.50 0.76 eortc recurrence score 8.2 ± 4 7.8 ± 4.1 0.59 eortc progression score 9.3 ± 4.6 8.8 ± 4.6 0.59 follow up time (month) 32.3 ± 5.3 32.1 ± 5.2 0.99 operation time (min) 52.5±24.8 51.7±24.5 0.87 mean ± sd and median (min-max) 45 (15-120) 45 (15-120) hospitalisation time (day) 1.3 ± 0.6 1.8 ± 1.11 0.02* mean ± sd and median (min-max) 1(1-4) (1-6) (*) statistically significant difference, eortc: european organization for research and treatment of cancer figure 1. flow chart of patients’ enrollment. obturator nerve block and turt-doluoglu et al. vol 19 no 6 november-december 2022 446 usg image, a 50 mm insulated needle parallel to the long axis of the probe was guided through the skin to the anterior branch of the obturator nerve. when contraction was observed at 0.3-0.5 ma in the adductor muscle groups and the aspiration became negative, 1% lidocaine, maximum 10 ml, was injected to block the nerve. the operation was started 10 minutes after the injection. obturator reflex was considered as adductor muscle contraction severe enough to affect the surgeon's resection. all turbt operations were performed by the same surgeon. demographic data and clinical features are included gender, age, asa score, body mass index (bmi), tumor side, tumor number, and tumor size. the 2006 eortc scoring model was used for the recurrence and progression prediction score. indications for the second turbt were determined according to the eau nmibc guidelines. all second turbts were performed 2-6 weeks after the first operation.(7) a full dose of bcg treatment for 1 year in moderate-risk patients and for 1-3 years in high-risk patients was planned. follow-up of all patients included in the study was planned as cystoscopy and cytology every 3 months for 2 years, then cystoscopy and cytology every 6 months for up to 5 years. detection of the first recurrence at 3 months of cystoscopy was defined as early recurrence, and detection of the first recurrence at any cystoscopy after 3 months of cystoscopy was defined as late recurrence. progression was defined as detection of t2 tumor pathology or local-distance metastasis during follow-up. early and late recurrence, tumor progression, obturator reflex beat, incomplete resection, perforation, presence of muscle layer in pathology, second turbt application, operation time, postoperative hospital stay, and complications were compared between the two groups. recurrence-free survival (rfs) and progression-free survival (pfs) were evaluated. the main complications were identified as infection (postoperative fever > 38.2 °c) and the need for reoperation during hospitalization. serious complications such as septic shock and acute abdomen were evaluated. statistical analysis data analysis was performed with the software program pasw 23 (spss, ibm, chicago, il). whether obturator nerve block and turt-doluoglu et al. onb group (n=51) nonbgroup (n=53) p value gender (n,%) 0.93 male 43 (84.3) 45 (84.9) female 8 (15.7) 8 (15.1) asa(n,%) 0.72 1 4 (7.8) 4 (7.5) 2 23 (45.1) 28 (52.8) 3 24 (47.1) 21 (20.2) tumor site(n,%) 0.40 right 32 (62.7) 29 (54.7) left 19 (37.3) 24 (45.3) tumor number(n,%) 0.53 solitary 25 (49) 30 (56.6) multiple 26 (51) 23 (43.4) tumor stage(n,%) 0.99 ta 27 (52.9) 28 (52.8) t1 24 (47.1) 25 (47.2) tumor grade(n,%) 0.88 low 19 (37.3) 19 (35.8) high 32 (62.7) 34 (64.2) cis (concomitant)(n,%) 0.801 present 5 (9.8) 6 (11.3) not present 46 (90.2) 47 (88.7) eortc riskclassification(n,%) 0.891 i̇ntermediate 17 (33.3) 17 (32.1) high 34 (66.7) 36 (67.9) table 2. distribution of the bacteria by gender between the groups data are shown as n (%). onb group (n=51) nonbgroup (n=53) p value present not present present not present obturator reflex 5 (9.8) 46 (90.2) 21 (39.6) 32 (60.4) 0.001* i̇ncomplete resection 1 (2) 50 (98) 8 (15.1) 45 (84.9) 0.031* bladder perforation 1 (2) 50 (98) 4 (7.5) 49 (92.5) 0.363 complication 3 (5.9) 48 (94.1) 8 (15.1) 45 (84.9) 0.127 detrusormuscle in specimen 45 (88.2) 6 (11.8) 37 (69.8) 16 (30.2) 0.021* second turbt 25 (49) 26 (51) 30 (56.6) 23 (43.4) 0.439 second turbt due toabsenceof detrusormuscle 3/25 (12) 22/25 (88) 11/30 (36.7) 19/30 (63.3) 0.037* early recurrence 5 (9.8) 46 (90.2) 11 (20.8) 42 (79.2) 0.122 late recurrence 10 (19.6) 41 (80.4) 20 (37.7) 33 (62.3) 0.041* tumor progression 3 (5.9) 48 (94.1) 7 (13.2) 46 (86.8) 0.32 (*) statistically significant difference.tur-bt:transurethral resection of bladder tumor table 3. surgical data, complications and oncological results. urological oncology 447 the continuous variables fit the normal distribution was evaluated with the kolmogorov-smirnov test and p-p plot. data that fit to the normal distribution are shown as mean ± standard deviation, and data that do not fit are shown as median (minimum-maximum) and interquartile ranges (iqr). categorical variables are shown as frequencies and percentage. pearson's chi-square and fischer's exact test were used to compare categorical data between groups, and independent sample t-test was used together with levene’s test for equality of variances to compare continuous data. rfs and pfs were evaluated by kaplan-meier analysis. calculation of rfs was based on the first detected recurrence or the last follow-up visit without recurrence. calculation of pfs was based on the first detected progression or the last follow-up visit without progression. a value of p < 0.05 was considered statistically significant. results of the 154 patients identified at baseline, 9 did not meet the inclusion criteria. of the 145 patients who met the inclusion criteria, 18 were excluded from the study because they had a previous diagnosis of bladder cancer and 4 did not accept the operation. according to the computerized randomization list, 61 patients were assigned to the onb group and 62 patients were assigned to the nonb group. while our study, which started with 123 patients, was continuing, 13 subjects were excluded from the study because they were in the low risk group for eortc and 6 of them did not refer for follow-up. our study was completed with a total of 104 patients (figure 1). the demographic and clinical characteristics of the patients and the operation data are listed in tables 1 and 2. operative and oncological outcomes and complications are compared in table 3. the presence of obturator reflex occurred in 5 (9.8%) of 51 patients in the onb group and in 21 (39.6%) of 53 patients in the nonb group (p = .001). in turbt, incomplete resection of the tumor was detected in 1 (2%) of 51 patients in the onb group and in 8 (15.1%) of 53 patients in the nonb group (p = .031). the presence of detrusor muscle in the specimen was detected in 45 (88.2%) of 51 patients in the onb group and 37 (69.8%) of 53 patients in the nonb group (p = .021). while the second turbt was performed in 25 (49%) patients in the onb group, it was performed in 30 (56.6%) patients in the nonb group. second turbt was performed in 3 (12.0%) of 25 patients in the onb group and in 11 (36.7) of 30 patients in the nonb group because of the absence of detrusor muscle in the specimen without t1 tumor or incomplete resection (p = .037). in our study, bladder perforation was observed in 1 (2%) patient in the onb group, while it was observed in 4 (7.5%) patients in the nonb group (p = .3). all patients with perforation were evaluated extraperitoneally, and none of the patients needed additional intervention after one week of bladder catheterization. postoperative hematuria and fever were observed in 3 patients (5.9%) in the onb group and in 8 patients (15.1%) in the nonb group (p = .10). severe hematuria was not detected in any patient in both groups. tumor recurrence at the 3rd month cystoscopy was observed in 5 (9.8%) patients in the onb group, while it was observed in 11 (20.8%) patients in the nonb group (p = .12). late tumor recurrence was observed in 10 patients (19.6%) in the onb group, and in 20 patients (37.7%) in the nonb group (p = .041). the number of patients with progression was 3 (5.9%) in the onb group, while it was 7 (13.2%) in the nonb group (p = .32). the median follow-up time of the study was32 (23-41) months. the rfs rate at 12th month was 84% in the onb group, 69% in the nonb group, 79% in the onb group at 36th month, and 58% in the nonb group at 36 months, the pfs rate was 94% in the onb group, while it was 85% in the nonb group (figures 2 and 3). there was a statistically significant difference between the groups in rfs (p = .041) (28.5-34.4 95% ci) , but figure 2. comparison of rfs rates of the groups. obturator nerve block and turt-doluoglu et al. vol 19 no 6 november-december 2022 448 no significant difference was found in pfs (p = .20) (37.1-40 95% ci). the median operation times and iqr of the patients were found as 45(15-120) minutes and 30; 45(15-120) minutes and 30 in the onb and nonb groups, respectively (p = .80). the median postoperative hospitalization and iqr were found as 1 (1-4) days and 1;1 (1-6) days and 1 in the onb and nonb groups, respectively (p = .02). discussion in the current study, onb group when compared to nonb group; early and late tumor recurrence, obturator reflex beat, incomplete tumor resection, postoperative complication rate and duration of hospitalization were significantly reduced; the presence of muscle tissue in pathology was found to be significantly increased. adductor muscle contraction due to obturator nerve stimulation during turbt can cause bleeding, incomplete resection, hematoma, bladder perforation, and extravesical spread of the tumor.(8) in order to prevent the obturator reflex, succinylcholine was used immediately before tumor resection in a study conducted by cesur et al, and the obturator reflex was successfully prevented in all 52 patients in succinylcholine applied group. in the onb group, obturator reflex was prevented in 33 out of 39 (84.6%) patients. however, all patients had to undergo general anesthesia in succinylcholine applied group and no evaluation of the oncological results was performed in their study.(9) the efficacy of onb(10), which was 83.8% when performed blind, was 89.4-100% when performed with nerve stimulation technique.(11,12) more recently, usg-guided onb techniques have been used, reporting a reduced incidence of vascular injury due to better nerve visualization as well as higher onb success rates. in our study, all onbs were performed with nerve stimulation technique under usg. the incidence of obturator reflex in onb+ groups varies between 0% and 14%, and between 16% and 92% in onbgroups in the literature.(5,6,13-15) in our study, the obturator reflex rate was 9.8% in the onb group and 39.6% in the nonb group (p = .001). most of the these studies in the literature were performed by anesthesiologists. for this reason, the primary end-point of these studies focused on whether there was an obturator reflex, and these studies were lacking in terms of midlong term oncological results. in our study, oncological results were followed up for an average of 32 months. residual tumor tissue due to incomplete resection during turbt increases the tumor recurrence rate. in the study of jancke et al., the recurrence rate was found to be significantly higher in cases in which residual tumor was found in the pathology in the nmibc compared to cases in which no tumor was detected.(16) erbay et al. reported incomplete resection rates as 36% and 12% in onband onb+ groups, respectively(6), similarly bolat et al. reported these rates as 22.9% and 2.9% in onband onb+ groups, respectively, and found a statistically significant difference.(5) in our study, the rate of incomplete resection was found to be 15.1% in the nonb group and 2% in the onb group (p = .03), which was thought to contribute to the reduction in late recurrence rates and improvement in rfs. the presence of the detrusor muscle in the turbt specimen is crucial for accurate staging.(17) the absence of the detrusor muscle is an important risk factor for inadequate staging, which may result in inadequate management.(18) studies have shown that detrusor muscle is absent in 15% to 66% of turbt specimens taken without performing onb.(19-21) in their retrospective study erbay et al. reported the rate of absence of detrusor muscle in the turbt specimen as 26.5% and 4.2% in the onband onb+ groups, respectively, and found a statistically significant difference.(6) in our study, it was found to be 30.2% in the nonb group and 11.8% in the onb group (p = .03). our study showed that onb significantly increased the presence of the detrusor muscle figure 3. comparison of pfs rates of the groups. obturator nerve block and turt-doluoglu et al. urological oncology 449 in the specimen of patients with intermediate-high risk lateral wall nmibc. some studies suggest that if muscle is present in the primary turbt, a second turbt may not be necessary for high risk nmibc. it is shown that the potential benefits of second turbt should be carefully weighed against the health care burden and side effects of the procedure.(22-24) in our study, second turbt was performed in 25 of 51 patients in the onb group and in 30 of 53 patients in the nonb group. we evaluated patients who underwent second turbt only because of the absence of detrusor muscle in the specimen, without the presence of t1 tumor or incomplete resection. these were found to be 3 (12%) of 25 patients in the onb group and 11 (36.7%) of 30 patients in the nonb group (p = .03), and it was found that the need for second turbt due to the absence of detrusor muscle could be significantly reduced with onb. in this way, the presence of detrusor muscle can be increased with onb, and a significant reduction in health care burden and side effects due to unnecessary second turbt can be achieved. in a study evaluating the prediction of recurrence and progression in nmbic patients, important prognostic factors were mentioned as number of tumors, tumor size, number of recurrences within 1 year, t-stage of tumor, presence of cis, and tumor grade.(25) in our study, there was no difference in these prognostic factors between the groups. according to the eortc risk classification, 17 (32.1%) of 53 patients in the nonb group were found to be at intermediate risk, 36 (67.9%) high risk; in the onb group, 17 (33.3%) of 51 patients were found to be at intermediate risk, 34 (66.7%) at high risk, and no difference was found between the groups. there are many factors that affect recurrence and progression in nmibc other than the obturator reflex. in our study, these factors were found to be similar in both groups. so, confounding factors that could affect the result were minimized and the possibility of bias was reduced. in their retrospective studies, tekgül et al. reported the recurrence rate in the first 12 months as 25% and 9% in the onband onb+ groups(2), respectively, similarly erbay et al. reported the recurrence rate in the first 12 months as 24% and 6% in the onband onb+ groups, respectively.(6) in our study, the early recurrence rate was 9.8% in the onb group and 20.8% in the nonb group (p = .12); late recurrence rate was 19.6% in the onb group and 37.7% in the nonb group (p = .04). it was found that onb significantly increased rfs (p = .04). we thought that these results were due to the decrease in incomplete resection due to the occurrence of less obturator reflexes in patients with onb, and the increase in the presence of detrusor muscle in the resection material. in the present study, the rate of progression was found to be 5.9% in the onb group and 13.2% in the nonb group (p = .20). onb was found to reduce the rate of progression, but no significant difference was found. there are studies showing the efficacy of onb in preventing resection complications in bladder tumors in the lateral wall.(16,26) during turbt, bladder perforation, hematoma and severe bleeding may occur due to the obturator reflex. it has been reported that bladder perforation in turbt significantly reduces disease-free survival and significantly increases tumor progression in case of development of recurrence.(27) comparing bladder perforation in onband onb+ groups, erbay et al. reported the rates of perforation as 4% and 0%6, respectively, and bolat et al. reported these rates as 5% and 0%5 in onband onb+ groups, respectively. in our study, it was found as 7.5% in the nonb group and 2% in the onb group (p = .10). all of the perforations were detected extraperitoneally and conservative treatment was applied. the perforation rate decreased in patients who underwent onb, but no significant difference was detected similar to the literature. duration of hospitalization directly affects hospital-acquired infections and cost.(28) in our study, the postoperative duration of hospitalization was found as 1.3 ± 0.6 days in the onb group and 1.8±1.1 days in the nonb group (p = .02). thus, it was thought that onb could significantly reduce duration of hospitalization and reduce hospital-acquired infections and costs. the main limitation of our study is the small sample size, as we only included patients with lateral wall intermediate and high-risk bladder tumors. patients in the study are currently being followed to investigate the mid-term efficacy of onb on relapse rate, relapse time, and progression. to obtain more precise results, future studies should be conducted with larger batches over a longer period of time. conclusions our study showed that spinal anesthesia combined with onb prevents the obturator reflex, reduces incomplete resection, and increases the presence of detrusor muscle tissue in the resection material. for these reasons, it was determined that it reduces the recurrence rate and increases disease-free survival. it was also found that onb shortens the postoperative duration of hospitalization. conflict of interest the authors declare that there is no conflict of interest. references 1. cambier s, sylvester rj, collette l et al. eortc nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non–muscle-invasive stage ta–t1 urothelial bladder cancer patients treated with 1–3 years of maintenance bacillus calmetteguérin. european urology 2016;69:60-9. 2. tekgül zt,divrik rt, turan m,konyalioğlu e, şimşek e, gönüllü m. impact of obturator nerve block on the short-term recurrence of superficial bladder tumors on the lateral wall. urol j 2014;11:1248-52. 3. panagoda pi, vasdev n, gowrie-mohan s. avoiding the obturator jerk during turbt. currurol 2018;12:1-5. 4. deliveliotis c, alexopoulou k, picramenos d,econornacos g, goulandris n, kostakopoulosa. the contribution of the obturator nerve block in the transurethral resection of bladder tumors. acta urolbelg 1995;63:51-4. 5. bolat d, aydogdu o, tekgul zt et al. impact of nerve stimulator-guided obturator nerve block on the short-term outcomes and complications of transurethral resection of bladder tumour: a obturator nerve block and turt-doluoglu et al. vol 19 no 6 november-december 2022 450 prospective randomized controlled study. can urol assoc j 2015;9:e780-84. 6. erbay g, akyol f, karabakan m,celebi b, keskin e, hirik e. effect of obturator nerve block during transurethral resection of lateral bladder wall tumors on the presence of detrusor muscle in tumor specimens and recurrence of the disease. kaohsiung j med sci 2017;33:8690. 7. babjuk m, burger m, compérat em et al. european association of urology guidelines on non-muscle-invasive bladder cancer (tat1 and carcinoma in situ) 2019 update. eur urol 2019;76:639-57. 8. akata t, murakami j, yoshinaga a. lifethreatening haemorrhage following obturator artery injury during transurethral bladder surgery: a sequel of an unsuccessful obturator nerve block. acta anaesthesiol scand 1999;43:784-88. 9. cesur m, erdem af, aliciha,yapanoglu t, yuksek ms, aksoy y. the role of succinylcholine in the prevention of the obturator nerve reflex during transurethral resection of bladder tumors. saudi med j 2008;29:668-71. 10. augspurger rr, donohue re. prevention of obturator nerve stimulation during transurethral surgery. j urol1980;123:170-72. 11. kobayashi m, takeyoshi s, takiyama r et al. [a report on 107 cases of obturator nerve block]. masui 1991;40:1138-43. japanese. 12. gasparich jp, mason jt, berger re. use of nerve stimulator for simple and accurate obturator nerve block before transurethral resection. j urol1984;132:291-93. 13. lee sh, jeong cw, lee hj,yoon mh, kim wm. ultrasound guided obturator nerve block: a single interfascial injection technique. j anesth2011;25:923-26. 14. bourjilag,noh e. effect of obturator nerve block during transurethral resection of lateral bladder wall tumors: a comparison of monopolar and bipolar tur-bt regarding the presence of detrusor muscle in tumor specimens and recurrence of disease. journal of medicine in scientific research 2020;3:448. 15. khorrami mh, javid a, saryazdi h,javid m.transvesical blockade of the obturator nerve to prevent adductor contraction in transurethral bladder surgery. j endourol2010;24:1651-54. 16. jancke g, rosell j, jahnson s. residual tumour in the marginal resection after a complete transurethral resection is associated with local recurrence in ta/t1 urinary bladder cancer. scand j urol nephrol 2012;46:343-47. 17. akand m, muilwijk t, raskin y,de vrieze m, joniau s, van der aa f. quality control indicators for transurethral resection of non-muscle-invasive bladder cancer. clin genitourin cancer. 2019 aug;17:e784-e92. 18. kurth kh, bouffioux c, sylvester r,van der meijden ap, oosterlinck w, brausi m. treatment of superficial bladder tumors: achievements and needs. the eortc obturator nerve block and turt-doluoglu et al. genitourinary group. eur urol 2000;37 suppl 3:1-9. 19. dalbagni g, herr hw, reuter ve. impact of a second transurethral resection on the staging of t1 bladder cancer. urology 2002;60:82224; discussion 824-5. 20. cheng l, neumann rm, weaver al et al. grading and staging of bladder carcinoma in transurethral resection specimens. correlation with 105 matched cystectomy specimens. am j clin pathol2000;113:275-79. 21. wijkström h, norming u, lagerkvist m,nilsson b, näslund i, wiklund p. evaluation of clinical staging before cystectomy in transitional cell bladder carcinoma: a longterm follow-up of 276 consecutive patients. br j urol1998;81:686-91. 22. angulo jc, palou j, garcía-tello a,de fata fr, rodríguez o, villavicencio h. second transurethral resection and prognosis of highgrade non-muscle invasive bladder cancer in patients not receiving bacillus calmetteguérin. actasurolesp2014;38:164-71. english, spanish. 23. gontero p, sylvester r, pisano f et al. the impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with t1 high-grade/grade 3 bladder cancer treated with bacille calmette-guérin. bju int 2016;118:44-52. 24. svatek rs, hollenbeck bk, holmäng s et al. the economics of bladder cancer: costs and considerations of caring for this disease. eur urol2014;66:253-62. 25. sylvester rj, van der meijden ap, oosterlinck w et al. predicting recurrence and progression in individual patients with stage ta t1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials. eur urol2006;49:466-5; discussion 475-7. 26. tatlisen a, sofikerim m. obturator nerve block and transurethral surgery for bladder cancer. minerva urolnefrol2007;59:137-41. 27. comploj e, dechet cb, mian m et al. perforation during tur of bladder tumours influences the natural history of superficial bladder cancer. world j urol2014;32:121923. 28. giraldi g, montesano m, sandorfi f,iachini m, orsi gb. excess length of hospital stay due to healthcare acquired infections: methodologies evaluation. ann ig 2019;31:507-16. urological oncology 451 urological oncology discriminant efficacy of mpmri for variant pathology associated with prostate adenocarcinoma hikmet köseoğlu1*, halime çevik cenkeri2, tolga eroğlu3, berrin yalçın4 purpose: implementation of multiparametric magnetic resonance imaging (mpmri) for prostate adenocarcinoma’s variant pathology requires awareness. the aim of this retrospective study was to investigate the discriminant efficacy of multiparametric magnetic resonance imaging modality for variant pathology associated with prostate adenocarcinoma. methods: consecutive 247 prostate cancer patients who underwent radical prostatectomy in our university-based hospital between october 2014 and october 2019, were retrospectively reviewed. data of mpmri-associated contrast enhancements, t2 signals, apparent diffusion coefficients (adc), ages, and psa values were compared. clinical and demographic data of patients were noted including associated variant pathologies and reports of preoperative mpmri images. results: among the patients, 63 (26%) had variant pathology and 14 (22%) had mpmri before primary prostate biopsy. the group with variant pathology and the control group had similar perfusion curves and increased contrast when compared for mpmri parameters, but different adc values for each of the adjusted b-values for 400, 800 and 1400. conclusion: our study demonstrates that mpmri appears to have no role in distinguishing rare variant pathologies associated with prostate adenocarcinoma despite different adc values. keywords: prostate adenocarcinoma; prostate cancer variants; mpmri; apparent diffusion coefficient. 1health sciences university, hamidiye faculty of medicine, istanbul health practice and research center, department of urology, istanbul, turkey. 2okan university, faculty of medicine, department of radiology. 3semdinli state hospital, department of urology, hakkari, turkey. 4health sciences university, hamidiye faculty of medicine, istanbul health practice and research center, department of radiation oncology, istanbul, turkey. *correspondence: associate professor (urology), febu, fecsm, facs. orcid: 0000-0001-5678-4981; phone : + 90 530 551 99 33. e-mail address: hikmet.koseoglu@gmail.com. received october 2022 & accepted february 2023 introduction prostate cancer is the most common malignancy in men after lung cancer(1). in recent years, prostate biopsy has been the first step to rule out malignancy, though it has low diagnostic efficiency of 30% for psa ≥ 4ng/ml in older men(2). recently, multiparametric magnetic resonance imaging (mpmri) has been introduced into the clinical practice to decrease those unnecessary prostate biopsies and their associated complications as well as to have better information about the location, grade, and extent of the tumor compared to other imaging modalities(3-5). the ability of mpmri to differentiate malignancy depends on its multiple sequences including t1-weighted imaging (t1wi), t2-weighted imaging (t2wi), dynamic contrast imaging (dce), and diffusion-weighted imaging (dwi). these two last sequences further provide functional information about tissues including diffusion reflected by the b-values (amount of diffusion weight) in dwi and perfusion in dce. the apparent diffusion coefficient (adc) map from multiple b-values is a quantitative measure of tissue diffusion(3). increasing the b-value, suppresses the signal of normal prostate tissue making tumoral tissue more prominent(5). likewise, in active surveillance patients prior to primary or secondary biopsy, the utility of adc parameters in mpmri has been shown to improve overall sensitivity while maintaining the specificity for the detection of prostate cancer(6). though adenocarcinoma is the most commonly encountered malignant histopathologic diagnosis of prostate, there are also substantial numbers of variant pathologies associated with primary adenocarcinoma(7). however, variant pathologies are suggested to be associated with higher isup scores and worse prognoses including earlier biochemical recurrence and metastatic lesions at an earlier course of the disease(8,9). although many studies have been conducted on different b-values in the diagnosis of prostate cancer, there is no study in the literature on prostate cancer variants (10,11). nonetheless, if this accuracy can be determined in advance with mpmri for variant pathologies related to prostate cancer, more accurate and faster planning for a treatment modality might be possible. therefore, in this study, it was aimed to determine the role of mpmri to differentiate rare variant pathologies related with prostate cancer. urology journal/vol 20 no. 3/ may-june 2023/ pp. 157-161. [doi:10.22037/uj.v20i.7468] materials and methods in this retrospective cohort study, we analyzed the pathology reports of all consecutive patients who underwent radical prostatectomy operation in our university-based hospital between october 2014 and october 2019. in all mri recordings similar protocol settings were utilized with the same software and scanner hardware which is 1.5t ge signa voyager (general electric, milwaukee, wi). in supine position, anterior surface and posterior multiphase array coils were used in all imaging studies. our mpmri protocol included axial t1 (tr 595, te 12), axial, sagittal and coronal t2-weighted (te 107, tr 4400), diffusion-weighted (dw) (b-values of 400, 800 and 1400 mm/s2), and dynamic contrast-enhanced (dce) sequences. dynamic contrast enhancement (dce) technique: axial plan t1 gre, injection: 0.1 mmol/kg at 3 ml/s. field of view (fov): 120200 mm and slice thickness 3 mm for all images and no gap. adc calculation of high b-value 1400 s/mm². diffusion-weighted mri apparent diffusion coefficient (adc) and dce subtract maps (sub, computed as the difference between the phase corresponding to the contrast bolus arrival and the baseline phase) were computed using the scanner software. all patients’ mpmri records which are retrospective in nature were re-verified for their imaging findings by an expert radiologist (5 year-experience in prostate mpmri interpretation). for each study, the diagnostic quality and that sub was based upon subtraction of baseline pre-contrast images from first bolus arrival phase were confirmed. regions of interest (roi) were manually outlined on the t2 ax, adc, and sub series for the tumor-suspicious area, monitoring the matching slice in all other series for the given study. overall, pi-rads v2 was assessed for each study with automatically calculated mean adc value for the roi areas. clinical and demographic data of all patients who underwent radical prostatectomy during above dates were noted including associated variant pathologies and reports of preoperative mpmri images, if performed, were noted. patients with prostate cancer, mpmri-associated contrast enhancement, t2 signals, apparent diffusion coefficients (adc), and age and psa values were compared with the control group patients. statistical analyses were performed with spss statistics software (ibm corp. released 2011. ibm spss statistics for windows, version 20.0. armonk, ny: ibm corp.). comparisons of groups were done with chisquare test and student’s t test where appropriate. the mean values were presented with their 95% confidence intervals. roc curve was used to illustrate related sensivity and specificity of adc values. statistical significance was set at less than 0.05. results a total of 247 consecutive patients who underwent radical prostatectomy were included in the study. the mean age of all patients were 62.82 years (95% confidence interval (ci) 62.05-63.63 ). mean body-mass index (bmi) of the patients was 26.79 kg/m2 (95% ci 26.31-27.27). mean preoperative psa value was 13.84 ng/ml (95% ci 11.46-16.22). approximately two-thirds of the patients had one or more co-morbid diseases with the commonest ones as hypertension (41%), diabetes mellitus (20%) and cardio-vascular diseases (15%). the histopathological isup grade of prostate adenocarcinoma was ≤ 2 in 78% and ≥ 3 in the rest. patients were followed up with a mean follow up time of 4.05 ± 1.73 years. of the total patients, 70% received no further adjuvant therapy, whereas 28% received further radiotherapy with or without androgen deprivation therapy. the rest 2% received androgen deprivation therapy only. four percent progressed clinically to necessitate chemotherapy. sixty-three of all patients (26%) were associated with variant pathology and 14 (22%) had mpmri prior to primary prostate biopsy. associated variant prostate cancer pathologies were intraductal type adenocarcinoma (79%), foamy gland type adenocarcinoma (14%), and ductal type adenocarcinoma (7%). the mean age and bmi of the patients or rates of co-morbidities did not differ statistically between groups of prostate adenocarcinomas with or without asmpmri in prostate cancer variant pathologieskoseoglu et al. variant pathology absent variant pathology present p value surgical margin negative 131 (73%) 28 (44%) surgical margin positive 48 (27%) 35 (56%) < 0.001 extracapsular extension (ece) absent 143 (80%) 38 (60%) extracapsular extension (ece) present 37 (20%) 25 (40%) 0.004 lymphovascular invasion negative 162 (90%) 41 (65%) lymphovascular invasion positive 18 (10%) 22 (35%) < 0.001 perineural invasion negative 56 (31%) 13 (21%) perineural invasion positive 124 (69%) 50 (79%) 0.144 pn 168 (93%) 49 (78%) pn+ 12 (7%) 14 (22%) 0.001 table 1. the pathological prognostic factors compared according to the presence of associated variant pathology. variant pathology absent variant pathology present mean [%95 ci] mean [%95 ci] p value preoperative psa (ng/ml) 7.99 [6.07-9.91] 12.96 [8.49-17.43] 0.064 preoperative psa density (ng/ml2) 0.33 [0.26-0.41] 0.46 [0.33-0.59] 0.095 adc (mm2/sec) (b=400) 1136 [911.12-1360.88] 1124.64 [906.74-1342.54] 0.709 adc (mm2/sec) (b=800) 937.20 [740.18-1134.22] 919.57 [740.69-1098.45] 0.585 adc (mm2/sec) (b=1400) 702.30 [583.48-821.12] 661.86 [517.70-806.01] 0.666 table 2. psa, psa density, and diffusion pattern values of all prostate cancer patients compared according to the presence of variant pathology. vol 20 no 3 may-june 2023 158 urological oncology 159 sociated variant pathology. the pathological prognostic factors related to the prostate specimen including surgical margin involvement, presence of extracapsular extension, lymphovascular invasion, perineural invasion and tumoral pelvic lymph nodal involvement (pn+) are compared according to the presence of associated variant pathology in table 1. in both groups, perineural invasion was similarly higher but all other worse prognostic factors were significantly higher in the variant associated group. figure 1. variant focal point in the left peripheral zone with hypointensity on t2-weighted image (a), hyperintensity on diffusion-weighted (b-1400) image (b), decreased apparent diffusion coefficient (elips) (c), and focal early enhancement on dynamic mri (d). figure 2. roc curve analysis of all adc values including b values for 400, 800, and 1400 to discriminate variant associated pathology. mpmri in prostate cancer variant pathologieskoseoglu et al. psa and psa density values together with diffusion pattern values are shown in table 2. a variant focal point in the left prostatic lobe which shows diffusion restriction (b: 1400) on the adc map is shown in figure 1. when compared in terms of mpmri parameters, those with variant pathologies and the control group had similar perfusion curves and increased contrast values, but different adc values for each of the adjusted b values for 400, 800, and 1400, however, this result was statistically insignificant. a roc curve analysis of all adc values including b values for 400, 800, and 1400 to discriminate variant associated pathology from acinar prostate carcinoma is shown in figure 2. when adc values were analyzed in subgroups of isup grades (≤ 2 versus ≥ 3) adc values did not differ significantly in whole or subgroups of prostate cancer according to the presence of variant pathology. discussion for the management of prostate cancer, not only early diagnosis of prostate cancer but also identification of its associated prognostic factors like associated variant pathology is uttermost important due to its worse prognosis(8,9). multiparametric mri has been proven to have better diagnostic ability with its included multiple various sequences, in prostate cancer and today it provides valuable information in the staging, risk assessment and diagnosis of clinically significant prostate cancer within the prostate imaging reporting and data system (pi-rads) scoring which was created by the european society of urogenital radiology (esur) first created this system in 2012 and further improved with the joint participation of esur, the american college of radiology (acr)(3,4). in prostate cancer, the permeability of water molecules in the intracellular and extracellular environment is blocked by cell membranes, thereby inhibiting the diffusion of water molecules. this diffusion restriction is measured by the b-value and adc. the b-value in dwi shows the strength and timings of magnetic field gradients applied to the patient therefore reflecting the diffusion. adc in diffusion-weighted imaging is a quantitative measurement of the current and the distance that water molecules move. while the b-value in prostate cancer is found to be higher than that of in the normal tissue, the adc value is found lower(3). it is recommended to use at least two b-values which are 50–100 sec/mm2, 800–1000 sec/ mm2 or if possible 1400 –2000 sec/ mm2(3). therefore, in this study, we presented three different b values of 400, 800, and 1400 sec/ mm2 and compared results for each of them. in general practice, after the patient is informed about the morbidity and mortality of the supposed treatments according to the patient's age, chronic diseases, sexual activity expectation, and anxiety status; (open, laparoscopic, or robotic) radical prostatectomy, radiotherapy, hormone therapy, active follow-up, watchful waiting, or their combination modalities are determined together with the patient. this delicate decision making might be harder with upgraded isup in radical prostatectomy specimen and associated variant pathologies(12). the who classification has defined variant pathologies associated with prostate cancer(13). here in our patients the common associated variant pathologies were intraductal type, foamy gland type and ductal type in decreasing order. however, variant pathologies are not mpmri in prostate cancer variant pathologieskoseoglu et al. always detected even histopathologically as they were shown to be deceptively benign-appearing variants(14). more care has to be taken during the management of prostate cancer with associated variant pathology as its prognosis worse compared to the acinar prostate adenocarcinoma(2,3). intraductal carcinoma of the prostate (idc-p) has been suggested to show a strong association with aggressiveness of prostate cancer, with a significantly higher frequency in high-risk disease(15). it was suggested that recognition and systematic reporting of idc-p might improve patient risk stratification(15). there is very scarce data related to adc values in diagnosis of variant pathologies associated with prostate carcinoma. therefore, our study provides a clinical data related to use of adc values to identify this clinically important associated variant pathology. in another recent study, adc values of 15 patients with gleason score 7 and intraductal component (idc) prostate cancer was compared with two 15-patient nonidc groups with gleason score 7 and >7(16). there was found no significant difference in mean adc, which is the similar result in our study which included more patients and more variant subtypes(16). in our study, the patients with the variant pathologies and the patients without associated variant pathologies had similar perfusion curves and increased contrast enhancements and those values were not statistically significant. however, the b values set for 400, 800, and 1400 each had different adc values. the low number of sample groups in both studies prevents reaching a definitive conclusion. conclusions in this small cohort, mpmri appears to have no role in distinguishing rare variant pathologies associated with prostate adenocarcinoma despite different adc values. therefore, further studies with higher number of patients are needed to support or discard the possible diagnostic ability of mpmri for identification variant pathology. acknowledgement it was presented as poster in the 40th congress of the société internationale d’urologievirtual, 10-11 october 2020. conflict of interest the authors declare that they have no conflicts of interest. references 1. sung h, ferlay j, siegel rl, laversanne m, soerjomataram i, jemal a et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021; 71:209-49. 2. catalona wj, richie jp, dekernion jb, ahmann fr, ratliff tl, dalkin bl et al. comparison of prostate specific antigen concentration versus prostate specific antigen density in the early detection of prostate cancer: receiver operating characteristic curves. j urol. 1994; 152:2031-6. 3. barentsz jo, richenberg j, clements r, choyke p, verma s, villeirs g, et al; european society of urogenital radiology. esur vol 20 no 3 may-june 2023 160 prostate mr guidelines 2012. eur radiol. 2012; 22:746-57. 4. turkbey b, rosenkrantz ab, haider ma, padhani ar, villeirs g, macura kj, et al. prostate imaging reporting and data system version 2.1: 2019 update of prostate imaging reporting and data system version 2. eur urol. 2019; 76:340-51. 5. ueno y, takahashi s, ohno y, kitajima k, yui m, kassai y, et al. computed diffusionweighted mri for prostate cancer detection: the influence of the combinations of b-values. br j radiol. 2015; 88:20140738. 6. syer tj, godley kc, cameron d, malcolm pn. the diagnostic accuracy of high b-value diffusionand t2-weighted imaging for the detection of prostate cancer: a meta-analysis. abdom radiol (ny). 2018; 43:1787-97. 7. humphrey pa. histopathology of prostate cancer. cold spring harb perspect med. 2017 ;7:a030411. 8. mazzucchelli r, lopez-beltran a, cheng l, scarpelli m, kirkali z, montironi r. rare and unusual histological variants of prostatic carcinoma: clinical significance. bju int. 2008; 102:1369-74. 9. zelic r, giunchi f, fridfeldt j, carlsson j, davidsson s, lianas l, et al. prognostic utility of the gleason grading system revisions and histopathological factors beyond gleason grade. clin epidemiol. 2022 18; 14:59-70. 10. rosenkrantz ab, hindman n, lim rp, das k, babb js, mussi tc,et al. diffusion-weighted imaging of the prostate: comparison of b1000 and b2000 image sets for index lesion detection. j magn reson imaging. 2013; 38:694-700. 11. ueno y, kitajima k, sugimura k, kawakami f, miyake h, obara m,et al. ultra-high b-value diffusion-weighted mri for the detection of prostate cancer with 3-t mri. j magn reson imaging. 2013; 38:154-60. 12. watts k, li j, magi-galluzzi c, zhou m. incidence and clinicopathological characteristics of intraductal carcinoma detected in prostate biopsies: a prospective cohort study. histopathology. 2013; 63:574-9. 13. humphrey pa, moch h, cubilla al, ulbright tm, reuter ve. the 2016 who classification of tumours of the urinary system and male genital organs-part b: prostate and bladder tumours. eur urol. 2016; 70:106-19. 14. humphrey pa. variants of acinar adenocarcinoma of the prostate mimicking benign conditions. mod pathol. 2018;31: s6470. 15. porter lh, lawrence mg, ilic d, clouston d, bolton dm, frydenberg m, et al. systematic review links the prevalence of intraductal carcinoma of the prostate to prostate cancer risk categories. eur urol. 2017; 72:492-5. 16. currin s, flood ta, krishna s, ansari a, mcinnes mdf, schieda n. intraductal carcinoma of the prostate (idc-p) lowers apparent diffusion coefficient (adc) values among intermediate risk prostate cancers. j mpmri in prostate cancer variant pathologieskoseoglu et al. magn reson imaging. 2019; 50:279-87. urological oncology 161 urol_montage.pdf sexual dysfunction and infertility 40 urology journal vol 6 no 1 winter 2009 andropause in indian men a preliminary cross-sectional study apul goel, rahul janak sinha, divakar dalela, satyanarain sankhwar, vishwajeet singh introduction: the purpose of this study was to determine the frequency of androgen decline in the aging male (adam) in a group of indian men working in the health sector. materials and methods: a free medical health checkup camp was organized for the male workers aged between 40 and 60 years employed in surgical departments of our hospital. of 180 listed male workers, 170 attended this camp and 157 eligible men participated in the study. after clinical history and systemic inquiry, the participants were requested to complete the saint louis university’s adam questionnaire, and their serum levels of free and total testosterone were measured. results: symptomatic andropause was found in 106 men (67.5%) on the basis of their responses to the questionnaire, of whom 41 (38.7%) had low serum free testosterone levels and 32 (30.2%) had low serum levels of total testosterone. fifty-one men were asymptomatic according to the questionnaire and in this group, 11 (21.6%) had low serum free testosterone levels and 6 (11.8%) of these had low total testosterone levels. the frequency of andropause was 33.1% on the basis of low serum free testosterone levels and it was 26.1% when both symptoms and low serum free testosterone levels were taken into account. conclusion: in our study, the high frequency of symptoms related to adam was unusual. this might be due to the nature of the questionnaire itself. serum free testosterone measurement may be a better single test for diagnosis of hypogonadism than serum total testosterone measurement. urol j. 2009;6:40-6. www.uj.unrc.ir keywords: andropause, aging, epidemiology, india department of urology, chhatrapati shahuji maharaj medical university, lucknow, uttar pradesh, india corresponding author: rahul janak sinha, ms, mch c/o dr sheela sharma, o/83, doctor’s colony, kankarbagh, patna 800020, bihar, india tel: +91 941 500 3051 e-mail: rahuljanaksinha@rediffmail.com received september 2008 accepted december 2008 introduction andropause or androgen decline in the aging male (adam) is a syndrome characterized by multiple clinical manifestations including erectile dysfunction, decreased libido, osteoporosis, generalized weakness, etc. its occurrence is poorly documented and dichotomy exists regarding a true and accurate definition. clinical diagnosis is problematic, since either serum testosterone levels or symptoms cannot accurately predict this condition. for diagnostic purpose, clinical judgment along with symptoms and a low testosterone level is considered important. this scenario is not always achievable and in such cases, a therapeutic trial is acceptable on the basis of symptoms alone.(1) most of the literature on this subject is from europe or north america.(2) we report a preliminary study documenting the frequency of adam in men aged between 40 and 60 years living in a city in india. andropause in indian men—goel et al urology journal vol 6 no 1 winter 2009 41 material and methods a general free-of-charge health checkup camp was advertised and mandated for all male employees aged between 40 and 60 years working in various subspecialties of surgical departments (including surgical gastroenterology, urology, neurosurgery, etc) in various capacities such as clerks, ward and operation theatre assistants, nurses, etc. this was done in order to assess andropause frequency by a standardized questionnaire and to obtain blood sample for serum testosterone estimation. we screened volunteers for any coexisting disease and excluded those having chronic liver disease, chronic kidney disease, chronic heart disease, or any other diseases or conditions requiring medications that could affect serum testosterone assay. ethical clearance for this study was obtained from the institutional ethics committee and was in accordance with the declaration of helsinki. this camp was organized for a 1-week period in april, 2007. the workers who presented in the morning would undergo the free checkup camp if they had not attended a night duty the previous night. all participants were asked to fill a form comprising of information on age, occupation, comorbid conditions, drug intake, and past illnesses. a thorough physical examination was done. investigations deemed necessary to rule out any coexisting disease or even other investigations not related to andropause per se were done for free (eg, ultrasonography for benign prostatic enlargement, urinalysis for those complaining of burning in micturition, blood glucose estimation for diabetics complete blood count, serum creatinine estimation, liver function tests, electrocardiography, and ultrasonography of the abdomen if required). we used an interviewer-administered vernacular version of the saint louis university’s adam questionnaire (appendix).(1,3) an interviewer who understood the significance and meaning of these questions asked the questions in hindi language which is the spoken language in the northern india. serum testosterone (total and free) level estimation was performed simultaneously using enzyme-linked immunosorbent assay (drg international inc, mountainside, new jersey, usa). blood samples for this purpose were withdrawn between 8 am to 11 am. the reference range of serum total testosterone for men was between 2 ng/ml and 6.9 ng/ml and that of free testosterone level was 15 ± 7 pg/ml as per the standardized value with the enzymelinked immunosorbent assay kit. the upper and lower limits of the serum testosterone might vary between different populations and also according to the laboratory kit being used for measurement. the measurement was standardized according to the information supplied by the manufacturer of this kit. results of the 180 listed male workers who were between 40 and 60 years old, 170 attended the free health camp. the volunteers were informed about the plan of this camp for doing a free survey for andropause. this was done when they came to the camp in order to prevent selection/participation bias. their consent was taken for enrolling them in the andropause survey. of 170 participants, 157 were found eligible and were included in this study. thirteen volunteers were excluded because of having comorbid conditions including diabetes mellitus (6 patients), hypertension (6 patients), and others (1 with vitiligo who was on intermittent phototherapy). the mean age of the enrolled volunteers was 53.1 years (range, 40 to 60 years). the mean body weight was 64.3 kg (range, 54 kg to 78 kg) and the mean height was 167.4 cm (range, 158 cm to 180 cm). on the basis of the saint louis university’s adam questionnaire, 106 of the total of 157 participants (67.5%) tested positive for symptoms of andropause (mean age, 53.5 years; range, 40 to 60 years), of whom 41 (38.7%) were found to have a serum free testosterone level lower than the normal (mean, 5.55 pg/ ml; range, 3.09 pg/ml to 7.08 pg/ml) and 32 (30.2%) had a low total testosterone level (mean, 1.5 ng/ml; range, 1.1 ng/ml to 1.9 ng/ml). the remaining 33 symptomatic men had normal total and free testosterone levels (mean age, 51.8 years; range, 40 to 60 years). fifty-one of the 157 participants were asymptomatic (32.5%) on the basis of the answers to the questionnaire, 11 of andropause in indian men—goel et al 42 urology journal vol 6 no 1 winter 2009 these men (21.6%; mean age, 55.1 years; range, 46 to 60 years) were found to have low serum free testosterone levels (mean, 6.4 pg/ml; range, 4.1 pg/ml to 7.4 pg/ml) and 6 (11.8%) had low serum total testosterone levels (mean, 1.4 ng/ml; range 1.2 ng/ml to 1.9 ng/ml). discussion the exact prevalence of adam is not known; however, it is anticipated that as the life span of human beings is increasing, the prevalence of this condition is also on the rise. the massachusetts male aging study reported a crude incidence rate of 12.3 per 1000 person-years, leading to a prevalence of 481 000 new cases of adam per year in american men aged 40 to 69 years old.(2) the prevalence of adam has not been reported from most of the asian countries and few reports exist regarding the status of adam in asia.(4-6) to estimate the prevalence of this condition in india, we performed a pilot study in a small number of volunteers working in the surgical departments at our hospital. india is a conservative country and many in the age group of 40 to 60 years are not comfortable in talking about their sexual life. we had the feeling that if we announced a camp only for andropause then it might not attract enough participants and perhaps even lead to selection/ participation bias. therefore, we decided to name this camp a free general health checkup camp, but those referred were first fully informed of the program. in this manner, voluntary participation was increased while the chances of selection/ participation bias (that volunteers with some sexual problems only will attend the camp) were minimized. of the 3 commonly used questionnaires,(1) the saint louis university’s adam questionnaire was chosen because of its simplicity. this questionnaire has been tested and reported previously.(3,7) ideally, the questionnaire should been validated in indian population before its use, but the saint louis university’s adam questionnaire has not been validated in indian population and this is one of the weaknesses of this study. in our study an unusually high number of volunteers, 106 of 157 (67.5%), reported symptoms of adam on the basis of the saint louis university’s questionnaire. this high frequency of andropause seen in our study could be due to the nature of the questionnaire itself. the questionnaire was structured on a “yes/no” format and the volunteers did not have the scope of reporting that they had only mild symptoms. many volunteers who had mild symptoms might have been wrongly picked up as symptomatic for andropause on the basis of this questionnaire. some questions like “have you noticed a recent deterioration in your ability to play sports?” may not be relevant in some countries like india where most people above 40 years of age do not play sports. similarly, many of our volunteers reported that answers to questions 2, 3, 8, and 10 were quite close to each other (appendix). the saint louis questionnaire states that if the answer to question 1 or question 7 is “yes,” then the patient is considered to be most probably positive for andropause. these two questions are direct and most of the patients who were positive for andropause on the basis of symptoms answered “yes” to these two questions. on the basis of serum biochemical evaluation, 52 of 157 participants (33.1%) were found to have low free serum testosterone levels. however, the serum total testosterone levels were found to be low in 38 participants (24.2%) only. this could have happened due to the fact that normal total testosterone levels have a wide normal range and do not decline as rapidly as do free and bioavailable (free and albuminbound) testosterone concentrations.(8-11) the more pronounced decrease in free compared to total testosterone is explained by the agedependent increase in the binding capacity of sex hormone-binding globulin (1.2% per year). many investigators have suggested that measurement of bioavailable and/or free testosterone is a better investigation for diagnosing andropause.(12,13) the ideal test in men suspected of hypogonadism is the measurement of free testosterone by the equilibrium dialysis method.(13) this method is difficult to perform, not automated and inaccessible to most clinicians. measurement of free testosterone by radioimmunoassay method is widely available but unreliable.(13) we have evaluated serum testosterone levels using the andropause in indian men—goel et al urology journal vol 6 no 1 winter 2009 43 enzyme-linked immunosorbent assay which is a reliable method. the reported prevalence of biochemical hypogonadism is about 7% in the age group younger than 60 years old and increases to 20% in those older than 60 years.(14) in the present study, biochemical hypogonadism (based on more accurate serum free testosterone levels) was observed in 52 (33.1%) out of 157 participants while 41 volunteers (26.1%) revealed both symptomatic as well as biochemical hypogonadism (positive symptoms as well as low free serum testosterone levels). the frequency of biochemical hypogonadism reported in our study (33.1%) is similar to that found in a study on 316 canadian physicians aged 40 to 62 years. low bioavailable testosterone levels (< 70 ng/dl) were present in 25% of these physicians; the questionnaire identified this group with a sensitivity of 88% and a specificity of 60%.(3) serum testosterone levels show diurnal variation and there is also substantial variation (~20%) from week to week.(15) therefore, 2 testosterone measurements at least a week or two apart are recommended for diagnosing adam and starting treatment.(1) we measured serum testosterone at a single point which may have overestimated or underestimated this condition and this is another weakness of this study. given this fact, the volunteers who were diagnosed as having adam were informed about the shortcomings of this study. they were advised not to start any treatment until and unless they underwent further tests to confirm the findings of this study. also, the considerable number of patients with symptoms of hypogonadism on the basis of questionnaire but with normal serum testosterone levels found in our patients could be because of the nature of the adam questionnaire itself. another weakness of this study is the small number of participants on the basis of which it would be difficult to comment whether the findings reflect the corresponding male population in the entire country. it would suffice to state at this point that all queries cannot be answered through this pilot study alone. the frequencies were not calculated separately for individual age groups due to small numbers in such subgroups. on statistical analysis, the small numbers in individual subgroups did not justify any comment on the impact of age on the frequency of adam in these volunteers. the strength of this study lies in the fact that it was conducted on a well-selected population employed in the health sector. the participants were literate and provided complete information related to their medication and treatment history. they were unaware of the real purpose of this study before inclusion and they were able to give feedback regarding the problems or confusions that they had in answering the saint louis university’s questionnaire. validating any questionnaire requires money, manpower, and justification for conducting such an exercise. this study perhaps lays some groundwork to conduct further studies either to validate such questionnaires in the indian population or to estimate the prevalence in indian men on a larger scale. the need of the hour is perhaps a questionnaire constructed with indian population in mind which is more in sync with our social customs. regarding biochemical indicators of adam, free serum testosterone levels may be a better test to diagnose adam.(1) other biochemical parameters need to be discovered, which will make the task of defining andropause easier. conclusion on the basis of this study, it seems that adam is prevalent in our country. validated questionnaires and further studies may shed more light on the concept of adam. acknowledgement we would like to thank the members of the research cell of chhatrapati shahuji maharaj medical university (king george’s medical university), lucknow, india for approving this research project and giving us the financial aid which made this study possible. the authors thank dr rupin shah ms, mch (consultant urologist and andrologist, mpuh, nadiad, india) for his constant support and guidance. andropause in indian men—goel et al 44 urology journal vol 6 no 1 winter 2009 appendix the androgen deficiency in aging male (adam) questionnaire(1) a positive answer represents yes to 1 or 7 or any 3 other questions 1. do you have a decrease in libido? yes/no 2. do you have a lack of energy? yes/no 3. do you have a decrease in strength and/or endurance? yes/no 4. have you lost height? yes/no 5. have you noticed a decreased enjoyment of life? yes/no 6. are you sad and/or grumpy? yes/no 7. are your erections less strong? yes/no 8. have you noticed a recent deterioration in your ability to play sports? yes/no 9. are you falling asleep after dinner? yes/ no 10. has there been a recent deterioration in your work performance? yes/no conflict of intrest none declared. references 1. morales a, morley j, heaton jpw. androgen deficiency in the aging male. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 850-62. 2. araujo ab, o‘donnell ab, brambilla dj, et al. prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the massachusetts male aging study. j clin endocrinol metab. 2004;89:5920-6. 3. morley je, charlton e, patrick p, et al. validation of a screening questionnaire for androgen deficiency in aging males. metabolism. 2000;49:1239-42. 4. li jy, li xy, li m, et al. decline of serum levels of free testosterone in aging healthy chinese men. aging male. 2005;8:203-6. 5. reyes ja, 3rd, tan da, quimpo ja, et al. the philippine male aging survey. aging male. 2004;7:22735. 6. ichioka k, nishiyama h, yoshimura k, itoh n, okubo k, terai a. aging males’ symptoms scale in japanese men attending a multiphasic health screening clinic. urology. 2006;67:589-93. 7. tancredi a, reginster jy, schleich f, et al. interest of the androgen deficiency in aging males (adam) questionnaire for the identification of hypogonadism in elderly community-dwelling male volunteers. eur j endocrinol. 2004;151:355-60. 8. vermeulen a. clinical review 24: androgens in the aging male. j clin endocrinol metab. 1991;73:221-4. 9. ferrini rl, barrett-connor e. sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. am j epidemiol. 1998;147:750-4. 10. morley je, kaiser f, raum wj, et al. potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. proc natl acad sci u s a. 1997;94:7537-42. 11. nahoul k, roger m. age-related decline of plasma bioavailable testosterone in adult men. j steroid biochem. 1990;35:293-9. 12. tenover js. declining testicular function in aging men. int j impot res. 2003;15 suppl 4:s3-8. 13. morales a, lunenfeld b. investigation, treatment and monitoring of late-onset hypogonadism in males. official recommendations of issam. international society for the study of the aging male. aging male. 2002;5:74-86. 14. vermeulen a, kaufman jm. ageing of the hypothalamo-pituitary-testicular axis in men. horm res. 1995;43:25-8. 15. morley je, patrick p, perry hm, 3rd. evaluation of assays available to measure free testosterone. metabolism. 2002;51:554-9. editorial comment the paper by goel and colleagues addressed an important but neglected issue in the field of men’s health. the international society for the study of the aging male has considered the process of andropause as a “syndrome.” this syndrome is characterized by decreased serum androgen, with or without a decreased genomic sensitivity to androgens.(1) due to the lack of a universally accepted definition for andropause, limited ‘‘reliable’’ data exist on its real prevalence. this study has shown symptomatic andropause in 67.5% of studied men aged from 40 to 60 years, which seems very high. different values and subtypes of measured testosterone used in different studies make it difficult to compare their results to the existing epidemiological data. nevertheless, in a wellandropause in indian men—goel et al urology journal vol 6 no 1 winter 2009 45 conducted longitudinal study by harman and coworkers, the reported rates for reduced levels of free testosterone were 9% for men aged from 50 to 59 years and 34% for men aged between 60 and 69 years.(2) the prevalence of hypogonadism in other studies is similar. wishart and colleagues demonstrated that 25% of men over 65 years old have serum testosterone levels less than 300 ng/dl.(3) for detecting hypogonadism, the saint louis university’s androgen decline in the aging male questionnaire is a valid test, but its specificity is low.(4) this tool must be coupled with a complete clinical evaluation, and the definition of hypogonadism should depend on both biochemical and functional criteria.(5) nowadays, bioavailable testosterone testing in replacement of or addition to the traditional total testosterone and direct free testosterone assays is recommended. it more accurately reflects the clinical androgen state of the patient.(6) in addition, there is considerable interindividual and intra-individual variability in androgen levels. at least 2 samples in different days are needed to draw accurate estimation of serum androgen. additionally, indicative threshold for hypoandrogenemia is an important issue. usually, the lower limit of the reference range in young men is used for defining a cutoff value for hypoandrogenemia in elderly men.(7) a low testosterone level can also be indicative of an underlying pituitary disorder; therefore, measurement of serum luteinizing hormone and follicle-stimulating hormone might be helpful for distinguishing between these two entities (true andropause and pituitary disorder). the clinical significance of serum androgens declines in aging men is still unclear, and there is disagreement as to whether a specific syndrome of androgen deficiency or “andropause” exists. therefore, further well-designed, and largepopulation-based studies in different ethnicities are needed to establish the accurate prevalence of andropause and its clinical implications in aged men. mohammad reza safarinejad associate editor, urology journal references 1. morales a, lunenfeld b. investigation, treatment and monitoring of late-onset hypogonadism in males. official recommendations of issam. international society for the study of the aging male. aging male. 2002;5:74-86. 2. harman sm, metter ej, tobin jd, pearson j, blackman mr. longitudinal effects of aging on serum total and free testosterone levels in healthy men. baltimore longitudinal study of aging. j clin endocrinol metab. 2001;86:724-31. 3. wishart jm, need ag, horowitz m, morris ha, nordin be. effect of age on bone density and bone turnover in men. clin endocrinol (oxf). 1995;42:141-6. 4. martinez-jabaloyas jm, queipo-zaragoza a, rodriguez-navarro r, queipo-zaragoza ja, gil-salom m, chuan-nuez p. relationship between the saint louis university adam questionnaire and sexual hormonal levels in a male outpatient population over 50 years of age. eur urol. 2007;52:1760-7. 5. morley je. the need for a men’s health initiative. j gerontol a biol sci med sci. 2003;58:614-7. 6. lepage r. measurement of testosterone and its subfractions in canada. clin biochem. 2006;39:97-108. 7. t’sjoen g, goemaere s, de meyere m, kaufman jm. perception of males’ aging symptoms, health and well-being in elderly community-dwelling men is not related to circulating androgen levels. psychoneuroendocrinology. 2004;29:201-14. reply by author as the average lifespan is increasing across the globe due to better healthcare, the entity lateonset hypogonadism (loh) is being appreciated more by the physicians. interest in this field has increased exponentially over the last decade and has led to further research and development of better tools for investigation. leading luminaries in this field are working closer to reach common ground.(1) this means that the current set of recommendations are undergoing changes and it might be a while before consensus is reached on how to define andropause, whom to define as “andropausal,” and how to treat this entity. we used the androgen decline in the aging male (adam) questionnaire and assessed serum testosterone values (both total and free) to reach our conclusions; so our results are still consistent with the latest recommendations as they are based on both symptomatic as well as biochemical analyses.(1) we agree with dr andropause in indian men—goel et al 46 urology journal vol 6 no 1 winter 2009 safarinejad that more studies on andropause in men from different ethnic backgrounds are needed. our study was a pilot project to estimate the probable frequency of symptomatic hypogonadism in a subpopulation of urban indian men. hence, follicle-stimulating hormone and luteinizing hormone were not assessed. we do not have access to assays of bioactive testosterone, so it could not be assessed. even though symptomatic hypogonadism was higher in our study, less than half the men who were symptomatic on the adam scale had low testosterone levels. this is consistent with the low specificity of the adam questionnaire. the incidence of symptomatic loh was 33.1% in this study. this is higher than reported by some studies(2); but is in keeping with the findings reported by others.(3) we sincerely hope that the current deliberations on loh by the international community shall help in establishing a format for research which is acceptable to the majority of physicians working in this field. comparisons of various aspects of loh amongst men from different ethnic backgrounds then may become easier. rahul janak sinha, vishwajeet singh department of urology, chhatrapati shahuji maharaj medical university, lucknow, uttar pradesh, india references 1. wang c, nieschlag e, swerdloff r, et al. investigation, treatment, and monitoring of late-onset hypogonadism in males: isa, issam, eau, eaa, and asa recommendations. eur urol. 2009;55:121-30. 2. harman sm, metter ej, tobin jd, pearson j, blackman mr; baltimore longitudinal study of aging. longitudinal effects of aging on serum total and free testosterone levels in healthy men. baltimore longitudinal study of aging. j clin endocrinol metab. 2001;86:724-31. 3. morley je, charlton e, patrick p, et al. validation of a screening questionnaire for androgen deficiency in aging males. metabolism. 2000;49:1239-42. urology journal peer review running head: laparoscopic versus open in pd catheter insertion laparoscopic versus conventional open peritoneal dialysis catheter insertion in china: a meta-analysis macheng lu1, cong cheng1, ye zhang1* 1 department of general surgery, nanjing medical university affiliated wuxi people's hospital, wuxi, jiangsu province, china. keywords: catheter placement; peritoneal dialysis; complications; meta-analysis; laparoscopy abstract purpose: to compare the risk of complications between laparoscopic peritoneal dialysis (pd) catheter placement and open pd catheter placement. methods: we searched numerous databases, including sinomed, cnki, cqvip, wanfang, pubmed, web of science, ovid, cochrane and scopus, for published randomized controlled trials (rcts) and non-randomized controlled trials (non-rcts) . results: ten studies were included(n=1341). the overall statistical results showed that patients receiving laparoscopic insertion of the pd catheter had a lower risk of catheter migration, inadequate drainage and blockage. the risk of leakage was higher in the laparoscopic group in studies performed prior to 2015; in studies performed after 2015, the risk of leakage was lower than in the conventional open-placement group. for the risk of developing pain, the risk was lower in the subgroup of laparoscopic patients starting pd within 1 day after catheter insertion; however, there was no significant difference between the subgroups starting pd 1 week or 2 weeks after catheter insertion. the risk outcome for abdominal bleeding was similar to that for pain, with a lower risk in the subgroup of laparoscopic patients starting pd within 1 day. the overall research quality was moderate. conclusion: laparoscopic placement of the pd catheter has unique advantages over conventional open surgical placement, especially in special conditions such as emergency initiation. in addition, we found that some factors that were previously considered irrelevant may have an impact on the results for asians. however, this conclusion still needs to be substantiated by further large samples in multicenter, high quality randomized controlled trials (rcts). introduction in recent years, with the increase in hypertension, type 2 diabetes and an ageing population, the number of people with end-stage renal disease (esrd) is increasing worldwide(1). renal replacement therapy, which is still the main treatment for esrd patients, involves renal transplantation, hemodialysis and peritoneal dialysis (pd). due to the shortage of kidney transplant donors, hemodialysis and pd are currently the main treatment options. compared to hemodialysis, pd offers lower treatment costs, easier access to treatment sites and less dietary control(2). however, the way in which pd catheters are inserted remains controversial. to determine the optimal approach for inserting the pd catheter, there have been several published meta-analyzes that have compared the open-surgery and laparoscopic methods in terms of the risk of complications(3-7). however, the results of these studies seem to be slightly different from our clinical experience in some aspects. we believe that regional differences are one of the reasons for this situation. therefore, we try to focus on a smaller scope, so as to reduce this bias, and further obtain more targeted and definite results. to provide more targeted basis for asian doctors to choose pd placement method. in this meta-analysis, we systematically reviewed and analyzed previous randomized controlled trials (rcts) and non-randomized controlled trials (non-rcts) that studied chinese pd patients to compare complications of laparoscopic and conventional open pd placement. methods protocol registration we registered the protocol for this meta-analysis with prospero (crd42022296373). search strategy we conducted a comprehensive search by searching the sinomed, cnki, cqvip, wanfang, pubmed, web of science, ovid , cochrane databases and scopus and obtained 4940 results. we searched all the literatures until november 1, 2021.we did not set any language restrictions and used the following mesh terms: "laparoscopes", "peritoneal dialysis", "catheters, indwelling" and their corresponding free words. we considered all potentially eligible studies for review, regardless of primary outcome or language. in addition, we also manually searched citations of key articles to obtain two relevant results. selection criteria we conducted the screening and selected controlled studies that met the criteria. we set the selection criteria for the meta-analysis in accordance with the picos criteria(8). the specific criteria were: 1) population: chinese patients with an esrd requiring dialysis treatment; 2) intervention: laparoscopic pd catheter placement; 3) comparison: conventional open pd catheter placement; 4) outcome: complications; 5) study design: clinical experimental studies including rcts and non-rcts. we excluded all studies that did not meet these requirements, including studies in which the subjects were designated as children and elderly, those in which the procedure involved an emergency start or a specific procedure, those involving the same sample, and those that did not meet the picos criteria described above. any disagreements that arose were communicated and resolved by a third investigator. the following data was extracted from each of the selected studies: total number of patients and groups, study approach, interventions, number of postoperative complications (including catheter shift, leak, peritonitis, exit-and-tunnel infections, inadequate catheter drainage, blockage, abdominal bleeding, pain, hernia). study risk of bias assessment: all selected studies were assessed for risk of bias by two independent researchers. rcts were assessed according to the revised cochrane risk-of-bias tool(9) for randomized trials, and nonrcts were assessed according to the minors(10). disagreements between the two investigators were resolved by a third investigator after discussion. resume the statistical analysis: we evaluated the outcomes of laparoscopic and conventional open surgery in pd placement by 9 outcome indicators: catheter shift, peritubular leakage, peritonitis, exit-site and tunnel infection, inadequate catheter drainage, blockage, abdominal bleeding, pain and hernia. and these indicators were used as dichotomous variables to calculate the relative risk (rr). in this meta-analysis, we used revman 5.4.1 software (revman international, inc., new york, ny, provided by the cochrane collaboration) and stata 17 (statacorp llc, inc., texas, provided by statacorp llc) for data analysis. we considered p ＜ 0.05 to be statistically significant. for dichotomous variable data, we used the mantel-haenszel method(11). we defined the criteria for heterogeneity (i²) as follows: i² ≤ 25 was considered ground heterogeneity; 25 ＜ i² ≤ 50 was considered medium heterogeneity; 50 ＜ i² ≤ 75 was considered high heterogeneity; and i²>75 was considered to be a large difference between studies. for studies with low and medium heterogeneity, we adopted a fixed effects model, while for studies with higher heterogeneity, we used a random effects model and use metaregression model to detect the source of heterogeneity. we explored the extent to which the studies influenced the combined effect size and the robustness of the results by excluding one study at a time, recalculating the combined effect size and comparing it with the results of the meta-analysis before the exclusion. if the results did not change significantly after the exclusion, the sensitivity was considered to be low and the results were regarded as more robust and credible. conversely, if the exclusion yielded widely different or even diametrically opposed conclusions, we considered this to indicate higher sensitivity and less robust results; therefore, great care was taken when interpreting the results and drawing conclusions. in this case, the results suggested the presence of important and potentially biasing factors related to the effect of the intervention, which required further clarification of the source of these factors and adjustment of possible influencing factors in subgroup analysis. we used gradepro 3.6 software (mcmaster university and evidence prime inc., hamilton, canada, provided by gradepro gdt) to assess the quality of the included studies. results study selection in the initial search, we obtained 4940 results. of these, 4938 were from databases and 2 were from citation searches of key literature. in the first screening, we selected 18 articles that might meet the requirements of this study by reading the title, authors and abstract. of these 18 articles, we excluded 8 by carefully reading the full text. ultimately, ten studies(12-21) with a total sample size of 1341 were included in this meta-analysis. four rcts(12-15) and six non-rcts(16-21) were included. the characteristics of these studies (country, design, sample size, age, follow-up and outcomes) are described in table 1. the screening process is represented in the flow diagram shown in figure 1. risk of bias in studies: as shown in figure 2, three rcts had moderate quality, as well as a lower risk of bias, with the exception of one study which was of low quality and had a higher risk of bias, according to the revised cochrane risk-of-bias tool for randomized trials. the six additional non-rcts were of moderate quality with an average score of 15 on the minors scale table 2. we use the funnel plot to estimate whether there is bias in the included study, and use the trim and filling method to determine whether the main source of bias is publication bias. sensitivity analysis: in conducting the sensitivity analyzes, we made decisions to exclude or perform subgroup analyzes as appropriate by carefully reading and analyzing the highly heterogeneous literature, followed by discussion. this is described below. catheter shift there were nine studies(13-21) that evaluated the occurrence of catheter dislocation in a total of 1251 patients. of these, 512 patients underwent laparoscopy for pd catheter placement, compared to 739 patients undergoing conventional open surgery. after statistical analysis, heterogeneity was very low (i² = 0%), so we used a fixed effects model. the results of the statistical analysis showed that patients who underwent laparoscopy for pd placement had a significantly lower risk of catheter migration (p ＜ .00001, rr = 0.15, 95% confidence interval [ci]: 0.07 to 0.29). this is shown in figure 3 ⅰ. leak all ten studies(12-21) evaluated the occurrence of leakage in a total of 1341 patients. of these, 559 patients underwent laparoscopy with pd catheter placement, while 782 patients underwent conventional open surgery. after statistical analysis, the heterogeneity was high (i² = 56%), so we used a random effects model. the results of the overall statistical analysis showed that patients who underwent laparoscopic pd placement had a higher risk of postoperative leakage than those who underwent conventional open surgery, but the results were not statistically significant (p = 0.80, rr = 1.11, 95% ci: 0.50 to 2.48; figure 3 ⅱ). we found that publication time is the main source of heterogeneity, after careful reading of the full text and discussion, we divided the ten studies with leakage in the outcomes into two subgroups by study date (post-2015(12,13,17,18) and pre-2015(14-16,19-21)) for statistical analysis, as shown in figure 3 ⅲ. both subgroups had low heterogeneity of studies within the group (study date after 2015, i² = 0%; study date before 2015, i² = 0%). the statistical results showed that in the post-2015 subgroup, patients who underwent laparoscopic pd placement had a significantly lower risk of postoperative leakage than controls who underwent conventional open surgical placement (p = .007, rr = 0.23, 95% ci: 0.08 to 0.67). conversely, in the pre2015 subgroup, traditional open pd placement was associated with a lower risk of leakage than laparoscopic pd placement (p = .0003, rr = 2.44, 95% ci: 1.50 to 3.99). in addition, there was significant heterogeneity between the two subgroups in the statistical analysis of this outcome (i² = 93.6%), which was highly suggestive that the date of the study was an important factor in the outcome. peritonitis ten studies(12-21) looked at the progression of peritonitis in 1341 patients. a total of 559 patients underwent laparoscopy for pd catheter insertion, compared to 782 patients who had opensurgery pd placement. we selected a fixed effects model because the heterogeneity was moderate (i² = 50%) after statistical analysis. the statistical analysis revealed a trend toward decreased incidence of postoperative peritonitis after laparoscopic pd installation compared to open-surgery placement, although the difference was not statistically significant (p =0.52, rr = 0.92, 95% ci: 0.73 to 1.18; figure 3 ⅳ). exit-site and tunnel infection in a total of 611 patients, seven investigations(12-14,17-19,21) looked at the occurrence of exit-site and tunnel infection. in these studies, 279 patients had laparoscopic pd catheterization versus 332 patients with conventional open-surgery insertion. heterogeneity was low (i² = 0%) after statistical analysis, hence a fixed effects model was chosen. the statistical analysis revealed that laparoscopic pd placement had a lower incidence of exit-site and tunnel infection compared to traditional open placement, although the difference was not statistically significant (p =0.31, rr = 0.72, 95% ci: 0.38 to 1.37; figure 3 ⅴ). inadequate catheter drainage a total of 580 patients were studied in five investigations(13,14,18-20) to see if they had inadequate catheter drainage. of these patients, 240 of them received laparoscopic pd catheter placement versus 340 patients who underwent traditional open-surgery insertion. heterogeneity was low (i² = 0%) after statistical analysis, hence a fixed effects model was adopted. patients who underwent laparoscopic pd installation had a significantly decreased risk of inadequate catheter drainage (p = .0010, rr = 0.33, 95% ci: 0.17 to 0.64), according to the statistical analysis (figure 3 ⅵ). blockage three studies(13,14,17) including a total of 213 patients looked at the incidence of blockage. a total of 105 patients had laparoscopic pd catheter implantation compared to 108 patients who underwent open surgery. we selected a fixed effects model since the heterogeneity was modest (i² = 0%) after statistical analysis. patients who underwent laparoscopic pd catheter implantation had a considerably decreased risk of catheter occlusion (p =0.05, rr = 0.31, 95% ci: 0.10 to 0.98), according to the statistical analysis shown in figure 4 ⅰ. abdominal hemorrhage four studies(17-20) evaluated the occurrence of abdominal bleeding in a total of 493 patients. of these, laparoscopic pd catheter placements were performed in 195 cases, while 298 cases underwent conventional open surgery. after statistical analysis, heterogeneity was moderate (i² = 42%), so we used a fixed effects model. the results of the statistical analysis showed a trend toward a lower incidence of abdominal hemorrhage with laparoscopic pd placement compared to conventional open-surgery placement, but the difference was not statistically significant (p =0.07, rr = 0.61, 95% ci: 0.36 to 1.03), as shown in figure 4 ⅱ. we performed a subgroup analysis based on the time of pd initiation after catheter placement. as hong et al. 2019(17) did not record the start time, it was excluded from the subgroup analysis. we divided the remaining three studies into groups '1 day' (1 study(18)) and '2 weeks' (2 studies(19,20)) according to the pd start delay. heterogeneity in the subgroups was low (group '1 day', i² = /; group '2 weeks', i² = 0%). in the subgroup starting pd on the same day, the risk of abdominal hemorrhage was lower in the laparoscopic group (p = .008, rr = 0.24, 95% ci: 0.08 to 0.69); in the subgroup starting 2 weeks after conventional surgery, there was little difference in the risk of abdominal hemorrhage between the laparoscopic and open-surgery groups (figure 4 ⅲ). pain a total of 799 patients were studied in four investigations(14,16,20,21) to see if they experienced pain. of these, 290 patients had laparoscopic pd catheter placement, whereas 509 had traditional open-surgery placement. we selected a random effects model because the heterogeneity was high (i² = 57%) after statistical analysis. the statistical analysis revealed a trend toward decreased pain occurrence with laparoscopic pd installation compared to open surgical placement, but the difference was not statistically significant (p =0.06, rr = 0.44, 95% ci: 0.18 to 1.05, figure 4 ⅳ). following sensitivity analyzes, we determined that differences in the time to begin pd after surgery were the most likely source of heterogeneity, so we decided to divide the four studies into three groups reflecting this statistic based on the delay before beginning pd: 2 weeks (2 studies(14,20)), 1 week (1 study(21)) and 1 day (1 study(16)). for these subgroups, the heterogeneity of studies was modest (group '2 weeks', i² = 37%; group '1 week', i² = /; group '1 day', i² = /). statistical results showed the risk of pain was significantly lower in the laparoscopic group than in the conventional open-surgery group in group '1 day' (p = .007, rr = 0.06, 95% ci: 0.01 to 0.47), while the laparoscopic group showed a lower tendency to develop pain at a start time of 1 week postoperatively, but the results were not statistically significant (p =0.08 rr = 0.60, 95% ci: 0.34 to 1.06). in the pd subgroup starting 2 weeks postoperatively, the difference between the laparoscopic and open-surgery groups was minimal (p = 0.48, rr = 0.61, 95% ci: 0.16 to 2.38; figure 4 ⅴ). hernias a total of 364 patients were studied in four studies(14,15,17,21) to determine if they developed hernias. in 156 of these cases, laparoscopic pd catheter implantation was performed, whereas 208 of the cases required open-surgery placement. we selected a fixed effects model since the heterogeneity was considerable (i² = 40%) after statistical analysis. the statistical analysis revealed a tendency toward decreased incidence of hernias with laparoscopic pd implantation compared to open surgical installation, but the difference was not statistically significant (p =0.69, rr = 0.81, 95% ci: 0.30 to 2.22); figure 4 ⅵ). publication bias after evaluation, we found that there was a large bias in the analysis involving leak, peritonitis, exit-site and tunnel infection and hernias. we used the trim and filling method to evaluate the source of bias, and finally ruled out the possibility that the bias mainly came from publication bias. certainty of evidence all of the statistical evidence was graded moderate or lower, and most of the reasons for downgrading the evidence were the risk of bias, as summarized below in figure 5. discussion in our statistics, patients who underwent laparoscopic pd placement had a significantly lower risk of catheter migration, poor drainage, blockage and pain compared to those who underwent conventional open surgery. most other indicators showed a trend toward a lower risk of complications in patients undergoing laparoscopy, although the results were not statistically significant. surprisingly, patients who underwent laparoscopic pd placement showed a trend toward a higher risk of catheter leakage in contrast to the other results in the overall statistics, but again the results were not statistically significant. catheter-related disfunction is a common cause of pd failure. the correct positioning of the catheter is one of the keys to effective pd — the catheter needs to be inserted correctly and stably into either the rectal bladder trap (in male patients) or the rectal uterine trap (in female patients). however, over time, various factors may cause the tip of the catheter to migrate out of the pelvis, thus severely compromising the effectiveness of pd(2). in the statistics of this study, we found that laparoscopy for pd placement significantly reduced the risk of catheter drift. this is most likely due to the advantages of laparoscopy in terms of visualization and operability, allowing operations such as fixation of the pd catheter to be performed under the scope. this is consistent with the results of previously published articles. leakage is likewise one of the complications that affects the outcome of pd(2). we found that taking 2015 as the boundary, the trend of catheter leakage in the previous and subsequent research results showed an opposite result. we speculate that this may be due to the impact of some asian studies published around 2015 on doctors' surgical decisions in asia (22,23). but this difference has been covered up in the global research. unfortunately, due to the lack of details included in the experiment, we cannot determine the main reason for this difference. infection is one of the most important factors affecting the outcome of pd. in our results, the laparoscopic pd placement method does not offer much advantage over the conventional open procedure in terms of reducing the risk of infection. this is in line with the findings of strippoli(24) and hagen(23). of the ten studies included in this meta-analysis, three explicitly stated that cephalosporin antibiotics (or vancomycin if the patient had a cephalosporin allergy) were used to prevent infection before and after placement; the other seven studies did not state the antibiotic used. such differences are likely to have biased the results.. in our statistics, we found that in studies with early postoperative initiation of pd, laparoscopy showed an advantage over conventional open surgery in terms of lower incidence of abdominal bleeding and pain; in studies with delayed initiation of pd, this advantage tended to be smaller with the conventional 2-week delayed initiation. the risk of peritoneal hemorrhage as well as pain was almost the same between the two groups in the study with delayed starts. the initiation of pd is generally at least two weeks after pd catheter placement(25). nowadays, pd has become one of the main choices for the treatment of acute kidney injury (aki). our results provide some basis for asian doctors to choose pd catheterization for aki patients who need early drainage. there were some limitations to our study. as there were too few rct studies, we also included non-rctshowever, patients with these non-rcts are grouped voluntarily after doctors introduce the advantages and disadvantages of the two surgical methods. there are significant subjective factors, which greatly increases the possibility of confounding bias in the study. also, these non-rcts did not indicate whether adjustment was made for confounding factors during the analysis of results, which further increased the obstacles to obtaining accurate results in this study. in the study of small sample, there may be sparse-data bias due to too few complications. in the analysis of some data, due to the increase of heterogeneity, the random effect model is used, which further improves the proportion of small sample research in the meta-analysis, thus increasing the possibility of sparse-data bias(26). as a result, some possible differences are covered up. according to our quality of evidence evaluation, the majority of the statistical analyzes had a moderate level of evidence, with two additional studies showing a low level. the included studies also failed to record many details, such as the type of catheter and the bmi, which are likely to have impacted the meta-analysis results. in addition, recent studies have found that serum potassium can be an independent risk factor for catheter dysfunction(27), however, no studies have considered serum potassium as an influencing factor in their studies, which is also likely to create bias. conclusion according to our analysis, laparoscopic pd placement significantly reduces the risk of catheter displacement, leakage, insufficient catheter drainage, and blockage in asian patients. in addition to these advantages, laparoscopic pd placement in patients upon emergency initiation of pd shows a reduction in abdominal bleeding and pain, but this advantage diminishes with the delay in pd initiation. overall, the laparoscopic technique should be one of the recommended procedures for pd placement under current general conditions and offers significant advantages over the traditional open-surgery procedure, especially in specific conditions such as emergency initiation. although our study still has limitations, it nonetheless provides a concrete answer to the current controversial surgical approach. however, more and larger rcts are still needed to provide stronger evidence for surgical options. acknowledgement we thank international science editing (http://www.internationalscienceediting.com) for editing this manuscript. conflict of interest all authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. references: 1. kanda h, hirasaki y, iida t, et al. perioperative management of patients with endstage renal disease. j cardiothorac vasc anesth. 2017;31(6):2251-2267 2. smith bm, dan ag. operative technique for laparoscopic placement of continuous ambulatory peritoneal dialysis catheter. j laparoendosc adv surg tech a. 2020;30(7):815819 3. hagen sm, lafranca ja, steyerberg ew, ijzermans jn, dor fj. laparoscopic versus open peritoneal dialysis catheter insertion: a meta-analysis. plos one. 2013;8(2):e56351 4. qiao q, zhou l, hu k, et al. laparoscopic versus traditional peritoneal dialysis catheter insertion: a meta analysis. ren fail. 2016;38(5):838-848 5. stack m, price n, ronaldson j, et al. laparoscopic versus open peritoneal dialysis catheter insertion for the management of pediatric acute kidney injury. pediatr nephrol. 2016;31(2):297-303 6. sun ml, zhang y, wang b, et al. randomized controlled trials for comparison of laparoscopic versus conventional open catheter placement in peritoneal dialysis patients: a meta-analysis. bmc nephrol. 2020;21(1):60 7. xie h, zhang w, cheng j, he q. laparoscopic versus open catheter placement in peritoneal dialysis patients: a systematic review and meta-analysis. bmc nephrol. 2012;13:69 8. centre for reviews and dissemination: systematic reviews: crd’s guidance for undertaking reviews in health care. york: university of york. 2006 9. higgins jp, altman dg, gøtzsche pc, et al. the cochrane collaboration's tool for assessing risk of bias in randomised trials. bmj. 2011;343:d5928 10. slim k, nini e, forestier d, et al. methodological index for non-randomized studies (minors): development and validation of a new instrument. anz j surg. 2003;73(9):712-716 11. mantel n, haenszel w. statistical aspects of the analysis of data from retrospective studies of disease. j natl cancer inst. 1959;22(4):719-748 12. jia bj, cao wj, li j. operational skills and clinical prognosis evaluation of peritoneal dialysis catheterization. china medical device information. 2019;25(08):44-45 13. li zl, li yl, a lm, li s, zhu zk. comparison of clinical efficacy between laparoscopic peritoneal dialysis catheterization and open peritoneal dialysis catheterization. xinjiang journal of traditional chinese medicine. 2018;36(01):28-30 14. xu t, zang l, xie jy, et al. efficacy and safety of laparoscopic and conventional placement of peritoneal dialysis catheters in patients with esrd. chinese journal of nephrology,dialysis & transplantation. 2010;19(05):430-434 15. qiao q, lu gy, xu dy, zhou xj, li l. a comparison of two methods for catheterization in peritoneal dialysis. jiangsu medical journal. 2012;38(23):2812-2814 16. ao x, zhou ql, nie wn, ouyang rl. clinical comparison of peritoneal dialysis catheter placement under laparoscope and by conventional surgical methods. chinese journal of blood purification. 2012;11(10):544-548 17. hong bl, zhang wy, li sp, et al. clinical advantages of laparoscopic tenckhoff tube. journal of critical care in internal medicine. 2019;25(02):139-140+143 18. tang lh, lin lg, ling jh, lin jp, xie p. comparison on the clinical efficacy of laparoscopic and open surgery in placement of peritoneal dialysis catheters. journal of qiqihar medical university. 2019;40(05):575-577 19. xie p, yuan l, liu f. the comparision of efficacy and safety between laparoscopic and conventional placement of peritoneal dialysis catheters. hebei medicine. 2014;20(04):562-566 20. xiong f, dong jw, li hb, et al. influence of laparoscopic peritoneal dialysis catheterization on postoperative complications. chinese journal of clinicians(electronic edition). 2011;5(06):1724-1727 21. zhou cm, zhao x, zhang jh, et al. comparison of laparoscopic and open surgical placement of peritoneal dialysis catheters. journal of xinjiang medical university. 2014;37(05):598-602 22. qiu h, hong m, zhang dw, zheng hg. comparison of coiled versus straight end peritoneal dialysis catheters on complication incidence and catheter survival: a meta analysis. chinese journal of blood purification. 2014;13(10):689-694 23. hagen sm, lafranca ja, ijzermans jn, dor fj. a systematic review and meta-analysis of the influence of peritoneal dialysis catheter type on complication rate and catheter survival. kidney int. 2014;85(4):920-932 24. strippoli gf, tong a, johnson d, schena fp, craig jc. catheter-related interventions to prevent peritonitis in peritoneal dialysis: a systematic review of randomized, controlled trials. j am soc nephrol. 2004;15(10):2735-2746 25. crabtree jh, shrestha bm, chow km, et al. creating and maintaining optimal peritoneal dialysis access in the adult patient: 2019 update. perit dial int. 2019;39(5):414436 26. richardson db, cole sr, ross rk, et al. meta-analysis and sparse-data bias. am j epidemiol. 2021;190(2):336-340 27. zhao l, yang j, bai m, et al. risk factors and management of catheter malfunction during urgent-start peritoneal dialysis. front med (lausanne). 2021;8:741312 corresponding author: ye zhang, md; laparoscopic surgery, nanjing medical university affiliated wuxi people's hospital,299 qingyang road,wuxi, jiangsu province, 214023, china tel: +8615335205233, email: zhangye2002520@aliyun.com figure legends: figure 1. flow chart of the studies included in the meta-analysis. figure 2. risk-of-bias summary graph for rcts. the green symbol indicates a low level of bias, red represents a high level of bias, and yellow indicates that the risk of bias was unclear. figure 3.ⅰ) forest plot of risk ratios for the incidence of catheter shift after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅱ) forest plot of risk ratios for the incidence of leaks after laparoscopic and conventional pd catheter insertion. ci: confidence interval.; ⅲ) forest plot of risk ratios for the incidence of leaks in the subgroups “study date ≥2015” and “study date <2015” after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅳ) forest plot of risk ratios for the incidence of peritonitis after laparoscopic and conventional pd catheter insertion. ci: confidence interval.; ⅴ) forest plot of risk ratios for the incidence of exit-site and tunnel infection after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅵ) forest plot of risk ratios for the incidence of inadequate catheter drainage after laparoscopic and conventional pd catheter insertion. ci: confidence interval. figure 4.ⅰ) forest plot of risk ratios for the incidence of blockage after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅱ) forest plot of risk ratios for the incidence of abdominal hemorrhage after laparoscopic and conventional pd catheter insertion. ci: confidence interval.; ⅲ) forest plot of risk ratios for the incidence of abdominal hemorrhage in subgroups “2 weeks” and “1 day” after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅳ) forest plot of risk ratios for the incidence of pain after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅴ) forest plot of risk ratios for the incidence of pain in the subgroups “2 weeks”, “1 week” and “1 day” after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅵ) forest plot of risk ratios for the incidence of hernias after laparoscopic and conventional pd catheter mailto:zhangye2002520@aliyun.com insertion. ci: confidence interval. figure 5. question: should laparoscopic or conventional open surgery be used for pd catheter placement? figure 1. flow chart of the studies included in the meta-analysis. figure 2. risk-of-bias summary graph for rcts. the green symbol indicates a low level of bias, red represents a high level of bias, and yellow indicates that the risk of bias was unclear. figure 3.ⅰ) forest plot of risk ratios for the incidence of catheter shift after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅱ) forest plot of risk ratios for the incidence of leaks after laparoscopic and conventional pd catheter insertion. ci: confidence interval.; ⅲ) forest plot of risk ratios for the incidence of leaks in the subgroups “study date ≥2015” and “study date <2015” after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅳ) forest plot of risk ratios for the incidence of peritonitis after laparoscopic and conventional pd catheter insertion. ci: confidence interval.; ⅴ) forest plot of risk ratios for the incidence of exit-site and tunnel infection after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅵ) forest plot of risk ratios for the incidence of inadequate catheter drainage after laparoscopic and conventional pd catheter insertion. ci: confidence interval. figure 4.ⅰ) forest plot of risk ratios for the incidence of blockage after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅱ) forest plot of risk ratios for the incidence of abdominal hemorrhage after laparoscopic and conventional pd catheter insertion. ci: confidence interval.; ⅲ) forest plot of risk ratios for the incidence of abdominal hemorrhage in subgroups “2 weeks” and “1 day” after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅳ) forest plot of risk ratios for the incidence of pain after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅴ) forest plot of risk ratios for the incidence of pain in the subgroups “2 weeks”, “1 week” and “1 day” after laparoscopic and conventional pd catheter insertion. ci: confidence interval; ⅵ) forest plot of risk ratios for the incidence of hernias after laparoscopic and conventional pd catheter insertion. ci: confidence interval. figure 5. question: should laparoscopic or conventional open surgery be used for pd catheter placement? tables: table 1. main characteristics of the included studies. abbreviations: rct, randomized controlled trials; non-rct, non-randomized controlled trials. study country design sample size age（year) followup(month) outcomes laparos copic convent ional laparos copic conven tional total early late ao et al. 2012 china nonrct 141 216 39.9 40.6 40.32 1 12 complication s hong et al. 2019 china nonrct 30 33 52.10 1 36 complication s jia et al. 2019 china rct 47 43 46.72 46.22 46.48 complication s li et al. 2018 china rct 50 50 55.42 57.51 56.47 17.68 complication s qiao et al. 2012 china rct 58 58 47.64 24 complication s tang et al. 2019 china nonrct 76 69 58.4 57.3 57.88 24 complication s xie et al. 2014 china nonrct 8 20 60.3 55.9 57.16 24 complication s xiong et al. 2011 china nonrct 81 176 57.1 55.8 56.21 16.8 complication s xu et al. 2010 china rct 25 25 53.68 59.2 56.44 9.91 complication s zhou et al. 2014 china nonrct 43 92 48.07 48.48 48.35 1 complication s table 2. risk of bias in published non-randomized controlled trials. (minors scale) study minors ao et al. 2012 hong et al. 2019 tang et al. 2019 xie et al. 2014 xiong et al. 2011 zhou et al. 2014 1. a stated aim of the study 2 1 1 2 2 2 2. inclusion of consecutive patients 2 0 2 2 2 2 3. prospective collection of data 2 1 2 2 2 2 4. endpoint appropriate to the study aim 2 2 2 2 2 2 5. unbiased evaluation of endpoints 0 0 0 0 0 0 6. follow-up period appropriate to the major endpoint 1 1 2 1 2 1 7. loss to follow up not exceeding 5% 1 1 1 1 1 1 8. a control group having the gold standard intervention 0 0 0 0 0 0 9. contemporary groups 2 2 2 2 2 2 10. baseline equivalence of groups 1 1 1 1 1 1 11. prospective calculation of the sample size 1 1 2 2 2 1 12. statistical analyzes adapted to the study design 1 1 1 1 1 1 total 15 11 16 16 17 15 urol_montage.pdf urology for people 69urology journal vol 6 no 1 winter 2009 what’s up in urology journal, winter 2009? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. the persian translation of this article is available from www.uj.unrc.ir. important note. it is noteworthy that the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2009;6:69-70. www.uj.unrc.ir get ride of the remaiders of kideny stones extracorporeal shock wave lithotripsy is a treatment option for people with kidney stones. in this method, high-intensity acoustic pulses are used to focus on the stones and break them up without surgical operation. the broken stones can pass the urinary system and be excreted by urine. however, some fragments of stones might be still large and their passage might take a long time or even not possible. dr djaladat and his colleagues in bandar-abbas, iran, tried an oily preparation that has been suggested for easier passage of kidney stones. they performed shock wave lithotripsy in their patients and then divided them into 2 groups. one group received the oily preparation called rowatinex for a period of time after lithotripsy and the other received placebo, a capsule similar in shape and color to rowatinex but with no therapeutic effect. they found that this oily preparation does not improve the final outcome of lithotripsy, but it accelerates excretion of the remainders of the stone. so, such preparations might be suggested by the doctors who treat your stones, just to shorten the convalescence period. see page 9 for full-text article incidental diagnoses when you go to hospital for flank pain renal colic is a pain in the flanks caused by kidney stones. to identify the stone, several diagnostic methods may be used. recently using ct scan has gained popularity. ct is a highly accurate imaging method that shows inside the body very clearly. so, any kind of disease can be detected by ct other than the kidney stone. dr ather and his colleagues in pakistan reviewed their experience with ct in 4000 patients who had renal colic. about 10% of the patients had problems in their stomach other than kidney stone or as the real cause of pain. about 1% had a tumor in their stomach. so, ct scans could incidentally find diseases early before they show themselves with symptoms that make the patient visit a doctor. one with a serious hidden problem in his or her stomach must be lucky to have a kidney stone too! see page 14 for full-text article prostate cancer: how to know its seriousness? prostate-specific antigen, often known as psa, is a marker that is measured in blood to find out whether a man might have prostate cancer. researchers have proposed some other ways to use psa in men with prostate cancer; a useful estimate is to know how soon psa rises to a doubled value. the doubling time of psa can help us know the nature of the prostate cancer: how fast it is growing and to what extent it has expanded. dr nowroozi and his colleagues in urology for people 70 urology journal vol 6 no 1 winter 2009 imam khomeini hospital, tehran, calculated the doubling time of psa in a group of men with prostate cancer. they found that those with a doubling time shorter than 12 months had a more aggressive tumor that is more difficult to be treated. to know the nature of the tumor, physician should take a biopsy specimen of the prostate and send it to a pathologist. this may take time and any easier way to know if the tumor is aggressive can help them start the proper treatment sooner. doubling time of psa has been recently attracted researchers and it may have its own place in the diagnosis and treatment of prostate cancer. see page 27 for full-text article menopause in men?! women experience a decline in their sexual hormones when they reach the age of about 45 to 50 years. this is called menopause. such an entity is suggested in men too, namely andropause. andropause is characterized by a decline in testosterone, the sexual hormone in men and a series of manifestations such as impotence, decreased sexual desire, osteoporosis, and generalized weakness. other than measuring testosterone levels in blood, symptoms of this condition can be used for evaluating men who have andropause. a questionnaire has been designed in st louis university in the united states that can help the physician diagnose andropause. dr goel and his research team in india used this questionnaire and also measure testosterone levels in a group of men aged 40 to 60 years working in a hospital. they found that based on the questionnaire, about two-thirds of them would have andropause, which is an unusually high rate. according to the testosterone levels, however, only one-third had andropause. dr goel and his colleagues concluded that they should have their own questionnaire designed specifically for indian men in order to evaluate andropause in their population of men. overall, they think that andropause must be common in indian men older than 40 years. see page 40 for full-text article avicenna’s knowledge on bladder stone in the second part of his article series about avicenna, dr madineh continued comparing the canon of medicine with the current medicine. in this part, he described the surgical treatment of bladder stone. it is surprising for us to know that 1000 years ago, they used to perform surgery for urinary stones. avicenna was aware of the risk of surgery in an era without antibiotics; however, he suggests surgery in some special conditions and explains surgical methods in detail. he warns physicians of sophisticated anatomy of the bladder and its nearby organs, nerves, and blood vessels. also, he describes all difficulties and complications that the surgeons might encounter and provides them with practical solutions. his preciseness and skillfulness are astonishing. for those interested in the history of science and islamic medical history, we recommend reading this article. see page 63 for full-text article ureteroscopic lithotripsy in reverse trendelenburg position and intraoperative furosemide cheng-jing zhang*, song xue, ren-fu chen, zhen song, jun-qi wang, ru-min wen, huan cheng , ke-yu gao purpose: upward stone migration is a significant problem during ureteroscopic lithotripsy (ursl) for upper ureteral stone, especially in absence of a ureteral occlusion device. in this study, we evaluated the novel strategy of reverse trendelenburg position (rtp) and intraoperative diuresis for ursl without ureteral occlusion devices to avoid upward migration. materials and methods: from march 2018 to may 2020, a total of 119 ursls were performed for upper ureteral stone (6-15 mm) with 67 procedures in rtp and 52 procedures in conventional lithotomy position (clp). 20 mg of intravenous furosemide was administered prior to stone fragmentation with holmium laser only in rtp group. patient demographics, stone side, stone size and operative characteristics were recorded and compared between the two groups. results: patient data, stone side and size were similar in the two groups. all procedures were complete without conversion to open surgery and major complications. there was no significant difference in the mean operative time (47.9 ± 7.7 min vs 45.3 ± 7.0 min, p = .062) and mean hospital stay (3.9 ± 0.9 d vs 4.0 ± 1.0 d, p = .336) between the rtp and clp group. stone upward migration was significantly less in rtp group (3.0%, 2/67) than in clp group (19.2%, 10/52) (p = .005). stone-free rate at one month after initial treatment was 92.5% in rtp group and 73.1% in clp group (p = .004). conclusion: the strategy of placing the patient in rtp and intraoperative administration of intravenous furosemide is simple, feasible and cost-effective in preventing stone upward migration during ursl with holmium laser in absence of a ureteral occlusion device for upper ureteral stone. keywords: diuresis; position; upward migration; ureteral stone; ureteroscopic lithotripsy introduction the surgical management of urinary calculi has changed considerably from the open approach to the minimally invasive approach over the past three decades. four minimally invasive treatment modalities, including extracorporeal shockwave lithotripsy (swl), ureteroscopic lithotripsy (ursl), laparoscopic lithotomy and percutaneous nephrolithotomy, are now available for ureteral stone. ursl is one of the preferred treatments for ureteral stone in many urologic centers, as it renders low cost and significantly great stone-free rate(1-4). the quick technological advances in laser and miniaturization of endoscopic devices have permitted to use ursl in larger and complex stones. stone migration during ursl is always the major problem, especially for the upper ureteral stone. the migrating stones may necessitate additional procedures including intraoperative use of the flexible ureteroscope and ureteral stenting, or secondary procedures such as postoperative swl and reoperation, which result in an increase in operative time and medical expenses. several devices have been used to prevent stone migration and achieved a high success rate(5). however, these department of urology, the affiliated hospital of xuzhou medical university, xuzhou, p. r. china. *correspondence: department of urology, the affiliated hospital of xuzhou medical university, xuzhou, p. r. china. tel: +86 516 85805287. fax: +86 516 85601527. e-mail: chengjingzh@163.com. received january 2022 & accepted july 2022 commercial devices may be expensive and unavailable in many countries. in our center, a novel strategy of reverse trendelenburg position (rtp) and intraoperative administration of intravenous furosemide is introduced to prevent stone migration during ursl for upper ureteral stone. we here describe our experience and the efficacy of this method. materials and methods study design and patients between march 2018 and may 2020, 112 patients with upper ureteral stone (6-15 mm) underwent ursls with holmium laser in our center, in which 67 procedures were performed in rtp and 52 procedures were performed in conventional lithotomy position (clp). the patients enrolled in this retrospective study were adult patients with radiological evidence of ureteral stone on plain x-ray film of the kidneys, ureter, and bladder (kub) and/or noncontrast computed tomography (ct) scan. stone location was defined as upper ureter if the stone was located cranial to the sacroiliac joint according to the preoperative imaging. the radiological size of the stone was determined by measuring the longest urology journal/vol 19 no. 5/ september-october 2022/ pp. 352-355. [doi: 10.22037/uj.v19i03.7163] endourology and stone disease diameter of the stone. the included patients were adult patients with solitary stone with size ≤ 15 mm in the upper ureter. exclusion criteria included a history of any intervention on the corresponding ureter, urinary tract abnormalities, recent active infection, coagulopathy, pregnancy, radiolucent stone, hypokalemia, serum creatinine levels ≥ 1.5 mg/dl, and severe hydronephrosis. severe hydronephrosis was defined as the presence of renal pelvis dilation along with all calyces dilatation and thinning of the renal parenchyma in imaging. the study was approved by the institutional review board of the affiliated hospital of xuzhou medical university (no: xyfy2017012). all patients were informed of related complications and the possibility of conversion to other procedures preoperatively. surgical procedures in the rtp group, the patients were initially placed in the lithotomy position under general anaesthesia. a 6/7.5 f rigid ureteroscope (richard wolf, knittlingen, germany) was inserted into the bladder through the urethra under visual guidance and then introduced into ureter orifice with the guidance of a flexible 0.035-in guidewire (zebra, boston scientific, usa). advancement of the ureteroscope within the ureter was performed with low irrigation pressure. a safety guide wire was inserted beyond the target stone once the stone was endoscopically identified in the ureter. then, the ureteroscope was reintroduced into the ureter beside the safety guide wire and the irrigation was discontinued. 20 mg of intravenous furosemide with simultaneous intravenous fluid infusion was given to obtain a high urine flow. during the onset of action about five minutes after intravenous administration, the 550-um laser fibre was placed on stone through the ureteroscope and the operating table was tilted to 30° of rtp. the holmium laser generator (versapulse powersuite 100w, lumenis, israel) was applied as an energy source set at 0.8-1.0 j and a rate of 6-10 hz. with the minimum irrigation pressure to maintain a clear vision, the stone was fragmented using laser lithotripsy into particles less than 3 mm in size, which would spontaneously pass. a stent was placed at the end of the procedure for 2 weeks, unless there were complications, a solitary kidney or ureter stricture, where internal stent remained for 4-12 weeks. ursl in the clp group was performed in the same way as in the rtp group, except that patients were placed in lithotomy position and without use of intravenous furosemide throughout lithotripsy procedure. outcome analysis all patients underwent kub for detection of stone upward migration at one day and noncontrast ct for determination of stone-free rate at one month after ursl respectively. stone-free was defined as absence of residual fragments being visible in the imaging studies, whereas stone upward migration was defined as a stone fragment measuring > 3 mm pushed back into the pelvicalyceal system. patient demographics, stone side, stone size and operative characteristics were recorded. the unpaired t-test was used for comparison of consecutive variables. chi-square test was used for comparison of categorical data and fisher’s exact test was performed when the expected cell count in more than 25% of cases was less than 5. binary logistic regression analysis was applied to estimate the effect of novel strategy of position and diuresis on stone migration. a value of p < .05 was accepted as statistically significant. results 67 ursls performed on 63 patients in rtp group and 52 ursls performed on 49 patients in clp group were included in this study. bilateral procedures on the same occasion were performed on 4 patients in rtp group and 3 patients in clp group respectively. patient data, stone side and size were similar in the two groups. (table 1) all procedures were complete without conversion to open surgery and major complications. the mean operative time for rtp group (47.9 ± 7.7 min) was slightly longer than for clp group (45.3 ± 7.0 min) (p = .062). there was no significant difference in mean hospital stay (3.9 ± 0.9 d vs 4.0 ± 1.0 d) between the rtp and clp group (p = .336). stone-free rate at one month after initial treatment was 92.5% in rtp group and 73.1% in clp group (p = .004). (table 2) postoperative complications were graded according to the modified clavien classification(6). stone upward migration (grade ⅲ) was significantly less in rtp group (3.0%, 2/67) than in clp group (19.2%, 10/52) (p = .005) (table 2). the binary logistic regression analysis showed a significant association between the novel strategy and stone migration (95% confidence interval: ureteroscopic lithotripsy in position and diuresis -zhang et al. table 1. demographic data and swl success rate comparisons between pcn and no pcn groups rtp group clp group p value procedures, n 67 52 gender, n (%) 0.673 male 45 (67.2) 33 (63.5) female 22 (32.8) 19 (36.5) age (yr) 43.6 ± 10.4 41.4 ± 12.1 0.283 body mass index (kg/m2) 23.3 ± 3.0 22.2 ± 3.2 0.067 stone size (mm) 11.1 ± 1.8 10.5 ± 2.1 0.108 stone side, n (%) 0.713 left 39 (58.2) 32 (61.5) right 28 (41.8) 20 (38.5) hydronephrosis, n (%) 0.772 mild 50 (74.6) 40 (76.9) moderate 17 (25.4) 12 (23.1) abbreviations: rtp, reverse trendelenburg position; clp, conventional lithotomy position. endourology and stones diseases 263 vol 19 no 5 september-october 2022 353 1.7-37.0, odds ratio = 7.7, p = .01). auxiliary treatment was performed at one month postoperatively. of the two patients with migrating stones in rtp group, one was rendered stone-free with an adjuvant swl procedure, while the remaining one patient underwent flexible ureteroscopy after swl failure. six cases of migrating stone were successfully managed with the auxiliary swl and the remaining four cases were fragmented to dust using the holmium laser with flexible ureteroscopy in clp group. other complications in this study included hematuria, fever and ureteral perforation. no significant differences were found in these complications between the two groups. in 9.0% (6/67) of procedures in rtp group and 5.8% (3/52) of procedures in clp group (p = .730), mild gross hematuria (grade ⅰ) developed intraoperatively and disappeared in postoperative 2-3 days. transient fever (grade ⅰ) was seen in 4.5% (3/67) of procedures in rtp group and 7.7% (4/52) of procedures in clp group (p = .698), which resolved with conservative treatment. ureteral perforation (grade ⅲ) was encountered in 3.0% (2/67) of procedures in the rtp group and 1.9% (1/52) in the clp group (p = 1.000). the perforation was minor and was managed by indwelling a ureteral stent for 12 weeks without discontinuing the lithotripsy. no ureteral avulsion occurred in this study. (table 2) discussion ursl can be performed more safely and with a higher success rate due to the advent of progressively smaller ureteroscopes and more efficient lithotripsy modalities (1). continuous high-pressure irrigation for obtaining a clear operative visual field may result in an ascending stone, which may complicate the procedure. stone migration is also influenced by the type of lithotripter, the site and size of ureteral stone, and degree of hydronephrosis and proximal ureteral dilation. upward migration of ureteral stone is the leading cause of ursl treatment failure and the reported rate of occurrence ranges from 28% to 60% (7). the more proximal to the renal pelvis the ureteral stone is located, the higher is the risk of upward migration. in an early study, knispel et al reported that the migration rate was 40% for proximal ureteral stone and 5% for distal ureteral stone respectively(8). thus, extensive efforts have been made to minimize the risk of upward migration during ursl. various ureteral occlusion devices have been created specially to prevent upward stone migration and assist with fragment extraction. the stone cone was used by maislos and colleagues in 19 consecutive cases of proximal-ureteral stones with 100% success, and no need for additional procedures(9). in a randomized trial for proximal-ureteral stones by wang and associates, nt trap group achieved no cases of stone migration and a 100% of stone-free rate one week after operation in the studied group of 56 cases(10). other occlusion devices, such as accordion, lithocatch and backstop, have also been introduced into the market in recent years. although clinical studies have indicated significant reduction in stone migration, every device has its limitations and equipment costs that preclude its routine utilization during ursl. more importantly, the occlusion devices are not always available in some urologic center. several strategies have been employed to reduce upward stone migration. the holmium laser can be selected as energy source for ursl as it presents a significant reduction in upward stone migration when compared with other lithotripter types (11,12). yoo and associates introduced anterograde irrigation-assisted ursl with reduced risk of stone migration into kidney and decreased operation time(13). however, this strategy with the requirement of preoperative percutaneous nephrostomy is an appropriate option only for those patients with complicated urinary tract infection. controlling irrigation pressure and altering patients’ position are simple procedure modifications to minimize upward stone migration. lowering irrigation pressure for visibility maintenance and placing the patient in rtp optimizing the gravity has been tried(14-16). yoo and associates’ study supports that increasing pressure beyond the stone can reduce the risk of upward stone migration(13). intravenous administration of furosemide is a noninvasive and fast method to increase intrapelvic pressure. to our knowledge, the effect of rtp with administration of furosemide on upward stone migration has not been evaluated in ursl. using gravity by alterations in the angle of inclination effectively reduced stone retropulsion during ursl in an in vitro model(17). to utilize gravity and negative pressure during ursl, canguven and colleagues placed the patients in rtp and decreased the pressure below the ureteral stone by pulling back the ureteroscope(18). in this study, 20 mg of intravenous furosemide was used to increase the pressure beyond the ureteral stone in patients placed in rtp. stone upward migration was significantly less in rtp group than in clp group, suggesting that the maneuver aided decreasing the upward stone migration during ursl. achieving a stone-free status is important, since small residual stone fragments may act as a nidus for growth. the stonefree rate was significantly higher in rtp group than in clp group. the difference should be associated with decreased stone upward migration and increased stone table 2. demographic data and swl success rate comparisons between pcn and no pcn groups for propensity-score matching rtp group clp group p value operative time (min) 47.9 ± 7.7 45.3 ± 7.0 0.062 hospital stay (d) 3.9 ± 0.9 4.0 ± 1.0 0.336 stone-free, no. (%) 62 (92.5) 38 (73.1) 0.004 complications, no. (%) upward migration (grade ⅲa) 2 (3.0) 10 (19.2) 0.005 hematuria (grade ⅰa) 6 (9.0) 3 (5.8) 0.730 fever (grade ⅰa) 3 (4.5) 4 (7.7) 0.698 perforation (grade ⅲa) 2 (3.0) 1 (1.9) 1.000 abbreviations: rtp, reverse trendelenburg position; clp, conventional lithotomy position. amodified clavien classification(6). ureteroscopic lithotripsy in position and diuresis -zhang et al. endourology and stones diseases 354 dust expulsion. it was in agreement with a study conducted by ziaee and colleagues, in which the position and diuresis had been used to enhance stone-free rate after swl for renal stone(19). there were no major complications in this study. the upward migration rate was 3.0% for the upper ureteral stone in rtp group. the rate was lower than most of previously reported rates for ursl without use of an occlusive device(15,20). a decision analysis by ursiny and eisner showed that it became cost-effective to use an anti-retropulsion device at a retropulsion rate of more than 6.3% (21). urologists may assess retropulsion rates to determine whether an anti-retropulsion device would be beneficial in clinical setting. the migration rate of 3.0% in this study suggests that this strategy could be considered in absence of an anti-retropulsion device. there are several limitations in this study. first, this is a retrospective study with small sample size and confined to a single center. second, there is lack of stone composition in this study, which may influence the stone migration. third, the results may be affected by renal function because of demand for use of furosemide. it would have been interesting if patients in clp also underwent intravenous furosemide. thus, further studies are needed to confirm our results. conclusions the results of this study show that position and diuresis can be used to reduce upward stone migration in the absence of a ureteral occlusion device during ursl for upper ureteral stone. the strategy of placing the patient in rtp and intraoperative administration of intravenous furosemide is simple, feasible and cost-effective in preventing ureteral stone upward migration during ursl with holmium laser. conflict of interest the authors report no conflict of interest. references 1. lam js, greene td, gupta m. treatment of proximal ureteral calculi: holmium:yag laser ureterolithotripsy versus extracorporeal shock wave lithotripsy. j urol. 2002; 167:1972-6. 2. hollenbeck bk, schuster tg, faerber gj, wolf js jr. comparison of outcomes of ureteroscopy for ureteral calculi located above and below the pelvic brim. urology. 2001; 58:351-6. 3. hendrikx aj, strijbos we, de knijff dw, kums jj, doesburg wh, lemmens wa. treatment for extended-mid and distal ureteral stones: swl or ureteroscopy? results of a multicenter study. j endourol. 1999; 13:72733. 4. bagley dh. expanding role of ureteroscopy and laser lithotripsy for treatment of proximal ureteral and intrarenal calculi. curr opin urol. 2002; 12:277-80. 5. bastawisy m, gameel t, radwan m, ramadan a, alkathiri m, omar a. a comparison of stone cone versus lidocaine jelly in the prevention of ureteral stone migration during ureteroscopic lithotripsy. ther adv urol. 2011; 3:203-10. 6. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 7. chow gk, patterson de, blute ml, segura jw. ureteroscopy: effect of technology and technique on clinical practice. j urol. 2003; 170:99-102. 8. knispel hh, klän r, heicappell r, miller k. pneumatic lithotripsy applied through deflected working channel of miniureteroscope: results in 143 patients. j endourol. 1998; 12:513-5. 9. maislos sd, volpe m, albert ps, raboy a. efficacy of the stone cone for treatment of proximal ureteral stones. j endourol. 2004; 18:862-4. 10. wang cj, huang sw, chang ch. randomized trial of ntrap for proximal ureteral stones. urology. 2011; 77:553-7. 11. marguet cg, sung jc, springhart wp, et al. in vitro comparison of stone retropulsion and fragmentation of the frequency doubled, double pulse nd:yag laser and the holmium:yag laser. j urol. 2005; 173:1797-800. 12. yu w, cheng f, zhang x, et al. retrograde ureteroscopic treatment for upper ureteral stones: a 5-year retrospective study. j endourol. 2010; 24:1753-7. 13. yoo j, lee sj, choe hs, kim hy, lee jh, lee ds. anterograde irrigation assisted ureteroscopic lithotripsy in patients with percutaneous nephrostomy. int braz j urol. 2019; 45:406-7. 14. dretler sp. ureteroscopy for proximal ureteral calculi: prevention of stone migration. j endourol. 2000; 14:565-7. 15. feng c, ding q, jiang h, et al. use of ntrap during ureteroscopic holmium:yag laser lithotripsy of upper ureteral calculi. minim invasive ther allied technol. 2012; 21:78-82. 16. kesler ss, pierre sa, brison di, preminger gm, munver r. use of the escape nitinol stone retrieval basket facilitates fragmentation and extraction of ureteral and renal calculi: a pilot study. j endourol. 2008; 22:1213-7. 17. patel rm, walia as, grohs e, okhunov z, landman j, clayman rv. effect of positioning on ureteric stone retropulsion: 'gravity works'. bju int. 2019; 123:113-7. 18. canguven o, boz m, bulbul m, selimoglu a, albayrak s. withdraw of the ureteroscope causes fragmented ureter stones to disperse. int braz j urol. 2013; 39:756-7. 19. ziaee sa, hosseini sr, kashi ah, samzadeh m. impact of sleep position on stone clearance after shock wave lithotripsy in renal calculi. urol int. 2011; 87:70-4. 20. jiang h, wu z, ding q, zhang y. ureteroscopic treatment of ureteral calculi with holmium: yag laser lithotripsy. j endourol. 2007; 21:151-4. 21. ursiny m, eisner bh. cost-effectiveness of anti-retropulsion devices for ureteroscopic lithotripsy. j urol. 2013; 189:1762-6. endourology and stones diseases 265 ureteroscopic lithotripsy in position and diuresis -zhang et al. vol 19 no 5 september-october 2022 355 endourology and stone disease comparison of stone dusting efficiency when using different energy settings of holmium: yag laser for flexible ureteroscopic lithotripsy in the treatment of upper urinary tract calculi shulian chen#, ni fu#, wei cui, zeju zhao, xu luo* purpose: the aim of this study is to evaluate the impact of different pulse energy settings on dusting efficiency in flexible ureteroscopic lithotripsy (fursl) for the treatment of upper urinary tract calculi. materials and methods: data of 88 consecutive patients who underwent fursl for upper urinary tract calculi by a single surgeon in our department from august 2017 to august 2018 were reviewed retrospectively. lumenis power suite 100w lithotripter with a 200 μm laser fiber was used to comminute stones. according to energy settings, patients were divided into three groupslow energy group (le: 0.3-0.6j), middle energy group (me: 0.71.0j), high energy group (he: 1.1-1.5j). frequency was set at 30hz in all patients. anova and chi square tests were applied to compare the difference of the mean lithotripsy and operation time, early stone-free rate (esfr), overall stone-free rate (osfr) and complication rate. results: a total of 32, 36 and 20 patients were included in the le, me and he groups, respectively. there was no difference in the age, gender distribution or in any other stone characteristics among the three groups. the mean lithotripsy time of le, me, he was 10.9 ± 7.6, 16.1 ± 7.0, 23.0 ± 15.0 min respectively. the mean operation time of the three groups was 16.9 ± 7.7, 22.3±7.1, 29.2±14.9 min respectively. there were significant differences on the mean lithotripsy time (p = 0.002) and the mean operation time (p = 0.001) among the three groups. the stone-free rate was 31.8% and 87.5% respectively in esfr and osfr. no statistical significance was detected among the three groups in terms of the esfr (p = 0.89), osfr (p = 0.86), and complication rate (p = 0.97). conclusion: in fursl with dusting, low energy (0.3-0.6j) is more efficient than middle (0.7-1.0j) and high energy (1.1-1.5j). as energy increased, dusting efficiency decreased dramatically. consequently, we recommend low pulse energy (0.3-0.6j) as the optimal dusting strategy for fursl. keywords: flexible ureteroscope; ho: yag laser; intracorporeal lithotripsy; upper urinary tract calculi introduction urolithiasis is a common health disorder in the world and it has already put a heavy burden on the global health system(1). the goal of treatment is to achieve the highest stone-free rate with the least invasion(2). percutaneous nephrolithotomy (pcnl) and flexible ureteroscopic lithotripsy (fursl) are two main minimal invasive procedures for the treatment of upper urinary tract stones(3). in the last decade, with the development of ureteroscope and intracorporeal lithotripters, fursl is rapidly becoming the first-line modality(4). advances in ho:yag laser play a key role in this process. with an excellent safety profile and the ability of comminuting any type of urinary stones, the ho:yag laser is currently the most efficient intracorporeal lithotrite(5). though widely used in fursl, the optimal power settings of ho:yag laser, however, is still inconclusive. options for fursl include dusting and basketing (fragmentation). dusting is to dust stone into small fragments for passive elimination. and basketing is to break stone into discrete fragments for active extraction. advantages of dusting are shorter operative time, lower cost, decreased ureteral trauma, which make it a department of urology, affiliated hospital of zunyi medical college, zunyi, guizhou, china. # these authors contributed equally to this work. correspondence: department of urology, affiliated hospital of zunyi medical college 149 dalian road, zunyi, guizhou, 563000, china. tel: 86-189-8496 5855. fax: 86-0851-28608067. e-mail: lx@zmc.edu.cn. received november 2018 & accepted march 2019 good choice for fursl(6,7). in contrast to basketing, low energy/high frequency is often suggested for dusting in the literature(8). however, there is scant evidence to compare different energy settings on the dusting efficiency during fursl. whether increasing pulse energy will increase dusting efficacy or shorten lithotripsy time remains unknown. therefore, we conducted this study by retrospectively analyzing our consecutive fursl cases using different energy settings in our department in order to provide practical results for urologists. patients and methods study population we retrospectively analyzed the data of 88 consecutive patients who underwent fursl for upper urinary tract calculi from august 2017 and august 2018 by a single surgeon in our department. patient selection was according to the following inclusion and exclusion criteria. the study was approved by the research ethics board of affiliated hospital of zunyi medical college. inclusion criteria: 1. age > 18 years. 2. free of uretero-stenosis. 3. solitary stone in unilateral proximal ureter or kidney. urology journal/vol 17 no. 3/ may-june 2020/ pp. 224-227. [doi: 10.22037/uj.v0i0.4955] exclusion criteria: 1. upj obstruction. 2. high insertion of the ureter. 3. horseshoe kidney. 4. medullar sponge kidney. 5. polycystic kidney. 6. stones in a caliceal diverticulum or infundibular stenosis. 7. renal insufficiency or chronic kidney disease (stage 3a or higher; glomerular filtration rate < 45ml/minute). 8. transplant kidneys. 9. pregnancy. 10. stone diameter > 2.5cm. 11. severe hydronephrosis. according to the settings of ho: yag laser pulse energy, patients were divided into three groupslow energy group (le: 0.3-0.6j), middle energy group (me: 0.71.0j), high energy group (he: 1.1~1.5j). surgical technique patients with urinary tract infection or positive culture received appropriate antimicrobial drugs prior to fursl. two weeks before operation, a 4.7fr ureteral stent was inserted. under general anesthesia, patients were placed in the dorsal lithotomy and, simultaneously, intravenous antibiotics were given. using 8.5fr rigid ureteroscope, the ureteral stent was removed, then a 0.035-mm and another 0.038-mm guidewire were placed. under the guidance of guidewire, a ureteral access sheath (12/14f) was inserted. flexible ureteroscope of 8.5/9.9fr (olympus urf-v) and lumenis power suite 100w lithotripter with a 200 μm laser fiber were used for fragmentating stones. the holmium laser was set at an energy level of 0.3-1.5 j and at a frequency of 30 hz. the stone was comminuted into small fragments for passive elimination. the criteria for terminating laser lithotripsy were complete fragmentation (residual fragments ≤2 mm). after lithotripsy, a 4.7 fr double-j stent was placed. all patients were treated with tamsulosin hydrochloride (0.2mg) one time per day. outcome assessment stone clearance was assessed using kub and ultrasound for patients with radiopaque stones and ct for those with radiolucent stones at 1 day (early stonefree rate, esfr) and 3 months (overall stone-free rate, osfr). stone-free status was defined as the absence of fragments or residual fragments < 2 mm in the upper urinary tract. the operation time was calculated from the insertion of a rigid ureteroscope to the final catheterization at the end of the procedure. the lithotripsy time was calculated from the first launch to the removal of the laser fiber. the preoperative factors analyzed included the stone dimension (cm), age, sex, lower pole calculi or non-lower pole calculi, stone mean ct value (hu). the dimension was evaluated on a plain kub film, in inconclusive situations with radiolucent stones, a ct was performed. meanwhile, we evaluated intraoperative and postoperative complications using the clavien–dindo classification system. statistical analysis spss 20 software was used for statistical analysis. normality and homogeneity of variances tests were initially performed. analysis of variances (anova) were used to compare age, mean lithotripsy and operation time, stone size, and ct value. chi-square tests were used for the comparison of gender, stone location, esfr, osfr, and complication rate. statistical significance was set at p < 0.05. results laser energy settings for rirs-chen et al. table 1. patient demographic characteristics of different energy setting groups total le me he p value n = 88 n = 32 n = 36 n = 20 age; mean±sd, year 44.5 ± 12.1 44.4 ± 12.1 42.1 ± 12.4 46.8 ± 12.0 0.73 gender, no. (%) 0.95 male 59(67.0) 21(65.6) 24(66.7) 14(70.0) female 29(33.0) 11(34.4) 12(33.3) 6(30.0) stone diameter (cm); mean±sd 1.6 ± 0.5 1.5 ± 0.5 1.5 ± 0.5 1.7 ± 0.6 0.57 mean stone ct value (hu); mean±sd 829.6 ± 247.8 7 78.43 ± 229.45 838.2 ± 289.4 862.3 ± 236.9 0.59 stone location, no. (%) 0.89 proximal ureter 24(27.3) 12(37.5) 8(22.2) 4(20.0) renal pelvis 29(33.0) 7(21.9) 15(41.7) 7(35.0) upper or middle calyx 13(14.7) 4(12.5) 6(16.7) 3(15.0) lower calyx 22(25.0) 9(28.1) 7(19.4) 6(30.0) le: 0.3-0.6j/30hz; me: 0.7-1.0j/30hz; he: 1.1-1.5j/30hz; parameter total (n=88) groups p-value le me he lithotripsy time (min) 16.1±11.1 10.9 ± 7.6 16.1±7.0 23.0 ± 15.0 0.002 operation time(min) 22.1±11.2 16.9 ± 7.7 22.3±7.1 29.2 ± 14.9 0.001 no. stone free early 28 (31.8) 9 (28.1) 12(33.3) 7(35.0) 0.847 overall 77 (87.5) 28 (87.5) 32(88.9) 17(85.0) 0.915 dindo-modified clavien grade complications i 5 (5.7) 2(6.3) 2 (5.6) 1(5.0) 0.969 ii 4 (4.5) 1(3.1) 2 (5.6) 1(5.0) 0.967 iii 0 (0.0) 0(0.0) 0 (0.0) 0 (0.0) iv/v 0 (0.0) 0(0.0) 0 (0.0) 0 (0.0) le: 0.3-0.6j/30hz; me: 0.7-1.0j/30hz; he: 1.1-1.5j/30hz; table 2. comparison of operation parameters and complication rates of different energy vol 17 no 03 may-june 2020 225 there were 88 consecutive patients: 59 males and 29 females. the mean patient age was 44.5 ± 12.1 years. there was a total of 22 lower calyceal stones and 66 non-lower calyceal stones. the mean stone diameter was 1.6 ± 0.5cm, with mean ct value 829.6 ± 247.8 hu. differences of age, gender, stone diameter, ct value, stone location among the three groups were not significant. details are shown in table 1. the mean lithotripsy time of le, me, he was 10.9±7.6, 16.1 ± 7.0, 23.0 ± 15.0 min respectively. the mean operation time of the three groups was 16.9 ± 7.7, 22.3 ± 7.1, 29.2 ± 14.9 min respectively. there were significant differences on the mean lithotripsy time (p = 0.002) and the mean operation time (p = 0.001) among the three groups. the overall stone-free rate was 31.8% and 87.5% respectively in esfr and osfr. and no statistical significance was detected on the esfr (p = 0.89) and osfr (p = 0.86) among the three groups. according to the clavien–dindo classification system, 5 patients were grade i (5.7%), 4 patients were grade ii (4.5%), no patient was grade iii/iv/v (0%), and the total complication rate was 10.2%, and there was no significant difference among the different power settings. data in details are presented in table 2. discussion we report what is to our knowledge the first clinical results of the correlation between energy settings and dusting efficiency. for clinical application of dusting in fursl, most studies recommended low power/high frequency (lp/hf) laser settings. however, this deduction mainly comes from laboratory results. these studies only looked into the scientific rationale around energy settings under the condition of fixed stone hardness and lithotripsy space, and provided some indications for clinical application(9-11), but they never took the effect of movement of stones with breaths, variable stone density or renal anatomical factors on the lithotripsy efficiency into consideration as clinical scenario (12,13). to investigate the optimal dusting energy settings of ho:yag laser in clinical application, we retrospectively analyzed 88 consecutive upper urinary tract stone cases underwent fursl. our data demonstrated that le group generated the shortest lithotripsy and operation time with comparable esfr, osfr and complication rate when compared with me and he groups. during fursl with dusting technique, our aim is to comminute stone into small fragments so that they can be easily expulsed through urinary tract without causing pain or obstruction. usually, two modes can be used, dusting (low energy-high frequency) and popcorn effect (high energy-high frequency), which consist of a wide range of pulse energy settings(14,15). a previous study from pietropaolo and his colleagues combined dusting and pop-dusting technique to break stone into submillimeter fragments for passive elimination with 100w laser and showed higher sfr compared to our study with longer operative time(16). using constant laser settings in our study might account for this disparity. some significant pieces are remaining at the end of lithotripsy which can be better addressed with popcorn effect(4). tracey et al. using dusting technique with ultra-high pulse frequencies (80hz), showed comparable sfr with retrieval(17). the efficiency of popcorn effect, another dusting technique, was also be assessed in vitro. studies from wollin and aldoukhi found popcorn effect is more efficient in smaller space with a moderate energy (at least 0.5j per pulse) and higher frequencies(8,18). however, in clinical, there is rare study to compare the dusting efficiency of different energy settings. in our study, the pulse frequency was fixed at 30hz, the lithotripsy and operation time was inversely proportional to pulse energy. when pulse energy exceeded 1j, the dusting efficiency decreased dramatically. our results are in accordance with the rationale concluded from laboratory studies-high pulse energy settings are not suitable for dusting technique in fursl. two factors may account for this. first, larger fragments produced by high pulse energy floated in the renal pelvis with irrigation and significantly increased the fragmenting difficulty and lithotripsy time(19). second, high pulse energy resulted in more retropulsion which increase the distance between the fiber tip and the stone and reduce lithotripsy efficiency(20). there are some limitations to this study. this is a retrospective study from a single center, the confounding factors and measurement bias cannot be minimized as much as they could be in prospective, randomized study. another limitation of this study is that not all possible laser settings were tested because of case constraints. although several in vitro studies investigated the optimal power settings of ho:yag laser, no systematic in vivo study exists to verify previous results(9,21,22). this study is an initial report and may provide some guidance for clinical practice. conclusions in fursl with dusting, low pulse energy (0.3-0.6j) is more efficient than middle (0.7-1.0j) and high pulse energy (1.1-1.5j). as energy exceeded 1.0j, dusting efficiency decreased dramatically. consequently, we recommend low pulse energy (0.3-0.6j) as the optimal dusting strategy for fursl. conflict of interest the authors report no conflict of interest. funding this study was supported by the science and technology department of guizhou province (grant no. 20157493). references 1. pearle ms, calhoun ea, curhan gc. urologic diseases in america project: urolithiasis. j urol. 2005;173:848-57. 2. radfar mh, basiri a, nouralizadeh a, et al. comparing the efficacy and safety of ultrasonic versus pneumatic lithotripsy in percutaneous nephrolithotomy: a randomized clinical trial. european urology focus. 2017;3:82-8. 3. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016;13:2899-902. 4. doizi s, traxer o. flexible ureteroscopy: technique, tips and tricks. urolithiasis. endourology and stones diseases 226 laser energy settings for rirs-chen et al. 2018;46:47-58. 5. kronenberg p, somani b. advances in lasers for the treatment of stones-a systematic review. curr urol rep. 2018;19:45. 6. matlaga br, chew b, eisner b, et al. ureteroscopic laser lithotripsy: a review of dusting vs fragmentation with extraction. j endourol. 2018;32:1-6. 7. humphreys mr, shah od, monga m, et al. dusting versus basketing during ureteroscopy-which technique is more efficacious? a prospective multicenter trial from the edge research consortium. j urol. 2018;199:1272-6. 8. aldoukhi ah, roberts ww, hall tl, teichman jmh, ghani kr. understanding the popcorn effect during holmium laser lithotripsy for dusting. urology. 2018. 9. kronenberg p, traxer o. in vitro fragmentation efficiency of holmium: yttriumaluminum-garnet (yag) laser lithotripsy--a comprehensive study encompassing different frequencies, pulse energies, total power levels and laser fibre diameters. bju int. 2014;114:261-7. 10. wezel f, hacker a, gross aj, michel ms, bach t. effect of pulse energy, frequency and length on holmium:yttrium-aluminumgarnet laser fragmentation efficiency in nonfloating artificial urinary calculi. j endourol. 2010;24:1135-40. 11. vassar gj, teichman jm, glickman rd. holmium:yag lithotripsy efficiency varies with energy density. j urol. 1998;160:471-6. 12. gucuk a, yilmaz b, gucuk s, uyeturk u. are stone density and location useful parameters that can determine the endourological surgical technique for kidney stones that are smaller than 2 cm? a prospective randomized controlled trial. urol j. 2018. 13. sari s, ozok hu, topaloglu h, et al. the association of a number of anatomical factors with the success of retrograde intrarenal surgery in lower calyceal stones. urol j. 2017;14:4008-14. 14. li r, ruckle d, keheila m, et al. highfrequency dusting versus conventional holmium laser lithotripsy for intrarenal and ureteral calculi. j endourol. 2017;31:272-7. 15. chawla sn, chang mf, chang a, lenoir j, bagley dh. effectiveness of high-frequency holmium:yag laser stone fragmentation: the "popcorn effect". j endourol. 2008;22:645-50. 16. pietropaolo a, jones p, whitehurst l, somani bk. role of 'dusting and pop-dusting' using a high-powered (100 w) laser machine in the treatment of large stones (>/= 15 mm): prospective outcomes over 16 months. urolithiasis. 2018. 17. tracey j, gagin g, morhardt d, hollingsworth j, ghani kr. ureteroscopic high-frequency dusting utilizing a 120-w holmium laser. j endourol. 2018;32:290-5. 18. wollin da, tom wr, jiang r, simmons wn, preminger gm, lipkin me. an in vitro evaluation of laser settings and location in the efficiency of the popcorn effect. urolithiasis. 2018. 19. marguet cg, sung jc, springhart wp, et al. in vitro comparison of stone retropulsion and fragmentation of the frequency doubled, double pulse nd:yag laser and the holmium:yag laser. j urol. 2005;173:1797-800. 20. lee h, ryan rt, teichman jm, et al. stone retropulsion during holmium:yag lithotripsy. j urol. 2003;169:881-5. 21. sea j, jonat lm, chew bh, et al. optimal power settings for holmium:yag lithotripsy. j urol. 2012;187:914-9. 22. spore ss, teichman jm, corbin ns, champion pc, williamson ea, glickman rd. holmium: yag lithotripsy: optimal power settings. j endourol. 1999;13:559-66. laser energy settings for rirs-chen et al. vol 17 no 03 may-june 2020 227 pictorial urology 202 urology journal vol 7 no 3 summer 2010 filarial labial chylorrhoea an uncommon problem in an endemic region urol j. 2010;7:202. www.uj.unrc.ir a 15-year-old girl presented with history of wetting her underwear intermittently by milky white fluid for the past 2 years. initially, there were small papular lesions that subsequently transformed into milky fluid-filled vesicles that ruptured intermittently. discharge increased in the evening and after prolonged erect posture. there was no pedal edema and her physical development was normal. examination revealed many 1 to 5-mm whitish-yellow papulovesiculous eruptions on both labia majora with thickening of the labial skin. laboratory examination showed normal hematology, blood sugar, cholesterol, and creatinine. aspirated fluid from vesicles was milky and its triglyceride level was 2.2 mmol/l. abdominal computed tomography scan was normal. patient responded to treatment by diethylcarbamazine and dietary modifications (low fat with medium chain triglyceride). compression garments were worn and hypertonic saline was administered over the labial lesions, as previously described by our group.(1) filariasis has many different manifestations, including hydrocele and chyluria.(2) in secondary chylous reflux, lymphatic vessels become obstructed and lead to incompetent valves, resulting in reflux into the lower limbs and the genitalia. abhishek jain, nisar ahmad, apul goel* department of urology, king george medical university, lucknow, india *e-mail: goelapul1@rediffmail.com references 1. gupta a, dalela d, vasudeva p, sankhwar sn, goel a. scrotal chylorrhoea: images of uncommon scrotal fluid discharge. urology. 2009;73:1227-8. 2. mcaleer sj, johnson cw, johnson wd. tuberculosis and parasitic and fungal infections of the genitourinary system. in: wein aj, kavousi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. 9 ed: philadelphia: w.b. saunders; 2007:436-70. unclassified holmium laser in comparison with transurethral resection of the bladder tumor for non-muscle invasive bladder cancer: randomized clinical trial with 18-month follow-up mohammad reza razzaghi1, mohammad mohsen mazloomfard1*, mahmoud yavar1, sheida malekian2, pouria mousapour1 purpose: to evaluate the safety and efficacy of holmium laser resection of the bladder tumor (holrbt) vs. transurethral resection of bladder tumor (turbt) as the first treatment modality for non-muscle-invasive bladder cancer (nmibc). materials and methods: eighty-eight patients with primary non-muscle invasive bladder cancer were allocated randomly in two groups who were treated with holrbt or turbt. the intraoperative and postoperative characteristics and complications of the holrbt and turbt groups were compared. the data of operation time, obturator nerve reflex rate, bladder perforation, bladder irrigation, catheterization time, hospital stay, and 1, 3, 6, 12, 18 months recurrence free survivals were considered in two groups. results: there was no significant difference in operative duration among the two groups. compared with the turbt group, holrbt group had fewer intraoperative and postoperative complications, including obturator nerve reflex, transient hematuria, and postoperative bladder irritation. there were no significant differences among the two groups in the transfusion rate and occurrence of urethral strictures. patients in the holrbt group had less catheterization and hospitalization time in comparison to those in the turbt group. there were no significant differences in the overall recurrence rate among the turbt and holrbt groups. conclusion: holrbt can be regarded as a safe and efficient method with several advantages over turbt. holrbt can be used as an alternative procedure for turbt in patients with non-muscle invasive bladder cancer. keywords: bladder tumor; transurethral resection; complications; laser. introduction bladder cancer is one of the most common urolog-ic malignances. approximately 75%-85% of the newly diagnosed bladder cancers are confined to the mucosa (ta or tis) or submucosa (t1), which is known as non-muscle-invasive bladder cancer (nmibc).(1,2) gold standard technique of transurethral electroresection of bladder tumor (turbt) is the most commonly used surgical procedure for treating nmibc patients.(3,4) however, this procedure could result in serious complications such as obturator nerve reflex, bladder perforation, stricture of the ureteral ostium, and post-operative bleeding especially in patients who take anticoagulants therapy.(5-8) to overcome the possible morbidities, various procedures operating with different systems and application techniques are recently available for the treatment of nmibc, such as holmium resection of bladder tumor (holrbt). recent studies evaluated the efficacy and safety of holrbt technique in the treatment of nmibc. however, most reports have planned holrbt as a secondary treatment for patients with confirmed pathologic diagnosis.(9-17) 1laser application in medical sciences research center (lamsrc), shahid beheshti university of medical sciences. 2department of internal medicine, tajrish hospital, shahid beheshti university of medical sciences. *correspondence: laser application in medical sciences research center (lamsrc), shohada-e tajrish medical center, qods sq. tehran, iran. tel: +98 21 22718021, fax: +98 21 22749221, mobile: +98 912 214 7949. e-mail: mazloomfard@gmail.com received june 2020 & accepted april 2021 in a study by zhu et al. on patients with nmibc, it was found that holrbt was superior to turbt in terms of intraoperative complications with a similar recurrence-free survival rate in both procedures.(18) in this clinical trial study, the feasibility and postoperative outcomes of holrbt as the first-line treatment in nmibc were investigated and compared with turbt as a gold-standard treatment. materials and methods study population from 2017 to 2019, 123 patients with the presence of a suspicious lesion on imaging (ultrasound scan, computed tomography, and magnetic resonance imaging) were assessed for eligibility to enter the study. all patients underwent cystoscopy for once under sedation and cold-cup biopsy was obtained from all cases. then bimanual bladder examination was performed at the same time. cystoscopically and pathologically proven primary bladder tumors [nmibc (ta and t1)] were included in this study. all patients requested surgical treatments and were fully informed and provided written consent. urology journal/vol 18 no. 4/ july-august 2021/ pp. 460-465. [doi: 10.22037/uj.v18i.6319] thirty-five patients were excluded from the study because of reported hydronephrosis and/or stage t3 and t4 of bladder tumor on imaging; the presence of carcinoma in situ at cold-cup biopsy, upper urinary tract tumor, untreated urinary infection, recurrent bladder cancer, and tumor diameter more than 3 centimeters in cystoscopy and disability or decline to give fully informed consent. the remained eighty-eight patients underwent physical examination and standard urological evaluation consisted of blood tests including blood cell count and serum chemistry. the design of this research was approved by the bioethics board of the medical laser application research center and it conformed to the ethical guidelines of the 1975 helsinki declaration. the trial is registered at iranian registry of clinical trials, irct201701078146n18. study design this was a single-center (with balanced randomization [1:1]) parallel-group study conducted in the urology department of tajrish hospital in tehran, iran. patients were randomly assigned one of two groups according to the method of treatment: turbt group and holrbt group. simple randomization was performed using computerized random numbers. the sample size was determined based on our unpublished pilot study with table 1. baseline characteristics of patients and tumor features of both groups. variable a turbt (n = 39) holrbt (n = 40) p-value gender (%) male 35 (89.7) 38 (95) 0.3 female 4 (10.3) 2 (5) median age, yr ± sd 68.2 ± 9.8 65.8 ± 10.8 0.3 location (%) lateral 15 (38.5) 18 (45) 0.3 other 24 (61.5) 22 (55) tumor multiplicity (%) single 23 (58.9) 25 (62.5) 0.63 multiple 16 (41.1) 15 (37.5) mean tumor size, mm ± sd 22.2±8.1 19.8 ± 10.7 0.25 t stage (%) ta 26 (66.7) 25 (62.5) 0.47 t1 13 (33.3) 15 (37.5) grade (%) low 33 (84.6) 35 (87.5) 0.69 high 6 (15.4) 5 (12.5) abbreviations: turbt = transurethral resection of bladder tumor; holrbt= holmium laser resection of bladder tumor; sd = standard deviation. a continuous variables were compared by independent samples t-test figure 1. flow diagram.turbt = transurethral resection of bladder tumor; holrbt= holmium laser resection of bladder tumor holrbt vs. turbt-razzaghi et al. unclassified 461 vol 18 no 4 july-august 2021 462 regard to early recurrent rate of bladder tumor after the procedures. with consideration of type 1 statistical error <5%; and type 2 statistical error < 20% and a dropout rate of 10%, a sample size of 44 patients in each group was estimated. during the study, 5 and 4 participants dropped out due to changing the medical center, detected urinary tract infection, or missing follow up. a total of 39 and 40 patients completed an 18-months follow-up in the turbt and holrbt groups, respectively and their data were included in the final analysis. a summary of the study design and follow-up is provided in figure 1. surgical technique pre-operative evaluation including laboratory tests and cardiovascular consultation were performed in all cases. anti-platelet and anticoagulant drugs were stopped at least 1 week before the operation. all procedures were carried out under spinal anesthesia in the lithotomy position. turbt and holrbt were performed by two different urologists who had previous experience of the procedures. in group 1, monopolar turbt was performed in the standard manner with a 26 fr storz continuous irrigation resectoscope. in group 2, surgery was performed using holmium-yag laser (iranian national institute for laser science and technology; model: pms 5644) in a pulsed wave mode. after introducing the 550-nm laser fiber through a 22 fr continuous-flow laser cystoscope with irrigation of normal saline 0.9%, pulses of laser energy were fired at the papillary component of the tumor with a paintbrush type technique. the power is usually set at 0.9 j energy and frequency rate of 15-20 hz while it was especially decreased to 0.6 j energy set near the bladder neck, trigon, and ureteric orifice area. the fiber was held 2 to 3mm away from the tissue. the exophytic component was treated and continued until the superficial muscle layer was visualized and ablated about 5 mm away from the tumor edge. when bleeding was observed, the laser beam was directed to that region to achieve hemostasis. after complete resection, careful coagulation of the tumor base and surrounding mucosa was done. in both groups, multiple cold-cup biopsies were obtained from the tumor bed in order to take superficial and profound tissue samples. all of the specimens were sent for pathologic evaluation. finally, a three-way 20 fr foley catheter was inserted and irrigated by normal saline in cases with hematuria. routine blood biochemistry profile was checked at 6 hours and the day after the operation. the patients were discharged if no hematuria was detected. foley catheter was removed one day after cessation of hematuria. the patients were informed about possible late complications and the time of next necessary follow-up procedure. the use of postoperative intravesical chemotherapy was considered according to the european association of urology recommendations.(5) outcome assessment the data related to operating time, obturator nerve reflex rate (spasm of adductor muscles of thigh due to obturator nerve stimulation), bladder perforation rate, gross hematuria, and bladder irritation rate, catheterization time, hospital stay, and histological results were recorded. clinical and pathological stages were evaluated for all the patients according to the tnm 2010 staging system.(5) surveillance cystoscopy and urine cytology were used to detect the recurrence free interval as the primary study endpoint. a case of recurrence was considered to variable a turbt (n = 39) holrbt (n = 40) p-value mean operative time, min ± sd 26 ± 10.5 28.5 ± 12 0.3 mean serum sodium, mmol/l ± sd preoperative 136.6 ± 4.0 137.7 ± 2.9 0.62 postoperative 135.9 ± 4.1 135.7 ± 3.9 0.39 p value 0.16 0.09 mean hemoglobin, g/l ± sd preoperative 13.0 ± 1.8 13.1 ± 1.8 0.41 postoperative 12.9 ± 1.8 12.9 ± 1.9 0.78 p value 0.32 0.3 mean hospital stays, d ± sd 3.5 ± 1.1 0.5 ± 0.8 < 0.01* mean catheterization time, h ±sd 2.5 ± 1.1 1.1 ± 0.6 < 0.01* mean irrigation fluid, l ±sd 9.5 ± 3.3 8.6 ± 3.2 0.16 intraoperative complications obturator nerve reflex (%) 6 (15.4) 0 (0) 0.02* transient hematuria (%) 11 (28.2) 2 (5) 0.01* blood transfusion (%) 2 (5.1) 0 (0) 0.5 bladder perforation (%) 3 (7.7) 0 (0) 0.2 early (<30d) post-operative complications clot retention (%) 1 (2.6) 0 (0) 0.7 irritative symptom (%) 22 (56.4) 8 (20) 0.002* late (>30d) post-operative complications urethral stricture (%) 2 (5.1) 0 (0) 0.5 recurrent of tumor (%) 6 (15.4) 7 (17.5) 0.7 one month (%) 0 (0) 0 (0) three months (%) 1 (2.6) 1 (2.5) six months (%) 3 (7.7) 4 (10) twelve months (%) 2 (5.1) 2 (5) eighteen months (%) 0 (0) 0 (0) table 2. intraoperative, early, and late postoperative outcomes as well as complications of patients of both groups abbreviations: turbt = transurethral resection of bladder tumor; holrbt= holmium laser resection of bladder tumor; sd= standard deviation; ns= non-significant; *= statically significant. a continuous variable were compared by independent samples t-test holrbt vs. turbt-razzaghi et al. be an event on the day of cystoscopy. the starting point was taken as the date of surgery. these parameters were assessed at 1, 3, 6, 12 and 18 months after the surgery. data analysis was performed using spss software (statistical package for the social sciences, v. 21.0; spss inc, chicago, il, usa) using student’s t-test, chisquare test and fisher's exact test when appropriate. a p value < 0.05 was considered as statically significant. results the mean ± sd age of the patients was 68.2±9.8 years in the turbt group and 65.8±10.8 years in the holrbt group (p = 0.3) with a male to female ratio of 90% and 95% respectively (p = 0.3). as shown in table 1, tumor characteristics in the holrbt and turbt groups were comparable for stage (p = 0.47), grade (p = 0.69), multiplicity (p = 0.63), location (p = 0.3), and size (p = 0.25). in turbt and holrbt groups, the operation times were 26 ± 10.5 vs. 28.5 ± 12 minutes (p = 0.3); foley catheterization times, 2.5±1.1 vs. 1.1 ± 0.6 hours (p < 0.01); and postoperative hospital stays were 3.5 ± 1.1 vs. 0.5 ± 0.8hours (p < 0.01) respectively. table 2 shows the baseline characteristics and detailed perioperative variables including operative duration, hospital stay, change in hemoglobin and serum level of sodium, and volume of irrigation solution. among patients of turbt, bladder perforation was observed in 3 (7.7%) patients, 2 (5.1%) required blood transfusion, and 6 (15.4%) developed obterator nerve reflex during surgery; whereas none of these complications were observed in the holrbt group. three patients with bladder perforation were managed successfully with conservative treatment including prolonged catheterization. the proportion of patients needing postoperative bladder irrigation due to transient hematuria in the holrbt group was 5% and in the turbt group was 28.21% (p = 0.01). figure 2 depicts the overall recurrence free survival in the holrbt and turbt groups. overall recurrence rate throughout the 18-months of follow up were 6 (15.4%) and 7 (17.5%) in the turbt and holrbt groups respectively. the kaplan-meier curve showed no significant difference in the overall recurrence-free rate between the holrbt and turbt groups (p = 0.7). all the recurrent cases had high grade tumors which shows a significant association between grade and recurrence (p = 0.04). the peri-ureteral lesions also had a higher recurrence rate (p = 0.002). discussion turbt is still the gold standard treatment in patients with bladder tumors.(19) despite its proven clinical outcome, the rate of intraoperative and postoperative morbidity led to the development of alternative surgical methods looking for producing equal results at a lower rate of intraand postoperative complications. shortterm morbidity rate of 43.3% and a mortality rate of 0.1% along with a 3% transfusion rate were reported for turbt.(20) in an attempt to minimize the morbidity of turbt, a number of minimally invasive procedures are being developed. the first laser treatment for bladder tumor was reported by staehler et al. in 1978, using nd: yag laser.(9) then, holmium laser was introduced and en-bloc resection of bladder tumors was performed by saito in 2001.(11) in this study, the researchers show that holrbt as a first-line therapy for papillary bladder tumor can be an effective treatment with minimal complications in comparison to conventional turbt especially in subjects with non-muscle-invasive tumors with size figure 2. kaplan-meier estimate of recurrence-free survival in holrbt vs turbt group. holrbt vs. turbt-razzaghi et al. unclassified 463 vol 18 no 4 july-august 2021 464 less than 3 cm, solitary tumors, and low-grade malignancies. most relevant complications of turbt include obturator nerve reflex (9%; range: 5–50), bleeding requiring blood transfusion (3%; range: 0–9), bladder perforation (1%; range: 0–10), clot retention (4.9%; range: 0–39), and urinary tract infection (4.1%; range: 0–22). (20) also, the rate of urinary tract infection has shown to be higher in patients under turbt method compared to those treated with holrbt technique.(21,22) in the current study, obturator nerve reflex, transient hematuria, and irritative symptoms were reported to be more frequent after turbt than holrbt procedure. yarvandi et al. suggested that the use of thulium laser is a more feasible and effective method to prevent leg jerking in patients with bladder tumor.(23) some authors published that holrbt had shorter operation time as well as catheterization time, and less hospital stay than turbt.(22,24) however, in our study, the operation time difference between the two groups was not significant. recent eau-guideline recommend en-bloc resection using holmium-yag laser in selected exophytic tumors which provide high quality resected specimens with the presence of detrusor muscle in 96-100% of cases. (5) the review by teng(25) demonstrated that holrbt is safe and effective for low-grade papillary urothelial carcinoma or low-grade early tnm-stage urothelial carcinoma. based on eau guideline-2020 and the eortc genito-urinary cancer group, the non-muscle invasive bladder tumor recurrence rate was reported between %15 and 60%.(5) we found that there was no significant difference in the overall recurrence rate among the turbt and holrbt groups. all these recurrences developed in high grade tumors as well as peri-ureteral lesions. eissa et al. ()26), reported that local recurrence occurred in 28% of patients. it was noted that 57% of cases with recurrence showed some degree of dysplasia or malignancy in the lateral margin. in a meta-analysis by teng et al.(25), there was no significant difference in the 1-year recurrence free survival between the two groups. however, the 2-year recurrence free survival favored the holrbt group. this might partly be because of the insufficient resection depth of lateral-wall tumor during turbt, in order to reduce the risk of bladder perforation.(25) in holrbt, the holmium laser can instantly coagulate the blood and lymph vessels, reducing the chance of intraoperative dissemination of the cancer cells. besides, holmium laser can resect neoplasm as well as adjacent tissues en bloc without touching the tumor, reducing the possibility of recurrence in situ.(27) inability to design a double-blind clinical trial due to the different types of procedure and non-blindness of observers were major limitations of this study. other main limitations include small sample size and exclusion of high-risk patients. finally, the holrbt therapeutic method can be regarded as a safe and efficient technique which has some advantages over turbt including lower complication rate, lower medical costs, shorter hospital stay.18 in fact, holrbt could be used as an alternative therapeutic procedure for turbt in terms of non-muscle invasive papillary urothelial carcinoma. however, further studies could be conducted with larger sample size, multi-center sampling, with inclusion of high-risk patients to attain more definite results. also, comparison of different laser may also be considered for further studies among subjects to determine the best laser modality. conclusions the gold standard treatment in patient suffering non-muscle invasive papillary urothelial carcinoma is turbt. according to our study holrbt, as an alternative approach for turbt, offers a safe and feasible procedure in the management of patients with papillary urothelial and the rate of intraoperative events such as obturator nerve reflex and bladder perforation and bleeding has been less observed than turbt. conflict of interest the authors do not have any proprietary interests in this study. references 1. cheung g, sahai a, billia m, dasgupta p, khan ms. recent advances in the diagnosis and treatment of bladder cancer. bmc med. 2013;11:13, 8 pages. 2. pasin e, josephson dy, mitra ap, cote rj, stein jp. superficial bladder cancer: an update on etiology, molecular development, classification, and natural history. rev urol. 2008;10:31-43. 3. anastasiadis a, de reijke tm. best practice in the treatment of nonmuscle invasive bladder cancer. ther adv urol. 2012;4:13-32. 4. strope sa. comparative effectiveness research in urologic cancers. cancer treat res. 2015;164:221-235. 5. babjuk m, böhle a, burger m, capoun o, cohen d, compérat em, hernández v, kaasinen e, palou j, rouprêt m, van rhijn bw. eau guidelines on non–muscle-invasive urothelial carcinoma of the bladder: update 2016. european urology. 2017 ;71:447-61. 6. furuse h, ozono s. transurethral resection of the bladder tumour (turbt) for non-muscle invasive bladder cancer: basic skills. int j urol. 2010;17:698-699. 7. aldousari s, kassouf w. update on the management of non-muscle invasive bladder cancer. can urol assoc j. 2010;4:56-64. 8. josephson dy, pasin e, stein jp. superficial bladder cancer: part 1. update on etiology, classification and natural history. expert rev anticancer ther. 2006;6:1723-1734. 9. zarrabi a, gross aj. the evolution of lasers in urology. ther adv urol. 2011;3:81-89. 10. das a, gilling p, fraundorfer m. holmium laser resection of bladder tumors (holrbt). tech urol. 1998;4:12-14. 11. saito s. transurethral en bloc resection of bladder tumors. j urol. 2001;166:2148-2150. 12. johnson de. use of the holmium:yag (ho:yag) laser for treatment of superficial bladder carcinoma. lasers surg med. 1994;14:213-218. 13. mazo eb, chepurov ak. [the holmium laser in the treatment of bladder cancer patients]. urol nefrol. 1996;4:34-35. holrbt vs. turbt-razzaghi et al. 14. syed ha, biyani cs, bryan n, brough sj, powell cs. holmium:yag laser treatment of recurrent superficial bladder carcinoma: initial clinical experience. j endourol. 2001;15:625627. 15. hossain mz, khan sa, salam ma, hossain s, islam r. holmium yag laser treatment of superficial bladder carcinoma. mymensingh med j. 2005;14:13-15. 16. muraro gb, grifoni r, spazzafumo l. endoscopic therapy of superficial bladder cancer in high-risk patients: holmium laser versus transurethral resection. surg technol int. 2005;14:222-226. 17. soler-martinez j, vozmediano-chicharro r, morales-jimenez p, et al. holmium laser treatment for low grade, low stage, noninvasive bladder cancer with local anesthesia and early instillation of mitomycin c. j urol. 2007;178:2337-2339. 18. zhu y, jiang x, zhang j, chen w, shi b, xu z. safety and efficacy of holmium laser resection for primary nonmuscleinvasive bladder cancer versus transurethral electroresection: single-center experience. urology. 2008;72:608-612. 19. ouzaid i, panthier f, hermieu jf, xylinas e. contemporary surgical and technical aspects of transurethral resection of bladder tumor. translational andrology and urology. 2019 ;8:21. 20. bansal a, sankhwar s, goel a, kumar m, purkait b, aeron r. grading of complications of transurethral resection of bladder tumor using clavien–dindo classification system. indian journal of urology: iju: journal of the urological society of india. 2016 jul;32(3):232. 21. kramer mw, bach t, wolters m, et al. current evidence for transurethral laser therapy of non-muscle invasive bladder cancer. world j urol. 2011;29:433-442. 22. kramer, m.w., et al. current evidence of transurethral en-bloc resection of nonmuscle invasive bladder cancer. eur urol focus, 2017. 3: 567. 23. yarandi va, khatami f, aghamir sm. the obturator nerve reflex after thulium laser vs. monopolar transurethral resection of bladder tumors: a randomized clinical trial. urology journal. 2020 jun 18. 24. chen gf, shi tp, wang bj, wang xy, zang q. efficacy of different resections on nonmuscle-invasive bladder cancer and analysis of the optimal surgical method: j biol regul homeost agents. 2015 apr-jun;29(2):465-70. 25. teng jf, wang k, yin l, et al. holmium laser versus conventional transurethral resection of the bladder tumor. chin med j (engl). 2013;126:1761-1765. 26. eissa a, zoeir a, ciarlariello s, sarchi l, sighinolfi mc, ghaith a, puliatti s, inzillo r, rizzo m, rocco b, micali s. en-bloc resection of bladder tumors (erbt) for pathological staging: the value of lateral margins analysis. minerva urologica e nefrologica= the italian journal of urology and nephrology. 2020 jan 29. 27. syed ha, talbot n, abbas a, et al. flexible cystoscopy and holmium:yttrium aluminum garnet laser ablation for recurrent nonmuscle invasive bladder carcinoma under local anesthesia. j endourol. 2013;27:886-891. holrbt vs. turbt-razzaghi et al. unclassified 465 review interferential electrical stimulation efficacy in the management of lower urinary tract dysfunction in children: a review of the literature lida sharifi-rad1,2, seyedeh-sanam ladi-seyedian1, abdol-mohammad kajbafzadeh1* purpose: lower urinary tract dysfunction (lutd) is the most common problem of the referral children to the pediatric urology clinics. if this condition does not treat early in life, it will be a lifelong problem. during recent decades, electrical stimulation therapy has been expanded and extensively used for the treatment of lutd in both adults and children. the aim of this review is to suggest clinicians an updated understanding of effects of interferential (if) electrical stimulation therapy in management of lutd in children. materials and methods: the search was performed in databases of medline, pubmed, google scholar, ,and scopus for information about if electrical stimulation and its application using search words such as “ if electrical stimulation”, “transcutaneous if electrical stimulation” , “if therapy ” , “ electrical stimulation”, “voiding dysfunction” , “ lutd”, “ urinary incontinence” and “ children”. as this review focuses on the answer of this question “does transcutaneous if electrical stimulation has effect on management of lutd in children?” we included the reference list of articles identified by this search strategy and selected those we judged relevant according to our keywords. clinical trial studies in english were included. categorical data were reported as frequencies and percentages. results: eleven studies were included in this review. the success rate of if therapy in these studies has been reported from 61% to 90% of children with lutd and urinary incontinence. conclusion: if electrical stimulation is an effective, safe and reproducible option to manage lutd and urinary incontinence in children. keywords: electrical stimulation; children; lower urinary tract dysfunction; voiding dysfunction introduction lower urinary tract dysfunction (lutd) is an ex-clusive term that contains different conditions such as dysfunctional voiding, urinary incontinence, overactive bladder (oab), underactive bladder and etc.(1) additionally, lutd is the most common problem of the referral children to the pediatric urology clinics. if this condition does not treat early in life, it will be a lifelong problem. accordingly, optimal clinical management and outcome measures for this condition are important to allow for the best allocation of office and healthcare system resources.(2) the first step in the treatment of lutd, is patient and family education on voiding habits, pelvic floor muscles (pfm) function, hydration and timed voiding (standard urotherapy). in addition, many pharmacological treatments have been developed showing several side effects in children.(3) nowadays pfm retraining and biofeedback therapy are the firstline treatment for the cases with dysfunction voiding after failure of simple conservative managements.(4) 1pediatric urology and regenerative medicine research center, pediatric center of excellence, children’s medical center, tehran university of medical sciences, tehran, iran (iri) 2department of physical therapy, pediatric center of excellence, children’s medical center, tehran university of medical sciences, tehran, iran (iri) *correspondence: pediatric urology and regenerative medicine research center, pediatric center of excellence, children’s medical center, no. 62, dr. gharib st. , keshavarz blvd, tehran 1419433151, iran (iri) tel/fax: +982166565400. e-mail: kajbafzd@sina.tums.ac.ir. received november 2020 & accepted july 2021 furthermore, electrical stimulation has been used after failure of medication or biofeedback in several studies. (5) during recent decades, electrical stimulation therapy has been expanded and extensively used for the treatment of lutd in both adults and children.(6,7) several therapeutic electrical devices have been developed since johann gottlob krüger reported the treatment of a patient by electricity in 1743. electrical currents via stimulating nerves or muscles are used for pain relief, blood flow improvement, muscle spasm relief, wound healing, muscle retraining and strengthening.(8) on the other hand, electrical currents can affect sensory, motor, glandular, and secretory function as well. some chemical changes have also been reported after electrical stimulation therapy, for example; increasing beta-adrenergic activity, reducing cholinergic activity and changes in neurotransmitter availability (dopamine, serotonin, vasopressin, and nitric oxide).(9) moreover, electrical currents can cause reduction in detrusor pressure as well as increasing the bladder capacity or compliance.(10-13) urology journal/vol 18 no. 5/ september-october 2021/ pp. 469-476. [doi: 10.22037/uj.v18i.6558] interferential (if) electrical stimulation as a medium frequency current penetrates with low skin impedance, delivers without pain and targets deeper tissue, has been utilized more than two decades to treat oab, urinary incontinence and to reinforce the pelvic floor in women patients.(14) recently, application of if electrical stimulation for treatment of slow transient constipation in children was reported.(15,16) if currents are produced after crossing of two different medium-frequency currents of 4000 hz by applying four surface electrodes on the body (figure 1). thus an amplitude-modulated current will be generated in the deep tissue such as bladder or the pelvic floor.(17) despite the lack of certainty about the mechanism of action of if electrical stimulation, in the last decade this technique has been widely used for the treatment of oab syndrome, urinary incontinence and chronic pelvic pain/painful bladder syndrome in women patients. this review aimed to address the answer of this question “does transcutaneous if electrical stimulation has effect on management of lutd in children?” material and methods the search was performed in databases of medline, pubmed, google scholar, ,and scopus for information about if electrical stimulation and its application using search words such as “ if electrical stimulation”, “transcutaneous if electrical stimulation” , “if theraauthor study purpose study design participants outcome measures intervention, frequency, duration results and year mauroy et al, 38 efficacy of if current pilot study 10 children urodynamic parameters 6 to 20 stimulation sessions 90% of patients 1992 on bladder instability and resolution of once per week were clinically incontinence and urodynamically improved kajbafzadeh et al, effect of if on rct 30 children urodynamic 18 stimulation sessions 78% of patients 26 2009 urodynamic parameters, with parameters 3 times per week were clinically and incontinency myelomeniand resolution and ngocele of incontinence urodynamically improved yazdanpanah et al, comparing the effects rct 75 children symptoms 3 weeks (5 times /week) 61% of patients 39 2012 of desmopressin and if improvement if therapy or desmopresin in if group were therapy on nocturnal and responded to enuresis in children recurrence rate the treatment lee et al,40 efficacy of if on pilot study 10 children symptoms improvement six sessions (once a week) 90% of patients 2013 patients with medication and resolution of were completely refractory enuresis incontinence or partially responded to treatment kajbafzadeh et al, efficacy of if on rct 54 children symptoms improvement 15 sessions ( two times/week) 67 % of 41 2015 nocturnal enuresis and resolution of incontinence patients in if group responded to the treatment kajbafzadeh et al, efficacy of if on rct 36 children urodynamic parameters 15 sessions ( two times/week) 77 % of 42 2016 non-neuropathic and resolution of patients in if underactive bladder symptoms group responded to the treatment zivkovic et al, fficacy of if and rct 79 children urodynamic parameters 10 sessions (5 times/ week) 73 % of 43 2017 diaphragmatic ebreathing and resolution of patients in if exercises on bladder and symptoms group bowel dysfunction responded to the treatment rafaqat et al,44 effectiveness of quasi40 children resolution of symptoms 8 weeks most of the 2017 if current on experimental according to filled out patients overactive study questionnaires responded to the bladder syndrome if therapy ladi-seyedian et al, effectiveness of if rct 46 children urodynamic parameters 10 sessions ( once a week) 82% of 45 2019 current on non and resolution of patients in if neuropathic urinary incontinence group responded incontinence to the treatment sharifi-rad et al, impact of if therapy on rct 23 children uroflowmetry/emg and 10 sessions ( once a week) most of the 46 2019 primary bladder neck resolution of symptoms patients dysfunction responded to the treatment abdelhalim et al, a comparative study of rct 52 children quality of life and 18 sessions (3 sessions per week) most of the 47 2019 if therapy and tens on resolution of enuresis patients children with primary responded to nocturnal enuresis the treatment table1. studies on interferential current therapy in children with lower urinary tract dysfunction electrostimulation in lutd of children-sharifi-rad et al. review 470 vol 18 no 5 september-october 2021 471 py ” , “ electrical stimulation”, “voiding dysfunction” , “ lutd”, “ urinary incontinence” and “ children”. as this review focuses on the effects of transcutaneous if electrical stimulation in the management of lutd in children, we included the reference list of articles identified by this search strategy and selected those we judged relevant according to our keywords. we only included studies with participants up to 18 years of age. outcomes of interest included patient-reported outcomes, such as change in symptoms, change in scores of validated questionnaires, or uroflowmetric parameters, and the episodes of urinary incontinence. eligibility assessment was performed independently by two reviewers who screened papers titles and abstracts. clinical trial studies that publishing in english were included. case reports were excluded. one review author extracted the following data from included studies and the second author checked the extracted data. disagreements were resolved by discussion between the two review authors; if no agreement could be reached, it was planned a third author would decide. as there were limited studies on the application of transcutaneous if electrical stimulation for management of different kinds of lutd in children, eleven studies were included in this review. categorical data were reported as frequencies and percentages. results physiological and therapeutic effects of interferential current the exact mechanism that if electrical stimulation affects the lower urinary tract function is not completely clear. it is suggested that the if therapy decreases the stimulation of cutaneous sensory nerves near the electrodes in contrast to raising the stimulation of deep nerves.(18) if current is often remarked to be more acceptable, as it generates lower discomfort than some other types of electrical stimulation. this current causes vasodilatation in the peripheral vasculature through chemical changes and sympathetic reflex inhibition.(19) many investigators believe that low frequency currents can selectively use to stimulate the autonomic nervous system.(20,21) also, if therapy is an effective modality for the treatment of patients with urinary incontinence such as stress and urge incontinence in adults.(22,23) it is suggested that pelvic floor if electrical stimulation can result in reflex inhibition of the pelvic nerves and increasing bladder capacity (figure 2). in addition, afferent pudendal nerve stimulation will activate hypogastric efferent and causes reduction in sympathetic activity in order to stop or delay involuntary contractions. (24) the pelvic floor plays a significant role in this system of sacral reflexes. the activated efferent fibers of the pelvic floor influence the sacral level of the neural network that controlling bladder and bowel function. moreover, rhythmic contraction and stimulation of the pelvic floor can coordinate voiding function (figure 3).(25-27) an incompetent urethral sphincter can cause stress urinary incontinence whilst urge incontinence is resulted from uninhibited detrusor muscle contractions. recent studies have reported that if therapy has considerable results in the treatment of patients with stress incontinence, urge incontinence, or both.(28) laycock and green demonstrated the best frequency of stimulation and position of the electrodes for treatment of incontinence.(29) they reported that specific electrode positions can cause higher circulation of the currents in the pelvic floor. therefore, it causes the greater muscle activity compared to a pressure probe method.(29) the possible mechanisms that if therapy could improve oab have been previously described.(30) it is including (1) stimulation of the somatosensory nerve in the pudendal region that inhibiting the efferent activities of the pelvic nerve (action on the micturition center in the brainstem and the spinal cord) (2) increasing the pelvic blood flow and (3) improving the urine pooling function of the bladder by sympathetic nerve inhibition.(30) the lower rate of stimulation frequency represents an attempt to excite figure 1. pattern of interference currents in if therapy electrostimulation in lutd of children-sharifi-rad et al. small afferent fibers in the pudendal nerve that have a slow conduction velocity. this modulated low frequency current will generate reflex inhibition of detrusor following contraction of the slow twitch fibers in the pfms.(17,31) also, some investigators evaluated the role of if therapy in the treatment of anorectal incontinence. (32,33) nowadays, if current is used more and more to treat some of bowel motility disorders including: dyspepsia(34), irritable bowel syndrome(35), functional constipation(36), neuropathic constipation(37) and slow transit constipation in children and adults.(22) application of interferential current in children with lutd there are limited studies on the application of transcutaneous if electrical stimulation for the management of lutd and urinary incontinence in children (table 1). as the results of if therapy for management of oab and urinary incontinence in adult patients were favorable, use of if current in pediatric patients seems to be effective. 1. in a study by mauroy et al. 20 patients with unstable bladder who had no response to medical therapy (anticholinergic) were treated by if current.(38) each patient received 6 to 20 if stimulation sessions for once a week in children and twice a week in adults. authors reported that urinary incontinence improved in 18 patients. moreover, no adverse effects and recurrences of the symptoms were observed at 18 months of follow up. they believed that this reliable technique constitutes an alternative to other retraining stimulation methods.(38) 2. in 2009, the first study on the efficacy of if electrical stimulation in children with neuropathic bladder was published.(27) in this study 30 myelomeningocele children with intractable urinary incontinency due to neuropathic detrusor overactivity had been enrolled and randomly allocated into case group (20 children) who underwent if electrical stimulation and control group (10 children) who underwent sham stimulation. eighteen-session of pelvic if electrical stimulation for 20 minutes 3 times per week was performed. the results revealed that 78% of patients in the case group obtained continence immediately after if therapy which was maintained in 60% of them at 6 months of follow up. (27) 3. the positive results of this study in children with neuropathic bladder led to performing other studies during the next few years on children with lower urinary tract symptoms and voiding disorders. yazdanpanah et al. compared the effect of desmopressin on 39 children who had primary nocturnal enuresis with 36 enuretic children who underwent if therapy.(39) they reported that if group had a complete response in 25%, partial response in 36.1% and no response in 38.9% of patients while the desmopressin group had a complete response in 87.2%, and no response in 12.8% of patients. also, the relapse rate in if and desmopressin groups were 61% and 87.2%, respectively. the author concluded that although the success rate in desmopressin group was higher than if group, if therapy is a cost-effective and safe modality in the treatment of primary enuresis in children due to limited treatment courses (three weeks if therapy in contrast to 6 months of desmopressin therapy), lower relapse rate, and no side effects. (39) 4. lee and park evaluated the effect of salvage if therapy on 10 children with medication-refractory enuresis. (40) treatment was performed once a week, 20 minutes per treatment session, 6 times per cycle. after each cycle, an interview was performed and voiding diaries were filled out. they observed a full response in 1 patient (10%); a good response in 1 patient (10%); a partial response in 7 patients (70%); and no response in 1 patient (10%). the authors concluded that if therapy is a safe treatment and would have beneficial effects in carefully selected patients.(40) 5. the efficacy of transcutaneous if electrical stimulation and standard urotherapy in the treatment of children with primary nocturnal enuresis was studied in 2015. (41) fifty four children with primary nocturnal enuresis were enrolled and divided into two groups. children in figure 2. view of crossing currents from each channel along the pelvic floor. review 472 electrostimulation in lutd of children-sharifi-rad et al. vol 18 no 5 september-october 2021 473 the control group underwent only standard urotherapy. children in the case group were treated with standard urotherapy plus 15 courses of if electrical stimulation. generally, 15/27 (55.5 %) and 6/27 (22 %) of children in the case and control groups respectively responded to the treatment at the 1-year follow up.(41) different results of these three studies on children with primary nocturnal enuresis probably relate to various positions for placement of the electrodes on the body, different amplitude frequency, number of treatment sessions and solely usage or combination of if therapy with other treatments. 6. underactive bladder is a form of lutd that is defined as impaired detrusor contractility and the need to increase intra-abdominal pressure for complete voiding. (1) children with underactive bladder usually have a low voiding frequency, episodes of hesitancy, urge urinary incontinence or overflow incontinence, a large-capacity bladder with incomplete emptying and high post-void residue urine volume which often present with urinary tract infections.(1) in a recent randomized clinical trial, if electrical stimulation was used to manage this type of lutd in children.(42) thirty six children were enrolled and assigned into two equal treatment groups. the control group underwent only standard urotherapy including diet, hydration, scheduled voiding and toilet training, plus pelvic floor and abdominal muscles relaxation exercises. children in the if group not only underwent standard urotherapy and pelvic floor and abdominal muscles relaxation exercises, but also received if stimulation for 15 sessions, 2 times per week. the authors reported that the voiding frequency significantly increased after if therapy in the if group, compared with the control group. nighttime wetting was improved in all children who had this symptom before the treatment in the if group. overall, the if group had significantly better outcomes compared to the control group.(42) 7. the significant improvement of bladder and bowel dysfunction in children was recently reported by adding trans-abdominal if electrical stimulation to the diaphragmatic breathing exercises and behavioral modification compared to only diaphragmatic breathing exercises and behavioral modification.(43) since bowel and bladder are likewise innervated, this experiment can support the concept that electrical stimulation is able to affect the function of both sympathetic and parasympathetic nerve fibers in the sacral nerves. it was shown that treatment of constipation significantly reduced lower urinary tract symptoms in children with bladder dysfunction.(43) they reported a significant improvement in defecation frequency and fecal incontinence only in children who underwent if therapy. additionally, a significant improvement in lower urinary tract symptoms and post-void residual urine was seen in these patients. bell-shaped uroflowmetry curve was observed in 73.3% of children who underwent if therapy and exercise.(43) 8. in addition, the effects of if current on oab in children were newly studied.(44) in this study, a total of 40 children with mild, moderate and severe oab symptoms score underwent 8 weeks of if therapy. this was a quasi-experimental study. standard questionnaire was used for measurement through which results were calculated in this study. complete information about the patients including their bio data, symptomatology was entered in a performa and then data was entered on the basis of overactive bladder symptom score scoring system. in this study, if current was used on s2 and s3 dermatome. the data was collected before and after the treatment. the study showed improvement of lower urinary tract symptoms such as daytime wetting, frequency and urgency in most of the patients after the treatment.(44) 9. functional urinary incontinence in children improved with additional pelvic if electrical stimulation compared to biofeedback therapy alone in a recent study.(45) figure 3. mechanism of action of if current in the lower urinary tract, spine and brain. electrostimulation in lutd of children-sharifi-rad et al. in this study, 46 anatomically and neurologically normal children with functional urinary incontinence were evaluated. children were allocated into two treatment groups. twenty three patients underwent biofeedback therapy in addition to if electrical stimulation while 23 patients received only biofeedback therapy for 10 sessions, once a week. improvement of urinary incontinence was significantly higher in if + biofeedback group compared to only biofeedback therapy at 1 year follow up. daytime wetting was improved in 19/23(82%) and 13/23(56.5%) of children in if + biofeedback and biofeedback only groups respectively, after the treatment. no significant difference was observed in uroflowmetry measures between two groups after the treatment. this study demonstrated that combination of biofeedback and transcutaneous if electrical stimulation was an effective method for the management of functional urinary incontinence in children.(45) 10. primary bladder neck dysfunction defines as an impaired, delayed or incomplete opening of the bladder neck during micturition, resulting in a weak urinary stream without anatomical obstruction.(1) newly, the impact of transcutaneous if electrical stimulation on primary bladder neck dysfunction in children was studied. this survey was done on 23 neurologically and anatomically normal children. included participants had different lower urinary tract symptoms such as hesitancy, straining, urinary incontinence and constipation with no sufficient response to medical treatment (αblocker) for at least 6 months. if electrical stimulation was performed for 20 minutes, 15 sessions, two times per week. all children were symptomatic and had abnormal urine flow pattern with an electromyography (emg) lag time of more than 6 s on uroflowmetry with emg. in addition, alpha blocker therapy was continued during if therapy. the authors observed a significant improvement in mean maximum and average urine flow rates as well as mean emg lag time and post-void residual volume after the treatment (all p < 0.05).(46) they concluded that increases in mean maximum and average urine flow rates in their patients indicated that pelvic if therapy and behavioral modification improved voiding dysfunction in most of the patients and probably decreased bladder neck activity during voiding.(46) 11. in another new study the immediate and short-term effects of if currents and transcutaneous electrical nerve stimulation (tens) in the treatment of children with primary nocturnal enuresis was compared. fifty two children at the age of 7 to 14 years old were randomly assigned into two groups (26 children for each group). electrical therapy was performed for 20 minutes, 3 times per week until 6 weeks in both if and tens groups. the authors measured the patient’s outcome with the number of wet nights, and quality of life through pediatric incontinence questionnaire before treatment, after the last session and 6 months later. they reported that the number of wet nights reduced significantly in both groups with better outcome in if group. also quality of life was significantly improved after the treatment in both groups with better outcome in if group (p < 0.05). the authors concluded that, although if therapy and tens had immediate and shortterm impact on improvement of primary nocturnal enuresis in children, the outcome was better in if group than tens group.(47) we searched the literature up to may, 2020. there were a few studies with small sample sizes on the application of transcutaneous if electrical stimulation in the management of lutd and urinary incontinence in children, however, the success rate of if therapy in these studies has been reported from 61% to 90%. level 1 evidence is produced by few studies for the efficacy of if current in the treatment of lutd in children. it seems that if therapy to be an efficacious and safe treatment for lutd and urinary incontinence in children that could be highly recommended. (48) nevertheless, this evidence needs to be confirmed by further good quality randomized controlled studies and meta-analysis of them. little is known about the effects of the electric stimulation parameters and the stimulation protocols on if electrical stimulation efficacy in children. further studies are needed to identify the best electric parameters and the best protocols for every indication as well as possible effects of a combination therapy with drugs, standard urotherapy and exercises. additionally, different results of reviewed studies probably relate to various positions for placement of the electrodes on the body, different amplitude frequency, number of treatment sessions and solely usage or combination of if therapy with other treatments. it is important the placebo effects of if therapy to be considered. few data are available on using of sham stimulation (28) in control group in order to offset placebo effects. according to the published data, if therapy is a safe and well tolerated modality in children. nevertheless, future studies will have to include safety data of the technique. studies on subgroups of patients in the different indications considered are needed, to find patients more prone to respond to this treatment, with the aim to reduce the number of patients unsuccessfully treated, thus reducing the costs. no long term studies are available, therefore, further long term studies are needed. further studies on alternative possible treatments (e.g. home based transcutaneous stimulation) are also needed. moreover, few data are available about possible mechanisms of action of if electrical stimulation. therefore, studies on animal models and on humans, possibly using central nervous system functional imaging techniques are to be encouraged. future studies with larger sample size, multicenter study and long term follow up are required to help better understanding of if therapy. the main limitation of this review was that this study was not a systemic review with meta-analysis. a few numbers of studies was another limitation of this review. conclusions if electrical stimulation is an effective modality in the management of children with lutd. results from randomized controlled studies demonstrate that the success rate of if therapy is statistically superior to that of placebo. if therapy is safe, with no major complications reported in literature. promising results, to be confirmed by randomized controlled studies, have been obtained in bowel and urinary disorders in children. further studies are needed to assess the exact role of if therapy in these indications and to evaluate the long term outcomes. future studies are needed to obtain better understanding of if therapy in children and bring the best application of it to the clinical setting. references 1. austin pf, bauer sb, bower w, chase j, franco review 474 electrostimulation in lutd of children-sharifi-rad et al. vol 18 no 5 september-october 2021 475 i, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the international children's continence society. neurourol urodyn. 2016; 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52:409-15. 48. afshar k, dos santos j, blais as, kiddoo d, dharamsi n, wang m, et al. canadian urological association guideline for the treatment of bladder dysfunction in children. can urol assoc j. 2021; 15:13-18. review 476 electrostimulation in lutd of children-sharifi-rad et al. storz medical lithotripsy index predicts success of shock wave lithotripsy in ureteric stones sarp korcan keskin1,2*, mandy spencer3, benjamin w turney1 purpose: the aim of this study is to evaluate the factors affecting treatment success in patients who underwent shock wave lithotripsy (swl) for ureter stones and to investigate the effect of storz medical lithotripsy index (smli) on treatment effectiveness in ureteric stones. method: prospective data were collected on patients undergoing swl treatment for ureter stones between january 2013 and may 2021. stone location, number, and size were determined with non contrast ct (ncct) for all patients. all patients underwent swl with a storz modulith slk lithotripsy machine with local anaesthesia. the total amount of energy applied to the stone was calculated using the storz medical lithotripsy index (smli). all patients were evaluated for stone-free status by x-ray at least 2 weeks after treatment. the success of the procedure was defined as the patient being completely stone free (sf) or detection of residual fragments < 4 mm that did not require further treatment results: a total of 1199 patients with ureter stones were included in the study. the mean age of the patients was 43.11 ± 10.65 (18-73), and the mean bmi was 27.87±8.12(19.02-38.65). during swl, 89.3% of patients demonstrated excellent pain tolerance (1070/1199). a total of 119 patients could not tolerate pain during swl (10.7%). treatment success was associated with fewer treatment sessions (2.04±1.64 vs. 2.50 ± 1.48; p < 0.001), smaller stone size (7.35±2.99 vs. 9.02 ± 3.81; p < 0.001) and higher smli/stone size (29.70 ± 17.48 vs. 24.98±16.01; p < 0.001). in the univariate and multivariate regression analysis, the factors affecting the success of the treatment were the number of sessions (or: 1.147), stone size (or: 1.112), smli/stone size (or: 1.115) and pain tolerance (or: 0.740). conclusion: in the treatment of ureteral stones with swl, number of sessions, stone size, smli/stone size, and pain tolerance are the factors affecting success. smli per stone size is a statistically significant factor for predicting swl success. keywords: urolithiasis; swl; treatment; predictive factor; smli; ureteric stones introduction urolithiasis is one of the most common diseases treated by urologists(1). in recent years, the prevalence of urolithiasis has increased to 10.6% in men and 7.1% in women. high recurrence rates (39% at 15 years) are seen in both genders(2). urinary stones have the potential to recur in two-thirds of patients within 20 years, and stone recurrence can be lifelong(3). therefore, with the important developments in technology, minimally invasive treatment options have gained great importance in order to minimize the cost and harms of repetitive treatments(4). numerous options are available for the treatment of urolithiasis, including shock wave lithotripsy (swl), ureteroscopy, as well as open or laparoscopic procedures(5, 6). the application of these treatment methods differs for each patient and the response to the treatment may be different for each patient(7,8). swl is a minimally invasive treatment method commonly used to treat patients with upper urinary tract stones. stone clearance rates were determined between 69-96% for ureteral stones in high-volume centers(9). 1oxford university hospitals, nhs foundation trust, urology department, uk. 2bahcesehir university medical school, department of urology, uk. 3oxford university hospitals, nhs foundation trust, radiology department, uk. *correspondence: consultant urological surgeon, oxford university hospitals, uk. adjunct professor, bahcesehir university medical school, dept of urology, istanbul, turkey. tel: +44 0755 4373556. email: urologum@gmail.com, sarp.keskin@ouh.nhs.uk. received august 2022 & accepted january 2023 treatment success depends on appropriate patient selection, improved swl efficacy, and optimal disease management. in the current literature, there are various reported factors that can affect stone clearance rates (10,11). clinical parameters such as the patient's body mass index, stone location, skin-to-stone distance, stone diameter or stone volume, and hounsfield unit values are among the strong predictive parameters for treatment success(8,12,13). in storz medical swl devices, the total energy applied to the stone is also measured with a proprietary storz medical lithotripsy index (smli). there is very limited data about the effectiveness of treatment success according to the dose of applied energy(4). the aim of this study is to evaluate the factors affecting treatment success in a large cohort of patients who underwent swl and to investigate the effect of smli on treatment effectiveness. methods patients who received swl treatment for ureteral stones between january 2013 and may 2021 were included in urology journal/vol 20 no. 4/ july-august 2023/ pp. 203-207. [doi:10.22037/uj.v20i.7410] endourology and stone diseases the study. written informed consent was obtained from each patient. the study was designed in accordance with the declaration of helsinki. stones were detected with non-contrast computed tomography (ncct). patients with pregnancy, multiple kidney stones, active urinary infection, irregular coagulopathy and using anticoagulants were excluded from the study. the study design is retrospective. the sample size was obtained with all patients who met the inclusion criteria between the specified dates. stone localization, number and stone size of the patients were determined with the help of ncct. all patients were treated on a storz modulith slk-f2 lithotripsy machine without anaesthesia. x-ray and ultrasound were used to target the stone. swl was performed by one of the team of trained radiographers. the study protocol with a protocol of 4000 shocks at 2hz.the total amount of energy applied to the stone was recorded using the storz medical lithotripsy index (smli). no patients had stents in situ and no medical expulsive therapy was given before or after the treatment. recording only the maximum energy level and the number of shocks in the treatment reports may be misleading and it may not be understood whether sufficient energy has been applied to the stone. smli was created by storz medical to control the applied energy. smli refers to the energy applied during a shock wave therapy. smli gives a net number representing the total energy dissipated in an average area of 12 mm. typical values for smli observed in clinical practice range from 180-220 for most stones. however, depending on the individual stone characteristics, lower and higher values will suffice. the number of shock waves, energy level, smli values, patient position, stone targeting method (x-ray or ultrasound), radiation dose received, and patient pain tolerance evaluations during swl were recorded. an experienced operator is required to provide pain control. while the pain tolerance of patients who can tolerate appropriate energy during eswl is evaluated as excellent, lowering the energy level due to pain or interrupting the procedure is classified as pain intolerance(14). all patients were evaluated for stone-free by x-ray at least 2 weeks after treatment. ultrasonography or ncct was used to assess stone free status. the success of the procedure was defined as the patient being stone free (sf) or detection of fragments < 4 mm. statistical analysis data were evaluated with spss 25.0 (ibm, ny, usa) statistics program. the normality of the distribution of the data was questioned with the kolmogorov-smirnov test and q-q plot. independent sample t-test and mann whitney u test were used. factors affecting stonefree success were evaluated with univariate and multivariable logistic regression analysis(model: tretment counts, stone size(mm), number of shocks, energy level, smli, smli/stone size, radiation dose, side (ref:right), patient position(ref:supine), imaging (ref:x-ray), site (ref:lower ureter), pain tolerance (ref:excellent); (assumption linearity 69.9%)). roc curves were created and areas under the curves (auc) were calculated to compare the predictive power of different features. significant p value was determined as < 0.05. results a total of 1199 patients with ureter stones were included in the study. the mean age of the patients was 43.11 ± 10.65(18-73), and the mean bmi was 27.87 ± 8.12(19.02-38.65). during swl, 89.3% of patients demonstrated excellent pain tolerance (1070/1199). a total of 119 patients could not tolerate pain during swl (10.7%). demographic characteristics of the patients are given in table 1. during swl, 89.3% of patients demonstrated excellent pain tolerance (1070/1199). a total of 119 patients could not tolerate pain during swl (10.7%). the procedure was mostly performed under x-ray guidance endourology & stone diseases 204 storz medical lithotripsy index predicts success of swl-keskin et al. n=1199 treatment counts 2.18 ± 1.60(1-10) stone size(mm) 7.85 ± 3.34(2-23) number of shocks (median(iqr) 2790 (200-3000) energy level 6.27 ± 1.32(1-8) smli 193.98 ± 91.25 radiation dose (median(iqr) 480 (100-750) side right 498 (41.5%) left 701 (58.5%) patient position supine 1087 (90.7%) prone 112 (9.3%) imaging x-ray 1179 (98.3%) ultrasonud 20 (1.7%) site upper ureter 671(55.9%) lower ureter 528(44.1%) table 1. patient demographics ` succesfull(n=838) unsuccesfull(n=361) p treatment counts 2.04 ± 1.64 2.50 ± 1.48 < 0.001 stone size(mm) 7.35 ± 2.99 9.02 ± 3.81 < 0.001 number of shocks 2822.40 ± 1938.60 2696.99 ± 906.63 0.240 energy level 6.29 ± 1.33 6.24 ± 1.32 0.574 smli 194.19 ± 92.04 193.48±89.53 0.920 smli/stone size 29.70 ± 17.48 24.98 ± 16.01 < 0.001 radiation dose 479.47 ± 393.23 466.48 ± 370.46 0.594 side right 355 (42.4%) 143 (39.6%) 0.375 left 483 (57.6%) 218 (60.4%) patient position supine 765 (91.3%) 322 (89.2%) 0.279 prone 73 (8.7%) 39 (10.8%) imaging x-ray 823 (98.2%) 356 (98.6%) 0.585 ultrasonud 6(1.8%) 4(1.4%) site upper ureter 470(56.1%) 224(62%) 0.032 lower ureter 368 (43.9%) 137 (38%) table 2. comparison of the factors affecting the success of eswl (98.3%) and in the supine position (90.7%). complete stone clearance was achieved in 50.4% (604/1199) of the patients. the number of patients with clinically insignificant residual fraction were 228 (19.5%). overall success rate was therefore 69.9%. a total of 361 patients (30.1%) did not respond to treatment. treatment success was associated with fewer treatment sessions (2.04 ± 1.64 vs. 2.50 ± 1.48; p < 0.001), smaller stone size (7.35 ± 2.99 vs. 9.02 ± 3.81; p < 0.001) and higher smli/stone size (29.70 ± 17.48 vs. 24.98 ± 16.01; p < 0.001) (table 2). better success and fewer treatment sessions were seen in the patient group with better pain tolerance (p = 0.001). a significant positive correlation was found between smli and the number of shocks and energy levels (r = 0.567 for number of shocks, r = 0.409 for energy levels). in the univariate and multivariate regression analysis, the factors affecting the success of the treatment were the number of sessions (or: 1.147), stone size (or: 1.112), smli/stone size (or: 1.115), and pain tolerance (or: 0.740) (table 3). in the roc curve analysis for smli/stone size, a cutoff value of 18.92 has a sensitivity of 74% and a specificity of 66.9% (auc: 0.699, ci 95%: 0.588-0.712) . discussion this study, in line with other research demonstrates that the success of swl depends on stone size, number of treatment sessions. patients who can tolerate pain have fewer sessions and their success in treatment increases. this study is the first to evaluate the value of smli and smli/stone size. swl is an effective, minimally invasive treatment method with similar effects and complication rates as retrograde urethrography in the treatment of many stones(12,15). among the factors affecting the success of swl, there are many factors related to the technical features of the device, stone characteristics and the structure of the patient(10). according to the literature, while the success of swl is 80-85% in stones less than 20 mm, the success falls between 30-65% in stones over 20 mm(16,17). the decrease in the chance of success, especially in lower pole stones, was seen as a challenge for swl. however, several studies have demonstrated good outcomes with lower pole stones(4,18-20). in our study, the success of swl in lower calyceal stones was found to be 65.5%. the patients' ability to tolerate pain during swl both reduces the number of sessions and affects the success of the treatment. patients that tolerate the treatment well allow better stone targeting and reduced stone excursion due to respiration and patient movement. an experienced operator is required to ensure that adequate coupling is achieved for pain control. it is also extremely important for the operator to increase the voltage in gradual increments to aid the development of pain tolerance. our study is based on the fact that a patient’s pain tolerance affects swl treatment and its clinical outcomes. energy levels are reduced for patients with lower pain threshold making total stone disintegration less likely. it shows that under simple non-opioid analgesia, there are a number of independent predictors for increased pain tolerance during swl. this results in better stone-free status in a reduced number of swl sessions(21). in our study, it was determined that the treatment success was better in the group that tolerated the pain and indirectly the number of sessions was less. with the widespread use of ncct, the burden of urinary tract stones has been evaluated more easily. the size of the stone is typically measured as its maximal diameter. due to the irregular structure of the stones, 3d stone volume measurements have also been used (22). in a study in which the effect of stone burden on the success of swl was evaluated, a significant difference was found between the mean stone volumes in the successful and fragmented groups. for stone volumes over 500mm3, the success rate dropped to 27% (23). in a similar study, stone size was determined as the most important parameter in predicting the success of swl (24). in our study, stone size was found to be larger in the group with unsuccessful swl treatment (p < 0.001, or: 1.112). smli is a measure of total power delivered by the machine in a treatment session this reflects ramping up or down of the energy settings throughout the treatment and any adjustments in frequency (hz). it does not reflect how much power hits the stone. i.e. even if the targeting is not accurate it could still record a high smli. assuming that a consistent number of shockwaves accurately target the stone, it would be expected that higher smlis would be associated with greated treatment success. in a small study of 109 patients the smli/stone size ratio was significant(4). however, the sample size of the study is small. in this study, a cut-off value for smli was not specified and it was argued that it could be done in further studies. in our study conducted with a total of 2429 patients, it was found that the smli value had an independent effect on the success of swl. successful smli/stone univariable analysis multivariable analysis p or ci %95 p or ci %95 tretment counts 0.008 1.120 1.077-1.195 < 0.001 1.147 1.090-1.207 stone size(mm) < 0.001 1.163 1.085-1.146 <0.001 1.112 1.084-1.141 number of shocks 0.162 1.000 1.000-1.002 energy level 0.593 0.961 1.046-1.316 smli 0.681 0.998 0.997-1.000 smli/stone size 0.001 1.001 0.998-1.003 < 0.001 1.115 0.997-1.122 radiation dose 0.976 1.002 0.978-1.012 side (ref:right) 0.889 0.937 0.783-1.121 patient position(ref:supine) 0.425 0.835 0.737-1.112 imaging (ref:x-ray) 0.321 0.749 0.410-1.368 site (ref:lower ureter) 0.227 1.331 0.979-1.809 pain tolerance (ref:excellent) < 0.001 0.716 0.625-0.821 < 0.001 0.740 0.650-0.843 table 3. univariate and multivariable analysis storz medical lithotripsy index predicts success of swl-keskin et al. vol 20 no 4 july-august 2023 205 size threshold value was determined as 20.72. with these findings, increasing the power proportionally to the stone size and determining the effective power in patients who underwent swl will significantly affect the success of stone-free. the study is the first in which smli was evaluated and a threshold score was found to be a factor affecting the success of swl. the study has some limitations. the first of these is that the study was conducted retrospectively. another limitation is the short follow-up period after swl. due to the heterogeneity of the patients, the sensitivity of the smli cut-off score was low. further studies evaluating the effect of smli in more homogeneous patient groups are needed. conclusions in the treatment of urinary tract stones with swl, stone site, stone size, smli, and pain tolerance are the factors affecting treatment success. smli is a surrogate for the power delivered by the storz modulith lithotripter and may have some predictive value in treatment success. conflict of interest none as declared by the authors. references 1. jan h, akbar i, kamran h, khan j. frequency of renal stone disease in patients with urinary tract infection. j ayub med coll abbottabad. 2008;20:60-2. 2. rule ad, lieske jc, li x, melton lj, 3rd, krambeck ae, bergstralh ej. the roks nomogram for predicting a second symptomatic stone episode. j am soc nephrol. 2014;25:2878-86. 3. andrabi y, patino m, das cj, eisner b, sahani dv, kambadakone a. advances in ct imaging for urolithiasis. indian j urol. 2015;31:185-93. 4. snicorius m, bakavicius a, cekauskas a, miglinas m, platkevicius g, zelvys a. factors influencing extracorporeal shock wave lithotripsy efficiency for optimal patient selection. wideochir inne tech maloinwazyjne. 2021;16:409-16. 5. simforoosh n, radfar mh, valipour r, dadpour m, kashi ah. laparoscopic pyelolithotomy for the management of large renal stones with intrarenal pelvis anatomy. urol j. 2020;18:40-4. 6. ziaee sa, hosseini sr, kashi ah, samzadeh m. impact of sleep position on stone clearance after shock wave lithotripsy in renal calculi. urol int. 2011;87:70-4. 7. bajaj m, smith r, rice m, zargar-shoshtari k. predictors of success following extracorporeal shock-wave lithotripsy in a contemporary cohort. urol ann. 2021;13:282-7. 8. kim jk, ha sb, jeon ch, oh jj, cho sy, oh sj, et al. clinical nomograms to predict stonefree rates after shock-wave lithotripsy: development and internal-validation. plos one. 2016;11:e0149333. 9. nielsen tk, jensen jb. efficacy of commercialised extracorporeal shock wave lithotripsy service: a review of 589 renal stones. bmc urol. 2017;17:59. 10. pareek g, hedican sp, lee ft, jr., nakada sy. shock wave lithotripsy success determined by skin-to-stone distance on computed tomography. urology. 2005;66:941-4. 11. abe t, akakura k, kawaguchi m, ueda t, ichikawa t, ito h, et al. outcomes of shockwave lithotripsy for upper urinarytract stones: a large-scale study at a single institution. j endourol. 2005;19:768-73. 12. fankhauser cd, hermanns t, lieger l, diethelm o, umbehr m, luginbühl t, et al. extracorporeal shock wave lithotripsy versus flexible ureterorenoscopy in the treatment of untreated renal calculi. clin kidney j. 2018;11:364-9. 13. taguchi k, cho sy, ng ac, usawachintachit m, tan yk, deng yl, et al. the urological association of asia clinical guideline for urinary stone disease. int j urol. 2019;26:688709. 14. berwin jt, el-husseiny t, papatsoris ag, hajdinjak t, masood j, buchholz n. pain in extracorporeal shock wave lithotripsy. urol res. 2009;37:51-3. 15. iqbal n, malik y, nadeem u, khalid m, pirzada a, majeed m, et al. comparison of ureteroscopic pneumatic lithotripsy and extracorporeal shock wave lithotripsy for the management of proximal ureteral stones: a single center experience. turk j urol. 2018;44:221-7. 16. ullah a, zubair m, khan n, malik a. frequency and factors effecting non clearance of lower pole renal stones. j ayub med coll abbottabad. 2015;27:384-7. 17. cui h, thomee e, noble jg, reynard jm, turney bw. efficacy of the lithotripsy in treating lower pole renal stones. urolithiasis. 2013;41:231-4. 18. waqas m, saqib iu, imran jamil m, ayaz khan m, akhter s. evaluating the importance of different computed tomography scanbased factors in predicting the outcome of extracorporeal shock wave lithotripsy for renal stones. investig clin urol. 2018;59:2531. 19. massoud am, abdelbary am, al-dessoukey aa, moussa as, zayed as, mahmmoud o. the success of extracorporeal shock-wave lithotripsy based on the stone-attenuation value from non-contrast computed tomography. arab j urol. 2014;12:155-61. 20. chung vy, turney bw. the success of shock wave lithotripsy (swl) in treating moderatesized (10-20 mm) renal stones. urolithiasis. 2016;44:441-4. 21. kang dh, cho ks, ham ws, lee h, kwon jk, choi yd, et al. comparison of high, intermediate, and low frequency shock wave lithotripsy for urinary tract stone disease: systematic review and network metaanalysis. plos one. 2016;11:e0158661. 22. ouzaid i, al-qahtani s, dominique s, hupertan v, fernandez p, hermieu jf, et storz medical lithotripsy index predicts success of swl-keskin et al. endourology & stone diseases 206 al. a 970 hounsfield units (hu) threshold of kidney stone density on non-contrast computed tomography (ncct) improves patients' selection for extracorporeal shockwave lithotripsy (eswl): evidence from a prospective study. bju int. 2012;110(11 pt b):e438-42. 23. bandi g, meiners rj, pickhardt pj, nakada sy. stone measurement by volumetric threedimensional computed tomography for predicting the outcome after extracorporeal shock wave lithotripsy. bju int. 2009;103:5248. 24. el-nahas ar, el-assmy am, mansour o, sheir kz. a prospective multivariate analysis of factors predicting stone disintegration by extracorporeal shock wave lithotripsy: the value of high-resolution noncontrast computed tomography. eur urol. 2007;51:1688-93; discussion 93-4. storz medical lithotripsy index predicts success of swl-keskin et al. vol 20 no 4 july-august 2023 207 case report 136 urology journal vol 5 no 2 spring 2008 adult mesoblastic nephroma a case with fatal recurrence mohammad kazam moslemi urol j. 2008;5:136-7. www.uj.unrc.ir keywords: congential mesoblastic nephroma, adult, kidney neoplasms department of urology, kamkar hospital, qom university of medical sciences, qom, iran corresponding author: mohammad kazam moslemi, md no 44, yaseri alley, bagheri st, abbasabad st, somayyeh st, qom 3715694969, iran tel: +98 251 783 2820 fax: +98 251 771 3473 e-mail: moslemi_urologist@yahoo.com received september 2007 accepted march 2008 introduction congenital mesoblastic nephroma is the most common tumor of the kidney in infants, with a mean age at diagnosis of 3.5 months, but it has been rarely reported in adults. (1-3) treatment outcome is the usually excellent only with radical surgery.(4) we report this very rare tumor in an adult that presented with a huge abdominal mass. case report the patient was a 22-year-old man admitted to the gastroenterology department due to abdominal pain, anorexia, and early satiety. on physical examination, a huge abdominal mass was easily palpated. on ultrasonography, a large mass in the right kidney was detected. abdominopelvic computed tomography with intravenous and oral contrast media showed the mass originated from the right kidney with the largest superoinferior diameter of 25 cm from the liver to the pelvic brim (figure 1). the patient underwent right radical nephrectomy. a large thoracoabdominal incision was made. after opening the layers, a large mass occupying half of the abdomen in the right side was seen. the mass adhesions were released and radical nephrectomy was performed. the tumor weighed 5400 g. pathologic examination was in favor of mesoblastic nephroma, a cellular variant consisting of epithelial and stromal components, both with high stromal cellularity (figure 2). due to the benign nature of the tumor, the patient figure 1. extension of the tumor to the pelvic cavity was demonstrated by computed tomography. figure 2. mesoblastic nephroma with interlacing sheets of connective tissue cells (hematoxylin-eosin, × 100). adult mesoblastic nephroma—moslemi urology journal vol 5 no 2 spring 2008 137 did not receive chemotherapy. however, the tumor recurred in the nephrectomy site 2 years after the operation, and in this stage, the patient refused chemoradiotherapy and died 1 year after recurrence. discussion mesoblastic nephroma is a distinctive tumor that is seen mostly in early infancy in 2 feature of classic and cellular (atypical) variants. there are 3 histologic subtypes of classic, cellular, and mixed. the tumor occurs more commonly in boys and is usually unilateral.(4) mesoblastic nephroma rarely occurs in adulthood, and in this age group, it still is poorly characterized. to our knowledge, this is the first reported case of adult mesoblastic nephroma from iran. it is also a rare entity in the world literature; by 2007, a total of 38 cases of adult mesoblastic nephroma have been reported.(3) the collective data obtained from 22 cases by truong and colleagues showed that the patients were predominantly women, aged ranging from 19 to 78 years, who were asymptomatic or had nonspecific signs and symptoms referable to a renal mass.(1) the tumors were 2 cm to 24 cm, well circumscribed, and partially encapsulated. they displayed a solid or cystic cut surface, with a wide range of cytological differentiation. the stomal cells were composed of fibroblasts, myofibroblasts, and smooth muscle cells in various combinations. adult mesoblastic nephroma displays a distinctive morphologic spectrum that parallels that of its pediatric congener. it probably is a benign tumor that can be treated successfully by complete excision. the collecting duct differentiation expressed by most tubules and cysts of adult mesoblastic nephroma implies ureteral bud which is the exclusive embryologic origin of collecting duct, as an important element in the histogenesis of this rare but fascinating type of tumor. the presence of epithelial elements with tubular conformation surrounded by a spindlecell component is greatly useful to perform the differential diagnosis between this entity and others of greater clinical significance.(2) complete excision is curative for most patients with mesoblastic nephroma. local recurrence and metastasis can occur, particularly with the cellular variant of the tumor. neither chemotherapy, nor radiation therapy is routinely recommended.(1) conflict of interest none declared. references 1. truong ld, williams r, ngo t, et al. adult mesoblastic nephroma: expansion of the morphologic spectrum and review of literature. am j surg pathol. 1998;22:827-39. 2. nakano m, kawamoto s, kanimoto y, et al. [a case of mesoblastic nephroma in an adult patient]. hinyokika kiyo. 2000 sep;46(9):623-6. japanese. 3. torres gómez fj, silva abad a, galán p. [adult’s mesoblastic nephroma. report of a case with aggressive course]. arch esp urol. 2007;60:72-5. spanish. 4. ritchey ml, shamberger rc. pediatric urologic oncology. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 3898. v07_no_4.pdf miscellaneous 262 urology journal vol 7 no 4 autumn 2010 open prostatectomy versus transurethral resection of the prostate, where are we standing in the new era? a randomized controlled trial nasser simforoosh, hamidreza abdi, amir hossein kashi, samad zare, ali tabibi, abdolkarim danesh, abbas basiri, seyed amir mohsen ziaee purpose: to compare peri-operative and short-term complications of open transvesical prostatectomy (op) as well as its functional outcomes with transurethral resection of the prostate (turp) in management of benign prostatic hyperplasia with prostates sized 30 to 70 g. materials and methods: hundred patients who were candidate for the prostate surgery with prostates between 30 to 70 g randomly underwent op or turp. secondary endpoints included international prostate symptom score, residual urine volume, surgical complications, and patients’ quality of life. patients were followed up for 6 to 12 months after the operation. results: fifty-one and 49 patients underwent op and turp, respectively. median (interquartile range) of peak flow rate improvement was 11.1 (7.6 to 14.2) and 8.0 (2.2 to 12.6) in op and turp groups, respectively (p = .02). international prostate symptom score improvement did not reveal statistically significant difference between treatment groups. re-operation due to residual prostate lobe, urethral stricture, and urinary retention was performed in 8 patients in turp group versus no patient in op group (p = .006). dysuria was more frequent in patients that underwent turp (p < .001). hospitalization duration was slightly longer in patients that underwent op (p = .04). patients’ quality of life was better in the op group (p = .04). conclusion: open transvesical prostatectomy is an acceptable operation for the prostates sized 30 to 70 g. higher peak flow rate improvement, better quality of life, less frequent dysuria, less need to re-operation, and its ease of learning make open prostatectomy a suitable option to be discussed in patients parallel to turp. urol j. 2010;7:262-9. www.uj.unrc.ir keywords: open prostatectomy, transurethral resection of prostate, lower urinary tract symptoms, urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran corresponding author: nasser simforoosh, md department of urology, shahid labbafinejad medical center, 9th boustan st., pasdaran ave., tehran, iran tel/fax: +98 21 2258 8016 e-mail: simforoosh@iurtc.org.ir received january 2010 accepted april 2010 introduction open transvesical prostatectomy (op) and transurethral resection of the prostate (turp) are two old surgical procedures performed for patients with benign prostatic hyperplasia (bph). currently, turp is considered as the reference or standard treatment for the prostate less than 70 to 80 g.(1-3) nevertheless, op is still being performed for operations of the prostates that are candidate for turp in many developing and even developed countries, as the percent of op in the late 1990’s and early 2000 in sweden,(4) france,(5) italy,(6) and the mediterranean open prostatectomy versus turp—simforoosh et al 263urology journal vol 7 no 4 autumn 2010 coasts(7) ranged from 14% to 40%. in the 21st century, with advances in surgical methods and anesthesia, the complications of op have decreased relative to the reports of the old times. besides, patients are satisfied with op regarding its functional outcome and durability. open transvesical prostatectomy is not currently recommended for moderate-sized prostates while, as mentioned above, a large percent of such operations are performed through the open approach. some authors considered comparing op with newer methods unethical(8) while there has not been good quality evidence for the comparison of op with turp.(3,9) we aimed to compare the peri-operative and short-term complications of op as well as its functional outcomes with turp that is considered as the standard treatment for 30 to 80 g prostates and based this comparison with objective measurements like peak flow rate (pfr). materials and methods hundred patients who had referred to urology outpatient clinic of shahid labbafinejad medical center (a tertiary referral hospital in tehran, iran) between 2005 and 2007, and were candidates for the prostate surgery were enrolled in this study. indications for the prostate surgery included lower urinary tract symptoms despite maximal medical therapy, frequent urinary tract infections, hematuria unresponsive to medical therapy, high serum creatinine that decreased with urethral catheter placement, and urinary retention despite medical therapy. taking the history and physical examination, including digital rectal examination, were performed by a urologist. laboratory evaluations included serum level of creatinine, serum level of prostate-specific antigen (psa), urine analysis, and urine culture. ultrasonography of the kidneys, the bladder, and the prostate were also performed. thereafter, patients were referred to the operating room for cystoscopy and transrectal ultrasonography of the prostate to assess the prostate size. patients with high serum level of psa underwent transrectal ultrasound guided biopsy of the prostate (5 cores from each lobe). if the prostate size in transrectal ultrasonography was within the 30 to 70 g and the posterior urethra revealed obstructive pattern in cystoscopy, patients were assigned to treatment groups based on the allocation protocol. the random allocation protocol was based on randomly produced numbers stratified on the surgical american society of anesthesiology (asa) risk score. random numbers were produced by epi info software and were used to allocate subjects in each of the asa risk scores (i to iii) separately. patients with a bladder stone larger than 2 cm, large bladder diverticula, previous urethral surgery, suspicious mass in digital rectal examination, history of the prostate operation, the prostate size outside the range of 30 to 70 g in transrectal ultrasonography, and those with pathology report other than bph in transrectal prostate biopsy were excluded from the study. finally, 100 patients remained for the analysis (figure). open transvesical prostatectomy was performed as described by freyer(10) by two senior urology residents supervised by attending urologists. transurethral resection of the prostate was carried out with 25 f wolf resectoscopes by two surgeons with more than 10 years of experience. the obvious different nature of surgeries (op versus turp) made blinding impossible both for the surgeon and the patients. data were collected during the operation, postoperative hospitalization, and when patients referred to the clinic at 8 to 12 months postoperatively. in the clinic visit, complications after discharge from the hospital, including dysuria, episodes of cystitis, epididymitis, retrograde ejaculation, and re-operation as well as international prostate symptom score (ipss) and patients’ quality of life were recorded and their pfr was measured. the patients’ quality of life was assessed by a single question as suggested by batista-miranda and colleagues.(11) the primary endpoint of interest was improvement in patients open prostatectomy versus turp—simforoosh et al 264 urology journal vol 7 no 4 autumn 2010 postoperative pfr compared to their preoperative values (postop pfr– preop pfr). secondary endpoints were ipss improvement (preop ipss – postop ipss), residual urine volume reduction, re-operation, dysuria, episodes of cystitis, epididimytis, retrograde ejaculation, incontinence, and patients’ quality of life at 8 to 12 months after the operation.(11-14) the objective of this study was to show at least 2.5 ml/s improvement in pfr in patients who underwent op compared with subjects that underwent turp. considering a power of 0.9, 0.05 type i error and 3.7 ml/s standard deviation for pfr,(14) 46 samples were needed for each treatment group. to compensate for a presumed 10% loss to follow-up, 102 total samples were needed. this study was approved by the ethics committee of urology and nephrology research center, which has adopted codes of ethics to guide human experimentations. all the patients were informed about the study objectives and interventions. a written informed consent was obtained from each patient. statistical analysis was done by spss software (statistical package for the social science, version 16.0, chicago, illinois, usa). categorical variables were analyzed by chi-square or fisher exact test as appropriate. quantitative variables were analyzed by t test or mann-whitney test. intention to treat analysis was considered for all analyses. no subgroup analysis was planned. two-sided p values less than .05 were considered statistically significant. assessed for eligibility (n = 256) randomized enrollment excluded (n = 156): not meeting inclusion criteria (n = 141) refused to participate (n = 15) lost to follow-up (n = 0) lost to follow-up (n = 1) one patient died on the first postoperative day analyzed (n = 50 for postoperative outcomes; n = 51 for operative outcomes) analyzed (n = 49) allocated to intervention (n = 51) received allocated intervention (n = 49) did not receive allocated intervention (n = 2): did not return for surgery allocated to intervention (n = 52) received allocated intervention (n = 51) did not receive allocated intervention (n = 1): did not return for surgery allocation follow-up analysis flow diagram of patients. open prostatectomy versus turp—simforoosh et al 265urology journal vol 7 no 4 autumn 2010 results the flow chart of patients has been outlined in figure. fifty-one and 49 patients underwent op and turp, respectively. patients’ demographic characteristics before the operation are presented in table 1. the only statistically significant difference in pre-operative variables was for age with a mean difference of 10 years between op and turp groups. american society of anesthesiology risk score categories 1, 2, and 3 were observed in 4, 31, and 16 patients in the op group versus 3, 29, and 17 patients in the turp group (p > .05). peri-operative and late postoperative data are presented in table 2. early postoperative complications (during hospitalization) were observed in 4 patients in op group (urinary leak after suprapubic catheter removal in 3 patients and gastrointestinal bleeding in 1 patient) and in 3 patients in turp group (gross hematuria with clot passage in 2 patients and 1 case of suprapubic catheter insertion because of urinary retention after urethral catheter removal and failure to insert another urethral catheter). no episodes of transurethral resection syndrome and no documented thromboembolic events were observed. one patient in op group died the day after the operation. he was a 73-year-old man, who was candidate for surgery because of medical therapy failure. he had history of palpitations and his asa risk score was iii (high). his pre-operative electrocardiogram revealed poor r progression. operation duration was 55 minutes and he received one unit packed cell intra-operatively. pre-operative and postoperative serum level of hemoglobin was 13.1 and 12.1 mg/dl, respectively. postoperative creatinine level was 1.2 mg/dl. his postoperative pulse rate and blood pressure were within the normal limits. bladder irrigation output was light bloody washing serum and discontinued on the first postoperative day (16 hours after the surgery). he complained of heart burn on the first postoperative day and received ranitidine tablets. he fainted on his way to the toilet and had cardiac arrest, which did not respond to cardiopulmonary resuscitation. the patient’s family did not agree with an autopsy to reveal the cause of death. during 8 to 12-month follow-up, re-operation was performed in 8 patients in turp group as follows: 4 patients underwent repeated turp, 2 patients were operated for urethral/bladder neck stricture, and suprapubic catheter was inserted in 2 patients because of urinary retention and failure to pass a urethral catheter. no re-operation was performed for op patients. urge incontinence was observed in 2 patients in each group. in the op group, incontinent patients recovered 3 and 6 months after the operation. in the turp group, one patient recovered 6 months after the variable* op patients (n = 51) turp patients (n = 49) p age, years 71.7 ± 7.3 61.0 ± 8.0 < .001 body mass index 24.6 ± 3.3 24.4 ± 3.2 ns prostate size in trus, g 47.9 ± 12.2 44.4 ± 8.9 ns ipss 27.1 ± 7.1 27.1 ± 7.7 ns peak flow rate, ml/s 7.0 (0 to 9.4) 8.1 (2.8 to 10.4) ns prostate-specific antigen, mg/dl 2.6 ± 1.0 2.3 ± 1.0 ns urinary incontinence 19 (37) 17 (35) ns surgery indication ns medical therapy failure 31 (61) 34 (69) retention 18 (35) 12 (24) frequent uti 1 (2) 0 (0) hematuria 0 (0) 1 (2) creatinine rise 0 (0) 3 (6) residual urine volume, ml 62 (25 to 110) 47 (19 to 93) ns table 1. patients’ characteristics in op and turp groups before the operation. op indicates open transvesical prostatectomy; turp, transurethral resection of the prostate; trus, transrectal ultrasonography; ipss, international prostate symptom score; and uti, urinary tract infection. *data are presented as n(%), mean ± sd, or median (interquartile range). open prostatectomy versus turp—simforoosh et al 266 urology journal vol 7 no 4 autumn 2010 operation and the other one complained from urge incontinence 12 months after the operation. he used one pad every day. early postoperative complications (clot retention and postoperative fever) and late complications (incontinence, cystitis, epididymitis, retrograde ejaculation, and dysuria) are presented in table 2. hospitalization duration was slightly longer in patients that underwent op (table 2). patients’ overall quality of life at 8 to 12 months after the operation was better in the op group compared with the turp group. discussion open transvesical prostatectomy is currently regarded as the only procedure that completely relieves prostatic obstruction.(2,9,15) it is usually used for large prostates or when another pathology necessitating open intervention such as multiple bladder stones coexists.(16) previously, turp was the most commonly used operation for obstruction relief and accounted for 60% to 97% of the prostate operations.(4-7,17) the use of op is now mostly confined to less developed countries with little expertise or experience in endoscopy.(18) currently, laser vaporization technology and holmium laser enucleation of the prostate are revolutionary techniques with little morbidity and equivalent success to op or turp, and are promising to be the new gold standard treatments of bph, irrespective of the prostate size.(19-21) but the main drawbacks for laser technology are its high cost and difficult learning curve(20,21) that make it unsuitable. currently, few centers in the middle east offer holmium laser enucleation of the prostate. transurethral resection of the prostate has been declared as the reference or standard treatment for the prostates less than 70 to 80 g;(1-3,22) however, it has been clearly stated that turp has not passed the formal pathways of a new surgical method evaluation(23) and its comparison with op has been based on retrospective, open, and single center series.(3,23) since the indications for turp and op are variable op patients (n = 50)* turp patients (n = 49) p anesthesia: spinal/general 50/1* 49/0 ns opioid administration, mg 7.2 ± 9.2† 7.9 ± 10.6† ns transfusion 4 (8) 5 (10) ns clot retention 0 (0) 6 (12) .01 resected prostate weight, g 34.5 ± 11.6 31.0 ± 15.2 ns postoperative fever 3 (6) 5 (10) ns time to catheter removal, days 7 (5 to 10) 5 (3 to 7) ns time to work, days 14 (14 to 30) 14 (9 to 23) ns re-operation 0 (0) 8 (16) .003 incontinence 0 (0) 1 (2) ns impotence‡ 3 (6) 1 (2) ns cystitis 2 (4) 2 (4) ns epididymitis 4 (8) 6 (12) ns retrograde ejaculation 17 (34) 19 (39) ns dysuria 14 (28) 35 (71) < .001 ipss improvement 22.3 ± 7.4 20.4 ± 8.3 ns pfr improvement, ml/s 11.1 (7.6 to 14.2) 8.0 (2.2 to 12.6) .02 ruv reduction, ml 60 (25 to 110) 47 (19 to 90) ns qol score at 6 to 12 months 2.3 ± 1.0 2.8 ± 1.4 .04 table 2. comparing operative and postoperative variables in op and turp patients. op indicates open transvesical prostatectomy; turp, transurethral resection of the prostate; ipss, international prostate symptom score; pfr, peak flow rate; qol, quality of life; and ruv, residual urine volume. data are presented as n (%), mean ± sd, or median (interquartile range). *one patient in the op group died the day after the surgery; therefore, follow-up is available on 50 patients. †opioid administration to control pain after the operation was necessary in 23 patients (45%) in op group and 27 patients (55%) in turp group (p > .05). ‡new impotence that was observed after the surgery. open prostatectomy versus turp—simforoosh et al 267urology journal vol 7 no 4 autumn 2010 different, best comparisons are possible only through randomized controlled trials (rct).(14) to the best of our knowledge, only one rct has compared op with turp,(9,12,13,24,25) which was done in the pre psa era and included the following limitations: 1) almost 15% of patients in each group were proved to have malignant pathology. the rate of complications (both early and late) and poor outcomes were substantially higher in patients with a malignant histology. today, the prostate cancer that is screened by psa measurement is a contraindication for op. 2) transurethral resection of the prostate was performed by experienced urologists while op was done by 8 registrars and 3 urologists. 3) the rate of some reported complications were totally different from later reports. for example, urethral stricture was reported higher in op patients while many later studies reported higher stenosis/ stricture in turp patients.(3,26,27) 4) the attrition rate in 5-year follow-up was high, which was unequally distributed between treatment groups (25.6% for turp patients and 6.3% for op patients). a later report by jenkins and colleagues considered any clinical trials comparing op versus turp unethical.(8) their argument was based on the reported higher mortality rate of op (around 10%)(28,29) versus turp (less than 3%) in older patients, especially those over the age of 80 years. however, recent large series reported no difference in mortality or myocardial infarction between op and turp.(26,30-32) mortality rate for op in the most recent series is less than 1%.(14,26) therefore, we think that recruiting patients for the prostate surgery in a clinical trial for comparing op versus turp is no longer unethical and such comparison has been done recently for op and laser(33) or photoselective enucleation.(34) we think that although op is associated with more morbidity(9,14) regarding scar line and more hospitalization stay, but it results in better ipss, pfr improvement,(2,9,15) less re-operation rate,(3,14,26,35) and less dysuria.(9,12,24) postoperative dysuria is bothersome and refractory to treatment.(12) in this study, patients in op and turp groups were comparable at baseline except for age. age was associated neither with primary nor with secondary outcomes evaluated in this study. nevertheless, we cannot exclude the possibility that difference in age might affect the observed differences of this study. the average pfr improvement in patients that underwent op was 3.1 m/s higher than turp group (p = .02). restricting meyhoff and associates’ study results to patients with benign histology, both pfr and mean urinary flow rates were also higher in op group.(13) other retrospective studies support the higher pfr improvement in patients who underwent op.(3) we did not observe statistically significant improvement in ipss or residual urine volume between the two study groups. some reports support better ipss improvement and less residual urine volume in op operations.(2-3,12,14,24) we observed no statistically significant association between the prostate size and the magnitude of pfr, ipss, or residual urine improvement in either group. immediate postoperative complications in op group were mostly related to leakage after suprapubic catheter removal (3 subjects) and were managed conservatively by keeping urethral catheter for a longer time. postoperative complications in patients that underwent turp were mostly related to bleeding (2 subjects) and clot retention (6 subjects). higher re-operation rate has been reported in patients who underwent turp due to a higher stenosis/stricture rate in this group. re-operation rates less than 5% have been reported in one-year follow-up.(3,26,30,35,36) in this study, the re-operation rate during one-year follow-up (16%) is higher than western reports, but a recent slovakian study reported an immediate (up to 4 weeks after operation) complication rate of 38% and 13% complication rate during one-year follow-up,(37) which is close to our findings. another important finding in this study is the higher frequency and duration of dysuria in patients that underwent turp (the latter was not statistically significant). dysuria duration was reported higher by meyhoff and colleagues in patients who underwent turp, but was not open prostatectomy versus turp—simforoosh et al 268 urology journal vol 7 no 4 autumn 2010 statistically significant.(24) higher dysuria and irritative symptoms have been noticed by other investigators in patients undergoing turp.(9) persistent irritative symptoms have been reported to be a major problem in operations that leave the heated damaged tissue in situ(9) as these symptoms are more resistant to treatment.(12) in economic points of view, the costs of op and turp were almost the same with less than 0.5% difference.(38) even in western countries, where the cost of turp is higher than op, it has been suggested that this benefit will be overbalanced five years after the operation, due to higher reoperation rate in turp patients.(27) in summary, although op seems more invasive due to the low midline incision (that is extraperitoneal, without incising any muscles), but on the other hand, the following advantages should also be considered: 1) open transvesical prostatectomy in this study and also in meyhoff and associates’ study was performed by senior residents while turp was performed by expert urologists.(25) nonetheless, the results were better with op; 2) extra morbidity associated with op is not considerable as indicated before;(9) 3) open transvesical prostatectomy is associated with less re-operation rate bringing forward the suggested issue that “is a little more morbid operation better or another less invasive operation that needs more re-operation?”;(9) 4) less clot retention and rebleeding;(25) 5) specially, better improvement in pfr (which is the main goal in management of patients with bph) and ipss; 6) equivalent shortterm and probably less long-term cost. we think that op should be offered in any consultation with patients for the prostate operations. conclusion open transvesical prostatectomy is a safe operation in 30 to 70 g prostates with few complications in comparison with turp. open prostatectomy is accompanied by better outcome in relieving obstruction and less dysuria and re-operation. the authors believe that op can be learned easily and recommend it as a suitable surgical option to be discussed parallel with turp in patients with 30 to 70 g prostates. conflict of interest none declared. references 1. de la rosette j, alivizatos g, madersbacher s, et al. guidelines on benign prostatic hyperplasia. european urology association. 2009, pp 35. 2. jepsen jv, bruskewitz rc. recent developments in the surgical management of benign prostatic hyperplasia. urology. 1998;51:23-31. 3. reich o, gratzke c, stief cg. techniques and longterm results of surgical procedures for bph. eur urol. 2006;49:970-8; discussion 8. 4. ahlstrand c, carlsson p, jonsson b. an estimate of the life-time cost of surgical treatment of patients with benign prostatic hyperplasia in sweden. scand j urol nephrol. 1996;30:37-43. 5. lukacs b. management of symptomatic bph in france: who is treated and how? eur urol. 1999;36 suppl 3:14-20. 6. serretta v, morgia g, fondacaro l, et al. open prostatectomy for benign prostatic enlargement in southern europe in the late 1990s: a contemporary series of 1800 interventions. urology. 2002;60:623-7. 7. mozes b, cohen yc, olmer l, shabtai e. factors affecting change in quality of life after prostatectomy for benign prostatic hypertrophy: the impact of surgical techniques. j urol. 1996;155:191-6. 8. jenkins bj, sharma p, badenoch df, fowler cg, blandy jp. ethics, logistics and a trial of transurethral versus open prostatectomy. br j urol. 1992;69:372-4. 9. tubaro a, carter s, hind a, vicentini c, miano l. a prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. j urol. 2001;166:172-6. 10. freyer pj. a new method of performing perineal prostatectomy. br med j. 1900;1:698-9. 11. batista-miranda je, diez md, bertran pa, villavicencio h. quality-of-life assessment in patients with benign prostatic hyperplasia: effects of various interventions. pharmacoeconomics. 2001;19:1079-90. 12. meyhoff hh, nordling j, hald t. clinical evaluation of transurethral versus transvesical prostatectomy. a randomized study. scand j urol nephrol. 1984;18:201-9. 13. meyhoff hh, nordling j, hald t. urodynamic evaluation of transurethral versus transvesical prostatectomy. a randomized study. scand j urol nephrol. 1984;18:27-35. 14. varkarakis i, kyriakakis z, delis a, protogerou v, deliveliotis c. long-term results of open transvesical prostatectomy from a contemporary series of patients. urology. 2004;64:306-10. 15. mcconnell jd, barry mj, bruskewitz rc. benign prostatic hyperplasia: diagnosis and treatment. agency for health care policy and research. clin pract guidel quick ref guide clin. 1994;1-17. open prostatectomy versus turp—simforoosh et al 269urology journal vol 7 no 4 autumn 2010 16. servadio c. is open prostatectomy really obsolete? urology. 1992;40:419-21. 17. bruskewitz r. management of symptomatic bph in the us: who is treated and how? eur urol. 1999;36 suppl 3:7-13. 18. meier de, tarpley jl, imediegwu oo, et al. the outcome of suprapubic prostatectomy: a contemporary series in the developing world. urology. 1995;46:40-4. 19. fried nm. new laser treatment approaches for benign prostatic hyperplasia. curr urol rep. 2007;8:47-52. 20. kuntz rm. current role of lasers in the treatment of benign prostatic hyperplasia (bph). eur urol. 2006;49:961-9. 21. kuntz rm. laser treatment of benign prostatic hyperplasia. world j urol. 2007;25:241-7. 22. fitzpatrick jm. millin retropubic prostatectomy. bju int. 2008;102:906-16. 23. fitzpatrick jm, mebust wk. minimally invasive and endoscopic management of benign prostatic hyperplasia. in: walsh pc, retik ab, vaughan j, e.d., et al., eds. campbell’s urology. vol 2. 8 ed. philadelphia saunders; 2002:1412. 24. meyhoff hh, nordling j. long term results of transurethral and transvesical prostatectomy. a randomized study. scand j urol nephrol. 1986;20: 27-33. 25. meyhoff hh, nordling j, hald t. transurethral versus transvesical prostatectomy. physiological strain. scand j urol nephrol. 1985;19:85-91. 26. madersbacher s, lackner j, brossner c, et al. reoperation, myocardial infarction and mortality after transurethral and open prostatectomy: a nationwide, long-term analysis of 23,123 cases. eur urol. 2005;47:499-504. 27. woodward r, boyarsky s, barnett h. discounting surgical benefits. enucleation versus resection of the prostate. j med syst. 1983;7:481-93. 28. sach r, marshall vr. prostatectomy : its safety in an australian teaching hospital. br j surg. 1977;64:210-4. 29. singh m, tresidder gc, blandy jp. the evaluation of transurethral resection for benign enlargement of the prostate. br j urol. 1973;45:93-102. 30. koshiba k, egawa s, ohori m, uchida t, yokoyama e, shoji k. does transurethral resection of the prostate pose a risk to life? 22-year outcome. j urol. 1995;153:1506-9. 31. seagroatt v. mortality after prostatectomy: selection and surgical approach. lancet. 1995;346:1521-4. 32. shalev m, richter s, kessler o, shpitz b, fredman b, nissenkorn i. long-term incidence of acute myocardial infarction after open and transurethral resection of the prostate for benign prostatic hyperplasia. j urol. 1999;161:491-3. 33. kuntz rm, lehrich k, ahyai s. transurethral holmium laser enucleation of the prostate compared with transvesical open prostatectomy: 18-month follow-up of a randomized trial. j endourol. 2004;18:189-91. 34. alivizatos g, skolarikos a, chalikopoulos d, et al. transurethral photoselective vaporization versus transvesical open enucleation for prostatic adenomas >80ml: 12-mo results of a randomized prospective study. eur urol. 2008;54:427-37. 35. wasson jh, bubolz ta, lu-yao gl, walker-corkery e, hammond cs, barry mj. transurethral resection of the prostate among medicare beneficiaries: 1984 to 1997. for the patient outcomes research team for prostatic diseases. j urol. 2000;164:1212-5. 36. roos np, wennberg je, malenka dj, et al. mortality and reoperation after open and transurethral resection of the prostate for benign prostatic hyperplasia. n engl j med. 1989;320:1120-4. 37. bardos a, hornak m, novotny v. [transurethral resection of the prostate in the treatment of benign prostatic hyperplasia]. bratisl lek listy. 2001;102: 79-83. 38. ilker y, tarcan t, akdas a. economics of different treatment options of benign prostatic hyperplasia in turkey. int urol nephrol. 1996;28:525-8. v08_no_1_print_3.pdf pediatric urology 38 urology journal vol 8 no 1 winter 2011 evaluation of lower urinary tract symptoms in children exposed to sexual abuse ali yildirim,1 nihat uluocak,2 dogan atilgan,2 mustafa ozcetin,3 fikret erdemir,2 ozgur boztepe2 purpose: to evaluate the lower urinary tract symptoms (luts) in children that are exposed to sexual abuse. materials and methods: fifty-two patients, including 8 male and 44 female children/adolescents presented with sexual abuse to the outpatient clinics were evaluated retrospectively (group 1). in group 1, the subjects were categorized into sexual touch (n = 35) and sexual penetration (n = 17). all the patients were evaluated with a detailed medical history, physical examination, and a dysfunctional voiding and incontinence scoring system questionnaire. thirty age-matched children were evaluated as a control group (group 2). results: the mean age of the patients was 12.2 ± 3.6 years and 12.0 ± 4.5 years in groups 1 and 2, respectively (p = .848). the mean age of the subjects in sexual touch and sexual penetration groups was 10.8 ± 3.6 years and 14.9 ± 1.5 years, respectively. the difference between sexual touch and sexual penetration groups was statistically significant (p = .0001). the incontinence rate was 30.76% and 23.3% in groups 1 and 2, respectively. this difference was not statistically significant (p = .640). the rates of daytime incontinence, nocturnal enuresis, diurnal incontinence, urgency, and continence maneuvers were 25.7%, 17.1%, 22.9%, 42.9%, and 20%, respectively, in sexual touch group, while they were found to be 5.9%, 0%, 0%, 17.6%, and 5.9%, respectively, in sexual penetration group. conclusion: although a significant association was not detected between sexual abuse and luts, it was seen that luts, such as urinary incontinence and urgency, were higher in children exposed to sexual abuse than the control group. urol j. 2011;8:38-42. www.uj.unrc.ir keywords: sex offenses, child, urinary incontinence 1department of forensic medicine, faculty of medicine, gaziosmanpasa university, tokat, turkey 2department of urology, faculty of medicine, gaziosmanpasa university, tokat, turkey 3department of pediatrics, faculty of medicine, gaziosmanpasa university, tokat, turkey corresponding author: dogan atilgan, md fakültesi, üroloji ad 60100, tokat, turkey tel: +90 533 312 9667 fax: +90 356 212 9417 e-mail: datilgan@msn.com received april 2010 accepted july 2010 introduction since ancient times, sexual abuse has been an important public health problem, which can be encountered globally without discriminating between ethnic, religious, or socioeconomic groups. sexual abuse is defined by international society for the prevention of child abuse and neglect as a social and medical problem in which a child under the age of consent is involved in an act resulting in sexual satisfaction of an adult or connivance of such an act. (1) although child sexual abuse is a frequently encountered condition which generally lasts for years, it is the most challenging diagnosis among various types of child maltreatment due to attempts to hide the act. although data relating to the prevalence of child sexual abuse differ widely, actual rates were reported to be 7% to 12% in luts in sexual abused children—yildirim et al 39urology journal vol 8 no 1 winter 2011 women and 5% to 8% in men.(1) sexual abuse can be seen in both children and adults. the importance of evaluation of child abuse in terms of its associated social and psychological dimensions is well-known.(2) child sexual abuse is defined as the involvement of a child in a sexual activity that he or she does not fully comprehend, is unable to give informed consent to, or for which the child is not developmentally prepared, or else that violates the laws or social taboos of the society.(3,4) in children exposed to sexual abuse, in addition to psychiatric disorders, such as anxiety, depression, substance dependence, borderline personality disorders, and post traumatic stress disorder, the presence of lower urinary tract symptoms (luts) have been reported in a limited number of studies.(5,6) apart from anatomopathologic and neurological causes, such as daytime lower urinary tract conditions, ectopic ureter, extrophy, epispadias, and urethral valve, luts usually develop because of bladder filling and/or voiding dysfunction. daytime lower urinary tract conditions which is seen at different rates ranging between 2% and 20%, encompass urgency, incontinence, weak stream, hesitancy, frequency, and all dysfunctional forms of urinary incontinence due to pediatric urinary tract infections.(7,8) extremely limited number of publications related to urinary system disorders in children exposed to sexual abuse are cited in the literature, which have reported the emergence of genitourinary symptoms, such as vaginal pain, enuresis, dysuria, frequency, and urgency versus daytime incontinence.(9) in this study, we evaluated the correlations between luts and age, gender, socioeconomic, and cultural levels of the sexual abused victims. materials and methods between november 2005 and december 2008, 862 subjects presented with sexual abuse to the outpatient clinics of department of forensic medicine. dysfunctional voiding and incontinence symptoms score guestionnaires were completed during face to face interview.(10) subjects with recurrent urinary tract infections, vesicoureteral reflux, neurogenic bladder, structural urinary tract abnormalities, and those with a history of pelvic surgery were excluded from the study. fifty-two patients, including 8 male and 44 female children/adolescents were evaluated retrospectively (group 1). in group 1, the subjects were categorized into two groups based on the type of sexual abuse as sexual touch (n = 35) and sexual penetration (n = 17). thirty age-matched children were evaluated as a control group (group 2). statistical analysis was done using spss (statistical package for the social sciences, version 18.0, spss inc, chicago, illinois, usa) software. for intergroup comparisons of categorical variables used in the study, chi-square test was utilized, while categorical variables were expressed as numerical values and percentages. for comparison of patients’age in sexual touch and sexual penetration groups, independent two-sample t-test was used. p values less than .05 were considered statistically significant. results the mean age of the patients was 12.2 ± 3.6 years and 12.0 ± 4.5 years in group 1 and group 2, respectively (p = .848). in group 1, the mean age of the subjects in sexual touch group and sexual penetration group was 10.8 ± 3.6 years and 14.9 ± 1.5 years, respectively. the difference between sexual touch and sexual penetration groups was statistically significant (p = .0001). victims of the sexual abuse were distributed based on their age as follows: 5 years ( n = 2; 3.8%), 6 years (n = 3; 5.8%), 7 years (n = 5; 9.6%), 8 years (n = 1; 1.9% ), 9 years (n = 2; 3.8%), 10 years (n = 1; 1.9%), 11 years (n = 4; 7.7%), 12 years (n = 5; 9.6%), 13 years (n = 5; 9.6%), 14 years (n = 4; 7.7%), 15 years (n = 11; 21.2%), 16 years (n = 4; 7.7%), and 17 years old (n = 4; 7.7%). the incontinence rate was 30.76% and 23.3% in groups 1 and 2, respectively. this difference was not statistically significant (p = .640). the rates of the bladder dysfunctions in children exposed to sexual abuse are depicted in table 1. luts in sexual abused children—yildirim et al 40 urology journal vol 8 no 1 winter 2011 as table shows, in sexual penetration group, nocturnal enuresis and diurnal incontinence were not detected. the urgency rate was 20% in the control group. the maternal and paternal educational levels of the sexual abuse survivors are demonstrated in table 2. discussion urinary incontinence which affects the psychological and social well-being of victims and parents has been defined by international children continence society as an inability to keep urine in the bladder with ensuing involuntary. daytime luts refers to dysfunctional bladder disorders, including uropathies and neuropathies, and are reportedly seen in 2% to 20% of pediatric population.(8,9) in the age group ranging between 6 to 12 years, daytime incontinence is seen more frequently in girls relative to boys (3.1% versus 2.1%).(11) the incidence of combined daytime incontinence in girls and boys has been reported as 1.5% and 2.8%, respectively.(12) within this age group, the incidence of urgency is reported to be 4.7% in girls and 1.3% in boys,(11) while the corresponding percentages for nocturnal incontinence are 1.5% and 8.9%, respectively.(11-14) in this study, the incontinence and urgency rates in groups 1 and 2 were found to be 30.76% and 34.6%, and 23.3% and 20%, respectively. several factors, including central or peripheral nervous system, local or systemic mediators, and psychologic status of the person may play a role in the normal voiding pattern.(15-17) any anatomic, functional, and neurologic impairment in any phase of the normal micturition cycle leads to urinary dysfunction. the etiologies of voiding dysfunctions are analyzed in two main groups as filling and voiding phase dysfunctions. among filling phase disorders, overactive bladder, urgency syndrome, underactive, or high-compliance neurogenic bladder (lazy bladder syndrome) can be enumerated, while sphincter insufficiencies constitute voiding phase disorders. we also recognize that neurogenic disorders, previous surgical interventions, congenital, metabolic, and psychogenic factors, and miscellaneous infections can impair normal physiologic mechanism of micturition. in addition to above-mentioned factors, in a limited number of studies, sexual abuse has been implicated in the etiopathogenesis of voiding dysfunction.(18) childhood sexual abuse is a complex problem with social, moral, and emotional dimension and is not usually disclosed to anyone, which prevents obtainment of precise and complete information about its actual incidence. it was found that as children grow older, they are exposed to various types of sexual abuse, and mind-body integration is broken. in our study, victims in the sexual penetration group are apparently older than those in the sexual touch group. the prevalence estimated to be 1.3/1000, which was reportedly higher in girls as in our study.(19) in another study, prevalence of childhood sexual abuse was detected to be in a much higher range (7% to 38%).(20,21) sexual abuse can be in the form of non-contact sexual touch (n = 35) sexual penetration (n = 17) daytime incontinence 9 (25.7%) 1 (5.9%) enuresis 6 (17.1%) diurnal incontinence 8 (22.9%) continence maneuvers 7 (20%) 1 (5.9%) urgency 15 (42.9%) 3 (17.6%) table 1. bladder dysfunctions in children exposed to sexual abuse sexual touch (n = 35) sexual penetration (n = 17) sexual touch (n = 35) sexual penetration (n = 17) illiterate 4 (11.42%) 0 primary school 28 (80%) 16 (94.11%) 27 (77.14%) 12 (70.58%) secondary school 2 (5.71%) 2 (5.71%) 2 (11.76%) high school 1 (2.85%) 1 (5.88%) 5 (14.28%) 3 (17.64%) university 1 (2.85%) table 2. the parental educational level of the children exposed to the sexual abuse luts in sexual abused children—yildirim et al 41urology journal vol 8 no 1 winter 2011 sexual abuse (obscene talks or voyeurism), sexual touch (touching private parts of the body), oral sex (oral-vaginal, oral-penile, or oral-anal intercourses), interfemoral contact, sexual penetration (vaginal, anal, or genital penetration with a finger or a foreign substance), sexual exploitation, child pornography, and child prostitution.(22) in our study, subjects were categorized in sexual touch and sexual penetration groups. although a very strong correlation exists between non-sexual abuse, and lower socioeconomic level,(23) in subjects of sexual abuse, the situation is still under debate. however, lower socioeconomic level has been detected in patients who referred for assessment of sexual abuse. even if association between childhood sexual abuse and socioeconomic status is not clear cut, it is markedly correlated with the parental educational level.(24) in our study, 28 (80%) mothers and 27 (77%) fathers in the sexual touch group were of primary school graduates. various studies have demonstrated the association between sexual abuse and pelvic pain, headache, gastroenterologic, and genitourinary symptoms.(25-29) in the afore-mentioned studies, psychologic problems have taken the lead, without attempting evaluation of luts. apparently, very limited number of studies have investigated the association between sexual abuse and luts. in adults who were exposed to sexual abuse during childhood, daytime lower urinary tract conditions can be seen more frequently when compared with those without such a history, and these complaints might extend into advanced ages. in a study by delago and colleagues on 161 female subjects exposed to sexual abuse, the authors detected genitourinary symptoms, such as dysuria and genital pain to be 47.7% and 71.6% in the sexual penetration group, while the corresponding percentages in the sexual touch group were 24.7% and 31.5 %, respectively.(30) in a study by klausner and associates, the incidence of urgency was found to be 20.1%,(21) while it was 42.9% in our study. in our study, it was seen that luts were much higher in sexual touch group than sexual penetration group, which may be due to the lower mean age in the sexual touch group. conclusion although a significant association was not detected between sexual abuse and luts, it was seen that luts, such as urinary incontinence and urgency were higher in children exposed to sexual abuse than the control group. therefore, potential luts should be taken into consideration in evaluation of children exposed to sexual abuse. scarcity of the subjects and lack of psychiatric evaluation of the children exposed to sexual abuse are limitations of this study. thus, further investigations with larger number of participants and detailed psychiatric evaluations should be performed to reveal etiopathogenesis of the association between sexual abuse and luts. conflict of interest none declared. references 1. gorey km, leslie dr. the prevalence of child sexual abuse: integrative review adjustment for potential response and measurement biases. child abuse negl. 1997;21:391-8. 2. burnam ma, stein ja, golding jm, et al. sexual assault and mental disorders in a community population. j consult clin psychol. 1988;56:843-50. 3. world health organization. managing child abuse: a handbook for medical officers. new delhi: world health organization, regional office for south-east asia, 2004 4. preventing child maltreatment: a guide to taking action and generating evidence. geneva, switzerland: who press, world health organization; 2006. 5. beitchman jh, zucker kj, hood je, dacosta ga, akman d. a review of the short-term effects of child sexual abuse. child abuse negl. 1991;15:537-56. 6. beitchman jh, zucker kj, hood je, dacosta ga, akman d, cassavia e. a review of the long-term effects of child sexual abuse. child abuse negl. 1992;16:101-18. 7. hellstrom al, hanson e, hansson s, hjalmas k, jodal u. micturition habits and incontinence in 7-year-old swedish school entrants. eur j pediatr. 1990;149: 434-7. 8. sureshkumar p, craig jc, roy lp, knight jf. daytime urinary incontinence in primary school children: a population-based survey. j pediatr. 2000;137:814-8. 9. klevan jl, de jong ar. urinary tract symptoms and urinary tract infection following sexual abuse. am j dis child. 1990;144:242-4. luts in sexual abused children—yildirim et al 42 urology journal vol 8 no 1 winter 2011 10. akbal c, genc y, burgu b, ozden e, tekgul s. dysfunctional voiding and incontinence scoring system: quantitative evaluation of incontinence symptoms in pediatric population. j urol. 2005;173:969-73. 11. forsythe wi, redmond a. enuresis and spontaneous cure rate. study of 1129 enuretis. arch dis child. 1974;49:259-63. 12. lee sd, sohn dw, lee jz, park nc, chung mk. an epidemiological study of enuresis in korean children. bju int. 2000;85:869-73. 13. jarvelin mr, vikevainen-tervonen l, moilanen i, huttunen np. enuresis in seven-year-old children. acta paediatr scand. 1988;77:148-53. 14. butler rj, heron j. the prevalence of infrequent bedwetting and nocturnal enuresis in childhood. a large british cohort. scand j urol nephrol. 2008;42:257-64. 15. fowler cj, griffiths d, de groat wc. the neural control of micturition. nat rev neurosci. 2008;9: 453-66. 16. reitz a, wefer b, schurch b. new understanding of central and peripheral interaction between bladder and sphincter function. eau update series. 2004;2: 153-60. 17. schulman sl. voiding dysfunction in children. urol clin north am. 2004;31:481-90, ix. 18. norredam m, crosby s, munarriz r, piwowarczyk l, grodin m. urologic complications of sexual trauma among male survivors of torture. urology. 2005;65: 28-32. 19. walrath c, ybarra m, holden ew, liao q, santiago r, leaf p. children with reported histories of sexual abuse: utilizing multiple perspectives to understand clinical and psychosocial profiles. child abuse negl. 2003;27:509-24. 20. finkelhor d. the international epidemiology of child sexual abuse. child abuse negl. 1994;18:409-17. 21. klausner ap, ibanez d, king ab, et al. the influence of psychiatric comorbidities and sexual trauma on lower urinary tract symptoms in female veterans. j urol. 2009;182:2785-90. 22. faller kc. child sexual abuse: an interdisciplinary manual for diagnosis, case management, and treatment: columbia university press; 1989. 23. yates tm, dodds mf, sroufe la, egeland b. exposure to partner violence and child behavior problems: a prospective study controlling for child physical abuse and neglect, child cognitive ability, socioeconomic status, and life stress. dev psychopathol. 2003;15:199-218. 24. bagley c, mallick k. prediction of sexual, emotional, and physical maltreatment and mental health outcomes in a longitudinal cohort of 290 adolescent women. child maltreat. 2000;5:218-26. 25. link cl, lutfey ke, steers wd, mckinlay jb. is abuse causally related to urologic symptoms? results from the boston area community health (bach) survey. eur urol. 2007;52:397-406. 26. randolph me, reddy dm. sexual abuse and sexual functioning in a chronic pelvic pain sample. j child sex abus. 2006;15:61-78. 27. domino jv, haber jd. prior physical and sexual abuse in women with chronic headache: clinical correlates. headache. 1987;27:310-4. 28. delvaux m, denis p, allemand h. sexual abuse is more frequently reported by ibs patients than by patients with organic digestive diseases or controls. results of a multicentre inquiry. french club of digestive motility. eur j gastroenterol hepatol. 1997;9:345-52. 29. kawsar m, long s, srivastava op. child sexual abuse and sexually transmitted infections: review of joint genitourinary medicine and paediatric examination practice. int j std aids. 2008;19:349-50. 30. delago c, deblinger e, schroeder c, finkel ma. girls who disclose sexual abuse: urogenital symptoms and signs after genital contact. pediatrics. 2008;122: e281-6. letter impact of the covid-19 pandemic on urology practice in indonesia: a nationwide survey firstly discovered on december 2019 in wuhan, china, coronavirus disease 2019 (covid-19) has spread rap-idly and widely throughout the world.1 the first positive case in indonesia was confirmed in early march 2020 and this number has increased exponentially until today. this pandemic has forced changes in many aspects of life including healthcare practices. even though management of covid-19 is a “different field” to urology practice, covid-19 is having a great impact on daily urology practice. therefore, we conducted a nationwide survey to investigate the impact of the covid-19 pandemic on urology practice in indonesia through a survey. a survey was distributed using survey monkey (www.surveymonkey.com), a cloud-based online survey, in april 2020 to urologists registered in the indonesian urology association (iua) database and urology residents in all centres across indonesia. some of the questions within the survey were adapted from questionnaire developed by societe internationale d’ urologie (siu).2,3 demographic, practice pattern of urologist, and prioritization of surgery during covid-19 pandemic was investigated by this survey. for urologist practice pattern, this survey also differentiated and compared between public and private practice. of the total 485 eligible urologists and 220 eligible urology residents as a respondent, 369 urologists (76% response rate) who came from 30 out of 34 provinces and 220 urology residents (100% response rate) participated in this study with 89.7% and 97.7% overall completeness, respectively. the urologist’s median (range) of age is 40 (30-77) years old and urology resident’s median (range) of age is 30 (24-38) years old. thirty-five out of 369 urologists (9.5%) and 59 out of 220 (24.8%) had been appointed as suspected case with two urologists and five urology residents had tested positive for covid-19. several strategies had been developed by urologists and their hospitals to adjust towards the covid-19 epidemic situation, such as physician rotation and reduction of working hours. in terms of urology resident training, indonesia has five urology centres, each of which has affiliated hospitals where residents undergo rotation. however, during covid-19 period, all centres called resident back from the affiliated hospitals, except bandung urology center in west java province. outpatient services during covid-19 pandemic during this pandemic, more than two-thirds of respondents still preferred to continue face-to-face consultation in both public and private hospital. only small proportion of respondents (2.2% in public hospital and 6.2% in private hospital) stopped all outpatient clinic consultation. surgery services during covid-19 pandemic the survey found that more than 60% of urologists preferred to postpone the majority (66%) or all elective surgery in both public and private hospitals. moreover, 77% and 68% respondents cancelled the surgery if the patient had covid-19 related symptom or required intensive care unit service after the surgery, respectively. amongst urologists who continued to conduct elective surgeries, most conducted covid-19 screening as part of elective surgery preoperative preparation (74.6% and 81.7% at public and private hospitals, respectively). more than 50% of the urologists who continued to conduct elective surgery had never performed laparoscopic surgery in their practice. however, of those who had previously performed laparoscopic surgery, the majority (95.3% at public hospitals and 97.1% at private hospitals) did not continue to perform laparoscopic procedures during the covid-19 pandemic. measures that had been taken to prevent sars-cov-2 transmission in public or private hospitals, included reducing the number of operating rooms (ors), reducing the number of staff (59.5% and 63.9%, respectively), and not rotating staff in the or during surgery (26.6% and 33.6%). a small proportion of respondents (1.2%) had cancelled surgery that required general anaesthesia (ga) or had entered the or after the intubation was completed by the anaesthesiologist. when treating patients who required emergency surgery, most urologists (80.7% and 84.3% at public and private hospitals, respectively) treated patients as covid-19 positive. use of personal protective equipment the survey showed that surgical mask (> 90% in both public and private hospital), face shields (about 80% in both public and private hospital), medical gloves (about 80% in both public and private hospital), and surgical cap (about 80% in both public and private hospital) were well utilized and provided by the hospital for urologist and urology resident. medical gown availability was appeared to be more limited among urology residents as compared to urologists (about 80% for urologist vs 60% for urology resident). for n95 mask, the survey revealed that only nur rasyid1*, ponco birowo1, dyandra parikesit2, fakhri rahman1 1department of urology, cipto mangunkusumo hospital faculty of medicine, universitas indonesia. 2department of urology, universitas indonesia hospital faculty of medicine, universitas indonesia. *correspondence: urology department, cipto mangunkusumo hospital, faculty of medicine universitas indonesia, jakarta, indonesia. tel. +62 21-3152892. e-mail: nur.rasyid@gmail.com. received april 2020 & accepted july 2020 urology journal/vol 17 no. 6/ november-december 2020/ pp. 677-679. [doi: 10.22037/uj.v16i7.6459] 60% of urologist and urology resident used this type of mask at public hospitals as compared to more than 90% of urologists in private hospital (however only provided by 50% private hospital). selection and prioritisation of surgery the urologists’ and urology residents’ opinions regarding selection and prioritisation of surgery is shown in figure 1. since the number of covid-19 patients is still increasing in indonesia, adjustments to this situation are vital to healthcare providers in order to provide the best service to patients during the pandemic, while still maintaining the highest possible safety. from the data retrieved from the survey, it found two urologists and five urology residents reported having contracted covid-19. to prevent further spread of infection in the future for healthcare provider and patient in the hospital, several step should be made, such as zoning to separated non-covid-19 patient from covid-19 patient, screening of covid-19 using polymerase chain reaction (pcr) test to all elective surgery patient, ppe utilization and its provision by both hospital and the government, excellent patient selection for elective surgery, and optimization of tele-consultation. regarding urology service, (iua), as an organization accommodating all indonesian urologists, has published recommendations for urologists during the figure 1. selection and prioritisation of surgery: (a) urologists’ surgery selection, (b) urology residents’ opinions towards surgery selection, (c) urologist’s assessment of surgery priorities, and (d) urology residents’ opinions of surgery priorities vol 17 no 06 november-december 2020 678 covid-19 pandemic. these recommendations cover outpatient clinics, surgery services, ppe use, and patient selection,4 thus could be useful guidance for indonesian urologist to provide best care to patients during covid-19 pandemic, while still maintaining safety of their own health. this survey showed that face-to-face consultation remained the primary consultation method for outpatient services. even though telemedicine is being developed and the indonesian government had been proactive by providing national policy support and for the development of telemedicine, telemedicine is still unpopular among urologists of whom less than one quarter have used it.5,6 therefore, this covid-19 pandemic should be a momentum to develop this online consultation tool. in addition to emergency surgery, there are several urological procedures which are recommended to be done due to risk of disease progression. iua recommends that procedures for patients with severe disease should to not be deferred, including surgery for muscle invasive bladder cancer or in situ bladder cancer, testicular tumours, ct3+ kidney tumours, high-risk prostate cancer which cannot be treated by radiation therapy, upper tract urothelial tumours, adrenal cortical carcinoma, and penile tumours. to help urologist or other surgeon decided surgery prioritization, a scoring tool could be used, such as medically necessary, time-sensitive (ments) scoring system.7 this survey had a high response rate and provides a picture of the impact of covid-19 on urology practices in indonesia. this survey revealed that the covid-19 pandemic impact urology services in indonesia which could be seen in reduce of elective surgery number and outpatient clinic practice pattern. moreover, no difference was observed between public and private hospital during covid-19 pandemic. references 1. li q, guan x, wu p, wang x, zhou l, tong y, et al. early transmission dynamics in wuhan, china, of novel coronavirus–infected pneumonia. n engl j med. 2020;382:1199– 207. 2. gravas s, bolton d, gomez r, klotz l, kulkarni s, tanguay s, et al. impact of covid-19 on urology practice: a global perspective and snapshot analysis. j clin med. 2020;9:1730. 3. gravas s, fournier g, oya m, summerton d, mario r, chlosta p, et al. prioritising urological surgery in the covid-19 era : a global reflection on guidelines. eur urol focus. 2020. doi: 10.1016/j.euf.2020.06.006. 4. rasyid n, atmoko w, daryanto b, wahyudi i, hamid arah. rekomendasi pelayanan urologi terkait covid-19. 1st ed. rasyid n, atmoko w, daryanto b, wahyudi i, hamid arah, editors. jakarta: ikatan ahli urologi indonesia; 2020. 5. marcelo a, ganesh j, mohan j, kadam db, ratta bs, kulatunga g, et al. governance and management of national telehealth programs in asia. stud health technol inform. 2015;209:95–101. 6. varghese s, scott re. categorizing the telehealth policy response of countries and their implications for complementarity of telehealth policy. telemed j e-health. 2004;10:61–9. 7. prachand et al. medically necessary, time sensitive procedures: scoring system to ethically and efficiently manage resource scarcity and provider risk during the covid-19 pandemic. j am coll surg 2020;231:281-8. case report 679 urol_montage.pdf erratum 71urology journal vol 6 no 1 winter 2009 erratum on page 255 of volume 5, number 4 of the urology journal (autumn 2008), the name of the second author, sepideh vahhabi, had been missed in the revised manuscript (effect of saffron on semen parameters of infertile men) submitted to the journal’s web site. the names of the authors should have read as follows: mohammad heidary,1 sepideh vahhabi,2 jahanbakhsh reza nejadi,3 bahram delfan,3 mehdi birjandi,2 hossein kaviani,2 soudabeh givrad4 1department of urology, lorestan university of medical sciences, khorramabad, iran 2shohada-e-ashayer hospital, lorestan university of medical sciences, khorramabad, iran 3department of anesthesiology, lorestan university of medical sciences, khorramabad, iran 4urology and nephrology research center, shahid beheshti university (mc), tehran, iran urol j. 2009;6:71. www.uj.unrc.ir case report 133urology journal vol 7 no 2 spring 2010 bilateral laparoscopic anatrophic nephrolithotomy for managing staghorn renal calculi akbar nouralizadeh, nasser simforoosh, parham masoudi, mohammad hossein soltani, ahmad javaherforooshzadeh urol j. 2010;7:133-5. www.uj.unrc.ir keywords: calculi, laparoscopy, nephrolithotomy, pyelography urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran corresponding author: akbar nouralizadeh, md urology and nephrology research center, no.103, 9th boustan st, pasdaran ave.,tehran, iran tel: + 98 21 2256 7222 fax: + 98 21 2256 7282 e-mail: nouralizadeh@yahoo.com received february 2009 accepted october 2009 figure 2. sutures were buttressed by hemostatic clip instead of knots. figure 1. stone was removed from nephrotomy incision on brodel line. introduction in the current age of minimally invasive therapy, it is reasonable to offer open nephrolithotomy as the first line treatment for patients with complete staghorn renal calculi and/or infandibular stenosis. (1) the role of laparoscopic surgery as a minimally invasive method to manage staghorn renal calculi was formerly discussed only in limited articles.(2-4) in this case, we performed bilateral laparoscopic anatrophic nephrolithotomy (lan) for managing bilateral staghorn renal calculi in two separate sessions. case report the patient was a 52-year-old man who presented to the urology clinic with abdominal pain. ultrasonography revealed a large renal stone measuring 52 mm and mild hydronephrosis in the right side as well as a 56-mm stone with focal stasis in the left side. intravenous pyelography confirmed bilateral radiolucent staghorn renal calculi with mild stasis in both kidneys. the patient underwent right lan, which was performed transperitonealy via 4 ports in the right flank position. after superior retraction of the spleen and the liver, and medial mobilization of the colon, the renal pedicle was exposed. only the renal artery was clamped using a bulldog clamp. a nephrotomy incision was made on the brodel line (figure 1). then, the stone was extracted from the bilateral laparoscopic nephrolithotomy—nouralizadeh et al 134 urology journal vol 7 no 2 spring 2010 abdominal cavity using a surgical glove as an endo-bag. later, the incision was closed using 0 vicryle continuous sutures and sutures were buttressed by hemostatic clip instead of knots (figure 2). a ureteral stent was not inserted. the patient underwent left lan 6 months later with similar technique. during the right lan, blood loss was 235 ml; warm ischemia time was 26 minutes and operative time was 165 minutes. pre and postoperative serum creatinine were 1.9 and 1.85 mg/dl, respectively. hospital stay was 6 days and this period was uneventful. postoperative ultrasonography showed no residual stone. intravenous pyelography was performed 3 months after the operation and showed proper excretion of the right kidney (figure 3). no blood transfusion was needed in the left lan. warm ischemia time was 28 minutes and operative time was 180 minutes. pre and postoperative serum creatinine were 1.62 and 1.75 mg/dl, respectively. hospital stay was 6 days and because of drain leakage, a ureteral stent was inserted. thereafter, leakage was stopped the day after stent insertion. computed tomography performed 6 weeks later, revealed no residual stones (figure 4). discussion at present, there is no clear threshold to define whether a staghorn stone is amenable to open stone surgery or to a minimally invasive technique; and the surgeon’s judgment, experience, and instrument availability are the most important factors in this regard.(5) in spite of great advance in endoscopic procedures, in specific circumstances such as large stone volume, complexity of stone, and anatomical abnormality, the staghorn renal calculi need to be managed with open stone surgery. open anatrophic nephrolithotomy provides a 91% to 94% stonefree rate(6) and may be a cost-effective alternative to multiple endourological treatment sessions, but it is associated with some postoperative morbidities and prolonged recovery;(4) thus, laparoscopy has gained increasing importance for managing staghorn renal calculi. meria and colleagues concluded that laparoscopic pyelolithotomy could be considered as an alternative to percutaneous nephrolithotomy for large pelvic stones(7) and deger and associates reported the first use of lan for a staghorn stone in adult patients.(8) in 2008, simforoosh and figure 4. computed tomography 6 weeks after the second operation: no stone was seen in both of the kidneys. figure 3. intravenous pyelography 3 months after the first operation: proper excretion of the right kidney without residual stones. bilateral laparoscopic nephrolithotomy—nouralizadeh et al 135urology journal vol 7 no 2 spring 2010 coworkers reported 5 patients who underwent ipsilateral lan with acceptable stone-free rate and low morbidity.(2) by presenting this case, we cannot recommend laparoscopy as the method of choice for staghorn renal calculi, due to our small sample size, but with further investigations, lan may be considered as a suitable alternative to open stone surgery to manage staghorn renal calculi in the future. conflict of interest none declared. references 1. paik ml, wainstein ma, spirnak jp, hampel n, resnick mi. current indications for open stone surgery in the treatment of renal and ureteral calculi. j urol. 1998; 159(2): 374-8. 2. simforoosh n, aminsharifi a, tabibi a, et al. laparoscopic anatrophic nephrolithotomy for managing large staghorn calculi. bju int. 2008; 101(10): 1293-6. 3. nambirajan t, jeschke s, albqami n, abukora f, leeb k, janetschek g. role of laparoscopy in management of renal stones: single-center experience and review of literature. j endourol. 2005; 19(3): 353-9. 4. kaouk jh, gill is, desai mm, et al. laparoscopic anatrophic nephrolithotomy: feasibility study in a chronic porcine model. j urol. 2003; 169(2): 691-6. 5. segura jw, preminger gm, assimos dg, et al. nephrolithiasis clinical guidelines panel summary report on the management of staghorn calculi. the american urological association nephrolithiasis clinical guidelines panel. j urol. 1994; 151(6): 164851. 6. assimos dg, wrenn jj, harrison lh, et al. a comparison of anatrophic nephrolithotomy and percutaneous nephrolithotomy with and without extracorporeal shock wave lithotripsy for management of patients with staghorn calculi. j urol. 1991; 145(4): 710-4. 7. meria p, milcent s, desgrandchamps f, mongiat-artus p, duclos jm, teillac p. management of pelvic stones larger than 20 mm: laparoscopic transperitoneal pyelolithotomy or percutaneous nephrolithotomy? urol int. 2005; 75(4): 322-6. 8. deger s, tuellmann m, schoenberger b, winkelmann b, peters r, loening sa. laparoscopic anatrophic nephrolithotomy. scand j urol nephrol. 2004; 38(3): 263-5. case report 136 urology journal vol 7 no 2 spring 2010 external genitalia entrapment a case report walid massoud, pascal hajj, ayman awad, joseph chabenne, pascal eschwege, stéphane droupy, yacine hammoudi, gérard benoît urol j. 2010;7:136-7. www.uj.unrc.ir keywords: male genitalia, ischemia, wounds and injuries urology department, bicêtre hospital, le kremlin-bicêtre, france correponding author: massoud walid , md chu de bicêtre, department of urology, 78, rue du général leclerc, 94275, le kremlin-bicêtre, france tel : +33 699 114 939 fax : +33 145 212 047 e-mail : walidmassoud@yahoo.fr received march 2009 accepted july 2009 introduction external genitalia entrapment (ege) is a rare clinical entity requiring urgent and efficient management.(1) if left untreated, it may result especially in vascular compromise to the external genitalia soft tissue structures. (2) management poses unique challenges to the treating physician through variable presentation as well as the lack of specifically designed treatment options. case report the fire brigade brought a 45-yearold schizophrenic man to the emergency department with a 5-hour history of ege in a thick nonexpandable silver ring. he was anxious and in a considerable pain. the glans and the penis shaft had been cyanosed and enlarged with an obvious swelling of the scrotum and foreskin (figure 1). in fact, the patient suffered from a behavioral disorder and in his past medical history, we noted a traumatic colic perforation by a foreign body. this time, the entry had begun with one testis followed by the other one and finished with the penis. the patient had used oil to facilitate the maneuver. on physical examination, he complained of numbness of the glans and the penile dorsal artery pulse was bearly perceptible. he had voiding difficulties, but was not in acute urinary retention. under neuroleptic analgesia, a malleable retractor was negotiated under the ring to safeguard the underlying skin (figure 2) and the ring was figure 1. cyanosed and enlarged glans with an obvious swelling of the scrotum and foreskin. figure 2. malleable retractor negotiated under the ring to safeguard the underlying skin. external genitalia entrapment— massoud et al 137urology journal vol 7 no 2 spring 2010 cut in 2 places with a diamond-tipped oscillating splint saw. the whole procedure took about 1 hour. after removing the ring, the circulation and the skin color were quickly restored to the external genitalia, which were undamaged. there was an unremarkable change on scrotal ultrasonography. the swelling gradually subsided and the patient was capable of urinating. on the follow-up of 2 and 6 months, the uroflowmetry showed a maximum flow rate around 25 ml/s and the scrotal ultrasonography demonstrated a normal vascularization and trophicity of the testicular parenchyma. discussion a strangulation metal ring is occasionally encountered in urologic emergencies.(3,4) external genitalia entrapment is rarer than penile entrapment, but is a more serious emergency condition, which can lead to infarction.(5-8) various nonmetallic and metallic constricting objects, including bottles, rings, hairs, threads, steel nuts, rubber bands, etc(3,4,9,10) are placed on the external genitalia to increase sexual performance or because of autoerotic intentions. (4,6) in the worldwide literature, penile entrapment has been reported,(3-14), but to our best knowledge, this is the first report of external genitalia entrapment. the main objective in this situation is decompression to facilitate free blood flow and micturition.(4,6) metallic rings rarely cause severe mechanical injuries, but they can lead to severe vascular complications.(4) various procedures have been proposed, including the common metal ring cutter, cutting tang, metal saw, dremel moto-tool kit, anspach cement eater, high-speed dental drill, string method, and wrapping by package cord.(3-5,8-10,13-15) removal of strangulating constricting devices requires resourcefulness to perform the removal simply and effectively, and with as little discomfort for the patient as possible. in some cases, a little premedication is helpful; however, only very few patients require general anesthesia.(4) conflict of interest none declared. references 1. xu t, gu m, wang h. emergency management of penile strangulation: a case report and review of the chinese literature. emerg med j. 2009;26:73-4. 2. ivanovski o, stankov o, kuzmanoski m, et al. penile strangulation: two case reports and review of the literature. j sex med. 2007;4:1775-80. 3. pannek j, martin w. penile entrapment in a plastic bottle. j urol. 2003;170:2385. 4. perabo fg, steiner g, albers p, muller sc. treatment of penile strangulation caused by constricting devices. urology. 2002;59:137. 5. may m, gunia s, helke c, kheyri r, hoschke b. penile entrapment in a plastic bottle a case for using an oscillating splint saw. int urol nephrol. 2006;38: 93-5. 6. maruschke m, seiter h. [total infarction of the penis caused by entrapment in a plastic bottle]. urologe a. 2004;43:843-4. 7. kore rn, blacklock ar. ring the fire brigade. br j urol. 1996;78:948. 8. osman m, al kadi h, al hafi r. gangrene of the penis due to strangulation by a metallic ring. scand j urol nephrol. 1996;30:77-8. 9. mcgain f, freedman d. penile entrapment in a bottle: the case for using a diamond-tipped portable glass saw. bju int. 1999;83:1071-2. 10. huang jk, holt d, philp t. penile constriction by foreign bodies: the use of a dental drill. br j urol. 1997;79:801. 11. drachenberg d, nguan c, norman rw, lawen j. penile entrapment injury: a case report. can j urol. 1999;6:709-12. 12. kadioglu a, cayan s, ozcan f, tellaloglu s. treatment of penile incarceration in an impotent patient. int urol nephrol. 1995;27:639-41. 13. vahasarja vj, hellstrom pa, serlo w, kontturi mj. treatment of penile incarceration by the string method: 2 case reports. j urol. 1993;149:372-3. 14. bhat al, kumar a, mathur sc, gangwal kc. penile strangulation. br j urol. 1991;68:618-21. 15. tobe t, igarashi t, murakami s. strangulation of the scrotum by a metal ring. br j urol. 1994;73:711. reconstructive surgery 115urology journal vol 7 no 2 spring 2010 ventral bulbar augmentation a new technical modification of oral mucosa graft urethroplasty for stricture of the proximal bulbar urethra divakar dalela, rahul janak sinha, satya narayan sankhwar, vishwajeet singh purpose: complication rates with ventral onlay technique of oral mucosa graft urethroplasty have been attributed to the poor ventral support for the graft. we herein describe a new technique which overcomes these problems and also discuss the short-term follow-up. materials and methods: in a prospective study conducted between january 2006 and june 2008, 13 patients with proximal stricture of the bulbar urethra underwent ventral bulbar augmentation. in this technique, the graft was sutured only to the bulbar urethra and the rest of spongiosal tissue was closed superficially. longitudinal incisions were given in the partial depth of the bulb, adjacent to the suture line and were sutured together over the first suture line. results: the mean follow-up period was 16.4 months (range, 6 to 30 months). two of the patients developed restricture; one at the proximal anastomosis of the graft with native urethra and one at the distal anastomosis. remaining 11 patients have satisfactory postoperative uroflow rates and are doing well. the success rate at the last follow-up was 84.6%. conclusion: this technique exploits the local bulbar anatomy by successfully moving the lateral bulbar tissue medially, below the ventrally placed mucosal graft. this results in a thicker ventral bulbar platform which provides enhanced support to the graft. urol j. 2010;7:115-119. www.uj.unrc.ir keywords: urethral stricture, treatment outcome, oral mucosa department of urology, csmmu (formerly kgmu), lucknow, (u.p.), india corresponding author: rahul janak sinha, ms, mch department of urology, csmmu (kgmu), lucknow, 226003, india tel: +91 941 500 30 51 e-mail: rahuljanaksinha@rediffmail.com received february 2009 accepted october 2010 introduction ventral onlay is one of the successful techniques of oral mucosa graft urethroplasty, especially for strictures in the bulbar urethra. (1) despite its popularity, ventral onlay is plagued by complications like fistula, sacculation, and pseudodiverticulum formation, which in turn may cause postvoid dribbling and ejaculatory failure. sequestration of the semen and residual urine inside the pseudodiverticulum may further compromise state of the adjacent urethra and lead to recurrent stricture disease.(2) ventral bulbar augmentation (vba) is a new technical modification which brings the lateral spongiosal tissue ventro-medially. this modification decreases the complication rates of ventral onlay and enhances the success rates by augmenting the thickness of that portion of the bulb, which forms the base for the ventral graft. initially, vba was performed on a few patients as a pilot project.(3) since the results were encouraging, a prospective study was undertaken ventral bulbar augmentation—dalela et al 116 urology journal vol 7 no 2 spring 2010 to assess the impact of vba in larger number of patients suffering from stricture of the proximal bulbar urethra. materials and methods in this prospective study conducted between january 2006 and june 2008, 13 patients with stricture of the proximal bulbar urethra underwent vba urethroplasty. an inclusion criterion was stricture length more than 2 cm. thus, patients having short stricture (< 2cm) were excluded. nine patients did not know the cause of their stricture, in 2 of the patients it was due to the urethral catheterization and in the remaining 2, it was due to trauma. the mean duration of the disease was 27 months (range, 3 months to 4 years). four patients had co-morbid conditions at the time of admission, 1 patient was positive for hepatitis b surface antigen (not having active liver disease), 2 patients had diabetes mellitus (controlled on medication), and 1 was hypertensive (controlled on medication). the site of stricture was the proximal bulbar urethra in all the 13 patients. seven patients had undergone at least one prior procedure; 3 of these had undergone optical internal urethrotomy once, 2 of them had undergone urethral dilatation a couple of times, 1 patient had undergone both urethral dilatation and optical internal urethrotomy and 1 patient was admitted with suprapubic catheter (spc) in situ, since he had gone into acute urinary retention and could not be catheterized per urethra. remaining 6 patients presented to the outdoor patient department with chief complaint of decreased urinary stream and frequency. routine laboratory and specific radiological investigations like retrograde urethrography and voiding cystourethrography were performed. uroflowmetry study with post-void residual urine measurement was done in those patients who were not catheterized at the time of admission and could void with a reasonable flow (patients on catheter or those with poor flow were excluded). mean stricture length was 3.1 cm (range, 2.1 to 4.9 cm). the duration of operation was slightly longer with vba compared to ventral onlay technique performed in the bulbar urethra (approximately, 15 to 20 minutes longer); the mean operative time was 195 minutes (range, 160 to 200 minutes). this could be due to the initial learning curve with the first few operations, since we did not divide the patients into subgroups due to small sample size. intra-operative blood loss was negligible and none of the patients required postoperative blood transfusion. one patient suffered from brief hypotension during the surgery, but was adequately resuscitated and did not have any postoperative sequel. postoperative complications were documented during the hospital stay and when the patient came for follow-up at regular time interval. procedure two surgical teams worked simultaneously with separate instruments for graft harvest and the perineal exposure. the oral mucosa graft was harvested under local anesthesia from the inner cheek as per our technique.(4-6) the technique of vba was performed on all the 13 patients by a single surgeon (dd) under regional anesthesia (spinal or epidural). a midline perineal incision was used for the bulbar urethra dissection. the graft was sutured only to the mucosal edges of the stricture defect as in ventral onlay (figure 1). a continuous 4-0 monofilament poliglecaprone-25 suture was then applied taking thin bites through the superficial portion of the bulb and closing the bulbar urethra. the inverted raw edges formed a vascularized bed for the buccal mucosal graft. figure 1. transverse section and front view of the bulbar urethra, respectively, demonstrating that the graft is sutured only to the mucosa. a b ventral bulbar augmentation—dalela et al 117urology journal vol 7 no 2 spring 2010 approximately, 5 mm on either side of this suture line, longitudinal incisions were given in partial depth of the bulb and the medial edges were sutured together over the first suture line (figure 2). the lateral edges of incision were then sutured as a third layer (figure 3). fibrofascial adhesions which adhere to the lateral aspect of the bulb and the undersurface of the perineal membrane were separated by blunt dissection, which permitted medial advancement of the bulbar tissue (figure 4). closure of the perineal incision was done in the conventional manner over a per-urethral catheter (puc). we do not insert a drain or spc on routine basis. in the postoperative phase, the patients were put on anti-erection drugs, such as diazepam. patients were discharged within a week with puc and spc (if inserted) in situ and called after 2 weeks in the outdoor patient department, where further investigations were ordered. pericatheter study was done, if no extravasation was visible, puc was removed and the patient was given a voiding trial. if the flow was satisfactory, spc was removed after a couple of days. uroflow study with post-void residual urine measurement was done and repeated at regular intervals during the follow-up period. if the patient complained of poor flow or the flow was less than 14 ml/s, then additional investigations like retrograde urethrography or cystoscopy were advised. statistical analysis the data were entered in the ms-excel computer program and all the analyses were carried out using spss (statistical package for the social science, version 15.0, spss inc, chicago, illinois, usa) software. the mean and standard deviations were calculated for continuous variables such as age and different lengths variables, and proportions (percentages) were calculated for discrete variables. chi-square test was used to compare dichotomous/categorical variables. paired t test was used to detect significance from baseline value to follow-up time in case of continuous variables and unpaired t test was used to detect the difference between two continuous variables. a p value less than .05 was considered statistically significant. figure 2. transverse and front view demonstrating parallel incisions adjacent to the midline. a b figure 3. front view demonstrating the closure in 2 layers over the previous closure. a b figure 4. cross-section view and front view demonstrating the concept of medial transposition of the ventral tissue by closure in 2 layers. a b ventral bulbar augmentation—dalela et al 118 urology journal vol 7 no 2 spring 2010 results the mean age of the patients was 34.7 years (range, 23 to 54 years). the mean follow-up period was 16.4 months (range, 6 to 30 months). in the immediate postoperative period, all the patients were symptom free. none of the patients developed a graft pseudodiverticulum, stenosis, fistula, or sacculation. of 13 patients, 2 developed restricture after 5 months and 7 months of their surgery, respectively. in 1, the stricture was at the proximal anastomosis of the graft with native urethra and in the other at the distal anastomosis. both the patients had initial encouraging postoperative uroflowmetry, but unfortunately, that deteriorated within 6 months of follow-up. both of them were subjected to one episode of optical internal urethrotomy and now the stricture has stabilized and they are doing well at a follow-up of 8 months and 14 months each. remaining 11 patients have satisfactory postoperative uroflow rates and are doing well. age, etiology, duration of disease, previous procedures, and co-morbid conditions had no statistical impact on the success rate, probably due to the small sample size. similarly, duration of the operation, stricture length, and graft length had no statistical impact on the success. patients were considered successful if they did not undergo any postoperative intervention and their uroflow rates were >14 ml/s. therefore, the success rate at the last follow-up was 84.6%. discussion spongioplasty after ventral onlay has been described earlier in the literature.(7-9) the technique of vba exploits local bulbar anatomy and successfully moves the lateral bulbar tissue ventromedially below the ventrally placed mucosal graft (figure 4). this modification is carried out by performing an epithelium-tourothelium anastomosis in which the spongiosum is avoided (figure 1); the adventitia of the corpus spongiosum is available for closure over the graft and allows the percolating blood of the spongiosum to provide vascularity to the graft. this step also adds a backing of support, which prevents any outpouching or sacculation. it has led to a high success rate in the long term.(7-10) morey and colleagues(7) operated on patients who had complex refractory strictures of the bulbar urethra and achieved 92% success rate. elliott and coworkers(8) assessed their long-term results in 60 patients; of these, 49 had undergone previous attempt at repair. bulbar stricture repair was successful in 54 patients (90%). kellner and associates(9) performed ventral onlay urethroplasty and spongioplasty on 18 patients and stated that 87% success rate was durable over the long term. hence, our success rate, albeit a little lower, is similar to that described in the literature. the only drawback of vba is that it is difficult to perform in a fibrosed bulbar urethra since fine dissection is difficult to perform due to dense adhesions. perforation of the bulb may occur which can cause bleeding. this obscures the local anatomy resulting in poor quality of spongioplasty and increases the operative time, ultimately leading to poor results. in these subjects, we prefer conventional ventral onlay. conclusion ventral bulbar augmentation is a good option for patients having stricture of the proximal bulbar urethra. patient selection is an important criterion before attempting this technique. further studies are required with a larger number of patients and a longer follow-up to validate the findings of this study. conflict of interest none declared. references 1. wessells h. ventral onlay graft techniques for urethroplasty. urol clin north am. 2002;29:381-7, vii. 2. dubey d, kumar a, bansal p, et al. substitution urethroplasty for anterior urethral strictures: a critical appraisal of various techniques. bju int. 2003;91: 215-8. 3. dalela d, sinha rj, sankhwar s, singh v. vid-06.04: ventral bulbar augmentation [vba]: a technique to enhance support of buccal mucosal graft placed ventrally for proximal bulbar urethral strictures. urology. 2007;70:186. 4. goel a, dalela d, sinha rj, sankhwar sn. harvesting buccal mucosa graft under local infiltration analgesiaventral bulbar augmentation—dalela et al 119urology journal vol 7 no 2 spring 2010 -mitigating need for general anesthesia. urology. 2008;72:675-6. 5. sinha rj, singh v, sankhwar sn. does tobacco consumption influence outcome of oral mucosa graft urethroplasty? urol j. 2010;7:45-50. 6. sinha rj, singh v, sankhwar sn, dalela d. donor site morbidity in oral mucosa graft urethroplasty: implications of tobacco consumption. bmc urol. 2009;9:15. 7. morey af, mcaninch jw. when and how to use buccal mucosal grafts in adult bulbar urethroplasty. urology. 1996;48:194-8. 8. elliott sp, metro mj, mcaninch jw. long-term followup of the ventrally placed buccal mucosa onlay graft in bulbar urethral reconstruction. j urol. 2003;169:1754-7. 9. kellner ds, fracchia ja, armenakas na. ventral onlay buccal mucosal grafts for anterior urethral strictures: long-term followup. j urol. 2004;171:726-9. 10. markiewicz mr, lukose ma, margarone je, 3rd, barbagli g, miller ks, chuang sk. the oral mucosa graft: a systematic review. j urol. 2007;178:387-94. igf-1-induced muscle-derived stem cells as a potential treatment of stress urinary incontinence in female rats chunjing chen1, ying xu2, yanfeng song1* purpose: stress urinary incontinence (sui) is prevalent among elderly women. this study aimed to discuss the potential of muscle-derived stem cells (mdscs)-based therapy in treating sui by exploring the effect of insulin-like growth factor-1 (igf-1) on transplanted mdsc and urethral sphincter function. materials and methods: bilaterally pudendal nerve-transected (pnt) female rats were divided into four groups: sham, pnt+ phosphate buffered solution (pbs) injection, pnt+igf-1/mdscs and pnt+ green fluorescent protein (gfp)/mdscs. igf-1 was expressed in mdscs by lentiviral vector. viable mdscs were detected by laser scanning confocal microscopy (lscm). the expression of myosin heavy chain (myhc), vascular endothelial growth factor (vegf), vegf receptor 2 (vegfr-2), microvessel density (mid) and urethral resistance function were assessed. results: igf-1 promoted the survival and differentiation of mdscs. igf-1-expressing mdscs facilitated local angiogenesis and muscle fiber regeneration, and alleviated symptoms of sui. conclusion: igf-1-expressing mdscs may be used as a novel treatment for patients with sui. keywords: insulin-like growth factor-1; muscle-derived stem cells; myogenic differentiation; pro-survival; stress urinary incontinence introduction urinary incontinence (ui) describes the loss of blad-der control, often leading to the accidental leakage of urine. ui is especially common among elderly women, with over 200 million cases worldwide(1). the most common subtype of ui, stress urinary incontinence (sui) refers to urine loss triggered by physical activities, such as coughing and exercise. the pathophysiology of sui has been associated with the apoptosis of urethral sphincter cells in aging women. risk factors for sui also include obesity, nerve injuries, pregnancy and childbirth. to maintain urinary continence, the pudendal nerves that regulate the external urethral sphincter are stimulated, resulting in urethral contraction. currently, transurethral bulking agent injection is a widely used minimally invasive procedure to increase urethral resistance. however, such operation can only relieve the symptoms and does not completely eradicate the ui condition, and the injection of materials (bulking agents) into the tissues surrounding the urethra can lead to serious complications. the advancement in tissue engineering suggests a new potential in using muscle-derived stem cells (mdscs)-based therapy to regenerate and restore the urethral function in sui patients(2,3). during myogenesis, myoblasts, or skeletal muscle precursors proliferate and differentiate, followed by an increase in the expression of muscle-specific genes. subsequently, my1fuzong clinical medical college of fujian medical university, fuzhou, fujian 350025, china. 2fujian provincial maternity and children’s hospital, affiliated hospital of fujian medical university, fuzhou, fujian 350005, china. *correspondence: fuzong clinical medical college of fujian medical university, fuzhou, fujian 350025, china. fax: 86-0598-8803363. e-mail: yanfengsonglove@126.com. received november 2021 & accepted september 2022 oblasts fuse into multinucleate myofibers, forming new skeletal muscle(4). in adults, cells capable of becoming myoblasts remain inactive as satellite cells until injury, during which they will proliferate and fuse to repair the damaged muscle(4). thus, the regeneration of skeletal muscle tissue is dependent on the number of satellite cells, which declines with aging(5). on the other hand, mdscs can serve as precursors of the satellite cells in adults, aiding in muscle repair(6). however, it remains unknown whether mdscs would go through myogenic differentiation in sui patients after implantation. igf-1, a peptide growth hormone and an anti-aging factor, can alleviate the age-related muscle atrophy while facilitating cell proliferation in adult rats after muscle damage(7). on the cellular level, igf-1 plays dual roles in inhibiting apoptosis and promoting differentiation of transplanted myoblast cells(8,9). another study showed that igf-1 could promote proliferation and myogenic differentiation of urethral rhabdosphincter satellite cells(10). therefore, igf-1 may be able to mediate the growth of skeletal muscle substitutes and the restoration of muscle function in vivo(11). herein, we hypothesized that igf-1 could promote better viability, growth and differentiation of mdscs, aiding in the restoration of urethral sphincter function in sui patients. to test our hypothesis, we used bilateral pudendal nerve-transected female rats as the model for sui to investigate the effects of igf-1 on mdscs. urology journal/vol 19 no. 6/ sep[november-december 2022/ pp. 452-459. [doi:10.22037/uj.v19i.7066] female urology materials and methods experimental animals and model establishment the animal study was approved by our hospital institutional animal care and use committee. sixty 4-weekold female rats were randomly assigned to four groups: sham (s), pnt+pbs injection (p), pnt+gfp/mdscs injection (m) and pnt+igf-1/mdscs injection (i). all but sham rats received bilateral pudendal nerve transection (pnt) (12). briefly, the rats were anesthetized by chloral hydrate [0.3 ml/100g, intraperitonal (i.p.)]. following a bilateral dorsal longitudinal incision, the pudendal nerve was isolated with operating microscope. the pudendal nerve was transected in a 2cm segment on both sides of the vertebral column. sham rats were put through the same surgical procedures with the exception of pudendal nerve transection. animal treatment two weeks post-pnt/sham, transplantation was performed. each rat was anesthetized and urethra was isolated. an injection was made on each side of the 1/3 upper middle urethra (0.5cm to the bladder, 3 and 9 o’clock) with a micro-syringe. sham rats received the same surgical intervention without injection. group p was microinjected with 50 µl 1xpbs. group m was injected with 50 µl gfp/mdscs (1 x 106 /50 µl pbs). group i was injected with 50 µl igf-1/mdscs (1 x 106 /50 µl pbs). each group was then subdivided into 1-week (n=5), 2-week (n=5) and 4-week (n=5) subgroups randomly. lentiviral vector construction and titer determination rat igf-1 cdna (genechem, shanghai, china) was cloned into gfp-carrying igf-1 recombinant lentiviral vector (pgc-fu) (genechem, shanghai, china), confirmed by sequencing (invitrogen) (supplementary table 1). lentiviral titer was determined by real-time fluorescence quantitative pcr (rt-qpcr). briefly, 293t cells (1 x 105 cells/500 µl/well) were passaged in 24-well tc plate every 48 hours. lentiviral extract was serial-diluted in dmem/f12 medium (10% fbs) and mixed with 293t. the infected cells were incubated at 37c, 5% co2. after 4 days, rna was extracted with l ml trizol (invitrogen) and treated with 20µl rna enzyme inhibitor (rnasin), and concentration was determined by spectrophotometer. rna was reverse-transcribed to cdna with m-mlv (promega); β-actin and egfp were amplified with sybr® premix ex taq (takarabio) (supplementary table 1). ∆ct was used to calculate titer in each sample. ∆ct >2 was considered significant. female urology 453 igf-1, mdscs in sui-chen et al. figure 1. purification and lentiviral transduction of mdscs. (a) p3-mdscs were isolated from the hind gastrocnemius and examined for cd34 and cd45 by flow cytometry, and immunostaining for sca-1 and desmin by immunofluorescence and immunocytochemistry, respectively. (b) similar morphological changes were observed in gfp/mdscs and igf-1/mdscs, shown in the upper panels; more than 90% of mdscs were infected by lentivirus vector as indicated by gfp fluorescence in the lower panels. (c) the expression of igf-1 was dependent on the levels of moi. the error bar representing mean and 95% ci. *indicates significant difference as compared to other groups (p < 0.05). lentiviral transduction of mdscs p3-mdscs were transduced with gfp-expressing lentiviral vector (gfp/mdscs), or with gfp-igf1-expressing bicistronic vector (igf-1/mdscs). transduction efficiency was assessed by fluorescence microscopy (olympus, japan). mdscs isolation mdscs were obtained from the hind gastrocnemius of 3-weeks-old wistar female rats by modified preplate technique(13). briefly, gastrocnemius muscles were removed, minced and dissociated with enzyme. rapidly adhering cells (racs) and slowly adhering cells (sacs) containing mdscs were obtained and were further purified preplating at each passaging step. mdscs purity assessment immunostaining and flow cytometry were used to assess cell purity. cd34, cd45, sca-1 and desmin were used to identify myogenic progenitors(14). p3-mdscs were washed with pbs and digested with 1% pancreatin. digestion was stopped 10% fetal bovine serum (fbs). cells were separated and was adjusted to 1 x 106 under microscope. mouse anti-cd34 (rat) pe-labeled monoclonal (santa cruz biotechnology) and mouse anti-cd45 (rat) pe-labeled monoclonal (biolegend) were added respectively, and sample was assessed on flow cytometer (becton-dickinson, usa) after 30min incubation at 37℃. meanwhile, cover slips were placed in the 6-well cell culture plates, where pancreatin-digested p3-mdscs were inoculated (0.5×105/ml/well). coverslip was treated with neutral balsam, followed by 3% hydrogen peroxide. coverslip was blocked by goat serum for 20min, and incubated in rabbit anti-sca-1 polyclonal (1:100, pharmingen, usa) or anti-desmin (1:100, boster biological technology co.ltd, china) at 4℃ overnight. coverslip was incubated in fitc-labeled igg (1:64) at 37℃ in dark for 45 min. coverslip was washed, dried, mounted, imaged at 200x magnification (olympus cx40). urodynamic test urodynamics were examined to assess urethral sphincter function. briefly, the rats were anesthesized to isolate the bladder. infusion pump and pressure sensor were connected to the urodynamic equipment (mms, netherlands). after emptying the bladder via grede method(15), sterile saline was infused into bladder at 5 ml/h, and voiding was observed. once the blue urine flowed out, maximum bladder capacity (mbc) was determined. the bladder was emptied multiple times and was filled with saline to half mbc. abdomen was gently pressed until urine was produced to determine the abdominal leak point pressure (alpp). the bladder was emptied and re-infused three times. h&e and masson staining all animals were euthanized four weeks post-injection. figure 2. the effect of igf-1 on mdsc survival and the expression of myhc. the isolated and transplanted mdscs in proximal urethra were examined for the effect of igf-1 on the mdsc survival and the expression of myhc. (a) mdsc survival in igf-1/mdscs and gfp/mdscs groups was shown. red arrows denote mdscs labelled with gfp. the error bar representing mean and 95% ci. *indicates statistical significance between two groups (p < 0.05). (b) mdsc differentiation in igf-1/mdscs and gfp/mdscs groups was shown. white arrows denoted myhc labelled with tirtc. igf-1, mdscs in sui-chen et al. vol 19 no 6 november-december 2022 454 to evaluate pathological changes in the urethra, proximal urethral tissues were embedded in paraffin, sectioned into 5-µm thick slices, and collected for routine h&e and masson’s trichrome staining (sigma, usa). for each group, four specimens were imaged at 200x magnification (olympus cx40 & imaging micropublisher 5.0 ptv). immunohistochemical analysis immunohistochemical analysis was performed on 8-µm thick cryo-sectioned slices and paraffin proximal urethra sections. sections were incubated with primary antibodies at 4 °c overnight, including rabbit anti-fviii r ag polyclonal antibody (zymed, usa; 1:100), mouse anti-myhc (rat) monoclonal antibody (abcam, uk; 1:200) and rabbit anti-vegf polyclonal antibody figure 3. sui symptoms after mdsc transplantation shown by urodynamic test. after mdsc transplantation, alpp and mbc were measured at different time all groups, including igf-1/mdscs, gfp/mdscs, pbs, and sham. similar results were observed in three independent experiments. *indicates significant difference as compared to the group pbs (p < 0.05). figure 4. pathological analysis of urethra four weeks after injection. the proximal urethral tissue samples were collected and processed for (a) h&e and (b) masson’s trichrome staining. (c) muscle to collagen ratio for each of the four groups was presented in chart. $, # and *indicate significant difference in comparision to other groups (p < 0.05). igf-1, mdscs in sui-chen et al. female urology 455 (sigma, usa, 1:100). sections were treated with corresponding secondary antibodies (1:100) for 45 min at room temperature. for each group, four specimens and five randomly selected fields were imaged under laser scanning confocal microscopy (lscm) (m510, zeiss, germany), and cx40 microscope (olympus). in the images, cells in blood vessels and the smooth muscle layer, as well as the rhabdosphincter layer in the sections, stained red while collagens stained blue. image analysis was done as described above and quantified figure 5. microvessel density analysis of rat urethra and the detection of vegf/ vegfr-2. four weeks after injection, proximal urethral tissue samples were collected from each of the four groups. results from three independent experiments were summarized in error bar representing mean and 95% ci. #, & and *indicate significant difference as compared to other groups (p < 0.05). (a) samples were processed for microvessel density analysis via immunohistochemistry of fviii-r ag. the arrows indicated newborn microvessels. (b) the expression of vegf was examined by immunohistochemistry. the arrows indicated vegf positive staining. (c) western blot analysis showed the level of vegfr-2 in the proximal urethral tissue samples. β-actin was used as an internal control. igf-1, mdscs in sui-chen et al. vol 19 no 6 november-december 2022 456 using the image-pro plus 6.0 image software. the software can automatically distinguish regions stained with different colors and accurately measure the areas of muscle and collagen to yield a muscle/collagen ratio. western blot total protein was extracted from urethra tissues lysates; protein concentration was determined by bca assay. proteins were separated by sds-page and electrotransferred to polyvinylidene fluoride (pvdf) membranes. all membranes were blocked by 3% bovine serum albumin (bsa) for 3 h at room temperature. membranes were incubated in primary antibody (anti-vegfr2, abcam; 1:200) overnight at 4 °c. β-actin was used as an internal control. after incubation in secondary antibody (1:100) for 45 min at room temperature, proteins were visualized by chemiluminescence (ecl) solution. statistical analysis results (mean ± sd) were analyzed with spss20.0. normality and homogeneity of variance test of the sample were performed previous to the statistical analysis. differences among groups and time points were analyzed by two-way anova and least-significant difference (lsd) test was used as post-hoc test, whenever a significant difference was found by the anova. unpaired t-test was applied for compare means of two groups. p < 0.05 was considered statistically significant. results purification and lentiviral transduction of mdscs after purification, mdscs expressed cd34 but not cd45 (figure 1a a,b), eliminating the possible contamination of hematopoietic stem cells(14). sca-1 and desmin by immunofluorescence and immunocytochemistry respectively showed that about 60% of the cell suspension was mdscs undergoing myogenic differentiation (figure 1a c,d)(14). after transduction, more than 90% of mdscs was infected by the igf-1-carrying lentivirus vector (2×108 tu/ml) in both gfp/mdscs group and igf-1/mdscs group, as indicated by gfp fluorescence (figure 1b). lastly, we noticed that the expression of igf-1 increased at higher multiplicity of infection (moi) (figure 1c). moi=30 was used as the optimal condition in subsequent analyses. igf-1 enhances mdsc survival and differentiation we next tested the effect of igf-1 on the survival and differentiation of mdscs. the isolated and transplanted mdscs in proximal urethra were identified by gfp. mdscs were found in the submucosa and muscular layer of middle urethra (figure 2a a). cell survival was higher in the igf-1/mdscs group compared to that in the gfp/mdscs group (figure 2a b; p < 0.05), in line with a previous study (16). next, we assessed myhc expression, a marker for later-stage muscle-specific protein in the igf-1/mdscs and gfp/mdscs groups. as expected, igf-1/mdscs showed higher expression of myhc, suggesting that igf-1 could promote mdsc differentiation (figure 2b). urodynamic testing after cell injection, six rats were withdrawn from the study due to urethra congestion or infection. abdominal leak point pressure (alpp) and maximum bladder capacity (mbc) after cell injection were assessed at three time points (1-week, 2-week, 4-week) (figure 3). at all time-points, alpp and mbc in the igf-1/mdscs and gfp/mdscs groups were significantly higher than those injected with pbs (p < 0.05), and slightly lower than sham rats (p > 0.05). these results suggested that mdsc transplantation could relieve sui symptoms in rats after pnt. furthermore, we noticed that there was an increase in alpps and mbc in the igf-1/mdscs treatment group in comparison to the gfp/mdscs group, but the difference was not statistically significant (p > 0.05). morphological changes in urethra h&e and masson’s trichrome staining revealed uniformly arranged tissues, including epithelium, connective tissue, striated muscle and smooth muscle in normal rat urethra (figures 4a and 4b). on the other hand, urethra samples from pbs-treated sui rats displayed denaturation, atrophy, unclear structure and sparse arrangement of striated muscles, as well as unclear collagen fibers (figures 4a and 4b). after mdsc transplantation, sui rats showed newly formed capillaries and muscle fibers with less fibrosis and clear morphology of collagen fibers, suggesting repair of damaged muscle tissues. in addition, igf-1/mdscs rats showed regenerated urethral morphology than gfp/mdscs rats (figures 4a and 4b). specifically, we noticed significantly higher muscle-to-collagen ratio in igf-1/mdscs rats, suggesting that igf-1 could promote the survival and differentiation of mdscs in sui rats (figure 4c). mdscs pretreated with igf-1 enhance cell neoangiogenesis fviii-r ag was used as a marker to quantify microvessel density(17) and its expression was mainly detected in a triated muscle layer (figure 5a). the expression of fviii-r ag in the igf-1/mdscs group and gfp/mdscs group were significantly higher than pbs and sham rats, suggesting that mdsc transplantation could lead to the formation of more microvessels (figure 5a, p < 0.05). additionally, there was a significant difference in the level of fviii-r ag between igf-1/mdscs and gfp/mdscs groups (figure 5a, p < 0.05). vascular endothelial growth factor (vegf), which promotes the growth of new blood vessels(18), was detected in the epithelial cells and muscle cells of middle urethra (figure 5b). the expression of vegf in igf-1/mdscs rats and gfp/mdscs rats was significantly higher than sham and pbs rats (figure 5b, p < 0.05). additionally, there was a significant difference between igf-1/mdscs and gfp/mdscs groups (p< 0.05). next, we examined the level of vegfr-2, the receptor of vegf(19). the expression of vegfr-2 in igf-1/mdscs and gfp/ mdscs groups was significantly higher than that in the pbs and the sham groups (p < 0.05). in addition, there was a significant difference in the level of vegfr-2 between igf-1/mdscs and gfp/mdscs groups (p < 0.05) (figure 5c). taken together, our results suggested that mdsc transplantation could trigger neoangiogenesis, which was further enhanced by igf-1. discussion ui is affecting over 200 million people worldwide. as the most common type of ui, sui was found to affect roughly one-third of the women, greatly reducing their igf-1, mdscs in sui-chen et al. female urology 457 quality of life(20). with the rapid development of tissue engineering techniques, stem cell therapy has shown some potential in sui treatment(6). mdscs can differentiate into muscle cells without inducing agents and have been successfully used as sui therapy(3). however, the promising therapeutic effect of mdscs depends heavily on the cell viability and differentiation at the transplanted site. the survival rate of those implanted cells is often limited due to negative host factors, including hypoxia, ischemia and oxidative stress. our study showed that igf-1 promoted viability and differentiation of mdscs in sui rats. specifically, urodynamic testing showed that mdsc treatment could alleviate the symptoms in sui rats. additionally, igf-1 facilitated the formation of new capillaries and muscles fibers with less fibrosis. this is the first time that igf1 was shown to enhance myogenic differentiation of transplanted mdscs in the urethra after damage. urodynamic testing reflects the functional changes of the neural-controlled urethral sphincter and is widely used in the diagnosis of urinary incontinence. our study showed that alpps and mbc were significantly higher in mdsc-treated rats and their levels would further elevate with igf-1 treatment. the results suggested that mdsc therapy could restore urethral sphincter continence while igf-1 further improved the efficacy of such treatment. however, previously, our group has shown that there was no significant difference in leak point pressure (lpp) after mdsc or mdsc fibrin glue (fg) mixture treatment. it is possible that fibrin glue has a short half-life time and was degraded soon after the treatment, leading to a decrease in the curative effect of the implanted cells. however, lentiviral vector transduction allowed igf-1 to be constitutively expressed, maintaining its level in mdscs. subsequently, igf-1-expressing mdscs could efficiently alleviate the symptoms of sui in rats by regenerating muscle fibers, thereby restoring their sphincter function. here we report several speculations regarding the underlying mechanisms of igf-1 acting on urethra rhabdosphincter. an earlier study reported that igf-1 aided in the myogenic differentiation of human urethral rhabdosphincter (rs) satellite cells via pi3-k, a signal transduction pathway that mediates metabolism, cell proliferation and survival, as well as angiogenesis(10). therefore, we speculated that through interaction with players of pi3-k, igf-1 was able to upregulate protein synthesis essential to tissue regeneration, leading to restored urethra sphincter function26. furthermore, our results suggested that igf-1 could suppress fibrosis, which improved the efficiency of muscle regeneration after tissue damage. lastly, igf-1 is a potent neurotrophic factor and was reported to promote nerve regeneration. therefore, igf-1 might also play a role in the nerve re-domination of the urethral sphincter, improving urethral sphincter function. angiogenesis accelerates local blood circulation and is essential for regeneration-dependent muscle repair. therefore, it is beneficial for the survival and growth of the implanted cells. our results showed that the density of new capillaries, as well as the expression of vegf/vegfr-2 protein, was significantly higher in igf-1-treated rats. vegf/ vegfr-2 pathway is a key regulator of blood vessel formation28. we speculated that igf-1 could stimulate the production of vegf in mdsc in urethral sphincter, promoting angiogenesis. it was previously reported that vegf could undergo autocrine or paracrine upregulation in mdsc. subsequently, vegf binds to vegfr-2 and promotes the formation of new blood vessels(21,22). on the other hand, due to the multilineage differentiation potential of mdscs, it is also possible that igf-1 could stimulate mdscs to differentiate into vessel-like structures. more experiments are needed to investigate whether angiogenesis at the implanted site correlates to the better survival and growth of mdscs. lastly, our findings in the current study should be considered in the light of some limitations that need to be further explored. first, we established the sui model by bilateral pnt, which could not represent all physiopathologic phenotypes in patients. thus, additional studies are needed to assess the clinical application of our study. second, our results suggested that igf-1 facilitated the growth of transplanted cells, yet its potential adverse effect, such as tumorigenesis, remains to be addressed. moreover, we have not examined the clinical potential of igf-1-expressing mdscs, as in whether it could improve the urethral sphincter function in elderly patients. concusions taken together, in this study, we expressed igf-1 in mdsc through lentiviral transduction and we showed that igf-1 could promote the survival, growth and differentiation of transplanted mdscs. in addition, we showed that igf-1-expressing mdscs could mitigate the symptoms of sui in rats by regenerating of muscle fibers and local blood capillaries. in summary, our study illustrated the clinical potential of igf-1-expressing mdscs. we hope that this study will aid in the development of stem cell therapy for patient with sui. acknowledgments we thank dr. aa and dr. bb for their contribution to revising this manuscript and giving significant input. this work was supported by the key science and technology planning project of fujian province, china [grant number 2014j0102], and the national natural science foundation of china [grant number 81070473]. conflict of interest the authors report no conflict of interest. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/47 references 1. norton p, brubaker l. urinary incontinence in women. lancet. 2006;367:57-67. 2. furuta a, jankowski rj, pruchnic r, yoshimura n, chancellor mb. the potential of muscle-derived stem cells for stress urinary incontinence. expert opin biol ther. 2007;7:1483-6. 3. carr lk, steele d, steele s, et al. 1-year follow-up of autologous muscle-derived stem cell injection pilot study to treat stress urinary incontinence. int urogynecol j pelvic floor dysfunct. 2008;19:881-3. 4. alberts b, johnson a, lewis j, raff m, roberts k, walter p. genesis, modulation, igf-1, mdscs in sui-chen et al. vol 19 no 6 november-december 2022 458 and regeneration of skeletal muscle. molecular biology of the cell. 2002available from: https://www.ncbi.nlm.nih.gov/books/ nbk26853/. 5. wilkinson dj, piasecki m, atherton pj. the age-related loss of skeletal muscle mass and function: measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans. ageing res rev. 2018;47:123-32. 6. musavi l, brandacher g, hoke a, et al. muscle-derived stem cells: important players in peripheral nerve repair. expert opin ther targets. 2018;22:1009-16. 7. vinciguerra m, musaro a, rosenthal n. regulation of muscle atrophy in aging and disease. adv exp med biol. 2010;694:211-33. 8. yanagiuchi a, miyake h, nomi m, takenaka a, fujisawa m. modulation of the microenvironment by growth factors regulates the in vivo growth of skeletal myoblasts. bju int. 2009;103:1569-73. 9. sadat s, gehmert s, song yh, et al. the cardioprotective effect of mesenchymal stem cells is mediated by igf-i and vegf. biochem biophys res commun. 2007;363:674-9. 10. gu x, fan l, ke r, chen y. rhgf interacts with rigf-1 to activate the satellite cells in the striated urethral sphincter in rats: a promising treatment for urinary incontinence? arch gynecol obstet. 2018;298:1149-57. 11. sato m, ito a, kawabe y, nagamori e, kamihira m. enhanced contractile force generation by artificial skeletal muscle tissues using igf-i gene-engineered myoblast cells. j biosci bioeng. 2011;112:273-8. 12. hijaz a, daneshgari f, cannon t, damaser m. efficacy of a vaginal sling procedure in a rat model of stress urinary incontinence. j urol. 2004;172:2065-8. 13. arsic n, mamaeva d, lamb nj, fernandez a. muscle-derived stem cells isolated as non-adherent population give rise to cardiac, skeletal muscle and neural lineages. exp cell res. 2008;314:1266-80. 14. qu-petersen z, deasy b, jankowski r, et al. identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. j cell biol. 2002;157:851-64. 15. damaser ms, broxton-king c, ferguson c, kim fj, kerns jm. functional and neuroanatomical effects of vaginal distention and pudendal nerve crush in the female rat. j urol. 2003;170:1027-31. 16. chen c, xu y, song y. igf-1 gene-modified muscle-derived stem cells are resistant to oxidative stress via enhanced activation of igf-1r/pi3k/akt signaling and secretion of vegf. mol cell biochem. 2014;386:167-75. 17. wang d, stockard cr, harkins l, et al. immunohistochemistry in the evaluation of neovascularization in tumor xenografts. biotech histochem. 2008;83:179-89. 18. shibuya m. vascular endothelial growth factor (vegf) and its receptor (vegfr) signaling in angiogenesis: a crucial target for antiand pro-angiogenic therapies. genes cancer. 2011;2:1097-105. 19. smith nr, baker d, james nh, et al. vascular endothelial growth factor receptors vegfr-2 and vegfr-3 are localized primarily to the vasculature in human primary solid cancers. clin cancer res. 2010;16:3548-61. 20. xue k, palmer mh, zhou f. prevalence and associated factors of urinary incontinence in women living in china: a literature review. bmc urol. 2020;20:159. 21. bösmüller h, pfefferle v, bittar z, et al. microvessel density and angiogenesis in primary hepatic malignancies: differential expression of cd31 and vegfr-2 in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. pathol res pract. 2018;214:1136-41. 22. wang x, bove am, simone g, ma b. molecular bases of vegfr-2-mediated physiological function and pathological role. front cell dev biol. 2020;8:599281. igf-1, mdscs in sui-chen et al. female urology 459 urol_montage.pdf point of technique 47urology journal vol 6 no 1 winter 2009 polytetrafluoroethylene vascular graft as a rescuer of short renal vessels during kidney transplantation gholam hossein naderi,1 darab mehraban,2 seyed mohammad kazemeyni,2 seyed reza yahyazadeh,2 amir hossein latif3 urol j. 2009;6:47-9. www.uj.unrc.ir keywords: kidney transplantation, polytetrafluoroethylene, blood vessel prosthesis, renal artery, renal vein 1department of kidney transplantation, shariati hospital, tehran university of medical sciences, tehran, iran 2department of urology, shariati hospital, tehran university of medical sciences, tehran, iran 3students’ scientific research center, school of medicine, tehran university of medical sciences, tehran, iran corresponding author: gholamhossein naderi, md department of kidney transplantation, shariati hospital, jalal-e-al-e-ahmad hwy, tehran, iran tel: +98 21 8490 2406 fax: +98 21 8863 3039 e-mail: gh_naderi2000@yahoo.com received april 2008 accepted november 2008 introduction short or damaged renal vessels represent a serious challenge during kidney transplantation. the increasing risk of thrombosis, bleeding, or compromised kidney function often leads to declining the donated kidneys with damaged vessels.(1) we here describe 5 kidney transplantations in which a polytetrafluoroethylene (ptfe) vascular graft was interposed between the short renal vessels and the recipient’s vessels. the ptfe graft was used both as arterial and venous grafts. we could not use either of the described techniques as a means of lengthening the vessels(2,3); therefore, we used a synthetic vascular graft for our patients. technique the patients’ characteristics are listed in table 1. we used the ptfe vascular graft (gore-tex, wl gore & associates, newark, delaware, usa) as an arterial graft in 2 kidney allograft recipients and as a venous graft in 3 others with short donor’s renal vessels during kidney transplantation (figure). in recipients 1 and 2, the graft was used to make end-to-end (recipient 1) and end-to-side (recipient 2) anastomoses between the donor’s renal artery and the recipient’s external iliac artery (table 1). in these 2 cases, the donor’s renal veins were anastomosed end-to-side to the external iliac veins. in the 3 other recipients, shortness of the donor’s renal veins made us use the ptfe vascular graft as a venous graft for lengthening the veins and making end-to-end anastomoses between the renal veins and external iliac veins (table 2). the donor’s renal arteries and external iliac arteries were successfully anastomosed by end-to-side anastomoses without any problems. patient age, y sex primary disease donor source graft indication 1 36 male gn living unrelated excision of the artery because of lymphocele and narrowing 2 36 male graft loss cadaver shortness of the donor’s accessory renal artery 3 53 female vur and ureteral obstruction living unrelated shortness of donor’s renal vein 4 53 male graft loss living unrelated shortness of donor’s renal vein 5 36 male hypertension living unrelated shortness of donor’s renal vein table 1. demographic and clinical characteristics of kidney allograft recipients with polytetrafluoroethylene graft for renal vessels* *gn indicates glomerulonephritis and vur, vesicoureteral reflux. vascular graft for kidney transplantation—naderi et al 48 urology journal vol 6 no 1 winter 2009 we did not use anticoagulant drugs in any of our patients, and they received only conventional immunosuppressive drugs. results the outcomes are listed in table 2. the experience of using the ptfe vascular graft as venous and arterial grafts during kidney transplantation was successful in all of our patients, and postoperative doppler ultrasonography showed no complications in any of them. the median follow-up period was 1.0 year (range, 0.5 to 6.0 years). all of the signs and symptoms existing due to end-stage renal failure before the transplantation were completely disappeared after the operation in our patients, and none of them experienced any kind of rejection. serum creatinine level decreased remarkably and the median last creatinine level among these patients was 1.20 mg/dl (range, 1.12 mg/dl to 1.40 mg/dl). no complications were reported during the follow-up period. discussion short and damaged vessels extend the length of the warm ischemia time during renal vessel anastomosis in kidney transplantation. various methods have been described to repair these vessels, but most of them may cause serious adverse effects.(4) the use of synthetic vascular grafts such as ptfe can solve the problems without those adverse effects. however, there are few reported cases in which a ptfe vascular graft was used for reconstruction of the short or damaged renal vessels during kidney transplantation. delpin described 2 cases of short renal vein repairs with the use of ptfe vascular grafts without any complications.(5) in another report, blacklock and colleagues(6) described a successful case of renal autotransplantation with interposed ptfe vascular graft as a cure of loin pain/hematuria syndrome. in another study, kamel and colleagues(7) described 3 cases in which the ptfe graft was used as a vascular graft during kidney transplantation. they did not report any patient graft type ptfe length, cm ptfe diameter, cm anastomosis type serum creatinine at discharge, mg/dl follow-up, y last serum creatinine, mg/dl 1 arterial 4 0.6 end-to-end, external iliac artery 1.70 6.0 1.40 2 arterial 7 0.6 end-to-side, external iliac artery 1.60 2.0 1.20 3 venous 4 0.6 end-to-end, external iliac vein 1.60 1.0 1.30 4 venous 4 0.6 end-to-end, external iliac vein 1.10 1.0 1.20 5 venous 4 0.6 end-to-end, external iliac vein 1.00 0.5 1.12 table 2. outcome of kidney transplantation and polytetrafluoroethylene (ptfe) graft for renal vessels left, ischemia in the lower pole of the transplanted kidney was seen before the use of polytetrafluoroethylene graft. right, all ischemic manifestations disappeared when the graft was used for anastomosis of the accessory renal artery with the external iliac artery (recipient 2). vascular graft for kidney transplantation—naderi et al urology journal vol 6 no 1 winter 2009 49 technical problems or complications. our report added 5 new cases of ptfe graft use as a renal vascular graft, as both arterial and venous grafts, to what has been described to date. four of our patients were receiving a kidney from living unrelated donors. the use of ptfe vascular graft as a renal venous graft in 3 of the patients adds another successful experience to what has been reported previously. since there were only 2 reported cases of ptfe usage as a renal venous graft before,(5) we hope that by adding 3 new cases to the literature, its utilization in the future will increase. in our cases, the patients had uneventful follow-up periods that convince the surgeons to use it more assuredly. systemic heparin was not used for any of the patients due to the reported increased risk of bleeding and the greater need for blood transfusion in transplant surgeries associated with heparin use.(8) our report provides an easy-to-use technique for solving the problems of short and damaged renal vessels during kidney transplantation. although we did not experience any complications in the use of the ptfe grafts, there is little information in the literature pertaining to the long-term outcome of the ptfe grafts in kidney transplantation. most of the long-term data on the use of the ptfe grafts originate from its application in lower limb revascularization.(9,10) those grafts tend to be long with a slow blood flow, while the ptfe grafts in kidney transplantation are short in length and have a high blood flow. therefore, it seems renal ptfe grafts may have better long-term results than those used in lower limb revascularization. acknowledgment we would like to appreciate all of the patients who let us use and publish their medical information. this study was supported by neither the manufacturers nor the importer companies. the ptfe grafts were provided by cardiac surgery department of our hospital. conflict of interest none declared. references 1. goel mc, flechner sm, el-jack m, et al. salvage of compromised renal vessels in kidney transplantation using third-party cadaveric extenders: impact on posttransplant anti-hla antibody formation. transplantation. 2004;77:1899-902. 2. barry jm, morris pj. surgical techniques of renal transplantation. in: morris pj, editor. kidney transplantation, principles and practice. 5th ed. philadelphia: wb saunders; 2001. p. 159-71. 3. simforoosh n, aminsharifi a, tabibi a, fattahi m, mahmoodi h, tavakoli m. right laparoscopic donor nephrectomy and the use of inverted kidney transplantation: an alternative technique. bju int. 2007;100:1347-50. 4. baptista-silva jc, medina-pestana jo, verissimo mj, castro mj, demuner ms, signorelli mf. right renal vein elongation with the inferior vena cava for cadaveric kidney transplants. an old neglected surgical approach. int braz j urol. 2005;31:519-25. 5. delpin es. brief report: successful extension of the transplant renal vein with a synthetic vascular graft. bol asoc med p r. 1997;89:206-7. 6. blacklock ar, raabe al, lam ft. renal autotransplantation with interposed ptfe arterial graft: not necessarily a cure for loin pain/haematuria syndrome. j r coll surg edinb. 1999;44:134. 7. kamel mh, thomas aa, mohan p, hickey dp. renal vessel reconstruction in kidney transplantation using a polytetrafluoroethylene (ptfe) vascular graft. nephrol dial transplant. 2007;22:1030-2. 8. mohan p, murphy dm, counihan a, cunningham p, hickey dp. the role of intraoperative heparin in cyclosporine treated cadaveric renal transplant recipients. j urol. 1999;162:682-4. 9. prager m, polterauer p, bohmig hj, et al. collagen versus gelatin-coated dacron versus stretch polytetrafluoroethylene in abdominal aortic bifurcation graft surgery: results of a seven-year prospective, randomized multicenter trial. surgery. 2001;130:40814. 10. prager mr, hoblaj t, nanobashvili j, et al. collagen versus gelatine-coated dacron versus stretch ptfe bifurcation grafts for aortoiliac occlusive disease: longterm results of a prospective, randomized multicenter trial. surgery. 2003;134:80-5. 1 risk factors for infectious complications of ureteroscopy after obstructive acute pyelonephritis katsuhiro ito*, toshifumi takahashi, shinya somiya, toru kanno, yoshihito higashi, hitoshi yamada department of urology, ijinkai takeda general hospital, kyoto, japan 28-1 moriminami-cho, ishida fushimi-ku, kyoto 601-1495, japan *corresponding author: katsuhiro ito department of urology, ijinkai takeda general hospital, kyoto, japan 28-1 moriminami-cho, ishida fushimi-ku, kyoto 601-1495, japan tel: 81-75-572-6331 fax: 81-75-571-8877 e-mail: itokatsu@kuhp.kyoto-u.ac.jp running title: complications for urs after urosepsis keywords: lithotripsy, laser; postoperative complications; pyelonephritis; sepsis; ureteroscopy; urolithiasis. 2 abstract objectives: to identify risk factors for infectious complication of ureteroscopy after obstructive acute pyelonephritis (oapn). patients and methods: this single-center, retrospective cohort study (#20200002, retrospectively registered in february 1st, 2020) included patients who underwent emergency drainage for oapn and subsequently underwent ureteroscopic stone removal between january 2006 and december 2020. multivariable analysis was conducted using demographic and stonerelated factors to determine those that could predict postoperative febrile urinary tract infection (uti). results: overall, 432 patients underwent ureteroscopy after oapn. the stone-free rate was 84.3%, whereas the overall and major complication rates were 17.6% and 3.2%, respectively. a total of 70 (16.2%) patient developed febrile uti, among whom 34 (7.9%) and 11 (2.5%) developed sepsis and severe sepsis, respectively. multivariable analysis identified diabetes mellitus [odds ratio (or) 1.98, 95% confidence interval (ci) 1.05–3.74], duration from drainage to surgery >1 month (or 2.28, 95% ci 1.20–4.74), and simultaneous retrograde intrarenal surgery (or 2.96, 95% ci 1.35–6.48) as significant risk factors for uti. after dividing patients into low(0), intermediate(1), and high(2–3) risk groups according to the number of factors they had, the risk of postoperative uti was 6.3%, 14.5%, and 27.7%, respectively (p for trend <0.001). conclusions: patients who underwent ureteroscopy after oapn were at risk for postoperative uti, despite its efficacy. simultaneous retrograde intrarenal surgery should be carefully planned, especially for patients with diabetes mellitus or extended surgery wait times. 3 main text 1. introduction obstructive acute pyelonephritis (oapn) secondary to ureteral stones is a urologic emergency that requires urgent drainage of the urinary collecting system through stenting or percutaneous nephrostomy (pns). given its frequently progression toward sepsis, oapn can be life-threatening, with reported mortality rates around 2% (1, 2). the importance of managing oapn has been increasing given the rising trend in oapn cases and associated sepsis (3). after recovery from oapn, patients are required to remove obstructive stones. however, the recurrence of infection following the surgical procedure has remained a concern. although patients with previous oapn are at high risk for postoperative complications (4-6), the optimal management for these patients has yet to be elucidated. recently, several studies have shown the outcomes after urs with previous oapn (611). these studies identified several risk factors for postoperative complications. one study revealed that complete removal of stone is necessary to avoid oapn recurrence(8). however, the safety of retrograde intrarenal surgery (rirs) to remove concomitant renal stone has not been known. moreover, short interval from oapn to surgery may increase complications(10), whereas the longer duration of drainage tube placement has been associated with postoperative infection(11). how and when the infected stones should be treated has been unanswered. thus, the current study aimed to determine the outcomes of urs after oapn across a large number of patients, as well as assessing the putative risk factors including rirs and the interval from oapn to urs, in order to establish better management of patients undergoing stone removal after oapn. 4 2. materials and methods 2.1 patients this study was approved by the institutional review board (#20200002, retrospectively registered in february 1st, 2020). data for patients who were referred to our hospital, were diagnosed with oapn secondary to urinary calculi, and underwent emergency drainage from january 2004 to december 2020 were retrospectively analyzed. the criteria of opn are 1) apparent obstructive stones 2) body temperature > 38°c or presence of symptoms which strongly suggest systemic inflammation. among them, patients who did not underwent definitive treatment or underwent treatment other than urs (percutaneous nephrolithotripsy, shockwave lithotripsy, or nephrectomy) were excluded. 2.2 treatment drainage of oapn was performed mainly through ureteral stenting. retrograde placement of a 6-fr ureteral stent was performed under transurethral anesthesia with/without sacral spinal anesthesia. when retrograde placement was impossible, pns using a 7-fr pigtail stent was performed under local anesthesia. adequate antibiotics according to urine culture were administered until the infection was cleared. definitive stone removal via urs was performed after completing the course of antibiotics. preoperative first generation cephalosporins or the other susceptible antibiotics in accordance with urine culture were administered. during urs, the ureter was carefully evaluated using semi-rigid ureteroscopy to identify stones or stricture. when rirs was performed, a ureteral access sheath (12/14-fr or 14/16-fr) was inserted. flexible ureteroscopy (urf-v3, 8.4-f. or urf-v, 9.9-fr, olympus) was used for renal calculi fragmentation with a 200-mm holmium laser fiber. a postoperative double-j stent was placed for 3–4 days, while postoperative antibiotics were provided for 2–3 days. 5 2.3 data collection and outcomes the primary outcome was postoperative infectious complications using rigorous criteria based on the literature (12). postoperative urinary tract infection (uti) was defined as an infection that required antibiotic administration beyond the prophylactic dose. sepsis was defined as uti with systemic inflammatory response syndrome [two or more of the following four criteria: (1) temperature >38°c or <36°c, (2) heart rate >90 beats per min or paco2 <32 mmhg, (3) respiratory rate >20 per min, (4) white blood cell count >12,000 /mm3 or <4,000 /mm3]. severe sepsis was defined as sepsis with organ dysfunction. the following basic patient characteristics and previously reported risk factors for postoperative complications were collected from patient records: age, sex, body mass index (bmi), eastern cooperative oncology group performance status (ecog-ps), presence of diabetes mellitus, leucocyte counts and c-reactive protein at presentation of oapn, admission in intensive care unit, type of preoperative drainage (stent or pns), days from drainage to surgery, operative time, and stone factors. stone factors comprised maximum size (diameter), stone burden (sum of all diameters), location, postoperative stone-free status (zero fragment on plain abdominal radiography), and stone composition. results of urine culture were not included in the analysis given that all patients with oapn should theoretically have bacteriuria. 2.4 statistical analysis all statistical analyses were performed using ezr (saitama medical center, jichi medical university), a graphic user interface for r (r foundation for statistical computing, version 2.13.0) (13). univariate and multivariable logistic regression analyses were performed to identify risk factors for postoperative infectious complications. the assumption of linearity for 6 quantitative predictors were graphically assessed. variables included during multivariable analysis were those p value > 0.2 during univariate analysis, factors associated with oapn (type of drainage, infection stone), as well as those determined to be risk factors of urs based on latest systematic reviews (14, 15), namely sex, diabetes mellitus, and operative time > 75 min. we aimed to collect at least 10 events per variable. since the incidence of postoperative uti has been reported to be around 10%(6-11), we needed to include at least 500 patients for 5 variables. because location of the stone and surgical procedures had multicollinearity, only surgical procedures were included for multivariable analysis. for model building, we performed stepwise regression by akaike information criterion. based on the multivariable analysis, we aimed to divide patients according to the number of risk factors. the cochranarmitage test was used to test for trends, whereas p values <0.05 indicated of statistical significance. 7 3. results overall, 558 patients were referred to our hospital with oapn secondary to urinary calculi and underwent emergency drainage. the among them, 15 died due to oapn or other causes, 37 experienced spontaneous passages of stones, and 74 underwent definitive treatment other than urs (12 percutaneous nephrolithotripsy, 57 shockwave lithotripsy, and 5 nephrectomy). ultimately, 432 patients were enrolled in this study. patient characteristics are detailed in table 1. accordingly, patients had a mean age of 69.8 years, with 265 (61.3%) females. this cohort included 79 (18.3%) patients with diabetes mellitus and 176 (40.7%) patients with ecog-ps ≥ 2. the median c-reactive protein and leucocyte counts were 13.1 mg/dl and 11100 /ml, respectively. fifty-two (12.0%) patients required intensive care unit hospitalization. emergency drainage was conducted via ureteral stent in 408 (94.4%) patients and pns in 24 (5.6%) patients. a total of 55 (12.7%) patients had a waiting time of more than 1 month, while the mean duration from drainage to urs was 20.9 days. the mean maximum stone size and stone burden was 12.1 and 21.8 mm, respectively. during surgery, 124 (28.7%) stones were located at the ureter, 61 (14.1%) at the kidneys, and 247 (57.2%) at both the ureter and kidneys. among the 308 patients with renal stones, 258 (83.8%) underwent rirs. of the 124 patients with ureteral stone alone, 60 (48.4%) needed rirs for fragment that were pushed up during surgery. perioperative outcomes are summarized in table 2. accordingly, the mean operative time was 61.7 min, while 364 (84.3%) patients achieved stone-free status after a single session. auxiliary shockwave lithotripsy was performed in 22 cases, whereas secondary procedures were necessary for 3 patients (2 urs and 1 stent). no perioperative mortality was observed. a total of 70 (16.2%) patient had uti, among whom 34 (7.9%) and 11 (2.5%) developed sepsis and severe sepsis, respectively. three patients required additional drainage tube replacement. five had nonurological infections, two had cardiovascular complications, and two had 8 perirenal hemorrhage, all of which were recovered without surgical intervention. results for univariate and multivariable logistic regression analyses for postoperative uti are presented in table 3. the linearity of quantitative measures was graphically assessed (supplementary figure 1). based on the assessment and previous report(11), operation time was dichotomized. univariate analysis identified the presence of diabetes mellitus, duration from drainage to surgery >1 month, stone burden, simultaneous rirs, and operation time >75 min. as potential risk factors (p value < 0.2) associated with postoperative uti. meanwhile, multivariable analysis identified the combination of diabetes mellitus [odds ratio (or) 1.82, 95% confidence interval (ci) 0.96–3.35, p = 0.06], duration from drainage to surgery >1 month (or 1.85, 95% ci 0.88–3.72, p = 0.09), and presence of rirs (or 6.30, 95% ci 2.62–16.45, p < 0.001 for rirs alone, or 2.69, 95% ci 1.28–6.40, p = 0.01 for rirs + urs) as highest aic values. patients were then divided into low(0), intermediate(1), and high(2–3) risk groups according to the numbers of risk factors (diabetes mellitus, drainage to surgery >1 month, and rirs use). the risk of uti and sepsis stratified according to risk groups are illustrated in figure 1. accordingly, postoperative uti occurred in 6.3%, 14.5%, and 27.7% of the patients in the low-, intermediate-, and high-risk groups, respectively (p for trend < 0.001). similarly, the risk of postoperative sepsis was 2.5%, 10.3%, and 17.6% in the low-, intermediate-, and high-risk group, respectively (p for trend < 0.001). 9 4. discussion the current study examined urs outcomes of 432 patients after oapn. the stonefree rate was 84.3%, while 17.6% of the patients experienced complications, most of which were uti. multivariable analysis identified diabetes mellitus, duration from drainage to surgery >1 month, and rirs as significant predictors of postoperative uti. our results showed that uti rates after urs among patients with previous oapn reached 16%. apart from current study, only a single prospective study and five retrospective studies had examined the outcomes of urs specifically in patients after oapn(6-11). the prospective study that examined 82 urs procedures reported a complication rate of 4% (7), whereas one retrospective study that analyzed 115 urs providers after oapn reported a postoperative uti rate of 27.8%(10). these varying complication rates indicate that differences in patient characteristics or procedures performed in these studies have considerable impact on postoperative morbidity. the current study found that rirs was strongly associated with postoperative uti. high intrarenal pressure during renal stone treatment had been reported to cause absorption of irrigation fluid containing bacteria, which may lead to uti (16). in particular, one study reported higher intrarenal pressures during rirs than during pcnl (17). although ureteral access sheaths decrease intrarenal pressure, it may to be not enough to maintain safe levels of pressure when irrigation pressure is high (17). in fact, infectious complication rates in the current study remained high even though ureteral access sheaths were utilized during rirs in almost all patients. rirs has not been considered a risk factor for infectious complications among patients who underwent surgery without previous oapn (4, 14). even after a complete course of antibiotics for oapn, biofilms attached to the stent may serve as source of bacteria. another possible explanation is that infected kidneys may be vulnerable to intrarenal pressure. as such, rirs should be carefully prepared in patients with previous oapn. given that the stone-free 10 rate was not a significant factor, two-stage surgery may be considered for patients with simultaneous ureter and renal stones. nevertheless, the safety of the staged surgery requires further examination. the present study found that a duration from drainage to urs exceeding 1 month was significantly associated with postoperative uti. previous reports have shown that a stent dwelling time of over 1 month was a risk factor of post-urs sepsis (5, 18), although the indication for stent placement in the aforementioned studies include little oapn cases. more specifically, one study reported ureteral stent placement > 21 days for patients with preoperative oapn as a risk factor of postoperative uti(11). prolonged stent dwelling time leads to bacterial colonization of the stent (19), which has been associated with postoperative uti (20). moreover, patients with diabetes mellitus or bacteriuria are at increased risk for stent colonization (20, 21). given that all patients with oapn had bacteriuria during stent insertion, this study implies that urs should be performed earlier after they recover from oapn. interestingly, our results showed that the female sex was not associated with infectious complications, despite all of the latest systematic reviews identifying it as a significant risk factor (14, 15, 22). female patients are prone to bacterial invasion given their shorter urethra. considering that all patients with oapn had infected urine, the impact of sex seems to be minimal. some limitations of the current study should be acknowledged when interpreting the results. first, given the retrospective design and long study period, surgical and perioperative management was not standardized. improved instrument and patient care may affect outcomes. prospective multi-center studies are necessary to validate our findings and determine the optimal management for patients with oapn. second, this study focused on urs outcomes after oapn, with almost all stones being treated with urs. given that those who underwent rirs were at high risk for uti, minimally invasive percutaneous nephrolithotripsy or 11 endoscopic combined with intrarenal surgery may be beneficial for patients with oapn who had ipsilateral renal stones. the role of surgery other than urs should be further studied. third, this study did not analyze the type of infecting organism. recent reports have shown that antimicrobial resistance was associated with severity of oapn or postoperative sepsis (23, 24). appropriate management for multidrug-resistant organism should therefore be investigated in the future. 12 5. conclusions patients with previous oapn were at risk for postoperative infectious complications. multivariable analysis identified diabetes mellitus, duration from drainage to surgery >1 month, and simultaneous rirs as significant predictors of postoperative uti. our study suggested that simultaneous rirs should be carefully planned, especially for patients with diabetes mellitus or long waiting times for urs. summary 432 patients with ureteral stone removal after obstructive urinary tract infection were analyzed. diabetes, the longer interval from prior infection to surgery, and simultaneous renal stone removal increase urinary tract infection recurrence. 13 author contributions all authors contributed to the study conception and design. material preparation, data collection and analysis were performed by k. i, t. t and s. s. the first draft of the manuscript was written by k. i and all authors commented on previous versions of the manuscript. all authors read and approved the final manuscript. conflict of interest none of the authors have any competing financial interests. no funding exists. 14 references [1] yoshimura k, utsunomiya n, ichioka k, ueda n, matsui y, terai a. emergency drainage for urosepsis associated with upper urinary tract calculi. j urol. 2005; 173: 458-62. 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[24] senocak c, ozcan c, sahin t et al. risk factors of infectious complications after flexible uretero-renoscopy with laser lithotripsy. urol j. 2018; 15: 158-63. 16 tables table 1. characteristics of the study population n 432 age, years 69.8 ± 15.0 sex, female 265 (61.3) bmi, kg/m2 21.5 ± 4.6 diabetes mellitus 79 (18.3) ecog-ps ≥2 176 (40.7) c-reactive protein, mg/dl 11.1 (5.6–20.6) leukocyte counts, 103/ml 11.4 (8.3–15.1) intensive care unit admission 52 (12.0) type of drainage stent 408 (94.4) pns 24 ( 5.6) drainage to op >1 month, yes 55 (12.7) maximum stone size, mm 10.0 (7.0–15.0) stone burden, mm 16.5 (9.5–29.4) stone location at surgery ureter 124 (28.7) kidney 61 (14.1) ureter + kidney 247 (57.2) urs+rirs 318 (73.6) data are presented as mean ± sd, median (interquartile range), or number (%). stone burden refers to the sum of all stone diameters. bmi, body mass index; ecog-ps, eastern cooperative oncology group performance status; pns, percutaneous nephrostomy; rirs, retrograde intrarenal surgery; urs, ureteroscopy. 17 table 2. surgical outcomes of ureteroscopy n 432 operation time, min 61.7±36.1 stone-free status 364 (84.3) infection stone 137 (31.7) auxillary treatment 25 (5.8) postoperative complications 76 (17.6) uti 70 (16.2) sepsis 34 (7.9) severe sepsis 11 (2.5) infection other than uti 5 (1.2) cardiovascular 2 (0.4) perirenal hemorrhage 2 (0.4) data are presented as mean ± sd or number (%). infection stones include struvite, carbonate apatite, and ammonium urate. uti, urinary tract infection. 18 table 3. univariate and multivariable regression analyses for postoperative urinary tract infection 1 univariate multivariable final model variables or (95% ci) p value or (95% ci) p value or (95% ci) p value age, year 1.00 (0.99–1.02) 0.58 sex, female 1.08 (0.64–1.83) 0.78 1.23 (0.70–2.22) 0.48 bmi, kg/m2 1.03 (0.97–1.08) 0.35 diabetes mellitus, yes 1.88 (1.03–3.40) 0.038 1.94 (1.00–3.65) 0.04 1.82 (0.96–3.35) 0.06 ecog-ps ≥2 0.84 (0.49–1.42) 0.50 type of drainage, pns 0.73 (0.21–2.51) 0.61 0.72 (0.16–2.28) 0.62 drainage to surgery >1 month, yes 2.20 (1.14–4.24) 0.019 1.90 (0.90–3.84) 0.08 1.85 (0.88–3.72) 0.09 number of stones 0.97 (0.83–1.12) 0.72 stone burden, mm 1.01 (1.00–1.02) 0.18 1.00 (0.99–1.02) 0.57 stone location at surgery ureter ref <0.001 kidney 4.23 (1.98–9.30) ureter + kidney 1.29 (0.68–2.57) type of procedure urs ref <0.001 ref <0.001 ref <0.001 rirs 6.79 (2.86–17.59) 5.77 (2.37–15.21) 6.3 (2.62–16.45) urs+rirs 2.56 (1.22–6.06) 2.42 (1.11–5.88) 2.69 (1.28–6.4) operation time, >75 min 1.54 (0.89–2.60) 0.11 1.27 (1.69–2.31) 0.44 stone-free status, yes 0.89 (0.45–1.75) 0.73 19 infection stone, yes 1.34 (0.78–2.28) 0.29 1.12 (0.61–2.03) 0.70 stone burden refers to the sum of all stone diameters. 1 bmi, body mass index; ci confidence interval; ecog-ps, eastern cooperative oncology group performance status; or, odds ratio; pns, 2 percutaneous nephrostomy; rirs, retrograde intrarenal surgery; urs, ureteroscopy. 3 20 figure legends fig. 1 risk of postoperative urinary tract infection and associated sepsis stratified according to risk group [low (number of risk factors: 0), intermediate (number of risk factors: 1), and high (number of risk factors: 2–3) risk] supplementary figure 1. the scatter plots to assess the linearity between continuous predictor variables and the logit of the outcome. favorable response of pembrolizumab as second-line therapy for advanced urothelial carcinoma with only small lesions to not be considered measurable by recist yoshifumi kadono1*, shohei kawaguchi1, takahiro nohara1, kazuyoshi shigehara1, kouji izumi1, taiki kamijima2, chikashi seto2, akinobu takano3, satoshi yotsuyanagi3, ryunosuke nakagawa4, tohru miyagi4, shuhei aoyama5, hideki asahi6, rie fukuda7, atsushi mizokami1 purpose: pembrolizumab is currently considered the standard second-line treatment for advanced urothelial carcinoma (uc). this study aimed to investigate the efficacy and safety of pembrolizumab in patients with advanced uc in real-world data, which is not well-reported. materials and methods: the study included 97 patients with advanced uc whose lesions were classified according to the response evaluation criteria in solid tumors (recist). the median age was 73 years. nineteen patients (20%) with performance status (ps) 2–4 were included. the percentages of liver, lung, bone, and lymph node metastasis were 18%, 27%, 19%, and 76%, respectively. the efficacy, safety, and risk factors for prognosis were evaluated for patients with and without measurable lesions. results: the best response was complete response in nine patients (9%) and partial response in 16 patients (17%). the median progression-free survival and overall survival were 3.7 months (95% confidence interval [ci]: 2.8– 4.7) and 11.8 months (95% ci: 6.7–17.0), respectively. twenty-one (22%) patients had no measurable lesions per recist. in univariate and multivariate analysis, ps 2–4 and lesions by recist were identified as factors associated with short overall survival (os). the median os of 18.3 months in patients without lesions by recist was significantly longer than the median os of 6.7 months in patients with lesions by recist (p = .012). conclusion: we demonstrated that good ps 0–1 and no measurable lesions, especially small lesions, by recist were favorable prognostic factors in patients with advanced uc treated by pembrolizumab. keywords: urothelial carcinoma; pembrolizumab; performance status; small lesions; recist introduction methotrexate, vinblastine, doxorubicin, and cispla-tin (m-vac) chemotherapy,(1) and gemcitabine and cisplatin chemotherapy for advanced urothelial carcinoma (uc) are established treatments.(2) platinum-based chemotherapies as first-line treatment for advanced uc are effective, but few cases have achieved complete remission. historically, there has been no effective second-line treatment after failure of first-line chemotherapy for advanced uc. in a randomized, phase 3 study (keynote-045) for patients with advanced uc after failure of platinum-based chemotherapy, treatment with pembrolizumab, a highly selective, humanoid monoclonal antibody against programmed death 1 (pd-1), resulted in longer overall survival (os) than existing second-line chemotherapy (10.3 months vs 7.4 months) and achieved a 27% reduction in death risk.(3) in addition, the incidence of treatment-related adverse events (aes) was lower with pembrolizumab, 1department of integrative cancer therapy and urology, kanazawa university graduate school of medical science, kanazawa, japan. 2department of urology, toyama prefectural central hospital,toyama, japan. 3department of urology, kouseiren takaoka hospital, takaoka, toyama, japan. 4department of urology, ishikawa prefectural central hospital, kanazawa, ishikawa, japan. 5department of urology, noto general hospital, nanao, ishikawa, japan. 6department of urology, kaga medical center, kaga, ishikawa, japan. 7department of urology, fukui-ken saiseikai hospital, fukui, japan. *correspondence: department of integrative cancer therapy and urology, kanazawa university graduate school of medical science, 13-1 takara-machi, kanazawa, ishikawa 920-8640, japan. tel: +81-76-265-2393. e-mail: yskadono@yahoo.co.jp. received january 2021 & accepted august 2021 including fewer high-grade (grade 3–5) aes that resulted in treatment discontinuation.(3) however, in the cited clinical trial, the inclusion of participants was limited by cancer and patient status, such as measurable lesions evaluated by the response evaluation criteria in solid tumors (recist) and the eastern cooperative oncology group performance status (ecog-ps). (3) therefore, real-world clinical practice data on pembrolizumab for advanced uc is needed. in this study, we retrospectively investigated the efficacy and safety of pembrolizumab in patients with advanced uc in real-world data from kanazawa university and related hospitals. patients and methods this study was approved by the ethics review board of our institution and related hospitals (no. 2018-082, 2847), and we informed all patients that they could opt out at any time. we retrospectively evaluated advanced urological oncology urology journal/vol 19 no. 3/ may-june 2022/ pp. 202-208. [doi:10.22037/uj.v18i.6652] table 1. demographics of the study population variable median (range) or n (%) total number of patients 97 age, years 73 (48 to 85) male/female 69 (71) / 28 (29) current or former smoker/non-smoker 60 (62) / 37 (38) primary tumor site, upper urinary tract 42 (43) / 55 (57) pure uc in histologic testing 86 (89) / 11 (11) radical surgery of the primary lesion 48 (50) / 49 (50) ecog ps, 0-1/2-4 78 (80) / 19 (20) number of prior regimens, 1/2/3 67 (69) / 27 (28) /3 (3) number of prier platinum agent courses 4 (1 to 30) metastatic sites, liver/lung/bone/lymph node* 17(18) / 26(27) / 18(19) / 74(76) lesions by recist evaluation, yes/no 76 (78) / 21(22) number of metastatic organs, 1/2/3/4/5* 22(23) / 43(44) / 21(22) / 7(7) / 4(4) time from previous chemotherapy, <3 / >3 months 78 (80) / 19 (20) uc, urinary carcinoma; ecog ps, eastern cooperative oncology group perfromance status; recist, response evaluation criteria in solid tumor. * the lesions were evluated and reported by doctors in charge. urological oncology 114 pembrolizumab for uc with small lesions-kadono et al. vol 19 no 3 may-june 2022 203 figure1: kaplan–meier curves of progression-free survival (pfs) (a), overall survival (os) (b) and duration of response (dor) in patients with determined objective response (c). a b c pembrolizumab for uc with small lesions-kadono et al. table 2. univariate and multivariate analyses of prognostic factors for overall survival with pembrolizumab therapy univariate multivariate reference category* hr (95% ci) p-value hr (95% ci) p-value age, years 0.971 (0.938-1.005) 0.091 0.967 (0.933-1.002) 0.067 continuous gender 0.737 (0.413-1.318) 0.304 male/female ecog ps 7.474 (3.955-14.124) < 0.001 8.189 (4.178-16.051) < 0.001 ps2-4/ps0-1 smoking status 1.122 (0.639-1.970) 0.687 current+former/never primary tumor site 1.710 (0.999-2.926) 0.05 1.679 (0.968-2.914) 0.065 upper tract uc/bt histologic testing 1.930 (0.907-4.105) 0.088 1.409 (0.649-3.058) 0.385 with others/pure uc radical surgery of the primary lesion 0.775 (0.453-1.325) 0.351 yes/no lesions evaluated by recist 2.445 (1.187-5.037) 0.015 2.333 (1.096-4.968) 0.028 yes/no time from previous chemotherapy 1.321 (0.643-2.713) 0.448 <3 months/>3months hr, hazard ratio, ecog ps, eastern cooperative oncology group performance status; recist, response evaluation criteria in solid tumor. *in a categorical values, the right side is the reference. urological oncology 204 figure2: kaplan–meier curves of progression-free survival (pfs) (a), and overall survival (os) (b) in each patient with or without lesions evaluated by response evaluation criteria in solid tumors (recist) criteria a b and recurrent uc patients who were treated with pembrolizumab after progression of platinum-based chemotherapy at our and related hospitals from january 2018 to october 2019. the recurrence of uc and the timing of pembrolizumab administration were determined by the doctors in charge. pembrolizumab was administered at a dose of 200 mg every three weeks until discontinuation due to disease progression or unacceptable aes. we obtained medical records, and clinical features were recorded, including age, sex, smoking status, primary tumor site, histology, metastatic organs, duration since previous chemotherapy, and ecog-ps. treatment efficacy was assessed according to recist version 1.1,(4) wherein non-measurable lesions, such as small lesions or bone metastasis, with a 20% (and over 5 mm) increase in total diameter size or a new lesion were defined as progressive disease (pd); lesions with a 30% decrease in total diameter size were defined as partial response (pr); and the disappearance of all measurable lesions indicated complete response (cr). the objective response rate (orr) was defined as the proportion of pr and cr, and disease control rate (dcr) was defined as the proportion of pr, cr, and stable disease (sd). progression-free survival (pfs) was calculated from the commencement of pembrolizumab to radiographic or clinical disease progression or death. the durable response rate (drr) and duration of response (dor) from the commencement of pembrolizumab to radiographic or clinical disease progression or death of cr and pr patients were also calculated. os was calculated from the commencement of pembrolizumab to death or the time of last follow-up. pseudoprogression (pp) was defined as a response to treatment after an initial increase in the volume of cancer lesions or with the appearance of new lesions subsequently followed by disease stabilization or a disease response before confirming the progression with a second assessment using imaging evaluation.(5) hyperprogression (hp) was defined as rapid tumor progression after the initiation of pembrolizumab.(6) toxicity, including immune-related adverse events (irae), was assessed according to the common terminology criteria for adverse events version 4.0.(7) the categorical variables used for calculating the incidence and percentage of each factor as well as the continuous variables were summarized as their median and range. when making comparisons, the chi-square test was used for categorial variables, while the mann-whitney u test was used for continuous variables. pfs and os were estimated using kaplan–meier methods, and the differences were evaluated using the log-rank test. cox proportional hazards models were used to identify the prognostic factors for os. all data analyses were performed using spss for windows (spss inc., chicago, il), taking p-value < 0.05 as statistically significant. results the study included 97 patients with advanced uc who were treated with pembrolizumab after platinum-based chemotherapy at kanazawa university and seven related hospitals. the characteristics of the patients are presented in table 1. twenty-one (22%) patients had no measurable lesions by recist (6 cases of small lymph node metastasis only; 8 cases of unmeasured primary and lymph node metastasis; and 7 cases of small visceral metastasis, including unmeasured bone metastasis). nineteen (20%) patients were ecog-ps 2–4. the median follow-up period after pembrolizumab commencement was 7.8 months (range 0.4–24.8 months). the number of deaths during follow-up were 55 (57%) patients. the causes of death were uc in 47 (85%) patients, aes in four (7%) patients, acute myeloid leukemia (aml) in two (4%) patients, suicide in one (2%) patient, and unknown cause in one (2%) patient, respectively. the best response was cr in nine (9%) patients, pr in 16 (17%) patients, sd in 26 (27%) patients, and pd in 46 (47%) patients. therefore, the orr was 26% and dcr was 49%. the median pfs and os were 3.7 months (95% confidence interval (ci): 2.8–4.7) and 11.8 months (95%ci: 6.7–17.0), respectively (figure 1a, b). at 12 months after pembrolizumab commencement, the drr was 79%. at the time of last follow-up, 16 out of 25 (64%) patients with a response continued to show a response. the median dor was not reached (figure 1c). pp was observed in three (3%) patients and hp was observed in nine (9%) patients. the median os of patients with hp was 28 days (range 10–43 days). we investigated variables that predict shorter os. in univariate and multivariate analysis, ps 2–4 lesions by recist were identified as factors associated with short os (table 2). the pfs of patients without lesions by recist was longer than that of patients with lesions by recist; however, it was not statistically significant (p = .088) (figure 2a). the median os of 18.3 months in patients without lesions by recist was significantly longer than the median os of 6.7 months in patients with lesions by recist (p = .012) (figure 2b). the best response of patients with and without lesions by recist were cr 4 cases (5%), pr 13 cases (17%), sd 17 cases (22%), and pd 42 cases (56%) versus cr 5 cases (24%), pr 3 cases (14%), sd 9 cases (43%), and pd 42 cases (19%), respectively (p = .004). severe aes (including grade 3–5 aes) were observed in 18 (19%) patients. interstitial pneumonia was the most frequent grade 3–5 ae in this study. other types of pneumonia included one pneumocystis pneumonia and one bronchial pneumonia. five (5%) patients died after pembrolizumab treatment because of aes. two (2%) patients died of interstitial pneumonia, one (1%) of pneumocystis pneumonia, one (1%) of ulcerative colitis, and one (1%) of aml, respectively. two (2%) patients with persistent bone marrow suppression caused by previous chemotherapy suffered with aml after two and four administrations of pembrolizumab, respectively. discussion we report the clinical outcome after pembrolizumab in japanese patients with advanced uc. the most significant difference in patient background between this real-world study and keynote045 arises from the fact that patients with poor ps and no measurable lesions, as defined by recist, cannot be included in clinical trials. there have been some reports of poor prognosis in patients with poor ps;(1,8) however, to the best of our knowledge, we could not find a report that examined the prognosis of patients without lesions by recist treated by immune checkpoint inhibitors. non-measurable lesions defined by recist are small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurological oncology 116 pembrolizumab for uc with small lesions-kadono et al. vol 19 no 3 may-june 2022 205 urable lesions.(4) lesions considered truly non-measurable included: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.(4) in this study, all the cases, which had only non-measurable lesions defined by recist, had only small lesions. the median pfs and os were 3.7 months and 11.8 months, respectively, and the orr was 26%. these outcomes were slightly better than the keynote-045 trial.(3) this might be because of the patients’ backgrounds. poor prognostic factors after systemic treatment for advanced uc are poor ps and visceral metastases,(9-12) especially liver metastases.(13) in the keynote-045 trial, the proportion of ps 0–1, ps 2, and ps 3–4 participants were 97.1%, 2.9%, and 0%, respectively.(3) in our study, the proportion of patients with ps 2–4 was 20%. the evaluation of risk factors for os revealed poor ps and badly affected os. the median os of patients with ps 0–1 and ps 2–4 was 17.7 months and 1.4 months, respectively (data not shown). the inclusion criteria for keynote-045 trial for cancer status determined at least one measurable lesion evaluated by recist version 1.1.(3) in our study, 21 cases (22%) did not have lesions per recist. the visceral metastases and liver metastases, which were reported as poor prognostic factors,(9-13) were 62% and 18% in our study, compared to 89% and 34% in keynote-045.(3) in our study, patients with good ps 0–1 and without measurable lesions by recist, which were good prognostic factors for os (table 2), would contribute to the improved outcomes of our study. in clinical practice, we often determine that the lesion has metastasized due to its growth over time. in particular, with regard to the evaluation of lymph node metastasis, recist does not result in the evaluation of metastasis until the lymph nodes are more than 15 mm in short diameter. in actual clinical practice, we rarely wait to treat lymph node metastases until they grow to that size. in fact, in this study, most of the patients without recist-evaluated lesions had small lymph node and visceral metastases. in the present study, treatment was initiated before the size of the lesion was assessed as metastatic by recist, and the period of earlier intervention can be considered as the time until the lesion grew to a measurable size by recist, which may be counted as a prolonged prognosis. however, since the median difference was about 12 months (figure 2b), it is conceivable that early intervention may have had a greater therapeutic effect. basic research reported that pd-1-positive cd8-positive t-cell infiltration was higher in early-stage tumors with smaller size, and the efficacy of anti-pd-1 antibody was higher, suggesting the usefulness of early therapeutic intervention with immunotherapeutic agents.(14) in fact, in this study, orr was better in the group of patients without recist-evaluated lesions. although this study showed a high short-term efficacy for small lesions, the results of kaplan–meier analysis showed that treatment efficacy and survival approached the long-term (figure 2a, b). the durable effect of long-term treatment may depend more on the immunity of the individual than on the size of the lesion. the long-term effects of the treatment need to be examined with an extended observation period. after treatment with immune checkpoint inhibitors, atypical patterns of response, such as pp and hp, were reported. the pp is characterized by a transient increase followed by a decrease in tumor size.(5) the histopathological findings of the lesion biopsies revealed the presence of inflammatory infiltration or necrosis; therefore, pp is possibly associated with the infiltration of active t cells and other immune cells at the lesion.(15) rosenberg et al reported that pp was observed in 20 (6%) out of 310 patients with advanced uc who were treated with atezolizumab after progression of platinum-based chemotherapy.(16) sharma et al reported that pp was observed in 24 (9%) out of 265 patients with advanced uc who were treated with nivolumab after progression of platinum-based chemotherapy.(17) in our study, we observed pp in three (3%) patients. hp was defined as a rapid increase in tumor growth rate.(18) there were few reports of hp of uc. hwang et al reported that hp in patients with uc treated with pd-1/pd-l1 inhibitors was observed in 12 (11.9%) out of 101 patients.(19) higher crp, neutrophil count, and volume of target lesions were reported to be associated with increased risks of hp.(20) in our study, 9 patients progressed rapidly after pembrolizumab treatment, and these patients were defined as hp. all patients had multiple lesions with poor ecog ps. eight patients were ps 2-4, and the other, who was ps 1, had liver, brain, peritoneal, and lymph node metastases without removal of the primary lesion. the median os of these 9 patients was 29 days (range 11–43 days). all patients died before the first scheduled imaging evaluation; therefore, there were no imaging data to evaluate the actual progressions of the cancer, and it was difficult to distinguish these cases as hp or natural course. in our study, 51 (53%) patients experienced aes, including 18 (19%) patients with severe aes (grade 3 or more), and 5 (5%) with death (grade 5). the frequency of aes in our study was higher than that in the keynote-045 trial.(3) the median age in our study was higher than the median age of patients in the keynote-045 trial (73 vs 67 years, respectively),3 which might affect the proportion of aes.(21) interstitial pneumonia was observed in 10 patients (10%) in all grade and 8 patients (8%) in grade 3–5. in our study, 5 patients died after pembrolizumab treatment. one of the deaths was due to pneumocystis jirovecii pneumonia. cases with pneumocystis jirovecii pneumonia caused by immunosuppression for immune checkpoint-related toxicity have been reported.(22) therapy-related myelodysplastic syndrome or aml with chemotherapy for solid cancer is well known;(23) however, a report of aml after an immune checkpoint inhibitor was not found. the two cases of aml after pembrolizumab treatment each received 26 and 27 courses of platinum-based chemotherapy before pembrolizumab commencement and suffered chronic bone marrow suppression at the commencement of pembrolizumab; therefore, it was unclear whether the onsets of aml were the natural course after long-term chemotherapy or irae. the limitations of our study are its retrospective design, small cohort, and short follow-up period. our study revealed the features of pembrolizumab treatment for advanced uc current clinical practice in japan. we could discuss the difference between clinical trial and real clinical practice; therefore, we also investigated the cohort whose background was incompatible with a clinpembrolizumab for uc with small lesions-kadono et al. urological oncology 206 vol 19 no 3 may-june 2022 207 ical trial, such as patients with poor ps and low volume or unmeasurable cancer status as evaluated by recist. conclusions in conclusion, we demonstrated that good ps 0–1 and no measurable lesions, especially small lesions, by recist were favorable prognostic factors in patients with advanced uc treated by pembrolizumab. a favorable response to immunotherapeutic agents was observed when the lesions were small. hp was observed mostly in poor ps patients with high volume lesions. atypical aes, such as, pneumocystis pneumonia and aml, were observed in our cohort. this was a small size pilot study; therefore, a larger study population and longterm follow-up data are needed to clarify our outcomes. acknowledgements the authors would like to thank the following individuals and institutions that participated in this study for their invaluable help with data collection: hiroaki iwamoto, hiroshi yaegashi, and masashi iijima of the department of integrative cancer therapy and urology in kanazawa university graduate school of medical science kanazawa, kanazawa, japan; yuuta takezawa and kazuaki machioka of the department of urology, toyama prefectural central hospital, toyama, japan; jirou sakamoto of the department of urology, kouseiren takaoka hospital, takaoka, toyama, japan; kazuhiko shibata of the department of medical oncology, kouseiren takaoka hospital, takaoka, toyama, japan; satoko urata, mitsuo ofude, and takao nakashima of the department of urology, ishikawa prefectural central hospital, kanazawa, ishikawa, japan; hiderou minami and osamu ueki of the department of urology, noto general hospital, nanao, ishikawa, japan; masaharu nakai and kazunori kobashi of the department of urology, kaga medical center, kaga, ishikawa, japan; masato yagisawa, masashi takeda, and hidekazu yamamoto of the department of urology, fukui-ken saiseikai hospital, fukui, japan; atsuya takimoto, ryou satou, sotaro miwa, and kiyoshi koshida of the national hospital organization kanazawa medical center, kanazawa, japan. conflict of interest the authors have stated that they have no conflicts of interest. references 1. tamura d, jinnouchi n, abe m, et al. prognostic outcomes and safety in patients treated with pembrolizumab for advanced urothelial carcinoma: experience in realworld clinical practice. int j clin oncol. 2020; 25: 899-905. 2. von der maase h, hansen sw, roberts jt, et al. gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase iii study. j clin oncol. 2000; 18: 3068-3077. 3. bellmunt j, de wit r, vaughn dj, et al. pembrolizumab as second-line therapy for advanced urothelial carcinoma. n engl j med. pembrolizumab for uc with small lesions-kadono et al. 2017; 376: 1015-1026. 4. eisenhauer ea, therasse p, bogaerts j, et al. new response evaluation criteria in solid tumours: revised recist guideline (version 1.1). eur j cancer 2009; 45: 228-247. 5. chiou vl and burotto m. pseudoprogression and immune-related response in solid tumors. j clin oncol. 2015; 33(31): 3541-3543. 6. kim jy, lee kh, kang j, et al. hyperprogressive disease during anti-pd-1 (pdcd1) / pd-l1 (cd274) therapy: a systematic review and meta-analysis. cancers (basel). 2019; 11(11), doi: 10.3390/cancers11111699. 7. institute nc. common terminology criteria for adverse 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single-arm, multicentre, phase 2 trial. lancet. 2016; 387: 1909-1920. 17. sharma p, retz m, siefker-radtke a, et al. nivolumab in metastatic urothelial carcinoma after platinum therapy (checkmate 275): a multicentre, single-arm, phase 2 trial. lancet oncol. 2017; 18: 312-322. 18. champiat s, dercle l, ammari s, et al. hyperprogressive disease is a new pattern of progression in cancer patients treated by antipd-1/pd-l1. clin cancer res. 2017; 23: 19201928. 19. hwang i, park i, yoon sk and lee jl: hyperprogressive disease in patients with urothelial carcinoma or renal cell carcinoma treated with pd-1/pd-l1 inhibitors. clin genitourin cancer. 2020; 18:e122-e133. 20. sasaki a, nakamura y, mishima s, et al. predictive factors for hyperprogressive disease during nivolumab as anti-pd1 treatment in patients with advanced gastric cancer. gastric cancer. 2019; 22: 793-802. 21. baldini c, martin romano p, voisin al, et al. impact of aging on immune-related adverse events generated by anti-programmed death (ligand)pd-(l)1 therapies. eur j cancer. 2020; 129: 71-79. 22. schwarz m, kocher f, niedersuess-beke d, et al. immunosuppression for immune checkpoint-related toxicity can cause pneumocystis jirovecii pneumonia (pjp) in non-small-cell lung cancer (nsclc): a report of 2 cases. clin lung cancer. 2019; 20: e247-e250. 23. morton lm, dores gm, schonfeld sj, et al. association of chemotherapy for solid tumors with development of therapy-related myelodysplastic syndrome or acute myeloid leukemia in the modern era. jama oncol. 2019; 5: 318-325. pembrolizumab for uc with small lesions-kadono et al. urological oncology 208 dna hypermethylation of a panel of genes as an urinary biomarker for bladder cancer diagnosis petros georgopoulos1, maria papaioannou2, soultana markopoulou3, aikaterini fragou2, george kouvatseas4 , apostolos apostolidis1* purpose: several studies have shown frequent changes in dna methylation in bladder cancer (bca), which vary among different geographical areas. the aim of this study is to examine the diagnostic accuracy of a panel of dna methylation biomarkers in a greek clinical setting contributing to the development of a universal panel of urine biomarkers. materials and methods: individuals with primary bca and control individuals matching the gender, age and smoking status of the cancer patients were recruited. dna methylation was assessed for the gene promoters of rassf1, rarb, dapk, tert and apc in urine samples collected by spontaneous urination using quantitative methylation specific pcr (qmsp). all genes had been previously separately associated with bca. results: fifty patients and 35 healthy controls were recruited, with average age of 70.26 years and average smoking status of 44.78 pack-years. in the bca group, dna methylation was detected in 27 (61.4%) samples. rassf1 was methylated in 52.2% of samples. only 3 (13.6%) samples from the control group were methylated, all in the rassf1 gene promoter. the specificity and sensitivity of this panel of genes to diagnose bca was 86% and 61% respectively. the rassf1 gene could diagnose bca with specificity 86.4% and sensitivity 52.3%. conclusion: promoter dna methylation of this panel of five genes could be further investigated as urine biomarker for the diagnosis of bca. the rassf1 could be a single candidate biomarker for predicting bca patients versus controls. studies are required in order to develop a geographically adjusted diagnostic biomarker for bca. keywords: urinary bladder neoplasms; dna methylation; rassf1; urine biomarker introduction at present, the gold standard for bladder cancer (bca) diagnosis is cystoscopy and urine cytology. cystoscopy is invasive, cost-intensive, has an 8590% sensitivity and involves a low risk of urine tract infection, hematuria and suboptimal compliance with management recommendations(1). urine cytology is non-invasive, has low sensitivity in low-grade tumors (16%) and a variable interpretation among pathologists(2). several urinary-based bca biomarker tests have been developed to improve the detection of bca including the urovysion (sensitivity 72%, specificity 72%), immonocyt (sensitivity 67-86%, specificity 75-79%), btastat (sensitivity 58-71%, specificity 73%), btatrack (sensitivity 69-71%, specificity 66-90%), nmp22 (sensitivity 71-73%, specificity 73-78%), but are mostly lacking randomized controlled trials to establish their efficacy(3). the application of epigenetics may allow for a risk-adapted approach and more cost-effective method 12nd department of urology, aristotle university of thessaloniki, papageorgiou general hospital, thessaloniki, greece. 2laboratory of biological chemistry, school of medicine, aristotle university of thessaloniki, greece. 3pharmacology department, school of medicine, aristotle university of thessaloniki, greece. 4health data specialists (heads), athens, greece. *correspondence: professor of urology-neurourology 2nd department of urology, aristotle university of thessaloniki, “papageorgiou” general hospital, ring road, nea efkarpia,56403 thessaloniki, greece. tel. +30 2310 991476, fax. +30 2310 681022, e-mail: zefxis@yahoo.co.uk. received march 2021 & accepted octobr 2021 of diagnosis of bca. numerous epigenetic changes such as dna methylation, histone modifications, microrna expression and nucleosome positioning are characteristic of the epigenome of bca cells(4,5,6). in urine samples, dna methylation in rassf1 (ras association domain family member 1), dapk (death associated protein kinase), rarb (retinoic acid receptor, beta), tert (telomerase reverse transcriptase) and apc (apc regulator of wnt signaling pathway) gene promoters has been strongly associated with bca (7,8,9). rassf1 promoter methylation is significantly higher in both bca tissue, compared to adjacent macroscopically non-cancerous bladder tissue, and in urine samples of bca patients compared to healthy controls (10). similarly, hypermethylation of dapk promoter is almost six times more frequent in bca patients than in healthy individuals (or: 5.81; 95%ci: 3.83-8.82, p < .00001)(11). finally, the hypermethylation of tert leads to upregulated activity of the enzyme resulting in cancer cells’ immortalization (9). to date, no single diagnostic biomarker could replace cystoscopy as the primary diagnostic tool for urological oncology urology journal/vol 19 no. 3/ may-june 2022/ pp. 214-220. [doi:10.22037/uj.v18i.6743] vol 19 no 3 may-june 2022 100 bca(12). as, additionally, geographical and ethnic differences in methylation patterns exist(13), a more potent panel of diagnostic biomarkers may be in demand. the aim of this study was to explore the diagnostic potential of a panel of five hypermethylated gene promoters, whose sensitivity and specificity have been proven when studied in a separate fashion. ideally, this would lead to the development of a dna methylation-based diagnostic protocol in urine samples and optimization of its sensitivity and specificity. materials and methods study design – participants this was a prospective, case-control study conducted in the urology department of a public teaching hospital. the hospital’s review board and the local university bioethics committee approved the study protocol. the study has been registered in the australian new zealand clinical trials registry (registration reference: actrn12620000258954). urine samples were collected following written informed consent from patients who consecutively attended the cystoscopy clinics, from june 2014 till december 2016. recruits were subjects with non-muscle invasive or muscle invasive bca who were able to provide a urine sample and undergo a cystoscopy before any treatment for bca. control subjects matching the gender, age and smoking status of the bca patients were recruited among healthy volunteers with no known urological disease or malignancy (table 1). individuals with metastasis in urinary bladder or other malignancies were excluded. eighty-five subjects were recruited, 50 patients and 35 healthy controls, with an average age of 70.26 years and average smoking status 44.78 pack-years. all individuals were caucasian. eighty-four percent of patients were diagnosed with non-muscle invasive bca (57% ta and 27% t1 grade), 11% with muscle invasive cancer and 5% with carcinoma in situ (cis)(table 1). sample collection urine samples (approximately 50 ml) were prospectively collected before scheduled cystoscopy or any specific treatment in sterile container with urine preservative (norgen biotek corp., thorold, canada), in a blinded fashion and were stored according to manufactures’ instructions for maximum two years at room temperature until dna extraction. no sample was first morning urine. patients with positive urine culture were excluded from the study as well as all otherwise healthy individuals but with urinary tract symptoms. dna extraction and treatment dna was extracted from urine sediments using the cells and tissue dna isolation kit (norgen biotek corp., thorold, canada). both integrity and purity were confirmed via spectrophotometry and agarose gel electrophoresis. extracted dna was stored at -40°c until the modification with sodium bisulfite using the ez dna methylation-goldkit (zymo research, orange, ca). modified dna was then stored at -20°c until further analysis. gene promoter methylation assay quantification of the percentage of methylation of dna in the gene promoter of dapk(14), apc(15), rar-β2 (15), rassf1(14) and tert(14) was performed with luna universal probe qpcr master mix (new england biolabs, massachusetts, usa), according to the manufacturer's instructions and performed on applied biosystems dna methylation in urine for bladder cancer diagnosis – georgopoulos et al. table 1. demographic characteristics of patients and controls patients controls p-value n 44 22 < . 05 age, year; mean ± sd (range) 70.78 ± 9.6 (46 – 88) 69,05 ± 10,9 (50-86) < .05 smoking status, pack years; median/ mean ± sd (range) 45, iqr 64 (0 – 168) 61,7 ± 44,5 (0-168) < . 05 ptalg 22 (50%) ptahg 3 (7%) pt1lg 2 (4%) pt1hg 10 (23%) cis 2 (5%) pt2 5 (11%) gene primer/ probe sequence apc[13] forward 5’-gaaccaaaacgctccccat-3’ reverse 5’-ttatatgtcggttacgtgcgtttatat-3’ probe 5’-/56-fam/cccgtcgaa/zen/aacccgccgatta/31abkfq/3’ dapk[12] forward 5’-tcgtcgtcgtttcggttagtt-3’ reverse 5’-tccctccgaaacgctatcg-3’ probe 5’-/56-fam/cgaccataa/zen/acgccaacgccg/31abkfq/3’ rarb[13] forward 5’-gggattagaattttttatgcgagttgt-3’ reverse 5’-taccccgacgatacccaaac-3’ probe 5’-/56-fam/tgtcgagaa/zen/cgcgagcgattcg/31abkfq/3’ rassf1[12] forward 5’-attgagttgcgggagttggt-3’ reverse 5’-acacgctccaaccgaatacg-3’ probe 5’-/56-fam/cccttcca/zen/acgcgcca/31abkfq/3’ tert[12] forward 5’-ggattcgcgggtatagacgtt-3’ reverse 5’-cgaaatccgcgcgaaa-3’ probe 5’-/56-fam/cccaatccc/zen/tccgccacgtaaaa/31abkfq/3’ actb [12] forward 5’-tggtgatggaggaggtttagtaagt-3’ reverse 5’-aaccaataaaacctactcctcccttaa-3’ probe 5’-/56-fam/accaccacc/zen/caacacacaataacaaacaca/31abkfq/3’ table 2. the sequences of primers and probes for the quantitative methylation specific real-time pcr vol 19 no 3 may-june 2022 215 urological oncology 216 steponeplus real time pcr system (thermo fisher scientific, inc.). 30 ng of modified dna were used in each reaction. the cycling conditions were as follows: 95˚c for 1 min, then 40 cycles of 95˚c for 30 sec, 60˚c for 30 sec. the primers and probe were designed to specifically amplify the bisulphite-converted promoter of the gene of interest and their sequences are listed in table 2. positive and negative controls were used and the methylation status of the genes was calculated by the stepone™ and steponeplus™ software v2.0 software. no further sequencing of the samples was conducted since the method was specific enough. all primers were synthesized by idt (integrated dna technologies, iowa, united states). in order to quantify and compare the amplification products, cq data corresponding to the target genes were normalized relative to those of the internal housekeeping gene, actin beta (actb)(14). furthermore, a standard 100% methylated control human dna and a 100% non-methylated control human dna were used (epitect pcr control dna set, qiagen, germany. methylation specific quantitative pcr (msp-qpcr) was run in duplicate. all laboratory methods and analyses were performed at the laboratory of biological chemistry of the medical school, aristotle university of thessaloniki. statistical analysis sample size calculation. assuming that the percentage of dna methylation among controls is 20%(10), and the desired or will be 4, then the total sample size needed would be 78 subjects (39 patients and 39 controls) in order to achieve 80% power with alpha set at 5% (for each of the 5 biomarkers) based on pearson chi-square test for two proportions. since this was a pilot study, no correction for multiple testing was made. statistical tests. descriptive statistics, univariate analysis, shapiro wilk normality test, mann-whitney for comparison of two independent non-parametric samples as well as multivariate and exact logistic regression were used for all variables with meaningful number of data points between patients and controls. roc analysis was performed. results dna was successfully extracted from 66 urine samples; 44 patients and 22 healthy controls. dna was found to be methylated in 27 (61.4%) patient samples as opposed to only 3 of 22 (13.6%) control-samples (p < .001). rassf1 was hypermethylated in 52.2% of patients followed by apc (34%), rarβ (22.7%), dapk (2.2%) and tert (2.2%). the only gene promoter that was methylated in controls was rassf1. the gene promoters were hypermethylated in 57% of individuals with non-muscle invasive bca; in particular, 24% of them had one, 16% two, 14% three, 3% four and none five hypermethylated gene promoters. by comparison, 80% of subjects with muscle invasive tumor had hypermethylated gene promoters: 20% one, 40% two and 20% three genes respectively. according to the grade classification of tumors, the gene promoters were hypermethylated only in 50% of the patients with low-grade urothelial cancer (one in 29%, two in 17% and three in 4%) while up to 72% of patients with high grade or cis had hypermethylated gene promoters (one in 17%, two in 22%, three in 28% and four in 5%)(figure 1). the hypermethylation was not significantly different between patients with muscle and non-muscle invasive bca as well as between patients with high-grade and low-grade (p = .369 and p = .148, respectively). the gene promoters of dapk and tert were hypermethylated in one patient each. according to our statistical analysis the specificity and sensitivity of this diagnostic panel of biomarkers were 86.4% and 61.4%, respectively, while the positive and negative predictive values were estimated at 90% and 53%, respectively. the area under the curve (auc = .76) derived from a multivariate logistic regression model (table 3). the diagnostic panel was considered positive when it had at least one methylated promoter. a multivariate logistic regression model with rassf1, apc and rar-b2 as predictors estimated an area under odds ratio estimates using ml effect point estimate 95% wald two-sided confidence p-value limits rar_b2 > 999.999 < .001 > 999.999 .9577 rassf1 4.098 .976 17.202 .0540 apc > 999.999 < .001 > 999.999 .9496 table 3. the two multiple logistic models with the same predictors but with different estimation methods: * indicates a median unbiased estimate. table 3a. model 1, using ml logistic regression table 3b. model 2, using exact logistic regression exact odds ratios parameter estimate 95% two-sided confidence p-value limits rar_b2 1.056 * .056 infinity .9730 rassf1 3.987 .855 26.001 .0874 apc 2.937 * .450 infinity .3655 auc specificity sensitivity area 95% ci p-value cut-off diagnostic panel 86.4 61.4 0.76 .67-.85 < .0001 at least one methylated dapk 100 2.3 0.51 .49-.53 .3173 methylated rar-b2 100 22.7 0.61 .55-.67 .0004 methylated tert 100 2.3 0.51 .49-.53 .3173 methylated rassf1 86.4 52.3 0.69 .59-.79 .0003 methylated apc 100 34.1 .67 .59-.74 < .0001 methylated multiple logistic regression model of apc, rar-b2, rassf1 86.4 61.4 .76 .67-.85 < .0001 predicted probability = .78 table 4. the cut-off, sensitivity, specificity and auc (95% ci), p-value for all markers and logistic models dna methylation in urine for bladder cancer diagnosis – georgopoulos et al. vol 19 no 3 may-june 2022 100 the curve (auc) of .76. (table 4 and figure 2). due to the high correlation observed, only rassf1, apc and rar-β2 promoters remained in the model; however, apc and rar-β2 had very unstable estimates (quasi-complete separation of data points was detected). thus, further analysis using exact logistic regression was performed in order to explore the multicollinearity effects (tables 3a, b). as a result, rassf1 gene promoter could be a single candidate for predicting patients versus controls with specificity 86.4% and sensitivity 52.3%. the odds ratio (or) and auc estimates for the diagnostic biomarker rassf1 are shown in tables 3 and 4. further analysis was performed for the diagnostic accuracy of the current panel for mibc or high-grade tumors. based on the 5-year recorded prevalence of bca in the greek population(16) and the known prevalence of 20-30% for mibc or high-grade tumors among firstly diagnosed bca patients, we calculated that the current panel had a positive predictive value of .21 and a negative predictive value of .86, with .86 specificity and .72 sensitivity. discussion in this pilot, controlled study the gene promoters of individuals with bca were more commonly hypermethylated compared to healthy controls. the panel of genes tested was found to have 86.4% specificity and 61.4% sensitivity in the diagnosis of bca, quite similar to the specificity and sensitivity of the rassf1 promoter gene alone (86.4% and 52.3% respectively with or 6.9). despite the relatively small sample size, the study sample reflects the disease’s demographics. in general, non-muscle invasive cancer (nmibc) can be found in 70-80% of all bca and only 10-30% constitute muscle invasive bca (mibc)(17). in our sample 84% of the patients had nmibc and 11% mibc. regarding the diagnostic potential of the hypermethylated gene promoters’ panel of our study, the sensitivity (61%) is lower compared to the cystoscopy’s sensitivity for all kinds of bca (68-83%) but higher compared to cytology, particularly for low-grade tumors (50%)(18). furthermore, the specificity is considerably higher than the cytology’s specificity for patients with low-grade cancer and comparable to the specificity of the invasive cystoscopy(4). however, the diagnostic accuracy of the methylation of the panel of twist family bhlh transcription factor 1 (twist1) and nidogen 2 (nid2) genes as urine biomarker was higher than the diagnostic accuracy of our panel of genes, with 90% sensitivity and 93% specificity(19). similarly, a meta-analysis and systematic review of 24 articles revealed that the overall sensitivity and specificity of dna methylation urine biomarkers was 84% and 92% respectively, higher than our results(20). studies by zhang et al. and van der heijden et al. achieved higher auc (.894 and .874 respectively) compared to our study’s auc (.7634) (21,22). however, zhang et al. investigated the diagnostic potential of a panel of seven gene promoters in a non-caucasian (chinese) population, while van der heijden et al. were focused on monitoring bca and not on diagnosis. but since dna methylation varies among different human groups regarding macroand micro-geographical scales, numerous studies from different areas are required in order to investigate the methylation profile of the patients with bca across human populations(13,23). this may lead to a common panel of gene promoters that could be used worldwide to differentiate the bca from healthy subjects but, in addition, a more individual approach may be necessary depending on subjects’ figure 1. the frequency and the type of the hypermethylated genes among the different histological types of bca dna methylation in urine for bladder cancer diagnosis – georgopoulos et al. vol 19 no 3 may-june 2022 217 urological oncology 218 residency. our results also indicate that the hypermethylation of suppressor gene promoter of rassf1 might be a potential single urine biomarker in bca with specificity 86.4%, sensitivity 52.3% and or 6.9. by contrast, a previous study which investigated the diagnostic accuracy of rassf1 in bca, showed lower specificity and sensitivity of rassf1 than in our study (17% and 58% respectively), whereas a recent meta-analysis revealed that the risk for bca in those individuals who have hypermethylated rassf1 promoter in urine samples was 95% ci:9.25-42.45, or = 19.82; (10,24). this risk was found to be higher among mixed-race individuals (95% ci: 8.39 65.05, or = 23.36;) and asians (95% ci: 15.01 38.69, or = 24.10) and lower for caucasians (95% ci:6.47 30.25, or = 13.99) (all p < .0001). rassf1 can constitute a fairly unique diagnostic biomarker for bca since methylation of rassf1 is rarely detected in normal bladder tissue(25). functional analysis of rassf1 shows a potential involvement in inhibition of cell proliferation, promoting cell apoptosis and aging and the maintenance of microtubule stability. it is also known that the expression of rassf1 is absent in many tumor cells as a consequence of methylation of gene promoter(25). however, chen et al. found that the use of a panel of genes had higher diagnostic accuracy compared to the use of a single gene promoter(19). in our study population, the gene promoter of dapk was hypermethylated only in one patient contrary to a meta-analysis concluding that dapk promoter methylation was associated with bca risk (95% ci = 3.83-8.82, or:5.81, p < .00001)(11). similarly, the gene promoter of tert was methylated in only one subject with bca; a recent study by a research group suggests that thor (tert hypermethylated oncological region) hypermethylation is associated with disease progression and increased tert expression, which leads to carcinogenesis(9). to date, there are no published studies to confirm whether our results reflect a low prevalence of tert and dapk promoter in the greek population. an attempt was made to explore the diagnostic accuracy of our panel of genes for mibc or high-grade tumors. we found a high negative predictive value of .86, with .86 specificity and .72 sensitivity previous literature has sparsely investigated the value of methylation biomarkers in the diagnosis of mibc or high-grade tumors. in a recent study, molecular analysis of the methylation profile of the promoters of p14arf, p16ink4a, rassfigure 2. roc curve and auc for the gene panel. dna methylation in urine for bladder cancer diagnosis – georgopoulos et al. vol 19 no 3 may-june 2022 219 f1a, dapk and apc from urine sediments demonstrated correlations with bca grade and stage(7), while other researchers found that the progression to mibc in patients with primary ptag1/2 bca could be predicted with the methylation analysis of the gene promoters tbx2 and tbx3(26). finally, 13.6% of our study controls had methylated the rassf1 gene promoter, in accordance with a previous survey, which showed that 12% of the loci in apparently normal urothelium from bladders with cancer were hypermethylated, indicating an epigenetic field defect (27). in the control group, we detected dna in 63% of the urine samples, which can be explained by the decreased cell exfoliation of normal urothelium(28). furthermore it has been shown that the procedure for collection of urine sediments can be influenced by the co-sedimentation of normal cells and the presence of crystals and substances that may inhibit downstream pcr analyses (29). finally, our study was adequately powered and achieved an or(6.9) higher than the initially desired or = 4. the attained sample size of the control group was almost half of the initially planned. this might have had an effect on the genes with nonsignificant results especially for apc where methylation was 34% as opposed to 13.6% of the control samples. cost-effectiveness is always an issue with novel technologies. the detection of hypermethylation of specific genes from urine samples has been previously shown to be cost-effective in the diagnosis of bca(20,30). when using our panel of genes, the real costs were significantly lower than cystoscopy costs in the greek national healthcare system (89 euro vs. 230 euro). however, the cost-effectiveness needs to be examined in light of the diagnostic accuracy of our panel of genes which remains to be proven in larger longitudinal case-control studies. future studies could explore the diagnostic potential of our panel of genes in different geographical areas at a national level, additionally testing the role of this gene promoter panel in blood samples of bca patients, in order to obtain a circulating liquid biopsy setting. the limitations of our study are the small sample size and a lower diagnostic accuracy compared to some previous studies but as it is already mentioned, dna methylation varies among different human populations and therefore external validation of these findings with larger prospective studies is mandatory. additionally, clinical comorbidities or concurrent use of medications potentially able to alter urine composition were not investigated for associations with dna methylation status of our gene panel. however, none of our study patients was treated with chemotherapeutic drugs targeting epigenetic modifications before urine sample collection and all individuals with previous or other current malignancies were excluded. patients with urolithiasis were also excluded as well as all otherwise healthy individuals but with urinary tract symptoms. conclusions results of this study suggest that methylation of the proposed panel of genes could be a promising urine biomarker for the diagnosis of bca, but this needs to be confirmed with validation studies within different human populations in order to develop a “universal” or “generic” test that can detect, in principle, any bca. the methylation of rassf1 gene promoter itself could be a potential single urine biomarker. it would be intriguing to verify in the future whether dna hypermethylation of this five-promoter gene panel can correlate with the pharmacological response to drugs conventionally used in bca treatment. acknowledgments dr lakis liloglou, b.sc.(hons), ph.d. senior lecturer in molecular oncology, molecular and clinical cancer medicine, university of liverpool for his invaluable help in critically reviewing the manuscript. conflict of interest author a. apostolidis has received research and travel grants, speaker and consultancy honoraria from astellas pharma greece, research and travel grants from pierre fabre medicament, research and travel grants from mavrogenis (coloplast gr), research and travel grants from ariti s.a., unrestricted grants from demo pharmaceuticals. the other authors have nothing to disclose. references 1. karaoglu i, van der heijden ag, witjes ja. the role of urine markers, white light cystoscopy and fluorescence cystoscopy in recurrence, progression and follow-up of nonmuscle invasive bladder cancer. world j urol. 2014;32:651-9. 2. yafi fa, brimo f, steinberg j, aprikian ag, tanguay s, 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lind ge, guldberg p, dahl c. dna-methylation-based detection of urological cancer in urine: overview of biomarkers and considerations on biomarker design, source of dna, and detection technologies. int j mol sci. 2019;20:2657. 30. beltrán-garcía j, osca-verdegal r, menamollá s, garcía-giménez jl. epigenetic ivd tests for personalized precision medicine in cancer. front genet. 2019;10:621. urology journal peer review running head: prostate-specific antigen density and pi-rads category 3 significant prostate cancer in patients with pi-rads category 3 lesions: a singlecenter, retrospective cohort study burçin tunç * (orchid id: 0000-0001-5560-6761), mert gençtürk** (orchid id: 0000-0001-9866-4312) adem aktürk** (orchid id: 0000-0002-6478-1999) fatih kantarci** (orchid id: 0000-0003-0801-3589) *surp pırgiç armenian hospital, i̇stanbul, turkey, department of urology ** surp pırgiç armenian hospital, i̇stanbul, turkey, department of radiology keywords: prostate cancer, multiparametric prostate mri, pi-rads score, psad, sensitivity. abstract purpose: the prostate imaging-reporting and data system (pi-rads) category 3 is the most ambiguous lesion with a variable clinically significant prostate cancer (cspca) detection rate. prostate-specific antigen density (psad) has been investigated as an adjunctive factor to improve the diagnostic efficiency of pi-rads categories. this study aimed to investigate the utility of psad as an adjunctive factor in predicting cspca risk in patients with pi-rads 3 lesions. materials and methods: the patients with an initial pi-rads 3 category lesion (n=142) scheduled for systematic and magnetic resonance imaging-guided prostate biopsy between 2018 and 2022 were retrospectively evaluated. demographic and clinical variables, including psad, were collected. the rate of cspca was the primary outcome. the impact of psad on the cspca detection rate was the secondary outcome. results: the median age was 62 years. the rate of cspca was 8.5% (n=12). the patients with cspca have significantly lower prostate volüme and higher psad levels than those without cspca (p=0.016 and p=0.012). the cut-off values of psad in predicting cspca in all pi-rads 3 patients and patients with cspca and clinically insignificant prostate cancer (n=26) were ≥0.181 ng/ml2. the sensitivity and specificity values for psad ≥0.181 ng/ml2 were of 75% (95% ci: 42.8%-94.5%) and 81.5% (95% ci: 73.4%-88.0%) in predicting cspca among pi-rads 3 category. conclusion: psad values higher than 0.181 ng/ml2 can be used as an adjunctive clinical parameter in predicting cspca in patients with pi-rads 3 lesions and differentiating cspca from clinically insignificant prostate cancer cases. introduction multiparametric magnetic resonance imaging (mpmri) of the prostate gland is the gold standard for diagnosing and evaluating prostate cancer (1-3). the prostate imaging-reporting and data system (pi-rads) categories have been developed to diminish variation in the acquisition, interpretation, and reporting of prostate mpmri examinations (2, 4, 5). its latest version (v2.1) has been designed to improve detection, localization, characterization, and risk stratification in patients with suspected cancer to treat naïve prostate glands (4, 6). a 5-point scale of the pirads v2 is used to describe the lesions indicating the likelihood of clinically significant prostate cancer (cspca); as the higher risk with the pi-rads category 5 (2, 6, 7). depending on the institutions and reader expertise, the different pi-rads categories have variable cancer detection rates (1, 5). among these categories, pi-rads 3 lesions are ambiguous, representing a gray zone between chronic inflammation, indolent stromal hyperplasia, clinically insignificant prostate cancer, and invasive pathologies (1, 5, 8). biopsy procedures are not recommended for lesions with a pi-rads score <3 due to mpmri’s high negative predictive values of up to 95% (9-11). the cspca rates for pi-rads category >3 lesions ranged from 62% to 92%, leading to a general recommendation to biopsy these lesions (9, 12). however, pi-rads 3 category is the most challenging scenario, with 60-85% of unnecessary biopsies and a 60% of clinically insignificant prostate cancer (cispca) detection rate (9, 13). besides, the cspca detection rates for these lesions show significant variations (2, 14, 15). although several guidelines, including the british nice and the european association of urology, recommend performing biopsy procedures for the prostatic pi-rads 3 lesions, overdiagnosis, and overtreatment choices might be possible (16). so, there is still a debate about whether a biopsy should be performed for pi-rads 3 lesions (1, 2, 5, 15, 17, 18). several clinical and imaging findings as the metric risk factors, including prostate-specific antigen density (psad), have been proposed to stratify the risk of prostate cancer and improve the predictive power of mpmri to detect cspca in patients with pi-rads 3 lesions (1, 5, 7, 19, 20, 21). that way, it is possible to manage the selection of the most appropriate subset of patients with pi-rads 3 lesions to be biopsied. previous studies reported promising results about the combined use of psad in patients with pi-rads 3 lesions (6, 7, 20, 21). however, conflicting results with heterogeneous evidence have shown little diagnostic value of psad to the pi-rads classification (22-24). so, the reliability of psad combined with the pi-rads category remains controversial. this study aimed to evaluate the cspca rates among patients with pi-rads 3 lesions and investigate the utility of psad as an adjunctive factor in predicting cspca risk in patients with pi-rads 3 lesions. materials and methods study this study was a retrospective, single-center analysis of all consecutive patients with an initial pi-rads 3 category lesion scheduled for systematic and mpmri-guided prostate biopsy procedures in the urology and interventional radiology clinics surp pırgic armenian hospital, istanbul, turkey. patients with the pi-rads categories of at least three were referred to the hospital as the referral center for the prostatic biopsy approaches. the local institutional review board approved the study (institutional review board, surp pırgic armenian hospital, 30.12.2021-734). the study was conducted following the principles of the declaration of helsinki. the written informed consent could not be taken from the patients due to the retrospective design of the study and the unanimity of data. patients all patients who underwent the systematic and mpmri-based targeted biopsy approaches between 2018 and 2022 were evaluated in the study. all biopsy procedures were performed transrectally. we did not include the patients with prior prostate cancer therapy, 5-α reductase inhibitors treatment within three months of the biopsy, and previous prostate biopsy. three hundred eight patients underwent prostatic biopsy approaches. the radiological diagnoses of pi-rads categories 4 (n=130, 42.2%) and 5 (n=36, 11.7%) were excluded. in the end, 142 patients (46.1%) with pi-rads 3 category lesions were included in the study. interventions as a general policy, we initially performed a mpmri-based targeted biopsy in all patients, followed by a systematic biopsy. this institution performed the mpmri images with a 3.0 tesla mri (signatm pioneer airtm, ge healthcare, united states). the mpmri images with good imaging quality obtained in the other imaging centers were loaded into the radiology information system. one experienced radiologist (mg) with more than ten years of experience in prostate mpmri studies reviewed the images. any lesion with the highest pi-rads score was regarded as the dominant lesion in the case of multiple lesions with different scores. the biopsy procedures were performed according to previously defined principles (25, 26). a 12-core systematic ultrasound-guided prostate biopsy and 3 to 10-core mpmri-guided targeted biopsy (median 5) procedures were performed by a urologist (bt) with at least ten years of experience with performing standard biopsies and the radiologist (mg) with more than ten years of experience in performing mpmri-guided targeted biopsy procedures. the median number of positive core biopsies for the systematic and mpmri-based targeted approaches were six and three. a cytopathologist with more than eleven years of experience performed the histopathological evaluation of the biopsy specimens. variables data about the demographic and clinical variables, including serum prostate-specific antigen (psa), prostate volume (ml), psa density (psad) (ng/ml2), number and the maximum diameter of prostatic lesion or lesions, the gleason scores of each positive core, anteriorly located lesions, and the histopathological diagnoses were collected using the hospital information system and the medical files of the patients. according to the 2014 international society of urological pathology (isup) grade, the grades were specified in the final pathology report (26). prostate cancer with a gleason score of 6 was defined as cispca. the scores greater than six were considered cspca. groups based on the isup grades, the patients with benign prostatic hyperplasia or cispca were grouped as group 1. group 2 included the patients with cspca. statistical analysis the rate of cspca detection rate was the primary outcome. the secondary outcome was to analyze the impact of psad on the cancer detection rate. descriptive statistics were given as a median with an interquartile range of 25% (iqr1) and an interquartile range of 75% (iqr3) for continuous variables depending on their distribution. we added the median difference estimates with 95% confidence intervals (cis). numbers and percentages were used for categorical variables. the normality of the numerical variables was checked by the kolmogorov-smirnov and shapiro-wilk tests and by q-q plots and histograms. the pearson chi-square test compared differences between categorical variables in a 2x2 table setup when the cell numbers were five or more. in the rxc table setup, the fisher's exact test was used when the cell numbers were less than 5. the mann-whitney u test compared two independent groups where numerical variables were without normal distribution. the receiver operating characteristic (roc) curves were constructed, and areas under the curve (aucs) were estimated. sensitivity, specificity, positive and negative predictive values (ppv and npv), and accuracy of the psad based-model were calculated to analyze the optimal sensitivity of prostate cancer. for sensitivity and specificity calculations, we added 95% ci values. the spss 20.0 software (chicago, illinois, us) was used for statistical analysis. in all statistical analyses, the significance level (p-value) was set at 0.05. results the median age of the patients with pi-rads category 3 was 62 years (57-67 years). there were 12 patients (8.5%) with cspca in the study group. the isup grades were 3+4 and 4+3 in 11 and one patient. the cispca detection rate was 18.3% (n=26). the diagnoses of cspca and cispca (n=38) were obtained in 21 (55.3%) and three patients (7.9%) via the systematic and mpmri-based targeted biopsy approach. in 14 patients (36.8%), both approaches were positive for the diagnosis. the number of patients was 130 and 12 in groups 1 and 2. table 1 compares the demographic and clinical parameters of the groups. the prostate gland volume was significantly lower in group 2 than in group 1 (p=0.016). we detected a significant difference in psad levels between the groups (p=0.012). the psad levels in group 2 were significantly higher than in group 1 (median 0.195 ng/ml2 vs. 0.12 ng/ml2). the groups were similar considering age, psa level, the diameter and number of the lesions, and the proportion of anteriorly located lesions (p=0.102, p=0.810, p=0.598, p=0.171, and p=0.460, respectively) (table 1). the receiver operating characteristics curve analysis revealed that the cut-off value for psad in detecting cspca was 0.181 ng/ml2 (auc=0.719, 95% ci: 0.537-0.900, p=0.013) (figure 1). the grouping based on the cut-off value of psad also revealed a significant difference between the groups (p<0.001). the diagnostic efficacy of the psad-based model in diagnosing cspca in patients with pirads 3 lesions is summarized in table 2. there were nine and 97 true positive and negative cases. the cut-off psad level ≥0.181 ng/ml2 had sensitivity and specificity values of 75% (95% ci: 42.8%-94.5%) and 81.5% (95% ci: 73.4%-88.0%) in predicting cspca among the patients in the pi-rads 3 category. the npv, ppv, and overall diagnostic accuracy of the psad-based model were 97%, 29%, and 80.9% (table 3). using psad to tailor the management to diagnose prostate cancer revealed that there would be three patients with the under-diagnosis of cspca (25%). the overdiagnosis rate was 18.5% (22 cases out of 119). however, it would avoid 97 prostate biopsy procedures (81.5%) to increase the detection rate of cspca from 8.5% to 29.0% (nine cases out of 31 biopsy procedures) (table 2). the comparison of the patients with cispca and cspca is given in table 4. the patients were similar in age and lesional characteristics, including the diameter and number of the lesions and the proportion of anteriorly located lesions (p=545, p=0.411, p=0.505, and p=0.656, respectively). although psa levels were higher in patients with cspca than those with cispca, the difference was insignificant (p=0.609). in patients with cspca, we detected significantly smaller prostate volumes and higher psad values than those with cispca (p=0.021 and p=0.010). the receiver operating characteristics curve analysis revealed that the cut-off value for psad in detecting cspca among all patients with a diagnosis of prostate cancer (n=38) was 0.181 ng/ml2 (auc=0.763, 95% ci: 0.568-0.958, p=0.012) (figure 2). the grouping based on the cut-off value of psad also revealed a significant difference between the groups (p<0.001) (table 3). the psad level ≥0.181 had sensitivity and specificity values of 75% and 87.0% in predicting cspca among patients with prostate cancer (n=38). discussion this study showed that the rate of cspca in patients with pi-rads 3 lesions was 8.5%. our findings revealed the higher accuracy rates of the psad-based model in discriminating cspca pathology in patients with pirads-3 lesions and differentiating between cspca and cispca pathology in the same patient group. based on these findings, we recommend using psad levels to decide on the diagnostic interventions for patients with pi-rads 3 lesions. the overall detection rate of cspca shows variations from 4% to 43% in patients with pirads 3 lesions (1-3, 9, 13-15, 17, 18, 27-29). the rate of cspca was 8.5% in our study, which is within the reported ranges in the literature. pepe et al. (29) reported a rate of 25.4% for cspca in patients with pi-rads 3 lesions. the rate for cscpa in the prostatic lesions with a pi-rads score of less than 3 was 8.7% in this study. besides the heterogeneity in the patient groups and the reader-dependent characteristic of the mpmri technique, the variable experiences of the radiologists with different learning curve practices in prostate mri interpretation might also impact this great range (3, 30). the true incidence of cspca might also differ in surgical specimens (9, 14). an overestimation is a possibility in prostate biopsies. as an institutional policy, we combined mpmri-targeted and standard biopsy procedures to diagnose cspca. in that way, our study's findings may be more reliable considering the under or over-estimation problems. the cut-off analysis for psad has been performed in different studies that included patients with pi-rads 3 lesions. other studies investigated reproducing an optimal threshold for all pirads lesions (27, 31-37). in these studies, different accuracy rates have been reported (15, 35). the minimum and maximum values of psad levels ranged from 0.07 to 1.5 ng/ml2 (3, 7, 9, 15, 17, 37). however, the cut-off value of 1.5 ng/ml2 for psad has been studied more frequently than the other psad values (7, 34, 38). frisbie et al. (34) stratified the different cutoffs of psad to determine pi-rads risk behavior. they thought that a psad of 0.1 ng/ml2 could be more helpful in obtaining increased clinical utility. roscigno et al. (31) stratified the patients according to two different psad cut-off values as ≥0.2 ng/ml2 and <0.1 ng/ml2. so, we may think that an optimal threshold has not been reproduced yet (15). the present study found that psad higher than 0.181 ng/ml2 was significantly associated with cspca. besides, this psad value was a valuable threshold in differentiating cspca from cispca for pi-rads 3 lesions. several authors reported that many biopsies would be avoided using psad as a cofactor for the pi-rads system (9). we also showed that a threshold value of psad would be essential in preventing unnecessary biopsy procedures consistent with others (34). so, psad should be considered an adjunctive/complementary factor for indeterminate prostatic lesions like pi-rads 3. the psad has also been used in predicting the degree of the upgrade of the gleason scores under active surveillance (1, 35). they reported that psad significantly increased in cspca patients during the follow-up period (39). roscigno et al. (40) analyzed the role of mpmri and several clinical parameters, including psad, in predicting disease reclassification of patients on active surveillance. they showed that a 0.1 unit increase in psad was an independent risk factor in predicting grade 2 prostate cancer during confirmatory or follow-up biopsy. a risk stratification based on pirads and psad values was recommended to avoid unnecessary biopsies during active surveillance. others thought psad is a valuable clinical parameter for pending cases to decide whether to trigger or postpone biopsy (41). the impact of pi-rads 3 diagnosis on the long-term outcomes of the underlying prostatic pathology has been studied. boschheidgen et al. (1) showed that a pi-rads upgrade occurs in patients diagnosed with prostate cancer after 12-24 months. they also reported a downgrade in the pi-rads category for the pi-rads 3 lesions without prostate cancer diagnosis after 25-36 months. therefore, they did not recommend early follow-up imaging for patients with pi-rads 3 lesions (1). although we did not perform a long-term analysis of our patient group, there are several clinically practical issues for psad during the diagnosis and follow-up of such patients. previous studies analyzed several clinical predictors for cspca identification in patients with pi-rads 3 lesions. age, diameter, prostatic volume, and psa are independent predictors (3, 5, 7, 18). alan et al. (7) stratified the pi-rads 3 lesions according to lesion diameter (<1 cm vs. >1 cm) and psad levels (<0.15 ng/ml2 vs. ≥ 0.15 ng/ml2). they found no missing patients with cspca if he has a lesion larger than 1 cm and a psad level higher than 0.15 ng/ml2. nevertheless, the lesion diameter in predicting cspca has been questioned in several studies. different threshold measurements for the lesion diameter range from 0.5 cm to 1.5 ng/ml2. it is generally believed that pi-rads 3 lesions <0.5 cm was not likely to represent clinically significant disease (3). in this study, we could not detect significant differences in age, tumor diameter, and psa levels between patients with and without cspca. however, the prostatic volume in patients with cspca was significantly lower. the findings of several studies in which smaller prostate volume was associated with prostate cancer supported our findings (3, 18, 32). although using psad in patients with larger prostate glands may be less sensitive for further analysis, we recommend that the clinical parameters be considered as a possible adjunctive factor to tailor the management and follow-up of the patients with suspicious prostatic lesions. the utility of clinical-radiomic models has also been investigated in different patient groups for prostate cancer (2, 5, 19). the term “radiomics” has gained popularity over the last decades. it is a technique in which the medical images of the patients are extracted and analyzed regarding their quantitative characteristics (5). the mpmri-based radiomic features and the gleason grading have been used simultaneously in distinguishing cspca (2, 5). li et al. (2) incorporated radiomics features and psad for discriminating cspca from non-cipca among pi-rads 3 lesions. in this study, we did not evaluate such imaging characteristics considering the quality of the images. some images were obtained in other centers, and transferring may negatively impact the image quality. the diagnostic efficacy of 68ga-prostate-specific membrane antigen (psma) positron emission tomography/computed tomography has been studied in patients with cspca. the expression of prostate-specific membrane antigen in most primary and metastatic prostate cancer cases led to its increased popularity in clinical practice (42). besides, pepe et al. (43) reported reasonable accuracy rates compared to mpmri-targeted biopsy. they thought such new technologies might improve the detection rate of prostate cancer via a systematic biopsy approach. the retrospective design was the major limitation of our study. our study was a retrospective analysis of the patients with pi-rads 3 lesions in a single institution. the majority of the patients were referred to a mpmri targeted biopsy facility. therefore, the gold standard pathological report for the prostatectomy specimens in patients who underwent surgical treatment and the follow-up data needed to be included. this factor might be the other limiting factor. conclusion: considering psad values higher than 0.181 ng/ml2 as a clinical parameter in managing patients with pi-rads 3 lesions leads to the higher diagnostic accuracy of mpmri-based diagnosis. in that way, it is more apparent in deciding which patients with pi-rads 3 lesions require biopsy. the number of unnecessary prostate biopsies 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prostate cancer using prostate imaging reporting and data system score and prostate-specific antigen density in biopsy-naive and prior biopsy-negative patients. prostate int. 2020;8(3):125-129. 39. washington sl 3rd, baskin as, ameli n, et al. mri-based prostate-specific antigen density predicts gleason score upgrade in an active surveillance cohort. ajr am j roentgenol. 2020;214(3):574-578. 40. roscigno m, stabile a, lughezzani g, et al. multiparametric magnetic resonance imaging and clinical variables: which is the best combination to predict reclassification in active surveillance patients? prostate int. 2020;8(4):167-172. 41. venderink w, van luijtelaar a, bomers jgr, et al. results of targeted biopsy in men with magnetic resonance imaging lesions classified equivocal, likely or highly likely to be clinically significant prostate cancer. eur urol. 2018;73(3):353-360. 42. pepe p, pepe l, cosentino s, ippolito m, pennisi m, fraggetta f. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer res. 2022;42(6):3011-3015. 43. pepe p, pepe l, tamburo m, marletta g, pennisi m, fraggetta f. targeted prostate biopsy: 68ga-psma pet/ct vs. mpmri in the diagnosis of prostate cancer. arch ital urol androl. 2022 26;94(3):274-277. tables table 1. demographic and clinical characteristics of the study group (n=142) overall (n=142) group 1 (n=130) group 2 (n=12) p age (year) † 62 (60.0-64.0) [57-67] 62 (60-63) [5766] 66 (57-72] [6170] 0.102 prostate volume (ml) † 54 (49.0-57.0) [42-70] 55 (51-58) [4271] 42.4 (25.+56) [26-55] 0.016 psa (ng/ml) † 7.1 (6.2-8.0) [5.1-9.0] 7 (6.2-7.8) [5.29.0] 8.15 (4.6-10.0) [4.7-9.8] 0.810 psad (ng/ml2) † 0.13 (0.1140.141] [0.0910.176] 0.124 (0.1130.135) [0.0920.161] 0.195 (0.1080.267) [0.1460.249] 0.012 psad group ‡ low 100 97 (81.5) 3 (25.0) <0.001 high 31 22 (18.5) 9 (75.0) missing 11 (7.7) 11 0 diameter (mm) † 10 (10.0-10.0) [6-12] 10 (9-10) [8-12] 10.5 (9-14] [913] 0.598 number of lesions † 1 (1-1] [1-2] 1 (1-1] [1-2] 1.5 (1-2) [1-2] 0.171 anterior lesion † 26 (18.3) 23 (17.7) 3 (25.0) 0.460 †: median (95% ci) [iqr1-iqr3], ‡: n (%) ci: confidence interval, iqr: interquartile range. group 1: patients with benign prostatic hyperplasia and clinically insignificant prostate cancer, group 2: patients with clinically significant prostate cancer, psa: prostate-specific antigen, psad: prostate-specific antigen density. table 2. the diagnostic efficacy of psad-based model in diagnosing cspca in patients with pi-rads 3 lesions. cspca positive (n=12) negative (n=119) psad groups high (n=31) 9 22 low (n=100) 3 97 cspca: clinically significant prostate cancer, psad: prostate-specific antigen density. table 3. accuracy analysis of high psad levels in diagnosing cspca in patients with pi-rads 3 lesions. tp (n) fp (n) fn (n) tn (n) sensitivity (%) [95% ci] specificity (%) [95% ci] ppv (%) npv (%) accuracy (%) high psad (≥0.181 ng/ml2) 9 22 3 97 75 [42.8%94.5%] 81.5 [73.4%88.0%] 29 97 80.9 psad: prostate-specific antigen density, cspca: clinically significant prostate cancer, tp: true positive, fp: false positive, fn: false negative, tn: true negative, ppv: positive predictive value, npv: negative predictive value. table 4. demographic and clinical characteristics of the patients with cispca and cspca. patients with cispca (n=26) patients with cspca (n=12) p age (year) † 64 (61-68) [60-68] 66 (57-72) [61-70] 0.545 prostate volume (ml) † 55 (48-74) [45-74] 43 (25-56) [26-55] 0.021 psa (ng/ml) † 6.4 (5.2-8.8) [5.08.2] 8.2 (4.6-10) [4.7-9.8] 0.609 psad (ng/ml2) † 0.124 (0.084-0.147) [0.080-0.149] 0.195 (0.108-0.297) [0.146-0.249] 0.010 psad group ‡ low 20 (87.0) 3 (25.0) <0.001 high 3 (13.0) 9 (75.0) diameter (mm) † 10 (8-12) [7-12] 11 (9-14) [9-11] 0.411 number of lesions † 1 (1-2) [1-2] 1.5 (1-2) [1-2] 0.505 anterior lesion† 4 (15.4) 3 (25.0) 0.656 †: median (95% ci) [iqr1-iqr3], ‡: n (%) ci: confidence interval, iqr: interquartile range. group 1: patients with benign prostatic hyperplasia and clinically insignificant prostate cancer, group 2: patients with clinically significant prostate cancer, psa: prostate-specific antigen, psad, prostate-specific antigen density. legends for figures: figure 1. the receiver operating characteristics curve analysis of psad in detecting cspca in the overall study group (n=142). figure 2. the receiver operating characteristics curve analysis of psad in detecting cspca in all patients with a diagnosis of prostate cancer (n=38). endourology and stone disease 149urology journal vol 5 no 3 summer 2008 effect of thymoquinone on ethylene glycol-induced kidney calculi in rats mousa-al-reza hadjzadeh,1 nama mohammadian,2 zeynab rahmani,1 fatemeh behnam rassouli1 introduction: the aim of this study was to investigate the effects of thymoquinone, a major component of nigella sativa seeds on ethylene glycolinduced kidney calculi in rats. materials and methods: sixty male wistar rats were randomly divided into 6 groups (intact control, ethylene glycol control, and 4 experimental groups) and treated for 28 days according to the protocol of the study. the rats in experimental groups received ethylene glycol and intraperitoneal injection of thymoquinone either from the first day of the study or the 15th day, with either doses of 5 mg/kg or 10 mg/kg. blood and 24-hour urine samples were collected at baseline and on day 28. urine oxalate and citrate and serum electrolytes were also measured. on day 29, all rats were decapitated and their kidney specimens were studied. results: on day 28, urine oxalate concentration significantly decreased in the experimental groups compared to the ethylene glycol group (p < .001). also, serum calcium levels were significantly higher in the experimental groups (p = .001). calcium oxalate deposits were smaller in the experimental groups than the ethylene glycol group. the mean number of deposits was lower in these groups, too (p < .001). treatment with the lower dose of thymoquinone was associated with fewer deposits. conclusion: thymoquinone significantly decreased the number and size of calcium oxalate deposits in the renal tubules. the dose and duration of treatment, however, does not have a linear relation with the outcomes. further studies on thymoquinone as a preventive and therapeutic drug for kidney calculi are suggested. urol j. 2008;5:149-55. www.uj.unrc.ir keywords: urinary calculi, rats, thymoquinone, calcium oxalate, ethylene glycol 1department of physiology, mashhad university of medical sciences, mashhad, iran 2departemnt of pathology, ghaem hospital, mashhad university of medical sciences, mashhad, iran corresponding author: mousa-al-reza hadjzadeh, md, phd department of physiology, ghaem hospital, mashhad university of medical sciences, mashhad, iran tel: +98 511 844 0350 fax: +98 511 844 0350 e-mail: hajzadehmr@mums.ac.ir received january 2008 accepted may 2008 introduction invasive procedures for the treatment of urinary calculi may cause serious complications and they also impose a great load of costs to the healthcare system. (1,2) in traditional medicine, there are noninvasive treatment options for urinary calculi that are worth to undergo scientific evaluation. nigella sativa l (ns) seeds (known as black seed in iran) have been used for this purpose in folk medicine for centuries.(3,4) we have previously shown the preventive effect of ethanolic extract of ns seeds on calculus formation,(5) and other investigators have demonstrated its increasing effect on glutathione content in the kidney and also its anti-inflammatory, antioxidant, and analgesic activities.(6-8) as a thymoquinone and ethylene glycol-induced kidney calculi—hadjzadeh et al 150 urology journal vol 5 no 3 summer 2008 major component of ns seeds, thymoquinone was reported to reduce blood pressure and heart rate, prevent chromosomal aberrations, and act as anticonvulsant, antioxidant, and a scavenger of free radicals and superoxide anions.(9-13) of other effects of thymoquinone are hepatoprotective activity, improvement of cisplatin-induced nephrotoxicity, inhibition of cyclooxygenase pathway and eicosaniod generation in leukocytes, and inhibition of 5-lipooxygenase products.(14-18) in our previous study, we used ethylene glycol (eg) to induce kidney calculus formation in rats and found that ns can inhibit this effect. metabolites of eg such as glycolaldehyde, glycolate, and oxalate can induce tissue damage, hyperoxaluria, and calcium oxalate (caox) calculi.(19,20) to scrutinize the exact mechanism of ns effect on the kidney, we decided to test its components on the kidneys of rats who were fed by eg. the aim of this study was to investigate the effects of thymoquinone as a major component of ns seeds on eg-induced caox kidney calculi in rats. materials and methods we randomly divided 60 male wistar rats into 6 groups of 10 (groups a to f). they weighted 190 ± 20 g. all groups of rats were kept at 25 ± 2˚c with a standard diet and tap drinking water and were treated according to the protocol of the study for 28 days. rats in group a (intact controls) received tap drinking water, and those in group b (eg controls) received 1% eg (merck kgaa, darmstadt, germany) in drinking water for 28 days. rats in groups c to f received thymoquinone (aldrich, wi, usa) with different protocols as well as the same dosage of eg as those in group b; in groups c and d, thymoquinone, 5 mg/kg/d, was administered as intraperitoneal injection from day 1 and day 15 to the end of the experiment, respectively. rats in groups e and f were treated by 10 mg/ kg/d of thymoquinone from day 1 and day 15, respectively. the animal procedures were complied with the international guidelines and national laws, and the study was approved by mashhad university of medical sciences. twenty-four-hour urine samples were collected on the first and 28th days of the study, while each rat was kept in a separate metabolic cage. blood was also collected from the cavernous sinus on the same days. serum levels of calcium, potassium, and magnesium were measured by enzymatic method, flame photometer, and xylidyl blue reaction, respectively. urine oxalate and citrate were measured by enzymatic methods (darman kaw, tehran, iran) with an autoanalyzer. all rats survived until day 29 when they were decapitated by guillotine. their kidneys were removed, weighed, and kept in formalin for histological studies. five-μm sections were prepared from both kidneys, and the slides were stained with hematoxylin-eosin method. the slides were examined under light microscope and caox deposits were determined. aggregations of caox deposits (tubules containing deposits) were counted in 10 microscope fields. data were expressed as mean ± standard deviation and were analyzed by the kruskal-wallis test to find the differences among all groups, and mannwhitney u test for comparison between each two groups. a p value less than .05 was considered significant. results no caox deposits or other pathological defects were found in different segments of the nephrons of the rats in group a (intact controls; figure 1). on the other hand, many caox deposits were found in the proximal tubules, loops of henle, distal tubules, collecting ducts, and calyxes of the rats in group b (eg controls; figure 2). aggregations were composed of 3 to 4 large polygonal crystals in different parts of the tubules. renal tubular dilation with epithelial damage and leukocyte reaction were also observed on pathology examination (figure 3). the mean number of caox deposits in 10 microscopic fields was 28.0 ± 3.2 in group b, which was significantly more than that in group a (p = .001; figure 4). in the kidney specimens of group c, a few thin and tiny crystals of caox were detected in different parts of the tubules (mean, 1.4 ± 0.9; p = .001, compared with group b). tiny calcium oxalate crystals were also detected in different thymoquinone and ethylene glycol-induced kidney calculi—hadjzadeh et al urology journal vol 5 no 3 summer 2008 151 segments of the nephrons in group d (with thymoquinone started on day 15). the rats in this group had less deposits than those in group b, too (mean, 2.2 ± 1.0; p = .001). thymoquinone was administered with a higher dose in groups e and f. crystals in different parts of nephrons in the kidney specimens of these groups were also thin, small, and fewer compared with those in group b (mean, 5.2 ± 1.6 and 14.6 ± 3.0, respectively; p = .001 and p = .03). the number of caox crystals in experimental groups c and d was not statistically different from that in group a. the number of the deposits in group d was significantly less than that in group f (p = .008); however, the difference between groups c and e was not significant. urine oxalate concentration of the rats was higher in group b than in group a on day 28 (p < .001). also, its concentration was higher in group b than in any of the experimental groups (c to f) on day 28 (figure 5). urine samples of the rats in group c had a lower levels of oxalate than those figure 1. left, normal medullary and papillary tubules in the kidney of a wistar rat (hematoxylin-eosin, × 20). right, normal tubular and collecting ducts (hematoxylin-eosin, × 40). figure 2. left, tubular calcium oxalate deposits (arrows) in a rat treated with ethylene glycol (hematoxylin-eosin, × 40). right, multiple tabular calculi (arrows) in the same rat (hematoxylin-eosin, × 40). figure 3. renal tubular dilation with epithelial damage and leukocyte reaction, producing granular and leukocytic cast (hematoxylin-eosin, × 40). thymoquinone and ethylene glycol-induced kidney calculi—hadjzadeh et al 152 urology journal vol 5 no 3 summer 2008 in group e (p = .003), but the difference between groups d and f was insignificant. table 1 shows urine citrate concentrations at baseline and the end of the study. urine citrate of the rats in group a was significantly higher than those in group b and the experimental groups except for group d. no difference was found between group b and the experimental groups in urine citrate concentration. serum potassium concentrations in group b and group a were not significantly different, but it was lower in all the experimental groups than in group b (table 2). concerning serum calcium levels, rats in group b had a lower concentration on day 28 than those in any of the other groups (table 3). however, no significant difference was found between serum magnesium levels of the studied groups on day 28 (p = .74; kruskal-wallis test). finally, the extracted kidneys were weighed and compared between the groups. the kidneys in group b was 62% heavier than those in group a (mean, 2.81 ± 0.26 g versus 1.73 ± 0.07 g, respectively). the kidneys in the experimental groups, although had a lower weight, were not significantly different from those in group b. the figure 4. the number of calcium oxalate crystal deposits (in 10 microscopic fields) in the kidneys of the rats at the end of the experiment. data are expressed as mean ± standard deviation. the kruskal-wallis test demonstrated a significant difference between the six groups (p < .001). figure 5. the 24-hour urine oxalate concentration in different groups of rats on day 28. the kruskal-wallis test showed a significant difference between the six groups (p < .001). thymoquinone and ethylene glycol-induced kidney calculi—hadjzadeh et al urology journal vol 5 no 3 summer 2008 153 mean weight of the kidneys were 1.86 ± 0.08 g, 1.63 ± 0.09 g, 1.76 ± 0.09 g, and 1.94 ± 0.11 g in groups c, d, e, and f, respectively. discussion according to our results, thymoquinone has a preventive effect on caox calculi formation in the kidneys of rats. in a similar way, thymoquinone has a disruptive effect on caox crystals formed by eg, demonstrating a therapeutic effect on kidney calculi in rats (figure 4). to our best knowledge, this is the first report on the effects of thymoquinone on kidney calculi. thymoquinone, as a major component of ns seeds, has been reported to reduce blood pressure and heart rate, prevent chromosomal aberrations, and act as anticonvulsant, antioxidant, and a scavenger of free radicals and superoxide anions.(9-13) of other effects of thymoquinone are hepatoprotective activity, improvement of cisplatin-induced nephrotoxicity, inhibition of cyclooxygenase pathway and eicosaniod generation in leukocytes, and inhibition of 5-lipooxygenase products.(14-18) we found that with a dose of 5 mg/kg, thymoquinone had a potent preventive effect on calculus formation and a highly disruptive effect on caox kidney calculi. we also tried 10 mg/ kg of thymoquinone and documented its potent preventive effect on kidney calculus formation and a moderate effect on disruption of the kidney calculi. these data suggest that lower doses of thymoquinone might be more effective on the treatment of caox kidney calculi. in a study on the effect of thymoquinone on lipid profile of rats, bamosa and colleagues tested intraperitoneal injection of thymoquinone with varying doses of 0.4 mg/kg to 8 mg/kg. they found that there was no linear association of the dose and lowering effect of thymoquinone on serum lipids. the highest dose they used (8 mg/kg) had toxic effects.(21) this is in accordance with our findings. unpublished data at our university have shown that oral thymoquinone with a dose of 0.4 mg/kg could disrupt caox calculi in rats’ kidney.(22) it has been reported that an ethyl-acetate phase remnant fraction and n-butanol fraction from aqueous-ethanolic extract of ns seeds had preventive effects on eg-induced kidney calculi.(22) both polar and nonpolar components are present in ethyl-acetate phase remnant fraction and only nonpolar components are present in n-butanol phase of the extract. thymoquinone is the major nonpolar compound in the extracts of ns seeds; it urine citrate, mg/dl group baseline day 28 p† a 31.75 ± 3.25 32.27 ± 3.35 … b 29.37 ± 3.12 19.37 ± 2.52 .04 c 32.90 ± 3.51 12.90 ± 3.51 .01 d 29.34 ± 2.82 21.34 ± 2.22 .13 e 33.96 ± 3.83 13.96 ± 4.83 .01 f 32.18 ± 3.23 12.18 ± 1.93 .002 table 1. urine citrate concentrations before and after the study period in control and experimental groups* *data are expressed as mean ± standard deviation. no difference was found between the groups on day 0 (baseline); however, the kruskal-wallis test showed a significant difference between the groups (p = .007) on day 28. the differences between the experimental groups (c to f) and group b were insignificant. †p values are related to comparisons of the values on day 28 between group a and other groups (mann-whitney u test). serum potassium, mg/dl group baseline day 28 p† a 4.94 ± 0.20 6.22 ± 0.62 .09 b 5.04 ± 0.18 4.94 ± 0.22 … c 5.24 ± 0.25 0.80 ± 8.20 .008 d 5.04 ± 0.26 0.60 ± 8.40 .008 e 5.34 ± 0.29 0.47 ± 7.02 .008 f 5.26 ± 0.25 0.93 ± 6.30 .03 table 2. serum potassium concentrations before and after the study period in control and experimental groups* *data are expressed as mean ± standard deviation. no difference was found between the groups on day 0 (baseline); however, the kruskal-wallis test showed a significant difference between the groups (p = .006) on day 28. †p values are related to comparisons of the values on day 28 between group b and other groups (mann-whitney u test). serum calcium, mg/dl group baseline day 28 p† a 9.16 ± 0.16 9.18 ± 0.18 .008 b 9.26 ± 0.22 8.28 ± 0.30 ... c 9.26 ± 0.16 11.66 ± 0.89 .008 d 9.04 ± 0.16 11.20 ± 0.31 .008 e 9.14 ± 0.20 10.08 ± 0.26 .008 f 9.04 ± 0.24 10.58 ± 0.52 .008 table 3. serum calcium concentrations before and after the study period in control and experimental groups* *data are expressed as mean ± standard deviation. no difference was found between the groups on day 0 (baseline); however, the kruskal-wallis test showed a significant difference between the groups (p = .001) on day 28. †p values are related to comparisons of the values on day 28 between group b and other groups (mann-whitney u test). thymoquinone and ethylene glycol-induced kidney calculi—hadjzadeh et al 154 urology journal vol 5 no 3 summer 2008 was concluded by researchers that thymoquinone might be the main compound with preventive effect on kidney calculus formation in these studies.(22) these reports are in agreement with our data in the present study. calcium oxalate crystals in tubules may damage epithelial cells that leads to production of superoxide anions and free radicals and induction of hetrogenic crystal nucleation.(23-25) on the other hand, thymoquinone, as an active quinine, has antioxidant effect, scavenges free radicals and superoxide anions, and inhibits cyclooxygenase and 5-lipoxygenase pathways; therefore, it inhibits inflammatory products.(17,18) consequently, it can be suggested that a part of its effects on prevention and disruption of caox calculi is due to these roles.(13,18,26) thymoquinone has an antibacterial effect, and therefore, calculi with a bacterial origin such as struvite calculi may be prevented by thymoquinone.(27,28) urine oxalate concentration was also decreased by thymoquinone which is in agreement with its preventive effects on the caox kidney calculi. however, thymoquinone had no significant effect on the weight of the kidney which in part may be due to very short period of the treatment. conclusion according to our results, intraperitoneal injection of thymoquinone was effective for prevention and treatment of caox kidney calculi in rats. a dose of 5 mg/kg of thymoquinone significantly decreased the number and size of caox deposits in different segments of the renal tubules. a higher dose of thymoquinone had also preventive and therapeutic effects on caox kidney calculi, although the therapeutic effect of thymoquinone with a dose of 5 mg/kg was more potent. further studies to determine the same effects on human beings are recommended. conflict of interest none declared. references 1. menon m, resnick mi. urinary lithiasis: etiology, diagnosis, and medical management. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 3229-305. 2. coe fl, evan a, worcester e. kidney stone disease. j clin invest. 2005;115:2598-608. 3. aqili khorasani mh. nigella sativa. in: aqili khorasani mh, editor. makhzan-al-adviah. tehran: islamic publishing and educational organization; 1992. p. 556-8. 4. mir heidar h. nigella sativa. in: mir heidar h, editor. encyclopedia of medicinal plants of iran. 6th ed. tehran: islamic culture press; 2004. p. 211-4. 5. hadjzadeh ma, khoei a, hadjzadeh z, parizady m. ethanolic extract of nigella sativa l seeds on ethylene glycol-induced kidney calculi in rats. urol j. 2007;4:8690. 6. khan n, sharma s, sultana s. nigella sativa (black cumin) ameliorates potassium bromate-induced early events of carcinogenesis: diminution of oxidative stress. hum exp toxicol. 2003;22:193-203. 7. al-ghamdi ms. the anti-inflammatory, analgesic and antipyretic activity of nigella sativa. j ethnopharmacol. 2001;76:45-8. 8. burits m, bucar f. antioxidant activity of nigella sativa essential oil. phytother res. 2000;14:323-8. 9. hosseinzadeh h, parvardeh s. anticonvulsant effects of thymoquinone, the major constituent of nigella sativa seeds, in mice. phytomedicine. 2004;11:56-64. 10. hosseinzadeh h, parvardeh s, nassiri-asl m, mansouri mt. intracerebroventricular administration of thymoquinone, the major constituent of nigella sativa seeds, suppresses epileptic seizures in rats. med sci monit. 2005;11:br106-10. 11. el tahir ke, ashour mm, al-harbi mm. the cardiovascular actions of the volatile oil of the black seed (nigella sativa) in rats: elucidation of the mechanism of action. gen pharmacol. 1993;24:112331. 12. aboul-ela ei. cytogenetic studies on nigella sativa seeds extract and thymoquinone on mouse cells infected with schistosomiasis using karyotyping. mutat res. 2002;516:11-7. 13. badary oa, taha ra, gamal el-din am, abdel-wahab mh. thymoquinone is a potent superoxide anion scavenger. drug chem toxicol. 2003;26:87-98. 14. daba mh, abdel-rahman ms. hepatoprotective activity of thymoquinone in isolated rat hepatocytes. toxicol lett. 1998;95:23-9. 15. mansour ma, ginawi ot, el-hadiyah t, el-khatib as, al-shabanah oa, al-sawaf ha. effects of volatile oil constituents of nigella sativa on carbon tetrachloride-induced hepatotoxicity in mice: evidence for antioxidant effects of thymoquinone. res commun mol pathol pharmacol. 2001;110:239-51. 16. badary oa, nagi mn, al-shabanah oa, al-sawaf ha, al-sohaibani mo, al-bekairi am. thymoquinone ameliorates the nephrotoxicity induced by cisplatin in rodents and potentiates its antitumor activity. can j physiol pharmacol. 1997;75:1356-61. 17. houghton pj, zarka r, de las heras b, hoult jr. fixed oil of nigella sativa and derived thymoquinone thymoquinone and ethylene glycol-induced kidney calculi—hadjzadeh et al urology journal vol 5 no 3 summer 2008 155 inhibit eicosanoid generation in leukocytes and membrane lipid peroxidation. planta med. 1995;61:33-6. 18. el-dakhakhny m, madi nj, lembert n, ammon hp. nigella sativa oil, nigellone and derived thymoquinone inhibit synthesis of 5-lipoxygenase products in polymorphonuclear leukocytes from rats. j ethnopharmacol. 2002;81:161-4. 19. halabe a, shor r, wong nl, sutton ra. effect of vitamin d3 on the conversion of ethylene glycol to glycolate and oxalate in ethylene glycol-fed rats. clin chim acta. 2003;330:135-9. 20. coe fl, evan a, worcester e. kidney stone disease. j clin invest. 2005;115:2598-608. 21. bamosa ao, ali ba, al-hawsawi za. the effect of thymoquinone on blood lipids in rats. indian j physiol pharmacol. 2002;46:195-201. 22. eftekhari m. effect of thymoquinone on kidney stone in rat [dissertation]. mashhad (iran): faculty of pharmacy in mashhad university of medical sciences; 2006. 23. zabihi n, khajavi rad a, hajzadeh mr, monavar n, rakhshandeh h. preventive effect of total extract and ethyl-acetate fraction of nigella sativa on renal stone in the rat. in: proceedings of the 18th iranian congress of physiology and phyarmacology; 2007 aug 26-30; mashhad, iran. mashhad: mashhad university of medical sciences; 2007. p. 245. 24. monavar n, khajzvi rad a, hajzadeh mr, rakhshandeh h. preventive effect of n-butanol fraction of nigella sativa on renal stone in the rat. in: proceedings of the 18th iranian congress of physiology and phyarmacology; 2007 aug 26-30; mashhad, iran. mashhad: mashhad university of medical sciences; 2007. p.160. 25. khan sr, thamilselvan s. nephrolithiasis: a consequence of renal epithelial cell exposure to oxalate and calcium oxalate crystals. mol urol. 2000;4:305-12. 26. el-dakhakhny m, madi nj, lembert n, ammon hp. nigella sativa oil, nigellone and derived thymoquinone inhibit synthesis of 5-lipoxygenase products in polymorphonuclear leukocytes from rats. j ethnopharmacol. 2002;81:161-4. 27. kramer g, klingler hc, steiner ge. role of bacteria in the development of kidney stones. curr opin urol. 2000;10:35-8. 28. mouhajir f, pedersen ja, rejdali m, towers ghn. antimicrobial thymohydroquinones of moroccan nigella sativa seeds detected by electron spin resonance. pharm biol. 1999;37:391-5. urological oncology the role of 68ga-psma pet/ct scan in patients with prostate adenocarcinoma who underwent radical prostatectomy mehmet hamza gultekin1*, emre demirci2, fethi ahmet turegun1, levent kabasakal3, onur erdem sahin3, meltem ocak4, bulent onal1, ahmet erozenci1 purpose: to determine whether a 68ga-psma pet/ct scan evaluation before radical prostatectomy (rp) is an effective imaging modality for clinical local and lymph node (ln) staging compared with the pathological results. materials and methods: we performed a preoperative 68ga-psma pet/ct scan in 51 patients with prostate cancer (pca), who were scheduled for an rp operation between january 2014 and june 2016 in our clinic. the correlation between the rp pathology and the results of the 68ga-psma pet/ct scan was investigated. results: when the 68ga-psma pet/ct scan results were evaluated according to the risk groups, intraprostatic activity was found in 5 of 12 patients (41.7%) in the low-risk group, 15 of 19 patients in the intermediate risk group (78.9%), and 90% patients in the high-risk group. the 68ga-psma pet/ct scan sensitivity, specificity, positive and negative predictive values and accuracy were calculated as 58.2%, 75.3%, 84.4%, 44%, and 63%, respectively for intraprostatic tumor localization; 68.4%, 75%, 61.9%, 80%, and %72.6%, respectively for extracapsular extension; 63.6%, 92.3%, 70%, 90%, and 86%, respectively for seminal vesicle involvement; 50%, 100%, 100%, 88%, and 89.3%, respectively for ln metastasis. conclusion: the 68ga-psma pet/ct scan accurately demonstrates intraprostatic tumor localization in high-risk group and presence of seminal vesicle involvement, which can help to accurately detect the target lesion before prostate biopsy. in addition, with its high sensitivity and specificity values, 68ga-psma pet/ct is a valuable imaging method for the assessment of ln metastasis in intermediateand high-risk groups and also provides accurate nodal staging before rp. keywords: lymph node dissection; pet; prostate cancer; prostate-specific membrane antigen; tnm staging introduction the primary tools for the early detection of pca are digital rectal examination, serum prostate-specific antigen (psa) level, and transrectal ultrasound-guided prostate biopsy (trus-bx). nowadays, multiparametric prostate mri provides valuable information in local staging, detection of intra-prostate tumor focus, and especially extracapsular extension.(1,2) nevertheless, the diagnostic performance of mpmri is not satisfactory, with broad sensitivity (58-97%), specificity (23-87%), and accuracy (44-87%) in detecting clinically important prostate cancer.(3) c therefore, there is a need for more effective imaging modalities that can be used in diagnosis, risk assessment, staging, and follow-up in pca. molecular image information with high target-to-background ratios could therefore potentially overcome shortcomings in primary staging. different from psa, prostate-specific membrane antigen (psma) is a glutamate carboxypeptidase ii integral merman glycoprotein, found to be denser in pca than in 1department of urology, cerrahpaşa school of medicine, istanbul university-cerrahpaşa, istanbul, turkey. 2department of nuclear medicine, yeditepe university school of medicine, istanbul, turkey. 3department of nuclear medicine, cerrahpasa medical faculty, istanbul universitycerrahpasa, istanbul, turkey 4department of pharmaceutical technology, pharmacy faculty, istanbul *university, istanbul, turkey. *correspondence: department of urology cerrahpaşa school of medicine, istanbul university-cerrahpaşa, istanbul, turkey telephone: +90 505 244 49 62 facsimile: +90 212 414 30 00. e-mail: mhamzagultekin@hotmail.com. received april 2020 & accepted december 2020 other tissues (kidney, small intestine proximal segment, salivary glands).(4) psma is a cell surface protein which is not secreted from the site it is located.(5,6) the ability of psma to be internalized within the cell where the ligand (e.g., antibody derivatives) is attached due to enzyme activity and its transmembrane location has made it an important target for diagnostic and therapeutic use. (7) today, there are many radio-labeled psma derivatives developed for the diagnosis and treatment of pca by targeting psma in nuclear medicine applications. (7-11) recent studies have shown that glu-nh-co-nhlys(abx) [hbed-ccpsma], a urea-based inhibitor of psma labeled with 68ga, is a superior method than [18f]-fech for the detection of pca recurrence and metastases for these purposes.(12) 68ga-psma pet/ct scan has shown improved detection specificity and detection rates for pca compared to standard imaging approaches.(13) the aim of this study was to determine whether a preoperative 68ga-psma pet/ct scan obtained is an effective imaging modality for clinical local (t) and ln (n) urology journal/vol 18 no. 1/ january-february 2021/ pp. 58-65. [doi: 10.22037/uj.v16i7.6165 ] staging in patients with pca scheduled for rp surgery in comparison with the actual pathological data. patients and methods study population between january 2014 and june 2016, a preoperative 68ga-psma pet/ct was performed on 51 patients who were planned to undergo rp operation and provided informed consent and data was collected by prospective manner. included in the study were patients with non-metastatic prostate cancer from all risk groups, who were scheduled to undergo rp with/without extended ln dissection. the psma pet/ct scan had to be performed within 12 weeks before surgery. patients that had received hormone treatment prior to surgery, had a history of pelvic radiation, or were diagnosed with cancer elsewhere within the last five years (except for successfully treated squamous or basal cell carcinoma of the skin) were excluded from the study. the ethics committee approval was obtained with irb number of 284452. the correlation between the pathological data obtained by rp and the results of the preoperative 68ga-psma pet/ct scan was investigated. the prostatectomy specimen served as the reference standard. pet/ct imaging with 68ga-psma and image analysis pet / ct imaging was performed using a ct-integrated pet scanner biograph 6 (siemens, knoxville, tennessee, usa) 60-90 min after the intravenous injection of 74-185 mbq mci 68ga-psma, which was prepared with a fully automated radiopharmaceutical synthesis device based on a modular concept (eckert & ziegler eurotope, berlin, germany). the raw images prostate cancer staging with 68ga-psma pet/ct scan-gultekin et al. table 1. baseline characteristics of patients. characteristicsa mean age ± sd (year) 63.5 ± 7.06 (46-78) mean psa ± sd (ng/ml) 14.6 ± 15.2 (3.2-71) preoperative gleason score 3+3 isup grade 1 22 (43.1 %) 3+4 isup grade 2 15 (29.4%) 4+3 isup grade 3 9 (17.6%) 4+4 isup grade 4 4 (7.8%) 4+5 isup grade 5 1 (1.9%) clinical t stage ≤ t2a 28 (54.9 %) t2b 6 (11.8%) ≥ t2c 17 (33.3 %) eau risk classification low-risk 12 (23.5 %) intermediate-risk 19 (37.2 %) high-risk 20 (39.2 %) postoperative gleason score 3+3 isup grade 1 7 (13.7 %) 3+4 isup grade 2 21 (41.1 %) 4+3 isup grade 3 14 (27.4 %) 4+4 isup grade 4 6 (11.7 %) 4+5 isup grade 5 3 (5.8 %) figure 1. diagram of the prostate with numbered localizations used to evaluate intraprostatic tumor localization. figure 2. the psma pet/ct image of patient with prostate cancer showing intraprostatic tumor localization. the white arrows on the left show intraprostatic tumor localization on the psma pet/ ct image. the white arrow in the maximum intensity projection view indicate intraprostatic tumor localization and also kidneys, ureters, small intestine, bladder wall, salivary and lacrimal glands received a physiological activity distribution. vol 18 no 1 january-february 2021 59 were processed with appropriate iterative reconstruction techniques to obtain pet, ct and pet-ct fusion sections in the axial, coronal and sagittal planes with a thickness of approximately 0.5 cm by two experienced nuclear medicine specialists (l.k. and e.d.), who were blinded to the clinical data and evaluated the each image individually. if the findings were incompatible, the final decision was made by consensus. in the standard pathology report, the right and left apical, median and base localizations were indicated for intraprostatic tumor localization, and tumor localization was evaluated separately in each of the six quadrants on the 68ga-psma pet/ct images. any degree of radiotracer uptake higher than intraprostatic background activity considered as “positive” according the six-quadrant template. (figure 1) using these images, extracapsular extention, seminal vesicle (sv) involvement, ln metastasis, solid organ metastasis, and bone metastasis were also assessed. the radiopharmaceutical involvement in both primary and metastatic lesions was investigated, and the results were compared with the findings of final pathology and other imaging modalities if available. surgical intervention and histopathological assessment the patients included in the study underwent open surgery. a risk of nodal metastases over 5% in briganti nomogram was excepted as an indication to perform nodal sampling by an extended nodal dissection.(14) the areas of ln dissection were planned bilaterally from the obturator fossa, lns around the common iliac artery up to the level of the ureteric crossing, and the nodes on the external iliac artery and the vein, and the nodes around the internal iliac artery. the pathological examination of the prostatectomy material was undertaken according to the recommendations of the international society of urological pathology consensus conference.(15) a standard pathological evaluation was carried out in a reference pathology clinic. tumor percentage involvement (tpi) was used to determine the tumor burden of the prostate. tumor involvement of each slide was estimated by the percentage of slides containing prostate cancer. estimation of tpi for the entire prostate was completed by summing each individual slide and averaging the results from all slides analyzed. urological oncology 60 table 2. comparative evaluation of the tumor volume, psa value, biopsy gleason score, and prostatectomy gleason score with the results of the 68ga-psma pet/ct scan. area under the curve 95% confidence interval p value lower bound upper bound tumor volume .704 .513 .853 .034 psa value .620 .465 .768 .206 biopsy gs/ isup grade .714 .547 .881 .026 prostatectomy gs/ isup grade .817 .689 .945 .001 abbreviations: gs, gleason score; isup, international society of urological pathology; psa, prostate-specific antigen. figure 3. the psma pet/ct image of patient with prostate cancer showing intraprostatic tumor localization and lymph node metastasis. the white, red and yellow arrows show intraprostatic tumor localization, bilateral obturator lymph nodes, and perirectal lymph nodes, respectively on the psma-pet ct scan. figure 4. the psma pet/ct image of patient with prostate cancer showing seminal vesicle involvement. the white arrows show the seminal vesicle involvement on the psma-pet ct scan. prostate cancer staging with 68ga-psma pet/ct scan-gultekin et al. statistical analysis the study variables were stratified as numerical or categorical. the numerical variables were calculated as means and standard deviations and presented as minimum and maximum values, and the categorical variables as frequencies and percentages. the nominal categorical variables were assessed using the chi-square test. a receiver operating characteristic (roc) curve analysis was undertaken to determine the threshold value with the best possible sensitivity and specificity. the sensitivity, specificity, positive prediction value (ppv), negative prediction value (npv), and accuracy were calculated for the detection of intraprostatic tumor localization, extracapsular extension, sv involvement, and ln metastases, by psma pet/ct. to assess the agreement between the final pathology and preoperative psma pet/ct, we used kappa test. the kappa value < 0.20 is reflecting a slight, values of 0.21-0.40 are considered fair, 0.41-0.60 moderate, 0.61-0.80 good, 0.81-1 almost perfect agreement.(16) all statistical analyses were performed using spss version 20.0. the level of significance was set at p < 0.05. results there were 51 patients with a mean age of 63.5 ± 7.06 (46-78) years and a mean psa value of 14.6 ng / ml ± 1 5.2 (3.2-71). gs as shown by isup grade, european association of urology (eau) risk group classification, and clinical t stage were shown in table 1. a total of 26 patients had an increased gs after the operation compared to the preoperative period. the results of the 68ga-psma pet/ct scan did not affect the surgical decision. in 39 patients (76.5%), the 68ga-psma pet/ct scan showed an uptake of tracer in at least one intraprostatic focus. these patients had a mean tpi of 26.13 ± 24.82 %. the remaining 12 patients with a negative scan had a mean tpi of 12 ± 14.99 %. when the roc curve analysis was performed according to tpi in the postoperative pathology, statistically significant differences were found. the roc curve analysis revealed a cut off value of > 12% tpi with a sensitivity of 0.67, specificity of 0.75 and auc of 0.704 (95% ci, .513-.853; p = .034). when the results of the 68ga-psma pet/ct scan were evaluated together with the preoperative psa values, they were not statistically correlated , and according to the roc curve analysis, the area under the curve was 0.620 (95% ci, .465-.786; p = .206) (figure 5, table 2). the preoperative prostate biopsy and postoperative prostatectomy gs/isup grade was comparatively evaluated with the results of the 68ga-psma pet/ct scan. preoperative gs/isup grade was statistically significant with auc of 0.714 (95% ci, .547-.881; p = .026) table 3. psma pet-ct results according to intraprostatic tumor localization, seminal vesicle involvement, and lymph node staging. sensitivity specificity ppv npv accuracy kappa intraprostatic tumor localization total 58.2% 75.3% 84.4% 44% 63.4% kappa=.279, p < .005 low-risk 39% 96.9% 94.1% 58.1% 66.6% kappa=.141, p =. 076 intermediate-risk 43.4% 73.6% 76.7% 39.4% 53.5% kappa=.184, p = .037 high-risk 76.5% 45.4% 86.2% 30.3% 70.8% kappa=.361, p < .005 extracapsular extension total 68.4% 75% 61.9% 80% 72.6% kappa=.425, p = .002 low-risk na na na na na intermediate-risk 40% 64.3% 28.6% 71.4% 57.9% kappa=.038, p = .865 high-risk 78.6% 50% 78.6% 50% 70% kappa=.286, p = .201 seminal vesicle involvement total 63.6% 92.3% 70% 90% 86% kappa=.580, p < .005 low-risk na na na na na intermediate-risk 66.6% 87.5% 50% 93.3% 84.2% kappa=.477, p = .035 high-risk 62.5% 91.6% 83.3% 78.5% 80% kappa=.565, p = .010 lymph node staging total 50% 100% 100% 88% 89.3% kappa=.521, p=.004 low-risk na na na na na intermediate-risk 50% 100% 100% 91.6% 92.3% kappa=.629, p = .015 high-risk 50% 91.6% 66.6% 84.6% 81.2% kappa=.505, p = .024 figure 5. roc curve analysis comparing the tumor volume and preoperative psa values with psma pet-ct. figure 6. roc curve analysis comparing preoperative and postoperative isup grade with psma pet-ct. prostate cancer staging with 68ga-psma pet/ct scan-gultekin et al. vol 18 no 1 january-february 2021 61 in roc curve analysis. for the postoperative gs/isup grade, it was also achieved statistically significant level with auc of 0.817 (95% ci, .689-.945; p = .001) in roc curve analysis (figure 6, table 2). the roc curve analysis revealed a cut off value of > isup grade 1 for both preoperative and postoperative pathology. concerning the evaluation of intraprostatic tumor localization separately for each quadrant, the 68ga-psma pet/ct scan had a sensitivity of 58.2%, specificity of 75.3%, ppv of 84.4%, npv of 44%, accuracy of 63.4%, compared with the postoperative pathology results. when further analyzed using kappa test, kappa value of .279 (p < .05), and the results of 68ga-psma pet/ ct fairly agreed those of standard pathological analysis (table 3). when subgroup analysis of the 68ga-psma pet/ct scan results according to the eau risk groups were done, we found at least one intraprostatic activity in 41.7% of the patients (5 of 12) in the low-risk group, 78.9% (15 of 19) in the intermediate-risk group, and 95% (19 of 20) in the high-risk group. when we compared the pathologic intraprostatic tumor localization with the 68ga-psma pet/ct scan results only for the high-risk group, we found that the latter had a sensitivity of 76.5%, specificity of % 45.4, accuracy of 70.8%, and provided better results in this group of patients compared to pathological analysis. (kappa=.361, p < .005) in the final pathology reports ece were seen in 21 patients in all risk groups. while not seen in low-risk patients, it was seen in 36.8% (7 out of 19) of patients in the intermediate-risk group and 70% (14 out of 20) of patients in the high-risk group. when we compared the pathologic ece with the 68ga-psma pet/ct scan results, we found that the 68ga-psma pet/ct scan had a sensitivity of 68.4%, specificity of 75%, ppv of 61.9%, npv of 80%, accuracy of 72.6% (kappa=.425, p = .002). in subgroup analysis high-risk group had a sensitivity of 78.6%, specificity of 50%, ppv of 78.6%, npv of 50%, and accuracy value of 70% (kappa=.286, p = .201). the 68ga-psma pet/ct scan was compared with the postoperative pathology findings in terms of identifying sv involvement, and the sensitivity, specificity, ppv, npv, and accuracy values of the 68ga-psma pet/ ct scan were calculated as 63.6%, 92.3%, 70%, 90% and 86%, respectively (kappa=.580, p<.005). in subgroup analysis intermediate-risk group had a sensitivity of 66.6%, specificity of 87.5%, ppv of 50%, npv of 93.3%, and accuracy value of 84.2% (kappa = .477, p = .035) and in high-risk group this analysis was seen as 62.5%, 91.6%, 83.3%, 78.5% and 80% respectively (kappa=.565, p = .010).(table 3) pathologic ln metastasis was detected in six of 28 patients (21.4%) who underwent expanded pelvic ln dissection (figures 2, 3). in patients who underwent this procedure, the mean and total number of dissected lns were found to be 28.5 (6-41) and 829, respectively. in total, metastasis was detected in 20 lns (2.4%). when the ln positivity and negativity rates in the 68ga-psma pet/ct scan images were analyzed, this method had a sensitivity of 50%, specificity of 100%, ppv of 100%, npv of 88%, and accuracy value of 89.3%,and 68ga-psma pet/ct scan moderately agreed with pathological findings (kappa=.521, p = .004).(table 3). in subgroup analysis intermediate-risk group had a sensitivity of 50%, specificity of 100%, ppv of 100%, npv of 91.6%, and accuracy value of 92.3% (kappa=.629, p = .015), and in high-risk group this analysis was seen as 50%, 91.6%, 66.6%, 84.6% and 81.2% (kappa = .505, p = .024) respectively. (table 3) lastly, according to the long term follow up two patients died, five patients lost to follow-up. the remaining 44 patients were evaluated according to the biochemical recurrence (bcr). 15 patients had biochemical recurrence with one ln metastasis and three local recurrences. patients who occurred ln metastasis or local recurrence were all with adverse preoperative psma findings (such as ece, sv involvement, and ln metastasis). bcr treated with hormonal treatment and/ or external beam radiotherapy. none of the patients in low-risk group developed bcr, although, four patients in intermediate-risk group and 11 patients in high risk group developed bcr. when we evaluated adverse imaging findings in psma and bcr in high-risk group patients, 68ga-psma pet/ct scan had a sensitivity of 63.2%, specificity of 88%, ppv of 80%, npv of 75.9%, and accuracy value of 77.3% (kappa=.625, p ≤ .005) discussion psma is a cell surface protein that is not secreted from the site it is located, and it is denser in pca than in other tissues (kidney, small intestine proximal segment, salivary glands).(5,6) the ability of psma to be internalized within the cell where the transmembrane location and ligand (e.g., antibody derivatives) are bound due to enzyme activity has made it an important target for diagnostic and therapeutic purposes.(17) today, many radio-labeled psma derivatives have been developed for use in nuclear medicine applications in the diagnosis and treatment of pca by targeting psma.(7-11) in our study, when intraprostatic tumor localization was separately evaluated for each quadrant, although the 68ga-psma pet/ct scan did not completely agree those of the standard pathological analysis; it provided better results in high-risk group of patients compared to pathological analysis. in order to investigate the localization and spread of primary pca, fendler et al. compared the imaging and histopathological segments of the 68ga-psma pet/ct scan patients before rp and the sensitivity, specificity, ppv, npv, and accuracy of this method were found to be 67%, 92% 42% and 72%, respectively.(18) in another research, authors determined that for predicting intra-prostate tumor localization in the high-risk patient group, the sensitivity, and specificity, ppv and npv of 68ga-psma pet /ct was 92%, %92, 96%, and 85%, respectively.(19) above mentioned studies included high-risk patients in their studies, and when we performed a subgroup analysis with a highrisk group, our results fall in range in between those two studies. the extracapsular extension (ece) in pca affects both prognoses of the patient and the appropriate surgical strategy.(20) nerve-sparing surgery is not seen as a viable option in patients with positive ece, and therefore functional results are compromised.(21) in our study, when we compared the pathologic ece with the 68ga-psma pet/ct scan results, we found that the 68ga-psma pet/ct scan had moderately agreed with final pathology (kappa = .425, p = .002). mpmrg with high tissue recognition power has been used extensively for t staging in the last one decade. in a meta-analysis urological oncology 62 prostate cancer staging with 68ga-psma pet/ct scan-gultekin et al. conducted in 2016, authors demonstrated that mpmri has a low sensitivity on ece (0.57, 95% ci, 0.49–0.64) but a high specificity (0.91, 95% ci, 0.88–0.93).(22) in another study that evaluates head to head comparison of mpmrg and 68ga-psma pet/ct, authors reported that psma had a higher sensitivity (78% vs. 54%, p = 0.013) and similar specificity (94% vs. 94%) than mpmrg according to the ece assessment.(23) we think that the reason why our results are seen inferior from the literature may be due to the weak scatter correction of the device we use. the sv involvement of pca is directly proportional to increased ln invasion and increased tumor recurrence. the knowledge of sv involvement at the time of diagnosis is important for the evaluation of prognosis and planning of treatment. in the current study, for the evaluation of sv involvement, 68ga-psma pet/ ct was moderately agreed with postoperative pathology findings (kappa = .580, p < .005). fendler et al. used the 68ga-psma pet/ct scan for local staging of the pca and found that 11 patients (out of 21 patients 52%) had pathologically proven sv involvement. the authors also stated that the 68ga-psma pet/ct scan provided acceptable results at accuracy of 86%. (18) in a recent study that compares final pathology and 68ga-psma pet/ct scan results, sensitivity, specificity, positive and negative predictive value for detection of sv involvement by psma pet/ct were 58%, 96%, 78% and 90% respectively.(24) our results were consistent with existing literature.(18,24) the status of lns in newly diagnosed pca is an important factor in planning treatment. the gold standard of ln staging is ln dissection. in addition, eau recommends a metastasis assessment and ln staging to be performed with ct or mri in intermediate and highrisk patients with pca. the guideline states that psma shows more sensitive detection on ln staging in an evidence-based manner. also, it was mentioned that results from randomized controlled trials are awaited, before putting the psma result into the decision-making process of the treatment of prostate cancer.(25) in a meta-analysis published in 2008, hövels et al. reported that the sensitivity of ct and mri in ln staging was 42% and 39%, respectively, and the specificity was 82% for both.(26) however, these imaging methods only provide morphological data and assess ln metastasis based on the size of the ln; therefore, they are not adequate in ln staging. in our study, we had 28 patients (21.4%) who underwent eplnd in intermediate and high-risk groups. the 68ga-psma pet/ct scan had a sensitivity of 50%, specificity of 100%, ppv of 100%, npv of 88%, and accuracy of 89.3%. in the similar group of patients maurer et al. reported to have 65.9% sensitivity, 98.9% specificity, and 88.5% accuracy in detecting ln.(27) in a relatively small sample sized study (130 vs 27), which was conducted by van leeuwen et al., the authors found a sensitivity of 64%, specificity of 95%, ppv of 88%, and npv of 82% in patient-based statistical analysis and their results were very similar with our study.(28) meanwhile, in a study conducted by abdollah et al., it was reported that removal of a minimum of 20 lns in pelvic ln dissection provided 90% real ln staging.(29) in their respective studies, maurer and van leeuwen dissected a mean of 5.6-6 lns, which were below the minimum number of lns to be removed. we dissected a mean of 28.5 (6-41) lns, thus, we consider that we achieved adequate ln staging for each patient. psa measurement is the most important clinical marker showing the course of the disease after prostate cancer surgery. in addition, the most important reason for psa increases or not decreases in the postoperative period is the pre-rp clinical stage of the disease. ln involvement, extracapsular extension, and sv involvement are well described poor prognostic indicators of the initial response to rp.j(30) in our study, the relationship between advanced psma findings and bcr were evaluated and a good agreement was found in the kappa test. (kappa=.625, p ≤ .005) in addition, in a study conducted by nandurkar et al., it was stated that when there is an extraprostatic disease in preoperative psma pet, bcr can be seen at a high rate and these patients can be candidates for multimodal methods.31 we also think that the data on this subject should be increase. this study has certain limitations such as the number of patients was relatively small. due to the limited budget and ethical problems, we included only patients who were diagnosed with prostate cancer and scheduled to undergo rp into our study, and we did not perform external validation by imaging patients who were not diagnosed with pca. however, the nuclear medicine specialists were aware that all patients were diagnosed with pca and scheduled for an rp operation. further prospective studies are essential to provide an understanding of the value of 68ga-psma pet/ct scan in determining the clinical stages in pca. well-designed controlled trials evaluating the management and outcome of patients using psma pet/ct are needed to make an informed decision concerning the treatment of these patients. conclusions the 68ga-psma pet/ct scan accurately demonstrates intraprostatic tumor localization especially in high-risk groups and may help to accurately detect the target lesion before prostate biopsy. the 68ga-psma pet/ct scan accurately demonstrates presence of seminal vesicle involvement and moderately demonstrates extracapsular extenision. in addition, with its high sensitivity and specificity values, 68ga-psma pet/ct is a valuable imaging method for assessment of ln staging in intermediateand high-risk groups and also provides accurate ln staging before rp. these promising results for ln staging indicate that 68ga-psma pet/ ct might become the standard imaging method for this purpose in the future. acknowledgment this work was financially supported by the scientific research projects coordination unit of istanbul university, under the project number 32724. data presented previously at 3th national urological surgery congress. 2 – 6 november 2016 antalya turkey (oral presentation) ss 06 conflict of interest the authors declare that they have no conflict of interest. references 1. de rooij m, hamoen eh, witjes ja, barentsz jo, rovers mm. accuracy of magnetic resonance imaging for local staging of prostate cancer: a diagnostic meta-analysis. prostate cancer staging with 68ga-psma pet/ct scan-gultekin et al. vol 18 no 1 january-february 2021 63 eur urol. 2016;70:233-45. 2. zhang f, liu cl, chen q, shao sc, chen sq. accuracy of multiparametric magnetic resonance imaging for detecting extracapsular extension in prostate cancer: a systematic review and meta-analysis. br j radiol. 2019;92:20190480. 3. futterer jj, briganti a, de visschere p, et al. can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging? a systematic review of the literature. eur urol. 2015;68:1045-53. 4. schülke n, varlamova oa, donovan gp, et al. the homodimer of prostate-specific membrane antigen is a functional target for cancer therapy. proc natl acad sci u s a 2003;100:12590-5. 5. sweat sd, pacelli a, murphy gp, bostwick dg. prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. urology 1998;52:637-40. 6. mannweiler s, amersdorfer p, trajanoski s, terrett ja, king d, mehes g. heterogeneity of prostate-specific membrane antigen(psma) expression in prostate carcinoma with distant metastasis. pathol oncol res 2009;15:167-72. 7. eder m, schäfer m, bauder-wüst u, et al. 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staging of radical prostatectomy specimens. working group 1: specimen handling. mod pathol 2011;24:6-15. 16. landis jr, koch gg. the measurement of observer agreement for categorical data. biometrics. 1977;33:159-74. 17. ghosh a, heston wd. tumor target prostate specific membrane antigen (psma) and its regulation in prostate cancer. j cell biochem 2004;91:528-39. 18. fendler wp, schmidt df, wenter v, et al. 68ga-psma-hbed-cc pet/ct detects location and extent of primary prostate cancer. j nucl med 2016;57:1720-1725. 19. rahbar k, weckesser m, huss s, semjonow a, breyholz hj, schrader aj, et al. correlation of intraprostatic tumor extent with ⁶⁸gapsma distribution in patients with prostate cancer. j nucl med 2016;57:563-7. 20. mikel hubanks j, boorjian sa, frank i, gettman mt, houston thompson r, rangel lj, bergstralh ej, jeffrey karnes r. the presence of extracapsular extension is associated with an increased risk of death from prostate cancer after radical prostatectomy for patients with seminal vesicle invasion and negative lymph nodes. urol oncol. 2014;32:26.e1-7. 21. nguyen ln, head l, witiuk k, et al. the risks and benefits of cavernous neurovascular bundle sparing during radical prostatectomy: a systematic review and meta-analysis. j urol. 2017;198:760-9. 22. de rooij m, hamoen eh, witjes ja, et al. accuracy of magnetic resonance imaging for local staging of prostate cancer: a diagnostic meta-analysis. eur urol 2016;70:233-45. 23. chen m, zhang q, zhang c, et al. comparison of 68ga-prostate-specific membrane antigen (psma) positron emission tomography/ computed tomography (pet/ct) and multiparametric magnetic resonance imaging (mri) in the evaluation of tumor extension of primary prostate cancer. transl androl urol. 2020;9:382-90. 24. dekalo s, kuten j, mabjeesh nj, beri a, even-sapir e, yossepowitch o. 68ga-psma pet/ct: does it predict adverse pathology findings at radical prostatectomy? urol oncol 2019;37:574.e19-24. 25. mottet n, van den bergh rcn, briers e, et al. eau guidelines on prostate cancer. european prostate cancer staging with 68ga-psma pet/ct scan-gultekin et al. urological oncology 64 vol 18 no 1 january-february 2021 65 association of urology. https://uroweb.org/ guideline/prostate-cancer/ edn. presented at the eau annual congress barcelona 2019. eau guidelines office, arnhem, the netherlands. isbn 978-94-92671-04-2. 26. hövels am, heesakkers ra, adang em, et al. the diagnostic accuracy of ct and mri in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. clin radiol 2008;63:387-95. 27. maurer t, gschwend je, rauscher i, et al. diagnostic efficacy of 68gallium-psma positron emission tomography compared to conventional imaging in lymph node staging of 130 consecutive patients with intermediate to high-risk prostate cancer. j urol 2016;195:1436-43. 28. van leeuwen pj, emmett l, ho b, et al. prospective evaluation of 68galliumpsma positron emission tomography/ computerized tomography for preoperative lymph node staging in prostate cancer. bju int 2016;119:209-15 29. abdollah f, sun m, thuret r, et al. lymph node count threshold for optimal pelvic lymph node staging in prostate cancer. int j urol 2012;19:645-51. 30. liss ma, lusch a, morales b, et al. robotassisted radical prostatectomy: 5-year oncological and biochemical outcomes. j urol 2012;188:2205-11. 31. nandurkar r, van leeuwen p, stricker p, et al. 68ga-hbedd psma-11 pet/ct staging prior to radical prostatectomy in prostate cancer patients: diagnostic and predictive value for the biochemical response to surgery. br j radiol. 2019;92:20180667. prostate cancer staging with 68ga-psma pet/ct scan-gultekin et al. case report 203urology journal vol 7 no 3 summer 2010 laparoscopic removal of retained surgical gauze seyed habibollah mousavi-bahar, mohammad ali amirzargar urol j. 2010;7:203-5. www.uj.unrc.ir keywords: surgical sponge, foreign bodies, laparoscopic surgery department of urology, hamadan university of medical sciences, hamadan, iran corresponding author: seyed habibollah mousavi-bahar, md department of urology, shahid beheshti hospital, hamadan university of medical sciences, hamadan, iran tel: +98 811 823 0829 fax: +98 811 838 1035 e-mail: shmbahar@yahoo.com received february 2009 accepted august 2009 introduction term of gossypiboma (textiloma, cottonoid, gauzoma, and muslinoma) is used to describe a retained surgical pad or gauze in the body after an operation. retained postoperative foreign bodies, of which sponges are the most common, is a preventable condition and almost always iatrogenic.(1,2) gossypiboma may present acutely or subacutely and some times it may be symptom free.(1,3) laparoscopic removal of retained surgical pad, gauze, and instruments has already been reported.(3-7) herein, we present a case of abdominal gossypiboma 4 years after hysterectomy. we used laparoscopy as the therapeutic tool. case report a 53-year-old woman presented with acute right renal colic. after medication and pain relief, she was sent for radiologic examination. a 10-mm stone in the right distal ureter and a forgotten surgical gauze in the left side of the pelvis were seen on kidneys, ureters, bladder x-ray (figure 1). the ureteral stone was confirmed by intravenous pyelography. she had undergone abdominal hysterectomy 4 years earlier and had vague abdominal discomfort and anorexia after the operation. on abdominal examination, there was a hypogasteric vague tenderness and firmness. laboratory findings were within normal limits. computed tomography scan revealed a foreign body measured 5 × 3.5 cm with heterogeneous internal structure in the left iliac fossa that had been surrounded by the small intestine and the colon (figure 2). transurethral figure 1. kidneys, ureters, bladder x-ray shows right distal ureteral stone and retained gauze in the left side of the pelvis. figure 2. computed tomography scan reveals a mass measuring 5 × 3.5 cm. laparoscopy for foreign body—mousavi-bahar and amirzargar 204 urology journal vol 7 no 3 summer 2010 ureterolithotripsy and laparoscopy were planned. under general anesthesia and lithotomy position, ureteroscopy and pneumatic lithotripsy were performed, particles of calculi were removed, and a 4f-ureteral catheter was inserted. thereafter, laparoscopy was done in supine position with a 12-mm infra-umbilical port and two 5-mm ports in the left and right lower quadrants. the omentum adhered to the abdominal wall and the small bowel loops, and the sigmoid colon adhered to the gauze, which together made up a mass. the gauze had been sealed with the peritoneum and its radiologic green marker was seen through the peritoneum (figure 3). using sharp dissection, the omentum and bowel loops were carefully separated. the sponge was removed by making an incision in the peritoneal part of the mass. after irrigation and suction of the bed of the mass, a nelaton catheter was left in place as a drain. the patient was out of bed on the 1st postoperative day and started oral fluids from the 2nd postoperative day. there was no complication during and after the surgery, and the patient was discharged on the 4th postoperative day. discussion leaving gauze or rarely instruments behind after any surgery is a misadventure and is solely iatrogenic.(1,8,9) swabs, packs, towels, or instruments may be left in the body cavities after the surgery.(9) gawande and colleagues studied 61 patients with retained foreign bodies. they found surgical sponge in 69% of subjects and instruments such as clamp, retractor, and electrode in 31%.(10) gossypiboma is most frequently diagnosed in the intra-abdominal cavity; however, it can also be seen in the vagina, the spinal canal, the face, the brain, the paraspinal muscles, the thorax, the legs, and the shoulders. (11,12) rodrigues and associates reported a case with a 33 cm × 5 cm ribbon malleable retractor retained intra-abdominally for 14 years.(6) we had also a case of retained malleable retractor inside the abdomen for 45 days (unpublished personal experience). gawande and associates reported that the incidence of gossypiboma and retained instruments varied from 1/8801 to 1/18 760 of inpatient operations at general hospitals. it has been estimated that more than 1500 cases of retained foreign bodies occur annually in the usa.(10) several risk factors have been reported for leaving sponge and instruments, including an emergency operation, an unexpected change in procedure, long duration operations, hurried sponge counts, inexperienced staff, inadequate number of staff, change in operating room staff, patients’ unstable condition, and obesity of patients.(2,10,11) clinical symptoms of gossypiboma may vary from mild discomfort, pain, and malabsorption syndrome to severe pain, fever, and bowel obstruction and can present years after the initial surgery.(3) about one third of patients with gossypiboma remain asymptomatic and are either detected by radiologic investigations such as computed tomography scan or intraoperatively after the initial operations are long forgotten. (1,8,11) if the patient is asymptomatic and retained surgical sponge is diagnosed accidentally, it is recommended to be removed surgically or endoscopically.(11) laparoscopy was found to provide a quicker diagnosis. the added advantage of providing a simultaneous therapeutic benefit further supports laparoscopic intervention.(3) there have been many reports on laparoscopic removal of foreign or migrated bodies. rodrigues and colleagues reported laparoscopic removal of a retained large malleable retractor 14 years after initial procedure.(6) sharifiaghdas and coworkers figure 3. radiologic green marker is seen through peritoneal layer. laparoscopy for foreign body—mousavi-bahar and amirzargar 205urology journal vol 7 no 3 summer 2010 reported a case of migrated intrauterine device into the peritoneal cavity that was removed laparoscopically.(4) singh and colleagues reported a case of laparoscopic diagnosis and removal of sponge 14 days after the surgery,(3) while olivier and devriendt reported laparoscopic removal of a gauze pad left in the abdomen for 22 years.(5) our case presented with renal colic and her retained gauze was detected accidentally; however, she had mild abdominal discomfort and malabsorption. after radiologic investigation, we decided to remove the ureteral stone and forgotten gauze in a same session anesthesia. we did both surgeries endoscopically. every effort should be made to prevent this medical misadventure. if we keep vigilance and good operating room staff, gossypiboma occurrence can be prevented. recently, all operating rooms have been equipped with laparoscopic set and laparoscopic surgeries are done routinely. therefore, laparoscopic surgery is an excellent method for rapid diagnosis and easily removal of the forgotten pads or instruments, and can be used in early or delayed diagnosed cases. conflict of interest none declared. references 1. cheng tc, chou as, jeng cm, chang py, lee cc. computed tomography findings of gossypiboma. j chin med assoc. 2007;70:565-9. 2. bani-hani ke, gharaibeh ka, yaghan rj. retained surgical sponges (gossypiboma). asian j surg. 2005;28:109-15. 3. singh r, mathur rk, patidar s, tapkire r. gossypiboma: its laparoscopic diagnosis and removal. surg laparosc endosc percutan tech. 2004;14:304-5. 4. sharifiaghdas f, mohammad ali beigi f, abdi h. laparoscopic removal of a migrated intrauterine device. urol j. 2007;4:177-9. 5. olivier f, devriendt d. laparoscopic removal of a chronically retained gauze. acta chir belg. 2003;103:108-9. 6. rodrigues d, perez ne, hammer pm, webber jd. laparoscopic removal of a retained intraabdominal ribbon malleable retractor after 14 years. j laparoendosc adv surg tech a. 2006;16:369-71. 7. ibrahim im. retained surgical sponge. surg endosc. 1995;9:709-10. 8. sharma d, pratap a, tandon a, shukla rc, shukla vk. unconsidered cause of bowel obstruction-gossypiboma. can j surg. 2008;51:e34-5. 9. szentmariay if, laszik a, sotonyi p. sudden suffocation by surgical sponge retained after a 23-year-old thoracic surgery. am j forensic med pathol. 2004;25:324-6. 10. gawande aa, studdert dm, orav ej, brennan ta, zinner mj. risk factors for retained instruments and sponges after surgery. n engl j med. 2003;348: 229-35. 11. erdil a, kilciler g, ates y, et al. transgastric migration of retained intraabdominal surgical sponge: gossypiboma in the bulbus. intern med. 2008;47: 613-5. 12. alis h, soylu a, dolay k, kalayci m, ciltas a. surgical intervention may not always be required in gossypiboma with intraluminal migration. world j gastroenterol. 2007;13:6605-7. analysis and validation of key genes related to radiosensitivity in prostate cancer wen-lin huang1, yong xu1* purpose: to investigate the potential relationship between differential gene expression, biological function enrichment, and disease prognosis affecting the sensitivity of prostate cancer radiotherapy by bioinformatics analysis. materials and methods: retrieve and obtain data on differential gene expression of prostate cancer radiosensitivity in the geo database (gsm3954350, gsm3954351, gsm3954352), ger2 tool to screen and analyze the differential genes, enrichr database for enrichment analysis of go and kegg, use cytoscape software builds protein-protein interaction (ppi) networks and analyzes key genes. results: a total of 7041 differentially expressed genes were screenedout, including 3842 high expression genes and 3199 low expressed genes. the top 20 differentially expressed genes were selected for further analysis. their biological functions are mainly enriched in the following aspects: “cell communication” and “signal transduction”; cytological components are mainly located outside the cell; molecular functions are enriched in structural molecular activity, receptor binding, serine-like peptidase activity, etc. the kegg enrichment analysis showed that the differentially expressed genes were mainly enriched in the mismatch repair pathway, non-homologous terminal binding pathway and so on. survival analysis showed that vgf gene was associated with the prognosis of prostate cancer patients receiving radiotherapy, and high expression of vgf significantly reduced progression-free survival(pfs) in these patients(hr = 4.84, 95% ci: 1.34-17.5, p = .016). conclusion: this study identified key genes associated with radiation sensitivity in prostate cancer and verified the relationship between the vgf gene and patient prognosis. keywords: prostate cancer; radiosensitivity; bioinformatics introduction prostate cancer is a malignant tumor with a high incidence rate, currently highest in north america and europe, followed by asia and africa. a study by basiri et al. showed ethnic differences in prostate cancer risk in iran, the most populous multi-ethnic country in the middle east(1). according to the american cancer society's epidemiological survey: the death rate of prostate cancer has been declining for more than 20 years, although this number has stabilized in recent years(2-3).the challenge for us is how to continue to reduce this number and enable prostate cancer patients to gain more benefits from treatment. radiotherapy is playing an increasingly important role in the treatment of prostate cancer, with the continuous improvement of radiotherapy equipment and methods, its application in the treatment of various stages of prostate cancer has achieved good treatment results(4-5). nevertheless, as tumor cells develop resistance to radiotherapy, its efficacy will gradually be limited, and the patient’s tumor progression will follow(6-7). the mechanism of radioresistance in prostate cancer cells still remains unclear, pi3k/akt and mtor signaling pathways, dna repair, autophagy, and epithelial mesenchymal transformation probably take part in this process(8). therefore, exploring the factors that affect the sensitivity of prostate can1department of urology, zhu zhou central hospital, zhu zhou, hunan, china. *correspondence: 116 changjiang nan road, zhuzhou, 412007, hunan, telephone:18670872766. email: 278449242@qq.com. tigerhnll@126.com. received august 2021 & accepted february 2022 cer radiotherapy is of great significance to improve the therapeutic effect. the gene expression omnibus (geo) of the national center for biotechnology information is currently the largest and most comprehensive public gene expression database, it has been widely used in the study of differential gene expression in tumors(9). in this study, we downloaded three microarray data sets from the geo database to identify key genes that affect the sensitivity of prostate cancer radiotherapy and analyze their biological functions. materials and methods data acquisition search for publicly published gene chips in the geo database (https://www.ncbi.nlm.nih.gov/geo/):①the search term is "prostate cancer", "radiotherapy"; ②the species is "human". finally, three data sets were obtained (gsm3954350, gsm3954351, and gsm3954352). the experimental group was radiotherapy-insensitive patients, and the control group was radiotherapy-sensitive patients. download the differentially expressed gene data and use the difference log fold change >2 and adjust < 0.05 as the screening conditions for the difference genes. urological oncology urology journal/vol 20 no. 1/ january-february 2023/ pp. 22-28. [doi:10.22037/uj.v19i.6967] functional enrichment analysis the differentially expressed genes were converted into names of the same type, and functional enrichment analysis was performed based on geneontology (go) and kyoto encyclopedia of genesand genomes (keeg). evaluate their functional associations through the string database (http://strin abstract db.org). the degree score greater than 0.4 is considered significant. the degree for the association of these genes was analyzed with cytoscape software (version 3.6.0), and build a visual hub gene network was established statistical analysis statistical analysis was carried out with spss25.0 software, measurement data used t test; count data used chi-square test, p < 0.05 indicated that there was a statistical difference. for kaplan–meier curves, p-values and hazard ratio (hr) with 95% confidence interval (ci) were generated by log-rank tests and univariate cox proportional hazards regression. all analytical methods above and r packages were performed using r software version v4.0.3 (the r foundation for statistical computing, 2020). p < 0.05 was considered as statistically significant. vol 19 no 4 july-august 2022 308 table 1. 20 differentially expressed genes gene logfc p.valve gcg 5.50042646 3.07e-07 il7 -4.55450931 1.86e-06 ccl2 -4.31805385 6.30e-06 csf3 -3.75601818 7.42e-06 il7r 5.01631541 4.28e-05 igfbp3 -3.69658348 8.43e-05 bdkrb1 -3.69396659 8.79e-05 gja1 4.82279894 9.96e-05 adcy5 -3.47914908 1.15e-04 grpr -3.23563766 1.27e-04 flt3lg -3.20223477 1.54e-04 adra2c -3.17089892 1.63e-04 bmp7 -3.10999178 2.03e-04 vgf 3.63181712 2.53e-04 ghr -3.06502295 2.92e-04 fgf13 2.93364754 3.16e-04 ltbp1 -3.03787139 3.25e-04 eva1a -2.95634334 3.37e-04 qrfpr -2.88320079 3.42e-04 gpr143 2.79000942 3.56e-04 figure 1. differential gene expression volcano map of gsm3954350, gsm3954351, gsm3954352 data sets（thered dots represent genes with significantly up-regulated expression, green dots represent genes with significantly down-regulated expression, and black dots represent genes with no differentially expressed expression） rank name score 1 gcg 13 2 il7 10 2 ccl2 10 4 csf3 9 5 il7r 8 6 igfbp3 7 6 bdkrb1 7 6 gja1 7 9 adcy5 6 9 grpr 6 9 flt3lg 6 12 adra2c 5 12 bmp7 5 12 vgf 5 12 ghr 5 12 fgf13 5 17 ltbp1 4 17 eva1a 4 17 qrfpr 4 17 gpr143 4 table 2. hub gene sequencing. key genes for radiosensitivity of prostate cancer –huanget al. vol 20 no 1 january-february 2023 23 results differential gene screening we retrieved the geo database for gene expression of prostate cancer patients with radioresistance after radiotherapy(gsm3954350,gsm3954351, gsm3954352), a total of 7041 differentially expressed genes were found, of which 3842 were highly expressed and 3199 were lowly expressed. the top 20 (table 1) genes with differential expression levels were selected for further analysis (figure 1). among them, the genes with high expression were gcg, il7r, gja1, vgf, fgf13, gpr143, while the genes with low expression wereil7, ccl2, csf3, igfbp3, bdkrb1, adcy5, grpr, flt3lg, adra2c, bmp7, ghr, ltbp1, eva1a, qrfpr. go and kegg enrichment analysis goenrichment analysis was used to analyze the biological process (bp) of the differential genes, suggesting that their functions may be mainly enriched in the following aspects (figure.2): “cell communication” （65%， p = 0.004）and “signal transduction” （65%， p = 0.007）; cytological components are mainly extracellular（24.8%, p = 0.036） (figure 3). key genes for radiosensitivity of prostate cancer –huanget al. urological oncology 24 figure 2. go analysis of differential gene: biological process（biological processes(bp) are significantly enrichedin“cellcommunication”and“signal transduction”） figure 3. go analysis of differential gene: cellular components（cellular component (cc) annotation showed that the gene products mainly enriched in the extracellular,24.8%,p=0.036） molecular functions(mf) are mainly enriched in structural molecular activity, receptor binding, serine-like peptidase activity, etc. (figure 4). enrichment analysis of kegg signaling pathway showed that the differential genes mainly concentrated in the cytokine-cytokine receptor interaction, hematopoietic cell lineage and other pathways (figure 5). protein-protein interactive analysis use the online analysis tool of the string database to evaluate the association with the screened genes(10), the correlation was further analyzed with cytoscape (version 3.6.0). a hub gene network was established (figure 6), and the degree of association for hub genes and other genes was ranked (table 2). these genes indicate possible targets for radioresistance in prostate cancer. prognosis analysis figure 4. go analysis of differential gene: cellular components（cellular component (cc) annotation showed that the gene products mainly enriched in the extracellular,24.8%, p = 0.036） figure 5. enrichment analysis of kegg signaling pathway of differential genes（kegg pathway enrichment analysis: the top 10 pathways with significant enrichment of differential genes, *stands for p-value） key genes for radiosensitivity of prostate cancer –huanget al. vol 20 no 1 january-february 2023 25 we obtained information on 41 prostate cancer patients who received radiotherapy and completed rna sequencing from the cancer genome atlas (tcga) database. we analyzed the expression levels of the above genes in these patient samples, and performed survival analysis using the kaplan-meier method. the results suggest that the expression of vgf gene is related to the prognosis of these patients. we drew the kaplan-meier curve of vgf gene (figure 7). thus, patients with high vgf expression had significantly lower progression-free survival (pfs) than those with low vgf expression.(hr = 4.84, 95% ci: 1.34-17.5,p = .016) discussion figure 6. hub gene network urological oncology 26 figure 7. kaplan-meier survival analysis of vgf gene. key genes for radiosensitivity of prostate cancer –huanget al. with the in-depth research on prostate cancer, its treatment methods have become more efficient and diversified, the progress of treatment methods must be guided by the smallest risk in exchange for higher curative benefits. protecting the body's functions as much as possible and improving the quality of life should be the objective of treatment. due to recent research progress, for some prostate cancer patients with specific stages, radiotherapy has benefited more than 90% of them(11-13), however, for patients who relapse after receiving radiotherapy, the occurrence of radioresistance in cancer cells is a main reason(14). the current prognosis and risk score system of prostate cancer still lacks the assessment of radiosensitivity, exploring the causes of radioresistance in prostate cancer cells will help improve the therapeutic effect and application range of radiotherapy(15). radioresistance in prostate cancer is highly unpredictable and is currently thought to be driven by multiple cellular processes that allow cancer cells to adapt to routine radiation doses(16-17). in this study, we obtained 3 gene expression data sets on radiosensitivity of prostate cancer from geo database, and screened out the top 20 differentially expressed genes, among which 6 genes were up-expression (gcg, il7r, gja1, vgf, fgf13, gpr143) and 14 genes were decreased expression(il7, ccl2, csf3, igfbp3, bdkrb1, adcy5, grpr, flt3lg, adra2c, bmp7, ghr, ltbp1, eva1a, qrfpr). the biological processes of these differential genes are mainly enriched in the following aspects: “cell communication” and “signal transduction”.the enrichment analysis of kegg signaling pathway showed that these differential genes were mainly concentrated in cytokine-cytokine receptor interaction, hematopoietic cell lineage and other pathways, and the results of go analysis suggest that gene products are enriched in the extracellular matrix during the performance of their functions. this provides a general direction for our next research: for example, during cell-cell communication and signal transduction, some different genes activate some unusual functions that lead to radioresistance of tumor cells. raw counts and corresponding clinical information were obtained from the cancer genome atlas (tcga) dataset (https:// portal.gdc.com) of rna sequencing data (level 3) from 41 patients with prostate cancer who underwent radiotherapy. log rank was used to test km survival analysis to compare survival differences between the two or more groups mentioned above. high expression of vgf gene was found to significantly shorten pfs in prostate cancer patients receiving radiotherapy, however, the specific mechanism of action still needs further experimental verification. the study by seifertetal(15). showed that prostate cancer patients with high expression of vgf and low expression of grpr had a higher recurrence rate, they also demonstrated in vitro that inhibition of vgf expression can improve the sensitivity of radiotherapy, which was consistent with our research results. in fact, vgf was closely related to the prognosis of various cancers(18-19), therefore, we speculate that the correlation between vgf and radiosensitivity may be related to the epithelial-mesenchymal transition (emt) induced by it(20). in addition, although previous studies have confirmed that ccl2 is a key factor involved in the invasion and metastasis of prostate cancer (21). however, mai et al. found that the high expression of ccl2 was not only significantly correlated with the recurrence of nasopharyngeal carcinoma(npc), but also that inhibition of ccl2 could enhance the radiosensitivity of npc cells. combined with the study of kalbasi et al(22). in pancreatic cancer, it could be speculated that: ccl2 may promote the radioresistance of cancer cells by recruiting monocytes/macrophages, and the specific mechanism of which deserves further analysis. these researchers have made great contributions to the research in this field, and other hub genes obtained in this study are also valuable for further research. we noticed that among the hub genes obtained in this study, there are many genes related to blood glucose regulation and human immune system regulation, such as gcg, adcy5, igfbp3, csf3, ccl2, il7r, etc, which also provides potential directions for further research. the next step, however, must demonstrate a causal relationship between radiosensitivity and tumor progression: that is, radiosensitivity leads to tumor progression rather than poor radiation response due to tumor progression. currently, there is a lack of studies on the use of radiotherapy alone for prostate cancer, so there are many biases in the study of the effects of radiotherapy, which also need to be addressed. conclusions through the analysis of the differential genes related to the sensitivity of prostate cancer, the key genes found in this study can help to understand the potential molecular mechanism of prostate cancer 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network-based analysis of prostate cancer cell lines reveals novel marker gene candidates associated with radioresistance and patient relapse. plos computational biology, 2019; 15: e1007460. 16. bonkhoff h . factors implicated in radiation therapy failure and radiosensitization of prostate cancer. australasian radiology, 2012; 2012:584. 17. chaiswingl , weiss h l , jayswal r d , et al. profiles of radioresistance mechanisms in prostate cancer. critical reviews in oncogenesis, 2018,;23:39. 18. marwitzs ,heinbockel l , scheufele s , et al. epigenetic modifications of the vgf gene in human non-small cell lung cancer tissues pave the way towards enhanced expression. clinical epigenetics, 2017; 9:1-3. 19. wang xiuxing,prager briana c,wuqiulian et al. reciprocal signaling between glioblastoma stem cells and differentiated tumor cells promotes malignant progression.cell stem cell, 2018; 22: 514-28.. 20. hwang w, chiu y f, kuo m h, et al. expression of neuroendocrine factor vgf in lung cancer cells confers resistance to egfr kinase inhibitors and triggers epithelial-tomesenchymal transition. cancer research, 2017; 77: 3013-26. 21. lin t h, liu h h, tsai t h, et al. ccl2 increases αvβ3 integrin expression and subsequently promotes prostate cancer migration. biochimica et biophysica acta (bba)-general subjects, 2013; 1830: 491727. 22. kalbasi a, komar c, tooker g m, et al. tumor-derived ccl2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. clinical cancer research, 2017; 23: 137-148. urological oncology 28 key genes for radiosensitivity of prostate cancer –huanget al. the effect of intracavernosal injection of stem cell in the treatment of erectile dysfunction in diabetic patients: a randomized single-blinded clinical trial mahboubeh mirzaei1, mohammadali bagherinasabsarab1, hamid pakmanesh1*, reza mohammadi1, mohammad teimourian2, alireza farsinejad3, yunes jahani4 purpose: the prevalence of erectile dysfunction in men is increasing. as well, the prevalence of diabetes, as one of the causes of sexual dysfunction, is rising in many countries. due to the failure of common therapies in some patients with sexual dysfunction, it is necessary to develop an effective alternative treatment, such as stem cell therapy, for this problem. materials and methods: in this randomized single-blinded clinical trial, 20 diabetic patients with erectile dysfunction, who were resistant to common treatments, were selected and divided into two groups of intervention and control (n=10 per group). autologous mesenchymal stem cells (mscs) were extracted from oral mucosa and then infused via intracavernosal injection (50-60 ×106 cells) to the participants of the intervention group. normal saline was injected in the control group. the patients were followed up with the international index of erectile function (iief5) questionnaire, as well as color doppler duplex ultrasound. peak systolic velocity (psv), end diastolic velocity (edv), and resistance index (ri) were determined three and six months after the interventions. results: the mean iief5 scores in the intervention group were 7.2 ± 2.1, 9.2 ± 3.4, and 10.6 ± 4.7 before, three months, and six months after the injection, respectively, showing a significant ascending trend (p = 0.01). comparing the intervention and control groups, there was a significant difference in the iief5 score change during six months after the injection (p = 0.02). regarding the psv and ri of penis vessels, there were no statistically significant differences between the two groups. however, these parameters showed upward and improving trends in the intervention group. conclusion: intracavernosal injection of stem cells improved sexual function and psv and ri indices of penile arteries in diabetic patients. keywords: diabetes; sexual dysfunction; intracavernosal stem cell injection introduction erectile dysfunction is defined as the inability to achieve sufficient erection for successful penetration.(1) underlying causes are divided into psychological, organic, and a combination of these groups. organic causes include neurogenic, vascular, hormonal, intracavernosal (e.g. structural), and pharmacological types.(2) erectile dysfunction is also seen following pelvic surgeries such as radical prostatectomy or after pelvic trauma, which are mainly considered as neurogenic etiologies.(3,4) common treatments for erectile dysfunction include oral phosphodiesterase 5 (pde5i) inhibitors, prostaglandin suppositories (alprostadil), intracavernosal injection of vasoactive agents, vacuum erection devices, and penis implants. psychosexual interventions have also a valuable role in the treatment process.(2,4) all patients should be counseled to adjust their lifestyle including diet modification, quitting smoking, reducing alcohol consumption, losing weight, and exercising.(2) the first line treatment of erectile dysfunction is using 1department of urology, kerman university of medical sciences, kerman, iran. 2department of urology, babol university of medical sciences, babol, iran. 3cell therapy and regenerative medicine comprehensive center, kerman university of medical sciences, kerman, iran. 4modeling in health research center, institute for future studies in health, kerman university of medical sciences, kerman, iran. *correspondence: clinical research development unit, shahid bahonar hospital, kerman, iran. postal code: 761374181 tel/fax: +9832237115. email: h_pakmanesh@kmu.ac.ir. received october 2020 & accepted august 2021 oral pde5is (such as sildenafil). these are guanidine monophosphate analogues which bind to the catalytic domain of pde5 and inhibit its hydrolytic activity.(5) in recent years, the popularity of stem cell therapy to treat erectile dysfunction has increased. the exact mechanisms of this method; however, are not yet clear. until now, the stem cells derived from the bone marrow, fat, muscle, urine, neural crest, and endothelial precursors have been studied to treat sexual dysfunction.(6) mesenchymal stem cells (mscs) have the capacity to differentiate into a variety of cell types including muscle, cartilage, bone, and fat. (7) mscs, through several mechanisms (e.g., paracrine effects and secreting cytokines and growth factors), can lead to immunomodulation, a reduction in inflammation, and improvement of healing process.(6,8,9) stem cells can also produce smooth muscle, endothelium, and neurons.(6) the potential of stem cells for treating erectile dysfunction has been investigated in multiple studies.(6,10-16) it has been shown that injecting stem cells to human and animal models is safe and effective and generates potent andrology urology journal/vol 18 no. 6/ november-december 2021/ pp. 675-681. [doi: 10.22037/uj.v18i.6503] effects. although a role for paracrine effects of stem cells has been proposed, the potential mechanisms by which stem cells promote their therapeutic effects are not yet well-understood.(14) nevertheless, stem cell therapy in patients with erectile dysfunction seems a safe strategy without adverse side effects.(14,15) considering the above-mentioned, further studies are needed to accurately assess the therapeutic potential of stem cells in patients with sexual dysfunctions.(6) this is important to know that many patients fail to respond to conventional drug therapies and need an alternative treatment. in this study, we aimed to investigate the effectiveness of intracavernosal injection of stem cells to treat erectile dysfunction in diabetic patients and improve their quality of life. materials and methods in this randomized single-blinded clinical trial, 20 diabetic patients aged 50-70 years with erectile dysfunction, who were referred to the urology clinic of bahonar hospital in kerman in 2019 were selected and divided into two groups of intervention and control (n=10 per group). these patients were non-respondents to the common treatments of erectile dysfunction, including pde5i. they had received all available treatments based on patients’ acceptance, indications, and contraindications and were resistant to all these treatments. they had been diagnosed with diabetes and erectile dysfunction without any other underlying disease sample size according to similar studies, our sample size was determined using the following formula: where α = 0.05 (type 1 error), β = 0.90 (study power), σ = 0.5 (standard deviation based on the study of yiou et al., (10) and d= 1 (effect size), which means that the study will be able to detect 1 unit of change in sexual performance with 90% power. based on this, "n" was calculated 5 per group, which considering a possible loss of samples, n=10 per group was considered as the final sample size. randomization this was a single-blinded study (main researcher physician is aware). the block randomization method was used including five blocks with each block consisting of two patients from each of the intervention and control groups (i.e., four subjects per block) to proceed with a balanced distribution of all 20 patients (10 subjects per group). study protocol initial assessments included taking a history of prior illnesses, physical examination, blood pressure measurement, checking sexual status, and cardiac function via visiting a cardiologist. the international erectile dysfunction index questionnaire (iief5) was filled for all the patients. laboratory tests included testosterone, prolactin, fasting blood sugar (fbs), lh, fsh, tsh, hba1c, cholesterol (ldl, hdl), triglyceride, liver enzymes, and psa. in addition, doppler ultrasound of penis vessels was performed before the intervention. patients with confirmed diagnoses of diabetes and sexual dysfunction, bmi of 20-25, and without any other diseases were enrolled. those with laboratory or clinical signs of other disorders (especially diseases associated with erectile dysfunction) were excluded from the study. the iief5 questionnaire consists of 5 questions (provided at the end of the article). in the intervention group, after local anesthesia, a tissue sample with a diameter of about 0.5 cm was obtained from oral mucosa so that there was no need for sutures. the samples were placed in phosphate buffer solution (pbs) containing antibiotics and amphotrypsin and immediately sent to the university stem cell storage center. in the control group, obtaining oral mucosa was only pretended by inserting a swap into the patients’ mouth. the mucosal tissues were washed 3 times with pbs containing antibiotics and amphotrypsin and then cut into small pieces under sterile conditions. afterwards, they were incubated in dmem culture medium containing 4 mg/ml dyspase enzyme and 3 mg/ml type 1 collagenase at 4 °c for 24 hours. after that, the enzyme-containing medium was gently removed and replaced with dmem containing 15% fbs and 1% antibiotic (penicillin/streptomycin). incubation continued in a 5% co 2 incubator with 95% humidity at 37 ° c for at least 10 days to allow the cells to grow. the adherent cells were then treated with trypsin, and after being detached, poured into t25 flasks and incubated under the same condition mentioned above. finally, stem cell markers (cd 73+, cd90+, cd105+, cd34-, cd45-) were examined by flow cytometry to stem cell therapy for erectile dysfunction-mirzaei et al. parameters intervention control p value mean (sd) median (iqr) mean (sd) median (iqr) age (year) 63.8 (7.4) 65 (7.5) 65.6 (5.1) 67.5 (7.75) 0.56 diabetes duration (year) 10.4 (3.5) 10.5 (6.75) 10.1 (3.1) 10 (5.75) 0.78 table 1. the means of age and diabetes duration in the intervention and control groups. andrology 676 time intervention control the sum of scores (t) p value the sum of scores (t) p value mean (sd) mean (sd) before injection (baseline) 7.2 (2.1) 0.01 7.2 (2.1) 0.87 3 months post-injection 9.2 (3.4) 7.2 (2.0) 6 months post-injection 10.6 (4.7) 7.3 (2.1) table 2. the score obtained from the international erectile dysfunction index questionnaire in the intervention and control groups at 0, 3 and 6 months after the injection. verify the purity, and if the purity was more than 95%, the cells were harvested for injection as a suspension. after obtaining adequate number of stem cells (50-60 × 106), they were frozen and sent to the urology operating room where, after thawing and diluting with 0.9% normal saline (up to 2 ml), they were injected to the patients of the intervention group (1 ml into each corpus cavernosum). the bottom of penis was clamped with a band before the injection and then opened 3 minutes after the injection. in the control group, normal saline was injected into the corpus cavernosum. the patients were followed up by filling the iief5 questionnaire, performing color doppler duplex ultrasound to obtain psv, edv and ri parameters, as well as determining fbs and hba1c at three and six months after the injection. in addition, morning erections were daily recorded by the patients. the patients were encouraged to have intercourse at least three times a week and use pde5i (tadalafil 10 mg) during the sexual relationship. the complications of the injection (pain, swelling, ecchymosis, etc.) were checked and recorded at each visit. they were fully explained about the stem cell therapy and their disease, and for ethical considerations, their written informed consent was obtained. this study was approved by the ethics committee of kerman university of medical sciences (ir.kmu.ah.rec.1398.115). question intervention control baseline 3rd month 6th month p value baseline 3rd month 6th month p value q1 mean (sd) 1.67 (0.5) 2.11 (0.92) 2.56 (1.02) 0.007 1.80 (0.63) 1.90 (0.31) 1.70 (0.48) 0.472 q2 mean (sd) 1.60 (0.69) 2.20 (1.2) 2.50 (1.3) 0.008 1.40 (0.51) 1.60 (0.51) 1.50 (0.52) 0.472 q3 mean (sd) 1.30 (0.67) 1.60 (0.84) 1.90 (1.19) 0.028 1.30 (0.48) 1.30 (0.48) 1.40 (0.51) 1 q4 mean (sd) 1.20 (0.42) 1.60 (0.84) 1.80 (1.03) 0.019 1.2 (0.42) 1.2 (0.42) 1.2 (0.42) 1 q5 mean (sd) 1.50 (0.52) 1.80 (0.63) 2 (1.20) 0.042 1.50 (0.52) 1.40 (0.51) 1.50 (0.52) 0.819 table 3. the mean scores of individual questions of the international erectile dysfunction index questionnaire in the intervention and control groups at 0, 3 and 6 months after the injection. figure 1. consort diagram of the study. stem cell therapy for erectile dysfunction-mirzaei et al. vol 18 no 6 november-december 2021 677 this study was approved under the registration code of irct20190517043609n1 in iranian registry for clinical trials. the study protocols are available at this database. statistical analysis finally, the data was analyzed by spss (version 22) statistical software. for describing the data, mean, standard deviation, frequency, and percentage were used. age, diabetes duration, fbs, and hba1c were compared between the groups using mann-whitney u test. the mean scores of the questionnaire, psv, edv, and ri were compared preand post-intervention using the friedman test. results in this study, 20 diabetic patients with erectile dysfunction were selected and divided into two groups of intervention and control, 10 patients per group (figure 1). the patients were recruited from 22 september 2019 to 19 february 2020. for all the participants, diabetes was under control after the intervention and during the six-month follow-up. the mean ages of the patients in the intervention and control groups were 63.8 ± 7.4 and 65.6 ± 5.1 years, respectively. the mean values of fbs at the baseline and six months after the intervention were 118 ± 9.5 and 117 ± 9.3 in the intervention group and 116 ± 9.3 and 118 ± 9.4 in the control group, respectively. the mean values of hba1c at the baseline and six months after the intervention were 6.8 ± 2.1 and 6.7 ± 2 in the intervention group and 6.7 ± 2.05 and 6.8 ± 2.15 in the control group, respectively. the mean durations of diabetes were 10.4 ± 3.5 and 10.1 ± 3.1 years in the intervention and control groups, respectively. according to the mann-whitney u test, the means of age and diabetes duration were not significantly different between the intervention and control groups (p > 0.05, table 1). according to the friedman test, the means of total iief5 score in the intervention group were 7.2 ± 2.1 (before the injection, baseline), 9.2 ± 3.4 (the third month after the injection), and 10.6 ± 7.4 (the sixth month after the injection), which showed a statistically significant improving trend (p = 0.01). in the control group, the means of total iief5 scores at baseline, three months, and six months after the injection were 7.2 ± 2.1, 7.2 ± 2, and 7.3 ± 2.1, respectively, showing an insignificant almost constant trend (p = 0.87). comparing the two intervention and control groups according to the mann-whitney u test, the total iief5 score was significantly different at sixth month after the injection (p = 0.02, table 2). based on the results of the friedman test obtained in the intervention group, the mean scores related to each question (q1, q2, q3, q4, q5) of the questionnaire showed a statistically significant ascending trend in all the questions from the baseline towards the end of the follow-up period. in the control group, the trend was significant in none of the questions (table 3). regarding the question related to acquiring sufficient erection for penetration after sexual arousal (q2), out of 10 patients in the intervention group, two patients in half of the occasions and two patients in more than half of the occasions were able to achieve that at three months post-injection. at six months after the intervention, 4 patients were able to acquire adequate erections to penetrate in more than half of the occasions. based on the results of the friedman test, in color doppler ultrasound of penis vessels, the means of psv index in the intervention group were 8.26 ± 4.12, 9.14 ± 2.56, and 10.22 ± 2.09 at the time of injection (zero month), three, and six months after the injection, respectively. this showed an ascending, but statistically insignificant trend (p-value = 0.67). the means of psv in the control group were 8.21 ± 4.1, 8.29 ± 3.91, and 8.20 ± 3.87 at baseline, the third, and sixth month after the injection, respectively, indicating an almost constant and statistically insignificant trend (p = 0.11). there was no statistically significant difference between the two groups comparing psv index, as evidenced by the friedman test (p = 0.25, table 4). the means of edv index in the intervention group were 1.8 ± 0.86, 2.13 ± 0.92, and 1.93 ± 0.85 at the time of injection (zero month), the third, and the sixth month after the injection, respectively. this trend was not statistically significant (p-value = 0.36). the mean edv values in the control group were obtained 1.95 ± 0.83, 2.02 ± 0.81, and 1.99 ± 0.81 before, three months, and six months after the injection, respectively. this trend was also not statistically significant (p = 0.49). there was no statistically significant difference between the two groups regarding edv index (p = 1, table 5). the mean values of ri in the intervention group were 0.77 ± 0.04 (baseline), 0.76 ± 0.09 (the third month post-injection), and 0.81 ± 0.06 (the sixth month post-injection) showing a slight upward and improving but statistically non-significant trend (p = 0.15). in the time intervention control psv p value psv p value mean (sd) median (iqr) mean (sd) median (iqr) before injection (baseline) 8.26 (4.12) 7.7 (7.92) 0.67 8.21 (4.10) 7.5 (8.32) 0.11 3 months post-injection 9.14 (2.56) 8.7 (4.45) 8.29 (3.91) 7.5 (7.72) 6 months post-injection 10.22 (2.09) 9.7 (3.55) 8.20 (3.87) 8.25 (7.47) table 4: the trend of mean psv index in the intervention and control groups at 0, 3, and 6 after the injection. stem cell therapy for erectile dysfunction-mirzaei et al. time intervention control edv p value edv p value mean (sd) median (iqr) mean (sd) median (iqr) before injection (baseline) 1.80 (0.86) 1.8 (1.62) 0.36 1.95 (0.83) 2 (1.68) 0.49 3 months post-injection 2.13 (0.92) 2.4 (1.92) 2.02 (0.81) 2 (1.25) 6 months post-injection 1.93 (0.85) 2.1 (1.60) 1.99 (0.81) 1.9 (1.45) table 5. the trend of mean edv index in the intervention and control groups at 0, 3, and 6 after the injection. andrology 678 control group, mean ri values were recorded as 0.75 ± 0.03, 0.73 ± 0.05, and 0.74 ± 0.04 before the injection, and three and six months after the injection, respectively. likewise, this descending trend was not statistically significant (p-value = 0.49). no statistically significant difference was noted between the two groups comparing the ri index (p = 0.057, table 6). morning erection was reported by one patient from the intervention group at three-month and by another patient from the same group at six-month post-injection. no patients in the control group reported morning erection during the six months follow-up. none of the patients in neither the control nor the intervention group reported injection-related complications (bleeding, hematoma, ecchymosis, abscess, etc.) after six months follow-up. the trends of the iief5 score, psv, edv, and ri index in the intervention and control groups at 0, 3 and 6 months after the injection have been shown in figure 2. discussion the interest in treating erectile dysfunction with stem cell injection is increasing.(6) the resistance of many patients to conventional therapies further highlights the need to develop new alternative treatments. intracavernosal stem cell injection, the method studied here, can role as an effective option in this field and effectively improve these patients’ quality of life. in a study by peak et al. in 2016, they evaluated the effectiveness of multiple stem cell types in treating erectile dysfunction and showed that injected stem cells had paracrine effects on penis tissue and could differentiate to a variety of cells including smooth muscle cells, vascular endothelial cells, and neurons, suggesting prominent effects and excellent safety for this therapeutic method.(6,14) the recent study supports the positive effects of stem cell injection in the treatment of erectile dysfunction in diabetic patients, as observed in the present study. in this study, we showed that intracavernosal injection of autologous mesenchymal stem cells (50-60 × 106) improved sexual function in most diabetic patients. there were also improvements in psv and ri indices in color doppler ultrasound of penis vessels in these patients. regarding the total iief5 score, a statistically significant difference was noted between the intervention and control groups at sixth-month post-injection. considering adequate erection for penetration after sexual arousal (the second question of the questionnaire), out of 10 patients in the intervention group, two patients in half of the cases and two other patients in more than half of the cases achieved sufficient erections to enter at three months after the injection. after a six-month follow-up, four patients who received stem cell injection acquired enough erection for penetration in more than half of the cases. in a similar study, bahk et al. in 2010 investigated the effects of the intracavernosal injection of 15 × 106 cord blood mesenchymal stem cell stem cell therapy for erectile dysfunction-mirzaei et al. figure 2. the trends of the international erectile dysfunction index (a), psv (b), edv (c), and ri index (d) in the intervention and control groups at 0, 3 and 6 months after the injection. time intervention control ri p value ri p value mean (sd) median (iqr) mean (sd) median (iqr) before injection (baseline) 0.77 (0.04) 0.79 (0.09) 0.15 0.75 (0.03) 0.74 (0.06) 0.49 3 months post-injection 0.76 (0.09) 0.76 (0.09) 0.73 (0.05) 0.75 (0.08) 6 months post-injection 0.81 (0.06) 0.80 (0.14) 0.74 (0.04) 0.75 (0.08) table 6. the trend of mean ri index in the intervention and control groups at 0, 3, and 6 after the injection. vol 18 no 6 november-december 2021 679 in combination with oral pde5i in seven diabetic patients with erectile dysfunction and revealed that after six months, two patients achieved successful erection for penetration. finally, they concluded that stem cell injection had beneficial effects on the treatment of erectile dysfunction in diabetes and recommended further studies on larger statistical populations.(13) the results of the recent study were similar to ours; however, the rate of erection achievement was higher in our report (40% vs. 28%), which can be due to the higher dose of stem cells used in our study (50-60 × 106 vs. 15 × 106). in addition, the types of the stem cells used in these two studies were different (autologous mesenchymal vs. cord blood mesenchymal stem cells). overall, both studies indicated the beneficial effects of stem cell injection in the treatment of erectile dysfunction in diabetic patients. in another study in 2018, al demour et al. infused 30 × 106 bone marrow-derived mesenchymal stem cells (bm-mscs) via intracavernosal injection to four diabetic patients at two 30-day apart occasions and reported significant improvements based on the iief-15 score within 12 months of the injection.(15) so, the results of the recent study, like ours, supported the beneficial effects of this therapeutic method in diabetic patients. in another study by levy et al. in 2016, the effect of intracavernosal injection of placental stem cells in combination with oral pde5i in the treatment of erectile dysfunction was assessed in eight patients. the findings showed that two patients within two months and three patients within three months nailed sufficient erections for sexual contact. similar to our study, the trends of iief5 scores were not statistically significant at six-week, threemonth, and six-month compared to the injection time. (17) the positive effects of stem cells in this condition can be related to their paracrine effects on the penis, which can promote the differentiation of smooth muscle cells, endothelial cells, as well as neurons, improving erectile dysfunction in patients with diabetes; nevertheless, the exact mechanisms are yet to be divulged. in this study, out of 10 patients in the intervention group and based on total iief5 score, 6 patients reported improvements in sexual function and erection within six-month follow-up. in a similar study by yiou et al.(2016), they injected stem cells (either 20 × 106 or 200 × 106 bm-mscs) to 12 patients who developed erectile dysfunction following radical prostatectomy. in combination with oral pde5i, nine out of 12 patients declared significant improvements in erectile function, (10) which was slightly greater than the ratio obtained in our study, which may be related to the differences in the infused doses and the nature of the stem cells used in our study compared with the recent report. in another study by haar et al. in 2016, adipose-derived stem cells (adscs) were injected into 17 men who developed erectile dysfunction following radical prosatectomy and failed to respond to routine treatments. overall, erectile function improved in eight of 17 patients, which enabled them to have sex (an improvement rate of 47%),(11) which was lower in comparison with our study (improvement of 60%). nevertheless, the results of the recent study were similar to our study, showing the positive effects of stem cell injection in improving erectile dysfunction in about half of the patients. in this study, of the 10 patients in the intervention group, one patient at three-month and another patient at six-month follow-up (two patients in total) reported morning erection. in a similar study by bahk et al. ,(13) morning erection was reported in two of seven patients. in general, the results of these two studies indicated an improvement in the sexual function of patients following stem cell injection. in our study, color doppler ultrasound of penis vessels retrieved the mean psv values of 8.26, 9.14, and 10.22 at baseline (before the injection), and the third and sixth month after the injection, respectively, in the intervention group. although showing an upward and improving trend, but this was not statistically significant. our finding was similar to that of levy et al.(17) who also reported a remarkable improvement in psv; nevertheless, the trend was statistically significant only at six-month follow-up. overall, stem cell injection seems to have a significant impact on psv index on color doppler ultrasound of penis, which can be a predictor of improved sexual function in patients. this can be related to the ability of stem cells to differentiate to endothelial cells , ultimately leading to improved erectile function in diabetic patients via boosting the angiogenic network of the penis.(6) considering the edv index in color doppler ultrasound of penis, the mean values of edv in the intervention group were 1.8 (baseline, zero time), 2.13 (the third month after the injection), and 1.93 (the sixth month after the injection). the trend was also not statistically significant. these results were similar to the study of levy et al.(17) who noted insignificant and undesirable changes in edv. we noticed no side effects of intracavernosal stem cell injection during a six-month follow-up period. in this regard, our observation was similar to those of levy et al.(17) and yiou et al.(10). in contrast, haar et al.(11) in their study on 17 patients reported redness and swelling at the injection site in two patients, as well as penis hematoma, and scrotum, each in one patient. al demour et al. also noticed no considerable adverse effects on the function of the gastrointestinal, respiratory, cardiovascular, and nervous systems after two years of follow up.(15) according to a review study in 2021,(14) a drawback of nearly all studies in this area was the lack of a control group in assessing the safety and efficiency of the procedure, which in our study, this drawback was addressed by incorporating a control group. overall, intracavernosal stem cell injection appears to be a safe method with a low rate of complications. another advantage of this therapeutic strategy is its positive effects on erectile dysfunction even after one injection. the therapeutic effects are generally longterm and more effective than other methods, obviating the need for using various drugs. although the potential mechanisms of stem cells’ actions are unclear,(12,14) it seems that the proliferation of mscs can lead to immunomodulation and alleviation of inflammation via exerting paracrine effects on the production of cytokines and growth factors. in addition, stem cells can directly differentiate into smooth muscle and endothelial cells, as well as neurons.(6) this method also has lower costs compared with other methods such as implementing prosthesis. finally, we observed no side effects in this study, indicating the excellent safety of this method. however, the efficiency of the method can be affected by the dose and nature of infused cells, the frequency of infusion, the underlying erectile dysfunction, and duraandrology 680 stem cell therapy for erectile dysfunction-mirzaei et al. tion of follow up, which all should be considered when interpreting outcomes. due to our relatively low sample size, caution must be taken when generalizing our finding to other patient with erectile dysfunction. the limitations of this study included low sample size, one occasion of infusing cells, and the reluctance of some patients to receive the injection due to unpleasant feelings. conclusions due to the resistance of many patients with sexual dysfunction, especially in the case of concomitant diabetes, to conventional drug therapies, it is necessary to discover new alternative treatments for these patients. based on our findings, it can be concluded that intracavernosal stem cell injection improves sexual function, as well as psv and ri ultrasound parameters in most diabetic patients. for obtaining more accurate conclusions, it is recommended to conduct studies on larger populations. funding this study was supported by kerman university of medical sciences. conflict of interests none to declare. references 1. health nio. nih consensus conference. impotence. nih consensus development panel on impotence. jama. 1993;270:83-90. 2. shamloul r, ghanem h. erectile dysfunction. the lancet. 2013;381:153-65. 3. lue t. physiology of penile erection and pathophysiology of erectile dysfunction and priapism. campbell's urology. 1998:1157-79. 4. mulhall jp, bella aj, briganti a, mccullough a, brock g. erectile function rehabilitation in the radical prostatectomy patient. j sex med. 2010;7:1687-98. 5. brant wo, bella aj, lue tf. treatment options for erectile dysfunction. endocrinol metab clin north am. 2007;36:465-79. 6. peak tc, anaissie j, hellstrom wj. current perspectives on stem cell therapy for erectile dysfunction. sex med rev. 2016;4:247-56. 7. park js, suryaprakash s, lao y-h, leong kw. engineering mesenchymal stem cells for regenerative medicine and drug delivery. methods. 2015;84:3-16. 8. lin c-s. advances in stem cell therapy for the lower urinary tract. world j stem cells. 2010;2:1. 9. xin z-c, xu y-d, lin g, lue tf, guo y-l. recruiting endogenous stem cells: a novel therapeutic approach for erectile dysfunction. asian j androl. 2016;18:10. 10. yiou r, hamidou l, birebent b, bitari d, lecorvoisier p, contremoulins i, et al. safety of intracavernous bone marrow-mononuclear cells for postradical prostatectomy erectile dysfunction: an open dose-escalation pilot study. eur urol. 2016;69:988-91. 11. haahr mk, jensen ch, toyserkani nm, andersen dc, damkier p, sørensen ja, et al. safety and potential effect of a single intracavernous injection of autologous adipose-derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label phase i clinical trial. ebiomedicine. 2016;5:204-10. 12. levy ja, marchand m, iorio l, cassini w, zahalsky mp. determining the feasibility of managing erectile dysfunction in humans with placental-derived stem cells. j osteopath med. 2016;116:e1-e5. 13. bahk jy, jung jh, han h, min sk, lee ys. treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: preliminary report of 7 cases. exp clin transplant. 2010;8:150-60. 14. protogerou v, chrysikos d, karampelias v, spanidis y, el bisari s, troupis t. erectile dysfunction treatment using stem cells: a review. medicines. 2021;8:2. 15. al demour s, jafar h, adwan s, alsharif a, alhawari h, alrabadi a, et al. safety and potential therapeutic effect of two intracavernous autologous bone marrow derived mesenchymal stem cells injections in diabetic patients with erectile dysfunction: an open label phase i clinical trial. urol int. 2018;101:358-65. 16. protogerou v, michalopoulos e, mallis p, gontika i, dimou z, liakouras c, et al. administration of adipose derived mesenchymal stem cells and platelet lysate in erectile dysfunction: a single center pilot study. bioengineering. 2019;6:21. 17. cassini w, zahalsky mp. determining the feasibility of managing erectile dysfunction in humans with placental-derived stem cells. j am osteopath assoc. 2016;116:e1. stem cell therapy for erectile dysfunction-mirzaei et al. vol 18 no 6 november-december 2021 681 letter to editor dear editor with warm greetings is the plume of the surgery on the covid 19 patient in the pandemic era (world fight) definitely safe? what must to do?!!!! with becoming the corona virus pandemic in iran and the world it is important for the surgeons care of all the corona patients if he or she must be operated surgically. as it is a rule that the safety of the patients and all the workers of the operating room is one of the important responsibilities of the physician which we discuss for it in this letter. inducing of the aerosol in the cauterization depends to the temperature as the temperature increases the formation of aerosol will be increased (1) this aerosol contains 95 % water and 5% particles (1) these particles contain blood and tissue also it may contain the corona virus which lives for three hours in the place. the aerosol contains bacteria and virus which may be spread in the space and in the further place, the presence of the virus and bacteria in the aerosol have been confirmed which including hpv virus and aids virus and hepatitis b virus and mycobacterium tuberculosis (2) which may induce an infection of the surgeon and the staff of the operating room and also it may contaminate the garments of the staff of the operating room. the presence of the virus covid 19 in the urine of the patient with covid 19 virus-positive has been confirmed (3). the surgical smoke contains much toxic gas, specifically benzene and butadiene like in the smoke of the cigar rete and 10 and 17 times more than in the secondhand smoker (4). in turp (trans urethra prostate resection) 16 kinds of the carcinogen gas and in turbt (transurethral resection bladder tumor) 39 kinds of carcinogen gas have been detected and in a study laparoscopic nephrectomy was associated with 5 kinds of the carcinogen gas (5,6) but in the pandemic covid 19 virus the transmission of the virus by surgery as an aerosol cannot be excluded (7). the aerosol in the operating room must be considered a one of the important problems which must be defeated by the negative pressure and the suctioning. for the safety of surgeons and the staff of the theater room, especially for the caring in the operation of a patient suspicious to covid 19 defeating aerosol by precious negative pressure and suctioning looks justice until the presence of the definitive evidence about the absence of the covid 19 in the surgery smoke of the suspicious to co vid 19 will be provided (7). with best regards afshar zomorrodi , professor of urology and kidney transplant , head of organ transplantation and urology department, tabriz university of medical science 1jonathan pavlinec and li-ming su ,surgical smoke in the era of the covid-19 pandemicdis it time to reconsider policies on smoke evacuation? the journal of urology® https://doi.org/10.1097/ju.0000000000001142 vol. 204, 642-644, october 2020 printed in u.s.a 2baki ekci, easy-to-use electrocautery smoke evacuation device for open surgery under the risk of the covid-19 pandemic, journal of international medical research,2020 ,48(8) 1–7 3ling y, xu sb, lin yx et al: persistence and clearance of viral rna in 2019 novel coronavirus disease rehabilitation patients. chin med j (engl) 2020; 133: 1039 4liu y, song y, hu x et al: awareness of surgical smoke hazards and enhancement of surgical smoke prevention among the gynecologists. j cancer 2019; 10: 2788 5. zhao c, kim mk, kim hj et al: comparative safety analysis of surgical smoke from transurethral resection of the bladder tumors and transurethral resection of the prostate. urology 2013; 82: 744. 6. choi sh, kwon tg, chung sk et al: surgical smoke may be a biohazard to surgeons performing laparoscopic surgery. surg endosc 2014; 28: 2374 7-30. pavan n, crestani a, abrate a, et al. risk of virus contamination through surgical smoke during minimally invasive surgery: a systematic review of literature on a neglected issue revived in the covid19 pandemic era [published online ahead of print, 2020 jun 5]. eur urol focus 2020: s2405-4569: 30156-5. doi: 10.1016/j.euf.2020.05.021 running head: effect of iv antibiotic use on the ed in elderly with utis. effects of an initial single dose of intravenous antibiotics on emergency department revisits among elderly patients with urinary tract infections ho sub chung1, sung jin bae1, myeong namgung2, yoon hee choi3, jae young choi4, dong hoon lee1* 1 department of emergency medicine, chung-ang university gwangmyeong hospital, college of medicine, chung-ang university, seoul, republic of korea 2 department of emergency medicine, college of medicine, chung-ang university, seoul, republic of korea 3 department of emergency medicine, ewha womans university mokdong hospital, college of medicine, ewha womans university, seoul, republic of korea 4 department of urology, college of medicine, yeungnam university, gyeongsan, republic of korea corresponding author: dong hoon lee, m.d., ph.d. department of emergency medicine, chung-ang university gwangmyeong hospital,college of medicine, chung-ang university, 110, deokan-ro, gwangmyeong-si, gyeonggi-do, seoul, republic of korea tel.: +822 2222-6751 fax: +822 2222-1366 phone: 82-10-9348-6992 e-mail: emdhlee@cau.ac.kr mailto:emdhlee@cau.ac.kr abstract purpose: urinary tract infection (uti) is the second most common infectious disease among older adults. it is important that the treatment strategy used for older patients with utis in the emergency department (ed) be adequate. the effectiveness of an initial single dose of intravenous antibiotics in the ed for treating utis has not been extensively studied. therefore, we investigated the clinical outcomes of single-dose intravenous antibiotic administration before discharge from the ed in elderly patients with utis. materials and methods: this retrospective study was conducted among patients who visited two academic tertiary hospitals in seoul, south korea. we included all patients older than 65 years of age with uti who visited the ed and were directly discharged between 1 january and 31 december 2019 (n = 429). the patients were divided into two groups according to whether they received a single dose of intravenous antibiotics before ed discharge. results: patients who received intravenous antibiotics had a higher 72-hour revisit rate (43 [15.4%] vs 10 [6.7%], p = .009) and a longer mean duration of therapy (total days of antibiotics use) (11 [4.00 – 15.00] vs 5 [3.00 – 11.00], p < .001) than patients who received only oral antibiotics. however, the rate of admission after revisits did not differ significantly between the groups (27 [62.8%] vs 5 [50.0%], p = .492). conclusion: older patients with severe utis were prescribed intravenous antibiotics in the ed. decisions on admission or discharge should be made carefully for older patients with utis who are prescribed intravenous antibiotics in the ed. keywords: administration, intravenous; older adults; anti-bacterial agents; emergency department; infusions, intravenous; infusions, parenteral; urinary tract infection introduction urinary tract infection (uti) is the second most common infection among older patients, and utis account for approximately 5% of all emergency department (ed) visits in the united states each year (1). the clinical presentation of uti varies from asymptomatic bacteriuria to severe sepsis. utis in older patients who are asymptomatic or who present with mild symptoms can easily be managed with antibiotics, but these infections can develop into severe sepsis if treatment is delayed (2). therefore, a sufficient understanding of the spectrum of utis and the choice of appropriate treatment plans are crucial, especially for older patients with utis. antibiotics should be used promptly when patients in the ed are diagnosed or suspected of having utis. according to the severity of the infection, patients are admitted or discharged by emergency physicians. patients identified with severe conditions usually undergo empiric broad-spectrum intravenous antibiotic therapy. in the case of patients who are to be discharged from the ed, oral antibiotics may be prescribed after the administration of intravenous antibiotics in the ed. conversely, oral antibiotics may be prescribed without the administration of intravenous antibiotics. according to the 2018 korean guidelines for uti, for patients with acute pyelonephritis not requiring hospitalization, a single dose of intravenous antibiotics should be administered, followed by oral antibiotics, until culture results are obtained (3). although the recommendation grade is strong, this recommendation is based on expert opinion with limited evidence (4). the effectiveness of an initial single dose of intravenous antibiotics for patients with utis in the ed has been studied, and the results are varied. in one study of adult patients with utis, intravenous antibiotic use was associated with a decrease in ed revisits (5). however, in a study of children with utis, intravenous antibiotic use in the ed had no benefit on clinical outcomes (6). no study has assessed the effects of intravenous antibiotic use for older patients with utis. therefore, we investigated the clinical outcomes of older patients with utis in the ed according to the use of single-dose intravenous antibiotic administration before ed discharge. materials and methods study design and population this retrospective study was conducted among patients who visited two academic tertiary hospitals in seoul, south korea. electronic registry data were collected from the national emergency department information system (nedis), managed by the national emergency medical center. nedis is a prospective database of the demographic and baseline clinical characteristics of patients from all emergency healthcare facilities in the republic of korea. the sample size for was measured by using the g*power program. considering power of 0.80, alpha level of 0.05 and confidence interval 95%, we found the required sample size was 342. the total number of patients who presented to the two study eds between 1 january and 31 december 2019 was 94,803 (figure 1). patients who visited the ed for trauma and non-medical reasons and those under 65 years old were excluded. codes from the international classification of diseases 10th revision (icd-10) for uti, cystitis (icd-10 n30, n39.0), and pyelonephritis (n10, n15.1, n16) were used to identify uti diagnoses. patients diagnosed with utis and directly discharged from the ed were included. individuals who had been admitted to the ward, were transferred to other hospitals, were discharged against medical advice, had previous visits for uti in the previous 30 days, or had received multiple doses of intravenous antibiotics were excluded. after exclusions, 429 patients were enrolled in this study. the enrolled patients were divided into two groups: the single intravenous antibiotics group (those who received a single dose of intravenous antibiotics in the ed and were directly discharged with oral antibiotic prescriptions) and the only oral antibiotics group (those who were prescribed only oral antibiotics without intravenous antibiotics). the single intravenous antibiotics group had 279 (65%) patients, whereas the only oral antibiotics group had 150 (34.9%) patients. this study was approved by the relevant institutional review board (irb no. 2022-05-005). due to the study's retrospective design and the use of anonymized patient data, the requirement for informed consent was waived. baseline characteristics study variables included patient demographics (such as age and sex), initial vital signs (pulse rate, respiratory rate, and body temperature), systolic blood pressure, diastolic blood pressure, mental status, quick sequential (sepsis-related) organ failure assessment (qsofa) score, and korean triage and acuity scale (ktas) level. the korean triage and acuity scale (ktas) was developed as a triage tool and comprises five acuity levels: level 1 (resuscitation), level 2 (emergency), level 3 (urgent), level 4 (less urgent), and level 5 (non-urgent), in which lower numbers indicate a higher level of urgency. data on cultured strains, antibiotic types, and antibiotic susceptibility profiles were also included. clinical outcomes the primary outcome was the 72-hour ed revisit rate, and the secondary outcome was admission following a 72-hour ed revisit and duration of therapy. the duration of therapy was defined as the total duration of antibiotic use. additionally, symptoms related to the reasons for revisits were recorded. statistical analysis categorical variables are expressed as counts and percentages, and continuous variables are expressed as mean ± standard deviation. for continuous variables, the independent t-test was used for normally distributed data, and the mann–whitney u test was used for skewed data. the pearson chi-square test or the fisher exact test was used for nominal variables; in particular, the fisher exact test was applied when more than 20% of cells had expected frequencies less than 5. continuous variables are expressed as the mean ± standard deviation or median (interquartile range), and categorical variables are expressed as counts and percentages. logistic regression was used to investigate the clinical factors associated with revisits. differences with p < .05 were considered statistically significant. all statistical analyses were performed using spss statistics for windows, version 26.0 (ibm corp., armonk, ny, usa). results baseline characteristics there was no statistical difference between the two groups regarding age or sex (table 1). the single intravenous antibiotics group had a significantly lower mean systolic blood pressure at ed admission. the mean respiratory rate and body temperature at ed admission were significantly higher in the single intravenous antibiotics group. the single intravenous antibiotics group had a significantly larger proportion of patients categorized as ktas levels 2 (emergency) and 3 (urgent) and a lower proportion categorized as level 4 (less urgent). clinical outcomes the proportion of 72-hour revisits was significantly higher in the single intravenous antibiotics group (table 2). however, there was no significant intergroup difference in the rate of admissions after revisits. the duration of therapy was significantly longer in the intravenous antibiotics group. in the univariate analysis, only single intravenous antibiotics were associated with revisits (table 3). fever, urinary symptoms, dyspnoea, and poor oral intake were the symptoms associated with reasons for revisits most commonly identified in the single intravenous antibiotics group (table 4). in the only oral antibiotics group, the reasons for revisits were fever, urinary symptoms, general weakness, and poor oral intake. there was no statistical differences were observed regarding reasons of revisit symptoms. urinary tract infection pathogens the most frequently identified bacterium in both groups was escherichia coli, followed by enterococcus species, klebsiella pneumoniae, and proteus mirabilis. in 45 cases, urine culture yielded no bacterial growth. in 25 cases, no culture test was performed, and in six cases, the samples were contaminated (table 5). in the single intravenous antibiotics group, the most commonly identified pathogen was escherichia coli, followed by enterococcus species, klebsiella pneumoniae, and proteus mirabilis. there was no growth in 23 cultures in the single intravenous antibiotics group, whereas culture was not performed in nine cases, and three samples were contaminated in this group. in the only oral antibiotics group, the most identified pathogen was escherichia coli, followed by streptococcus species, staphylococcus species, and citrobacter freundii. there was no growth in 22 cultures, cultures were not performed in 16 cases, and three samples were contaminated in this group. antibiotic types and susceptibility third-generation cephalosporins were the most prescribed antibiotic category in both groups, followed by fluoroquinolones (table 6). the total sensitivity was 60.7% in the single intravenous antibiotics group and 74.3% in the only oral antibiotics group. specifically for third-generation cephalosporins, the sensitivity rates were 63.6% and 76.9% in the single intravenous antibiotics and only oral antibiotics groups, respectively. for fluoroquinolones, the sensitivity rates were 57.1% in the single intravenous antibiotics group and 65.5% in the only oral antibiotics group. discussion in the present study, older patients with utis treated with single intravenous antibiotics before ed discharge had a higher 72-hour ed revisit rate and longer duration of antibiotic treatment. moreover, single-dose intravenous antibiotic administration before ed discharge was the only clinical factor associated with revisits (table 3). however, there were no differences between the groups in admission rates following ed revisits (table 2) or reasons for revisits (table 4). although the groups were not compared in terms of disease severity, the single intravenous antibiotics group had a lower mean systolic blood pressure, higher mean respiratory rate, higher mean body temperature, and lower mean ktas level (which indicated more urgency) at the time of ed presentation (table 1). although ed physicians tend to prescribe intravenous antibiotics for patients with more severe disease, it is difficult to determine whether this tendency affected the final treatment plan. generally, ed physicians use intravenous antibiotics assuming that quickly raising the blood concentration of antibiotics will benefit patients' clinical outcomes. in a previous investigation of utis in patients aged 29 days to 2 years, patients who received parenteral antibiotics before discharge from the ed had a higher rate of 72-hour revisits (6). in contrast, in adult patients with utis aged over 18 years, intravenous antibiotic use before ed discharge has been associated with fewer ed revisits within 72 hours of discharge (5). these conflicting study results make it difficult to determine the administration of intravenous antibiotics in the ed. in this study, the patients in the intravenous antibiotics group were older and had a higher heart rate and lower systolic and diastolic blood pressure than those in the only oral antibiotics group. therefore, the group that received intravenous antibiotics had signs of worse disease severity at initial ed presentation, which aligns with our results. thus, ed physicians could have prescribed intravenous antibiotics to patients with relatively severe utis. utis are among the commonest diagnoses in patients with ed revisits (7). moreover, patients aged over 65 years have been shown to make significantly more return visits to the ed (8). therefore, quick diagnoses and appropriate antibiotic management are important for older patients with utis visiting the ed. a high proportion of older patients show asymptomatic bacteriuria and are less likely to show typical clinical features of uti, making diagnosis difficult (9). the diagnostic challenges could result in delayed treatment for utis, leading to ed revisits. additionally, prescribing resistant antibiotics is known to increase ed revisit rates (8). however, in the ed setting, since it takes time to obtain culture results, antibiotics are administered without considering microbiological information, despite the prevalence of increasing antibiotic resistance. to the best of our knowledge, no published study has investigated the effects of intravenous antibiotics on older patients with utis in the ed. the most common pathogen causing uti in this study was escherichia coli (58.5%, table 5), followed by enterococcus species, klebsiella pneumoniae, and proteus mirabilis, which are similar results to those of a previous study (10). according to a report on the antibiotic susceptibility of escherichia coli in community-acquired utis from 2008 to 2017 in korea, the susceptibility to ciprofloxacin decreased from 79.5% (2008) to 58.6% (2017), whereas that to cefotaxime decreased from 95.5% (2008) to 68.0% (2017) (11). although susceptibility was not assessed for the same condition, the results were similar in the previous study. in our study, the susceptibilities to fluoroquinolone in the intravenous and oral-only groups were 57.1% and 65.5%, respectively. for third-generation cephalosporins, the susceptibility was 63.6% in the intravenous antibiotics group and 76.9% in the without intravenous antibiotics group (table 6). these high rates of antibiotic resistance imply the necessity of further evaluation of domestic antibiotic resistance. due to increasing antibiotic resistance, an update of the domestic guidelines that includes predicting antibiotic-resistant organisms and selecting the types, optimal doses, routes, and durations of antibiotic regimens based on a local antibiogram is necessary. in this study, the revisit rate and total treatment duration were higher in the single intravenous antibiotics group, but there was no significant intergroup difference in admission rates. our findings suggest that, in the case of older patients with utis in the ed prescribed intravenous injections, decisions between admission or discharge should be made more carefully and that the worsening of symptoms should be explained in more detail to patients discharged from the ed. this study had several limitations. first, the study was conducted in two academic tertiary hospitals in the capital of south korea; therefore, this study may not have represented the health behaviour of the entire older population in the country. second, due to the study's retrospective nature, there may have been a selection bias while selecting the two groups. third, the enrolled patients were not classified by severity, and the effect of single-dose intravenous antibiotics before ed discharge could not be compared in patients with the same severity. finally, as uti treatment was started before the culture result was obtained in the ed setting, this study included every older patient diagnosed with or was clinically suspected of having uti regardless of the culture result. moreover, patients with inappropriate urine culture results (not performed, contaminated sample, no growth of microorganisms) were included. thus, patients without utis could have been included, which may have affected the results. conclusions older patients with utis who received initial single intravenous antibiotics before ed discharge had more revisits to the ed and longer durations of antibiotic treatment than patients who received only oral antibiotics. older patients with utis with relatively severe symptoms were prescribed intravenous antibiotics in the ed. decisions on admission or discharge should be made more carefully in older patients with utis prescribed intravenous antibiotics in the ed. acknowledgement the authors received no specific funding for this work. conflict of interest no conflict of interest to declare. references 1. rowe ta, juthani-mehta m. diagnosis and management of urinary tract infection in older adults. infect dis clin north am. 2014;28(1):7589. https://doi.org/10.1016/j.idc.2013.10.004 pmid:24484576 2. gharbi m, drysdale jh, lishman h, et 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(ref. 9 "lutters, vogt-ferrier") 10. bader ms, loeb m, brooks aa. an update on the management of urinary tract infections in the era of antimicrobial resistance. postgrad med. 2017;129(2):242https://doi.org/10.1093/cid/ciq257 https://www.ncbi.nlm.nih.gov/pubmed/21292654 https://doi.org/10.1007/s40121-021-00469-9 https://www.ncbi.nlm.nih.gov/pubmed/34121165 https://doi.org/10.1542/peds.2018-0900 https://www.ncbi.nlm.nih.gov/pubmed/30131437 https://doi.org/10.1001/jama.2016.0649 https://www.ncbi.nlm.nih.gov/pubmed/26881369 https://doi.org/10.1016/j.ajem.2017.06.041 https://www.ncbi.nlm.nih.gov/pubmed/28655424 https://doi.org/10.1002/14651858.cd001535 258. https://doi.org/10.1080/00325481.2017.1246055 pmid:27712137 11. kim yj, lee jm, cho j, lee j. change in the annual antibiotic susceptibility of escherichia coli in community-onset urinary tract infection between 2008 and 2017 in a tertiary care hospital in korea. j korean med sci. 2019;34(34):e228. https://doi.org/10.3346/jkms.2019.34.e228 pmid:31456383 corresponding author: dong hoon lee, m.d., ph.d. department of emergency medicine, chung-ang university gwangmyeong hospital, college of medicine, chung-ang university, 110, deokan-ro, gwangmyeong-si, gyeonggi-do, seoul, republic of korea tel.: +822 2222-6751, fax: +822 2222-1366, e-mail: emdhlee@cau.ac.kr https://doi.org/10.1080/00325481.2017.1246055 https://www.ncbi.nlm.nih.gov/pubmed/27712137 https://doi.org/10.3346/jkms.2019.34.e228 https://www.ncbi.nlm.nih.gov/pubmed/31456383 figure legends figure 1. inclusion and exclusion flow diagram table 1. baseline characteristics of enrolled patients variables single-dose intravenous antibiotics (n = 279) only oral antibiotics (n = 150) p-value age (y) a 78.27 ± 7.66 77.62 ± 8.16 .420 sex b .679 male 73 (26.1) 36 (24.0) female 206 114 vital signsa systolic blood pressure (mmhg) 135.44 ± 24.51 142.85 ± 25.70 .004 diastolic blood pressure (mmhg) 72.91 ± 15.74 75.98 ± 16.74 .061 pulse rate (beats/min) 92.42 ± 16.11 90.38 ± 18.83 .262 respiratory rate (breath/min) 20.05 ± 1.42 19.68 ± 0.96 .001 body temperature (oc) 37.56 ± 1.10 36.87 ± 0.81 <.001 mental status b .315 alert 269 (96.4) 148 (98.6) verbal response 7 (2.5) 2 (1.3) painful response 3 (1.0) 0 unresponsive 0 0 qsofa ≥2b 4 (1.4) 1 (0.6) .480 ktas triage category b <.001 level 1 resuscitation 0 0 level 2 emergent 13 (4.6) 3 (2.0) level 3 urgent 186 (66.7) 82 (54.6) level 4 less urgent 69 (24.7) 63 (42.0) level 5 non urgent 11 (3.9) 2 (1.3) avalues are given as mean ± standard deviation bvalues are given as number (%) abbreviations: ktas, korean triage and acuity scale; los, length of stay; qsofa, quick sequential (sepsis-related) organ failure assessment table 2. clinical outcomes of urinary tract infections among older individuals variable single intravenous antibiotics (n = 279) only oral antibiotics (n = 150) p-value 72-hour ed revisitsa 43 (15.4) 10 (6.7) .009 admissions after 72-hour ed revisita 27 (62.8) 5 (50.0) .492 duration of therapy (days)b 11 (4.00 – 15.00) 5 (3.00 -11.00) <.001 avalues are given as number (%) bvalues are given median (iqr) abbreviation: ed, emergency department table 3. logistic regression analysis of revisit predictors variable univariate analysis multivariate analysis non-72-hour ed revisit 72-hour ed revisit n = 376 n = 53 p-value or b p-value age (y) a 77.84 ± 7.87 79.49 ± 7.31 .149 sex; male b 90 (23.9) 19 (35.8) .062 systolic blood pressure (mmhg) a 137.89 ± 25.73 134.83 ± 29.08 .426 diastolic blood pressure (mmhg) a 74.10 ± 16.23 71.17 ± 18.73 .229 pulse rate (beats/min) a 91.29 ± 17.21 92.72 ± 20.65 .582 respiratory rate (breaths/min) a 19.88 ± 1.26 19.75 ± 3.28 .779 body temperature (oc) a 37.28 ± 1.04 36.85 ± 5.42 .566 altered mental status b 12 (3.2) 0 .187 qsofa ≥2b 5 (1.3) 0 .398 ktas category ≤3 b 244 (64.9) 39 (73.6) .211 single intravenous antibiotics b 236 (62.8) 43 (81.1) .009 2.551 (1.243 – 5.236) 0.936 .011 avalues are given as mean ± standard deviation bvalues are given as number (%) table 4. reasons for revisits variable single intravenous antibiotics (n = 43) only oral antibiotics (n = 10) pvalue reason of revisit symptoms .146 fever 21 (48.8) 4 (40.0) dyspnoea 7 (16.3) 0 general weakness 0 1 (10.0) urinary symptoms 8 (18.6) 4 (40.0) poor oral intake 5 (11.6) 1 (10.0) flank pain 2 (4.7) 0 values are given as number (%) table 5. common pathogens associated with urinary tract infections rank name total n (%) single intravenous antibiotics (n = 279) only oral antibiotics (n =150) 1st escherichia coli 251 (58.5) 178 (63.8) 73 (48.7) 2nd enterococcus species 20 (4.6) 17 (6.1) 3 (2.0) 3rd klebsiella pneumoniae 17 (3.9) 15 (5.4) 2 (1.3) 4th proteus mirabilis 15 (3.5) 12 (4.3) 3 (2.0) 5th citrobacter freundii 14 (3.3) 8 (2.8) 6 (4.0) 6th streptococcus species 13 (3.0) 5 (1.8) 8 (5.3) 7th staphylococcus species 13 (3.0) 5 (1.8) 8 (5.3) 8th pseudomonas aeruginosa 10 (2.4) 4 (1.4) 6 (4.0) no growth 45 (10.5) 23 (8.2) 22 (14.7) culture not performed 25 (5.8) 9 (3.2) 16 (10.6) contamination 6 (1.4) 3 (1.1) 3 (2.0) values are given as number (%) table 6. antibiotic types and susceptibility antibiotics used single intravenous antibiotics (n = 279) sensitivity (%) only oral antibiotics (n =150) sensitivity (%) total antibiotics used 244 60.7 109 74.3 third-generation cephalosporin 140 (57.3) 63.6 78 (52) 76.9 fluoroquinolone 84 (34.4) 57.1 29 (19.3) 65.5 carbapenem 17 (6.0) 64.7 0 fosfomycin 0 2 (1.3) 100 piperacillin/tazobactam 3 (1.0) 0 0 excluded data no growth 23 (8.2) 22 (14.6) culture not performed 9 (3.2) 16 (10.6) contamination 3 (1.0) 3 (2.0) values are given as number (%) incidence, risk factors, risk assessment model and compliance of patients on anticoagulants for asymptomatic venous thromboembolism in nononcological urological inpatients kaixuan li1, quan zhu1, haozhen li1, ziqiang wu1, feng han1, zhengyan tang1,2** zhao wang1* purpose: to study the incidence, risk factors for developing asymptomatic venous thromboembolism and the compliance of patients on anticoagulants for asymptomatic venous thromboembolism (vte) in nononcological urological medium-high risk inpatients, and build a risk assessment model (ram) for early screening for asymptomatic vte. materials and methods: we conducted a retrospective analysis of 573 inpatients admitted to a nononcological urological ward of a tertiary hospital in china from january 1, 2017, to june 30, 2019. data were collected using the electronic medical record system, and patients underwent a follow-up by phone 6 months after discharge. results: among the 573 medium-high risk inpatients, 73 (15.4%) were diagnosed with vte, including 20 (4.2%) symptomatic and 53 (11.2%) asymptomatic. prior history of vte, a history of anticoagulants or antiplatelet agents before admission, and d-dimer ≥ 1 were the potential risk factors identified for asymptomatic vte. patients with poor awareness of vte and its dangers, and patients who lived more than 1 hour away from the hospital had a high probability of poor compliance with anticoagulation therapy after discharge. using d-dimer (1.785 μg/ml), we built a ram for the early diagnosis of asymptomatic vte. conclusion: we found that patients with urinary nontumor vte had low compliance with anticoagulation therapy after discharge. the key factors for determining asymptomatic vte in nononcological urological inpatients included prior history of vte, a history of taking anticoagulants or anti-platelet agents before admission, and d-dimer ≥ 1. furthermore, we found that the threshold of d-dimer should be elevated to 1.785 μg/ml to predict asymptomatic vte. keywords: asymptomatic; nononcological; compliance; risk assessment model; urology; venous thromboembolism 1department of urology, xiangya hospital central south university, changsha 410008, china. 2provincial laboratory for diagnosis and treatment of genitourinary system disease, changsha 410000, china. kaixuan li and quan zhu contributed equally to the article. *correspondence: department of urology, xiangya hospital central south university; changsha, 410008, china. tel: +86-15116358241, e-mail: xywangz07@163.com. **department of urology, xiangya hospital central south university; changsha, 410008, china. tel: +86-13507318268, e-mail: xytzyan@163.com. received july 2021 & accepted november 2021 unclassified introduction venous thromboembolism (vte), which denotes both pulmonary embolism (pe) and deep vein thrombosis (dvt), is a common cause of morbidity and mortality after urological surgeries. vte was a particularly common problem in the past, with an estimated 22% incidence rate due to no prophylaxis for patients who underwent pelvic surgeries(1). although the occurrence of vte has decreased in recent years, including for both uro-oncologic and nononcological surgeries(2,3), vte is still a serious perioperative adverse event. furthermore, it places a heavy burden on the healthcare systems and brings about higher mortality with potentially fatal pe. vte can be either symptomatic or asymptomatic, with the former often being much easier for clinicians to identify. asymptomatic vte can also cause fatal pe and it is associated with an increased risk in all-cause mortality(4). the european association of urology (eau) and the canadian urological association (cua) recommend providing perioperative thromboprophylaxis for both symptomatic and asymptomatic vte(5,6). however, the evidence grades in these guidelines are relatively weak, for example, in eau guidelines, the recommended levels of prophylaxis for many urological nontumor surgeries are weak, including transurethral resection of the prostate (turp), prostatectomy, laparoscopic without pelvic lymph node dissection (plnd), nephrectomy, and reconstructive pelvic surgery et al(6). and whether thromboprophylaxis for asymptomatic vte can balance thrombosis prevention and bleeding remains uncertain(7). although the caprini risk assessment tool is recommended to evaluate the occurrence of postoperative vte(8), a high proportion of patients after urological surgeries are still classified into the high-risk group. this suggests that the validity of this evaluation model is open to question. one way we felt this issue could be overcome was by building a risk assessment model (ram) for vte. in recent years, urologists have paid increasing attention to the occurrence and prevention of perioperative urology journal/vol 20 no. 1/ january-february 2023/ pp. 56-65. [doi:10.22037/uj.v18i.6893] vte. however, noncancer urological patients have still not received much attention from urologists. the incidence of vte after urological nononcological surgeries is considered to be relatively low, but the results of our prior study and other research have contradicted this idea(9,10). the main urinary system nononcological diseases are urinary stones, benign prostate hyperplasia, ureteral stricture, varicocele, renal cyst, urethral stricture, stress urinary incontinence, and others. although physical and drug therapies to prevent thrombosis are conducted across the globe, vte-related mortality after urological nononcological surgery remains a concern. moreover, few studies have focused on asymptomatic vte in urological nononcological hospitalized patients, and thus this issue remains unresolved for nononcological urologists. at present, most research on vte compliance focuses on the prevention of postoperative thrombosis in non-urologic patients. for example, a prior compliance study compared the benefits of using either preventive anticoagulants with those from using mechanical methods to prevent vte after gynecological tumor surgery and total hip and knee replacement surgery(11-13). however, there are few relevant studies on the compliance of vte anticoagulation therapy after discharge, especially in patients with non-tumor vte in the urology department. when evaluating the effect of anticoagulant therapy, we feel it is important to understand the patient's compliance with anticoagulant therapy. for this reason, the main aim of our preliminary study was to retrospectively investigate the incidence rates, risk factors, and compliance of nononcological inpatients in urology. using these data, we then established a ram for the screening of asymptomatic vte by using the appropriate threshold of d-dimer. materials and methods study population this was a retrospective, single-center, cohort study approved by the ethics committee of xiangya hospital (no. 2019030078). consecutive inpatients who were admitted to the nononcological urological unit and who underwent diagnostic imaging (including computed tomography, pulmonary angiography and ultrasound) becharacteristics asymptomatic vte symptomatic vte p-value age (years) 65.53 ± 10.08 59.00 ± 12.61 .024* ≤ 65 28 (52.8%) 12 (60.0%) ≥ 66 25 (47.2%) 8 (40.0%) gender .977 male 32 (60.4%) 12 (60.0%) female 21 (39.6%) 8 (40.0%) bmi(kg/m2) 22.64 ± 2.79 23.25 ± 3.18 .462 ≤ 18.5 3 (5.7%) 1 (5.0%) 18.5-23.9 33 (62.3%) 8 (40.0%) ≥ 23.9 17 (32.1%) 11 (55.0%) d-dimer (μg/ml, max) 2.34 (1.23-3.53)# 6.68 ± 9.81 .829 caprini score(max) 5.87 ± 2.21 6.15 ± 4.74 .800 asa score 3.00 (2.00-3.00)# 2.77 ± 0.93 .886 operation time(min) 87.88 ± 49.49 81.38 ± 59.52 .721 intraoperative blood loss (ml) 20.00 (5.00-100.00)# 44.46 ± 81.96 .266 table1. comparison between inpatients with asymptomatic and symptomatic vte abbreviations: vte, venous thromboembolism; bmi, body mass index; asa, american society of aneshesiologists physical status classification system #median and interquartile range *statistically significant (α = 0.05) characteristics no. of sample size asymptomatic vte univariate analysis unadjustd or (95%ci) n (%) incidence (%) total 553 (100.0%) 53 (100%) 9.6% emergency surgery no 520 (94.07%) 49 (92.4%) 9.4% p = .545 # 1.0 yes 33 (5.97%) 4 (7.6%) 12.1% 1.3 (0.4-3.9) gender male 350 (65.67%) 32 (60.38%) 9.1% p = .643 1.0 female 203 (34.33%) 21 (39.62%) 10.3% 1.1 (0.6-2.0) age (years) ≤ 65 375 (67.81%) 28 (52.83%) 7.5% p = .014 1.0 ≥ 66 178 (32.19% ) 25 (47.17%) 14.0% 2.0 (1.1-3.6) * bmi (kg/m2) 18.5-23.9 304 (54.97%) 37 (69.81%) 10.5% p = .182# 1.0 ≥24 38 (6.87%) 4 (7.55%) 12.2% 0.8 (0.3-2.5) 24-27.9 133 (24.05%) 9 (16.98%) 6.8% 0.5 (0.2-1.1) ≥28 64 (11.57%) 3 (5.66%) 4.7% 0.4 (0.1-1.2) 35-39.9 14 (2.53%) 0 0% abbreviations: vte, venous thromboembolism; or, odds ratios; bmi, body mass index. *statistically significant (α = 0.05) # fisher’s exact test table 2. baseline characteristics associated with asymptomatic vte. asymptomatic venous thromboembolism-li et al. vol 20 no 1 january-february 2023 57 tween january 1, 2017, and june 30, 2019, at xiangya hospital were enrolled in our study. inclusion and exclusion criteria patients were regarded as medium-high risk inpatients and advised to finish diagnostic imaging if they had one or more of the following situations: over 75 years old, had prior vte, a body mass index over 35 kg/m2, a first degree relative (parent, full sibling, or child) with vte, or a d-dimer value over 0.5 μg/ml. for patients assessed as medium-high risk inpatients, we will perform d-dimer examinations after admission and after surgery. patients were excluded if they were younger than 18 years old, had postoperative pathological examination results that showed malignancy, or had incomplete clinical medical records. in total, 573 eligible inpatients were selected for the study (figure 1). procedures asymptomatic vte was defined when a hospitalized vte patient displayed no vte related symptoms (such as swelling and painful in the lower limbs, pain in lower limbs, decreased spo 2 , dyspnea, chest pain, or an electrocardiogram (ecg) performance with unstable circulation)(14). patients who were assessed with medium-high thrombosis risk inpatients underwent doppler ultrasound examination of lower extremity blood vessels after admission and after surgery, and 25 postoperative patients underwent pulmonary artery cta for the occurrence of suspicious symptoms of pulmonary embolism like difficulty breathing, chest pain, etc. all the data were retrospectively collected from the electronic medical record system (emrs) and anesthetic records in xiangya hospital through each inpatient’s unique id number. in addition, the caprini ram was also collected and it was invented by caprini et al. caprini ram is based on the risk of the risk factors to stratify the patients for vte risk. for patients with a very low risk of vte (caprini score of 0), additional prevention is not recommended. for patients with low risk of vte (caprini score of 1-2), mechanical or drug prevention is recommended. patients with intermediate risk of vte (caprini score of 3-4) to high risk (caprini score of ≥ 5) are recommended for anticoagulant alone or combined with mechanical prevention(15). the occurrence of vte was detected by the imaging procedure reports, diagnosed by board-certified radiologists as well as the course records written by attending doctors. preoperative bleeding was defined as hematuria, blood in the stool, and bleeding in other parts of the body. regardless of the size (massive or small) and location (proximal or distal) of the thrombus, once the vte occurred in the deep veins of the lower extremities or the pulmonary artery and its branches, we considered that a vte event had occured. the occurrence of sepsis was defined according to the sepsis 3 criteria and the calculation formula for creatinine clearance (cockcharacteristics no. of sample size asymptomatic vte univariate analysis unadjustd or (95% ci) n (%) incidence (%) hypertension no 368 (66.55%) 18 (33.96%) 9.5% p = .934 1.0 yes 185 (33.45%) 18 (33.96%) 9.7% 1.0 (0.6-1.9) diabetes no 493 (89.15%) 4 (7.55%) 9.9% p = .416 1.0 yes 60 (10.85%) 4 (7.55%) 6.7% 0.6 (0.2-1.9) prior vte no 524 (95.30%) 13 (24.53%) 7.6% p < .001# 1.0 yes 29 (4.70%) 13 (24.53%) 44.8% 9.8(4.4-21.9) * family history of vte no 522 (94.39%) 3 (5.66%) 9.6% p = 1.000# 1.0 yes 31 (5.61%) 3 (5.66%) 9.7% 1.0 (0.3-3.4) history of varicose veins in the lower extremities no 534 (96.56%) 4 (7.55%) 9.2% p = .099# 1.0 yes 19 (3.44%) 4 (7.55%) 21.1% 2.6 (0.8-8.3) history of surgery within a month no 520 (94.03%) 6 (11.32%) 9.0% p = .117 # 1.000 yes 33 (5.97%) 6 (11.32%) 18.2% 2.2 (0.9-5.7) anticoagulants or anti-platelet agents prescription before admission no 534 (96.56%) 6 (11.32%) 8.8% p = .006# 1.0 yes 19 (3.44%) 6 (11.32%) 31.6% 4.8(1.7-13.2) * copd no 544 (98.37%) 1 (1.89%) 9.6% p = .599 # 1.0 yes 9 (1.63%) 1 (1.89%) 11.1% 1.2 (0.1-9.6) coronary atherosclerotic heart disease no 517 (93.49%) 1 (1.89%) 10.1% p = .238# 1.0 yes 36 (6.51%) 1 (1.89%) 2.8% 0.3 (0.0-1.9) other cardiovascular diseases no 529 (95.66%) 3 (5.66%) 9.5% p = .494 # 1.0 yes 24 (4.34%) 3 (5.66%) 12.5% 1.4 (0.4-4.8) cancer history no 533 (896.38%) 2 (3.77%) 9.6% p = 1.000 # 1.0 yes 20 (3.62%) 2 (3.77%) 10.0% 1.1 (0.2-4.7) cerebral stroke history no 525 (94.94%) 4 (7.55%) 9.3% p = .331# 1.0 yes 28 (5.06%) 1.6 (0.5-4.9) table 3. characteristics of medical history associated with asymptomatic vte. abbreviations: vte, venous thromboembolism; copd, chronic obstructive pulmonary disease; or, odds ratios. *statistically significant (α = 0.05) # fisher’s exact test asymptomatic venous thromboembolism-li et al. unclassified 58 croft-gault equation) was conducted based on creatinine levels(15,16). at 6 months after discharge, we checked on each patients’ thrombosis progression through a phone follow-up. if we were unable to follow-up with a patient after 3 consecutive days of attempts, they were excluded from our study. statistical analysis all statistical analyses were performed using sas version 9.3 software (sas institute inc., cary, nc, usa). categorical variables were described using frequency and percentage while means and standard deviations were applied to the continuous variables. a chi-square testing and independent t test were used to assess the risk factors for asymptomatic vte to compare asymptomatic and symptomatic vte. the minimum expected cell frequency was accessed, and when the data did not meet pearson's χ 2 test conditions (e ≥ 5 and n ≥ 40), fisher exact test is used. the normality and homogeneity of variance were assessed, and median and interquartile range of variables with skewed distribution were reported. when the p-values were under 0.1 in the univariate analyses, the related factors were chosen to be evaluated by multivariable logistic regression analysis. a receiver operating characteristic (roc) curve was plotted by referring to the sensitivity vs. 1 – specificity of d-dimer level. the areas under the curve (aucs), cutoff value sensitivity, specificity, negative predictive value (npv), positive predictive value (ppv) and youden index were used to assess the prediction model in this study. a p-value of < .05 was considered to be statistically significant. results of the 592 patients selected in the initial sample, 19 (3.2%) patients were excluded based on the exclusion criteria, leaving a total of 573 patients for our study. among these patients, 73 (15.4%) were diagnosed with vte, including 20 (4.2%) symptomatic vte patients and 53(11.2%) asymptomatic patients. the diagnoses of the patients include urinary stones (305, 53.2%), benign prostate hyperplasia (58, 10.1%), benign adrenal characteristics no. of sample size asymptomatic vte univariate analysis unadjustd or (95% ci) n (%) incidence (%) preoperative bleeding no 521 (94.21%) 48 (90.57%) 9.2% p = .218# 1.0 yes 52 (5.79%) 5 (9.43%) 15.6% 1.8 (0.7-5.0) preoperative sepsis no 526 (95.12%) 48 (90.57%) 9.1% p = .167 # 1.0 yes 27 (4.88%) 5 (9.43%) 18.5% 2.3 (0.8-6.2) creatinine clearance levels (ml/min)a 0.6(0.5-0.8) <15 45 (8.14%) 8 (15.09%) 17.8% p = .001# 1.0 15-29 37 (6.69%) 5 (9.43%) 13.5% 0.7 (0.2-2.4) 30-59 179 (32.37%) 24 (45.28%) 13.4% 0.7 (0.3-1.7) 60-90 227 (41.05%) 16 (30.19%) 7.0% 0.4 (0.1-0.9) * d-dimer (μg/ml,max) 2.1 (1.3-3.3) * < 0.5 135 (24.41%) 6 (11.32%) 4.4% p=.001# 1.0 0.5-1 104 (18.81% ) 4 (7.55%) 3.8% 0.9 (0.2-3.1) ≥1 314 (56.78%) 43 (81.13%) 13.7% 3.4 (1.4-8.2) * caprini score, max 1.6 (0.9-2.7) ≤2 19 (3.44%) 2 (3.77%) 10.5% p = .125 # 1.0 3-4 191 (34.54%) 12 (22.64%) 6.3% 0.6 (0.1-2.8) ≥5 343 (62.02%) 39 (73.58%) 11.4% 1.1 (0.2-4.9) re-admission surgery no 548 (99.10%) 52 (98.11%) 9.5% p =.397# 1.0 yes 5 (0.90%) 1 (1.89%) 20.0% 2.4 (0.3-21.7) complications no 536 (96.93%) 50 (94.34%) 9.3% p = .217# 1.0 yes 17 (3.07%) 3 (5.66%) 17.6% 2.1 (0.6-7.5) table 4. other related characteristics associated with asymptomatic vte. abbreviations: vte, venous thromboembolism; or, odds ratios. a.creatinine clearance levels were calculated with the use of the cockcroft–gault equation *statistically significant (α = 0.05) # fisher’s exact test variable characteristics adjusted or p-value aor 95% ci age 58.69 ± 12.81 1.0 .9-1.0 .112 prior vte 10.0* 3.9-25.9 < .001 anticoagulants or anti-platelet agents prescription before admission 4.2* 1.3-13.9 .019 creatinine clearance levels (ml/min)a 63.91 ± 29.06 1.0* 1.0-1.1 .023 d-dimer, (μg/ml,max) 2.65 ± 4.74 0.2* .1-.4 < .001 history of varicose veins in the lower extremities 1.5 .4-5.7 .552 abbreviations: vte, venous thromboembolism; or, odds ratios. *statistically significant (α = 0.05) baseline level(p < 0.1) table 5. clinical factors associated with asymptomatic vte based on multivariable logistic regression analysis asymptomatic venous thromboembolism-li et al. vol 20 no 1 january-february 2023 59 tumor (39, 6.8%), ureteral stricture (24, 4.2%), varicocele (12, 2.1%), renal cyst (19, 3.3%), urethral stricture (10, 1.7%), stress urinary incontinence (15, 2.6%), others (91, 15.9%). when comparing the baseline characteristics between asymptomatic and symptomatic vte, only age showed a significant difference, which suggested that asymptomatic vte was more common in older inpatients (table1). table 2 shows the patient characteristics associated with asymptomatic vte. there is a statistically significant difference in age (adjusted odds ratio (or) = 2.2, 95%ci: 1.1-3.6), with age ≥ 66 having a higher risk of asymptomatic vte compared to those aged ≤ 65. table 3 shows the characteristics of medical history associated with asymptomatic with patients who had prior vte (aor = 9.8, 95%ci: 4.4-21.9) and who had received anticoagulant or antiplatelet agent use before admission (aor = 4.8, 95%ci: 1.7-13.2) being more vulnerable to asymptomatic vte. other characteristics which may contribute to asymptomatic vte were also analyzed. table 4 shows creatinine clearance (aor = 0.6, 95%ci: 0.5-0.9) to be a protective factor for asymptomatic vte while d-dimer (aor = 2.1, 95%ci: 1.3-3.3) appears as a potential risk factor, with patients with d-dimer ≥ 1 being significantly associated with a susceptibility toward asymptomatic vte. multivariable logistic regression analysis was carried out to combine all the potential risk factors for asymptomatic vte mentioned above (table 5). the linearity for quantitative predictors was assessed, and the multicollinearity problem was avoided (.794, 95%ci: .741.848). the auc for the logistic regression model was calculated (figure 2). hosmer-lemeshow goodness of fit test was used to evaluate the calibration ability of the prediction model. the results show that hosmer-lemeshow χ 2 =10.725, p = .218 > .05, suggesting that the difference between the predicted value of the model and the actual observed value is not statistically significant, and the prediction model has good calibration ability. patients who experienced prior vte (aor = 11.3, 95%ci: 4.4-29.0), received anticoagulant d-dimer prediction of asymptomatic vte(95% ci) observed asymptomatic vte (95% ci) total no yes no n 96 1 97 % of predicted asymptomatic vte 99.0% (99.5%-99.7%) 1.0% (0.3%-4.5%) 100.0% % of observed asymptomatic vte 63.6% (57.8%-76.9%) 6.7% (3.0%-30.4%) % of total patients 57.8% (52.6%-70.0%) 0.6% (0.3%-2.7%) yes n 55 14 69 % of predicted asymptomatic vte 79.7% (77.1%-85.0%) 20.3% (15.0%-22.9%) 100.0% % of observed asymptomatic vte 36.4% (25.7%-40.6%) 93.3% (50.8%-99.7%) % of total patients 33.1% (23.3%-36.9%) 8.4% (4.6%-9.6%) total n 151 15 166 % of observed asymptomatic vte 100.0% 100.0% 100.0% % of total patients 91.0% 9.0% 100.0% table 6. cross tabulation of d-dimer to predict the occurrence of asymptomatic vte abbreviations: vte, venous thromboembolism. variable overallpopulation(n = 56) good compliance (n =27) poor compliance(n = 24) p -value or value level of education grade school and illiteracy 17 (33.3%) 8 9 p = .91 1.0 junior high school and technical secondary school 15 (29.4%) 8 7 1.9 (0.3-10.5) high school 11 (21.6%) 6 5 1.5 (0.3-8.4) undergraduate and junior college 8 (15.7%) 5 3 1.4 (0.2-8.9) admission time 2017/01/01-2017/12/31 8 (15.7%) 4 4 p =.235 1.0 2018/01/01-2018/12/31 22 (43.1%) 9 13 2.0 (0.4-10.5) 2019/01/01-2019/06/30 21 (41.2) 14 7 2.9 (0.8-10.0) understanding of vte and its dangers understand 37 (72.5%) 25 12 p = .001 1.0 don't understand 14 (27.5%) 2 12 12.5 (2.4-64.9)* patient satisfaction with hospital treatment satisfied 43 (84.3%) 24 19 p = .571 1.0 not satisfied 8 (15.7%) 3 5 2.1 (0.5-10.0) self-rated general health lower than average 4 (7.8%) 1 3 p = .256 1.0 average 42 (82.4%) 22 20 0.3 (0.0-3.2) higher than average 5 (9.8%) 4 1 0.1 (0.0-2.0) time spending on the journey to the hospital < 1h 16 (31.4%) 12 4 p = .033 1.0 ≥ 1h 35 (68.6%) 15 20 4.0 (1.1-14.9)* transportation to the hospital car 31 (60.8%) 17 14 p = .622 1.0 train 12 (23.5%) 5 7 1.4 (0.3-6.8) bus 8 (15.7%) 5 3 2.3 (0.4-14.6) abbreviations: vte, venous thromboembolism; or, odds ratios; pe, pulmonary embolism. *statistically significant (α = 0.05) table 7. univariate analysis of compliance with anticoagulation therapy after discharge, good compliant group vs poor compliant group asymptomatic venous thromboembolism-li et al. unclassified 60 or antiplatelet agent use before admission (aor = 4.5, 95%ci: 1.3-14.9) and had a d-dimer ≥ 1 (aor = 4.6, 95%ci: 1.55-13.5) had a positive association with a susceptibility towards asymptomatic vte. futhermore, a roc curve was created to evaluate the ability of the d-dimer value to discriminate between the symptomatic vte and non-vte patients (figure 3). the aucs for d-dimer diagnosis of thrombosis is .715 (95%ci: .634-.797). and the cut-off point of d-dimer for the diagnosis of asymptomatic vte (the threshold value of d-dimer was determined when the sum of sensitivity and specificity was at its maximum) was 1.785. this means that patient who had a d-dimer value ≥ 1.785 were asymptomatic vte. we further assessed the ram by 4-fold cross-validation, and found its sensitivity was 93.3% (50.8%99.7%), specificity is 63.6% (57.8%-76.9%), misdiagnosis rate is 36.4% (25.7%-40.6%); missed diagnosis figure 1. flowchart of patient selection. figure 2. roc curve analysis for the logistic regression model. asymptomatic venous thromboembolism-li et al. vol 20 no 1 january-february 2023 61 rate is 6.7% (3.0%-30.4%), ppv is 20.3% (15.0%22.9%), npv is 99.0% (99.5%-99.7%), correct rate is 69.3% and youden index is 40.7% (table 6). as for the compliance of anticoagulant medication for asymptomatic vte, among the 53 patients, 2 were excluded due to contact being lost. after discharge from the hospital, a further 2 of these patients developed lower extremity pain, 1 patient developed lower extremity swelling, 1 patient had worsening hematuria (which improved 10 days after stopping rivaroxaban), and no patients developed dyspnea, chest pain, or other pe symptoms. the compliance of anticoagulant therapy after discharge was mainly evaluated as either “good” or “poor”. good compliance was defined if a patient took the anticoagulant drugs regularly and underwent re-examination at the vascular surgery clinic within the time specified by the doctor. among 51 patients, 46 (90%) took rivaroxaban after discharge from hospital, 4 (8%) warfarin, and 1 (2%) aspirin. 27 patients (52.9%) had good compliance with anticoagulation therapy and 24 patients (47.1%) had poor compliance. from our univariate analysis, we found that patients with a poor awareness of vte and its dangers (p = .001; 95%ci: 2.406-64.932), and patients who lived more than 1 hour away from the hospital (p = .033; 95%ci: 1.07414.896), were more likely to have a poor compliance with anticoagulant therapy after discharge, the difference being statistically significant. (table 7). discussion vte is a serious complication during hospitalization, and its incidence of vte in the nononcological unit of urology has still not received much attention, especially for asymptomatic vte. we estimated the incidence and risk factors of asymptomatic vte, and built an ram for asymptomatic vte in urological nononcological inpatients. our results cast new light on the incidence of vte in urological nononcological medium-high risk inpatients, with the ram performing well and yielding good results. among the 573 inpatients who took part in our study, 73 (15.4%) were diagnosed with vte, including 20 (4.2%) symptomatic and 53(11.2%) asymptomatic patients. we found that among asymptomatic vte and symptomatic vte patients, older patients were more likely to be asymptomatic (65.53 ± 10.08 vs 59.00 ± 12.61, p = .024). this result might be due to the low responsiveness and sensitivity of the older patients, or because the clinical manifestations were atypica,l hidden, or absent, and therefore could not truly reflect the condition. a large number of clinical studies have shown that asymptomatic vte remains common despite anticoagulant therapy(16). for this reason, it is important to identify the risk factors associated with asymptomatic vte to improve its early diagnosis. according to our multivariable logistic regression analysis, we found that prior vte, administering anticoagulants or antiplatelet agents to patients before admission, or a d-dimer ≥ 1 figure 3. roc curve analysis to evaluate the ability of d-dimer roc = receiver operating characteristic asymptomatic venous thromboembolism-li et al. unclassified 62 were potential risk factors. interestingly, older age was not a risk factor for asymptomatic vte based on multivariable analysis even though age was independently associated with asymptomatic vte in other studies(17). prior history of vte is widely perceived to be a risk factor, regardless of whether it is symptomatic or asymptomati(18,19). it is also easy to understand why administering anticoagulant or antiplatelet agent to paeitnes before admission is also a risk factor, as patients who need to take anticoagulants or antiplatelet agents are more vulnerable to vte due to their hypercoagulable state of the blood. as for the d-dimer value, our results were similar to those of other studies, which found it to be significantly associated with asymptomatic vte(20,21). interestingly, when d-dimer is considered to be a risk factor for asymptomatic vte, its value is often higher than the prescribed abnormal value (0.5 μg/ml) (something to be discussed in more detail below). furthermore, creatinine clearance levels between 60 and 90 ml/min were considered to be a protective factor for asymptomatic vte patients, which is consistent with other research(22). however, some or estimates and confidence limits are inflated which suggesting sparse-data bias.the majority of data with missing or zero values are included in the data set. quartile division or cutting off deletion value are used to modify proper data sets. as far as we are concerned, there are no specific anticoagulation strategy in the current guidelines for urological nononcological asymptomatic vte, and there are few randomized clinical trials evaluating the effectiveness and safety of anticoagulation for asymptomatic dvt. yugo et al retrospectively evaluated 300 patients with asymptomatic lower extremity dvt and found that most asymptomatic dvt patients had undergone long-term anticoagulation therapy, due to the risk of major bleeding(23). our ram assessed the risk of asymptomatic vte was based on the d-dimer value, which was recommended to predict vte in the guidelines of the american college of chest physicians(15). d-dimer is produced during the endogenous fibrinolysis of blood clots and plays an important role in the diagnosis algorithm to rule out vte. it is considered to be the best biomarker for the early screening of vte due to its high sensitivity but does have a poor specificity, and thus false-positive d-dimer results may occasionally occur(24). balogun et al found that, a d-dimer cut-off point of 1660 ng/ ml in the 48 hours following a stroke could effectively distinguish the asymptomatic vte patients, with a diagnosis rate of 72% (13/18)(25). this suggests d-dimer might be a sensitive predictor for asymptomatic vte. in our study, we noticed that d-dimer ≥ 1 μg/ml was a risk factor for asymptomatic vte, and that it might increase the likelihood of asymptomatic vte by about 4.6 times. however, a d-dimer level < 1 μg/ml had no statistical difference when compared with a level < 0.5 μg/ml. in our ram, the threshold value of d-dimer was determined when the sum of sensitivity and specificity was at its maximum and the cut-off point was 1.785. the sensitivity of this ram was 71.7%, specificity 69%, and npv 95.8%. other studies have used d-dimer to assess the risk of vte. for instance, shi et al. reported in a study of gynecologic malignancy inpatients that the d-dimer threshold needed to be raised to 1.5 μg/ml, with a sensitivity of 87.5%, a specificity 93.8%, and npv 99.2% in patients with gynecologic malignancies(26). another study indicated that d-dimer ≥ 0.89 μg/ml might be more suitable for urological oncological patients, reporting a sensitivity of 83.9%, and a specificity of 80.0%(27). different groups of people have their own suitable cutoff values. nevine et al stratified the d-dimer cutoff according to age, and found that sensitivity was compromised in patients older than 80 years(28). douma et al. defined a new d-dimer cutoff value as patient's age x 10 in patients aged > 50 years and greatly increased the proportion of older patients in whom pe could be safely excluded(29). our own aim was to build a ram for the early detection of asymptomatic vte in urological nononcological inpatients. our study found that only 27 (52.9%) patients with nontumor vte in the urology department received anticoagulation therapy according to the requirements of the medical advice after discharge. this ratio was far lower than the ratio of good compliance with postoperative preventive anticoagulant therapy reported in other literature(12,30). among our 51 vte patients, 14 (27.0%) patients did not understand what vte was and what its dangers were. combining the experience of clinical work and the analysis of data, we found that this was mainly due to 2 reasons.(1) urinary nontumor patients, all were hospitalized because of urological diseases. during the hospitalization period, they were found to have vte by accident. vte was not the main reason for their visit.(2) apart from 15.7% of patients had an undergraduate and junior college degree, with the education level of the remaining patients being low, limiting their understanding of the disease. our research also found that patients who spend more than 1 hour on the journey to hospital had poor compliance with re-examination at vascular surgery within the time specified by the doctor. this made the length of the journey an important indicator affecting patient compliance(12,30). long distances increase the cost of travel and require more time, reducing the willingness of patients to undergo re-examination. furthermore, after visiting a higher-level hospital, patients were also unwilling to visit a lower-level hospital closer to their homes. it is also important to mention that our study had certain limitations. first, it was a single-center, retrospective analysis, and retrospective bias might be present. second, the study only enrolled urological nononcological inpatients admitted to hospital from january 1, 2017, to june 30, 2019, restricting the sample size through an insufficient time span. third, vte in some asymptomatic patients might have gone undetected due to the patients’ normal d-dimer value or due to their being evaluated as low risk by the in-hospital vte risk assessment team. despite the above limitations, we were still able to use some risk factors, such as d-dimer, to build a ram for the early screening of asymptomatic vte. conclusions we found that prior vte, use of anticoagulants or antiplatelet agents before admission, or a d-dimer ≥ 1 were potential risk factors for the patients in our study. we also found that the more appropriate threshold of d-dimer (at least in chinese urological nononcological inpatients) for asymptomatic vte should be elevated to 1.785. in addition, patients with asymptomatic vte asymptomatic venous thromboembolism-li et al. vol 20 no 1 january-february 2023 63 have low compliance with anticoagulation therapy after discharge. urologists should strengthen hospitalization education, carry out targeted instructions, and follow-up regularly after discharge. conflict on interest there are no conflicts of interest. references 1. allgood r, cook j, weedn r, speed h, whitcomb w, greenfield l. prospective analysis of pulmonary embolism in the postoperative patient. surgery. 1970;68:11622. 2. chen e, papa n, lawrentschuk n, bolton d, sengupta s. incidence and risk factors of venous thromboembolism after pelvic urooncologic surgery--a single center experience. bju int. 2016;null:50-3. 3. tyson m, castle e, humphreys m, andrews p. venous thromboembolism after urological surgery. j urol. 2014;192:793-7. 4. kalayci a, gibson c, chi g, et al. asymptomatic deep vein thrombosis is associated with an increased risk of death: insights from the apex trial. thromb haemost. 2018;118:2046-52. 5. violette p, lavallée l, kassouf w, gross p, shayegan b. canadian urological association guideline: perioperative thromboprophylaxis and management of anticoagulation. can urol assoc j. 2019;13:105-14. 6. tikkinen k.a.o., cartwright r, gould m.k., et al. eau guidelines on thromboprophylaxis in urological surgery european association of urology. eur urol. 2017. 7. chan n, stehouwer a, hirsh j, et al. lack of consistency in the relationship between asymptomatic dvt detected by venography and symptomatic vte in thromboprophylaxis trials. thromb haemost. 2015;114:1049-57. 8. grant p, greene m, chopra v, bernstein s, hofer t, flanders s. assessing the caprini score for risk assessment of venous thromboembolism in hospitalized medical patients. am j med. 2016;129:528-35. 9. singh d, lawen j, alkhudair w. does pretransplant obesity affect the outcome in kidney transplant recipients? transplant proc. 2005;37:717-20. 10. meriwether k, antosh d, knoepp l, chen c, mete m, gutman r. increased morbidity in combined abdominal sacrocolpopexy and abdominoplasty procedures. int urogynecol j. 2013;24:385-91. 11. wiznia dh, swami n, nguyen j, et al. patient compliance with deep vein thrombosis prophylaxis after total hip and total knee arthroplasty. hematol rep. 2019;11:7914. 12. marchocki z, norris l, o'toole s, gleeson n, saadeh fa. patients' experience and compliance with extended low molecular weight heparin prophylaxis post-surgery for gynecological cancer: a prospective observational study. int j gynecol cancer. 2019. 13. chan jcy, roche sj, lenehan b, o'sullivan m, kaar k. compliance and satisfaction with foot compression devices: an orthopaedic perspective. arch orthop trauma surg. 2007;127:567-71. 14. matsuoka y, morimatsu h. incidence rates of postoperative pulmonary embolisms in symptomatic and asymptomatic patients, detected by diagnostic images a single-center retrospective study. circ j. 2019;83:432-40. 15. gould mk, garcia da, wren sm, et al. prevention of vte in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidencebased clinical practice guidelines. chest. 2012;141:e227s-e77s. 16. olson sr, shatzel jj, deloughery tg. asymptomatic "breakthrough" thrombosis and anticoagulant "failure": keep calm and carry on. res pract thromb haemost. 2019;3:498502. 17. gainsbury ml, erdrich j, taubman d, et al. prevalence and predictors of preoperative venous thromboembolism in asymptomatic patients undergoing major oncologic surgery. ann surg oncol. 2018;25:1640-5. 18. pedersen mh, wahlsten lr, grønborg h, gislason gh, petersen mm, bonde an. symptomatic venous thromboembolism after achilles tendon rupture: a nationwide danish cohort study of 28,546 patients with achilles tendon rupture. am j sports med. 2019;47:3229-37. 19. yukizawa y, inaba y, kobayashi n, kubota s, saito t. current risk factors for asymptomatic venous thromboembolism in patients undergoing total hip arthroplasty. mod rheumatol. 2019;29:874-9. 20. demelo-rodríguez p, cervilla-muñoz e, ordieres-ortega l, et al. incidence of asymptomatic deep vein thrombosis in patients with covid-19 pneumonia and elevated d-dimer levels. thromb res. 2020;192:23-6. 21. tasaka n, minaguchi t, hosokawa y, et al. prevalence of venous thromboembolism at pretreatment screening and associated risk factors in 2086 patients with gynecological cancer. the journal of obstetrics and gynaecology research. 2020;46:765-73. 22. janus n, mahé i, launay-vacher v, laroche j, deray g. renal function and venous thromboembolic diseases. j obstet gynaecol res. 2016;41:389-95. 23. yamashita y, shiomi h, morimoto t, et al. asymptomatic lower extremity deep vein thrombosis clinical characteristics, management strategies, and long-term outcomes. circ j. 2017;81:1936-44. 24. kesieme, kesieme. deep vein thrombosis: a clinical review. j blood med. 2011;2:59-69. 25. balogun i, roberts l, patel r, pathansali r, kalra l, arya r. clinical and laboratory predictors of deep vein thrombosis after acute asymptomatic venous thromboembolism-li et al. unclassified 64 stroke. thromb res. 2016;142:33-9. 26. shi j, ye j, zhuang x, cheng x, fu r, zhao a. application value of caprini risk assessment model and elevated tumor-specific d-dimer level in predicting postoperative venous thromboembolism for patients undergoing surgery of gynecologic malignancies. j obstet gynaecol res. 2019;45:657-64. 27. shi a, huang j, wang x, et al. postoperative d-dimer predicts venous thromboembolism in patients undergoing urologic tumor surgery. urol oncol. 2018;36:307.e15-.e21. 28. kassim na, farid tm, pessar sa, shawkat sa. performance evaluation of different d-dimer cutoffs in bedridden hospitalized elderly patients. clin appl thromb hemost. 2016;23:998-1004. 29. douma r, le gal g, söhne m, et al. potential of an age adjusted d-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. bmj. 2010;340:c1475. 30. hordern ce, bircher cw, prosser-snelling ec, fraser fk, smith rp. patient compliance with postnatal thromboprophylaxis: an observational study. j obstet gynaecol. 2015;35:793-6. asymptomatic venous thromboembolism-li et al. vol 20 no 1 january-february 2023 65 v07_no_4.pdf point of technique 270 urology journal vol 7 no 4 autumn 2010 endoscopic treatment of a primary prostatic hydatid cyst a mini-invasive therapeutic approach satâa sallami,1 yassine nouira,1 sami ben rhouma,1 monia tanguour,2 karim cherif,1 sabeur rebai,1 nidhameddine kchir,2 ali horchani1 urol j. 2010;7:270 www.uj.unrc.ir keywords: echinococcosis, prostate, cyst, ultrasonography, endoscopy 1department of urology, la rabta 2department of pathology, la rabta corresponding author: satâa sallami, md department of urology, la rabta tunisia tel : +216 2338 7359 e-mail: sataa_sallami@yahoo.fr received april 2010 accepted june 2010 introduction hydatid disease (hd) is a major health problem in developing countries. the disease is endemic in areas where the raising of sheep and cattle is common. tunisia is a country of endemic hydatic pathology in stockbreeding areas with an incidence of 11.3/ 100000.(1) all the organs in the human body may be affected by hd. excluding the liver and the lungs, all of the other organs are considered as uncommon locations. urinary tract involvement is not common, accounting for only 2% to 4% of cases.(2) the localization in the prostate is extremely rare.(3) open surgical management has been the treatment of choice in most cases.(4) in this report, we present, to the best of our knowledge, a new endoscopic approach to treat a prostatic hydatid cyst. case report a 46-year-old man, with no medical history, was referred to our center with lower urinary tract symptoms. he came from the west region of tunisia (endemic zone of hd). he had been complaining of difficult micturition, weak stream, frequency, sensation of incomplete emptying, and terminal dribbling of urine for 3 months. he reported pelvic pain and anejaculation. he also reported passage of soft grape-like material in the urine. digital rectal examination revealed an enlarged prostate with a firm, non tender cystic mass above the prostate. complete blood count, routine blood chemistry, and urinalysis were within the normal limits. chest x-ray was normal. pelvic ultrasonography showed a large pelvic cyst displacing the bladder upward. transrectal ultrasonography showed a 70 × 60 mm cystic mass without any solid components in the pelvis, presumed to be a prostatic cyst, with otherwise normal findings of upper abdominal structures. computed tomography scan of the abdomen and the pelvis revealed a large cyst (80 × 70 × 60 mm) situated below the bladder in the prostate area. it displaced the bladder upward and anteriorly and the rectum posteriorly (figure 1). after administration of intravenous contrast medium, a hyperdense rim around the mass was revealed (figure1). this cystic tumor was prostate cyst—sallami et al 271urology journal vol 7 no 4 autumn 2010 homogeneous with a thick wall bosniak type ii and without any septations. casoni’s intradermal test and enzyme-linked immunosorbent assay were negative. two differential diagnoses were made: utricle cysts or hydatid cysts (hc) of the prostate. technique endoscopic treatment was planned in the lithotomy position under spinal anesthesia. the patient underwent cystoscopy that showed obstruction of the prostatic urethra because of a bulged posterior urethra wall. the posterior wall of the prostatic urethra was incised with cold knife (figure 2). care was taken to spare the bladder neck and verumontanum to prevent retrograde ejaculation and incontinence. thereafter, 10% hydrogen peroxide was injected into the cyst cavity as a scolecidal agent, followed by aspiration of the cyst fluid. the cyst wall was opened (figure 3), accompanied by immediate suction of the residual fluid and daughter cyst, to avoid local spillage. then, the germinal layer of the cyst was completely removed to avoid recurrence. the cyst was washed again with hydrogen peroxide for 5 minutes. all procedures were done under endoscopic direct vision and transrectal ultrasonography guidance. a trans-ureter tube drain was left in the prostatic cavity and a 16f foley catheter in the bladder. results the postoperative course was uneventful, with minimal pain that was relieved with a nonsteroidal anti-inflammatory drug. the urethral figure 2. endoscopic view: incision of the posterior wall of the prostatic urethra. figure 3. endoscopic view: endoscopic aspect of the cystic wall. figure 1 a. computed tomography scan reveals a pelvic cystic mass displacing the bladder anteriorly. b & c. computed tomography scan shows a hyperdense rim around the mass after administration of intravenous contrast medium. a b c prostate cyst—sallami et al 272 urology journal vol 7 no 4 autumn 2010 drain and the foley catheter were removed after 4 days, and the patient voided well with no residual urine. the patient was discharged on the third postoperative day. symptom-free recovery was completed in 3 weeks. histopathologic examination of the cyst wall showed hc with an inner nucleated germinal layer which contained scoleces of the parasite. at sixteen-month follow-up, the patient was symptom-free, with unobstructed urinary flow, no residual urine, and normal ejaculation. ultrasonography did not reveal any recurrence or local complication. discussion hydatidosis (hd) is a human disease with a cosmopolitan distribution caused by the larval form of taenia echinococcus, which lives in the gut of the dog, wild canines, and other carnivorous animals that represent the definitive host, and involves both domestic and wild animals. humans become the accidental intermediate hosts by ingesting taenia eggs. ecchinococcus is endemic in many countries where sheep, dogs, and human live in close contact. the sheep–dog cycle is dominant in north africa, middle east, india, and the sheeprearing areas of south america and australia.(4) hydatidosis can be present in all parts of the human body, but the most affected organs are the liver (65%) and the lungs (25%). involvement of the urogenital tract is rare (2% to 4%). involvement of the pelvic organs such as the prostate and the seminal vesicles is very rare and has been reported in only sporadic cases.(3,5-8) even in endemic countries, involvement of the prostate is extremely rare. in a series of 265 extra-pulmonary hc collected over 18 years in our hospital, bellil and colleagues found that hc involved mainly the kidney (24.1%), the central nervous system (22.6%), and the liver (19.6%). the prostate gland was infected in only two cases (0.75%).(7) the hydatid embryo may reach the retroperitoneum either by passing through the liver into the portal system and hence, into the retroperitoneal lymph or directly from the gastrointestinal tract into the lymphatic system.(9) hydatidosis may affect any ages, but usually affects patients between the third and fifth decades of life who live in endemic areas.(7) there are no specific symptoms and signs, and hc at any location may remain silent for many years. in prostatic infestation, the usual presentations are lower urinary tract symptoms and urinary retention.(6) voiding symptoms were attributable to infravesical obstruction through compression of the prostatic urethra. they may present with perineal pain during ejaculation or defecation, recurrent epididymitis, and hematospermia. we report a case of lower urinary tract symptoms caused by a prostatic hc, which is an uncommon presentation. hydaturia is a pathognomonic sign. it involves passage of grape-like material in the urine, which results from a connection between the cyst and urinary system. this could occur secondary to spontaneous rupture of the cyst into the renal collecting system or after iatrogenic resection of part of the cyst wall through the urethra in case of prostatic involvement.(3,6) diagnosis of hc is based on a combination of imaging techniques and immune diagnostic tests such as the casoni (intradermal), weinberg (complement fixation), indirect hemagglutination, and enzyme-linked immunosorbent assay. however, these serologic tests are not specific for hd, and may be negative as it was in our case.(4) the radiological appearances of hd on ultrasonography, computed tomography scan, or magnetic resonance imaging are very characteristic and these are the modalities of choice in investigating a patient with suspected pelvic hd.(2,5) cysts may be unilocular or multilocular, thin or thick–walled, and with homogenous contents or a fluid–fluid interface. then, as they gradually mature, new cysts form, giving the appearance of a multilocular cyst.(4,5). computed tomography scan or magnetic resonance imaging is very useful not only for the diagnosis in rare locations like the pelvis, but also for accurate localization of the cyst as well as its wall and internal structures.(5) in our case, we relied on the characteristic radiologic appearance prostate cyst—sallami et al 273urology journal vol 7 no 4 autumn 2010 of the cyst in conjunction with the high clinical suspicion. cysts of the prostate gland can be classified into 6 categories, including 1) isolated medial cysts; 2) cysts of the ejaculatory duct; 3) simple or multiple cysts of the parenchyma; 4) complicated infectious or hemorrhagic cysts; 5) cystic tumors; and 6) cysts secondary to a parasitic disease. the differential diagnosis includes prostatic cysts, ejaculatory duct diverticulum, wolffian or müllerian duct remnant cysts, cyst of the vas deferens, the bladder diverticulum, dilated seminal vesicles secondary to infection or obstruction, and less frequently, cystadenoma of the prostate.(10) although hc represents a benign disease, treatment has to be considered mandatory in symptomatic and viable cysts because of the risk of severe complications.(4) open surgery remains the most commonly employed approach for the management of hd. removal of the intact cyst offers the fewest complications and the best prognosis.(4) recently, percutaneous management of renal hd as in hepatic location was described. the technique entails percutaneous puncture of the cyst, aspiration of cyst fluid, introduction of a scolecidal agent, and reaspiration and has provided a useful alternative to surgery.(11) moreover, radiofrequency thermal ablation, in an ex-vivo pilot experimental study in animal models, appears to be very effective in killing hc of explanted liver and lung. but, in vivo studies are required to confirm and validate this new therapeutic approach.(12) in open surgery, the cyst could be removed intact, but during endoscopy, the cyst should be opened. therefore, the cyst cavity should be filled with scolecidal agents in cases where intra-operative opening of the cyst is anticipated. one of the following agents can be used: 10% formalin, 30% sodium chloride, 1% iodine, 0.5% silver nitrate, or hydrogen peroxide.(4) formalin10% is no longer used in the treatment of hc of the liver because it was incriminated in the genesis of postoperative sclerosing cholangitis.(13) we use either 30% saline solution or hydrogen peroxide. systemic antihelmenthic therapy such as albendazole was indicated by some authors to provide sufficient antihelminthic cover in the body to prevent recurrence of the cyst. in a recent prospective study by arif and colleagues on 64 patients having hepatic hc with follow-up of 5 to 6 years, it was concluded that pre-operative albendazole is a safe and an effective adjuvant therapy in the treatment of hydatid liver disease. in patients who did not receive any albendazole therapy, recurrence rate was 18.75% whereas recurrence was 4.16% in patients who received albendazole therapy.(14) laparoscopic treatment of hc was previously reported.(3,15) to the best of our knowledge, we present the first report of endoscopic excision of a prostatic hc. the key steps were injection of a scolecidal agent, aspiration of the cyst contents before opening it, suction of any residual fluid inside the cavity as soon as the cyst is opened, and removal of all the germinal layer of the cyst wall. this approach provids the advantage of complete removal of the cyst wall in a minimally invasive fashion. conflict of interest none declared. references 1. achour n, dammak j, zouari b, et al. [epidemiology of hydatid cyst in tunisia (apropos of 4124 cases of surgically treated patients 1977-1982)]. tunis med. 1988;66:21-5. 2. gharbi ha, hassine w, brauner mw, dupuch k. ultrasound examination of the hydatic liver. radiology. 1981;139:459-63. 3. el-kappany ha, el-nahas ar, el-nahas ha. laparoscopic excision of prostatic hydatid cyst: case report and review of literature. j endourol. 2005;19:290-4. 4. horchani a, nouira y, kbaier i, attyaoui f, zribi as. hydatid cyst of the kidney. a report of 147 controlled cases. eur urol. 2000;38:461-7. 5. saglam m, tasar m, bulakbasi n, tayfun c, somuncu i. trus, ct and mri findings of hydatid disease of seminal vesicles. eur radiol. 1998;8:933-5. 6. houston w. primary hydatid cyst of the prostate gland. j urol. 1975;113:732-3. 7. bellil s, limaiem f, bellil k, et al. [descriptive epidemiology of extrapulmonary hydatid cysts: a report of 265 tunisian cases]. tunis med. 2009;87:123-6. 8. deklotz rj. echinococcal cyst involving the prostate cyst—sallami et al 274 urology journal vol 7 no 4 autumn 2010 prostate and seminal vesicles: a case report. j urol. 1976;115:116-7. 9. selvaggi fp, fabiano g, santacroce s, traficante a. a retrovesical echinococcal cyst: unusual cause of acute urinary retention. eur urol. 1978;4:60-2. 10. galosi ab, montironi r, fabiani a, lacetera v, galle g, muzzonigro g. cystic lesions of the prostate gland: an ultrasound classification with pathological correlation. j urol. 2009;181:647-57. 11. baijal ss, basarge n, srinadh es, mittal br, kumar a. percutaneous management of renal hydatidosis: a minimally invasive therapeutic option. j urol. 1995;153:1199-201. 12. lamonaca v, virga a, minervini mi, et al. cystic echinococcosis of the liver and lung treated by radiofrequency thermal ablation: an ex-vivo pilot experimental study in animal models. world j gastroenterol. 2009;15:3232-9. 13. belghiti j, benhamou jp, houry s, grenier p, huguier m, fekete f. caustic sclerosing cholangitis. a complication of the surgical treatment of hydatid disease of the liver. arch surg. 1986;121:1162-5. 14. arif sh, shams ul b, wani na, et al. albendazole as an adjuvant to the standard surgical management of hydatid cyst liver. int j surg. 2008;6:448-51. 15. seven r, berber e, mercan s, eminoglu l, budak d. laparoscopic treatment of hepatic hydatid cysts. surgery. 2000;128:36-40. running head: bladder and rectal injury during ureteroscopic lithotripsy -yu et al. a case of bladder and rectal injury due to dislodgement of leg brace during ureteroscopic lithotripsy chunhong yu, 1 junjiang liu, 2 qingle xu, 2 helong xiao, 2 bo gao, 2 liuxiong guo, 2 shoubin li 2* 1 department of health examination center, hebei general hospital, shijiazhuang, hebei 050051, china 2 department of urology, hebei general hospital, shijiazhuang, hebei 050051, china dear editor: the lithotomy position is commonly used in urological surgery. dislodgement of the leg brace can lead to accidental injury to patient or surgical staff. if the displacement happened during the operation, it can lead to more serious consequences. bladder and rectal injury due to leg brace dislodgement has not been reported. how to deal with this situation is a challenge for surgeons. a 66-year-old man admitted to the hospital due to "intermittent pain in the left lumbar region for more than 30 days". ct scan showed a calculus in the upper left ureter, measuring about 15 (long diameter) × 9 (transverse diameter) mm. holmium laser lithotripsy was performed after routine perioperative preparation. the right leg brace suddenly fell off during the operation, and the patient’s body slid down consequently, which caused the front end of the ureteroscope pierced the posterior wall of the bladder and the anterior wall of the rectum. the treatment plan was formulated after multidisciplinary discussion during the operation, that is, enteroscopy and enteroscopic closure of rectal perforation after ureteral stent placement and catheterization. a perforation with a diameter of about 3mm was observed in the anterior rectal wall nearly 10 cm from the anus (figure 1). no damage was found in other sites. several titanium clips were used to close the rectal perforation under enteroscope. the patient fasted for 2 days after operation and was given a broadspectrum antibiotic (meropenem). haematological analysis revealed mild leukocytosis (white blood cell count: 9.56×109/l), which returned to normal on postoperative day 3. postoperative pelvic ct examination did not show any significant signs of peritonitis (figure 2). a liquid diet was started on postoperative day 3. the patient was discharged after the urinary catheter was removed two weeks after surgery. rectal injury is mostly caused by nosocomial factors, such as colonoscopy, (1) and bladder perforation usually occurs in case of medical injuries or traumas. (2) if the injury is lower than the peritoneal reflex, it will lead to severe perirectal infection without peritonitis symptoms or vesicorectal fistula, and may be life-threatening. while, there is a lack of consensus on the optimal treatment protocol for rectal injury by now. the traditional treatment is colostomy and colon diversion, and the colon is reduced after the rectal perforation heals.( 3 ) with the development of enteroscopic techniques, small clean perforations in retum can be treated with enteroscopic titanium clip closure.(2) in the present case, no bowel preparation was performed preoperatively, which posed a great challenge to deal with the rectal perforation. we finally treated the rectal perforation with titanium clip closure and bladder perforation with indwelling catheter. this situation and corresponding treatment measures has not been reported before, and this reminds us that small perforations, even in the absence of bowel preparation, can be considered for a one-stage colonoscopic management of the perforation to avoid more invasive management. there are several reasons for the successful management of this rare case. firstly, early detection and timely treatment is the key point. according to literature reports, the intestinal perforation found within 24 hours after colonoscopy is tends to be repaired by one-stage intestine neoplasty. while, the perforation found 24 hours later is more likely to be operated by enterostomy.(4) secondly, the perforation caused by ureteroscope is small, which makes it possible to seal it with titanium clip under enteroscope. finally, the rectal injury is non pyrogenic. if it is a pyrogenic injury, it will lead to tissue degeneration and difficult wound healing. in conclusion, intraoperative emergency is an uncommon but serious event. routine checking the relevant equipments should be mandatory to ensure the safety of patients and medical staffs. proper treatment plan is beneficial to the rehabilitation of patient and can avoid doctor-patient disputes. conflict of interest no potential conflict of interest was reported by the authors. reference 1. kones o, akarsu c, acar t, alis h. endoscopic repair of rectal perforation due to colonoscopy with a clamp method. j turksurg. 2018;34:80-82. 2. matlock ka, tyroch ah, kronfol zn, mclean sf, pirela-cruz ma. blunt traumatic bladder rupture: a 10-year perspective. j am surg. 2013;79:589-593. 3. benjelloun eb, ahallal y, khatala k, souiki t, kamaoui i, taleb ka. rectal impalement with bladder perforation: a review from a single institution. j urol ann. 2013;5:249-254. 4. iqbal cw, cullinane dc, schiller hj, sawyer md, zietlow sp, farley dr. surgical management and outcomes of 165 colonoscopic perforations from a single institution. arch surg. 2008;143(7):701-6. corresponding author: shoubin li, md; department of urology, hebei general hospital, shijiazhuang, hebei 050051, china. tel: +86 0311 85988751, e-mail: hbghurology@163.com figure legends: mailto:hbghurilogy@163.com figure 1. a perforation with a diameter of about 3mm was observed in the anterior rectal wall (indicated by an arrow) under colonoscopy. figure 2. ct scan shows a nodular high-density shadow (titanium clips) in the rectal cavity, without fluid or gas accumulation around the rectum. editorial 191urology journal vol 4 no 4 autumn 2007 editorial independence surrounding controversies urol j. 2007;4:191. www.uj.unrc.ir the world association of medical editors defines editorial independence as: full control over the editorial content of the journal, regardless of conflicts with the commercial success of the publication or the owners’ interests.(1) fortunately, our editorial advisory board recently met to discuss this issue. separation of the editorial decisions from financial issues is essential to ensure editorial independence. there are outright threats to continued editorial independence. we reaffirm the core value of editorial freedom. the committee on publication ethics has published a draft code of conduct for medical editors proposing a framework in detail for the relationship between the journal editors and the owners.(2) the role of the editors is to ensure accuracy of the material published for which they have to rely on the authors as well as an efficient review process. authors should submit the ethical clearance or approval by the ethics committee for any research work. however, the editor is still responsible for checking out if there is any unethical work submitted for publication. the controversy surrounding most of journals appears to focus on whether the associations which are the owners of a journal can offer complete independence to its editors. for instance, one decisive issue is advertising; policy and practices with respect to advertising and sponsorship must be clear. to date, no systematic review has been done to evaluate the level of separation of advertising and editorial decisions.(3) editorial decisions should not be influenced by advertising or sponsorship, being made without consideration of the advertising or sponsorship scheduled to appear. we emphasize that separation of editorial decisions from financial issues is essential to ensure editorial independence. the other issue that must be dealt with by the editor is scientific misconduct. obviously, the goal of a scientific journal, searching for scientific truths, should not be confused with those of the public press. usually, editors are the first to detect any possible misconduct by all the people involved in the course of publication of any article. while they protect the confidentiality of unconfirmed cases, they have the duty to scrutinize, inform the authors, and ask for explanation. on the other hand, all reasonable critical responses to any published material should be published in the form of a “letter to editor,” unless the editors have a convincing reason for not doing so. in our journal’s policy, complying with the guidelines of the international committee of medical journal editors(4) has been adopted, in which the definition of editorial freedom by the world association of medical editors has been considered(1): editors-in-chief and the owners of their journals both want the journals to succeed but they have different roles. the editorsin-chief ’s primary responsibilities are to inform and educate readers, with attention to the accuracy and importance of journal articles, and to protect and strengthen the integrity and quality of the journal and its processes. owners (whether professional associations or for-profit companies) support the core values and policies of their organization and are ultimately responsible for all aspects of publishing the journal, including its staff, budget, and business policies. the relationship between owners and editors-inchief should be based on mutual respect and trust, and recognition of each other’s authority and responsibilities. conflicts can damage both the intellectual integrity and reputation of the journal and its financial success. thus, the editor-in-chief will take full responsibility for editorial content and failure to autonomously scrutinize and investigate any possible misconduct corresponds to a shortcoming on the editor’s part. mohammad reza safarinejad associate editor, urology journal references 1. world association of medical editors [homepage on the internet]. wame policy statements [cited 2007 oct 1]. available from: http://www.wame.org/wamestmt.htm 2. committee on publication ethics [homepage on the internet]. guidelines on good publication practice [cited 2007 oct 1]. available from: http://www. publicationethics.org.uk/reports/1999/index_html 3. macdonald n, downie j. editorial policy: industry funding and editorial independence. cmaj. 2006;174:1817. 4. international committee of medical journal editors [homepage on the internet]. uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication [cited 2007 oct 1]. available from: http://www.icmje.org unclassified a proposal for data registry system for urologic cancers in iran fatemeh simforoosh1, nasser simforoosh2, mehdi dadpour1, mohammad hadi radfar2* purpose: data registries are organized systems that facilitate the collection, storage, and analysis of data related to a specific disease in a defined population. here we introduce a data registry system which was designed to cover the four most common urologic cancers (prostate, bladder, renal, and testis). materials and methods: all contributing centers can enter data into the system after logging in with their unique usernames and passwords. in this system, the information of each individual patient will be entered in several structured forms covering various steps of management of the patients. results: our proposed registry is an interactive, web-based database designed to collect complete data of patients with common urological cancers. we devised a council that functions as the central committee that will initiate, supervise, and monitor all steps of the projects including data collection, data audit, as well as data analysis and publication. to facilitate manuscript publication, the system will provide assistance and support throughout all the steps of statistical analysis and manuscript preparation. conclusion: this proposed registry can have a national target and is designed to provide evidence-based information that could support strategic planning and national multi-centric studies. keywords: disease-specific outcomes; epidemiology; population-based; prospective registries; urologic malignancies introduction in recent years, cancer has become one of the most common causes of mortality in almost all countries across the globe. cancer is the first and second leading cause of death in developed and developing countries, respectively(1). despite the recent advancements in cancer treatment, cancer-related complications contribute to the death of many people annually(2). data registry has an important role in cancer surveillance. it provides an overview of where we stand in terms of cancer prevalence and incidence(3). subsequently, this data can be used to plan and evaluate cancer control strategies and interventions(4). nevertheless, single center cohort studies are non-optimal because of strict inclusion and exclusion criteria, highly selective patient groups, as well as feasibility and cost issues (5). to overcome this limitation, during the past two decades, cancer registry systems have been introduced. these organized systems facilitate collection, storage, and analysis of data related to a specific disease in a defined population(6). in recent years, the prevalence of cancer has been increasing in iran(3). in fact, cancer is the second most common chronic non-communicable disease in iran, and the most prevalent cause of death after heart diseases, accidents and other natural phenomena(7). advances in diagnostic methods, rapid industrialization and modernization, and significant life style and environmental changes are thought to account for this rise in cancer 1shahid labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. 2urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. mhadirad@yahoo.com received april 2021 & accepted june 2021 prevalence(8). prostate, renal, bladder, and testis cancer are the most common urologic malignancies. thus far, many modalities have been introduced to prevent, treat and improve the long-term outcome of these cancers. although much progression has been made to decrease disease progression and improve cancer-specific survival, there is still a need for further research and studies(9-11). it is worthy to note that prostate and bladder cancer are among the five most common non-cutaneous cancers in iranian males(12). after realizing the importance of the presence of a national cancer registry, a data registry system was designed by the urology department of shahid labbafinejad hospital to cover the four most common urologic cancers (prostate, bladder, renal and testis). the objective of this data registry is to collect data related to urologic cancers at a national level and to provide the required evidence for strategic planning. the goals can be mentioned in more detail as the following: creating a national network of clinical centers and urologists, providing strong infrastructure and support for urology research, creating a national platform that enables prospective and precisely-designed studies to be performed at a large scale, and collection and dissemination of national data related to urologic cancers and urology practice in iran. urology journal/vol 19 no. 3/ may-june 2022/ pp. 238-240. [doi:10.22037/uj.v18i.6790] vol 19 no 3 may-june 2022 100 materials and methods all contributing centers can enter data into the system after logging in with their unique usernames and passwords. in this data registry system, the information of each individual patient will be entered in several structured forms covering various steps of the management of patients. to design data entry forms containing a comprehensive set of important characteristics and variables impacting on diagnosis, treatment algorithms, and follow up of each cancer, authors searched in pubmed and studied several published articles focused on different aspects of each cancer. the content validity of the questionnaire for data entry has been verified by three urologists after the summarization of the retrieved articles. as an example of data collection forms, prostate cancer forms and its included variables are briefly described here. prostate cancer data is collected in ten forms including general data, preoperative data, trus biopsy, radical prostatectomy operative data, pathology, post-operative data, follow up, radiotherapy, hormone therapy, and summary. each form constitutes of several related variables and provides comprehensive data regarding certain aspects of the disease (supplementary table 1). these data have already been recorded electronically at the time of admission with patients’ permission and the data accuracy is confirmed by the relevant physicians. at the same time, patients are informed that their information will be entered into the data registry system. we intend to recheck the data accuracy at random intervals through re-interviewing random patients and visiting the medical centers which recorded the information. all of these data will be available on the website for the defined users. furthermore, the program provides reports from entered data in excel format which facilitates statistical evaluation of the data. results urological cancers data registry (ucdr): the ucdr is an interactive, web-based data registry system designed to collect complete data of patients with common urological cancers. ucdr is easily accessible on the web and can be used by several centers around the country. hence, multicentric prospective data on each cancer patient can be recorded from the first visit until the last follow up. moreover, the general structure of the data registry system can be used to design detailed registry for any other disease in the field of urology. ucdr council: iucd council is the central committee that will initiate, supervise, and monitor all steps of the projects including data collection, data audit, as well as data analysis and publication. all content of the website is subject to copyright owned by ucdr. iucd council will check the validity of submitted data both online and on-site. ucdr will check the validity of data on-site by randomly assigning supervisors to visit the contributing centers. publication: to facilitate manuscript publication, ucdr will provide assistance and support throughout all the steps of statistical analysis and manuscript preparation. ucdr will assign an epidemiologist/biostatistician and a medical editor to actively assist in preparing the manuscripts. after data collection, subjects of interest for analysis will be suggested by the contributors and ucdr council. the council will consider the suggestions and will finally select the specific subject for analysis. the contributor who has suggested the chosen subject and/or the council will be responsible for performing statistical analysis and preparing the final manuscript. discussion a healthcare data registry system as a tool for collection and storage of data related to certain diseases and patient management constitutes of uniform structured forms containing comprehensive data elements. the data registry system facilitates performing precise research projects in various aspects of the included diseases and their management. also, healthcare data registry systems help diplomacy makers to design effective community-oriented programs based on the real situation of the country. the clinical research office of the endourological society (croes) and international registry in organ donation and transplantation (irodat) are two international data registries in the field of endourology and organ donation providing data registry systems and supporting research projects. a global network is provided by the clinical research office of the endourological society (croes) to promote and support high quality international patient-centered research in a transparent way and to make the implementation of research projects possible. it provides a web-based data collecting and management system and prepares the infrastructure to manage such multicenter studies, including evaluation of the quality of the projects, data collection, statistical analysis and preparation of manuscripts. through the website: www.croesoffice. org. the users all over the world can collect data with a single username and password for all croes studies. many new projects can be defined after being approved by the involved steering committee. to ensure a reliable dataset, all data are controlled daily by croes data managers and data collection progress is continuously monitored. global percutaneous nephrolithotomy (pcnl) study, global ureterorenoscopy (urs) study, global greenlight laser study, global renal mass study, and global narrow band imaging (nbi) study are five projects that croes is conducting(13). international registry in organ donation and transplantation (irodat) is the first registry which contains statistics on deceased/living donors and transplants. eighty six countries with organ donation or transplantation activity have submitted data to irodat since 1998. the data from each participant country is inserted into the web form data registry system (https://www. irodat.org) and could be verified by contacting the official reporter when needed. the irodat team could provide specialized reports in case of specific investigations and studies(14). taking examples from similar national and international health registry systems, we designed a data registry system in the field of four common urology cancers to facilitate research, and community-oriented policy making for effective management of the cancers. conclusions data registry has an important role in cancer research, and can aid in the development and evaluation of cancer control strategies. by developing cancer registry systems, we can collect and store data of specific malignancies and use it for future planning. also, these systems allow us to perform data analysis and gain information data registry system for urologic cancers-simforoosh et al. vol 19 no 3 may-june 2022 239 unclassified 238 about the epidemiology of cancers, as well as to generate research ideas with the aim of improving cancer management and survival. iucd, as a national cancer registry system, is designed to provide evidence-based information that could support strategic planning and national multi-centric studies. acknowledgment research reported in this publication was supported by elite researcher grant committee under award number 958889 from the national institute for medical research development (nimad), tehran, iran. conflict of interest all authors declare that they have no conflict of interests references 1. center m, siegel r, jemal a. global cancer facts & figures. atlanta: american cancer society. 2011;3:1-52. 2. mohammadi g, akbari me, mehrabi y, ghanbari motlagh a. quality assessment of the national cancer registry in iran: completeness and validity. int j cancer manag. 2016;9:e8479. 3. basiri a, eshrati b, zarehoroki a, et al. incidence, gleason score and ethnicity pattern of prostate cancer in the multiethnicity country of iran during 2008-2010. urol j. 2020;17:602-6. 4. white mc, babcock f, hayes ns, et al. the history and use of cancer registry data by public health cancer control programs in the united states. 2017;123 suppl 24:4969-76. 5. dahm p, n'dow j, holmberg l, hamdy f. the future of randomised controlled trials in urology. eur urol. 2014;66:1-3. 6. gandaglia g, bray f, cooperberg mr, et al. prostate cancer registries: current status and future directions. eur urol. 2016;69:9981012. 7. dolatkhah r, somi mh, kermani ia, et al. increased colorectal cancer incidence in iran: a systematic review and meta-analysis. bmc public health. 2015;15:997. 8. farhood b, geraily g, alizadeh a. incidence and mortality of various cancers in iran and compare to other countries: a review article. iran j public health. 2018;47:309-16. 9. tannock if. improving treatment for advanced prostate cancer. new england journal of medicine. 2019;381:176-7. 10. gillessen s, attard g, beer tm, et al. management of patients with advanced prostate cancer: report of the advanced prostate cancer consensus conference 2019. eur urol. 2020;77:508-47. 11. graham j, heng dyc, brugarolas j, vaishampayan u. personalized management of advanced kidney cancer. am soc clin oncol educ book. 2018;38:330-41. 12. rafiemanesh h, rajaei-behbahani n, khani y, et al. incidence trend and epidemiology of common cancers in the center of iran. glob j health sci. 2015;8:146-55. 13. van rees vellinga s, de la rosette j. the croes data management system: a glimpse behind the scenes. j endourol. 2011;25:1-5. 14. manyalich m, gómez mp, reis dl. international registry in organ donation and transplantation (irodat) 2016 worldwide data. transplantation. 2018;102:s800. outcome of surgery in patients with penile fractures-mazdak et al. vol 19 no 2 march-april 2022 153unclassified 240 urol_montage.pdf case report 50 urology journal vol 6 no 1 winter 2009 wünderlich syndrome from a malignant epithelioid angiomyolipoma miguel angel arrabal-polo,1 miguel arrabal-martin,1 francisco palao-yago,1 antonio jiménez-pacheco,2 olga fernanda garcia-galvis,3 armando zuluaga-gomez1 urol j. 2009;6:50-3. www.uj.unrc.ir keywords: kidney neoplasms, angiomyolipoma, hemorrhage, epithelioid cells, renal cell carcinoma 1department of urology, san cecilio university hospital, granada, spain 2department of urology, santa ana hospital, motril, granada, spain 3department of pathology, granada university, granada, spain corresponding author: miguel angel arrabal-polo, md avenida doctor oloriz, 18. pc 18012, granada, spain tel: +34 95 802 3084 fax: +34 95 802 3084 e-mail: arrabalp@ono.com received august 2008 accepted december 2008 introduction angiomyolipoma of the kidney has classically been considered as a tumor of the connective tissue composed of fat, vascular tissue, and smooth muscle. in most cases, it is a tumor with benign behavior that may appear sporadically or associated with tuberous sclerosis syndrome. macroscopically, these tumors are greyish yellow in color, and under an optical microscope, they are characterised by presenting the three components described. in recent years, several authors have published cases of epithelioid angiomyolipomas characterized by a minimal presence of fat in the tumor, positive for the melanoma-specific antigen, hmb45,(1) and on occasion, positive for desmin, melan-a, and others.(2,3) computed axial tomography and nuclear magnetic resonance studies hardly differentiate epithelioid angiomyolipomas from renal cell carcinoma.(3) we present a case of malignant epithelioid angiomyolipoma in a woman with no tuberous sclerosis, the debut of which was spontaneous retroperitoneal hemorrhage causing hypovolemic shock that required left radical nephrectomy. case report a woman aged 47 years old with no medical background of interest presented to the accident and emergency service complaining of sudden spontaneous pain in the left renal fossa and left abdomen, accompanied by nausea and vomiting. during clinical examination, blood pressure of 120/65 mm hg and a heart rate of 90 per minute were recorded, and the pain was localized in the left half of the abdomen and left renal fossa, with no signs of peritoneal irritation. on blood tests, hemoglobin was 9.5 g/dl; hematocrit, 29%; platelet count, 230 × 109/l; and hematite, 3 640 000/μl. urine sediment was normal. the most significant finding of a single abdominal radiography was the lack of vision of the left psoas line. treatment was begun with serum therapy, analgesia, and clinical observation. one hour later, the patient presented arterial hypotension (90/50 mm hg), tachycardia (130 per minute), peripheral hypoperfusion, and a generally poor condition, which was controlled by administering 1000 ml of crystalloids. abdominopelvic computed axial tomography revealed retroperitoneal hematoma from the left subdiaphragmatic region to the left pelvic region, with wünderlich syndrome from a malignant angiomyolipoma—arrabal-polo et al urology journal vol 6 no 1 winter 2009 51 morphological changes in the upper pole of the left kidney (figure 1). a second blood test showed a decrease in the hematite count to 2 730 000/μl; hemoglobin, to 7 g/dl; and hematocrit, to 21%. three hematite units were transfused. left lumbotomy was performed, extracting a large quantity of serohematic clots and liquid, with hemorrhage persisting from the upper half of the left kidney that could not be controlled, making it necessary to perform a pedicle ligature and left nephrectomy. postoperatively, the patient progressed well. control clinical studies revealed only an increase in the tumor marker ca125 (70.45 ui/ml; reference level, < 35 ui/ ml), with all other analytical parameters within the reference ranges (hematite count, 4100000/μl; hemoglobin, 13.4 g/dl; hematocrit, 37%; urea, 25.4 mg/dl; creatinine, 0.8 mg/dl; and prolactin, 22.9 ng/ml). histology of the sample revealed that the tumor was composed of thick-walled smooth-muscled blood vessels, most notably in the perivascular areas, mixed with mature fatty tissue (figure 2). sandwiched between these two components, solid areas of large mononuclear or multinuclear areas were observed, with a pleomorphic hyperchromatic nucleus, prominent nucleolus, and abundant cytoplasm, clear in most cases, and eosinophilic in others. high atypical mitotic activity and necrotic areas were also seen, showing evident proliferative activity and malignance. immunohistochemical study showed reactivity in the epithelioid cells for hmb-45, melan-a, and smooth-muscle actin and desmin, with a greatly figure 1. a, presence of hematoma in the left subdiaphragmatic region. b, nodule of fatty density, 4 × 3 × 4.5 cm, at the upper pole of the left kidney, suggesting angiomyolipoma, with major perirenal hematoma displacing forward towards the pancreas, stomach, spleen, and left kidney. hypodense image suggests cyst of the liver in segment 6. c, retroperitoneal hematoma displacing left kidney and pancreas with circumaortic left kidney vein. d, image of the same retroperitoneal hematoma extending towards the pelvis with free liquid in the douglas space. wünderlich syndrome from a malignant angiomyolipoma—arrabal-polo et al 52 urology journal vol 6 no 1 winter 2009 increased cell proliferation index (ki67). twelve months after the treatment, the patient was free of disease. discussion owing to the difficulty of differential diagnosis of renal angiomyolipoma from other tumoral entities of the kidney, the hmb-45 positivity in renal angiomyolipomas was first proposed in 1991, favoring its histological and immunohistochemical differentiation.(1) in 1947, apitz described perivascular epithelioid cells for the first time as abnormal myoblasts inside angiomyolipomas.(4) thereafter, these cells began to be described more accurately, proving positive for hmb-45, desmin, melan-a, hmsa-1, and other markers, leading to the proposal of a new tumoral entity called perivascular epithelioid cell tumor (namely, pecoma).(5) the epithelioid variety of angiomyolipoma has been defined histologically as the presence of pure epithelioid cells with positive melanogenesis markers, without the presence of adipocytes or vascular tissue. however, some classical angiomyolipomas present epithelioid cells with an atypical component, a high proliferative index and focal necrosis indicating a malign tumoral process that may be considered as epithelioid angiomyolipoma.(5) genetic studies have been performed confirming the existence of allelic disorders in chromosome 16p (gene tsc2), which may alter the route rev/mtor/p70s6k and are present in pecomas and angiomyolipoma.(5,6) the expression of such growth factors as cd117 or, as in our case, ki67 has been observed, as well as figure 2. a, staining by hematoxylin-eosin shows thick-walled blood vessels, smooth muscle, and mature fatty tissue with atypical cells of epithelioid appearance. b, immunohistochemistry with reactivity for smooth-muscle actin. c, immunohistochemistry with focal reactivity for hmb-45. d, immunohistochemistry with focal reactivity for melan-a. wünderlich syndrome from a malignant angiomyolipoma—arrabal-polo et al urology journal vol 6 no 1 winter 2009 53 disorders in the tumor-suppressant gene p53.(7,8) in one published case, the presence of very high prolactin levels was seen, which returned to normal after the tumor was removed.(2) it is far from easy to carry out an epithelioid angiomyolipoma diagnosis using imaging techniques, particularly when it comes to differentiating it from renal cell carcinoma. for this reason, radical nephrectomy is usually indicated after computed axial tomography or nuclear magnetic resonance studies. the main treatment applied in such patients is usually radical nephrectomy, with adjuvant therapy in these cases being the subject of some controversy, although these tumors have been described as being chemosensitive to doxorubicin, d-carbacin, ifosfamide, cyclophosphamide, and cisplatin.(3) cases have been described of metastasis extending into the liver, bone, and retroperitoneum either during diagnosis or after a period of monitoring,(9) making it vitally important to establish a clear adjuvant therapy for this patient group. the incidence of epithelioid angiomyolipoma is thought to be underestimated owing to the difficulties to date differentiating it in diagnosis from liver cell carcinoma, with many diagnoses given as liver cell carcinoma actually being epithelioid angiomyolipoma.(10) we consider the exploration of preoperative differential diagnosis of this pathology using imaging techniques, enabling us to apply a better therapeutic strategy. great progress has been made in the histological and immunohistochemical fields, making it easier for us to arrive at microscopic diagnosis, although we still need further studies to allow the etiology and etiological factors involved, adjuvant therapy and short-term and long-term prognosis for these patients to be determined. conflict of interest none declared. references 1. pea m, bonetti f, zamboni g, et al. melanocytemarker-hmb-45 is regularly expressed in angiomyolipoma of the kidney. pathology. 1991;23:185-8. 2. quek ml, soni ra, hsu j, skinner dg. renal epithelioid angiomyolipoma associated with hyperprolactinemia. urology. 2005;65:797. 3. park hk, zhang s, wong mk, kim hl. clinical presentation of epithelioid angiomyolipoma. int j urol. 2007;14:21-5. 4. apitz k. die geschwulste und gewebsmissbildungen der nierenrinde. ii midteilung. die mesenchymalen neubildungen. virchows arch. 1943;311:306-27. 5. martignoni g, pea m, reghellin d, zamboni g, bonetti f. pecomas: the past, the present and the future. virchows arch. 2008;452:119-32. 6. pan cc, chung my, ng kf, et al. constant allelic alteration on chromosome 16p (tsc2 gene) in perivascular epithelioid cell tumour (pecoma): genetic evidence for the relationship of pecoma with angiomyolipoma. j pathol. 2008;214:387-93. 7. makhlouf hr, remotti he, ishak kg. expression of kit (cd117) in angiomyolipoma. am j surg pathol. 2002;26:493-7. 8. ma l, kowalski d, javed k, hui p. atypical angiomyolipoma of kidney in a patient with tuberous sclerosis: a case report with p53 gene mutation analysis. arch pathol lab med. 2005;129:676-9. 9. gupta c, malani ak, gupta v, singh j, ammar h. metastatic retroperitoneal epithelioid angiomyolipoma. j clin pathol. 2007;60:428-31. 10. pea m, bonetti f, martignoni g, et al. apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. am j surg pathol. 1998;22:180-7. v08_no_1_print_3.pdf urological oncology 43urology journal vol 8 no 1 winter 2011 predictive factors for prostatic involvement by transitional cell carcinoma of the bladder ali tabibi, nasser simforoosh, mahmoud parvin, hamidreza abdi, ahmad javaherforooshzadeh, farhat farrokhi, mohammad hossein soltani purpose: to evaluate the predictive factors for prostatic involvement according to the bladder transitional cell carcinoma (tcc) characteristics in a prospective study. materials and methods: hundred patients with the bladder tcc who had undergone standard radical cystoprostatectomy were enrolled in this study. a number of factors, including vascular and perineural invasion, number of tumors, maximum diameter of the tumor, presence of carcinoma in situ, distance between the tumor and the bladder neck, grade, and local stage of the tumor were recorded, and their relationships with prostatic involvement were studied. in addition, hydronephrosis and age of the patients were included in the analysis. results: the mean age of the patients was 62.6 ± 10.8 years. of a total of 100 patients, 21 (75%) were found to have prostatic involvement with tcc. univariate statistical analysis showed that vascular invasion and the distance between the tumor and the bladder neck were significantly related to the prostatic involvement (p = .001 and p < .001) and tumor stage had relatively low p value (p = .08). in the logistic regression, only the distance between the tumor and the bladder neck was found to be significantly related to the prostatic involvement (p = .004). conclusion: this study demonstrated that distance between the tumor and the bladder neck is a predictive factor for prostatic involvement; hence, prostate-sparing or capsule-sparing cystectomy in patients with tumors in short distances from prostatovesical junction is not rationale and should be avoided. urol j. 2011;8:43-7. www.uj.unrc.ir keywords: urinary bladder neoplasms, transitional cell carcinoma, cystectomy, prostate urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran corresponding author: ali tabibi, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: dralitabibi@gmail.com received october 2009 accepted june 2010 introduction primary transitional cell carcinoma (tcc) in the prostate is rather uncommon (3%) and the prostate is usually involved by expansion of the bladder cancer.(1) previously, prostatic involvement through bladder tcc has been reported in 7% to 48% of the patients undergoing radical cystectomy.(1-3) a number of studies have evaluated long-term survival, organ preservation protocol, and functional outcomes of surgery in invasive bladder cancer. they concluded that radical cystoprostatectomy is an ideal alternative to treatment of muscleinvasive bladder cancer.(4,5) sexual dysfunction, including erection, ejaculation, and fertility issues, due to cutting of neurovascular bundle during excision of the prostate and incontinency are the most prostatic involvement by tcc of the bladder—tabibi et al 44 urology journal vol 8 no 1 winter 2011 important concerns in this procedure; hence, modified techniques have gained broad attention.(5) the use of nerve-sparing radical cystectomy in selected patients has led to proper clinical and functional outcomes without compromising cancer control.(6) preservation of sexual function and continence improvement, especially for nighttime,(7) have encouraged urologists to perform prostate-sparing radical cystectomy with neobladder reconstruction.(8) using prostatesparing technique without suitable case selection through determining prognostic factors before operation leads to risky events, such as higher local and distant recurrences.(9) in this prospective study, we decided to complete our previous survey performed in 2005(10) by using a larger group of patients and evaluating the relationship between different variables of the bladder tcc and the risk of the prostatic involvement. materials and methods between january 2003 and february 2007, this prospective study was performed in shahid labbafinejad medical center. all patients with proven bladder tcc who underwent standard radical cystoprostatectomy with en bloc excision of the bladder, the prostate, and the seminal vesicles were included in this study. patients with a history of previous surgery on the bladder or the prostate, systemic chemotherapy, and previous pelvic or lower abdominal radiotherapy were excluded. one hundred patients, who had the inclusion criteria, were enrolled in the study and written informed consents were taken from each of them. pathologic examination was performed by a single pathologist. characteristics of the tumors, including the number of the tumors (single or multiple), maximum diameter of the tumors in centimeter, tumor distance from the bladder neck (td), existence of carcinoma in situ (cis), tumor grade (low or high), local stage (non muscle invasive, t2, t3, and t4), and vascular and perineural invasion were also recorded. prostatic involvement by tcc was also assessed by the same pathologist. presence of hydronephrosis was assessed by pre-operative ultrasonography or computed tomography scan. prostatic involvement was classified into three subgroups, including urethral invasion, stromal invasion, or both. statistical analysis was performed by spss (statistical package for the social sciences, version 13, spss inc., chicago, illinois, usa) software. relationship between each single factor and the prostatic involvement was evaluated by chi-square test. the differences in age and td between the patients with or without prostatic involvement were analyzed by the student’s t test and kolmogorov-smirnov test. all factors that assumed to have significant effects were analyzed by using logistic regression (backward wald method) afterwards. the receiver operating characteristic curve was used to select a cutoff point with the best diagnostic accuracy for continuous variables. results the mean age of the patients was 62.6 ± 10.8 years at the time of surgical operation. of a total of 100 patients, 28 had prostatic involvement: 21 (75%) subjects had tcc in their prostates and 7 (25%) had adenocarcinoma. of 21 patients with prostatic tcc, 8 (38.2%) had tcc in the urethra, 6 (28.5%) in the stroma, and 7 (33.3%) in both. the characteristics of the patients and the tumors in the two groups of positive and negative prostatic involvement are shown in table. univariate analysis demonstrated that from the assessed ten factors, only vascular invasion (p = .001; odds ratio, 5.13; 95% confidence interval, 1.85 to 14.24) and td (p < .001; odds ratio, 7.74 ; 95% confidence interval, 2.37 to 25.26) had significant relationships with the prostatic involvement. in the second step, vascular invasion and td in addition to the tumor stage were entered into the logistic regression model. we calculated tumor stage in association with two aforesaid factors because of its relatively small p value (p = .08) and the fact that it had been found to be a significant factor in some previous studies.(11) the logistic regression analysis showed that only td had a significant relationship with the prostatic involvement (p = .004). the receiver operating characteristic curve showed prostatic involvement by tcc of the bladder—tabibi et al 45urology journal vol 8 no 1 winter 2011 high sensitivity and specificity (area under the curve: 0.78 – sensitivity: 81.0%, specificity: 74.6%) (figure), and the odds ratio for a td less than 0.65 cm was 7.74. discussion invasive bladder tcc as a life-threatening disease is associated with high mortality rate if left untreated. aggressive surgical treatment by performing radical cystectomy, in comparison with the organ preservation modality and chemoradiotherapy, has better long-term survival and lower local recurrences.(12,13) previously, patients who underwent radical cystoprostatectomy would suffer from comprehensive morbidity, such as incontinency, sexual dysfunction, and infertility problems, especially if they were young; thus, a large number of patients refused to accept this treatment. after considerable advance in surgical techniques and using orthotopic urinary diversion with acceptable functional outcomes and significant impact on the quality of life in the majority of patients,(14) the patients were encouraged to undertake radical cystectomy. nerve-sparing radical cystoprostatectomy has been performed with good results and improved sexual function without compromising the cancer control.(6) prostate-sparing cystectomy has been advocated rationally because of preserving the potency, fertility, and continency. average incidence of prostatic involvement by tcc by routine selective sections was 21.8% (nearly similar to our result: 21%) and 36.7% by whole mount sections.(15) pagano and colleagues defined two distinct clinicopathological features for prostatic involvement by bladder tcc: stromal invasion either by extravesical extension of the bladder tumor (pt4a) or secondary to prostatic urethral involvement.(16) schellhammer and associates revealed that long-term survival significantly would depend on the presence prostatic involvement† factors positive negative p odds ratio 95% confidence interval age, mean, y 62.8 ± 11.45 62.5 ± 10.7 .92 … -5.96 to 5.42 td, mean, cm 0.40 ± 0.38 1.34 ± 1.13 < .001 7.74 2.37 to 25.26 tumor stage non muscle invasive 3 (14.3) 22 (27.8) t2 9 (42.9) 35 (44.3) t3 5 (23.8) 19 (24.1) t4 4 (19.0) 3 (3.8) .08 … … cis 7 (33.3) 24 (30.4) .79 1.14 0.41 to 3.20 vascular invasion 13 (61.9) 19 (24.1) .001 5.13 1.85 to 14.24 perineural invasion 7 (33.3) 22 (27.8) .62 1.29 0.46 to 3.63 multifocal disease 12 (57.1) 31 (39.2) .14 3.14 0.78 to 5.47 high grade disease 15 (71.4) 47 (59.5) .32 1.07 0.60 to 4.85 hydronephrosis 8 (38.1) 27 (34.2) .74 1.18 0.44 to 3.21 17 (81.0) 66 (83.5) .50 0.84 0.24 to 2.90 characteristics of patients with bladder tcc* *tcc indicates transitional cell carcinoma; td, tumor distance from the bladder neck; and cis, carcinoma in situ. †values in parentheses are percents. receiver operating characteristic curve shows the sensitivity and 1 specificity of the tumor distance from the bladder neck for the prostatic involvement by transitional cell carcinoma. prostatic involvement by tcc of the bladder—tabibi et al 46 urology journal vol 8 no 1 winter 2011 or absence of stromal invasion (22% versus 50%).(17) njinou ngninkeu and coworkers in a retrospective study on 76 patients demonstrated that invasion by direct extension from the prostatic urethra has better prognosis than extension from the bladder wall (49% versus 29% free survival rate).(18) but ayyathurai and colleagues emphasized that depth of invasion (stromal versus non-stromal) is more important than mode of invasion.(19) spitz and associates performed the prostatesparing approach on 4 patients for the first time.(20) vallancien and coworkers treated 100 patients with the bladder tcc by this technique; however, they did not delineate predictive factors. therefore, indications for excluding the patients were based on abnormal prostate biopsy according to abnormal digital rectal examination or serum prostate-specific antigen.(21) hautmann and stein matched the pathological stage of 252 patients who underwent prostatesparing procedure with the other 646 patients who had standard radical cystectomy. they inferred that distant recurrence in the first group was twice the second one.(9) in another study, 25 patients who underwent the prostate-sparing cystectomy with normal serum level of prostatespecific antigen and negative transurethral resection of the prostate had worse cancer control and better functional outcomes than standard radical cystectomy.(22) there are different comments on the role of pre-operative transurethral biopsy of the prostate to detect the prostate invasion by the bladder tcc;(15,23) thus, attentions have been attracted to the clinicopathological characteristics of the bladder tcc for predicting the prostatic involvement. nixon and colleagues argued that of 159 patients evaluated by pre-operative cystoscopy, only 5 subjects who were believed to have normal urethra had prostatic carcinoma.(24) several studies concentrated on clinicopathological characteristics of the bladder tcc to predict the prostatic involvement for determining the type of urinary diversion and/or the prostate-sparing. basiri and coworkers reported that grading and staging of the primary tumor have considerable correlation with the prostate invasion.(25) in other study, presence of cis and tumor multifocality had prognostic values for prostatic urethral involvement.(24) recently, patel and associates reported that 39.3% of patients undergoing radical cystectomy had different types of urothelial prostatic involvement. furthermore, cis and trigonal invasion of the bladder tumor were major risk factors for the prostatic involvement.(26) in our study, univariate analysis demonstrated that of the assessed factors, only vascular invasion (p = .001) and td (p < .001) had significant correlation with the prostatic involvement and the logistic regression analysis showed that only td had a significant effect on involvement of the prostate by tcc (p = .004). these results are nearly similar to our previous analysis on 60 patients, but the important difference is the cutoff point of 0.65 cm for td in comparison to 0.55 cm in the previous assessment.(10) this prospective study showed that distance between the tumor and the bladder neck in pre-operative cystoscopy has considerable value for managing the bladder tcc, determining the type of urinary diversion, and the use of prostatesparing technique. due to the possibility of the prostate adenocarcinoma, missing prostatic involvement, and local recurrence in the prostatesparing , the position of this surgery regarding oncological results is still under debate. however, the quality of life of these patients may be better than the standard cystectomy. conclusion among various factors, only distance between the tumor and the bladder neck had a significant predictive value on the prostatic involvement. although vascular invasion may increase the risk of invasion, but in comparison with the previous studies, tumor multifocality, grade, stage, and cis do not show any obvious correlation with prostatic involvement in the bladder tcc.(24,25) therefore, it is reasonable to avoid the prostatesparing or capsule-sparing cystectomy in patients with the bladder tumors very close to the bladder neck. however, it does not mean that when the distance of the bladder tumor from the bladder neck is sufficient, we can perform this surgery properly, because further evaluations with a prostatic involvement by tcc of the bladder—tabibi et al 47urology journal vol 8 no 1 winter 2011 larger group of patients may modify the final conclusion. conflict of interest none declared. references 1. wood dp, jr., montie je, pontes je, vanderbrug medendorp s, levin hs. transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. j urol. 1989;141:346-9. 2. reese jh, freiha fs, gelb ab, lum bl, torti fm. transitional cell carcinoma of the prostate in patients undergoing radical cystoprostatectomy. j urol. 1992;147:92-5. 3. revelo m, cookson m, chang s, shook m, smith j. incidence and location of prostate and urothelial carcinoma in prostates from cystoprostatectomies: implications for possible apical sparing surgery. j urol. 2004;171:646-51. 4. montie je. against bladder sparing: surgery. j urol. 1999;162:452-5; discussion 5-7. 5. schoenberg mp, gonzalgo ml. management of invasive and metastatic bladder cancer. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campell-walsh urology. vol 3. 9 ed: philadelphia: saunders; 2007: 2471. 6. kessler tm, burkhard fc, studer ue. clinical indications and outcomes with nerve-sparing cystectomy in patients with bladder cancer. urol clin north am. 2005;32:165-75. 7. steers wd. voiding dysfunction in the orthotopic neobladder. world j urol. 2000;18:330-7. 8. hart s, skinner ec, meyerowitz be, boyd s, lieskovsky g, skinner dg. quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit, cutaneous or urethral kock pouch. j urol. 1999;162:77-81. 9. hautmann re, stein jp. neobladder with prostatic capsule and seminal-sparing cystectomy for bladder cancer: a step in the wrong direction. urol clin north am. 2005;32:177-85. 10. tabibi a, simforoosh n, parvin m, abadpour b, abdi h, khafri s. prediction of prostatic involvement by transitional cell carcinoma of the bladder using pathologic characteristics of the bladder tumor. urol j. 2006;3:145-9. 11. liedberg f, chebil g, davidsson t, malmstrom pu, sherif a, mansson w. [transitional cell carcinoma of the prostate in cystoprostatectomy specimens]. aktuelle urol. 2003;34:333-6. 12. ghoneim ma, el-mekresh mm, el-baz ma, el-attar ia, ashamallah a. radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. j urol. 1997;158:393-9. 13. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001;19:666-75. 14. mcguire ms, grimaldi g, grotas j, russo p. the type of urinary diversion after radical cystectomy significantly impacts on the patient›s quality of life. ann surg oncol. 2000;7:4-8. 15. lerner sp, shen s. pathologic assessment and clinical significance of prostatic involvement by transitional cell carcinoma and prostate cancer. urol oncol. 2008;26:481-5. 16. pagano f, bassi p, ferrante gl, et al. is stage pt4a (d1) reliable in assessing transitional cell carcinoma involvement of the prostate in patients with a concurrent bladder cancer? a necessary distinction for contiguous or noncontiguous involvement. j urol. 1996;155:244-7. 17. schellhammer pf, bean ma, whitmore wf, jr. prostatic involvement by transitional cell carcinoma: pathogenesis, patterns and prognosis. j urol. 1977;399-403. 18. njinou ngninkeu b, lorge f, moulin p, jamart j, van cangh pj. transitional cell carcinoma involving the prostate: a clinicopathological retrospective study of 76 cases. j urol. 2003;169:149-52. 19. ayyathurai r, gomez p, luongo t, soloway ms, manoharan m. prostatic involvement by urothelial carcinoma of the bladder: clinicopathological features and outcome after radical cystectomy. bju int. 2007;100:1021-5. 20. spitz a, stein jp, lieskovsky g, skinner dg. orthotopic urinary diversion with preservation of erectile and ejaculatory function in men requiring radical cystectomy for nonurothelial malignancy: a new technique. j urol. 1999;161:1761-4. 21. vallancien g, abou el fettouh h, cathelineau x, baumert h, fromont g, guillonneau b. cystectomy with prostate sparing for bladder cancer in 100 patients: 10-year experience. j urol. 2002;168:2413-7. 22. saidi a, nahon o, daniel l, lay f, lechevallier e, coulange c. [prostate-sparing cystectomy: long-term functional and oncological results in a series of 25 cases]. prog urol. 2004;14:172-7; discussion 6. 23. donat sm, genega em, herr hw, reuter ve. mechanisms of prostatic stromal invasion in patients with bladder cancer: clinical significance. j urol. 2001;165:1117-20. 24. nixon rg, chang ss, lafleur bj, smith jj, cookson ms. carcinoma in situ and tumor multifocality predict the risk of prostatic urethral involvement at radical cystectomy in men with transitional cell carcinoma of the bladder. j urol. 2002;167:502-5. 25. basiri a, ozhand a, karami h, parham ha, safarinejad mr. the frequency of prostatic involvement in radical cystectomy specimens for transitional cell carcinoma of the bladder. j pak med assoc. 2008;58:479-81. 26. patel sg, cookson ms, barocas da, clark pe, smith ja, jr., chang ss. risk factors for urothelial carcinoma of the prostate in patients undergoing radical cystoprostatectomy for bladder cancer. bju int. 2009;104:934-7. letter can short anogenital distance cause chronic prostatitis? ayhan verit1, fatma ferda verit2 chronic prostatitis/chronic pelvic pain syndromes (cp/cpps) are a widespread pathology with unknown etiology without a proved treatment algorithm. neurologic, endocrine and immune systems, and oxidative stress, infections are ranked in the physiopathology. anogenital distance (agd) as a marker for the degree of antenatal exposure of androgens that link to some disorders of androgen-sensitive tissues especially of urogenital system. in this study, we aimed a construct a hypothesis that improper development of perineum and pelvic bottom due to the insufficient embryologic androgen exposure, which can be detected by reduced agd, can form histologic/clinic cp in adulthood through the physical forces that resulted in stretched prostate via chronic hypoxia induced oxidative stress and failed immune mechanisms. agd, unlike the previous published ones, suggested as a real physical scale to detect narrowed pelvic bottom other than an endocrine related biomarker. key words: chronic prostatitis; chronic pelvic pain syndromes (cp/cpps); anogenital distance; etiology of cp; treatment of cp 1univ. of health sciences, fatih sultan mehmet hospital, dept. of urology , istanbul, turkey. 2univ. of health sciences, istanbul hospital, dept. of obstet. & gyn. istanbul, turkey. correspondence: fatih sultan mehmet hospital, dept. of urology, içerenköy / ataşehir tr34752 istanbul, turkey. phone : +90 216 578 30 00. fax: + 90 216 575 04 06. e mail: veritayhan@yahoo.com. received february 2021 & accepted april 2021 chronic prostatitis (cp) with largely unknown etiol-ogy is pathology without proven treatment strategy(1). immune dysfunction and elevated oxidative stress that both may be triggered by local ischemia are some reported physiopathologic events in the etiology of cp besides the ranking the endocrine, neurologic and infectious ones(2-4). anogenital distance (agd) is correlated with antenatal androgen activity and associated with some androgen-sensitive disorders such as prostate cancer, male infertility, hypospadias, cryptorchidism and extends to bph and premature ejaculation(5-6). however, unlike the previous ones, our aim is to point the possibility of this physical marker as a physical dysfunction, not the endocrine related disorder, defining the etiology of cp through the physical compression inside the narrowed perineum. perineal wall can be considered as the bottom of pelvis that roughly may be defined geometrically as the apex of the reversed cone. while the external superficial anatomical tip of this cone was noted in an anterior-posterior line as agd, the internal side of this anatomical line mark behind the perineal wall can be expressed as the place between the lower urinary tract mainly urethra and rectum. prostate is the unique parenchymal organ without a true capsule of this location, thus, it is not illogical to hypotheses that narrowing of this internal side of cone may compress directly and chronically the parenchyma of prostate with its neurovascular bundle that result in chronic hypoxia. in this mechanism, we think that posteriorly-denonvilliers fascia and anteriorly-os pubis have the special role that reflecting the pressure on the prostate. moreover, the ability of stabilizing effect of urethra, prostatic ligament and endopelvic fascia, should be mentioned among the stabilizators in freezing prostate in any direction including lateral movements which prevents to avoid the direct chronic pressure on prostatic tissue. furthermore, in the current treatment of cp, the resolving of the constipation is the initial goal of the clinician as the first step of management strategies due to the foresight to get rid of internal pressure of the colonic-rectal involvement to reduce the intra-abdominal pressure on the neighborhoods locations. the strength of compressor mechanism may deem to increase by narrowing of the defined area that can be estimated by measurement of agd in regard of the aim this study. this zone incurs the highest gravity pressure that give rise to the “pelvic organ prolapses” in women, however there is no real counterpart pathology in men related with trapped strain. in parallel, this up position may superpose the severity of lower abdomen venous pathologies such as hemorrhoids and pelvic congestion syndrome that all thought to have common origin(7-10). moreover, flavonoids with their beneficial effects on vessels are well-known systemic medication for revealing rectal hemorrhoids also showed to be effective in cp treatment that confirms varicose impairment extends to prostate in theory(11). as a result, the accumulation of hydraulic venous pressure also seems to increase the intraprostatic strain, or vice versa. present defined condensed physical pressure on prostate facilitates to occur intra/periprostatic varicose disorder may appear clinically as cp. all in all, as a sub hypothesis, we claimed that prostate also the target of varicose disturbance as its anatomically neighborhoods structures. we think that the histological appearance of this mechanism, that resulted from local inflammatory reaction related with improper immune response and oxidative stress due to the chronic hypoxia, reported as cp (6080%) and no bacterial induction confirmed in most of them and even this hypoxic media can also induce bacterial one(12). urology journal/vol 18 no. 3/ may-june 2021/ pp. 353-354. [doi: 10.22037/uj.v18i.6687] in-utero anti-androgens/estrogens were also showed to induce dose dependent histologic postpubertal prostatitis in animal models(13). actually it may be presumed that early androgen insufficiency which the cause of shortened agd, also prepare the histologic/clinical basement for cp that superpose impact of ischemia induce cp later in adulthood life described in the present hypotheses. nevertheless, do we also speculate that there is no separate endocrinologic etiology in cp without the mechanism of shortening agd and the present mechanism begin to work in intrauterine life and progress life-long via accumulation of the ischemic inflammation? it should be reminded that perineal “pain” and “tenderness” are some of the common symptoms of cp that may arise prostate itself or the perineum which surely be the direct target of synchronous above mentioned physical forces and chronic ischemia at the external side of prostate location(14). to conclude, agd can not only supply information about the male disorders of urogenital system via embryologic hormonal pathways, but also, may be a physical sign of the histologic/clinical prostatitis and this may lead novel decompression surgeries. references: 1. mändar r, korrovits p, rahu k, et al. dramatically deteriorated quality of life in men with prostatitis-like symptoms. andrology. 2020;8:101-109. 2. ihsan au, khan fu, khongorzul, et al. role of oxidative stress in pathology of chronic prostatitis/chronic pelvic pain syndrome and male infertility and antioxidants function in ameliorating oxidative stress. biomed pharmacother. 2018;106:714-723. 3. zhao q, yang f, meng l, et al. lycopene attenuates chronic prostatitis/chronic pelvic pain syndrome by inhibiting oxidative stress and inflammation via the interaction of nfκb, mapks, and nrf-2 signaling pathways in rats. andrology. 2020;8:747-755. 4. liu y, mikrani r, xie d, et al. chronic prostatitis/chronic pelvic pain syndrome and prostate cancer: study of immune cells and cytokines. fundam clin pharmacol. 2020;34:160-172. 5. cowin pa, gold e, aleksova j, et al. vinclozolin exposure in utero induces postpubertal prostatitis and reduces sperm production via a reversible hormone-regulated mechanism. endocrinology. 2010;151:783792. 6. kutluhan ma, şahin a, ürkmez a, et al. the relationship between anogenital distance and benign prostate hyperplasia-related lower urinary tract symptoms. andrologia. 2020 apr 9:e13589. doi: 10.1111/and.13589. 7. yetkin e. hemorrhoid, internal iliac vein reflux and peripheral varicose vein: affecting each other or affected vessels? phlebology. 2015;30:145. 8. gearhart sl. “surgery” (chp.13), in oxford american handbook of clinical medicine. eds flynn aj, choi mj, dwight l. (new york ny: 2nd edition, oxford university press), 2013;438-517. 9. venbrux ac, lambert dl. embolization of the ovarian veins as a treatment for patients with chronic pelvic pain caused by pelvic venous incompetence (pelvic congestion syndrome). curr opin obstet gynecol. 1999;11:395-399. 10. gami b. hemorrhoids – a common ailment among adults, causes & treatment: a review. int j pharm pharm sci. 2011;3:5-12. 11. sahin a, kutluhan ma, yildirim c, urkmez a, akan s, verit a. results of purified micronized flavonoid fraction in the treatment of categorized type iii chronic pelvic pain syndrome: a randomized controlled trial. aging male. 2019;16:1‐6. 12. villeda-sandoval ci, herrera-cáceres jo, ruiz-hernández ja, castillo-de-león j, castillejos-molina ra, rodriguezcovarrubias f. the significance of histological chronic prostatitis in transrectal prostate biopsy. austin j urol. 2014;1:5. 13. schreiber e, alfageme o, garcia t, et al. oral exposure of rats to dienestrol during gestation and lactation: effects on the reproductive system of male offspring. food chem toxicol. 2019;128:193‐201. 14. issberner u, reeh pw, steen kh. pain due to tissue acidosis: a mechanism for inflammatory and ischemic myalgia? neurosci lett. 1996;208:191-194. letter 354 running head: ar interactors in prostate cancer-wang et al. integrative analysis of androgen receptor interactors aberrations and associated prognostic significance in prostate cancer zhu wang and ying zhang contributed equally to this study. zhu wang, ying zhang, qiong deng, jianwen zhang, xisheng wang*, hui liang* urology department, affiliated hospital of longhua shenzhen, southern medical university, shenzhen, guangdong 518109, china keywords: androgen receptor; prostate cancer; castration resistant prostate cancer; neuroendocrine prostate cancer; interactors corresponding author: xisheng wang, phd hui liang, m.d. department of urology, people’s hospital of longhua, southern medical university, shenzhen 518109, guangdong, china; tel: +86 755 27741585-8689 fax: +86 755 27700520 e-mail: 18923877315@163.com; lianghui8689@smu.edu.cn mailto:18923877315@163.com mailto:lianghui8689@smu.edu.cn abstract purpose: much progress has been made by directing against ar pathway in the treatment of prostate cancer in past decades. however, ar-interactors related metastatic castration resistant prostate cancer eventually developed. here, we aimed to characterize the aberrations and therapeutic implication in advanced disease. materials and methods: string database, ualcan web portal and cbioportal platform was used to analyze the ar interaction network, gene alterations, as well as the prognostic significance. go and keeg analysis was performed to characterize the functional enrichment of the identified ar-interactors. results: ten first shell ar-interactors were identified, among of which foxa1 and pelp1 was significantly up-regulated, while ccnd1, ctnnb1, ncoa4 and hsp90aa1 exhibited a significantly decreased pattern. the median survival period of altered group (n = 227) was 70 months (95% ci, 60-105m), while that of non-altered group (n = 545) was 141 months (95% ci, 115.13-na, p < 0.001). go and kegg enrichment showed that the identified ar-interactors were particularly enriched in prostate cancer and thyroid hormone signaling pathway, as well as endocrine resistance. conclusion: the ar-interactors might be useful markers for prostate cancer diagnosis and prognosis, and provide a new sight for revealing the molecular mechanism of crpc progression. keywords: androgen receptor, prostate cancer, interactors, castration-resistance introduction prostate cancer is ranked the second most common male malignancies, and the fifth leading cause of cancer death among men worldwide (1). to inhibit or block androgen receptor (ar) signaling pathway by androgen deprivation therapy (adt) by chemical or surgical castration is the first-line treatment for advanced metastatic prostate cancer. however, with the progression of the disease, a variety of molecular mechanisms lead to the restoration of activity of ar signaling pathway, and then termed castrationresistant prostate cancer (crpc) (2,3). accumulating evidence assigns a key role to the continuous activation of the androgenic receptor (ar) signaling pathway in crpc progression, as well as alternative independent routes (2,4-6). in the classical ar signaling pathway, ar translocates into the nucleus with the ligandbinding domain occupied by androgen, to govern the target gene expression via dnabinding domain binds to androgen-responsive elements (are) and recruits additional coregulators and transcriptional modulators (7,8). the transcriptional activity of ar signaling is greatly modulated by a number of coregulators (such as ep300 [e1a binding protein p300], src1 [steroid receptor coactivator-1] and src3 [steroid receptor coactivator 3]) (9,10), and several key proteins including foxa1 (forkhead box protein a1), pten (phosphatase and tensin homolog), erbb2 (erb-b2 receptor tyrosine kinase 2) and erbb3 (erb-b2 receptor tyrosine kinase 3) (11,12). in addition, ar crosstalk pathways including mapk, pten/pi3k/akt/mtor pathway, stat3, wnt/β-catenin and other signaling pathways play an important role in promoting the transformation of crpc (13,14). overall, these key modulators and signaling molecules are just the tip of the iceberg of a coordinated and may redundant network that acts in concert with ar signaling pathway to promote tumor growth and development in prostate cancer. at present, significant progress has been made in understanding the mechanism of crpc, and several novel ar-directed therapies have been developed and clinically validated. enzalutamide is the first second-generation nonsteroidal antagonist with a strong binding affinity to ar, could significantly prolong overall survival (os) time for patients with lethal metastatic crpc, which thus been approved by the us food and drug administration (fda) for the treatment of crpc in 2012 (15-17). abiraterone acetate (aa), an inhibitor of the steroidal enzyme 17α-hydroxylase/c17-20 lyase (also known as cyp17a1 or p450c17) playing a central role in androgen biosynthesis from the adrenal glands (18,19), demonstrated to improve os time in patients who had chemonaive and docetaxel pretreated, becoming a therapeutic alternative to docetaxel and enzalutamide for metastatic castration-resistant prostate cancer (mcrpc) (18). darolutamide is another newly developed non-steroidal androgen receptor antagonist and recently approved for the treatment of non-metastatic castration-resistant prostate cancer (nmcrpc) (17,20,21). several other targeting agents and new therapeutic modalities such as poly adp ribose polymerase (parp) inhibitors, histone deacetylase (hdac) inhibitors and prostate-specific membrane antigen (psma)-ligand therapy are developed or being tested in clinical trials (22,23). however, lots of patients will ultimately develop subsequent resistance to the individual agents via various complicated mechanisms, such as continuously active, truncated ar splice variant-7 (ar-v7)(24), bypass and alternative pathway of ar signaling. to identify the right agents or better the right combination and proper sequencing of treatments are becoming challenge in the near future. here, we comprehensively evaluated the expression and alteration of ar and its interactors from the existing database by bioinformatics method. so as to provide a new insight for the study of prostate cancer progression mechanism and prognosis evaluation. materials and methods string analysis the string protein network database (http://string-db.org/), a web resource for protein-protein physical and functional interactions (25), was used to compute the protein-protein interaction (ppi) network between ar and its related factors as previously reported (26). we selected protein by name from the menu bar, entered the protein name ar, and selected organism homo sapiens. the network provides a summary of all the evidence channels, including based on certified database, experimental verification, gene proximity, co-expression, homology speculation and text mining, to create the link between the protein nodes. a brief description of the colored lines and nodes is provided, to determine the relationship between ar and its related factors. the confidence score was set to medium (score > 0.400). a list with details of 10 proteins identified as first shell interactors of ar using the string database was showed in table 1. ualcan analysis http://string-db.org/ ualcan web-portal (http://ualcan.path.uab.edu), an integrated cancer data analysis platform based on the data of the caner genome atlas (tcga) (27), was used to evaluate the expression of ar and its interactors in prostate cancer according to the online instructions. the symbols of target genes were typed into the scan box and the tcga dataset (prostate adenocarcinoma) was chose, and mrna expression, survival (with tumors categorized into low and high expression groups), correlation, and pancancer view was explored. cbioportal analysis the cbioportal (http://cbioportal.org) for cancer genomics is a publicly available platform for exploring, visualizing, and analyzing multidimensional tumor genomics and clinical data. using the cbioportal database, we created a virtual study using a combination of data provided by 16 prostate cancer studies (supplementary table s1), which including 6270 samples of 5981 patients (accessed on 14th march 2022). the genetic alterations of ar and identified ar-interactors were evaluated as described previously (28). the overall survival (os) and disease-free survival (dfs) differences between altered group and unaltered group of the query genes were simulated, and the results were displayed as kaplan-meier plots with p values from a logrank test (29). go enrichment and keeg pathways analysis gene-ontology (go) functional enrichment analysis was performed to investigate the biological significance of ar-interactors, which includes biological processes (bp), cellular components (cc) and molecular functions (mf). the enrichment factor is presented as log10(observed/expected). the benjamini-hochberg (bh) adjustment was http://ualcan.path.uab.edu/ applied for multiple associations, and p < 0.05 was recognized as significant. kyoto encyclopedia of genes and genomes (keeg) enrichments were analyzed to determine the most enriched signaling pathway of ar-interactors involved in. statistical analysis in survival data, the median was estimated based on the kaplan-meier estimate of the survivor function. the statistical analysis was performed in the software of spss statistics 25.0. p < 0.05 was recognized statistically significant. results first shell interactors of ar identified by the string database the string database (http://string-db.org/) was used to simulate the protein interaction network between ar and other interactors. limiting the number of confirmed/predicted first shell interactors to a maximum of 10. confidence interaction score was set to medium (score > 0.400). results showed that an eleven proteins network includes ar, ccnd1 (cyclin d1), ctnnb1(catenin beta 1, also known as βcatenin), foxa1, hsp90aa1 (heat shock protein 90 alpha family class a member 1), mdm2 (mouse double minute 2, human homolog of p53-binding protein), ncoa1 (nuclear receptor coactivator 1), ncoa2 (nuclear receptor coactivator 2), ncoa4 (nuclear receptor coactivator 4), pelp1 (proline, glutamate and leucine rich protein 1) and src (steroid receptor coactivator) was computed using the string interaction database (figure 1a). http://string-db.org/ the number of interaction network nodes is 11, the number of edges is 33, the average node degree is 6, the average local clustering coefficient is 0.815, the expected number of edges is 21, and the ppi enrichment p value is 0.00943. in addition, a ppi network with number of first shell interactors limited to 20 was simulated with medium confidence (score > 0.400) and showed in figure 1b. ten additional ar interactors were added to the network, including smad3 (smad family member 3), ep300, klk3 (kallikrein related peptidase 3), stat3 (signal transducer and activator of transcription 3), pik3r1 (phosphoinositide-3-kinase regulatory subunit 1), kat5 (lysine acetyltransferase 5), ncor1 (nuclear receptor corepressor 1), ncor2 (nuclear receptor corepressor 2), kdm1a (lysine demethylase 1a) and ezh2 (enhancer of zeste 2). (supplementary table s2). these data indicated that ar interaction network is complicated and exerted a complex with little is known in prostate cancer development. expression profile of ar and its interactors in prostate cancer the mrna expression levels of ar and its 10 first shell interactors were analyzed using ualcan web-portal (http://ualcan.path.uab.edu) in prostate adenocarcinoma. among these 11 proteins, we found that foxa1 and pelp1 were significantly up-regulated in prostate cancers compared to normal prostate tissues (p < 0.001, < 0.001). on the contrary, ccnd1, ctnnb1, ncoa4 and hsp90a was significantly down regulated in prostate cancer (p = 0.0197, < 0.001, 0.0072, 0.0122). the expression levels of ar, mdm2, ncoa1, ncoa2 and src exhibited no significantly changes (p = 0.322, 0.2054, 0.0543, 0.5982). (figure 2 and supplementary table s3). http://ualcan.path.uab.edu/ overview of ar-interactor alterations in prostate cancer sixteen prostate cancer datasets, which including 5981 patients / 6270 samples, from the cbioportal database were involved. the parameters of genomic profiles, mutations and dna copy number alterations (cnas) were specified by default. our results showed a visual summary of alterations across 16 prostate cancer datasets based on the query of ar and its interactors (ar, ccnd1, ctnnb1, foxa1, hsp90aa1, mdm2, ncoa1, ncoa2, ncoa4, pelp1 and src). the quired genes were altered in 34% (2139/6270) samples, including 17.86% amplification and 11.97% mutation in prostate carcinoma. mutation is the main alteration type in prostate small cell carcinoma (29.41%, 5/17), neuroendocrine prostate carcinoma (nepc, 18.84%, 13/69) and castration-resistant prostate cancer (crpc, 11.43%, 8/70) as showed in figure 3a. the details of the genomic alterations of ar and its interactors across the prostate cancer samples were summarized in the oncoprint tab (figure 3b). for ar, the frequency of alteration is 18%, mainly including gene amplification and mutation. the alteration rate of foxa1 was 12%, and the main variation type was gene amplification. the alteration frequency of src was 0.9%, which relatively lower than other ar-interactors. alteration landscape of ar-interactors in prostate cancer the alterations of all ten ar-interactors were showed in figure 4. it’s well known that ar acts as an important driver in the castration resistance, and ar amplification and mutation are critical mechanisms contribute to the progression (30,31). here, we found that the amplification of ar was occurred in 14.22% prostate cancers, remarkably, 8.57% crpc samples have ar mutation. the most common alteration type of cnnd1, mdm2 and ncoa2 was amplification, accounted for 3.6%, 1.47% and 9.52% respectively. ncoa2, also known as src-2, was more frequently amplified or upregulated in patients with metastatic pca, facilitated the development of crpc (32). interestingly, the androgen deprivation treatment could also induce ncoa2 expression, which in turn activated pi3k signaling and promoted pca metastasis and castration resistant progression (32). these findings indicated that the amplification of arinteractors including ncoa2, mdm2 and cnnd1, might highly correlated with tumor progression and act as critical regulators in crpc. in present study, we found that mutation was most frequently observed in ctnnb1, foxa1 and hsp90a in all types of prostate cancer. notably, the foxa1 gene was mutated in 29.41% prostate small cell carcinomas. foxa1, a known direct interacting ar cofactor, with high frequency mutations in coding and noncoding sequences leading to functional alterations, was recognized as drivers in prostate cancer progression (11,31). ctnnb1 is an important coactivator downstream of the oncogenic wnt signaling pathway. therefore, mutations in the ctnnb1 gene have been implicated in oncogenesis of many cancers (33). however, the high incidence mutations of ctnnb1 related functional alterations in pca were not quite clear. prognostic impact of ar-interactor alterations in prostate cancer prognostic impact of alterations of individual ar-interactor was investigated by cbioportal platform. the results were displayed as kaplan-meier plots with p values from a logrank test. results showed that among the 10 first shell ar interactors, 6 of them (ccnd1, mdm2, ncoa4, ncoa2, pelp1, ctnnb1 and foxa1) were significantly associated with the inferior overall survival (os) as shown in figure 5. a previous study reported that ncoa2 was altered in 13% of the cohort, which associated with poor outcomes in metastatic castration‐resistant prostate cancer (mcrpc) (34). in addition, the other four ar-interactors (hsp90aa1, ncoa1, and src) with alterations have no significant impacts on the prognosis of prostate cancer (data not shown). importantly, we found that patients with dual ar and ar-interactors alterations had significantly shorter disease-free survival (dfs) and overall survival (os) on univariable analyses. the median survival time of altered group (n = 227) was 70 months (95% ci, 60-105m), while that of unaltered group (n = 545) was 141 months (95% ci, 115.13 -not available (na), p < 0.001). the dfs in the altered group (n = 82) was 110.16 months (95% ci, 64.66 na), however, the disease-free survival time in the unaltered group (n = 533) is na, p = 0.0552 (figure 6, supplementary table s4 and s5). these findings indicated that ar-interactors altered-grouping might be a stronger predictor of poor prognosis than ar-interactor aberrations alone. go enrichment analysis of ar-interactors we analyzed the corresponding go terms of the ar-interactors. a total of 168 go terms were exported. from the overall go terms distribution, the bp terms indeed are more informative and significant. in detail, 142 were bp go terms, 5 were cc go terms and 21 were mf go terms (supplementary table s6). here, all 5 cc terms and the top 10 enriched bp terms and mf terms were selected and presented according to the strength of the terms (figure 7). among the 10 selected bp terms, “cellular response to thyroglobulin triiodothyronine (go:1904017)” and “positive regulation of epithelial cell proliferation involved in prostate gland development (go:0060769)” obtained the highest strength value (figure 7a). which indicated that the ar-interactors were mainly involved in prostate cell proliferation, differentiation and prostate gland development. the enriched cc go terms showed that all the ar-interactors were functional located in the nucleus (figure 7b). apart from the bp and cc go terms, the top 10 enriched mf go terms were mainly includes transcription factor/nuclear receptor binding and signaling receptor binding (figure 7c), which have been confirmed to be essential for the initiation and development of prostate cancer. additionally, we performed keeg pathway enrichment analysis to determine the predictive signaling pathways of identified ar-interactors. kegg enrichment showed that the identified ar-interactors were particularly enriched in thyroid cancer, bladder cancer, prostate cancer and thyroid hormone signaling pathway, as well as endocrine resistance (figure 7d and supplementary table s7). these results indicated that the first shell ar-interactors were located in the nucleus and widely involved in prostate cancer development through transcriptional regulation. discussion ar signaling pathway is recognized as a driver of prostate cancer initiation, progression and recurrence, hence, androgen-deprivation therapy directed toward a reduction in serum androgens and the inhibition of ar is generally the first-line therapy adopted (5). however, multi-patients will experience cancer progression to crpc, which currently incurable and with a worse outcome(35). although several therapeutic agents have been approved and applied in clinical treatment for crpc, an urgent need for the rational biomarkers and treatment strategies to improve survival is indeed. mounts of studies have focused and evidenced that continuously active of ar signaling pathway through mutations, splice variants, and aberrant coregulation critically contributes to tumor progression (36,37). few studies attended the aberrations of arinteractor gene group and its prognostic significance in the pca initiation and progression. here, we comprehensively evaluated the aberrations of ar-interactors from the existing database by bioinformatics method, provided new insights for the study of prostate cancer progression mechanism and prognosis evaluation. a 11-protein interaction network was computed, which including ar, ccnd1, ctnnb1, foxa1, hsp90aa1, mdm2, ncoa1, ncoa2, ncoa4, pelp1 and src. of which foxa1 and pelp1 was significantly up-regulated in prostate cancers. on the contrary, ccnd1, ctnnb1, ncoa4 and hsp90aa1 was significantly downregulated in cancer tissues as compare to normal control. foxa1 (forkhead box a1) also known as hepatocyte nuclear factor 3-alpha, is an important pioneer factor directly interacts with ar to drive the growth and survival of prostatic cells (11). the increased expression of foxa1 could suppress stat2 dna-binding activity and interferon (ifn) signaling gene expression, promote cancer immuneand chemotherapy resistance in prostate cancer (38). pelp1 is a scaffolding protein that acts as a coregulator of several nuclear hormone receptors and sequence-specific transcription factors, which is upregulated in several cancers and playing essential roles in hormonal signaling, cell cycle progression and therapy resistance (39). particularly, pelp1 could facilitate 17-estradiol (e2)-induced activation of ar signaling by forming a protein complex with ar, provide cancer cells with a distinct growth and survival advantage in the absence of androgen (39,40). these findings indicated that the co-expression of ar, foxa1 and pelp1 might has critical significance in prostate cancer initiation and development. the ccnd1 gene could directly bind to the n-terminus of ar and function as a cosuppressor to inhibit ligand-dependent ar activation (41). however, contradictory data have been reported that ccnd1 could enhance dht-induced prostate cancer cellular proliferation and facilitate the resistance of prostate cancer cells to dna damage therapies (42,43). here, we demonstrated that ccnd1 was significantly down-regulated in primary prostate cancers, and the patients with alteration of ccnd1 have poor overall survival. further investigations of the mechanism of ccnd1 in prostate cancer development is in need. ctnnb1(β-catenin) is an intracellular scaffold protein that interacts with adhesion molecules, transmembrane‑type mucins, signaling regulators and epigenetic or transcriptional regulators, plays crucial role in cell adhesion, proliferation and multiple cellular signaling pathways (44). increasing evidence indicated that wnt/ctnnb1 signaling is an important ar-independent pathway in contributing to prostate cancer progression and acquisition of resistance(45-47). here, we found that ctnnb1 was significantly down-regulated in primary prostate cancers, and the main alteration type was mutation, which might play critical role in prostate cancer progression. however, the mechanism remains unclear. ncoa4 (nuclear receptor coactivator 4), was also known as androgen receptor-associated protein 70 (ara70), which could enhance the androgen receptor transcriptional activity by binding to the nterminus of ar in prostate cancer cells (48). hsp90aa1 (hsp90α) interacts and supports numerous oncoproteins that promote oncogenesis, including ar functional maturation and stability. co-targeting hsp90 and ar strategy can achieve a better blockade of androgen signaling than targeting ar or hsp90 alone to enhance prostate cancer cell death (49). however, in this study we found that ncoa4 and hsp90aa1 was downregulated in prostate cancers, with the mechanism unknown. this study systematically analyzed the expression, alteration and interaction of ar and its first shell interactors in prostate cancer, as well as the effects on the prognosis. among the 10 first shell ar interactors, 6 of them (ccnd1, mdm2, ncoa4, pelp1, ctnnb1 and foxa1) were negative associated with the overall survival time. remarkably, there was significant difference of the overall survival and disease-free survival between the altered group and unaltered group, which suggested that the arinteractor group might be a useful prognostic indicator for prostate cancer. we found that the ar-interactors were related to 168 go terms, most of which were associated with prostate cell proliferation, differentiation and prostate gland development, as well as transcriptional binding process, provides new sights for further study of the molecular mechanism of crpc progression. conclusion taking together, present study comprehensively analyzed the ar and its first shell interactors expression and alterations in prostate cancer. the ar-interactor gene set could provide new sights for prostate cancer treatment, and might be a useful marker for the prognosis of prostate cancer. further investigations are needed to better understand the significance of ar-interactors in prostate cancer initiation, progression and therapeutic resistance. however, despite the comprehensive analyses of ar and ar-interactors, we acknowledge several limitations of our study. the expression and alteration data were obtained and analyzed from different database portals, which may limit the confidence and generalizability of our findings. acknowledgments the authors thank the ualcan web-portal (http://ualcan.path.uab.edu), cbioportal datasets (http://cbioportal.org) and string database (http://string-db.org/) for their free use. this study was financially supported by shenzhen 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centenera mm, carter sl, gillis jl, et al. co-targeting ar and hsp90 suppresses prostate cancer cell growth and prevents resistance mechanisms. endocr relat cancer. 2015;22:805-18. figure legends figure 1 first shell ar-interactors identification based on the string database. (a) first shell ar-interactors limited to 10 with a medium confidence (score > 0.400). (b) ar-interactors limited to 20 with medium confidence (score > 0.400). figure 2 expression profiles of ar-interactors in prostate cancer by ualacn. graphs showing expression level of ar and 10 first shell ar-interactors using ualcan web-portal in normal prostate and primary tumors. red boxplot depicts the expression level of quired gene in primary tumors, while blue boxplot indicate expression in normal samples. **, p < 0.05; ***, p < 0.0001. figure 3 the integrated alteration distribution and the oncoprint tabs of arinteractors. (a) alterations distribution was based on cancer types. histogram indicates the alteration frequencies of the ar-interactors according to cancer types. (b) the oncoprint tab summarizes genomic alterations of the quired genes across a set of prostatic samples. each row represents a gene, and each column represents a tumor sample. red bars indicate gene amplifications, blue bars are homozygous deletions, and green squares are nonsynonymous mutations. figure 4 alteration distribution of ar-interactors. histogram indicates the alteration frequencies of the queried gene according to cancer types. red bars indicate gene amplifications, blue bars are homozygous deletions, and green squares are nonsynonymous mutations. figure 5 prognostic impact of ar-interactor alterations in prostate cancer. the impacts of ar-interactors (hsp90aa1, ncoa1 and src) on os with no-significance (p > 0.05) are not showed. 95% ci, 95% confidence interval. figure 6 the survival tab of integrated impacts of ar-interactor alterations on prognostics. (a) overall survival. (b) disease free survival. figure 7 functional enrichment analysis of ar-interactors. (a) bp go terms. (b) cc go terms. (c) mf go terms. (d) top 20 of keeg pathways enrichment analysis. table 1. list of first shell interactors of ar identified by the string database accession symbols description confidence score p10275 ar androgen receptor p24385 ccnd1 g1/s-specific cyclin-d1 0.998 p35222 ctnnb1 catenin beta-1 0.999 p55317 foxa1 hepatocyte nuclear factor 3-alpha 0.999 p07900 hsp90aa1 heat shock protein hsp 90-alpha 0.999 q00987 mdm2 e3 ubiquitin-protein ligase mdm2 0.998 q15788 ncoa1 nuclear receptor coactivator 1 0.999 q15596 ncoa2 nuclear receptor coactivator 2 0.999 q13772 ncoa4 nuclear receptor coactivator 4 0.999 q8izl8 pelp1 proline-, glutamic acidand leucine-rich protein 1 0.999 p12931 src proto-oncogene tyrosine-protein kinase src 0.999 vol 19 no 3 may-june 2022 100 the association of cell surface fibromodulin expression and bladder carcinoma ali ahmad bayat1, niloufar sadeghi1, ali salimi1, ghazaleh fazli1, mohammad reza nowroozi2, solmaz ohadian moghadam2, amin radmanesh3,4, mohsen tabasi3,5, ali reza sarrafzadeh6, omid zarei7, hodjattallah rabbani1* purpose: fibromodulin (fmod) is a secretory protein which is considered a major component of extracellular matrix. its dysregulation in different types of cancer implies it as a promising target for cancer therapy. within the scope of its rather wide expression in different tumors, we studied the expression of fmod and the effect of anti-fmod antibody in bladder cancer cells in order to identify new target for diagnostic and therapeutic interventions. we report here for the first time the expression of fmod in bladder cancer cell lines in comparison to the normal cell line and tissues. methods: a peptide-based produced anti-fmod murine monoclonal antibody (mab) (clone 2c2-a1) was applied for evaluation of fmod expression in bladder cancer and normal tissues by immunohistochemistry (ihc) staining. furthermore, the expression of fmod was examined in human bladder cell lines, 5637 and ej138, as well as a non-cancerous human cell line, human fetal foreskin fibroblast (hfff), by immunocytochemistry (icc) and flow cytometry. the apoptosis induction of anti-fmod mab was also evaluated in bladder cancer cells. results: ihc and icc analyses revealed that the qualitative expression of fmod in bladder cancer tissues and cell lines is higher than in normal tissues and cell lines. flow cytometry analyses revealed that 2c2-a1 mab could recognize fmod expression in 84.05 ± 1.85%, 46.1 ± .4% , and 2.56 ± 1.26% of 5637, ej138, and hfff cells, respectively. an effective apoptosis induction was detected in 5637 and ej138 cells with no significant effect on hfff cell. conclusion: to our knowledge, this is for the first time reporting surface expression of fmod in bladder cancer. this significant surface expression of fmod in bladder cancer with no expression in normal bladder tissues and the capacity of inducing apoptosis through directed targeting of fmod with specific monoclonal antibody might candidates fmod as a diagnostic marker as well as a potential immunotargeting with monoclonal antibody. keywords: bladder cancer; fibromodulin; flow cytometry; monoclonal antibody introduction one of the major obstacles in combating bladder cancer is to identify new specific markers for targeted therapy and diagnosis. although several markers such as urovysion, nmp22 (nuclear matrix protein 22), bta (bladder tumor antigen), and immunocyt/ ucyt+(1) have shown their specificity in diagnosis and treatment of bladder cancer but still their function and effectivity are not enough good. regardless of several strategies for bladder cancer therapy(2), about 5,490 new cases and 200,000 deaths were reported annually worldwide. this high rate of incidence and mortality highlights the importance of novel 1monoclonal antibody research center, avicenna research institute, acecr, tehran, iran. 2uro-oncology research center, tehran university of medical sciences, tehran, iran. 3legal medicine research center, legal medicine organization, tehran, iran. 4department of tissue engineering and applied cell sciences, shahid beheshti university of medical sciences, tehran, iran. 5molecular biology unit, pasteur institute of iran, tehran, iran. 6 department of pathology, khatam al anbia hospital, tehran, iran. 7 cellular and molecular research center, research institute for health development, kurdistan university of medical sciences, sanandaj, iran. *correspondence: monoclonal antibody research center, avicenna research institute, acecr, tehran, iran p.o. box: 19615-1177 tel: +98 21 22432020.fax: +98 21 22432021 received september 2020 & accepted july 2021 therapies for the treatment of bladder cancer(3). recently, we have introduced two novel targets of ror1(4) and sortilin (under review), highly expressed in bladder tumors. both markers have a cell surface expression with different functions. ror1 plays an important role in proliferation, differentiation, metastasis, and polarization(5). in contrast, sortilin is functioning as a sorter in cytoplasm with only less than 10% surface expression(6). apparently, the functional property and cellular localization have an effect on cellular function in normal and pathological conditions. to add additional markers to the list, we have sought the functional role of fibromodulin in this cancer. fibromodulin is a member of small leucine-rich repeat urological oncology urology journal/vol 19 no. 3/ may-june 2022/ pp. 189-195. [doi: 10.22037/uj.v18i.6461] proteoglycans (slrps) family and also is an important component of extracellular matrix (ecm)(7). fmod gene encodes a 42-80 kda protein in different types of connective tissues such as cartilage, sclera, tendon, skin and cornea(8), and also a 55-75 kda protein in chronic lymphocytic leukemia (cll)(9). fmod has significant roles in various physiological processes such as angiogenesis, regulation of transforming growth factor beta (tgf-β) activity, apoptosis, differentiation of human fibroblasts into pluripotent stem cells, and inflammatory mechanisms. also fmod has been considered as a new tumor-related antigen(10). the cell surface expression of fmod has been studied in several cancers including b-cll(11,12), prostate cancer(13), and glioblastoma,(14) with a lack of comprehensive study in bladder cancer. the assessment of fmod surface expression in bladder cancer cells might introduce fmod as a diagnostic and therapeutic target(9, 11,15,16). in this study we used icc, ihc, and flow cytometry techniques to explore the expression profile of fmod and its functional role in bladder cancer in order to find a novel diagnostic method as well as a novel target to combat this malignancy. materials and methods cell culture human bladder cancer cells lines, ej138 (invasive transitional bladder carcinoma) (ncbi code: c429; ecacc number: 85061108), 5637 (non-invasive grade ii transitional bladder carcinoma) (ncbi code: c450; ecacc number: dsmz no: acc 35) and human normal cell hfff (human caucasian fetal foreskin fibroblast) (ncbi code: c107) cells were purchased from national cell bank of iran (pasteur institute, tehran, iran). all cell lines were cultured in rpmi-1640 medium (gibco, grand island, ny, usa), containing 10% fetal bovine serum (fbs) (gibco invitrogen, usa), penicillin (100 u/ml), streptomycin (100 µg/ml) (gibco, ny, usa) and incubated at 37 °c under 5% co 2 and 95% humidity conditions. immunohistochemistry (ihc) formalin-fixed paraffin-embedded (ffpe) of human normal bladder (national forensic organization, tehran, iran) and high grade human bladder carcinoma (imam khomeini hospital, tehran, iran) specimens were cut to a 4 µm of thickness using a microtome instrument and were mounted on positively charged slides. the sections were deparaffinized using xylene, and then dehydrated with decrement concentrations of ethanol. antigen retrieval was performed by heating the slides at 94 °c for 30 min in citrate buffer (10 mm, ph: 6). after three times washing with tris-buffered saline (tbs) containing .1% bsa in ph: 7.4 (tbs-bsa), the slides were treated by 3% h 2 o 2 (diluted in tbs) for 15 min in dark and at room temperature (rt) to eliminate the endogenous peroxidase activity. goat serum (5% in 2.5% tbsbsa) was added to the sides for 30 min for blocking. anti-fmod mab clone 2c2-a1, anti-beta actin, and mouse igg isotype control antibodies (padzaco., tehran, iran) (10 µg/ml concentration diluted in 2.5% tbs-bsa) were added to slides for 60 minutes at rt in a humidified chamber followed by three times washing and incubating with envision (biogenex, united states) detection system for 30 min at rt. afterward, 3, 3'-diaminobenzidine (dab) chromogen (biogenex, united states) solution was added and mayer’s hematoxylin (merck, darmstadt, germany) was employed for counterstaining. the sections were extensively washed with deionized water and dehydrated by ethanol in a decremental manner. finally, the slides were mounted using entellan (merck, darmstadt, germany) and observed under a fluorescent microscope (olympus, tokyo, japan)(17). immunocytochemistry(icc) the cells were seeded at a density of 2×104 on 8-well coverslips (germany, marienfeld gmbh, lauda-königshofen) using complete rmpi-1640 medium and incubated overnight at 37 °c in moistened air with 5% co 2 . after overnight incubation, the slides were washed and fixed with cold acetone (at -20 °c) for 2 min following by twice washing with pbs and drying at 4 °c for 30 min. the slides were washed by tbs (ph: 7.4) and tbs-bsa three times (3×3min). in order to prevent the unspecific binding sites, blocking was performed using 10% sheep serum in a 1% tbs-bsa buffer for 30 min at rt. the slides were incubated with 10 µg/ml anti-fmod mab or isotype control mabs diluted in 2.5% tbs-bsa for 60 min at rt. the slides were then washed and re-incubated with fitc-conjugated sheep anti-mouse ig (padzaco., tehran, iran) at rt for 45 min. to counterstain the cell nuclei, 1µg/ ml dapi (4`,6-diamidino-2-phenylindole m) (usa, calbiochem) was used for 5 min(18). finally, the slides were mounted using 50% tbsglycerol and subjected to a fluorescent microscope (olympus bx51, tokyo, japan). flow cytometry analysis all cell lines were cultured to reach a confluency of 70-80%, harvested by citrate buffer, washed three times using pre-cold phosphate-buffered saline (pbs) and blocked with 5% sheep serum for 30 min at 4 °c. the harvested cells were incubated with 10 µg/ml anti-fmod mab or isotype control mab for one hour at 4 °c followed by washing with pre-cold pbs and urological oncology 190 table 1. flow cytometry on bladder cancer and normal cell lines cell line antibody mfib popc mfi×pop ej138 antifmod maba 19.3 46.6 899.38 isotype control 11.1 3.34 37.07 5637 antifmod mab 43.4 85.9 3728.06 isotype control 33.7 8.72 293.86 hfff antifmod mab 2.64 1.37 3.61 isotype control 1.39 0.862 1.2 a monoclonal antibody b mean fluorescence intensity c percentage of positivity fibromodulin expression in bladder carcinoma-bayat et al. vol 19 no 3 may-june 2022 100 incubated with fitc-conjugated sheep anti-mouse ig (1:50 dilution) for 45 min at 4 °c in a dark place. finally, the cells were washed with pbs and analyzed using flomax software (partec, nuremberg, germany) (19). the average total cell surface expression of fmod was determined by multiplying of mean fluorescence intensity (mfi) to the percentage of positivity (pop) (mfi×pop)(20). cell apoptosis assay the cells were seeded in a six-well plate (1x106 /well) and treated with 10 µg/ml anti-fmod mab or isotype control mab for 6 and 12h. the cells were detached and washed for three times using pre-cold pbs and infigure 1. detection of fibromodulin (fmod) in formalin-fixed paraffin-embedded bladder cancer and normal tissues by immunohistochemistry (ihc). a) bladder carcinoma tissue stained by mouse igg isotype control antibody b) bladder carcinoma tissue stained by anti-beta actin antibody c) normal bladder tissue stained by anti-fmod murine monoclonal antibody (mab) clone 2c2-a1 d) bladder carcinoma tissue anti-fmod mab clone 2c2-a1. envision detection system (biogenex, united states) was employed for signal detection and mayer’s hematoxylin was used for counterstaining in all slides (original magnification, ×50). figure 2. detection of fibromodulin (fmod) in bladder carcinoma cell lines by immunocytochemistry (icc). the upper panels are 5637, ej138 and hfff cells stained by anti-fmod murine monoclonal antibody (mab) clone 2c2-a1 and the lower panels are 5637, ej138 and hfff cells stained by mouse igg isotype control antibody as primary antibodies. fitc-conjugated sheep anti-mouse antibody was used as secondary antibody and dapi was used for counterstaining the nucleus (blue). fibromodulin expression in bladder carcinoma-bayat et al. vol 19 no 3 may-june 2022 191 cubated with 1 µl annexin v-fitc (bd biosciences, san jose, ca) and 2 µl propidium iodide (pi) (bd biosciences, san jose, ca) for 15 min at rt in the darkness. the percentage of apoptotic cells as well as live cells were measured using partec pas iii flow cytometer (partec gmbh, germany). the data were analyzed by flowjo software version 10(21). statistical analysis statistical analysis was carried out by one-way and twoway anova. the results were illustrated as mean ± sd and p-values less than .05 were considered statistically significant. results immunohistochemical staining for evaluation of fmod expression immunohistochemistry results of the stained human bladder carcinoma tissues (using anti-fmod mab clone 2c2-a1) showed high level of fmod expression in comparison to the normal bladder tissues. the expression of beta-actin as positive control was observed while no signal detected in isotype control (figure 1). detection of fmod by immunocytochemistry the immunocytochemistry results in bladder cancer cell lines (5637 and ej138) and human normal cell line (hfff) were also demonstrated in figure 2. two bladder cancer cell lines expressed fmod, while no signal was detected in normal cell line. cell surface fmod expression by flow cytometry the average expression of fmod in two human bladder cancer cell lines was 84.05 ± 1.85% of 5637 and 46.1 ± .4% of ej138 cells. in contrast, only 2.56 ± 1.26% of hfff cells showed fmod expression (negative control). the arbitrary values of mean fluorescent intensity multiply percentage of positivity (mfi × pop) were 3728.06 for 5637, 899.38 for ej138 and 3.61 for hfff cells (figure 3) (table 1). apoptosis induction by flow cytometry for 6 hours incubation, the percentage of apoptosis was 12.7 ± 3.1% (early apoptosis) and 7.7 ± 0.3% (late apoptosis) for 5637 cells. ej138 cells showed a 18.2 ± 9.5% (early apoptosis) and 4.97 ± 2.3% (late apoptosis), while hfff normal cells showed a 2.51 ± .0.9% (early apoptosis) and .34 ± 0.04 % (late apoptosis). the 12 hours incubation, showed a 6.7 ± 0.01% and 11.8 ± 1.5% for 5637 cells, 9.5 ± 1.4% and 24.05 ± 5.6% for ej138 cells, and 1.08 ± 0.9% and 3.1 ± 0.05% for hfff cells, respectively. the isotype control mab also could not induce significant apoptosis in all examined cells (figure 4). discussion in recent years, the role of ecm components in cancer pathogenesis and their importance in cancer progression, have gained more attention(22,23). although, fibromodulin is one of the active proteoglycan of ecm but its pathophysiological role in cancer development and progression is not yet fully understood. in the present study, the expression of fmod was assessed with three different readout systems such as ihc, icc and flow cytometry by anti-fmod mab. the immunohistochemistry results revealed a higher fmod expression in bladder cancer tissues in comparison with normal samples (figure 1). both bladder cancer cell lines were expressed fmod in immunocytochemistry experiments, while no signal was detected in human normal hfff cell (figure 2). reyes et.al. reported overexpression of fmod in rat prostate cancer urological oncology 192 figure 3. detection of fibromodulin (fmod) in bladder carcinoma and normal cell lines using flow cytometry. a) anti-fmod mab clone 2c2-a1 could detect fmod in 85.9 % and 46.6% of 5637, and ej138 cells as bladder cancer cell lines and 1.30% of hfff cells as a normal cell. the left diagrams are the obtained values for isotype controls in all three cell lines. b) the bar graph of fmod expression average in 5637, ej138, and hfff cells (**: p ≤ .01; ***: p ≤ .001) fibromodulin expression in bladder carcinoma-bayat et al. vol 19 no 3 may-june 2022 100 cell lines by microarray at transcript level(24). the expression of fmod has also been shown in human prostate cancer cells at transcript and protein levels (25). the aberrant expression of fmod in different cancers such as b-cll(11,12), prostate cancer(13), and glioblastoma(14) has also been reported. in our study, such overexpression of fmod was detected in bladder cell lines and tissues from primary bladder carcinoma patients. this probably marks fmod as a tumor-associated marker (25). the flow cytometry results revealed that 2c2-a1 mab could detect cell surface fibromodulin in 84.05 ± 1.85% and 46.1 ± .4% of 5637 and ej138 bladder cancer cells, respectively (figure 3). the differences in fmod expression level might be related to the origin and nature of the cells. the 5637 cell line is known as a non-invasive grade ii while the ej138 cells is considered as an invasive transitional bladder carcinoma(26). lower expression of fmod in ej138 is associated to an invasive phenotype of bladder cancer which could be used as a differential marker in bladder carcinoma grading. to validate the high level expression of fmod and its relationship to invasiveness of bladder carcinoma, an extended study on a large group of patients is necessary. retrospective studies have reported that fmod is a cytosolic or secretory protein especially in normal cells (12) with no cell surface expression. here, we revealed that fmod is not only localized to cytoplasm environment, but also expressed on cell surface(9). in flow cytometry assays, for obtaining an arbitrary value and estimating the average number of receptors on both cell lines, mfi was multiplied to the percentage of reactivity(20). by using this arbitrary value one may discriminate between cancer and inflammation conditions as there are always trace amount of protein expression in inflammatory conditions compare to higher expression in cancerous cells. our findings revealed significant apoptosis induction in both bladder cancer cells upon treatment with 2c2-a1 mab (figure 4). the high percentage of apoptosis in both bladder cell lines and neglectable apoptosis induction in normal hfff cells might indicate fmod as a survival factor. fmod modulates tgf-β functions such as apoptosis figure 4. measurement of apoptosis in bladder carcinoma and normal cell lines using flow cytometry. a) detection of early and late apoptosis after 6 hours of treatment of the cells by anti-fmod monoclonal antibody (mab) clone 2c2-a1. the percentage of viable cells after treatment were 77.5 and 72% for 5637 and ej138 (as bladder cancer cell lines) respectively and 97.5% for hfff cells. b) the bar graph of apoptosis induction for 6 hours incubation by anti-fmod mab clone 2c2-a1. c) the same experiment after 12 hours treatment, the percentage of viable cells were reduced to 58.4% in 5637 and 35.9% in ej138 cells, the viable cells percentage for hfff was same to the result of 6 hours treatment. d) the bar graph of apoptosis induction for 12 hours incubation by anti-fmod mab clone 2c2-a1. the mouse igg isotype control mab did not induce apoptosis in the examined cells also the anti-fmod antibody could did not induce apoptosis in hfff cells as a normal cell line (*: p ≤ .05; **: p ≤ .01). fibromodulin expression in bladder carcinoma-bayat et al. vol 19 no 3 may-june 2022 193 through its binding site inhibiting the role of tgf-β in apoptosis induction(10). apparently, anti-fmod antibody blocks the binding site of fmod to tgf-β which subsequently increases apoptosis. interestingly, in vitro apoptosis induction by anti-fmod, occurred in the lack of any immune system mediators such as antibody dependent cell mediated cytotoxicity (adcc) and complement dependent cell cytotoxicity (cdc). therefore, we speculate that using anti-fmod antibody as anti-cancer agent strengthens the property of anti-fmod antibody. another output from current study might be the use of anti-fmod antibody as a diagnostic tool for immunoassay-based detection and characterization of bladder cancer cells. gpianchored phenomenon might expand this hypothesis to other secreted proteoglycans such as prelp, decorin, biglycan, lumican, keratocan, and osteoadherin(9). it is wise to study the cell surface expression of other proteoglycans in bladder carcinoma. common strategies for treatment of bladder cancer such as surgery, radiation therapy, intravesical chemotherapy such as mitomycin c and intravesical immunotherapy like bacillus calmette-guerin (bcg)(27) have side effects on cancer targeted therapy. consequently, targeting by therapeutic agents especially monoclonal antibodies might be considered as an option for treatment of bladder cancer. the current diagnostic methods for bladder carcinoma include an invasive method such as cystoscopy and biopsy and non-invasive method like urine cytology, ctsacn and mri(28). several markers like urovysion, nmp22, bta and immunocyt/ucyt+ are also used for detection of bladder carcinoma. although these tests are highly sensitive and specific, they are expensive(29). using specific monoclonal antibodies reduces many of such complications. therefore, a noninvasive diagnostic as well as a monitoring technique using immunohistochemistry and urine samples from patients with bladder cancer using anti-fmod antibody in flow cytometry technique is recommended. this study indicates the critical role of fmod in bladder cancer cell surviving, therefore could be applied as a valuable target in bladder cancer therapeutics. the results from this part are in line with our previously reports emphasizing usefulness of fmod targeting by monoclonal antibody and silencing its gene using sirna as a cancer therapy strategy in cll(9,30). the cell surface expression of fmod and survival dependency of bladder cancer cells to its signaling pathway, suggest fmod as a promising 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metastasisassociated genes in rat prostate cancer cell lines. biomedica. 2007;27:190-203. 25. reyes n, benedetti i, bettin a, rebollo j, geliebter j. the small leucine rich proteoglycan fibromodulin is overexpressed in human prostate epithelial cancer cell lines in culture and human prostate cancer tissue. cancer biomarkers : section a of disease markers. 2016;16(1):191-202. 26. luo y, zhu yt, ma ll, pang sy, wei lj, lei cy, et al. characteristics of bladder transitional cell carcinoma with e-cadherin and n-cadherin double-negative expression. oncol lett. 2016;12(1):530-6. 27. malmström p-u, sylvester rj, crawford de, et al. an individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin c versus bacillus calmette-guérin for non– muscle-invasive bladder cancer. european urology. 2009;56(2):247-56. 28. zhu cz, ting hn, ng kh, ong ta. a review on the accuracy of bladder cancer detection methods. journal of cancer. 2019;10(17):4038-44. 29. he h, han c, hao l, zang g. immunocyt test compared to cytology in the diagnosis of bladder cancer: a meta-analysis. oncology letters. 2016;12(1):83-8. 30. farahi l, ghaemimanesh f, milani s, et al. anchored fibromodulin as a novel target in chronic lymphocytic leukemia: diagnostic and therapeutic implications. iranian journal of immunology : iji. 2019;16(2):127-41. fibromodulin expression in bladder carcinoma-bayat et al. vol 19 no 3 may-june 2022 195 v07_no_4.pdf clinical pathology case 275urology journal vol 7 no 4 autumn 2010 a complication after percutaneous nephrolithotomy farzaneh sharifiaghdas, nasser simforoosh, ardalan ozhand urol j. 2010;7:275-7. www.uj.unrc.ir urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, m.c., tehran, iran case presentation a 24-year-old woman with left renal pelvis and lower calyceal stones was admitted for percutaneous nephrolithotomy (pcnl) (figure 1). the surgery was uneventful. nephrostomy tube and ureteral stent were removed on the 2nd postoperative day. soon after, urine leakage from the site of the nephrostomy tube and fever developed. temperature was as to 20 000/mm3, with neutrophils as the dominant part (80%), was reported. double j stent was inserted through ureteroscope. on the 3rd postoperative day, the patient showed signs and symptoms of obstipation, vomiting, abdominal tenderness and rebound tenderness, and high fever. plain abdominal x-ray at supine and upright position revealed air fluid level and no evidence of gas pattern in the pelvis (rectum) and sentinel loop in the left upper quadrant (figure 2). chest x-ray revealed pleural effusion in both sides (figure 3). quiz what could be the possible cause of the abdominal pain and obstipation? what is your suggestion as the next step of diagnosis and treatment? figure 1. intravenous urography demonstrates a 3-cm stone in the left kidney. a b clinical pathology case 276 urology journal vol 7 no 4 autumn 2010 patient was discharged thereafter. differential diagnoses for this patient are as follows: 1bowel injury: that may mimic signs and symptoms of urinoma. but by the bladder drainage and placement of double-j ureteral stent, patient’s symptoms will not disappear and will deteriorate continuously. 2splenic and liver injury: in which, the serum level of hemoglobin decreases. there is a distention of abdominal cavity, and the patient suffers from signs and symptoms of shock. 3pleural effusion: patient complains from fever and dyspnea. chest x-ray reveals a blunted costovertebral angle. the bowel movement decreases; thus, the patient may have vomiting in absence of obstipation. plain abdominal x-ray reveals air fluid pattern level. conservative treatment with potassium chloride (kcl) 30 meq /day, ceftriaxone 1 gr twice/ day, and metronidazole 500 mg three times/day was started. the patient was under close followup. abdominopelvic computed tomography scan with contrast medium showed a huge retroperitoneal urinoma, which extended from the lower pole of the left kidney to the ipsilateral pelvic cavity. a massive pleural effusion was also seen in both sides (figure 1). indwelling urethral catheter was placed into the bladder and the patient was kept nil per os (npo) until the 7th postoperative day. on the 7th postoperative day, the patient showed signs of bowel movement, defecation, and gas passage. vomiting stopped and the temperature became normal (37.1ºc). repeated ultrasonography and chest x-ray on the 7th postoperative day revealed a normal kidney without any evidence of urinoma or pleural effusion (figure 2). the figure 2. plain abdominal radiography shows multiple air fluid level patterns and empty pelvic cavity. figure 3. chest x-ray reveals bilateral pleural effusion. answers: clinical pathology case 277urology journal vol 7 no 4 autumn 2010 4ileus: it is usually related to decreased serum level of potassium, and mimics all signs and symptoms of urinoma formation. this case highlights that urinary leakage and urinoma formation may mimic the signs and symptoms of iatrogenic bowel injury, and conservative treatment is successful in management of this condition. figure 1. abdominopelvic computed tomography demonstrates a huge urinoma extending to the ipsilatral pelvic cavity. figure 2. normal chest x-ray after conservative treatment. vol 19 no 1 january-february 2022 138 the validity of neutrophil/lymphocyte ratio as a predictive factor for systemic inflammatory response syndrome after flexible ureteroscopy lithotripsy renran bai1#, liang gao1#, li jiang,1 yongbo chen2, qing jiang 1* purpose: to explore the risk factors and predictive factors of systemic inflammatory response syndrome (sirs) after flexible ureteroscopy (furs) for upper urinary tract stones. materials and methods: patients who underwent furs from january 2014 to september 2019 were retrospectively analyzed, which were divided into the sirs group and non-sirs group. clinical data of all patients, including gender, age, american society of anesthesia score, diabetes, etc., were collected. univariate and multivariate logistic regression was used to determine the independent risk factors for sirs after furs, and the receiver operating characteristic (roc) curve was drawn to verify the validity of the results. in addition, patients from october 2019 to january 2020 were prospectively collected to verify the results. results: a total of 369 patients were retrospectively included. univariate analysis showed significant differences in postoperative stone residuals (p = 0.039), preoperative neutrophil/ lymphocyte ratio (nlr) (p < 0.001), and lymphocyte/monocyte ratio (lmr) (p = 0.001) between two groups. further, preoperative nlr and postoperative stone residuals were independent according to multivariate logistic regression analysis. the optimal cut-off value of preoperative nlr by roc curve was 2.61, and the area under roc curve was 77.9%. prospective analysis based on 53 patients showed that the incidence of sirs in patients with nlr > 2.61 was significantly higher than that in other patients. (rr = 4.932, p = 0.040). conclusion: preoperative nlr can be used as a predictive factor for sirs in patients with furs according to our study. it may provide an evidence for clinicians to make preoperative decisions or medical plans. keywords: furs; sirs; neutrophil/lymphocyte ratio; inflammation introduction the application of flexible ureteroscope had a his-tory of more than 50 years since it was firstly used in 1964(1). with the rapid improvement of endoscopies in recent years, flexible ureteroscope was widely used in the diagnosis and treatment of urinary diseases(2). though flexible ureteroscopy (furs) had gradually become one of the main choice for upper urinary tract stones because of its safety and effectiveness(3), complications were also reported. a retrospective study showed that the incidence of infectious complications after furs ranged from 1.7% to 18.8%, including fever, septicemia and septic shock(4). without timely treatment, patients might rapidly deteriorate to serious complications, such as urogenic sepsis, septic shock, or even multiple organ dysfunction syndrome. it was estimated that the mortality was reported to be 10-20% in simple sepsis, 20-50% in severe sepsis, and 40-80% in septic shock(5). therefore, it was very important to predict the infectious complications after an operation on upper urinary tract stones. previous studies had reported that the neutrophil/lymphocyte ratio (nlr), platelet/lymphocyte ratio (plr), and lymphocyte/monocyte ratio (lmr) could predict the infection and prognosis for tumor patients(6,7). however, it was still obscure whether they could predict the occurrence of systemic inflammatory response syndrome (sirs) after furs. therefore, we aimed to explore the risk factors of sirs after furs and the clinical significance of nlr, plr and lmr in predicting sirs after furs. materials and methods general information a total of 369 patients with upper urinary stones who underwent furs in the second affiliated hospital of chongqing medical university from january 2014 to september 2019 were retrospectively included. according to whether these patients were diagnosed with sirs after operation, they were divided into the sirs group and nonsirs group. in total, there were 29 males and 14 females with an average age of 54.9 ± 11.3 years were included in the sirs group, and 223 males and 103 females with an average age of 51.1 ± 12.7 years were included in non-sirs group. further, the data of 53 patients from october 2019 to january 2020 were prospectively collected to verify the results. inclusion and exclusion criteria inclusion criteria: all patients with upper urinary tract 1department of urology, the second affiliated hospital of chongqing medical university, china 74#linjiang road, chongqing, cn 400010. 2peoples hospital of deyang city, china 173#northern taishan road, deyang, cn 618000. *correspondence: department of urology, the second affiliated hospital of chongqing medical university, 74# linjiang road chongqing, cn 400010 phone: +86135 0834 6066. email: jiangqing066@163.com. received november 2020 & accepted may 2021 endourology and stone disease urology journal/vol 19 no. 1/ january-february 2022/ pp. 17-21. [doi: 10.22037/uj.v18i.6570] stones treated by furs. exclusion criteria: (1) patients who met at least one of sirs diagnostic criterions before operation(10).(2) patients with tumors, hematological diseases or other diseases.(3) patients with abnormal urinary system anatomy, such as horseshoe kidney, polycystic kidney, ureteropelvic junction obstruction, etc.(4) patients needing simultaneous operations; (5) pregnant women or children. all patients underwent routine urine examination and culture to determine whether patients were suffered from urinary tract infection. if infection existed, sensitive antibiotics would be intravenously used. following, the operation could be performed after the infection was controlled and urine culture was negative. antibiotics were routinely used for no more than 48 hours after operation, which would be prolonged if infections could not be controlled(8). surgical procedures the operation was performed by a senior doctor (q. jiang). after general anesthesia, a lithotomy position was adopted. the first-stage double-j stent in a part of patients would be taken out. following, the ureter would be examined by ureteroscope (9.5f storz), and a guide wire would be placed before the flexible ureteroscope sheath (14f cook) inserted. further, the flexible ureteroscope (7.5f storz) accompanying by a holmium laser (200um) was used for lithotripsy with energy of 1j and a frequency of 20hz. after the stones were crushed, they would be removed using a basket as much as possible. finally, a 5f double-j stent and catheter would be inserted. for some patients with bilateral operation, the contralateral would be treated by the same method. importantly, the blood routine for the diagnosis of sirs was immediately tested after surgery to avoid possible bias. research indicators gender, age, american society of anesthesia (asa) score, diabetes, previously urinary system surgery on the affected side, stone burden, unilateral or bilateral surgery, preoperative double-j stent indwelling, opertable 1. the demographic characteristics and surgery-related data of included patients. overall non-sirs group sirs group p 95% ci number of patients (n) 369 326 43 age (years old, mean ± sd) 51.6 ± 12.6 51.1±12.7 54.9 ± 11.3 0.063 -7.782-0.207 gender ((n, %) 0.898 0.530-2.062 -male 252 (68.3%) 223 (68.4%) 29 (67.4%) -female 117 (31.7%) 103 (31.6%) 14 (32.6%) stone surgery history (n, %) 110 (29.8%) 95 (29.1%) 15 (34.9%) 0.439 0.666-2.548 -pcnl 17 (4.6%) 15 (4.6%) 2 (4.7%) -eswl 41 (11.1%) 38 (11.7%) 3 (7.0%) -urs/furs 43 (11.7%) 34 (10.4%) 9 (20.9%) -open surgery 9 (2.4%) 8 (2.5%) 1 (2.3%) diabetes (n,%) 55 (14.9%) 52 (16.0%) 3 (7.0%) 0.120 0.118-1.325 asa score(mean±sd) 2.1 ± 0.4 2.1 ± 0.4 2.1 ± 0.4 0.772 -0.104-0.140 stone burden(cm2, mean±sd) 1.04 ± 0.90 1.04 ± 0.88 1.06 ± 1.05 0.931 -0.301-0.275 operation time(min, mean±sd) 69.4±36.6 69.6 ± 37.1 67.8 ± 33.3 0.766 -9.928-13.456 preoperative serum reatinine(n,%) 0.872 0.261-3.127 -normal 341 (92.4%) 301 (92.3%) 40 (93.0%) -elevated 28 (7.5%) 25 (7.7%) 3 (7.0%) postoperative stone residuals (n, %) 0.039 1.026-4.256 -no 300 (81.3%) 270 (82.8%) 30 (69.8%) -yes 69 (18.7%) 56 (17.2%) 13 (30.2%) preoperative nlr(mean±sd) 2.75 ± 1.47 2.60 ± 1.26 3.90 ± 2.28 < 0.001 -1.749-0.847 preoperative plr(mean±sd) 130.15 ± 51.55 128.70 ± 50.04 141.16 ± 62.40 0.136 -28.885-3.957 preoperative lmr(mean±sd) 4.96 ± 2.36 5.12 ± 2.40 3.82 ± 1.66 0.001 0.556-2.038 unilateral or bilateral (n,%) 0.498 0.564-3.237 -unilateral 321 (87.0%) 285(87.4%) 36 (83.7%) -bilateral 48 (13.0%) 41(12.6%) 7 (16.3%) preoperative d-j stent(n,%) 0.151 0.034-1.911 -no 340 (92.1%) 298 (91.4%) 42 (97.7%) -yes 29 (7.9%) 28 (8.6%) 1 (2.3%) nlr could predict sirs after furs abbreviations: pcnl: percutaneous nephrolithotripsy; eswl: extracorporeal shock wave lithotripsy; urs: ureteroscopy lithotripsy; furs: flexible ureteroscopy; asa: american society of anesthesiologists score; nlr: neutrophil/lymphocyte ratio; plr: platelet/lymphocyte ratio; lmr: lymphocyte/monocyte ratio; ci: confidence interval; sirs: systemic inflammatory response syndrome. figure 1. the roc of preoperative nlr. endourology and stones diseases 18 vol 19 no 1 january-february 2022 138 ation time, postoperative stone residuals, preoperative serum creatinine, and nlr, plr, and lmr from preoperative blood routine within 3 days were collected. in addition, postoperative kub without stones or residuals smaller than 3mm was defined as no stone residual(11). more, the stone burden was calculated by multiplying the longest diameter of the perpendicular diameter of the stone. in patients with multiple stones, the total stone burden was calculated as the sum of the burden of each stone. (cm2)(9). the collection and evaluation of all data was carried out by one researcher (r. bai). sirs standard postoperative patients who met two or more items of the following criteria could be diagnosed as sirs(10) (including 1) white blood cell count < 4 × 109 or > 12 × 109, or immature cell > 10%; 2) body temperature t > 38℃ or < 36℃; 3) heart rates > 90 bpm; 4) respiratory rates > 20/min, or paco2 < 32 mmhg. statistical methods the data were processed by spss17.0 software. the continuous data were shown as mean ± standard deviation (sd), and the counting data were shown as number and rate. moreover, t-test and chi-square tests were respectively used to compare these data between groups. a logistic regression analysis was used to determine possible risk factors, and the receiver operating characteristic (roc) curve was used to calculate the maximum sum of sensitivity and specificity to be the optimal cut-off point of independent risk factors. p < 0.05 was regarded to be statistically significant. results this study was approved by the ethics committee of the second affiliated hospital of chongqing medical university (approval number: 2020519). in retrospective analysis, the average age of all patients was 51.6 ± 12.6 years. postoperative stone residuals were significantly more in sirs group (30.2% vs 17.2%, p = 0.039). a total of 110 (29.8%) patients had experienced at least one treatment because of upper urinary tract stones before, including shock wave lithotripsy (swl), ureteroscopy lithotripsy (urs), furs, percutaneous nephrolithotripsy (pcnl), or open surgery. in addition, compared to the patients in non-sirs group, the preoperative nlr was significantly higher (3.90 ± 2.28 vs 2.60 ± 1.26, p < 0.001) and the preoperative lmr was significantly lower (3.82 ± 1.66 vs 5.12 ± 2.40, p = 0.001) for patients in sirs group. however, no significant differences between the two groups could be found in age (p = 0.063), asa score (p = 0.772), stone burden (p = 0.931), operation time (p = 0.766), preoperative serum creatinine (p = 0.872), diabetes (p = 0.120), unilateral or bilateral surgery (p = 0.498), preoperative double-j stent indwelling (p = 0.151), and plr value (p = 0.136), respectively. no patient dead from sirs and other complications. the detailed demographic characteristics and clinical data of all patients had been shown in table 1. multivariate logistic regression analysis showed that preoperative nlr (or = 1.497, 95% ci 1.156 1.938, p = 0.002) and postoperative stone residuals (or = 2.592, 95% ci 1.092 6.153, p = 0.031) were independent risk factors which could lead to sirs after furs. however, the effect of preoperative lmr became insignificant (p = 0.205). (table 2) roc curve showed that the best cut-off value of preoperative nlr was 2.61, with a sensitivity of 67.4% (95% ci 0.513 0.805), specificity of 61.0% (95% ci 0.555 0.663), positive predictive value of 18.7% (95% ci 0.130 0.258), and negative predictive value of 93.5% (95% ci 0.890 0.962). the area under roc curve could be calculated to be 77.9% (p < 0.001, 95% ci 0.706 0.852) (figure 1). further, to verify the results, 53 patients who received furs treatment from october 2019 to january 2020 were prospectively analyzed. all patients met the inclusion criteria. according to whether the preoperative nlr value was less than 2.61, the patients were divided into two groups (table 3). the incidence of sirs between two groups showed a significant difference (rr = 4.932, p = 0.040). discussion the feasibility, safety and effectiveness of furs for upper ureteral stones had been verified for a long time(12). however, complications were also reported, such as renal colic, urinary tract infection, stone street formation, ureteral stent-related symptoms and ureteral stricture, etc(13). infection was one of the most common complications. if untreated, it could rapidly develop into sirs, bacteremia and even sepsis. up to now, many studies had been carried out to explore the risk factors of infection after furs. in fan’s study(4), preoperative pyuria, infectious stone and operation time was found to be closely related to infection after furs. while senocak et al. believed that positive urine culture before surgery would an important factor(15). further, ozgor et al. found that risk factors of operation time longer than 60 min, renal function and age might be independent for furs related infection(16). however, there was no consensus on this issue. in our study, we found that patients with stone residuals after furs had a higher risk to sirs, which was similar to a retrospective study for patients after pcnl(17). the reason for stone residuals leading to fever or infection p or 95% ci age 0.078 1.030 0.997-1.065 gender 0.928 1.037 0.471-2.282 stone surgery history 0.305 1.494 0.693-3.219 diabetes 0.154 0.389 0.106-1.424 asa score 0.242 0.521 0.174-1.554 stone burden 0.986 1.004 0.635-1.588 operation time 0.413 0.995 0.984-1.007 preoperative serum reatinine 0.295 0.457 0.106-1.977 postoperative stone residuals 0.031 2.592 1.092-6.153 preoperative nlr 0.002 1.497 1.156-1.938 preoperative plr 0.252 0.995 0.988-1.003 preoperative lmr 0.205 0.868 0.698-1.080 unilateral or bilateral 0.738 1.198 0.417-3.443 preoperative d-j stent 0.216 0.268 0.033-2.157 table 2. multivariate logistic regression results. abbreviations: or: odds ratio; ci: confidence interval; asa score: american society of anesthesiologists score; nlr: neutrophil/lymphocyte ratio; plr: platelet / lymphocyte ratio; lmr: lymphocyte / monocyte ratio. nlr could predict sirs after furs vol 19 no 1 january-february 2022 19 endourology and stones diseases 20 might be that the fragments of residuals contained bacteria or endotoxins(18). in another study, degirmenci et al. obtained a similar result(19). they believed that the infectious complications caused by residual fragments would be due to microorganisms, which might easily enter vessels through the damaged endothelium, thus leading to systemic complications, including sirs. another reason might be that the residual fragments or powder blocked the double-j stent, resulting in evidently increased pressure in renal pelvis. it would be more helpful to bacteria migration and endotoxins absorption. however, some researchers argued that there was insignificant relationship between residuals and postoperative infectious complications(10,20). therefore, this result needed to be further verified. the concept of nlr was first put forward by goodman et al(21). in 1995, they found that nlr was more sensitive than white blood cell count in the diagnosis of appendicitis. subsequently, more and more studies proved that nlr was related to the severity of sepsis(22). in addition, several studies had reported that preoperative nlr and plr could be used as predictors for sirs or sepsis after pcnl(8,9,14). however, their role in furs was still obscure. the results from roc curve and prospective analysis in our study showed that when the nlr value was higher than 2.61, sirs would be easier to occur after operation. but, the best cutoff point in sen’s study was reported to be 2.50(8). gurol et al. proposed that the best nlr cutoff point for predicting bacteremia and septicemia was 5.0(23). this difference might be caused by different ethnic groups(24). further studies had shown that the increase of nlr would related to the levels of plasma pro-inflammatory cytokines, such as il-1, il-6, il-7, il-8, il-12, etc(25). accumulation of these cytokines in the tissue microenvironment could lead to excessive inflammation. more, hwang et al.(26) believed that neutrophils responded rapidly to infection, resulting in a sharp increase in affected areas. on the other hand, the release of various anti-inflammatory cytokines could induce immunosuppression and evident lymphocyte apoptosis. another study demonstrated that neutrophil apoptosis could be delayed in patients with severe sepsis(27). summarizing, preoperative nlr might be useful as a predictor for sirs after furs(28). some study proved that plr and lmr was also related to infection. a meta-analysis mentioned that plr was associated with helicobacter pylori infection(29), while others confirmed that lmr was associated with viral infection(30). however, insignificancies were found for these two parameters in our study. finally, several limitations in this study should be considered. at first, this study was a single-center retrospective study, a selection bias could not be avoided though a prospective analysis was also carried out. secondly, there was no bacterial culture of urine and stones during/after the operation, some parameters could not be included for analysis, such as pyuria, infectious stones, etc. therefore, the results of this study needed to be further verified. conclusions according to our results, preoperative nlr might be a simple and noninvasive method for predicting the occurrence of postoperative sirs. those patients with preoperative nlr greater than 2.61 and postoperative stone residuals should be more concerned. conflict of interest the authors have no conflicts of interest to declare. references 1. marshall vf. fiber optics in urology. j urology 1964;91:110-114 2. forbes cm, lundeen c, beebe s, et al. device profile of the lithovue single-use digital flexible ureteroscope in the removal of kidney stones: overview of safety and efficacy. expert rev med devic 2020; 17: 1257-64. 3. knoll t, jessen jp, honeck p, wendtnordahl g. flexible ureterorenoscopy versus miniaturized pnl for solitary renal calculi of 10–30 mm size. world j urol 2011;29:755-9. 4. fan s, gong b, hao z, et al. risk factors of infectious complications following flexible ureteroscope with a holmium laser: a retrospective study. int j clin exp med 2015;8:11252. 5. wagenlehner fme, tandogdu z, bjerklund johansen te. an update on classification and management of urosepsis. curr opin urol nlr ≥ 2.61 nlr < 2.61 p 95% ci number of patients (n) 22 31 sirs (n, %) 7 (31.8%) 2 (6.5%) 0.040 1.130-21.523 age(mean ± sd) 49.41 ± 14.47 46.52 ± 14.78 gender (n, %) -male 16 (72.7%) 22 (71.0%) -female 6 (27.3%) 9 (29.0%) stone surgery history (n, %) 6 (27.3%) 4 (12.9%) diabetes (n, %) 1 (4.5%) 4 (12.9%) stone burden(cm2, mean±sd) 0.86 ± 0.72 0.77 ± 0.38 preoperative serum reatinine (n, %) 5 (22.7%) 6 (19.4%) postoperative stone residuals (n, %) 1 (4.5%) 1 (3.2%) unilateral or bilateral (n, %) -unilateral 19 (86.4%) 30 (96.8%) -bilateral 3 (13.6%) 1 (3.2%) preoperative d-j stent (n, %) 1 (4.5%) 6 (19.4%) table 3. verification results of preoperative nlr in predicting the occurrence of sirs. abbreviations: nlr: neutrophil/lymphocyte ratio; ci: confidence interval; sirs: systemic inflammatory response syndrome. nlr could predict sirs after furs vol 19 no 1 january-february 2022 138 2017;27:133-7. 6. hu h, yao x, xie x, et al. prognostic value of preoperative nlr, dnlr, plr and crp in surgical renal cell carcinoma patients. world j urol 2017; 35: 261-70. 7. rajwa p, życzkowski m, paradysz a, bujak k, bryniarski p. evaluation of the prognostic value of lmr, plr, nlr, and dnlr in urothelial bladder cancer patients treated with radical cystectomy. eur rev med pharmaco 2018; 22: 3027-37. 8. consensus group of chinese expert for prevention of surgical site infection in urology. consensus of chinese experts on prevention of surgical site infection in urology (version 2019). chinese journal of urology 2019: 4014. 9. sen v, bozkurt ih, aydogdu o, et al. significance of preoperative neutrophil– lymphocyte count ratio on predicting postoperative sepsis after percutaneous nephrolithotomy. kaohsiung j med sci 2016;32:507-13. 10. levy mm, fink mp, marshall jc, et al. 2001 sccm/esicm/accp/ats/sis international sepsis definitions conference. crit care med 2003;31:1250-6. 11. mi q, meng x, meng l, chen d, fang s. risk factors for systemic inflammatory response syndrome induced by flexible ureteroscope combined with holmium laser lithotripsy. biomed res int 2020;2020:1-5. 12. chen h, chen g, zhu y, yang z, xiong c, pan y. analysis of prestenting on outcomes of flexible ureteroscopy for upper urinary urolithiasis: a historical control study. urol int 2019; 102: 175-80. 13. dingwen g, sixing y. present situation and prospect of soft ureteroscopy in the treatment of renal calculi. journal of clinical urology, 2014;029:452-7. 14. cetinkaya m, buldu i, kurt o, inan r. platelet-to-lymphocyte ratio: a new factor for predicting systemic inflammatory response syndrome after percutaneous nephrolithotomy. urol j 2017;14:4089-93. 15. senocak c, ozcan c, sahin t, et al. risk factors of infectious complications after flexible uretero-renoscopy with laser lithotripsy. urol j 2018;15:158-63. 16. ozgor f, sahan m, cubuk a, et al. factors affecting infectious complications following flexible ureterorenoscopy. urolithiasis 2019;47:481-6. 17. gutierrez j, smith a, geavlete p, et al. urinary tract infections and post-operative fever in percutaneous nephrolithotomy. world j urol 2013;31:1135-40. 18. mariappan p, smith g, bariol sv, moussa sa, tolley da. stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study. j urology 2005;173:1610-4. 19. degirmenci t, bozkurt ih, celik s, et al. does leaving residual fragments after percutaneous nephrolithotomy in patients with positive stone culture and/or renal pelvic urine culture increase the risk of infectious complications? urolithiasis 2019;47:371-5. 20. draga rop, kok et, sorel mr, bosch rjlh, lock tmtw. percutaneous nephrolithotomy: factors associated with fever after the first postoperative day and systemic inflammatory response syndrome. j endourol 2009;23:9217. 21. goodman da, goodman cb, monk js. use of the neutrophil:lymphocyte ratio in the diagnosis of appendicitis. am surg 1995;61:257-9. 22. zahorec r. ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill. bratislavské lékarské listy, 2001,102:5. 23. gurol g, ciftci ih, terzi ha, et al. are there standardized cutoff values for neutrophillymphocyte ratios in bacteremia or sepsis? j microbiol biotechn 2015;25:521-5. 24. azab b, camacho-rivera m, taioli e. average values and racial differences of neutrophil lymphocyte ratio among a nationally representative sample of united states subjects. plos one 2014;9:e112361. 25. motomura t, shirabe k, mano y, et al. neutrophil–lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. j hepatol 2013;58:58-64. 26. hwang sy, shin tg, jo ij, et al. neutrophilto-lymphocyte ratio as a prognostic marker in critically-ill septic patients. the american journal of emergency medicine 2017;35:2349. 27. taneja r, parodo j, jia sh, et al. delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity*. crit care med 2004;32:1460-9. 28. aghamir smk, mojtahedzadeh m, meysamie a, et al. comparison of systemic stress responses between percutaneous nephrolithotomy (pcnl) and open nephrolithotomy. j endourol 2008;22:2495500. 29. russell cd, parajuli a, gale hj, et al. the utility of peripheral blood leucocyte ratios as biomarkers in infectious diseases: a systematic review and meta-analysis. j infection 2019;78:339-48. 30. mcclain mt, park lp, nicholson b, et al. longitudinal analysis of leukocyte differentials in peripheral blood of patients with acute respiratory viral infections. j clin virol 2013;58:689-95. nlr could predict sirs after furs vol 19 no 1 january-february 2022 21 the safety of continuing low-dose aspirin therapy perioperatively in percutaneous nephrolithotomy: a systematic review and meta-analysis yang pan1, mingming xu1, jiaqi kang1, shangren wang1, xiaoqiang liu1* purpose: aspirin is often stopped prior to percutaneous nephrolithotomy (pcnl) due to surgical bleeding risk. however, this practice is mainly based on expert opinion, and mounting evidence suggests holding aspirin perioperatively might not be more harmful than once thought. in this systematic review and meta-analysis, we aimed to discuss the safety of continuing low-dose aspirin perioperatively in pcnl. materials and method: we performed a comprehensive literature search in pubmed, embase, web of science, and cochrane library to identify relevant studies up to december 31st, 2021. the robins-i (risk of bias in non-randomized studies of interventions) tool was used to evaluate the quality of the included studies. the safety was assessed by all kinds of perioperative complications and bleeding complications mainly. egger's test estimated publication bias. the statistical analyses were performed using rev-man 5.3 and stata 15.1 software. results: overall, four eligible studies with a total of 1054 patients were included in our study. the meta-analysis results revealed that operative time (95%ci: -14.20 4.50, md = -4.85, p = .31), hospital durations (95%ci: -1.80 0.50, md = -0.65, p = .26), stone size (95%ci: -2.90 0.67, md = -1.11, p = .22), and estimated blood loss (95%ci: -17.15 0.47, md = -8.34, p = .06) were not significantly different between the continuing low-dose aspirin group and the control group. moreover, there were no significant differences in total complication rate (25% vs 27.9%, 95%ci: -0.07 0.08, rd = 0.00, p = .94) and serious complication rate (6.0% vs 3.0%, 95%ci: -0.08 0.06, rd = -0.01, p = .84) between the two groups. similarly, no significant differences were observed in terms of bleeding complication rate (8.3% vs 14.0%, 95%ci: -0.04 0.06, rd = 0.01, p = .75), transfusion rate (5.4% vs 10.8%, 95%ci: -0.04 0.04, rd = -0.00, p = .98), and postoperative thrombotic events rate (0.6% vs 0.2%, 95%ci: -0.03 0.02, rd = -0.00, p = .85). sensitivity analysis suggested that our results were convincing and no publication bias was observed with the egger’s test (p = .112). conclusion: it appears that continuing low-dose aspirin therapy perioperatively in pcnl might be relatively safe. however, further well-designed prospective studies with a large sample size are needed to confirm and validate our findings. keywords: aspirin; percutaneous nephrolithotomy; safety; systematic review; meta-analysis introduction nephrolithiasis is a common disease affecting the general population. for stones larger than 2 cm or stones in the lower pole of the kidney, percutaneous nephrolithotomy (pcnl) is commonly used and recommended by the guidelines for its efficacy and safety(1). in some suitable cases, technological advances in retrograde intrarenal surgery (rirs) have also permitted us to approach those stones of ≥ 2 cm(2,3). renal hemorrhage is one of the more frequent and worrisome complications of pcnl(4). blood transfusion, embolization, and even nephrectomy have been reported to manage severe bleeding(5). due to these complications and risks, aspirin, as an antiplatelet agent, was traditionally discontinued perioperatively to prevent bleeding. moreover, pcnl is categorized as a high-risk procedure for bleeding and the recommendations of the european association of urology (eau) include the suspension of aspirin before proceeding with this kind of procedure(1). however, what interested us was that some reports described that pcnl could be safely performed despite continued aspirin therapy(6-8). in addition, when considering aspirin cessation before surgery, there was an increased risk of cardiovascular events(9,10), which may be associated with aspirin withdrawal syndrome(11). therefore, we conducted this systematic review and meta-analysis of available literature to evaluate the safety of continuing low-dose aspirin therapy perioperatively in the patients who had undergone pcnl. materials and methods this meta-analysis was performed based on the guidelines outlined in the preferred reporting items for systematic reviews and meta-analysis (prisma) statement(12). search strategy we performed a systematic literature search of electronic databases, including cochrane library, pubmed, embase, web of science, and china national knowledge infrastructure. the time range of articles search was set from database building to december 31st, 2021. the search strategy was as follows: (“nephrolithotomy, percutaneous” or “nephrolithotomies, percutaneous” or “percutaneous nephrolithotomies” or “percu1department of urology, tianjin medical university general hospital, tianjin, china. *correspondence: department of urology, tianjin medical university general hospital, tianjin 30052, china. tel: +86 13820915038, fax: +86-22-60814889, e-mail: xiaoqiangliu1@163.com received january 2022 & accepted june 2022 urology journal/vol 19 no. 4/ july-august 2022/ pp. 253-261. [doi: 10.22037/uj.v18i.7170] review taneous nephrolithotomy” or “pcnl” or “pnl”) and (“aspirin” or “acetylsalicylic acid” or “acid, acetylsalicylic” or “2-(acetyloxy)benzoic acid” or “asa” or “acylpyrin” or “aloxiprimum” or “colfarit” or “dispril” or “easprin” or “ecotrin” or “endosprin” or “magnecyl” or “micristin” or “polopirin” or “polopiryna” or “solprin” or “solupsan” or “zorprin” or “acetysal”). all identified studies were then reviewed for eligibility. the reference lists and citations from key studies were also reviewed for additional eligible studies associated with our topic. inclusion and exclusion criteria the studies were included in the meta-analysis if the following inclusion criteria were met: 1) study types: randomized controlled trials (rcts) or retrospective case-control design; 2) included urolithiasis patients who had undergone pcnl; 3) evaluated the safety of continuing low-dose aspirin therapy perioperatively; 4) conducted the safety comparison between the continuing low-dose aspirin therapy group and the control group; 5) provided sufficient data to calculate and analyze. besides, the exclusion criteria were as follows: 1) conference abstract; 2) guidelines; 3) review; 4) case report; 5) editorial comment; 6) animal studies; 7) non-comparative studies; 8) repeated publication. data extraction and outcome measurement all eligible articles and available data from the enrolled studies were extracted, respectively, by two independent reviewers and then checked by each other. if any disagreement appeared, a third reviewer would join in and discuss it with them to reach a consensus. data were extracted from each paper separately and outcome measures were set as follows: first author, publication year, country, study design, study period, techniques used for percutaneous renal access, tract size, number of the surgeon(s), and surgical experience of the surgeon(s), sample size, age, body mass index (bmi), gender ratio, stone size, operative time, and hospital durations. the safety was assessed by all kinds of intraor postoperative complications. serious complications were defined as clavien-dindo grade iiia or higher based on the modified clavien-dindo system. the major complications which occurred with aspirin during pcnl were bleeding. postoperative thrombotic events were also an important concern, especially for patients without continuing aspirin therapy. therefore, our study also focused on these major complications and analyzed the relevant results. besides, hemoglobin drop and estimatendourology and stones diseases 180 table 1. characteristics and quality evaluation of included studies author year country study study technique for tract no. surgical cqc design period renal access size (fr) surgeon experience scores a leavitt et al. 2014 american case–control jul. 2012 to mar. 2014 balloon/amplatz dilators 30fr 3 experienced 8 otto et al. 2017 american case–control feb. 2012 to dec. 2015 balloon/amplatz dilators 30fr 1 experienced 8 wang et al. 2019 china case–control jul. 2014 to jul. 2017 amplatz dilators 18fr 1 experienced 7 falahatkar et al. 2021 iran cross-sectional mar. 2012 to dec. 2018 amplatz dilators 28/30 fr 1 experienced 8 abbreviations: cqc, cambridge quality checklists figure 1. flow diagram of identification and screening of eligible studies (prisma flow diagram). safety of continuing aspirin during pcnl-pan et al. vol 19 no 4 july-august 2022 254 ed blood loss were compared and analyzed. hemoglobin drop meant that the postoperative hemoglobin level decrease compared with that of pre-operative evaluation. quality assessment of included studies the quality of the included studies was assessed by two independent reviewers. the most precise tool to assess the quality of included articles is the risk of bias scales. if the articles were randomized, the cochrane risk of bias tool (rob2) was used(13). for papers reporting on non-randomized controlled studies, the robins-i (risk of bias in non-randomized studies of interventions) tool was applied to assess the risk of bias(14). the robins-i was used to assess the methodological quality of non-randomized studies on seven domains: confounding factors, selection of participants into the study, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported results. each domain was classified as having low, moderate, serious, critical, or no information available for risk of bias. the overall risk of bias for the studies was determined by combining the levels of bias in each domain. moreover, we also appraised study quality by using the cambridge quality checklists(15), which could assess the quality of correlational evidence for risk and protective factors (on the basis of sampling, participation rates, sample size, and measurement reliability), temporal evidence (whether data are cross-sectional, retrospective, or prospective), and causal evidence (whether there is variation in the risk or protective factor, change in outcomes is analyzed, and confounding is accounted for). abbreviations: bmi, body mass index; m, male; f, female; na, not available. data was presented as “the continuing low-dose aspirin group / the control group”. a median. table 2. demographic and clinical characteristics of included patients study sample age bmi gender stone operative hemoglobin estimated blood hospital size (n) (years) (kg/m2) (m: f) size (mm) time (mins) drop (g/dl) loss (ml) duration (days) leavitt et al. 2014 15 69 a 31.1 a 11:4 21 ± 11 74 a 1.9 a 150 a 2.0 a 38 62 a 32.9 a 19:19 23 ± 14 77 a 2.3 a 125 a 2.0 a otto et al. 2017 67 66 ± 10 32.1 ± 9 37:30 37 ± 16 163 ± 62 0.99 ± 1.1 44 ± 45 3.2 ± 2.7 207 52 ± 15 30.3 ± 9 100:107 40 ± 19 190 ± 67 0.94 ± 0.96 54 ± 48 3.2 ± 3.8 wang et al. 2019 44 58.74 ± 10.06 na na 20.60 ± 5.21 28.27 ± 7.08 na 44.94 ± 21.24 na 40 50.40 ±12.49 21.33 ± 5.00 27.02 ± 5.12 51.70 ± 34.22 falahatkar et al. 2021 40 60.08 ± 9.45 28.59 ± 4.91 16:24 32.85 ± 16.37 43.20 ± 21.37 1.02 ± 1.31 na 1.25 ± 0.98 603 48.66 ± 12.32 27.85 ± 4.89 331:272 33.27 ± 13.22 44.83 ± 16.84 1.43 ± 1.44 2.43 ± 1.27 safety of continuing aspirin during pcnl-pan et al. figure 2. results of the risk of bias assessment using robins-i scale. review 255 endourology and stones diseases 182 statistical analysis the mean difference (md) and the risk difference (rd) were used to compare continuous and dichotomous variables, respectively. the relevant results were shown in the forest plot. the quantity of heterogeneity among these articles was tested by cochrane q test and higgins i2 value. the fixed-effects model was used if heterogeneity was thought to be acceptable (i2 < 50%); otherwise, a random-effects model was used. p values of dichotomous and continuous variables were calculated by mantel–haenszel (mh) test and inverse-variance (iv) weighting, respectively. the z test determined all the pooled effects. the sensitivity analysis was performed to explain the high heterogeneity using an article-by-article culling method. the publication bias was estimated by egger's test. the statistical analysis was performed using manager 5.4 (cochrane collaboration, oxford, uk) and stata 15.1 (college station, texas, usa). results of the risk of bias assessment using robins-i were analyzed and visualized using the r software (version 4.1.2, “robvis” package). for all statistical analyses, a two-sided p < .05 was considered statistically significant. results literature search and study characteristics a prisma flow chart of screening and selection results was shown in figure 1. after searching databases systematically, we identified 68 potentially relevant articles. no additional records were identified through other sources. there were 53 different articles after removing duplicates. according to the inclusion and exclusion criteria, 43 articles were excluded after reviewing their titles or abstracts. the remaining 10 studies were assessed for eligibility by reading full texts. after a full-text review, four eligible studies with a total sample size of 1054 patients were included in the meta-analysis finally(16-19). table 3. intraor postoperative complications of the included patients study no. (%) of no. (%) of no. (%) of no. (%) of no. (%) of postoperatives total complications serious complications* bleeding complication needing transfusion thrombotic event leavitt et al. 2014 5 (29%) a 1 (6%) a 3 (18%) a 3 (18%) a 0 14 (33%) a 7 (16%) a 8 (19%) a 6 (14%) a 0 otto et al. 2017 23 (34.4%) 7 (10.4%) 2 (3.0%) 1 (1.5%) 1 (1.5%) 55 (26.6%) 12 (5.8%) 6 (2.9%) 2 (1.0%) 0 wang et al. 2019 1 (2.3%) 0 0 0 0 3 (7.5%) 3 (7.5%) 1 (2.5%) 0 2 (5%) falahatkar et al. 2021 13 (32.5%) 2 (5.0%) 9 (22.5%) 5 (12.5%) 0 177 (29.4%) 5 (0.8%) 110 (18.2%) 88 (14.6%) 0 data was presented as “the continuing low-dose aspirin group / the control group”. * clavien iiia or greater. a total number of pcnl procedures as denominator. figure 3. forest plot of clinical characteristics including stone size, hospital duration, estimated blood loss, and operative time between the continuing low-dose aspirin group (group a) and the control group (group b). safety of continuing aspirin during pcnl-pan et al. vol 19 no 4 july-august 2022 256 the characteristics and quality evaluation of eligible studies are reported in table 1. overall, the quality of retrospective case-control studies was relatively high. only one study was considered as a serious risk of bias based on the robins-i assessment. the whole results of the risk of bias assessment using robins-i were shown in figure 2. in addition, the majority of studies reported the demographic and clinical characteristics such as patients’ average age, bmi, sex ratio, and stone size. the demographic and clinical characteristics of figure 5. forest plot of bleeding complication rate, needing transfusion rate, and postoperative thrombotic events rate between the continuing low-dose aspirin group (group a) and the control group (group b). figure 4. forest plot of total complication rate and serious complication rate between the continuing low-dose aspirin group (group a) and the control group (group b). safety of continuing aspirin during pcnl-pan et al. review 257 enrolled patients were summarized in table 2. perioperative and clinical characteristics the meta-analysis results revealed that operative time (95%ci: -14.20 4.50, md = -4.85, p = .31; figure 3) and hospital durations (95%ci: -1.80 0.50, md = -0.65, p = .26; figure 3) were both not significantly different between the continuing low-dose aspirin group and the control group. however, significant heterogeneity was reported (p = .006, i² = 80%; and p = .009, i² = 85%, respectively, figure 3). similarly, no significant differences were observed in terms of stone size (95%ci: -2.90 0.67, md = -1.11, p = .22; figure 3) and estimated blood loss (95%ci: -17.15 0.47, md = -8.34, p = .06; figure 3). the heterogeneity was low (p = .83, i2 = 0%; and p = .72, i2 = 0%; respectively). in addition, three studies reported that there was no difference in the change of hemoglobin, hematocrit, or serum creatinine between the two groups. total complications and serious complications the results of complications were summarized and listed in table 3. all eligible studies reported total complication rate. the total complication rate was presented in figure 4. there was no statistically significant difference in the total complication rate between two groups (25% vs 27.9%, 95%ci: -0.07 0.08, rd = 0.00, p = .94; figure 4). the heterogeneity was also relatively low (p = .29, i2 = 20%; figure 4). serious complications were defined as clavien-dindo grade iiia or higher based on the modified clavien-dindo system. similarly, no statistically significant difference was reported in the serious complication rate between two groups (6.0% vs 3.0%, 95%ci: -0.08 0.06, rd = -0.01, p = .84; figure 4), however, relatively high heterogeneity was reported (p = .07, i² = 57%; figure 4). major complications the meta-analysis results revealed that no significant differences were observed in terms of bleeding complication rate (8.3% vs 14.0%, 95%ci: -0.04 0.06, rd = 0.01, p = .75; figure 5), needing transfusion rate (5.4% vs 10.8%, 95%ci: -0.04 0.04; rd = -0.00, p = .98; figure 5), and postoperative thrombotic events rate (0.6% vs 0.2%, 95%ci: -0.03 0.02; rd = -0.00, p = .85; figure 5). moreover, there was no significant heterogeneity (p = .71, i² = 0%; p = .94, i² = 0%; and p = .51, i² = 0%; respectively; figure 5). sensitivity analysis and publication bias after the research by otto et al. was excluded, the i2 value in operative time changed from 80% to 0%. the analysis suggested that this study might be the major cause of the heterogeneity for operative time. the heterogeneities for other results were relatively low and still stable, when we got rid of one or two studies every time from the meta-analysis. therefore, the sensitivity analysis suggested that our results were convincing. in addition, no publication bias in the primary outcome (total complications) was observed with the egger’s test (p = .112, figure 6). discussion many urologic surgeries including prostate biopsies, renal biopsies, robot-assisted radical prostatectomy, and kidney transplants have been reported to have no significant increase in the risk of major bleeding complications and transfusion rate with a continuation of perioperative aspirin(20-26). based on our systematic review and meta-analysis, we further find that there might be no significantly higher risk of bleeding during pcnl for patients continuing low-dose aspirin therapy. the risk factors for bleeding after pcnl are complex. figure 6. egger’s plot for total complications rate. safety of continuing aspirin during pcnl-pan et al. vol 19 no 4 july-august 2022 258 some studies show that upper caliceal puncture, solitary kidney, staghorn stone, multiple punctures, surgeon experience, and the presence of diabetes mellitus are factors associated with increased risk for bleeding during pcnl(27,28). the other important factors relevant to bleeding during pcnl include larger tract size, longer surgical duration, greater stone burden, the workload of the surgical surgeon, and so on(29). different pcnl techniques could also influence bleeding and complications. all kinds of techniques associated with reducing bleeding during pcnl have been reported, and one predominant technique is to decrease the size of percutaneous renal access because renal access has a potential impact on renal tissue and blood loss. a smaller tract could prevent the parenchymal and infundibular trauma, thereby resulting in less hemorrhage and lower pcnl-associated complication rates. the most notable ones are mini pcnl where sheaths from 15 fr to 20 fr are deployed, and ultra-mini pcnl where sheath sizes range from 11 fr to 14 fr(30). compared to standard pcnl, the hemoglobin drop, reported pain, need for transfusion, and duration of hospitalization were all lesser in patients who had undergone mini-pcnl and ultra mini pcnl(31). there is no certainty as to whether aspirin was the responsible factor for bleeding disparities in some small studies(32,33). furthermore, the eau guidelines recommended that temporary discontinuation or bridging of antithrombotic therapy in high-risk patients should be decided in consultation with the patient’s internist(1). those patients who reported in the included studies used aspirin mainly for primary or secondary cardiovascular prevention such as prior myocardial infarction, transient ischemic attack or stroke, coronary artery disease or stent, peripheral artery disease or stent. they were considered relatively high risk. the surgical team did not play a decisive role in initiating or ending aspirin use. the continued and uninterrupted aspirin therapy perioperatively was based on mutual decision making between the patient, cardiologist and or neurologist, anesthesiologist, and urologist. moreover, the included studies showed that there was no significant difference in other variables, which can affect bleeding such as stone size and operative time, between the two groups; therefore, the main factor that can affect bleeding in the two groups might be whether to continue low-dose aspirin therapy perioperatively. the included studies reported the rate of need for transfusion ranging from 0 to 18% in the continuing lowdose aspirin group and from 0 to 14.6% in the control group, with no significant difference. no deaths or admission to intensive care centers were reported. our systematic review of these studies shows the safety of continuing low-dose aspirin therapy during pcnl. the 81-100mg dose aspirin was applied in most patients and this suggested that continuing 81-100mg dose aspirin therapy might not increase the risk of bleeding in the perioperative period of pcnl. what should be emphasized is that preventing cardiovascular and cerebrovascular events might be more critical than prevention of perioperative bleeding. aspirin is an important drug for those at high risk of life-threatening cardio-vascular diseases and the main reason for its use. in addition, these high-risk patients are those in whom cessation of aspirin poses the greatest risk (34). routinely, aspirin will be discontinued 7 days before the surgery and the aspirin withdrawal syndrome may significantly increase the risk of cardiovascular and cerebrovascular events(11). this syndrome peaks around the time of the surgical operation(35). the only randomized controlled study and a meta-analysis concluded that continuation of perioperative aspirin was associated with one third lower risk of major adverse cardiac events(35,36). in conjunction with our analysis in bleeding complications, aspirin played an important role in reducing the risk and severity of thromboembolic complications when compared to those that discontinued aspirin. in two studies included in our systematic review, we found one postoperative thrombotic event occurred in continuing low-dose aspirin group(18); furthermore, two patients in the discontinuing group did need angioembolization for bleeding(17). this information indicates that postoperative thrombotic events may also occur in the continuing aspirin group, and severe bleeding may also occur in the discontinuing group. as a result, it seems that there might be no obvious corresponding relationship about the continuation of low-dose aspirin perioperatively and occurring cardiovascular events in patients who need pcnl(18). in the present study, major complications were made up of bleeding complications and postoperative thrombotic events. there was no significant difference found in major complications in these studies, as well as length of stay, frequency of readmission, and changes in hemoglobin, hematocrit and serum creatinine levels. the continuation of aspirin seems not to influence renal function or the incidence of other complications, concluding that continuing low-dose aspirin might be relatively safe in the pcnl surgery. we recognize certain limitations of this study. first, this systematic review and meta-analysis had the limited number of studies involved and the relatively small sample size. second, these included studies were almost single-center and retrospective. third, the small patient cohort and short follow-up make the evidence level of our study relatively weak. it is possible that some bleeding events or thromboembolic events could have been missed during the short period. thus, the generalizability of our outcomes might be limited. further randomized, multi-center trials will contribute objective evidence to these aspects. despite these limitations, this systematic review and meta-analysis provides valuable evidence and reference for continuing low-dose aspirin therapy perioperatively during pcnl. even though our findings all preferred that it was safe to perform pcnl in patients with continuing low-dose aspirin therapy (81-100mg), it was still hard for us to draw such definitive conclusions due to given limited available evidence. patients who have been receiving aspirin therapy should be informed of the risks in detail before making decisions to continue the aspirin therapy during pcnl or not. therefore, larger prospective studies or randomized controlled trials (rct) should be done to confirm and validate our findings. conclusions it appears that continuing low-dose aspirin therapy perioperatively in the patients had undergone pcnl might be relatively safe. considering the number of studies involved and the relatively lack of evidence, larger and prospective randomized controlled studies should be done to confirm and validate our findings. safety of continuing aspirin during pcnl-pan et al. review 259 acknowledgement our project was supported by national natural science foundation of china (no. 82171594). the role of the funders was in the design and writing the study. conflict on interest the authors declare that they have no competing interests. references 1. türk c, petřík a, sarica k, seitz c, skolarikos a, straub m, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 2. barone b, crocetto f, vitale r, di domenico d, caputo v, romano f, et al. retrograde intra renal surgery versus percutaneous nephrolithotomy for renal stones >2 cm. a systematic review and meta-analysis. minerva urol nefrol. 2020;72:441-50. 3. lai d, he y, li x, chen m, zeng x. rirs with vacuum-assisted ureteral access sheath versus mpcnl for the treatment of 2-4 cm renal stone. biomed res int. 2020;2020:8052013. 4. labate g, modi p, timoney a, cormio l, zhang x, louie m, et al. the percutaneous nephrolithotomy global study: classification of complications. j endourol. 2011;25:127580. 5. keoghane sr, cetti rj, rogers ae, walmsley bh. blood transfusion, embolisation and nephrectomy after percutaneous nephrolithotomy (pcnl). bju int. 2013;111:628-32. 6. otto b, lutfi f, gupta m, terry r, bird vg. the effect of continued aspirin therapy in patients undergoing pcnl. journal of endourology. 2016;30:a370-a1. 7. tran t, parkhomenko e, thai j, blum k, gupta m. continuing 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terry rs, lutfi fg, syed js, hamann hc, gupta m, et al. the effect of continued low dose aspirin therapy in patients undergoing percutaneous nephrolithotomy. j urol. 2018;199:748-53. 19. wang wg, wang cy, jia k, lu zp. the effect of hemorrhage and safety of perioperative aspirin administration on minimal percutaneous nephrostolithotomy. international journal of urology and nephrology. 2019:833-6. 20. leyh-bannurah sr, hansen j, isbarn h, steuber t, tennstedt p, michl u, et al. open and robot-assisted radical retropubic prostatectomy in men receiving ongoing lowdose aspirin medication: revisiting an old paradigm? bju int. 2014;114:396-403. 21. maan z, cutting cw, patel u, kerry s, pietrzak p, perry mj, et al. morbidity of transrectal ultrasonography-guided prostate biopsies in patients after the continued use of low-dose aspirin. bju int. 2003;91:798-800. 22. giannarini g, mogorovich a, valent f, morelli g, de maria m, manassero f, et al. continuing or discontinuing low-dose aspirin before transrectal prostate biopsy: results of a prospective randomized trial. urology. 2007;70:501-5. 23. mackinnon b, fraser e, simpson k, fox jg, geddes c. is it necessary to stop antiplatelet agents before a native renal biopsy? nephrol dial transplant. 2008;23:3566-70. 24. nayak-rao s. percutaneous native kidney biopsy in patients receiving antiplatelet agentsis it necessary to stop them routinely? indian j nephrol. 2015;25:129-32. 25. eng m, brock g, li x, chen y, ravindra kv, buell jf, et al. perioperative anticoagulation and antiplatelet therapy in renal transplant: is there an increase in bleeding complication? clin transplant. 2011;25:292-6. 26. naspro r, lerner lb, rossini r, manica m, safety of continuing aspirin during pcnl-pan et al. vol 19 no 4 july-august 2022 260 woo hh, calopedos rj, et al. perioperative antithrombotic therapy in patients undergoing endoscopic urologic surgery: where do we stand with current literature? minerva urol nefrol. 2018;70:126-36. 27. el-nahas ar, shokeir aa, el-assmy am, mohsen t, shoma am, eraky i, et al. postpercutaneous nephrolithotomy extensive hemorrhage: a study of risk factors. j urol. 2007;177:576-9. 28. ramon de fata f, perez d, resel-folkersma l, galan ja, serrano a, servera a, et al. analysis of the factors affecting blood loss in percutaneous nephrolithotomy: a registry of the spanish association of urology in the supine position. actas urol esp. 2013;37:52732. 29. kukreja r, desai m, patel s, bapat s, desai m. factors affecting blood loss during percutaneous nephrolithotomy: prospective study. j endourol. 2004;18:715-22. 30. mishra dk, bhatt s, palaniappan s, reddy tvk, rajenthiran v, sreeranga yl, et al. mini versus ultra-mini percutaneous nephrolithotomy in a paediatric population. asian j urol. 2022;9:75-80. 31. haghighi r, zeraati h, ghorban zade m. ultra-mini-percutaneous nephrolithotomy (pcnl) versus standard pcnl: a randomised clinical trial. arab j urol. 2017;15:294-8. 32. vollstedt a, bustos nh, eisner b, dagrosa l, pais v. is it safe to continue anti-platelet and anticoagulation therapy in patients undergoing percutaneous nephrolithotomy (pcnl)? a nested case control study. journal of urology. 2016;195:e506. 33. johnson e, bechis s, deshmukh s, barboglioromo p, eisner b, pais jr v. impact of perioperative anticoagulation on incidence of bleeding complications in patients undergoing percutaneous nephrolithotomy. journal of urology. 2013;189:e632. 34. collet jp, montalescot g, blanchet b, tanguy ml, golmard jl, choussat r, et al. impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. circulation. 2004;110:2361-7. 35. biondi-zoccai gg, lotrionte m, agostoni p, abbate a, fusaro m, burzotta f, et al. a systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. eur heart j. 2006;27:2667-74. 36. oscarsson a, gupta a, fredrikson m, jarhult j, nystrom m, pettersson e, et al. to continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial. br j anaesth. 2010;104:305-12. safety of continuing aspirin during pcnl-pan et al. review 261 covid-19 vaccine and male fertility 1vijay kumar* and 1manpreet kaur 1department of microbiology, kurukshetra university, kurukshetra, haryana, india. *corresponding author: vijaykuk@kuk.ac.in as world is going through the covid-19 pandemic, the mass vaccination of newly approved vaccines for covid-19 has begun around the world. there has been some concern among the vaccine recipients regarding the potential effect of vaccine on male fertility. does covid-19 affect the male reproductive health? does covid-19 vaccine impair the sperm parameters? as angiotensin-converting enzyme 2 (ace2) receptors plays a key role in pathogenesis of covid-19. so, the cells which show high level of ace2 expression can be a target and directly damaged by the virus1. many research studies have shown that high expression level ace2 is detected in testicular cells, like seminiferous duct cells, spermatogonia, leydig cell and sertoli cells1,2. this expression of ace2 testicular cells is related to age2. in a study, the expression was found to be highest in patients aged 30, which was higher than the patients who in their twenties, whereas it was lowest in 60-year-old patients2. this might indicate that young male patients are at higher risk of testicular damage by covid-19 than older patients. another possibility of testicular damage has also been hypothesized which is mediated by secondary immunological and inflammatory response, which is elevated during the severe viral infection in the testicles due to high load of virus in blood stream leading to testicles. covid-19 infection could decrease also male fertility through various pathogenic mechanisms, like increasing oxidative stress and increasing the dna methylation and fragmentation. there can be direct damage to the leidig cells and spermatocytes through ace enzyme. furthermore, the persistence of high temperature during active viral infection in blood can damage the blood-testis barrier (btb) thereby leading to entry of viruses in seminiferous tubules. this supports that testicular infection due to sars-cov-2-induced orchitis might damage btb and allow the shedding of virus into semen. so, theoretically, there is a possibility that covid-19 infection can damage the testicular cells being the potential target for infection and subsequently leading to infertility. mailto:vijaykuk@kuk.ac.in a number of clinical trials have been done to determine the safety of these vaccines, but, their impact on male fertility has not been investigated yet. some of the studies have found the significant negative impact of sars-cov-2 infection on sperm parameters. covid-19 affects sexual function and sexual activity. a study from china has reported the reduced sexual activity in 37% of those surveyed, during the early in the pandemic. in that study 44% have reported a decrease in the number of sexual partners3. on the other hand, minimal change in sexual activity was suggested in a study from bangladesh, india, and nepal. the first report of the impact of sarscov-2 infection on semen parameters came from holtmann and others4. they found that semen parameters were impaired in the patients after a moderate infection whereas; mild infection was less likely to cause this effect. there have been very few studies regarding the impact of covid-19 vaccine of sperm parameters. in conducted studies the results are also not reliable as sample size of the study is small; the population is hetergenous, a lot of variables have to consider for evaluating of male fertility. in a study, the effect of two mrna vaccines, bnt162b2 (pfizer-biontech) and mrna1273 (moderna) was studied on sperm parameters before and after the covid-19 vaccination in 45 volunteers between 18 to 50 years of age. no significant decrease was observed in any of the sperm parameters after 2 doses of covid-19 mrna vaccine5. similar results were seen in another study conducted on 43 male patients after vaccination with bnt162b2 vaccine. it was suggested that as the vaccine contain only mrna and not the live virus, it would be unlikely to impact the sperm parameters by vaccine. in a post from society for male reproduction and urology (which is a professional group of american society for reproductive medicine) on 9th january, 2021 published that there are no data about the impact of the covid-19 vaccine on male or female fertility. only about 16% of men experienced fever after second dose of pfizer/biontech covid-19 vaccine during the clinical trial which might have caused temporary declines in sperm production which would be similar to or less than if the individual experienced fever from developing covid-19 or for other reasons. so unless new conclusive data is published, there is no definitive data to support possibility of direct testicular damage due to virus invasion of due to inflammatory response in response to binding of sars-cov2 virus to ace2 receptors. as far as covid-19 vaccination is concerned, there is no significant data that is does affect sperm whereas sars-cov-2 infection does impair sperm. follow-up investigative studies have to be conducted for evaluation of male fertility. references: 1. fan, c., li, k., ding, y., lu, w. & wang j. ace2 expression in kidney and testis may cause kidney and testis damage after 2019-ncov infection, medrxiv doi: https://doi.org/10.1101/2020.02.12.20022418 (2020). 2. shen, q., xiao, x., aierken, a., liao, m. & hua j. the ace2 expression in sertoli cells and germ cells may cause male reproductive disorder after sars-cov-2 infection. https://doi.org/10.1111/jcmm.15541 (2020). 3. doring, n. how is the covid-19 pandemic affecting our sexualities? an overview of the current media narratives and research hypotheses. arch. sex behav. 49(8):1–14 (2020). 4. holtmann, n., edimiris, p., andree, m., doehmen, c., baston-buest, d., adams, o., kruessel, j. s. & bielfeld, a. p. assessment of sars-cov-2 in human semen-a cohort study. fertil. steril. 114(2): 233-238 (2020) 5. safrai, m., reubinoff, b. & ben-meir, a. bnt162b2 mrna covid-19 vaccine does not impair sperm parameters. medrxiv doi: https://doi.org/10.1101/2021.04.30.21255690 (2021). competing interests: authors have no competing interests. https://doi.org/10.1101/2021.04.30.21255690 urol_montage.pdf endourology and stone disease 9urology journal vol 6 no 1 winter 2009 effect of rowatinex on calculus clearance after extracorporeal shock wave lithotripsy hooman djaladat,1 khatereh mahouri,2 fatemeh khalifeh shooshtary,1 azadeh ahmadieh3 introduction: our aim was to evaluate the effect of rowatinex, an essential oil preparation of terpenic type, on kidney calculi clearance after extracorporeal shock wave lithotripsy (swl). materials and methods: a randomized controlled trial was performed at hormozgan hospital in bandar abbas, iran, on 100 patients with 10-mm to 20-mm kidney calculi. they underwent swl, and then, they were randomly assigned into 2 groups to receive either rowatinex, 100 mg, 3 times per day, or placebo after swl. the patients were followed up with plain abdominal radiography, ultrasonography, and excretory urography (if required), 2 and 4 weeks postoperatively. results: two weeks following swl, 6 (12%) and 9 (18%) patients in the rowatinex and control groups had fragmented calculi without clearance, 26 (52%) and 24 (48%) had less than 50% clearance, 9 (18%) and 15 (30%) had more than 50% but not total clearance, and 9 (18%) and 2 (4%) patients were stone free, respectively. rowatinex had a significant effect on the stone-free rate (p = .02). four weeks post-swl, 3 (7.3%) and 7 (14.6%) other patients in the rowatinex and control groups became stone free, respectively. overall, rowatinex had no significant effect on the stone-free rate (p = .46). no complications or differences between the two groups in symptoms and signs were reported. conclusion: rowatinex does not have a significant effect on clearance rate of kidney calculi after swl. however, it can accelerate calculus passage after 2 weeks, and it does not have any significant adverse effects. urol j. 2009;6:9-13. www.uj.unrc.ir keywords: urinary calculi, lithotripsy, therapy, terpenes, prospective studies 1department of urology, mohammadi hospital, hormozgan university of medical sciences, bandar abbas, iran 2department of community medicine, hormozgan university of medical sciences, bandar abbas, iran 3department of oral medicine, beheshti university of medical sciences, tehran, iran corresponding author: hooman djaladat, md mohammadi hospital, jomhoori blvd, bandar abbas, iran tel: +98 21 6671 7447 fax: +98 21 6671 7447 e-mail: hoomanj@hums.ac.ir received march 2008 accepted november 2008 introduction urinary calculus is the most common disorder of the urinary tract after urinary tract infections and prostate disease. the challenge of urologists to treat patients with upper urinary tract calculi is to choose the best treatment option according to the characteristics of the patient and the calculus.(1-3) in the past 2 decades, extracorporeal shock wave lithotripsy (swl) has revolutionized management of kidney calculi. however, the presence of calculus fragments after swl is common and calculus clearance is not achieved immediately. residual fragments larger than 5 mm usually indicate treatment failure.(4) most of small fragments pass spontaneously and their clearance failure probably leads to further complications and subsequent interventions.(2) several studies have demonstrated rowatinex after shock wave lithotripsy—djaladat et al 10 urology journal vol 6 no 1 winter 2009 that medical management of residual fragments may improve the outcome of swl.(4) siller and colleagues(5) investigated the effect of rowatinex, an essential oil preparation of terpenic type,(6) in the clearance of residual fragments after swl and showed an 82% stone-free rate by day 28 in patients who used rowatinex. this report, to our knowledge, is the only report available in the literature on the effect of rowatinex on calculus clearance after swl. to better address the issue, we performed a randomized single-blind clinical trial to determine the effect of rowatinex on the clearance of kidney calculi after swl. materials and methods participants we performed a randomized single-blind clinical trial at hormozgan hospital in bandar abbas, iran, between october 2005 and december 2006. patients who were admitted to undergo swl were approached and those with renal pelvis or caliceal calculi sized between 10 mm and 20 mm were selected. the exclusion criteria were ureteral and bladder calculi, drug hypersensitivity, history of kidney surgery or any urological interventions, pregnancy, and breast feeding. calculus location and size were assessed using plain abdominal radiography and ultrasonography. excretory urography was also used, if needed. study design the review board and ethics committee of hormozgan university of medical sciences approved the study and all patients provided written informed consent before participation. eligible patients were enrolled in the study and randomly assigned to receive either rowatinex (rowa pharmaceuticals, cork, ireland) or placebo for 1 month after swl. rowatinex capsules, 100 mg, were administered 3 times a day in the study group. rowatinex is a terpenic mixture is composed of pinene, camphene, anethol, borneol, cineol, fenchone, and olive oil.(6) a modulith slk machine equipped with a cylindrical electromagnetic shock wave source (storz medical, tuttlingen, switzerland) was used to perform lithotripsy. all patients received a mean of 3400 ± 200 shocks (range, 2800 to 4000 shocks) with an energy level of 50.0 ± 3.5 kv (range, 40 to 60 kv) and a mean frequency of 2 shocks per second. the patients were followed up by history, physical examination, and radiological studies, 2 and 4 weeks postoperatively and whenever they would seek medical care. plain abdominal radiography and ultrasonography results were reported by one expert radiologist. also, excretory urography would be done if required. results were compared in terms of patients’ symptoms and signs such as renal colic, gastrointestinal problems, calculus passage, and clearance rate (fragmented, < 50% cleared (1% to cleared or stone free). total calculus clearance was defined as undetectable calculi on plain abdominal radiography and ultrasonography or excretory urography in a symptom-free patient after swl. statistical analyses data were analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa). the chi-square test was used to compare categorical variables and the student t test for continuous ones between the two groups. a p value less than .05 was considered significant. results patients from october 2005 to december 2006, a total of 545 patients were referred to undergo swl in our lithotripsy center, of whom 255 met the study criteria and 100 accepted to be enrolled in the trial. they were randomly assigned to receive rowatinex capsules (n = 50) or placebo (n = 50), and all of them completed the study course. the baseline characteristics were generally similar between the two groups (table). efficacy two weeks following lithotripsy in the rowatinex group, fragmented calculi without clearance were seen in 6 patients (12.0%), less than 50% clearance in 26 (52.0%), and 50% or higher clearance (but not total clearance) in 9 rowatinex after shock wave lithotripsy—djaladat et al urology journal vol 6 no 1 winter 2009 11 patients (18.0%). nine patients (18.0%) were stone free after swl. in the control group, 9 patients (18.0%) had fragmented calculi without clearance, 24 (48.0%) had less than 50% clearance, 15 (30%) had 50% or higher clearance, and 2 (4%) had total calculus clearance (figure 1). the stone-free rate was significantly higher in the rowatinex group than the control group (p = .02) in the rowatinex group, calculus clearance correlated with age (p = .03), but not with sex, calculus size, or calculus location (p = .16, p =.25, and p = .89, respectively). in the control group, no significant correlation was seen between calculus clearance and age, sex, calculus size, or calculus location (p = .64, p = .65, p = .08, and p = .92, respectively). four weeks after swl, we followed up 89 patients who were not stone free at the 2-week follow-up visit. in the rowatinex group, fragmentation only, less than 50% clearance, 50% or higher clearance, and total clearance were seen in 5 (12.2%), 22 (53.7%), 11 (26.8%), and 3 (7.3%) patients, respectively. in the controls, 6 (12.5%), 19 (39.6%), 16 (33.3%), and 7 (14.6%) patients had fragmentation only, less than 50% clearance, 50% or higher clearance, and total clearance, respectively (figure 2). overall, there were no significant differences in the stone-free rate between the two groups (p = .46). age, gender, calculus size, and calculus location had no significant effect on calculus clearance in neither of the groups (rowatinex group: p = .34, p = .28, p = .51, and p = .66, respectively; control group: p = .65, p = .22, p = .58, and p = .08, respectively). tolerability two weeks post-swl, 6 patients (12.0%) suffered from renal colic, while 21 (22.0%) had calculus passage without colicky pain in the rowatinex group. none of the patients experienced significant gastrointestinal discomfort or any other side effects. in the control group, renal colic was reported by 2 patients (4.0%) and calculus passage without colicky pain by 24 (48.0%). after 4 weeks, 1 patient (2.4%) in the rowatinex group experienced renal colic and 10 (24.4%) passed the calculi without colicky pain. there was no report of significant gastrointestinal or any other side effects during the second 2 weeks after swl. in the control group, 1 patient (2.4%) had renal characteristics rowatinex group control group number of patients 50 50 mean age, y 38.3 ± 16.4 40.9 ± 14.0 males 30 (60.0) 29 (58.0) calculus size, mm 10 24 (48.0) 23 (46.0) 11 to 19 15 (30.0) 18 (36.0) 20 11 (22.0) 9 (18.0) calculus location renal pelvis 19 (38.0) 28 (56.0) upper calyxes 6 (12.0) 2 (4.0) middle calyxes 10 (20.0) 9 (18.0) lower calyxes 15 (30.0) 11 (22.0) baseline characteristics of patients with and without rowatinex after shock wave lithotripsy figure 1. outcomes 2 weeks after shock wave lithotripsy in patients with rowatinex and controls. figure 2. outcomes 4 weeks after shock wave lithotripsy in patients with rowatinex and controls. rowatinex after shock wave lithotripsy—djaladat et al 12 urology journal vol 6 no 1 winter 2009 colic and 15 (31.3%) had calculus passage without colicky pain. the differences were insignificant at 2 and 4 post-swl weeks (p = .32 and p = .77, respectively). discussion the purpose of this study was to evaluate the effect of rowatinex on clearance of kidney calculi after extracorporeal swl. it has been generally assumed that swl is the first-line management option for 10-mm to 20-mm kidney calculi. although it is a less invasive procedure for treatment of such calculi, calculus clearance is not achieved immediately and most of fragments pass spontaneously during the first months after lithotripsy.(1,2) residual fragments are important as they may lead to obstruction, recurrent infection, or calculus regrowth. medical therapy has been shown to be effective in prevention of calculus growth and recurrence.(4,7) cicerello and colleagues showed the efficacy of alkaline citrate in the clearance of residual fragments after swl in patients with calcium and struvite calculi.(8) they explained that persistence and regrowth are common in the natural history of residual calculus fragments. citrate improved the outcome of these calculi by increasing the clearance of residual particles. other medications, like tamsulosin and thiazides have been shown to enhance calculus clearance in patients with kidney calculus undergoing swl.(12,13) rowatinex is an essential oil preparation of terpenic type composed of pinene (3%), camphene (15%), borneol (10%), anethol (4%), and cineol (3%) in olive oil, which has been suggested for the treatment of urolithiasis, nephrolithiasis, renal colic, and other urological problems.(6,9,10) to our knowledge, there is not much data in the literature to explain the exact mechanism of action of rowatinex. however, it is assumed to improve renal blood flow, thus stimulating the kidneys and giving rise to increased urine excretion, and to have antispasmodic effect to facilitate passage of the calculi. there are some studies that have evaluated the effect of rowatinex in the treatment of urolithiasis. in an early study, miller(11) reported 65% success in spontaneous expulsion of calculi in 40 patients with urolithiasis who received rowatinex. this was a study on ureteral calculi in patients without a history of swl. in our study, the total calculus clearance (stone-free rate) in the rowatinex group was 24% in comparison with 18% in the control group, 1 month post-swl (p = .46). the slight difference between these two studies might be due to various calculus locations. also, the overall lower clearance rate in our study in comparison to the reports in the literature might be due to special climate conditions in our region (it is considerably hot and humid in bandar abbas), shorter period of follow-up assessments, and relatively higher frequency of lower caliceal calculi. mukamel and associates,(9) in a study on patients with renal colic, noted an insignificantly higher rate of calculus expulsion in the rowatinex group when compared to a control group (61% versus 28%, respectively). they reported no serious side effects with rowatinex. engelstein and colleagues evaluated the effect of rowatinex in patients with ureteral calculi in a case-control study.(6) they concluded that early treatment with rowatinex might be helpful for patients with ureteral calculi before other invasive procedures are applied. the only study that evaluated the effect of rowatinex on the clearance of kidney calculi after swl was carried out by siller and colleagues.(5) they administered rowatinex on 50 patients with kidney calculi after swl. they showed that 82% of patients were stone free 1 month after lithotripsy. reports on other drugs have also been relatively promising. losek and mauro(12) studied the effect of tamsulosin on calculus clearance after swl. they showed that the 12-week kidney calculus clearance was 60% in the control group compared to 78.5% in the tamsulosin group (p = .04). arrabal-martin and coworkers evaluated the effect of thiazides on clearance of kidney calculi after swl. the percentage of global expulsion of lithiasis was significantly greater in patients on thiazides in contrast to controls (72% versus 36%; p = .03). in our study, 2 weeks following swl, the stonefree rate was significantly different between rowatinex after shock wave lithotripsy—djaladat et al urology journal vol 6 no 1 winter 2009 13 the patients on rowatinex and the controls (18% versus 4%, p = .02). however, other swl outcome measurements such as patients’ symptoms and signs, renal colic, gastrointestinal problems, and calculus passage were not significantly different between the two groups. four weeks post-swl, rowatinex did not show any significant effect on the overall calculus clearance rate or other outcome measures of the patients in comparison with placebo. thus, we can conclude that rowatinex might be effective in accelerating calculus passage, but it has no effect on the overall outcome. the weakness of our study is the limited number of studied patients. it is somehow due to the rigid inclusion and exclusion criteria we set. also in our region, ureteral calculi that were not included in our study are much more common than kidney calculi. conclusion rowatinex has no significant effect on clearance rate of kidney calculi after swl. however, early after therapy with rowatinex, calculus clearance might be achieved in a greater number of patients, which means that rowatinex can accelerate calculus passage, while having no significant side effects. acknowledgment we wish to thank dr zare for his help with the manuscript. conflict of interest none declared. references 1. stoller ml, bolton dm. urinary stone disease. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 15th ed. new york (usa): lange medical books/mcgraw-hill; 2000. p. 291-320. 2. pearl sm, lotan y. urinary lithiasis: etiology, epidemiology and pathogenesis. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1363-73. 3. lingeman je, matlaga br, evan ap. surgical management of upper urinary tract calculi. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1431-58. 4. tan yh, wong m. how significant are clinically insignificant residual fragments following lithotripsy? curr opin urol. 2005;15:127-31. 5. siller g, kottászs s, pálfi z. rowatinex kapszula hatékonyságának vizsgálata eswl-kezelés után keletkezett kõfragmentumokra. magyar urologia. 1998;10:139-46. 6. engelstein d, kahan e, servadio c. rowatinex for the treatment of ureterolithiasis. j urol (paris). 1992;98:98-100. 7. fine jk, pak cy, preminger gm. effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. j urol. 1995;153:27-32. 8. cicerello e, merlo f, gambaro g, et al. effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolithiasis patients. j urol. 1994;151:5-9. 9. mukamel e, engelstein d, simon d, servadio c. the value of rowatinex in the treatment of ureterolithiasis. j urol (paris). 1987;93:31-3. 10. al-mosawi aj. a possible role of essential oil terpenes in the management of childhood urolithiasis. therapy. 2005;2:237-47. 11. miller r. [experiences in the treatment of urolithiasis with rowatinex]. fortschr med. 1967;85:39-42. german. 12. losek rl, mauro ls. efficacy of tamsulosin with extracorporeal shock wave lithotripsy for passage of renal and ureteral calculi. ann pharmacother. 2008;42:692-7. 13. arrabal-martin m, fernandez-rodriguez a, arrabalpolo ma, garcia-ruiz mj, zuluaga-gomez a. extracorporeal renal lithotripsy: evolution of residual lithiasis treated with thiazides. urology. 2006;68:956-9. 1 renal complications following covid-19 vaccination author: zohreh jadali1 1department of immunology, school of public health, tehran university of medical sciences. tehran, iran. corresponding author’s address: department of immunology, school of public health, tehran university of medical sciences. tehran, iran. p.o.box: 6446 tehran 14155, iran. telephone: 6462268-6465404, fax:(+98 21) 6462267 email: zjadali@razi.tums.ac.ir and zjadali@yahoo.co.uk type of manuscript: letter running title: covid 19 vaccines and urinary system key words: vaccination, covid-19, renal complications. word count: 710 total number of pages: 2 there is no conflict of interest. zohreh jadali orchid 0000-0002-3836-5262 approval of the final version of the manuscript; elaboration and writing of the manuscript; critical review of the literature; critical review of the manuscript. to editor i would appreciate consideration of the enclosed manuscript for publication in urology journal. i will send a copyright agreement and declaration of conflict of interest form signed by author. this manuscript is letter to editor. it must be mentioned that the content has not been published or submitted for publication elsewhere. in addition any financial support or relationships that may pose conflict of interest. yours sincerely dr zohreh jadali corresponding author’s address: department of immunology, school of public health, tehran university of medical sciences. tehran, iran. p.o.box: 6446 tehran 14155, iran. telephone: 6462268-6465404 fax: (+98 21) 6462267 email: zjadali@razi.tums.ac.ir zjadali@yahoo.co.uk type of manuscript : letter to editor 2 covid-19 vaccines provide a powerful strategy against coronavirus pandemic. they prevent the spread of disease, reduce hospitalization and disease severity. despite clear benefits of vaccination programs, covid-19 vaccines are not risk-free and adverse events can sometimes occur after vaccination. most of these adverse reactions are mild and are more common. the array of mild symptoms can include fever/chills, headache, lethargy, or injection site reactions like edema, erythema, or pain and usually disappear within a few days. nonetheless, there have been some reports of new-onset or exacerbation of glomerular diseases following covid-19 vaccines. based on the available literature, iga nephropathy (igan) or minimal change disease(mcd) are the most common forms of covid-19 vaccine-associated glomerular disease. but, a small number of vaccine recipients also develop other diseases such as membranous nephropathy, anti– neutrophil cytoplasmic antibody–associated vasculitis, anti–glomerular basement membrane disease, and igg4 renal disease.(1) the exact molecular pathogenesis of kidney side effects of covid-19 vaccines remains unclear. immune derangement would seem to play an important role in the onset and progression of these complications. interestingly, different types of immune response seems to be a critical determinant of the ultimate progression of glomerular disease. for instance, dysregulation of antibodymediated humoral immune response plays important roles in the development and progression of igan after vaccination. in contrast, dysregulated t-cell is essential for podocyte injury as a hallmark of mcd. molecular mimicry is another possible mechanism for the induction of vaccineassociated autoimmunity.(2) sequence homology between certain viral proteins and human proteins, may contribute to immune attack against self antigens. bystander activation may also offer a plausible explanation for vaccine-induced autoimmune activation. immune system's reaction to the vaccine may trigger cellular damage and exposure of self-hidden (sequestered) antigens. the detection of these antigens by the immune system can result in antigen presentation to autoreactive cells and development of glomerular diseases. another point that must be kept in mind is a probable relationship between the appearance of glomerular complications and the different forms of technology that have been applied for the production of covid-19 vaccines. at present, the four main types of covid-19 vaccines are available: mrna-based, viral vector, inactivated and protein subunit. all of them rely on the viral spike protein (s) of sars-cov-2 but there are differences between these four different categories of vaccines with respect to the presentation of s protein to the immune system. s protein is essential for viral replication and is important for inducing long-lived neutralizing antibodies. among these four types of vaccines, mrna vaccines have shown to induce more potent immune responses than others. this ability can strengthen virus-specific responses and vaccine efficacy that is important in disease prevention. but at the same time, host immune response against mrna vaccines is accompanied by increased production of t cell cytokines such as interferon γ, tumor necrosis factor α and interleukin 2. the early t cell activation and the overproduction of inflammatory cytokines in disease-susceptible individuals, can be considered as part of mechanisms that may trigger podocytopathies and production of disease-specific antibodies.(3,4) vaccine-related adverse events in patients with renal failures like patients with autoimmune kidney diseases is another point of focus. such individuals are considered to be good vaccine candidates because they are at higher risk of severe illness from the coronavirus. on the other hand, these patients with weak immune systems (immunocompromised) often have to be treated with 3 immunosuppressive drugs.(5) unfortunately, currently there are not enough data to show the safety, efficacy and immunogenicity of covid-19 vaccines in these patients as a result of their exclusion from all major clinical trials of vaccine candidates against covid-19. therefore, there are different questions needed to be addressed, such as the effect of immunosuppression on immune responses against sars-cov-2 vaccination, the potential of covid-19 vaccine in inducing autoimmunity or relapse of the autoimmune diseases. it seems that timing of vaccination is an important concern in patients who have been treated with immunosuppressive drugs because these medication can weaken the immune response of patients. overall, renal adverse effects following covid-19 vaccination are not abundant but can lead to serious health problems. there are controversies about the causal relationship between covid-19 vaccination and these adverse events. therefore, more studies are required to further elucidate whether these associations are plausible. references: 1. li nl, coates pt, rovin bh. covid-19 vaccination followed by activation of glomerular diseases: does association equal causation? kidney int. 2021;100(5):959-65. 2. ellul ma, benjamin l, singh b, lant s, michael bd, easton a, et al. neurological associations of covid-19. lancet neurol. 2020;19(9):767-83. 3. de fabritiis m, angelini ml, fabbrizio b, cenacchi g, americo c, cristino s, et al. renal thrombotic microangiopathy in concurrent covid-19 vaccination and infection. pathogens. 2021;10(8):1045. 4. lebedev l, sapojnikov m, wechsler a, varadi-levi r, zamir d, et al. minimal change disease following the pfizer-biontech covid-19 vaccine. am j kidney dis. . 2021;78(1):1425. 5. prendecki m, willicombe m, mcadoo sp. covid-19 vaccination in patients with immunitymediated kidney disease. nat rev nephrol. 2021;17(12):790-1. the effect of l-carnitine and coenzyme q10 on the sperm motility, dna fragmentation, chromatin structure and oxygen free radicals during, before and after freezing in oligospermia men negin chavoshi nezhad1, zakaria vahabzadeh2, azra allahveisie3, khaled rahmani4, amir raoofi5, mohammad jafar rezaie6*, masoumeh rezaei7, maria partovyan8 purpose: the aim of the present study is to assess the effect of l-carnitine and coenzyme q10 (coq10) on human sperm motility, dna fragmentation, chromatin structure, and reactive oxygen species (ros) during, before and after freezing in oligospermia men. materials and methods: semen was collected from 30 oligospermic men, who referred to infertility clinic of beasat hospital in sanandaj, iran. the samples of each individual were divided into 8 equal parts: 1. control group before freezing; 2. incubated with l-carnitine; 3. incubated with coenzyme q10; 4. incubated with the combination of l-carnitine + coq10; 5. control freezing group; 6. the experimental freezing group with l-carnitine; 7. the experimental freezing group with coenzyme q10 and 8. the experimental freezing with the combination of l-c + coq10. sperm motility was assessed by wet mount method. dna fragmentation was evaluated by scd (sperm chromatin desperation), ros, was evaluated by quantitative fluorescence reaction, and chromatin deficiency was determined by chromatin staining (cma3). results: antioxidant treatments, significantly reduced the number of ros + in the pre and post freezing groups. significant improvement was seen in the sperm motility of class b in the pre freezing groups with l-carnitine. antioxidants also reduced the percentage of dna fragmentation and protamine deficiency in pre-and post-freezing. conclusion: addition of coq10 and l-carnitine to human sperm medium significantly reduced the number of ros. this reduction in ros reduced sperm damage during cryopreservation. keywords: coenzyme q10; l-carnitine; oligospermia; reactive oxygen species; sperm introduction infertility is an important medical and social problem in the world since 15% of couples are infertile; 40% of them are infertile because of male factor infertility, 40% because of female factor infertility, and in the remainder, both factors are associated(1). male infertility can be due to oligospermia, which has a sperm count of less than 15 to 20 million per ml in 16% of the 41% infertile couples(2). with the advent of art (assisted reproductive technology), it has become possible to treat infertile men. the quality of semen in some diseases, such as oligospermia, is crucial for the success 1 msc of anatomical sciences, department of anatomical sciences, school of medicine, kurdistan university of medical sciences, kurdistan, iran. 2 assistant professor of clinical biochemistry, liver and digestive research center, research institute for health development, kurdistan university of medical sciences, kurdistan, iran. 3 assistant professor of reproductive biology, fertility and infertility research center, besat medical education and treatment center, kurdistan university of medical sciences, kurdistan, iran. 4 assistant professor of epidemiology, liver and digestive research center, research institute for health development kurdistan university of medical sciences, kurdistan, iran. 5 leishmaniosis research center, department of anatomy, sabzevar university of medical sciences, sabzevar, iran 6 associate professor of anatomical sciences, fertility and infertility research center, besat medical education and treatment center, kurdistan university of medical sciences, kurdistan, iran. 7 assistant professor of obstetrics and gynecology, fertility and infertility research center, besat medical education and treatment center, kurdistan university of medical sciences, kurdistan, iran. 8 msc of anatomical sciences, department of anatomical sciences, school of medicine, kurdistan university of medical sciences, kurdistan, iran. *correspondence: associate professor of anatomical sciences, department of anatomical sciences, school of medicine, kurdistan university of medical sciences, kurdistan,iran.tel: 09123728582. e-mail: rezaiemjafar@gmail.com. received august 2020 & accepted january 2021 of art(3). recently, much attention has been paid to the influence of ros on sperm quality. despite the advancement of art techniques, gametes and embryos when handled, prepared and manipulated for art procedures, are exposed to various potential ros-inducing factors(3). another method used in art to maintain the ability of men reproduction is cryopreservation techniques (freezing and thawing process). most damage occurs during freezing and thawing. major causes of damage during freezing are ros formation and cell dehydration, which disrupt the cell wall and intracellular organelles. many in vitro and in vivo studies have urology journal/vol 18 no. 3/ may-june 2021/ pp. 330-336. [doi: 10.22037/uj.v16i7.6400] andrology recommended the use of antioxidants as an adjunct to infertility treatment to improve sperm quality(4). coq10 is an essential component for electron transport in oxidative phosphorylation of mitochondria. coq10 function as a potent antioxidant in testicular, and high levels of its reduced form ubiquinol are present in sperm(5,6). in the mammalian epididymis, the free l-carnitine is taken up from the blood plasma, transported into the epididymal fluid and into the spermatozoa, and accumulated as both free and acetylated l-carnitine(7). in humans and experimental models, carnitines play an important role in sperm energy metabolism and provide the primary fuel for sperm motility(8). previous studies have shown that seminal-free l-carnitine content correlates with the number of sperms and sperm motility. carnitine, as a water-soluble antioxidant, protects the plasma membrane of sperm from damage by free radicals and prevents the oxidation of proteins, pyruvate and lactate and also, protect sperm dna against the damage induced by ros(7,8). in this study, it is tried to improve the quality of sperm parameters of oligospermia men by using l-carnitine and coq10. patients and methods inclusion criteria and exclusion criteria inclusion criteria, men with oligospermia and 25-40 years of age with abnormal spermogram should be done at least two examinations in two to three months, according to the who. exclusion criteria included: patients over 40 years of age with underlying factors such as varicocele, testicular atrophy, ejaculatory disorders, patients with azoospermia, sertoli cell syndrome and endocrine and anatomical disorders, seminal specimens which contained abundant bacteria and suspected of infection and the presence of leukocytes more than one million / ml(2). semen collection the samples were collected from patients after 3 to 4 days of abstinence and they completely agreed to participate in experimental tests by completing the consent form before collecting the sample. the supernatants sample were kept in a 37 ° c incubator without co 2 for liquefaction for 20 to 30 minutes. toxicity test was performed to obtain a responsive dose of l-carnitine and l-carnitine and coenzyme q10 in male infertilitychavoshi nezhad et al. figure 1. scd test under light microscope; normal sperm have large halo (a) around the head. abnormal sperm have a small halo (b) or no halo (c). figure 2. ros +spermatozoa under fluorescence microscopy with a wavelength of 535-485 nm. vol 18 no 3 may-june 2021 331 coq10 to prevent sperm infection. we obtained this dose at 100 µm(9). experimental groups each individual sample was divided into 8 equal parts. control group was prepared without any intervention and freezing (control before freezing); group 2 was incubated with l-carnitine (100 µm) for one-hour; group 3 was incubated with coq10 (100 µm) for one hour; group 4 was incubated with l-carnitine and coq10 (100 µm) for one hour; group 5 (freezing control group) was mixed and frozen only with human sperm preservation medium (hspm); group 6 was frozen with coq10 (100 µm) and hspm; group 7 was frozen with l-carnitine (100 µm) and hspm and group 8 was frozen with the combination of 100 µm (l-carnitine+ coq10) and hspm for two weeks. samples were then analyzed to evaluate parameters such as ros, protamine, dna fragmentation and motility according to who standards(9). freezing and thawing method to reduce the damage caused by freezing and thawing, one-step freezing method was used. the sample was held in the vapor phase for ten minutes before being plunged into liquid nitrogen. sperms were mixed with hspm cryopreservation medium in 1: 1 ratio and they were transferred to cryovials. after 7 minutes of freezing treatment, the cryovials were placed on nitrogen vapor for 10 minutes and finally stored in a nitrogen tank. after 2 weeks, the sperms were thawed. they were placed under running water for 1 to 2 minutes to reach normal temperature(10). motility determination sperm motility was assessed by wet mount method which included 3 types of progressive motility. it refers to sperms that swim in a mostly straight line or large circles in class (a). non-progressive motility refers to sperms that do not travel in straight lines or swim in very tight circles in group (b) and sperms with no motion in group (c). at first, 10 µl of sperm sample was placed on the slide and on a 22 × 22 lamellae and it was examined with 40 lenses and the percentage of class a-b-c sperm motility was counted(11). dna fragmentation determination scd testing is one of the methods used to assess sperm dna damage. sperm dna damage is detected by the presence of extracellular chromatin haloes around the sperm nucleus. normal sperms have a large halo and abnormal sperms have a small halo or no halo around the head. dfi (dna fragmentation index) was calculated with halo larger than or equal to sperm head and abnorfigure 3. a: luminous yellow sperm has protamine deficiency (cma3 +). b: sperm has normal protamine levels (cma3-) figure 4. comparison of sperm motility in different experimental and control groups l-carnitine and coenzyme q10 in male infertilitychavoshi nezhad et al. vol 18 no 3 may-june 2021 325andrology 332 vol 18 no 2 march-april 2021 mal sperm (non-halo or smaller sperm head) around the sperm head during staining. 30 µl of spermatozoa was mixed with 70 µl of low melting agarose at 37 °c. the mixed sample was placed on a slide pre-coated with 65% agarose for 4 minutes at 4°c. then, the lamellae were separated from the surface of the slide, and each slide was horizontally immersed in .08 normal hydrochloric acid solution for 7 minutes at room temperature and in the darkness. it was then placed in a lubricant solution for 25 minutes. each slurry was washed with distilled water for 5 minutes and dehydrated in 70, 90, 100% alcohol 2 minutes, and then stained with wright’s color solution and washed with ordinary water after 10 minutes. then, it was examined by light microscopy at a magnification of 100 (figure 1)(12). ros measurement we used dcfda cellular ros detection assay kit to measure the ros of the sperm samples for each group (figure 2)(13). determination of protamine deficiency to evaluate deficiency of protamine, smear was prepared from the samples and investigated by chromycina3 (cma3) staining(22). after staining, sperms were observed and counted under each fluorescence microscope at a magnification of × 60. the percentage of bright yellow spermatozoa was recorded as cma3+ (sperms lacking protamine deficiency) (figure 3)(14). data analysis data analysis was conducted in spss software version 22 using mann-whitney test. results in all the groups, motility factors, ros, dna fragmentation and protamine were evaluated and compared and p < .05 was considered significant. the results of the statistical analysis of these data are as follows: figure 4 shows the mean percentages of different classes of motility and the level of significance between the experimental groups. by examining the results of the above diagram, in both pre and post freezing conditions, three drug treatments were able to increase sperm motility (a-b-c) compared to the pre and post freezing control group, (l-carnitine , coq10 , l-carnitine + coq10). significant increase in class b ( p = .004) with l-carnitine was seen in before freezing group. overall freezing significantly decreased all three a-b-c mofigure 5. comparison of mean ros in different experimental and control groups figure 6. comparison of mean percentage of dna fragmentation in experimental and control groups l-carnitine and coenzyme q10 in male infertilitychavoshi nezhad et al. vol 18 no 3 may-june 2021 333 tions in the control group. freezing had the greatest effect on decreasing a motility (progressive motility), and increasing c motility (no progressive motility). by the addition of these antioxidants, this decrease in progressive motility was partially prevented. l-carnitine had the most effect on the improvement of three classes of motility in after freezing group. according to figure 5, with the addition of coq10 and l-carnitine to the sperms of the control group, there was a significant decrease in ros mean compared to the control group (respectively p = .04, p = .03 and l carnitine + coq10 group p = .2). there is an overall increase in the average ros. adding antioxidants significantly reduced the ros mean compared to the freezing control group. (l-carnitine (p = .01) , coq10 (p = .01) , l-carnitine +coq10 (p = .03)). according to figure 6, no significant change in the reduction of dna fragmentation was observed with the addition of q10 and l-carnitine separately and in combination before cryopreservation. after freezing, dna fragmentation increased, but the addition of these treatments decreased in dna fragmentation compared to the freezing control group. the increasing effect of cryopreservation on dna fragmentation in the cryopreservation control group was significant (p < .001). also, addition of coq10 and l-carnitine to the sperm of the control group increased the number of sperms with normal protamine but this difference was not significant (l-carnitine , q10 , l-carnitine + q10) (p ≤ .05) (figure 7). freezing reduces protamine in spermatozoa. with the addition of antioxidants, the average number of spermatozoa with normal protamine increased compared to the freezing control group, but it was not significant (l-carnitine , q10, carnitine + q10) (p ≥ .05) (figure 7). discussion the present study demonstrated l-carnitine and coenzyme q10 effects on the sperm motility, dna fragmentation, chromatin structure and oxygen free radicals during, before and after freezing in oligospermia men. in oligozoospermic patients, the spermatozoa are the predominant source of ros and generate extremely high levels of ros compared to those produced by spermatozoa from normal fertile men(15). the most important strategy to reduce oxidative stress is to use antioxidant-supplemented. our results showed l-carnitine and coq10 significantly improved sperm motility before and after freezing. freezing shows a decrease in all three types of sperm motility. but antioxidants partially prevented this reduction. the most effective treatment was l-carnitine treatment. l-carnitine had the greatest improvement in sperm motility in class b before freezing and class c after freezing. decreased motility has been shown to be due to ros-induce, primarily h2o2-mediated, peroxidation of lipids in the sperm membrane decreasing flexibility and by inhibition of motility mechanisms. the reduction in sperm motility is proportional to the amount of lipid peroxidation(15). ros-induced damage of mitochondrial dna leads to decreased atp and energy availability, impeding sperm motility(16). previous studies showed that quaternary antioxidant increased sperm motility by reducing sperm lipid peroxidation. these results are in line with the results of our study(5,17). melissa rossi et al. showed that the addition of q10 antioxidant to horse sperm freezing medium did not increase the sperm motility. this result was inconsistent with our study, which may be due to the different types of samples as well as differences in the method of freezing(18). according to other studies, antioxidants appear to reduce atpase k+ / na pump activity, reduce phosphorylation of axonal proteins and alter membrane permeability by reducing membrane peroxidation (resulting from oxidative stress). finally, sperm motility was maintained(15,16). in the present study, l-carnitine and coq10 reduced dna damage before and after cryopreservation. free radicals have the ability to directly damage sperm dna by attacking the purine and pyrimidine bases(19). ros cause damage via single and double strand dna breaks, cross links, and chromosomal rearrangements(20). infertile men often have deficient protamination which may make their sperm dna more vulnerable to ros damage(21). a study by talevi et al. using an antioxidant compound (zinc, d –aspartate, coq10) in in-vitro environment showed increased sperm dna figure 7. comparison of the mean of protamine in experimental and control groups l-carnitine and coenzyme q10 in male infertilitychavoshi nezhad et al. vol 18 no 3 may-june 2021 327andrology 334 vol 18 no 3 may-june 2021 335 integrity and prevented fragmentation in oligospermic patients(5). the researchers also showed that addition of coq10 antioxidant to sperm freezing medium had a significant effect on reducing sperm dna fragmentation after cryopreservation(22). according to the results of other research, it seems that antioxidants prevent the oxidation of purine and pyrimidine bases by eliminating free radicals which leads to preventing the breakage of one or two strands of dna. they also prevent the formation of transverse cells between dna and protein and, ultimately, maintain chromatin structure and dna integrity(19-21). the study showed that addition of coenzyme antioxidants coq10 and l-carnitine decreased the number of ros-positive spermatozoa before and after cryopreservation. the freezing process produces ros. but these antioxidants significantly reduced the number of ros-positive sperm in the pre and post vitrification treatment groups. in vitro incubation of sperm in the absence of seminal plasma shows a significant increase in markers for oxidative stress(23). according to research, it seems that antioxidants prevent sperm membrane lipid peroxidation and ultimately protect sperm by removing oxygen free radicals and oxidative stress (24). in the present study, the addition of coq10 and l-carnitine reduced the number of protamine deficient sperms compared to the pre-cryopreserved control group, but had no significant effect. oxidative stress may affect the levels of protamine through influencing the spermatogenesis process. proteins are one of the main targets for oxidative damage(25) and cysteine residues are particularly sensitive to oxidation because the thiol group (-sh) in cysteine can be oxidized(26). a recent study showed that l-carnitine and coenzyme in 40 µg dose improve protamine deficiency(27). also, aliabad et al., explained that l-carnitine and acetyl l-carnitine improved protamine by acetyltransferase (ache) transfer(28). conclusions the use of antioxidants in-vitro in the clinical laboratory setting during art procedures should also be considered, alongside improvement of art techniques and optimization of the laboratory environment. addition of coq10 and l-carnitine antioxidants to human sperm medium by reducing the number of ros, improves motility, protamine deficiency and reduces dna percentage of sperm fragmentation before and after freezing. undeniably, excessive ros leading to oxidative stress conditions has a serious impact on the outcome of assisted reproduction which leads to lower fertilization, implantation and pregnancy rates. in conclusion, prophylactic oral antioxidant therapy and supplementation of medium for culture, incubation/handling and cryopreservation can possibly improve gamete quality and fortify the developing embryo. however, the appropriate antioxidants and dosages (whether as a sole compound or as a combination) for different forms of infertility issues still remain an ongoing area of research. acknowledgement this study was approved in fertility and infertility research center, besat medical education and treatment center, kurdistan university of medical sciences, as a research project. the authors would like to thank dr. mohammad jafar rezaie and appreciate her support for the preparing of this manuscript. conflicting interest the authors declared no potential conflicts of interest. references 1. khadim a.h.a., al-wayelli d.a.o.j., al rekabe bkk., evaluation of serum fsh, lh and testosterone levels in infertile patients affected with different male infertility factors after iui technique. thi-qar med j. 2010; 4: p. 112-122. 2. dohle, g., weidner w., jung a., guidelines on male infertility. europ urol j. 2005; 48: p. 703-711. 3. palermo, g., joris h, devroey p., pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. lancet j. 1992; 340: p. 17-18. 4. balercia, g., buldreghini e, vignini a, et al., coenzyme q10 treatment in infertile men with idiopathic asthenozoospermia: a placebocontrolled, double-blind randomized trial. fertil steril j. 2009; 91: p. 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on dna integrity, and implications for art. advances in urol. 2011; 2012. 11. taylor, c.t., antioxidants and reactive oxygen species in human fertility. environmental tox and pharma j. 2001; 10: p. 189-198. 12. delamiir e., and gagnon c., reactive oxygen species and human spermatozoa. depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility. andro j. 1992; 13: p. 379-386. 13. hammadeh m., radwan m., al-hasani s. comparison of reactive oxygen species concentration in seminal plasma and semen parameters in partners of pregnant and nonpregnant patients after ivf/icsi. reprod biomed j. 2006;13: p. 696-706. 14. nasr e., abasi h, razavi s., varicocelectomy: semen parameters and protamine deficiency. l-carnitine and coenzyme q10 in male infertilitychavoshi nezhad et al. international andro j. 2009; 32: p. 115-122. 15. morielli t, o’flaherty c. oxidative stress impairs function and increases redox protein modifications in human spermatozoa. reprod j . 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vitrification in normozoospermia. thammasat uni. 2015. 23. kobayashi t., miyazaki t., natori m., protective role of superoxide dismutase in human sperm motility: superoxide dismutase activity and lipid peroxide in human seminal plasma and spermatozoa. hum reprod. 1991; 6: p.987–91. 24. alkan i, simsek f, haklar g, et al. reactive oxygen species production by the spermatozoa of patients with idiopathic infertility: relationship to seminal plasma antioxidants. urol j. 1997; 157: p.140–3. 25. jung t, bader n, grune t. oxidized proteins: intracellular distribution and recognition by the proteasome. arch biochem biophys. 2007; 462: p.231–237. 26. erenpreiss j, spano m, erenpreisa j, sperm chromatin structure and male fertility: biological and clinical aspects. asian androl j . 2006; 8: p.11–29. 27. fakhridlin m., jabbar y., majida m.h., effect of lcarnitine and coq10 addition to smart pro medium on human sperm concentration, sperm morphology. iosr j of pharma and biol sciences 2017;12: p.51-55. 28. aliabadi e., soleimani m., h.d., borzoei z., effects of l-carnitine and l-acetyl-carnitine on testicular sperm motility and chromatin quality. iran reprod med j. 2012; 10: p. 77– 82. l-carnitine and coenzyme q10 in male infertilitychavoshi nezhad et al. andrology 336 the effects of tranexamic acid on bleeding control during and after percutaneous nephrolithotomy (pcnl): a randomized clinical trial mohammad reza mokhtari1, saman farshid1, parisa modresi2,4, farzad abedi3,4 purpose: tranexamic acid is a fibrinolysis suppressor that is used for a variety of bleeding control procedures such as hematuria, surgery bleeding, and trauma caused bleeding. the advantages of using tranexamic acid are bleeding control and less need for blood transfusion. materials and methods: this double blind clinical trial was conducted on 108 patients in imam khomeni hospital, urmia, iran 2013-14. the control and intervention groups consisted of 54 randomly selected participants each. the intervention group received 1gr of intravenous tranexamic acid with initiation of surgery and 500mg orally each 8hrs afterwards up to three days. the control group received placebo capsules containing starch of the same form. results: the mean term of hospitalization in the intervention group was significantly shorter than that of the control group (p < 0.001). the difference between the two groups in terms of preoperative hemoglobin was not significant. however, the decrease in postoperative hemoglobin, intraoperative hemoglobin count in washing liquid, and hemoglobin count in the intervention group were significantly different from those of the control group (p < 0.001). conclusion: the findings showed that tranexamic acid decreased bleeding during pcnl and the need for blood transfusion. it also decreased the hospitalization time. keywords: tranexamic acid; bleeding; percutaneous nephrolithotomy; iran introduction percutaneous nephrolithotomy (pcnl) is one of the minimally invasive and efficient methods to treat kidney stones. this treatment is the first-line treatment for large or complex renal pelvis stones and lower calyx stones. it is recommended for large, rigid and infectious, and obstructive upper ureteral stones when extracorporeal shock wave lithotripsy is not effective(1). studies have shown that the success rate of this method is more than 90%; whoever, bleeding is one of the serious and prevalent side-effects that lowers hemoglobin level down to 2.1-3.3g/dl. although most of the bleeding cases are treatable, about 0.8% of cases have severe bleedings that need kidney arthrography(2,3). in general, intraoperative and postoperative bleeding happens in 5.7%-23% of patients under pcnl(4). in general, there are different methods to control intraoperative bleeding including anti-fibrinolytic materials like tranexamic acid (txa) that suppresses plasminogen – plasmin conversion and controls bleeding(5). the txa is a suppressor of fibrinolysis and it is used to treat specific types of bleeding such as hematuria, postoperative bleeding, and trauma bleeding. it helps the patients by 1department of urology and nephrology, urmia university of medical sciences, urmia, iran. 2department of pathology, faculty of medicine, kurdistan university of medical sciences, sanandaj, iran. 3department of urology, faculty of medicine, kurdistan university of medical sciences, sanandaj, iran. 4clinical research development center, kowsar hospital, kurdistan university of medical sciences, sanandaj, iran. *correspondence: facuty of medicine, kurdistan university of medical sciences, pasdaran ave, sanandaj, iran . tel: +989146039122. e-mail: dr.f.abediurologist@gmail.com. received october 2020 & accepted july 2021 controlling blood loss and attenuating the need for blood transfusion(6-8). taking into account the high prevalence of kidney stones in iran and that there is a paucity of studies on the effects of txa on bleeding during and after pcnl, the present study is an attempt to examine the effects of txa on bleeding during and after pcnl. materials and methods study design and participants totally, 108 patients in imam khomeini hospital in urmia– iran took part in this double blind clinical trial study in 2013-2014. inclusion criteria were having kidney or upper ureteral stone (stones bigger than 2cm at pelvic or upper calices and bigger than 1.5cm of lower calices), failed eswl, and candidate of pcnl. in addition, patients with a history of dvt, pte, and cr>1.5, drug allergy, cerebral arteries damage or sah, color blindness, using ocp pills, using coagulation factors, surgery and heart valve transplantation were excluded (figure 1). the intervention and control groups each included 54 individuals who were randomly allocated. the intervention group received txa (1gr intravenously at the beginning and 5mg orally every 8hrs for urology journal/vol 18 no. 6/november-december 2021/ pp. 608-611. [doi: 10.22037/uj.v18i.6505] endourology and stone disease 3days) and the control group received normal saline and placebo capsules (starch) of the same form and dose. the surgeon and patients were blind to the allocation of participants and the patients signed an informed letter of consent. a 5f ureteral catheter was affixed to the patients in lithotomic position and then pcnl surgery was performed in the prone position. all the operations were performed by one surgeon. to determine the effects of medication on intraoperative bleeding, intraoperative mean hemoglobin count in the return washing liquid (the washing liquid samples were collected in one container routinely and then 10cc of the sample was sent to a lab). based on the total volume of the washing liquid, the volume of lost blood during the operation was calculated. for the two groups, hb and hct were measured 24hrs before and 48hrs after the operation to determine the effectiveness of the medicine in controlling postopfigure 1. consort flow diagram tranexamic acid on bleeding control in pcnl-mokhtari et al. variable intervention n (%) control n (%) p-value age (mean ± sd) 39.5 ± 14.01 (26.2-48.7) 42.4 ± 11.21 (34.1-50.3) .12 sex male 28 (51.9) 30 (55.6) .70 female 26 (48.1) 24 (44.4) eswl no 31 (57.4) 30 (55.6) .974 1 10 (18.5) 10 (18.5) >1 13 (25.9) 14 (24.1) location middle calyx 10 (18.5) 13 (21.4) .492 upper calyx 6 (11.1) 8 (14.8) ureter 1 (1.9) 3 (5.6) lower calyx 37 (68.5) 30 (55.6) pelvis kidney parenchyma normal 43 (79.6) 46 (85.2) .44 decreased 11 (20.4) 8 (14.8) transfusion yes 1 (1.9) 6 (11.1) .05 no 53 (98.1) 48 (88.9) size of stone (mean ± sd) 36.16 ± 13.71 (28.4-45.2) 35.81 ± 13.16 (27.9-44.6) .89 the number of tracts taken (mean ± sd) 1.22 ± 0.46 (1.08-1.36) 1.27 ± 0.45 (1.04-1.32) .52 time of operation (hour) (mean ± sd) 2.07 ± 0.51 (1.65-2.54) 2.16 ± 0.49 (1.57-2.43) .37 time of hospitalization (day) (mean ± sd) 2.88 ± 0.63 (1.95-3.24) 3.46 ± 0.81 (2.74-3.87 < 0.001 hemoglobin before surgery (mean ± sd) 13.36 ± 2.08 (11.20-14.12) 12.99 ± 1.52 (11.35-14.12) .30 hemoglobin after surgery (mean ± sd) 12.37 ± 1.58 (10.84-14.01) 10.72 ± 1.47 (9.47-11.03) < 0.001 liquid hemoglobin (mean ± sd) 18.38 ± 7.73 (13.52-23.45) 28.22 ± 8.5 (22.34-36.54) < 0.001 decreased hemoglobin after surgery (mean ± sd) 0.98 ± 0.98 ( 2.27 ± 0.89) < 0.001 table 1. comparisons of the parameters between the two groups of patients during and after percutaneous nephrolithotomy (pcnl) vol 18 no 6 november-december 2021 609 endourology and stones diseases 610 erative bleeding. moreover, the number of blood units were logged and compared between the patients(9,10). the factors under study were demographical variables, number of accesses, total blood loss, operation term, hospitalization time, period of using analgesics, and analgesic dose. pharmaceutical side-effects in the two groups were recorded. in the case of thrombotic side-effects, the medicine would not be administered anymore and the specific treatment for the side-effect or other side-effects would be implemented. ethical considerations this study was approved by the ethics committee of urmia university of medical sciences (ir. umsu.rec.1392.162) and id of trial registry ( r c t 2 0 1 8 0 6 2 5 0 4 0 2 3 2 n 4 ) . statistical analysis frequency and percentage of each one of the variables were determined in the two groups and independent qualitative and quantitative variables were analyzed using chi square test and t-test. data analyses were performed in stata 14 (p < 0.05). results the effect of txa on controlling bleeding during and after pcnl operation was examined in an intervention and a control group each with 54 members (figure 1). the mean age of the participants in the intervention and control groups was 39.5 and 42.4 years respectively. the number of men in the intervention and control group was 28 (51.9%) and 30 (55.6%) respectively. totally, 13 (24.1%) in the intervention group and 14 (25.9%) in the control group had a history of eswl and there was no significant difference between the two groups in this regard (p = 0.97). the highest frequency of stones in the two groups was at the lower and mid kidney and there was no significant difference between the two groups in terms of normal and attenuated renal parenchyma (p = 0.44). the mean size of stones, obtained tract, and time duration of operation are listed in table 1. thrombotic side-effects were not reported in any of the patients in the intervention group and only 38 patients (70.4%) reported nausea. the mean time of hospitalization in the intervention group was significantly shorter than that of the control group (p < 0.001). there was no significant difference between the two groups in terms of preoperative hemoglobin count. however, postoperative hemoglobin, liquid hemoglobin, and decrease in hemoglobin count in the intervention group had a significant decrease compared to the control group (p < 0.001) (table 1). the side-effects of txa including thrombotic side-effects (severe pain in the chest, groin, and splint, sudden headache, vision disorders, speech problem, and weakness of limbs) and non-thrombotic side-effects (dizziness, weakness, blood pressure decrease, nausea, diarrhea, and vomiting) were examined. as the results showed, none of the former side-effects were reported in the intervention. as to non-thrombotic side-effects in the intervention group, 38 patients (70.4%) reported nausea and 16 patients (29.6%) reported vomiting. discussion the highest frequency of stone in both groups was at the lower and mid kidney and there was no significant difference between the two groups in terms of normal and attenuated kidney parenchyma. siddiq et al. reported that the highest frequency of stone was at the lower and pelvic areas, while there was no significant difference between the intervention and control groups. their findings are consistent with the present findings(11). hospitalization time and the need for blood injection were significantly lower in the intervention group compared to the control group. in addition, preoperative hemoglobin levels in the two groups were not significantly different. on the other hand, postoperative hemoglobin, liquid hemoglobin, and hemoglobin count decline in the intervention group was significantly lower than that of the control group. mohammadi et al. reported that the mean level of postoperative hemoglobin in txa group was significantly higher than that in the control group (normal saline)(12). yao et al. studied patients with polycystic and showed that bleeding term and the volume of injected blood in txa patients was significantly lower than those in the control group(13). mihai et al. showed that the need for blood injection in the intervention group was less than that in the control group and that the use of txa in pcnl was safe, economic, and acceptable(14). siddiq et al. reported that hemoglobin and hematocrit levels in intervention and control groups were not significantly different and the mean level of changes in hemoglobin level in the placebo group after the operation was higher than that of the intervention group. they also showed that the need for blood injection in txa group was significantly less than the placebo group(11). using txa in pcnl operation attenuates bleeding and hemoglobin loss. studies have shown that a decrease in intraoperative bleeding decreases the operation time duration, mortality rate, and side-effects in patients(15, 16). yao et al. reported that creatinine serum level and egfr in txa group were at desirable levels(13). the results showed that there was no thrombotic side-effect in the intervention group and non-thrombotic side-effects were observed in 38 patients (70.4%) as nausea and 16 patients (29.6%) as vomiting. rashid et al. reported that the side-effects in the intervention group were bleeding (4%), pcs rapture (4%), and uti and fever (16%); and in group b were bleeding (8%), pcs rapture (8%), and uti and fever (20%). these differences were not significant(17). as the results showed, postoperative fever is one of the most common side-effects of pcnl (32.7%) and the sepsis rate ranges from 0.97% to 4.7% (18). conclusions the results showed that using txa in pcnl surgery attenuated bleeding, the need for blood transfusion, and hospitalization time. acknowledgement the study was sponsored by the deputy of research and technology of urmia university of medical scienc¬es, urmia, iran. conflict on interest the authors declare that there is no conflict of interest. references 1. skolarikos a, alivizatos g, de la rosette j. percutaneous nephrolithotomy and its legacy. tranexamic acid on bleeding control in pcnl-mokhtari et al. eur urol. 2005;47(1):22-8. 2. meng x, bao j, mi q, fang s. the analysis of risk factors for hemorrhage associated with minimally invasive percutaneous nephrolithotomy. biomed res int. 2019. 3. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51(4):899906. 4. rahmani mm am, gholami mahtaj l et al. comparison of bleeding complication of percutaneous nephrolithotomy in patients with and without previous open nephrolithotomy surgery. quarterly journal of sabzevar university of medical sciences. 2013;20(4):556-62. 5. casati v, sandrelli l, speziali g, calori g, grasso ma, spagnolo s. hemostatic effects of tranexamic acid in elective thoracic aortic surgery: a prospective, randomized, doubleblind, placebo-controlled study. j thorac cardiovasc surg. 2002;123(6):1084-91. 6. urban d, dehaeck r, lorenzetti d, guilfoyle j, poon m-c, steele m, et al. safety and efficacy of tranexamic acid in bleeding paediatric trauma patients: a systematic review protocol. bmj open. 2016;6(9):e012947. 7. huang f, wu d, ma g, yin z, wang q. the use of tranexamic acid to reduce blood loss and transfusion in major orthopedic surgery: a meta-analysis. j surg res. 2014;186(1):31827. 8. mohammadi m, nouri-mahdavi k, barzegar a. effects of tranexamic acid on bleeding and hemoglobin levels in patients with staghorn calculi undergoing percutaneous nephrolithotomy: randomized controlled trial. iran j med sci. 2019. 9. radfar mh, basiri a, nouralizadeh a, shemshaki h, sarhangnejad r, kashi ah, narouie b, soltani am, nasiri m, sotoudeh m. comparing the efficacy and safety of ultrasonic versus pneumatic lithotripsy in percutaneous nephrolithotomy: a randomized clinical trial. eur urol focus. 2017 feb 1;3(1):82-8. 10. basiri a, nouralizadeh a, kashi ah, radfar mh, nasiri mr, zeinali m, sarhangnejad r, hosseini-sharifi sh. x-ray free minimally invasive surgery for urolithiasis in pregnancy. urol j. 2016 mar 5;13(1):2496-501. 11. siddiq a, khalid s, mithani h, anis s, sharif i, shaikh j. preventing excessive blood loss during percutaneous nephrolithotomy by using tranexamic acid: a double blinded prospective randomized controlled trial. j. urol. surg. 2017;4(4):195. 12. mohammadi m, nouri-mahdavi k, barzegar a. effects of tranexamic acid on bleeding and hemoglobin levels in patients with staghorn calculi undergoing percutaneous nephrolithotomy: randomized controlled trial. iran j med sci. 2019;44(6):457-64. 13. yao q, wu m, zhou j, zhou m, chen d, fu l, et al. treatment of persistent gross hematuria with tranexamic acid in autosomal dominant polycystic kidney disease. kidney blood press res. 2017;42(1):156-64. 14. cauni v, mihai v, barbilian c, dragutescu m, buraga i. the use of tranexamic acid for preventing hemorrhagic complications during percutaneous nephrolithotomy. eur. urol. suppl. 2017;16(11):e2972. 15. kumar s, randhawa ms, ganesamoni r, singh sk. tranexamic acid reduces blood loss during percutaneous nephrolithotomy: a prospective randomized controlled study. j urol. 2013;189:(5.1757-61) 16. el-nahas ar, eraky i, shokeir aa, shoma am, el-assmy am, el-tabey na, et al. percutaneous nephrolithotomy for treating staghorn stones: 10 years of experience of a tertiary-care centre. arab j urol. 2012;10(3):324-9. 17. rashid ao, ahmed hk, ali dmk. the use of tranexamic acid in percutaneous nephrolithotomy. a randomized controlled study (local experience). open j. urol. 2018;8(12):317. 18. vorrakitpokatorn p, permtongchuchai k, raksamani e, phettongkam a. perioperative complications and risk factors of percutaneous nephrolithotomy. j med assoc thai. 2006;89(6):826. tranexamic acid on bleeding control in pcnl-mokhtari et al. vol 18 no 6 november-december 2021 611 pictorial urology 80 urology journal vol 7 no 2 spring 2010 solitary renal actinomycosis urol j. 2010;7:80. www.uj.unrc.ir a 53-year-old man, who was a recurrent stone former and diabetic, presented with left flank pain, pyuria, and fever. he had undergone multiple interventions for removal of the left kidney stones and retained ureteral double-j stent. all blood and urine investigations were unremarkable and negative for fungus and tuberculosis. computed tomography scan revealed an edematous left kidney with poorly enhancing upper pole having dilated calyces with hyperdense contents suggestive of abscess (figure 1). ultrasonography-guided aspiration of left renal abscess grew pseudomona aeruginosa. thereafter, patient underwent left laparoscopic nephrectomy. on gross examination, yellow sulfur granules in the dilated upper pole calyceal system were seen (figure 2). microscopic examination of the sulfur granules demonstrated homogenous eosinophilic hyaline material coating actinomyces colonies surrounded by a dense lymphoplasmacytic infiltrate (splendore-hoeppli phenomenon) with concomitant pyelonephritis (figure 3). the patient was discharged on long-term doxycycline as he was allergic to penicillin. solitary renal actinomycosis can present as pyelonephritis, renal/perinephric abscess, or renal mass. (1) multiple interventions, recurrent urinary tract infection, retained double-j stent, uncontrolled diabetes mellitus, and untreated dental caries are predisposing factors for this disease. with development of effective antibiotics, the challenge now lies in the clinician’s ability to make the correct diagnosis, thus, ensuring timely recognition and renal salvage if possible. (2) ajay shetty, arvind ganpule, mahesh r desai* muljibhai patel centre for research in nephro-urology, dr. virendra desai road, nadiad, gujarat, india *e-mail:mrdesai@mpuh.org references 1. whisenand jm, moore v. hydrodynamics of upper urinary tract after mucosal ureterosigmoidostomy; case report. trans west sect am urol assoc. 1950;17:90-6; disc 106-10. 2. dhanani nn, jones dm, grossman hb. medical management of renal actinomycosis. j urol. 2004; 171:2373-4. running head: effects of lrhc on varicocele-jin et al. effects of liver-regulating herb compounds on varicocele-associated testicular dysfunction through restoring hormones and spermatocytes apoptosis guorong jin1, jianrong liu2*, caiyun ding1, yuehong ma1, haizhen yin1, lina dong1, fang zhang1, qin qin2, songdan gao1 1central laboratory, shanxi provincial people's hospital, affiliate of shanxi medical university, taiyuan 030012, china 2department of reproductive medicine, shanxi provincial people's hospital, affiliate of shanxi medical university, taiyuan 030012, china keywords: varicocele; infertility; alternative medicine; apoptosis abstract purpose: varicocele is considered as one of the causes for male infertility. though varicocelectomy is suppose to improve semen parameters in adult infertile men, some patients with varicocele were still infertile after varicocelectomy.. previous studies showed traditional chinese medicine, liver-regulating herb compounds (lrhc) could improve the semen quality and increase fertility rates of infertile patients with varicocele. this study aimed to throw light on the mechanism of lrhc on varicocele-associated infertility. materials and methods: rats with varicocele-induced were treated with lrhc at dosage of 1ml/100g by intragastric administration for 90 days. the effects of lrhc on hormones and spermatocytes apoptosis were examined using elisa assay, western blotting, and flow cytometry. results: rats induced with varicocele showed higher level of follicle stimulating hormone (fsh) in serum, which was brought back to normal level by lrhc. after treating with lrhc, both testicular tissue in vivo and sertoli cell tm4 cells in vitro showed elevated expressions of fshr. cell viabilities of tm4 cells and spermatocyte gc-2 cells were improved by lrhc treatment under normoxia and hypoxia condition. moreover, lrhc protected gc-2 cells from apoptosis induced by hypoxia. the expression of bax reduced, while that of bcl-2 increased after treating with lrhc. conclusion: this study revealed that lrhc had protective effects on spermatogenic disturbance caused by varicocele through regulating hormones and reducing spermatogenic cell apoptosis under hpoxia condition. introduction varicocele is an abnormal dilation, elongation and tortuosity of the tendril venous plexus within the spermatic cord; it is prevalent worldwide with 10%-15% overall incidence. varicoceles are found in 19%-41% of men with primary infertility and 45%-81% of those with secondary infertility.(1) among infertile patients with poor semen quality, the incidence of varicocele is 25%, while that in normal people is 12%.(2) varicocele has been considered as one of the causes of male infertility. the current treatment for varicocele-associated infertility is varicocelectomy, which may improve pregnancy rates and sperm concentration in adult infertile men.(3) however, during our clinical practice, we found that some patients are still infertile after surgery. therefore, it is of great practical significance to find alternative treatment for varicocele-associated infertility. liver-regulating herb compounds (lrhc) is a chinese herb mixture including cyperus rotundus，seeds of litchi chinensis sonn，angelica sinensis，cynanchum otophyllum，pericarpium citri reticulatae，and citrus aurantium. our previous clinical practice suggested that lrhc achieved a good therapeutic effect for varicocele-associated infertility.(4) the average sperm motility and sperm count of infertile patients with varicocele significantly improved after taking lrhc for 2 to 4 courses. in rats with varicocele, lrhc could ameliorate histological appearance and ultrastructure of seminiferous tubules damaged by varicocele.(5) however, the effects of lrhc on hormones and spermatocytes apoptosis are still not clear. spermatogenesis failure caused by varicocele is considered as the cause for male infertility.(6) spermatogenesis is regulated by neuroendocrine, especially the hypothalamic-pituitarygonadal axis. the hypothalamus secretes gonadotropin-releasing hormone (gnrh), which stimulates the pituitary gland to secrete follicle-stimulating hormone (fsh) and luteinizing hormone (lh). then lh promotes the secretion of testosterone (t) by leydig cells. fsh binds with fsh receptor (fshr) on the surface of sertoli cells, affecting the maturation, proliferation and function of sertoli cells independently or in synergy with t.(7) except for affecting hormones, testicular hypoxia induced by varicocele could promote testicular cell apoptosis. spermatogenic cells, sertoli cells and leydig cells are sensitive to hypoxia; cell apoptosis induced by hypoxia have a negative effect on spermatogenesis.(8) in this study, we tried to verify whether lrhc could regulate the hormone levels in rats with varicocele which may be helpful to understand the molecular mechanisms of treating varicocele-associated infertility by lrhc. materials and methods animals a total of twenty-three eight-week-old male sprague-dawley rats weighing about 250g were included in this study. all of rats were maintained under controlled conditions with a 12/12 h light-dark cycle at 24℃ and were given free access to water and food. twenty-three rats were randomly divided into three groups: control group (rats undertaken sham operation, n = 8), varicocele group (rats with varicocele-induced, n = 8), and lrhc group (rats with varicoceleinduced treated by lrhc, n = 7). rats were sacrificed at the end of the study by intraperitoneal injection of pentobarbital sodium. all rat experiments were performed in compliance with the guide for care and use of laboratory animals and were approved by independent ethics committee of shanxi provincial people’s hospital (ethics committee approval number: provincial medical opinions 2021 no.8). animal experiment design for varicocele group, experimental rat model of varicocele was made as previously described.(4) briefly, the rats were anesthetized by intraperitoneal injection of 40 mg/kg pentobarbital sodium. after making an abdominal midline incision and exposing the left kidney, left renal vein, adrenal vein, and testicular vein, we loosely tied the left renal vein using a 3-0 silk suture in a diameter of 0.64 mm. partial ligation of the left renal vein decreased its diameter to approximately half. the abdominal midline incision was sewed up. then the rats were fed for 48 days to develop varicocele. for control group, rats underwent a sham operation which is similar to the above procedure without the left renal vein ligation. for lrhc group, rats were induced varicocele as above described. after 48 days of varicocele induction, rats were treated with lrhc (1ml/100g) by intragastric administration for 90 days. physiological saline (1ml/100g) was used in the control group and varicocele group instead of lrhc. collection of serum and testes after 90 days of treatment, all of rats were sacrificed and blood was collected from heart and then centrifuged at 4000 rpm for 10 min to separate the serum. the serum was used to examine the concentration of fsh, lh, t, and also used for cell treatment. the serum was stored at -80℃ before performing elisa. the left testes were collected by orchiectomy. the testes were homogenized for protein extraction. enzyme linked immunosorbent assay (elisa) testicular protein was extracted by homogenizing testicular tissue in physiological saline. the content of fsh, lh, t in serum and testicular tissues were examined using commercially available elisa kits (elabscience biotechnology co.,ltd, wuhan, china), according to the manufacturer's instructions. the absorbance at 450nm was read using a synergytm 4 multi– mode reader (biotek, winooski, usa). western blotting the procedure of western blotting was as previously described.(4) the antibodies used were as follows: anti-fhsr antibody (abcam, cambridge, usa), anti-β-actin antibody (boster biotechnology co., wuhan, china), anti-bax antibody (boster biotechnology co., wuhan, china), anti-bcl-2 antibody (boster biotechnology co., wuhan, china), anti-gapdh (boster biotechnology co., wuhan, china). the relative intensity of protein bands was quantified using image j software (national institute of health, md, usa). cell culture and cck-8 assay the sertoli cell line tm4 and spermatocyte cell line gc-2 were purchased from american type culture collection (atcc). tm4 cells were cultured in dmem/f12 medium, supplemented with 10% fetal bovine serum (fbs). gc-2 cells were cultured in dmem medium supplemented with 10% fbs. all cells were kept at 37℃ with 5% co2. for cck-8 assay, tm4 or gc-2 cells were plated at 50-70% confluence and were treated with 10 % rat serum from experimental rats. lrhc-containing serum was used at the concentration of 0%, 5% and 10%. control rat serum was used to supplement with lrhccontaining serum to reach the final concentration of 10%. cells treating with rat serum were cultured under normoxia or hypoxia (1% oxygen concentration) condition for 24h. then cell viabilities were tested using a commercial cck-8 kit (dojindo, shanghai, china), following the manufacturer's instructions. real-time pcr total rna were extracted from tm4 cells that treated by rat lrhc-containing serum. then cdna was synthesized and real-time pcr was performed. the primers used were as followings: fshr forward primer: 5’ ggcggcaaacctctgaactt 3’; reverse primer: 5’ tcagatccttttccataactgggt 3’. β-actin forward primer: 5’ ctaggcaccagggtgtgatg 3’; reverse primer: 5’ tctccatgtcgtcccagttg 3’. cell apoptosis analyses cell apoptosis of gc-2 cells treating with different concentrations of lrhc-containing serum was analyzed by flow cytometry using an annexin v/pi apoptosis detection kit (keygen biotech, jiangsu, china). the proportion of cells in different apoptosis status was determined using the fc500 flow cytometer. the excitation and emission wavelength of flowcytometry for annexin and pi were as follows, annexin v-fitc (ex=488 nm, em=530 nm); pi (ex=488nm,em=630nm). statistical analyses each experiment was replicated three times. the statistical analyses were performed using spss 13.0 software (spss inc., chicago, il, usa). the results were shown as the mean with 95% confidence intervals (cis). one-way anova were used for statistical analysis. shapirowilk test and levene test were used to test the normality and homogeneity of variance, respectively. lsd test was used for multiple comparisons between groups if they met homogeneity of variance; otherwise dunnett's t3 test was used. p values of < .05 were considered statistically significant. restults the effect of lrhc on the hormone secretion of rats with varicocele fsh, lh and t are important hormones involved in spermatogenesis. we examined the concentrations of fsh, lh and t in testicular tissues and serum from rats using elisa (figure 1). we found that the content of fsh in testicular tissue was not affected by varicocele inducing and lrhc treatment. however, in serum, higher level of fsh was observed in rats with varicocele as compared with control rats (6.59 [95% ci: 4.26-8.91] vs 2.31 [95% ci: 1.85-2.77]); and the increased level was attenuated by lrhc application. the content of lh was higher in testicular tissues from rats with varicocele than that in control rats (0.24 [95% ci: 0.19-0.29] vs 0.14 [95% ci: 0.11-0.19]), which was not influenced by lrhc. in serum, there is no difference in the content of lh among groups. the concentration of t was higher in serum from rats with varicocele than that in control rats (7.78 [95% ci: 7.02-8.55] vs 2.80 [95% ci: 2.07-3.53]). rats with varicocele treated with lrhc showed the highest level of t both in testicular tissue and in serum. the effect of lrhc on the expression of fshr in vivo and in vitro fshr is the molecular marker of sertoli cell, and it affects the function of sertoli cells. after treating varicocele-induced rats with lrhc, we analyzed the effect of lrhc on expression of fshr. in testicular tissues, western blotting results showed that the expression of fshr in varicocele-induced rats did not alter. however, after taking lrhc, the varicocele-induced rats showed elevated expression level of fshr than control rats (figure 2a-b). in mouse sertoli tm4 cells, the fshr expression was detected by real-time pcr after treating with 0% (control), 5% and 10% lrhc-containing serum. the results showed significantly up-regulated expression of fshr in tm4 cells treating with 10% lrhccontaining serum, when compared with control cells (figure 2c). the effect of lrhc on cell viability and apoptosis it has been found that varicocele induced hypoxia and apoptosis of testicular tissue which contributed to the pathophysiology of varicocele. we consequently tested the effects of lrhc on testicular cell viability under normoxia and hypoxia condition. in gc-2 cells, lrhc treatment improved the cell viability significantly under both normoxia and hypoxia condition, especially at the 10% concentration (figure 3a). in tm4 cells maintained at normoxia, lrhc treatment improved the cell viability slightly, while the alteration did not reach to statistically significant. under the hypoxia condition, lrhc treatment at the 10% concentration dramatically increased the tm4 cell viability (figure 3b). since gc-2 cell viability was more sensitive for lrhc treatment, the cell apoptosis of gc-2 cells affected by lrhc was further analyzed. the results of flow cytometry showed that the amount of apoptotic cells increased significantly after hypoxia (1% oxygen) treatment for 24h. the apoptosis rate increased from (11.45 ± 0.50) % to (15.51 ± 0.81) %. after treating with lrhc at the 5% and 10% concentration, the cell apoptosis rate reduced to (13.34 ± 0.74) % and (11.85 ± 0.74) %, respectively (figure3c-d). the expressions of apoptosis related proteins were detected by western blotting. under the hypoxia condition, the expression of pro-apoptotic protein bax increased slightly, while that of anti-apoptotic protein bcl-2 increased significantly. after treating with lrhc, the bax expression was significantly reduced, while the expression bcl-2 was dramatically upregulated (figure 3e-f). discussion in varicocele, hormonal perturbation is induced and thus spermatogenesis impaired, which is considered as the pathogenesis of varicocele-associated infertility. high fsh level has a relationship with worse sperm quality(9), making fsh an indicator for the diagnosis of impaired spermatogenesis, with a sensitivity of 88.9% and a specificity of 94.1%.(10) it has been reported that varicocele could increase the fsh and lh levels, while decrease t level in the serum, which may contribute to poor sperm quality.(11,12) traditional chinese medicines turned to regulate the hormones to improve infertility rate. in this study, we found an upregulated level of fsh in varicocele-induced rats. the damage of spermatogenesis in varicocele results in the compensatory high level of fsh. lrhc treating brought fsh level back to a normal level, implying lrhc could improve spermatogenesis and the decrease in fsh level might be a result of negative feedback loop activation. additionally, lrhc could elevate t level dramatically. varicocele is associated with hypogonadism; and low level of t could affect the process of spermatogenesis. dramatically high level of t elevated by lrhc meant this medicine could improve the testicular function. this result should further be verified in clinical patients. taken together, lrhc may play positive effects on varicoceleassociated infertility in a direct testis-oriented action. in testicular tissue, smoothly spermatogenesis relies on the cooperation of several functional cell types, including spermatogenic cells, sertoli cells, and leydig cells. sertoli cells form a niche for germ cell maturation, and they construct the blood-testis barrier through tight junction formation.(13) moreover, sertoli cells function as “nurse cells” and provide nutritional support for developing germ cells, which is pivotal during spermatogenesis.(14) the proliferation, maturation, and function of sertoli cells are regulated by fsh. by binding with fshr, fsh promotes sertoli cell proliferation and maturation, increases sertoli cell number, and determines testicular size.(15) absence of fsh or fshr considerably decreases the sertoli cell number by 30–45%, compared with normal testicular development.(7) in this study, we found that lrhc could improve the fshr level in varicocele testes as well as in tm4 cells. providing more fshr for fsh to bind with, the serum level of fsh may reduce dramatically. thus, lrhc may exert active roles on spermatogenesis through supporting and protecting the functions of sertoli cells. amounts of studies indicated that varicocele could induce tissue hypoxia and apoptosis which contributed to the pathophysiology of varicocele-associated infertility.(16) hypoxia could result in severe chronic oxidative and nitrosative stress in testicular tissues of patients with varicocele. consequently, this chronic stress leads to impaired spermatogenesis and produces poor sperms.(17) in vitro, hypoxia induced the spermatocyte cell apoptosis in a time-dependent manner.(18) in this study, we cultured gc-2 cells under the hypoxia condition to mimic the testicular physiological environment of varicocele. we found that lrhc could improve the cell viabilities and protect gc-2 cells from apoptosis induced by hypoxia. oxidative stress (os) has been considered as a major contributory factor to varicocele-associated infertility.(19) excessive os causes alteration in testicular microenvironment and sperm dna fragmentation, which further induces germ cell damages. it is possible that lrhc could decrease oxidative stress and thus protect sperms cells from apoptosis.the exact mechanism that lrhc improves cell viability and protects cells from apoptosis induced by hypoxia needs further studies. conclusion in conclusion, lrhc can restore the damaged testicular function. it also exerts a function on fsh/fshr system, improves cell viability and protects cell from apoptosis. this study may provide some insight into the molecular mechanism of lrhc treating the varicoceleassociated infertility. acknowledgements this work was supported by national natural science foundation of china [grant number 81973864]. we thank laboratory animal center (animal laboratory of nephrology, shanxi provincial people’s hospital, taiyuan, china) for raising the experimental rats. conflict of interest the authors declare no conflict of interest. references 1. pastuszak aw, wang r. varicocele and testicular function. asian j androl. 2015;17:659-67. 2. chiba k, ramasamy r, lamb dj, lipshultz li. the varicocele: diagnostic dilemmas, therapeutic challenges and future perspectives. asian j androl. 2016;18:276-81. 3. fallara g, capogrosso p, pozzi e, et al. the effect of varicocele treatment on fertility in adults: a systematic review and meta-analysis of published prospective trials. eur urol focus. 2023;9:154-61. 4. liu j, wang h. clinical study on "shenqu zhuyu decoction" in treating varicocele and resultant infertility. shanghai j tradit chin med. 2005;39:33-4. 5. lu x, liu j, yin h, et al. effects of liver‐regulating herb compounds on testicular morphological and ultrastructural changes in varicocele rats through scf/c-kit pathway. andrologia. 2020;52:e13658. 6. panner selvam mk, baskaran s, agarwal a, henkel r. protein profiling in unlocking the basis of varicocele-associated infertility. andrologia. 2021;53:e13645. 7. oduwole oo, peltoketo h, huhtaniemi it. role of follicle-stimulating hormone in spermatogenesis. front endocrinol (lausanne). 2018;9:763. 8. kang c, punjani n, lee rk, li ps, goldstein m. effect of varicoceles on spermatogenesis. semin cell dev biol. 2022;121:114-24. 9. bach t, pfeiffer d, tauber r. baseline follicle-stimulating hormone is a strong predictor for the outcome of the gonadotrophin-releasing hormone test in young men with unilateral mediumor high-grade varicocele. bju international. 2006;98:619-22. 10. schreiber g, görnig m, zollmann c. [current aspects of hormone diagnosis in andrology--predictive values for the preservation of spermatogenesis]. wien med wochenschr. 1997;147:84-9. 11. luo dy, yang g, liu jj, yang yr, dong q. effects of varicocele on testosterone, apoptosis and expression of star mrna in rat leydig cells. asian j androl. 2011;13:28791. 12. pasqualotto ff, lucon am, de góes pm, et al. semen profile, testicular volume, and hormonal levels in infertile patients with varicoceles compared with fertile men with and without varicoceles. fertil steril. 2005;83:74-7. 13. mruk dd, cheng cy. the mammalian blood-testis barrier: its biology and regulation. endocr rev. 2015;36:564-91. 14. frança lr, hess ra, dufour jm, hofmann mc, griswold md. the sertoli cell: one hundred fifty years of beauty and plasticity. andrology. 2016;4:189-212. 15. schubert m, pérez lanuza l, gromoll j. pharmacogenetics of fsh action in the male. front endocrinol (lausanne). 2019;10:47. 16. shokoohi m, khaki a, shoorei h, khaki aa, moghimian m, abtahi‐eivary sh. hesperidin attenuated apoptotic‐related genes in testicle of a male rat model of varicocoele. andrology. 2019;8:249-58. 17. razi m, tavalaee m, sarrafzadeh‐rezaei f, et al. varicocoele and oxidative stress: new perspectives from animal and human studies. andrology. 2020. 18. zhou j, qian cy, tong rq, et al. hypoxia induces apoptosis of mouse spermatocyte gc2 cells through activation of autophagy. cell biol int. 2018;42:1124-31. 19. arya d, balasinor n, singh d. varicocoele-associated male infertility: cellular and molecular perspectives of pathophysiology. andrology. 2022;10:1463-83. corresponding author: jianrong liu, ph.d; department of reproductive medicine, shanxi provincial people's hospital, affiliate of shanxi medical university, taiyuan, china. tel: +86 351 4960046, fax: +86 351 4960046, e-mail: liujianrong3@sina.com figure1: the effect of lrhc on the hormone secretion of rats with varicocele. the levels of fsh, lh and t in serum as well as testicular tissues were examined by elisa. lrhc abrogated the up-regulated level of fsh in serum caused by varicocele. lrhc increased the level of t in testicular tissue as well as in serum from rats with varicocele. figure 2: the effect of lrhc on the expression of fshr. (a) the expression of fshr in testicular tissues from control rats, rats with varicocele, and rats with varicocele treated with lrhc were detected by western blotting. (b) the result of western blotting was quantified by image j software. higher expression of fshr was detected in lrhc treating group than that in control group. (c) mouse sertoli cells tm4 were treated with lrhc-containing rat serum at concentrations of 0% (control), 5% and 10%. the expression of fshr was detected by real-time pcr, showing higher expression in cells treated with 10% lrhc-containing serum, than that in control cells. figure 3: the effect of lrhc on the cell viability and cell apoptosis. (a) mouse spermatocyte gc-2 cell viability was tested using cck-8 assay. blank group indicated gc-2 cells cultured in the regular medium (containing 10% fbs). control serum group indicated cells treated with 10% control rat serum. 5% lrhc serum group indicated cells treated with 5% lrhc-containing serum, supplement with 5% control rat serum. 10% lrhc serum group indicated cells treated with 10% lrhc-containing rat serum. (b) cell viability of mouse sertoli cell tm4 cells was tested. (c) the cell apoptosis of gc-2 cells was examined by annexin v/pi staining followed by flow cytometry. (d) statistical analysis of the flow cytometry results. cell apoptosis was induced by hypoxia, while lrhc-treating significantly reduced the apoptosis rate in a concentration-related pattern. (e) the protein expressions of bax and bcl-2 in gc-2 cells treated with control serum or lrhc-containing serum. (f) the results of western blotting were quantified. the expression of bax was decreased by lrhc treating, while that of bcl-2 was increased. oncological outcomes of neoadjuvant gemcitabine plus carboplatin versus gemcitabine plus cisplatin in locally advanced bladder cancer: a retrospective analysis bahram mofid1, abolfazl razzaghdoust1, mahdi ghajari2, abbas basiri1, mohammad-reza fattahi3, mohammad houshyari2, anya jafari2*, farzad taghizadeh-hesary2* purpose: cisplatin-based neoadjuvant chemotherapy (nac) is the standard of care in non-metastatic muscle-invasive bladder cancer (mibc). there are limited data regarding the alternative choices for cisplatin-ineligible patients. this study has investigated the oncological outcomes of gemcitabine plus cisplatin (gem/cis) and gemcitabine plus carboplatin (gem/carbo) in this setting. materials and methods: one hundred forty consecutive patients with mibc (ct2–t4a) receiving neoadjuvant gem/cis or gem/carbo before chemoradiation (crt) or radical cystectomy (rc) were retrospectively evaluated between april 2009 and april 2019. patients with ecog performance status 2, creatinine clearance < 60 ml/min, hydronephrosis, ejection fraction < 50%, or single kidney received gem/carbo. the complete clinical response (ccr) and overall survival (os) of nac regimens were compared. prognostic significance was assessed with cox proportional hazards model. results: in total, 79 patients (56.4%) received gem/cis. the ccr was not significantly different between gem/ cis and gem/carbo regimens (38.7% vs. 36.2%, p = .771). after nac, 79 patients (56.4%) received crt, and other cases underwent rc. after a median follow-up of 43 months, patients in the gem/cis group had significantly better os than gem/carbo (median os: 41.0 vs. 26.0 months, p = .008). multivariable cox proportional hazards models identified ct4a stage (95% confidence interval [95% ci]: 1.001–4.85, hazard ratio [hr] = 2.08, p = .03) and ccr (95% ci: 0.26–0.99, hr = 0.51, p = .04) as the only independent prognostic factors of os, and ruled out the type of nac regimen. conclusion: the choice of nac (between gem/cis and gem/carbo) is not the predictor of survival and both regimens had similar ccr. keywords: bladder cancer; carboplatin; cisplatin; complete clinical response; neoadjuvant chemotherapy; overall survival; prognostic factors introduction bladder cancer (bc) is the 12th most common ma-lignancy and the 13th leading cause of cancer-related mortality worldwide.(1) urothelial cell carcinoma (ucc) is the most frequent primary bc that accounts for 95% of cases, most of which are diagnosed at an early stage. this highlights the importance of locoregional therapy.(2) for better management, bc is classified into three distinct categories: non-muscle invasive bc, muscle invasive bc (mibc), and metastatic bc. taking a step back, primary radical cystectomy (rc) was the standard treatment in mibc. investigators realized that distant metastasis was the main pattern of recurrence after rc.(3) therefore, neoadjuvant chemotherapy (nac) was proposed and dramatically improved the clinical outcomes of rc.(4) alternative to rc, radiotherapy 1urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. 2department of clinical oncology, shohada-e tajrish educational hospital, shahid beheshti university of medical sciences, tehran, iran. 3nephrology and urology research center, baqiyatallah university of medical sciences, tehran, iran. *correspondence: department of clinical oncology, shohada-e tajrish hospital, tehran, postal code: 19839-63113, iran. tel: (+98)-912-6086713, fax: (+98)-21026651517, e-mail: f_taghizadeh@sbmu.ac.ir **department of clinical oncology, shohada-e tajrish hospital, tehran, postal code: 19839-63113, iran. tel: (+98)-912-5491074, fax: (+98)-21-22760999, e-mail: anyajafari@yahoo.com received may 2021 & accepted february 2022 is an available choice—in case of complete response to nac—to exclude the morbidity of surgery.(5) currently, cisplatin-based neoadjuvant regimens such as gemcitabine plus cisplatin (gem/cis) and methotrexate, vinblastine, doxorubicin plus cisplatin (mvac) are the standard regimens.(4) despite these advantages, nac is not widely employed in patients who are unfit for cisplatin-based nac, including patients with eastern cooperative oncology group (ecog) performance state of 2, single kidney, hydronephrosis, creatinine clearance (crcl) < 60 ml/min, grade 2 of neuropathy, hearing loss, or cardiac failure class iii (based on new york heart association classification).(6) studies have demonstrated that 30–50% of the bc patients are ineligible for cisplatin.(7) a carboplatin-based regimen could be a viable option for patients unfit for cisplatin. the use of carboplatin instead of cisplatin was investigated in other cancers such urological oncology urology journal/vol 19 no. 5/ september-october 2022/ pp. 371-378. [doi:10.22037/uj.v19i.6841] as malignant mesothelioma and lung cancers.(8-10) currently, there is a paucity of convincing data supporting the use of carboplatin (as nac) in mibc patients who are ineligible for receiving cisplatin.(11) a few studies assigned a comparative response rate and survival;(12-15) however, a more recent retrospective cohort demonstrated superior pathologic response and survival in the cisplatin group.(16) this discrepancy might originate from selecting treatment regimens with totally different agents [i.e., mvac (as the cisplatin-based regimen) vs. gem/carbo (as the carboplatin-based regimen)] in two studies(13,14) or unbalanced sample sizes in two other studies that could impact the power of the results.(12,16) considering these issues, this retrospective cohort was therefore designed to compare the clinical response and survival of a standard cisplatin-based nac (gem/cis) and a carboplatin-based regimen (gemcitabine plus carboplatin [gem/carbo]) in mibc. neoadjuvant carboplatin in locally advanced bladder cancer-mofid et al. table 1. baseline characteristics and treatment types of the study population characteristics total (n = 140) gem/cis (n = 79) gem/carbo (n = 61) p-value age, mean (sd), years 66.3 (10.4) 61.4 (9.0) 72.8 (8.4) < .001 sex, n (%) .813 female 10 (7.1) 6 (7.6) 4 (6.6) male 130 (92.8) 73 (92.4) 57 (93.4) tumor stage, n (%) .360 t2 80 (57.1) 47 (59.5) 33 (54.1) t3 48 (34.3) 28 (35.4) 20 (32.8) t4a 11 (7.9) 4 (5.1) 7 (11.5) missing 1 (0.7) 0 1 (1.6) nodal status, n (%) .831 negative 102 (72.8) 57 (72.2) 45 (73.8) positive 38 (27.2) 22 (27.8) 16 (26.2) tumor grade, n (%) .279 low 4 (2.8) 4 (5.1) 0 high 136 (97.2) 75 (94.9) 61 (100) creatinine clearance, mean (sd), ml/min 59.0 (20.5) 69.9 (18.6) 44.8 (12.9) .003 previous bcg therapy, n (%) .129 no 106 (75.7) 56 (70.9) 50 (82.0) yes 34 (24.3) 23 (29.1) 11 (18.0) smoking status, n (%) .611 no 81 (57.8) 44 (55.7) 37 (60.6) yes 59 (42.2) 35 (44.3) 24 (39.4) following treatment, n (%) .510 radical cystectomy 61 (43.6) 34 (43.1) 27 (44.3) chemoradiotherapy 79 (56.4) 45 (56.9) 34 (55.7) abbreviations: bcg, bacillus calmette guerin; gem/carbo, gemcitabine plus carboplatin; gem/cis, gemcitabine plus cisplatin; sd, standard deviation covariates without complete response (n = 83) with complete response (n = 50) p-value age, n (%) .516 ≤ 65 yr 43 (65.1) 23 (34.9) > 65 yr 40 (59.7) 27 (40.3) sex n (%) .999 female 6 (60.0) 4 (40.0) male 77 (62.6) 46 (37.4) tumor stage, n (%) .536 t2 45 (58.4) 32 (41.6) t3 31 (67.4) 15 (32.6) t4a 7 (70.0) 3 (30.0) nodal status, n (%) .320 negative 63 (64.9) 34 (35.1) positive 20 (55.5) 16 (44.6) tumor grade, n (%) .999 high 81 (62.3) 49 (37.7) low 2 (66.7) 1 (33.3) chemotherapy regimen, n (%) .771 gem/cis 46 (61.3) 29 (38.7) gem/carbo 37 (63.8) 21 (36.2) creatinine clearance, n (%) .570 ≥ 60 ml/min 34 (59.6) 23 (40.4) < 60 ml/min 49 (64.4) 27 (35.6) previous bcg therapy, n (%) .806 yes 63 (63.0) 13 (39.4) no 37 (37.0) smoking status, n (%) .906 no 49 (64.5) 27 (35.5) yes 34 (61.8) 21 (38.2) table 2. association of covariates with the clinical complete response to chemotherapy abbreviations: bcg, bacillus calmette guerin; gem/carbo, gemcitabine plus carboplatin; gem/cis, gemcitabine plus cisplatin. urological oncology 372 urological oncology 291 materials and methods the ethical approval was provided by the ethical committee of the shahid beheshti university of medical sciences (xxx.rec.1399.016). study population in this retrospective cohort study, the data from all consecutive patients with mibc treated with gem/cis or gem/carbo as the nac (before crt or rc) from april 2009 to april 2019 were collected. the diagnosis of ucc was based on transurethral resection for bladder tumor (turbt) results. participants who had t2–t4an0–1m0 (based on american joint committee on cancer, 7th edition) urothelial carcinoma based on physical exam, turbt, and computed tomography (ct) scan of chest, abdomen, and pelvis were enrolled. the cases recruited before january 1, 2010 (the release date of ajcc 7th edition) were re-evaluated for the possible changes in the t and n categories. patients’ data, including demographic features, clinical and pathologic characteristics, treatment schedules, and outcomes, were collected from medical records. the irb of the shahid beheshti university of medical sciences approved the research. the irb waived informed consent due to the retrospective nature of the study. the study was conducted per the principles of the declaration of helsinki and current ethical guidelines. treatment and evaluation within four weeks after maximal turbt, patients were permitted to receive nac with four cycles of gem/cis (gemcitabine 1000 mg/m² on days 1 and 8 plus cisplatin 35 mg/m² on days 1 and 2, every 21 days) or gem/carbo regimen (gemcitabine 1000 mg/m² on days 1 and 8 plus carboplatin area under the curve [auc] 4 on day 1, every 21 days). patients with ecog performance status 2, creatinine clearance < 60 ml/min (using cockcroft-gault equation (17)), hydronephrosis, ejection fraction < 50%, or single kidney received gem/ carbo regimen. patients with ecog 0-1 were eligible for gem/cis, and those with ecog 3-4 were not candidates for chemotherapy. during the administration of treatment, the daily dose of regimens could be adjusted according to the frequency and severity of adverse effects. clinical response (yctnm) was evaluated according to recist (response evaluation criteria in solid tumors) 1.1 criteria using cystoscopic tumor-site biopsy, urine cytology, and restaging ct scan within four weeks. thereafter patients with incomplete responses to nac proceeded to immediate rc. patients who were unfit for surgery, patients with a complete response to nac, or those who were unwilling to undergo rc received crt. crt was carried out in 2 distinct approaches, 1) node-negative patients: whole bladder to a total prescribed dose of 64 gy, 2) node-positive pacovariates hazard ratio (95% ci) p-value hazard ratio (95% ci) p-value univariable analysis multivariable analysis a pre-treatment covariates nac regimen, gem/cis 1 (reference) .010 1 (reference) .402 gem/carbo 1.88 (1.16-3.03) 1.28 (0.70-2.36) creatinine clearance, ≥ 60 ml/min 1 (reference) .011 1 (reference) .333 < 60 ml/min 1.90 (1.16-3.11) 1.34 (0.71-2.52) age, ≤ 65 yr 1 (reference) .014 1 (reference) .161 > 65 yr 1.82 (1.13-2.94) 1.47 (0.84-2.57) tumor stage, t2 1 (reference) 1 (reference) t3 1.08 (0.65-1.78) .766 0.97 (0.58-1.63) .905 t4a 2.41 (1.06-5.46) .034 2.08 (1.001-4.85) .033 nodal status, negative 1 (reference) .095 positive 1.52 (0.93-2.50) tumor grade, high 1 (reference) .300 low 2.89 (0.39-21.54) gender, female 1 (reference) .545 male 1.36 (0.49-3.75) smoking status, no 1 (reference) .741 yes 1.08 (0.67-1.72) previous bcg therapy, yes 1 (reference) .836 no 1.05 (0.62-1.80) post-treatment covariates ccr no 1 (reference) .007 1 (reference) .041 yes 0.45 (0.26-0.80) 0.51 (0.26-0.99) following treatment radical cystectomy 1 (reference) .018 1 (reference) .399 chemoradiotherapy 0.55 (0.34-0.90) 0.78 (044-1.38) table 3. univariable and multivariable analysis of factors related to overall survival. abbreviations: bcg, bacillus calmette guerin; ccr, complete clinical response; gem/carbo, gemcitabine plus carboplatin; gem/cis, gemcitabine plus cisplatin; nac, neoadjuvant chemotherapy. a chemotherapy regimen, creatinine clearance, age, and tumor stage were included in the pre-treatment multivariable model. besides, clinical complete response and following treatment were included in the post-treatment model. neoadjuvant carboplatin in locally advanced bladder cancer-mofid et al. vol 19 no 5 september-october 2022 373 tients: whole bladder + pelvic lymph nodes 45 gy, then boost to the whole bladder to a total prescribed dose of 64 gy. radiotherapy was delivered five days per week at a 1.8 gy daily dose. cisplatin 15 mg/m2 plus fluorouracil 400 mg/m2 was administered during radiotherapy on days 1–3, 8–10, and 15–17. after chemoradiation, patients were re-evaluated with cystoscopy and chest, abdomen, and pelvic ct scans, and regular follow-up was performed for patients at 6-month intervals. endpoints in this study, complete clinical response (ccr) and overall survival (os) were evaluated as the primary and secondary objectives, respectively. the ccr was defined as negative results for cystoscopic tumor-site biopsy, urine cytology, and imaging (chest, abdomen, and pelvic ct scans) four weeks after nac, and os was defined as the time from the start of nac until death from any cause. in addition, the association of covariates with ccr and the prognostic significance of them on the os of patients were evaluated. statistical analysis categorical variables were summarized as numbers and percentages and were compared using the pearson chisquare test. continuous variables were summarized using mean and standard deviation, and intergroup values were compared using the independent t-test. os was calculated using the kaplan–meier method, and intergroup differences were compared with a log-rank test. potential prognostic factors for os were assessed with univariable and multivariable cox proportional hazards models. all factors exhibiting significant association with os in the univariable analyses were included in a multivariable model. the follow-up time was estimated using the reverse kaplan-meier method.(18) all analyses were performed using ibm spss statistics, version 26. the statistical significance level was set to 0.05, except for including covariates into multivariable analysis that p-value was set to 0.20 to impede missing the possible potential predictive factors.(19) results from april 2009 to april 2019, 140 patients with mibc who received nac before crt or rc were enrolled in the study. patients had a mean age of 66.3±10.4 years, and 130 cases (92.8%) were male. compared to the gem/cis, patients in the gem/carbo group were older (mean age 61.4 ± 9 vs. 72.8 ± 8.4, p < .001). ucc was the only pathology diagnosis, which was high grade in 136 patients (97.2%). the tumor stage was clinical (c) t2 in 80 patients (57.1%), ct3 in 48 patients (34.3%), and ct4a in 11 patients (7.9%) (clinical staging of one patient was not available), and nodal status was negative in 102 patients (72.8%) without significant difference between groups (p > .05). in total, 79 (56.4%) and 61 (43.6%) patients received gem/cis and gem/carbo as nac. the mean crcl was 59.0 ml/min, which was significantly higher in the cisplatin group (69.9 vs. 44.8 ml/min, p = .003). other baseline characteristics were comparable across the groups (table 1). overall, 128 patients (91.7%) received optimal chemotherapy cycles, which was not statistically different between gem/cis (93.6%, 74 cases) and gem/carbo (88.5%, 54 cases) groups (p = 0 .44). this subgroup did not differ significantly in baseline characteristics compared to the suboptimal group [optimal vs. suboptimal: male sex p = .32, t stage p = .53, n status p = .36, tumor grade p = studies type number of patients nac regimen treatment outcomes p-value cis carbo cis carbo cis carbo mertens et al. retrospective cohort 83 23 gem/cis gem/carbo nac + rc ccr (%) 33.7 26.7 .65 (2012) mvac median dss (m) 20 18 .18 median os (m) 22 22 .36 iwasaki et al. (2013) retrospective cohort 34 34 mvac gem/carbo nac + rc ppr (%) 62 53 .62 3-years rfs (%) 79 75 .85 schinzari et al. (2017) clinical trial (phase ii) 30 42 gem/cis gem/carbo nac + rc pcr (%) 36 23.8 .35 median dfs a (m) 40 22 .57 median os a (m) 48 > 50 .89 anan et al. retrospective cohort 43 280 gem/cis gem/carbo nac + rc pcr (%) 5.7 17 nr (2017) 5-year pfs a (%) 78 70 .32 5-year os a (%) 72 70 .24 peyton et al. retrospective cohort 250 32 ddmvac gem/carbo nac + rc ppr 52 (ddmvac) 27 .03 (2018) gem/cis 41.3 (gem/cis) pcr 41.3 (ddmvac) 9.4 .05 24.5 (gem/cis) 2-year os (%) 73.3 (ddmvac) 34.8 .002 62 (gem/cis) current study retrospective cohort 79 61 gem/cis gem/carbo nac + rc ccr (%) 38.7 36.2 .77 (2021) nac + crt median os (m) 41 26 .008 table 4. characteristics of studies comparing clinical outcomes of a neoadjuvant carboplatin-based regimen with standard cisplatin-based regimen. abbreviations: carbo, carboplatin-based; ccr, complete clinical response; cis, cisplatin-based; crt, chemoradiation; ddmvac, dose-dense mvac; dfs, disease-free survival; dss, disease-specific survival; gem/carbo, gemcitabine plus carboplatin; gem/cis, gemcitabine plus cisplatin; mvac, methotrexate, vinblastine, doxorubicin plus cisplatin; nac, neoadjuvant chemotherapy; nr, not reported; os, overall survival; pcr, complete pathological response; pfs, progression-free survival; ppr, partial pathological response; rc, radical cystectomy; rfs, relapse-free survival. a estimated based on the kaplan-meier curves neoadjuvant carboplatin in locally advanced bladder cancer-mofid et al. urological oncology 374 urological oncology 293 .54, smoking status p = .69, and previous bcg therapy p = .60). after nac, 79 patients (56.4%) received crt and other cases underwent immediate rc (p = .90). [table 1 near hear] association between chemotherapy regimen and tumor response of the study population, 50 cases (37.6%) attained ccr that was not significantly different between gem/cis and gem/carbo regimens (38.7 vs. 36.2%, p = .771). likewise, the rate of ccr was not significantly associated with age (p = .51), sex (p = .99), tumor stage (p = .53), nodal involvement (p = .32), tumor grade (p = .99), and crcl (p = .57). the detailed results of ccr based on covariates are presented in table 2. [table 2 near hear] association between chemotherapy regimen and survival following a median follow-up of 43 months (95% confidence interval [95% ci]: 36.3–49.6 months), 71 patients (50.7%) died. in total, the median os of patients receiving nac was 33 months (95% ci: 24.3– 41.6 months), which was significantly longer in gem/ cis group (median os 41.0 months [95% ci: 37–44.9] vs. 26.0 months [95% ci: 17–35], p = .008) (figure 1-a). concerning patients who completed four cycles of nac, the median os was 33 months, including 40 months (95% ci: 32.3–47.6) and 26 months (95% ci: 17–34.9) for gem/cis and gem/carbo groups, respectively (p = .015). prognostic factors of survival univariable analysis of pre-treatment covariates refigure 1. kaplan-meier curves of overall survival based on the significant pre-treatment factors, a) nac regimen, b) creatinine clearance, c) age, and d) tumor stage, and post-treatment factors, e) complete clinical response, f) post-neoadjuvant treatment. neoadjuvant carboplatin in locally advanced bladder cancer-mofid et al. vol 19 no 5 september-october 2022 375 vealed that nac regimen (gem/carbo: 95% ci: 1.16– 3.03, hazard ratio [hr] = 1.88, p = .01), crcl (crcl < 60 ml/min: 95% ci: 1.16–3.11, hr = 1.90, p = .01), age (> 65 years: 95% ci: 1.13–2.94, hr = 1.82, p = .01), and tumor stage (ct4a: 95% ci: 1.06–5.46, hr = 2.41, p = .03) were significantly associated with os. figure 1 illustrates the comparison of os based on the significant preand post-treatment covariates. on multivariable analysis, presence of ct4a disease (95% ci: 1.001–4.85, hr = 2.08, p = .03) was identified as an independent risk factor for shorter os. of note, due to the significant correlation between nodal status and tumor stage (p < .0001), the nodal status was not included in the multivariable model. [figure 1 near hear] in univariable analysis of post-treatment covariates, both ccr (95% ci: 0.26–0.80, hr = 0.45, p = .007) and the treatment following nac (95% ci: 0.34–0.90, hr = 0.55, p = .01) were found to have significant association with os. multivariable analysis outlined ccr (95% ci: 0.26–0.99, hr = 0.51, p = .04) as the independent prognostic factor of os (table 3). [table 3 near hear] discussion level 1 evidence has demonstrated that cisplatin-based nac (mvac, gem/cis) has improved the os of rc in mibc.(4) the standard nac regimen, however, has not been established for patients who are unfit for cisplatin that constitute 30–50% of bc patients.(4,7,20) therefore, this study—among a few others (table 4)— was conducted firstly to compare the clinical response and survival of a carboplatin-based (gem/carbo) nac against the standard cisplatin-based regimen (gem/ cis); secondly, to find the relevant prognostic factors. [table 4 near hear] in summary, this study demonstrated comparable ccr between induction gem/cis and gem/carb in patients with mibc. in addition, the multivariable analysis showed that the choice of nac between gem/cis and gem/carbo had no independent effect on os. this might reside in the similar mode of action and pharmacodynamic between cisplatin and carboplatin; both platinum agents induce apoptosis through the formation of dna adducts, and the intracellular concentration of both is regulated by a common influx (i.e., copper transporter ctr1) and efflux proteins (i.e., atp7a-b). (21,22) the comparable results for ccr (gem/cis 38.7 vs. gem/carbo 36.2%, p = .77) is consistent with the mertens et al. study.(14) this finding is also in line with the iwasaki et al. and schinzari et al. studies that reported comparable partial pathological response (ppr) to mvac versus gem/carbo regimens (53 vs. 62%, p = .6) and complete pathological response (pcr) to gem/ cis versus gem/carbo (36 vs. 23.8%, p = .35), respectively.(13,15) in the present study, in contrast to the iwasaki et al. and anan et al. studies, the median survival rates between cisplatinand carboplatin-based nac (41 vs. 26 months, p = .008) were not comparable. (13,23) this might root in the selection bias of this study that patients in the gem/carbo group were significantly older with lower crcl (both with poorer prognosis). peyton et al. demonstrated shorter 2-year os in carboplatin-based regimen (34.8 [gem/carbo] vs. 73.3 [dosedense mvac (ddmvac)], 62% [gem/cis], p = .002) that was confirmed in multivariable analysis (gem/cis [reference = 1], ddmvac [95% ci: 0.17–1.06, hr = 0.42, p = .07], gem/carbo [95% ci: 1.16–3.44, hr = 2, p = .01]).(16) in the current study, however, the multivariable analysis did not confirm the preliminary results. this is explained in detail in the following paragraph. in summary, all the aforementioned studies except for one (peyton et al. study) agree with the similar response (clinical, pathological) to nac between carboplatin and cisplatin-based regimens. on survival analysis, 4 of 6 studies showed comparable survival between study groups, and the other 2 (peyton et al. and current studies) reported shorter os in the carboplatin-based group that might be affected by selection bias. on univariable analysis of pre-treatment covariates, predictors of worse os were gem/carbo regimen, crcl < 60 ml/min, age > 65 years, and t4 tumors. however, multivariable analysis ruled out the prognostic significance of the nac regimen. it confirmed peyton et al.’s findings, in which the advanced tumor stage was an independent predictor for the poor os.(16) in the current study, os was considerably longer than that reported by mertens et al. (median os 33 vs. 22 months) using similar chemotherapy regimens, which could be due in part to the lower proportion of patients with ct4 disease in this study (7.9 vs. 48.3%). this finding highlights the advanced tumor stage as an independent prognostic factor in this setting.(14) univariable analysis of post-treatment covariates put forward the ccr and crt—against rc—as the prognostic factors of os. however, multivariable analysis ruled out crt that might originate from our approach, of which patients with ccr to nac (with better prognosis) were proceeded to crt and confirmed ccr as an independent prognostic factor of os. this finding is consistent with the literature highlighting the pcr as the prognostic factor of disease-specific survival and os.(14,15) in this study, the complete response to nac was not associated with variables such as age, sex, clinical tumor stage, and smoking history. so far, few other studies have intended to find predictive factors of response to nac. in a large series, zargar et al. stated that any downstaging of tumors (ppr and pcr) is reduced by nearly 40% in ct3–4 tumors.(24) subsequently, peyton et al. demonstrated that ddmvac provides more downstaging of the tumor (vs. gem/cis: 95% ci: 1.10–3.09, odds ratio [or] = 1.84, p = .02 ).(16) a more recent analysis showed that neutrophil-to-lymphocyte ratio (nlr) > 3 could predict decreased response to nac; however, it did not demonstrate an association with age, sex, tumor stage, and smoking that confirms the findings of the present study.(25) accordingly, over the last decade, investigators have tried to introduce predictive biomarkers (e.g., somatic ercc2 mutation); however, none are yet validated for routine clinical use.(25,26) along with preceding comparative studies, several other retrospective studies have reported the clinical outcomes of carboplatin-based nac in mibc. koie et al. (2015) showed a significant reduction in local (5.4 vs. 14.3%), regional (5.4 vs. 22.3%), and distant recurrence (3.8 vs. 20%) after neoadjuvant gem/carbo compared to rc alone.(27) murasawa et al. reported improvement in 5-year os (79.5 vs. 53.8%), 5-year disease-free survival (dfs) (75.5 vs. 55.4%), pcr (16.3%), and rc with negative surgical margins (100 vs. 87.7%) after neoadjuvant gem/carbo versus rc alone in cisplatin-ineligible mibc patients.(28) likewise, koie et al. (2014) vol 19 no 4 july-august 2022 294 neoadjuvant carboplatin in locally advanced bladder cancer-mofid et al. urological oncology 376 demonstrated a significant improvement in 5-year os and dfs with neoadjuvant gem/carbo before rc (98.6 vs. 66.6% and 94.2 vs. 72.7% respectively) in patients with ct2 bladder cancer.(29) overall, these findings might address the feasibility of neoadjuvant carboplatin-based chemotherapy for patients who are ineligible for cisplatin. the limitations of the present study need to be considered, including its retrospective design, no randomization, variable post nac treatments. due to its retrospective nature, selection and information bias cannot be totally excluded. the bias effect of uncontrolled confounding factors is required to be acknowledged as well. the nac dose density, treatment delay, dose adjustment, or safety were not included in the analysis. in addition, using clinical response as a primary endpoint, a proportion of patients who had a persistent disease in rc specimen were ignored. also, the short follow-up for the survival data and failure to report the other oncological endpoints (e.g., dss, dfs) are acknowledged. despite these limitations, this is one of the largest series comparing the oncological outcomes of a carboplatin-based nac with a standard cisplatin-based regimen in mibc. moreover, the study groups of the current study are more balanced in sample size (in comparison with peyton et al. and anan et al. studies) that could enhance the power of the results. conclusions this study showed that the choice of nac between gem/carbo and gem/cis in mibc has no impact on ccr and os. also, it suggested that advanced tumor stage and ccr are two independent prognostic factors in this setting. hence, gem/carbo seems to be an appropriate option for patients with mibc who are unfit for cisplatin to enable them to benefit from nac advantages. randomized comparative trials are required to delineate the efficacy of neoadjuvant carboplatin-based regimens definitively. acknowledgments this study was supported by the urology and nephrology research center, shahid beheshti university of medical sciences. references 1. sung h, ferlay j, siegel rl, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin.n/a. 2. al-husseini mj, kunbaz a, saad am, et al. trends in the incidence and mortality of transitional cell carcinoma of the bladder for the last four decades in the usa: a seerbased analysis. bmc cancer. 2019;19:46. 3. li g, niu h-m, wu h-t, et al. effect of cisplatin-based neoadjuvant chemotherapy on survival in patients with bladder cancer: a meta-analysis. clinical and investigative medicine. 2017e81-e94. 4. hamid arah, ridwan fr, parikesit d, widia f, mochtar ca, umbas r. meta-analysis of neoadjuvant chemotherapy compared to radical cystectomy alone in improving overall survival of muscle-invasive bladder cancer patients. bmc urol. 2020;20:158. 5. mirza a, choudhury a. bladder preservation for muscle invasive bladder cancer. bladder cancer. 2016;2:151-63. 6. galsky md, hahn nm, rosenberg j, et al. a consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. the lancet oncology. 2011;12:211-4. 7. einstein dj, sonpavde g. treatment approaches for cisplatin-ineligible patients with invasive bladder cancer. curr treat options oncol. 2019;20:1-13. 8. santoro a, o'brien me, stahel ra, et al. pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the international expanded access program. j thorac oncol. 2008;3:756-63. 9. rossi a, di maio m, chiodini p, et al. carboplatin-or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the cocis meta-analysis of individual patient data. database of abstracts of reviews of effects (dare): quality-assessed reviews [internet]. 2012. 10. vasconcellos vf, marta gn, da silva em, gois af, de castria tb, riera r. cisplatin versus carboplatin in combination with third‐ generation drugs for advanced non‐small cell lung cancer. cochrane database syst rev. 2020. 11. ho gy, woodward n, coward ji. cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies. crit rev oncol hematol. 2016;102:37-46. 12. anan g, hatakeyama s, fujita n, et al. trends in neoadjuvant chemotherapy use and oncological outcomes for muscle-invasive bladder cancer in japan: a multicenter study. oncotarget. 2017;8:86130. 13. iwasaki k, obara w, kato y, takata r, tanji s, fujioka t. neoadjuvant gemcitabine plus carboplatin for locally advanced bladder cancer. jpn j clin oncol. 2013;43:193-9. 14. mertens ls, meijer rp, kerst jm, et al. carboplatin based induction chemotherapy for nonorgan confined bladder cancer—a reasonable alternative for cisplatin unfit patients? the journal of urology. 2012;188:1108-14. 15. schinzari g, monterisi s, pierconti f, et al. neoadjuvant chemotherapy for patients with muscle-invasive urothelial bladder cancer candidates for curative surgery: a prospective clinical trial based on cisplatin feasibility. anticancer res. 2017;37:6453-8. 16. peyton cc, tang d, reich rr, et al. downstaging and survival outcomes associated with neoadjuvant chemotherapy regimens among patients treated with cystectomy for muscle-invasive bladder cancer. jama oncol. 2018;4:1535-42. 17. cockcroft dw, gault h. prediction of creatinine clearance from serum creatinine. nephron. 1976;16:31-41. neoadjuvant carboplatin in locally advanced bladder cancer-mofid et al. vol 19 no 5 september-october 2022 377 urological oncology 378 18. schemper m, smith tl. a note on quantifying follow-up in studies of failure time. control clin trials. 1996;17:343-6. 19. schwender h. david w. hosmer, stanley lemeshow, susanne may: applied survival analysis: regression modeling of time-to-event data: springer nature bv; 2012. 20. koshkin vs, barata pc, rybicki la, et al. feasibility of cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer patients with diminished renal function. clin genitourin cancer. 2018;16:e879-e92. 21. sousa gfd, wlodarczyk sr, monteiro g. carboplatin: molecular mechanisms of action associated with chemoresistance. brazilian journal of pharmaceutical sciences. 2014;50:693-701. 22. li t, peng j, zeng f, et al. association between polymorphisms in ctr1, ctr2, atp7a, and atp7b and platinum resistance in epithelial ovarian cancer. int j clin pharmacol ther. 2017;55:774-80. 23. anan g, hatakeyama s, fujita n, et al. trends in neoadjuvant chemotherapy use and oncological outcomes for muscle-invasive bladder cancer in japan: a multicenter study. oncotarget. 2017;8:86130-42. 24. zargar h, espiritu pn, fairey as, et al. multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. eur urol. 2015;67:241-9. 25. black aj, zargar h, zargar-shoshtari k, et al. the prognostic value of the neutrophilto-lymphocyte ratio in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy. paper presented at: urologic oncology: seminars and original investigations, 2020. 26. van allen em, mouw kw, kim p, et al. somatic ercc2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. cancer discov. 2014;4:1140-53. 27. koie t, ohyama c, yamamoto h, et al. differences in the recurrence pattern after neoadjuvant chemotherapy compared to surgery alone in patients with muscle-invasive bladder cancer. med oncol. 2015;32:421. 28. murasawa h, koie t, ohyama c, et al. the utility of neoadjuvant gemcitabine plus carboplatin followed by immediate radical cystectomy in patients with muscle-invasive bladder cancer who are ineligible for cisplatinbased chemotherapy. int j clin oncol. 2017;22:159-65. 29. koie t, ohyama c, yamamoto h, et al. neoadjuvant gemcitabine and carboplatin followed by immediate cystectomy may be associated with a survival benefit in patients with clinical t2 bladder cancer. med oncol. 2014;31:949. neoadjuvant carboplatin in locally advanced bladder cancer-mofid et al. the effect of action research on neobladder function training in patients with orthotopic ileal neobladders: a prospective cohort study chun-xiu xiao1#, wei zhang2#, bing-xin lin2* purpose: this study aims to evaluate the effects of action research on neobladder function training in patients with orthotopic ileal neobladders. methods: a total of 68 patients with orthotopic ileal neobladders were randomly divided into two groups: a control group (31 patients) and an experimental group (37 patients). patients in the control group received neobladder function training, while patients in the experimental group received neobladder function training based on the action research method. the effects of neobladder function training in all patients were evaluated after three months. results: (1) the differences between the two groups in the micturition time interval, urine volume per time, number of incidences of nocturia, and urinary continence rate (day time and night time) were statistically significant (p < 0.05). (2) compared to the control group (241.6 ± 42.3 ml, 15.1 ± 4.9 ml/s, 23.1 ± 9.9 cmh 2 o, 63.6 ± 22.3 ml), the bladder capacity (292.6 ± 66.9 ml), maximum urinary flow rate (19.2 ± 6.5 ml/s), and bladder detrusor pressure (31.2 ± 11.4 cmh 2 o) of the experimental group increased, while the residual urine volume (47.2 ± 21.1 ml) decreased (p < 0.05). conclusion: neobladder function training based on the action research method can improve the neobladder function of patients with orthotopic ileal neobladders. keywords: action research; orthotopic ileal neobladder; neobladder function introduction bladder cancer is the ninth most common cancer and the second most common urologic malignancy worldwide (1). currently, the most effective method for the treatment of invasive bladder cancer is radical cystectomy with an orthotopic ileal neobladder(2). this method of bladder replacement is closest to the normal physiological state of the human body and has gradually become the recommended approach for urine diversion(2). however, as the intestine—which is a replacement for the new bladder—does not have sensory function and active contraction ability, it is prone to complications, such as urinary incontinence, urinary retention, hydronephrosis, and renal damage(3). to enable patients to adapt to the new urination mode and improve their urination function, urine storage, and urine control, postoperative training of the function of the new bladder is particularly important. however, after the training, patients often continue to have problems, such as night dysuria and urinary incontinence(1). therefore, it is particularly important to improve the effectiveness of new bladder function training. action research is also known as a problem-solving approach. it is a research method that closely combines work with problem solving and carries out a spiral cycle of planning, action, observation, and reflection(4). it has 1department of nursing, fujian medical university union hospital, fuzhou 350001, china. 2department of urinary surgery, fujian medical university union hospital, fuzhou 350001, china. *correspondence: department of urinary surgery, fujian medical university union hospital, no. 29 of xin quan road, gulou district, fuzhou 350001, china. tel: +86-0591-86218417. e-mail: linbingxin1344@163.com received april 2020 & accepted april 2021 been increasingly applied in nursing research: tong et al.(5) for example, applied the method to hemophiliac patients with total knee arthroplasty, finding that it led to a significant reduction in the incidence of bleeding and a significant increase in the range of movements (rom). li et al.(6) used the method in the feeding of patients with senile dementia, bringing the diet nursing of the patients closer to clinical practice. tian et al.(7) provided nursing interventions based on action research to patients with cerebral infarction, finding that it could significantly improve a patient’s neurological function and ability to carry out everyday tasks. as the effectiveness of action research in the training of orthotopic ileum neobladders has not yet been reported, the present study aims to explore the application value of action research in neobladder function training in these patients. patients and methods patients a total of 68 male patients who underwent radical cystectomy between january 2014 and june 2018 in the urology departments of the top three hospitals were enrolled in this study. inclusion criteria: (1) invasive bladder urothelial carcinoma confirmed by pathological examination; (2) paurology journal/vol 18 no. 5/ september-october 2021/ pp. 525-529. [doi: 10.22037/uj.v18i.6167] urological oncology tients were able to communicate; (3) informed consent was obtained from the patient and their family. exclusion criteria: (1) distant metastases of cancer; (2) other serious diseases. the patients were split into two groups—a control group (31 patients) and an experimental group (37 patients)—using assignments by a random number table and grouping of the assigned numbers by a special person. the study used a single blind design: the follow-up specialist and the statistics specialist were blinded, but the nurse in charge of the health research was not. ethics approval the institutional review board of the hospital approved the study protocol. all enrolled patients or their family members provided signed informed consent prior to participation. study design the study aimed to investigate the effect of action research on new bladder function training. first, the problems that exist in new bladder function training in patients with orthotopic ileal neobladders were identified. three spiral circulation processes (cycles) of action research were then used to solve each problem. all the nurses who participated in the study had worked as nurses for more than five years and attended a training course on the action research method. problem identification patients with orthotopic ileal neobladders are prone to urinary incontinence and other complications after surgery(8). therefore, it is necessary to identify an effective bladder training mode to improve bladder urination function after surgery. however, there is currently no uniform method for urination function exercise in patients with orthotopic ileal neobladders after radical resection of bladder cancer. in the present study, a self-developed questionnaire was used to investigate the problems of neobladder function training in 68 patients with orthotopic ileal neobladders. the results revealed that 70.7% of patients considered the teaching of new bladder training methods by nurses difficult to understand and easy to forget. it was also found that 77.6% of the patients continued to lack knowledge of the importance of new bladder function training, and 91.4% believed it necessary to improve the training methods. these results provide a reference for improving neobladder training. planning both groups received routine new bladder function training, including pelvic floor muscle training and levator ani muscle training, according to clinical urological disease treatment guidelines(9). the day before surgery, each patient was evaluated by a urological specialist nurse and guided through routine bladder function training(10), which consisted of (1) pelvic floor muscle exercises and(2) levator ani muscle training exercises. after surgery, the patients were given (3) urine storage function training and (4) urine control mode training. (1) pelvic floor muscle exercises: the patient should be in a supine position, a sitting position, or a walking position, breathe deeply, and contract the pelvic floor muscles for 10–15 seconds, then relax for 10 seconds, and repeat 30 times, 3 times a day. (2) levator ani muscle training exercises: the patient should breathe in quietly and contract his abdominal muscle, gluteus muscle, anal sphincter muscle, and pudendal muscle simultaneously for 15–18 seconds, then breathe out and relax, and repeat 30 times, 3 times a day. (3) urine storage function training: a regular clamping catheter and an appropriate clamping catheter were used. initially, urine was released once every 30 minutes, which was gradually increased to once every hour. the urine storage capacity of the new bladder was observed. (4) urine control mode training: in the process of urination the patient should consciously contract the perineum, stop urination, and then relax the muscles of the perineum to continue urination, repeating until his bladder is empty. this should be repeated two or three times a day. in addition to this training, the experimental group was given intervention using the action research method. action the members of the research team undertook a threeday training course, which included (1) the concepts of a new bladder, pelvic floor muscles, the levator ani muscle, and other anatomical positions; (2) the surgical methods, indications, and possible postoperative complications of radical cystectomy for orthotopic ileal neobladders; (3) the purpose and significance of new bladder function training; (4) the methods of new bladder function training. figure 1. action research spiral action research in training of neobladder-xiao et al. urological oncology 526 the day before surgery, members of the research team gave one-on-one lectures to each patient and their family, instructing patients on how to perform the functional exercises and giving them demonstrations. patients were followed up after discharge to survey the status of the training. observation, reflection, revision, and implementation cycle 1 (1) observation and reflection: regarding the timing of the training and education materials, it was found that, prior to surgery, patients were worried about the effects, complications, and prognosis of the surgery; as such, they were absent-minded or inattentive during the training. after the operation, they were weak and uncomfortable due to multiple drainage tubes, so they could not attentively listen and understand the training. regarding the content of the training and education materials, it was found that most patients felt it was difficult to master the pelvic floor muscle training. (2) revision of intervention plans and measures: the timing of the training and distribution of education materials was adjusted. in this revised approach, the training and education materials were given to each patient three days before surgery to ensure they fully understood the importance of the training. the day before the operation, patients in the same department shared their experience of bladder function training to help eliminate their concerns. three to five days after surgery, the researchers gave instructions to each participant one-on-one and emphasized the importance of the training. patients were able to ask questions at any time during the process to ensure that they understood the training. the education materials were also altered using cartoons to make them easier to understand. these materials focused on the new bladder, the pelvic floor muscle, the characteristics of the post-operative urination method, and possible complications. cycle 2 (1) observation and reflection: during the follow-up after discharge, it was found that the new bladder function training of patients was relatively casual and that the patients could not recall the recent conditions of their urination. this made it difficult to make a clinical diagnosis with the bladder training method. (2) revision of intervention plans and measures: patients were taught to set alarm clocks to remind them to do their training exercises and were instructed to maintain a urination diary. the main contents of the diary included the number of urinations within 24 hours and any nocturnal urination, the interval between urinations, the volume of each urination, the number of urinary incontinences, and whether there were any accompanying symptoms (such as intermittent urination, sense of urine insufficiency, and dysuria). after discharge, a clinical nurse was responsible for a weekly telephone follow-up, which focused on three things: investigating compliance with the new bladder function training, asking for information from the urination diary, and timely correction of bad behaviors and habits. cycle 3 (1) observation and reflection: the patients indicated that maintaining a urination diary was too complicated and that they often forgot to use it. (2) revision of intervention plans and measures: a tabular urination diary was established, in which patients only needed to mark √ or × under the corresponding content. as the urination diary initially contained too many pages, which was not conducive to use, the updated diary had one table for each month. for easy storage, patients could also maintain a one-page urine diary a day. evaluating indicators three months after surgery, the urinary control indexes, including the interval time between two urinations, the volume of each urination, number of incidences of nocturia, rate of urine control during the day (the number of daytime controllability/the total number of daytime urinations), and rate of urine control at night (the number of night-time controllability/the total number of nighttime urinations) were measured for both groups. this was the primary clinical outcome. the secondary clinical outcome was measuring the urinary flow mechanics indexes, including bladder volume (the volume of urine stored when the bladder is full), residual urine volume (the amount of urine left in the bladder after urination), maximum urine flow rate (the maximum volume of urine discharged from the urethra per unit time), and pressure of the bladder detrusor muscle (pressure caused by contraction and relaxation of the bladder detrusor). the urinary flow mechanics were operated by a qualified medical technician using a urodynamic analyzer from beijing leiborui medical technology co., ltd. statistical analysis the measurement data were expressed as `x ± standard deviation (sd), and a t test was used for comparison between the two groups. count data were expressed in ratio or rate, and a chi-squared test was used for comparison between the two groups. all statistical analyses were carried out using ibm spss 17.0 for windows (ibm corp., new york, ny, usa). p < 0.05 was considered statistically significant. results table 1 shows the results of the comparisons between table 1. comparison of general data between the two groups group n age /year education tumor staging pathologic type middle school school t2 t3 epithelioma squamous cell gland cell education education carcinoma carcinoma control group 31 50.1 ± 12.8 21 10 14 17 29 1 1 experimental group 37 51.5 ± 13.9 23 14 16 21 34 2 1 t/χ2 1.85 0.23 0.025 1.3 p 0.17 0.632 0.874 0.522 action research in training of neobladder-xiao et al. vol 18 no 5 september-october 2021 527 the two groups in terms of micturition time interval, volume of urine per time, number of incidences of nocturia, and urinary continence rate in the daytime and night-time. compared with the control group, the micturition time interval and volume of urine per time increased (p < 0.05), the number of nocturia decreased (p < 0.05), and the rate of urine control in the daytime and night-time increased (p < 0.05) in the experimental group. table 2 shows the results of the comparisons between the two groups in terms of bladder capacity, maximum urinary flow rate, bladder detrusor pressure, and residual urine volume. the bladder capacity, maximum urinary flow rate, and bladder detrusor pressure were higher in the experimental group than in the control group (p < 0.05), while the residual urine volume was lower in the experimental group than in the control group (p < 0.05). discussion action research(11) aims to develop a research process that allows researchers to discovers problems, formulate plans to solve the problems, implement the plans, observe the implementation process, analyze the results of the implementation, and re-plan where necessary, thereby solving problems in clinical practice (see figure 1). experience suggests that an action research approach is particularly relevant when treating patients with chronic diseases and complex care needs(4). in the present study, the action research method was applied in the training of neobladder function in patients with orthotopic ileal neobladders. no significant differences were found in the ages, education levels, tumor staging, and pathologic types of the patients in the two groups, which provided a justification for the study. the results of the urination and the urinary control indexes revealed that the micturition time interval and urine volume per time increased, the number of incidences of nocturia decreased, and the urinary continence rate in the daytime and night-time increased in the experimental group compared with the control group. the results of the urinary flow mechanics indexes revealed that bladder volume, maximum urine flow rate, and pressure of the bladder detrusor muscle were higher in the experimental group than in the control group, while the residual urine volume was lower in the experimental group than in the control group. conventional new bladder function training mainly consists of health education given during hospitalization combined with follow-up after discharge, and the impact of the training is not effectively monitored. furthermore, the timing of the pre-operative health education is not appropriate and the educational materials are not focused, so patients cannot fully grasp the content. in the present study, patients in the experimental group received training with the action research method applied, allowing appropriate measures to be implemented to improve the effectiveness of the training. throughout the research process, the four steps of planning, action, observation, and reflection were carried out in three spiral cycles to develop a more effective new bladder function training program(12-13). the process emphasized each patient’s feelings and sought solutions when problems were encountered. as a result, the education materials and standardized teaching process were formulated in a more targeted manner, and the patients were given the details of the practical problems encountered in new bladder function training to help them understand why the training was required. through the step-by-step training of bladder filling and regular emptying, the pelvic floor muscles were repeatedly contracted and relaxed to improve the storage, urination, and urine control of the new bladder. a voiding diary is a commonly used diagnostic tool to aid clinicians in treatment planning for patients with urinary incontinence(14). in the present study, a tabular urination diary was developed and made into a book, in which patients only needed to mark √ or × under the corresponding content. this was a simpler and easier approach to the diary, allowing the patients to become active managers instead of passive participants, thereby increasing their enthusiasm for the new bladder function training. the present study found that it is also important to explain the purpose and method of the new bladder function training and of maintaining a urination diary to the patient’s family members, as it enables the patient to obtain their support and encouragement. telephone follow-up acts as another form of social support(15-16), making patients feel valued and encouraging them to continue with the training. during a telephone follow-up, patients can actively consult relevant knowledge, theretable2. results of urination and urinary control indexes (`x±s). group n micturition time urine volume (ml) number of nocturia urinary continence urinary continence rate interval (h) rate in day-time (%) in night-time (%) control group 31 2.3 ± 0.8 218 ± 58.1 3.4 ± 1.5 77.4 71.0 experimental group 37 3.5 ± 1.1 265 ± 69.1 2.5 ± 1.0 94.6 91.9 t/χ2 4.37 8.92 1.93 4.33 5.08 p 0.02 < 0.01 0.03 0.04 0.03 group n bladder residual urine maximum urinary bladder detrusor capacity (ml) volume (ml) flow rate (ml/s) pressure (cmh 2 o) control group 31 241.6 ± 42.3 63.6 ± 22.3 15.1 ± 4.9 23.1 ± 9.9 experimental group 37 292.6 ± 66.9 47.2 ± 21.1 19.2 ± 6.5 31.2 ± 11.4 t/χ2 9.83 8.61 9.52 11.86 p < 0.01 < 0.01 0.02 < 0.01 table 3. results of urinary flow mechanics indexes (`x±s). action research in training of neobladder-xiao et al. urological oncology 528 by further strengthening the importance of the training. the results of the present study are limited by the small sample size and short evaluation period. therefore, these results may not apply to all patients with orthotopic ileum neobladders in different areas of china or in other populations. the patients were also from a single institution, which may cause site bias. although the present results suggest that the application of the action research method to neobladder function training in patients with orthotopic ileum neobladders would improve the effect of the training, larger prospective multicenter studies with longer application periods are needed to confirm the results. conclusions the results of the present study suggest that the application of the action research method to the neobladder function training of patients with orthotopic ileum neobladders could improve the urination status of these patients, thereby enhancing their quality of life. acknowledgement the study was sponsored by the national key clinical specialty discipline construction program of china (no. 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results from a randomized clinical trial abdolreza mohammadi1, leonardo oliveira reis2, alireza khajavi3, leila zareian baghdadabad1, seyed mohammad kazem aghamir1* objective: this study aimed to evaluate the impact of the skin-to-stone distance in the supine and prone positions on the outcome of shockwave lithotripsy of kidney stones. methods: in a prospective randomized clinical trial study, 81 patients that candidates for shockwave lithotripsy (swl) of kidney stones were randomly divided into two groups to perform swl in the prone position (40 patients) or conventional supine position (41 patients). demographic data, stone characteristics, skin–to–stone distances (ssd) in ct, ssd during swl with an ultrasound probe in prone and supine positions, total shock wave rate, total energy (kilovolt), visual analog scale (vas), complications (clavien-dindo scale system), and swl success rate evaluated in two intervention and control groups. all statistical analysis was performed by independent t-test, chi-square test, fisher exact test, paired t-test, and spss 22.0 software for windows. results: there were no significant differences between demographic characteristics, swl sessions, the median number of swls, the median swl time, median total energy, vas, and complications in the two groups. the sfr was numerically higher in the prone swl group than in the supine swl group (80% vs. 73.2%) but was not significantly different (p = 0.468). also, the inline ultrasound (us) measuring of the ssd in the prone position was significantly different from us ssd measures in the supine position in the two groups (ps = 0.001 and 0.024). the mean ssd was lower in the us measurement during the swl process that measured in supine and prone position than the ct measurement (73.5 vs. 101.1), which means the routine ssd measured by ct scan is higher than ssd in the us probe measurement during swl. conclusion: the prone position swl modification could be effective in obese patients with a bmi of more than 30 and increase the stone-free rate (p=0.039) with a similar safety profile and comparable vas score. it seems the ssd measured by the ultrasound is a more accurate dynamic measurement during the swl and needs to define the ssd according to the ssd calculation by the us probe of the therapy head. sfr was numerically higher in the prone compared with the supine treatment groups keywords: skin-to-stone distance; shock wave lithotripsy; supine position; prone position introduction according to the recent european urology associa-tion and american urological association guidelines update, shock wave lithotripsy (swl) can consider for the treatment of renal stones (≤ 2 cm), except in lower renal pole stones with unfavorable anatomy stated(1, 2). the main factors that influence the success of swl are stone size, location, composition, density, and renal anatomy characteristics. also, the body habitus (body mass index, bmi) affects the result of swl as the skin-to-stone distance (ssd) of more than 10 cm is associated with decreasing swl success rate(3,4). the conventional position of patients during swl is the supine position. however, in some instances, the patient's position needed to be adjusted to a prone position to enhance the shock wave transmission. the most frequent situations mentioned in the literature are distal 1urology research center, tehran university of medical sciences, tehran, iran. 2uroscience and department of surgery (urology), school of medical sciences, university of campinas, unicamp and pontifical catholic university of campinas, puc-campinas,campinas, são paulo, brazil. 3student research committee, school of allied medical sciences, shahid beheshti university of medical sciences, tehran, iran. *correspondence: urology research center, sina hospital, hassan abad sq., imam khomeini, tehran, iran. tel: (+9821) 6634 8560 . fax: (+9821) 6634 8561.email: mkaghamir@tums.ac.ir.ave., tehran, iran. received august 2022 & accepted january 2023 ureteral stones, pelvic kidneys, crossed ectopic kidneys, horseshoe kidneys, and proximal ureteral stones(5,6). among the factors mentioned earlier, the only modifiable factor is ssd. some studies evaluating the estimated length of the nephrostomy tube during the percutaneous nephrolithotomy (pcnl) mentioned that in the prone position redistributing adipose tissue, the ssd decreased(7). with this concept of reducing ssd in the prone position, we designed a prospective study to evaluate the effect of the prone position on the success rate of swl in kidney stones. materials & methods in a prospective randomized clinical trial study from 30/09/2021 to 25/04/2022 patients with kidney stones urology journal/vol 20 no. 3/ may-june 2023/ pp. 136-143. [doi:10.22037/uj.v20i.7418] endourology and stone disease less than 2 cm eligible for swl were included in our study after signing the written informed consent from persian registry for stones of urinary system (persus). the ethical committee of the tehran university of medical sciences approved this study (ir.tums. medicine.rec.1399.1035) and the iranian registry of clinical trials (irct20190624043991n17). the exclusion criteria were age less than 18, renal anomalies (horseshoe kidney, pelvic kidney, and ureter pelvic junction obstruction), chronic kidney disease (ckd), concurrent renal and ureteral stones, severe cardiopulmonary dysfunction, single kidney, uncontrolled hypertension, and failed swl (history of > 2 swl). the enrollment summary is represented based on consort guidelines in figure 1. the laboratory tests were routinely performed on all patients, including cbc. diff, creatinine, urine culture, and coagulative tests (pt, ptt, inr). the low-dose spiral computed tomography (ct) scan was performed on all patients in both standard supine and prone positions to compare the differences between ssd in the two positions. the piezoelectric (wolf piezo lith 3000, gmbh, knittlingen, germany)) with a focal size of 2mm and 16.5 cm depth of penetration was routinely utilized in our center with the inline ultrasound-guided probe (3.5 mhz). the patients were divided into two groups to perform swl in the prone or conventional supine position. considering the stone-free proportions of 81.3 % and 82.4 % for the supine and prone positions, respective, reported by zomorrodi et al (2006), significance level of 95 %, statistical power of 80 %, and the least detectable group difference of 30 %, the sample size for each group was estimated to be 42 patients. the patients were randomly allocated to groups using the randomization blocks of sizes 2 and 4. the prophylactic antibiotic was administrated to all patients. we started the swl process with a standard low voltage protocol (12-15 kv) in the first 500 sw and gradually increased the energy to 24 kv with the shock wave (sw) rate between 60 to 90 sw/ min. we do not routinely prescribe the per-procedure analgesic to patients, but routinely they receive light sedation. if patients have intolerable pain, we prescribe ketorolac to the patients (30 mg slow in infusion). demographic data, stone size, location, laterality, and density (hu) were evaluated. the ssd was measured in supine and prone positions by mean skin–to–stone distances at 0, 45, and 90 degrees in ct scan and also with an ultrasound probe during swl. the total shock wave rate and energy (kilovolt) were recorded for two groups. the visual analog scale (vas) of pain was used for pain analysis during the swl process. the complications were assessed according to the clavien-dindo scale system. the success rate was evaluated 1 and 3 months after swl with a spiral ct scan. stone-free was considered less than 4 mm residual stone fragments(8). the patient's position is depicted in figure 2. the discrete variables are reported using number (percent). the continuous ones are described using mean (standard deviation, sd) or median (interquartile range, iqr), depending on whether the data is normally or non-normally distributed. the chi-squared test was used to compare discrete variables between two groups, replaced with the fisher’s exact test in the case of observation less than 5 in the table. the independent t-test and mann-whitney test compared the continuous variables between groups, in the case of normal and non-normal variables, respectively. the pearson correlation coefficients measured the associations between continuous variables. the normality was assessed based on the skewness and kurtosis measures in the ranges of (-1.5,1.5) and (1.5,4.5) [hair, j.f., 2009. multivariate data analysis]. moreover, homogeneity of variance was assed using levene's test. finally, the mantel-haenszel chi-squared test assessed the heterogeneity between the bmi strata (<30 vs ≥30). all statistical analysis was performed by spss 22.0 software for windows. prone position and stone free status in swl-mohammadi et al. endourology and stones diseases 8 table 1. a description of variables, comparing between two groups. variables groups p-value supine prone sex (male), number (percent) 30 (73.2 %) 22 (55.0 %) 0.088 stone number (one), number (percent) 38 (92.7 %) 38 (95.0 %) 0.665 side (left), number (percent) 22 (53.7 %) 21 (52.5 %) 0.917 location, number (percent) lp 10 (24.4 %) 8 (20.0 %) 0.962 mp 15 (36.6 %) 16 (40.0 %) p 13 (31.7 %) 12 (30.0 %) up 3 (7.3 %) 4 (10.0 %) analgesic (yes), number (percent) 22 (53.7 %) 20 (50.0 %) 0.742 cdg complication (>0), number (percent) 32 (78.0 %) 29 (72.5 %) 0.243 swl session (one), number (percent) 41 (100 %) 38 (95.0 %) 0.241 swl history (no), number (percent) 38 (92.7 %) 33 (82.5 %) 0.194 previous stent (no), number (percent) 35 (85.4 %) 32 (80.0 %) 0.523 age (year), mean (sd) 44.9 (12.6) 40.7 (8.9) 0.090 bmi (kg/m2), mean (sd) 28.8 (4.7) 28.4 (5.3) 0.662 ≥30 16 (39.0 %) 17 (42.5 %) 0.750 size (mm), mean (sd) 11.3 (3.3) 12.1 (3.1) 0.251 ac (cm), mean (sd) 100.0 (11.7) 95.1 (17.9) 0.154 hu, mean (sd) 686.9 (283.2) 707.7 (296.8) 0.748 vas, median (iqr) 4 (4-6) 4 (4-6) 0.891 no sws required analgesic, median (iqr) 800 (0-1000) 400 (0-1350) 0.923 # of sws, median (iqr) 3600 (3000-3700) 3600 (3550-3800) 0.217 sw time, median (iqr) 65 (55-65) 60 (60-70) 0.574 total energy (kv), median (iqr) 18 (17.5-18.5) 18 (17.5-18.25) 0.948 hn grade, median (iqr) 2 (1-3) 2 (1-3) 0.856 sfr (yes), number (percent) 30 (73.2 %) 32 (80.0 %) 0.468 lp: lower pole, mp: middle pole, p: pelvis, up: upper pole, cdg: clavien-dindo group, swl: shock wave lithotripsy, sws(shock waves), sw(shock wave)bmi: body mass index, us: ultrasound, ssd: skin-to-stone distance, ct: computed scan, hu: hounsfield unit, ac: abdominal circumference, vas: visual analog scale, hn: hydronephrosis, sfr: stone free rate review 137 results a total number of 97 patients were eligible initially in our study. after excluding 12 patients depicted in flowchart 1, the total number of 85 patients was randomly divided, 43 into supine group swl and 42 patients in prone swl group. two patients lost the follow-up in both groups, so the final sample consisted of 41 patients in the supine and 40 prone groups, respectively. as depicted in table 1, there were no significant differences between age, sex, bmi, abdominal circumference (ac), and stone characteristics (number, laterality, size, location, density) in the two groups. the median number of shock waves (sw), the median swl time, and the median total energy were not significantly different between the two groups. we also evaluated the analgesic use, the number of sw's needed for analgesics, and the vas between the two groups. there were no significant differences between the two groups. there were no significant differences between the two groups regarding the previous history of swl and ureteral stents before swl. there were no significant differences between the two groups regarding clavien-dindo complications. most of the complications were grade 1 and 2 of clavien in two groups. the sfr was higher in the prone swl group than in the supine swl group (80% vs. 73.2%) but was not significantly different (p = 0.468). according to the sfu classification, the hydronephrosis grading that may influence the sfr was not significantly different between the two groups (p = 0.856). we measured the ssd parameters in two groups using the ct imaging performed in supine and prone positions. the us and ct ssds in the prone and supine measurements are presented in table 2, comparing the two groups. the ssd measures in the patients who underwent prone swl (ct ssd) were 97.6 and 96.3 in the supine and prone positions ct imaging, respectively, which were not significantly different (p = 0.453). the ssd measures in the patients who underwent supine swl (ct ssd) were 108.7 and 101.1 in the supine and prone positions ct imaging, respectively, which means we have fewer ssd measures in the prone ct imaging this group (p = 0.004). also, the ct ssd in supine position ct imaging is 108.7 and 97.6, significantly different between supine swl and prone swl groups (p = 0.029). in both supine and prone groups, us ssd/prone and us ssd/supine were significantly different (p = 0.001 and 0.024, respectively). ct ssd/prone and us ssd/prone were significantly different (both ps < 0.001). also, the mean ssd was lower in the us measurement during the swl process measured in the supine and prone position than the ct measurement (73.5 vs. 101.1), which means the routine ssd measured by ct scan is higher than ssd in the us probe measurement during swl. next, the pearson correlations between bmi, ac, size, and the us and ct measurements are reported in table 2, separated for the groups. applying the bonferroni correction for multiple comparisons, the significant correlations are presented in bold font. as depicted in table 3, the abdominal circumference increases with increasing bmi in two groups (direct correlation: 0.76 and 0.71). with increasing bmi, in the prone swl group, the ct ssd in the supine position had a direct correlation, but this correlation was not seen in the supine swl group. the us ssd in two positions (supine and prone) is directly correlated in two intervention groups (supine and prone). also, the ct ssd in two positions (supine and prone) is directly associated with two intervention groups (supine and prone swl). finally, the position and failure of the sfr association were assessed stratified for bmi. the risk ratios (rrs) were measured for each stratum, taking the supine group as the reference. the findings are presented in table 4 and figure 3. while no position-sfr association was obtained in the non-obese patients, the prone position revealed a significantly lower failure in the sfr in obese persons (5.9% vs. 37.5%). besides, the robotic & laparoscopic urology 429endourology and stone diseases 92 table 2. . the us and ct ssds in the prone and supine measurements were compared between two groups variables groups p-value supine prone us ssd/prone, mean (sd) 72.8 (13.7) 69.8 (15.6) 0.364 us ssd/supine, mean (sd) 76.2 (13.3) 72.8 (15.5) 0.292 ct ssd/prone, mean (sd) 101.1 (19.4) 96.3 (22.8) 0.308 ct ssd/supine, mean (sd) 108.7 (23.1) 97.6 (21.7) 0.029 supine group bmi ac size us ssd/prone us ssd/supine ct ssd/prone ct ssd/ supine bmi 1 ac 0.76 1 size 0.14 0.01 1 us ssd/prone 0.43 0.45 0.01 1 us ssd/supine 0.37 0.32 0.01 0.89 1 ct ssd/prone 0.34 0.39 -0.04 0.46 0.35 1 ct ssd/supine 0.47 0.54 0.03 0.50 0.39 0.73 1 prone group bmi ac size us ssd/prone us ssd/supine ct ssd/prone ct ssd/ supine bmi 1 ac 0.71 1 size 0.17 0.28 1 us ssd/prone 0.57 0.59 0.39 1 us ssd/supine 0.42 0.35 0.31 0.87 1 ct ssd/prone 0.72 0.63 0.29 0.69 0.58 1 ct ssd/supine 0.71 0.59 0.29 0.76 0.67 0.88 1 table 3. pearson correlation coefficients, separated for the groups. prone position and stone free status in swl-mohammadi et al. vol 20 no 3 may-june 2023 138 rrs of non-obese and obese groups were significantly different (p = 0.039). discussion shock wave lithotripsy (swl) is a non-invasive modality for managing symptomatic renal stones up to 2cm, except in lower pole renal stones with unfavorable anatomy in many guidelines because the anatomical characteristic of lower pole influences stone-free stone rate(1,2,9). the main factors that influence swl success rate are stone factors, anatomical factors, patient factors, equipment availability, and good performance of the swl process(10). the store-related factors such as stone size, density, location, and composition are not modifiable and are related to the constitutional characteristics of the stone. the anatomical factors are especially important in the lower pole stones and include unfavorable factors that decrease swl success rate: infundibular length> 3-4 cm, short infundibular width <4-5 mm, infundibulopelvic angle <70 degrees(11). the other anatomical factors are renal anomalies such as ureteropelvic junction obstruction (upjo), horseshoe kidney, ureteral strictures, and pelvic kidneys(12). the equipment availability and operator experience are endourology and stones diseases 271endourology and stones diseases 10 groups supine prone rr (95% ci) p-value bmi <30 no sfr, 5 (20.0 %) 7 (30.4 %) 1.52 (0.56-4.13) 0.511 ≥30 number (percent) 6 (37.5 %) 1 (5.9 %) 0.16 (0.02-1.16) 0.039 table 4. the position and failure of the sfr association stratified for bmi. rr: risk ratio; ci: confidence interval figure 1. all participants' enrollment summary is represented based on the consort (consolidated standards of reporting trials) 2010 checklist. prone position and stone free status in swl-mohammadi et al. review 139 also essential for the swl's success(13). some studies investigated the inclined body position (30 degrees of head-down position) on swl success and concluded that this body modification increases the stone-free rate of lower pole stones(14). among the patient factors, the main factor is bmi reflected in many studies on the skin-to-stone distance (ssd) and correlated to the patient's bmi. the ssd, more than 10-11cm, was a negative factor in the success of swl(15). the conventional position of the patient during swl is the supine position. sometimes, we cannot perform swl in the supine position, and the prone position is suggested for the swl process. the first report of prone swl stated lower ureteral stones, pelvic kidneys, horseshoe kidneys, and recently proximal ureteral stones(5,6,16). the prone figure 2. the swl machine(a) and the swl in the prone position(b) figure 3. the position-sfr association, which is not sfr percentages, is stratified for body mass index. rr: risk ratio prone position and stone free status in swl-mohammadi et al. vol 20 no 3 may-june 2023 140 position success in proximal and distal ureteral stone was explained in many studies and mentioned that this position is a safe and effective supine position with the same safety profiles(17). there is contradictory evidence regarding changing the skin-to-stone parameter in different body positions. in a study by abouelleil et al., they evaluated the effect of body position (prone and supine) in changing the ssd before pcnl. they performed ct urography on 48 patients in supine and prone positions. the ssd significantly decreased in the prone position compared to the supine position(7). with the concept that the prone position probably decreases the ssd and this change may favor the swl success rate, we designed a study to compare the ssd measures in prone and supine positions with low dose protocol ct scan before swl. we also recorded the ssd measures during swl in prone and supine positions with an ultrasound probe of the therapy head. then swl was performed in renal stone in two different (prone and supine) positions. some concerns exist regarding increasing the complication in a prone position, such as bowel perforation. however, this complication rate is rarely mentioned in case reports and the literature(18,19). the other drawback of the prone position may cause interference of bowel gas with the shock wave and reduce the transmission of energy. however, our study did not find a problem with the bowel gas due to the patients' instructions before swl (light meal and dimethicone the night before swl). in a survey by göktas et al. on 96 patients with proximal ureteral stones, the patients were divided randomly to perform swl in prone and supine positions; their results revealed that the supine position decreases the number of shocks per session with a better pain profile. however, in our study, the pain profile was similar in supine and prone positions(20). in an exciting study by ossandon et al., to increase the swl stone-free rate, they evaluated the effect of the modification in lithotripsy table height (lth) on swl success; with the rising the table height on z-axis, the distance between stone and propagated sw decreased and efficacy of swl will be increased(21). in a study by ziaee et al., they evaluated the impact of sleep position on the effectiveness of shock wave lithotripsy (swl) in renal calculi. they concluded that stone-free patients was higher in the group of patients who slept ipsilaterally relative to the kidney stone compared with patients who slept on the contralateral side(22). in another interesting study by karatzas et al., they studied impact of modified lateral position on success of the swl. they compared a group of obese patients (19 patients) that swl performed in lateral position with a similar group of obese patients (17 patients) that swl was done on standard supine position. they concluded that the modified lateral position for renal calculi in obese patients was feasible and safe. in addition, it was faster than in the supine position since it overcomes technical difficulties(23). cakiroglu et al. evaluated the effect of mild hydronephrosis and different position during swl on the success rate of swl in 371 patients with lower pole renal stones. the patients were randomly divided into three supine, prone, and prone positions with a full bladder and positions with mild hydronephrosis. they concluded that mild hydronephrosis and prone position increase stone-free rate in lower pole stones after swl. because the entire bladder and oral hydration may increase the hydrostatic pressure of the renal system and enhance the stone fragments' passage, the prone position due to the effect of gravity may increase the stone-free rate (24). in our study, the ssd parameter was not significantly decreased during the prone position; however, in obese patients, the efficacy of swl was amplified in the prone swl process. some proposed drawbacks for a prone position include increasing intra-abdominal pressure, so we excluded severe cardiopulmonary disease patients from our study. some studies on swl of the lower ureteral stone stated that the prone position is associated with more discomfort, but others mentioned contradictory results(25). our study did not show a difference between the two groups regarding the vas. in a comprehensive review study by li et al. on swl of lower ureteral stone in two different supine and prone positions, the number of sw, total sw energy, and swl session were not significantly different in the two groups. however, the stone-free rate was higher in the supine group. the safety profile was the same in the two groups, and complications were reported as rare(17). there was no significant difference between the two groups regarding the number of the sws, swl sessions, pain scales, and total energy in our study. however, the stone-free rate was better in the prone position than the supine position in obese patients with bmi >30. in a study by hara et al. on swl of ureteral stones, it was concluded that the rotated-prone position (30-degree deviation to the ventral plane) results in a better sw transmission than the conventional prone position for distal ureteral stones(26). many studies confirmed the positive effects of the combination of hydration, local mechanical percussion, and inversion therapy after swl in the stone passage, especially in lower pole stone(27). in a prospective study by leong et al., they evaluated the effect of swl with simultaneous inversion in patient position (head down position to 30 degrees) during the swl process on two matched groups of patients with lower pole renal stone. they concluded that this modification in patient position during swl had a 1.28 times improvement in stone-free rate and could be used during swl(28). in a study by bohris et al., they evaluated the impact of abdominal compression on decreasing kidney movement during breathing. they found that the stone targeting and efficacy of swl significantly were improved(29). we believe that with proper analgesic administration to patients during swl, the kidney movement related to breathing will be reduced. a study by kang et al. evaluated the relation between the patient's position and pain score (vas) during swl; their patients were positioned in the lateral and supine positions and concluded that the supine position is associated with higher pain scores(30). there was no significant difference between the two groups regarding the vas in our study. to our knowledge, this study is the first one that compares the two different supine and prone positions in kidney stones swl. although seems that the prone and supine have equivalent outcome, this study confirms the positive effect of prone position swl on the stonefree rate in patients with bmi>30. also, the important point that should be considered in practice is that the ssd measures were significantly lower in the us than the ct measures; this finding may be realized that the prone position and stone free status in swl-mohammadi et al. review 141 standard definition of the ssd according to the ct should be changed to the us parameters as the therapy head compression on the skin during the swl decrease the ssd. our study had some strengths and limitations. the study was prospective; the patient was followed up for three months for stone-free rate status, and the follow-up imaging was a ct scan with high accuracy for detecting residual fragments. our limitation is the small number of cases and lack of stone samples for analysis. we believed this prone modification could be effective in obese patients and increase the stone-free rate. conclusions the prone position swl modification could be effective in obese patients with a bmi of more than 30 and increase the stone-free rate with a similar safety profile and comparable vas score. it seems the ssd measured by the ultrasound is a more accurate dynamic measurement during the swl and needs to define the ssd according to the 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1994;26(1):13-6. 20. göktaş s, peşkircioğlu l, tahmaz l, kibar y, erduran d, harmankaya ç. is there significance of the choice of prone versus supine position in the treatment of proximal ureter stones with extracorporeal shock wave lithotripsy? eur urol. 2000;38(5):618-20. prone position and stone free status in swl-mohammadi et al. vol 20 no 3 may-june 2023 142 21. ossandon e, recabal p, acevedo c, flores jm, marchant f. the lithotripsy table height: a novel predictor of outcome in shockwave lithotripsy. int braz j urol. 2011;37(3):35561. 22. ziaee sam, hosseini sr, kashi ah, samzadeh m. impact of sleep position on stone clearance after shock wave lithotripsy in renal calculi. urol int. 2011;87(1):70-4. 23. karatzas a, gravas s, tzortzis v, aravantinos e, zachos i, kalogeras n, et al. feasibility and efficacy of extracorporeal shock-wave lithotripsy using a new modified lateral position for the treatment of renal stones in obese patients. urol res. 2012;40(4):355-9. 24. cakiroglu b, sinanoglu o, akgün fs, arda e, yuksel i, akdere h. does mild hydronephrosis induced by full-bladder improve outcomes in patients undergoing shock wave lithotripsy for lower calyceal stones?: a prospective randomized study. urol j. 2018;15(3):92-5. 25. lu j, sun x, he l. sciaticum majus foramen and sciaticum minus foramen as the path of swl in the supine position to treat distal ureteral stone. urol res. 2010;38(6):417-20. 26. hara n, koike h, bilim v, takahashi k, nishiyama t. efficacy of extracorporeal shockwave lithotripsy with patients rotated supine or rotated prone for treating ureteral stones: a case-control study. j endourol. 2006;20(3):170-4. 27. ahmed a-f, shalaby e, maarouf a, badran y, eladl m, ghobish a. diuresis and inversion therapy to improve clearance of lower caliceal stones after shock wave lithotripsy: a prospective, randomized, controlled, clinical study. indian journal of urology: iju: indian j urol. 2015;31(2):125. 28. leong ws, liong ml, liong yv, wu db-c, lee swh. does simultaneous inversion during extracorporeal shock wave lithotripsy improve stone clearance: a long-term, prospective, single-blind, randomized controlled study. urology. 2014;83(1):40-4. 29. bohris c, stief cg, strittmatter f. improvement of swl efficacy: reduction of the respiration-induced kidney motion by using an abdominal compression plate. j endourol. 2016;30(4):411-6. 30. kang jh, lee sw, moon sh, sung hh, choo sh, han dh. relationship between patient position and pain severity during shock wave lithotripsy for renal stones with the modulith slx-f2 lithotripter: a matched case-control study. korean j urol. 2013;54(8):531-5. prone position and stone free status in swl-mohammadi et al. review 143 circumcision with thermocautery after local anesthesia in males: a retrospective single-center study with 1821 patients mehmet uysal1*, ahmet şanlı2 purpose: this study aimed to examine the short and long-term complications of thermocautery-assisted circumcisions with local anesthesia done in a sterile environment in operating room conditions, accompanied by literature. materials and methods: the participants who consecutively underwent thermocautery-assisted circumcision with local anesthesia from june 2018 to may 2019 were included in the study. they were one month-17 years old, same ethnic origin, in same location. the age groups were compared in terms of complications. results: the participant age and surgical duration means were 4.89 ± 2.08 (30 days-17 years) years old and 7.484 ± 1.524 (5-20 minutes) minutes, respectively. complications were observed in fifty-three participants or 2.9% of the whole observation set. the participants under intervals of one six months and over 6 years of age had significantly lower complication rates when compared to the other participants, and this comparison was statistically significant (p = 0.001). conclusion: the study results demonstrated that circumcision with thermocautery after local anesthesia is a viable, reliable, and effective method. it can be assumed that circumcisions in males especially may be effective in 1-6 months, and over 6 years of age. parents choose this method because it is more appropriate and eliminates the risk of general anesthesia. keywords: circumcision; children; local anesthesia; complication; thermocautery introduction circumcision is the surgical removal of the skin covering the tip of the penis (prepuce)(1). it is commonly conducted in neonates, infants, and males for religious, cultural, and medical reasons. an estimated one in three males worldwide is circumcised, with nearly universal coverage in some surroundings. in 2011, an estimate by an independent researcher found global male circumcision prevalence to be 37–40 %.(2,3). the increased risk for urinary tract infection (uti) in uncircumcised boys is highest with an incidence rate of 1% for boys less than 2 years of age. they found the single risk factor of lack of circumcision to confer a 23.3% lifetime chance of uti.(4). apart from medical reasons, circumcision is performed to protect against sexually transmitted diseases, and mostly for traditional and religious reasons(5,6). complications related to the factors such as anatomical anomalies, clinical comorbidity, surgical methods used, and age of patients are seen in 1-4% of all circumcision procedures(7,8). circumcision methods are classified into 3 main groups according to kaplan and baskin: open surgery (sleeve method, dorsal slit, and excision, guillotine method), sheldon method (such as mogen clamp, circumcision shield), and special circumcision clamps(9,10). thermocautery has also been proven to be a cheap and practical circumcision method, and it has become more popular. this study aims to examine the types and frequency of complications of circumcision by using 1karaman training and research hospital, pediatric surgery, karaman, turkey. 2karaman training and research hospital, urology, karaman, turkey. *correspondence: department of pediatric surgery, karaman training and research hospital, 70200,karaman, turkey. tel: 90338 2263266 e-mail:drmyzuysal3@gmail.com. received march 2021 & accepted october 2021 thermocautery with local anesthesia and conveying our experiences. materials and methods study population this study was conducted by ethics committee approval obtained from karamanoğlu mehmetbey university faculty of medicine (issue 01/date 27.01.2021). it was started with 2245 participants registered for circumcision in our hospital's database, but 1821 participants coming for control on the 10th day, 1st month, and 1st year after circumcision were included. the data of patients circumcised by a pediatric surgery specialist doctor between june 2018 and may 2019 were retrospectively retrieved and included in the study at the karaman training and educational hospital pediatric surgery clinic in turkey. all participants were living in karaman, turkey and all of them were of the same ethnic origin. candidates aged one month-17 years who underwent circumcision with local anesthesia were included in this cross-sectional retrospective study. participants who had comorbid diseases, such as undescended testis were excluded. in addition, consent forms were obtained from the legal representatives of the patients for the use of the medical images. the patients were recorded by local voluntary agencies before the date of circumcision. all patients were examined before surgical intervention. all operations were carried out by one pediatric surgery specialist. as a local pediatric urology urology journal/vol 19 no. 3/ may-june 2022/ pp. 221-227. [doi:10.22037/uj.v19i.6748] anesthetic, 20 mg /ml lidocaine hcl and 0.025 mg/ml adrenaline and bupivacaine 5 mg /ml were used together. the penile block was imposed on the radix and circumference of the penis; 2–5 ml of local anesthetic was used according to the patients’ age, and weight. regularly, the penis was cleaned with batticon and covered with a sterile surgical cover. approximately 10 minutes after the injection of local anesthesia, the prepuce was retracted to prevent glans injury. the prepuce was held using two clamps placed obliquely at an angle close to 15-20°, with its ventral part facing upwards. thus, the meatus and frenulum were protected from injury. the guillotine technique was used in all circumcisions performed with thermocautery included in our study. in this method, after the prepuce is suspended with clamps, the surgeon pulls the glans down with the thumb and index finger of one hand and places the flat clamp on the prepuce in the other hand so that it is above the glans. the prepuce is cut with a scalpel over the clamp. then, the mucosa is held with clamps and the excess is excised. the skin and mucous membranes of participants were sutured all around with separate sutures (figure 2-3). in this method, it should be ensured that the glans remain under the clamp. otherwise, there may be serious glans injuries(1). the skin of participants was held and stabilized on the anterior and posterior sides by the clamp and preputial tissue was cut just above the clamp (figure 2) using a thermocautery device (thermo-med qx 2100; thermo medical, adana, turkey (figure 4). the settings of the thermocautery device were established according to the participant’s age: 500°c was used for patients under 2 years of age; 550-650°c was used for patients of 2-10 years of age,, and 700–750°c was used for patients older than 10 years of age. after bleeding was controlled, mucosal coherence in patients under 2 years of age was provided with two 5/0 absorbable sutures at 3,6,9 and 12 o’clock positions. a 4/0 absorbable suture was used in participants aged 2-10 years of age, with four sutures at 3, 6, 9, and 12 o’clock positions. finally, in patients older than 10 years of age, 3/0 absorbable suture was used with six sutures positioned at 2, 4, 6, 8,10, and 12 o’clock. the wound was then dressed with a nitrofurazone-containing bandage. participants were observed for 2 hours postoperatively and analgesics were prescribed before discharge. the first follow-up was performed by the operating team, and 10 days after the operation, the wound dressing was removed in the pediatric surgery outpatient clinic, and a return to daily life was recommended. afterward, the participants and their parents were advised to continue their daily life routines. possible complication clavien-dindo classification perioperative bleeding (n:2 ) 3a early postoperative (< 10 days) bleeding (n:12 ) 3a infection (n:8 ) 2 convulsion (n:7) 2 inability to urinate (n:1) 2 late postoperative (> 10 days) trapped penis (n:2) 3a meatal stenosis (n:5) 2 epidermal granuloma and inclusion cyst (n:4) 3a adhesion of mucosa or skin to glans (n:6) 3a glans skin bridge (n:1) 3a sekonder phimosis (n:4) 2 urethral fistula (n:1) 3b table 1. thermocautery circumcision complication rates circumcision with thermocautery-uysal et.al. figure 1. complication rates in circumcised children by age group. pediatric urology 222 complications were explained to participants and parents, and we asked them to visit the hospital if they developed any symptoms, such as penile bleeding, discoloration, or shape changes. in these cases, participants were evaluated, followed, and treated by the first author of this article. there were not given oral antibiotics to use prophylactically or at home. we recommended ibuprofen to children as an analgesic after 1-year-old, and paracetamol before 1 year of age. the perioperative complications group included bleeding during the cir¬cumcision or the hospital stay. the early post¬operative complications group included complications emerging during the first ten days after discharge from the hospital. the long-term complications group included those complications occurring ten or more days after discharge from the hospital. statistical analysis the observation set, which consisted of those patients circumcised using the thermocautery-assisted method, was evaluated with the statistical package for the so¬cial sciences software (spss inc.chicago, il, usa). the data distribution was examined using the kol¬mogorov-smirnov test. the continuous variables were expressed as the mean ± standard deviation (range: minimum-maximum), and the appropriate categorical variables were denoted as the numbers and percentages. the chi-squared and mann-whitney u tests were ap¬plied to evaluate the categorical data and the quantita¬tive variables, respectively. two-tailed p values of less than 0.05 were accepted as statistically significant. results the number of participants included in the study according to age groups was as follows; 30 days-6 months 630 (34.6%), 6-12 months 358 (19.7%), 1-3 years 152 (8.3%),3-6 years 54 (3%), 6-17 years 627 (34.4%). the mean age of the participants was 4.89 ± 2.08 years old (range: 50 days–17 years old). the average surgical duration was 7.48 ± 1.52 minutes (range: 5-20 min¬utes). the complication rates for the age groups of participants included in the study were as follows; 30 days6 months 2 (0.3%), 6-12 months 17 (4.7%), 1-3 years 22 (14.4%), 3-6 years 10 (18.5%), 6-17 years 2 (0.3%) (figure 1). complications were observed in fifty-three participants or 2.9% of the whole dataset. the complications of participants were evaluated according to the modified clavien-dindo classification method (table 1). two (0.11%) of the participants had bleed¬ing from the suture line, which was classified as a pe-rioperative complication. the bleedings of them were stopped immediately via cauterization. twenty-eight (1,54%) of the participants who underwent circumcision had postoperative early complications. eight (0.44%) infections and twelve (0.66%) bleeding cases were classified as early postoperative early complications. the infection was treated with antibiotics and dressing. due to a ligated artery, a four-year-old participant had frenular artery bleeding on the first day after the circumcision and it was controlled after taking to the operating room. five of all participants who developed circumcision bleeding were controlled by stitching under local anesthesia. the ages of them were 11,22 months, 3, 4, and 5.5 years old, respectively. six of all participants had dorsal vein bleeding that was treated via vein ligation. the ages of them were 10,16,18,22 months, and 3, and 4 years old, respectively. seven (0.38%) of all patients evolved convulsions due to local anesthesia. the ages of them were 8, 9, 10, 10 months, and three of them were one year old, respectively. four of these convulsions were as nystagmus form and 3 were as the tonic-clonic form. the reason figure 2. surgical step of thermocautery circumcision. figure 3. 1st-month control after circumcision circumcision with thermocautery-uysal et.al. vol 19 no 3 may-june 2022 223 for the high number of convulsions under 1 year of age may be an allergy to bupivacaine. all convulsions were followed by rectal diazepam (0.5 mg/kg) for 24 hours. in one case (0.05 %) a 2.5-year-old participant could not urinate for the first 8 hours after local anesthesia, but this participant urinated spontaneously without a urinary catheter. twenty-three (1,26%) of the participants who underwent circumcision had late complications. the penises of two participants were trapped and they were surgically circumcised again. a total of five participants whose ages were 7,10,12,17,21 months during the circumcision required urethral dilatations after one month because of meatal stenosis. a one-year-old participant developed meatitis ten days after the circumcision, while a two-year-old participant had the same issue one month after the circumcision. both children were medically treated. epidermal granüloma and inclusion cysts in the dorsal or ventral part of the penis were removed from the suture line with local anesthesia in 4 (0.22%) cases. the ages of these children were 4,9,14 months, and 2.5 years, respectively. after circumcision, six of 7 (0.38%) cases were opened by simply retracting, while the skin bridge in one case was cut with a scalpel. although we coagulated the vessels by holding them one by one, we saw ecchymotic changes in the skin in one case after circumcision, and lacerations due to a burn at the edge of the skin during the procedure in 3 cases. finally, one participant had a glans-skin bridge complication six months after the circumcision, and he was treated surgically. secondary phimosis was detected in 4 (0.21%) of our cases and they were treated by circumcision revision. the ages of them were 10, 14 months, and 1.5, and 2 years, respectively. urethral injury and fistula occurred in a 4-year-old patient with an urethral ventral chord. about one year later, urethral fistula repair was performed under general anesthesia. except for four participants, complications were only ob¬served in children older than six months and younger than six years old. the participants who were younger than six months or over 6 years of age had significantly lower complication rates when compared to the other patients, and this comparison was statistically significant (p = 0.001). discussion in this study, the age groups of participants were compared in terms of complications. it was also demonstrated that it can be presumed that circumcisions in males especially may be effective in 1-6 months, and over 6 figure 4. thermocautery device circumcision with thermocautery-uysal et.al. pediatric urology 224 kidney transplantation 136 years of age circumcision has been around for centuries. it is done as a routine for all newborn infant males in muslim countries, reaching almost 100% (if no contraindications), in hospitals in saudi arabia. circumcision continues to be done for a variety of religious, cultural, and medical reasons. the overall prevalence of circumcision in the united states is estimated to be about 80% for males, with most of these procedures performed in newborns(12). a recent meta-analysis included 140 journal articles that came to the same conclusion; early infant male circumcision has immediate and lifelong benefits. it was shown to protect against urinary tract infections, phimosis, inflammatory skin conditions, candidiasis, various sexually transmitted diseases (stds) in both sexes, genital ulcers, and penile, prostate, and cervical cancer (13). male circumcision has a low incidence of adverse events overall, especially if the procedure was performed during the first year of life(14). the risk is further decreased and might be prevented, with careful consideration of the penile anatomy and the correct use of surgical equipment by trained clinicians in sterile environments. although there are different studies of the vari¬ous circumcision methods in the literature, researchers are still debating the most convenient circumcision age and the safest circumcision method. the applied tech¬nique should be practical, cheap, and safe, and it should induce very few or no complications. for this purpose, we compared the thermocautery-assisted method with the other circumcision methods in terms of the early and long-term complications. the early complications include bleeding, pain, inadequate skin removal, in¬fection, chordee, iatrogenic hypospadias, glanular ne¬crosis, and glanular amputation. the long-term com¬plications include epidermal inclusion cysts, suture sinus, penile adhesions, phimosis, urethrocutaneous fis¬tula, trapped penis, meatitis, and meatal stenosis(15-17). in addition, hydronephrosis and permanent renal damage can be caused by meatal stenosis (18). in our study, we didn’t see hydronephrosis and permanent renal damage caused by meatal stenosis. the thermocautery-assisted technique exploits the heat energy used for cauterizing. when compared with the monopolar cautery technique, which uses an electrical current, the thermocautery-assisted method carries the heat locally. according to the skin features of the pa¬tient, the heat levels are adjustable on the most recent¬ly developed thermocautery devices. previous studies have shown that optimum hemostasis is achieved with a temperature ranging between 100°c and 400°c(19). it has been shown that the thermocautery technique results in similar wound healing when com¬pared to the scalpel technique(20). according to our observations, the circumcision line usually heals within 5 days before six months and 7 days after six months when using the thermo¬cautery technique. we observed that the wound heal¬ing was extended to 20 days in only two patients in our data set. their ages are 8 and 10 years old during the circumcision. in addition to that knowledge, urinary retention was observed in one patient in our thermocautery-assisted circumcisions. saraçoglu et al. compared the thermocautery technique with conventional circumcisions in their prospective study. hyperesthesia of the glans penis was observed in 12% of the patients with the thermocautery method and 10% of the patients with the surgical method(21). this pa¬per provides a complete evaluation of the thermocau¬tery-assisted circumcision technique with respect to the shortand long-term complications. the patients in our dataset were followed up postoperatively for ten days, one month, and one year. in a study carried out in england, 66519 circumcisions were reported, with a complication rate of 2%(22). in the present study, similar to the literature, the most common early circumcision complication was found to be bleeding (0.77% of 1821 participants). hospital stay during the circumcision is short outpatient surgery and increases patient and parent satisfaction(23). we applied local anesthesia to all our patients before circumcision. it was first reported in a study that lidocaine with epinephrine had a protective effect against bupivacaine toxicity and that it increased the asystole dura¬tion and improved hemodynamic parameters. chiu et al. added adrenaline to lidocaine and reported that its addition prolongs the duration of anesthesia(24). in our cases, bupivacaine and lidocaine with epinephrine were given concurrently before the operation, and the most commonly observed problem was mucosal edema, which was seen in one-quarter of the patients. we believe that mucosal edema is a commonly observed but unheeded complication in thermocautery-assisted circumcision. ngcobo and colleagues(25) reported that 30% of the patients experienced penis swelling on the second day after surgery, which was a slightly higher rate than in our findings; however, the surgical procedure was not made clear. secondary phimosis can be seen due to fibrosis, which occurs especially after circumcision with cautery in which the electric current is not controlled(26). secondary phimosis was detected in 4 (0.21%) of our cases and they were treated with circumcision revision. urethral injuries often occur in circumcisions performed by people with limited experience and are due to urgent stitching due to bleeding during circumcision (26), and their treatment is in the form of primary urethral repair. in one case of our circumcision which had a urethral chordee was injured from the urethra (0.05%) during the operation and then we repaired the urethral fistula with general anesthesia over one year. frenulum injury was observed in 1.57% of patients but was resolved with treatment. wound recovery, after thermocautery-assisted circumcision, is reported to occur in 1 week(27). similarly, we observed that healing started on the fourth day after the operation, and total recovery occurred in ten days. the ancillary technique leads to an increase of penis size, is safe and easy to perform, and does not increase significantly operative time or complication rate of the conventional procedure(28). according to our observations, the circumcision line usually heals within 10 days under 6 months of age when using the thermocautery technique. we observed that the wound healing was extended overe three weeks in five patients in our data set, but their circumcision ages were over one year. this paper provides a complete evaluation of the thermocautery-assisted circumcision technique with respect to the shortand longterm complications. the patients in our dataset were followed up postoperatively for one month to one year. circumcision with thermocautery-uysal et.al. vol 19 no 3 may-june 2022 225 pediatric urology 226 urethral injury and fistula occurred in a 4-year-old patient with a urethral ventral chordee. his urethral plate was very thin and weak, so a urethracutaneous fistula occurred. about one year later, urethral fistula repair was performed under general anesthesia. prolongation of postoperative discharge time after general anesthesia often causes pain, nausea, and vomiting. no nausea and vomiting were observed in our cases. all our patients were discharged on the day of the operation. adequate sedation, anxiolysis, and analgesia in circumcision cases a safe perioperative process should be planned. circumcision was not preferred for the first month because there may be additional problems such as neonatal jaundice and bleeding in newborns under 1 month. since a newborn baby can establish a cause-effect relationship with the events around him at the 6th month and after birth, we recommend more circumcision with the thermocautery method after local anesthesia before the 6th month. conclusions the main advantages of this technique can be that it is performed fairly quickly and allows for much more circumcision in all age groups of children in areas where the cost and availability of general anesthesia are prohibited. circumcision with thermocautery after local anesthesia is a viable, reliable, and effective method for circumcisions in males especially 1-6 months, and over 6 years of age. parents choose this method because it is more appropriate and eliminates the risk of general anesthesia. acknowledgments all authors contributed to the study’s conception and design. the study were performed material preparation (mehmet uysal), data collection (mehmet uysal) and analysis (mehmet uysal, ahmet şanlı). the first draft of the manuscript was written by (mehmet uysal) and all authors commented on previous versions of the manuscript. all authors read and approved the final manuscript. there is no financial and material support should mention for this study. conflict of interest all authors have no conflicts of inrest to declare. this study wasn’t supported by any research fund references 1. başaklar c. çocuklarda sık 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mid-level workers in tshwane district, south africa: a retrospective analysis. plos one. 2018; 13(1):190795. 26. balkan e, kılıç n. sünnet ve komplikasyonlar. güncel pediatri 2005; 2: 22-23. 27. tuncer aa and erten eea. examination of short and long term complications ofthermocautery, plastic clamping, and surgical circumcision techniques. pak j med sci 2017;33: 1418-1423. 28. carmine p, mario f, antonio g, et.al. circumferential dissection of deep fascia as ancillary technique in circumcision: is it possible to correct phimosis increasing penis size? bmc urol. 2021 feb 3;21(1):15. circumcision with thermocautery-uysal et.al. vol 19 no 3 may-june 2022 227 effect of selenium and vitamin e on the level of sperm hspa2+, intracellular superoxide anion and chromatin integrity in idiopathic asthenoteratozoospermia: a double-blind, randomized, placebocontrolled trial parvin sabeti1, soheila pourmasumi 2, 3* , niloofar fagheirelahee 4 purpose: male infertility accounts for about half of all infertility cases. asthenoteratozoospermia is a severe form of male infertility. free radicals play an important role in infertility. in a previous study we found that asthenoteratozoospermic men had a lower mean percentage of sperm hspa2+ and higher intracellular anion superoxide than normozoospermia. antioxidants are thought to be able to counteract the negative effects of free radicals. we explored the efficacy of vitamin e in combination with se on the level of sperm hspa2+, intracellular anion superoxide, and chromatin integrity in these patients. materials and methods: 60 patients entered the study. they were randomized to the treatment group of oral se (200 µg) in combination with vitamin e (400 units) for 3 months (n = 30) or placebo (n = 30). semen samples were obtained and assessed for sperm parameters, intracellular o2-, protamine deficiency, sperm hspa2+ and apoptotic spermatozoa at baseline and after the treatment phase. results: there were no significant differences in baseline semen parameters, intracellular o2protamine deficiency, sperm hspa2+ and apoptotic spermatozoa between the treatment and placebo groups. there was a statistically significant decrease in sperm apoptosis and the level of anion superoxide (p = .001) and an increase in sperm motility and viability (p = .001) in the treated group, but no significant difference was found in the percentage of sperm hspa2+ and sperm protamine deficiency compared with baseline. moreover, no significant change was found in these parameters in the placebo group after 3 months. conclusion: our results showed that administration of vitamin e and selenium for three months may improve sperm motility and viability by decreasing intracellular anion superoxide and sperm apoptosis in asthenoteratozoospermic infertile men. we suggest that consuming these supplements before assisted reproductive technology (art) may improve outcomes in these patients. keywords: infertility; male; selenium; vitamin e; hspa2 protein introduction male factor infertility is a common cause of in-fertility and accounts for about 30% to 40% of infertility. common causes of male infertility include gene mutations, aneuploidy, varicocele, radiation, chemotherapy, genital tract infections, and erectile dysfunction(1). but sometimes other factors such as high levels of reactive oxygen species (ros) can affect sperm as they pass through the ducts, causing subfertility or infertility. it has been reported that ros may be a causative factor in 30–80% of infertile men(2). the cause of infertility in about 60%–75% of infertile men is unclear. this is called idiopathic infertility(3). sperm are able to produce low levels of ros, which are involved in their critical functions. as a result of an error in spermiogenesis, sperm with a large amount of extra cytoplasm are released. this extra cytoplasm contains additional enzymes that promote ros production by the redox system in the cytoplasmic membrane. superoxide anion and hydroxyl radicals are 1department of anatomy, faculty of medicine, kurdistan university of medical sciences, sanandaj, iran. 2non-communicable diseases research center, rafsanjan university of medical sciences, rafsanjan, iran. 3clinical research development unit (crdu), moradi hospital, rafsanjan university of medical sciences, rafsanjan, iran. 4student research committee, iran university of medical sciences, tehran, iran. *correspondence: shohada street, moradi hospital, rafsanjan university of medical science, rafsanjan, iran. tel: +98 913391204. email: spourmasumi@yahoo.com. received june 2020 & accepted september 2020 the most important free radicals from oxygen derivatives. oxidative stress (os) occurs as a result of an imbalance between the produced ros and antioxidant defense, neutralizing their toxicity and resulting in sperm dna damage, reduced sperm motility, and fertilization potential(4,5). on the other hand, a study reported that the percentage of sperm hspa2+ in infertile individuals was lower than in fertile individuals. hspa2 plays a role in repairing dna fractures and replacing histones with protamine during nuclear sperm compaction. decreased expression of this protein is associated with increased aneuploidy, dna fragmentation, apoptosis, and defect in histone protamine translocation(6-8). in a previous study in this field, it was also found that infertile patients with asthenoteratozoospermia had a lower mean percentage of sperm hspa2+ and higher intracellular anion superoxide than normozoospermic men(9). one of the most important antioxidant molecules against oxidative damage is vitamin e. this molecule is mainly located in the cell membrane and it prevents liandrology urology journal/vol 18 no. 5/ september-october 2021/ pp. 549-555. [doi: 10.22037/uj.v18i.6325] pid peroxidation and cell membrane damage by neutralizing free radicals and enhancing other antioxidants(10). selenium (se) is an essential dietary micronutrient required for reproductive functions such as testosterone metabolism and about 20-40% of infertile men who have deficiency in sperm production have been linked to selenium deficiency(11). kaushal et al. found that variation in the amount of selenium can lead to os and thereby affect reproductive potential(12). this demonstrates the importance of nutrition at the molecular level. in this study, we investigated the effect of daily oral supplementation of se and vitamin e on the level of intracellular superoxide anion, sperm hspa2 +, protamine deficiency, and sperm parameters in teratoasthenozoospermia men. materials and methods a double-blind, randomized, placebo-controlled trial study was conducted on 60 infertile men with asthenoteratozoospermia (atz) (with normal morphology lower than 4% and total motility lower than 40%) at royan research and clinical center for infertility (tehran, iran) from june 2014 to june 2016. all participants in this study were blinded to the intervention until the study was completed. each participant randomly received two packs of pills in different colors from a doctor who was unaware of their contents and the record book remained in their hands until the end of the study. the treatment group received a daily supplement of vitamin e (400 iu) combined with selenium (200µg)(13) and the placebo group received two tablets of placebo for 3 months. also, all patients were followed up by researchers during the study, and any adverse events were addressed. out of 117 patients were included in this study, 54 patients were excluded due to drug cessation and incomplete consumption (n = 12) and/or declined to participate (n = 42) (figure 1). semen samples were evaluated in two groups, treatment and placebo. participants who met the study criteria, and who consented to participate were entered into the study. inclusion criteria comprised history of infertility of at least one year despite regular unprotected intercourse; seminal analysis showing normal morphology lower than 4% and total motility lower than 40% as defined by who manual for semen analysis, (2010). exclusion criteria comprised the cases with leukocytospermia (>1×106 wbc/ml), oligo and azoospermia, varicocele, cancer, endocrine disorders, genital tract infection, autoimmune disease, cryptorchidism, smoking or alcohol consumption which may impact the intracellular ros, and patients who received chemotherapy, radiotherapy, and recent antioxidant intake. the study adhered to the local ethical protocol. semen samples were obtained at baseline and after the treatment phase and were analyzed in accordance with who criteria. semen collection and analyses semen samples were obtained by masturbation after sexual abstinence of 2 to 4 days. after liquefaction in the lab at 37°c , samples were assessed for sperm parameters, intracellular o2, protamine deficiency, sperm hspa2+, and apoptotic spermatozoa. semen analysis semen samples were collected into sterile containers in the laboratory by masturbation and after complete liquefaction at room temperature (22º c) for 30 min, they were assessed for macroscopic parameters such as color, ph, ejaculate volume, and viscosity. an aliquot of the sample was evaluated for sperm concentration, total motility, and morphology according to who criteria (who, 2010)(14). first, sperm concentration and total motility were assessed by casa, then reanalyzed manually by a single experienced technician. the semen samples were mixed well; 10 µl of the sample was placed on a clean glass slide that had been stored at 37 °c and it was covered with a coverslip. the samples were placed on the heating stage of a microscope at 37 °c and were immediately observed at ×400 magnification. sperm vitality and morphology in 200 spermatozoa per slide were evaluated by two experienced technicians using the eosin/nigrosine and papanicolaou staining, respectively. the same experienced technician performed all the semen analyses. assessment of intracellular o2, hspa2 and apoptotic spermatozoa by flowcytometry dhe (dihydroethidium) is a specific probe for o2-. and a cell permeable stain. sperm suspension was incubated with dhe (1.25µm; sigma) at 25 °c for 25 antioxidants and male infertility – sabeti et al. sperm parameters vit e+ selenium(n=30) placebo(n=30) pvalue male age, year; mean ± sd (range) 31.90 ± 3.68 33.46 ± 3.72 0.107 sperm volume. ml; mean ± sd (range) 3.35 ± 0.35 3.51 ± 0.27 0.125 sperm ph; mean ± sd (range) 7.31 ± 0.13 7.27 ± 0.07 0.467 vitality; mean ± sd (range) 55.16 ± 14.84 56.64 ± 14.24 .975 sperm concentration ×106/ml; mean ± sd (range) 40.46 ± 18.51 43.86 ± 19.66 .893 total motility, %; mean ± sd (range) 28.88 ± 6.66 29.47 ± 5.77 .987 normal morphology, %; mean ± sd (range) 1.83 ± .74 2.03 ± .80 .799 cma3+,%; mean ± sd (range) 37.06 ± 6.24 35.69 ± 5.05 .782 hspa2+ ,%; mean ± sd (range) 22.26 ± 7.48 22.56 ± 6.37 .998 dhe+ ,%; mean ± sd (range) 35.40 ± 6.26 35.02 ± 5.58 .995 yo+ ,%; mean ± sd (range) 37.07 ± 8.40 40.97 ± 8.75 .345 table 1. demographic characteristics, sperm analysis and the dhe cma3, hspa2 and yo levels before treatment in two study groups abbreviations: cma3= chromomycine a3 staining, hspa2= heat-shock protein a2, dhe = dihydroethidium, yo= yo-pro-1 iodide. note: values are presented by mean± sd. paired sample t-test was used to compare dependent variables. p-value<0.05 was considered statistically significant. by comparing the hormonal levels in sertraline and control group we founded that fsh, lh and testosterone levels all increased in the sertraline group, but this increase was only significant for fsh (p < 0.05). there was no significant difference in lh, fsh and testosterone levels between the 80th day and 170th day in the control group (p > 0.05) andrology 550 min. dhe is oxidized by o2and produces ethidium bromide which binds to the sperm dna and emits red fluorescence which is then analyzed by a flowcytometer (facs caliber; bd biosciences, usa) between 590 and 700 nm. yo-pro-1 iodide (y3603life technology) was used as a counterstain dye for dhe and excluded the apoptotic spermatozoa(9,15). to measure the percentage of hspa2+ spermatozoa, all samples were washed twice in cold phosphate – buffered saline (pbs, gibco, usa), 4% paraformaldehyde was added and samples were incubated for 20 min at room temperature, and then centrifuged for 5 min at 300g. test fractures were permeable in 5% triton x-100 for 5 min and they were incubated overnight with the primary anti-hspa2 antibody (santa cruz co.) at a dilution of 1:100 in 3% bovine serum albumin (bsa; sigma co.) at 4 °c; control samples were incubated under the same conditions with 3% bsa. two samples were washed and incubated with pe-conjugated donkey anti-goat igg (1:200, santa cruz co.) in 1.5% bsa at 4 ⁰c for 1 h. after washing, bd facs caliber flow-cytometry was used for further analysis(16). we assessed at least 10000 spermatozoa in each sample using the flowcytometry software (flowjo 7.6.1) and expressed in percentage. chromomycin a3 (cma3) staining for protamine deficiency assessment chromomycin a3 (cma3), is an indirect assessment for protamine content that competes with protamine to bind dna. using this procedure the semen samsperm parameters vit e+ selenium(n=30) placebo (n=30) pvalue sperm volume, ml; mean ± sd (range) 3.06 ± 0.21 3.32 ± 0.19 0.001 sperm ph; mean ± sd (range) 7.25 ± 0.11 7.33 ± 0.08 0.02 vitality; mean ± sd (range) 69.86 ± 12.56 46.75 ± 12.74 0.0001 sperm concentration ×106/ml; mean ± sd (range) 40.66 ± 17.15 42.20 ± 18.93 .989 total motility, %; mean ± sd (range) 44.39 ± 8.91 29.11 ± 5.09 0.0001 normal morphology, %; mean ± sd (range) 2.16 ± 1.05 1.66 ± 0.75 .110 cma3+,%; mean ± sd (range) 36.76 ± 5.96 37.13 ± 5.11 .994 hspa2+,%; mean ± sd (range) 22.49 ± 7.10 22.08 ± 5.58 .995 dhe+,%; mean ± sd (range) 26.61 ± 7.66 38.96 ± 5.13 0.0001 yo+,%; mean ± sd (range) 28.34 ± 10.58 44.02 ± 8.36 0.0001 table 2. comparison of the levels of lh, fsh and testosterone between 80th and 170th day in sertraline and control group. abbreviations: cma3= chromomycine a3 staining, hspa2= heat-shock protein a2, dhe = dihydroethidium, yo= yo-pro-1 iodide note: values are presented by mean ± sd. independent sample t-test was used to compare dependent variables. p-value < 0.05 was considered statistically significant. figure 1. study design, and distribution of patients into treatment antioxidants and male infertility – sabeti et al. vol 18 no 5 september-october 2021 551 ples were washed with pbs, smears of them were prepared and dried. then, they were fixed in carnoy,s solution (methanol/glacial acetic: 3:1) at 4 ⁰c for 10 min, stained with 100µl of cma3 (0.25 mg/ml) (sigma co.) for 25 min in dark at room temperature and mounted with buffered glycerol. we counted 200 spermatozoa under a fluorescence microscope at 1000x magnification in all samples. spermatozoa with normal protamine content (cma3 – negative) and spermatozoa with protamine deficiency are stained dull green and bright yellow, respectively(9). this study was approved by institutional review board of yazd research and clinical center for infertility and informed consent forms were signed by all participants. ethical committee registration: yazd research and clinical center for infertility, ethical code: 342/26/693 clinical trial registration: irct20140409017210n2 statistical analysis statistical analysis was performed using spss software, (version 16.0, spss inc., chicago, il, usa). the data distribution was normalized with k-s test. independent sample t-test was used to compare two study groups. paired sample t test was used to compare pre and post-treatment parameters. one-way analysis of variance (anova) was used for comparison of parameters between groups. two tailed p-value less than 0.05 was considered as statistically significant outcome for the measured cases. all data was presented as mean ± standard deviation. results demographic characteristics in two study groups before treatment (vit e+ selenium and placebo) are summarized table 1. demographic characteristics and sperm parameters were similar between the two groups. also, comparison of post-test seminal parameters, the level of dhe, cma3+, hspa2+ and yo+ between two groups are shown in table 2. comparison of pre and post treatment seminal parameters, the level of dhe, cma3+, hspa2+ and yo+ in two study groups are summarized in table 3. sperm concentration there were no differences between the two groups before treatment (p = .893) and post treatment (p = .989) (tables 1 and 2 respectively). there were no statically significant changes in sperm concentration in placebo (p = .986) and vit e+ selenium group (p = 1.000) groups after 3 months (table 3). sperm total motility there was no difference between two groups before treatment (p = .987), but it was significant post treatment (p = .0001) (table 1 and table 2).while for the placebo group no change was observed (p = .99), the increase in the vit e+ selenium group was highly significant (p = .0001) (table 3). normal morphology there were also no differences between the two groups before treatment (p = .799) and post treatment (p = .110). in placebo (p =.345) and treatment group (p =. 43, no significant changes were observed after 3 months. sperm vitality there was no difference for the comparison between two groups at the baseline (p = .975) but it increased in the treatment group significantly. (p = .0001) (table 1 and table 2, respectively). while sperm vitality decreased in the placebo group significantly after 3 months (p =.030), and it increased in vit e+ selenium group significantly (p = .001) (table 3). semen volume there was no statistically significant difference between the two groups before treatment (table 1). comparison between post-treatment groups showed changes were significant and in the placebo group volume increased significantly (table 2). pre and post-treatment comparison showed a significant decrease in volume in vit e+ selenium group (table 3). sperm ph there was no statistically significant difference between the two groups before treatment (table 1). comparison between post-treatment groups showed changes were significant and in the placebo group ph increased significantly (table 2). pre and post-treatment comparison showed there was no statistically significant difference between pre and post-treatment with vit e+ selenium (table 3). percentage of sperm cma3+ there was significant difference between the two groups pre-treatment (p = .782) and post-treatment (p = .994) (table 1 and table 2). no changes occurred in percentage of sperm cma3+ in placebo vit e+ selenium group, (p =.756) (p =.997), after 3 months (table 3). percentage of sperm hspa2+ there were also no differences between the two groups pre-treatment (p = .998) and post-treatment (p = .995) (table 1 and table 2). percentage of sperm hspa2+ +, andrology 337 sperm parameters vit e+ selenium(n=30) pvalue placebo (n=30) pvalue pre-treatment post-treatment pre-treatment post-treatment sperm volume. ml; mean ± sd (range) 3.35 ± 0.35 3.06 ± 0.21 0.0001 3.51 ± 0.27 3.32 ± 0.19 0.045 sperm ph; mean ± sd (range) 7.31 ± 0.13 7.25 ± 0.11 0.171 7.27 ± 0.07 7.33 ± 0.08 0.102 vitality; mean ± sd (range) 55.16 ± 14.84 69.86 ± 12.56 .0001 56.64 ± 14.24 46.75 ± 12.74 .030 sperm concentration ×106/ml; mean ± sd (range) 40.46 ± 18.51 40.66 ± 17.15 1.000 43.86 ± 19.66 42.20 ± 18.93 0.986 total motility, %; mean ± sd (range) 28.88 ± 6.66 44.39 ± 8.91 0.0001 29.47 ± 5.77 29.11 ± 5.090 0 .997 normal morphology, %; mean ± sd (range) 1.83 ± .746 2.16 ± 1.05 .430 2.03 ± .80 1.66 ± .75 0.345 cma3+, %; mean ± sd (range) 37.06 ± 6.24 36.76 ± 5.96 .997 35.69 ± 5.05 37.13 ± 5.14 0.756 hspa2+, %; mean ± sd (range) 22.26 ± 7.48 22.49 ± 7.10 .999 22.56 ± 6.37 22.08 ± 5.58 0.992 dhe+ , %; mean ± sd (range) 35.40 ± 6.26 26.61 ± 7.66 .0001 35.02 ± 5.58 38.96 ± 5.13 0.074 yo+ , %; mean ± sd (range) 37.07 ± 8.40 28.34 ± 10.58 .002 40.97 ± 8.75 44.02 ± 8.36 0.563 table 3: comparison of the pre and post treatment seminal parameters, the level of dhe cma3, hspa2 and yo in two study groups. abbreviations: cma3= chromomycine a3 staining, hspa2= heat-shock protein a2, dhe = dihydroethidium, yo= yo-pro-1 iodide note: values are presented by mean± sd. paired sample t-test was used to compare dependent variables. p-value<0.05 was considered statistically significant. antioxidants and male infertility – sabeti et al. andrology 552 in both groups, showed no significant changes after 3 months (table 3). intracellular o2 there was no difference between the two groups before treatment (p = .995) but it was decreased in post-treatment significantly (p = .0001) (table 1 and table 2). pre and post-treatment placebo groups showed no change (p = .074) in the level of intracellular o2, though in the vite+ selenium group it decreased significantly after 3 months(p =.0001) (table 3). percentage of apoptotic spermatozoa there was no difference between the two groups before treatment (p = .345) but a significant decrease was observed in vite+ selenium group (p = .0001) (table 1 and table 2). in the placebo group, no change was observed (p = .563), but in the vit e+ selenium group, the percentage of apoptotic spermatozoa decreased significantly after 3 months (p =.002) (table 3). discussion infertility is a common medical and social problem that affects about one out of eight couples and approximately 40–50% is due to “male factor” (16, 17). asthenoteratozoospermia is a severe form of male infertility and our findings in the previous study showed that they have a higher level of intracellular superoxide anion compared to normosospermic men(9). antioxidants are molecules that are able to reduce or inhibit oxidative stress by scavenging free radicals. when the concentration of free radicals in the body increases, the endogenous antioxidant system is compromised and unable to fully protect the body. in this situation, the use of exogenous antioxidants in dietary supplements or medications can be helpful(18). there are several antioxidants in seminal plasma which improve sperm quality. some of them are vitamins e and c, along with selenium and zinc, which are constituents of the antioxidant system(19). selenium is an essential element in the biosynthesis of the hormone testosterone and sperm formation and is the constituent of different selenoproteins. at least 25 selenoproteins in human and animals are known and are involved in maintaining the normal structure of sperm (20). 20 to 40% of infertile men whose infertility is related to decreased sperm production is due to selenium deficiency(21). it is involved in the structure of the enzyme glutathione peroxidase, which is an important antioxidant and a marker for oxidative stress(22). oral supplementation of selenium (50 microgram) has been reported to significantly increase in sperm parameters, serum testosterone and glutathione levels. also, serum mda significantly decreased in patients after treatment(11). in a study, selenium levels were assessed in idiopathic infertile men. in this study, selenium concentration in the seminal plasm and sera of 60 infertile men with oligospermia and azoospermia was measured (case group) along with 40 fertile men with normozoospermia (control group). they concluded that the mean serum selenium level in infertile men with oligospermia was significantly higher than in infertile men with azoospermia and a significant inverse relationship between selenium levels and sperm count was found. they also found that there was a relationship between selenium levels in the plasma seminal and other sperm parameters(23). hamza et al. investigated the protective and antioxidant effects of selenium nanoparticles (se np) on testicular structure changes in male mice treated with monosodium glutamate (msg). senp is known as a flavor enhancer that has toxic effects on the male reproductive system. they found that, senp inhibit testicular injury and improve the antioxidant state in male mice treated with msg(24). in a study by scott et al., 96 infertile men were treated with selenium or selenium in combination with vitamin e, a and c and they showed significant improvements in sperm motility(25). in another study, selenium and n-acetyl-cysteine administration in infertile men with idiopathic oligo-asthenoteratospermia for 30 weeks improved all sperm parameters(26). vitamin e is a fat-soluble vitamin that is able to neutralize free radicals and protects cell membranes against the ros by preventing lipid peroxidation as well as enhancing the function of other antioxidants(27). in summary, the mechanism by which vitamin e protects cells from oxidative stress includes maintaining normal glutathione levels as an intracellular scavenger of free radicals, protecting cell membranes by inhibiting peroxidation, and clearing cells of ros(28,29), and reduced apoptosis(30). on the effect of vitamin e, keshtgar et al. showed one hour invitro incubation of semen samples from teratozoospermia patients with vitamin e significantly increased sperm motility and viability, but sperm dna fragmentation and acrosome reaction did not change (31). kemal ener et al. found that oral administration of vitamin e increased sperm parameters after varicocelectomy but it was not statistically significant(32). inhibition of ros production in infertile men with vitamin e administration has also been reported(33). abad and colleagues designed a study in which 20 infertile asthenoteratozoospermic men were treated with a multi antioxidants combined with vitamin e and selenium for 3 months. the results showed a significant improvement of dna integrity and significant increase in concentration, motility, vitality, and normal morphology(34). in 2020, matorras r. et al. examined the effect of vitamin e administration on men from infertile couples on sperm parameters and art results in a double-blind randomized study. vitamin e improved sperm parameters but they did not find a significant difference between the vitamin e treatment and the placebo groups. however, administration of vitamin e significantly increased live birth rates compared with placebo, and a tendency to achieve better results was seen in other ivf parameters in the treatment group(35). in this study, the effect of se as a component of antioxidant system and vitamin e on different parameters, intracellular anion superoxide, sperm apoptosis, and sperm chromatin deficiency was studied. abad and colleagues designed a study in which 20 infertile asthenoteratozoospermic men were treated with multi antioxidants combined with vitamin e and selenium for 3 months. the results showed a significant improvement of dna integrity and a significant increase in concentration, motility, vitality, and normal morphology(34). moreover, moslemi et al. confirmed the protective and beneficial effects of selenium–vitamin e supplementation on semen parameters and pregnancy rate. in this study, idiopathic asthenoteratospermia men received daily supplements of vitamin e in combination with selenium for 100 days and they showed an increase in antioxidants and male infertility – sabeti et al. vol 18 no 5 september-october 2021 553 sperm motility and morphology(13). our investigation showed that se (200 µg) in combination with vitamin e (400 units) for 3 months has a potential effect on the reduction of sperm apoptosis and level of anion superoxide and also increases sperm motility and viability (table 3). in addition, we found that in comparison with posttest in the treatment group, the level of intracellular o2.and apoptotic spermatozoa were lower than placebo group significantly in the final visit (p = .0001) (table 2); also, sperm total motility and vitality were significantly higher (p = .0001) (table 2). high levels of intracellular superoxide anion in men with asthenoteratozoospermia(9) can increase sperm apoptosis. on the other hand, the high presence of polyunsaturated phospholipids in sperm membrane, makes it very sensitive to high levels of ros and increases the processes of lipid peroxidation(36), reducing sperm motility and vitality. vitamin e is able to directly neutralize the anion superoxide(37). in addition, a significant positive correlation has been found between serum selenium concentration and glutathione peroxidase (gsh-px)(38). gsh is a major antioxidant enzyme and a selenoprotein which protects the organism from oxidative stress by reducing reactive oxygen species(39). therefore, according to the results of the current study, we may be able to say that, vitamin e and selenium in these patients play a role in free radicals removal and reduction of ros and this reduction can lead to improving sperm motility, viability, and apoptosis. also, we observed no change in the level of sperm protamine deficiency and hspa2 after treatment. hspa2 is involved in histone-protamine translocation. therefore, no change in sperm protein deficiency after treatment may be attributed to the lack of change in hspa2 level. according to the inclusion and exclusion criteria, the selection of patients was one of the major limitations of this study. because, many patients with asthenoteratozoospermia consumed alcohol or drugs in varying amounts, and some took a variety of antioxidants and medications, and this makes it very difficult to follow these patients. another problem was the measurement of intracellular superoxide anion by flow cytometry in this trial study. because it is a compound that must be quickly coordinated and measured with the flow cytometry department. based on the results of this study, we propose other studies in higher populations in which pregnancy rates are also measured. conclusions our results showed that the administration of vitamin e and selenium for three months decreased the level of intracellular anion superoxide in asthenoteratozoospermic men which may lead to improved motility, reduced apoptosis, and increased sperm viability in these patients. however, it does not affect the sperm hspa2 + as well as sperm protamine deficiency level in them. in conclusion, administration of vitamin e and selenium may have a positive effect as a low-cost supplement to improve sperm parameters in infertile asthenoteratozoospermic men and prescribing them before using assisted reproductive techniques (art) may improve outcomes. we also believe that the limitation of changes in sperm parameters to the period of administration may be due to the lack of effect of these supplements on factors such as hspa2 in these patients. acknowledgment this paper, derived from the ph.d. thesis in reproductive biology, has been funded by the shahid sadoughi university of medical sciences, yazd, iran. references 1. jungwirth a, diemer t, dohle g, giwercman a, kopa z, krausz c, et al. guidelines on male infertility. eur urol. 2015;62:324-32. 2. wagner h, cheng jw, ko ey. role of reactive oxygen species in male infertility: an updated review of literature. arab j urol. 2018;16:3543. 3. wu w, shen o, qin y, niu x, lu c, xia y, et al. idiopathic male infertility is strongly associated with aberrant promoter methylation of methylenetetrahydrofolate reductase (mthfr). plos one. 2010;5:e13884. 4. sabeti p, pourmasumi s, rahiminia t, akyash f, talebi ar. etiologies of sperm oxidative stress. int j reprod biomed. 2016;1:231-40. 5. agarwal a, virk g, ong c, du plessis ss. effect of oxidative stress on male reproduction. world j mens health. 2014;32:1-17. 6. motiei m, tavalaee m, rabiei f, hajihosseini r, nasr‐esfahani mh. evaluation of hspa 2 in fertile and infertile individuals. andrologia. 2013;45:66-72. 7. esfahani mh, abbasi h, mirhosseini z, ghasemi n, razavi s, tavalaee m, tanhaei s, deemeh mr, ghaedi k, zamansoltani f, rajaei f. can altered expression of hspa2 in varicocele patients lead to abnormal spermatogenesis?. int j fertil steril. 2010;4:104-13. 8. lima sb, cenedeze ma, bertolla rp, hassun filho pa, oehninger s, cedenho ap. expression of the hspa2 gene in ejaculated spermatozoa from adolescents with and without varicocele. fertil steril. 2006;86:1659-63. 9. sabeti p, amidi f, kalantar sm, gilani mas, pourmasumi s, najafi a, et al. evaluation of intracellular anion superoxide level, heat shock protein a2 and protamine positive spermatozoa percentages in teratoasthenozoospermia. i int j reprod biomed. 2017;15:279-286. 10. alahmar at. role of oxidative stress in male infertility: an updated review. j hum reprod sci 2019;12:4-18. 11. morbat mm, hadi am, hadri dh. effect of selenium in treatment of male infertility. exp tech urol nephrol. 2018;1:1-4. 12. kaushal n, bansal m. selenium variation induced oxidative stress regulates p53 dependent germ cell apoptosis: plausible involvement of hsp70-2. eur j nutr. 2009;48:221-7. 13. moslemi mk, tavanbakhsh s. selenium– vitamin e supplementation in infertile men: effects on semen parameters and pregnancy antioxidants and male infertility – sabeti et al. andrology 554 vol 18 no 5 september-october 2021 555 rate. int j gen med. 2011;4:99-104. 14. cooper tg, noonan e, von eckardstein s, auger j, baker h, behre hm, et al. world health organization reference values for human semen characteristics. hum reprod update. 2010;16:231-45. 15. mahfouz rz, du plessis ss, aziz n, sharma r, sabanegh e, agarwal a. sperm viability, apoptosis, and intracellular reactive oxygen species levels in human spermatozoa before and after induction of oxidative stress. fertil steril. 2010;93:814-21. 16. lotti f, maggi m. sexual dysfunction and male infertility. nat rev urol. 2018;15:287307. 17. kumar n, singh ak. trends of male factor infertility, an important cause of infertility: a review of literature. j hum reprod sci. 2015;8:191-6. 18. majzoub a, agarwal a. systematic review of antioxidant types and doses in male infertility: benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. arab j urol. 2018 ;16:113-24. 19. rezaeian z, yazdekhasti h, nasri s, rajabi z, fallahi p, amidi f. effect of selenium on human sperm parameters after freezing and thawing procedures. asian pac j reprod.. 2016;5:462-6. 20. mistry hd, pipkin fb, redman cw, poston l. selenium in reproductive health. am j obstet gynecol. 2012;206:21-30. 21. griffin j, wilson j. disorders of the testes. harrisons principles of internal medicine. 1998:2087-96. 22. hariharan s, dharmaraj s. selenium and selenoproteins: it’s role in regulation of inflammation. inflammopharmacology. 2020:1-29. 23. akinloye o, arowojolu a, shittu o, adejuwon c, osotimehin b. selenium status of idiopathic infertile nigerian males. biol trace elem res. 2005;104:9-18. 24. hamza rz, diab ae-aa. testicular protective and antioxidant effects of selenium nanoparticles on monosodium glutamateinduced testicular structure alterations in male mice. toxicol rep. 2020;7:254-60. 25. scott r, macpherson a, yates r, hussain b, dixon j. the evect of oral selenium supplementation on human sperm motility. br j urol. 1998;82:76-80. 26. safarinejad mr, safarinejad s. efficacy of selenium and/or n-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. j urol. 2009;181:741-51. 27. alahmar at. the effects of oral antioxidants on the semen of men with idiopathic oligoasthenoteratozoospermia. clin exp reprod med. 2018;45:57-66. 28. krishnamoorthy g, venkataraman p, arunkumar a, vignesh r, aruldhas m, arunakaran j. ameliorative effect of vitamins (α-tocopherol and ascorbic acid) on pcb (aroclor 1254) induced oxidative stress in rat epididymal sperm. reprod toxicol. 2007;23:239-45. 29. takhshid ma, tavasuli ar, heidary y, keshavarz m, kargar h. protective effect of vitamins e and c on endosulfan-induced reproductive toxicity in male rats. iran j med sci. 2012;37:173-80. 30. serbecic n, beutelspacher sc. anti-oxidative vitamins prevent lipid-peroxidation and apoptosis in corneal endothelial cells. cell tissue res. 2005;320:465-75. 31. keshtgar s, fanaei h, bahmanpour s, azad f, ghannadi a, kazeroni m. in vitro effects of α‐tocopherol on teratozoospermic semen samples. andrologia. 2012;44:721-7. 32. ener k, aldemir m, işık e, okulu e, özcan mf, uğurlu m, et al. the impact of vitamin e supplementation on semen parameters and pregnancy rates after varicocelectomy: a randomised controlled study. andrologia. 2016;48:829-34. 33. ross c, morriss a, khairy m, khalaf y, braude p, coomarasamy a, et al. a systematic review of the effect of oral antioxidants on male infertility. reprod biomed online. 2010;20:711-23. 34. abad c, amengual m, gosálvez j, coward k, hannaoui n, benet j, et al. effects of oral antioxidant treatment upon the dynamics of human sperm dna fragmentation and subpopulations of sperm with highly degraded dna. andrologia. 2013;45:211-6. 35. matorras r, pérez-sanz j, corcóstegui b, pérez-ruiz i, malaina i, quevedo s, aspichueta f, crisol l, martinez-indart l, prieto b, expósito a. effect of vitamin e administered to men in infertile couples on sperm and assisted reproduction outcomes: a double-blind randomized study. f&s reports. 2020;1:219-26. 36. lopalco p, vitale r, cho ys, corcelli a, lobasso s. alteration of cholesterol sulfate/ seminolipid ratio in semen lipid profile of men with oligoasthenozoospermia. front physiol. 2019;10:1344. 37. agarwal a, nallella kp, allamaneni ss, said tm. role of antioxidants in treatment of male infertility: an overview of the literature. reprod biomed online. 2004;8:616-27. 38. pilarczyk b, jankowiak d, tomza-marciniak a, pilarczyk r, sablik p, drozd r, et al. selenium concentration and glutathione peroxidase (gsh-px) activity in serum of cows at different stages of lactation. biol trace elem res. 2012;147:91-6. 39. lubos e, loscalzo j, handy de. glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. antioxid redox signal. 2011;15:1957-97. antioxidants and male infertility – sabeti et al. endourology and stone disease 156 urology journal vol 5 no 3 summer 2008 prevalence of symptomatic urinary calculi in kerman, iran ali asghar ketabchi, gholam abbas aziziolahi introduction: in a cross-sectional study, we evaluated the prevalence of symptomatic urinary calculi in kerman, iran. materials and methods: a total of 2431 citizens of kerman were surveyed from september of 2005 to april 2006. the study population was selected by cluster method from 5 different areas, and 100 houses in each area were randomly approached. questions on the urinary symptoms consisted of flank pain, urogenital pain, dysuria or any difficulty in urination, and alterations in urine color. individuals with a suspicion of urinary calculi based on their symptoms were evaluated by physical examination, laboratory investigations, and plain abdominal radiography. ultrasonography and intravenous urography were done if required to confirm the diagnoses. results: of 2431 individuals, 196 (8.1%) had symptoms in favor of urinary calculus diagnosis, of whom 47 (24.0%) had urinary calculi (prevalence of symptomatic urolithiasis was 1.9%). of the patients, 35 (74.5%) were underweight. compared to the other participants, the patients with urinary calculus were younger (p = .001) and a larger proportion of them had a positive family history of urinary calculi (14.9% versus 6.5%; p = .02) and were rug weavers and office employees. dependency on opium and its derivative was significantly more frequent in patients with urinary calculi (25.5% versus 0.2%; p = .001). conclusion: this study showed that the prevalence of symptomatic urinary calculi in this hot and dry area is relatively high. according to our findings, the other factors including specific occupations, malnutrition, and substance use may also have influence on the rate of urinary calculus formation. therefore, to prevention and early treatment of urinary calculi, evaluation of potential predisposing conditions should be considered with special attention to regional factors. urol j. 2008;5:156-60. www.uj.unrc.ir keywords: urinary calculi, iran, epidemiology, occupations, substance-related disorders, genetics department of urology, shafa hospital, kerman university of medical sciences, kerman, iran corresponding author: ali asghar ketabchi, md shafa hospital, shafa st, kerman, iran tel: +98 341 211 5780 fax: +98 341 2115803 e-mail: mrketabchi@yahoo.com received october 2007 accepted june 2008 introduction prevalence of urinary calculi is estimated to be 1% to 5% worldwide, 2% to 13% in developed countries (with a great variation among them), and 0.5% to 1% in developing countries.(1-4) one study showed that about 20% of patients with recurrent calculi who underwent surgical operation for obstruction or infection went on developing mild renal insufficiency.(1) moreover, urinary calculus is one of the most costly diseases in the world. for instance, in the united states alone 0.9% of hospitalized patients suffering urinary calculi, and in 1993, the yearly cost of this disease was reported to be us $ 1.83 million.(5) these facts symptomatic urinary calculi in kerman—ketabchi and aziziolahi urology journal vol 5 no 3 summer 2008 157 necessitate the emphasis on prevention measures, and as a result, on understanding the predisposing factors of urinary calculi. it has been reported that urinary calculi have different prevalence rates among different races and ethnicities.(3,4) based on the environmental conditions and the individual characteristics of the patient, urinary calculi tend to develop, recur, and increase morbidities. geographical characteristics may be indirect predictors of calculus formation, through their effect on temperature and humidity. also, the temperature of the environment has been reported to affect the incidence of urinary calculus disease.(6) finally, nutrition and body weight are of other associated factors that can be related to the socioeconomic and cultural characteristics of an area.(7-10) overall, evaluation and understanding the contributors to urinary calculus formation in different geographical areas is the primary step for prevention and treatment of patients suffering this problem. we, however, lack enough nationwide information of urinary calculus disease in iran. in this study, we designed the primary research in kerman (a city in the vicinity of iran’s deserts) on the prevalence and associated factors of urinary calculi. materials and methods this cross sectional study on the prevalence of urinary calculi was carried out in kerman, iran, from september of 2005 to april 2006. kerman is a city in the southwest of iran, in the vicinity of loot and dasht-e-kavir deserts. the environmental characteristics of the city make the citizens prone to urinary calculus formation. the population is relatively homogenous and some specific occupations such as rug waiving are the prominent activities of the people. we considered these characteristics in our epidemiologic evaluation of urinary calculi. in addition, kerman is on the transport way of drug trafficking from afghanistan; consequently, substance use is a challenge in the healthcare system of the city, which was addressed in this study. the study was approved by the ethics committee of kerman university of medical sciences. in order to investigate the prevalence of urinary calculi, we calculated a sample size of 2000 people considering the worldwide prevalence of 5% (α = 5% and d = 1%),(1-4) but for more confident results, we considered 2500 individuals. the population samples were selected by cluster method from 5 different areas, and 100 houses in each area were randomly approached. finally, 2431 individuals consented and participated in this study. the national healthcare personnel interviewed the families by door-to-door visits. they filled in a questionnaire on demographic information, urinary calculus symptoms, individual and family history of urinary calculus formation, and the use of opium and its derivatives (evaluated via semistructured interview based on the diagnostic and statistical manual-iv criteria for opioid dependence).(11) questions on the urinary symptoms consisted of flank pain, urogenital pain, dysuria or any difficulty in urination, and alterations in urine color. individuals with a suspicion of urinary calculi based on their symptoms were referred to the urology clinic. they were evaluated by physical examination, laboratory investigations, and plain abdominal radiography. ultrasonography and intravenous urography were done if required to confirm the diagnoses. patients with urinary calculi were identified and compared with those without urinary symptoms. the collected data were analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). either the t test or the chi-square test was used for comparisons between the two groups of the study, where appropriate. dichotomous variables were demonstrated as percentages and the absolute values, and the continuous variables as mean ± standard deviation. a p value less than .05 was considered significant. results of 2431 individuals, 196 (8.1%) had symptoms in favor of urinary calculus diagnosis. ultimately, 47 of 196 individuals (24.0%) had urinary calculi, and the prevalence of symptomatic urolithiasis was 1.9% (95% confidence interval, 1.4% to 2.5%). most of the detected calculi (78.7%) were located in the kidneys (figure). of note, 21 patients symptomatic urinary calculi in kerman—ketabchi and aziziolahi 158 urology journal vol 5 no 3 summer 2008 (44.7%) with urinary calculi did not have any classic clinical symptoms and diagnosis was made based on nonspecific manifestations in primary evaluation, confirmed by further laboratory and imaging tests. the patients’ body mass index was calculated and it was found that 35 (74.5%) were underweight. compared to the other participants, the mean age of the patients with urinary calculus was significantly lower (p = .001), but sex distribution was not different between the two groups (table). family history of urinary calculi was more frequent in patients with urinary calculi than in participants without urinary symptoms (14.9% versus 6.5%; p = .02). furthermore, among the patients with urinary calculi, significantly larger proportions were rug weavers and office employees, while a small percentage of them were housewives (table). finally, dependency on opium and its derivative was significantly more frequent in patients with urinary calculi (25.5% versus 0.2%; p = .001). discussion in the present study, we found that the prevalence of symptomatic urinary calculi in kerman was 1.9%. this rate is relatively high, especially when compared to the prevalence rates in developing countries.(1-4) given that our detected urinary calculi did not include asymptomatic ones, it can be speculated that the overall prevalence of urinary calculi in kerman is even higher. it seems that a potential factor in calculus formation in this area is the special geographic condition of kerman province that is surrounded by 2 deserts of iran (dasht-e-kavir and kavir-e-loot). like other hot and dry geographic “stone belts”, such as the southeastern united states, climate of kerman may affect urinary calculus formation in our population. in the stone belt of the southeast of the united states, 19.2 per 10 000 hospital admissions are due to urinary calculi.(12) thus, this special geographical condition (dry and hot climate) might have some influence on the prevalence of urinary calculus formation in our region. however, the causative relation of the location of the calculi in 47 patients with urinary calculi. characteristic patients with calculi other participants p number of individuals 47 2384 … sex male 26 (55.3) 1212 (50.8) female 21 (44.7) 1172 (49.2) .54 mean age, y 25.8 ± 5.1 43.6 ± 7.8 .001 family history of urinary calculi 7 (14.9) 155 (6.5) .02 bmi, kg/m2 17.0 ± 1.5 25.0 ± 2.0 .001 opium dependency 12 (25.5) 4 (0.2) < .001 job rug weaver 21 (44.7) 417 (17.5) < .001 office employee 16 (34.0) 604 (25.3) .18 farmer 3 (6.4) 110 (4.6) .47 house wife 2 (4.3) 698 (29.3) < .001 others 5 (10.6) 555 (23.3) < .001 work experience 32.0 ± 8.5 22.0 ± 2.5 < .001 characteristics of patients with urinary calculi compared with individuals without urinary symptoms in kerman* *values in parentheses are percents. continuous variables are demonstrated as mean ± standard deviation. bmi indicates body mass index. symptomatic urinary calculi in kerman—ketabchi and aziziolahi urology journal vol 5 no 3 summer 2008 159 temperature of the environment has not been elucidated yet, and some have disputed this issue.(13,14) curhan and colleagues performed a large cohort study in the united states and suggested that the magnitude of the “stone belt” effect was modest compared with previous estimates.(14) as we showed in the present study, some other factors that have direct or indirect relation with the environmental parameters may play a role in calculus formation. for instance, urinary calculi were more frequent among rug weavers (a most common occupation in this area). these workers have the physical activity, sitting for a long time while weaving, and may very little amount of liquid intake. atan and colleagues, proposed a higher risk of calculus formation in hot occupational environments,(6) a factor which might explain, at least partly, the high incidence in our study population. another interesting factor in our study was substance abuse. urinary calculi were more frequent opium-addicted people. there is a lack of knowledge on the relation of substance use and calculus formation that warrants further evaluations in our region. we speculate that other than the probable direct effects of opioids on the urinary tract, this finding can be explained by the associated factors such as the nutritional and socioeconomic status of substance-dependent people. fifteen percent of the sufferers from urinary calculi in our study had a positive family history of calculus formation. therefore, the inheritance and family factors cannot be ruled out. earlier, ahmadi asr badr and colleagues reported a high frequency of positive family history among the patients with calculi in iran.(15) nonetheless, multivariate analyses are required to confirm the strength of family history as an independent predictor of urinary calculus, because family members have other characteristics in common than genetic resemblances, too. unlike the reports of some researchers that overweight predisposes to urinary calculus formation,(16) our group of urinary calculus formers were mainly among underweight (mean body mass index, 17.0 ± 1.5 kg/m2). we think that people suffering a poor nutrition do not receive sufficient minerals and vitamins necessary for prevention of calculus production, since it is believed that a corrected diet can reduce calculus formation.(17) however, to determine exact relations of this factor with urinary calculi, it is recommended to further researches by multivariable studies as case-control, cohort studies. conclusion urinary calculus is the third most common problem in urology clinics after urinary tract infections and prostate diseases. also, it is the most costly disease worldwide that needs a good management and prevention. our nationwide information on the prevalence and characteristics of urinary calculi is not complete yet. however, we can portrait the disease and its specific feature in our province by the findings of this study. although a definite conclusion still remains to be made, we know that special attention to the occupation and substance use may help us to diagnose and prevent urinary lithiasis in kerman. the regional effects such as the so-called “stone belt” should be also considered in our future investigations. acknowledgment the authors thank dr ali reza ghaffari (psychiatrist) for contributing to the planning and design of opium addiction (dependency) questionnaire of this study. financial support kerman university of medical sciences financially supported this study. conflict of interest none declared. references 1. menon m, koul h. clinical review 32: calcium oxalate nephrolithiasis. j clin endocrinol metab. 1992;74:703-7. 2. ramello a, vitale c, marangella m. epidemiology of nephrolithiasis. j nephrol. 2000;13 suppl 3:s45-50. 3. kim h, jo mk, kwak c, et al. prevalence and epidemiologic characteristics of urolithiasis in seoul, korea. urology. 2002;59:517-21. symptomatic urinary calculi in kerman—ketabchi and aziziolahi 160 urology journal vol 5 no 3 summer 2008 4. lee yh, huang wc, tsai jy, et al. epidemiological studies on the prevalence of upper urinary calculi in taiwan. urol int. 2002;68:172-7. 5. clark jy, thompson im, optenberg sa. economic impact of urolithiasis in the united states. j urol. 1995;154:2020-4. 6. atan l, andreoni c, ortiz v, et al. high kidney stone risk in men working in steel industry at hot temperatures. urology. 2005;65:858-61. 7. hiatt ra, ettinger b, caan b, quesenberry cp, jr., duncan d, citron jt. randomized controlled trial of a low animal protein, high fiber diet in the prevention of recurrent calcium oxalate kidney stones. am j epidemiol. 1996;144:25-33. 8. shah pj, green na, williams g. unprocessed bran and its effect on urinary calcium excretion in idiopathic hypercalciuria. br med j. 1980;281:426. 9. rao pn, gordon c, davies d, blacklock nj. are stone formers maladapted to refined carbohydrates? br j urol. 1982;54:575-7. 10. li mk, kavanagh jp, prendiville v, buxton a, moss dg, blacklock nj. does sucrose damage kidneys? br j urol. 1986;58:353-7. 11. cooper je. on the publication of the diagnostic and statistical manual of mental disorders: fourth edition (dsm-iv). br j psychiatry. 1995;166:4-8. 12. brikowski th, lotan y, pearle ms. climate-related increase in the prevalence of urolithiasis in the united states. proc natl acad sci u s a. 2008;105:9841-6. 13. al-hadramy ms. seasonal variations of urinary stone colic in arabia. j pak med assoc. 1997;47:281-4. 14. curhan gc, rimm eb, willett wc, stampfer mj. regional variation in nephrolithiasis incidence and prevalence among united states men. j urol. 1994;151:838-41. 15. ahmadi asr badr y, hazhir s, hasanzadeh k. family history and age at the onset of upper urinary tract calculi. urol j. 2007;4:142-5. 16. siener r, glatz s, nicolay c, hesse a. the role of overweight and obesity in calcium oxalate stone formation. obes res. 2004;12:106-13. 17. porena m, guiggi p, micheli c. prevention of stone disease. urol int. 2007;79 suppl 1:37-46. unclassified urology journal/vol 19 no. 4/ july-august 2022/ pp. 329-332. [doi:10.22037/uj.v18i.6797] efficiency of hyperbaric oxygen therapy combined with negative-pressure wound therapy in the treatment strategy of fournier’s gangrene –a retrospective study łukasz michalczyk1*,agnieszka grabińska2, beata banaczyk1, marek braszko1,aneta andrychowicz3, tomasz ząbkowski2, 3 purpose: fournier’s gangrene (fg) is a serious, aggressive, and often fatal multi-organism infection that affects the soft tissues of the perineum, rectum, and external genitalia. this study aimed to analyse the treatment’s strategies of fg. materials and methods: this was a retrospective study of 35 patients with a diagnosis of fg admitted between 2016 and 2021. the diagnosis of fg was established on a clinical basis. data on patient’s age, sex, comorbidities, laboratory results (c-reactive protein (crp), white blood cell (wbc), hematocrit (hct), platelets (plt), sodium, potassium, creatinine, procalcitonin, international normalized ratio (inr), and gangrene culture), extent of resection, antibiotics used, and hospitalisation time were obtained. the extent of resection was assessed on a scale of 1–5. results: the study group consisted of all men (n=35) aged 24–85 (mean, 58) years. in 13/35 (37%) patients, hyperbaric oxygen therapy (hbot) combined with negative-pressure wound therapy (npwt) was used as a treatment for wound healing in fournier’s syndrome (group 1), and in 22/35 (63%) patients, open standard wound care was used (group 2). there were no fatalities in group 1, but four deaths (18%) were noted in group 2. the median extent of resection was 3 in group 1 and 2 in group 2. there was a correlation between the extent of resection and the use of hbot combined with npwt. the hospitalisation time was much shorter in group 2 (mean, 23 days) than in group 1 (mean, 26 days). conclusion: hbot and npwt (group 1) showed advanced wound healing with a high efficiency rate. the longer median hospitalisation time in this group may be related to the severity of the injury. keywords: fournier gangrene; treatment; wounds introduction fournier’s gangrene (fg) is a serious, aggressive, and often fatal multi-organism infection that affects the soft tissues of the perineum, rectum, and external genitalia. it is an anatomical subcategory of necrotising fasciitis with a similar aetiology and treatment strategy. this disease was first described by jean alfred fournier, who described five cases in young men. fg is 10 times more common in men than in women and can occur at any age.(1) it usually causes painful swelling of the scrotum or perineum with sepsis. physical examination revealed small areas of necrotic skin with erythema and swelling. in the more advanced stage of the disease, there is a foul-smelling discharge. mortality increases due to risk factors such as immunosuppression, diabetes, alcoholism, arteriosclerosis, malnutrition, recent urethral or perineal surgery, hiv infection, liver disease, leukaemia, and obesity.(2) insidious onset of the disease occurs in 40% of cases, and unrecognised pain causes a delay in treatment. fg can be caused by trauma, insect bites, or unsafe sexual practices.(3) computed tomography or magnetic reso1department of urology and oncological urology, praski hospital, warsaw, poland. 2department of urology, military institute of medicine, warsaw, poland. 3urological outpatient clinic, warsaw, poland. *correspondence: department of urology and oncological urology, praski hospital, warsaw, poland. e-mail: lukamichalczyk@gmail.com. received april 2021 & accepted august 2021 nance imaging may contribute to the assessment of the degree of rectal involvement.(3) the degree of internal necrosis is usually higher, as indicated by the external symptoms. surgical debridement should be performed within 24 h, as delayed or incorrect surgery may result in increased mortality. immediate initiation of empiric broad-spectrum parenteral antibiotic therapy, which provides adequate protection against all likely microorganisms, is recommended. the suggested regimen usually includes a broad-spectrum penicillin or a third-generation cephalosporin (in combination with a beta-lactamase inhibitor), gentamicin, metronidazole, and clindamycin.(3) hyperbaric oxygen therapy (hbot) is increasingly used in the treatment of severe soft tissue infections, especially fg. the use of hbot supports the main components of treatment, i.e. surgical intervention and broad-spectrum antibiotic therapy.(4) the interdisciplinary treatment of fg consists of a combination of surgical and urological interventions, antibiotic therapy, negative-pressure wound therapy (npwt), hbot, and plastic reconstructive procedures. wound healing methodologies can remain classically driven but have also evolved with advances over time. one of the ongoing sea changing currents is the use of npwts. in many ways, npwts and all their variants share similar mechanisms of action and challenges to their usage, as we see in hbots.(5) this study aimed to analyse the treatment’s strategies of fg. materials and methods study population this was a retrospective study of 35 patients with a diagnosis of fg admitted between 2016 and 2021. the data were collected from the analysis of medical records at the department of urology and oncological urology, praski hospital, and the department of urology, military institute of medicine in warsaw, poland. the study participants were from mazovia province, 33 were polish, 1 ukrainian and 1 indian. all patients signed the informed consent that their medical data might be used in the future as part of a retrospective study. the datasets analyzed during the current study were anonymised before we used it for the purpose of current study. the diagnosis of fg was established on a clinical basis. data on patient’s age, sex, comorbidities, laboratory results (c-reactive protein (crp), white blood cell (wbc), hematocrit (hct), platelets (plt), sodium, potassium, creatinine, procalcitonin, international normalized ratio (inr), and gangrene culture) extent of resection, antibiotics used, and hospitalisation time were obtained. the extent of resection was assessed on a scale of 1–5 as follows: 1, lesion only on the scrotum; 2, scrotum + perineum; 3, scrotum + perineum + buttocks; 4, scrotum + perineum + buttocks + orchidectomy; and 5, scrotum + perineum + buttocks + orchidectomy + lower abdomen + thighs. inclusion and exclusion criteria the inclusion criteria were: inflammatory infiltration, swelling of the perineum and / or urogenital area and / or external genitalia and skin necrosis, the patient's condition requiring immediate resection of affected lesions + systemic inflammatory response syndrome (sirs). the exclusion criteria were: inflammatory infiltration, edema of the perineum and / or urogenital area and / or external genital organs without elevation of inflammatory parameters , a testicular abscess, and scrotal abscess. in this study, all patients with fg were divided into two groups: group 1 (n=13), hbot and npwt, and group 2 (n=22), open standard wound care. statistical analysis data analysis was performed using ibm statistical package for the social sciences (ibm spss statistics corp.; armonk, ny, usa) version 26 for windows. univariate analyses (chi-square test and student’s t-test) were used for comparison. statistical significance was set at p < 0.05. descriptive data are presented as parametric and nonparametric data. results the study group consisted of all men (n=35) aged 24– 85 (mean, 58) years. in 13/35 (37%) patients, hbot combined with npwt was used as a treatment for wound healing in fournier’s syndrome (group 1), and in 22/35 (63%) patients, open standard wound care was used (group 2). there were no fatalities in group 1, but four deaths (18%) were noted in group 2 (table 1). table 1 compares the groups in terms of the incidence of diabetes, hypertension (ht), cancer, and mortality. the numbers and percentages of the aforementioned phenomena in each of the groups were presented and using the chi-square test, it was established whether there were statistically significant differences between the groups. as it turned out, no statistically significant differences were found in terms of diabetes, ht, cancer, and deaths. it is worth noting, however, that a significantly higher percentage of deaths and neoplasms occurred in group 2 than in group 1. in turn, a clearly greater percentage of patients with arterial ht occurred in group 1 than in group 2. among the comorbidities, diabetes mellitus (dm) was noted in four patients in group 1 and seven in group 2. in contrast, there were seven patients in group 1 and seven patients in group 2 who had arterial ht. in both groups, seven neoplasms, including kidney cancer, bladder cancer, prostate cancer, colorectal cancer, brain cancer, and lung cancer, were noted. group 2 had six cases of cancer, while group 1 had one case (table 1). escherichia coli, pseudomonas aeruginosa, and en group 1 hbot + npwt (n=13) group 2 open standard wound care (n=22) test chi-2 n % n % chi-2 p dm (n) 4 31% 7 32% 0.004 0.948 ht (n) 7 54% 7 32% 1.652 0.199 neoplasm (n) 1 8% 6 27% 1.958 0.162 mortality (n) 0 0% 4 18% 2.669 0.102 table 1. comparison of group 1 hyperbaric oxygen therapy + negative-pressure wound therapy and group 2 open standard wound care in dm, hypertension, neoplasm, and mortality. group 1 hbot + npwt (n=13) group 2 open standard wound care (n=22) u mann -whitney test me me z p age (median age) 53 61.5 -1.059 0.29 hospitalization time (days) 26 23 -0.803 0.422 extent of resection (median) 3 2 -2.989 0.003* table 2. comparison of group 1 hyperbaric oxygen therapy + negative-pressure wound therapy and group 2 open standard wound care in age, hospitalisation time, and extent of resection. treatment strategy of fournier’s gangrenemichalczyk et al. vol 19 no 4 july-august 2022 330 terococcus faecalis are usually detected in cultures of gangrene. antibiotic therapy included, in particular, the use of metronidazole, vancomycin, clindamycin, meropenem, tazocin, and linezolid. the median extent of resection was 3 in group 1 and 2 in group 2. there was a correlation between the extent of resection and use of hbot combined with npwt. the hospitalisation time was much shorter in group 2 (mean, 23 days) than in group 1 (mean, 26 days) (table 2). table 2 compares the groups in terms of age (in years), length of hospital stay (in days), and extent of resection (on a scale of 1–5). the medians were presented separately in each group and were established using the mann–whitney u test to determine whether there were statistically significant differences between the groups. no significant differences were noted between the groups in terms of age and length of hospital stay. patients in group 2 had a clearly higher median age than those in group 1. on the other hand, a significantly greater range of resections occurred in group 1 than in group 2. discussion fg was first characterised as a rapidly progressing idiopathic infection, including necrotising infection of the external genitals and perineum in both sexes.(6) despite aggressive wide-spectrum antibiotic treatment, aggressive surgical debridement, intensive care, and anaesthesia, the mortality rates are reported to be as high as 43% in some series. in addition, diabetes plays a key role, as approximately 60% of patients with fg have diabetes.(6) the treatment process for fg should be initiated as early as possible. the gold standard for decreasing mortality is early and aggressive debridement and the use of wide-spectrum antibiotics.(7) in this study, we applied the interdisciplinary treatment of fg consisting of a combination of surgical and urological interventions, antibiotic therapy, npwt, hbot, and plastic reconstructive procedures. li et al. showed the beneficial influence of hbot on the survival rate in patients with fg in a shock status. the authors indicated the key role of adjuvant hbot in promoting the bactericidal effect. hbot improves tissue perfusion and promotes angiogenesis and fibroblast proliferation in addition, it causes an increase in collagen synthesis and oxygen levels in tissues (table 3). the results of the study by li et al. showed that patients who received hbot had a significant improvement in survival (100%) compared with those who did not receive hbot(66.7%).(8) in our study, there were no fatalities in group 1 (hbot therapy + npwt), but four deaths were noted in group 2 (18%) in a study by tutino et al., mortality was not associated with the adjunction of hbot to surgical debridement plus antibiotic therapy. it is claimed that the only factor that adversely affects prognosis is a delay between admission and surgical debridement.(9) assenza et al. analysed six male cases of fg and concluded that npwt is a time-saving method. they confirmed the high efficiency of npwt, including a decrease in hospitalisation time, number of medications, and improvement of quality of life.(10) similarly, cuccia et al. assessed the results of npwt within postoperative wound therapy in six cases with a very extensive fg (mean fgsi, 10.5). npwt was evaluated as an effective treatment strategy for wound cleaning. this therapy contributed to decreasing hospitalisation time.(11) another study showed similar results in the hospitalisation time and reconstruction rate between npwt and standard wound therapy of fg. however, the most important role of npwt is to decrease the re-debridement rates and dressing frequency.(12) in this study, the median extent of resection was 3 in group 1 and 2 in group 2. there was a correlation betable 3. analysis of previous studies on fg management. reference study design intervention primary endpoint secondary endpoint number of patients limitation hung et al. [1] retrospective adjuvant hbot mortality septick shock survival 60 retrospective design. observational study insufficiency of some data within the registry. inability to access all data. schneidewind systematic review adjuvant hbot mortality rate or duration of inpatient 376 only english and et al. [2] (all types of study overall survival treatment. german publication designs were included ) duration of intensive included. care treatment. number heterogeneous data. of surgical debridement. retrospective design quality of life of included publication. li et al. [8] retrospective adding hbot to mortality number of surgical 28 retrospective design. observational study conventional therapy debridement. indwelling small sample size. drainage tube time. curative time tutino et al. [9] retrospective hbot length of hospital stay mortality 23 retrospective design. observational study small sample size assenza et al. [10] retrospective vac therapy reducing in number of lengh of hospital stay 6 retrospective design. observational study (1 pt. with hbot) dressing small sample size cuccia et al. [11] retrospective treatment algorithm with reducing in the number 6 retrospective design. observational study vac therapy and hbot of surgical debridement small sample size. lack of control group. balli et al. [12] retrospective vac therapy mortality rate hospitalisation 33 retrospective design. observational study time. re-debridement rate. small sample size. reconstruction rate. treatment strategy of fournier’s gangrenemichalczyk et al. unclassified 331 tween the extent of resection and use of hbot combined with npwt. the study limitations were a low availability of hbot and a hospitalization time. conclusions hbot and npwt (group 1) showed advanced wound healing with a high efficiency rate. specialists should consider implementing these treatment strategies in their practices to manage difficult wounds as either separate or combined strategies. the longer median hospitalisation time in this group may be related to the severity of injury. conflict of interest there is no conflict of interest. references 1. ming-chan h, chia-lin c, li-chin c, et al. the role of hyperbaric oxygen therapy in treating extensive fournier's gangrene. urol. sci. 2016; 27: 148-53. 2. schneidewind l, anheuser p, schönburg s, wagenlehner fme, kranz j. hyperbaric oxygenation in the treatment of fournier’s gangrene: a systematic review. urol. int. 2021; 105: 247-56. 3. krishna gowtham v, vaishnavi a, bhargav narendra j. case report on fournier’s gangrene. world journal of current med. and pharm. research 2020; 2: 191-3. 4. wilkinson d, doolette d. hyperbaric oxygen treatment and survival from necrotizing soft tissue infection. arch. surg. 2004; 139: 1339– 45. 5. kirby j. hyperbaric oxygen therapy and negative pressure as advanced wound management. mo med. 2019;116:192-4. 6. hong ks, yi hj, lee ra, kim kh, chung ss. prognostic factors and treatment outcomes for patients with fournier’s gangrene: a retrospective study. int. wound j. 2017;14:1352–8. 7. unalp hr, kamer e, derici h, et al. fournier’s gangrene: evaluation of 68 patients and analysis of prognostic variables. j postgrad. med. 2008;54:102-5. 8. li c, zhou x, liu lf, qi f, chen jb, zu xb. hyperbaric oxygen therapy as an adjuvant therapy for comprehensive treatment of fournier's gangrene. urol. int. 2015; 94: 4538. 9. tutino r, colli f, rizzo g, et al. which role of hyperbaric oxygen therapy in the treatment of fournier’s gangrene? a retrospective study. research square 2020: 1-15. 10. assenza m, cozza v, sacco e, et al. vac (vacuum assisted closure) treatment in fournier’s gangrene: personal experience and literature review. clin. ter. 2011;162:e1-5. 11. cuccia g, mucciardi g, morgia g, et al. vacuum-assisted closure for the treatment of fournier’s gangrene. urol. int. 2009;82:42631. 12. bali zu, akdeniz cb, müezzinoğlu t, üçer o, kara e. comparison of standard open wound care and vacuum-assisted closure therapy in fournier’s gangrene. j urol. surg. 2020;7:42-5. treatment strategy of fournier’s gangrenemichalczyk et al. vol 19 no 4 july-august 2022 332 unclassified a modified disposable circumcision suture device with application of plastic sheet to avoid severe bleeding after circumcision miao li1, xiaojie ang1, weiguo chen1, nianxin gai1, jiangnan xu1, jiawei you1*, yuhua huang1*, jianquan hou1* purpose: to evaluate the effectiveness of a modified disposable circumcision suture device (dcsd) with application of plastic sheet to avoid severe bleeding after circumcision and compare the surgical effects and other postoperative complications of two dcsds. materials and methods: a total of 943 excess foreskin patients from january 2018 to january 2020 who underwent circumcision using two different dcsds were recruited. preoperative characteristics (patient age, height and weight), main surgical outcomes (surgical time, intraoperative blood loss, incision healing time) and postoperative complications (postoperative hemorrhage and hematoma rate, edema rate, incision infection rate, residual staples rate) were collected and analyzed. patients' "satisfaction" or "dissatisfaction" was also investigated. results: preoperative characteristics showed no significant statistical difference. the modified dcsd group has a lower intraoperative bleeding, postoperative hemorrhage or hematoma rate and residual staples rate compared with the conventional group. incision healing time and incision infection rate between the two groups were similar. nevertheless, conventional group has a shorter surgical time, a lower edema rate and a higher satisfaction rate. conclusion: the modified dcsd with application of plastic sheet can avoid severe bleeding after circumcision effectively and can be served as a new choice for circumcision. keywords: circumcision; disposable circumcision suture device; excess foreskin; hemorrhage; modified introduction redundant prepuce and phimosis are common an-drology diseases. it can cause inflammation of the glans, dysuresia, carcinoma of penis, and premature ejaculation.(1) circumcision is the most effective method for treatment of prepuce and phimosis. it's also an effective prevention of sexually transmitted diseases such as hiv and papillomavirus infection.(2,3) methods for circumcision have been developed rapidly, from conventional circumcision, sleeve circumcision, to shang ring circumcision, ali's clamp technique.(4,5) in recent years, a novel disposable circumcision suture device (dcsd) has been favored by numbers of urologists due to its advantages of shorter operation duration, less blood loss and better cosmetic appearance.(6) however, some complications of dcsd have also been reported.(7) since the wound is sutured by staples, rather than traditional surgical suture, the most common and serious complication is postoperative hemorrhage and hematoma. most of the time, patients need an urgent pressure dressing or require a surgical intervention for evacuation of hematoma and suture hemostasis. it makes a huge impact on patients, both physically and psychologically. here, we introduce a modified disposable circumcision suture device with application of a plastic sheet and compare the surgical effects and postoperative complications of two dcsds. 1department of urology, the first affiliated hospital of soochow university, suzhou, jiangsu, china. *correspondence: department of urology, the first affiliated hospital of soochow university, 188 shizi road, suzhou 215006, people's republic of china. tel: +8618906210606; e-mail: urologistlee@163.com; received august 2021 & accepted january 2022 materials and methods study population our study is approved by our institutional review board (clinical trial identifier: 323) and all the patients were given anonymity and informed consent. the data was collected from january 2018 to january 2020. patients underwent circumcision with two different disposable circumcision suture devices. type a (langhe circumcision suture) is the conventional disposable circumcision suture device without plastic sheet (figure 1a, c, e); type b (huang circumcision suture) has a modified plastic sheet before the staple reservoir and after triggering the device, the plastic sheet is fixed on the wound (figure 1b, d, f). the choice of dcsd followed patients' preference and they were not informed of the advantages or disadvantages of the two dcsds. before the surgery, the informed consent was signed. in order to help the bell-like inner pole insert into the ostium praeputiale, phimosis patients need an incision of the foreskin, which affects the quantification of blood loss. so, phimosis patients were excluded. patients with systemic hematological diseases were also excluded. for the patients suffering from infection of glans penis, circumcision must be performed after infection was controlled. operative procedures all the surgeries were performed by the same surgeon. urology journal/vol 19 no. 2/ march-april 2022/ pp. 152-156. [doi: 10.22037/uj.v18i.6977] vol 19 no 2 march-april 2022 153 first, the surgical area was fully disinfected and a local dorsal penile nerve block was performed. dcsd mainly consists of an outer pole, a bell-like inner rod, an adjusting knob and suture staple, (figure 1a, b, c). the modified dcsd has a plastic sheet before the staple reservoir (figure 1d). devices of different sizes were designed to fit different penis sizes. circumcision using dcsd approach was performed as jingen wang et al. described.(8) briefly, we inserted the bell-like inner rod into the ostium praeputiale at first. and then, we fixed the foreskin onto the rod, and inserted the end of the rod into the outer pole. after adjusting the cutting position, dcsd was triggered. the redundant foreskin was removed and the staples were sutured at the incision at the same time. the frenulum was retained when circumcision was performed. differently, type a dcsd has no plastic sheet, and the staples were placed at the incision directly (figure 1e). type b dcsd has a modified plastic sheet, and the staples were placed at the plastic sheet before being fastened on the wound (figure 1f). and this modified plastic sheet could apply pressure to prevent bleeding from the wound. all patients in the two groups were dressed with a self-adhesive flexible bandage and prescribed oral antibiotics for 3 days. the pressure bandage should keep dry and clean, and it was removed 3 days after surgery. after that, the wound was cleaned every day until all the staples dropped out and the follow-up lasted 1 month at least until the incision was completely healing. circumcision group conventional group (n = 552) modified group (n = 391) p-value age, years; 28.1 ± 11.4 26.9 ± 10.8 .095 bmi, kg/m2; 23.73 ± 1.37 23.56 ± 1.26 .052 surgical time, min; 5.2 ± 1.0 7.7 ± 1.4 < .001* intraoperative bleeding, ml; 4.6 ± 0.9 2.3 ± 1.2 < .001* postoperative hemorrhage and hematoma rate 13/552 (2.4%) 2/391 (0.5%) .026* incision healing time, day; 7.9 ±1.2 8.1 ±1.1 .062 edema rate 247/552 (44.7%) 208/391 (53.2%) .011* incision infection rate 93/552 (16.8%) 77/391 (19.7%) .263 residual staples rate 109/552 (19.7%) 17/391 (4.3%) < .001* satisfaction rate 536/552 (97.1%) 344/391 (88.0%) < .001* table 1. comparison of operative and postoperative characteristics between the two groups. abbreviations: bmi, body mass index; * statistical difference. values are mean ± sd. figure 1. structural composition and postoperative appearance of two dcsds. a and b structural composition of dcsd ① bell-like inner rod ② outer pole ③ adjusting knob ④ safety-cap. c suture staple of the conventional dcsd. d plastic sheet before the staple reservoir of the modified dcsd. e postoperative appearance of the conventional dcsd. f postoperative appearance of the modified dcsd a modified dcsd to avoid severe bleeding -li et al. unclassified 154 evaluations 1. preoperative characteristics of the patients were collected, including patient age, height and weight, and body mass index (bmi) was calculated. 2. surgical time: it's the operation duration from the initiation to the end of operation. 3. intraoperative bleeding: it's estimated by 5cm × 5cm gauzes which could suck 3.25ml blood.(9) 4. postoperative hemorrhage and hematoma rate: patients with active bleeding or progressively larger hematoma (figure 2c.d). 5. incision healing time: when the wound healed completely, healing time was recorded. 6. edema rate: patients developed edema when pressure bandage was removed (figure 2a.b). 7. incision infection rate: incision with exudation or secretion of tissue fluid and would not heal. 8. residual staples rate: patients who come back to remove the residual staples 1 month after surgery. 9. satisfaction rate: patients' "satisfaction" or "dissatisfaction" with their cosmetic penis appearances and the whole recovery process. statistical analysis spss version 20.0 was used for statistical analyses. numerical data were presented as mean ± standard deviation (sd) and compared by independent t test. normality and homogeneity of variance were assessed before independent t test. wilcoxon rank sum test was used for data with non-normal distributions. categorical data were presented as frequencies and percentages and compared by chi-square test or fisher’s exact test. p < .05 was considered statistically significant. results there were total 943 patients with excess foreskin enrolled in our study. 552 patients chose type a (langhe circumcision suture) dcsd for circumcision, and here we defined it as the "conventional group". on the other hand, 391 patients chose type b (huang circumcision suture) dcsd, and we defined it as the "modified group". the patients' age and bmi between the two groups showed no significant statistical difference (p = .095 and .052 respectively). surgical time in the conventional group was significantly shorter than that in the modified group (p < .001). however, intraoperative blood loss in the conventional group was higher than that in the modified group (p < .001). at the follow-up, in modified group, postoperative hematoma occurred in only two patients. one patient's hematoma occurred after 3 days from the pressure bandage was removed. another one occurred after strenuous exercise. in the conventional group, postoperative hemorrhage and hematoma occurred in 13 patients, which showed a significantly higher rate than modified group (2.4% versus 0.5%, p = .026). figure 2c.d were representative postoperative hematoma and hemorrhage patients. incision healing time and incision infection rate between the two groups showed no significant statistical difference (p = .062 and p = .263 respectively). after patients' pressure bandage was removed, edema rate was calculated. we found that in the modified group, edema rate was significantly higher than conventional group (53.2% versus 44.7%, p = .011). figure 2a.b were representative edema patient in two groups. at 1-month visit, most patients experienced spontaneous removal of wound staples. residual staples rate in conventional group and modified group were 19.7% and 4.3% (p < .001) respectively. interestingly, satisfaction figure 2. a representative edema of the modified dcsd. b representative edema of the conventional dcsd. c a postoperative hematoma case of the conventional dcsd. d a postoperative hemorrhage case of the conventional dcsd. a modified dcsd to avoid severe bleeding -li et al. vol 19 no 2 march-april 2022 100 rate in modified group was lower than conventional group (88.0% versus 97.1%, p < .001) despite its lower intraoperative bleeding, postoperative hemorrhage and hematoma rate. all the detailed data was shown in table 1. discussion although circumcision is an effective method in preventing sexually transmitted diseases and curing refractory balanitis, many people underwent circumcision just on account of religious obligation.(10,11) postoperative complications may be an important factor preventing people from circumcision. in some western countries, iatrogenic phimosis was reported as a common complication after circumcision with thermocautery.(12) in south africa, where hiv infection rates are high, voluntary medical male circumcision remains suboptimal, with safety concerns identified as a barrier to uptake.(13) on account of this, new safe and efficient circumcision devices are urgently needed which might promote the prevalence of voluntary medical male circumcision. in recent years, with the development of minimally invasive surgery and improvement of people's perception of circumcision's importance, acceptability for circumcision is gradually increasing in china. a novel type of dcsd was widely used by urologists in china these years.(14) it has also been reported in the west and is loved by many doctors thanks to its advantages of shorter operation duration, less blood loss and better cosmetic appearance.(15) however, some problems of dcsd were reported. for example, patients with severe phimosis need to cut the prepuce which undoubtedly increases the risk of intraoperative bleeding.(16) there is a risk of hemorrhage for patients operated with dcsd, since the wound was stapled together instead of suture. postoperative hemorrhage and hematoma may be the most common and serious complication.(17) it makes huge impact on patients, both physically and psychologically. so, many urologists are searching for a modified method to reduce bleeding.(18) in our department, another modified dcsd was used recently. this new dcsd has a modified plastic sheet. it can exert a pressure on the wound while the staples are used to fix the wound. in our study, we compared the surgical effects and postoperative complications of two dcsds. the patients' age and bmi between the two groups showed no significant statistical difference, excluding the effects of age and bmi on this study. we found that the modified group had a lower intraoperative blood loss and postoperative hemorrhage or hematoma rate (p < .001and p = .026 respectively), mainly thanks to the compression of the plastic sheet on the wound as mentioned before. on the contrary, conventional dcsd has no plastic sheet and the staples fix the incision wound directly. occasionally, some vessels between the fixed staples might cause subsequent bleeding or hematoma. at the same time, incision healing time and incision infection rate between the two groups showed no significant statistical difference (p = .062 and p = .263 respectively), indicating that this plastic sheet wouldn't affect wound healing or lead to incision infection. however, patients undergoing circumcision with modified dcsd were characterized by a higher edema rate than conventional group (p = .011). it's attributed to that the compression of the plastic sheet on the wound can cause impairment of lymphatic reflux. however, the edema can be controlled effectively when appropriate decongestant medications are used. we can also cut plastic sheet every two or three staples with scissors when the bandage is removed. and at that time, the wound is almost healed and postoperative hemorrhage or hematoma would scarcely occur. at 1-month visit, we compared the residual staples rate between the two groups. we found that the conventional group's residual staples rate was significantly higher than that of the modified group. we believe that the staples were sutured at the incision directly in the conventional group and some staples were embedded tightly in tissue or scar. it's difficult for these staples to drop out spontaneously and patients had to come back to hospital to remove the residual staples. at last, the patients' satisfaction rate was compared between two groups. despite modified group's lower intraoperative bleeding, postoperative hemorrhage and hematoma rate, patients in conventional group seemed to be more satisfied with their cosmetic penis appearances and experience in the recovery process. most unsatisfied patients in modified group complained about the edema, since the edema could be observed directly and it caused their discomfort and worry for a long time. nevertheless, there are several limitations within the present study. first, all the operations were performed on outpatients, and patients went back home after observation of 30-60min. different nursing care in different families might affect the outcome of surgery. this provided a potential confounding bias of the present investigation. second, though bmi between the two groups were comparable, difference in bmi between the patients with hemorrhage and the patients without hemorrhage was not investigated. in terms of this issue, we will carry out further research in future study. conclusions our study introduces a modified dcsd widely used in china recently with application of a plastic sheet. it has advantages of lower intraoperative bleeding, postoperative hemorrhage or hematoma rate and residual staples rate. furthermore, it won't affect incision healing time and incision infection rate. nevertheless, we should care about patients who used this modified dcsd, for its higher edema rate. acknowledgement the present study was supported by the national natural scientific foundation of china grants (nos. 81772708). conflict of interest the authors report no conflict of interest. references 1. zhang sj, zhao ym, zheng sg, xiao hw, he ys. correlation between premature ejaculation and redundant prepuce. zhonghua nan ke xue. 2006;12:225-7. 2. sharma al, hokello j, tyagi m. circumcision as an intervening strategy against hiv acquisition in the male genital tract. pathogens. 2021;10. 3. smith js, backes dm, hudgens mg, et al. male circumcision reduces penile hpv incidence and persistence: a randomized a modified dcsd to avoid severe bleeding -li et al. vol 19 no 2 march-april 2022 155 unclassified 156 controlled trial in kenya. cancer epidemiol biomarkers prev. 2021;30:1139-48. 4. mu j, fan l, liu d, zhu d. a comparative study on the efficacy of four types of circumcision for elderly males with redundant prepuce. urol j. 2020;17:301-5. 5. senel fm, demirelli m, oztek s. minimally invasive circumcision with a novel plastic clamp technique: a review of 7,500 cases. pediatr surg int. 2010;26:739-45. 6. huo zc, liu g, li xy, et al. use of a disposable circumcision suture device versus conventional circumcision: a systematic review and meta-analysis. asian j androl. 2017;19:362-7. 7. huang c, song p, xu c, wang r, wei l, zhao x. comparative efficacy and safety of different circumcisions for patients with redundant prepuce or phimosis: a network meta-analysis. int j surg. 2017;43:17-25. 8. wang j, zhou y, xia s, et al. safety and efficacy of a novel disposable circumcision device: a pilot randomized controlled clinical trial at 2 centers. med sci monit. 2014;20:45462. 9. hughes k, chang yc, sedrak j, torres a. a clinically practical way to estimate surgical blood loss. dermatol online j. 2007;13:17. 10. gao y, yuan t, zhan y, et al. association between medical male circumcision and hiv risk compensation among heterosexual men: a systematic review and meta-analysis. lancet glob health. 2021;9:e932-e41. 11. dogan g. the effect of religious beliefs on the publication productivity of countries in circumcision: a comprehensive bibliometric view. j relig health. 2020;59:1126-36. 12. akyuz o, cam k. the management of phimosis seen after circumcision with thermocautery. urol j. 2020;17:50-4. 13. muchiri e, charalambous s, ginindza s, et al. description of adverse events among adult men following voluntary medical male circumcision: findings from a circumcision programme in two provinces of south africa. plos one. 2021;16:e0253960. 14. rao jm, huang h, chen t, et al. modified circumcision using the disposable circumcision suture device in children: a randomized controlled trial. urology. 2020;143:206-11. 15. pozza d, pozza c, mosca a, pozza m. preputial circumcision performed with a new mechanical stapling tool. the "langhe disposable circumcision suture device". preliminary experiences. arch ital urol androl. 2020;91:261-2. 16. su q, gao s, chen j, et al. a comparative study on the clinical efficacy of modified circumcision and two other types of circumcision. urol j. 2020;18:556-60. 17. hinkle le, toledo c, grund jm, et al. bleeding and blood disorders in clients of voluntary medical male circumcision for hiv prevention eastern and southern africa, 2015-2016. mmwr morb mortal wkly rep. 2018;67:337-9. 18. jiang w, fu jl, guo wl, et al. a modified pressure dressing to avoid severe bleeding after circumcision with a disposable circumcision suture device and a discussion on the mechanism of bleeding with the disposable circumcision suture device. sex med. 2021;9:100288. a modified dcsd to avoid severe bleeding -li et al. v07_no_4.pdf case report 278 urology journal vol 7 no 4 autumn 2010 percutaneous drainage for treatment of prostate abscess abbas basiri, ahmad javaherforooshzadeh urol j. 2010;7:278-80. www.uj.unrc.ir keywords: prostate, abscess, drainage, prostatic diseases urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran corresponding author: abbas basiri, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir received june 2010 accepted july 2010 introduction prostate abscess is a rare infection and can be treated by antibiotic administration and drainage.(1) the reported mortality rate of the prostate abscess is between 3% and 16%.(1,2) in patients refractory to medical treatment, surgical interventions are advocated. we report a patient with the prostate abscess who was treated with percutaneous drainage. case report a 67-year-old man with obstructive urinary symptoms and prostatespecific antigen level of 8.9 ng/ml underwent transperineal prostate biopsy. three days later, the patient addressed herself to the emergency ward with fever, chills, and poor general condition. on physical examination, his blood pressure, pulse rate, and temperature were 130/80 mmhg, 105 per minute, and 39°c, respectively. in rectal examination, the patient had a huge enlarged prostate with a prominent left lobe. urine and blood cultures, prior to starting the antibiotic therapy, both exhibited escherichia coli. transabdominal ultrasonography of the prostate showed a hypoechoic mass with abundant debris in the left prostatic lobe. computed tomography (ct) scan revealed a 5 × 8-cm homogenous mass with a low density on the same region of the prostate (figure 1). the patient received vancomycin, metronidazole, and ceftazidime intravenously. thereafter, he underwent percutaneous drainage because of unresponsiveness to medical therapy. prostate abscess was drained transperineally using transrectal ultrasonography (trus) guidance (figure 2) and figure 1. computed tomography scan shows a homogenous mass with low density in the left prostatic lobe. prostate abscess—basiri and javaherforooshzadeh 279urology journal vol 7 no 4 autumn 2010 a suprapubic cystostomy was created. a pigtail catheter was inserted into the abscess and irrigation was done twice a day using saline and antibiotics. on the 5th day, after discontinuing pus discharge, the pigtail catheter and the cystostomy were removed. one month thereafter, the symptoms were resolved and the abscess diminished in size in the ct scan (figure 3). but the patient referred to our clinic again with obstructive symptoms and medical treatment was started de novo. due to failed medical treatments, open prostatectomy was performed 5 months later. the patient is completely symptom-free now. discussion the prostate abscess is an uncommon disease with the incidence rate of 0.5%.(3) the most common symptoms of the disease are dysuria, frequency, perineal pain, fever, chills, and low back pain.(4,5) it mostly occurs in the 5th and 6th decades of life and the most common organism is staphylococcus aureus.(1-2,6) transrectal ultrasonography is the most common diagnostic method of the prostate abscess and is a good guide for aspiration, percutaneous drainage, and assessment of the response to the treatment.(1,7-9) in a study on 9 patients with the prostate abscess who had undergone perineal drainage and catheter insertion to remove the discharge without irrigation, two patients experienced the recurrence of the abscess in 1-month follow-up and underwent antibiotic therapy and drainage again.(2) in another study, 6 patients with the prostate abscess underwent perineal aspiration using trus, and one patient experienced recurrence of the abscess, who underwent transurethral resection of the prostate.(7) in our patient, drainage was performed transperineally under local anesthesia with the guide of trus using a stent for 5 days and washing with normal saline and antibiotics. in the 3-year follow-up with ct and trus, no recurrence was observed. therefore, this method can be proposed as a less invasive and less morbid method for the treatment of the prostate abscess. however, further studies are required in this regard. conflict of interest none declared. references 1. ludwig m, schroeder-printzen i, schiefer hg, weidner w. diagnosis and therapeutic management of 18 patients with prostatic abscess. urology. 1999;53: 340-5. 2. granados ea, caffaratti j, farina l, hocsman h. prostatic abscess drainage: clinical-sonography correlation. urol int. 1992;48:358-61. 3. granados ea, riley g, salvador j, vincente j. prostatic abscess: diagnosis and treatment. j urol. 1992;148:80-2. figure 2. transrectal ultrasonography, arrow demonstrates the needle. figure 3. arrow demonstrates pigtail catheter inserted into the prostate. prostate abscess—basiri and javaherforooshzadeh 280 urology journal vol 7 no 4 autumn 2010 4. savarirayan s, shenykin y, gerard p, wise gj. staphylococcus periprostatic abscess: an unusual cause of acute urinary retention. urology. 1995;46:573-4. 5. bachor r, gottfried hw, hautmann r. minimal invasive therapy of prostatic abscess by transrectal ultrasound-guided perineal drainage. eur urol. 1995;28:320-4. 6. meares em, jr. prostatic abscess. j urol. 1986;136:1281-2. 7. collado a, palou j, garcia-penit j, salvador j, de la torre p, vicente j. ultrasound-guided needle aspiration in prostatic abscess. urology. 1999;53: 548-52. 8. lim jw, ko yt, lee dh, et al. treatment of prostatic abscess: value of transrectal ultrasonographically guided needle aspiration. j ultrasound med. 2000;19:609-17. 9. barozzi l, pavlica p, menchi i, de matteis m, canepari m. prostatic abscess: diagnosis and treatment. ajr am j roentgenol. 1998;170:753-7. running title: perioperative outcomes of concomitant holep and inguinal hernioplasty perioperative outcomes of inguinal hernioplasty along with holmium laser enucleation of the prostate (holep) authors: carlos ignacio calvo de la barraa email: cicalvo@uc.cl juan cristóbal bravo izurietaa email: jcbravo1@uc.cl renato navarro caponea email: rinavarro@uc.cl rodrigo cañas ramirezb email: rcanas1@uc.cl felipe pastén alcaínob email: fgpasten@uc.cl ignacio san francisco reyesa sanfranciscoignacio@gmail.com (corresponding author) (a) departamento de urología, pontificia universidad católica de chile. (b) escuela de medicina, pontificia universidad católica de chile. corresponding author: dr. ignacio san francisco reyes email: sanfraciscoignacio@gmail.com address: san francisco de asis, ma, 35, las condes, rm, chile phone: +56979961781 key words: benign prostatic hyperplasia; complications; herniorraphy; holmium; prostatectomy. abstract purpose: inguinal hernias and benign prostatic hyperplasia (bph) can coexist in about one fifth of patients undergoing bph surgery. there is scarce evidence about performing laser enucleation along with open inguinal hernia repair. our goal is to describe the perioperative outcomes of performing both surgeries in the same operating session compared to doing holep alone. materials and methods: a retrospective analysis of patients undergoing holep and hernioplasty with mesh in the same anesthetic time (group b) at an academic center was conducted. they were compared to a randomly picked control group of patients submitted to holep alone (group a). preoperative, operative and postoperative features were compared among both groups. results: 107 patients submitted to holep alone were compared to 29 combined approach patients (holep + hernia repair). patients in group a were found to be older and had larger prostates. group b showed a significant longer operative time. length of stay and duration of catheter was comparable among groups. in multivariate analysis, the combined approach was not associated to a higher complication rate. conclusions: performing benign prostatic hyperplasia surgery with holep in conjunction with open inguinal hernioplasty is not related to a higher length of stay or a significantly increased risk of morbidity. introduction benign prostatic hyperplasia (bph) and inguinal hernia are common pathologies, both of which increase their frequency in the elderly subjects.(1) given the global population aging, encountering both entities in the same patient is fairly common. moreover, traditional literature estimates the prevalence of inguinal hernias in patients undergoing surgery for bph to be around 15-25 %.(2) several case series have reported both open simple prostatectomy and transurethral resection of the prostate (tur-p) conducted along with inguinal hernia repair, these reports have shown acceptable morbidity rates.(3) also, the advent of new technologies has improved long-term outcomes and has decreased morbidity from endoscopic prostate surgery. holmium laser enucleation (holep) has become the gold standard treatment for large adenomas and has relevant hemostatic advantages over traditional tur-p.(4,5) there is a lack of literature reporting the execution of holep in conjunction with inguinal hernioplasty. this investigation aims to show a university hospital experience in the concomitant performance of holep and inguinal hernioplasty, with a focus on perioperative morbidity. we postulated that both procedures can be carried out with a comparable morbidity and thus could be considered an eventual standard in the surgical management of this type of patients. materials and methods a retrospective study was conducted including patients who underwent surgery for bph alongside unilateral inguinal hernia surgery between 2008 and 2020 at an academic hospital in chile. inclusion criteria comprise all patients who underwent bph surgery in the form of holep and a concomitant open hernia repair(group a), this was compared to a random control group of patients who underwent holep alone. roughly a 1:3 proportion (holep + hernia: holep) was achieved. patients with other surgical techniques for bph or laparoscopic hernia repair were excluded.. data was collected from the institutional electronic records, with the approval of the ethical review board. pre-surgical variables were collected such as age, the presence of hypertension / diabetes, asa score, and the use of anticoagulation or antiplatelet therapy. perioperative variables included surgical time, blood transfusion rate, grams of resected tissue, length of stay, days of catheterization, etc. finally, a thorough search for complications and readmissions in the first 30 days after surgery was performed; these were classified by clavien-dindo. medical complications and the ones related to the bph surgery were counted, whereas complication inherent to hernia repair like hematoma were not, with the purpose of making a fair comparison. following institutional protocols, all patients were asked to suspend clopidogrel at least five days before surgery and to keep aspirin in case of high thromboembolic risk. patients on coumarins or novel anticoagulants were asked to stop them for 72 hours prior surgery. time for restart of anticoagulation was dependent on surgeon’s discretion. they were asked to have a negative urine culture prior to the intervention. surgeries were conducted under general anesthesia; hernia repair was carried out firstly, using the lichtenstein technique with a prolene mesh. after that, enucleation was carried out using a storz® laser resectoscope, and a 550 um holmium laser fiber (lumenis pulse 120h ®) set at 1.5-2 j and 35-45 hz. a piranha® (wolf) morcelator was utilized for extraction. a 22 fr dufour catheter with bladder irrigation was installed upon the end of the surgery. depending on hematuria and treating urologist criteria, the catheter was removed on postoperative day 1 or 2, unless the patient was assessed to be at a higher risk for a failed trial of void, in which case patients were discharged with the catheter for an in-office trial of void. significant hematuria was defined as either the necessity of bed-side clot evacuation or hematuria that lengthened hospital stay for more than two days due to irrigation requirement. this complication was classified as clavien-dindo grade i unless the patient required revision in the operating room. all variables were compared between both groups. categorical variables were analyzed with chi-square test and continuous variables with mann whitney u test (non-parametric). multivariate analysis was performed with binary logistic regression. statistical analysis was conducted with ibm spss statistics v25 (armonk, ny: ibm corp) and significance was set at p<0.05. results by january 2021, 758 holep had been carried out in our center. one hundred and thirtysix patients were included in this research: 107 in group a (holep) and 29 in group b (holep+hernia repair). preoperative characteristics are described in table 1. patients in group a were found to be older (p: <0.01) compared to those submitted to a combined surgery, also they had greater prostate size (p: <0.01), a higher rate of diabetes (p: .03), and more patients had an indwelling catheter prior surgery (p: .04). perisurgical outcomes are depicted in table 2. there was a significant difference in surgical time (p: <0.01), adding roughly 1.5 hours for patients undergoing both surgeries. the resected prostate tissue was larger in group a (p: <0.01). despite these differences, the length of stay and the days of postoperative indwelling catheter were comparable. regarding postoperative results (table 3), a higher rate of complication was observed in group b which was not statistically significant (20.7% vs 13.1%, p: .14). there were no differences in transfusion requirement (p: .27), readmissions at 30 days (p: .19), urinary tract infection (p: .29), significant hematuria (p: .63), length of stay (p: .47) and postoperative days with indwelling catheter (p .36). there were no complications clavien-dindo iii or greater in either group. in order to assess the risk for more complications that the combined surgery could impose, a multivariate analysis was performed (table: 4). adjusting for age and operative time the combined approach did not seem to impose a significant higher risk. discussion benign prostatic hyperplasia is a common condition that affects about 80% of men over their 70s. (6) enucleation of the prostate has become a widespread option for the treatment of any gland size. for many, holep is considered the gold standard treatment of prostates over 80 grams.(7) additionally, inguinal hernias are a fairly common problem which is present in 5-10% of the global population, making hernioplasty one of the most frequent procedures performed worldwide.(8,9) even though the coexistence of these pathologies is not rare, especially in the setting of an aging population, is it still unclear whether their joint occurrence is a fortuitous event or they have a causeeffect relationship. (10). previous literature has shown no greater morbidity associated with performing inguinal hernioplasty alongside with a tur-p surgery, even taking into account the risk of mesh infection, which seems negligible in some reports. (11,12) in the last decade there has been a lack of publications regarding the combination of hernioplasty with newer technologies to treat bph. to our knowledge, this report might be the first one to compare the surgical results and morbidity of patients who undergo holep and inguinal hernioplasty in the same operating room session. although we lack a formal cost analysis, taking into account our patients' bills, there is at least a 20% reduction in the billing figure when conducting both surgeries in a single session compared to doing them in two different occasions, possibly making it a cost-effective approach. in our center, most urologists have gone through general surgery residency prior to their urology training. this allows the same surgeon to carry out both procedures and avoids the necessity of coordination with another team. thus, a retrospective comparison was made, analyzing 29 patients who underwent both surgeries, and comparing them with 107 holep patients. the results of this report must be looked at over the fact that both groups have some differences. patients who underwent the combined surgery were younger and consequently had a smaller prostate size. additionally, patients in the control group had a higher rate of previous indwelling catheters, which could be a sign of a more advanced stage of their disease. this divergence could be explained by the surgeon's preference to select fitter patients to undergo both procedures. the difference between the operative time of both approaches is mostly secondary to the hernia repair itself and some additional time related to position changing skin preparation, and sterile draping. taking into account this likely selection bias, we could not find that carrying out both procedures leads to more morbidity even after adjusting for confounders variables.. furthermore, adding the second surgery did not affect length of stay nor readmissions, which also could add to cost-efficiency of this approach. one of thelimitations of this research is its retrospective nature, which makes its accuracy dependent on the reported clinical records. as already mentioned, both groups differed on their baseline characteristics. also, even though our center has a broad experience in holep; the number of patients submitted to both procedures is low, which reduces the statistical power of the results. conclusion performing benign prostatic hyperplasia surgery with holep in conjunction with open inguinal hernioplasty is not related to a higher length of stay or a significantly increased risk of morbidity. centers in which this approach is feasible could take this strategy in consideration. references 1. devarajan r, jaganathan rs, harriss dr, chua cb, bishop mc. combined transurethral prostatectomy and inguinal hernia repair: a retrospective audit and literature review. bju int. 1999 oct;84(6):637–9. 2. othman i, abdel-maguid af. combined transurethral prostatectomy and inguinal hernioplasty. hernia j hernias abdom wall surg. 2010 apr;14(2):149–53. 3. johnson ok. simultaneous open preperitoneal repair of inguinal hernia with open prostatectomy for benign prostate hyperplasia. trop doct. 2015 jan;45(1):42–3. 4. cornu jn, ahyai s, bachmann a, de la rosette j, gilling p, gratzke c, et al. a systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. eur urol. 2015 jun;67(6):1066–96. 5. cornu jn, herrmann t, traxer o, matlaga b. prevention and management following complications from endourology procedures. eur urol focus. 2016 apr;2(1):49–59. 6. management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: aua guideline part ii-surgical evaluation and treatment pubmed [internet]. [cited 2022 nov 6]. available from: https://pubmed-ncbi-nlm-nihgov.pucdechile.idm.oclc.org/34384236/ 7. das ak, teplitsky s, humphreys mr. holmium laser enucleation of the prostate (holep): a review and update. can j urol. 2019 aug;26(4 suppl 1):13–9. 8. dabbas n, adams k, pearson k, royle gt. frequency of abdominal wall hernias: is classical teaching out of date? jrsm short rep [internet]. 2011 jan [cited 2022 nov 6];2(1). available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3031184/ 9. miyajima a. inseparable interaction of the prostate and inguinal hernia. int j urol off j jpn urol assoc. 2018 jul;25(7):644–8. 10. sentürk ab, ekici m, sahiner it, tas t, cakiroglu b. relationship between lower urinary tract symptoms and inguinal hernia. arch ital urol androl organo uff soc ital ecogr urol e nefrol. 2016 dec 30;88(4):262–5. 11. cimentepe e, inan a, unsal a, dener c. combined transurethral resection of prostate and inguinal mesh hernioplasty. int j clin pract. 2006 feb;60(2):167–9. 12. gonzález-ojeda a, marquina m, calva j, mendoza a, de la garza l. combined inguinal herniorrhaphy and transurethral prostatectomy. br j surg. 1991 dec;78(12):1443–5. table 1: preoperative characteristics characteristics total (n=136) holep (n=107) holep + hernia (n= 29) pvalue age (years)* 72 (67-77) 72.5 (68-77) 65.5 (58.5-72.5) <0.01 dm 29 (21.3%) 27 (25.25%) 2 (6.9%) .03 hta 73 (53.6%) 56 (52.3%) 17 (59%) .54 asa i ii 25 98 20 (18.7%) 78 (72.9%) 5 (17%) 20 (69%) .85 .67 iii 9 7 (6.5%) 2 (6.9%) .94 use of anti-aggregant 24 (17.6%) 17 (15.8%) 7 (24%) .30 use of anti-coagulant 14 (10.2%) 13 (12.1%) 1 (3%) .17 preoperative psa (ng/dl)* 3.2 (0.8-5.5) 3 (0.7-5.3) 3.8 (1.3-6.3) .53 prostate volume (ml)* 84.5 (62-109) 89.5 (65-117 73.5 (56-88) <0.01 preoperative indwelling catheter 39 (28.67%) 35 (33%) 4 (14%) .04 * median (q1-q3) p-values were calculated with chi-square for categorical variables and u mannwhitney for numeric variables. table 2: perioperative results characteristics total (n=136) holep (n=107) holep + hernia (n= 29) p-value operating time* (min) 120 (100-180) 120 (90180) 217.5 (180-242) <0.01 red blood cell transfusion rate 1 (0.7%) 1 (0.9%) 0 .27 days of postoperative hospitalization* 3 (2-4) 3 (2-4) 3(2-4) .47 resected volume (ml)* 40 (26-60) 43 (30-64) 26 (16-41) <0.01 discharged with catheter 26 (19.1%) 24(22.4%) 2 (7%) .06 days of postoperative catheterization* 3 (2-4) 3 (2-4) 3 (2-3) .36 *median (q1-q3) p-values were calculated with chi-square for categorical variables and u mannwhitney for numeric variables. table 3: comparison of 30-day complication rate results total (n=136) holep (n=107) holep + hernia (n= 29) p-value complication rate 20 (14.7%) 14 (13.1%) 6 (20.7%) .30 complication ≥ iii 0 0 0 detail according to grade: grade i-delirium hematuria -arrhythmia -polyuriagrade ii uti 3 (2.2%) 7 (5.1%) 1 (0.7%) 1 (0.7%) 12 (8.8%) 3 (2.8%) 5 (4.6%) 0 1 (0.9%) 8 (7.4%) 0 2 (6.8%) 1 (3.4%) 0 4 (13.7%) .36 .63 .05 .60 .29 30-day re-admission 6 (4.4%) 6 (5.6%) 0 .19 table 4; multivariate analysis of predictors for 30-day complications. variable or 95% ci p-value surgery holep holep+hernia ref. 2.9 0.6-14 0.18 age (years) 1.06 0.98-1.14 0.10 operative time (min) 0.99 0.99-1.00 0.84 v08_no_1_print_3.pdf reconstructive surgery 48 urology journal vol 8 no 1 winter 2011 dorsal versus ventral oral mucosal graft urethroplasty jalil hosseini, ali kaviani, mokhtar hosseini, mohammad mohsen mazloomfard, abdollah razi purpose: to evaluate success rate of dorsal versus ventral oral mucosal graft for anterior urethroplasty. materials and methods: in a retrospective study, the results of the ventral and dorsal oral mucosal graft (omg) anterior urethroplasty were assessed in 24 and 29 patients, respectively. demographic and clinical characteristics of subjects were gathered from the medical records. results: patients were followed up for a mean duration of 32 months (range, 25 to 51 months). the success rates of dorsal and ventral anterior omg urethroplasty were 83.3% and 75.8%, respectively (p = .5). at penile site, dorsal and ventral omg were done for 9 and 10 patients with stricture lengths of 3.7 ± 1.1 cm and 3.9 ± 1.2 cm, respectively (p = .7). success rates of dorsal and ventral penile omg were 88.9% and 70%, respectively (p = .3). at the bulbar site, dorsal and ventral omg were performed on 15 and 19 patients with stricture lengths of 4.1 ± 1.1cm and 4.2 ± 1.5 cm, respectively (p = .7). the success rates of dorsal and ventral bulbar omg were 80% and 79%, respectively (p = .94). conclusion: oral mucosal graft is a versatile and an effective procedure for management of strictures throughout the anterior urethra, and in experienced hands, the outcomes are similarly favorable whether a dorsal or ventral approach is taken. urol j. 2011;8:48-53. www.uj.unrc.ir keywords: mouth mucosa, transplantation, urethral stricture, reconstructive surgical procedures, postoperative complications infertility and reproductive health research center, department of reconstructive urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran corresponding author: jalil hosseini, md infertility and reproductive health research center, department of reconstructive urology, shohadae-tajrish hospital, shahid beheshti university of medical sciences, tehran, iran tel: +98 21 2243 2558 fax: +98 21 2203 8462 e-mail: jhosseinee@gmail.com received august 2009 accepted may 2010 introduction the urethra is divided into anterior and posterior (membranous and prostatic) parts. the anterior part is surrounded by the corpus spongiosum, and includes two segments; the bulbar urethra, which is surrounded by the bulbospongiosus muscle, and the penile urethra that runs from the distal margin of the bulbospongiosus muscle to the fossa navicularis and external meatus.(1) each of these areas is prone to strictures of its own particular type. urethral stricture is a complicated disease representing a therapeutic challenge.(2) buccal mucosal grafting (bmg) has gained widespread acceptance for urethroplasty of both urethral stricture and hypospadias repair during the past 10 years.(3) initial success with the oral mucosal graft (omg) to repair anterior urethral strictures has been noticeable.(4-7) however, follow-up in most series is short and techniques vary with series reporting ventral and dorsal onlay grafts. (4,6) in this retrospective study, we report the long-term follow-up of the ventrally and dorsally placed oral mucosal onlay graft in the anterior urethral reconstruction. oral mucosal graft urethroplasty—hosseini et al 49urology journal vol 8 no 1 winter 2011 materials and methods a total of 53 patients with anterior urethral (penile or bulbar) stricture longer than 3 cm underwent omg urethroplasty between january 2000 and january 2006. the results were obtained from medical records. the etiologies of the strictures were trauma in 9, infection in 9, iatrogenic in 8, failed hypospadias in 7, and unknown etiologies in 20 patients. patients with lichen sclerosus, previous failed open urethroplasty, unwillingness to participate, and who needed complicated surgeries were excluded from the study. all of the operations have been done by the same surgical team. anterior urethroplasty has been performed using two methods: ventral and dorsal omg groups. according to the location of the urethral stricture, ventral and dorsal omg were further categorized to penile and bulbar segments. surgical technique after providing nasal tube general anesthesia, oral mucosa was harvested from the inner side of the patient’s cheek. graft bed was sutured using 4-0 plain sutures. after trimming the graft and removing any remaining fat, buccal graft was used for urethroplasty (figure 1). urethral plate preparations were performed by delicate dissection of the penile or bulbar urethra from surrounding tissue followed by an adopted technique, which provided a ventral or dorsal cut with appropriate calibration of the distal and proximal urethral lumen. in ventral bmg technique, graft was sutured to the urethral plate using 5-0 vicryl sutures. thereafter, the graft was covered by dartos fascia in the penile group or spongiosum tissue in the bulbar group (figure 2). in dorsal omg technique, the graft was put and sutured to cavernous bed and after that, graft was sutured to margin of the opened urethra using 5-0 vicryl sutures (figure 3). all the patients had urethral catheter for 14 days after the surgery. the patients were put on regular follow-up at 3, 6, 12, 18, and 24-month clinical visits, and urethrocystoscopy was performed at 6 and 18 months postoperatively. if patients had any recent voiding problems, they underwent immediate cystoscopy. demographic characteristics, stricture length based on intra-operative measurement, etiology of urethral stricture, success rate, and complications of both ventral and dorsal omg were compared between two groups. the clinical outcome was considered a failure if any postoperative procedure was needed, including dilation. data were analyzed using spss (statistical package for the social sciences, version 14.0, spss inc., chicago, illinois, usa) software. mann-whitney, chi-square, and fisher’s exact tests were performed, if appropriate, with a significance level set at p < .05. results the mean age of the patients was 23 years (range, figure 1. buccal graft harvesting and trimming. figure 2. ventral onlay buccal mucosal grafting in penile urethra. oral mucosal graft urethroplasty—hosseini et al 50 urology journal vol 8 no 1 winter 2011 17 to 81 years) and they had been followed up for a mean of 32 months (range, 25 to 51 months). there were no significant differences in the two groups and their subgroups in terms of mean patients’ age, mean stricture length, or etiology. total success rates of dorsal and ventral anterior omg urethroplasty were 83.3% and 75.8%, respectively (p = .5). early complications of oral graft harvesting consisted of cheek swelling and perioral numbness in 4 (7.5%) patients, with spontaneous resolution. as it can be observed in table 1, at penile site, dorsal and ventral omg were done for 9 and 10 patients with stricture lengths of 3.7 ± 1.1 cm and 3.9 ± 1.2 cm, respectively (p = .7). etiologies of stricture in the penile urethra are also listed in table 1. there were no early postoperative complications, such as wound infections, hematomas, and bleeding requiring transfusion. in the dorsal omg group, stricture developed in 1 patient with a previous failed hypospadiasis repair, at 3 months after the operation, which was managed with periodic urethral dilation. conversely, in the ventral omg group, urethrocutaneous fistula developed in 2 subjects, who were successfully treated by another omg urethroplasty; and stricture developed in 1 patient. success rates of dorsal and ventral penile site of anterior urethral stricture penile bulbar site of omg dorsal ventral p dorsal ventral p number (%) 9 (47.3) 10 (52.7) 15 (44.1) 19 (55.9) age (year ± sd) 42.1 ± 8.4 (19 to 75) 41 ± 7.5 (17 to 71) .84 44.3 ± 9.7 (21 to 73) 44.7 ± 8.9 (22 to 81) .9 stricture length (cm ± sd) 3.7 ± 1.1 (3.0 to 5.5) 3.9 ± 1.2 (3.0 to 5.0) .7 4.1 ± 1.1 (3.5 to 6.0) 4.2 ± 1.5 (3.5 to 6.5) .7 etiologies idiopathic (%) 3 (33.3) 3 (30) .88 6 (40) 8 (42.1) .9 trauma (%) 0 (0) 0 (0) 4 (26.6) 5 (26.3) .69 instrumentation (%) 1 (11.1) 1 (10) .93 3 (20) 3 (15.7) .75 infection (%) 2 (22.2) 2 (20) .91 2 (13.3) 3 (15.7) .84 failed hypospadiasis repair (%) 3 (33.3) 4 (40) .76 0 (0) 0 (0) total complications (%) 1 (11.1) 3 (30) .31 3 (20) 4 (21) .94 stricture (%) 1 (11.1) 1 (10) .93 2 (13.3) 3 (15.7) .84 fistula (%) 0 2 (20) .47 0 (0) 0 (0) graft infection (%) 0 0 0 (0) 0 (0) wound hematoma (%) 0 0 1 (6.6) 1 (5.2) .86 success rate (%)† 88.9 70 .3 80 79 .94 table 1. demographic, operation, and complication data of dorsal versus ventral omg with respect to bulbar or penile origin* *omg indicates oral mucosal graft. †total success rate: dorsal omg: (20/24) 83.3% and ventral omg: (22/29) 75.8% figure 3. dorsal onlay buccal mucosal grafting in bulbar urethra. oral mucosal graft urethroplasty—hosseini et al 51urology journal vol 8 no 1 winter 2011 omg were 88.9% and 70%, respectively (p = .3). on the other hand, at the bulbar site, dorsal and ventral omg were performed on 15 and 19 patients with stricture lengths of 4.1 ± 1.1cm and 4.2 ± 1.5 cm, respectively (p = .7). no significant difference was detected between etiologies of bulbar stricture in these groups (table 1). there were 5 strictures in patients that underwent bulbar urethroplasty, including 2 subjects in dorsal and 3 in ventral group. all of them developed at 6 months after the surgery and were managed by urethral dilatation with an acceptable urine flow. wound hematoma was detected in 1 patient of each group and was treated by dressing without any graft infection. the success rates of dorsal and ventral bulbar omg were 80% and 79%, respectively (p = .94). discussion treatment of urethral stricture diseases includes numerous reconstructive surgical techniques. the urologist must be familiar with all of these different techniques to be able to deal with any type of urethral stricture.(8) the choice of reconstructive technique depends on the stricture length, degree of spongiofibrosis, and surgeon’s preference and experience.(9) innovation of an ideal urethroplastic donor tissue was initially challenging. previously, full thickness skin grafts from hair-bearing sites of the body showed promising results. however, these grafts were associated with complications.(10) the use of omg as a donor tissue in urethroplastic reconstruction consists of autologous transplantation of nonkeratinized oral mucosa to the urethra for repair of a variety of urological defects.(10) oral mucosal graft has a thick epithelium rich in elastin, making it durable and easy to handle. the lamina propria is thin compared to that of the bladder mucosa and skin, facilitating inosculation and neovascularization. it has a high capillary density and is easily harvested, with immunologic properties similar to that of the urothelium.(3,11,12) the gold standard treatment for stricture of the urethral lumen is relatively well-preserved, is omg urethroplasty.(1) recent controversy has surrounded whether to insert this tissue in a ventral or dorsal position.(13) suggested benefits of dorsal onlay graft consist of less bleeding from the thinner dorsal spongiosum, application of the graft to the tunica albuginea of the corpora cavernosa providing a more stable base to allow better fixation of the graft, facilitating the acquisition of a richer blood supply, and reducing contracture during healing.(14) pansadoro and colleagues reported a success rate of 98% for 56 patients who received dorsal onlay bmg. only 1 patient having a recurrence was found on postoperative urethrography.(5) dubey and associates reported a success rate of 87% in 16 patients undergoing dorsal onlay bmg.(15) andrich and coworkers compared results of ventral onlay with dorsal onlay buccal mocosal bulbar urethroplasty. after a follow-up of 48 to 60 months, success rates of 86% and 95% were reported in ventral and dorsal onlay groups, respectively.(6) in 2005, barbagli and colleagues repaired 50 bulbar urethral strictures with bmg. the graft was placed on the ventral, dorsal, and lateral bulbar urethral surface in 17, 27, and 6 patients, respectively. the ventral, dorsal, and lateral graft provided success rates of 83%, 85%, and 83%, respectively. the authors suggested that different position of the grafts showed no difference in the success rate.(13) in our study, the surgery was successful in 27 (79.5%) patients. the 19 ventral grafts provided success in 15 (79%) subjects and failure in 4 (21%). the 15 dorsal grafts provided success in 12 (80%) patients and failure in 3 (20%). our lower success rates in comparison with other studies could be due to consideration of wound hematoma or postoperative urethral dilation as a failure. therefore, if we do not take wound hematoma into account, our trials success rates rise to 86.6% and 84.2% for dorsal and ventral grafting, respectively. the results of both ventral and dorsal omg reported in the literature are summarized in table 2. to repair the glandular and penile shaft urethra, buccal mucosa of the inner lip and cheek are preferred, respectively.(17) both ventral and dorsal grafting were applied for penile stricture, but because of the relative deficiency of covering tissues in the penile urethra, there is reduced oral mucosal graft urethroplasty—hosseini et al 52 urology journal vol 8 no 1 winter 2011 potential for the survival of ventrally applied free grafts.(18) metro and colleagues reported their 8-year experience of using buccal mucosa to treat both hypospadias and urethral strictures. six of 14 patients had recurrent stricture requiring further intervention, giving a success rate of only 57.1%.(19) fichtner and associates published their long-term outcomes in 17 patients who underwent ventrally applied bmg with a success rate of 88.2%.(3) dubey and coworkers reported a series of 43 patients undergoing dorsal onlay buccal mucosal urethroplasty for penile strictures; 28 underwent single-stage operations and 15 two-stage procedures. they reported success rates of 85.7% and 86.7% for single and two-stage procedures, respectively.(20) the outcomes of penile urethroplasty using oral mucosa are summarized in table 3. our experience for penile omg urethroplasty show that success rate of dorsal penile omg was greater than the ventral one (88.9% versus 70%). although it is not statically significant (p = .3), this suggests a higher potential risk of failure, especially for fistula formation in the ventral grafting group. therefore, it is better to avoid ventral onlay of oral mucosa in the distal anterior urethra because of potential poor outcomes. age, urethral stricture length, number of previous operations, extent of dissection, and the primary etiology of the urethral stricture may play some roles in the recurrence of strictures.(12) in our study, 7 patients experienced initial stricture failure recurred during the first 6 postoperative months. a graft such as oral mucosa carries no blood supply of its own. its survival depends on the absorption of nutrients from a wellvascularized recipient bed (imbibition phase) and later, on the in-growth of capillaries from the recipient bed to the graft (inosculation phase).(23) early failure of a free graft can result from inadequacy of either phase and frequently reflects a poorly-vascularized recipient bed, infection, or hematoma. late restricture may owe study participants follow-up, month success rate, % ventral onlay oral mucosal bulbar urethroplasty current study 19 24 79 andrich et al(6) 29 60 86 barbagli et al(13) 17 42 83 fichtner et al(3) 15 72 87 pansadoro et al(5) 9 41 89 dubey et al(15) 7 45 77.8 dorsal onlay oral mucosal bulbar urethroplasty current study 15 24 80 pansadoro et al(5) 56 41 98 dubey et al(15) 15 22 87 andrich et al(6) 42 60 95 barbagli et al(13) 27 42 85 xu et al(16) 12 57 75 table 2. outcomes of ventral and dorsal onlay oral mucosal bulbar urethroplasty study participants follow-up, month success rate, % ventral onlay oral mucosal penile urethroplasty current study 10 24 70 fichtner et al(3) 17 72 88.2 metro et al(19) 14 60 57.1 dubey et al(20) 15 24 86.7 dorsal onlay oral mucosal penile urethroplasty current study 9 24 88.9 venn and mundy(21) 8 36 100 dubey et al(22) 14 32 78.6 andrich and mundy(17) 41 60 100 table 3. outcomes of ventral and dorsal onlay oral mucosal penile urethroplasty oral mucosal graft urethroplasty—hosseini et al 53urology journal vol 8 no 1 winter 2011 to progression of the original disease. however, initial failure in most subjects can be converted to long-term success with urethral dilatation.(24) we realize that the study could have some weaknesses. the main bias is that the study has low number of patients, especially in the penile group. hence, we recommend comparing of these two methods with more subjects under additional assessment and long-term follow-up. conclusion in summary, omg is versatile and effective for strictures throughout the anterior urethra, and in experienced hands, the outcomes are similarly favorable whether a dorsal or ventral approach is taken. acknowledgements the authors appreciate infertility and reproductive health research center, shahid beheshti university of medical sciences, for supporting this study, and would like to especially thank negin alizadeh for grammatical assistance. conflict of interest none declared. references 1. andrich de, mundy ar. what is the best technique for urethroplasty? eur urol. 2008;54:1031-41. 2. andrich de, mundy ar. outcome of different management options for full-length anterior urethral strictures. j urol. 2009;181:13. 3. fichtner j, filipas d, fisch m, hohenfellner r, thuroff jw. long-term outcome of ventral buccal mucosa onlay graft urethroplasty for urethral stricture repair. urology. 2004;64:648-50. 4. barbagli g, palminteri e, rizzo m. dorsal onlay graft urethroplasty using penile skin or buccal mucosa in adult bulbourethral strictures. j urol. 1998;160:1307-9. 5. pansadoro v, emiliozzi p, gaffi m, scarpone p. buccal mucosa urethroplasty for the treatment of bulbar urethral strictures. j urol. 1999;161:1501-3. 6. andrich de, leach cj, mundy ar. the barbagli procedure gives the best results for patch urethroplasty of the bulbar urethra. bju int. 2001;88:385-9. 7. hosseini j, soltanzadeh k. a comparative study of long-term results of buccal mucosal graft and penile skin flap techniques in the management of diffuse anterior urethral strictures: first report in iran. urol j. 2004;1:94-8. 8. peterson ac, webster gd. management of urethral stricture disease: developing options for surgical intervention. bju int. 2004;94:971-6. 9. berger ap, deibl m, bartsch g, steiner h, varkarakis j, gozzi c. a comparison of one-stage procedures for post-traumatic urethral stricture repair. bju int. 2005;95:1299-302. 10. markiewicz mr, lukose ma, margarone je, 3rd, barbagli g, miller ks, chuang sk. the oral mucosa graft: a systematic review. j urol. 2007;178:387-94. 11. duckett jw, coplen d, ewalt d, baskin ls. buccal mucosal urethral replacement. j urol. 1995;153:1660-3. 12. mehrsai a, djaladat h, salem s, jahangiri r, pourmand g. outcome of buccal mucosal graft urethroplasty for long and repeated stricture repair. urology. 2007;69:17-21; discussion 13. barbagli g, palminteri e, guazzoni g, montorsi f, turini d, lazzeri m. bulbar urethroplasty using buccal mucosa grafts placed on the ventral, dorsal or lateral surface of the urethra: are results affected by the surgical technique? j urol. 2005;174:955-7; discussion 7-8. 14. patterson jm, chapple cr. surgical techniques in substitution urethroplasty using buccal mucosa for the treatment of anterior urethral strictures. eur urol. 2008;53:1162-71. 15. dubey d, kumar a, bansal p, et al. substitution urethroplasty for anterior urethral strictures: a critical appraisal of various techniques. bju int. 2003;91:215-8. 16. xu ym, qiao y, sa yl, et al. substitution urethroplasty of complex and long-segment urethral strictures: a rationale for procedure selection. eur urol. 2007;51:1093-8; discussion 8-9. 17. andrich de, mundy ar. substitution urethroplasty with buccal mucosal-free grafts. j urol. 2001;165:1131-3; discussion 3-4. 18. wessells h, mcaninch jw. current controversies in anterior urethral stricture repair: free-graft versus pedicled skin-flap reconstruction. world j urol. 1998;16:175-80. 19. metro mj, wu hy, snyder hm, 3rd, zderic sa, canning da. buccal mucosal grafts: lessons learned from an 8-year experience. j urol. 2001;166:1459-61. 20. dubey d, kumar a, mandhani a, srivastava a, kapoor r, bhandari m. buccal mucosal urethroplasty: a versatile technique for all urethral segments. bju int. 2005;95:625-9. 21. venn sn, mundy ar. urethroplasty for balanitis xerotica obliterans. br j urol. 1998;81:735-7. 22. dubey d, sehgal a, srivastava a, mandhani a, kapoor r, kumar a. buccal mucosal urethroplasty for balanitis xerotica obliterans related urethral strictures: the outcome of 1 and 2-stage techniques. j urol. 2005;173:463-6. 23. baskin ls, duckett jw. buccal mucosa grafts in hypospadias surgery. br j urol. 1995;76 suppl 3:23-30. 24. elliott sp, metro mj, mcaninch j. long-term followup of the ventrally placed buccal mucosa onlay graft in bulbar urethral reconstruction. j urol. 2003;169:1754-7. case report 206 urology journal vol 7 no 3 summer 2010 four cases of entero pouch fistula after orthotopic neobladder mohammad hatef khorrami, darab moshtaghi, amir javid urol j. 2010;7:206-8. www.uj.unrc.ir keywords: fistula, urinary bladder neoplasms, cystectomy department of urology, isfahan university of medical sciences, isfahan, iran corresponding author: amir javid, md n.18, jamal alley, khorram st., isfahan, iran tel: +98 913 115 4886 fax: + 98 311 386 5281 e-mail: amirjavid2000@yahoo.com received april 2009 accepted july 2009 introduction radical cystoprostatectomy in the male patients and anterior pelvic exenteration in the female patients, coupled with en bloc pelvic lymphadenectomy, remain the standard surgical approaches to muscle-invasive bladder carcinoma in the absence of metastatic disease. entero pouch fistula is a rare complication of orthotopic neobladder. the development of neobladder-enteric fistulas after orthotopic bladder reconstruction has been reported in large series of patients.(1-6) in the absence of infection, sepsis, or fecaluria, a trial of conservative management with a low residue diet and prolonged catheter drainage are recommended before proceeding to operative repair.(7,8) however, there are few articles on the management of entero pouch fistulas in the literature.(1-4) in this study, we presented 4 cases with poor response to conservative management. case report all the cases were male patients suffering from muscle invasive bladder cancer. they had undergone orthotopic urinary diversion using 30 to 40 cm of the ileum. a vesicoenteric fistula developed as early as 8 days to as late as 2 months after the procedure. all of the cases were admitted and diagnosed using computed tomography (ct) cystography and oral activated charcoal test. after confirming the fistula, patients were treated conservatively by total parenteral nutrition (tpn), antibiotic therapy, and continuous catheter drainage. case 1 a 67-year-old man underwent radical cystectomy. on the 8th postoperative day, while the patient was on normal diet and had no abdominal symptom or defecation problem, fecal materials were found in the urine. upper gastrointestinal (gi) series and ct scan with oral contrast were not diagnostic. thereafter, we used oral activated charcoal to confirm the fistula. after 10 days, in spite of fasting, tpn, antibiotic therapy, and continuous catheter drainage, the patient was still symptomatic. since the patient’s condition was deteriorating, open surgery was performed. we could not find a fistula during the operation; hence, pouch resection and ileal conduit diversion were carried out. the patient was discharged with a stable condition after 10 days. case 2 a 70-year-old man had undergone ileal orthotopic pouch neobladder reconstruction. thirty days after the operation, the patient returned entero pouch fistula with neobladder—khorrami et al 207urology journal vol 7 no 3 summer 2010 with fecaluria. retrograde pouchogram showed an entero pouch fistula (figure 1). the patient was treated with continuous neobladder drainage, oral fluoroquinolones, and tpn. after 12 days, the patient’s condition suddenly deteriorated and he died with septic shock. case 3 a 48-year-old man had undergone radical cystectomy. two months after the operation, the patient returned with fecaluria. retrograde pouchogram was not diagnostic, but oral activated charcoal test confirmed the fistula. total parenteral nutrition, prolonged catheter drainage, and oral fluoroquinolones were administered for 10 days, but oral activated charcoal test was still positive. the patient was discharged with low residue diet, prolonged catheter drainage, and oral fluoroquinolones. however, after 2 months of conservative management, feces materials were still visible in the urine bag. upper gi series and pouchogram were not diagnostic. performing surgery via previous surgical scar (lower midline), all adhesion bands were released and fistula was repaired. after 3 weeks, oral activated charcoal test became negative and the patient was discharged. case 4 a 56-year-old man had undergone radical cystectomy and orthotopic urinary diversion in another center. after 2 weeks, when the patient was ready to be discharged, he noticed fecal materials in his urine. he was referred to our center and pouchography revealed an entero pouch fistula (figure 2). we recommended surgery, but the patient refused. after 4 months, the patient is still under antibiotic therapy, low residue diet, and neobladder drainage. he is still symptomatic and repeated pouchography confirmed the fistula persistence. discussion orthotopic bladder substitution is an effective and desirable method of urinary reconstruction after radical extirpative procedures. although it is rare, fistula formation can occur either as an early or late complication, and is seen more frequently in patients treated with radiation.(1) conduits and pouches can open to nearly all the surrounding figure 1. pouchography shows vesicoenteric fistula. figure 2. pouchography in a patient suspected for entero pouch fistula. entero pouch fistula with neobladder—khorrami et al 208 urology journal vol 7 no 3 summer 2010 pelvic structures, including the small bowel, the colon, the rectum, the vagina, and the iliac vessels. in review of literature, conservative therapy with a low residue diet and continuous catheter drainage of the reservoir are recommended. surgical excision of the fistula is necessary if conservative therapy fails.(1,2,5,6) interposition of the omentum between the pouch and the enterocolonic anastomosis is recommended in patients who have previously received pelvic radiation.(1) in a study, the conservative management was proposed in cases who had a normal nutritional status, with no sepsis, no obstruction, and no organ impairment. the treatment consisted of hyperalimentation, fasting or low residue diet, and continuous urinary drainage.(6-8) although it is not required for the diagnosis of an entero pouch fistula, hyperchloremic metabolic acidosis should raise clinical suspicion of fistula in the presence of gi symptoms, especially when there has been no previous metabolic abnormality.(1) in this study, conservative management using tpn, antibiotic therapy, and catheter drainage for 10 days was not successful to be recommended. two of the patients underwent surgery, the third case died of septic shock, and the forth one is still symptomatic after 4 months of conservative management. we believe that open surgery should not be postponed, especially when the patient is deteriorating. when there are suspicious materials in the urine or hyperchloremic metabolic acidosis exists, entero pouch fistula should be ruled out. in this study, of 4 patients, only 2 had diagnostic pouchogram, and upper gi series yielded inconclusive results. therefore, other diagnostic modalities like oral activated charcoal test must be utilized. we administered oral activated charcoal and then observed urine for black material to confirm entero pouch fistula in suspicious cases. (8) recently, magnetic resonance imaging has been introduced as an effective method to detect fistula and determine its location.(9) examining the anastomotic site and then all sites of adhesion between the intestine and pouch with high intraluminal pressure during the operation is an effective method to detect fistula opening in the intestine. actually, finding fistula is a challenging part of this surgery. conflict of interest none declared. references 1. tarter th, kawachi mh, wilson tg. entero-pouch fistula: a rare complication of right colon continent urinary diversion. j urol. 1995;154:364-6. 2. basiri a, mo’oudi e, akhavizadegan h, shakhssalim n. a novel surgical technique to localize small enteropouch fistula. bmc urol. 2005;5:16. 3. okada y, arai y, oishi k, takeuchi h, yoshida o. [urinary diversion with kock pouch: clinical results in 75 cases focusing on late complications]. hinyokika kiyo. 1988;34:1179-84. 4. arai y, kuo yj, kihara y, okuno h, okada y, yoshida o. [clinical experience with the kock continent ileal urinary reservoir]. hinyokika kiyo. 1988;34:272-9. 5. hautmann re, miller k, steiner u, wenderoth u. the ileal neobladder: 6 years of experience with more than 200 patients. j urol. 1993;150:40-5. 6. deliveliotis c, picramenos d, macrichoritis c, kiriazis p, kostakopoulos a. ileoneobladder-enteric fistula: a rare early post-operative complication treated conservatively. br j urol. 1995;76:407-8. 7. shackley dc, brew cj, bryden aa, et al. the staged management of complex entero-urinary fistulae. bju int. 2000;86:624-9. 8. pontari ma, mcmillen ma, garvey rh, ballantyne gh. diagnosis and treatment of enterovesical fistulae. am surg. 1992;58:258-63. 9. ravichandran s, ahmed hu, matanhelia ss, dobson m. is there a role for magnetic resonance imaging in diagnosing colovesical fistulas? urology. 2008;72: 832-7. 1 running head: urodynamic study and sedation in women-saberi et al. effect of rectal midazolam on pain, stress, and cooperation of patient during urodynamic test in women: a randomized clinical trial narjes saberi*¹, aygineh hayrabedian², hamid mazdak3, razieh hassannejad4, mahtab zargham5, mehrdad mohammadi sichani6, mahboubeh mirzaei7 1: assistant professor of urology department of urology, school of medicine nour & aliasghar hospital isfahan university of medical sciences 2: instructor of operating room department, school of nursing and midwifery isfahan university of medical sciences 3: associate professor of urology department of urology, school of medicine al-zahra hospital isfahan university of medical sciences 4: assistant professor of biostatistics, isfahan cardiovascular research center, cardiovascular research institute, isfahan university of medical sciences, isfahan, iran. 5: associate professor of urology department of urology, school of medicine al-zahra hospital isfahan university of medical sciences 6: associate professor of endourology department of urology, school of medicine al-zahra hospital isfahan university of medical sciences 7: assistant professor, department of urology, kerman university of medical sciences, kerman, iran key words: cooperation; midazolam; pain; sedation; stress; urodynamic; women 2 abstract: purpose: the urodynamic study is an invasive test, and causes pain and stress in the patient. we have investigated the effect of rectal midazolam sedation on the pain, stress, and cooperation of women performing urodynamic study. materials and methods: at the present randomized clinical trial (rct) from january to july of 2021 a total of 84 women were prospectively randomized to undergo urodynamic study with or without sedation. the primary outcome of interest was experienced pain during urodynamic study. in the intervention group, after monitoring baseline vital signs (heart rate, blood pressure, o2 saturation), sedation was done with rectal midazolam at a dose of 0.3 mg/kg (maximum 15 mg). completing the procedure, after recovery from sedation patients were asked to fill a self-assessed visual analog pain scale (vas, 0-10), 5-point visual stress scale (15) and, patient collaboration level during urodynamic study was evaluated by nurse with a researcher-made tool (0-3). in the control group test was performed in routine practice with no sedation. baseline vital signs measured pre and intra-procedural time, as well as their experienced pain, stress, and cooperation levels were recorded. results: 84 female cases were evaluated. in terms of comparison of changes in pre and intratest physiologic parameters, results showed that there were no significant differences between the two groups for all physiologic parameters: sbp, dbp, pr, spo2. analysis of the pain score showed that it was lower in the intervention group, and there was a significant difference in pain score between the two groups (p =.024). while the stress and corporation scores were not reported statistically significant (p=.388 and p=.955, respectively). conclusion: sedation with rectal midazolam in adult women before uds is safe and effective in reducing pain but is not effective in reducing stress and increasing cooperation. the amount of pain based on the visual analog pain scale is mild and although this method is safe, its use routinely is not recommended. introduction: the urodynamic study (uds) is an invasive test that allows the assessment of lower urinary tract symptoms in women. urethral and rectal catheterization is necessary for this test. the patient must urinate in the presence of a technologist in an unknown environment. these may lead to pain and stress and affect the test results and patient cooperation.(1-4) various methods have been implemented in previous studies to solve this problem, such as the use of educational pamphlets, a head pad, and videos or the playback of music or inhalation of vegetable oils 3 during testing.(5-10) sedation with midazolam before uds is another method used in various studies for children, and has been effective at calming the child and performing the test better without affecting the test results.(11-15) midazolam is a benzodiazepine with sedative and anti-anxiety effects which provides partial ante-grade amnesia. with a rapid-onset and short-effect, it can be administered through various ways such as oral, nasal, intravenous, and rectal. it has no serious side effects.(12,13) no studies have assessed the effect of sedation on adult females undergoing uds. we have investigated the effect of rectal midazolam sedation on the pain, stress, and cooperation of women performing uds. patients and methods study population in the present study participants were women who were diagnosed with lower urinary tract symptoms (luts) from january to july of 2021. patients were enrolled in the study after a routine pre-procedural evaluation. inclusion criteria were the women between the age of 2080 years old who were referred to our urodynamic center for evaluation of lower urinary tract symptoms. exclusion criteria were active urinary tract infection, history of cardiovascular and respiratory disease, known psychiatric diseases, neurologic disorders, spinal cord injury, any analgesic use in the last 24 hours, and anxiolytic or sedative drug use 10 days before the test. by researchers study objectives were explained to each of the participants and informed consent was obtained. ethics committee approval was obtained from isfahan university of medical sciences. ethical code was ××× and irct code was ×××. patients’ enrollment algorithm has been illustrated in figure 1. study design this study was a prospective single center, parallel-group randomized clinical trial with balanced randomization [1:1] which was performed in outpatient urodynamic clinic of khorshid hospital in isfahan, iran. sample size was calculated considering 0.62 t expected difference between with and without sedation groups in the primary outcome of interest. 4 considering type i error of 0.05 and type ii error of 0.2 based on n = [ 2(z1−α 2⁄ +z1−β) 2 δ2 + z1−α 2⁄ 2 4 ](4), 42 samples were estimated in each group. therefore, 84 samples were needed totally. patients were randomly assigned to one of the two groups of with and without sedation (42 patients in each group). randomization was done using computerized random numbers. the allocated procedure for each patient was recorded in concealed envelopes. considering inclusion/exclusion criteria and after achieving patient’s agreement on participation, the concealed envelopes were opened by one of the researchers and the allocated procedure was performed as explained below. procedure technique all procedures in both groups were performed by standardized uds (uroflowmetry and pressure-flow study) along with emg (electromyelography) according to the international continence society recommendations. all cases were conducted in an outpatient urodynamic clinic managed by a female urologist with the assistance of an experienced and special urodynamic nurse. in the intervention group (with sedation), before the procedure after monitoring baseline vital signs (heart rate, blood pressure, o2 saturation), sedation was done at a dose of 0.3 mg/kg (maximum 15 mg) of midazolam. midazolam was administered rectally using an 8 fr feeding tube by the urodynamic nurse. fifteen minutes later the vital signs were re-evaluated, the next uroflowmetry was done, and the post-void residue was measured, then pre-lubricated gel urethral(7 fr) and rectal catheters(9 fr) were introduced, and three electrodes were attached to the perineum to record emgs by a single urodynamic nurse in a dorsolithotomy position. after installing the catheters a pressure-flow study was performed using the standard method according to ics recommendations.(16) the electrodes and catheters were finally removed at the end of the procedure. in the control group (without sedation) all steps of test were performed in routine practice with no sedation. baseline vital signs measured pre and intra-procedural time in both groups. outcome assessment the primary outcome of interest was pain during uds, so after completing the procedure, when recovery from sedation was achieved patients in the intervention group were asked to fill a self 5 assessed visual analog pain scale (vas, 0-10), but in the intervention group immediately after the procedure, level of pain was evaluated and recorded. as secondary outcomes, patient’s stress and collaboration during uds were respectively evaluated with a 5-point visual stress scale (1-5) and a researcher-made collaboration level tool (0-3). statistical analysis quantitative variables were expressed as mean ± sd and qualitative variables were expressed as counts (percent). independent t-test was used to compare mean of quantitative variables between groups. chi-square test was applied to compare the distribution of categorical variables across study groups. exact test was used if the main assumption underlying chisquare test, no expected cell counts less than 1 and at most 20% of expected cell counts less than 5, was not met. the differences of peri and intra-procedural physiologic parameters in each group were assessed by non-parametric wilcoxon signed ranks test. we applied analysis of covariance (ancova) to compare mean changes in pre and intra-test physiologic parameters between two groups. mann-whitney non-parametric test based on peri and intraprocedural differences was alternative one when the assumptions of ancova or student ttest were not met. the assumptions underlying independent t-test including normality and homogeneity of variance were assessed by shapiro-wilk and levene’s tests, respectively. the main assumptions underlying ancova including homogeneity of variance and no interaction between group (groups of study) and covariate (pre measurement) variables were also evaluated by levene’s test and including interaction terms in regression model, respectively. all analyses were performed using ibm spss statistics 25 (ibm corp. released 2017. ibm spss statistics for windows,version 25.0. armonk, ny: ibm corp). p value < .05 was considered statistically significant. results: from january to july 2021, 352 women were referred to our urodynamic center, of which 84 females aged 20-65 years were included in the study. the rest either did not meet the inclusion criteria or did not agree to participate in the study figure 1. the mean age of the 42 patients in intervention group was 46.55 ± 12.64 years and 42 patients in control group was 55.48 ± 17.05 years and there was significant difference in age between two groups [mean 6 difference, 95%ci: -8.93, (-15.50,-2.35); p =.008]. the mean weight of patients in intervention and control groups was 73.10 ± 12.32 and 74.93 ± 14.26 kg, respectively. no significant difference was found in weight distribution between two groups [mean difference, 95%ci: -1.83, -7.68, 4.02); p =.535] table 1. regarding the differences of peri-procedural physiologic parameters in each group, in sedated group sbp [mean difference, 95%ci: -3.09, -6.05,-0.14); p =.045], dbp [mean difference, 95%ci: -1.67, -3.19,-0.14); p =.035], and spo2 [mean difference, 95%ci: -0.48, -0.84,-0.11); p =.021] were statistically significant, but in non-sedated group only pr was significant [mean difference, 95%ci: -2.70, -4.79,-0.61); p =.026] table 2 figure 2. in terms of comparison of changes in pre and intra-test physiologic parameters, results showed that there were no significant differences between the two groups for all physiologic parameters: sbp (p-value=.416), dbp (p-value=.520), pr(p-value=.075), spo2 (pvalue=.066) table 3. analysis of the pain score showed that it was lower in intervention group, and there was significant difference in pain score between two groups (p=.024). while the stress and corporation scores were not reported statistically significant (p=.388 and p=.955, respectively) figure 3. further analysis showed that there are no significant differences in mean age among pain intensity and stress level (p=.481, p=.667, respectively). comparison of pain intensity between the two groups based on the three ranks including severe, moderate, and mild showed that there is no significant relationship between pain intensity and study groups table 4. discussion: in this study (rct), we investigated the effect of sedation with rectal midazolam on pain, stress, and cooperation of adult women during an uds. according to the results, the effects of rectal midazolam in reducing pain were significant but did not affect patients' stress and cooperation. in this study, the rectal midazolam sedation in women was safe. fluctuations in vital signs and o2 saturation were not significant before and after midazolam administration, compared to the control group. the mean score of pain and stress based on the visual analog scale in both groups were reported to be in the mild range and shows that uds is well-tolerated in adult women with or without sedation. 7 previous studies examining patients' pain and stress during uds have reported similar results in terms of pain and stress.(1,4,17) in xavier biardeau's study, about 60% of people experienced pain. pain score was higher in men and younger people.(2) in another study, women's attitudes toward uds have been specifically examined and according to their results 42% of women experienced stress during the test and 27% reported moderate to severe pain. the pain was less at older ages and women who were referred from specialized urogynecology centers.(17) in another study conducted specifically on women, the mean pain rate based on a visual analog scale was 1.5 out of 10, which was slightly lower than our results, and the mean stress was 1.8 out of 10. the pain was more common in women with overactive bladder and painful bladder syndrome and younger women with a history of depression.(4) numerous studies have examined the effects of different items to reduce pain and stress during the uds. two studies have examined the result of listening to music, none of them has not been effective in reducing pain and stress.(5,7) in one of these studies, the use of educational pamphlets was also examined simultaneously, which also have no significant effect on reducing pain and stress.(5) another study examined the effect of inhaling vegetable oils such as salvia sclarea or lavandula angustifolia on reducing stress in patients during an uds. according to the results of this study, inhaling lavandula oil reduces stress in women, and inhaling salvia sclarea oil calmed down.(9) in animal studies, the effect of midazolam on uds results has been investigated. studies in female cats have shown that alertness has no effect on urodynamic variables in cats and sedation with midazolam reduces animal stress during testing.(18,19) the effects of midazolam administration in different routes (oral, nasal, and rectal) have been studied in several studies in children to reduce stress and perform uds and other painful interventions better and easier.(11-13,20) contrary to the theory that benzodiazepines can relax the pelvic floor muscles and alter uds results,. in these studies it was seen that the use of midazolam in children did not change the test results and due to the sedative and anti-stress effects of midazolam, the test was performed more easily in children. also, in all these studies, the use of midazolam to any of the ways has been safe and effective, as well as effective in calming children and performing the test better.(11-13) to date, no study has examined the effect of rectal midazolam in adult women uds before. 8 according to the results of our study rectal midazolam has been effective in reducing patients' pain during the test and this method can be used in patients who experience more pain and do not cooperate properly due to pain or in women with underlying conditions and diseases which raises the possibility of more pain tolerance such as painful bladder syndrome. because the pain intensity during the test is in the mild range in our and the similar studies, apply of this sedation method for all women to reduce pain in the uds does not seem appropriate. in our study, due to ethical considerations, the test was performed once in patients and it was not possible to evaluate the effects of midazolam on test results and it was the limitation of our study. conclusion: according to the results of our study, the use of rectal midazolam in adult women before uds is safe and effective in reducing pain, but is not effective in reducing stress and increasing cooperation. the amount of pain based on visual analog pain scale is mild and although this method is safe, its use routinely is not recommended. acknowledgments: we would also like to thank urodynamic clinic staff of khorshid hospital in isfahan, iran who cooperated in the implementation of this study. conflicts of interest: none of the authors of this study, individuals or devices have a conflict of interest in writing or publishing this article. data availability: the data used to support the findings of this study are included within the article. funding: nil. patient consent: the authors certify that they have obtained all appropriate patient consent forms. all patients have signed an informed written consent for demographics and other clinical information to be 9 reported in the journal. the patients understood that their name and initials will not be published and due efforts will be made to conceal identity. permission of reproduce material from other sources: no permission is needed. clinical trial registration: irct code of this study (irct20210122050105n1) was received on 25/01/2021. ethics of approval: this study was registered as a research project in the vice chancellor for research of the faculty of medicine in isfahan university of medical sciences and on 03/01/2021 from the ethics committee in biomedical research ethics code with reference number ir.mui.med. received rec.1399.881. the subject has obtained the patients’ informed written consent to publish their information and details. references: 1. ku jh, kim sw, kim hh, et al. patient experience with a urodynamic study: a prospective study in 208 patients. j. urol., balt. 2004;171:2307-2310. 2. biardeau x, lam o, ba v, campeau l, corcos j. prospective evaluation of anxiety, pain, and embarrassment associated with cystoscopy and urodynamic testing in clinical practice. urol. assoc. j. 2017;11:104. 3. yokoyama t, nozaki k, nose h, et al. tolerability and morbidity of urodynamic testing: a questionnaire-based study. urology. 2005;66:74-76. 4. yeung jy, eschenbacher ma, pauls rn. pain and embarrassment associated with urodynamic testing in women. . int urogynecol j . 2014;25:645-650. 5. diri ma, çetinkaya f, gül m. the effects of listening to music on anxiety, pain, and satisfaction during urodynamic study: a randomized controlled trial. urol. int. 2019;103:444449. 6. kim jw, kim hj, park yj, et al. the effects of a heating pad on anxiety, pain, and distress during urodynamic study in the female patients with stress urinary incontinence. neurourol. urodyn. 2018;37:997-1001. 10 7. shim js, chae jy, kang sg, et al. can listening to music decrease pain, anxiety, and stress during a urodynamic study? a randomized prospective trial focusing on gender differences. urology. 2017;104:59-63. 8. solomon er, ridgeway b. interventions to decrease pain and anxiety in patients undergoing urodynamic testing: a randomized controlled trial. neurourol. urodyn. 2016;35:975-979. 9. seol gh, lee yh, kang p, et al. randomized controlled trial for salvia sclarea or lavandula angustifolia: differential effects on blood pressure in female patients with urinary incontinence undergoing urodynamic examination. j altern complement med. 2013;19:664670. 10. greenstein a, bar‐yosef y, chen j, matzkin h. does information provided to men before a urodynamic study affect their expectation of pain? bju int. 2005;96:1307-1309. 11. bozkurt p, kilic n, kaya g, et al. the effects of intranasal midazolam on urodynamic. bju int. 1996;78:282-286. 12. özmert s, sever f, tiryaki ht. evaluation of the effects of sedation administered via three different routes on the procedure, child and parent satisfaction during cystometry. springerplus. 2016;5:1-7. 13. özmert s, sever f, ti̇ryaki̇ ht. rektal midazolam sedasyonunun çocuklarda sistometrik parametrelere etkisi. turk. j. pediatr. 2018;12:163-167. 14. stokland e, andréasson s, jacobsson b, jodal u, ljung b. sedation with midazolam for voiding cystourethrography in children: a randomised double-blind study. pediatr radiol. 2003;33:247-249. 15. thevaraja ak, batra yk, rakesh sv, et al. comparison of low‐dose ketamine to midazolam for sedation during pediatric urodynamic study. pediatr anaesth. 2013;23:415-421. 16. rosier pf, schaefer w, lose g, et al. international continence society good urodynamic practices and terms 2016: urodynamics, uroflowmetry, cystometry, and pressure‐ flow study. neurourol urodyn. 2017;36:1243-1260. 11 17. gorton e, stanton s. women's attitudes to urodynamics: a questionnaire survey. int. j. obstet. gynaecol. 1999;106:851-856. 18. li wj, kim jm, oh s-j. effects of level of consciousness on urodynamic procedure in female cats. j korean med sci. 2011;26:803-806. 19. cohen ta, westropp jl, kass ph, pypendop bh. evaluation of urodynamic procedures in female cats anesthetized with low and high doses of isoflurane and propofol. am j vet res. 2009;70:290-296. 20. ameda k, kakizaki h, yamashita t, et al. feasibility of urodynamic study (combined cystometry and electromyography of the external urethral sphincter) under general anesthesia in children. int j ural. 1997;4:32-39. corresponding author: dr. narjes saberi, assistant professor of urology department of urology, school of medicine nour & ali-asghar hospital isfahan university of medical sciences, kargar street, 1 st shahid mahmoodreza mahdavi street, isfahan, iran. e-mail: narjessaberi@gmail. com table 1. demographic characteristics of each groups. variable sedated group (n = 42) non-sedated group (n = 42) p-value age, year; mean ± sd 46.55 ± 12.64 55.48 ± 17.05 .008 weight, kg; mean ± sd 73.10 ± 12.32 74.93 ± 14.26 .535 p-value obtained based on independent t-test. table 2. comparison of peri-procedural physiologic parameters in each group. variable sedated group (n = 42) pvalue non-sedated group (n = 42) p-value 12 pre-test intra-test pre-test intra-test sbp, mmhg; mean ± sd 112.86± 16.273 109.7± 13.523 .045 118.25±17.670 115±15.359 .097 dbp, mmhg; mean ± sd 75.48±10.866 73.81±11.033 .035 79.75±10.975 78.75±8.825 .384 pr, b.p.m; mean ± sd 82.24±12.579 82.02±10.706 .690 81.65±16.041 78.95±14.131 .026 spo2, %; mean ± sd 95.38±2.141 94.90±2.229 .021 94.60±2.898 94.75±2.239 .856 abbreviations: sbp, systolic blood pressure; dbp, diastolic blood pressure; pr, pulse rate; spo2 , blood oxygen saturation. p-value obtained based on wilcoxon signed ranks test. table 3. comparison of peri-procedural physiologic parameters between two groups variable p-value sbp, mmhg; .416a dbp, mmhg; .520b pr, b.p.m; .075a spo2, %; .066 b a p-value obtained based on ancova b p-value obtained based on mann-whitney test for peri and intra-procedural differences. table 4. comparison of intra-test pain intensity between the two groups p-value obtained based on exact test. variable intensity sedated group (n = 42) non-sedated group (n = 42) p-value pain[n(%)]? mild 37 (88.1%) 27 (67.5%) .101 moderate 4 (9.5%) 10 (25.0%) severe 1 (2.4%) 3 (7.5%) 13 figure 1 : consort 2010 flow diagram assessed for eligibility (n=352) excluded (n=268) not meeting inclusion criteria (n=230 ) spinal cord injury or neurologic disease (n=70) known respiratory or cardiac disease (n= 50) known psychiatric disease (n= 30) consumption of sedative or analgesic drugs (n=80) declined to participate (n=30 ) other reasons (n=8 ) analysed (n=42) excluded from analysis (n= 0 ) allocated to intervention (n=42) received allocated intervention ( urodynamic test with sedation) (n=42 ) did not receive allocated intervention (n=0 ) allocated to control group (n=42) received allocated intervention( urodynamic test without sedation) (n=42 ) did not receive allocated intervention (n= 0 ) analysed (n=42) excluded from analysis (n= 0 ) allocation analysis randomized (n= 84) enrollment 14 figure 2: comparison of changes in physiological parameters in two groups 15 1 2 2 2 2 2 16 figure 3. comparison of pain(1), stress(2)and corporation(3) scores between sedated (a) and non-sedated (b) groups 3 running head: turp+pae vs. turp for giant bph patients-zhiyu et al. two-year outcomes after transurethral prostate resection post-prostatic artery embolization versus transurethral prostate resection alone for giant benign prostatic hyperplasia zhang zhiyu1*, song zhen1*, zhou qi2*, huang yuhua1, ouyang jun1, zhang xuefeng1 1 department of urology, the first affiliated hospital of soochow university, suzhou, china 2 department of reproductive medicine center, the first affiliated hospital of soochow university, suzhou, china * these authors contributed equally to this work. keywords: giant benign prostatic hyperplasia; transurethral resection of the prostate; prostatic artery embolization; efficacy abstract purpose: to compare the long-term (two-year) efficacy between transurethral resection of the prostate (turp) after prostatic artery embolization (pae) and turp only for patients with giant (>100 ml) benign prostatic hyperplasia. materials and methods: we retrospectively analyzed data from 61 and 150 patients with giant benign prostatic hyperplasia treated with pae+turp or turp alone, respectively, from january 2015 to march 2020. we compared index changes before and after surgery. results: the operative time, intraoperative blood loss, postoperative bladder irrigation time, and catheter retention time in the pae+turp group were lower than those of the turp group, while the speed of resection of the lesion and hospitalization costs were more significant (p < 0.05). international prostate symptom score (ipss), quality of life (qol), prostate volume, maximum urinary flow rate, detrusor pressure of maximum urinary flow rate, prostate-specific antigen, and urodynamic obstruction were better in the pae+turp group than the turp group at 24 months (p < 0.05). regarding ipss and qol scores at 24 months postoperatively compared with the preoperative period, the pae+turp group was better than the turp group in terms of the storage period, voiding period, and qol (p < 0.05). the distribution of postoperative adverse event severity classes was comparable between the groups (p = 0.984). conclusion: in contrast to turp alone, pae + turp is more expensive but provides better postoperative outcomes; there is no significant difference in terms of the severity grade distribution of postoperative complications. introduction benign prostatic hyperplasia (bph) severely affects the quality of life (qol) of middle-aged and older men, with incidence rates ranging from 50% in the sixth decade to nearly 90% in the eighth decade of life.(1) bph presents with enhanced urination frequency, urgency, and progressive urinary difficulty, facilitating the formation of urinary stones, urinary retention, urinary tract infections, and chronic kidney disease. conservative treatment of bph is less effective than other treatment strategies, and surgery is thought to be the most efficacious. although several surgical options are available, transurethral resection of the prostate (turp) is the procedure of choice for patients who have failed pharmacological treatment with adenomas less than 80 ml.(2) despite the efficacy of this treatment, few studies have reported differences among treatment strategies for large prostates (≥ 100 ml). previous studies have shown that direct surgery may be associated with longer operative times and increased blood loss for these older male patients, increasing the procedure’s risks.(3) prostatic artery embolization (pae) improves bladder outlet obstruction due to bph and reduces the incidence of post-turp complications.(4-5) however, the exclusive use of pae to treat bph is controversial, and many clinicians recommend a combined approach with other treatments to improve lower urinary tract symptoms (luts). pae plays an adjunctive role in this combination.(6) previous work has shown that turp combined with pae can reduce the blood supply to the augmented area, reducing intraoperative bleeding, improving the procedure's safety, and shortening the operative time. in the present study, we compared the long-term efficacy, safety, and complications of pae+turp versus turp alone to manage giant bph (> 100 ml) with a two-year follow-up. patients and methods study population data from 201 patients with large bph from the first affiliated hospital of soochow university was collected from january 2015 to march 2020. of these 201 patients, 61 were treated with pae + turp, and 150 were treated with turp alone. the patients were then followed up for two years. the international prostate symptom score (ipss) and other outcomes were assessed 24-months postoperatively. additionally, differences in the follow-up indicators of two surgical approaches at each time point were noted. in the initial cohort, excluding missing data, loss to follow-up, or death, 167 patients were followed up for 24-months (52 pae + turp and 115 turp). inclusion criteria: (1) bph patients with moderate-to-severe luts and significantly impaired qol (i.e., ipss > 8 and qol score > 3); (2) poor results from medication or refusal to take medication; (3) recurrent episodes of hematuria, urinary retention, or urinary tract infection; (4) secondary hydronephrosis of the upper urinary tract with or without renal impairment; (5) urodynamic examination suggesting bladder outflow tract obstruction with no abnormal bladder function; (6) a prostate volume (pv) > 100 cm3. exclusion criteria: (1)patients with imaging data suggesting severe internal iliac artery or prostatic artery sclerosis and tortuous vessels, detrusor weakness or neurogenic lower urinary tract dysfunction, comorbid urethral strictures, large bladder diverticula, bladder stones, or prostate cancer, severe cardiac, hepatic, or renal insufficiency or coagulation dysfunction; (2) allergy to iodine-containing contrast media or contraindications to magnetic resonance imaging; (3) prior history of prostate surgery, or iliac artery embolization. the study was conducted in accordance with the declaration of helsinki (as revised in 2013). the study was approved by the ethics committee of the first affiliated hospital of soochow university (no. 139) and informed consent was taken from all individual participants. operative method turp three experienced surgeons performed the turp technique. under intravenous inhalation compound anesthesia, a german wolf bipolar prostate electrospectroscope and the supporting photography system were used to observe the lesion and surrounding tissue. the power of the electrospectroscope was set at 100–120 w, and the power of electrocoagulation was 60–80 w. the f26 electrospectroscope was slowly placed to explore the patient's verumontanum, urethra, ureteral orifice, prostate, and bladder, carefully observing the prostate lesion from the verumontanum to the bladder neck orifice. then, the bladder neck opening and the verumontanum were used as markers. middle lobe hyperplasia requires tissue excision within the 5 to 7 o'clock range. lateral lobe hyperplasia requires tissue excision within the 1 to 11 o'clock range (as deep as possible into the surgical envelope of the prostate). finally, the gland surrounding the verumontanum was excised. electrocoagulation was performed to stop the bleeding and repair the wound. an ellik was used to aspirate the tissue fragments for pathological examination. postoperatively, an f20 balloon catheter was left in place, and the bladder was flushed with saline until the fluid color became transparent. pae+turp two experienced interventional surgeons performed the pae technique. an f16 urinary catheter was placed before the procedure. the balloon was filled with 10 ml of contrast mixed with a 0.9% sodium chloride solution, and the urinary catheter was gently pulled back to place the balloon at the urethra internal orifice. after the successful induction of local anesthesia, the modified seldinger technique was used to puncture the right femoral artery, and a 5-f cobra arterial catheter (cook, usa) was placed in the anterior trunks of both internal iliac arteries. the x-ray tube was tilted 35° to the same side, and 9–12 ml of iodixanol contrast was injected at 3–4 ml/s and a pressure of 300 psi (1 psi = 6.895 kpa) for internal iliac arteriography to identify the prostatic artery preliminarily. a 2.6-f stride microcatheter (asahi, japan) was inserted super-selectively into the prostatic artery using the coaxial microcatheter technique. the microcatheter's location, the prostatic artery's course, and surrounding traffic branches were clarified using imaging. the prostatic arteries (pa) were embolized bilaterally by slowly injecting 100–300 μm tripropylene gelatin microspheres (embosphere, merit medical systems, usa) and an appropriate amount of gelatin sponge particles through a microcatheter. the end-point of embolization was complete retention of the contrast agent in the prostate gland. the microcatheter was withdrawn, and another internal iliac artery angiogram was performed to assess the extent of the embolism and to observe the presence of other collateral blood supply. the procedure was concluded after confirming that there was no staining in the prostate parenchyma, and the puncture site was dressed with pressure and bed rest for 6–8 h. a successful pae technique was defined as bilateral super-selective cannulation and embolization of the prostatic artery. based on tang et al.’s research,(3) turp was performed on day three after pae. data collection data were collected preoperatively (baseline), intraoperatively, postoperatively, and at 3-, 6-, 12-, and 24-months of follow-up. preoperative data included the patient's age, diabetes mellitus, high blood pressure, body mass index, prostate-specific antigen (psa), pv assessed by magnetic resonance imaging, postvoid residual urine (pvr) volume assessed by ultrasound, ipss, qol score, national institutes of health-chronic prostatitis symptom index (nih-cpsi), international index of erectile function short form 5, maximum urinary flow rate (qmax) by free-flowmetry, and detrusor pressure of maximum urinary flow rate (pdetqmax). intraoperative and postoperative metrics included american society of aneshesiologists (asa) scores, operative time, the weight of tissue removed, speed of lesion removal, intraoperative blood loss (the blood loss was calculated at the end of turp as the product of irrigating fluid volume and haemoglobin content divided by the preoperative blood haemoglobin concentration (7)), postoperative bladder irrigation time, postoperative catheter retention time, length of hospital stay, cost (including surgery costs, hospital costs, anesthesia, drugs and others), and clavien-dindo system grading.(8) all follow-up visits were conducted during urology clinic hours, and patients completed surveys before the clinic visit without the physician. the metrics recorded at each visit included adverse events based on the improved clavien system, the common terminology criteria for adverse events (ctcae),(4) and the baseline metrics used to assess efficacy. urodynamic measurements were performed at baseline and the 6-, 12-, and 24-month postoperative follow-ups. maximum urinary flow rate tests were substituted in the third postoperative month to assess the effects of surgery. statistical analysis graphpad prism 9 and spss 26 were used for statistical analysis. r (4.2.1) was used to calculate sample size. quantitative data were expressed as mean ± standard deviation, and the mann-whitney u-test was used to compare means between groups. count data were expressed as frequencies (%), and the chi-square test and fisher’s exact test were used to compare groups. for ipss and qol 24-months after surgery, the extent of improvement in voiding, obstruction, irritation symptoms, and qol was evaluated using the validity evaluation index. the safety of the procedures was assessed according to the clavien grading system and the ctcae. the validity evaluation index was defined as the ratio of the indexes reviewed 24 months after surgery to the preoperative indexes, with ≤ 0.25 rated as excellent, ≤0.5 as good, ≤0.75 as average, and >0.75 as poor. a p<0.05 was considered significantly different. results baseline characteristics according to the calculation result of r, the minimum sample size was 50.(9) patient inclusion and distribution during follow-up (including reasons for data deletion) are illustrated in a flow chart (figure 1). the average ages of patients in the pae + turp and turp groups were 73.49 ± 8.48 and 72.47 ± 7.12 years, respectively. preoperative psa, pv, pvr, qmax, pdetqmax, ipss scores, qol scores, or other baseline data were similar between groups ( p> 0.05, table 1). safety and complications there were no deaths in the perioperative period in either group. postoperatively, there were 100 adverse events in the pae + turp group and 256 in the turp group (table 2). the distribution of adverse events in terms of severity was similar between the groups (p = 0.984, table 2). clavien grades ≤ ⅱ and ≥ ⅲ accounted for 96.7 % and 3.3 % of the patients, respectively, and the number of complications with clavien grades ≥ ⅲ occurred in two and five cases, respectively, in both groups (p = 0.984, table 3). comparison of clinical data compared with the turp group, the pae + turp group had shorter operative time (68.56 ± 14.98 min vs. 128.40 ± 27.51 min, p < 0.001), faster resection of the adenoma (73.34 ± 8.14 g/h vs. 45.33 ± 7.06 g/h, p < 0.001), less intraoperative blood loss (34.02 ± 14.91 ml vs. 65.87 ± 43.94 ml, p < 0.001), less postoperative bladder irrigation time (1.66 ± 0.87 days vs. 2.43 ± 1.38 days, p < 0.001) and catheter retention time (7.59 ± 2.04 days vs. 9.11 ± 3.48 days, p = 0.011); however, the costs of pae + turp were higher relative to turp alone (42369.71 ± 13722.51 rmb vs. 26214.28 ± 6910.75 rmb, p < 0.001). in contrast, the asa scores, weight of resected tissue and length of hospital stay were similar between two groups (p > 0.05, table 3). comparison of follow-up metrics from baseline to 24-months post-surgery in both groups, ipss, qol, nih-cpsi, pv, pvr volume, qmax, pdetqmax, psa, and urodynamic obstruction (ics) were markedly better relative to baseline (figure 2). at 3-months post-surgery, both groups’ ipss scores and qmax (p > 0.05) were similar. however, at 6-, 12-, and 24-months post-surgery, the ipss scores and qmax were significantly lower in the pae + turp group than in the turp group (p < 0.05, figure 2a and 2g). at 3-, 6-, and 12-months post-surgery, the qol scores between the two groups were similar (p > 0.05). however, at 24-months, the qol scores in the pae + turp group were significantly lower than those in the turp group (p < 0.05, figure 2b). the nih-cpsi scores in the pae + turp group were significantly higher than those in the turp group at 3-, 6-, and 12months post-surgery (p < 0.05). the nih-cpsi scores were similar between the groups at 24-months (p > 0.05, figure 2c). the pv was significantly lower in the pae + turp group than in the turp group at 3-, 6-, 12-, and 24-months (p < 0.05, figure 2e). the international index of erectile function short form 5 score and pvr volume were similar between the groups (p > 0.05, figures 2d and 2f). there was no apparent discrepancy in psa between the two groups at 3and 6-months post-surgery (p > 0.05), whereas psa in the turp group was significantly higher than those in the pae + turp group at 12and 24-months post-surgery (p < 0.05, figure 2i). finally, pdetqmax and ics were similar between the two groups at 6-months post-surgery (p > 0.05); however, the values were better in the pae + turp group than in the turp group at 12and 24 months (p < 0.05, figure 2h and 2j). validity evaluation at 24-months post-surgery, 167 patients in both groups showed apparent improvement in the ipss and qol scores compared with baseline values (p < 0.05, table 4). although the ipss and qol scores increased in both groups at 12-months post-surgery, the pae + turp group showed significantly better improvement than the turp group in total ipss scores, voiding period, storage period, and qol scores (p < 0.05). the pae + turp group showed more significant improvement in voiding symptoms than in storage symptoms, with 42.3% and 36.5% rated excellent, respectively. however, the opposite was true for the turp group, with 11.3% and 19.1% being rated excellent. discussion bph is the most common reason for luts in middle-aged and older men. furthermore, approximately 25–60% of men will suffer from bph during their lifetime,(10) and 25% will suffer from moderate-to-severe luts, characterized by urinary voiding and storage problems.(11) the initial treatment regimen for bph is usually pharmacological, with alpha-blockers and 5-alpha-reductase inhibitors being the drugs of choice.(12) despite advances in modern drug therapy, 30% of 40-year-old men who live to age 80 undergo surgery because of failure of drug therapy.(13) following european or american urological guidelines, tuip (transurethral incision of the prostate) is recommended for pv less than 30 cm3, (14-15) while turp is the gold standard for patients with a prostate volume of less than 80 ml and moderate-to-severe luts secondary to prostate obstruction.(15). in recent decades, turp has shown promising clinical efficacy; however, it is accompanied by several complications, including the need for blood transfusion (2.0–8.4%),(16-17) retrograde ejaculation (23%),(18) urinary incontinence (3%),(19) urinary tract infection (7.7%),(18) urethral stricture (6.2%),(18) and transurethral resection syndrome (0.8–1.4%).(16-17) for patients with larger pv, turp may not resect all hyperplastic tissue completely, and there is a high risk of complications and postoperative recurrence.(20) traditionally, open prostatectomy has been chosen to treat large bph; however, most middle-aged and elderly bph patients, especially high-risk patients, have difficulty tolerating this procedure. anesthesia and postoperative complications are the primary problems faced by elderly patients with large glands and multiple underlying diseases such as coronary artery disease and cerebral infarction, for whom the choice of surgical approach remains unclear.(21) and our study provides some reference for clinical urologists in choosing surgical options for patients with large-volume prostate. in recent years, minimally invasive interventional procedures have been used to prevent or treat bleeding before and after prostate surgery because there is less trauma, lower risk, faster recovery, and no need for general anesthesia.(21) pae is emerging as a preferred minimally invasive therapy, with data published on more than 1,000 pae cases showing clinical outcomes similar to those of turp.(22) theurich et al.(11) showed that 24-months after pae, there was a 21%, 44%, and 55% reduction in pv, pvr and ipss, respectively. additionally, the authors noted significant improvements in qol (60%), storage (–50%), and voiding (–58%) symptoms (p < 0.001).(10) a recent meta-analysis (15) of six high-quality randomized controlled studies showed that pae does not improve pv and qmax as much as turp; however, it generates similar improvements in ipss, qol, psa, and pv, with a lower incidence of sexual dysfunction. these findings suggest that pae could be an alternative therapy for patients with bph who are unwilling to undergo surgery or have contraindications to surgery. patients with bph have increased levels of angiogenic factors in the glandular tissues and increased microvascular density, which leads to the proliferation of prostatic interstitial cells, which leads to less urinary tract obstruction. pae causes local tissue ischemia and hypoxia by selective embolization of the pa, which decreases plasma testosterone levels and reduces smooth muscle alpha-adrenergic receptors, leading to decreased pv and bladder neck relaxation, ultimately relieving luts.(23-24) although pae treats prostate bleeding and severe luts, it does not entirely alleviate bladder outlet obstruction caused by a large gland. because if this, many patients (21%) undergo more invasive therapy within 24-months after pae owing to unsatisfactory outcomes.(3) from these lines of evidence, the choice of pae as the firstline therapy option for bph remains controversial. in the current study, we performed pae before turp to help reduce intraoperative bleeding, shorten operation time and minimize postoperative complications for patients with advanced age, underlying disease, or coagulation disorders. few studies have reported the combination of turp and pae, and there is an absence of large-scale and long-term studies to assess this therapy's sustained efficacy and safety in treating giant ( ≥ 100 ml) prostate enlargement. the pa is small in diameter (approximately 0.5–2.0 mm) and has a complex origin, including the subvesical artery, the inferior rectal artery, the internal pudendal artery, the obturator artery, and the vas deferens arteries. the subvesical artery is the most common, followed by the inferior rectal artery.(25) the key to pae for bph is highly dependent on the precise recognition and embolization of the pa. middle-aged and elderly patients often have severe arteriosclerosis, resulting in tortuous and narrowed vessels that cause pae procedures to fail or necessitate unilateral embolization. for these patients, the efficacy of unilateral pae is worse than that of bilateral pae, and postoperative prostate collateral vessel reconstruction and residual prostate tissue regeneration can lead to re-obstruction of the prostate.(26) for this reason, only patients with successful bilateral pa embolization were included in this study to reduce bias and improve the accuracy of our results. common complications after pae include hematuria, urinary retention, urinary tract infection, and ischemia of the bladder wall and glans penis; however, these complications do not require surgical correction and usually self-resolve.(13) a recent small retrospective analysis by tang et al.(3) with limited follow-up showed better outcomes, more safer and fewer postoperative complications of pae + turp for treating patients with giant bph than turp alone. however, this study had a small sample size and lacked reliable long-term follow-up data; therefore, the longterm treatment effect of pae + turp to treat large bph remains questionable. our study has several significant findings beyond the study conducted byyang et al.(3) first, the pae + turp group had lower operative time, intraoperative blood loss, postoperative bladder irrigation time, and catheter retention time than the turp group, while the speed of lesion resection and cost were higher than in the turp group; these findings agree with the previous studies.(7) our findings suggest that turp combined with pae therapy (despite the higher expense) can reduce intraoperative bleeding and lower the risk of surgery, making the procedure faster and resulting in a shorter postoperative recovery time. the reason for longer catheterization time than that in literature (27) on turp of our study is to prevent secondary bleeding caused by premature removal of catheter and reduce the probability of postoperative urethral stricture. second, at 24-months post-surgery, the pae + turp regimen showed significantly better ipss, qol, pv, qmax, psa, and ics than the turp group. additionally, compared to the turp group, the validity evaluation index showed a more significant improvement in ipss and qol postoperative scores in the pae + turp group relative to baseline, demonstrating the satisfactory long-term results of pae + turp in patients with giant bph. finally, we found a comparable distribution of postoperative adverse event severity classes in the pae + turp and turp alone groups, suggesting that pae as a preoperative adjunctive therapy has a minor impact on postoperative complications after turp; this finding was not reported in previous studies. to note, with the rapid development of modern surgical armamentarium of bph surgery,(28) endoscopic enucleation of the prostate (eep) techniques, such as holmium laser enucleation of the prostate (holep),(29) were reported to show the ability to surpass turp both in outcomes and safety for giant prostates, implying the use of more choices for patients with giant bph. our study has some limitations. first, this single-center study included a relatively small sample that may not reflect key sociographic clinical differences. second, the follow-up time of our study was short. future studies should follow up patients for at least 5 years to fully assess the long-term efficacy of treatment. lastly, we only compared the differences in the outcomes between turp and pae + turp, while theurich et al.(10) reported that only pae could help improve voiding and storage symptoms. due to the limitations of this study, these data must be validated in longterm, multicenter, prospective clinical controlled trials. moreover, we will compare differences between pae, turp, and pae + turp in future studies. conclusion in summary, our research indicates that pae + turp is a more suitable surgical option for patients with large-volume prostate (> 100 ml) than turp alone. it can accelerate recovery and significantly improve postoperative quality of life without apparent increase in risk. acknowledgement the study was supported by science and technology program of suzhou (slj201906). all the raw data can be accessible from https://figshare.com/s/39b3cb32feb925a1458c. conflict of interest the authors report no conflict of interest. references 1. langan rc. benign prostatic hyperplasia. prim care. 2019;46:223-32. 2. capdevila f, insausti i, galbete a, sanchez-iriso e, montesino m. prostatic artery embolization versus transurethral resection of the prostate: a post hoc cost analysis of a randomized controlled clinical trial. cardiovasc intervent radiol. 2021;44:1771-7. https://figshare.com/s/39b3cb32feb925a1458c 3. tang y, wang rl, ruan dd, et al. retrospective observation of the efficacy and safety of prostatic artery embolization combined with transurethral resection of the prostate and simple transurethral resection of the prostate in the treatment of large (> 100 ml) benign prostatic hyperplasia. abdom radiol (ny). 2021;46:5746-57. 4. abt d, müllhaupt g, hechelhammer l, et al. prostatic artery embolisation versus transurethral resection of the prostate for benign prostatic hyperplasia: 2-yr outcomes of a randomised, open-label, single-centre trial. eur urol. 2021;80:34-42. 5. lebdai s, chevrot a, doizi s, et al. surgical and interventional management of benign prostatic obstruction: guidelines from the committee for male voiding disorders of the french urology association. prog urol. 2021;31:249-65. 6. ayyagari r, powell t, staib l, et al. prostatic artery embolization using 100300-μm trisacryl gelatin microspheres to treat lower urinary tract symptoms attributable to benign prostatic hyperplasia: a single-center outcomes analysis with medium-term follow-up. j vasc interv radiol. 2020;31:99-107. 7. ekengren j, hahn rg. blood loss during transurethral resection of the prostate as measured by the hemocue photometer. scand j urol nephrol. 1993;27:5017. 8. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 9. chow s, shao j, wang h. sample size calculations in clinical research (2nd ed.). chapman & hall/crc biostatistics series; 2008. page 61. 10. knight gm, talwar a, salem r, mouli s. systematic review and meta-analysis comparing prostatic artery embolization to gold-standard transurethral resection of the prostate for benign prostatic hyperplasia. cardiovasc intervent radiol. 2021;44:183-93. 11. theurich at, leistritz l, leucht k, et al. influence of prostate artery embolization on different qualities of lower urinary tract symptoms due to benign prostatic obstruction. eur urol focus. 2022;8:1323-30. 12. xu xf, liu gx, zhu c, et al. α1-blockers and 5α-reductase inhibitors are the most recommended drugs in treating benign prostatic hyperplasia: an evidence-based evaluation of clinical practice guidelines. front pharmacol. 2020;11:311. 13. neymark ai, karpenko aa, neymark ba, et al. superselective prostatic artery embolization in the treatment of large benign prostatic hyperplasia. urologia. 2021;88:374-81. 14. sarier m, duman i, kilic s, et al. comparative results of transurethral incision with transurethral resection of the prostate in renal transplant recipients with benign prostate hyperplasia. urol j. 2018;15:209-213. 15. xu z, zhou z, mu y, cai t, gao z, liu l. an updated meta-analysis of the efficacy and safety of prostatic artery embolization vs. transurethral resection of the prostate in the treatment of benign prostatic hyperplasia. front surg. 2021;8:779571. 16. reich o, gratzke c, bachmann a, et al. morbidity, mortality and early outcome of transurethral resection of the prostate: a prospective multicenter evaluation of 10,654 patients. j urol. 2008;180:246-9. 17. ahyai sa, lehrich k, kuntz rm. holmium laser enucleation versus transurethral resection of the prostate: 3-year follow-up results of a randomized clinical trial. eur urol. 2007;52:1456-63. 18. gilling p, barber n, bidair m, et al. three-year outcomes after aquablation therapy compared to turp: results from a blinded randomized trial. can j urol. 2020;27:10072-9. 19. bachmann a, tubaro a, barber n, et al. a european multicenter randomized noninferiority trial comparing 180 w greenlight xps laser vaporization and transurethral resection of the prostate for the treatment of benign prostatic obstruction: 12-month results of the goliath study. j urol. 2015;193:570-8. 20. suskind am, walter lc, zhao s, finlayson e. functional outcomes after transurethral resection of the prostate in nursing home residents. j am geriatr soc. 2017;65:699-703. 21. bilhim t, bagla s, sapoval m, carnevale fc, salem r, golzarian j. prostatic arterial embolization versus transurethral resection of the prostate for benign prostatic hyperplasia. radiology. 2015;276:310-1. 22. insausti i, sáez de ocáriz a, galbete a, et al. randomized comparison of prostatic artery embolization versus transurethral resection of the prostate for treatment of benign prostatic hyperplasia. j vasc interv radiol. 2020;31:88290. 23. sun f, crisóstomo v, báez-díaz c, sánchez fm. prostatic artery embolization (pae) for symptomatic benign prostatic hyperplasia (bph): part 2, insights into the technical rationale. cardiovasc intervent radiol. 2016;39:161-9. 24. noor a, fischman am. prostate artery embolization as a new treatment for benign prostate hyperplasia: contemporary status in 2016. curr urol rep. 2016;17:51. 25. moya c, cuesta j, friera a, gil-vernet sedó jm, valderrama-canales fj. cadaveric and radiologic study of the anatomical variations of the prostatic arteries: a review of the literature and a new classification proposal with application to prostatectomy. clin anat. 2017;30:71-80. 26. tang y, zhang jh, zhu yb, et al. effect of superselective prostatic artery embolization on benign prostatic hyperplasia. abdom radiol (ny). 2021;46:1726-36. 27. sun f, sun x, shi q, zhai y. transurethral procedures in the treatment of benign prostatic hyperplasia: a systematic review and meta-analysis of effectiveness and complications. medicine (baltimore). 2018;97(51):e13360. 28. reichelt ac, suarez-ibarrola r, herrmann trw, miernik a, schöb ds. laser procedures in the treatment of bph: a bibliometric study. world j urol. 2021;39:2903-11. 29. das ak, teplitsky s, humphreys mr. holmium laser enucleation of the prostate (holep): a review and update. can j urol. 2019;26(4 suppl 1):13-19. correspongding author: zhang xuefeng, ph.d. the first affiliated hospital of soochow university, suzhou city, jiangsu province, prc. tel: +86 13041470376 e-mail: drzhangxuefeng@126.com. figure legends figure 1. flow chart of the distribution of patients during the study period. pae, prostatic artery embolization; turp, transurethral resection of the prostate. figure 2. time course of parameters of urodynamics. a. ipss, b. qol, c. nih-cpsi, d. iief-5, e. pv, f. pvr volume, g. qmax, h. pdetqmax, i.psa, j. urodynamic obstruction(ics). points were showed as mean and standard deviation. the number of enrolled patients varied with the changes of the follow-up visits and there were 61 patients in pae+turp group and 150 patients in turp group at baseline, 61 patients in pae+turp group and 149 patients in turp group at 3-month visit, 61 patients in pae+turp group and 149 patients in turp group at 6-month visit, 59 patients in pae+turp group and 142 patients at 12-month visit, 52 patients in pae+turp group and 115 patients in turp group at 24-month visit. *, p < 0.05; **, p < 0.01; ***, p < 0.001. table 1. comparison of baseline characteristics of all enrolled patients between pae + turp group and turp group. characteristic pae+turp turp p n 61 150 hbp (yes / no), n (%) 33 (15.6 %) / 28 (13.3 %) 72 (34.1 %) / 78 (37 %) .515 dm (yes / no), n (%) 6 (2.8 %) / 55 (26.1 %) 22 (10.4 %) / 128 (60.7 %) .475 age (yr), mean ± sd 73.49 ± 8.48 72.47 ± 7.12 .183 bmi (kg/m2), mean ± sd 24.28 ± 3.24 24.33 ± 3.20 .964 psa (ng/ml), mean ± sd 6.95 ± 3.53 7.03 ± 3.35 .813 pv (ml), mean ± sd 123.60 ± 29.29 123.50 ± 25.32 .473 pvr volume(ml), mean ± sd 166.5 ± 125.00 143.5 ± 7.97 .538 ipss, mean ± sd 26.95 ± 4.55 26.53 ± 3.87 .377 qol, mean ± sd 5.00 ± 0.77 4.95 ± 0.61 .702 qmax (ml/s),mean±sd 5.63 ± 2.91 6.28 ± 2.80 .096 pdetqmax (cmh2o), mean ± sd 87.26 ± 22.44 82.23 ± 19.67 .166 nih-cpsi, mean ± sd 31.31 ± 5.49 31.53 ± 4.15 .591 iief-5, mean ± sd 10.70 ± 5.36 11.09 ± 4.48 .316 pae, prostate artery embolization; turp, transurethral resection of the prostate; hbp, high blood pressure; dm, diabetes mellitus; bmi, body mass index; psa, prostate specific antigen; pv, prostate volume; pvr, postvoid residual; ipss, international prostate symptom score; qol, quality of life; qmax, maximum urinary flow rate; pdetqmax, detrusor pressure of maximum urinary flow rate; nih-cpsi, national institutes of health-chronic prostatitis symptom index; iief, international index of erectile function; sd, standard deviation table 2. distribution and managements of adverse events after operation in pae+turp group and turp group based on common terminology criteria for adverse events (ctcae). type of complications pae+turp group turp group managements hematuria, mild 15 14 hemostatic drug application, bladder flushing, urinary canal traction hematuria, severe 1 7 blood transfusion, surgical hemostasis irritation, pain, discomfort 41 137 acesodyne, antispasmodic drug urinary tract infection 36 80 anti-infective drug urinary retention 3 13 catheterization strictures (meatal) 2 4 urethral dilatation strictures (bladder neck) 0 1 transurethral resection of the bladder neck other adverse events 2 9 total 100 256 pae, prostate artery embolization; turp, transurethral resection of the prostate table 3. comparison of intraoperative and postoperative indexes between pae + turp group and turp group. characteristic pae+turp turp p n 61 150 asa scores, n(%) .4303 characteristic pae+turp turp p i 17 (8.1 %) 48 (22.7 %) ii 39 (18.5 %) 92 (43.6 %) iii 5 (2.4 %) 10 (4.7 %) operation time (min), mean ± sd 68.56 ± 14.98 128.40 ± 27.51 < .001 resected tissue weight (g), mean ± sd 96.97 ± 26.99 96.14 ± 24.23 .859 speed of excised lesion (g/h), mean ± sd 73.34 ± 8.14 45.33 ± 7.06 < .001 intraoperative blood loss (ml), mean ± sd 34.02 ± 14.91 65.87 ± 43.94 < .001 postoperative bladder flushing time (d), mean ± sd 1.66 ± 0.87 2.43 ± 1.38 < .001 postoperative catheter retention time (d), mean ± sd 7.59 ± 2.04 9.11 ± 3.48 .011 hositalization time (d), mean ± sd 3.93 ± 1.44 4.27 ± 1.53 .057 cost (rmb), mean ± sd 42369.71 ± 13722.51 26214.28 ± 6910.75 < .001 clavien grade, n (%) .984 ≤ii 59 (28.0 %) 145 (68.7 %) ≥iii 2 (0.9 %) 5 (2.4 %) asa, american society of aneshesiologists; pae, prostate artery embolization; turp, transurethral resection of the prostate; rmb, chinese yuan; sd, standard deviation table 4. comparison of the ratio of parameters of ipss and qol at 24 months after operation between pae+turp group (n=52) and turp group (n=115). item group curative effect grade case percentage(%) p ipss score ratio pae+turp excellent 17 32.7 % .002 good 35 67.3 % average 0 0 % poor 0 0 % turp excellent 13 11.3 % good 99 86.1 % average 3 2.6 % poor 0 0 % voiding score ratio pae+turp excellent 22 42.3 % < .001 good 30 57.7 % average 0 0 % poor 0 0 % turp excellent 13 11.3 % good 97 84.4 % average 5 4.3 % poor 0 0 % storage score ratio pae+turp excellent 19 36.5 % .039 good 33 64.5 % average 0 0 % poor 0 0 % turp excellent 22 19.1 % good 91 79.1 % average 2 1.7 % poor 0 0 % qol pae+turp excellent 16 30.8 % .012 good 35 67.3 % average 1 1.9 % poor 0 0 % turp excellent 16 13.9 % good 82 71.3 % average 16 13.9 % poor 1 0.9 % pae, prostate artery embolization; turp, transurethral resection of the prostate; ipss, international prostate symptom score; qol, quality of life endourology and stone disease 148 urology journal vol 7 no 3 summer 2010 comparison of intranasal desmopressin and intramuscular tramadol versus pethidine in patients with renal colic samad hazhir, yadollah ahmadi asr badr, javad nasiri darabi purpose: to study the safety and efficacy of intranasal desmopressin and intramuscular tramadol versus pethidine for treatment of renal colic. materials and methods: a total of 90 adult patients who presented with renal colic to the emergency wards were recruited in this study. the patients were randomly assigned to receive 100 mg intramuscular tramadol, 40 μg intranasal desmopressin, or 40 μg intranasal desmopressin plus 100 mg intramuscular tramadol. the severity of the pain was assessed using visual analogue scale. results: the studied patients consisted of 49 men and 41 women with the mean age of 35.20 ± 13.26 years (range, 16 to 82 years). there was no statistically significant difference regarding the mean age (f [2, 89] = 2.98, p = .056) and gender differences (x2 = 3.3, df = 2, p = .19) in three groups. there was also no statistically significant difference considering pain relief in 3 studied groups (p = .2). conclusion: we concluded that narcotics such as pethidine can not be replaced by tramadol in patients with renal colic, but tramadol, desmopressin, or both in combination can reduce pethidine requirement. urol j. 2010;7:148-51. www.uj.unrc.ir keywords: renal colic, tramadol, desmopressin department of urology, tabriz university of medical sciences, tabriz, iran corresponding author: samad hazhir, md department of urology, tabriz university of medical sciences, tabriz, iran tel: +98 914 115 7380 fax: +98 411 6693 2230 e-mail: samadhazhir@yahoo.com received july 2009 accepted february 2010 introduction urinary stone is a common urological disease. most patients present with sudden and severe pain while excreting a urinary calculus. the pain, called renal colic, can be localized in the flanks or refers to the inguinal and the genitalia areas depending on the place of the calculus in the urinary tract. renal colic is caused by expansion of the renal capsule due to the passage of the calculus from the ureter which has a colic nature, ie, the pain of the patient exacerbates with each ureteral peristalsis trying to expel the calculus, then, the pain will decrease after some time and again this process will be repeated. large stones logged in the renal pelvis may be painless, but can result in renal dysfunction. hematuria may be another sign of the urinary calculus.(1) pain relief is the first issue which should be addressed in patients with renal colic. spasmolytic drugs such as hyoscine and dicyclomine are traditionally prescribed for renal colic. there is no evidence that buscopon (hyoscine butylbromide) reduces the need for narcotics in renal colic.(2) nonsteroidal anti-inflammatory drugs such as diclofenac, while inhibiting desmopressin and tramadol in renal colic—hazhir et al 149urology journal vol 7 no 3 summer 2010 prostaglandins release, might be the next choice,(3,4) but its paranteral form is not available in iran. the common recommended treatment is narcotics such as pethidine or morphine, but they accompany with some side effects and difficulties. first, narcotics are not available in all the clinics, especially private clinics. therefore, tramadol is used for treatment of renal colic in some clinics.(5,6) the second problem, with regard to prescription of narcotics, is related to their abuse. there are other treatments for acute renal colic. aminophylline infusion also reduces the pain and narcotics requirement.(7) active topical heating is an easy way to alleviate the pain of patients suffering from renal colic in an emergency ward. (8) tamsulosin (an alpha blocker) may be useful in provoking stone passage in patients without previous interventions such as transurethral ureterolithotripsy or extracorporeal shock wave lithotripsy.(9,10) kidney, ureter, and bladder x-ray (kub), computed tomography (ct) scan, and ultrasonography are diagnostic tools for renal colic.(11) accuracy of ct scan is more than ultrasonography.(12) this study was performed to investigate the effectiveness of intramuscular tramadol, intranasal desmopressin,(13-15) or both in patients with renal colic. materials and methods this clinical trial was carried out on 105 adult patients who presented with renal colic to the emergency wards of imam khomeini and sina hospitals, in tabriz, iran from february 2006 to october 2007. exclusion criteria were having taken any treatment before referring, being allergic to tramadol, or being hypertensive. the written informed consents were obtained form each patient. patients who were consented were recruited in this study. the presence of ureteral stone was confirmed using ultrasonography and kub. the subjective symptom, pain, was evaluated by visual analogue scale. the visual analogue scale is a conventional 10-point pain scale with a score of 10 representing the worst pain.(16) the study patients were randomly assigned into 3 groups according to the table of random numbers. the first group was treated with 100 mg intramuscular tramadol and their pain severity was subjectively and objectively examined every 10 minutes. the patient was asked to determine the severity of his or her pain at 10, 20, and 30 minutes after receiving the medication. the positive response was defined as complete pain relief after 30 minutes. in non-responsive patients, narcotics were administered. the second group received 40 μg intranasal desmopressin and was monitored every 10 minutes. the third group received 40 μg intranasal desmopressin plus 100 mg intramuscular tramadol and was monitored every 10 minutes assessing the pain severity. of 105 patients, 15 subjects were not able to tolerate the pain for 30 minutes. therefore, they left the study at the first minutes after therapeutic intervention and were treated with usual narcotics. review of literature on the effects of different drugs on pain relief in renal colic determines that the required sample size with adequate power is 90. p values less than .05 were considered statistically significant. results the studied patients consisted of 49 men and 41 women with the mean age of 35.20 ± 13.26 years (range, 16 to 82 years) (table 1). patients were similar in terms of baseline characteristics, including age (f [2, 89] = 2.98, p = .056) and sex (x2 = 3.3, df = 2, p = .19). repeated anova measures showed that there was no statistically significant difference treatment group age range (years) mean age ± standard deviation 1 16 to 82 37.13 ± 13.88 2 18 to 57 30.50 ± 10.11 3 19 to 75 37.96 ± 14.52 table 1. age of the study patients desmopressin and tramadol in renal colic—hazhir et al 150 urology journal vol 7 no 3 summer 2010 considering pain relief in 3 studied groups (p = .2) (figure). this means that the effect of the 3 types of treatments was similar, with regard to patient’s satisfaction, and none of them had superiority over others. of patients in tramadol, desmopressin, and tramadol plus desmopressin groups, 50%, 33.3%, and 46.7% required pethidine administration, respectively (table 2). there was no significant differences between study groups (x2 = 1.90, df = 2, p = .38). but the number of subjects needed pethidine after receiving desmopressin spray was lower than the other two groups (p = .034). women were 10% more likely to need pethidine. adverse events of patients who received desmopressin, 2 developed vertigo which resolved spontaneously within 10 minutes and one with the history of carpopedal spasm of the right hand experienced it, which was managed medically. discussion in a study by moro and colleagues in 1999, the effect of desmopressin on acute ureteral obstruction was studied by measurement of intra-ureteral pressure in 24 rats. they found a significant reduction in intra-ureteral mean pressure.(14) this can explain the mechanism of pain relief with desmopressin administration. lopes and associates divided 61 patients with renal colic into 3 groups and treated them with desmopressin, diclofenac, or combination of both. they observed that all 3 treatment methods led to the pain relief, but desmopressin relieved the pain less than the other 2 modalities within 20 to 30 minutes. however, some patients showed complete response to desmopressin.(13) our findings are consistent with that study. in another study by eray and coworkers in 2002, the effect of single dose of intramuscular tramadol was compared with mepridine in treating renal colic. pain relief was achieved in both groups, but mepridine was more effective. most patients required mepridine administration within 30 minutes.(6) in our study, 50% of the patients who received tramadol also required pethidine. constantinides and colleagues studied 108 patients with renal colic who received 40 μg intranasal desmopressin. fifty-eight patients (53.7%) recovered within 30 minutes, while 44 patients (40.7%) did not respond to desmopressin and received prostaglandin inhibitor drugs, and 6 remainders required intramuscular pethidine.(15) el-sherif and associates compared the efficacy of intranasal desmopressin and intramuscular diclofenac sodium in renal colic management. they administered 40 μg intranasal desmopressin for 18 patients. the pain of 8 patients (44.4%) relieved completely within 30 minutes while 10 subjects required intramuscular diclofenac and their pain relieved completely within 30 minutes. desmopressin plus diclofenac was effective for pain relief in more than 90% of the patients.(3) we used both drugs separately and pethidine was used when the patients’ pain did not improve. drug combination resulted in a decrease in percentage of pain relief across study groups. ppositive response (%)pethidine required (%)study groups (n) .0515 (50)15 (50)tramadol (30) .03420 (66.7)10 (33.3)desmopressin (30) .07116 (53.3)14 (46.7)tramadol plus desmopressin (30) table 2. groups’ difference considering need to pethidine after treatment intervention desmopressin and tramadol in renal colic—hazhir et al 151urology journal vol 7 no 3 summer 2010 pethidine administration. the number of subjects required pethidine in group 3 was more than group 2. we concluded that simultaneous administration of tramadol and desmopressin has no synergistic effect. however, further researches are required in this regard. we found that all three treatment regimens led to pain relief in renal colic, but pethidine was more effective than others. conclusion intranasal desmopressin relieved pain in about one third of the patients; thus, it is not as effective as narcotics. in addition, tramadol was more effective than desmopressin. conflict of interest none declared. references 1. kobayashi t, nishizawa k, mitsumori k, ogura k. impact of date of onset on the absence of hematuria in patients with acute renal colic. j urol. 2003;170:1093-6. 2. holdgate a, oh cm. is there a role for antimuscarinics in renal colic? a randomized controlled trial. j urol. 2005;174:572-5; discussion 5. 3. el-sherif ae, salem m, yahia h, al-sharkawy wa, al-sayrafi m. treatment of renal colic by desmopressin intranasal spray and diclofenac sodium. j urol. 1995;153:1395-8. 4. vernon mp, jack ws, dean ga. pathophysiology of urinary tract obstruction. in: wein ag, kavoussi lr, novick ag, partin aw, peters ca, eds. campbellwalsh urology. vol 2. 9 ed: philadelphia: saunders; 2007:1211-15. 5. grond s, sablotzki a. clinical pharmacology of tramadol. clin pharmacokinet. 2004;43:879-923. 6. eray o, cete y, oktay c, et al. intravenous singledose tramadol versus meperidine for pain relief in renal colic. eur j anaesthesiol. 2002;19:368-70. 7. djaladat h, tajik p, fard sa, alehashemi s. the effect of aminophylline on renal colic: a randomized double blind controlled trial. south med j. 2007;100:1081-4. 8. kober a, dobrovits m, djavan b, et al. local active warming: an effective treatment for pain, anxiety and nausea caused by renal colic. j urol. 2003;170:741-4. 9. dellabella m, milanese g, muzzonigro g. randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi. j urol. 2005;174:167-72. 10. dellabella m, milanese g, muzzonigro g. efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. j urol. 2003;170:2202-5. 11. kobayashi t, nishizawa k, watanabe j, ogura k. clinical characteristics of ureteral calculi detected by nonenhanced computerized tomography after unclear results of plain radiography and ultrasonography. j urol. 2003;170:799-802. 12. palmer js, donaher er, o›riordan ma, dell km. diagnosis of pediatric urolithiasis: role of ultrasound and computerized tomography. j urol. 2005;174: 1413-6. 13. lopes t, dias js, marcelino j, varela j, ribeiro s, dias j. an assessment of the clinical efficacy of intranasal desmopressin spray in the treatment of renal colic. bju int. 2001;87:322-5. 14. moro u, de stefani s, crisci a, de antoni p, scott ca, selli c. evaluation of the effects of desmopressin in acute ureteral obstruction. urol int. 1999;62:8-11. 15. constantinides c, kapralos v, manousakas t, mitropoulos d, alamanis c, dimopoulos c. management of renal colic with intranasal desmopressin spray. acta urol belg. 1998;66:1-3. 16. gould d, kelly d, goldstone l, gammon j. examining the validity of pressure ulcer risk assessment scales: developing and using illustrated patient simulations to collect the data information point: visual analogue scale. j clin nurs. 2001;10: 697-706. a new technique for continent urinary diversion: initial experience and description of the technique dario del biondo1*, giorgio napodano1, ferdinando di giacomo2, dante dino di domenico3, bruno feleppa1, sertac yazici4, aniello rosario zito1 purpose: orthotopic neobladder is a well-established surgical solution for continent urinary diversion after radical cystectomy. nevertheless, it still represents a challenging surgery. some critical issues of orthotopic bladder substitution include relevant complication rates, renal function impairment, urinary incontinence and patient quality of life. we present a new ileal neobladder technique, vesuvian orthotopic neobladder (von), performed for the first time at our institution in 2020. the main purpose of this new surgical procedure is to simplify and speed up the reservoir reconstruction through a ten standardized technical steps and obtain an appropriate bladder capacity at the same time. methods: inclusion criteria were muscle-invasive bladder carcinoma or non muscle-invasive high risk bladder cancer patients fit for bladder substitution. the exclusion criteria were locally advanced cancer, presence of hydronephrosis, renal or hepatic impairment. a chest-abdominal ct scan and urinary cytology were performed before the procedure. patients received neoadjuvant chemotherapy, as required. overall, operative time, bladder reconfiguration time, hospitalization time, catheterization time were recorded. all complications associated with the procedure were classified according to the clavien dindo score. the bladder volume was evaluated by ultrasound three months after the surgery. results: a total of six male patients diagnosed with non-metastatic muscle-invasive or high-risk non-muscle invasive bladder cancer who underwent radical cystectomy followed by von reconfiguration were included in the study. mean age was 62.8 (± 4.9) years; all selected patients enjoyed good health conditions (charlson comorbidity index 4-6). one patient presented with high-risk non-muscle invasive bladder cancer. four patients received neoadjuvant chemotherapy. mean overall operative time was 273.3 (±18.6) minutes. average time for neobladder reconstruction was 63.7 (± 16.1) minutes. there were no intraoperative complications. a single case of urethral anastomosis leakage occurred and was treated conservatively. bladder volume on ultrasound evaluation ranged between 250 and 290 ml. day time and nocturnal continence were observed in four and three patients, respectively. conclusion: the new von technique is a good alternative to traditional orthotopic bladder procedures. von reconstruction seems to offer the advantage of speeding up the procedure, reducing intestinal compromise with good storage capacity. the ten surgical steps can be considered a good starting point for further improvements in surgical technique. more robust data regarding the number of procedures and the duration of follow-up is required. keywords: neobladder; bladder cancer; urinary diversion; vesuvian orthotopic neobladder introduction bladder cancer (bc) is the 11th most common cancer worldwide and the second most common urological malignancy(1,2). radical cystectomy (rc) with urinary diversion is the standard treatment recommended for patients with non-metastatic muscle invasive bladder cancer (mibc) and for selected patients with high‐risk non-muscle‐invasive bladder cancer (nmibc). urinary diversion is the second important step after rc. over the past century, there has been an evolution of methods for lower urinary tract reconstruction following cystectomy, from being simple means of diverting urine to techniques allowing normal voiding pattern through the intact native urethra(3). these inno1department of urology, ospedale del mare, naples, italy. 2department of urology, irccs – crob, rionero in vulture, italy. 3department of urology, ospedale sacro cuore di gesù fatebenefratelli, benevento, italy. 4department of urology, hacettepe university school of medicine, ankara, turkey. correspondence: department of urology, ospedale del mare via enrico russo, naples, italy. e-mail: dariodelbiondo@libero.it. received december 2021 & accepted june 2022 vations in urinary diversion should allow patients to lead a near-normal lifestyle, eliminating the need for a urostomy and maintaining urinary continence. several techniques using ileum or colon for continent urinary diversion have been developed: camey reservoir, hautmann neobladder, studer pouch, “t” pouch, padua ileal neobladder, cecal, ileocecal and sigmoid reservoirs(4-10). despite extensive experience with these techniques, there is no consensus on the reservoir configuration that provides the best results. moreover, orthotopic neobladder remains a challenging and time-consuming procedure, burdened with a considerable rate of complication. we describe a novel orthotopic neobladder technique in patients with bladder cancer and fit for urology journal/vol 19 no. 4/ july-august 2022/ pp. 300-306. [doi:10.22037/uj.v19i.7088] urological oncology bladder substitution. our primary aim is to simplify and speed up the reconstruction of the neobladder through a practical technique which can be reproduced easily. materials and methods patients with non-metastatic muscle-invasive or highrisk non-muscle invasive bladder cancer and fit for bladder substitution, based on age, life expectancy, comorbidities and patient’s preferences, were included in the study. exclusion criteria were locally advanced cancer, presence of hydronephrosis, renal or hepatic failure. all patients underwent a routine preoperative examination, consisting of chest-abdominal computed tomography and urinary cytology. all cases were discussed by a multidisciplinary team, and neoadjuvant chemotherapy was administered as required. written informed consent was obtained from all patients following explanation of the surgical approach. neobladder reconstructions were performed by the same surgical team to avoid bias due to differences in surgical skills. all data were entered prospectively into an institutional database. in particular, overall operative time, bladder reconfiguration time, hospitalization and catheterization time were analyzed. all complications associated with the procedure were recorded and categorized according to the clavien-dindo score(11). retrograde cystography was performed on day 7 and on day 15 prior to removal of urethral catheter if no urine leakage occurred (figure 7). bladder volume was evaluated by ultrasound three months after the surgery. day and night time continence were defined as no pad use. surgical technique the vesuvian neobladder was constructed with 36 cm of ileum, isolated about 15-20 cm from the ileocecal valve. the neobladder configuration takes shape through 10 steps as described below. 1. selection of the intestinal loop, isolation of the loop and lateral-lateral anastomosis of the ileum with two 60/80 mm mechanical staplers (figures 1 and 2). 2. on the loop obtained, two 1.5 cm incisions are made: they are perpendicular to the mesentery at 12 and 24 cm from the right apex of the loop (figures 2 and 3). 3. the caudal horn is made by the introduction of a 60 mm stapler through the first incision (figure 3). 4. the left horn is made by inserting a 60 mm stapler through the second incision (figure 4a). 5. after removing the central part of the metal suture exceeding the intestinal resection (figure 4b), the afferent and efferent stumps are sutured together with a 60 mm mechanical stapler forming the right lateral horn (figure 4c). 6. a clover structure is obtained with three syma new technique if urinary diversion-del biondo et al. figure 1. selection of the intestinal loop, isolation of the loop and lateral-lateral anastomosis of the ileum with 2 mechanical staplers of 60/80 mm. patient 1 2 3 4 5 6 age (years) 72.4 59.8 63.4 59.9 61.1 60.2 smoker 30/day no former 20/ day no 20/ day cci 5 4 6 4 4 4 bmi 22.6 26.3 25.3 26.4 25.2 29.8 comorbidities copd ht ht, dm, chronic hepatitis chronic hepatitis ht ht asa score 3 2 3 2 2 3 clinical stage ct2n0m0 ct2n0m0 ct1n0m0+cis ct2n0m0 ct2n0m0 ct2n0m0 neoadjuvant ctx no yes no yes yes yes table 1. patient characteristics abbreviations: cci: charlson comorbidity index; bmi: body mass index; copd: chronic obstructve pulmonary disease; ht: hypertension; dm: diabetes mellitus; asa score: american society of anesthesiology score; ctx: chemotherapy. urological oncology 301 metrical horns. 7. the ureters are cannulated with 8fr ureteral catheters. the ureters are placed ipsilaterally to the horns and the uretero-neovesical anastomosis is performed in detached 3-0 monofilament stitches with anti-reflux technique. then, ureteral catheters are passed contralaterally through the anterior wall of the neobladder(figure 5). 8. the right ureter is anastomized at the level of the right lateral horn. the left ureter is anastomized similarly at the level of the apex of the left horn, at the site of the incision used for stapler’s introduction. after removing part of the suture made by the stapler on the right lateral horn, an opening of about 2-cm in diameter is obtained which is used to make the anastomosis of the ureter with anti-reflux technique: the ureter is spatulated dorsally and fixed to the anterior edge of the opening with three detached 3-0 monofilament stitches. in this way, the length of the ureter is sufficient to cover the entire area. the posterior margin of the opening is fixed to the ureter and the lateral margins are brought together to embrace the ureter with two 3-0 monofilament stitches passing through the anterior wall of the ureter (figures 6a and 6b). the same procedure is repeated on the left side. 9. the anastomosis with the urethra is performed with five detached 2-0 monofilament stitches at the apex of the caudal horn, at the site of the incision used for the stapler using 22 ch neobladder catheter with 15 cc in the balloon (figure 6c). 10. ureteral catheters are passed contralaterally through the abdominal wall to which they are fixed with 2-0 silk stitches. this concludes the packaging for the vesuvian orthotopic neobladder. results we performed vesuvian orthotopic neobladder from december 2020 to july 2021 in 6 male patients with ages ranging from 59.9 to 72.4 years. all selected patients enjoyed good health conditions (charlson comorbidity index 4-6) and none had previously undergone abdominal surgery. one patient presented with t1hg (high grade) and cis (carcinoma insitu), refractory to intravesical bcg (bacillus calmette-guerin) therapy. preoperative patient characteristics are listed in table 1. the mean overall operative time was 273.3 (±18.6) minutes. neobladder reconstruction time ranged from 48 to 80 minutes (average 63.7, ±16.1) [table 2]. no intraoperative complications occurred. we also did not encounter any complications in the early postoperative period, such as infection or urinary retention. one patient reported urethral anastomosis urine leakage on cystography and he was treated conservatively. after 30 days from surgery, the cystography was negative for leakage and then the bladder catheter was removed. patient 1 2 3 4 5 6 estimated blood loss (ml) 320 240 210 250 190 210 intraoperative transfusion rate (%) 0 0 0 0 0 0 operative time (min) 260 300 270 290 270 250 reconstruction time (min) 80 75 70 53 56 48 hospitalization (days) 15 17 14 13 15 20 catheterization time (days) 21 22 21 18 19 30 pathological stage pt3an0 pt1n0 pt1n0+cis pt3an0 pt2bn0 pt3bn0 table 2. operative outcomes. figure 2. selection of the intestinal loop, isolation of the loop and lateral-lateral anastomosis of the ileum with 2 mechanical staplers of 60/80 mm. vol 19 no 4 july-august 2022 302 a new technique if urinary diversion-del biondo et al. the bladder volume measured by ultrasound 3 months after the surgery ranged between 250 and 290 ml (mean 272.5, sd 17.1). no significant differences were found between preoperative and postoperative 3rd month serum creatinine and egfr values (data not shown). all patients, with the exception of two, reported full daytime urinary continence. nocturnal continence was reported by three patients (table 3). discussion radical cystectomy with urinary diversion is the standard treatment recommended for non-metastatic mibc and an option for high‐risk nmibc. orthotopic neobladder is the preferred option by patients undergoing rc, because it preserves quality of life better compared to other types of urinary diversions(12). the long-term results are valid and therefore, more investment is being made in the training of surgeons in the operative procedure and the number of patients who get neobladder in recent years is steadily increasing(13,14). the new techniques of the neobladder are able to achieve anatomical and physiological objectives, almost similar to the native bladder(15). nevertheless, it is very difficult for the surgeons to master the key step and the learning curve is very long(16). the objective pursued in the vesuvian ortothopic neobladder was to obtain an easy, fast and reproducible technique, at the same time ensuring an adequate neovesical volume. moreover, another relevant issue concerns the non-antiperistaltic horn that avoids neovescicoureteral reflux and hydronephrosis that accompany other techniques(17,18,19). compared to a y-shaped neobladder, our technique is just as easy to do and it optimizes the final volume achieved with the same length of ileal loop used, because the loop is completely detubulated contrary to the y technique. in fact, in the y technique, the right horn is present with active and contrary peristalsis to that of the ureter, while in our vesuvian technique this problem is eliminated because both ureters are anastomized in two horns obtained from complete detubularization of the loop(20,21). we believe that another advantage of our technique is that the ureters are anastomosed ipsilaterally to the neobladder horns. so, we don’t have to cross the left ureter to the right side or vice versa. in this way, the ureters are left in their anatomical position with no kinking and less risk for ischemia. laparoscopic and robotic approaches for radical cystectomy and intracorporeal neobladder have been described in recent years(14,22, 23,24). since laparoscopic and robotic suturing for the construction of the neobladder is a challenging procedure, the use of a stapler may facilitate the procedure, and thus reduce the operating time significantly. compared to the vesica ileale padovana technique, our approach offers the advantage of being completely done with the use of staplers(14,22). we believe that our results will encourage the use of stapler more frequently for intracorporeal robotic neobladder approach(22,23). the non-spherical configuration of our technique could be considered as a restrictable 3. functional outcomes. patient 1 2 3 4 5 6 day time continence no yes yes yes yes no night time incontinence no no yes yes yes no neobladder volume (ml) n/a 270 290 280 250 n/a abbreviations: n/a: not applicable. figure 3. two 1.5 cm incisions are made perpendicular to mesentery at 12 and 24 cm from the right apex of the loop. urological oncology 303 a new technique if urinary diversion-del biondo et al. kidney transplantation 136 tion, since the spherical configuration is the ideal form for maintaining a good storage volume. however, it should also be emphasized that our neobladder is packaged with 36 cm of ileum, one of the shortest lengths used among the neobladder packaging techniques, but obtaining an excellent final volume, which is between 250 and 290 cc. this can only be an advantage for the patient's future well-being(12,25). however, we believe there is a need for more comprehensive and robust data on larger series and longer follow-up. conclusions the new vesuvian orthotopical neobladder technique is a good alternative to traditional orthotopic bladder procedures and offers the advantage of speeding up the procedure, using a shorter bowel length and obtaining a good storage capacity. the ten surgical steps can be considered as a good starting point for additional surgical technique upgrades. more robust data, concerning number of procedures and length of follow-up, are required. figure 4. a 60-mm stapler is introduced through the first incision to make the caudal horn (4a), followed by a second 60-mm stapler through the second incision for the left horn (4b). after removal of the central part of the metal suture exceeding the intestinal resection, the afferent and efferent stumps are sutured together with a 60-mm mechanical stapler forming the right lateral horn (4c). figure 5. the ureters are cannulated with 8fr ureteral catheters. the ureters are placed homolaterally to the horns and the uretero-neovesical anastomosis is performed in detached 3-0 monofilament stitches with anti-reflux technique (6a, 6b). then ureteral catheters were passed contralaterally through the anterior wall of the neobladder. the anastomosis with the urethra is packaged with five detached 2-0 monofilament stitches at the apex of the caudal horn, site of the incision used for the stapler using 22 ch neobladder catheter with 15cc in the balloon (6c). vol 19 no 4 july-august 2022 304 a new technique if urinary diversion-del biondo et al. figure 6. the ureters are cannulated with 8fr ureteral catheters. the ureters are placed homolaterally to the horns and the uretero-neovesical anastomosis is performed in detached 3-0 monofilament stitches with anti-reflux technique (6a, 6b). then ureteral catheters were passed contralaterally through the anterior wall of the neobladder. the anastomosis with the urethra is packaged with five detached 2-0 monofilament stitches at the apex of the caudal horn, site of the incision used for the stapler using 22 ch neobladder catheter with 15cc in the balloon (6c). figure 7. the cystometric image of the neobladder on day 15. urological oncology 305 a new technique if urinary diversion-del biondo et al. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2020. ca cancer j clin. 2020;70:730. 2. sung h, ferlay j, siegel rl, et al. global cancer statistics 2020: globcan estimates of imcidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021;71:209-249. 3. aboumarzouk om, drewa t, olejniczak p, chlosta pl. laparoscopic radical cystectomy: neobladder or ileal conduit, debate still goes on. cent european j urol. 2014;67(1):9-15. 4. lilien om, camey m. 25-year experience with replacement of the human bladder (camey procedure). j urol. 2017 ;197:s173-s179. 5. hollowell cm, christiano ap, steinberg gd. technique of hautmann ileal neobladder with chimney modification: interim results in 50 patients. j urol. 2000 ;163:47-50. 6. studer ue, varol c, danuser h. orthotopic ileal neobladder. bju int. 2004 ;93:183-93. 7. stein jp, skinner dg. surgical atlas: the orthotopic t-pouch ileal neobladder. bju int. 2006 ;98:469-82. 8. kostakopoulos n, protogerou v, skolarikos a, et al. vip neobladder (padovana) reconstruction following radical cystectomy for bladder cancer complications, functional outcome and quality of life evaluation in 95 cases. ann ital chir. 2015 ;86:362-7. 9. fisch m, wammack r, thüroff j, hohenfellner r. the “mainz pouch” for bladder augmentation, bladder substitution, and continent urinary diversion. arch esp urol. 1992 ;45:903-14. 10. almassi n, bochner bh. ileal conduit or orthotopic neobladder: selection and contemporary patterns of use. curr opin urol. 2020 ;30:415-420. 11. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year classification. ann surg. 2009;250:187-96. 12. ali as, hayes mc, birch b, et al. health related quality of life (hrqol) after cystectomy: comparison between orthotopic neobladder and ileal conduit diversion. eur j surg oncol. 2015 ;41:295-9. 13. roghmann f, becker a, trinh qd, et al. updated assessment of neobladder utilization and morbidity according to urinary diversion after radical cystectomy: a contemporary uspopulation-based cohort. can urol assoc j. 2013 ;7:e552-60. 14. janssen gwb, ramkumar rr, lee bh, van der heijden ag. orthotopic urinary diversions after radical cystectomy for bladder cancer: lessons learned last decade. curr opin urol. 2021;31:580-85. 15. prcic a, begic e. complications after ileal urinary derivations. med arch. 2017 ;71:320324. 16. collins jw, tyritzis s, nyberg t, et al. robotassisted radical cystectomy (rarc) with intracorporeal neobladder what is the effect of the learning curve on outcomes? bju int. 2014 ;113:100-7. 17. steers wd. voiding dysfunction in the orthotopic neobladder. world j urol. 2000 ;18:330-7. 18. lee ks, montie je, dunn rl, lee ct. hautmann and studer orthotopic neobladders: a contemporary experience. j urol. 2003 ;169:2188-91. 19. barre ph, herve jm, botto h, camey m. update on the camey ii procedure. worl j urol. 1996;14:27-8. 20. hassan aa, elbendary m, radwan m, et al. long-term evaluation of modified orthotopic y-shaped ileal neobladder (tanta pouch) with left retro-colic chimney. int urol nephrol. 2020 ;52:681-686. 21. fontana d, bellina m, fasolis g, et al. y-neobladder: an easy, fast, and reliable procedure. urology. 2004;63:699-703. 22. dal moro f. "vesica patavina" (lat.). j robot surg. 2017 ;11:289-290. 23. bachour k, faiena i, salmasi a, et al. trends in urinary diversion after radical cystectomy for urothelial carcinoma. world j urol. 2018 ;36:409-416. 24. desai mm, gill is, de castro abreu al, et al. robotic intracorporeal neobladder during radical cystectomy in 132 patients. j urol. 2014; 192: 1734-1740. 25. philip j, manikandan r, venugopal s, desouza j, javlé pm. orthotopic neobladder versus ileal conduit urinary diversion after cystectomy--a quality-of-life based comparison. ann r coll surg engl. 2009 ;91:565-9. vol 19 no 4 july-august 2022 306 a new technique if urinary diversion-del biondo et al. comparison of the effect of steroids on the treatment of phimosis according to the steroid potencies jae-wook chung1†, hyun tae kim1†, se won jang1, yun-sok ha1, tae-hwan kim1, tae gyun kwon1,2, jun nyung lee1* purpose: this study aimed to evaluate the outcomes of topical steroid therapy according to potency as the first-line treatment for boys with symptomatic phimosis. materials and methods: from april 2017 to march 2019, we retrospectively reviewed 45 boys with severe phimosis (kikiros retractability grade 4 or 5) who presented with phimosis-related complications. during the first year of the study period, methylprednisolone aceponate (mpa, advantan®, potent topical steroid) was administered in 24 boys. hydrocortisone butyrate (hcb, bandel®, moderately potent topical steroid) was administered in 21 boys in the subsequent period. topical steroids were administered for 4–8 weeks in all patients. success of the therapy was determined by two conditions at 3 months after therapy: achieving kikiros grade 3 and less with disappearance of symptoms. results: of 45 boys, 35 (77.8%) achieved success of the therapy. mean age was 46.64±22.42 months. recurrence of phimosis with clinical complications was confirmed in three of 35 patients with initial success (8.6%) during the follow-up period. all boys with recurrence showed remission after additional topical steroid therapy. success rate of the mpa group was higher than that of the hcb group (91.7% and 61.9% respectively, p = .029). side effects associated with the topical steroid application were not observed in all children. conclusion: topical steroid application is an effective and safe procedure as first-line treatment in symptomatic boys with severe phimosis. moreover, the potency of topical steroids for the treatment of phimosis is considered a factor affecting the success rate. keywords: phimosis; steroid; potency introduction phimosis is a common disease in the field of pediatric urology.(1) phimosis is a condition in which the prepuce cannot be retracted over the glans penis, owing to narrowing of the preputial orifice or adhesions between the glans and prepuce. of newborn boys, 96% have nonretractable foreskin,(2) which is considered to be physiological phimosis. generally, adhesions between the prepuce and glans separate gradually with growth. ballooning of the prepuce on urination can contribute to resolution of physiological phimosis. it resolves in 50% of boys by one year of life but may persist in 6–10% of boys aged 3–9 years.(3) although most phimosis cases resolve over time without any symptoms or sequelae, severe phimosis may lead to inflammation of the foreskin and underlying glans (balanoposthitis), urinary retention, and urinary tract infection (uti), thus requiring treatment.(4) historically, circumcision has been the first treatment of phimosis. however, recently, topical corticosteroid application has become an efficient, safe, and less invasive alternative treatment.(5) numerous topical steroid therapies have been success1 department of urology, school of medicine, kyungpook national university, daegu, republic of korea. 2 joint institute for regenerative medicine, kyungpook national university, daegu, republic of korea. *correspondence: department of urology, school of medicine, kyungpook national university, daegu, republic of korea tel: +82-53-200-2166. fax: +82-53-200-2027. e-mail: ljnlover@gmail.com † the authors contributed equally to this work. received november 2020 & accepted august 2021 fully performed in the treatment of phimosis. several randomized placebo controlled trials have shown that various corticosteroids had 68–96% of efficacy.(6) furthermore, many clinical trials concerning phimosis therapy have demonstrated that treatment outcomes were most successful when the topical steroid is applied with gentle stretching or traction of the foreskin. (7,8) however, there are few studies comparing phimosis treatment according to topical steroid potency. therefore, we evaluated the outcomes of topical steroid therapy according to potency as the first-line treatment for boys with symptomatic phimosis. materials and methods this is a retrospective observational study of a single pediatric urology center. the present study was approved by the ethics committee (irb number: khun 2020-03-026). this study was performed in accordance with the ethical standards laid down in the 1964 declaration of helsinki and its later amendments. from april 2017 to march 2019, we retrospectively analyzed the data of 45 consecutive pediatric patients with a nonretractile severe phimosis (kikiros retractapediatric urology urology journal/vol 18 no. 6/ november-december 2021/ pp. 652-657. [doi: 10.22037/uj.v18i.6574] bility grade 4 or 5) who presented with phimosis-related complications, such as balanoposthitis, ballooning of the prepuce, uti, and voiding dysfunction. study population and patients’ enrollment are shown in figure 1. patients who had previously underwent phimosis treatment or had recurrent balanoposthitis or recurrent uti were excluded from this study. if the patients shows signs of secondary (pathological) phimosis which is typically caused by balanitis xerotica obliterans (bxo) such as cicatrizing prepuce scarring, pallor of the preputial opening or contracted white fibrous ring around the preputial orifice, circumcision was performed. there were 2 cases of bxo and we excluded these patients. patients with unavailable medical records or poor compliance to steroid treatment or without agreement for informed consent were excluded. phimosis grade was evaluated according to the classification of kikiros and woodward.(5,9,10) grade classifications are as follows; 1) grade 0, full retraction, not tight behind the glans, or easy retraction limited only by congenital adhesions to the glans; 2) grade 1, full retraction of foreskin, tight behind the glans; 3) grade 2, partial exposure of the glans, prepuce (no congenital adhesions) limiting factor; 3) grade 3, partial retraction, meatus just visible; 4) grade 4, slight retraction but some distance between the tip and glans, i.e., neither the meatus nor glans can be exposed; and 5) grade 5, absolutely no retraction (figure 2). topical steroids were used for 4–8 weeks in all patients. initial success of therapy was determined by two condieffect of topical steroid on phimosis according to potency-chung et al. variablesa all n=45 hcb n=21 mpa n=24 p-value age (months), continuous 46.64 ± 22.42 51.05 ± 26.04 42.79±18.40 0.222 age (months), categorical 0.322 < 36 months 14 (31.1%) 5 (23.8%) 9 (37.5%) ≥ 36 months 31 (68.9%) 16 (76.2%) 15 (62.5%) phimosis-related symptoms before steroid treatment balanoposthitis 19 (42.2%) 11 (52.4%) 8 (33.3%) 0.197 ballooning of the prepuce 21 (46.7%) 12 (57.1%) 9 (37.5%) 0.188 uti 4 (8.9%) 1 (4.8%) 3 (12.5%) 0.611 voiding dysfunction 14 (31.1%) 5 (23. %) 9 (37.5%) 0.322 kikiros grade at presentation 0.443 iv 37 (82.2%) 16 (76.2%) 21 (87.5%) v 8 (17.8%) 5 (23.8%) 3 (12.5%) steroid treatment duration (weeks) 5.93 ± 1.70 5.90 ± 1.76 5.96 ± 1.68 0.917 follow-up period (months) 14.62 ± 6.92 10.14 ± 6.37 18.54 ± 4.69 < 0.001 table 1. clinical characteristic of the two treatment groups adata are presented as mean±sd or number (percent) abbreviations: hcb, hydrocortisone butyrate; mpa, methylprednisolone aceponate; uti, urinary tract infection. figure 1. study population and patients’ enrollment. vol 18 no 6 november-december 2021 653 pediatric urology 654 tions at 3 months after therapy: achieving kikiros grade 3 and less with disappearance of symptom. recurrence was defined as the reappearance of grade iv or v phimosis or related symptoms during the follow-up period after the evaluation of the initial success. at the first visit and during the follow-up period, the assessment including physical examination of phimosis was performed by a single pediatric urologist with more than 10 years of experience (j.n. lee). during the first year of the study period (april 2017 to march 2018), methylprednisolone aceponate (mpa, 1mg/g, advantan®, potent topical steroid) was administered in 24 boys (53.3%). hydrocortisone butyrate (hcb, 1mg/g, bandel®, moderately potent topical steroid) was administered in 21 boys (46.7%) in the subsequent year (april 2018 to march 2019). the use of topical steroid ointment was explained to the parents and the steroid was applied to the patients by parents. the parents were educated about the possible adverse effect of the topical steroid. the application of topical steroid with gentle retraction of the prepuce was performed after washing and cleansing the penis. this regimen was repeated twice daily during the whole treatment period. age, phimosis-related complications before and after steroid treatment, kikiros grade before and after steroid treatment, combined comorbidities, periods of steroid variables all n=45 hcb n=21 mpa n=24 p-value success 35 (77.8%) 13 (61.9%) 22 (91.7%) 0.029 kikiros grade after steroid treatment na 0 5 (11.1%) 1 (4.8%) 4 (16.7%) 1 5 (11.1%) 2 (9.5%) 3 (12.5%) 2 7 (15.6%) 2 (9.5%) 5 (20.8%) 3 18 (40.0%) 8 (38.1%) 10 (41.7%) 4 8 (17.8%) 7 (33.3%) 1 (4.2%) 5 2 (4.4%) 1 (4.8%) 1 (4.2%) kikiros grade ≥ 4 after steroid treatment 10 (22.2%) 8 (38.1%) 2 (8.3%) 0.029 phimosis-related symptoms after steroid treatment 6 (13.3%) 4 (19.0%) 2 (8.3%) 0.396 balanoposthitis 1 (2.2%) 1 (4.8%) 0 (0.0%) ballooning of the prepuce 3 (6.7%) 1 (4.8%) 2 (8.3%) uti 0 (0.0%) 0 (0.0%) 0 (0.0%) voiding dysfunction 2 (4.4%) 2 (9.5%) 0 (0.0%) circumcision after steroid treatment 6 (13.3%) 4 (19.0%) 2 (8.3%) 0.396 recurrence in the success group 3/35 (8.6%) 1/13 (7.7%) 2/22 (9.1%) 0.999 table 2. comparison of the scores of the patients and the control group. abbreviations: hcb, hydrocortisone butyrate; mpa, methylprednisolone aceponate; na, nonavailable; uti, urinary tract infection. figure 2. phimosis grading system according to the classification of kikiros and woodward. effect of topical steroid on phimosis according to potency-chung et al. treatment, follow-up periods, circumcision after steroid treatment, success rate, and recurrence rate were analyzed between the two groups. we used student’s t-test for continuous variables and chi-square test or fisher’s exact test for noncontinuous variables. multivariate logistic regression model was used to analyze the variables such as age (continuous or categorical), phimosis-related complications and kikiros grade before treatment, steroid type, and treatment duration which can affect treatment outcome. statistical analyses were performed using spss for windows version 23 (ibm corp., armonk, ny, usa), and statistical significance was established with a p < .05. results patient’s demographic features and clinical characteristics before steroid treatment are shown in table 1. the mean age was 46.64 ± 22.42 months. 19 (42.2%) patients showed balanoposthitis, 21 (46.7%) ballooning of the prepuce, 4 (8.9%) uti, and 14 (31.1%) voiding dysfunction. kikiros grade iv at presentation was noted in 37 patients (82.2%) and v in 8 patients (17.8%). the mean duration of steroid treatment was 5.93 ± 1.70 weeks. the mean follow-up period was 14.62 ± 6.92 months, and the mpa group were followed longer (10.14 ± 6.37 versus 18.54 ± 4.69, p = .001) than the hcb group. table 2 shows outcomes of steroid treatment. overall success rate was 35/45 (77.8%), and there was a significant difference in success rate between the two groups (13/21 [61.9%] versus 22/24 [91.7%], p = .029). persistence of severe phimosis after steroid treatment was shown in 10 patients (22.2%). eight patients (38.1%) and 2 patients (8.3%) in the hcb and mpa groups, respectively, showed persistent severe phimosis (p = .029). phimosis-related symptoms after steroid treatment were observed in 4 patients in the hcb group and 2 patients in the mpa group (p = .396). circumcision was recommended in children with persistent symptoms concurrent of phimosis. furthermore, circumcision was recommended in symptomatic patients with severe phimosis, and 6 patients (13.3%) underwent the procedure (4 in the hcb group and 2 in the mpa group). during the follow-up period of 14.6 months, recurrence of severe phimosis with clinical complications was observed in 3 of 35 patients (8.6%) with initial success. all boys with recurrence showed remission after additional topical steroid therapy using mpa. side effects associated with topical steroid application were not observed in all children. multivariate logistic regression model analyses for predicting success showed that steroid type according to potency was the only independent factor for predicting success (hcb versus mpa, odds ratio [or] = 17.705 [1.566-200.219], p = .020) (table 3). discussion this study evaluated the outcomes of topical steroid therapy according to potency as the first-line treatment for boys with symptomatic phimosis. before the 1990– 2000s, circumcision was the only treatment available for children with phimosis. however, with the introduction of topical steroids and its popularization, surgery has become controversial among pediatric surgeons in the treatment of phimosis.(11) corticosteroids can be classified according to their potency although the standards of classification vary slightly from each country. among the topical steroids that we used in this study, hcb can be classified in the moderately potent group (category ii/iv) and mpa in the potent group (category iii/iv).(13,14) recently, topical steroid application is thought to be an effective and safe first-line medical therapy for the treatment of symptomatic phimosis in boys.(5) steroid promotes the resolution of phimosis through anti-inflammatory and immunosuppressive mechanisms, thus inhibiting local edema, fibrin deposition, and collagen synthesis.(14) several randomized placebo controlled trials have demonstrated that topical steroids had significant impact on partial or complete clinical resolution of phimosis.(11,15,16) in 2006, lee et al. evaluated 78 male infants with febrile uti and nonretractile phimosis who were prospectively randomized into the hydrocortisone (n = 39) and control (n = 39) groups.(17) they demonstrated that the response rate in the hydrocortisone group was 89.7% (35/39), which was significantly higher than the rate (20.5%; 8/39) in the control group. in 2009, letendre et al. performed double-blind, randomized, placebo controlled study to compare 2 months twice daily treatment of emollient cream (placebo group 1, n = 25) and variables phimosis, n p-value persistence n = 10 improvement n = 35 univariate multivariate or (95% ci) age (months), continuous 54.10 ± 30.01 44.51 ± 19.77 0.237 age (months), categorical 0.999* age < 36 3 11 age ≥ 36 7 24 balanoposthitis before treatment 3 16 0.481* ballooning before treatment 5 16 0.999* uti before treatment 0 4 0.561* voiding dysfunction before treatment 4 10 0.700* kikiros grade 0.059* iv 6 31 v 4 4 steroid type 0.029* 0.020 17.705 (1.566-200.219) hcb 8 13 mpa 2 22 periods of steroid treatment (months) 8.00 ± 3.27 6.23 ± 2.62 0.082 table 3. univariate and multivariate analyses predicting success. *fisher’s exact test abbreviations: or, odds ratio; uti, urinary tract infection; hcb, hydrocortisone butyrate; mpa, methylprednisolone aceponate. effect of topical steroid on phimosis according to potency-chung et al. vol 18 no 6 november-december 2021 655 pediatric urology 540 0.1% triamcinolone (experimental group 2, n = 21).(16) the success rate in group 1 was significantly lower than in group 2 (9 patients [39%] versus 16 [76%]). next, if we attend to the long-term results and side effects of topical steroid therapy as the first-line treatment for symptomatic phimosis, there are several studies performed previously. ku et al. performed prospective study including 108 boys who were treated with 0.05% betamethasone ointment from august 2001 to july 2014.(18) age ranged from 0.03 to 12.9 years. the success rate of first treatment course was 81.5%, and 60.2% of boys remained free from phimosis upon latest assessment. there were no side effects and follow-up period ranged from 0.4 to 4.4 years (mean follow-up period: 2.45 years). another study done by ghysel et al. in 2009 demonstrated long-term efficacy of topical application of a potent corticoid cream and skin stretching in the treatment of phimosis.(7) 462 prepubertal boys were included and 400/462 boys (86%) had a retractable prepuce after 6 weeks of treatment. after a median follow-up of 22 months, the treatment continued to be successful in 383/462 boys (83%). no local or systemic side effects were noted throughout the entire observation period. furthermore, there was a study which demonstrated that topical clobetasol propionate used twice daily for clinical treatment of phimosis did not affect the hypothalamus-pituitary-adrenal axis in most patients.(19) although there are many trials on topical steroid application as first-line medical treatment for phimosis, there are few trials comparing these various topical steroids according to potency. interestingly, the high-potency steroids, such as clobetasol and betamethasone, did not show superiority compared with low-to medium-potency steroids, such as hydrocortisone.(6) similarly, there is a more recent randomized open-label trial that compared topical prescription triamcinolone and over-thecounter hydrocortisone for the treatment of phimosis. in 2019, chamberlin et al. compared over-the-counter hydrocortisone 1% cream (very mild potency) and prescription triamcinolone 0.1% cream (median potency) for the medical management of symptomatic phimosis. (5) with a total of 32 boys completing the 12-week trial, the success rates were 61.5 % in the hydrocortisone arm and 68.4% in the triamcinolone arm. they revealed that there was no statistical difference between the two arms. on the contrary, in 2013, sookpotarom et al. evaluated whether the half-strength formula (0.02%) of betamethasone is as effective as 0.05 % betamethasone. (10) two strengths, 0.05% (n = 23) and 0.02% (n = 24), were randomly applied to 47 patients twice daily for 2 months. phimosis grade in the half-strength group was significantly lower than that in the 0.05% betamethasone group. similarly, in this study, we demonstrated that the success rate of the mpa group (potent topical steroid, category iii/iv) was significantly higher than that of the hcb group (moderately potent topical steroid, category ii/iv) (91.7% and 61.9%, respectively), and there were no serious side effects of topical steroid in the two groups. the real mechanism of action of the steroid is still unclear although it has been suggested that steroid acts through either a local anti-inflammatory process(20) or improvement of elasticity of the skin through the synthesis of elastic or collagen fibers.(21) nevertheless, we can provide assurances to parents that pediatric urology 433 the topical steroid is safe and produces nearly no local side effects in the treatment of phimosis. our trial to verify the effect of potency of topical steroid in the treatment of phimosis would be beneficial in counseling patients with respect to no established topical steroid regimen currently available. the limitations of the current study include a single-center study design, relatively small cohort size, short follow-up period, heterogeneous groups of patients, absences of control group and randomization, and retrospective nature of data collection. a retrospective study may always lead to a sampling bias. first of all, potential bias can exist due to the fact that two different topical steroid were applied in two different consecutive years leading to a difference in follow-up period between the groups. in addition, higher portion of patients under 36 months in the mpa group, although it is not statistically significant, could have functioned as crucial bias in determining the observed results of present study. finally, we believe that a strict adherence to the treatment regimen does not always occur when it comes to any treatment of children. in the near future, further large-scale population-based prospective studies of multi-institutional research involving whole factors concerning phimosis management should be performed. conclusions topical steroid application is an effective and safe procedure as first-line treatment in symptomatic boys with severe phimosis. in addition, the potency of topical steroids for the treatment of phimosis is considered a factor affecting the success rate. acknowledgements this research was supported by the basic science research program through the national research foundation of korea (nrf) & funded by the korean government (msit) (2018r1c1b5040264) (2019r1a2c1004046) (2019r1f1a1044473) (2019r1h1a1079839) (2020r1a2b5b03002344) (2020r1i1a3071568). conflict of interest none of the authors has any personal or financial con¬flict of interest. references 1. morris bj, matthews jg, krieger jn. prevalence of phimosis in males of all ages: systematic review. urology. 2020;135:12432. 2. shankar kr, rickwood am. the incidence of phimosis in boys. bju int. 1999;84:101-2. 3. oster j. further fate of the foreskin. incidence of preputial adhesions, phimosis, and smegma among danish schoolboys. arch dis child. 1968;43:200-3. 4. dewan pa, tieu hc, chieng bs. phimosis: is circumcision necessary? j paediatr child h. 1996;32:285-9. 5. chamberlin jd, dorgalli c, abdelhalim a, et al. randomized open-label trial comparing topical prescription triamcinolone to over-thecounter hydrocortisone for the treatment of phimosis. j pediatr urol. 2019;15:388 e1e5. 6. moreno g, corbalan j, penaloza b, pantoja t. effect of topical steroid on phimosis according to potency-chung et al. pediatric urology 656 vol 18 no 6 november-december 2021 657 topical corticosteroids for treating phimosis in boys. cochrane database syst rev. 2014cd008973. 7. ghysel c, vander eeckt k, bogaert ga. longterm efficiency of skin stretching and a topical corticoid cream application for unretractable foreskin and phimosis in prepubertal boys. urol int. 2009;82:81-8. 8. zampieri n, corroppolo m, camoglio fs, giacomello l, ottolenghi a. phimosis: stretching methods with or without application of topical steroids? j pediatr. 2005;147:705-6. 9. kikiros cs, beasley sw, woodward aa. the response of phimosis to local steroid application. pediatr surg int. 1993;8:329-32. 10. sookpotarom p, asawutmangkul c, srinithiwat b, leethochawalit s, vejchapipat p. is half strength of 0.05 % betamethasone valerate cream still effective in the treatment of phimosis in young children? pediatr surg int. 2013;29:393-6. 11. esposito c, centonze a, alicchio f, savanelli a, settimi a. topical steroid application versus circumcision in pediatric patients with phimosis: a prospective randomized placebo controlled clinical trial. world j urol. 2008;26:187-90. 12. torrelo a. methylprednisolone aceponate for atopic dermatitis. int j dermatol. 2017;56:6917. 13. luger ta. balancing efficacy and safety in the management of atopic dermatitis: the role of methylprednisolone aceponate. j eur acad dermatol venereol. 2011;25:251-8. 14. favorito la, gallo cbm, costa ws, sampaio fjb. ultrastructural analysis of the foreskin in patients with true phimosis treated or not treated with topical betamethasone and hyaluronidase ointment. urology. 2016;98:138-43. 15. letendre j, barrieras d, franc-guimond j, abdo a, houle am. topical triamcinolone for persistent phimosis. j urol. 2009;182:175963. 16. pileggi fde o, vicente ya. phimotic ring topical corticoid cream (0.1% mometasone furoate) treatment in children. j pediatr surg. 2007;42:1749-52. 17. lee jw, cho sj, park ea, lee sj. topical hydrocortisone and physiotherapy for nonretractile physiologic phimosis in infants. pediatr nephrol. 2006;21:1127-30. 18. ku wh, chiu bsk, huen kf. outcome and recurrence in treatment of phimosis using topical betamethasone in children in hong kong. j paediatr child h. 2007;43:74-9. 19. pileggi fo, martinelli ce, tazima mfgs, daneluzzi jc, vicente yamva. is suppression of hypothalamic-pituitaryadrenal axis significant during clinical treatment of phimosis? j urology. 2010;183:2327-31. 20. hammarstrom s, hamberg m, duell ea, stawiski ma, anderson tf, voorhees jj. glucocorticoid in inflammatory proliferative skin disease reduces arachidonic and effect of topical steroid on phimosis according to potency-chung et al. hydroxyeicosatetraenoic acids. science. 1977;197:994-6. 21. nuutinen p, riekki r, parikka m, et al. modulation of collagen synthesis and mrna by continuous and intermittent use of topical hydrocortisone in human skin. brit j dermatol. 2003;148:39-45. pediatric urology 95urology journal vol 7 no 2 spring 2010 idiopathic hypercalciuria in children with vesico ureteral reflux and recurrent urinary tract infection hashem mahmoodzadeh, ahmadali nikibakhsh, mohammad karamyyar, shahsanam gheibi, shima gholizadeh, hamidreza hooshmand purpose: our aim was to determine association of vesicoureteral reflux (vur) and idiopathic hypercalciuria in children with recurrent and single episode of urinary tract infection (uti). materials and methods: the study group consisted of 45 children with vur and recurrent uti, and 2 control groups: 45 normal healthy children (control group 1) and 45 children with vur and single episode of uti (control group 2). idiopathic hypercalciuria was defined as urine calcium to creatinine ratio more than 0.8 (mg/mg) in infants younger than 1 year old, and more than 0.2 (mg/mg) in older children (without any detectable causes for hypercalciuria). results: the study group consisted of 26 (57.8%) girls and 19 (42.2%) boys, with the mean age of 41.14 ± 22.1 months. nine (20%) subjects had hypercalciuria. the control group 1 composed of 22 (48.9%) girls and 23 (51.1%) boys, with the mean age of 43.98 ± 16.23 months. in this group, 6 subjects (13.3%) with hypercalciuria were detected. the control group 2 composed of 23 (51.1%) girls and 22 (48.9%) boys, with the mean age of 39.96 ± 24.2 months. in group 2, 7 subjects (15.6%) with hypercalciuria were detected. conclusion: comparison between such results was not statistically significant. despite reports of different studies about accompanying of hypercalciuria with recurrent uti with or without anatomical abnormalities, according to the present study, idiopathic hypercalciuria is not a major contributing factor to recurrent uti in children with vur. urol j. 2010;7:95-8. www.uj.unrc.ir keywords: vesico ureteral reflux, hypercalciuria, recurrent urinary tract infection department of pediatric, urmia university of medical sciences, urmia, iran corresponding author: ahmad ali nikibakhsh, md shahid motahari pediatric hospital, kashani st., urology-nephrology and transplantation research center, urmia, iran tel: +44 1222 5777 fax : +44 1346 1524 e-mail: anikibakhsh@yahoo.com received july 2009 accepted january 2010 introduction urinary tract infection (uti) is known as one of the most frequent diseases in pediatric medicine. due to its harmful effects on the renal tissue, uti’s importance is undeniable.(1-3) there are many factors that can predispose occurrence of uti, including anatomic abnormalities, vesico ureteral reflux (vur), dysfunction of the bladder, etc. another factor that is suggested as a facilitating cause of recurrent uti is idiopathic hypercalciuria (ih).(4-10) idiopathic hypercalciuria is a common disorder in children and can present with a range of clinical manifestations such as hematuria, voiding dysfunction, abdominal pain, flank pain, nephrolithiasis, and osteoporosis.(11) micro crystals of calcium oxalate, which cause trauma and damages to the mucosa of the lower urinary tract, can lead to voiding dysfunction and recurrent uti. according to some reports, vur hypercalciuria in children with vur—mahmoodzadeh et al 96 urology journal vol 7 no 2 spring 2010 is one of the facilitative factors of uti, but the latest researches have showed that vur has been detected in less than 50% of subjects with recurrent uti.(12,13) until the roles of such etiological factors for uti are fully understood, complete prevention of the upper urinary tract infection and scarring is unlikely. study of non anatomic problems, such as hypercalciuria (with or without vur) as predisposing factors of the recurrent uti, gained its importance. in the present study, we have tried to determine association of vesicoureteral reflux and idiopathic hypercalciuria in children with recurrent and single episode of urinary tract infection. materials and methods this case control study was carried out between october 2007 and april 2008 in shahid motahari pediatric hospital in urmia, iran. the study group composed of 45 children older than 2 months and younger than 6 years with vur who were also suffering from recurrent uti (presence of more than 2 uti attacks during 6 months). exclusion criteria were: 1. children with secondary vur (neurogenic bladder, bladder obstruction, and other detectable bladder abnormalities). 2. children who have been hospitalized for a long time because of a special illness like major fracture in extremities or who have been bed rest for a long time. 3. children who received corticosteroids or diuretics in the last month, or high dose calcium and vitamin d in the last 6 months. 4. children with renal dysfunction and low glomerular filtration rate. two control groups were selected for this study: control group 1: healthy children that were selected among those who referred to health centers of the city, without any special disease. control group 2: children with vur, but with single uti. the control groups were matched with the subjects, regarding the age and sex. thereafter, the calcium to creatinine ratio was measured from the second morning urine sample by professional laboratory technicians. all laboratory studies were performed by only one laboratory technician who was expert in investigation of urine calcium level using the auto-analyzer device (standard hitachi 9/2, model 2006). idiopathic hypercalciuria was defined as urine calcium to creatinine ratio more than 0.8 (mg/ mg) in infants younger than 1 year old, and more than 0.2 (mg/mg) in older children (without any detectable causes for hypercalciuria).(11) voiding cystourethrography was the standard for diagnosing vur and grading was defined according to the international reflux grading system. eventually, the one-way anova test was used for evaluation of the mean age of control and study groups, chi-square test for analyzing data and logistic regression test for omitting the confounder’s variables effects. p values less than .05 were considered statistically significant. results the study group consisted of 26 (57.8%) girls and 19 (42.2%) boys, with the mean age of 41.14 ± 22.1 months. nine (20%) subjects with hypercalciuria were detected (tables 1 and 3). in logistic regression analysis after entering confounder variables such as age and sex, no variable was detected in the final model. the control group 1 consisted of healthy children without vur and uti, composed of 22 (48.9%) title number mean age girl boy p healthy control group 45 43.98 ± 16.23 48.9% 51.1% .095 single uti and vur 45 39.96 ± 24.2 51.1% 48.9% .083 recurrent uti and vur 45 41.14 ± 22.1 57.8% 42.2% .880 table 1. demographic findings hypercalciuria in children with vur—mahmoodzadeh et al 97urology journal vol 7 no 2 spring 2010 girls and 23 (51.1%) boys, with the mean age of 43.98 ± 16.23 months. in this group, 6 subjects (13.3%) with hypercalciuria were detected (tables 1 and 3). the control group 2 consisted of children with primary vur, but without recurrent uti (single uti), composed of 23 (51.1%) girls and 22 (48.9%) boys, with the mean age of 39.96 ± 24.2 months. in the control group 2, 7 subjects (15.6%) with hypercalciuria were detected (tables 1and 3). discussion in the present study, the rate of hypercalciuria in the study group was 1.54 folds more than control group 1 (p = .690) and 1.35 folds more than control group 2 (p = .890). in fact, the prevalence of hypercalciuria among subjects with vur and recurrent uti did not have significant differences in comparison with the healthy subjects and single uti. also, comparison between control groups 1 and 2 was not significant (p = .450). therefore, when the rate of hypercalciuria in children with vur (in bath study group and control group 2) and healthy subjects were compared, there was not any significant differences (p = .507). the pathophysiologic mechanism of hypercalciuria as a facilitative factor to recurrent uti can be explained by the damage and trauma that can occur to the epithelial cells of the urinary tract mucosa due to micro crystals formation. such damage can interfere with the natural defiance of uroepithelial cells, and on the other side, the dysfunction of the bladder can be occurred as a predisposing factor for recurrent uti.(8-10) a few studies have been reported on the accompanying of hypercalciuria in children with vur. in a study in iran, the prevalence of hypercalciuria in children with uti and in healthy control group was reported to be 34% and 8%, respectively.(5) vachvanichsanong and colleagues(8) reported that 85% of hypercalciuric patients with recurrent uti did not demonstrate anatomical abnormalities of the urinary tract. this study has advocated the investigation of urinary calcium excretion in children with recurrent uti, but without anatomical abnormalities. in a study by biyikli and associates,(7) the accompanying of hypercalciuria with uti was detected in 43% of children. the age of the study group was more than 5 years and their results showed that 37.5% of hypercalciuric patients had predisposing urinary tract abnormality, including urolethiasis. moreover, there had been a statistically significant difference between hypercalciuric children with uti and control group. in other study carried out by lopez and colleagues,(9) the children with uti and without any anatomic abnormality who were also suffering from hypercalciuria were treated to eliminate hypercalciuria. in 95% of children, after treatment of hypercalciuria, no uti was detected; hence, it was concluded that hypercalciuria can be as a predisposing factor for recurrent uti. there are a few studies in which hypercalciuria has been studied in children with vur. garcia and colleagues reported the prevalence of title vur number (percent) hypercalciuria p vur grade 1 2 3 4 5 … … single uti and vur … 20 (44.4%) 22 (48.9%) 3 (6.7%) … 7 .690 recurrent uti and vur 8 (18%) 18 (40%) 13 (29%) 5 (11%) 1(2%) 9 .450 table 2. vur grading and hypercalciuria title recurrent uti and vur single uti and vur healthy control group odds ratio p number 45 45 45 … … hypercalciuria 17.8% 13.2% 1.35 .507 hypercalciuria (number) … 15.6% (7.0) 13.2% 1.18 .450 hypercalciuria 20.0% (9.0) … 13.2% (6.0) 1.54 .690 hypercalciuria 20.0% (9.0) 15.6% (7.0) … 1.28 .890 table 3. hypercalciuria (in case and control groups) hypercalciuria in children with vur—mahmoodzadeh et al 98 urology journal vol 7 no 2 spring 2010 hypercalciuria and vur in the study group and control group to be 18.7% and 15.1%, respectively (not significant differences).(14) in other study by noe and coworkers on 46 children with vur,(15) the prevalence of hypercalciuria was studied. it was concluded that the prevalence of hypercalciuria in children with vur was 58.6%, which was significantly more than healthy children. it is important to say that children with urolithiasis were included in this study, which naturally increased the rate of hypercalciuria. in our study, the prevalence of hypercalciuria in children with recurrent uti and vur has not significant differences in comparison with control groups (vur with single uti and healthy children). there are some important points about our study in comparison with other studies, which may have its own effects on our results, including the sample size, selection of patients without urolithiasis, and local high prevalence of hypercalciuria. conclusion despite reports of different studies about accompanying of hypercalciuria with recurrent uti with or without anatomical abnormalities, according to the present study, idiopathic hypercalciuria is not a major contributing factor to recurrent uti in children with vur. conflict of interest none declared. references 1. kantele a, palkola n, arvilommi h, et al. local immune response to upper urinary tract infections in children. clin vaccine immunol. 2008;15:412-7. 2. hellerstein s. long-term consequences of urinary tract infections. curr opin pediatr. 2000;12:125-8. 3. [no author listed]. practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. american academy of pediatrics. committee on quality improvement. subcommittee on urinary tract infection. pediatrics. 1999;103:843-52. 4. stojanovic vd, milosevic bo, djapic mb, bubalo jd. idiopathic hypercalciuria associated with urinary tract infection in children. pediatr nephrol. 2007;22:1291-5. 5. nikibakhsh aa, mahmoudzadeh h, karami y, ghafari ali, yekta zahra vm. hypercalciuria associated with recurrent urinary tract infections in children. med j tabriz university of med sci. 2007. 6. sadeghi-bojd s, hashemi m. hypercalciuria and recurrent urinary tract infections among children in zahedan, iran. j pak med assoc. 2008;58:624-6. 7. biyikli nk, alpay h, guran t. hypercalciuria and recurrent urinary tract infections: incidence and symptoms in children over 5 years of age. pediatr nephrol. 2005;20:1435-8. 8. vachvanichsanong p, malagon m, moore es. urinary tract infection in children associated with idiopathic hypercalciuria. scand j urol nephrol. 2001;35:112-6. 9. lopez mm, castillo la, chavez jb, ramones c. hypercalciuria and recurrent urinary tract infection in venezuelan children. pediatr nephrol. 1999;13:433-7. 10. nicolaidou p, georgouli h, getsi v, et al. urinary excretion of endothelin-1 in children with absorptive idiopathic hypercalciuria. pediatr nephrol. 2003;18:1157-60. 11. srivastava t, schwaderer a. diagnosis and management of hypercalciuria in children. curr opin pediatr. 2009;21:214-9. 12. gordon i, barkovics m, pindoria s, cole tj, woolf as. primary vesicoureteric reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and meta-analysis. j am soc nephrol. 2003;14:739-44. 13. mingin gc, hinds a, nguyen ht, baskin ls. children with a febrile urinary tract infection and a negative radiologic workup: factors predictive of recurrence. urology. 2004;63:562-5; discussion 5. 14. garcia-nieto v, siverio b, monge m, toledo c, molini n. urinary calcium excretion in children with vesicoureteral reflux. nephrol dial transplant. 2003;18:507-11. 15. noe hn, stapleton fb, jerkins gr, roy s, 3rd. clinical experience with pediatric urolithiasis. j urol. 1983;129:1166-8. urology journal peer review running head: the effect of ventilation mode on renal mobility during rirs the effect of ventilation mode in anesthesia on renal mobility during retrograde intrarenal surgery. single-blind randomized study. cagri doğan1*, murat akgül1, ayhan şahin2, cenk murat yazıcı1, mehmet fatih şahin1, enes altın1, anıl keleş1 cagri dogan. namik kemal university faculty of medicine, department of urology, tekirdag/turkey orcid: 0000-0001-9681-2473 email: drcagridogan@gmail.com tel: +90558908805 *corresponding author murat akgul namik. kemal university faculty of medicine, department of urology, tekirdag/turkey orcid id 0000-0001-6187-1940 email: drmuratakgul@gmail.com tel: +905053399602 ayhan sahin. namik. kemal university faculty of medicine, department of anesthesiology and reanimation, tekirdag/turkey orcid id: 0000-0002-3539-2353 email: asahin@nku.edu.tr tel:+905324730503 cenk murat yazici. namik kemal university faculty of medicine, department of urology, tekirdag/turkey orcid :0000-0001-6140-5181 email: drcenkyazici@yahoo.com tel: +905068554625 mehmet fatih şahin namik kemal university faculty of medicine, department of urology, tekirdag/turkey orcid :0000-0002-0926-3005 email: mfatihsahin@gmail.com mailto:drcagridogan@gmail.com mailto:drmuratakgul@gmail.com mailto:asahin@nku.edu.tr mailto:drcenkyazici@yahoo.com tel: +905555511871 enes altin namik kemal university faculty of medicine, department of urology, tekirdag/turkey orcid :0000-0000-5723-0793 email: drenesaltin@gmail.com tel: +905556151925 anil keles namik kemal university faculty of medicine, department of urology, tekirdag/turkey orcid :0000-0001-6522-0862 email: anilkeles1903@gmail.com tel: +905557221693 key words: renal mobility, rirs, mechanical ventilation, general anesthesia, nephrolithiasis, ureteroscopy abstract purpose renal mobility can present challenges for surgeons during stone fragmentation. the respiratory setup of the mechanical ventilator during rirs might affect renal mobility. the aim of this study was to evaluate the effect of high ventilation (hv) and standard ventilation (sv) modes on renal mobility during rirs. materials and methods patients who underwent rirs at a single center between november2020andnovember2021 were retrospectively included in the study. renal mobility was measured under fluoroscopic view in hvandsv modes during retrograde pyelography. the surgeon, who was absolutely blind about mechanical ventilation modes, was asked to assess the renal movement grade. after the ventilation mode was changed, the surgeon reassessed renal mobility. the data and the surgeon’s assessment were recorded and compared to each other. results a total of 86 patients with a mean age of 48.6 ± 15.7 years were included in the study. there was a significant difference between the sv and hv modes in terms of renal mobility in fluoroscopic view (17.1±6.1 mm and 13.6 ± 5.2mm, respectively; p=0.007). according to the surgeon’s assessments, the grade of renal mobility was found to be significantly higher in the sv group 2.8 ±1.1 compared to the hv group 2.2 ± 0.8 (p=0.001). renal movement increased significantly under fluoroscopic vision as the renal grading of the surgeon increased(p=0.013). this data demonstrated that the surgeon’s assessment of renal mobility was significantly correlated with fluoroscopic kidney movement. conclusion kidney movement was decreased significantly in hv mode during rirs according to both fluoroscopic findings and surgeon assessment. most surgeries of mobile kidneys were performed in hv mode, due to the surgeon’s preference. key words: renal mobility, rirs, mechanical ventilation, general anesthesia, nephrolithiasis, ureteroscopy introduction retrograde intrarenal surgery (rirs) has been widely accepted and has become one of the most promising surgeries for the treatment of kidney stone (1). retrograde intrarenal surgery is usually performed under general anesthesia (ga), but it can also be performed under regional anesthesia (spinal or epidural). surgeons generally prefer general anesthesia during the operation due to the surgical field stability and to avoid possible complications related to patient factors. general anesthesia also enables the surgeons to change respiration frequency and tidal volume to decrease renal mobility (1). several patient and stone related factors have been evaluated to document their effect on the safety and efficacy of rirs, but there are limited data about the effect of renal mobility on rirs (2–4). the stone-free status of rirs depends on multiple factors, including patient-related properties and stone-related properties. some factors can affect stone-free status and complications; these include stone volume, stone density, preoperative urine culture status, presence of previous extracorporeal shock wave lithotripsy (esl), number of stones, and the usage of a ureteral access sheath (4,5). although several variables related to patient and stone characteristics have been evaluated, there are limited data about the effect of renal mobility on the efficacy and safety of rirs. renal mobility during the surgery might be a significant factor that could affect rirs success and safety. excessive renal mobility is one of the main challenges for the rirs procedure. during the stone dusting, surgeons prefer to have an immobile stone to maximize their ability to eliminate the target. any manipulations that decrease the mobility of the stone might increase the success rate of the rirs. many techniques have been described to reduce renal mobility, such as abdominal belt application, periodic apnea technique, and high-frequency jet ventilation, but none of them has gained acceptance. abdominal belt application, the oldest method, was used in the past during esl to reduce renal mobility, but it has not gained acceptance due to insufficient efficiency (6,7). the periodic apnea technique, which was described by emiliani, was a promising method; however, the possibility of metabolic complications(hypercapnia) was a major disadvantage for this technique (8). highfrequency jet ventilation (hfjv) may also be used during the rirs procedure, but this technique does not allow for the use of inhalation-type anesthetics, and the end-tidal carbon dioxide and exhaled air volume cannot be monitored by the anesthetist (9). for these reasons, any type of ventilation technique that will decrease the renal mobility during rirs may have a significant advantage for the surgeon. in this study, we aimed to compare the effects of standard ventilation (sv) mode with high ventilation (hv) mode on renal mobility during rirs. the study's primary aim was to evaluate ventilation modes' effect on renal mobility during rirs. the secondary aim was to confirm the relationship between renal mobility under a fluoroscopic view and the surgeon’s assessment of renal mobility during the surgical procedure. materials and methods after the approval of the local ethical committee (no:2020.214.09.01), the patients who underwent rirs by the same surgeon for the treatment of kidney stone at a single center between november 2020 and november 2021 were retrospectively included in the study. sample size of our study was calculated as 80 participants according to g power analysis software (version 3.1.9.7). (effect size 0.5, alfa error 0.05, power 0.80). randomization of participants was performed by using randomization software on the website. (https://www.randomizer.org) written informed consent was given to all patients before the surgery. patients younger than 18 years old; patients with a renal anomaly, a solitary kidney, a bleeding disorder, proximal ureteral stone, or multiple stones; and patients who had undergone previous ipsilateral percutaneous nephrolithotomy and/or open renal surgery were excluded from the study. in order to standardize the study population, patients who were treated without the insertion of an access sheath and surgeries that were performed with regional anesthesia were also excluded from the study. a standard protocol of general anesthesia was given to all patients by the same anesthesiologist to prevent possible bias. the preoperative evaluation was performed with history taking; physical examination; laboratory analyses, including urinalysis, urine culture, and serum creatinine level; and radiological evaluation with non-contrast computerized tomography (ncct). patients with a positive urine culture were treated with antibiotics according to the antibiogram, and surgeries were performed under sterile urine. the demographic and clinical characteristics of the patients, including age, gender, body mass index, urine culture status, presence of hydronephrosis, stone volume, stone density, surgical side, and the presence of preoperative double j stent, were noted. the stone volume was measured using the three-dimensional formula described by sorokin et al. (10). surgical technique was defined in our previous study (5). we used the same size laser probe (272 nm) for the stone dusting procedure was performed under 0.8 joule and 10 frequencies by holmium laser (quanta system 2015, italy), and stone fragments were broken into small pieces by using the popcorn mode of the laser. (1 joule, 15 frequency). patients with residual stone fragment<4 mm was defined as stone free. anesthesia protocol the patients received 2 mg midazolam im (intramuscular) as a premedication and were monitored with three-channel electrocardiography, noninvasive blood pressure, peripheral oxygen saturation, and bispectral index (bis) in the operating room. the anesthesia was introduced intravenously with 2–3 mg/kg of propofol, 1 mcg/kg of fentanyl, and 0.6 mg/kg of rocuronium. after ensuring adequate muscle relaxation, orotracheal intubation was carried out by an experienced anesthesiologist. anesthesia was maintained with1–2% sevoflurane in 4 l of 40%:60%o2 and air mixture. remifentanil infusion was used at0.1–2 mcg/kg/min after intubation during the surgery. the concentrations of sevoflurane and remifentanil were set to a target bis level between 40and 60. intravenous rocuronium was administered in a dose of 0.1mg/kg to maintain adequate muscle relaxation. a drager primus (germany) device was used for mechanical ventilation. the tidal volume and frequency were determined by the machine according to patient’s age and weight with end-tidalco2 levels of 30–35 mmhg. sv mode was defined as8–10 ml/kg tidal volume and10–15 respirations/min. during hv mode, the tidal volume was decreased to6–8 ml/kg and the frequency was increased to15–18 respirations/min. no changes were made in the inspiratory expiratory ratio (1:2), fio2, and positive end-expiratory pressure (peep) parameters. all surgeries were started with sv mode without the knowledge of the surgeon. the surgeon was asked to grade the renal mobility, and the mode was changed to hv mode after grading. the surgeon was then asked to grade the renal mobility under hv mode. then the surgeon decided to perform the surgery under the ventilation mode that he found more comfortable. the surgery was started with cystoscopy and retrograde pyelography. during the retrograde pyelography, the researcher marked the tip of the lower calyx on the fluoroscopy screen (siemens siremobil compact l, germany) during the maximum inspiration and expiration phases of the sv and hv modes. the distances of the tip of the lower calyx on the fluoroscopy screen at respiration phases at both ventilation modes were measured. a demonstration of kidney movement is shown in figure 1. in order to decrease the radiation exposure of the patients, the fluoroscopy was used during one inhalation and one exhalation period. then, the surgeon was invited to the operating theater to proceed with the surgery. the surgeon was totally blind of the ventilation modes. during the stone fragmentation, the researcher asked the surgeon to classify the renal mobility according to the classification described by gadzhiev et al. (11). renal mobility classifications were described as follows: grade 1, very mobile kidney (extremely poor conditions for dusting); grade 2, significantly mobile (unsatisfactory conditions for dusting); grade 3, slightly mobile (satisfactory conditions for dusting); grade 4, almost immobile (good conditions for dusting); and grade 5, completely immobile (excellent conditions for dusting). this classification system was used in reverse to prevent confusion in our study. so, we defined that grade 1 renal mobility was identified as a completely immobile kidney, whereas grade 5 renal mobility was a very mobile kidney. as the surgeon defined the degree of renal mobility, the ventilation mode was changed and the surgeon was asked again to assess the renal mobility. the surgeon decided to continue the surgery on the ventilation mode that he found more comfortable. statistical procedure all data were evaluated using spss statistics, version 25 (ibm; armonk, ny, usa) software. the distribution of data was evaluated by the kolmogorov-smirnov test. a chi-square test was performed for nominal variables in the groups. an independent t-test and one-way ancova were used to analyze the parametric data. mann-whitney u, chi-square, fisher’s exact chisquare, and kruskal-wallis tests were used for the analysis of nonparametric data. results a total of 86 patients with a mean age of 48.6 ± 15.9 were enrolled in the study. there were 50(58.1%) female and 36(41.9%) male patients. the mean operation time and the stone-free rate of the study population were 73.3 ±28.4 min and 70.9%, respectively. postoperative complications were observed in 11(12.8%) patients. the most frequent complications were hematuria, fever, and flank discomfort, which were classified as clavien grade 1–2 complications. we observed that there was no ventilation mode–related complications during surgery in our study. the demographic and stone-related properties of the patients and complications of the surgeries are given in table 1. in order to evaluate the accordance between the surgeon’s assessment and renal mobility, we compared the surgeon’s renal mobility evaluation with the fluoroscopic measurements. the mean fluoroscopy time during renal movement was 3.14±0.36 sec. the mean distance of lower pole localizations in fluoroscopic images was 14.5 ±5.3 mm in patients that the surgeon reported as grade 1 renal mobility during sv mode. the distance increased to 25.1 ± 1.4 mm in patients whom the surgeon reported the renal mobility as grade 5 (p<0.001). similar findings were also observed during hv mode. the renal mobility of all patients was also calculated under fluoroscopic view, and there was a significant difference between the sv and hv modes during the surgery (17.1 ± 6.1 mm and 13.7 ± 5.8 mm, respectively; t(3,01)=76.1, p=0.007). the distance of lower pole localizations increased significantly as the renal grading of the surgeon increased (p=0.013). this data demonstrated that the surgeon’s assessment of renal mobility was significantly correlated with the fluoroscopic movement of the renal unit (table 2). according to the surgeon’s assessment, the grade of renal mobility was found to be significantly higher in the sv group (2.8 ±1.1) compared to the hv group (2.3 ± 0.9, t(-14.7)=83.5 p=0.001). the renal mobility degree was reported as grade 3 and higher in 5 (59.3%) patients during sv mode. as the mode changed to hv mode, the surgeon reported a renal mobility regression in 44(82.3%) patients and preferred to continue in this mode. however, when the surgeon graded the renal mobility as grade 1 and 2 in 35(40.7%) patients, he preferred to continue in hv mode with only 8(22.9%) of these patients (p<0.001). as a result, a total of 52 (60.5%) surgeries were performed under hv mode and 34 (39.5%) surgeries were performed under sv mode. when we compared the ventilation modes, demographic properties, and stonerelated properties, we found similar intraoperative surgical variables, operation time, stone-free rates, and postoperative complications between the groups (table 3). discussion usage of flexible ureteroscopy for the treatment of kidney stone has increased over the last two decades (12). renal mobility may be one of these challenges, and we believe that it is an underestimated subject. previous studies have shown that renal mobility can affect the results of esl, and less renal mobility can improve the success rates of esl (13–15). this may also be true for rirs that targets stones in mobile kidneys by laser fiber, which is a challenging situation for surgeons. for this reason, any manipulation that decreases renal movement during rirs may affect surgical success and surgery-related complications. as a possible factor for renal mobility, we compared two different ventilation modes during rirs. according to our knowledge, this is the first study comparing renal movement during sv and hv modes under fluoroscopic vision. the fluoroscopic findings showed that renal movement during sv mode was significantly higher than renal movement during hv mode (17.1 ± 6.1 mm and 13.7 ± 5.8 mm, respectively; p=0.007). the difference in renal movement during sv and hv mode was also noticed by the surgeon during rirs. the surgeon preferred to continue the surgery under hv mode for nearly 80% of the patients with grade 3 and higher renal mobility. however, the same preference was observed for nearly 20% of patients with grade 1 and 2 renal mobility. therefore, the alteration of ventilation mode from sv to hv during rirs should be considered, especially in grade 3 and higher renal mobility. there were two studies in the literature investigating the effect of ventilation mode on renal mobility during rirs (11,16). one of these studies was carried out by gadzhiev et al. they found that renal mobility decreased significantly during small-volume but high-frequency jet ventilation mode (11). according to their results, the authors concluded that decreasing the tidal volume and increasing the respiration frequency during general anesthesia was an effective method to limit renal mobility during rirs. we also observed similar findings that renal mobility decreased significantly during hv, when the tidal volume was decreased and the respiration frequency was increased. in gadzhiev et al., the authors evaluated the renal mobility according to the surgeon’s assessment, which might be a subjective finding. one of the main differences in our study was the usage of fluoroscopic vision. through fluoroscopic measurement, we were able to demonstrate the renal mobility more objectively and combine our findings with the surgeon’s assessment. another study related to ventilation mode and renal mobility during rirs was performed by kourmpetis et al. the authors evaluated the effect of low ventilation (lv) mode (respiration frequency ≤ 8/min and tidal volume < 500 ml) on rirs and reported that it provided better conditions for stone fragmentation during rirs. during this ventilation mode, the tidal volume and respiratory frequency were both decreased. as a result, the end-tidal co2 increased to 50 mmhg during lv mode, and the authors indicated that hypercapnia may lead to cardiovascular diseases, increased intracranial pressure, metabolic acidosis, and hyperkalemia (16,17). however, we did not observe hypercapnia during hv mode. decreasing the tidal volume with respiratory frequency increment did not adversely affect the physiological respiratory functions. the post-operative complication rates after the rirs procedure varies between 7.9% and 20.5%. the post-operative complication rates of our study confirmed the literature with %12.8. we also observed that there was no ventilation mode–related complications during surgery in our study (18). all of the studies documented a decrease in renal mobility during rirs by their special ventilation modes. the common property of these special ventilation modes was the decrease in tidal volume. this data showed that tidal volume is a significant parameter for renal mobility during rirs. decreasing the tidal volume without a change in respiratory frequency may lead to non-physiological results, like hypercapnia. we showed that hv mode was a safe and effective method to decrease renal mobility during rirs. our study had some limitations. the first limitation was its retrospective nature. however, the data of the study was obtained during surgery, which might decrease the bias that may possibly result from retrospective evaluation. the second limitation was the lack of patient randomization. all patients were started on sv and changed to hv mode. the surgeon was totally blind for the ventilation modes and assessed the surgery in a blind fashion. the study was designed to evaluate the effect of ventilation modes on the renal mobility during rirs. for this reason, we were not able to evaluate the effect of ventilation modes on the efficacy and safety of rirs. the other limitation of the study was the number of participants. we believe that prospective-randomized studies with a high number of participants are needed to understand better the effect of ventilation modes on renal mobility. another limitation of the study was that this study could be performed with two or more blind surgeons. a study designed with an interpersonal assessment of renal mobility could gain more scientific power. conclusions renal mobility during rirs decreased significantly during hv mode. both fluoroscopic findings and the surgeon’s assessment documented this finding. the decrease in renal mobility was more apparent in patients with highly mobile kidneys. surgeons might consider changing the ventilation mode to hv when they feel uncomfortable during rirs due to renal mobility. conflict of interest the authors report no conflict of interest. references 1. c. türk , a. neisius, a. petřík, c. seitz, a. skolarikos , b. somani, k. thomas, g. gambaro. eau 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(2016). stone volume is best predictor of operative time required in retrograde intrarenal surgery for renal calculi: implications for surgical planning and quality improvement. urolithiasis, 44(6), 545–550. https://doi.org/10.1007/s00240016-0875-8 11. gadzhiev, n., oibolatov, u., kolotilov, l., parvanyan, s., akopyan, g., petrov, s et al. (2019). reducing kidney motion: optimizing anesthesia and combining https://doi.org/10.1007/s00240-016-0875-8 https://doi.org/10.1007/s00240-016-0875-8 respiratory support for retrograde intrarenal surgery: a pilot study. bmc urology, 19(1), 61. https://doi.org/10.1186/s12894-019-0491-3 12. geraghty, r. m., jones, p., & somani, b. k. (2017). worldwide trends of urinary stone disease treatment over the last two decades: a systematic review. j endourol., 31(6), 547–556. https://doi.org/10.1089/end.2016.0895. 13. harrogate, s. r., yick, l. m., williams, j. c., jr, cleveland, r. o., & turney, b. w. (2016). quantification of the range of motion of kidney and ureteral stones during shockwave lithotripsy in conscious patients. j endourol., 30(4), 406–410. https://doi.org/10.1089/end.2015.0388. 14. ozgür, a., & yalm iker, n. (2005). extracorporeal shock wave lithotripsy of renal pelvis stones with pck stonelith lithotripter. int urol nephrol., 37(1), 9–11. https://doi.org/10.1007/s11255-004-6085-2 15. sorensen md, bailey mr, shah ar, et al. quantitative assessment of shockwave lithotripsy accuracy and the effect of respiratory motion. j endourol 2012;26:1070– 1074. 16. kourmpetis, v., dekalo, s., levy, n., nir, t., bar-yosef, y., beri, a., et al. (2018). toward respiratory-gated retrograde intrarenal surgery: a prospective controlled randomized study. jendourol.,32(9), 812–817. https://doi.org/10.1089/end.2018.0231. 17. wong dt, yee aj, leong sm, chung f. the effectiveness of apneic oxygenation during tracheal intubation in various clinical settings: a narrative review. can j anesth can d’anesthésie. 2017;64(4):416–27. 18. grosso, a. a., sessa, f., campi, r., viola, l., polverino, p., crisci, a.,et al. (2021). intraoperative and postoperative surgical complications after ureteroscopy, retrograde intrarenal surgery, and percutaneous nephrolithotomy: a systematic https://doi.org/10.1186/s12894-019-0491-3 https://doi.org/10.1007/s11255-004-6085-2 review. minerva urol. nephrol., 73(3), 309–332. https://doi.org/10.23736/s27246051.21.04294-4 correspondence author ass. prof. cagri dogan m.d namik kemal university, faculty of medicine tekidag/turkey email: drcagridogan@gmail.com tel: +90558908805 table-1 all of the patients’ demographics number of patients 86 age (year) 48.6±15.8 mailto:drcagridogan@gmail.com gender male (%) female (%) 50(58.1) 36(41.9) bmi (kg/m2) 27.5±4.9 stone location upper calyx (%) lower calyx (%) middle calyx (%) pelvis calyx (%) 10(11.6) 29(33.8) 11(11.8) 36(41.8) surgical side left (%) right (%) 42(48.8) 44(51.2) stone size (mm3) 472.1 (min 9.44max 3563.2) stone density (hu) 1027.8±290.1 operation time (min) 73.3±28.4 postoperative complications (%) clavien-dindo classifications grade 1 hematuria (%) fever (%) grade 2 flank discomfort (%) grade 3a stent migrations (%) grade 3b pelvicalyceal extravasation (%) grade 4a urosepsis (%) grade 4b multiorgan dysfunction (%) grade 5 death (%) 11 (12.8%) 4(36.3) 2(18.2) 2(18.2) 1(9.1) 1(9.1) 1(9.1) 0 0 stone free rate (%) 51(70.9) * all decimals were rounded table-2 comparison of degree of renal mobility with renal mobility under fluoroscopic view degree of renal mobility 1 2 3 4 5 p value number of patients in standard ventilation mode (n) 12 23 22 27 2 fluoroscopic distance during standard ventilation mode (mm) 14.51±5.35 13.91±5.79 16.95±5.98 20.78±4.91 25.01±1.41 <0.001 number of patients in high ventilation mode (n) 17 30 32 5 2 fluoroscopic distance during high ventilation mode (mm) 10.22±4.67 14.25±5.02 14.93±5.22 15.41±4.97 17.26±5.08 0.013 table-3 demographic and clinical properties in standard and high ventilation mode standard ventilation (n:34) high ventilation (n:52) age (year) 51,8±17,1 46,5±14,6 bmi (kg/m²) 26,70±4,52 28,04±5.06 gender male (%) female (%) 21(61.8) 13 (38.2) 29(55.8) 23(44.2) surgical side left (%) right (%) 20(58.8) 14(41.2) 22(42.3) 30(57.7) stone location upper calyx (%) lower calyx (%) middle calyx (%) 4(11.8) 13(38.2) 5(14.7) 6(11.5) 16(30.8) 6(11.5) pelvis calyx (%) 12(35.3) 24(46.2) stone size (mm3) 726.8 (25.2-2658.6) 675.7(42.4-3245.7) stone density (hu) 1046,1±336.9 1015,7±257.6 operation time (min) 75,88±33.51 71,63±24.44 laser time (min) 50 (10-135) 45 (10-120) total laser pulse 11467(893-65063) 12550(2191-82465) stone-free status yes (%) no (%) 22(64.7) 12(35.3) 39(75.0) 13(25.0) postoperative complication yes (%) no (%) 4(11.8) 30(88.2) 7(13.5) 45(86.5) legends to figures figure-1 the demonstration of measurement of renal mobility under fluoroscopic view. a: measurement of kidney movement in standard ventilation mode during expiration and inspirium by software (7.4mm). b: measurement of kidney movement in high ventilation mode during expiration and inspirium by software (3.7mm). firstly, resident marked the tip of lower calyx on the fluoroscopic images and drew a line through to vertebrae during the maximum inspiration and expiration phases of the standard and high ventilation modes. then the difference between the inspiration and expiration lines was calculated by software. https://www.seslisozluk.net/expiration-nedir-ne-demek/ https://www.seslisozluk.net/inspirium-nedir-ne-demek/ https://www.seslisozluk.net/expiration-nedir-ne-demek/ https://www.seslisozluk.net/inspirium-nedir-ne-demek/ female urology role of urodynamic study in the management of pelvic organ prolapse in women azar daneshpajooh1*, mahboubeh mirzaei2, tania dehesh3 purpose: pelvic organ prolapse (pop) and lower urinary tract symptoms (luts) usually coexist and are common among women. since the efficacy of urodynamic studies (uds) in evaluating these conditions is subject to controversy, this study aimed to assess the accordance between urodynamic findings and luts and to determine the importance of uds in women with pop. methods: this cross-sectional study was conducted on women over 18 years with symptomatic pop referred to the female urology clinic of kerman university of medical sciences, kerman, iran, during 2017-2018. patients who met the inclusion criteria were included in the study with informed consent. the pelvic floor disability index (pfdi-20) was completed for each patient. pelvic examination was performed using the pelvic organ prolapse quantification system (popq). subsequently, multi-channel uds was performed, and the findings were analyzed in spss 20, using chi-square or fisher’s test. results: a total of 200 women with symptomatic pop were included in the study. stress, urge, and mixed urinary incontinence showed significant accordance with the urodynamic findings (urodynamic stress incontinence and/ or detrusor overactivity). however, there was no significant relationship between urinary voiding luts and urodynamic findings. conclusion: uds should be performed for selective patients with pop. according to the results of the present study, uds can help us provide consultation for pop patients with voiding luts. however, in pop patients with urinary incontinence, this test cannot provide further information and should be performed based on the patient’s condition. keywords: pelvic organ prolapse; urodynamic study; urinary incontinence; voiding dysfunction introduction pelvic organ prolapse (pop), defined as the herni-ation of the pelvic organs to or beyond the vaginal wall, is a common condition affecting millions of women. pop and urinary incontinence (ui) have significant impacts on women’s quality of life, affecting their daily activities, sexual function, and social interactions(1-5). the odds of developing pop increase by 40% with every ten-year increase in age(6). therefore, as the population age advances, the economic burden of pop treatment increases. pop has various symptoms, including the lower urinary tract symptoms (luts) (e.g., storage symptoms, voiding symptoms, and ui)(7). urodynamic studies (uds), especially cystometry and pressure flow study, have become standard tools for the evaluation of patients with pop and luts. several studies have documented the use of uds to demonstrate sui on prolapse reduction in women with pop. furthermore, uds is used for the evaluation of concomitant storage symptoms to demonstrate detrusor overactivity(8). however, the correlation between pop symptoms and uds is not completely clear, and performing the uds is costly(9-13). 1clinical research center, shahid bahonar hospital, kerman university of medical sciences, kerman, iran. 2department of urology, shahid bahonar hospital, kerman university of medical sciences, kerman, iran. 3department of biostatistics and epidemiology, school of public health, kerman university of medical sciences, kerman, iran. * correspondence: gharani ave, shahid bahonar hospital, urology department, kerman,iran. tel: 0098-9131982191 email address: azdaneshpajooh@yahoo.com. received august 2020 & accepted february 2021 this study aimed to assess the luts based on questionnaire in patients with pop, urodynamic findings of patients with pop, the need for uds in the examination of these patients. methods this cross-sectional study was conducted on women referred to the female urology clinic of kerman university of medical sciences, kerman, iran, during 20172018. women with symptomatic pelvic organ prolapse were considered eligible for the study. the inclusion criteria were as follows: being over 18 years old and having symptomatic pop stage ≥1. on the other hand, the exclusion criteria were as follows: having active infection of the urogenital system, urethral stricture, bladder stones, neurological disorders, urogenital cancer, and history of a gynecological procedure such as pop surgery or hysterectomy, as well as consuming drugs affecting the urinary system. a total of 200 women, who met the inclusion criteria, entered the study with informed consent. their demographic information, medical history, and obstetric history were recorded. moreover, the pelvic floor disabilurology journal/vol 18 no. 2/ march-april 2021/ pp. 209-213. [doi: 10.22037/uj.v18i.6408] vol 18 no 2 march-april 2021 210 ity index (pfdi-20) was completed for all patients, and the udi6 section of this questionnaire was used to assess the lower urinary tract symptoms in such a way that if the answer to each question was yes with a score of 2,3, or 4, then the answer was interpreted as “yes”, otherwise the answer was considered “no”. we assessed urinary incontinence and voiding luts based on questions 16 and 17 and question 19 respectively in addition to the history. the pelvic organ prolapse quantification system (popq) was used to perform the pelvic examinations. urine culture and bladder ultrasound scan were also used before uds. next, multi-channel uds, including uroflowmetry, filling cystometry, and pressure flow study were performed by medkonsult medical technology (mmt) urodynamic system (model: uromic blues). all women were studied with uds by a female urologist using a standardized protocol in accordance with urodynamic practices guidelines of international continence society (ics). we used proper pessaries for prolapse reduction to detect occult sui in cases with high stage prolapse (3 and 4). the terminology used to describe the uds terms and observation were based on ics standardization committee(14) bladder outlet obstruction was considered based on the blaivas and groutz nomogram(15) and detrusor underactivity was defined as voiding detrusor contraction of less than10 cm h2o and mfr less than 15 cc/s.(8). the statistical analysis was performed using spss version 20. the chi-square test was conducted for investigating the relation between two discrete variables. if more than 25% of cells had expected counts of less than 5, fischer’s exact test was performed. the ethics committee of kerman university of medical sciences approved the present study. results a total of 200 women over 18 years with symptomatic pop were evaluated in this study. the mean age and parity of the participants were 53.22 ± 11.35 years and 5.65±4.12, respectively. also, 108 (54.5%) women had reached the age of menopause. the urinary symptoms section (udi-6) of pfdi-20 showed that 94 (47%) women were suffering from voiding luts, 97 (48.5%) from stress ui (sui), 62 (31%) from urge ui (uui), and 46 (23 %) from mixed ui (mui). on the other hand, 41 (20.5 %) of the women did not have any complaints of ui. in terms of age, the prevalence of sui, uui, and mui was 8.3%, 8%, and 6.4%, respectively, in women aged between 18 and 35 years. also, the prevalence of sui, uui, and mui was 34%, 32.3%, and 36.2% in women aged 36-50 years, respectively. finally, in women over 51 years of age, the prevalence of sui, uui, and mui was 57.7%, 59.7%, and 57.4%, respectively. according to the results of popq, the prevalence of anterior compartment prolapse stages, in descending order, was as follows: stage 2 (64%), stage 3 (29.7%), stage 1 (3.6%), and stage 4 (2.6%). moreover, the prevalence of posterior compartment prolapse stages, in descending order, was as follows: stage 2 (59%), stage 3 (25.1%), stage 1 (13.3%), and stage 4 (2.6%). and finally, the prevalence of apical prolapse stages, in descending order, was as follows: stage 2 (84.6%), stage 1 (7.7%), and stage 4 (7.7%). relationship between ui based on the questionnaire and pop severity in examination no significant relationship was found between ui in the questionnaire and pop severity (table 1). urodynamic findings the results of uds in patients with pop are presented in (table 2). relationship between ui based on the questionnaire and urodynamic findings overall, 71 (73%) of women with sui based on the questionnaire (n=97) had si according to the urodynamic test. moreover, two out of 103 women, who had not complained of sui, were found to have si according to the urodynamic test. there was a significant relationship between this compliant and urodynamic findings (p < 0.001) (table 3). the present results showed that 40 (64.5%) of patients with uui based on the questionnaire (n=62) had detrusor overactivity (do) according to the urodynamic test. also, 25.8% of these women had detrusor overactivity incontinence (doi). three (2%) out of 138 women, who did not complain of uui, showed signs of do on the urodynamic test one of whom (0.7%) had doi. there was a significant relationship between this compliant and urodynamic findings (p < 0.001). also, 21.7% of women with mui (n=46) had do and si, based on the urodynamic test. only one of the patients with sui had concomitant do and si, according to the urodynamic test. the relationship between this condition and urodynamic findings was significant (p < 0.001) (table 3). relationship between voiding luts based on the questionnaire and pop severity on examination the results showed that 20%, 47.5%, 51.7%, and 60% of patients with stage 1, 2, 3, and 4 pop complained of difficulty in bladder emptying, respectively. however, table 1. the relation between stages of pop and different types of ui based on pfdi questionnaire scores sui uui mui yes no p-value yes no p-value yes no p-value stage1 4 7 0.236 3 8 0.895 3 8 0.192 stage2 56 69 38 87 23 102 stage3 35 24 20 39 19 39 stage4 2 3 1 4 1 4 n % detrusor overactivity 43 21. 5 urodynamic stress incontinence 73 36.5 reduced bladder sensation 22 11 increased bladder sensation 2 1 bladder outlet obstruction 10 5 underactive detrusor 18 9 mean sd cystometric capacity 328.66cc 81.5 maximum flow rate 24 cc/s 18.89 post void residual 21.5 cc 3.47 detrusor pressure at maximum flow 23.72 cm3 18.89 table 2. characteristics of urodynamic tests in women with pop (n=200) urodynamic in pelvic organ prolapse-daneshpajooh et al. no significant relationship was observed between the stage of pop and voiding luts (p > 0.05) (table 4). relationship between voiding luts based on the questionnaire and urodynamic findings the mean values of the maximum flow rate (mfr) in patients with stage 1, 2, 3, and 4 pop were 24, 22, 20, and 16 cc/s, respectively. patients with mfr<12 cc/s and detrusor pressure (pdet) at qmax>25 cmh2o were considered to have a bladder outlet obstruction (boo), while those with mfr<12 cc/s and pdet at qmax<20 cmh2o were considered to have an underactive detrusor (uad). among 94 patients with voiding luts based on the questionnaire, 5.3% had boo, 9.6% an underactive bladder (uab), and 85.1% were normal. also, among 106 patients without voiding luts according to the questionnaire, 4.7% had boo, 8.5% uab, and 86.5% were normal. based on these findings, no significant relationship was found between the patient’s history and urodynamic findings (p > 0.05) (table 5). discussion uds is one of the available methods for evaluating luts in order to determine the function of bladder and urethra. this method is normally used before pop interventions, with or without anti-incontinence surgery, to make or confirm a diagnosis, predict the treatment outcomes, and facilitate discussion during counseling. however, there are disagreements regarding the effectiveness of these studies, and the correlation between the patients’ symptoms and urodynamic findings is controversial. this study addresses how patients' clinical symptoms relate to our findings in the urodynamic study and whether it is necessary to perform the test before prolapse surgery. in a study by james l et al., conducted in the united states on the importance of uds in women with pop and ui, it was found that the need for uds before surgery was under question. however, there is less controversy over the importance of uds in patients who are candidates for further surgeries or have postoperative symptoms(16). a study conducted in 2017 revealed that patients with simple ui could undergo surgery without uds. this is due to the fact that the results of preoperative uds would not cause significant changes in the outcomes of surgery. however, uds is advised for patients with complex sui to ensure the necessity of surgery and avoid unnecessary procedures(17). notwithstanding, the final decision may vary for each person, based on the clinical examination(18). relationship between the questionnaire results and pop severity according to a study by lena dain et al. in israel, an increase in the prolapse stage leads to a notable rise in urinary symptoms, such as voiding luts, sui, and uui (19). however, no significant relationship was found between the pop severity and the patient's symptoms, based on the questionnaire results in the present study. uds in patients with pop and sui uds is commonly used to assess sui associated with the reduction of prolapse (also known as occult or latent sui), which occurs in women with pop only after the prolapse is reduced. several studies have documented the use of uds in detecting sui among women with pop; however, its impact on postoperative outcomes remains highly debated. in a study by mouritsen l et al. (2003) conducted in denmark on the symptoms of patients with prolapse, 13-65% of women without complaints of sui showed symptoms of si on the urodynamic test, after prolapse reduction (occult sui). therefore, they concluded that patients with prolapse, who do not complain of sui, should be evaluated using uds before surgery(20). in another study by balci et al. (2017), conducted in istanbul, turkey, 287 patients with pop were evaluated. according to this study, 20 out of 85 patients who had not complained of sui had si based on the urodynamic test, and the prevalence of occult sui (osi) was reported to be 23.5% (21). in the present study, 73% of patients with sui based on the questionnaire showed signs of si on the urodynamic test (urodynamic si). also, 2 (1.94%) out of 103 patients, who had not complained of this condition, developed usi (osi). overall, the relationship between this complaint and urodynamic findings was significant (p < 0.001). since the urodynamic results were in accordance with the questionnaire results, uds does not seem to have a significant value in evaluating sui in patients with pop. table 3. the relation between different types of ui based on questionnaire and urodynamic tests. do usi yes n (%) no n (%) yes n (%) no n (%) p-value uui yes n=62 40(64.5) 22(35.4) < 0.001 no n=138 3(2.17) 135(97.8) sui yes (n=97) 71(73) 26(27) < 0.001 no (n=103) 2(1.94) 101(77.7) mui yes (n=46) 10(21.7) 36(78.3) 10(21.7) 36(78.3) < 0.001 no (n=154) 1(0.6) 153(99.4) 1(0.6) 153(99.4) voiding luts yes n (%) no n (%) p-value stage1 (n=15) 3(20) 12(80) 0.158 stage2(n=122) 58(47.5) 64(52.5) stage3(n=58) 30(51.7) 28(48.3) stage4(n=5) 3(60) 2(40) table 4. the relation between stages of pop and voiding luts. boo uab normal p-value voiding luts yes n=94 5(5.3%) 9(9.6%) 80(85.1%) 0.943 no(n=106) 5(4.7%) 9(8.5%) 92(86.5%) table 5. the relation between voiding luts and urodynamic test in women with pop. urodynamic in pelvic organ prolapse-daneshpajooh et al. female urology 211 vol 18 no 2 march-april 2021 212 uds in patients with pop and storage luts moreover, uds is used for evaluating concomitant storage symptoms in pop patients. storage symptoms are reported in up to 86% of patients with pop. caruso et al. conducted a study on 537 patients with ui in 2010 and showed that 278 patients had a history of uui, 58.6% of whom had do, based on the urodynamic test. furthermore, according to the urodynamic test, 45.7% of patients with a history of sui (n=306) had usi. it was concluded that there was a significant relationship between ui, based on the patient’s medical history, and urodynamic findings(22). in another study by foster et al. (2007), only 2% of patients with a history of uui had do according to the urodynamic test. they concluded that there was no significant relationship between the overactive bladder (oab) symptoms and do on the urodynamic test, which is inconsistent with the findings of the present study(23). in a study conducted in 2011 in europe, aiming to assess the relationship between urodynamic findings and urinary symptoms in women with prolapse, a total of 802 patients were evaluated. the results showed that 61.8% of these patients had sui symptoms, and 68.6% had symptoms of oab. moreover, 33.8% and 18.7% of patients had urodynamic si and do, respectively, and 24.3% had concomitant urodynamic si and do. it was concluded that ui and oab had independent relationships with si and do on the urodynamic test. they also mentioned that alternative methods, such as questionnaire and cystoscopy, could not be more effective than uds, although the effectiveness of uds in preoperative evaluation is under question. therefore, uds is suggested as the gold standard in the evaluation of urinary disorders before prolapse surgery to prevent unexpected postoperative outcomes(24). in the present study, 64.5% of patients with uui based on the questionnaire (n=62) had do, according to uds. also, 25.8% of these patients had doi. moreover, 3 (2%) out of 138 patients, who had not complained of uui, showed signs of do on the urodynamic test, one of whom (0.7%) had concomitant uui. the relationship between this complaint and urodynamic findings was significant (p < 0.001). since uds findings were in accordance with the questionnaire results, uds does not seem to have a high value in evaluating the storage symptoms of patients with pop. uds in patients with pop and voiding luts another use of uds is the evaluation of voiding symptoms or elevated post-void residual (pvr) urine in patients with pop. bladder outlet obstruction (boo) is a common urodynamic finding among women with advanced pop. however, these symptoms may improve after the surgical correction of prolapse due to the resolution of obstruction. in this regard, lena dain et al. (2010) conducted a study in israel and examined 81 women with prolapse. the results showed that 17.5% of patients with a history of voiding luts (n=40) had boo based on the urodynamic test. moreover, 7.3% of women who did not have a history of voiding luts (n=40) showed signs of obstruction on the urodynamic test. therefore, no significant relationship was found between voiding luts and urodynamic findings in patients with prolapse(19). in the present study, uds revealed that 5.3% and 9.6% of patients with voiding luts (n=94), according to the questionnaire, had boo and uab, respectively. also, according to uds, 4.7% and 8.5% of patients without voiding luts in the questionnaire (n=106) had boo and uab, respectively. based on these results, no significant relationship was found between medical history and urodynamic findings (p > 0.05). therefore, voiding luts based on questionnaire does not necessarily predict objective boo in uds, which occurred in only a small proportion of symptomatic patients and were not more prevalent in this group compared with asymptomatic patients. findings of the present study confirm the results of the study by lena dain, which showed that uds with the reduction of prolapse could help us evaluate the detrusor function and boo. in contrast, questionnaires do not provide accurate information in this area. however, the effectiveness of uds in predicting the probability of pop repair failure and postoperative voiding dysfunction or oab is controversial(22,25-27). this issue was not investigated in the present study due to the limitations of the research, and therefore, further research is suggested in this area. conclusions in terms of ui, considering the correlation between the symptoms based on the questionnaire and urodynamic findings, performing uds cannot provide further information in patients with clinical sui as well as in those with overactive bladder symptoms. additionally, there was no significant relationship between voiding luts based on the questionnaire and urodynamic findings, therefore, performing uds can help us consult the patients more effectively regarding this issue. references 1. digesu ga, chaliha c, salvatore s, et al. the relationship of vaginal prolapse severity to symptoms and quality of life. bjog. 2005; 112:971–6. 3. 2. cheon c, maher c. economics of pelvic organ prolapse surgery. int urogynecol j. 2013; 24:1873–6. 3. barber md. maher c. epidemiology and outcome assessment of pelvic organ prolapse. int urogynecol j. 2013; 24:1783-90 4. garshasbi a , faghih-zadeh s, falah n.the status of pelvic supporting organs in a population of iranian women 18 68 years of age and possible related factors.arch iran med.2006;9:124-8. 5. stanton sl, hilton p, norton c, cardozo l. clinical and urodynamic effects of anterior colporrhaphy and vaginal hysterectomy for prolapse with and without incontinence. br j obstet gynaecol .1982; 89:459. 6. al-mandeel h, ross s, robert m, milne j. incidence of stress urinary incontinence following vaginal repair of pelvic organ prolapse in objectively continent women. neurourol urodyn. 2011; 30:390. 7. katie n. ballert, md. urodynamics in pelvic organ prolapse when are they helpful and how do we use them? urol clin n am. 2014; 409–417. 8. brucker b, nitti v w. urodynamic and videourodynamic evaluation of the lowerurinary tract.in: campbellwalsh-wein urology; urodynamic in pelvic organ prolapse-daneshpajooh et al. 2020. chapter 114: p.2550-2579 9. elser dm, moen md, stanford ej, et al. abdominal sacrocolpopexy and urinary incontinence: surgical planning based on urodynamics. am j obstet gynecol .2010; 202: 375.e1–5 10. araki i, haneda y, mikami y, et al. incontinence and detrusor dysfunction associated with pelvic organ prolapse: clinical value of preoperative urodynamic evaluation. int urogynecol j pelvic floor dysfunct. 2009; 20:1301–6. 11. roovers jp, oelke m. clinical relevance of urodynamic investigation tests prior to surgical correction of genital prolapse: a literature review. int urogynecol j pelvic floor dysfunct 2007; 18: 455–60 12. fletcher sg, haverkorn rm, yan j, et al. demographic and urodynamic factors associated with persistent oab after anterior compartment prolapse repair. neurourol urodyn .2010; 29:1414–8. 13. wolter ce, kaufman mr, duffy jw, et al. mixed incontinence and cystocele: postoperative urge symptoms are not predicted by preoperative urodynamics. int urogynecol j .2011; 22:321–5. 14. abrams, p. et al., the standardisation of terminology of lower urinary tract function: report from the standardisation sub‐ committee of the international continence society. neurourol urodyn. 2002. 21: p. 167178. 15. blaivas j, groutz a. bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. neurourol urodyn. 2000;19:553-64 16. whiteside jl.making sense of urodynamic studies for women with urinary incontinence and pelvic organ prolapse.urol clin north am. 2012;39:257-63. 17. bradley cs, nygaard ie. vaginal wall descensus and pelvic floor symptoms in older women. obstet gynecol. 2005; 106:759–66. 18. gajewski jb. decisions regarding use of urodynamic studies in stress urinary incontinence must be made on a case-by-case basis.can assoc j.2017;11:116. 19. lena d,ron a,talma r,et al .urodynamic finding in women with pelvic organ prolapse and obstructive voiding symptoms.int j gynecol obstet.2010;111:119-21. 20. mouristen l, larsen jp. symptoms bother and popq in women referred with pelvic organ prolapsed. int urogynecol j pelvic floor dysfunct.2003;14:122-7. 21. balci b k, ugurlucan f g, yasa c, et al. 6-year experience in the diagnosis and treatment of occult urinary incontinence in women with pelvic organ prolapsed. eur j obstet gynecol reprod biol. 2017; 210:265-969. 22. caruso d, kanagarajah p, cohen b, et al. what is the predictive value of urodynamics to reproduce clinical findings of urinary frequency, urge urinary incontinence, and/or urodynamic in pelvic organ prolapse-daneshpajooh et al. female urology 213 urol_v07_no4_print_2.pdf case report 281urology journal vol 7 no 4 autumn 2010 malignant sertoli cell tumor of the testis with a large retroperitoneal mass in an elderly man david golombos,1 daniel brison,1 hossein sadeghi-nejad2 urol j. 2010;7:281-3. www.uj.unrc.ir keywords: sertoli cell tumor, testis, testicular neoplasms, pathology, complications 1department of surgery, division of urology, umdnj-new jersey medical school, newark, new jersey, usa 2department of surgery, division of urology, umdnj-new jersey medical school, newark, new jersey, division of urology, new \ � ��] � ��� �>**��� ��� ���� �� � ���� ����*�x����y������? � ��?� university medical center, ���? � ��?��h ��\ � ���x�> corresponding author: �� ������ y(�4h ������� �#zz���!���� ���>� �����? � ��?�� new jersey, 07601, usa ̂�<�`z��!z�q"��#$## {�|<�`z��!z�q"��!z�q e-mail: hossein@ix.netcom.com received july 2009 accepted march 2010 introduction we report a malignant sertoli cell tumor distinguished clinically by its rapid enlargement, early metastasis, and age of presentation. case report a 78-year-old man presented with a new growth in his right testis which was uncomfortable, but not painful. he reported a progression in growth over the past few months, and stated that it was doubled in size in the previous month. his past medical history included mumps as a child, hypertension, and recurrent urolithiasis with reported spontaneous passage of calcium oxalate calculi several months prior to this presentation. physical exam revealed a moderately enlarged right hydrocele and a firm right testicular mass as well as right inguinal adenopathy consisting of non-tender, small nodes. there was no evidence of gynecomastia. complete blood cell count, blood chemistry, and urine analysis were within normal limits, and serum tumor markers, including human chorionic gonadotropin and alphafetoprotein were negative. serum levels of estrogen and testosterone were not initially measured. scrotal ultrasonography revealed an area of mixed echogenicity in the midlower portion of the right testis measuring 4.0 × 2.1 × 2.3 cm with increased flow on color doppler ultrasonography consistent with a testicular neoplasm, as well as a large right hydrocele. computed tomography scan revealed multiple enlarged retroperitoneal lymph nodes and a large aortocaval lymph node measuring 4.2 × 2.1 cm. right inguinal orchiectomy was performed without complication and the patient was discharged from the hospital the following day. serum level of testosterone was within the normal range (287.13 ng/dl) at 11 months after the orchiectomy. on gross inspection, the specimen included the testis with attached spermatic cord and surrounding soft tissue, measuring 5.3 × 4.5 × 4 cm. sectioning revealed the testis that weighed 53 gr and a 4 × 4 × 3.5-cm firm mass, with solid white to yellow cut surfaces replacing 95% of the testis tissue. the tumor focally invaded the surrounding tunica albuginea, and 3 small solid yellow nodules were identified on the surface of the parietal tunica vaginalis. furthermore, one solid nodule measuring 0.9 × 0.7 × 0.5 cm was identified in the spermatic cord. microscopic examination revealed a sertoli cell tumor with focal necrosis, vascular invasion, and testicular sertoli cell tumor—golombos et al 282 urology journal vol 7 no 4 autumn 2010 direct extension into the spermatic cord and tunica vaginalis. a high mitotic count of 15 per 10 high-power fields was noted. the tumor cells were positive for inhibin and focally positive for neuron specific enolase. computed tomography guided biopsy of the retroperitoneal lymph nodes was offered to the patient on multiple occasions, but he refused any further diagnostic tests. the patient was counseled extensively regarding the risks and benefits of retroperitoneal lymph node dissection. he decided not to undergo the procedure. at the time of the 1-year follow-up visit, the patient’s aortocaval lymph node had increased in size to 4.3 × 9.6 cm and there was an additional new lymph node in the pelvis with central necrosis measuring 3.3 × 2.6 cm. the patient again elected to continue observation and refused a diagnostic biopsy or retroperitoneal lymph node dissection. discussion sex cord-stromal tumors account for approximately 4% of the testicular neoplasms, with sertoli cell tumors comprising 0.4% to 1.5% of all primary testicular tumors.(1,2) in spite of their rarity, sertoli cell tumors have been rather heterogeneous and much debate has revolved around their distinguishing characteristics, clinical course, and potential for malignancy. (3) two distinct subtypes have emerged from careful study, a large cell calcifying sertoli cell tumor, first described in 1980, exhibits diffuse intratabular and extratubular calcification, and has been known to exhibit virilization and extragonadal manifestations.(4) the second variety, a sclerosing sertoli cell tumor, was first described by zuckerberg and colleagues in 1991.(3) this subtype, distinguished by extensive hypocellular, collagenous stroma separating clusters of sertoli’s cell, is the least reported one and has questionable malignant potential, with only one reported tumor showing evidence of malignant features pathologically, but with no evidence of metastasis before the patient suffered from a cardiac related death. even after distinct subtype classification had been established, the low incidence of these tumors makes appreciation for histological variability difficult and subtyping a challenge, as factors such as the degree of sclerosis weigh heavily upon the categorization. for example, microscopic and histological analysis of the tumor in our patient originally yielded a diagnosis of a sclerosing sertoli cell tumor. however, consultation with armed forces institute of pathology confirmed the diagnosis of a malignant sertoli cell tumor, but the degree of hyalinization of the stroma was not enough to categorize this as a sclerosing sertoli cell tumor. furthermore, the largest series of sertoli cell testicular tumors in the literature, consisting of 60 subjects with sertoli cell tumors, not otherwise specified, found a tendency in the older literature to report the neoplasm now figure 1. abdominal computed tomography scan showing the largest of multiple retroperitoneal lymph nodes, an aortocaval node measuring 4.2 × 2.1 cm. figure 2. histology of tumor showing trabecular/acinar arrangement of malignant sertoli cells. focal necrosis can be seen in the upper left corner of figure 2a. a b testicular sertoli cell tumor—golombos et al 283urology journal vol 7 no 4 autumn 2010 recognized as a juvenile granulosa cell tumor as a sertoli cell tumor, and a similar tendency to label other neoplasms as sertoli cell tumors that would be best placed in other categories, including sertoli-leydig cell tumors. they believed that this inconsistency weighs heavily on reported clinical features, including the age of presentation and frequency of gynecomastia.(5) with this in mind, we feel it is important to accurately document the clinical manifestations and pathologic features of these tumors, especially those that are malignant. although the large size (> 5 cm), poor tumor demarcation, invasion to adjacent structures, blood vessel and lymphatic invasion, and increased mitotic activity (> 5 mitotic figures per 10 high-power fields) are all suggestive of malignant potential, the designation of malignancy can be made certainty only in the presence of metastasis.(6) the first and most common site of metastatic disease of patients with sex cord-stromal tumors is the retroperitoneal lymph nodes,(7) and according to the literature, about 10% to 12% of these tumors have evidence of metastasis.(1,4) the malignant tumor in our patient appears to be aggressive when compared to the 60 tumors analyzed by young and associates. in his study, the mean age of presentation and the average duration of a “slowly enlarging” mass were 45 and 3.7 years, respectively. only four patients had metastatic disease at the time of presentation. of whom, in only two, vascular invasion, necrosis, nuclear pleomorphism, and mitotic rate >5 were all present.(5) our patient presented with an enlarging mass over only months (doubling in size over the last month), had 4.2 × 2.1 cm retroperitoneal mass, and while slightly missing the large size criterion for pathologic malignancy, was significant for the remainder of the aforementioned standards. furthermore, this patient’s age of 78 years is a rarity amongst this variety of tumor, as approximately one-third of the recorded patients with sertoli cell tumors have been 12 years or younger.(6) while it has been observed that in sertoli cell tumors, benign neoplasms occurred at a younger mean age than those proven to be malignant,(8) the oldest patient reported in the young and colleagues’ study was 80 years old (a benign tumor),(5) and in a study by lindegaard and mørck on metastasizing sertoli cell tumors, only one patient, a 79-year-old man, exceeded the age of our patient.(1) conflict of interest none declared. references 1. lindegaard m, mørck h. metastasizing sertoli cell tumours of the human testis--a report of two cases and a review of the literature. acta oncol. 1990;29:946. 2. anderson g. sclerosing sertoli cell tumor of the testis: a distinct histological subtype. j urol. 1995;154:1756-8. 3. zukerberg l, young r, scully r. sclerosing sertoli cell tumor of the testis: a report of 10 cases. am j surg pathol. 1991;15:829. 4. proppe k, scully r. large-cell calcifying sertoli cell tumor of the testis. american journal of clinical pathology. 1980;74:607. 5. young rh, koelliker dd, scully re. sertoli cell tumors of the testis, not otherwise specified: a clinicopathologic analysis of 60 cases. am j surg pathol. 1998;22:709-21. 6. richie jp, steele gs. neoplasms of the testis. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. 9 ed: phladelphia:w.b. saunders; 2007: 928 . 7. mosharafa aa, foster rs, bihrle r, et al. does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumors? cancer. 2003;98:753-7. 8. kratzer ss, ulbright tm, talerman a, et al. large cell calcifying sertoli cell tumor of the testis: contrasting features of six malignant and six benign tumors and a review of the literature. am j surg pathol. 1997;21:1271-80. review effects of androgen deprivation therapy on covid-19 in patients with prostate cancer: a systematic review and meta-analysis amirali karimi1, ali nowroozi1, sanam alilou1, erfan amini1,* purpose: transmembrane serine protease 2 (tmprss2) facilitates sars-cov-2 cellular entry. androgens regulate this protein and may increase the risk of covid-19. therefore, androgen deprivation therapy (adt) may protect patients with prostate cancer from sars-cov-2 infection or decrease the severity of the disease. therefore, we conducted a meta-analysis to study the effect of androgen deprivation therapy (adt) on covid-19 in patients with prostate cancer. methods: we systematically searched pubmed, embase, scopus, and cochrane databases. all records underwent a two-step screening process to identify the eligible studies. the registered prospero number of this study was crd42021228398. we evaluated the effect of adt on the risk of infection, hospitalization, icu admission, and mortality. results: six studies met inclusion criteria and were evaluated in this study. we performed meta-analysis on four eligible studies. the overall incidence of covid-19 was 2.65% among patients with prostate cancer receiving adt. covid-19 mortality rate was about 22.7% in adt (+) patients. adt did not decrease the risk of any of the major outcomes; infection risk (or= 0.63, 95% ci= 0.271.48, p = 0.29), hospitalization rate (or= 0.51, 95% ci= 0.102.53, p = 0.41), icu admission (or= 1.11, 95% ci= 0.432.90, p = 0.82), and mortality risk (or= 1.21, 95% ci= 0.344.32, p = 0.77). conclusion: we did not observe a protective effect on the risk of infection, hospitalization, icu admission, and mortality in patients receiving adt; therefore, it should not be considered as a prophylactic or treatment for covid-19. on the other hand, adt did not increase the mortality and morbidity of covid-19 and should be considered a safe treatment for patients with prostate cancer during the pandemic. further studies are necessary to confirm our findings. keywords: androgens; covid-19; prostatic neoplasms; sars-cov-2 introduction as of january 27th, coronavirus disease 2019 (covid-19) has imposed a tremendous human toll of 99,638,507 deaths and 2,141,468 cases since its inaugural.(1,2) this devastating burden resulted in an explosion of ideas and hypotheses to cure or prevent the disease.(3) androgen deprivation therapy (adt) turned out to be one of these hypothetical solutions.(4-7) transmembrane serine protease 2 (tmprss2) facilitates severe acute respiratory syndromecoronavirus-2 (sars-cov-2) cellular entry and serves as the principal protease in this process.(8-12) tmprss2 initiates viral fusion and host cell-receptor binding by cleaving the sars-cov-2 spike (s) protein and angiotensin-converting enzyme2 (ace-2).(11-15) many patients with prostate cancer also suffer from tmprss2 fusion as a common genetic abnormality in this disease.(6) higher testosterone levels upregulate tmprss2 and can theoretically increase the risk of viral transmission.(4,5) earlier studies raised the idea that the increased risk of infection and mortality in men might correlate with this molecular phenomenon.(16-19) therefore, adt raised 1uro-oncology research center, tehran university of medical sciences, tehran, iran. *correspondence: uro-oncology research center, tehran university of medical sciences, tehran, iran. amini.erfan@gmail.com received february 2021 & accepted july 2021 hopes as a novel approach to fight covid-19.(4-6) adt is a standard treatment for many patients with high-risk and advanced prostate cancer.(20-24) this approach constitutes various treatments with similar ideas, ranging from bilateral orchiectomy, to novel medications such as lhrh (luteinizing hormone-releasing hormone) antagonists and cyp17 inhibitors.(6,25-27) to examine the aforementioned hypothesis, several articles assessed the outcomes of covid-19 in patients with prostate cancer who received adt compared with those who did not. in this meta-analysis, we aim to examine the effect of adt prescribed for prostate cancer patients on their risk of covid-19 infection and the subsequent outcomes. materials and methods design this study was conducted in accordance with preferred reporting items for systematic reviews (prisma) 2020 guidelines. we systematically searched pubmed, scopus, embase, and cochrane libraries on december 26th. the retrieved records followed a two-step screening process. first, the articles were screened based on urology journal/vol 18 no. 6/ november-december 2021/ pp. 577-584. [doi: 10.22037/uj.v18i.6691] the overall coherence of their title and abstract to our inclusion criteria. the qualified articles were assessed by their full-texts, and the eligible articles were included for the qualitative and quantitative synthesis. this meta-analysis was registered in prospero (international prospective register of systematic reviews) with the id crd42021228398. pico 1. population: patients with prostate cancer 2. intervention: receiving adt 3. comparison: not receiving adt 4. outcomes: 1) covid-19 infection risk; 2) covid-19 severity risk, including: 1. hospitalization risk, 2. icu admission, and 3. mortality risk search strategy we searched the keywords for adt and covid-19 using the search strategy [c]. [androgen deprivation therapy] (title/abstract) or [androgen deprivation therapies] (title/abstract) or [androgen targeted therapy] (title/abstract) or [androgen targeted therapies] (title/abstract) or [androgen deprivation] (title/abstract) or [androgen] (title/ abstract) [covid-19] (title/abstract) or [sars-cov-2] (title/abstract) or [sars-cov2] (title/abstract) or [novel coronavirus] (title/abstract) or [2019-ncov] (title/abstract) [a] and [b] inclusion/exclusion criteria original clinical articles, from the start of the pandemic until december 26th, demonstrating the effect of adt on the covid-19 were included. no language restriction was considered in this study. exclusion criteria were the following: 1) review, guidelines, editorials, or other articles not possessing original data 2) case reports 3) incomplete projects and clinical trials 4) animal and laboratory studies without clinical data data acquisition and analysis we completely read the full-texts and extracted the data into an excel sheet. we classified the major extracted outcomes into four categories and estimated their risks; id first author country type of study newcastle-ottawa scale (nos) risk of bias assessment selection comparability exposure total score (out of 9) 1 klein, e. a. (29) usa prospective cohort **** ** *** 9 2 koskinen, m. (30) finland retrospective cohort **** ** ** 8 3 montopoli, m. (31) italy retrospective cohort **** ** 6 4 patel, v. g. (32) usa retrospective cohort **** ** ** 8 5 caffo, o. (33) italy retrospective cohort *** ** 5 6 caffo, o. (34) italy retrospective cohort *** *** 6 table1. characteristics and nos risk of bias assessment scale of the studies androgen deprivation therapy and covid-19karimi et al. review 578 figure 1. prisma flow diagram of the study selection process covid-19 infection, hospitalization, icu (intensive care unit) admission, and mortality. besides the abovementioned four major outcomes, we also extracted country, population, mean age, and comorbidities into the same excel sheet. higgins i2 test was utilized to examine heterogeneity among the studies. i2 levels of above 40% represented heterogeneity among data of the subgroups and warranted a random effects analysis.(28) we used fixed effect analysis to evaluate the groups that were classified as low in the heterogeneity test. we used egger’s test and funnel plot to assess the potential publication bias for each major outcome in this study. meta-analyses were conducted using the latest version of the cochrane review manager released in september 2020 (revman 5.4.1). publication bias and pooled analyses were performed using stata version 16. the visualizations for each part were illustrated using their corresponding software. we used odds ratio (or) to assess the outcomes and p= 0.05 as the threshold of significance. risk of bias assessment newcastle-ottawa scale (nos) risk assessment tool was applied to calculate the risk of bias of the included studies. this tool provides a maximum score of nine for each study in three categories of selection, comparability, and exposure. results we identified 50 non-duplicate records by searching pubmed, embase, scopus, and cochrane databases. following the title/abstract and full-text screening, six related original articles were included for conducting this systematic review. four studies were eligible for meta-analysis as they comprised both adt (+) and adt (-) groups (figure 1).(29-32) the remaining two studies comprised only adt (+) patients, and did not have adt (-) controls. therefore, they were excludid first author total no. age dosage and comorbidities total no. of assessed (b) (mean ± sd) duration of adt infected patients variables 1 klein, e. a. (29) total: 1779 total: 74.1 ± 10.3 n/a 1. smoking history: total: 102 covid-19 infection adt (+): 304 adt (+): 75.7 ± 10.9 adt (+): 68.1% adt (+): 17 hospitalization adt (-): 1475 adt (-): 73.8 ± 10.2 adt (-): 59.3% adt (-): 85 icu admission (p < .009) (p < .005) death 2. immune-suppressive disease: adt (+): 34.2% adt (-): 27.5% (p = .02) 3. steroid use: adt (+): 43.8% adt (-): 23.3% (p < .001) 4. asthma: adt (+): 9.2% adt (-): 14.2% (p = .02) 5. no significant difference in htn, cad, hf, and diabetes mellitus. 2 koskinen, m. (30) total: 352 total: 77.2 ± 9.0 n/a no significant differences total: 17 covid-19 infection adt (+): 134 adt (+): 78.4 ± 8.1 in: htn, cad, copd, adt (+): 6 icu admission adt (-): 218 adt (-): 76.5 ± 9.4 diabetes mellitus, adt (-): 11 arrhythmia, smoking history 3 montopoli, m. (31) total: 42434 n/a n/a n/a total: 118 covid-19 infection adt (+): 5273 adt (+): 4 disease severity adt (-): 37161 adt (-): 114 hospitalization icu admission death 4 patel, v. g. (32) n/a n/a 1. gnrh analog/agonis 1. metastatic disease: total: 58 hospitalization within 3 months and/or adt (+): 64% adt (+): 22 o 2 supplementation 2. documented adt (-): 0% adt (-): 36 intubation death testosterone concentrations (p < .001) ≤ 50 ng/dl within 6 months 2. underlying pulmonary of covid-19 diagnosis disease: adt (+): 27% adt (-): 6% (p = .02) 3. no significant difference in other comorbidities (not mentioned specifically) 5 caffo, o. (33) 1949 median age: 74.5 n/a n/a 36 covid-19 infection hospitalization death 6 caffo, o. (34) 1433 75.4 ± 9.6 median duration: 50 n/a 34 covid-19 infection months (iqr: 19-66) hospitalization icu admission o 2 supplementation intubation death table 2. characteristics of prostate cancer patients with sars-cov-2 infection in the included studies a abbreviations: sd: standard deviation, adt: androgen deprivation therapy, icu: intensive care unit, htn: hypertension, cad: coronary artery disease, hf: heart failure, n/a: data “not available”, copd: chronic obstructive pulmonary disease, gnrh: gonadotropin releasing hormone, iqr: interquartile range, b total number applies to the prostate cancer patients reported in each study. for the last two studies, all of the patients received adt. androgen deprivation therapy and covid-19karimi et al. vol 18 no 6 november-december 2021 579 ed from meta-analysis between adt (+) and adt (-) groups.(33,34) in addition, these studies were performed on a similar population. therefore, if both studies reported a variable in adt (+) patients, we only considered the larger study.(33) table 1 describes the risk of bias for the included studies. five studies (three of those included in the comparative analysis) belonged to italy and the usa, both highly stormed by the covid-19 pandemic. most studies scored well according to the nos (mean ± sd = 7 ± 1.1). baseline characteristics mean patient age was comparable between adt (+) and adt (–) groups in one study(30) whereas another study reported higher mean age among adt (+) patients (mean age: 75.7 vs. 73.8, p < .009) (table 2).(29) three studies reported comorbidities.(29,30,32) although one study reported similar frequency of various comorbidities in adt (+) and (-) groups,(30) two other studies review 580 figure 2. pooled analysis of covid-19 rate in patients receiving adt figure 3. meta-analysis of the subgroups with high heterogeneity androgen deprivation therapy and covid-19karimi et al. reported higher comorbidity rates among adt (+) patients.(29,32) in patel et al. study, patients using adt endured higher rates of metastatic (64% vs. 0%, p < .001) and underlying pulmonary diseases (27% vs. 6%, p = .02).(32) patients receiving adt in klein et al.'s study were more likely to have smoking history (68.1% vs. 59.3% p < .005), immune-suppressive disease (34.2% vs. 27.5%, p = .02), and steroid use (43.8% vs. 23.3%, p < .001), and less likely to have a history of asthma (9.2% vs. 14.2%, p = .02).(29) covid-19 infection risk pooled analysis showed that sars-cov-2 infection rate among patients receiving adt was 2.65% (figure 2).(29-31,33) adt was not associated with a decreased covid-19 infection risk (95% ci: 0.27-1.48, or = 0.63, p = .29) (figure 3). components of disease severity hospitalization risk: hospital admission was recorded in 62.1% of the infected patients in the adt (+) group (figure 4).(29-33) adt use did not affect the risk of hospitalization (95% ci: 0.10-2.53, or = 0.51, p = .41) (figure 3). icu admission risk: one study combined data of icu admission with mortality.(30) we assumed all these patients as requiring icu admission; however, we did not utilize these data to assess mortality risk. among adt (+) patients who were infected with sars-cov-2, 18.3% required icu admission (figure 5)(29-32,34) and adt did not decrease the likelihood of icu admission (95% ci: 0.43-2.90, or = 1.11, p = .82) (figure 6). mortality risk: we included five appropriate studies to estimate the mortality rate and association between adt use and risk of mortality.(29-33) the mortality rate was about 22.7% (figure 7) and was not associated with adt use (95% ci: 0.34-4.32, or = 1.21, p = .77) (figure 3). publication bias we performed egger’s test and funnel plot to test publication bias of all the four major outcomes. none of the variables had significant publication bias: covid-19 infection (p for egger’s test = .50, funnel plot as supplementary figure 1), hospitalization (p = .59, supplementary figure 2), icu admission (p = .98, supplementary figure 3), mortality (p = 0.58, supplementary figure 4). discussion we found that adt use could not reduce covid-19 infection, hospitalization, icu admission, or mortality risks. on the other hand, they also did not face elevated risks of complications related to adt. prostate cancer patients who are receiving adt usually suffer from more comorbidities, advanced disease, and higher risk of mortality.(21,35) three studies that were included in the comparative analysis reported the patients’ age and underlying disease status. overall, patients in the adt (+) group seemed to have more comorbidities than adt (-) patients. this may mask the potential protective effects of adt on covid-19.(29,30,32) sars-cov-2 infection rate among adt (+) patients was 2.65%. this rate might be associated with both underestimation and overestimation. most studies were from italy and the usa, two of the world's worst-hit countries with the potential to overestimate the risk of infection. on the other hand, missing many patients with milder symptoms who did not seek care might underestimate the true rate of covid-19 in the adt (+) figure 4. pooled analysis of hospitalization rate in covid-19 patients receiving adt androgen deprivation therapy and covid-19karimi et al. vol 18 no 6 november-december 2021 581 patients. the main limitation of this meta-analysis is the limited number of studies and patients due to the novelty of the subject. results were not adjusted for confounding factors including comorbidities and disease stage. the dosage and duration of adt was also not mentioned in most of the studies. our study is the first meta-analysis on this subject, providing valuable information on adt and the risk of covid-19 and included studies were relatively homogeneous in terms of methodology. more investigations are needed to better identify the role of adt in covid-19. conclusions adt showed a modest protective effect on covid-19 and only one of the five parameters were associated with adt use. however, adt did not increase the morbidity and mortality related to covid-19. therefore, adt should be considered safe and physicians should not hesitate to administer this treatment to the candidates during the pandemic. further studies with larger sample size are necessary to obtain more definitive results. conflicts of interest the authors declare that they have no conflicts of interest. review 582 figure 5. pooled analysis of icu admission rate in covid-19 patients receiving adt figure 6. meta-analysis of the subgroups with low heterogeneity androgen deprivation therapy and covid-19karimi et al. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/33 references 1. organization wh. who coronavirus disease (covid-19) dashboard. https://covid19. who.int/. 2. mehraeen e, karimi a, barzegary a, et al. predictors of mortality in patients with covid-19-a systematic review. eur j integr med. 2020;40:101226. 3. venkatesh v. impacts of covid-19: a research agenda to support people in their fight. int j inf manage. 2020;55:102197. 4. bennani nn, bennani-baiti im. androgen deprivation therapy may constitute a more effective covid-19 prophylactic than therapeutic strategy. ann oncol. 2020;31:1585-6. 5. cattrini c, bersanelli m, latocca mm, conte b, vallome g, boccardo f. sex hormones and hormone therapy during covid-19 pandemic: implications for patients with cancer. cancers. 2020;12:1-13. 6. neil ab, jillian o, tanya d, et al. covid-19 and androgen-targeted therapy for prostate cancer patients. endocr relat cancer. 2020;27:r281-r92. 7. o'callaghan me, jay a, kichenadasse g, moretti kl. androgen deprivation therapy in unlikely to be effective for treatment of covid-19. ann oncol. 2020;31:1780-2. 8. mollica v, rizzo a, massari f. the pivotal role of tmprss2 in coronavirus disease 2019 and prostate cancer. future oncology. 2020;16:2029-33. 9. deng q, rasool ru, natesan r, asangani ia. therapeutic targeting of tmprss2 andace2 as a potential strategy to combat covid-19. clinical cancer research. 2020;26. 10. mjaess g, karam a, aoun f, albisinni s, roumeguère t. covid-19 and the male susceptibility: the role of ace2, tmprss2 and the androgen receptor. prog urol : journal de l'association francaise d'urologie et de la societe francaise d'urologie. 2020;30:484-7. 11. john j, kesner k. covid-19: the androgen hypothesis. african journal of urology. 2020;26. 12. hoffmann m, kleine-weber h, schroeder s, et al. sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor. cell. 2020;181:271-80.e8. 13. matsuyama s, nao n, shirato k, et al. enhanced isolation of sars-cov-2 by tmprss2-expressing cells. proc natl acad sci u s a. 2020;117:7001-3. 14. shang j, wan y, luo c, et al. cell entry mechanisms of sars-cov-2. proc natl acad sci u s a. 2020;117:11727-34. 15. heurich a, hofmann-winkler h, gierer s, liepold t, jahn o, pöhlmann s. tmprss2 and adam17 cleave ace2 differentially and only proteolysis by tmprss2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. j virol. 2014;88:1293-307. 16. strope jd, chau ch, figg wd. are sex discordant outcomes in covid-19 related to sex hormones? semin oncol. 2020;47:335-40. 17. yanez nd, weiss ns, romand j-a, treggiari mmjbph. covid-19 mortality risk for older men and women. bmc public health. 2020;20:1-7. 18. sharma g, volgman as, michos edjcr. figure 7. pooled analysis of mortality rate in covid-19 patients receiving adt androgen deprivation therapy and covid-19karimi et al. vol 18 no 6 november-december 2021 583 sex differences in mortality from covid-19 pandemic: are men vulnerable and women protected? jacc case rep. 2020;2:1407-10. 19. dana pm, sadoughi f, hallajzadeh j, et al. an insight into the sex differences in covid-19 patients: what are the possible causes? prehosp disaster med. 2020;35:438-41. 20. pagliarulo v, bracarda s, eisenberger ma, et al. contemporary role of androgen deprivation therapy for prostate cancer. eur urol. 2012;61:11-25. 21. sharifi n, gulley jl, dahut wl. androgen deprivation therapy for prostate cancer. jama. 2005;294:238-44. 22. rusthoven cg, jones bl, flaig tw, et al. improved survival with prostate radiation in addition to androgen deprivation therapy for men with newly diagnosed metastatic prostate cancer. j clin oncol. 2016;34:2835-42. 23. keating nl, malley ajo, smith mr. diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. j clin oncol. 2006;24:4448-56. 24. saylor pj, smith mr. adverse effects of androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer. j natl compr canc netw. 2010;8:211-23. 25. klotz l, boccon-gibod l, shore nd, et al. the efficacy and safety of degarelix: a 12-month, comparative, randomized, openlabel, parallel-group phase iii study in patients with prostate cancer. bju international. 2008;102:1531-8. 26. attard g, reid ah, yap ta, et al. phase i clinical trial of a selective inhibitor of cyp17, abiraterone acetate, confirms that castrationresistant prostate cancer commonly remains hormone driven. j clin oncol. 2008;26:456371. 27. donnell ao, judson i, dowsett m, et al. hormonal impact of the 17alpha-hydroxylase/ c(17,20)-lyase inhibitor abiraterone acetate (cb7630) in patients with prostate cancer. br j cancer. 2004;90:2317-25. 28. higgins j, thomas j, chandler j, et al. cochrane handbook for systematic reviews of interventions. version 6.2, 2021. 29. klein ea, li j, milinovich a, et al. androgen deprivation therapy in men with prostate cancer does not affect risk of infection with sars-cov-2. the journal of urology. j urol . 2021 205(2):441-443 30. koskinen m, carpen o, honkanen v, et al. androgen deprivation and sars-cov-2 in men with prostate cancer. ann oncol. 2020;31:1417-8. 31. montopoli m, zumerle s, vettor r, et al. androgen-deprivation therapies for prostate cancer and risk of infection by sars-cov-2: a population-based study (n = 4532). ann oncol. 2020;31:1040-5. 32. patel vg, zhong x, liaw b, et al. does androgen deprivation therapy protect against severe complications from covid-19? ann oncol. 2020;31:1419-20. 33. caffo o, zagonel v, baldessari c, et al. on the relationship between androgen-deprivation therapy for prostate cancer and risk of infection by sars-cov-2. ann oncol. 2020;31:14156. 34. caffo o, gasparro d, di lorenzo g, et al. incidence and outcomes of severe acute respiratory syndrome coronavirus 2 infection in patients with metastatic castration-resistant prostate cancer. eur j cancer. 2020;140:1406. 35. nima s, james lg, william ld. an update on androgen deprivation therapy for prostate cancer. endocr relat cancer. 2010;17:r305-r15. review 584 androgen deprivation therapy and covid-19karimi et al. female urology the long-term effects of transurethral bladder neck incision in the treatment of female bladder neck obstruction yan qin, liyang wu, fei wang, chaohua zhang, peng zhang*, xiaopeng hu purpose: to investigate the long-term effects of transurethral bladder neck incision (tubni) for female primary bladder neck obstruction (pbno). materials and methods: we retrospectively reviewed seventy women diagnosed with bladder neck obstruction by video-urodynamic study (vuds). tubni was performed for each patient, with incisions made at 2 different sites on the bladder neck. postoperatively, patients were assessed by international prostate symptom score (ipss), quality of life (qol) and uroflowmetry. results: follow-up data were available for 4-108 months (median 42 months) postoperatively. during follow-up, the ipss, qol, time to maximum uroflow rate, postvoid residual urine volume decreased significantly after tubni compared with preoperative [13.0 (10.0, 15.0) versus 3.0 (3.0, 8.0), p ＜ .001], [5.0 (5.0, 5.0) versus 2.0 (1.0, 3.0), p ＜ .001], [9.0 (5.0, 37.0) versus 6.1 (4.2, 8.7), p ＜ .001], [77.5 (23.5, 165.8) versus 0.0 (0.0, 30.0), p ＜ .001]. the maximum uroflow rate, average uroflow rate and the voided volume increased significantly compared with preoperative [7.0 (4.0, 10.3) versus 19.8 (12.8, 25.2), p ＜ .001], [3.0 (2.0, 5.0) versus 8.0 (4.9, 10.7), p ＜ .001] and [156.5 (85.0, 211.3) versus 261.3 (166.2, 345.6), p ＜ .001]. several complications were identified after surgery, including bladder neck reobstruction, urethral stricture, and stress urinary incontinence, the corresponding number was 5 (7.1%), 7(10%) and 7(10%). successful operation was achieved in 60/70 (85.7 %) patients. conclusion: pbno is a very rare yet easily treatable condition. vuds is the primary diagnostic tool for the diagnosis of bladder neck obstruction in women, while tubni can effectively relieve obstruction symptoms and improve the quality of life for patients. keywords: female bladder neck obstruction; video-urodynamic study; transurethral bladder neck incision; urinary incontinence; urethral stricture introduction female bladder neck obstruction is an uncommon condition compared with men and is observed in 1%-16% of women deemed to have bladder outlet obstruction.(1)the precise cause of pbno has not been elucidated and the etiology has been attributed to detrusor bladder neck dyssynergia, bladder neck hypertrophy secondary to a distal urethral obstruction, fibrosis of the bladder neck, striated muscle extends from the external sphincter to the bladder neck, and increased sympathetic activity at the bladder neck.(2,3) there are numerous causes of bladder outlet obstruction in women, which can generally be divided into anatomical causes and functional causes. anatomical causes are more common and can be extrinsic (pelvic organ prolapse or post-anti-incontinence procedure), urethral (stricture, meatal stenosis, urethral caruncle, fibrosis or diverticulum) or luminal (stone, bladder or urethral tumor, ureterocele or foreign body)(4) functional obstruction can be diagnosed only during the act of voiding because no obvious anatomic abnormality will be associated with the patient's symptoms. functional causes may be a consequence of improper external striated sphincter relaxation or contraction during department of urology, beijing chao-yang hospital, capital medical university, beijing 100020, china. *correspondence: department of urology, beijing chao-yang hospital, capital medical university, beijing 100020, china. tel: +86 13611046169. e-mail: seabottlezp@126.com. received january 2022 & accepted september 2022 voiding caused by senile bladder changes, neurological diseases, diabetes mellitus, other peripheral neuropathy, or non-neurogenic causes. the two most common functional causes are dysfunctional voiding (dv) and pbno.(5,6) although they have similar presentations, their etiology and therapy are completely different. pbno may present with a variety of symptoms, including voiding or obstructive symptoms (decreased force of stream, hesitancy, intermittent stream, incomplete emptying), storage or irritative symptoms (frequency, urgency, urinary incontinence, nocturia) or a combination of both.(7) pbno in women is a video-urodynamic diagnosis whose hallmarks include high detrusor pressure (maximal detrusor pressure at the maximum flow rate, pdet. qmax＞20cm h 2 o), a low flow rate (maximum flow rate, qmax <12 ml/s), radiographic evidence of nonfunneling at the bladder neck with the relaxation of the striated sphincter, and no evidence of distal obstruction. (8,9) treatment options for pbno include watchful waiting, pharmacotherapy, and surgical intervention.(10) for patients having poor responses to medication, those experiencing severe medicinal side effects, and those who are unwilling or incompetent to perform clean intermittent self-catheterization, tubni is a treatment option urology journal/vol 20 no. 1/ january-february 2023/ pp. 41-47. [doi:10.22037/uj.v19i.7174] with excellent therapeutic results. the main concerns of bladder neck incision in females are the development of postoperative stress urinary incontinence (sui) and urethral stricture. we present a retrospective analysis of treatment in female bladder neck obstruction, with special emphasis on surgical therapy and complications in the post-operative period. materials and methods study population this study retrospectively collected the data from 70 female patients underwent tubni in urology of beijing chao-yang hospital between april 2012 to december 2020 which collected by the electronic medical record system. all the patients underwent physical examination, a comprehensive medical history, blood routine detection, serum, and urine biochemistry, while all patients filled ipss and qol questionnaires. uroflowmetry was performed in all patients to initially assess the qmax. if qmax <12 ml/s, we tentatively considered the presence of bladder outlet obstruction (boo). vuds was performed on all patients to verify the cause of difficult voiding. the most common symptoms on admission included frequency, urgency, difficult micturition, and urinary retention. all patients were treated with α-blockers for at least 1 month. tamsulosin, prazosin, or terazosin was prescribed at different times, patients who improved after pharmacotherapy were excluded from the study. inclusion and exclusion criteria patients were included in the study if they met the inclusion criteria: (i) age ＞ 18 years; (ii) vuds showed pdet.qmax＞ 20cm h 2 o, or qmax < 12 ml/s; (iii) treatment by tubni; (iv) complete medical history information. patients with other urinary diseases, such as dysuria caused by neurogenic bladder, urethral neoplasms, urethral diverticulum, and pelvic organ prolapse, or who were unable to complete follow-up were excluded from the study. procedures uroflowmetry was performed in all patients for preliminary assessment of maximum urinary flow rate. the postvoid residual (pvr) was measured with ultrasonography (netherlands, mms company, bladder scan bvi 6100). vuds was performed for all the patients using a laborie urodynamic system (canada, laborie) and the x-ray (siemens access uroskop). vuds was accomplished according to the instructions of the international continence society.(11) vuds was performed with a 6f dual-lumen catheter with an infusion of 15% meglumine diatrizoate at a rate of 20-40 ml/min. the abdominal pressure was recorded with a cook 8f abdominal pressure tube mounted to a balloon inflated with 5 ml of normal saline. fluoroscopy of the urinary bladder and the urethra was performed with a c-arm fluoroscope (siemens medical solutions) placed projecting at 45° from the buttock so that the bladder neck and the urethra could be demonstrated properly. after catheterization, the postvoid residual urine was evacuated and measured. vuds was performed with the patient sitting on a chair, whereas the bladder neck and external sphincter urodynamics were monitored simultaneously using c-arm fluoroscopy. during the filling phase, the patients were asked to cough or other abdominal pressure rises several times to ensure that the abdominal and intravesical pressure signals respond equally. prevention of liquid leaks and air bubbles in the pressure tubing system is needed throughout testing and should be corrected when identified. when the cystometric capacity was reached, the patients were asked to urinate into the uroflowmeter with the urethral catheter and rectal tube in place. cine-fluoroscopy was performed during the filling and voiding phases. during the voiding phase, the opening of the bladder neck and the urethra were carefully inspected. bladder neck obstruction in women was defined as the lack of a ‘funnel shape’ of the bladder neck during voiding, at the same time with the pdet.qmax＞20cm h 2 o, or qmax <12 ml/s.(9,12-14) tubni was performed for all the patients. the operation was performed in the lithotomy position and it is performed through a 24-f resectoscope using the bipolar electrode. endoscopic incisions typically are made characteristics number of patients percentage age, years, mean ± sd 54.9±13.5 bmi, kg/m2, mean ± sd 24.3±3.6 difficult micturition symptoms 68 97.1 recurrent urinary tract infections 11 15.7 urinary retention 6 8.6 perineal or pelvic pain 9 12.9 combined with sui 2 2.9 combined with urethral stricture 5 7.1 high serum creatinine 3 4.3 table 1. clinical data of patients presenting with symptoms. abbreviations: sd, standard deviation; bmi, body mass index; sui, stress urinary incontinence. parametersa preoperative 95% ci postoperative 95% ci z-value p-value ipss 13.0 (10.0,15.0) 12.3-13.8 3.0 (3.0,8.0) 4.4-6.2 -6.797b ＜.001 qol 5.0 (5.0,5.0) 4.8-5.1 2.0 (1.0,3.0) 2.2-2.9 -6.796b ＜.001 qmax (ml/s) 7.0 (4.0,10.3) 6.6-8.7 19.8 (12.8,25.2) 18.1-21.9 -7.254c ＜.001 qave (ml/s) 3.0 (2.0,5.0) 2.9-3.9 8.0 (4.9,10.7) 7.1-8.8 -6.697c ＜.001 tqmax (s) 9.0 (5.0,37.0) 22.5-49.1 6.1 (4.2,8.7) 5.6-10.8 -4.858b ＜.001 pvr (ml) 77.5 (23.5,165.8) 79.9-126.2 0.0 (0.0,30.0) 14.0-34.1 -5.560b ＜.001 voiding volume (ml) 156.5 (85.0,211.3) 128.4-170.8 261.3 (166.2,345.6) 247.1-312.34 -5.978c ＜.001 abbreviations: ci, confidence interval; ipss, international prostate symptom score; qol, quality of life; qmax, maximum uroflow rate; qave, average uroflow rate; tqmax, time to maximum uroflow rate; pvr, postvoid residual urine volume. adata were presented as m(p25, p75) and compared by wilcoxon signed ranks test. bbased on positive ranks. cbased on negative ranks. table 2. comparison of ipss, qol and parameters of uroflowmetry before and after bladder neck incision. bladder neck obstruction and transurethral bladder neck incision et al. urological oncology 42 at the bladder neck and proximal urethral at two different positions. in 42 patients, the incision was performed at 3and 9 o’clock position, and other 28 patients were performed at 1-2 and 10-11 o’clock position. before making the incision, we utilized a cystoscope to repeatedly check the location of the urethral sphincter, which was situated 1.5-2cm outward from the bladder neck and looked endoscopically as a circular contractable ring. we began by incising open the bladder neck and extending the incision far beyond feasible till no fibfigure 1. a: transurethral view during endoscopic incision of the bladder neck in a patient. b: the trabecular structure of the bladder can be seen under endoscope (arrow). c: transurethral bladder neck incision at 11 o’clock position. d: transurethral bladder neck incision at 2 o’clock position. figure 2. preoperative vuds in a patient who presented with difficult micturition symptoms. a radiograph was obtained at the maximum detrusor pressure and showed that the bladder neck did not open as a ‘funnel shape’ during voiding (arrow), the patient was unable to void and had a detrusor pressure＞90cmh 2 o. bladder neck obstruction and transurethral bladder neck incision qin et al. vol 20 no 1 january-february 2023 43 er circle could be visible at the bladder neck and the fat could be visualized. careful should be taken not to damage the external urethral sphincter (figure 1). a 22f foley catheter was used for 5-7 days after the operation. furthermore, patients had bladder neck obstruction combined with sui, a tension-free vaginal tape (tvt) was performed 3 months after tubni if necessary. urethral dilation before tubni was performed for those patients combined with urethral stricture patients. evaluations we contacted all patients by telephone and asked them to revisit our clinic for follow-up examinations. the follow-up ipss, qol, uroflowmetry, and all postsurgical complications, such as bladder neck recontracture, urethral stricture, and sui were all recorded. pre and post-operative data of ipss score, qol score, qmax, average uroflow rate (qave), time to maximum uroflow rate (tqmax), postvoid residual urine volume (pvr), and the voided volume in each patient were all compared. statistical analysis measurement data were tested for shapiro-wilk normality. continuous variables with normal distribution were presented as means ± standard deviation (sd) and compared by paired t-test. while continuous variables with non-normal distribution were reported as median with interquartile range (p25, p75) and compared by wilcoxon signed-rank test. a p value of less than 0.05 was considered statistically significant. all statistical analyses were performed using spss statistical software version 26.0 (ibm, chicago, il, usa). results a total of 70 female patients underwent complete investigations and follow up. the median follow-up duration was 42 months (range, 4-108). the mean age was 54.9±13.5(95% ci: 51.6-58.1) years and the mean body mass index (bmi) was 24.3±3.6 (95% ci: 23.4-25.2) kg/m2. the duration of lower urinary tract symptoms in all patients ranged from 4 month to 30 years (median 4.9 years). table 1 lists patient baseline characteristics. common presenting symptoms include difficult micturition symptoms (n = 68, 97.1%), recurrent urinary tract infections (n = 11, 15.7%), urinary retention (n = 6, 8.6%), perineal or pelvic pain (n = 9, 12.9%), combined with sui (n = 2, 2.9%), combined with urethral stricture (n = 5, 7.1%), and high serum creatinine(n = 3, 4.3%). a comparison of the preoperative and postoperative data was listed in table 2. the ipss, qol, tqmax, and pvr decreased significantly after tubni compared with preoperative [13.0 (10.0, 15.0), 95% ci: 12.3-13.8] versus [3.0 (3.0, 8.0), 95% ci: 4.4-6.2], [5.0 (5.0, 5.0), 95% ci: 4.8-5.1] versus [2.0 (1.0, 3.0), 95% ci: 2.2-2.9], [9.0 (5.0, 37.0), 95% ci: 22.5-49.1] versus [6.1 (4.2, 8.7), 95% ci: 5.6-10.8], [77.5 (23.5, 165.8), 95% ci: 79.9-126.2 ] versus [0.0 (0.0, 30.0), 95% ci: 14.0-34.1] (all p ＜.001). the qmax, the qave and the voided volume increased significantly [ 7.0 (4.0, 10.3), 95% ci: 6.6-8.7] versus [19.8 (12.8, 25.2), 95% ci: 18.1-21.9], [3.0 (2.0, 5.0), 95% ci: 2.9-3.9] versus [8.0 (4.9, 10.7), 95% ci: 7.1-8.8] and [156.5 (85.0, 211.3), 95%ci: 128.4-170.8] versus [261.3 (166.2, 345.6), 95% ci: 247.1-312.34] (all p ＜.001). vuds revealed the simultaneous presence of high detrusor pressure and low flow rate, and synchronous fluoroscopy indicated that the bladder neck did not open adequately (remained closed or narrow on fluoroscopic images) during voiding. the maximal detrusor pressure at the maximum uroflow rate was 38.5 (28.064.5) cmh2o. the qmax was 7.0 (4.0, 10.3) ml/s. all patients presented with non-funnel bladder neck during voiding. after the tubni procedure, follow-up uroflowmetry showed that the patient’s condition was improving meaningfully, and we considered qmax greater than 12ml/s to indicate that the operation was successful. (figures 2 and 3). figure 3. postoperative uroflowmetry in a patient able to void with a maximum uroflow rate of 43.2 ml/s and postvoid residual urine volume of 0 ml. bladder neck obstruction and transurethral bladder neck incision et al. urological oncology 44 several complications were identified after surgery, including bladder neck recontracture, urethral stricture, and sui. 5 (7.1%) women underwent multiple tubnis because of recurrent bladder neck obstruction, of these, a second tubni was performed in 4 patients, and a third tubni was performed in 1 patient. the second and third incisions were made in the same positions as the first, all these patients experienced alleviation of their difficult voiding symptoms after repeated tubni. 7 (10%) patients experienced urethral stricture after tubni and 6 were relieved after receiving intermittent urethral dilation. 7 (10%) patients suffered from sui, of which 4 slight symptom patients were relieved after kegel exercises, and 3 severe patients refused to have the second surgery due to poor body condition and chose to wear the diaper. finally, symptoms were not ameliorated in 10 of 70 (14.3%) patients, including 3 with sui and 1 with urethral stricture, 6 patients experienced no significant postoperative relief in spite of no complications occurred. discussion the understanding of the presentation, diagnosis, and treatment of pbno has developed over the last 20 years. pbno is a functional condition that is caused by inadequate bladder neck that open during voiding, the features are low flow and high pressure. nevertheless , many women void normally with low detrusor pressures (less than 10 cmh 2 o) and can empty the bladder with a good urinary flow rate, which may in part be since many women void by pelvic relaxation or abdominal straining (by habit) without needing to generate significant detrusor pressures.(13) therefore, the diagnosis criteria for women and men were not completely uniform. in women, there is no consensus regarding a cutoff for detrusor pressure and flow rate diagnostic of obstruction, although some have defined it based on urodynamic parameters.(1,13) since 1998, a series of criteria have been proposed. chassange et al.(14) proposed the first cut points for obstruction, qmax＜15 ml/s, and pdet.qmax＞20 cm h 2 o. groutz et al.(8) defined the criteria as qmax＜12 ml/s and pdet. qmax＞20 cm h 2 o. gammie et al.(15) used qmax＜12 ml/s and pdet. qmax＞40 cm h2o to define the presence of obstruction. however, vuds is the most accurate method for the diagnosis of female bladder neck obstruction. in our study, the diagnostic criteria were pdet.qmax＞20cm h 2 o, qmax <12 ml/s, or radiographic evidence of nonfunneling at the bladder neck during voiding. treatment options for pbno in females included watchful waiting, pharmacotherapy, and surgical intervention. clean intermittent self-catheterization or α-blockers is the first-line treatment, if therapy becomes necessary. the next therapeutics possibility is the transurethral incision of the bladder neck.(16) transurethral incision seem to be the preferred treatment with the expectation of eminent results. however, no agreement has been reached on where to cut the bladder neck in women. turner-warwick et al.(17) first described the concept of bladder neck incision in 1973, they made a single midline incision anteriorly to avoiding the risk of subsequent fistulation into the vaginal vault, which can follow posterior or posterolateral incision. kumar et al.(18) chose a single incision was made at the 12 o’clock position from 2 mm proximal to the bladder neck to the mid urethra. they reported the 6 patients who underwent bladder neck incision showed dramatic improvement in symptoms, peak flow, and post-void residual. however, 3 patients (50%) underwent a repeat tubni after 12 months because their symptoms recurred. these results implied that tubni is an effective treatment for female with bladder neck obstruction, but, a single incision at the 12-o’clock position could not thoroughly relieve the obstruction. blaivas et al. (1) chose the 5and 7-o’clock positions as the incision site. 6 patients (85.7%) considered themselves cured of lower urinary tract symptoms and 1 was improved, and these authors did not report complications of vaginal wall injuries. peng et al.(19) also chose the 5and 7-o’clock positions as the incision site. they reported the overall satisfactory rate was good (91%), but several patients suffered urethralvaginal fistula. as we were cautious that a single incision would not adequately relieve the obstruction, we performed 2 different incisions for all of the patients in our study, and none of them developed a vesicovaginal fistula postsurgical. 60/70 (85.7 %) patients were considered to have successfully recovered after the tubni. moreover，in our study, 2 (2.9%) patients had pbno combined with sui before the surgery, their obstruction symptoms were relieved after tubni. they were assessed symptoms and uroflowmetry at 3 months postoperatively, ipss decreased from 16 to 1 and 6 to 3 respectively, qmax improved 6 ml/s to 23.5 ml/s and 10 ml/s to 30.7 ml/s respectively. then tvt was performed for two women and their leakage symptoms were also relieved successfully after second operation as planned. therefore, we recommend that tubni and tvt should be performed sequentially for those patients who have both pbno and sui, and good results could be expected. 5 (7.1%) patients combined with urethral stricture before the tubni. these patients were performed several urethral dilations before and after tubni, these individuals underwent several urethral dilation procedures and their symptoms were successfully addressed. in our experience, tubni combination with urethral dilation is an excellent treatment for females with pbno combined with urethral stricture. furthermore, of 70 patients, 3 had high serum creatinine. kumar et al.(20) studied 13 patients who presented in renal failure with obstructive voiding symptoms or retention. the symptoms were relieved with the help of α-blockers, bladder neck incision, and clean intermittent self-catheterization. they suggested that bladder neck obstruction is a rare cause of renal failure which can be corrected if treated appropriately. notably, 3 patients had high serum creatinine levels before surgery, and 6 had urinary retention, and their serum creatinine levels returned to normal after tubni. we considered that elevated creatinine may be associated with more severe boo and a longer duration of boo. the urinary retention makes the patient vulnerable to infection, which further deteriorates renal function. proper tubni can relieve the pbno and protect renal function. several complications postsurgical were identified in this study, including bladder neck reobstruction, urethral stricture, and sui. five patients suffered reobstruction of the bladder neck post tubni, while their symptoms were relieved after multiple tubnis. seven (10%) patients experienced urethral stricture after tubni and 6 were alleviated after consecutive urethral bladder neck obstruction and transurethral bladder neck incision et al. vol 20 no 1 january-february 2023 45 dilations. sui was indeed the main complication. overzealous therapy has been attributed to incontinence in numerous studies. the external urethral sphincter must be identified when the incision is performed. the most prevalent complication of striated sphincter damage is urinary incontinence. the incision should be restricted to the proximal third of the urethra, and it should be carefully controlled. this could be beneficial for preventing urinary incontinence.(18) sui are highly prevalent among women, especially in older women, and sui is associated most often with pelvic floor muscle laxity. multiple risk factors have been proposed and studied for the development of sui in women, such as age, obesity body index, vaginal delivery, and hormone replacement therapy.(21-23) cavkaytar et al.(24) reported that kegel exercises have been found effective in women with urinary stress and mixed incontinence, and the improvement was more prominent in women with sui. in our group, 7 (10%) patients suffered from mild sui after operation. the age was 68.8 (range 55-82) years. the mean bmi was 27.6 (range 24-35.7) kg/m2. these results suggest that age and obesity may be risk factors for sui after tubni. although the external urethral sphincter was not damaged during tubni, these post-operative sui patients did not show obvious leakage symptoms before tubni. we deduced that the obvious bladder neck resistance covered sui symptoms, and that once the resistance was removed by tubni, the urinary incontinence that should have occurred became obvious. after exercising kegel exercises, four patients with minor symptoms were all relieved. the remaining three patients, who refused the second procedure due to their terrible physical situation, were required to wear diapers. these were the problems we need to solve in the feture. conclusions primary bladder neck obstruction is one of the commonest causes of lower urinary tract symptoms in women. although bladder neck obstruction has non-specific manifestations, the main symptoms including voiding, obstructive, storage and irritative symptoms. the diagnosis of bladder neck obstruction in women can be successfully made by uroflowmetry, cystoscopy, and video-urodynamic study combined with clinical presentation. transurethral bladder neck incision is an effective therapy for bladder neck obstruction. careful, sufficiently deep incisions at 2 different positions can ensure its success, and attention should be paid to complications such as bladder neck reobstruction, urethral stricture, and stress urinary incontinence. to the best of our knowledge, this is a relatively large sample of patients with bladder neck obstruction who underwent transurethral bladder neck incision with few complications. ultimately, we recommend that long-term postoperative follow-up and positive treatment of related complications should be performed. acknowledgements this study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. conflict on interest the authors reporrt no conflict of interest. references 1. blaivas jg, flisser aj, tash ja. treatment of primary bladder neck obstruction in women with transurethral resection of the bladder neck. the journal of urology. 2004;171:11725. 2. zhang p, wu z-j, xu l, yang y, zhang n, zhang x-d. bladder neck incision for female bladder neck obstruction: long-term outcomes. urology. 2014;83:762-6. 3. king ab, goldman hb. bladder outlet obstruction in women: functional causes. current urology reports. 2014;15:436. 4. goldman hb, zimmern pe. the treatment of female bladder outlet obstruction. bju int. 2006;98 suppl 1. 5. markic d, maricic a, oguic r, et al. transurethral bladder neck incision in women with primary bladder neck obstruction. wien klin wochenschr. 2014;126:217-22. 6. brucker bm, fong e, shah s, kelly c, rosenblum n, nitti vw. urodynamic differences between dysfunctional voiding and primary bladder neck obstruction in women. urology. 2012;80:55-60. 7. padmanabhan p, nitti vw. primary bladder neck obstruction in men, women, and children. current urology reports. 2007;8:379-84. 8. groutz a, blaivas jg, chaikin dc. bladder outlet obstruction in women: definition and characteristics. neurourology and urodynamics. 2000;19:213-20. 9. zhang p, yang y, wu z-j, zhang x-d, zhang c-h. video-urodynamics study on female patients with bladder neck obstruction. chin med j (engl). 2012;125:1425-8. 10. huckabay c, nitti vw. diagnosis and treatment of primary bladder neck obstruction in men. current urology reports. 2005;6:2715. 11. drake mj, doumouchtsis sk, hashim h, gammie a. fundamentals of urodynamic practice, based on international continence society good urodynamic practices recommendations. neurourol urodyn. 2018;37:s50-s60. 12. kuo h-c. videourodynamic characteristics and lower urinary tract symptoms of female bladder outlet obstruction. urology. 2005;66:1005-9. 13. nitti vw, tu lm, gitlin j. diagnosing bladder outlet obstruction in women. the journal of urology. 1999;161:1535-40. 14. chassagne s, bernier pa, haab f, roehrborn cg, reisch js, zimmern pe. proposed cutoff values to define bladder outlet obstruction in women. urology. 1998;51:408-11. 15. gammie a, kirschner-hermanns r, rademakers k. evaluation of obstructed voiding in the female: how close are we to a definition? current opinion in urology. 2015;25:292-5. 16. jin x-b, qu h-w, liu h, li b, wang j, zhang y-d. modified transurethral incision for primary bladder neck obstruction in women: a method to improve voiding function without bladder neck obstruction and transurethral bladder neck incision et al. urological oncology 46 urinary incontinence. urology. 2012;79:3103. 17. turner-warwick r, whiteside cg, worth ph, milroy ej, bates cp. a urodynamic view of the clinical problems associated with bladder neck dysfunction and its treatment by endoscopic incision and transtrigonal posterior prostatectomy. br j urol. 1973;45:44-59. 18. kumar a, mandhani a, gogoi s, srivastava a. management of functional bladder neck obstruction in women: use of alpha-blockers and pediatric resectoscope for bladder neck incision. the journal of urology. 1999;162:2061-5. 19. peng ch, kuo hc. transurethral incision of bladder neck in treatment of bladder neck obstruction in women. urology. 2005;65:2758. 20. kumar a, banerjee gk, goel mc, mishra vk, kapoor r, bhandari m. functional bladder neck obstruction: a rare cause of renal failure. the journal of urology. 1995;154:1869. 21. bedretdinova d, fritel x, panjo h, ringa v. prevalence of female urinary incontinence in the general population according to different definitions and study designs. european urology. 2016;69:256-64. 22. newman dk. stress urinary incontinence in women. am j nurs. 2003;103(8). 23. reynolds ws, dmochowski rr, penson df. epidemiology of stress urinary incontinence in women. current urology reports. 2011;12:3706. 24. cavkaytar s, kokanali mk, topcu ho, aksakal os, doganay m. effect of home-based kegel exercises on quality of life in women with stress and mixed urinary incontinence. j obstet gynaecol. 2015;35:407-10. bladder neck obstruction and transurethral bladder neck incision et al. vol 20 no 1 january-february 2023 47 cytotoxic effect of saffron stigma aqueous extract on human prostate cancer and mouse fibroblast cell lines hassan ahmadnia1*, jalil tavakkol afshari2, jamshid tabeshpour3, mehdi younesi rostami4, ehsan mansourian5, alireza akhavan rezayat5, azam brook2 purpose: several lines of experimental evidence have shown that saffron has anticarcinogenic effects. this study aimed at evaluating the possible anticancer effect of saffron stigma aqueous extract on human prostate cancer (pc3) and mouse fibroblast cells (l929) as non-cancerous control cells. materials and methods: saffron stigma aqueous extract at concentrations of 100, 200, 400, 600, 800, 1600 and 3200 μg/ml were prepared. pc3 and l929 cells were incubated with different concentrations of saffron extracts in different time intervals (24, 48, 72, 96 and 144 hours). mtt assay was used for each cell line to investigate the cytotoxic effect of saffron. morphological alterations were also observed under light inverted microscope. results: in fibroblast cell line after 24 hours, saffron extract did not affect significantly the normal cells and they were intact in morphologic view. after 96 hours in the cells with highest concentration (1600 μg/ml), cell death and cellular form changes as well as severe granulation was observed. in prostate cell line after 24 hours, the only changes were observed in cells with the concentration of 1600 μg/ml. the cells were granulated and the form of the cells were spherule. after 72 hours, in group with the concentration of 1600 μg/ml, severe granulation was observed and the cell count decreased and some cells were dead. conclusion: saffron aqueous extract has an in vitro inhibitory effect on the proliferation of human prostate cell and mouse l929 cells which is dose-dependent. keywords: saffron aqueous extract; l929 cells; pc3 cells; anticancer effect; mtt assay; cytotoxic effect introduction the most prevalent visceral malignant neoplasm in men, prostate cancer is responsible for one third of all such cancers.(1) according to american cancer society, 220,000 americans have been diagnosed with prostate cancer, annually.(2) different kinds of treatments have been introduced for prostate cancer such as cabazitaxel, docetaxel and mitoxantrone.(3) but, unfortunately, a variety of adverse effects following synthetic medicines are observed in the clinical settings.(3) to minimize such adverse effects, many researchers have been persuaded to search for herbal therapies with the least adverse effects such as adiantum venusutum(4), abelmoschus moschatus(5) and aspidosperma tomentosum.(6) herbal medicine is a new alternative therapy in cancer patients.(7) consumption of certain botanicals could be associated with reduced cancer incidence. one of these botanical agents is crocus sativus l., commonly known as saffron. it is a stemless herb of the iridaceae family that is widely cultivated in iran and other countries. in the world, 205 tons of saffron are produced every year, 1urology, endoscopic & minimally invasive surgery research center, ghaem hospital, faculty of medicine, mashhad university of medical sciences, mashhad, iran 2immunology research center, bu-ali research institute, mashhad university of medical sciences, mashhad, iran 3faculty of pharmacy, damghan bransh, islamic azad university, damghan, iran. 4department of urology, imam hospital, mazandaran university of medical sciences, sari, iran. 5department of urology, faculty of medicine, mashhad university of medical sciences, mashhad, iran. *correspondence: urology, endoscopic & minimally invasive surgery research center, ghaem hospital, faculty of medicine, mashhad university of medical sciences, mashhad, iran. e-mail: ahmadniah@mums.ac.ir received june 2020 & accepted november 2020 while iran has an important role in this production as the grand producer (80 percent of total). khorasan province, sited at north east of iran, accounts for 137 tons of the above-mentioned totals.(8-10) mostly used as a spice, flavoring agent, food coloring and herbal medicine, saffron is produced from dried red stigma with a small portion of the yellowish stamina attached.(9) the stigmas of saffron has been demonstrated to have several components including carotenoids, crocin, crocetin, picrocrocin, anthocyanin, lycopene, monoterpene aldehydes and safranal as well as proteins, sugars, vitamins, flavonoids, amino acids and minerals (figure 1).(11-15) anticancer(9), anti-inflammatory(16), antidepressive(17), antioxidant(18) and antibacterial(19) activities of saffron have been established by many researchers as its pharmacological effects. since 1990, research has been focused on anti-carcinogenic activity of saffron.(7, 8) saffron and its main components have shown anti-tumor and anti-carcinogenic activities both in vitro and in vivo.(7-9, 20) as far as we know, the possible effects of saffron on prostate cancer has not been evaluated and reported. urological oncology urology journal/vol 18 no.6/ november-december 2021/ pp. 633-638. [doi: 10.22037/uj.v16i7.6331] therefore, this study aimed to evaluate the in vitro cytotoxic effects of saffron stigma aqueous extract on prostate cell line and non-neoplastic fibroblast cells of mouse as a normal cell line. materials and methods preparation of saffron extract saffron harvested from saffron farms of a city of khorasan province (ghaen), was used in this experiment. 15 g of ground petal stigma was mixed with 400 ml of distilled water in a soxhlet extractor for 18 h, to prepare saffron aqueous extract. then, to be sterilized, it was concentrated to 100 ml with a rotatory evaporator in low pressure and filtered through a 0.2-mm filter. the obtained solution was kept at 4°c to 8°c. different concentrations of saffron extract (100, 200, 400, 600, 800, 1600 and 3200 μg/ml) were prepared immediately and refrigerated before the experiments. urological oncology 634 figure 1. molecular structures of the most important carotenoid secondary metabolites of saffron. figure 2. after 48 hours of incubation with the concentration of 400 μg/ml, pc3 cells were granulated and spheroid (left picture) in comparison with the cells which were not incubated with saffron extract, as a control group (right picture). the absorbance of the dye was read at ex: 488 nm, em: 585 nm. cytotoxic effect of saffron stigma aqueous extract-ahmadnia et al. morphologic observation of cell lines human prostate carcinoma cells (pc3) and mouse fibroblast cell lines (l929) were bought from the national cell bank of iran (pasture institute, tehran, iran). both of the cell lines were cultured and passaged. trypan blue test was used to determine cell viability. equal parts of 0.4% trypan blue dye to the cell suspension were added to obtain a 1 to 2 dilution and weremixed by pipetting up and down. the incubation time was less than three minutes at room temperature. the percentage of viable cells were calculated by dividing the number of viable cells by the number of total cells and multiplying by 100 or % viable cells. six-well plates were used for both cell lines. in each well, 5 × 105 pc3 cells or 2 × 105 l929 cells were cultivated in dulbecco’s modified eagle’s medium (sigma-aldrich, st louis, missouri, usa) with 10% fetal calf serum (gibco, paisley, uk). the media were supplemented with 100 iu/ml streptomycin and 100 iu/ml penicillin (jaberebn-e-hayan, cytotoxic effect of saffron stigma aqueous extract-ahmadnia et al. figure 3. viability percent for pc3 and l929 cells after 24, 48, 72, 96 and 144 h incubation with different concentrations of saffron extract. figure 4. after 72 h incubation, the pc3cells incubated with 400 μg/ml of saffron extract were granulated and spheroid with reduction in cell counts (left picture) in comparison with the cells which were not incubated with saffron extract as a control group (right picture). the absorbance of the dye was read at ex: 488 nm, em: 585 nm. vol 18 no 6 november-december 2021 635 tehran, iran). the cells were incubated at 37°c in a humidified 5% co 2 atmosphere for 24 h. then, the cells were exposed to saffron extract as follows: the media (2 ml capacity) were replaced with fresh media and plates were incubated with different concentrations of saffron extract (100, 200, 400, 600, 800, 1600 and 3200 μg/ ml) in the situation aforementioned for 24, 48, 72, 96 and 144 h, and the cells were observed by light inverted microscope for morphological alterations. each extract concentration was observed 3 times to check their reliability. the viability of the cells was determined to be higher than 95% during the experiment. quantitative assessment surviving cells (percent) compared to the controls = (optical density of treated cells in each well × 100)/ (mean optical density of control ) the absorbance of trypan blue dye was read using fluorescence microplate reader (ex: 488 nm, em: 585 nm). statistical analysis data are presented as mean ± sd. statistical analyses were performed in graph pad prism software version 8.0. results effect of saffron on l929 cell viability and morphological alterations incubation of l929 cells with different concentrations of saffron extract for 24 h, did not significantly affect the cells and they were intact in morphological view. in addition, there were no changes in number, cytoplasm, and nucleus of the cells. incubation of the cells with 1600 μg/ml of saffron extract for 48 and 72 hours, showed a slight granulation of the cells while no changes in number, cytoplasm, and nucleus of the cells were observed. after 96 and 144 hours, at the concentration of 800 μg/ml, the cells were larger and granulated while at the concentration of 1600 μg/ml, cell death, cellular form changes and severe granulation were noticed (figure 2). effect of saffron on pc3 cell viability and morphological alterations pc3 cells were granulated and the form of the cells were spherule when they were exposed to 1600 μg/ml of saffron extract for 24 hours. after 48 and 72 hours of treatment (400, 600 and 800 μg/ml), the cells were granulated and spheroid, while at the concentration of 1600 μg/ml, severe granulation was observed and the cells count decreased and some cells were dead (figures 2,3,4). the half maximal inhibitory concentration (ic50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function which was calculated for pc3 cells to be 400 to 800 μg/ml. granulated and dead cells were noticed at the concentration of 1600 μg/ml, after 144 h of treatment (figure 5). discussion prostate cancer is a commonly diagnosed cancer in men, and dietary chemoprevention was considered due urological oncology 636 figure 5. after 144 h, the pc3 cells incubated with 400 μg/ml of saffron extract were granulated and spheroid with reduction in cell counts, presenting the cellular death (left picture) in comparison with the cells which were not incubated with saffron extract as control group (right picture). the absorbance of the dye was read at ex: 488 nm, em: 585 nm. cytotoxic effect of saffron stigma aqueous extract-ahmadnia et al. to its slow growth rate and its long incubation period. different herbal extracts has shown noticeable benefits such as pomegranate, green tea in chemoprevention of prostate cancer.(21,22) several effects were recognized for saffron such as anti-carcinogenic, decreasing blood pressure, and controlling tonic-clonic and absence seizures.(10) saffron can cure coronary heart disease and hepatitis, and promote immunity.(23) there are several reports demonstrating the anti-carcinogenic effects of saffron extract, either inhibition of new tumors formation or shrinkage of existing tumors. the anticancer activity of saffron against a wide spectrum of tumors, such as leukemia, transitional cell carcinoma, ovarian carcinoma, colon adenocarcinoma, rhabdomyosarcoma, papilloma, squamous cell carcinoma, and soft tissue sarcoma have been demonstrated.(7,9,10,15,20,23-26) the inhibitory effects of saffron aqueous extract on the growth of both tcc 5637 and normal l929 cell lines have been reported(10) as we observed in our research. moreover, increasing saffron concentrations results in a reduction in the cell survival percent of healthy l929 cells. higher saffron concentrations seem to reduce the cell survival rate of healthy cells up to 50% in longer incubation time. salomi et al. reported anti-promoting and non-mutagenic activity of saffron extract.(7) protective effect of crocin against adverse consequence of hepatocarcinogenic materials has been demonstrated.(15) in addition, different in vitro studies have reported the protective effects of crocin such as inhibition of intracellular nucleic acid synthesis(11) and inhibition of proliferation of promyelocytic leukemia cells in a dose-dependent manner.(12, 20) saffron extract in combination of vitamin e has been shown to protect rats against cisplatin toxicity. (15) a significant inhibitory effect of ethanolic extract of saffron on the colony formation and intracellular dna and rna synthesis of hela cells (cervix epitheloid carcinoma cells) was reported by abdullaev and frenkel. (26) growth delay of papilloma, decreased incidence of squamous cell carcinoma and soft tissue sarcoma in mice treated by saffron, have been reported.(20) although saffron extract has well-documented antitumor effects, the cellular mechanisms responsible for these effects remain ill-defined. different hypotheses have been suggested for the antitumor mechanism of saffron such as the inhibitory effect on dna and rna synthesis without any effect on protein synthesis and the inhibitory effect on free radicals which is thought to be due to carotenoid component of saffron.(10,20) it is suggested that saffron (dimethyl-crocetin) disrupts dna-protein interactions e.g. topoisomerases ii, which is essential for cellular dna synthesis.(20) the anti-tumor components of saffron were reviewed by some researchers. crocin isolated from saffron inhibits pc12 (rat’s pheochromocytoma cell line) cell growth with increased synthesis of glutathione. the mechanism behind its antigrowth effect could be the possible decrease in tumor necrosis factor-alpha levels.(27) conclusions this research demonstrates in vitro cytotoxic effects of saffron on human prostate cell lines. in fact, saffron extract possesses in vitro inhibitory effect on the proliferation of pc3 cells in a dose-dependent manner. more studies need to be accomplished to use saffron as a chemopreventive agent in prostate cancer treatment. acknowledgement authors are thankful to the vice chancellor of research, mashhad university of medical sciences for financial support. the results described in this paper are part of a medical thesis. conflict of interest the authors declare that there is no conflict of interest. references 1. schroder fh, hugosson j, roobol mj, et al. screening and prostate-cancer mortality in a randomized european study. n engl j med. 2009;360:1320-8. 2. cokkinides v, albano j, samuels a, ward m, thum j. american cancer society: cancer facts and figures. atlanta: american cancer society. 2005; 3. de bono js, oudard s, ozguroglu m, et al. prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. the lancet. 2010;376:1147-1154. 4. viral d, shivanand p, jivani np. anticancer evaluation of adiantum venustum don. j young pharm. 2011;3:48-54. 5. gul mz, bhakshu lm, ahmad f, kondapi ak, qureshi ia, ghazi ia. evaluation of abelmoschus moschatus extracts for antioxidant, free radical scavenging, antimicrobial and antiproliferative activities using in vitro assays. bmc complem altern m. 2011;11:64. 6. kohn l, pizao p, foglio m, et al. antiproliferative activity of crude extract and fractions obtained from aspidosperma tomentosum mart. rev bras pl med. 2006;8:110-115. 7. salomi mj, nair sc, panikkar kr. inhibitory effects of nigella sativa and saffron (crocus sativus) on chemical carcinogenesis in mice. nutr cancer. 1991;16:67-72. 8. bharali r, tabassum j, azad mr. chemomodulatory effect of moringa oleifera, lam, on hepatic carcinogen metabolising enzymes, antioxidant parameters and skin papillomagenesis in mice. asian pac j cancer prev. 2003;4:131-9. 9. abdullaev fi. cancer chemopreventive and tumoricidal properties of saffron (crocus sativus l.). exp biol med (maywood). 2002;227:20-5. 10. feizzadeh b, afshari jt, rakhshandeh h, rahimi a, brook a, doosti h. cytotoxic effect of saffron stigma aqueous extract on human transitional cell carcinoma and mouse fibroblast. urol j. 2008;5:161-7. 11. abdullaev fi. inhibitory effect of crocetin on intracellular nucleic acid and protein synthesis in malignant cells. toxicol lett. 1994;70:24351. 12. tarantilis pa, morjani h, polissiou m, manfait m. inhibition of growth and induction of differentiation of promyelocytic leukemia cytotoxic effect of saffron stigma aqueous extract-ahmadnia et al. vol 18 no 6 november-december 2021 637 (hl-60) by carotenoids from crocus sativus l. anticancer res. 1994;14:1913-8. 13. escribano j, alonso gl, coca-prados m, fernandez ja. crocin, safranal and picrocrocin from saffron (crocus sativus l.) inhibit the growth of human cancer cells in vitro. cancer lett. 1996;100:23-30. 14. giaccio m. crocetin from saffron: an active component of an ancient spice. crit rev food sci nutr. 2004;44:155-72. 15. das i, chakrabarty rn, das s. saffron can prevent chemically induced skin carcinogenesis in swiss albino mice. asian pac j cancer prev. 2004;5:70-6. 16. hosseinzadeh h, younesi hm. antinociceptive and anti-inflammatory effects of crocus sativus l. stigma and petal extracts in mice. bmc pharmacol. 2002;2:7. 17. hosseinzadeh h, karimi g, niapoor m. antidepressant effects of crocus sativus stigma extracts and its constituents, crocin and safranal, in mice. j med plant res. 2004;3:4858. 18. makhlouf h, saksouk m, habib j, chahine r. determination of antioxidant activity of saffron taken from the flower of crocus sativus grown in lebanon. afr j biotechnol. 2011;10:8093-8100. 19. nakhaei m, khaje-karamoddin m, ramezani m. inhibition of helicobacter pylori growth in vitro by saffron (crocus sativus l.). iran j basic med sci. 2008;11:91-96. 20. nair sc, kurumboor sk, hasegawa jh. saffron chemoprevention in biology and medicine: a review. cancer biother. 1995;10:257-64. 21. gasmi j, sanderson jt. growth inhibitory, antiandrogenic, and pro-apoptotic effects of punicic acid in lncap human prostate cancer cells. j agric food chem. 2010;58:1214912156. 22. khan n, adhami vm, mukhtar h. review: green tea polyphenols in chemoprevention of prostate cancer: preclinical and clinical studies. nutr cancer. 2009;61:836-41. 23. deng y, guo zg, zeng zl, wang z. [studies on the pharmacological effects of saffron(crocus sativus l.)--a review]. zhongguo zhong yao za zhi. 2002;27:565-8. 24. dufresne c, cormier f, dorion s. in vitro formation of crocetin glucosyl esters by crocus sativus callus extract. planta med. 1997;63:150-3. 25. nair sc, pannikar b, panikkar kr. antitumour activity of saffron (crocus sativus). cancer lett. 1991;57:109-14. 26. abdullaev fi, frenkel gd. effect of saffron on cell colony formation and cellular nucleic acid and protein synthesis. biofactors. 1992;3:2014. 27. ochiai t, soeda s, ohno s, tanaka h, shoyama y, shimeno h. crocin prevents the death of pc-12 cells through sphingomyelinaseceramide signaling by increasing glutathione synthesis. neurochem int. 2004;44:321-30. urological oncology 638 cytotoxic effect of saffron stigma aqueous extract-ahmadnia et al. urol_montage.pdf case report 54 urology journal vol 6 no 1 winter 2009 small cell carcinoma encountered in a urinary bladder diverticulum apostolos p labanaris,1 vahudin zugor,2 robert smiszek,1 reinhold nützel,1 reinhard kühn1 urol j. 2009;6:54-6. www.uj.unrc.ir keywords: small cell carcinoma, urinary bladder diseases, diverticulum, treatment 1department of urology, martha maria medical center, nurnberg, germany 2department of urology, salzgitter medical center, salzgitter, germany corresponding author: apostolos p labanaris, md department of urology, martha maria medical center, stadenstrasse 58, 90409 nürnberg, germany phone: +49 911 959 1351 fax: +49 911 959 1352 e-mail: labanaris@web.de received december 2007 accepted may 2008 introduction bladder tumors arising within a diverticulum are uncommon and pose a unique diagnostic and therapeutic challenge. the reported incidence ranges from 0.8% to 10.0%, with the most common histological subtype being transitional cell carcinoma followed by squamous cell carcinoma.(1) additionally, small cell carcinoma of the bladder is a rare and highly aggressive tumor which tends to progress and metastasize within a few months after diagnosis and provides very poor prognosis.(2) it presents with the histopathologic, immunohistochemical, and ultrastructural characteristics and light microscopic features common to all neuroendocrine tumors observed in other organs, especially the lung.(3) since cramer and colleagues(4) reported the first case of a small cell carcinoma of the urinary bladder in 1981, nearly 160 cases have been reported.(5) however, small cell carcinoma encountered in a bladder diverticulum has been described in only 5 patients in the literature.(4,6-8) we present a new case of this rare entity disease. case report a 65-year-old man presented to our department with gross hematuria accompanied by irritative symptoms in november 2005. he did not have any other existing comorbidity or a history of nicotine abuse. urinalysis revealed numerous erythrocytes, but the urine culture was negative for microorganisms. abdominal ultrasonography revealed a solid figure 1. small cell carcinoma within a bladder diverticulum was located in the left lateral bladder wall. figure 2. a poorly differentiated muscle-invasive small cell carcinoma was seen (hematoxylin-eosin, × 100). small cell carcinoma in a bladder diverticulum—labanaris et al urology journal vol 6 no 1 winter 2009 55 tumor within a bladder diverticulum located in the left lateral bladder wall (figure 1). cystoscopy confirmed this finding and transurethral resection of the tumor was performed. the histopathologic assessment showed a highly cellular poorly differentiated carcinoma with no mixed histology that invaded the detrusor muscle (figure 2). in immunhistochemical staining, tumor cells expressed neuroendocrine markers, synaptophysin and chromogranin a. a diagnosis of small cell carcinoma with a clinical stage t2 grade 3 was made. after a detailed staging workup, including bone scan and computed tomography of the chest, abdomen, and brain, no metastasis were noted. knowing that treatment of bladder small cell carcinoma requires a multidisciplinary approach and after discussing with the patient the possible therapeutic approach, a combination of surgery (partial cystectomy with lymph node dissection) coupled with adjuvant chemotherapy and radiotherapy was decided. the final pathology results from the partial cystectomy specimen exhibited small cell carcinoma with a clinical stage t3 grade 3. the patient was then treated with 3 cycles of cisplatin and etoposide, as well as radiotherapy with 60 gy. the patient passed away 16 months later after being diagnosed with metastases to the bone, liver, and brain. discussion epidemiologic studies have found that the incidence of small cell carcinoma of the bladder is between 0.35% and 0.70%, making it one of the rarest tumors of the bladder.(9) the clinical presentation does not differ from that of other bladder tumors, and gross hematuria is the most common symptom. bladder small cell carcinoma tends to follow the metastatic trend of transitional cell carcinoma (tcc), with the most common sites being the regional and distant lymph nodes, liver, and bone.(6) bladder tumors originating within a diverticulum are also uncommon and challenging. they occur mainly as a result of increased intravesical pressure secondary to bladder outlet obstruction or may infrequently result from congenital disarrangement of muscle fibers at the ureterovesical junction. contrary to the normal bladder wall, lack of muscle fibers in the diverticulum makes it difficult to stratify the tumors into superficial and invasive bladder cancer. in addition, the paucity of muscle fibers beyond the mucosa theoretically allows the tumor to invade earlier and more easily than in a normal bladder wall containing thick muscle. the cause and histogenesis of small cell carcinoma of the urinary bladder is unknown. ali and coworkers(10) proposed that malignant transformation of bladder neuroendocrine cells gives rise to bladder small cell carcinoma. a second possibility is that these tumors arise from poorly defined submucosal or muscularis cells of neural crest origin. finally, these tumors may arise through a process of metaplasia from conventional high-grade transitional cell carcinoma. this would explain the common coexistence of tcc in up to two-thirds of patients diagnosed with small cell carcinoma.(11) it is noteworthy that, choong and colleagues(6) reported on a series of 44 patients treated at their institution, emphasising that 20% of the patients were diagnosed incidentally on follow-up surveillance cystoscopy after resection for tcc and when patients underwent cystectomy for tcc. macroscopically, these tumors are usually polypoid lesions, frequently ulcerated and ranging in size from 4 cm to 10 cm. they most commonly occur on the lateral walls (54%), followed by the posterior wall (20%), trigone (10%), dome (8%) and anterior wall (8%).(11) the differential diagnosis of primary bladder small cell carcinoma includes small cell metastasis from other sites (eg, the prostate), a poorly differentiated tcc, and primary or secondary lymphomas.(12) it is very difficult to determine this tumor with imaging studies.(13) computed tomography imaging features in the first reports were a large, locally aggressive, relatively wellenhancing, broad-based polypoid intramural mass, with possible distant metastasis at the time of diagnosis or during follow-up period.(13) diagnosis of small cell carcinoma in the bladder depends on histopathological recognition. immunohistochemical staining presenting tumor neuroendocrine differentiation is helpful. small cell carcinoma in a bladder diverticulum—labanaris et al 56 urology journal vol 6 no 1 winter 2009 neuroendocrine markers, synaptophysin and chromogranin a staining, are typical for small cell carcinoma.(5) with the recognition of the high metastatic potential with bladder small cell carcinoma, even in the setting of clinically localized disease, the optimal treatment strategy still remains unknown. abbas and colleagues reported on 106 patients with small cell carcinoma of the bladder, in which the mean survival was 19.6 months, and the 5-year survival was 8%, indicating that surgical treatment alone is unlikely to be curative.(2) choong and colleagues concluded that all patients with bladder small cell carcinoma should undergo radical cystectomy unless metastatic disease is present.(6) siefker-radtke and associates suggested that preoperative chemotherapy followed by radical cystectomy may be the optimal strategy, even in the setting of clinically localized cancer.(14) although aceptable survival has been reported using an integrated chemo-radiation regimen,(9) sejima and miyagawa reported that a successful course of chemotherapy and radiotherapy as determined by pathology did not necessarily correlate with the patient’s eventual clinical course.(15) they suggested that combination adjuvant chemotherapy be performed no matter how effective the neoadjuvant therapy plus radical surgery ultimately proves. we used a combination of partial cystectomy with lymph node dissection and adjuvant chemotherapy and radiotherapy. partial cystectomy has been earlier used in combination with chemotherapy and/or radiation therapy. podesta and true(16) reported two cases of pt3 tumors managed with partial cystectomy. one patient received adjuvant radiation therapy and was disease free at 78 months. we believe that treatment of small cell carcinoma of the bladder requires a multidisciplinary approach. a combination of surgery (radical cyctectomy, partial cystectomy, or transurethral resection) coupled with aggressive combination chemotherapy (neoadjuvant and adjuvant) and/or radiotherapy is the treatment of choice. conflict of interest none declared. references 1. micic s, ilic v. incidence of neoplasm in vesical diverticula. j urol. 1983;129:734-5. 2. abbas f, civantos f, benedetto p, soloway ms. small cell carcinoma of the bladder and prostate. urology. 1995;46:617-30. 3. cheng c, nicholson a, lowe dg, kirby rs. oat cell carcinoma of urinary bladder. urology. 1992;39:504-7. 4. cramer sf, aikawa m, cebelin m. neurosecretory granules in small cell invasive carcinoma of the urinary bladder. cancer. 1981;47:724-30. 5. trias i, algaba f, condom e, et al. small cell carcinoma of the urinary bladder. presentation of 23 cases and review of 134 published cases. eur urol. 2001;39:85-90. 6. choong nw, quevedo jf, kaur js. small cell carcinoma of the urinary bladder. the mayo clinic experience. cancer. 2005;103:1172-8. 7. mills se, wolfe jt, 3rd, weiss ma, et al. small cell undifferentiated carcinoma of the urinary bladder. a light-microscopic, immunocytochemical, and ultrastructural study of 12 cases. am j surg pathol. 1987;11:606-17. 8. davis mp, murthy ms, simon j, wise h, minton jp. successful management of small cell carcinoma of the bladder with cisplatin and etoposide. j urol. 1989;142:817. 9. lohrisch c, murray n, pickles t, sullivan l. small cell carcinoma of the bladder: long term outcome with integrated chemoradiation. cancer. 1999;86:2346-52. 10. ali sz, reuter ve, zakowski mf. small cell neuroendocrine carcinoma of the urinary bladder. a clinicopathologic study with emphasis on cytologic features. cancer. 1997;79:356-61. 11. kuroda n, hayashi y, nishida y, itoh h. combined small and transitional cell carcinoma of the urinary bladder with ca19-9 production. pathol int. 1999;49:462-7. 12. nejat rj, purohit r, goluboff et, petrylak d, rubin ma, benson mc. cure of undifferentiated small cell carcinoma of the urinary bladder with m-vac chemotherapy. urol oncol. 2001;6:53-5. 13. kim jc. ct features of bladder small cell carcinoma. clin imaging. 2004;28:201-5. 14. siefker-radtke ao, dinney cp, abrahams na, et al. evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the m. d. anderson cancer experience. j urol. 2004;172:481-4. 15. sejima t, miyagawa i. ‘successful’ chemoand radiotherapy prior to radical cystectomy does not necessarily correlate with clinical course in small cell carcinoma of the bladder. urol int. 2005;74:286-8. 16. podesta ah, true ld. small cell carcinoma of the bladder. report of five cases with immunohistochemistry and review of the literature with evaluation of prognosis according to stage. cancer. 1989;64:710-4. short-term outcomes of water vapor therapy (rezūm) for bph/luts in the first czech cohort roman wasserbauer1,2, dalibor pacik1,3, gabriel varga1,2, vitezslav vit,1,2 jiri jarkovsky4, michal fedorko1,2* purpose: to evaluate the short-term results of water vapor therapy (rezūm) for bph/luts in the first cohort of czech patients. materials and methods: patients with bph and moderate to severe luts (n = 76) who underwent rezūm treatment from december 2019 to july 2020 were included in the prospective study. prior to the procedure, they completed the ipss and oabv8 questionnaires and underwent uroflowmetry, transrectal ultrasound of the prostate, and psa sampling. the parameters before and 3 months after the procedure were compared and statistically evaluated. results: the study protocol was completed by 92% of patients (n = 70). we observed a significant increase in qmax (median 17.7 vs. 8.8 ml/s, p < .001), qave (9 vs. 4.5 ml/s, p = .001) and voided volume (241 vs. 171 ml, p < .001) and a significant reduction in post-void residual (average 17.5 vs. 67.7 ml), prostate volume (39.3 vs. 62.3 ml) and total psa (median 1.9 vs. 2.5 ng/ml, resp. p values < .001). there was also a significant decrease in oabv8 score (average 7.6 vs. 16.6, p < .001) and ipss qol (1.6 vs. 4.0, p = .037). the improvement in the ipss score was apparent, yet statistically insignificant (6.8 vs. 16, p = .079). conclusion: water vapor therapy is an effective and safe method of bph/luts treatment in the short-term. keywords: benign prostatic hyperplasia; lower urinary tract symptoms; minimally invasive treatment; vapor; water introduction benign prostatic hyperplasia (bph) is a common cause of lower urinary tract symptoms (luts) in an aging population. after failure of pharmacotherapy or in case of other bph-related complications, surgical treatment is indicated. standard methods include transurethral resection of the prostate (turp), open adenomectomy or laser enucleation of the prostate(1). one of the new minimally invasive methods of treatment is rezūm, a method that uses a radiofrequency generator to convert water into water vapor, which causes coagulation necrosis of prostate cells by convective conduction of heat in prostate tissue(2). data regarding the efficacy and safety of rezūm are primarily based on one large randomized controlled study, further supported by a few retrospective, prospective or crossover studies(3). the effectiveness of this method is most often evaluated by uroflowmetry (qmax – maximum flow rate, pvr – postvoid residual) and ipss (international prostate symptom score) questionnaire including qol (quality of life) assessment. in the randomized, sham-controlled study, the most significant improvement in qmax (maximum urinary flow) and ipss scores was achieved after 3 months, however, durable symptom relief and flow rate im1department of urology, university hospital brno, jihlavská 20, 625 00 brno, czech republic 2faculty of medicine, masaryk university brno, kamenice 5, 625 00 brno, czech republic 3urologie prof. pacík, lidická 13, 602 00 brno, czech republic 4institute of biostatistics and analyses, masaryk university brno, kamenice 3, 625 00 brno, czech republic *correapondence: department of urology, university hospital brno, jihlavská 20, 625 00 brno, czech republic. tel: +420 602 752 505, fax: +420 532 23 2306, e-mail: fedorko.michal@fnbrno.cz received may 2021 & accepted september 2021 provement were observed even 5 years after the procedure(4). usually, prostates 30-80 g are indicated for the procedure. a study evaluating the effect of the rezūm method even for larger prostates 80-150 g is already underway(5). compared to standard surgical methods, no effect on sexual function or erection has been reported. mcvary did not describe any de novo erectile dysfunction after the procedure and during one year there was no deterioration of sexual function compared to the initial values according to the iief-ef and msqh-ejd questionnaires(6). the incidence of complications is reported to be low, usually mild and resolving in the order of days to weeks, 75% occurring within 1 month of the procedure(7). the need for surgical re-treatment is 4.4%, which is significantly lower compared to other minimally invasive methods such as transurethral needle ablation (tuna), transurethral microwave therapy (tumt) or prostatic urethral lift (pul)(4). in the long term, late complications such as urethral stricture or bladder neck sclerosis, known after standard surgical techniques, have not been reported(4,7). the aim of this prospective study was to evaluate the short-term results of the minimally invasive treatment with the rezūm method in the first cohort of patients treated at a center in the czech republic, one of three centers in the world where a pilot study with this method took place(2). unclassified urology journal/vol 18 no. 6/ november-december 2021/ pp. 699-702. [doi: 10.22037/uj.v18i.6843] materials ans methods study population the prospective study included patients with bph and moderate to severe luts (n = 76) who underwent surgical treatment with the minimally invasive rezūm method (rezūm system, boston scientific, marlborough, ma) between december 2019 and july 2020. inclusion and exclusion criteria patients with ipss score ≥ 8 (moderate and severe luts) and prostate size ≤ 150 ml, in whom surgical treatment was indicated due to the unsatisfactory effect of pharmacotherapy, were included. permanent catheter after the trial without the catheter in patients with urinary retention was allowed. patients with prostates > 150 ml, suspicious digital rectal examination (dre) or untreated urinary tract infection were excluded. evaluations all patients underwent standard pre-follow-up examinations, including dre, prostate specific antigen (psa), transrectal prostate ultrasound (trus), uroflowmetry (ufm), postvoid residual (pvr) and completed the international prostate symptom score (ipss) and oabv8 (overactive bladdervalidated 8-question screeener). the same examinations were performed 3 months after the procedure. all patients signed an informed consent for the procedure and the study was approved by the local ethics committee (approval no. 101119 / ek). procedure the operation was performed by one surgeon at the department of urology, university hospital brno. the number of injections depended on the size of the prostate with the interval of 1 cm in the caudal direction, starting from distal to the bladder neck. two to three injections were applied to one lobe (in one case only, four injections were needed for a large prostate), in the case of the expressed middle lobe another 1-2 injections were added. the procedure was performed in 92% in analgosedation. the vast majority of patients went home on the day of surgery; only one patient was hospitalized at his own request until the catheter extraction. the catheter was normally extracted on days 5 to 7 after the procedure. statistical analysis preoperative and postoperative values of the monitored parameters were compared and statistically evaluated at the 5% level of significance. data normality was tested using the shapiro-wilk test. paired t-test was used for normally distributed data, and wilcoxon paired test was used for the others. the results were evaluated using ibm® spss® statistics version 27. results input characteristics of patients and values of monitored parameters are presented in table 1. eleven patients (14.5%) had urinary retention before treatment, of which six patients had a catheter inserted at the time of surgery. ninety-six percent of patients underwent follow-up examinations three months after surgery (n = 73). in the six patients who had a permanent urinary catheter inserted before surgery, it was not possible to compare some parameters before and after surgery, so these patients were not included in the evaluation of these parameters. two patients did not return for the check-up due to the covid epidemic; the third was outside of the czech republic long-term due to personal reasons. the first monitored group of parameters were the findings at ufm (table 2). three months after surgery, there was a significant increase in qmax, qave and voided volume and a decrease in postvoid residual (p < .001). the reduction in urination time was not statistically significant (p = .089). comparing the scores from the ipss and oabv8 questionnaires (table 2) showed a significant improvement in the qol domain of the ipss questionnaire (question 8, p = .037) and in the overall oabv8 score (median after and before surgery 6 and 16, respectively, p < .001). the median ipss score after and before surgery was 6 and 20, respectively. despite the distinct decrease, it closely did not reach the statistical significance (p = .079). after the procedure, there was a significant reduction in psa levels and prostate volume according to trus measurements (respective p-value < .001). of the complications that persisted for more than one week, haematuria occurred in 15% (n = 11), urinary tract infection in 12% (n = 9), urinary retention in 7% (n = 5), urgency in 5% (n = 4), clot retention in 4% (n = 3) and erectile dysfunction in 1% (n = 1). although a validated satisfaction questionnaire was not used, up to 96% of patients expressed satisfaction with the condition after surgery and would recommend the procedure to others, two patients were only partially satisfied and one patient was indicated for turp due to persistent urinary retention. n (%) number of patients 76 (100 %) age average (sd) 65.3 (7.1) median 66 min-max 49-81 type of anesthesia analgosedation 70 (92.1) general 1 (1.3) local 5 (6.6) length of hospital stay (days) average (sd) 0.2 (0.7) median 0 min-max 0-5 prostate volume (ml) average (sd) 61.8 (29.2) median 52 min-max 20-149 psa (ng/ml) average (sd) 3.5 (2.8) median 2.5 min-max 0.2-13.9 ipss score average (sd) 19.1 (6.3) median 20 min-max 6-30 ipss qol average (sd) 4.0 (1.1) median 4 min-max 1-6 oabv8 score average (sd) 16.5 (7.6) median 16 min-max 3-40 table 1. characteristics of the study group. abbreviations: ipss, international prostate symptom score; oabv8, overactive bladder-validated 8-item screener; psa, prostatic specific antigen; qol, quality of life; sd, standard deviation. water vapor therapy of bph/luts – wasserbauer et al. unclassified 700 vol 18 no 6 november-december 2021 701 discussion minimally invasive methods of bph treatment are methods that burden the patient as little as possible, are sufficiently effective and safe, and have a minimal incidence of serious complications. these include methods such as hifu (high-intensity focused ultrasound), tumt, tuna, selective prostate embolization, intraprostatic ethanol application or prostate stent implantation. newer methods include pul and rezūm(8). both of these methods are entering common clinical practice(9). the rezūm method is often compared to the pul for similar indications and results. while the principle of pul is, in addition to the mechanical opening effect of the device, tissue ischemia with subsequent atrophy and resorption of prostate tissue(10), in rezūm the result of water vapor is coagulative necrosis, which in several weeks leads to resorption of necrotic tissue and reduction of prostate volume. our center was a part of a multicenter pilot study, in which 18 patients were treated with the rezum system in 2014-2015. based on this study, the fda then enabled a larger clinical study to be conducted in the united states(7). the method was introduced into clinical practice in the czech republic at the end of 2019, which enabled the procedure to be performed on a larger number of patients. the presented cohort of patients is the first group evaluated in this way not only within the czech republic, but also the central european region. short-term treatment results were published in a pilot prospective study by dixon et al.(11) and the work of mcvary(12). in the available studies with 1-2 years of follow-up, the mean changes in ipss score, qol, qmax and pvr reach 45-60%, 38-59%, 44-72% and 11-35%, respectively. clavien i-ii short-term complications include urinary retention, dysuria, urgency, urinary tract infection and, gross hematuria whereas few iii-iv complications such as sepsis or clot retention have been reported(4). our results correspond with these results. we observed an overall lower incidence of adverse events compared to the dixon study. haematuria was more common in our cohort (15% vs. 13%); on the contrary, the incidence of urinary retention was lower (7% vs. 33%). other complications are not comparable due to the low number of patients. the initial results of a similar short-term multicenter italian study in 135 patients(13) showed a significant reduction in ipss score after 3 months (4.2 vs. 21, p < .0001). there was also an apparent decrease in the ipss score in our cohort (6.8 vs. 16), but it did not reach statistical significance by a small margin (p = .079). we recorded a lower incidence of acute urinary retention (7% vs. 11.8%) and, conversely, a higher incidence of urinary tract infection (12% vs. 6%). the limitation of our study is the short follow-up time and the smaller number of patients, which is due to the short time that the device has been available on the market. however, published work demonstrates a long-lasting effect of treatment even after 5 years of follow-up, concerning the reduction of ipss by 48% and improvement of qmax and quality of life by 44% and 45%, respectively (4). the strength of the study is its prospective nature, as well as the fact that all procedures were performed by only one surgeon with experience from the pilot study. from the point of view of the benefit for the patient, we consider an independent assessment of qol according to ipss to be important, which in the short-term follow-up showed a significant improvement. longer term preoperatively 3 months after surgery p-value qmax (ml/s) n = 68 n = 68 average ± sd (range) 8.8 ± 3.7 (1.0-18.6) 16.9 ± 5.7 (2.0-33.0) < .001 median 8.8 17.7 qave (ml/s) n = 67 n = 67 average ± sd (range) 4.8 ± 2.0 (1.0-12.6) 9.0 ± 3.4 (1.0-19.0) .001 median 4.5 9 v (ml) n = 68 n = 68 average ± sd (range) 196.8 ± 109.1 (3-497) 260.7 ± 126.2 (45-606) < .001 median 177 241 pvr (ml) n = 67 n = 67 average ± sd (range) 67.7 ± 98.1 (0-760) 17.5 ± 47.6 (0-373) < .001 median 50 0 t (s) n = 66 n = 66 average ± sd (range) 45.0 ± 21.7 (7-125) 30.7 ± 15.0 (10-84) .089 median 42 27 ipss score n = 72 n = 72 average ± sd (range) 19.0 ± 6.4 (6-30) 6.8 ± 4.3 (0-21) .079 median 20 6 ipss qol n = 72 n = 72 average ± sd (range) 4.0 ± 1.1 (1-6) 1.6 ± 0.9 (0-4) .037 median 4 2 oabv8 n = 72 n = 72 average ± sd (range) 16.6 ± 7.5 (5-40) 7.6 ± 4.8 (1-23) < .001 median 16 6 prostate volume (ml) n = 73 n = 73 average ± sd (range) 62.3 ± 29.7 (20-149) 39.3 ± 18.8 (16-92) < .001 median 52 34 tpsa (ng/ml) n = 70 n = 70 average ± sd (range) 3.4 ± 2.8 (0.2-13.9) 2.3 ± 1.8 (0.2-9.2) < .001 median 2.5 1.9 table 2. comparison of uroflowmetry parameters, scores from questionnaires, prostate volume by transrectal ultrasound and total psa values. abbreviations: ipss, international prostate symptom score; oabv8, overactive bladder-validated 8-item screener; pvr, post-void residual; qave, average flow; qmax, maximum flow; qol, quality of life; sd, standard deviation; t, voiding time; tpsa, total prostatic specific antigen; v, voided volume. water vapor therapy of bph/luts – wasserbauer et al. follow-up and more patients are needed to confirm our results. studies in larger prostates and in patients with preoperative urinary retention are also needed in the future. in this regard, published data on 37 patients have so far demonstrated spontaneous micturition after surgery in 70% of patients who had a preoperative urinary catheter(14). we did not assess the impact on erectile or ejaculatory function. according to available studies, the impact of rezūm is minimal. anejaculation within the first 3 months occurs in less than 3% and only one retrospective study reported de novo erectile dysfunction in 3% of patients(15). an important limitation concerning more frequent implementation of the procedure in the czech republic is the lack of reimbursement from public health insurance, so the procedure is covered by the patient. conclusions water vapor therapy using the rezūm system leads to a significant increase in qmax, qave, voided volume and a significant decrease in post-void residual, oabv8 score, prostate size and total psa during short-term follow-up. the quality of life of patients after the operation is significantly higher compared to the condition before the operation. confirmation of these promising results in a larger group of patients and with a longer follow-up period is a prerequisite for the extension of this new minimally invasive treatment to routine clinical practice. conflict of interest there is no potential conflict of interest to declare. references 1. gravas s, cornu jn, gacci m et al. eau guidelines on management of nonneurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo). in: eau guidelines. 2021 ed. arnhem, the netherlands: eau guidelines office; 2021. pp.1 – 82. 2. dixon cm, rijo cedano e, mynderse la, larson tr. transurethral convective water vapor as a treatment for lower urinary tract symptomatology due to benign prostatic hyperplasia using the rezūm(®) system: evaluation of acute ablative capabilities in the human prostate. res rep urol. 2015;7:13–18. 3. doppalapudi sk, gupta n. what is new with rezūm water vapor thermal therapy for luts/bph? curr urol rep. 2021;22:4. 4. mcvary kt, gittelman mc, goldberg ka et al. final 5-year outcomes of the multicenter randomized sham-controlled trial of a water vapor thermal therapy for treatment of moderate to severe lower urinary tract symptoms secondary to benign prostatic hyperplasia. j urol. 2021;206:1-9. 5. boston scientific corporation. minimally invasive prostatic vapor ablation multicenter, single arm study for the treatment of bph in large prostates (rezūm xl) [internet]. clinicaltrials.gov; 2020 august [accessed april 18 2021]. report no.: nct03605745. available from https:// clinicaltrials.gov/ct2/show/nct03605745. water vapor therapy of bph/luts – wasserbauer et al. 6. mcvary kt, gange sn, gittelman mc, goldberg ka, patel k, shore nd, et al. erectile and ejaculatory function preserved with convective water vapor energy treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: randomized controlled study. j sex med 2016;13:924–33. 7. dixon cm, cedano er, pacik d, vit v, varga g, wagrell l, et al. two-year results after convective radiofrequency water vapor thermal therapy of symptomatic benign prostatic hyperplasia. res rep urol. 2016;8:207–16. 8. magistro g, weinhold p, stief cg, graztke c. the new kids on the block: prostatic urethral lift (urolift) and convective water vapor energy ablation (rezum). curr opin urol. 2018;28:294-300. 9. das ak, han tm, uhr a, roehrborn cg. benign prostatic hyperplasia: an update on minimally invasive therapy including aquablation. can j urol. 2020;27:2-10. 10. woo hh, chin pt, mcnicholas ta et al. safety and feasibility of the prostatic urethral lift: a novel, minimally invasive treatment for lower urinary tract symptoms (luts) secondary to benign prostatic hyperplasia (bph). bju int. 2011;108:82–8. 11. dixon c, cedano er, pacik d et al. efficacy and safety of rezūm system water vapor treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia. urology. 2015;86:1042–7. 12. mcvary kt, roehrborn cg. three-year outcomes of the prospective, randomized controlled rezūm system study: convective radiofrequency thermal therapy for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. urology. 2018;111:1–9. 13. siena g, cindolo l, ferrari g et al. water vapor therapy (rezūm) for lower urinary tract symptoms related to benign prostatic hyperplasia: early results from the first italian multicentric study. world j urol. 2021;31:1-6. 14. mcvary kt, holland b, beahrs jr. water vapor thermal therapy to alleviate catheterdependent urinary retention secondary to benign prostatic hyperplasia. prostate cancer prostatic dis. 2020;23:303-308. 15. mollengarden d, goldberg k, wong d, roehrborn c. convective radiofrequency water vapor thermal therapy for benign prostatic hyperplasia: a single office experience. prostate cancer prostatic dis. 2018;21:379–85. unclassified 702 review 71urology journal vol 7 no 2 spring 2010 penile reconstruction evaluation of the most accepted techniques alireza babaei,1 mohammad reza safarinejad,2 farhat farrokhi,2 elham iran-pour2 purpose: loss of the penis can have a devastating effect on the lives of sufferers with significant psychogenic implications. penile reconstruction or phallus construction poses a difficult challenge and a demanding problem to the urologists and plastic surgeons. different techniques have been used for construction of a total penis and reconstruction of severely injured penis. the objective of this review was to determine the efficacy, advantages and disadvantages of the most popular penile reconstruction (pr) and phallus construction techniques. materials and methods: we searched without language restriction medline, pre-medline embase, and the cochrane central register of controlled trials (central) from january 1960 to january 2009. in addition, we searched the citation lists of relevant articles and book chapters. studies evaluating the functional and cosmetic results of different techniques of total phallus construction (tpc) and penile reconstruction (pr) were identified. two authors independently evaluated studies for selection, study quality, and extracted data. the primary outcome was creation of a sensate and cosmetically acceptable phallus. the secondary outcomes were competent neourethra that allows voiding in comfortable position, sexual intercourse, and the rate of complications. results: one hundred and forty-six studies with a total of 1622 patients were included in this review. conclusion: data from the available studies are insufficient to recommend any technique for tpc or pr. in the absence of evidence to support any method, the review authors recommend the one-stage tpc or pr. further studies are warranted, preferably multi-centered studies. urol j. 2010;7:71-8. www.uj.unrc.ir keywords: penis, reconstructive surgical procedures, gender assignment 1department of plastic surgery, aja university of medical sciences, tehran, iran 2urology and nephrology research center, shahid beheshti university, mc, tehran, iran corresponding author: mohammad reza safarinejad, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2277 0954 e-mail: safarinejad@unrc.ir received june 2009 accepted december 2009 introduction background total phallus construction (tpc) or penile reconstruction (pr) is indicated for loss of the penis due to various causes such as trauma, burns, animal bites, congenital anomalies, self-amputation, malignancy, gender dysphoria, and etc.(1,2) penile loss negatively affects different aspects of life, psychological status, and social relationships as well as the relationship with the partner. the type and extent of the penile loss varies from minimal partial to total. the value of the various microsurgical techniques for replantation of the penis remains uncertain.(3) a variety of operative techniques have been developed in order to restore the functional and esthetical male genitalia. the main penile reconstruction methods—babaei et al 72 urology journal vol 7 no 2 spring 2010 goals of the surgery are creation of a cosmetically acceptable sensate penis, incorporation of the urethra that extends up to the distal tip which permits voiding in a comfortable position, and providing enough bulk to allow the insertion and retain a permanent penile prosthesis for sexual intercourse. in addition, the donor-site should cause minimal secondary morbidity and should be easy to conceal. however, penile reconstructive operations have generally been challenging not only for the limited availability of the donor materials, but also for requirements (mainly sexual intercourse, normal appearance, and voiding) that must be addressed.(4,5) phallus construction requires a holistic multidisciplinary team approach, involving both the urological reconstructive and plastic surgeon. total phallus construction may be considered in patients with severe congenital penile defect and gender reassignment, and in those who have suffered from penile loss resulting from various causes. historically, several techniques have been described for tpc. the first tpc was done in 1936 by bogoras,(6) who used a traditional tubed pedicle flap without including a competent neourethra. penile rigidity was obtained by inclusion of a rib cartilage inside the flap. this method required multiple staged surgeries without cosmetically acceptable phallus. afterward, bogoras technique was improved by creating a penis which incorporated a neourethra using the ‘tube within a tube’ design.(7,8) during the past two decades, the advent of microsurgical techniques and well-designed composite flaps have made great advances in pr. various surgical techniques have been used for pr, among them are pedicled flaps,(9,10) pedicled myocutaneous flaps,(11) free skin flaps,(2,12,13) and combined osteocutaneous flaps.(4,12) as pedicled flaps, gracilis,(14,15) iliac,(16,17) fibula,(16,18,19) scrotal,(20,21) groin,(22,23) and abdominal tube flaps(10,11) have been used with various success rates. despite great advances in microsurgical techniques, and penile revascularizations,(24) management of any type of penile loss remains a challenging task for urologists and plastic surgeons. choosing an appropriate donor/graft material and technique is a crucial aspect of successful pr and ideal functional outcome of surgery. in this study, using comprehensive in depth review, we assessed the functional outcomes and patients’ satisfaction with the use of the most accepted procedures for tpc and pr techniques. objectives we determined the overall efficacy and complications of the most popular tpc and pr techniques in patients who have had a partial or total penile reconstruction. we also characterized the anatomical, physiological, and cosmetic features and feasibility of the procedures as well as the short-term and long-term clinical results. the main outcome was creation of sensate and cosmetically acceptable penis. secondary outcomes included competent neourethra that allows voiding and sexual intercourse, and the rate of complications. complexity of techniques, configuration, good function, and deformity of the donor-site were also assessed. materials and methods criteria for considering studies for this review: types of studies all published studies evaluating surgical techniques for tpc and pr were included. controlled clinical trials and case reports were to be considered in the absence of randomized controlled trials. types of participants participants were from all ages that have undergone tpc or pr. search methods for identification of studies we searched medline from january 1960 to january 2009 with the following search terms: phalloplasty, penile reconstruction, penile cancer, penis, trauma, reconstructive surgical procedures, surgical flaps, amputation of penis, penile reconstruction and penile cancer, penile reconstruction and amputation of penis data collection and analysis eligibility in this review, one reviewer evaluated the titles penile reconstruction methods—babaei et al 73urology journal vol 7 no 2 spring 2010 and abstracts obtained from our literature search and assessed all possibly relevant articles to determine eligibility. extraction two authors independently collected the study characteristics and data, and disagreements were resolved by discussion. results types of surgery radial free forearm flap(18,25-39) radial free forearm flap (rfff) was originally described by song and colleagues in 1982.(40) later, chang and hwang used this technique successfully for tpc in 7 patients following penile amputation.(41) radial free forearm flap technique has proven to be superior to all other techniques.(25) fifteen patients, who had a subtotal penectomy for penile or urethral cancer, had undergone total phallic reconstruction using rfff.(25) all patients had cosmetically acceptable phallus and 14 were able to void while standing. in this study, only 7 patients had insertion of a penile prosthesis, of whom 5 could engage in sexual intercourse. the most common complications were urethral strictures (3, 20%) and fistula formation (4, 26.7%). hu and associates(10) identified success rates of 3 penile reconstruction techniques (lower abdominal pedicled fascia flaps, para-umbilical island flaps, and free forearm flaps) in 44 patients. half of the flaps survived in patients receiving lower abdominal pedicled fascia flaps, but neopenis survived in 100% of patients with para-umbilical island flaps and free forearm flaps. the authors concluded that the best methods for pr are the para-umbilical island flaps and free forearm flaps. in other study, 22 cases of primary female-to-male trans-sexuals had undergone phalloplasty using free radial forearm osteocutaneous flaps. twenty-one subjects (95.5%) had complete flap survival. the most common complications were urethrocutaneous fistula (40.9%) and urethral stricture (13.7%). no complete flap loss occurred and 1 patient developed partial loss (10% reduction). significant donor-site morbidity was noted in 9.1% of the subjects. the entire reconstructed penis gained protective sensation within 9 months. of 22 subjects, 9 engaged in sexual intercourse and all of them rated their sexual performance “satisfactory”. leriche and coworkers analyzed the long-term results of rfff in 56 trans-sexuals, retrospectively.(36) the subjects were followed up for 11 to 204 months (mean, 110 months). the flap survived in 53 (95%) of the cases and 51 (93%) of the patients reported normal-appearing external genitalia. flap and prosthesis complications were noted in 25% and 29% of the subjects, respectively. in addition, 7 of 19 patients (37%) who had undergone urethroplasty, developed complex urethral strictures and fistula that led to perineal urethrostomy. the authors concluded that phalloplasty using rfff leads to good results in term of flap survival and patient satisfaction; however, there are noticeable complications. in other study, during a 5-year period, 56 phallus constructions using sensate free forearm flaps were done for 56 primary female trans-sexuals by fang and colleagues.(39) the urethrocutaneous fistula rate was high (67.9%), therefore, fang and associates proposed a tubed graft of vaginal mucosa which had less complications and a lower fistula rate. mutaf described the first nonmicrosurgical use of the radial forearm flap for pr in 4 patients. (28) with this technique, an osteocutaneous radial forearm flap is elevated as a reverse-flow island flap and used to create a neophallus in the classic “tube within a tube” design. all of the patients had good results. the author concluded that although radial forearm flap is a multistage technique, it is easy to be carried out and does not necessitate the sophisticated equipment and skill of microsurgery. free sensate osteocutaneous fibula flap(4,18,19,42-48) free sensate osteocutaneous fibula flap was first described for total penile construction by sadove and colleagues in 1993.(44) schaff and papadopulos reported neophallus creation with free sensate osteofasciocutaneous fibula in 31 and radial forearm flap in 6 female-to male trans-sexuals. (18) penile reconstruction methods—babaei et al 74 urology journal vol 7 no 2 spring 2010 partial flap necrosis occurred in 16.1% and 16.6% of patients with fibula and forearm flaps, respectively. the most common complications were urethral stricture (32.4%) and fistula (16.2%). subjects with fibula flap reported a better sexual intercourse compared to the forearm group. the donor-site morbidity was comparable in both groups. in other study, free prelaminated and sensate osteofasciocutaneous fibula flap was done in 32 female-to-male trans-sexuals.(19) total and partial necrosis of fibula flap occurred in 2 and 4 patients, respectively. urethral strictures (10) and fistula (7) were the most common complications. significant variation in size, length, shape, and stiffness of the constructed phallus were not seen. patients had acceptable tactile as well as the erogenous sensation in the neophallus. all subjects had good sexual intercourse and the donor-site morbidity was moderate. in other study by sengezer and associates, 18 biological male patients with penile loss resulting from various causes had undergone total penile reconstructions with sensate osteocutaneous free fibula flap.(4) of a total of 18 subjects, 1 patient developed flap failure. interestingly, no urethral fistula was observed, and only 1 patient developed urethral stricture. sexual intercourse and orgasm were satisfactory in most of the patients. the results of the bone viability investigations are consistent with viability of the bone grafts. free scapular flap(2,12,49) free scapular flap technique was first described by rohrich and colleagues.(50) they used a combined latissimus dorsi-scapular free flap for simultaneous penis and perineum reconstruction. this simple technique is a practical method, which yields appropriate configuration, satisfactory penile function, and less donor-site morbidity.(12) yang and coworkers reconstructed 20 patients with penile loss using this technique.(2) the rate of postoperative viable flap was 100%. in these subjects, complications such as urethral fistula, prosthesis infection, or extrusion were not reported. the authors concluded that the scapular free flap is an ideal flap that yields satisfactory penile function and cosmetic appearance. in another study, 15 men aged 20 to 48 years underwent the free scapular skin flap for penile reconstruction.(12) of reconstructed penis, 14 (93.3%) patients were satisfied with good esthetic results as well as functionality. in this study, sensory nerves were not transferred, but the flap regained sensitivity within 6 months. the scapula may be used for obtaining penile rigidity; nonetheless, its configuration is difficult. therefore, insertion of a penile prosthesis should be done. vertical rectus abdominis flap(11,51,52) vertical rectus abdominis flap was first described by santi and associates.(52) it is suitable for immediate one-stage penile reconstruction; however, information about this technique is very scarce. kayes and colleagues used vertical rectus abdominis flap for pr in 4 patients with advanced penile cancer.(11) all grafts were viable and patients’ satisfaction was excellent. davies and matti used the deep inferior epigastric flap to construct a phallus in 3 trans-sexuals and 1 pseudohermaphrodite. all subjects were extremely satisfied with their surgery.(53) suprapubic abdominal wall flap bettocchi and coworkers reported the results of pedicled pubic phalloplasty in 85 female-tomale trans-sexual patients.(9) three patients had complete loss of the reconstructed phallus due to a gangrenous infection. the cosmetic outcome was rated as good, by both patient and surgeon, in 58 (71%) of the subjects. the neourethra complications were high (75%). of 85 patients, 64% and 55% developed urethral stricture and fistula, respectively. the authors believe that creation of the neourethra in 2 stages has less urethral complications. perineal fistula occurred in 94% and 24% of the one-stage and twostage operations, respectively. sixteen patients were able to engage in sexual intercourse without prosthesis. discussion the ultimate goals in pr are as follows: the penis should have adequate size and bulk with enough rigidity, the constructed phallus should have enough protective, tactile, and erogenous penile reconstruction methods—babaei et al 75urology journal vol 7 no 2 spring 2010 sensation and should provide adequate urethra up to the glans without any fistula.(54) recently, the use of a radial forearm flap has become the most popular technique to reconstruct a neophallus. however, it has its own limitations such as urethral fistula and penile fibrosis as a result of the tissue atrophy. in addition, the donor-site morbidity is a great concern with this technique. forearm free flap phalloplasty also provides excellent long-term satisfaction in patients with bladder exstrophy. (33,55) in an earlier study, using radial forearm flap in 5 trans-sexual subjects, disappointing results and high incidence of complications have been reported.(56) the main complications, advantages, disadvantages, and limitation of forearm free flap are as bellow: complications: overall complication rate and donor-site morbidity may occur in 45% of subjects. (38) the most common complications are related to neourethra. the reported urethral complications greatly vary in different studies (0 to 60%), which may be related to surgeons’ experience and equipment used to construct neophallus. advantages: good cosmetic result by forming a cylindrical phallus, creation of an acceptable sensate phallus,(25) providing good sensory nerves for its neurovascular pedicle,(12) excellent phallus sensation if the nerve is well-functioned,(54) and well-vascularized neourethra that allows voiding from a standing position.(29,47) disadvantages: sacrificing a trunk artery of the forearm decreases muscle function of the forearm,(2) large donor-site depressive scar, urethral fistula, and need for microvascular anastomosis,(57) thin subcutaneous tissue, less tissue for transfer, thin reconstructed phallus,(12) erosion of the penile prostheses in significant number of subjects due to softening of the flaps,(4) and susceptibility of the radial bone to fracture as a result of being thin and unicortical.(4) limitations: unsuitable to reconstruct the urethra in patients with thick hair.(2) once the new phallus has been reconstructed, providing adequate rigidity for sexual intercourse remains a major challenge. various different solutions have been proposed, including the autologous bone, the autogenous cartilage rods,(58) silicone prostheses,(59,60) and the autologous engineered cartilage rods.(61) but, the best results have been reported by inserting an inflatable penile prosthesis.(62) with radial free forearm flap technique, penile rigidity can be obtained by inclusion of the radius bone. one can harvest this forearm free flap with thin unicortical radius bone. the longterm survival of this bone has not been shown adequately.(54) indeed, the resorption of the bone, fracture, and perforation are the potential complications that can lead to failure.(47,63) felici and felici, after a 10-year experience with neophallus construction in female to male gender reassignment surgery and with more than 100 patients treated, introduced a new technique. (64) they performed 6 neophallus constructions with free anterolateral thigh flap. the esthetic results of the neophallus were suitable, the flap achieved sensation and an erectile prosthesis could be easily inserted. use of the anterolateral thigh flap for penile construction eliminates various concerns about the forearm donor-site morbidity. (64) satisfactory results with free anterolateral thigh flap have also been reported by other authors.(65,66) the scapular free flap technique is a practical method, which yields appropriate configuration, satisfactory penile function, and less donor-site morbidity.(12) due to adequate amount of tissue, the scapular free flap is an ideal donor-site for harvesting large amount of flap. in addition, owing to constant vascularity and sufficient blood supply, few donor-site morbidities are encountered.(2) the advantages of this technique are ideal donor-site for obtaining great amount of flap, and easier intra-operative vascular anastomosis due to inferior epigastric artery and vein long pedicle. disadvantages include difficulty of nerve transfer and being inappropriate to reconstruct the urethra in hirsute patients.(2) the advantages of the rectus abdominis flap over other flaps include a strong tissue paddle for filling tissue defects and a very good blood supply through segmental penile reconstruction methods—babaei et al 76 urology journal vol 7 no 2 spring 2010 perforators of the superior and inferior epigastric arteries. thus, large defects on both donor and recipient sites can be easily covered with primary closure. however, this method is contraindicated in obese patients and subjects who have preexisting midline and paramedian scars.(11) phallus construction with free sensate fibula flap gives good cosmetic and functional results.(4) sengezer and colleagues recommended the free sensate osteocutaneous fibula flap as the standard technique in penile reconstruction.(4) conclusion the literature lacks enough data concerning the detailed erogenous and tactile sensibility, and erectile capability of the reconstructed neophalluses. of penile reconstruction techniques, free radial forearm and sensate osteocutaneous free fibula flaps are the most accepted ones that provide phallic rigidity. the scarcity of detailed data in the urologic and plastic surgery literature raises assumption about the true efficacy and morbidity of each technique. reconstructing a neophallus with enough rigidity to permit sexual intercourse and penetration has remained a great challenge in the field of urology. conflict of interest none declared. references 1. perovic sv, djinovic rp, bumbasirevic mz, santucci ra, djordjevic ml, kourbatov d. severe penile injuries: a problem of severity and reconstruction. bju int. 2009;104:676-87. 2. yang m, zhao m, li s, li y. penile reconstruction by the free scapular flap and malleable penis prosthesis. ann plast surg. 2007;59:95-101. 3. babaei ar, safarinejad mr. penile replantation, science or myth? a systematic review. urol j. 2007;4:62-5. 4. sengezer m, ozturk s, deveci m, odabasi z. long-term follow-up of total penile reconstruction with sensate osteocutaneous free fibula flap in 18 biological male patients. plast reconstr surg. 2004;114:439-50; discussion 51-2. 5. khouri rk, young vl, casoli vm. long-term results of total penile reconstruction with a prefabricated lateral arm free flap. j urol. 1998;160:383-8. 6. bogoras n. plastic construction of penis capable of accomplishing coitus. zentralbl chir. 1936;63:1271–6. 7. maltz m. evolution of plastic surgery. new york,: froben press; 1946. 8. gillies h. congenital absence of the penis. br j plast surg. 1948;1:8-28. 9. bettocchi c, ralph dj, pryor jp. pedicled pubic phalloplasty in females with gender dysphoria. bju int. 2005;95:120-4. 10. hu zq, hyakusoku h, gao jh, aoki r, ogawa r, yan x. penis reconstruction using three different operative methods. br j plast surg. 2005;58:487-92. 11. kayes oj, durrant ca, ralph d, floyd d, withey s, minhas s. vertical rectus abdominis flap reconstruction in patients with advanced penile squamous cell carcinoma. bju int. 2007;99:37-40. 12. wang h, li sk, yang my, et al. a free scapular skin flap for penile reconstruction. j plast reconstr aesthet surg. 2007;60:1200-3. 13. kao xs, kao jh, ho cl, yang zn, shi hr. one-stage reconstruction of the penis with free skin flap: report of three cases. j reconstr microsurg. 1984;1:149-53. 14. persky l, resnick m, desprez j. penile reconstruction with gracilis pedicle grafts. j urol. 1983;129:603-5. 15. hanash ka, tur jj. one-stage plastic reconstruction of a totally amputated cancerous penis using a unilateral myocutaneous gracilis flap. j surg oncol. 1986;33:250-3. 16. lai cs, chou ck, yang cc, lin sd. immediate reconstruction of the penis with an iliac flap. br j plast surg. 1990;43:621-4. 17. acland rd. the free iliac flap: a lateral modification of the free groin flap. plast reconstr surg. 1979;64:30-6. 18. schaff j, papadopulos na. a new protocol for complete phalloplasty with free sensate and prelaminated osteofasciocutaneous flaps: experience in 37 patients. microsurgery. 2009;29:413-9. 19. papadopulos na, schaff j, biemer e. the use of free prelaminated and sensate osteofasciocutaneous fibular flap in phalloplasty. injury. 2008;39 suppl 3:s62-7. 20. goodwin we, scott ww. phalloplasty. j urol. 1952;68:903-8. 21. mazza on, cheliz gm. glanuloplasty with scrotal flap for partial penectomy. j urol. 2001;166:887-9. 22. mcgregor ia, jackson it. the groin flap. br j plast surg. 1972;25:3-16. 23. perovic s. phalloplasty in children and adolescents using the extended pedicle island groin flap. j urol. 1995;154:848-53. 24. babaei ar, safarinejad mr, kolahi aa. penile revascularization for erectile dysfunction: a systematic review and meta-analysis of effectiveness and complications. urol j. 2009;6:1-7. 25. garaffa g, christopher na, ralph dj. total phallic reconstruction in female-to-male transsexuals. eur urol. 2009. 26. solinc m, kosutic d, stritar a, planinsek f, mihelic m, lukanovic r. preexpanded radial forearm free flap for one-stage total penile reconstruction in female-to-male penile reconstruction methods—babaei et al 77urology journal vol 7 no 2 spring 2010 transsexuals. j reconstr microsurg. 2009;25:395-8. 27. ramesh s, serjius a, wong tb, jagjeet s, john r. two stage penile reconstruction with free prefabricated sensate radial forearm osteocutaneous flap. med j malaysia. 2008;63:343-5. 28. mutaf m. nonmicrosurgical use of the radial forearm flap for penile reconstruction. plast reconstr surg. 2001;107:80-6. 29. garcia de alba a, de la pena-salcedo ja, lopez-monjardin h, clifton jf, palacio-lopez e. microsurgical penile reconstruction with a sensitive radial forearm free flap. microsurgery. 2000;20:181-5. 30. pei gx, li k, xie c. reconstruction of the penis after severe injury. injury. 1998;29:329-34. 31. rashid m, afzal w, ur rehman s. single stage reconstruction of the amputated penis using a microsurgical radial forearm flap transfer. j pak med assoc. 1998;48:82-5. 32. mackay dr, pottie r, kadwa ma, stott rs. reconstruction of the penis using a radial forearm free flap. a case report. s afr med j. 1989;76:278-80. 33. timsit mo, mouriquand pe, ruffion a, et al. use of forearm free-flap phalloplasty in bladder exstrophy adults. bju int. 2009;103:1418-21. 34. lumen n, monstrey s, ceulemans p, van laecke e, hoebeke p. reconstructive surgery for severe penile inadequacy: phalloplasty with a free radial forearm flap or a pedicled anterolateral thigh flap. adv urol. 2008704343. 35. lumen n, monstrey s, selvaggi g, et al. phalloplasty: a valuable treatment for males with penile insufficiency. urology. 2008;71:272-6; discussion 6-7. 36. leriche a, timsit mo, morel-journel n, bouillot a, dembele d, ruffion a. long-term outcome of forearm flee-flap phalloplasty in the treatment of transsexualism. bju int. 2008;101:1297-300. 37. kim sk, lee kc, kwon ys, cha bh. phalloplasty using radial forearm osteocutaneous free flaps in female-to-male transsexuals. j plast reconstr aesthet surg. 2009;62:309-17. 38. fang rh, kao ys, ma s, lin jt. phalloplasty in female-to-male transsexuals using free radial osteocutaneous flap: a series of 22 cases. br j plast surg. 1999;52:217-22. 39. fang rh, lin jt, ma s. phalloplasty for female transsexuals with sensate free forearm flap. microsurgery. 1994;15:349-52. 40. song r, gao y, song y, yu y, song y. the forearm flap. clin plast surg. 1982;9:21-6. 41. chang ts, hwang wy. forearm flap in one-stage reconstruction of the penis. plast reconstr surg. 1984;74:251-8. 42. dabernig j, chan lk, schaff j. phalloplasty with free (septocutaneous) fibular flap sine fibula. j urol. 2006;176:2085-8. 43. capelouto cc, orgill dp, loughlin kr. complete phalloplasty with a prelaminated osteocutaneous fibula flap. j urol. 1997;158:2238-9. 44. sadove rc, sengezer m, mcroberts jw, wells md. one-stage total penile reconstruction with a free sensate osteocutaneous fibula flap. plast reconstr surg. 1993;92:1314-23; discussion 24-5. 45. dabernig j, shelley o, cuccia g, schaff j. urethral prelamination in penile reconstruction with an osteocutaneous free fibular flap. j plast reconstr aesthet surg. 2006;59:561-2. 46. hage jj, winters ha, van lieshout j. fibula free flap phalloplasty: modifications and recommendations. microsurgery. 1996;17:358-65. 47. papadopulos na, schaff j, biemer e. long-term fate of the bony component in neophallus construction with free osteofasciocutaneous forearm or fibula flap in 18 female-to-male transsexuals. plast reconstr surg. 2002;109:1025-30; discussion 31-2. 48. papadopulos na, schaff j, biemer e. usefulness of free sensate osteofasciocutaneous forearm and fibula flaps for neophallus construction. j reconstr microsurg. 2001;17:407-12. 49. yang my, li sk, li yq, et al. [penile reconstruction by using a scapular free flap]. zhonghua zheng xing wai ke za zhi. 2003;19:88-90. 50. rohrich rj, allen t, lester f, young jp, katz sl. simultaneous penis and perineum reconstruction using a combined latissimus dorsi-scapular free flap with intraoperative penile skin expansion. plast reconstr surg. 1997;99:1138-41. 51. vesely j, barinka l, santi p, berrino p, muggianu m. reconstruction of the penis in transsexual patients. acta chir plast. 1992;34:44-54. 52. santi p, berrino p, canavese g, galli a, rainero ml, badellino f. immediate reconstruction of the penis using an inferiorly based rectus abdominis myocutaneous flap. plast reconstr surg. 1988;81:961-4. 53. davies dm, matti ba. a method of phalloplasty using the deep inferior epigastric flap. br j plast surg. 1988;41:165-8. 54. yavuz m, dalay c, kesiktas e, ozerdem g, kesiktas nn, acarturk s. contact high-tension electrical burn to the penis: reconstruction of the defect with free radial forearm fasciocutaneous flap and silicon rod, a case report. burns. 2006;32:788-91. 55. de fontaine s, lorea p, wespes e, schulman c, goldschmidt d. complete phalloplasty using the free radial forearm flap for correcting micropenis associated with vesical exstrophy. j urol. 2001;166:597-9. 56. matti ba, matthews rn, davies dm. phalloplasty using the free radial forearm flap. br j plast surg. 1988;41:160-4. 57. koshima i, nanba y, nagai a, nakatsuka m, sato t, kuroda s. penile reconstruction with bilateral superficial circumflex iliac artery perforator (scip) flaps. j reconstr microsurg. 2006;22:137-42. 58. yoo jj, lee i, atala a. cartilage rods as a potential material for penile reconstruction. j urol. 1998;160:1164-8; discussion 78. 59. grabstald h. postradical cystectomy impotence treated by penile silicone implant. n y state j med. 1970;70:2344-5. penile reconstruction methods—babaei et al 78 urology journal vol 7 no 2 spring 2010 60. lash h. silicone implant for impotence. j urol. 1968;100:709-10. 61. yoo jj, park hj, lee i, atala a. autologous engineered cartilage rods for penile reconstruction. j urol. 1999;162:1119-21. 62. hage jj, bouman fg, de graaf fh, bloem jj. construction of the neophallus in female-to-male transsexuals: the amsterdam experience. j urol. 1993;149:1463-8. 63. santanelli f, scuderi n. neophalloplasty in female-tomale transsexuals with the island tensor fasciae latae flap. plast reconstr surg. 2000;105:1990-6. 64. felici n, felici a. a new phalloplasty technique: the free anterolateral thigh flap phalloplasty. j plast reconstr aesthet surg. 2006;59:153-7. 65. kimata y, uchiyama k, ebihara s, et al. anterolateral thigh flap donor-site complications and morbidity. plast reconstr surg. 2000;106:584-9. 66. kimura n, satoh k, hasumi t, ostuka t. clinical application of the free thin anterolateral thigh flap in 31 consecutive patients. plast reconstr surg. 2001;108:1197-208; discussion 209-10. v08_no_1_print_3.pdf cellular and molecular urology 54 urology journal vol 8 no 1 winter 2011 isolation of human adult stem cells from muscle biopsy for future treatment of urinary incontinence farzaneh sharifiaghdas,1 maryam taheri,1 reza moghadasali2 purpose: to find a suitable and cost-effective technique for isolation and culture of muscle-derived stem cells (mdscs) obtained from muscle biopsy in large quantities. materials and methods: a small muscle biopsy was taken from 10 donor rectus muscles in patients undergoing open abdominal surgery for any reason and transported on ice to the laboratory. the isolation of mdscs was performed by two techniques; preplate and tissue explants. initially, the isolation was carried out by preplating technique. however, enzymatic digestion of muscle biopsy in preplate technique compromised the integrity of important surface antigens of resident muscle stem cells and led to dysfunctional sorted cells. also, many of the cells were lost in this technique and low numbers of mdscs were yielded upon processing. thus, we changed condition of centrifuge, but it did not affect cell numbers and their integrities. to overcome these problems, the technique was changed to tissue explants technique. results: during the first 4 days in explant medium culture, activated satellite cells detached, migrated, and slowly divided. the mdscs proliferated around the native myofiber and after 2 to 3 weeks, individual muscle cells appeared elongated and fused to create large multinucleated myotubes. on immunofluorescent staining, these emerged cells were positive for desmin and pax7 and flow cytometry analysis revealed that these cells were cd45-, cd56+, and variable in cd34. conclusion: we concluded that tissue explant method is a suitable and costeffective technique for isolation and culture of mdscs from muscle biopsy in large quantities. urol j. 2011;8:54-9. www.uj.unrc.ir keywords: urinary incontinence, muscle cells, stem cells, tissue culture techniques 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran 2department of stem cells, shahid beheshti university of medical sciences, royan institute, tehran, iran corresponding author: farzaneh sharifiaghdas, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 22567222 fax: +98 21 22567282 e-mail: fsharifiaghdas@yahoo.com received june 2010 accepted june 2010 introduction there are over 200 million people throughout the world who suffer from incontinence, a condition that is associated with social impact and a reduced quality of life.(1) stress urinary incontinence (sui) has been reported as the most common type of urinary incontinence, and cellular therapy with stem cells is a new approach to the treatment of sui.(2) according to previous studies, isolation of muscle-derived stem cells (mdscs) from muscle biopsy can be done through two techniques; preplate and tissue explant. however, enzymatic digestion of the muscle biopsy in preplate technique can compromise the integrity of important surface antigens of resident muscle stem cells, resulting in dysfunctional sorted cells, which makes the method difficult to be reproduced.(2) also, many of the stem cells for future treatment of urinary incontinence—sharifiaghdas et al 55urology journal vol 8 no 1 winter 2011 cells are lost in this technique and low numbers of mdscs are yielded upon processing. whereas the primary tissue explant technique could facilitate the proliferation of mdscs from muscle biopsies in vitro. we demonstrated that desmin-positive cd45cd56+ pax7+ cells isolated by this method keep their self-renewal capacity and could then be either passaged or differentiated, resulting in the fusion of most of the mononucleated cells to produce large multinucleated myotubes. materials and methods stem cell sources cell isolation: preplate and tissue explant techniques the isolation of mdscs was performed using previously described preplating technique.(3,4) a small muscle biopsy (0.5 × 0.5 cm2) was taken from 10 donor rectus muscles in patients undergoing abdominal surgery for any reason and was collected in phosphate buffer saline medium (pbs; gibco, cat no.21600-051) with penicillin 0.05 μ/ml and streptomycin 0.05 μg/ ml transported on ice. in laboratory, the muscle biopsy was taken out of the transport media and placed in a sterile petri dish. then, it was minced and chopped with razor blades. the minced skeletal biopsy was subjected to a triple digest strategy. first, it was placed in a collagenase iv, solution 0.2% (gibco, cat no.17104-019) for 1 hour at 37°c, with agitation every 10 minutes. the solution was centrifuged at 300 × g for 8 minutes, and the supernatant was discarded. thereafter, the muscle biopsy pellet was resuspended in dispase 0.3% (gibco, cat no.17105041) for 45 minutes at 37°c with agitation every 10 minutes. the solution was centrifuged at 300 × g for 8 minutes and the supernatant was discarded. finally, it was resuspended in trypsin– ethylenediaminetetraacetic acid (edta) 0.1% (gibco, cat no.25300) for 30 minutes at 37°c, with agitation every 10 minutes. the solution was centrifuged at 300 × g for 8 minutes, and the supernatant was discarded. then, the cell suspension was added to a collagen-coated flask (nalgene, cat no.5409) in dulbecco’s modified eagles medium (dmem; gibco, cat no.12800116), containing 10% fetal bovine serum (fbs; gibco, cat no. 10270-106), 10% horse serum, 1% penicillin-streptomycin (gibco, cat no. 15070), 2mm l-glutamine (lglu) (gibco, cat no. 25030), and 0.5% chick embryo extract: gibco-brl). after 1 hour, non adherent cells in suspension were removed and transferred to a second flask for a period of 2 hours. fresh medium was added to the first set of adherent cells (preplate1, pp1) and this procedure was continued for pp3 through pp6 at subsequent 24-hour intervals. according to previous researches performed by this technique, six cultures of adherent cells were produced with different adhesion characteristics. since in this study triple digest strategy led to dysfunctional sorted cells and the number of cells was very low, we changed condition of centrifuge to 1500 × g for 5 minutes, but it did not affect cell numbers and properties. to resolve these problems, the technique of isolation of mdscs was changed from preplate to tissue explant technique.(5,6) in this technique, the minced muscle biopsies were cultured as explant in explant medium (m199, gibco, cat no.31150) and fbs 10% at 37°c, and 5% co2. flow cytometry flow cytometry was used at 2 to 3 weeks and 6 to 7 weeks to analyze the mdscs population for the expression of surface proteins; cd45, cd34, and cd56. cells were washed in pbs + fbs medium (dulbecco’s phosphate buffer saline; gibco, cat no.21600-051, containing 0.5% fetal bovine serum; gibco, cat no. 10270-106) and were fixed by paraformaldehyde 2% (sigma, cat no. 58h0914). cells were again washed and permeated by triton x-100 (sigma, cat no. t8787). thereafter, the cells were washed and divided into four equal aliquots; three for combination of various monoclonal antibodies and one for control labeling as isotope igg. predetermined optimal amount of monoclonal antibodies (cd45, cd34, and cd56) (miltenyi biotec, cd45, cat no.130-080-202, cd34, cat no.130-081-001, and cd56, cat no.130-090-755) were added directly to each tube for 30 minutes. these primary antibodies were conjugated with fluorescence isothiocyanate and phycoerythrin. stem cells for future treatment of urinary incontinence—sharifiaghdas et al 56 urology journal vol 8 no 1 winter 2011 finally, the cells were washed and fixed with pbs + fb+ paraformaldehyde. then, the cells were subjected to flow cytometry using bd facs calibur flow cytometer and cellquest pro software. immunocytochemistry to assess the expression of proteins in relation to myogenic differentiation status, immunofluorescent analysis was performed for pax7 and desmin. cells were washed with pbs solution and fixed with paraformaldehyde 4%. then, cells were washed with pbs + tween 20 (sigma, cat no.p9416) solution twice, permeated with triton x-100 solution, and washed again with pbs + tween 20 solution twice. the cells were incubated at room temperature for 1 hour with primary antibody anti-desmin (santa cruz biotechnology, cat no.sc-14026) and anti-pax 7 (abcam, cat no.ab34360). after being rinsed with pbs + tween 20 solutions, cells were incubated with secondary antibody (fluorescence isothiocyanate) (sigma, cat no. f1262) for 1 hour at room temperature. for visualizing, nuclei cells were washed and analyzed on an olympus ckx 41 fluorescent microscope and olympus dp71 camera. results cell growth during the first 4 days in explant medium culture, activated satellite cells detached, migrated, and divided slowly. we observed that mdscs had proliferated around the native myofiber and after 2 to 3 weeks, individual muscle cells appeared elongated and fused to create large multinucleated myotubes (figure 1). flow cytometry and immunocytochemistry we examined the population of mdscs isolated by explant technique twice; at 2 to 3 weeks and 6 to 7 weeks. this flow cytometry technique was used to analyze the mdscs population for the expression of surface proteins; cd45, cd34, and cd56. the total percentage of mdscs at 2 to 3 weeks and 6 to 7 weeks were 4.21% and 5.91% for expressing cd45, 16.21% and 12.55% for expressing cd34, and 58.57% and 48.29% for expressing cd56, respectively. these results are demonstrated in figure 2 by histograms. immunochemical staining revealed that mdscs were positive for desmin and pax7 (figure 3). figure 2. mean percentage of mdscs populations expressing cell surface proteins cd45, cd34, and cd56. figure 1. a) during the first 4 days in explant medium culture, activated satellite cells detached and migrated from muscle biopsy b) at 2 to 3 weeks, individual muscle cells appeared elongated and fused to create large multinucleated myotubes. a b stem cells for future treatment of urinary incontinence—sharifiaghdas et al 57urology journal vol 8 no 1 winter 2011 discussion multipotent stem cells have the ability to proliferate and differentiate into different cell lines. tissue engineering is a new science to regenerate tissues based on the use of stem cells.(7) the two general types of stem cells that are potentially useful for the treatment are embryonic stem cells and adult stem cells. the practical use of embryonic stem cells is restricted because of potential regulatory problems and ethical considerations. however, there are no significant ethical issues that are related to the use of adult stem cells.(1) satellite cells are a subpopulation of skeletal muscle-derived cells that are capable of self renewal and regenerating the muscle after injury, the same as the stem cells. satellite cells, described in the classical work of mauro,(8)are situated on the surface of the myofiber between the figure 4. working model demonstrates quiescent satellite cells which are heterogeneous for pax7 protein. figure 3. (a and b) immunofluorescent staining for detection of pax7, and (c and d) desmin in mdscs derived from muscle biopsy by tissue culture explant technique. a c b d merge merge counterstain counterstain stem cells for future treatment of urinary incontinence—sharifiaghdas et al 58 urology journal vol 8 no 1 winter 2011 myofiber plasmalemma and its covering basement membrane. various cell surface makers have been identified to purify adult stem cell population from skeletal muscle, including c-kit, sca-l, and cd34. although nearly all muscle-derived hematopoietic progenitor cells are derived from cd45+ cells, common molecular phenotypes of mdscs are sca-l+, cd45-, and various amounts of cd34.(9) it appears that the difference with other markers might be due to culture conditions associated with different techniques or culturing protocols of different laboratories.(7) in the present study, sca-l was not evaluated since the human antibody of sca-l was not available. mean expression of cd45 and cd34 at 2 to 3 weeks and 5 to 6 weeks were 5.06% and 14.38%, respectively. we observed that cd45 is not a marker of mdscs and 95% of our cells were cd45-. peault and colleagues(10)and kayhanian and associates(11) proposed cd56 as another marker for myogenic cells, which had the mean expression of 53.53% in our study. deasy and coworkers suggested that pax7 could be considered as a marker of the muscle satellite cell, since it is necessary and sufficient for specifying of myogenic cells.(7) however, a recent study using human biopsies aimed at identifying satellite cells in vivo and revealed cells within the satellite cell position, but failed to express pax7.(12) some researchers think that various pax7 expressions may also result from the proliferative or cycling status of satellite cells.(7) by working model that is indicated in figure 4, olguin and olwin described that satellite cells are heterogeneous for pax7 protein in quiescent state.(13) activation of satellite cells induces up regulation of myod. proliferating myoblasts are heterogeneous and positive for both myod and pax7. a small number of cells differentiate early, and induce myogenin and lose pax7 expression. another small group of cells can act as myoblast precursors. it is assumed that co-expression of both myod and pax7 is necessary for myoblasts to prevent premature differentiation and keep them in a proliferative state. for the cells committed to differentiation, the myosine program goes forward, pax7 is down regulated and myod family transcription factors are up regulated. a small number of precursor cells will go opposite, up regulate pax7 and down regulate myod, and form a new satellite pool. rouger and colleagues used m-cadherin, pax7, and desmin expression to determine the rate of respective progression of cells toward end stage myogenic differentiation.(14) in this study, our cells were highly positive for immunostaining of pax7and desmin. conclusion we found that explant tissue culture is a suitable technique for isolation of mdscs in large quantities and this method precludes the possible enzymatic destruction of functional stem cell markers on cell surface. also, we demonstrated that mdscs with desmin positive markers (cd45-, cd34+/-, cd56+, and pax7+) have self-renewal properties and could then differentiate to myoblast, resulting in fusion of most of the mononucleated cells to produce large multinucleated myotubes in vitro. however, further studies are needed to demonstrate the applicability of these myotubes as external sphincter. conflict of interest none declared. references 1. furuta a, carr lk, yoshimura n, chancellor mb. advances in the understanding of sress urinary incontinence and the promise of stem-cell therapy. rev urol. 2007;9:106-12. 2. tang yl, shen l, qian k, phillips mi. a novel two-step procedure to expand cardiac sca-1+ cells clonally. biochem biophys res commun. 2007;359:877-83. 3. jankowski rj, haluszczak c, trucco m, huard j. flow cytometric characterization of myogenic cell populations obtained via the preplate technique: potential for rapid isolation of muscle-derived stem cells. hum gene ther. 2001;12:619-28. 4. royer cl, howell jc, morrison pr, srour ef, yoder mc. muscle-derived cd45-sca-1+c-kitprogenitor cells give rise to skeletal muscle myotubes in vitro. in vitro cell dev biol anim. 2002;38:512-7. 5. rosenblatt jd, lunt ai, parry dj, partridge ta. culturing satellite cells from living single muscle fiber explants. in vitro cell dev biol anim. 1995;31:773-9. stem cells for future treatment of urinary incontinence—sharifiaghdas et al 59urology journal vol 8 no 1 winter 2011 6. bischoff r. proliferation of muscle satellite cells on intact myofibers in culture. dev biol. 1986;115:129-39. 7. deasy bm, li y, huard j. tissue engineering with muscle-derived stem cells. curr opin biotechnol. 2004;15:419-23. 8. mauro a. satellite cell of skeletal muscle fibers. j biophys biochem cytol. 1961;9:493-5. 9. seale p, ishibashi j, scime a, rudnicki ma. pax7 is necessary and sufficient for the myogenic specification of cd45+:sca1+ stem cells from injured muscle. plos biol. 2004;2:e130. 10. peault b, rudnicki m, torrente y, et al. stem and progenitor cells in skeletal muscle development, maintenance, and therapy. mol ther. 2007;15:867-77. 11. kayhanian h, jones s, phillips j, lewis m, brown r, mudera v. host muscle cell infiltration in cell-seeded plastic compressed collagen constructs. j tissue eng regen med. 2009;3:72-5. 12. reimann j, brimah k, schroder r, wernig a, beauchamp jr, partridge ta. pax7 distribution in human skeletal muscle biopsies and myogenic tissue cultures. cell tissue res. 2004;315:233-42. 13. olguin hc, olwin bb. pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal. dev biol. 2004;275:375-88. 14. rouger k, fornasari b, armengol v, et al. progenitor cell isolation from muscle-derived cells based on adhesion properties. j histochem cytochem. 2007;55:607-18. reconstructive surgery 120 urology journal vol 7 no 2 spring 2010 tunica albuginea urethroplasty for panurethral strictures raj k mathur, adittya sharma purpose: to assess the efficacy of tunica albuginea urethroplasty for pan urethral stricture management as an alternative approach to conventional dorsal buccal mucosal graft urethroplasty, especially in cases with unavailability of healthy buccal mucosa. materials and methods: eighty-six patients with panurethral strictures underwent tunica albuginea urethroplasty at our center with follow-ups at 6, 12, 24, and 36 months. results were assessed by comparative analysis of preoperative and postoperative patient’s satisfaction (based on symptoms) along with retrograde urethrography, urethrosonography, and uroflowmetry. ten patients from the successful group underwent postoperative urethroscopic examination. results: counting good and fair results as successful (satisfied and not requiring revision urethroplasty), success (good + fair) rate was 95.3% at immediate postoperative and at 6 months. results reduced to 93% at 12 months, 90.7% at 24 months, and 89.5% at the end of 36 month follow-up. failure (poor results requiring revision urethroplasty) rate was 10.5% at the end of the 3 years of follow-up. conclusion: tunica albuginea urethroplasty runs over the concept of urethral groove and the ease of procedure with adequately satisfactory results provides decent outcomes. tunica albuginea urethroplasty gives advantage of local availability and achieving patent distensible urethra without any graft. urethroscopy of these subjects, by direct visualization shows the area of roof formed by tunica appears well covered with urothelium, further substantiating its ability to maintain patency and distensibility of the urethra. urol j. 2010;7:120-4. www.uj.unrc.ir keywords: urethral stricture, male urologic surgery, reconstructive surgical procedure, postoperative complications, recurrence, treatment outcome department of surgery, m.g.m medical college, m.y.h group of hospitals, indore, madhya pradesh, india, 452001 corresponding author: raj k. mathur, md department of surgery, m.y. hospital and m.g.m medical college, indore, madhya pradesh, india, 452001 tel: + 91 731 270 0374 e-mail: rkmmyh60@yahoo.com received may 2009 accepted november 2009 introduction panurethral stricture is the hardest nut to crack among all strictures, as patients’ miseries cannot be overlooked and moreover when treated, results are not as good as one’s desire. infection being a part and parcel of panurethral strictures, causes severe spongiofibrosis and in worst cases lichen sclerosus et atrophicus which literally eats up the entire urethra, makes the task an uphill struggle for the urologist. as panurethral strictures are very long, the only treatment modality is substitution urethroplasty with a graft or flap. it is very important to harvest a longer graft which is not always possible, especially when healthy oral mucosa is not available due to the habit of tobacco chewing and many a times the penile skin is not available due to genital infections. we have evolved a simple and an effective alternative approach, tunica albuginea urethroplasty (tau), for treating long strictures. based on the concept of supraurethral or subcavernosal groove,(1) urethroplasty using tunica albuginea—mathur and sharma 121urology journal vol 7 no 2 spring 2010 the urethral continuity is maintained by the tunica albuginea of corpora cavernosa presents at the urethral groove, which is capable of providing patent distensible neourethra of its own without the need of any graft or flap.(2) materials and methods between july 1992 and september 2006, a total of 86 patients with panurethral strictures underwent single stage tau after pre-operative assessment on the basis of patient symptoms, contrast retrograde urethrography, urethrosonography, and uroflowmetry (possible only in patients not having suprapubic catheter at time of presentation). after urethral reconstruction, the perurethral catheter was left in situ for 6 weeks. patients were evaluated using retrograde urethrography, urethrosonography, uroflowmetry, and patient’s satisfaction, immediate postoperatively and at 6, 12, 24, and 36 months. results were assessed by comparing pre and postoperative variables and patient’s satisfaction (table 1) (figure 1). ten patients were chosen for postoperative urethroscopy to visualize the patent neourethra and to analyze how the tunica albuginea maintains the urethral continuity without any graft or flap. urethroscopy was also performed in 2 patients with poor results to enable us to assess the pathogenesis of restricture. operative procedure involved tau for anterior urethral strictures, in which edges of dorsal urethrotomy were sutured to the edges of the urethral groove.(3) hence, roof of the neourethra was formed by the tunica albuginea of the corpora cavernosa. in cases where prostato-membranous urethral distraction defect was also present, the strictured membranous urethra was completely excised and prostatic urethra was anastomosed to the bulbar urethra in a u shape with 3 stitches (at 3, 6 and 9 o’clock position), namely u-shaped prostatobulbar anastomosis (uspba).(4) results the mean age of the participants was 44 years (range, 18 to 60 years) and two-third of the patients belonged to young middle-aged group (20 to 45 years). traumatic followed by iatrogenic post catheterization strictures were the most common type of strictures (table 2). almost all of the panurethral strictures were either caused by inflammation or had inflammation as a co-existing factor. of 86 patients, 62 (72%) had a suprapubic good fair poor retrograde urethrography good caliber partial narrowing at stricture site persistent stricture urethro-sonography patent and distensible lumen patent lumen with decreased distensibility stricture present uroflowmetry qmax >20 ml/s qmax 15 to 20 ml/s qmax <15 ml/s patient’s satisfaction satisfactory voiding, no instrumentation needed satisfactory voiding, but required ≤ 1 dilatation per year not satisfied, not voiding or voiding with thin stream, needed multiple dilatations or repeat surgery table 1. postoperative result assessment criteria figure 1. pre-operation; multiple penile urethral strictures postoperation; wide patent urethra after tunica albuginea urethroplasty urethroplasty using tunica albuginea—mathur and sharma 122 urology journal vol 7 no 2 spring 2010 catheter in situ for complete urinary retention. seventy-five patients (87%) had some form of intervention (urethrotomy, dilatation, or urethroplasty) before referring to us. the mean length of the stricture was 12.5 cm (range, 8.0 to 16.5 cm). based on our standard criteria, results were divided as successful (good + fair; satisfied with no or minimal intervention, and not require revision urethroplasty) and failure (poor; requiring revision urethroplasty). immediate postoperatively and at 6 months follow-up, success rate was 95.3% (75 + 7 = 82), which reduced to 93.0% (74 + 6 = 80) at 12 months, 90.7% (72 + 6 = 78) at 24 months, and 89.5% (72 + 5 = 77) at the end of 36 month follow-up with overall failure rate of 10.5% after 36 months from the procedure (table 3). three patients with lichen sclerosus developed urethrocutaneous fistula. such patients ultimately required 2-stage urethroplasty for final correction of the stricture. ten patients from the successful group (6 good results and 4 fair results), who underwent urethroscopy, allowed us to visualize the neourethra formed by tunica albuginea of corpora cavernosa. it was observed that the roof of the neourethra formed by tunica albuginea of corpora cavernosa was smoothly covered by the re-grown urothelium along with a patent and distensible lumen. in the fair result group, there was a patent, distensible lumen, but the mucosa was rough at places. in some cases, there was a tendency of formation of some flimsy adhesions, which were broken with a single dilatation, leaving behind a rough mucosa. two poor result patients, on urethroscopy, displayed an initial patent neourethra, followed by gradual narrowing and ultimately ending at a distal collapsed lumen (figure 2). continued inflammation and excessive surrounding spongiofibrosis ultimately led to restricture formation. urethroscopic findings of good, fair, and poor results are summarized in table 4. discussion procedures like penile ‘q’ flap have been mentioned to provide longer substitution material; however, the procedure is extremely labor-intensive and is among the most difficult and tedious procedures in reconstructive urology. (5) understandably, other flap techniques are also not the easiest to master, because despite being technically very sound, if not done well, will ultimately result in poorer outcome.(6) on the contrary, buccal mucosa graft procedures, which have been very successful in medium-sized strictures, are not very feasible because of the length of stricture in this case.(7) reports suggest that even in dorsal onlay grafting, buccal mucosal and penile skin grafts have shown similar results, while both proving superior to flap techniques. therefore, it is not the type of graft rather than the site of graft which is finally responsible for the success of the procedure.(6) probably, it is the tunica albuginea present at the urethral groove which is ultimately responsible for maintaining the continuity of neourethra even if the graft is not taken up. hence, tunica albuginea is the best substitution material available in the nearest results 6 months 12 months 24 months 36 months good 75 (87.2%) 74 (86.0%) 72 (83.7%) 72 (83.7%) fair 07 (8.1%) 06 (7.0%) 06 (7.0%) 05 (5.8%) poor 04 (4.7%) 06 (7.0%) 08 (9.3%) 09 (10.5%) table 3. results of urethroplasty at different follow-up periods good fair poor urethroscopy wide patent distensible lumen, regular mucosa patent lumen with decreased distensibility, some mucosal irregularities distal obliterated lumen, not possible to negotiate scope further table 4. urethroscopic findings penile + bulbar penobulbar + membranous traumatic 36 18 iatrogenic 16 02 inflammatory 07 02 idiopathic 03 02 total [86] 62 24 table 2. site and etiology of stricture urethroplasty using tunica albuginea—mathur and sharma 123urology journal vol 7 no 2 spring 2010 vicinity of the urethra.(8) tunica albuginea urethroplasty gives certain advantages in the prospect of urethroplasty. procedure is simple and less time consuming, as no graft or flap is harvested or applied. tunica albuginea is the locally available connective tissue which is very durable, also very distensible. procedure is possible in subjects where healthy buccal mucosa is not available due to habit of tobacco chewing, also in very long strictures where very long substitutes are difficult to harvest. u-shaped prostatobulbar anastomosis is done for panurethral strictures with prostato-membranous distraction defect along with tau for penile and bulbar stricture part. u-shaped prostatobulbar anastomosis is advantageous as it avoids ring anastomosis (only 3 stitches are taken); hence, avoiding risk of ring stricture formation, which has been found to be the cause of restricture after urethroplasty in some studies.(9) also, it figure 2. (a) good result; showing patent distensible roof of neourethra formed by tunica albuginea of corpora cavernosa with smooth mucosal lining (b) fair result; showing patent lumen with some mucosal irregularities (c) poor result; showing diffused fibrotic narrowing with collapsed lumen (d) poor result; showing circumferential scarring proximal to wide neourethra urethroplasty using tunica albuginea—mathur and sharma 124 urology journal vol 7 no 2 spring 2010 maintains the blood supply of the urethra by avoiding round the clock stitches, because near the apex of the prostate the neurovascular bundle divides into two parts: a larger anterior part and a smaller posterior part. the anterior part crosses the membranous urethra, then the bulb of the penis at the 1 and 11 o’clock positions, and finally enters the corpora cavernosa. the posterior part crosses the membranous urethra more posteriorly to enter the bulb of the penis. (10) thus, avoiding stitches at dorsal aspect of anastomosis, ie, from 10 to 2 o’clock position, there are less risk of compromise of blood supply to the urethra and thereafter, ischemia and fibrosis, and most importantly, less chances of impotence postoperatively after uspba.(4) as there has already been a lot of fibrosis and precarious blood in complex strictures, this technique gives a wider anastomosis and avoids compromise of already precarious vascular supply in complex strictures. the fiber composition of tunica albuginea of corpora cavernosa and spongiosum are the same in histology, composing of inner circular layer from which radiates intercavernosal and spongiosal pillars to augment septum to provide essential support avoiding excess fibrosis, thereby abating stricture. it has been further confirmed by urethroscopy that tunica albuginea and perineal membrane can maintain urethral patency and distensibility, and area of roof where no graft is placed appears to be covered with urothelium in most of the subjects. tunica albuginea is itself sufficient to allow regrowth of urothelium and give patent distensible lumen. however, ultimate proof of urothelium covering over tunica will be the urethroscopic biopsy, wherein it is not wise to traumatize the urethra of a good result satisfied patient just for the sake of histological evidence of success of the procedure. treatment modalities for urethral strictures are continuously evolving day by day with ongoing research. our prior 15-year experience of tau and uspba treating urethral stricture has been satisfactory for strictures of various etiology and site, proving its value in curing most difficult panurethral strictures. conclusion we concluded that this approach is, hence, surely a useful, easy, and effective tool in the armamentarium of urologists, especially for patients who want to avoid cosmetic deformities caused by penile skin grafts and not having healthy oral mucosa owing to the habit of tobacco chewing. conflict of interest none declared. references 1. monseur j. [a new procedure for urethroplasty for urethral stricture: reconstruction of the urethral canal by means of suburethral strips and the subcavernous groove]. j urol nephrol (paris). 1969;75:201-9. 2. kumar mr, himanshu a, sudarshan o. technique of anterior urethroplasty using the tunica albuginea of the corpora cavernosa. asian j surg. 2008;31:134-9. 3. mathur rk, himanshu a, sudarshan o. technique of anterior urethra urethroplasty using tunica albuginea of corpora cavernosa. int j urol. 2007;14:209-13. 4. mathur rk, aggarwal h, odiya s, lubana ps. u-shaped prostatobulbar anastomosis for urethral injury after pelvic trauma. anz j surg. 2008;78:605-9. 5. morey af, tran lk, zinman lm. q-flap reconstruction of panurethral strictures. bju int. 2000;86:1039-42. 6. barbagli g, morgia g, lazzeri m. retrospective outcome analysis of one-stage penile urethroplasty using a flap or graft in a homogeneous series of patients. bju int. 2008;102:853-60. 7. shah sa, ranka p, choudhary r, dhawan m, vishnagara m. buccal mucosal dorsal substitution urethroplasty in recurrent anterior urethral stricture. indian j surg. 2003;19:152. 8. iselin ce, webster gd. dorsal onlay graft urethroplasty for repair of bulbar urethral stricture. j urol. 1999;161:815-8. 9. barbagli g, guazzoni g, palminteri e, lazzeri m. anastomotic fibrous ring as cause of stricture recurrence after bulbar onlay graft urethroplasty. j urol. 2006;176:614-9; discussion 9. 10. jordan gh, schlossberg sm. surgery of the penis and urethra. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 1. 9 ed: philadelphia: saunders; 2007:1023-97. preoperative urine analysis is an effective tool to predict fever after miniaturized percutaneous nephrolithotomy on large renal stones ze hong lu1, tsung yen lin1, ho shiang huang1,2, chan jung liu1* purpose: to investigate the preoperative and intraoperative potential risk factors associated with miniaturized percutaneous nephrolithotomy (mpcnl) fever in the treatment of patients with large renal stones. materials and methods: all patients with renal stones larger than 2.5 cm, who had undergone mpcnl, were included in the period between april 2018 and september 2019. logistic regression analyses were performed to identify clinical variables associated with post-operative fever (>38°c). results: a total of 53 patients were enrolled for whom the median maximal stone length was 3.08 cm. 24 (45%) patients had a fever after mpcnl. significantly more patients with urine wbc ≥ 27(/hpf) had a fever after surgery (p = 0.004). no significant between-group differences in urine cultures were found for the fever and non-fever groups (p = 0.094). stepwise and multivariable logistic regression analyses all revealed that urine wbc ≥ 27(/ hpf) is the only risk factor for developing post-mpcnl fever. based on the highest body temperature, all of the patients were assigned into no fever, mild fever (37.5 ≤ temp < 38.0), and fever groups, and an ordinal logistic regression analysis still supported the premise that the result of urine analysis is strongly associated with post-mpcnl fever. conclusion: large renal stones are challenging to treat and associated with severe complications. approximately 45% of large renal stone patients treated via mpcnl developed a fever. urine wbc can easily and directly predict the risk of fever. keywords: renal stone; urolithiasis; percutaneous nephrolithotomy; urine analysis; urinary tract infection; fever; sepsis introduction percutaneous nephrolithotomy (pcnl) is the stand-ard of care for the treatment of large renal stones, defined as larger than 2cm(1). although pcnl is considered to be the most effective therapy, it is definitely associated with high risks of complication. some publications have even reported complication rates up to 83% following pcnl(2). high complication rates contributed to less than 4% nonendourologists performing this surgery(3). pcnl carries two major concerns for complications. bleeding accounts for most of the pcnl complications, and the incidence of blood transfusion has been reported from 5.5% to 18%(4,5). given the advancement in surgical techniques and equipment, miniaturized pcnl (mpcnl) was developed in an effort to reduce bleeding related to standard pcnl. according to uaa (urology association of asia) guidelines(6), mpcnl is recommended for renal stones size < 3.03.5cm with good surgical outcome and less morbidity. however, relatively small tract size restricted the efficacy of stone removal and therefore increased the risks of post operation fever(7). in consideration of infectious complications, few studies have used mpcnl to treat large renal stones, which was defined as “partial or complete renal stones filling the renal pelvis and one or more calices with diameter of at least 3 cm”(1,8). even utilizing pcnl on large renal stones, experienced urologists didn’t have universal consensus on preoperative antibiotics strategies to prevent infection(8). in this retrospective study, we aimed to investigate the preoperative and intraoperative potential risk factors associated with post-mpcnl fever in the treatment of patients with large renal stones. material and methods study design and population we retrospectively recruited reviewed patients from a single tertiary referral medical center between april 2018 and september 2019. the patients who fulfilled the definition of large renal stones and underwent mpcnl were included(8). the reviewed data included patient demographics, body weight, and height on the admission day, and systemic diseases on medical records (e.g., diabetes mellitus (dm), hypertension (htn), and cardiovascular disease). preoperative laboratory investigations included urine analysis, midstream urine culture, complete blood count, renal, liver function tests, and electrolytes. differentiation of white blood cells was also done on preoperative survey. the plate1department of urology, national cheng kung university hospital, college of medicine, national cheng kung university, tainan 70403, taiwan. 2department of urology, college of medicine, national cheng kung university, tainan 70101, taiwan. *correspondence: department of urology, national cheng kung university hospital, college of medicine, national cheng kung university, tainan 70403, taiwan.dragon2043@hotmail.com. received september 2020 & accepted september 2021 endourology and stone disease urology journal/vol 18 no. 6/ november-december 2021/ pp. 600-607. [doi: 10.22037/uj.v18i.6463] let-to-lymphocyte ratio (plr) and neutrophil-to-lymphocyte ratio (nlr) were defined as the ratios of the absolute platelet, lymphocyte, and neutrophil counts, respectively. at the last outpatient clinics visit before surgery, midstream urine culture was collected from all the patients. all the patients were admitted one day before surgery. if the urine culture was negative, prophylactic intravenous (iv) broad-spectrum antibiotic was given after admission based on the recommendations from american urology association guideline(9). in our hospital, cefuroxime is given as prophylactic antibiotics prior to operation in a negative urine culture patient. the patients who had positive urine culture were given with appropriate oral form or iv form antibiotics for 7 days according to sensitivity tests. all the patients had at least one abdominal computed tomography (ct) before surgery. the maximal stone length was calculated based on ct images by the operator, and in cases of multiple stones, the stone length was calculated by adding the length of the longest axis of each stone. the mean attenuation levels in hounsfield units (hus) were measured by ct. we used the biggest circular diameters to cover the stone and calculated the average hu values. stone clearance was assessed intraoperatively by direct renoscopy and postoperatively by radiography images. all patients underwent a plain abdominal film one month after mpcnl to see any residual stones. stone free was defined as either complete clearance or clearance with insignificant residual fragments less than 4 mm in size on the follow-up imaging(10). operation details all the operations were performed by the same experienced surgeon at our hospital using a 1stage procedure. after induction of general anesthesia, a ureter occlusive catheter was retrogradely placed to the target kidney by cystoscopy. percutaneous access was performed using an 18-gauge needle under combined echo and fluoroscopic assistance. after successful access, a guidewire was inserted into the collecting system and table 1. demographics and baseline characteristics of the patients. non fever (n=29) n (%) fever (n=24) n (%) p value a age (years) median (iqr) 62.00 (55.00, 65.00) 63.00 (55.00, 66.50) 0.642 gender male 19 (65.52) 11 (45.83) 0.246 female 10 (34.48) 13 (54.17) bmi (kg/m2) < 25.0 13 (44.83) 11 (45.83) 1.000 ≥ 25.0 16 (55.17) 13 (54.17) median (iqr) 25.60 (22.70, 29.99) 25.05 (22.95, 26.98) 0.655 stone size < 30 12 (41.38) 12 (50.00) 0.726 ≥ 30 17 (58.62) 12 (50.00) median (iqr) 30.84 (25.58, 38.09) 30.73 (23.60, 42.52) 0.964 operation time < 120 9 (31.03) 3 (12.50) 0.202 ≥ 120 20 (68.97) 21 (87.50) median (iqr) 130.00 (110.00, 180.00) 120.00 (175.00, 180.00) 0.123 urine wbc(/hpf) < 27 20 (68.97) 6 (25.00) 0.004 ≥ 27 9 (31.03) 18 (75.00) median (iqr) 19.00 (6.00, 33.00) 87.00 (22.50, 278.00) 0.007 wbc < 10000 28 (96.55) 20 (83.33) 0.164 ≥ 10000 1 (3.45) 4 (16.67) median (iqr) 6500.00 (5100.00, 7600.00) 7250.00 (6250.00, 7950.00) 0.133 gfr < 90 13 (44.83) 12 (50.00) 0.921 ≥ 90 16 (55.17) 12 (50.00) median (iqr) 96.14 (72.35, 107.66) 87.43 (63.45, 115.39) 0.480 plr <110 11 (37.93) 7 (29.17) 0.705 ≥ 110 18 (62.07) 17 (70.83) median (iqr) 125.83 (92.05, 173.27) 157.37 (106.57, 226.79) 0.085 nlr <5 28 (96.55) 18 (75.00) 0.038 ≥5 1 (3.45) 6 (25.00) median (iqr) 1.91 (1.43, 2.68) 2.01 (1.34, 4.62) 0.416 hydronephrosis no 13 (44.83) 7 (29.17) 0.376 yes 16 (55.17) 17 (70.83) hu 900 no 7 (24.14) 6 (25.00) 1.000 yes 22 (75.86) 18 (75.00) diabetes mellitus no 25 (86.21) 20 (83.33) 1.000 yes 4 (13.79) 4 (16.67) uc no 25 (86.21) 15 (62.50) 0.094 yes 4 (13.79) 9 (37.50) achi-square test or fisher’s exact test for categorical variables / mann-whitney u test for continuous variables. preoperative urine wbc predicts post-pcnl fever lu et al. vol 18 no 6 november-december 2021 601 endourology and stones diseases 602 the tract was dilated using balloon dilators until an 18 amplatz sheath can be placed. mini-nephroscopy (12 fr richard wolf) was inserted into the amplatz sheath and stones were disintegrated using holmium laser. holmium:yttrium-aluminum-garnet (ho:yag) laser 60 w is generated by sphinx 60(lisa laser, pleasanton, ca, usa) with setting of energy from 0.5-1.5j and frequency from 6-20 hz for fragmentation(11). the stone fragments were removed with forceps. after the completion of stone extraction, a 6 fr double j catheter was inserted. a 14f nephrostomy tube was placed at the end of each surgery. the operative time was calculated from the insertion of the cystoscopy to the completion of nephrostomy tube placement. fever definition and management ear temperatures were recorded every 2 hours after surgery on all patients. fever was defined as body temperature > 38 °c. for every patient, the highest body temperatures were recorded. the normal range of ear temperature is between 35.7 to 37.5 degree(12). based on the highest body temperature, we further separated non-fever group into no fever and mild fever group (37.5 ≤ temp < 38.0). all fever patients are treated with iv form antibiotics which are adjusted by urine culture results. the choices of definite antibiotics in fever group are listed in supplementary data. the treatment duration is 7 to 14 days with oral or iv form antibiotics according to european association of urology (eau) infections guidelines(13). if there are no available culture results, antibiotics is given with second or third generation of cephalosporin by eau guidelines recommendation(13). crude or p-value adjusted or a p-value adjusted or b p-value adjusted or c p-value (95 % ci) (95 % ci) (95 % ci) (95 % ci) age (years) 1.02 (0.97-1.08) 0.412 age (per 10 years) 1.24 (0.74-2.06) 0.412 gender male ref. female 2.25 (0.74-6.81) 0.153 bmi (kg/m2) 0.93 (0.80-1.08) 0.334 bmi <25.0 ref. ≥25.0 0.96 (0.32-2.85) 0.942 stone size 1.01 (0.96-1.06) 0.723 stone size <30 ref. ≥30 0.71 (0.24-2.10) 0.531 operation time 1.01 (0.99-1.02) 0.217 operation time < 120 ref. ref. ≥ 120 3.15 (0.74-13.34) 0.119 5.30 (1.02-27.55) 0.047 urine wbc 1.00 (0.99-1.00) 0.860 urine wbc (/hpf) < 27 ref. ref. ref. ref. ≥ 27 6.67 (1.98-22.44) 0.002 5.48 (1.57-19.10) 0.008 5.08 (1.39-18.60) 0.014 8.86 (2.35-33.42) 0.001 wbc 1.00 (1.00-1.00) 0.094 wbc < 10000 ref. ≥ 10000 5.60 (0.58-53.94) 0.136 gfr 0.99 (0.98-1.01) 0.406 gfr < 90 ref. ≥ 90 0.81 (0.28-2.40) 0.707 plr 1.01 (0.99-1.02) 0.121 plr < 110 ref. ≥ 110 1.48 (0.47-4.72) 0.503 nlr 1.20 (0.87-1.66) 0.261 nlr < 5 ref. ref. ref. ≥ 5 9.33 (1.04-84.02) 0.046 5.82 (0.58-58.46) 0.135 5.22 (0.48-56.94) 0.175 hydronephrosis no ref. yes 1.97 (0.63-6.20) 0.245 hu 900 no ref. yes 0.95 (0.27-3.35) 0.942 diabetes mellitus no ref. yes 1.25 (0.28-5.63) 0.771 uc no ref. ref. yes 3.75 (0.98-14.33) 0.053 1.52 (0.27-8.58) 0.633 table 2. results of operations. a multivariable logistic regression analysis of variables (p-value < 0.05 in univariate logistic regression analysis). aic: 65.61 b multivariable logistic regression analysis of variables (p-value < 0.1 in univariate logistic regression analysis). aic: 67.45 c stepwise logistic regression for variables entry in model p < 0.1 p < 0.05 & stay in model p < 0.1 p < 0.05. aic: 63.97 preoperative urine wbc predicts post-pcnl fever lu et al. statistical analysis all categorical variables were analyzed by chi-square test or fisher’s exact test. the mann-whitney u test was used to compare continuous variables. for the comparison of three groups, kruskal-wallis tests were used to analyze continuous variables. multiple logistic regression analysis was used to determine any risk factors associated with fever. the variables were selected if their p values were less than 0.10 in univariate logistic regression analysis. for the comparison of three groups, ordinal logistic regression analysis was conducted. all analyses were conducted using spss statistical software (versions 16; spss inc., chicago, ca, usa). two-tailed p < 0.05 was considered statistically significant. results a total of 53 patients were enrolled and 56.6% of them were male. the median maximal stone length was 3.08 cm (95% ci=2.98 to 3.57). most of the patients were above 60 years old (58.5%). the mean age was 59.91 years old (sd=10.99). the overall stone-free rate was 67.9 % (36 of 53 patients). 45.3% (24 of 53 patients) patients had fever after the operation. we compared the baseline characteristics between the fever and the non-fever groups (table 1). the demographic characteristics were generally similar in each group. only urine wbc was significantly different between the two groups. among all, only 9 patients didn’t have pyuria before surgery. significantly more patients with urine wbc ≥ 27 had fever after surgery (p = 0.004). no significant difference in urine culture was found between the two groups (p = 0.094). the logistic regression analysis (table 2) indicated that urine wbc ≥ 27(/hpf) is the risk factor for developing post-mpcnl fever. the association between urine culture and post-mpcnl fe non fever (n=21) n (%) mild fever (n=8) n (%) fever (n=24) n (%) p valuea age (years) median (iqr) 58.00 (52.00, 65.00) 62.50 (57.50, 66.50) 63.00 (55.00, 66.50) 0.661 gender male 15 (71.43) 4 (50.00) 11 (45.83) 0.232 female 6 (28.57) 4 (50.00) 13 (54.17) bmi (kg/m2) < 25.0 8 (38.10) 5 (62.50) 11 (45.83) 0.570 ≥ 25.0 13 (61.90) 3 (37.50) 13 (54.17) median (iqr) 25.90 (23.92, 30.08) 23.65 (22.62, 26.40) 25.05 (22.95, 26.98) 0.512 stone size < 30 11 (52.38) 1 (12.50) 12 (50.00) 0.156 ≥ 30 10 (47.62) 7 (87.50) 12 (50.00) median (iqr) 27.77 (23.50, 36.93) 36.14 (31.65, 42.28) 30.73 (23.60, 42.52) 0.160 operation time < 120 7 (33.33) 2 (25.00) 3 (12.50) 0.246 ≥ 120 14 (66.67) 6 (75.00) 21 (87.50) median (iqr) 120.00 (110.00, 155.00) 160.00 (115.00, 240.00) 175.00 (120.00, 180.00) 0.130 urine wbc (/hpf) < 27 15 (71.43) 5 (62.50) 6 (25.00) 0.006 ≥ 27 6 (28.57) 3 (37.50) 18 (75.00) median (iqr) 15.00 (5.00, 33.00) 24.50 (9.00, 101.50) 87.00 (22.50, 278.00) 0.016 wbc < 10000 20 (95.24) 8 (100.00) 20 (83.33) 0.355 ≥ 10000 1 (4.76) 0 (0.00) 4 (16.67) median (iqr) 6600.00 (4800.00, 8500.00) 6000.00 (5450.00, 6650.00) 7250.00 (6250.00, 7950.00) 0.188 gfr < 90 11 (52.38) 2 (25.00) 12 (50.00) 0.430 ≥ 90 10 (47.62) 6 (75.00) 12 (50.00) median (iqr) 88.56 (72.35, 110.80) 100.32 (71.58, 105.49) 87.43 (63.45, 115.39) 0.671 plr < 110 8 (38.10) 3 (37.50) 7 (29.17) 0.798 ≥ 110 13 (61.90) 5 (62.50) 17 (70.83) median (iqr) 121.22 (89.56, 165.01) 145.98 (94.22, 180.08) 157.37 (106.57, 226.79) 0.188 nlr < 5 20 (95.24) 8 (100.00) 18 (75.00) 0.091 ≥ 5 1 (4.76) 0 (0.00) 6 (25.00) median (iqr) 1.78 (1.36, 2.50) 2.31 (1.69, 3.19) 2.01 (1.34, 4.62) 0.519 hydronephrosis no 9 (42.86) 4 (50.00) 7 (29.17) 0.440 yes 12 (57.14) 4 (50.00) 17 (70.83) hu 900 no 3 (14.29) 4 (50.00) 6 (25.00) 0.136 yes 8 (85.71) 4 (50.00) 18 (75.00) diabetes mellitus no 18 (85.71) 7 (87.50) 20 (83.33) 1.000 yes 3 (14.29) 1 (12.50) 4 (16.67) uc no 19 (90.48) 6 (75.00) 15 (62.50) 0.094 yes 2 (9.52) 2 (25.00) 9 (37.50) table 3. difference in clinical features and laboratory findings of mpcnl patients subsequently happening fever (temp ≥ 38.0), mild fever (37.5 ≤ temp < 38.0) or not (temp < 37.5). a chi-square test or fisher’s exact test for categorical variables / kruskal-wallis test for continuous variables. preoperative urine wbc predicts post-pcnl fever lu et al. vol 18 no 6 november-december 2021 603 endourology and stones diseases 604 ver revealed a marginal trend toward significance before adjustment (p = 0.053). however, the significance blunted after adjustment (p = 0.369). in ordinal logistic regression analysis (table 4), urine culture and nlr revealed significance in univariate analysis, but there was no statistical significance in multivariable logistic regression analysis. stepwise and multivariable logistic regression analysis also suggested that urine wbc ≥ 27(/hpf) is still the risk factor for developing post-mpcnl fever. according to akaike information criterion (aic) which is listed in table 2 and table 4, stepwise logistic regression is the best-fit model. based on the highest body temperature, all the patients were assigned to no fever, mild fever, and fever groups (table 3). only 8 patients were in the mild fever group. most clinical characteristics were not significantly different. only urine wbc was significantly different between the three groups. we used ordinal logistic regression analysis to find any risk factors for developing fever (table 4). only urine wbc ≥ 27(/hpf) could predict whether the patients had fever after mpcnl. the area under the curve for wbc ≥ 27 (/hpf) was 0.72 (figure 1). using the cutoff of wbc ≥ 27 (/hpf), the sensitivity was 75% and specificity 69%, with an odds ratio of 6.67 (1.98-22.44; p value = 0.002). the bacteria type of urine culture and stone composition of those patients are listed in supplementary table. gram-negative bacteria, such as proteus mirabilis, klebsiella pneumoniae and escherichia coli were the most common pathogens from urine culture. in both fever and non-fever groups, calcium oxalate stone was the leading composition from stone analysis. in fever group, average fever lasting days was 1.67 days, only 4 patients had fever lasting more than two days including the operation day, and the onset day of fever was on post-operative day (pod) 0 and 1 in most crude or (95 % ci) p-value adjusted or a (95 % ci) p-value adjusted or b (95 % ci) p-value adjusted or c (95 % ci) p-value age (years) 1.03 (0.98-1.08) 0.236 age (per 10 years) 1.34 (0.83-2.17) 0.236 gender male ref. ref. female 2.48 (0.86-7.11) 0.091 1.83 (0.54-6.13) 0.331 bmi (kg/m2) 0.91 (0.79-1.05) 0.210 bmi < 25.0 ref. ≥ 25.0 1.28 (0.46-3.55) 0.639 stone size 1.02 (0.98-1.08) 0.347 stone size < 30 ref. ≥ 30 1.04 (0.37-2.88) 0.944 operation time 1.01 (0.99-1.02) 0.116 operation time < 120 ref. ref. ≥ 120 2.86 (0.81-10.13) 0.104 5.29 (1.24-22.57) 0.025 urine wbc 1.00 (0.99-1.00) 0.611 urine wbc (/hpf) < 27 ref. ref. ref. ref. ≥ 27 5.70 (1.88-17.25) 0.002 4.16 (1.29-13.36) 0.017 3.83 (1.18-12.48) 0.026 8.26 (2.43-28.02) 0.001 wbc 1.00 (1.00-1.00) 0.150 wbc < 10000 ref. ≥ 10000 4.93 (0.56-43.54) 0.152 gfr 1.00 (0.98-1.01) 0.542 gfr < 90 ref. ≥ 90 1.05 (0.38-2.91) 0.921 plr 1.01 (0.99-1.02) 0.104 plr <110 ref. ≥110 1.42 (0.48-4.16) 0.525 nlr 1.22 (0.89-1.69) 0.217 nlr <5 ref. ref. ref. ≥5 8.43 (1.00-71.13) 0.050 3.78 (0.41-34.89) 0.241 4.59 (0.47-44.82) 0.190 hydronephrosis no ref. yes 1.68 (0.59-4.82) 0.336 hu 900 no ref. yes 0.66 (0.20-2.17) 0.492 diabetes mellitus no ref. yes 1.19 (0.29-4.95) 0.813 uc no ref. ref. ref. yes 4.03 (1.08-15.06) 0.038 1.81 (0.40-8.20) 0.439 1.40 (0.28-6.87) 0.681 table 4. ordinal logistic regression analysis of risk factors for fever among mpcnl patients. a multivariable logistic regression analysis of variables (p-value < 0.05 in univariate logistic regression analysis). aic: 103.91 b multivariable logistic regression analysis of variables (p-value < 0.10 in univariate logistic regression analysis). aic: 104.98 c stepwise logistic regression for variables entry in model p < 0.10 p < 0.05 & stay in model p < 0.10 p < 0.05. aic: 99.18 preoperative urine wbc predicts post-pcnl fever lu et al. cases. the details fever pattern were listed in supplementary table. discussion in the current study, we analyzed the risk factors for developing fever after mpcnl treatment on large renal stones. numerous studies have studied the contributing factors for infectious complications after pcnl, but few aimed at mpcnl. lai et al. had conducted a meta-analysis on 2018 and a total of 24 studies were recruited, of which 12 were prospective and 12 were retrospective(14). in all the prospective studies, preoperative urine culture, intraoperative renal pelvic urine culture, and stone culture have been associated with fever after pcnl. only preoperative urine culture and stone culture were found to be significantly associated with infection of all the retrospective studies. however, stone culture is not a common preoperative exam in all medical facilities. besides, the exam should rely on urinary tract stone specimens, which are usually taken from surgery. therefore, it is unlikely to have results soon after surgery. taken together, although the stone culture appears to be the strongest risk factor on literature, stone culture is only available after pcnl and, therefore, cannot be used to prevent infectious complications. urine cultures, including preoperative midstream urine and intraoperative renal pelvis urine, are also associated with post pcnl infectious complications(15,16). even some studies found that intraoperative renal pelvis urine was more predictable than preoperative urine culture (17,18). the finding was offset by the meta-analysis results(14). besides, intraoperative renal pelvis urine culture was performed during operation and the culture may take 5 days to have the results, which indicates that intraoperative renal pelvis urine culture was not a practical tool for predicting post-pcnl fever. preoperative midstream urine culture is a common practice to detect latent bacteria in the urinary tract in most facilities. however, the accuracy of midstream urine culture for predicting infectious complications after pcnl is always questioned. a prospective study revealed near half positive stone culture patients had negative preoperative midstream urine culture. consequently, the author concluded that although preoperative midstream urine culture should be collected, neither a positive nor a negative midstream urine culture influences the risk of postoperative systemic inflammatory response syndrome (sirs). in the current study, we only had the results of midstream urine culture rather than stone culture or renal pelvis urine culture. no matter in univariable or multivariable analysis, the result of midstream urine culture can’t be the predictor to distinguish whether the patient will have fever after mpcnl or not. in contrast, the result of urine analysis can strongly predict post mpcnl fever even by the use of stepwise logistic regression. in analysis of mild fever and fever groups, urine wbc ≥ 27 was still strongly associated with post-surgery fever using ordinal logistic regression. all the solid evidence above highly suggested that urine wbc alone can reliably predict the risk of post-mpcnl fever. the first introduction of the technique of mpcnl was in 1997, which was using an 11~15fr sheath on pediatric stone patients by jackman et al. and helal et al(19,20). afterward, mpcnl is generally accepted as tract sizes between 14 fr and 22 fr, although a clear definition remains controversial(21). echo, fluoroscopy or combined guided tract creation are applied in mpcnl currently(22). in our hospital protocol, we combine ultrasound and fluoroscopy guidance to create tract. the first step is ultrasound guided needle placement, and then position confirmation by fluoroscopy. ultrasonography guided calyx access has been proved feasibility, but some pitfalls have been found such as minimal hydronephrosis, superior pole approach or high lying kidneys(23) with figure 1. roc curve of urine wbc on post-mpcnl fever. auc, area under curve. preoperative urine wbc predicts post-pcnl fever lu et al. vol 18 no 6 november-december 2021 605 endourology and stones diseases 606 bare ultrasound guidance. a prospective and randomized trial(22) showed combined ultrasonographic and fluoroscopic guidance for percutaneous renal access in mini-percutaneous nephrolithotomy is safe and effective especially in complex renal stone. ultrasonic and pneumatic lithotripsy devices have showed efficacy and safety in pcnl(24) due to narrow working channel of nephroscopes in mpcnl, holmium laser (sphinx 60, lisa laser, pleasanton, ca, usa) is applied in our institute. however, small diameter dual energy lithotripsy has showed comparable stone clearing in mpcnl(25). it needs further investigations and large size studies in the future. most available evidence support the role of mpcnl is more suitable for smaller rather than larger renal stones >20 mm(21). the main reasons for the limitations are increased operation time(26) and concerning infectious complications. in the literature, fever occurred in 21%39.8% of patients who underwent pcnl, but small number of patients progressed to sepsis or even mortality(27). during any endoscopic surgeries, irrigation is always requested to maintain a clear visual field. high intrapelvic pressure (ipp) caused by irrigation can lead to pyelovenous and pyelolymphatic backflow, which will transmit bacteria and endotoxin into the systemic circulation and infectious complications develop(28). comparing with standard pcnl, miniaturized percutaneous sheath restricted efficient circulation of irrigation fluid and then ipp increased during mpcnl (29). theoretically, mpcnl could be prone to have post-surgery fever, and a study confirmed this hypothesis with the result of nearly two times higher incidence of fever after mpcnl compared with the standard(7). in our results, near half of the patients had fever episodes after mpcnl, but only 4 patients (7.5%) persisted fever more than two days after the operation (including the operation day). none of them had septic shock or sepsis. the findings can be explained by the hypothesis mentioned above that transient peak ipp leads to fever but is soon ameliorated under an adequate control of outflow with a jj catheter insertion or nephrostomy tube placement. there are limited studies assessing mpcnl on large renal stones until very recently. kandemir et al. and güler et al. all introduced the outcomes of mpnl in the treatment of renal stones ≥ 3cm(30,31). the stone free rate (sfr) reported in two studies were 75.0% and 76.5%, respectively. in discordance with the literature, we have found an obvious lower sfr (67.9%). the reasons for the different results obtained in the present study might be that 8 of them (15.0%) were cases with complete staghorn stones. accumulative evidence suggests that staghorn stones are the most difficult to achieve stone clearance. besides, the number of cases enrolled in the present cohort is relatively small. the difference in a few cases could easily affect the proportion of the outcome. there are some limitations to this study. first, the study was based on retrospective patient data from a single center. large-scale and prospective design studies will be needed for further analysis. second, we did not discuss the relationship between fever and residual stone. besides, the stone sizes in the current study ranged too wide, which would limit the specificity of the analysis. in contrast, it is worthy to mention that this is the first study to analyze the possible factors contributing to fever after mpcnl in the treatment of kidney stones larger than 3cm. our investigation is also the first one to use the peak body temperature to ordinally evaluate post-mpcnl infectious complications rather than fever or not. the ordinal logistic regression analysis definitely strengthens our findings. conclusions in patients with large renal stones, mpcnl is associated with adequate stone clearance rate but high incidence of post-surgery fever. urine wbc alone rather than urine culture can reliably predict the risk of post-mpcnl fever. using the cutoff of wbc ≥ 27, the predictive sensitivity was 75% and specificity was 69%. acknowledgements we are grateful to associate professor sheng-hsiang lin for providing the statistical consulting services from the biostatistics consulting center, clinical medicine research center, national cheng kung university hospital. this study was funded by the national cheng kung university hospital (nckuh-11002035). conflicts of interest the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/28 references 1. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016;69:475-82. 2. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899-906; discussion 3. oberlin dt, flum as, bachrach l, matulewicz rs, flury sc. contemporary surgical trends in the management of upper tract calculi. j urol. 2015;193:880-4. 4. liatsikos en, kallidonis p, stolzenburg ju, et al. percutaneous management of staghorn calculi in horseshoe kidneys: a multi-institutional experience. j endourol. 2010;24:531-6. 5. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015;67:125-37. 6. taguchi k, cho sy, ng ac, et al. the urological association of asia clinical guideline for urinary stone disease. int j of urol. 2019;26:688-709. 7. wu c, hua lx, zhang jz, zhou xr, zhong w, ni hd. comparison of renal pelvic pressure and postoperative fever incidence between standardand mini-tract percutaneous nephrolithotomy. kaohsiung j med sci. 2017;33:36-43. 8. schoenthaler m, hein s, seitz c, et al. the stone surgeon in the mirror: how are germanspeaking urologists treating large renal stones preoperative urine wbc predicts post-pcnl fever lu et al. vol 18 no 6 november-december 2021 607 today? world j urol. 2018;36:467-73. 9. lightner dj, wymer k, sanchez j, kavoussi l. best practice statement on urologic procedures and antimicrobial prophylaxis. j urol. 2019101097ju0000000000000509. 10. resorlu b, oguz u, resorlu eb, oztuna d, unsal a. the impact of pelvicaliceal anatomy on the success of retrograde intrarenal surgery in patients with lower pole renal stones. urology. 2012;79:61-6. 11. ganesamoni r, sabnis rb, mishra s, et al. prospective randomized controlled trial comparing laser lithotripsy with pneumatic lithotripsy in miniperc for renal calculi. j endourol. 2013;27:1444-9. 12. geneva, ii, cuzzo b, fazili t, javaid w. normal body temperature: a systematic review. open forum infect dis. 2019;6:ofz032. 13. bonkat g, pickard r, bartoletti r, et al. eau guidelines on urological infections. eur urol. 201722-6. 14. lai ws, assimos d. factors associated with postoperative infection after percutaneous nephrolithotomy. rev urol. 2018;20:7-11. 15. mariappan p, smith g, bariol sv, moussa sa, tolley da. stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study. j urol. 2005;173:1610-4. 16. korets r, graversen ja, kates m, mues ac, gupta m. post-percutaneous nephrolithotomy systemic inflammatory response: a prospective analysis of preoperative urine, renal pelvic urine and stone cultures. j urol. 2011;186:1899-903. 17. dogan hs, sahin a, cetinkaya y, akdogan b, ozden e, kendi s. antibiotic prophylaxis in percutaneous nephrolithotomy: prospective study in 81 patients. j endourol. 2002;16:64953. 18. margel d, ehrlich y, brown n, lask d, livne pm, lifshitz da. clinical implication of routine stone culture in percutaneous nephrolithotomy--a prospective study. urology. 2006;67:26-9. 19. jackman sv, docimo sg, cadeddu ja, bishoff jt, kavoussi lr, jarrett tw. the "mini-perc" technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol. 1998;16:371-4. 20. helal m, black t, lockhart j, figueroa te. the hickman peel-away sheath: alternative for pediatric percutaneous nephrolithotomy. j endourol. 1997;11:171-2. 21. ruhayel y, tepeler a, dabestani s, et al. tract sizes in miniaturized percutaneous nephrolithotomy: a systematic review from the european association of urology urolithiasis guidelines panel. eur urol. 2017;72:220-35. 22. zhu w, li j, yuan j, et al. a prospective and randomised trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini‐percutaneous nephrolithotomy. bju int. 2017;119:612-8. 23. basiri a, kashi ah, zeinali m, nasiri m, sarhangnejad r, valipour r. ultrasoundguided access during percutaneous nephrolithotomy: entering desired calyx with appropriate entry site and angle. int braz j urol. 2016;42:1160-7. 24. radfar mh, basiri a, nouralizadeh a, et al. comparing the efficacy and safety of ultrasonic versus pneumatic lithotripsy in percutaneous nephrolithotomy: a randomized clinical trial. eur urol focus. 2017;3:82-8. 25. timm b, farag m, davis nf, et al. stone clearance times with mini-percutaneous nephrolithotomy: comparison of a 1.5 mm ballistic/ultrasonic mini-probe vs. laser. can urol assoc j. 2021;15:e17. 26. lahme s. miniaturisation of pcnl. urolithiasis. 2018;46:99-106. 27. wollin da, joyce ad, gupta m, et al. antibiotic use and the prevention and management of infectious complications in stone disease. world j urol. 2017;35:1369-79. 28. jung h, norby b, frimodt-moller pc, osther pj. endoluminal isoproterenol irrigation decreases renal pelvic pressure during flexible ureterorenoscopy: a clinical randomized, controlled study. eur urol. 2008;54:1404-13. 29. tepeler a, akman t, silay ms, et al. comparison of intrarenal pelvic pressure during micro-percutaneous nephrolithotomy and conventional percutaneous nephrolithotomy. urolithiasis. 2014;42:275-9. 30. kandemir e, savun m, sezer a, erbin a, akbulut mf, sarilar o. comparison of miniaturized percutaneous nephrolithotomy and standard percutaneous nephrolithotomy in secondary patients: a randomized prospective study. j endourol. 2019. 31. guler a, erbin a, ucpinar b, savun m, sarilar o, akbulut mf. comparison of miniaturized percutaneous nephrolithotomy and standard percutaneous nephrolithotomy for the treatment of large kidney stones: a randomized prospective study. urolithiasis. 2019;47:28995. preoperative urine wbc predicts post-pcnl fever lu et al. is a safety guide wire necessary for transurethral lithotripsy using semi-rigid ureteroscope? results from a prospective randomized controlled trial abbas basiri1*, jean de la rosette2, milad bonakdar hashemi1, hamidreza shemshaki1, ali zare3, nasrin borumandnia1 purpose: experts recommend us to keep a safety guidewire during the process of upper urinary tract endoscopy, though there is a lack of high-level evidence to support the efficacy and safety of this opinion. this study was conducted to compare the outcome of ureteral stone breakage in the presence or absence of a safety guidewire. materials and methods: patients candidate for endoscopic breakage of ureteral stone using a semi-rigid ureteroscope, were randomly assigned in two groups based on keeping a safety guidewire (group1) or removing the guidewire (group2) before the process of breaking ureteral stone by lithoclast. demographic factors, history of previous stone treatment, kidney function, stone location, symptoms duration and severity were recorded for each patient. primary outcomes included success rate of stone treatment and secondary outcomes included number of attempts to enter to ureter, success rate of ureteral entry, success rate of stone achievement, stone migration rate and the success rate of ureteral stent insertion. the recorded data were entered to the spss software and descriptive statistical analysis including power calculation and non-inferiority design for the primary and secondary outcomes, was performed. p-value less than 0.05 was considered significant. results: from january 2016 till may 2018, 320 patients were randomized with 160 patients in each arm. considering the cases who were missed due to follow-up loss, there were 153 patients in group 1 and 147 patients in group 2 at the end of the study. baseline data were equally distributed in both groups. based on the initial analysis, the studied variables had no significant difference between two groups; though, according to the subgroup analysis of patients with proximal ureter stones, patients in group 1 had higher rates of ureteral injury comparing to the patients in group 2 (p = 0.03). conclusion: according to our findings, keeping the safety guidewire through the process of endoscopic stone breakage (stone size: less than 1.5cm) seems to add no significant benefit to the procedure outcome, while it increases the ureteral injuries in the proximal ureter stones, but not in mid or distal ureter stones. keywords: ureteroscopy; safety guide wire; randomized controlled trial introduction during the past decade, we have witnessed a sig-nificant change in the treatment armamentarium and treatment algorithm for the management of urinary stones. on one hand, this has been fueled by the development of smaller sized endoscopic instruments for ureteroscopy, flexible endoscopes for retrograde intrarenal surgery, and miniaturization of percutaneous endoscopes(1-3). on the other hand, the centralization of care has resulted in high volume centers with specialist care performed by surgeons with a high-level experience resulting in better surgical outcomes and fewer complications(4). guidelines recommend the use of a safety guidewire to secure safe access to the ureter during ureteroscopy for the treatment of urinary stones(5). a possible ureter1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2department of urology, istanbul medipol university, istanbul, turkey. 3department of urology, shahid saddughi university of medical sciences, yazd, iran. *correspondenceurology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. tel: +98-21-22567222. fax: +98-21-22567282. email: basiri@unrc.ir received october 2020 & accepted january 2021 al lesion or even avulsion may result in a complicated procedure once a safety guidewire is not in place(6,7). regardless of the complication, the safety guidewire ensures the ability to place a ureteral stent at the end of a ureteroscopic procedure(8). however, one may ask if the historical dogma of always using safety guidewires in endourologic procedures is still applicable? while nowadays, the endourological environment has raised the safety and precision of the procedure to a new level that may alleviate the routine use of a safety guidewire. on the other hand, some reports showed disadvantages regarding the use of safety guidewires during ureteroscopy(9). the forces needed to insert and retract the endoscope during ureteroscopy with a safety guidewire in place are considerably higher when compared with procedures that not include a safety guidewire(10). although not completely confirmed, this fact raises the urology journal/vol 18 no. 5/ september-october 2021/ pp. 497-502. [doi: 10.22037/uj.v16i7.6511] endourology and stone disease question if actually, the placement of a safety guidewire could eventually increase the risk of harming the ureter in some patients(11). foregoing reports show successful ureteroscopy without any guidewire in place. however, none of them are high power randomized clinical studies and could not address the question of whether a safety guidewire is necessary during ureteroscopy or not. therefore, this randomized clinical study was designed to compare the efficacy and safety of ureteroscopy with and without a safety guidewire in patients with ureteral stones. methods and materials this prospective randomized trial was registered at http://www.clinicaltrials.gov (unique protocol id: q12133) and received approval from the urology and nephrology research center (unrc) (ethical code: ir.sbmu.unrc.1396.41). the study was conducted from january 2016 to may 2018 and enrolled patients (≥ 18 years old) with ureteral stones (≤ 1.5 cm) that didn’t pass the stone spontaneously within two weeks following diagnosis. patients with ureter stones ≤ 1.5 cm, confirmed via ultra-sonography and non-contrast enhanced computed tomography (ct). exclusion criteria included pregnancy, pelvic kidney, transplant kidney, uncorrected coagulopathy, skeletal disorder, history of ureteral stenosis, history of ureteral surgery, positive urine culture, any urinary diversions and need for emergency ureteroscopy. of the 360 patients treated for ureteral stones during the study period, 40 patients were excluded because of exclusion criteria. of the remaining 320 patients, 153 received ureteroscopy with a safety guidewire (group 1), and 147 received ureteroscopy without a safety guidewire (group 2). the discrepancy between the numbers is because of lost to follow-up (figure 1). intravenous second-generation cephalosporin or ciprofloxacin was administered 30 minutes before the induction of anesthesia in all cases. all ureteroscopy started with an 8-french semi-rigid ureteroscope, and if there was stricture or tightness in moving the ureteroscope, a 6-french semi-rigid ureteroscope was also used. assessment baseline data including age, gender, body mass index, stone location, ureteral side, stone surface, the status of kidneys (single or double), degree of hydronephrosis (according to society of fetal ultrasound), pain severity and serum creatinine were captured. the pain was evaluated with a visual analog scale (vas) with scores ranging from zero to 10 (0 for no pain and 10 for intolerable pain). based on a table of random numbers generated by random allocation software, the patients were assigned to two groups: ureteroscopy with safety guidewire versus ureteroscopy without safety guidewire and the surgeries were conducted by residents that had an experience of at least 100 ureteroscopy during their education. the pre-operative, baseline characteristics of the two groups are shown in table 1. the primary outcome was the rate of ureteral injuries. the ureteral injuries were graded according to the european association of urology guidelines: grade i: mucosal abrasion; grade ii: ureteral perforation; grade iii: intussusception/avulsion. secondary outcomes included peri-operative data (number of attempts to enter to the ureter, the success rate of ureteral entry, the success rate of stone access, stone migration rate, the success rate of ureteral stent insertion, operative time, conversemirigid ureteroscopy with and without safety guide wire-basiri et al. figure 1. consolidated standards of reporting trials (consort) diagram. *sgw: safety guide wire endourology and stones diseases 498 vol 18 no 5 september-october 2021 499 sion to open surgery) and postoperative data including 2 weeks and 3 months’ success rate of stone treatment (residual stone < 4mm), pain severity, and presence of hydronephrosis. the minimum number of required samples in each of the two groups using the following statistical relationship is 134 patients in each group(12): considering about 20% of the sample loss, 160 patients in each group were included. statistical analysis neither the examiner nor the patient was aware of the type of treatment that was used during the evaluation. thus the data recorded for each follow-up evaluation were double-blind. if the data were distributed normally, we used an independent t-test to compare means. otherwise, the mann whitney test was used. categorical data were compared between groups using chisquare or fisher exact tests. we performed analysis using spss software (version 20.0 for windows). the statistical significance was set to p < 0.05. endoscopic technique all procedures were performed with 8 and 6 french (fr) wolf urethroscopes. in order to have a better visibility and smooth passage of devices such as double-j characteristic safety guide wire (n=153) no safety guide wire (n=147) p value age (year) 43.64 ± 12.66 41.99 ± 11.73 0.24 gender (male) 124 (81%) 106 (72.1%) 0.08 bmi 28.2 ± 10.12 26.3 ± 9.31 0.35 stone surface (mm2) 63.12 ± 9.12 56.14 ± 9.43 0.36 time of symptom to treat (day) 25.16 ± 23.64 22.20 ± 33.68 0.38 preoperative creatinine 1.39 ± 1.10 1.44 ± 1.90 0.77 pain severity 1.91 ± 1.06 2.09 ± 1.03 0.37 solitary kidney 8 (5.2%) 5 (3.4%) 0.57 history of stone treatment 18 (11.8%) 10 (6.8%) 0.17 history of abdominal surgery 28 (18.3%) 25 (17%) 0.88 side of ureteral stone (right) 79 (51.6%) 64 (43.5%) 0.17 ureteral stone location proximal 33 (21.6%) 32 (21.8%) 0.25 middle 55 (35.9%) 40 (27.2%) distal 64(41.8%) 75 (51.0%) severity of hydronephrosis no 7 (4.6%) 9 (6.2%) 0.86 1 57 (37.3%) 53 (39.5%) 2 52 (34%) 47 (32%) 3 30 (19.6%) 23 (15.6%) 4 7 (4.6%) 10 (6.8%) table1. the pre-operative, baseline characteristics of the two groups data was presented as n (%) and mean ± sd. bmi: body mass index outcome safety guide wire (n=153) no safety guide wire (n=147) p value size of ureteroscope 6 24 (15.7%) 15 (10.2%) 0.17 8 129 (84.3%) 132 (89.8%) number of attempts to enter to ureter 1.6 ± 1.3 1.5 ± 1.4 0.34 success rate of ureteral entry 152 (99.3%) 145 (98.6%) 0.62 success rate of stone achievement 147 (96.1%) 140 (95.2%) 0.78 stone migration rate 42 (27.5%) 29 (19.7%) 0.13 success rate of ureteral stent insertion 152 (99.3%) 147 (100%) 0.99 severity of ureteral injury* no 79 (51.6%) 93 (63.3%) 0.18 i 51 (33.3%) 40 (27.2%) ii 20 (13.1%) 13 (8.8%) iii 3 (2.0%) 1 (0.7%) operative time (min) 24.5 ± 11.5 25.1 ± 10.7 0.65 2-week follow up success rate of stone treatment 120 (78.4%) 124 (84.4%) 0.24 pain severity 0.54 (0.63) 0.51 (0.61) 0.64 no hydronephrosis 93 (60.8%) 100 (68.0%) 0.58 3-month follow up success rate of stone treatment 147 (96.1%) 143 (97.3%) 0.75 pain severity 0.08 (0.28) 0.12 (0.32) 0.38 no hydronephrosis 148 (96.7%) 143 (97.3%) 0.79 table2. peri and post-operative outcomes between two groups data was presented as n (%) and mean ± sd; *ureteral injury as in european association guideline including i: mucosal abrasion; ii: ureteral perforation; iii: intussusception / avulsion observation: hydronephrosis decreases with time. question: how many had hydronephrosis at baseline semirigid ureteroscopy with and without safety guide wire-basiri et al. through the ureters, all procedures was operated initially by 8-fr ureteroscope. the procedure was continued by a 6-fr ureteroscope, in cases there was a clear stricture that make it difficult to pass through the ureter.. in the next step, cystoscopy was performed to visualize the bladder, exclude any gross lesion, and to localize the ureteric orifice. then, a safety guidewire was passed through the ureteric orifice into the ureter,the ureteroscope followed the route and continued until reaching the stone. from this point forward, we divided the cases into two groups based on the presence or absence of safety guide wire in the process of stone breakage; for “group 1” the guidewire was gently guided forward to pass the stone and was inserted in the ureter after the stone (and if it was not possible to pass the stone, the guidewire was inserted beside the stone). ureteroscope was ejected and reinserted in the ureter using a new guidewire; by the next step, the stone was broken by lithoclast, both guide wires were removed and the ureteral stent was inserted. for “group 2” the guide wire and ureteroscope were guided through the ureter to the stone location, then the guide wire was removed and lithoclast was installed to break the stone. then, the ureteroscope and lithoclast were removed and the ureteral stent was inserted. the ureteral stent was removed after four to six weeks in both groups of patients. results the consolidated standards of reporting trials (consort) diagram in figure 1 shows the process for participant inclusion. the pre-operative such as the history of stone surgery, history of stone treatment, ureteral stone location, and ureteral stone side were not significantly different between the two groups (p ˃ 0.05) (table 1). the severity of ureteral injury according to the european association of urology (eau) grading was not significantly different between the two groups (p = 0.18). peri-operative outcomes included the success rate of ureteral stones characteristic safety guide wire (n=33) no safety guide wire (n=32) p value age (year) 43.75 ± 11.95 42.31 ± 13.30 0.65 gender (male) 27(81.8%) 19 (59.4%) 0.047 bmi 26.9 ± 8.32 27.3 ± 10.11 0.43 stone surface (mm2) 56.32 ± 11.10 52.13 ± 9.61 0.52 time of symptom to treat (day) 20.15 ± 10.84 18.87 ± 13.30 0.67 preoperative creatinine 1.35±0.7 1.58 ± 1.84 0.51 pain severity 1.78±1.08 1.84 ± 0.98 0.83 solitary kidney 1(3%) 2 (6.3%) 0.613 history of stone treatment 6(18.2%) 5 (15.6%) 0.783 history of abdominal surgery 1(3%) 6 (18.8%) 0.054 side of ureteral stone (right) 21(63.6%) 15 (46.9%) 0.174 severity of hydronephrosis no 2 (6%) 0 (0%) 0.269 1 10 (30.3%) 9 (28.1%) 2 14 (42.4%) 14 (43.8%) 3 6 (18.2%) 4 (12.5%) 4 1 (3%) 5 (15.6%) table 3. the pre-operative, baseline characteristics of the two groups for proximal data was presented as n (%) and mean ± sd. bmi: body mass index outcome safety guide wire (n=33) no safety guide wire (n=32) p value size of ureteroscope 6 8 (24.2%) 1 (3.1%) 0.03 8 25 (75.8%) 31 (96.9%) number of attempts to enter to ureter 1.51±0.79 1.22±0.66 0.03 success rate of ureteral entry 33 (100%) 32 (100%) success rate of stone achievement 32 (97.0%) 31(96.9%) stone migration rate 14 (42.4%) 10 (31.3%) 0.44 success rate of ureteral stent insertion 33 (100%) 32 (100%) severity of ureteral injury* no 15 (45.5%) 23 (71.9%) 0.03 i 12 (36.4%) 6 (18.8%) ii 6 (18.2%) 3 (9.4%) iii 0 0 operative time (min) 25.3±12.5 26.1±11.4 0.51 2-week follow up treatment success rate 20 (60.6%) 26 (81.3%) 0.10 pain severity 0.54 (0.56) 0.53 (0.62) 0.92 no hydronephrosis 21 (63.7%) 19 (59.4%) 0.37 3-month follow up treatment success rate 30 (90.9%) 28 (87.5%) 0.71 pain severity 0.06 (0.24) 0.06 (0.25) 0.97 no hydronephrosis 32 (96.9%) 32 (100%) 0.53 table4. peri and post-operative outcomes between two groups for proximal ureteral stones data was presented as n (%) and mean ± sd; *ureteral injury as in european association guideline including i: mucosal abrasion; ii: ureteral perforation; iii: intussusception / avulsion semirigid ureteroscopy with and without safety guide wire-basiri et al. endourology and stones diseases 500 vol 18 no 5 september-october 2021 501 stone achievement, stone migration rate, the success rate of ureteral stent insertion were not significantly different between the two groups (table 2). post-operative follow-up showed no significant difference between two groups at 2 weeks and 3-month (table 2). also, we performed an outcome analysis based on the stone location. while there was no significant difference between the two groups with proximal ureteral stone (table 3), a higher rate of injuries was found when using a safety guidewire compared to not using a safety guidewire in patients with proximal ureteral stone (table 4) (p = 0.03). discussion this well-powered study confirms that overall outcomes of semirigid ureteroscopy (urs) not using a safety guidewire is not inferior to semirigid ureteroscopy using a safety guidewire. however, for patients with proximal ureter stones, the use of a safety guidewire resulted in a higher injury rate when compared to patients treated without a safety guidewire. this finding provides new insights into the position of the use of safety guidewire for semirigid ureteroscopy. the use of a safety guidewire during endoscopic procedures in the upper urinary tract was originally intended to help straighten and stabilize the ureter, allow navigation through edematous, narrowed or otherwise defective sections, and facilitate placement of ureteral stents when necessary. since the advent of ureteroscopy in the late 1980s, however, advances in technology have led to the development of a smaller caliber ureteroscope (7). besides, urologists have become increasingly experienced with ureteroscopic procedures, and some urologists forego the use of the safety wire in routine cases to improve visualization and manipulation of the ureteroscope. ulvik and colleagues evaluated diversities in norwegian urologists’ personal preferences in the endoscopic management of ureteral calculi and showed a safety guidewire was routinely inserted alongside the ureteroscope by 79.3% of the physicians, while the rest employed a safety guidewire only in complicated cases (13). dickstein and colleagues have performed a retrospective chart review to determine the safety and feasibility of dispensing with the guidewire in patients undergoing ureteroscopy for renal or ureteropelvic junction stones and showed no intraoperative complications, including loss of access, ureteral perforation or the need for a percutaneous nephrostomy tube(14). they concluded that the use of a safety guidewire is not necessary for routine cases of ureteroscopic laser lithotripsy in patients with an uncomplicated ureteropelvic junction or renal stones. however, they recommend that a safety wire should still be used in complicated cases, such as those involving encrusted ureteral stents, ureteral strictures, urinary diversions, or concomitant ureteral stones. however, this study is retrospective evaluation and suffers from a level of evidence to confirm this concept. our study using randomized controlled design has shown, no inferiority in complication rates for not using a safety guidewire compared when using safety guidewire for ureteroscopy on the other hand higher rate of injuries was found in the safety guidewire group compared with non-safety guidewire groups in upper ureteral stones. eandi and colleagues examined a porcine animal model to evaluate the impact of the presence of a safety guidewire during ureteroscopy and showed the presence of a safety guidewire adjacent to the endoscope inhibits the passage of the ureteroscope in an in vitro animal model (15). ulvik and colleagues iv an in vivo study investigated whether the presence of a safety guidewire during ureteroscopy in a normal clinical setting will influence pushing and pulling forces exerted on a semirigid ureteroscope and showed the safety guidewire may even increase the risk of ureteral injuries(9). johnson and colleagues studied retrospectively a single-surgeon prospective database of flexible ureteroscopy and showed stone-free rates after primary treatment of ureteral calculi were 93, 96, and 100% for a proximal, middle and distal third location, respectively. our results are in agreement with this study, but in a randomized controlled study manner and using semi-rigid ureteroscope(16). there are only two comparative studies available in the literature that studied the role of a safety guidewire for semi-rigid and flexible ureteroscope. moran and bratslavsky(17) compared a total of 340 none using safety guidewire flexible ureteroscopy with 1,500 using safety guidewire laser lithotripsies. targeted stone destruction occurred in 98% of these cases and the stone-free rates were lower (326/340) for those that did not use a safety guidewire. failures in this cohort were infrequent and occurred in seven patients with high-grade obstruction and/or impacted calculi. on the other hand, in the entire series of 1,500 patients, the targeted stone destruction occurred in 98% and the stone-free rate was 96%, with results identical to the technique without the safety wire. there were no complications in the group without a safety wire secondary to loss of upper tract access. in this study, only flexible ureteroscopy was performed, which is not available in all centers because of cost and special expertise and the design of the study is the collection of the data from non-randomize trials. ulvik et al. compared the results of urs for the treatment of ureteral stones at two different hospitals where the safety guidewire was either routinely used or omitted(13). the reported success rates of passing the ureteroscope through the ureteral orifice, the ability to access the ureteral stone, and the ability to place a ureteral stent when needed after the endoscopy were not significantly different between the two groups of patients. there was no significant difference in the overall intraoperative complication rates at the two hospitals. the overall stone-free rates were 77.1% and 85.9% with and without the safety guidewire. according to the stone location, the stone-free rates were 61.2 and 70.2% for upper, 72.6, and 81.1% for mid, and 89.8 and 93.9% for distal ureteral stones with and without safety guidewire, respectively. a significant increase in the number of patients (14 patients, 3.4%) was found to have post endoscopic ureteral stenosis at the hospital where the safety guidewire was routinely used than at the hospital where a safety guidewire was omitted (six patients, 1.2%). although this study confirms our results, it is obvious that this is not rct and may contain many biases regarding patient selection, technical aspect, and level experience of operators. our results were in agreement with these two studies, however, we have not found any post-operative stenosis in our patients. to our best knowledge, our study is the first randomized controlled trial comparing using or not using safety semirigid ureteroscopy with and without safety guide wire-basiri et al. guidewire in the new era of endourology practice. moreover, the procedures were performed by residents. this makes the current data even more generalizable. it may be needed further study with a larger number of patients to evaluate this concept more precisely. one of the limitations of the study is that the surgery was not performed by a specific surgeon. in addition, we can mention the other limitation is being small number of patients in each group. conclusions not using a safety guidewire has not resulted in inferior outcomes compared with using a safety guidewire in the endoscopic management of ureteral stones less than 1.5cm. references 1. van cleynenbreugel b, kılıç ö, akand m. retrograde intrarenal surgery for renal stones part 1. turk j urol. 2017;43(2):112-21. 2. erbin a, ucpinar b, cubuk a, yazici o, uysal h, savun m, et al. the impact of sheath size in miniaturized percutaneous nephrolithotomy in adult patients; a matched-pair analysis. urol j. 2019;16(6):536-40. 3. gucuk a, yilmaz b, gucuk s, uyeturk u. are stone density and location useful parameters that can determine the endourological surgical technique for kidney stones that are smaller than 2 cm? a prospective randomized controlled trial. urol j. 2019;16(3):236-41. 4. sprunger jk, herrell sd, 3rd. techniques of ureteroscopy. the urologic clinics of north america. 2004;31(1):61-9. 5. rukin nj, somani bk, patterson j, grey br, finch w, mcclinton s, et al. tips and tricks of ureteroscopy: consensus statement part i. basic ureteroscopy. cent european j urol. 2015;68(4):439-46. 6. molina wrj, pessoa rr, silva rdd, gustafson d, nogueira l, meller a. is a safety guidewire needed for retrograde ureteroscopy? rev assoc med bras (1992). 2017;63(8):71721. 7. senocak c, ozcan c, sahin t, yilmaz g, ozyuvali e, sarikaya s, et al. risk factors of infectious complications after flexible uretero-renoscopy with laser lithotripsy. urol j. 2018;15(4):158-63. 8. sarica s, akkoc y, karapolat h, aktug h. comparison of the use of conventional, hydrophilic, and gel-lubricated catheters concerning urethral microtrauma, urinary system infection, and patient satisfaction in patients with spinal cord injury: a randomized controlled study. eur j phys rehabil med. 2010;46(4):473-9. 9. ulvik ø, wentzel-larsen t, ulvik nm. a safety guidewire influences the pushing and pulling forces needed to move the ureteroscope in the ureter: a clinical randomized, crossover study. j endourol. 2013;27(7):850-5. 10. whitehurst la, somani bk. semi-rigid ureteroscopy: indications, tips, and tricks. urolithiasis. 2018;46(1):39-45. 11. muslumanoglu ay, fuglsig s, frattini a, labate g, nadler rb, martov a, et al. risks and benefits of postoperative double-j stent placement after ureteroscopy: results from the clinical research office of endourological society ureteroscopy global study. j endourol. 2017;31(5):446-51. 12. ye t, yi y. sample size calculations in clinical research, third edition, by sheinchung chow, jun shao, hansheng wang, and yuliya lokhnygina: chapman & hall/ crc biostatistics series, new york, taylor & francis, 2017, 510 pp., $99.95 (hardback), isbn: 978-1-138-74098-3. stat theory relat fields. 2017;1:1-2. 13. ulvik o, ulvik nm. diversity in urologists' personal preferences in the ureteroscopic management of ureteral calculi in norway. scand j urol. 2013;47(2):126-30. 14. dickstein rj, kreshover je, babayan rk, wang ds. is a safety wire necessary during routine flexible ureteroscopy? j endourol. 2010;24(10):1589-92. 15. eandi ja, hu b, low rk. evaluation of the impact and need for use of a safety guidewire during ureteroscopy. j endourol. 2008;22(8):1653-8. 16. johnson gb, portela d, grasso m. advanced ureteroscopy: wireless and sheathless. journal of endourology. 2006;20(8):552-5. 17. bratslavsky g, moran me. current trends in ureteroscopy. urol clin north am. 2004;31(1):181-7, xi. semirigid ureteroscopy with and without safety guide wire-basiri et al. endourology and stones diseases 502 long-term outcomes of distal hypospadias repair: a patients’ point of view alexis belgacem1, laurent fourcade1, romain pelette2, etienne bouchet2, victor lescure2, walter bertherat2, grazia spampinato1, jean-luc alain1, aurélien descazeaud2, quentin ballouhey1* purpose: to assess the long-term outcomes of patients treated for distal hypospadias. assessment of long-term follow-up for a homogeneous population with hypospadias is difficult and there has consequently been a paucity of publications in this regard. materials and methods: a retrospective review was carried out to compile cases of distal hypospadias operated at our center between 1990 and 1999 according to the magpi procedure. four parameters were evaluated based on four validated questionnaires: health-related quality of life (sf-36), genital self-perception (pps), self-esteem (rosenberg self-esteem scale), and erectile function (iief). results: a total of 77 patients who had undergone magpi surgery for hypospadias during the specified period were selected. sufficient clinical data were available for 51 patients and only 15 of these patients were included, after a median follow-up of 22 years (20-26). their outcomes were compared with those for a population of 15 matched circumcised men and 15 matched uncircumcised men. no significant difference was found between the patients and the control groups in terms of the score for quality of life (p = .29). there were, however, significant differences in the scores for self-perception of the penile cosmetic appearance (13.3 vs. 15.8; p < .01), self-esteem (30.6 vs. 35.8; p < .01), and erectile function (31.4 vs. 33.7; p = .04) between the patients and the controls. lower self-esteem correlated with poor genital self-perception (r = .92). conclusion: this study confirms that adult patients operated for distal hypospadias have poor genital self-perception. this poor genital perception correlated with lower self-esteem. keywords: hypospadias; magpi; long-term outcomes; self-esteem introduction hypospadias exhibits a broad spectrum of severity, and a multitude of surgical reconstructive techniques have been devised that are aimed at correcting this congenital abnormality. even for the specific distal type of hypospadias, the large variety of procedures reflects the absence of an established gold standard for treatment. irrespective of the choice of the technique used, there is not a clear consensus regarding the indication for surgery in case of very distal hypospadias due to the substantial cosmetic considerations involved. there is a paucity of published data regarding the cosmetic and self-estimated outcomes of hypospadias. most of the published series to date have been in regard to short-term cosmetic outcomes reflecting the opinions of the parents and the surgeon. definitive urinary functional outcomes can be addressed in adolescence.(1) it is, however, more difficult to obtain data regarding sexual function and self-estimated cosmetic outcomes, as this requires long-term close follow-up.(2) there have been few reports to date of long-term outcomes, particularly in regard to distal hypospadias.(3) similar long-term cos1service de chirurgie pédiatrique, hôpital mère-enfant, centre hospitalier universitaire de limoges, 8 avenue dominique larrey, 87042 limoges, france. 2service de chirurgie urologique, hôpital dupuytren, centre hospitalier universitaire de limoges, 2 avenue martin luther king, 87000 limoges, france. *correspondence: service de chirurgie pédiatrique, hôpital mère-enfant, centre hospitalier universitaire de limoges, 8 avenue dominique larrey 87042 limoges, france tel: +33/6 32 85 96 60; fax: +33/5 55 55 86 82, email: q.ballouhey@gmail.com received march 2020 & accepted september 2020 metic and functional issues can be expected for operated patients and patients without hypospadias.(2) the rationale to operate distal hypospadias during early childhood should take into account cosmetic and ethical considerations. the fundamental question is whether esthetic correction is indicated before the patient has the capacity to provide their informed consent4. there has been no large-scale study to date comparing the longterm outcomes of adult patients who have or who have not been operated for distal hypospadias. the key issue remains the self-perception of patients regarding their hypospadias. most of the data published to date has been in regard to medium-term follow-up series with heterogeneous types of hypospadias and follow-up durations.(5,6) of note, there has been one study that reported a similar health-related quality of life for operated patients and controls.(4) no study, however, has focused on the self-estimated outcomes for adult patients operated for distal hypospadias during childhood. to address these issues, we focused on a particular population: patients with distal hypospadias operated with a single repair technique. the primary endpoint of the pediatric urology urology journal/vol 18 no. 5/ september-october 2021/ pp. 537-542. [doi: 10.22037/uj.v16i7.6172] present study was to report the long-term outcomes for such patients in terms of the functional parameters, effects on sexual performance, and health-related quality of life (hrqol) after reconstructive surgery for distal hypospadias with long-term (> 20 years) follow-up. the secondary endpoint was to compare these parameters with those of the general population without hypospadias. methods study population the patients had to be at least 20 years of age to be considered eligible for this study. a retrospective review was carried out to compile cases of hypospadias operated between 1990 and 1999 for distal hypospadias. this study was approved in 2019 by the ethics committee of the university hospital of limoges as reference number 309-2019-75. inclusion and exclusion criteria the primary endpoint was the long-term outcomes of patients treated for distal hypospadias in terms of functional outcomes, effects on sexual performance, and general quality of life. a total of 138 medical files of patients who had a procedure code compatible with hypospadias repair at our institute between 1 january 1990 and 31 january 1999 were reviewed in order to select patients who were between 20 and 30 years of age in 2019 and who had undergone primary hypospadias repair. only patients with distal hypospadias repair according to the meatal advancement and glanuloplasty (magpi) procedure were included in the present study. we selected these patients to obtain a homogeneous populong-term outcomes of hypospadias-belgacem et al. variables (min-max)a total group 1circumcised group 2uncircumcised p-value number 30 15 15 age 28.0 (21-39) 28.8 (21-38) 27.2 (21-39) .48 age at surgery (months) 42.4 (13-65) 42.4 (13-65) none penile score (ppps) 15.8 (13-18) 16.5 (15-18) 15.2 (13-18) .07 length 2.2 (2-3) 2.4 (2-3) 2.2 (2-3) meatus 2.9 (2-3) 3.0 (2-3) 2.9 (2-3) glans 2.6 (2-3) 2.8 (2-3) 2.6 (2-3) skin 2.2 (2-3) 2.8 (2-3) 2.2 (2-3) axis 2.6 (2-3) 2.8 (2-3) 2.6 (2-3) appearance 2.2 (2-3) 2.4 (2-3) 2.2 (2-3) erectile function (iief) 33.7 (30-35) 33.8 (33-35) 33.6 (30-35) .44 self-esteem (rosenberg) 35.8 (28-40) 36.5 (28-39) 34.9 (28-40) .19 quality of life (euroqol5d) 91.3 (65-100) 92.1 (75-100) 90.3 (65-100) .56 table 1. characteristics of the control group comprising unoperated and circumcised men abbreviations: ppps: pediatric penile perception score; iief: international index of erectile function a the continuous variables were compared using a parametric test (student’s t-test) and non-a parametric test (mann-whitney test) figure 1. study flow diagram. pediatric urology 538 lation with high expectations regarding the cosmetic results. distal hypospadias was defined as a preoperative meatal position distal to and including mid-penile shaft cases. these patients did not have preoperative penile curvature. out of a total of 104 patients, 23 underwent tubularized incised plate repair, 4 underwent mathieu repair, and 77 underwent magpi procedures. the only exclusion criterion was insufficient data regarding short-term follow-up of the patients. during the follow-up, the patients were asked to complete a questionnaire regarding their genital self-perception. if they were no longer included in close follow-up, they were also invited to consult with the dedicated urology unit of our institute. the control group comprised men without hypospadias who agreed to anonymously complete the same questionnaire. each patient was matched according to age at the time of the surgery and age in 2019 to two adult controls without hypospadias from both a circumcised and an uncircumcised patient population. the circumcised group was compared to the uncircumcised group, and the hypospadias group was compared to the total control group. four parameters were evaluated based on four validated questionnaires. health-related quality of life (hrqol) the 36-item medical outcomes study short-form questionnaire (sf-36) was used to assess the hrqol.(7) this scale has been validated and has been determined to be reliable for our population (reliability coefficient of 0.75).(8) subscales of each domain (physical function, role limitations, bodily pain, general health perception, mental health, role limitations due to emotional problems, vitality, and social function) were scored from 0 to 100, with higher scores indicating a better hrqol. genital self-perception (pps) penile cosmetic self-perception was evaluated according to the penile perception score.(9) this instrument consists of the following four items for the participants to evaluate their genitals, with a 4-point scale ranging from very dissatisfied (0) to very satisfied (3): the position and shape of the meatus, the shape of the glans, the shape of the shaft skin, and the general appearance of the penis. the pps score ranges from 0 to 12. it is a recognized score in the domain of hypospadias, although it has yet to be shown to be a validated patient-reported outcome instrument.(10) we also assessed two additional items included in the pediatric pps because their absence is a limitation according to the literature: the length and the axis of the penis.(2, 11) self-esteem the rosenberg self-esteem scale, which is a widely used self-report instrument for disorders such as sexual development, was chosen to evaluate the participants’ level of self-esteem.(12) self-esteem is tightly linked to happiness.(13) this 10-item scale measures overall self-worth by assessment of both positive and negative feelings about oneself. all of the items are rated using a 4-point likert scale ranging from ‘strongly agree’ to ‘strongly disagree’. erectile function and orgasmic function the international index of erectile function was used to measure erectile and orgasmic functions in the past 6 months. the erectile function subscale has a maximum domain score of 30 and an organic function subscale of 10.(14) higher scores correspond to better functions. this scoring method was validated many years ago and it is commonly used in publications relating to studies of hypospadias.(3,14) statistical analysis the data were analyzed using prism 8.2.1® mac® software (graphpad software, san diego, california, usa). the comparative statistics were performed using fisher’s exact test for the categorical variables, a parametric test (student’s t-test) for the data with a normal distribution (means and the corresponding sd are presented), and a non-parametric test (mann-whitney test) for the data without a normal distribution (medians and the iqr are presented). a p-value of less than 0.05 was considered significant. results a total of 77 patients operated for distal hypospadias in the specified period were selected. no postoperative complications occurred after a median follow-up of 15 months (range 1-63). no cases involving penile curvature or a short penis length were noted. clinical data were available for 51 patients to calculate the postoperative pps score. the patients were contacted using their parents’ addresses or through social networks. the correct contact details and addresses of the patients were ultimately only available for 45 of the patients. a total of twenty-nine patients could be reached by phone, of whom twenty-two were lost to follow-up (figure 1). no variables (min-max)a patients control group p-value number 15 30 age 24.3 (20-30) 28.0 (21-39) .02 age at surgery (months) 42.3 (12-78) 42.4 (13-65) (circumcision) .86 penile score (ppps) 13.3 (10-17) 15.8 (13-18) < .001 length 2.0 (1-3) 2.2 (2-3) .052 meatus 2.1 (0-3) 2.9 (2-3) < .001 glans 2.5 (2-3) 2.6 (2-3) .0081 skin 2.2 (1-3) 2.3 (2-3) axis 2.3 (1-3) 2.6 (2-3) appearance 2.4 (2-3) 2.3 (2-3) erectile function (iief) 31.4 (14-35) 33.7 (30-35) .04 self-esteem (rosenberg) 30.6 (24-37) 35.8 (28-40) .0001 quality of life (euroqol5d) 94.3 (80-100) 91.3 (65-100) .29 table 2. comparison of the scores of the patients and the control group. abbreviations: ppps: pediatric penile perception score; iief: international index of erectile functiona the continuous variables were compared using a parametric test (student’s t-test) and a non-parametric test (mann-whitney test) long-term outcomes of hypospadias-belgacem et al. vol 18 no 5 september-october 2021 539 additional postoperative complications were noted, nor did any further surgery take place. none of the patients indicated that they suffered from urinary functional impairment. one patient died of an unrelated cause. five patients returned to the dedicated consultation unit for a medical examination and a uroflowmetry test. only 15 patients complied with the study requirements by returning the questionnaire after a median follow-up of 22 years (iqr 20,26), their median age was 24.3 years (iqr 20,27). according to surgeons, the median short-term postoperative pps score was 17.8 (range 1718), which was representative of the magpi population 17.7 (range 17-18) in this study period. their outcomes were compared to those for a population of 15 matched circumcised men (median age 28.8 years (iqr 21,38)) and 15 matched uncircumcised men (median age 27.2 years (iqr 21,39)). no differences were found for the scores of the four parameters that were assessed between the circumcised and the uncircumcised population (table 1). thus, we decided to compare the operated patients with all of the controls by combining both the circumcised and the uncircumcised men. the control subjects were older than the patients (28.0 vs. 24.3 years of age; p < .05), although the median age at the time of the surgery was the same for both groups (table 2). there was not a significant difference between the patients and the control group in terms of the quality of life (p = .29). there was a significant difference, however, regarding the penile cosmetic self-perception (13.3 vs. 15.8; p < .01). this difference was mainly due to the following items: the length (2.0 vs. 2.2; p = .052), the meatus (2.1 vs. 2.9; p < .001), and the axis (2.3 vs. 2.6; p = .0081) of the penis (table 2). there was also a significant difference in the self-esteem score (30.6 vs. 35.8; p < .01) and the erectile function score (31.4 vs. 33.7; p = .04). two patients had not yet had a sexual partner. lower self-esteem correlated with poor genital self-perception (r = .92; p < .01). no association could be found between lower self-esteem and reduced erectile function. discussion our results indicate that adult men operated on for distal hypospadias have lower self-esteem and penile perception scores compared with controls. the quality of life was comparable to that of the controls, as has also been reported for a population of patients with heterogeneous operated hypospadias.(4) this study was the first to present long-term self-perception outcomes. the authors pointed out that the limitations of their study comprised the late age at which the surgical procedure was performed (more than 4 years of age), heterogeneous types of hypospadias and surgical techniques, and the exclusive use of circumcised men as controls. there is a paucity of studies regarding long-term follow-up of hypospadias because the transition between pediatric and adult urology is not systematic for most patients.(15-17) the most common reason for genital dissatisfaction in hypospadias patients is inadequate penile size, while the experience with masturbation appears to be similar to that of the general population.(18) it is well known that men with corrected hypospadias suffer from sexual inhibition and fear of being ridiculed, while those with proximal hypospadias are also more likely to be dissatisfied with their genital appearance.(17,19-21) no long-term-follow studies are available specifically for distal hypospadias. the present study showed that the perceived quality of life was the same for the patients, despite reduced erectile function compared to the controls. the main bias in regard to the erectile function item was that two of the patients had not yet engaged in sexual intercourse. there was no difference, however, in the overall erectile function score when these two patients were excluded from the patient group. recent studies have found that laypersons are not troubled by the penile appearance after hypospadias repair and that women perceive the genitals of men with distal hypospadias as being similar to the genitals of non-affected, circumcised men.(22,23) similarly, men with non-operated hypospadias often find that some of their sexual partners or medical professionals are not aware of their hypospadias. in the present study, the patients expressed clear displeasure regarding the length, meatus, and axis of their penis, whereas the overall appearance was rated as being similar in both groups.(24,25) as described previously, these concerns did not appear to impact the overall quality of life.(4) particularly in case of distal hypospadias, it is likely that the main reason for the stated low level of satisfaction with their penile appearance could be considered to be part of their lower overall self-esteem. self-esteem was distinctly lower in the patients: 8 (53%) of them had a score below 30, which means that specific psychological support is required. the underlying reason for this is not clear, however. indeed, the role of surgical treatment may be of little or no relevance as circumcised patients do not exhibit the same psychological profile. most of the patients contacted by phone stated that they did not remember undergoing the surgery during their childhood. however, the emotional reaction of the parents in regard to the hypospadias appears to be critically important for the patients’ psychological development. (26) this information may be of considerable relevance to practitioners who treat patients with hypospadias and their families with the aim of preventing the development of feelings of shame and negative genital perception.(27,28) when these patients undergo counseling, they should be provided support to develop a positive genital self-perception, as poor genital self-perception has been shown to correlate with an impaired mental health-related quality of life.(4) our data confirm the need for long-term follow-up to allow patients to address concerns regarding their genitals.(2,6) the main limitations of this study are the small number of patients and the possibility of selection bias for patients who agreed to participate in the survey. another limitation is the absence of an ideal control group of adult patients with hypospadias but who did not undergo surgical correction. conclusions the findings of the current study confirm poor genital self-perception of adult patients operated from distal hypospadias. this poor genital perception correlated with lower self-esteem. consequently, for clinical management, we suggest that adult hypospadias patients are made more aware of the fact that their penile appearance is often a non-issue for laypersons. early and long-term follow-up of patients and their parents could prevent this negative genital and overall self-perception from taking hold. the main limitation of this study long-term outcomes of hypospadias-belgacem et al. pediatric urology 540 relates to its long follow-up retrospective design with many consecutive biases. further prospective studies with larger numbers of patients are necessary to confirm this negative perception despite a normal perception of genital appearance. conflict of interest the authors declare that they have no conflicts of interest. references 1. hueber pa, antczak c, abdo a, francguimond j, barrieras d, houle am. longterm functional outcomes of distal hypospadias repair: a single center retrospective comparative study of tips, mathieu and magpi. j pediatr urol. apr 2015:68.e1-7. 2. van der horst hj, de wall ll. hypospadias, all there is to know. eur j pediatr. 2017;176:435441. 3. van den dungen ial, rynja sp, bosch jlhr, de jong tpvm, de kort lmo. comparison of preputioplasty and circumcision in distal hypospadias correction: long-term follow-up. j pediatr urol. 2019;15:47.e1-47.e9. 4. ruppen-greeff nk, weber dm, gobet r, landolt ma. health-related quality of life in men with corrected hypospadias: an explorative study. j pediatr urol. 2013;9:5518. 5. chertin b, natsheh a, ben-zion i, et al. objective and subjective sexual outcomes in adult patients after hypospadias repair performed in childhood. j urol. 2013;190(4 suppl):1556-60. 6. örtqvist l, andersson m, strandqvist a, et al. psychosocial outcome in adult men born with hypospadias. j pediatr urol. 2017;13:79.e179.e7. 7. ware je. sf-36 health survey update. spine (phila pa 1976). 2000;25:3130-9. 8. brazier je, harper r, jones nm, et al. validating the sf-36 health survey questionnaire: new outcome measure for primary care. bmj. 1992;305:160-4. 9. weber dm, landolt ma, gobet r, kalisch m, greeff nk. the penile perception score: an instrument enabling evaluation by surgeons and patient self-assessment after hypospadias repair. j urol. 2013;189:189-93. 10. sullivan kj, hunter z, andrioli v, et al. assessing quality of life of patients with hypospadias: a systematic review of validated patient-reported outcome instruments. j pediatr urol. 11. weber dm, schönbucher vb, landolt ma, gobet r. the pediatric penile perception score: an instrument for patient selfassessment and surgeon evaluation after hypospadias repair. j urol. 2008;180:1080-4. 12. van de grift tc, cohen-kettenis pt, de vries alc, kreukels bpc. body image and selfesteem in disorders of sex development: a european multicenter study. health psychol. 2018;37:334-343. pediatric urology 433 long-term outcomes of hypospadias-belgacem et al. 13. rosenberg m. rosenberg self-esteem scale. in: princeton, ed. princeton university press ed. 1965. 14. rosen rc, riley a, wagner g, osterloh ih, kirkpatrick j, mishra a. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997;48:82230. 15. aho mo, tammela ok, tammela tl. aspects of adult satisfaction with the result of surgery for hypospadias performed in childhood. eur urol. 1997;32:218-22. 16. bracka a. a long-term view of hypospadias. br j plast surg. may 1989;42:251-5. 17. rynja sp, de kort lm, de jong tp. urinary, sexual, and cosmetic results after puberty in hypospadias repair: current results and trends. curr opin urol. nov 2012;22:453-6. 18. moriya k, kakizaki h, tanaka h, et al. long-term cosmetic and sexual outcome of hypospadias surgery: norm related study in adolescence. j urol. 2006;176:1889-92; discussion 1892-3. 19. rynja sp, de jong tp, bosch jl, de kort lm. functional, cosmetic and psychosexual results in adult men who underwent hypospadias correction in childhood. j pediatr urol. 2011;7:504-15. 20. örtqvist l, fossum m, andersson m, et al. long-term followup of men born with hypospadias: urological and cosmetic results. j urol. 2015;193:975-81. 21. wang ww, deng ch, chen lw, zhao ly, mo jc, tu xa. psychosexual adjustment and age factors in 130 men undergone hypospadias surgery in a chinese hospital. andrologia. 2010;42:384-8. 22. ruppen-greeff nk, landolt ma, gobet r, weber dm. appraisal of adult genitalia after hypospadias repair: do laypersons mind the difference? j pediatr urol. feb 2016;12:32.e18. 23. ruppen-greeff nk, weber dm, gobet r, landolt ma. what is a good looking penis? how women rate the penile appearance of men with surgically corrected hypospadias. j sex med. 2015;12:1737-45. 24. fichtner j, filipas d, mottrie am, voges ge, hohenfellner r. analysis of meatal location in 500 men: wide variation questions need for meatal advancement in all pediatric anterior hypospadias cases. j urol. 1995;154:833-4. 25. dodds pr, batter sj, shield de, serels sr, garafalo fa, maloney pk. adaptation of adults to uncorrected hypospadias. urology. 2008;71:682-5. 26. easson wm. psychopathological environmental reaction to congenital defect. j nerv ment dis. 1966;142:453-9. 27. schönbucher vb, landolt ma, gobet r, weber dm. health-related quality of life and psychological adjustment of children and adolescents with hypospadias. j pediatr. 2008;152:865-72. 28. schönbucher vb, landolt ma, gobet r, vol 18 no 5 september-october 2021 541 weber dm. psychosexual development of children and adolescents with hypospadias. j sex med. 2008;5:1365-73. long-term outcomes of hypospadias-belgacem et al. pediatric urology 542 review 192 urology journal vol 4 no 4 autumn 2007 genetics of azoospermia: current knowledge, clinical implications, and future directions. part ii y chromosome microdeletions hossein sadeghi-nejad,1 farhat farrokhi2 introduction: we reviewed the most recent advances in the genetics of male infertility focusing on y chromosome microdeletions. materials and methods: we searched the literature using the pubmed and skimmed articles published from january 1998 to october 2007. the keywords were the y chromosome, microdeletions, male infertility, and azoospermia factor (azf). the full texts of the relevant articles and their bibliographic information were reviewed and a total of 78 articles were used. results: three regions in the long arm of the y chromosome, known as azfa, azfb, and azfc, are involved in the most frequent patterns of y chromosome microdeletions. these regions contain a high density of genes that are thought to be responsible for impaired spermatogenesis. in 2003, the y chromosome sequence was mapped and microdeletions are now classified according to the palindromic structure of the euchromatin that is composed of a series of repeat units called amplicons. although it has been shown that the azfb and azfc are overlapping regions, the classical azf regions are still used to describe the deletions in clinical practice. conclusion: y chromosome microdeletions are the most common genetic cause of male infertility and screening for these microdeletions in azoospermic or severely oligospermic men should be standard. detection of various subtypes of these deletions has a prognostic value in predicting potential success of testicular sperm retrieval for assisted reproduction. men with azoospermia and azfc deletions may have retrievable sperm in their testes. however, they will transmit the deletions to their male offspring by intracytoplasmic sperm injection. urol j. 2007;4:192-206. www.uj.unrc.ir keywords: male infertility, azoospermia, genetic diseases, chromosome aberrations, y chromosome, intracytoplasmic sperm injection 1department of urology, hackensack university medical center and umdnj new jersey medical school, hackensack, new jersey and section of urology, va new jersey health care system, east orange, new jersey, usa 2urology and nephrology research center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: farhat farrokhi, md urology and nephrology research center no 44, 9th boustan, pasdaran, tehran, iran tel: +98 21 2259 4204 fax: +98 21 2259 4204 e-mail: farrokhi@unrc.ir introduction one in 20 men suffers from male infertility, and pure male-factor infertility comprises approximately one-third of all infertilities. a great proportion of these patients have primary spermatogenesis failure with a genetic cause.(1) with the advent of accurate diagnostic tools and recent knowledge of the y chromosome map, the genetic aberrations responsible for infertility are more easily recognized. moreover, men with azoospermia or severe oligospermia caused by some of these genetic defects can undergo sperm retrieval techniques and potentially father their own children. thus, a definite diagnosis of the causal factors of spermatogenesis impairment can determine the therapeutic approaches and predict success rate of the treatment. on the other hand, since the use of testicular sperm extraction (tese) and intracytoplasmic sperm injection (icsi) can bypass the natural selection of intact spermatozoa, there have been consistent concerns about y chromosome microdeletions—sadeghi-nejad and farrokhi urology journal vol 4 no 4 autumn 2007 193 the possibility of transmitting genetic disorders to the offspring.(2) the scenario is further complicated by the presence of a y chromosome microdeletion (ycm). these structural genetic abnormalities form various genotypes that result in diverse unpredictable phenotypes, warranting further elucidation of their role in infertility and their influence on the assisted reproductive technologies (art) outcomes. y chromosome microdeletions are the most frequently observed structural abnormalities in the male-specific region of the y chromosome,(2) and of primary spermatogenesis failures, 15% are related to at least 6 known major ycm patterns.(1) interestingly, these microdeletions have been reported to occur in fertile men, as well.(3,4) microdeletions are present in 5% to 10% of infertile men.(5) specifically, they have been reported in 2% to 3% of the candidates for icsi, 6% to 16% of azoospermic men, and 4% to 5.8% of those with severe oligospermia.(2,6) limited studies in the middle east have been done; ycms were reported in 3.2% of men with idiopathic azoospermia or oligospermia in saudi arabia, in 3.3% of those in turkey, and in 2.6% in kuwait.(7-9) in iran, studies on small numbers of patients showed that 5% to 24.2% of infertile men with idiopathic severe spermatogenesis impairment had these genetic aberrations.(10-12) deletions in the y chromosome are mostly de novo.(13) however, several cases of natural transmission of the microdeletion have been reported to date.(14-19) since tiepolo and zuffardi reported cytologically detectable deletions of the proximal yq in azoospermic men,(20) a tremendous amount of research has been done to scrutinize the mechanism of developing and characteristics of these deletions. in 1996, vogt and colleagues identified 3 recurrently deleted regions in yq11. these were termed the azoospermia factor (azf), and the 3 regions were named as azfa, azfb, and azfc.(21) our understanding of these regions, however, has been revolutionized by recent sequencing of the y chromosome and determining the breakpoints of the deletions. it is now hypothesized that most of the azf microdeletions are generated by intrachromosomal homologous rearrangements of the genetic material by crossing over (recombination) occurring between a series of repeated sequence blocks that have nearly identical structures.(22) notwithstanding the large body of information gained on the y chromosome during the last decade, it is still not possible to attribute spermatogenic function to definite genes, because each of the deletions usually removes multiple genes.(18) consequently, it is not clear whether the resulted phenotype is caused by the loss of all genes in a region or by disruption of a major gene whose expression alone is responsible for spermatogenesis.(5) furthermore, the known patterns of deletions are variable in details and preclude clear classification of men with a specific type of deletion.(23) it should be added that there is no association between the length of the deletion and the semen quality or the testicular histology.(2) despite these challenges, the current knowledge provides us with a helpful view of the genetic causes of azoospermia that can be utilized in practice. this article is the second part of the review we performed on the genetics of male infertility. in part i, genetic causes of male infertility in karyotypic abnormalities, obstructive azoospermia, and idiopathic hypogonadotropic hypogonadism were discussed.(24) in this review, we report the latest findings about ycms and discuss their clinical implications. to update our previous article published in 1997 on the subject,(25) we performed an extensive search on the pubmed for the relevant articles that appeared from 1998 to october 2007. the keywords were y chromosome, microdeletion, male infertility, and azf. other specific words were researched during the study if needed. we reviewed 99 papers and their bibliographic information; of these, 78 with the most relevant and valid information were included in the final analysis. y chromosome structure since the early 20th century, in which the y chromosome used to be known as a genetic wasteland, revolutionary changes have been made in our knowledge of this chromosome.(22) currently, we know that the y chromosome is functional for spermatogenesis and is, at the same time, polymorphic.(26) accordingly, multiple y chromosomes have developed during human evolution distinguished now by a rooted pedigree of at least 153 y chromosome haplogroups around the world.(26) generally, of the 60 mb length of the y chromosome, 3 mb belongs to pseudoautosomal y chromosome microdeletions—sadeghi-nejad and farrokhi 194 urology journal vol 4 no 4 autumn 2007 regions and 57 mb to a nonrecombining region that contains heterochromatic and euchromatic regions (figure 1). the euchromatin embraces most of the known genes in the y chromosome. in the primary attempts to map the y chromosome, vollrath and colleagues subdivided yq11, the region in which they found deletions, into 23 intervals termed 5a to 5q and 6a to 6f.(28) vogt and coworkers established another sequence-tagged site deletion map dividing yq11 into 25 intervals of d1 to d25 (figure 1).(29) today, the y chromosome has been sequenced completely and its genomic sequence is available (http://www.ensembl.org/homo-sapiens/ mapveiw?chr=y). by sequencing the y chromosome in 2003, skaletsky and colleagues proposed a new model for analysis of the male-specific region of the y chromosome.(22) they showed that the malespecific region of the y chromosome comprises 95% of the y chromosome length, and that it is a mosaic of heterochromatic and euchromatic sequences. heterochromatin is located among repeated genes, gene families, and palindromic motifs.(2) the euchromatic dna sequences on the y is about 23 mb including 8 mb on the short arm and 14.5 mb on the long arm.(22) there are 3 classes of euchromatic sequences (figure 2): those transposed from the x chromosome during the process of the evolution of the y (x-transposed), those somewhat similar to sequence information from the x chromosome (x-degenerate), and those repeated units across the proximal short arm of the yp and across most of the yq (amplicons).(22) the x-transposed regions, with a combined length of 3.4 mb, are almost identical to the dna sequences in figure 1. pseudoautosomal and nonrecombining regions on the y chromosome.(27) the nonrecombining region is 57 mb in length and encompasses euchromatic regions that harbor almost all recognized genes responsible for spermatogenesis. the heterochromatin consists of 3 regions: a large part of the distal yq, the centromere, and a newly discovered very small region within the euchromatic region of the yq.(22) mapping of this region has evolved in the recent decade. vollrath and colleagues introduced their map in 1992.(28) later in 1996, vogt and colleagues proposed d1 to d25 in which the azf regions were identified.(21) in the latest model by skaletsky and associates, massive palindromic regions (p1 to p8) are introduced and it has been found that the azfb and azfc overlap.(22) y chromosome microdeletions—sadeghi-nejad and farrokhi urology journal vol 4 no 4 autumn 2007 195 the xq21. the x-transposed sequences are the result of a massive x-to-y transposition that had occurred about 3 million years ago, after the divergence of the human and chimpanzee lineages. within the xtransposed segments, only 2 protein-encoding genes have been identified (tgif2ly and pcdh11y).(22) the x-degenerate regions, with a combined length of 8.5 mb, are dotted with single-copy genes or pseudogenes that are mostly expressed ubiquitously (i.e. expressed in multiple organs in the body and not confined to a specific tissue). these genes are about 60% and 90% similar to their x-linked homologues and are thought to be relics of ancient autosomal chromosomes from which the x and y chromosomes originated. the sex-determining gene (sry) is located in this region. the sry gene expresses a transcription factor that switches on the genes that direct the development of male structures in the embryo. the genes recognized in the azfa (dby and usp9y) are also located in the x-degenerate region.(22,26) the most sophisticated regions of the y chromosome are the unique ampliconic regions in the euchromatin that are 10.5 mb long overall. amplicons are families of units composed of nucleotide sequences that are markedly similar to each other.(2) they are located in 7 segments that are scattered across the euchromatin in the long arm and proximal short arm of the y chromosome. amplicons harbor the highest density of the y chromosome genes that are exclusively expressed in the testes. genes related to the azfb and azfc are located in the ampliconic regions.(26) the array of the amplicons forms 8 palindromes (p1 to p8) that are the most pronounced structural features of the ampliconic region (figure 3). each figure 2. three classes of the euchromatin and their relation to the azf regions are depicted. there are 7 ampliconic, 8 xdegenerate, and 2 x-transposed regions. the azfa is located in the x-degenerate region. all the protein-encoding genes in the azfc are in the ampliconic regions, but the genes in the azfb are located in both amplicons and x-degenerate region.(22) figure 3. palindromic structure of the y chromosome. as an example, the structure of p1 to p3 is shown. each palindrome consists of a set of amplicons that is repeated reversely. thus, the palindrome reads the same in either direction. in addition to the palindromes, there are 5 sets of amplicons that are widely spaced inverted repeats (irs) with small lengths.(22) y chromosome microdeletions—sadeghi-nejad and farrokhi 196 urology journal vol 4 no 4 autumn 2007 palindrome is comprised of 2 groups of amplicons with similar but inverted arrangements. in other words, a palindrome is a dna sequence containing different amplicons which has a twin along the chromosome that read the same in a reverse direction.(1) most of the recognized genes that are deleted in infertile men are located in the palindromic regions of the yq. genes on y chromosome to date, 122 genes and 110 pseudogenes have been identified in the y chromosome (available from http://www.gdb.org/gdbreports/ genebychromosome.y.alpha.html, last updated, december 2, 2007). however, the exact role of these genes in spermatogenesis is not elucidated because microdeletions that cause spermatogenesis impairment usually include more than 1 gene, so that the role of each deleted gene cannot be specified. some genes have been considered to have a major part in spermatogenesis, but in most cases, reports of deletions in fertile or subfertile men have questioned their specific function. so far, only 1 isolated yq gene mutation has been reported that leads to spermatogenesis failure.(30,31) the abovementioned impediments have confined research on ycms to identification of the deleted regions and the group of genes they usually harbor. defining the classical azf regions was the primary step. however, the newly identified breakpoints for deletions along the male-specific region of the y chromosome do not necessarily conform to the azf pattern. in addition, it has been shown that the azfb and azfc are overlapping regions.(32) nonetheless, microdeletions are still described in relation to their location in the 3 classical azf regions.(2,5,33,34) azoospermia factor in 1996, vogt and colleagues conducted a large collaborative study and screened 370 men with idiopathic azoospermia or severe oligospermia for submicroscopic deletions in the yq. thirteen of these men had microdeletions mapping to 3 different regions designated, from proximal to distal, as azfa, azfb, and azfc.(21) there are at least 14 proteinencoding y gene families in the azf loci (table 1).(26) deletions of these genes occur as 6 classical types of yq deletions: azfa, azfb, azfc, azfbc, n um be r of d el et ed c op ie s g en e s ym bo l g en e n am e n um be r of c op ie s e xp re ss io n lo ca tio n a zf l oc at io n c om pl et e a zf a c om pl et e a zf b (p 5/ p ro xi m al p 1) a zf bc (p 5/ di st al p 1) a zf c* u s p 9y u bi qu iti n s pe ci fic p ro te as e 9 y 1 u bi qu ito us x -d eg en er at e a z f a 1 0 0 0 d b y d ea d b od y y 1 u bi qu ito us x -d eg en er at e a z f a 1 0 0 0 r b m y r n a -b in di ng m ot if yli nk ed 6 o nl y te st is a m pl ic on s a z f b 0 6 6 0 h s f y h ea tsh oc k tr an sc rip tio n f ac to r y 2 te st is , k id ne y a m pl ic on s a z f b 0 2 2 0 p r y p t p -b l r el oa te d y 2 o nl y te st is a m pl ic on s a z f b 0 2 2 0 x k r y x -k el l b lo od g ro up p re cu rs or r el at ed y 2 o nl y te st is a m pl ic on s a z f b 0 1 1 0 r p s 4y 2 r ib os om al p ro te in s 4 y l in ke d 2 1 te st is , p ro st at e x -d eg en er at e a z f b 0 1 1 0 s m c y s el ec te d m ou se c d n a y 1 u bi qu ito us x -d eg en er at e a z f b 0 1 1 0 e if 1a y e ss en tia l i ni tia tio n tr an sl at io n f ac to r 1a y 1 u bi qu ito us x -d eg en er at e a z f b 0 1 1 0 c d y c hr om od om ai n y 4 o nl y te st is a m pl ic on s a z f b an d a z f c† 0 2 2 0 to 2 d a z d el et ed in a zo os pe rm ia 4 o nl y te st is a m pl ic on s a z f c 0 2 4 0 to 4 b p y 2 b as ic p ro te in y 2 3 o nl y te st is a m pl ic on s a z f c 0 1 3 0 to 3 c s p g 4l y c ho nd ro iti n su lfa te p ro te og ly ca n 4 li ke y 2 o nl y te st is a m pl ic on s a z f c 0 0 2 0 to 2 g o lg a 2l y g ol gi a ut oa nt ig en , g ol gi n s ub fa m ily a 2 li ke y 2 o nl y te st is a m pl ic on s a z f c 0 0 2 0 to 2 ta bl e 1. p ro te in -e nc od in g g en e f am ili es o n th e a zo os pe rm ia f ac to r r eg io ns (2 3, 26 ,3 2) *c om pl et e an d pa rt ia l a z f c de le tio ns u su al ly s ho w v ar ia tio ns in th e de le tio ns o f t he g en es . †c d y 1 is lo ca te d in th e a z f c an d c d y 2, in th e a z f b. o ne c op y of th e c d y 1 is in th e ov er la pp ed r eg io n of th e a z f c w ith a z f b. y chromosome microdeletions—sadeghi-nejad and farrokhi urology journal vol 4 no 4 autumn 2007 197 azfabc, and partial azfc (figure 4).(1) the most common deletions are in the azfc and azfb. partial and complete azfc deletions are seen in 60% of the ycms, and the azfb is the deletion site of about 16% of azf deletions in infertile men.(11) in total, 35% of the deletions are azfb, azfbc, or azfabc.(1) only 2% to 5% of the deletions are seen in the azfa region.(11,18) omrani and coworkers in northwestern iran showed that 24 out of 99 patients with azoospermia or severe oligospermia (24.2%) had microdeletions in the azf region, but no microdeletions were found in fertile men. the deletions comprised the azfc (87.5%) and azfb (29.2%) regions.(10) their relatively high frequency of ycms is yet to be confirmed by studies on larger samples and newer diagnostic instruments. in a study on 247 saudi men with idiopathic azoospermia or oligospermia, 3.2% had ycm, consisted of 6 in the azfc, 1 in the azfb, and 1 in both azfa and azfc.(7) azfa complete deletion of azfa is associated with azoospermia and no foci of testicular spermatozoa.(2,18) azfa region harbors 2 proteinencoding genes of usp9y, and dby (recently called ddx3y) that are involved in deletions. they are both located in the x-degenerate region of euchromatin and have homologous genes on the x chromosome. the dead box y gene (dby) encodes a putative rna helicase.(34) foresta and colleagues showed a major role of dby in the azfa region in spermatogenesis.(35) the ubiquity-specific protease 9y gene (usp9y, previously known as dffry) encodes a protease involved in the regulation of protein metabolism.(34) this gene is the only one in the azf region that has been found to be deleted in isolation; its deletion was associated with severe oligospermia and azoospermia in the 2 reported cases, the histology of both of which was indicative of hypospermatogenesis.(30,31) however, krausz and colleagues in 2006 reported the first case of azfa partial deletion involving usp9y that was transmitted naturally from a father to his son; isolated deletion of the usp9y was found in 2 generations of 2 families. they concluded that usp9y might have a fine-tuning role (rather than an essential role) that improves efficiency in spermatogenesis.(18) figure 4. six types of azf microdeletions and the resulted phenotypes are shown. the most common deletion patterns are the azfc and partial azfc deletions. the partial deletions in the azfc have several forms with different phenotypes in each population. partial azfa and azfb are the other conditions that are rare.(1,2) sco indicates sertoli cell-only. y chromosome microdeletions—sadeghi-nejad and farrokhi 198 urology journal vol 4 no 4 autumn 2007 azfb complete deletion of azfb is associated with azoospermia and no foci of testicular spermatozoa.(11) the known protein-encoding genes in this region that are associated with spermatogenesis are eif1ay, rps4y2, and smcy that are located in x-degenerate euchromatin, and hsfy, xkry, pry, and rbmy that are in the ampliconic regions (table 1). the first proposed gene responsible for azfb deletions was the rbmy.(21) the rbmy gene family encodes testisspecific rna binding proteins that are exclusively expressed in the germ cells.(36) there are 6 copies of this gene family in the azfb.(22) ferlin and colleagues questioned the essential role of this gene in spermatogenesis; they found severe spermatogenesis failure in men with a partial azfb deletion that had removed smcy, eif1ay, rps4y2, and hsfy, but not the rbmy.(37) heat shock transcription factor, y-linked gene (hsfy) is a newly discovered gene involved in ycm that encodes a protein similar to those regulated by the heat shock factor family. the hsfy protein is expressed in sertoli cells and spermatogenic cells and it has been shown that in mammalian tastes, heat shock proteins have a role in spermatogenesis.(38) shinka and colleagues reported the predominant expression of hsfy in the testes and deletion of hsfy along with rbmy in 2 azoospermic men.(38) sato and colleagues found that the expression of hsfy was altered in men with sertoli cell-only (sco) syndrome and maturation arrest.(39) another gene on which some researchers have focused is the eif1ay that ubiquitously encodes an essential translation initiation factor.(27) kleiman and colleagues showed that the absence of expression of eif1ay might contribute to azoospermia.(34) they also studied the expression of the pry, another gene in the azfb, and found that its absence of expression resulted in testes without germ cells.(34) azfc the azfc is a 4.5-mb region of the euchromatin and its complete deletion is one of the most frequent causes of male infertility.(40) partial deletion of azfc is another frequent pattern. recently, zhang and coworkers found partial azfc deletions in the pedigrees of complete azfc deletion carriers and concluded that partial deletions of azfc could increase the risk of complete azfc deletion.(40) the role of these deletions in spermatogenesis is controversial. spermatozoa can be found in the ejaculate or the testicular tissue of 50% of men with azfc microdeletions.(2) fertility may occur in the presence of partial azfc deletions with various lengths; several cases of fathering children have been reported, but in all of them, the azfc deletions are transmitted to the male offspring, and interestingly, the sons have phenotypes not necessarily similar to their fathers.(14,16,17,19) the azfc contains 8 gene families including bpy2, cdy, daz, cspg4ly, golgazly, tty3.1, tty4.1, and tty7.1, the 5 former of which are protein-encoding genes that are thought to be associated with spermatogenesis (table 1).(26) there are 3 copies of the bpy2, 2 copies of the cdy1, and 4 copies of the daz. the first recognized gene in the azfc was daz which was described in 1995 by reijo and colleagues.(41) the daz gene belongs to a gene family including boule and dazl autosomal single-copy genes.(2) this gene encodes rna-binding proteins that are exclusively expressed in the germ cells.(34) copies of daz in a y chromosome are almost identical.(42) the 2 clusters of these genes are inverted pairs of daz1/daz2 and daz3/ daz4.(43) deletion of each member of daz may have different effects.(44) deletions in daz2, daz3, and daz4 copies are found in both fertile and infertile men and are described as familial variants inherited from father to son.(45) however, daz1/ daz2 deletions were reported to be restricted only to infertile men.(45) expression of daz1 seems to be essential for spermatogenesis, but a recent case of fertile man with daz1 deletion has been reported.(45,46) the chromodomain y gene (cdy1) encodes a protein involved in dna remodeling.(34) kleiman and colleagues showed that cdy1 transcripts correlate with complete spermatogenesis.(47) the 2 copies of cdy1 (known as cdy1a and cdy1b) are located in the azfc; however, one copy is in a region that is now shown to have an overlap with azfb. thus, azfb and azfbc deletions may remove one copy of cdy1.(32) two other copies of the cdy gene family (cdy2) are located in the azfb. azfd in 1999, kent-first and colleagues described a y chromosome microdeletions—sadeghi-nejad and farrokhi urology journal vol 4 no 4 autumn 2007 199 fourth azf region between the azfb and azfc, termed the azfd,(4) which was associated with mild oligospermia or abnormal sperm morphology.(4,48) later, cram and colleagues described azfcd deletions in candidates for icsi.(49) muslumanoglu and colleagues reported that three-fourth of their cases of azf deletions had azfd deletions.(48) in patients with sco syndrome, deletion of a single locus in the azfd, as well as an azfc deletion, was noted. this locus (sy152) is located proximal to the azfc and one of the daz copies. despite the initial excitement about this discovery, the existence of the azfd region was seriously questioned. noordam and colleagues discussed that the deletions in these single loci can be a polymorphism instead of “disease-causing deletions.(50)” moreover, according to the new models, the azfb overlaps the proximal azfc and there is no distinct area between these regions.(32) the azfd sequence-tagged sites are in fact within the azfc and are deleted in some types of partial azfc deletions. the current consensus expert opinion is that azfd does not exist and that the initial reporting of the whole concept was the result of significant technical flaws. currently, azfd is not considered in clinical practice. new aspects of y chromosome microdeletions in the past few years, the molecular mechanism of ycm was recognized to be derived from the homologous recombination between identical sequence blocks. this resulted in assays of the ycms according to new patterns that did not completely correspond to the classical azf regions. in 2001, kuroda-kawaguchi and colleagues determined the complete nucleotide sequence of azfc and proposed the structure of 6 families of massive repeat units (amplicons) that constitute a complex of 3 palindromes.(42) later in 2002, repping and colleagues further investigated the azfb and azfbc deletions and determined their breakpoints.(32) the y chromosome was mapped by skaletsky and colleagues in 2003.(22) this led to the researchers’ attention being focused on the homologous recombinations between the amplicons, especially in partial azfc deletions. the azfa, however, was an exception: the x-degenerate region of the euchromatin was involved and deletions could not be explained by breakpoints between the amplicons. in 2000, kamp and colleagues found that the proximal breakpoints of the azfa were located in a long retroviral sequence block and the distal breakpoints in a homologous herv15 sequence block.(51) they assumed that intrachromosomal recombination events between the two homologous retroviral sequence blocks in the proximal yq11 are probably the causative agents for most of the azfa microdeletions observed in men with sco syndrome. a mean value of 792 kb was estimated for their molecular lengths.(51) studying the azfc was a trigger to the introduction of the palindromic structure of the y chromosome. kuroda-kawaguchi and colleagues sequenced the entire azfc region and found 6 distinct families of amplicons ranging from 115 kb to 678 kb in length (named after colors: yellow, green, blue, turquoise, gray, and red).(42) members of each amplicon family are nearly identical and each of these occurs 2 to 4 times along the euchromatin (figure 5). together, they account for 93% of the azfc and contain rbmy, pry, bpy2, daz, cdy1, cspg4ly, and golga2ly genes.(42) the azfc is particularly susceptible to deletions because its structure is completely composed of the amplicons.(44) according to the ampliconic sequences, the classical complete azfc deletion encompasses a 3.5-mb totally ampliconic region between 2 blue amplicons (b2 and b4) that occurs by homologous recombination (b2/b4 recombination).(2) other potential recombinations were then studied for explanation of partial deletions. repping and colleagues described a partial deletion in the azfc termed gr/gr in infertile men (one of the g1/g2, r1/r2, or r2/r4 deletion patterns that remove half of the azfc). the gr/gr deletion was associated with varying degrees of spermatogenesis failure.(23) yen hypothesized a b1/b3 recombination as a potential mechanism of partial azfc deletion that removes the proximal portion of the azfc.(52) its role in infertility is not known yet, since it has been found in a small number of fertile and infertile men.(23,54) in 2004, repping and colleagues described b2/b3 recombination (also called g1/g3), a 1.8-mb deletion that removes half of the azfc region, including 12 members of 8 testis-specific gene families (figure 5).(53) this deletion was also identified by y chromosome microdeletions—sadeghi-nejad and farrokhi 200 urology journal vol 4 no 4 autumn 2007 fernandes and coworkers in a separate publication.(55) the roles of partial azfc deletions (gr/gr and b2/ b3) in spermatogenesis failure are controversial.(40,44) the azfb and azfbc deletions were studied in 2002 by repping and colleagues,(32) one year after the introduction of the palindromic structure of the azfc by kuroda-kawaguchi and colleagues.(42) repping and coworkers found that azfb deletions were extended from palindrome p5 to the proximal arm of palindrome p1, which is 1.5 mb within the azfc.(32) the azfbc deletions were extended from p5 to the distal arm of p1 (figure 6). the p5/proximal p1 deletion (azfb) encompasses up to 6.2 mb and removes 32 genes and transcripts figure 5. the amplicons and palindromes in the azfc in relation to the protein-encoding genes are demonstrated. below, the common types of deletions (partial and complete) are seen. the b2/b4 recombination removes all the azfc. the gr/gr deletion appears with various patterns (g1/g2, r1/r3, and r2/r4) that remove different sets of genes.(23,42,52,53) figure 6. the azfb and azfbc deletions are now described as p5/proximal p1 and p5/distal p1 deletions, respectively. the azfb deletion removes 6.2 mb of the yq, and the azfbc, 7.7 mb of this region. the deleted genes in each pattern are demonstrated.(32) y chromosome microdeletions—sadeghi-nejad and farrokhi urology journal vol 4 no 4 autumn 2007 201 and the p5/distal p1 (azfbc) is 7.7 mb, removing 42 genes and transcripts (table 1).(32) accordingly, all the protein-encoding genes associated with spermatogenesis in the azfb and azfc are included in the p5/distal p1 deletion and all except cspg4ly and golga2ly are involved in the p5/proximal p1 (complete azfb) deletion. these 2 deletions are massive, removing one-fourth to one-third of the euchromatin of the y chromosome, and cause azoospermia. genotype-phnotype associations in clinical practice, information about the azf deletions has a predictive role for art outcomes. hopps and associates demonstrated that men with azfa, azfb, and azfbc have no possibility of sperm retrieval through tese, while isolated azfc is associated with successful tese in 75% of the cases.(56) in concert with their findings, krausz and colleagues demonstrated that azfc deletions are associated with sperm retrieval in half of the cases, while in complete azfa and azfb deletions, the probability of finding mature spermatozoa by tese is virtually nil.(57) however, it should be noted that partial deletions in the azfa and azfb, although extremely rare, have been reported with natural transmission of the deletions to the offspring.(15,18) in effect, complete azfa and azfb deletions are known to correspond to the sco syndrome and spermatogenic arrest, respectively, while partial azfb or azfc and complete or partial azfc deletions lead to variable phenotypes from hypospermatogenesis to the sco syndrome.(2) two possible explanations for genotype-phenotype dissociation in ycms are the markers and techniques used to identify the deletions and the reportedly progressive regression of the germinal epithelium over time in men with these deletions.(11) the progressive nature of spermatogenesis failure has been reported by some authors,(11,14) indicating that partial deletions may cause subfertility that progresses to azoospermia over time.(58,59) however, oates and coworkers found a fluctuation, but not decrease, in sperm count during a 7-year period in 42 men with azfc deletions.(60) one other factor is the key to interpret conflicting results of the influence of partial azfc deletions: the y chromosome lineage on which the deletion has arisen.(43) y chromosome lineage or haplotype is a monophyletic group of y chromosomes defined by slowly mutating binary markers. some haplotypes are confined to particular populations. in europe for instance, there are 5 or 6 major y chromosome haplogroups. thus, the influence of azfc partial deletions should be assessed based on the ethnic groups and their genetic characteristics of the y chromosome.(43) the gr/gr and b2/b3 partial azfc deletions have been studied in different haplogroups. surprisingly, although the b2/b3 deletion removes daz3/daz4 and bpy2.2/bpy2.3, it is not associated with spermatogenesis failure as it is seen in a large population of men in the northern europe.(55) likewise, in east asian populations, b2/b3 deletion was not linked with infertility, suggesting a polymorphism with limited or no effect on fertility.(33,40) however, the gr/gr deletions may have a limited effect on fertility in some specific y chromosome haplogroups.(43) it has been proposed that the gr/gr deletion has occurred multiple times during human evolution and the fertility status of individuals carrying the gr/gr deletion is unknown.(43) in eastern asians, the gr/gr deletions are seen in 8% to 10% of men.(44,61) zhang and colleagues reported that this deletion did not render an increased risk of infertility,(61) but they later found a gr/gr deletion in the pedigrees of complete azfc deletion carriers and concluded that partial deletions of azfc could increase the risk of complete azfc deletion.(40) in an australian population, the gr/gr deletion was associated with infertility (but not with the severity of spermatogenesis impairment) and it was even more frequent than complete azfc deletion.(62) on the other hand, although giachini and colleagues found an association of the gr/gr deletion with infertility in italian men, they reported that cryptorchidism and varicocele were also present in 3 out of 7 men with this deletion.(63) as an explanation of these controversial results, a secondary duplication of b2/ b4 was found by repping and colleagues among gr/ gr deletion cases that might rescue the phenotype.(43) the daz gene family is the main protein-encoding gene family that may have a role in these deletions. repping and colleagues introduced 3 types of gr/gr deletions, not all of which included the daz1/daz2 cluster or the daz3/daz4 cluster.(23) later, machev and colleagues found 4 types of gr/gr deletions and showed that only deletions containing daz3/daz4 y chromosome microdeletions—sadeghi-nejad and farrokhi 202 urology journal vol 4 no 4 autumn 2007 plus cdy1a were linked with infertility.(46) diagnosis and treatment in younger patients who are diagnosed early in their fertile years, progressive decrease in testicular spermatogenic activity over time is an indication for potential cryopreservation of ejaculated spermatozoa to avoid invasive techniques in the future.(2,11,57) otherwise, art/icsi, combined with sperm retrieval techniques such as tese in selected azoospermic men, can be a treatment of choice for infertile men with ycm. as mentioned above, some ycms remove the chance of successful art, while patients with other types of deletions such as azfc deletions may have retrievable sperm in their testes.(56,57) of note, rare cases of successful icsi have been reported in patients with partial azfb deletions.(6) successful art/icsi in men with ycm and subsequent fertilization and childbirth has been reported frequently. however, van golde and colleagues reported that although successful pregnancy and childbirth are readily achievable in ycm men, fertilization rate by icsi in men with azfc deletions was significantly lower than that in other icsi candidates.(64) intracytoplasmic sperm injection is associated with some risks for the offspring if the father harbors y chromosome aberrations. only 2% to 3% of the icsi candidates harbor y microdeletions. (2) however, it is estimated that if one-half of all azoospermic men were to undergo icsi, the incidence of male infertility would double within seven generations, a great proportion of which would be due to y deletions transmitted to the sons.(65) hence, the main issue of concern is that men with ycm who have intratesticular spermatozoa will almost certainly pass the deletion to male offspring through art/ icsi.(2) in practice, several cases of azfc deletion transmissions by icsi have been reported.(49,66,67) also, katagiri and colleagues have reported sperm retrieval and fathering of a son with identical deletion in a man with partial azfb deletion.(6) it has been reported that icsi per se is not a risk factor for generation of yq deletions.(1) on the other hand, some reports indicate that the incidence of chromosomal abnormalities after icsi, including de novo deletions, is higher in the offspring of men with genetic aberrations compared to the general male population.(68,69) for the first time, kent-first and colleagues evaluated icsi-conceived sons for y microdeletions in 1999. they found 1 boy with a de novo deletion while his father did not have any deletions.(4) furthermore, although microdeletions seem to be stable when inherited by icsi,(70) lee and colleagues reported vertical transmission of azf deletions in 4 fetuses conceived by icsi, in 2 of which the deletion was expanded compared to that in the fathers.(68) second, although no other abnormality in the icsi-conceived sons of fathers with azf deletions is reported, it may still be too early to reach any conclusions. although the data suggest that there are no health implications other than infertility associated with this type of vertical transmission, it is important to remember that the first generation of babies with ycm has not yet reached maturity.(71) third, new techniques bypass the natural selection of spermatozoa and may, at least theoretically, allow entry of poor-quality sperm into the reproductive process.(72) van golde and colleagues found a poorer embryo quality in icsi-conceived offspring of men with azfc deletions.(64) they hypothesized that azfc deletions may cause impairment of the spermatozoa quality or may adversely affect sperm function in the fertilization process. this lowers the chance of conceiving boys, as supported by their icsi data.(64) fourth, the relationship of ycms and other genetic lesions to male infertility continues to be an area of concern and should be considered in studies on the risks of icsi.(1) rucker and coworkers showed that of 17 candidates for tese who had ycm, 5 had additional karyotypic abnormalities.(72) patsalis and colleagues suggested that there might be a potential risk of chromosomal aneuploidy for male offspring born to fathers with ycm.(73) siffroi and colleagues reported that a significant fraction of spermatozoa from men with ycm are nullisomic for sex chromosomes, indicating a potential risk for the offspring to develop 45,x turner syndrome or other abnormalities.(74) also, in 46,xy/45,x mosaic patients with sexual ambiguity a high incidence of azfc deletions can be found.(11) finally, dewan and colleagues found that azfc microdeletions were significantly more frequent in y chromosome microdeletions—sadeghi-nejad and farrokhi urology journal vol 4 no 4 autumn 2007 203 men from couples with recurrent pregnancy loss than in fertile and infertile men. these men had 3 or more microdeletions. the authors suggested that the proximal azfc region might play an important role in maintaining gestation.(75) table 2 summarizes the risks of icsi for men with ycm. the omnipotence of tese/icsi has reduced the need for seeking the etiology of spermatogenesis failure, while pretreatment diagnosis can result in a more appropriate knowledge-based therapy. regarding the risks depicted above, testing for y chromosome microdeletions is an important factor in counseling before icsi.(71) long-term follow-up studies of icsi-induced offspring are recommended for icsi candidates .(73) also, in men with hypospermatogenesis caused by ycms, transfer of 45,x embryos may occur through icsi; therefore, systematic screening should be emphasized.(73) today, most andrology and infertility centers routinely offer y chromosome testing to men with severe spermatogenesis failure, especially before art treatment.(1) the criteria to perform ycm analysis and the laboratory methods used play an important role. in addition, practical issues might alter the indications because of problems related to the availability of technical expertise, prohibitive costs, and lack of insurance coverage.(76) overall, screening is definitely suggested for men with sperm count of 1 × 106/ml or less,(69) but many experts suggest 5 × 106/ml as the cutoff point, since 10.5% of patients with a sperm count less than 5 × 106/ml may harbor microdeletions; this is also the criterion for chromosome analysis.(27,70,77) concerning the laboratory methods, the sequence-tagged sites and their number to be screened are the important factors to determine the accuracy of screening protocol.(78) recently, high-resolution microarrays for chromosome screening and microchip devices for electrophoresis have been developed.(1) these devices require small amounts of dna and little time for analysis,(79) and when combined by multiplex polymerase-chain reaction assays, they can be useful for detection of deletions in the azf.(79) in case y microdeletions are discovered in the male infertility workup, the decision to proceed with icsi is tied to the certain knowledge that male offspring will be infertile by definition. interestingly, giltay and colleagues showed that more than half of the patients who tested positive for chromosomal aberrations decided to go ahead with icsi.(80) a thorough genetic consultation should be offered and the physician should confirm the couples’ understanding of the potential risks to their child. in such cases, sex selection by preimplantation genetic diagnosis assays and female embryo selection is an option for some couples. conflict of interest none declared. acknowledgement the authors wish to thank dr mohammad reza safarinejad and dr nasim zamani who reviewed our papers and also ms mojgan khoddam for her technical support. references 1. cram ds, osborne e, mclachlan ri. y chromosome microdeletions: implications for assisted conception. med j aust. 2006;185:433-4. 2. georgiou i, syrrou m, pardalidis n, et al. genetic and epigenetic risks of intracytoplasmic sperm injection method. asian j androl. 2006;8:643-73. 3. pryor jl, kent-first m, muallem a, et al. microdeletions in the y chromosome of infertile men. n engl j med. 1997;336:534-9. 4. kent-first m, muallem a, shultz j, et al. defining regions of the y-chromosome responsible for male infertility and identification of a fourth azf region (azfd) by y-chromosome microdeletion detection. mol reprod dev. 1999;53:27-41. 5. ferlin a, arredi 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test in male infertility? j med genet. 2005;42:497-502. 64. van golde rj, wetzels am, de graaf r, tuerlings jh, braat dd, kremer ja. decreased fertilization rate and embryo quality after icsi in oligozoospermic men with microdeletions in the azoospermia factor c region of the y chromosome. hum reprod. 2001;16:289-92. 65. faddy mj, silber sj, gosden rg. intra-cytoplasmic sperm injection and infertility. nat genet. 2001;29:131. 66. kamischke a, gromoll j, simoni m, behre hm, nieschlag e. transmission of a y chromosomal deletion involving the deleted in azoospermia (daz) and chromodomain (cdy1) genes from father to son through intracytoplasmic sperm injection: case report. hum reprod. 1999;14:2320-2. 67. page dc, silber s, brown lg. men with infertility caused by azfc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. hum reprod. 1999;14:1722-6. 68. lee sh, ahn sy, lee kw, kwack k, jun hs, cha ky. intracytoplasmic sperm injection may lead to vertical transmission, expansion, and de novo occurrence of y-chromosome microdeletions in male fetuses. fertil steril. 2006;85:1512-5. y chromosome microdeletions—sadeghi-nejad and farrokhi 206 urology journal vol 4 no 4 autumn 2007 69. land ja, evers jl. risks and complications in assisted reproduction techniques: report of an eshre consensus meeting. hum reprod. 2003;18:455-7. 70. aittomaki k, wennerholm ub, bergh c, selbing a, hazekamp j, nygren kg. safety issues in assisted reproduction technology: should icsi patients have genetic testing before treatment? a practical proposition to help patient information. hum reprod. 2004;19:472-6. 71. reyes-vallejo l, lazarou s, morgentaler a. y chromosome microdeletions and male infertility: who should be tested and why? bju int. 2006;97:441-3. 72. rucker gb, mielnik a, king p, goldstein m, schlegel pn. preoperative screening for genetic abnormalities in men with nonobstructive azoospermia before testicular sperm extraction. j urol. 1998;160:2068-71. 73. patsalis pc, sismani c, quintana-murci l, talebbekkouche f, krausz c, mcelreavey k. effects of transmission of y chromosome azfc deletions. lancet. 2002;360:1222-4. 74. siffroi jp, le bourhis c, krausz c, et al. sex chromosome mosaicism in males carrying y chromosome long arm deletions. hum reprod. 2000;15:2559-62. 75. dewan s, puscheck ee, coulam cb, wilcox aj, jeyendran rs. y-chromosome microdeletions and recurrent pregnancy loss. fertil steril. 2006;85:441-5. 76. aknin-seifer ie, lejeune h, touraine rl, levy r. y chromosome microdeletion screening in infertile men in france: a survey of french practice based on 88 ivf centres. hum reprod. 2004;19:788-93. 77. quilter cr, svennevik ec, serhal p, et al. cytogenetic and y chromosome microdeletion screening of a random group of infertile males. fertil steril. 2003;79:301-7. 78. briton-jones c, haines cj. microdeletions on the long arm of the y chromosome and their association with male-factor infertility. hong kong med j. 2000;6:184-9. 79. umeno m, shinka t, sato y, et al. a rapid and simple system of detecting deletions on the y chromosome related with male infertility using multiplex pcr. j med invest. 2006;53:147-52. 80. giltay jc, kastrop pm, tuerlings jh, et al. subfertile men with constitutive chromosome abnormalities do not necessarily refrain from intracytoplasmic sperm injection treatment: a follow-up study on 75 dutch patients. hum reprod. 1999;14:318-20. corrigendum notice the authors of a previously published article [ureterorenoscopy with stenting and its effect on female sexual function. urol j. 2017;14:3059‐63.] stated that they have missed to include an author on the submission. we have received a letter signed by all authors confirming the above issue. therefore, based on this correction “ramazan asci” is added as the third author on the submission. the corrected name of submission and authors would be: [ekrem akdeniz, mustafa suat bolat, ramazan asci. ureterorenoscopy with stenting and its effect on female sexual function. urol j. 2017; 14: 3059-63.] corrigendum 432 v07_no_4.pdf review 215urology journal vol 7 no 4 autumn 2010 kidney removal the past, presence, and perspectives a historical review more than 140 years have passed since the first documented planned nephrectomy. throughout all these years, people gained significant knowledge on the renal functions and diseases, and what is more, the surgical workshop underwent considerable improvement. initially, the kidney removal operations were performed due to ureterovaginal fistulas and renal lithiasis. later, they were executed mainly in patients with renal tumors, whereas today, the number of these surgeries tend to decrease to the benefit of nephron sparing procedures. current nephrectomies are more and more often performed in case of organ donation, what will probably remain the most significant indication for the kidney removal in close future. while the first surgeries were executed with classical surgical methods, nowadays, after years of studies concerning nephron sparing and minimally invasive operations, we can see surgeries carried out through natural body orifices with robotic assistance. in relation to simple surgical operation based on ligation of 3 tubular anatomic structures, we can perceive the true scope of the progress that occurred in surgery. the aim of this article is to present the evolution of indications and operating techniques utilized to remove the kidney in chronological aspect. urol j. 2010;7:215-23. www.uj.unrc.ir keywords: nephrectomy, organ preservation, kidney failure department of urology, medical centre of postgraduate education, warsaw, poland corresponding author: poland e-mail: slawomir.poletajew@gmail.com received october 2010 accepted october 2010 the first nephrectomy the possibility to undertake the attempt to remove the kidney in human beings was related with decades of research on the method of operation and the influence it has on physiological processes. experiments used the model of the dog, and of the first researchers of the kidney removal issue, we can enumerate hendrik von roonhuysen (1672), giuseppe zambeccarius (1678), and stephan blanchard (1698). tests performed on dogs that underwent unilateral nephrectomy revealed compensative hypertrophy of the remaining kidney and have ultimately proved that the animal with only one kidney can survive.(1) the first nephrectomy performed on a human was executed in 1868 by a canadian surgeon, william hingston from hôtel dieu hospital in montreal. however, this achievement was not announced due to the failure of the surgery; the patient died on the operating table, immediately after the removal of the kidney.(2) as documents stated, gustav christoph jakob friedrich ludwig simon, a german surgeon who carried out nephrectomy in 1869, is the pioneer of the kidney removal surgeries. he was an expert in surgical treatment of kidney removal—poletajew et al 216 urology journal vol 7 no 4 autumn 2010 ureterovaginal fistulas and was the author of the so-called ‘german method’. margaretha kleb was one of the patients operated by simon; she was a 46-year-old patient with left-sided ureterovaginal fistula, being a complication related with surgical removal of uterus with adnexa. simon undertook three attempts to close the fistula, but all three endeavors turned out to be inefficient. only the left kidney removal could constitute the final solution of the clinical problem. after several dozens of experimental operations on 30 dogs, simon decided to operate his patient. the surgeon considered sepsis as the most serious complication, yet pre-operative evaluation of the contralateral kidney function and manner of ligation of the renal peduncle were also significant problems. the surgery was performed on 2 august 1869 in heidelberg, germany. the patient was anesthetized with chloroform. simon took advantage of lumbar access, mainly due to complications during abdominal operations, which were quite frequent at that time. renal peduncle was ligated with silk suture. the surgery lasted 40 minutes and ended with success. postoperative period was complicated with infection of the wound, pneumonia, and erysipelas. kleb left her bed 28 days after the surgery, and she was discharged from hospital after following two months.(1,3) hingston and simon were certainly the first surgeons who operated with the aim to remove the kidney. nonetheless, even before 1868 when testing surgical specimens, surgeons sporadically found the kidney in tissue block.(4) a german gynecologist, otto spiegelberg, was one of those who decided to describe this event. in 1867 in when operating echinococcal cyst. all in all, it is hard to establish the date of the first surgical kidney removal. nephrectomy in the 19th century the first nephrectomies finally proved that it is possible to remove one kidney in a human being and that a patient can survive with only one kidney. however, these operations slowly gained acceptance of surgeons. this was related initially with extremely high rate of peri-operative mortality, reaching even up to 50%. simon performed his second nephrectomy in 1871. the patient died 31 days after the operation. the most frequent problems tragically complicating the postoperative course were infections of surgical wound, at that time referred to as hospital gangrene and sepsis.(5) the highest percentage of failures was observed after procedures performed in patients with a renal tumor; however, there were not too many of these operations during those days. postoperative mortality rate due to renal tuberculosis, hydronephrosis, or urolithiasis in most of the patients did not exceed 40% (table 1).(6) at the end of the 19th century, joseph lister, being in charge of surgical department at king’s college university hospital in london, initiated antiseptics. introducing activities proposed by lister, including washing and disinfecting surgical tools and hands with carbolic acid before the operation, into surgical practice had a noteworthy result in reduction of peri-operative mortality.(7) johann anton von mikulicz-radecki from surgery clinic of jagiellonian university, who introduced cotton surgical gloves in 1885 and sterile face masks covering the face of a surgeon in 1896, and william stewart halsted from john hopkins university in baltimore, who proposed replacing cotton gloves with rubber ones in 1889, followed the ideas suggested by lister.(8,9) the year of 1886 is considered as the beginning of aseptics, since ernst von bergmann, surgeon from berlin university, was the first person to perform steam sterilization in that year.(10) increase in the number of performed surgeries, including nephrectomy, was the aftermath of the abovementioned events. by the end of the 19th century, name of surgeon number of operations mortality [%] schede 38 21 bardenheuer 37 21.6 israel 37 16.2 czerny 33 51 thornton 25 20 kuster 14 28.5 tuffier 8 37.5 total 192 27 table 1. postoperative mortality rate among patients who underwent nephrectomy, operated by the most eminent urologists of the 19th century.(6) kidney removal—poletajew et al 217urology journal vol 7 no 4 autumn 2010 more than 300 surgical kidney removals have been performed in europe and america, whereas 55 of them were carried out on patients with renal tumor.(11) simultaneously, people gained knowledge on renal anatomy and surgical workshop was being perfected. in 1895, a romanian anatomist and urologist, dimitrie gerota, described topographical anatomy of the kidney, including presence of renal fascia. the end of the 19th century can be also enlisted within the turbulent period related with development of surgical instruments. as far as the kidney removal aspect is concerned, instruments proposed and perfected by julesémile péan, emil theodor kocher, jean guyon, david satinski, and others seem to be of most considerable significance. popularization of hemostatic clamps helped to cease bleeding from the blood vessels. yet, what still remained to be the problem was the dangerous parenchymal bleeding, until now treated by cauterization with hot iron. in 1896, arsène jacques d’arsonval was the first one to take advantage of electrocoagulation with the use of diathermy.(12) retroperitoneal and transperitoneal access initially, the surgeries were being performed from retroperitoneal approach. in 1878, emil theodor kocher, from surgery clinic of university of bern, removed the kidney via transperitoneal approach, opening the peritoneal cavity with medial incision.(13) in 1913, a norwegian surgeon, atle berg, modified the operation performed by kocher. he used lateral incision and also proposed mobilization of the colon to visualize the renal peduncle better as well as to increase the security of the procedure. berg is considered to be the first surgeon who removed neoplastic thrombus from the inferior caval vein in a patient with a renal tumor.(14) in the light of relatively bad results of transperitoneal nephrectomy, in 19th century and in the beginning of the 20th century, the retroperitoneal access was much more frequently used. differences resulted from high rate of abdominal complications after transperitoneal surgeries. the most often observed complications included repeatedly infection of peritoneum with critical outcome. introduction of antiseptics to medicine and perfection of operating techniques had influence on improvement of outcomes and resulted in regained initial interest in transperitoneal access in the surgeons. at that time, the most considerable advantage of these operations lied in the possibility to visually evaluate the second kidney. nephrectomy in the 20th century the first half of the 20th century constituted a restless period concerning the development of suturing materials. in the face of increasing anatomic and physiological knowledge as well as surgical progress, lack of methods related with reliable vessel treatment and wound closure methods stood as one of the most noteworthy complaints reported by surgeons. in 1906, franz kuhn, a german surgeon, elaborated a sterilization method for chromic catgut, the first suturing material in history, which was made of ram intestine, especially for surgical needs. two years later, kuhn persuaded carl braun, a german businessman, to produce sterile catgut on a wide scale. whereas, during the 30s of the 20th century, production of the first synthetic sutures and non-absorbable sutures was initiated.(15) despite the development and perfection of surgical tools, the beginning of the 20th century still faced the problem of blood loss during the kidney removal, which was insufficiently solved and caused mortal complications in hundred cases. popularization of hemotherapy, whose history began to quicken in the beginning of the 20th century, became a solution for the problem. in 1901, karl landsteiner separated blood groups, while in 1910, ludwik hirszfeld and emil von dungern revealed inheritance of group features. thereafter, physicians performed transfusions only of blood with group compliance, except for the ‘o’ group, which was referred to as the ‘universal’ group and was transfused irrespective of the blood group of the patient. in 1915, results of tests by richard lewinsohn provided knowledge on possibility of blood conservation kidney removal—poletajew et al 218 urology journal vol 7 no 4 autumn 2010 with the use of sodium citrate. blood transfusions became simple life-saving procedures.(16) in face of popularization concerning ether anesthesia, next to perfection of anesthetic devices and tubes used for endotracheal administration of anesthetic agents, popularity of nephrectomy increased. the discovery of penicillin was the most important event in the 20th century, which significantly increased the number of performed renal operations, but also became the propulsive power of the whole surgery. in 1928, alexander fleming initiated a new era of surgical treatment. in the era of general anesthesia, efficient antibiotic therapy, developing transfusiology, vast instrumentarium, and reliable suturing materials, the kidney removal gained popularity, and at the same time, became the subject of numerous researches, discoveries, and innovations. less frequently nephrectomy was performed due to infective renal diseases, whereas the number of patients operated on due to complicated renal lithiasis and renal tumors increased. in 1945, ernest k landsteiner performed the first temporary kidney transplant in peter bent brigham hospital in boston. the organ collected from a deceased donor was transplanted to a young pregnant woman with acute renal insufficiency in the course of gestosis.(17) nine years later, joseph e. murray made the first successful transplantation of the kidney collected from a live donor. transplantation was performed between twins, and the transplanted kidney functioned for nine months.(18) evolution of indications for nephrectomy gained considerable pace during the seventies. since then, we can observe constant growth of morbidity rate of renal cancer, probably related with a change in biology of the tumor. simultaneously, the number of renal transplantations increases, including collections from living organ donors. what is more, as far as renal lithiasis treatment is concerned, endoscopic methods have finally superseded classical surgery. nephron sparing surgeries the first nephron sparing surgeries were performed a dozen years or more after the first total nephrectomies. in 1884, spencer wells accidentally removed the third part of the kidney while performing surgical removal of perirenal fibroadenoma.(19) in 1890, vincenz czerny performed the first scheduled operation of partial nephrectomy in a patient with angiosarcoma.(20) what is interesting is the fact that the operation was performed in the same clinic where 21 years earlier simon had performed the first nephrectomy. between 1879 and 1900, intensive studies on safety related with removing a part of the kidney were conducted. tillman, tuffier, bardenheuer, paoli, and many other researchers made attempts to find the answer for questions related with renal function, compensating mechanisms, and the minimal amount of the kidney essential for the patient to survive.(21) the initial enthusiasm associated with nephron sparing procedures restrained frequent complications following these types of surgeries. fear of urologists concerning massive bleeding during or after the operation and urinary fistulas, next to poor outcomes of oncological treatment significantly reduced the popularity of partial nephrectomy. finally, during the first half of the 20th century, nephron sparing operations were mainly reserved only for selected patients, treated due to nonneoplastic renal diseases, including cysts, limited hydronephrosis, and fistulas. researches by albert goldstein and benjamin s. abeshouse (1937) as well as carl semb (1950) and andre dufour (1951) contributed to increased interest-related nephron sparing operations. these surgeons included an overall number of 321 procedures of partial kidney removal in their analyses. results of their tests proved that these operations are not related with increased risk of bleeding or urinary fistulas. goldstein and abeshouse concluded that small tumors and tumors of moderate size situated at one of the poles of the kidney may be removed by partial resection. nevertheless, the researchers reserved that this type of action is contraindicated in patients with healthy second kidney.(22) for many years, despite encouraging results of selected studies, partial nephrectomy was not kidney removal—poletajew et al 219urology journal vol 7 no 4 autumn 2010 recommended due to doubtful oncological purity and technical drawback. patients with one kidney, renal insufficiency, or with both kidneys being sick constituted an exception. in 1963, urologists focused on researches by charles robson from university of toronto.(23) robson proved significant improvement in tenyear survival in 88 patients suffering from renal cancer who underwent radical procedure. due to good outcomes of treatment, radical nephrectomy became a standard of proceedings in patients with renal tumors, delaying the issue of nephron sparing procedures for the next several years. during the 70s, nephron sparing surgery slowly gained new supporters. studies by eugene poutasse on technique related with partial kidney resection with consideration of segmental vascularization and researches by kerr and klotz on renal hypothermia enabling to prolong the time of operation without the fear of ischemia or excessive bleeding were of considerable significance for these changes. in the beginning of the eighties, urologists could take advantage of certain methods related with partial renal resection and renal reconstruction as well as humble experience. on the other hand, the improvement and increase of accessibility of the kidney imaging methods caused significant increase in the number of detected small, asymptomatic renal tumors. licht and novick published the first study on partial nephrectomy on a large group of patients in 1993. during observation lasting for three years on 241 patients with healthy second kidney, only 2 cases of local recurrence and 95% survival were reported.(24) herr and fergany independently published similar results of treatment within a longer period of observation.(25, 26) during the last years of the 20th century, nephron sparing procedures gained wide acceptance as a method of treatment for patients with small, peripherally located renal tumors. following years strengthened the position of partial nephrectomies. indications for the surgery were expanded with tumors located within the core of renal medulla and tumors reaching up to 7 cm. according to herr, the significant growth in the number of executed nephron sparing surgeries may be explained with the fact that the majority of currently detected renal tumors have a diameter of about 4 cm, benign character, or beneficial biology, and global renal function is better in patients with two kidneys.(5) videoscopic nephrectomy during the first years when laparoscopy was present in surgery, performing nephrectomy with laparoscopic method seemed impossible. size of the kidney stood as the main obstacle, as they excluded the possibility to remove it from the abdominal cavity through port or by means of mini-laparotomic incision. the problem was solved with construction of non-permeable, strong sac (lapsac) and morcellator. in 1991, american ralph clayman from washington university school of medicine in st. louis, taking advantage of laparoscopic method, preparated a kidney and then placed it inside the sac and minced it with the help of morcellator. thereafter, the kidney could have been removed from peritoneal cavity through an 11-mm incision.(27) the volume of the retroperitoneal space was the initial obstacle on the route to endoscopic kidney removal from lumbar access. operating within this cavity with working tools was dangerous, and sometimes also impossible. in 1992, durga gaur from department of urology in bombay hospital conquered these hardships. thanks to using a balloon of simple construction, he enlarged the working cavity and removed the kidney with endoscopic method from retroperitoneal access (retroperitoneoscopy).(28,29) reports by clayman and gaur started a still ongoing discussion concerning indications, difficulties, and outcomes of the kidney removal surgery performed with the help of the abovementioned means. analyses reveal predominance of laparoscopic and retroperitoneoscopic techniques over open surgery. when compared with classical surgeries, minimally invasive operations have no influence on the result of oncological treatment and do not increase the risk of surgical complications. they are connected with lesser blood loss, smaller requirement for kidney removal—poletajew et al 220 urology journal vol 7 no 4 autumn 2010 analgesic drugs during postoperative period, and shortening the period of hospitalization and the time essential to return to full vital activity. among the disadvantages of video surgeries, one can enumerate factors that are less significant as far as therapy is concerned, namely costs, technical difficulty of the procedure, and the time it lasts until operators gain experience. discussion on comparing laparoscopic operations with retroperitoneoscopic surgery evokes numerous emotions among researchers. retroperitoneal access found its initial usage in operating small kidneys or removing lesions located on its posterior surface. during the following years, the list of contraindications related with such operation decreased. recently, retroperitoneoscopic nephrectomy has been definitely advised against only in cases of large kidneys and advanced neoplastic process.(30) throughout recent years, many urologists took the effort to compare operations from the retroperitoneal and transperitoneal access. presented results do not show the preponderance of any of these methods, as in both methods, we can observe similar outcomes of treatment and comparable technical difficulties. analyzing the history of laparoscopic kidney removal surgery, one cannot forget to mention the use of this technique in collecting the organ for transplantation. in 1995, 41 years after the first open living donor nephrectomy, lloyd e. ratner from johns hopkins university school of medicine, baltimore, executed a similar procedure with laparoscopic method.(31) pioneer surgery performed on a human being was preceded with experiences on swine models, and results of these studies were published by gill a year before (table 2).(32) hand-assisted laparoscopic nephrectomy bearing in mind the idea of connecting minimally invasive surgery with potential provided by classical surgery, a technique of hand-assisted laparoscopy was elaborated. in 1997, stephen y. nakada from university of wisconsin medical school in madison described the first nephrectomy within this modification (hand-assisted laparoscopic nephrectomy–haln).(33) introducing the hand into the operating field through laparotomy enables palpable evaluation and removal of the whole kidney, and what is more, haln is characterized by smaller degree of difficulty in comparison with traditional laparoscopic surgery. studies comparing haln with open nephrectomy reveal advantages of minimally invasive operations in relation to haln, proving its superiority. less unequivocal conclusions may be drawn from tests comparing haln with traditional laparoscopic nephrectomy. these procedures are characterized by parallel parameters related with the course of the operation (time of operation, blood loss, oncological radicalness in case of oncological surgeries, and time of warm ischemia in case of the kidney collection) and postoperative period (pain ailments, time of introducing complete diet, and period of hospitalization). hand-assisted laparoscopic surgeries are less beneficial as far as the economic aspect is concerned. author of laparoscopic nephrectomy is one of the enthusiasts supporting haln. during annual congress of american urological association held in 2000, when clayman commented the hal technique, admitted that ‘one hand is worth more than thousand trocars’. robotic-assisted nephrectomy robotic-assisted laparoscopic nephrectomy (raln) is worth mentioning. introduction of robotic assistants was proposed to increase the precision of movements within the operating field and was related with economic intentions. the assumption was to reduce the number of members within the operating team to minimum. usually, the procedure is performed by a surgeon 1869 retroperitoneal nephrectomy, gustav simon (heidelberg) 1878 transperitoneal nephrecotmy, emil kocher (bern) 1890 partial nephrectomy, vincezn czerny (heidelberg) 1913 removal of neoplastic thrombus from inferior caval vein, atle berg (oslo) 1954 living donor nephrectomy, joseph murray (boston) 1990 laparoscopic nephrectomy, ralph clayman (st. louis) table 2. the most important dates in the history of renal surgeries. kidney removal—poletajew et al 221urology journal vol 7 no 4 autumn 2010 with assistance of one or two robots. first relations on experimental usage of this method in animals date back to 1994. initially, robotic assistants were controlled by an experienced urologist present in the operating theater.(34) in 1995, the first 4 nephrectomies performed in people with assistance of two robots, of which one controlled the camera and was controlled with foot pedal and the second one was the ‘hook robot’ and was controlled with a hand, were described. authors of the first publication emphasized that procedures performed with robotic assistance are characterized by safety and time of operation similar to typical laparoscopic operations. they also indicated that in case of serious peri-operative complications, human assist is inevitable.(35) simultaneous usage of achievements in telemedicine and robots allowed to perform the first ‘distant’ surgery, without presence of the surgeon in the operating theater. in 2000, this method was used in an experimental swine kidney removal surgery, which was performed with three robots.(36) similar procedure was successfully performed a year later in a human being.(37) until today, there were a relatively small number of studies comparing raln with standard laparoscopic operation, hand-assisted laparoscopic surgery in literature. majority of studies prove lack of advantages related with the use of robots, the surgery lasts longer and obtained outcomes are similar. selected authors emphasize the value of raln in perfecting operating techniques by urologists with moderate experience in laparoscopy. during the last months, we could observe publication of studies on results of roboticassisted partial and living donor nephrectomies. in case of these procedures, urologists frequently indicate the problem concerning the reliable treatment of the kidney peduncle.(38-40) towards the lack of studies covering large groups of patients undergoing raln, the economic aspect has not yet been finally evaluated. laparo-endoscopic single-site surgery laparo-endoscopic single-site surgery modification lies in the use of one multichannel port and curved endoscopic tools. since 2008, the literature has provided single reports on laparoscopic nephrectomy performed with means of one port. the cosmetic effect is the obvious advantage of the laparo-endoscopic single-site surgery. results of previous examinations are promising. most of the authors consider them safe and practicable.(41) usually, operators place the port in the navel, which intensified the positive cosmetic outcome of the operation. what is worth mentioning is the fact that the number of previously performed laparoscopic nephrectomies in modification with the use of single port is still insignificant. hence, finally, this method should be considered as an experimental method, which still does not have a certain place in history of renal surgery. natural orifice transluminal endoscopic surgery natural orifice transluminal endoscopic surgery technique is currently enumerated among the most advanced minimally invasive techniques in surgery. natural orifice transluminal endoscopic surgery takes advantage of operative access through natural body orifices, which allows to reduce the number or even eliminate skin incisions, decrease the pain intensity during postoperative period, and to limit the risk of postoperative hernias. the use of natural orifice transluminal endoscopic surgery in selected patients (obese patients, burns, and infections within the skin of the abdomen) may facilitate the conditions of operation and allow using anesthesia other than general anesthesia. in 2001, the kidney preparated with laparoscopic method was removed from the abdominal cavity through the vagina.(42) this notion inspired a group of physicians, who a year later undertook the attempt to perform the whole operation by means of transvaginal access. six nephrectomies were performed on swine model. in 5 cases, the surgery was performed with the use of one standard port and in one, it was possible to execute the surgery without additional ports, namely entirely through vagina. the two abovekidney removal—poletajew et al 222 urology journal vol 7 no 4 autumn 2010 mentioned modifications of operations lasted on average 210 to 360 minutes.(43) during the following years, the swine model was used to perform the kidney removal surgeries from the access through the stomach, the anus, and the bladder. the first report on using natural body orifices in order to remove the kidney in human dates back to 2008. then, the brazilian team operated a 23-year-old woman with recurring infections of the urinary system resulting from an inactive kidney. the surgery was executed with the use of two standard abdominal ports and transvaginal access. authors of the publication indicated problems related with the use of flexible endoscopic tools to visualize and maintain intra-abdominal structure.(44) the first reports on the operation performed entirely through transvaginal access were published in 2009.(45) conflict of interest none declared. references 1. moll f, rathert p. the surgeon and his intention: gustav simon (1824-1876), his first planned nephrectomy and further contributions to urology. world j urol. 1999;17:162-7. 2. cohen j. sir william hingston. can j surg. 1996;39:422-7. 3. simon g. extirpation einer niere am menschen. dtsch klin. 1870;22:137-9. 4. novick a, streem s. surgery of the kidney. in: walsh pc, retik ab, vaughan jed, wein aj, eds. campbell’s urology: 7 ed. wb saunders; 1998:29733061. 5. herr hw. a history of partial nephrectomy for 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urol. 2001;165. 43. gettman mt, lotan y, napper ca, cadeddu ja. transvaginal laparoscopic nephrectomy: development and feasibility in the porcine model. urology. 2002;59:446-50. 44. branco aw, branco filho aj, kondo w, et al. hybrid transvaginal nephrectomy. eur urol. 2008;53:1290-4. 45. kaouk jh, haber gp, goel rk, et al. pure natural orifice translumenal endoscopic surgery (notes) transvaginal nephrectomy. eur urol. 2010;57:723-6. tissue engineering of bone regeneration within self-assembly peptide scaffolds 1 comparison of ibuprofen with ketorolac on the control of renal colic pain: a meta-analysis of randomized controlled studies fuxian cai, yougang liao, shichun jiang, yuan cao, yaodong wang fuxian cai:caixianfu@126.com, yougang liao:522756563@qq.com, shichun jiang:244208954@qq.com, yuan cao:373329819@qq.com, yaodong wang:wang990023@163.com department of urology, mianyang central hospital address correspondence to: yaodong wang; e-mail: wang990023@163.com; telephone: 0860431889809900; fax number: 0860431889809900; postal address: no.12, changjia lane, jiongjie street, fucheng district, mianyang, sichuan, 621877, china,; conflicts of interest and source of funding:none. abstract introduction: the comparison of ibuprofen with ketorolac remains controversial for the pain control of renal colic. we therefore conduct this meta-analysis to compare the analgesic efficacy of ibuprofen with ketorolac for renal colic. methods: we have searched pubmed, embase, web of science, ebsco, and cochrane library databases through december 2022 for randomized controlled trials (rcts) assessing the analgesic efficacy of ibuprofen in comparison with ketorolac for renal colic. this meta-analysis was performed using the random-effect or fixed-effect model based on the heterogeneity. results: four rcts were included in the meta-analysis. in patients with renal colic 2 pain, intravenous ibuprofen and ketorolac produced comparable pain scores at 15 min (md=-0.46; 95% ci=-1.24 to 0.31; p=0.24), 30 min (md=-0.81; 95% ci=-1.75 to 0.31; p=0.09), 60 min (md=-0.63; 95% ci=-1.40 to 0.13; p=0.10) and 120 min (md=-0.74; 95% ci=-2.18 to 0.70; p=0.31), as well as adverse events (or=0.95; 95% ci=0.61 to 1.49; p=0.83). conclusions: ibuprofen can obtain the comparable analgesic efficacy to ketorolac for renal colic pain. key words: renal colic pain, ibuprofen, ketorolac, pain control, randomized controlled trials. introduction renal colic caused by nephrolithiasis has become one of the most commonly factors of acute pain 1-3. it is estimated that 11% of men and 7% of women suffer from renal colic pain 4. the ureteric obstruction by stones lead to increase intraluminal pressure and stimulate the nerves in lamina propria, followed by the increase in pain intensity 5, 6. the pathophysiology of renal colic pain included local synthesis of eicosanoids (e.g. prostaglandin e2 and prostacyclin 2) and nitric oxide 7. renal colic pain mainly results from the contraction in urethral smooth muscle, alteration in local blood flow rate and the increase in urinary tract pressure 8. current analgesic drugs for renal colic pain included non-steroidal anti-inflammatory drugs (nsaids) and opioid analgesics 9, 10. opioids have important benefits to indirectly alleviate pain intensity, while nsaids are used to control renal colic pain by attenuating the production of prostaglandins 11, 12. however, opioids may be associated with some serious events including hypotension, respiratory depression, apnea and even intolerance or addictions 13. the most frequently used nsaids for renal colin is ketorolac, which is a non-selectively cyclooxygenase (cox) inhibitor that acts as dual cox-1/cox-2 inhibitor 14. ibuprofen may have higher analgesic efficacy and lower incidence of adverse effects in controlling renal colic pain compared to ketorolac treatment 4. several studies have compared ibuprofen with ketorolac for the pain relief of renal colic, but the results are not well establish 4, 15, 16. this meta-analysis of rcts aims to 3 compare the analgesic efficacy of ibuprofen with ketorolac in the control of renal colic. materials and methods this systematic review and meta-analysis were performed based on the guidance of the preferred reporting items for systematic reviews and meta-analysis statement and cochrane handbook for systematic reviews of interventions 17, 18. no ethical approval and patient consent were required because all analyses were based on previous published studies. literature search and selection criteria we have systematically searched several databases including pubmed, embase, web of science, ebsco, and the cochrane library from inception to november 2022 with the following keywords: “ibuprofen” and “ketorolac” and “renal colic”. the reference lists of retrieved studies and relevant reviews were also hand-searched and the process above was performed repeatedly in order to include additional eligible studies. the inclusion criteria were presented as follows: (1) study design was rct, (2) patients were diagnosed with renal colic, and (3) intervention treatments aimed to compare ibuprofen with ketorolac. data extraction and outcome measures some baseline information was extracted from the original studies, and they included first author, number of patients, age, female, history of renal stone, baseline pain intensity and detail methods in two groups. data were extracted independently by two investigators, and discrepancies are resolved by consensus. the primary outcomes were pain scores at 15 min and 30 min after the drug administration. secondary outcomes included pain scores at 60 min and 120 min, as well as adverse events. quality assessment in individual studies the methodological quality of each rct was assessed by the jadad scale which consisted of three evaluation elements: randomization (0-2 points), blinding (0-2 points), dropouts and withdrawals (0-1 points) 19. one point would be allocated to 4 each element if they were conducted and mentioned appropriately in the original article. the score of jadad scale varied from 0 to 5 points. an article with jadad score ≤2 was considered to be of low quality. the study had high quality if jadad score≥3 20, 21. statistical analysis we assessed mean difference (md) with 95% confidence interval (ci) for continuous outcomes and odd ratio (or) with 95% cis for dichotomous outcomes. heterogeneity was evaluated using the i2 statistic, and i2 > 50% indicated significant heterogeneity 21, 22. the random-effect model was used when encountering significant heterogeneity, and otherwise fixed-effect model was applied. we searched for potential sources of heterogeneity for significant heterogeneity. sensitivity analysis was performed to detect the influence of a single study on the overall estimate via omitting one study in turn or performing the subgroup analysis. results were considered as statistically significant for p<0.05. all statistical analyses were performed using review manager version 5.3 (the cochrane collaboration, software update, oxford, uk). results literature search, study characteristics and quality assessment figure 1 showed the detail flowchart of the search and selection results. 114 potentially relevant articles were identified initially. finally, four rcts were included in the meta-analysis 4, 15, 16, 23. the baseline characteristics of four included rcts were shown in table 1. these studies were published between 2018 and 2022, and the total sample size was 571. among the included rcts, intravenous ibuprofen was administered at the dose of 800 mg, while intravenous ketorolac was used at the dose of 30 mg. among the four included rcts, three studies reported pain scores at 15 min,30 min and 60 min 4, 15, 16, two studies reported pain scores at 120 min 4, 15, and three studies reported adverse events 15, 16, 23. jadad scores of the four included studies varied from 3 to 5, and all studies had high quality based on the quality assessment. primary outcomes: pain scores at 15 min and 30 min 5 the random-effect model was used for the analysis of primary outcomes. the results found that compared to ketorolac group for renal colic pain, ibuprofen showed similar pain scores at 15 min (md=-0.46; 95% ci=-1.24 to 0.31; p=0.24) with significant heterogeneity among the studies (i2=96%, heterogeneity p<0.00001, figure 2) and pain scores at 30 min (md=-0.81; 95% ci=-1.75 to 0.31; p=0.09) with significant heterogeneity among the studies (i2=96%, heterogeneity p<0.00001, figure 3). the funnel plots (figure 4) were not symmetrical, suggesting some publication bias. sensitivity analysis significant heterogeneity remained for primary outcomes. however, there was still substantial heterogeneity when performing the sensitivity analysis by omitting one study in turn. secondary outcomes in comparison with ketorolac group for renal colic pain, ibuprofen resulted in comparable pain scores at 60 min (md=-0.63; 95% ci=-1.40 to 0.13; p=0.10; figure 5) and 120 min (md=-0.74; 95% ci=-2.18 to 0.70; p=0.31; figure 6). there was no statistical difference of adverse events between two groups (or=0.95; 95% ci=0.61 to 1.49; p=0.83; figure 7). discussion our meta-analysis included four rcts and 571 patients with renal colic pain. the results found that ibuprofen obtains comparable analgesic efficacy to ketorolac treatment in renal colic patients, as evidenced by the similar pain scores at 15 min, 30 min, 60 min and 120 min between two groups. in addition, the incidence of adverse events such as nausea and vomiting were similar between ibuprofen and ketorolac. both ibuprofen and ketorolac are dual cox-1/cox-2 inhibitors. cox-1 is constitutively located in wide range of cells particularly in platelets and gastrointestinal tract, while cox-2 expression is induced in the presence of inflammation 24-27. ibuprofen is able to inhibit cox-1 2.5 times less than cox-2, while ketorolac has lower binding capacity to cox-2 than ibuprofen. these suggests that ibuprofen theoretically provided better analgesic efficacy and lower risk 6 of adverse events 28. however, our meta-analysis found that ibuprofen obtains the comparable efficacy to ketorolac for the pain relief of patients with renal colic, and these two drugs had similar incidence of adverse events mainly including nausea and vomiting. considering the heterogeneity, there was still significant heterogeneity when performing the sensitivity analysis by omitting one study in turn. three factors may account for it. firstly, the pain intensity may differ in various patient samples. secondly, history of renal stone may affect the assessment of analgesic efficacy. thirdly, the different combination methods of drug administration may cause some bias. several limitations exist in this meta-analysis. firstly, our analysis is based on only four rcts, and more rcts with large sample size should be conducted to explore this issue. secondly, there is significant heterogeneity for the primary outcomes, which may result from different methods of drug administration and baseline pain intensity. finally, it is not feasible to perform the analysis of some important outcomes such as the requirement of additional analgesics. conclusion ibuprofen may be equally effective for the relief of renal pain compared to ketorolac. compliance with ethical standards disclosure of potential conflicts of interest the authors declare no conflict of interest. research involving human participants and/or animals not applicable. table 1 characteristics of included studies no . author ibuprofen group ketorolac group jada score s numbe r age femal e (n) histor y of renal stone (n) baseline pain intensity methods numbe r age femal e (n) histor y of renal stone (n) baseline pain intensity methods 7 1 safaie 2022 65 39.5±12. 5 19 14 8.4±0.8 intravenou s 800 mg ibuprofen 65 39.3±12.4 18 11 8.4±0.8 intravenou s 30 mg ketorolac 4 2 yazdani 2021 62 35.2±7.6 3 15 8.93±0.3 8 intravenou s 800 mg ibuprofen 59 35.29±6.6 6 19 9.06±0.4 6 intravenou s 30 mg ketorolac 4 3 forouzanfa r 2019 120 38.7 ± 11.6 39 33 7.8±1.2 intravenou s 800 mg ibuprofen 120 38.7 ± 13.0 41 39 8.0±1.2 intravenou s 30 mg ketorolac 5 4 shaker 2018 35 38.29 ± 11.71 7 22 intravenou s 800 mg ibuprofen 35 36.51 ± 11.64 4 18 intravenou s 30 mg ketorolac 3 figure legend figure. 1 flow diagram of study searching and selection process. figure. 2 forest plot for the meta-analysis of pain scores at 15 min. figure. 3 forest plot for the meta-analysis of pain scores at 30 min. figure. 4 funnel plot for the meta-analysis of pain scores at 15 min (a) and pain scores at 30 min (b). figure. 5 forest plot for the meta-analysis of pain scores at 60 min. figure. 6 forest plot for the meta-analysis of pain scores at 120 min. figure. 7 forest plot for the meta-analysis of adverse events. figures 8 figure. 1 figure. 2 figure. 3 figure. 4 9 figure. 5 figure. 6 figure. 7 references 1. patti, l., leslie, s. w.: acute renal colic. in: statpearls. treasure island (fl): statpearls publishing copyright © 2022, statpearls publishing llc., 2022 2. doty, e., digiacomo, s., gunn, b. et al.: what are the clinical effects of the different emergency department imaging options for suspected renal colic? a scoping review. j am coll emerg physicians open, 2: e12446, 2021 3. ac, c. m., faza, c., castro bigalli, a. a. et al.: intravenous amide anesthetics to treat pain associated with renal colic in the emergency department: a systematic review. arch acad emerg med, 8: e27, 2020 4. yazdani, p.: comparative study of individual pain relief effect of 2 intravenous ibuprofen intravenous morphine, intravenous 3 ketorolac separately in renal colic patient ed. journal of critical reviews, 31: 278, 2021 5. al-terki, a., el-nahas, a. r., abdelhamid, u. et al.: development and validation of a score for emergency intervention in patients with acute renal colic secondary to ureteric stones. arab j urol, 18: 236, 2020 6. thom, c., eisenstat, m., moak, j.: point-of-care ultrasound identifies urinoma complicating simple renal colic: a case series and literature review. j emerg med, 55: 96, 2018 7. shokeir, a. a.: renal colic: pathophysiology, diagnosis and treatment. eur urol, 39: 241, 2001 8. sahlén, k., dahlman, p., brekkan, e. et al.: predictive value of secondary signs of obstruction in follow-up computed tomography of ureteral stones: a study with dynamic computed tomography. scand j urol, 52: 59, 2018 10 9. holdgate, a., pollock, t.: systematic review of the relative efficacy of non-steroidal anti-inflammatory drugs and opioids in the treatment of acute renal colic. bmj, 328: 1401, 2004 10. thia, i., saluja, m.: an update on management of renal colic. aust j gen pract, 50: 445, 2021 11. bultitude, m., rees, j.: management of renal colic. bmj, 345: e5499, 2012 12. pathan, s. a., mitra, b., cameron, p. a.: a systematic review and meta-analysis comparing the efficacy of nonsteroidal anti-inflammatory drugs, opioids, and paracetamol in the treatment of acute renal colic. eur urol, 73: 583, 2018 13. yazdani, r., saeedi, m., amirshekari, t. et al.: intravenous paracetamol, morphine, or ketorolac for the treatment of renal colic: a randomized double blind clinical trial. journal of research in medical and dental science, 6: 169, 2018 14. brown, j.: diagnostic and treatment patterns for renal colic in us emergency departments. int urol nephrol, 38: 87, 2006 15. safaie, a., tavoli, m., babaniamansour, s. et al.: intravenous morphine plus ibuprofen or ketorolac versus intravenous morphine alone in reducing renal colic pain intensity in emergency department: a randomized, double-blind clinical trial. turkish journal of emergency medicine, 22: 8, 2022 16. forouzanfar, m. m., mohammadi, k., hashemi, b. et al.: comparison of intravenous ibuprofen with intravenous ketorolac in renal colic pain management; a clinical trial. anesth pain med, 9: e86963, 2019 17. moher, d., 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23. shaker, s. h., borghei, s. a.: comparing the efficacy of intravenous ketorolac versus intravenous ibuprofen in relieving renal colic pain; a randomized clinical trial. journal of nephropharmacology, 7: 122, 2018 24. jackson, l. m., wu, k. c., mahida, y. r. et al.: cyclooxygenase (cox) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa. gut, 47: 762, 2000 25. de gaetano, g., donati, m. b., cerletti, c.: prevention of thrombosis and vascular inflammation: benefits and limitations of selective or combined cox-1, cox-2 and 5-lox inhibitors. trends pharmacol sci, 24: 245, 2003 26. jones lipinski, r. a., thillier, y., morisseau, c. et al.: molecular docking-guided synthesis of nsaid-glucosamine bioconjugates and their evaluation as cox-1/cox-2 inhibitors with 11 potentially reduced gastric toxicity. chem biol drug des, 98: 102, 2021 27. hussein, a. h. m., khames, a. a., el-adasy, a. a. et al.: design, synthesis and biological evaluation of new 2-aminothiazole scaffolds as phosphodiesterase type 5 regulators and cox-1/cox-2 inhibitors. rsc adv, 10: 29723, 2020 28. veronica mahon, d., dmitri chamchad, m., jay, c.: a randomized double-blind comparison of iv ibuprofen vs. iv ketorolac to prevent postoperative pain after scheduled cesarean section. j int j health sci, 4: 1, 2016 laparoscopic urology 152 urology journal vol 7 no 3 summer 2010 primary left upper quadrant (palmer’s point) access for laparoscopic radical prostatectomy i̇lter tüfek, haluk akpınar, cüneyd sevinç, ali rıza kural purpose: although palmer’s point approach is described for upper urinary tract laparoscopy, we use this technique routinely for robotic and standard laparoscopic radical prostatectomy and we describe our experience with this approach. materials and methods: since 2004, palmer’s point veress entry has been used to create pneumoperitoneum in 126 robotic and 21 standard laparoscopic radical prostatectomies. on the left side, a 2-mm transverse skin incision was made 3 cm below the left costal margin on the midclavicular line. through this incision, a veress needle was inserted to create pneumoperitoneum. results: the mean patients’ age and body mass index were 59.7 years (range, 37 to 73 years) and 27.92 kg/m2 (range, 22 to 39 kg/m2), respectively. thirty-eight patients had prior abdominal operations. the mean number of punctures performed was 1.08 per case. in 93 % of the subjects, veress needle was inserted during the first attempt. the mean time to establish pneumoperitoneum was 5.63 minutes (range, 4 to 8 minutes). no major entrance injuries occurred. conclusion: palmer’s point upper quadrant veress needle access may be a safe and effective method of establishing pneumoperitoneum in patients subjected to robotic and standard laparoscopic radical prostatectomy. urol j. 2010;7:152-6. www.uj.unrc.ir keywords: laparoscopy, prostatectomy, prostatic neoplasms, robotics istanbul bilim university, istanbul, turkey corresponding author: i̇lter tüfek, md fulya mah. mehmetçik cad. hüseyin cahit yalcın sok, no. 134394, mecidiyeköy, istanbul, turkey tel: +90 532 292 0069 fax: +90 212 224 4982 e-mail: iltertuf@gmail.com received september 2009 accepted april 2010 introduction laparoscopic surgery is an important part of urologic practice. establishing pneumoperitoneum is an important step in laparoscopic surgery; however, serious complications may occur during this part of the procedure. in a recent review, establishing initial pneumoperitoneum accounted for 6% to 57% of injuries occurring during laparoscopy.(1) various techniques have been described to perform insufflation and place trocars. classic closed pneumoperitoneum (veress), open (hasson) pneumoperitoneum, direct trocar insertion through a small incision in the peritoneum, disposable shielded trocars, radially expanding trocars, and visual entry systems are used for laparoscopic entry.(2) the most widely utilized techniques are the closed veress technique, open hasson technique, and direct trocar insertion without pre-existing pneumoperitoneum.(3) to minimize entrance injuries, especially in those patients with prior abdominal operations and intraperitoneal adhesions, alternative entry sites to the closed insertion of a veress needle at paraumbilical region palmer’s point access for laparoscopic prostatectomy—tüfek et al 153urology journal vol 7 no 3 summer 2010 have been advocated. palmer described the use of the left subcostal pararectus region as the primary puncture site, known as palmer’s point (figure 1). (4) this technique has mainly been employed for procedures in the upper abdomen. in this study, we describe our experience with using palmer’s point access for robotic and standard laparoscopic radical prostatectomy. materials and methods since 2004, palmer’s point veress entry has been used to create pneumoperitoneum in 126 robotic and 21 standard laparoscopic radical prostatectomies. all operations were performed by the same team. surgical team consisted of 4 surgeons who had significant open radical prostatectomy experience. after completing the learning curve for the upper tract laparoscopy, 21 transperitoneal laparoscopic radical prostatectomies were performed. the team completed 4-day da vinci robotic laparoscopy training course in february, 2005. our robot assisted radical prostatectomy program began in march, 2005. we used transperitoneal approach similar to vattikuti institute prostatectomy technique with small modifications. under general anesthesia, the patients were prepped and draped from the nipples to the genitalia and the mid-thigh, including the perineum. in supine position, a nasogastric tube was placed. as described in the literature, on the left side, a 2-mm transverse skin incision was made 3 cm below the left costal margin on the midclavicular line. through this incision, a veress needle was inserted to create pneumoperitoneum. prior to insufflation, appropriate positioning of veress needle in the peritoneal cavity was confirmed. initial return of blood, urine, or intestinal content is the indicator of inappropriate positioning. a 10-ml syringe containing 2 ml of saline was attached to stopcock of veress needle and was aspirated. proper positioning should result in air return; not blood, urine, or intestinal content. thereafter, the saline in the syringe was pushed through veress needle and the syringe was removed leaving a small droplet on the stopcock. proper positioning should result in uninhibited leakage of the saline into the abdomen. initial co2 insufflation was done with low flow (1 l/min) and the intra-abdominal pressure was monitored. if the initial pressure did not exceed 8 mmhg, the flow rate was increased to 30 l/ min. intra-abdominal pressure was set to 20 mmhg. the time between veress needle incision and achieving the intra-abdominal pressure of 20 mmhg was defined as pneumoperitoneum time. once pneumoperitoneum was established, a 12-mm optic trocar was inserted around the umbilicus and the remaining trocars were placed under direct laparoscopic vision. in the patients with prior abdominal operations, the initial trocar was most remote from the old incision. depending on the size of this trocar, often 4 mm 30° cystoscope was used for initial exploration. after exploring intraperitoneal cavity, other ports were placed under direct vision following necessary adhesiolysis. results the mean patients’ age and body mass index (bmi) were 59.7 years (range, 37 to 73 years) and 27.92 kg/m2 (range, 22 to 39 kg/m2), respectively. thirty-eight patients had prior abdominal operations, including hernia repair, appendectomy, and cholecystectomy and 10 of them had more than 1 operation. mean veress puncture number was 1.08 (range, 1 to 3). in 93% of the patients, veress needle was inserted successfully at the first attempt, while in 7%, more than 1 veress needle insertion attempt was needed. this failure rate was not related with bmi figure 1. palmer’s point. palmer’s point access for laparoscopic prostatectomy—tüfek et al 154 urology journal vol 7 no 3 summer 2010 and prior abdominal operations. mean time to establish pneumoperitoneum was 5.63 minutes (range, 4 to 8 minutes). in 8 patients with prior abdominal operations and in 1 patient with virgin abdomen, there were significant intraperitoneal adhesions involving periumbilical veress needle insertion site. during initial palmer’s point veress insertion, the omentum was traversed in 6 patients, but there were no adverse sequelae. no major entrance injury was encountered. in addition to patients’ demographics, prior abdominal operations, numbers of veress puncture attempts, time to create pneumoperitoneum are shown in table. discussion in recent years, laparoscopy has become a less invasive and acceptably safe surgical alternative to open surgery for treatment of urologic problems. establishing pneumoperitoneum is the first and one of the most important steps for optimal surgical outcome. however, serious complications like visceral and vascular injuries may occur during this step. veress needle insertion to establish pneumoperitoneum is thought to be one of the most difficult parts of the laparoscopy. (5) about 50% of all laparoscopic complications occur during laparoscopic entry and can be related to the entry technique.(6-8) the closed veress technique, the open hasson, and direct trocar insertion through a small peritoneal incision without pre-existing pneumoperitoneum techniques are most commonly employed for laparoscopic entry. (3) the veress needle was developed in 1938 by veress, a hungarian internist, to insufflate the pleural space to create a pneumothorax. it is the most commonly used, and also a quick method for establishing pneumoperitoneum.(9,10) the classic open technique was first described in 1971 by hasson.(11) this approach is associated with minimal risks of gas embolism, pre-peritoneal insufflation, and bowel and vascular injury.(11-13) it is favored by many laparoscopic surgeons, especially general surgeons. direct trocar insertion without pneumoperitoneum was first described by dingfelder in 1978 (14) and is the least used entry technique. potential benefits of the direct trocar insertion technique are shorter operation time, easy recognition of vascular/ visceral injuries, and low probability of entry failure.(15-19) this technique is claimed to reduce the number of blind steps from three with veress needle (insertion, insufflation, and trocar insertion) to just one (trocar insertion).(3) the traditional site of initial access for closed veress entry is the periumbilical area. previous laparotomy, history of generalized peritonitis, inflammatory bowel disease, obesity or anorexia, pregnancy (>16 weeks gestation), or presence of large intra-abdominal mass are the risk factors for entrance injuries.(20) for patients with increased risk of entrance injuries, open entry or an alternative site for closed entry has to be preferred. open entry does not eliminate the risk of the bowel injury. it has been shown that up to 50% of patients with midline incision and 20% with low transverse incision have some degree of periumbilical bowel adhesions.(21) also, good vision of the peritoneal cavity through a 10-mm incision is not always possible with open entry. this is especially an issue with obese patients. palmer, a gynecologist, described the left upper quadrant access as a safe alternative site for closed veress entry, especially for patients with prior abdominal operations and intraperitoneal adhesions, to minimize entrance injuries.(4,22) as chung and colleagues suggested, we have been using palmer’s point veress needle insertion routinely for upper urinary tract laparoscopy since 2001.(23) palmer’s point access is effective and safe when splenomegaly and gastric distention are not present, especially in obese patients.(24-28) mean age (years) 59.7 (37 to 73) mean bmi (kg/m2) 27.92 (22 to 39) history of prior abdominal operations 38† open appendectomy 18 open cholecystectomy 9 inguinal hernia repair 15‡ (13 open, 2 lap) lap cholecystectomy 4 lap umbilical hernia repair 2 mean veress puncture number 1.08 (1 to 3) mean pneumoperitoneum establishment time (min) 5.63 (4 to 8) demographic and operative characteristics. †10 patients had more than 1 abdominal operation. ‡5 with polypropylene mesh. palmer’s point access for laparoscopic prostatectomy—tüfek et al 155urology journal vol 7 no 3 summer 2010 in gynecologic literature, palmer’s point veress needle insertion has been restricted to small case series with no follow-up evaluations.(24,25) in a relatively large series, left upper quadrant cannula insertion was performed in 60 patients for pelvic gynecologic surgery. in 51 (88%) of these patients, indications of left upper quadrant cannula insertion were prior laparotomy or laparoscopy with suspected adhesions. in this series, in 21% of women, primary umbilical cannula insertion could have been unsafe due to adhesions. no intra-operative complications have been reported. subcutaneous fat is less prominent in the upper abdomen compared with the umbilical area. (28) the costal margin tents the peritoneum anteriorly. palmer’s point is also rarely affected by adhesions in part due to presence of the liver and the stomach. furthermore, major vascular structures are distant from palmer’s point with the interposition of other organs. in addition to these advantages, in our experience, palmer’s point veress insertion is easy to learn. to the best of our knowledge, routine veress needle insertion through palmer’s point for robotic and standard laparoscopic radical prostatectomy has not been reported in the literature before. the extra 2-mm incision made for palmer’s point veress insertion is not used as a trocar site for pelvic laparoscopy. we have not found it to cause gas leakage, postoperative pain, or bleeding (figure 2). in low-risk patients, entry complications are rare in both open hasson and closed veress techniques. in a review article by molloy and associates, entry related bowel and vascular complications occurred in approximately 0.1% of the patients.(3) there is no clear evidence for the optimal form of laparoscopic entry in the low-risk patients. on the basis of evidence investigated in a recent review, there appears to be no verification of benefit in terms of safety of one technique over another.(29) while a randomized trial might define which approach is the best, power calculations suggest that 800 000 laparoscopy procedures would be required for such a study.(20) conclusion instead of using different entry techniques according to the patient’s characteristics, using the same method for every patient seems to be more feasible and easy to learn. palmer’s point upper quadrant access can be routinely used for both upper and lower urinary tract laparoscopy in all patients. acknowledgements the authors are thankful to prof. dean assimos from urology department of wake forest university medical school who assisted in preparing and reviewing this article. conflict of interest none declared. references 1. chandler jg, corson sl, way lw. three spectra of laparoscopic entry access injuries. j am coll surg. 2001;192:478-90; discussion 90-1. 2. vilos ga, ternamian a, dempster j, laberge py, the society of obstetricians and gynaecologists of c. laparoscopic entry: a review of techniques, technologies, and complications. j obstet gynaecol can. 2007;29:433-65. 3. molloy d, kaloo pd, cooper m, nguyen tv. laparoscopic entry: a literature review and analysis of techniques and complications of primary port entry. aust n z j obstet gynaecol. 2002;42:246-54. 4. palmer r. safety in laparoscopy. j reprod med. 1974;13:1-5. 5. see wa, fisher rj, winfield hn, donovan jf. laparoscopic surgical training: effectiveness and figure 2. port placement for robotic radical prostatectomy with a three arm da vinci surgical system and veress needle at palmer’s point. palmer’s point access for laparoscopic prostatectomy—tüfek et al 156 urology journal vol 7 no 3 summer 2010 impact on urological surgical practice patterns. j urol. 1993;149:1054-7. 6. harkki-siren p, kurki t. a nationwide analysis of laparoscopic complications. obstet gynecol. 1997;89:108-12. 7. jansen fw, kapiteyn k, trimbos-kemper t, hermans j, trimbos jb. complications of laparoscopy: a prospective multicentre observational study. br j obstet gynaecol. 1997;104:595-600. 8. neudecker j, sauerland s, neugebauer e, et al. the european association for endoscopic surgery clinical practice guideline on the pneumoperitoneum for laparoscopic surgery. surg endosc. 2002;16:1121-43. 9. wherry dc, marohn mr, malanoski mp, hetz sp, rich nm. an external audit of laparoscopic cholecystectomy in the steady state performed in medical treatment facilities of the department of defense. ann surg. 1996;224:145-54. 10. patel dn, parikh mn, nanavati ms, jussawalla mj. complications of laparoscopy. asia oceania j obstet gynaecol. 1985;11:87-91. 11. hasson hm. a modified instrument and method for laparoscopy. am j obstet gynecol. 1971;110:886-7. 12. ballem rv, rudomanski j. techniques of pneumoperitoneum. surg laparosc endosc. 1993;3:42-3. 13. sigman hh, fried gm, garzon j, et al. risks of blind versus open approach to celiotomy for laparoscopic surgery. surg laparosc endosc. 1993;3:296-9. 14. dingfelder jr. direct laparoscope trocar insertion without prior pneumoperitoneum. j reprod med. 1978;21:45-7. 15. yerdel ma, karayalcin k, koyuncu a, et al. direct trocar insertion versus veress needle insertion in laparoscopic cholecystectomy. am j surg. 1999;177:247-9. 16. borgatta l, gruss l, barad d, kaali sg. direct trocar insertion vs. verres needle use for laparoscopic sterilization. j reprod med. 1990;35:891-4. 17. byron jw, markenson g, miyazawa k. a randomized comparison of verres needle and direct trocar insertion for laparoscopy. surg gynecol obstet. 1993;177:259-62. 18. hasaniya nw, kosasa ts, shieh t, nakayama rt. direct laparoscopic entry using a sharp and dull trocar technique. obstet gynecol. 1996;88:620-1. 19. copeland c, wing r, hulka jf. direct trocar insertion at laparoscopy: an evaluation. obstet gynecol. 1983;62:655-9. 20. jansen fw, kolkman w, bakkum ea, de kroon cd, trimbos-kemper tc, trimbos jb. complications of laparoscopy: an inquiry about closedversus openentry technique. am j obstet gynecol. 2004;190: 634-8. 21. audebert aj, gomel v. role of microlaparoscopy in the diagnosis of peritoneal and visceral adhesions and in the prevention of bowel injury associated with blind trocar insertion. fertil steril. 2000;73:631-5. 22. mayol j, garcia-aguilar j, ortiz-oshiro e, de-diego carmona ja, fernandez-represa ja. risks of the minimal access approach for laparoscopic surgery: multivariate analysis of morbidity related to umbilical trocar insertion. world j surg. 1997;21:529-33. 23. chung hj, meng mv, abrahams hm, stoller ml. upper quadrant access for urologic laparoscopy. urology. 2003;62:1117-9. 24. chang fh, chou hh, lee cl, cheng pj, wang cw, soong yk. extraumbilical insertion of the operative laparoscope in patients with extensive intraabdominal adhesions. j am assoc gynecol laparosc. 1995;2:335-7. 25. howard fm, el-minawi am, deloach ve. direct laparoscopic cannula insertion at the left upper quadrant. j am assoc gynecol laparosc. 1997;4: 595-600. 26. parker j, reid g, wong f. microlaparoscopic left upper quadrant entry in patients at high risk of periumbilical adhesions. aust n z j obstet gynaecol. 1999;39:88-92. 27. patsner b. laparoscopy using the left upper quadrant approach. j am assoc gynecol laparosc. 1999;6: 323-5. 28. tulikangas pk, nicklas a, falcone t, price ll. anatomy of the left upper quadrant for cannula insertion. j am assoc gynecol laparosc. 2000;7: 211-4. 29. ahmad g, duffy jm, phillips k, watson a. laparoscopic entry techniques. cochrane database syst rev. 2008cd006583. running head: pre vs post-uds levofloxacin related to uti-rahardjo et al. comparison of the effectiveness of pre-urodynamic single-dose levofloxacin with post-urodynamic levofloxacin for three days related to the incidence of urinary tract infection: a randomized control trial harrina e. rahardjo1, fina widia1, mega anara manurung1, indra wicaksono1, soefiannagoya soedarman1, haryo prakoso adhi purwanto1, ahmad aulia rizaly1, kevin leonardo2, andika afriansyah3* 1department of urology, faculty of medicine, universitas indonesia – cipto mangunkusumo hospital, jakarta, indonesia. 2division of urology, department of surgery, persahabatan hospital, jakarta, indonesia 3division of urology, department of surgery, persahabatan hospital faculty of medicine, universitas indonesia, jakarta, indonesia abstract purpose: the current study aims to compare the effectiveness of pre-urodynamic single-dose levofloxacin and post-urodynamic levofloxacin for three days related to the incidence of urinary tract infections post-urodynamic examination. materials and methods: this is a single-blind randomized clinical trial conducted in three outpatient urology centers in jakarta: cipto mangunkusumo general hospital, siloam asri hospital, and persahabatan general hospital using a consecutive sampling method between july 2019 february 2022. the outcome of the study is the incidence of urinary tract infections in both treatment groups. urinary tract infection was defined as a patient with one or more clinical symptoms of lower urinary tract infection and one or more urinalysis parameters positive for urinary tract infections. chi-square was used to evaluate the association where p < 0.05 was used to determine statistical significance. results: a total of 126 patients (63 patients in each arm) were included in the evaluation and analysis. overall, urinary tract infections were detected in 25 cases (19.8%), 12 patients from the pre-urodynamic antibiotic group (9.5%) and 13 patients from the post-urodynamic antibiotic group (10.3%) (p = .823). e.coli was the most common bacteria found in the urine culture. conclusion: the efficacy of a single dose of 500 mg of levofloxacin given one hour before urodynamic study is comparable to that of a once-daily dose of 500 mg of levofloxacin for three days following urodynamic study. there is no significant difference between a single dose of 500 mg of levofloxacin administered one hour before the urodynamic study and a once-daily dose of 500 mg of levofloxacin for three days following the urodynamic study related to urinary tract infections prevention post-urodynamic examination. keywords: antibiotic, levofloxacin, prophylaxis, randomized trial, urinary tract infection, urodynamic study introduction the urodynamic study (uds) is an essential examination in the field of urology. using uds, the lower urinary tract function can be assessed, and the underlying diagnosis causing the lower urinary tract symptoms can be determined. however, given the invasive nature of the procedure, the risk of the patient contracting a urinary tract infection (uti) after the study is high. the incidence of acquired uti (asymptomatic or symptomatic) following uds varies widely; however, literature report rates range from 1.5 to 36%.(1-3) for this particular reason, prophylactic antibiotics are given to avoid post-urodynamic infections. this statement is also supported by the results of a 2016 study by rahardjo, et al. in which administration of prophylactic antibiotics for 3 days after urodynamics was able to reduce the rate of uti by 55% compared to a placebo.(4) moreover, considering the increasing number of urodynamic examinations(5), the incidence of infection and the cost of administrating prophylactic antibiotics after urodynamics has become burdens on health services.(2-3) in previous studies, researchers have identified that administering levofloxacin for three days after uds has high efficacy in preventing utis after uds.(1) moreover, several additional studies have also shown that single-dose prophylactic antibiotics have satisfactory efficacy in preventing utis after uds.(6-9) the administration of single-dose antibiotics in preventing infection after certain invasive procedures have proven not only to have good efficacy but also to have better cost-efficiency.(10-14) this study aims to determine whether a single dose of levofloxacin 1 hour before the procedure may show equal, or even better efficacy than a daily dose for three days after uds. an equal or better efficacy may indicate lower usage of antibiotics, leading to better cost-efficiency and better compliance from patients.(15) materials and methods study population this is an experimental study with a single-blinded randomized clinical trial design to compare the number of utis in a group of patients who received a single dose of 500 mg of levofloxacin one hour before the urodynamic study and patients who received levofloxacin 500 mg qd for three days after urodynamic study. the study was conducted in three outpatient urology centers in jakarta: cipto mangunkusumo general hospital, siloam asri hospital, and persahabatan general hospital, between july 2019 february 2022, and it was registered with clinical-trials.gov number nct05219877. calculation of the sample is made based on the calculation of proportions for two independent groups from previous literature. considering the possibility of drop-out, it is decided that the number of samples taken is at least 100 patients. the balanced blocked randomization technique (block size of 4) was used to determine the sample treatment group for the study. allocation concealment was performed in this study. the subject and physician who performed the uds study were aware of which treatment protocol the patient received. however, the investigators (the doctor who examines and assesses if clinical uti was present in the patients after antibiotic administration, the urodynamic nurses, and also the laboratory worker) were not aware of which drug regimen was administered to the research subjects. the main outcome of the study was to assess whether the administration of a single dose of 500 mg levofloxacin is more effective than a once-daily dose of 500 mg levofloxacin for three days in preventing uti as an adverse event of urodynamic study. while the secondary outcomes were microorganism data in urine culture that cause utis in our population, clinical diagnoses for performing uds, and sex difference correlation to the incidence of uti post-uds. the ethical clearance number for the study ket-542/un2.f1/etik/ppm.00.02/2019 was approved and issued by the faculty of medicine, universitas indonesia ethics committee. the research was conducted in accordance with the declaration of helsinki. all patients provided written informed consent before the start of the trial. inclusion and exclusion criteria the data were collected using a consecutive sampling method until the required number of subjects was reached. the inclusion criteria were men and women above the age of 18 who underwent uds and were willing to participate in the study. patients who had at least one of the following exclusion criteria were not included in the study: allergy to levofloxacin, history of antibiotics consumption in 1 month before the study, pregnancy, uncontrolled and untreated diabetes mellitus, use of a urinary catheter, uti confirmed by urinalysis before the study, or refusal to participate. before uds, patients were required to undergo urinalysis to confirm whether the patients suffering from a uti or not. if a uti was confirmed, the patient was excluded from the study. procedures patients who were willing to participate and did not meet any of the exclusion criteria were randomly divided into two groups: those receiving a single dose of 500 mg levofloxacin 1 hour before uds, and those receiving a once-daily dose of 500 mg levofloxacin for three consecutive days after uds. according to the standard uds procedure, those eligible for the uds underwent the procedure. four days after uds, the patients were followed up using urinalysis and checked for clinical symptoms related to uti. after the urinalysis results were obtained and clinical symptoms assessed, patients who had confirmed utis were required to undergo urine culture and antibiotics sensitivity testing. a urinary tract infection is defined based on the results of urinalysis in which one of the following conditions is present: leukocyturia (found > 5 leukocytes/per field view), a positive result of bacteria, nitrite, and/or leukocyte esterase. statistical analysis a descriptive report was used to describe each subject, including their age, gender, and reason for undergoing uds, whereas analytic studies were utilized to compare the event of uti in the pre-urodynamic antibiotic group and the post-urodynamic antibiotic group. the chisquare test was used to compare the association between utis and the treatment groups, if no expected cell count was less than 1 and at most 20% of the expected cell counts less than 5, otherwise fisher’s exact test was chosen. relative risk (rr) and its 95% confidence interval (ci) were used to analyze the data. the statistical analysis was performed using ibm spss statistics version 23. a p value < 0.05 was used to determine statistical significance. results one hundred eighty-three patients were assessed for eligibility. forty-four patients were excluded due to the use of a urinary catheter (n = 29), having a documented uti before the uds study (n = 12), prior antibiotic use (n = 2), and undergoing surgery (n = 1). five participants declined to take part in this study. one hundred thirty-four patients who were willing to participate and had no exclusion criteria were divided into two groups randomly: 67 patients who received a single dose of 500 mg levofloxacin 1 hour before uds, and 67 patients who received a once-daily dose of 500 mg levofloxacin for three days after uds. four patients from the group who received antibiotics before uds were lost to followup. meanwhile, three patients from the group who received antibiotics after uds were also lost to follow-up, and one had to discontinue the intervention due to hematuria experienced two days after uds, requiring further evaluation and treatment. in total, 63 patients from each group were analyzed. figure 1 presents a flow diagram of the randomized trial. the characteristics of the patients who underwent uds in each group are presented in table 1. the clinical diagnoses for performing uds were lower urinary tract symptoms (luts) (n=80 patients; 63,4%), overactive bladder (oab) (n = 34 patients; 27%), stress urinary incontinence (sui) (n = 5; 4%), history of urinary retention (n = 5; 4%), neurogenic bladder (n = 1; 0.8%), and enuresis (n = 1; 0.8%). during the filling phase, 56 patients (44.4%) had small bladder capacity, 33 patients (26.2%) had detrusor overactivity, 17 patients (13.5%) had low bladder compliance, 8 patients (6.3%) had large bladder capacity, 3 patients (2.4%) had stress urodynamic incontinence, and 1 patient (0.8%) had detrusor overactivity incontinence. a patient could have more than one diagnosis during the filling phase. in the voiding phase, forty-eight patients (38.1%) had detrusor underactivity and 49 patients (38.9%) had a bladder outlet obstruction. during this phase, the patients could also receive multiple diagnoses. normal urodynamic results were found in 12 patients (9.5%) in both the filling and voiding phases. overall, utis were found in 25 cases (19.8%) of the 126 post-uds patients (12 of 63 patients from the pre-urodynamic antibiotic group (9.5%) and 13 of 63 patients from the posturodynamic antibiotic group (10.3%); p = .823). fifteen of them (five in pre-urodynamic antibiotic group and ten in post-urodynamic antibiotic group) were male patients. six (9.5%) patients from the pre-urodynamic antibiotic group were symptomatic utis while 8 patients (12.7%) from the post-urodynamic antibiotic group had symptomatic utis. e.coli was the most common bacteria found in the urine culture followed by k.pneumonia and s.epidermidis. we also discovered ten patients with utis who had no bacterial growth in their urine culture/isolation. a comparison of the uti cases in both groups is presented in table 2. discussion the urodynamic study (uds) is a widely used diagnostic tool in the evaluation of patients with voiding dysfunction, urinary incontinence, bladder outlet obstruction, and neurogenic bladder. despite the aseptic procedure, patients still have a chance of developing urinary tract infections (utis) as one of the most common complications associated with uds. therefore, prophylactic antibiotics, which vary considerably in the choice of antimicrobial agents and routes of administration, are often used in several urologic invasive procedures to prevent utis afterward. however, previous studies regarding the use of prophylactic antibiotics post-uds have revealed inconsistent results. there is no consensus in the literature regarding antibiotic prophylaxis for urodynamic investigation. the incidence of utis after uds was found to be 19.8% in this study. the present finding was similar when compared to a prior study conducted in 2016.(4) several studies have reported incidences of acquired utis (asymptomatic or symptomatic) after urodynamic examination ranging between 1.5 and 36%.(1,3,16-17) this large discrepancy may be due to the time of urine testing, catheterization technique, the difference in study populations in terms of age or underlying problems, the uds performance method, and different definitions of urinary tract infections.(18-20) several studies do not support routine prophylaxis, as there is no significant improvement in the overall prevalence of utis after urodynamic investigation. meanwhile, other studies suggest that prophylaxis is useful.(21-23). although the results of different studies are conflicting, two previous meta-analyses reported that the use of prophylactic antibiotics reduced the bacteriuria risk caused by urodynamic tests.(1,3) according to rahardjo et al.(4), a three-day course of 500mg of levofloxacin daily could decrease the incidence of symptomatic utis from 28.6% to 12.7%. on the other hand, a single dose of antibiotics within an hour before uds appears to be a suitable option for reducing the incidence of symptomatic utis in patients with neurogenic bladder and asymptomatic bacteriuria who undergo uds.(24) to date, no clinical trial has been performed regarding the timing of prophylactic antibiotics, and to our knowledge, the present study is the first randomized trial to compare prophylactic antibiotics given preurodynamic study and post-urodynamic study concerning post-uds utis. this study shows that there is no significant difference in the group of patients who received a single dose of 500 mg levofloxacin one hour before the uds and patients who received levofloxacin 500 mg qd for three days after the uds in terms of uti incidence. in the aua best practice policy for antibiotic prophylaxis, fluoroquinolones are designated as first-line prophylaxis. alternative antimicrobials include cotrimoxazole, aminoglycoside, ampicillin, cephalosporin, and amoxicillin/clavulanate. however, when selecting a prophylactic antibiotic, local microorganisms, and their sensitivity-resistance data patterns, patient allergies, preceding urine cultures, and antibiotic cost should all be considered.(25) the provider's clinical judgment must always be taken into account. our study also found that there was no difference in the incidence of utis postprocedural between male and female patients, although 15 out of 25 were male patients. this finding contradicts the previous study that identified one of the important predictors of post-uds utis including the male sex (p = .02).(26) the use of single-dose antibiotics as prophylaxis for infection has been studied throughout the decades.(27-29) the studies have shown that the efficacy of shorter single-dose antibiotic administration is comparable to longer regimens.(2728,30) a shorter regimen also reduces cost and workload and improves patient comfort. given the fact that in this study, the number of patients who suffered from utis post-uds was similar between each group in a descriptive fashion, we can conclude that the efficacy of a single dose of 500 mg levofloxacin one hour before uds is similar to that of a qd administered for three days after uds. this fact provides the patient and the healthcare provider with a choice of which antibiotic regimen suits the patient’s needs and comfort. conclusion the efficacy of a single dose of 500 mg of levofloxacin administered one hour before uds is comparable to that of a once-daily dose of 500 mg of levofloxacin for three days following uds. there is no significant difference between a single dose of 500 mg of levofloxacin administered one hour before the urodynamic study and a once-daily dose of 500 mg of levofloxacin for three days following the urodynamic study related to urinary tract infections prevention post-urodynamic examination. this information allows healthcare providers to choose which antibiotic regimen best matches the needs of their patients, taking into account cost, compliance, and the local microorganism sensitivity resistance data. acknowledgments this work was funded by the operational grant of cipto mangunkusumo general hospital (hk.01.07/3.3/8470/2019), subjected to the first author. conflict of interest statement the authors declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article. approval of the research protocol the ethical clearance number for the study ket-542/un2.f1/etik/ppm.00.02/2019 was approved by the faculty of medicine, universitas indonesia ethics committee, and the research was conducted in accordance with the declaration of helsinki. informed consent all patients provided written informed consent before the start of the trial. registration of the studies this study was registered with clinical-trials.gov number nct05219877. references 1. rahardjo he, tirtayasa pmw, afriansyah a, parikesit d, akbar mi. the effectiveness of a three day course antibiotic post-urodynamic study in preventing lower urinary tract infection. acta med indones. 2016;48:84–90. 2. dray e, mueller er. use of urodynamic studies among certifying and recertifying urologists from 2003 to 2014. urol. pract. 2017;4:251–6. 3. kumalawati j, handimulya d, solin r. bacterial and antibiotics susceptibility profile at cipto mangunkusumo general hospital january-june 2020. kumalawati j, handimulya d, solin r, editors. jakarta: department of clinical pathology cipto mangunkusumo general hospital; 2020. 147–153 p. 4. copcoat mj, reed c, cumming j, shah pjr, worth phl. is antibiotic prophylaxis necessary for routine urodynamic investigations?: a controlled study in 100 patients. br. j. urol. 1988;61:302–3. 5. kartal ed, yenilmez a, kiremitci a, meric h, kale m, usluer g. effectiveness of ciprofloxacin prophylaxis in preventing bacteriuria caused by urodynamic study: a blind, randomized study of 192 patients. urology. 2006;67:1149–53. 6. peschers um, kempf v, jundt k, autenrieth i, dimpfl t. antibiotic treatment to prevent urinary tract infections after urodynamic evaluation. int urogynecol j. 2001;12:254–7. 7. siracusano s, knez r, tiberio a, alfano v, giannantoni a, pappagallo g. the usefulness of antibiotic prophylaxis in invasive urodynamics in postmenopausal female subjects. int urogynecol j. 2008;19:939–42. 8. westen ehmn, kolk pr, van velzen cl, unkels r, mmuni ns, hamisi ad, et al. single-dose compared with multiple day antibiotic prophylaxis for cesarean section in low-resource settings, a randomized controlled, noninferiority trial. acta obstet gynecol scand. 2015;94:43–9. 9. duff p. antibiotic selection in obstetrics: making cost-effective choices. clin obstet gynecol. 2002;45:59–72. 10. esposito s. is single-dose antibiotic prophylaxis sufficient for any surgical procedure?. j chemother. 1999;11(6):556–64. 11. slobogean gp, o’brien pj, brauer ca. single-dose versus multiple-dose antibiotic prophylaxis for the surgical treatment of closed fractures. acta orthopaedica. 2010;81:256–62. 12. tamayo e, gualis j, flórez s, castrodeza j, eiros bouza jm, álvarez fj. comparative study of single-dose and 24-hour multiple-dose antibiotic prophylaxis for cardiac surgery. j. thorac. cardiovasc. surg.. 2008;136:1522–7. 13. davey p, scott cl, brown e, charani e, michie s, ramsay cr, et al. interventions to improve antibiotic prescribing practices for hospital inpatients (updated protocol). cochrane database of systematic reviews. 2017. 14. r. foon, p. toozs-hobson, and p. latthe, “prophylactic antibiotics to reduce the risk of urinary tract infections after urodynamic studies,” cochrane database of systematic reviews, vol. 10, p. cd008224, 2012. 15. latthe, p. m., foon, r., & toozs‐hobson, p. prophylactic antibiotics in urodynamics: a systematic review of effectiveness and safety. neurourol urodyn. 2008;27:167-173. 16. okorocha i, cumming g, gould i. female urodynamics and lower urinary tract infection. bju int. 2002;89:863-7 17. onur r, ozden m, orhan i, et al. incidence of bacteraemia after urodynamic study. j hosp infect. 2004;57:241-4. 18. l. bombieri, d. a. dance, g. w. rienhardt, a. waterfield, and r. m. freeman, “urinary tract infection after urodynamic studies in women: incidence and natural history,” bju int. 1999;83:392–5 19. ghanbari, z., haghollahi, f., eftekhr, t., froghifar, t., shariat, m., hajihashemy, m., & ayati, m. rate of urinary tract infection after urodynamic study in pelvic floor clinic. caspian j intern med. 2020;11:100. 20. nóbrega, m. m., auge, a. p. f., de toledo, l. g. m., da silva carramão, s., frade, a. b., & salles, m. j. c. bacteriuria and urinary tract infection after female urodynamic studies: risk factors and microbiological analysis. am j infect control. 2015;43:1035-39. 21. cutinha pe, potts lk, fleet c. morbidity following pressure flow studies (pfs). are prophylactic antibiotics necessary? neurourol urodyn. 1996;15:304-5. 22. baker kr, drutz hp, barnes md. effectiveness of antibiotic prophylaxis in preventing bacteriuria after multichannel urodynamic investigations: a blind, randomized study in 124 female patients. am j obstet gynecol. 1991;165:679-81. 23. payne sr, timoney ag, mckenning st et al. microbiological look at urodynamic studies. lancet 1988;2:1123–1126 24. thodthasri, t., chetchotisakd, p., kharmwan, s., & anunnatsiri, s. antibiotic prophylaxis prior to urodynamic study in patients with neurogenic bladder and asymptomatic bacteriuria: a randomized controlled trial. j med assoc thai. 2021;104:56-62. 25. wolf js, bennett cj, dmochowski rr, hollenbeck bk, pearle ms, schaeffer aj. best practice policy statement on urologic surgery antimicrobial prophylaxis. j urol. 2008;179:1379–90. 26. nadeem m, sheikh mi, sait ms, emmanuel n, sheriff mk, masood s. is urinary tract infection after urodynamic study predictable?. urol. sci.. 2017;28:240-2. 27. barie ps. modern surgical antibiotic prophylaxis and therapy--less is more. surg infect. 2000;1:23–9. 28. dipiro jt, cheung rpf, bowden ta, mansberger ja. single dose systemic antibiotic prophylaxis of surgical wound infections. am. j. surg. 1986;152:552-9. 29. carbón c. single‐dose antibiotic therapy: what has the past taught us? j. clin. pharmacol.. 1992;32:686–91. 30. wu xy, cheng y, xu sf, ling q, yuan xy, du gh. prophylactic antibiotics for urinary tract infections after urodynamic studies: a meta-analysis. biomed res. int.. 2021. corresponding author: andika afriansyah division of urology, department of surgery, persahabatan hospital, jl. persahabatan raya no. 1, pulo gadung, jakarta timur, dki jakarta 13230, indonesia tel: +6281298355047, email: andikaafriansyah@gmail.com table 1. subject characteristics receiving single dose 500 mg levofloxacin 1 hour prior to uds (n = 63) receiving daily dose 500 mg levofloxacin for 3 days after uds (n = 63) age, year; mean ± sd (range) 52.75 ± 16.36 (18-84) 53.78 ± 17.17 (18-84) sex, n (%) male female 33 (26.2) 30 (23.8) 38 (30.2) 25 (19.8) clinical diagnosis for performing uds, n luts oab stress urinary incontinence history of urinary retention enuresis neurogenic bladder 39 16 4 3 1 0 41 18 1 2 0 1 uds = urodynamic study; luts = lower urinary tract symptom; oab = overactive bladder table 2. urinary tract infections (utis) post-urodynamic study in both groups uds = urodynamic study; utis = urinary tract infections receiving single-dose 500mg levofloxacin 1 hour prior to uds (n = 63) receiving daily dose 500mg levofloxacin for 3 days after uds (n = 63) rr (95% ci) p-value number of uti cases postuds, n (%) 12 (19) 13 (20.6) .92 (.45-1.86) .823 uti by gender male (n=71), n female (n=55), n 5 7 10 3 .58 (.22-1.51) 1.94 (.57-6.75) .263 .294 symptomatic utis, n (%) 6 (9.5) 8 (12.7) .75 (.28-2.04) .571 positive urine culture, n (%) 6 (9.5) 4 (6.3) 1.5 (.44-5.06) .510 type of bacteria found in urine culture, n e. coli k. pneumoniae s. epidermidis no growth no urine culture data 2 3 1 4 2 3 1 0 6 3 figure 1. diagram of the randomized trial of pre-urodynamic single-dose levofloxacin and post-urodynamic levofloxacin for three days related to the incidence of utis reconstructive surgery 178 urology journal vol 7 no 3 summer 2010 complications of transverse distal penile island flap urethroplasty of complex anterior urethral stricture abimbola o. olajide,1 abdulkadir a. salako,2 ademola a. aremu,3amogu k. eziyi,1 folakemi o. olajide,4 oluseyi o. banjo2 purpose: to report the complications of transverse distal penile island flap urethroplasty for urethral reconstruction in adult patients with long/ multiple segments anterior urethral stricture. materials and methods: this prospective study was carried out on 55 patients with complex anterior urethral stricture to study complications of transverse distal penile island flap urethroplasty in two teaching hospitals between june 2002 and december 2008. pre-, intraand postoperative information were collected on a pro forma to generate data, which was analyzed. results: the patients’ mean age was 43.83 years (range, 19 to 73 years). the leading etiology of the stricture was urethral inflammation (76.4%) with the commonest complication being infection: wound infection in 9.1%, urosepsis in 3.6%, and epididymo-orchitis in 1.8% of the subjects. conclusion: transverse distal penile island flap urethroplasty has a remarkable outcome in treatment of a long/multiple segment urethral stricture with few manageable complications. urol j. 2010;7:178-2. www.uj.unrc.ir keywords: urethral stricture, island flap, reconstructive surgical procedures 1department of surgery, ladoke akintola university of technology, osogbo, osun state, nigeria 2department of surgery, obafemi awolowo university, ile-ife, osun state, nigeria 3department of radiology, ladoke akintola university of technology, osogbo, osun state, nigeria 4department of community health, obafemi awolowo university, ile-ife, osun state, nigeria corresponding author: abimbola o olajide, md department of surgery, ladoke akintola university of technology teaching hospital, idi seke, osogbo, osun state, nigeria tel: +234 803 725 1893 e-mail: lajidea@yahoo.com received july 2009 accepted january 2010 introduction reconstruction of the urethral stricture is one of the oldest problems in reconstructive surgery, which can pose a great challenge to a surgeon.(1) it represents a significant part of the workload of the urologists. there are two main approaches to open surgical reconstruction of the urethra in patients with urethral stricture: resection of the stricture with endto-end anastomosis and substitution techniques by grafts or flaps. the latter technique is often used for complex strictures in which resection and anastomosis are not possible.(2) a urethral stricture is considered complex when it has focally dense segment(s), a long length, or multiplicity with or without associated defi ciency of the penile skin. complex strictures pose problems to the man agement, due to their length and associated spongiofibrosis.(3) a variety of donor tissues have been used both experimentally and clinically for repair of complex urethral strictures, including the penile or preputial skin,(4) the bladder mucosa,(5) the buccal mucosa,(6) the tunica vaginalis,(7) the peritoneum,(8) and the intestinal submucosa.(9) transverse distal penile island flap, as described by quartey in 1983,(2) has been used for one-stage urethral reconstruction and has led to good functional and cosmetic results penile island flap in urethral stricture—olajide et al 179urology journal vol 7 no 3 summer 2010 in the past three decades.(10,11) the penile skin is supplied axially by superficial external pudendal vessels and is well-vascularized; it is hairless and the pedicle can be constructed; hence, the skin can reach anywhere from the external meatus to the prostatic urethra for reconstruction as a patch or tube.(2) the total impact of transverse distal penile island flap on the patient is still unknown; hence, further studies of postoperative complications are still necessary.(12) we report the complications of transverse distal penile island flap urethroplasty for urethral reconstruction in adult patients with long/multiple segments anterior urethral stricture. materials and methods this prospective study was carried out between june 2002 and december 2008 on 55 patients with complex anterior urethral stricture treated by transverse distal penile island flap urethroplasty by the same team of surgeons in two referral centers. thereafter, patients were followed up for a period of 1 to 5 years, and those who left the follow-up in less than 1 year were excluded from the study. pre-operative history, investigations, intra-operative stricture length, and postoperative complications were all recorded according to a pre-determined pro forma. retrograde urethrography (pericatheter) was performed at 3 weeks postoperatively. urethral catheter was removed thereafter and the patient was discharged and referred to the follow-up clinic. the outcome of the reconstruction was assessed by patient’s subjective evaluation of his pre-operative symptoms, direct observation of the urine stream during micturition, and postoperative retrograde urethrography at 3 to 6 weeks. the outcome was considered satisfactory when there was resolution of the pre-operative symptoms, patent lumen with smooth outline on retrograde urethrogram, a good stream of urine on direct observation, flow rate > 15ml/sec, or ultrasonography observation of post-void residual urine < 100ml. the complications noted were grouped into early (within 21 days postoperation) and late (after 21 days postoperation). the data were analyzed using spss software (statistical package for the social science, version 14.0, spss inc, chicago, illinois, usa). p values less than .05 were considered statistically significant. results the patients’ mean age was 43.83 years (range, 19 to 73 years). thirty-nine patients (71%) had urethral dilatation in peripheral hospitals and 47 patients (85.5%) had urinary diversion with suprapubic cystostomy before presentation to our clinics. the etiologies of the stricture are shown in table 1, with inflammation as the leading cause (76.4%). forty-four patients (80.0%) had significant growth of bacteria on urine culture, while 8 (14.5%) had no significant bacterial growth, and the remaining 3 (5.5%) had mixed growth of organism (probably contaminants). the mean stricture length was 4.9 cm (range, 2.5 to 14 cm). there were multiple stenotic segments in 42 patients (76.4%). postoperative complications were seen in 13 patients, with a complication rate of 23.6% (tables 2 and 3). among the 5 patients with perineal wound infection (figure 1), 2 had systemic manifestations of urosepsis with fever, chills, and rigor. three patients developed temporary urethrocutaneous etiology frequency percentage (%) inflammation 42 76.4 trauma 9 16.4 instrumentation 1 1.8 unknown 3 5.5 table 1. etiology of the stricture complications frequency percentage (%) perineal wound infection 5 9.1 urosepsis 2 3.6 urethrocutaneous fistula 3 5.5 penile skin necrosis 2 3.6 epididymo-orchitis 1 1.8 scrotal hematoma 2 3.6 total no of patients 9 16.4 table 2. early postoperative complications complications frequency percentage (%) recurrence 1 1.8 urethral diverticulum 3 5.5 total no of patients 4 7.3 table 3. late postoperative complications penile island flap in urethral stricture—olajide et al 180 urology journal vol 7 no 3 summer 2010 figure 1. severe perineal wound infection. figure 2. postoperative pericatheter urethrogram showing a urethrocutaneous fistula which closed spontaneously. figure 3. penile skin (donor site) ulcer. figure 4. retrograde urethrogram showing urethral diverticulum at the site where the flap was sutured to the urethra as an onlay repair. penile island flap in urethral stricture—olajide et al 181urology journal vol 7 no 3 summer 2010 fistula, which closed spontaneously before 6 weeks postoperation (figure 2) and 1 had partial necrosis of the ventral penile skin in addition, which was treated with serial wound debridement and culture sensitive antibiotics (figure 3). three patients had asymptomatic urethral diverticulum seen on their postoperative retrograde urethrography (figure 4). the hospitalization stay ranged between 18 and 32 days with the mean of 21.42 days. one patient presented 2 years after treatment with recurrence of the stricture, which had to be treated by twostaged substitution urethroplasty. overall success rate of the procedure was 98.2%. discussion single stage repair of a long segment urethral stricture using a well-vascularized flap is superior to the multiple stage procedure. since single stage repair is more cost-effective and also reduces the risks of multiple anesthesia and surgeries; hence, it is more acceptable and satisfying to the patient. (13) however, one of the factors determining the success rate is the availability of an appropriate vascularized skin flap. when a vascularized skin flap is not available, attendant complications like recurrence and urethrocutaneous fistula may make a single stage substitution urethroplasty a sub-optimal alternative.(12) the transverse distal penile island flap raised from the distal penile skin can be used as a tube or a patch for the repair of urethral stricture.(13-16) in 55 patients that were treated by transverse distal penile island flap in this study, infective complications were the commonest complication (14.6%). this can presumptively be explained by the high rate of pre-operative urinary tract infection with positive culture in 80% of the patients. in addition, a larger percentage of these patients have had one or more attempts at treatment before presentation (urethral dilatation (71%) and/or suprapubic cystostomy (85.5%)), which are likely to increase the infective complications. although urinary tract infection is often present because of associated stasis of urine, early presentation by patients or early referral to urologists by general practitioners in peripheral hospitals can reduce pre-operative instrumentation and subsequently infective complications. one of the advantages of the vascularized flap over graft is its ability to survive when there is infection or severe periurethral fibrosis, since the vascularized flap does not depend on the blood supply of the native tissue. (17,18) of 150 patients treated by quartey in 1993, there was no flap necrosis, even in the presence of pre-existing fistula or peri-urethral abscesses.(19) mcaninch also reported success in 66 patients treated by distal penile flap.(20) recurrence is usually due to incomplete opening of the urethral lumen and the surrounding fibrotic tissue when urethrotomy is done during the operation. hence, it is recommended to extend the incision made on the urethra during surgical repair into the adjacent normal urethral mucosa distal and proximal to the stricture site.(12) in this study, of a total of 55 patients, only one recurrent stricture was reported (recurrence rate of 1.8%). there was no permanent urethrocutaneous fistula; the 3 reported fistulas closed spontaneously on conservative therapy within 3 weeks of follow-up. we observed that if there is no residual stricture distal to the fistula, the fistula is likely to close spontaneously. other authors have reported similarly low incidence of urethrocutaneous fistula following the use of distal penile flap for the repair of urethral stricture, which explains the recommendation of a single stage procedure with a vascularized flap for complex anterior urethral stricture.(14-16) distal penile flap has, thus, emerged as the most versatile tissue transferred for a long segment urethral stricture.(21) an asymptomatic urethral diverticulum was demonstrated on the postoperative urethrogram in 3 patients. a huge urethral diverticulum can be troublesome with terminal dribbling or recurrent urinary tract infection. this can be prevented if the urethrotomy incision is made on the dorsal surface of the urethra such that the flap is applied to close the defect on the dorsal surface of the urethra.(22,23) rao and associates used the dorsal urethrotomy incision with dorsal onlay flap with no recurrence of stricture and no penile island flap in urethral stricture—olajide et al 182 urology journal vol 7 no 3 summer 2010 diverticulum. they concluded that dorsally placed flap is anatomically and functionally more logical compared to the traditional ventrally placed flap. (24) occurrence of diverticulum could have been prevented in our patients if urethrotomy incision was made on the dorsal surface of the urethra. conclusion in complex anterior urethral stricture, where the stricture length precludes excision and anastomosis, with extensive spongiofibrosis and risk of infection threatening the use of graft, a single stage repair is still possible with a distal penile island skin flap. transverse distal penile island flap has a good outcome with few complications that are treatable. conflict of interest none declared. references 1. angermeier kw, jordan gh, schlossberg sm. complex urethral reconstruction. urol clin north am. 1994;21:567-81. 2. quartey jk. one-stage penile/preputial cutaneous island flap urethroplasty for urethral stricture: a preliminary report. j urol. 1983;129:284-7. 3. souza gf, calado aa, delcelo r, ortiz v, macedo a, jr. histopathological evaluation of urethroplasty with dorsal buccal mucosa: an experimental study in rabbits. int braz j urol. 2008;34:345-51; discussion 51-4. 4. stock ja, cortez j, scherz hc, kaplan gw. the management of proximal hypospadias using a 1-stage hypospadias repair with a preputial free graft for neourethral construction and a preputial pedicle flap for ventral skin coverage. j urol. 1994;152:2335-7. 5. memmelaar j. use of bladder mucosa in a one-stage repair of hypospadias. j urol. 1947;58:68-73. 6. burger ra, muller sc, el-damanhoury h, tschakaloff a, riedmiller h, hohenfellner r. the buccal mucosal graft for urethral reconstruction: a preliminary report. j urol. 1992;147:662-4. 7. snow bw, cartwright pc. tunica vaginalis urethroplasty. urology. 1992;40:442-5. 8. shaul db, xie hw, diaz jf, mahnovski v, hardy be. use of tubularized peritoneal free grafts as urethral substitutes in the rabbit. j pediatr surg. 1996;31:225-8. 9. kropp bp, ludlow jk, spicer d, et al. rabbit urethral regeneration using small intestinal submucosa onlay grafts. urology. 1998;52:138-42. 10. osegbe dn, ntia i. one-stage urethroplasty for complicated urethral strictures using axial penile skin island flap. eur urol. 1990;17:79-84. 11. parsons kf, abercrombie gf. transverse preputial island flap neo-urethroplasty. br j urol. 1982;54:745-7. 12. al-qudah hs, santucci ra. extended complications of urethroplasty. int braz j urol. 2005;31:315-23; discussion 24-5. 13. pansadoro v, emiliozzi p, gaffi m, scarpone p, depaula f, pizzo m. buccal mucosa urethroplasty in the treatment of bulbar urethral strictures. urology. 2003;61:1008-10. 14. bhandari m, palaniswamy r, achrekar kl, rajagopal v. strictures of the penile urethra. br j urol. 1983;55:235-8. 15. zinman l. optimal management of the 3to 6-centimeter anterior urethral stricture. curr urol rep. 2000;1:180-9. 16. jordan gh, devine pc. management of urethral stricture disease. clin plast surg. 1988;15:493-505. 17. morey af, duckett cp, mcaninch jw. failed anterior urethroplasty: guidelines for reconstruction. j urol. 1997;158:1383-7. 18. andrich de, mundy ar. surgery for urethral stricture disease. vol 13: medical economics; 2001:32-44. 19. quartey jk. one-stage transverse distal penile/ preputial island flap urethroplasty for urethral stricture. ann urol (paris). 1993;27:228-32. 20. mcaninch jw. reconstruction of extensive urethral strictures: circular fasciocutaneous penile flap. j urol. 1993;149:488-91. 21. santucci ra, mario la, mcaninch jw. anastomotic urethroplasty for bulbar urethral stricture: analysis of 168 patients. j urol. 2002;167:1715-9. 22. andrich de, greenwell tj, mundy ar. the problems of penile urethroplasty with particular reference to 2-stage reconstructions. j urol. 2003;170:87-9. 23. andrich de, dunglison n, greenwell tj, mundy ar. the long-term results of urethroplasty. j urol. 2003;170:90-2. 24. rao hs, bhandari m, dubey d. dorsal placement of the pedicled preputial/penile onlay flap for anterior urethral stricture: is it more logical? arch esp urol. 2001;54:749-55. predictor factors of female sexual distress in a population-based sample of iranian women: a path analysis fatemeh bayat1,2, giti ozgoli3*, zohreh mahmoodi4, malihe nasiri5 purpose: to investigate the direct and indirect effects of demographic characteristics, relationship satisfaction, and psychological factors on female sexual distress (fsd) using path analysis. materials and methods: this study was conducted in two stages. initially, we obtained the fsd predictor factor's conceptual model through a literature review and expert panel. in the second stage, a population-based cross-sectional study on 207 non-pregnant and married women (without any age restriction) in zanjan, iran was conducted. fsds-r, fsfi-6, dass-21, and gemrel standard questionnaires and the demographic researcher-made questionnaire were used in this study. results: sexual function (sf) had the strongest relationship with fsd from the direct path (β = -.49) and overall effect (β = -.58). the highest indirect effect belonged to depression-anxiety-stress level (β = .284) mediated by sf (β = -.42) and relationships satisfaction with spouse (β = -.20). age difference (β = -.13) and relationships satisfaction with spouse (β = -.19) had only a direct effect on fsd. marriage duration had only indirect effect on fsd through mediating role on sf (β = -.26) and depression-anxiety-stress level (β = -.15). conclusion: among the predictor factors investigated in this study, sexual dysfunction is the most important predictor of fsd. in addition; men older than their spouses, longer marriage duration, relationship dissatisfaction with the spouse and higher rate of depression-anxiety-stress have positive correlation with sd. therefore, we should offer a combination of the mentioned factors in providing care for women with sd. keywords: sexual health; sexual dysfunction; psychological factors; path analysis. introduction female sexual distress (fsd) can be defined as one's negative feelings about sex life and includes feelings of embarrassment, blame, frustration, anxiety, fear, and anger in women.(1) it is the most important predictor of marital quality of life.(2) fsd has been included in new definitions of sexual dysfunction and has been emphasized as a diagnostic criterion (the diagnostic and statistical manual of mental disorders, fifth edition (dsm-5)). sexual dysfunction is usually characterized by a significant clinical impairment in one's ability to have sexual respond or experience sexual pleasure(3) in iran, the prevalence rate of sexual dysfunction among reproductive-age women was estimated to be 52% (95% ci: 39-66).(4) in the united states, shifren et al. reported that the prevalence of sexual dysfunction was 43.1% in the general female population, whereas the prevalence of fsd was only 22.2% in these women. 1department of midwifery, school of nursing and midwifery, zanjan university of medical sciences, zanjan, iran. 2student research committee, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. 3midwifery and reproductive health research center, department of midwifery, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. 4social determinants of health research center, alborz university of medical sciences, karaj, iran. 5department of basic sciences, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, ir iran. *correspondence: midwifery and reproductive health research center, department of midwifery, school of nursing and midwifery, shahid beheshti university of medical sciences, tehran, iran. tel/fax: +989123223453, email: g.ozgoli@gmail.com received july 2022 & accepted january 2023 (5) furthermore, fsd has been reported even in healthy women without sexual dysfunction.(6) as such, knowing the differences between sf and fsd is crucially important. it also shows the significance of evaluating the predictors of fsd apart from sexual dysfunction and beside it. fsd lowers one's overall well-being and quality of life. (7) sexual satisfaction, emotional intimacy and self-confidence, higher self-esteem and a more positive body image have been observed in people without fsd.(8) generally, the consideration and evaluation of fsd is crucially important for therapists as women with fsd are more likely to seek treatment and discuss these problems with a doctor. conversely, people without fsd, despite suffering from sexual dysfunction will not try to treat their dysfunction.(9) there is no consensus about the main cause of fsd in women. it was observed in the studies of bancroft et female urology urology journal/vol 20 no. 3/ may-june 2023/ pp.173-180. [doi:10.22037/uj.v20i.7375] al. and garaham et al. that mental health and relationship satisfaction with the spouse/sexual partner played a more substantial role than sf in predicting fsd.(10, 11) however, in the study of hendrickx et al. sf was the main predictor of fsd in women.(12) some studies have also investigated the effect of demographic factors such as age, age difference with spouse, level of education, and marriage duration on female fsd.(11,13,14) nourani et al. reported more fsd in marriages where the woman was older than her husband.(13) in addition to disagreements, variables that affect fsd, either directly or indirectly, are not fully known. given the fact that no study examined the role of depression-anxiety-stress, sf, relationship satisfaction with the spouse, duration of marriage, and age difference between the couples in women's sexual distress through one model, this path analysis was conducted to investigate the predictors of fsd. variable no. (%) mean ± sd (max-min) woman's education illiterate 4 (1.9) primary education 3 (1.4) lower secondary 8 (3.9) higher secondary 3 (1.4) diploma 18 (8.7) associate degree 15 (7.2) bachelor's degree 97 (46.9) master's degree 41 (19.8) phd 18 (8.7) husband's education illiterate 3 (1.4) primary education 4 (1.9) lower secondary 10 (4.8) higher secondary 4 (1.9) diploma 36 (17.4) associate degree 18 (8.7) bachelor's degree 68 (32.9) master's degree 41 (19.8) phd 23 (11.1) woman's occupation employed 110 (53.1) housewife 97 (46.9) woman's age 37.02 ± 9.34 (20-70) husband's age 41.32 ± 9.86 (25-74) marriage duration 13.78 ± 11.25 (0-55) stress level 7.19 ± 4.85 (0-19) 6 (3-11)* anxiety level 4.32 ± 4.05 (0-18) 3 (1-7)* depression level 4.27 ± 4.12 (0-17) 3 (1-7)* relationship satisfaction with spouse 28.02 ± 6.45 (5-35) sexual function 19.96 ± 6.59 (1-30) sexual distress 19.96 ± 6.59 (1-12) table 1. demographic characteristics of each group * skewed distribution: 50th percentile (25th percentile – 75th percentile) predictors of female sexual distress -bayat et al. figure 1. conceptual model of the predictors of female sexual distress vol 20 no 3 may-june 2023 174 female urology 175 material and methods study design and population this study conducted in two stages. in the first stage, the conceptual model of path analysis was initially obtained using a review of the literature and the sessions held with a group of experts and researchers in the field of sexual and reproductive health as well as biostatistics experts (figure 1). in the second stage, this population-based cross-sectional study was conducted from december 2021 to january 2022 in zanjan iran. the aim of the study was to evaluate some predictors of fsd in married women without age restriction. after receiving the necessary permissions for sampling in zanjan, the conventional sampling was conducted by the researcher. the participants were recruited online or by going to public places, comprehensive health centers, or hospitals. after explaining the objectives of the research to the participants and obtaining their informed consent, the link of the electronic questionnaire designed in the porsline software (https://porsline.ir) was sent to them. the questionnaires were completed by self-report. for the uneducated or semi-educated participants, the researcher completed the questionnaires through interviews. the researcher completed questionnaires in a quiet environment where the privacy of the participants was kept. inclusion and exclusion criteria inclusion criteria were being married, monogamous and non-pregnant women who were not in their postpartum period (42 days after delivery) and had sex at least in the recent three months. there was no age restrictions. the only exclusion criterion was wrong answer to the accuracy question, this question measures your exactitude; please select the number 15: a) 25 b) 55 c) fifteen d) sixteen). sample size path analysis method was used in this study to investigate the conceptual model of the research (figure 1). in this method, the researcher uses statistical mechanisms to simultaneously examine the interaction of several variables as direct and indirect effects.(15) according to kline (2005), if the model is complex, the sample size is suggested to be at least 200. another criterion is the ratio of the number of free parameters to the sample size, which should be 1/20 or at least 1/10.(16) in this study, there were 5 free parameters (20×5=100) (sf, relationship satisfaction with spouse, depression-anxiety-stress levels, marriage duration and age difference between couples). however, considering the sample size of at least 200 subjects as the base, the number of eligible participants in this study was 207 subjects. instruments the following tools were used in this survey: demographic questionnaire: this questionnaire included age and education level of the spouses, marriage duration and occupation of the wife. we obtained the age difference by subtracting the woman's age from the man's . the result will be negative if the woman is older than the man (age difference = husband age wife age). female sexual distress scale-revised (fsds-r): the study was confirmed by three questions fsds-r. items of this scale are scored based on a 5-point likert scale variable p-value 1 2 3 4 5 6 7 8 9 10 1 sexual distress 1 2 sexual function -.68 1 < .001 3 relationship satisfaction with spouse -.55 .59 1 < .001 < .001 4 depression-anxiety-stress levels .46 -.38 -.39 1 < .001 < .001 <.001 5 age difference -.14 .04 -.04 -.01 1 .04 .53 .48 .84 6 woman's age .46 -.22 -.1 -.15 -.13 1 .50 .001 .14 .02 .059 7 husband's age -.01 -.19 -.11 -.15 .31 .89 1 .78 .004 .08 .02 < .001 < .001 8 marriage duration .008 -.19 -.06 -.15 .06 .88 .88 1 .91 .005 .36 .03 .32 < .001 < .001 9 woman's education .04 .14 .02 -.01 -.26 -.38 -.49 -.56 1 .54 .03 .78 .76 <.001 < .001 < .001 <.001 10 husband's education -.01 .20 .16 -.1 -.18 -.3 -.3 -.41 .65 1 .81 .003 .01 .12 .009 < .001 < .001 < .001 < .001 table 2. correlation matrix for the variable of sexual distress, sexual function, relationship satisfaction with spouse, depression-anxiety-stress levels, age difference, woman's age, husband's age, marriage duration, woman's education, husband's education variable un-standard β direct effect (95% ci) p-value indirect effect total effect 1 marriage duration .023 .023 2 age difference -.09 (-.086 , -.094) .007 -.09 3 depression-anxiety-stress levels .054 (.053 , .055) <.001 .076 .13 4 sexual function -.24 (-.236 , -.244) <.001 -.047 -.287 5 relationship satisfaction with a spouse -.09 (-.086 , -094) <.001 -.094 table 3. indirect effects on female sexual distress (fsd) predictors of female sexual distress -bayat et al. female urology 175 ranging from 0 (never) to 4 (always). the total score of the questionnaire, calculated by adding the score of 3 items, is between 0 and 12, and the higher the score, the more will be fsd.(1) the persian version of this tool has an appropriate validity and reliability in the iranian population.(17) female sexual function index-6 items (fsfi-6): this questionnaire has been extracted by isidori et al. from the 19-item version of fsfi. like the original version, this version also examines women's sexual dysfunction in the recent 4 weeks of their life. the items related to sexual desire and satisfaction are scored based on a 5-point likert scale from 1 to 5. the items related to lubrication, arousal, orgasm and pain are scored based on a 6-point likert scale from 0 to 5. adding the scores of the six subscales together, the total score of the scale is obtained. the total score ranges from 2 to 30, where the higher the score, the better is the sf. the sensitivity and specificity of the test in diagnosing sexual dysfunction was optimal and the internal consistency and reliability of the test-re-test was good.(18) psychometric evaluation of the persian version was performed in the iranian population and the reliability of the scale was reported to be good.(19) global measure of relationship satisfaction (gmrel): this scale measures a person's satisfaction with their overall relationship with their spouses in 5 items (very satisfied/very dissatisfied, very pleasant /very unpleasant, very good/very bad, very positive/very negative, very valuable/valueless) based on a 7-point likert score ranging from 1 (lowest satisfaction) to 7 (highest satisfaction). the total score of the questionnaire is between 5 and 35, where the higher the score, the more will be one's satisfaction with the overall relationship with the spouse.(20) the convergent validity of this scale with the marital life satisfaction scale was favorable in the iranian population.(21) depression, anxiety and stress scale-21 items (dass21): this 21-item scale includes three self-report scales of depression, anxiety and stress. seven questions have been designed for each scale based on a 4-point likert scale including not at all (0), low, medium, and high (3).(22) this study used the persian version of the questionnaire which has good validity and reliability in the iranian population.(23) ethical consideration this research project was confirmed by the ethics committee of shahid beheshti university of medical sciences with the ethics code of ir.sbmu.pharmacy.rec.1400.010. we explained the research objects to the participants and received informed oral and written consent. x2 df x2/df cfi gfi nfi rmsea p-value model 4.52 5 .9 1 .99 .99 .001> .47 standard x2/df < (3), > .9 > .9 > .9 < .08 > .05 table 4. goodness of fit indices figure 2. path analysis (standard β) model for the predictors of female sexual distress *: p-valve <.05 **: p-valve <.001 abbreviation: cmin/df=chi-square/degrees of freedom ratio, rmsea= root mean square error of approximation, nfi= normed fit index, cfi= comparative fit index, gfi= goodness of fit index. predictors of female sexual distress -bayat et al. vol 20 no 3 may-june 2023 176 female urology 177 statistical analysis when the questionnaires were completed, the data were extracted and analyzed through appropriate statistical tests and using statistical package for the social sciences (spss) (version 25) and linear structural relations (lisrel) (version 8.8) software. central tendency and dispersion were used to describe the observations, path analysis was used to identify the most important indices and the significance level (p) was considered to be < .05. most important goodness of fit indices were used to confirm the final model (table 4). results in this population-based research, from the 208 participants, a 59-year-old housewife with primary education, who answered the accuracy question incorrectly, was excluded from the study. all the participants were urbanites and lived in zanjan city. the mean age of participants was 37.02 ± 9.34 years old. demographic information and the mean of other investigated variables are shown in table 1. table 2 shows, except marriage duration, all variables of the conceptual model are significantly correlated with fsd. marriage duration is also significantly correlated with sf. the results of path analysis, indicating the direct, indirect, and total effect of fsd predictors, are shown in table 4 and figure 2. based on the results of path analysis, sf (β = -.49) among investigated factors had the most significant and direct negative relationship with fsd. in other words, decreasing the score of sf increased the score of fsd. marriage duration (β = .12) had the most significant positive and indirect relationship with fsd. thus, increased duration of the marriage, by its mediating role and reducing sf (β = -.26), also reducing depression-anxiety-stress level (β = -.15), had increased fsd. sf (β = -.58) among investigated factors also had the highest total relationship with fsd. sf, in addition to the mentioned direct path, reduces fsd through indirect path (β = .52), that is, by mediating relationship satisfaction with the spouse and increasing it. the depression-anxiety-stress levels (β = .20) had a significant positive and direct relationship with fsd; so that increased levels of one's depression-anxiety-stress, increased their fsd. in terms of the indirect path, the level of stress-anxiety-depression increased fsd through the mediating role of sf and relationship satisfaction with the spouse, and reducing these two variables. relationship satisfaction with the spouse (β = -.19) and age difference (β = -.13) had a significant relationship with fsd in one path; so that the higher the score of relationship satisfaction with the spouse, the more was the level of fsd. moreover, the older the man (positive age difference), the lower was the level of fsd. the results of the model's goodness of fit indices are indicative of the desirability, goodness of fit and the rationality of the relationships of the adjusted variables based on the conceptual model. accordingly, the fitted model is not significantly different from the conceptual model (table 4). discussion path analysis was used in this study to investigate some predictor factors of fsd in the general population of figure 3. path analysis, un-standard β (95% ci) model for the predictors of female sexual distress *: p-valve < .05 **: p-valve < .001 predictors of female sexual distress -bayat et al. female urology 177 non-pregnant women without age restrictions. as a limited number of studies have investigated fsd in iran, the present study was the first path analysis which evaluates the predictors of fsd in the general population of iranian women. it was revealed in this study that the variables of age difference and relationship satisfaction with the spouse directly and the variables of marriage duration indirectly predicted sd through the mediating role of sf. however, sf and depression-anxiety-stress variables have both direct and indirect effects. the variable of sf, through its direct and indirect effects, was the strongest predictor of fsd among investigated factors in this study. in line with our study, hendrickx et al. also showed that all types and severities of sexual dysfunction predict fsd.(12) in the study of bancroft et al. mental health and relationship satisfaction with the spouse were more powerful variables than sf in predicting fsd in older women.(10) unlike our study whose participants were non-clinical and with young mean age (20-70 years), elderly clinical subjects with impaired sf were investigated in the study of bancroft et al. therefore, it can be said that in the general and young population, sf is a stronger variable than mental health and relationship satisfaction in explaining fsd. it was observed in this path analysis that the level of depression-anxiety-stress not only mediated the variables of sf and relationship satisfaction with the spouse, but also had a direct and positive effect on fsd. thus, the higher the level of depression-anxiety-stress, the more was the level of fsd. the relationship between fsd and mental health problems (depression-anxiety-stress) has been demonstrated in various studies.(11,24) in the study of forbes and baillie, a common and latent factor was the cause of mental disorders and sexual problems. (24) pascol et al. indicated that factors such as stress, anxiety, and depression might cause sd by creating emotional distress in the relationship of couples.(25) according to evidence, depression and mental health problems lead to fsd not the other way around.(10) psychological stressors can also interfere with sf through psychological and physiological mechanisms. according to hamilton et al., stress and depression were strongly associated with sexual dysfunction in women.(26) in addition to the sexual dysfunction related depression, anxiety also leads to fsd in women.(27) in the study burri et al. there was a strong genetic component between anxiety and sf and a relatively weaker genetic component between anxiety sensitivity and fsd. moreover, anxiety sensitivity can probably affect women's sf by regulating their emotional experiences. consequently, women with no anxiety problems are more likely than anxious women to adapt to their emotional and sexual relationships and use coping strategies.(28,29) as shown in the path analysis model, marriage duration increased fsd by reducing sf and the level of depression-anxiety-stress. the marital adjustment increases with the marriage duration, so the decrease in depression-anxiety-stress may be due to this.(30) although improving mental health status reduces sexual distress, the increase in sexual dysfunction resulting from the increase in the duration of marriage has more effect on fsd. similar to our study, alidost et al. observed that increased duration of marriage could reduce sf.(31) in the study of witting et al. the duration of the relationship increased both fsd and sexual dysfunction. this might be due to the increased knowledge of women of their sexual preferences, feelings of comfort, acceptance and their sexual desires.(14) in this study, the variable of relationship satisfaction with the spouse had a direct effect on fsd; it also played the role of a mediating variable for sf and the level of depression-anxiety-stress in predicting fsd. as such, high levels of sf reduced fsd through increasing the score of relationship satisfaction with the spouse. conversely, high level of depression-anxiety-stress increased fsd by decreasing the score of relationship satisfaction with the spouse. in line with the present study, in the study of alizadeh and farnam in iran, emotional intimacy was significantly higher in people without distress than those with fsd.(8) hendrickx et al. observed that sexual dysfunction caused interpersonal distress by affecting the relationship satisfaction with the sexual partner.(12) in the study of graham et al. lower levels of fsd were observed in women with sexual dysfunction who had enjoyed better emotional-sexual intimacy. (11) this is maybe due to the fact that those with better relationship satisfaction use it as a defense mechanism against sexual problems, thereby demonstrating less fsd and anxiety.(32) additionally, women who have a good relationship with their sexual partner express their sexual needs more easily and are less likely to suffer from fsd.(33) in this study, women's age had a significant positive correlation with sf but not with fsd. similar to our study, graham et al. indicated that despite the increase of sexual dysfunction in older women, fsd did not increase in them or increased so mildly.(11) in the study of rosen et al. also there was a u-shaped relationship between age and fsd. although there is a low prevalence of sexual dysfunction in young women, they experience more distress. by contrast, older women and postmenopausal women do not feel distressed and are less worried about their dysfunction.(34) getting older, women consider sexual dysfunction a biological and ordinary issue and, thus, express less anxiety and distress than younger women, and adapt more easily to this problem.(35) given the nature of the present study, which examined the linear relationship between variables, no significant relationship was observed between the age of women and fsd. the age difference between the woman and her husband in this study was from -9 to +21 years, which was significantly correlated with fsd (r = -.14, p = .03). according to the results of path analysis, age difference directly predicted fsd. as such, the more the age difference between the couples (when man is older), the less was fsd in women. inverse age difference in the qualitative study of noorani et al. which was conducted in iran, caused fsd and anxiety. this is because women are worried that they will grow old sooner than their husbands and will gradually lose their physical attractiveness.(13) another study was conducted in iran where the highest sexual satisfaction was observed in the group of no age difference. however, this study did not examine the marriages in which women were older. (36) thus, the difference may be because of this. the most important strength of this study is that it goes beyond the mere investigation of sf and addresses fsd as an important diagnostic feature of these disorders. it answers the question of whether fsd can be better explained through the combination of communicational, psychological, sexual, and demographic factors. acpredictors of female sexual distress -bayat et al. vol 20 no 3 may-june 2023 178 female urology 179 cording to the results, fsd is related not only to sexual dysfunction, that plays an important role in explaining it, but also to psychological, communication and demographic variables. moreover, examining the demographic and underlying factors, this study identified the population that was at risk of fsd. self-selection bias and sample size were among the limitations of this pilot study. although illiterate and semi-literate women also participated in the study, most of them were highly educated and all of them were urbanite. accordingly, the results of the study should be interpreted more cautiously. conclusions among the investigated factors in this study, sexual dysfunction is the most important predictor of fsd. the high level of depression-anxiety-stress and marriage duration are predictors of fsd through mediating role of sexual functioning. sexual dysfunction and high level of depression-anxiety-stress can also predict fsd through mediating role of reducing the relationship satisfaction with the spouse. moreover, psychological factors have direct and positive effects on fsd. in this study, we observed the low or inverse age difference between a woman and her husband is one of the main predictors of fsd, indicating the role of cultural and social factors in causing fsd in iranian women. this study provided a more complete understanding of the current situation of fsd predictors. this cross-sectional study, only investigated some predicting factors of fsd and further studies, enable us gain more compressive understanding of other predicting factors as well. since longer marriage duration, lower age difference and sometimes, reverse age difference may increase fsd, prevention and intervention programs should be considered more in women who are at risk. acknowledgement we would like to express our gratitude to the "research and technology chancellor" of shahid beheshti university of medical sciences that approved this project, zanjan university of medical sciences, which provided the sampling conditions, and the women who participated in this research. conflict of interest the authors report no conflict of interest. references 1. derogatis l, clayton a, lewis-d'agostino d, wunderlich g, fu y. validation of the female sexual distress scale-revised for assessing distress in women with hypoactive sexual desire disorder. jsm. 2008;5:357-64. 2. blumenstock sm, papp lm. sexual distress and marital quality of newlyweds: an investigation of sociodemographic moderators. fam relat . 2017;66:794-808. 3. edition f. diagnostic and statistical manual of mental disorders. am psychiatric assoc. 2013;21:591-643. 4. ghiasi a, keramat a. prevalence of sexual dysfunction among reproductive-age women in iran: a systematic review and meta-analysis. jmrh . 2018;6:1390-8. 5. shifren jl, monz bu, russo pa, segreti a, johannes cb. sexual problems and distress in united states women: prevalence and correlates. obgyn. 2008;112:970-8. 6. burri a, rahman q, spector t. genetic and environmental risk factors for sexual distress and its association with female sexual dysfunction. psychol med. 2011;41:2435-45. 7. khorshidi m, alimoradi z, bahrami n, griffiths md. predictors of women’s sexual quality of life during the covid-19 pandemic: an iranian cross-sectional study. sex relatsh ther. 2022;37:1-14 8. alizadeh a, farnam f. coping with dyspareunia, the importance of inter and intrapersonal context on women’s sexual distress: a population-based study. reprod health. 2021;18:1-11. 9. 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sexual dysfunction in the general population: exploring factors associated with low sexual function and sexual distress. jsm. 2008;5:1681-93. 34. rosen rc, shifren jl, monz bu, odom dm, russo pa, johannes cb. epidemiology: correlates of sexually related personal distress in women with low sexual desire. jsm. 2009;6:1549-60. 35. howard j, o'neill s, travers c. factors affecting sexuality in older australian women: sexual interest, sexual arousal, relationships and sexual distress in older australian women. climacteric. 2006;9:355-67. 36. shahvary z, gholizade l, hoseiny sm. determination of some related factors on women sexual satisfaction gachsaran (southwest of iran). goums. 2010;11:51-109. vol 20 no 3 may-june 2023 180 urological oncology 99urology journal vol 7 no 2 spring 2010 accurate cut-off point for free to total prostatespecific antigen ratio used to improve differentiation of prostate cancer from benign prostate hyperplasia in iranian population houshang amirrasouli,1 faranak kazerouni,1 mohammad sanadizade,2 javad sanadizade,2 nasser kamalian,3 mohammadtaha jalali,4 khosro rahbar,5 kamran karimi2 purpose: our aim was to determine a more predictive cut-off value for free to total prostate-specific antigen ratio (f/tpsa) to better differentiate prostate cancer (pca) from benign prostate hyperplasia (bph) in iranian patients with serum psa levels between 4 and 20 ng/ml. materials and methods: this study was performed on 332 men with serum tpsa level of 4 to 20 ng/ml. all patients underwent transrectal ultrasound guided biopsies. serum levels of tpsa and fpsa were measured by roche immunoassay elecsys 2010. relationship between f/tpsa and cases of pca was determined. results: prostate cancer detected in 49 (15%) patients. incidence of pca for serum tpsa level < 10ng/ml and serum tpsa level of 10.1 to 20 ng/ ml was 17 (6.7%) and 32 (39.5%), respectively. mean f/tpsa value was significantly lower in pca patients (0.12 ± 0.01) than in benign histology group (0.16 ± 0.03). among patients with serum psa level of 4 to 10 ng/ml (n = 251), mean f/tpsa in benign histology group (n = 234) was 0.16 ± 0.08 and in pca group (n = 17) was 0.13 ± 0.06 (p < .05). for serum psa level of 10.1 to 20 ng/ml (n = 81), mean f/tpsa in benign histology group (n = 49) was 0.16 ± 0.08 and in pca group (n = 32) was 0.12 ± 0.05 (p < .05). the cut-off value of 0.12 produced 76% sensitivity and 71 % specificity, whereas the cut-off value of 0.14 yielded 83.5 % sensitivity and 61% specificity. conclusion: determination of f/tpsa ratio improves differentiation of pca from bph. we recommend a cut-off value of 0.14 to be applied to iranian patients. urol j. 2010;7:99-104. www.uj.unrc.ir keywords: prostatic neoplasm, prostate-specific antigen, benign prostate hyperplasia, early detection of cancer, biopsy 1department of laboratory medicine, faculty of paramedical sciences, shahid beheshti university, mc, tehran, iran 2department of urology, mehrad general hospital, tehran, iran 3department of pathology, medical school of tehran university of medical sciences, tehran, iran 4department of laboratory medicine, faculty of paramedical sciences, ahvaz university of medical sciences, ahvaz, iran 5department of nephrology, taleghani hospital, shahid beheshti university, mc, tehran, iran corresponding author: houshang amirrasouli, phd department of laboratory medicine, faculty of paramedical sciences, shahid beheshti university, mc, tehran, iran tele: +98 912 1147 233 fax: +98 21 2200 8155 e-mail: houshangan@sbmu.ac.ir received may 2009 accepted october 2010 introduction measurement of serum level of prostate specific antigen (psa) is widely used for early detection of prostate cancer (pca) and to monitor the clinical manifestation of patients with pca. (1) it must be stressed that psa is not pca specific, but tissue specific, and non-malignant disorders such as benign prostate hyperplasia (bph) or prostatitis can affect serum psa concentration. (2) moreover, a number of studies demonstrated that not every case of pca increases the psa level. (3,4) in practice, the use of psa for clinical staging is restricted.(5) various adjustments, cut-off point for free/total psa—amirrasouli et al 100 urology journal vol 7 no 2 spring 2010 such as psa density (psa divided by prostate volume) or blood based molecular diagnostics, psa discriminating by age, and psa velocity have therefore been attempted to improve the diagnostic value of psa associated parameters,(6,7) but the procedures are rather complicated.(7) in plasma, psa exists predominantly as a complex with serine protease inhibitors such as α1-antichymotrypsin, α1-protease inhibitor, and α2-macroglobulin. approximately, 10% to 30% of total psa (tpsa) is not bound to serum proteins and is called free psa (fpsa). numerous studies have demonstrated a lower ratio of fpsa to tpsa (fpsa/tpsa) in patients with pca, calculated as a percentage of fpsa.(8,9) this implies that the accurate measurement of serum fpsa level is critical for patients whose serum levels of total psa falls between 4 and 10 ng/ml and who do not exhibit abnormal findings upon digital rectal examination (dre). free to total psa ratio (f/ tpsa) is used to enhance the specificity of cancer detection. partin and colleagues(10) reported that f/tpsa in serum more accurately distinguishes pca from a nonmalignant disease; thereby, avoiding unnecessary biopsies with negative results for cancer. in particular, f/tpsa has been shown to be more precise as an indicator for prostate biopsies in men with serum tpsa levels less than 10 ng/ml.(11,12) in some western countries a cut-off value between 0.20 and 0.25 for f/t psa has been recommended. (13,14) this study was carried out in order to determine the cut-off value of the f/tpsa in iranian population. materials and methods this study was performed in mehrad general hospital between october 2005 and october 2006. the subjects were chosen from patients who referred to the hospital mostly for routine checkup, although number of them had complaints such as frequency and dysuria. prior to dre, fpsa and tpsa were measured for all these patients using the roche immunoassay elecsys 2010. three hundred and forty-one patients with the mean age of 62 years and serum psa levels between 4 and 20 ng/ml were recruited in this study. none of them had urinary tract infection such as prostatitis. all of the participants gave their written informed consent and agreed to proceed with study protocol. thereafter, serum fpsa and tpsa were measured again. free to total psa ratio was calculated from dividing fpsa by tpsa. all patients were referred for 10-core prostate biopsies using transrectal ultrasound. a sextant biopsy was performed from the apex and base of the right and left parasagittal planes of the prostate with 10 core biopsies, including an additional 3 cores from the peripheral zone positioned more laterally on each side. nine patients refused to undergo biopsy leaving a final study population of 332. each core was histologically examined for pathological grading and mapping. two experienced pathologists independently performed histopathological examinations. pathologists did not know free and total psa values. demographic and clinical characteristics of patients with and without prostate pca were compared using student t-test. receiver operating characteristics (roc) curves were generated for fpsa, tpsa, and f/tpsa. p value less than .05 was considered statistically significant. results of 332 participants, 283 (85%) had benign histology, while 49 (15%) had pca. incidence of pca for serum tpsa level < 10ng/ml and serum tpsa level of 10.1 to 20 ng/ml was 17 (6.7%) and 32 (39.5%), respectively. age, fpsa, and tpsa were similar for the cancer and benign histology groups (table 1). benign histology group (n = 283) prostate cancer group (n = 49) p age (yrs) 62.66 ± 7.8 (48 to 63) 64.17 ± 8.1 (51 to 76) .59 psa (ng/ml) 8.52 ± 2.08 (4.2 to 14.2) 10.25 ± 3.76 (6.08 to 19.2) .132 fpsa (ng/ml) 1.1 ± 0.7 (0.08 to 2.4) 0.98 ± 0.6 (0.05 to 1.9) .124 f/tpsa 0.16 ± 0.03 (0.05 to 0.36) 0.12 ± 0.01 (0.08 to 0.21) .015 table 1. characteristics of benign histology group and prostate cancer group* *psa indicates prostate-specific antigen; fpsa, free psa and f/tpsa, free to total psa ratio. cut-off point for free/total psa—amirrasouli et al 101urology journal vol 7 no 2 spring 2010 mean f/tpsa in benign histology group was 0.16 ± 0.03 and in prostate cancer patients was 0.12 ± 0.01 (p < .05). even after stratification of patients into 2 groups with serum psa levels of 4.1 to 10 ng/ml (n = 251) and 10.1 to 20 ng/ ml (n = 81), mean f/tpsa showed significant difference between two groups (p < .05) (table 2). among patients with serum psa levels of 4.1 to 10 ng/ml, mean f/tpsa in benign histology group (n = 234) was 0.16 ± 0.08 and in pca group (n = 17) was 0.13 ± 0.06 (p < .05). for serum psa level of 10.1 to 20 ng/ml, mean f/tpsa in benign histology group (n = 49) was 0.16 ± 0.08 and in pca group (n = 32) was 0.12 ± 0.05 (p < .05) (table 3). the roc curves for tpsa range, fpsa, and f/ tpsa ratio are shown in figure. comparisons were made for the area under each roc curve (auc) (table 4). as shown in table 4, auc is significantly higher for f/tpsa (0.695) than for tpsa (0.602), and fpsa (0.554) indicating that f/tpsa is more predictive of pca. overall f/tpsa cut-off of 0.12 produced sensitivity of 76% and specificity of 71%, while for cut-off value of 0.14, sensitivity and specificity were 83% and 61%, respectively (table 5). 4.1 to 10 ng/ml (n = 251) 10.1 to 20 ng/ml (n = 81) benign histology group prostate cancer group benign histology group prostate cancer group no. of patients 234 17 49 32 f/tpsa 0.16 ± 0.08 (0.05 to 0.28) 0.13 ± 0.06 (0.06 to 0.21) 0.16 ± 0.08 (0.05 to 0.29) 0.12 ± 0.05 (0.07 to 0.19) table 3. comparison of the free to total psa ratio between benign histology group and prostate cancer group for psa levels of 4.1 to 10 ng/ml and 10.1 to 20 ng/ml* *f/tpsa, indicates free to total prostate-specific antigen ratio. f/tpsa 0.04 0.10 0.12 0.14 0.16 0.18 0.2 0.8 sensitivity (%) 0 75 76 83 92 95 98 100 specificity (%) 100 77 71 61 50 42 38 16 table 5. sensitivity and specificity of f/tpsa ratio* f/tpsa, indicates free to total prostate-specific antigen ratio. free to total psa ratio total psa ng/ml benign histology group prostate cancer group p 4.1 to 10.0 0.16 0.13 .017 10.1 to 20.0 0.16 0.12 .015 table 2. comparison of the free to total psa ratio between benign histology group and prostate cancer group bhg: benign histology group; psa: prostatic specific antigen roc curve of psa, fpsa, and f/tpsa ratio. the auc for the f/tpsa ratio (0.695) was largest, followed by the tpsa (0.602), and then fpsa (0.554) roc: receiver operating characteristics, psa: prostate specific antigen, fpsa: free psa, f/t: free to total, auc: area under the curve auc 95%ci p tpsa 0.602 (0.425 to 0.779) .138 fpsa 0.554 (0.369 to 0.739) .138 f/tpsa 0.695 (0.529 to 0.861) .011 table 4. area under the curve for the differentiation of prostate cancer from benign histology group* *auc, indicates area under the curve; 95% ci, 95% confidence interval; tpsa, total prostate-specific antigen; fpsa, free psa and f/t psa, free to total psa ratio. cut-off point for free/total psa—amirrasouli et al 102 urology journal vol 7 no 2 spring 2010 discussion it is a common belief among many urologists that measurement of serum level of total psa plays an important role in the early diagnosis of pca.(1) however, serum level of total psa may increase in some benign prostate diseases,(2) and on the other hand, in some patients with pca, low serum psa levels may be reported.(3,4) therefore, there is an essential need for another modality with high specificity and sensitivity which can be used to differentiate benign disease from prostate carcinoma. the prostate-specific antigen adjusted for the transition zone volume, psa velocity, age specific psa, and molecular forms of psa are among these screening tools that can enhance the accuracy of diagnosis;(6,7) however, they have their own limitations.(7) development of immunoassays specific for different forms of psa helped in measuring free psa in the presence of complex forms; hence, it is possible to calculate the percentage of free psa or free to total psa ratio.(15) free to total psa ratio, as first shown by stenman and colleagues,(8) and christensson and associates, (16) can more efficiently distinguish subjects with bph from those with cancer than serum tpsa levels alone.(17) different f/tpsa values in men with and without cancer can be used to determine cut-offs for doing prostate biopsy. use of f/tpsa can reduce unnecessary biopsies in patients undergoing evaluation for pca. in this way, yet some prostate cancers will not be detected.(13) it is widely accepted that in patients with elevated serum psa concentration, men with pca tend to have lower f/tpsa values than men with benign prostate disease.(13,18) our study also supports this, showing that f/tpsa was significantly lower in prostate cancer group than benign histology group. even, when patients were subdivided into groups with serum psa levels of lower and higher than 10ng/ml, mean f/tpsa showed statistically significant differences. our results showed that regardless of psa, mean f/tpsa is a useful diagnostic modality for detecting pca. in our study, of 332 patients with serum psa levels between 4 and 20 ng/ml, only 15% had histologically proven pca, which is much lower than values used in western countries. this can be explained by wide different geographical prevalence of pca. the incidence of pca in asian countries is much lower than those observed in north american and north and western european countries, with southern european and south american countries displaying an intermediate incidence rate.(19) in addition, different nutritional status, prostate biopsy techniques, and perhaps different pathological examination methods are among confounding factors.(20) defining a proper cut-off value for f/tpsa is crucial, since it could offer better pca detection. in this study, in order to determine the proper cut-off value, roc curves were generated. our results disagree with finding of safarinejad in iranian men.(20) in this population-based study, 3 670 iranian men older than 40 years were mass checked by psa-based screening. the author concluded that a f/tpsa threshold at ≤0.18 rather than ≤0.15 increased the sensitivity for detecting cancer from 85.2% to 94.5% while falsepositives decreased by 30.8%. in another study by hosseini and colleagues,(21) 3758 volunteer iranian men older than 40 were mass checked by psa-based screening and dre. in that study, conventional systematic sextant biopsies, which accounted for 6 of the 10 cores in their biopsy scheme, detected 71% of the cancers. therefore, some pca will be ignored even with prostate biopsy. based on our results, f/tpsa (auc, 0.695; 95% ci, 0.529 to 0.896) is more predictive of cancer than fpsa and tpsa for patients with tpsa values of 4 to 20 ng/ml. when f/tpsa cut-off value was set at 0.12, sensitivity and specificity were 76% and 71%, respectively and when it was raised to 0.14, sensitivity increased to 83%, but the specificity reduced to 61%. since there is no single cut-off value that would simultaneously yield high sensitivity and high specificity, a definite decision for prostate biopsy based on f/ tpsa values would be challenging. cut-off value of 0.12 will detect 76% of cancers, but would subject 39% of men without cancer to prostate biopsy. on the other hand, cut-off value of 0.14 will improve cancer detection, detecting 83.5% of cancer patients with 49% false-positive rate. cut-off point for free/total psa—amirrasouli et al 103urology journal vol 7 no 2 spring 2010 in order to achieve the same sensitivity and specificity in the western countries, a lower cutoff value should be considered. hence, cut-off value of 0.14 is suggested as a more appropriate cut-off value for iranian patients. lower cutoff value for our patients compared to western countries is due to racial differences in f/tpsa value and cancer prevalence.(22) therefore, clinical application of commonly used f/tpsa values of 0.2 to 0.25 to justify prostate biopsy is not applicable for all ethnic groups. conclusion measurement of f/tpsa improves differentiation of pca from bph. with serum psa level of 4 to 20 ng/ml, a cut-off value of 0.14 is recommended. further population-based studies are required to elaborate more accurate f/tpsa ratio. acknowledgement this study was sponsored by faculty of paramedical sciences, shahid beheshti university of medical sciences and by mehrad general hospital. conflict of interest none declared. references 1. catalona wj, richie jp, ahmann fr, et al. comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. j urol. 1994;151:1283-90. 2. dalva i, akan h, yildiz o, telli c, bingol n. the clinical value of the ratio of free prostate specific antigen to total prostate specific antigen. int urol nephrol. 1999;31:675-80. 3. stamey ta, yang n, hay ar, mcneal je, freiha fs, redwine e. prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. n engl j med. 1987;317:909-16. 4. carter hb. prostate cancers in men with low psa levels--must we find them? n engl j med. 2004;350:2292. 5. partin aw, yoo j, carter hb, et al. the use of prostate specific antigen, clinical stage and gleason score to predict pathological stage in men with localized prostate cancer. j urol. 1993;150:110-4. 6. lacher da, thompson td, hughes jp, saraiya m. total, free, and percent free prostate-specific antigen levels among u.s. men, 2001-04. adv data. 20061-12. 7. lieberman s. can percent free prostate-specific antigen reduce the need for prostate biopsy? eff clin pract. 1999;2:266-71. 8. stenman uh, leinonen j, alfthan h, rannikko s, tuhkanen k, alfthan o. a complex between prostatespecific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. cancer res. 1991;51:222-6. 9. harris r, lohr kn. screening for prostate cancer: an update of the evidence for the u.s. preventive services task force. ann intern med. 2002;137: 917-29. 10. partin aw, catalona wj, southwick pc, subong en, gasior gh, chan dw. analysis of percent free prostate-specific antigen (psa) for prostate cancer detection: influence of total psa, prostate volume, and age. urology. 1996;48:55-61. 11. bangma ch, kranse r, blijenberg bg, schroder fh. the value of screening tests in the detection of prostate cancer. part ii: retrospective analysis of free/total prostate-specific analysis ratio, agespecific reference ranges, and psa density. urology. 1995;46:779-84. 12. catalona wj, smith ds, wolfert rl, et al. evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. jama. 1995;274:1214-20. 13. catalona wj, partin aw, slawin km, et al. use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. jama. 1998;279:1542-7. 14. ito k, yamamoto t, ohi m, kurokawa k, suzuki k, yamanaka h. free/total psa ratio is a powerful predictor of future prostate cancer morbidity in men with initial psa levels of 4.1 to 10.0 ng/ml. urology. 2003;61:760-4. 15. leinonen j, lovgren t, vornanen t, stenman uh. double-label time-resolved immunofluorometric assay of prostate-specific antigen and of its complex with alpha 1-antichymotrypsin. clin chem. 1993;39: 2098-103. 16. christensson a, bjork t, nilsson o, et al. serum prostate specific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer. j urol. 1993;150:100-5. 17. catalona wj, smith ds, ratliff tl, basler jw. detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. jama. 1993;270:948-54. 18. gann ph, ma j, catalona wj, stampfer mj. strategies combining total and percent free prostate specific antigen for detecting prostate cancer: a prospective evaluation. j urol. 2002;167:2427-34. 19. parkin dm, whelan sl, ferlay j, storm hh. cancer incidence in five continents: intl agency for research on cancer; 2006. 20. safarinejad mr. population-based screening for prostate cancer by measuring free and total case report 136 urology journal vol 7 no 2 spring 2010 external genitalia entrapment a case report walid massoud, pascal hajj, ayman awad, joseph chabenne, pascal eschwege, stéphane droupy, yacine hammoudi, gérard benoît urol j. 2010;7:136-7. www.uj.unrc.ir keywords: male genitalia, ischemia, wounds and injuries urology department, bicêtre hospital, le kremlin-bicêtre, france correponding author: massoud walid , md chu de bicêtre, department of urology, 78, rue du général leclerc, 94275, le kremlin-bicêtre, france tel : +33 699 114 939 fax : +33 145 212 047 e-mail : walidmassoud@yahoo.fr received march 2009 accepted july 2009 introduction external genitalia entrapment (ege) is a rare clinical entity requiring urgent and efficient management.(1) if left untreated, it may result especially in vascular compromise to the external genitalia soft tissue structures. (2) management poses unique challenges to the treating physician through variable presentation as well as the lack of specifically designed treatment options. case report the fire brigade brought a 45-yearold schizophrenic man to the emergency department with a 5-hour history of ege in a thick nonexpandable silver ring. he was anxious and in a considerable pain. the glans and the penis shaft had been cyanosed and enlarged with an obvious swelling of the scrotum and foreskin (figure 1). in fact, the patient suffered from a behavioral disorder and in his past medical history, we noted a traumatic colic perforation by a foreign body. this time, the entry had begun with one testis followed by the other one and finished with the penis. the patient had used oil to facilitate the maneuver. on physical examination, he complained of numbness of the glans and the penile dorsal artery pulse was bearly perceptible. he had voiding difficulties, but was not in acute urinary retention. under neuroleptic analgesia, a malleable retractor was negotiated under the ring to safeguard the underlying skin (figure 2) and the ring was figure 1. cyanosed and enlarged glans with an obvious swelling of the scrotum and foreskin. figure 2. malleable retractor negotiated under the ring to safeguard the underlying skin. external genitalia entrapment— massoud et al 137urology journal vol 7 no 2 spring 2010 cut in 2 places with a diamond-tipped oscillating splint saw. the whole procedure took about 1 hour. after removing the ring, the circulation and the skin color were quickly restored to the external genitalia, which were undamaged. there was an unremarkable change on scrotal ultrasonography. the swelling gradually subsided and the patient was capable of urinating. on the follow-up of 2 and 6 months, the uroflowmetry showed a maximum flow rate around 25 ml/s and the scrotal ultrasonography demonstrated a normal vascularization and trophicity of the testicular parenchyma. discussion a strangulation metal ring is occasionally encountered in urologic emergencies.(3,4) external genitalia entrapment is rarer than penile entrapment, but is a more serious emergency condition, which can lead to infarction.(5-8) various nonmetallic and metallic constricting objects, including bottles, rings, hairs, threads, steel nuts, rubber bands, etc(3,4,9,10) are placed on the external genitalia to increase sexual performance or because of autoerotic intentions. (4,6) in the worldwide literature, penile entrapment has been reported,(3-14), but to our best knowledge, this is the first report of external genitalia entrapment. the main objective in this situation is decompression to facilitate free blood flow and micturition.(4,6) metallic rings rarely cause severe mechanical injuries, but they can lead to severe vascular complications.(4) various procedures have been proposed, including the common metal ring cutter, cutting tang, metal saw, dremel moto-tool kit, anspach cement eater, high-speed dental drill, string method, and wrapping by package cord.(3-5,8-10,13-15) removal of strangulating constricting devices requires resourcefulness to perform the removal simply and effectively, and with as little discomfort for the patient as possible. in some cases, a little premedication is helpful; however, only very few patients require general anesthesia.(4) conflict of interest none declared. references 1. xu t, gu m, wang h. emergency management of penile strangulation: a case report and review of the chinese literature. emerg med j. 2009;26:73-4. 2. ivanovski o, stankov o, kuzmanoski m, et al. penile strangulation: two case reports and review of the literature. j sex med. 2007;4:1775-80. 3. pannek j, martin w. penile entrapment in a plastic bottle. j urol. 2003;170:2385. 4. perabo fg, steiner g, albers p, muller sc. treatment of penile strangulation caused by constricting devices. urology. 2002;59:137. 5. may m, gunia s, helke c, kheyri r, hoschke b. penile entrapment in a plastic bottle a case for using an oscillating splint saw. int urol nephrol. 2006;38: 93-5. 6. maruschke m, seiter h. [total infarction of the penis caused by entrapment in a plastic bottle]. urologe a. 2004;43:843-4. 7. kore rn, blacklock ar. ring the fire brigade. br j urol. 1996;78:948. 8. osman m, al kadi h, al hafi r. gangrene of the penis due to strangulation by a metallic ring. scand j urol nephrol. 1996;30:77-8. 9. mcgain f, freedman d. penile entrapment in a bottle: the case for using a diamond-tipped portable glass saw. bju int. 1999;83:1071-2. 10. huang jk, holt d, philp t. penile constriction by foreign bodies: the use of a dental drill. br j urol. 1997;79:801. 11. drachenberg d, nguan c, norman rw, lawen j. penile entrapment injury: a case report. can j urol. 1999;6:709-12. 12. kadioglu a, cayan s, ozcan f, tellaloglu s. treatment of penile incarceration in an impotent patient. int urol nephrol. 1995;27:639-41. 13. vahasarja vj, hellstrom pa, serlo w, kontturi mj. treatment of penile incarceration by the string method: 2 case reports. j urol. 1993;149:372-3. 14. bhat al, kumar a, mathur sc, gangwal kc. penile strangulation. br j urol. 1991;68:618-21. 15. tobe t, igarashi t, murakami s. strangulation of the scrotum by a metal ring. br j urol. 1994;73:711. urol_montage.pdf case report 57urology journal vol 6 no 1 winter 2009 giant cystadenoma of prostate ajit j thomas,1 yogesh mistry,2 ganesh gopalakrishnan1 urol j. 2009;6:57-9. www.uj.unrc.ir keywords: prostate neoplasms, retroperitoneal neoplasms, cystadenoma, male 1department of urology, christian medical college, vellore, tamil nadu, india 2department of pathology, christian medical college, vellore, tamil nadu, india corresponding author: ajit j thomas, md department of urology, christian medical college, ida scudder rd, vellore 632004, tamil nadu, india tel: +91 416 228 2111 fax: +91 416 228 2035 e-mail: ajthomas@fastmail.fm received december 2007 accepted march 2008 introduction giant cystadenomas of prostate are rare entities.(1) the ideal management of these lesions is unclear as only few isolated reports exist in the literature.(2-4) we report a case of prostate cystadenoma that had recurrent growth due to incomplete tumor resection. it appears that anything short of complete resection can cause recurrence as evident from a literature search by the authors. case report a 57-year-old man had presented with acute urinary retention 1.5 years earlier, and subsequent evaluation had revealed a cystic multiloculated mass compressing the bladder. an excision biopsy had been done, reported as benign. he had been symptom-free for nearly 1 year until he had experienced burning micturition and difficulty in passing urine, once again. he had been found to have a regrowth of the mass, and laparotomy and incomplete removal of the mass had been performed in january 2007. the remnant had been reportedly marsupialized to the peritoneal cavity due its predominantly cystic nature. the patient, however, had recurrence and presented to our institution in may 2007 with a mass in the lower abdomen. he had no lower tract symptoms this time and his bowel habits were figure 1. contrast enhanced computed tomography revealed a large heterogeneous, multiloculated, predominantly cystic mass in the pelvis arising from below the bladder extending up to the lower abdomen. note the bladder (with contrast) pushed to the right. figure 2. areas of tumor were revealed on pathology examination composed of closely packed glands, lined by double layers of inner columnar secretory cells without significant cytological atypia and outer preserved basal cell layer. also can be seen is papillary infolding of the epithelium (hematoxylineosin, × 400). giant cystadenoma of prostate—thomas et al 58 urology journal vol 6 no 1 winter 2009 normal. he had no history of hematuria or fever, either. physical examination revealed a wellhealed midline scar with a firm globular mass in the abdomen, extending from just above the umbilicus to the pelvis. the lower limit of the swelling could not be assessed. rectal examination disclosed a large pelvic mass, from which the prostate was indistinguishable. contrastenhanced computed tomography revealed a large heterogeneous, multiloculated, predominantly cystic mass in the pelvis arising from below the bladder extending up to the lower abdomen, probably from the seminal vesicle or the prostate and pushing the bladder to the right (figure 1). the patient underwent laparotomy and a tense multiloculated firm-to-cystic mass was found arising from the bladder base into the abdominal cavity well above the level of the umbilicus. bladder sparing surgery was done as the frozen section and the aspirate from the cyst pointed to a benign lesion (figure 2). the bladder was bivalved, the ureters canulated, and the entire mass dissected off the bladder. immunohistochemistry tests were performed, and the specimen was stained positive for prostatespecific antigen (figure 3). the patient had an uneventful recovery. he was voiding satisfactorily and to completion. ultrasonography 3 months after the operation showed a clear prostatic fossa and no sign of recurrence (figure 4), and serum prostate-specific antigen level was 0.4 ng/ml. discussion cystadenoma of the prostate is often categorized as retrovesical mesenchymal tumors not only on account of its rarity, but also because of the fact that distinguishing it from cystadenocarcinoma as well as the other tissue elements can be difficult.(2) the cystic spaces of the cystadenoma is lined by a single layer of cuboidal cells, with nuclei presenting no atypia or prominent nucleoli. these cells appear similar to the prostatic acinar columnar cells that co-express prostate-specific antigen and prostate acid phosphatase. the outer basal layer is preserved (figure 2). in contrast, the cells lining the cystadenocarcinoma show nuclear stratification, papillary proliferations, and roman arch structures. nuclear enlargement and prominent nucleoli are uniformly present. the growth pattern of the cystadenocarcinoma is invasive, with haphazard destruction of intervening prostatic parenchyma and aggressive invasion into the periprostatic adipose tissue.(2) prostate-specific antigen staining can disclose the prostatic origin of this lesion.(3,5) the clinical features of these lesions have been well described.(1) they present with voiding problems, are located retrovesically, and are often adherent to the bladder base. they may cause hydroureteronephrosis. they tend to be multiloculated and hence need to be managed by complete excision.(4) the presented patient had undergone incomplete removal before presenting to us; hence, he had 2 recurrence episodes. figure 4. follow-up ultrasonography showed clear prostatic fossa, and no recurrence was noticed. figure 3. immunohistichemistry examination showed lining epithelium exhibiting strong and diffuse immunostaining for monoclonal prostate-specific antigen. (monoclonal prostatespecific antigen, × 200) giant cystadenoma of prostate—thomas et al urology journal vol 6 no 1 winter 2009 59 in conclusion, retrovesical cystadenoma should be considered as a differential diagnosis in a mass of pelvic origin. it is important to determine the source of the lesion and an attempt at complete removal should be made while excising the lesion. conflict of interest none declared. references 1. maluf hm, king me, deluca fr, navarro j, talerman a, young rh. giant multilocular prostatic cystadenoma: a distinctive lesion of the retroperitoneum in men. a report of two cases. am j surg pathol. 1991;15:131-5. 2. tuziak t, spiess pe, abrahams na, wrona a, tu sm, czerniak b. multilocular cystadenoma and cystadenocarcinoma of the prostate. urol oncol. 2007;25:19-25. 3. choi yh, namkung s, ryu by, choi kc, park ye. giant multilocular prostatic cystadenoma. j urol. 2000;163:246-7. 4. rusch d, moinzadeh a, hamawy k, larsen c. giant multilocular cystadenoma of the prostate. ajr am j roentgenol. 2002;179:1477-9. 5. varma m, morgan m, jasani b, tamboli p, amin mb. polyclonal anti-psa is more sensitive but less specific than monoclonal anti-psa: implications for diagnostic prostatic pathology. am j clin pathol. 2002;118:202-7. new section in urology journal pictorial urology pictorial urology is a section for publishing interesting images of medical conditions. any kind of images (pictures, radiological images, pathologic images, etc) that show a typical, unique, or rarely seen variety of a condition related to urology, or those with a highly educational value can be submitted to this section. however, the section is not a place for case reports. only high-quality images that are not submitted or published elsewhere will be considered for publication. to submit an image, please send the materials via e-mail (urol_j@unrc.ir) and notice “pictorial urology” in your e-mail title. a maximum of 4 images can be submitted. a short title and accompanied by a legend of no more than 200 words is required. a short description of the case and images, as well as a brief discussion on the images should be provided in the text. no more than 3 references can provided for the text. for photographs of an identifiable patient, a written consent is required. no more than 3 authors can be listed for this section. construction of a novel ferroptosis-related prognostic risk signature for survival prediction in clear cell renal cell carcinoma patients fucai tang1*, jiahao zhang2*, langjing zhu3*, yongchang lai1, zhibiao li4, zeguang lu5, zhicheng tang4, yuexue mai2 , rende huang6, zhaohui he1 purpose: targeted ferroptosis is a reliable therapy to inhibit tumor growth and enhance immunotherapy. this study generated a novel prognostic risk signature based on ferroptosis-related genes (frgs), and explored the ability in clinic for clear cell renal cell carcinoma (ccrcc). materials and methods: the expression profile of mrna and frgs for ccrcc patients were exacted from the cancer genome atlas (tcga) database. a ferroptosis-related prognostic risk signature was constructed based on univariable and multivariable cox-regression analysis. kaplan-meier (km) survival curves and receiver operating characteristic (roc) curves were performed to access the prognostic value of riskscore. a nomogram integrating riskscore and clinical features was established to predict overall survival (os). based on differentially expressed genes between highand low-os groups with 5-year os, function enrichment analyses and single-sample gene set enrichment analysis (ssgsea) were investigated to immune status. results: a 9-frgs prognostic risk signature was constructed based on 37 differentially expressed frgs. roc and km curves showed that riskscore has excellent reliability and predictive ability; cox regression disclosed the riskscore as an independent prognosis for ccrcc patients. then, the c-index and calibration curve demonstrated the good performance of the nomogram in the training and validation cohort, and its predictive ability better than other features. immune-related biological processes were enriched by function enrichment analysis, and the immune-related cells and functions were differential by ssgsea between highand low-os groups. conclusion: our study identified and verified a novel 9-frgs prognostic signature and nomogram to predict os, providing a novel sight to explore targeted therapy of ferroptosis for ccrcc. keywords: clear cell renal cell carcinoma; ferroptosis; immunity; prognosis; nomogram; survival introduction renal cell carcinoma (rcc) is one of the ten most common cancers in the world, which accounts for more than 90% of all renal cell carcinoma types, ranking sixth in men and tenth in women, and clear cell renal cell carcinoma (ccrcc) is the most common subtype of rcc, of which ccrcc is 75% of rcc.(1,2) at present, the research showed that the risk factors for rcc are smoking, obesity, hypertension, and chronic kidney disease.(1) in recent years, there has been a broad advance in the development of treatments for ccrcc, including targeted therapy, chemotherapy, and immunotherapy, of which therapy of immune checkpoint inhibitors is considered a more effective therapy for ccrcc patients. 1department of urology, the eighth affiliated hospital, sun yat-sen university, shenzhen, guangdong, 518033, china. 2the sixth clinical college of guangzhou medical university, guangzhou, guangdong, 511436, china. 3department of nephrology, the eighth affiliated hospital, sun yat-sen university, shenzhen, 518033, china. 4the third clinical college of guangzhou medical university, guangzhou, guangdong, 511436, china. 5the second clinical college of guangzhou medical university, guangzhou, guangdong, 511436, china. 6the kindmed school of laboratory medicine of guangzhou medical university, guangzhou, guangdong, 511436, china. * fucai tang, jiahao zhang, and lang-jing zhu contributed equally to this work. *correspondence: department of urology, the eighth affiliated hospital, sun yat-sen university, shennan zhong road #3025, futian district, shenzhen, 518033 guangdong, china. e-mail address: hechh9@mail.sysu.edu.cn. received september 2021 & accepted april 2022 (3) however, the targets of immune therapy still need to be supplemented and improved. in addition, most patients with ccrcc are diagnosed in the advanced stage, because the early-phase symptoms of ccrcc are not apparent and tnm staging is not an effective predictor of early ccrcc.(4) therefore, it is essential to evaluate the prognosis of ccrcc precisely. meanwhile, the need for accurate biomarkers still has not been met plus the high heterogeneity of ccrcc.(1) as a new nonapoptotic form of cell death based on regulated necrosis by the iron-dependent lipid peroxidation, ferroptosis has different properties in morphology and biochemistry as well as gene signature compared to apoptosis, necrosis, and autophagy.(5,6) ferroptosis is primarily due to the accumulation of cellular reactive urological oncology urology journal/vol 19 no. 4/ july-august 2022/ pp. 289-299. [doi:10.22037/uj.v19i.6999] oxygen species (ros) caused by lipid peroxidation exceeding the scavenging power of ros that bases on the redox ability maintained by phospholipid hydroperoxidase and glutathione (gsh), and specifically, the reason for ferroptosis is divided to the cysteine deprivation-caused ferroptosis and phospholipid glutathione peroxidase 4 (gpx4) inhibition-induced ferroptosis.(5,7) and ferroptosis is not only intimately correlated to lots of biological metabolic processes, such as the metabolism of amino acid, iron, polyunsaturated fatty acid, and biosynthesis soon, but also related to a variety of disease processes, especially breast cancer, renal cell carcinoma, and liver cancer so on.(5,8) ferroptosis-induction combination with immunotherapy is becoming a new alternative therapeutic method for cancer gradually.(9) the latest research exhibited, as the vital tumor suppressor in ccrcc, vhl can decrease the lipid storage and highly express relevant genes of oxidative phosphorylation and fatty acid metabolism to promote ferroptosis. the other side of the shield, gs, gls, gclc, gclm, and slc7a11 were positively correlated with ferroptosis in ccrcc.(10) these corresponding genes are about glutathione metabolism. however, the relationship between these genes and prognosis is still unknown, and we still need to find more relevant ferroptosis-genes about the prognosis of ccrcc patients. in this study, we analyzed the ferroptosis-related genes (frgs) to complete the construction and validation of the novel prognostic multi-gene signature for ccrcc patients in the tcga cohort. then, combined with clinical information and risk score, the nomogram was constructed and validated. finally, to reveal the potential mechanism, function enrichment analysis and ssgsea score of immune status were performed. we presented the following article/case in accordance with the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (tripod) reporting checklist (https://www.equator-network.org/ reporting-guidelines/tripod-statement/). materials and methods data acquisition and study population a brief flow chart to study design is shown in supplementary figure s1. the rna sequencing expression profile and relevant clinical information for ccrcc patients were downloaded and exacted from the cancer genome atlas (tcga, https://cancergenome.nih.gov/, date: september 18, 2020 to january 20, 2021). specifically, for inclusion criteria, these included patients must have complete clinical information, including age, gender, tumor grades, tumor stages, follow-up time, and survival status. for exclusion criteria, patients with less than one month in follow-up and missing clinical information were excluded. ultimately, 502 ccrcc tissue novel prognostic frgs for ccrcc – tang et al. table 1. baseline clinicopathological features of patients with ccrcc variablesa training cohort (n=251) validation cohort (n=251) total (n=502) p-value gender .452 male 82 (32.7) 90 (35.9) 172 (34.3) female 169 (67.3) 161 (64.1) 330 (65.7) age (years) 59.4 ± 12.5 61.1 ± 11.9 60.3 ± 12.1 .230 grade .324 g1/g2 109 (43.4) 120 (47.8) 229 (45.6) g3/g4 142 (56.6) 131 (52.2) 273 (54.4) stage .584 stage i 125 (49.8) 126 (50.2) 251 (50.0) stage ii 28 (11.2) 25 (10.0) 53 (10.6) stage iii 62 (24.7) 54 (21.5) 116 (23.1) stage iv 36 (14.3) 46 (18.3) 82 (16.3) status .776 alive 169 (67.3) 166 (66.1) 335 (66.7) dead 82 (32.7) 85 (33.9) 167 (33.3) adata are presented as mean ± sd or number (percent) variables univariable cox analysis multivariable cox analysis hr 95%ci p-value hr 95%ci p-value gender male reference reference female 0.95 0.60-1.50 .827 age 1.02 1.00-1.04 .039 1.02 1.00-1.04 .121 grade g1/g2 reference reference g3/g4 2.64 1.60-4.38 < .001 1.41 0.81-2.45 .224 stage reference stage i reference reference stage ii 1.10 0.44-2.72 .839 0.92 0.37-2.30 .854 stage iii 2.46 1.38-4.40 .002 1.54 0.81-2.83 .199 stage iv 8.85 5.05-15.51 < .001 4.67 2.45-8.80 < .001 riskscore 2.72 2.10-3.52 < .001 2.11 1.58-2.80 < .001 table 2. univariable and multivariable cox regression analysis for os in ccrcc patients from the training cohort abbreviations: hr, hazard ratio. vol 19 no 4 july-august 2022 290 urological oncology 291 samples and 72 normal samples were adopted. founded on reverse kaplan‐meier (k‐m) method, the median follow-up time in the study group was 4.90 years, while the median follow-up time in the control group was 4.41 years. as death status of patients was regarded as the end of our study, the censoring proportion of the training and testing group were 67.3% and 66.5% in km survival analysis, respectively. the frgs were obtained from the world's first database of ferroptosis (ferrdb, http://www.zhounan.org/ferrdb/) (supplementary table s1).(11) the frgs with evidence level of "verificated" were included, which required convincing evidence from strict tests such as pharmacological or genetic inhibition or activation tests in humans. all the data via tcga and ferrdb were both so publicly available and accessible. finally, 113 frgs were included in the study. the differentially expressed frgs identification the differentially expressed genes (degs) between tumor tissues and tumor-adjacent normal tissues in the tcga cohort were identified by combining the expression profile of 113 frgs using the “limma” r package with a false discovery rate (fdr) < 0.05 and | log2(fold change) | >1 considered as statistical significance. the heatmap of the degs was drawn using the r package “heatmap”. the tcga cohort including 502 ccrcc samples was allocated randomly and averagely in the figure 1. the heatmap of 37 ferroptosis-related degs in renal tissue between normal and tumor from tcga. the red represents up-regulation, whereas the blue represents down-regulation. the columns of the heatmap are samples, and the rows are different genes in the figure. figure 2. prognosis and correlation analysis of 14 frgs. (a) the forest plot of univariable cox regression analysis between gene expression and os. the plot displayed the prognostic ability of the fourteen frgs included in the 37 degs. the blue square indicated that the hazard ratio is less than 1, and the red one is greater than 1. and the length of the blue purple line represents the 95% confidence interval. (b) the network showing the correlation of 14 frgs. the correlation coefficients are represented by green and red line whose depth means the degree of correlation. red represents positive correlation, while green represents the negative correlation, and each region area of the network figure represents the relative abundance of 14 gene expression profiles. novel prognostic frgs for ccrcc – tang et al. training cohort (n=251) and internal validation cohort (n=251) by using a stratified random split in the r package “caret”. then, based on these degs, the prognosis-related frgs were obtained by univariable cox analysis in the training cohort. finally, the correlation of prognosis frgs was analyzed by r package “corrplot” based on pearson method. a model of prognostic frgs signature construction and evaluation to identify the independent risk prognostic genes and build an optimal prognostic model, multivariable cox regression analysis was utilized to identify frgs signature based on the lowest akaike information criterion (aic) value to by forward and backward stepwise regression method. the normalized expression matrix of candidate ferroptosis-related prognostic degs was treated as an independent variable and os and status of patients in the training cohort as a response variable. the prognostic risk score of the ccrcc patients was calculated based on a linear combination of the regression coefficients and the normalized expression level of gene expression. the calculation formula used for the analysis was as follows: where coefi represents the corresponding regression coefficient, expi is the value of each gene's expression. according to the median value of the risk score in the training cohort and validation cohort, the patients of the training and validation cohorts all were classified into high-risk and low-risk groups. to observe whether the highand risk-group can be divided based on the expression of modeling frgs in order to explore the difference between two risk groups form expression, principal component analysis (pca) was carried out using the r package “scatterplot3d” in the training and validation cohort. then, we transformed variables into 3 principal components by the dimension reduction. for the survival analysis of each gene, the survival curves were plotted by km method. the time-dependent roc curve was plotted to calculate the area under the roc curve and evaluate the predictive power of the prognostic model founded on signatures at 1-, 3-, and 5-year survival. prognostic predictive nomogram construction and validation univariable and multivariable cox regression analyses were applied to assess whether prognostic riskscore was independent of other clinical features of ccrcc and to screen for independent prognostic factors, which can verify further the prognostic value of riskscore model. a prognostic predictive nomogram was established by multivariable cox regression to forecast 1-, 3-, and 5-year os of ccrcc patients in the tcga, including all prognostic parameters. meanwhile, we calculated the calibration plot, the harrell's c-index, and auc of the roc curve for the nomogram to evaluate the accuracy and power of the nomogram, whose analysis was performed using the r package. the c-index could be contributed to assess the consistency between the actual outcome frequencies and the model prediction probabilities. besides, another predictor for 5-year os was evaluated by roc values, such as risk score, age, grade, and stage. function enrichment and immune status analysis according to the 50% probability value of the nomogram predicted in the 5-year os, the ccrcc patients of tcga were divided into two groups. the 5-year os probability of the high-os group was greater than 50%, and the 5-year os probability of the low-os group was less than 50%. the genes with greater or equal to 1 in figure 3. construction of the 9 frgs prognostic risk signature model. the group of figures on the left is for the training group (a, c, e), and the other set of figures on the right is for the validation group (b, d, f). (a, b) risk score distribution curves of ccrcc patients according to the median value. (c, d) the scatter diagram shows that distributions of survival times and status to ccrcc patients between high-risk group and low-risk group in the tcga cohort. (e, f) heatmaps of expression for 9 risk genes in the high-risk (blue) and lowrisk (pink) group of os model. novel prognostic frgs for ccrcc – tang et al. vol 19 no 4 july-august 2022 292 urological oncology 293 2-fold change ((| log2fc |≥ 1) and fdr ≤ 0.05 were considered the threshold of degs between the 5-year low-os and high-os group. these degs were visualized by the volcano plot. and the "clusterprofiler" r package was used by conducting gene ontology (go) and kyoto encyclopedia of genes and genomes (kegg) analyses for the degs. the ssgsea was applied to evaluate the infiltrating score of immune cells and the immune-related pathways or functions activity. and the relevant supplementary table 2 included the annotated gene set file. the ssgsea scores of immune cells and pathways or functions between the 5-year low-os and high-os group were compared by the wilcoxon test. all statistical data were analyzed by r software (version 4.0.2) for windows. the results with p < 0.05 were considered statistically significant, and all reported p values were two-tailed. statistical analysis the clinical features between the training and validation cohorts used the chi-squared to compare their discrepancy. the os between different risk groups was contrasted using the log-rank test. the ssgsea scores of immune cells and pathways or funtions between 5-year low-os and high-os group were compared by the wilcoxon rank-sum test. all statistical data were analyzed by r software (version 4.0.2) for windows. the results with p < 0.05 were considered statistically significant, and all reported p values were two-tailed. results screening for prognostic frgs in the ccrcc patients the 37 degs of 113 frgs were identified between 502 ccrcc tumor tissues and 72 normal renal tissues in the tcga-kirc dataset, among which 18 genes were up-regulated and 19 genes were down-regulated. the heatmap of the 37 degs was constructed in figure 1. according to the principle of random allocation and 1:1 equal allocation, we divided 502 patients into a training group and a verification group, with 251 cases in each group. the detailed clinicopathological features of these patients have been summarized in table 1, including gender, age, grade, stage, and status. by the chi-squared, the p values of all features were all greater than .05, which indicated that baseline clinicopathological feature had no statistical difference between the training group and the validation group. furthermore, we performed the univariable cox regression analysis for the expression of degs of training cohort to better understand the prognostic role of degs in ccrcc patients. the result of forest plot showed that mt1g, figure 4. prognostic analysis and validation of the 9-gene ferroptosis-related signature model in the tcga cohort. the group of figures on the left is for the training group (a, c, e), and the other set of figures on the right is for the validation group (b, d, f). (a-b) the kaplan-meier survival curves of the high-risk and low-risk group in the train set and validation set. (c-d) roc curve was used to evaluate the prediction efficiency of the prognostic signature in the train set and validation set. (e-f) pca scatter plot of ferroptosis-associated genes between highand low-risk groups. the legend indicates the color of the different risk: red, high sick; blue, low risk. novel prognostic frgs for ccrcc – tang et al. chac1, taz, cdkn2a, cbs, cd44, ptgs2, slc7a11, and tf were risk factors with hr (hazard ratio) > 1, while ca9, got1, pebp1, akr1c1, and miox were protective factors with hr < 1 in ccrcc patients (p value < .05 in 14 genes) (figure 2a). the correlation and interaction between these genes were presented in figure 2b, which indicated that three pairs of positive genes were more related than others, including got1 and akr1c1, got1 and pebp1, miox and pebp1. construction and validation of a prognostic model a prognostic model basing the expression profile of the 14 genes was established by the multivariable cox regression analysis, which identified the 9-gene signature (mt1g, ca9, chac1, taz, cdkn2a, got1, pebp1, akr1c1, slc7a11). and then we obtained the risk score calculation formula as follows: riskscore= 0.103 × expression value of mt1g +(-0.228 × expression value of ca9) + 0.333 × expression value of chac1 + 0.493 × expression value of taz + 0.285 × expression value of cdkn2a + (-0.376× expression value of got1) + 0.377 × expression value of pebp1 + (-0.276 × expression value of akr1c1) + 0.751 × expression value of slc7a11. the patients were divided into highand low-risk groups by median value of risk model scoring formula in the training and validation cohort (figure 3a-3b). both the training and validation groups showed significantly higher mortality rates in the high-risk group than in the low-risk group (figure 3c-3d). the heatmap displayed that the expression of the 9 risk signatures was consistent in the training and validation groups (figure 3e-3f). our study found that high-risk ccrcc patients had a significantly worse os than those in the low-risk counterparts from kmsurvival curves basing the risk score (figure 4a-4b). and the time-dependent roc curves demonstrated that the risk model basing 9-gene signature harbored a positive ability to predict os in the training and validation groups, and the auc of training cohort reached 0.754 at 1 year (95%ci, 0.650-0.857),0.735 at 2 years (95%ci, 0.6450.825), and 0.727 at 3 years (95%ci, 0.648-0.807), and the auc reached 0.704 at 1 year (95%ci, 0.587-0.822), figure 5. construction and validation of the nomogram model to predict os of ccrcc patients in the tcga dataset. (a) nomogram based on age, grade, stage, and risk score, was used to predict the 1-, 3and 5-year survival probability of ccrcc patients in the training cohort. the calibration curves of the nomogram showed the os probability of prediction at 1-, 3-, and 5-year in the tcga training cohort (b-d) and validation cohort (e-g). the time-dependent roc curves for the 5-year os nomogram, risk score, stage, grade, age and gender in the training cohort (h) and validation cohort (i). novel prognostic frgs for ccrcc – tang et al. vol 19 no 4 july-august 2022 294 urological oncology 295 00.673 at 2 years (95%ci, 0.583-0.764), and 0.705 at 3 years (95%ci, 0.626-0.783) in the validation cohort (figure 4c-4d). finally, pca analysis was performed and confirmed that patients in highand low-risk groups were distributed in discrete directions to indicate the difference of risk groups (figure 4e-4f). independent prognostic predictors evaluation of the 9-gene signature the univariable and multivariable cox proportional regression analysis were performed to evaluate whether the 9-gene risk signature can consider as an independent decisive factor of os with ccrcc patients in the training cohort. as shown in table 2, univariable cox analysis revealed that the risk score was significantly associated with shorter os (95% ci: 2.10–3.52; hr: 2.72; p < .001), as was multivariable cox analysis (95% ci: 1.58–2.80; hr: 2.11; p < .001), which indicated that the risk score served as one of the independent prognostic factors. in addition, grade (g3/g4) and stage (ⅲ, ⅳ) were significantly correlated with poor survival of ccrcc patients in the other clinicopathologic variables of univariable analysis. interestingly, stage ⅳ was also an independent prognostic risk factor. constructing and validating the predictive nomogram further, we established a nomogram and used it to predict the probability of 1-year, 3-year, and 5-year os in the ccrcc patients from the training cohort (figure 5a). four prognostic predictors of age, grade, stage, and risk score were included in the nomogram. the c-index of the nomogram for os was 0.790 (95% ci, 0.740-0.840) in the training cohort and 0.765 (95% ci, 0.714-0.816) in the validation cohort, whose results showed that nomogram had a stable and accurate predictive power. according to the nomogram calibration curve evaluation, it showed that the os predicted to value the matches well with the actual value and wonderful prediction performance, especially the prediction performance of 5-year os (figure 5b-5g). in addition, we also drew the roc curve based on the nomogram, riskscore, stage, grade, age, and gender. the auc values for training set nomogram, riskscore, stage, grade, age, and gender were respectively 0.824, 0.795, 0.735, 0.692, 0.562, 0.496, while auc values of valifigure 6. functional enrichment analysis of degs between the high-os and low-os groups. the volcano plot on the upper left (a) is the result of the degs of two different os groups, and the red is up-regulation of gene expression and the green is down-regulation of gene expression. rectangles is shown that the most significant go enrichment (b) and kegg pathways (c) based on the degs. the color represents q-value and the length of abscissa represents count. the red rectangles highlight the overlap of the immune-related pathways. novel prognostic frgs for ccrcc – tang et al. dation set were respectively 0.767, 0.707, 0.684, 0.641, 0.583, and 0.495 (figure 5h-5i). it is shown that the prediction ability of nomogram was best in the ccrcc patients. functional analysis of deg between the lowand high-os groups using the nomogram to evaluate the 5-year os probability of all ccrcc patients in tcga, we obtained a median of 50% probability of 5-year survival to divide into the highand low-os group in the ccrcc patients. the r package “limma” was used to identify 468 degs between the highand the low-os group, including 150 up-regulated genes and 318 down-regulated genes (figure 6a). go and kegg enrichment analyses were performed to investigate the potential biological function and pathway in these degs. in the biological process (bp), the enrichment of degs was the highest in the complement activation pathway. it is interesting that the enrichment of the first ten bp is related to the immune pathway. in cell composition (cc), the enrichment factor of immunoglobulin complex is the highest, while the antigen-binding enrichment is the highest in terms of molecular function (mf) (figure 6b). meanwhile, the kegg analysis showed that the main enrichment processes are complement and coagulation cascades pathway, mineral absorption, and viral protein interaction with cytokine and cytokine receptor pathway (figure 6c). the red rectangle of go and kegg pathway analysis plot revealed that the degs of highand low-os groups were mainly enriched in pathways of immune-related biological processes. immune status in the lowand high-os groups finally, we further explored the immune status by quantifying the enrichment levels of different immune cell subtypes, functions, or pathways with ssgsea score in ccrcc. the 16 immune cells and 13 immune-related function scores were obtained and analyzed in the discovery set using ssgsea. overall, the distribution of immune status was different between the 5-year high and low-os groups, with most of the immune cell and immune-related pathways or function scores higher in the low-os group than the high-os group (figure 7a). it is shown that adcs, cd8+ t cells, macrophages, follicular helper t cell (tfh), helper t cells (th1 and th2), and til infiltration were higher in the 5-year low-os group (p < 0.05), while idcs and mast cells infiltration were higher in the 5-year high-os group (p < 0.05) (figure 7b). among them, cd8+ t cells, t helper cells, til, and macrophages are the most common immune cell populations in the ccrcc patients. interestingly, according to the expression of immune function (figure 7c), only the score of type ii ifn response in the high-os group is significantly higher than in the low-os group. however, the type i ifn response in the high-os group is lower than in the low-os group. the immune scores of mhc class i, cytolytic-activity, figure 7. the ssgsea analysis of different immune status between 5 year high-os group and low-os group. (a) the heatmap showed that the score of immune cell and immune-related pathways or functions in the ccrcc patients of high-os group (green) and low-os group (orange). the color of different clinicopathological parameters are shown as annotations, while the immune status scores is also indicated by a color bar. green means low score and red means high score. (b-c) the scores of 16 immune cells (b) and 13 immune-related functions (c) of the high-(blue) and low-(red) os groups are revealed in these boxplots. novel prognostic frgs for ccrcc – tang et al. vol 19 no 4 july-august 2022 296 and hla are highest in the function enrichment. discussion the development of ccrcc is strongly associated with the loss of the vhl gene, loss of chromosome 3p, and the occurrence of extrachromosomal mutational events. (12) according to the tnm stage, the 5-year survival rate can reach 80% to 90% for patients with early stage ⅰ and ⅱ ccrcc, while it is around 60% for stage ⅲ, and less than 10% for patients with advanced stageⅳ ccrcc. (13) meanwhile, the 5-year survival rate for metastatic ccrcc patients is between 10% and 20%.(12) therefore, it is important and urgent to explore the biomarkers and therapeutic targets of ccrcc. in this study, we systematically investigated the 113 frgs expression profile of the tumor and normal issues for ccrcc patients from the tcga database, as well as the association of frgs with os to construct a novel ferroptosis-related prognostic gene risk signature. nine risk signatures (mt1g, ca9, chac1, taz, cdkn2a, got1, pebp1, akr1c1, slc7a11) were obtained by the univariable and multivariable cox regression analysis to contribute a new prognostic model in the training cohort. then, a new nomogram combining the ferroptosis-related riskscore model and clinical features was developed in ccrcc patients. based on the roc curve, the predictive efficiency of nomogram for the 5-year os group was the best (auc=0.813 in the training cohort; auc=0.790 in the validation cohort). in addition, the predictive ability of riskscore is better than tumor stage and histological grade. what’s more, compared with wu’s prediction performance (auc=0.73) of the survival model on ccrcc frgs, our risk signature performed similar reliable and accurate.(14) to explore the difference between highand low-os groups ccrcc patients, degs functional enrichment analyses showed that immune-related pathways were highly enriched in the go and kegg analysis, which proclaims that there is a close relationship between ferroptosis and tumor immunity. further demonstrated by ssgesa, tumor tissue had different degrees of immune cell subsets infiltration, with the immune cell and immune-related pathways or functions score was significantly different between highand low-os groups in ccrcc patients. the prognostic risk gene signature model was composed of 9 frgs (mt1g, ca9, chac1, taz, cdkn2a, got1, pebp1, akr1c1, slc7a11). based on the ferrdb database including experimental evidence, the related mechanisms between these genes and ferroptosis processing have been confirmed by published experimental papers in some tumors, of which five of prognostic model genes (chac1, taz, cdkn2a, got1, pebp1) have been proved to promote ferroptosis by validated experiments, while another four genes (mt1g, ca9, akr1c1, slc7a11) inhibit ferroptosis. (11) besides, wu et al. and chang et al. also used frgs to construct a prognostic model in ccrcc, including got1 and slc7a11.(14,15) therefore, got1 and slc7a11 may be considered as important signatures in ccrcc. as a component of the cystine/glutamate antiporter and target of p53, slc7a11 was up-regulated to increase cystine intake and inhibit ros–induced ferroptosis when p53 was knocked down.(16) furthermore, slc7a11 overexpression had been closely associated with poor prognosis in several cancers, while knockdown of slc7a11 can hinder cancer proliferation, novel prognostic frgs for ccrcc – tang et al. invasion, and metastasis by participating in several pathways, including the regulation of oxidative stress and immune regulation.(17) cdkn2a, a tumor suppressor gene, partook in the modulation of ferroptosis by the p53-dependent and a p53-independent manner when cdkn2a was activated, and both processes were closely related to slc7a11.(18) the involvement of the p53 pathway was also mentioned in the kegg analysis. a study showed that ccrcc patients had a significantly worse prognosis when cdkn2a was mutated. (19) downregulation of mt1g in ccrcc patients may render tumor cells growth-arrested, induce apoptosis, and promote promoter methylation, which is similar to the role downregulating mt1g inducing ferroptosis. (20,21) . as a metalloenzyme, ca9 has been reported to contribute to ferroptosis through iron overload and trigger lipid peroxidation when it was knocked down under hypoxia in malignant mesothelioma cells.(22) the high expression of ca9 is related to good outcomes and can be used as a prognostic biomarker for ccrcc.(23) pertinent mechanisms of other genes affecting the prognosis of ccrcc through ferroptosis remain to be clarified by more experiments. immunotherapy has gradually become a new clinical strategy for cancer treatment, especially for ccrcc. however, more effective targets are needed for immunotherapy of ccrcc, and the potential regulation among targets still needs to be supplemented. based on go analysis and kegg analysis, we found unsurprisingly that the first ten enrichment pathways of bp, the first two enrichment pathways of cc and mf, and the first pathway of kegg are all related to immune pathways, which mainly touch upon complement pathway, humoral and cellular immune response, metabolism of immune complexes, immune biological processes related to immunoglobulin pathway. according to the ssgsea score, the antigen presentation process (including the score of adcs, idcs, macrophages, and apc co-stimulation) was significantly different between the 5-year low-os and high-os group. in another study, it was found that early ferroptosis has immunogenicity and can promote the maturation of bone-marrow derived dendritic cells, thus promoting the immune response to enhance tumor immunity, whether in vivo or vitro. (24) and a recent study reported that ferroptosis-related cells were also swallowed and cleared by macrophage in vitro human monocyte-derived macrophages culture, like apoptosis, because ferroptosis cells may release phosphatidylserine to induce macrophage phagocytosis themselves.(25) interestingly, the high infiltration of cd8+ t cells was located in the low-os group of our study. as braun et al reported, the high infiltration of cd8+ t cells was also associated with a poor prognosis in ccrcc patients.(26) activation of immunotherapy increased cd8+ t cells, which promoted lipid peroxidation and ferroptosis of tumor cells by releasing interferon-gamma (ifnγ) and downregulating slc7a11 and slc3a2.(27) however, increased expression of cd36 in tumor-infiltrating cd8+ t cells induced ferroptosis, resulting in decreased cytotoxic cytokines and loss of antitumor activity of cd8+ t cells.(28) therefore, the mechanism of action between ccrcc immune infiltration of cd8¬+ t cells and ferroptosis requires elucidation from further experiments. meanwhile, a higher response of the type ii ifn and a lower immune score of check point were urological oncology 297 shown in the 5-year high-os group. it is proved by the experiments that blocking checkpoint was conducive to enhance the ferroptosis process by increasing the release of ifnγ.(27) gpx4 is essential for t cell immunity expansion and promotes maintenance of cd8+ t cells.(29) in the previous study, the glutathione metabolic system carried a big weight in ccrcc.(12) and gpx4 of glutathione metabolic system has been advised as a treatment target of ccrcc patients, but there is no reliable and safe ferroptosis therapy in clinic.(30) therefore, ferroptosis-related immunotherapy is expected to become a new clinical treatment strategy for ccrcc. nevertheless, there are some limitations to our current study. first, we established and validated the prognostic model only with the expression profile of ccrcc in retrospective data from tcga. this requires prospective cohort studies to validate this prognostic model. second, it should be noted that founded on univariable cox regression, the possibility of sparse-data bias occurred in the patients with stage iv in order to lead to the risk bias of exaggeration in a relevant hr and confidence interval. besides, the mechanism and pathway of ferroptosis in ccrcc patients still need to be further explored. ultimately, even though 9 frgs novel genes are significantly related to the survival of ccrcc patients and become new treatment targets possibly, the relationship among frgs, riskscore and immune activity needs to be further constructed for an exact connection and validation through more experiments. conclusions in summary, our study established a novel prognostic model of 9 frgs risk signatures and promising prognostic nomogram for ccrcc patients, and validated its reliability successfully. our study provided an accurate and reliable prediction efficiency and an individualized treatment strategy to ccrcc patients. furthermore, our study may help researchers to probe the possible biological mechanisms between tumor immunity and ferroptosis in ccrcc. conflicts of interest all authors declare that they have no conflict of interest with the state. all authors have completed the icmje uniform disclosure form. acknowledgement the present study was supported by the national key research and development program of china (contract no. 2018yfa0902801), national natural science foundation of china (contract no. 81803576), guangdong basic and applied basic research foundation (contract no. 2020a1515010152), public health research project in futian district, shenzhen (contract no. ftws2020026), the research start-up fee for the eighth affiliated hospital, sun yat-sen university (contract no. zdbykyqdf005), and the sixth clinical college of guangzhou medical university (contract no.2020aly05). supplementary materials supplementary table s1 is the acquisition of validated ferroptosis-genes’ names and associated information from the ferrdb database. supplementary table s2 is related data information for ssgsea. supplementary figure s1 shows the study design flow. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/38 references 1. hsieh jj, purdue mp, signoretti s, et al. renal cell carcinoma. nat rev dis primers. 2017;3:17009. 2. capitanio u, bensalah k, bex a, et al. epidemiology of renal cell carcinoma. eur urol. 2019;75:74-84. 3. vuong l, kotecha rr, voss mh, hakimi aa. tumor microenvironment dynamics in clearcell renal cell carcinoma. cancer discov. 2019;9:1349-57. 4. majer w, kluzek k, bluyssen h, wesoly j. potential approaches and recent advances in biomarker discovery in clear-cell renal cell carcinoma. j cancer. 2015;6:1105-13. 5. stockwell br, friedmann angeli jp, bayir h, et al. ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. cell. 2017;171:273-85. 6. dixon sj, lemberg km, lamprecht mr, et al. ferroptosis: an iron-dependent form of nonapoptotic cell death. cell. 2012;149:106072. 7. gao m, yi j, zhu j, et al. role of mitochondria in ferroptosis. mol cell. 2019;73:354-63 e3. 8. lippmann j, petri k, fulda s, liese j. redox modulation and induction of ferroptosis as a new therapeutic strategy in hepatocellular carcinoma. transl oncol. 2020;13:100785. 9. xu t, ding w, ji x, et al. molecular mechanisms of ferroptosis and its role in cancer therapy. j cell mol med. 2019;23:4900-12. 10. miess h, dankworth b, gouw am, et al. the glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. oncogene. 2018;37:5435-50. 11. zhou n, bao j. ferrdb: a manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations. database (oxford). 2020;2020. 12. hsieh jj, le vh, oyama t, et al. chromosome 3p loss-orchestrated vhl, hif, and epigenetic deregulation in clear cell renal cell carcinoma. journal of clinical oncology : official journal of the american society of clinical oncology. 2018;36:jco2018792549. 13. jonasch e, gao j, rathmell wk. renal cell carcinoma. bmj. 2014;349:g4797. 14. wu g, wang q, xu y, li q, cheng l. a new survival model based on ferroptosis-related genes for prognostic prediction in clear cell renal cell carcinoma. aging. 2020;12:1493348. 15. bai d, feng h, yang j, et al. genomic analysis uncovers prognostic and immunogenic characteristics of ferroptosis for clear cell renal cell carcinoma. molecular therapy nucleic acids. 2021. 16. jiang l, kon n, li t, et al. ferroptosis as a p53-mediated activity during tumour novel prognostic frgs for ccrcc – tang et al. vol 19 no 4 july-august 2022 298 suppression. nature. 2015;520:57-62. 17. lin w, wang c, liu g, et al. slc7a11/xct in cancer: biological functions and therapeutic implications. am j cancer res. 2020;10:310626. 18. chen d, tavana 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with early ferroptotic cancer cells induces efficient antitumor immunity. j immunother cancer. 2020;8. 25. kloditz k, fadeel b. three cell deaths and a funeral: macrophage clearance of cells undergoing distinct modes of cell death. cell death discov. 2019;5:65. 26. braun da, hou y, bakouny z, et al. interplay of somatic alterations and immune infiltration modulates response to pd-1 blockade in advanced clear cell renal cell carcinoma. nat med. 2020;26:909-18. 27. wang w, green m, choi je, et al. cd8(+) t cells regulate tumour ferroptosis during cancer immunotherapy. nature. 2019;569:270-4. 28. ma x, xiao l, liu l, et al. cd36-mediated ferroptosis dampens intratumoral cd8(+) t cell effector function and impairs their antitumor ability. cell metab. 2021;33:100112.e5. 29. matsushita m, freigang s, schneider c, et al. t cell lipid peroxidation induces ferroptosis and prevents immunity to infection. j exp med. 2015;212:555-68. 30. zou y, palte mj, deik aa, et al. a gpx4dependent cancer cell state underlies the clearcell morphology and confers sensitivity to ferroptosis. nat commun. 2019;10:1617. novel prognostic frgs for ccrcc – tang et al. urological oncology 299 v07_no_4.pdf pictorial urology 224 urology journal vol 7 no 4 autumn 2010 tuberous sclerosis complex urol j. 2010;7: . www.uj.unrc.ir a 30-year-old woman presented to our outpatient clinic with a painless left abdominal mass, which had gradually increased in size over the past two years. she gave history of seizures at one year of age. her general and neurological examinations were normal. she had a large left flank mass, which was bimanually palpable and ballotable. contrast enhanced computed tomography revealed a large well-circumscribed heterogenous retroperitoneal mass measuring 25 × 20 cm arising from the left kidney with predominant fat attenuation. multiple smaller lesions were seen in the opposite kidney. features were suggestive of diffuse angiomyolipomatosis of the kidneys. hypodense lesions were also seen involving the lungs lymphangioleiomyomatosis and the liverhepatic angiomyolioma, a rare finding. a diagnosis of tuberous sclerosis complex (tsc) was made and presence of other stigmata of the syndrome was ruled out. she underwent a nephron sparing excision of the left renal mass and the diagnosis of angiomyolipoma was confirmed on histopathology examination. she made an uneventful recovery. regular follow-up and screening of family members were advised. tuberous sclerosis complex is a multisystem, autosomal dominant disorder resulting from mutations of tsc1 or tsc2 genes.(1) the diagnostic criteria of tsc consist of a set of major and minor features. (2) management of tsc must include appropriate diagnosis and long-term follow-up enabling early recognition of potential life-threatening complications. finally, genetic counseling should be offered to patients to aid with family planning. thampi john nirmal department of urology, christian medical college, vellore, india e-mail: nirmaltj@gmail.com references 1. crino pb, nathanson kl, henske ep. the tuberous sclerosis complex. n engl j med. 2006;355:1345-56. 2. roach es, dimario fj, kandt rs, northrup h. tuberous sclerosis consensus conference: recommendations for diagnostic evaluation. national tuberous sclerosis association. j child neurol. 1999;14:401-7. 1 running head: ct in eaml the value of computed tomography in the diagnostic and prognostic prediction of renal epithelioid angiomyolipoma authors：jun zhang, ms1,2, †; xiao-jian xu, ms2, †; zong-xin chen, bs2, †; zheng-yu zhu, ms2, miao li, ms2; jian-quan hou, md1* 1department of urology, dushu lake hospital affiliated to soochow university; 9 chongwen road, suzhou city, jiangsu province, china 2department of urology, the first affliated hospital of soochow university; 188 shizi road, suzhou city, jiangsu province, china †jun zhang, xiao-jian xu, zong-xin chen contributed equally to this study, and are the cofirst authors of this article abstract purpose: this study aimed to assess the importance of computed tomography (ct) imaging in the diagnostic and prognostic evaluation of renal epithelioid angiomyolipoma (eaml). materials and methods: this study comprised 63 patients diagnosed with renal eaml in the first affiliated hospital of soochow university during 2010-2021, who met the inclusion criteria. the clinical, pathological, and therapeutic features were analyzed to determine the optimum diagnostic and therapeutic approaches. results: of the 63 participants, 20 were men and 43 women aged 24-74 years (average, 45.5 years). in 35 and 28 participants, the tumor was located on the left and right sides, respectively. all the patients underwent ct scanning. most of the patients (54/63) with eamls 2 demonstrated hyperattenuation, one showed isoattenuation, and eight showed hypoattenuation compared with renal parenchyma on unenhanced ct images. the diameter of each tumor was 2-25 cm (average, 5.6 cm). all the participants underwent surgical treatment. of these, 53 were followed up for 4-128 months (median, 64 months). among the followed-up patients, one died of the tumor, one died due to acute severe pancreatitis, and two had an ipsilateral recurrence. conclusions: eaml is a relatively rare renal angiomyolipoma depleted in fat. a characteristic of hyperattenuation on unenhanced ct images in eaml can help distinguish this tumor from clear cell renal cell carcinoma. surgical resection is the main treatment. most eamls are benign, and only a few have malignant potential. however, post-surgery recurrence and metastasis may occur, especially in elderly patients, and thus close follow-up is recommended. keywords: computed tomography; eaml; epithelioid angiomyolipoma; fat-poor aml; renal neoplasm introduction angiomyolipoma (aml) is one of the most common renal benign tumors, with an incidence of approximately 130/100,000, that originates from the mesenchymal tissue (1). epidemiological studies have revealed that aml accounts for approximately 1% of all renal tumors globally. the world health organization (who) classified aml into two types in 2016: classical and epithelioid(2). the former is a benign tumor composed of various proportions of mature blood vessels with abnormally thick walls, fusiform or epithelioid smooth muscle cells, and adipocytes. epithelioid angiomyolipoma (eaml) is mainly composed of a prominent epithelioid component, with spindle and giant cells; it occasionally contains a minimal amount of adipose tissue (tends to be < 5%) (3,4). 3 to date, most studies on malignant eaml have been case reports(5). therefore, our current understanding of its clinical and pathological characteristics is insufficient. whether eaml is benign or malignant is controversial, and the who has not yet commented on whether malignant aml truly exists. although the imaging features of the classical aml have been well described, the imaging appearance of eaml is relatively uncharacterized because of the rarity of the tumor. additionally, distinguishing this tumor from clear cell renal cell carcinoma (ccrcc) is often difficult due to some of the intrinsic imaging characteristics of eaml, and thus preoperative misdiagnosis is extremely common. the main treatment of renal cancer is surgical resection, and hence some patients with eaml are over-treated, such as through radical nephrectomy, which may impair renal function. this study aimed to analyze the clinical data from 63 patients with eaml, who were treated in our hospital from 2010 to 2021, to evaluate the value of computed tomography (ct) imaging in the diagnostic and prognostic evaluation of eaml. materials and methods this study was approved by the ethics committee of the first affiliated hospital of soochow university, china (2022; approval no. 23) and carried out following the approved guidelines of the committee. written informed consent was obtained from all patients. the pathology database of the first affiliated hospital of soochow university was retrospectively searched using the keywords "eaml" and “ccrcc” (in chinese), and 63 cases of renal eaml, accounting for 4.7% of all the renal aml cases (1340 cases in total) in the hospital during the same period (2010-2021), were identified. eaml was defined as polygonal 4 cells with clear-to-eosinophilic cytoplasm and round-to-oval nuclei(6). atypical eaml was defined as epithelioid cells with abundant cytoplasm, vesicular nuclei, prominent nucleoli, and nuclear size more than twice the size of the nuclei of the adjacent cells. "progressor" eaml was defined as the presence of progression, including local recurrence, distant metastasis, and death due to the disease. the hospitalization records, including the clinical characteristics, imaging results, and treatment types, of all the eligible patients were reviewed. we extracted and analyzed the data from the medical records and postoperative pathological results of the patients, and reexamined the abdominal ct and ultrasound results of the patients in the inpatient database. based on the findings from unenhanced ct, each tumor was classified as hyperattenuating, isoattenuating, or hypoattenuating in comparison to the renal parenchyma (cortex). the followup data were obtained by contacting the patients via phone call or from the outpatient department of urology. the survival status of each patient was confirmed by phone call. spss statistics 20.0 was used for statistical analyses. discrete and continuous variables were compared using the chi-square and t tests, respectively. results the detailed clinical data of all 63 patients with eaml and 64 patients with ccrcc are summarized in table 1. of the 63 patients with eaml, 20 were men and 43 were women aged 24-74 years (average, 45.5 years). among these patients, 58 (92%) were asymptomatic and diagnosed with eaml during physical examination, 4 (6.3%) had waist pain and discomfort, and 1 (1.5%) exhibited hematuria as the main manifestation compared with ccrcc. patients 5 with eaml were less likely to have clinical symptoms (p < 0.05) and an earlier age of onset (p < 0.05). no patient had any clinical history of tuberous sclerosis complex (tsc). all the patients underwent ct, and 10 patients additionally underwent magnetic resonance imaging (mri). of all the tumors, 35 and 28 were on the left and right kidneys, respectively. the clinical imaging results showed that the diameter of each tumor was 2-25 cm (average, 5.6 cm). preoperatively, 36 cases of renal malignant tumors were misdiagnosed, including 30 cases of rcc and 6 cases of renal mesenchymal malignant tumors. women were more common among patients with eaml (20 and 43 were male and female patients, respectively) compared with those with ccrcc (39 and 25 were male and female patients, respectively) (p < 0.05). fat components were detected on the unenhanced ct images of 8 of 63 patients. the intratumoral hyperattenuation was observed in 54 patients (fig. 1), 1 showed isoattenuation, and 8 showed hypoattenuation (the fat component in fig. 2) compared with the renal parenchyma. we found that the tumor in patients with eaml showed hypoattenuation on ct scans, whereas patients with ccrcc showed hypoattenuation (p < 0.05). hemorrhage and necrosis, which appeared as mildly low-density regions compared with the adjacent tumor tissues, occurred in 10 cases (fig. 3). heterogeneous and relatively homogenous enhancements were observed in 23 and 40 cases, respectively. upon evaluating the pattern of the dynamic enhancement, 35 lesions were categorized as “rapid wash-in and rapid wash-out” and 28 lesions were categorized as “rapid wash-in and slow wash-out” (“washin enhancement pattern” meant that ct attenuation increased from the unenhanced to arterial and venous phases; “wash-out enhancement pattern” meant that ct attenuation decreased from the venous to delayed phase). additional classical aml was detected in eight cases. 6 among the 63 patients included in the study, all underwent surgical interventions. specifically, 7 patients underwent radical nephrectomy, 7 partial nephrectomy, 10 laparoscopic radical nephrectomy, and 39 laparoscopic partial nephrectomy. patients with eaml were more likely to choose the option of preserving the kidney unit compared with patients with ccrcc (p < 0.05). eaml was categorized into pure (epithelial component >80%) and partial (10% < epithelial component < 80%) eaml based on the proportion of postoperative pathological epithelioid components. of all the cases, 39 were pure eaml and 24 were partial eaml. however, no statistically significant difference was observed in sex, age, maximum tumor diameter, and surgical methods between the pure and partial eaml cases. the tumor profile was mainly grayish-yellow and grayish-white in 54 of 63 patients. atypia cells (8/63) and hemorrhage and necrosis (5/63) were rare. the results of the immunohistochemical analysis (melan-a/hmb (β‐hydroxy β‐methylbutyrate) 45/ki67/s100/sma (smooth muscle actin)/cd34 staining) of 51 patients are presented in table 1. of the 63 registered patients, we could not determine the survival status of 10 patients (they did not provide their phone numbers, or the numbers provided were outdated). the remaining 53 patients were followed up for 4-128 months (median, 64 months). among these, 49 patients did not show disease progression. however, two patients who underwent laparoscopic partial nephrectomy had a local recurrence 18/24 months after the surgery. these patients were not treated with any additional surgery and instead received chemotherapy. another patient died of severe cancer cachexia 12 months after the surgery. additionally, one patient died of acute severe pancreatitis 23 months after the surgery (excluded from the followup). 7 the pathological features of the progressors and non-progressors among the 52 followedup patients with eaml are depicted in table 2. no pathological or prognostic difference was found between the hyperattenuating and isoattenuating tumors. discussion in 2004, the who defined eaml as a renal stromal tumor with malignant potential. approximately one third of patients develop distant metastases. eaml was first reported by mai et al. in 1996, and it accounted for 4.6%-7.7% of all aml cases globally. the average age of eaml onset has been reported as 40 years, and the incidence in men and women is approximately 1:1. in this study, the average age of the onset was 45 years, and the men-towomen ratio was close to 1:2, which was different from the reported ratio. clinical manifestations patients with eaml have an insidious onset similar to patients with classical aml, and tumors are usually detected due to physical examination or imaging. dickinson (7) et al. discovered that 82%-94% of patients with lesions measuring > 4 cm complained of clinical symptoms, and 50%-60% had concomitant bleeding. of the 63 patients in this study, 5 visited physicians because of significant symptoms; 4 had a backache, and 1 showed hematuria. all the tumors measured > 7 cm. one of the cases involving backache was proved to be malignant. these data suggested that the larger the lesion, the greater the probability of manifesting a clinical symptom. imaging features 8 unlike typical amls with relatively characteristic imaging findings, eaml cases often mimic rcc, renal sarcoma, or aml, with minimal or no fat on imaging evaluation, which may lead to misdiagnosis. to date, the imaging characteristics of eaml have been much less reported than the histopathological features because most of the imaging findings are individual reports. hyperattenuation ( > 45 hu) in unenhanced ct has been regarded as a characteristic finding of eaml and entails higher density than the healthy renal parenchyma, a bulging contour of the affected kidney, markedly heterogeneous enhancement, large lesion size on presentation, a complete capsule with distinct edges, and occasionally regional lymph-node metastases (5,8). the unenhanced ct images showed hyperattenuation in 54 of the 63 cases, isoattenuation in 1 case, and hypoattenuation (as a fat component) in 8 cases, whereas ccrcc often presented isoattenuation or hypoattenuation. the tumor components showed low intensities on t2-weighted images in 6 of the 10 cases for which mri findings were available. several studies have reported that aml with abundant smooth muscle and little or no fat on pathological examination (aml with minimal fat) appears as hyperattenuation and t2-lowintensity masses(9-12). liu (13) et al. found that most eamls, with or without a fat component, appeared hyperattenuated in precontrast ct images and demonstrated a dynamic enhancement pattern of rapid wash-in to slow wash-out. this phenomenon is thought to correlate with the following pathological characteristics: an abundance of abnormal vessels, higher cellular density and decreased tumor stroma, presence of a complete capsule, and lack of draining vessels. the amount of mature fat in an eaml tumor is extremely small; still, the fat tissue can be detected in some cases. we could detect the fat tissue in the ct image of the patient, with 9 hyperattenuation on the edge of the tumor. this patient experienced a recurrence of the tumor after the surgery. hence, it is important to exercise caution in diagnosing aml solely based on a ct image displaying a tumor with fat; further examination may be needed to avoid misdiagnosis. the patient currently has a postoperative recurrence, but a statistically significant analysis cannot be performed due to the small sample size of our study. currently, no evidence indicating that eaml with additional classical aml presents a more complicated scenario than traditional aml, or that there is an increased risk of recurrence following surgery. nevertheless, any additional risk that may be posed by the fat content should not be ignored. we believe that small tumors, such as those sized 4-5 cm on a typical ct image, can be judged as eaml relatively accurately. however, if the tumor is > 7 cm or accompanied by necrosis, a typical image with hyperattenuation is not present. a correct diagnosis cannot be made in such cases, and a radical nephrectomy may be the optimal choice. pathological characteristics microscopically, the tumor cells were observed to be arranged in solid nests or diffuse sarcoma-like structures, and necrosis was common. varying degrees of heteromorphism, cytoplasmic eosinophilia, and hyperchromatic nuclei were observed, and vesicles, nucleoli, and mitosis could be seen. melanin deposition or plasmaor rhabdoid-like differentiation can easily be misdiagnosed as rcc or metastatic melanoma. therefore, the immunohistochemical analysis plays an essential role in diagnosing eaml, which is characteristically positive for hmb 45 expression and displays sma and melanin co-expression. s-100 and ki-67 may also be expressed in small amounts. in this study, most patients exhibited the expression of hmb 45, s-100, and sma. this observation was different from that of lei et al.(14) they found that 10 most patients did not express s-100, and some had a slight or focal expression of melan-a or ki-67. regarding the diagnostic method for eaml, nese et al.(15). proposed the following risk factors for malignant eaml: (1) presence of tuberous sclerosis or association with aml; (2) tumor size > 7.7 cm; (3) carcinoma-like histology; (4) extra-renal extension or renal-vein invasion; and (5) necrosis. they also proposed that tumors with 0-1, 2-3, and 4-5 risk factors should be classified into the low-, middle-, and high-risk groups, respectively. a total of 52 patients were followed up in this study, including 37 in the low-risk group, 12 in the intermediate-risk group, and 3 in the high-risk group. further, 1/3 of the patients in the high-risk group died during the follow-up period, 2/3 were in good physical conditions during the follow-up period, and 2/12 in the middle-risk group had ipsilateral recurrence. other patients were in good health. treatment to date, surgery has been the optimal approach to treat eaml. many previous studies (1,16,17) reported that local recurrence or distant metastasis generally occurred 1.5–9 years after the surgery. zomboni et al.(18) reported that eaml belonged to a family of perivascular epithelioid cell tumors (pecoma), similar to lymphagioleiomyomas and clear cell “sugar” tumors of the lung and pancreas. of the 53 followed-up patients, only 1 died of tumor progression. the surgical method used was radical nephrectomy. two patients experienced tumor recurrence during the follow-up period, which was not life-threatening. the surgical method used was laparoscopic partial nephrectomy. therefore, we believed that although renal eaml was a potentially malignant tumor, nephron-preserving nephrectomy was a better choice than radical nephrectomy because the former procedure provided patients with a 11 relatively better quality of life than the latter. bissler et al.(19) reported 25 patients with aml who received rapamycin treatment. after 12 months of treatment, their tumor volume was reduced to 53% of the original, but the tumor volume increased to 86% of the original 1 year after discontinuing the chemotherapy. therefore, eaml may be sensitive to chemotherapy. however, long-term follow-up is required to confirm this conclusion. heidi et al.(20) examined 15 patients with pecoma and found that the mammalian target of the rapamycin (mtor) cascade, which was related to tumorigenesis, was always activated in these tumors. recently, tomasz et al.(21) investigated the effect of sirolimus in the long-term treatment of pecoma and found that sirolimus had a definite therapeutic effect in the long-term targeted therapy of pecoma. guo et al.(22) explored the effect of everolimus in invasive malignant renal eaml. they found that the mtor inhibitor could effectively treat patients with invasive malignant renal eaml. patients with tsc might benefit more from the therapy than those without tsc. this observation suggested that patients might benefit from mtor inhibitors, but further studies should be performed to validate this observation. based on the current findings, we believed that nephron-preserving nephrectomy was safe for patients without lymph-node metastasis and tumor thrombosis. however, examining the long-term survival prospects requires long-term follow-up. all the therapies, including surgery, chemotherapy, and molecularly targeted drugs, may be beneficial to patients for their long-term survival. prognosis renal eaml has a certain malignant potential. nese et al.(15) followed up with 41 patients with eaml and found that 17% and 49% had recurrence and metastasis, respectively, and 33% 12 died of the disease. brimo et al.(23) found that 26% of the patients in their cohort had recurrence and metastasis. however, he et al. reported that only a small proportion of patients (5%) had tumor progression. aydin et al.(6) found no tumor progression in 15 of 16 patients with eaml. only one patient, with pure eaml, in their group developed lung and abdominal lymph-node metastases and then died of tumor 2 months after the surgery; no tumor progression was detected in the remaining patients during the follow-up period. among the followed-up patients in our study, only one died of the tumor and two had an ipsilateral recurrence, accounting for a low frequency of progression among all the followed-up patients. nevertheless, we found that elderly patients were more likely to have tumor recurrence and progression than young patients. in this study, the average age of patients in the nonprogressor and progressor groups was significantly different (45.2 and 63.7 years, respectively; p＜0.05). combining our pathology and follow-up results and comparing the ct results in a limited number of cases, we proposed the following hypothesis: (1) the mass measured > 7 cm, or the mass protruded from the kidney; (2) the ct result suggested internal necrosis; (3) patients had lymph-node or distant metastasis; and (4) patients were aged >50 years), leading to a relatively poor prognosis. this study had 12 patients with tumors >7 cm in diameter. of these patients, one died due to the tumor (aged 74 years, and the maximum diameter of the tumor 22 cm; necrosis in the tumor and local lymph-node metastasis). additionally, one patient (aged 67 years, and the maximum diameter of the mass 7 cm; no necrosis or metastasis) showed ipsilateral recurrence of the mass. as eaml tumors always appear enhanced in ct images, we believe that the characteristics of “rapid wash-in and rapid wash-out,” or “rapid wash-in and slow wash-out” cannot be used as the criteria for distinguishing eaml cases from renal 13 cancer or as prognostic factors. many patients with no progression carried the defined highrisk factors, which will be closely examined during the follow-up with these patients. our findings showed that the risk of recurrence and death in eaml was relatively small, with no significant difference in prognosis between patients undergoing radical nephrectomy and those undergoing partial nephrectomy. therefore, we believe that partial nephrectomy is a more suitable treatment option for a patient with eaml than radical nephrectomy, provided that the conditions of the patient permit. however, if the preoperative diagnosis suggests the presence of malignant tumors, radical nephrectomy may be the preferred treatment option and close follow-up is recommended. limitations the present study had several limitations. first, the number of patients was not sufficient. thus, further evaluations using a large number of patients from multiple centers are necessary to confirm our findings. second, it was difficult to design prospective studies because of the rare nature of the disease. we could not establish uniform surgical resection standards; the histopathology of these lesions was mainly evaluated postoperatively. elderly patients tended to have tumor recurrence and progression. finally, most patients did not receive imaging follow-up because their tumors were misdiagnosed at that time as benign. conclusions eaml is a tumor with potential malignancy. ct can be used for the differential diagnosis of eaml and ccrcc, which are mainly detected using unenhanced ct. once diagnosed, active treatment options such as radical/partial nephrectomy and molecular-targeted drugs 14 should be considered. it is crucial to closely monitor patients, especially elderly individuals, through regular follow-up examinations. acknowledgment this study was supported by the key disciplines of jiangsu province (project number: zdxka2016012). conflicts of interest none. references 1. mai kt, perkins dg, collins jp. epithelioid cell variant of renal angiomyolipoma. histopathology. 1996;28:277-80. 2. montironi r, cheng l, scarpelli m, lopez-beltran a. pathology and genetics: tumours of the urinary system and male genital system: clinical implications of the 4th edition of the who classification and beyond. eur urol. 2016;70:120-3. 3. halpenny d, snow a, mcneill g, torreggiani wc. the radiological diagnosis and treatment of renal angiomyolipoma-current status. clin radiol. 2010;65:99-108. 4. huang kh, huang cy, chung sd, pu ys, shun ct, chen j. malignant epithelioid angiomyolipoma of the kidney. j formos med assoc. 2007;106:s51-4. 5. tsai cc, wu wj, li cc, wang cj, wu ch, wu cc. epithelioid angiomyolipoma of the kidney mimicking renal cell carcinoma: a clinicopathologic analysis of cases and literature review. kaohsiung j med sci. 2009;25:133-40. 6. aydin h, magi-galluzzi c, lane br, et al. renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. am j surg pathol. 2009;33:289-97. 7. dickinson m, ruckle h, beaghler m, hadley hr. renal angiomyolipoma: optimal treatment based on size and symptoms. clin nephrol. 1998;49:281-6. 8. cui l, zhang jg, hu xy, et al. ct imaging and histopathological features of renal epithelioid angiomyolipomas. clin radiol. 2012;67:e77-82. 9. jinzaki m, tanimoto a, narimatsu y, et al. angiomyolipoma: imaging findings in lesions with minimal fat. radiology. 1997;205:497-502. 10. hafron j, fogarty jd, hoenig dm, li m, berkenblit r, ghavamian r. imaging characteristics of minimal fat renal angiomyolipoma with histologic correlations. urology. 2005;66:1155-9. 11. silverman sg, mortele kj, tuncali k, jinzaki m, cibas es. hyperattenuating renal masses: etiologies, pathogenesis, and imaging evaluation. radiographics. 2007;27:1131-43. 15 12. low g, sahi k, dhliwayo h. low t2 signal intensity on magnetic resonance imaging: a feature of minimal fat angiomyolipomas. int j urol. 2012;19:90-1. 13. liu y, qu f, cheng r, ye z. ct-imaging features of renal epithelioid angiomyolipoma. world j surg oncol. 2015;13:280. 14. lei jh, liu lr, wei q, et al. a four-year follow-up study of renal epithelioid angiomyolipoma: a multi-center experience and literature review. sci rep. 2015;5:10030. 15. nese n, martignoni g, fletcher cd, et al. pure epithelioid pecomas (so-called epithelioid angiomyolipoma) of the kidney: a clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification. am j surg pathol. 2011;35:161-76. 16. pea m, bonetti f, martignoni g, et al. apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. am j surg pathol. 1998;22:180-7. 17. desai s, hejmadi r, krishnamurthy s, chinoy rf. renal angiomyolipoma. a clinicopathologic, immunohistochemical, and follow-up study of 46 cases. am j surg pathol. 2001;25:972-3. 18. zamboni g, pea m, martignoni g, et al. clear cell "sugar" tumor of the pancreas. a novel member of the family of lesions characterized by the presence of perivascular epithelioid cells. am j surg pathol. 1996;20:722-30. 19. bissler jj, mccormack fx, young lr, et al. sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. n engl j med. 2008;358:140-51. 20. kenerson h, folpe al, takayama tk, yeung rs. activation of the mtor pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. hum pathol. 2007;38:1361-71. 21. switaj t, sobiborowicz a, teterycz p, et al. efficacy of sirolimus treatment in pecoma-10 years of practice perspective. j clin med. 2021;10. 22. guo g, gu l, zhang x. everolimus in invasive malignant renal epithelioid angiomyolipoma. front oncol. 2020;10:610858. 23. brimo f, robinson b, guo c, zhou m, latour m, epstein ji. renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. am j surg pathol. 2010;34:715-22. corresponding author address： jian-quan hou, md department of urology, dushu lake hospital affiliated to soochow university; 9 chongwen road, suzhou city, jiangsu province, china email: dsh_hou@126.com tel: +8615850115650 16 tables and legends to figures： table 1. clinical data of the patients diagnosed with eaml (n = 63) and ccrcc (n = 64) baseline data eaml (n = 63) ccrcc (n = 64) p gender male/female = 20/43 male/female = 39/25 .001 mean age/years 45.5 (24 74) 58.3 (23 85) <.0001 max diameter ≤ 4cm: n = 36; 4 7 cm: n = 15; 7 10 cm: n = 5; ≥ 10 cm: n = 7; ≤ 4cm: n = 38; 4 7 cm: n = 18; 7 10 cm: n = 6; ≥ 10 cm: n = 2; .364 location upper pole: n = 15; middle pole: n = 20; lower pole: n = 28; upper pole: n = 18; middle pole: n = 22; lower pole: n = 24; .716 ct attenuation (hu) hyper-attenuation: n = 54; iso-attenuation: n = 1; hypo-attenuation: n = 8; hyper-attenuation: n = 0; iso-attenuation: n = 4; hypo-attenuation: n = 60; <.0001 atypia (yes/no) 8/57 64/0 <.0001 necrosis (yes/no) 5/58 12/52 .116 cystic degeneration (yes/no) 2/61 3/61 .508 hemorrhage (yes/no) 5/58 9/55 .396 calcification (yes/no) 0/63 2/62 .496 associated symptoms waist pain: n = 4; hematuria: n = 1; none: n = 58 waist pain: n = 11; hematuria: n = 8; none: n = 45; .006 involvement range confined to kidney right: n = 27； left: n = 29, (n = 56); right: n = 31； left: n = 19, (n = 50); .175 17 beyond kidney right: n = 1； left: n = 6, (n = 7); right: n = 6； left: n = 8, (n = 14); .337 distant metastasis 0 2 tumor embolus 0 4 lymph nodes metastasis 2 6 surgical method radical nephrectomy: n = 17 (laparoscopic 10, traditional 7); partial nephrectomy: n = 46 (laparoscopic 39, traditional 7); radical nephrectomy: n = 40 (laparoscopic 32, traditional 8); partial nephrectomy: n = 24 (laparoscopic 23, traditional 1); <.0001 ihc stain melan-a 29 (+); /2 (-); /32 (unclear) hmb-45 42 (+); /4(-); /17(unclear) ki-67 45 (+, 2 30%); /3 (-); /15 (unclear) s100 29 (+); /16(-); /18 (unclear) sma 46 (+); /17 (unclear) cd34 27(+); /8(-); /29 (unclear) follow-up data follow up patients 53 64 p follow up duration/month 64 (4 128) 68.5 (2 72) survival status alive: n = 51; dead: n = 2; alive: n = 36; dead: n = 28; <.0001 recurrence 2 patient suffered ipsilateral recurrence in 18/24months postoperation respectively. 6 <.0001 death 1 patient died from serious cancer cachexia 12 months postoperatively; 1 patient died from acute severe 28 18 pancreatitis 23 months postoperation metastasis 0 4 abbreviations: ccrcc, clear cell renal cell carcinoma; eaml, epithelioid angiomyolipoma; hu, hounsfield unit. melan-a, melanoma antigen recognized by t cells (mart-1); hmb 45, β‐hydroxy β‐ methylbutyrate 45; sma, smooth muscle actin. comparison of pathological features between the eaml and ccrcc. the chi-square test was used for the gender, max diameter, location, ct attenuation (hu), atypia, necrosis, cystic degeneration, hemorrhage, calcification, associated symptoms, surgical method, survival status; the t test was used for the other parameters. 19 table 2. comparison between nonprogressors and progressors mean non-progressors (n = 49) progressors (n = 3) * p age/years 45.2 63.7 .024 ratio of male/female 0.36 (13/36) 2 (2/1) .196 max diameter/cm 5.827 ± 0.835 10.17 ± 5.019 .228 ct attenuation (hu) hyper/non-hyper (44/5) hyper/non-hyper (3/0) 1.0 percentage of epithelioid cells pure/partial (27/22) pure/partial (3/0) .253 necrosis 3/46 1/3 .217 percentage of atypia cells 8/49 1/3 .442 of the 63 patients, 53 were followed up for 4-128 months (median, 64 months). among these, 49 had no progression, 2 had disease recurrence in 18/24 months postoperatively, 1 died of the tumor, and 1 died of acute severe pancreatitis 23 months after the surgery (we ruled out this patient). comparison of pathological features between the non-progressors and progressors. the chisquare test was used for the male/female ratio, ct attenuation (hu = hounsfield units), and percentages of epithelioid, necrotic, and atypia cells; the t test was used for the other parameters. 20 figure 1. a 63-year-old woman with a homogeneous solid lesion. (a) unenhanced ct image showed a hyperattenuating mass in the right kidney (arrows). no fat density was detected. (b and c) dynamic contrast-enhanced ct image showed a homogeneously enhanced tumor in the corticomedullary and early excretory phases (arrows in b and c, respectively). (d) hematoxylin-and-eosin staining. the visual field is abundant with epithelioid cells, containing red cytoplasm and large nuclei; nucleoli are visible, with a certain degree of pleomorphism and mitotic figures (original magnification, ×100). figure 2. a 50-year-old man with a heterogeneous solid lesion, who suffered from an ipsilateral recurrence 18 months after the surgery. (a) unenhanced ct image showed a hypoattenuating mass in the right kidney (the arrows show the fat-enriched regions), with a hyperattenuating part on edge. (b and c) dynamic contrast21 enhanced ct image showed a heterogeneous enhanced tumor in the corticomedullary and early excretory phases (arrows in b and c, respectively). (d) hematoxylin-and-eosin staining. the epithelioid cells were diffuse and surrounded by many fatty cells (original magnification, ×100). figure 3. a 74-year-old man with a heterogeneous solid lesion, who died 12 months after the surgery. (a) an unenhanced ct image showed a heterogeneous solid-type lesion, with a hyperattenuating part on the edge. (b and c) dynamic contrast-enhanced ct image showed a heterogeneous solid-type lesion-enhanced tumor in the corticomedullary and early excretory phases (arrows in b and c, respectively). (d) hematoxylin-and-eosin staining. consistent with eaml, the tumor was massive with hemorrhagic necrosis. the tumor cells invaded the perirenal fat tissue, and some of them contained large atypia, prominent nucleoli, and a few pathological mitotic figures (original magnification, ×100). postoperative pulmonary complications after percutaneous nephrolithotomy under spinal anesthesia abdullah açıkgöz1*, burak kara2, kadir önem3, mehmet çetinkaya4 purpose: to evaluate risk factors and outcomes of pulmonary complications (pcs) in percutaneous nephrolithotomy (pcnl) under spinal anesthesia (sa). material and method: 286 patients who underwent pcnl under sa between 2017 and 2021 were identified retrospectively and divided into group 1 (clinically significant pcs) and group 2 (no clinically significant pcs). demographic, preoperative, and intraoperative variables and postoperative outcomes were compared between both groups. independent risk factors for pcs were evaluated by univariable and multivariable logistic regression analyses. results: pcs were noted in 90 patients (31.5%). advanced age (p = .011), high body mass index (bmi) (p < .001), and the presence of chronic obstructive pulmonary disease (copd) (p < .001) were risk factors for pcs. conclusion: sa is an effective method of anesthesia for all pcnl patients and carries a lower rate of pcnl-associated pcs. risk factors for pcs after pcnl were advanced age, obesity, and preoperative copd. keywords: pulmonary complication; percutaneous nephrolithotomy; spinal anesthesia introduction percutaneous nephrolithotomy (pcnl) has been es-tablished as a minimally invasive treatment for the removal of kidney stones(1). however, pcnl is associated with several complications, including extravasation of fluid and urine, need for blood transfusion, and septicemia. postoperative pulmonary complications (pcs) include atelectasis, pneumothorax, hemo or hydrothorax, pleural effusion, pulmonary edema, pneumonia, and acute respiratory distress syndrome(2). patients undergoing pcnl are at increased risk for pcs due to several factors. first, the surgical site is near the diaphragm. hence, the pleural cavity and lung can be injured, especially when approaching the stone through the upper pole of the kidney(3). second, the urologist uses large volumes of irrigation fluids during the procedure which may cause pulmonary congestion and edema(4). the overall rate of pleural injury ranges between 0.3 and 1% during percutaneous access puncture for pcnl. injury may manifest as hydro or hemothorax, pneumothorax, or hydropneumothorax and as many as 64% of patients with pleural injury require chest tube drainage(4,5). pcs are a significant cause of postoperative mortality(4). pcnl is commonly performed under general anesthesia (ga). pcs such as respiratory tract infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, 1istinye university school of medicine, department of urology, istanbul, turkey. 2vm medicalpark private hospital, department of urology, samsun, turkey. 3ondokuz mayis university school of medicine, department of urology, samsun, turkey. 4mugla sitki kocman school of medicine, department of urology, mugla, turkey. correspondence: istinye university school of medicine, department of urology, istanbul, turkey. tel: +905306627811. e-mail: draacikgoz@yahoo.com. received november 2021 & accepted october 2022 bronchospasm, aspiration pneumonitis, and acute respiratory distress syndrome are more commonly associated with ga than with regional anesthesia. other risk factors include comorbidities such as cardiovascular system disease (cvd), hypertension (ht), diabetes mellitus (dm), chronic obstructive pulmonary disease (copd), and obesity(6,7). previous studies on pcs following pcnl focussed on pcnl under ga(3-5,8,9). no study has assessed pcs following pcnl under spinal anesthesia (sa). we hypothesized that performing this procedure under sa may help protect pulmonary function. in this study, we aimed to evaluate risk factors for pcs following pcnl under sa. patients and methods study population our study retrospectively reviewed 420 patients who underwent pcnl in our clinic between 2017 and 2021. all patients were scheduled for pcnl operation under spinal anesthesia by two urologists. typically patients with any contraindication to spinal anesthesia (e.g. spinal deformity) underwent general anesthesia and were excluded from the study. 134 patients were excluded from the study due to any contraindication to spinal anesthesia, repeated pcnl, absent preoperative and postoperative chest x-rays, or incomplete medical records. patients were evaluated with renal function tests, blood counts, coagulation profiles, urine analyses, and urology journal/vol 20 no. 1/ january-february 2023/ pp. 1-6. [doi: 10.22037/uj.v19i.7089] endourology and stone disease urine culture sensitivity. patients with positive urinary cultures were given appropriate antibiotic treatment and underwent surgery after urine cultures were sterile. the hemoglobin and creatinine levels were measured 24 hours preoperatively and 24 hours postoperatively. the stone surface area was calculated as the maximum diameter ×width ×π × 0.25. the hospital stay time was calculated from the day before surgery to the day of discharge. all patients were examined by non-contrast abdominal computed tomography (ct), and chest radiography before surgery. pulmonary functional test was performed for patients who had respiratory distress and a history of copd. chest x-ray was performed on all patients one day after pcnl. patients with pcs were called for follow-up one week later. surgical technique a ureteric catheter was placed via cystoscopy into the upper ureter or renal pelvis. renal access was achieved in a prone position under fluoroscopic guidance. the access tract was dilated with an amplatz dilator or telescopic metal dilator to 30 fr at which point the amplatz sheath was placed. a 24 fr nephroscope was introduced to the collecting system and the stone was pulverized witan h ultrasonic or pneumatic lithotripter. stone fragments equal to or smaller than 4 mm were considered clinically insignificant residual fragments. after the lithotripsy, re-entry malecot nephrostomy or double j catheter was inserted over the amplatz wire within the kidney and the ureteral catheter was withdrawn. the operative time was defined as the time from the introduction of the 18-gauge coaxial needle into the patient’s skin to the placement of the nephrostomy tube. sa procedure after receiving 3-5 mg midazolam and 15 ml/kg saline intravenously for 15 min, all patients were positioned laterally onto the operating side and a mixture of 15-20 mg of 0.5% bupivacaine hydrochloride and 25 mcg fentanyl was given via a spinal needle inserted into the subarachnoid space through the l3-l4 intervertebral space. patients with pcs determined by postoperative chest x-ray were examined by a pulmonologist. pcs were diagnosed as follows criteria: sinus blunting, pleural effusion, pulmonary consolidation, atelectasis, and diaphragm elevation. statistical analysis the research data were uploaded and evaluated using ibm statistical package for social sciences 21. descriptive statistics of categorical variables are presented as numbers and percentages. descriptive statistics of numerical variables are presented as mean (±) standard deviation for normally distributed variables and as median (min-max) for non-normally distributed variables. cross tables were used to compare categorical variables and "pearson chi-square test" and "yates continuity correction" were applied. the conformity of numeripcnl under spinal anesthesia pulmonary complicationsacikgoz egit al. table 1. patient demographics descriptive statistics variables gender, % male 52.8 female 47.2 age (year) mean ± sd 50,985 ± 15,718 side % right kidney 46.5 left kidney 53.5 bmi (kg/m2) mean ± sd 29.92±6.01665 comorbidities % • ht 43.4 • dm 23.4 • copd 17.5 • cvd 17.1 preop hemoglobin (g/dl) mean±sd 13.57 ± 1.86 postop hemoglobin (g/dl) mean±sd 12.25 ± 1.9 preop creatinine (mg/dl)mean±sd 1.03 ± 0.58 postop creatinine (mg/dl) mean±sd 1.03 ± 0.33 stone burden (mm2)mean±sd 428 ± 423 operation time (minute)mean±sd 46 ± 24 endourology and stones diseases 2 variables group 1* group 2** (p-value) age (year) (mean±sd) 49.30 ± 15.72 54.72 ± 15.24 0.011a gender% female 44.9 52.2 0.249b male 55.1 47.8 side % right kidney 44.4 51.1 0.290b left kidney 55.6 48.9 bmi (kg/m2) (mean±sd) 28.84 ± 5.24 32.65 ± 7.32 < 0.001a comorbidities % • dm 61.2 38.8 0.184c • ht 63.7 36.3 0.124b • copd 40.0 60.0 < 0.001b • cvd 51.0 49.0 0.006c preop hemoglobin (g/dl)(mean±sd) 13.58 ± 1.89 13.56±1.81 0.940a preop creatinine (mg/dl) mean ± sd 1.0 ± 0.49 1.1 ± 0.73 0.268d *no clinically significant pcs **clinically significant pcs numerical variables conforming to normal distribution are presented as mean ± standard deviation, and non-conforming numerical variables as median (range). categorical variables are expressed as number (% column percentage) a:independent samples ttest b:pearson chi¬-squaretest c: yatescontinuitycorrection test d: mann-whitney u test, p < .05, p <.001 table 2. demographic variables by groups. cal variables to normal distribution was examined using visual (histogram and probability graphs) and analytical methods (kolmogorov smirnov / shapiro-wilk tests). "independent samples t-test" was used for statistical significance between groups for variables that fit a normal distribution. the homogeneity of the intergroup variances of normal variables was evaluated using the "levene test". the "mann-whitney u" test was used to compare numerical variables that were not normally distributed. "univariable and multivariable binary logistic regression analysis" was used to determine the risk factors affecting postoperative pulmonary complications. statistical significance levels were accepted as p < .05. results our study examined 151 male and 135 female patients who underwent pcnl under sa. mean age ± sd was 50,985 ± 15,718 years. pcnl was performed on the right renal unit in 133 patients and the left renal unit in 153 patients. 27 patients underwent pcnl with 2 punctures. the mean bmi was 29,92 kg/m2. comorbidities were observed with a frequency of 17.1% to 43.4% as seen in table 1. patients were evaluated for pcs after pcnl and divided into groups with clinically significant pcs (group 1) and no clinically significant pcs (group 2). no patient had severe pulmonary symptoms after pcnl. pcs were defined according to the postoperative chest x-ray and examination of the pulmonologist and noted in 31.5% of patients. 27 (9.4 %) patients had left costophrenic angle blunting due to minimal pleural effusion, 20 (6.9 %) had moderate pleural effusion, 10 (3.4 %) had ipsilateral diaphragm elevation, 21 (7.3%) had atelectasis and 12 (4.1 %) had pulmonary consolidation. the mean age and bmi of the patients who developed atelectasis were high. in addition, 14 of these patients had chronic obstructive pulmonary disease, 15 had coronary artery disease, and 15 had dm. no patient had a pneumothorax. all patients with pcs were followed conservatively and did not require additional intervention such as chest tube insertion. there were significant differences in age, bmi, and incidence of preoperative copd between the two groups (p = .011, p < .001, and p < .001, respectively). demographic variables by groups have been illustrated in table 2. no significant differences were found between the two groups in terms of the operation time, stone burden, access site, and hospitalization time. intraoperative variables by groups have been illustrated in table 3. independent risk factors for pcs were evaluated by univariable and multivariable logistic regression analyses and outlined in table 4. a univariable logistic regression analysis revealed that advanced age, high bmi, supracostal approach, and the presence of preoperative cvd and copd were associated with pcs after pcnl under sa. a multivariable logistic regression analysis revealed that a high bmi (or = 1.084, p < .001) and the presence of preoperative copd (or = 3.402, p = .004) were significantly associated with pcs after pcnl under sa (table 4). during supracostal access, 17 patients (5.9 %) complained about ipsilateral shoulder pain during the puncture. the access point was changed immediately to prevent the development of pcs. discussion pcs are a significant cause of postoperative mortality and strategies to reduce them are under continual study(10). in our study, pcs were noted in 31.5% of patients. no pcs required surgical intervention in our series. yu et al. classified pcs according to the definition of kronke et al(11) and they reported that the incidence of clinically significant pcs was 32.5%(3). palnizky et al. reported that 8 patients (8%) had pcs, 7 with pneumothorax managed with a chest drain, and 1 patient had atelectasis and pleural effusion and died on the 24th postoperative day due to respiratory failure(4). annaji et al. reported that 7 patients (6.3%) had pcs, 6 with pneumothorax, and 1 with atelectasis who died on the first postoperative day due to respiratory failure; all 6 occurrences of pneumothorax were managed with a chest drain(5). munver et al. reported that 8 patients had pcs, 7 with intraoperative hemothorax/hydrothorax, 2 with deep venous thrombosis/pulmonary embolus, and 1 with pneumothorax(8). khrishna et al. reported that 12 patients had pcs, all of them with pneumothorax and they were managed with a chest drain(9). solakhan et al., compared two different anesthesia methods in patients endourology and stones diseases 354 vol 20 no 1 january-february 2023 3 variables group 1* group 2** (p-value) operation time, minute mean ± sd 45 ± 23 48 ± 25 0.586c stone burden, mm2 mean ± sd 428 ± 430 429 ± 410 0.831c access point, % upper pole 63.5 36.5 0.586a middle pole 69.2 30.8 lower pole 71.4 28.6 surgical approach, % supracostal 59.7 40.3 0.103b subcostal 71.2 28.8 hospitalization, day(mean±sd) 1.30 ± 0.73 1.27±0.70 0.775c table 3. intraoperative variables by groups. *no clinically significant pcs **clinically significant pcs numerical variables that do not conform to normal distribution are presented as median (range) categorical variables are expressed as numbers (% column percentage). a: pearson chi¬-squaretest b: yatescontinuitycorrection test c: mann-whitney u test pcnl under spinal anesthesia pulmonary complicationsacikgoz egit al. undergoing pcnl, it was reported that atelectasis developed in 8 patients (1.4%) only in the ga group(12). the common feature of the previous 6 studies is that pcnl was performed under ga. in our retrospective study, we evaluated pcs after pcnl under sa. it is well known that many pcs, such as atelectasis and pneumonia, seem to be related to ga-induced impairment of respiratory activity(13). regional anesthesia eliminates the need for airway manipulation and one study associated it with a 50% reduction in pcs(14). in sa, spontaneous breathing is preserved causing less cephalad displacement of the diaphragm and less atelectasis. consequentially, closing capacity and functional residual capacity are less affected and pulmonary gas exchange is better maintained(15). moreover, it is known that sa offers less cardiopulmonary depression, improved perioperative hemodynamic stability, decreased intraoperative blood loss, improved postoperative analgesia, decreased opioid consumption, decreased postoperative nausea and vomiting, and therefore reduced pacu and duration of hospital stay(16). these factors make regional anesthesia a popular alternative. in our study, 44% of patients had a bmi of >30 kg/ m2 and we found that bmi was associated with pcs according to univariable and multivariable analysis. yu et al. also found a similar association between bmi and pcs(3). in obese patients, functional residual lung capacity and total lung capacity are compromised. further, venous return is reduced due to inferior vena cava compression. intubation difficulties may also occur in obese patients. due to highly probable complications in morbidly obese patients, sa may be a better alternative for these patients(12). in our study, increased age was associated with pcs according to univariable analysis. age is an independent risk factor for the development of pcs even after adjustment for comorbid conditions. more detailed age stratification shows an increased risk of pcs as age increases. compared with patients < 60 years, the or (95% ci) for pcs for 60to 69-year-olds was 2.1 (1.72.6) and for 70to 79-year-olds, it was 3.1 (2.1-4.4). older patients are more likely to be frail, and frailty has also been shown to be associated with pcs, even when adjusted for age(17). systemic diseases such as ht, cvd, dm, and copd have previously been associated with a higher risk for pcs(18). the presence of comorbid disease in our patients ranged from 17.1% to 43.4% and pcs were associated with copd according to multivariable analysis. in a previous report, patients with copd were 300-700 % more likely to suffer pcs compared to patients without copd(19). surgery conducted only with epidural anesthesia demonstrated a 50% reduction in the risk of postoperative pneumonia in copd patients(14). in contrast, the anterior spread of local anesthetic may result in phrenic nerve palsy causing diminished respiratory function, especially in copd patients, so the level of anesthesia should be carefully controlled(20). in this present study, the stones of 63 (22 %) patients were located in the upper pole of the kidney. the puncture was performed supracostally in 67 patients (23.4 %). in supracostal access, our findings suggest that sa is effective in preventing pcs. in ga, authors found that pcs occurred more frequently upon intercostal access compared to subcostal access(3). sa was sufficient in patients who performed supracostal access. it is known that sa can be used to anesthetize up to the t4 level and may allow adequate access to supracostal and intercostal spaces and is suitable for pcnl, particularly for stones in the upper pole of the kidney(21). basiri et al. reported that only increasing anesthesia duration is associated with increased pain during operation but they could not find other statistically significant predictors of insufficient analgesia based on patients' demographics, stone characteristics, or access location(22). also, dar et al. reported that there was no significant difference between the epidural and general anesthesia groups in terms of stone localization and stone burden(23). one advantage of sa in preventing pcs is that during pcnl, the patient can immediately report sudden difficulty breathing and shoulder pain suggestive of a pleural puncture(24). whereas, pleural injuries in ga are mostly diagnosed in the immediate postoperative period with shortness of breath, fever, and radiological evidence(25). although our patients had no severe pulmonary symptoms postoperatively, pulmonary changes were detected endourology and stones diseases 265endourology and stones diseases 4 or: p < .05; p < .001; p <.10 variables univariable analysis multivariable analysis or (%95 ci) (p-value) or (%95ci) (pvalue) age (year) 1.021 (1.005-1.038) 0.012 0.996 (0.976-1.017) 0.719 gender 1.341(0.813-2.212) 0.250 side 0.763(0.463-1.259) 0.290 preop hemoglobin (g/dl) 0.995 (0.870-1.138) 0,940 preop creatinine (mg/dl) 1.097 (0.722-1.666) 0,664 postop hemoglobin (g/dl) 1.025 (0.899-1.169) 0.711 postop creatinine (mg/dl) 0.701(0.319-1.541) 0.377 bmi (kg/m2) 1.107(1.060-1.156) < 0.001 1.084(1.032-1.139) 0.001 comorbidities dm 1.536(0.868-2.719) 0.141 ht 1.481(0.896-2.447) 0.125 cvd 2.487(1.327-4.661) 0.004 0.911(0.391-2.123) 0.829 copd 4.400(2.327-8.321) < 0.001 3.402 (1.481-7.811) 0.004 swl history 1.057(0.517-2.159) 0.880 stone burden (mm2) 1.000(0.999-1.001) 0.988 surgical approach (supracostal, subcostal) 1.671(0.946-2.953) 0.077 1.245 (0.666-2.326) 0.492 operation time (minute) 1.004(0.994-1.014) 0.428 table 4. univariable and multivariable logistic regression analyses. pcnl under spinal anesthesia pulmonary complicationsacikgoz egit al. in the chest x-ray. this result demonstrated the importance of chest x-rays after pcnl. in this present study, we noticed ipsilateral shoulder pain in 17 patients (5.9 %) during the puncturing when using a supra coastal access. puncturing was immediately stopped and the patient was instructed to slightly inhale and hold their breath while we changed the access point, using the triangulation technique to reach the upper pole of the kidney. we changed the puncture point using the triangulation technique and our success and complication rate did not change since we could enter the same calyx. tepeler et al. compared the bull-eye and triangulation techniques in terms of success and complication rates. they demonstrated that both access techniques were associated with similar operative times, hospitalization times, and success and complication rates(26). during a supracostal approach, in particular, patients under sa can follow verbal commands and control their respiration to the prevention of pulmonary events(27). because the patients can report these symptoms during access, lung or pleural injuries can be detected early, and the development of pcs can be prevented. for this reason, the choice of anesthesia matters to fast-track the patient in a safe condition. to prevent pcs, patients need to breathe comfortably after the surgery. therefore, the use of deep breathing exercises and incentive spirometry is recommended in the postoperative period to prevent pcs(28). patients undergoing sa practice deep breathing exercises and incentive spirometry more readily than ga because they have less postoperative pain and lower analgesic requirements(29). solakhan et al. reported that the narcotic analgesic requirement was 33.4 % in the ga group and 10.9 % in the sa group(12). finally, it has been suggested that sa and epidural anesthesia are more beneficial for pulmonary functions in both obese and advanced copd patients(15,30). for these reasons, sa can mitigate pcs in pcnl. limitations of this study include the fact that we didn't have a ga group and no postoperative pulmonary function tests were performed. conclusions in this study, we found that sa is an effective anesthesia method for all pcnl patients and carries a lower rate of pcs. risk factors for pcs following pcnl were advanced age, obesity, and preoperative copd. patients should be evaluated with pulmonary function tests and chest x-rays in terms of pulmonary functions in the preoperative and postoperative period, with pulmonary symptoms. especially elderly, obese and copd patients should be carefully monitored for pcs. conflict of interest the author declares no conflict of interest. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. rock p, rich pb. postoperative pulmonary complications. current opinion in anesthesiology. 2003;16:123-31. 3. yu j, choi jm, lee j, et al. risk factors for pulmonary complications after percutaneous nephrolithotomy: a retrospective observational analysis. medicine. 2016;95. 4. palnizky g, halachmi s, barak m. pulmonary complications following percutaneous nephrolithotomy: a prospective study. curr urol. 2013;7:113-6. 5. annaji j, brindha r, sowmya s. postoperative pulmonary complications among patients undergone percutaneous nephrolithotomy. international journal of medical and dental sciences. 2015795-801. 6. harris m, chung f. complications of general anesthesia. clin plast surg. 2013;40:503-13. 7. stenberg e, szabo e, näslund i, group sosrs. is glycosylated hemoglobin a1 c associated with increased risk for severe early postoperative complications in nondiabetics after laparoscopic gastric bypass? surg obes relat dis. 2014;10:801-5. 8. munver r, delvecchio fc, newman ge, preminger gm. critical analysis of supracostal access for percutaneous renal surgery. j urol. 2001;166:1242-6. 9. reddy s, shaik ab. outcome and complications of percutaneous nephrolithotomy as primary versus secondary procedure for renal calculi. international braz j urol. 2016;42:262-9. 10. smetana gw. postoperative pulmonary complications: an update on risk assessment and reduction. cleve clin j med. 2009;76:s60. 11. kroenke k, lawrence va, theroux jf, tuley mr. operative risk in patients with severe obstructive pulmonary disease. arch intern med. 1992;152:967-71. 12. solakhan m, bulut e, erturhan ms. comparison of two different anesthesia methods in patients undergoing percutaneous nephrolithotomy. urology journal. 2019;16:246-50. 13. warner do, weiskopf rb. preventing postoperative pulmonary complications: the role of the anesthesiologist. the journal of the american society of anesthesiologists. 2000;92:1467-72. 14. van lier f, van der geest pj, hoeks se, et al. epidural analgesia is associated with improved health outcomes of surgical patients with chronic obstructive pulmonary disease. the journal of the american society of anesthesiologists. 2011;115:315-21. 15. duggan m, kavanagh bp, warltier dc. pulmonary atelectasis: a pathogenic perioperative entity. the journal of the american society of anesthesiologists. 2005;102:838-54. 16. movasseghi g, hassani v, mohaghegh mr, et al. comparison between spinal and general anesthesia in percutaneous nephrolithotomy. anesthesiology and pain medicine. 2014;4. 17. smetana gw, lawrence va, cornell je. preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the american college of physicians. ann intern med. 2006;144:581-95. 18. silva dr, gazzana mb, knorst mm. merit of preoperative clinical findings and functional pulmonary evaluation as predictors of pcnl under spinal anesthesia pulmonary complicationsacikgoz egit al. vol 20 no 1 january-february 2023 5 postoperative pulmonary complications. rev assoc med bras. 2010;56:551-7. 19. mcalister fa, khan na, straus se, et al. accuracy of the preoperative assessment in predicting pulmonary risk after nonthoracic surgery. am j respir crit care med. 2003;167:741-4. 20. lumb a, biercamp c. chronic obstructive pulmonary disease and anaesthesia. continuing education in anaesthesia, critical care and pain. 2014;14:1-5. 21. kim ss, lee jw, yu jh, sung lh, chung jy, noh ch. percutaneous nephrolithotomy: comparison of the efficacies and feasibilities of regional and general anesthesia. korean journal of urology. 2013;54:846. 22. basiri a, kashi ah, zeinali m, nasiri mr, valipour r, sarhangnejad r. limitations of spinal anesthesia for patient and surgeon during percutaneous nephrolithotomy. urology journal. 2018;15:164-7. 23. dar ma, malik sa, dar ya, et al. comparison of percutaneous nephrolithotomy under epidural anesthesia versus general anesthesia: a randomized prospective study. urology annals. 2021;13:210. 24. kamal m, sharma p, singariya g, jain r. feasibility and complications of spinal anaesthesia in percutaneous nephrolithotomy: our experience. journal of clinical and diagnostic research: jcdr. 2017;11:uc08. 25. bjurlin ma, o'grady t, kim r, jordan md, goble sm, hollowell cm. is routine postoperative chest radiography needed after percutaneous nephrolithotomy? urology. 2012;79:791-5. 26. tepeler a, armağan a, akman t, et al. impact of percutaneous renal access technique on outcomes of percutaneous nephrolithotomy. j endourol. 2012;26:828-33. 27. singh v, sinha rj, sankhwar s, malik a. a prospective randomized study comparing percutaneous nephrolithotomy under combined spinal-epidural anesthesia with percutaneous nephrolithotomy under general anesthesia. urol int. 2011;87:293-8. 28. hall jc, harris j, tarala r, tapper j, chnstiansen k. incentive spirometry versus routine chest physiotherapy for prevention of pulmonary complications after abdominal surgery. the lancet. 1991;337:953-6. 29. liu x, huang g, zhong r, hu s, deng r. comparison of percutaneous nephrolithotomy under regional versus general anesthesia: a meta-analysis of randomized controlled trials. urol int. 2018;101:132-42. 30. adams j, murphy p. obesity in anaesthesia and intensive care. br j anaesth. 2000;85:91108. endourology and stones diseases 6 pcnl under spinal anesthesia pulmonary complicationsacikgoz egit al. case report off clamping laparoscopic resection of an extreme rare renal mesenchymal tumor: an angiomyolipoma of renal capsule nasser simforoosh1 , milad bonakdar hashemi1*, arsalan aslani1 ,sahand mohammadzadeh2 1urology department, faculty of medicine lampung university / abdul moeloek general hospital, lampung, indonesia. 2medical doctor, faculty of medicine lampung university, lampung, indonesia. *correspondence: urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. phone: +98-21-22567222. cell: +98-912-3630125. fax: +98-21-22567282. email: miladbonakdar@gmail.com received october 2020 & accepted february 2021 renal mesenchymal tumors are described as neoplasms with vascular, fibrous, and adipose tissues. the renal lipoma is an extremely rare renal mesenchymal tumor, typically originating from renal capsule and it is usually presented as well circumscribed homogenous fat containing mass. angiomyolipoma (aml) is the most common benign mesenchymal renal tumor which is composed of mature epithelioid cells. the renal aml usually presented as exophytic, non-infiltrative, and fat contain tumor. the well differentiated renal retroperitoneal liposarcoma and lipoma seem to be misdiagnosed by exophytic renal angiomyolipoma but the renal aml usually arises from renal parenchyma with characteristic images. a 37-year-old woman came to our clinic with rapid growth renal mass and pain. the spiral abdominopelvic computed tomography scan (ct-scan) showed well-circumscribed hypoheterodense fat-containing mass near to middle pole of the right kidney with minimal fat stranding without neovascularity and cortical defect. the patient underwent off-clamping laparoscopic resection of renal mass with pre-operative impression: liposarcoma versus lipoma of the kidney. the cross-section of the surgical specimen revealed irregular lobulated fatty tissue with hemorrhagic streaks. definite diagnosis was made by immunohistochemistry study. spindle cells and epithelioid cells are diffusely and strongly positive for α-smooth muscle actin. the perivascular cells and epithelioid cells are positive for hmb-45 and melanin. the immunostaining pattern was compatible with angiomyolipoma that originated from renal capsule. in our experience, a rapid growing mass that is accompanied by pain draws the attention to malignant process. the renal aml rarely arises from renal capsule without characteristic images so having high doubt may lead to proper pre-operative diagnosis. keywords: laparoscopy; off clamping; capsular; angiomyolipoma introduction renal mesenchymal tumors are described as neoplasms with vascular, fibrous and adipose tissues. accord-ing to clinical and pathological features, renal mesenchymal tumors include benign and malignant tumors such as leiomyoma, leiomyosarcoma, lipoma, liposarcoma, and angiomyolipoma (aml)(1). renal lipoma is an urology journal/vol 18 no. 5/ september-october 2021/ pp. 703-705. [doi: 10.22037/uj.v18i.6512] figure1. pre-operation abdomino-pelvic ct-scan extremely rare renal mesenchymal tumor, typically originating from the renal capsule and it is usually presented as well-circumscribed homogenous fat-containing mass(2,3). angiomyolipoma (aml) is the most common benign mesenchymal renal tumor which is composed of mature epithelioid cells and originates from renal cortex. the renal aml usually presents as exophytic, non-infiltrative, and fat-containing tumor. it is composed of variable amounts of fat, smooth muscle, and abnormal blood vessels. the aml is usually asymptomatic and diagnosed incidentally but the most common symptoms are flank pain and hematuria(4). the well differentiated renal retroperitoneal liposarcoma and lipoma seem to be misdiagnosed by exophytic renal angiomyolipoma but the renal aml usually arises from renal parenchyma with characteristic images(5). we present an extreme rare capsular renal tumor with unusual clinical presentation. case presentation a 37-year-old woman came to our clinic with a chief compliant of non-colic right flank pain that underwent abdominopelvic ultrasonography and abdominopelvic computed tomography scan (ct-scan). compared to previous imaging, there was a significant increase in size. recent ct-scan showed well-circumscribed hypoheterodense fat-containing mass at the middle pole of the right kidney with minimal fat stranding without neovascularity and cortical defect (figure 1). the patient was scheduled for laparoscopic resection of renal tumor with an impression of renal lipoma or a well-differentiated renal liposarcoma. thirty minutes before surgery one gram cephazolin was intravenously injected. after general anesthesia, patient’s position was changed to left lateral decubitus, laparoscopic ports (3,3,3,10 mm (umbilicus port)) were inserted in a triangular shape and ascending colon was medialized. the perinephric fat was dissected up to gerota’s fascia and renal hilum vessels were dissected. the tumor was attached to renal capsule with a very small peduncle and it was extended into the perirenal adipose tissue (figure 2a). we used bipolar for clamping the pedicle then the tumor was resected with a safety margin without main renal vessels clamping and finally the bed of tumor was free of blood (figure 2b). the frozen section was sent to pathologist and it was confirmed that the margin of resection was free of case report 413 off clamping resection of renal angiomyolipoma-simforoosh et al. figure 3a: tumor showing adipocytes, proliferating spindle cells, and thickened vessels (40x). 3b: the spindle cells and epithelioid cells are diffusely and strongly positive for α-smooth muscle actin (×10). the perivascular cells and epithelioid cells are positive for hmb-45 (×10). case report 704 figure 2: a: macroscopic appearance of the renal capsular tumor. the tumor was attached to the renal capsule by a small peduncle. b: the bed of tumor without any obvious bleeding. c: macroscopic view of the resected mass. tumor. the cross-section of the surgical specimen revealed irregular lobulated fatty tissue with hemorrhagic streaks measuring 5.5*5*3 cm (figure 2c). cut sections showed solid homogenous fatty tissue with thin fibrous strands. histological examination revealed mature adipose tissue and large thick-walled vessels surrounded by few layers of epithelioid cells with mildly pleomorphic nuclei, clear to eosinophilic cytoplasm without mitotic activity, atypia, or necrosis. the permanent diagnosis was highly suggestive of angiomyolipoma. definite diagnosis was made by immunohistochemistry study. spindle cells and epithelioid cells are diffusely and strongly positive for α-smooth muscle actin (figure 3a). the perivascular cells and epithelioid cells are positive for hmb-45 and melanin (figure 3b). the immunostaining pattern was compatible with angiomyolipoma. discussion renal mesenchymal tumors include benign and malignant tumors such as leiomyoma, leiomyosarcoma, lipoma, liposarcoma, and angiomyolipoma(6). the tumor originates from renal capsule or exophytic fat-containing renal tumor conflict the pre-operation diagnosis with retroperitoneal tumor which originates from tissues near kidney(5). the renal mesenchymal tumors which arise from renal capsule include leiomyoma, lymphangioma, solitary fibrous tumor, leiomyosarcoma, angiosarcoma, and renal lipoma and are extremely rare renal tumors. the well-differentiated renal liposarcoma cannot be distinguished from renal lipoma and fat-containing benign renal lesions(7). the aml is the most common mesenchymal renal tumor and it is usually sporadic with middle-aged woman predominance (8). aml in spiral abdomino-pelvic ct-scan usually appears as heterogeneous mass with various proportions of fat and soft tissue angiogenesis(9). the exophytic renal aml cannot be easily differentiated from renal lipoma or liposarcoma however the presence of neovascularity and renal cortical defect are infavor of renal aml so meticulous evaluation of pre-operative imaging is recommended(8). in a review of the literature four cases of aml arising from renal capsule were reported and in their experience, there were not possible to make a definitive diagnosis before histopathologic evaluation(1,5,10). three of them underwent open radical nephrectomy and only one underwent laparoscopy surgery in which partial nephrectomy was performed, we suggest macroscopic evaluation of mass and frozen pathology evaluation during the surgery which sometimes prevents from a radical approach in benign renal lesions with unusual pre-operative clinical and radiological presentations. in this study there was a rapid growing mass that was accompanied by pain which draws the attention to malignant process, a well-circumscribed fatty mass without visible renal cortical vessel and parenchymal defect that we cloud not clearly differentiate between renal lipoma and liposarcoma, so the definite diagnosis was not possible based on preoperative imaging. the prolonged ischemic times during partial nephrectomy is associated with increased risk of acute kidney injury, decreasing early post-operative gfr, and increasing chance of stage 4 chronic kidney disease(11). the off clamping partial nephrectomy prevents ischemia-reperfusion injury and leads to saving functional outcomes without adverse effects on operation time, hospital stay, and complication rates(12). in our center, we prefer off clamping laparoscopic surgery in cases with small or exophytic renal tumor that is determined by tumor characteristic at the time of surgery. in this case, the tumor had a small peduncle that was suitable for off-clamping resection of tumor without resection of renal parenchyma. references 1. katabathina vs, vikram r, nagar am, tamboli p, menias co, prasad sr. mesenchymal neoplasms of the kidney in adults: imaging spectrum with radiologicpathologic correlation. radiographics. 2010;30:1525-40. 2. vukmirović f, vukmirović m, vukmirović i, kavarić p. renal lipoma: a case report. open medicine. 2013;8:328-30. 3. ke hl, hsiao hl, guh jy, liu cs, huang ch, wu wj. primary intrarenal lipoma: a case report. kaohsiung j med sci. 2005;21:383-6. 4. sant gr, heaney ja, ucci aa, jr., sarno rc, meares em, jr. computed tomographic findings in renal angiomyolipoma: an histologic correlation. urology. 1984;24:2936. 5. kodama k, takase y, motoi i, saito k. offclamp laparoscopic partial nephrectomy for a fat-poor angiomyolipoma arising from the renal capsule: a case report. case rep urol. 2012;2012:484790. 6. sidhu h, kamal a. giant renal leiomyoma: a case report. radiol case rep. 2020;15:515-8. 7. shastri c, kumar j, jaiswal s, mandhani a. renal dedifferentiated liposarcoma with intracaval tumor thrombus: a rare case. indian j urol. 2012;28:208-10. 8. ellingson jj, coakley fv, joe bn, qayyum a, westphalen ac, yeh bm. computed tomographic distinction of perirenal liposarcoma from exophytic angiomyolipoma: a feature analysis study. j comput assist tomogr. 2008;32:548-52. 9. prasad sr, sahani dv, mino-kenudson m, et al. neoplasms of the perivascular epithelioid cell involving the abdomen and the pelvis: cross-sectional imaging findings. j comput assist tomogr. 2007;31:688-96. 10. labrune m, gayral f, chagnon s, musset d. [angiomyolipoma of the renal capsule. case report]. sem hop. 1983;59:482-4. 11. gill is, kamoi k, aron m, desai mm. 800 laparoscopic partial nephrectomies: a single surgeon series. j urol. 2010;183:34-41. 12. wszolek mf, kenney pa, lee y, libertino ja. comparison of hilar clamping and nonhilar clamping partial nephrectomy for tumours involving a solitary kidney. bju int. 2011;107:1886-92. case report 212case report 428 off clamping resection of renal angiomyolipoma-simforoosh et al. vol 18 no 6 november-december 2021 705 urol_montage.pdf pediatric urology 19urology journal vol 6 no 1 winter 2009 fistula repair after hypospadias surgery using buccal mucosal graft jalil hosseini, ali kaviani, mojtaba mohammadhosseini, alireza rezaei, iraj rezaei, babak javanmard introduction: the aim of this study was to evaluate the success rate of urethrocutaneous fistula repair using buccal mucosal graft in patients with a previous hypospadias repair. materials and methods: we reviewed records of our patients with urethrocutaneous fistula developed after hypospadias repair in whom buccal mucosal graft fistula repair had been performed. all of the patients had been followed up for 24 postoperative months. a successful surgical operation was defined as no fistula recurrence or urethral stricture. retrograde urethrography and urethrocystoscopy would be performed in patients who had any history of decreased force and caliber of urine or any difficulty in urination. results: fistula repair using buccal mucosa patch graft had been done in 14 children with urethrocutaneous fistula developing after hypospadias reconstruction. the mean age of the children was 8.70 ± 1.99 years old (range, 4 to 11 years). seven fistulas were in the midshaft, 4 were in the penoscrotal region, and 3 were in the coronal region. repair of the fistulas was successful in 11 of 14 patients (78.6%). in the remaining children, the diameter of the fistula was smaller than that before the operation, offering a good opportunity for subsequent closure. conclusion: our findings showed that fistula repair using buccal mucosal graft can be one of the acceptable techniques for repairing fistulas developed after hypospadias repair. urol j. 2009;6:19-22. www.uj.unrc.ir keywords: hypospadias, postoperative complications, cutaneous fistula, surgical flaps, reoperation reconstructive urology section, shohada-e-tajrish hospital, shahid beheshti university (mc), tehran, iran corresponding author: jalil hosseini, md department of urology, shohada-etajrish hospital, tajrish sq, tehran, iran tel: +98 21 2271 8001 fax: +98 21 2271 9017 e-mail: sjhosseinee@yahoo.com received august 2008 accepted november 2008 introduction urethrocutaneous fistula is the most common problem in hypospadias repair. the reported incidence varies from 5% to as much as 55%, depending on the severity of the initial deformity.(1-3) many techniques have been described for correction of urethrocutaneous fistula. where enough intact penile skin is available, simple closure of a fistula is used. skin flaps are used for repairing fistulas that are too large for simple closure, provided that the local skin is pliable and adequate.(4) a paucity of local tissue and subsequent skin coverage is the challenge in many cases. in such cases, extragenital tissue, splitthickness and full-thickness skin grafts, and bladder mucosa have been proposed as the alternative donor sites.(4-9) buccal mucosa has been used with good results in complex urethral reconstruction and bulbar urethral stricture for more than 15 years(4,10,11); however, hypospadias fistula repair by mucosal graft—hosseini et al 20 urology journal vol 6 no 1 winter 2009 few reports suggest that this tissue may be used for fistula closure. we reviewed our clinical experience in urethrocutaneous fistula repair using a buccal mucosal graft in patients with a history of previous hypospadias repair. materials and methods patients we performed a retrospective study on patients with urethrocutaneous fistula developing after hypospadias repair who were treated at the reconstructive urology section in shohada-etajrish hosptial in tehran, iran. hospital and follow-up records of patients with buccal mucosal graft fistula repair between 2000 and 2005 were reviewed. urethrocystoscopy had been done in all patients before the operation. our exclusion criteria for this study were urethral diverticulum and urethral stricture or multiple urethral fistulas needing total breakdown of fistula repair or any kind of surgical intervention to address the strictures. we included patients with meatal stenosis if it could be dilated with nonsurgical methods. surgical technique a circumferential incision was made around the fistula, and the urethral wall was dissected from the surrounding tissue. in patients with more than 1 fistula that were not too large or too far apart needing total previous repair breakdown, we incised the tissue between the fistulas and turn them into 1 fistula defect. a suitable size of buccal mucosa patch was harvested from the inner part of the cheek. after tailoring the graft to the defect size and removing its fat, the mucosal graft was sutured over the defect to the urethral epithelium using 5-0 vicryl separate sutures. the graft was then covered by a dartos flap which was prepared from the adjacent area. the skin was closed with 4-0 vicryl interrupted sutures. an indwelling silicone urethral catheter was inserted for 10 to 14 days. all of the patients were discharged 3 to 5 days postoperatively. follow-up all of the patients had been followed up for 24 months with monthly clinical visits for 3 months, and then, clinical visits every 3 months until 24 months after the operation. retrograde urethrography and urethrocystoscopy had been performed in patients who had any history of decreased force and caliber of urine or any difficulty in urination to rule out any urethral structure. we considered the operation successful if we would not notice any fistula recurrence or urethral stricture during the 24-month follow-up period. results we had 14 patients with urethrocutaneous fistula developed after hypospadias repair who had undergone buccal mucosa patch graft. the mean age of patients was 8.70 ± 1.99 years old (range, 4 to 11 years). their characteristics are listed in the table. seven fistulas were in the midshaft, 4 in the penoscrotal region, and 3 in the coronal region. seven patients had fistulas larger than 4 mm and 6 had more than 1 fistula. none of the patients needed total previous repair breakdown. there were 6 patients who had 2 previous fistula repairs using local tissue. repair of the fistulas using buccal mucosa graft was successful in 11 of 14 patients (78.6%). in successful cases, the urinary stream was good after removal of the catheter. three patients (21.4%) returned with recurrent fistula, 1 of which was in the coronal, the second in the midshaft, and the third in the penoscrotal regions. in these patients, the patient age, y number offistulas location of fistulas 1 4.0 1 midshaft 2 10.3 2 midshaft 3 9.1 2 coronal 4 9.0 1 midshaft 5 6.0 3 penoscrotal 6 11.0 1 midshaft 7 7.1 1 coronal 8 11.0 2 penoscrotal 9 8.3 1 midshaft 10 7.0 2 coronal 11 9.0 1 midshaft 12 11.0 2 midshaft 13 10.0 1 penoscrotal 14 9.0 1 coronal characteristics of patients with fistulas after hypospadias repair hypospadias fistula repair by mucosal graft—hosseini et al urology journal vol 6 no 1 winter 2009 21 diameter of the fistula was significantly smaller than that before the operation, offering a good opportunity for subsequent closure. two of the patients with failed fistula repair had a history of a failed previous fistula repair. discussion urinary fistula is a common complication of hypospadias repair. there are some different surgical options for repairing such fistulas. the size and location of the fistula and status of the surrounding skin usually determine the optimum technique.(4) it is believed whenever good penile skin is available, it should be used as the first choice.(12) however, each repair attempt may further deplete local resources for any repair that would be required later. in these cases, an extragenital tissue source is required.(4) when good penile skin is available, simple closure of a fistula is done. the problem of this technique, however, is that the overlying suture lines form a potential risk of recurrence.(4,7) the published data show that the success rate of the first simple closure of fistula after hypospadias repair is 71% to 92%.(4,7) skin flaps are used for repairing fistulas that are too large for simple closure, provided that the local skin is pliable and adequate.(4,8,9) richter and colleagues(1) reported their experience in the management of recurrent urethrocutaneous fistulas of 28 patients, in order to understand the outcome of secondary repair of a failed fistula closure after hypospadias surgery. they had 12 coronal fistulas which were converted into coronal hypospadias. thereafter, the urethral plate was tubularized using a wider strip (thiersch tube) with (n = 3) or without (n = 9) a relaxing midline incision (reddy-snodgrass). of the 12 repairs, 11 were successful. in 7 children, the cause of the fistula was a urethral diverticulum, which was successfully excised and closed in multiple layers (well voiding and no stricture or fistula). in 4 children (1 with multiple fistulas), the repair of the fistulas included island onlay flap or a buccal mucosal graft (n = 2). all of the 4 patients achieved a successful outcome.(1) if local tissue cannot be used for hypospadias fistula repair because of extensive scar formation or a compromised vascular supply, buccal mucosal grafts can provide a reliable option.(1) many authors have recommended buccal mucosal graft in secondary and complex hypospadias repair.(13-15) there are some reports about successful use of buccal mucosa in urethral fistula repair. in 1994, nahas and nahas reported successful use of buccal mucosal graft fistula repair in 1 patient.(12) kiss and colleagues used the same technique in 7 patients with an 85% success rate.(4) in 2006, barbagli and colleagues used buccal mucosa graft technique for repairing fistula after hypospadias reconstruction in 18 patients and yielded an 82% overall success rate.(16) our overall success rate of 78.6%, which is compatible with the results of the above studies, suggests that buccal mucosal graft is an appropriate alternative material for repairing fistulas developing after hypospadias repair. the main risk factor of fistula recurrence in our patients was a previous fistula repair and the resultant scar tissue of previous surgeries. other studies have shown that risk factors of operative failures are wound infection, urine extravasation, hematoma, ischemia, necrosis of the flap and graft, and errors in design, technique, and postoperative care.(16) this technique is especially advantageous in patients with multiple previous urethral surgeries and scarred local tissues that precludes the use of local skin for such repairs. the disadvantage of this technique is that it is a more demanding surgery than a simple closure technique and it is still prone to necrosis and other local complications. in fact, complications following childhood hypospadias repair are still difficult to treat, and a high failure rate is seen in repeat surgical operations.(16) penile urethroplasty, whether an onstage or a multistage repair, is intrinsically prone to complications such as hematoma or infection, which in turn can lead to secondary complications such as fistula, which do not occur in the bulbar or posterior urethra.(17) the ideal surgical method for complex penile repairs has not been established, and surgeons must have different reconstructive techniques in their armamentarium to choose the best approach to the individual patient.(18) conclusion the best surgical method for treatment of hypospadias fistula repair by mucosal graft—hosseini et al 22 urology journal vol 6 no 1 winter 2009 urethrocutaneous fistula after hypospadias reconstruction repair is still unknown, and different reconstructive techniques should be considered to choose the best approach based on the individual characteristics of the patient. our experience showed that buccal mucosa graft hypospadias repair is one of the acceptable techniques that can be taken into consideration for repairing the fistula of a previous hypospadias repair. conflict of ineterst none declared. references 1. richter f, pinto pa, stock ja, hanna mk. management of recurrent urethral fistulas after hypospadias repair. urology. 2003;61:448-51. 2. secrest cl, jordan gh, winslow bh, et al. repair of the complications of hypospadias surgery. j urol. 1993;150:1415-8. 3. smith pj, townsend pl, hiles jr, bryson jr. hypospadias--problems of postoperative fistulae formation and a modified 2-stage procedure to reduce these. br j urol. 1976;48:703-7. 4. kiss a, pirot l, karsza l, merksz m. use of buccal mucosa patch graft for recurrent large urethrocutaneous fistula after hypospadias repair. urol int. 2004;72:329-31. 5. redman jf. results of undiverted simple closure of 51 urethrocutaneous fistulas in boys. urology. 1993;41:369-71. 6. dubois r, pelizzo g, nasser h, valmalle af, dodat h. [urethral fistulas after surgical treatment of hypospadias. apropos of a series of 74 cases]. prog urol. 1998;8:1029-34. french. 7. latifoglu o, yavuzer r, unal s, cavusoglu t, atabay k. surgical treatment of urethral fistulas following hypospadias repair. ann plast surg. 2000;44:381-6. 8. elbakry a. management of urethrocutaneous fistula after hypospadias repair: 10 years’ experience. bju int. 2001;88:590-5. 9. voges ge, riedmiller h, hohenfellner r. tunica vaginalis free grafts for closure of urethrocutaneous fistulas. urol int. 1990;45:88-91. 10. hensle tw, kearney mc, bingham jb. buccal mucosa grafts for hypospadias surgery: long-term results. j urol. 2002;168:1734-6. 11. baskin ls, duckett jw. buccal mucosa grafts in hypospadias surgery. br j urol. 1995;76 suppl 3:2330. 12. nahas bw, nahas wb. the use of a buccal mucosa patch graft in the management of a large urethrocutaneous fistula. br j urol. 1994;74:679-81. 13. snodgrass w, elmore j. initial experience with staged buccal graft (bracka) hypospadias reoperations. j urol. 2004;172:1720-4. 14. sahin c, seyhan t. use of buccal mucosal grafts in hypospadia-crippled adult patients. ann plast surg. 2003;50:382-6. 15. marte a, cotrufo am, del monaco c, di iorio g, de pasquale m. [mouth mucosa free-flap grafts in repeat operations of hypospadias]. minerva pediatr. 2000;52:713-7. italian. 16. barbagli g, de angelis m, palminteri e, lazzeri m. failed hypospadias repair presenting in adults. eur urol. 2006;49:887-94. 17. andrich de, greenwell tj, mundy ar. the problems of penile urethroplasty with particular reference to 2-stage reconstructions. j urol. 2003;170:87-9. 18. gottesman je, pellettiere ev, kilmer w. recurrence of wilms tumor--twenty-three years later. urology. 1981;17:268-9. endourology and stone disease 24 urology journal vol 5 no 1 winter 2008 percutaneous nephrolithotomy in patients with solitary kidney mohammad reza darabi mahboub, mohammad hadi shakibi introduction: the aim of this study was to evaluate percutaneous nephrolithotomy (pcnl) in the patients with solitary kidneys. materials and methods: between 1995 and 2005, we had 11 patients with a solitary kidney and kidney calculi who underwent pcnl at our center. tubeless and standard pcnls were performed in 3 and 7 patients. in 1 patient, we could not achieve access to the system due to the stricture of the infundibulum. results: the calculi were extracted or fragmented successfully in 10 patients. in 2 patients with residual calculi, a double-j catheter was inserted and extracorporeal shock wave lithotripsy (swl) was performed. retroperitoneal hematoma was detected in 3 cases by ultrasonography 1 week after the procedure, which was treated conservatively. also, fever occurred in 3 patients after the procedure which was treated successfully. the patients were discharged on the 3rd and 4th postoperative days. conclusion: although pcnl is accompanied by the risk of complications such as severe bleeding that may result in kidney loss in patients with a solitary kidney, the rate of success and complications seem to be similar to the other patients if careful operation and correct selection of candidates are done. therefore, we recommend cautious performance of pcnl in patients with solitary kidneys. keywords: percutaneous nephrolithotomy, solitary kidneys, nephrostomy, urinary calculi department of urology, imam reza hospital, mashhad university of medical sciences, mashhad, iran corresponding author: mohammadreza darabi, md department of urology, imam reza hospital, mashhad, iran tel: +98 511 854 3031 e-mail: j_darabi@yahoo.com received december 2006 accepted may 2007 introduction percutaneous nephrolithotomy (pcnl) was firstly introduced in 1976 as a method of treatment for kidney calculi.(1) the advent of new instruments and techniques of this procedure helped urologists to perform pcnl with a high level of accuracy and less complications. given its less morbidity and costs and shorter convalescence period, nowadays, pcnl is the treatment of choice for large and complex calculi. it is now the preferred method of treatment in patients with calculi not appropriate for extracorporeal shock wave lithotripsy (swl).(2) almost all of the pyelocaliceal calculi can be treated by pcnl. however, since bleeding is a common complication of this procedure, nephrectomy might be needed to be performed in case of uncontrollable bleeding.(2-12) therefore, pcnl in solitary kidney patients should be performed with great caution. in this study, we evaluated pcnl in patients with solitary kidneys. materials and methods between 1995 and 2005, we had 11 patients with calculi in their solitary kidney who were admitted urol j. 2008;5:24-7. www.uj.unrc.ir percutaneous nephrolithotomy for solitary kidneys—darabi et al urology journal vol 5 no 1 winter 2008 25 to imam reza hospital for pcnl. the patients had a solitary functioning kidney as a result of agenesis in 4 (36.4%), previous nephrectomy in 4 (36.4%), and no function in the contralateral kidney in 3 (27.3%). function of the kidneys was assessed by dimercaptosuccinic acid renography. potential complications and the anticipated rate of success were explained for the patients and after taking written consent, pcnl was performed. routine laboratory tests including complete blood count, fasting blood glucose, blood urea nitrogen, serum creatinine, serum uric acid, blood group and rh, urinalysis, and urine culture were performed before the procedure. in the children, hypercalciuria, hyperuricosuria, hypercalcemia, hyperuricemia, serum and urine levels of sodium and potassium, and serum level of parathormone were evaluated, as well. radiological assessments including ultrasonography, abdominal radiography, and intravenous urography were performed in all patients. after reserving 2 blood units, the patient was secured in the prone position by giving a 30°c angle to the bed. for fluoroscopic guidance, contrast medium was injected by the appropriate pcnl needle. then, we entered the targeted calyx. the tract was dilated up to 28 f or 30 f, amplatz sheath was placed, and nephroscopy was performed. after removing the blood clots and evaluating the system, calculi smaller than 1 cm in diameter were removed using a forceps. pneumatic, ultrasound, laser, and finally, electrohydraulic lithotripsy were performed and fragments were removed by grasping. nephrostomy tube was placed at the end of the procedure. in 3 cases, we performed tubeless pcnl. results data on the characteristics of the patients and the outcomes are listed in the table. the mean age of the patients was 38.8 ± 16.1 years (range, 6 to 62 years). they were 8 men (72.7%) and 3 women (27.3%). the mean size of the calculi was 18.6 ± 5.7 mm (range, 8 mm to 25 mm). one of the patients was a 6-year-old child with an 8-mm calculus in the renal pelvis. seven patients (63.6%) had a single calculus in the renal pelvis, 3 (27.3%) had a single calculus in the lower calyx, and 1 (9.1%) had multiple calculi in the lower calyx and pelvis. history of calculus passage was recorded in 6 patients (54.6%). seven patients (63.6%) had undergone swl before pcnl. the calculus had been fragmented into pieces in 2 of them and in 5, the procedure had failed. these patients became candidates for pcnl. access to the system was not possible in 1 patient due to the stricture of the infundibulum. in 8 patients (72.7%), the calculi were completely removed and the patients became stone free. the calculi were fragmented and removed using pneumatic and ultrasonic lithotripters in 7 and 3 patients, respectively. in the 2 remaining patients (18.2%), a double-j catheter was inserted and swl was performed later. no intra-operative complication occurred and urine output was favorable after the procedure. patients age, y sex calculus size, mm calculus location previous swl*† contralateral kidney outcome 1 54 male 15 pelvis failed nephrectomy stone free 2 6 male 8 lower calyx … agenesis stone free 3 28 female 18 lower calyx failed agenesis stone free 4 32 female 22 pelvis … nonfunctioning stone free 5 48 male 25 pelvis and lower calyx failed agenesis residue 6 29 male 25 pelvis failed nephrectomy stone free 7 48 male 20 pelvis failed nonfunctioning stone free 8 50 male 15 pelvis … nonfunctioning stone free 9 62 female 25 lower calyx failed nephrectomy residue 10 26 male 20 pelvis failed nephrectomy failed access 11 44 male 12 pelvis … agenesis stone free characteristics and clinical outcome of percutaneous nephrolithotomy in patients with a solitary kidney *swl indicates shock wave lithotripsy. †ellipses indicate that swl had not been attempted. percutaneous nephrolithotomy for solitary kidneys—darabi et al 26 urology journal vol 5 no 1 winter 2008 in 3 patients (27.3%), retroperitoneal hematoma was detected which was spontaneously resolved. fever developed in 3 patients (27.3%) after the procedure which was treated with wide-spectrum antibiotics. in tubeless method, the patients were discharged at the 3rd postoperative day, while the patients who had undergone standard procedure, were discharged at the 4th day. one week postoperatively, control ultrasonography was performed and retroperitoneal hematoma was detected in 2 patients (18.2%), which were treated conservatively. discussion complications of pcnl are more important in patients with solitary kidneys in comparison with patients with 2 intact kidneys. bleeding is the major concern in them and if it become uncontrollable, nephrectomy may be required. the collecting system is surrounded by an arteriovenous complex with approximately 20% of the cardiac output. segmental and interlobar arteries and veins are the most important surrounding vessels. access to the pyelocaliceal system may cause trauma and severe bleeding with an average hemoglobin loss of 2.1 g/dl to 3.3 g/dl.(3-7) treatment of complex and staghorn calculi that involve multiple calyxes needs several tracts for better access to the system which result in more extensive bleeding.(5,12) blood transfusion is usually required in 1% to 11% of patients who undergo pcnl and in 2 % to 53% of those with staghorn calculi.(2-11) none of our patients had a staghorn calculus and we did not have any case of transfusion. most of the bleeding cases caused by pcnl are treated conservatively. about 0.8% of the cases need angio-embolization for the treatment of uncontrollable bleeding.(13) severe bleeding may take place during the passage of the needle, the tract dilation or nephroscopy, after the procedure, and after removing the staghorn calculi. placement of a nephrostomy tube and clumping it for 10 minutes is usually enough for controlling the bleeding. the kaye tamponade catheter(14) should be inserted if bleeding is not controlled by the nephrostomy tube and angiography should be immediately performed for the diagnosis of arteriovenous fistula or false aneurism. angiography is both for diagnosis and treatment, because both arteriovenous fistula and false aneurism are well treated by embolization. in case of the continuation of bleeding or lifethreatening bleeding, partial and even total nephrectomy may be needed.(13) in patients with a solitary kidney, this complication may result in anephric status and permanent need for hemodialysis. other complications of pcnl do not usually lead to nephrectomy and pcnl can be a good choice to remove complex calculi.(15) it has been shown that percutaneous nephrostomy can increase the chance of successful lithotripsy in the patients with a solitary kidney and opaque calculi.(16) in the literature review, there are a few reports on limited number of patients with a solitary kidney who have undergone pcnl without any complications.(15,17,18) our patients had solitary kidneys and swl failed or it was not indicated because of the density and location of the calculus. surgery was necessary to be performed and also regarding our experience (performing at least 2000 pcnls so far). we carried out tract dilation in all steps under the guidance of fluoroscopy. this method was successful and the results were not very different from the results in patients with 2 kidneys. concerning the risk of the surgical procedures in these patients, pcnl can be a safe method if the surgeon is experienced enough. conclusion percutaneous nephrolithotomy is recommended to be performed in patients with solitary kidneys by experienced surgeons with caution. however, patients with very large or staghorn calculi are not good candidates for pcnl due to the risk of severe bleeding. conflict of interest none declared. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. segura jw, preminger gm, assimos dg, et al. percutaneous nephrolithotomy for solitary kidneys—darabi et al urology journal vol 5 no 1 winter 2008 27 nephrolithiasis clinical guidelines panel summary report on the management of staghorn calculi. the american urological association nephrolithiasis clinical guidelines panel. j urol. 1994;151:1648-51. 3. pardalidis np, smith ad. complications of percutaneous renal procedures. in: smith ad, editor. controversies in endourology. 1st ed. philadelphia: wb saunders; 1995. p. 179. 4. kessaris dn, bellman gc, pardalidis np, smith ag. management of hemorrhage after percutaneous renal surgery. j urol. 1995;153:604-8. 5. jou yc, cheng mc, lin ct, chen pc, shen jh. nephrostomy tube-free percutaneous nephrolithotomy for patients with large stones and staghorn stones. urology. 2006;67:30-4. 6. rodrigues netto n jr, lemos gc, palma pc, fiuza jl. staghorn calculi: percutaneous versus anatrophic nephrolithotomy. eur urol. 1988;15:9-12. 7. kahnoski rj, lingeman je, coury ta, steele re, mosbaugh pg. combined percutaneous and extracorporeal shock wave lithotripsy for staghorn calculi: an alternative to anatrophic nephrolithotomy. j urol. 1986;135:679-81. 8. snyder ja, smith ad. staghorn calculi: percutaneous extraction versus anatrophic nephrolithotomy. j. urol. 1986;136:351-4. 9. schulze h, hertle l, kutta a, graff j, senge t. critical evaluation of treatment of staghorn calculi by percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy. j urol. 1989;141:822-5. 10. assimos dg, wrenn jj, harrison lh, et al. a comparison of anatrophic nephrolithotomy and percutaneous nephrolithotomy with and without extracorporeal shock wave lithotripsy for management of patients with staghorn calculi. j urol. 1991;145:710-4. 11. lam hs, lingeman je, barron m, et al. staghorn calculi: analysis of treatment results between initial percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy monotherapy with reference to surface area. j urol. 1992;147:1219-25. 12. martin x, tajra lc, gelet a, dawahra m, konan pg, dubernard jm. complete staghorn stones: percutaneous approach using one or multiple percutaneous accesses. j endourol. 1999;13:367-8. 13. gupta m, ost mc, shah jb, mcdougall em, smith ad. percutaneous management of the upper urinary tract. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1523-60. 14. kaye kw, clayman rv. tamponade nephrostomy catheter for percutaneous nephrostolithotomy. urology. 1986;27:441-5. 15. liu g, yan gq. [the treatment choice of solitary kidney complicated with complex calculi report of 42 cases]. zhonghua wai ke za zhi. 2005;43:936-9. chinese. 16. gorelov s, zedan f, startsev v. the choice of urinary drainage in patients with ureteral calculi of solitary kidneys. arch ital urol androl. 2004;76:56-8. 17. rana am, mithani s. tubeless percutaneous nephrolithotomy: call of the day. j endourol. 2007;21:169-72. 18. yaycioglu o, egilmez t, gul u, turunc t, ozkardes h. percutaneous nephrolithotomy in patients with normal versus impaired renal function. urol res. 2007;35:101-5. characteristics of double-j stent encrustations and factors associated with their development jian huang1,2*, weizhou wu1*, shike zhang1*, yapeng huang1, tao zeng1, lingyue an1, yeping liang1, jinkun huang1, hans-göran tiselius3, guohua zeng1#, wenqi wu1,4# purpose: to evaluate the chemical composition of double-j stent encrustation and to assess risk factors associated with their development. materials and methods: patients who had double-j stents removed between july 2016 and june 2017 were recruited for this study prospectively. the clinical features of the patients were recorded and the composition of encrustation material was analyzed by infrared spectroscopy. results: encrustments from a total of 372 double-j stents were collected. the mean age of patients was 50.4±13.1 years and deposits possible to analyze were obtained from 228 males (61.3%) and 144 females (38.7%). calcium oxalate monohydrate was the most common constituent of stone and encrustments. the encrustation rate of vesical coils was significantly higher than that of renal coils (p < 0.001). there was no significant difference in chemical composition between stone and encrustation regarding renal (p = 0.086) and vesical coils (p = 0.072). the only predictive risk factor for the development of encrustation on double-j stents was indwelling time. this phenomenon was observed in both renal (p < 0.001) and vesical coils (p = 0.021). interestingly, patient with chronic kidney disease (ckd) was associated with less risk of encrustation on both renal (p < 0.001) and vesical coils (p = 0.001). conclusion: the chemical composition of double-j stent encrustation was the same as the urinary stone. the prevention strategy for stone composition is also suitable for the prevention of encrustation of double-j stent. the only predictive factor for double-j stent encrustation was the indwelling time. ckd patient was shown to be less at risk for the development of encrustation. keywords: double-j stent; encrustation; chemical composition; urolithiasis; renal coil; vesical coil introduction in 1967, zimskind et al. were the first to use silicone ureteral splints to remedy ureteral obstruction(1). in 1978, finney introduced a neoteric double-j stent with a hook molded into each end with the purpose of adding a self-retaining function and preventing migration(2). with this innovation, double-j stent became a fundamental device in many urological procedures such as the management of patients with obstructing ureteral stone, ureteral or ureteropelvic junction strictures, retroperitoneal tumors or fibrosis. also, stent is regular after laparoscopic or open urologic surgery(1,3). the double-j stent serves as a significant therapeutic option to moderate the obstruction and counteract renal failure (4). however, there are several side effect accompanied by the insertion of double-j stent, such as flank pain, storage symptoms, dysuria and hematuria, etc.(5). moreover, as a foreign body within the collecting system, there is 1department of urology, minimally invasive surgery center, the first affiliated hospital of guangzhou medical university, guangdong key laboratory of urology, guangzhou institute of urology, guangzhou, china. 2laboratory of urology, affiliated hospital of guangdong medical university, zhanjiang, guangdong, china. 3division of urology, department of science, intervention and technology, karolinska institute, stockholm, sweden. 4department of urology, the second affiliated hospital of guangzhou medical university. *correspondence: 1department of urology, minimally invasive surgery center, the first affiliated hospital of guangzhou medical university, guangdong key laboratory of urology, guangzhou institute of urology, guangzhou, china. 2department of urology, the second affiliated hospital of guangzhou medical university tel: +86 13609089242. fax: 0086-2034294141. e-mail: wwqwml@163.com. received november 2020 & accepted july 2021 concern that the double-j stent will be subject to deposition of organic and mineral material, contributing to the formation of stone and encrustation(6-7). accordingly, it was assumed that encrustation on stents was caused by deposition of layers of organic material, uropathogens and salt in urine(8). it’s reported that the bacteria adhering to a double-j stent is the main process of biofilm formation. the aggregation of the biofilm produced by the bacteria and the precipitated urinary components causes the formation of double-j stents encrustation(9-12). encrustation may occur on renal and vesical coils of double-j stent. severe encrustation of the stent may prevent stent removal in the traditional, routine transurethral manner. the removal of encrusted stents, thus, is a challenging problem of clinical urology(13). focusing on methods aiming at prevention of encrustation is important. there is, however, a shortage of information on the characteristic of stent encrustation, such as their risk endourology and stone disease urology journal/vol 19 no. 1/ january-february 2022/ pp. 22-27. [doi: 10.22037/uj.v18i.6578] vol 19 no 1 january-february 2022 138 risk factors of double-j stent encrustations-huang et al. renal coil vesical coil index value encrustation (%) no encrustation (%) p value or encrustation (%) no encrustation (%) p value or total, n (%) 372 (100) 239 (64.2) 133 (35.8) 277 (74.5) 95 (25.5) age, years 50.4±13.1 50.4±13.3 50.1±12.8 0.855 50.3±13.0 50.4±13.6 0.969 gender, n (%) 0.439 0.841 0.498 0.846 male 228 (61.3) 143 (62.7) 85 (37.3) 167 (73.2) 61 (26.8) female 144 (38.7) 96 (66.7) 48 (33.3) 110 (76.4) 34 (23.6) bmi, kg/m2 23.6±3.7 23.6±3.7 23.6±3.7 0.929 23.6±3.7 23.6±3.5 0.831 frequent stone 177 (47.6) 117 (66.1) 60 (33.9) 0.477 0.857 138 (78) 39 (22) 0.140 0.701 former, n (%) hydronephrosis, 270 (72.6) 175 (68.4) 95 (35.2) 0.710 1.094 207 (76.6) 63 (23.3) 0.113 1.502 n (%) chronic renal 67 (18.0) 30 (44.8) 37 (55.2) < 0.001 0.372 39 (58.2) 28 (41.8) 0.001 0.392 insufficiency, n (%) preoperative urinary 145 (39.0) 91 (62.8) 54 (37.2) 0.632 0.900 108 (74.5) 37 (25.5) 0.994 1.002 tract infection, n (%) stone location, n (%) ureter 84 (22.6) 55 (65.3) 29 (34.5) 0.789 1.072 68 (81.0) 16 (19.0) 0.121 1.606 kidney 228 (61.3) 151 (66.2) 77 (33.8) 0.316 1.248 164 (71.9) 64 (28.1) 0.159 0.703 kidney and ureter 60 (16.1) 33 (55.0) 27 (45.0) 0.103 0.629 45 (75.0) 15 (25.0) 0.917 1.034 stone free status, 232 (62.4) 149 (64.2) 83 (35.8) 0.990 0.997 175 (75.4) 57 (24.6) 0.581 1.144 n (%) ureteral and/or 60 (16.1) 43 (71.7) 17 (28.3) 0.190 1.497 51 (85.0) 9 (15.0) 0.041 2.156 ureteropelvic junction stricture, n double-j stent caliber, n (%) 0.213 1.313 0.210 1.350 5 fr 152 (40.9) 92 (60.5) 60 (39.5) 108 (71.1) 44 (28.9) 6 fr 220 (59.1) 147 (66.8) 73 (33.2) 169 (76.8) 51 (23.2) indwelling time, n (%) < 0.001 0.019 ≤ 14 days (9.5±3.5)d 48 (12.9) 17 (35.4) 31 (64.6) 28 (58.3) 20 (41.7) >14 days-1 month 133 (35.8) 85 (63.9) 48 (36.1) 99 (74.4) 34 (25.6) (24.1±4.7)d > 1 month-2 months 170 (45.7) 121 (71.2) 49 (28.8) 131 (77.1) 39 (22.9) (39.4±7.6)d > 2 months 21 (5.6) 16 (76.2) 5 (23.8) 19 (90.5) 2 (9.5) (108.9±70.6)d stone composition, n (%) calcium oxalate 163 (58.8) 103 (63.2) 60 (36.8) 0.657 0.893 120 (73.6) 43 (26.4) 0.637 1.137 monohydrate calcium oxalate 21 (7.6) 14 (66.7) 7 (33.3) 0.811 1.122 16 (76.2) 5 (23.8) 0.698 1.228 dihydrate ammonium 8 (2.9) 5 (62.5) 3 (37.5) 1 0.925 4 (50) 4 (50) 0.294 0.365 magnesium 40 (14.4) 28 (70.0) 12 (30.0) 0.413 1.353 31 (77.5) 9 (22.5) 0.449 1.358 phosphate uric acid carbonate apatite 43 (15.5) 26 (60.5) 17 (28.3) 0.572 0.825 28 (65.1) 15 (34.9) 0.234 0.658 table 1. general characteristics of patients with stent encrustations figure 1. distribution of stone and renal coil encrustation composition. p = 0.086 as analyzed with bowker’s test of symmetry. figure 2. distribution of stone and vesical coil encrustation composition. p=0.072 as analyzed with bowker’s test of symmetry. vol 19 no 1 january-february 2022 23 endourology and stones diseases 24 factors or chemical composition. for that reason, we prospectively collected data of patients with double-j stents in order to explore the features of stent encrustation by separately considering renal and vesical coils. the aim was to evaluate the chemical composition of double-j stent encrustation and identify risk factors involved in the encrustation process. patients and methods this study was approved by the ethics review board of the first affiliated hospital of guangzhou medical university, guangzhou, china. informed consent was obtained from all individual patients included in the study. all double-j stents were obtained from patients who had been subject to stent removal at the first affiliated hospital of guangzhou medical university. from july 2016 to june 2017, a total of 372 patients with the removal of double-j stents that had been part of their clinical treatment were recruited prospectively. all of the double-j stents were made of a material with a variety of medical applications, polyurethane, the most common polymeric biomaterial used in modern double-j stents(14). the baseline characteristics included age, gender, body mass index (bmi), frequent stone former, presence or absence of hydronephrosis, chronic kidney disease (ckd), preoperative urinary tract infection, stone location, stone free status, ureteral and/or ureteropelvic junction strictures, double-j stent caliber, indwelling time, stone and the encrustation composition. the variables were analyzed in a logistic regression model, with the aim to find factors associated with the development of encrustation. to further elucidate the importance of the duration of stent treatment, the indwelling time was sub-grouped into four intervals: ≤ 14 days, >14 days to 1 month, >1 month to ≤ 2 months and >2 months. generally, patients with indwelling time of double-j stent longer than 1 month were related to the ureteral stricture, ureteral injury or the delay of double-j stent removal with patients’ personal reason. patients eligible for inclusion in the present study were those who were planned for removal of 5fr or 6fr double-j stents inserted because of urolithiasis and/or ureteral/ureteropelvic junction strictures after nephroscope, ureteroscopy, laparoscope or open surgery. computed tomography (ct) scanning was used for the diagnosis of urinary stones. ureteral and/or ureteropelvic junction strictures were diagnosed with intravenous pyelography (ivp), ct urography or ureteroscopy. the exclusion criteria were as follows: 1) a serious medical history of blood disease, family history of hereditary diseases, and other unusual conditions; 2) anatomical malformations including scoliosis, ectopic kidney, horseshoe kidney and polycystic kidney; 3) patients planned for urinary diversion or renal transplantation; 4) the stent was displaced. moreover, only the data from the initial stent episode were included in case the same patient had been subject to repeated stent treatment. patients with severe stone disease (frequent stone formers) were defined by frequent recurrence of stone after treatment or by stone surgery more than three times. the definition of ckd is described as the presence of kidney damage (usually defined as urinary albumin excretion of ≥ 30 mg/day or equivalent) or decreased kidney function (detected as estimated glomerular filtration rate (egfr) < 60 ml/min/1.73m2) for three or more months, irrespective of the cause. chronic kidney disease epidemiology collaboration (ckd-epi) creatinine equation was used for the evaluation of the estimated glomerular filtration rate (egfr)(15). all patients were examined with plain film of kidney-ureter-bladder (kub) and urinary ultrasound imaging before extraction of the stent. patients were considered stone-free when no residual stones were detected in ct, kub or urinary ultrasound examinations before extraction of the double-j stents. hydronephrosis was evaluated by a ct examination or ultrasonography, defined by dilatation of the renal pelvis or calices to a diameter exceeding 10mm according to the modification of the grignon grade system(16). preoperative urinary tract infection was defined as a mid-stream sample of urine indicating bacterial growth ≥ 105 cfu/ml, or with a high level of leukocytes (sensitivity threshold: 104 leukocytes/mm3) or nitrites in the urine test strips, or with a positive urinary culture(17-18). presence of encrustation vesical coil total renal coil encrustation no encrustation encrustation 221 18 239 no encrustation 56 77 133 total 277 95 372 table 2. mcnemar test for double-j stent encrustation of renal and vesical coils. index kidney univariate multivariable or 95% ci p value or 95% ci p value age 1.002 0.985-1.018 0.854 gender 0.841 0.543-1.304 0.439 bmi 1.003 0.946-1.062 0.929 frequent stone former 0.857 0.560-1.311 0.477 hydronephrosis 1.094 0.682-1.755 0.710 chronic renal insufficiency 0.372 0.217-0.638 < 0.001 0.339 0.194-0.593 < 0.001 preoperative urinary tract infection 0.900 0.583-1.388 0.632 stone location 1.085 0.817-1.441 0.573 stone free status 0.997 0.644-1.545 0.990 ureteral and/or ureteropelvic junction stricture 1.497 0.816-2.746 0.192 double-j stent caliber 1.313 0.855-2.018 0.214 indwelling time ≤14 days < 0.001 < 0.001 >14 days to 1 month 3.229 1.621-6.433 0.001 3.366 1.669-6.788 0.001 >1 month to ≤2 months 4.503 2.285-8.873 < 0.001 5.006 2.499-10.026 < 0.001 >2 months 5.835 1.819-18.716 0.003 5.691 1.747-18.540 0.004 stone composition 1.011 0.870-1.174 0.889 table 3. factors associated with the development of double-j stent encrustation of kidney. risk factors of double-j stent encrustations-huang et al. vol 19 no 1 january-february 2022 138 was considered when visible chemical and mineralogical deposits covered the surface or lumen of the renal and vesical coils (approximately 6-8cm at each end of the stent). their chemical composition was analyzed by infrared spectroscopy (thermo scientific nicolet is5). under sterile conditions, the double-j stents were removed cystoscopically with an alligator forceps under local anesthesia. stent fragments were dried by heating at 70ºc for 12 hours and then cooled at room temperature. subsequently, approximately 1mg of the dried encrustation sample scraped from stent was evenly mixed with 200mg of potassium bromide, powdered, compressed into a small tablet, and finally scanned by fourier transform infrared spectroscopy(19,20). according to the major chemical component that was recorded, the composition was classified as follows: calcium oxalate monohydrate, calcium oxalate dihydrate, ammonium magnesium phosphate, uric acid and carbonate apatite. in view of the rarity of cystine, ammonium urate, calcium phosphate, xanthine and 2,8-dihydroxyadenine, these constituents were referred to “other composition”. the composition of the stone was compared with the composition of encrustation at the renal and vesical coils of the stent. statistical analysis the spss software version 16.0 was used to perform the statistical analysis. the significance level was defined as p-values less than 0.05. continuous variables were presented as means ± standard deviation (sd). categorical variables were expressed as frequency and percentage. mcnemar test was used for group comparison. bowker’s test of symmetry was used to compare the composition of urinary stones and double-j stent encrustation. unconditional logistic regression was used and expressed as odds ratios (or) and 95% confidence intervals (95% ci) to identify independent factors associated with the formation of stent encrustation. variables with p-values less than 0.1 in univariate analysis were regarded as important factors, and they were further examined in the multivariable analysis. results a total of 372 double-j stents were collected prospectively and included in this study. patients’ demographics and the characteristics of patients with or without encrustation were listed in table 1. the mean age of patients was 50.4 ± 13.1 years. there were 228 males (61.3%) and 144 females (38.7%) with a male to female ratio of 1.60:1. the most common stone constituent was calcium oxalate monohydrate (58.8%). there were 77 stents without any encrustation. a total of 277 stents were encrusted with vesical coil and 239 stents had encrustation in the renal coil. the encrusted rate of vesical coils (74.5%) was significantly higher than that in the renal coil (64.2%) when analyzed with the mcnemar method (p < 0.001) (table 2). figure 1 and figure 2 show the comparison between the composition of stone and encrustation. only those patients with analysis of stone and encrustation simultaneously were included. a comparison with bowker’s test of symmetry didn’t demonstrate any significant difference about the chemical composition between stone and double-j stent encrustation in both of renal (178 patients, p = 0.086) and vesical (201 patients, p = 0.072) coils. this result means that the composition of double-j stent encrustation was more likely to be the same as that of the stone. a regression analysis model was established to analyze the potential variables that were related to the formation of double-j stent encrustation (table 3 and table 4). the parameters including age, gender, body mass index (bmi), frequent stone former, hydronephrosis, preoperative urinary tract infection, stone location, stone free status, ureteral and/or ureteropelvic junction stricture, double-j stent caliber and stone composition had no effect on the formation of encrusted double-j stents when analyzed in the logistic regression model. the only predictive risk factor for development of stent encrustation was the indwelling time for both renal (p < 0.001) and vesical (p = 0.021) coils. interestingly, ckd patient was shown to be less risk for development of encrustation of renal (or 0.339, 95% ci: 0.194-0.593, p < 0.001) and vesical (or 0.383, 95% ci: 0.217-0.675, p = 0.001) coils. discussion identification of the characteristics of double-j stent encrustation and search for related factors are of importance for the prevention and treatment of encrustation. observations in this study indicated that the vesical coil was more prone to encrustation than the renal coil. the table 4. factors associated with the development of double-j stent encrustation of bladder. bladder index univariate multivariable or 95% ci p value or 95% ci p value age 1.000 0.982-1.018 0.969 gender 0.846 0.522-1.372 0.499 bmi 1.007 0.945-1.073 0.831 frequent stone former 0.701 0.438-1.124 0.141 hydronephrosis 1.502 0.907-2.487 0.114 chronic renal insufficiency 0.392 0.225-0.684 0.001 0.383 0.217-0.675 0.001 preoperative urinary tract infection 1.002 0.621-1.615 0.994 stone location 0.808 0.599-1.090 0.162 stone free status 1.144 0.709-1.844 0.581 ureteral and/or ureteropelvic 2.156 1.018-4.569 0.045 junction stricture double-j stent caliber 1.350 0.844-2.160 0.211 indwelling time ≤14 days 0.025 0.021 >14 days to 1 month 2.080 1.039-4.161 0.039 2.128 1.051-4.308 0.036 >1 month to ≤ 2 months 2.399 1.220-4.717 0.011 2.580 1.294-5.146 0.007 > 2 months 6.786 1.417-32.485 0.017 6.546 1.351-31.706 0.020 stone composition 1.018 0.861-1.204 0.835 risk factors of double-j stent encrustations-huang et al. vol 19 no 1 january-february 2022 25 only risk factor for the formation of encrustation was the time that stent had been indwelling in the collecting system. ckd was found to associate with less double-j stent encrustation. this series of measurements provide the first report on a reduced risk of stent encrustation in patients with ckd. in this study, the vesical coil was observed to have a higher rate of encrustation than the renal coil. the underlying cause is probably attributable to the storage function of urine in the bladder, with increased exposure time of the stent to urine. furthermore, sighinolfi et al. reported that urinary tract infection was related to encrustation of vesical coils(6). lower urinary tract infection is more common than upper urinary tract infection, which might provide another explanation for the fact that vesical coils have a higher rate of encrustation than renal coils. however, in our series, preoperative urinary tract infection did not affect the encrustation of double-j stent in the regression model. it was a shortcoming that the current research lacks data of postoperative urinary tract infection, which might be more persuasive to explain the connection between urinary tract infection and double-j stent encrustation. rouprêt et al. recorded a 71.4% correlation between stent encrustation and stone composition and concluded that analysis of the chemical composition of encrustation could be a possible method for conclusions on stone composition in the case of a stone has not been acquired for analysis(21). similar findings were also described by bariol and colleagues(22). in our series, the bowker’s test of symmetry conducted to authenticate the chemical composition of double-j stent encrustations was more likely to be the same as that of the urinary stone, which means the prevention strategy for stone composition is also useful for the prevention of encrustations of double-j stent. rouprêt et al. indicated that there was no significant difference in the composition of encrustation at the ends of the stent(21). moreover, our series presented that calcium oxalate monohydrate was found to be the most common stone or encrustation component. calcium oxalate monohydrate is mainly associated with hyperoxaluric states(23). it can also come from the crystalline conversion of calcium oxalate dihydrate, thus, be initiated by transient hypercalciuria(24,25). venkatesan and colleagues blamed the encrustation of calcium oxalate to a consequence of its poor solubility(26). after adjustment of all statistically significant variables from the univariate analysis, the multivariable logistic regression model indicated that indwelling time was the only predictive risk factor associated with encrusted double-j stents in both renal and vesical coils. the same phenomenon was also described by sancaktutar and eisenberg et al.(27,28). the rate of chemical and mineralogical encrustation increases with the indwelling time. sighinolfi et al. have mentioned that urolithiasis patients, especially in frequent stone formers, were related to the burden of renal coil encrustation(6). however, urinary tract infection and patient’s aging were the risk variables contributing to the higher degrees of vesical coil encrustation. this phenomenon was related to a bladder outlet dysfunction. in this series, patient with ckd was associated with less risk of double-j stent encrustation for both renal and vesical coils. there is reason to convince that ckd as a special physiological status being against the formation of kidney stones. craver and colleagues conducted a cross-sectional study for the analysis of mineral metabolism alterations in ckd(29). a total of 1836 patients were included and classified into stages 1-5. results indicated that there is an associated fall in urine calcium excretion when gfr declines. it is well recognized that urine calcium is one of the most important critical risk factors for stone formation(23,30). marangella et al. investigated in 171 patients with chronic renal insufficiency, presented that multiple changes in renal pathophysiology were connected to the onset of renal insufficiency, which result in a sharp decrease in the urine saturation with respect to calcium salts(31). these changes account for the decrease in the stone recurrence rate in the impaired gfr patients. also, the reduction in urine calcium excretion in patients with ckd seems to contribute to the less double-j stent encrustation. there are several shortcomings inherent in the design of this study to which attention should be paid. firstly, lack of data of postoperative urinary tract infection, bacteriuria, medication therapy, daily water intake and diet, did not enable us to exactly elucidate the possible impact of infection, medication therapy, daily water intake and diet on encrustation. secondly, stent characteristics were heterogeneous both in terms of brand and length. finally, without the degree of quality of encrustation, hindering us to further understand the relationship of encrustation and indwelling time. conclusions in this series, the chemical composition of double-j stent encrustation was more likely to be the same as that of the urinary stone, which means the prevention strategy for stone composition is also useful for the prevention of encrustation of double-j stent. the results showed that ckd patient had less risk on development of encrustation. indwelling time was the only predictive risk factor for development of double-j stent encrustation. the observations provides a basis for further considerations on the prevention and treatment of patients with double-j stent encrustation. acknowledgement this work was financed by national natural science foundation of china (81570633) and the science and technology project of guangdong province, (2017b030314108) and education bureau project of guangdong province (2018kzdxm056). references 1. zimskind pd, fetter tr, wilkerson jl. clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically. j urol. 1967;97:840-4 2. finney rp. experience with new double j ureteral catheter stent. j urol. 1978;120:67881. 3. borboroglu pg, kane cj. current management of severely encrusted ureteral stents with a large associated stone burden. j urol. 2000;164:648-50. 4. fiuk j, bao y, calleary jg, schwartz bf, denstedt jd. the use of internal stents in chronic ureteral obstruction. j urol.2015;193:1092-100. 5. lange d, bidnur s, hoag n, chew bh. risk factors of double-j stent encrustations-huang et al. endourology and stones diseases 26 vol 19 no 1 january-february 2022 27 ureteral stent-associated complications-where we are and where we are going. 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rössler d. submicroscopic investigations on calcium oxalate stone genesis. eur urol. 1979;5:13643. 25. schubert g, brien g. crystallographic investigations of urinary calcium oxalate calculi. int urol nephrol. 1981;13: 249 26. venkatesan n, shroff s, jeyachandran k, doble m. effect of uropathogens on in vitro encrustation of polyurethane double j double-j stents. urol res. 2011;39:29-37. 27. sancaktutar aa, tepeler a, söylemez h, et al. a solution for medical and legal problems arising from forgotten double-j stents: initial results from a reminder short message service (sms). urol res. 2012;40:253-8. 28. eisenberg ml, lee kl, stoller ml. endoscopic management of retained renal foreign bodies. urology. 2012;73:1189-94. 29. craver l, marco mp, martínez i, et al. mineral metabolism parameters throughout chronic kidney disease stages 1-5--achievement of k/ doqi target ranges. nephrol dial transplant. 2007;22:1171-6. 30. curhan gc, willett wc, speizer fe, stampfer mj. twenty-four-hour urine chemistries and the risk of kidney stones among women and men. kidney int. 2007;59:2290-8. 31. marangella m, bruno m, cosseddu d, et al. prevalence of chronic renal insufficiency in the course of idiopathic recurrent calcium stone disease: risk factors and patterns of progression. nephron. 1990;54:302-6. risk factors of double-j stent encrustations-huang et al. effect of the external physical vibration lithecbole on the discharge of upper urinary stones: a systematic review and meta-analysis zi-hao xu1, jian-lin lv1, shuang zhou1, chun-ping jia1, hao wang1* purpose: the external physical vibration lithecbole (epvl) is a new device that accelerates the discharge of urinary stones by changing the patient's body position and providing multi-directional simple harmonic waves. it is clinically employed to improve the stone-free rate (sfr). however, it is not widely accepted in clinical practice due to the lack of high-level evidentiary support and a standard protocol. the present meta-analysis aims at the evaluation of the efficacy and safety of epvl treatment in improving the sfr. methods: this study was a systematic review and meta-analysis. a systematic literature review was conducted using pubmed, scopus, embase, medline, the web of science, and the cochrane library to find randomized controlled trials (rcts) as recent as april 2020 that evaluated the efficacy and safety of epvl treatment for patients with stones/residual stones in the upper urinary tract. results: in total, 7 prospective studies with 1414 patients were included. compared with patients in the control group, patients treated with an epvl (the intervention group) had higher sfrs (95% ci: 0.59-0.86, rr = 0.71, p = .0004) and lower complication rates (95% ci: 1.37-3.12, rr = 2.07, p = .0006). in a subgroup analysis based on previous surgery (eswl, rirs), the intervention group had an improved sfr as compared to the control group (95% ci: 0.59-0.95, rr = 0.75, p = .02; 95% ci: 0.56-0.73, rr = 0.64, p < .00001, respectively). in a subgroup analysis based on stone location, the sfrs for stones in the upper/middle/lower calyx and renal pelvis were significantly higher in the intervention group than in the control group: for residual stones in the upper and middle calyx, 95% ci: 0.63-0.98, rr = 0.79, and p = .03; for residual stones in the lower calyx, 95% ci: 0.54-0.75, rr = 0.64, and p < .00001; for residual stones in the renal pelvis, 95% ci: 0.47-0.79, rr = 0.61, and p = .0002. however, the sfrs for ureter stones were not significantly different between groups (95% ci: 0.82 -1.05, rr = 0.93, p = .23). conclusion: the external physical vibration lithecbole can effectively improve the sfr after eswl and rirs without significant side effects, especially for residual stones in the upper/middle/lower calyx and renal pelvis. keywords: external physical vibration lithecbole; upper urinary stones; residual stones, meta-analysis introduction urinary tract stones are a common urological dis-ease, and create life and economic burdens for about 5-15% of the world's population.(1,2) with the development of technology, several surgical procedures can be used to treat stones, including extracorporeal shock wave lithotripsy (eswl), retrograde intrarenal surgery (rirs), percutaneous nephrolithotomy (pcnl), and laparoscopic surgery. because surgical equipment and treatment concepts are continuously updated, the phenomenon of residual stones has been greatly improved. however, the presence of residual stones after surgery remains a bothersome problem for urologists. residual stones can potentially reaggregate and grow, thereby causing recurrent stone formation, infection, renal colic, obstruction, and eventually kidney failure.(3) many methods can promote the discharge of residual stones, including drinking more water, exercising more, medical expulsive therapy (met), and percussion, diudepartment of urology, the affiliated jiangning hospital with nanjing medical university, nanjing, jiangsu 211100, china. *correspondence: department of urology, the affiliated jiangning hospital of nanjing medical university, no. 168 gushan road, dongshan street, nanjing 211100, china. tel: +86-25-52178496; fax: +86-25-52178496. e-mail: luanshiwhxx01@163.com. received august 2020 & accepted january 2021 resis, and inversion (pdi).(4-7) some emerging technologies, such as the use of iron oxide microparticles and ultrasonic propulsion, can also improve the stone removal rate;(8,9) however, these two technologies have not been widely used in clinical practice. recently, based on the principles of pdi treatment, the external physical vibration lithecbole (epvl) device has been designed to discharge stone fragments. the device mainly provides harmonic vibration via stationary and mobile vibrators, thereby pushing the stones to discharge from the body. several randomized controlled trials (rcts) have compared the efficacy and safety of the epvl in treating upper urinary tract residual stones. in 2015, a study conducted by long et al. showed that, in the treatment of lower-pole renal stones, the stone removal rate of the epvl plus eswl group reached 76.5%, while that of the group that received eswl treatment alone was only 43.8% (p = 0.008).(10) epvl treatment can also accelerate the discharge of residual stones after rirs. zhang et al.(11) designed a prospective randomized controlled study to determine the length of time between urology journal/vol 18 no. 1/ january-february 2021/ pp. 19-27. [doi: 10.22037/uj.v0i0.6417] review rirs and epvl treatment that can achieve the best therapeutic effect for patients with residual stones; the results showed that the earlier the treatment, the higher the stone removal rate, and the greater the reduction of corresponding complications. however, to date, no systematic review or meta-analysis has evaluated the effectiveness of epvl. therefore, a systematic review and meta-analysis were conducted to assess the efficacy and safety of the epvl in the treatment of upper urinary tract stones or stone fragments. materials and methods literature search the systematic review was performed according to the cochrane review guidelines and the prisma (preferred reporting items for systematic reviews and meta-analyses) guidelines. a systematic literature review using pubmed, scopus, embase, medline, the cochrane library, and the web of science was performed to identify rcts that had assessed the efficacy and safety of the epvl in the treatment of upper urinary tract stones or stone fragments. the search strategy was [("inversion" or "vibration" or "epvl") and ("stone" or "calculus" or "urolithiasis")]. the reference lists of relevant publications were also checked to identify any additional potential studies, and the potentially eligible studies from the cited references in the enrolled papers were also assessed. in addition, abstract booklets and presentations from annual academic con table 1. baseline characteristics of individual studies included in the meta-analysis. study country study design mean age (t/c, years) bmi (t/c) sample size (t/c) le quality long et al. 2016 (10) china rct 44 ± 9.5/45 ± 9.9 25.2 ± 3.4/25.6 ± 2.9 34/37 1b 3 wu et al.2017 (15) china rct 47.1 ± 1.0/46.9 ± 1.2 24.5 ± 0.3/24.1 ± 0.3 87/86 1b 5 liu et al. 2017 (12) china rct 37.4 ± 15.3/38.3 ± 16.8 na/na 236/222 1b 3 wu et al. 2018 (14) china rct 42.9 ± 1.5/42.7 ± 1.3 23.6 ± 0.3/23.8 ± 0.3 76/77 1b 5 tao et al.2018 (13) china rct 49.3 ± 6.1/50.4 ± 5.7 23.6 ± 2.9/23.1 ± 3.3 127/144 1b 5 jing et al.2018 (16) china rct 38.7 ± 10.72/38.2 ± 10.6 24.1 ± 2.98/23.9 ± 2.6 56/56 1b 4 zhang et al.2019 (11) china rct 47.58 ± 10.26a 23.95 ± 2.91a 45a 1b 5 49.72 ± 11.2b 24.78 ± 3.17b 44b 51.83 ± 9.31c 24.06 ± 3.56c 42c /47.04 ± 9.1d /24.55 ± 3.59d /45d abbreviations: t/c: treatment group vs. control group. a, b, c, d: the study by zhang et. al (2019) reports three treatment groups, a, b and c, and group d is the control group. figure 1. flow chart of the study selection. the effect of epvl on upper urinary stones-xu et al. review 20 vol 18 no 1 january-february 2021 21 ferences were also consulted, and the corresponding authors of unpublished studies were contacted via email. the literature retrieval was halted in april 2020. two of the authors (zi-hao xu and hao wang) independently and thoroughly carried out the literature search, article selection, quality assessment, and data extraction, and disagreements were resolved by an open discussion with a third reviewer. inclusion and exclusion criteria the inclusion criteria for eligible studies were as follows: (1) the report of rcts; (2) the comparison of epvl treatment with conservative non-intervention; (3) the report of sufficient data, including the stone size and stone location; (4) published in english. the exclusion criteria were as follows: (1) reviews, editorials, or conference abstracts; (2) repeated publications; (3) retrospective studies; (4) published in languages other than english. assessment of the quality of studies and data extraction the grade system was used to assess the level of evidence (le), and the jadad scale was used to assess the methodological quality of all included studies. furthermore, the cochrane risk-of-bias tool was utilized to evaluate the potential kinds of bias. the extracted data included the study design, methodological quality, stone size, previous surgery, stone location, treatment method, follow-up time, stone-free rate (sfr), and stone-related complications. in the control group, patients were recommended to increase their physical activity and fluid intake. in the intervention group, table 2a. detailed comparisons and results of eligible studies. study previous stone stone intervention follow-up time no. of no. of surgery location size strategy (t/c) stone-free complications patients (t/c) (t/c) long et al. eswl lower 6-20 mm epvl/ 3 weeks 26 (76.5%) 5 (14.7%) 2016 calyx before observation /18 (48.6%) /6 (16.2%) eswl wu et al. rirs upper ≤4 mm epvl/ 4 weeks 78 (89.7%) 6 (6.9%) 2017 urinary after rirs observation /52 (60.5%) /28 (32.2%) liu et al. na distal ureter 3.2-10 mm epvl + 2 weeks 223 (94.5%) na/na 2017 tamsulosin/tamsulosin /208 (93.7%) wu et al. eswl upper ≤15 mm epvl/ 4 weeks 69 (90.8%) 2 (2.6%) 2018 urinary before observation /58 (75.3%) /5 (6.5%) eswl tao et al. eswl upper 10-20 mm epvl/ 4 weeks 117 (92.1%) 11 (8.7%) 2018 urinary before observation /121 (84%) /10 (6.9%) eswl jing et al. eswl upper largest epvl/ 4 weeks 31 (55.4%) 24 (42.9%) 2018 urinary stone observation /13 (23.2%) /38 (67.9%) diameter 8-15 mm before eswl zhang et al. rirs unilateral ≤4 mm epvla, b, c 4 weeks 41a (91.1%) 4a (8.9%) 2019 renal after rirs /observationd 37b (84.1%) 8b (18.2%) 32c (76.2%) 10 c (23.8%) /23d (51.1%) /21d (46.7%) figure 2. comparison between total sfrs for patients in the treatment (epvl) and control groups. the effect of epvl on upper urinary stones-xu et al. vol 18 no 1 january-february 2021 39 patients were treated with an epvl device beside the above recommendations. the recording of complications included the reported effects of the treatment, such as hematuria, leukocyturia, and lumbago. statistical analysis the methodological assessment was accomplished using revman 5.3 software. because the sfr and complications in all included studies were dichotomous variables, the pooled risk ratios (rrs) with 95% confidence intervals (cis) were implemented for statistical analysis. subgroup analyses were conducted according to the stone location and complication type. the statistical heterogeneity among the included studies was assessed by chi-square tests based on q and i2 statistics (minimal heterogeneity: 0-25%, moderate heterogeneity: 25-50%, significant heterogeneity: >50%.) fixed-effect models were used to analyze the heterogeneous data (i2 < 50%), and random-effects models were used to analyze the heterogeneous data (i2 > 50%). a two-sided p-value < 0.05 was considered to be statistically significant. furthermore, the potential heterogeneity and publication bias were tested by performing subgroup pooled analysis and sensitivity analysis, and by creating funnel plots. results in total, 235 references were obtained from the initial examination. after screening layer-by-layer, 7 rct studies(10-16) comprising 1414 patients were ultimately included. the basic features of the included studies are reported in tables 1 and 2. as reported in these studies, 747 patients received epvl treatment for upper urinary tract stones or stone fragments, while 667 patients were allocated to the control group. all included studies had a low risk of bias, but the performance bias was high. the risk of bias for each included study is summarized in table 3. regardless, the evaluation of the results was blinded and relatively objective. sfr all the included studies(10-16) reported sfrs after intervention, and the sfr was concluded based on imaging (ultrasound, kub, non-contrast ct scan when necessary) reflecting the discharge of residuals stones. the epvl (intervention) group presented obviously higher sfrs than the control group (95% ci: 0.59-0.86, rr = 0.71, p = .0004) with random effects, but there was a significant heterogeneity among these studies (i2 = 92%), as presented in figure 2. therefore, a subgroup analysis based on previous surgery (eswl, rirs) in the intervention group was performed, and an improved sfr was found as compared to the control group (95% ci: 0.59-0.95, rr = 0.75, p = .02 and 95% ci: 0.560.73, rr = 0.64, p < .00001, respectively) (figure 3). in a subgroup analysis based on stone location, the sfrs for stones in the upper/middle/lower calyx and the renal pelvis were significantly higher in the intervention group than in the control group: for residual stones in the upper and middle calyx, 95% ci: 0.63-0.98, rr = 0.79, and p = .03; for residual stones in the lower calyx, 95% ci: 0.54-0.75, rr = 0.64, and p < .00001; for residual stones in the renal pelvis, 95% ci: 0.47-0.79, rr = 0.61, and p = .0002. however, the sfrs for ureter stones were not significantly different between groups (95% ci: 0.82 -1.05, rr = 0.93, p = .23) (figure 4). complications the overall complication rates between the intervention group and the control group are presented in figure 4. data on complications in the epvl and control groups were provided for a total of 220 events in six studies.(10,11,13-16) in the meta-analysis, the complication table 2b. types of complications. study treatment group observation group hematuria lumbago leukocyturia dizziness hematuria lumbago leukocyturia dizziness long et al. 2016 2 2 na 1 4 2 na na wu et al. 2017 3 na 3 na 18 na 10 na liu et al. 2017 na na na na na na na na wu et al. 2018 1 na 1 na 3 na 2 na tao et al. 2018 na na na 7 na na 3 na jing et al. 2018 14 9 1 na 19 14 3 na zhang et al. 2019 2a/5b/5c na 2a/3b/5c na 11 na 10 na abbreviations: t/c: treatment group vs. control group; na: not available. a, b, c, d: the study by zhang et al. (2019) reports three treatment groups, a (3 days after rirs), b (7 days after rirs), and c (14 days after rirs), and group d is the observation group. study random allocation blinding of blinding of incomplete selective outcome other sequence generation concealment participants outcome outcome data reporting bias (selection bias) (selection bias) (performance bias) assessment (attrition bias) (reporting bias) (detection bias) long et al. 2016 low unclear high low low unclear low wu et al. 2017 low low high low low low low liu et al. 2017 unclear unclear high low low unclear unclear wu et al. 2018 low low high low low low low tao et al. 2018 low low high low low low low jing et al. 2018 low unclear high low low unclear low zhang et al. 2019 low unclear high low low low low table 3. risk of bias of included studies. the effect of epvl on upper urinary stones-xu et al. vol 18 no 1 january-february 2021 23 rate was found to be significantly lower in the intervention group than in the control group (95% ci: 1.373.12, rr = 2.07, p = .0006) (figure 5) with random effects, and also exhibited significant heterogeneity (i2 = 57%). subgroup meta-analysis was then carried out figure 3. comparison of sfrs for different previous surgeries in patients in the epvl and control groups. as subsequently described, and the results are exhibited in figure 6. 1. hematuria five studies including 775 participants (384 in the intervention group and 391 in the control group) reportfigure 4. comparison between sfrs for different stone locations in patients in the epvl and control groups. the effect of epvl on upper urinary stones-xu et al. vol 18 no 1 january-february 2021 41 ed the incidence of hematuria after treatment. the rate was significantly lower in the intervention group than in the control group (95% ci: 1.62-3.45, rr = 2.37, p < .00001), and low heterogeneity was detected among these studies (i2 = 20%). 2. lumbago only two studies reported the incidence of lumbago after treatment. there was no significant difference between the intervention and control groups (95% ci: 0.72-2.88, rr = 1.44, p = .31). 3. leukocyturia four studies including 704 participants (350 in the intervention group and 354 in the control group) reported the incidence of leukocyturia after treatment. the rate was significantly lower in the intervention group than in the control group (95% ci: 1.68-5.12, rr = 2.93, p = .0001), and no heterogeneity was detected among these studies (i2 = 0.0%). 4. dizziness only two studies reported the incidence of dizziness after treatment. there was no significant difference between the intervention and control groups (95% ci: 0.11-1.25, rr = 0.37, p = .11). figure 5. comparison between complication rates of patients in the epvl and control groups. figure 6. comparison of complication rates for different types of complications in patients in the epvl and control groups. the effect of epvl on upper urinary stones-xu et al. review 24 vol 18 no 1 january-february 2021 25 sensitivity analysis and publication bias to examine the stability of the outcome, a sensitivity analysis was conducted. after the research by liu et al.(12) was excluded, the i2 value changed from 92% to 82%, indicating that this research was the main cause of the heterogeneity. the forest plot without the inclusion of liu et al.’s article is presented in figure 7. all included studies reported sfrs, and a funnel plot for the sfr was created. the results demonstrate that there existed some publication bias, as the funnel plot was not symmetric (figure 8). discussion the problem of residual stones has plagued urologists for decades. although surgery can be performed to remove most stones, and while complete stone removal can be achieved in some patients, residual stones remain an unavoidable problem. additionally, 43-77% of asymptomatic residual stones will progress accordingly, causing corresponding symptoms.(17,18) in 2000, honey et al.(4) reported for the first time that pdi therapy can effectively promote the excretion of calculus in the kidney. a meta-analysis showed that pdi therapy can improve the discharge of calculus after eswl (or: 0.62; 95% ci: 0.47-0.82). although it has been concluded that pdi therapy is effective, only two related studies were included, and evidence of its effectiveness is lacking. moreover, because the percussion in pdi therapy is not widely promoted in clinical practice, there have been few relevant studies. however, the epvl device has gradually been used clinically since its invention in china, and many researchers have conducted related clinical studies. this equipment includes a rotating bed and a physical vibration device, which accelerates the discharge of stones by changing the patient's body position and providing multi-directional simple harmonic waves. the epvl figure 7. sensitivity analysis forest plots. figure 8. funnel plot of publication bias. the effect of epvl on upper urinary stones-xu et al. vol 18 no 1 january-february 2021 43 is primarily used as an adjuvant treatment of residual stones after eswl and rirs. in 2019, a meta-analysis conducted by chung et al. revealed that residual stones are more common after eswl and rirs than after pcnl, with likelihoods reaching 23.1-91.5% and 45.6-96.7%, respectively.(19) however, in the present subgroup analysis, epvl treatment was found to better prevent residual stones after these two treatments. the location of residual stones is a significant factor that affects their removal rate.(20) due to the effect of gravity, stones remaining in the lower half of the kidney account for a large proportion, and are more difficult to remove than residual stones in the upper and middle areas.(21,22) however, the present subgroup analysis revealed that epvl treatment can solve this problem very well; it can significantly improve the sfr in the lower kidney, and also in other parts of the kidney. the ureter is also a common site of urinary tract stones, but the subgroup analysis demonstrated that epvl treatment has no significant effect on the sfr of ureteral stones. a prospective study conducted by liu et al.(12) showed that epvl treatment can achieve the same stone removal rate as medical expulsive therapy (met) for lower ureteral stones of less than 10 mm in size, and there was no significant difference between the rate of stone discharge in the epvl group and the met group; researchers performed surgery on patients whose stones had not passed after two weeks, and found that their ureters had strictures. the safety of epvl treatment is also an important issue that must be considered in clinical practice. there have been no reports of serious complications in many known studies; while there have been reports that patients experienced dizziness, nausea, and skin redness after receiving epvl treatment, these side-effects all relieved themselves. the epvl is a physical therapy device, and is a safe and non-invasive treatment method. the subgroup analysis of the probability of complications revealed that patients who received epvl treatment had a lower probability of complications, including hematuria, lumbago, leukocyturia, and dizziness. epvl treatment was found to reduce the phenomena of hematuria and leukocyturia, which are usually caused by the movement of stones in the ureter to the mucosa. it is believed that the following two factors led to this result: first, the vibration waves generated by the two epvl vibrators can separate the stones from the ureter, and can also push the stones forward, thereby reducing the likelihoods of stones incarcerated in the ureter and inflammation; second, the vibration waves drive the movement of the stones, thereby improving the rate of stone discharge and reducing the occurrence of related complications. in the present analysis, lumbago and dizziness were not found to be necessarily related to whether patients received epvl treatment; however, the occurrence of these two complications in all experiments was relatively small. it was also found that the current efficacy of epvl treatment has certain defects; as an emerging technology, the epvl device has not been widely used in clinical practice, and a specific treatment process and specifications have not yet been formed. all patients must drink water before receiving epvl treatment, but there is no obvious conclusion regarding the specific amount. additionally, scholars have not yet proposed the best position of the epvl device during the main treatment period or the method of vibration wave transmission. moreover, the rotation of the rotating bed allows the patient to assume a high dorsal position to facilitate the discharge of stones, but there is no clear conclusion about which angles of rotation can achieve the best effect. standardized treatment programs and prospective rcts involving more centers may be more objective in evaluating this technique. this meta-analysis had several limitations. first, only 7 rcts were included in this study, and the sample sizes used for subgroup analysis were small and differed greatly. second, there were also certain differences between the experimental plans of each group for the exploration of the therapeutic effect of epvl treatment, thereby leading to the risk of bias. in future related studies, more rigorous prospective rcts are needed. conclusions in summary, the results of the current meta-analysis provided evidence that, as compared with the control group, patients who received epvl treatment had higher stone clearance and fewer related complications. the removal rates of stones in the upper/middle/lower calyx and renal pelvis were significantly higher in the intervention group, and significant side effects were not reported. therefore, epvl treatment is an effective and repeatable method for the discharge of residual stones. conflict of interests the authors declare that they have no conflicts of interest. references 1. moe ow. kidney stones: pathophysiology and medical management. lancet. 2006;367:333-44. 2. farhan m, nazim sm, salam b, ather mh. prospective evaluation of outcome of percutaneous nephrolithotomy using the ‘stone’nephrolithometry score: a singlecentre experience. arab journal of urology. 2015;13:264-9. 3. raja a, hekmati z, joshi hb. how do urinary calculi influence health-related quality of life and patient treatment preference: a systematic review. j. endourol. 2016;30:727-43. 4. honey rjda, luymes j, weir mj, kodama r, tariq n. mechanical percussion inversion can result in relocation of lower pole stone fragments after shock wave lithotripsy. urology. 2000;55:204-6. 5. pace kt, tariq n, dyer sj, weir mj, d'a. honey rj. mechanical percussion, inversion and diuresis for residual lower pole fragments after shock wave lithotripsy: a prospective, single blind, randomized controlled trial. j. urol. 2001;166:2065-71. 6. buchholz n-p, meier-padel s, rutishauser g. minor residual fragments after extracorporeal shockwave lithotripsy: spontaneous clearance or risk factor for recurrent stone formation? j. endourol. 1997;11:227-32. 7. liu lr, li qj, wei q, liu zh, xu y. percussion, diuresis, and inversion therapy the effect of epvl on upper urinary stones-xu et al. review 26 vol 18 no 1 january-february 2021 27 for the passage of lower pole kidney stones following shock wave lithotripsy. cochrane database syst rev. 2013. 8. tan yk, mcleroy sl, faddegon s, et al. in vitro comparison of prototype magnetic tool with conventional nitinol basket for ureteroscopic retrieval of stone fragments rendered paramagnetic with iron oxide microparticles. j. urol. 2012;188:648-52. 9. shah a, harper jd, cunitz bw, et al. focused ultrasound to expel calculi from the kidney. j. urol. 2012;187:739-43. 10. long q, zhang j, xu z, et al. a prospective randomized controlled trial of the efficacy of external physical vibration lithecbole after extracorporeal shock wave lithotripsy for a lower pole renal stone less than 2 cm. j. urol. 2016;195:965-70. 11. zhang y, xu c, wang y, et al. when is the best time to perform external physical vibration lithecbole (epvl) after retrograde intrarenal surgery (rirs): a multi-center study based on randomized controlled trials. urolithiasis. 2019. 12. liu g, cheng y, wu w, et al. treatment of distal ureteral calculi using extracorporeal physical vibrational lithecbole combined with tamsulosin: a new option to speed up obstruction relief. j. endourol. 2018;32:161-7. 13. tao r, tang q, zhou s, jia c, lv j. external physical vibration lithecbole facilitating the expulsion of upper ureteric stones 1.0-2.0 cm after extracorporeal shock wave lithotripsy: a prospective randomized trial. urolithiasis. 2020;48:71-7. 14. wu w, yang z, tang f, et al. how to accelerate the upper urinary stone discharge after extracorporeal shockwave lithotripsy (eswl) for < 15 mm upper urinary stones: a prospective multi-center randomized controlled trial 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retrograde intrarenal surgery for treatment of renal stones: a systematic review and network meta-analysis. plos one. 2019;14:e0211316. 20. wen cc, nakada sy. treatment selection and outcomes: renal calculi. urol. clin. n. am. 2007;34:409-19. 21. brownlee n, foster m, griffith dp, carlton ce. controlled inversion therapy: an adjunct to the elimination of gravity-dependent fragments following extracorporeal shock wave lithotripsy. j. urol. 1990;143:1096-8. 22. sampaio f, aragao a. inferior pole collecting system anatomy: its probable role in extracorporeal shock wave lithotripsy. j urol. 1992;147:322-4. the effect of epvl on upper urinary stones-xu et al. running head: intravesical gemcitabine versus intravesical bcg-ansari djafari et al. intravesical gemcitabine versus intravesical bacillus calmette-guerin for the treatment of intermediate-risk non-muscle invasive bladder cancer: a randomized controlled trial anahita ansari djafari1, babak javanmard2*, mohammadreza razzaghi2, seyyed ali hojjati1, zahra razzaghi2, saba faraji3, amirhossein rahavian4 , maryam garousi5 1 urology department , school of medicine , shahid beheshti university of medical sciences, tehran, iran. 2 laser application in medical sciences research center, shahid beheshti university of medical sciences, tehran, iran. 3 department of psychiatry, roozbeh hospital, tehran university of medical sciences, tehran, iran. 4 andrology research center, yazd reproductive sciences institute, shahid sadoughi university of medical sciences, yazd, iran. 5 radiation oncology department, iran university of medical sciences, tehran, iran. key words: bcg , bladder cancer , gemcitabine , intravesical therapy abstract purpose: the most common adjuvant therapy known for non-invasive muscle bladder cancer (nmibc) is intravesical bacillus calmette-guerin (bcg). intravesical chemotherapy drugs like gemcitabine can also be used post-turbt, which is considered as a good alternative for bcg, or can be used as a second-line treatment. due to the common side effects of bcg, the use of chemotherapy drugs as intravesical treatments is currently increasing. materials and methods: 117 intermediate-risk nmibc cases were included in this study. all the patients underwent turbt surgery and received 1 gr intravesical gemcitabine immediately after performing the surgery. the patients were then divided into two groups, either receiving intravesical gemcitabine or intravesical bcg weekly for 6 weeks. the patients were followed up with cystoscopy. results: most patients were men who had smoking risk factors. the youngest patient was 36 years old and the oldest one was 88 years old. the rate of side effects in the group receiving gemcitabine (13.6%) was much lower than the group receiving bcg (44.8%). (p-value = 0.016). the recurrence rate during a one year period was lower in the group consisting of patients receiving gemcitabine compared to the group receiving bcg (19 patients vs. 23 patients) (p-value = 0.401) conclusion: the efficacy of intravesical gemcitabine and intravesical bcg was almost equal in the treatment of intermediate-risk nmibcs. the adverse effects of gemcitabine were found to be significantly lower than bcg. due to causing fewer complications, gemcitabine can be known as a good alternative, especially among elderly patients with comorbidities. introduction bladder cancer currently is the tenth most common cancer worldwide. as well, it is the sixth most common cancer among men, and the seventeenth most common cancer among women (1). more than 90% of bladder cancers are diagnosed in cases aged over 55 years old, and the prevalence is about four times higher in men than in women (2). correspondingly, its most common symptom is hematuria, which can be microscopic or gross. other symptoms may include suprapubic pain, painful urination, dysuria or frequency. of note, in some patients, it is asymptomatic (3). the strongest risk factor of bladder cancer is tobacco smoking. besides age and smoking, there are some other risk factors for bladder cancer such as workplace exposures, arsenic in the water, race, heredity, and lack of fluid intake (4). various studies have been previously performed on the roles of genetics and heredity in the development of bladder cancer, and the role of several genes, including myc, fibroblast growth factor receptor (fgfr), tumor protein 53 (tp53), and retinoblastoma protein 1 (rb1), has been proven so far (5). about 70% of bladder cancers are non-muscle invasive bladder cancer (nmibc), which includes carcinoma in situ (cis) and papillary carcinomas of stages ta and t1 (6). nmibc cases can be divided into the following three categories: low risk, intermediate-risk, and high-risk patients. according to the american urological association (aua) guideline, intermediate-risk patients are categorized into low-grade ta (recurrence < 1 year, solitary > 3 cm or multifocal), high-grade ta < 3 cm, and low-grade t1 groups (7). (table 1) the main treatment for nmibcs is transurethral resection of bladder tumor (turbt) and then, depending on the pathology and risk classification, intravesical treatments are performed if needed (3). in patients with muscle-invasive bladder cancer, performing more invasive treatments such as radical cystectomy or chemotherapy and radiotherapy, is suggested (8). in an intermediate-risk patient, a clinician should consider adjuvant therapy, including the administration of a six-week course of intravesical chemotherapy or immunotherapy (4). in this regard, the most common intravesical treatment is bacillus calmette-guerin (bcg), which has been used to treat bladder cancer since the 1970s. the treatment with bcg is in the form of six induction cycles and if necessary, maintenance therapy is followed as well (9). the recurrence rate of bladder cancer is high. in nmibcs, the recurrence rate is between 60 and 70%. in particular, the recurrence rate in the intermediate-risk group over a one-year period is about 38%. accordingly, this rate reaches about 62% for a 4–year period of follow-up. the intravesical treatments could reduce the recurrence rate. bcg injection can also reduce the recurrence rate by about 30-40%. for intravesical therapy, chemotherapy drugs such as mitomycin c, gemcitabine, and epirubicin can be used post-turbt, which is a good alternative treatment for bcg or a second-line treatment. gemcitabine has an anti-tumor activity and due to having proven effect on the treatment of metastatic and advanced bladder cancers, it is used in the treatment of nmibcs (4,6,10,11). due to the common side effects of bcg, which can range from dysuria to sepsis, the use of chemotherapy drugs as intravesical treatments is increasing (12). the most common side effects of intravesical gemcitabine may include cystitis, hematuria, and skin reactions (13). considering that few studies has been conducted on comparing bcg and gemcitabine , we designed and performed the phase iii clinical trial to assess the effectiveness of intravesical gemcitabine, compared to intravesical bcg. patients and methods study population the patients participating in the current study were those with non-muscle invasive urothelial carcinoma of bladder, the subgroup of intermediate-risk. this study was done from march 2019 to december 2021, including the newly-diagnosed patients and patients with a history of bladder cancer who met the study criteria, in shohada-e tajrish hospital. the inclusion criteria were no previous history of bladder cancer or a history of pta low-grade transitional cell carcinoma (tcc) and those who did not receive intravesical therapy. additionally, the patients should be in the intermediate-risk group category. the exclusion criteria were immunodeficiency, pregnancy, and bladder rupture during turbt. there was no age or sex restriction in this study. patients who could not have regular follow-up or did not tolerate intravesical treatment were excluded from the study (22 patients). also, 2 patients were excluded from the study due to death. other patients had regular follow-up with cystoscopy every 3 months for at least one year. finally, 141 patients were enrolled in the present study, of whom 117 patients had the inclusion criteria and were divided into the two groups. figure 1 shows the process of admitting the patients and dividing them into the case and control groups. study design this study was a prospective single-center, parallel-group randomized clinical trial performed in a referral hospital in tehran, iran. considering type i error of 0.05 and type ii error of 0.1, 57 samples were needed in each study group. thereafter, the patients were randomly divided into the two groups a and b using the simple randomization method. the group a patients were treated with intravesical gemcitabine and the group b patients were treated with intravesical bcg. all the patients were aware of their treatment process and there was no blindness in the study. all the patients received 1 gr vial of gemcitabine immediately after turbt surgery. afterward, group a patients were followed by intravesical injection of 1 gr vial of gemcitabine, weekly for a 6-week duration. each vial was then dissolved in 50 ccs of normal saline and entered the bladder through nelaton catheter. the patients emptied their bladder after 2 hours. the treatment of the group b was performed by the intravesical injection of bcg vial, weekly for a 6-week duration. each vial was dissolved in 50 ccs of normal saline and entered the bladder through nelaton catheter. the patients emptied their bladder after 2 hours. patients were informed of their participation in each group. thereafter, they underwent cystoscopy every 3 months for one year. next, according to the guideline, the follow-up was continued by cystoscopy. the patients' results and data were recorded in a pre-prepared checklist and then statistical analysis was performed. informed consent was obtained from each patient. this study was approved by the ethics committee of the shahid beheshti university of medical sciences (ir.sbmu.msp.rec.1399.773). as well, it was approved by the iranian registry of clinical trials (irct20200402046915n1). surgical procedure all the included patients underwent antibiotic therapy before surgery and underwent turbt by a single urologist. the masses were completely resected. if bladder perforation was suspected, gemcitabine injection was not performed for the patients. afterward, the patients underwent cystoscopy for follow-up. in case of any recurrence, the patients underwent turbt by the same surgeon. outcome assessment the main outcome of this study was the comparison of the effects of gemcitabine and bcg on reducing recurrence of bladder cancer in the studied patients, at least one year from intravesical injection. the recurrence was evaluated and then confirmed by cystoscopy. secondary outcomes included the caused side effects following intravesical treatment. possible complications have been questioned, evaluated, and finally recorded. moreover, some variables such as the number of tumors, tumor location in the bladder, the initial pathology, and possible risk factors of the patients were examined. statistical methods the obtained data were analyzed with spss statistical for windows version 23. quantitative and qualitative variables were described using mean ± sd and frequency (percent), respectively. the chi-square test was used for comparing data between the two groups. p-values less than 0.05 were considered as statistically significant. results patients were divided into two groups receiving intravesical gemcitabine (n=59) and intravesical bcg (n=58). the maximum follow-up period of the patients was two years (6 patients). the mean duration of follow-up was 13.74 ± 3.44 months. patient’s characteristics were also similar in both groups and there was no significant difference in this respect. (table 2) most of the included patients were men (78.63%) who had a risk factor of smoking (79.48%). the youngest patient was 36 years old and the oldest one was 88 years old. in terms of educational level, most of the patients in both groups were under diploma. despite the fact that the most common reason for referring patients was gross hematuria, most of them referred to the clinic on an outpatient basis. in 17.09% of the patients, the mass was found incidentally and the patient had no symptoms. there was no significant difference between the two study groups in terms of tumor characteristics. (table 3) 62.39% of all the cases had a solitary tumor. 60.68% of the patients had lg ta pathology reports, followed by hg ta (27.35%) and the lowest rate was lg t1 (11.96%). in the group receiving gemcitabine, the most common site of the tumor was the posterior wall of the bladder (18.7%) and in the bcg group, the most common site was the left lateral wall of the bladder (21.8%). in general, the most common sites of mass in the patients' bladder were the followings: right wall, left wall, and posterior wall. the most uncommon site of the mass was the prostatic urethra (only one patient). no specific area of the bladder was statistically significant in either group. in terms of the caused side effects, the difference between the two groups was significant. (table 4) the rate of side effects in the group receiving gemcitabine (13.6%) was much lower than the group receiving bcg (44.8%). (p-value = 0.016) the most common adverse effect in both groups was cystitis, including symptoms such as dysuria, frequency, and urgency. three patients needed hospitalization due to these side effects, all of whom were in the bcg group. notably, the severity of the disease increased in 7 patients (5.98%) during the treatment period, of whom 3 patients were in the group receiving gemcitabine and 4 patients were in the group receiving bcg. the recurrence rate during one year period was lower in the group of the patients receiving gemcitabine compared to the group receiving bcg (19 patients vs. 23 patients), but this difference was not significant.(pvalue = 0.401) in total, in the group receiving gemcitabine, treatment was successful in 40 patients (67.79%) and no recurrence occurred, and in the bcg group, the rate was 35 patients (60.34%). the mean survival time of recurrence in gemcitabine group was 14.36 ± 0.73 months and in bcg group was 13.60 ± 0.77 months. (pvalue = 0.415). the recurrence rate in each group at 3-month interval is shown in table 3 and figure 2. bcg might prolong the peak recurrence rate than gemcitabine. discussion the bcg vaccine was firstly developed by albert calmette over a hundred years ago. its effect on bladder cancer was proposed by dr. alvaro morales about forty years ago. in 1990, bcg was approved by the food and drug administration (fda) for the treatment of nmibc and then became the first-line drug in nmibc up to now (14) . intravesical bcg is associated with developing some complications that sometimes lead patient to discontinue the treatment. about 19% of the patients are forced to discontinue their treatment during the maintenance therapy with bcg. accordingly, these complications include hematuria, urinary tract infection, epididimo-orchitis, bladder contracture, systemic bcg infection, and urosepsis (15,16) . ryan l.steinberg et al. in their study have discussed the use of intravesical chemotherapy drugs, including mitomycin c, gemcitabine, and epirubicin for nmibc cases. these drugs have fewer side effects and in some cases have equal or even better efficacy compared to bcg (17) . ak das et al. in their research have shown that intravesical chemotherapy in nmibc is associated with the reduced cancer-specific mortality, but it has no effect on overall mortality rate (18) . intravesical chemotherapy drugs cause very few side effects, most of which was dysuria (18,19) . in our study, 19 patients in the gemcitabine group had a recurrence during one-year follow-up, which was 32.2%. in the bcg group, 23 patients had a recurrence, the rate which was equal to 39.7%. despite lower recurrence rate in the group receiving gemcitabine, this difference was not significant (p-value = 0.401). ma han et al. have reviewed 7 studies with a total of 1222 patients, which showed that gemcitabine reduced recurrence and progression of bladder cancer among high-risk nmibcs compared to bcg (20) . similar studies have also shown the superiority of gemcitabine over bcg and mitomycin in reducing recurrence and disease’s progression in nmibcs (10) . in addition, 8 patients receiving gemcitabine (13.6%) developed some adverse effects, most of which were cystitis and none of them required hospitalization. in the bcg group, 26 patients developed adverse effects (44.8%), of whom 3 patients required hospitalization. accordingly, the most common complications in this group included cystitis and suprapubic discomfort. it is noteworthy that the complications in gemcitabine were significantly less than bcg (p-value = 0.016). fewer side effects can lead to better patient reception and the continuation of the full treatment process. this is especially important among the elderly with comorbidities. in similar studies, the side effects caused by gemcitabine were significantly lower than those of bcg (17,21) . in a study by prasanna t et al., the rate of the bcg complications was about 44%, while gemcitabine caused side effects in only 7% of patients (10) . in a study that compared the side effects of intravesical gemcitabine and bcg in 592 patients with nmibc, cooper et al. have found that the amount of physical pain in the gemcitabine group was higher than that of bcg, while the rate of hematuria in the bcg group was much higher compared to the other group (22) . despite all the benefits of using gemcitabine, bcg is still used as the first line of treatment in nmibc. this may possibly be due to the extensive studies on bcg and its proven role in this field (21) . due to its efficacy and fewer side effects, gemcitabine may be known as a viable alternative to bcg. in the current study, there were some potential limitations, including the limited sample size, duration of the patients' follow-up, and the covid-19 pandemic, which affected the patients’ follow-up. a study on the comparison of the high-risk group with the intermediate-risk group is also needed. conclusion this study results indicate that gemcitabine has a lower recurrence rate compared to bcg, but this difference was not significant. therefore, the efficacy of both drugs is almost equal in the treatment of intermediate-risk patients. however, the side effects of gemcitabine are significantly lower than those of bcg. due to causing fewer complications, it can be a good alternative, especially among elderly patients with comorbidities. certainly, further studies with greater statistical population and more follow-up time duration are needed to determine if gemcitabine can be known as the first-line treatment in nmibc. acknowledgement the authors would like to thank the staff of shohada-e tajrish hospital for their care and sacrifices in the patients’ treatment. conflict of interest the authors declare no conflict of interest. references 1. sung h, ferlay j, siegel rl, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021 may;71:209-49. 2. saginala k, barsouk a, aluru js, rawla p, padala sa, barsouk a. epidemiology of bladder cancer. med sci. 2020 mar;8:15. 3. lenis at, lec pm, chamie k. bladder cancer: a review. jama. 2020 nov 17;324:1980-91. 4. chang ss, boorjian sa, chou r, et al. diagnosis and treatment of non-muscle invasive bladder cancer: aua/suo guideline. j urol. 2016 oct;196:1021-9. 5. cumberbatch mg, jubber i, black pc, et al. epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018. eur urol. 2018 dec 1;74:784-95. 6. wang tw, yuan h, diao wl, yang r, zhao xz, guo hq. comparison of gemcitabine and anthracycline antibiotics in prevention of superficial bladder cancer recurrence. bmc urol. 2019 dec;19:1-5. 7. woldu sl, bagrodia a, lotan y. guideline of guidelines–non-muscle invasive bladder cancer. bju int. 2017 mar;119:371. 8. patel vg, oh wk, galsky md. treatment of muscle‐invasive and advanced bladder cancer in 2020. ca cancer j clin. 2020 sep;70:404-23. 9. alhunaidi o, zlotta ar. the use of intravesical bcg in urothelial carcinoma of the bladder. ecancermedicalscience. 2019;13. 10. prasanna t, craft p, balasingam g, haxhimolla h, pranavan g. intravesical gemcitabine versus intravesical bacillus calmette–guérin for the treatment of non-muscle invasive bladder cancer: an evaluation of efficacy and toxicity. front oncol. 2017 nov 2;7:260. 11. zhang j, li m, chen z, ouyang j, ling z. efficacy of bladder intravesical chemotherapy with three drugs for preventing non-muscle-invasive bladder cancer recurrence. j healthc eng. 2021 nov 30;2021. 12. peyton cc, chipollini j, azizi m, kamat am, gilbert sm, spiess pe. updates on the use of intravesical therapies for non-muscle invasive bladder cancer: how, when and what. world j urol. 2019 oct;37:2017-29. 13. li r, li y, song j, et al. intravesical gemcitabine versus mitomycin for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized controlled trial. bmc urol. 2020 dec;20:1-8. 14. mukherjee n, julián e, torrelles jb, svatek rs. effects of mycobacterium bovis calmette et guérin (bcg) in oncotherapy: bladder cancer and beyond. vaccine. 2021 dec 8;39:7332-40. 15. felipe lm. review of urological complications in bcg immunotherapy for nonmuscle invasive bladder cancer. immunome res. 2021;17:1-2. 16. koch ge, smelser ww, chang ss. side effects of intravesical bcg and chemotherapy for bladder cancer: what they are and how to manage them. urology. 2021 mar 1;149:11-20. 17. steinberg rl, thomas lj, o’donnell ma. combination intravesical chemotherapy for non–muscleinvasive bladder cancer. eur urol focus. 2018 jul 1;4:503-5. 18. das ak, mishra dk, gopalan ss. effect of intravesical chemotherapy on the survival of patients with non-muscle-invasive bladder cancer undergoing transurethral resection: a retrospective cohort study among older adults. medrxiv. 2021 jan 1. 19. tabayoyong wb, kamat am, o’donnell ma, et al. systematic review on the utilization of maintenance intravesical chemotherapy in the management of non–muscle-invasive bladder cancer. eur urol focus. 2018 jul 1;4:512-21. 20. han ma, maisch p, jung jh, et al. intravesical gemcitabine for non-muscle invasive bladder cancer: an abridged cochrane review. investig clin urol. 2021 nov;62:623. 21. ye z, chen j, hong y, xin w, yang s, rao y. the efficacy and safety of intravesical gemcitabine vs bacille calmette-guerin for adjuvant treatment of non-muscle invasive bladder cancer: a metaanalysis. onco targets ther. 2018;11:4641. 22. kuperus jm, busman rd, kuipers sk, et al. comparison of side effects and tolerability between intravesical bacillus calmette-guerin, reduced-dose bcg and gemcitabine for non-muscle invasive bladder cancer. urology. 2021 oct 1;156:191-8. corresponding author: babak javanmard, m.d. shohada-e tajrish hospital, shahid beheshti university of medical sciences, tehran, iran. tel: +98 9125888600 fax: +98 21 22829356 e-mail: drbabakjavanmard@gmail.com figure legends figure 1. patients’ enrollment algorithm figure 2. kaplan-meier estimates of disease-free survival time with gemcitabine versus bcg. bcg, bacillus calmette-guerin table 1. non-muscle invasive bladder cancer risk stratification by american urological association (aua) guideline . lg : low grade , punlmp : papillary urothelial neoplasm of low malignant potential , hg : high grade , cis : carcinoma in situ , lvi : lymphovascular invasion , bcg : bacillus calmetteguerin low risk lg solitary tumor ta <3cm , punlmp intermediate risk recurrence within 1 year lg ta , lg ta solitary tumor > 3 cm , lg ta multifocal , lg t1 , hg ta <3 cm high risk hg ta >3 cm , hg t1 , cis , any recurrence hg ta , variant histology , lvi , hg prostatic urethral involvement , bcg failure in hg patients table 2. patients characteristics . gem : gemcitabine , bcg : bacillus calmette-guerin patient characteristics gem (n=59) bcg (n=58) mean age, years 63.95 ± 10.5 62.36 ± 10.9 sex male 47 (79.7%) 45 (77.6%) education level les than high school diploma high school diploma bachelor’s degree or higher 32 (54.2%) 16 (27.1%) 11 (18.6%) 29 (50%) 21 (36.2%) 8 (13.8%) referral situation clinic emergency 45 (76.3%) 14 (23.7%) 47 (81%) 11 (19%) reason for referral gross hematuria microscopic hematuria suprapubic pain incidental finding 41 (69.5%) 5 (8.5%) 3 (5.1%) 10 (16.9%) 35 (60.3%) 12 (20.7%) 1 (1.7%) 10 (17.2%) smoking 48 (81.4%) 45 (77.6%) opium 24 (40.7%) 24 (41.1%) high risk job 6 (10.2%) 4 (6.9%) table 3. tumor characteristics . gem : gemcitabine , bcg : bacillus calmette-guerin , lg : low grade , hg : high grade tumor charectristics gem (n=59) bcg (n=58) p-value number of tumor foci single multiple 35 (59.3%) 24 (40.7%) 38 (65.5%) 20 (34.5%) 0.489 first pathology stage lg ta hg ta lg t1 37 (62.7%) 15 (25.4%) 7 (11.9%) 34 (58.6%) 17 (29.3%) 7 (12.1%) 0.885 place of tumor involvement posterior urethra trigone right ureteral orrifice left ureteral orrifice right wall left wall anterior wall posterior wall dome neck 0 (0%) 9 (8.4%) 8 (7.5%) 6 (5.6%) 18 (16.8%) 16 (14.9%) 8 (7.4%) 20 (18.7%) 10 (9.3%) 12 (11.2%) 1 (1%) 14 (13.8%) 4 (3.9%) 7 (6.9%) 19 (18.8%) 22 (21.8%) 5 (4.9%) 19 (18.8%) 5 (4.9%) 5 (4.9%) 0.302 0.210 0.227 0.694 0.708 0.203 0.452 0.982 0.221 0.099 table 4. response to therapy . gem : gemcitabine , bcg : bacillus calmette-guerin , ci : confidence interval , lft : liver function test parameter gem (n=59) bcg (n=58) risk ratio (ci) p-value recurrence within one year yes no 19 (32.2%) 40 (67.8%) 23 (39.7%) 35 (60.3%) 0.81 (0.49-1.32) 0.401 tumor progression by stage 3 (5.1%) 4 (6.9%) 0.73 (0.17-3.15) 0.680 recurrence in 1st follow-up recurrence in 2nd follow-up recurrence in 3rd follow-up recurrence in 4th follow-up 5 (8.5%) 10 (16.9%) 8 (13.6%) 6 (10.2%) 8 (13.8%) 8 (13.8%) 3 (5.2%) 10 (17.2%) 0.62 (0.22-1.79) 1.25 (2.53-2.94) 2.62 (0.73-9.39) 0.58 (0.22-1.52) 0.360 0.636 0.120 0.266 adverse events allergic reaction rise in lft urosepsis cystitis gross hematuria suprapubic discomfort systemic bcg infection no adverse event 0 (0%) 0 (0%) 0 (0%) 4 (6.8%) 1 (1.7%) 3 (5.1%) 0 (0%) 51 (86.4%) 2 (3.4%) 0 (0%) 2 (3.4%) 11 (19%) 1 (1.7%) 9 (15.5%) 1 (1.7%) 32 (55.2%) 0.19 (0.01-4.01) 0.19 (0.01-4.01) 0.36 (0.12-1.05) 0.98 (0.06-15.35) 0.33 (0.09-1.15) 0.33 (0.01-7.88) 0.016 0.150 0.999 0.150 0.049 0.990 0.063 0.311 0.0001 endourology and stone disease 28 urology journal vol 5 no 1 winter 2008 delayed versus same-day percutaneous nephrolithotomy in patients with aspirated cloudy urine masoud etemadian,1 ramin haghighi,1 ali madineay,1 adel tizeno,1 seyed mohammad fereshtehnejad2 introduction: we present our experience in continuing percutaneous nephrolithotomy (pcnl) versus delayed pcnl when purulent fluid is aspirated during access to the pyelocaliceal system. materials and methods: this randomized controlled study was carried out on patients who had purulent urine in the pyelocaliceal system at the initial puncturing during pcnl. patients with recent untreated urinary tract infection, thick or foul pus in aspirated urine, fever, and immunocompromised condition were excluded. thirty-one patients were randomly divided into 2 groups. in group 1, pcnl was continued, but in group 2, nephrostomy tube was placed and pcnl was performed 10 days later after documented sterile nephrostomy urine. the preoperative and postoperative findings were compared. results: there were 16 and 15 patients in groups 1 and 2, respectively. all patients had negative urine cultures for microorganisms, preoperatively. the purulent aspirated fluid was infected in 43.8% and 40.0% of the patients in groups 1 and 2, respectively. postoperative fever was seen in 25.0% and 26.7% of the patients, respectively. no statistical differences were observed between the two groups in terms of bacteriuria, bacteremia, positive calculus cultures, or stone-free rates, and duration of hospitalization between groups 1 and 2, respectively. more analysis with linear regression model showed that postoperative positive blood culture (p < .001), fever (p = .001), and postoperative positive urine culture (p = .02) correlated with duration of hospitalization. conclusion: in the absence of untreated recent uti and aspiration of thick or foul pus, continuing pcnl can be safe while purulent urine is encountered. keywords: urinary tract infection, percutaneous nephrolithotomy, suppuration 1department of endourology, shaheed hasheminejad kidney center, iran university of medical sciences, tehran, iran 2medical students research committee, iran university of medical sciences, tehran, iran corresponding author: masoud etemadian, md department of urology, shaheed hasheminejad hospital, vanak sq, tehran, iran tel: +98 21 8864 4444 fax: +98 21 8864 4447 e-mail: etemadian@hotmail.com received september 2007 accepted january 2008 introduction technical advances and increased experience have resulted in considerable refinement of the percutaneous approach to kidney calculi. significant reductions in morbidity and costs have occurred because of the development of nephrostomy tract balloon dilators, improved grasping instruments, and the use of improved methods of calculus fragmentation and removal. (1,2) however, even in experienced hands, major and minor complications may be occurring in 1.1% to 7% and 11% to 25% of patients, respectively.(3,4) therefore, more efforts have been performed to minimize the complications of percutaneous approach to kidney urol j. 2008;5:28-33. www.uj.unrc.ir percutaneous nephrolithotomy and cloudy urine—etemadian et al urology journal vol 5 no 1 winter 2008 29 calculi. one of these is recently focused on the patients with purulent fluid culture.(5) some patients undergoing percutaneous nephrolithotomy (pcnl) have purulent fluid in the pyelocaliceal system at the time of puncture. on the other hand, aspiration of incidentally detected purulent fluid at the time of puncture in patients who are candidates for pcnl, when there is no fever and bacteriuria or recent urinary tract infection (uti), is not common. current recommendation in these situations is to place nephrostomy tube and postpone pcnl until the urine from the nephrostomy tube is clear and sterile.(5) we challenged this strategy with this prospective comparative study by continuing pcnl in selected number of patients with purulent fluid and comparing the results with the ones who underwent delayed pcnl. materials and methods patients between march 2005 and july 2007, a total of 520 patients underwent pcnl at our center. the present randomized controlled trial study was carried out on patients who had purulent urine in the pyelocaliceal system at initial puncture. the study was approved by the medical ethics committee of iran university of medical sciences. patients with recent untreated uti, thick or foul pus in aspirated urine, fever, diabetes mellitus, and immunocompromised status were excluded. of 45 patients with purulent urine, 31 met our inclusion criteria and all of them provided written informed consent. the enrolled patients were randomly divided into 2 groups using simple randomization method with the help of a computer-generated table of random numbers. group 1 consisted of 16 patients who underwent pcnl at the same day of aspiration, and in 15 patients in group 2, pcnl was performed 10 days after insertion of nephrostomy tube following purulent urine aspiration. sterile nephrostomy urine was documented in all of the patients of group 2. preoperative care all of the patients had documented negative urine cultures preoperatively. all of the patients received intravenous cefazolin, 1 g, 1 hour preoperatively. an intravenous aminoglycoside was also started on for all of the patients when purulent urine was encountered, and it was continued in the postoperative period until the results of urine and blood cultures were ready. preoperative routine evaluations were done in all of the patients. routine preoperative laboratory tests were unremarkable. surgical technique tubeless pcnl with ureteral catheter placement was performed in the two groups either at the same day of purulent urine aspiration or 10 days thereafter, all by the same surgeon. in both groups, access to the pyelocaliceal system, preferably through the lower calyx, was achieved under fluoroscopic guidance. with the patient under general anesthesia, a 5-f open-ended ureteral catheter was passed cystoscopically and secured to a foley catheter. then the patient was placed in the prone position. access was achieved by advancement of an 18-gauge translumbar angiography needle in the plane of the fluoroscope beam. tract was dilated over the wire to 30 f using one-shot method. a 30-f amplatz sheath was placed. the calculi were fragmented using pneumatic lithotripter, and in some cases, plus ultrasonic lithotripter. additional tracts were created whenever necessary with the aim of complete calculus clearance and drainage of all obstructed calyces. nephroscopy and calculus fragmentation were performed in low pressure field through the procedures. after complete calculus clearance was confirmed fluoroscopically and endoscopically, the 5-f ureteral catheter was left in place. then the amplatz sheath was removed and nephrostomy was not placed in any of the patients. postoperative care closed observation and checking of vital signs were performed for all of the patients after the procedure. noncontrast computed tomography (ct) was done on the first postoperative day. data including operative time, duration of hospital stay, stone-free rate, cultures of the percutaneous nephrolithotomy and cloudy urine—etemadian et al 30 urology journal vol 5 no 1 winter 2008 purulent fluid, laboratory studies and cultures of urine and blood, and rate of fever and sepsis episodes were recorded. in addition, calculus cultures were performed in all of the patients. statistical analyses data were analyzed using the spss (statistical package for the social sciences, version 13.0, spss inc, chicago, ill, usa). the student t test, and the mann-whitney u test, and the chisquare test were used for comparisons between the two groups. also, linear regression model was performed to evaluate the factors affecting duration of hospital stay. quantitative variables were provided as mean standard deviation. p values less than .05 were regarded significant. results all of the patients completed the study. they were 22 men (71.0%) and 9 women (29.0%) with a mean age of 42.2 12.5 years (range, 19 to 68 years). as it is listed in table 1, the patients’ demographic and clinical characteristics were similar in the two groups. the mean age, sex distribution, operative time, and calculus size and composition did not differ significantly between the two groups. additionally, all patients had documented negative urine cultures for microorganisms, preoperatively. the purulent aspirated fluid was infected in 43.8% and 40.0% of the patients in groups 1 and 2, respectively. enterobacteriaceae were the only detected bacteria, with escherichia coli to be the most common bacterium in both groups. urine cultures in group 1 showed escherichia coli in 4 patients, proteus mirabilis in 2, and pseudomonas aeruginosa in 1. in group 2, urine cultures revealed escherichia coli in 4 patients, proteus mirabilis in 1, and klebsiella pneumoniae in 1. four patients in each group developed mild fever (< 38.5°c) who were treated conservatively. one patient in group 1 developed severe fever (39°c) that was managed conservatively. his hospital stay lasted 7 days. additional blood cultures were negative in this patient. parameter group 1 (same-day pcnl) group 2 (delayed pcnl) p patients 16 15 … age, y 42.2 ± 12.4 42.1 ± 13.0 .99 sex female 12 (75.0) 10 (66.7) male 4 (25.0) 5 (33.3) .70 calculus size, mm 33.94 ± 5.26 36.20 ± 5.43 .25 stone composition calcium oxalate 10 (62.5) 9 (60.0) uric acid 2 (12.5) 2 (13.3) struvite 4 (25.0) 4 (26.7) .99 operative time, min 68.1 ± 14.9 67.3 ± 14.6 .89 number of tracts 1.3 ± 0.5 1.3 ± 0.5 .79 blood transfusions 1 (6.3) 2 (13.3) .60 postoperative results positive urine culture 5 (37.5) 33.3 .81 positive purulent fluid culture 7 (43.8) 6 (40.0) .83 positive blood culture 1 (6.3) 1 (6.7) .58 fever negative 12 (75.0) 11 (73.3) < 38.5°c 3 (18.8) 4 (26.7) > 38.5°c 1 (6.3) 0 .56 stone-free rate, % 93.7 93.3 .77 duration of hospitalization, d 2.7 ± 1.4 2.5 ± 0.9 .96 table 1. demographic and clinical parameters in patients who underwent percutaneous nephrolithotomy (pcnl) just after aspiration of cloudy urine (groups 1) or 10 days thereafter (group 2)* *values in parentheses are percents. values of continuous variables are demonstrated as mean ± standard deviation. ellipsis indicates not applicable. percutaneous nephrolithotomy and cloudy urine—etemadian et al urology journal vol 5 no 1 winter 2008 31 no statistical differences were observed between two groups in terms of bacteriuria, bacteremia, positive calculus cultures, or postoperative fever. additionally, there were no significant differences in the stone-free rate (93.7% versus 93.3%, p = .77) and duration of hospitalization (2.69 ± 1.40 days versus 2.53 ± 0.91 days, p = .96) between groups 1 and 2, respectively. however, more analysis with linear regression model showed that postoperative positive blood culture (p < .001), fever (p = .001), and postoperative positive urine culture (p = .02) significantly correlated with duration of hospitalization (p < .001, r2 = 0.895). table 2 outlines the results of linear regression model. discussion percutaneous extraction of kidney calculi in patients whose urines are sterile is considered to be a clean-contaminated surgery. postoperative infections, if any, are thought to be the result of the urethral catheter, nephrostomy tube, obstructed calyxes or pelvis, calculus-bearing bacteria, and blood transfusion.(6) it is not uncommon to find purulent fluid at the time of achieving access during pcnl. the aspirated fluid is not always infected, but the microorganisms which are more implicated are the gram-negative bacteria. aron and colleagues(7) reported that fewer than half of the patients in their series had organisms recovered on the culture of the purulent fluid from the kidney, indicating that the pus may be sterilized by previous antibiotic use or that it may represent a sterile inflammatory tissue response to the calculus. even turbidity secondary to macroscopic crystalline or amorphous calculi debris can cause such a fluid.(7) a patient with intracollecting system abscess, such as a pyocalix or pyonephrosis secondary to infection and distal obstruction, presents with an acute septicemia or a chronic condition. the patient’s symptoms may be so minimal if they suffer from a chronic condition. fever and a slight flank discomfort might be the only symptoms which are prone to negligence. these patients may have only a mild leukocytosis and the urine culture is often negative for infection.(8) it is usually advised not to attempt to perform pcnl in such situations. it is reported that after 5 to 7 days of antibiotic coverage, the urine cultured from the bladder and the drained catheter is usually sterile. at this time, therapy for kidney calculi can be safely pursued.(9) in a study of the cultures of urinary calculi obtained from patients with preoperative bacteriuria, it was revealed that 77% of the calculi harbored bacteria.(10) hence, urinary calculi provide a good condition for the bacteria. on the other hand, the presence of sterile urine in a patient with calculus does not preclude postoperative bacteriuria. charton an coworkers(11) recorded a 35% incidence of bacteriuria after pcnl among patients with sterile preoperative urine culture in whom prophylactic antibiotic therapy was not used. in another study to evaluate the risk factors of postoperative complications of pcnl, vorrakitpokatorn and colleagues(12) reported that infection is the most serious complication of pcnl and increase length of hospital stay, and antibiotics started at the beginning of the surgery could not always prevent this event. complications during or after pcnl may be present with an overall rate of up to 83%, of which fever is a frequent one.(13) the reported frequency of fever after pcnl is between 25.8% and 35% in the current literature.(13-16) variable unstandardizedcoefficient b (se) standardized coefficient beta t p constant 2.01 (0.09) … 22.30 < .001 postoperative positive blood culture 2.15 (0.32) 0.55 6.64 < .001 postoperative fever 0.77 (0.21) 0.35 3.65 .001 postoperative positive urine culture 0.48 (0.19) 0.20 2.48 .02 table 2. linear regression model for prediction of hospital stay duration (r2 = 0.895)* *ellipsis indicates not applicable. se indicates standard error. percutaneous nephrolithotomy and cloudy urine—etemadian et al 32 urology journal vol 5 no 1 winter 2008 the duration of surgery and the amount of irrigation fluid can be significant risk factors for postoperative fever.(17) systemic absorption of irrigation fluid containing bacteria or endotoxin may lead to fever and urosepsis after percutaneous nephrolithotomy.(18) fluid can be absorbed through pyelovenous-lymphatic back-flow, pyelotubular backflow, and forniceal rupture.(18) in our study, when purulence was encountered after amplatz sheath placement, we sucked out all the fluid and then gently irrigated the pyelocaliceal system directly under low pressure without the use of nephroscope. saltzman and coworkers(19) showed that using a nephroscopy sheath results in lower intrarenal pressure than using a telescopic dilating system in creating the nephrostomy tract. in another study by troxel and low,(18) 64% and 24% of the patients with infectious and noninfectious calculi had postpcnl fever, respectively. they suggested that there was no association between renal pressure greater than 30 mm hg and fever; however, postoperative fever and pcnl done for infectionrelated calculi were correlated significantly. conversely, urosepsis during pcnl can be catastrophic despite prophylactic antibiotic therapy and sterile preoperative urine.(20,21) sepsis may seen in 0.3% to 2.5% of patients undergoing pcnl.(3,4) vorrakitpokatorn and colleagues(12) reported septic shock in 4.7% of patients. there are various putative factors and variables that may predict the development of postoperative sepsis.(20) bladder urine culture has been found to correlate poorly with infection in the upper urinary tract.(21) it has been postulated that bacteria in the calculus may be responsible for systemic infection. on the other hand, positive calculus culture and pelvic urine culture are better predictors of potential urosepsis than bladder urine. therefore, routine collection of these specimens is recommended.(20) finding pus during the performance of a pcnl should alert one to the possibility of sepsis, which can occur whether the procedure is completed in the same setting or in two stages.(7) sepsis after pcnl indicates a poor technique with high pressure within the collecting system during manipulation. this problem can be avoided by using continuous flow instruments or an amplatz sheath.(18,22) for this reason, we used amplatz sheath in all of the patients in our study. it is advised that all patients undergoing percutaneous procedures should have urine cultures preoperatively with the administration of an appropriate antibiotic to sterilize the urine. in a randomized prospective study, inglis and tolley showed that prophylactic antibiotic treatment reduced the incidence of uti in patients with preoperative sterile urine who underwent pcnl (2% versus 12% with and without antibiotic prophylaxis, respectively).(23) hosseini and colleagues(24) showed that when the urologist incidentally find purulent fluid in the puncture site, performing pcnl is possible with full antibiotic coverage in the same session. we also found prompt pcnl when purulent fluid is aspirated during the procedure is safe; however, there were factor such as fever, positive blood culture, and positive urine culture could potentially increase the length of hospitalization. we performed the procedure in selected patients with cloudy urine at the time of pcnl and the same-day pcnl was done considering factors mentioned above. we did not have any infectionrelated complication. conclusion same-day pcnl in patients with aspirated cloudy urine can be performed if a low pressure 30-f amplatz sheath is used, increasing intrarenal pressure during the procedure is avoided, multiple tracts are obtained if needed, and good antibiotic coverage is considered. however, in patients with obstructing semiopaque calculi, leukocytosis, untreated recent uti, and aspiration of thick or foul pus, it is safer to drain the urine through percutaneous nephrostomy tube alone and postpone pcnl to a later time. in the absence of the above factors, we do not face any uncontrollable complications with continuing pcnl, if the pyelocaliceal system is drained completely. however, regarding our small sample size, it seems that statistical powers of the test are not high enough. therefore, large prospective studies with greater sample sizes are required to validate our conclusions. percutaneous nephrolithotomy and cloudy urine—etemadian et al urology journal vol 5 no 1 winter 2008 33 conflict of interest none declared. references 1. pietrow pk, auge bk, zhong p, preminger gm. clinical efficacy of a combination pneumatic and ultrasonic lithotrite. j urol. 2003;169:1247-9. 2. auge bk, sekula jj, springhart wp, zhu s, zhong p, preminger gm. in vitro comparison of fragmentation efficiency of flexible pneumatic lithotripsy using 2 flexible ureteroscopes. j urol. 2004;172:967-70. 3. lam hs, lingeman je, mosbaugh pg, et al. evolution of the technique of combination therapy for staghorn calculi: a decreasing role for extracorporeal shock wave lithotripsy. j urol. 1992;148:1058-62. 4. segura jw, preminger gm, assimos dg, et al. nephrolithiasis clinical guidelines panel summary report on the management of staghorn calculi. the american urological association nephrolithiasis clinical guidelines panel. j urol. 1994;151:1648-51. 5. viville c, giron jp. [endoscopic and percutaneous treatment of purulent retention caused by obstructive calculi of the upper urinary tract. observations apropos of 6 case reports]. j urol (paris). 1988;94:317-8. french. 6. baude c, long d, chabrol b, wherlin p, gelet a, moskovtchenko jp. [antibiotic prophylaxis with cefotiam in percutaneous nephrolithotomy]. pathol biol (paris). 1989;37:673-6. french. 7. aron m, goel r, gupta np, seth a. incidental detection of purulent fluid in kidney at percutaneous nephrolithotomy for branched renal calculi. j endourol. 2005;19:136-9. 8. brennan re, pollack hm. nonvisualized (“phantom”) renal calyx: causes and radiological approach to diagnosis. urol radiol. 1979;1:17-23. 9. meretyk s, bigg s, clayman rv, kavoussi lr, mcclennan bl. caveat emptor: caliceal stones and the missing calix. j urol. 1992;147:1091-5. 10. larsen eh, gasser tc, madsen po. antimicrobial prophylaxis in urologic surgery. urol clin north am. 1986;13:591-604. 11. charton m, vallancien g, veillon b, brisset jm. urinary tract infection in percutaneous surgery for renal calculi. j urol. 1986;135:15-7. 12. vorrakitpokatorn p, permtongchuchai k, raksamani eo, phettongkam a. perioperative complications and risk factors of percutaneous nephrolithotomy. j med assoc thai. 2006;89:826-33. 13. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899906. 14. sharifi aghdas f, akhavizadegan h, aryanpoor a, inanloo h, karbakhsh m. fever after percutaneous nephrolithotomy: contributing factors. surg infect (larchmt). 2006;7:367-71. 15. rao pn, dube da, weightman nc, oppenheim ba, morris j. prediction of septicemia following endourological manipulation for stones in the upper urinary tract. j urol. 1991;146:955-60. 16. lee wj, smith ad, cubelli v, et al. complications of percutaneous nephrolithotomy. ajr am j roentgenol. 1987;148:177-80. 17. doğan hs, sahin a, cetinkaya y, akdoğan b, ozden e, kendi s. antibiotic prophylaxis in percutaneous nephrolithotomy: prospective study in 81 patients. j endourol. 2002;16:649-53. 18. troxel sa, low rk. renal intrapelvic pressure during percutaneous nephrolithotomy and its correlation with the development of postoperative fever. j urol. 2002;168:1348-51. 19. saltzman b, khasidy lr, smith ad. measurement of renal pelvis pressures during endourologic procedures. urology. 1987;30:472-4. 20. mariappan p, smith g, bariol sv, moussa sa, tolley da. stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study. j urol. 2005;173:1610-4. 21. mariappan p, tolley da. endoscopic stone surgery: minimizing the risk of post-operative sepsis. curr opin urol. 2005;15:101-5. 22. kim sc, kuo rl, lingeman je. percutaneous nephrolithotomy: an update.curr opin urol. 2003;13:235-41. 23. inglis ja, tolley da. antibiotic prophylaxis at the time of percutaneous stone surgery. j endourol 1988,2:5962. 24. hosseini mm, basiri a, moghaddam sm. percutaneous nephrolithotomy of patients with staghorn stone and incidental purulent fluid suggestive of infection. j endourol. 2007;21:1429-32. v07_no_4.pdf pictorial urology 225urology journal vol 7 no 4 autumn 2010 gas in the renal area emphysematous pyelonephritis urol j. 2010;7:225. www.uj.unrc.ir a 37-year-old diabetic woman presented to the emergency department with a week’s history of high fever, abdominal pain, and vomiting. she was febrile, tachypneic, tachycardic, and hypotensive. her laboratory investigations revealed a total lymphocyte count of 6000/cu mm, with 6% band forms and 87% neutrophils. her platelet count and creatinine level were 15 000/cu mm and 2.6 mg/dl, respectively. her blood and urine cultures were positive for escherichia coli. arterial blood gas revealed metabolic acidosis. plain x-ray of the abdomen showed a reniform shaped presence of air in the right renal area. a diagnosis of emphysematous pyelonephritis was made based on the classical presence of air within the kidney. she underwent initial hemodynamic stabilization and a bedside placement of a percutaneous nephrostomy along with culturespecific parenteral antibiotics. with the above conservative measures, she dramatically improved and had a normal creatinine (1.1 mg/dl) ten days later at discharge. the treatment of emphysematous pyelonephritis has undergone a paradigm shift, from nephrectomy to percutaneous drainage and antibiotics. there are a number of studies which substantiate that even in the more serious forms (viz., class 3/4), percutaneous drainage along with appropriate parenteral antibiotics are sufficient. (1) predictors of mortality in this disease are thrombocytopenia, shock, altered sensorium, and ongoing need for dialysis.(2) although our patient had two of the four poor prognostic factors at presentation, she improved remarkably with bedside drainage, highlighting the importance of early diagnosis and prompt treatment. this image stresses the need to aggressively investigate the unresolved case of an acute abdomen. john samuel banerji department of urology, christian medical college, vellore, tamil nadu, india e-mail: johnsbanerji2002@yahoo.co.in references 1. somani bk, nabi g, thorpe p, hussey j, cook j, n’dow j. is percutaneous drainage the new gold standard in the management of emphysematous pyelonephritis? evidence from a systematic review. j urol. 2008;179:1844-9. 2. aswathaman k, gopalakrishnan g, gnanaraj l, chacko nk, kekre ns, devasia a. emphysematous pyelonephritis: outcome of conservative management. urology. 2008;71:1007-9. endourology and stone disease 207urology journal vol 4 no 4 autumn 2007 transureteral lithotripsy versus extracorporeal shock wave lithotripsy in management of upper ureteral calculi a comparative study mohammad reza nikoobakht, ala emamzadeh, amir reza abedi, kamran moradi, abdolrasoul mehrsai introduction: our aim was to compare transureteral lithotripsy (tul) and extracorporeal shock wave lithotripsy (swl) in the management of upper ureteral calculi larger than 5 mm in diameter. materials and methods: patients who had upper ureteral calculi between 5 mm and 10 mm in diameter were enrolled in this clinical trial. the calculi had not responded to conservative or symptomatic therapy. semirigid ureteroscopy and pneumatic lithotripsy were used for tul in 52 patients and swl was performed in 48. analysis of the calculi compositions was done and the patients were followed up by plain abdominal radiography and ultrasonography 3 month postoperatively. results: the stone-free rates were 76.9% in the patients of the tul group and 68.8% in the patients of the swl group. these rates in the patients with mild or no hydronephrosis were 85.7% and 59.1% for the swl and tul groups, respectively. in the tul group, half of the patients with no hydronephrosis developed upward calculus migration. the stone-free rates were 75.0% and 89.3% for the patients with moderate hydronephrosis and 70.0% and 100.0% for those with severe hydronephrosis in the swl and tul groups, respectively. all of the failed cases were treated by double-j stenting and tul or swl successfully. there were no serious complications. upward calculus migration after tul was more frequent in cases with no hydronephrosis or mild hydronephrosis (41.0%). conclusion: upper ureteral calculi smaller than 1 cm can be safely and effectively managed using semirigid ureteroscopy and pneumatic lithotripsy. however, the swl approach has still its role if an experienced endourologist is not available. urol j. 2007;4:207-11. www.uj.unrc.ir keywords: urinary calculi, ureter, shock wave lithotripsy, transureteral lithotripsy urology research center, sina hospital, tehran university of medical sciences, tehran, iran corresponding author: mohammad reza nikoobakht, md urology research center, sina hospital, hassanabad sq, tehran 1995345432, iran tel: +98 21 6670 1041 fax: +98 21 6671 7447 e-mail: nikoobakht_m@hotmail.com received november 2006 accepted june 2007 introduction the optimal treatment option for ureteral calculi is a controversial issue. for proximal ureteral calculi, the options are extracorporeal shockwave lithotripsy (swl) with or without calculus manipulation, ureteroscopy, percutaneous nephrolithotomy (pnl), and rarely, open or laparoscopic surgery. size of the calculus is the most significant factor affecting calculus passage.(1) it has been shown that for calculi smaller than 4 mm, 4 mm to 6 mm, and larger than 6 mm, the rates of spontaneous passage are 80%, 59%, and 21%, respectively.(2) the rate of spontaneous passage is highly dependent on calculus location, as well. passage rates from the proximal, middle, and distal ureteral calculi are reportedly 22%, 46%, and 71%, respectively.(3) transureteral and extracorporeal shockwave lithotripsy—nikoobakht et al 208 urology journal vol 4 no 4 autumn 2007 most of the published studies have focused on the management of the distal ureteral calculi. although ureteral calculi are known to fragment less frequently than kidney calculi, swl has remained their preferred treatment method because of its minimally invasive nature.(1-4) transureteral lithotripsy (tul) has been recommended as the first-line therapy for patients in whom swl fails.(5) the introduction of small-caliber semirigid ureteroscopes, as well as the holmium: yttrium-aluminum-garnet laser, has substantially improved the stone-free rate and decreased the risk of complications resulting from ureteroscopy.(6,7) however, the magnitude and rate of introduction and the acceptance of new technology are major determinants of total healthcare costs.(8) in this respect, urologists are becoming more accountable for the economics of healthcare and should consider the true total costs of different treatment modalities.(9,10) to date, few studies have compared the optimal therapy for the management of small-sized upper ureteral calculi. park and associates compared the results of swl and tul for proximal and distal ureteral calculi and showed that whereas the efficacy of swl dropped significantly for calculi larger than 1 cm in comparison with smaller calculi (83.6% versus 42.1%), the stone-free rate with ureteroscopic manipulation was not affected by the calculus size (88.9% versus 86.6%).(11) we compared ureteral lithotripsy with semirigid ureteroscopy and lithotripsy (using pneumatic lithotripter) with swl for the management of upper ureteral calculi sized larger than 5 mm in diameter. materials and methods in this comparative study conducted from march 2005 to march 2006 at sina hospital in tehran, iran, we enrolled 100 patients who had upper ureteral calculi between 5 mm and 10 mm in diameter. patients with contraindications of swl (pregnancy, hemostatic disorders, calcified aortic aneurysm, and morbid obesity) were excluded from the study. after discussing the available therapeutic modalities and their advantages and disadvantages, 52 patients chose tul and 48 chose swl. all of the patients underwent preoperative ultrasonography, intravenous urography, and routine laboratory tests. the swl was performed after 12 hours of fasting and mild intestinal preparation. electromagnetic machine (siemens lithostar, siemens, erlangen, germany) was used for lithotripsy of a maximum 3 sessions (1 session every week for 3 weeks) with 3000 shocks per session using a power of 18.1 kv to 19 kv. during the swl, 1000 ml of normal saline was administered. all of the patients were discharged on the same day with oral analgesics and diuretic (hydrochlorothiazide, 50 mg per 12 hours). excessive fluid consumption was also recommended to the patients. in the tul group, the patients were admitted to the hospital 24 hours preoperatively. on the day of operation, calculus location was being checked by plain abdominal radiography. the procedure was carried out under spinal anesthesia. ureteroscopic evaluation after introducing guide wire was done using a semirigid 9.6-f wolf ureteroscope (richard wolf gmbh, knittlingen, germany), and pneumatic swiss lithoclast (electro medical systems, le sentie, switzerland) was used with a 0.8-mm probe for calculus fragmentation. to avoid migration of calculi, low-pressure fluid stream (ultraviolet ray sterilized tape water), and if indicated, 4-f stone baskets were used. ureteral stent for 24 hours, and in case of ureteral injury, double-j stent for 4 weeks were placed. like in the swl group, hydrochlorothiazide and excessive fluid consumption for 3 months postoperatively were recommended. three months postoperatively, all of the patients were followed by plain abdominal radiography and ultrasonography. the same endourologist and the same postoperative nursing team managed and supervised all of the patients. those with residual calculi sized less than 5 mm were considered stone free. the cost, sick leave, postoperative pain, success rate, and complications of both therapeutic approaches were compared. for statistical analyses, the chi-square test was used. results table 1 shows demographic and clinical characteristics of the patients in the swl and tul groups. three months postoperatively, 40 out of 52 patients (76.9%) in the tul group and 33 out of 48 (68.8%) in the swl group were stone free (table 2). in all patients of the tul group, all failures were due to upward calculus migration. concerning hydronephrosis severity, 5 patients out of 10 (50.0%) in the tul group with no transureteral and extracorporeal shockwave lithotripsy—nikoobakht et al urology journal vol 4 no 4 autumn 2007 209 hydronephrosis developed upward calculus migration which mandated double-j stenting. these patients were referred for swl, all of whom were stone free after this procedure. their calculi size ranged from 6 mm to 8 mm. in patients with mild hydronephrosis, stone-free rate was 75.0% (8 of 12 patients) and 85.7% (12 of 14 patients) in the tul and swl groups, respectively. failed tuls were due to calculus migration and double-j stenting plus swl therapy was successful. the 2 failed swls were stented and re-swl was performed successfully. in the patients with moderate or severe hydronephrosis and failed tul, double-j stent was inserted and retained for 4 weeks, and those with moderate or severe hydronephrosis and failed swl underwent tul and double-j stenting which were successful. postoperative severe pain and limited gross hematuria were the most frequent complications in the patients of the swl and tul groups, respectively (table 2). results of the calculi analyses are shown in table 2. most of the failed swl therapies were in cases of cystine or calcium phosphate calculi. finally, there was no major difference between the treatment costs in the two groups (swl, us $ 250 versus tul, us $ 310), while the sick leave (postoperative home rest) in the swl group was more (12 days versus 3 to 5 days) due to the repeated admissions to the hospital. discusson location, composition, and size of the ureteral calculus, duration of the disease, associated pain, anatomic variations, infection, patient’s expectancy, therapeutic cost, and equipments availability are all the factors upon which management approaches of ureteral calculi are chosen. the length of time a calculus remains in the ureter becomes significant when obstruction occurs; even with complete ureteral obstruction, irreversible loss of kidney function does not occur before 2 weeks, but it can progress to total renal unit loss in 6 weeks.(12) a study on 54 patients with ureteral calculi showed that 28% of patients had impairment of kidney function at presentation. interestingly, small calculi were as likely to cause impaired kidney function as larger calculi. patients who underwent early intervention (within less than 7 days) had a better outcome than did patients with delayed intervention.(13) because the patient’s symptoms and calculus size do not predict loss of kidney function, and because there is no clear time threshold for irreversible damage, intervention should be strongly considered in any patient with ureteral obstruction unless close monitoring of kidney function is available.(13,14) we considered every ureteral calculus sized greater than 5 mm that had not responded to symptomatic or conservative therapy as a urologic emergency. features swl tul p outcomes stone-free patients 33 (68.8) 40 (76.9) .04 stone-free patients in hydronephrosis groups no or mild 12 (85.7) 13 (59.1) .03 moderate 18 (75.0) 25 (89.3) .04 severe 7 (70.0) 2 (100.0) .01 complications febrile uti 0 1 (1.9) postoperative fever 3 (6.3) 1 (1.9) macroscopic hematuria 2 (4.2) 24 (46.2) ureteral perforation 0 3 (5.8) severe pain 8 (16.7) 2 (3.8) calculus migration 0 12 (23.1) table 2. outcomes and complications after swl and tul* *values in parentheses are percents. swl indicates shock wave lithotripsy; tul, transureteral lithotripsy; and uti, urinary tract infection. characteristic swl tul number of patients 48 52 mean age (range), y 41.1 (18 to 69) 35.7 (21 to 46) sex male 35 (72.9) 40 (76.9) female 13 (37.1) 12 (23.1) hydronephrosis no 0 10 (19.2) mild 14 (29.2) 12 (23.1) moderate 24 (50.0) 28 (53.8) severe 10 (20.8) 2 (3.8) calculus side right 18 (37.5) 22 (42.3) left 30 (62.5) 30 (57.7) mean calculus size, mm 8 (16.7) 9 (17.3) calculus type oxalate 22 (45.8) 38 (73.1) cystine 3 (6.3) 1 (1.9) uric acid 6 (12.5) 1 (1.9) calcium phosphate 2 (4.2) 0 unknown 15 (31.3) 12 (23.1) table 1. demographic and clinical features of patients in swl and tul groups* *values in parentheses are percents unless otherwise indicated. swl indicates shock wave lithotripsy and tul, transureteral lithotripsy. transureteral and extracorporeal shockwave lithotripsy—nikoobakht et al 210 urology journal vol 4 no 4 autumn 2007 the panel on ureteral calculi clinical guideline of the american urological association suggested that swl, by whatever technique (push-back or in situ), should be the primary approach for calculi smaller than 1 cm in the proximal ureter.(15) this recommendation is based on a meta-analysis of all articles on ureteral calculi published over a 30-year period from 1966 to 1996. the results were analyzed for swl in situ, swl after push-back technique, swl after stent insertion, pnl, ureteroscopy, and open calculus surgery. for calculi smaller than 1 cm in diameter, the stone-free rates by swl and ureteroscopy were 84% and 56%, respectively, and for calculi larger than 1 cm, 72% and 44%, respectively.(15) our study revealed better success rate with ureteroscopic approach, especially in patients with higher grades of hydronephrosis. these results were similar to the results of a study by yagisawa and associates.(16) they compared swl and ureteroscopy with pneumatic lithotripsy for impacted ureteral calculi, and although the stone-free rate at 1 month was 100% for patients treated with ureteroscopy, all the calculi treated by swl required further auxiliary endoscopic manipulation. in our study, the costs were relatively similar in both approaches. however, swl machines are still nonportable and expensive. on the other hand, the portability, cost efficacy, and durability of pneumatic lithotripters and semirigid ureteroscopes make tul an approach comparable with swl for small upper ureteral calculi. especially, with regard to the advent in anesthetic approaches for such interventions, tul can be an outpatient treatment option. however, patients with nonimpacted upper ureteral calculi should be referred directly for swl, while it is much reasonable to refer those with impacted calculi for tul. a review of the literature shows excellent results for ureteroscopic lithotripsy using the holmium laser for proximal as well as distal ureteral calculi, with a mean stonefree rate of 95% associated with a low perforation and stricture rate of about 1%. these results are equivalent or superior to the results achieved by swl for proximal ureteral calculi.(1,4,6,7) we used pneumatic lithoclast, despite the risk of calculus migration with this type of management, but still its low cost, portability, availability, and durability in comparison with laser machines, makes it attractive in our country. calculus composition is another challenge to decision making. spiral noncontrast computed tomography (ct) is often used for detecting ureteral calculi,(17) and concerning studies using ct attenuation values to predict calculus composition,(18) it may become a valuable aid in determining ureteral calculus composition before treatment. this excessive evaluation may add extra cost to swl approach, while there is no need for determining calculus composition before tul. the only real challenge to the use of ureteroscopic approach plus pneumatic lithotripsy for the management of upper ureteral calculi is upward calculus migration, especially in those without hydronephrosis or with mild hydronephrosis. this issue was previously resolved by using holmium laser for calculus fragmentation with high safety and success rate,(11) but still the cost burden of laser machine and probe are the limitations. albeit partially, we resolved this problem by using weak irrigation stream system once reaching the calculus without using additional auxiliary devices (like baskets), and if required, by closing the input and opening output irrigation access to make reciprocal downward stream that helped to draw the calculus towards the lithotripter probe and ureteroscope head. we think that initial swl trial in those with no hydronephrosis or with mild hydronephrosis is more logical, and initial tul approach is more suitable for those with moderate or severe hydronephrosis. finally, we believe that the experience and preference of the endourologist in calculus managements still have their priority in this field of surgery. conclusion with the advent of new anesthesia methods and ureteroscopic equipments, upper ureteral calculi smaller than 1 cm can be initially managed ureteroscopically by experienced surgeons safely and effectively, especially if there is high index of suspicion of impacted or swl-resistant calculi. the experience of the endourologist is very important in making decision. conflict of interest none declared. references 1. anderson kr, keetch dw, albala dm, chandhoke ps, mcclennan bl, clayman rv. optimal therapy for the distal ureteral stone: extracorporeal shock wave transureteral and extracorporeal shockwave lithotripsy—nikoobakht et al urology journal vol 4 no 4 autumn 2007 211 lithotripsy versus ureteroscopy. j urol. 1994;152:62-5. 2. ueno a, kawamura t, ogawa a, takayasu h. relation of spontaneous passage of ureteral calculi to size. urology. 1977;10:544-6. 3. morse rm, resnick mi. ureteral calculi: natural history and treatment in an era of advanced technology. j urol. 1991;145:263-5. 4. eden cg, mark ir, gupta rr, eastman j, shrotri nc, tiptaft rc. intracorporeal or extracorporeal lithotripsy for distal ureteral calculi? effect of stone size and multiplicity on success rates. j endourol. 1998;12:30712. 5. pace kt, weir mj, tariq n, honey rj. low success rate of repeat shock wave lithotripsy for ureteral stones after failed initial treatment. j urol. 2000;164:1905-7. 6. lam js, greene td, gupta m. treatment of proximal ureteral calculi: holmium:yag laser ureterolithotripsy versus extracorporeal shock wave lithotripsy. j urol. 2002;167:1972-6. 7. wu cf, shee jj, lin wy, lin cl, chen cs. comparison between extracorporeal shock wave lithotripsy and semirigid ureterorenoscope with holmium:yag laser lithotripsy for treating large proximal ureteral stones. j urol. 2004;172:1899-902. 8. jewett ma, bombardier c, menchions cw. comparative costs of the various strategies of urinary stone disease management. urology. 1995;46:15-22. 9. guyatt g, drummond m, feeny d, et al. guidelines for the clinical and economic evaluation of health care technologies. soc sci med.1986;22:393-408. 10. challah s, mays nb. the randomised controlled trial in the evaluation of new technology: a case study. br med j (clin res ed). 1986;292:877-9. 11. park h, park m, park t. two-year experience with ureteral stones: extracorporeal shockwave lithotripsy v ureteroscopic manipulation. j endourol. 1998;12:5014. 12. vaughan ed jr, gillenwater jy. recovery following complete chronic unilateral ureteral occlusion: functional, radiographic and pathologic alterations. j urol. 1971;106:27-35. 13. irving so, calleja r, lee f, bullock kn, wraight p, doble a. is the conservative management of ureteric calculi of > 4 mm safe? bju int. 2000;85:637-40. 14. whitfield hn. the management of ureteric stones. part ii: therapy. bju int. 1999;84:916-21. 15. segura jw, preminger gm, assimos dg, et al. ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. the american urological association. j urol. 1997;158:1915-21. 16. yagisawa t, kobayashi c, ishikawa n, kobayashi h, toma h. benefits of ureteroscopic pneumatic lithotripsy for the treatment of impacted ureteral stones. j endourol. 2001;15:697-9. 17. older ra, jenkins ad. stone disease. urol clin north am. 2000;27:215-29. 18. mostafavi mr, ernst rd, saltzman b. accurate determination of chemical composition of urinary calculi by spiral computerized tomography. j urol. 1998;159:673-5. unclassified a comparative study on the clinical efficacy of modified circumcision and two other types of circumcision quanxin su1,2, shenglin gao1, jiasheng chen1, chao lu1, weijiang mao1, xingyu wu1, lifeng zhang1*, li zuo1** purpose: to compare the clinical effects of three methods of circumcision: modified circumcision, traditional circumcision, and disposable suturing device circumcision. materials and methods: male patients (n = 241) with redundant prepuce and/or phimosis were included in a clinical trial from january 2019 to march 2020. patients were divided into 3 groups based on the surgical method: group a, traditional circumcision (n = 79); group b, modified circumcision (n = 80); and group c, disposable suturing device circumcision (n = 82). results: the operation times in groups a, b, and c were 25.2 ± 3.3 min, 10.2 ± 2.7 min, and 6.7 ± 1.4 min, respectively. the volumes of intraoperative blood loss in groups a, b, and c were 12.7 ± 2.3 ml, 8.1 ± 3.4 ml, and 2.2 ± 0.8 ml, respectively (p < 0.05). groups a and b were superior to group c in terms of the 6-h postoperative visual analog scale score and appearance satisfaction (p < 0.05). there were no obvious differences in the 7-day postoperative pain score and total healing time (p > 0.05). the operating expenses in groups a and b were lower than that in group c (p < 0.05). conclusion: modified circumcision, with its advantages of shorter operation time, less blood loss and pain, lower cost, and better postoperative penile appearance, is easily accepted by patients and deserves wide clinical application. keywords: redundant prepuce; phimosis; disposable circumcision suture devices; postoperative complications. introduction redundant prepuce and phimosis are common male external genital diseases, and circumcision is the first-choice therapy for such diseases.(1) due to the long operation duration, great intraoperative blood loss, and prolonged postoperative healing course, traditional circumcision has lower acceptance in patients. in recent years, disposable circumcision sutures with the advantages of incisions with favorable appearance, less bleeding, and short operation time have been widely used, gradually replacing traditional circumcision.(2) however, with their popularity in the clinic, some problems have also been identified. herein, we aimed to examine the operation time, intraoperative blood loss, postoperative complications, complete healing time of the incision, and surgical satisfaction in order to evaluate the surgical outcomes of three different types of male circumcision. materials and methods study population the data was collected from january 2019 to march 2020. three different types of circumcision were con1department of urology, the affiliated changzhou no. 2 people’s hospital of nanjing medical university, changzhou 213003, jiangsu, china. 2dalian medical university, dalian, liaoning, china. *correspondence: lifeng zhang, department of urology, the affiliated changzhou no. 2 people’s hospital of nanjing medical university, changzhou 213003, jiangsu, china. tel:+86 519 88123501. e-mail: nj-likky@163.com. **department of urology, the affiliated changzhou no. 2 people’s hospital of nanjing medical university, changzhou 213003, jiangsu, china. phone:+86 519 88123501. e-mail: zuoli1978@hotmail.com. received april 2020 & accepted october 2020 ducted in adult patients with redundant prepuce or phimosis in our department, where the choice of the surgical method followed patients’ preference. a total of 241 patients were enrolled in the study and all patients enrolled have completed follow-up. in accordance with the different surgical methods, the patients were divided into the following groups: group a (traditional circumcision, n = 79), group b (modified circumcision, n = 80), and group c (suturing device circumcision, n = 82). there were no significant differences between the three groups in terms of the indications for male circumcision (p > 0.05). the patient characteristics of the three groups are illustrated in table 1. the study was approved by the ethics committee of our hospital, and every participant provided written informed consent. the study excluded patients with foreskin balanitis, glans or prepuce tumors, abnormal penis development, occult penis, diabetic complications, or abnormal hematological examination results. the postoperative routine follow-up lasted 3 months. surgical procedures three groups of patients underwent the same preoperative preparation: supine position, routine preparation urology journal/vol 18 no. 5/ september-october 2021/ pp. 556-560. [doi: 10.22037/uj.v16i7.6193] of the skin, routine field disinfection with povidone iodine, and spreading of a towel, with 2% lidocaine block anesthesia of the penile dorsal nerve which children used 10ml and adults used 15-20ml based on height and weight. all patients were wrapped around the cutting edge with vaseline-coated gauze after the surgery, and the outer layer was properly pressurized and bandaged using elastic bandages. patients with high risk of thrombus were treated with nadroparin calcium (qd). the gauze was removed 3 days after the surgery and medicine was changed once every 2 days. group a first, the foreskin inner and outer plates were lifted using artery forceps at the 3 and 9 o’ clock positions, resulting in perpendicular positioning of the penis. second, between the two artery forceps, at the 12 o’ clock position, dissection scissors were used to make an incision (the dorsal slit) extending up to but not beyond the coronary sulcus. redundant foreskin was then removed symmetrically on both sides. third, the bleeding vessels were then tied off using sutures, and the skin edges were approximated using sutures beginning at the frenulum. group b first, the foreskin inner and outer plates were lifted using artery forceps at the 6 and 12 o’clock positions, resulting in perpendicular positioning of the penis. second, the redundant foreskin was clamped using long straight forceps carefully, while the long axis of the forceps extended from the 6 o’clock to the 12 o’clock position. the 6 o'clock position was slightly higher than the 12 o'clock position. third, the redundant foreskin was excised with the outer aspect of the forceps using a scalpel. the inner plate length was then trimmed appropriately. fourth, the bleeding vessels were then tied off using sutures, and the skin edges were approximated using sutures beginning at the frenulum. (figure 1) group c first, an appropriate circumcision suture device was selected according to the penis circumference (used toncare circumcision suture devices).(figure2). second, the prepuce was clamped using 2–3 artery forceps and lifted to place the glans receiver socket on the glans. the redundant prepuce was then fixed to the bell pole using the tie. third, the bell pole was inserted into the center of the housing carefully. the adjustment knob was installed and tightened clockwise to align the end of the bell pole with the top of the adjustment knob. after removing the safety catch, the handles were grasped to excise the redundant prepuce. fourth, the entire bell stand was detached, followed by pressure bandaging of the surgical wound. evaluations in order to evaluate the clinical outcomes, we measured and recorded various intraoperative and postoperative parameters, including the ① operation duration (the time spent from the onset of anesthesia to the end of surgery), ② blood loss during the operation (calculated by 5 cm×5 cm gauze pads that could absorb 5 ml of blood), ③ postoperative pain scores [calculated using the internationally recognized visual analogue scale (vas) score], ④ postoperative complications assessment (including postoperative edema, bleeding, infection, and other surgical complications), ⑤ wound healing period (the time from the day of the surgery to the day of complete wound healing), ⑥ operating expenses, ⑦ appearance satisfaction (follow-up of patients 1 month after the surgery, including incision healing, cutting edge neatness, residual foreskin symmetry, and appropriate frenulum length; the patient satisfaction was reported as "satisfactory" and "dissatisfactory"), and ⑧ sexual function (follow-up of patients 3 months after the surgery). statistical analysis spss 22.0 statistical software was used to process the data. measurement data are presented as means ± standard deviations (range: minimum–maximum). one-way analysis of variance was conducted to compare the differences in the mean among the 3 groups, q test was used for pairwise comparisons between groups, and the x2 test was used for the comparison of rates. p-values < 0.05 were accepted as statistically significant. results operation time, volume of intraoperative blood loss, and operating expenses the operation time and volume of blood loss in groups b and c were significantly lower than those in group a (p < 0.05). the costs of the operation were similar be table 1. general information about the three groups variables a (n = 79) b (n = 80) c (n = 82) p-value age (yr) 26.8 ± 5.3 26.7 ± 6.1 26.5 ± 6.0 > 0.05 mean±sd(range) (5 65) (5 68) (6 67) redundant prepuce 55 56 49 > 0.05 phimosis 24 24 33 > 0.05 variables a (n = 79) b (n = 80) c (n = 82) p-value operation time; min 25.2 ± 3.3 10.2 ± 2.7* 6.7 ± 1.4*△ < 0.001 intraop blood loss; ml 12.7 ± 2.3 8.1 ± 3.4* 2.2 ± 0.8*△ < 0.05 operating expenses; yuan 743 ± 83 739 ± 77 1590 ± 170*△ < 0.001 6h pain; score 6.5 ± 1.3 3.9 ± 1.4* 3.9 ± 1.1*△ < 0.05 7d pain; score 3.3 ± 1.5 3.1 ± 1.3 2.9 ± 1.4 > 0.05 total healing time; day 13.5 ± 3.7 13.2 ± 2.2 12.7 ± 2.2 > 0.05 edema 16(20.3) 9(11.3) 3(3.7)*△ < 0.05 infection 3(3.8) 0(0) 1(1.2) > 0.05 hematoma 1(1.3) 1(1.3) 5(6.1)*△ < 0.05 compared to group a, *p < 0.05; compared to group b, △p < 0.05 group a: traditional circumcision, group b: modified circumcision, group c: suturing device circumcision. table 2. comparison of observation indexes of the three groups clinical effects of modified circumcision-su et al. group a: traditional circumcision, group b: modified circumcision, group c: suturing device circumcision. vol 18 no 5 september-october 2021 557 tween groups a and b, which were significantly lower than those in group c (p < 0.05) (table 2). postoperative pain score and total healing time the 6-h postoperative pain scores in groups b and c were lower than those in group a (p < 0.05). there were no significant differences in the 7-day postoperative pain scores and total healing times among all three groups (p > 0.05) (table 2). postoperative complications complications occurred in 39 of 241 patients, with an incidence rate of 16.1%. the complication rates in groups b and c were lower than that in group a (p < 0.05), with no significant difference between groups b and c (p > 0.05). compared to those in the other two groups, the incidence of edema in group c was lower, but the incidence of hematoma was higher (p < 0.05) (table 2). appearance satisfaction and erectile function the appearance satisfaction in groups b and c were higher than those in group a (p < 0.05), with no significant difference between groups b and c (p > 0.05). in terms of the impact on sexual and erectile function, four patients reported that their sexual function improved, with no significant difference among the three groups (p > 0.05) (table 3). discussion phimosis and redundant prepuce are common diseases of the male external genitalia. with many complications, male health is severely affected, and circumcision is the most effective treatment for these diseases. studies have shown that circumcision reduces the incidences of urinary tract infections and penile cancer. (3,4) moreover, circumcision significantly reduces the spread of human immunodeficiency virus, human papillomavirus, herpes simplex virus, and other sex-related diseases.(5-8) while reducing the risk of gynecologic inflammation in these patients’ sexual partners, circumcision has also become an important component of global health intervention strategies.(9,10) other studies have shown that circumcision can improve male sexual function and prolong sexual life.(11) circumcision has greatly reduced the incidence of prepuce glans and penile tumors, and its surgical method is constantly improving. although traditional circumcision is effective, its shortcomings are also obvious, such as the long operation time, bleeding, postoperative edema, obvious pain, and unsatisfactory postoperative appearance.(12,13) although modern medicine has applied absorbable sutures to traditional circumcision and electrosurgical hemostasis on bleeding points during the operation, which has reduced the ligation of bleeding points and the fear caused by stitching removal. traditional circumcision is still feared by many patients. in recent years, the appearance of circumcision sutures has significantly improved these problems. circumcision suture devices are a novel type of instrument for redundant prepuce cutting and anastomosis. the principle is similar to that of stomach tubes and intestinal staplers. the two steps of incision and suturing are completed simultaneously in an instant, which significantly simplifies the procedure. in this study, patients who used disposable circumcision staplers had short operative time, less bleeding, less postoperative pain, variables a (n = 79) b (n = 80) c (n = 82) p-value appearance;satisfaction/dissatisfaction; n 63/16 75/5* 77/5* < 0.05 sexual function impact; n 1 1 2 > 0.05 table 3. comparison of appearance satisfaction and sexual function among the three groups compared to group a, *p < 0.05 group a: traditional circumcision, group b: modified circumcision, group c: suturing device circumcision. unclassified 558 figure1. surgical procedures for modified circumcision. clinical effects of modified circumcision-su et al. and high profile satisfaction, which is consistent with previous studies.(14,15) however, with the popularity of its clinical application, suturing also exposes some problems, such as greater hematoma after the surgery, shorter frenulum, and greater operating expenses. this study also confirmed these problems. the reason may be that there is a gap between the suture nails; if the blood vessels are not stapled or nailed off, bleeding or even hematoma may occur. meanwhile, a surgeon cannot directly assess the excision site of the foreskin inner plate during the surgery, resulting in a significantly increased risk of an excessively short postoperative frenulum.(16,17) in addition, we also found some other problems in the process of research. ①disposable suture device is not suitable for patients with severe adhesion of prepuce and penis and difficult to put clock seat. ②patients with severe phimosis need to cut the prepuce from the center of the back of the penis to a suitable position until it can be put into the bell seat before applying the ring cutter, which undoubtedly increases the risk of intraoperative bleeding. ③for some children, there is no suitable disposable suture device size for them. in this study, the position of the coronal sulcus was determined in the modified circumcision, which can accurately control the length of the frenulum from the coronary sulcus, and avoid the frenulum being too long or too short after circumcision. moreover, it can keep the uniform distance from the coronal sulcus, cut the redundant prepuce, keep the incision edge neat, and have high satisfaction with the appearance after operation. at the same time, we pruned the redundant inner plate after cutting the redundant prepuce to avoid the problem of redundant prepuce in patients with phimosis. compared with the traditional operation group, the modified operation group had less postoperative complications. the rate of postoperative edema in modified group was lower than that in the traditional group. the reason is that we have further trimmed the redundant inner plates on the basis of traditional operation. although there is no significant advantage in postoperative edema compared with the disposable circumcision suture devices group, the postoperative edema in modified group was mild swelling and could gradually subside within only 4-5 days. the study shows that diosmin and maizhiling have certain curative effect on edema after prepuce operation.(18)the operation cost of the modified group was significantly lower than that of the stapler group. meanwhile, the modified operation is suitable for patients including phimosis and children. in addition, penis is a sexual organ, so it is very important to pay attention to the changes of sexual function after the operation. at present, there are few studies focusing on the changes of sexual function after prepuce. some studies suggest that circumcision can reduce the risk of premature ejaculation in men.(19) in this study, all three groups had patients who complained that the ejaculation latency was longer than before, suggesting that their sexual ability was improved after the operation. however, the follow-up data of patients obtained in this study are less and a larger sample study is needed in the follow-up. conclusions in conclusion, our observations and discoveries suggest that all 3 types of surgical methods have their own features. strikingly, in contrast to the other two circumcision methods, we found that modified circumcision preserves the advantages of the suture and overcomes the drawbacks of the traditional procedure. with a low cost of surgery, a similar treatment effect to that of circumcision sutures can be achieved. together, novel improved circumcision is beneficial to promote in primary hospitals and economically underdeveloped areas, which has significant clinical application value. acknowledgments this study was supported by a grant from the national natural science foundation (no. 81902565), young scientists foundation of changzhou no.2 people’s hospital (2019k008), changzhou sci & tech program (cj20190100). jiangsu province 333 high-level talent training project (lifeng zhang), changzhou health commission young talent plan (no. czqm2020065), changzhou no. 2 people's hospital young scientists foundation (yjrc202039), innovation team grant (xk201803), faculty funding (yjxk202013). conflict of interest the authors declare no conflict of interest. references 1. dunsmuir wd, gordon em. the history of circumcision. bju int 1999;83 suppl 1:1-12. 2. gu c, tian f, jia z, et al. introducing the quill device for modified sleeve circumcision with subcutaneous suture: a retrospective study of 70 cases. urol int 2015;94:255-61. 3. eisenberg ml, galusha d, kennedy wa, et al. the relationship between neonatal circumcision, urinary tract infection, and health. world j mens health 2018;36:176-82. 4. larke nl, thomas sl, dos santos silva i, et al. male circumcision and penile cancer: a systematic review and meta-analysis. cancer causes control 2011;22:1097-110. 5. rositch af, mao l, hudgens mg, et al. risk of hiv acquisition among circumcised and figure2. toncare circumcision suture devices. clinical effects of modified circumcision-su et al. vol 18 no 5 september-october 2021 559 uncircumcised young men with penile human papillomavirus infection. aids 2014;28:74552. 6. zhu yp, jia zw, dai b, et al. relationship between circumcision and human papillomavirus infection: a systematic review and meta-analysis. asian j androl 2017;19:125-31. 7. aung et, fairley ck, tabrizi sn, et al. detection of human papillomavirus in urine among heterosexual men in relation to location of genital warts and circumcision status. sex transm infect 2018;94:222-5. 8. gray rh, kigozi g, serwadda d, et al. male circumcision for hiv prevention in men in rakai, uganda: a randomised trial. lancet 2007;369:657-66. 9. grabowski mk, kong x, gray rh, et al. partner human papillomavirus viral load and incident human papillomavirus detection in heterosexual couples. j infect dis 2016;213:948-56. 10. tobian aa, gray rh, quinn tc. male circumcision for the prevention of acquisition and transmission of sexually transmitted infections: the case for neonatal circumcision. arch pediatr adolesc med 2010;164:78-84. 11. nakyanjo n, piccinini d, kisakye a, et al. women's role in male circumcision promotion in rakai, uganda. aids care 2019;31:44350. 12. huo zc, liu g, li xy, et al. use of a disposable circumcision suture device versus conventional circumcision: a systematic review and meta-analysis. asian j androl 2017;19:362-7. 13. wu x, wang y, zheng j, et al. a report of 918 cases of circumcision with the shang ring: comparison between children and adults. urology 2013;81:1058-63. 14. han h, xie dw, zhou xg, et al. novel penile circumcision suturing devices versus the shang ring for adult male circumcision: a prospective study. int braz j urol 2017;43:736-45. 15. lv bd, zhang sg, zhu xw, et al. disposable circumcision suture device: clinical effect and patient satisfaction. asian j androl 2014;16:453-6. 16. shen j, shi j, gao j, et al. a comparative study on the clinical efficacy of two different disposable circumcision suture devices in adult males. urol j 2017;14:5013-7. 17. tobian aa, adamu t, reed jb, et al. voluntary medical male circumcision in resource-constrained settings. nat rev urol 2015;12:661-70. 18. yuan y, zhang z, cui w, et al. clinical investigation of a novel surgical device for circumcision. j urol 2014;191:1411-5. 19. morris bj, krieger jn. does male circumcision affect sexual function, sensitivity, or satisfaction?--a systematic review. j sex med 2013;10:2644-57. unclassified 560 clinical effects of modified circumcision-su et al. comparison of sexual behavior and inflammatory parameters in prostate cancer patients with control group: prospective controlled study erdal benli1, ahmet yuce1*, abdullah cirakoglu1, ibrahim yazici1, ismail nalbant2 purpose: in spite of extraordinary developments in diagnostic and treatment methods for prostate cancer (pca), the reason for this disease is not known. our study aimed to compare men in the pca group with a control group in terms of sexual behavior like partner numbers and ejaculation frequency, and inflammatory parameters examined in serum. material and methods: this study was performed prospectively between 2013 and april 2020 and the record system was kept by a single doctor. patients were prospectively recorded by a single person. patients with diagnosis of pca were compared with a control group in terms of sexual behavior and in terms of inflammatory parameters like neutrophil lymphocyte ratio (nlr, neutrophil count/lymphocyte count), systemic inflammatory index (sii, neutrophil count x platelet count/lymphocyte count). results: in this study, median marriage age was 18 ± 6 years in the control group and 20 ± 2.97 in the pca group (p = .001). the median lifelong partner number was observed to be 1 ± 1 in the control group and 1 ± 9 in the pca group (median ± iqr). additionally, lifelong median ejaculation frequency was determined as 12 ± 5 for controls and 10 ± 4 for the pca group. inflammatory markers examined in serum and sii scores were observed to be statistically significantly increased in the cancer group. conclusion: the sexual behavior and inflammatory parameters among patients with pca diagnosis were identified to be significantly high compared to the control group and appear to be possible correctable risk factors. informing men about sexual behavior from an early age and taking precautions for people at risk in the early period may be protective against this disease. keywords: prostate cancer; inflammation; sexual behavior introduction prostate cancer (pca) is among the most commonly seen cancers in men and comprises 15% of newly-diagnosed cases.(1) in spite of developments in diagnosis and treatment, many people die due to this disease. intense research continues around the world to prevent this disease. while some risk factors like age and family history have been defined, the definite cause is still unknown.(2) however, people with certain behavior or living in certain regions are known to have increased pca incidence. additionally, when people living in regions with low risk of pca move to riskier regions, the pca development risk of these people displays similarities to people living in this region.(3,4) when all this information is assessed together, it brings to mind that there are some preventable risk factors contributing to development of pca. the most notable among these risk factors is sexual behavior. sexual behavior without control, especially, is an important public health problem around the world. it is considered to be a risk factor for development of pca. studies associated pca with many sexual behaviors like age of first sexual relations, number of partners and ejaculation frequency. however, the underlying cause has not been fully revealed. among the causes given most focus is the accumulation of a variety of tox1department of urology, ordu university, faculty of medicine, ordu, turkey. 2department of urology, etlik lokman hekim hospital, ankara, turkey. *correspondence: department of urology, faculty of medicine, ordu university, ordu 52200, turkey. tel: +90 506 217 6164, e-mail: ahmetyuce7@gmail.com. received september 2020 & accepted july 2021 ic matter in prostate tissue or the inflammatory process caused by microbial agents.(5,6) however, it is difficult to reach a definite conclusion from studies on this topic because there is no standardization of topics like patient selection, information gathering method and time. most were performed retrospectively. to our knowledge, to date there is no study comparing the sexual behavior and inflammatory parameters of prostate cancer patients with healthy people. this study was prospectively planned to resolve this deficiency about the topic. the aim of the study was to compare sexual behavior and inflammatory markers measured in serum among people with prostate cancer diagnosis with healthy peers. additionally, to identify whether there are precautions which can be recommended to protect healthy people from cancer. materials and methods study population from april 2013 to april 2020, information from male patients aged over 40 years attending hospital was recorded prospectively by a single expert. all patient data, diagnosis, and follow-up duration were prospectively recorded by a doctor specialized in the topic. patients were persuaded to provide accurate information during their first interview. they were told that this was urology journal/vol 19 no. 2/ march-april 2022/ pp. 101-105. [doi: 10.22037/uj.v18i.6464] urological oncology important for treatment. if they did not remember the answer to questions or did not want to answer, it was not recorded in the study. patients had sexual behavior like age of first sexual relations, number of sexual partners and monthly ejaculation numbers and laboratory values recorded in detail. patients gave permission for information to be used in research. blood samples were taken in the morning after overnight fasting. blood samples of patients were taken after underlying pathologies like uti were excluded during the first visit. patients were assessed for prostate cancer with psa and digital rectal examination (dre). causes such as constipation, urinary tract infection (uti) and urethral interventions which may cause benign psa elevation were excluded. high values were checked 2 weeks later. psa value > 4 ng/ml or suspect dre findings were accepted as biopsy criteria and the study included patients positive for pca as a result of prostate biopsy. patients attending check-ups with no complaints with psa value ≤ 3 ng/ml and without suspect dre were included in the control group. the control group was randomly selected from among people with similar basic features to the control group. the study was performed in a single tertiary hospital serving a region with population of nearly 800,000, very homogeneous structure and receiving very little immigration. the two groups were similar in terms of risk factors like nutrition, genetic and environmental factors. procedures patients were divided into 2 groups of the control group and prostate cancer (pca) group. the study recorded a total of 654 patients abiding by the criteria including 263 pca patients and 392 control patients. parameters like age, comorbid diseases, sexual behavior (like age of marriage, number of partners, mean ejaculation frequency), psa value, sedimentation, c-reactive protein (crp), neutrophil lymphocyte ratio (nlr, neutrophil count/lymphocyte count), and systemic inflammatory index (sii, neutrophil count x platelet count/lymphocyte count) were compared between the groups. inclusion and exclusion criteria the study included circumcised male patients over the age of 40 years, who granted consent, could remember sexual behavior and did not avoid talking about these topics. patients who could not remember or did not want to talk about sexual behavior, who spoke inconsistently during examinations, with cognitive disorders, using psychiatric medication or with psychiatric disease, with previous pca diagnosis, uti or history of pelvic radiotherapy and, for the control group patients with elevated psa values, were excluded from the study. the study received permission from the local ethics committee (number: 025/2020). statistical analysis data obtained in the research was analyzed with the statistical package for the social sciences (spss) version 21 program. descriptive statistics are number and percentage for categoric variables and mean, standard table 1. distribution of demographic characteristics groups characteristics control (n=392) pca (n=262) p value age (years) 61.81 ± 8.49a 67.65 ± 9.08 a .001** height (cm) 170.11 ± 6.49a 170.36 ± 7.03a .635 waist circumference 100.09 ± 9.55a 99.23 ± 10.78a .307 bmi 27.43 ± 3.62a 27.54 ± 4.17a .728 alcohol use (%) 13 26.5 .001** smoking (%) 53.2 60.9 .057 diabetes mellitus (%) 21.8 15.8 .063 lung disease (%) 9 12.2 .199 hypertension (%) 35.4 39.4 .307 cvd % 22.1 21.5 .856 a mean ± sd; * = p < .05; ** = p = .001 abbreviations: pca, prostate cancer; bmi, body mass index; cvd, cardiovascular disease. groups p value features control (n=392) pca (n=262) psa (ng/ml) 1.03 ± 1.15b 8.29 ± 13.28 b .001** testosterone (ng/dl) 5.87 ± 2.97b 5.34 ± 2.7b .024* fasting blood sugar (mg/dl) 103 ± 21b 104 ± 21b .881 creatinine (mg/dl) 0.85 ± 0.18b 0.86 ± 0.22b .455 crp (mg/dl) 0.15 ± 0.27b 0.24 ± 0.64b .001** fibrinogen (mg/dl) 320.00 ± 89b 332.50 ± 125b .001** sedimentation (mm/h) 13.00 ± 11b 16.50 ± 22b .001** nlr 1.81 ± 0.93b 2.14 ± 1.25b .001** sii 390.25 ± 251.76b 470.12 ± 308.72b .001** table 2. distribution of laboratory parameters b median ± iqr, * = p < .05; ** = p = .001 abbreviations: psa, prostate specific antigen; cpr, c-reactive protein; nlr, neutrophil count/lymphocyte count; sii, systemic inflammatory index. effect of sexual behavior on prostate cancer-benli et al. vol 19 no 2 march-april 2022 102 vol 19 no 2 march-april 2022 100 deviation, median, minimum and maximum values with interquartile range (iqr) for numerical variables. normal distribution of numerical variables was assessed with the kolmogorov-smirnov test. for comparison of numerical variables, the student t test was used for variables abiding by parametric conditions, while the mann whitney u test was used for variables not abiding by parametric conditions. analysis of categoric variables used the chi-square test. in situations with type 1 error level below 5%, p < .05 was accepted as statistically significant. results the study used data collected from a total of 654 patients, with 262 (40.1%) in the pca and 392 (59.9%) in the control group. mean age was identified as 61.81 ± 8.49 (41-85) years in the control group and 67.65 ± 9.08 (43-97) years in the pca group (p < .001). the comorbid diseases and habits of groups are given in table 1. laboratory parameters (median ± iqr) were compared in the control and pca patients. median psa values were 1.03 ± 1.15 (0.10 3) ng/ml in the control group and 8.29 ± 13.28 (4.10 1381) ng/ml in the pca group (p = .001). testosterone levels were 5.87 ± 2.97 (1.3213.90) ng/dl and 5.34 ± 2.7 (2.31-16.14) ng/dl, respectively (p = .024). when groups were compared in terms of crp, fibrinogen, nlr and sii score, inflammatory markers were identified to increase in the cancer group. this increase was statistically significant (table 2). the groups were compared in terms of marital age, lifelong number of sexual partners and monthly ejaculation frequency. as data were non-parametric, results are given as median (mean rank) ± iqr. when groups were compared in terms of sexual behavior, median age of marriage was 18 (261.63) ± 6 years in the control group and 20 (323.23) ± 5 years in the pca group (p = .001). the lifelong median number of partners was 1 (299.87) ± 1 in the control group and 1 (367.75) ± 9 in the pca group (p = .001) and this difference was significant. additionally, the lifelong median ejaculation frequency (monthly) was determined as 12 (382.53) ± 5 for controls and 10 (230.02) ± 4 for the pca group (p = .001) (table 3). discussion though some risk factors have been defined like aging, family history and genetic features, the definite cause is still unknown. like many cancers, it is considered that multifactorial risk factors are effective. the aim of this study was to investigate whether there was a correlation between sexual behavior, inflammatory parameters in serum and pca. in this study, the most important finding is that there was a correlation between pca with sexual behavior and inflammatory parameters compared to the control group. it is known that the incidence of pca increases in people living in certain regions or with certain forms of behavior. a study in our neighboring country of iran reported the 3-year cancer frequency per 100,000 people was 11.2%.(7) studies on this topic have reported that asian males have 10-15 times increased pca risk compared to males living in western countries, while african-american males have 1.6 times increased pca risk compared to caucasians.(8) the difference in this disease between geographies is implied to be possibly due to some risky personal behaviors related to this disease. there is increasing evidence showing sexual behavior, a significant health problem around the world, is an important risk factor for pca development. this topic + attracted attention to sexual behavior like partner numbers, especially, but also age of first sexual relations and ejaculation frequency.(9) some studies have investigated the correlation between ejaculation frequency and pca. rider et al. reported that in the absence of risky sexual behavior, increased ejaculation frequency has protective effects against pca. (10) another study by jian et al. reported that there was a significant correlation between sexual behavior like reduced sexual partner numbers, advanced age for first sexual relations and moderate levels of ejaculation frequency with reduced pca risk.(11) some authors reported the protective ejaculation frequency is 1-4 times per week.(12) in our study, the cancer group was identified to have reduced ejaculation frequency compared to the control group. the protective number is not known in our study. in spite of broad investigation of the literature about ejaculation, the protective effect is not fully understood. according to the most accepted view, increased ejaculation frequency is effective by preventing accumulation of some carcinogenic material within prostate fluid.(13,14) we think ejaculation may be effective through a different route. like the mechanical cleaning effect of urine, frequent ejaculation may prevent access to or colonization of prostatic tissue by a variety of microorganisms. additionally, sexual activity means a certain level of physical activity, mental calmness and better communication with partners. in conclusion, continuing active sexual life may have beneficial contributions by making the person feel good about themselves, and have positive effect on the vascular system by better perfusion and oxygenation of tissues leading to benefits for immune system cells. this is very important for the battle with cancer cells. we think there is a need for more comprehensive studies to say anything definite about this topic. increased partner numbers is an important public health problem increasing the risk of many sexually-transmitted diseases. many studies have proposed that sexual activities without control and with many people is an important risk factor for pca development.(15) a meta-analysis by jian et al. investigated the correlation beeffect of sexual behavior on prostate cancer-benli et al. groups features control (n=392) pca (n=262) p value age of marriage (yearly) 18 ± 6 (10-35)b 20 ± 5 (12-58)b .001 number of sexual partners 1 ± 1 (0-200)b 1 ± 9 (0-1000)b .001 frequency of ejaculation (monthly) 12 ± 5 (4-64)b 10 ± 4 (0-30) b .001 b median ± iqr (min-max) table 3. distribution of sexual behavior vol 19 no 2 march-april 2022 103 urological oncology 104 tween partner numbers and pca. the authors reported that each increase in partner numbers by 10 increased cancer risk by 1.1 times.(11) these results were supported by other researchers. in our study, the partner number was significantly increased in the pca group compared to the control group. the reason for the correlation between partner numbers and pca has not been fully explained. one of the views proposed about this topic associates increased sexual activity with high androgen levels and proposed that high hormone levels may trigger cancer development. (16) however, many studies have shown no relation between pca and androgens. in our study, contrarily, the cancer group had reduced androgen levels compared to the control group. this is not surprising to us; we know the androgen levels reduce in elderly patients. another view which is a focus in the correlation between partner numbers and cancer is the inflammatory process caused by sexually transmitted infections (sti).(17-19) independent of vector, there are studies in the literature reporting sti experienced in any period of life increases cancer risk by 50%.(20,21) we know the correlation between cancer and the inflammatory process from many cancers in the gastrointestinal system, thyroid, pancreas, bladder and pleura. (22,23) chronic inflammation results in collection of many immune system cells and increases in a variety of mediators and cytokines. increasing reactive oxygen species (ros) in this process affect the physiological conditions required by normal cells. if this toxic material is not removed from tissues, lipid peroxidation and dna injury may develop.(24,25) in prostate tissue, chronic infection beginning for a variety of reasons may begin the cancer development process with the same mechanism. (26,27) a study by taghavi et al. supports this view. the authors investigated the correlation between polyomavirus hominis 1 (bk virus, bkv), known to cause latent infection, with prostate specimens. the results of the study reported the bkv infection was more prevalent compared to bph in pca specimens. in our study, inflammatory parameters were investigated differently to many studies. inflammatory parameters examined in serum from pca patients were identified to be increased compared to the control group. according to our knowledge, this study is the first to compare prostate cancer patients in terms of partner numbers and inflammatory parameters to date. in spite of not knowing std history, we think agents transmitted through the sexual route with increased partner numbers may have caused a chronic inflammatory process triggering cancer development in patients included in the study. we do not fully know why these patients married at younger ages and how partner numbers and ejaculation frequency changes in which periods of life. sexual relations with many partners at younger ages may cause marriage at later ages and less sexual relations after marriage. the results of our study identified that the number of partners was increased and the ejaculation frequency was reduced in the pca group compared to the control group. additionally, compared to the control group, the pca group had increased inflammatory parameters like crp, sedimentation, fibrinogen, nlr in serum and sii. people included in the study were statistically similar in terms of geography, genetics and nutritional characteristics, which is very important in terms of homogenization. this allows the opportunity to compare people with similar features (control and pca group) in terms of sexual behavior and inflammatory parameters. these results show that in addition to unchangeable risk factors like aging, genetics and family history, there are risk factors which are preventable with simple precautions. when the literature and our study results are interpreted together, sexual behavior appears to be a changeable risk factor for prevention of cancer. there are some limitations to our study. the first is that information related to sexual life was based on patient statements. it is not possible to know if there were situations involving forgetting or purposely providing misleading information. however, information was not obtained from patients with any survey or by telephone. all diagnosis and treatment processes were completed by the same person. this situation is important in terms of receiving accurate information from patients and for standardization of the study. it is not known if the group used as control in the study included undiagnosed cancer cases (due to silent progression of many cancer cases, lack of reliable psa value). additionally, in the cancer group, there was no evidence for diseases related to stis available, like serologic tests. however, this situation is valid for the control group. conclusions in conclusion, this prospective study obtained important results. it was identified that the partner number was increased and ejaculation frequency reduced in the pca group compared to the control group and that these patients married at later ages. additionally, an increase in systemic inflammatory markers was observed in the cancer group. these results show the presence of increased inflammatory processes in the pca group with increased partner numbers. these results, when assessed with the literature, lead to consideration that increased partner numbers and reduced ejaculation frequency may begin or ease the inflammatory background for cancer development. these results indicate there are some precautions that may be taken for this disease. providing necessary sexual information from a young age, taking protective precautions against sexually transmitted diseases and increasing the frequency of ejaculation were identified as changeable behaviors for pca. conflict of interest the authors report no conflict of interest. references 1. soerjomataram i, lortet-tieulent j, parkin dm et al. global burden of cancer in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions. lancet. 2012;380:1840-50. 2. discacciati a, wolk a. lifestyle and dietary factors in prostate cancer prevention. recent results cancer res. 2014;202:27-37. 3. cook ls, goldoft m, schwartz sm, weiss ns. incidence of adenocarcinoma of the prostate in asian immigrants to the united states and their descendants. j urol. 1999;161:152-5. 4. hemminki k, li x. cancer risks in secondgeneration immigrants to sweden. int j cancer. 2002;99:229-37. effect of sexual behavior on prostate cancer-benli et al. vol 19 no 2 march-april 2022 100 5. nelson wg, de marzo am, isaacs wb. mechanisms of disease prostate cancer. n engl j med. 2003;349:366-81. 6. taylor ml, mainous ag, wells bj. prostate cancer and sexually transmitted diseases: a 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winikoff s, landsittel dp et al. multianalyte profiling of serum cytokines for detection of pancreatic cancer. cancer biomark. 2005;1:259-69. 26. battisti v, bagatini md, maders ld et al. cholinesterase activities and biochemical determinations in patients with prostate cancer: influence of gleason score, treatment and bone metastasis. biomed pharmacother. 2012;66:249-55. 27. shukla s, srivastava jk, shankar e et al. oxidative stress and antioxidant status in high-risk prostate cancer subjects. diagnostics (basel). 2020;10:126. 28. taghavi a, mohammadi-torbati p, kashi ah, rezaee h, vaezjalali m. polyomavirus hominis 1(bk virus) infection in prostatic tissues: cancer versus hyperplasia. urol j. 2015;12:2240-4. effect of sexual behavior on prostate cancer-benli et al. vol 19 no 2 march-april 2022 105 vol 19 no 2 march-april 2022 100 risk factors for failure of endoscopic management of stone-related ureteral strictures teruaki sugino1, kazumi taguchi1*, shuzo hamamoto1, tomoki okada1, masahiko isogai1, yutaro tanaka1, rei unno1, yasuhiro fujii1,2, takashi hamakawa1,3, ryosuke ando1, atsushi okada1, takahiro yasui1 purpose: to investigate factors determining the outcomes of endoscopic management for stone-related ureteral stricture. materials and methods: data of patients who underwent endoscopic surgery for ureteral stricture due to stones from january 2016 to april 2020 were retrospectively analyzed. we compared cases successfully treated with endoscopic surgery with cases that resulted in failure. we focused on factors associated with treatment success, including cause and length of stricture, methods of stricture treatment, surgical time, and duration of hydronephrosis before the treatment. treatment success was defined as improvement in hydronephrosis status. results: nineteen patients were treated for stone-related ureteral stricture. hydronephrosis was successfully improved in 12 patients (63.2%). seven patients with failed endoscopic management had ureteroscopic lithotripsy-related stricture, whereas 3/12 (25.0%) patients with ureteroscopic lithotripsy-related stricture and 7/12 (58.3%) patients with impacted stone-related stricture were successfully treated by endoscopic management (p = .004). the prevalence of stricture length > 15 mm was significantly higher in the patients with failed management than in the patients with successful management (71.4 vs 16.6%, p = .046). intraoperative endoscopic observation demonstrated that the mucosa of the ureteroscopic lithotripsy-related stricture had ischemic appearance with relatively long stricture length (p = 0.13) compared to the impacted stone-related stricture. no association was observed between treatment outcome and method of endoscopic management, including laser incision, balloon dilation, or both. conclusion: ureteroscopic lithotripsy as a cause and stricture length > 15 mm could affect the success rate of endoscopic management of ureteral stricture. in such cases, reconstructive management should probably be considered in the early stages. keywords: hydronephrosis; impacted stones; ureteral stricture; ureteroscopy introduction in recent years, the prevalence of ureteral stones has been consistently increasing in the world due to the effects of the increasing incidence of obesity and changes in dietary habits.(1,2) ureteroscopic lithotripsy (ursl) has become a common treatment for middle and lower ureteral stones.(3,4) although it is effective and minimally invasive, it could cause significant complications such as intraoperative ureteral injury, bleeding, infection, and postoperative ureteral strictures (us).(5) us is reported to occur in 1–4% of patients after ordinary ursl; however, it occurs in 7.8–24% of patients when ursl is performed for impacted stones. (6–8) moreover, there are non-iatrogenic ureteric strictures such as those associated with impacted stones or chronic inflammatory disorders.(9,10) the main purpose of the management of us is to improve hydronephrosis and protect renal function.(11) recently, a wide variety of therapeutic options have become available to urologists, such as endoscopic management and open/laparoscopic/robot-assisted reconstruction. laser incision (li) and balloon dilation (bd) as endoscopic management techniques for benign us have been described in previous reports; razdan et al. reported that these techniques had a success rate of 74% in 50 patients.(9) further, may et al. reported that 27.5% of 40 patients were successfully managed with endoscopic techniques.(12) the factors that influence the success rate of the endoscopic management of us (e.g., the cause and length of the stricture, the duration of hydronephrosis, the surgical management technique, and the number of placed ureteral stents) are controversial. to identify the factors associated with successful endoscopic management of us, we retrospectively investigated patients who underwent endoscopic management for benign us related to ureteral stones and/or their treatments. materials and methods study population the present cross-sectional study was approved by the institutional review board of the nagoya city university hospital. all patients provided informed consent for the use of their data. 1department of nephro-urology, nagoya city university, graduate school of medical sciences, nagoya, japan. 2department of urology, social medical corporation kojunkai daido hospital, daido clinic, nagoya, japan. 3department of urology, nagoya city east medical center, nagoya, japan. *correspondence: department of nephro-urology, nagoya city university, graduate school of medical sciences, 1, kawasumi, mizuho-cho, mizuho-ku, nagoya 467-8601, japan. tel.: +81-52-853-8266x, fax: +81-52-852-3179, e-mail: ktaguchi@med.nagoya-cu.ac.jp. received february 2021 & accepted july 2021 endourology and stone disease urology journal/vol 19 no. 2/ march-april 2022/ pp. 95-100. [doi: 10.22037/uj.v18i.6697] patients who underwent endoscopic management for us between january 2016 and april 2020 were analyzed. these patients were referred to our hospital for endoscopic management of ureteral stricture due to impacted stones or postoperative complications after laser ureteric lithotripsy. they underwent li and/or bd management and one or two ureteral stents or a nephrostomy catheter were placed at the end of the surgery. patients with a solitary kidney, urinary diversion, poorly controlled diabetes, and those who were pregnant were excluded from this study. we obtained patients’ demographics, such as sex, age, and body mass index (bmi), from the medical records. additionally, the laterality, location, cause, and length of the us, as well as the status of hydronephrosis were also captured. the us related to ursl was defined as follows: us with damage caused by either the laser or access sheath during ursl, which was not detected during previous surgery. in contrast, the us related to an impacted stone was defined as follows: us following stone impaction without damage caused by either the laser or access sheath during ursl, which was detected during previous surgery. regarding hydronephrosis, grade 0 hydronephrosis was defined as no swelling of the renal pelvis or calyx, grade 1 as swelling of the renal pelvis, grade 2 as swelling of the renal calyx, grade 3 as swelling of the renal pelvis and calyx, and grade 4 as swelling of the renal pelvis and calyx with bending of the ureter. surgical parameters, including surgical time, and success or failure of treatment were analyzed. success of treatment was defined as improvement in the status of hydronephrosis examined by either ultrasonography or computed tomography conducted 3 months after removing the ureteral stents. the urine flow through the treated ureter was confirmed by retrograde pyelography when the ureteral stents were removed. surgical techniques all patients were placed under general anesthesia, and the operation was performed in the lithotomy position. before treatment, the status of the stricture was confirmed using retrograde ureteropyelography. a 6.0 fr semi-rigid ureteroscope (olympus, tokyo, japan) was inserted and used to observe the stricture site. then, we inserted a 0.035-inch hydrophilic guide wire through the stricture site. bd was conducted when the diameter of the stricture allowed the insertion of the uro max ultra™ before inflation; otherwise, li was performed instead. in contrast, both procedures were conducted with mucosal findings of rigid appearance. as for the li procedure, we cut the mucosa and muscular layer of the stricture site (including 5 mm before and after) using a 272 μm fiber (cyber ho, quanta system, milan, italy) until we could visualize the fat tissue outside of the ureter. the energy setting was 6.0 w (1.0 j × 6 hz) and the incision was conducted using the ‘soft tissues’ mode. for the bd, we dilated the ureteral lumen up to 15 fr using a balloon catheter (uro max ultra™; boston scientific japan, tokyo, japan). one or two double-j ureteral stents (4.7 or 6.0 fr, inlay optima™, bd, franklin lakes, nj and 4.8 fr, tria™, boston scientific, marlborough, ma), chosen by the main operator, were placed into the ureter at the end of procedures. endoscopic management of ureteral strictures-sugino et al. table 1. patient characteristics, surgical data, and treatment classifications (success or failure) factor overall (n = 19) failure (n = 7) success (n = 12) p valueb age (years)a 69 [58, 73] 71.5 [58.0, 75.3] 60.0 [58.0, 66.0] 0.253 sex male 12 (63.2%) 3 (42.9%) 9 (75.0%) 0.326 female 7 (36.8%) 4 (57.1%) 3 (25.0%) bmi (kg/m2) a 24 [21, 26.9] 25.0 [24.0, 26.9] 23.5 [20.8, 26.5] 0.611 preoperative hydronephrosis grade 1 3 (15.8%) 0 (0.0%) 3 (25.0%) 0.61 grade 2 5 (26.3%) 2 (28.6%) 3 (25.0%) grade 3 5 (26.3%) 2 (28.6%) 3 (25.0%) grade 4 6 (31.6%) 3 (42.9%) 3 (25.0%) duration of hydronephrosis before 4.0 [2.5, 5.5] 5.0 [3.5, 5.0] 4.0 [2.0, 7.5] 0.898 surgery (months) a laterality right 11 (57.9%) 3 (42.9%) 8 (66.7%) 0.38 left 8 (42.1%) 4 (57.1%) 4 (33.3%) location proximal 7 (36.8%) 2 (28.6%) 6 (50.0%) 0.63 distal 12 (63.2%) 5 (71.4%) 6 (50.0%) cause of stricture ursl 10 (52.6%) 7 (100%) 3 (25.0%) 0.004 impacted stone 7 (36.8%) 0 (0.0%) 7 (58.3%) other 2 (10.6%) 0 (0.0%) 2 (16.7%) length of stricture (> 15 mm) 7 (36.8%) 5 (71.4%) 2 (16.6%) 0.045 prestenting 5 (26.3%) 0 (0.0%) 5 (41.7%) 0.106 surgical time (min) a 71.0 [64.5, 93.5] 69.0 [64.5, 83.5] 76.0 [63.8, 95.0] 0.554 endoscopic management laser incision (li) and balloon dilation (bd) 8 (42.1%) 4 (57.1%) 4 (33.3%) 0.481 li 2 (10.6%) 0 (0.0%) 2 (16.6%) bd 3 (15.8%) 0 (0.0%) 3 (25.0%) drainage single stent 8 (42.1%) 1 (14.3%) 7 (58.3%) 0.12 double stents 9 (47.3%) 4 (57.1%) 5 (41.7%) nephrostomy tube 1 (5.3%) 1 (14.3%) 0 (0.0%) duration of the post-surgery follow-up (days) a 654[546, 1134.5] 618[516.5, 652] 563[877.5, 1304] 0.384 abbreviations: bmi, body mass index; ursl, ureteroscopic lithotripsy; li, laser incision; bd, balloon dilation amedian [25%, 75% interquartile range]. bcomparison between the failure and success groups endourology and stones diseases 96 vol 19 no 2 march-april 2022 100 statistical analysis non-normally distributed variables are expressed as medians (25%, 75% interquartile range). categorical variables are presented as frequencies (percentages). data were analyzed using ezr for r (r project 3.6.3, r foundation for statistical computing, vienna, austria) (13). to compare the patients with failed or successful management and the factors associated with the cause of us, the fisher’s exact test and mann-whitney u tests were used. the correlation coefficient between the length of us and perioperative parameters was computed using spearman's rank correlation coefficient. results a total of 19 patients were identified as having undergone endoscopic treatment for us after laser lithotripsy for ureteral stones. the characteristics of the patients and surgical data are summarized in table 1. preoperative hydronephrosis was grade 1 in 3 patients (15.8%), grade 2 in 5 (26.3%), grade 3 in 5 (26.3%), and grade 4 in 6 (31.6%). the median duration of hydronephrosis before surgery was 4.0 months. the stricture cause was identified as ursl in 10 patients (52.6%), impacted stone in 7 (36.8%), and chronic inflammatory disorders in 2 (10.5%). seven patients had a us longer figure 1. (a) findings from ureteroscopy of ursl-related us. the ureteral mucosa appeared white and poor blood vessels were observed. (b) findings from ureteroscopy of impacted stone-related us. relatively normal blood vessels were observed on the mucosa. ursl, ureteroscopic lithotripsy; us, ureteral stricture figure 2. (a) correlation between length of us and bmi, duration of hydronephrosis and surgical time. the correlation coefficient (r) was computed using spearman's rank correlation coefficient. (b) comparison of perioperative parameters between ursl-related and impact stone-related us. bmi, body mass index; ursl, ureteroscopic lithotripsy; us, ureteral stricture endoscopic management of ureteral strictures-sugino et al. vol 19 no 2 march-april 2022 97 endourology and stones diseases 98 than 15 mm. prestenting 3 months before surgery was performed in 5 patients (26.3%). eight patients (42.1%) underwent both li and bd. two patients (10.6%) underwent li alone, while 3 (15.8%) underwent bd alone. a single stent was placed in 8 patients (42.1%) and double stents were placed in 9 (47.3%). we were unable to perform li or bd in 3 patients (15.8%) as the stricture was too severe. specifically, although we were able to insert the guidewire in 1 patient, imaging of the direction of incision was not possible and we placed a ureteral stent. in the other 2 patients, we were not able to insert the guidewire at all and we placed a nephrostomy tube in 1 patient. the median duration of the post-surgery follow-up was 654 days. table 1 also classifies the data as treatment success or failure. the success rate of the treatment was 63.2% (12/19). ursl-related us occurred in 7 and 3 patients in the failure and success groups, respectively (p = .004). the ureteral mucosa appeared to become white in color and poor blood vessels were observed in ursl-related us (figure 1a). contrarily, all 7 patients with impacted stone-related us were successfully treated with endoscopic management. relatively normal blood vessels were observed on the mucosa in the impacted stone-related us (figure 1b). five patients in the failure group (71.4%) had a us longer than 15 mm, whereas only 2 patients in the success group (16.6%) had a us longer than 15 mm (p = .045). based on the post-surgery follow-up, 2 patients in the success group (16.6%) underwent re-treatment. specifically, 1 patient had the ureteral stent replaced and the other had li at 1257 and 1735 days, respectively, from the first endoscopic surgery. furthermore, 3 patients in the failure group (42.9%) underwent open surgeries and 1 patient (14.3%) underwent bd again. the correlation between length of us and other perioperative parameters, as well as the comparison of perioperative parameters between ursl-related and impacted-stone related us are shown in figure 2a and 2b. the correlation coefficients between length of us and bmi, duration of hydronephrosis, and surgical time were 0.023, 0.097, and 0.078, respectively (p = .93, .69, and .75). the median bmi, duration of hydronephrosis, surgical time, and length of us in the patients with ursl-related and impacted stone-related us were 24.4 and 26.6 kg/m2, 4.5 and 4.0 months, 70.5 and 77.5 minutes, and 17.0 and 7.0 mm, respectively (p = .67, .69, .81, and .13). discussion the development and innovation of endourologic tools has enabled urologists to choose endoscopic management techniques, such as endoureterotomy and endoscopic dilation, for patients with us.(14) these techniques are safer and less invasive than open surgical repair; however, success rates vary widely between reports.(9,15) we would investigate the factors that influence the success rate of the management for stone-related us. intraoperative ureteral damage during ursl is one of the causes of us.(6) us caused by ureteral damage is associated with ischemic changes, which results in lower success rates following treatment for us.(7) on the other hand, it is reported that stones embedded in the ureteral mucosa stimulate inflammation, which might result in us.(16) us caused by stones embedded in the ureteral wall does not always involve ischemic changes; therefore, relatively normal blood vessels may be observed on the mucosa (figure 1b) and it is likely to be curable with additional treatment.(11) netto et al. reported that the success rates of bd for non-ischemic and ischemic us were 89 and 29%, respectively(17). in the current study, 52.6% of the uss were related to ursl; the success rate of the management for ursl-related us was significantly lower compared to that of the management for impacted stone-related us. the mucosal change in ursl-related us indicated ischemic change, which could result in a poor success rate. there were no significant differences in perioperative parameters, including the length of us, between the patients with ursl-related and impacted stone-related us. these data suggest that treating ursl-related us with endoscopic management is challenging. us length is thought to be an important predictor of the outcome after endoscopic management for us in several reports. netto et al. reported a lower success rate for the management of uss longer than 10 mm.(17) thomas et al. reported a poorer outcome of bd for uss longer than 15 mm.(18) meretyk et al. reported that the 20 mm length was the most reliable predictor of success rate of li.(15) the current study demonstrated that more than 70% of patients in whom endoscopic treatment failed had a us longer than 15 mm. moreover, the length of us poorly correlated with other perioperative parameters. according to these data, which are consistent with previous reports, our study revealed that a length of 15 mm was likely to be an important factor to affect success rate of endoscopic treatment. prior studies report that the duration of the us is associated with the success rate for endoscopic management. byun et al. reported that the duration of us (shorter or longer than 3 months) was an important factor that affected the success rate.(19) in contrast, wolf et al. reported that the duration of the us did not significantly affect the success rate of us treatment.(20) in the current study, the median duration of hydronephrosis before surgery was not significantly different between the patients with endoscopic treatment failure and success. the success rate of li using a holmium yag laser was reported to be 67-68.4%.(21,22) moreover, previous reports demonstrated that the success rate of bd for us was 50-76%.(23,24) a holmium yag laser with both cutting and coagulating functions provides precise incision to a depth of the fat tissue outside of the ureter with effective hemostatic effect.(25) we assumed that the combination of li and bd enabled the equally centered expansion of the lumen on the incision line, which prevented restenosis. however, the current study showed that there were no significant differences in the management between the patients with success or failure; 57% patients underwent both li and bd in the failure group, whereas 33.3% patients underwent both procedures in the success group. ureteral stents are preoperatively used for avoiding infection and kidney failure before the management of urolithiasis. they dilate the ureteral lumen and straighten the ureter, which makes it easy to insert a ureteroscope or ureteral access sheath.(26) for these reasons, prestenting would also elevate the success rate of endoscopic management for us. in our study, all 5 patients with prestenting had successful endoscopic management; therefore, we believe prestenting could contribute endoscopic management of ureteral strictures-sugino et al. vol 19 no 2 march-april 2022 100 to improved treatment success rates. the placement of two ureteral stents was first reported in cases of malignant obstruction.(27) the authors suggested that two stents have more power to stand up to the comprehensive force of the tumor than one thick stent. the use of two ureteral stents has been applied for the management of benign us.(9,28,29) some urologists prefer to insert as large of a ureteral stent as possible; however, larger stents cause ischemia of the ureter, which tend to develop restenosis.(29) it is reported that two stents slide against each other via peristalsis of the ureter, which maintain the expanded lumen.(30) this motion may prevent ischemia or pressure necrosis of the ureter, which is believed to result in a better success rate; however, our study showed no statistical difference in treatment success rates between the patients with single and double stents. our study is limited by its relatively small number of patients. due to the nature of the disease, it was difficult to collect a large number of cases, even in this multicenter study. therefore, we could not perform the multivariate logistic regression and interaction analysis of risk factors for unsuccessful treatment and care should be taken when interpreting the results. however, the significance of this study lies in the fact that it focused on the stricture associated with urinary stones and identified a lower success rate of us endoscopic management following damage during ursl. moreover, given that identifying the beginning of us development was difficult without close monitoring, we may not have been able to provide an accurate estimate of the us duration. furthermore, although improvement of hydronephrosis was defined as successful in this study, other factors, e.g., change in split renal function, should have been assessed as well. despite these limitations, we believe that our study findings will be helpful for choosing endoscopic management or other options, such as open/ laparoscopic/robot-assisted reconstruction, as treatment for stone-related us. conclusions ursl as the cause of us and us with a length of > 15 mm could affect the success rate of the endoscopic management of us. in such cases, reconstructive management for us should probably be considered in the early stages. acknowledgement not applicable conflict of interest the authors declare no competing interests. references 1. curhan gc. epidemiology of stone disease. urol clin north am. 2007;34:287-93. 2. ando r, nagaya t, suzuki s, et al. kidney stone formation is positively associated with conventional risk factors for coronary heart disease in japanese men. j urol. 2013;189:1340-6. 3. preminger gm, tiselius hg, assimos dg, et al. 2007 guideline for the management of ureteral calculi. j urol. 2007;178:2418-34. 4. taguchi k, cho sy, ng ac, et al. the urological association of asia clinical guideline for urinary stone disease. int j urol. 2019;26:688-709. 5. geavlete p, georgescu d, nita g, et al. complications of 2735 retrograde semirigid ureteroscopy procedures: a single-center experience. j endourol. 2006;20:179-85. 6. gdor y, gabr ah, faerber gj, et al. success of laser endoureterotomy of ureteral strictures associated with ureteral stones is related to stone impaction. j endourol. 2008;22:250711. 7. roberts ww, cadeddu ja, micali s, et al. ureteral stricture formation after removal of impacted calculi. j urol. 1998;159:723-26. 8. fam xi, singam p, ho cck, et al. ureteral stricture formation after ureteroscope treatment of impacted calculi: a prospective study. korean j urol. 2015;56:63-7. 9. razdan s, silberstein ik, bagley dh. ureteroscopic endoureterotomy. bju int. 2005;95:94-101. 10. ramanathan r, kumar a, kapoor r, et al. relief of urinary tract obstruction in tuberculosis to improve renal function: analysis of predictive factors. br j urol. 1998;81:199-205. 11. lang ek, fritzsche pf. ureteral strictures. in: lang ek, editor. radiology of the lower urinary tract. berlin: springer-verlag; 1994. p. 33-40. 12. may pc, hsi rs, tran h, et al. the morbidity of ureteral strictures in patients with prior ureteroscopic stone surgery: multi-institutional outcomes. j endourol. 2018;32:309-14. 13. kanda y. investigation of the freely available easy-to-use software 'ezr' for medical statistics. bone marrow transplant. 2013;48:452-8. 14. richter f, irwin rj, watson ra, et al. endourologic management of benign ureteral strictures with and without compromised vascular supply. urology. 2000;55:652-7. 15. meretyk s, albala dm, clayman rv, et al. endoureterotomy for treatment of ureteral strictures. j urol. 1992;147:1502-6. 16. dretler sp, young rh. stone granuloma: a cause of ureteral stricture. j urol. 1993;150:1800-2. 17. netto júnior nr, ferreira u, lemos gc, et al. endourological management of ureteral strictures. j urol. 1990;144:631-4. 18. thomas r. choosing the ideal candidate for ureteroscopic endoureterotomy. j urol. 1993;149:314a. 19. byun ss, kim jh, oh sj, et al. simple retrograde dilation for treatment of ureteral strictures: etiology-based analysis. yonsei med j. 2003;44:273-8. 20. wolf js jr, soble jj, ratliff tl, et al. ureteral cell cultures ii. collagen production and response to pharmacologic agents. j urol. 1996;156:2067–72. 21. singal rk, denstedt jd, razvi ha, et al. holmium: yag laser endoureterotomy for treatment of ureteral stricture. urology. endoscopic management of ureteral strictures-sugino et al. vol 19 no 2 march-april 2022 99 1997;50:875-80. 22. lane br, desai mm, hegarty nj, et al. long-term efficacy of holmium laser endoureterotomy for benign ureteral strictures. urology. 2006;67:894-7. 23. schondorf d, meierhans-ruf s, kiss b, et al. ureteroileal strictures after urinary diversion with an ileal segment-is there a place for endourological treatment at all? j urol. 2013;190:585-90. 24. laven ba, o'connor rc, gerber gs, et al. long-term results of endoureterotomy and open surgical revision for the management of ureteroenteric strictures after urinary diversion. j urol. 2003;170:1226-30. 25. johnson de, cromeens dm, price re. transurethral incision of the prostate using the holmium: yag laser. lasers surg med. 1992;12:364-9. 26. shields jm, bird vg, graves r, et al. impact of preoperative stenting on outcome of ureteroscopic treatment for urinary lithiasis. j urol. 2009;182:2768-74. 27. liu js, hrebinko rl. the use of 2 ipsilateral ureteral stents for relief of ureteral obstruction from extrinsic compression. j urol. 1998;159:179-81. 28. christman ms, kalmus a, casale p. morbidity and efficacy of ureteroscopic stone treatment in patients with neurogenic bladder. j urol. 2013;190:1479-83. 29. ibrahim hm, mohyelden k, abdel-bary a, et al. single versus double ureteral stent placement after laser endoureterotomy for the management of benign ureteral strictures: a randomized clinical trial. j endourol. 2015;29:1204-9. 30. isogai m, hamamoto s, hasebe k, et al. dual ureteral stent placement after redo laser endoureterotomy to manage persistent ureteral stricture. iju case rep. 2020;3:93-5. endoscopic management of ureteral strictures-sugino et al. endourology and stones diseases 100 case report 60 urology journal vol 5 no 1 winter 2008 a primary carcinoid tumor of kidney muhammad rafique keywords: carcinoid tumor, kidney neoplasms, cushing syndrome department of urology, nishtar medical college, multan, pakistan corresponding author: muhammad rafique, md no 5, altaf town, tariq rd, multan, pakistan tel: +92 61 457 1544 e-mail: rafiqanju@hotmail.com received june 2007 accepted september 2007 introduction carcinoid tumors frequently develop in the gastrointestinal tract and the respiratory system.(1) those originating from the kidneys are exceptionally rare. less than 45 cases of primary carcinoid tumors of the kidney have been reported in the english literature, so far.(2-4) we herein report another case of primary renal carcinoid tumor found in a 44-year-old woman. case report a 44-year-old woman presented with a 6-month history of increasing constant left flank pain. she had no urinary symptoms. her past medical history was unremarkable. on physical examination, a left flank mass was bimanually palpable. laboratory test results including blood counts, blood chemistry, and urinalysis were normal. ultrasonography and computed tomography of the kidneys revealed an 8 × 6.5cm heterogenous mass in the lower pole of the left kidney. chest radiography showed no abnormal findings. renal cell carcinoma was suspected and the patient underwent left radical nephrectomy. on surgery, the tumor had replaced most of the middle and lower pole of the left kidney. no extrarenal or renal vein invasion or lymphadenopathy was observed. pathologic examination showed the tumor with tubules and acini lined by cells with uniform round nuclei and pink cytoplasm (figure). scanty mitoses were seen. staining with monoclonal antibodies showed the tumor tissue to be positive for neuron specific enolase, chromogranin, urol j. 2008;5:60-1. www.uj.unrc.ir left, the tumor tissue composed of tubules and acini lined by cells with uniform round nuclei and pink cytoplasm are seen (hematoxylin-eosin, × 200). right, high-power microphotograph of the same field of the specimen is shown (hematoxylin-eosin, × 400). primary carcinoid tumor of kidney—rafique urology journal vol 5 no 1 winter 2008 61 cytokeratin mnf, and cytokeratin cam 5.2. the tumor was confined within the renal capsule and no perinephric invasion was detected. the hilar blood vessels and the ureter were free of tumor. diagnosis of carcinoid tumor was made in the kidney. postoperative recovery was uneventful. postoperative colonoscopy and upper gastrointestinal endoscopy revealed no abnormality pertaining to gastrointestinal source of the tumor. urinary 5-hydroxyindoleacetic acid level was within the reference range 3 months after the operation. the patient remained free of symptoms and no radiologic evidence of recurrence was found at 5-year follow-up. discussion carcinoid tumors are thought to arise from neuroendocrine cells. primary carcinoids of the kidney have no predilection for a specific sex, age group, or side of the tumor. although their etiology is not well understood, there is increased risk of developing carcinoid tumor in patients with horseshoe kidney and other congenital malformations.(5) these tumors usually present with vague symptoms and signs. flank pain and mass are common presenting symptoms, but an overt endocrine disturbance including carcinoid or cushing syndrome has been reported.(6,7) fever, hematuria, and obstructive voiding symptoms are other presenting symptoms of these patients. therefore, the clinical picture is not generally different from that of a renal cell carcinoma. carcinoid tumors are usually well circumscribed, tan to yellow, solid fleshy tumors with areas of necrosis and cystic degeneration. most carcinoid tumors of the kidney are large at the time of nephrectomy, and as exemplified in our case, replace a major portion of the renal parenchyma. primary carcinoid tumors of the kidney are similar to those in other sites of the body. tumor cells are arranged in ribbons, festoons, and solid nests. neoplastic cells are uniform cuboidal to columnar cells with abundant pink granular cytoplasm and small, round, and regular centrally located nuclei. mitotic activity and vascular invasion are rare. usually, carcinoid lesions in the kidneys exhibit a less aggressive biologic behavior than renal cell carcinoma, but undoubtedly they have a malignant potential and metastases have been reported. histological features are usually not helpful in predicting biological behavior of such tumors; however, stage at presentation is the most important factor in determining the outcome.(5,8) conflict of interest none declared. references 1. kulke mh, mayer rj. carcinoid tumors. n engl j med. 1999;340:858-68. 2. kuroda n, katto k, tamura m, et al. carcinoid tumor of the renal pelvis: consideration on the histogenesis. pathol int. 2008;58:51-4. 3. siquini w, stortoni p, criante p, et al. primary carcinoid tumour of the kidney. a case report and review of the literature. chir ital. 2007;59:559-63. 4. chung hy, lau wh, chu sm, collins rj, tam pc. carcinoid tumour of the kidney in a chinese woman presenting with loin pain. hong kong med j. 2007;13:406-8. 5. krishnan b, truong ld, saleh g, sirbasku dm, slawin km. horseshoe kidney is associated with an increased relative risk of primary renal carcinoid tumor. j urol. 1997;157:2059-66. 6. moulopoulos a, dubrow r, david c, dimopoulos ma. primary renal carcinoid: computed tomography, ultrasound, and angiographic findings. j comput assist tomogr. 1991;15:323-5. 7. hannah j, lippe b, lai-goldman m, bhuta s. oncocytic carcinoid of the kidney associated with periodic cushing’s syndrome. cancer. 1988;61:213640. 8. raslan wf, ro jy, ordonez ng, et al. primary carcinoid of the kidney. immunohistochemical and ultrastructural studies of five patients. cancer. 1993;72:2660-6. v08_no_1_print_3.pdf miscellaneous 60 urology journal vol 8 no 1 winter 2011 role of color doppler ultrasonography in evaluation of scrotal swellings pattern of disease in 120 patients with review of literature syed amjad ali rizvi,1 ibne ahmad,2 mohammed azfar siddiqui,2 samreen zaheer,2 kaleem ahmad3 purpose: to determine the value of color doppler ultrasonography (cdus) as a routine investigational method for diagnosis of scrotal pathologies. materials and methods: this prospective observational study (case series) was carried out over a period of 16 months on 122 patients in the age range of 13 to 70 years old, who presented with scrotal swellings. after adequate history taking and examination, cdus was performed. the diagnosis of the surgeon and that of radiologist were compared with final outcome, which was based on course and outcome of the disease, fine needle aspiration cytology results, and operative findings. results: the final diagnoses were epididymitis or epididymo-orchitis (46), hydrocele (26), varicocele (16), testicular malignancy (16), orchitis (6), testicular torsion (4), spermatic cord injury (2), hematocele (2), and pyocele (2). color doppler ultrasonography accurately diagnosed all cases of epididymitis or epididymo-orchitis, spermatic cord injury, testicular torsion, varicocele, and hydrocele (sensitivity 100% and specificity 100%). of 16 subjects diagnosed as testicular malignancy on cdus, only 14 were subsequently found to have malignancy. two cases of orchitis were wrongly diagnosed as malignancy. similarly, of 6 patients diagnosed as orchitis, 1 was found to have seminoma (sensitivity 87.5% and specificity 66.7%). overall sensitivity of cdus in diagnosing scrotal diseases was 98% while specificity was 66.7%. conclusion: color doppler ultrasonography is an excellent, a safe, and reliable method for evaluating patients with scrotal diseases. it aids in diagnosis of testicular tumors and reduces the number of unnecessary exploratory operations. it is especially important in conditions like testicular torsion where immediate diagnosis is required. urol j. 2011;8:60-5. www.uj.unrc.ir keywords: scrotum, color doppler ultrasonography, retrospective studies 1department of surgery, jawaharlal nehru medical college, a.m.u., aligarh, india 2department of radiodiagnosis, jawaharlal nehru medical college, a.m.u., aligarh, india 3department of radiodiagnosis, b.p. koirala institute of health sciences, dharan, nepal corresponding author: mohammed azfar siddiqui, md department of radiodiagnosis, jawaharlal nehru medical college, amu, aligarh-202002, india tel: +91 971 936 1454 e-mail: drazfarsiddiqui@gmail.com received may 2010 accepted august 2010 introduction color doppler ultrasonography (cdus) is an important tool for diagnosis of scrotal diseases because of its ability to depict anatomy and perfusion in real time.(1) diagnosis of scrotal diseases has always been a challenge for the clinician due to non-specific signs and symptoms.(2) the causes of scrotal swelling can be classified as acute and non-acute. acute causes include torsion, trauma, abscess, and orchitis. nonacute causes include hydrocele, scrotal hernia, lymphocele, and others. scrotal lesions can also be classified as testicular and extratesticular. the common ultrasonography in scrotal swellings—rizvi et al 61urology journal vol 8 no 1 winter 2011 testicular lesions are torsion, trauma, neoplasms, and inflammatory conditions. extratesticular lesions include lesions of the spermatic cord, the epididymis, and the scrotal wall. this distinction is important because extratesticular masses are almost always benign while intratesticular solid masses may be malignant. ultrasonography plays a major role in distinguishing intratesticular from extratesticular abnormalities. materials and methods this prospective observational study (case series) was conducted in the jawaharlal nehru medical college hospital (jnmch), amu aligarh over a span of 16 months from september 2008 to january 2010. the study was approved by the ethical committee of the hospital and a written informed consent was taken from each patient. inguinoscrotal hernia and undescended testis were the exclusion criteria. a total of 122 patients in the age range of 13 to 70 years old, with scrotal pathologies were included in the study. two subjects were lost in the follow-up period. after adequate history taking and physical examination, cdus was performed. the patients were scanned with the linear color doppler multi-frequency (7 to 9 mhz) transducer using logiq 500 (ge wipro) ultrasound machine and sagittal and transverse images were obtained. additional views were also obtained in coronal and oblique planes, with the patient being upright and performing valsava maneuver. diagnostic accuracy of cdus was determined by comparing it with the final diagnosis, which was based on clinical outcome (ie, positive response to medical treatment), operative findings, fine needle aspiration cytology (fnac), and histopathological examination results. results the majority of the patients with acute scrotal condition were in their 2nd and 3rd decades of life whereas those presenting with testicular masses were in their 5th and 6th decades. with the help of cdus, the diagnoses of epididymitis and epididymo-orchitis were made in 46 out of 52 patients who presented with clinical suspicion (figure 1). all of these 46 patients were conservatively managed and follow-up cdus revealed resolution of findings. all patients with symptoms of varicocele were in their 2nd and 3rd decades of life. of 14 patients, 10 were clinically diagnosed with unilateral and 4 with bilateral varicoceles. these patients were subjected to cdus, which showed multiple serpiginous anechoic structures adjacent to upper pole of the testis and head of the epididymis with venous flow that accentuated on performing valsalva maneuver or making the patient upright (figure 2). doppler ultrasonography confirmed the presence of unilateral varicocele in 8 patients, figure 1. epididymitis. longitudinal ultrasonographic image of the right testis demonstrates enlarged, thickened, and heterogeneous epididymis. doppler ultrasonography shows an increase in vascular flow. figure 2. varicocele. color doppler ultrasonography demonstrates multiple serpentine vascular channels within the scrotum, which become more prominent after valsalva maneuver. ultrasonography in scrotal swellings—rizvi et al 62 urology journal vol 8 no 1 winter 2011 but detected bilateral varicocele in 2 subjects that were clinically diagnosed as unilateral varicocele. it also confirmed bilaterallity of varicocele in 4 patients. further, 2 patients who presented with infertility and had normal scrotum clinically were diagnosed as case of varicocele on cdus. twenty-six patients with clinical suspicion of hydrocele were also subjected to cdus, which supported the diagnosis. color doppler ultrasonography also found hydrocele in 4 clinically unsuspected subjects. on aspiration, only 26 were found to have hydrocele while hematocele and pyocele were found in 2 others. four patients were clinically diagnosed as cases of testicular torsion. color doppler ultrasonography showed absent intratesticular blood flow confirming the diagnosis. surgery was done, which supported the diagnosis. two patients who presented with history of trauma to the scrotum were also diagnosed as a case of traumatic spermatic cord injury. the patients were managed with antibiotics, and follow-up examination showed complete resolution of inflammatory changes in all the patients. fine needle aspiration cytology was not required. therefore, we found that cdus was 100% sensitive and 100% specific for diagnosing scrotal diseases other than testicular masses (tables 1 and 2). twenty-two patients who presented with enlargement of the scrotum were clinically labeled as cases of testicular mass. the size of the lesion ranged from 1.1 cm to 5.5 cm. they were subjected to cdus, which showed localized involvement in 36.6% and diffuse involvement in 63.4%. increased vascularity was revealed in all the subjects, and diagnoses of testicular mass and orchitis were made in 16 and 6 patients, respectively. subsequently, all 16 subjects with diagnosis of testicular mass were subjected to fnac. fourteen out of 16 patients turned out to be seminoma (figure 3) while 2 misdiagnosed subjects turned out to be orchitis. six out of 22 clinically diagnosed cases of testicular mass were labeled as orchitis on cdus (figure 4). however, fnac results showed one of them to be seminoma. color doppler ultrasonography was 87.5% sensitive and 66.7% specific in diagnosing testicular masses (tables 1 and 3). in all confirmed cases of seminoma, orchidectomy was performed and fnac diagnoses were comparable to final histopathological examination. overall sensitivity of cdus in the diagnosis of lesion clinical diagnosis cdus diagnosis intervention final outcome 1 epididymitis/ epididymo-orchitis 52 46 antibiotics epididymitis/ epididymo-orchitis 46 2 spermatic cord injury 2 2 antibiotics spermatic cord injury 2 3 testicular torsion 4 4 surgery testicular torsion 4 4 testicular mass 22 testicular mass – 16 fnac seminoma – 14 orchitis – 2 orchitis 6 fnac orchitis – 4 seminoma – 2 5 varicocele 14 16 --varicocele – 16 6 hydrocele 26 30 aspiration hydrocele – 26 hematocele – 2 pyocele – 2 table 1. the clinical diagnosis, cdus diagnosis, and final outcome* *cdus indicates color doppler ultrasonography; and fnac, fine needle aspiration cytology. doppler diagnosis final outcome total disease present disease absent disease present 98 0 98 disease absent 0 0 0 98 0 98 table 2. sensitivity and specificity of color doppler ultrasonography in diagnosis of scrotal diseases other than testicular masses *sensitivity: 98/ 98 + 0 × 100 = 100% specificity: 0/0 + 0 × 100 = 100% ultrasonography in scrotal swellings—rizvi et al 63urology journal vol 8 no 1 winter 2011 doppler diagnosis fnac diagnosis* total positive negative tumor 14 2 16 non tumor 2 4 6 16 6 22 table 3. sensitivity and specificity of color doppler ultrasonography in diagnosis of testicular masses *fnac indicates fine needle aspiration cytology. †sensitivity: 14/14 + 2 × 100 = 87.5% specificity: 4/4 + 2 × 100 = 66.7% *sensitivity: 112/112 + 2 × 100 = 98.0% specificity: 4/4 + 2 × 100 = 66.7% table 4. overall sensitivity and specificity of color doppler ultrasonography in diagnosis of scrotal diseases doppler diagnosis final outcome total disease present disease absent disease present 112 2 114 disease absent 2 4 6 114 6 120 figure 3. seminoma. (a) longitudinal ultrasonographic image of the right testis demonstrates a diffuse homogeneous mass with scattered microlithiasis and associated hydrocele. (b) doppler ultrasonographic image shows a generalized increase in testicular vascular flow. figure 4. orchitis. color doppler ultrasonography of the scrotum reveals hypoechoic left testis with markedly increased vascularity, compared with normal echogenic right testis showing normal vascularity. ultrasonography in scrotal swellings—rizvi et al 64 urology journal vol 8 no 1 winter 2011 scrotal diseases was 98% while specificity was 66.7% (table 4). discussion grey scale ultrasonography is a well-established modality for diagnosis of scrotal diseases; however, the major limitation of conventional grey scale ultrasonography is lack of specificity for parenchymal changes. also benign and malignant lesions cannot be distinguished on the basis of ultrasonography alone.(3) furthermore, in painful scrotum, grey scale ultrasonography cannot accurately differentiate testicular torsion from epididymo-orchitis. william and colleagues studied 5 patients in whom no intratesticular blood flow was identified on symptomatic side while normal flow was detected on the opposite side. however, on grey scale ultrasonography, no abnormality could be detected in 3 patients while 2 subjects had non-specific findings.(4) color doppler ultrasonography has many advantages over conventional ultrasonography. in addition to detecting non-specific grey scale changes that can occur with testicular ischemia, it also shows blood flow in testicular arteries. till recently, radionuclide scanning has played an important role in evaluation of equivocal cases of acute scrotal diseases. it has provided useful information regarding scrotal blood flow.(5) however, it cannot accurately depict the anatomy.(6) middleton and associates evaluated 28 patients with acute scrotal pain by cdus and scintigraphy. while cdus correctly diagnosed all the subjects, scintigraphy failed to reach the diagnosis in one.(7) also cdus was more rapid, non-invasive, and at least as accurate as scintigraphy.(8) accurate clinical diagnoses of scrotal diseases are difficult as most patients present with similar signs and symptoms.(2) color doppler ultrasonography is currently the most important imaging modality available for diagnosis of scrotal pathologies. it allows accurate evaluation of scrotal conditions as well as normal anatomy. becker and coworkers concluded a sensitivity of 90.5% and specificity of 98.3% in diagnosis of testicular torsion.(9) süzer and colleagues found cdus to be 100% sensitive and 100% specific in diagnosis of acute scrotal conditions.(10) in our study, of 26 patients who had acute presentation, 23 were diagnosed with epididymitis or epididymo-orchitis. in all the patients, the epididymis was enlarged, hypoechoic, and hyperemic. in 5 patients, in addition to the epididymis, the testis was also hypoechoic and hyperemic. two patients were diagnosed as cases of testicular torsion. both patients showed mild enlargement, hypoechoic echotexture, and markedly decreased vascularity. color doppler ultrasonography showed sensitivity and specificity of 100%, respectively, in diagnoses of inflammatory scrotal diseases and testicular torsion. thus, our observations are comparable to previous studies. however, cdus is not without pitfalls. zoller and associates concluded that detection of intratesticular blood flow cannot exclude testicular torsion.(11) derouet and coworkers observed ultrasonography to be 90% sensitive and 55% specific in detection of testicular neoplasms(12) whereas gallardo agromayor and colleagues reported sensitivity of 100% for ultrsonography in diagnosing testicular neoplasm.(13) in the present study, cdus showed a sensitivity of 87.5% and specificity of 66.7% in detection of testicular neoplasms, which is compatible with the study carried out by derouet and associates. in our series, 90% of seminomas appeared as solid, homogenous, hypoechoic, and hypervascular lesions compared to normal testicular tissue. in our study, all cases of varicocele were accurately diagnosed and also one patient, who presented with infertility and had no findings on clinical examination, was diagnosed with varicocele. other investigations like magnetic resonance imaging can be applied when ultrasonography proves inconclusive. its use in scrotal diseases is increasing;(14-16) however, it is more expensive and not always available. nuclear scintigraphy, which has high sensitivity and specificity in differentiating ischemia from infarction, cannot accurately distinguish ischemia from conditions such as hydrocele, spermatocele, and inguinal hernia and is uncommon due to high accuracy ultrasonography in scrotal swellings—rizvi et al 65urology journal vol 8 no 1 winter 2011 of cdus.(5) therefore, cdus with its high sensitivity and specificity is the most important investigation for diagnosis of scrotal diseases, presenting especially in emergency clinical setting. conclusion we conclude that cdus, which can simultaneously display scrotal anatomy and perfusion, is an excellent, a safe, and reliable method for evaluating patients with scrotal diseases, whether acute or chronic. it helps to improve patient’s management, especially by preventing unnecessary surgical exploration. it is also convenient and easy to perform. but it has its own limitations, including difficulty in detecting intratesticular flow in small children and requiring adequate expertise and experience.(17) its results are also equipment dependent. conflict of interst none declared. references 1. lerner rm, mevorach ra, hulbert wc, rabinowitz r. color doppler us in the evaluation of acute scrotal disease. radiology. 1990;176:355-8. 2. pavlica p, barozzi l. imaging of the acute scrotum. eur radiol. 2001;11:220-8. 3. mishkin fs. differential diagnostic features of the radionuclide scrotal image. ajr am j roentgenol. 1977;128:127-9. 4. middleton wd, thorne da, melson gl. color doppler ultrasound of the normal testis. ajr am j roentgenol. 1989;152:293-7. 5. lutzker lg, zuckier ls. testicular scanning and other applications of radionuclide imaging of the genital tract. semin nucl med. 1990;20:159-88. 6. riley tw, mosbaugh pg, coles jl, newman dm, van hove ed, heck ll. use of radioisotope scan in evaluation of intrascrotal lesions. j urol.1976;116: 472-5. 7. middleton wd, siegel ba, melson gl, yates ck, andriole gl. acute scrotal disorders: prospective comparison of color doppler us and testicular scintigraphy. radiology. 1990;177:177-81. 8. fitzgerald sw, erickson s, dewire dm, et al. color doppler sonography in the evaluation of the adult acute scrotum. j ultrasound med. 1992;11:543-8. 9. becker d, burst m, wehler m, tauschek d, herold c, hahn eg. [differential diagnosis of acute testicular pain using color-coded duplex ultrasonography: difference between testicular torsion and epididymitis]. dtsch med wochenschr. 1997;122:1405-9. 10. süzer o, ozcan h, küpeli s, gheiler el. color doppler imaging in the diagnosis of the acute scrotum. eur urol. 1997;32:457-61. 11. zoller g, kugler a, ringert rh. [“false positive” testicular perfusion in testicular torsion in power doppler ultrasound]. urologe a. 2000;39:251-3. 12. derouet h, braedel hu, brill g, hinkeldey k, steffens j, ziegler m. [nuclear magnetic resonance tomography for improving the differential diagnosis of pathologic changes in the scrotal contents]. urologe a. 1993;32:327-33. 13. gallardo agromayor e, pena gomez e, lopez rasines g, et al. [testicular tumors. echographic findings]. arch esp urol. 1996;49:622-6. 14. nagler-reus m, guhl l, volz c, wuerstlin s, arlart ip. [magnetic resonance tomography of the scrotum. experiences with 129 patients]. radiologe. 1995;35:494-503. 15. terai a, yoshimura k, ichioka k, et al. dynamic contrast-enhanced subtraction magnetic resonance imaging in diagnostics of testicular torsion. urology. 2006;67:1278-82. 16. watanabe y, dohke m, ohkubo k, et al. scrotal disorders: evaluation of testicular enhancement patterns at dynamic contrast-enhanced subtraction mr imaging. radiology. 2000;217:219-27. 17. atkinson go, jr., patrick le, ball ti, jr., stephenson ca, broecker bh, woodard jr. the normal and abnormal scrotum in children: evaluation with color doppler sonography. ajr am j roentgenol. 1992;158:613-7. kidney transplantation 34 urology journal vol 5 no 1 winter 2008 symptomatic lymphocele after kidney transplantation a single-center experience mohammad ali zargar-shoshtari, mohammadjavad soleimani, hormoz salimi, kaveh mehravaran introduction: in a retrospective study, we evaluated the frequency, clinical presentation, and management of lymphocele in kidney transplant recipients operated on in a single center. materials and methods: between september 1984 and june 2005, we had 2147 kidney transplantations from living donors. during the follow-up period, ultrasonography was performed in symptomatic patients and those with elevated serum creatinine level postoperatively. other radiological procedures were done in complicated cases. patients with lymphocele were treated by percutaneous drainage with or without injection of sclerotizing agent (povidone iodine). if recurrence occurred, surgical intraperitoneal drainage was performed. in cases with multiloculated collection or inappropriate access for percutaneous drainage, the primary approach was surgical intraperitoneal drainage. results: symptomatic lymphocele collection was seen in 17 kidney recipients of our series (0.8%; 95% confidence interval, 0.4% to 1.2%). it presented with elevation of serum creatinine concentrations (47.1%), pain and abdominopelvic swelling (29.4%), and lower extremity edema (23.5%). percutaneous drainage was used for the treatment of lymphocele in 11 patients, but recurrence occurred in 7 (63.6%). these cases were treated with open surgical drainage. in 6 patients, the primary approach was surgical intraperitoneal drainage, because of multiloculated collection or inappropriate access for percutaneous drainage. all of the patients were treated successfully and no graft loss occurred during the follow-up period. conclusion: symptomatic lymphocele is an uncommon complication after kidney transplantation. surgical intraperitoneal drainage is the most effective approach for the management of symptomatic lymphocele.keywords: kidney transplantation, lymphocele, treatment, drainage shaheed hasheminejad kidney transplantation center, iran university of medical sciences, tehran, iran corresponding author: mohammad ali zargar-shoshtari, md shaheed hasheminejad hospital, vanak sq, tehran, iran tel: +98 21 8852 6900 fax: +98 21 8852 6901 e-mail: dr.zargarm@gmail.com received october 2007 accepted december 2007 introduction one of the urological complications in kidney transplant recipients is lymphocele which is a fluid collection between the kidney allograft and the bladder. it is an uncommon complication (0.6% to 18%) caused primarily by extravasation of the lymph from the lymphatic vessels injured during preparation of the iliac vessels of the recipient and unligated lymphatic system from the renal hilum of the donor.(1,2) other factors such as acute rejection, urinary obstruction, and graft decapsulation may contribute to the development of lymphocele.(3) patients are usually asymptomatic and spontaneous resolution occurs after a few months. however, large lymphoceles may manifest by edema in the inguinal regions, deterioration of kidney function, fever, lymphedema of the ipsilateral urol j. 2008;5:34-6. www.uj.unrc.ir lymphocele after kidney transplantation—zargar-shoshtari et al urology journal vol 5 no 1 winter 2008 35 leg, and even compressive syndrome of the vena cava or the portal vein.(4) therapy of large symptomatic lymphocele involves 2 basic methods of surgical approaches with internal drainage and marsupialization, and percutaneous puncture and drainage.(4,5) some of the most common manifestations are bulging of the surgery site, kidney allograft dysfunction, and ipsilateral or bilateral edema of the lower extremities.(1-6) they have usually been treated successfully without graft loss.(6) in this retrospective study, we evaluated the incidence, clinical presentation, and management of lymphocele in our large population of kidney allograft recipients in a single center. materials and methods between september 1984 and june 2005, we had 2147 kidney transplantations at hasheminejad kidney transplantation center in tehran, iran. transplanted patients were 1185 men and 962 women with ages ranged from 4 to 59 years. the allograft source was a living donor in all of the patients. the procedure was a retransplantation in 186 patients (8.7%). surgical operations were done in accordance with the standard technique of kidney transplantation in which the allograft was placed in the iliac fossa (usually in the right side) and its vessels were anastomosed to the iliac vessels and the ureter was implanted into the bladder using extravesical technique. all lymphatic vessels encountered during dissection of the iliac vessels were ligated. stenting of the implanted ureter was used in all of the cases. during the follow-up period, ultrasonography was performed only in symptomatic patients and those with serum creatinine elevation postoperatively. other radiological procedures such as the renal scintigraphy, computed tomography, intravenous urography, and magnetic resonance imaging were done if necessary. we managed symptomatic patients by percutaneous drainage with or without injection of sclerotizing agent (povidone iodine). if recurrence occurred, surgical intraperitoneal drainage was performed. in cases with multiloculated collection or inappropriate access for percutaneous drainage, the primary approach was surgical intraperitoneal drainage. results symptomatic lymphocele collection was seen in 17 kidney recipients of our series (0.8%; 95% confidence interval, 0.4% to 1.2%). these episodes developed between 10 to 90 days after transplantation (median, 6 weeks). the patients were 8 men and 9 women aged 24 to 53 years old at the time of transplantation. one of the patients had received her second kidney allograft. the clinical manifestations of posttransplant lymphocele were variable. it presented with elevated serum creatinine levels in 8 patients (47.1%), pain and abdominopelvic swelling in 5 (29.4%), and lower extremity edema in 4 (23.5%). diagnosis of lymphocele was confirmed by ultrasonography and renal scintigraphy. computed tomography was performed in 2 complicated cases. percutaneous drainage was used for the treatment of lymphocele in 11 patients, and for 6 of whom injection of povidone-iodine was carried out too. re-accumulation of lymph occurred in 7 of 11 patients (63.6%) with percutaneous drainage. three of these patients had povidoneiodine injection. these cases were treated successfully with open surgical procedure. in the remaining 6 patients, the primary approach was surgical intraperitoneal drainage, because of multiloculated collection or inappropriate access for percutaneous drainage. with a median followup of 14 months, there was no graft loss or any other complications in these patients. discussion the reported incidence of symptomatic lymphocele following kidney transplantation ranges from 0.6% to 18% in the literature.(1,2,6) however, there are some series with higher or lower frequencies of this complication; in a study on 138 case of transplantation, atray and colleagues reported 36 patients with lymphocele (26%).(7) in another study by gupta and associates on 680 patients with kidney transplantation, symptomatic lymphocele was found in 11 patients.(8) the frequency of symptomatic lymphocele formation in our study was 0.8% which seems to be low compared to the reported incidences in other studies. we did not screen lymphocele after kidney transplantation—zargar-shoshtari et al 36 urology journal vol 5 no 1 winter 2008 all of the kidney recipients postoperatively and only symptomatic patients were evaluated and diagnosed with lymphocele. screening is not usually done and most of the studies have reported symptomatic cases, but different diagnostic approaches and surgical techniques may cause discrepancies in the incidences reported by different centers. on the other hand, in contrast to our series, other studies are on kidney allografts that have not been harvested only from living donors. samhan and al-mousawi showed that the incidence of symptomatic lymphocele is more when cadaveric kidney allografts are used. (6) hence, this can be another cause of increased incidence of lymphocele in some studies. lymphocele develops primarily by extravasation of the lymph from the lymphatic vessels injured during the preparation of the iliac vessels of the recipient and unligated lymphatic vessels from the renal hilum of the donor. other factors such as acute rejection, urinary obstruction, and graft decapsulation may contribute to its development. (3) also, the use of some immunosuppressive drugs such as sirolimus may be associated with a significant increase in lymphocele formation, but their role has not been confirmed in all studies.(9) although lymphocele formation is harmless and asymptomatic in many cases, in some instances, it can seriously affect kidney graft function and necessitates intervention.(6) treatment of lymphoceles should start with minimally invasive measures. percutaneous treatment is considered as the first-line modality for pelvic lymphoceles due to its effectiveness, widespread applicability on an outpatient basis, ease of the procedure, and low complication rate.(10) in our study, although percutaneous drainage was successful in some patients, re-accumulation of lymphocele was noticed in majority of them. intraperitoneal drainage, either as a primary intervention, or after failure of prolonged percutaneous aspiration results in permanent cure of the condition.(6) it is noteworthy that laparoscopic surgery has become widely accepted for the treatment of lymphocele following kidney transplantation. however, open drainage should be performed in patients with wound complications and in those with a small lymphocele adjacent to the vital renal structures.(11,12) conclusion symptomatic lymphocele is an uncommon complication after kidney transplantation. in our experience, surgical intraperitoneal drainage is the most effective approach for the management of this complication. conflict of interest none declared. references 1. shokeir aa, el-diasty ta, ghoneim ma. percutaneous treatment of lymphocele in renal transplant recipients. j endourol. 1993;7:481-5. 2. dubeaux vt, oliveira rm, moura vj, pereira jm, henriques fp. assessment of lymphocele incidence following 450 renal transplantations. int braz j urol. 2004;30:18-21. 3. hamza a, fischer k, koch e, et al. diagnostics and therapy of lymphoceles after kidney transplantation. transplant proc. 2006;38:701-6. 4. martínez jabaloyas jm, morera martínez j, pontones moreno jl, et al. [lymphocele as a complication of renal transplantation]. actas urol esp. 1994;18:10610. spanish. 5. huilgol ak, sundar s, karunagaran sg, sudhakar s, sreenivasa prasad ma, ravindran t. lymphoceles and their management in renal transplantation. transplant proc. 2003;35:323. 6. samhan m, al-mousawi m. lymphocele following renal transplantation. saudi j kidney dis transpl. 2006;17:34-7. 7. atray nk, moore f, zaman f, et al. post transplant lymphocele: a single centre experience. clin transplant. 2004;18 suppl 12:46-9. 8. gupta rs, niranjan j, srivastava a, kumar a. lymphoceles following renal transplantation : comparison of open surgical and laparoscopic deroofing. indian j urol. 2002;18:36-47. 9. tondolo v, citterio f, massa a, et al. lymphocele after renal transplantation: the influence of the immunosuppressive therapy. transplant proc. 2006;38:1051-2. 10. karcaaltincaba m, akhan o. radiologic imaging and percutaneous treatment of pelvic lymphocele. eur j radiol. 2005;55:340-54. 11. fuller tf, kang sm, hirose r, feng s, stock pg, freise ce. management of lymphoceles after renal transplantation: laparoscopic versus open drainage. j urol. 2003;169:2022-5. 12. bailey sh, mone mc, holman jm, nelson ew. laparoscopic treatment of post renal transplant lymphoceles. surg endosc. 2003;17:1896-9. v07_no_4.pdf case report 284 urology journal vol 7 no 4 autumn 2010 disfiguring abdominal mass due to a huge extraordinary calyceal diverticulum ali kaviani, jalil hosseini, behzad lotfi, reza valipour, irandokht sadeghian urol j. 2010;7: -6. www.uj.unrc.ir keywords: diverticulum, kidney calices, kidney diseases, flank pain department of urology, shohadauniversity, mc, tehran, iran corresponding author: ali kaviani, md department of urology, shohadauniversity, mc, tehran, iran fax : +98 21 2273 6386 e-mail: akaviani@hotmail.com received april 2009 accepted october 2009 introduction a calyceal diverticulum is a urine-containing congenital or acquired anatomical abnormality of the pyelocaliceal system lined with transitional cell epithelium. urine fills this cystic area through a narrow forniceal channel or infundibulum.(1-3) the etiology of pyelocaliceal diverticulum is believed to be congenital.(2,4) calyceal diverticulum seen in the upper (70%), mid (12%), or lower (18%) calyx, arises frequently from the posterior aspect of the kidney and is usually unilateral. although the typical calyceal cyst is smaller than 1 cm,(5) some larger ones are occasionally detected. here, we report a huge extraordinary 18 × 16 cm calyceal diverticulum in a 19-year-old woman. case report a 19-year-old woman with the chief complaint of left flank pain was referred to our clinic two months before admission. a left flank mass was detected during physical examination. urine analysis and other laboratory data were within normal limits. ultrasonography showed a huge cystic lesion in the left kidney. in diethylene triamine pentaacetic acid scan, a mild to moderate functional impairment of the left kidney as well as a photopenic zone above the left kidney were found. computed tomography (ct) scan confirmed a 180 × 160 mm cystic lesion located in the superior part of the left kidney (figure 1). magnetic resonance urography showed a suspicious connection to the upper calyceal system of the left kidney (figure 2). the connection was confirmed by retrograde ureterography that was compatible with a huge left calyceal system diverticulum (figure 3). after placement of a ureteral catheter, we approached the left kidney through a left flank incision (figure 4). by removing the thin figure 1. computed tomography scan revealed a 180 × 160-mm cystic lesion located in the superior part of the left kidney. calyceal diverticulum—kaviani et al 285urology journal vol 7 no 4 autumn 2010 upper part of the calyceal diverticulum wall, we injected methylene blue through ureteral catheter in order to identify the calyceal infundibulum, which was then incised and marsupialized to the renal pelvis (figure 5). after introducing a double-j ureteral stent and a nephrostomy tube, we closed the calyceal bed on itself in a water tight fashion. nephrostomy tube and double-j stent were removed one and four weeks after the operation, respectively. pathologic examination revealed calyceal diverticulum. discussion pyelocalyceal diverticulum is an unusual disorder, in which a urine-filled cavity is connected to the renal calyx or the pelvis by a narrow or stenotic isthmus. it is lined with non-secretory transitional epithelium and is filled by urine via the adjacent collecting system.(1-3) most patients with pyelocalyceal diverticulum are asymptomatic and have been discovered figure 4. access through left flank incision. figure 5. incision and marsupialization of the calyceal wall. figure 2. a suspicious connection to the left kidney’s upper calyceal system in magnetic resonance urethrography. figure 3. a huge left calyceal system diverticulum was detected in retrograde ureterography. calyceal diverticulum—kaviani et al 286 urology journal vol 7 no 4 autumn 2010 mostly accidentally on imaging modalities such as intravenous urography (ivu), renal ultrasonography, ct scan, magnetic resonance imaging, and retrograde pyelography.(6-8) communicating renal cyst, renal cortical abscess, pseudodiverticulum, and tuberculosis are the differential diagnoses for pyelocaliceal diverticulum.(2,9,10) the incidence rate of pyelocaliceal diverticulum is about 0.21% to 0.45%, based on accidental findings in ivu, and is similar in both children and adults.(2,4,11,12) pyelocaliceal diverticulum can mimic malignant or infected cyst in ultrasonography; hence, ivu and contrastenhanced ct scan are essential to confirm the diagnosis when ultrasonographic findings suggest the presence of renal cystic lesions. calyceal diverticulums are usually less than 1 cm in diameter.(4) however, hosomi and colleagues (13) and hulbert and associates (14) reported a 3 × 3 cm and 7.5 cm calyceal diverticulum, respectively. to the best of our knowledge, we have not come across any report of a similar huge 16 × 18 cm calyceal diverticulum. conflict of interest none declared. references 1. middleton aw, jr., pfister rc. stone-containing pyelocaliceal diverticulum: embryogenic, anatomic, radiologic and clinical characteristics. j urol. 1974;111:2-6. 2. siegel mj, mcalister wh. calyceal diverticula in children: unusual features and complications. radiology. 1979;131:79-82. 3. timmons jw, jr., malek rs, hattery rr, deweerd jh. caliceal diverticulum. j urol. 1975;114:6-9. 4. wolf j. caliceal diverticulum and hydrocalyx: laparoscopic management. urol clin north am. 2000;27:655-60. 5. canales b, monga m. surgical management of the calyceal diverticulum. curr opin urol. 2003;13:255-60. 6. wulfsohn ma. pyelocaliceal diverticula. j urol. 1980;123:1-8. 7. davidson a, hartman d, choyke p, wagner b. davidson’s radiology of the kidney and genitourinary tract: saunders; 1999. 8. jain m, grover s, kumar a, mohanty n. images: pyelocalyceal diverticulum. ind j radiol image. 2004;14:279. 9. shalhav a, soble j, nakada s, wolf jr j, mcclennan b, clayman r. long-term outcome of caliceal diverticula following percutaneous endosurgical management. j urol. 1998;160:1635-9. 10. krzeski t, witeska a, borowka a, pypno w. diverticula of renal calyces. int urol nephrol. 1981;13:231-5. 11. landry jl, colombel m, rouviere o, et al. long term results of percutaneous treatment of caliceal diverticular calculi. eur urol. 2002;41:474-7. 12. zanollo a, bono av, landini a. [diverticulosis of the renal calices and pelvis]. minerva urol. 1968;20:51-63. 13. hosomi m, oka t, miyake o, matsumiya k, takaha m, pak s. spontaneous rupture of pyelocaliceal diverticulum. urol radiol. 1989;11:136-8. 14. hulbert jc, lapointe s, reddy pk, hunter dw, castaneda-zuniga w. percutaneous endoscopic fulguration of a large volume caliceal diverticulum. j urol. 1987;138:116-7. point of technique 125urology journal vol 7 no 2 spring 2010 laparoscopic flap pyeloplasty in a child with ectopic pelvic kidney abbas basiri,1 sadrollah mehrabi,2 hossein karami3 urol j. 2010;7:125-7. www.uj.unrc.ir keywords: laparoscopy, ureteral obstruction, postoperative complications, length of stay 1department of urology, urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran 2department of urology, shahid beheshti hospital, yasouj university of medical sciences, yasouj, iran 3department of urology, kerman university of medical sciences, kerman, iran corresponding author: sadrollah mehrabi, md department of urology, shahid beheshti hospital, yasouj, iran tel: +98 741 222 1811 fax: +98 741 222 1811 e-mail: mehrabi390@yahoo.com received january 2009 accepted november 2010 introduction ureteropelvic-junction-obstruction (upjo) occurs in 22% to 37% of ectopic kidneys.(1) laparoscopic dismembered pyeloplasty (ldp) is an acceptable treatment for upjo in pediatric patients with orthotropic kidneys.(2,3) laparoscopic flap techniques have less favorable results than ldp in adult patients with orthotropic kidneys.(3) to our best knowledge, laparoscopic flap pyeloplasty of upjo has not been previously reported in pediatric patients with pelvic kidneys. we report laparoscopic treatment of upjo due to high insertion in a child with a pelvic kidney. case report a 7-year-old girl with mild right flank and lower abdominal pain since 4 months ago presented to our center for further evaluation. her weight was 20 kg, and she had a history of one episode of lower urinary tract infection 3 years ago without recurrence. physical examination was unremarkable, except presence of mild periumbilical tenderness and a palpable mild tender mass in the same area which was a pelvic kidney. laboratory data, including renal function tests, urine analysis, and culture were normal. abdominal ultrasonography revealed left malrotated kidney and right pelvic kidney with severe hydronephrosis and normal ureter. intravenous urography (figure 1), voiding cystourethrography, retrograde pyelography, magnetic resonance urography, technetium99m diethylenetriaminepentaacetic acid (99mtc-dtpa) renal scan, and diuretic renography revealed upjo of right ectopic kidney with normal bladder (figure 1). the patient underwent laparoscopic pyeloplasty. figure 1. right pelvic kidney with hydronephrosis due to ureteropelvic-junction-obstruction is seen. lk indicates left kidney and u; ureter. laparoscopic pyeloplasty in ectopic pelvic kidney—basiri et al 126 urology journal vol 7 no 2 spring 2010 technique operation was performed under general anesthesia in supine position via transperitoneal approach by four 5-mm trocars. one trocar was held in the superior umbilicus for laparoscopic lens and three 5-mm (working ports) trocars were placed in the right and left midclavicular lines at levels of umbilicus and left anterior axillary line. after insufflating co2 and visualizing abdomen, the pelvis of the right kidney was detected in the pelvic area. after incising posterior peritoneum covering the pelvis, ureteropelvic junction as well as dilated and malrotated pelvis were detected easily (figure 2). ureteropelvic junction position was high inserted, but because the inferior portion of the pelvis was near the lower pole infundibulum and there would be some tension and also risk of injury to the lower pole infundibulum if we tried for y-v plasty, we decided to repair obstruction by flap technique. harvested flap about 3 cm in length and 1 cm in width was developed from the pelvis to the lower pole infundibulum and directed downward near spatulated ureter. after holding a double-j stent by antegrade technique, anastomosis was done over a double-j stent in 2 layers using 5-0 vicryl suture (figure 3). after closure of flap and the pelvis, peritoneum was closed and a tube drain was held in the field. whole operation time was 140 minutes and there was not any intra and post operative complication. results drain and foley catheter were removed on the 4th postoperative day and the patient was discharged figure 2. dilated pelvis (p) with adjacent ureter (u) is seen. k indicates kidney. figure 3. the created flap (f) is sutured to spatulated ureter (su) over a double-j ureteral stent. lc indicates left colon and o; omentum. figure 4. pre-operative renogram shows deteriorated right kidney function (a). at 3-month postoperative renogram, right kidney demonstrated normal function with nearly normal washout time (b). laparoscopic pyeloplasty in ectopic pelvic kidney—basiri et al 127urology journal vol 7 no 2 spring 2010 with double-j ureteral stent in place and prophylactic antibiotic on the 5th postoperative day. ureteral stent was removed after 4 weeks, and at 3-month follow-up, 99mtc-dtpa scan and diuretic renogram revealed no obstruction with significant improvement in washout time (figure 4). discussion the laparoscopic approach provides all the benefits of minimally invasive procedures to the patient with entopic kidneys.(4) laparoscopic dismembered pyeloplasty, although technically challenging, provides excellent results for extrinsic or complicated upjo with success rates approaching those of traditional open pyeloplasty.(5,6) in a study by klingler and colleagues for comparing open versus laparoscopic pyeloplasty in adult patients with nonectopic kidneys, success rate was 96% for ldp, 93.4% for open pyeloplasty, and 73.3% for laparoscopic non dismembered pyeloplasty (lndp).(4) in another study by casale and associates comparing ldp and lndp in pediatric patients with orthotropic kidneys, the mean operation time was 3.1 hours in two groups, but success rate was poor in lndp (43%) compared to ldp (94%).(3) to our best knowledge, this is the first report on laparoscopic flap pyeloplasty of upjo in a child with a pelvic kidney and acceptable operation time, with minimal blood loss. laparoscopic flap pyeloplasty is indicated when dismembered and y-vplasty is not possible. this technique is feasible and provides excellent exposure. conflict of interest none declared. references 1. wadhwa p, hemal ak. case report: transmesocolic laparoscopic reconstruction of ureteropelvic junction obstruction in pelvic kidney associated with extrarenal calices. j endourol. 2006;20:188-90. 2. kutikov a, resnick m, casale p. laparoscopic pyeloplasty in the infant younger than 6 months--is it technically possible? j urol. 2006;175:1477-9; discussion 9. 3. casale p, grady rw, joyner bd, zeltser is, figueroa te, mitchell me. comparison of dismembered and nondismembered laparoscopic pyeloplasty in the pediatric patient. j endourol. 2004;18:875-8. 4. klingler hc, remzi m, janetschek g, kratzik c, marberger mj. comparison of open versus laparoscopic pyeloplasty techniques in treatment of uretero-pelvic junction obstruction. eur urol 2003;44:340-5. 5. gupta n, mandhani a, sharma d, kapoor r, dubey d, kumar a. is laparoscopic approach safe for ectopic pelvic kidneys? urol int. 2006;77:118-21. 6. pardalidis np, papatsoris ag, kosmaoglou ev. endoscopic and laparoscopic treatment of ureteropelvic junction obstruction. j urol. 2002;168:1937-40. letter reply letter to: retrograde intrarenal surgery vs. percutaneous nephrolithotomy vs. extracorporeal shock wave lithotripsy for lower pole renal stones 10-20 mm : a meta-analysis and systematic review alkan cubuk*, orkunt özkaptan, ahmet şahan we read the article entitled ‘’retrograde intrarenal surgery vs. percutaneous nephrolithotomy vs. extracor-poreal shock wave lithotripsy for lower pole renal stones 10-20 mm : a meta-analysis and systematic review’’ published in urology journal(1). the topic is still hot in the urology regarding lower pole kidney stones in 10-20 mm diameters. although extracorporeal shock wave lithotripsy (eswl), retrograde intrarenal surgery (rirs) and percutaneous nephrolitotomy (pcnl) are the available options for the patients with lower pole renal stones 10-20 mm diameter, the decision making among the methods is still controversy. this manuscript is valuable in this regard. at the present manuscript the authors prepared a very comprehensive meta-analysis of existing evidence to quantify and compare the safety and efficacy of pcnl, rirs and eswl for lower pole renal stones 10-20mm. they emphasized longer operative time of pcnl and rirs compared to eswl. they also reported higher stone free rate, the lower retreatment rate and auxiliary procedure following pcnl with longest hospital stay for pcnl. when it comes to eswl, the lowest sfr, the higher retreatment rate and auxiliary procedure rate, but a shorter operative time and the shortest hospital stay was reported. the authors indicated stone to skin distance (ssd) as an unfavorable factor for eswl. this issue is also reported in current literature. ssd was calculated by measuring the distance from the stone to the skin in three angles (0°, 45° and 90°) and the cut-off value for swl failure was reported in a wide scale from 100 mm to 119 mm(2,3). at the present study the authors presented 10 mm as a predictive value for a criteria of swl failure. this statement seems to be not correct totally also 10 mm is an impossible value for ssd. in our opinion it was caused by a misspelling, and a correction may be informative for the readers. references: 1. junbo l, yugen l, guo j, jing h, ruichao y, tao w. retrograde intrarenal surgery vs. percutaneous nephrolithotomy vs. extracorporeal shock wave lithotripsy for lower pole renal stones 10-20 mm : a meta-analysis and systematic review. urol j. 2019: 5;16(2):97-106. 2. pareek g, hedican sp, lee ft jr, nakada sy. shock wave lithotripsy success determined by skin-tostone distance on computed tomography. urology 2005: 66(5):941–944. 3. langenauer j, betschart p, hechelhammer l,et al. advanced non-contrasted computed tomography postprocessing by ct-calculometry (ct-cm) outperforms established predictors for the outcome of shock wave lithotripsy. world j urol. 2018:36(12):2073-2080. dr. lütfi kirdar training and research hospital, istanbul, turkey. *correspondence: dr. lütfi kirdar training and research hospital, istanbul, turkey. alkancubuk@hotmail.com. received december 2020 & accepted january 2021 urology journal/vol 18 no. 3/ may-june 2021/ pp. 351-352. [doi: 10.22037/uj.v16i7.6590] re :“reply letter to: retrograde intrarenal surgery vs. percutaneous nephrolithotomy vs. extracorporeal shock wave lithotripsy for lower pole renal stones 10-20 mm : a meta-analysis and systematic review” reply by author thank you very much for your careful reading of our research(1) and your valuable comments. it is necessary for us to explain your questions. in our article(1), we indicated stone to skin distance (ssd) as an unfavorable factor for eswl. as you said this issue was also reported in current literature, and ssd was calculated by measuring the distance from the stone to the skin in three angles (0°, 45° and 90°) and the cut-off value for swl failure was reported in a wide scale from 100 mm to 119 mm(2,3). so the statement that stone to skin distance (ssd) as an unfavorable factor for eswl is no wrong. what is controversial is the range of this value. in our paper(1), we mentioned “long skin-to-stone distance (> 10mm)”, and the figure of 10mm is controversial. the original manuscript and references are consulted by us. we find that this description is indeed wrong. this correct value should be 10cm, and the mistake was also indeed caused by spelling. we also think that a correction may be informative for the readers, and this description should be corrected to “long skin-to-stone distance (> 10cm)”. thank you again for your good suggestions. your suggestions will benefit more readers. i believe that with our efforts, urology journal will become better and better. references 1. junbo l, yugen l, guo j, jing h, ruichao y, tao w. retrograde intrarenal surgery vs. percutaneous nephrolithotomy vs. extracorporeal shock wave lithotripsy for lower pole renal stones 10-20 mm : a meta-analysis and systematic review. urol j. 2019: 5; 16(2):97-106. 2. pareek g, hedican sp, lee ft jr, nakada sy. shock wave lithotripsy success determined by skin-tostone distance on computed tomography. urology 2005: 66(5):941–944. 3. langenauer j, betschart p, hechelhammer l,et al. advanced non-contrasted computed tomography postprocessing by ct-calculometry (ct-cm) outperforms established predictors for the outcome of shock wave lithotripsy. world j urol. 2018:36(12):2073-2080. 1department of urology, chengdu second people's hospital, chengdu 610000, sichuan, p.r. china. 2department of urology, affiliated hospital of north sichuan medical college, nanchong 637000, sichuan, p.r. china. *correspondence: department of urology, chengdu second people's hospital, qingyunnan road 10, jinjiang district, chengdu, 610017, sichuan, china. e-mail: laifei1221@163.com. received & accepted junbo liu1, tao wu2, fei lai 1* letter 352 pediatric urology urology journal/vol 20 no. 3/ may-june 2023/ pp. 162-166. [doi: 10.22037/uj.v20i.7438] analysis of the curative effect of tubularized incised plate urethroplasty for distal hypospadias with the dysplastic corpus spongiosum covering technique linghua ji1*, shuqing chen2*, yuehua chen1, jun zhao1, qiyou yin1, hua xian1, wenliang ge1# purpose: to investigate the use of tubularized incised plate (tip) urethroplasty for distal secondand third-degree hypospadias to free the dysplastic forked corpus spongiosum and buck’s fascia, which are used as a covering material for the new urethra, thereby reducing the incidence of urinary fistula and other complications in the coronal sulcus. materials and methods: clinical data of 113 patients with distal hypospadias treated with tip urethroplasty from january 2017 to december 2020 were retrospectively analyzed. the study group comprised 58 patients (use of dysplastic corpus spongiosum and buck’s fascia to cover the new urethra), and the control group comprised 55 patients (use of dorsal dartos fascia to cover the new urethra). results: all children were followed up for more than 12 months. in the study group, 4 patients developed urinary fistulas, 4 developed a urethral stricture, and no case developed glans fissure. in the control group, 11 patients developed urinary fistulas, 2 developed a urethral stricture, 3 developed a glans cracking. conclusion: using the dysplastic corpus spongiosum to cover the new urethra increases the amount of tissue in the coronal sulcus and reduces the incidence of urethral fistula, but it may increase the incidence of urethral stricture. keywords: buck's fascia; dartos fascia; corpus spongiosum; dysplasia; hypospadias; tip operation introduction hypospadias is a common congenital malformation of the urinary system and requires early treatment. the incidence rate of hypospadias is high in boys, and it is increasing year by year.(1) tip urethroplasty was first performed by snodgrass in 1990 and officially reported in 1994.(2) tip urethroplasty is a simple operation that can retain the urethral plate to the greatest extent and has a relatively low postoperative complication rate, and the urethral orifice is similar to that of the normal urethra. it has quickly become the mainstream operation for distal hypospadias. however, the incidence of urethral fistula, especially at the coronal sulcus, has been the most common in tip, which is related to the thin skin, less tissue, poor blood supply at the coronal sulcus, and the intersection of the two tissues.(3,4) during the operation of 58 patients with distal hypospadias from january 2017 to december 2020, we dissociated the dysplastic corpus spongiosum and buck's fascia together as the covering material of the new urethra, hoping to reduce the incidence of urethral fistula and observe the incidence of other complications. we conducted a retrospective comparative study between this method and traditional tip surgery, and now the results are reported as follows. 1 department of pediatric surgery, affiliated hospital of nantong university, nantong, 226001, jiangsu, china. 2.department of medical college of nantong university, nantong, 226001, jiangsu, china. *correspondence: department of pediatric surgery, affiliated hospital of nantong university, nantong, 226001, jiangsu, china. tel: 13962854122. fax: 13962854122. e-mail: gewl@ntu.edu.cn received november 2022 & accepted january 2023 materials and methods study population and study design 113 cases of hypospadias were distal type (i-ii°), without chordee or chordee angle <15°. tip covered by hypoplastic corpus spongiosum and its continuous buck's fascia was classified as the study group, and tip covered by dorsal dartos fascia was regarded as the control group. all patients were operated for the first time and were completed by the same surgeon. except for other system malformations and surgical contraindications, the routine examination before operation was performed. the study has been approved by the ethics committee of the hospital. the treatment effects of the two groups were compared quantitatively by comprehensive evaluation methods such as the incidence of complications and the questionnaire of family members' satisfaction. surgical technique pull the penis head (figure 1a, 2a), and cut the membranous part of the urethral opening to the proximal end to the normal corpus spongiosum. cut parallel along both sides of the urethral plate and extend to the front of the penis head, leaving the urethral plate about 1cm wide. cut parallel along both sides of the urethral plate and extend to the front of the penis head, leaving the urethral plate about 1cm wide. make a circular incision about 0.5cm from the inner prepuce plate to the coronal sulcus, and separate and deglove the dorsal side of the penis along the surface of buck's fascia. pay attention not to damage the poorly developed and forked corpus spongiosum in this step. after degloving, according to the urethral inner diameter and penis development, select f8 silicone double chamber bladder urinary tube as the stent tube and drain urine, and carefully free the poorly developed corpus spongiosum on both sides of the urethral plate (figure 1b, 2b), the lateral buck's fascia was dissociated together, and then the distal cavernous body was dissociated from the surface of the tunica albuginea, so that the cavernous bodies on both sides were sutured to the midline without tension to cover the new urethra. then free the glans to fully expand both sides of the glans, and trim the tissues in the glans to achieve the effect of reducing the volume in the glans, so that when the glans is sutured, it can wrap the urethra without tension. the urethral plate is cut longitudinally in the middle, reaching the shallow surface of the white membrane of the corpus cavernosum of the penis. the urethral plate wraps around the urinary tube without tension, and the 6-0 absorbable thread is turned inward to form a new urethra. the dysplastic corpus spongiosum and buck's fascia bifurcated on both sides of the urethral plate were sutured to the midline to cover the coronal sulcus of the new urethra (figure 1c, 2c). properly cut the foreskin and then sew and wrap the penis (figure 1d, 2d). the gauze was removed 5 days after operation, and the catheter was removed 2 weeks after operation on average. evaluations and follow-up recheck at 4 weeks, 8 weeks, 16 weeks and 32 weeks after operation, and then every half a year. during the period, the evaluation of the patient's family members on the penis appearance, urination, hygiene and the number of operations was collected through a questionnaire to obtain a comprehensive satisfaction evaluation. statistical analysis outcome measures: age, bmi, complications (urinary fistula, urethral stricture, incision infection and rupture, urethral diverticulum), satisfaction pre-operation and 4, 8, 16 and 32 weeks after operation. shapiro wilk function was used to test the normality of measurement data, levene test was used to test the homogeneity of variance, and independent measurement data conforming to the normal distribution was expressed in . the two groups were compared by independent sample t-test; the measurement data that do not conform to the normal distribution are expressed by the median (interquartile interval), and the independent samples are tested by wilcoxon test of two independent samples. the counting data were expressed in percentage, and the comparison of counting variables (complication rate) was performed by χ2 test or fisher exact test, p < 0.05 indicates that the difference is statistically significant. results 113 patients in the study group and the control group were followed up for more than 1 year. there were 58 patients in the study group and 55 patients in the control group. the average age of patients in the study group was 31.7 ± 6.76 months, while that in the control group was 30.7 ± 4.74 months. there was no significant difference (p > 0.05). there was no significant difference tip with corpus covernusum covering method-ji et al. variables research group control group t p age, months; mean ± sd (range) 31.7 ± 6.76 30.7 ± 4.74 0.919 0.36 bmi, kg/m2; mean ± sd (range) 23.8 ± 2.48 24.1 ± 2.28 -0.467 0.64 table 1. comparison of basic information of two groups of patients. figure 1. pictures of key surgical steps: 1a. penis head traction; 1b. free bifurcated dysplastic corpus spongiosum and its continuous buck's fascia after degloving penile skin (as shown by the blue arrow); 1c. close the cavernous body and buck's fascia to cover the new urethra (as shown by the yellow arrow); 1d. penis appearance after urethroplasty. figure 2. hand drawing of key surgical steps: 2a. penis head traction; 2b. free bifurcated dysplastic corpus spongiosum and its continuous buck's fascia after degloving penile skin (as shown by the blue arrow); 2c. close the cavernous body and buck's fascia to cover the new urethra (as shown by the yellow arrow); 2d. penis appearance after urethroplasty. pediatric urology 163 between the two groups in bmi (p > 0.05). the overall complication rate in the study group (13.79%) was lower than that in the control group (29.09%), with a statistically significant difference (95%ci: 0.15-1.00, or = 0.39, p = 0.047). the overall incidence of urinary fistula was 6.9% and 20% respectively, with a statistically significant difference (95%ci: 0.09-0.99, or = 0.39, p = 0.041); there were 1 case of coronary fistula in the study group and 8 cases in the control group. the difference between the two groups is statistically significant (95%ci: 0.01-0.83, or = 0.10, p = 0.015). there was no statistically significant difference between the two groups in penile body fistula (95%ci: 0.12-7.39, or = 0.95, p > 0.05). in the study group, urethral stricture occurred in 4 cases (6.9%), without glans dehiscence; in the control group, urethral stricture was found in 2 cases (3.64%), and glans dehiscence in 3 cases (5.45%). the satisfaction scores of the pre-operation and 32 weeks after surgery, and the difference between satisfaction scores of 32 weeks after surgery and the pre-operation were compared. there was no significant the difference between the two groups in preoperative satisfaction scores (p > 0.05), but there was significant difference between satisfaction scores of 32 weeks after surgery and the difference of 32 weeks after surgery and the pre-operation in two groups (p < 0.001). discussion hypospadias is caused by the fusion obstacle of the urethral fold at the midline, which leads to the cracking of the ventral urethra, and the absence or dysplasia of the corpus spongiosum and deep and superficial fascia at the ventral urethral orifice of the penis.(5) surgery is the only treatment option for hypospadias.(6) urinary fistula is one of the most common complications of hypospadias. the main reasons include poor blood supply of new urethral covering materials, high tension, less coverage levels, lack of experience of surgeons and so on.(7) therefore, adding reliable covering materials between the new urethra and the skin is very important to reduce the incidence of postoperative complications of hypospadias. in 2000, yerkes first reported a bifurcation deformity of the penile corpus spongiosum in patients with hypospadias and used it as a new urethral covering material to establish the novel “y-to-i technology,” which is considered to have the effect of reducing the incidence of urinary fistula.(8) in this study, we selected cases of distal hypospadias as the research object. there were 58 cases in the study group, and 4 cases had urinary fistula. the incidence of urinary fistula was 6.9%, which was significantly lower than 20% in the control group (p = 0.04). dodat has achieved good results in the treatment of distal hypospadias with spongioplasty.(9) he believes that this operation is applicable to all distal hypospadias, which can effectively reduce the incidence of urinary fistula and reduce the difficulty of correcting penile curvature. bhat found that the thicker the cavernous body, the lower the incidence of urinary fistula after tip. (10) it is suggested that cavernoplasty of penis should be taken as a necessary step. we believe that because most of the urethral cavernous bodies of the proximal hypospadias penis are stunted or missing, while most of the distal hypospadias penis has a relatively thick dysplastic corpus spongiosum (as shown in figure 1b), which is y-shaped and distributed on both sides of the urethral plate, with rich blood supply. using it as a covering material can effectively increase the tissue thickness of the new urethra. at the same time, this method can make the repaired penis more similar to the normal penis structure and obtain a more satisfactory appearance. in the control group, the dorsal dartos fascia transfer was used to cover the new urethra. because the blood supply of the dartos fascia flipped from the dorsal side of the penis to the ventral side was poor, and the adhere of tissue was poor, there was a high possibility of ischemic necrosis and tissue contracture after operation, which led to a high incidence of urinary fistula and glans cracking. hafez used the pedicled dartos fascia flap and cavernous body as the covering material when performing tip surgery on patients with scrotal hypospadias, and believed that the pedicled dartos fascia was the key to reduce postoperative complications.(11) in this regard, the operator believes that proximal hypospadias often need to cross the urethral plate, which can lead to more blood supply damage. at the same time, proximal hypospadias have high urethral orifice, early urethral development "stagnation", and poor development of corpus spongiosum, resulting in poor blood supply of covering materials and weak tissue volume.(12) therefore, this operation is not suitable for the treatment of proximal hypospadias. after verification, bhat believed that there was no difference between the dysplastic corpus spongiosum and dartos' fascia in reducing urinary fistula.(10) hayashi believes that spongioplasty cannot reduce the incidence of urinary fistula in tip surgery.(13) it may be that the bifurcated corpus spongiosum fits closely with its concomplications research group n (%) control group n (%) or and 95%ci p total complications 8 (13.79) 16(29.09) 0.39 (0.15, 1.00) 0.047 urinary fistula 4 (6.90) 11 (20.00) 0.30 (0.09, 0.99) 0.041 urethral stricture 4 (6.90) 2 (3.64) 1.95 (0.27, 22.43) 0.680 glans fissure 0 (0.00) 3 (5.45) table 2. comparison of complications between the two groups. satisfaction score research group control group wilcoxon p pre-operation 10.0 (8.0,11.0) 10.0 (9.0,11.0) 1621.5 0.879 32 weeks after operation 24.5 (23.3,25.0) 23.0 (20.5,24.0) 2417 < 0.001 difference 14.0 (13.0,16.0) 13 (11.0,14.5) 2219.5 < 0.001 table 4. comparison of patients' satisfaction between the two groups. tip with corpus covernusum covering method-ji et al. vol 20 no 3 may-june 2023 164 tinuous bucks fascia, and excessive dissociation damages the blood supply, resulting in a high incidence of urinary fistula. in this study, the overall incidence of urinary fistula in the study group and the control group were 6.9% and 20% respectively, with a statistically significant difference. it may be related to the way that we use "from far to near" to dissociate the corpus spongiosum and its successive buck's fascia together. on the one hand, we can avoid excessive dissociation of the dysplastic cavernous body to damage its blood supply; on the other hand, because the blood supply of the corpus spongiosum moves from the proximal to the distal, this method is more in line with its blood supply direction, which can minimize the damage to the blood supply, and at the same time, we can restore the original anatomical structure as much as possible, reduce the incidence of urinary fistula, especially at the coronary sulcus (p = 0.015). however, in this study, it was found that the incidence of urethral stricture in the study group was slightly higher than that in the control group, which may be related to the increased amount of tissue on the surface of the new urethra after cavernous body coverage, resulting in urethral stricture. however, the number of cases in this group is small, and more samples are needed for further analysis. at the same time, during the operation, we found that after the free anatomy of the poorly developed corpus spongiosum in most patients, its length is limited, and it can't cover all the new urethra, but only the coronal sulcus, which only increases the amount of tissue in the coronal sulcus. this may be related to the lower incidence of urinary fistula in the coronal sulcus in this experiment than in the control group (the incidence of urinary fistula in the coronal sulcus in the study group is 1.72%, and 14.55% in the control group). in the surgical satisfaction survey, there was no difference between the two groups in preoperative satisfaction, but the satisfaction score of the study group was higher than that of the control group 32 weeks after surgery, with a statistically significant difference (p < 0.001). during the operation, we routinely dissociate the two wings of the glans, trim the redundant tissues of the two wings of the glans, so as to fully "reduce the volume" of the glans, make the glans wrap around the new urethra without tension, and conduct parallel tension free suture, in order to reduce the incidence of glans cracking after the operation, and obtain a more similar appearance to the normal glans, so using this operation can obtain better penile function and appearance. however, ceccarelli believed that the short-term evaluation results could not reflect the impact of surgery on life and sexual psychology in adolescence and adulthood, so long-term follow-up and intervention were needed. (14) murat gul believed that the long-term follow-up cooperation rate of most patients who received early surgical treatment was low.(15) long term follow-up data are also lacking for this surgical method. in addition, this study is a single center case study, and there may be selection bias in sample selection. as an exploratory study, the total number of samples in this study is 113, which may lead to deviation in data analysis results due to the small number of patients. there are few variables collected in this study, and there may be confounding factors that are not observed. conclusions to sum up, our surgical method of covering the new urethra with free dysplastic corpus spongiosum and its continuous buck's fascia can reduce the damage to the blood supply of the dysplastic cavernous body on the one hand, and on the other hand, while restoring the original anatomical structure, it can maintain a good blood supply of the covering material, and it is convenient to obtain materials, which effectively reduces the incidence of urinary fistula at the coronary sulcus of distal hypospadias, at the same time, the appearance of the repaired penis is more similar to that of the normal penis, which is easier to be recognized by patients and their families. however, long-term follow-up is needed to understand the impact of surgery on the life and sexual psychology of patients in adulthood. acknowledgments this research is supported by national natural science foundation of china (82171587). we thank angela morben, dvm, els, from liwen bianji (edanz) (www.liwenbianji.cn), for editing the english text of a draft of this manuscript. conflict of interest all authors acknowledge that there is no conflict of interest. references 1. yuehua li, meng mao, li dai, et al. time trends and geographic variations in the prevalence of hypospadias in china. birth defects res a clin mol teratol. 2012; 94: 3641. 2. snodgrass w. tubularized, incised plate urethroplasty for distal hypospadias. j urology. 1994; 151: 464-5. 3. k l m pfistermuller, a j mcardle, p m cuckow. meta-analysis of complication rates of the tubularized incised plate (tip) repair. j pediatr urol. 2015; 11: 54-9. 4. warren snodgrass, gwen grimsby, nicol corbin bush. coronal fistula repair under the glans without reoperative hypospadias glansplasty or urinary diversion. j pediatr urol. 2015; 11: 39. e1-4. 5. marjan joodi, forouzan amerizadeh, seyed mahdi hassanian, et al. the genetic factors contributing to hypospadias and their clinical utility in its diagnosis. j cell physiol. 2019; 234:5519-5523. 6. salim bilici 1, tamer sekmenli, mustafa research group n (%) control group n (%) or and 95%ci p fistula of penis 3 (5.17) 3 (5.45) 0.95 (0.12, 7.39) 0.947 coronal sulcus fistula 1 (1.72) 8 (14.55) 0.10 (0.01, 0.83) 0.015 table 3. comparison of the location of urinary fistula between the two groups. tip with corpus covernusum covering method-ji et al. pediatric urology 165 gunes, ilhan gecit, vedat bakan, daghan isik. comparison of dartos flap and dartos flap plus spongioplasty to prevent the formation of fistulae in the snodgrass technique. int urol nephrol. 2011; 43: 943-8. 7. xu haihua, xu guodong, zhang fuyi, chen ziying, wang xiaojia. application of multiple urethral with lateral fascia plate and dorsal pedicled transfer fascia flap during snodgrass operation. chin j pediatr surg. 2021; 42: 114117 8. e b yerkes, m c adams, d a miller, j c pope 4th, r c rink, j w brock 3rd. y-to-i wrap: use of the distal spongiosum for hypospadias repair. j urol. 2000; 163:1536-8. 9. h dodat, j-l landry, c szwarc, s culem, f-j murat, r dubois. spongioplasty and separation of the corpora cavernosa for hypospadias repair. bju int. 2003; 91:528-31. 10. amilal bhat, karamveer sabharwal, mahakshit bhat, ramakishan saran, manish singla, vinay kumar. outcome of tubularized incised plate urethroplasty with spongioplasty alone as additional tissue cover: a prospective study. indian jurol. 2014; 30:392-7. 11. ashraf t hafez, tamer helmy. tubularized incised plate repair for penoscrotal hypospadias: role of surgeon’s experience. urology. 2012; 79: 425-7. 12. bao xingqi, study on abnormal development of corpus spongiosum in patients with hypospadias. shanghai: children's hospital affiliated to shanghai jiaotong university. 2019 13. yutaro hayashi, kentaro mizuno, yoshinobu moritoki, et al. can spongioplasty prevent fistula formation and correct penile curvature in tip urethroplasty for hypospadias? urology. 2013; 81:1330-5. 14. pier luca ceccarelli, laura lucaccioni, francesca poluzzi , et al. hypospadias: clinical approach, surgical technique and long-term outcome. bmc pediatr. 2021; 21:523. 15. murat gul, simone hildorf, mesrur selcuk silay. sexual functions and fertility outcomes after hypospadias repair. int j impot res. 2021; 33:149-163. tip with corpus covernusum covering method-ji et al. vol 20 no 3 may-june 2023 166 1 running head: the effect of lowering the dose of corticosteroid in post-operative complications of kidney transplant patients. lowering the dose of corticosteroid regimen in kidney transplantation: is it effective in decreasing post-operative surgical complications? nasser simforoosh1, amirhossein nayebzade2*, mehdi dadpour3, atefe eslami4 nasser simforoosh : md; email: n.simforoosh@gmail.com; orcid: 000-0003-4135-342x; urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran amirhossein nayebzade : md; e.mail: nayebzade.amir@gmail.com; orcid: 0000-00031607-8104; urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran mehdi dadpour : md; e.mail: mehdi_dadpour@yahoo.com; orcid: 0000-0003-3550-3778; urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran atefe eslami : md; e.mail: atefe.esl7020@gmail.com; orcid: 0000-0001-8027-6258; urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran corresponding author: amirhossein nayebzade : md; e.mail: nayebzade.amir@gmail.com; orcid: 0000-00031607-8104; urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran email : nayebzade.amir@gmail.com key words: kidney transplantation; corticosteroid; administration and dosage; postoperative complications; survival analysis https://journals.sbmu.ac.ir/urolj/index.php/uj/article/view/6858 mailto:n.simforoosh@gmail.com https://journals.sbmu.ac.ir/urolj/index.php/uj/article/view/6858 2 abstract purpose: to investigate the impact of reducing post-operative oral corticosteroid regimen on associated postoperative surgical complication rate, patient and graft survival in kidney transplant patients. materials and methods: in this retrospective cohort study, we enrolled patients who received kidney transplant during two periods of distinct corticosteroid protocols. 592 patients in group 1 received prednisone 2 mg/kg (maximum dose 120 mg) on post-operative days (pod) 1, 2 and 3, 1mg/kg for a week, and tapered it to 10 mg by 3 months post-transplant and sustained the daily 10mg from 3 months post-transplant as maintenance therapy. 639 patients in group 2 received prednisone 50 mg on pod 1, 40mg on pod 2, 30mg on pod 3, 20mg on pod 4, 15mg on pod 5 and continued with 10mg daily from pod 6, as maintenance therapy. the two groups were similar in terms of other immunosuppression drug regimen. results: 75 (12.7%) patients in group 1 and 24 (3.4%) patients in group 2 developed corticosteroid-related postoperative surgical complications (p < .001). wound infection (p = .035), incisional hernia (p = .003), infectious collection (p = .004), post-op hemorrhage (p = .005) and ureteral fistula (p = .076) occurred with lower frequency in group 2. patient survival (1-year: 97.3% vs 97.1%, respectively; p = .85, 5-year: 89.9% vs 94.9%, respectively; p = .06) and graft survival (1-year: 94.6% vs 93.3%, respectively; p = .29, 5-year: 81.2% vs 85.1%, respectively; p = .39) were similar in both groups. conclusion: post-operative corticosteroid dosage decrement through our protocol would lessen the serious associated postoperative surgical complications, without negative impacts on overall patient and graft survival. 3 introduction corticosteroids are an important part of the immunosuppression regimen following kidney transplantation. corticosteroids are used to prevent graft rejection through the capability of immunosuppression and anti-inflammatory effect. since its introduction in the 1960s, it has been accepted that corticosteroid has been playing a significant role in increasing the graft survival (1, 2). however, taking corticosteroid may be associated with various post-operative surgical complications including wound infection, incisional hernia, lymphocele, wound or anastomosis healing impairment and bleeding, probably due to interference with the tissue healing process (37). occurrence of these steroid-related side effects is accompanied with additional costs, posttransplant noncompliance and decreased graft survival (8). it is interesting to know that prednisone is the immunosuppressive drug that the kidney transplant recipients who survived, would most like not to take (9). monitoring the side effects of oral corticosteroids alongside with the disease process seems necessary to decide how to reduce the dose of corticosteroids, post-operatively (10). nowadays, to minimize the steroid-related complications, steroid minimization protocols are taken into consideration. (8). many efforts have been made either to avoid taking steroids or decrease the dosage through other immunosuppressive drugs replacement (11, 12). however, the main concern in this respect is how corticosteroid minimization would affect the graft and the patient survival. in this study, we aimed to investigate if decreasing post-operative oral corticosteroid regimen following kidney transplantation would reduce the postoperative surgical complication rate, with no change in patient and graft survival. 4 materials and methods study population in this retrospective cohort study, we enrolled patients who received kidney transplant during two periods of distinct corticosteroid protocols in our center between 2013 and 2019. a total number of 592 patients who received first kidney transplantation between jan 2013 and jan 2016 (group 1) were compared to 639 patients receiving kidney alone transplant between jan 2016 and jan 2019 (group 2). the follow-up of all patients in both groups started at the time of surgery and continued until the end of 2022. exclusion criteria exclusion criteria were patients with multi-organ transplantation, repeated kidney transplantation in the same recipients, history of corticosteroid usage for whatever reason like autoimmune disease and loss to follow up. immunosuppression protocols in group 1, patients received prednisone 2 mg/kg (maximum dose 120 mg) on post-operative days (pod) 1,2 and 3, 1 mg/kg for a week, and tapered to 10 mg by 3 months post-transplant and continued with 10mg daily from 3 months post-transplant as maintenance therapy. in group 2, patients received prednisone 50 mg on pod 1, 40mg on pod 2, 30mg on pod 3, 20mg on pod 4, 15mg on pod 5 and continued with 10mg daily from pod 6, as maintenance therapy. all patients in both groups were similar in chronic immunosuppression maintenance including mycophenolate mofetil and tacrolimus. evaluations 5 we used electronic medical records and organ transplant tracking record database to extract the variables. all the kidney transplantation survival data in our center are registered in collaborative transplant study (cts) of heidelberg, prospectively. the primary goal of this study is to evaluate and compare the associated postoperative surgical complications including incisional hernia, lymphocele information requiring percutaneous drainage or exploration, hemorrhage which lead to exploration; nephrectomy or anastomosis repair, infectious collection formation, wound infection, ureteral stenosis and ureteral fistula leading to exploration between the two groups. the secondary goal is to compare the patient and graft survival between these two groups. the study protocol was approved by the institutional board of research and committee of medical ethics (code: ir.sbmu.msp.rec.1398.690). this study was conducted in accordance with the declaration of helsinki. statistical analysis all the statistical analyses were performed using spss software version 25.0 (ibm, chicago, illinois, usa). data are shown as mean ± standard deviation (sd) and frequency (percentage) for quantitative and qualitative variables, respectively. the normality of data distribution was assessed using the kolmogorov-smirnov test. the independent sample t test or mann-whitney test was also used to compare the mean outcome quantities between the two groups studied. chi square test or fisher exact test (where the 20% of expected cell counts were less than 5) was also used to compare qualitative factors between the two groups. kaplan-meier survival analysis along with log rank test was performed by cts of heidelberg to compare patient and graft survival between the study groups. univariable and multivariable logistic regression analysis was used to assess the effect of variables on binary outcomes. the normality of data distribution 6 was assessed using the kolmogorov-smirnov test and also graphically through q-q plot. in this study, p-value of less than 0.05 was considered as statistically significant. results in this study, we evaluated the data of 1231 patients who underwent kidney transplantation. table 1 shows the patients characteristics of group 1 and 2, separately. a total number of 99 (8.04%) patients including 75 (12.7%) in group 1 and 24 (3.8%) in group 2 developed corticosteroid-associated postoperative surgical complications (p < .001). wound infection (p = .035), incisional hernia (p = .003), infectious collection formation (p = .004) and post-op hemorrhage (p = .005) occurred with significantly lower frequency in group 2. ureteral fistula was also decreased in group 2 but not significant (9 in group 1 versus 3 in group 2, p = .076). table 2 shows the types of postoperative complications among group 1 and 2, separately. after adjusting the covariates, in a multivariate logistic regression, the corticosteroid dosage group was an independent predictor for infectious collection formation (or[ci]: 0.05[0.0070.37]; p = .004), wound infection (or[ci]: 0.45[0.21-0.94]; p = .035) and postoperative bleeding (or[ci]: 0.12[0.028-0.530]; p = .005). we did not perform multivariate analysis for incisional hernia because it did not occur to any patient in the low-dose group at all (table 3). figure 1a shows the kaplan-meier overall patient survival, comparing group 1 with group 2. patient survival was similar between two groups, 1-year survival: 97.3% vs 97.1%, respectively; (p = .85), 3-year survival: 94.3% vs 95.5%, respectively; (p = .38), 5-year survival: 89.9% vs 94.9%, respectively; (p = .06). figure 1b shows the kaplan-meier graft survival comparing the two groups. graft survival was also similar between the two groups. 1-year survival: 94.6% vs 7 93.3%, respectively; (p = .29), 3-year survival: 88.2% vs 89.1%, respectively; (p = .81), 5-year survival: 81.2% vs 85.1%, respectively; (p = .39). discussion steroids are used against inflammation, edema and autoimmunity and have a role in the treatment of a wide range of diseases. considering its benefits, in this study we intended to address its disadvantages including post-surgical complications following kidney transplantation. tissue-healing process following vascular anastomosis, ureterovesical reimplantation and abdominal wall repairment begins immediately in kidney transplant patients. it is proven that corticosteroids would affect all major steps of healing process including inflammatory, proliferative and remodeling phases. by inhibiting vascular permeability and leukocyte adhesion, steroids impair the initiation of tissue matrix layout and healing process (13, 14). conventionally, high-dose corticosteroids are used immediately following kidney transplantation, just when the tissue-healing process has begun. this effect led us to the hypothesis that using high dose steroids post-operatively might increase surgical complications. many studies have evaluated the role of corticosteroids in postoperative complications in different types of surgeries. hasselgren et al. (6) found out in a prospective study of 1243 different surgeries that treatment with high-dose steroids is associated with high wound infection rate. golub et al. (15) in a retrospective study of 764 patients who underwent intestinal anastomoses found out that the use of corticosteroids could predict anastomotic leakage. in a retrospective cohort study of post-operative complications after esophagectomy, jeong et al. (16) realized that using corticosteroids may be related to graft dehiscence and fistula. weisberger et al. (5) analyzed the impact of corticosteroid use on free flap reconstruction and concluded that chronic corticosteroid usage conferred 8 increased major bleeding complications requiring blood transfusion by a factor of four. in a multivariate analysis, togo et al. (4) discovered that steroid use is a risk factor for incisional hernia following partial hepatectomy. fink et al. (7) showed that patients with history of using corticosteroids are at a higher risk of vascular complications and post-surgical bleeding following transfemoral aortic valve implantation. based on the findings of these studies and other similar studies, and in agreement with the association of corticosteroids usage and postoperative healing process, we hypothesized that we could reduce the post-surgical complications by corticosteroid dosage decrement following kidney transplantation. in this study, we experienced 8 incisional hernias in group 1 (high-dose steroid), some of whom were inoperable (figure 1), while no patients in group 2 (low-dose steroid) suffered an incisional hernia post-operatively (p < .05). some studies address the issue of association between steroid usage and incisional hernia following liver transplantation (17-20) but to our best knowledge, there is no study in the literature having specifically evaluated this relationship in kidney transplant recipients. in addition, we observed a considerable decrease of ureteral fistula in the low-dose group (9 versus 3, p = .076). given that ureteral fistula is a rare complication following transplantation, we believe that with a larger sample size, a significant p-value may be achievable. collins et al. (21) showed that the use of corticosteroid may interfere with the healing of vesicovaginal and urethrovaginal fistula when an early repair is attempted but to our best knowledge, no study has been designed to evaluate the association of corticosteroid dosage and ureteral fistula following kidney transplantation yet. we observed a significant decrease of wound infection and infectious collection formation during corticosteroid dosage decrement (22 versus 11 p = .035, 17 versus 1 p = .04, respectively). ahern et al. (22) in a study about general infectious complications associated with renal transplant, concluded that the incidence of serious 9 infections was higher in recipients receiving high-dose steroid versus recipients receiving lower doses of steroids. wound infections were easily managed in low-dose steroid groups patients, while we faced a few refractory wound infections among high-dose steroid group, which needed to be left open and required regular washing for a long time period. we did not observe changes in lymphocele formation incidence in different corticosteroid dosage recipients. in a univariate analysis, khauli et al. (23) detected high-dose corticosteroid as a risk factor for lymphocele development beside acute tubular necrosis and rejection in kidney recipients. however, in the multivariate analysis only rejection rather than corticosteroid dosage was a predictor for lymphocele formation in their study. our results showed that our corticosteroid minimization protocol would reduce the serious postoperative surgical complication rate, without negative impacts on patient and graft survival. there are some studies in the literature, which are comparable to our results regarding corticosteroid dosage decrement and survivals. in a comparative study about patient and graft survival among 1689 patients with historical approach and 2097 patients in early steroid withdrawal group following kidney transplantation, adebiyi et al. (24) showed no difference in patient survival but better death-censored graft survival in the second group. in a large study, luan et al. (25) evaluated the data of 95,755 kidney transplant recipients, 16,491 (17.2%) of whom were steroid-free at discharge. it was interesting to notice that steroid-free regimen was associated with a reduced risk for graft failure and death. in a study about corticosteroid minimization protocol, jaber et al. (26) found out that early steroid withdrawal (day 6, postoperatively) would not affect the graft survival. in a 15-year period kidney transplantation study, serrano et al. (27) evaluated 1553 patients and concluded that rapid discontinuation of prednisone does not lead to a decrease in patient or graft survival. these two 10 recent studies evaluated the association of corticosteroid dosage decrement and medical steroids side effects, the patient and graft survival. along with reducing medical steroid-associated side effects, similar to us, they found out that reducing steroid dosage would not adversely impact on patient and graft survival. they, however, did not investigate the relationship between corticosteroid dosage decrement and post-operative surgical complications. our patient survival kaplan-meier curves (fig 1a) show that as the follow-up time increases, patient survival decreases further in high-dose corticosteroid group than low-dose corticosteroid group. in other words, high-dose post-operative corticosteroid is associated with lower patient survival in the long term, probably through increasing the risk of medical comorbidities including diabetes mellitus, osteoporosis, ischemic heart disease. based on our results, early steroid decrement has promising outcomes and deserves more attention in renal transplant patients to prevent serious post-transplant surgical complications, a goal that has been underappreciated in the literature. nevertheless, it is evident that careful monitoring of the patient and graft function seems to be necessary. we perform kidney transplantation from living or deceased donor in our center (28, 29) and including a high proportion of living donors in this study is different in comparison to many other studies. retrospective nature is the main limitation of this study and prospective studies through randomized clinical trial settings seem to be mandatory to confirm our findings. large or estimates and ci due to low rate of some surgical complications were another limitation of this study. conclusion reducing the dose of corticosteroid through our protocol seems to be beneficial following kidney transplantation. our study indicates that post-operative corticosteroid dosage decrement would 11 lessen the post-operative surgical complications including incisional hernia, wound infection, infectious collection formation, post-operative hemorrhage and ureteral fistula without negative impacts on overall patient and graft survival. acknowledgement we would like to thank collaborative transplant study (cts) team, heidelberg university hospital, for their assistance with kaplan-meier survival analysis. conflict of interest all authors declare that they have no conflict of interests. references 1 tarantino a, montagnino g, ponticelli c. corticosteroids in kidney transplant recipients. safety issues and timing of discontinuation. drug safety 1995; 13 (3): 145-156. 2 citterio f. steroid side effects and their impact on transplantation outcome. transplantation 2001; 72 (12 suppl): s75-80. 3 yasir m, goyal a, sonthalia s. corticosteroid adverse effects. statpearls, treasure island (fl): statpearls publishing copyright © 2022, statpearls publishing llc. 2022. 4 togo s, nagano y, masumoto c et al. outcome of and risk factors for incisional hernia after partial hepatectomy. j gastrointest surg 2008; 12 (6): 1115-1120. 5 weisberger js, oleck nc, ayyala hs et al. analysis of the impact of chronic corticosteroid use on free flap reconstruction. microsurgery 2021; 41 (1): 14-18. 6 hasselgren po, säljö a, fornander j et al. postoperative wound infections in patients with long preoperative hospital stay. acta chir scand 1982; 148 (6): 473-477. 7 fink n, segev a, barbash i et al. vascular complications in steroid treated patients undergoing transfemoral aortic valve implantation. catheter cardiovasc interv 2016; 87 (2): 341-346. 8 matas aj. minimization of steroids in kidney transplantation. transplant international : official journal of the european society for organ transplantation 2009; 22 (1): 38-48. 9 prasad gv, nash mm, mcfarlane pa et al. renal transplant recipient attitudes toward steroid use and steroid withdrawal. clinical transplantation 2003; 17 (2): 135-139. 12 10 de lucena dd, rangel é b. glucocorticoids use in kidney transplant setting. 2018; 14 (10): 1023-1041. 11 hricik de, kupin wl, first mr. steroid-free immunosuppression after renal transplantation. journal of the american society of nephrology : jasn 1994; 4 (8 suppl): s10-16. 12 hricik de, o'toole ma, schulak ja et al. steroid-free immunosuppression in cyclosporine-treated renal transplant recipients: a meta-analysis. journal of the american society of nephrology : jasn 1993; 4 (6): 1300-1305. 13 ismael h, horst m, farooq m et al. adverse effects of preoperative steroid use on surgical outcomes. am j surg 2011; 201 (3): 305-308; discussion 308-309. 14 wang as, armstrong ej, armstrong aw. corticosteroids and wound healing: clinical considerations in the perioperative period. am j surg 2013; 206 (3): 410-417. 15 golub r, golub rw, cantu r, jr. et al. a multivariate analysis of factors contributing to leakage of intestinal anastomoses. j am coll surg 1997; 184 (4): 364-372. 16 jeong h, choi jw, ahn hj et al. the effect of preventive use of corticosteroids on postoperative complications after esophagectomy: a retrospective cohort study. scientific reports 2019; 9 (1): 11984. 17 garmpis n, spartalis e, schizas d et al. incisional hernias post liver transplantation: current evidence of epidemiology, risk factors and laparoscopic versus open repair. a review of the literature. in vivo 2019; 33 (4): 1059-1066. 18 kahn j, müller h, iberer f et al. incisional hernia following liver transplantation: incidence and predisposing factors. clin transplant 2007; 21 (3): 423-426. 19 janssen h, lange r, erhard j et al. causative factors, surgical treatment and outcome of incisional hernia after liver transplantation. br j surg 2002; 89 (8): 1049-1054. 20 gómez r, hidalgo m, marques e et al. incidence and predisposing factors for incisional hernia in patients with liver transplantation. hernia 2001; 5 (4): 172-176. 21 collins cg, collins jh, harrison br et al. early repair of vesicovaginal fistula. american journal of obstetrics and gynecology 1971; 111 (4): 524-528. 22 ahern mj, comite h, andriole vt. infectious complications associated with renal transplantation: an analysis of risk factors. yale j biol med 1978; 51 (5): 513-525. 23 khauli rb, stoff js, lovewell t et al. post-transplant lymphoceles: a critical look into the risk factors, pathophysiology and management. j urol 1993; 150 (1): 22-26. 24 adebiyi o, umukoro p, sharfuddin a et al. patient and graft survival outcomes during 2 eras of immunosuppression protocols in kidney transplantation: indiana university retrospective cohort experience. transplantation proceedings 2021; 53 (10): 2841-2852. 25 luan fl, steffick de, gadegbeku c et al. graft and patient survival in kidney transplant recipients selected for de novo steroid-free maintenance immunosuppression. american journal of transplantation : official journal of the american society of transplantation and the american society of transplant surgeons 2009; 9 (1): 160-168. 26 jaber jj, feustel pj, elbahloul o et al. early steroid withdrawal therapy in renal transplant recipients: a steroid-free sirolimus and cellcept-based calcineurin inhibitorminimization protocol. clinical transplantation 2007; 21 (1): 101-109. 27 serrano ok, kandaswamy r, gillingham k et al. rapid discontinuation of prednisone in kidney transplant recipients: 15-year outcomes from the university of minnesota. transplantation 2017; 101 (10): 2590-2598. 13 28 simforoosh n, bassiri a, ziaee sa et al. laparoscopic versus open live donor nephrectomy: the first randomized clinical trial. transplant proc 2003; 35 (7): 25532554. 29 simforoosh n, basiri a, tabibi a et al. technical challenges and innovations in kidney transplantation: experience with over 5000 cases. exp clin transplant 2020; 18 (suppl 1): 10-15. 14 tables table1. patients’ characteristics of group 1 and 2. group 1 group 2 p-value number (n) 592 639 age (±sd) 40 (±15) 41 (±17) 0.148 sex (f/m) 206/386 213/426 0.588 bmi (±sd) 24.30 (±4.89) 24.54 (±5.11) 0.386 pre-op dm (%) 112 (19%) 129 (20.2%) 0.585 pre-op htn 412 (69.7%) 450 (70.4%) 0.786 donour type (living/cadaver) 309/283 320/319 0.458 table2. types of postoperative complications among group 1 and 2. group 1 group 2 p-value odds ratio (95%ci) lymphocele 5 (0.8%) 4 (0.6%) 0.654 0.740 (0.198-2.767) incisional hernia 8 (1.4%) 0 (0%) 0.003 infectious collection 17 (2.9%) 1 (0.2%) 0.004 0.053 (0.007-0.400) ureteral fistula 9 (1.5%) 3 (0.5%) 0.076 0.306 (0.082-1.134) ureteral stenosis 6 (1%) 3 (0.5%) 0.275 0.461 (0.115-1.850) wound infection 22 (3.7%) 11 (1.7%) 0.035 0.454 (0.218-0.944) hemorrhage (anastomosis leakage) 15 (2.5%) 2 (0.3%) 0.005 0.121 (0.028-0.530) any kind of side effects 75 (12.7%) 24 (3.8%) <0.001 0.269 (0.167-0.432) 15 table3. multivariable logistic regression of the postoperative complications after adjusting the covariates. p-value odds ratio (95%ci) lymphocele .557 .67(.17, 2.55) infectious collection .004 .05(.007, .37) ureteral fistula .084 .31(.08, 1.16) ureteral stenosis .241 .43(.10, 1.75) wound infection .035 .45(.21, .94) hemorrhage (anastomosis leakage) .005 .12(.02, .53) overall complications <.001 .27(.68, 1.67) figures figure 1a. the kaplan-meier overall patient survival, comparing group 1 with group 2. note: patient survival was similar between two groups. figure 1b. the kaplan-meier graft survival comparing the two groups. note: graft survival was also similar between the two groups. endourology and stone disease urology journal/vol 20 no. 2/ march-april 2023/ pp. 102-108. [doi: 10.22037/uj.v20i.7576] national lifetime prevalence and demographic factors of urolithiasis in iran abbas basiri1, amir hossein kashi1, hossein salehi omran1*, nasrin borumandnia1, shabnam golshan1, behzad narouie2, sakineh hajebrahimi3, hayat mombeini4 purpose: to estimate the current lifetime prevalence of urolithiasis at the national level in iran and investigate the potential influential demographic factors in different geographical areas. materials and methods: an epidemiological study was conducted between october 2020 and november 2022 in 31 provinces of iran at the national level. data was obtained through telephone interviews with households. items in the interview included questions about the current and past episodes of urolithiasis, family history of urolithiasis, and demographic and environmental variables of potential interest in urolithiasis. results: a total of 44186 participants were investigated from 31 provinces of iran. the overall percentage of those with lifetime prevalence of urolithiasis was 6.6%, including 7.9% for males and 5.3% for females (p < .001). in addition, with regard to the residential location, men were 53% (7.9% vs. 5.2%) more susceptible than women to urinary stones in urban areas and 36% (7.8% vs. 5.7%) more susceptible in rural areas. out of 31 provinces, the sistan-baluchistan province had the highest lifetime prevalence (15.6%) and the golestan province had the lowest (2.1%). the lifetime prevalence of urolithiasis in the rural areas was 6.8% versus 6.5% in the urban areas (p = .29). regarding age differences, the lifetime urolithiasis prevalence has increased up to the age of 70 years. in addition, the most prominent increase in the lifetime prevalence was observed in the age range of 20 to 60 years (from 0.9% to 11.8%). the ethnicity with the highest lifetime prevalence rate of urolithiasis was the baluch ethnicity (18%). conclusion: generally, 6.6% of iranian population suffers from urinary stones during their lifetime. urolithiasis prevalence has increased 0.06% annually compared to the latest national study that took place 15 years ago. this increasing trend seems to be less prominent than other countries. according to our findings, urinary stones are more prevalent in men than in women and in the third to sixth decade of life. baluch ethnicity is associated with the highest lifetime prevalence rate of urolithiasis and there is no significant difference between rural and urban areas. however, the ratio of male to female risk of urolithiasis is higher in urban areas compared to rural areas. keywords: national study; epidemiology; urolithiasis; prevalence; iran; demographic factors introduction the worldwide estimated prevalence of urolithiasis ranges from 1 to 13 percent in different countries of the world and demographic factors such as age, race, and gender are some of the known factors that can affect this prevalence(1-3). the prevalence rate has increased in recent years and it is predicted that this number will rise more in the coming decades due to the environmental changes like global warming(4-6). with regard to the prevalence and occurrence of this disease, several articles have been published globally and in asia which have discussed the effects of individual features(7-11). however, few studies in iran have evaluated the prevalence or incidence of urinary stone disease at the national level. the latest published national study focusing on the epidemiology of urolithiasis dates back to 15 years ago(12). taking into account the above elaborations, we per1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. 2department of urology, zahedan university of medical sciences, zahedan, iran. 3research center for evidence-based medicine, iranian ebm center: a joanna briggs institute center of excellence, tabriz university of medical sciences, tabriz, iran. 4ahvaz jundishapur university of medical sciences, ahvaz, iran. *correspondence: urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran. phone: +989112107247. email: hosseinsalehiomran@gmail.com. received december 2022 & accepted february 2023 formed an epidemiological study on urolithiasis at the national level and investigated the potential influential demographic factors in different geographical parts of iran in a cross-sectional study from october 2020 to november 2022. materials and methods the iran national stone survey (inss) was a national epidemiological study of urolithiasis approved by the iranian national institute for medical research development (nimad) under the approved number: 989248 and approved ethic number of ir.nimad. rec.1399.113. the protocol of the inss study is briefly summarized below: the estimated prevalence population of iran was based on the 2017 census and the estimated yearly growth rate of each province was based on the estimation of the iranian national statistics center divided to the urban or rural areas(13). the design of the study was to approach households and to enroll every member of the selected households. the average number of people in each household was estimated to be 3.3 according to the latest census data of 2017(13). according to previous studies, the estimated prevalence of nephrolithiasis in iran is about 5%(12). considering a relative precision of 0.05, the required sample size for this study was at least 29196 participants across the country (14). since we planned to perform multi-stage random sampling, by considering design effect, approximately at least 1.5 times, equivalent to 43794 participants would be required. therefore, at least 13271 households were required to reach the total calculated population. as the coverage of household telephone is 98.8% at the national level based on the report by statistical centre of iran(15), we chose to use phone numbers to randomly select households from each province. for each selected household, a local telephone interviewer was planned and conducted by the representatives of the local medical university (especially in turkish-speaking areas, the province of sistan-baluchistan, bushehr, and khuzestan) who were carefully instructed by the inss core personnel on the interview items. for every selected household, information of any resident member of the household was questioned by the interviewers. items in the interview included questions about the current and past episodes of urolithiasis, family history of urolithiasis, and demographic or environmental variables of potential interest in urolithiasis. the lifetime prevalence of urolithiasis was defined as any history of stone formation or spontaneous stone passage in the entire lifetime of the respondents. the completed interviews were recorded in pre-planned data entry software and centrally controlled and checked by the core steering committee of inss at the urology and nephrology research center (unrc). in case of non-response in each call, calls were done again the next day and two days later at three different times of the day. in cases of no response after seven phone calls, the number was recorded as no-answer and rest of the numbers on the list were called. statistical analysis descriptive characteristics are presented as mean with standard deviation (sd) for quantitative variables or as a number and percentage for categorical variables. frequency (percent) gender female 22076 (50%) male 22110 (50%) age < 20 11153 (25.4%) ≥ 20, ˂ 50 20471 (46.7%) ≥ 50 12222 (27.9%) educational level preschool 5234 (11.9%) school 16660 (37.7%) diploma 10588 (24.0%) academic 11660 (26.4%) ethnicity fars 26469 (60.0%) turk 8519 (19.3%) lor 3423 (7.7%) kurd 3357 (7.6%) arab 1092 (2.5%) baluch 1068 (2.4%) others 202 (0.5%) employment unemployed 16704 (37.8%) kid and preschool 2248 (5.1%) student of school or university 10938 (24.8%) employed 14294 (32.3%) urban or rural rural 11719 (26.5%) urban 32467 (73.5%) table 1. the distribution of participants’ demographic factors province sample size frequency (percent) 95.0 % ci urban 95.0 % ci rural 95.0 % ci frequency(percent) frequency(percent) east azarbaijan 2147 188 (8.8%) 7.6%-10.0% 150 (9.7%) 8.3%-11.2% 38 (6.3%) 4.6%-8.5% west azarbaijan 1800 102 (5.7%) 4.7%-6.8% 81 (6.9%) 5.6%-8.4% 21 (3.4%) 2.2%-5.0% ardabil 651 54 (8.3%) 6.4%-10.6% 36 (7.6%) 5.4%-10.2 18 (10.3%) 6.4%-15.4% isfahan 2796 196 (7.0%) 6.1%-8.0% 178 (7.2%) 6.3%-8.3% 18 (5.4%) 3.4%-8.3% alborz 1483 67 (4.5%) 3.5%-5.7% 50 (3.6%) 2.7%-4.7% 17 (15.6%) 9.7%-23.3% ilam 317 14 (4.4%) 2.6%-7.1% 10 (4.6%) 2.4%-8.0% 4 (4.0%) 1.4%-9.3% bushehr 948 57 (6.0%) 4.6%-7.7% 46 (7.0%) 5.2%-9.2% 11 (3.8%) 2.0%-6.4% tehran 7274 368 (5.1%) 4.6%-5.6% 333 (4.9%) 4.4%-5.4% 35 (7.8%) 5.6%-10.6% chahar mahal bakhtiari 553 51 (9.2%) 7.0%-11.8% 40 (11.1%) 8.2%-14.7 11 (5.7%) 3.0%-9.6% south khorasan 420 19 (4.5%) 2.8%-6.8% 15 (6.1%) 3.6%-9.6% 4 (2.3%) 0.8%-5.4% central khorasan 3534 206 (5.8%) 5.1%-6.6% 142 (5.5%) 4.7%-6.4% 64 (6.8%) 5.3%-8.5% north khorasan 474 23 (4.9%) 3.2%-7.1% 16 (6.1%) 3.6%-9.4% 7 (3.3%) 1.5%-6.4% khuzestan 2585 146 (5.6%) 4.8%-6.6% 109 (5.6%) 4.6%-6.7% 37 (5.8%) 4.2%-7.8% zanjan 574 36 (6.3%) 4.5%-8.5% 22 (5.7%) 3.7%-8.3% 14 (7.6%) 4.4%-12.0% semnan 383 21 (5.5%) 3.5%-8.1% 16 (5.2%) 3.2%-8.2% 5 (6.4%) 2.5%-13.5% sistan-baluchistan 1539 240 (15.6%) 13.8%-17.5% 126 (16.4%) 13.9%-19.1% 114 (14.8%) 12.4%-17.5% fars 2663 238 (8.9%) 7.9%-10.1% 179 (9.6%) 8.3%-11.0% 59 (7.4%) 5.7%-9.4% qazvin 706 36 (5.1%) 3.7%-6.9% 29 (5.6%) 3.8%-7.8% 7 (3.8%) 1.7%-7.3% qom 950 49 (5.2%) 3.9%-6.7% 22 (3.3%) 2.1%-4.9% 27 (9.5%) 6.5%-13.3% kurdistan 896 48 (5.4%) 4.0%-7.0% 34 (5.5%) 3.9%-7.5% 14 (5.1%) 2.9%-8.2% kerman 1699 146 (8.6%) 7.3%-10.0% 95 (9.7%) 7.9%-11.6% 51 (7.1%) 5.4%-9.2% kermanshah 1067 86 (8.1%) 6.5%-9.8% 58 (7.2%) 5.6%-9.1% 28 (10.7%) 7.4%-14.9% kohgiluyeh and boyer-ahmad 390 27 (6.9%) 4.7%-9.8% 15 (6.9%) 4.1%-10.8 12 (7.0%) 3.9%-11.5% golestan 1021 21 (2.1%) 1.3%-3.1% 15 (2.8%) 1.6%-4.4% 6 (1.3%) 0.5%-2.6% gilan 1389 100 (7.2%) 5.9%-8.6% 41 (4.7%) 3.4%-6.2% 59 (11.6%) 9.0%-14.6% lorestan 964 75 (7.8%) 6.2%-9.6% 49 (7.9%) 5.9%-10.2% 26 (7.6%) 5.2%-10.8% mazandaran 1795 84 (4.7%) 3.8%-5.7% 57 (5.5%) 4.2%-7.0% 27 (3.6%) 2.4%-5.1% markazi 783 66 (8.4%) 6.6%-10.5% 54 (9.0%) 6.9%-11.4% 12 (6.6%) 3.7%-11.0% hormozgan 806 31 (3.8%) 2.7%-5.3% 14 (3.8%) 2.2%-6.2% 17 (3.8%) 2.3%-5.9% hamadan 947 57 (6.0%) 4.6%-7.7% 31 (5.2%) 3.6%-7.2% 26 (7.5%) 5.1%-10.6% yazd 632 61 (9.7%) 7.5%-12.1% 53 (10.0%) 7.6%-12.7% 8 (7.9%) 3.8%-14.4% total 44186 2913 (6.6%) 6.4%-6.8% 2116 (6.5%) 6.3%-6.8% 797 (6.8%) 6.4%-7.3% table 2. the lifetime prevalence of urolithiasis in different provinces of the country with regard to residential location epidemiology of urolithiasis in iran-basiri et al. vol 20 no 2 march-april 2023 103 estimates of percent prevalence and 95% confidence interval (ci) were computed. odds ratios (or) were reported to compare the odds of kidney stone in age, sex, and ethnicity groups. results totally 35986 residential households were called, 23055 calls were not answered after seven calls. a total of 12931 contacts were successfully made with households but 952 households refused to cooperate with the study. finally, 11979 households cooperated and agreed to provide the required information by the interviewer. the gathered data provides information of 44186 individuals. the mean ± sd (range) age of the participants was 36 ± 21 (0-110) years and the mean ± sd (range) number of household members was 4 ± 1 (115). participants’ distribution according to the individual and ethnic characteristics is demonstrated in table 1. prevalence and geographical distribution maps generally, 6.6% (2913 people) out of 44186 participants reported to have at least one urinary stone episode in their lifetime (lifetime prevalence). in table 2, lifetime prevalence of urolithiasis and its distribution in different provinces are illustrated. the highest lifetime stone prevalence was observed in the sistan-baluchistan province (15.6%) and the lowest was observed in the golestan province (2.1%). the lifetime urolithiasis prevalence separately for provincial rural and urban areas is demonstrated in figures 1 and 2. the highest prevalence of provincial urban areas was observed in the sistan-baluchistan province while the highest provincial urolithiasis prevalence in rural areas belonged to the alborz province. distribution of the lifetime urolithiasis prevalence according to individual and ethnic characteristics according to the findings, among 2913 participants who had suffered from urolithiasis at least one time in their whole life, the lifetime risk of having stone in men was 48% more than women (7.9% vs. 5.3%; p < .001). in addition, with regard to the residential location, men were 53% (7.9% vs. 5.2%) more susceptible to stones in urban areas and 36% (7.8% vs. 5.7%) in rural areas. table 3. the lifetime prevalence distribution of urolithiasis according to ethnicity and demographic factors urolithiasis or (95.0 % ci) p value no yes gender female 20904 (94.7%) 1172 (5.3%) ref < 0.001 male 20369 (92.1%) 1741 (7.9%) 1.52 (1.41, 1.64) age; years < 20 11051 (99.1%) 102 (0.9%) ref ≥ 20 ,< 50 19179 (93.7%) 1292 (6.3%) 7.29 (5.95, 8.94) < 0.001 ≥ 50 10739 (87.9%) 1483 (12.1%) 14.96 (12.22, 18.31) < 0.001 residence location rural 10922 (93.2%) 797 (6.8%) ref 0.289 ethnicity urban 30351 (93.5%) 2116 (6.5%) 1.04 (0.96 , 1.13) fars 24862 (93.9%) 1607 (6.1%) ref turk 7926 (93.0%) 593 (7.0%) 1.15 (1.05, 1.27) 0.003 lor 3172 (92.7%) 251 (7.3%) 1.22 (1.06, 1.40) 0.004 kurd 3162 (94.2%) 195 (5.8%) 0.95 (0.81, 1.11) 0.548 arab 1033 (94.6%) 59 (5.4%) 0.88 ( 0.67, 1.15) 0.884 baluch 876 (82.0%) 192 (18.0%) 3.39 (2.87, 3.99) < 0.001 others 189 (93.6%) 13 (6.4%) 1.06 (0.60, 1.87) 0.829 age; years people interviewed people with lifetime stone number (%) 95.0% ci for percent total < 10 4033 35 (0.9%) 0.6%-1.2% ≥ 10, < 20 7120 67 (0.9%) 0.7%-1.2% ≥ 20, < 30 6567 194 (3.0%) 2.6%-3.4% ≥ 30, < 40 7152 465 (6.5%) 5.9%-7.1% ≥ 40, < 50 6752 633 (9.4%) 8.7%-10.1% ≥ 50, < 60 5544 652 (11.8%) 10.9%-12.6% ≥ 60, < 70 4056 527 (13.0%) 12.0%-14.1% ≥ 70, < 80 1954 229 (11.7%) 10.4%-13.2% ≥ 80, < 90 603 67 (11.1%) 8.8%-13.8% ≥ 90 65 8 (12.3%) 6.0%-21.9% men <10 1913 16 (0.8%) 0.5%-1.3% ≥ 10, < 20 3612 36 (1.0%) 0.7%-1.4% ≥20, <30 3362 102 (3.0%) 2.5%-3.7% ≥ 30, < 40 3467 285 (8.2%) 7.3%-9.2% ≥40, <50 3258 384 (11.8%) 10.7%-12.9% ≥ 50, < 60 2752 387 (14.1%) 12.8%-15.4% ≥ 60, < 70 2098 310 (14.8%) 13.3%-16.3% ≥ 70, < 80 1052 141 (13.4%) 11.4%-15.6 ≥ 80, < 90 375 48 (12.8%) 9.7%-16.5% ≥ 90 47 7 (14.9%) 6.9%-27.0% women < 10 2120 19 (0.9%) 0.6%-1.4% ≥ 10, < 20 3508 31 (0.9%) 0.6%-1.2% ≥ 20, < 30 3205 92 (2.9%) 2.3%-3.5% ≥ 30, < 40 3685 180 (4.9%) 4.2%-5.6% ≥ 40, < 50 3494 249 (7.1%) 6.3%-8.0% ≥ 50, < 60 2792 265 (9.5%) 8.4%-10.6 ≥ 60, < 70 1958 217 (11.1%) 9.7%-12.5% ≥ 70, < 80 902 88 (9.8%) 7.9%-11.8 ≥ 80, < 90 228 19 (8.3%) 5.3%-12.4% ≥ 90 18 1(5.6%) 0.6%-23.2% table 4. the lifetime prevalence distribution in different decades of life in total and separately for men and women epidemiology of urolithiasis in iran-basiri et al. endourology and stone diseases 104 the mean ± sd age of patients with urolithiasis was 49.2 ± 15.9 years. considering gender classification, mean ± sd age was 49.8 ± 15.8 years in men and 48.3 ± 16.1 years in women. in addition, the age group under 20 years old was less susceptible to stone compared to other age groups (p < .001). the lifetime prevalence of urolithiasis in the rural areas was 6.8% versus 6.5% in the urban areas (p = .29). regarding ethnicity, the lifetime risk of urolithiasis in the lor and turk ethnicities have been observed to be 21% and 15% higher respectively, compared to the fars ethnicity, which was considered as the reference category (p = .004 and p = .003, respectively). on the other hand, the lifetime prevalence in the arab and kurd ethnicities were reported to be 11% and 4% lower respectively than the fars ethnicity (p = .88 and p=.55, respectively). at last, the baluch community had three times more risk of urolithiais than the fars ethnicity (p < .001). the distribution of lifetime prevalence according to individual and ethnic features can be observed in detail in table 3. distribution of the lifetime prevalence of urinary stones in different decades of life is shown in table 4 with and without gender classification. as expected, the lifetime urolithiasis prevalence has increased up to the age of 70 years. in addition, the most prominent increase in lifetime prevalence was observed in the age of 20 to 60 years (from 0.9% to 11.8%). the lifetime prevalence trend of urolithiasis in different decades of life has been illustrated in figure 3. discussion according to our findings, the lifetime prevalence of urolitiasis was estimated to be 6.6% in the iranian population. out of 31 provinces, the sistan-baluchistan province had the highest (15.6%) and the golestan province had the lowest (2.1%) lifetime prevalence. in addition, the risk of having stone was about 1.5 times higher in males compared to females. urolithiasis was not significantly more common in rural areas than urban areas of the country. regarding age differences, the lifetime prevalence of urinary stones has increased up to 70. in addition, the most prominent increase in lifetime prevalence was observed in the third to sixth decade of life (rom 0.9% to 11.8%) the ethnicity with the highest prevalence of urolithiasis was the baluch ethnicity. few studies have been conducted on the lifetime prevalence of urolithiasis in the recent years in iran at the national level. the latest published study dates back to 15 years ago by safarinejad et al(12) in which 8413 participants were randomly selected from 30 counties in iran and were interviewed. the lifetime prevalence of urolithiasis was estimated to be 5.7% in that study which was 0.9% lower than our study (6.6%). this difference can be partly explained by the passage of 15 years of that study and also the increasing trend of urolithiasis prevalence in the middle east(16). in addition, this upward trend is also observed in other countries around the world(1). in an epidemiological study by chewcharat et al(4), it was estimated that the prevalence rate of nephrolithiasis in the united states has increased by an annual rate of 0.16% which was higher than the estimated annual rise in our country (0.06%). this difference might be justified by the growing trend of industrialization existing in western countries.(17). it has been estimated that 1%-19.1% of the population suffers from urolithiasis in different countries of asia. on the other hand iran is considered among the countries with medium prevalence of urinary tract stones(9). in a cross-sectional study by nassir et al(10) conducted on february 2017 in makkah region of saudi arabia, a total of 1056 participants were investigated through direct interviews. they were questioned about lifetime prevalence and demographic features which showed that the estimated lifetime prevalence was 6.2% in that region which was close to our study (6.6%), suggesting the similarity in the prevalence of urolithiasis in this figure 1. geographical distribution map of the lifetime prevalence of urolithiasis in the rural population of iran epidemiology of urolithiasis in iran-basiri et al. vol 20 no 2 march-april 2023 105 region. however, in a cross-sectional study by muslumanoglu et al(18) on 2468 participants from 33 provinces of turkey, a 11.1% lifetime history of urolithiasis was reported. this higher prevalence rate in turkey in comparison with other neighboring countries is probably due to the pattern of industrialization similar to western countries(17). similarly, articles published in the eastern asia have elucidated that the lifetime prevalence of urolithiasis figure 2. geographical distribution map of the lifetime prevalence of urolithiasis in the urban population of iran is higher than the western asian countries such as our country. in a study by zeng et al(19), 12570 individuals in general population of china were investigated from may 2013 to july 2014. they were interviewed by questionnaires including the history of urolithiasis in their lifetime along with demographic features. the lifetime prevalence was estimated to be 15.5% in the whole country that is higher than our country (6.6%). this might be explained due to different dietary habits figure 3. the lifetime prevalence trend of urolithiasis in different decades of life epidemiology of urolithiasis in iran-basiri et al. endourology and stone diseases 106 (such as high meat and salt consumption) and genetic factors(20,21). likewise, studies from industrialized western countries have shown relatively higher prevalence rates than our country. for instance, in a cross-sectional study by vega et al(22) in spain, 2444 individuals were investigated and interviewed by telephone and questioned about demographic and socioeconomic variables along with history of formation or passage of urinary stones in their lifetime. in total population, estimated lifetime prevalence of urolithiasis was reported to be 14.6% which is higher than our country. this difference can be justified due to western dietary habit (higher meat and lower vegetable consumption) compared to our country(21,23). in parallel, in a nationwide epidemiological study from the united states of america, hill et al(24) evaluated 10521 participants from 2015 to 2018 and reported a lifetime prevalence of 11% among us population in that period of time which is meaningfully higher than our prevalence rate. it seems that higher body mass index (bmi) and prevalence of obesity along with western dietary habits lead to higher lifetime prevalence in that study compared to our country (21,23,25,26). in terms of racial and ethnic factors, the baluch ethnicity had the highest lifetime prevalence compared to other provinces in our study (p < .001). however, no significant difference was reported by the latest published study(12), which evaluated this aspect of urolithiasis at the national level. it can be due to smaller sample size of that study (8413) compared to our study (44186) in addition to using local interviewers in our article, which have made our findings more reliable and more accurate. regarding gender, men were 48% more prone to urinary stone compared to women in our study, which was generally similar to other articles, which evaluated this aspect of urolithiasis. this finding might be due to difference in employment rate between men and women in iran and also other countries(13,27,28). in a cohort study by dr. khalili and colleagues(29) on 10000 participants from rafsanjan city, odds of having a urinary stone was 57% more in men which was similar to our article (52%). several articles in industrialized countries like china(19) and the united states(30) have mentioned similar findings with less significant differences (21% and 27%, respectively) which might be due to higher participation of women in industry as labor force in those countries compared to our country(28,31). regarding residential location, uroloithiasis was more common in men compared to women in both urban and rural areas in our study. nevertheless, the between-gender difference was less significant in rural areas (36%) than urban areas (53%), which might be explained by the difference in rate of unemployment in females between rural and urban areas(13,28,32). the lifetime prevalence of urolithiasis has increased up to the age of 70 years in our study. in addition, this upward trend was more prominent between the age of 20 to 60 years (3rd to 6th decades of life) denoted by the highest slope of the fitted regression line in figure 3 (from 0.9% to 11.8%%). it might be indicated that incidence rate of urinary stones in this age group is higher than other age ranges. in a study by nassir et al(10), which had been briefly mentioned above, a positive linear correlation was reported between participants’ age and lifetime prevalence of urolithiasis. in addition, middle aged population had more increasing trend of lifetime prevalence compared to other age ranges which was similar to our findings. our study had some limitations. the most important was the long period of conduction due to the large sample size and covid-19 pandemic. this could affect the results of our study. in addition, prevalence-incidence bias and unmeasured probable confounding variables were also among our limitations in this study. however, large statistical sample size compared to other studies, in addition to using local interviewers have made our findings more accurate and more reliable. conclusions generally, 6.6% of population in iran suffers from urolithiasis during their lifetime. urinary stone prevalence has increased 0.06% annually since the last national study that took place 15 years ago. urolithiasis is observed to be more prevalent in men than women and in the baluch people than other ethnicities. the age range of 20 to 60 years has a more prominent increasing trend in urolithiasis prevalence compared to other age groups and there is no significant difference between rural and urban areas. however, the ratio of male to female risk of urolithiasis is higher in urban areas compared to rural areas. acknowledgement this study was supported by the national institute for medical research development (nimad) (the ethics code of ir.nimad.rec.1399.113). we would like to appreciate iran telecommunication organization, all the interviewers who were involved in this study in all provinces, and also all the families who were interviewed for their cooperation. conflict on interest the authors report no conflict of interests. references 1. lang j, narendrula a, el-zawahry a, sindhwani p, ekwenna o. global trends in incidence and burden of urolithiasis from 1990 to 2019: an analysis of global burden of disease study data. european urology open science. 2022;35:37-46. 2. scales cd, curtis lh, norris rd, et al. changing gender prevalence of stone disease. the journal of urology. 2007;177:979-82. 3. sirohi m, katz bf, moreira dm, dinlenc c. monthly variations in urolithiasis presentations and their association with meteorologic factors in new york city. journal of endourology. 2014;28:599-604. 4. chewcharat a, curhan g. trends in the prevalence of kidney stones in the united states from 2007 to 2016. urolithiasis. 2021;49:27-39. 5. brikowski th, lotan y, pearle ms. climate-related increase in the prevalence of urolithiasis in the united states. proceedings of the national academy of sciences. 2008;105:9841-6. 6. shajari a, sanjerehei mm. modeling the distribution of urolithiasis prevalence under epidemiology of urolithiasis in iran-basiri et al. vol 20 no 2 march-april 2023 107 projected climate change in iran. urolithiasis. 2015;43:339-47. 7. scales jr cd, smith ac, hanley jm, saigal cs, project udia. prevalence of kidney stones in the united states. european urology. 2012;62:160-5. 8. abufaraj m, al karmi j, yang l. prevalence and trends of urolithiasis among adults. current opinion in urology. 2022;32:425-32. 9. liu y, chen y, liao b, et al. epidemiology of urolithiasis in asia. asian journal of urology. 2018;5:205-14. 10. nassir am. prevalence and characterization of urolithiasis in the western region of saudi arabia. urology annals. 2019;11:347. 11. tasian ge, ross me, song l, et al. annual incidence of nephrolithiasis among children and adults in south carolina from 1997 to 2012. clinical journal of the american society of nephrology. 2016;11:488-96. 12. safarinejad mr. adult urolithiasis in a population-based study in iran: prevalence, incidence, and associated risk factors. urological research. 2007;35:73-82. 13. iran sco. iran 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https://www. ilo.org/wcmsp5/groups/public/---dgreports/--stat/documents/projectdocumentation/ wcms_153116.pdf. accessed 7 december, 2022. epidemiology of urolithiasis in iran-basiri et al. endourology and stone diseases 108 running head: identify prostate biopsy candidateswagaskar et al development and external validation of a prediction model to identify candidates for prostate biopsy authors: vinayak g wagaskar mbbs, mch1*, anna lantz md1, stanislaw sobotka phd dsc1, parita ratnani mph, bds1, sneha parekh mbbs1, ugo giovanni falagario md1, li li md, phd3, sara lewis md2, kenneth haines iii md3, sanoj punnen4 , peter wiklund md1, ash tewari mbbs, mch1 affiliations: 1 department of urology, icahn school of medicine at mount sinai hospital, new york, ny, usa 2 department of radiology, icahn school of medicine at mount sinai hospital, new york, ny, usa 3 department of pathology, icahn school of medicine at mount sinai hospital, new york, ny, usa 4 department of urology, university of miami, miller school of medicine, miami, usa. 2 abstract purpose: prostate biopsies are associated with infectious complications and approximately 80% are either benign or clinically insignificant prostate cancer. our aim is to develop and independently validate prediction model to avoid unnecessary prostate biopsies by predicting clinically significant prostate cancer (cspca) materials and methods: retrospective analysis of single-center cohort (mount sinai hospital, ny) of 1632 men who underwent systematic or combined systematic and magnetic resonance imaging (mri)/ultrasound fusion targeted prostate biopsy between 2014-2020. external cohort (university of miami) included 622 men that underwent biopsy. outcome for predicting cspca was defined as international society of urologic pathology (isup) gleason grade 2 on biopsy. multivariable logistic regression analysis was performed to build nomogram using coefficients of logit function. nomogram validation was performed in external cohort by plotting receiver operating characteristics (roc). we also plotted decision curve analysis (dca) and compared nomogram-predicted probabilities with actual rates of cspca probabilities in external cohort. results: of 1632 men, 43% showed cspca on biopsy. psa density, prior negative biopsy, and prostate imaging and reporting data system (pi-rads) scores 3, 4, and 5 were significant predictors for cspca. roc for prediction of cspca was 0.88 in external cohort. there was agreement between predicted and actual rate of cspca in external cohort. dca demonstrated net benefit using the model. using the prediction model at threshold of 30, 35% of biopsies and 46% of diagnosed indolent pca could be avoided, while missing 5% of cspca. conclusion: using our prediction model can help reduce unnecessary prostate biopsies with minimal impact on cspca detection rates. keywords: biopsy; logistic models; magnetic resonance imaging; nomograms; prostate cancer. 3 1. introduction prostate cancer (pca) is the second deadliest cancer in men in the united states. in 2019, there were 174,650 new diagnoses of pca and 31, 620 prostate cancer deaths.(1) there is an ongoing debate around the degree of benefit from the screening for pca given the poor diagnostic performance of prostate specific antigen (psa) and the tumor agnostic nature of conventional trans rectal ultrasound (trus)-guided biopsy, which has moderate ability to risk stratify patients using biopsy findings. recent studies estimate that more than 80% of the million biopsies performed annually in the united states may be unnecessary,(1,2) resulting in patient morbidity and tremendous financial strain on the healthcare system that potentially could be avoided. studies have shown that trus-guided biopsies are associated with infectious complications in 5-7% of cases, approximately 3% of which require hospitalization.(3,4) poor diagnostic accuracy with standard screening methods, psa and digital rectal exam (dre), has generated interest in multi-parametric magnetic resonance imaging (mpmri), which has been investigated in a number of trials. the precision study reported promising results with mpmri for reducing unnecessary biopsies, yet men with negative mri did not undergo biopsy.(5) oishi et al reported detection of 38% pca and 18% clinically significant prostate cancer (cspca) rates in men with negative mpmri.(6) 4 mpmri has the potential to improve patient selection for biopsy.(7) to optimize mpmri as a screening tool, given its limitations, it will be important to consider relevant clinical variables, including age and family history, as well as prior history of biopsy, and the results of standard screening tools, such as psa density (psad), and dre findings, in addition to mpmri results for identifying cspca. the objective of our study was to develop and externally validate a risk prediction tool for cspca in order to identify men who might safely avoid prostate cancer biopsy and thus to reduce the burden of unnecessary biopsies and overtreatment using both clinical parameters and mpmri results. 2. material and methods 2.1 study population with the approval of the institutional review board (gco 19-1711), we retrospectively reviewed our institution’s prostate biopsy database to extract patient records. between january 2014 and march 2020, 1678 men underwent biopsy by a single expert surgeon (a.k.t.) with 20 years’ experience. these didn’t include biopsies with a previous or current history of prostate cancer. 2.2 inclusion and exclusion criteria indications for biopsy were psa >4ng/ml and 4kscore of >7%; psad >1.5; suspicious dre; or prostate imaging and reporting data system (pi-rads) scores of 3, 4, or 5 on mpmri, or a combination of any of the above. exclusion criteria were contra-indication for mpmri (n=23); prior hormone therapy or radiation (n=10); or missing data on family history of prostate cancer, history of prior negative biopsy or dre (n=13). in total, 1632 men were eligible for inclusion in the analysis. for external validation, a cohort of 622 men that underwent systematic or combined systematic and mri/ultrasound fusion biopsy for psa > 4 5 ng/ml or suspicious dre, or pi-rads 3, 4 or 5 score at university of miami was used. all research was conducted with informed consent and irb approval. 2.3 procedures all men underwent standardized mpmri prior to prostate biopsy. examinations were compliant with american college of radiology recommendations for technical specifications and were performed using clinical 3-tesla mri systems equipped with an 18-element phased-array pelvic coil. mpmpi results were evaluated according the prostate imaging and reporting data system version 2 (pi-rads v2) by clinical radiologists with experience in prostate imaging.(8) all men underwent either systematic or systematic and mri-trusfusion targeted biopsy in the case of a positive mri (pi-rads >3), and 2-4 extra cores were taken from each lesion. all biopsies were performed by a single experienced urologist (a.k.t.) using an artemis mri/us fusion device (innomedicus, cham, switerzland) using a spring-loaded biopsy gun and 18 gauge needles. biopsies samples were reviewed by an experienced genitourinary pathologist (k.h.iii). 2.4 evaluation and statistical analysis for our prediction model, the outcome for predicting cspca was defined as a isup gleason grade of > 2 on biopsy; men with this outcome were considered cases. men who showed no cancer on biopsy or with a isup gleason grade 1 were considered controls. descriptive statistics for the two groups were performed. continuous variables were reported as median and interquartile range (iqr) and were compared using a mann-whitney test. categorical variables were reported as rates and were tested with a chi-square test, as appropriate. the prediction model included age, family history of prostate cancer, history of negative prior biopsy, psad, dre findings, or mpmri findings of a pi-rads score as variables. pi6 rads scores of 1 and 2 were grouped for the purpose of analysis. psad was calculated from the prostate volume from mri findings. nomogram validation was performed in external cohort of 622 men by grouping them into deciles based on their nomogram-predicted probabilities and then comparing the mean prediction of the group with the observed proportion of men with cspca. using nomogramderived probability cut-offs, we calculated the number of biopsies that could be avoided without missing cspca in the external cohort. decision curve analysis (dca) was performed to evaluate the performance of the prediction model. statistical analyses were performed using stata 12 (statacorp lp, college station, tx, usa) and sas 9.4 (sas institute, cary, nc, usa). all tests were two-tailed with a significance level of p<0.05. 3 results a total of 1632 men were included in the analysis. of 1632 men, 701(43%) were diagnosed with cspca. the median age was 64 years (iqr 58, 69), 65 years (iqr 59, 68); median psa was 5.1 ng/ml (iqr 3,7, 7.6), 6.4 ng/ml (iqr 4.8, 9,5); and median psa density was 0.09 ng/ml2 (iqr 005, 0.14), 0.16 ng/ml2 (iqr 0.11, 0.26) for controls and cases, respectively. while in an external cohort of 622 men, 173 (28%) were diagnosed with cspca. the median age was 61 years (iqr 60,69), 60 years (iqr 60,70); median psa was 5.6 ng/ml (iqr 4,8.1), 6.8 ng/ml (iqr 5,9.4) and median psa density was 0.09 ng/ml2 (iqr 0.06,0.14), 0.18 ng/ml2 (iqr 0.12, 0.27) for controls and cases, respectively.(table 1). 3.4 univariable and multivariable analysis predicting cspca in univariate analysis, psad, family history of prostate cancer, prior negative biopsy, dre findings, and pi-rads 3, 4 and 5 emerged as significant predictors of cspca. in multivariate 7 analysis, family of prostate cancer, history of prior negative biopsy, psad, and pi-rads scores of 3, 4, and 5 were significantly associated with cspca (all p<.01 (table 2). 3.5 construction and validation of a nomogram to estimate risk of cspca a nomogram was created to predict the presence of cspca (fig. 1). auc for predicting cspca was 0.88 in an external cohort (fig. 2). we evaluated the nomogram’s calibration by comparing predicted and actual probabilities of cspca in the external cohort (fig. 3). there was an agreement between predicted and actual rate of probabilities for cspca as seen by points at the diagonal line. in an external cohort, dca plot for predicting cspca showed superior clinical prediction of pi-rads score vs our model or psad for 20-65% nomogram derived probabilities (fig. 4). using our model in external cohort, 10% of biopsies could be avoided without missing cspca, avoiding 21% of benign biopsies and 13% of indolent pca (fig. 5) additionally, 15%, 20%, 25%, 30%, and 35% of biopsies could be avoided while missing 3%, 4%, 5%, 9%, and 12% of isup gleason grade 2 pca, respectively, avoiding 29%, 40%, 51%, 58%, and 66% of benign biopsies, respectively, and avoiding 21%, 26%, 31%, 39%, and 46% of clinically insignificant pca, respectively. figure 5 demonstrates the percentage of biopsies that could be avoided without significantly affecting detection of isup gleason grade 3 and > 4-5. 4 discussion: we have developed and independently validated a prognostic tool for use in primary work-up to predict cspca in men for whom biopsy is being considered. our model confers two key benefits. 1) it reduces number of biopsies without compromising detection of cspca (2) our 8 model shows efficacy of pi-rads scores, psad, and history of prior negative biopsy for prediction of cspca. the increasing number of prostate biopsies in recent years has focused the attention,, on the complications associated with these procedures. common non-fatal complications after biopsy include pain, bleeding, and voiding dysfunction. less common, but potentially fatal complications, include post-biopsy blood stream infections.(9) additionally, we have seen a rising prevalence of antibiotic-resistant bacterial infections with biopsy-related infectious complications.(10) at the same time, standard systematic prostate biopsy is associated with increased detection of indolent or clinically insignificant pca[11]. our model shows that a significant number of biopsies could be avoided with only a modest impact on detection of cspca, reducing unnecessary biopsies and the risk of associated complications. a number of prediction calculators for diagnosing cspca have been developed. the rotterdam european randomized study of screening for prostate cancer risk calculators (erspc-rcs) help to avoid unnecessary transrectal ultrasound-guided systematic biopsies (trus-bx).(12) different from most prior studies, our model was both internally and externally validated to show the robustness of risk estimation. lee et al., have built a prediction calculator for diagnosing cspca based on age, psad, history of prior negative biopsy, and mri pi-rads score.(13) they showed that 10% of biopsies could be avoided using their model missing 17% of clinically insignificant pca and 3% of cspca. in our study, nonetheless, avoiding 10% of biopsies would have missed 13% of clinically insignificant prostate cancers and just 1% of cspca. a prediction calculator developed by van leeuwen et al., based on age, psa, dre, prostate volume, prior biopsy, and mri pi-rads lesion, showed 28% reduction of biopsies while missing 26% of clinically insignificant prostate cancers and 3.5% of cspca. (14) of note, in this study men were biopsied using transperineal mapping biopsies with a median of 30 cores. our model show that mpmri pi-rads scores of 3, 4, and 5 are significant for predicting cspca. mpmri has mediated visualization and localization of tumors owing to its capacity for soft-tissue contrast, better resolution, and ability to image functional parameters.(15) we, along with others, have found that psad is also a significant predictor of cspca and can aid in reducing unnecessary biopsies.(16) furthermore, studies have also shown prior negative biopsy as a predictor for avoiding repeat biopsies. (17) and lee et al., found that mpmri pirads scores 3, 4, and 5, psad, and history of prior negative biopsy in combination are strong predictors for diagnosing cspca.(16) similar to our study, in the reduce trial, family history of prostate cancer was not associated with prostate cancer diagnosis in men in north america.(18) in the sthlm3 study, auc for age or family history alone was 0.59 (0.57-061) 9 for predicting cspca, suggesting minimal utility as compared to auc of .63 for dre alone, a finding similar to our own (auc for dre alone of 0.61). we recognize that our study has a number of limitations. first, our cohort is based on stringent biopsy selection criteria which could affect generalizability. consequently, our cspca detection rate of 43% is higher than other studies. (13-14, 16) inclusion of psa and 4kscores and/or inclusion of mri for selection for biopsy may account for this higher detection rate as described in our previously published paper.(19) additionally, all biopsies were performed by a single experienced, high-volume expert, which could affect generalizability. finally, this study was conducted in a single center and our outcomes may not be reproducible. 5 conclusion we have developed an easily accessible tool to assist clinicians in biopsy decision making and patient counselling for men at risk for pca. using our novel prediction model could significantly reduce the large number of biopsies that detect benign or clinically insignificant pca, while missing only a small proportion of cspca. our results demonstrate the importance of combining psad, prior negative biopsy, and mpmri pi-rads score for predicting cspca. acknowledgment: we thank ms sima rabinowitz for editorial revision. conflicts of interest: none references 1. siegel rl, miller kd, jemal a. cancer statistics, 2019. ca cancer j clin. 2019;69:734. 2. parekh dj, punnen s, sjoberg dd, et al. a multi-institutional prospective trial in the usa confirms that the 4kscore accurately identifies men with high-grade prostate cancer. eur urol. 2015;68:464-70. 10 3. halpern ja, shoag je, artis as, et al. national trends in prostate biopsy and radical prostatectomy volumes following the us preventive services task force guidelines against prostate-specific antigen screening. jama surg. 2017;152:192-98. 4. loeb s, carter hb, berndt si, ricker w, schaeffer em. complications after prostate biopsy: data from seer-medicare. j urol. 2011;186:1830-34. 5. kasivisvanathan v, rannikko as, borghi m, et al. mri-targeted or standard biopsy for prostate-cancer diagnosis. nemj. 2018;378:1767-77. 6. oishi m, shin t, ohe c, et al. which patients with negative magnetic resonance imaging can safely avoid biopsy for prostate cancer? j urol. 2019;201:268-76. 7. delongchamps nb, portalez d, bruguière e, et al. are magnetic resonance imagingtransrectal ultrasound guided targeted biopsies noninferior to transrectal ultrasound guided systematic biopsies for the detection of prostate cancer? j urol. 2016;196:1069-75. 8. weinreb jc, barentsz jo, choyke pl, et al. pi-rads prostate imaging – reporting and data system: 2015, version 2. eur urol. 2016;69:16-40. 9. borghesi m, ahmed h, nam r, et al. complications after systematic, random, and image-guided prostate biopsy. eur urol. 2017;71:353-65. 10. aly m, dyrdak r, nordström t, et al. rapid increase in multidrug-resistant enteric bacilli blood stream infection after prostate biopsy—a 10-year population-based cohort study. the prostate. 2015;75:947-56. 11. schröder fh, hugosson j, roobol mj, et al. screening and prostate cancer mortality: results of the european randomised study of screening for prostate cancer (erspc) at 13 years of follow-up. lancet. 2014;384:2027-35. 12. roobol mj et al. a risk-based strategy improves prostate-specific antigen–driven detection of prostate cancer, eur urol 2010. 57:79-85. 13. lee sm, liyanage sh, wulaningsih w, et al. toward an mri-based nomogram for the prediction of transperineal prostate biopsy outcome: a physician and patient decision tool. urol oncol. 2017;35:611-18. 14. van leeuwen pj, hayen a, thompson je, et al. a multiparametric magnetic resonance imaging-based risk model to determine the risk of significant prostate cancer prior to biopsy. bju int. 2017;120:774-81. 15. fütterer jj, briganti a, de visschere p, et al. can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging? a systematic review of the literature. eur urol. 2015;68:1045-53. 16. nordström t, akre o, aly m, grönberg h, eklund m. prostate-specific antigen (psa) density in the diagnostic algorithm of prostate cancer. prostate cancer prostatic dis. 2018;21:57-63. 17. j.g. rivas, m. alvarezmaestro, m. czarniecki, s. czarniecki, m.r. socarras, s. loeb. negative biopsies with rising prostate-specific antigen. what to do? emj urol.2017:76-82 18. thomas ja, 2nd, gerber l, moreira dm, et al. prostate cancer risk in men with prostate and breast cancer family history: results from the reduce study (r1). j intern med. 2012;272:85-92. 19. wagaskar vg, sobotka s, ratnani p, young j, lantz a, parekh s, et al. a 4k score/mri-based nomogram for predicting prostate cancer, clinically significant prostate cancer, and unfavorable prostate cancer. cancer rep (hoboken). 2021;4:1357. 11 corresponding author: vinayak g wagaskar mbbs, mch department of urology, icahn school of medicine at mount sinai hospital, 1425 madison avenue, new york, ny 10029, usa e-mail address: vinayakwagaskar99@gmail.com vinayak.wagaskar@mountsinai.org phone number: +1-2122414812 fax number: +1-6465378508 orcid id: 0000-0001-8027-6661 table 1. comparison of factors between cases and controls for cspca mssm*(n=1632) um**(n=622) factors cases n=701 controls n=931 p-value cases n=173 controls n=449 p-value age years (median, iqr) 65 (59, 69) 64 (58, 69) .449 60 (60, 70) 61 (60, 69) .6283 psa, ng/ml (median, iqr) 6.4 (4.8, 9.5) 5.1 (3.7, 7.6) <.0001 6.8 (5, 9.4) 5.6 (4, 8.1) <.0001 psad (median, iqr) 0.16 (0.11,0.26) 0.09 (0.05,0.14) <.0001 0.18 (0.12,0.27) 0.09 (0.06, 0.14) <.0001 family history pc <.0001 .8834 negative 467 (66.6 %) 740 (79.5 %) 135(82.3%) 337(81.8%) positive 234 (33.4 %) 191 (20.5%) 29 (17.7%) 75 (18.2%) pnb <.0001 .0001 no 685 (97.7%) 624 (67.0%) 135(78.0%) 277(61.7%) yes 16 (2.3%) 307 (33.0%) 38 (22.0%) 172(38.3%) dre <.0001 .0016 normal 382 (54.5%) 703 (75.5%) 110(63.6%) 342(76.2%) mailto:vinayakwagaskar99@gmail.com mailto:vinayak.wagaskar@mountsinai.org 12 suspicious 319 (45.5%) 228(24.5 %) 63 (36.4%) 107(23.8%) mri lesion pi-rads <.0001 <.0001 0-2 68 (9.7%) 414 (44.5%) 11 (6.4%) 171(38.0%) 3 62 (8.8%) 201 (21.6%) 17 (9.8%) 136(30.3%) 4 342(48.8%) 255 (27.4%) 90 (52.0%) 118(26.2%) 5 229 (32.7%) 42 (4.5%) 55 (31.8%) 24 (5.5%) isup gleason grade 0 0 546 (58.6%) 0 328(73.0%) 1 0 385(41.4%) 0 121(27.0%) 2 341 (48.6%) 0 77 (44.6%) 3 165 (23.5%) 0 29 (16.7%) 0 4 120 (17.1%) 0 29 (16.7%) 0 5 75 (10.7%) 0 38 (22.0%) 0 *mssm: mount sinai school of medicine, **um-university of miami (external validation cohort), abbreviations: cspcaclinically significant prostate cancer; iq rangeinterquartile range; psaprostate specific antigen; psad-prostate specific antigen density; pc-prostate cancer; pnbprior negative biopsy; dredigital rectal examination; mrimagnetic resonance imaging; pi-radsprostate imaging reporting and data system version 2; isup international society of urologic pathology. table 2: multivariable analysis predicting presence of cspca variable estimate standard error odds ratio 95% ci p-value (ul, ll) age 0.007 0.011 1.007 0.91,1.01 .496 fh 0.464 0.176 1.590 1.1,1.9 .008 pnb -2.958 0.366 0.052 0.04,0.06 .000 psad 4.576 0.737 97.138 86, 103 .000 dre 0.400 0.171 1.492 1.1,1.9 .020 pi-rads .000 pi-rads 3 0.938 0.257 2.555 1.4,3.2 .000 13 pi-rads 4 2.151 0.203 8.595 4.4,13.1 .000 pi-rads 5 2.612 0.273 13.621 9.2,21.1 .000 abbreviations: cspcaclinically significant prostate cancer; ciconfidence interval ; ulupper limit; ll-lower limit; pnbprior negative biopsy; psadprostate specific antigen density; fh-family history; dredigital rectal examination finding; pi-radsprostate imaging reporting and data system. supplementary table: number of biopsies performed and missed in an external cohort for clinically significant prostate cancer as per nomogram-derived cut-offs probability cspca cut-off (%) biopsy performed, n (%) biopsy not performed, n (%) cspca missed, n for clinically significant prostate cancer sensitivity (%) specificity (%) ppv (%) npv (%) 10 510/539 29 (5.4) 0 99.6 9.86 49.8 96.5 15 451/539 88 (16.3) 9 96.5 27.8 54.6 89.8 20 410/539 129 (23.9) 11 95.7 41.6 59.5 91.5 25 376/539 163 (30.2) 19 92.6 50.7 62.8 88.3 30 354/539 185 (34.3) 24 90.6 56.7 65.3 87.0 abbreviations: cspcaclinically significant prostate cancer; ppvpositive predictive value; npvnegative predictive value. figure legends figure 1. nomogram for predicting presence of cspca at the time of biopsy. the reading of cancer probability from nomogram can be described in following steps: 1. locate the patient’s variable age on corresponding axis. 2. then draw a line straight download to the score axis to determine how many points towards the probability of cancer the patient receives for his age. 3. repeat the process for each additional variable [family history, prior negative biopsy, dre, pi-rads score]. 4. sum the points for each of the predictors. 5. locate the final sum on the total score axis. 6. draw a line straight up to find 14 patient’s probability [prob] of having cancer. total scores correspond to a probability value for cspca. dredigital rectal examination. pirads –pi-rads score on mri abbreviations: pcprostate cancer, cspcaclinically significant prostate cancer; psa densityprostate specific antigen density; dredigital rectal examination finding; pi-rads prostate imaging reporting and data system. figure 2. area under curve predicting cspca in external cohort using variables used to build model. abbreviations: cspcaclinically significant prostate cancer; ciconfidence interval; psa densityprostate specific antigen density; dredigital rectal examination finding; mri magnetic resonance imaging; pi-radsprostate imaging reporting and data system. figure 3: calibration curve in the external cohort. predictive probabilities of cancer for each case in the external cohort are sorted by probability of clinically significant prostate cancer calculated from the training model respectively. each point (average of 60 subsequent cases) illustrates the comparison between predictive probability (calculated from the training model) and actual cancer rate for this group of cases. points at the diagonal line (0, 0 and 1, 1), show the agreement between predicted and actual rate of cancer and validate training model. figure 4. decision curve analyses showing the net benefit associated with the use of nomogram-derived probability for prediction of clinically significant prostate cancer (figure 3b) in an external cohort vs relying on psa density or pi-rads score alone. abbreviations: psa densityprostate specific antigen density; pi-rads – prostate imaging reporting and data system. figure 5. graph showing number of biopsies that can be avoided in an external cohort using the prediction tool predicting clinically significant prostate cancer. figure 1 15 16 figure 2. 17 figure 3. 18 figure 4. 19 figure 5. pictorial urology 79urology journal vol 7 no 2 spring 2010 simultaneous computed tomography and seminal vesiculography in a patient with ejaculatory duct obstruction urol j. 2010;7:79. www.uj.unrc.ir a 32-year-old man presented with primary infertility. he had azoospermia with low volume ejaculate. physical examination was normal. transrectal ultrasonography (trus) revealed grossly dilated seminal vesicles. no other genitourinary tract abnormality was noted. he underwent trus-guided aspiration of the seminal vesicles with simultaneous instillation of contrast media and methylene blue dye into the seminal vesicles. the aspirate showed scanty sperms. conventional radiograph (figure 1) and simultaneous computed tomography (ct) and seminal vesiculogram images (figure 2) were taken, which revealed the spectacular appearance of huge seminal vesicles and retrograde flow of contrast media into the proximally dilated system upto the epididymis. the dilated ejaculatory duct anatomy could be seen with exceptional clarity. the patient underwent transurethral resection of the ejaculatory ducts on the same day until free flow of methylene blue was noted from a wide open orifice (figure 3). postoperatively, he developed seminal vesiculitis which was treated with oral ciprofloxacin. he showed a delayed return of sperms into the ejaculate at 9 months. transrectal ultrasonography alone is insufficient for the diagnosis of ejaculatory duct obstruction.(1) only about half of the patients with trus findings show confirmed obstruction on additional diagnostic evaluation such as examination of trus-guided aspirate, instillation of colored dye, and seminal vesiculography.(2) computed tomography and seminal vesiculography may be combined easily at the time of contrast instillation and gives excellent anatomical detail. further studies are needed to better elucidate the role of imaging with ct in patients with obstructive azoospermia. sanjay sinha*, sreenivasa r siriguri, rama subba rayudu departments of urology and radiology, medwin hospital, chirag ali lane, hyderabad-500001, india *e-mail: drsanjaysinha@hotmail.com references 1. goluboff et, stifelman md, fisch h. ejaculatory duct obstruction in the infertile male. urology. 1995;45:925-31. 2. purohit rs, wu ds, shinohara k, turek pj. a prospective comparison of 3 diagnostic methods to evaluate ejaculatory duct obstruction. j urol. 2004;171:232-5; discussion 5-6. 1004 | case report primary hydatid cyst of the kidney in a 10 year old boy ali tehranchi,1 hamid mohammadi bukani, 1 ali modabberi delshad, 1 sepehr hamedanchi1 keywords: case reports; kidney diseases; hydatid cyst; echinococcosis; humans introduction kidney involvement in echinococcosis is extremely rare, accounting for only 2-3% of all cases. primary involvement of the kidney with sparing the liver and lungs is even more rare.(1) we report a rare case of primary renal hydatid disease presenting with suprapubic and left loin pain. in this case, the disease mimicked renal tumor. successful treatment was accomplished using radical nephrectomy. case report a 10 year old boy, living in a rural environment, presented to our hospital with chief complaint of dull pain in left loin and lower abdomen for the last month. the patient had no history of urinary tract infection, hematuria or hydatiduria. his medical history was unremarkable, however he had a history of being in contact with livestock and sheepdogs. on physical examination, there was only mild tenderness in suprapubic and left loin areas, and no mass was palpable in the abdomen. his body temperature and the rest of systemic examination were normal. urine analysis and serum blood chemistry were normal. the chest x-ray was normal (fig 1). the ultrasound revealed a multiseptate cystic mass measuring 50 × 52 mm in diameter in the lower pole of the left kidney (fig 2). other abdominal organs were normal. computed tomography (ct) scanning confirmed ultrasonographic findings and the mass was consistent with bosniak class iv cysts (fig 3). correspondence address: hamid mohammadi bukani, md urology and nephrology research center, department of urology, imam medical center, urmia university of medical sciences, urmia, iran tel: +984413459538 fax: +984413469935 e-mail: hamid_boukani@ yahoo.com received may 2011 accepted august 2011 1urology and nephrology research center, department of urology, imam medical center, urmia university of medical sciences, urmia, iran case report 1005vol. 10 | no. 3 | summer 2013 |u r o lo g y j o u r n a l a provisional diagnosis of a malignant cystic mass was made and anterior subcostal transperitoneal approach for radical nephrectomy was elected. the patient didn’t received preoperative albendazole. the mass had extensive adhesions to the left colonic mesentery, which might be a characteristic sign for hydatid disease. the kidney was removed intact without rupture. gross pathologic examination showed a cystic structure in the lower pole of the kidney with parenchymal destruction, which was surrounded by a thin rim of renal cortex (fig 4). the histopathological examination revealed a hydatid cyst with three layers. adjacent renal tissue showed severe infiltration of eosinophils and lymphocytes. because of complete specimen removal without spillage, after the surgery the patient was not given albendazole, and he was referred to infectious disease clinic. discussion according to the age of the patient and findings of abdominal ct scan, preoperative differential diagnoses were multilocular cyst, cystic renal cell carcinoma, cystic wilms’ tumor and hydatid cyst. hydatidosis, caused by echinococcus spp. (e. granulosus and e. multilocularis in iran) is one of the most important zoonotic diseases. ingesting embryonated eggs through material contaminated infects humans; the larvae reach systemic circulation and transport to the liver, lungs and other organs. the asymptomatic period is too long and the disease might be diagnosed even after 20-25 years post infection.(2) the most common symptoms are palpable mass, flank pain, hematuria, malaise, and fever. hydaturia is a pathognomonic sign. its origin is a grape-like material in the urine resulting from the rupture of the cysts into the collecting system. hydatid cyst of the kidney | tehranci et al figure 1. chest x-ray. figure 2. the ultrasound showing a multiseptate cystic mass. figure 3. ct scan showing a bosniak class iv cystic mass in the left kidney. 1006 | it has been reported in 5% to 25% of all renal hydatidosis cases. in a study of 11 patients with renal hydatidosis 7 (63.6%) had flank pain, 1 (9.1%) had post ejaculation pain, and 3 (27.3%) were asymptomatic.(3) primary hydatidosis of the kidney is very rare, even in endemic areas such as iran. diagnosis of the hydatid cyst is made on the basis of serologic tests and/or imaging studies. the possibility of a striking clinical resemblance between a hydatid cyst and malignant disease of the kidney has been emphasized in the english literature. we also indicated this important point in our patient. in conclusion, the most important factor in the diagnosis of hydatid disease is the high index of suspicion about its possibility. primary hydatidosis of the kidney should always be considered in the differential diagnosis of any cystic renal mass in the pediatric groups, even in the absence of accompanying involvement of liver or other visceral organs.(4) conflict of interest none declared. references 1. mongha r, narayan s, kundu ak. primary hydatid cyst of the kidney and ureter hydatiduria; a case report. indian j urol. 2008;24:116-7. 2. rokni mb. echinococcosis / hydatidosis in iran. iranian j parasitol. 2009;4:1-16. case report figure 4. gross pathologic examination of the left renal mass. 3. zargar-shoshtari m, shadpour p, robat-moradi n, moslemi m. hydatid cyst of urinary tract: 11 cases at a single center. urol j. 2007;4:41-5. 4. hallaji f, varedi p, mahmoodi s, noroozi sg, mostafavi h, mostafavi sr, jouibari km. hydatid disease: a cause of renal cystic masses in children. pediatr nephrol. 2009 jun;24:1251-2. running head：predictors of upstaging to pt3a in renal carcinoma risk factors and oncologic outcomes for clinical t1 renal cell carcinoma upstaging to pathological t3a and the construction of predictive model: a retrospective study huadong wang1†, keruo wang2†, chuanfeng liu2, guixin wang2, yaru liu3, gang li2* 1 department of urology, tianjin baodi hospital, baodi clinical college of tianjin medical university, tianjin, china 2 department of urology, tianjin institute of urology, the second hospital of tianjin medical university, tianjin, china, 3 department of emergency, the second hospital of tianjin medical university, tianjin, china, huadong wang and keruo wang contributed equally to this work. keywords: carcinoma, renal cell, upstaging, recurrence free survival, risk factor, nomogram abstract purpose: the study is intended to identify the independent predictors of clinical t1 (ct1) renal cell carcinoma upstaging to pathological t3a (pt3a) and construct the predictive nomogram model. methods: the data of ct1 renal cell carcinoma was collected from patients who were treated in the second hospital of tianjin medical university from january 2010 to december 2016. mann–whitney u and chi-square tests were performed to analyze continuous and categorical variables respectively. univariate and multivariate logistic regression were used to identify the predictors of upstaging. kaplan-meier method, log-rank test and cox regression were performed to analyze survival materials. results: among 1,376 ct1 renal cell carcinoma patients, 75 patients were observed upstaging to pt3a, accounting for 5.5%. there were 6 potential predictors of upstaging, i.e age, clinical symptom, tumor size, fuhrman grade, tumor necrosis and tumor edge regularity. the 5-year recurrence free survival probabilities of upstaging and non-upstaging patients were 73.3% and 91.1%, respectively and upstaging was an independent predictor of recurrence free survival. two predictive nomograms were constructed and the c-index of them were 0.842 and 0.806, and the calibration curve and decision curve analysis showed highly clinical accuracy of the nomograms. conclusions: two nomogram models were built to predict the probability of ct1 renal cell carcinoma upstaging to pt3a with highly accuracy and specificity. upstaging was an independent risk factor of recurrence free survival for ct1 renal cell carcinoma patients. introduction renal cell carcinoma (rcc) accounts for 2–3% of all human cancers, and it has become the third most common genitourinary malignancy (1). most cases lack symptoms such as abdominal pain, haematuria or abdominal masses, as the majority rccs are incidental findings on abdominal imaging, including ultrasound (us), computed tomography (ct), magnetic resonance imaging (mri). nowadays, the clinical diagnosis of rcc relies heavily on a triphasic ct scan, as it has high sensitivity and specificity for determination of the size, location and staging of tumor. in the guidelines of nccn and eau 2021, nephron sparing surgery (nss) is recommended for treatment of t1 rcc, which provides similar long-term oncologic outcomes as radical nephrectomy (rn). nss is also indicated for some technically feasible t2 rcc patients, such as bilateral renal tumors, isolated kidney or poor renal function (2). however, the first choice for t3a rcc is rn. previous studies have shown that the sensitivity and specificity of imaging tests for rcc vary significantly (3). with the development of clinical and pathological staging of rcc, it has become not rare for ct1 rcc upstaging to pt3a. it is difficult to determine the stage of rcc accurately only by preoperative imaging for some t1 cases, and previous literature offers conflicting results regarding the associated factors and prognosis for pt3a upstaging (4-8). therefore, risk factors and prognosis of pt3a upstaging are of vital importance for clinical treatment. our study is intended to investigate the risk factors and oncologic outcomes for ct1 rcc upstaging to pt3a, and construct predictive nomogram models of upstaging. as far as we know, the existing predictive model of upstaging are not accuracy enough and no research has included tumor necrosis in ct and tumor edge irregularity in the study. the result of our study found that age, clinical symptom, tumor size, fuhrman grade, tumor necrosis in ct and tumor edge regularity were independent predictors of upstaging and two nomograms were constructed based on them. upstaging was an independent predictor of recurrence free survival (rfs) for ct1 rcc patients. our study included more predictors of upstaging and increased the discrimination and diagnostic efficacy of the nomogram. materials and methods patients and study design the study was approved by the institutional review board of tianjin medical university. a retrospective analysis was performed on 1,376 patients with ct1 rcc who underwent nss or rn from january 2010 to december 2016, and 1,238 (90.0%) patients were followed up. both nss and rn surgery were performed by open or laparoscopy approach. clinical and pathological stages were determined by the surgeon according to the preoperative ct or mri findings, and were confirmed in collaboration with the radiologist and pathologist according to the eighth edition of the tnm classification of the american joint committee on cancer. pt3a was defined as tumor extension into rv (renal vein) or segmental branches, invasion of pelvicalyceal system, or invasion of pf (perirenal fat) and/or sf (sinus fat) but not beyond gerota’s fascia. histological subtypes were assessed by heidelberg classification, and nuclear grading was performed by fuhrman’s grading system. upstaging was defined as the final pathology at pt3a for ct1 rcc patients. recurrence was determined by follow-up imaging and/or presence of pathological specimen. the patients were also classified according to the depth of the tumor, and exophytic tumor was defined when ≥ 50% of the tumor protruded externally from the parenchymal surface. tumor necrosis in ct was defined as low-dense areas of tumor not enhancing during renal contrast-enhanced ct. tumor edge irregularity was defined as follows: a mass with smooth margin but prominent nodules from part of it, which was defined as "lobular” (figure 1a); and a mass with blurred margin, i.e unclear margin between tumor and renal parenchyma (figure 1b); or a mass with completely irregular margin, regardless of the clarity between tumor and renal parenchyma, with completely non-elliptical shape (figure 1c). renal sinus compression was defined as direct contact and compression between tumor and collecting system (figure 1d). evaluation was conducted for patient demographics (sex, age, body mass index (bmi), chronic disease (hypertension, diabetes), clinical symptom (hematuria, abdominal pain, abdominal mass)), type of nephrectomy, imaging (tumor size, tumor necrosis, tumor edge regularity, renal sinus compression) and pathological data (histology, fuhrman grade, surgical margin status, pathological stage), follow-up duration, site and time to recurrence. patients included in the study met the following inclusion criteria (figure 2): (i) treated surgically in the second hospital of tianjin medical university without anti-tumor therapy before surgery; (ⅱ) pathologically diagnosed as rcc; (ⅲ) with complete imaging data of kidney before surgery, including non-enhanced or contrast-enhanced ct, mri, etc.; (ⅳ) tumor size in imaging ≤7cm; (ⅴ) with complete clinicopathological data and survival information. the exclusion criteria included: (ⅰ) pathologically diagnosed as non-rcc; (ⅱ) maximum tumor size in imaging ＞ 7 cm; (ⅲ) suffered from other types of cancer; (ⅳ) with rcc history, bilateral rcc or multiple rccs. (ⅴ) with missing clinicopathological, or imaging data; (ⅵ) underwent renal biopsy or renal radiofrequency ablation without nss or rn. statistical analysis continuous variables were described as mean value ± standard deviation, and categorical variables were described as frequency and percentage. mann-whitney u test was used for the comparison of continuous variables. chi-square and fisher’s probability test were performed for the comparison of categorical variables. chi-square test was used when no expected cell count less than 1 and at most 20% of expected cell counts less than 5 and fisher’s exact probability test was used when expected cell count less than 1. in the logistic regression model, the linear relationship between the continuous independent variables and the dependent variable is verified by the box-tidwell method. all continuous independent variables have a linear relationship with upstaging. univariate and multivariable logistic regression were performed to select independent predictors of ct1 rcc upstaging to pt3a. for the selected predictors, nomogram plots were constructed, and the calibration curve and decision curve analysis were performed. kaplan-meier curves and log-rank test were conducted for survival analysis. the proportional hazard and linearity was validated by cumulative hazard function method for cox regression and all variables meet the proportional hazard and linearity assumption. univariate and multivariable cox proportional hazard models were performed to determine the independent predictor of rfs for ct1 rcc patients. the variable selection algorithm for multivariable logistic and cox regression analyses was ‘forward likelihood ratio’. the follow-up time for survival analysis was from the day of performing the nephrectomy to december 2018. there are 160 rcc patients censored in our study, which accounts for 12.9% of all 1238 rcc patients with survival data. the reasons for censoring include losing contact with patients or their families, patients didn’t cooperate with follow-up survey and withdrew from the retrospective study and patients died of any reasons. we define tumor size as categorical variables when performing logistic and cox regression analysis, and the cut-off value was 4cm for tumor size. furthermore, age were regarded as continuous variables when constructing nomogram predictive model. spss (version 24) and r software (version 3.5.2) were used for data processing, and statistical significance was defined as p <0.05. results patients’ demographics and pathological characteristics of 1,376 ct1 rcc patients, 75 patients (5.5%) were noted with postoperative upstaging to pt3a, and 73 patients had detailed postoperative pathological information. overall, thirty-nine (53.4%) patients were found to have pf invasion, 8 (11.0%) with sf invasion, 1 with collecting system invasion, 21 (28.8%) with renal or segmental rv invasion, and 4 (0.05%) with both rf and rv invasion. the clinical and pathological features of rcc patients by upstaging status are shown in table 1. patients upstaging to pt3a were older (63.08 vs. 57.34 years, p < .001), with larger tumor size (5.24 vs. 3.95cm, p < .001) and higher fuhrman grade (37.3% vs. 7.5%, p < .001). clinical symptoms including hematuria, abdominal pain and abdominal palpable mass were more common in patients upstaging to pt3a (46.7% vs. 25.2%, p < .001). for imaging features, tumor necrosis (40% vs. 19.9%, p<.001), irregular tumor edge (73.3% vs. 59.0%, p < .001) and closer to the collecting system or sinus were more likely to result in upstaging to pt3a. patients upstaged to pt3a were more likely to have undergone rn (92.1% vs. 70%, p < .001) as compared with non-upstaged patients. among the three clinical symptoms, the most common one was abdominal pain which accounts for 14.7% and 26.7% of all non-upstaging and upstaging patients. patients with abdominal pain (p = .006) and abdominal masses (p < .001) differed in non-upstaging and upstaging groups with statistical significance. analysis of predictors for upstaging and rfs univariate and multivariate logistic regression were performed to identify the independent predictors of upstaging, with the results shown in table 2. the fuhrman grade (or = 5.37; 95% ci: 3.05-9.47, p < .001), clinical symptom (or = 2.19, 95% ci: 1.31-3.68, p = .003), tumor size (or = 2.97; 95% ci: 1.60-5.51, p = .001), age (or = 1.05; 95% ci: 1.02-1.07, p = .001), tumor necrosis (or=2.76; 95% ci: 1.62-4.72, p = .001) and tumor edge irregularity (or = 2.55; 95% ci: 1.44-4.52, p = .002) were independent predictors of upstaging. the differences of rfs between different clinical and pathological characteristics were also compared with kaplan-meier method and log-rank test (supplementary figure 1). the result showed that only fuhrman nuclear grade (log-rank, p=0.045) and upstaging (log-rank, p<0.001) were significantly related to the rfs of ct1 rcc patients (figure 3a, b). the 5-year rfs probabilities were 73.3% and 91.1% for upstaging and non-upstaging to pt3a rcc patients. the result of univariate and multivariate cox regression showed that only postoperative upstaging was an independent predictor of rfs for ct1 rcc patients (hr = 2.55; 95% ci: 1.58-4.12, p < .001) (table 3). a total of 1,238 patients (90.0%) were followed up and were included in the survival analysis. the median (iqr) follow-up duration was 51 (35-69) months, during which local recurrence and distant metastasis were observed in 6 (8%) and 16 (21.3%) patients in pt3a group. in contrast, 56 (4.8%) and 86 (7.4%) patients without upstaging were noted with local recurrence and distant metastasis respectively. tumor progression of 1,238 patients was shown in table 4. construction and validation of nomogram model nomogram model (figure 4a) for predicting upstaging to pt3a was constructed based on the result of univariate and multivariate logistic regression. the roc curve was plotted based on the nomogram model, with the c-index of the nomogram of 0.842 (figure 4b). bootstrap selfsampling method and calibration curves were employed to validate the nomogram model. a 1000 time self-sampling was adopted for the calibration curve, and it was be proven that the calibration curve fits well with the ideal curve (figure 4c). the result of decision clinical analysis (figure 4d) also showed that the clinical applicability of the nomogram model was better than that of single factors. considering fuhrman grade is an postoperative parameter for most patients not undergoing renal biopsy before surgery, the logistic regression and nomogram plotting were also performed (figure 5a) with the other 5 preoperative parameters, which showed statistical significance(table 5). the roc curve, calibration curve and decision curve analysis were also performed, and the c-index of the nomogram model with preoperative parameters was 0.806 (figure 5b-d). discussion based on the tnm staging system, pt3a rcc includes tumor extending into renal or renal segmental vein, pf or sf, collecting system but not beyond gerota’s fascia (1). at present, clinical diagnosis and staging of rcc mainly relies on non-enhanced ct combined with contrast-enhanced ct with higher accuracy. it is generally believed that blurred margin of peritumoral fat and irregular tumor nodules infiltrating peritumoral fat indicate pf infiltration for exophytic rcc according to the images. while the irregular margin, unclear boundary of sf or pf and tumor necrosis may imply the possibility of t3a for endophytic rcc (3). previous studies have indicated that the incidence of upstaging to pt3a was from 4.8% to 31% (4,9), while the incidence of upstaging was 5.5% in our current study. the result of our study suggested that age was associated with upstaging, which confirmed the result of the previous study that the risk of upstaging in rcc increased in older patients (10). moreover, clinical symptom was an independent predictor of upstaging and the proportion of symptomatic patients in the upstaging group were significantly higher (11). as the classic triad of flank pain, palpable abdominal mass and visible haematuria is rare (6–10%) and correlates to advanced disease and aggressive histology in rcc, attention should be taken to the risk of upstaging when clinical symptoms occur in rcc patients. the proportion of irregular tumor edge was higher in the upstaging group as an independent predictor, and some studies suggested that the biopsy at irregular tumor edge could confirm the pathological stage during surgery (12-13). one of our previous studies reported that there was statistical significance of overall survival (os) and cancer-specific survival (css) in different tumor growth patterns for rcc patients, including single nodule pattern, multinodule fusion pattern and infiltration pattern . after the comparison of the image characteristics in different tumor growth patterns, it was found that tumor margin for rcc patients with infiltrative growth pattern seemed to be more irregular (14). as a consequence, tumour edge irregularity was defined in details and the relationship was examined between it and upstaging. our study has confirmed tumor edge irregularity as an independent predictor of upstaging. collins and chen et al. found that tumor necrosis in pathology was an independent prognostic factor for rcc patients and had higher probability to infiltrate collecting system, resulting in poor prognosis (15-16). sokhi et al. reported that tumor necrosis in ct, irregular tumor edge and direct contact between tumor and pf or sf could increase the probability of local invasion (3). our study found that tumor necrosis in imaging was an independent predictor for upstaging. previous studies have shown that tumor size was an important predictor of prognosis for pt3a rcc patients and upstaging, which is consistent with the result of our study. all-cause mortality increased by about 8% and cancer specific survival (css) decreased by about 14% for each 1cm increased in tumor size (17-18). many studies have shown that fuhrman grade was closely related to upstaging for rcc patients, and higher fuhrman grade reflected higher tumor invasiveness (6,11). three hundred and ninety (30%) non-upstaging rcc patients received nss, with the positive surgical margin (psm) rate of 1.4%. only 6 (7.9%) patients upstaging to pt3a rcc patients received nss and no psm was found. several studies reported that psm was an independent predictor of upstaging, closely related to poor prognosis (19-21). as psm rate can not be statistically analyzed in our study, it was not included in the nomogram model. the result of our study showed that patients receiving rn had a higher probability of upstaging , but the type of nephrectomy was not an independent predictor of upstaging. ct1 rcc patients who underwent rn were more likely to be detected with pf and sf invasion than nss, leading to a higher probability of upstaging to pt3a. furthermore, this association may be the result of selection bias, since patients with tumors of more“aggressive” features were more likely to undergo rn. many studies reported the correlation between renal scores and upstaging, fuhrman nuclear grade and prognosis. when comparing the relationship between variables in renal scores and upstaging, tumor size and renal mass’s hilar location seem to be more important . however, only tumor size is an independent predictor of upstaging after multivariate logistic regression in our study. the previous study suggested that ct1 rcc patients upstaging to pt3a might increase the risk of local recurrence and be associated with poor prognosis(22-23). lee et al. indicated that patients with ct1 upstaging to pt3 had poorer rfs, css and os as compared with non-upstaging patients(10). lai et al. compared the differences of oncological outcomes between 55 ct1 rcc patients upstaging to pt3a and 374 pt1 non-upstaging rcc patients, and the result showed that upstaging patients had low os and high recurrence rates(24). however, some studies also reported no difference of prognosis between upstaging and non-upstaging rcc patients(9). it was found in our study that upstaging was an independent prognostic factor of rfs for ct1 rcc patients. previous study has developed a nomogram model based on multiple preoperative blood indexes and oncological characteristics with the c-index of 0.756 and 0.712 in the training and validation cohorts. age, the ratio of the tumor maximum and minimum diameter, fibrinogen and tumor size were included in the nomogram model(25). the c-index of our nomograms are 0.842 and 0.806, which is higher than the existing nomogram. we also performed calibration curve and decision curve analysis. furthermore, our study firstly defined the ‘tumor edge irregularity’ in detail on the basis of our previous study.and found that it is an independent predictor of upstaging. physicians could use nomogram plots to predict the patients’ risk of upstaging and prognosis accurately and could also treat patients with higher risk by more aggressive approaches, including removing more peritumoral fat during surgery, performing rn rather than nss, shortening the follow-up interval, etc. there are still limitations in our study. firstly, this is a single-center retrospective study, and multi-center and prospective studies are required to validate the model in the future. secondly, the large difference of sample size between the two groups in our study may reduce the statistical efficiency, yet not affect the result of the statistical inference. thirdly, the follow-up management of rcc patients is not standardized and the duration of follow-up needs to be extended to minimize the missing data. conclusion in conclusion, the rate of ct1 upstaging to pt3a for rcc patients can not be negligible (5.5%), and postoperative upstaging was an independent predictor of rfs. age, clinical symptom, tumor size, fuhrman grade, tumor necrosis in ct and tumor edge regularity were independent predictors for upstaging and two nomogram models were built based on them with excellent discrimination and better clinical application. rn should routinely remove all pf, which may contribute to the diagnosis of pathological staging and may reduce the risk of tumor residual or local recurrence. authors’ contributions (i) conception and design: hdw, gl (ii)administrative support:gl, krw, yrl (iii) provision of study materials or patients:gl, cfl, gxw (iv) collection and assembly of data:hdw, krw, yrl (v) data analysis and interpretation:hdw, gxw (vi) manuscript writing: all authors (vii) final approval of manuscript: all authors huadong wang and keruo wang contributed equally to this work. acknowledgements this study was supported by the the second hospital of tianjin medical university. we also thank patients and their families for participating in this study. funding this study was supported by the tianjin municipal natural science foundation (grant no. 21jcybjc01690). ethical statement the trial was conducted in accordance with the declaration of helsinki (as revised in 2013). the study was approved by committee review board of the second hospital of tianjin medical university and informed consent was taken from all individual participants. conflict of interest the authors declare that they have no competing interests. references 1. williamson sr, taneja k, cheng l. renal cell carcinoma staging: pitfalls, challenges, and updates. histopathology. 2019; 74: 18-30. 2. rinott mizrahi g, freifeld y, klein i, et al. comparison of partial and radical laparascopic nephrectomy: perioperative and oncologic outcomes for clinical t2 renal cell carcinoma. j endourol. 2018; 32: 950-4. 3. sokhi hk, mok wy, patel u. stage t3a renal cell carcinoma: staging accuracy of ct for sinus fat, perinephric fat or renal vein invasion. br j radiol. 2015; 88: 20140504. 4. ramaswamy k, kheterpal e, pham h, et al. significance of pathologic t3a upstaging in clinical t1 renal masses undergoing nephrectomy. clin genitourin cancer. 2015; 13: 3449. 5. ljungberg b, bensalah k, canfield s, et al. eau guidelines on renal cell carcinoma: 2014 update. eur urol. 2015; 67: 913-24. 6. gorin ma, ball mw, pierorazio pm, et al. outcomes and predictors of clinical t1 to pathological t3a tumor up-staging after robotic partial nephrectomy: a multi-institutional analysis. j urol. 2013; 190: 1907-11. 7. nayak jg, patel p, saarela o, et al. pathological upstaging of clinical t1 to pathological t3a renal cell carcinoma: a multi-institutional analysis of short-term outcomes. urology. 2016; 94: 154-60. 8. veccia a, falagario u, martini a, et al. upstaging to pt3a in patients undergoing partial or radical nephrectomy for ct1 renal tumors: a systematic review and meta-analysis of outcomes and predictive factors. eur urol focus. 2021; 7: 574-81. 9. ghanie a, formica mk, wang d, bratslavsky g, stewart t. pathological upstaging of clinical t1 renal cell carcinoma: an analysis of 115,835 patients from national cancer data base, 2004-2013. int urol nephrol. 2018; 50: 237-45. 10. lee h, lee m, lee se, et al. outcomes of pathologic stage t3a renal cell carcinoma upstaged from small renal tumor: emphasis on partial nephrectomy. bmc cancer. 2018; 18: 427. 11. jeong sh, kim jk, park j, et al. pathological t3a upstaging of clinical t1 renal cell carcinoma: outcomes according to surgical technique and predictors of upstaging. plos one. 2016; 11: e0166183. 12. sumie s, kuromatsu r, okuda k, et al. microvascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors. ann surg oncol. 2008; 15: 1375-82. 13. jeong su, park jm, shin sj, et al. prognostic significance of macroscopic appearance in clear cell renal cell carcinoma and its metastasis-predicting model. pathol int. 2017; 67: 610-9. 14. li g, xiao t, wang k, et al. histopathological validation of safe margin for nephronsparing surgery based on individual tumor growth pattern. world j surg oncol. 2021; 19: 255. 15. collins j, epstein ji. prognostic significance of extensive necrosis in renal cell carcinoma. hum pathol. 2017; 66: 108-14. 16. chen l, ma x, li h, et al. influence of tumor size on oncological outcomes of pathological t3an0m0 renal cell carcinoma treated by radical nephrectomy. plos one. 2017; 12: e0173953. 17. li l, shi l, zhang j, fan y, li q. the critical impact of tumor size in predicting cancer special survival for t3am0m0 renal cell carcinoma: a proposal of an alternative t3an0m0 stage. cancer med. 2021; 10: 605-614. 18. lam js, klatte t, patard jj, et al. prognostic relevance of tumour size in t3a renal cell carcinoma: a multicentre experience. eur urol. 2007; 52: 155-62. 19. rothberg mb, paulucci dj, okhawere ke, et al. a multi-institutional analysis of the effect of positive surgical margins following robot-assisted partial nephrectomy on oncologic outcomes. j endourol. 2020; 34: 304-11. 20. ryan st, patel dn, ghali f, et al. impact of positive surgical margins on survival after partial nephrectomy in localized kidney cancer: analysis of the national cancer database. minerva urol nephrol. 2021; 73: 233-44. 21. tellini r, antonelli a, tardanico r, et al. positive surgical margins predict progressionfree survival after nephron-sparing surgery for renal cell carcinoma: results from a single center cohort of 459 cases with a minimum follow-up of 5 years. clin genitourin cancer. 2019; 17: e26-e31. 22. wang hk, zhu y, yao xd, et al. external validation of a nomogram using renal nephrometry score to predict high grade renal cell carcinoma. j urol. 2012; 187: 1555-60. 23. tay mh, thamboo tp, wu fm, et al. high r.e.n.a.l. nephrometry scores are associated with pathologic upstaging of clinical t1 renal-cell carcinomas in radical nephrectomy specimens: implications for nephron-sparing surgery. j endourol. 2014; 28: 1138-42. 24. lai gs, li jr, wang ss, et al. survival analysis of pathological t3a upstaging in clinical t1 renal cell carcinoma. in vivo. 2020; 34: 799-805. 25. cao c, kang x, shang b, et al. a novel nomogram can predict pathological t3a upstaged from clinical t1a in localized renal cell carcinoma. int braz j urol. 2022; 48: 784-94. corresponding author: gang li，md，phd. department of urology, tianjin institute of urology, the second hospital of tianjin medical university, tianjin 300211, china. tel: +86 13752222379 email: 797980@sina.com figure 1. irregular tumor edge of renal cell carcinoma in contrast-enhanced ct (a) a mass with smooth margin and prominent nodules from part of it; (b) a mass with blurred margin; (c) a mass with completely irregular and non-elliptical shape; (d) renal sinus compression in contrast-enhanced ct figure 2. flow diagram of the clinical t1 renal cell carcinoma patients included in the study. figure 3. comparison of recurrence free survival of clinical t1 renal cell carcinoma patients between (a) fuhrman i-ii and fuhrman iii-iv; (b) upstaging and non-upstaging to pt3a. figure 4. (a) nomogram model of ct1 renal cell carcinoma upstaging to pt3a. (b) roc curve of the nomogram model for upstaging. (c) calibration curve of the nomogram model for upstaging. (d) decision curve analysis of the nomogram model for upstaging. figure 5. (a) nomogram model of preoperative patameters for ct1 renal cell carcinoma upstaging to pt3a. (b) roc curve of the nomogram model of preoperative parameters for upstaging. (c) calibration curve of the nomogram model of preoperative parameters for upstaging. (d) decision curve analysis of the nomogram model of preoperative parameters for upstaging. supplementary figure 1. comparison of recurrence free survival of clinical t1 renal cell carcinoma patients between different clinicopathologial and imaging features. table 1. clinical and pathological characteristics of patients by upstage status. variable non-upstaging (n=1301) upstaging (n=75) p-value age (years) 57.34±10.88 63.08±10.17 <0.001 sex (%) (male) 923(70.9) 56(74.7) 0.489 bmi 25.51±3.27 24.68±3.10 0.492 side (%) (left) 672(51.7) 39(52.0) 0.953 smoke (%) 535(41.1) 32(42.7) 0.792 clinical symptom 328(25.2) 35(46.7) <0.001 hematuria (%) 126(38.4) 11(31.4) 0.161 abdominal pain（%） 191(58.2) 20(57.1) 0.006 abdominal mass (%) 11(3.3) 4(11.4) <0.001 hypertension (%) 667(51.3) 42(56.0) 0.425 diabetes (%) 216(16.6) 15(20.0) 0.444 tumor size (cm) 3.95±1.51 5.24±1.35 <0.001 tumor exophytic (%) 605(46.5) 31(41.3) 0.383 nearness to the collecting system or sinus (%) 0.001 ≥7mm 394(30.3) 10(13.3) 4-7mm 326(25.1) 15(20.0) <4mm 581(44.7) 50(66.7) necrosis (%) 259(19.9) 30(40) <0.001 tumor edge (%) (irregular) 767(59.0) 55(73.3) <0.001 renal sinus compression (%) 692(53.2) 46(61.3) 0.171 histology (%) 0.128a clear cell 1136(87.3) 59(78.7) papillary 45(3.5) 3(4.0) chromophobe 52(4.0) 5(6.7) others 68(5.3) 8(10.7) fuhrman grade (%) <0.001 low grade (i-ii) 1204(92.5) 47(62.7) high grade (iii-iv) 97(7.5) 28(37.3) type of nephrectomy (%) <0.001 nss 390(30.0) 6(7.9) rn 911(70.0) 70(92.1) psm (%) 18(1.4) 0(0) bmi, body mass index; psm, positive surgical margin; nss, nephron sparing surgery; rn, radical nephrectomy. afisher’s exact test table 2. univariate and multivariate logistic regression analysis of predictors for upstaging to pt3a univariate analysis multivariate analysis or 95%ci p value or 95%ci p value age (continuous) 1.05 1.03-1.08 <0.001 age (continuous) 1.05 1.02-1.07 0.001 necrosis 2.68 1.66-4.34 <0.001 necrosis 2.76 1.62-4.72 0.001 clinical symptom 2.60 1.62-4.16 <0.001 clinical symptom 2.19 1.31-3.68 0.003 nearness to the collecting system or sinus 0.001 ≥7mm 1(reference) 4-7mm 1.81 0.80-4.09 0.152 <4mm 3.39 1.70-6.77 0.001 tumor edge 0.015 tumor edge 0.001 regular 1(reference) regular 1(reference) irregular 1.92 1.13-3.23 irregular 2.55 1.44-4.52 fuhrman grade <0.001 fuhrman grade <0.001 i-ii 1(reference) i-ii 1(reference) iii-iv 7.40 4.43-12.33 iii-iv 5.37 3.05-9.47 tumor size <0.001 tumor size 0.001 <4cm 1(reference) <4cm 1(reference) 4-7cm 5.56 3.20-9.65 4-7cm 2.97 1.60-5.51 or, odds ratio; 95% ci, 95% confidence interval. table 3. univariate and multivariate cox regression analysis for predictors of recurrence free survival univariate analysis multivariate analysis hr 95%ci p value hr 95%ci p value age (continuous) 1.01 1.00-1.03 0.167 sex 0.800 male 1.05 0.73-1.51 female 1(reference) bmi 0.96 0.91-1.01 0.094 side 0.104 left 0.76 0.55-1.06 right 1(reference) smoke 1.03 0.74-1.43 0.874 clinical symptom 1.25 0.89-1.77 0.204 hypertension 1.08 0.78-1.49 0.665 diabetes 1.09 0.71-1.67 0.690 necrosis 1.38 0.95-1.99 0.092 exophytic 1.02 0.73-1.41 0.921 nearness to the collecting system or sinus ≥7mm 1(reference) 4-7mm 0.96 0.61-1.51 0.855 <4mm 1.03 0.69-1.53 0.903 tumor edge 0.368 regular 1(reference) irregular 1.17 0.83-1.64 renal sinus compression 0.94 0.68-1.30 0.714 histology clear cell 0.77 0.41-1.49 0.428 papillary 0.67 0.23-1.95 0.456 chromophobe 0.52 0.16-1.66 0.269 others 1(reference) fuhrman grade 0.045 fuhrman grade 0.352 i-ii 1(reference) i-ii 1(reference) iii-iv 1.62 1.01-2.60 iii-iv 1.27 0.77-2.09 tumor size 0.537 <4cm 1(reference) 4-7cm 0.90 0.65-1.26 type of nephrectomy 0.727 nss 0.94 0.65-1.36 rn 1(reference) upstage 2.73 1.73-4.31 <0.001 upstage 2.55 1.58-4.12 <0.001 bmi, body mass index; psm, positive surgical margin; nss, nephron sparing surgery; rn, radical nephrectomy; hr, hazard ratio; 95% ci, 95% confidence interval. table 4. tumor progression of 1238 patients non-upstaging （n=1163） upstaging （n=75） tumor progression 142 (12.2) 22 (29.3) local recurrence (%) 56 (39.4) 6 (36.4) distant metastasis (%) 86 (60.6) 16 (72.7) lung 40 10 bone 31 4 retroperitoneal lymph node 21 2 liver 18 1 pancreas 17 0 brain 15 5 table 5. multivariate logistic regression of preoperative parameters multivariate analysis or 95%ci p value age (continuous) 1.05 1.02-1.07 <0.001 necrosis 2.64 1.58-4.40 <0.001 tumor edge 0.002 regular 1(reference) irregular 2.36 1.36-4.09 clinical symptom 2.40 1.46-3.94 0.001 tumor size <0.001 <4cm 1(reference) 4-7cm 5.21 2.96-9.18 or, odds ratio; 95% ci, 95% confidence interval. andrology the effect of autologous temporal fascia graft on erectile function and psychometric properties in peyronie’s disease patients mahmut ulubay*, ekrem akdeniz purpose: the aim of this study is to evaluate the results of the surgical technique used by the authors on peyronie's disease (pd) patients who underwent surgical treatment with a temporalis fascia autograft. materials and methods: patients with normal erectile functions and > 60° penile curvature who underwent surgical treatment with temporalis fascia autografts were included in this retrospective study. the patients were recruited between january 2017 and may 2021. preoperative assessment included the international index of erectile function erectile function (iief-ef) score, penile duplex and penile curvature angle measurement. postoperative self-reports, penile deformity, iief-ef scores and the patient global impression of improvement (pgi-i) questionnaire were assessed every three months. results: twenty-two patients with a mean age of 52.09 ± 6.61 years were included in the study, and no major complications developed in any case. postoperative assessment revealed curvature relapse in seven patients (31.8%), although no intervention was performed on five patients with < 20° curvature. six patients experienced a postoperative decrease in penile length and erectile function was completely preserved in 68.18%. the mean level of satisfaction with surgery measured using the visual analogue scale was 79.13 ± 21.23. conclusion: the temporalis fascia graft, thin and durable graft, is a highly successful therapeutic option in the surgical treatment of pd patients and a good alternative in terms of its cosmetic and functional results. key words: peyronie’s disease; temporalis fascia; autologous graft; curvature. introduction peyronie’s disease (pd) is a benign soft tissue dis-ease characterized by the involvement of the tunica albuginea layer of the penis. although the pathophysiology of the disease has not been fully explained, the most widely accepted theory involves fibroblast proliferation with inflammation caused by recurrent traumas that results in abnormal collagen accumulation.(1) this accumulation of collagen produces fibrous tissue, and this gives rise to pathologies such as pain, penile deformity and sexual dysfunction. estimates of the prevalence of pd in the general population are inconsistent and not entirely reliable, although a number of prevalence studies have been reported from across the world. (2) however, a recent survey from turkey suggests that the prevalence of definitive and probable cases of pd in the country is approximately 5.3%.(3) pd consists of two phases: acute and chronic. the chronic phase is known as the fibrotic phase, during which the pain regresses, hard palpable calcific plaques form and penile deformity stabilizes. it thus results in the formation of an inelastic plaque in the tunica albuginea. although spontaneous recovery has been reported in 3-13% of patients, the manifestation worsens in 30-50%, and these generally require active treatment. however, no change is observed in 47-67% of patients. (4) when the disease becomes stable, surgical treatment is the gold standard in severe cases. surgical treatment for pd can be categorized into three main groups. the department of urology, samsun training and research hospital, samsun university, samsun 55090, turkey. *correspondence: department of urology, samsun training and research hospital, samsun university, samsun 55090, turkey. tel: +90 542 422 51 89, fax: +90 362 277 85 69, e-mail: drmahmutulubay@gmail.com. received july 2022 & accepted december 2022 first involves interventions in which the convex part of the penis exhibiting curvature is shortened, the second involves interventions in which the concave part of the penis with curvature is extended and the third involves penile prosthesis implantation. the choice of surgery depends on the localization of the curvature, the type of deformity, penile length and the presence of erection. tunical shortening procedures are preferred for curvatures < 60° and grafting methods for those > 60°. (5) there are four different graft types for pd: autografts, allografts, xenografts and synthetic grafts.(6) each has its own specific advantages and disadvantages.(7) autologous grafts are very economical, entail a low infection risk and exhibit good integration into host tissue. however, their main disadvantage is the higher morbidity compared to other graft types due to the lengthy surgery times.(8) in light of all these aspects, autologous grafts are recommended in many guidelines in the current age of cost awareness. indeed, the autologous temporal fascia graft is recommended in the guidelines of the european association of urology (eau) and the canadian urological association.(6,9) although many guidelines recommend the temporal fascia graft, to the best of our knowledge, only one study to date has been conducted on it.(10) the aim of this study is to evaluate the surgical and functional efficiency of corporoplasty surgery performed with a temporal graft, and consider its effects on post-surgery sexual functions and postoperative complications. urology journal/vol 20 no. 1/ january-february 2023/ pp. 48-55. [doi:10.22037/uj.v19i.7376] materials and methods study population following the receipt of ethical committee approval (samsun training and research hospital, medical ethics committee, ref no. goka/2020/8/3 date: 05.06.2020), data from patients with no or mild erectile dysfunction (ed) who had undergone surgical treatment at the samsun university, samsun training and research hospital, department of urology involving temporal fascia autografts due to > 60° curvature between january 2017 and may 2021 were evaluated retrospectively. patients with no or mild ed after evaluation based on the international index of erectile function erectile function (iief-ef) domain, but with difficulty in coital activity, with stable pd of > 6 months, with > 60° curvature and with a minimum follow-up period of one year were included in the study. the following criteria were used for patient exclusion: 1. patients with mild to moderate, moderate, or severe ed before surgery; 2. patients with < 60° penile curvature; 3. patients with previous histories of penile surgery; 4. patients with pd durations of less than six months and 5. patients who underwent penile prosthesis implantation, nesbit or plication techniques during surgery. case no. age (years) ca(degree) cd dd (months) st (mins) plaque (i/e) hs (day) follow-up (months) cas 1 42 60 lateral 8 88 i 3 33 no 2 42 75 lateral 12 95 i 3 15 no 3 42 70 dorsal 18 120 i 3 18 no 4 43 80 lateral 14 100 i 3 15 no 5 44 90 ventral 12 84 i 3 24 no 6 48 85 dorsal 15 100 e 3 27 < 20° 7 49 65 ventral 20 90 i 3 21 no 8 50 82 dorsal 18 110 i 3 18 < 20° 9 51 70 dorsal 15 80 i 3 12 no 10 51 75 dorsal 18 90 i 3 18 no 11 52 74 ventral 12 105 i 3 15 no 12 53 67 lateral 15 75 i 3 21 no 13 53 90 dorsal 15 95 i 3 24 < 20° 14 54 95 dorsal 12 80 i 3 15 no 15 55 70 ventral 15 110 e 3 24 50° 16 57 88 dorsal 14 100 e 3 15 <20° 17 58 70 lateral 16 90 i 4 15 no 18 59 95 dorsal 15 100 e 3 18 no 19 59 70 lateral 24 120 i 4 30 60° 20 59 80 dorsal 12 80 i 3 18 no 21 62 80 dorsal 18 90 e 3 18 no 22 63 90 dorsal 15 130 i 3 21 < 20° table 1. patients’ demographics and clinical data abbreviations: ca, curvature angle; cd, curvature direction; dd, disease duration; i/e, incision/excision; hs, hospital stay; st, surgical time; hs, hospital stay; cas, curvature after surgery. case no. iief-ef score before surgery iief-ef score after surgery penile length before surgery (cm) penile length after surgery (cm) 1 26 24 12.4 13 2 25 25 13.1 13.6 3 25 26 12.9 13.9 4 24 25 13.2 14.1 5 25 26 13.7 14.6 6 25 26 13.4 12.9 7 26 26 12.8 13.6 8 25 25 14.1 13.2 9 26 25 13.5 14.4 10 26 26 12.7 13.7 11 24 25 13.8 14.5 12 24 25 13.1 13.9 13 26 24 14.2 13.5 14 24 23 12.3 13.3 15 25 24 12.6 12.6 16 25 26 14 13.5 17 25 26 13.7 14.4 18 24 25 12.6 13.2 19 23 19 12.9 12.4 20 23 24 13.1 13.5 21 23 23 12.4 12.2 22 23 22 13.5 14 abbreviation: iief-ef, international index of erectile function erectile function. table 2. preoperative and postoperative assessment of iief-ef scores and penile length temporal graft and peyronie’s disease-ulubay et al. vol 20 no 1 january-february 2023 49 histories, physical examination results, age, anatomic abnormalities of the urinary tract, drug use and american society of anesthesiologists (asa) scores were recorded. all patients underwent detailed penile examinations after intracavernous 20-μg prostaglandin e1 injection. all patients’ penile lengths were measured before surgery. penile curvature angles were measured using a protractor after penile rigidity was achieved. for penile curvature measurement, a midline beginning from the proximal penile shaft was determined using a ruler. a straight line was then drawn from the starting point of the curve to the glans, such as to intersect with the straight rule in the midline. the degree of curvature was determined by protractor measurements of the angle between the two intersecting lines. plaque location, number and size were noted in detail. before surgery, every patient was alerted to the risks of the intervention and the possibility of postoperative discomfort, recurrence of the curvature, glans hypoesthesia and de novo ed. for cosmetic reasons, temporal grafts were employed only for patients with hair or using hairpieces in daily life. all patients provided detailed forms consenting to the use of their clinical details in scientific research, as required within the scope of our hospital’s regulations. table 3. preoperative and postoperative patient satisfaction case no. satisfaction with surgery patient global impression of improvement willingness to the repeat procedure willingness to recommend the procedure 1 90 very much better yes yes 2 85 very much better yes yes 3 90 much better yes yes 4 90 very much better yes yes 5 95 very much better yes yes 6 90 very much better yes yes 7 85 much better yes yes 8 60 a little better yes yes 9 92 very much better yes yes 10 90 very much better yes yes 11 86 very much better yes yes 12 85 very much better yes yes 13 82 a little better yes yes 14 95 very much better yes yes 15 30 no change no no 16 88 very much better yes yes 17 92 very much better yes yes 18 85 much better yes yes 19 10 much worse no no 20 80 much better yes yes 21 65 a little better yes yes 22 76 much better no no figure 1. the different stages of the operation: (a) artificial erection was achieved; (b) the neurovascular bundle was mobilised; (c) marking of the incision region; (d) an h-shaped incision was made on the plaque; (e) the autograft was filled in the defect area; (f) control of the penis with an artificial erection. temporal graft and peyronie’s disease-ulubay et al. andrology 50 surgical technique after all patients had been given preoperative prophylactic antibiotics, the surgical procedure was performed under general anaesthesia.(11) following degloving with a peripheral incision, artificial erection was achieved by means of saline injection. buck’s fascia was dissected first. following dissection from the tunica albuginea, the neurovascular bundle was then very carefully mobilised widely between the tip and the base of the penis using surgical loupes. the urethra was mobilised in ventral curvature using a parallel incision. an h-shaped incision was made on the plaque, which was either removed or mobilised at the corporal body and left in place. mostly calcified and large plaques were excised (figure 1). simultaneously with the surgical procedure, the temporal fascia to be used as the autograft was removed by an otorhinolaryngologist using a standard technique with an auricular incision and adapted to the donor site area on a back-table. the autograft was then laid with the outer face facing outwards, and the defect area was filled using a waterproof 5-0 prolene suture in both dorsal and ventral curvatures. any leakage or residual curvature was checked by means of intraoperative erection. if complete straightening was not achieved, fixation and additional small plications were applied from the contralateral side of the penis to complete the straightening. if significant curvature was still observed, additional incision and grafting were performed. using surgical loupes, the neurovascular band was protected and buck’s fascia was sutured with 3-0 vicryl. the surgical incision was closed, and an elastic band was stretched and placed firmly around the penis in a vertical manner for sufficient haemostatic pressure. all operations were performed by the same surgeon (m.u.). removal of the temporal fascia graft the temporal muscle was accessed through a 1.5 cm horizontal incision made from the upper border of the auricula 1 cm towards the superior. the temporal fascia was located, and the fibrous tissues attached to it were dissected. the temporal fascia, measuring 4 x 5 cm in figure 2. harvesting the temporal fascia graft: (a) the incision region; (b) harvesting the graft. figure 3. visual analogue scale assessing patient satisfaction with the operation on a scale of 0 – 100. temporal graft and peyronie’s disease-ulubay et al. vol 20 no 1 january-february 2023 51 size, was released from the lower edge and removed with a scalpel (figure 2). the graft was taken to the back-table and laid on a glass plate. the surrounding alveolar and adventitial tissues were cleaned. the donor site was then prepared for the graft, which was subsequently harvested. the graft was then washed in saline solution and made ready for the surgical site. postoperative evaluation the urethral catheter was removed on postoperative day one. antibiotic therapy continued for two days. the elastic bandage was removed 48 hours post-operation. the patients were discharged on day three, and postoperative 0.1 mg ethinyl estradiol tablets were given orally for two weeks in order to prevent undesired reflex erections that might damage the graft sutures. the patients were advised to discontinue ethinyl estradiol therapy two weeks after surgery and to massage the penis by stretching it lightly twice a day for five minutes. starting from the first postoperative month, phosphodiesterase-5 inhibitors (tadalafil 5 mg) were administered twice a week for two months to increase penile vasodilation. patients were told to avoid sexual intercourse for six weeks. patients’ iief-efs, penile deformities, penile lengths and surgery and donor site areas were initially evaluated and recorded one month post-operation and subsequently, once every three months. all patients were asked to complete the iief-ef and patient global impression of improvement (pgi-i) questionnaires. the iief-ef questions 1, 2, 3, 4, 5 and 15 were employed. the six items on the iief-ef include detailed questions concerning erection frequency, erection firmness, penetration ability, maintenance frequency, maintenance ability and erection confidence. participants needed to report sexual activity at least once during the four weeks before responding to the questions. each item was based on a five-point likert scale.(12) each patient’s responses to all six items of the iief-ef were summed to yield a total ef score, ranging from six to 30. scores lower than 26 indicated the presence of ed (22-25 mild ed and 17-21 mild to moderate ed).(13) the pgi-i asks patients to compare their current condition with their preoperative state and is designed to assess the patient's impression of changes in his own condition. answers are given on a seven-point scale scored as 1: very much better; 2: much better; 3: a little better; 4: no change; 5: a little worse; 6: much worse; or 7: very much worse.(14) patient satisfaction with surgery was also measured numerically using a visual analogue scale from 0 (very dissatisfied) to 100 (very satisfied) (figure 3). levels of regret were investigated by asking about willingness to repeat the procedure and willingness to recommend it. data from patients’ final control visits were included in the study. statistical analysis the data were analyzed using the statistical package for social sciences (ibm corp., armonk, ny, usa) version 25 software. nominal data were expressed as frequencies and percentages while continuous data were expressed as mean ± standard deviation. the kolmogorov smirnov test and shapiro-wilk test were applied to determine the normality of distribution of continuous variables. the paired samples t test was employed to evaluate preand postoperative differences. p values < .05 were considered statistically significant. results twenty-two patients with a mean age of 52.09 ± 6.61 years were included in the study. two (9.1%) patients had diabetes mellitus (dm). the participants’ mean asa score was 1.68 ± 0.56, and their mean hospitalisation time was 3.09 ± 0.29 days. the mean disease duration was 15.13 ± 3.37 months, and eight (36.4%) patients had a previous history of unsuccessful medical treatment. none of the patients had previously received intralesional or topical therapies. all penile curvatures exceeded 60°, the mean curvature being 78.22° ± 10.12°. twelve (54.5%) patients had curvature in the dorsal area, six (27.2%) in the dorsolateral area and four (18.2%) in the ventral area. one (4.5%) patient had two plaques, while the rest had a single plaque. one curvature was present in all patients. the entire surgical period was 96.9 ± 14.45 min, including the removal and application of the temporal fascia graft. patient characteristics and outcomes are presented in table 1. six (27.27%) patients developed pain due to erection in the early postoperative period. although patients experienced mild symptoms in both the donor (harvest) and penile regions, such as swelling, numbness and rash that resolved within a few days, none developed severe complications such as wound infection and hematoma, and no graft rejection occurred. the mean follow-up time was 19.77 ± 5.37 months. curvature relapse was observed in seven (31.8%) patients. five of these seven were placed under clinical follow-up, the other two being re-operated. a temporal fascia graft was applied to the patient with a > 60° relapse curvature, while re-operation with nesbit suture was performed on the patient with a 50° curvature. no intervention was performed on the five patients with curvatures < 20°; they received conservative follow-up. when patients with curvatures < 20° were included, our success rate was 90.9%. mean preoperative penile length was 13.18 ± 0.57 cm, compared to 13.54 ± 0.66 cm after surgery. the difference was not statistically significant (p = .059). penile shortening was observed in six (27.2%) patients. no patients experienced decreased penile sensation. the mean preoperative iief-ef value among the patients in this study was 24.63 ± 1.04, compared to 24.54 ± 1.68 at the final check-ups. no significant difference was found between iief-ef values in the preoperative and postoperative periods (p = .831). erectile function was completely preserved in 68.1%. one patient had mild to moderate ed with an iief-ef score of 19 (before surgery it was 23) (table 2). the mean level of satisfaction with surgery measured using the visual analogue scale was 79.13 ± 21.23. analysis of the pg-i questionnaire responses showed that 17 (77.2%) patients felt either “very much” or “much” better. three patients (13.6%) reported being unwilling to repeat the procedure and would not recommend it to others (table 3). discussion the results of this study show that that the autologous temporal fascia graft, provides applicable, reliable and satisfactory results. pd is generally seen between the ages of 50 and 60, and the average age in the present study is similar to that of the previous literature.(6) full recovery occurred in 15 (68.18%) patients in this study and improvement (< 20° curvature, all dorsal, not hintemporal graft and peyronie’s disease-ulubay et al. andrology 52 dering coitus and not requiring medical or surgical treatment) in five (22.72%). two patients (9.1%) required re-operation (one repair with a temporal flap and one nesbit suture). our general success rate was 90.9%. only one previous study involved the temporal fascia. in their study of 12 patients, gelbard and hayden reported a success rate of 100%.(10) in another study of 12 patients in which the autologous fascia lata was used, kargı et al. also reported a success rate of 100%.(15) the present research involved the highest number of cases involving the use of the autologous fascia graft to date, and our general success rate is similar to that of the previous literature. tunical lengthening is one of the three major reconstruction types in penile curvature surgery.(6) this procedure is performed on patients with advanced penile curvature or hourglass deformity, the aim being to minimize the penile shortening. in this procedure, the graft material is an important aspect. the types of grafts most employed in previous studies are dermis grafts, with 718 patients, vein grafts, with 690 patients and buccal mucosa grafts, which are currently highly popular, with 137 patients. the general success rates of these grafts are 81.2%, 85.6% and 94.1%, respectively.(6) two studies were conducted with autologous fascial grafts in the literature, both reporting success rates of 100%. (10,15) this rate is much higher than with other autologous grafts (dermis, venous or buccal mucosa). however, the total number of patients in the studies conducted with autologous fascia are low, in the region of 24. this low number represents a handicap for autologous fascia. despite their low risk of infection and good integration into host tissue, morbidity with autologous grafts is higher than with other types of grafts due to their long surgical times and the involvement of a second surgical site during the operation.(7) thus, autologous grafts have recently fallen from favour since their extended surgery time increases morbidity.(16,17) in the present study, the mean total surgery time was 99.68 ± 17.92 min. a simultaneous operation was performed by an experienced otorhinolaryngologist in order to reduce the operative time, with a 4 x 5 cm temporal fascia flap being made ready for the donor site prior to preparation of the surgical bed. this bestowed a major advantage in terms of time. the average operative time in a study conducted with collagen sheets was 79 min.(18) average surgical times were 130 min in a study using lingual mucosa, 115 min in a study involving buccal mucosa, 66 min in a study using xenograft pericardium and 130.5 minutes in a study using autologous saphenous vein grafts, while studies using xenograft small intestinal submucosa (sis) have reported average surgical times of 151 to 165 min.(19–23) simultaneous otorhinolaryngologist support during the operation significantly reduced our operative time, with the entire duration being approximately that of non-autologous grafts. despite their high functional and anatomic success rates, autologous grafts can also cause long-term complications such as de novo ed, penile shortening, permanent or temporary penile curvature and short-term complications such as hematoma, contraction and penile desensitization in the graft area, although the incidences are low.(24) six patients in the present study experienced pain due to erection in the early postoperative period, although no specific analgesic therapy was administered. no severe complications such as wound infection in either the donor or surgical sites or hematoma occurred in any patients, and no graft rejection was observed. in their study involving the buccal mucosa, zucchi et al. observed no complications in the graft or surgical area, and the early postoperative period complications detected were similar to the results of the present study.(25) consistent with the present study, salem et al. observed no complications other than swelling and numbness in their lingual mucosa-based study.(19) in the only study conducted using temporal fascia in the literature, gelbard and hayden reported no major complications such as wound infection or hematoma in either the graft or surgical areas. pain resulting from erection did develop in their patients, although this resolved in the second postoperative week.(10) kargı et al. reported no complications in their study using autologous fascia lata.(15) in a study using sis material, valente et al. reported infective hematoma in one patient and postoperative pain resulting from erection in seven.(22) kayıgil et al. compared the effects of acellular matrix and autologous vein grafts and reported major complications such as haemorrhage and infection. (21) early complication rates for both autologous and non-autologous grafts are very low and similar to one another. none of the patients in the present study exhibited postoperative decreased penile sensation. furthermore, despite the low mean postoperative iief-ef values, there was no significant difference between preoperative and postoperative iief-ef evaluations. we attribute the decreased penile sensation in this study to the fact that we were very cautious during the neurovascular bundle dissection, surgical loupes were employed during the operation and no vascular injury occurred. postoperative penile shortening was noted in six patients. objective measurements revealed a postoperative penile shortening rate of 27.2%. currently, the most widely used grafts are made of allograft or xenograft pericardium or thin sis grafts made of type 1 collagen-based xenogeneic graft.(6–10) although the reported success rate for pericardium grafts in the literature is 56–100%, postoperative ed rates are 30–63% and penile shortening rates are between 0% and 33%. the equivalent rates for sis grafts are 55.6–100%, 0–55.6% and 0–66%, respectively.(6) in the present study, the success rate was 90.9%, the ed rate was 31.8% and the penile shortening rate was 27.2%. although our patient number was relatively low and the values cited for the other two grafts were derived from meta-analyses, these values nevertheless show that the temporal fascia graft has a level of success capable of competing with the other two grafts. the mean level of satisfaction with surgery measured using the visual analogue scale was 79.13 ± 21.23. analysis showed that 77.2% of patients felt “much better” compared to the preoperative period, although 13.6% reported being unwilling to repeat the procedure and that they would not recommend it to others. valente et al. reported an unwilling to repeat the procedure of 21.4% in their study involving a similar number of patients as the present research.(22) from that perspective, this study’s findings are consistent with valente et al.’s. the use of non-autologous grafts has increased as they do not cause secondary wounds and due to features such as easy availability, decreased operative time, easy temporal graft and peyronie’s disease-ulubay et al. vol 20 no 1 january-february 2023 53 use and low morbidity.(18) however, their principal disadvantage is their high cost.(16) the average price of biocompatible grafts commonly used in europe is between €500 and €1000, although with the use of postoperative vacuum devices, this can be as high as €1500–2000.(25) autologous grafts appear to represent a more appropriate option since they contain autologous tissue, pose no risk of foreign body reaction or allergy, are easily available during surgery and do not entail additional economic costs. although their principal disadvantage is surgical time, this can be eliminated with intraoperative support from other branches. buccal grafts can cause swelling in the mouth, numbness, and difficulty in chewing in the postoperative period. saphenous vein grafts can lead to prolonged lymphatic loss and lymphocele. tunica albugenia grafts are suitable for small-size, but not for larger defects. they also complicate future penile surgeries, such as prostheses. in the light of these features of autologous grafts, the temporal fascia offers significant advantages over other autologous grafts. the greatest advantage of temporal fascia grafts over allografts is their low cost, and that no immunological reaction develops to the temporal fascia. there are several limitations to this study, particularly its retrospective nature and the relatively low patient number. in addition, the important clinical factor of quality of life was not included in the study since it was not recorded regularly in the preoperative period. furthermore, significant factors such as postoperative levels of regret over surgery and partner satisfaction were not evaluated. finally, our follow-up period was relatively short, and our complication rates may possibly change over the long term. we think that longer follow-up studies with larger numbers of patients are needed to confirm the reliability of our findings. conclusions the temporal fascia is very easy to remove surgically, easy to manipulate due to its hard and thin membrane-shaped appearance, and can also quickly be prepared for the donor site area on the back table. we therefore conclude that, with its high success and low complication rates, the temporal fascia is the most suitable option for patients with mild ed but with large plaques and severe deformity. but prospective studies with a larger population and longer follow-up are needed to validate such findings. conflict of interest there is no conflict of interest in this study. references 1. chung e, gillman m, tuckey j, la bianca s, love c. a clinical pathway for the management of peyronie's disease: integrating clinical guidelines from the international society of sexual medicine, american urological association and european urological association. bju int. 2020;126(suppl 1):127. 2. stuntz m, perlaky a, des vignes f, kyriakides t, glass d. the prevalence of peyronie's disease in the united states: a population-based study. plos one. 2016;11(2):e0150157. 3. kadioglu a, dincer m, salabas e, culha mg, akdere h, cilesiz nc. a populationbased study of peyronie's disease in turkey: prevalence and related comorbidities. sex med. 2020;8:679–85. 4. rice pg, somani bk, rees rw. twenty years of plaque incision and grafting for peyronie’s disease: a review of literature. sex med. 2019;7:115e128. 5. bilgutay an, pastuszak aw. peyronie’s disease: a review of etiology, diagnosis, and management. curr sex health rep. 2015;7:117–31. 6. salonia a, bettocchi c, carvalho j, et al. european association of urology guidelines on sexual and reproductive health. https://uroweb.org/guideline/sexual-andreproductive-health/#8. access: 1 may 2021. 7. bajic p, siebert al, amarasekera ca, miller ch, levine la. comparing outcomes of grafts used in peyronie’s disease surgery: a systematic review. curr sex health rep. 2020;12:236–43. 8. brannigan re, kim ed, oyasu r, mcvary kt. comparison of tunica albuginea substitutes for the treatment of peyronie’s disease. j urol. 1998;159:1064–8. 9. bella aj, lee jc, grober ed, et al. 2018 canadian urological association guideline for peyronie’s disease and congenital penile curvature. can urol assoc j. 2018;12:e197209. 10. gelbard mk, hayden b. expanding contractures of the tunica albuginea due to peyronie’s disease with temporalis fascia free grafts. j urol. 1991;145:772–6. 11. rosenhammer b, sayedahmed k, fritsche hm, burger m, kübler h, hatzichristodoulou g. long-term outcome after grafting with small intestinal submucosa and collagen fleece in patients with peyronie's disease: a matched pair analysis. int j impot res. 2019;31(4):25662. 12. vickers aj, tin al, singh k, dunn rl, mulhall j. updating the international index of erectile function: evaluation of a large clinical data set. j sex med. 2020;17(1):12632. 13. yıkılmaz tn, öztürk e, hamidi n, selvi i̇, başar h, peşkircioğlu l. evaluation of sexual dysfunction prevalence in infertile men with non-obstructive azoospermia. arch ital urol androl. 2020;91(4):241-44. 14. viktrup l, hayes rp, wang p, shen w. construct validation of patient global impression of severity (pgi-s) and improvement (pgi-i) questionnaires in the treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. bmc urol. 2012;12:30. 15. kargi e, yeşilli c, hoşnuter m, akduman b, babuccu o, mungan a. relaxation incision and fascia lata grafting in the surgical correction of penile curvature in peyronie's disease. plast reconstr surg. 2004;113(1):254-9. 16. garcia-gomez b, ralph d, levine l, et al. temporal graft and peyronie’s disease-ulubay et al. andrology 54 grafts for peyronie's disease: a comprehensive review. andrology. 2018;6(1):117-26. 17. hatzichristodoulou g. novel approaches and new grafting materials in peyronie's disease reconstructive surgery. int j impot res. 2020;32(1):37‐42. 18. hatzichristodoulou g, fiechtner s, gschwend je, kübler h, lahme s. suture-free sealing of tunical defect with collagen fleece after partial plaque excision in peyronie’s disease: longterm outcomes of the sealing technique. eur urol suppl. 2017;16:e2152. 19. salem e, elkady eh, sakr a, et al. lingual mucosal graft in treatment of peyronie disease. urology. 2014;84:1374–7. 20. fabiani a, servi l, fioretti f, et al. buccal mucosa is a promising graft in peyronie's disease surgery. our experience and a brief literature review on autologous grafting materials. arch ital urol androl. 2016;88(2):115‐21. 21. kayigil o, ozcan mf, cakici ou. the comparison of an acellular matrix graft with an autologous venous graft in the surgical treatment of peyronie's disease. andrologia. 2019;51(1):e13168. 22. valente p, gomes c, tomada n. small intestinal submucosa grafting for peyronie disease: outcomes and patient satisfaction. urology. 2017;100:117–24. 23. cosentino m, kanashiro a, vives a, et al. surgical treatment of peyronie’s disease with small intestinal submucosa graft patch. int j impot res. 2016;28:106–9. 24. chung e. penile reconstructive surgery in peyronie disease: challenges in restoring normal penis size, shape, and function. world j mens health. 2020;38(1):1-8. 25. zucchi a, silvani m, pastore al, et al. corporoplasty using buccal mucosa graft in peyronie disease: is it a first choice?. urology. 2015;85(3):679-83. temporal graft and peyronie’s disease-ulubay et al. vol 20 no 1 january-february 2023 55 female urology automated urine particle analyzer uf-1000i can pre-estimate the treatment response of women’s uncomplicated urinary tract infections to antibiotics stephen shei-dei yang1, yi-sheng chen1, chun-chun yang2, shang-jen chang1* purpose: to evaluate the ability of bacterial scatter diagrams generated from the automated urine particle analyzer (uf-1000i, sysmex, kobe, japan) to pre-estimate the treatment efficacy of oral cefalexin in treating women with uncomplicated urinary tract infection (uuti). materials and methods: over 3 years, women 20-80 years old with symptoms suggestive of uuti (urinary tract infection symptoms assessment symptom score, ,utisa > 3) and bacteriuria (bacterial count ≥ 100/ul) were enrolled. after informed consent, patients took cephalexin 500mg 4 times/day for 7 days. the voided urine specimens were classified into rods or cocci/mixed group automatically through the built-in software of the uf1000i. patients were followed up with utisa on the 3rd day after treatment and returned to the clinic on the 7th day and followed for additional utisa and urine analysis. symptom and laboratory improvement were defined as utisa < 4 and bacterial count < 100/ul, respectively, on the 7th day. results: of 99 women (age: 49.91 ±15.32 years) eligible for analysis, 80 were classified as having urine that contained rods and 19 as cocci/mixed. symptom improvement was observed in 62 women in the rods group and 11 women in the cocci/mixed group (p = 0.08). laboratory improvement was noted in 64 women in the rods group and 10 women in the cocci/mixed group (p = 0.01). on day 7, treatment success with both symptom and laboratory improvement was more observed in rods than in cocci/mixed group (61.3% vs. 26.3%, p < 0.01). conclusion: the automatic urine particle analyzer can pre-estimate the treatment response of antibiotics in women with uuti. keywords: uncomplicated urinary tract infection; diagnosis; laser flow cytometry; fully automated urine particle analyzer; sysmex uf-1000i introduction urinary tract infection (uti) due to bacteria is one of the most common infections among humans, particularly in women. more than two-thirds of women will experience at least one episode of uti during their lifetime(1). although some experts suggested not using antibiotics to treat women’s uuti, empirical treatment has been frequently suggested to treat women with uncomplicated uti (uuti)(2). in taiwan, guidelines for treating utis suggest that nitrofurantoin, trimethoprim-sulfamethoxazole, first and second generation cephalosporin and quinolone are all reasonable choices for first line treatment(3). ampicillin, ampicillin/sulbactam, fluoroquinolone are regarded as alternative treatment choices. previous studies showed that gram negative rods are the major pathogens causing urinary tract infection and have lower susceptibility rates for trimethoprim-sulfamethoxazole (49%), ampicillin (30%), ampicillin/sulbactam (34%), but high susceptibility rate (81%) for cefazolin(4). hence, cephalexin was chosen as the first line empirical antibiotic. 1division of urology, taipei tzu chi hospital, taipei taiwan, and tzu chi university, hualien, taiwan. 2division of general laboratory, taipei tzu chi general hospital, new taipei, taiwan *correspondence: division of urology, taipei tzu chi hospital, taipei taiwan, 289 jianguo rd., sindian district, new taipei city, 231, taiwan. tel: +886-6628-9779 ext: 5713, fax: +886-6628-9009, e-,mail: krissygnet@gmail.com received october 2020 & accepted august 2021 however, treatment based on clinical symptoms without urinalysis or urine culture may lead to unnecessary use of antibiotics, increasing drug resistance to antibiotics and reduce response rate of treatment. the automated urine particle analyzer, sysmex uf-1000i (sysmex, kobe, japan), has served as an alternative to the expensive, time consuming and labor-intensive urine culture(5,6). the sysmex uf-1000i, designated for analyzing urine sediment at a throughput of 100 samples per hour, can rapidly quantify urine particles, including bacteria, white blood cells (wbcs), red blood cells (rbcs), epithelial cells and casts(7). using a specific reagent and dye in a separated analytical channel, the sysmex uf-1000i provides a fast, effective and reliable screening test by detecting and quantifying bacteria before culture. previous studies showed that the uf-1000i could predict significant bacterial growth in urine culture based on the bacterial count(8-10). the automated urine particle analyzer can also classify the morphology of bacteria in urine specimen into gram negative rods or cocci/mixed growth in the pre-analytical phase of urine culture with acceptable sensitivity and urology journal/vol 18 no. 6/ november-december 2021/ pp. 670-674. [doi: 10.22037/uj.v18i.6514] specificity(10). because gram negative rods have higher sensitivity to cephalexin, the identification of the morphology of bacteria (gram negative rods or cocci/mixed growth) in specimen thorough the automated urine particle analyzer may help clinicians pre-estimate the treatment response of uti in the clinical settings. therefore, we performed a prospective study to evaluate the treatment efficacy of cefalexin(3) in the management of uncomplicated uti in community dwelling women and monitored the course of symptoms change. finally, we could determine the ability of automated urine particle analyzer in pre-stimating the treatment response. materials and methods from july 2016 to june 2019, 188 women who visited the outpatient clinic in our department with symptoms suggestive of uti (frequency, urgency, dysuria, sense of incomplete emptying, suprapubic pain, low back pain and hematuria) were invited to join our study. the participant were asked to complete the urinary tract infection symptoms assessment (utisa) questionnaire(11). the utisa(appendix 1, 2), a valid self-admi1nistered questionnaire, has 14 items, with scores for each item ranging from 0 to 3. among the 14 items, seven were related to severity of symptoms and seven were related to quality of life. patients with an utisa symptom score of > 3 were considered to have uti and were enrolled to the study. then, they were asked to complete a questionnaire including baseline characteristics (age, menopause status, frequency of uti within 1 year before visit, previous abdominal surgery history, sexually active status in the past year, pregnancy status). the participants were asked to collect a mid-stream urine sample under the direction of the study nurse to lower the risk of specimen contamination. thereafter, 10 ml of the retrieved urine sample were put into a centrifuge tube (sy, shih-yung medical instruments co., ltd, taipei, taiwan) for automated urine particle analysis within 30 minutes after collection of the specimen. the bacteria were then classified and counted based on their size and staining characteristics. the automated urine particle analyzer generated the scatter diagram pattern with forward scatter (b_fsc, bacteria size) and fluorescent light intensity (b_flh, the nucleic acid content) emitted from each bacterium. for each sample with a bacteria count >100 bacteria/μl, the bacterial scatter diagram was classified as either rods or cocci/mixed by the software (sysmex uf-1000i; toa medical electronics, kobe, japan). the remaining sample was sent for quantitative urine culture using a 1μl inoculation loop and the commercial chromogenic agar medium (cps® id3, biomerieux, i′etoile, france). the culture plates were aerobically incubated at 35℃ for 18-24h and the quantification in cfu/ml was calculated after multiplying the dilution factor and the colonies on the agar plate. in the study, urine specimens with the growth of two or more species of bacteria without a dominant one were considered to be contaminated or mixed growth. statistical analysis data were expressed as mean standard deviation and analyzed by medcalc statistical software version 19.1 (medcalc software, ostend, belgium; https:// www.medcalc.org; 2019). the comparisons of demographic and voiding parameters between groups were table 1. determination and comparison of demographic variables in the two groups. menopause (+) n = 55 menopause(-) n = 44 p value age (years, ±sd) 60.6 ± 7.8 34.1±10.0 p<0.001 diabetes mellitus, n (%) 2.4% 18.2% p=0.042 childbirth history, n (%) 35.7% 87.3% p<0.001 abdominal surgery history, n (%) 21.5% 33.6% p=0.109 uti history in the recent 1 year (%) 50.5% 50.7% p=0.80 day 0 utisa score (mean±sd) 10.41 ± 3.73 11.09 ± 4.01 p=0.383 bacterial growth of urine specimens number (n) uf1000i classification gram (−) rods escherichia coli ≥ 105 cfu/ml 56 rods=53/cocci/mixed=3 103‐105cfu/ml 10 rods=6/cocci/mixed=4 klebsiella spp. ≥ 105 cfu/ml 3 rods=3 103‐105 cfu/ml 1 rods=1 proteus mirabilis ≥ 105 cfu/ml 5 rods=5 103‐105 cfu/ml 1 rods=1 citrobacter spp. ≥105 cfu/ml 2 rods=2 gram (+) cocci 7 streptococci spp. 3 cocci/mixed=2/rods=1 staphylococci spp. 3 cocci/mixed=1/rods=2 enterococci spp. 1 rods=1 group b streptococci 1 cocci/mixed=1 lactobacillus species 2 cocci/mixed=1/rods=1 two bacteria growth e.coli > 105+streptococcus sanguinis> 105 1 rods=1 mixed growth ≥105 cfu/ml 5 cocci/mixed=4/rods=1 103‐105 cfu/ml 5 cocci/mixed=3/rods=2 table 2. the sensitivity of uf1000i for specific bacteria species. automated urine particle analyzer and uti-yang et al. female urology 544 vol 18 no 6 november-december 2021 671 performed with an independent samples t-test (continuous demographic variables), chi-squared test (nominal data), and mann–whitney u-test (ordinal data). the serially measured follow up data between groups were compared with mixed model. a p-value of <0.05 was considered statistically significant. results there were 10 women who quited after enrollment without follow up data, 2 had elevated post-void residual urine, 4 without first urinalysis, and 23 women noncompliant to medication were excluded for analysis. we also excluded 40 (27.39%) women with a bacterial count <100/μl for analysis. the baseline characteristics of the included patients (n=99) are shown in table 1. none of the participants were pregnant at the time. mean age and utisa symptom scores on day 0 of the analyzed participants were 49.1 ± 15.9 years and 10.8 ± 4.0, respectively. of the 99 participants, 44% reported to be in menopause. the mean age between rods and cocci/mixed growth group were not comparable (49.6 ± 15.9 vs. 46.5 ±16.2, p = 0.45). the results of the bacterial growth in urine culture and the agreement between the uf-1000i classification (rods or cocci/mixed growth) and the results of the urine culture is listed in table 2. the analyzed specimens included 10 gram-positive bacteria (3 streptococci spp., 3 staphylococci spp., 1 enterococci spp., 1 group b streptococci, and 2 latobacillus species), and 11 specimens with two bacteria species or more that were regarded as mixed growth. for the gram-negative bacteriae, there were 66 escherichia coli, 4 klebsiella spp, 6 proteus mirabilis and 2 citrobacter spp. (table 2) the drug resistance to specific antibiotics of gram negative bacteria were listed in the supplement. the mean utisa symptom score improved from 10.8 ± 4.0 on day 0 to 2.4 ± 3.4 on day 7 (p < 0.01). of the 99 women, 80 (75.5%) had urine with rods and 19 (17.9%) had urine with cocci/mixed. symptom improvement (utisa<4 om day 7) was observed in 62 (77.5%) and 11 (57.89%) women with rods and cocci/mixed, respectively (p = 0.08). the comparisons of utisa over variable days of follow up between cocci/mixed and rods groups are shown in figure 1. the symptom improvement (utisa) in the rods group was not significantly better than the cocci/mixed group. (p = 0.08) laboratory improvement was noted in 64 (80.0%) and 10 (52.63%) women with rods and cooci/mixed, respectively (p = 0.01). on day 7, treatment success with both symptom and laboratory improvement was observed in 49/80 (61.3%) and 5/19 (26.3%) of rods and cocci/ mixed group, respectively. (p < 0.01). discussion this is the first prospective clinical study to evaluate the clinical usefulness of the automated urine particle analyzer (uf-1000i, sysmex, kobe, japan) in predicting treatment response of women’s uuti to antibiotics. the symptom and laboratory improvement rate on day 7 among all included patients were 73.7% and 74.7%, respectively. through the application of the scatter diagram generated from the uf-1000i, we may predict the treatment success of antibiotics in managing uuti in women. women in the cocci/mixed group had significantly lower laboratory (52.6% vs. 80.0%, p = 0.01) and overall treatment success rate (26.3% vs. 61.3%, p < 0.01). the symptom improvement rate was higher, but not statistically significant, in the rods group (77.5% vs. 57.89%, p = 0.08). the diagnosis of uuti is based on clinical symptoms and bacteriuria. in the clinic, we routinely checked urine analysis for patients with uuti for bacteriuria. the scatter diagram generated through the uf-1000i is automatically analyzed with the built-in software of the uf1000i and then classified into rods or cocci/mixed growth. therefore, the application of the scatter diagram did not lead to additional analysis time or costs. therefore, we recommended the routine use of scatter diagrams generated from uf-1000i as a diagnostic tool for uuti because of significant difference in overall treatment success rate between rods and cocci/ mixed groups figure 1. the change of symptom scores in subgroup patients. automated urine particle analyzer and uti-yang et al. female urology 672 infectious diseases society of america (idsa) and the european society for microbiology and infectious diseases suggest nitrofurantoin, sulfamethoxazole / trimethoprim and fosfomycin as first-line antibiotics for management of uncomplicated symptomatic urinary tract infections based on the availability, allergy history and tolerance(12). since the resistance rate of the only available first-line antibiotics in taiwan is sulfamethoxazole/trimethoprim which is associated with more than 20% resistance in our local area (supplement), we empirically used cephalexin for managing uuti in community-dwelling women. the resistance rate of e. coli to cefazolin is 15% in our community patients (supplement) and the other community in taiwan(13). overall, the symptom (utisa < 4 om day 7) and laboratory improvement (bacteria count <100 bacteria/μl day 7) in patients treated with cephalexin were observed in 73 (73.7%) and 74 (74.7%) patients, respectively. the overall treatment success with both symptom and laboratory improvement was observed in 54 (54.5%) patients. the results supported the suggestions of idsa that clinical cure (i.e. uti symptom resolution) is expected within three to seven days after antibiotics treatment(12) (figure 1). it is reasonable to repeat a urine tests if uti symptoms persist beyond seven days. this will minimize unnecessary treatment of patients with persistent uuti symptoms. urinary tract infection is ambiguously defined as lower urinary tract symptoms with positive urine culture without clear definition regarding the specific symptom and clear cut-off point for bacterial count(14). in this study, we adopted the criteria of utisa >3 as positive symptoms and bacteria count >=100/μl as having bacteriuria(9). utisa > 3 is associated with a good sensitivity (87.0%) and specificity (93.1%) for differentiating women with uuti from control(11). empirical treatment with antibiotics in women with lower urinary tract symptoms may be not advised. a significant proportion (40/174, 23.0%) of women with symptoms suggestive of uuti visiting urological clinics actually had low bacterial count which suggested that the symptoms may not be due to bacterial infection. previous studies had demonstrated the efficacy of the uf-1000i in rapid diagnosis of bacteriuria. a meta-analysis reviewed the related studies to determine the capabilities of the uf-1000i in detecting bacteriuria. the pooled sensitivities were 87% and specificities were 60% for bacteriuria(15). various cutoff points of bacterial count had been reported in uti screening and the variability could be attributed to different laboratories, patient populations, and the type of specimens. the bacterial scatter patterns generated from the bacterial laser diagram are classified when the bacteria count is > 100 bact/microliter which is in line with the results of the study by de rosa et al using bacterial count of 100/μl as cutoff point (sensitivity: 96.5%, specificity: 86.7%,(9)) the usefulness of routine urine culture in female patients with uuti has been questioned because voided urine culture may not perfectly reflect the true bacteriology in the bladder, especially for non-e coli related cystitis(16). since urine culture is expensive, labor-intensive, time-consuming, and prone to have false results, the uf-1000i provides cost-effective screening within 1 minute after urine sampling (100 samples/hour). in busy outpatient clinics, this means a real-time reporting that could reduce the blind initiation of antibiotics, and thus prevent unnecessary expenditure and drug treatment. the analyzed specimens included 8 gram-positive bacteria (3 streptococci spp., 3 staphylococci spp., 1 enterococci spp., and 1 group b streptococci.), and 11 specimens with two bacteria species or more that were regarded as mixed growth. since most cocci/mixed bacteria by the uf-1000i were skin flora or gram bacteria resistant to cephalexin, avoiding use of antibiotics or choosing alternative antibiotics targeted at gram positive bacteria may be helpful for clinical practice. however, the evidence supporting the use of alternative antibiotics require further studies. there are several limitations to our study. although the study is a prospective study evaluating the efficacy of the uf-1000i in predicting treatment outcomes of uuti, a major limitation is that there was limited number of patient samples tested. the limited number of participants failed to show significant difference in utisa scores improvement between rods and cocci/mixed gwoth cohorts. despite the limited number of participants, there existed significant differences in treatment response between rods and cocci/mixed growth group. second, the study was done at a single institution. further studies are still warranted to evaluate the generalizability of the u-1000i in other institutions and populations. further studies enrolling more patients in different areas with different antibiotics are warranted to prove the efficacy and exclude possible confounding factors. however, the strength of the study lies in that we used an objective parameter (bacterial count) and subjective symptom score (utisa) at initial visit and follow up to validate the predictive ability of the u-1000i. conclusions women who had uuti with urine samples exhibiting rods on automatic urine particle analyzer would have better treatment response to the use of first line antibiotics. based on the current findings, the uf1000i can help clinicians pre-estimate the treatment response of uuti in women. conflict on interest the authors declare to have no conflict of interest. acknowledgements the authors would like to thank sysmex taiwan for their technical assistance for providing the unlisted built-in software that could automatically classify the bacterial scatter diagram as either rods or cocci/mixed. this study was supported by a grant from the taipei tzu chi hospital, buddhist tzu chi medical foundation (grant no. tcrd-tpe109-rt-3). references 1. foxman, b., epidemiology of urinary tract infections: incidence, morbidity, and economic costs. dis mon, 2003. 49: p. 53-70. 2. whiteside, s.a., et al., ibuprofen lacks direct antimicrobial properties for the treatment of urinary tract infection isolates. j med microbiol, 2019. 68: p. 1244-1252. 3. guidelines for antimicrobial therapy of urinary tract infections in taiwan. j microbiol female urology 546 automated urine particle analyzer and uti-yang et al. vol 18 no 6 november-december 2021 673 immunol infect, 2000. 33: p. 271-2. 4. chen, l.f., et al., clinical characteristics and antimicrobial susceptibility pattern of hospitalized patients with community acquired urinary tract infections at a regional hospital in taiwan. healthc infect, 2013. 19: p. 20-25. 5. jolkkonen, s., et al., screening of urine samples by flow cytometry reduces the need for culture. j clin microbiol, 2010. 48: p. 3117-21. 6. gutierrez-fernandez, j., et al., performance of the sysmex uf1000i system in screening for significant bacteriuria before quantitative culture of aerobic/facultative fast-growth bacteria in a reference hospital. j appl microbiol, 2012. 113: p. 609-14. 7. monsen, t. and p. ryden, flow cytometry analysis using sysmex uf-1000i classifies uropathogens based on bacterial, leukocyte, and erythrocyte counts in urine specimens among patients with urinary tract infections. j clin microbiol, 2015. 53: p. 539-45. 8. geerts, n., et al., urine flow cytometry can rule out urinary tract infection, but cannot identify bacterial morphologies correctly. clin chim acta, 2015. 448: p. 86-90. 9. de rosa, r., et al., evaluation of the sysmex uf1000i flow cytometer for ruling out bacterial urinary tract infection. clin chim acta, 2010. 411: p. 1137-42. 10. yang, c.c., et al., rapid differentiation of cocci/mixed bacteria from rods in voided urine culture of women with uncomplicated urinary tract infections. j clin lab anal, 2017. 31:e22071.. 11. chang, s.j., et al., reliability and validity of a chinese version of urinary tract infection symptom assessment questionnaire. int braz j urol, 2015. 41: p. 729-38. 12. anger, j., et al., recurrent uncomplicated urinary tract infections in women: aua/ cua/sufu guideline. j urol, 2019. 202: p. 282-289. 13. yi-te, c., et al., urinary tract infection pathogens and antimicrobial susceptibilities in kobe, japan and taipei, taiwan: an international analysis. j int med res, 2019: p. 300060519867826. 14. finucane, t.e., 'urinary tract infection' and the microbiome. am j med, 2017. 130: p. e97-e98. 15. shang, y.j., et al., systematic review and meta-analysis of flow cytometry in urinary tract infection screening. clin chim acta, 2013. 424: p. 90-5. 16. donnenberg, m.s., uncomplicated cystitis-not so simple. n engl j med, 2013. 369: p. 1959-60. automated urine particle analyzer and uti-yang et al. female urology 674 1 why discovery of psa was not granted a nobel prize? author: oktay özman affiliation: urology department, the netherlands cancer institute, antoni van leeuwenhoek hospital, amsterdam, the netherlands oktay özman, corresponding author the netherlands cancer institute antoni van leeuwenhoek hospital, plesmanlaan 121, 1066 cx amsterdam, mobile: +31 6 23 03 54 02, e-mail: ozmanoktay@hotmail.com keywords: prostate-specific antigen, prostate cancer, nobel prize at the time, i was composing my thesis concerning prostate-specific antigen (psa) on diagnosis of prostate cancer (pca) and realized that psa, a unique biomarker ever affecting clinical practice of a commonly seen cancer comprehensively and radically, has took for granted for decades. yet, although being considered a groundbreaking discovery, psa was not awarded a nobel prize. i aimed to draw attention to psa discovery's lack of nobel prize acknowledgement despite its significance for pca clinical practice. the committee has some reasons for not considering discovery of psa for the prize. instead of therapeutic applications, the nobel prize is often given for advances that have a substantial influence on basic science. but still, in 2003, they rewarded the developments concerning magnetic resonance imaging1. this imaging modality may be seen as a sound clinical application that is also altering pca care nowadays. discoveries regarding micro-organisms, especially viruses like hepatitis-c virus (hcv), human papilloma virus, human immunodeficiency virus, which stand as underlying causes of cancers have been always a popular topic and researchers who involved in the topic dominated the prize2. discovery of hcv nearly coincided with the same time period of early psa studies. it is interesting to note that during the long duration of the award, not just psa but the whole pca research area has been disregarded. charles brent huggins received the lone pca research prize for his work on the hormonal treatment of the disease3. he shared the prize with another researcher who -againinvestigates the association of cancers and viruses. another committee policy-related reason for the omission of psa from being rewarded may be abundance of pioneers contributing the topic. based on widely spoken acknowledgement, psa was discovered by richard ablin in 19794. but this presumption conceals a more contentious issue than the ongoing discussion about the widespread use of psa in pca screening. for instance, a group of scientists led by t. ming chu, who carried out research into the topic concurrently with ablin patented 2 the molecule rather than ablin himself5. the backstory of the discovery is way more extensive. earliest studies reporting about a prostate-specific molecule is dating back the 60s. in terms of chronology, rubin hyman flocks may be the first person to discover the protein known as psa today, despite realizing only later that the protein he discovered was prostate-specific6. flocks set out with the intention of obtaining a prostate-specific protein during the planning phase of his studies. and he arrived precise deductions that are still valid today. one of the author's conclusions was that it is hard to isolate an antigen particularly for cancer because psa is the same in benign and malignant cells. despite the passage of over fifty years, no one is in a position to claim that flocks was wrong. the author also stated that semen agglutination is brought on by antibodies against certain prostatic tissues. today, we acknowledged that psa's sole function is liquefaction of semen. so, it is deemed necessary to claim that flocks is the researcher who comes closest to discovering psa by observing its existence and function, and foreseeing its largest flaw which continues to be the main frame of the most heated discussions in urology today. personally, i would cast my vote for him. as a result, no one received the biggest credit for discovering psa. instead, the generosity of cancer rather than the efforts of researchers was credited. another prostate-specific molecule (membrane antigen, psma) that pca cells overexpress and which has a game-changing impact on the management of the cancer, was such kind of prove of this generous disease originated from a troublesome organ. as living individuals, ablin and chu still can be candidates of the prize. but there is a final reason that makes prize committee carefull against advancements over psa molecule. after approving by fda, psa has been widespreadly used to screen pca. millions of patients diagnosed in early stages of the disease and had a cure chance. overuse of psa brought along with the terms insignificant cancer, active surveillance of cancer, overdiagnosis and overtreatment. in 2012, the united states preventive services task force (uspstf) recommended against the routine use of psa for mass screening, citing the aforementioned harms outweighing the benefits of screening. the recommendation quickly resulted in more advanced disease and more pca-related mortality7. uspstf loosened its recommendation against the use of psa in 2018 but even ablin, one of the pioneers, opposes psa as a screening tool. probably, nobel prize also heard of these contradictory voices arose from the side of psa. we must concur that the factors contributing to psa's underappreciation include the lack of a clear pioneer in its discovery and the contradictory opinions around its use. it looks like psa will wait to be rewarded till we come up with a far better application of it. references 1. wehrli fw. on the 2003 nobel prize in medicine or physiology awarded to paul c. lauterbur and sir peter mansfield. magn. reson. med. 51, 1-3 (2004). 2. lipsick j. a history of cancer research: tumor viruses. cold spring harb. perspect. biol. 13, a035774 (2021). 3 3. huggins c. how charles huggins made his nobel prize winning discovery--in his own words: an historic audio recording. interviewed by willard goodwin and elmer bell. prostate. 72, 1718 (2012). 4. rao ar, motiwala hg, karim om. the discovery of prostate-specific antigen. bju int. 101, 5-10 (2008). 5. research corporation. purified human prostate antigen. https://patents.justia.com/patent/4446122 (1981). 6. özman o, talat z, erözenci a. prostat spesifik antijen’in tarihi. lokman hekim dergisi. 9, 184-188 (2019) [in turkish]. 7. fleshner k, carlsson sv, roobol mj. the effect of the uspstf psa screening recommendation on prostate cancer incidence patterns in the usa. nat. rev. urol. 14, 26-37 (2017). https://patents.justia.com/patent/4446122 v08_no_1_print_3.pdf point of technique 66 urology journal vol 8 no 1 winter 2011 ureteroscopically assisted totally laparoscopic appendicocecostomy a minimally-invasive approach to an intra-operative complication alireza aminsharifi, reza niroomand, firoozeh afsar urol j. 2011;8:66-8. www.uj.unrc.ir keywords: neurogenic urinary bladder, appendix, laparoscopy, urinary diversion,cystostomy, urologic surgical procedures department of urology, shiraz nephrology urology research center, comparative medicine research center, shiraz university of medical sciences, shiraz, iran corresponding author: alireza aminsharifi, md department of urology, faghihi hospital, zand boulevard, shiraz, iran tel: +98 917 700 0656 fax: +98 711 233 0724 e-mail:aminsharifi_ar@yahoo.com received june 2010 accepted november 2010 introduction mitrofanoff appendicocecostomy technique, as an efficient and durable continent catheterizable stoma to the urinary reservoir, has been traditionally done through an open pfannenstiel or low midline abdominal incision.(1) however, in recent years, anecdotal cases of laparoscopic-assisted, roboticassisted, and totally laparoscopic mitrofanoff appendicovesicostomy have been reported.(2-5) here, we describe a patient treated using a totally laparoscopic appendicovesicostomy procedure with free-hand intracorporeal bowel repair. case report the patient was a 13-year-old boy suffered from insulin-dependent diabetes mellitus since infancy. he had a 1-year history of frequent episodes of urinary retention with overflow urinary incontinence. urodynamic studies showed flaccid neurogenic bladder and post-void residual urine of more than 2 liters. because of difficulties with selfcatheterization through the urethra, he was scheduled for laparoscopic appendicovesicostomy after providing informed consent for the possible need for open conversion. technique in the right lateral position, through 4-port transperitoneal laparoscopy, after applying a laparoscopic satinsky clamp at the base of the appendix with a 5-mm cecal cuff, the appendix with its cecal cuff was harvested while preserving the mesoappendix. the cecum was repaired with freehand intracorporeal laparoscopic suturing and knot-tying techniques with 3-0 polyglycolic acid stitches in two layers (figure 1-a). the tip of the appendix was excised and catheterized with an 8-f feeding tube to ensure patency, but the catheter could not be passed through the appendix. the appendix lumen was evaluated by passing an 8-f ureteroscope through a 5-mm laparoscopic port (figure 1-b), which revealed a hard fecalith at the base of the appendix. the fecalith was fragmented with a pneumatic lithotripter under direct vision via ureteroscope, and ease of catheterization was then checked and confirmed. after bladder mobilization, tunneled appendicovesical anastomosis was done over a 10-f catheter using 4-0 polyglycolic acid intracorporeal running stitches (figure 1-c). the flush stoma was laparoscopic appendicocecostomy—aminsharifi and niroomand 67urology journal vol 8 no 1 winter 2011 created in the right upper quadrant area at the site of the 5-mm trocar (figure 1-d). results the operation lasted 240 minutes. the bladder was drained with a foley catheter for 4 weeks when the internal foley as well as the appendiceal catheter were removed and the patient was able to catheterize his bladder via appendix stoma without difficulty every 4 hours (figure 2). no urine incontinence or stomal stenosis has occurred within the 6-month follow-up period. discussion in the past three decades, the mitrofanoff procedure has been shown to be efficient for reservoir drainage and to protect the upper urinary tract from the detrimental effects of a neurogenic bladder as well.(1) performing this procedure in a minimally-invasive manner is the ultimate goal. jordan and the colleagues were the first to introduce laparoscopy for this technique. they mobilized the cecum and the appendix laparoscopically and completed the procedure through a pfannenstiel incision.(2) because of the complexity of intracorporeal suturing during this technique, robotic-assisted laparoscopic appendicovesicostomy has been tried in recent years with successful outcome.(3) casale and associates were the first to report the feasibility of intracorporeal totally laparoscopic figure 1. a) cecal repair with free-hand intracorporeal laparoscopic suturing with vicryl 3-0 stitches. b) intraluminal visualization of the appendix with ureteroscope to relieve obstruction. c) appendiculovesical anastomosis with 4-0 polyglycolic acid intracorporeal running stitches. d) the flush stoma in the right upper quadrant at the site of the 5-mm trocar. a b c d appendix bladder laparoscopic appendicocecostomy—aminsharifi and niroomand 68 urology journal vol 8 no 1 winter 2011 appendicovesicostomy in 2004. they transected the appendix with an endoscopic stapling device, and tunneled appendicovesical anastomosis was done with intracorporeal suturing.(4) here, we presented our first experience with totally laparoscopic appendicovesicostomy in a child with flaccid neurogenic bladder. unlike others, we did not use an endoscopic stapler to transect the appendix, and we opted for intracorporeal bowel repair. appendiceal obstruction was successfully managed in a minimally-invasive manner. although laparoscopic appendicovesicostomy is a demanding procedure that requires experience with intracorporeal suturing and tying techniques, its clinical outcome is highly rewarding due to its minimally-invasive nature. acknowledegments we thank ehsan ghanbarifard for his aid in obtaining figures and editing the video and k. shashok (author aid in the eastern mediterranean) for help with the english in the manuscript. conflict of interest none declared. references 1. tekant g, emir h, eroglu e, et al. catheterisable continent urinary diversion (mitrofanoff principle)-clinical experience and psychological aspects. eur j pediatr surg. 2001;11:263-7. 2. jordan gh, winslow bh. laparoscopically assisted continent catheterizable cutaneous appendicovesicostomy. j endourol. 1993;7:517-20. 3. storm dw, fulmer br, sumfest jm. laparoscopic robot-assisted appendicovesicostomy: an initial experience. j endourol. 2007;21:1015-7. 4. casale p, feng wc, grady rw, joyner bd, lee rs, mitchell me. intracorporeal laparoscopic appendicovesicostomy: a case report of a novel approach. j urol. 2004;171:1899. 5. rosito t, andreoni cr, iizuca f, ortiz v, macedo a, jr. combined laparoscopic appendicovesicostomy (mitrofanoff) with nephrectomy and orchidopexy in an 8-year-old boy. j pediatr urol. 2008;4:317-8. figure 2. after laparoscopic appendicovesicostomy, the patient could catheterize himself easily and he was continent. clinical study of modified devine’s surgical technique in the treatment of concealed penis ziyi zhang1,2, hao wu1,2, weijiang mao1, shenglin gao1, li zuo1**, lifeng zhang1* purpose: this study aimed to observe the clinical effect of modified devine’s surgical technique in the treatment of concealed penis. materials and methods: from july 2015 to september 2020, fifty-six children with concealed penis were treated with modified devine’s technique. recorded the penile length and the satisfaction score preoperatively and postoperatively to confirm the effect of the surgery. followed up the penis for bleeding, infection and edema one week and four weeks after the operation. twelve weeks after the operation, we measured the length of the penis and observed whether there was a retraction. results: the length of the penis has been effectively lengthened(p < 0.001). there was significant improvement in parents’ satisfaction grades (p < 0.001). all the patients had different degrees of penile edema after the operation. most of the penile edema subsided about four weeks after the operation. no other complications occurred. no obvious penile retraction was found twelve weeks postoperative. conclusion: the modified devine’s technique was safe and effective. as a treatment for concealed penis, it is worthy of wide clinical application. keywords: concealed penis; devine; modified; curative effect evaluation; surgical treatment introduction concealed penis is a congenital penile disease, wherein the penis is concealed under the skin due to the abnormal development of the penile sarcoplasm(1). this affects the normal development of the penis, resulting in its short length, causing physical and mental stress to patients, and extensively affecting their sex lives in the future(2). a concealed penis can also increase the risk of urinary tract infections(3,4). penile plastic surgery is the main treatment for concealed penis. devine operation is often used in the treatment of such cases(5); however, during the surgery. without a v-y plasty, the post-surgical appearance of the penis is not similar to that of a conventional penis. in this study, we discuss the effects of the modified devine operation in the treatment of concealed penis(6). materials and methods study population from july 2015 to september 2020, fifty-six patients with concealed penis were treated with modified devine operation. the age ranged from 4 to 10 (6.9 ± 1.9) years, and the length of the penis was 0.9-3.7 (2.1 ± 0.4 cm preoperation. after evaluation, the p value of the penis length of patients is 0.754. obeys normal distribution. inclusive criteria: (1) the age of the patients 1department of urology, the affiliated changzhou no. 2 people's hospital of nanjing medical university, changzhou, china. 2dalian medical university, dalian 116044, china. * department of urology, the affiliated changzhou no. 2 people's hospital of nanjing medical university, 29 xinglong road, 213003 changzhou, china. email: nj-likky@aliyun.com. ** department of urology, the affiliated changzhou no. 2 people's hospital of nanjing medical university, 29 xinglong road, 213003 changzhou, china. email: 2031985672@qq.com received july 2021 & accepted march 2023 ranged from 4 to 10 years; (2) the penis was concealed under the skin. exclusion criteria: (1) surgical contraindications; (2) buried penis caused by obesity in children; (3) hypospadias or epispadias. (4) previous penile surgery. all patients signed informed consent before the operation. surgical procedures in the modified devine’s technique, general anesthesia was administered before the commencement of the operation. then, the inner and outer plates of the prepuce were incised circularly at the narrow area of prepuce; removed the narrow ring of the foreskin, resected the superfluous inner plate, and then, the superficial layer of the deep fascia was dissected to disconnect the thickened fibrous cord. to protect the patient's erectile function, extra caution was taken to protect dorsal blood vessels and nerves. the whole procedure should be performed snugly to the penile tunica albuginea. the prepubic fat pad was not excised. the next stage was to recover the penoscrotal angle(6). to restore the normal appearance of the penis, a y-shaped incision was made in the skin between the penis and the scrotum. be careful not to damage the scrotal arteries on both sides. continue eliminating pathological traction around the incision. completely circular resectted the dartos fascia at the bottom of the penis. the penoscrotal angle was also finished(7). the next stage is to find the body sururology journal/vol 20 no. 4/ july-august 2023/ pp. 229-233. [doi: 10.22037/uj.v20i.6900] pediatric urology face projection of the penile root. suture the dorsal side of the penis and the penile tunica albuginea at 2 o'clock, 10 o'clock and 12 o'clock of the dorsal root of the penis(8). which aimed to reduce the impact of pubic fat pad on penis exposure and prevent penis from contracting. the postoperative appearance of the concealed penis is also greatly improved. so the retracted penis was removed from pathological traction eventually and its original length was restored. sutured the incision after rigorous hemostasis. the individual steps of the surgical procedure was shown in figure 1. the incision was wrapped around the cutting edge with a vaseline-coated gauze, and the outer layer was properly pressurized and bandaged using elastic bandages. this was done without an indwelling catheter to avoid the pain caused due to it . patients with a high risk of thrombus were treated with nadroparin calcium. the medication was changed every 3 days. one week after the operation the gauze was removed (figure 2). evaluation evaluated the satisfaction score of the patients preoperative and twelve weeks after the operation. satisfaction score was assessed by questionnaire. one week after the operation, the gauze was removed to check for infection, edema, hemorrhage and skin necrosis in the incision site. four weeks after the operation, these were observed again. the length of the penis was measured postoperatively and twelve weeks after the operation. it was compared with original length of penis. to see if the length of the penis was retracted. statistical analysis spss 26.0 was employed for all statistical analyses. the measurement data was expressed as mean(sd), paired t-test was used for component comparison, p < 0.05 was considered to be statistically significant. surgical treatment of concealed penis-zhang et al. table 1. following up of penis length and satisfaction score variablesa pre-op post-op 12 weeks p-value penile length,cm,mean ± sd (range) 2.1 ± 0.4 3.3 ± 0.6 3.1 ± 0.6 < 0.001 satisfaction score (0~5) morphology 1.6 ± 0.5 4.5 ± 0.6 4.4 ± 0.6 < 0.001 penile length 2.2 ± 1.0 4.3 ± 0.7 4.3 ± 0.7 < 0.001 hygiene 1.7 ± 0.6 —— 4.8 ± 0.5 < 0.001 micturition 2.5 ± 0.2 3.4±0.3 4.4 ± 0.1 < 0.001 a:continuous variables were compared by independent samples t-test figure 1. surgical procedure of the modified devine’s operation. (a) incising circularly at the narrow area of prepuce and disconnecting the thickened fibrous cord. (b) completely circular resectted the dartos fascia and made a y-shaped incision. (c) suture the dorsal side of the penis and the penile tunica albuginea at the dorsal root of the penis. (d) sutured the incision after rigorous hemostasis. pediatric urology 230 results length the length of penis was 2.1±0.4cm preoperatively and 3.3±0.6cm postoperatively. twelve weeks after the surgery, the length of penis was 3.1 ± 0.6. which showed a significant increase in length. (p < 0.001, table1); twelve weeks after surgery, according to the clinical efficacy, the patients were divided into three groups: effective significantly showed that there was no retraction of the penis; effective showed that the penis had mild retraction; invalid showed that there was no significant change in the length of the penis. the results showed that only five patients had mild retraction. the retraction rate is 8.9%. satisfaction most patients have satisfactory results. the satisfaction score effect is judged from four aspects: morphology, penile length, hygiene and micturition. these four aspects are also the most troubling for patients and parents. judging from the results we get, the satisfaction scores have improved, the difference was statistically significant (p < 0.001, table 1). complications 56 cases of surgical patients all had different degrees of penile edema, but most of them resolved after 4 weeks. four patients had severe penile edema and subsided 7 weeks after the operation. no other complications like hemorrhage, infection and skin necrosis occurred. discussion concealed penis involves an abnormal development of the penile sarcoplasm(9). the elastic penile sarcoplasm becomes fibrous, leading to poor elasticity. the abnormal development of the penile sarcoplasm leads to the adhesion of the penis and its traction towards the body(10). the penis cannot be exposed normally, which affects the normal development of the penis and leads to a short appearance of the penis called “concealed penis”. additionally, a short appearance of the penis can also be caused by obesity. in the outpatient service, we also met a certain number of such patients. excessive adiposity can lead to penile shortness due to fatty accumulation under the pubic bone(11). however, the development of penile sarcolemma is normal in this condition. the original length of the penis can be restored by losing weight(12), and the development of the penis is not affected. for this kind of patients, we usually recommend that they should be reexamined after losing weight. the best way to treat a concealed penis is to operate it as soon as possible. however, there are many surgical methods for the treatment of a concealed penis, such as devine(5), shirk(13), and others. devine operation has been widely used in clinical practice as the main method of treating concealed penis. however, the traditional devine operation removes the fat pad on the pubic bone which increased the trauma; without recovering the penoscrotal angle leads to unsatisfactory postoperative appearance; the postoperative indwelling catheter female urology 169female urology 169 figure 2. comparison of surgical outcome. (a) preoperative appearance of penis. (b) postoperative appearance of penis. (c) postoperative visiting (one week after the operation). (d) postoperative visiting (four weeks after the operation). surgical treatment of concealed penis-zhang et al. vol 20 no 4 july-august 2023 231 also brings more pain to the patient. therefore, a modified devine operation was developed for the treatment of concealed penis. several improvements were made on the traditional devine operation: ① concealed penis is usually associated with foreskin stenosis. a ring incision was used to relieve the stricture of prepuce on the head of the penis. resect the redundant inner plate to accelerate the disappearance of postoperative lymphedema; ②made a y-shape incision at the angle of the penis scrotum, further remove the fiber cords located at the root of the penis, to recover the penoscrotal angle. which can considerably improve the cosmetic appearance. ③the subpubic fat pad was not removed, the operation injury was reduced;④find the surface projection of the penile angle, and suture the subcutaneous tissue with the penile angle to avoid the effect of fat pads on penis length, prevent further retraction of the penis and ensure the normal attachment between the penis and the skin. ⑤the operation was done without an indwelling catheter to avoid the pain caused due to it. we also counted the main reasons that bothered patients. find that forty-four percent of the patients came to the hospital because their penis was too short and their parents suspected that penis is stunted. twenty-one percent of patients came to the hospital because of recurrent urinary tract infection. twenty-nine percent of patients went to the hospital because of the redundant prepuce and phimosis, and later found out that it was a concealed penis. their parents afriad they missed the most appropriate stage of treatment, affecting the normal development of the penis. ridiculed by peers, affecting their mental health. greatly troubled their lives. therefore, we should pay more attention to the patients with redundant prepuce or phimosis to find out that whether they are combined with concealed penis. which also leads to dysuria and urinary tract infections. additionally, it has been reported that chronic inflammation caused by concealed penis may be a risk factor for penile cancer and gives rise to the possibility of penile resection(14,15). therefore, active early intervention is necessary. the study has some advantages. all the operations were performed by the same doctor. it ensures the consistency of surgical technology. at the same time, the short-term follow-up data were complete, and there were no patients loss to follow-up. but the study also has two limitations. the first is that the study is only a singlecenter study and lacks multicenter study. the second is that the study has a short follow-up time and lacks long-term follow-up. conclusions to sum up, for patients with concealed penis, the modified devine operation is safe, feasible and effective. it can release the penis from the traction of the dysplastic fibrous cords, restored the length of the penis. relieve the circumcision improved the hygiene condition effectively. at the same time, it also had a good cosmetic postoperative appearance. both the patients and their parents were satisfied with the operation. so it is worthy of clinical widely application. acknowledgement this work was supported by national natural science foundation of china (no. 81902565), changzhou science and technology plan (social development support) project (no.: ce20215034), jiangsu province "333 talents project", young scientists foundation of changzhou no.2 people’s hospital (2019k008), changzhou sci & tech program (cj20190100), young talent development plan of changzhou health commission (no.czqm2020065), funded by school-level discipline (no.yjxk202013), innovation team (no. xk201803) and top talent project of changzhou (no. rc201620). conflict on interest the authors report no conflict of interest. references 1. schloss wa. concealed penis. j urol. 1959;82:341. 2. yin wq, wang gy, wu kr. [a new procedure of penoplasty for concealed penis reduces postoperative preputial edema]. zhonghua nan ke xue. 2019;25:901-4. 3. ozkidik m, telli o, hamidi n, et al. concealed penis after circumcision: is it beneficial in lowering uropathogenic colonization in penile skin and preventing recurrence of febrile urinary tract infections? urol j. 2020;17:164-8. 4. hirsch k, schwaiger b, kraske s, wullich b. megaprepuce: presentation of a modified surgical technique with excellent cosmetic and functional results. j pediatr urol. 2019;15:401 e1e6. 5. xu xw, xu yt, shen zj, li dj, gu w, huang rq. [devine's technique with free skin grafting for concealed penis with prepuce deficit]. zhonghua nan ke xue. 2011;17:6257. 6. ge w, zhu x, xu y, chen y, wang j. therapeutic effects of modified devine surgery for concealed penis in children. asian j surg. 2019;42:356-61. 7. caione p, cavaleri y, gerocarni nappo s, collura g, capozza n. the concealed penis: the "two corners" surgical technique. minerva urol nefrol. 2019. 8. manasherova d, kozyrev g, gazimiev m. buried penis surgical correction: midline incision rotation flaps. urology. 2020;138:174-8. 9. chan ih, wong kk. common urological problems in children: prepuce, phimosis, and buried penis. hong kong med j. 2016;22:2639. 10. ngaage lm, lopez j, wu y, et al. uncovering the hidden penis: a novel nomenclature and classification system. ann plast surg. 2020. 11. smith-harrison li, piotrowski j, machen gl, guise a. acquired buried penis in adults: a review of surgical management. sex med rev. 2020;8:150-7. 12. fuller tw, theisen km, shah a, rusilko pj. surgical management of adult acquired buried penis. curr urol rep. 2018;19:22. 13. chen c, li n, luo yg, et al. effects of modified penoplasty for concealed penis in children. int urol nephrol. 2016;48:1559-63. 14. abdulla a, daya d, pinthus j, davies t. vol 20 no 3 may-june 2023 170 surgical treatment of concealed penis-zhang et al. pediatric urology 232 buried penis: an unrecognized risk factor in the development of invasive penile cancer. can urol assoc j. 2012;6:e199-202. 15. liu w, luo y, wang g, et al. conditional survival after surgery for patients with penile cancer. andrology. 2020;8:1744-52. surgical treatment of concealed penis-zhang et al. vol 20 no 4 july-august 2023 233 bladder cancer incidence in iran: results of the iranian national population-based cancer registry from 2014 to 2016 elham partovipour1, gholamreza roshandel1,2, ali motlagh1, fereshteh salavati1, gohar mohammadi3, masoud davanlou4, fereshteh asgari1, mostafa khoshaabi5, alireza raeisi6, reza malekzadeh7,8, afshin ostovar1,9* purpose: bladder cancer is a common cancer in the world with the highest rates in southern and western europe, north america, and western asia. it imposes a high economic burden to the health care system globally. the objective of this study is to provide the incidence of bladder cancer and its geographic distribution in iran in 2014, 2015 and 2016. materials and methods: data was extracted from the iranian national population-based cancer registry (inpcr) covering 98% of the total iranian population. we registered only those cases diagnosed with malignant primary tumors of the bladder in the national cancer information management system (cima). the main sources of data were pathology laboratories, hospitals, and death registry units. after quality assessment, analysis of data was performed and age standardized rates (asr) of bladder cancer were reported at national and subnational levels. results: we registered 5817, 5662, and 6630 new bladder cancer cases in 2014, 2015, and 2016, respectively with men counting 82% of cases in every year. the asr of bladder cancer in the total iranian population was 8.50 (95% ci: 8.28-8.72), 8.05 (95% ci: 7.83-8.27) and 8.74 (95% ci: 8.52-8.96) per 100,000 in those years. the male to female ratio was 5 every year. kerman has the highest asr in each of the years, respectively 15.49, 13.07 and 12.46, and ilam has the lowest asr during 2014 to 2015, respectively 4.27 and 3.50, and sistan and baluchestan has the lowest rate in 2016 (asr:3.56) in both sexes. conclusion: the highest incidence of bladder cancer was observed in the central, southern and northwestern parts of iran. through the analysis of the incidence patterns and the identification of risk factors associated with it, steps can be taken toward prevention and control measures. keywords: bladder cancer; incidence; registry; iran introduction bladder cancer with about 549,000 (asr: 5.7 per 100,000) annual cases is the tenth most incident cancer in the world (1) and the highest incidence rates reported in most developed countries; southern europe (asr: 15.2 per 100,000), western europe (asr: 13.2 per 100,000), north america (asr: 11.9 per 100,000) (2), and western asia (asr: 9.2 per 100,000)(1,3). according to globocan 2018, in asia, lebanon is reported as the highest incidence of bladder cancer and iran ranked sixth among other countries(1). as an expensive cancer to treat(4), in the european union, bladder cancer cost €4.9 billion, of which €2.9 billion was related to the health care system (59% of total economic burden)(5). 1national cancer registry secretariat, national cancer control committee, ministry of health, tehran, iran. 2golestan research center of gastroenterology and hepatology, golestan university of medical sciences, gorgan, iran. 3cancer research center, shahid beheshti university of medical sciences, tehran, iran. 4pathobiology laboratory, bahman hospital, tehran, iran. 5department of geospatial information system (gis), center of excellence in gis, k.n. toosi uni. of technology, tehran, iran. 6school of medicine, shiraz university of medical sciences, shiraz, iran. 7digestive disease research institute, tehran university of medical sciences, tehran, iran. 8deputy of research and technology, ministry of health and medical education, tehran, iran. 1,9osteoporosis research center, endocrinology and metabolism clinical sciences institute, tehran university of medical sciences, tehran, iran. *correspondence: osteoporosis research center, endocrinology and metabolism clinical sciences institute, tehran university of medical sciences, tehran, iran. tel: +98 21 81454234, e-mail: aostovar@tums.ac.ir. received march 2021 & accepted september 2021 based on the findings of recent studies in iran the incidence of bladder cancer is rising(6,7). an epidemiological and histological study of bladder cancer in iran indicated that the asr has increased from 8.35 to 14.42 (per 100,000) in men and from 2.12 to 3.78 in women between 2003 and 2008(7). another study in isfahan, a central province, showed that the incidence of this cancer was increasing (asr: 7.7 to 9.9 per 100,000) from 2011 to 2015(8). sex and age are also associated with the incidence of bladder cancer. globocan 2018 estimated that the asr of bladder cancer is approximately four times higher in men compared to women, worldwide(2). in europe in 2012, the incidence of bladder cancer in men and women were estimated to be 19.5 and 9.3 per 100,000, urological oncology urology journal/vol 19 no. 4/ july-august 2022/ pp. 274-280. [doi:10.22037/uj.v18i.6760] respectively(9). based on some studies in iran, bladder cancer incidence rate in men is 3 to 5 times those of women(4,7,8,10). bladder cancer incidence is associated with age and mostly has been seen in the elderly. the highest rate belongs to the individuals in their seventh and eighth decades of life(4,11). the incidence of bladder cancer varies based on socio-economic and life style risk factors. smoking, occupational and industrial exposures are among the main risk factors(3,11-14). schistosomiasis(3,7), human papilloma virus (hpv)(7), and arsenic-contaminated drinking or chlorinated water(13) are some other risk factors associated with bladder cancer. considering that population-based cancer registry has been carried out nationally since 2014 and cancer data are collected from at least three sources: pathology, clinical and death, and also since that year, the quality of cancer data has been accepted by the international agency for research on cancer (iarc) standards, we needed to do a study to determine the incidence of bladder cancer in iran and its geographical distribution in the country based on the latest and most accurate cancer data from 2014 to 2016. materials and methods study population this secondary data analysis was performed on newly diagnosed patients with primary bladder cancer registered in inpcr in three consecutive years (2014, 2015 and 2016). population statistics at provincial and national levels for those years were obtained from the statistics of the health deputy of the ministry of health (moh). total population of iran in 2014 and 2015 were estimated based on the 2011 national census to be 77,856,000 and 78,773,000, respectively(15). the population of 2016 was calculated from the national census data including bladder cancer in iran 2014 to 2016-partovipur et al. table 2. diagnosis methods for bladder cancer in inpcr, 2014, 2015 and 2016 diagnosis method mv clinical dco sex number percent number percent number percent 2014 male 4058 84.93 530 11.09 190 3.98 female 817 78.48 142 17 82 7.87 both 4875 83.78 672 11.55 272 4.67 2015 male 4153 89.99 256 5.55 206 4.46 female 888 85 85 8.1 74 7.06 both 5041 89.03 341 6.02 280 4.95 2016 male 4876 90.41 325 6.03 156 3.92 female 1001 85.77 102 8.74 64 5.48 both 5877 89.59 427 6.51 256 3.90 abbreviations: mv, microscopically verified. clinical, clinical investigation. dco, death certificate only urological oncology 204 40,498,442 men and 39,427,828 women which distributed in 31 provinces (figure 1 depicts the population pyramid of iran in 2016)(16). study design data on bladder cancer were derived from inpcr. a total of 64 universities of medical sciences (ums) are responsible for medical education as well as providing health services for the defined population in their catchment area. in brief, to cover all of the population, we considered all 64 ums as administrative units of the moh. therefore, the inpcr included 64 university-level secretariats, distributed in 31 provinces, and a national-level secretariat which leads all those university secretariats. each province has at least one university secretariat which is responsible for data gathering and processing. in the provinces with more than one university secretariats, data is merged by one of them as the provincial representative then submitted to the inpcr secretariat. population-based cancer registry in iran, follows the guidelines of iarc and north american association of central cancer registries (naaccr)(17-19). accordingly, the inpcr registered cases with new primary bladder tumors of malignant behavior, among which only invasive bladder cancer cases (behavior code = 3) were considered in this study. to determine the accurate geographical distribution of bladder cancer in different subdivisions, data of patients' residence was collected as a mandatory and an essential variable. the main data sources were pathology reports form public and private pathology laboratories, clinical/paraclinical data from public and private hospitals, and cancer mortality data which collected from death registry units of the representative ums. evaluations the web-based system of the inpcr, named cima, table 1. the number, crude rate and asr and 95% confidence interval (ci) of bladder cancer (per 100,000) in male and female in iran, 2014, 2015 and 2016. bladder cancer sex number crude rate asr 95% ci of asr 2014 male 4776 12.37 14.30 13.88-14.72 female 1041 2.74 2.97 2.79-3.15 both 5817 7.59 8.50 8.28-8.72 2015 male 4615 11.82 13.57 13.17-13.97 female 1047 2.72 2.86 2.68-3.04 both 5662 7.30 8.05 7.83-8.27 2016 male 5393 13.32 14.41 14.01-14.81 female 1167 2.96 2.99 2.81-3.17 both 6560 8.21 8.64 8.42-8.86 urological oncology 275 used for data entry, cleaning, processing, and transferring from ums secretariats to inpcr secretariat. upon entering bladder cancer data to the cima, new cases of bladder cancer were identified and coded using the international classification of diseases for oncology (icd-o-3)(20), then multiple primary tumors were evaluated according to iarc rules(21). internal consistency was checked for age, sex, and primary cancer site with the type of cancer using the iarc check tools, which is included in cima software package (22). to check for bladder cancer data completeness, the percentages of diagnostic methods including microscopically verified figure 1. population age pyramid of iran, 2016. figure 2. trend of bladder cancer incidence (asr) in iran, 2014 to 2016. bladder cancer in iran 2014 to 2016-partovipur et al. vol 19 no 4 july-august 2022 276 (mv%), clinical investigation (clinical %) and death certificate only (dco%) were compared to naaccr standards(19) (mv% > =80 and clinical% <15, dco% < 5). all the mentioned steps were taken by ums secretariats. in inpcr, the dataset submitted by ums secretariats were rechecked based on iarc standardized quality control indicators. statistical analysis quality controlled data was analyzed, after removing in situ cases (behavior code=2), using canreg5 software(23) and incidences reported as the numbers, percentage, crude rates, age specific incidence rates and asr, for the country and by province. to calculate the asrs, the age-specific incidence rate of 18 age groups was calculated by dividing the number of cases by the population of each age group per 100,000 population, and then the values obtained for standardization were multiplied by the world standard population defined for each age group. finally, the sum of the values obtained from the 18 groups is divided by the sum of the world standard population.the reference population used to calculate asrs was the world standard population in 18 age groups of 5 years (0–4, 5–9 ... 85+) considered per 100,000 population(24,25). using a method described by bray and ferlay, we calculated the 95% confidence intervals for asrs(26). ethical issues of this study were reviewed and approved by ethical committee of golestan universuity of medical sciences (ethics code: ir.goums.rec.1397.335). results overall, 5817, 5662 and 6630 new bladder cancer cases were registered in inpcr in 2014, 2015 and 2016 of which 4776, 4615 and 5433 were male, respectively (82% of cases, annually). the median of age in bladder cancer cases were calculated to be 64 years in men and 56 years in women in every year. the asr of bladder cancer was 8.50 (95% ci: 8.288.72), 8.05 (95% ci: 7.83-8.27) and 8.74 (95% ci: 8.52-8.96) per 100,000 in total iranian population from 2014 to 2016, respectively. the number, crude rates, asrs and 95% ci of bladder cancer by gender and year are presented in table 1. overall male to female ratio was 4.8, 4.7 and 4.7 in 2014, 2015 and 2016, respectively. the bladder cancer ranked as the seventh most incident cancer among diagnosed cancers after breast, prostate, skin (non-melanoma), stomach, colorectal and lung cancers during 2014 to 2015 and the sixth most common cancer among diagnosed cancers after breast, prostate, colorectal, skin (non-melanoma), and stomach in 2016. specifically, it ranked with fifth in males and thirteenth in females for all the three years. the trend of bladder cancer over three years is shown in figure 2. the highest incidence rates of bladder cancer become clear in sixth and seventh decades of life, figure 3 shows age specific incidence rates of bladder cancer in male and female in those three years. the distribution of incidence of bladder cancer (asr) urological oncology 277 figure 3. age specific incidence rates of bladder cancer (per 100,000) by sex, iran, 2014 to 2016. bladder cancer in iran 2014 to 2016-partovipur et al. is mapped in different regions and provinces of iran by sex in 2014, 2015 and 2016 in figure 4. the highest incidence rate of bladder cancer was reported from kerman province. of the total cases registered for bladder cancer, 4875, 5041 and 5877 cases were diagnosed by microscopic verification (mv=83.78%, 89.03% and 89.59%), 272, 280 and 256 cases were found from death certificate only (dco=4.67%, 4.95 % and 3.90%) and the remaining 672, 341 and 427 cases were diagnosed via clinical only or other clinical investigation methods (clinical: 11.55%, 6.02 % and 6.51%) in 2014, 2015 and 2016, respectively (table 2). transitional cell carcinomas (tcc) with 4661, 4610 and 5408 cases were 80 to 81% of bladder cancers in those years, respectively. discussion the asr of bladder cancer based on three recent cancer registry reports in 2014, 2015, and 2016 were about 8 per 100,000 ranked sixth and seventh among all cancers in iran. the bladder cancer was more prevalent in male (asr: 14 in male and asr: 3 in female) and older age groups. central, southern and northwestern parts of the country had a higher rates of bladder cancer. the incidence of bladder cancer in iran is considerably high compared to the rest of asia and many parts of the world. according to regional divisions listed by globocan 2018, iran ranked the first in the south-central asia and the third in neighboring countries after syria and turkey(1). this rank may be partly due to under-reporting of bladder cancer in other countries, however, numerous known behavioral and environmental risk factors should be taken into account in interpreting these findings, especially smoking, occupational and industrial exposures(3,11-13). smoking is known to be the main risk factor for bladder cancer with a strong association(9,14,27,28). some studies have demonstrated that the risk of bladder cancer occurrence is about four times higher in smokers than in non-smokers(29,30). therefore, it can be assumed that because smoking is more common in men than women, bladder cancer is more common in men and studies have mentioned that 50% of men and 25% of women with bladder cancer are smokers(27,28). in the latest survey of risk factors of non-communicable diseases risk factors in iran (steps) in 2016, the spatial distribution of tobaccos use is higher in bushehr, fars, azerbaijan-west, yazd, isfahan, and kerman which shows similarity to the geographic pattern of higher bladder cancer incidence(31). besides, the effect of opium in increasing the risk of bladder cancer incidence has been proven in different studies(32-35). latest estimations show that kerman ranks fifth in the country for opium and third for shire (combifigure 4. the distribution of age standardized incidence rates (asr) of bladder cancer in different regions and provinces of iran in 2014 (in the first row), 2015 (in the second row) and 2016 (in the third row), male, female and both sexes, respectively. bladder cancer in iran 2014 to 2016-partovipur et al. vol 19 no 4 july-august 2022 278 nation of opium residue and pure opium) consumption, which may be one of the major reasons for the increased incidence of bladder cancer in kerman(36). there is also a strong relationship between the use of opium and bladder cancer in shiraz city (located in the south of iran), which proposes opium as a major potential risk factor for bladder cancer in iran(37). apart from smoking and opium consumption, occupational risk factors, especially industrial exposures, are viewed as an important risk factor attributable to bladder cancers(3,11-14), accounting for 20-27%(12,38). similarly, a case control study about occupations and the risk of bladder cancer in yazd province located in the center of iran shows an increased risk of this cancer among a group working with metal compared to the control group(39). other risk factor proposed for bladder cancer is infectious diseases such as schistosomiasis(3,11), and hpv(7,40), the correlation between hpv infection and bladder transitional cell carcinoma in iran has reveals the presence of the hpv in 36.5% of tissue samples (40). in this study, the incidence of bladder cancer in men is 5 times that of women, many studies have shown this ratio 3 to 5 times(2,7,8,10). the highest incidence of bladder cancer is observed in people over 60 to 80 years of age. the results of this study indicated the highest incidence in the 60 and 70 decades(4,8,10,11,41). at the national level, the incidence of bladder cancer has not changed significantly over the years (figure 2). it should be noted that the completeness of bladder cancer cases collected from pathology laboratories in those years was 80% to 90% and is based on iarc standards (table 2). at the provincial level, however, kerman ranked first every three years while the rankings of the provinces have not been the same each year (figure 4). this can be a result of the under-reporting or over-reporting of bladder cancer in those provinces. in this regard, quality control procedures such as case-findings for under-reporting, eliminating duplicates for over-reporting and the subsequent accurate recoding of bladder cancer cases are necessary. by providing data for the upcoming years which is currently being collected and processed, the correct trend of bladder cancer incidence and its geographical distribution will be achieved. access to accurate bladder cancer data in provinces and their association with possible risk factors can be a starting point to control and prevention of bladder cancer in iran. one of the limitations of bladder cancer incidence studies is the incompatibility between studies which include in situ bladder cancers (behavior code = 2) in addition to the invasive cancers and the studies which are based only on invasive bladder cancers. conclusions in this study, the highest incidence of bladder cancer was observed in central, southern and northwestern parts of iran. continuous and annual studies of the incidence of bladder cancer incidence reveal a pattern of incidence among different geographical regions. through the analysis of these patterns and the identification of risk factors associated with bladder cancer (smoking, opium, occupational exposures and etc.), further steps can be taken toward prevention and control of this cancer. urological oncology 279 acknowledgments the authors would like to thank the staff of the cancer registry secretariat in all iran universities of medical sciences who did the valid and acceptable population-based cancer registry in those years. conflict of interest the authors had no conflict of interest to declare. references 1. international agency for research on cancer (iarc). global cancer observatory 2018. available from: https://gco.iarc.fr/ 2. bray f, ferlay j, soerjomataram i, et al. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2018; 68:394-424. 3. antoni s, ferlay j, soerjomataram i, et al. bladder cancer incidence and mortality: a global overview and recent trends. eur urol. 2017;71:96-108. 4. mahdavifar n, ghoncheh m fau pakzad r, pakzad r fau momenimovahed z, et al. epidemiology, incidence and mortality of bladder cancer and their relationship with the development index in the world. asian pac j cancer pre. 2016;17:381-6 5. leal j, luengo-fernandez r, sullivan r, et al. economic burden of bladder cancer across the european union. eur urol. 2016;69:43847. 6. koohi f , salehiniya h. the trend of incidence of bladder cancer in iran, 2003-2009. stud med sci. 2015;26:19. 7. rafiemanesh h, lotfi z, bakhtazad s, et al. the epidemiological and histological trend of bladder cancer in iran. j cancer res ther. 2018;14:532-6. 8. mazdak h , tolou-ghamari z. preliminary study of prevalence for bladder cancer in isfahan province, iran. arab j urol. 2018;16:260-210. 9. europin network of cancer registry (encr). estimated incidence and mortality of bladder cancer. 2012. available from: https://www. encr.eu/sites/default/files/factsheets/encr_ factcheet_bladder_cancer_2016.pdf. 10. sadeghi gandomani h, asgari tarazoj a, hadavand siri f, et al. essentials of bladder cancer worldwide: incidence, mortality rate and risk factors. vietnamese j biomed. 2017;4:1638-55. 11. mahdavi s, amoori n, salehiniya h, et al. trend of bladder cancer mortality in iran (2006 to 2010). injer. 2015;2:184-9. 12. burger m, catto jw, dalbagni g, et al. epidemiology and risk factors of urothelial bladder cancer. eur urol. 2013;63:234-41. 13. wong mcs, fung fdh, leung c, et al. the global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection. sci rep. 2018;8:1129. bladder cancer in iran 2014 to 2016-partovipur et al. 14. jafari-koshki t, arsang-jang s , mahaki b. bladder cancer in iran: geographical distribution and risk factors. ijcp. 2017;10:5610. 15. statistical cancer of iran (sci). population census. 2011. 16. statistical cancer of iran (sci).population estimation. 2016. 17. ferlay j, soerjomataram i, ervik m, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer. 2015;136:359-86. 18. curado m, edwards b, shin h, et al. cancer incidence in five continents-vol ix. iarc sci publ; 2008;160:1-837. 19. hafferkamp j. standards for cancer registries vol iii. north american association of central cancer registries (naaccr). 2008. 20. fritz a, percy c, jack a, et al. international classification of diseases for oncology (icd-o) – 3rd edition, 1st revision. who. 2013. 21. international agency for research on cancer (iarc). international rule for multiple primary cancers. lyon, france.2004. 22. international agency for research on cancer (iarc). check and conversion programs for cancer registries (iarc/iacr tools). lyon, france. 2005. 23. international agency for research on cancer (iarc). canreg5 [computer program]. lyon, france. 2019. 24. segi m. cancer mortality for selected sites in 24 countries (1950-57). tohoku university school of medicine. 1960. 25. jensen om, parklin dm , maclennan r. cancer registration: principles and methods. iarc. lyon, france. 1991. 26. forman d, bray f, brewster d , et al. cancer incidence in five continents-vol x. iarc. lyon, france. 2014:112-5. 27. letašiová s, medveďová a, šovčíková a, et al. bladder cancer, a review of the environmental risk factors. environ health. 2012;11:s11. 28. zeegers mp, kellen e, buntinx f, et al. the association between smoking, beverage consumption, diet and bladder cancer: a systematic literature review. world j urol. 2004;21:392-401. 29. lakkis na, adib sm, hamadeh gn, et al. bladder cancer in lebanon: incidence and comparison to regional and western countries. j moffitt cc. 2018;25:1073274818789359. 30. freedman nd, silverman dt fau hollenbeck ar, hollenbeck ar fau schatzkin a, et al. association between smoking and risk of bladder cancer among men and women. jama. 2011;306: 737-45. 31. non-communicable diseases research center (ncdrc). survey of risk factors (steps fact sheet). iran. 2016. 32. international agency for research on cancer (iarc). evaluate of the carcinogenicity of opium consumption. lyon, france.2020;126. 33. sheikh m, shakeri r, poustchi h, et al. opium use and subsequent incidence of cancer: results from the golestan cohort study. lancet glob health. 2020;8:649-60. 34. naghibzadeh-tahami a, marzban m, yazdifeyzabadi v, et al. is opium use associated with an increased risk of lung cancer? a casecontrol study. bmc cancer. 2020;20:807. 35. afshari m, janbabaei g, bahrami ma , et al. opium and bladder cancer: a systematic review and meta-analysis of the odds ratios for opium use and the risk of bladder cancer. plos one. 2017;12: 0178527. 36. shahesmaeili a, malekpour afshar r, sadeghi a , et al. cancer incidence in kerman province, southeast of iran: report of an ongoing population-based cancer registry, 2014. asian pac j cancer prev. 2018;19:153341. 37. akbari m, naghibzadeh-tahami a, khanjani n, et al. opium as a risk factor for bladder cancer: a population-based case-control study in iran. arch iran med. 2015;18:56771. 38. delclos gl , lerner sp. occupational risk factors. scand j urol nephrol. 2008;42:58-63. 39. farzaneh f, mehrparvar ah , lotfi mh. occupations and the risk of bladder cancer in yazd province: a case-control study. int j occup environ med. 2017;8:191-8. 40. barghi mr, hajimohammadmehdiarbab a fau moghaddam smmh, moghaddam sm fau kazemi b , et al. correlation between human papillomavirus infection and bladder transitional cell carcinoma. bmc infect dis. 2005;5:12. 41. malats n , real fx. epidemiology of bladder cancer. hematol oncol clin north am . 2015;29:177-89. bladder cancer in iran 2014 to 2016-partovipur et al. vol 19 no 4 july-august 2022 280 v07_no_4.pdf case report 287urology journal vol 7 no 4 autumn 2010 intestinal metaplasia of the renal pelvis kemal deniz,1 mehtap kala,2 3 urol j. 2010;7:287-9. www.uj.unrc.ir keywords: metaplasia, renal pelvis, immunohistochemistry, kidney, urothelium 1department of pathology, erciyes university, faculty of medicine, kayseri, turkey 2department of pathology, tekden 3department of urology, tekden corresponding author: department of pathology, erciyes university, faculty of medicine, kayseri, turkey fax: +90 352 651 6177 received july 2009 accepted january 2010 introduction renal pelvis is normally lined by urothelium and contains neither squamous nor intestinal epithelium. however, transitional cell epithelium undergoes phenotypic changes usually in the form of squamous metaplasia.(1) we report a rare case of intestinal metaplasia of the renal pelvis with cytokeratin profile and assessment of the tumor markers to set light to understand the pathogenesis of the multistep pathway through metaplasia to neoplasia. case report a 32-year-old man presented with left flank pain and dysuria. he had a history of urolithiasis for 3 years. physical examination revealed a nonpalpable left kidney. an intravenous pyelography showed a small nonfunctioning left kidney. no calculus was identified within the urinary tract. ultrasonography revealed a small kidney with dimensions of 9.5 × 5.3 cm. left nephrectomy was performed. gross examination of the surgical specimen revealed a shrunken kidney with dimensions of 6 × 3 × 2 cm. cut surface showed destruction of the normal parenchyma and thinning of the cortex (figure 1). the corticomedullary border was obscured with fatty infiltration. light microscopic examination revealed features of chronic pyelonephritis, including tubular atrophy with thyroidization of the remaining tubules, loss of glomerules, interstitial fibrosis, and lymphoplasmacytic infiltrate. the epithelial lining of the renal pelvis showed intestinal metaplasia with abundant goblet cells. gradual transition from urothelium to figure 1. cut surface of the nephrectomy specimen showing thinning of the cortex, dilatation of the calices, and fatty infiltration of the medulla. renal pelvis metaplasia—deniz et al 288 urology journal vol 7 no 4 autumn 2010 the intestinal epithelium was seen in the form of pyelitis glandularis (figure 2). no squamous metaplasia was observed. histologic examination did not reveal any dysplastic foci or invasive adenocarcinoma. immunohistochemical studies were performed and summarized in table. after 3 months of follow-up, the patient was asymptomatic and free of disease. discussion the intestinal metaplasia of the renal pelvis is very rare and to the best of our knowledge, only 15 subjects have been reported in english literature.(2-4) the ages ranged from 24 to 79 years old. the sex ratio is 3.6 to 1 (male to female ratio is 11 to 3) with a male predominance. almost all of the subjects have been reported to be associated with pyonephrosis or pyelonephritis. of reported subjects, 14 (93%) had calculi. six of the 15 subjects had both intestinal and squamous metaplasia, and the remaining cases had only intestinal metaplasia. intestinal metaplasia of the renal pelvis is an incidental histologic finding and the clinical presentation is nonspecific and mainly figure 2. hematoxylin and eosin photomicrographs showing atrophy of the renal parenchyma, pyelitis glandularis, and intestinal metaplasia, respectively. ck8 positivity in both normal and metaplastic urothelium; ck7 positivity in urothelium and negativity in intestinal metaplasia; ck20 positivity in the superficial layer of the urothelium and diffuse ck20 positivity in the metaplastic areas. p53 and p16 negativity in the urothelium and positive nuclear staining in the intestinal metaplasia. nuclear ki67 staining in urothelium and intestinal metaplasia. immunohistochemical staining pattern in transitional and metaplastic epithelium. transitional epithelium pyelitis glandularis intestinal epithelium ck5/6 + (basal cells) + (basal cells) ck7 + + ck8 + + + ck18 + + + ck19 + (focal) + (focal) ck20 + (superficial layer) + + p16 + (few cells) + p53 + (few cells) + ki67 <1 % <1 % 10% to 20% renal pelvis metaplasia—deniz et al 289urology journal vol 7 no 4 autumn 2010 depends on the underlying kidney disease. urothelium has a potential to undergo metaplastic changes, and chronic inflammation and irritation play critical roles in development of metaplastic changes. however, the mechanism of the glandular metaplasia is not well understood.(5) urothelium normally expresses simple epithelial cytokeratins such as ck7, ck8, ck18, ck19, ck20, and other isoforms in small amounts of ck5, ck4, and ck17. simple epithelial cytokeratins are present in all urothelial cell layers. cytokeratin 5 is expressed in basal cells and ck13 and ck20 are expressed in superficial umbrella cells.(6) in the present case, ck7, ck8, ck18, ck19, ck20, and ck5/6 expression are preserved in normal urothelium whereas metaplastic epithelium lost ck7, ck19, and ck5/6 expression and gained stronger ck20 expression. pyelitis glandularis showed a cytokeratin expression profile similar to the normal urothelium. these findings further support that pyelitis glandularis is a transition step in this metaplastic process. precancerous changes are thought to be present in the metaplastic changes and adenocarcinomas may arise from metaplastic changes of potentially unstable epithelium.(5) alterations in cell cycle regulators such as p16 and p53 are found in significant fractions of urothelial and nonurothelial carcinomas.(7) the p53 expression indicates loss of cell cycle control and is in favor of progression into dysplasia. the p53 gene product is known to modulate the transition from premalignant to malignant condition. it plays an early role in the neoplastic changes and its accumulation might occur in the nondysplastic gland before the phenotypic changes of neoplasia become apparent.(1,8) the pl6 (cdkn2a) is frequently involved in urinary bladder carcinogenesis and plays a role similar to p53.(9) in conclusion, urothelium begins to loss of cell cycle control assessed by p53 and p16 accumulation during the intestinal metaplasia and our study proves the hypothesis that metaplastic epithelium of the renal pelvis is at least potentially premalignant.(3) monitoring of the renal pelvic urothelium in the context of the pyelonephritis is difficult; therefore, nephrectomy will be the safest therapeutic strategy in long lasting cases. conflict of interest none declared. references 1. kunze e, francksen b. histogenesis of nonurothelial carcinomas of the urinary bladder from pre-existent transitional cell carcinomas. a histopathological and immunohistochemical study. urol res. 2002;30:66-78. 2. salm r. combined intestinal and squamous metaplasia of the renal pelvis. j clin pathol. 1969;22:187-91. 3. ward am. glandular neoplasia within the urinary tract. the aetiology of adenocarcinoma of the urothelium with a review of the literature. i. introduction: the origin of glandular epithelium in the renal pelvis, ureter and bladder. virchows arch a pathol pathol anat. 1971;352:296-311. 4. mathur s, singh mk, rao si, seth a. mucinous metaplasia of the renal pelvic epithelium in a case of recurrent urolithiasis and pyelonephritis. urol int. 2004;72:355-7. 5. manunta a, vincendeau s, kiriakou g, lobel b, guille f. non-transitional cell bladder carcinomas. bju int. 2005;95:497-502. 6. southgate j, harnden p, trejdosiewicz lk. cytokeratin expression patterns in normal and malignant urothelium: a review of the biological and diagnostic implications. histol histopathol. 1999;14:657-64. 7. schulz wa. understanding urothelial carcinoma through cancer pathways. int j cancer. 2006;119:1513-8. 8. toyoda h, mabuchi t, fukuda k. mucinous cystadenoma with malignant transformation arising in the renal pelvis. pathol int. 1997;47:174-8. 9. lopez-beltran a, sauter g, gasser t. infiltrating urothelial carcinoma. in: eble jn, sauter g, epstein ji, sesterhenn ia, eds. pathology and genetics of tumours of the urinary system and male genital organs.lyon, iarc pres; 2004:103-9. oncological outcomes of patients with non-clear cell renal cell cancers: subtypes of unclassified and translocation renal cell cancers fatih gokalp1, serdar celik2, tevfik sinan sozen3, abdurrahim haluk ozen4, guven aslan5, volkan izol6, sumer baltaci7, talha muezzinoglu8, bulent akdogan4, evren suer7, ilker tinay9 purpose: we aimed to compare oncological outcomes in the two rare subtypes, unclassified renal cell cancer (unrcc) and translocation rcc (trcc), vs clear cell rcc (ccrcc). materials and methods: between 2004 and 2019, from turkish urooncology society database, we identified 2324 patients for histological subtypes including 80 unrcc (3.4%), 19 trcc (0.8%) and 2225 ccrcc (95.8%). results: the overall (15.8%) and cancer-specific mortalities (11.1%) were found to be higher in trcc group and the recurrence free mortality (13.8%) was found to be higher in unrcc group. larger pathological tumor size (p = 0.012) and advanced pathological t stage (p = 0.042) were independent predictive factors on overall mortality in patients with unrcc tumors. conclusion: the oncological outcomes of the unrcc and trcc are worse than ccrcc and pathological tumor size and pathological stage are predictive factors for mortality in the unrcc. keywords: kidney; kidney cancer; oncology; pathology introduction the majority of the kidney cancers are diagnosed histologically as renal cell carcinoma (rcc). the most common subtypes are clear cell rcc (ccrcc), chromophobe rcc (chrcc), and papillary rcc (prcc). other histopathological subtypes, including unclassified rcc (unrcc) and translocation rcc (trcc), are rare and their frequencies are below 3% (1,2). with increasing recognition of the morphological overlap between subtypes, the spectrum of morphological patterns in unclassified rccs has widened and includes both low-grade and high-grade histological tumors(2). unclassified rccs refers to a histologically heterogeneous tumor spectrum, many of which are high-grade, present with more frequent nodal involvement or distant metastasis, and are reported to have lower survival rates(1,3). trcc is a group of tumors characterized by recurrent rearrangements at the xp11 locus or at the 6p21 locus(4). recently, the diagnosis of trcc, which is frequently seen in childhood, increases in adults with a more aggressive behavior compared to children(5). 1department of urology, hatay mustafa kemal university, school of medicine, hatay, turkey. 2department of urology, bozyaka training and research hospital, izmir, turkey. 3department of urology, gazi university, school of medicine, ankara, turkey. 4department of urology, hacettepe university, school of medicine, ankara, turkey. 5department of urology, dokuz eylul university, school of medicine, izmir, turkey. 6department of urology, cukurova university, school of medicine, adana, turkey. 7department of urology, ankara university, school of medicine, ankara, turkey. 8department of urology, manisa celal bayar university, school of medicine, manisa, turkey. 9department of urology, marmara university school of medicine, istanbul, turkey. *correspondence: hatay mustafa kemal university, faculty of medicine department of urology, 31060, antakya, turkey phone : + 90 326 229 1000 . fax: + 90 326 245 5305. e-mail : fatihgokalp85@gmail.com. received november 2021 & accepted june 2022 treatment strategies for unrcc are depending on tumor stage, amenability to resection, and comorbidities, similar to ccrcc. the data of neoadjuvant treatments is still limited and adjuvant treatment for local advanced disease has not showed any benefit for overall survival in patients with unfovarable rccs(6). the optimal treatment of trcc remains to be determined and recent data showed that trcc commonly did not respond to immunotherapy and chemotherapy when compared to ccrcc(7). in this study, we aimed to compare oncological outcomes in the two rare subtypes, unrcc and trcc, vs ccrcc. materials and methods between 2007-2019, total of 2324 patients who had undergone radical or partial nephrectomy from 15 center due to renal cell carcinoma (rcc) were evaluated retrospectively. study data were collected and managed using redcap (research electronic data capture) tools hosted at the urologic cancer database testis, urological oncology urology journal/vol 20 no. 1/ january-february 2023/ pp. 29-33. [doi:10.22037/uj.v19i.7091] turkish urooncology association (urocad-t). patients with a solitary kidney, other urological diseases, and other malignancies were excluded from the study. patients were divided into three groups as ccrcc, unrcc, and trcc according to rcc histopathological classification. the pathological specimens were evaluated using the 2016 world health organization classification system. demographic data including age, gender, bmi, tumor size, recurrence, and mortality status of the groups were collected from redcap database and compared. the recurrence-free survival (rfs), overall survival (os) and cancer-specific survival (css) data were investigated. the shapiro wilk test was used for determining the normality. the continuous variables were shown as mean and standard derivation. the categoric variables were shown as count and frequency. the chisquare test was used for comparison. the kruskal-wallis test was used for comparison and mann whitney u test was used for post hoc test. survival was analyzed using kaplan-meier estimate for histological subtypes between 2007-2019 and mean follow up for ccrcc is 24.6 ± 30.2 months. uniand multivariable cox regression was used to analyze prognostic factors for overall survival (os), recurrence-free survival (rfs) and cancer-specific survival (css). the variables entered the model as age, gender, bmi, pathological tumor size, pathological stage, radiological t3-4 stage, fuhrman 3-4. the p value of the model was meaningful for each group in first step. results we identified 2324 patients with rcc. the proportion of unrcc, trcc and ccrcc in the 2324 patients were 80 (3.4%), 19 (0.8%) and 2225 (95.8%), respectively. patient demographics are presented in table 1. the mean age was lower, and the female ratio was higher in the trcc group. radiological local invasion rate, tumor diameter and pt3a/b ratio were higher in unrcc (12.5%, 6.7 ± 4.5 cm and 25% respectively). fuhrman grade 3-4 ratio was also mostly observed in unrcc (79.7%). on the other hand, the pathological t4 stage rate was highest in the trcc group (21.1%). recurrences were found to be higher in unrcc group and no recurrence was observed in trcc possibly due to relatively short follow-up periods in this group compared to the other groups (table 1). the overall and cancer-specific mortalities were found to be higher in trcc group (figure 1 and 2 and table 1). the predictive factors affecting recurrence and overall mortality in unrcc and trcc groups are given in table 2. the recurrence rate was 13.8% in unrcc group (table 1) and none of the clinical and pathological factors were found to be statistically significant for recurrence in this group (table 2). overall mortality was 10% in unrcc group (table 1) and larger pathological tumor size (hr:1.203. 95%ci:1.042-1.388. p = 0.012) and advanced pathological t stage (hr:1.517. 95% ci:1.015-2.268. p = 0.042) were found to be independent predictive factors for overall mortality in patients with unrcc tumors (table 2). overall mortality was 15.8% in trcc group (table 1). although, larger pathological tumor size was found to be a significant factor for overall mortality on univariate analysis (5.9 ± 2.4 vs 9.5 ± 3.1. p = 0.035), this factor was not found to be an independent factor for overall mortality after the multivariate analysis (hr:1.673 95%ci:0.958-2.920. p = 0.070). discussion the behavior and prognosis of non-clearcell rcc is varies. unrcc molecular characterization is particularly different from ccrcc, such as frequently seen muoncological outcomes of non-clear cell renal cell cancers-gokalp et al. ccrcc (n=2225) (93%) unrcc (n=80) (3.3%) trcc (n=19) (0.8%) p age (years) a 57.2 ± 11.8 59.6 ± 10.8 34.5 ± 10* < 0.001 gender b female 788 (35.6) 28 (35.4) 12 (63.2)* 0.045 male 1425 (64.4) 51 (64.6) 7 (36.8)* bmi (kg/m2) a 28.1 ± 5 29 ± 7.4 25.5 ± 2.6 0.231 radiological tumor size (cm) a 5.5 ± 3.3 6.7 ± 4.5* 6.2 ± 2.3 0.003 tumor diameter b < 4cm 874 (39.4) 21 (26.3) 3 (15.8) 0.026 4-7cm 795 (35.8) 31 (38.8) 12 (63.2)* 7-10cm 378 (17) 18 (22.5)* 2 (10.5) >10cm 171 (7.7) 10 (12.5)* 2 (10.5) tumor involvement b locally 1984 (89.2) 70 (87.5) 17 (89.5) 0.894 locally invasive 241 (10.8) 10 (12.5) 2 (10.5) patological tumor size (cm) a 5.7 ± 3.3 7.6 ± 4.6* 6.5 ± 2.7 < 0.001 pathological stage b t1a 825 (37.1) 13 (16.3) 3 (15.8) < 0.001 t1b 632 (28.4) 16 (20) 10 (52.6)* t2a 242 (10.9) 13 (16.3) 2 (10.5) t2b 91 (4.1) 6 (7.5) 0 (0) t3a 290 (13) 18 (22.5)* 0 (0) t3b 19 (0.9) 2 (2.5)* 0 (0) t4 126 (5.7) 12 (15) 4 (21.1)* fuhrman grade b 1-2 1118 (61.7) 12 (20.3) 3 (42.9) < 0.001 3-4 693 (38.3) 47 (79.7) 4 (57.1)* upstaging to t3-4 b 314 (14.1) 28 (35)* 2 (10.5) < 0.001 recurrence b 149 (6.7) 11 (13.8)* 0 (0) 0.025 overall mortality b 73 (3.3) 8 (10) 3 (15.8)* < 0.001 cancer-specific mortality b 25 (1.1) 4 (5.3) 2 (11.1)* < 0.001 mean follow-up (month) a 24.6 ± 30.2 27.6 ± 31.6 16.1 ± 14 0.530 table 1. clinical, pathological and oncological data of patients with ccrcc, unrcc and trcc. *the values showed statistically significance a data was expressed as mean and standard derivation b data was expressed as count and frequency urological oncology 30 tations such as tp53, nf2, setd2, and bap1, while there are distinct differences such as lack of vhl alterations with unrcc(8,9). but it is difficult to determine the histopathological type correctly and it can be determined by histomorphology, immunohistochemical and molecular genetic tests in selected cases. the literature makes comparisons of histopathological one subtype with ccrcc. our study is an addition to literature because of compares subtypes within their self. in our study, the worst prognosis was seen in trcc, when compared with unrcc and ccrcc. karakiewicz et al. reported that fuhrman grade iii-iv and metastatic disease were higher in unrcc compared to ccrcc (80% vs. 37.8% and 54.1% vs. 16.8%, respectively) and mortality rate was 1.6 times higher in patients with unrcc compared to ccrcc(2). additionally, a novel study which assessed 136 unrcc and divided four patterns included: predominantly oncocytoma/chromophobe rcc-like phenotype, predominantly papillary rcc-like phenotype, predominantly clear cell rcclike phenotype, predominantly collecting duct-like phenotype, and pure sarcomatoid phenotype showed that he majority of the oncocytoma/chromohistological subtype recurrence overall mortality univariate p value multivariate hr (ci) univariate p value multivariate hr (ci) unrcc • age (year) 0.548 0.304 • gender 0.597 0.590 • bmi (kg/m2) 0.338 0.841 • pathological tumor size 0.070 0.043 1.203 (1.042-1.388) • pathological stage 0.216 0.031 1.517 (1.015-2.268) • radiological t3-4 stage 0.136 0.057 • fuhrman 3-4 0.482 0.647 trcc • age (year) 0.177 • gender 0.296 • bmi (kg/m2) 0.460 • pathological tumor size 0.035 1.673 (0.958-2.920) • pathological stage 0.419 • radiological t3-4 stage 0.702 • fuhrman 3-4 0.571 table 2. predictive factors affecting recurrence and overall mortality in unrcc and trcc groups. figure 1. cancer specific survival plots of ccrcc. unrcc and trcc. oncological outcomes of non-clear cell renal cell cancers-gokalp et al. vol 20 no 1 january-february 2023 31 phobe and clear cell rcc-like phenotypes were low stage (pt1 or pt2). the papillary rcc-like, collecting duct-like, and pure sarcomatoid phenotypes were mostly high stage (pt3 or pt4)(10). controversially, crispen et al. also reported that the fuhrman grade iii-iv was higher in unrcc group (p < 0.001) however, they found no difference in metastatic disease rate and overall survival rate between unrcc and ccrcc patients (p = 0.239, and p = 0.345, respectively)(11). additionally, a novel. study which assessed patients with unrcc showed that 58.8% of patients were in advanced stage and 76.5% had high fuhrman grade(12). in our study, like karakiewicz et al, we found that unrcc had higher upstaging and local recurrence rates and worse cancer specific survival compared to ccrcc. trcc also had heterogeneity in oncological outcomes due to genetic heterogeneity. trcc is a rare pathology and case series seen in childhood rcc and rarely adult age with an average age of onset of 50 years. the trcc in childhood is generally considered mild prognosis(13). the published studies pointed that the trcc in adults had worse prognosis than papillary rcc and may be comparable or worse than clear cell rcc(14). camparo et al. reported that the rate of pt3-4 and metastatic disease were 30% and 42% in patients with trcc. the recurrence rate was 32% and 16% of patients were died at a mean follow-up period of 29.5 months(15). similarly, our study showed that pt4 disease was higher in trcc group and pathological tumor size was found to be a predictive factor for overall mortality both in trcc and unrcc patients. limitations of the study: first, the lack of lymphadenectomy data and demographic data including comorbidities or smoking status is an important limitation. the literature demonstrated that the lymphnode dissection serves an important staging role by providing pathologic lymphnodestage, which has been independently associated with survival in nonmetastatic and metastatic renal cell carcinoma. however, literature also pointed that lymphnode dissection does not seem to provide a survival benefit for nonmetastatic or metastatic renal cell carcinoma, even in patients at increased risk for lymph node metastases. second, our study is a multicenter study which represents the data of major urooncology institutions nationwide. third, the absence of adjuvant treatment data is an important limitation regarding disease recurrence or progression, however due to the limited adjuvant treatment options in these rare histological subgroups, we believe this limitation should be accepted as a minor limitation. conclusions oncological outcomes of the trcc and unrcc are worse than ccrcc. pathological tumor size and pathological stage are predictive factors for mortality in the unrcc group. pathological tumor size is also a predictive factor for overall mortality for trcc. summary the rare histopathological subtypes, including unclassified rcc (unrcc) and translocation rcc (trcc) have worse outcomes. large pathological tumor size is found to be independent predictive factors for overall mortality in patients with unrcc tumors and trcc. additionfigure 4. overall survival plots of ccrcc, unrcc and trcc oncological outcomes of non-clear cell renal cell cancers-gokalp et al. urological oncology 32 ally, advanced pathological tumor stage are found to be independent predictive factors for overall mortality in patients with unrcc tumors. acknowledgments the authors thank the dr. nihat karakoyunlu, dr. özdal dillioğlu, dr. tayyar alp ozkan, dr. ozan bozkurt, dr. hayrettin sahin, dr. levent turkeri, dr. gokhan toktas, dr. saadettin eskicorapci, and dr. ender ozden for sharing data with us. conflict of interest the authors declared that there is no conflict of interest. references 1. zisman a, chao dh, pantuck aj, et al. unclassified renal cell carcinoma: clinical features and prognostic impact of a new histological subtype. j urol. 2002;168:950-5. 2. karakiewicz pi, hutterer gc, trinh qd, et al. unclassified renal cell carcinoma: an analysis of 85 cases. bju int. 2007;100:802-8. 3. amin mb, amin mb, tamboli p, et al. prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. am j surg pathol. 2002;26:28191. 4. sirohi d, smith sc, agarwal n, maughan bl. unclassified renal cell carcinoma: diagnostic difficulties and treatment modalities. res rep urol. 2018;10:205. 5. argani p, olgac s, tickoo sk, et al. xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. am j surg pathol. 2007;31:114960. 6. haas nb, manola j, uzzo rg, et al. adjuvant sunitinib or sorafenib for high-risk, nonmetastatic renal-cell carcinoma (ecogacrin e2805): a double-blind, placebocontrolled, randomised, phase 3 trial. the lancet. 2016;387:2008-16. 7. armah hb, parwani av. xp11.2 translocation renal cell carcinoma. arch pathol lab med. 2010;134:124-9. doi:10.5858/2008-0391rsr.1 8. hu zy, pang lj, qi y, et al. unclassified renal cell carcinoma: a clinicopathological, comparative genomic hybridization, and whole-genome exon sequencing study. int j clin exp pathol. 2014;7:3865. 9. chen yb, xu j, skanderup aj, et al. molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. nat commun. 2016;7:1-10. 10. perrino cm, grignon dj, williamson sr, idrees mt, eble jn, cheng l. morphological spectrum of renal cell carcinoma, unclassified: an analysis of 136 cases. histopathology. 2018;72:305-19. 11. crispen pl, tabidian mr, allmer c, et al. unclassified renal cell carcinoma: impact on survival following nephrectomy. urology. 2010;76:580-6. 12. çelik s, altay c, değer md, et al. postoperative and mid-term outcomes of unclassified renal cell carcinoma. uroonkoloji buelteni bull urooncology. 2021;20:117. 13. ellis cl, eble jn, subhawong ap, et al. clinical heterogeneity of xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage. mod pathol. 2014;27:875-86. 14. caliò a, segala d, munari e, brunelli m, martignoni g. mit family translocation renal cell carcinoma: from the early descriptions to the current knowledge. cancers. 2019;11:1110. 15. camparo p, vasiliu v, molinie v, et al. renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. am j surg pathol. 2008;32:65670. oncological outcomes of non-clear cell renal cell cancers-gokalp et al. vol 20 no 1 january-february 2023 33 a scoring system for optimal selection of endoscopic treatment for 1-2cm lower pole renal calculi yuleng huang1,# kaiwen li1,# wenzeng yang2, zhuohang li1, cheng liu1, cong lai1, yongzhong he3,** kewei xu1* purpose: to explore the establishment of a scoring system that can provide a reference for clinical decision making regarding the endoscopic treatment of 1-2 cm lower pole stones (lps). materials and methods: the data of patients with renal calculi who were treated with percutaneous nephrolithotomy (pcnl) or retrograde intrarenal surgery (rirs) in three hospitals from january 2013 to december 2017 were analyzed retrospectively. multivariable logistic analysis was performed to determine the statistically significant indicators and regression coefficients, which were used to construct the scoring system. the stone-free rate (sfr) and postoperative complication rates of pcnl and rirs within the two fractional segments of the scoring system were compared to select the optimal procedures. results: a total of 137 patients in the pcnl group and 152 patients in the rirs group were included in this study. five factors were found to be most predictive of endoscopic treatment choice: stone number, stone diameter, infundibulopelvic angle (ipa), infundibular length (il), and infundibular width (iw), yielding a total score ranging from 0-5. in the 0-2 segments, the rirs group had better outcomes than the pcnl group in terms of the postoperative complication rates (6.8% versus 18.0%, p = .026). in segments 3-5, the sfr of the pcnl group was significantly higher than that of the rirs group (88.5% versus 70.6%, p = .017). conclusion: our scoring system was based on the patient’s preoperative imaging examination to measure the stone number, stone diameter, ipa, il and iw. rirs was recommended at 0-2 segments, and pcnl was recommended at 3-5 segments. this new scoring system is expected to provide guidance for urologists to make endoscopic treatment decisions for 1-2 cm lps. keywords: percutaneous nephrolithotomy; retrograde intrarenal surgery; lower pole renal calculi; scoring system introduction lower pole stones (lps) are the most common renal calculi and are the most likely to require treatment because these types of stones are unlikely to be excreted automatically(1). endourological procedures, such as percutaneous nephrolithotomy (pcnl) and retrograde intrarenal surgery (rirs), are available treatments for lps, and several studies have compared the safety and efficacy of pcnl and rirs for lps(1-5). pcnl has a higher stone free rate (sfr) than rirs, but has higher complication rates, and the complications include bleeding, perinephric hematoma, organ injury, and urinary leakage(6-7). due to the development in endoscopic technology, rirs provides an alternative to pcnl, potentially achieving a comparable sfr and less morbidity than pcnl(1,2,5). there is still controversy regarding the use of pcnl or rirs for the treatment of 1-2 cm lps. in recent years, there have been many scoring systems used to 1department of urology, sun yat-sen memorial hospital, guangdong provincial key laboratory of malignant tumor epigenetics and gene regulation, sun yat-sen university, 107w yanjiang road, yuexiu district, guangzhou, guangdong, china 2department of urology, affiliated hospital of hebei university, baoding, hebei, 071000, p. r. china 3department of urology, fifth affiliated hospital of guangzhou medical university, guangzhou, guangdong, china #these authors contributed equally to this study. *correspondence: department of urology, sun yat-sen memorial hospital of sun yat-sen university, guangdong, china. e-mail: xukewei@mail.sysu.edu.cn. **department of urology, fifth affiliated hospital of guangzhou medical university, guangdong, china. e-mail: hyzprc@163.com. received january 2022 & accepted may 2022 predict sfr and the postoperative complications after calculi surgery, and these scoring systems include the guy's stone score (gss), croes nephrolithometric nomogram, s.t.o.n.e. score, s-resc score and so on. nevertheless, these scoring systems cannot be used to guide the choice of surgical procedure for 1-2 cm lps because these scoring systems can only predict a single surgical outcome. hence, we aimed to construct a new objective scoring system to distinguish the most suitable surgical methods for patients with 1-2 cm lps. herein, we derived a scoring system based on the preoperative stone characteristics to provide a basis for the choice between pcnl or rirs. materials and methods study population we performed a retrospective review of patients with 1-2 cm lps treated with either pcnl or rirs at sun yat-sen memorial hospital of sun yat-sen university, urology journal/vol 19 no. 5/ september-october 2022/ pp. 356-362. [doi: 10.22037/uj.v19i.7195] endourology and stone disease the fifth affiliated hospital of guangzhou medical university, and affiliated hospital of hebei university from january 2013 to december 2017. the following inclusion criteria were followed for selecting the patients to be included in the present study population: age between 18 and 75 years old, (2) either sex, and (3) lps with diameters between 1-2 cm as determined by non-contrast computed tomography (ct). the exclusion criteria were uncontrollable systemic hemorrhagic disease, anatomic abnormalities of the urinary tract, pregnancy, and active urinary tract infection. the demographic, clinical, and operative data were collected. surgical technique pcnl procedure: the patient was placed in the semisupine‐lithotomy or prone position. the tract was dilated to f18-22. the calculi were fragmented by ho:yag laser. a nephrostomy tube was inserted after surgery. none of these patients required staged procedures. rirs procedure: the patient was placed in the lithotomy position. a digital flexible ureteroscope was used to explore the renal calyx, and stones were fragmented by ho:yag laser. the stones were pulverized, and a basket was used if needed. none of these patients required staged procedures. outcome assessment the preoperative patient demographic characteristics were assessed. the stone characteristics were measured by using ct and intravenous urography (ivu). the infundibular length (il), infundibular width (iw) and pelvicalyceal height (pch) were measured by intravenous urography, as previously described by elbahnasy et al (8). the infundibulopelvic angle (ipa) was measured according to sampaio et al(9). il, and it was measured as the distance between the most distal point of the calyx containing the calculus and the midpoint of the lower lip of the renal pelvis (supplementary figure 1). the iw was measured as the narrowest point in the axis of the lower infundibulum (supplementary figure 2). the pch was measured as the distance between the lower lip of the renal pelvis and the bottom of the lower calyx (supplementary figure 3). the ipa was measured as the angle between the vertical pelvis axis and the vertical axis of the lower infundibulum (supplementary figure 4). stone free was defined as no residual stones or the presence of residual stones that were < 2 mm in diameter on the follow-up kub for positive stones or ct for negative stones 1 month after the operation. the postoperative complications were assessed according to the modified clavien–dindo classification system(10). scoring system we hypothesized that there were differences in the systemic or anatomical factors between patients treated with pcnl and those treated with rirs and that these factors would affect the choice of surgery. first, we compared the quantitative data between the pcnl group and the rirs group, and determined the optimal cutoff points of the statistically significant variables according to youden’s index value. then, we transformed these significant quantitative data into categorical variables. multivariable logistic analysis was performed to determine the statistically significant variables. we selected a base category and assigned it scoring system for endoscopic surgery of lower pole renal stones-huang et al. table 1. demographics and outcomes compared between pcnl group and rirs group characteristics and outcomes a pcnl rirs p-value age (years) 52 (45.5, 60.0) 51.5 (43.0, 61.0) .654 male gender 88 (64.2) 86 (56.6) .184 body mass index (kg/m2) 24.2 (21.4, 26.4) 23.4 (21.3, 26.0) .611 laterality .671 left 80 (58.4) 85 (55.9) right 57 (41.6) 67 (44.1) history of previous ipsilateral surgery 55 (40.1) 65 (42.8) .652 stone diameter (mm) 18.0 (13.0, 18.8) 13.0 (11.0, 15.8) < .001 sfr 122 (89.1) 119 (78.3) .014 postoperative complication rates 25 (18.2) 13 (8.6) < .001 clavien-dindo i 19 (13.9) 11 (7.2) clavien-dindo ii 4 (2.9) 2 (1.3) clavien-dindo iiia 2 (1.4) 0 (0.0) postoperative hospital stay (days) 7.0 (5.0, 8.0) 3.5 (3.0, 4.0) < .001 operative time (min) 55.0 (50.0, 60.0) 60.0 (55.0, 74.0) < .001 drop in hb (g/l) 11.0 (3.0, 19.0) 3.0 (-2.75, 9.0) <.001 increase in crea (µmol/l) 6 (-3.5, 12.0) 5 (-1.0, 11.0) .934 abbreviations: sfr, stone free rate; hb, hemoglobin; crea, creatinine. a data are presented as mean ± sd, m (q1, q3) or number (percent) endourology and stones diseases 269 factors area under the curve 95% confidence interval cutoff value youden’s index sensitivity specificity stone diameter 0.719 0.660-0.778 14.9 0.385 0.628 0.757 stone density values 0.625 0.561-0.689 1100.4 0.191 0.803 0.388 il 0.678 0.615-0.741 30.0 0.347 0.584 0.763 iw 0.657 0.594-0.720 5.02 0.296 0.697 0.599 ipa 0.639 0.574-0.703 89.95 0.295 0.638 0.657 table 2. baseline characteristics of the patients abbreviations: il, infundibular length, iw, infundibular width, ipa, infundibulopelvic angle. vol 19 no 5 september-october 2022 357 0 points in the scoring system. we calculated how far every category was from the base category in terms of regression units and set the minimum value as 1 point. we stratified the system into 0-2 segments and 3-5 segments based on the estimated clinical utility, which was achieved through a consensus of all investigators. we then compared the outcomes of pcnl and rirs within the two fractional segments of the scoring system to screen the optimal selection of endoscopic treatment for 1-2 cm lps. statistical analysis statistical analysis was performed by spss (ibm corp, version 22). quantitative data with a normal distribution are described by the mean ± sd, and data with a skewed distribution are reported by m (q1, q3). qualitative data were described by the frequency (percentage). a two-sample t test was performed to compare the mean values of the two groups if two independent samples were selected from two normally distributed populations in which the variance was equal; otherwise, the mann–whitney u test was performed. normality was assessed by the kolmogorov–smirnov test. homogeneity of variance was assessed by the f test. a chisquare test was applied to compare the two groups of qualitative data. the kruskal–wallis test was used to compare multiple groups of quantitative data and qualitative data. the likelihood ratio test of the conditional parameter estimation was used in a stepwise regression analysis of the multivariable logistic analysis, and the 95% confidence interval was calculated. p < .05 was considered statistically significant. urological oncology 198 univariable analysis multivariable analysis risk factors pcnl rirs p-value 95% ci (or) p-value stone number <.001 1.18-3.38 (1.997) .010 single 54 (39.4) 96 (63.2) multiple 83 (60.6) 56 (36.8) stone diameter <.001 1.457-4.197 (2.473) .001 >15mm 86 (62.8) 57 (37.5) ≤15mm 51 (37.2) 95 (62.5) ipa <.001 1.448-4.177 (2.459) .001 > 90° 62 (45.3) 108 (71.1) ≤90° 75 (54.7) 44 (28.9) il <.001 1.585-4.623 (2.707) .001 > 30mm 73 (53.3) 43 (28.3) ≤30mm 64 (46.7) 109 (71.7) iw <.001 1.297-3.812 (2.224) .004 > 5mm 69 (50.4) 109 (71.7) ≤5mm 68 (49.6) 43 (28.3) stone density values .003 > 1100hu 78 (56.9) 60 (39.5) ≤ 1100hu 59 (43.1) 92 (60.5) hydronephrosis .04 none or mild 102 (74.5) 128 (84.2) medium or severity 35 (25.5) 24 (15.8) abbreviations: il, infundibular length, iw, infundibular width, ipa, infundibulopelvic angle. table 3. postoperative clinical outcomes factors categories reference value ( wij ) points stone number single 0 = w1ref 0 multiple 1 1 stone diameter ≤15mm 0 = w2ref 0 ≤ 15mm 1 1 ipa > 90° 0 = w3ref 0 ≤90° 1 1 il ≤30mm 0 = w4ref 0 ≤ 30mm 1 1 iw > 5mm 0 = w5ref 0 ≤ 5mm 1 1 abbreviations: il, infundibular length, iw, infundibular width, ipa, infundibulopelvic angle. table 4. scoring system, factors, and categories figure 1. il measurement. scoring system for endoscopic surgery of lower pole renal stones-huang et al. endourology and stones diseases 358 results the present study included 289 patients, including 137 patients who underwent pcnl and 152 patients who underwent rirs. comparisons of the demographics and outcomes between the pcnl group and rirs group are listed in table 1. the sfr of the pcnl group was higher than that of the rirs group (89.1% versus 78.3%, p = .014), but the postoperative complication rates were also higher than those of the rirs group (18.2% versus 8.6%, p = .014). supplementary table 1 and table 2 list the characteristics and outcomes of the patients treated by pcnl or rirs among the three hospitals, and these characteristics were not significantly different. supplementary table 3 and table 4 show the quantitative and quantitative factors that were compared between the pcnl group and the rirs group. the roc curve was drawn according to the previous significant quantitative data (supplementary figure 5). table 2 shows the youden’s index used to determine the cutoff points of the stone diameter, stone density values, il, iw, and ipa. the calculated cutoff points of the stone diameter, stone density values, il, iw, ipa were 14.9 mm, 1100.4 hu, 30.0 mm, 5.02 mm, 89.95°, respectively. to facilitate calculation and memory, we decided to set the optimal cutoff points to their nearest integer: the stone diameter cutoff was 15 mm, the stone density value cutoff was 1100 hu, the il cutoff was 30 mm, the iw cutoff was 5 mm, and the ipa cutoff was 90°. 0-2 scores pcnl rirs p-value sfr a 45 (90.0) 95 (80.5) .131 postoperative complication rates 9 (18.0) 8 (6.8) .026 clavien-dindo i 7 (14.0) 7 (5.9) clavien-dindo ii 1 (2.0) 1 (0.8) clavien-dindo iiia 1 (2.0) 0 (0.0) 3-5 scores pcnl rirs p-value sfr 77 (88.5) 24 (70.6) .017 postoperative complication rates 16 (18.4) 5 (14.7) .618 clavien-dindo i 12 (13.8) 4 (11.8) clavien-dindo ii 3 (3.4) 1 (2.9) clavien-dindo iiia 1 (1.1) 0 (0.0) table 5. outcomes compared between pcnl group and rirs group in 0-2 scores and 3-5 scores. abbreviations: sfr, stone free rate. a data are presented as number (percent) endourology and stones diseases 271 figure 2. iw measurement. figure 3. pch measurement. figure 4. ipa measurement. scoring system for endoscopic surgery of lower pole renal stones-huang et al. vol 19 no 5 september-october 2022 359 table 3 shows the variables that were significant according to the univariate and multivariable analysis between the pcnl group and rirs group. the multivariable analysis indicated five factors that were most significantly associated with the optimal selection of endoscopic treatment for 1-2 cm lps: stone diameter, stone number, ipa, il, and iw. they were incorporated into the scoring system with the associated integer point values (table 4). in our study, we chose single stone number, stone diameter ≤ 15 mm, ipa > 90°, il ≤ 30 mm, and iw > 5 mm as the base categories. the surgical results were compared, as shown in table 5. in the 0-2 segments, the rirs group had better postoperative complication rates than the pcnl group (6.8% versus 18.0%, p = .026). in segments 3-5, the sfr of the pcnl group was significantly higher than that of the rirs group (88.5% versus 70.6%, p =.017). discussion to the best of our knowledge, the new clinical scoring system that is described by this study is the first scoring system to be derived that can predict the optimal treatment procedure for 1-2 cm lps. our data show that the quantitative effect of the five factors included in the scoring system can accurately predict the choice of surgical methods: rirs should be performed for 0-2 fractional segments, and pcnl should be performed for 3-5 fractional segments. ozturk et al retrospectively analyzed 144 cases of pcnl and 38 cases of rirs(11). the sfr of the pcnl group was 93.8%, and the postoperative complication rate was 13.2%. the sfr of the rirs group was 73.7%, and the postoperative complication rate was 5.3%. a clinical trial reported by bozzini et al included patients diagnosed with 1-2 cm single lower calyceal calculi on a plain ct scan and was the largest prospective multicenter randomized controlled trial to date(5). a total of 181 patients underwent pcnl with an sfr of 87.3% and a postoperative complication rate of 19.1%. a total of 207 patients underwent rirs with an sfr of 82.1% and a postoperative complication rate of 14.5%. the study showed that there was no significant difference in the sfr between the pcnl and rirs groups, but the difference in the postoperative complication rates between the two groups was close to a significant difference (p = .053). in our study, the safety and efficacy of pcnl and rirs are consistent with previous literature reports. the one-month sfr of pcnl was 89.1%, which was significantly higher than the 78.3% of rirs. the postoperative complication rate of pcnl was 18.2%, which was significantly higher than that of rirs (8.6%). five factors were included to construct the scoring system: stone diameter, stone number, ipa, il, and iw. the stone diameter and stone number represent the stone load, which may be the most important indicator affecting the outcome of endoscopic surgery. there was a decrease in the sfr, as well as an increase in the complication rates with increasing stone diameter and stone number when using pcnl or rirs. atalay’s study showed that the stone burden variables were influential predictors of sfr after pcnl (stone surface area, stone burden volume, and maximum stone size, p < .05)(12). in a prospective study, olbert et al found evidence from patients treated with pcnl that a large stone burden is a prognostic factor that predicts longer surgery and prolonged hospitalization(13). in li’s study, a high stone burden was found to significantly affect the occurrence of sirs after the rirs procedure(14). the pelvicalyceal anatomy, such as the ipa, il, and iw, was associated with sfr after rirs according to inoue’s univariate analysis(15). however, the ipa was the only negative risk factor found by the multivariable analysis. moreover, the pelvicalyceal anatomy does not have any effect on the outcome after pcnl(16). there are many indicators, such as hydronephrosis and urinary culture results, that were not incorporated into this scoring system. we speculate that there are two possible reasons: one is that these indicators themselves will not affect the outcomes of pcnl or rirs; the othvol 19 no 4 july-august 2022 272 figure 5. roc curve. scoring system for endoscopic surgery of lower pole renal stones-huang et al. endourology and stones diseases 360 urological oncology 200 er is that these indicators have the same degree of influence on pcnl or rirs, that is, they do not need to be included on the basis that they can equally affect the postoperative outcomes. all currently available pcnl or rirs outcome clinical scoring systems have advantages and disadvantages. in external validation and comparative studies, no system has proven to be superior, as compared to other systems. these scoring systems include different indicators and can only predict one surgical outcome. the s.t.o.n.e. score is based on factors determined through ct imaging, including the stone size, tract length, degree of obstruction, number of involved calyces, and stone essence(17). guy’s stone score is based on the stone location and renal anatomy(18). in daily clinical work, there are often a variety of surgical methods to choose from, so it is necessary to compare the strengths and weaknesses of these surgical methods. the ideal scoring system should be able to be applied when evaluating between the two surgical methods, and the ideal scoring system should have a high ability to predict sfr and complications. it also should be easy to apply in daily clinical practice and produce the greatest repeatable results with minimal subjectivity. we analyzed the factors that differed between the patients in the pcnl group and the rirs group through univariate and multivariable logistic analyses. the scoring system was divided into two intervals: rirs was recommended at 0-2, and pcnl was recommended at 3-5. the five indicators included in our scoring system are all easily accessible from imaging studies. the scoring process is simple and convenient. according to the scoring results, we can directly draw conclusions about the optimal endoscopic surgical method to perform. there are still some limitations in this study. this scoring system may not be applicable to any situation, such as patients with ipa values that are too small, il values that are too long, and iw values that are too narrow to perform rirs. urologists may be concerned about performing pcnl in solitary kidneys. due to this study’s retrospective research, sample size, research time and other reasons, more prospective studies need to be performed in the future to verify the role of the scoring system for guiding clinical work. conclusions we derived a scoring system, which includes the stone diameter, stone number, ipa, il, and iw, to facilitate scoring based on the preoperative imaging examination. when it is verified by further multicenter prospective studies, this scoring system is expected to provide guidance for urologists to make optimal endoscopic treatment decisions for 1-2 cm lps. acknowledgement this study was supported by research fund of the national natural of science foundation of china (no. 8207841), the science and technology program of guangzhou, china (no. 201803010029), sun yatsen clinical research cultivating program from sun yat-sen memorial hospital of sun yat-sen university (sys-c-201802). conflict of interest the authors report no conflict of interest. references 1. donaldson jf, lardas m, scrimgeour d, et al. systematic review and meta-analysis of the clinical effectiveness of shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy for lower-pole renal stones. eur urol. 2015; 67: 612-6. 2. zeng g, zhang t, agrawal m, et al. supermini percutaneous nephrolithotomy (smp) vs retrograde intrarenal surgery for 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2012; 61: 146-58. 7. donaldson jf, lardas m, scrimgeour d, et al. systematic review and meta-analysis of the clinical effectiveness of shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy for lower-pole renal stones. eur urol. 2015; 67: 612-6. 8. elbahnasy am, shalhav al, hoenig dm, et al. lower caliceal stone clearance after shock wave lithotripsy or ureteroscopy: the impact of lower pole radiographic anatomy. j urol. 1998; 159: 676-82. 9. sampaio fj, aragao ah. inferior pole collecting system anatomy: its probable role in extracorporeal shock wave lithotripsy. j urol. 1992; 147: 322-4. 10. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240: 205-13. 11. ozturk u, sener nc, goktug hn, nalbant i, gucuk a, imamoglu ma. comparison of percutaneous nephrolithotomy, shock wave lithotripsy, and retrograde intrarenal surgery for lower pole renal calculi 10-20 mm. urol int. 2013; 91: 345-9. 12. atalay ha, canat l, bayraktarlı r, alkan i, can o, altunrende f. evaluation of stone volume distribution in renal collecting system as a predictor of stone-free rate after scoring system for endoscopic surgery of lower pole renal stones-huang et al. vol 19 no 5 september-october 2022 361 percutaneous nephrolithotomy: a retrospective single-center study. urolithiasis. 2018; 46: 303-309. 13. olbert pj, hegele a, schrader aj, scherag a, hofmann r. preand perioperative predictors of short-term clinical outcomes in patients undergoing percutaneous nephrolitholapaxy. urol res. 2007; 35: 225-30. 14. li t, sun xz, lai dh, li x, he yz. fever and systemic inflammatory response syndrome after retrograde intrarenal surgery: risk factors and predictive model. kaohsiung j med sci. 2018; 34: 400-408. 15. inoue t, murota t, okada s, et al. influence of pelvicaliceal anatomy on stone clearance after flexible ureteroscopy and holmium laser lithotripsy for large renal stones. j endourol. 2015; 29: 998-1005. 16. binbay m, akman t, ozgor f, et al. does pelvicaliceal system anatomy affect success of percutaneous nephrolithotomy? urology. 2011; 78: 733-7. 17. okhunov z, friedlander ji, george ak, et al. s.t.o.n.e. nephrolithometry: novel surgical classification system for kidney calculi. urology. 2013; 81: 1154-9. 18. thomas k, smith nc, hegarty n, glass jm. the guy's stone score--grading the complexity of percutaneous nephrolithotomy procedures. urology. 2011; 78: 277-81. scoring system for endoscopic surgery of lower pole renal stones-huang et al. endourology and stones diseases 362 laparoscopic urology 157urology journal vol 7 no 3 summer 2010 laparoscopic bilateral retroperitoneal lymph node dissection in stage ii testis cancer abbas basiri,1 mohammad asl-zare,1 mehrdad mohammadi sichani,2 hooman djaladat3 purpose: we report our experience with laparoscopic bilateral retroperitoneal lymph node dissection (rplnd) in 4 patients with stage ii testis cancer. materials and methods: between january 2002 and january 2009, 4 patients with stage ii testis cancer underwent laparoscopic bilateral rplnd. in 2 patients, laparoscopic bilateral rplnd was performed for residual mass post-chemotherapy. we performed classic bilateral rplnd without patient repositioning. results: the procedure was done uneventfully without any major perioperative complication. the demanding part was contralateral, depending side dissection, which was accomplished with the help of a bowel retractor. patient repositioning was not necessary. conclusion: laparoscopic bilateral rplnd can be performed efficiently and safely in stage ii testis cancer, without need to repositioning and placement of trocar in contralateral side. urol j. 2010;7:157-60. www.uj.unrc.ir keywords: testis neoplasm, lymph node dissection, laparoscopy 1urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran 2alzahra hospital, isfahan university of medical sciences, isfahan, iran 3mohammadi hospital, hormozgan university of medical sciences, bandar abbas, iran corresponding author: abbas basiri, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir received june 2010 accepted july 2010 introduction carcinoma of the testis remains the most common malignancy in males 15 to 35 years old (1) and its primary landing sites for metastases are retroperitoneal lymph nodes. (2) laparoscopic retroperitoneal lymph node dissection (l-rplnd) was developed for diagnostic and therapeutic benefits of open retroperitoneal lymph node dissection, without its inherent morbidity in patients with clinical stage i nonseminomatous germ cell tumors (nsgct).(3-5) because of various advantages of l-rplnd, it has also been introduced in the management of stage ii testis cancer.(6,7) most urologists prefer the strategy of primary chemotherapy followed by l-rplnd for residual mass in advanced stage ii testis cancer. in such circumstances, l-rplnd has both diagnostic and curative intent. laparoscopic rplnd could also be performed as the first step (before chemotherapy) in patients with advanced stage ii testis cancer, but it has to be done bilaterally to remove not only the primary landing site, but also other possible sites of tumor spread.(6) bilateral l-rplnd has only been reported as a staged procedure. typically, laparoscopy is performed for unilateral dissection and for complete rplnd, repositioning of the patients is assumed to be necessary.(7) to the best of our knowledge, laparoscopic bilateral rplnd without patient repositioning has not been reported previously. laparoscopic rplnd—basiri et al 158 urology journal vol 7 no 3 summer 2010 materials and methods between january 2002 and january 2009, transperitoneal bilateral laparoscopic rplnd was performed on 4 patients with stage ii nsgcts. in 2 patients, laparoscopic bilateral rplnd was performed for residual mass after chemotherapy while the other 2 were before chemotherapy. pre and postoperative patients’ data are presented in table 1. under general anesthesia, patients were placed in semi-flank position. four trocars were used, including 3 midline ports and one in anterior axillary line at the level of the umbilicus. one additional port was placed for bowel retraction. the white line was incised and the colon was completely mobilized from one side to another until visualizing the ureter and the renal vein on the opposite side, to make sure that it is possible to have acceptable exposure to difficult dependent part. the target area for lymphatic dissection was between the two ureters laterally, renal veins superiorly, and iliac vessels inferiorly (figure 1). after contralateral side lymphatic dissection, between dependent ureter and the aorta or the inferior vena cava (figure 2), we continued to complete classic dissection in ipsilateral side. during contralateral side dissection, successful bowel retraction provided great help, especially in obese patients. in the presence of huge mass, lumbar vessels were transected for removal of reteroaortic and reterocaval lymphatic tissues. we figure 1. laparoscopic rplnd in a patient with primary left testis tumor. lrv, indicates left renal vein; and ivc, inferior vena cava. figure 2. contralateral (right sided) dissection in a patient with primary left testis tumor. ivc, indicates inferior vena cava. case 1 case 2 case 3 case 4 tumor side right right left right age (years) 25 27 35 28 bmi 20 23 22 28 tumor pathology embryonal cell carcinoma embryonal/immature teratoma yolk sac tumor embryonal cell carcinoma size of lymph nodes on ct scan 2 cm 4 cm 4 cm 3.5 cm pre-operative chemotherapy no no yes yes operative time (minutes) 440 340 420 240 hospital stay (days) 8 3 8 4 pre-operative hb (mg/dl) 14.7 16.6 14 15 postoperative hb (mg/dl) 14.3 15.6 13.7 14.6 complication lymphatic leakage nothing lymphatic leakage nothing follow-up (months) 66 9 3 3 recurrence no no no no open conversion no no no no table 1. pre and postoperative patients’ data that underwent classic laparoscopic rplnd laparoscopic rplnd—basiri et al 159urology journal vol 7 no 3 summer 2010 tried to preserve postganglionic fibers when we could clearly discriminate them. results bilateral laparoscopic rplnd was completed in all of the patients. conversion to open surgery was not necessary. operative time ranged from 240 to 440 minutes. no blood transfusion was required. no major intra or postoperative complications occurred. prolonged lymphatic leakage (7 days) was noted in 2 subjects that were managed conservatively. hospital stay was between 3 and 8 days. laparoscopic rplnd was successful to remove 20 to 37 lymph nodes. the related pathology is delineated in table 2. patients were followed up between 3 to 66 months, through which no relapses occurred. discussion open rplnd has been assumed as the gold standard for the surgical management of low stage nsgcts. laparoscopic rplnd has been proposed to be a minimally invasive and valuable alternative approach to open surgery.(8) it provides less morbidity and increases patient’s satisfaction with similar oncologic outcomes compared to open counterpart.(8,9) laparoscopic rplnd is traditionally indicated for low stage tumors which are candidate for unilateral modified dissection. whenever widespread retroperitoneal tumor is present, a complete bilateral rplnd is indicated.(7) laparoscopic bilateral rplnd was first proposed by palese and colleagues. they declared that although l-rplnd is a feasible operation in patients after chemotherapy, but it is challenging and should be reserved for the patients with limited retroperitoneal residual disease as well as institutions with considerable laparoscopic expertise.(10) benway and associates showed that in porcine model, laparoscopic bilateral rplnd is capable of providing lymph node yields similar to open rplnd, further supporting the potential for oncologic equivalency via a laparoscopic approach.(8) to the best of our knowledge, this is the first report on performing bilateral l-rplnd in human beings without the need for patient repositioning. we overcame the problem of difficult exposure to contralateral side using a bowel retractor from an additional port. in this study, the results in terms of disease-free and disease-specific survival were favorable. all of the 4 patients survived with no evidence of biochemical or disease recurrence in on average 20-month follow-up. in our series, dissection in contralateral side was feasible and efficient, but further studies with larger sample size are needed to better clarify this issue. laparoscopic rplnd has its own potential complications, mainly vascular. in some studies, high morbidity has been reported with this technique.(8) palese and colleagues reported that of 7 patients, 3 subjects (42%) who underwent post-chemotherapy l-rplnd had major complications, including iatrogenic cavotomy, renal and external iliac arteries injury, and duodenal perforation. interestingly, the only patient who underwent bilateral l-rplnd had no complication.(10) no major complication was seen in our patients. only 2 of them had lymphatic leakage which was managed with conservative treatment. our complication rate was much lower than the reported rate in the literature. this might be due to mainly small sample size, but improved case 1 case 2 case 3 case 4 cord stump negative negative negative negative para-aortic lymph nodes negative positive (3/3) positive (3/15) mature teratoma negative inter-aortocaval lymph nodes positive (2/5) negative positive(9/16) mature teratoma positive(6-cm mass) teratocarcinoma para-caval lymph nodes negative negative positive (1/6) mature teratoma negative table 2. pathology of lymph nodes laparoscopic rplnd—basiri et al 160 urology journal vol 7 no 3 summer 2010 experience and less desmoplastic reactions are also contributory factors. it has been assumed that repositioning of the patient from one side to the other side is the only way to obtain a total, although consecutive exposure of the retroperitoneum for l-rplnd. (7) according to our experience, we recommend using a bowel retractor with an extra port to overcome this issue. another issue is bilateral l-rplnd in obese patients. we recommend starting this procedure from contralateral (dependent) side, because edematous distended bowel will not hamper later ipsilateral dissection. conclusion bilateral l-rplnd is a feasible procedure in stage ii nsgcts. using a bowel retractor, we could omit the necessity of the patient repositioning for bilateral l-rplnd. experienced surgeons at dedicated centers are essential for such a complex surgical approach. conflict of interest none declared. references 1. williams sb, steele gs, richie jp. primary retroperitoneal lymph node dissection in patients with clinical stage is testis cancer. j urol. 2009;182: 2716-20. 2. corvin s, kuczyk m, anastasiadis a, stenzl a. laparoscopic retroperitoneal lymph node dissection for nonseminomatous testicular carcinoma. world j urol. 2004;22:33-6. 3. bhayani sb, ong a, oh wk, kantoff pw, kavoussi lr. laparoscopic retroperitoneal lymph node dissection for clinical stage i nonseminomatous germ cell testicular cancer: a long-term update. urology. 2003;62:324-7. 4. janetschek g, peschel r, hobisch a, bartsch g. laparoscopic retroperitoneal lymph node dissection. j endourol. 2001;15:449-53; discussion 53-5. 5. stephenson aj, sheinfeld j. the role of retroperitoneal lymph node dissection in the management of testicular cancer. urol oncol. 2004;22:225-33; discussion 34-5. 6. poulakis v, skriapas k, de vries r, et al. quality of life after laparoscopic and open retroperitoneal lymph node dissection in clinical stage i nonseminomatous germ cell tumor: a comparison study. urology. 2006;68:154-60. 7. steiner h, peschel r, janetschek g, et al. longterm results of laparoscopic retroperitoneal lymph node dissection: a single-center 10-year experience. urology. 2004;63:550-5. 8. benway bm, diaz dl, katz md, et al. open versus laparoscopic retroperitoneal lymph node dissection: assessing adequacy of dissection in a porcine model. j endourol. 2009;23:485-8. 9. skolarus ta, bhayani sb, chiang hc, et al. laparoscopic retroperitoneal lymph node dissection for low-stage testicular cancer. j endourol. 2008;22:1485-9. 10. palese ma, su lm, kavoussi lr. laparoscopic retroperitoneal lymph node dissection after chemotherapy. urology. 2002;60:130-4. v07_no_4.pdf endourology and stone disease 226 urology journal vol 7 no 4 autumn 2010 evaluation of the learning curve for percutaneous nephrolithotomy seyed amir mohsen ziaee, mehrdad mohammadi sichani, amir hossein kashi, mohammad samzadeh purpose: to determine the number of percutaneous nephrolithotomy (pcnl) operations which are required to achieve competence or excellence. materials and methods: one hundred and five consecutive pcnl operations performed by a fellow in endourology, with no previous experience in performing solo pcnl, were studied. operation duration, stone extraction percent, stone-free rate, number of access, tubeless cases, and complications were studied in sequential groups of 15 patients as the surgeon gained experience. results: operation duration decreased from the mean of 95.4 minutes in the first to 15th patients to 78.3 minutes in the 31st to 45th patients, and then remained unchanged. minor complications were only observed in the first to 45th patients. stone extraction percent increased from the mean of 88.3% in the first to 15th patients to 99.3% in 91st to 105th patients. percentage of patients with no residual fragments decreased from 53% in the first to 15th patients to 6.7% in the 91st to 105th patients. no statistically significant differences were observed in estimated blood loss or transfusion rate between sequential groups of subjects. conclusion: an improvement in operation duration was observed, and absence of complications was achieved after 45 cases. the improvement in stone clearance was observed up to the last subjects. competence and excellence were achieved after 45 and 105 operations, respectively. urol j. 2010;7:226-31. www.uj.unrc.ir keywords: percutaneous nephrolithotomy, percutaneous nephrostomy, clinical competence urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran corresponding author: mehrdad mohammadi sichani, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: m_mohammadi@med.mui.ac.ir received march 2010 accepted august 2010 introduction since introduction in 1976, percutaneous nephrolithotomy (pcnl) has revolutionized the stone surgery and has widely practiced all over the world. many modifications in this technique were later introduced that have made its learning process rather complicated and difficult.(1) as pcnl is currently considered as the treatment of choice for managing large renal stones,(2-4) every urologist should be able to perform this procedure. nevertheless, very few data are available to reach a sound conclusion for devising a training program.(1,5-6) to precisely prepare a training program for pcnl, its learning curve should be determined. learning curve is a theoretical concept that draws a surgeon’s performance against time axis. (1,5) the point at which no further improvement is observed,(5) or the point at which the slope of the line changes,(7) has been impact of learning curve on pcnl—ziaee et al 227urology journal vol 7 no 4 autumn 2010 suggested as the point of competence or learning, respectively. few studies have been performed to investigate pcnl learning curve,(1,5) in which operation duration and radiology screening time were employed to determine the curve.(5,8) as suggested before, these markers are not the best indicators of clinical performance(1,5,8) and there is still no consensus regarding the best practical clinical surrogate markers of performance in pcnl operations.(1) we studied pcnl learning curve of a surgeon using different indicators of performance. materials and methods one hundred and five consecutive pcnl operations for removal of large renal stones performed by a single surgeon were studied prospectively. the surgeon was a graduated urologist who was trained for fellowship in endourology and had no previous experience of performing solo pcnl. he had experience in performing other endourology procedures like ureteroscopy, transureteral lithotripsy, and percutaneous ultrasound-guided nephrostomy. shahid labbafinejead medical center is a busy tertiary referral hospital with an average of three pcnl operations on each working day. in our department, urology fellows first observe 30 operations, then, scrub as first aid in another 30 operations with a senior fellow, and thereafter, they perform pcnl while the senior fellow is scrubbed as first aid and interferes in case of any problem for another 30 operations. after the previous three steps, the fellow is allowed to perform solo pcnl unsupervised and asks for help if required. the studied pcnl operations were this latter group of unsupervised operations. the operation was performed as the standard procedure. briefly, after general anesthesia, a 5 or 6f ureteral catheter was inserted and fixed to a foley catheter. then, the patient was placed in a prone position with special care of pressure points. the desired calyx was punctured under the guidance of fluoroscopy and guidewire was inserted. the preferred contrast medium was air, but if it was helpless, a contrast medium would be injected. the dilation was performed with amplatz dilators in one shot manner in most of the patients and when it was impossible (mostly in patients with previous flank surgery and severe fibrosis), dilation was performed by serial metallic dilators. after amplatz sheath insertion, nephroscopy was performed and stones were fragmented by pneumatic lithotripter (litho crack, sp. swiss-germany) and removed. if the operation was straightforward with no significant bleeding, residual stone, and pelvicaliceal injury and if the ureteral catheter was in the pelvis, the procedure was terminated without nephrostomy insertion (tubeless pcnl). in other subjects, a 16f nephrostomy tube was placed. in tubeless cases, the ureteral catheter was removed after 48 hours and patients were discharged. in other cases, foley and ureteral catheters were removed the day after the surgery. nephrostomy tube was clamped 48 hours after the surgery and removed after 24 hours if no leakage or fever existed. in proximal ureteral stones, solitary kidneys, and patients with uremia, a double-j ureteral catheter was routinely inserted. in operations with supracostal or intercostal access, a chest x-ray was taken after the surgery. patients were followed up with kidney, ureter, bladder (kub) x-ray or ultrasonography the day after the operation, and any detectable residual stones were considered significant.(9) a total of 105 consecutive patients were divided into 7 groups, 15 subjects each. the operation duration, estimated blood loss (ebl), transfusion rate, minor and major complications, stonefree rate (sfr), stone extraction percent (sep), tubeless rate, number of access, and hospital stay were compared among various groups. estimated blood loss was calculated using the following formula: ebl = (hct before op – hct after op/ hct before op) × (weight × 85). stone extraction percent was determined by following formula: 1 – (stone surface at the end of the operation by fluoroscopy / stone surface before operation). stone surface was calculated as the product of maximal height and width of the stone.(10) stonefree patient was defined as a patient with no observable residual fragment in the postoperative kub x-ray. major and minor pelvicaliceal system injuries were defined as the rupture of the kidney pelvis and small injuries/tears of the pelvicaliceal impact of learning curve on pcnl—ziaee et al 228 urology journal vol 7 no 4 autumn 2010 system during the operation observed through a nephroscope, respectively. statistical analysis was carried out using the spss software (the statistical package for the social science, version 16.0, spss inc, chicago, illinois, usa). categorical data across groups were compared by chi-square test and continuous variables were compared by one-way analysis of variance (anova). in order to remove the confounding effect of stone size on the stone extraction percent, a multiple linear regression model was employed, in which in the first block stone size was entered into the model and then, patient’s sequence number was introduced. statistical significance was considered with the two-sided p value of less than .05. results demographic data are presented in table 1. the operative data are shown in tables 1 and 2. the operation duration was calculated for patients with a single access, excluding patients who had two-access points, because they were not equally distributed in different patients’ groups. the operation time decreased from the mean of 95.4 minutes for the first to 15th patients to 84.0 minutes for 16th to 30th patients, and thereafter, further decreased to 78.3 minutes for the 31st to 45th patients. afterward, little fluctuations were observed in the mean operation time in the next groups. this pattern, however, was not statistically significant (figure 1). stone extraction percent increased from the mean of 88.3% for the first 15 patients to 93.7% for 16th to 30th patients, and followed by, slow increase characteristics sex (male/female) 66/39 age, year (mean ± sd) 44.4 ± 14.8 body weight, kg (mean ± sd) 76.3 ± 17.2 previous renal surgery, % 24 (23) number of opaque stones, % 80 (76) side (left/right) 65/40 solitary kidney, % 7 (7) stone location, n (%) upper calyx middle calyx lower calyx multiple calices 4 (4) 6 (6) 83 (79) 12 (11) approach, n (%) subcostal intercostal supracostal multiple 94 (89) 3 (3) 1 (1) 7 (7) number of access, (%) one two 93 (89) 12 (11) table 1. demographic characteristics and operative data. characteristics patients order, mean ± sd or n (%) p 1 to 15 16 to 30 31 to 45 46 to 60 61 to 75 76 to 90 91 to 105 estimated blood loss, ml 328 ± 195 268 ± 244 412 ± 228 245 ± 126 422 ± 312 293 ± 193 301 ± 180 ns operation duration, minutes§ 99.3 ± 26.9 84.0 ± 18.5 78.3 ± 17.0 80.7 ± 23.4 89.0 ± 21.4 81.0 ± 19.7 87.7 ± 19.7 ns stone size > 5cm† 10 (67) 10 (67) 13 (87) 7 (47) 4 (27) 6 (40) 4 (27) .005 2-access-pcnl cases 3 (20) 0 (0) 0 (0) 1 (7) 3 (20) 3 (20) 2 (13) ns minor injury‡ 1 (7) 1 (7) 6 (40) 0 (0) 0 (0) 0 (0) 0 (0) .001 hospitalization, days 4.1 ± 1.3 3.3 ± 1.0 3.5 ± 1.2 3.6 ± 1.3 2.7 ± 0.6 2.8 ± 0.9 3.3 ± 1.5 .03 *chi-square for linear by linear association. §calculated for one-access operations. †any observable residual stone fragment in postoperative day kidney, ureter, bladder x-ray or ultrasonography. ‡includes small injuries of the minor and major calyces observed during the operation by nephroscope. table 2. operative and postoperative data according to patients’ groups. continuous line: percentage of patients with observable residual fragments (p = .006) dashed line: percentage of patients without nephrostomy at the end of operation (p = .002) figure 1. percentage of patients with observable residual fragments and percentage of tubeless subjects impact of learning curve on pcnl—ziaee et al 229urology journal vol 7 no 4 autumn 2010 to 95.7% for 76th to 90th patients and afterward, significant increase occurred up to 99.3% for the 91st to 105th patients (p = .04). considering patients with residual stones as depicted in table 2, a downward trend was observed from 53% for the first 15 patients up to 6.7% (1 patient) for the 91st to 105th patients (p = .006). all minor pelvicaliceal system injuries occurred in the first 45 patients (p = .001), which were managed conservatively by keeping nephrostomy tube for a longer duration. no pelvicaliceal system injuries were recorded after the first 45 patients (table 2). no major complications were observed in any patient. tubeless rate increased form no patient (0%) in the first 15 patients up to 30% in the 76th to 105th patients (p = .002). for internal control, we studied the stone size in various patients’ groups. the percentage of large stones (>5cm) increased from 67% in the 1st to 15th patients to 87% in 31st to 45th patients. this corresponds to a part of the learning curve where continuous improvement was observed in sep, operation duration, and residual fragments. then, we observed increasing ability of the surgeon to perform the operation despite increasing burden of the stones. the linear regression model revealed that after including stone size in the model, patients’ sequence number was still a statistically significant predictor of stone extraction rate (p = .004). the odds ratio for increase in stone extraction rate with the next patient was 1.09 (95% confidence interval: 1.03 to 1.15). no significant differences were observed in transfusion rate or ebl among patients’ groups. discussion stone surgery is a frequent practice in urology.(1,11) for training programs in urology, it is important to know the number of operations that makes a urology resident competent.(8) the length of training period is no longer an appropriate criterion for judging the competency, (8) as the number of operations vary greatly between teaching centers.(11) this is the reason why it is important to determine pcnl learning curve. defining pcnl learning curve has another major advantage. percutaneous nephrolithotomy has a steep learning curve that has made many urologists reluctant to perform this operation.(5,12-14) watterson and colleagues, reported that only 11% of urologists obtained the access themselves and many relied on a radiologist for this step of the procedure(15) that is the most difficult and important part of the operation.(1,2,8,9) it has been shown that stone clearance rates are better and complications are less when the access is obtained by a urologist.(15) therefore, by defining the learning curve and providing enough operations for training urologists, they will be more inclined to perform this operation after graduation and become involved in all steps of the operation.(16) learning curve is a diagram that depicts a surgeon’s ability against time.(5) this idea was first noted in laparoscopic surgery for cholelithiasis,(17-21) and in urology is mostly studied in cancer surgery.(1,5) a few studies have been completed on pcnl learning curve. a number of 60 operations have been suggested to gain competence, and over 115 operations to achieve excellence. nonetheless and as suggested before, the reduction of the operation duration demonstrates the surgeon’s familiarity with the technique, tools, and the aspects of puncturing target calyx more than the whole operation, and its reduction provides an estimate of the ability to perform the operation. furthermore, screening time reduction reflects an intricate part of the operation consisting of identifying and figure 2. stone extraction percentage in sequential groups of patients. impact of learning curve on pcnl—ziaee et al 230 urology journal vol 7 no 4 autumn 2010 puncturing target calyx.(8) these markers have been considered more as a financial aspect of the operation than competency.(9) the most important clinical aspects of competency are stone clearance and operation complications.(1,5,8) nevertheless, it has been suggested that clearance rate varies and depends on many factors, including stone composition, stone size, access type and numbers, and the number of involved calyces.(3) it has also been stated that the clearance rate depends more on the supervising surgeon’s experience than the operating surgeon.(8) in a study by tanriverdi and associates, stone clearance rate did not show any significant changes in sequential groups of patients. the authors concluded that a surgeon can meet this goal very soon in his first few patients’ operation.(5) in this study, sep has been calculated as a relevant clinical end point. the more complete is the removal of a stone with the smaller size of the residuals, the less ancillary procedures will be needed.(22-24) furthermore, we evaluated the number of patients without any residual stone fragments (sfr).(9) as shown in figure 1, better results are observed with more operations, and this improvement is observable until the 105th patient, where the sep and sfr are very acceptable (99.3% and 93.3%, respectively). although alteration in operation duration was not statistically significant, but showed an observable pattern of decrease from the 1st to 15th patients to the 31st to 45th patients. after little fluctuations in 46th to 90th patients, a small increase in operation duration was noticed in the 91st to 105th patients. this small increase could be attributed to the surgeon’s interest in removing the residual fragments totally and making the patient stone-free after acquiring basic competence in the procedure (figure 1). minor complications were observed only in the first 45 patients, which mostly occurred in the 31st to 45th patients (table 2). no further complications were observed in 46th to 105th patients. increased transfusion (not statistically significant) and complications rate in the 31st to 45th patients could be attributed to a higher percent of large stones, the presence of two patients with solitary kidneys with staghorn renal calculi, and the previous history of open stone surgery. considering decrease in operation duration and the absence of complications as a measure of competency, a surgeon would be able to reach this goal after 45 operations. if we consider acceptable stone extraction percent and residual rate as a measure of gaining excellence, a surgeon can approach this target after 105 operations as suggested before.(1) following limitations should be considered for this study: 1) this study reflects the learning curve of a single surgeon. there are also some published articles on the learning curves of other surgical procedures by a single surgeon.(25-28) nevertheless, there is interpersonal variations among learning curves of different surgeons based on their skills and expertise.(7) 2) the protocol of this study had minor differences with some previously published articles. in this study, we did not include the 30 operations that the surgeon was the principal surgeon and had aid of a supervising fellow scrubbed as the first aid. the reason was that the supervising fellow was easily involved in the operation in case of any trouble for the beginner surgeon. our beginner surgeon was a graduated urologist with the previous experience in endourology procedures. the results may be different for a urology resident. 3) the center in which this study was performed is a crowded referral center with a large volume of patients undergoing pcnl each day. the results for centers with fewer patients may be different. 4) the best imaging for residual stones after pcnl is computed tomography scan. we could not employ it in this study, as it is not a routine follow-up evaluation measure in our center. conclusion a surgeon without previous experience in solo pcnl reaches a plateau in operation duration and will be free from complications after 45 operations. improvement in stone clearance rate and stone extraction percent continues to be observed up to the 105th operation. impact of learning curve on pcnl—ziaee et al 231urology journal vol 7 no 4 autumn 2010 conflict of interest none declared. references 1. de la rosette jj, laguna mp, rassweiler jj, conort p. training in percutaneous nephrolithotomy--a critical review. eur urol. 2008;54:994-1001. 2. knoll t. editorial comment on: training in percutaneous nephrolithotomy--a critical review. eur urol. 2008;54:1003. 3. skolarikos a, alivizatos g, de la rosette jj. percutaneous nephrolithotomy and its legacy. eur urol. 2005;47:22-8. 4. wong my. an update on percutaneous nephrolithotomy in the management of urinary calculi. curr opin urol. 2001;11:367-72. 5. tanriverdi o, boylu u, kendirci m, kadihasanoglu m, horasanli k, miroglu c. the learning curve in the training of percutaneous nephrolithotomy. eur urol. 2007;52:206-11. 6. seitz c. editorial comment on: training in percutaneous nephrolithotomy--a critical review. eur urol. 2008;54:1002. 7. breda a. editorial comment on: training in percutaneous nephrolithotomy--a critical review. eur urol. 2008;54:1001-2. 8. allen d, o’brien t, tiptaft r, glass j. defining the learning curve for percutaneous nephrolithotomy. j endourol. 2005;19:279-82. 9. breda a. editorial comment on: the learning curve in the training of percutaneous nephrolithotomy. eur urol. 2007;52:211-2. 10. hyams es, bruhn a, lipkin m, shah o. heterogeneity in the reporting of disease characteristics and treatment outcomes in studies evaluating treatments for nephrolithiasis. j endourol. 2010;24:1411-4. 11. kauer pc, laguna mp, alivizatos g, et al. present practice and treatment strategies in endourological stone management: results of a survey of the european society of uro-technology (esut). eur urol. 2005;48:182-8. 12. kukreja r, desai m, patel s, bapat s. factors affecting blood loss during percutaneous nephrolithotomy: prospective study. j endourol. 2004;18:715-22. 13. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899906; discussion 14. sreenevasan g. urinary stones in malaysia--its incidence and management. med j malaysia. 1990;45:92-112. 15. watterson jd, soon s, jana k. access related complications during percutaneous nephrolithotomy: urology versus radiology at a single academic institution. j urol. 2006;176:142-5. 16. lee cl, anderson jk, monga m. residency training in percutaneous renal access: does it affect urological practice? j urol. 2004;171:592-5. 17. dashow l, friedman i, kempner r, rudick j, mcsherry c. initial experience with laparoscopic cholecystectomy at the beth israel medical center. surg gynecol obstet. 1992;175:25-30. 18. gates ea. new surgical procedures: can our patients benefit while we learn? am j obstet gynecol. 1997;176:1293-8; discussion 8-9. 19. nenner rp, imperato pj, alcorn cm. serious complications of laparoscopic cholecystectomy in new york state. n y state j med. 1992;92:179-81. 20. orlando r, 3rd, russell jc, lynch j, mattie a. laparoscopic cholecystectomy. a statewide experience. the connecticut laparoscopic cholecystectomy registry. arch surg. 1993;128:4948; discussion 8-9. 21. trondsen e, ruud te, nilsen bh, et al. complications during the introduction of laparoscopic cholecystectomy in norway. a prospective multicentre study in seven hospitals. eur j surg. 1994;160: 145-51. 22. osman mm, alfano y, kamp s, et al. 5-year-followup of patients with clinically insignificant residual fragments after extracorporeal shockwave lithotripsy. eur urol. 2005;47:860-4. 23. streem sb, yost a, mascha e. clinical implications of clinically insignificant store fragments after extracorporeal shock wave lithotripsy. j urol. 1996;155:1186-90. 24. sun by, lee yh, jiaan bp, chen kk, chang ls, chen kt. recurrence rate and risk factors for urinary calculi after extracorporeal shock wave lithotripsy. j urol. 1996;156:903-5; discussion 6. 25. mottrie a, de naeyer g, schatteman p, carpentier p, sangalli m, ficarra v. impact of the learning curve on perioperative outcomes in patients who underwent robotic partial nephrectomy for parenchymal renal tumours. eur urol. 2010; 58:127-32. 26. riedel bb, mildren me, jobe cm, wongworawat md, phipatanakul wp. evaluation of the learning curve for reverse shoulder arthroplasty. orthopedics. 2010; 237-41. 27. samadi db, muntner p, nabizada-pace f, brajtbord js, carlucci j, lavery hj. improvements in robotassisted prostatectomy: the effect of surgeon experience and technical changes on oncologic and functional outcomes. j endourol. 2010;24:1105-10. 28. zhao h, bu l, yang f, li j, li y, wang j. videoassisted thoracoscopic surgery lobectomy for lung cancer: the learning curve. world j surg. 2010;34:2368-72. v08_no_1_print_3.pdf review 1urology journal vol 8 no 1 winter 2011 advanced treatments in non-clear renal cell carcinoma el mehdi tazi,1 ismail essadi,1 mohamed fadl tazi,2 youness ahellal,2 hind m’rabti,1 hassan errihani1 purpose: to focus on the use of targeted therapies against the non-clear histologic subtypes of renal cell carcinoma (rcc); papillary i and ii, chromophobe, and collecting duct. the unique genetic and molecular profiles of each distinct non-clear kidney cancer subtype will be described, as these differences are integral to the development and effectiveness of the novel agents used to treat them. materials and methods: on the basis of medline database searches, we assessed all aspects of targeted therapy in non-clear cell rcc between 2000 and 2010. trials focusing on non-clear rcc or those that treated clear cell tumors along with significant numbers of non-clear subtypes will be discussed. the role of cytoreductive nephrectomy and the use of neoadjuvant and adjuvant targeted therapy will be reviewed. lastly, areas of future research will be highlighted. results: the majority of clinical trials testing novel targeted therapies have excluded non-clear subtypes, providing limited therapeutic options for patients with these diagnoses and their oncologists. conclusion: patients presenting with advanced non-clear pathology should undergo a thorough metastatic evaluation and, if appropriate, surgical evaluation to determine if nephrectomy, lymphadenectomy, and/ or metastectomy are warranted. aggressive surgical extirpation is often recommended. sunitinib also is adequately tolerated and oncologically active in subjects with non-clear histology. urol j. 2011;8:1-11. www.uj.unrc.ir keywords: kidney neoplasms, renal cell carcinoma, classification, mortality 1department of medical oncology, national institute of oncology, rabat, morocco 2department of urology, chu hassan ii, fez, morocco corresponding author: el mehdi tazi, md tel: +21 266 847 9120 fax: +21 253 767 2580 e-mail: moulay.elmehdi@yahoo.fr received november 2010 accepted february 2011 introduction background renal cell carcinoma (rcc) is among the most common adult malignancies in the united states, ranking fifth in men and eighth in women, with approximately 57 760 new cases diagnosed in 2009.(1) renal cell carcinoma is not a homogenous entity and a number of malignant histologic subtypes, such as clear cell, papillary, chromophobe, and collecting duct, are recognized by the heidelberg classification system (figure).(2) each rcc subtype is associated with unique genetic alterations, clinical characteristics, and sensitivity to treatment.(3-5) the systemic management of advanced and metastatic rcc has drastically altered over the past 5 years with the approval of a number of targeted agents, supplanting cytokine-based therapies as the treatment of non-clear renal cell carcinoma—tazi et al 2 urology journal vol 8 no 1 winter 2011 choice for the majority of patients with clear cell rcc.(6-8) despite these advances, the optimal treatment for patients with non-clear histologies remains undefined. this review will discuss the genetic and molecular biology of papillary, chromophobe, and collecting duct rcc and the targeted therapeutic strategies being employed to treat them. clear cell rcc, which is the most common histologic subtype of rcc and accounts for approximately 75% of the kidney cancer diagnoses,(9) provides the paradigm for translational research that takes bench top basic science to bedside therapies. mutations in the von hippel-lindau (vhl) gene, which is located on the short arm of chromosome 3 and serves as an autosomal dominant tumor suppressor, were identified by studying patients afflicted with hereditary and sporadic clear cell kidney cancer.(4,10,11) targeting the downstream transcriptional products resulting from mutational inactivation of the vhl gene, which are involved in angiogenesis and cellular proliferation and include vascular endothelial growth factor (vegf), transforming growth factor (tgf ), and platelet-derived growth factor (pdgf ),(12) allowed novel agents, such as sunitinib,(11) sorafenib,(13) and temsirolimus,(14) to be introduced against a disease that is notoriously resistant to cytotoxic chemotherapy and radiotherapy.(15) while these agents mark a major advance in the treatment of clear cell rcc, nearly every trial in which they were tested excluded the other subtypes of rcc, providing clinicians and their patients little guidance when selecting a systemic treatment for non-clear cell rcc. fortunately, the same methodology of studying the genetic and molecular characteristics of hereditary and sporadic non-clear cell rcc tumors has identified promising new pathways that are amenable to targeted therapy.(5) objective the primary aim of this review is to assess the development of targeted systemic therapies. this review will focus on the use of targeted therapies against the non-clear histologic subtypes of renal cell carcinoma; papillary i and ii, chromophobe, and collecting duct. histopathologically distinct non-clear renal epithelial neoplasms and their incidence. papillary type i 5% papillary type ii 10% chromophobe 5% non-clear renal cell carcinoma—tazi et al 3urology journal vol 8 no 1 winter 2011 materials and methods search strategy on the basis of medline database searches, we assessed all aspects of “targeted therapies in nonclear cell carcinoma” between february 2000 and december 2010. seventy-two articles were found to detail future strategies to understund and treat non-clear cell carcinoma on the basis of evolution in targeted therapies. results papillary renal cell carcinoma papillary rcc is the second most common histologic subtype of the kidney cancer, accounting for approximately 10% to 15% of cases and nearly 29% of all rccs in african americans.(9,16) it can be further categorized histologically into papillary types i and ii. emerging data suggests that there may be significant differences in the genetics and molecular pathways underlying different types of papillary rcc as well as disparate outcomes associated with these entities.(17) researchers and clinicians must take these differences into account when they design targeted therapies and treatment protocols for patients with papillary rcc. papillary type i rcc, in both the sporadic and hereditary forms, is associated with activating mutations of the methyl-nitroso-nitroguanidineinduced (met) oncogene on the long arm of chromosome 7.(18) these mutations result in ligand-independent activation of intracytoplasmic tyrosine kinase domains, which constitutively activate the hepatocyte growth factor/met pathway.(19,20) families with hereditary papillary renal cancer harbor germline mutations in met, usually accompanied by non-random duplication of the chromosome 7 bearing the mutated met allele. mutated met is passed to offspring in an autosomal dominant fashion with variable penetrance. phenotypically, patients with this gain of function germline mutation display bilateral multifocal papillary type i renal tumors.(20) activated somatic met mutations have also been identified in the tumors of patients with sporadic papillary type i rcc. while one study identified mutations in 13% of patients with all subtypes of non-familial papillary rcc, the prevalence of this genetic alteration in sporadic type i papillary rcc has not been adequately defined.(21) papillary type ii tumors are now recognized as a distinct entity and occur both sporadically and in patients who have the familial syndrome of hereditary leiomyomatosis and renal cell carcinoma (hlrcc).(22) the genetic alteration associated with hlrcc has been localized to chromosome 1 and the gene identified as fumarate hydratase (fh). fumarate hydratase functions as a classic tumor suppressor, with both copies inactivated in tumors. the mutation is transmitted in an autosomal dominant pattern with high penetrance.(23) patients with hlrcc are at risk for the development of papillary rcc. these tumors have characteristic large orangeophilic nuclei and a clear perinuclear halo, with a variety of architectural patterns, such as papillary, tubulo-papillary, tubular, solid, or mixed.(24) fumarate hydratase is a tricarboxylic acid (krebs) cycle enzyme that plays a crucial role in aerobic cellular metabolism.(25) one well-described consequence of fh inactivation is the generation of a pseudo-hypoxic state, characterized by the upregulation of hypoxiainducible factors (hif), similar to that seen in the vhl pathway, albeit by a different mechanism. isaacs and colleagues demonstrated that inactivation of fh and consequent accumulation of its substrate, fumarate, lead to inhibition of hif prolyl hydroxylase (hph), a critical enzymatic regulator of intracellular hif levels, through competitive inhibition.(25) inactivation of hph interferes with hydroxylation of hif at key proline residues and its subsequent recognition by the vhl complex; thus, preventing vhldependent proteosomal degradation of hifs. the resulting accumulation of hif leads to transcriptional overexpression of proangiogenic factors, such as vegf, as well as other genes, such as tgf, pdgf, and glucose transport (glut-1). in essence, this is an example of vhl-independent hif accumulation in fumarate hydratase deficient kidney cancer, resulting in increased amounts of proangiogenic and growth non-clear renal cell carcinoma—tazi et al 4 urology journal vol 8 no 1 winter 2011 factors.(25) there is currently no well-described sporadic counterpart to hlrcc-associated kidney cancer and no conclusive evidence that somatic fh mutations play a significant role in sporadic kidney cancer tumorigenesis. however, the role of mutations in fh and other krebs cycle enzymes, such as succinate dehydrogenase in the genesis of sporadic papillary rcc, is under evaluation. localized papillary rcc, which can be managed with surgical excision, has a more favorable prognosis than conventional clear cell.(26,27) however, metastatic papillary rcc portends a worse prognosis.(28) few trials have focused their attention on papillary rcc as the primary histologic tumor type; therefore, the majority of data available is from expanded access trials, retrospective studies, and subset analyses with the inherent limitations these methods imply. the advanced renal cell carcinoma sorafenib expanded access program allowed patients in the united states and canada with metastatic rcc to receive treatment with sorafenib prior to its regulatory approval. this non-randomized, open-label program treated 158 subjects with papillary rcc of a total of 1891 evaluable subjects (81% clear cell, 8% non-clear, and 11% unclassified histology).(29) of the 107 evaluable subjects with papillary rcc, 90 (84%) had a measurable response to treatment with 3 partial responders and 87 with stable disease for at least 8 weeks, while 17 (16%) subjects demonstrated early progression on treatment. the side effect profile for sorafenib was similar across histologic subtypes, and the authors concluded that sorafenib has some activity in papillary tumors. gore and associates treated 588 subjects with non-clear histology (not further subclassified) in their multi-center, international, non-randomized, expanded access compassionate use trial examining the safety and efficacy of sunitinib.(30) of these, 437 were evaluable; however, the trial did not predefine criteria for measuring response, which was instead determined according to local practice. a total of 48 (11%) subjects had an objective response (46 partial responses and 2 complete responses), while 250 (57%) had stable disease for 3 months. nearly one-third of the subjects (n = 139; 32%) progressed within 3 months. despite focusing on poor-prognosis populations that were typically excluded from other trials because of the presence of brain metastases, eastern cooperative oncology profile of sunitinib was similar to that seen in traditional patient populations.(11,31-33) the median overall survival (os) for subjects with non-clear rcc in this study was 13.4 months, which is an improvement over the historical control of 9.4 months (a historical control was used given the non-randomized design of this trial).(34) the lower overall response rate (11%) for the non-clear histology group may have been influenced by the lack of a protocol-mandated evaluation procedure and the dependence on local standards of care to measure changes in disease burden.(30) despite this limitation, the authors concluded that sunitinib is adequately tolerated and oncologically active in poor-prognosis populations, including subjects with non-clear histology, and that its use and further study are appropriate. choueiri and coworkers reported their retrospective multi-center review of 41 subjects with metastatic papillary rcc, who were treated with either sunitinib or sorafenib in the united states and france, which represents one of the largest papillary-only series published to date.(35) they found that although response rates were low (5% overall, 17% for sunitinib group), progression-free survival (pfs) was longer in those treated with sunitinib rather than sorafenib (11.9 months versus 5.1 months; p < .001). while the number of subjects in this retrospective analysis was small and the overall response rate was low, the pfs in patients treated with sunitinib is similar to that published for subjects with clear cell histology,(12) suggesting some activity for this agent. unfortunately, there was no stratification of subjects based on papillary i versus ii subtypes, which may indicate that the natural history and aggressiveness of these two entities were not adequately controlled in this trial. in contrast, a recent report from plimack and colleagues of their phase ii experience with sunitinib in 23 patients with advanced papillary non-clear renal cell carcinoma—tazi et al 5urology journal vol 8 no 1 winter 2011 rcc outlines the minimal activity associated with this drug and underscores the need to look beyond single agent vegf pathway antagonists.(36) no objective responses were seen in this prospective, single-arm study. eight patients had stable disease as their best response with a median pfs of only 1.6 months and median os of 10.6 months. similarly, ravaud and associates from the french genito-urinary group and the group of early phase trials examined sunitinib as a first-line therapy in subjects with locally advanced or metastatic papillary rcc in their on-going phase ii trial. their preliminary data on 5 subjects with papillary i and 23 subjects with papillary ii rcc found no papillary i responders and only 1 papillary ii partial response.(37) hudes and coworkers also included a significant number of subjects with non-clear histology in their global advanced rcc trial comparing temsirolimus, interferon alfa, or both for advanced rcc.(14) this international, multicenter, randomized phase iii trial treated a total of 626 subjects with poor-prognosis metastatic rcc. one hundred and twenty-four (20%) subjects were classified as having non-clear cell rcc. however, a central pathology review was not performed and further subclassification was not provided. subjects of all histologic types receiving temsirolimus monotherapy had a median os of 10.9 months, compared to 7.3 and 8.4 months for the groups receiving interferon alfa alone or temsirolimus plus interferon, respectively. likewise, median pfs times were 5.5, 3.1, and 4.7 months, respectively, using response evaluation criteria in solid tumor (recist) completed by independent radiologists. hazard ratios for os among the non-clear rcc subgroup also favored treatment with temsirolimus over interferon alfa. subsequent exploratory subset analyses based on tumor histology from global advanced rcc determined that 55 subjects had papillary rcc and that those in the temsirolimus group (n = 25) had prolonged os (11.6 versus 4.3 months, respectively) and pfs (7.0 versus 1.8 months, respectively) compared to those treated with interferon alfa (n = 30).(38) although these data represent an exploratory subset analysis, this report is significant in that temsirolimus is the only agent approved by the food and drug administration for advanced rcc that has been evaluated in non-clear cell rcc in a phase iii trial. these data suggest that mammalian target of rapamycin (mtor) inhibitors, either as single agents or in combination, should be further evaluated in papillary rcc in prospective studies. a prospective phase ii trial of everolimus, an oral mtor inhibitor, as monotherapy in advanced papillary rcc, is ongoing in europe. foretinib (also known as gsk1363089 or xl880) is an oral receptor tyrosine kinase inhibitor (tki) that targets c-met and vegfr2 and has been studied in a phase ii multi-center trial.(39) two different dosing regimens, a daily and an intermittent dosing regimen, were evaluated in this trial. interim data on the first 60 patients (37 in the intermittent dosing arm and 23 in the daily dosing cohort) were reported recently in abstract form. response evaluation criteria in solid tumor partial responses were seen in 7/53 evaluable patients, including 4/37 or 11% of patients receiving intermittent dosing and 3/16 or 19% of patients on the daily dosing regimen. in addition, over 70% of patients treated had stable disease, with the majority demonstrating some degree of tumor shrinkage. the drug was well-tolerated, with a side effect profile akin to that seen with other vegf receptor antagonists. the trial has completed accrual and final efficacy analysis is awaited. foretinib is the first met antagonist to be evaluated in papillary rcc and patients will be retrospectively stratified based on c-met status to determine if clinical efficacy is correlated with met activation. erlotinib is an oral epidermal growth factor receptor tyrosine kinase inhibitor. a multicenter phase ii trial of this agent in patients with locally advanced and metastatic papillary rcc reported an overall recist response rate of 11% (5/45 patients) with an additional 24 (53%) patients experiencing stable disease.(40) the 6-month pfs was only 29%; however, the median os was 27 months. although this was a single-arm, uncontrolled study, the os reported was higher than that has been reported for patients with metastatic papillary rcc.(34,35) addition of mtor inhibitors or vegf pathway non-clear renal cell carcinoma—tazi et al 6 urology journal vol 8 no 1 winter 2011 antagonists may potentiate the single agent activity of erlotinib. a phase ii trial of erlotinib in combination with bevacizumab is currently underway and is one of the trials designed to evaluate this strategy.(41) chromophobe renal cell carcinoma chromophobe rcc accounts for approximately 4% of all rccs(9) and is often detected while still confined to the kidney, as less than 5% of cases are metastatic at the time of diagnosis.(26,27) the mechanisms underlying the genesis of this subtype of rcc are not well-understood. however, studies focusing on a familial form of chromophobe kidney cancer are beginning to provide some early insights that might help elucidate the molecular pathways driving this malignancy. birt-hogg-dubé (bhd) is an autosomal dominant hereditary cancer syndrome associated with bilateral, multifocal chromophobe rcc. approximately, one-third of patients with bhd have this renal manifestation, with 5% demonstrating oncocytomas, and an additional 50% demonstrating hybrid chromophobe/ oncocytic tumors.(42,43) the bhd gene, flcn, located on the short arm of chromosome 17, was identified by genetic linkage analysis,(38,44) and is altered via insertion, deletion, or nonsense mutations in the germline of the vast majority of affected individuals.(45) the protein product of bhd, folliculin, functions as a tumor suppressor.(46) the function of folliculin and the consequences of folliculin loss in bhd are currently under study. available data indicate that folliculin is a component of the cellular energy sensing system and may interact with cellular activated mitogen protein kinase (campk) and mtor pathways. investigators at the national cancer institute have demonstrated mtor upregulation in flcn-/tumors, with activation of both mtorc1 and mtorc2 pathways.(47) additionally, the mtor inhibitor rapamycin appears to ameliorate the renal phenotype and prolong survival in conditional flcn-/mice. these data suggest a role for mtor inhibitors in the management of bhd-associated tumors. the relevance of the bhd and mtor pathways in sporadic chromophobe rcc is an area of active investigation. it is hoped that these studies will help identify rational targets and help determine the utility of mtor inhibitors in this patient population. upregulation of cellular proto-oncogenic receptor tyrosine kinase (c-kit) has also been associated with chromophobe rcc;(48) however, its precise role in the genesis and progression of these tumors is unclear. c-kit is a target that is amenable to pharmacologic inhibition, and several agents currently available, including imatinib, sunitinib, and sorafenib, have been shown to inhibit this molecule. like papillary rcc, chromophobe tumors have been excluded from many of the initial targeted therapy trials. the available data are even more limited given that chromophobe rcc is less common and less likely to metastasize than papillary rcc, making attempts at subset analyses tenuous. stadler and colleagues treated 20 subjects with chromophobe rcc as part of the advanced rcc sorafenib expanded access program.(29) they saw an overall disease control rate of 90%, with 1 (5%) partial response and 17 (85%) subjects with stable disease for at least 8 weeks, while 2 (10%) subjects had disease progression. chromophobe tumors were also included in the temsirolimus versus interferon alfa trial, but the published subgroup analysis by tumor histology only examined papillary tumors.(49) however, the os and pfs were prolonged in the aggregate non-clear group treated with temsirolimus, providing evidence, albeit weak, for the use of temsirolimus over interferon alfa in advanced chromophobe rcc. collecting duct renal cell carcinoma collecting duct rcc is extremely rare, accounting for less than 1% of all rccs(9) and is associated with a grave prognosis, with approximately one-third of patients having metastases at the time of diagnosis.(34) this malignancy is thought to arise from the collecting ducts of the renal medulla. medullary carcinoma is an especially virulent type of the collecting duct rcc that is associated with sickle cell trait and is often seen in young african american patients. due to the rarity of this disease, there is scant non-clear renal cell carcinoma—tazi et al 7urology journal vol 8 no 1 winter 2011 evidence to guide treatment recommendations, and no randomized clinical trials have been completed.(50) the strongest treatment evidence available comes from a phase ii multi-center trial of 23 treatment-naive metastatic subjects who were given gemcitabine plus cisplatin or carboplatin, depending on renal function.(51) this regimen was selected based on the histologic similarities between the collecting duct rcc and transitional cell carcinoma of the urinary bladder. oudard and associates found that 26% of subjects had a response to treatment per recist criteria (5 partial responses and 1 complete response) as measured by independent radiologic review; pfs was 7.1 months with an os of 10.5 months.(51) there is not enough data to comment on the role of tkis or mtor inhibitors in this type of rcc. clearly more therapeutic options are needed for this disease. cytoreductive nephrectomy, neoadjuvant, and adjuvant therapy cytoreductive nephrectomy (cn) followed by systemic interferon was shown in two randomized trials to provide a statistically significant, albeit limited, improvement in survival (13.6 months for cn plus interferon versus 7.8 months for interferon alone when these two trials were analyzed in combination).(52-54) based on these data, cn was adopted as the standard of care in the cytokine era. with the emergence of targeted therapies, the role of cn has not yet been directly re-evaluated with a randomized prospective study; however, the majority of subjects in the three major trials of sunitinib, sorafenib, and temsirolimus had undergone nephrectomy prior to receiving systemic therapy.(11-13) the exact mechanism by which cn confers a survival advantage is still being elucidated, but potential explanations include removing bulky primary tumors which act as immunologic sinks for antibodies and tumor reactive lymphocytes, delaying disease progression, decreasing disease burden,(55) and reducing the amount of growth factors secreted by the primary tumor.(56) while most of these hypotheses were invoked to explain the utility of cn followed by cytokine therapy, some of these mechanisms may also be relevant in the era of targeted therapies designed to disrupt the proangiogenic pathways that are activated in rcc. prospective data on the use of cn in combination with targeted therapies in the metastatic clear cell rcc population are limited and this approach warrants further study. phase iii studies of sunitinib alone versus sunitinib with cn (carmena) and pre-surgical versus postsurgical sunitinib (eortc) are currently ongoing in europe.(57) in non-clear histologies, data from studies examining the role of cn are limited and largely based on retrospective subgroup analyses.(28,34,58) recently, kutikov and colleagues published their series of 141 subjects, 98 of whom underwent cn and received systemic immunotherapy or targeted therapy between 1990 and 2008.(59) of 132 subjects with an identifiable rcc histology, 7 (5.3%) had papillary and 2 (1.5%) had collecting duct rcc. of these 9 subjects, 8 were able to receive systemic therapy following cn while 1 subject with the collecting duct rcc had rapid disease progression precluding systemic therapy. across all histologies, rapid disease progression was the reason why 13 of 43 subjects (30%) could not receive systemic therapy after cn. the authors found that only poor baseline ecog performance status predicted which subjects would not be able to receive post-cn systemic treatment, a conclusion that echoes those of prior studies.(60) some authors consider non-clear histology to be a relative contraindication to cn given the scant data available to support a survival advantage, the known morbidity, and possible mortality that is associated with the procedure.(57) however, given the limited systemic options available, aggressive surgical resection in appropriately selected candidates seems to offer the patient with advanced or metastatic non-clear rcc the best chance for prolonged survival currently available. additional trials are needed to address how to identify the optimal candidate for cn, which systemic targeted therapy agent or agents to use, and in what order to employ them. non-clear renal cell carcinoma—tazi et al 8 urology journal vol 8 no 1 winter 2011 neoadjuvant systemic therapy has been shown to benefit patients with advanced bladder, metastatic germ cell, and metastatic colon cancer. no trials directly address the use of neoadjuvant systemic targeted therapy for non-clear rcc, but several case series have been published and several centers, such as m.d. anderson cancer center, university of north carolina at chapel hill, and the cleveland clinic have active protocols addressing this issue; however, none are exclusively focused on non-clear histologies.(61) the goals of neoadjuvant therapy are to downstage the primary tumor in order to make extirpative surgery feasible or technically less challenging and to eradicate micrometastatic disease, as distant failure portends a poor prognosis.(55,62) a significant portion of patients undergoing aggressive surgical resection fails to receive systemic therapy because of rapid disease progression.one treatment strategy described by margulis and wood at m.d. anderson cancer center is to treat surgically unresectable patients with sunitinib for four weeks followed by restaging.(63) patients with a favorable response can proceed to extirpative surgery while those who fail to respond or progress are treated with a different systemic agent. the goal of this schema is to identify those patients who are likely to progress rapidly and therefore never receive adjuvant therapy after cn, and treat them systemically while avoiding the morbidity of major surgery. this is an intriguing study design and should be replicated in the setting of nonclear histology, particularly once active systemic agents become available. the use of cytokine therapy in the adjuvant setting to reduce the risk of distant failure following local treatment with curative intent was not found to be beneficial in patients with clear cell rcc.(64-66) adjuvant targeted therapies are now being evaluated with trials in the united states, europe, and asia.(8) for example, the eastern cooperative group sponsored assure (adjuvant sorafenib or sunitinib for unfavorable renal carcinoma) trial is open to all histologies except collecting duct or medullary carcinoma; enrollment is ongoing, but no results have been reported. southwest oncology group’s everest (everolimus in treating patients with kidney cancer who have undergone surgery) is open to all histologies except the collecting duct or medullary rcc and compares everolimus to placebo in the adjuvant setting. similarly, the industry-sponsored s-trac (sunitinib treatment of renal adjuvant cancer) is also open to all rcc subtypes except the collecting duct and is accruing subjects. the united kingdom’s medical research council-sponsored sorce (sorafenib in treating patients at risk of relapse after undergoing surgery to remove kidney cancer) is open to all histologies, but as expected in an adjuvant trial, nephrectomy is the only prior rcc treatment allowed. future research despite recent advances, there remains a paucity of effective systemic options directly applicable to advanced and metastatic non-clear cell rcc. histology-specific and mechanism-based studies addressing virtually all aspects of papillary, chromophobe, and the collecting duct rcc are essential for continued progress in our attempts to determine optimal management of these patients. the identification of several familial forms of renal cancer has greatly enhanced our ability to study and understand the genetic alterations and biochemical pathways unique to distinct subtypes of rcc. as with clear cell rcc, better molecular characterization will likely enable development of rational targeted strategies against other subtypes of familial kidney cancer as well as their sporadic counterparts. due to the rarity of these conditions, multi-center cooperative trials have the highest likelihood of accruing enough subjects to adequately power prospective studies. several agents currently available demonstrate modest activity in patients with non-clear cell rcc. trials investigating combinations of one or more of these agents, either administered in sequence or given concomitantly, may improve outcomes compared to monotherapy by allowing targeting of multiple pathways of tumorigenesis simultaneously. neoadjuvant targeted therapy with or without cn is likely to become increasingly relevant in the management of selected patients with advanced clear cell rcc. its role in the non-clear patient population non-clear renal cell carcinoma—tazi et al 9urology journal vol 8 no 1 winter 2011 must be elucidated further. risk factors other than performance status must be identified to properly stratify patients given the morbidity of cn and the high percentage of patients who rapidly progress despite systemic therapy. histology-specific circulating tumor markers are quite promising in this regard(61,67) and may help identify who should receive systemic treatment immediately instead of cn, as well as serve as non-radiographic (non-recist) surrogates or predictors of tumor response.(8) similarly, the optimal duration of and timing between neoadjuvant treatment and cn need further definition; however, reports have not described significant problems with wound healing or other increased morbidity thus far.(62,63,68) the impact of targeted therapies on patient’s quality of life must also be examined along with the more traditional oncologic endpoints of adverse events, disease progression, and survival.(69) targeted therapies offer tremendous therapeutic opportunities to patients, but also come with unique and often unavoidable side effects.(70) a number of validated, cancer-specific, and kidney cancer-specific instruments exist, but there are neither histology-specific nor widely accepted standard quality of life surveys for rcc at this time.(71) quality of life endpoints should be included in all prospective targeted therapy studies and considered as an essential component for multi-center and cooperative group trials in order to ensure that the goal of alleviating suffering is advanced along with the goals of prolonging survival and identifying cures for patients with non-clear rcc. conclusion targeted therapies have greatly expanded the treatment options available to patients with advanced and metastatic non-clear cell rcc. however, much work is needed in order to determine the optimal agent(s) against each histologic subtype. patients presenting with advanced non-clear pathology should undergo a thorough metastatic evaluation and, if appropriate, surgical evaluation to determine if nephrectomy, lymphadenectomy, and/or metastectomy are warranted. aggressive surgical extirpation is often recommended at the national cancer institute given the poor survival associated with these entities and the limited evidence available to drive the selection of systemic therapy. all patients should be encouraged to consider participating in clinical trials and referred to appropriate medical centers. at the present time, the literature offers limited support for the use of vegf and mtor inhibitors to treat patients with advanced or metastatic non-clear cell rcc. the results of prospective trials examining treatments for papillary, chromophobe, and the collecting duct rcc are eagerly awaited. conflict of interest none declared. references 1. jemal a, siegel r, ward e, hao y, xu j, thun mj. cancer statistics, 2009. ca cancer j clin. 2009;59:225-49. 2. pfaffenroth ec, linehan wm. genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. expert opin biol ther. 2008;8:779-90. 3. linehan wm, srinivasan r, schmidt ls. the genetic basis of kidney cancer: a metabolic disease. nat rev urol. 2010;7:277-85. 4. linehan wm, walther mm, zbar b. the genetic basis of cancer of the kidney. j urol. 2003;170:2163-72. 5. linehan wm, 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cytoreductive nephrectomy in metastatic renal cell carcinoma. curr opin urol. 2008;18:474-80. 68. margulis v, matin sf, tannir n, et al. surgical morbidity associated with administration of targeted molecular therapies before cytoreductive nephrectomy or resection of locally recurrent renal cell carcinoma. j urol. 2008;180:94-8. 69. buchanan dr, o’mara am, kelaghan jw, minasian lm. quality-of-life assessment in the symptom management trials of the national cancer institutesupported community clinical oncology program. j clin oncol. 2005;23:591-8. 70. saylor pj, michaelson md. new treatments for renal cell carcinoma: targeted therapies. j natl compr canc netw. 2009;7:645-56. 71. liu j, mittendorf t, von der schulenburg jm. a structured review and guide through studies on healthrelated quality of life in kidney cancer, hepatocellular carcinoma, and leukemia. cancer invest. 2010;28: 312-22. aykut aykaç performed his urology residency from ankara dışkapı yıldırım beyazıt training and research hospital, turkey. between 2016-2020, he worked as a faculty member at the karabuk university, faculty of medicine, department of urology. he became an associate professor of urology at eskişehir city hospital in 2021. he has various publications in the field of endourology, particularly in the treatment of stone diseases. i am aware that it is difficult to conduct scientific research. i see criticism as finalizing the prepared articles, such as a chef putting the final touch on a dish. as someone who looks at work from the outside, i have the opportunity to evaluate it more objectively. my main advantage according to the reader is that i have the chance to learn about the things i wonder about in the study. i would like to thank the editors of the journal who were deemed worthy of the best reviewer award, which honored me very much. best reviewer of the january-february 2022 issue aykut aykaç aykut aykaç february 2022 minimally invasive surgeries in the management of renal parapelvic cysts: a retrospective comparative study hualin chen1, yang pan1, xiaoxiang jin1, gang chen1* purpose: to compare the efficiency and safety of two minimally invasive surgeries, laparoscopy and flexible ureteroscopy (furs), in the management of renal parapelvic cysts. materials and methods: between january 2013 and april 2019, patients who suffered from parapelvic cysts and received furs or laparoscopy at our hospital were recruited for this study. all patients underwent biopsies of the cyst wall. primary outcome was treatment success, which was defined as symptomatic and radiological. during follow-up, telephone contact and ct scans were used to record any relevant symptoms and any recurrence, respectively. results: a total of 33 patients (22 in furs; 11 in laparoscopy) were included in this study. flank pain prior to the procedures were reported by 14/22 patients and 6/11 in furs and laparoscopy, respectively (p = .62), and patients had complete pain relief after the operation. the complication rate was significantly lower in the furs group than in the laparoscopy group (p = .01). minor complications were observed in 3/22 and 5/11 patients (grade 1 and 2) in the furs and laparoscopy group, respectively. all patients were controlled by conservative treatment. however, 1/11 major complication (grade 3b) was detected in the laparoscopy group and managed by ureteroscopy to remove the obstruction under general anesthesia. significant differences were found in operative time (p = .01) and postoperative hospital stay (p = .01), while medical expenses were similar between the two groups (p = .42). during follow-up, no recurrence was detected in ct scans. conclusion: in the management of parapelvic cysts, two minimally invasive surgeries were comparable in efficiency. however, furs was superior to laparoscopic unroofing with regard to the complication rate, operative time, and postoperative hospital stay. keywords: laparoscopy; parapelvic cyst; ureterorenoscopy introduction renal cysts are common with a prevalence of 5%. most renal cysts are asymptomatic and a benign disease in regard to the bosniak classification. thus, non-conservative treatment is not necessary for such cysts.(1) however, renal parapelvic cysts, accounting for a small part of renal cysts, may be accompanied by symptoms such as lumbago, hematuria, and infection.(2) moreover, it not only represents a diagnostic challenge due to its rarity and misdiagnosis as hydronephrosis by imaging,(3) but also leads to treatment difficulties due to its complexity and proximity to the renal hilum.(4) in the past decades, multiple minimally invasive treatment options including sclerotherapy, percutaneous aspiration, and laparoscopic unroofing have been explored by urologists.(5) for sclerotherapy, the potential risk factor is sclerosing agent extravasation into the retroperitoneum. as a result, severe perinephric inflammation, abscess or ureteropelvic junction obstruction (upjo) may develop. moreover, aspiration is associated with a relatively high recurrence rate. laparoscopic unroofing remains the most advantageous technique for the management of this disease, especially in complicated cases.(6) more recently, internal drainage by flexible ureteroscopy (furs) has been reported as an effective, feasible, and safe treatment option for parapelvic cysts.(7) however, there have been no studies comparing the efficacy and safety of the two minimally invasive surgeries, laparoscopic unroofing and furs in the management of parapelvic cysts. thus, we performed a cohort study to address this topic based on our single-center experience. materials and methods patients with the approval of the first affiliated hospital of chongqing medical university research ethics committee (chongqing, china), we retrospectively reviewed all patients suffering from renal parapelvic cysts between january 2013 and april 2019 at our hospital. written informed consent was obtained from all patients. the inclusion criteria were: (1) patients with symptoms such as flank pain, infection and/or hematuria, department of urology, the first affiliated hospital of chongqing medical university, chongqing, 400016, china. *correspondence: department of urology, the first affiliated hospital of chongqing medical university, chongqing, 400016, china. tel: +86-13668039053, fax: +86-23-89012919, email: chengang2308@163.com. received september 2020 & accepted january 2021 endourology and stone disease urology journal/vol 18 no. 4/ july-august 2021/ pp. 389-394. [doi: 10.22037/uj.v16i7.6466] (2) asymptomatic patients with large cysts which compressed the collecting system and caused urinary obstruction and hydronephrosis, which was described in a prior study in detail(7),(3) patients treated with furs or laparoscopy. all patients received preoperative computed tomography (ct) scans and intravenous urogram (ivu) to identify the characteristics of the parapelvic cysts (figure 1). patients whose cysts were suspected of malignancy in ct scans or patients with cardiopulmonary insufficiency or coagulation disorders or ureteral stricture history were excluded from this study. surgical procedures based on our experience and published literature, there are three subtypes of parapelvic cyst, including exogenous, mixed, and endogenous.(8) the classification was defined by the topographical relationship between cyst and the renal surface and the pelvis. the treatment modality, furs or laparoscopy, was decided by active discussion with patients, regardless of the subtype of the cysts. two surgeons with more than five-year surgical experience performed one type of operation each. in the furs group, patients were given general anesthesia and were placed in the lithotomy position. an 8-fr furs was inserted into the renal pelvis and the cyst wall (with typical characteristics, such as thin wall, pale blue membrane) could be observed. once the wall was identified, a 200-μm holmium laser fiber was adopted to incise the wall and coagulate the incision margin. subsequently, the inner cyst wall was examined to avoid the misdiagnosis of cystic renal cell carcinoma. if there was any partition in the cyst, it was cut with the laser to avoid recurrence. then, a 6-fr ureteral stent, which was removed one month post operation, was routinely placed with the proximal end inside the cyst to drain the cystic fluid. in the laparoscopic group, patients were given general anesthesia and were placed in the lateral decubitus position. the retroperitoneal approach was performed in all patients. primarily, three ports were placed as the way reported in a previous study.(9) with careful dissection, the parapelvic cyst was identified and then the cyst wall was incised with an ultrasonic scalpel and the cystic fluid was aspirated. then, the incision margin was coagulated with ultrasonic scalpel and the placement of a drainage tube and the wounds were sutured. ureteroscopic and laparoscopic biopsies were performed in all patients, and the specimens were sent for further pathological examination. baseline characteristics and outcomes baseline characteristics and outcome measurements were retrieved from the electronic medical record system. the former included gender, age, body mass index (bmi), size/side of cysts, and number of patients with symptoms. the size of cyst was measured by using its longest axis in the ct scans. outcomes were classified into primary and secondary. the primary outcome was defined as treatment success, which included symptomatic and radiological success. symptomatic success was defined as complete postoperative pain relief, and radiological success was defined as a decrease in cyst size by more than half of its previous size according to ct scans performed during follow up. preand postoperative flank pain intensity of patients were quantitatively evaluated by a 10-point visual analog scale ranging from 0 (no pain) to 10 (severest pain). meanwhile, pain was classified into three grades according to the score: slight (0-3), moderate (4-6), and severe (over 6). patient with a pain score > 3, or with a residual pain rating, was regarded as symptomatic failure. the others were categorized as having symptomatic success. secondary outcomes were regarded as operative time, length of hospitalization, complications, and medical expenses. complications were classified into minor (grade 2 or lower) and major (grade 3a or higher) according to the clavien-dindo classification.(10) the patients were followed up by telephone after discharge to record any symptom related to parapelvic cyst. on august 31, 2019, the deadline of our study, all patients were advised to have ct scans performed to detect any recurrences. statistical analyses chi-square test was performed to analyze dichotomous variables. for continuous variables, shapiro-wilk test was carried to analyze data for normality. we noticed that most continuous variables were not subject to a normal gaussian distribution. hence, non-parametric mann-whitney u test was used for the analysis of continuous variables. spss 22.0 was used to perform the statistical analyses. two-tailed p < .05 were considered statistically significant. results in total, 33 consecutive patients (22 in furs group and 11 in laparoscopic group) were included in the study. overall, more than 50% of patients presented with flank pain (63.6% vs. 54.5%, p = .62) and others had their parapelvic cysts revealed incidentally. there was no significant difference between the two groups with respect to age (p = .32), bmi (p = .91), gender (p = .11), cyst size (p = .10), laterality of cyst (p = .80). table 1 summarizes the demographics and baseline characterislaparoscopy and ureterorenoscopy in renal parapelvic cyst-chen et al. table 1. demographics and baseline characteristics of the patients. characteristic furs (n=22) laparoscopy (n=11) p-value a age, year 54.0 (45.0 63.0) 58.0 (53.0 64.0) .32 gender, male (%) 12 (54.6%) 6 (75. 0%) .11 bmi 24.1 (21.8 26.5) 23.5 (23.3 25.0) .91 flank pain (%) 14 (63.6%) 6 (54.5%) .62 cyst size, mm 5.6 (4.8 7.0) 4.9 (4.0 5.8) .10 laterality, l (%) 15 (68.2%) 5 (62.5%) .80 abbreviations: bmi, body mass index. values are presented as median (iqr) or number (percent). a categorical variables were compared by chi-square test. vol 18 no 4 july-august 2021 390 endourology and stones diseases 391 tics of the participating patients. in the furs group, one patient suffered from parapelvic cyst in the solitary kidney, and the renal function did not deteriorate after the procedure. one carried bilateral parapelvic cysts (right: 2.52 cm; left: 5.8 cm), and cyst at left side was managed (supplementary figure 1). the cyst of one case was difficult to be found with direct vision of furs alone. and around 2 ml methylene blue was injected into the cyst through percutaneous approach to dye the fluid. then, the cyst wall was located and incised successfully. one concomitant with ipsilateral large simple renal cyst (8 cm at diameter) was treated with laparoscopic unroofing simultaneously (supplementary figure 2). patients in the furs group had significantly shorter length of operative time and postoperative hospital stay than those in the laparoscopic group (p = .01, p = .01, respectively). the cost of hospitalization was similar between the two groups (p = .42). the complication rate was statistically lower in the furs group than that in the laparoscopic group (p = .01) (table 2). there was no intraoperative complication (massive bleeding, transfusion, etc.) recorded in the furs group. however, two cases (9.09%) of fever (grade 2) and one (4.55%) case of abdominal discomfort (grade 1) were recorded after the procedure, which were managed by intravenous antibiotics and conservative treatment, respectively. in the laparoscopic group, the mean blood loss was 95 ml. intraoperative massive hemorrhage (ranging from 150 to 400 ml) occurred in 4/11 (36.4%) patients (grade 1). one-unit blood transfusion was required by one (25%) patient (grade 2). 2/11 (18.2%) patients suffered from persistent postoperative urine leakage (more than 72 hours). one (50%) patient with fever was controlled by intravenous antibiotics (grade 2). another patient (50%) was suspected to have an obstruction in the ureter and received ureteroscopy and ureteral stenting under general anesthesia (grade 3b). all patients had negative pathologic findings in the cyst wall for malignancy. postoperatively, complete pain relief was observed in all patients with lumbago before the operation. during follow up, radiological success was observed in all patients (figure 2). discussion this was the first study to compare the efficacy and safety of laparoscopy and furs in the management of parapelvic cysts. the results revealed that both procedures were efficient. however, patients in the laparoscopic group had a statistically higher incidence of complications than those in the furs group. moreover, significantly longer operative time and postoperative hospital stay were seen in the laparoscopic group. through published studies investigating the treatment of parapelvic cysts, we noticed that most studies with a sample size of more than 10 cases were conducted in china,(1,2,9,11-21) while in western countries, most studies were case reports. firstly, the population of chinese studies was larger than that in western countries, indicating that more patients suffered from parapelvic cyst even though its rate of occurrence is rare. secondly, urologists in western countries performed surgery for symptomatic cysts, which were a small part of overall parapelvic cysts. while for asymptomatic cysts, active follow-up was recommended.(14-16,19-21) in china, actable 2. outcome measures outcomes furs (n=22) laparoscopy (n=11) p-value a treatment success 22 11 operative time, min 45.0 (28.8-56.3) 80.0 (70.0-95.0) .01 postoperative hospital stay, day 2.0 (1.8-3.0) 4.0 (3.0-7.0) .01 hospitalization expense, cny 37491.6 (20302.7-63842.8) 27293.5 (19495.3-46307.6) .42 pain score preoperation 5 (1-9) 6 (2-8) .45 postoperation 1 (1-2) 2 (1-3) .37 complications .01 <= grade 2 3 (13.6%) 5 (45.5%) >= grade 3a 0 1 (9.1%) f/u, mon 42.5 (20.5 53.5) 19.0 (9.0 55.0) .21 abbreviations: f/u, follow up. cny, chinese yuan. values are presented as median (iqr) or number (percent). a categorical variable was compared by chi-square test. p values in bold indicate significant results. figure 1. ivu demonstrated that the parapelvic cyst (arrow) compressed the collecting system and no contrast media entered the cyst. laparoscopy and ureterorenoscopy in renal parapelvic cyst-chen et al. cording to the recommendations of chinese urology association (cua) guidelines in 2014 and the latest edition of wu jieping urology in 2019, active management should be applied for asymptomatic patients with large (cut-off not defined) parapelvic cysts that caused massive normal renal parenchymal reduction, hydronephrosis, and/or urinary obstruction. additionally, wang et al.(7) performed furs for selective asymptomatic cyst larger than 4 cm, and a study by mao et al.(17) included asymptomatic patients with a cyst size larger than 3 cm. the cyst sizes in our study ranged from 3.8 cm to 9.5 cm. treatment success was achieved in all patients in our study. the result revealed that both two minimally invasive surgeries were efficient, and our result was conformant with previous studies.(1,2,9,11-13,17,18) however, the sample size was relatively small with weak statistical power, and the duration of the follow-up period may not be sufficient. the complication morbidity favored furs. overall, most intraand post-operative complications were minor (grade 2 or lower) and could be managed by conservative treatment. the only single major complication (grade 3b) occurred in the laparoscopic group. the patient developed persistent urine leakage, caused by a suspected obstruction in the ureter. thus, 5 days post laparoscopy, ureteroscopy and ureteral stent placement were performed with the patient under general anesthesia. during the procedure, calculus was discovered at the site of ureteropelvic junction and was pushed back into the pelvis with a ureteral stent. considering that the patient was suffering urine leakage and multiple kidney stones, lithotripsy was not performed. 36.4% of patients in the laparoscopic group developed intraoperative massive hemorrhage (blood loss amount over 100 ml). moreover, a single patient (25%) required blood transfusion. this may be due to the following: (1) two cysts were relatively large with sizes of 8.9 cm and 6.8 cm and(2) a further two cysts were strongly attached to the surrounding tissue, inducing extensive dissection and causing blood seepage. bleeding events may appear more serious compared with those reported in previous studies. however, the mean blood loss in our study was 95 ml, which is comparable to that in other studies.(15) no large number of hemorrhages were reported in the furs group. although the incision in the cyst in the furs group was performed blind, we adopted following key-steps to avoid hemorrhaging. first, the incision site was performed away from the renal calyceal and was at the most bulging site of the cyst. second, we performed the incision into the wall with an initial diameter of 0.5 cm, and the incision was broadened once the cyst was identified. third, the incision did not exceed the cyst-pelvic junction. demonstrated by the result in this study, patients in the furs group had a significantly shorter operation time and more rapid postoperative recovery compared to those in the laparoscopy group. however, in the laparoscopic approach, the surgeon had to place trocars (usually 3) and carefully dissect before the surgeon was able to incise the cyst wall, while the furs surgeon had direct access to the cyst wall through a natural orifice. this led to the advantage of shorter operation and hospitalization times. wang et al. reported their experiences in further shortening the operation time by modifying the furs procedure.(7) however, it is important to remember that the furs could not always identify the parapelvic cysts with untypical features (thick wall, ill-defined border, etc.). one cyst in our study was not identified using a ureteroscope alone. a modified procedure with methylene blue injection, which was reported in a previous study,(7) was adopted to dye the cystic fluid. although the cyst was successfully discovered and excised, the procedure took over two hours (median operative time was 45 minutes in furs group) to complete all the steps (re-sterilization, re-position, puncture and re-furs). kang et al. and wang et al. studied the modified strategy for locating the cyst and found that cysts with typical characteristics could be located with a ureteroscope alone, while those without, required multiple auxiliary procedures to help localization. disappointingly, we could not distinguish the two kinds of cysts by preoperative ct scans or ivu alone, suggesting that identification of the kind of cyst requires modified procedures and complicated techniques, which were unknown before the operation. thus, an evaluation system is required to avoid unnecessary punctures and complicated procedures. this study had several limitations. first, a small sample size with a retrospective nature was the main drawback, which may have resulted in potential selection bias. however, as one of the largest teaching hospitals in the southwest of china, our hospital patient number was large, and many patients from surrounding cities sought medical attention, indicating that the selection bias might be minimized. second, renogram was not applied to demonstrated urinary obstruction. third, even though no massive hemorrhage was reported in the litfigure 2. the ct imaging of one parapelvic cyst in the furs group before surgery (a) and 22 months after surgery (b). laparoscopy and ureterorenoscopy in renal parapelvic cyst-chen et al. vol 18 no 4 july-august 2021 392 endourology and stones diseases 393 erature for patients undergoing furs, we must keep in mind that the incision of the cyst wall was blindly performed and a ct angiogram or endoluminal doppler ultrasound should have been performed to avoid vessels in the common wall. in the future, well-designed, multiple-center studies with large sample size are required to further validate our findings. conclusions to the best of our knowledge, this is the first head-tohead comparative study conducted to explore two most commonly used minimally invasive surgeries in urological practice, furs and laparoscopy, in the management of renal parapelvic cysts. the results revealed that the two approaches were comparable in regard to the treatment efficiency, while the complication rate, operative duration, and length of postoperative hospital stay, favored furs. however, it should be noted that furs could not be used for the treatment of cortical cysts and the power of our study was not strong. for patients with parapelvic cysts, our initial experience could be applied in future decision making on the most applicable surgical technique. acknowledgment this work was supported by chongqing science and technology commission (cstc2015shmszx120067). conflicts of interest the authors report no conflicts of interest appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/27 references 1. kang n, guan x, song l, zhang x, zhang j. simultaneous treatment of parapelvic renal cysts and stones by flexible ureterorenoscopy with a novel four-step cyst localization strategy. int braz j urol. 2018;44:958-64. 2. zhao q, huang s, li q, et al. treatment of parapelvic cyst by internal drainage technology using ureteroscope and holmium laser. west indian med j. 2015;64. 3. choi hs, kim cs, bae eh, ma sk, kim sw. bilateral parapelvic cyst misdiagnosed as hydronephrosis. chonnam medical journal. 2019;55:65-. 4. rossi sh, koo b, riddick a, shah n, stewart gd. different successful management strategies for obstructing renal parapelvic cysts. urologia internationalis. 2018;101:3668. 5. agarwal m, agrawal ms, mittal r, sachan v. a randomized study of aspiration and sclerotherapy versus laparoscopic deroofing in management of symptomatic simple renal cysts. j endourol. 2012;26:561-5. 6. eissa a, el sherbiny a, martorana e, et al. non-conservative management of simple renal cysts in adults: a comprehensive review of literature. minerva urologica e nefrologica = the italian journal of urology and nephrology. 2018;70:179-92. 7. wang z, zeng x, chen c, wang t, chen r, liu j. methylene blue injection via percutaneous renal cyst puncture used in flexible ureteroscope for treatment of parapelvic cysts: a modified method for easily locating cystic wall. urology. 2018. 8. yu w, zhang d, he x, et al. flexible ureteroscopic management of symptomatic renal cystic diseases. the journal of surgical research. 2015;196:118-23. 9. chen z, chen x, luo yc, he y, li nn, wu zh. retroperitoneoscopic decortication of symptomatic peripelvic renal cysts: chinese experience. urology. 2011;78:803-7. 10. liu t, peng y, jia c, fang x, li j, zhong w. hepatocyte growth factor-modified adipose tissue-derived stem cells improve erectile function in streptozotocin-induced diabetic rats. growth factors. 2015;33:282-9. 11. yu w, zhang d, he x, et al. flexible ureteroscopic management of symptomatic renal cystic diseases. j surg res. 2015;196:11823. 12. wang z, zeng x, chen c, wang t, chen r, liu j. methylene blue injection via percutaneous renal cyst puncture used in flexible ureteroscope for treatment of parapelvic cysts: a modified method for easily locating cystic wall. urology. 2019;125:243-7. 13. shao z-q, guo f-f, yang w-y, et al. percutaneous intrarenal marsupialization of symptomatic peripelvic renal cysts: a singlecentre experience in china. scandinavian journal of urology. 2013;47:118-21. 14. shah jb, whitman c, lee m, gupta m. water under the bridge: 5-year outcomes after percutaneous ablation of obstructing parapelvic renal cysts. journal of endourology. 2007;21:1167-70. 15. roberts ww, bluebond-langner r, boyle ke, jarrett tw, kavoussi lr. laparoscopic ablation of symptomatic parenchymal and peripelvic renal cysts. urology. 2001;58:1659. 16. micali s, pini g, sighinolfi mc, de stefani s, annino f, bianchi g. laparoscopic simultaneous treatment of peripelvic renal cysts and stones: case series. j endourol. 2009;23:1851-6. 17. mao x, xu g, wu h, xiao j. ureteroscopic management of asymptomatic and symptomatic simple parapelvic renal cysts. bmc urol. 2015;15:48. 18. luo q, zhang x, chen h, et al. treatment of renal parapelvic cysts with a flexible ureteroscope. int urol nephrol. 2014;46:19038. 19. doumas k, skrepetis k, lykourinas m. laparoscopic ablation of symptomatic peripelvic renal cysts. j endourol. 2004;18:458. 20. camargo a, cooperberg mr, ershoff bd, rubenstein jn, meng mv, stoller ml. laparoscopic management of peripelvic renal cysts: university of california, san francisco, experience and review of literature. urology. laparoscopy and ureterorenoscopy in renal parapelvic cyst-chen et al. 2005;65:882-7. 21. basiri a, hosseini sr, tousi vn, sichani mm. ureteroscopic management of symptomatic, simple parapelvic renal cyst. j endourol. 2010;24:537-40. laparoscopy and ureterorenoscopy in renal parapelvic cyst-chen et al. vol 18 no 4 july-august 2021 394 miscellaneous 183urology journal vol 7 no 3 summer 2010 effects of isosorbide dinitrate on the urinary flow rate in patients with benign prostatic hyperplasia ali roshani,1 iraj khosropanah,1 mohammad salehi,1 alireza noshad kamran2 purpose: to compare the immediate effects of a systemic nitric oxide (no) donor with placebo on the uroflowmetric parameters in patients with benign prostatic hyperplasia (bph). materials and methods: eighty patients with the mean age of 61.5 years (range, 49 to 74 years) who suffered from bph were enrolled in the study. we examined peak flow rate, average flow rate, and residual urine in all the patients. then, patients were randomized to receive either 20 mg sublingual isosorbide dinitrate (isdn) (n = 40) or placebo (n = 40) 20 minutes prior to the second uroflowmetry, which was performed one day after the first test. results: the mean peak flow rate increased from 7.6 ± 0.41 ml/s to 10.2 ± 0.54 ml/s (p = .013) in the isdn group, while it increased +0.40 ml/s in the placebo group (p > .05). mean residual urine volume decreased significantly from 51 ± 3.1 ml to 29 ± 2.9 ml and from 56 ± 4.1 to 51 ± 2.6 in the isdn (p = .02) and the placebo groups (p > .05), respectively. at baseline, the mean arterial pressure was 95 ± 2.1 mmhg and under the influence of the no-donor, it decreased to 83 ± 1.9 mmhg, which was significant (p < .001). no significant changes of micturition parameters were found in the placebo group. conclusion: organic nitrates influence micturition parameters in patients with bph. this new approach could offer a potential pharmacological option to treat obstructive lower urinary tract symptoms. urol j. 2010;7:183-7. www.uj.unrc.ir keywords: benign prostatic hyperplasia, isosorbide dinitrate, flowmetry 1guilan urology research center, rasht, iran 2valiasr hospital, arak university of medical sciences, arak, iran corresponding author: alireza noshad kamran, md valiasr hospital, arak university of medical sciences, arak, iran tel: +98 861 223 1104 fax: +98 861 222 0224 e-mail: alireza_noshad@yahoo.com received january 2009 accepted march 2010 introduction benign prostatic hyperplasia (bph) is a significant health-care problem affecting millions of men worldwide. apart from the bothersome lower urinary tract symptoms (luts), bph can lead to the detrusor overactivity, urinary retention, recurrent urinary tract infections, bladder stone formation, and even renal insufficiency. medical therapy is usually administered for bothersome luts due to bph. alpha-blockers and 5αreductase inhibitors are the only agents recommended by different guidelines.(1,2) new pharmaceutical agents with acceptable cost and safety profile would be very welcome.(3) during the past few years, nitric oxide (no) has been found to be a fundamental biologic messenger mediating neurotransmission, smooth muscle relaxation, and vasodilation in various organs. (4-6) in the male genital tract, the bladder neck, the prostate, the vas deferens, the seminal vesicle, and the corpus isosorbide dinitrate in bph—roshani et al 184 urology journal vol 7 no 3 summer 2010 cavernosum were found to have high levels of calcium dependent nitric oxide synthase (nos) activity.(7) nitric oxide plays an important role in the autonomic innervation of all parts of the prostate tissue.(4,8) there is some evidence that drugs acting on no/ cyclic guanosine monophosphate (cgmp) pathway might have a potential role in treating subvesical obstruction caused by bph. (9-12) the hypothesis relies on the relaxing effect of no on the prostate smooth muscle cells that potentially decreases subvesical obstruction and improves both voiding and bothersome luts. phosphodiesterase-5 inhibitors, which increase cgmp levels in the lower urinary tract, have already been shown to have a beneficial influence on luts.(9) functional in vivo studies assessing the direct effect of no on the human lower urinary tract are rare. however, after oral administration in healthy humans, an no-donor had a functionally relevant effect on the resting tone and contractile properties of the human external urethral sphincter in vivo.(10) in a functional study on humans with spinal cord injury, subvesical obstruction caused by detrusor-sphincter dyssynergia was successfully reduced by oral administration of an no-donor.(11) recently, using pressure-flow studies, a significant reduction was reported in the bladder outlet resistance in healthy men within 20 minutes of sublingual administration of an no-donor.(12) some studies have investigated no-donors in men with bph, but the results are conflicting. the aim of our study was to evaluate the immediate effect of a sublingual administration of isosorbide dinitrate (isdn), as an no-donor, on the infravesical resistance in patients with bph. materials and methods this study was carried out on patients with luts suggestive of bph who referred to urology clinic of razi hospital in rasht between january 2007 and december 2007. eighty men with the mean age of 61.5 years (range, 49 to 74 years), who met the inclusion criteria, were enrolled in this study. the inclusion and exclusion criteria are listed in table 1. the study protocol was explained to all of the patients and written informed consents were obtained. the study was approved by the hospital’s ethics committee. we measured peak flow rate (q-max), average flow rate (q-ave), and voided volume using the urodyn rotating flowmeter (dantec, copenhagen, denmark) and residual urine volume by transabdominal ultrasonography after baseline evaluation, each patient was assigned in chronological order to one of the randomization numbers using a computer generated randomization list to receive either 20 mg sublingual isosorbide dinitrate (tolidarou pharmaceutical co.) (group 1, n = 40) or identical sublingual placebo tablet (group 2, n = 40), 20 minutes prior to the second uroflowmetry, which was performed with a one-day interval from the baseline test. both patients and researchers were blind to the drug/placebo groups. residual urine volume was measured again. blood pressure was monitored at baseline and 1 hour after drug or placebo administration. the urofowmetry strips were manually read in a blinded fashion by an independent investigator. to be considered valid, a flow reading required a total voided volume of at least 150 ml with the peak rate maintained for at least 2 seconds. baseline values were compared to the values after intervention by the paired t test. p values less than .05 were considered statistically significant. inclusion criteria age < 75 peak urinary flow ≤ 15ml/s total voided volume ≥ 150 ml prostate specific antigen ≤ 4 ng/ml international prostate symptom score (ipss) ≥ 8 prostate volume ≥ 20 cm3 exclusion criteria age >75 years or < 49 years evidence and suspicion of prostate cancer acute prostatitis residual urine volume > 150 ml serum creatinine level > 1.5 mg/dl neurogenic bladder dysfunction inability to spontaneous voiding history of prostate surgery or other transurethral procedures urinary tract infection contraindications of nitrates unstable cardiovascular disease maintenance nitroglycerin administration table 1. inclusion and exclusion criteria isosorbide dinitrate in bph—roshani et al 185urology journal vol 7 no 3 summer 2010 results the mean peak flow rate increased significantly from 7.6 ± 0.41 ml/s (range, 6.1 to 9.3 ml/s) to 10.2 ± 0.54 ml/s (range, 8.2 to 13.1 ml/s; p = .013) in the isdn group, while the mean peak flow rate change in the placebo group was about +0.40 ml/s and statistically insignificant (p > .05). mean residual urine volume decreased significantly from 51 ± 3.1 ml to 29 ± 2.9 ml and from 56 ± 4.1 to 51 ± 2.6 in the isdn (p = .02) and the placebo groups (p > .05), respectively (table 2). at baseline, the mean arterial pressure of the patients was 95 ± 2.1 mmhg (range, 86 to 115 mmhg) and under the influence of the nodonor, it decreased to 83 ± 1.9 mmhg (range, 74 to 92 mmhg), which was significant (p < .001). the drop in blood pressure was symptomatic in 7 patients as they reported dizziness after the intake of isdn in contrast to the placebo group, in which there was not any drop in the blood pressure. these symptoms, however, were mild and short lasting, and no subject was affected in a way that prevented him from completing the study. five of the subjects reported a headache after isdn administration. discussion nitric oxide produces smooth muscle relaxation by activating the soluble guanylate cyclase and hereby increasing the tissue levels of cgmp, which in turn interacts with various intracellular components that regulate activities of the contractile proteins.(13,14) nitric oxide donors activate the soluble guanylate cyclase and increase the tissue levels of cgmp.(15) exogenously applied no in solution or no-donors have been shown to cause relaxation in pre-contracted prostate tissue from rabbits, dogs, and humans.(8,16-18) several advantages of no-donors make the clinical evaluation of their effect on the infravesical resistance worthwhile. first, many no-donors are well-known drugs with good tolerability and long-established safety records .(19) second, different formulations are available. this is especially notable for fast-acting formulations with an onset of action within seconds to minutes. they can be used alone or in combination with classical medical luts therapies, but the possibility of increased adverse events, eg, hypotension, has to be taken into consideratin. possibly, fast-acting no-donors could also be used to treat acute urinary retention in an emergency setting. since there is evidence that alterations in the no-cgmp pathway are involved in the development of bph and that no has an antiproliferative effect on human prostate smooth muscle cells,(20) long-term use of no-donors may also prevent or slow down bph progression. furthermore, the no-cgmp pathway is suspected to be involved in the regulation of the threshold for afferent firing in the bladder.(21) nitric oxide could, therefore, have a beneficial effect on luts beyond the decrease of the infravesical resistance. parameters baseline after isdn p placebo group isdn group placebo group isdn group international prostate symptom score (ipss) 15.4 ± 2.1 15.8 ± 2.4 >0.05* prostate volume (cm3) 28 ± 2.6 29 ± 2.1 >0.05* peak urinary flow rate (qmax)(ml/s) 7.2 ± 0.61 7.6 ± 0.41 7.6 ± 0.44 10.2 ± 0.54 >0.05* 0.013† >0.05‡ residual urine volume (cc) 56 ± 4.1 51 ± 3.1 51 ± 2.6 29 ± 2.9 >0.05* 0.02† >0.05‡ mean arterial pressure (mmhg) 99 ± 1.6 95 ± 2.1 96 ± 2.2 83 ± 1.9 >0.05* 0.001† >0.05‡ table 2. mean variations in parameters during study period in two groups *baseline isdn group versus placebo group †isdn group before and after intervention ‡placebo group before and after intervention §isdn indicates isosorbide dinitrate isosorbide dinitrate in bph—roshani et al 186 urology journal vol 7 no 3 summer 2010 in this study, we administered only single dose of isdn to assess immediate effects on urinary flow rate, but in a non-randomized non-placebocontrolled study by klotz and colleagues, patients with bph with obstructive symptoms that were treated with oral isdn with the dosage of 60 to 120 mg per day for 3 months exhibited improvement in the mean peak flow rates.(22) reitz and associates recently showed the relaxing effect of sublingual isdn on the external urethral sphincter in spinal cord–injured patients as well as in healthy men within minutes after drug administration.(10,11) the most serious adverse effects of isdn were pounding headache, flashing, vertigo, palpitation, and nausea or vomiting.(23) in this study, we demonstrated a slight, but statistically significant increase of the peak urinary flow rate within 20 minutes after administration of an no-donor in men with bph. whether this influence affected the outflow region of the lower urinary tract as a functional unit or individual segments (eg, the bladder neck, the prostate, or the urethra) to a variable extent cannot be determined with this study. we also chose to administer a relatively high dose of isdn in this study to make sure that sufficient levels of the no-donor were present systemically during the second uroflowmetry. in some studies, however, the administration of 10 mg instead of 20 mg isdn is reasonable, since other studies have shown significant adverse effects with this dose.(10,11) our study had some limitations. first we did not measure no levels in the target region, namely the prostatic urethra and the bladder neck. second, learning curve might have affected the results of the second uroflowmetry. repeated uroflowmetry several hours after isdn administration would have been a convincing evidence for the specificity and short-term efficacy of isdn treatment when returning to pretreatment values. it should be emphasized that this is a preliminary study about a novel option in medical treatment of bph and any conclusion regarding the usefulness of this therapy can only be drawn from larger studies with long-term follow-up. conclusion a clinical improvement was found in micturition parameters in patients with bph after medication with nitrates. however, further controlled studies with larger sample are necessary to prove whether nitrates could eventually enrich the bph treatment. conflict of interest none declared. references 1. aua guideline on management of benign prostatic hyperplasia (2003). chapter 1: diagnosis and treatment recommendations. j urol. 2003;170:530-47. 2. madersbacher s, alivizatos g, nordling j, sanz cr, emberton m, de la rosette jj. eau 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (bph guidelines). eur urol. 2004;46:547-54. 3. roehrborn cg. drug treatment for luts and bph: new is not always better. eur urol. 2006;49:5-7. 4. burnett al. nitric oxide control of lower genitourinary tract functions: a review. urology. 1995;45:1071-83. 5. anggard e. nitric oxide: mediator, murderer, and medicine. lancet. 1994;343:1199-206. 6. moncada s, palmer rm, higgs ea. nitric oxide: physiology, pathophysiology, and pharmacology. pharmacol rev. 1991;43:109-42. 7. ehren i, adolfsson j, wiklund np. nitric oxide synthase activity in the human urogenital tract. urol res. 1994;22:287-90. 8. takeda m, tang r, shapiro e, burnett al, lepor h. effects of nitric oxide on human and canine prostates. urology. 1995;45:440-6. 9. sairam k, kulinskaya e, mcnicholas ta, boustead gb, hanbury dc. sildenafil influences lower urinary tract symptoms. bju int. 2002;90:836-9. 10. reitz a, bretscher s, knapp pa, muntener m, wefer b, schurch b. the effect of nitric oxide on the resting tone 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relaxation by several no donors and nitric oxide. naunyn schmiedebergs arch pharmacol. 1999;360:80-91. 16. hedlund p, ekstrom p, larsson b, alm p, andersson ke. heme oxygenase and no-synthase in the human prostate--relation to adrenergic, cholinergic and peptide-containing nerves. j auton nerv syst. 1997;63:115-26. 17. aikawa k, yokota t, okamura h, yamaguchi o. endogenous nitric oxide-mediated relaxation and nitrinergic innervation in the rabbit prostate: the changes with aging. prostate. 2001;48:40-6. 18. uckert s, kuthe a, jonas u, stief cg. characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. j urol. 2001;166:2484-90. 19. mamas ma, reynard jm, brading af. augmentation of nitric oxide to treat detrusor-external sphincter dyssynergia in spinal cord injury. lancet. 2001;357:1964-7. 20. guh jh, hwang tl, ko fn, chueh sc, lai mk, teng cm. antiproliferative effect in human prostatic smooth muscle cells by nitric oxide donor. mol pharmacol. 1998;53:467-74. 21. andersson ke, chapple cr, hofner k. future drugs for the treatment of benign prostatic hyperplasia. world j urol. 2002;19:436-42. 22. klotz t, mathers mj, bloch w, nayal w, engelmann u. nitric oxide based influence of nitrates on micturition in patients with benign prostatic hyperplasia. int urol nephrol. 1999;31:335-41. 23. garcia moll m. [principles and rules of the use of nitrates]. ann cardiol angeiol (paris). 1997;46:399-405. the association of penile fracture and female sexual abnormalities burhan baylan1,2*, i̇brahim kartal1,3, alihan kokurcan1 purpose: to study the effect of female sexual abnormalities on the etiology of penile fracture, which is an important urological emergency. materials and methods: the sexual function of the partners of patients with penile fracture (study group, n = 90) treated at our clinic and healthy women (control group, n = 90) were evaluated on a voluntary basis. in both groups, sexual function was evaluated with the female sexual function index (fsfi). each substance of the fsfi was evaluated separately by comparing both groups and the effect on the development of penile fracture was investigated. results: there was no difference in demographic and clinical characteristics between the study and control groups. evaluation of sexual function with fsfi revealed that the scores of vaginal lubrication, orgasm, satisfaction, and pain subscales were lower in the study group (p < .001). among these subscales, anorgasmia was determined as the factor with the largest effect on the development of penile fracture (or = 7.333, 95% ci = 2.666–20.166, p < .001). no correlation was found between the largest dimension of penile fracture and fsfi total and subscale scores in the study group. conclusion: we believe that female vaginal dryness and dyspareunia in particular are factors which could cause the development of penile fracture during sexual intercourse. the treatment could prevent the development of penile fracture in the male. keywords: penile fracture; sexual dysfunction; fsfi; vagina dryness; dyspareunia introduction penile fracture (pf) is a rare urological trauma de-fined as the rupture of the tunica albuginea of the corpus cavernosum after exposure of erected or semirigid penis to blunt trauma.(1,2) a sudden increase in intracorporeal pressure causes excessive strain on the tunica albuginea, thereby resulting in a fracture. in addition, involvement of or injury to the corpus spongiosum, urethra, and dorsal nerves and vessels can occur.(3) the etiology of pf is generally related to blunt trauma and sexual intercourse is the most common cause of pf. studies have shown that pf occurs more frequently in “man-on-top” and “doggy style” positions during sexual intercourse.(1) there is also data indicating that the “woman-on-top” position poses a significant risk of developing pf.(4) masturbation injuries and falls landing on an erect penis are other notable causes of penile fracture.(5) female sexual dysfunction (fsd) is a group of psychosexual disorders that disrupt the quality of life and includes all sexual problems related to arousal, orgasm, and dyspareunia, at the center of which lies sexual desire disorder. sexual dysfunction is seen at higher rates 1health sciences university, dışkapı yıldırım beyazıt training and research hospital, urology clinic, ankara, turkey. 2afyon health sciences university, department of urology, afyon, turkey. 3kütahya health sciences university, urology clinic, kütahya, turkey. *correspondence: afyon health sciences university, department of urology, afyon, turkey. phone:+905326665550. e-mail: baylanburhan@gmail.com. received may 2021 & accepted april 2022 and there is a negative correlation between sexual dysfunction and quality of life scores. menopausal women experience discomfort in expressing their sexual problems such as vaginal dryness and dyspareunia to their spouses. accordingly, we predicted that there are partner-related factors that can facilitate the development of pf during sexual intercourse. therefore, we aimed to investigate the presence of sexual abnormalities in the sexual partners of patients who developed pf and their effects on the development of pf. materials and methods participants the study was performed under the ethical principles of the declaration of helsinki, and approved by the local ethics committee of the institution. the patients who underwent surgical treatment with the diagnosis of penile fracture in the urology clinic of dışkapı yıldırım beyazıt training and research hospital between 2007 and 2018 and their sexual partners were evaluated prospectively. the participants were divided into two groups, i.e., study and control. the study urology journal/vol 19 no. 4/ july-august 2022/ pp. 320-324. [doi:10.22037/uj.v19i.6818] andrology group comprised partners of patients who developed pf during sexual intercourse. all penile fracture patients in the study group were diagnosed with penile fracture by physical examination and penile doppler ultrasonography doppler ultrasonography was applied to all patients with a suspected penile fracture on physical examination. tunica albuginea defect was detected in penile doppler ultrasonography. surgical exploration and penile fracture repair were performed on all patients in the study group. the control group included healthy women with matched demographic characteristics (age, education status, duration of marriage, and employment status) (table 1). all of the patients in the control group were randomly selected among the patients who applied to the urology outpatient clinic. all of the selected patients had a single sexual partner and the patients whose initial complaint was about sexual dysfunction were not included in the control group. it was questioned whether the sexual partners of the patients included in the control group had penile fracture surgery. sexual partners of patients who had undergone penile surgery for any reason were not included in the control group. after being informed about the study, all participants were included in the study on a voluntary basis. in both groups, patients who had previously undergone hysterectomy and oophorectomy, who received chemotherapy and radiotherapy, and who were diagnosed with lichen sclerosus and sjögren’s syndrome were not included in the study because they did not meet the inclusion criteria. furthermore, participants with concomitant sexually transmitted disease, history of malignancy, neurological and psychiatric diseases (depression, schizophrenia, or mental disability), thyroid dysfunction, liver dysfunction, unstable coronary heart disease, psychoactive substance dependence, use of drugs affecting sexual function (antipsychotics, antidepressants, antihistamines, or benzodiazepines), and those who were pregnant or in the first 3 months after birth were excluded from the study. the inclusion day of women in the study group was the day when surgical treatment of their partners was completed and their partners applied to the outpatient clinic for follow-up. all participants in both groups were evaluated with the female sexual function index (fsfi).7 the fsfi is a 19-item questionnaire in 6 subscales for the evaluation of female sexual function: desire (items 1, 2), arousal (items 3, 4, 5, 6), lubrication (items 7, 8, 9, 10 ), orgasm (items 11, 12, 13), satisfaction (items14, 15, 16) and pain (items 17, 18, 19). the fsfi evaluates sexual function throughout the last 4 weeks. in the subscale points, items 1,2, 15 and 16 are scored between 1 and 5. all the other items are scored between 0 and 5 with the added option of “no sexual activity”. total points can range from 2-36 with higher points indicating a less severe degree of sexual function disorder. 8,9 all participants were evaluated and compared individually for all items of fsfi and in terms of total fsfi score. statistical analyses were performed to determine the relationship between fsfi and etiology of pf. statistical analysis the distribution of continuous variables was determined by shapiro–wilk test. levene’s test was performed to evaluate the homogeneity of variance. descriptive statistics for continuous variables are shown as mean ± standard deviation (min–max) and for categorical data as number and percentage. intergroup comparisons were performed using student’s t-test. mann–whitney u-test was applied when parametric assumptions were not met. categorical data were analyzed by pearson’s chi-square test. degrees of association between continuous variables were evaluated by spearman’s rank-order correlation analyses. univariate logistic regression analyses were performed to determine whether subscale and total fsfi score had an effect on the likelihood of pf. odds ratio, 95% confidence interval, and wald statistics for fsfi total and each subscale scores were also calculated. data analysis was performed using ibm spss stapenile fracture and female sexual abnormalitiesbaylan et al. control group (n = 90) study group (n = 90) p-value age of partner (years) 40.9 ± 10.9 40.8 ± 11.6 .991† education level .682‡ primary school 15 (16.7%) 15 (16.7%) high school 42 (46.7%) 51 (56.7%) university 33 (36.7%) 24 (26.7) duration of marriage (years) 15.7 ± 10.4 15.4 ± 10.0 .890† employment status .606‡ unemployed 48 (53.3%) 42 (46.7%) employed 42 (46.7%) 48 (53.3%) table 1. comparisons of the sociodemographic characteristics of the study and control groups † student’s t-test, ‡ pearson’s chi-square test n = 90 history of penile fracture 3 (3.3%) laterality right 54 (60.0%) left 27 (30.0%) bilateral 9 (10.0%) fracture location 1 ventral 57 (63.3%) ventral+lateral 15 (16.7%) lateral 9 (10.0%) dorsal 6 (6.7%) dorsal+lateral 3 (3.3%) fracture location 2 mid 48 (53.3%) proximal 24 (26.7%) distal 18 (20.0%) largest dimension of penile fracture (mm) 7.38 ± 3.73 range of the largest dimension of penile fracture (mm) 0-15 hematuria 6 (6.7%) urethral trauma 6 (6.7%) history of urethral surgery 6 (6.7%) aubergine sign 87 (96.7%) rolling sign 72 (80.0%) additional trauma 9 (10.0%) table 2. demographic and clinical characteristics of the study group andrology 321 unclassified 238 tistics (version 17.0; ibm corporation, armonk, ny, usa). a p-value of <.05 was considered statistically significant. results the demographic and clinical characteristics of the study group are summarized in table 2. among the fsfi subscales, there was no significant difference between the study and control groups in terms of the scores of desire and arousal subscales (p = .893 and p = .935, respectively), whereas the scores of vaginal lubrication, orgasm, satisfaction, and pain subscales were significantly lower in the study group than in the control group (p < .001). similarly, total fsfi score was significantly lower in the study group than in the control group (p < .001; table 3). there was no significant association between the scores of desire and arousal subscales and the development of pf. each 1-point decrease in the score of the vaginal lubrication subscale resulted in a 2.221-fold increase in the likelihood of developing pf (95% ci = 1.389–3.552; p < .001). the likelihood of developing pf increased significantly as the score of the orgasm subscale decreased (or = 7.333, 95% ci = 2.666–20.166, p < .001). each 1-point decrease in the score of the satisfaction subscale resulted in a 5.946-fold increase in the likelihood of developing pf (95% ci = 2.198–16.087; p < .001). the likelihood of developing pf increased significantly as the score of the pain subscale decreased (or = 2.218, 95% ci = 1.350–3.644, p = .002). likelihood of developing pf increased significantly as total fsfi score decreased (or = 1.177, 95% ci = 1.071–1.294, p < .001; table 4). correlation coefficients and significance levels between age and the largest dimension of pf as well as fsfi total and subscale scores were examined in the study group. as age increased, total fsfi score and desire, arousal, vaginal lubrication, orgasm, and pain subscale scores decreased significantly (p < .05, all). however, no significant correlation was found between the largest dimension of pf and fsfi total and subscale scores (table 5). discussion pf is a rare urological emergency. its incidence can be lower than expected because some patients are reluctant to disclose this condition. globally, many studies have investigated the causes of pf in various regions of the world. while its most common etiology in western countries is sexual intercourse, the most common cause in eastern countries is penile manipulation during the practice of taghaandan.(10,11) the practice of taghaandan involves bending the distal part of the penis shaft by force while maintaining the proximal part in place to obtain penile detumescence. this can be associated with a lack of scientific knowledge about genital anatomy in that.(12,13) in an iranian study conducted by zargooshi, 76.4% of pf cases have been shown to be originating due to the practice of taghaandan.14 in addition, other causes such as masturbation, falling on an erect penis, and rolling over in bed have been reported in the etiology of pf.(15,16) the relationship between sexual position and pf has also been investigated. in a retrospective study, the “woman-on-top” position has been reported to be associated with a high risk of developing pf because movements are usually controlled by the female partner in that position. it has been shown that in the event that the penis slips out accidentally, full weight of the female body falls on the erect penis, causing fracture.(4) considering the physical characteristics of sexual intercourse, we believe that sexual dysfunction plays an equally important role as sexual position. in fact, fsfi-based comparisons clearly demonstrated this effect. it is now recognized worldwide that sexual health is important for general health and well-being.(17,18,19) from the perspective of women, the national health and social life survey using fsfi reported that 43% of american women aged 18–59 years have sexual dysfunction. it has been determined that women frequently experivol 19 no 2 march-april 2022 153 control group (n = 90) study group (n = 90) p-value † desire 4.04 ± 1.29 (1.8–6.0) 4.08 ± 1.22 (1.2–6.0) .893 arousal 3.76 ± 1.29 (1.2–5.7) 3.71 ± 1.13 (1.2–5.4) .935 vaginal lubrication 4.07 ± 1.43 (1.2–6.0) 2.72 ± 1.11 (1.2–5.1) <.001 orgasm 4.21 ± 1.48 (1.2–6.0) 1.67 ± .78 (1.2–3.6) <.001 satisfact ion 4.48 ± 1.35 (1.2–6.0) 2.37 ± .89 (1.2–5.6) <.001 pain 3.53 ± 1.49 (1.2–6.0) 2.27 ± 1.02 (1.2–4.8) <.001 total 24.10 ± 7.79 (7.8–35.1) 16.82 ± 5.19 (7.6–28.3) <.001 table 3. female sexual function index total and subscale scores of the control and study groups data are expressed as mean ± standard deviation (minimum–maximum), † mann–whitney u-test. odds ratio † 95% confidence interval wald statistic p-value lower limit upper limit desire .974 .647 1.467 .016 .900 arousal 1.036 .677 1.584 .026 .871 vaginal lubrication 2.221 1.389 3.552 11.098 <.001 orgasm 7.333 2.666 20.166 14.898 <.001 satisfaction 5.946 2.198 16.087 12.322 <.001 pain 2.218 1.350 3.644 9.895 .002 total 1.177 1.071 1.294 11.403 <.001 † effect of a 1-point reduction in total female sexual function index and subscale scores on penile fracture table 4. effect of total female sexual function index and subscale scores on penile fracture examined using univariate logistic regression analysis penile fracture and female sexual abnormalitiesbaylan et al. vol 19 no 4 july-august 2022 322 ence sexual problems including those related to lack of desire, arousal, vaginal wetness, orgasm, satisfaction, and pain.(20) differences in pf rates and etiology across countries are due to cultural differences and differences in patient behavior when applying to healthcare professionals. a large number of menopausal women with sexual problems are reluctant to undergo treatment. some patients believe that medical treatment is ineffective.(21) it has also been found that menopausal women experience discomfort in expressing their sexual problems such as vaginal dryness and dyspareunia to their spouses.(22) during the transition to menopause, women were found to experience a significant increase in vaginal dryness and dyspareunia as well as decreased sexual desire, sexual arousal, orgasm, sexual activity, and partner affection.(23) to the best of our knowledge, there is no study in the literature examining the relationship between fsd and pf. it is observed that women with vaginal dryness and dyspareunia have difficulty in expressing these problems to their spouses and physicians. as a result, difficulties in vaginal penetration due to vaginal dryness and dyspareunia, particularly during sexual intercourse, are very common. male partners generally desire to continue sexual intercourse despite this condition, particularly in the “man-on-top” position, wherein a larger thrust is applied to ensure vaginal penetration. similarly, in the “woman-on-top” position, with the desire of the female partner to continue sexual intercourse, high energy facilitates the development of pf, particularly in patients without full penile tumescence. in the present study, it was found that vaginal dryness and orgasm problems of the spouses of patients who developed pf during sexual intercourse were significant in terms of being a facilitating factor in pf development. anorgasmia may cause prolonged and violent intercourse and eventually fractures, which may be a confounding factor. furthermore, we observed that dyspareunia complaints were significantly more common in their spouses. there are certain limitations to this study. the sample size was relatively small, and the relationship between sexual position and pf could not be assessed because the patients avoided providing information about sexual position. conclusions sexual activity is vital for male quality of life. this can be severely affected after pf. in this respect, all factors that can facilitate pf development should be taken into consideration. vaginal dryness and dyspareunia in women are among the factors that can cause pf, par age largest dimension of penile fracture correlation coefficient p-value † correlation coefficient p-value † desire −.808 <.001 −.070 .739 arousal −.843 <.001 −.111 .598 vaginal lubrication −.660 <.001 .097 .646 orgasm −.392 .032 −.030 .887 satisfaction −.349 .059 .091 .664 pain −.644 <.001 −.044 .833 total −.758 <.001 .028 .894 table 5. significance levels and correlation coefficients between total female sexual function index and subscale scores and age and the largest dimension of penile fracture in the study group † spearman’s rank-order correlation analysis ticularly during sexual intercourse. we believe that increasing awareness about treatability among women with these complaints and increasing treatment rates will prevent the development of pf. conflict of interest the authors have declared no conflict of interest. references 1. barros, r., schulze, l., ornellas, a.a., et al. relationship between sexual position and severity of penile fracture. int j impot res. 2017; 29: 207–209. 2. de luca, f., garaffa, g., falcone, m., et al. functional outcomes following immediate repair of penile fracture: a tertiary referral centre experience with 76 consecutive patients. scand j urol. 2017; 51: 170–175. 3. agarwal, m.m., singh, s.k., sharma, d.k., et al. fracture of the penis: a radiological or clinical diagnosis? a case series and literature review. can j urol. 2009; 16: 4568–4575. 4. reis, l.o., cartapatti, m., marmiroli, r., et al. mechanisms predisposing penile fracture and long-term outcomes on erectile and voiding functions. adv urol. 2014; 2014: 768158. 5. ory j, bailly g. management of penile fracture. can urol assoc j. 2019 jun;13(6 suppl4):s72-s74. [pmc free article] [pubmed] 6. buster, j.e. managing female sexual dysfunction. fertil steril. 2013; 100: 905–915. 7. neijenhuijs, k. i., hooghiemstra, n., holtmaat, k., et al. the female sexual function index (fsfi)-a systematic review of measurement properties. j sex med. 2019; 16: 640–660. 8. rosen r, brown c, heiman j, et al. the female sexual functionindex (fsfi): a multidimensional self-report instrument for the assessment of female sexual function. j sexmaritalther. 2000;26: 191–208. 9. wiegel m, meston c, rosen r. the female sexual function index (fsfi): cross-validation and development of clinical cutoff scores. j sexmaritalther. 2005;31:1–20 10. hatzichristodoulou, g., dorstewitz, a., gschwend, j.e., et al. surgical management of penile fracture and long-term outcome on erectile function and voiding. j sex med. 2013; 10: 1424–1430. 11. koifman, l., barros, r., junior, r.a., et al. penile fracture: diagnosis, treatment and penile fracture and female sexual abnormalitiesbaylan et al. andrology 323 outcomes of 150 patients. urology. 2010; 76: 1488–1492. 12. zargooshi, j. penile fracture in kermanshah, iran: report of 172 cases. j urol. 2000; 164: 364–366. 13. zargooshi, j. penile fracture in kermanshah, iran: the long-term results of surgical treatment. bju int. 2002; 89: 890–894. 14. zargooshi, j. sexual function and tunica albuginea wound healing following penile fracture: an 18-year follow-up study of 352 patients from kermanshah, iran. j sex med. 2009; 6: 1141–1150. 15. amer, t., wilson, r., chlosta, p., et al. penile fracture: a meta-analysis. urol int. 2016; 96: 315–329. 16. taha, s.a., sharayah, a., kamal, b.a., et al. fracture of the penis: surgical management. int surg. 1988; 73, 63–64. 17. beigi, m. and fahami, f. a comparative study on sexual dysfunctions before and after menopause. iran j nurs midwifery res. 2012; 17: s72–75. 18. llaneza, p., fernandez-inarrea, j. m., arnott, b., et al. sexual function assessment in postmenopausal women with the 14-item changes in sexual functioning questionnaire. j sex med. 2011; 8: 2144–2151. 19. zhang, c., cui, l., zhang, l., et al. sexual activity and function assessment in middleaged chinese women using the female sexual function index. menopause. 2017; 24: 669– 676. 20. jaafarpour, m., khani, a., khajavikhan, j., et al. female sexual dysfunction: prevalence and risk factors. j clin diagn res. 2013; 7: 2877–2880. 21. ghazanfarpour, m., khadivzadeh, t., latifnejad roudsari, r., et al. obstacles to the discussion of sexual problems in menopausal women: a qualitative study of healthcare providers. j obstet gynaecol. 2017; 37: 660– 666. 22. nur'aini, afiyanti, y. and setyowati. sexual self-efficacy: affection, sexual communication, and self-acceptance as significant factors related to sexual function on menopausal women in indonesia. enferm clin. 2019; 29: 551–555. 23. thomas, h.n., neal-perry, g.s. and hess, r. female sexual function at midlife and beyond. obstet gynecol clin north am. 2018; 45: 709–722. penile fracture and female sexual abnormalitiesbaylan et al. vol 19 no 4 july-august 2022 324 case report 209urology journal vol 7 no 3 summer 2010 bilateral simple orthotopic ureteroceles with bilateral stones in an adult a case report and review of literature ali shamsa, amir abbas asadpour, mehran abolbashari, mohammad kazem hariri urol j. 2010;7:209-11. www.uj.unrc.ir keywords: ureterocele, calculi, complications, diagnosis, male ghaem hospital, mashhad university of medical sciences, mashhad, iran corresponding author: ali shamsa, md department of urology and kidney transplant, ghaem hospital, mashhad, iran tel: +98 915 115 5434 fax: +98 511 841 7404 e-mail: shamsaa@mums.ac.ir received april 2009 accepted november 2009 introduction ureterocele is dilation of the submucosal ureter due to delay in chawall’s membrane absorption. (1) ureteral atony and stagnation of urine in ureterocele precipitate stone formation.(2,3) we present a very rare case of bilateral simple orthotopic ureteroceles, complicated with bilateral stones. case report a 50-year-old man presented with dysuria. physical examination was unremarkable. laboratory tests were within normal limits, except presence of microscopic hematuria. he had no flank pain, urinary tract infection, or history of urinary stones. on the kidney, ureter, bladder x-ray, there were two opacities in the pelvic region (figure 1). intravenous pyelography revealed two heads of cobra (ureteroceles) with one stone in each (figure 2). cystoscopic figure 1. kidney, ureter, bladder x-ray revealed two opacities in the pelvic region. figure 2. on intravenous pyelography, two heads of cobra (ureterocele) were demonstrated. bilateral ureteroceles with stone—shamsa et al 210 urology journal vol 7 no 3 summer 2010 examination showed one stone in the left ureterocele and a dimple stone (occupying the ureterocele and the bladder) in the right one. both ureteroceles were unroofed transurethrally, and all of the stones were fragmentated using swiss lithoclast ureteroscope and cystoscope, and then removed with ellic evacuator. we followed the patient for 2 months with voiding cystourethrography and renal ultrasonography, and found neither reflux nor meatal stenosis (figure 3). on stone analysis, the composition of stone was calcium oxalate (100%). urinary minerals were within normal limits (24-h oxaluria, 0.05mmol/1700cc; 24-h calciuria, 133mg/1700cc). discussion ureteroceles are more common in women, with the female to male ratio of 4 to 1, and are almost always seen in white population, but stones in ureteroceles are mostly reported in men.(4) ureteroceles are bilateral in 10% and occur in 80% in upper poles in duplex systems.(3) solitary stone in single ureterocele is common, with the prevalence of 4% to 39%;(5) however, bilateral orthotopic ureterocele with stones in adult males is extremely rare.(2,6-8) to the best of our knowledge, only 9 cases have been reported in the literature. according to stephens and colleagues classification, ureteroceles are categorized into stenotic ureteroceles associated with unduplicated ureters and ureteroceles associated with duplex ureters.(1) the ureterocele with stenotic orifice is the most common type in single ureter system. single system ureteroceles usually occur in adults and are almost always intravesical. our case was also single system ureterocele. bilateral ureteroceles can present with symptoms other than pain. vasu and associates reported a case of bilateral ureteroceles with renal failure who recovered after treatment of his bilateral ureterocele.(9) hypertension(10) and severe ureteral dilatation(11) are other presenting symptoms of bilateral ureteroceles. ureteroceles may present without stones at first, but the patient may refer again with stone formation.(12) ureterocele, like ectopic ureter, may be diagnosed by prenatal ultrasonography and magnetic resonance imaging in certain cases, like maternal obesity and in the case of oligohydramnios.(3) bilateral ureteroceles are also diagnosed prenatally by ultrasonography. (13-15) endoscopic treatment is the standard modality for bilateral ureteroceles.(2) singh presented two bilateral ureteroceles with stones in two women that were managed by transverse meatotomy and stones were removed endoscopically.(2) van den hoek and colleagues managed a case of bilateral ureterocele with stone by heminephrectomy in one side and ureterocele incision on the other side (reflux occurred in the latter side).(16) there is a lot of interest in managing ureteroceles endoscopically. wines and o’flynn in 1972 suggested transurethral resection for treatment of ureteroceles, which often results in reflux. (17) our case underwent transurethral resection of ureterocele, which was a safe and an effective method. endoscopic puncture of ureterocele is another option with less likelihood of postoperative reflux. figure 3. postoperative voiding cystourethrography revealed no vesicoureteral reflux. bilateral ureteroceles with stone—shamsa et al 211urology journal vol 7 no 3 summer 2010 conflict of interest none declared. references 1. stephens fd, smith ed, hutson jm, coplen d. congenital anomalies of the urinary and genital tracts: isis medical media oxford; 1996:260. 2. singh i. adult bilateral non-obstructing orthotopic ureteroceles with multiple calculi: endoscopic management with review of literature. int urol nephrol. 2007;39:71-4. 3. schlussel rn, retik ab. ectopic ureter, ureterocele, and other anomalies of the ureter. in: wein aj, kavousi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 4. 9 ed: philadelphia: saunders; 2007:3398. 4. nash ag, knight m. ureterocele calculi. br j urol. 1973;45:404-7. 5. messing em, henry sc. stones in orthotopic, nonobstructing ureteroceles. j urol. 1979;122:403-4. 6. sylla c, diabate i, fall pa, et al. [ureterocele in adults. five case reports]. ann urol (paris). 2002;36:38-41. 7. rodriguez andres ja, escobal tamayo v, campa bortolo j, arrosagaray echetpare p. [orthotopic bilateral ureterocele]. arch esp urol. 1998;51:177-9. 8. fagnoni m, gallizia g. [bilateral ureterocele with calculosis. boot shaped dilatation of the juxtavesical ureter]. j urol nephrol (paris). 1977;83:637-43. 9. vasu ts, elliot wc, lai rs. bilateral ureteroceles progressing to reversible acute renal failure in an adult. can j urol. 2006;13:2993-6. 10. thilagarajah r, meganathan v, gleeson m. incidental bilateral ureteroceles presenting during investigation for hypertension. urology. 2000;55:947-8. 11. rabinowitz r, barkin m, schillinger jf, jeffs rd, cook gt. bilateral orthotopic ureteroceles causing massive ureteral dilatation in children. j urol. 1978;119:839-40. 12. gilbert wb, hernanz-schulman m, pope jct. development of small calculi in an infant with bilateral single system ureteroceles. j urol. 2001;166:1860-1. 13. sepulveda w, campana c, carstens e, rodriguez j. prenatal sonographic diagnosis of bilateral ureteroceles: the pseudoseptated fetal bladder. j ultrasound med. 2003;22:841-4; quiz 5-6. 14. sherer dm, hulbert wc. prenatal sonographic diagnosis and subsequent conservative surgical management of bilateral ureteroceles. am j perinatol. 1995;12:174-7. 15. schoenecker sa, cyr dr, mack la, shuman wp, lenke rr. sonographic diagnosis of bilateral fetal renal duplication with ectopic ureteroceles. j ultrasound med. 1985;4:617-8. 16. van den hoek j, montagne gj, newling dw. bilateral intravesical duplex system ureteroceles with multiple calculi in an adult patient. scand j urol nephrol. 1995;29:223-4. 17. wines rd, o’flynn jd. transurethral treatment of ureteroceles. a report on 45 cases mostly treated by transurethral resection. br j urol. 1972;44:207-16. novel technique in performing standard transperineal template prostate biopsies under local anaesthetic shady nafie1, christopher berridge1, masood a khan1* purpose: transperineal template prostate biopsies (tptpb) are now increasingly commonly performed for the diagnosis of prostate cancer. tptpb is traditionally performed under general anaesthetia. however, this poses a significant strain on hospital theatre capacity. as such, local anaesthetic (la) tptpb is becoming more popular. we describe a novel technique for performing the standard tptpb under la in the outpatient setting. materials and methods: between february 2019february 2021, 254 consecutive men (median age 69; range: 44-80 years) with a median psa of 8.7 ng/ml (range: 2.2-76) underwent l/a tptpb using our novel technique. this is whereby 50mls of 1% prilocaine was injected partially around the perineal skin and partially deep bilateral periprostatic areas. multiple simultaneous prostate biopsies were then taken with the standard template grid and stepper. results: a total of 250/254 (98.4%) men underwent successful l/a tptpb with a median visual analogue pain score of 4 (range: 2-8). the median prostate volume was 49cc (range: 14-240cc). the median number of cores taken were 18 (range: 14-24). a total of 163/250 men (65.2%) had a positive histology for prostate cancer with a median of 5 cores being involved with prostate cancer (range: 1-18). in addition, 101/163 men (62.0%) diagnosed with prostate cancer had either a gleason score 3+4 = 7 or greater. none experienced urosepsis and only 2/250 men (0.8%) had temporary urinary retention. conclusion: our novel la technique in performing the standard tptpb is safe, feasible, well tolerated and associated with a high rate of prostate cancer detection. keywords: anaesthetic; biopsy; local; perineum; prilocaine; prostate introduction over the past two decades the role of transrectal ul-trasound guided prostate biopsies, in the detection of prostate cancer, has been steadily falling out of favour due to its limited ability to accurately biopsy the prostate, in particular the anterior gland,(1,2) along with its associated risk of urosepsis in up to 5% of cases(3,4). as such, transperineal template prostate biopsies (tptpb) have increasingly become the standard diagnostic tool in obtaining adequate and accurate prostate tissue(5-7). in addition, multi-parametric magnetic resonance imaging (mpmri) of the prostate now plays an important role in directing biopsies to the most suspicious areas within the prostate; thereby increasing our ability to detect prostate cancer(8). however, as up to 20% of men with a negative mri scan of the prostate can still harbour clinically significant prostate cancer(8,9), it is important not only to be able to accurately take biopsies from the mri suspicious areas but also to perform saturation biopsies from all other areas of the prostate. tptpb has traditionally been performed under general anaesthetia (ga). however, the rapid rise, over the past two decades, in the number of men undergoing such a 1department of urology, leicester general hospital, university hospitals of leicester nhs trust, gwendolen road, leicester, le5 4pw, united kingdom. *correspondence: university hospitals of leicester nhs trust address: department of urology, university hospitals of leicester, leicester general hospital, gwendolen road, leicester, le5 4pw. tel: +44116 258 4449. fax: +44116 273 0639. email: masood.khan@uhl-tr.nhs.uk. received may 2021 & accepted october 2021 procedure has resulted in a great strain in gaining access to the operating theatres. to address this dilemma, a local anaesthetic (la) approach in performing tptpb has been increasingly desired. to date, the commonly used technique in performing la tptpb is by using precisionpointtm. unfortunately, not only does this technique add to the cost of performing such a procedure but there is some evidence that this technique may not be as accurate in detecting prostate cancer as the standard tptpb performed under ga(10,11). we, therefore, prospectively determined whether it is feasible to perform the standard tptpb using the template grid and a stepper by modifying the la technique. patients and methods between february 2019 and february 2021, a total of 254 consecutive men with no selection bias underwent tptpb under la in our unit by a single surgeon (mak). as previously described, all men had pre-procedure antibiotic cover with oral ciprofloxacin 500 mg, co-amoxiclav 625 mg and intravenous gentamicin 120 mg. the men were placed in the lithotomy position and the perineal area was shaved and cleaned with urological oncology urology journal/vol 19 no. 6/ november-december 2022/ pp. 433-437. [doi:10.22037/uj.v18i.6855] betadine®. the scrotum was lifted away and fixed in place using a mepore® sticky tape. a total of 50mls of prilocaine 1% was used as la. of the 50mls of 1% prilocaine approximately 25mls is applied to the skin and subcutaneous tissue covering a wide area around the right of the anal margin. thereafter, approximately 5 mlof la is injected immediately above the anal margin at a midline and a slim strip of area to the left of the anal margin in a distorted/skewed horse-shoe distribution using a 23g needle as shown in figure 1. the reason for this distribution of the la is that all biopsies (right and left) are exclusively taken from the widely infiltrated area on the right. the rationale for adding la to the other sites is that subsequently the ultrasound probe (bk medical pro-focus 2202, bk medical, mileparken, denmark) with endocavity balloontm is inserted in the rectum and held in place using a mechanical stepper arm (galil medical; crawley, sussex, uk). under ultrasound guidance (both sagittal and transverse views), a spinal needle (19g) is inserted to inject 10 ml each of prilocaine 1% in the peri-prostatic area between the rectum and denonvellier’s fascia (at the posterior lateral area of the apex of the prostate) on the right and left. hence, the spinal needle is inserted in the areas above and right of the anal margin previously injected by la (figure 1). in total, 50 ml of 1% prilocaine la is used. thereafter, the prostate volume is measured by ultrasound, and the gland is divided on the ultrasound screen into six areas (right anterior, right mid, right posterior, left anterior, left mid, left posterior). a standard 0.5 cm brachytherapy template grid is fixed to the mechanical arm (stepper) and placed over the right perineal area (figure 2). the stepper not only stabilizes the ultrasound probe but also permits the probe to be tilted in various angles thereby gaining access to the whole of the prostate for biopsy solely from the single area to the right of the anus (figure 2). thereby, by tilting the ultrasound probe we are able to access both the right and left lobes of the prostate via the anaesthetised right perineal area. tptpb is then carried out using the template grid and 18g needles. this enables multiple needles to be inserted at the same time ensuring that a wide spread of biopsies is taken (figure 2). the rational for the insertion of multiple simultaneous needles is that it enables us to take biopsies not only from the mri suspicious areas but also the surrounding and more distant areas. this ensures that targeted, as well as saturation biopsies, are taken. if a single needle is inserted each time a biopsy is taken then there is a risk of sampling the same area repeatedly; thereby risking reducing the cancer detection rate. cognitive mri fusion is used to take 4 biopsies from the mri suspicious areas and two biopsies each from all other areas. in cases where the pre-biopsy mri scan excluded any suspicious lesions within the prostate (i.e. negative mri), four biopsies are taken from each of the six areas to ensure that thorough saturation biopsies are undertaken. as such, between 14 urological oncology 372 figure 1: the marked region demonstrates the skewed horse-shoe area anaesthetised. x: represents the approximate places where the spinal needle is inserted to inject the deep peri-prostatic local anaesthetic around the right and left apical areas. novel transperineal prostate biopsies under local anaesthetic-nafie et al. vol 19 no 6 november-december 2022 434 urological oncology 291 and 24 biopsies were taken from each man. at the end of the procedure, each man was asked to complete a visual analogue score, where 1 is no pain and 10 is unbearable/severe pain. subsequently, the men returned to the waiting area, and were discharged home after voiding urine. this prospective study did not require ethical approval as this was a modified local anaesthetic approach in performing the standard transperineal template prostate biopsies which we have been performing under general anaesthetic in our institution since january 2008. in addition, all men were given written information regarding the procedure many days in advance of having the procedure. furthermore, on the day of the procedure all men were thoroughly counseled by both a qualified nurse and the operating surgeon before seeking the consent. results out of the 254 consecutive men, 4 (1.6%) did not tolerate the ultrasound probe under la, therefore the procedure was abandoned and referred for tptpb under ga. the 250 men who underwent the procedure had a median age of 69 years (range: 44-80) with a median psa of 8.7 ng/ml (range: 2.2-76) and a median prostate volume of 49 cc (14-240cc). a median of 18 cores (range: 24-14) were taken from each man with a median of 5 positive cores (range: 1-18). a total of 163/250 men (65.2%) had positive histology for prostate cancer. of these, 62(38.0%) had gleason score (gs) 3+3, 68(41.7%) had gs 3+4, 15(9.2%) had gs 4+3, 10(6.1%) had g4+4 and 8(4.9%) had gs 4+5 as shown in figure 3. the median pain score was 4 (range: 2-8). the inter-quartile range regarding the vas for pain is 2. in addition, the 1st quartile of the vas for pain was 3 and the 3rd quartile was 5. furthermore, none of the men experienced urosepsis and 2 had temporary post-procedure urinary retention (0.8%). there were no cases of significant urethral bleeding requiring hospital admission. discussion over the past two decades, tptpb has gained greater momentum in being the procedure of choice for adequately sampling the prostate. it carries the advantages over conventional trus guided prostate biopsies in being associated with a lower risk of urinary sepsis as well as having a higher yield in detecting prostate cancer due to being able to access all areas of the prostate. however, the rapid rise in the volume of tptpb being performed has added significantly to the burden on operative theatre utilisation as it is commonly performed under ga. in order to move tptpb out of the theatre environment and towards an out-patient scenario, great effort has been invested in developing la techniques for this increasingly common procedure. to our knowledge, our la technique is the first of its type to be described in the world literature, whereby novel transperineal prostate biopsies under local anaesthetic-nafie et al. figure 2: a: demonstrating the angle of the ultrasound probe with the template grid, stabilised by the stepper, required to take biopsies from the right areas of the prostate. the probe is then adjusted slightly to take biopsies from the left areas of the prostate. b: showing simultaneous insertions of multiple biopsy needles. c: sagittal ultrasound image of the multiple biopsy needles insertions. d: biopsy needle insertion sites around the anaesthetised perineal area (post-procedure) urological oncology 435 we have been able to perform the standard tptpb using the template grid and stepper along with multiple simultaneous needle insertions; which is currently the technique used when performing this procedure under ga. our experience has confirmed that it is feasible and safe to perform tptpb under la without compromising the areas sampled or the numbers of biopsies taken when compared with the standard tptpb under ga. in addition, our yield in detecting prostate cancer of 65% is consistent with the standard tptpb performed under ga(6,7). at present, there are few readily available systems for performing transperineal biopsies under la such as precisionpoint™ access system(10,11) and the camprobe (12). these systems have been shown to be effective in performing transperineal biopsies under la in the outpatient setting. however, they come with additional financial costs and are free-hand held devices, thus affecting the accuracy in taking biopsies from the appropriate/suspicious areas(13). in addition, as only a single needle can be inserted on each occasion a biopsy is taken, these two techniques are less predictable in ensuring that appropriate biopsies including saturation biopsies are taken. therefore, it can be debated whether such biopsy techniques are truly template biopsies. however, our technique using the template grid permitting the simultaneous insertion of multiple needles offers better needle distribution and ensures that the same point of the prostate is not sampled twice. furthermore, using the mechanical arm offers motion stability and precision in taking the biopsies. in addition, if a needle is not deemed to be in the correct position, it can easily be withdrawn and reinserted to an appropriate position as per cognitive mri fusion. conclusions our la technique, which is feasible, safe and well tolerated, enables us to perform the standard tptpb without compromising cancer detection rates. by avoiding the need for additional specialist equipment and moving this procedure to the out-patient setting will also have a significant cost and time saving benefit. conflict of interest the authors report no conflict of interest. references 1. king cr, mcneal je, gill h, presti jc, jr. extended prostate biopsy scheme improves reliability of gleason grading: implications for radiotherapy patients. int j radiat oncol biol phys. 2004;59:386-91. 2. han m, chang d, kim c, et al. geometric evaluation of systematic transrectal ultrasound guided prostate biopsy. j urol. 2012; 188: 2404-9. 3. grummet jp, weerakoon m, huang s, et al. sepsis and 'superbugs': should we favour the transperineal over the transrectal approach for prostate biopsy? bju int. 2014; 114: 384-8. 4. anastasiadis e, van der meulen j, emberton m. hospital admissions after transrectal ultrasound-guided biopsy of the prostate in men diagnosed with prostate cancer: a database analysis in england. int j urol. 2015; 22: 181-6. 5. chang dt, challacombe b, lawrentschuk n. transperineal biopsy of the prostate--is this the future? nat rev urol. 2013; 10: 690-702. 6. nafie s, mellon jk, dormer jp, khan ma. the role of transperineal template prostate biopsies in prostate cancer diagnosis in biopsy naive men with psa less than 20 ng/ml. prostate cancer prostatic dis. 2014; 17: 1703. 7. nafie s, pal rp, dormer jp, khan ma. transperineal template prostate biopsies in men with raised psa despite two previous sets of negative trus-guided prostate biopsies. world j urol. 2014; 32: 971-5. 8. brown lc, ahmed hu, faria r, et al. multiparametric mri to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the promis study. health technol assess. 2018; 22: 1-176. urological oncology 374 figure 3. distribution of the various histology types in men undergoing la tptpb (gs=gleason score) novel transperineal prostate biopsies under local anaesthetic-nafie et al. vol 19 no 6 november-december 2022 436 urological oncology 293 9. hanna n, wszolek mf, mojtahed a, et al. multiparametric mri/ultrasound fusion biopsy improves but does not replace standard template biopsy for the detection of prostate cancer. j urol. 2019; 202: 944-51. 10. meyer ar, joice ga, schwen zr et al. initial experience performing in-office ultrasoundguided transperineal prostate biopsy under local anesthesia using the precisionpoint transperineal access system. urology. 2018; 115: 8-13. 11. kum f, elhage o, maliyil j et al. initial outcomes of local anaesthetic freehand transperineal biopsies in the outpatient setting. bju int. 2020; 125: 244-52. 12. thurtle d, starling l, leonard k, stone t, gnanapragasam vj. improving the safety and tolerability of local anaesthetic outpatient transperineal prostate biopsies: a pilot study of the cambridge prostate biopsy (camprobe) method. j clin urol. 2018; 11: 192-9. 13. dundee pe, grummet jp, murphy dg. transperineal prostate biopsy: templateguided or freehand? bju int. 2015; 115: 6813. novel transperineal prostate biopsies under local anaesthetic-nafie et al. urological oncology 437 v07_no_4.pdf urology for people 290 urology journal vol 7 no 4 autumn 2010 urol j. 2010;7:290. www.uj.unrc.ir prostate surgery in elderly men the prostate gland is a thick ring of muscle and gristle which lies between the outlet of the bladder and the penis. it is rather like the bung in the outlet of a bottle, holding the outflow tube in place. it makes the fluid that carries sperm. sometimes the center of the prostate ring becomes narrow because of overgrowth. this is benign prostatic hyperplasia. this causes difficulty in passing urine, and back-pressure effects on the bladder and the kidneys. nearly one-third of men will need prostate surgery in their 70s. there are few methods to remove the enlarged section of the prostate. in transurethral resection of the prostate method the center of the prostate ring is widened by coring out the tissue using an instrument (resectoscope) passed up the penis. in open prostatectomy, the tissue is taken out by opening up the bladder through a cut just below the tummy button. most patients are numbed from the waist down with an injection in the back. if this is the case, you will be awake during the operation, but feel no pain. the operation takes about 40 to 60 minutes. see page 262 for full-text article bladder care and management in spinal cord injury the body’s urinary system has three major functions. it produces urine in the kidneys, stores urine in the bladder, and eliminates urine from the body through the urethra. nerves at the end of the spinal cord (sacral level) organize how the urinary system works. the changes that usually occur after a spinal cord injury (sci) are how the bladder and sphincter muscles work. after a sci, individuals usually can not feel when the bladder is full or they do not have the “urge” to urinate. after sci, a bladder management scheme enables you to plan for the bladder emptying in an acceptable mode when it is convenient for you. this helps you evade accidents and prevent infections. because each person’s injury is different, your doctor will probably perform some tests to determine how your bladder functions. you also require considering your hand function. how effortless is it for you to do your own bladder program? can you handle alone or will you need help? during your rehabilitation, you learn different methods to empty your bladder. the methods most frequently used are intermittent catheterization, indwelling urethral catheter (foley), and the condom external catheter for men. radical prostatectomy for prostate cancer unfortunately, prostate cancer is a relatively common cancer in men. with increasing patients’ awareness and widespread prostate-specific antigen (psa) testing, more than 650 000 men worldwide are diagnosed with prostate cancer every year. a radical prostatectomy means an operation to remove the entire prostate gland. often, a radical prostatectomy is performed using keyhole (laparoscopic) surgery. a long tube with a light at the tip is used to see inside the body. the prostate gland is cut away from adjacent tissues and removed through a small cut in the abdomen. the main advantage with this surgery is that you will not have a big wound in your abdomen afterwards. the endeavor of this type of surgery is to cure the cancer. your surgeon may suggest radical prostatectomy if your cancer has not spread outside your prostate, and you are younger, rather than older, and have a high grade tumor. after removal of the prostate, the urethra is sewn to the neck of the bladder over a urinary catheter. radical prostatectomy may result in erection problems (impotence) in up to 70% of men. impotence means you can not have an erection. this is more likely to occur if you are older. the operation can also cause problems controlling the flow of urine (incontinence). with modern surgery techniques, these evils are less common than they used to be. for many men, the incontinence is temporary and does not persist longer than 6 months. what’s up in urology journal, autumn 2010? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. editorial which medical specialties or subspecialties are at a higher risk of covid19infection or mortality? amir h kashi urology and nephrology research center (unrc), shahid labbafinajad hospital, shahid beheshti university of medical sciences (sbmu), tehran, iran. email: ahkashi@gmail.com despite the introduction of covid-19 vaccination more than one year ago and vaccination of a considerable percentage of the population in many developed countries, there is still a substantial infection and mortality rate of covid-19. for example, despite a full vaccination coverage of around 70% in germany the 7-day mortality of the country in the week preceding 26 november had been 1737 (about 250 deaths each day) which is a high number.(1) meanwhile, in some countries, high mortality has been reported in healthcare workers who has been fully vaccinated against covid-19 raising concerns on the safety of medical personnel in the pandemic despite vaccination.(2) previously we studied the infection and mortality rate of medical personnel in different specialties and subspecialties in our country during the early covid-19 period.(3) we observed that the highest infection rates were among the specialties of infectious diseases (3.14%) followed by neurology (2.18%), and internal medicine (2.13%). whilst the highest mortality rates were interestingly among specialties of forensic medicine (0.314%), anesthesiology (0.277%), urology (0.237%), and infectious diseases (0.20%) bearing only modest association with the distribution of infection rate among medical specialties.(3) while the reason for not observing a high match of infection and mortality rates among medical specialties needs further investigations, our findings deserve attention as some specialties which are not seemingly a frontline specialty (forensic medicine and anesthesiology) were associated with a high mortality rate. the observation of a still high mortality rate in medical personnel despite vaccination in some countries brings into attention once more the importance of protection of healthcare workers against covid-19 and once more adds importance to our previous report on the specialty-specific infection and mortality rate of medical personnel. references 1. organization wh. who covid-19 dashboard 2021 2. hitchings mdt, ranzani ot, torres mss, de oliveira sb, almiron m, said r, et al. effectiveness of coronavac among healthcare workers in the setting of high sars-cov-2 gamma variant transmission in manaus, brazil: a test-negative case-control study. lancet regional health americas. 2021;1:100025. 3. basiri a, zafarghandi m, golshan s, eshrati b, fattahi a, kashi ah. covid-19 infection and mortality rates within medical specialists and general practitioners and its comparison with the general population: a longitudinal nationwide study. iranian journal of public health. 2021;50(7):1421-7 urology journal/vol 19 no. 2/ march-april 2022/ pp. 159-159. [doi: 10.22037/uj.v18i.7097] miscellaneous 46 urology journal vol 5 no 1 winter 2008 urinary polymerase chain reaction for diagnosis of urogenital tuberculosis mohammad yazdani, shahrzad shahidi, majid shirani introduction: the aim of this study was to evaluate diagnostic value of urinary polymerase chain reaction (pcr) in urogenital tuberculosis (utb). materials and methods: in 33 patients with confirmed diagnosis of utb by urine culture and/or acid-fast staining, clinical symptoms and laboratory and radiological findings were evaluated. for each patient, 3 consecutive urine samples were examined by pcr for mycobacterium tuberculosis and the results were compared with the standard microbiological methods and radiological findings. results: the mean interval between the appearance of the symptoms and the diagnosis was 12.3 ± 12.2 months. symptoms were irritative bladder symptoms such as dysuria and diurnal or nocturnal frequency (51.5%), flank pain (27.3%), microscopic hematuria (18.2%), gross hematuria (9.1%), and suprapubic pain (9.1%). the laboratory findings included hematuria (27.3%), pyuria (12.1%), and hematuria with pyuria (48.5%). diagnosis of utb was made in 19 patients by positive urine culture for mt in 19 patients (57.6%), positive acid-fast staining in 6 (18.2%), and both in 8 (24.2%). intravenous urography showed abnormal findings in 16 patients (61.5%), including pyelocaliceal dilatation (26.9%), ureteral stricture and hydroureter (23.1%), multiple small caliceal deformities (15.4%), severe parenchymal destruction (11.5%), autonephrectomy (11.5%), and calcification (7.7%). urinary pcr was positive in 16 patients (48.5%) and in 10 (62.5%) with abnormal findings on intravenous urography. conclusion: a high index of suspicion is necessary for diagnosis of utb even in patients with nonspecific manifestations. urinary pcr is recommended for instant diagnosis and screening before further examinations, but it cannot be the sole diagnostic modality for diagnosis of utb. keywords: urogenital diseases, tuberculosis, mycobacterium tuberculosis, polymerase chain reaction department of urology, khorshid hospital, isfahan university of medical sciences, isfahan, iran corresponding author: mohammad yazdani, md department of urology, khorshid hospital, isfahan, iran tel: +98 913 116 1028 fax: +98 311 222 9284 e-mail: yazdani_k_m@yahoo.com received july 2007 accepted october 2007 introduction tuberculosis is still one of the major global health issues, especially in the developing countries. currently, it is the second cause of death due to infectious diseases following the acquired immunodeficiency syndrome, worldwide.(1) extrapulmonary tuberculosis constitutes up to 20% of the total cases of the disease, and with the involving rate of 14%, the urogenital system is of the most common affected sites.(1,2) clinical manifestations and paraclinical findings of urogenital tuberculosis (utb) are nonspecific, resulting in delayed diagnosis and treatment which can cause kidney dysfunction, ureteral stricture, and urol j. 2008;5:46-9. www.uj.unrc.ir diagnosis of urogenital tuberculosis—yazdani et al urology journal vol 5 no 1 winter 2008 47 shrunken bladder.(1) currently, diagnosis of utb is based on the acid-fast staining or urine sample culture. acid-fast staining is a rapid screening test, but it is not sensitive enough especially in the specimens obtained from extrapulmonary sites.(2,3) the more sensitive urine cultures in both solid and fluid media require 6 to 8 weeks and 13 days, respectively, to give the results with yet low sensitivity rates.(2,4-6) polymerase chain reaction (pcr) is an instant assay that recognizes very few amounts of bacterium within 24 to 48 hours and has been reported to be very useful for detection of mycobacterium tuberculosis (mt).(1,5-12) the sensitivity of this method has been variably reported to be 60% to 100% for diagnosis of utb.(1,2,13-16) we investigated urine samples of the patients with utb to evaluate the diagnostic potential of urinary pcr in patients with utb. materials and methods patients we enrolled patients with utb whose diagnosis had been confirmed by positive acid-fast staining and/or positive urine culture results for mt, but had not undergone treatment yet. they had been referred to the clinical centers affiliated to isfahan university of medical sciences to receive treatment. their demographic data, clinical symptoms, and laboratory and radiological findings were recorded. the pcr assay was performed on the collected urine samples of all patients for detection of mt. sampling method three consecutive early morning urine specimens were taken from each patient. twenty microliter of screening-processed distiller soluble 10% and 10 µl of proteinase k (20 µl/ml) were added to 200 ml of the centrifuged urine sample and incubated at 60°c for 8 hours. a specimen for pcr was then prepared using the standard dna extracting and phenol-chloroform method. the needed product was proliferated using the primers relevant to iso6110 insertion element regions (techgene international, les ulis, france) including: t g t g g t g g c c g g c g t g t c c g c c a a g c g c t g c c g c g c g a t c c g c the final product was assessed by electrophoresis for a 245-bp band correspondent to mt. results a total of 33 patients aged 47.3 ± 16.1 years (range, 20 to 75 years) with confirmed utb entered the study. of these, 13 (39.4%) were men and 20 (60.6%) were women. the mean interval between the appearance of the symptoms and the diagnosis was 12.3 ± 12.2 months (range, 1 to 48 months). manifestations of the disease included irritative bladder symptoms such as dysuria and diurnal or nocturnal frequency in 17 patients (51.5%), flank pain in 9 (27.3%), microscopic hematuria in 6 (18.2%), gross hematuria in 3 (9.1%), and suprapubic pain in 3 patients (9.1%). urethral discharge, scrotal sinus, and general weakness each were detected in 1 patient (3.0%). the laboratory findings included hematuria in 9 (27.3%), pyuria in 4 (12.1%), hematuria and pyuria in 16 (48.5%), and no significant pathologic findings in 4 (12.1%) of the patients. diagnosis of utb was made in 19 patients by positive urine culture for mt in 19 patients (57.6%), positive acid-fast staining in 6 (18.2%), and both in 8 (24.2%). intravenous urography (ivu) was performed in 26 patients, which showed abnormal findings in 16 patients (61.5%). the main findings on the ivu were pyelocaliceal dilatation in 7 (26.9%), ureteral stricture and hydroureter in 6 (23.1%), multiple small caliceal deformities in 4 (15.4%), severe parenchymal destruction in 3 (11.5%), autonephrectomy in 3 (11.5%), and calcification in 2 (7.7%). polymerase chain reaction assay detected mt in 16 patients (48.5%) in the studied group. in the patients with abnormal finding on the ivu, 10 (62.5%) had a positive pcr for mt. discussion diagnosis of utb is usually difficult since it manifests with nonspecific signs and symptoms. irritative voiding symptoms are the most common symptoms, as they were in our patients (51.5%); more than half of the patients had hematuria and pyuria, which is consistent diagnosis of urogenital tuberculosis—yazdani et al 48 urology journal vol 5 no 1 winter 2008 with the other studies.(1) abnormal radiological findings were previously reported in 63% to 95% of the patients.(1,17) the most common findings are pyelocaliceal dilatation (hydronephrosis, hydroureter, and hydrocalicosis) and calcification.(18) in our study, 61.5% of the ivus showed abnormal findings including pyelocaliceal dilatation, urethral stricture and hydroureter, multiple small caliceal deformities, severe parenchymal destruction and autonephrectomy, and calcification. these findings, however, cannot help us make a definite diagnosis, but utb should be always considered in the differential diagnoses, especially in endemic areas. diagnosis of utb is usually made very late.(19) therefore, using a more sensitive method for diagnosis of the disease is of special importance. for a prompt detection of mt, we can use pcr assay. the sensitivity of pcr on urine samples was previously reported to be between 60% and 100% for diagnosis of utb.(1,2,14-16) the results of pcr may be affected by metabolites, drugs, or other biologic materials in the fluids of the body.(4) there are enzyme inhibitors which may interfere with the routine pcr test. some methods have been proposed to overcome this problem including the use of a proteolytic enzyme or sonication methods.(2) nonhomogeneous distribution of bacteria is another reason for the false-negative results. the best method is to test several specimens from a patient and select qualified specimens with good concentrations before the analysis.(1) in our study, the test was positive in 16 of 33 patients with a sensitivity rate of 48.5%. the reason for such a low sensitivity, other than the aforementioned factors, might be the possibility of lack of bacilli in the samples due to periodic bacilli excretion in the urine samples. in other studies, pcr test and culture or smear were performed on the same urine sample simultaneously.(14-16) thus, we might have more positive tests if we had used urine samples which were positive for mt in culture or acid-fast staining. considering the mechanism of pcr assay and its ability to recognize very low amounts of the bacteria, it seems reasonable to report pcr highly positive if there is any bacterium in the sample and if the smear is positive. the important point in our study was the relationship between the abnormal findings on the ivu and positive pcr tests; the pcr sensitivity was higher in the patients with an abnormal ivu than in all of the patients. we can speculate that in more severe infections with changes detectable on imaging, greater excretion of the bacterium occurs in urine; consequently, pcr is more likely to be positive for mt. conclusion to diagnose utb, a strong clinical suspicion is needed. in clinically suspicious cases, ivu findings are suggestive but nonspecific. although pcr cannot be recommended as the only method in identification of utb, it can be considered as one of the instant diagnostic tools before performing the other tests which are time consuming. conflict of interest none declared. references 1. hemal ak, gupta np, rajeev tp, kumar r, dar l, seth p. polymerase chain reaction in clinically suspected genitourinary tuberculosis: comparison with intravenous urography, bladder biopsy, and urine acid fast bacilli culture. urology. 2000;56:570-4. 2. moussa om, eraky i, el-far ma, osman hg, ghoneim ma. rapid diagnosis of genitourinary tuberculosis by polymerase chain reaction and non-radioactive dna hybridization. j urol. 2000;164:584-8. 3. drobniewski fa, kent rj, stoker ng, uttley ah. molecular biology in the diagnosis and epidemiology of tuberculosis. j hosp infect. 1994;28:249-63. 4. manjunath n, shankar p, rajan l, bhargava a, saluja s, shriniwas. evaluation of a polymerase chain reaction for the diagnosis of tuberculosis. tubercle. 1991;72:21-7. 5. abe c, hosojima s, fukasawa y, et al. comparison of mb-check, bactec, and egg-based media for recovery of mycobacteria. j clin microbiol. 1992;30:878-81. 6. cho sn, van der vliet gm, park s, et al. colorimetric microwell plate hybridization assay for detection of amplified mycobacterium tuberculosis dna from sputum samples. j clin microbiol. 1995;33:752-4. 7. forbes ba, hicks ke. direct detection of mycobacterium tuberculosis in respiratory specimens in a clinical laboratory by polymerase chain reaction. j clin microbiol. 1993;31:1688-94. 8. kocagöz t, yilmaz e, ozkara s, et al. detection diagnosis of urogenital tuberculosis—yazdani et al urology journal vol 5 no 1 winter 2008 49 of mycobacterium tuberculosis in sputum samples by polymerase chain reaction using a simplified procedure. j clin microbiol. 1993;31:1435-8. 9. noordhoek gt, kaan ja, mulder s, wilke h, kolk ah. routine application of the polymerase chain reaction for detection of mycobacterium tuberculosis in clinical samples. j clin pathol. 1995;48:810-4. 10. tevere vj, hewitt pl, dare a, et al. detection of mycobacterium tuberculosis by pcr amplification with pan-mycobacterium primers and hybridization to an m. tuberculosis-specific probe. j clin microbiol. 1996;34:918-23. 11. kox lf, jansen hm, kuijper s, kolk ah. multiplex pcr assay for immediate identification of the infecting species in patients with mycobacterial disease. j clin microbiol. 1997;35:1492-8. 12. eisenach kd, sifford md, cave md, bates jh, crawford jt. detection of mycobacterium tuberculosis in sputum samples using a polymerase chain reaction. am rev respir dis. 1991;144:1160-3. 13. kamyshan is, stepanov pi, ziablitsev sv, et al. [role of polymerase chain reaction in diagnosing tuberculosis of the bladder and male sex organs]. urologiia. 2003;3:36-9. russian. 14. van vollenhoven p, heyns cf, de beer pm, whitaker p, van helden pd, victor t. polymerase chain reaction in the diagnosis of urinary tract tuberculosis. urol res. 1996;24:107-11. 15. missirliu a, gasman d, vogt b, poveda jd, abbou cc, chopin d. genitourinary tuberculosis: rapid diagnosis using the polymerase chain reaction. eur urol. 1996;30:523-4. 16. mukanbaev k, vladimirskiĭ ma, shipina lk, aleksandrov aa. [value of molecular biological methods in the diagnosis of urogenital tuberculosis]. probl tuberk. 2001;4:40-2. russian. 17. kollins sa, hartman gw, carr dt, segura jw, hattery rr. roentgenographic findings in urinary tract tuberculosis. a 10 year review. am j roentgenol radium ther nucl med. 1974;121:487-99. 18. wang lj, wu cf, wong yc, chuang ck, chu sh, chen cj. imaging findings of urinary tuberculosis on excretory urography and computerized tomography. j urol. 2003;169:524-8. 19. styblo k. recent advances in epidemiological research in tuberculosis. adv tuberc res. 1980;20:163. endourology and stone disease 212 urology journal vol 4 no 4 autumn 2007 intrathecal meperidine for prevention of shivering during transurethral resection of prostate maryam davoudi,1 seyed habib mousavi-bahar,2 afshin farhanchi1 introduction: the aim of this study was to investigate low-dose intrathecal meperidine for prevention or alleviation of shivering after induction of spinal anesthesia for transurethral resection of the prostate (turp). materials and methods: in a randomized controlled trial, 80 patients scheduled for turp under spinal anesthesia were assigned into two groups of case and control. spinal anesthesia was performed using 75 mg of hyperbaric lidocaine 5% plus meperidine, 15 mg, in the patients of the case group and the same dose of lidocaine plus normal saline in the patients of the control group. shivering episodes were recorded during the operation and in the recovery room. data on systolic blood pressure, heart rate, arterial oxygen saturation, and body temperature were collected before the induction of anesthesia; 5, 15, and 30 minutes after the induction; and in the recovery room. results: maximum level of sensory block was similar in the patients of the case and control groups. shivering was not seen in the patients who received meperidine, while in the control group, 11 (27.5%) experienced some degrees of shivering (p = .001). blood pressure, body temperature, and arterial oxygen saturation did not have a clinically significant change and they were not different between the two groups. side effects of opioids were unremarkable. conclusion: low-dose intrathecal meperidine is effective and safe in reducing the incidence of shivering associated with spinal anesthesia for turp. urol j. 2007;4:212-6. www.uj.unrc.ir keywords: transurethral resection of the prostate, meperidine, shivering, spinal anesthesia 1department of anesthesiology, school of medicine, hamadan university of medical sciences, hamadan, iran 2department of urology, school of medicine, hamadan university of medical sciences, hamadan, iran corresponding author: seyed habib mousavi-bahar, md department of urology, ekbatan hospital, hamadan, iran tel: +98 918 111 3612 fax: +98 811 827 6299 e-mail: shmbahar@umsha.ac.ir received march 2007 accepted september 2007 introduction hypothermia is one of the important complications of transurethral resection of prostate (turp). large volume of irrigating fluid at room temperature and its absorption can decrease the core temperature in the patients undergoing turp. the consequence is shivering, particularly in older patients with impaired thermoregulatory mechanism. on the other hand, spinal anesthesia, the technique of choice in turp, causes impairment of the thermoregulatory function of the autonomic system.(1) shivering may occur in up to 56.7% of the patients undergoing various surgeries with spinal anesthesia.(2) most of the patients undergoing turp are old and are likely to have both cardiovascular and pulmonary disorders (30% to 60%) and are, therefore, vulnerable to the complications such as shivering. severe shivering increases o2 consumption and co2 production; hence, cardiac output and minute ventilation should increase which are dangerous in patients with limited ventilatory and cardiac reserve.(3) as well as the undesirable cardiovascular effects, shivering can make surgical difficulties, dislodge clots, and increase postoperative bleeding. meperidine for treatment of shivering in transurethral resection of prostate—davoudi et al urology journal vol 4 no 4 autumn 2007 213 intravenous administration of drugs such as meperidine, clonidine, ketanserin, magnesium sulfate, and physostigmine has been suggested for the treatment of shivering. meperidine is unique among the opioids for its ability to effectively treat and prevent shivering.(4-6) in comparison to treatment, prevention of shivering has not been well investigated. chen and colleagues suggested that a small dose of intrathecal meperidine might decrease the incidence of shivering and discomfort associated with anesthesia in a nonpregnant population.(2) in another study, roy and associates showed that intrathecal meperidine with the dose of 0.2 mg/kg reduced the incidence and intensity of shivering associated with intrathecal anesthesia for cesarean section.(7) this double-blinded randomized controlled trial was performed to determine whether meperidine,15 mg, plus lidocaine, decreases the incidence of shivering during spinal anesthesia for turp surgery. materials and methods this study was approved by the ethics committee of hamadan university of medical sciences. between april 2005 and august 2005, we selected patients with physical status scores of i, ii, and iii (according to the classification of the american society of anesthesiologists) who were scheduled for turp at ekbatan hospital in hamadan, iran. patients with tremor, history of allergy, and conditions that contraindicated spinal anesthesia were excluded from the study. a total of 80 patients were selected and assigned into 2 experimental and control groups by simple randomization. meperidine injection was prepared by an anesthesiologist not involved in the study. after taking written informed consents, basic information including age, systolic blood pressure, heart rate, and arterial oxygen saturation were recorded. for induction of spinal anesthesia, all of the patients received ringer lactate solution (15 ml/kg). oxygen was administered by face mask. all intravenous fluids were warmed up to 37°c and the operating room temperature was maintained at 22°c to 25°c. spinal anesthesia was performed in the sitting position at the l3-l4 or l4-l5 interspaces with a midline approach using 25-gauge quincke needle. in the case group, drugs for spinal anesthesia consisted of hyperbaric lidocaine 5%, 75 mg, plus meperidine, 15 mg, while in the control group, the same dose of lidocaine plus normal saline was administered. after spinal anesthesia induction, the patients were secured in the supine position and the standard turp was performed. supplemental oxygen (5 l/min) was administered by a simple face mask during the operation and the recovery time. systolic blood pressure, heart rate, and arterial oxygen saturation were measured and recorded intermittently before induction, intra-operatively (5, 15, and 30 minutes after the induction of the anesthesia), and in the recovery room. axillary temperature was measured with a single calibrated mercury thermometer 3 minutes before induction, 30 minutes after induction, and in the recovery room by an anesthesiologist blinded to the study design. maximum level of sensory block was evaluated by pinprick. the incidence and severity of shivering were recorded during the operation and in the recovery room. hypotension was defined as a decrease in the systolic blood pressure to less than 90 mm hg or 20% less than the baseline value, which was treated with 5 mg to 10 mg of intravenous ephedrine. pruritus was treated with 25 mg of intravenous diphenhydramine, and intravenous metoclopramide, 10 mg, was administered for nausea and vomiting. shivering was graded with a scale described by crossley and mahajan as follows(8): zero, no shivering; 1, piloerection or peripheral vasoconstriction but no visible shivering; 2, muscular activity in only one muscle group; 3, muscular activity in more than one muscle group but no generalized shivering; and 4, shivering involving the whole body. the collected data were analyzed by the epi info 6 software (epi info, the centers for disease control and prevention, atlanta, georgia, usa). the chisquare test was used to compare qualitative variables, and repeated-measures analysis of variance was used to compare trends in numeral variables during the study course. a p value of less than .05 was considered statistically significant. results all of the 80 patients in the experimental and control groups completed the study and none meperidine for treatment of shivering in transurethral resection of prostate—davoudi et al 214 urology journal vol 4 no 4 autumn 2007 of them excluded from the analyses. there were no differences between the groups regarding the basic data including age and baseline systolic blood pressure, heart rate, arterial oxygen saturation, and body temperature. the operative time and maximum sensory level block were also similar in the two groups (table). eleven patients (27.5%) in the control group had some degrees of shivering while none of the patients in the experimental group experienced shivering (p = .001). evaluation of the shivering severity was not possible since shivering was not found in one of these groups. comparison of the patients’ body temperature showed a decrease in both groups without any significant difference (p = .46; figure 1). pruritus was not reported in any of the patients. nausea was seen in 2 patients (5.0%) of each group (p = .69) and vomiting occurred in 2 patients (5.0%) with meperidine and 1 (2.5%) in the control patients (p = .50). hypotension did not occur in any of the patients. comparison of hemodynamic changes for each interval showed that the decreasing trends in systolic blood pressure and heart rate were similar in both groups and there were no differences in these parameters during the study course between the two groups (p = .13 and p = .38, respectively; figure 2). use of supplemental oxygen resulted in increasing the arterial oxygen saturation during the operation, and its cessation caused a decrease in this variable at the end of the recovery period. trends in arterial oxygen saturation were similar in the two groups and the values measured were similar (p = .91; figure 2). discussion prevention of shivering is beneficial for the patients who undergo surgical operation, especially for the elderly. although irrigation with warmed solutions can reduce the risk of hypothermia and shivering in turp, it may increase bleeding because of vasodilatation.(2) on the other hand, intravenous injection of meperidine for the treatment of shivering can result in side effects such as hemodynamic changes, respiratory depression, nausea, vomiting, pruritus, and other opioid-related complications. however, systemic absorption and the resultant effects are unlikely if the intrathecal meperidine is administered in a low dose. on the basis of the findings in this study, low-dose intrathecal meperidine is not associated with the side effects. decreases in systolic blood pressure and heart rate were noted in the patients of both study and control groups that were probably due to the sympathetic block effect of spinal anesthesia. in a previous study, intramuscular injection of meperidine, 25 mg, reduced shivering from 56.7% to 10% in the patients with spinal anesthesia.(9) also, in 2 studies by chen and associates and roy and colleagues, it was found that adding meperidine to the anesthetic compound reduced shivering in the patients who variable study group control group number of patients 40 40 age, y 72.7 ± 9.3 70.0 ± 9.9 operative time, min 50.2 ± 14.2 56.4 ± 19.2 median highest blocked segment (range) t8 (t6 to t11) t8 (t7 to t11) mean baseline systolic blood pressure, mm hg 133.0 ± 21.2 142.8 ± 23.1 mean baseline heart rate, /min 71.6 ± 9.9 75.3 ± 16.5 mean baseline arterial oxygen saturation, % 94.8 ± 3.2 94.6 ± 1.9 demographic and baseline clinical data of patients with and without meperidine injection figure 1. changes in the body temperature in the patients who underwent spinal anesthesia with and without meperidine. measurements are: 1, before anesthesia induction; 2, half an hour after induction; and 3, in the recovery room. meperidine for treatment of shivering in transurethral resection of prostate—davoudi et al urology journal vol 4 no 4 autumn 2007 215 underwent spinal anesthesia.(2,7) in the study of roy and colleagues, administration of low-dose intrathecal meperidine was not associated with any side effects.(7) it seems unlikely that the antishivering effect of lowdose intrathecal meperidine was due to its systemic absorption.(7) meperidine is a combined μ-receptor and κ-receptor agonist. it seems that intravenous meperidine is much more effective in the treatment of shivering than the equi-analgesic doses of other μ-opioid agonists, and the antishivering effect of meperidine seems to be mediated by the κ-receptor agonist activity.(10-13) the same level of sensory block in the two groups of our study emphasizes that firstly, there were equal potential effects of block height on the development of hypothermia and shivering, and secondly, intrathecal meperidine did not influence sensory block height. however, regarding the reducing effects of other types of medications such as α1-adrenergic agonists, serotonin antagonists, and propofol on shivering, it is suggested that a nonopioid mechanism can be involved.(14) physostigmine as an effective treatment of shivering brings up the cholinergic mechanism. it is believed that central inhibition on thermoregulatory control is the mechanism of prevention of shivering by these drugs.(14) perhaps, meperidine is much more effective in the treatment of shivering due to its interaction with thermoregulation, besides its opioid effect. conclusion according to our results, adding a low dose of meperidine (15 mg) to the intrathecal anesthetic mixture for turp reduces the incidence of shivering without increasing the side effects. further studies are needed to replicate our results. conflict of interest none declared. financial support deputy of research, hamadan university of medical sciences was responsible for the financial support of this study acknowledgment we especially wish to thank mr mani kashani for figure 2. changes in the systolic blood pressure, heart rate, and arterial oxygen saturation before and after the induction in the patients who underwent spinal anesthesia with and without meperidine. measurements are: 1, before anesthesia induction; 2, five minutes after induction; 3, fifteen minutes after induction; 4, 30 minutes after induction; and 5, in the recovery room. meperidine for treatment of shivering in transurethral resection of prostate—davoudi et al 216 urology journal vol 4 no 4 autumn 2007 the statistical review of this study and the deputy of research, hamadan university of medical sciences that financially supported the study. references 1. morgan ge, mikhail ms, murray mj, et al. anesthesia for genitourinary surgery. in: murray mj, morgan ge, mikhail ms, editors. clinical anesthesiology. 3rd ed. new york: mcgraw-hill; 2002. p. 695-6. 2. chen jc, hsu sw, hu lh, et al. [intrathecal meperidine attenuates shivering induced by spinal anesthesia]. ma zui xue za zhi. 1993;31:19-24. chinese. 3. sheila mm, steven k. postoperative recovery. in: barash pg, cullen bf, stoelting rk, editors. clinical anesthesia. 3rd ed. philadelphia: lippincott-raven; 1997. p. 652. 4. alfonsi p, hongnat jm, lebrault c, chauvin m. the effects of pethidine, fentanyl and lignocaine on postanaesthetic shivering. anaesthesia. 1995;50:2147. 5. alfonsi p, sessler di, du manoir b, levron jc, le moing jp, chauvin m. the effects of meperidine and sufentanil on the shivering threshold in postoperative patients. anesthesiology. 1998;89:43-8. 6. monso a, riudeubas j, barbal f, laporte jr, arnau jm. a randomized, double-blind, placebo-controlled trial comparing pethidine to metamizol for treatment of post-anaesthetic shivering. br j clin pharmacol. 1996;42:307-11. 7. roy jd, girard m, drolet p. intrathecal meperidine decreases shivering during cesarean delivery under spinal anesthesia. anesth analg. 2004;98:230-4. 8. crossley aw, mahajan rp. the intensity of postoperative shivering is unrelated to axillary temperature. anaesthesia. 1994;49:205-7. 9. hu lh, chen jc, lee y, lai kb, wong kl, wei tt. [intramuscular meperidine for the prevention of shivering in spinal anesthesia]. ma zui xue za zhi. 1992;30:223-8. chinese. 10. pauca al, savage rt, simpson s, roy rc. effect of pethidine, fentanyl and morphine on postoperative shivering in man. acta anaesthesiol scand. 1984;28:138-43. 11. kurz m, belani kg, sessler di, et al. naloxone, meperidine, and shivering. anesthesiology. 1993;79:1193-201. 12. wang jj, ho st, lee sc, liu yc. a comparison among nalbuphine, meperidine, and placebo for treating postanesthetic shivering. anesth analg. 1999;88:686-9. 13. ikeda t, kurz a, sessler di, et al. the effect of opioids on thermoregulatory responses in humans and the special antishivering action of meperidine. ann n y acad sci. 1997;813:792-8. 14. coda ba. opioids. in: barash pg, cullen bf, stoelting rk, editors. clinical anesthesia, 4th ed. philadelphia: lippincott williams & wilkins; 2001. p. 353. fitri fareez ramli (b.med, md, mmedsci) is a lecturer at the department of pharmacology, faculty of medicine, national university of malaysia. he was graduated from gadjah mada university with his medical doctor degree and later worked as a medical doctor in numerous hospitals, including two psychiatric institutions in malaysia. he joined the current department as a lecturer in 2017 and later enrolled in the master’s degree in pharmacology program at the national university of malaysia. his dissertation was on health-seeking behaviour for erectile dysfunction in methadone maintenance treatment patients. his research interest spans widely in the pharmacology field, and he has a particular interest in psychopharmacology. he actively writes various articles that are published in various indexed journals and magazines. currently, he will read his doctor of philosophy in psychiatry at the university of oxford under the khazanah-oxford centre for islamic studies merdeka scholarship program. “being a reviewer for urology journal is an honour, particularly for a young academician as we are allowed to contribute to the society in a way to improve the quality of the scientific publication.” best reviewer of the may-june 2021 issue fitri fareez ramli fitri fareez ramli v08_no_1_print_3.pdf case report 69urology journal vol 8 no 1 winter 2011 a life-threatening escherichia coli meningitis after prostate biopsy zeliha kocak tufan, cemal bulut, tevfik yazan, cigdem hatipoglu, sebnem erdinc, sami kinikli, ali pekcan demiroz urol j. 2011;8:69-71. www.uj.unrc.ir keywords: escherichia coli, meningitis, prostate, antibiotic prophylaxis, beta-lactamases infectious diseases and clinical microbiology department, ankara training and research hospital, ankara, turkey corresponding author: zeliha kocak tufan, md ankara egitim ve arastirma klinik mikrobiyoloji klinigi, ulucanlar 06340, ankara, turkey tel: +90 505 483 6074 fax: +90 312 363 1218 e-mail: drztufan@yahoo.com received june 2009 accepted august 2010 introduction transrectal prostate biopsy (tpb) is used for diagnosis of the prostate cancer. although it seems to have fewer complications than other methods, infectious and noninfectious complications may occur following tpb. antibiotic prophylaxis is commonly used before the procedure, but because the resistant bacteria are increasing in the every day clinical practice, it may be ineffective to prevent infectious complications. lifethreatening meningitis after tpb is a very rare complication and to the best of our knowledge, just eight cases have been reported up to now.(1-8) here, we present an extended spectrum beta-lactamase producing escherichia coli (e. coli) meningitis after transrectal ultrasound guided prostate biopsy (trus-pb). case report a 75-year-old man presented to the emergency department with fever, altered mental status, nausea, and vomiting. on physical examination, his fever was 38.2oc, mental status was disorientated, conscience level was fluctuating, neck stiffness was remarkable, and kernig’s sign was positive. therefore, the patient was hospitalized with diagnosis of meningitis. he had undergone a trus-pb 4 days earlier and had been prescribed oral ciprofloxacin as a prophylactic measure starting 3 days before the biopsy. when he was admitted to the hospital, he was still using the antibiotic. remarkable laboratory findings were as follows: white blood cell of 15.3 × 103/μl, erythrocyte sedimentation rate of 86 mm/h, and c-reactive protein of 6.6 mg/dl. lumbar puncture was performed and cerebrospinal fluid (csf) analysis revealed opening pressure of 150 mmhg, white blood cell of 2780/mm3 (80% polymorphonuclear leukocytes), protein of 4285 mg/dl (pandy 3+), and glucose level of 35 mg/ dl (simultaneous serum level of glucose was 180 mg/dl). no bacterium was seen on direct microscopy of csf and injection of meropenem, 2 gr three times daily, was started empirically. extended spectrum beta-lactamase producing e. coli grew in csf culture. the bacterium was resistant to fluoroquinolones and amikacin as well as cephalosporins, but susceptible to carbapenems. on the 10th day of therapy, control lumbar puncture was performed meningitis after transrectal prostate biopsy—bulut et al 70 urology journal vol 8 no 1 winter 2011 and all biochemical analysis of csf turned to normal levels with a decreased cell count to 130 leukocyte/mm3. antibiotic therapy continued for 21 days and complete resolution of symptoms was achieved without any sequel. discussion transrectal ultrasound guided prostate biopsy has been a frequently used outpatient procedure with low major complication rates. however, its infective complications, such as bacteremia, sepsis, and septic shock, can be life-threatening. the main causative organisms are e. coli (most frequent), klebsiella pneumoniae, pseudomonas aeruginosa, and enterococcus subspecies. although the antibiotic prophylaxis has become a routine precaution before performing tpb, there is still no consensus on what to be used and when. fluoroquinolones seem to be the most frequently used antibiotics for prophylaxis followed by aminoglycosides, doxycycline, and metronidazole in the routine practice.(9) meningitis after tpb is a very rare complication and since the majority of the cases were reported in other languages than english, it was very difficult to compare those with our patient (table). it is not surprising that almost all the patients get prophylaxis with flouroquinolones, either ciprofloxacin or levofloxacin. timing of the antibiotic administration varies; shen and colleagues performed the procedure after three days of intravenous antibiotic prophylaxis while rodríguez-patrón and associates gave it two hours before.(1,7) our patient was also using ciprofloxacin three days before and four days after the procedure. the timing of development of meningitis after the procedure also varies; it was seven days for shen’s patient (1) while it was two days for erdogan’s,(3) and four days for ours. the organism responsible for the meningitis was e.coli for all the subjects and in ours as well. despite the ability of ciprofloxacin to penetrate into the prostate, it has to be used carefully because of the emerging resistance of e.coli to quinolones. feliciano and colleagues underlined the quinolone resistance in their article. they evaluated 1273 trus-pbs with 2.4% infective complications and found that the positive cultures of e.coli strains showed 89.5% quinolone resistance, while they were susceptible to amikacin, ceftriaxone, and ceftazidime.(10) does it mean that we can use cephalosporins for prophylaxis? we do not suggest that, since the more antibiotics are used, the more resistant bacteria you get. the main challenge in multi-drug resistant e. coli strains, like in our case, is that they show resistance to cephalosporins as well. starting the antibiotic treatment for meningitis with a cephalosporin, as is usually done, and waiting for the culture results could lead to a fatal outcome in patients who had undergone trus-pb and received some antibiotics already. with regard to this, we started carbapenem as the first-line medicine and the patient recovered quickly without any sequel. we want to underscore that if a patient gets prophylaxis, but still develops meningitis after trus-pb, the underlying pathogen can be multidrug resistant and the drug of choice has to be considered on this base. first author prophylaxis microorganismin csf therapy for meningitis outcome shen zj(1) metronidazole and levofloxacine multi-resistant e. coli carbapenem healed erdogan h(3) ciprofloxacin e.coli ceftriaxone healed alecsandru d(4) ciprofloxacin multi-resistant e.coli imipenem (followed by cefotaxime) healed samson d(5) ofloxacine and metronidazole multi-resistant e. coli ceftriaxone + gentamycin excitus meisel f(6) levofloxacine e.coli cefotaxime (plus ampicillin and netilmicin) healed rodríguez-patrón rr(7) ciprofloxacin multi-resistant e. coli meropenem healed sandvik a(8) nd e.coli nd nd nguyen bv(2) ciprofloxacin e.coli ceftriaxone + gentamycin healed meningitis after transrectal prostate biopsy* *csf indicates cerebrospinal fluid; and nd, no data was found. meningitis after transrectal prostate biopsy—bulut et al 71urology journal vol 8 no 1 winter 2011 conflict of interest none declared. references 1. shen zj, chen sw, wang h, zhou xl, zhao jp. life-threatening meningitis resulting from transrectal prostate biopsy. asian j androl. 2005;7:453-5. 2. nguyen bv, cottrel m, ralec b, et al. [a serious and unexpected infectious complication after transrectal prostate biopsy]. med mal infect. 2009;39:735-8. 3. erdogan h, ekinci mn, hoscan mb, erdogan a, arslan h. acute bacterial meningitis after transrectal needle biopsy of the prostate: a case report. prostate cancer prostatic dis. 2008;11:207-8. 4. alecsandru d, gestoso i, romero a, et al. e. coli multiresistant meningitis after transrectal prostate biopsy. scientificworldjournal. 2006;6:2323-6. 5. samson d, seguin t, conil jm, georges b, samii k. [multiresistant escherichia coli meningitis after transrectal prostate biopsy]. ann fr anesth reanim. 2007;26:88-90. 6. meisel f, jacobi c, kollmar r, hug a, schwaninger m, schwab s. [acute meningitis after transrectal prostate biopsy]. urologe a. 2003;42:1611-5. 7. rodríguez-patrón rodríguez r, navas elorza e, quereda rodríguez-navarro c, mayayo dehesa t. [meningitis caused by multiresistant e. coli after an echo-directed transrectal biopsy]. actas urol esp. 2003;27:305-7. 8. sandvik a, stefansen d. [escherichia coli meningitis following prostate biopsy]. tidsskr nor laegeforen. 1982;102:499-500. 9. burden hp, ranasinghe w, persad r. antibiotics for transrectal ultrasonography-guided prostate biopsy: are we practising evidence-based medicine? bju int. 2008;101:1202-4. 10. feliciano j, teper e, ferrandino m, et al. the incidence of fluoroquinolone resistant infections after prostate biopsy--are fluoroquinolones still effective prophylaxis? j urol. 2008;179:952-5; discussion 5. review 67urology journal vol 5 no 2 spring 2008 ureteral calculi in children what is best as a minimally invasive modality? abbas basiri, samad zare, nasser shakhssalim, seyed mohammadmehdi hosseini moghaddam introduction: minimally invasive treatment of ureteral calculi in children is a challenging topic. in an evidence-based review, we evaluated the efficacy and safety of extracorporeal shock wave lithotripsy (swl) and ureteroscopic modalities for this group of patients. materials and methods: in this study, we performed a comprehensive systematic review on articles appeared in the pubmed from 1998 to march 2008. we selected all papers addressing swl or ureteroscopic management of the ureteral calculi in children and determined the level of evidence of the presenting data. results: thirty-nine articles were reviewed and 24 with valid information on swl or ureteroscopic management of the pediatric ureteral calculi were analyzed. six articles (25%) were randomized controlled trials and 18 (75%) were retrospective case-controls or case series. the following data were extracted from the 24 articles: in swl groups, overall success rate was 84.1% (range, 71% to 100%) for the upper ureteral calculi and 76.2% (range, 19% to 91%) for the lower ureteral calculi. only 61% of the patients had only 1 treatment course, while 8% and 31% of the cases required 2 and more than 2 sessions of treatment, respectively. with ureteroscopic management, the overall success rates were 93.2% (range, 81% to 100%) and 74.4% (range, 20% to 100%) in the lower and upper ureteral calculi, respectively. conclusion: the main limitations of the series on minimally invasive treatment of pediatric ureteral calculi are lack of powerful randomized controlled trials or prospective data and insufficient patient numbers. therefore, it is difficult to draw absolute conclusions about successful treatment based on current knowledge. urol j. 2008;5:67-73. www.uj.unrc.ir keywords: urinary calculi, child, shock wave lithotripsy, ureteroscopy, treatment, randomized control trials urology and nephrology research center and department of urology, shahid labbafinejad medical center, shahid beheshti university (mc), tehran, iran corresponding author: abbas basiri, md urology and nephrology research center, no 44, 9th boustan, pasdaran, tehran 1666668111, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail: basiri@unrc.ir introduction management of ureteral calculi in children is usually a challenge to the treating urologist. fortunately, ureteral calculi are less frequent in children than in adults; only 7% of the total urinary calculi are seen in children.(1) more than 80% of the ureteral calculi pass spontaneously and do not require any intervention.(2) for those in whom the calculus is unlikely to pass, treatment methods can be invasive or noninvasive, depending on the presence of ureteral obstruction, intractable pain, urosepsis, persistent gross hematuria, degree of impaction, patient expectations, and surgeon’s experience.(3,4) initially, ureteral calculi in the pediatric age group was one of the contraindications ureteral calculi in children—basiri et al 68 urology journal vol 5 no 2 spring 2008 for extracorporeal shock wave lithotripsy (swl). after the study of newman and colleagues in 1986, swl was started on for children in some centers, and even infants as young as 6 months have been treated successfully.(5,6) important rules that have to be obeyed in the treatment of children are protecting the lung and the adjacent organs as much as possible, diminishing the number of swl sessions or auxiliary measures, and using ultrasonography more frequently than radiography for locating the calculus in order to avoid ionizing radiation.(7) during the last quarter of the 20th century, developments in endourology led to the safe use of ureteroscopy, and consequently, this form of treatment has become widely accepted for ureteral calculi in adults. however, the use of ureteroscopy in children has been limited.(8,9) the first reported ureteroscopy in children was performed by young and mckay with a standard pediatric cystoscope in a patient with a posterior urethral valve and a gross dilated upper tract.(10) early ureteroscopy procedures in children were performed using large-caliber ureteroscopes; this caused difficulties in advancement through the intramural tunnel, leading to injury of the ureteral mucosa.(11) although ureteroscopy has become a powerful diagnostic and therapeutic tool in children with the introduction of smallcaliber ureteroscopes, there have been few studies conducted on the safety and long-term effectiveness of ureteroscopy for the treatment of ureteral calculi in these patients.(12) in this article, we performed a systematic review on the minimally invasive treatment options for ureteral calculi in children. a comprehensive search was done via the mesh term and nonmesh term search protocol on the pubmed for the relevant articles that appeared from january 1998 to march 2008. the keywords were extracorporeal shock wave lithotripsy, transureteral lithotripsy, pediatric ureteral calculi, ureteral calculi, safety, and efficacy. other specific words were researched during the study if needed. levels of evidence classification of the levels of evidence was performed on the basis of a simplified oxford scaling system(13,14): level 1 evidence: good-quality randomized controlled trials (rcts) or meta-analyses of rcts level 2 evidence: low-quality rcts, clinical trials with pseudorandomized allocation or 1 arm, or meta-analyses of good-quality cohort studies level 3 evidence: good-quality retrospective casecontrol studies or good-quality case series level 4 evidence: low-quality retrospective casecontrol studies or low-quality case series we reviewed 39 articles and analyzed 24 of those with valid information about swl or ureteroscopic management of pediatric ureteral calculi.(1-4,7-9,11,12,15-29) ureteroscopy and swl for ureteral calculi had been reported in 20 (83.3%) and 9 (37.5%) articles, respectively. nineteen papers (79.2%) had a single-arm (clinical trials or case series) on either ureteroscopy or swl, and 5 papers (20.8%) had compared these two options in a double-arm fashion (rcts or case series).(11,12,15,16) only 1 article (4.2%) was an rct. all of the calculi in this study were located in the lower ureter. the levels of evidence were determined for these 24 articles. there were 1 (4.2%), 3 (12.5%), 10 (41.7%), and 10 (41.7%) articles classified in levels 1 to 4, respectively. details of the papers are outlined in table 1. results totally, treatment of 1027 children with ureteral calculi, consisting of 555 boys (54.1%) and 472 girls (45.9%), had been reported in the reviewed articles. the median age of the patients was 7.5 years (range, 1 to 17 years). in 380 patients (36.8%), the calculi were located in the upper ureter (above the pelvic brim) and in 647 (63.2%), the calculi had been detected in the lower ureter (under the pelvic brim). the median sizes of the upper and lower ureteral calculi were 7.7 mm (range, 4 mm to 15 mm) and 7.5 mm (range, 4 mm to 14 mm), respectively. extracorporeal shock wave lithotripsy and transureteral lithotripsy had been performed in 422 (41.1%) and 605 (58.9%) patients (table 1). follow-up had been done with plain abdominal radiography, ultrasonography, intravenous urography, and ureteral calculi in children—basiri et al urology journal vol 5 no 2 spring 2008 69 p at ie nt s c al cu lu s lo ca tio n, % n o a rt ic le le ve l o f e vi de nc e a rt ic le t yp e m od al ity g ir ls b oy s lo w er u pp er c al cu lu s s iz e, m m e ne rg y s ou rc e s te nt , % u re te ra l d ila tio n, % u re te ro sc op e, ty pe , f 1 d e d om in ic is e t a l(1 2) 1 r c t t u l & s w l 21 10 10 0 0 5 to 9 b al lis tic , l as er 0 0 s em iri gi d, 5 2 d og an e t a l(2 0) 2 c t t u l 15 20 92 8 4 to 1 5 la se r 10 0 10 0 r ig id , 8 to 1 1. 5 3 r au ch en w al d et a l(7 ) 2 c t s w l 41 39 58 42 9 to 1 5 … 0 0 4 s of er e t a l(2 ) 2 c t t u l 7 5 83 17 5 to 2 0 la se r 90 10 s em iri gi d, 6 .5 to 1 1. 5 5 o zg ur e t a l(2 4) 3 ca se s er ie s s w l 18 23 63 37 … … 20 0 6 o zb ey e t a l(2 2) 3 ca se s er ie s s w l 11 18 10 0 0 4 to 1 8 … 0 0 7 ta n et a l(1 5) 3 ca se s er ie s t u l & s w l 32 35 10 0 0 5 to 1 0 p ne um at ic 0 0 s em iri gi d, 8 8 d el ak as e t a l(2 3) 3 ca se s er ie s t u l & s w l 12 13 44 56 5 to 1 4 la se r 25 0 s em iri gi d, 8 9 e l a ss m y et a l(1 8) 3 ca se s er ie s t u l 16 17 88 12 4 to 1 5 la se r 85 0 s em iri gi d, 6 .5 to 1 0 10 t ho m as e t a l(9 ) 3 ca se s er ie s t u l 16 17 73 27 3 to 1 4 la se r 70 0 s em iri gi d, 8 to 11 .5 11 s at ar e t a l(1 9) 3 ca se s er ie s t u l 17 18 74 26 3 to 1 0 p ne um at ic 35 0 r ig id , 6 .5 to 1 0 12 k ur zr oc k et a l(2 1) 3 ca se s er ie s t u l 17 0 77 23 5 to 1 1 la se r 29 6 s em iri gi d, 6 13 b as si ri et a l(8 ) 3 ca se s er ie s t u l 35 31 89 11 5 to 1 5 la se r, p ne um at ic , e h , b as ke t 0 38 s em iri gi d, 8 to 11 .5 14 ta n et a l(2 5) 3 ca se s er ie s t u l 10 13 67 33 5 to 1 2 la se r , e h 91 17 s em iri gi d, 6 .5 to 8 15 b rin km an n et a l(1 7) 4 ca se s er ie s s w l 19 21 0 10 0 5 to 1 7 … 43 0 16 r az a et a l(1 ) 4 ca se s er ie s t u l 25 27 77 23 7 to 1 0 e h , l as er , b as ke t 0 0 s em iri gi d, 6 .8 17 ja ya nt hi e t a l(1 1) 4 ca se s er ie s t u l & s w l 24 17 10 0 0 7 to 1 2 la se r 9 0 s em iri gi d, 8 to 1 0 18 w ol lin e t a l(3 ) 4 ca se s er ie s t u l 9 10 69 31 7 to 9 la se r 0 0 f le xi bl e, 8 to 1 1. 5 19 la nd au e t a l(2 8) 4 ca se s er ie s t u l & s w l 17 21 50 50 6 to 9 … 39 0 … 20 r om er o et a l(2 6) 4 ca se s er ie s t u l 3 4 29 71 4 to 7 p ne um at ic 0 0 s em iri gi d, 8 21 le sa ni e t a l(2 9) 4 ca se s er ie s t u l 10 12 0 10 0 5 to 9 la se r 12 25 r ig id , 6. 5 to 1 1. 5 22 a rid og an e t a l(2 7) 4 ca se s er ie s t u l 31 25 65 35 5 to 1 2 p ne um at ic 41 25 r ig id , 6 .9 to 1 0 23 a l-b us ai dy e t a l(4 ) 4 ca se s er ie s t u l 12 14 58 42 4 to 2 2 la se r 25 0 r ig id , 8 24 s m al do ne e t a l(1 6) 4 ca se s er ie s t u l 35 32 56 44 5 to 1 0 la se r 76 44 s em iri gi d, 6 .9 & f le xi bl e, 7 .2 ta bl e 1. s um m ar iz ed d at a of 2 4 s el ec te d a rt ic le s on t re at m en t o f u re te ra l c al cu li in c hi ld re n* *r c t in di ca te s ra nd om iz ed c on tr ol le d tr ia l; c t, c lin ic al tr ia l; t u l, tr an su re te ra l l ith ot rip sy ; s w l, s ho ck w av e lit ho tr ip sy ; a nd e h , e le ct ro hy ra ul ic . e lli ps es in di ca te n ot a va ila bl e or n ot a pp lic ab le . ureteral calculi in children—basiri et al 70 urology journal vol 5 no 2 spring 2008 voiding cystourethrography in a few studies. the follow-up durations ranged from 3 months to 18 months. extracorporeal shock wave lithotripsy in almost all reports, swl had been performed by siemens or dornier lithotripters plus devices at prone position usually under dissociative anesthesia using ketamine (0.5 mg/kg) for most children, and sedation was sufficient for some children older than 14 years old. the devices were 1st-, 2nd-, and 3rd-generation lithotripters in 20%, 30%, and 50% of the cases, respectively. the shock wave had been delivered by undertable piezoelectric, electromagnetic, and electrohydraulic sources in 20%, 25%, and 55% of cases. the mean number of shock waves per session and power were 2724.68 ± 507.34 kv and 17.46 ± 1.13 kv, respectively. ninetyeight percent of swls had been done in an outpatient setting. contraindications for swl were coagulation disorders, pyelonephritis, and obstruction distal to calculi, nonfunctioning kidney, and hypertension.(17) extracorporeal shock wave lithotripsy procedures were carried out under ultrasonographic and fluoroscopic controls in 65% and 35% of cases, respectively. the overall success rates were 84.1% (range, 71% to 100%) in the upper ureteral calculi and 76.2% (range, 19% to 91%) in the lower ureteral calculi. only 61% of the patients had 1 treatment course, while 8% and 31% of cases required 2 and more than 2 sessions of treatment, respectively. de dominicis and associates reported the efficacy quotient of 30% and 70% for swl and ureteroscopic management of the lower ureteral calculi, respectively.(12) they reported steinstrasse in 4.2% of the patients who underwent swl. transient microscopic hematuria (100%) and bruising of the skin (80%) were the most common complications after swl (table 2). ureteroscopic management of ureteral calculi ureteroscopy had been performed by rigid, semirigid, and flexible ureteroscopes in 5 (26.5%), 11 (57.8%) and 3 (15.7%) of the articles. the sizes of the ureteroscopes were between 6.5 f and 11.5 f. the calculi had been fragmented by holmium laser (60%), pulsed-dye laser (8%), ultrasonic lithotripsy (5%), electrohydraulic lithotripsy (7%), and pneumatic lithotripsy (20%). the use of grasping forceps was limited to 3.5% of the ureteroscopic procedures. ureteral dilation had been performed in 18.6% of the cases, usually not required for ureteroscopes smaller than 8 f. thirty percent of the patients required ureteral drainage via a ureteral catheter or a double-j stent, and the most frequent indications for this intervention where calculi greater than 1 cm in diameter, obstructing calculi, complicated ureteroscopy, and malfunctioning kidney.(18-21) in almost all patients, treatment had been performed under general anesthesia. the overall success rate in the lower ureteral calculi was 93.2% (range, 81% to 100%), and it was 74.4% (range, 20% to 100%) in the upper ureteral calculi. the efficacy quotient for ureteroscopic management of pediatric ureteral calculi was 38% and 42% in 2 articles.(9,18) in el-assmy and colleagues’ study, the calculi were located in the lower ureter and upper ureter in 29 (88%) and 4 (12%) of the cases,(18) and in thomas and colleagues’ study, they were located in the lower ureter and upper ureter in 24 (73%) and 9 (27%) of the cases.(9) the need for repeated treatment were reported in 17% of ureteroscopic modalities. calculus migration was reported in 5.3% of the patients. transient hematuria was the most common minor complication (table 2). complications ureteroscopy, % swl, % major ureteral perforation 1.7 0 ureteral stricture 1.0 0 urosepsis/pyonephrosis 0.5 0.7 ureteral avulsion 0.4 0 nonfunctioning kidney 0.1 0.2 minor microscopic hematuria 100 100 skin bruising 0 80.0 gross hematuria 15.0 21.0 renal colic 7.1 7.9 fever (> 38°c) 4.3 10.0 urinary retention 7.0 0 mucosal tearing 3.5 0 table 2. complications of extracorporeal shock wave lithotripsy (swl) and ureteroscopic management of pediatric ureteral calculi ureteral calculi in children—basiri et al urology journal vol 5 no 2 spring 2008 71 discussion although swl offers the patient a less-invasive modality, it is associated with some inherent drawbacks. the success of the procedure is variable, with some large series reporting stonefree rates between 76% and 84% and repeated treatment rates of zero to 36%.(8,22,23) most children require general anesthesia for swl, which means if swl fails, the child will again be exposed to general anesthesia to undergo a salvage endourologic procedure. large calculi, cystine calculi, and radiolucent calculi are not suitable for treatment with swl.(16,24) ureteroscopy could be performed as an outpatient procedure in adults and the cost-effectivity was reported to be similar or even less than those for swl using a first-generation lithotripter.(11) however, this is rather controversial as there is wide variability in the success rate, the type of equipment, experience, and medical expenses among different countries and even institutions. the safety of ureteroscopy in pediatric age group has not been fully established.(23,25) it is difficult to draw conclusions on successful treatment based on calculus location in children due to the small patient numbers in most reports. however, success rates of treatment in proximal ureteral calculi in adults are lower than those for distal calculi, although the increased use of the holmium laser has improved these success rates dramatically.(19) depending on the location of the calculus, the success rate of ureteroscopy varies (range, 20% to 100% for calculi in the upper ureter, 36% to 83% for those in the middle ureter, and 81% to 100% for those in the lower ureter). although swl is more effective for upper ureteral calculi, ureteroscopy provides a favorable outcome for those in the middle ureter and the lower ureter. in addition, without question, ureteroscopy was more effective in the treatment of nonopaque ureteral calculi.(22) the main limitations of these series are selection bias, lack of powerful rcts or prospective data, insufficient patient numbers, limited follow-up information, and lack of a standard definition for stone-free status. the success rates for ureteroscopic laser lithotripsy and calculus extraction in children range from 86% to 100% in the literature, and secondary procedures usually increase this rate to nearly 100%.(9) although the size of the calculus in addition to its location may affect treatment efficacy and success, they did not affect the results of some studies, which may be due to the small number of patients with calculi in the upper ureter.(26) with an excellent technique and meticulous attention to details, significant complications occur in 0 to 7% of the cases.(5) overall, the incidence of ureteral stricture after ureteroscopy is 1% to 4% in adults, but rates specific to children are unknown due to the small patient numbers in most series. nonetheless, it has been documented that the recent advent of smaller instrumentation has decreased this risk to less than 1%.(4) shroff and watson described a child who developed a ureteral stricture after holmium laser lithotripsy. this complication was treated by holmium laser at a second ureteroscopy.(30) duration of ureteroscopy should be short, unnecessary manipulations should be avoided, and warm irrigation fluids should be used to avoid complications. the most frequent early complications of pediatric ureteroscopy are hematuria, renal colic, and urinary retention. according to this literature review, there is no need for dilation of the intramural ureter before each ureteroscopy. when dilation is required, it should be done only to the smallest size that will allow introduction of the ureteroscope. some reports suggested vesicoureteral reflux (11% to 17%) as a late complication of pediatric ureteroscopy secondary to dilation of the ureteral orifice when a large-caliber ureteroscope is used. however, because this complication is almost temporary and low-grade, it is not necessary that cystography be performed routinely after ureteroscopy.(24,27) in the earliest series of pediatric ureteroscopy, postoperative stents were inserted and tolerated well in all cases.(3,11,28) in 1996, kurzrock and colleagues reported that stent was not needed to be inserted in all patients and only 29% required it, which were removed after a short time.(21) sometimes, insertion of a stent may be advantageous although removal of the stent requires general anesthesia.(21) calculus analysis was available only in few ureteral calculi in children—basiri et al 72 urology journal vol 5 no 2 spring 2008 patients of the reviewed series. a comparison of calculus composition by ureteral and kidney location showed a significant preponderance of ureteral calcium calculi (92% versus 44%), and a trend toward more intrarenal cystine calculi (33% versus 8%) and sturvite calculi (22% versus zero).(2) metabolic abnormality was present in nearly 40% of the children in these series.(25) satisfaction of the patients is an important predictor of treatment efficacy that was not referred in these literatures. conclusion based on these data, swl is more effective for upper ureteral calculi, and ureteroscopy provides a favorable outcome for calculi in the middle and lower ureter. the main limitations of these series were selection bias, lack of powerful rcts or prospective data, insufficient patient numbers, limited follow-up information, and lack of a standard definition for stone-free status. therefore, it is still difficult to draw final conclusions about safety and efficacy of these modalities. in order to help shedding light on this subject, we have designed a nation-wide rct, the results of which will be released in the near future. conflict of interest none declared. references 1. raza a, smith g, moussa s, tolley d. ureteroscopy in the management of pediatric urinary tract calculi. j endourol. 2005;19:151-8. 2. sofer m, binyamini j, ekstein pm, et al. holmium laser ureteroscopic treatment of various pathologic features in pediatrics. urology. 2007;69:566-9. 3. wollin ta, teichman jm, rogenes vj, razvi ha, denstedt jd, grasso m. holmium:yag lithotripsy in children. j urol. 1999;162:1717-20. 4. al-busaidy ss, prem ar, medhat m, al-bulushi yh. ureteric calculi in children: preliminary experience with holmium:yag laser lithotripsy. bju int. 2004;93: 1318-23. 5. newman dm, coury t, lingeman je, et al. extracorporeal shock wave lithotripsy experience in children. j urol. 1986;136:238-40. 6. nazli o, cal c, ozyurt c, et al. results of extracorporeal shock wave lithotripsy in the pediatric age group. eur urol. 1998; 33:333-6. 7. rauchenwald m, colombo t, petritsch ph, vilits p, hubmer g. in situ extracorporeal shock wave lithotripsy of ureteral calculi with the mpl-9000x lithotriptor. j urol. 1992;148:1097-101. 8. bassiri a, ahmadnia h, darabi mr, yonessi m. transureteral lithotripsy in pediatric practice. j endourol. 2002;16:257-60. 9. thomas jc, demarco rt, donohoe jm, adams mc, brock jw, 3rd, pope jct. pediatric ureteroscopic stone management. j urol. 2005;174:1072-4. 10. young hh, mckay rw. congenital valvular obstruction of the prostatic urethra. surg gynecol obstet. 1929;48:509-35. 11. jayanthi vr, arnold pm, koff sa. strategies for managing upper tract calculi in young children. j urol. 1999;162:1234-7. 12. de dominicis m, matarazzo e, capozza n, collura g, caione p. retrograde ureteroscopy for distal ureteric stone removal in children. bju int. 2005;95:1049-52. 13. centre for evidence-based medicine [homepage on the internet]. bob phillips, chris ball, dave sackett, doug badenoch, sharon straus, brian haynes, martin dawes. levels of evidence and grades of recommendations. [cited 2008 jan 1]. available from: http://www.cebm.net/index.aspx?o=1047 14. nitti vw, blaivas jg. urinary incontinence: epidemiology, pathophysiology, evaluation and management overview. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbellwalsh urology. 9th ed. philadelphia: saunders; 2007. p. 2072. 15. tan mo, karaoglan u, sozen s, biri h, deniz n, bozkirli i. minimally invasive treatment of ureteral calculi in children. urol res. 2006;34:381-7. 16. smaldone mc, cannon gm, jr., wu hy, et al. is ureteroscopy first line treatment for pediatric stone disease? j urol. 2007;178:2128-31; discussion 31. 17. brinkmann oa, griehl a, kuwertz-broking e, bulla m, hertle l. extracorporeal shock wave lithotripsy in children. efficacy, complications and long-term followup. eur urol. 2001;39:591-7. 18. el-assmy a, hafez at, eraky i, el-nahas ar, el-kappany ha. safety and outcome of rigid ureteroscopy for management of ureteral calculi in children. j endourol. 2006;20:252-5. 19. satar n, zeren s, bayazit y, aridogan ia, soyupak b, tansug z. rigid ureteroscopy for the treatment of ureteral calculi in children. j urol. 2004;172:298-300. 20. dogan hs, tekgul s, akdogan b, keskin ms, sahin a. use of the holmium:yag laser for ureterolithotripsy in children. bju int. 2004;94:131-3. 21. kurzrock ea, huffman jl, hardy be, fugelso p. endoscopic treatment of pediatric urolithiasis. j pediatr surg. 1996;31:1413-6. 22. ozbey i, aksoy y, ziypak t, yapanoglu t, polat o, aksoy m. shock wave lithotripsy is effective and safe for distal ureteral calculi in children. urol res. 2007;35:237-41. 23. delakas d, daskalopoulos g, metaxari m, triantafyllou t, cranidis a. management of ureteral stones in pediatric patients. j endourol. 2001;15:675-80. ureteral calculi in children—basiri et al urology journal vol 5 no 2 spring 2008 73 24. ozgur tan m, karaoglan u, sozen s, bozkirli i. extracorporeal shock-wave lithotripsy for treatment of ureteral calculi in paediatric patients. pediatr surg int. 2003;19:471-4. 25. tan ah, al-omar m, denstedt jd, razvi h. ureteroscopy for pediatric urolithiasis: an evolving first-line therapy. urology. 2005;65:153-6. 26. romero otero j, gomez fraile a, feltes ochoa ja, fernandez i, lopez vazquez f, aransay bramtot a. [the lithiasis in the upper urinary tract in children: endourological treatment]. actas urol esp. 2007;31:532-8; discussion 8-40. spanish. 27. aridogan ia, zeren s, bayazit y, soyupak b, doran s. complications of pneumatic ureterolithotripsy in the early postoperative period. j endourol. 2005;19:50-3. 28. landau eh, gofrit on, shapiro a, et al. extracorporeal shock wave lithotripsy is highly effective for ureteral calculi in children. j urol. 2001;165:2316-9. 29. lesani oa, palmer js. retrograde proximal rigid ureteroscopy and pyeloscopy in prepubertal children: safe and effective. j urol. 2006;176:1570-3. 30. shroff s, watson gm. experience with ureteroscopy in children. br j urol. 1995;75:395-400. v08_no_1_print_3.pdf pictorial urology 12 urology journal vol 8 no 1 winter 2011 isolated renal hydatid cyst managed with partial nephrectomy urol j. 2011;8:12. www.uj.unrc.ir a 35-year-old woman presented with left upper quadrant abdominal pain for one year. there were no gastrointestinal symptoms. ultrasonography showed a cystic lesion in the left renal area. a computed tomography scan revealed a 10.5 cm × 9 cm × 8.5 cm heterogeneous cystic mass, occupying the superior pole of the left kidney. there were areas of calcification in the lower portion of the cyst. the cystic mass was abutting the tail of the pancreas, and was wedged between the splenic hilum, the upper pole of the left kidney, and the tail of the pancreas. there were no other similar intra-abdominal lesions. her investigations were unremarkable, except enzyme-linked immunosorbent assay that was positive for echinococcus granulosus. she was started on albendazole, 1 week pre-operatively. after decompressing the cyst, betadine 10% was instilled, which was then re-aspirated. thereafter, the patient underwent a partial nephrectomy. her postoperative recovery was uneventful. she was advised to continue albendazole for 4 weeks after the surgery. isolated renal hydatid cysts are rare, with treatment being primarily surgical.(1) various modalities can be chosen, based on the size of the cyst, location, and physician’s expertise. there have been a few reports of laparoscopic nephrectomy (2) and retroperitoneal excision of the cyst.(3) however, in our patient, the sheer size and proximity to the collecting system precluded safe laparoscopic excision, without spillage. john s banerji, antony devasia department of urology, christian medical college, ida scudder road, vellore, tamil nadu, india e-mail: johnsbanerji2002@yahoo.co.in references 1. gögüs ç, safak m, baltaci s, türkölmez k. isolated renal hydatidosis: experience with 20 cases. j urol. 2003;169:186-9. 2. shah k, ganpule a, desai m. isolated renal hydatid cyst managed by laparoscopic transperitoneal nephrectomy. indian j urol. 2009;25:531-3. 3. khan m, sajjad nazir s, ahangar s, farooq qadri s, ahmad salroo n. retroperitoneal laparoscopy for the management of renal hydatid cyst. int j surg. 2010;8:266-8. sociation council on hypertension, including the 2014 lifetime achievement award. he has an extensive news media profile. in 2018 he was made a member of the order of australia. one of his research interests is the health benefits of male circumcision, leading to 130 of his publications. his interest in circumcision stemmed from developing a better (molecular) test for use in cervical screening. it was then when he saw the research showing that women were at lower risk of cervical cancer if their male partner was circumcised. he was the first to invent and then competitively patent of the first use of pcr for viral detection in 1987. after many years of effort the use of pcr for detection of high-risk hpv types has replaced pap smears in many major countries in the world. he runs he circumcision academy of australia as secretary. in recent years he has been studying the molecular genetics and genomics of human longevity as well. his efforts, in collaboration with colleagues at the university of hawaii, helped secure a us national institutes of health 5-year center of biomedical research excellence grant of us$15 million. dr. morris regards critical evaluation of manuscripts during the peer-review process as being integral to achieving the high standard required for a manuscript to qualify for publication in a journal. he has extensive experience as a reviewer, having reviewed over 800 manuscripts in his 50+ year career. he believes that producing a worthwhile review on each occasion was helped by his skills in data evaluation and scientific writing as well as knowledge of the fields of research interest mentioned above. this has, moreover, helped the authors publish a higher-quality article. he has been glad to review manuscripts for the urology journal, particularly those involving male circumcision. best reviewer of the march-april 2022 issue brian j. morris brian j. morris april 2022 brian j. morris, dsc phd is professor emeritus in the school of medical sciences at the university of sydney in sydney, australia, where he has been since 1978 after 3 years of postdoctoral studies in the usa. dr. morris expertise includes molecular biology and genetics, which he has applied to the fields of cardiovascular diseases and to longevity. one of his research themes has focused on molecular mechanisms that control renin gene expression and identifying a role for the intrarenal renin-angiotensin system in the etiology of essential hypertension. dr. morris has 446 academic publications, and 547 conference abstracts. he has received major awards from the american heart asurological oncology prognostic impact of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma: data from a large population-based database yanal alnimer1*, ayman qasrawi2, donglin yan3, peng wang4 purpose: cytoreductive nephrectomy (cn) was considered a well-established treatment modality for patients with metastatic renal cell carcinoma (rcc) in the interferon era. however, its role after the introduction of multiple targeted therapies is less well established. herein, we evaluated the effect of cn on overall survival (os) on patients with rcc who were identified through the surveillance, epidemiology, and end results database (seer). materials and methods: a total of 5,483 patients with metastatic rcc were identified from 2010 to 2016 using the seer database. factors pertaining to the following variables were collected: presence or absence of cn; age; gender; grade; status of metastasis to bone, liver, lung and brain; tumor stage; nodal status; histological subtypes; and chemotherapy status. subjects who had cn were matched with those who did not in all previously mentioned covariates using inverse probability weighting. these weights were then used in adjusted cox regression models to report doubly robust estimates. results: cn was associated with 67% reduction in the hazards of death. advanced t-stage, n1 disease, advanced tumor grade, non-clear histology and metastasis to bone, liver, lung or brain are independent risk factors for death. patients with t4 disease benefited less of cn compared to those with t1 disease, while higher number of metastatic sites didn’t predict worse outcome among those who had cn. conclusion: cn could provide a survival advantage in favorable risk patients with rcc in the era of targeted therapy. keywords: cytoreductive nephrectomy; immunotherapy; interferon; metastatic renal cell carcinoma; overall survival introduction renal cell carcinoma (rcc) is an uncommon ma-lignancy that arises from the renal cortex. pathologically, rcc can be divided into several subtypes based on its morphology, molecular alterations, growth pattern, immunohistochemistry and cell of origin. clear cell histology (cc) comprises the majority of rcc subtypes (75-85%) while papillary, chromophobe, oncocytic and collecting duct tumors (of bellini) account for the rest.(1) cytoreductive nephrectomy (cn) was considered one of the main modalities of treatment in metastatic renal cell carcinoma (mrcc) in the era of interferon therapy. that was established after the publication of two randomized controlled trials; swog-8949 and eortc; both have shown a survival advantage in patients who were treated with cn along with interferon compared to those who received interferon therapy alone. the median survival of the combined treatment modalities was 11.1 months compared to 8.1 months for the interferon therapy alone in the swog 8949 trial and 17 vs. 7 months in the erotc trial.(2,3) patients with good performance status (0-1) were included in these trials regardless of their tumor burden. 1hospital medicine, virginia commonwealth university, richmond, virginia, 23284, u.s.a. 2division of hematology, bmt and cellular therapy, university of kentucky, lexington, kentucky 40536, u.s.a. 3division of medical oncology, university of kentucky, lexington, ky 40536, u.s.a. 4division of medical oncology, university of kentucky, lexington, ky 40536, u.s.a. *correspondence: hospital medicine, virginia commonwealth university, , 3600 w. broad street suite 115, richmond, va 23230 u.s.a.yanalalnimer@outlook.com. received december 2020 & accepted september 2021 however, the role of cn after the introduction of targeted therapies, which significantly improved survival in patients with mrcc, is still under debate. several non-experimental studies demonstrated a survival benefit for cn. however, these studies were subjected to several biases.(4) in regards to experimental studies, the carmena trial demonstrated non-inferiority of sunitinib compared to the cn followed by targeted therapy arm in patients with mrcc. however, around 15% of the trial participants deviated from their treatment assignment, which could have contributed to the non-inferiority result of this trial. also, the trial stratified patients based on their mskcc prognostic indicators which has lower prognostic value in the targeted therapy era compared to international metastatic renal cell carcinoma database consortium (imdc) prognostic indicators. moreover, there was slight imbalance in the t stage between both groups and exclusion of patients with low tumor burden which limits extrapolation of the trial results to this subgroup.(5) the surtime trial, a parallel randomized control trial that compared deferred cn after sunitinib to immediate cn. the trial did not show any difference in the progression free rate (pfr) between the groups who received an upfront cn urology journal/vol 19 no. 2/ march-april 2022/ pp. 111-119. [doi: 10.22037/uj.v18i.6593] followed by sunitinib compared to the one who deferred cn after sunitinib, but there was a statistically os advantage in the deferred cn arm.(6) the trial concluded that deferral of cn would help in identifying subjects with resistance to targeted therapy who are unlikely to benefit from cn. nonetheless, the trial was limited by poor accrual rate; imbalance between the two arms in the proportion of subjects with three or more poor surgical risk factors and locally advanced disease; and early trial termination which could have biased the result estimate away from the null. in another study using the imdc, data from 1658 subjects with mrcc were retrospectively analyzed. the trial demonstrated 40% reduction in the hazard of death in mrcc patients who cn (partial or total nephrectomy) (median, iqr, proportions) no surgery) (median, iqr, proportions) n 2991 (55%) 2492 (45%) median age (95% ci) 60 (20-85) years 64 (18-85) years gender male 2115 (71%) 1753 (70%) female 876 (29%) 739 (30%) number of metastatic sites 0 199 (8%) 549 (18%) 1 1172 (47%) 1872 (62%) 2 785 (32%) 505 (17%) 3 282 (11%) 88 (3%) 4 38 (2%) 7 (0.2%) given chemotherapy yes 1596 (53%) 1477 (59%) no 1395 (47%) 1015(41%) histology clear cell 2436 (81%) 1909 (77%) non-clear cell 555 (19%) 583 (23%) grade grade i / ii 528 (18%) 312 (13%) grade iii / iv 2099 (70%) 378 (15%) unknown 364 (13%) 1802 (72%) t stage t0 0 (0%) 33 (1%) t1/2 658 (22%) 869 (33%) t3 1518 (50%) 432 (17%) t4 282 (10%) 300(12%) tx 20 (1%) 483 (12%) unknown 513 (17%) 408 (16%) nodal positivity yes 631 (21%) 692 (28%) no 1758 (59%) 1075 (43%) unknown 602 (20%) 725 (29%) table 1. baseline characteristics for patients according to their cytoreductive nephrectomy (cn) status figure 1. weighted kaplan meier curves for the group who had cn and for those who didn’t. cytoreductive nephrectomy in metastatic rcc-alnimer et al. urological oncology 112 vol 19 no 2 march-april 2022 113 underwent cn after adjustment for prognostic covariates including imdc predictors. in this study, patients with estimated overall survival (os) of less than 12 months and those with four or more imdc prognostic indicators didn’t not benefit from cn.(7) on the other hand, cn was associated with improvement in os across all ranges of follow up in another retrospective study.(8) the latter study included subjects before the era of targeted therapy which limits drawing a firm causal conclusion of the effect of cn on survival after the era of targeted therapy. due to the controversy in the literature regarding the role of cn, we identified patients with de novo mrcc using the seer database after the approval of the targeted therapy. we studied the association between cn and os in these patients. also, we identified certain subgroups of patients who could benefit most from the cn. since cn was demonstrated to have survival benefit in mrcc patients in 2009(9), we have included the seer data between 2010-2016 to avoid any bias due to secular trend. materials and methods study population we used the seer database to identify subjects who were diagnosed with mrcc (tnm stage = m1) as their first malignancy from 2010 to 2016. the seer case listing session was used for analysis. information was extracted from the database named “"incidence seer 18 regs custom data (with additional treatment covariates that were strong predictors of treatment assignment. reference category estimate (or) 95% ci p_value age (years) 40-60 <40 1.28 0.55-2.78 0.55 > 60 0.69 0.30-1.49 0.37 sex = male female 1.09 0.84-1.41 0.50 race white black 1.14 0.74-1.72 0.54 other 1.40 0.79-2.55 0.27 t stage t2 0.75 0.53-1.08 0.12 t3 t1 3.03 2.13-4.31 < 0.001 t4 0.69 0.46-1.04 0.07 nodal status positive n0 0.36 0.28-0.48 < 0.001 grade grade ii 4.00 2.21-7.44 < 0.001 grade iii grade i 8.50 4.70-15.80 < 0.001 grade iv 25.4 13.39-49.55 < 0.001 histology = non-clear cell clear cell 0.80 0.58-1.11 0.17 number of metastatic sites no liver, bone, lung or 0.43 0.37-0.50 < 0.001 brain metastasis received chemotherapy no chemotherapy 0.62 0.48-0.80 < 0.001 table 2. results of the logistic regression comparing the variables that are associated with having cn. the following variables were included in the model to identify the variables that are strong confounders and are strongly associated with the exposure (probability of having cn): age; sex; race; t stage; nodal status; grade; histology; number of metastatic sites; and chemotherapy administration. figure 2. weighted kaplan meier curves for histological subtypes. cytoreductive nephrectomy in metastatic rcc-alnimer et al. urological oncology 114 fields), nov 2018 sub (1975-2016 varying)-database id: 30305". a total of 5,488 patients were identified as having microscopic confirmation of their metastatic disease. inclusion and exclusion criteria four patients with age of 18 years or less and one patient with missing patient identification number were excluded from the study population. therefore, a total variables a) regular model b) t stage interaction (aic 36198) c) number of metastatic sites (aic 36192) interaction (aic 36194) covariates that were reference estimate 95% ci p value estimate 95% ci p value estimate 95% ci p value strong predictors of category (hr) (hr) (hr) treatment assignment. age (years) 40-60 <40 1.24 0.84-1.84 0.29 1.24 0.83-1.85 0.28 1.26 0.85-1.89 0.25 >60 1.33 0.90-1.98 0.16 1.33 0.90-1.98 0.15 1.36 0.92-2.01 0.13 sex = male female 0.87 0.73-1.03 0.11 0.88 0.74-1.04 0.14 0.87 0.74-1.03 0.10 race white black 1.16 0.86-1.57 0.32 1.16 0.86-1.57 0.33 1.19 0.88-1.60 0.26 other 0.91 0.61-1.36 0.66 0.93 0.64-1.36 0.71 0.94 0.64-1.39 0.76 t stage t2 t1 0.97 0.76-1.25 0.82 0.82 0.55-1.22 0.34 0.96 0.74-1.23 0.72 t3 1.26 1.00-1.57 0.04 1.08 0.73-1.60 0.69 1.23 0.99-1.54 0.06 t4 1.51 1.14-2.00 0.004 1.17 0.73-1.87 0.51 1.49 1.12-1.98 0.005 nodal status positive n0 1.47 1.23-1.76 < 0.001 1.47 1.24-1.75 < 0.001 1.51 1.26-1.81 < 0.001 grade grade ii grade i 1.61 1.02 -2.54 0.042 1.63 1.03-2.56 0.04 1.56 0.99-2.44 0.05 grade iii 2.06 1.30-3.27 0.002 2.06 1.30-3.28 0.002 2.02 1.29-3.17 0.002 grade iv 2.58 1.62-4.11 < 0.001 2.57 1.61-4.11 < 0.001 2.54 1.61-4.00 < 0.001 histology = non-clear cell clear cell 1.92 1.54-2.39 < 0.001 1.94 1.57-2.42 < 0.001 1.94 1.57-2.39 < 0.001 number of metastatic sites to no liver, 1.62 1.45-1.80 < 0.001 1.62 1.46-1.80 < 0.001 1.79 1.48-2.16 < 0.001 bone, liver, lung or brain. bone, lung or brain metastasis underwent cytoreductive no cn 0.33 0.28-0.40 < 0.001 0.24 0.17-0.33 < 0.001 0.42 0.30-0.59 < 0.001 nephrectomy (cn) interaction term cn: t stage cn: t2 cn: t1 1.49 0.93-2.38 0.09 cn: t3 1.41 0.91-2.19 0.12 cn: t4 1.78 1.06-2.99 0.03 interaction term cn: 0.82 0.67-1.00 0.048 number of metastatic sites table 3. results of the weighted cox regression evaluating the effects of the following covariates on overall survival (os): age, sex, race, t stage, nodal status, grade, histological types, number of metastatic sites to bone, liver, lung and brain and cytoreductive nephrectomy. we adjusted for the chemotherapy variable in all models through stratification since the relationship between this variable and survival violates the proportional hazard assumption. a) regular model. b) second model with interaction with t stage. c) third model with interaction with number of metastatic sites. figure 3. weighted kaplan meier curves for the groups who had n0 disease and those who had n1 disease. cytoreductive nephrectomy in metastatic rcc-alnimer et al. vol 19 no 2 march-april 2022 115 of 5483 patients comprised the study population and were included in our analysis. methods the main purpose of our study is to identify the effect of cn on os on patients with mrcc. the following covariates of interest that should consider strong confounders for the effect of cn on os were extracted from the database: age at diagnosis, gender, tnm stage according the 7th american joint committee of cancer (ajcc) edition, nodal status, sites of metastasis (bone, liver, brain, and lung), tumor size, grade, histology, duration of follow-up, date of death or loss to follow up, status of chemotherapy, and type of surgical resection. in order to study the causal effect of cn on os, we matched subjects who had partial or total nephrectomy with those who didn’t using the weights that were created using the generalized boosted model (gbm). this method can achieve a good balance on the covariates of interest even in the absence of significant overlap in the propensity scores between the groups. we used the average treatment effect on the treated (att) estimates to study the potential outcome of patients who had cn figure 5. weighted kaplan meier curve for the groups with different number of metastatic sites. figure 4. weighted kaplan meier curves for the t-stage categories. cytoreductive nephrectomy in metastatic rcc-alnimer et al. urological oncology 116 if they did not have surgery. we matched patients who had cn with those who didn’t on the following covariates that we considered as a strong and intermediate confounder: age, gender, nodal status (n0, n1), chemotherapy status, t-stage (t1, t2, t3, t4), grade (well differentiated, moderately differentiated, poorly differentiated, undifferentiated), number of organs involved by metastasis(1,2,3,4), race (white, black, others) and histology (clear cell, non-clear cell). we categorized the age into three groups (less than 40, 40-60, more than 60), and chemotherapy was dichotomized as defined in the seer database into (yes, no or unknown). we created a variable that we named “number of metastatic sites”. this indicates the number of organs (brain, bone, liver, and lung) involved by metastasis. we used the twang package in r to balance these covariates by creating weights using the gbm. we didn’t use the tumor size as a covariate in our matching process since we considered the t-stage. stage and grade with values of x in the seer database were considered na in our dataset. nine patients with extreme weights were excluded from the final data analysis. supp. figure 1 (supplementary material) shows the propensity score distribution between patients who had cn and those who did not. supp. figure 2 (supplementary material) shows a significant decrease in the standardized mean difference (smd) in the pretreatment covariates between the group who had cn and those who did no’t. kaplan meier (km) curves for cn pretreatment covariates were created while considering the weights generated by the gbm. results of weighted km curves with log-rank test statistic are shown in figures. 1 to 6 (figures are reported only for the covariates that were significant predictor for survival in the cox-regression models). finally, we ran different models using the “svycoxph” command in r to account for the weights that were generated. all models included cn as an outcome and the following covariates: age, number of metastatic sites, t stage, nodal status, grade, gender, race, histology, and chemotherapy status. furthermore, different models were considered with an interaction term between cn and grade, cn and nodal status, cn and the number of metastatic sites, cn and the histological types and cn and t stage in addition to a model without any interaction term. because the km curves for the chemotherapy variable crossed each other, chemotherapy variable was stratified in cox regression analysis using strata analysis and therefore we did not generate a hazard estimate for this variable. models were compared using akaika information criteria (aic). running cox-regression with weights under survey command precluded performing likelihood ratio test on nested models. finally, we performed sensitivity analysis to assess our result sensitivity to an unobserved confounder. we relied on rosenbaum approach to evaluate the strength of the association of an unobserved confounder (u) to our exposure of interest (cn nephrectomy) and to our outcome (os) to change our results to non-significance. because this approach relies on 1:1 matching, we created a matched dataset between subjects who had cn and those who didn’t using the matchit package in r on the same covariates used in our primary analysis. we used a nearest matching method on propensity score with a caliper of 0.2 to achieve a good balance on the pretreatment covariates. in this analysis, 977 patients who had cn were matched to 977 patients who didn’t have cn (36% of the total cohort). sensitivity analysis was ran using rosenbaum spread sheet on survival outcome via wilcoxon rank test. results between 2010 and 2016, 5483 patients with mrcc were identified using the seer registry. the patients’ median age was 62 years old (range 18-85). the mafigure 6. weighted kaplan meier curves for the four levels of the tumor grade. cytoreductive nephrectomy in metastatic rcc-alnimer et al. vol 19 no 2 march-april 2022 117 jority were males (70%) and 4345 (79%) had cc histology while the rest had nonnuclear cell (ncc). ncc included patients with chromophobe, papillary, collecting duct, medullary, oxyphilic, squamous, transitional and sarcomatoid rcc. there was a total of 2996 (54%) patients who underwent partial or radical nephrectomy. baseline characteristics of the patients are summarized in table 1. after a median follow-up time of 9 months (3-83 months), the median overall survival (os) was 13 months. the median survival time for the cohort who had cn was 24 months (ci, 22-25) and 6 months (ci, 6-7) for patients who did not have surgery (p < 0.01, figure 2). grades iii and iv, n1 disease, higher number of metastatic sites, female gender, and non-clear cell histological types were associated with higher risk of death, while cn was associated with improvement in survival in weighted adjusted km curves using logrank test statistics. also, there was a statistically significant increase in the trend of using chemotherapy from 2000 to 2016 with a p value of 0.038 for the trend. on the other hand, there is a trend toward lower numbers of cn from 2010 to 2016 with a p value for a trend of 0.047 (supplementary material, supp. table 1). all potential confounder variables were included in a logistic regression model to identify variables that strongly predict treatment assignment (cn). patients with t3 stage, grade ii-iv, lower number of organ involvement with metastasis and those who didn’t receive chemotherapy were more likely to have cn. results of the logistic regression model are shown in table 2. all pretreatment covariates that were used in weighted matching between subjects who had cn and those who didn’t were included in the cox models to obtain a doubly robust estimate. all models with an interaction term have aic values slightly above the model without an interaction term, therefore, the latter model with an akika information criteria (aic) value of 36192 was considered the primary model for our results. in this model, cn was associated with 67% reduction in the risk of death in patients with mrcc (hr 0.33, 95% ci 0.28-0.40). non-clear cell histological subtype was independently associated with higher risk of death (hr 1.9, 95% ci 1.54-2.40). also, patients with nodal involvement and those with t4 disease had a statistically significant higher risk of death compared to those with n-0 and t0 disease (hr 1.50, 95% ci 1.23-1.75, and hr 1.5, 95% ci 1.14-2.0, respectively). moreover, for each one-point increase in the number of metastatic sites, there was a statistically significant increase in risk of death with a hr 1.60, 95%ci 1.45-1.80. finally, grades ii, iii and iv were independently associated with higher risk of death compared to grade i (hr 1.60, 95% ci 1.02-2.54; hr 2.1, 95% ci 1.3-3.3; and hr 2.58, 95% ci 1.62-4.11, respectively). results of doubly robust cox regression model are shown in table 3. only two models with an interaction term had a statistically significant p-value for the interaction. the test that included an interaction between tumor t stage and cn nephrectomy had a statistically significant interaction between cn and t-4 disease with a hr 1.78, 95% ci 1.10-2.99 (the aic for the model is 36198). this result indicates that patients with t4 stage who had cn had 78% higher risk of death compared to those with t1 disease who had cn. if there is no interaction under the multiplicative interaction model, we would expect the hr to be 0.28 (1.17; the hr for the t4 stage; multiplied by 0.24; the hr of cn). however, the current hazard of death for those who had cn and t4 disease is 0.5 (1.17; the hr for the t4 stage; multiplied by 0.24; the hr of cn, multiplied by 1.78; the hr for the interaction term). in other words, patients with t4 disease would benefit less from cn compared to those with t1 disease. similarly, the model that included an interaction term between surgery and number of metastatic sites showed a statistically significant estimate with a hr=0.82 (95% ci 0.67-0.997) indicating that patients with increased number of metastatic sites to bone, liver, lung or brain had 18% lower risk of death compared to those with no metastasis to bone, liver, lung or brain (the aic for this model is 36194)). under the assumption of no interaction and using the multiplicative interaction model between cn and number of metastatic sites, the hr of death for patients with higher metastatic sites who had cn should equal 0.75 (the hr for cn [0.42] multiplied by the hr for the increasing metastatic sites [1.79] under this model). however, when we multiply the estimates for patients who had cn (0.42) with the hr for the increased metastatic sites (1.79) and with the interaction term (0.82); the hr is 0.62. these results indicate that patients with increased metastatic sites would benefit more from cn compared to those with lower number of organ involvement. results of doubly robust cox regression model with interaction terms are shown in table 3. our sensitivity analysis showed an unobserved confounder (u) that increase the odds of having cn by 42% and being a near perfect predictor of os, would change our results toward the null. this u is plausible, since kps which is not included in our model, could have such an association and it implies that our results could be sensitive to bias. however, this sensitivity analysis should be interpreted with caution since only 36% of the total cohort (1954 patients) were included in this analysis. the results of our sensitivity analysis are demonstrated in the supplementary material (supp. table 2). discussion the two large prospective randomized trials that evaluated the role of cn in mrcc after the era of targeted have some limitations, mainly poor accrual, early trial termination and unbalanced randomization in regards to surgical risk factors and locally advanced disease in the surtime trial and deviation from the treatment assignment and inclusion of high risk patients for the carmena trial(méjean et al., 2018).(5) this highlights the importance of non-experimental study designs in evaluating the role of cn in mrcc patients. our data suggests a strong association between cn on os. the median os for the subjects who had cn was 24 months (ci, 22-25) compared to 6 months (ci, 6-7) for those who did not have cn with a hr of 0.33 (95%ci 0.28-0.40) in the doubly robust model in favor of cn. this is highly similar to an unadjusted weighted estimate (hr 0.38, 95%ci 0.33-0.44), indicating a great balance in all pretreatment covariates using an inverse probability weights on the treatment assigned (iptw). our results go in hand with the results from international metastatic rcc consortium (imrcc). in this study, subjects who had cn had an os of 20.6 months compared to 9.5 months for those without cn.(7) similarly, cytoreductive nephrectomy in metastatic rcc-alnimer et al. urological oncology 118 vaishampayan et al and pulmbo et al found that cn is associated with survival advantage in patients with locally advanced or mrcc using the seer database.(10,11) however, our study has a larger sample size with 2991 patients who underwent cn compared to 2483 patients who didn’t. also, we applied a doubly robust method with inverse probability weighting and adjustment in regression analysis. this enabled us to effectively adjust for the study confounders without excluding subjects from the cn group. this is important, because our inference measures the effect of cn on the whole subjects who had cn if they did not have surgery. furthermore, we conducted a sensitivity analysis to evaluate the strength of our association and the efficacy of cn on certain subgroups. in the surtime trial, patients with deferred cn had an os advantage compared to those with immediate cn. however, the trial result should be interpreted with caution due to early termination which could have biased the study estimate away from the null. also, higher number of subjects with surgical risk factors and t4 disease were assigned to immediate cn arm. the latter would support our result with a negative quantitative interaction between patients with t4 disease and cn and suggests that deferred cn could be the appropriate approach for patients with advanced t stage. we measured the average treatment effect on the treated (att) in our analysis. therefore, our results reflect the efficacy of cn on those who had cn if they did not have it. in our logistic regression model, subjects who didn’t receive chemotherapy by the time of cn, those with lower number of metastatic sites, and don’t have t4 disease were more likely to have cn and thus will have significant survival benefit from it. this supports the current practice, in which many centers perform cn for patients only with intermediateor low-risk groups. these can be defined as the presence of four of less of the following risk factors: sarcomatoid features, low serum albumin, t3 or t4 disease, retroperitoneal or supradiaphragmatic lymphadenopathy and symptoms from metastatic sites such as bone and brain.(12) other criteria could be used such as karnofsky index (kps) more than 80%, adequate organ function, ability to perform at least 75% tumor debulking and absence of extensive bone, liver and central nervous system metastasis.(13) furthermore, data from imrcc database revealed that patients who have four or more mskcc risk factors (less than 1 year of diagnosis, kps < 80%, serum lactate dehydrogenase >1.5, elevated serum calcium and low hemoglobin level) are unlikely to benefit from cn.(7) our analysis shows that higher number of metastatic sites, advanced tumor grade and t stage and non-clear histology are independent risk factors for higher mortality. although higher number of metastatic sites are associated with 60% higher hazard of death in our analysis, cn offers survival benefit among those subjects more than what would be expected taking into consideration their multiple organ metastases. this support providing cn to patients with more than one metastatic site if they are in good performance status and considered good surgical candidates. it is important to note here that there is a notable discrepancy between non-experimental studies that showed a significant survival benefit of cn in mrcc patients(7,10) and the randomized clinical trials (carmena and surtime clinical trials).(5,6) as noted earlier, in the surtime trial, quarter of the subjects who had immediate cn had three or more surgical risk factors. os in those subjects could be negatively affected by immediate cn. about half the subjects in the carmena trial had fallen into a poor risk category in the mskcc model. this could explain the discrepancy between these randomized trials and other non-experimental studies. this highlights the potential benefit of cn in low risk mrcc patients, and the need for a randomized control trial that is enriched with mrcc patients who have low risk features. moreover, there is lack of enough data on the appropriate timing of cn relative to targeted therapy. further research on this area could identify the appropriate timing for cn that improves os. since we were unable to capture all the confounding covariates using the seer database, we used the rosenbaum approach to test the strength of the association between cn and survival. because this method and many other sensitivity analysis approaches rely on 1:1 matching, we performed a 1:1 matching analysis. in our sensitivity analysis, our gamma value was 1.421, which indicates an unobserved confounder that has at least 42% odds of association with cn and near prefect predictor of survival would change our estimate on cn toward the null. usually, a gamma value of 4 or 5 will reflect a strong unbiased association. this indicates that our result is susceptible to bias and highlights the importance of conducting a randomized control trial with strict eligibility criteria to evaluate the effectiveness of cn after the introduction of targeted therapy. our study has some limitations. our analysis relies on an un-confounded assumption. however, given the limitations of the seer database, some important covariates were not included in our model such as kps, comorbidities and covariates pertaining to the mskcc risk model. this made our study susceptible to selection bias, namely confounding by indication. however, we used weights-based method to create a balanced dataset on all pretreatment variables that are strongly related to mrcc and to os. our new pseudo-dataset was well balanced on all pretreatment variables. also, we matched subjects on the distribution of chemotherapy variable. because patients with good performance status are more likely to receive chemotherapy, our analysis likely accounted for some confounding due to kps. metastatic disease was included as categorical variable for each site of metastasis (present or not) in the seer database with no detailed information pertaining to the tumor burden. this could have resulted in residual confounding that could have affected our study estimates. also, no information regarding the extent of nodal involvement in the seer database which precludes evaluating the effect of cn in patients with extensive lymphadenopathy. dalong cao et al. have used the seer database to evaluate the role of lymphadenectomy along with cn on survival using the seer database from 2006-2015.(14) in addition, vaishampayan et al. used the seer database from 2000-2013 to evaluate the effect of cn on survival.(10) we included data only from 2010-2017 only to avoid the secular trend that have been observed since the introduction of targeted therapies in 2009. many patients, particularly those without cn have missing values on tumor grade. this could possibly bias our results if these missing values were not missing at random (non-missingness). nonetheless, we matched cytoreductive nephrectomy in metastatic rcc-alnimer et al. vol 19 no 2 march-april 2022 100 both treatment groups on missing values which will decrease the bias. conclusions cn could provide a survival advantage to selected patients with mrcc, regardless of histology. the risks and benefits of surgery should be discussed thoroughly and offered to patients on a case-by-case basis. randomized trials with restricted inclusion criteria to lowrisk patients is needed to fully disentangle the causal effect of cn on survival, especially with the new era of widespread use of immune checkpoint inhibitors in patients with mrcc. acknowledgement we would like to thank russell-simmons from the research communication office for her final editing and comments that greatly helped in improving the final manuscript. conflict of interest the authors confirm that there is no conflict of interest regarding the publication of this paper. appendix https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryfiles/downloadpublic/37 references 1. thoenes w, störkel s, rumpelt hj. histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). the basic cytological and histopathological elements and their use for diagnostics. pathol res pract. 1986;181:12543. 2. mickisch gh, garin a, van poppel h, de prijck l, sylvester r, group eofratoceg. radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. lancet. 2001;358:966-70. 3. flanigan rc, salmon se, blumenstein ba, et al. nephrectomy followed by interferon alfa2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. n engl j med. 2001;345:1655-9. 4. graham j, bhindi b, heng dyc. the evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma. curr opin urol. 2019;29:507-12. 5. méjean a, ravaud a, thezenas s, et al. sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. n engl j med. 2018;379:417-27. 6. bex a, mulders p, jewett m, et al. comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the surtime randomized clinical trial. jama oncol. 2019;5:164-70. 7. heng dy, wells jc, rini bi, et al. cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the international metastatic renal cell carcinoma database cytoreductive nephrectomy in metastatic rcc-alnimer et al. consortium. eur urol. 2014;66:704-10. 8. hanna n, sun m, meyer cp, et al. survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a national cancer data base study. j clin oncol. 2016;34:3267-75. 9. motzer rj, hutson te, tomczak p, et al. overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. j clin oncol. 2009;27:3584-90. 10. vaishampayan u, george j, vigneau f. predictors of cytoreductive nephrectomy for metastatic kidney cancer in seer and metropolitan detroit databases. j kidney cancer vhl. 2019;6:13-25. 11. palumbo c, mistretta fa, knipper s, et al. contemporary cytoreductive nephrectomy provides survival benefit in clear-cell metastatic renal cell carcinoma. clin genitourin cancer. 2020;18:e730-e8. 12. motzer rj, russo p. cytoreductive nephrectomy patient selection is key. n engl j med. 2018;379:481-2. 13. fallick ml, mcdermott df, larock d, long jp, atkins mb. nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma. j urol. 1997;158:1691-5. 14. cao d, huang y, zhang c, et al. adverse effect of lymph node dissection in metastatic renal cell cancer patients treated with cytoreductive nephrectomy: a contemporary analysis of survival. j cancer. 2019;10:463946. vol 19 no 2 march-april 2022 119 clinical pathology case 128 urology journal vol 7 no 2 spring 2010 answer to clinical pathology case of winter 2010 there was residual tumor recurrence in the right pelvic fossa. patient underwent pelvic exploration and some sites of metastasis that were probably due to spillage in previous surgery were removed. alfa-fetoprotein and bhcg were normal 4 years post operation. urol j. 2010;7:128. www.uj.unrc.ir case report 55urology journal vol 5 no 1 winter 2008 priapism in a 15-year-old boy with major betathalassemia seyed amir mohsen ziaee, ahmad javaherforooshzadeh keywords: beta-thalassemia, priapism, adolescents department of urology, shaheed labbafinejad medical center, shaheed beheshti university of medical sciences, tehran, iran corresponding author: seyed amir mohsen ziaee, md department of urology, shaheed labbafinejad medical center, 9th boustan, pasdaran ave, tehran, iran tel: +98 21 2256 7222 fax: +98 212256 7282 e-mail: ziaee@hotmail.com received may 2007 accepted september 2007 introduction priapism (painful erection longer than 6 hours) is an uncommon disease that is almost always due to thromboembolic problems. it may occur at any age. the predisposing factors for priapism include thromboembolic disorders such as sickle cell anemia (sca, the most common cause), sicklebeta-thalassemia, diseases of the central nervous system and the spinal cord, metastatic cancers, trauma, iatrogenic factors, and infectious diseases (malaria and rabies).(1) we present an adolescent patient with major beta-thalassemia who suffered from an episode of priapism. to our knowledge, no other cases of priapism have been reported in association with major beta-thalassemia, to date. case report a 15-year-old boy presented with priapism lasted for 7 hours. the patient was admitted and conservative treatment including oxygenation, hydration, analgesics, and epinephrine injection (3 times with 20to 25-minute intervals) was initiated. after 10 hours, priapism was alleviated. at the time of reference, vital signs were as follows: body temperature, 37.2˚c; blood pressure, 100/70 mm hg; and pulse rate, 84/min. the patient was a known case of major beta-thalassemia, but he did not have any other special conditions including cardiac, pulmonary, or infectious diseases. no history of trauma was mentioned by the patient. splenectomy had been performed 8 years earlier and blood transfusion had been performed for several years until 5 years earlier. results of the laboratory tests were as follows: hemoglobin (hb), 10 g/dl; hematocrit, 31.5%; white blood cell count, 15.4 × 109/l; platelet count, 156.7 × 109/l; nucleated red blood cell count, 28 per 100 leukocytes; erythrocyte sedimentation rate, 14 mm/h; and serum ferritin, 696 ng/ml (reference range, 38 ng/ml to 457 ng/ml). on the blood smear, howell-jolly bodies, target cells, giant platelets, and hypochromia were present. direct coombs’ test and viral hepatitis tests including hepatitis b antigen and hepatitis c antibody were negative in the serum sample; however, serum was positive for hepatitis b surface antigen. on electrophoresis, the hba was 34.8% (reference range, 96.5% to 98.5%); hba2, 2.6% (reference range, 1.5% to 3.2%); hbf, 62.6% (reference range < 2%); and hbs, 0%. also, sickle cells were not detected in the smear. blood gas analysis of a sample taken from the corpus cavernosum demonstrated that priapism was urol j. 2008;5:55-6. www.uj.unrc.ir priapism in major beta-thalassemia—ziaee and javaherforooshzadeh 56 urology journal vol 5 no 1 winter 2008 low flow (venous type). other laboratory tests including serum electrolytes, coagulation tests, and liver, kidney, and thyroid function tests had normal results. after 24 hours, the patient was discharged in a good general condition. during a 2-year follow-up, no recurrence was reported. discussion we presented a case of priapism in an adolescent with major beta-thalassemia. regarding the lack of any other underlying disease or a history of trauma, it seems that in this particular patient, there was a causal link between priapism and major beta-thalassemia. to our knowledge, this is the first case of priapism with major betathalassemia as the only risk factor. in a study in italy, priapism was reported in a patient with intermediate thalassemia.(2) also, in 52 patients with priapism, fowler and colleagues showed that 20, 10, 19, and 3 patients had sca, sickle-c anemia, sickle trait, and sickle-beta-thalassemia, respectively. but, none of them had a major betathalassemia.(3) in children, the etiology of priapism is sca in 63% of cases and 6.4% of patients with sca experience priapism.(1) in sca-induced priapism, the disease is recurrent and gradually results in ischemia of the corpus cavernosum, venous obstruction, and impotence which is more common in adults.(1,4) therefore, although the disease is mostly prevalent in adolescents, the possibility of impotency is less than the adults.(4) most of the priapism episodes occur between 2 am to 6 am during the day. it usually occurs following dehydration and metabolic acidosis during the sleep.(1) the mechanism of priapism in sca is an increment in the blood concentration and changes in the form of hemoglobin. in betathalassemia, the mechanism might be related to hyperviscosity like other hemoglobinopathies.(4) the 2 types of the disease are venous, which is more common, and arterial.(4) we successfully treated our patient conservatively with oxygenation, hydration, analgesics, and epinephrine injection. the first therapeutic step is conservative treatment that has been efficient in many patients with hematologic diseases, and the vast majority of children will improve by medical treatment without the need for surgery. if resistant to the routine treatment modalities, priapism should be treated by surgical operation and spongicavernous shunt insertion.(1,5) conservative treatment in the first stage includes hydration, oxygenation, and metabolic alkalization (for reduction of sickling in sca). in the second stage, the treatment includes supertransfusion, erythrophoresis, irrigation, and injection of alpha-agonist drugs into the corpus cavernosum every 5 minutes after aspiration of 10 ml to 20 ml of blood.(6) conflict of interest none declared. references 1. lue tf. physiology of penile erection and pathophysiology of erectile dysfunction and priapism. in: walsh pc, retik ab, vaughan ed jr, et al, editors. campbell’s urology. 8th ed. philadelphia: wb saunders; 2002. p. 1610-2. 2. dore f, bonfigli s, pardini s, pirozzi f, longinotti m. priapism in thalassemia intermedia. haematologica. 1991;76:523. 3. fowler je jr, koshy m, strub m, chinn sk. priapism associated with the sickle cell hemoglobinopathies: prevalence, natural history and sequelae. j urol. 1991;145:65-8. 4. quirolo k, vichinsky e. hemoglobin disorders. in: behrman re, kliegmen rm, jenson hb, editors. nelson textbook of pediatrics. 17th ed. orlando, fl: wb saunders; 2004. p. 1624-9. 5. mantadakis e, cavender jd, rogers zr, ewalt dh, buchanan gr. prevalence of priapism in children and adolescents with sickle cell anemia. j pediatr hematol oncol. 1999;21:518-22. 6. adeyoju ab, olujohungbe ab, morris j, et al. priapism in sickle-cell disease; incidence, risk factors and complications – an international multicentre study. bju int. 2002;90:898-902. special feature 15urology journal vol 5 no 1 winter 2008 radiation safety issues in fluoroscopy during percutaneous nephrolithotomy pratik kumar introduction: fluoroscopy-guided intervention during percutaneous nephrolithotomy (pcnl) has become the order of the day. during this procedure, both the patient and the physician are exposed to some radiation. measurement of radiation doses in patients and personnel are important. patient radiation doses are used for comparison with other centers for achieving the best possible radiation practice. in addition, there are performance checks for the fluoroscopy machines so that x-ray emitting machines should work at the optimum level ie, producing good images at minimum possible radiation doses. materials and methods: this is a review of literature and discussion on radiation dose to patients and personnel, and on basic radiation safety tenets and their application in urological interventions of pcnl procedure. results: radiation doses during pcnl have gone down over the time due to advances in technology. however, as radiation is hazardous, there is no room for complacency. a hospital’s medical physicist may ensure even further reduction of x-ray dose by carrying out regular dosimetry and quality assurance tests on the fluoroscopy machines. a survey meter may provide an easy and quicker but not-so-accurate method for occupation exposure determination. conclusion: the practice of pcnl procedures seems to be quite safe with radiation point of view. the quick, easy, and economical method of estimation of radiation dose using survey meter may need further calibration with the standard thermoluminescence dosimetry method. setting optimum x-ray parameters, incorporation of filters, and quality assurance tests are a few areas where medical physicists may help in further reduction of radiation doses. keywords: radiation dose, percutaneous nephrolithotomy, fluoroscopy, thermoluminescent dosimetry medical physics unit, institute rotary cancer hospital, all india institute of medical sciences, new delhi, india corresponding author: pratik kumar, phd medical physics unit, institute rotary cancer hospital, all india institute of medical sciences, new delhi, india tel: +91 11 2659 4448 fax: +91 11 2658 8641 e-mail: drpratikkumar@gmail.com received september 2007 accepted january 2008 introduction fluoroscopic imaging during minimally invasive urological procedures has become an integrated part of the practice. fluoroscopy in endourology is used for guidance, image formation, verification of catheter placement, and localization of kidney calculi in extracorporeal shockwave lithotripsy (swl). percutaneous nephrolithotomy (pcnl) is a modality for treating large kidney calculi (2 cm in diameter or larger) for which swl has failed. during pcnl, fluoroscopy is used for calculus localization and also for making tract to the calculus. these procedures are generally carried out by urologists or by a team of radiologists and urologists. the longer use of fluoroscopy may urol j. 2008;5:15-23. www.uj.unrc.ir radiation safety during percutaneous nephrolithotomy—kumar 16 urology journal vol 5 no 1 winter 2008 entail higher x-ray radiation dose to the patient and the staff. this places an extra responsibility upon the urological staff performing fluoroscopic intervention to assess the radiation safety status in pcnl procedures. x-ray radiation which is used during the fluoroscopy to visualize inside the body is called ionizing radiation as it may ionize the interacting medium (here the human body) by knocking off an electron from the atom and thereby causing tissue damage. radiation is a form of energy and ionizing properties of x-ray photons is solely due to their energy. other nonionizing forms of radiation of the same family (called electromagnetic radiation) are microwave, radiofrequency, and light. a certain amount of unavoidable ionizing radiation exposure to all inhabitants of this earth comes all the time from cosmic rays and the radioactive substances in the earth crust and building material. this is called “background radiation.” although the amount of this background radiation varies from place to place, the average value of annual whole body radiation exposure due to background is estimated to be 1 msv to 2 msv.(1) many a medical exposures are much less than this kind of radiation. the risk of radiation at low dose is still debatable. the majority of the estimates of the risk at low doses have been derived from the risks at high doses (like atom bomb survivors in japan) by extrapolating it linearly to lower doses. presently, it is considered prudent to follow linear extrapolation risk estimate for low-level radiation although that may be an overestimation of the radiation risk. the aim of this paper is to review the status of radiation doses during pcnl procedures and also to sensitize urologists and other staff about the radiation risk they are involved, ways to reduce radiation dose, and the significance of the routine quality-assurance tests of the fluoroscopy machines. an extensive literature survey was carried out to know the status of radiation dose to the patient and the staff during pcnl. the author has already carried out the dosimetry of radiation dose in pcnl,(2) the results of which are discussed in this paper. the paper also provides the basic concept of radiation and radiation protection for better understanding of the subject. percutaneous nephrolithotomy and radiation there could be variation in procedures among different hospitals. however, the final mean radiation dose to the patient and the urologist was taken as the benchmark parameter for the comparison. at our center, the whole procedure of pcnl is carried out by urologists with the active assistance of anesthesiologist as the patient remains anesthetized during cystoscopy, ureteral catheterization, and ultimately, calculus removal. the establishment of the tract and dilation is done under multidirectional fluoroscopy equipped with a monitor. the urologist wears a 0.5-mm lead equivalent apron and thyroid collar as a radiation protection measure, while others assisting in the procedure wear only a lead apron. the x-ray machines are generally c-arm fluoroscopes with an undercouch x-ray tube, an image intensifier tube over the patient, and a monitor in front of the urologist. however, overcouch x-ray tube versions are also available in the market. the machines may have an automatic brightness control mode. this mode controls the x-ray parameters (x-ray tube kilovolt potential and current) automatically in real time depending upon the thickness and x-ray attenuation properties of the body part. at some centers, urologists may use radioprotective gloves during the procedure. at our center, first of all, a retrograde ureteral catheter is placed in the renal pelvis/superior calyx of the anesthetized patient under fluoroscopic guidance. then, the patient is turned to the prone position and location of the calculus in the kidney is confirmed using an iodinated contrast medium and fluoroscopy. the urologist establishes the tract by puncturing the desired calyx and dilating the tract again under fluoroscopy. the calculus is fragmented by pneumatic lithotripsy and fragments are extracted with forceps. fluoroscopy is again used to survey for any left-over calculus. measurement of radiation dose to human body during medical exposure is called radiation dosimetry. dosimetry may be carried out to radiation safety during percutaneous nephrolithotomy—kumar urology journal vol 5 no 1 winter 2008 17 know the patient skin entry radiation dose and also the occupational radiation dose received by the urologists and the assistant physicians during pcnl. dosimetry methods thermoluminescent dosimetry one way to measure skin doses in patients or occupational workers is using thermoluminescent dosimeter (tld). when the tld material is exposed to radiation, it absorbs energy and stores it in the form of excited electrons in the crystalline lattice. after exposure, these tld chips are heated to a high temperature (of the order of 250°c) in a controlled manner. on heating, the excited electrons fall back to their normal orbital state with the emission of visible light. the intensity of the light is measured by a photomultiplier tube system and is proportional to the radiation dose received by the tld material. the tld-100 is lithium fluoride and this variety of tld is tissueequivalent for the radiation. therefore, the doses received by the tld-100 chips may be regarded as the doses received by the human skin. the tld requires a calibration process before it may be used in routine dosimetry. for calibration, the tld chips are exposed to the known doses and then heated/read in the tld reader. the corresponding light emitted by the tld chips is noted down in terms of signal intensity. the curve between the known radiation doses and the corresponding signal intensity is known as calibration curve. the calibration curve of the tld-100 chips for our already published study is shown in figure 1. unknown doses to the tld chips placed during this study were read from this calibration curve. these tld chips can be reused after annealing. annealing is a process of heating these used tld chips to a very high temperature for about 2 hours in order to remove all previously stored or residual radiation doses. the tld chips can be pasted to the fingers of the dominant hand of the urologist. whenever radioprotective gloves are used, the tld chips should be pasted on the fingers under the gloves, so that the radiation dose to fingers can be measured. the tld chips over the gloves provide the idea of doses to fingers in case gloves are not used. however, one should keep in mind that x-ray parameters (kilovolt potential and milliamperes times × time in seconds) may be slightly lower in case of bare hands than with radioprotective gloves due to x-ray attenuation if automatic brightness control is operational. dose-area product meter another means for arriving at the radiation dose to the patient during fluoroscopy is the dose-area product (dap) meter. the x-ray dose decreases as the distance from x-ray tube increases (inverse square with distance [d], ie, 1/d2). as x-ray diverges with distance, the x-ray field (x-ray area or x-ray beam size) increases. x-ray field size increases proportionally to the square of the distance from the x-ray tube. therefore, product of the dose and x-ray field size is independent of the distance from the tube, and it has a unit of cgy.cm2 or gy.m2 (ie, dose × area) (figure 2). this dap value can be measured by a plate ionization chamber fitted to x-ray collimators. some of new fluoroscopy machines have built-in dap meter. figure 1. calibration curve for measurement of radiation dose by thermoluminescent dosimeter. radiation safety during percutaneous nephrolithotomy—kumar 18 urology journal vol 5 no 1 winter 2008 survey meter still another way to have an inkling of radiation doses at different points in the room is using a portable dose-rate meter which is, again, a portable ionization chamber. this is called survey meter as it is used to survey the radiation area. it gives the radiation dose reading in terms of rate, ie, dose per hour (cgy/h). unlike dap meter which can measure only direct radiation falling on the patient, dose-rate meter can measure the scattered dose reaching to the personnel standing nearby. however, dose-rate meter’s reading is not considered as reliable as the tld or the dap meter for dosimetry purposes. film dosimetry the patient’s skin radiation dose may be determined using newer type of radiochromic films, as well. radiochromic films are nearly opaque, of bright yellow color, self-developing (needs no processor), and light insensitive (unlike other films, they can be used in light and hence handling is easy). these films may be placed on the couch and under the patient, so that the patient lies on the films. for an undercouch x-ray tube, the x-ray passes through the couch and radiochromic film and then reaches the patient’s skin. the radiochromic films develop dark grey shade (black area) upon x-ray exposure due to polymerization process. the degree of blackness (optical density) is an indicator of the amount of exposure, and it can be measured with a reflective densitometer or a scanner after carrying out the proper calibration. the radiochromic films are also tissue-equivalent for radiation, and this means that the radiation dose measured by these films is equivalent to the dose received by the skin. these films are available in a bigger size of 14 × 17 in, so that shift in the couch and/or x-ray tube during pcnl procedure can be covered in the film. unlike in the case of small tld chips of 2 × 2 mm, there is no danger of the x-ray beam falling outside the big films. dosimetry results table 1 shows the radiation doses to patients and personnel during pcnl reported in the studies dates published from 1984 to 2006.(2-12) most of the authors have used the tld to measure radiation dose which is a standard practice. we also carried out the dose measurement in pcnl which was published in 2006.(2) table 2 shows the details of doses we reported in this study. the mean pcnl procedure time was 75 minutes (range, 30 to 150 minutes), and the mean exposure to fluoroscopy x-ray was 6.04 minutes (range, 1.80 to 12.16 minutes) per pcnl at our center. we also used a hand-held radiation survey meter to map the spatial scattered radiation distribution pattern around the patients. it gave an indication of trunk radiation dose to different personnel standing around the patient undergoing pcnl. the dose depends upon the distance of the measurement point from the scatterer (ie, the patient’s body at the couch), angle of incident radiation to the patient’s body, and the angular position of the personnel relative to the angle of incident radiation to below the couch. the doses measured by survey meter at these points are given in table 2. these readings were based upon the mean radiation exposure time in 50 cases, and therefore, represent mean doses during pcnl cases. figure 2. concept of dose-area product (dap) measurement in fluoroscopy. position 1 is at distance d from x-ray tube. let the x-ray area be a, and dose, d, at position 1. position 2 is at 2d distance (double of position 1) from the x-ray tube. x-ray area at position 2 will be 4 times ie, 4a due to divergence of the beam, but the x-ray dose will reduce to one-fourth, ie, d/4 due to doubling of the distance. however, the dap will remain the same at position 1 and position 2. it shows that dap value is independent of the distance from the x-ray tube, and therefore, it can be measured any where in the x-ray beam. the dap meter can be fitted in the x-ray tube housing or collimator, as well. radiation safety during percutaneous nephrolithotomy—kumar urology journal vol 5 no 1 winter 2008 19 discussion effects of radiation biological effects of radiation exposure can be generally classified into stochastic and deterministic effects. deterministic effects have a threshold dose below which there is no effect, but above it, all exposed people would bear the effects. the severity of these effects increases with dose. formations of cataract after exposure to eye lens and skin erythema are such examples. consequently, certain sensitive organs have been given a limit of annual radiation dose for professional radiation worker. stochastic effects have no threshold dose and the relationship between dose and radiation effect is probabilistic. the probability of occurrence of the effect increases with dose. cancer induction and genetic effects in the next progeny are of stochastic effects. it is evident from the above definitions that smaller radiation doses which are generally encountered in many diagnostic procedures may not exceed the threshold dose for deterministic effects, but there exists a probability (although small) for stochastic effects. tld (msv) survey meter (μsv) subject position dose (range) position dose (range) patient skin (kidney level) 0.56 (0.2 to 1.6) … … urologist fingers 0.28 (0.02 to 0.6) trunk level 24.9 (7.4 to 50.2) residents fingers 0.36 (0.06 to 2.2) trunk level 12.0 (3.6 to 24.3) technical assistant … … 80 cm from patient 2.6 (0.8 to 5.3) anesthetist … … 152 cm from patient 1.7 (0.5 to 3.5) staff at gate … … 200 cm from patient 0.2 (0.04 to 0.3) table 2. radiation dose per percutaneous nephrolithotomy procedure in author’s previous study(2)* *tld indicates thermoluminescence dosimetry. ellipses indicate that the parameter was not measured or not applicable. occupational study author (year) patient skin dose personnel dosimeter position dose comments kumari et al (2006)(2) 0.59 msv urologist urologist anesthetist fingers trunk trunk 360 µsv 56 µsv 2.38 µsv tld dose rate meter dose rate meter hellawell et al (2005)(3) … urologist urologist urologist urologist lower leg feet eyes hands 11.6 µgy 6.4 µgy 1.9 µgy 2.7 µgy tld tld tld tld allen et al (2005)(4) 406 cgy/cm2 … … … dap meter hellawell et al (2002)(5) 4.5 msv … … … dap meter giblin et al (1996)(6) … urologist assistant anesthetist head and neck head and neck head and neck 11000 µsv/h 500 µsv/h 900 µsv/h dose rate meter dose rate meter dose rate meter bowsher et al (1992)(7) … urologist urologist fingers forehead 145 µsv 120 µsv tld tld page and walker (1992)(8) … urologist urologist urologist eye hands thyroid 320 µsv 520 µsv 270 µsv tld tld tld law et al (1989)(9) … urologist urologist index finger thyroid 340 µsv 34.6 µsv tld tld geterud et al (1988)(10) 250 mgy urologist urologist urologist anesthetist left hand thyroid … thyroid 630 µgy 130 µgy 16 µsv 25 µgy tld tld effective dose tld rao et al (1987)(11) 10.2 msv urologist fingers 5800 µsv tld bush et al (1984)(12) 250 msv urologist collar level 100 msv tld outside lead apron table 1. radiation dose to patient and personnel per percutaneous nephrolithotomy procedure in literature* *tld indicates thermoluminescence dosimetry and dap, dose-area product. ellipses indicate that the parameter was not measured or not applicable. radiation safety during percutaneous nephrolithotomy—kumar 20 urology journal vol 5 no 1 winter 2008 radiation quantity and units radiation exposure in air is measured in roentgen, and the symbol of which is “r.” the absorbed dose to an organ or skin is measured in terms of rad (radiation absorbed dose) that is equivalent to 100 erg of energy deposited in 1 g of material (tissue).(13) the international unit for rad is gray (gy); 1 gy equals 100 rad. some types of radiation such as alpha ray coming out from radioactive material are more ionizing than x-rays. radiation effects depend upon the ionizing properties of radiation as well. all ionizing waves have been given a weight called radiation weighting factor. taking this factor into account, the quantity of radiation is called equivalent dose which is the absorbed dose multiplied by radiation weighting factor. the unit for equivalent dose is sievert (sv). the x-ray has a radiation weighting factor of 1, and therefore, its absorbed dose (gy) is equal to equivalent dose (sv). on the other hand, organs of the body differ between themselves in terms of sensitivity to radiation; therefore, a tissue weighting factor is also used for comparing whole body radiation dose and organ doses. when sensitivity of the organ is also taken into account, the radiation quantity is called effective dose that is achieved by the multiplication of equivalent dose and tissue weighting factor. the unit for effective dose is also seivert. the international commission on radiation protection (icrp) recommends an effective dose of 20 msv per year over a defined period of 5 years on average as the occupational dose limit.(14) similarly, the icrp recommends the annual limit for equivalent dose in the lens of the eye at 150 msv, in the skin at 500 msv, and in the extremities at 500 msv for the staff. there is no dose limit for a patient undergoing radiation investigation or therapy provided the practice is justifiable on the basis of medical benefits outweighing the radiation risk. however, for both patients and staff, the radiation dose should be as low as reasonably achievable (alara). the alara principle indicates that near-zero radiation target may be unreasonable (in view of all pervading background radiation), prohibitively expensive and cumbersome, and may deny potential benefits to patients. therefore, a judicious and cautious approach for using radiation in medicine is always warranted. fluoroscopic imaging is widely used for urological interventions. there are wide variations in practices followed in different institutions and countries. in some places, radiologists are also involved, while at our center, only urologists carry out the procedures. therefore, nontraditional radiation workers like urologists, residents of urology, technologists, anesthesiologists, and operating room staff should be aware of radiation doses they are involved. practice of measurement of radiation dose also sensitizes them towards the need of continuous vigil for radiation safety and also removes any unfounded fear of radiation. as practices differ from place to place, it is important to know the dose, so that the reference dose for a particular practice in a particular region may be developed and the practice may be compared with other regions as well. in fact, radiation dose to the patient during pcnl is such an important parameter that it may indicate the efficiency of the process. it has been reported that a novice urologist may achieve competency (based upon the operative time) after 60 cases of pcnl, but the excellence (based upon patients’ radiation dose) can be achieved only after 115 cases.(4) this underlines the importance of the measurement of radiation dose during pcnl cases at every center. table 1 gives the radiation doses to patients and personnel reported by different studies. patients’ skin dose reported in our earlier paper (0.59 ± 0.37 msv per pcnl) is quite lower than reported in late 1980s (10 msv to 250 msv).(10-12) probably, it is due to technological advances of fluoroscopic automatic brightness control and incorporation of filters. fluoroscopy time of 6.04 minutes in this study is slightly higher than the range of 2 to 4.4 minutes reported earlier and essentially indicates that the procedure has not changed much in terms of duration of fluoroscopic imaging over time.(7,9) exposure doses to the fingers of urologists and assisting urology residents in our earlier work were 0.28 msv and 0.36 msv, respectively. assisting urology residents received higher doses, since they were involved in fluoroscopy-guided radiation safety during percutaneous nephrolithotomy—kumar urology journal vol 5 no 1 winter 2008 21 retrograde passage of the ureteral catheter in addition to assisting in pcnl procedure. in our setup, urologists are involved in tract dilation and removal of calculus. exposure doses to urologists’ fingers in our work was in the similar range to those of other studies, except one which cited the figures dose at 5.8 msv per pcnl.(4,10-12) the icrp-60 report states that the annual dose limit to the extremities to be taken as 500 msv.(14) it shows that performing even 1000 pcnl procedures annually would keep the urologists’ finger dose well within this limit. our previous study explored the utility of radiation survey meter to arrive at an idea of trunk radiation dose for various occupational workers. it is evident that the trunk mostly receives the secondary scattered dose and the use of survey meter may yield a quick, easy, economical, but less accurate method of measurement of radiation dose. however, in the absence of costly but established tld system, the survey meter may prove handy. the trunk level radiation dose to the urologists measured by survey meter in this study was found to be 24.9 µsv per pcnl which was in the range of doses measured by tld placed at the thyroid, forehead, and collar levels reported in literature (34.6 µsv to 270 µsv per case).(3,5,7-10,12) however, further simultaneous tld-based and survey-meterbased confirmatory experiments of dosimetry are needed to arrive at some definite conclusion regarding survey meters’ use in knowing the approximate dose during intervention. all these measurements of radiation dose with tld in our published work were carried out after taping it over the lead gloves if worn. therefore, it means that fingers’ absorbed dose in pcnl would be further reduced if the glove is worn as some urologists did. all urologists, assistant urologists and technologists wore lead apron and some even wore thyroid shield and lead goggles. further reduction in dose may be achieved by proper collimation of radiation field and also by using some fluoroscopic drapes and radiation shield as demonstrated by some studies.(6,15) these are good-work practices and should be encouraged further in order to reduce population dose and to observe the alara principle. role of medical physicists the hospital’s medical physicists are involved with the x-ray engineer and the urologists to set the optimum milliampere tube-current, so that doses to the patient and the personnel may reduce further without compromising the image quality. in fact, there is a scope to identify the limit to achieve a suitable image for diagnosis at lower radiation and avoiding the images which may be more than the requirement but at higher doses. in other words, optimization of fluoroscopic image quality may be able to avoid undesirable radiation to patients and personnel alike. application of additional filters may also be explored to reduce the doses further. the hospital medical physicists may carry out a quality assurance test for matching of radiation field (exposed area) with the displayed field of view (fov) in fluoroscopy which generally has an undercouch x-ray tube and overcouch image intensifier. fluoroscopy has a fixed fov (circular or rectangular area appearing on the monitor) which means that it can only show that body part on the monitor which falls within its fov. any radiation hitting the image intensifier outside the fov is wasted but adds to the radiation dose to the patient’s and the scattered radiation dose to the personnel. the radiation field should not exceed 3% of the x-ray figure 3. schematic diagram of quality assurance test for matching x-ray field with the field of view (fov) in fluoroscopy. the inner circle is the fov and the outer rectangular area is the x-ray field. the error (excess of x-ray field over the fov) on x-axis is x1+x2 and that on y-axis is y1+y2. radiation safety during percutaneous nephrolithotomy—kumar 22 urology journal vol 5 no 1 winter 2008 to the image intensifier distance on any side of the fov (figure 3).(16) the author of the present paper found that the results for this experiment were beyond the limit for 2 out of 3 fluoroscopy machines, and consequently they were rectified by the engineers. there are other quality assurance tests as well to check the performance of fluoroscopy machines. these are checking of the performance of the automatic brightness control (wherever available); checking the focal spot size (x-ray target or source size) which should be 1.2 mm and 0.5 mm for large and small focuses, respectively; checking the resolution of the system, so that details of the image is visible at minimum possible radiation dose; and checking the possible image distortion and monitor resolution. the patient skin entrance radiation dose rate should not exceed 10 rad per minute except during film recording of fluoroscopic images or when an optional high level control is activated. the dose rate should be measured at 30 cm from the input surface of image intensifier in c-arm fluoroscope and at 1 cm above the table top in undercouch tube fluoroscope. the minimum permissible distance between x-ray source and the patient couch (skin) is 30 cm for mobile fluoroscope and 20 cm for image-intensified fluoroscopes used for specific surgical applications. even innocuous-looking lead apron should be checked at least once a year for any crack and hole to prevent any leakage of radiation through these defects. lead aprons should never be kept folded when not in use, rather they should be hanged on the hanger and put on a pedestal stand to prevent any crack at the place of fold. nowadays, angiography machines (which use fluoroscopy for cardiac and hepatobiliary therapeutic and diagnostic interventions) have pulsed fluoroscopy instead of continuous fluoroscopy and it helps to reduce the radiation dose to a large extent. incorporation of pulsed fluoroscopy in all interventional x-ray machines may be investigated in order to reduce the radiation dose further. other measures included in newer machines are displays of fluoroscopy time, total dap values and estimated skin dose, incorporation of region-of-interest fluoroscopy which has a low noise image in the center and surrounded by a low dose (noisy) region, and last image hold. some manufacturers provide additional shielding in the room (as ceilingsuspended lead glass) to optimize the occupational protection. the occupational workers who regularly work in fluoroscopy environment may be brought under regular personal dosimetry program of the country. in india, bhabha atomic research centre conducts tld badge service where a designated medical radiation worker wears a tld personal badge during his/her radiation job. this tld badge is read for radiation doses at every 3 months and dose data are complied and stored for annual and life-time radiation dose. conclusion this study reviewed radiation dose to the patient’s skin during pcnl based on the reports in the literature. it was found that doses have gone down with the advent of technology. however, keeping alara principle in mind, all personnel should use radiation protective gadgets and the people not involved directly in the procedure should stand at a feasible distance from the patients undergoing pcnl. the author’s earlier study showed that a dose rate meter (survey meter) may also be used for arriving at an estimate of personnel dose after proper comparative calibration with tld. this method would be fast, easy, and economical as compared to tld. also, this method would be suitable for smaller centers with no expensive tld system. the hospitals’ medical physicists may help further in reduction of radiation dose by undertaking a few additional explorations as suggested by this paper. conflict of interest none declared. references 1. hendee wr. real and perceived risks of medical radiation exposure. west j med. 1983;138:380-6. 2. kumari g, kumar p, wadhwa p, aron m, gupta np, dogra pn. radiation exposure to the patient and operating room personnel during percutaneous radiation safety during percutaneous nephrolithotomy—kumar urology journal vol 5 no 1 winter 2008 23 nephrolithotomy. int urol nephrol. 2006;38:207-10. 3. hellawell go, mutch sj, thevendran g, wells e, morgan rj. radiation exposure and the urologist: what are the risks? j urol. 2005;174:948-52. 4. allen d, o’brien t, tiptaft r, glass j. defining the learning curve for percutaneous nephrolithotomy. j endourol. 2005;19:279-82. 5. hellawell go, cowan nc, holt sj, mutch sj. a radiation perspective for treating loin pain in pregnancy by double-pigtail stents. bju int. 2002;90:801-8. 6. giblin jg, rubenstein j, taylor a, pahira j. radiation risk to the urologist during endourologic procedures, and a new shield that reduces exposure. urology. 1996;48:624-7. 7. bowsher wg, blott p, whitfield hn. radiation protection in percutaneous renal surgery. br j urol. 1992;69:231-3. 8. page je, walker wj. complications attributable to the formation of the track in patients undergoing percutaneous nephrolithotomy. clin radiol. 1992;45:20-2. 9. law j, inglis ja, tolley da. radiation dose to urological surgeons during x-ray fluoroscopy for percutaneous stone extraction. br j radiol. 1989;62:185-7. 10. geterud k, larsson a, mattsson s. radiation dose to patients and personnel during fluoroscopy at percutaneous renal stone extraction. acta radiol. 1989;30:201-5. 11. rao pn, faulkner k, sweeney jk, asbury dl, sambrook p, blacklock nj. radiation dose to patient and staff during percutaneous nephrostolithotomy. br j urol. 1987;59:508-12. 12. bush wh, brannen ge, gibbons rp, correa rj jr, elder js. radiation exposure to patient and urologist during percutaneous nephrostolithotomy. j urol. 1984;132:1148-52. 13. iverson c, flanagin a, fontanarosa pb, et al. american medical association manual of style. 9th ed. philadelphia: lippincott williams & wilkins; 1999. p. 505-6. 14. international commission on radiological protection [homepage on the internet]. summary recommendation [cited 2008 feb 1]. available from: http://www.icrp.org/docs/summary_b-scan_icrp_60_ ann_icrp_1990_recs.pdf 15. yang rm, morgan t, bellman gc. radiation protection during percutaneous nephrolithotomy: a new urologic surgery radiation shield. j endourol. 2002;16:727-31. 16. granger we jr, bednarek dr, rudin s. primary beam exposure outside the fluoroscopic field of view. med phys. 1997;24:703-7. case report 212 urology journal vol 7 no 3 summer 2010 diffuse aerodermectasia floating body sign michael plaza,1 justin la plante2 urol j. 2010;7:212-3. www.uj.unrc.ir keywords: scrotum, subcutaneous emphysema, genital diseases 1jackson memorial hospital, university of miami, miami, usa 2university of utah health sciences center, salt lake city, ut, usa corresponding author: michael plaza, md jackson memorial hospital, university of miami, 1611 nw 12th ave., west wing no.279, miami, fl 33136, usa tel: +1 704 779 5604 e-mail: mjplaza@yahoo.com received june 2009 accepted october 2009 introduction presence of subcutaneous air in the scrotum is a rare condition and only a few cases have been reported in the literature.(1) air in the scrotum secondary to trauma is even far less common and minimal discussion exists on this topic. we present a case of traumatic pneumoscrotum which was made unique by the fact that the amount of air introduced into the scrotum was so extensive that was dissected through the fat planes superiorly to the level of the scalp resulting in pneumoretroperitoneum and pneumomediastinum along the way. we discuss the presentation, clinical course, and treatment strategy of the patient. case report a 55-year-old man with the past medical history of schizophrenia was admitted for diffuse subcutaneous emphysema secondary to self-inflicted scrotal barotrauma. the patient inserted the tube into the scrotum and introduced air until he began to feel air tracking up to his neck from the suprapubic region. on physical examination, the patient had palpable crepitus of the abdomen, the chest, the neck, and the extremities. genitourinary examination demonstrated approximately 2 inches of the tube inserted into the scrotum with no bleeding around the site of insertion and no significant scrotal swelling. in addition, the patient had a nut and bolt through and through the urethra just below the coronal sulcus. computed tomography scan revealed diffuse subcutaneous air that extended from the patient’s proximal legs to his scalp, as well as pneumomediastinum and pneumoretroperitoneum. figure 1 demonstrates the contiguous figure 1. sagittal computed tomography scan of the abdomen and the pelvis in the lung window settings demonstrates subcutaneous air seen extending the length of the body. green arrow: pneumomediastinum; red arrow: subcutaneous emphysema pneumoscrotum—plaza and la plante 213urology journal vol 7 no 3 summer 2010 nature of the subcutaneous air as it extends the length of the body in a circumferential way. figure 2 demonstrates pneumomediastinum and represents the floating body sign, which refers to the radiographic appearance of subcutaneous air encircling the torso or any extremity. the nut and bolt were removed without difficulty and the tube was removed from the scrotum. the patient had no difficulty or pain while urinating. the patient was observed overnight for possible respiratory compromise and was discharged the next day without intervention. discussion our case illustrates the degree to which air may spread through out the soft tissues after initial introduction of air to the scrotum. for the development of diffuse aerodermectasia from an initial site of pneumoscrotum, a combination of two mechanisms of spread is suspected. air passed through the inguinal canal and into the paranephric space, then superiorly into the mediastinum, resulting in the visualized pneumoretroperitoneum and pneumomediastinum. the second mechanism is that air from the scrotum traversed through scarpa’s fascia to extend to the rest of the body’s subcutaneous soft tissues.(2) the clinical presentation of traumatic pneumoscrotum is typically impressive to the treating physician; however, it is not emergent and care is supportive. the patient should be observed for more serious complications such as pneumothorax or air within the neck subcutaneous tissues expanding and leading to suffocation. the differential of pneumoscrotum includes iatrogenic procedures such as endoscopy, infection as in the case of fournier’s gangrene, scrotal trauma, pneumothorax, and visceral perforation.(1-3) conflict of interest none declared. references 1. simaioforidis v, kontos s, fokitis i, lefakis g, koritsiadis s. subcutaneous emphysema of the scrotum (pneumoscrotum) due to traumatic pneumothorax: a case report. cases j. 2008;1:293. 2. watson hs, klugo rc, coffield ks. pneumoscrotum: report of two cases and review of mechanisms of its development. urology. 1992;40:517-21. 3. wakabayashi y, bush wh, jr. pneumoscrotum after blunt chest trauma. j emerg med. 1994;12:603-5. figure 2. axial computed tomography scan at the level of the heart in the lung window settings demonstrates subcutaneous emphysema encircling the thorax and well as a significant degree of pneumomediastinum. green arrow: pneumomediastinum; red arrow: subcutaneous emphysema sexual dysfunction and infertility 41urology journal vol 5 no 1 winter 2008 comparison of sertraline and citalopram for treatment of premature ejaculation turgay akgül, tolga karakan, ali ayyıldız, cankon germiyanoğlu introduction: we evaluated the efficacy of citalopram and sertraline in the treatment of premature ejaculation (pe). materials and methods: of 101 married men with pe, 80 were eligible and consented to participate in this randomized controlled trial. erectile dysfunction and administration of drugs for the treatment of pe were the exclusion criteria. the patients were evaluated using index of premature ejaculation (ipe) questionnaire and were randomly assigned into groups 1 (sertraline) and 2 (citalopram). they received one of these drugs for 8 weeks and then were re-evaluated by the ipe. pretreatment and posttreatment results were compared within and between the study groups. results: a total of 80 patients entered and completed the study. the mean age of the patients was 38.4 ± 7.7 in group 1 and 37.5 ± 6.9 in group 2 (p = .60). the mean pretreatment ipe scores were 21.4 ± 1.8 and 20.9 ± 1.3 in the patients of groups 1 and 2, respectively (p = .23). after 8 weeks, significant improvement was seen in both groups in terms of the ipe questionnaire results (39.8 ± 1.4; p < .001 and 39.5 ± 2.9; p < .001, respectively). however, the treatment response was not different between the 2 groups (p = .50). no serious adverse effects were detected in any of the patients and both drugs were tolerated well. conclusion: citalopram and sertraline are safe and effective in patients with pe. additionally, we failed to find any difference between the effects of these two drugs in the treatment of this condition. keywords: premature ejaculation, selective serotonin reuptake inhibitors, citalopram, sertraline department of urology, ankara training and research hospital, ankara, turkey corresponding author: turgay akgül, md no 11, sokak 18/406500, bahçelievler, ankara, turkey tel: +90 505 229 3859 fax: +90 312 240 2966 e-mail: turgayakgul@gmail.com received november 2007 accepted january 2008 introduction premature ejaculation (pe) is defined as “stressful recurrent ejaculation with minimal sexual stimulation and before the subject wish it” which is associated with “marked distress or interpersonal difficulty.(1)” it has been reported as the most common sexual problem in men with prevalence rates ranging from 9% to 31%.(2) it has been shown that the prevalence of pe in patients younger than 40 and older than 70 years is higher than 40% and less than 10%, respectively.(3) moreover, the association between pe and sexual function and satisfaction emphasizes clinical importance of this symptom.(4) the etiology of pe is unknown in most cases; however, a combination of organic and psychogenic urol j. 2008;5:41-5. www.uj.unrc.ir selective serotonin reuptake inhibitors and premature ejaculation—akgül et al 42 urology journal vol 5 no 1 winter 2008 factors is the most probable cause. although the basic treatment has been short-term directive sex therapy for a long time, pe is increasingly treated pharmacologically with a variety of different medications.(5) different treatment modalities including local anesthetic creams, selective serotonin reuptake inhibitors (ssris), clomipramine, posphodiesterase type 5 inhibitors, adrenergic α1-antagonists, and a centrally acting analgesic (tramadol) have been used for treatment of pe.(6) nowadays, a combined treatment protocol with drugs and psychotherapy is becoming the treatment of choice.(7) after studies evaluating clomipramine and paroxetine for the treatment of pe, the effectiveness of ssris in the treatment of pe has been established in numerous studies.(8,9) sertraline has also been found effective in the treatment of pe.(10,11) citalopram, another ssri, shows an effective antidepressant activity without important cardiotoxic, anticholinergic, and sedating effects and has been found effective in pe treatment.(12) in the present study, we aimed to evaluate and compare the efficacy of citalopram and sertraline in the treatment of premature ejaculation. materials and methods patients and treatment between june 2006 and february 2007, we recruited 101 married men who referred to our clinics for pe. men experiencing ejaculation within 2 minutes of penetration in 75% of their sexual intercourse attempts or more were considered to have pe. all patients were interviewed individually and a comprehensive history including marriage relation status and the partner’s obstetric features was taken. patients were included if they had a score of 22 or more on the erectile function domain of the international index of erectile function (iief).(13) patients with erectile dysfunction were excluded from the study. additionally, those with a history of vascular disease and those under treatment of pe by drugs such as organic nitrates or cytochrome p450 inhibitors were excluded. the eligible patients were given medical information about the treatment protocol. after providing oral consent, 80 patients were evaluated with the index of premature ejaculation (ipe) questionnaire(14) and were randomly assigned into groups 1 and 2. patients in group 1 received citalopram (relaxol, biofarma, istanbul, turkey), 20 mg/d, and those in group 2 received sertraline hydrochloride (lustral, pfizer, surrey, uk), 50 mg/d. at the end of the 8th week of treatment, the patients were re-evaluated using the ipe score by another clinician who was blind to the study protocol and the results were compared with the pretreatment values. index of premature ejaculation the previously validated ipe questionnaire(14) included 10 questions on sexual libido, frequency of erection enough for sexual intercourse, frequency of maintaining erection to complete sexual intercourse, intravaginal ejaculatory latency (ielt), difficulty in prolonged sexual intercourse, sexual satisfaction, partner’s sexual satisfaction, frequency of reaching orgasm in the partner, confidence in completing sexual activity, and frequency of feeling anxious, depressed, or stressed during sexual activity. each questionnaire was scored from 1 (never/almost never) to 5 (always/almost always). statistical analyses the collected data were analyzed using the spss software (statistical package for the social sciences, version 13.5, spss inc, chicago, ill, usa). differences in numerical values before and after the treatment were analyzed by the t test and paired t test. p values less than .05 were considered significant. results a total of 80 patients entered and complete the study (figure). the mean age of the patients was 38.4 ± 7.7 in group 1 and 37.5 ± 6.9 in group 2 (table 1). the mean pretreatment ipe scores were 21.4 ± 1.8 and 20.9 ± 1.3 in the patients of groups 1 and 2, respectively (p = .23). after 8 weeks, significant improvement was seen in both groups in terms of the ipe questionnaire results (table 2). however, the treatment response was not selective serotonin reuptake inhibitors and premature ejaculation—akgül et al urology journal vol 5 no 1 winter 2008 43 different between the 2 groups (p = .50). no serious adverse effects were detected in any of the patients. three patients (7.5%) in group 1 and 2 (5.0%) in group 2 had mild nausea at the beginning of the treatment. however, they could tolerate well and continued their treatment until the end of the study period. discussion the most studied neurotransmitter in the physiology of ejaculation is 5-hydroxytryptamine (5-ht),(16) which is an inhibitor of ejaculation acting via decreasing serotonin-induced dopamine. the ssris inhibit presynaptic reuptake of 5-ht in the central nervous system.(12) the effect of sertraline, a well-known ssri, on pe has been demonstrated in previous studies.(17) arafa and shamloul investigated the effect of sertraline, 50 mg daily, in a placebo-controlled study using an arabic translation of the ipe scoring system and confirmed the usefulness of sertraline for improvement of ejaculation time.(11) they also reported that treatment with sertraline had no negative impact on erectile function and libido, which is completely in accordance with our results. citalopram has also been previously investigated for the treatment of pe. this drug is different from other ssris because it does not inhibit any cytochrome p450 isoform and shows linear kinetics throughout the duration of the treatment.(18) it has also been stated that absorption of citalopram is not affected by food, and steady-state concentrations are reached within 1 to 2 weeks with once-daily dosage. (19,20) however, there are few studies in the literature about the efficacy of citalopram in pe. atmaca and colleagues investigated the efficacy of citalopram in pe and stated that it was more efficacious than placebo.(12) safarinejad the consolidated standards of reporting trials (consort) flowchart of the randomized study is shown.(15) features group 1citalopram group 2 sertraline p mean age, y 38.4 ± 7.7 (23 to 53) 37.5 ± 6.9 (27 to 52) .60 mean deliveries of partners 1.9 ± 1.6 (0 to 7) 1.8 ± 1.32 (0 to 5) .73 mean number of marriages 1.1 ± 0.3 (1 to 2) 1.2 ± 0.4 (1 to 2) .99 table 1. demographic and clinical features of patients with premature ejaculation who received either citalopram or sertraline* *values are demonstrated as mean ± standard deviation (range). patient groups baseline ipe posttreatment ipe p group 1 (citalopram) 21.4 ± 1.8 (18 to 26) 39.8 ± 1.4 (36 to 42) < .001 group 2 (sertraline) 20.9 ± 1.3 (18 to 23) 39.5 ± 2.9 (31 to 44) < .001 table 2. pretreatment and posttreatment scores of ipe in patients on citalopram and sertraline* *values are demonstrated as mean ± standard deviation (range). ipe indicates index of premature ejaculation. selective serotonin reuptake inhibitors and premature ejaculation—akgül et al 44 urology journal vol 5 no 1 winter 2008 and hosseini reported similar results with citalopram and showed improvement in the overall sexual satisfaction with citalopram which is in accordance with our findings.(20) in our study, citalopram was found to be effective according to the ipe questionnaire. however, we did not separately evaluate the effect of citalopram on sexual function. dosage is one of the important points in the treatment of pe. the ssris taken daily significantly delay ejaculation.(21,22) with daily administration of antidepressants, the delay of ejaculation usually occurs within 5 to 10 days.(23) although some authors have reported a 4-fold to 11-fold increase in ejaculation latency,(24,25) others have reported only a 1.3-fold increase when paroxetine, 20 mg, was taken as on-demand dosing 3-4 hours before intercourse.(26) daily treatment appears to be associated with better ejaculatory control than on-demand dosing; however, it leads to considerable drug exposure for events that usually do not occur everyday. by contrast, daily dosing removes the need to anticipate the occurrence of sexual intercourse 4 or 6 hours before it is likely to occur, which may put excessive pressure on the couple.(27) however, it has been hypothesized that long-term treatment with ssris leads to higher synaptic 5-ht levels than episodic treatment.(27) although there are still arguments about this subject, we prefer to administer daily dosage of ssris in the treatment of pe and, in our opinion, this regimen is more practical for evaluating the effectiveness of drugs. side effects are the major issues concerning daily treatment with ssris in depressive patients. their adverse effects include psychiatric, anticholinergic, and dermatologic reactions; changes in body weight; and cognitive impairment.(27) in the present study, we did not observe any clinically important side effect causing drug withdrawal. only 5 patients from both groups experienced mild nausea at the beginning of the treatment. the most widely used assessment guideline on pe is ielt.(28,29) it is important to consider that nearly half of the adult women suffer from sexual dysfunction and patients with pe may also have other sexual disturbances, which complicate the relationship between the partners more than before.(30) besides, many clinicians consider the stopwatch ielt measurement to be impractical in clinical use.(3) similarly, we think that ielt measurement method is not practical especially in conservative societies and can give misleading results due to reasons described before. therefore, we used the ipe scoring system that was firstly introduced by yuan and associates.(31) the lack of a control group that has not received any treatment or a placebo-control group is the limitation of our study. however, because the effectiveness of ssris in pe is already known, this condition cannot limit the importance of our results significantly. nevertheless, we believe that placebo-controlled studies with greater sample sizes are needed. conclusion using a validated questionnaire, we confirmed that citalopram and sertraline administered on a long-term daily basis are safe and effective in the patients with pe. however, we failed to find any significant difference between the effects of these two drugs in pe treatment. conflict of interest none declared. references 1. american psychiatric association. diagnostic and statistical manual of mental disorders (dsm iv). 4th ed. washington, dc: american psychiatric association; 1994. p. 509-11. 2. lewis rw, fugl-meyer ks, bosch r, et al. definitions, classifications and epidemiology of sexual dysfunction. in: lue tf, basson r, rosen r, giuliano f, khoury s, montorsi f, editors. sexual medicine. sexual dysfunctions in men and women. oxford (uk): health publication; 2004. p. 37-72. 3. jannini ea, lenzi a. epidemiology of premature ejaculation. curr opin urol. 2005;15:399-403. 4. rowland d, perelman m, althof s, et al. selfreported premature ejaculation and aspects of sexual functioning and satisfaction. j sex med. 2004;1:225-32. 5. lue tf, giuliano f, montorsi f, et al. summary of the recommendations on sexual dysfunctions in men. j sex med. 2004;1:6-23. 6. gurkan l, oommen m, hellstrom wj. premature ejaculation: current and future treatments. asian j androl. 2008;10:102-9. 7. perelman ma. a new combination treatment for selective serotonin reuptake inhibitors and premature ejaculation—akgül et al urology journal vol 5 no 1 winter 2008 45 premature ejaculation: a sex therapist’s perspective. j sex med. 2006;3:1004-12. 8. goodman re. the management of premature ejaculation. j int med res. 1977;5:78-9. 9. waldinger md, hengeveld mw, zwinderman ah. paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study. am j psychiatry. 1994;151:1377-9. 10. murat başar m, atan a, yildiz m, baykam m, aydogănli l. comparison of sertraline to fluoxetine with regard to their efficacy and side effects in the treatment of premature ejaculation. arch esp urol. 1999;52:1008-11. 11. arafa m, shamloul r. efficacy of sertraline hydrochloride in treatment of premature ejaculation: a placebo-controlled study using a validated questionnaire. int j impot res. 2006;18:534-8. 12. atmaca m, kuloglu m, tezcan e, semercioz a. the efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study. int j impot res. 2002;14:502-5. 13. rosen rc, riley a, wagner g, osterloh ih, kirkpatrick j, mishra a. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997;49:822-30. 14. althof s, rosen r, symonds t, mundayat r, may k, abraham l. development and validation of a new questionnaire to assess sexual satisfaction, control, and distress associated with premature ejaculation. j sex med. 2006;3:465-75. 15. moher d, schulz kf, altman dg. the consort statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. lancet. 2001;357:1191-4. 16. wolters jp, hellstrom wj. current concepts in ejaculatory dysfunction. rev urol. 2006;8:s18-25. 17. waldinger md, zwinderman ah, schweitzer dh, olivier b. relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and metaanalysis. int j impot res. 2004;16:369-81. 18. hyttel j. citalopram--pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. prog neuropsychopharmacol biol psychiatry. 1982;6:277-95. 19. barton dl, loprinzi cl, novotny p, et al. pilot evaluation of citalopram for the relief of hot flashes. j support oncol. 2003;1:47-51. 20. safarinejad mr, hosseini sy. safety and efficacy of citalopram in the treatment of premature ejaculation: a double-blind placebo-controlled, fixed dose, randomized study. int j impot res. 2006;18:164-9. 21. waldinger md, hengeveld mw, zwinderman ah, olivier b. effect of ssri antidepressants on ejaculation: a double-blind, randomized, placebocontrolled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. j clin psychopharmacol. 1998;18:274-81. 22. waldinger md, schweitzer dh, olivier b. ondemand ssri treatment of premature ejaculation: pharmacodynamic limitations for relevant ejaculation delay and consequent solutions. j sex med. 2005;2:121-31. 23. giuliano f, clément p. serotonin and premature ejaculation: from physiology to patient management. eur urol. 2006;50:454-66. 24. abdel-hamid ia, el naggar ea, el gilany ah. assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation. int j impot res. 2001;13:41-5. 25. mcmahon cg, touma k. treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies. j urol. 1999;161:1826-30. 26. waldinger md, zwinderman ah, olivier b. on-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixeddose study with stopwatch assessment. eur urol. 2004;46:510-5. 27. riley a, segraves rt. treatment of premature ejaculation. int j clin pract. 2006;60:694-7. 28. rowland dl, strassberg ds, de gouveia brazao ca, slob ak. ejaculatory latency and control in men with premature ejaculation: an analysis across sexual activities using multiple sources of information. j psychosom res. 2000;48:69-77. 29. choi hk, jung gw, moon kh, et al. clinical study of ss-cream in patients with lifelong premature ejaculation. urology. 2000;55:257-61. 30. moynihan r. the making of a disease: female sexual dysfunction. bmj. 2003;326:45-7. 31. yuan ym, xin zc, jiang h, et al. sexual function of premature ejaculation patients assayed with chinese index of premature ejaculation. asian j androl. 2004;6:121-6. ozlem bozkurt-girit is an assistant professor of biophysics at aydın adnan menderes university, turkey. she studied biology at middle east technical university, ankara, turkey. during her ph.d. studies, she has participated in a collaboration with berlin humboldt university, germany and carried out research as a visiting researcher in exercise metabolism research laboratory of university of birmingham, school of sports and exercise sciences, uk and mineralized tissue laboratory of hospital for special surgery, caspary research building, new york, usa. she has been specialized in biophysics following her ph.d. at the department of biological sciences in metu. her scientific interests include electrophysiological and molecular characterization of metabolic and neurological diseases, photodynamic and sonodynamic therapy and the use of spectroscopic and imaging techniques, including ft-ir spectroscopy and microspectroscopy. “being a reviewer for urology journal is an honor, as you are allowed to contribute to the scientific level of this journal. careful and fair-minded evaluation of scientific articles is an important scholarly contribution and a gratifying duty in academics. peer review is a vital process for any journal and enables publication of innovative research that meets the highest standards of quality. bozkurt-girit was chosen as the best reviewer(s) of the issue by the editorial board of the urology journal for his valuable and timely review of manuscript”. best reviewer of the july-august 2021 issue ozlem bozkurt-girit ozlem bozkurt-girit august 2021 the effect of melatonin on improving the benign prostatic hyperplasia urinary symptoms, a randomized clinical trial amirreza fotovat1, bahram samadzadeh2, mohsen ayati1, mohammad reza nowroozi1, seyed ali momeni1, samira yavari3, ali nasseri4, laleh sharifi1* urology journal/vol 19 no. 5/ september-october 2022/ pp. 406-411. [doi:10.22037/uj.v18i.6761] introduction benign prostatic hyperplasia (bph) is a common issue in men older than 40, and its incidence is increased by aging which leads to obstructive and irritating symptoms.(1) in recent years, different medical treatments, including α-blocker compounds such as tamsulosin(2), 5α-reductase inhibitors such as finasteride(3), were employed as a classic treatment. if the standard treatments do not relieve the symptoms, surgery is advised to patients. it has been shown that tamsulosin monotherapy cannot be effective enough and it is suggested to treat the patients with tamsulosin in accompanying with other treatments(4). there are studies that show improvements in urinary symptoms as well as quality of life of patients with bph after receiving tamsulosin in combination with different agents including solifenacin and mirabegron.(5,6) also, combination of tamsulosin plus the complementary and alternative medicine such as vitamins (c and d), herbal products (cucurbita maxima, capsicum annum, polygonum capsicatum) and amino acid l glutamine provides statistically significant benefits in terms of lower urinary tract storage related to bph compared to tamsulosin 0.4 mg/ day alone(7). melatonin is a hormone secreted by the pineal gland and its secretion is decreased by aging and plays a role in regulating the sleep-wake cycle.(8) it is used as a lowdose drug in dietary supplements in the improvement of insomnia with minimal side effects. some studies have shown that melatonin increases bladder capacity and reduces bladder contractions by inhibiting the calcium channels as well as strengthening the cerebral gabaergic system.(9) on the other hand, a study revealed that melatonin effectively reduces the growth of prostate epithelial cells by amplification of p27 gene transcription over mt(1) receptor-mediated stimulation of protein kinase a and protein kinase c.(10) as melatonin has a probable effect on growth of the prostate epithelial cells and bladder contraction, we hypothesized that adding melatonin to conventional treatment of patients with bph may reduce their urinary symptoms. therefore, due to the very low literature about the effect of melatonin on relief of bph symptoms in human(11), we intend to enroll a randomized double-blind clinical trial to investigate the effect of melatonin along with standard treatment on improving the bph urinary symptoms as well as patients’ quality 1uro-oncology research center, tehran university of medical sciences, tehran, iran. 2department of urology, school of medicine, kermanshah university of medical sciences, kermanshah, iran. 3department of anesthesiology, school of medicine, isfahan university of medical sciences, isfahan, iran. 4department of radiology, school of medicine, shiraz university of medical sciences, shiraz, iran. * correspondenc: uro-oncology research center, imam khomeini hospital complex, tehran university of medical sciences, tehran. iran. tel/fax: +98 (21) 66903063. email: l_sharifi@razi.tums.ac.ir. received march 2021 & accepted november 2021 unclassified purpose: to investigate the effect of melatonin along with tamsulosin in improving bph urinary symptoms. materials and methods: a total of 108 men with bph symptoms, age of ≥ 50 years, and international prostate symptom score (ipss) ≥ 8 entered into the parallel group randomized, double-blind clinical trial with balanced randomization. the treatment group received of 3mg melatonin plus 0.4mg tamsulosin and the control group received placebo plus 0.4mg tamsulosin. patients and physicians were concealed by sealed and opaque envelopes. symptoms were assessed at baseline and 1 month after treatment. finally all scores at the initial and end of the study were compared and analyzed using spss software. results: this study showed that adding melatonin to the classic treatment of bph patients with tamsulosin could significantly reduce the likelihood of nocturia by 2.39 times (95% ci: 1.07-5.32, or = 2.39, p = 0.033) and could also reduce the frequency of urination by 2.59 times (95% ci: 1.15-5.84, or = 2.59, p = 0.021). there was no statistically significant difference between the two groups in ipss, intermittency, incomplete emptying, straining, urgency, and weak stream. conclusion: melatonin plus tamsulosin treatment is associated with a significant improvement of nocturia and frequency in patients with benign proststic hyperplasia. however, it is necessary to do more studies. keywords: benign prostatic hyperplasia; melatonin; tamsulosin; nocturia; frequency of life due to their urinary problems. patients and methods study population patients who had referred to our center were included in this clinical trial if met the inclusion criteria: physician diagnosis of bph, older than the age of 50, complain of urinary problems and need to receive a classic treatment to control their urinary symptoms according to clinical signs and findings of sonography, psa level and ipss score more than 8. the potential sources of bias for the study were eliminated by excluding patients with the following characteristics from the study: suspected patients of having prostate cancer on examination or with high psa, urinary tract infection based on urine culture, nocturnal polyuria based on urine volume chart, urethral stenosis, history of any cancer, chemotherapy, radiotherapy, cardiopulmonary and cerebral diseases, hypertension, liver failure, and taking previous medications that affect urinary symptoms such as diuretics. also, we were sure that patients recruited for this study did not use immunosuppressive drugs, corticosteroids, sleeping pills, and antidepressants. included patients with bph symptoms underwent clinical examination, psa test, urine culture, and urine volume chart. this study was registered in the iranian registry of clinical trials (registration number: irct2015011314333n27 available at https://www. irct.ir/trial/13963). this study complies with the helsinki declaration and has been approved by the ethics committee of kermanshah university of medical sciences with the number of 420/7/3960/p. patients’ enrollment flow diagram has been illustrated in figure 1. study design this study was a single center, parallel group randomized, double-blind clinical trial with balanced ranletter 242 group variablea treatment (tamsulosin+melatonin) mean±sd control (tamsulosin+placebo) mean±sd p-value age(year) 64.48 ± 6.47 63.96 ± 5.56 .843 ipss at baseline 21.22 ± 5.89 21.44 ± 5.31 .922 ipss after treatment 15.11 ± 15.53 16.33 ± 4.75 .556 ipss difference 6.11 ± 2.36 5.00 ± 2.5 .348 table 1. comparison of age, ipss before treatment, ipss after treatment and ipss reduction difference in the treatment and control groups. abbreviations: ipss, international prostate symptom score a quantitative variables are compared by t_independent and u_mann–whitney tests a quantitative variables were compared by chi-square and fisher exact tests b response to treatment was determined by ipss and a reduction or increasing of at least one score after 1 month was considered as improvement and worsening respectively. variablea response to treatmentb treatment (tamsulosin+melatonin) number (%) control (tamsulosin+placebo) number (%) p-value nocturia improved 36 (66.6%) 25 (46.2%) not changed 15 (27.7%) 18 (33.3%) .045* worsen 3 (5%) 11 (20.3%) straining improved 22 (40.7%) 21 (38.8%) .928 not changed 23 (42.5%) 25 (46.2%) worsen 4 (7.4%) 8 (14.8%) frequency improved 33 (61.1%) 25 (46.2%) not changed 17 (31.4%) 15 (27.7%) .045* worsen 4 (7.4%) 14 (25.9%) intermitency improved 33 (61.1%) 32 (59.2%) not changed 16 (29.6%) 13 (24.07%) .529 worsen 5 (9.2%) 9 (16.6%) weak stream improved 29 (53.7%) 31 (57.4%) not changed 21 (38.8%) 16 (29.6%) .512 worsen 4 (7.4%) 7 (12.9%) incomplete emptying improved 21 (38.8%) 22 (40.7%) not changed 25 (46.2%) 19 (35.1%) .400 worsen 8 (14.8%) 13 (24.07%) urine urgency improved 35 (64.8%) 30 (55.5%) not changed 15 (27.7%) 17 (31.4%) 0.554 worsen 4 (7.4%) 7 (12.9%) quality of life due to improved 30 (55.5%) 28 (51.8%) urinary problems not changed 24 (44.4%) 26 (48.1%) .542 worsen 0 (0%) 0 (0%) table 2. comparison of characteristics between deceased and surviving patients melatonin and bph-fotovat et al. vol 19 no 5 september-october 2022 407 domization (1:1) which was carried out in the urology clinic of imam reza hospital in kermanshah, iran. based on the results obtained by drake et al (2004), the mean value of ipss in the melatonin and placebo groups was 27.8 ± 6.8 and 31.7 ± 7.6 respectively(11). considering confidence coefficient of 0.05 and study power of 80% (beta coefficient of .20), the sample size estimated in each trialed group was estimated to be 54 (totally 108). patients were randomly allocated to one of the two groups of the study. randomization was carried out using computerized random numbers. patients and physicians evaluating patients were uninformed about the allocation result. the assigned treatment for each patient was composed in a sealed and opaque envelope. after achieving eligibility criteria and obtaining written informed consent, the concealed envelopes were opened by one of the hospital employees and assigned participants to interventions. the allocated treatment was done as described below. intervention during 1 month of intervention, the treatment group received classic treatment including 0.4 mg tamsulosin plus 3 mg melatonin every night. on the other hand, the placebo group received classic tamsulosin treatment (0.4 mg) in addition to a placebo every night. questionnaire persian version of ipss questionnaire was completed for both intervention and control groups. the reliability and validity of the persian version of the ipss questionnaire were confirmed previously.(12) ipss questionnaire is utilized internationally to evaluate the symptoms of bph and measures the urinary symptoms. the score for each part varies from 0 to 5, and the patients with ipss ≥ 8 need to start treatment for their urinary symptoms (13,14). the questionnaire was completed at the entry time and 1 month later after receiving 1 month of treatment. comparing the initial and final questionnaires, a reduction of at least one score was considered as a sign of improvement. all participants answered a question about the quality of their urinary life at the beginning and at the end of the study. after completing the course of treatment, patients were asked about all the common side effects of tamsulosin(15) and melatonin(16). statistical analysis the gathered data were analyzed by spss software version 19. first, the normality of variables was assessed by the kolmogorov-smirnov test. thereafter, to compare quantitative variables in two groups of treatment and placebo, t_independent or u_mann–whitney tests were used and chi-square or fisher exact tests were used for qualitative variables. p values equal to or less than 0.05 were considered significant. the multivariable logistic regression modeling was used to assess the effects of melatonin on clinical symptoms with the presence of baseline variables of age and initial ipss score. to design the multivariable logistic regression figure 1. flow diagram of randomized clinical trial study evaluating the effect of melatonin on improving the bph urinary symptoms melatonin and bph-fotovat et al. unclassified 408 model, first, each of the variables that had a significant relationship with the dependent variable in the univariate analysis (with p value of less than .1) entered the final model. results comparison of the participants’ data showed that there was no significant difference between age, ipss score before and after treatment, and ipss difference of patients in the two groups of intervention and classic treatment (table 1). there was a significant difference between symptoms of nocturia and frequency of patients in the two groups. but symptoms of straining, intermittency, weak stream, incomplete emptying, urine urgency and quality of life due to urinary problems of patients were not significantly different among patients who had received melatonin in addition to standard treatment (table 2). dry ejaculation was the only reported side effect of tamsulosin in our study, seven (12.9%) of patients in the treatment group had reported dry ejaculation whereas 8 (14.8%) of patients in the control group reported it (p = .782). other known side effects of tamsulosin and melatonin were not found in any of the patients in this study. according to the multivariable logistic regression modeling with the presence of the parameters of patients’ age and baseline ipss, administration of melatonin could significantly reduce the likelihood of nocturia by 2.39 times (95% ci: 1.075.32, or = 2.39, p = .033). based on another multivariable logistic regression with the same baseline parameters, the use of melatonin could effectively reduce the risk for frequency of urination by 2.59 times (95% ci: 1.15-5.84, or = 2.59, p = .021). discussion bph is a common problem with increasing age in men that is accompanied by irritating and obstructive symptoms that sometimes lead to surgery due to lack of recovery. tamsulosin is an alpha-receptor blocker that is considered a standard treatment for patients. but, the result of a recent study showed that tamsulosin alone maybe not enough for a large prostate (> 40 mg) to maintain adequate symptom relief, and it is better to start with other medical options such as combined therapy.(17) a study by song y et al in 2020 showed that tamsulosin combined with solifenacin therapy was more effective in reducing the total international prostate symptom score (tipss), storage international prostate symptom score (sipss), quality of life (qol), and overactive bladder symptom score (oabss) in comparison with tamsulosin monotherapy treatment(5). moreover, kang tw et al in 2020 reported that a combination of tamsulosin and mirabegron might improve the quality of life of patients presenting with persistent storage symptoms after tamsulosin monotherapy. improved quality of life due to mirabegron compared with solifenacin could be associated with fewer adverse effects such as dry mouth and constipation.(6) in this study, we decided to investigate the combination of tamsulosin and melatonin on the improvement of urinary problems of bph patients. melatonin is a hormone secreted by the pineal gland at night that regulates the sleep-wake cycle. in recent years, melatonin has been used as a short-term dietary supplement in the treatment of sleep disorders(18), which has been approved by the european union due to its very low side effects (19). use of melatonin before phenylephrine reduces the contractile response of the bladder and reduces the peak contractile effect of bethanechol, kcl, and acetylcholine, and also potentiates the inhibitory effect of succinylcholine on bladder contractions, via inhibiting calcium channels(9). intracerebroventricular injection of melatonin increases bladder capacity and reduces its contractions through strengthening the gabaergic system(20). furthermore, an animal model study revealed that melatonin is a potent antioxidant which by increasing neuronal nitric oxide synthases (nnos) and decreasing inducible nitric oxide synthase (inos) leads to amelioration of bladder hyperactivity (21). interestingly, melatonin is effective in improving chronic bladder overactivity but has no significant effect in patients with acute bladder overactivity(22). it has been shown that melatonin is effective in inhibiting the growth and progression of prostate cancer by inducing apoptosis and preventing angiogenesis(23). also, it prevents prostate cancer metastasis by down-regulating matrix metallopeptidase 13 (mmp-13)(24) and delays the development of castration resistance in advanced prostate cancer by blocking androgen receptors(25). in this study, nocturia was significantly improved in the patients who were treated with melatonin plus tamsulosin compared to patients who received only tamsulosin. it must be taken into account that in addition to the possible role of melatonin on the bladder capacity, older adults are prone to nocturnal sleep disturbance, and melatonin can improve their circadian rhythm and a good night's sleep may result in diminishing the psychological need to go to the bathroom. pharmacological studies of melatonin in the treatment of bph are very limited. in the only study similar to our study that carried out by drake et al., a sample of 20 bph patients entered a randomized, double blind, placebo controlled crossover clinical trial to detect the effect of melatonin pharmacotherapy in the treatment of bph-related urinary symptoms. the primary endpoint was the mean change in nocturia episodes per night and secondary endpoints were mean changes in daytime urinary frequency, relative nocturnal urine volume and total ipss. that authors have declared that parallel group design would be appropriate for their study but they could not do it because it demands a larger sample size(11). drake et al. showed a considerable improvement in nocturia episodes per night which is parallel to our findings. however, they could not show any significant difference between 2 groups of patients who received melatonin and who did not receive in the ipss score, nocturnal urine volume, maximum urinary flow, and post-void residue(11). contradictory with drake et al. study, in our study frequency was significantly improved in patients who received melatonin. for explanation of this inconsistency, it should be noted that in the drake et al. study patients were deprived from a standard treatment but all of the patients in our study received the standard treatment and also received a higher melatonin dose (3 mg vers. 2 mg) that can be effective in improvement of bladder contractions. there was no statistically significant difference between the two groups in ipss score, intermittency, incomplete emptying, straining, urgency, and weak stream in our study. we showed that similar to other combinations of tammelatonin and bph-fotovat et al. vol 19 no 5 september-october 2022 409 sulosin that potentiate its effect, the quality of life due to urinary problems of our patients in the melatonin plus tamsulosin group was descriptively higher than tamsulosin monotherapy. however this difference was not statistically significant, but it could be related to the improvement of nighttime sleep and the improvement of patients’ frequency and nocturia symptoms. one of the limitations of this study was the lack of eurodynamic assessment due to financial constraints that could be useful in evaluating patients. dry ejaculation was descriptively lower in the melatonin plus tamsulosin, which may be due to the effect of melatonin on the mood of patients, but there was no significant difference between the two groups in this area. other known side effects of tamsulosin and melatonin were not found in any of the patients in this study; it can because of the exclusion of patients with underlying problems at the beginning of the disease. conclusions according to the findings of our study, the combination of melatonin and tamsulosin was drastically effective in treating the symptoms of frequency and nocturia in patients with bph. the results achieved by this study can be used to pave the avenue of improving the symptoms of patients with bph. we suggest conducting further pharmaceutical studies in this area to find a precise dose of melatonin as well as to assess its safety and efficacy in patients with underlying diseases. acknowledgement this study was approved by kermanshah university of medical sciences, as a research project. the authors would like to thank staffs of the urology clinic of imam reza hospital in kermanshah for their help in conducting this study. conflict of interest the authors report no 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guidelines: 2019 update. curr urol rep. 2020;21:32. 15. tamsulosin monograph for professionals. h t t p s : / / w w w . d r u g s . c o m / m o n o g r a p h / tamsulosin.html (retrieved 24 december 2019). 16. melatonin: side effects, uses, dosage (kids/ adults). https://www.drugs.com/melatonin. html. (retrieved 10 december 2019). 17. el-adawy ms, abdelaziz ay, salem a, et al. relation of baseline prostate volume to improvement of lower urinary tract symptoms due to tamsulosin monotherapy in benign prostatic hyperplasia: an exploratory, multicenter, prospective study. urology melatonin and bph-fotovat et al. unclassified 410 annals. 2020;12:271. 18. matheson e, hainer bl. insomnia: pharmacologic therapy. am fam physician. 2017;96:29-35. 19. european medicines agency (ema). circadin epar. https://www.ema.europa.eu/ en/documents/product-information/circadinepar-product-information_en.pdf (retrieved 31 may 2020). 20. matsuta y, yusup a, tanase k, ishida h, akino h, yokoyama o. melatonin increases bladder capacity via gabaergic system and decreases urine volume in rats. the journal of urology. 2010;184:386-91. 21. nomiya m, burmeister dm, sawada n, et al. effect of melatonin on chronic bladder‐ ischaemia‐associated changes in rat bladder function. bju int. 2013;112:e221-e30. 22. dobrek ł, thor pj. the influence of melatonin and agomelatine on urodynamic parameters in experimental overactive bladder model-preliminary results. postepy hig med dosw (online). 2011;65:725-33. 23. dauchy rt, hoffman ae, wren-dail ma, et al. daytime blue light enhances the nighttime circadian melatonin inhibition of human prostate cancer growth. comp med. 2015;65:473-85. 24. wang sw, tai hc, tang ch, et al. melatonin impedes prostate cancer metastasis by suppressing mmp-13 expression. j cell physiol. 2021;236:3979-90. 25. liu vws, yau wl, tam cw, yao k-m, shiu syw. melatonin inhibits androgen receptor splice variant-7 (ar-v7)-induced nuclear factor-kappa b (nf-κb) activation and nfκb activator-induced ar-v7 expression in prostate cancer cells: potential implications for the use of melatonin in castration-resistant prostate cancer (crpc) therapy. int j mol sci. 2017;18:1130. melatonin and bph-fotovat et al. vol 19 no 5 september-october 2022 411 v07_no_4.pdf endourology and stone disease 232 urology journal vol 7 no 4 autumn 2010 antiurolithiatic activity of pinus eldarica medw. fruits aqueous extract in rats hossein hosseinzadeh,1 ali-reza khooei,2 zahra khashayarmanesh,3 vahideh motamed-shariaty4 purpose: to evaluate the antiurolithiatic activity of pinus eldarica fruit on induced calcium oxalate nephrolithiasis in rats. materials and methods: calcium oxalate nephrolithiasis in rats was induced by administering ethylene glycol 1% for 30 days via drinking water. the prophylactic and therapeutic groups received p. eldarica fruit extract (500 and 1000 mg/kg/day) as well for 30 days and from the 14th day through the end of the experiment, respectively. the following variables were assessed; urine volume, urinary calcium excretion, and crystalluria. finally, rats’ kidneys were histopathologically examined. results: the aqueous extract prophylactic treatment (500 mg/kg/day) increased urinary calcium excretion. qualitative analysis of crystalluria and histopathologic examination showed that the administered dose of extract prevented stone formation in the kidneys significantly. the prophylactic treatment did not increase urine volume in comparison with ethylene glycol. stone formation did not decrease in the treatment group. conclusion: this study indicates that p. eldarica fruit extract prevents calcium oxalate deposition, without producing diuresis. urol j. 2010;7:232-7. www.uj.unrc.ir keywords: pinus, kidney calculi, calcium oxalate, ethylene glycol 1pharmaceutical research center, school of pharmacy, mashhad university of medical sciences, mashhad, iran 2department of pathology, imam mashhad university of medical sciences, mashhad, iran 3pharmaceutical chemistry department, school of pharmacy, mashhad university of medical sciences, mashhad, iran department of pharmacology, pharmaceutical research center, mashhad university of medical sciences, mashhad, iran corresponding author: pharmaceutical research center, school of pharmacy, mashhad university of medical sciences, mashhad, iran tel: +98 511 882 3252 fax: +98 511 882 3251 received july 2009 accepted february 2010 introduction urolithiasis is defined as the presence of one or more calculi in any location within the urinary tract. the disease affects 1% to 5% of the population in developed countries with a peak incidence between 20 and 50 years of age. men are three times more likely to be affected than women and the lifetime risk of developing a calculus in a caucasian man is nearly 20%.(1) it has been reported that 91% of the urinary calculi contain calcium in some form, while 8% and 1% are composed of uric acid and cystine, respectively. the calcium-containing calculi consist of pure or various amount of calcium components such as calcium oxalate monohydrate, apatite, calcium hydrogen phosphate, and calcium carbonate. in men, 70% to 80% of the calculi contain either calcium oxalate alone or in combination with apatite.(2) the family pinaceae (pine family) includes many conifers such as cedrus, abies, larix, picea, and pinus. the iranian pine, pinus eldarica, is famous as a tehran pine and is a tree with wide spacing between branches and stiff long dark green needles at maturity. scientific studies about p. eldarica are largely restricted to botanical research. this pinus eldarica medw and urolithiasis—hosseinzadeh et al 233urology journal vol 7 no 4 autumn 2010 plant consists of quercetin, pinene, myrcene, caryophyllene, camphene, and abietic acid. the main constituents of the leaf oil are germacrene d (26.6%), -caryophyllene (17.1%), -pinene (11.8%), -pinene (7.9%), elemicin (4.3%), and -humulene (4.2%). major components of the fruit oil are -caryophyllene (34.0%), -pinene (16.3%), longifolene (10.5%), -humulene (6.4%), -3-carene (6.3%), and -pinene (3.8%).(3) the compounds of turpentine oil from title pine species are relatively stable, and the oil content of the resin has been reported to be 15% to 19%, and varies between 9.7% to 19.3%. monoterpenes consist of -pinene (31.5% to 64.2%), -3carene (16.9% to 42.8%), and -pinene (2.5% to 11.7%) mainly. the contents of camphene, myrcene, limonene, -phellandrene, -terpinene, terpinolene, tricyclene, sabinene, and p-cymene are much smaller.(4) in traditional medicine, it is alleged that some species of pinus such as p. gerardiana wall clears fluids of the kidneys and the bladder, and strengthens them to store urine. it also treats polyurea (of renal or cystic origin) and stops the formation of stones and ulcers in the bladder.(5) in this study, we evaluated the antiurolithiatic activity of p. eldarica fruit on induced calcium oxalate nephrolithiasis in rats. materials and methods plant material. fruits of p. eldarica were collected from school of pharmacy in mashhad, iran. voucher samples were preserved for reference at the herbarium in department of pharmacognosy, school of pharmacy, mashhad. animals. adult wistar male and female rats (200 ± 10 g) were chosen for study. animals were housed in plastic cages in an animal colony room 12/12 hours light/dark cycle at 21 ± 2 °c with food and water ad libitum. all animal experiments were carried out in accordance with mashhad university of medical sciences, ethical committee acts. preparation of extract. in decoction method, the fruits powder (100 g) was added to one liter hot distilled water for 30 minutes and then filtered through cloth. the extract was then evaporated to dryness at 50 °c (yield: 5.5 % w/w). experimental protocol.(6-7) hyperoxaluria and calcium oxalate deposition in the kidneys were induced by ethylene glycol in the drinking water to a final concentration of 1% for 30 days to induce lithiasis. group 1 was given ethylene glycol 1% only for 30 days; group 2 received water plus normal saline; groups 3 and 4 (prophylactic groups) received ethylene glycol 1% plus the extract 500 or 1000 mg/kg/day for 30 days; groups 5 and 6 (therapeutic groups) received ethylene glycol 1% plus the extract 500 or 1000 mg/kg/day from the 14th day through the end of the experiment. urine samples (24-hour) were collected at 0, 7, 14, and 30 days. all agents were given via drinking water. to complete the treatment, on the 31st day, all rats were sacrificed and both kidneys of each rat were removed for histopathologic examination. removed kidneys were fixed in 10% buffered formalin (merk) overnight and then each was sliced longitudinally in 3 sections, including anterior, middle, and posterior parts of the kidney. thereafter, they were automatically processed and inserted in paraffin blocks, and at least 6 sections with 5 micron thickness were obtained from each kidney and stained by hematoxylin and eosin. for accurate microscopic evaluation, each stained tissue slice were divided into 8 parts encompassing the cortex and medulla, and from each part, a cortical and a medullary field were randomly studied by an olympus microscope, type bx 40, with a magnification of 400 x (10 × 40). so for both kidneys of a rat, 192 microscopic field-areas were evaluated and undoubted stones in renal tubules were calculated. calcium in urine was analyzed using atomic absorption spectroscopy. statistical analysis. data were presented as mean ± standard error. statistical analysis was performed by spss software (statistical package for the social science, version 13.0, spss inc, chicago, illinois, usa), using one-way anova followed by tukey-kramer post-hoc test for multiple comparisons. p values less than .05 were considered statistically significant. pinus eldarica medw and urolithiasis—hosseinzadeh et al 234 urology journal vol 7 no 4 autumn 2010 results urinary calcium. urinary calcium excretion was increased after 14 days by ethylene glycol treatment. the prophylactic treatment of extract (1 g/kg) increased calcium excretion during 7, 14, and 30 days of the treatment. the pretreatment effect of extract on urinary volume on day 30 is shown in figure 1. diuretic activity. after 7 days, a low dose of extract (prophylactic group) increased mildly the urine volume. ethylene glycol increased urine volume after 30 days of the treatment. practically, the extracts (treatment and prophylactic treatment) did not show diuretic activity compared with ethylene glycol group. the pretreatment effect of extract on urinary volume on day 30 is shown in figure 2. histopathologic findings. induced urinary stones by ethylene glycol were presented as well-formed crystalloid materials and more predominantly in cortical than medullary renal tubules (figure 3). also in severe nephrolithiasis, stones were observable in renal calyces. ethylene glycol dramatically induced stone formation in renal tubules. there was a considerable figure 1. effect of p. eldarica fruit extract on urinary concentrations of calcium in nephrolithiasis induced by ethylene glycol 1% after 30 days. values are expressed as mean ± s.e.m. p < .001 compared with distilled water; +p < .05 compared with ethylene glycol group, tukeykeramer test. figure 2. diuretic activity of p. eldarica fruit extract in rats on day 30. values are expressed as mean ± s.e.m. of 8 rats in each p p < .001 compared with distilled water, tukey-keramer test. figure 3. histopathologic appearances of many stones in an ethylene glycol-treated rat (x 100, hematoxylin and eosin). pinus eldarica medw and urolithiasis—hosseinzadeh et al 235urology journal vol 7 no 4 autumn 2010 reduction in stone formation by the kidney with prophylactic dose of extract (1 g/kg) (figure 4). the extract did not decrease the deposition of crystal in the treatment group (figure 5). some other considerable histopathologic findings such as focal renal tubular dilatation (due to tubular obstruction by the stones), focal tubular epithelial necrosis, and focal interstitial inflammation were also noted in some rats, but were not included in results (figure 6). discussion the prophylactic administration of p. eldarica fruit extract significantly inhibited the formation of calculi without diuretic activity. consistent with other studies,(7-9) ethylene glycol administration resulted in development of persistent crystal formation in the kidney in all the rats. histopathologic study also confirmed the deposition of calcium oxalate crystals and the protective effect of the prophylactic administration of p. eldarica fruit extract. ethylene glycol elevated the urinary concentration of calcium; thereby, contributed to renal stone formation like other experiments. unlike rats with urolithiasis, the level of calcium oxalate in the kidney tissue significantly reduced in rats that were pretreated with pinus extract. this is in contrast to the urine level of calcium, which was found to be higher than those with hyperoxaluria, demonstrating the presence of insignificant crystalluria. this effect has also been reported with green tea, which had inhibitory effect on calcium oxalate urolithiasis.(10) urinary calcium excretion increased gradually figure 5. effect of p. eldarica fruit extract on number of crystal deposited in the kidney of rats. values are expressed as mean ± p < .001 compared with distilled water; ++p < .01 compared with ethylene glycol group, tukey-keramer test. figure 4. histopathologic appearances of one cortical tubule in a pinus eldarica extract-pretreated rat (x 200, hematoxylin and eosin). figure 6. histopathologic appearances of tubular dilatation, interstitial inflammation, and leukocyte-cast formation in an ethylene glycol-treated rat (x 200, hematoxylin and eosin). pinus eldarica medw and urolithiasis—hosseinzadeh et al 236 urology journal vol 7 no 4 autumn 2010 after administration of green tea and it was significantly higher than those in control group at 21 days after administration. the inhibitory effect of green tea on calcium oxalate urolithiasis is most likely due to antioxidative effects.(9) the extract probably prevents urinary stone formation by excretion of small particles from the kidney and reducing the chance of them being retained in the urinary tract. therefore, we suggested that the p. eldarica fruit’s extract can maintain calcium oxalate particles dispersed in the solution and thus, allows them to be eliminated easily from the kidney. there was no apparent diuretic affect of the plant extract. the calcium excretion remained higher in treated than untreated rats; however, the reason is unclear and further analysis is needed to clarify this issue. the analysis of crystals in the kidney showed that rats in prophylactic group had less urolithiasis in the kidney. rats pretreated with the extract had limited calcium oxalate deposition. the therapeutic administration of the extract did not affect the stone formation; hence, it can be stated that the plant can not dissolve pre-existing particles. there is in vivo evidence that hyperoxaluriainduced peroxidative damage to the renal tubular membrane surface provides a favorable environment for individual calcium oxalate crystal attachment and subsequent development of the kidney stones. in a study, vitamin e administration completely prevented calcium oxalate crystal deposition in the kidney, by preventing hyperoxaluria-induced lipid peroxidation and tissue antioxidant imbalance.(11) there are many reports about antioxidant activity of pinus species.(12-14) thus, it is possible that the extract prevents stone formation via antioxidant effect. in another study, the rate of stone formation decreased markedly in those patients who were treated with non-steroidal anti-inflammatory drugs.(15,16) as some pinus species have antiinflammatory activity,(17) this effect may be a contributory factor in antiurolithiatic activity of p. eldarica extract as well. tubular epithelium damage by any process such as infectious agents and mineral forming nanobacteria, may trigger the stone formation cycle.(18) many pinus species have antibacterial activity and this effect may prevent mineral forming nanobacteria growth and stone formation.(19-22) conclusion we concluded that p. eldrica fruit extract has a potent prophylactic effect on calcium oxalate stone formation, confirming the folklore about its antiurolithiasis activity, which is apparently unrelated to diuretic effect. the mechanism underlying the dissolvable effect of the extract remains unclear, and further studies are needed to clarify this issue. acknowledgements financial support for this study was provided by iran national science foundation. the authors would like to thank mr mehdi shahrokhi roshtkhar for introducing pinus eldarica as an antiurolithiatic plant. conflict of interest none declared. references 1. thomas b, hall j. urolithiasis. surgery (oxford). 2005;23:129-33. 2. jethi r. urolithiasis in man. probe. 1982;21:277-80. 3. afsharypour s, sanaty f. essential oil constituents of leaves and fruits of pinus eldarica medw. the journal of essential oil research. 2005;17:327-8. 4. chudnyi av, rudenko ba. composition of turpentine oil from pinus eldarica medow. rast resur. 1982;18:252-5. 5. avicenna. 1024a. al qanun fil tibb, vol. 2. english translation by h.a. hameed: s.waris nawab, senior press superintendent, jamia hamdard printing press, new delhi; 1998:156-7. 6. hadjzadeh ma, mohammadian n, rahmani z, rassouli fb. effect of thymoquinone on ethylene glycol-induced kidney calculi in rats. urol j. 2008;5:149-55. 7. veena c, josephine a, preetha s, varalakshmi p. beneficial role of sulfated polysaccharides from edible seaweed fucus vesiculosus in experimental hyperoxaluria. food chemistry. 2007;100:1552-9. 8. mourad b, fadwa n, mounir t, abdelhamid e, mohamed fadhel n, rachid s. influence of pinus eldarica medw and urolithiasis—hosseinzadeh et al 237urology journal vol 7 no 4 autumn 2010 hypercalcic and/or hyperoxalic diet on calcium oxalate renal stone formation in rats. scand j urol nephrol. 2006;40:187-91. 9. christina aj, ashok k, packialakshmi m, tobin gc, preethi j, murugesh n. antilithiatic effect of asparagus racemosus willd on ethylene glycol-induced lithiasis in male albino wistar rats. methods find exp clin pharmacol. 2005;27:633-8. 10. itoh y, yasui t, okada a, tozawa k, hayashi y, kohri k. preventive effects of green tea on renal stone formation and the role of oxidative stress in nephrolithiasis. j urol. 2005;173:271-5. 11. thamilselvan s, menon m. vitamin e therapy prevents hyperoxaluria-induced calcium oxalate crystal deposition in the kidney by improving renal tissue antioxidant status. bju int. 2005;96:117-26. 12. busserolles j, gueux e, balasinska b, et al. in vivo antioxidant activity of procyanidin-rich extracts from grape seed and pine (pinus maritima) bark in rats. int j vitam nutr res. 2006;76:22-7. 13. jung mj, chung hy, choi jh, choi js. antioxidant principles from the needles of red pine, pinus densi fl ora. phytother res. 2003;17:1064-8. 14. packer l, rimbach g, virgili f. antioxidant activity and biologic properties of a procyanidin-rich extract from pine (pinus maritima) bark, pycnogenol. free radic biol med. 1999;27:704-24. 15. brundig p, borner rh. clinical results in the treatment of therapy-resistant calcium-stone formers with non-steroidal anti-inflammatory drugs. eur urol. 1987;13:49-56. 16. friedman mr. nonsteroidal anti-inflammatory drugs facilitate stone passage. urology. 1990;35:374. 17. vigo e, cepeda a, gualillo o, perez-fernandez r. invitro anti-inflammatory activity of pinus sylvestris and plantago lanceolata extracts: effect on inducible nos, cox-1, cox-2 and their products in j774a.1 murine macrophages. j pharm pharmacol. 2005;57:383-91. 18. kajander eo, ciftcioglu n, aho k, garcia-cuerpo e. characteristics of nanobacteria and their possible role in stone formation. urol res. 2003;31:47-54. 19. asiegbu fo, choi w, li g, nahalkova j, dean ra. isolation of a novel antimicrobial peptide gene (sp-amp) homologue from pinus sylvestris (scots pine) following infection with the root rot fungus heterobasidion annosum. fems microbiol lett. 2003;228:27-31. 20. digrak m, ilcim a, hakki alma m. antimicrobial activities of several parts of pinus brutia, juniperus oxycedrus, abies cilicia, cedrus libani and pinus nigra. phytother res. 1999;13:584-7. 21. oh-hara t, sakagami h, kawazoe y, et al. antimicrobial spectrum of lignin-related pine cone extracts of pinus parviflora sieb. et zucc. in vivo. 1990;4:7-12. 22. harada h, sakagami h, konno k, et al. induction of antimicrobial activity by antitumor substances from pine cone extract of pinus parviflora sieb. et zucc. anticancer res. 1988;8:581-7. v08_no_1_print_3.pdf pictorial urology 13urology journal vol 8 no 1 winter 2011 post circumcision “tri-balanic” penis urol j. 2011;8:13. www.uj.unrc.ir a 32-year old man presented to the outpatient clinic of our department complaining of intractable pain, considerable congestion, and edema of the glans of the penis. the patient was afebrile, complaining of dribbling and inability to urinate properly. the patient’s history included a recent (less than one month) operation for the penis circumcision in another institute, while the physical examination revealed glans lobulated and struggled. under general anesthesia, the stitches were released and the redundant part of the prepuce was excised as to release the compression of the glans, leaving the glans free and totally uncovered. following this procedure, the edema and congestion improved. this case represents a rare case of circumcision repair-induced paraphimosis. rules to be followed in order to avoid this complication are removal of adequate part of the prepuce, careful detachment of adhesions between the inner surface of the prepuce and superficial surface of the glans,(1) gentle removal of the smegma, extreme pull back of the prepuce behind the corona of the glans,(2) and careful ligation of the artery and veins.(3) konstantinos michalakis, ioannis ilias, charalambos asvestis elena venizelou general hospital, athens, greece e-mail: kostismichalakis@hotmail.com references 1. elder js. circumcision. bju int. 2007;99:1553-64. 2. muula a, prozesky h, mataya r, ikechebelu j. prevalence of complications of male circumcision in anglophone africa: a systematic review. bmc urol. 2007;7:4. 3. holman j, stuessi k. adult circumcision. am fam physician. 1999;59:1514-8. ticles is an important scholarly contribution and a gratifying duty in academics. peer review is a vital process for any journal and enables publication of innovative research that meets the highest standards of quality. chung, was chosen as the best reviewer of the issue by the editorial board of the urology journal for his valuable and timely review of manuscript”. best reviewer of the may-june 2022 issue jae-wook chung jae-wook chung june 2022 jae-wook chung is a professor of urologic oncology at the kyungpook national university, school of medicine, daegu, south korea. he specializes in urologic cancer, especially kidney cancer. he performed his urology residency and fellowship at kyungpook national university hospital. he received academic excellence award in 2021 annual meeting of korean urological association and 2022 annual meeting of korean pediatric urology. he awarded “being a reviewer for urology journal is an honor, as you are allowed to contribute to the scientific level of this journal. careful and fair-minded evaluation of scientific ar 1 running head: hifu and endoscopic resection for pca-pan et al. endoscopic resection improved high-intensity focused ultrasound ablation outcomes for prostate cancer: a meta-analysis of comparative studies yang pan1#, shangren wang1#, hang zhou1#, shuai niu1, xiaoqiang liu1* 1 department of urology, tianjin medical university general hospital, tianjin, china # contributed equally key words: prostate cancer; high-intensity focused ultrasound ablation; endoscopic resections; meta-analysis abstract purpose: high-intensity focused ultrasound ablation (hifu) is emerging as more data on its efficacy arises for prostate cancer (pca). however, it is indefinite whether to combine endoscopic resection and uncertain to say who the ideal candidates are for the combined treatment. therefore, we aimed to conduct a meta-analysis to compare outcomes of sole hifu therapy with that of hifu in combination with endoscopic resection in patients with localized pca. 2 materials and methods: electronic databases were searched following the prisma guidelines and picos formats. the inclusion criteria were as follows: 1) studies on hifu for pca patients; 2) comparative studies on hifu in combination with endoscopic resection for localized pca men. exclusion criteria include non-comparative studies and salvage hifu therapy. meta-analysis results were mainly present using forest plots. sensitivity analysis and egger's test were adopted to determine the stability and assess the publication bias. results: six comparative studies with 767 patients were eligible, including 487 cases in the combination therapy group and 280 cases in the monotherapy group. there was no statistical difference in age, preoperative psa levels, and prostate volume between two groups. no statistical difference was found in postoperative psa nadir (md=-0.02, 95%ci: -0.35 to 0.31, p=0.90), disease-free survival rate (rr=0.95, 95%ci: 0.83 to 1.09, p=0.47), and preoperative ipss score (md=-0.69, 95%ci: -1.63 to 0.26, p=0.15; i2=8%) between two groups. the combination therapy group had significantly lower postoperative ipss score (md=-5.49, 95%ci: -6.47 to -4.51, p<0.001) and shorter catheterization time (md=13.70, 95%ci: -19.24 to -8.16, p<0.001) than the monotherapy group. the rates of urinary incontinence (7.4% vs. 13.9%, rr=0.45, 95%ci: 0.29 to 0.70, p=0.0004; i2=4%), acute urinary retention (6.8% vs. 10.5%, rr=0.36, 95%ci: 0.14 to 0.89, p=0.03; i2=0%), urinary tract infection (10% vs. 33%, rr=0.27, 95% ci: 0.18 to 0.4, p<0.001; i2=0%), epididymitis (1.2% vs. 15.7%, rr=0.11, 95% ci: 0.02 to 0.59, p=0.01; i2=0%), and 3 urethral stricture (7.1% vs. 23.2%, rr=0.3, 95%ci: 0.18 to 0.51, p<0.001; i2=0%) in the combination therapy group were all significantly lower than that in the monotherapy group. sensitivity analysis revealed findings were convincing and no publication bias (p=0.62) was observed using egger’s test. conclusion: it appears that the addition of endoscopic resection to the hifu operation might not impact oncologic outcomes and could show better functional outcomes compared to the hifu monotherapy in localized pca patients. introduction prostate cancer (pca) is a common urological disease in males, with the prevalence being extremely relevant to age, which was approximately 155 per 100,000 in 55-59 years old, 510 per 100,000 in 65-69 years old, and 751 per 100,000 in 75-79 years old, respectively (1). a lot of localized pca usually expand tardily and might not result in destructive impacts throughout pca patients’ lifetime. however, some comorbidities like urinary tract obstruction and ache of bone metastases may result from clinically significant cancers. 4 over the past many years, prostate-specific antigen (psa) exams and prostate biopsy were two main methods applied for the diagnosis of pca. in recent years, some new techniques like multiparameter magnetic resonance imaging and genetic testing have been increasingly utilized as well (2). treatments of pca are based on lesion position and disease stage. active surveillance could avoid excessive clinical management and not impact the chance of cure (3); however, it is an observational treatment for patients with low risk disease (4). the objective of radical prostatectomy is the extermination of carcinoma and preservation of urinary function and erectile function. outcomes after radical prostatectomy are associated with both surgeon’s experience and the overall strength of the hospital (5, 6). in current clinical practice, ablation therapy represents a more recent concept among active surveillance, radiation, and definitive radical treatments. ablation therapy can target the most aggressive lesions of pca and preserve the function of non-invasive prostate tissue; thus, ablation therapies may minimize treatment toxicity and could provide relatively better equilibriums among functional and oncological outcomes (7). a previous consensus meeting reported that ablation therapy could be identified as the coagulative necrosis of index lesions (8). the distinguishing characteristic of ablation therapy is to directionally destroy pca lesions and protect adjacent normal tissue. common ablation therapies are mainly made up of focal laser ablation, cryotherapy ablation, and high-intensity focused ultrasound ablation (hifu) (9). these treatment methods use individual templates including 5 index lesion ablation, gland hemi-ablation, and whole-gland ablation (10). among available alternative therapeutic options for pca, hifu represents a promising technique. ultrasound waves had been first used to focus on and treat lesion tissues about 80 years ago (11). hifu can directly focus ultrasound waves on cancer tissue, which can heat the tissue and lead to coagulative necrosis (12). plenty of diseases such as uterine fibroids, liver tumors, and breast tumors have been managed by hifu and showed considerable efficacy and safety (13-15). in regards to urological diseases, hifu is regarded as an available treatment for localized pca patients, or regarded as a salvage treatment in failure cases after radiation treatment currently (16). panzone et al. reported that hifu was proved as an effective and feasible management for patients having localized pca with satisfying oncologic control and function preservation in the short term (17). schmid et al. also reported that ablation of pca diseased tissue using hifu therapy was feasible and presented a satisfactory incidence of perioperative adverse events (18). hifu is emerging as more data on its efficacy arises (19). when hifu is performed independently and not combined with other additional procedures, a frequent complication is the occurrence of urinary tract obstruction resulting from edema or fibering (20). subsequently, patients could be painful because urinary catheter was required to retain longer time for avoiding the occurrence of acute urinary retention (aur) or other serious complications. thus, an obvious downside is that the urinary catheter has to be indwelled for 2-3 weeks after hifu operation. the catheterization for a long time could result in 6 urinary tract infections (utis), urethral stenosis, and other comorbidities. many prior articles revealed a relatively high urethral stenosis rate after hifu. thus, experts advocate new opinions and ways in order to reduce postoperative urinary catheter indwelling time. some studies have reported that performing hifu combined with endoscopic resection could significantly decrease the incidence of prolonged catheterization retention significantly and result in a more favorable evolution in the international prostate symptom score (ipss) (21-28). however, it is indefinite whether to combine endoscopic resection. therefore, our meta-analysis aimed to analyze functional and oncologic outcomes and evaluate the feasibility and efficacy of hifu combined with endoscopic resection compared to sole hifu therapy in patients with localized pca. in doing so, our study could illustrate who the ideal candidates are for the treatment, such as smaller gland, no luts and so on. materials and methods search strategy the present systematic review and meta-analysis were performed as per the prisma guidelines. the research question was based on the picos rule: population (patients with pca), intervention (endoscopic resection in combination with hifu), comparison (sole hifu therapy), outcomes (treatments outcomes and follow-up outcomes), and study design (the type of studies in terms of their methods). 7 pubmed, embase, and cochrane library were systematically retrieved. the retrieval time range was set up to july 10, 2022. the searching keywords included: (“prostate cancer”) and (“high-intensity focused ultrasound ablation”) and (“endoscopic resection” or “bladder neck incision” or “urethrotomy” or “transurethral resection of prostate” or “holmium laser enucleation of the prostate”). all patients included in the results must be an adult. sole hifu therapy was defined as only hifu operation for pca and not using other surgeries. hifu with endoscopic resection meant that hifu operation and other endoscopic resection surgeries such as holep were both applied for managing pca. all identified studies were then reviewed for eligibility. the reference lists and citations from key studies were also reviewed for additional eligible studies associated with our topic. inclusion and exclusion criteria the inclusion criteria were as follows: 1) study types: prospective or retrospective comparative studies; 2) studies on hifu for pca cases; 3) comparative studies on hifu in combination with endoscopic resection for localized pca men. besides, the exclusion criteria were set according to the following items: 1) non-comparative studies; 2) salvage hifu therapy; 3) comment; 4) case report; 5) review; 6) repeated publication. data extraction and outcome measurement all available data in each eligible study were extracted, respectively, by two separate authors and next verified one another. if there was any controversy, a third author would participate in and debate with the previous two authors to make an agreement. meanwhile, 8 we tried our best to get in touch with the authors of each included study to demand complete data. we considered that the complete oncologic, functional, and other detailed data were extremely beneficial to better analyze relevant results of hifu combined with endoscopic resection for localized pca. functional outcomes included preoperative ipss score, postoperative ipss scores in 6 months, the urinary catheter indwelling time, urinary incontinence rate, and erectile dysfunction (ed). partial urinary symptoms were assessed using ipss score and then identified as mild symptoms (0-7 scores), moderate symptoms (8-19 scores), and severe symptoms (20-35 scores). partial sexual potency was assessed using the international index of erectile function (iief-5) score scale and then classified as severe ed (5-7 scores), moderate ed (8-11 scores), mild to moderate ed (12-16 scores), mild ed (17-21 scores), and no ed (22-25 scores). oncologic outcomes included postoperative psa nadir, average month to achieve psa nadir level, and 2-year disease-free survival rate (dfsr) after hifu operation. quality assessment the quality of eligible articles was evaluated, respectively, by two separate authors and then verified each other. newcastle–ottawa scale (nos) was applied for evaluating the quality of non-randomized controlled studies (29). the quality was evaluated using the total scores of 3 sections in the nos scale, which were comprised of subject selection, group comparability, and ascertainment of exposure or outcome. the assessed study was 9 identified as low-quality (0-3 scores), moderate-quality (4-6 scores), and high-quality (7-9 scores). statistical analysis categorical variables were present in the form of n (%). the mean difference (md) with their 95% confidence interval (ci) was used to assess the outcomes of pooling different measures in meta-analysis to yield a summary estimate. the risk ratios (rr) with 95%ci were used to compare dichotomous variables. the heterogeneity was analyzed using cochrane q test and higgins i2 value. the fixed-effects model was performed if the heterogeneity was acceptable (i2 < 50%), and the random-effects model was conducted if obvious heterogeneity existed (i2 ≥ 50%). moreover, we have accounted for some confounding covariates in our analysis, such as age, psa, and prostate volume. sensitivity analysis was applied for identifying the reliability of outcomes through excluding one study each time. egger's test was performed to analyze the publication bias. all statistical analysis was performed using review manager 5.4 and stata 15.1 software. the p-value of < .05 was considered statistically significant. results a prisma flow chart of screening articles was shown in figure 1. overall, 272 relevant studies were retrieved through pubmed, embase, and cochrane library. there were 60 remaining studies eligible for reading full text. eventually, six comparative studies were 10 included in quantitative synthesis (30-35). according to nos scale, 4 studies were identified as high-quality and 2 study was identified as moderate-quality. there was no low-quality study included in our review. the detailed results of quality assessment using nos scale were listed in table 1. most studies mentioned that endoscopic resection had been undergone in order to decrease prostatic volume or to manage patients complain of obstructive symptoms. some studies mentioned that when prostatic volume before hifu therapy was relatively small and less than 40 cc, endoscopic resection and hifu treatment were usually conducted in single session; when prostatic volume before hifu therapy was large and more than 40 cc, hifu would be performed after 2-4weeks of endoscopic resection. the type of hifu ablation was all whole-gland ablation in all included studies. totally, 767 pca men were involved, including 487 cases in the combination therapy group and 280 cases in the monotherapy group. according to d’amico criteria, 4 studies revealed that they used hifu to manage low, intermediate, and high-risk pca patients. even though high-risk pca cases had been treated by hifu, the proportion of these high-risk cases in the overall population was still relatively low (74/767, 9.6%). average age of all included cases distributed between 65.8 and 72.8 years old. metaanalysis results showed that no statistical difference was found in age between both groups (md = 0.15, 95% ci: -1.85 to 2.14, p = 0.89; i2 = 59%; figure 2a). moreover, the mean psa levels before hifu were distributed between 3.99 and 12.1 ng/ml in all included 11 studies. meta-analysis results showed that no statistical difference was found in psa levels before hifu between both groups (md = 0.22, 95% ci: -0.95 to 1.39, p = 0.71; i2 = 59%; figure 2b). similarly, the mean prostate volume before hifu was distributed between 19.9 and 38.9 ml in all included studies. meta-analysis results also showed that no statistical difference was found in prostate volume before hifu between both groups (md = -1.17, 95% ci: -2.61 to 0.26, p = 0.11; i2 = 0%; figure 2c). most studies provided follow-up serum psa levels and either the postoperative psa nadir level or latest psa level. average postoperative psa nadir was distributed between 0.007 and 0.846 ng/ml in all included studies, while mean months to psa nadir ranged from 3.5 to 15.1 months postoperatively. meta-analysis results showed that no statistical difference was found in postoperative psa nadir between both groups (md = -0.02, 95% ci: -0.35 to 0.31, p = 0.90; figure 3a). however, significant heterogeneity was reported (p = 0.01, i² = 78%, figure 3a). five studies reported the dfsr after hifu in the two groups, respectively. the dfsr in the short term was 82% (255/311) in the combination therapy group and 86% (197/229) in the monotherapy group. meta-analysis results showed that no statistical difference was found in the dfsr after hifu between both groups (rr = 0.95, 95% ci: 0.83 to 1.09, p = 0.47; figure 3b). some comparative studies reported preoperative and postoperative ipss score between both groups. meta-analysis results revealed that no statistical difference was found in 12 preoperative ipss score (md = -0.69, 95% ci: -1.63 to 0.26, p = 0.15; i2 = 8%; figure 4a). however, meta-analysis results revealed that the combination therapy group had a significantly lower postoperative ipss score than the monotherapy group (md = -5.49, 95% ci: -6.47 to -4.51, p < 0.001; i2 = 78%; figure 4b). four comparative studies that reported the postoperative urinary catheter indwelling time between both groups. meta-analysis results revealed that the combination therapy group also had a significantly shorter time than the monotherapy group (md = -13.70, 95% ci: 19.24 to -8.16, p < 0.001; i2 = 95%; figure 4c). five comparative studies reported the rate of urinary incontinence. the rates of urinary incontinence were 7.4% (32/433) and 13.9% (32/230) in the two groups, respectively. meta-analysis results revealed that the rate of urinary incontinence in the combination therapy group was significantly lower than that in the monotherapy group (rr = 0.45, 95% ci: 0.29 to 0.70, p = 0.0004; i2 = 4%; figure 5a). the rates of de novo ed postoperatively were 39.4% in the combination therapy group and 41.7% in the monotherapy group. meta-analysis results showed that no statistical difference was found in the postoperative ed rate between both groups (rr = 1.09, 95% ci: 0.59 to 2.02, p = 0.78; i2 = 83%; figure 5b). all included studies reported the rates of postoperative complications. the rates of aur (6.8% vs. 10.5%, rr = 0.36, 95% ci: 0.14 to 0.89, p = 0.03; i2 = 0%; figure 6a), utis (10% vs. 33%, rr = 0.27, 95% ci: 0.18 to 0.4, p < 0.001; i2 = 0%; figure 6b), 13 epididymitis (1.2% vs. 15.7%, rr = 0.11, 95% ci: 0.02 to 0.59, p = 0.01; i2 = 0%; figure 6c), and urethral stricture (7.1% vs. 23.2%, rr = 0.3, 95% ci: 0.18 to 0.51, p < 0.001; i2 = 0%; figure 6d) in the combination therapy group were all significantly lower than that in the monotherapy group. when removing the study by baumunk et al., i2 of postoperative psa nadir decreased from 78% to 0%. it indicated this research was the main reason for heterogeneity of postoperative psa nadir. heterogeneities of other outcomes were small and steady, while 1 or 2 studies were removed each time. thus, sensitivity analysis revealed our outcomes were reliable. moreover, no publication bias on outcomes such as the postoperative urinary catheter indwelling time (p = 0.109, figure 7a) and the rate of urethral stricture (p = 0.62, figure 7b) was observed with the egger’s test. discussion this study innovatively compared outcomes of hifu combined with endoscopic resection with that of sole hifu therapy in localized pca patients. meta-analysis of comparative studies revealed that the combination of endoscopic resection with hifu treatment might not impact postoperative psa nadir and dfsr. furthermore, we found that the combination therapy could 1) shorten postoperative urinary catheter indwelling time; 2) decrease the rates of postoperative urinary incontinence, aur, utis, epididymitis, and urethral stricture; and 3) improve postoperative urinary symptoms significantly. therefore, 14 the addition of endoscopic resection to the hifu treatment appeared not to impact oncologic outcomes and could show better functional results in localized pca men compared to the hifu monotherapy. moreover, patients with large prostate volume or luts might be ideal candidates to choose the combined resection therapy. according to previous experience, the urinary catheter was usually indwelled for approximately fourteen to twenty-one days after hifu operation (36, 37). furthermore, there were nearly a third of the patients needed additional treatments such as urethrotomy to treat obstruction postoperatively. to avoid the risk of prolonged urinary retention associated with post-hifu edema and the risk of urinary obstruction, endoscopic resection was performed preoperatively in many institutions. eau guidelines mention that the resection of the prostate or the bipolar enucleation could be proposed as the first choice for the operative treatment of relatively large prostatic volumes (38). the combination of endoscopic resection with hifu showed many benefits. calcifications on the prostatic transitional zone might influence the focus and efficacy of hifu surgery. endoscopic resection could eliminate these calcifications and subsequently reduce the operating time of hifu. moreover, endoscopic resection can decrease the diameter of anterior-posterior zone in the prostate with a relatively large volume, so using single-session hifu to manage pca in the peripheral zone could come true (35). two significant functional outcomes included urinary incontinence and ed after the hifu procedure. he et al. found that the overall incidences of urinary incontinence and ed post 15 hifu ablation operation were 10% and 44%, respectively (39). our study revealed similar rates of incontinence and ed post hifu ablation operation in localized pca with previous studies. moreover, we showed similar ed rates between the combination therapy group and the monotherapy group. however, the combination therapy group had a significantly lower rate of urinary incontinence in comparison with the monotherapy group ripert et al. conducted large-scale research to determine oncologic outcomes after hifu treatment without a combined endoscopic resection in localized pca men and revealed that the range of postoperative psa nadir value was 0.01-14 ng/ml (40). similarly, ganzer et al. also completed a single-center study on 538 pca men to assess oncologic results in a long period using hifu without a combined endoscopic resection for localized pca. they found that the exact rate of biochemical failure was 19 and 39% at postoperative five and ten years, respectively (41). our study found that the dfsr was almost consistent with these previous studies and no obvious difference was found in the dfsr between both groups. it seems that oncologic outcomes had not been impacted by the addition of endoscopic resection to the hifu operation. there were no comparative studies that reported the results of partial-gland hifu and endoscopic resection therapy. therefore, we did not analyze the therapeutic results using partial-gland hifu ablation in combination with endoscopic resection in the present study. whole-gland hifu ablation and partial-gland hifu ablation have their special advantages. regardless of the types of hifu ablation (whole-gland ablation, or partial-gland hifu 16 ablation), when hifu is performed independently, the disadvantages such as large volume prostate or calcifications on the prostate could still exist. thus, hifu combined with endoscopic resection might still be beneficial for patients using partial-gland hifu ablation. more prospective trials are also required to validate the exact differences between the partial-gland hifu ablation combined with endoscopic resection and the sole partial-gland hifu ablation therapy in localized pca patients. some limitations might exist in the present study. one of main limitations is that the published articles about hifu ablation and endoscopic resection for localized pca might exist potential heterogeneity. even though some international consensuses have attempted to promote terminology and follow-up of ablative treatment standards, outcomes reported by different hifu centers might still show potential variation (42-44). the methods of reporting outcomes of survey questionnaires and complications might also exist partial differences, even though the majority of studies used the validated survey questionnaires to obtain the postoperative outcomes. however, sensitivity analysis indicated the findings were relatively reliable and no obvious publication bias existed according to egger’s test. therefore, our study might still be helpful for providing some important information on hifu therapy in localized pca patients with a relatively high level of evidence. conclusion it appears that the addition of endoscopic resection to the hifu operation might not impact 17 oncologic outcomes and can improve localized pca men compared to hifu monotherapy. the endoscopic resection with hifu treatment might reduce prostate volume, shorten catheterization time, decrease postoperative urinary incontinence, aur, utis, epididymitis, and urethral stricture rates, and improve urinary symptoms in comparison with hifu treatment solely. proper case inclusion, experienced surgeons with excellent hifu experience, and a multicentric prospective randomized controlled trial with longer follow-up durations are required to confirm and validate our findings in the future. acknowledgement our study was funded by national natural science foundation of china (no. 82171594). conflict of interest the authors report no conflict of interest. references 1. grozescu t, popa f. prostate cancer between prognosis and adequate/proper therapy. j med life. 2017;10:5-12. 2. drost fh, osses df, nieboer d, steyerberg ew, bangma ch, roobol mj, et al. prostate mri, with or without mri-targeted biopsy, and systematic biopsy for detecting prostate cancer. cochrane database syst rev. 2019;4:cd012663. 18 3. mottet n, van 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localized prostate cancer and the impact of a combined resection. current urology reports. 2003;4:248-52. 35. horiuchi a, muto s, horie s. holmium laser enucleation of the prostate followed by high-intensity focused ultrasound treatment for patients with huge prostate adenoma and localized prostate cancer: 5-year follow-up. prostate international. 2016;4:49-53. 23 36. hopstaken js, bomers jgr, sedelaar mjp, valerio m, fütterer jj, rovers mm. an updated systematic review on focal therapy in localized prostate cancer: what has changed over the past 5 years? european urology. 2022;81:5-33. 37. uchida t, shoji s, nakano m, hongo s, nitta m, murota a, et al. transrectal highintensity focused ultrasound for the treatment of localized prostate cancer: eight-year experience. int j urol. 2009;16:881-6. 38. gratzke c, bachmann a, descazeaud a, drake mj, madersbacher s, mamoulakis c, et al. eau guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2015;67:1099-109. 39. he y, tan p, he m, hu l, ai j, yang l, et al. the primary treatment of prostate cancer with high-intensity focused ultrasound: a systematic review and meta-analysis. medicine (baltimore). 2020;99:e22610. 40. ripert t, azémar md, ménard j, barbe c, messaoudi r, bayoud y, et al. six years' experience with high-intensity focused ultrasonography for prostate cancer: oncological outcomes using the new 'stuttgart' definition for biochemical failure. bju int. 2011;107:1899-905. 41. ganzer r, fritsche hm, brandtner a, bründl j, koch d, wieland wf, et al. fourteen-year oncological and functional outcomes of high-intensity focused ultrasound in localized prostate cancer. bju int. 2013;112:322-9. 42. muller bg, van den bos w, brausi m, fütterer jj, ghai s, pinto pa, et al. follow 24 up modalities in focal therapy for prostate cancer: results from a delphi consensus project. world j urol. 2015;33:1503-9. 43. postema aw, de reijke tm, ukimura o, van den bos w, azzouzi ar, barret e, et al. standardization of definitions in focal therapy of prostate cancer: report from a delphi consensus project. world j urol. 2016;34:1373-82. 44. scheltema mj, tay kj, postema aw, de bruin dm, feller j, futterer jj, et al. utilization of multiparametric prostate magnetic resonance imaging in clinical practice and focal therapy: report from a delphi consensus project. world j urol. 2017;35:695-701. corresponding author: xiaoqiang liu, m.d. department of urology, tianjin medical university general hospital, tianjin, china. e-mail: xiaoqiangliu1@163.com 25 figure 1. flow diagram of identification and screening of eligible studies (prisma flow diagram). 26 figure 2. forest plots of age (a), preoperative psa levels (b), and preoperative prostate volume (c) between the combination therapy group and the monotherapy group. 27 figure 3. forest plots of postoperative psa nadir (a) and disease-free survival rate (b) between the combination therapy group and the monotherapy group. 28 figure 4. forest plots of preoperative ipss score (a), postoperative ipss score (b), and postoperative urinary catheter indwelling time (c) between the combination therapy group and the monotherapy group. 29 figure 5. forest plots of urinary incontinence (a) and erectile dysfunction (b) between the combination therapy group and the monotherapy group. 30 figure 6. forest plots of acute urinary retention (a), urinary tract infection (b), epididymitis (c), and urethral stricture (d) between the combination therapy group and the monotherapy group. 31 figure 7. egger’s plots for the postoperative urinary catheter indwelling time (a) and the rate of urethral stricture (b). 32 table 1. characteristics and quality evaluation of included studies author year study country study design study duration anesthesia ablation type nos score quality assessment a sumitomo et al. 2010 japan case-control study apr. 2002-mar. 2010 nr wholegland 8 highquality chaussy et al. 2003 germany case-control study nr spinal anesthesia wholegland 8 highquality poissonnier et al. 2007 france crosssectional study 19932003 nr wholegland 8 highquality otsuki et al. 2008 japan case-control study apr. 2015-aug. 2006 nr wholegland 4 moderatequality baumunk et al. 2013 germany case-control study 20052009 nr wholegland 7 highquality horiuchi et al. 2016 japan case-control study nov. 2006-apr. 2010 general anesthesia wholegland 6 moderatequality abbreviations: hifu, high-intensity focused ultrasound ablation; nos, newcastleottawa quality assessment scale; nr, not reported. aquality was evaluated by newcastle-ottawa quality assessment scale. v08_no_1_print_3.pdf case report 72 urology journal vol 8 no 1 winter 2011 extracorporeal shock wave lithotripsy-induced retroperitoneal hemorrhage in a case of upper ureteral calculus with angiomyolipoma rahul gupta, pankaj d, pranjal modi, jamal rizvi urol j. 2011;8:72-4. www.uj.unrc.ir keywords: lithotripsy, angiomyolipoma, hematoma, hemorrhage, ureteral calculi department of urology, institute of kidney diseases and research center, ahmedabad, gujarat, india corresponding author: rahul gupta, md institute of kidney diseases and research center, ahmedabad, gujarat, india tel/fax: +91 792 268 5605 e-mail: rajaguptadr@rediffmail.com received july 2009 accepted october 2009 introduction angiomyolipoma (aml) is considered as the most common cause of spontaneous renal hemorrhage.(1) however, the hemorrhage may be precipitated by the use of antiplatelet drugs, pregnancy, and trauma, or may occur spontaneously in a large size tumor. we present a case of isolated rightsided mid and upper pole aml associated with retroperitoneal bleeding following extracorporeal shock wave lithotripsy (swl) for right upper ureteric stone. to the best of our knowledge, this is the first case of lithotripsy-induced retroperitoneal bleeding in a patient with aml, with no prior history of bleeding diasthesis or use of antiplatelet agents. case report a 32-year-old man presented with a history of right flank pain that lasted for 2 months and was found to have right renal mid and upper pole 6 cm × 4.5 cm-sized aml with a 1-cm upper ureteral stone at the level of l2-l3 on contrast enhanced computed tomography (cect) of the abdomen and the pelvis (figure 1). he underwent swl, which was done using an electrohydraulic unit (direx digiscope rx-2). initially, 2000 shocks were given followed by 1800 shocks after 48 hours at settings 20 kv at pulse rate of 60/min and after 3 to 4 hours of second sitting of swl. figure 1. contrast enhanced computed tomography of the abdomen and the pelvis showing right upper ureteral calculus. a b retroperitoneal hemorrhage with swl—gupta et al 73urology journal vol 8 no 1 winter 2011 he developed sudden onset of severe abdominal pain, vomiting, giddiness, and perspiration. after initial management of hypovolemic shock, the patient was referred to our institute. the patient was pale, with pulse rate of 120/min and blood pressure of 100/60 mmhg. on examination, he had a palpable firm tender lump confined to the right side of the abdomen with renal angle fullness. laboratory investigations revealed hb of 8.0gm/ dl, packed cell volume of 22, and complete blood count of 10 400/cmm. coagulation profile as well as renal and liver function tests were normal. abdominal ultrasonography showed a large perinephric hematoma. patient was given blood transfusion and stabilized. contrast enhanced computed tomography of the abdomen and the pelvis revealed a large retroperitoneal hematoma and right upper ureteral stone with double j ureteral stent in situ (figure 2). the patient was subjected to clot removal, upperpole partial nephrectomy, and ureterolithotomy with double j stenting via right flank approach. histopathology of the mass was suggestive of aml. postoperative period was uneventful and he was discharged on the 6th postoperative day. double j ureteral stent was removed at 4 weeks and the follow-up ultrasonography of the kidney, the ureter, and the bladder region was normal. discussion angiomyolipoma (choristoma) is a benign clonal neoplasm composed of variable amounts of mature adipose tissue, smooth muscle, and thickwalled blood vessels, which occurs predominantly in the kidney. more than 50% of amls are incidental because of the more prevalent use of abdominal imaging for evaluation of a wide variety of nonspecific complaints. distinctive radiographic findings associated with aml allow a definitive diagnosis in the majority of subjects. contrast enhanced computed tomography of the abdomen and the pelvis has been the most useful and reliable diagnostic modality for this purpose. the presence of fat within a renal lesion on computed tomography scan (-20 hu or lower) is highly suggestive of aml.(2) common clinical presentations of aml include flank pain, hematuria, and palpable mass. massive spontaneous retroperitoneal hemorrhage due to rupture of aml is found in 10% of patients. presentation of acute flank pain, a palpable mass, and hypovolemic shock, also known as lenk’s triad, requires immediate management.(3) the majority of amls rupture spontaneously, this is attributed to the inherent abnormal elastinpoor vascular structure, which makes these lesions prone to aneurysm formation and rupture.(4) even a minimal straining in the form of valsalva maneuver can precipitate a life-threatening wünderlich syndrome, underlying the vascular fragility of this tumor.(5) renal hematomas following swl is wellknown.(6) factors that facilitate the renal hematomas following swl include number of shock waves, acute pyelonephritis, and the energy level at which the shock waves are delivered.(7-9) the most probable theory is the expansion of the bubbles in a vessel that resulting in its rupture leading to hemorrhage.(10) evans and colleagues noted that once the blood vessels have ruptured, blood gets collected as a pool resulting in greater potential for cavitation to occur; thus, forming a vicious cycle.(11) in our patient, the hemorrhage occurred after the second session of swl. the cause of bleeding can figure 2. a) large perinephric hematoma. b) upper ureteral calculus with double j stent in place. a b retroperitoneal hemorrhage with swl—gupta et al 74 urology journal vol 8 no 1 winter 2011 be attributed to the accidental shocks at highenergy settings to the aml during the swl of the upper ureteric calculus, which would have been used to attain fragmentation after the failed first sitting. this is possible; especially in non respiratory gated machines, where the kidney may receive shocks as a result of mismatch between timing of shock and respiratory movements. this would have precipitated the rupture of the fragile vessels within the aml, resulting in severe hemorrhage. in a patient with large retroperitoneal hematoma secondary to ruptured aml, the treatment modalities are stabilization of the patient followed by either therapeutic embolization or nephronsparing surgery. although angioembolization is a minimally-invasive option for management of renal aml, nephron-sparing surgery is an equally acceptable option, especially in life-threatening conditions. moreover, it provides the tissue for pathological diagnosis. our patient was stabilized and later cect of the abdomen and the pelvis was carried out. this gave us a clear picture of the degree of hematoma, size, and location of the aml lesion and that of the upper ureteral calculus. treatment options were discussed and we opted for a single stage definitive management of this complex rare case, which involved clot evacuation with partial nephrectomy and ureterolithotomy. extracorporeal shock wave lithotripsy in a case of aml can precipitate life-threatening hemorrhage, and hence, should be used judiciously. conflict of interest none declared. references 1. zhang jq, fielding jr, zou kh. etiology of spontaneous perirenal hemorrhage: a meta-analysis. j urol. 2002;167:1593-6. 2. sebastia mc, perez-molina mo, alvarez-castells a, quiroga s, pallisa e. ct evaluation of underlying cause in spontaneous subcapsular and perirenal hemorrhage. eur radiol. 1997;7:686-90. 3. pedemonte jg, degiovanni d, pusterla d, et al. [angiomyolipoma and lenk syndrome: case report]. actas urol esp. 2008;32:850-4. 4. eble jn. angiomyolipoma of kidney. semin diagn pathol. 1998;15:21-40. 5. lin hw, tsao yt, lin yf, lin sh. in-flight valsalva maneuver induced life-threatening wunderlich syndrome. am j emerg med. 2008;26:732 e5-6. 6. dhar nb, thornton j, karafa mt, streem sb. a multivariate analysis of risk factors associated with subcapsular hematoma formation following electromagnetic shock wave lithotripsy. j urol. 2004;172:2271-4. 7. willis lr, evan ap, connors ba, blomgren p, fineberg ns, lingeman je. relationship between kidney size, renal injury, and renal impairment induced by shock wave lithotripsy. j am soc nephrol. 1999;10:1753-62. 8. evan ap, connors ba, pennington dj, et al. renal disease potentiates the injury caused by swl. j endourol. 1999;13:619-28. 9. connors ba, evan ap, willis lr, blomgren pm, lingeman je, fineberg ns. the effect of discharge voltage on renal injury and impairment caused by lithotripsy in the pig. j am soc nephrol. 2000;11: 310-8. 10. zhong p, zhou y, zhu s. dynamics of bubble oscillation in constrained media and mechanisms of vessel rupture in swl. ultrasound med biol. 2001;27:119-34. 11. evan ap, willis lr, mcateer ja, et al. kidney damage and renal functional changes are minimized by waveform control that suppresses cavitation in shock wave lithotripsy. j urol. 2002;168:1556-62. introduction bladder cancer (bca) is the 10th most common malignancy according to the latest global cancer statistics, with an estimated 549,000 new cases and 199,000 deaths occurring per year(1). approximately 25% of patients with primary bca have been diagnosed with muscle invasive bladder cancer (mibc), and approximately 10-30% of non-muscle invasive bladder cancer (nmibc) can progress to mibc(2,3). accordingly, the treatment of bca is of great importance for urologists. radical cystectomy (rc) with extended pelvic lymphadenectomy is the guideline-recommended treatment for high-risk nmibc and mibc(4,5). open rc (orc) is considered one of the most invasive surgeries in urology and has serious perioperative complications(6,7). following rapid technical advances, laparoscopic radical cystectomy (lrc) has been widely accepted because of its minimal invasiveness, lower blood loss, and shorter hospital stay, while yielding equivalent or better outcomes for patients relative to orc(8-10). furthermore, one of the most important advantages of lrc is the lower incidence of postoperative ileus, which is the most frequent complication after cystectomy and a common reason for longer hospital stays(11). lrc also achieves better hemostasis due to pneumoperitoneum and precise visibility when performing the technique. however, the technical procedure for lrc is complicated, and the surgeon should have an excellent understanding of the pelvic anatomy. lrc is still a challenge due to the longer operation time and the need to establish pneumoperitoneum, especially for elderly or higher bmi patients(12). it is difficult to perform surgical manipulations in the insufficient operative space. thus, it is important to understand the pelvic anatomy precisely and improve the surgical procedure to decrease the incidence of complications and operating time in lrc. laparoscopic and robotic urology “two-zone and three-segment” laparoscopic radical cystectomy vs conventional laparoscopic radical cystectomy for male patients with bladder urothelial carcinoma: a retrospective analysis shouzhen chen1,2#, jianfeng cui1,2#, haoyu sun1,2, wenfu wang1,2, xigao liu1,2, dongqing zhang1,2, xianzhou jiang1,2, hu guo1,2, nianzeng xing3,4, yaofeng zhu1,2**, benkang shi1,2* purpose: the aim of this study was to introduce an advanced surgical technique for laparoscopic radical cystectomy (lrc), evaluate the perioperative outcome and compare it to that of conventional lrc (clrc). materials and methods: between march 2018 and march 2020, sixty patients were divided into the “two-zone and three-segment” laparoscopic radical cystectomy (ttlrc) group or the clrc group. patient baseline characteristics, preoperative characteristics and postoperative complications were collected. results: the ttlrc technique was developed based on the pelvic anatomy of six formalin fixed male cadavers. none of the patient baseline characteristics, including ecog-ps score, comorbidity, asa score and hb, were significantly different between the two groups (p > 0.05). there were significant differences in the operating time and estimated blood loss (total time: 3±0.2 vs 3.8 ± 0.4, p < 0.001; time to cystectomy and lymph node dissection: 1.7 ± 0.2 vs 2.2 ± 0.3, p < 0.001; estimated blood loss 182. 1± 18.8 vs 264.3 ± 27.4, p < 0.001). although there were no differences in late complications, early complications were significantly different between the two groups (p = 0.033). no statistically significant differences were found between the two groups in other outcomes (p > 0.05). conclusion: the ttlrc technique achieves a clearer surgical field, has a shorter operating time and produces less blood loss than clrc. it is safe and feasible for urologists to perform this improved lrc procedure. keywords: laparoscopic radical cystectomy; bladder cancer; outcome; complication; surgical technique 1department of urology, qilu hospital, cheeloo college of medicine, shandong university, jinan, 250012, china. 2key laboratory of urinary precision diagnosis and treatment in universities of shandong, jinan, 250012, china. 3department of urology, national cancer center/national clinical research center for cancer/cancer hospital, chinese academy of medical sciences and peking union medical college, no. 17, panjiayuan south li, chaoyang district, beijing, 100021, china. 4department of urology, beijing chaoyang hospital, capital medical university, beijing, 100020, china. *correspondence: department of urology, qilu hospital, cheeloo college of medicine, shandong university, jinan, shandong, 250012, china. e-mail: bkang68@sdu.edu.cn. ** department of urology, qilu hospital, cheeloo college of medicine, shandong university, jinan, shandong, 250012, china. e-mail: feng2209@163.com. #shouzhen chen and jianfeng cui are equal to this article. received july 2021 & accepted december 2021 urology journal/vol 19 no. 1/ january-february 2022/ pp. 34-40. [doi: 10.22037/uj.v19i.6919] vol 19 no 1 january-february 2022 138 herein, we performed an advanced surgery technique for lrc based on our pelvic anatomy research, named “two-zone and three-segment” laparoscopic radical cystectomy (ttlrc). we conducted a retrospective analysis to evaluate the efficiency and safety of ttlrc and compare it to conventional lrc (clrc). materials and methods patients patients who met the following conditions were excluded from this study: (1) any distant metastases; (2) autofigure 1. schematic model of “two-zone and three-segment” laparoscopic radical cystectomy. (a) lateral view. (b) anterior view. variables total (n=60) ttlrc (n=29) clrc (n=31) p-value age, year (mean ± sd) a 64.7 ± 10.9 65.3 ± 11.9 64.1 ± 10.0 0.668 history of smoking, n (%) 20 (33.3) 10 (34.5) 10 (32.3) 0.536 bmi (kg/m2) (mean ± sd) b 24.1 ± 3.3 24.0 ± 3.3 24.1 ± 3.3 0.777 ecog-ps score, n (%) 0.281 0 56 (93.3) 26 (89.7) 30 (96.8) ≥1 4 (6.7) 3 (10.3) 1 (3.2) comorbidity, n (%) 0.881 hypertension 19 (31.7) 8 (27.6) 11 (35.5) diabetes mellitus 14 (23.3) 7 (24.1) 7 (22.6) coronary artery disease 10 (16.7) 6 (20.7) 4 (12.9) chronic obstructive pulmonary disease 7 (11.7) 3 (10.3) 4 (12.9) others 3 (5.0) 1 (3.4) 2 (6.5) asa score, n (%) 0.538 1-2 53 (88.3) 26 (89.7) 27 (87.1) 3 7 (11.7) 3 (10.3) 4 (12.9) hb (g/l) b 122 ± 7.1 122.3 ± 7.0 121.6 ± 7.2 0.880 clinical stage, n (%) 0.538 nmibc 16 (26.7) 8 (27.6) 8 (25.8) mibc 44 (73.3) 21 (72.4) 23 (74.2) clinical tumor grade, n (%) 0.586 low 8 (13.3) 4 (13.8) 4 (12.9) high 48 (80.0) 24 (82.6) 24 (77.4) squamous cell carcinoma 2 (3.3) 0 (0) 2 (6.5) adenocarcinoma 2 (3.3) 1 (3.4) 1 (3.2) table 1. patient demographics and tumor characteristics abbreviations: ttlrc, “two-zone and three-segment” laparoscopic radical cystectomy; clrc, conventional laparoscopic radical cystectomy; sd, standard deviation; bmi, body mass index; ecog-ps, eastern cooperative oncology group performance status; hb, hemoglobin; nmibc, non-muscle invasive bladder cancer; mibc, muscle invasive bladder cancer a these variables were compared by independent samples t-test b these variables were compared by mann-whitney test ttlrc vs clrc in bladder cancer-chen et al. vol 19 no 1 january-february 2022 35 laparoscopic and robotic urology 36 immune disease; (3) cancer in other systems; (4) american society of anesthesiology (asa) grade > 3; (5) clinical stage t4; (6) previous pelvic radiotherapy; and (7) severe cardiopulmonary dysfunction preventing surgical tolerance. this retrospective analysis included the clinicopathologic and follow-up data of 60 patients with high-risk nmibc, mibc or other types of bca in qilu hospital of shandong university from march 2018 to march 2020. all patients were divided into 2 groups; 29 patients in the ttlrc group and 31 in the clrc group. none of the patients had neoadjuvant chemotherapy or radiotherapy. patients with lymph node-positive disease or locally advanced disease were treated with adjuvant chemotherapy. this study was approved by the institutional ethics committee of the qilu hospital of shandong university. written informed consent was obtained from all the patients in this study. all patients underwent routine laboratory tests, echocardiography, lung function tests, chest radiographs, computerized tomography (ct), magnetic resonance imaging (mri), urinary cytology and / or cystoscopy with tissue biopsy. all operations and perioperative management were performed by the same laparoscopic surgical team. all three surgeons (bk, xz and dq) in this study are well-experienced in performing lrc. bk performed 18 and 16, xz performed 7 and 9, and dq performed 4 and 6 ttlrc and clrc procedures, respectively. conventional laparoscopic radical cystectomy the basic procedures were performed as reported by campbell-walsh urology(13). the patient was placed in a dorsal supine position with a 15 25° trendelenburg position after general anesthesia. a five-port fan-shaped approach was used. the camera port was placed just above the umbilicus after establishment of pneumoperitoneum and the remaining four ports were placed in a fan shape. standard lymphadenectomy was first conducted after releasing the ureter. then, the posterior wall of the bladder was separated. the lateral ligaments of the bladder were dissected (figure 1a). the anterior plane was then established distally toward the prostate (figure 1b). the attachments of the prostatic apex to the pelvic floor were released, and the urethral catheter was removed. after dissection of the santorini venous plexus, the urethra was dissected. after laparoscopic cystectomy, urinary diversion, was performed with procedures such as the bricker operation of ureterocutaneostomy according to the patient’s preference. “two-zone and three-segment” laparoscopic radical ttlrc vs clrc in bladder cancer-chen et al. variables total (n=60) ttlrc (n=29) clrc (n=31) p-value operating time, hours (mean±sd) total timea 3.4 ± 0.5 3.0 ± 0.2 3.8 ± 0.4 < 0.001 time to cystectomy and lymph node dissectiona 1.9 ± 0.4 1.7 ± 0.2 2.2 ± 0.3 < 0.001 ebl, ml (mean±sd) a 224.6 ± 47.6 182.1 ± 18.8 264.3 ± 27.4 < 0.001 pelvic lymph node dissection, n (%) 0.538 standard 53 (88.3) 26 (89.7) 27 (87.1) extended 7 (11.7) 3 (10.3) 4 (22.9) urinary diversion type, n (%) 0.424 ureterocutaneostomy 4 8 (80.0) 24 (82.8) 24 (77.4) ileal conduit 12 (20.0) 5 (17.2) 7 (22.6) transfusion, n (%) 8 (13.3) 2 (6.9) 6 (19.4) 0.15 time to ambulation, day, median (range) 2 (2-4) 2 (2-4) 2 (2-4) 0.764 time to oral intake, day, median (range) 3 (2-5) 2 (2-4) 3 (2-5) 0.409 time to flatus, day, median (range) 2 (2-4) 2 (2-4) 2 (2-4) 0.803 hospital stay after surgery, day, median (range) 5 (4-9) 5 (4-6) 7 (4-9) < 0.001 table 2. perioperative characteristics. abbreviations: ttlrc, “two-zone and three-segment” laparoscopic radical cystectomy; clrc, conventional laparoscopic radical cystectomy; sd, standard deviation; ebl, estimated blood loss; min, minute a these variables were compared by mann-whitney test variables total (n=60) ttlrc (n=29) clrc (n=31) p-value pt stage, n (%) 0.631 cis 2 (3.3) 1 (3.4) 1 (3.2) ta/t1 7 (11.7) 3 (10.3) 4 (12.9) t2 26 (43.3) 10 (34.5) 16 (51.6) t3 16 (26.7) 10 (34.5) 6 (19.4) t4 9 (15.0) 5 (17.2) 4 (12.9) pathological tumor grade, n (%) 0.327 low 11 (18.3) 4 (13.9) 7 (22.6) high 44 (73.3) 24 (82.8) 20 (64.5) squamous cell carcinoma 2 (3.3) 0 (0) 2 (6.5) adenocarcinoma 3 (5.0) 1 (3.4) 2 (6.5) concomitant cis, n (%) 5 (8.3) 3 (10.3) 2 (6.5) 0.666 pn stage, n (%) 0.608 pn0 52 (86.7) 25 (86.2) 27 (87.1) pn+ 8 (13.3) 4 (13.8) 4 (12.9) table 3. pathological characteristics. abbreviations: ttlrc, “two-zone and three-segment” laparoscopic radical cystectomy; clrc, conventional laparoscopic radical cystectomy; cis, carcinoma in situ vol 19 no 1 january-february 2022 138 cystectomy the “two-zone and three-segment” laparoscopic radical cystectomy technique was developed based on the pelvic anatomy. six formalin-fixed male cadavers, which were provided by the institute of anatomy, shandong university, were used to conduct anatomical studies. according to the anatomical characteristics of the lateral vascular pedicles of the bladder, we defined 3 segments: the superior bladder artery segment, the bladder vein segment, and the inferior bladder artery segment (figure 2a). the inferior bladder artery segment is also called the prostatic vascular pedicle segment. “two-zone and three-segment” laparoscopic radical cystectomy was performed as follows. the umbilical artery was first identified after releasing the ureter. the umbilical artery lateral plane was established distally toward the pelvic floor, an important procedure of this technique. on the interior side of the plane was the “lateral vascular pedicles of bladder” zone, while on the opposite side of the plane was the “lymph node dissection” zone (figure 2b). standard pelvic lymphadenectomy was performed in the areas of the common, external and internal iliac arteries and the obturator. the superior bladder artery segment and the bladder vein segment were dissected (figure 2c-d). mobilization of the posterior wall of the bladder was performed. then, the inferior bladder artery segment was dissected. the next steps were the same as in the conventional methods. demographic parameters and follow-up the following demographic parameters were recorded and analyzed by clinical researchers with no association with the operations (jf and sz): preoperative baseline clinicopathological and laboratory data, such as age, gender, history of smoking, bmi, clinical tumor stage, and hemoglobin, were obtained from the electronic medical records. perioperative data, including operation time, estimated blood loss (ebl), blood transfusion, urinary diversion method, time to ambulation, time to bowel recovery, time to oral intake and hospital stay, and oncologic data, including pathologic tumor stage, grade and lymph node metastasis status, were also assessed. operation time was defined as the duration of anesthesia from the beginning to the end. pathological t stages were uniformly adjusted according to the 2009 tnm classification as approved by the union internationale contre le cancer (7th edition), and tumor grade was assessed based on the 2004 world health organization (who) classification guidelines(2,4). laparoscopic and robotic urology 506 figure 2. the “two-zone and three-segment” laparoscopic radical cystectomy techinique. (a) anatomical picture of the lateral vascular pedicles of the bladder, which consists of three segments: i, the superior bladder artery segment; ii, the bladder vein segment; and iii, the inferior bladder artery segment. (b) laparoscopic image showing the two zones: i, the lateral vascular bladder pedicle zone; and ii, the lymph node dissection zone. iii represents the umbilical artery, and iv represents the umbilical artery lateral plane, which was the boundary between the two zones. (c) dissecting the superior bladder artery segment. (d) dissecting the bladder vein segment. (e) dissecting the inferior bladder artery segment. ttlrc vs clrc in bladder cancer-chen et al. vol 19 no 1 january-february 2022 37 postoperative complications were recorded and categorized using the modified clavien-dindo classification complications system introduced by dindo d et al.(14), which includs five groups and two subgroups. complications were classified as early complications (within 30 days) and late complications (31-90 days). common comorbidities were also recorded in detail, including hypertension, diabetes mellitus, coronary artery disease, chronic obstructive pulmonary disease and other chronic diseases. patients were followed postoperatively at least every 3–4 months for the first 2 years, biannually for the next three years, and annually thereafter. postoperative complication data were obtained by either chart review or telephone contact follow-up. this research complied with the guidelines for human studies and the research was conducted ethically in accordance with the world medical association’s declaration of helsinki. the research was approved by ethics committee of shandong university qilu hospital. approved number: kyll-2020-264 statistical analysis statistical analysis was conducted using the statistical package for social science (spss for windows, version 23.0, spss inc., chicago, il) software. quantitative data are shown as the mean ± sd, and categorical data are presented as the frequency (%). pearson’s chi square test or fisher’s exact test was used to evaluate the differences between categorical variables, student’s t test (meet the normality of distribution and homogeneity) and mann-whitney test (meet the nonparametric test) were used for continuous variables in this study. two-sided p values of less than 0.05 were considered statistically significant. results patient characteristics the baseline characteristics are shown in table 1. of the 63 patients who underwent lrc at our institution from march 2018 to march 2020, 3 patients were excluded because of exclusion criteria. the mean (sd) age of the total patients was 64.7 (10.9), and among the 60 patients, 20 (33.3%) had a history of smoking. the mean (sd) body mass index (bmi) was 24.1 (3.3). sixteen patients (26.7%) were clinically diagnosed with nmibc, and 44 (73.3%) were clinically diagnosed with mibc. a low tumor grade was found in 8 patients (13.3%), and a high tumor grade was found in 48 (80.0%). the median (lower quartile, upper quartile) duration of follow-up was 26 (19.75, 31.25). none of the patient clinical characteristics, including ecog-ps score, comorbidity, asa score and hb, were significantly different between the ttlrc and clrc groups (p > .05). perioperative characteristics the perioperative characteristics of the two groups are shown in table 2. the operating time of the ttlrc group was significantly shorter than that of the clrc group (total time: 3.0 ± 0.2 vs 3.8 ± 0.4, p < .001; time to cystectomy and lymph node dissection: 1.7 ± 0.2 vs 2.2 ± 0.3, p < .001). additionally, the ebl of the ttlrc group was significantly lower than that of the clrc group (182.1 ± 18.8 vs 264.3 ± 27.4). fifty-three patients (88.3%) underwent standard pelvic lymph node dissection, and 7 (11.7%) underwent extended pelvic lymph node dissection. forty-eight patients (80.0%) underwent lrc with ureterocutaneostomy and 12 (20.0%) underwent lrc with ileal conduits. moreover, except for hospital stay after surgery, there were no significant differences between the two groups in the transfusion rate, time to ambulation, time to oral intake or time to flatus. the pathological characteristics of the patients are shown in table 3. both the ttlrc and clrc groups included one patient with cis each, and 5 patients were found to have concomitant cis, 3 and 2 in the ttlrc and clrc groups, respectively. no significant differences were found in pathological t stage, tumor grade or n stage (p > .05). postoperative complications the early and late postoperative complications of the two groups are shown in table 4. during the follow-up period, only one death occurred in both groups. according to the clavien-dindo classification of postoperative laparoscopic and robotic urology 38 table 4. complications characteristics by clavien-dindo classification. variables total (n = 60) ttlrc (n = 29) clrc (n = 31) clavien-dindo classification p-value early complications (≤ 30 day), n (%) 0.033 paralytic ileus 8 (13.3) 2 (6.9) 6 (19.4) i anemia 7 (11.7) 2 (6.9) 5 (16.1) ii hypokalemia 4 (6.7) 2 (6.9) 2 (6.5) ii urinary tract infection 3 (5.0) 1 (3.4) 2 (6.5) ii blood transfusions 2 (3.3) 1 (3.4) 1 (3.2) ii entorrhagia 4 (6.7) 2 (6.9) 2 (6.5) iii rectal injury 4 (6.7) 1 (3.4) 3 (9.7) iii acute coronary syndrome 3 (5.0) 1 (3.4) 2 (6.5) iv heart failure 2 (3.3) 1 (3.4) 1 (3.2) iv late complications (31-90 day), n (%) 0.729 hydronephrosis 4 (6.7) 2 (6.9) 2 (6.5) i pyelonephritis 3 (5.0) 1 (3.4) 2 (6.5) ii urinary tract infection 5 (8.3) 2 (6.9) 3 (9.7) ii pneumonia 5 (8.3) 2 (6.9) 3 (9.7) ii deep venous thrombosis 1 (1.7) 1 (3.4) 0 (0.0) ii ureteral stricture 2 (3.3) 1 (3.4) 1 (3.2) iii urolithiasis 3 (5.0) 2 (6.9) 1 (3.2) iii renal failure 2 (3.3) 1 (3.4) 1 (3.2) iii death 1 (1.7) 0 (0.0) 1 (3.2) v ttlrc vs clrc in bladder cancer-chen et al. vol 19 no 1 january-february 2022 39 complications, thirty-seven patients (61.7%) experienced early complications. eight and 16 minor (i-ii) complications and 5 and 8 major (iii-iv) complications were observed in the ttlrc and clrc groups, respectively. the common complications were paralytic ileus and anemia. there was a significant significance between the two groups in early complications (i-ii vs iii-iv, p = .033), not in late complications (i-ii vs iiiiv, p = .729). discussion radical cystectomy is one of the most difficult urological surgeries, and the lrc procedure is difficult to master and technically challenging. most patients with bca are elderly males whose pelvis is narrow, which could increase the difficulties of surgery. the present study is the first paper comparing ttlrc and clrc in male patients. these operations were performed by the same laparoscopic surgical team, including three surgeons, in a single center. we used 6 male cadavers to conduct pelvic anatomical research and developed the improved ttlrc technique. there were variations in the superior vesical artery segment among the cadavers. most superior vesical arteries are derived from the umbilical artery, and a few are derived from the internal iliac artery directly. therefore, it is important to expose bladder-associated vessels, such as the superior vesical artery, umbilical artery, and obturator artery. it is also important for experienced surgeons to learn the anatomy from cadavers. a more detailed evaluation of anatomy has allowed a better understanding of the variability of vessels, prevents disruption of vessels, and helps guide the operational procedure. in the ttlrc group, the bladder vein segment, including the many branches derived from the bladder vein and part of the large veins, was the most common bleeding site in lrc surgery. a ligasure or endovascular gastrointestinal anastomosis (endo-gia) stapler was used to rapidly dissect this segment to shorten the operating time. moreover, for male patients who desire retention of erectile function, we should avoid thermal damage to preserve the neurovascular bundles (nvbs), which is another important step for the patients. tong et al. reported the anterior approach lrc could modify the laparoscopic visualization and enlarge the working space. this procedure also reduces the operation time and ebl without causing substantial differences in perioperative complications(15). additionally, compared with clrc, the extraperitoneal lrc technique resulted in a shorter time to flatus and time to liquid intake but had no benefit on operation time(16). in the present study, the ttlrc group showed benefits in early complications and perioperative outcome, including operating time, time to cystectomy and lymph node dissection and ebl. from our study, there were several surgical benefits for the ttlrc group. first, we divided the surgical location into two zones to dissect the vessels and lymph nodes separately, which improved visualization of the anatomical hierarchies. moreover, for patients of older age or moderate comorbidity status, a modified surgery in which only the bladder was dissected while the lymph nodes were left intact was conducted to shorten the operating time and further reduce the risk of surgery. last, we defined the male bladder-associated region, and systematically introduced a ttlrc vs clrc in bladder cancer-chen et al. surgical procedure that could be useful for laparoscopic-naive urologists. urinary diversion approaches can be divided into ureterocutaneostomy, ileal conduit and orthotopic neobladder. in addition, most of the complications are related to the use of the bowel. ureterocutaneostomy is the simplest form of diversion and has a lower complication rate(17). here, the incidence of ileus was lower in patients who underwent ureterocutaneostomy than in those described in other studies(18). ureterocutaneostomy was performed in more patients in the ttlrc group, which might be a potential factor influencing the shorter operation time. furthermore, extended lymph node dissection and ileal conduit diversion were performed more often in the clrc group, which also might have affected the operation time. there are a few limitations in this study. first, patients were recruited from a single center in this study, which could have caused selection bias. second, the sample size was small, and future studies should include an enlarged sample size. third, this is a retrospective study, not a randomized controlled trial, which is needed to improve the power in drawing a definitive conclusion in a future study. last, a comparison of the long-term clinical outcomes between ttlrc and clrc should be collected and analyzed in future studies. conclusions in conclusion, we studied the pelvic anatomy based on cadavers, and defined the zones and segments used for surgery to develop the “two-zone and three-segment” lrc procedure, whose outcomes were compared with conventional lrc. compared with clrc, ttlrc has several advantages, including a clearer surgical field, a shorter operating time and less blood loss. it is safe and feasible for urologists to perform this improved lrc procedure. acknowledgments this study was supported by the national natural science foundation of china (grant no. 81900637 to bk.shi, grant no. 81800672 to sz chen), the tai shan scholar foundation (ts201511092 to bk shi) and primary research & development plan of shandong province (2019gsf108123 to sz chen). conflicts of interest the authors have declared that no conflicts of interest exist. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2018;68:394424. 2. soukup v, čapoun o, cohen d, et al. prognostic performance and reproducibility of the 1973 and 2004/2016 world health organization grading classification systems in non-muscle-invasive bladder cancer: a european association of urology non-muscle invasive bladder cancer guidelines panel systematic review. eur urol. 2017;72:80113. 3. abufaraj m, dalbagni g, daneshmand s, et al. the role of surgery in metastatic bladder cancer: a systematic review. eur urol. 2018;73:543-57. 4. alfred witjes j, lebret t, compérat em, et al. updated 2016 eau guidelines on muscleinvasive and metastatic bladder cancer. eur urol. 2017;71:462-75. 5. williams sb, shan y, jazzar u, et al. comparing survival outcomes and costs associated with radical cystectomy and trimodal therapy for older adults with muscle-invasive bladder cancer. jama surg. 2018;153:881-9. 6. tang k, xia d, li h, et al. robotic vs. open radical cystectomy in bladder cancer: a systematic review and meta-analysis. eur j surg oncol. 2014;40:1399-411. 7. cao q, li p, yang x, et al. laparoscopic radical cystectomy with pelvic re-peritonealization: the technique and initial clinical outcomes. bmc urol. 2018;18:113. 8. novara g, catto jw, wilson t, et al. systematic review and cumulative analysis of perioperative outcomes and complications after robot-assisted radical cystectomy. eur urol. 2015;67:376-401. 9. sathianathen nj, kalapara a, frydenberg m, et al. robotic assisted radical cystectomy vs open radical cystectomy: systematic review and meta-analysis. j urol. 2019;201:715-20. 10. bochner bh, dalbagni g, sjoberg dd, et al. comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial. eur urol. 2015;67:1042-50. 11. novotny v, hakenberg ow, wiessner d, et al. perioperative complications of radical cystectomy in a contemporary series. eur urol. 2007;51:397-401; discussion -2. 12. zeng s, zhang z, yu x, et al. laparoscopic versus open radical cystectomy for elderly patients over 75-year-old: a single center comparative analysis. plos one. 2014;9:e98950. 13. mann u, ramjiawan r, nayak jg, patel p. heterogeneity in urology teaching curricula among canadian urology residency programs. can urol assoc j. 2021;15:e41-e7. 14. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 15. tong s, yang z, zu x, et al. anterior versus posterior approach laparoscopic radical cystectomy: a retrospective analysis. world j surg oncol. 2019;17:9. 16. feng l, song j, wu m, tian y, zhang d. extraperitoneal versus transperitoneal laparoscopic radical cystectomy for selected elderly bladder cancer patients: a single center experience. int braz j urol. 2016;42:655-62. 17. longo n, imbimbo c, fusco f, et al. complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. bju int. 2016;118:521-6. 18. li j, yang f, he q, wang m, xing n. laparoscopic radical cystectomy with intracorporeal ileal conduit: one center experience and clinical outcomes. int braz j urol. 2019;45:560-71. ttlrc vs clrc in bladder cancer-chen et al. laparoscopic and robotic urology 40 urol_montage.pdf urological oncology 23urology journal vol 6 no 1 winter 2009 bladder neck preservation during radical retropubic prostatectomy and postoperative urinary continence ali razi, seyed reza yahyazadeh, mohammad ali sedighi gilani, seyed mohammad kazemeyni introduction: bladder neck-sparing modification of radical retropubic prostatectomy has been reported to lower the risk of urinary incontinence after prostatectomy. we reviewed the outcomes in men with prostate cancer who had undergone prostatectomy with either bladder neck preservation or bladder neck reconstruction. materials and methods: in this retrospective study, a total of 103 patients who had undergone radical retropubic prostatectomy were assessed. the patients were divided into two groups of bladder neck preservation (51 patients) and bladder neck reconstruction (52 patients). we compared frequency of biochemical failure, bladder neck stricture, and urinary incontinence between these two groups. biochemical failure was defined as a serum prostate-specific antigen level higher than 0.2 ng/ml and its rising trend in at least 2 postoperative subsequent measurements. continence was defined as no need to use sanitary pads or diapers. results: the two groups were comparable in terms of age, serum prostatespecific antigen level, gleason score, and prostate volume. after a mean follow-up period of 32.5 months, all patients with bladder neck preservation and 46 (88.5%) with bladder neck reconstruction were continent (p = .03). there were no significant differences in the frequency of biochemical failure and bladder neck stricture that required dilation between the two groups of the patients. conclusion: bladder neck preservation during radical retropubic prostatectomy may improve long-term results of urinary continence and be effective in eradicating prostate cancer without increasing the recurrence rate. urol j. 2009;6:22-6. www.uj.unrc.ir keywords: radical prostatectomy methods, postoperative complications, urinary incontinence department of urology, shariati hospital, tehran university of medical sciences, tehran, iran corresponding author: ali razi, md department of urology, shariati hospital, north karegar st, tehran, iran tel: +98 912 159 0209 fax: +98 21 880 26010 e-mail: reza_mehr@yahoo.com received december 2007 accepted november 2008 introduction since the initial report of anatomic radical prostatectomy, refinements in the surgical technique have been made. researchers have proposed that preservation of as much of the bladder neck as possible at the time of removal of the prostate can speed up the return of urinary control after radical retropubic prostatectomy.(1-9) klein was the first to suggest that modification of the bladder neck resection and reconstruction at the time of radical retropubic prostatectomy might influence urinary control.(1) the majority of the studies indicate that there is little difference in the bladder neck preservation during radical prostatectomy—razi et al 24 urology journal vol 6 no 1 winter 2009 positive margin rates (bladder neck only) with this modification. nonrandomized controlled trials suggest that there may be small differences in the early (3 to 6 months) return of urinary control with little or no difference in long-term (l-year) urinary control using this method.(4,5,9) however, a high rate of positive margins in some studies makes this modification questionable.(8) in this study, we tried to determine whether the bladder neck-sparing modification of radical retropubic prostatectomy alters the likelihood of urinary incontinence after radical retropubic prostatectomy. materials and methods a retrospective analysis was performed on the clinical, pathologic, and follow-up findings in 103 patients who had undergone radical retropubic prostatectomy between 1999 and 2006. all surgical operations had been done by one surgeon at shariati hospital in tehran, iran. the patients were divided into 2 groups of bladder neck preservation (group 1) and bladder neck reconstruction (group 2). bladder neck reconstruction in group 2 had been done according to the classic tennis racket closure technique and spared within the first modified one. recurrence was defined as biochemical failure documented with a serum prostate-specific antigen (psa) level higher than 0.2 ng/ml and its rising trend in at least 2 postoperative subsequent measurements. continence was defined as no need to use sanitary pads or diapers. the student t test was used to compare continuous variables and the chi-square test or fisher exact test to compare categorical variables between the two groups. a p value less than .05 was considered significant. results the mean age of the patients was 64.9 ± 7.0 years (range, 35 to 78 years). their mean serum psa was 21.1 ± 20.9 ng/ml (range, 1.2 ng/ ml to 100 ng/ml) preoperatively. the mean gleason score and prostate weight were 6.1 ± 1.3 (range, 3 to 9) and 52.6 ± 22.8 g (range, 20 g to 130 g), respectively. of the patients, 51 had undergone radical retropubic prostatectomy with bladder neck preservation (group 1) and 52 had undergone the same operation with bladder neck reconstruction (group 2). there were no differences in characteristics of the patients between the two groups (table 1). after a mean follow-up period of 32.5 months (range, 6 to 84 months), the frequency of biochemical failure was not different between the two groups (table 2). all patients in group 1 and 46 (88.5%) in group 2 were continent (p = .03). the overall urinary incontinence frequency was 5.8% (6 patients). stricture of the bladder neck at the anastomosis site requiring transurethral dilation occurred in 3 (5.9%) and 4 (7.7%) patients in groups 1 and 2, respectively. patients with prostatectomy outcome bladder neck preservation bladder neck reconstruction p age, y 64.8 ± 5.9 65.0 ± 7.5 .80 psa, ng/ml 16.8 ± 15.4 23.3 ± 23.0 .10 gleason score 6.2 ± 1.2 6.0 ± 1.4 .30 prostate weight, g 52.1 ± 24.5 52.8 ± 22.1 .90 table 1. characteristics of patients with radical retropubic prostatectomy and bladder neck preservation or reconstruction patients with prostatectomy outcome bladder neck preservation bladder neck reconstruction p urinary continence 51 (100) 46 (88.5) .03 biochemical failure 6 (11.8) 14 (26.9) .05 bladder neck stricture 3 (5.9) 4 (7.7) .51 *numbers in parentheses are percents. table 2. outcome of radical retropubic prostatectomy with bladder neck preservation or reconstruction* bladder neck preservation during radical prostatectomy—razi et al urology journal vol 6 no 1 winter 2009 25 discussion in the present study, we compared the outcome of bladder neck preservation with bladder neck reconstruction while retropubic prostatectomy and found that even after a mean 32.5-month follow-up period, urinary continence rate was significantly higher in the bladder neck preservation group. this is in contrast to other reports suggesting that there might be a small difference in the short-term (3 to 6 months) and little or no difference in the long-term likelihood of urinary control return.(4,9) braslis and colleagues studied on a large nonrandomized series of 134 men who underwent radical retropubic prostatectomy with bladder neck preservation. margin rates (36.6%) and presence of tumor at or near the bladder neck (7.5%) were investigated. the authors reported return of continence in only 36 of the 134 patients during a 3-month period. their results indicated that 67% did not wear pads, 19% occasionally wore a pad, and 14% were incontinent.(3) lowe compared bladder neck preservation with bladder neck resection in a group of 200 men. continence rates in the first and second groups were reported to be 23.3 % and 11.2% at month 1, 44% and 62% at month 3, 70% and 82% at month 6, and the same at month 12 after the operation. lowe concluded that bladder neck preservation hastened the return of urinary control, but did not improve the overall continence in long-term.(4) shelfo and colleagues reviewed the miami cohort of 365 patients and reported a low rate of anastomosis stricture, no compromise of the surgical margins, and improved continence rate of 88% by 6 months after bladder neck preservation method of the surgery.(5) soloway and neulander reported only l% bladder neck stricture rate and l% positive margins at the bladder neck site in their series of more than 600 men who had undergone bladder neck-sparing surgery. they suggested that extensive resection at the bladder neck did not add to the curative nature of the procedure yet did not elaborate in detail on the return of urinary control.(7) however, deliveliotis and coworkers could not find any difference in incontinence rates in the long-term (1 year) and only found a significant difference in the shortterm (3 to 6 months) with preservation of the bladder neck.(9) in our study, biochemical failure rate of the bladder neck preservation group was slightly lower than the classic prostate resection group. all of the abovementioned studies appear to agree with the first goal of radical prostatectomy, namely cancer control. they also seem to agree that there is little difference in the positive margin rates (bladder neck only) with bladder neck preservation. however, the retrospective nature of our study is a considerable limitation, which mandate larger randomized prospective studies with longer follow-up periods in the future. although the negative frozen-section pathology report of bladder neck margin during surgery was the major indicator of bladder neck preservation technique, we mostly performed this type of surgery in sequence of the traditional bladder neck reconstruction surgery, and therefore, this will be another limitation of our study. conclusion we concluded that bladder neck preservation during radical retropubic prostatectomy may improve the long-term results of urinary continence, and it can be effective in eradicating prostate cancer without increased risk of recurrence. however, larger randomized prospective studies with longer follow-up periods are necessary for further elucidation of the role of bladder neck preservation during radical retropubic prostatectomy. conflict of interest none declared. references 1. klein ea. early continence after radical prostatectomy. j urol. 1992;148:92-5. 2. licht mr, klein ea, tuason l, levin h. impact of bladder neck preservation during radical prostatectomy on continence and cancer control. urology. 1994;44:883-7. 3. braslis kg, petsch m, lim a, civantos f, soloway ms. bladder neck preservation following radical prostatectomy: continence and margins. eur urol. 1995;28:202-8. bladder neck preservation during radical prostatectomy—razi et al 26 urology journal vol 6 no 1 winter 2009 4. lowe ba. comparison of bladder neck preservation to bladder neck resection in maintaining postrostatectomy urinary continence. urology. 1996;48:889-93. 5. shelfo sw, obek c, soloway ms. update on bladder neck preservation during radical retropubic prostatectomy: impact on pathologic outcome, anastomotic strictures, and continence. urology. 1998;51:73-8. 6. poon m, ruckle h, bamshad br, tsai c, webster r, lui p. radical retropubic prostatectomy: bladder neck preservation versus reconstruction. j urol. 2000;163:194-8. 7. soloway ms, neulander e. bladder-neck preservation during radical retropubic prostatectomy. semin urol oncol. 2000;18:51-6. 8. srougi m, nesrallah lj, kauffmann jr, nesrallah a, leite kr. urinary continence and pathological outcome after bladder neck preservation during radical retropubic prostatectomy: a randomized prospective trial. j urol. 2001;165:815-8. 9. deliveliotis c, protogerou v, alargof e, varkarakis j. radical prostatectomy: bladder neck preservation and puboprostatic ligament sparing--effects on continence and positive margins. urology. 2002;60:855-8. editorial comment in a study on the rate of continence after 2 surgical techniques for radical retropubic prostatectomy (rrp), razi and his colleagues concluded that saving bladder neck results in a better continence rate; a short, practical, and logic conclusion. i have no doubt that the study comes from one of our country’s few high-volume centers for rrp. as regards 100 rrps in a period of 7 to 8 years, we find out that they have 1 or 2 rrps in a month, and this is far more than the figures in many of our urology wards that have no or a limited experience in the field. so, their great efforts should be really appreciated. however, this study has a number of limitations. the first and most important is a methodological one. this study is a retrospective case series, and automatically, its level of evidence is 3 and the grade of recommendation for such studies is c. it means that any conclusion from the study should be extrapolated very cautiously. the second limitation is a selection bias. razi and colleagues had done 52 bladder neck reconstructing rrps and later on changed their technique to a bladder neck-saving rrp performing on 51 patients more. there was no randomization. the patients were operated sequentially and the experience of the surgeon has had deep influence on the superior continence rate of the patients undergoing bladder neck-saving rrp. defining continence as complete dryness (not even leak of a drop of urine or wearing one protection pad a day, while we know that in the other studies, patients who use 1 pad a day are considered continent), and having all patients in bladder neck-saving group, continent without even a case of positive surgical margin is more than excellent result. and the last problem is with me not with the study; i hardly ever can convince myself to justify rrp of any modification in patients with a prostate volume more than 100 ml, aged older than 70 years, a prostate-specific antigen higher than 20 pg/ml, and a gleason score of 8 or more. saeed shakeri department of urology, shahid faghihi hospital, shiraz university of medical sciences, shiraz, iran e-mail: shakeris@sums.ac.ir best reviewer of the july-august 2022 issue mohamed elawdy mohamed elawdy august 2022 mohamed elawdy is a graduate of mansoura urology and nephrology institute in egypt and working as a urology specialist (a) at the ministry of health, sultanate of oman. he is an international fellow, thomas jefferson university, philadelphia, usa and ecfmg certified. mohamed published more than 30 articles and reviewed more than 70 articles for different journals. in addition, he is an instructor in medical research, biostatistics, and scientific publication and teaches this industry to all medical professionals. he is also the author for ureteral fistulae chapter for “the ureter, comprehensive review”. karsiyakali n. is a urology specialist. he was awarded the title febu in 2019. he has published twenty papers in international peer-reviewed journals and thirteen papers in national peer-reviewed journals. he is currently working in an uro-oncology fellowship programme on robotic surgery in acıbadem, m.a. aydınlar university, altunizade hospital, i̇stanbul, turkey. bozkurt-girit was chosen as the best reviewer(s) of the issue by the editorial board of the urology journal for his valuable and timely review of manuscript”. best reviewer of the september-october 2021 issue karsiyakali n karsiyakali n october 2021 vol 19 no 1 january-february 2022 138 unclassified does the resected prostatic weight ratio affect the clinical outcomes in men who underwent bipolar transurethral resection of the prostate? peng zhang1, wenkui dong2, tao liu1, tongzu liu1, xing huang1,3* purpose: bipolar transurethral resection of the prostate (turp) is an effective and safe alternative to monopolar turp. the aim of this study was to investigate the influence of resected prostate weight on the clinical outcome improvement after bipolar turp for benign prostatic hyperplasia (bph) patients. materials and methods: a total of 233 men with bph who underwent bipolar turp were included in this prospective study. international prostate symptom score (i-pss), quality of life (qol), maximum flow rate (qmax) and post-void residual urine volume (pvr) were assessed preoperatively and 3 months postoperatively. the relationship between the resected prostatic weight ratio (rpwr, %) and clinical improvement was investigated. results: significant improvements in qmax, pvr, i-pss and qol were found 3 months after operation, and qmax was correlated with rpwr (r = 0.1521, p = .020). the rpwr was significantly higher in patients with postoperative qmax > 20 ml/s (p = .049). moreover, qmax at 3-month follow-up was higher in patients with rpwr over 50% than patients with rpwr between 0–25% (p < .05). in addition, patients with larger prostate volume tended to gain better qmax and i-pss postoperatively (p < .05). conclusion: the rpwr exerts an influence on postoperative qmax, rather than i-pss and qol score, and patients with larger prostate volume tend to gain better clinical outcomes from bipolar turp than those who with smaller prostates. keywords: benign prostatic hyperplasia; bipolar; clinical outcome; organ weight; transurethral resection of prostate introduction benign prostatic hyperplasia (bph) is one of the most common diseases in the aging male with prevalence increasing with age. lower urinary tract symptoms (luts) caused by benign prostatic obstruction (bpo) secondary to bph continue to pose a major problem for the contemporary medical care system. although luts/bph is not often life-threatening, the impact of luts/bph on patients’ quality of life (qol) can be significant and should not be underestimated.(1) transurethral resection of the prostate (turp) is the gold standard for the surgical management of bph, removing the adenomatous tissue by physically cutting away areas of excess prostatic cell growth in order to improve urinary function in men.(2) the therapeutic efficacy of turp in improving patients’ urinary flow and relieving luts, as assessed by international prostate symptom score (i-pss), has a success rate of 85-90%. (3) however, this monopolar electrocautery technique has some disadvantages, including the absorption of irrigation fluid resulting in transurethral resection (tur) syndrome, bleeding, incontinence, and so on.(4,5) therefore, prostate volume is a critical attribute for surgical 1department of urology, zhongnan hospital of wuhan university, wuhan 430071, china. 2department of urology, laohekou no.1 people’s hospital, laohekou 441800, china. 3center for evidence-based and translational medicine, zhongnan hospital of wuhan university, wuhan 430071, china. peng zhang and wenkui dong contributed equally to this study. *correspondence: department of urology, and center for evidence-based and translational medicine, zhongnan hospital of wuhan university, wuhan 430071, china. tel: +86 027 67813104, fax: +86 027 67813104, e-mail: hxsurgeon@whu.edu.cn received may 2021 & accepted november 2021 technique selection. according to the european association of urology guidelines, turp is the current surgical standard procedure for men with prostate sizes of 30 80 ml. the most significant recent technical modification of turp is the incorporation of bipolar technology. bipolar turp addresses a major limitation of monopolar turp by allowing performance using normal saline. thus, the risk of dilutional hyponatremia or tur syndrome has been expected to be eliminated allowing for longer and safer resection.(6) therefore, bipolar turp can be applied safely in patients with prostate gland larger than 80 ml, even over 100 ml.(7,8) however, it is not entirely clear as to how much clinical outcome improvement after bipolar turp is related to the extent of tissue resection which is achieved. in this prospective trial, we investigated the relationship between extent of prostatic tissue resection and symptom improvement after bipolar turp in men with luts/bph. materials and methods patients and study design this prospective study was performed at the departurology journal/vol 19 no. 1/ january-february 2022/ pp. 83-88. [doi: 10.22037/uj.v18i.6856] ment of urology, zhongnan hospital of wuhan university, between february 2017 and august 2018. the study was approved by the medical ethics committee of zhongnan hospital of wuhan university (approval date is 30.9.2016 and decision number is 2016028), and written informed consents were obtained from patients recruited into the study. the inclusion criteria were age 50 years or greater, medication failure, and bothersome moderate-to-severe luts secondary to bph. exclusion criteria included: documented or suspected prostate cancer, neurogenic bladder, bladder calculus or tumor, previous prostate surgery, urethral stricture, unable to be placed in lithotomy position, and bleeding disorders. preoperatively, all patients had undergone basic evaluation including a digital rectal examination as well as assessment of i-pss, qol, pvr and prostate volume (estimated by transrectal ultrasound). patients who had been scheduled for surgery underwent urinary flow rate measurements (laborie uroflowmetry, mississauga, canada) to determine the maximum flow rate (qmax). surgical procedures and follow-up bipolar turp was carried out in normal saline, and the irrigation fluid was a 0.9% sodium chloride solution. bipolar turp was conducted according to the principles of endoscopic electrosurgery described previously. (9) the resected tissues were weighted in the operating room immediately after the completion of bipolar turp. at the end of the procedure, a 22-fr 3-way foley catheter was placed for continuous bladder irrigation until the urine was clear. catheter was removed routinely on the 3-rd day following bipolar turp, and patients were usually discharged 1 day after catheter removal. follow-up of the study patients was done with examinations 3 months after bipolar turp, and treatment efficacy was evaluated by qmax, pvr, i-pss and qol. statistical analysis descriptive statistics were used, including the number and percentage, and the average and sd. statistical analysis was done by comparison of means with the t-test for paired or independent samples, as appropriate. one-way anova was used for a significance test of more than two samples mean differences. non-parametric test was used when the data did not follow a normal distribution. pearson correlation analysis was applied to evaluate relationship between continuous variables. data were analyzed with graphpad prism 5.0 with 2-sided p < .05 considered statistically significant. results a total of 233 men (mean age 71.2 years, range 55-90) who underwent bipolar turp for luts/bph were enrolled in this study. the mean body mass index (bmi) was 23.69 (sd 3.40, range 17-36), the mean preoperative prostate volume was 64.44 ml (sd 35.51, range 11-216) and the weight of resected tissue (wrt) was 28.38 g (sd 17.71, range 4-100). the resected prostatic weight ratio (rpwr, %) was calculated as wrt/prostate volume, giving the percentage of the resected tissue during the procedure. the mean rpwr was 46.25% (sd 19.59, range 12-97). age (figure 1a), bmi (figure 1b) and wrt (figure 1c) were correlated with preoperative prostate volume (r = 0.1407, p = .032; r = 0.2261, p = .001; r = 0.7296, p < .000). the evaluated parameters before and 3 months after bipolar turp are given in table 1. qmax, pvr, i-pss and qol at 3-month follow-up compared to preoperative values were marked and statistically significant. table 1. the evaluated parameters (means ± sd) before and 3 months after bipolar turp qmax (ml/s) pvr (ml) i-pss (0-35) qol (0-6) preoperative 7.15 ± 3.36 96.66 ± 121.80 24.10 ± 5.72 4.85 ± 0.87 postoperative 17.13 ± 5.66 11.02 ± 18.42 7.09 ± 4.60 1.86 ± 1.33 p-value < .000 < .000 < .000 < .000 paired samples t test or non-parametric test. abbreviations: qmax, maximum flow rate; pvr, post-void residual urine volume; i-pss, international prostate symptom score; qol, quality of life. table 2. the evaluated parameters (means ± sd) before (pre) and 3 months after (post) bipolar turp in subgroups of patients with different size (small to large) of prostate volumes prostate volume (ml) patients (n) age (years) bmi wrt (g) rpwr (%) ≤ 30 30 69.33 ± 6.75 22.13 ± 3.35 11.10 ± 4.09 54.21 ± 21.42 30 60 98 70.37 ± 7.37 23.78 ± 3.46 21.26 ± 9.96 * 47.67 ± 20.66 60 90 55 72.09 ± 7.69 23.41 ± 3.08 33.45 ± 13.65 * 44.45 ± 17.62 > 90 50 72.84 ± 7.00 24.75 ± 3.32 * 47.12 ± 20.02 * 40.68 ± 16.72 * p-value .095 .016 < .000 .021 one-way anova test.* p, compared to the smallest prostate volume (≤ 30 ml) abbreviations: bmi, body mass index; wrt, weight of resected tissue; rpwr, resected prostatic weight ratio; qmax, maximum flow rate; pvr, post-void residual urine volume; i-pss, international prostate symptom score; qol, quality of life continued qmax (ml/s) pvr (ml) i-pss (0-35) qol (0-6) pre post pre post pre post pre post 7.72 ± 3.65 12.72 ± 5.39 110.50 ± 116.30 20.00 ± 28.80 24.43 ± 5.80 9.53 ± 5.33 4.80 ± 0.89 2.20 ± 1.38 7.00 ± 3.25 17.12 ± 5.38 * 90.54 ± 111.30 9.72 ± 15.66 24.70 ± 5.37 7.05 ± 5.02 * 4.89 ± 0.85 1.97 ± 1.35 6.65 ± 3.53 18.33 ± 5.82 * 103.40 ± 152.30 8.51 ± 14.70 24.15 ± 5.29 6.44 ± 3.75 * 4.95 ± 1.01 1.51 ± 1.15 7.66 ± 3.21 18.49 ± 4.97 * 92.92 ± 108.90 10.92 ± 18.23 22.66 ± 6.63 6.42 ± 3.63 * 4.72 ± 0.73 1.84 ± 1.38 .302 < .000 .852 .101 .404 < .05 .214 .088 resected tissue ratio and outcomes after bipolar turp-zhang et al. unclassified 84 vol 19 no 1 january-february 2022 85 bipolar turp provides subjective (i-pss, qol) and objective (qmax, pvr) symptom improvement after the operation. at 3-month follow-up, qmax (figure 2a) showed a significant correlation with rpwr (r = 0.1521, p = .020), however, there was no significant correlation between rpwr and pvr (figure 2b), i-pss (figure 2c) or qol (figure 2d) 3 months postoperatively (p = .945, p = .243, p = .154). furthermore, rpwr was significantly higher in patients with qmax > 20 ml/s postoperatively than that in patients with qmax ≤ 20 ml/s postoperatively (50.11 ± 19.81 % vs. 44.82 ± 19.37 %, p = .049) (figure 3a). however, there was no significant difference of rpwr between patients with i-pss ≤ 7 and > 7 at 3-month follow-up (figure 3b). in order to determine the influence of rpwr on the objective (qmax) and subjective (i-pss) indicators in patients after bipolar turp, rpwr was divided into four levels with equal distance, i.e. 0-25%, 25%-50%, 50%-75% and 75%-100%. there were no differences of the preoperative qmax and i-pss among patients with different levels of rpwr (figure 3c and 3e). the qmax at 3-month follow-up was higher in patients with rpwr between 50%-75% or 75%-100% than that in figure 1. correlation between age (a), bmi (b), wrt (c), rpwr (d) and preoperative prostate volume, respectively. figure 2. correlation between qmax (a), pvr (b), i-pss (c), qol (d) and rpwr at 3-month follow-up, respectively. resected tissue ratio and outcomes after bipolar turp-zhang et al. patients with rpwr between 0–25% (18.32 ± 6.06 or 18.10 ± 6.62 vs. 13.47 ± 5.42, p < .05) (figure 3d). however, there was no significant difference of i-pss at 3-month follow-up among patients with different levels of rpwr (figure 3f). the evaluated parameters before and 3 months after bipolar turp in subgroups of patients with different size (≤ 30 ml, 30-60 ml, 60-90 ml, and > 90 ml) of prostate volumes are shown in table 2. there were significant differences in the mean wrts between these groups (p < .000). among these four groups with increasing prostate volumes, patients with larger prostate volume tended to gain better qmax (p < .000) and i-pss (p < .05) postoperatively. discussion the perioperative morbidity of monopolar turp in terms of blood loss and fluid absorption is related to the size of the prostate. the complications increase with increasing resection time and resected tissue volume following monopolar turp.(1) indeed, complete resection of the adenomatous tissue is not absolutely necessary in order to reduce the complications of turp in clinical practice, as long as the relief from bpo is achieved. (10) nevertheless, the association between the amount of resected prostate tissues and clinical outcome improvement in men with luts/bph remains to be uncovered. for the patients with luts/bph, the most important outcome parameters are the subjective and objective symptom improvements as assessed by symptom scores and uroflowmetry.(11) in a prospective study, hakenberg et al. found early symptom improvement after turp depended on the amount of tissue removed while the relationship was weak, and the symptomatic improvement after turp was not primarily dependent on the relative completeness of the resection.(10) the most significant recent technical modification of turp is the incorporation of bipolar technology allowing performance in normal saline. more and more studies have shown that bipolar turp is an effective/ safe conventional turp alternative with the potentiality in decreasing perioperative/similar short-term complication rates.(12-15) bipolar turp has a reduced risk of hyponatremia and tur syndrome, which allows for longer resection times and surgery on larger glands. (1,7,8,13) so far there is few studies on clinical outcome improvements after bipolar turp regarding to the extent of resected tissues. previous studies and analyses have confirmed that baseline prostate volume is related to progression of bph as resected tissue ratio and outcomes after bipolar turp-zhang et al. figure 3. differences of rpwr between patients with qmax > 20 ml/s and ≤ 20 ml/s (a), and patients with i-pss ≤ 7 and > 7 (b) at 3-month follow-up, respectively. differences of qmax (c, d) and i-pss (e, f) before and 3 months after bipolar turp among patients with different levels of rpwr. unclassified 86 vol 19 no 1 january-february 2022 87 well as to negative outcomes related to bph, and can also predict response to therapy.(16) however, prostate size is obviously different among men with bph, and solely using the absolute amount of resected tissue may not accurately reflect the therapeutic efficacy of transurethral prostatectomy. therefore, a relative rpwr, calculated as wrt/prostate volume, was adopted in our study to predict the efficacy of bipolar turp. in the present study, we found that age, bmi and wrt were correlated with preoperative prostate volume, while a negative correlation was revealed between rpwr and the prostate volume (figure 1). as men age, symptoms worsen and obstruction and prostate volume increase.(16) in addition, with prostate volume increasing, wrt during bipolar turp increases accordingly, which is consistent with the previous study of conventional turp.(10) however, for patients with larger prostate glands, even if enough adenomatous tissues were removed, rpwr will still be low since the preoperative prostate volume was too large. the rpwr was significantly correlated with qmax at 3-month follow-up in our study, and higher in patients with qmax > 20 ml/s than that in patients with qmax ≤ 20 ml/s postoperatively (p = .049). in addition, patients with rpwr over 50% will have higher postoperative qmax than patients with rpwr between 0–25% (p < .05). these findings suggest that rpwr can be used to predict the efficacy of bipolar turp, that is more than half amount of the prostate volume should be removed in order to gain better qmax improvement after bipolar turp. on the contrary, there was no significant correlation between rpwr and i-pss or qol 3 months after bipolar turp. symptom scores including i-pss and qol are obtained through questionnaires with subjective features, and many other factors (prolonged tissue healing, scar formation, shrinkage of the prostatic fossa, adaption of the bladder to the altered outflow conditions) will influence the degree of luts over the first 6 postoperative months.(10) individual symptom resolution after turp may be prolonged in up to 15% of cases and can take up to 12 months.(17) therefore, rpwr cannot be used to predict i-pss and qol improvement at the early stage after bipolar turp. in the present study significant improvements in qmax, pvr, i-pss and qol were found 3 months after bipolar turp. recently stucki et al(18) reported in their prospective randomized trial that the preoperative to postoperative improvements in i-pss, qmax and pvr were highly significant in bipolar turp group at 3-month follow-up, which is consistent with our results. furthermore, patients with larger prostate volume tended to gain better qmax and i-pss improvements after bipolar turp, which has also been proved in conventional turp.(10) there are some limitations in this study. first of all, the follow-up periods were too short, just 3 months after bipolar turp. therefore, more studies with longer follow-up periods are needed in the future. secondly, the prostate tissue weight reduction due to vaporization process occurring during bipolar turp was ignored. the weight of the adenoma lost due to vaporization during turp accounted for 30.10 ± 7.71% of total prostate weight reduction.(19) however, tissue lost due to vaporization may be less in bipolar turp than that of conventional turp because bipolar turp leads to less heat in the prostatic tissue surrounding the electrode.(20) conclusions in the present study, rpwr is associated with qmax improvement after bipolar turp, while there was no correlation between rpwr and postoperative i-pss/ qol improvements. in addition, patients with larger prostate volume tend to gain better clinical outcomes from bipolar turp than those with smaller prostates. prostate volume is a critical attribute for surgical technique selection. further researches with long-term follow-up among patients undergoing bipolar turp are worthy to be carried out. conflict of interest none declared. references 1. foster he, barry mj, dahm p, et al. surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: aua guideline. j urol. 2018;200:612-9. 2. sofimajidpour h, khoshyar a, zareie b, sofimajidpour h, rasouli ma. comparison of the effectiveness and safety of transvesical open prostatectomy versus transurethral resection of the prostate in patients with benign prostatic hyperplasia with a prostate weight of 65-40 gram. urol j. 2020;18:28994. 3. reich o, gratzke c, stief cg. techniques and long-term results of surgical procedures for bph. eur urol. 2006;49:970-8. 4. rassweiler j, teber d, kuntz r, hofmann r. complications of transurethral resection of the prostate (turp)--incidence, management, and prevention. eur urol. 2006;50:969-79. 5. liang x, wu w, huang y, et al. safety of surgery in benign prostatic hyperplasia patients on antiplatelet or anticoagulant therapy: a systematic review and metaanalysis. urol j. 2020;18:151-9. 6. mamoulakis c, de la rosette j. bipolar transurethral resection of the prostate: darwinian evolution of an instrumental technique. urology. 2015;85:1143-50. 7. huang jy, li s, yang zh, zeng xt, wang xh. efficacy and safety of plasmakinetic resection of the prostate in patients with a prostate gland larger than 80 cc: 30-month follow-up results. j endourol. 2015;29:9258. 8. coskuner er, ozkan ta, koprulu s, dillioglugil o, cevik i. the role of the bipolar plasmakinetic turp over 100 g prostate in the elderly patients. int urol nephrol. 2014;46:2071-7. 9. starkman js, santucci ra. comparison of bipolar transurethral resection of the prostate with standard transurethral prostatectomy: shorter stay, earlier catheter removal and fewer complications. bju int. 2005;95:69-71. 10. hakenberg ow, helke c, manseck a, wirth mp. is there a relationship between the amount of tissue removed at transurethral resection resected tissue ratio and outcomes after bipolar turp-zhang et al. unclassified 88 of the prostate and clinical improvement in benign prostatic hyperplasia. eur urol. 2001;39:412-7. 11. hakenberg ow, pinnock cb, marshall vr. does evaluation with the international prostate symptom score predict the outcome of transurethral resection of the prostate? j urol. 1997;158:94-9. 12. kwon js, lee jw, lee sw, choi hy, moon hs. comparison of effectiveness of monopolar and bipolar transurethral resection of the prostate and open prostatectomy in large benign prostatic hyperplasia. korean j urol. 2011;52:269-73. 13. bhansali m, patankar s, dobhada s, khaladkar s. management of large (>60 g) prostate gland: plasmakinetic superpulse (bipolar) versus conventional (monopolar) transurethral resection of the prostate. j endourol. 2009;23:141-5. 14. yousef aa, suliman ga, elashry om, elsharaby md, elgamasy ael n. a randomized comparison between three types of irrigating fluids during transurethral resection in benign prostatic hyperplasia. bmc anesthesiol. 2010;10:7. 15. ho hs, cheng cw. bipolar transurethral resection of prostate: a new reference standard? curr opin urol. 2008;18:50-5. 16. nickel jc. benign prostatic hyperplasia: does prostate size matter? rev urol. 2003;5(suppl 4):s12-7. 17. hakenberg ow, pinnock cb, marshall vr. the follow-up of patients with unfavourable early results of transurethral prostatectomy. bju int. 1999;84:799-804. 18. stucki p, marini l, mattei a, xafis k, boldini m, danuser h. bipolar versus monopolar transurethral resection of the prostate: a prospective randomized trial focusing on bleeding complications. j urol. 2015;193:1371-5. 19. szopinski t, golabek t, chlosta p, borowka a. determination of prostate adenoma weight reduction due to vaporisation process occurring during transurethral resection of the prostate. wideochir inne tech maloinwazyjne. 2014;9:404-8. 20. wendt-nordahl g, häcker a, fastenmeier k, et al. new bipolar resection device for transurethral resection of the prostate: first ex-vivo and in-vivo evaluation. j endourol. 2005;19:1203-9. resected tissue ratio and outcomes after bipolar turp-zhang et al. dorsal versus ventral dartos flap to prevent fistula formation in tubularized incised plate urethroplasty for hypospadias doğakan yiğit1*, dinçer avlan2 purpose: the purpose of this study is to evaluate the results of two different flap procedures for the prevention of urethrocutaneous fistula in hypospadias patients undergoing tubularized incised plate urethroplasty . patients and methods: we retrospectively reviewed 89 patients who underwent hypospadias repair. the standard technique of tubularized incised plate urethroplasty was used. there were 45 patients in group 1 and 44 patients in group 2, in which ventral and dorsal dartos flaps were used to cover the neourethra respectively. surgical complications were assessed as the main outcomes. the results were analyzed with chi-square and mann-whitney u tests. results: there was no significant difference between the groups in terms of age and meatus location. we observed postoperative surgical complications in 15 (33.3 %) patients in group 1 and in 4 (9.1 %) patients in group 2. the complications noted in the group 1 were urethrocutaneous fistula in 10 patients ( 22.2 %) and meatal stenosis in 5 patients ( 11.1 %). in group 2, fistula was observed in 2 patients (4.6 %) and stenosis in again 2 patients (4.6 %). urethrocutaneous fistulas occurred statistically more frequently when ventral based dartos flaps were used (p < .05). conclusion: several flap procedures and their modifications have been suggested to avoid fistula formation. within these procedures, dartos flaps are reported to be very useful for primary distal or proximal hypospadias repair and reoperations. in this study, we concluded that vascularized dorsal preputial dartos flap procedure is safe and more effective than ventral based flap in the prevention of fistula formation. keywords: dartos flap; hypospadias; tubularized incised plate urethroplasty; urethrocutaneous fistula 1department of pediatric surgery and pediatric urology, health sciences university prof. dr. cemil taşçıoğlu city hospital, i̇stanbul, turkey. 2department of pediatric surgery and pediatric urology, trakya university hospital, edirne, turkey. *correspondence: department of pediatric surgery and pediatric urology , i̇stanbul , turkey. tel : +90 212 3145500. fax : +90 212 3145512. e-mail: dogakanyigit@gmail.com received december 2021 & accepted june 2022 introduction hypospadias is one of the most common malforma-tions of the external male genitalia and the incidence is about 1/200 to 1/300 of live births(1). although, numoreous different techniques are described for hypospadias repair, complications, such as urethrocutaneous fistula and urethral stenosis, still remain a major problem in a significant amount of patients(2). tubularized incised plate urethroplasty (tipu) has gained vast popularity among pediatric urologists for hypospadias repair, because of its low complication rate and better cosmetic results, especially anatomical appearance of glans with slit like meatus(3). however, urethrocutaneous fistula formation and meatal stenosis still exist as common complications, which are reported as high as 16 25 % and 15 21 % respectively(4,5,6,7). other possible complications of tipu procedure are wound dehiscence, urethral diverticula, skin necrosis, penile necrosis, and hematoma(7). one of the most important factors in reducing fistula formation in hypospadias repair is the application of a protective intermediate layer between the neourethra and the skin. for this reason, several flap procedures and their modifications have been suggested to avoid fistula formation(8-12). within these procedures, dartos flaps are reported to be very useful for primary distal or proximal hypospadias repair and the reoperations(9,11). in this study, we aimed to investigate the efficacy of dorsal preputial dartos flap and ventral dartos flap in the prevention of fistula formation in tipu surgery. patients and methods study population after approval from the ethics committee (08.06.2021/1915), we retrospectively reviewed the records of 89 patients who had undergone hypospadias repair in the pediatric surgery and the pediatric urology departments of prof.dr.cemil taşçıoğlu city hospital and trakya university hospital between 2015 and 2020 . patients of only two surgeons were enrolled in the study. patients who were operated on with tipu procedure for distal and midpenile hypospadias were included in the study. study design this study was designed as a retrospective study and conducted with patients of two different centers. patients’ files, examination notes and surgery notes were investigated and surgical complications, mainly urethrocutaneous fistula and meatal stenosis were recorded. urology journal/vol 19 no. 4/ july-august 2022/ pp. 315-319. [doi:10.22037/uj.v19i.7098] pediatric urology inclusion criteria patients operated with tipu procedure for distal and midpenile hypospadias were included in the study. patients with proximal hypospadias, even if they were operated on with single stage tipu procedure, and patients with repeated tipu procedures were not included in the study. surgical technique the standard technique of tipu was used for hypospadias repair in all patients. briefly; after placing a traction suture at the tip of the glans, a u-shaped incision extending along the edges of the urethral plate to healthy skin, proximal to the hypospadiac meatus is made. then, penis was degloved and if there is any chordee, it was corrected by dorsal plication. the urethral plate was widened by a deep midline incision including the mucosa and submucosa from the midglandular meatus to the tip of the urethral plate. this incised urethral plate was then tubularized in a one layer running subcuticular fashion with absorbable 6/0 or 7/0 polydioxanone sutures (pds, ethicon) over a 6 –or 8fr. feeding tube, depending on the age and the width of native urethral plate. in group 1 (ventral based dartos flap n=45), after completion of urethroplasty, a ventral based vascularized dartos flap was created from both the right and the left side of the urethral corporal groove (figure 1a,1b). the dissection was terminated before the native meatus was reached to avoid any injury threatening vascular supply of the flap. to cover neourethra completely, the flap was fixed into the lateral recesses of the raised glans’ wings with absorbable sutures. in group 2 (dorsal preputial dartos flap n=44), the sutures were placed to the borders of the inner face of the prepuce, and the flap was incised just into the subcutaneous tissue level. the underlying dartos layer was sharply dissected to the base of the penis. thus, a vascularized dorsal preputial dartos flap was harvested (figure 2). the flap was then rotated from the lateral side of the penis to cover the neourethra, and sutured around the neomeatus and inner surface of the glandular wings on each side, using interrupted absorbable sutures. in both groups; the glandular wings were brought gently together with no tension and closed over the neourethra and dartos flap. in all patients, the ure group 1 (n=45) group 2 (n=44) p value age (years) mean ± sd 4.8 ± 2.5 5.4 ± 2.5 .182a median ( iqr) 4.0 (3.0-6.5) 5.0 (4.0-7.0) mean difference: 0.6 follow-up (months) mean ± sd 25.6 ±11.7 26.5 ± 13.0 .858a median ( iqr) 24.0 (21.0-36.0) 24.0 (12.0-36.0) mean difference: 0.9 n (%) n (%) distal penile 40 (88.9 %) 38 (86.4 %) .714b mid penile 5 (11.1 %) 6 (13.4 %) chordee 9 (20 %) 6 (13.4 %) .423b table 1. clinical features of the patients amann whitney u test bchi-square test figure 1. a: ventral appearance of the ventral based flap. b: appearance from above the flap dartos flap to prevent fistula formation in hypospadias – yiğit et.al vol 19 no 4 july-august 2022 316 thral catheter was removed 1 week after the operation. until the time of catheter removal, oral antibiotics and anticholinergics were used to prevent postoperative infection and urinary leakage due to bladder irritation. evaluation surgical complications were collected retrospectively as the main outcomes of this trial. the total number of surgical complications and specifically the rate of fistula formation were compared between the two different flap techniques used. statistical analysis the data were analyzed using ibm spss version 26.0 (ibm corp. released 2019. ibm spss statistics for windows, version 26.0. armonk, ny: ibm corp) statistical software. the continuous variables were presented as mean ± sd and median (minimum-maximum) values; the categorical variables were presented as numbers and percentages. mann-whitney u test was used to compare the mean age of the two groups. type of hypospadias, chordee and complication percentages of two groups were compared using chi-square test and fisher’s exact test respectively. results 89 patients with distal and midpenile hypospadias who were operated on with tipu technique were included in the study. the mean age of the patients was 5.1 years (range 1-12). 78 patients had distal penile and 11 patients had midpenile hypospadias. there was no significant difference between the groups in terms of age, meatus location, and the presence of chordee (p > .05) clinical features of the patients are shown in table 1. mean follow-up was 25.6 ±11.7 (median:24, iqr:2136) months for group 1 and 26.5±13.0 ( median:24, iqr :12-36) months for group 2. there was no statistical significance between groups in terms of follow-up duration (p = .858) we recorded postoperative complications in 15 patients (33.3 %) in group 1, and in 4 patients (9.1 %) in group 2. in group 1, urethrocutaneous fistula was detected in 10 patients (22.2 %), and meatal stenosis in 5 patients (11.1 %). there was urethracutaneous fistula in all patients who also had meatal stenosis. in group 2, fistula was detected in 2 patients (4.6 %) and stenosis in 2 patients (4.6 %). all patients with meatal stenosis had also urethrocutaneous fistula. these patients were easily treated with urethral dilatation. the frequency of fistula was found to be statistically higher in group 1 patients ( 95 % ci : 1.14558.83 , or = 5.892 , p < .05). there was no significant difference between the groups in terms of stenosis frequency (95% ci : 0.2807 24.22 , or = 2.083 , p = .284 ). complications belonging to the groups are listed in table 2. in the postoperative dartos flap to prevent fistula formation in hypospadias – yiğit et.al group 1 (n=45) group 2 (n=44) total (n = 89) or (95%ci) p value fistula 10 (22.2%) 2 (4.6 %) 12 (13.4 %) 5.892 (1.14558.83) .029a stenosis 5 (11.1%) 2 (4.6%) 7 (7.8 %) 2.083 (0.2807, 24.22) .676a total 15 (33.3%) 4 (9.1) 19 (21.3 %) 4.912 (1.379, 22.43) .005b table 2. postoperative complications afisher’s exact test bchi-square test figure 2. dorsal preputial dartos flap is rotated from the lateral side of the penis. pediatric urology 317 period, we did not detect any vascular complications of the flap or penile rotation in any patient. discussion although there are many different surgical techniques for hypospadias repair, the ideal surgical procedure with the least complication rate is yet to be described. tipu operation has gained respect by pediatric urologists for the treatment of many different types of hypospadias (3,13,14) . moreover, tipu has been used not only for primary hypospadias repair surgery but also used for reoperation of hypospadias(15,16). despite obvious excellent surgical results with this technique, urethrocutaneous fistula still remains to be a complication even in well-experienced hands. the rates of fistula for tipu procedure in distal and proximal types of hypospadias and in the reoperation cases as well were reported in a variable range of 0-to-33 % (4,5,13,15,16). the risk of fistula formation without a flap, covering neourethra, is higher than the techniques where a flap was used. telfer et al. reported that using a protective intermediate layer reduced the fistula rate from 64 to 4.5 %(17) . one of the most important factors in avoiding the fistula formation is to cover the noeurethra with a second layer. it has been suggested that the interposition of a well vascularized tissue between neourethra and penile skin reduces the incidence of fistula(3,8,18) . initially, an epithelialized skin flap technique was described by smith in 1973 as an intermediate layer(19) . since then, various procedures and different tissues such as de-epithelialized skin, tunica vaginalis, and dartos flaps were described to solve this problem. baccala et al. have used de-epithelialized dorsal skin flaps as interposed tissue to cover neourethra(12). shanberg et al. have reported that a lateral based de-epithelialized skin flap was successfully used in reoperated hypospadias patients(20). although snodgrass has described using a dorsal based dartos flap in the original article of himself in 1994, many pediatric urologists have already used ventral based dartos flap and its modifications in tipu. furness reported that using the ventral based vascularized dartos flap to cover the neourethra in tipu , has a success rate of 98.2 % without any major complications(21). in a recent study by carmine et al., dissection of fascial flaps also demonstrated a reduction in stenotic complications even in the surgical correction of phymosis(22). in a prospective randomized comparative study, savanelli et al. showed that the use of ventral based vascularized subcutaneous dartos tissue has reduced fistula formation compared to noncovered urethroplasty in tupu repair for distal hypospadias(23) . the fistula rate was reported as 3.8% in this study. soygur et al. have used the ventral based dartos flap in combination with mucosal collars as an effective modification. the authors reported that the incidence of the fistula was 8.3 %(11) . in addition, it was revealed in a study that using ventral based dartos flap in several different kinds of urethroplasty reduced the fistula formation(10). on the other hand, smith used the ventral based pedicle flap for covering the neourethra in tipu in 64 patients and reported that fistula rate was 12,5 % (24). on the contrary, our fistula rate in group 1 was 22.2 %. probably, the most important reason of a high fistula rate in our study was technical failure in the preparation of the ventral based flap, which resulted in insufficient blood supply of the flap itself or a very thin flap tissue, which compromised the perfusion. in the original article of snodgrass, a transverse island of dorsal subcutaneous tissue was used to cover the neourethra(3) . later on, different reports reported mobilizing a vascularized pedicle flap from dorsal prepuce and transposing it to the ventral side of the penis(25,26) . because the latter technique was reported to cause some potential complications such as penile torsion, chordee or skin loss, sözübir and snodgrass performed a pedicled dartos flap, which was buttonholed and transposed ventrally for urethral coverage(18). however, we suggest that if the dorsal dartos is dissected deeply through the radix of penis without causing any tension of skin, these complications can easily be avoided. fistula rates in tipu using dorsal preputial dartos flap have been reported to vary from 0 % to 13 % (8,18). furthermore, there are studies suggesting that the use of a double dorsal dartos flap was more effective than a single layer flap(9,27). the fistula rate after using a double flap was reported as 0 % in both studies. jia et al. compared the complication results of tipu repair using either dorsal dartos flap or meatus-based ventral dartos flap(28). they reported ventral skin necrosis in 2.7 % of patients and penile rotation in 3.8% of patients in the dorsal dartos flap group (p = .039, p = .016 respectively) fistula rates were found to be 2.7% in the dorsal dartos flap group and %2.9 meatus-based ventral dartos flap group (p = .902). in another study, fahmy et al. compared the results of dartos flap and tunica vaginalis flap and stated that complication rates were the lowest in the patients with double dartos flap (p = .004)(29) . he also stated that there may be complications such as vascular and penile rotation with the dartos flap. in our study group 2 consisted of patients that we used dorsal preputial dartos flap. the flap was harvested from preputial skin and deeply dissected to the radix penis, and then the flap was transposed from the left or right side to the ventral aspect of the penis. penile rotation was avoided because the flap has dissected without tension through the radix penis. besides, we have not detected any vascular complications in our dorsal flaps. the use of this technique achieved satisfactory outcomes in our patients. in this group, all fistulas developed only in association with meatal stenosis. we suppose that the meatal stenosis could be the underlying reason for urethrocutaneous fistula formation. the strength of this study is that it was conducted with a homogenous patient group with similar age and similar type of hypospadias. the weakness of this study is that it is a retrospective study. further prospective studies will help to confirm our results. conclusions in conclusion, tipu repair represents an effective procedure to treat patients with hypospadias.. the dorsal preputial dartos flap provided a much better outcomes and less fistula formation in our study. we explain the advantages of this technique is possibly a thicker, wider and more vascularized flap tissue compared to a ventral based flap, which led us to name it as “the blanket of neourethra” or “the omentum of the penis”. we believe that the vascularized dorsal dartos flap procedure is safer and more effective than ventral based flap to prevent fistula formation. dartos flap to prevent fistula formation in hypospadias – yiğit et.al vol 19 no 4 july-august 2022 318 conflict of interest the authors have no conflict of interest to disclose. references 1. baskin ls, colborn t, hime k. hypospadias and endocrine disruption: is there a connection ? environ health perspect. 2001;109:1175 83 2. manzoni g, bracka a, palminter e, marrocco g. hypospadias surgery: when, what and by whom. bju int. 2004; 94:1188-95 3. snodgrass w. tubularized incised plate urethroplasty for distal hpospadias. j urol. 1994; 151:464-5 4. guralnick ml, al-shammari a, williot pe, leonard mp. outcome of hypospadias repair using the tabularized incised plate urethroplasty. can j urol. 2000; 7: 986-91 5. elicevik m, tireli g, sander s. tubularized incisd plate urethroplasty: 5 years experience eur urol. 2004; 46: 655-9 6. güler y. tipu outcomes for hypospadias treatment and predictive factors causing urethrocutaneous fistula and external urethral meatus stenosis in tipu: clinical study. andrologia 2020;52 e13668. doi: 10.1111/ and.13668. epub 2020 jun 5 7 . alshafei a, cascio s, boland f, o’shea n, hickey a, quinn f. comparing the outcomes of tubularized incised plate urethroplasty and dorsal inlay graft urethroplasty in children with hypospadias: a systematic review and meta-analysis. j pediatr urol 2020;16:154-61 8. djordjevic mi, perovic sv, slavkovic z, djakovic n. longitudinal dorsal dartos flap for prevention of fistula after a snodgrass hypospadias procedure. eur urol 2006; 50: 53-7 9. bakan v, yildiz a. dorsal double-layer dartos flap for preventing fistula formation in the snodgrass technique. urol int. 2007; 78: 2414 10. hayashi y, kojima y, nakane a, karakoma s, tozawa k, kohri k. ventral based dartos flap for the prevention of the urethrocutaneous fistula urethroplasy. int j urol 2007; 14:725-8 11. soygur t, arikan n, zumrutbas ae, gulpinar o. snodgrass hypospadias repair with ventral based dartos flap in combination with mucosal collars. eur urol 2005; 47: 879-84 12. baccala aa, ross j, detore n, kay r. modified tabularized incised plate urethroplasty (snodgrass) procedure for hypospadias repair urology 2005; 66:1305-06 13. snodgrass w, yucel s. tubularızed incised plate for midshaft and proximal hypospadias repair. j urol 2007;177:698-702 14. mustafa m. the concept of tubularized incised plate hypospadias repair for different types of hypospadias. int urol nephrol 2005; 37:89-91 15. borer jg, bauer sb, peters ca, diamond da, atala a, cilento bg, et al. tubularized incised plate urethroplasty: expanded use in primary and repeat surgery for hypospadias. j urol. 2001; 165: 581-5 16. nguyen mt, snodgrass w. tubularized incised plate hypospadias reoperation. j urol. 2004; 171: 2404-06 17. telfer jr, quaba aa, kwai ben i, et al. an investigation into the role of waterproofing in a two-stage hypopsadias repair. br plast surg. 1998; 51:542-6 18. sozubir s, snodgrass wt. a new algorithm for primary hypospadias repair based on tip urethroplasty. j pediatr surg 2003; 38:115761 19. smith d. a de-epithelialized overlap, flap technique in the repair of hypospadias. br j plast surg. 1973; 26:106-8. 20. shanberg am, sanderson k, duel b. re operative hypospadias repair using snodgrass incised plate urethroplasty. bju int. 2000; 87: 544-7 21. furness pd iii. successful hypospadias repair with a ventral based vascular drtos pedicle for urethral coverage. j urol. 2003; 169:1825-7 22. carmine p, mario f, antonio g, et.al. circumferential dissection of deep fascia as ancillary technique in circumcision: is it possible to correct phimosis increasing penis size? bmc urol. 2021; 21:15 23. savanelli a, esposito c, settimi a. a prospective randomized comparative study on the use of ventral subcutaneous flap to prevent fistulas in the snodgrass repair for distal hypospadias. world j urol. 2007; 25: 641-5 24. smith dp. a comprehensive analysis of a tabularized incised plate hypospadias repair. urology 2001; 57:778-82 25. snodgrass w, koyle m, manzoni g, hurwitz r, caldomone a, erlich r. tubularized incised plate hypospadias repair: results of a multicenter experience j urol. 1996; 156: 83941 26. cheng ey, vemulapalli sn, kropp bp. et al. snodgrass hypospadias repair with vascularized dartos flap: the perfect repair for virgin cases of hypospadias. j urol. 2002; 168:1723-6 27. kamal ba. double dartos flap in tabularized incised plate hypospadias repair. urology 2005; 66:1095-8 28. jia w, liu g, zhang l, et. al. comparison of tubularized incised plate urethroplasty combined with a meatus-based ventral dartos flap or dorsal dartos flap in hypospadias. pediatr surg int. 2016;32 : 411-5 29. fahmy o, khairıl-asri mg, schwentner c, et al. algorithm for optimal urethral coverage in hypospadias and fistula repair: a systematic review. eur urol. 2016; 70 : 293-8 dartos flap to prevent fistula formation in hypospadias – yiğit et.al pediatric urology 319 letter is uro-oncological surgery safe during the covid-19 pandemic? comparative morbidity and mortality in patients undergoing surgery 2019-2020 bravo jc1, navarro r2, rojas p1, hinrichs l2, schalper m2, zúñiga a1, san francisco if1 the sars-cov-2 infection has resulted in an unprecedented pandemic and with it, lots of international efforts have been made to guide health care workers and to optimize resources to address this crisis(1). one of the most important efforts is graphed in the european association of urology’s guideline (april, 2020) followed by many countries, but recently called into question by a. kashi in its last editorial article(2). due to this guideline, many elective surgeries had to be suspended or postponed, providing only time-dependent surgeries, such as emergency surgical pathologies or oncological surgeries(3). patients undergoing oncological surgery, represent a vulnerable group to sars-cov-2 infection. additionally, they have a higher risk of suffering pulmonary complications due to the pro-inflammatory surgical effect, immunosuppressive response, and mechanical ventilation(4,5). but in practice, there is currently limited data on the mortality and complications of infected patients undergoing uro-oncological surgery, with few series reports on surgical outcomes during this time. international studies have reported 30-day mortality of 20-25%, respiratory morbidity of 50-51.2%, and mortality of patients with specific respiratory morbidity that reaches 38%(6-7). we made an observational study based in a prospective database of urological oncological surgery. its data were obtained during the 2020 mandatory confinement period compared to the same period in 2019 with 45 days of post-surgery follow-up. a specific analysis of morbidity and mortality was made for all patients submitted to the department's uro-oncological surgery subgroup. demographic, clinical, and perioperative variables such as age, sex, specific comorbidities, and pre-surgical global comorbidity were recorded through the charlson comorbidity score, used to guide the global state of comorbidity in the groups studied. the type of surgery, the approach, the type of anesthesia, time of hospital stay, mortality, and morbidity were also added as variables according to the clavien-dindo classification (cd) and the comprehensive complication index (cci) for postoperative complications(8). the objective was to compare surgical morbidity and mortality during the pandemic versus an average year in urological cancer surgery to determine the safety of the surgery. during the studied period, 684 surgeries were performed in 2019 and a total of 265 surgeries were performed during the equivalent period in 2020. the detail of the distribution of surgeries is presented in figure 1. regarding the specific analysis of the uro-oncological surgery subgroup, in 2019, 165 oncological urology surgeries were performed versus 85 in 2020. for global comorbidity, the median of the charlson comorbidity score were 5 and for respectively (both iqr=3). specific comorbidity frequencies showed no important difference between both group (2019 and 2020) and having ≥ two comorbidities were no related with greater cd or cii. the variables measured in the surgical procedures did not show significant differences either. the clavien-dindo post-surgery morbidity ≥ 3 in 2020 was 2.3% (n=2), and 6% in 2019 (n=10). in 2020, 9 patients were readmitted (10.5%). one patient (1.1%) was re-interfered, with a perioperative mortality of 1.1%. in 2019, 21 patients (12.7%) were readmitted. seventeen patients (10.3%) were re-interfered, with a perioperative mortality of 1.8%. the median number of days hospitalized was 2 (iqr=2) in 2020 and 3 (iqr=3) in 2019. specific respiratory morbidity was also studied, present in 1.2% (n= 2) of those operated on in 2019, and keeping a null incidence during 2020 (p= 0.308). the perioperative mortality of the sample was 1.8% in the 2019 cohort and 1.1% in 2020 (p= 0.70). finally, 17 patients (10.13%) from the 2019 serie were re-operated, versus a single patient in 2020 (1.1%) (p= 0.008). regarding the procedure, in our center, when the covid-19 pandemic status was declared, our institution proposed an specific admission protocol graphed in figure 2. the results displayed there, show us that there were no significant differences in the type of population admitted to uro-oncological surgery, their demographic classification, or their measured comorbidities, nor was there a difference in the primary outcomes measured: perioperative morbidity and mortality. this could be interpreted, therefore, as the success of the protocol and the measures implemented in our centers. kashi’s editorial reviewed the outcomes of the different protocols for surgery admission and how they affected to stop the secondary surges of the pandemic, concluding that “postponement is not a panacea for dealing with sequential surges of covid-19 and the decision to postponement may culminate in doing the surgery in a worse situation”. we contribute to the debate showing that postoperative morbimortality reported were lower than those shown in the literature and similar to that historically reported by our centers. we suggest that it is safe to operate patients with urological cancer following the appropriate protocols during a pandemic, and as kashi mentioned, it should be dependent on the availability of hospital beds, personal protective equipment, and other necessary resources in every specific country or province. the pandemic almost completely changed our way of working, 1urology department, pontificia universidad católica de chile, medical school, santiago, chile. 2pontificia universidad católica de chile, medical school, santiago, chile. *correspondence: urology department, pontificia universidad católica de chile, medical school, santiago, chile. address: diagonal paraguay 362, santiago, chile. phone: +56979961781. email: isanfrancisco@med.puc.cl. received february 2021 & accepted may 2021 urology journal/vol 18 no. 3/ may-june 2021/ pp. 355-357. [doi: 10.22037/uj.v18i.6711] however, conducting adequate protocols the outcome of patients undergoing genitourinary cancer surgeries figure 1. detail of the distribution of urological surgeries by subgroup in both years. the figure shows the comparison between the two cohorts and the total number of surgeries and by subtype in each one of them figure 2. outline of the protocol used in our centers for admission to surgery in covid-19 related period: in an outpatient surgery, as a preoperative requirement a covid-19 pcr is requested two days before surgery. if the result is positive for covid-19, the surgery is postponed. if the test result is negative for covid-19, the patient can be admitted for surgery. in a hospitalized patient, the case is discussed between the treating team and the operation room management team, always requiring a previous negative covid-19 pcr result on a recent sample. in an emergency surgery, the patient is operated without delay with the necessary measures to prevent transmission, assuming the patient was positive for covid-19. should not be affected. letter 356 vol 18 no 3 may-june 2021 357 references 1. lobo f, stacy l, langer m, et al. collaborative co. a systematic review on guidelines and recommendations for urology standard of care during the covid-19 pandemic. european urology focus 6 (2020) 1070–1085 2. ghahestani sm, kashi ah. guidelines for urological surgeries in the covid-19 pandemic: is it time for revision? urol j. 2021 jan 9;17(6):560-561. doi: 10.22037/ uj.v17i6.6610. pmid: 33432567. 3. american college of surgeons. local resumption of elective surgery guidance. american college of surgeons. ; 2020. 4. besnier e, tuech jj, schwarz l. we asked the experts: covid-19 outbreak: is there still a place for scheduled surgery? "reflection from pathophysiological data". world j surg. 2020;44(6):1695-8. 5. huang c, wang y, li x, et al. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet. 2020;395(10223):497-506. 6. collaborative co. mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov-2 infection: an international cohort study. lancet. 2020;396(10243):27-38. 7. lei s, jiang f, xia zy. author's reply clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of covid-19 infection. eclinicalmedicine. 2020:100363. 8. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240(2):205-13 best reviewer of the september-october 2022 issue taras shatylko taras shatylko october 2022 taras shatylko is a urologist in v.i. kulakov national medical research center (moscow, russia). he earned his medical degree and basic urological training from v.i. razumovsky saratov state medical university. after finishing post-graduate training he underwent a specialization in uro-oncology and andrology. he participated in numerous courses, workshops, masterclasses and observerships organized by entities such as european school of urology, open medical institute and european school of oncology. his candidate thesis is dedicated to personalized approach in prostate cancer detection, focusing on the use of artificial neural networks to predict clinically significant cancer by pre-biopsy parameters, proper choice of anesthesia and magnetic resonance imaging to improve detection rates. currently he works on a doctoral thesis which explores the role of surgery to improve male reproductive function. another research area of interest to him is proteomics and lipidomics in urology and andrology. dr. shatylko was a co-investigator in several major clinical trials in the field of uro-oncology, specifically on treatment of castration-resistant prostate cancer and metastatic urothelial carcinoma. his teaching activity covers general urology, andrology and uro-oncology for medical students, residents, postgraduate students and doctors receiving continuous medical education. dr. shatylko is a frequent speaker at urological conferences in russia and abroad. he published over 70 articles in russian language and international peer-reviewed journals. dr. shatylko is also a reviewer for respected medical journals, including urology journal. beyond general urology and endoscopic urology, his practical interests focus on surgical andrology, urethral reconstruction, urological conditions in pregnancy and robotic urology. he specializes in surgical sperm retrieval techniques, including microdissection testicular sperm extraction (microtese), and is considered to be an opinion leader in male infertility, hypogonadism and related conditions. «peer review is an important step for any manuscript. a reviewer should be able to see the paper from a different perspective, pointing out the discrepancies and flaws in its structure and content, which were overlooked by the authors. as an author myself, i’d like to point out that there’s nothing wrong with it. when you focus on your topic too much, your vision becomes somewhat blurred, and that’s when you need a good reviewer. sometimes the reviewer’s input in a successful article is almost as significant as the authors’. one may compare it to a midwife’s art when a new piece of knowledge is born.» running head: recovery of parenchymal thickness after pyeloplastyyayla et al. what is the critical age for the improvement of parenchymal thickness after pyeloplasty? derya yayla¹, gokhan demirtas¹, bilge karabulut¹, huseyintugrul tiryaki¹ ¹department of pediatric urology, ministry of health ankara city hospital, ankara, turkey abstract purpose the most important point in cases of ureteropelvic junction obstruction (upjo) is to decide on the need and timing of surgical treatment. renal damage may become irreversible as the duration of the obstruction is prolonged. worsening of hydronephrosis and decrease in renal parenchymal thickness after pyeloplasty may herald an irreversible renal damage. it is important to know at what age this damage begins. in this study, we aimed to determine the relationship between the age of the patients at the time of pyeloplasty performed for upjo and parenchymal recovery. materials and methods in our study, 156 patients (mean age: 43.5 months) who underwent pyeloplasty with the diagnosis of upjo between 2007 and 2019 were evaluated retrospectively. demographic characteristics, ultrasonographic (usg) and nuclear renal scintigraphy findings, previous surgeries of the patients were recorded. results numerical variables were evaluated statistically, and the best cut-off point was determined. parenchymal thickening was determined as the most important criterion in postoperative renal recovery which was more evident at early ages. based on statistical assessments , the cut-off age for renal parenchymal recovery was determined as 38 months. while parenchymal recovery was inadequate after pyeloplasty performed in patients older than 38 months, the most significant improvement in renal functions was seen in children younger than 13 months of age. conclusions pyeloplasty should be performed in patients with upjo before development of severe renal damage. statistically, the best parameter to evaluate the recovery after pyeloplasty is the change in parenchymal thickness. with advancing age, it is impossible to reverse the obstructive nephropathy keywords: ages; child; renal parenchymal thickness; pyeloplasty; ureteropelvic junction obstruction, introduction antenatal hydronephrosis most frequently (10-30%) due to ureteropelvic junction obstruction (upjo) is seen in approximately 1% of all pregnancies (10-30 %) (1,2). the prevalence of upjo is estimated to be one in 1500 live births with a male to female ratio of 3-4 to1 (3). the diagnosis is usually made during prenatal ultrasonography screening (4,5). as an easily accessible, inexpensive, noninvasive, and non-ionizing imaging technique, renal ultrasound (us) is the preferred modality for the diagnosis and monitoring of the patients with pediatric hydronephrosis. in previous patient cohorts, longitudinal evaluation of children with severe hydronephrosis has demonstrated improvement in renal functions in approximately 90% of children monitored non-operatively (6). gradually worsening hydronephrosis detected on serial ultrasonograms is often considered a risk factor for loss of renal function (7,8). unfortunately, renal ultrasound imaging is influenced by hydration status of the patients, presence of bladder pathologies, and personal skill of the ultrasonographer (9). in our study we tried to exclude these confounding factors with serial ultrasonographic examinations performed. diuretic renography is the standard test recommended to evaluate split differential renal function (drf) among children with hydronephrosis (10). use of this modality requires intravenous administration of radioactive agent and placement of a urethral catheter. therefore, the desire for close patient monitoring must be balanced with the morbidity of ionizing radiation and catheterization. diuretic renography is often used to assess ultrasonographic findings in detail before surgery. accepted indications for surgical intervention include worsening hydronephrosis detected on serial ultrasound imagings, renal function loss, or relevant symptoms such as pain, and signs of recurrent pyelonephritis (11). additionally, the ideal imaging interval is unknown and inter-rater reliability of sfu (society of fetal urology) grading system on renal ultrasound varies (12). renal parenchymal echogenicity can also be used to predict relative renal function on diuretic renography, but increases in renal echogenicity are often late-stage changes associated with permanent renal damage (13). it is important to distinguish patients who will recover spontaneously from those who require surgical treatment to preserve their renal functions. current protocols focus on close conservative monitoring. in cases with asymptomatic hydronephrosis, surgical intervention is decided if there is thinning of the renal parenchyma and renal drainage disorder observed in renal scintigraphy (14). surgery was performed for those presenting with signs and symptoms of severe obstructive uropathy including renal parenchymal thinning, worsening hydronephrosis, flank pain, estimated glomerular function rate (egfr) below 40% or 10% reduction in renal function during follow-up as revealed in renal scintigraphy. in those with high-grade obstruction, cortex thinning is more important than the anteroposterior diameter (apd) of renal pelvis and caliectasis. in this case, the possibility of exposure to irreversible renal damage may be higher (15). after pyeloplasty, cases are evaluated by the presence of dilatation in the collecting system and by us monitoring of the renal parenchymal thickness. the characteristics of the renal parenchyma draws less attention in children with upjo than evaluation of renal pelvis and calyceal dilatation. evaluation of the renal parenchyma is very important for an estimation of renal functional reserve. onen et al. proposed a grading system for hydronephrosis by combining the degree of pelvicalyceal dilatation with the percentage loss in renal parenchyma (16). reduction pyeloplasty is performed in many centers, but it is not indicated unless a significant and gradual increase in renal pelvis dilatation is noted . however, recovery of normal renal parenchymal thickness is accepted as an indicator of improvement in renal functions. in addition, pre-, and post-operative renal scintigraphies may be comparatively evaluated at the risk of radiation exposure. achievement of recovery or stabilization of renal functions after pyeloplasty in upjo cases may be related to the timing of the intervention. delayed pyeloplasty in the follow-up of patients may cause irreversible damage to renal functions. in our study, we aimed to determine whether there is a relationship between the increase in renal parenchyma thickness, which is an indicator of improvement in renal function after surgery, and the age at which pyeloplasty was performed. materials and methods the records of all pediatric pyeloplasty cases in a single center covering the period from january 2007 to march 2019 were retrospectively reviewed. children who had undergone all tests and examinations preoperatively including ultrasound (us) and nuclear renography scans were included in the study voiding cystourethrography was performed for those who had undergone pyeloplasty within the first 6 years of their lives, had urinary tract infection, and ureteral dilatation detected in ultrasonography in the following years. children who had suspected voiding symptoms (including abnormal urine stream) , ureteral dilatation, duplex collecting system, fused kidneys, bilateral renal pelvis dilatation, or any bladder abnormality in the us were excluded from the present study. nine vesicourethral reflux patients detected on voiding cystourethrography were also excluded from the study. a total of 156 pyeloplasties (mean age 43.5 months; median age 17.9 months; 45 female, and 111 male patients) who were operated in a single center (ankara city hospital) were included in the study. surgery was performed on those with severe obstruction. for the determination of surgical indications, ultrasonography and renal scintigraphy findings were evaluated as a whole. our pyeloplasty indications were as follows; 1the presence of ultrasonographic findings indicating decrease in renal parenchymal thickness, increases in the degree of hydronephrosis (calyceal dilatation, gradual and continuous expansion of collecting system,) and in the anteroposterior diameter (apd) of renal pelvis 2renal scintigraphy findings associated with a renal function percentage below 40% or 10% decrease in the percentage of the differential renal function estimated during follow-up, obstruction curve, and prolongation of half-life (t 1/2) of the agent used in diuretic renography 3-especially in older children, those who presented with pain together with findings of hydronephrosis (35.9%) were considered symptomatic and underwent surgery. all patients underwent dismembered pyeloplasty surgery using anderson-hynes technique through a mini flank incision using a retroperitoneal approach. a perinephric drain and a urethral catheter were inserted in all patients. intraoperatively, crossing renal vessels (11.5%) and relatively narrow segments (88.5%) were detected. external intrarenal stents or double-j stents were used in all pyeloplasties. double-j stents were removed four, and pyelostomy catheters 10 days after surgery. antibiotic treatment was used for one week postoperatively, then prophylactic antibiotherapy was continued for one month to prevent development of indwelling catheter -related infection. demographic and clinical data related to gender, and age of the patients, laterality of hydronephrosis, indication of the first pyeloplasty, presence of a crossing vessel, history of prenatal hydronephrosis and/or urinary tract infection, us findings and percentage of renal function demonstrated on nuclear renogram and evidence of reflux (if any) were collected . additionally, patients’ pre-and postoperative 2nd-year apd, calyceal diameters, and renal parenchymal thickness were recorded. after the obstruction is removed, it takes approximately 2 years for the renal pelvis to gain full flexibility (30). for these reasons, second-year us findings were taken into account instead of early or latest follow-up us findings. postoperatively all children were followed up for at least 2 years, (mean 6.7 years). statistical analysis data were analyzed retrospectively. ibm spss statistics ver. 23.0 (ibm corp., armonk ny) was used for statistical analysis. the fitness of numerical variables to normal distribution was examined using kolmogorov-smirnov test. qualitative variables were summarized by numbers and percentages, and numerical variables by mean ± standard deviation (sd) and median (iqr). the values of both groups were compared with the mann-whitney u test. roc curve was used to evaluate the diagnostic performance of numerical variables and to determine the best cut-off point. the value with the highest youden index (sensitivity+specificity-1) score was determined as the optimum cut-off point. the sensitivity, specificity, positive and negative predictive values of the test were calculated according to the determined cut-off point. a value of p<0.05 was considered statistically significant. results after reviewing the surgical database, 176 pyeloplasty cases were detected during the study period. twenty pyeloplasty cases including patients with ureterovesical obstruction (n=1), bilateral upjo (n=4), horseshoe kidney (n=5), multicystic kidney (n=1), ectopic kidney (n=1), atrophic kidney (n=1), a duplex system (n=3) were excluded. cases with bilateral hydronephrosis were not included in the study, considering that comparison of parenchymal thickness between both kidneys would not be accurate. finally a total of 156 children were enrolled in the study (table 1). first of all, statistical analysis was performed to see if there was any improvement in parenchymal thickness under and over 1yearold infants. pyeloplasty (41%) performed in 64 children under 1 year of age, significantly increased postoperative renal parenchymal thickness compared to those above 1 year of age (p = .029) (table 2a). in the postoperative follow-ups, we observed that the decrease in renal calyx diameter (p= .075) and the change in pelvis diameter were not significantly (p= .207) different in children aged less than 1 year compared to those above 1 year of age (table 2a). postoperatively, renal mag-3 scans were performed in 81 patients with absolute indications. the increase in differential renal function in postoperative renal mag-3 scintigraphies was 2.31% on average (±1.83 sd) when compared with preoperative values. insignificant improvement was observed in renal functions according to age as evidenced in renal mag-3 scintigraphy (p= .338). a positive weak correlation was found when the relationship between the improvement in renal differential function and renal parenchymal recovery of 81 patients who underwent renal mag-3 scintigraphy after pyeloplasty was examined statistically using pearson correlation analysis (r 0.23, p= .037). renal mag-3 scintigraphy was not required in remaining 75 patients who had significant improvement as observed in postoperative us performed such as absence of parenchymal thickening without any increase in pelvic diameter. in the follow-up of 156 patients, an indwelling ureteral catheter was left in situ in 10 (6.4%) patients due to temporary stenosis, while 3 (1.9%) patients underwent re-pyeloplasty within the first year. we can correctly classify those with or without adequate improvement in operated cases with upjo with 79% (auc± std. error: 0.79±0.046) change in parenchymal thickness. the best cut-off point to identify those with and without improvement is determined by using youden index. the roc curve was used to evaluate the diagnostic performance of numerical variables and to determine the best cut-off point (figure 1a, 1b). taking the 1.5 value as the best cut-off point for the change in parenchymal thickness, this test had 51% sensitivity and 99% selectivity. there was a significant difference between the age of the patients and the degree of recovery obtained in renal functions (p <0.01). sufficient recovery in renal functions was achieved in younger children (median (iqr): 12 (38.9) months) compared to those older ones (median (iqr): 42.8 (92.7) months). the best cut-off age for sufficient recovery was 38 months. using 38 months of age as a cut-off point, we can determine the sufficiency of recovery in renal functions with 61% sensitivity and 72% selectivity (table 3). statistically, the best parameter to evaluate the recovery after the operation is the change in parenchymal thickness (p= .029). in our study we determined that the possibility of reversing the kidney damage caused by the obstruction statistically disappeared as the child gets older. the most striking postoperative improvement in parenchymal thickness compared to preoperative values was achieved in cases younger than 13 months (table 2b). when pyeloplasty surgery is delayed for a long time, then the chance of parenchymal healing is reduced.. in our study, the cut-off age for parenchymal thickening was determined as 38 months. pyeloplasty should be performed in upjo patients before severe renal damage occurs. especially in pyeloplasty performed in children over 42 months, parenchymal healing was found to be statistically almost nonexistent. discussion in order to prevent renal damage, appropriate follow-up and timely surgical treatment are important criteria in patients with asymptomatic upjo with a history of antenatal hydronephrosis. if surgery is delayed, irreversible losses in kidney function occur (17-20). preoperative renal dilatation and parenchymal thinning are expected to improve in the postoperative period in patients operated within appropriate time frame. we observed that postoperative renal parenchymal recovery is achieved in statistically significantly lesser number of patients older than 38 months of age who were operated in our clinic. since the rate of antenatal diagnosis has increased in upjo cases today, it is possible to be operated on at an earlier age. in the literature, surgical indications have been usually reported as renal deterioration, urinary obstruction, and urinary tract infection. indications for surgical intervention comprise impaired split renal function (< 40%), a decrease in split renal function of > 10% in subsequent studies, poor renal drainage after the administration of furosemide, increased anteroposterior pelvic diameter as detected on the us, and grade iii and iv dilatation as defined by the society for fetal urology (20-23). upjo has been reported in up to 54% of cases depending on the degree of prenatal hydronephrosis (24). in our study, antenatal hydronephrosis were at a rate close to that reported in the literature (51%). since our patients had a history of antenatal hydronephrosis, close follow-up with ultrasound was available. thus, our patients had the chance to undergo pyeloplasty in case of need at a young age. in our study, pyeloplasty was performed in patients younger than 2 (53.2%), and 3 years of age (60%). renal ultrasound is the cornerstone in the diagnostic pathway of children with hydronephrosis. the most reliable and reproducible measurement is the anteroposterior diameter of the renal pelvis the degree of dilatation of the calyces and parenchymal thinning are also very important parameters in the analysis of the degree of hydronephrosis (15). the success of pyeloplasty is determined based on the resolution of pelvicalyceal dilatation and recovery of normal parenchymal thickness as observed on serial ultrasonographic examinations. after pyeloplasty, a decrease in the degree of hydronephrosis on us, absence of parenchymal loss and improvement in renal drainage as observed on renograms indicate the success of the surgery. a renal ultrasound is performed 6-8 weeks after pyeloplasty or stent removal to ensure that the pelvicaliectasis and parenchymal thickness have improved. an overall decrease in the degree of pelvicalectasis over time is a good indication that the obstruction is relieved. while the expected maximum improvement in renal function and drainage is seen in the first year after the operation, this period may extend up to 2 years (25). for this reason, in our cases parenchymal thickness, diameters of renal pelvis and calyces were evaluated by the us in the second postoperative year. approximately, 23% of congenital hydronephrotic kidneys followed with an observational approach eventually required surgical intervention (26). the observational protocol should consist of obtaining serial renal usgs. due to its wide availability and noninvasive nature, renal ultrasonography has become the primary initial diagnostic tool for the identification and evaluation of prenatal and postnatal hydronephrosis. parenchymal thinning may be an evidence of chronic renal obstruction (27). since we performed excision and reduction of the renal pelvis in our series cited in the literature, renal pelvis diameter was not an accurate parameter in the postoperative follow-up of our cases. however, in the follow-up of the patients, the anteroposterior diameter of the renal pelvis and the thickness of the renal parenchyma were monitored closely. while reduction pyeloplasty is being performed in many centers, the follow-up of patients based on the decrease in the degree of renal dilatation is not instructive unless there is a significant increase, but improvement in parenchymal thickness is accepted as an indicator of improvement in renal function. it is more appropriate to monitor the degree of improvement in renal functions with changes in renal parenchymal thickness and width of calyces detected on serial us performed during postoperative follow-up instead of apd. renal scintigraphy is applied more limitedly during the follow-up of the patients due to radiation exposure. renal scintigraphy was evaluated in 81 of our cases in the sixth month postoperatively. an average of 2.31% (±1.83 sd) improvement in renal functions was observed in the scintigraphy performed in the 6th month postoperatively. in our study, a positive weak relationship was found when the pearson correlation analysis was performed between the improvement of renal differential function and renal parenchymal recovery of 81 patients who underwent renal scintigraphy after pyeloplasty, (r= .23, p= .037). in patients who underwent scintigraphy after pyeloplasty, improvement in renal function was correlated with the measurements of parenchymal thickening in ultrasonography. recovery of renal function occurs not only in patients allocated to surgical correction after delivery due to poor renal function but also in those on conservative treatment who required pyeloplasty due to deteriorating renal function during observation (28). normally functioning kidneys may deteriorate during observational follow-up period, however renal functions of many patients will recover after pyeloplasty (29). pyeloplasty in children with upjo should be done before serious renal damage develops. the most statistically significant parameter showing postoperative improvement in our study was the favourable change in renal parenchymal thickness (p= .029). conclusions in our study, we found that the recovery of normal parenchymal thickness was less frequently achieved in children with upjo who were operated on after 38 months of age. in cases of upjo, we found that postoperative renal parenchymal healing or thickening was more important for the success of pyeloplasty in patients younger than 38 months relative to older children. the authors believe that the decision for pyeloplasty should be made carefully, especially in asymptomatic upjo patients younger than 38 months. because after this age, delayed pyeloplasty may not achieve recovery of renal functions. acknowledgement author contributions the above-listed authors (derya yayla, gokhan demirtas, bilge karabulut, huseyin tugrul tiryaki) were involved in the design of the submitted study, acquisition, analysis, and interpretation of the data, drafting of the manuscript and editing it for accuracy and content. each author approved the final draft of the manuscript before submission. additionally, all authors agreed to be responsible for all aspects of the submitted work. funding any specific grant was not received for this research from funding agencies in the public, commercial, or not-for-profit sectors. conflict on interest the authors declare that they have no conflict of interest. the research protocol was approved by the institutional review board of ankara city hospital (date:……; registration no:. ) informed consent was obtained from the parents of the children included in the study . all procedures performed were in accordance with the ethical standards of our institutional research committee and with the 1964 helsinki declaration and its later amendments. registry and registration no. of the study: ministry of health in turkey, ankara city hospital no:1 clinical trials ethics committee chairman, ethics committeee1-20-592, 2020 references 1. sverker ek, lidefeldt kj, varricio l. fetal hydronephrosis; prevalence, natural history and postnatal consequences in an unselected population. acta obstet gynecol scand, 86: 1463, 2007 2. dias cs, silva jmp, pereira ak et al. diagnostic accuracy of renal pelvic dilatation for detecting surgically managed ureteropelvic junction obstruction. j urol. 2013;190 (2):661–6 3. schlomer bj, cohen ra, baskin ls. renal imaging: congenital anomalies of the kidney and urinary tract. pediatric and adolescent urologic imaging. springer; 2014; 155–98 4. dhillon h. prenatally diagnosed hydronephrosis: the great ormond street experience. 1998 5. lim dj, park j-y, kim jh et al. clinical characteristics, and outcome of hydronephrosis detected by prenatal ultrasonography. j korean med sci. 2003;18(6):859 6. koff sa, campbell, kd: the nonoperative management of unilateral neonatal hydronephrosis: the natural history of poorly functioning kidneys. j urol, 152: 593, 1994 7. heinlen je, manatt cs, bright bc et al. operative versus nonoperative management of ureteropelvic junction obstruction in children. urology, 73: 521, 2009 8. karnak i, woo ll, shah sn et al. results of a practical protocol for the management of prenatally detected hydronephrosis due to ureteropelvic junction obstruction. pediatr surg int, 25: 61, 2009 9. keays ma, guerra la, mihill j et al. reliability assessment of society for fetal urology ultrasound grading system for hydronephrosis. the journal of urology, 180: 1680, 2008 10. shokeir aa. the diagnosis of upper urinary tract obstruction. bju int, 83: 893, 1999 11. heinlen je, manatt cs, bright bc et al. operative versus nonoperative management of ureteropelvic junction obstruction in children. urology, 73: 521, 2009 12. kim sy, kim mj, yoon cs et al. comparison of the reliability of two hydronephrosis grading systems: the society for foetal urology grading system vs. the onen grading system. clinical radiology, 68: e484, 2013 13. chi t, feldstein va, nguyen ht. increased echogenicity as a predictor of poor renal function in children with grade 3 to 4 hydronephrosis. j urol, 175: 1898, 2006 14. peters ca. congenital ureteropelvic junction obstruction: a pragmatic approach. pediatric urology: springer; 2015; 89–101 15. kelley jc, white jt, goetz jt et al. sonographic renal parenchymal measurements for the evaluation and management of ureteropelvic junction obstruction in children.front pediatr. 2016 may 6;4:436. doi: 10.3389/fped.2016.00042. ecollection 2016.pmid: 27200323 16. onen a. an alternative grading system to refine the criteria for severity of hydronephrosis and optimal treatment guidelines in neonates with primary upj-type hydronephrosis. j pediatr urol (2007) 3:200 17. tabari ak, atqiaee, moharjerzadeh l et al. early pyeloplasty versus conservative management of severe ureteropelvic junction obstruction in asymptomatic infants. j ped surg. 2019.08.006 epub 2019 aug 28 18. thorup j, jokela r, cortes d et al. the results of 15 years of consistent strategy in treating antenatally suspected ureteropelvic junction obstruction. bju int 2003;91:850-2 19. subramaniam r, kouriefs c, dickson ap. antenatally detected ureteropelvic junction obstruction: concerns about conservative management. bju int 1999; 84: 335-8 20. fernbach, s k, et al. ultrasound grading of hydronephrosis: introduction to the system used by the society for fetal urology. pediatrradiol, 1993. 23: 478 21. hanna mk. antenatal hydronephrosis and ureteropelvic junction obstruction: the case for early intervention. urology 2000; 55: 612-5.3-psooy k, pike jg, leonard mp. long-term follow-up of pediatric dismembered pyeloplasty: how long is long enough? j urol (2003) 169(5):1809–12 discussion 12; author reply 12 22. babu r, rathish vr, sai v. functional outcomes of early versus delayed pyeloplasty in prenatally diagnosed ureteropelvic junction obstruction. j pediatrurol 2015; 11: 63.e1-5 23. o’reilly ph, consensus committee of the society of radionuclides in nephrourology. standardization of the renogram technique for investigating the dilated upper urinary tract and assessing the results of surgery. bju int 2003; 91: 23943. 15. lupton ew, testa hj, o'reilly ph, et al. diuresis 24. lee rs, cendron m, kinnamon dd et al: antenatal hydronephrosis as a predictor of postnatal outcome: a meta-analysis. pediatrics 2006; 118: 586 25. thorup j, jokela r, cortes d, nielsen oh. the results of 15 years of consistent strategy in treating antenatally suspected ureteropelvic junction obstruction. bju int 2003;91:850-2 26. molina caf, facincani i, muglia vf, araujo wm, cassini mf, tucci s. postnatal evaluation of intrauterine hydronephrosis due to ureteropelvic junction obstruction. acta cir bras (2013) 28 suppl 1:33-6 27.onen a. grading of hydronephrosis: an on going challenge. front pediatr. 2020 aug 27;8:458. doi̇: 10.3389/fped.2020.00458. e collection 2020 28. chertin b, pollack a, koulikov d, et al. does renal function remain stable after puberty in children with prenatal hydronephrosis and improved renal function after pyeloplasty? j urol october 2009 vol. 182, 1845-1848 29.nordonström j, koutozi g, holmdahl g et al. changes in differential renal function after pyeloplasty in infants and children. j pediatrurol 2020 jun;16(3): 329.e1-329.e8. doi: 10.1016/j.jpurol.2020.02.002. epub 2020 feb 11 30. psooy k, pike jg, leonard mp. long-term follow-up of pediatric dismembered pyeloplasty: how long is long enough? j urol 2003;169(5):1809-12 correspondence author address: derya yayla, md ministry of health ankara city hospital, pediatric urology department universiteler neighborhood bilkent street no:1 06800 çankaya-ankara turkey e-mail: dryayla@yahoo.com phone number: +90 5053572662 fax number: +90 3125526000 table 1. demographic characteristics of patients variables patients,n % gender female 45 28.8 male 111 71.2 age (mean±sd, median (iqr)) * 43.5±42.8 17.9 (64.0) age groups ≤ 13 months 67 42.9 ≤38 months 96 61.5 > 42 months 52 33.3 laterality right 52 33.3 left 104 66.7 minimal pelvicaliectasis in the contralateral kidney 89 57.0 neurological disorders 8 5.1 duchenne muscular dystrophy 1 neurofibromatosis type 1 1 down syndrome 1 hydrocephalus 1 macrocephalus 2 hypotonia 1 castello’s syndrome 1 indications for the first pyeloplasty history of prenatal hydronephrosis 80 51.3 abdominal pain 56 35.9 history of urinary tract infection 20 12.8 causative factors relatively narrow segments 138 88.5 crossing vessel 18 11.5 differential renal function as detected in renal scintigraphy ≤20% 12 7.7 21-40% 83 53.2 41-55% 57 36.5 > 55% 4 2.6 postoperative differential renal function as detected in renal scintigraphy 2.31% (±1.83 sd) rate of increase 81 51.6 vesicourethral reflux (vur) vur (n) 9 vur (%) 5.2 *: mean ± standard deviation (sd) and median (iqr) values are presented table 2. ultrasonographic and scintigraphic variables by age groups (2a, 2b) variables ≤ 1 year > 1 year p value mean±sd median (iqr) mean±sd median (iqr) differantial renal function of scintigraphy 3.3±9.3 3 (7) 1.8±6.9 3 (6) .338 calyceal diameter -7.8±7.6 -7.5 (8) -11.6±11.8 -9 (8) .075 pelvic diameter -17.3±13.3 -17.5 (14) -20.7±14.4 -18 (13) .207 parenchymal thickness 3.3±2.2 4 (2) 2.5±2.5 2 (3) .029* 2a) mean variables by under 1 year old and above groups sd: standard deviation, iqr: interquartile range (mean±sd) *: p< 0.05 variables ≤ 13 month mean±sd 13-38 month mean±sd > 42 month mean±sd differential renal function of scintigraphy 3.3±9.3 1.8±6.8 1.2±6.2 calyceal diameter -7.8±7.6 -11.5±11.8 -9.2±10.3 pelvic diameter -17.3±13.3 -20.2±14.4 -19.7±13.4 parenchymal thickness 3.3±2.2 2.6±2.5 1.9±2.1 2b) mean variables by cut-off age groups sd: standard deviation (mean±sd) table 3. test performance by age and parenchymal thickening variables cut-off auc sensitivity specificity ppv npv age ≥ 38.0 .68 .61 .72 .52 .79 improvement in upjo ≥ 0.50 .79 .51 .99 .96 .83 fig 1. roc curve for (1a) age, (1b) improvement in upjo: a) ages of the patients with diagnosis of upjo b) improvement in upjo urological oncology 161urology journal vol 5 no 3 summer 2008 cytotoxic effect of saffron stigma aqueous extract on human transitional cell carcinoma and mouse fibroblast behzad feizzadeh,1 jalil tavakkol afshari,2 hassan rakhshandeh,3 alireza rahimi,1 azam brook,2 hassan doosti4 introduction: saffron has been suggested to have inhibitory effects on tumoral cells. we evaluated the cytotoxic effect of aqueous extract of saffron on human transitional cell carcinoma (tcc) and mouse non-neoplastic fibroblast cell lines. materials and methods: human tcc 5637 cell line and mouse fibroblast cell line (l929) were cultivated and incubated with different concentrations of aqueous extract of saffron stigma (50 μg/ml to 4000 μg/ml). cytotoxic effect of saffron was evaluated by morphologic observation and 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay after 24, 48, 72, and 120 hours in each cell line. results: after 24 hours, morphological observations showed growth inhibitory effects at saffron extract concentrations higher than 200 μg/ml for l929 cells and at concentrations of 50 μg/ml to 200 μg/ml for the tcc cells. these changes became more prominent after 48 hours. however, significant growth inhibitory effects of the extract were shown at concentrations of 400 μg/ml and 800 μg/ml. higher concentrations of saffron correlated inversely with cell population of both cell lines. significant reduction of the survived cells was seen at concentrations of 400 μg/ml and 2000 μg/ml for tcc and l929 cell lines, respectively. after 120 hours, decrease in the percentage of survived cells at higher concentrations of saffron extract was seen in both cell lines. at a concentration of 800 μg/ml, the survived l929 cells plummeted to less than 60% after 120 hours, while no tcc cells survived at this time. no l929 cells survived at 2000 μg/ml. conclusion: saffron aqueous extract has inhibitory effects on the growth of both tcc 5637 and normal l929 cell lines. this effect is dose dependent. urol j. 2008;5:161-7. www.uj.unrc.ir keywords: crocus sativus, antineoplastic agents, transitional cell carcinoma, fibroblast 1department of urology, ghaem hospital, mashhad university of medical sciences, mashhad, iran 2immunology and cell culture laboratory, immunology research center, bu-ali research institute, mashhad, iran 3department of pharmacology, medical plants research center, mashhad university of medical sciences, mashhad, iran 4department of statistics, ferdowsi university, mashhad, iran corresponding author: behzad feizzadeh, md department of urology, ghaem hospital, mashhad, iran tel: +98 511 841 7404 fax:+98 511 841 7404 e-mail: behzadfeizzadeh@yahoo.com received may 2007 accepted june 2008 introduction efforts to find any therapeutic options for cancers have guided the investigators to consider even herbal medicine to be tested. treatment of bladder cancer was the subject of our interest that led us to study alternative therapies such as the use of herbs. bladder cancer is the 5th most common cancer with a high rate of mortality and morbidity.(1) transitional cell carcinoma (tcc) is the most common bladder tumor which can be induced directly by cigarette smoking and environmental factors.(2) occupational exposure risk factors include aromatic amines, industrial saffron and transitional cell carcinoma—feizzadeh et al 162 urology journal vol 5 no 3 summer 2008 dyes and solvents, plastic painting, rubber, heavy metals, mixtures of polycyclic aromatic hydrocarbones, etc.(3) we sought to investigate saffron and its potential effect on cancerous cells. saffron (crocus sativus l) is one of the worthiest perennial flowers with a violet color and usually 3 golden petal stigma in the iridaceae family (figure 1). it has been used as a food spice since the ancient times.(4,5) some of saffron’s chemical ingredients are carbohydrates, minerals, vitamins (especially riboflavin and thiamin), and pigments including crocin, anthocyanin, carotene, and lycopene.(5) anticarcinogenic activity of saffron was reported in the beginning of 1990 and research on this subject has increasingly continued during the past decade.(6) saffron and its main ingredients have shown antitumor and anticarcinogenic activities both in vitro and in vivo.(6,7) to date, however, there has not been any report in literature on saffron effects in bladder cancer. we studied in vitro cytotoxic effect of saffron aqueous extract on tcc cell line proliferation and non-neoplastic fibroblast cells of mouse as a normal cell line. materials and methods preparation of saffron extract saffron harvested from saffron farms of ghaen (a city in the northeast of iran) was used in this study. aqueous extract was prepared with 15 g of its ground petal stigma and 400 ml of distilled water in a soxhlet extractor for 18 hours. the prepared extract was concentrated to 100 ml with a rotatory evaporator in low pressure and filtered through a 0.2-mm filter to be sterilized. the resultant solution was stored at 4°c to 8°c. various concentrations of saffron (50 μg/ml, 100 μg/ml, 200 μg/ml, 400 μg/ml, 800 μg/ml, 1000 μg/ml, 2000 μg/ml, and 4000 μg/ml) and a control solution without saffron extract were prepared immediately and refrigerated before the experiments. morphologic observation of cell lines human transitional carcinoma cells (tcc 5637) and mouse fibroblast cell line (l929) were provided from the national cell bank of iran. the tcc cell line 5637 is an epitheliallike adherent cell line originally taken from the primary bladder carcinoma and l929 cell morphology is similar to fibroblast derived from mouse c3h/an connective tissue. both of the cell lines were retrieved and cell passage was done. the viability of cells was determined by trypan blue test. six well plates for tcc 5637 cells and similar plates for l929 cells were used. in each well, 5 × 105 neoplastic cells or 2 ×105 normal cells were placed. the cells were cultivated in dulbecco’s modified eagle’s medium (sigmaaldrich, st louis, missouri, usa) with 10% fetal calf serum (gibco, paisley, uk). the media were supplemented with 100 iu/ml of penicillin and 100 iu/ml of streptomycin (jaberebn-e-hayan, tehran, iran). the cells were incubated at 37°c in a humidified 5% co2 atmosphere for 24 hours. then, exposing the cells to saffron extract was started: first, the media (2 ml capacity) were replaced with similar new media. then the plates were incubated with different concentrations of saffron extract (zero to 4000 μg/ml) at 37°c in a humidified 5% co2 atmosphere for 24, 48, 72, and 120 hours, and the cells were observed under the light inverted microscope for morphological alterations. the observation was done 3 times for each of the extract concentrations to check its reliability. viability of cells throughout the experiment was always higher than 95% as determined by trypan blue. figure 1. saffron and its stigma. saffron and transitional cell carcinoma—feizzadeh et al urology journal vol 5 no 3 summer 2008 163 quantitative assessment in vitro cytotoxicity of saffron aqueous extract was determined using 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (mtt) colorimetric assay. this method was first described by mosmann in 1983 and modified by alley and colleagues.(8,9) a total of 2000 normal cells and 5000 neoplastic cells from both cell lines were cultured after cellular passage and viability test in five 96-well plates. every 3 well groups were marked for each concentration of extract and recorded in files as case and similarly as control groups. the plates were incubated for 24 hours, and thereafter, the cells were exposed to the extract as follows: the first culture medium of each plate was changed by fresh culture medium (200 μl). different concentrations of extract were prepared and added to 3 well groups, which contained tcc 5637 or l929 cell lines. no extract was added to the control group. plates were incubated in a humidified 5% co2 atmosphere, and after 24 hours, 1 plate was chosen randomly and growth medium was removed. for each 200 μl of the growth medium, 25 μl of mtt solution was added (sigma, missouri, usa) and incubated for 4 hours. after removing the growth medium and shaking microplates for 2 to 3 minutes, dissolvation of crystals in 200 μl of dimethyl sulfoxide and 25 μl of glycine buffer was achieved. the absorbance of formazan dye was recorded at 570 nm using enzyme-linked immunosorbent assay plate reader. the last stages were reported in the same manner for the second, third, and fourth plates after 48, 72, and 120 hours. the optical density read from the extract treated wells was converted to a percentage of living cells against the control using the following formula: surviving cells (%) compared to the controls = optical density of treated cells in each well × 100/ mean optical density of control cells statistical analyses data were analyzed by 1-way analysis of variance (anova), followed by the tukey multiple range tests for significant differences. the spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa) was used for analyses. p values less than .05 were considered significant. results morphological alterations l929 cell line. after 24 hours, saffron extract did not affect significantly the normal cells and they were intact in morphologic view. there were no changes in number, cytoplasm, and nucleus of the cells. however, in higher concentrations (> 200 μg/ml) decreased intercellular connections as the only notable alteration was apparent. after 48 hours, cell population increased at concentrations of 50 μg/ml, 100 μg/ml, and 200 μg/ml. at higher concentrations (400 μg/ml and 800 μg/ ml), cytotoxic effects were prominent. nearly, all cells were granulated, cell proliferation stopped, and cellular detachment was significant. after 72 to 120 hours, the process was followed similarly to the second day (figure 2). tcc 5637 cell line. after 24 hours, at the saffron extract concentrations of 50 μg/ml, 100 μg/ml, and 200 μg/ml, cell population decreased compared with the control group, and intercellular connections were also disrupted. at the concentrations of 400 μg/ml and 800 μg/ml, pigmentation increased and cellular detachment and vacuolization was apparent. at the concentration of 2000 μg/ml, 85% to 90% of cells were destroyed. after 48 hours, decrease in cell population and intercellular disruption, vacuolation, and pigmentation were apparent at concentrations of 50 μg/ml, 100 μg/ml, and 200 μg/ml. at the concentration of 800 μg/ml, most of the cells were destroyed. after 72 and 120 hours, all these alterations were significant (figure 3). quantitative results quantitative assessment was done by mtt assay. the results of the absorbance according to the extract concentration and cell population after 120 hours are shown in figure 4. there was a significant correlation between the increasing extract concentration and decreasing of cell population. no survived cell was detected after saffron and transitional cell carcinoma—feizzadeh et al 164 urology journal vol 5 no 3 summer 2008 120 hours at saffron extract concentrations of 2000 μg/ml and 400 μg/ml in the l929 and the tcc 5637 cell lines, respectively. in similar extract concentrations higher than 50 μg/ml, the percentage of survived tcc cells was less than survived l929 cells. also, gradient of both curves in figure 4 are the same after concentrations of 50 μg/ml up to 1000 μg/ml and 2000 μg/ml. figure 2. effect of aqueous extract of saffron on l929 morphology at a concentration of 400 μg/ml. a is the control l929 and b to f, are the l929 cells after 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours of exposure to saffron extract, respectively. figure 3. effect of aqueous extract on tcc 5637 morphology at a concentration of 400 μg/ml. a is the control tcc 5637 and b to f, are the tcc 5637 cells after 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours of exposure to saffron extract, respectively. saffron and transitional cell carcinoma—feizzadeh et al urology journal vol 5 no 3 summer 2008 165 in the beginning of the study, no significant difference was seen in cell population between the two cell lines. therefore, both cell lines were enrolled to our study in similar conditions. data analysis showed a good correlation between extract concentrations and cell viability in both cell lines during the study. of course, this was more significant in the tcc cell line on the first day of the study (r = 0.9, p = .001). after 24 hours, cell population decreased in correlation with increasing extract concentrations, but the decrease was more significant in the tcc cells compared to the l929 cells. in both cell lines, correlation between increasing concentration and percentage of survived cells was significant (p = .001, r2 = 0.88, and β = -0.00003 for tcc; p = .004, r2 = 0.771, and β= -0.00006 for l929). after 120 hours, decrease in the percentage of the survived cells due to increasing concentration of saffron extract was seen in both cell lines, and at the concentrations of 800 μg/ml and 1000 μg/ml, the relation was linear. there was a significant correlation between increasing concentration and the percentage of the survived cells in both cell lines (p < .001, r2 = 0.453, and β = -0.0001 for tcc; p = .001, r2 = 0.398, and β = -0.0002 for l929). discussion treatment of bladder cancer is based on the stage of cancer. in lower stages, treatment includes resection and also intravesical therapies, especially with bacillus calmette-guerin. other antitumor agents can be helpful, but extensive research is required to confirm their clinical applicability. we demonstrated in vitro cytotoxic effect of saffron on human tcc cell lines. in a review of the literature, we found no report of saffron extract effects on tcc cell lines. saffron is a plant which grows mostly in spain and iran, and in a smaller scale in greece, turkey, india, and some other countries.(10) saffron is usually used as a food spice, but some other effects such as anticarcinogenic effect, decreasing blood pressure, and controlling tonic-clonic and absence seizures have been reported so far.(5) in addition, saffron is used in cosmetic products.(11) there are several reports on the anticarcinogenic effects of saffron.(6,7) in a research on ethanolic extract of saffron on hela cells (cervix epitheloid carcinoma cells), abdullaev and frenkel documented the a significant inhibitory effect of colony formation and intracellular dna and rna synthesis.(12) they performed another study on a549 cells (lung adenocarcinoma cells), wi-38 (normal lung fibroblast-like cells), and va-13 (wi-38 cells which were transformed by sv-40 viruses), and showed that malignant cells were more sensitive to the inhibitory effect of saffron on dna and rna synthesis in comparison with normal cells.(13) the involved chemical ingredients in the antitumor effect of saffron has been investigated by some researchers. in one study, it was shown that crocin isolated from saffron inhibits pc-12 (rat’s pheochromocytoma cell line) cell growth with increased synthesis of glutathione.(14) it was also shown that saffron inhibited the carcinogenesis caused by chemical substances in mouse’s skin, which was probably due to modulator of phase 2 of detoxification enzymes such as glutathione peroxidase, catalase, and superoxide desmutase.(15) in one research on chemoprevention,(16) saffron ingredients were separated by high performance liquid chromatography and photodiode array methods; 12 chemical ingredients were tested by colony formation assay: crocin-1, crocin-2, crocin-3, figure 4. effect of aqueous extract of saffron on the percentage of survived tcc 5637 and l929 cells after 120 hours. saffron and transitional cell carcinoma—feizzadeh et al 166 urology journal vol 5 no 3 summer 2008 trans-crocin-2, trans-crocin-3, trans-crocin-4, cis-crocin-3, 4-hydroxy-2,6,6-trimethyl-1cyclohexene-1-carboxaldehyde-diglycosilkaempferol, picrocrocin, acid form of picrocrocin, safranal, and crocetin. in vitro inhibitory effect of some extracted ingredients on different types of human malignant cells was observed. in addition, no toxic or mutagenic effect was seen, and the authors concluded that saffron could be used as a chemopreventor in clinical studies.(16) antitumor mechanism of saffron is not well understood to the present time; however, different hypotheses have been proposed for its mechanism, eg, inhibitory effects of free radical chain reactions. saffron includes carotenoid ingredients which are fat solvable and can act as free radical inhibitors.(17) inhibition of intracellular dna and rna synthesis without any effect on protein synthesis has been reported as a role for carotenoid ingredients of saffron.(18) researchers have suggested transformation of carotenoid to retinoid, interaction of carotenoid with topoisomerase ii (the enzyme which interferes in dna-protein interactions),(19) and absorption of extracellular fluid due to swelling and local membrane envagination.(20) saffron also contains lectins which may cause antitumor effects of saffron.(21) in addition, apoptosis is induced by crocin.(22) in a research on pc-12 cells, crocin caused inhibition of cell growth by its effects on tumor necrosis factoralpha.(14) however, our knowledge on the exact mechanisms of antitumor effect of saffron needs to be expanded to weigh up its clinical usage. conclusion our study showed that saffron aqueous extract has an in vitro inhibitory effect on the proliferation of human tcc and mouse l929 cells which is dose dependent. acknowledgment we would like to thank the research deputy of mashhad university of medical sciences for financial support and mrs yaghoti, the secretary of department of urology, for her kind cooperation. conflict of interest none declared. references 1. karakiewicz pi, benayoun s, zippe c, et al. institutional variability in the accuracy of urinary cytology for predicting recurrence of transitional cell carcinoma of the bladder. bju int. 2006;97:997-1001. 2. pelucchi c, bosetti c, negri e, malvezzi m, la vecchia c. mechanisms of disease: the epidemiology of bladder cancer. nat clin pract urol. 2006;3:327-40. 3. peng cc, chen kc, peng ry, su ch, hsieh-li hm. human urinary bladder cancer t24 cells are susceptible to the antrodia camphorata extracts. cancer lett. 2006;243:109-19. 4. abdullaev fi, riveron-negrete l, caballero-ortega h, et al. use of in vitro assays to assess the potential antigenotoxic and cytotoxic effects of saffron (crocus sativus l.). toxicol in vitro. 2003;17:731-6. 5. abdullaev fi, espinosa-aguirre jj. biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials. cancer detect prev. 2004;28:426-32. 6. salomi mj, nair sc, panikkar kr. inhibitory effects of nigella sativa and saffron (crocus sativus) on chemical carcinogenesis in mice. nutr cancer. 1991;16:67-72. 7. dufresne c, cormier f, dorion s. in vitro formation of crocetin glucosyl esters by crocus sativus callus extract. planta med. 1997;63:150-3. 8. mosmann t. rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. j immunol methods. 1983;65:5563. 9. alley mc, scudiero da, monks a, et al. feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. cancer res. 1988;48:589-601. 10. abdullaev fi. cancer chemopreventive and tumoricidal properties of saffron (crocus sativus l.). exp biol med (maywood). 2002;227:20-5. 11. abdullaev f. crocus sativus against cancer. arch med res. 2003;34:354. 12. abdullaev fi, frenkel gd. effect of saffron on cell colony formation and cellular nucleic acid and protein synthesis. biofactors. 1992;3:201-4. 13. abdullaev fi, frenkel gd. the effect of saffron on intracellular dna, rna and protein synthesis in malignant and non-malignant human cells. biofactors. 1992;4:43-5. 14. ochiai t, soeda s, ohno s, tanaka h, shoyama y, shimeno h. crocin prevents the death of pc-12 cells through sphingomyelinase-ceramide signaling by increasing glutathione synthesis. neurochem int. 2004;44:321-30. 15. das i, chakrabarty rn, das s. saffron can prevent chemically induced skin carcinogenesis in swiss albino mice. asian pac j cancer prev. 2004;5:70-6. saffron and transitional cell carcinoma—feizzadeh et al urology journal vol 5 no 3 summer 2008 167 16. abdullaev jafarova f, caballero-ortega h, riveron-negrete l, et al. [in vitro evaluation of the chemopreventive potential of saffron]. rev invest clin. 2002;54:430-6. 17. molnar j, szabo d, pusztai r, et al. membrane associated antitumor effects of crocine-, ginsenoside and cannabinoid derivates. anticancer res. 2000;20:861-7. 18. nair sc, kurumboor sk, hasegawa jh. saffron chemoprevention in biology and medicine: a review. cancer biother. 1995;10:257-64. 19. smith ta. carotenoids and cancer: prevention and potential therapy. br j biomed sci. 1998;55:268-75. 20. escribano j, rios i, fernandez ja. isolation and cytotoxic properties of a novel glycoconjugate from corms of saffron plant (crocus sativus l.). biochim biophys acta. 1999;1426:217-22. 21. abdullaev fi, de mejia eg. antitumor effect of plant lectins. nat toxins. 1997;5:157-63. 22. thatte u, bagadey s, dahanukar s. modulation of programmed cell death by medicinal plants. cell mol biol (noisy-le-grand). 2000;46:199-214. v08_no_1_print_3.pdf case report 75urology journal vol 8 no 1 winter 2011 intrarenal mature cystic teratoma with renal dysplasia kamal v kanodia urol j. 2011;8:75-6. www.uj.unrc.ir keywords: teratoma, renal dysplasia, kidney neoplasms, dermoid cyst department of pathology, laboratory medicine and transfusion services, and immuno hematology, india corresponding author: kamal v kanodia, md department of pathology, laboratory medicine and transfusion services, and immuno hematology, india e-mail: kamalkanodia@yahoo.com received july 2009 accepted february 2010 introduction teratoma of the kidney is exceptionally infrequent.(1,2) most subjects in which this diagnosis has been considered represent either retroperitoneal teratoma with renal extension or wilms’ tumor with teratoid features.(3) we report intrarenal teratoma with renal dysplasia in a 6-month-old boy. case report a 6-month-old boy presented with lump in the right hypochondriac region noticed by his mother. there was no history of hematuria, pyuria, fever, anorexia, or vomiting. abdominal examination revealed a firm mass moving up and down with respiration in the right hypochondriac region. ultrasonography and abdominal computed tomography scan revealed a cystic mass arising from the right kidney. on investigations, his serum level of creatinine, hemoglobin, and total leukocyte count were 0.62 mg/ dl, 10.4 gm/dl, and 16 000/cmm, respectively. liver function tests were within the normal limits. urine analysis was unremarkable. surgical exploration through an anterior subcostal transperitoneal incision revealed a tense cystic mass arising from the kidney. right nephrectomy was done. the pathological gross examination of the kidney revealed a cystic mass on the outer surface measuring 6.0 cm in size. cut surface showed a cavity filled with jelly-like material, clear fluid, and calcified material. remaining part of the kidney was unremarkable. microscopic examination of the cystic mass revealed presence of extensive cartilage, sebaceous glands, ciliated columnar epithelial cells, and scattered serous material. endodermal, ectodermal, and mesodermal elements were all noted in the tumor (figure 1). the neighboring renal parenchyma showed primitive glomeruli figure 1. cartilage with glands (hematoxylin and eosin stain ×100). renal dysplasia in teratoma—kanodia 76 urology journal vol 8 no 1 winter 2011 surrounded by primitive tubules and collecting ducts in the mildly edematous parenchyma (figure 2). the histopathological diagnosis was mature cystic teratoma of the kidney with renal dysplasia. discussion teratoma is a tumor with tissue or organ components resembling normal derivatives of all three germ layers. teratomas have been reported to contain the hair, the teeth, the bone, and rarely the eyeball, the torso, the hand, the feet, or other limbs. the kidney is one of the least common sites for teratoma and other germ cell tumors.(4) benign cystic renal teratomas are uncommon clinical entities. renal teratomas are rare and most have been dismissed as retroperitoneal teratomas secondarily invading the kidney or wilms’ tumor with teratoid feature.(4) a benign cystic renal teratoma associated with ipsilateral hydronephrosis, urinary tract infection, and spontaneous abortion with histological confirmation was noted in a 25-year-old woman.(4) otani and colleagues reported a case of intrarenal teratoma with multiple cystic masses in the upper and lower poles of the left kidney on computed tomography scan in a 6-year-old boy.(5) glazier and associates reported a left renal teratoma with a cystic mass on ultrasonography in a 59-year-old woman.(1) ishii and coworkers reported a large right intrarenal teratoma in a 3-month-old girl.(2) primary renal carcinoid tumors associated with teratoma are also noted. kojiro and colleagues reported a large carcinoid tumor (17cm) with a cystic teratoma in a 40-year-old man.(6) kim and suh reported a primary carcinoid tumor in a mature teratoma of the kidney in a 39-year-old woman.(7) we have reported an intrarenal mature cystic teratoma with renal dysplasia in a 6-monthold boy with histological confirmation. teratomas are usually benign; however, malignant metastases have been seen in some well-differentiated teratomas of other organs and could presumably occur with those arising in the kidney.(8) although true intrarenal teratomas are extremely rare, they must be considered in the diagnosis of abdominal masses in children and adults. they should be distinguished from teratoid wilms’ tumor and other renal cystic lesions. conflict of interest none declared. references 1. glazier wb, lytton b, tronic b. renal teratomas: case report and review of the literature. j urol. 1980;123:98-9. 2. ishii c, singleton eb, gresik mv. computerized tomography demonstration of an intrarenal teratoma. j urol. 1987;137:272-3. 3. yoo j, park s, jung lee h, jin kang s, kee kim b. primary carcinoid tumor arising in a mature teratoma of the kidney: a case report and review of the literature. arch pathol lab med. 2002;126:979-81. 4. nzegwu ma, aligbe ju, akintomide gs, akhigbe ao. mature cystic renal teratoma in a 25-year-old woman with ipsilateral hydronephrosis, urinary tract infection and spontaneous abortion. eur j cancer care (engl). 2007;16:300-2. 5. otani m, tsujimoto s, miura m, nagashima y. intrarenal mature cystic teratoma associated with renal dysplasia: case report and literature review. pathol int. 2001;51:560-4. 6. kojiro m, ohishi h, isobe h. carcinoid tumor occurring in cystic teratoma of the kidney: a case report. cancer. 1976;38:1636-40. 7. kim j, suh k. primary carcinoid tumor in a mature teratoma of the kidney: ultrasonographic and computed tomographic findings. j ultrasound med. 2004;23:433-7. 8. prasad sb. intrarenal teratoma. postgrad med j. 1983;59:111-2. figure 2. primitive glomeruli with tubules (hematoxylin and eosin stain, ×100). running head: pkrp in patients taking low-dose aspirin-wu et al. the safety and efficacy of bipolar plasma-kinetic transurethral resection of the prostate in patients taking low-dose aspirin jie wu 1#, hongyan li2#, rongzhen tao1#, qinglai tang 1 * 1 the department of urology, the affiliated jiangning hospital of nanjing medical university, nanjing, china; 2 the department of rheumatology and immunology department, the affiliated jiangning hospital of nanjing medical university, nanjing,china; # these authors contributed equally to this work keywords: aspirin; benign prostatic hyperplasia; bipolar plasma-kinetic transurethral resection of the prostate; efficacy; safety abstract purpose: to explore the safety and efficacy of bipolar plasma-kinetic transurethral resection of the prostate in patients taking low-dose aspirin. materials and methods: benign prostatic hyperplasia (bph) patients who underwent surgical treatment from november 2018 to may 2020 were retrospectively analyzed,divided into two groups according to whether taking 100mg aspirin daily aspirin or not. the perioperative indexes, complications and sequelae also were used to evaluate safety. the efficacy was evaluated by the functional outcomes in 3,6,12 months. results: there were no statistical differences in the baseline characteristics or perioperative indicators and complications and sequelae, except for a longer operative time(90.49 ± 14.34 vs 84.95 ± 15.49; 95%ci: 0.26-10.83; p = .040) and a shorter hospital stay time(hst) (8.52 ± 1.55 vs 9.09 ± 1 .50; 95% ci: 0.21-1.11; p = .042) in the non-aspirin group. during the 12-months follow-up period, the functional outcomes of the two groups were significantly improved except international index of erectile function (iief-5). conclusion:based on our research results, pkrp a safe and effective method for patients with bph who taking 100mg aspirin daily. introduction benign prostatic hyperplasia (bph) is a common cause of lower urinary tract symptoms (luts) in elderly men (1).although medical management have been shown to be effective in the treatment of bph(2). for patients with severe luts due to bph, minimally invasive treatment or surgical treatment is still the preferred option. for many years, transurethral resection of the prostate (turp) has been regarded as the "gold standard" for the treatment of bph(3).the field of minimally invasive surgery in which bph causes lower urinary tract symptoms (luts) has undergone extraordinary progress over recent years.bipolar plasma-kinetic transurethral resection of the prostate(pkrp) has the same efficacy as turp, and its perioperative complications are much lower than that of turp, it is widely used in clinics(4,5). nowadays, urologists are facing more and more patients with a variety of diseases. among them, patients with cardiovascular and cerebrovascular diseases take long-term low-dose aspirin to prevent thrombosis(6), which significantly increases the risk of urological surgery. this study is based on our clinical observation that some patients with bph take long-term low-dose aspirin. in this study,we explore the safety and efficacy of pkrp in patients taking aspirin. materials and methods study population this retrospective study was initiated by the affiliated jiangning hospital of nanjing medical university in january 2022. the clinical data and follow-up data of bph patients who underwent surgical treatment at the department of urology, the affiliated jiangning hospital of nanjing medical university from november 2018 to may 2020 is analyzed retrospectively. according to whether to take 100mg aspirin daily, the included patients are divided into aspirin group and non-aspirin group. the flow diagram shown in fig.1 was used to describe the study. inclusion and exclusion criteria all included patients were diagnosed with bph by urinary system b-ultrasound who had been treated conservatively for more than one year. urodynamic examination revealed bladder neck obstruction, the maximum urine flow rate(qmax) was less than 15ml/s, and postvoid residual(pvr) was greater than 60ml.exclusion criteria included history of prostate surgery, urethral stricture, neurogenic bladder,detrusor weakness,bladder tumor,bladder diverticulum and postoperative pathological diagnosis of prostate cancer, patients who might be taking other anti-coagulants drugs. surgical technique all patients were operated by one urologist with more than 10 years of experience in prostatectomy.after connecting the resection ring to the plasma ultra-pulse generator (bowa, ,german), a 26 ch resectoscope (storz,german) was used to perform the operation under continuous irrigation with 0.9% nacl.the surgeon inserted an electric resection mirror to gradually remove the benign prostatic hyperplasia tissue in the order of middle lobe, right lobe, left lobe and parietal lobe, starting from the bladder neck and ending at the seminal caruncle. during surgery, the surgeon took care to recognize the distal signs of the bladder neck and to preserve it as intact as possible. the wound surface was electrocoagulated to stop bleeding thoroughly, and the fragmented tissues were sucked out with ellik balls and submitted for pathological examination. a 22 ch three-cavity catheter connected to the irrigation system is inserted into the bladder. evaluations the baseline characteristics including age, prostate volume(pv), body mass index(bmi), total prostate-specific antigen (tpsa), were recorded. the primary endpoints were the perioperative indexes, complications and sequelae including intraoperative blood loss(bll), operation time(ot), bladder irrigation time(bit), indwelling catheter time(ict), hospital stay time(hst), transurethral resection syndrome(turs), intraoperative blood transfusion(ibt), postoperative bleeding(pb), bladder spasm(bs), postoperative urethral stricture(pus), retrograde ejaculation(re), temporary incontinence(ti), bladder neck contracture (bnc). we estimated intraoperative blood loss by the following formula: estimated blood loss (ml) =(preoperative hemoglobin postoperative hemoglobin)/ preoperative hemoglobin) body weight (kg) × 7% × 1000. the secondary endpoints were functional outcomes including maximum urinary flow rate (qmax), international prostate symptoms score (ipss), post-void residual urine volume (pvr), quality of life(qol), and international index of erectile function (iief). statistical analysis ibm®spss®statistics20.0 was applied for statistical analysis. the variables are expressed in the form of mean±standard deviation(sd), or median and inter quartile range(iqr). student's t test, mann-whitney u test and χ2 test or fisher’s test (expected value <5) were used analyze our data. ethical statement the study was conducted in accordance with the declaration of helsinki (as revised in 2013). the study was approved by the ethics committees at the affiliated jiangning hospital of nanjing medical university. informed consent was obtained from all individual participants. results a total of 125 patients with bph who underwent pkrp were included in this study. of these patients,58 patients (aspirin group) had been taking aspirin(100 mg per day) regularly. and they didn’t stop taking aspirin throughout the perioperative period.the other 67 patients(non–aspirin group) didn’t taking aspirin or any other anticoagulants. as shown in table 1, there were no differences between the two groups in terms of age,bmi, pv, tpsa, qmax, pvr, ipss, qol and iief-5. perioperative indicators,complications and postoperative sequelae have been illustrated in table 2 and table 3. the ot of the non-aspirin group was longer(90.49 ± 14.34 vs 84.95 ± 15.49; 95%ci: 0.26-10.83; p = .040).and the hst was shorter than that of the aspirin group(8.52 ± 1.55 vs 9.09 ± 1 .50; 95% ci: 0.21-1.11; p = .042). however, there were no significant difference in bll, bit and ict ,turs, ibt, pb, bs, pus,re,ti, and bnc. as shown in table 4 and fig 2, during the 12-month follow-up period, the qol, ipss, qmax, and pvr of the two groups were significantly improved, and there was no significant difference in iief-5. nevertheless, there was no significant difference in the above indicators between the two groups at 3, 6, and 12 months. discussion with the advancement of living and medical level, many countries in the world have entered an aging society. about 50% of men develop bph at the age of 50, and about 80% of 80-year-old men suffer from bph(7).although traditional turp has been proven to be an effective and relatively safe method for the treatment of bph patients, a wide range of innovative endoscopic techniques have challenged traditional turp's role in the treatment of bph (4,5,8,9). the 2019 european urology guidelines recommends pkrp technology for the treatment of bph, and the recommendation level is a(10). in 2004, pkrp was first applied to bph treatment. in the process of pkrp treatment of bph, plasma vaporizes the surface of the prostate tissue and the tissue below about 2mm to form a uniform coagulation layer, which quickly closes the capillaries, deep arterioles and venules, thus achieving a rapid and effective hemostasis(11).in addition, the temperature of the wound surface of pkrp surgery is maintained at 40°c to 70°c, which greatly reduces thermal damage(12).therefore, pkrp is regarded as a safe and effective endoscopic option for the treatment of bph. aspirin, also known as acetylsalicylic acid, is a kind of white crystal or crystalline powder(13). after nearly a hundred years of clinical application, it has proved to be effective in relieving mild or moderate pain, preventing platelet aggregation and thrombosis (13,14). some of patients with bph are accompanied by cardiovascular and cerebrovascular diseases. in the past, these patients undergoing turp need to stop aspirin one week before the operation in order to prevent excessive bleeding during the operation(15). however, for these patients, stopping aspirin greatly increases the risk of thrombosis and even endanger their lives(16,17). this study suggested that there was no significant difference in the patient preoperative information between the aspirin group and the non-aspirin group. however,the operation time of the aspirin group is shorter than that of the non-aspirin group. in our study, the patients in the aspirin group stayed in hospital longer than who in the nonaspirin group. patients in the aspirin group were accompanied by cardiovascular and cerebrovascular diseases. patients in the aspirin group were tended to accompanie by cardiovascular and cerebrovascular diseases. the patients require additional examinations, such as cerebral ct scanning, before surgery. in addition, cardiovascular and neurology departments should be involved in the preoperative evaluation of these patients. it greatly increases the length of hospital stay before surgery. there was no difference between the two groups in the other indicators(bll, bit and ict) and the complications(turs, ibt, pb and bs) during the perioperative period. previous metaanalysis has shown that pkrp had better hemostatic effect than traditional turp(5).and according to an international multidisciplinary expert consensus established by american urological association(aua) and international consultation on urological disease (icud), patients who continue to take low-dose aspirin are less likely to have serious bleeding complications in the numerous urological procedures (17).therefore, we believe that pkrp is safe in the treatment of patients taking aspirin with pbh. as shown by our results, the treatment effect(qmax, pvr, ipss) and qol have been significantly improved in 3 months, 6 months and 12 months after the operation, whether the patient is taking aspirin or not. neither of the two groups showed significant improvement in erectile function. most previous studies have shown that pkrp has no significant effect on improving erectile function (18-20).however, the iief-5 reported by xu cheng was improved after pkrp surgery(21)we believe that a large amount of reliable follow-up data is still needed to further verify the influence of pkrp on erectile function. in our study, we did not find significant differences in the follow-up indicators and complications between the aspirin group and non-aspirin group. a previous study has shown that minimally invasive pkerp may be considered a safe and effective treatment option for bph patients receiving oral anticoagulant therapy and/or platelet aggregation inhibitors(22). currently, there are many studies on pkrp. nonetheless there are few reports on pkrp in patients taking aspirin. this study explores the safety and efficacy of pkrp in patients taking aspirin for the first time. our research still has the following limitations: the sample size included in the study is limited and the follow-up time is relatively short. this study is a single-center retrospective cohort study. in addition, this study lacked an exploration of patients with bph taking two or more anticoagulants. conclusion based on our research results, pkrp a safe and effective method for patients with bph who maintained on low-dose aspirin. acknowledgement the authors are grateful to the entire staff of the department of urology,and the affiliated jiangning hospital of nanjing medical university.the study was supported by nanjing medical science and technology development fund(no.ykk22224). conflict of interest the authors report no conflict of interest. references 1. devlin cm, simms ms, maitland nj. benign prostatic hyperplasia what do we know? bju int.2021;127:389-399. 2. gupta k, yezdani m, sotelo t, aragon-ching jb. a synopsis of drugs currently in preclinical and early clinical development for the treatment of benign prostatic hyperplasia. expert opin investig drugs.2015;24: 1059-73. 3. noble sm, ahern am, worthington j, et al. the cost-effectiveness of transurethral resection of the prostate vs thulium laser transurethral vaporesection of the prostate in the unblocs randomised controlled trial for benign prostatic obstruction. bju int.2020;126: 595-603. 4. falsaperla m, cindolo l, saita a, et al. transurethral resection of prostate: technical progress by bipolar gyrus plasma-kinetic tissue management system.minerva urol nefrol.2007; 59: 125-9. 5. li s, kwong js, zeng xt, et al. plasmakinetic resection technology for the treatment of benign prostatic hyperplasia: evidence from a systematic review and meta-analysis. sci rep.2015;5: 12002. 6. rhee tg, kumar m, ross js, coll pp. age-related trajectories of cardiovascular risk and use of aspirin and statin among u.s. adults aged 50 or older, 2011-2018. j am geriatr soc 2021;69: 1272-1282. 7. vuichoud c, loughlin kr. benign prostatic hyperplasia: epidemiology, economics and evaluation. can j urol.2015; 22:1-6. 8. sajan a, mehta t, desai p, isaacson a, bagla s. minimally invasive treatments for benign prostatic hyperplasia: a cochrane network meta-analysis. bju int.2022; 33: 359-367. 9. dean e, bruce g, steven l, naeem b, kevin cz, bilal c. new technologies for treatment of benign prostatic hyperplasia. urol clin north am.2022;49: 11-22. 10. gravas s, cornu jn, gacci m, et al. eau guidelines: management of nonneurogenic male luts. european association of urology. 2019. 11. dincel c, samli mm, guler c, demirbas m, karalar m. plasma kinetic vaporization of the prostate: clinical evaluation of a new technique. j endourol.2004;18: 293-8. 12. xiao kw, zhou l, he q, et al. transurethral endoscopic enucleation of the prostate using a diode laser versus bipolar plasmakinetic for benign prostatic obstruction: a meta-analysis. lasers med sci.2020;35: 1159-1169. 13. ricciotti e, fitzgerald ga. aspirin in the prevention of cardiovascular disease and cancer. annu rev med.2021;72: 473-495. 14. lewis hd, davis jw, archibald dg, et al. protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. results of a veterans administration cooperative study. n engl j med.1983；309: 396403. 15. collet jp, himbet f, steg pg.myocardial infarction after aspirin cessation in stable coronary artery disease patients. int j cardio.2000;l76: 257-8. 16. gerstein ns, schulman pm, gerstein wh, petersen tr, tawil i. should more patients continue aspirin therapy perioperatively?: clinical impact of aspirin withdrawal syndrome. ann surg.2012;255: 811-9. 17. culkin dj, exaire ej, green d, et al.anticoagulation and antiplatelet therapy in urological practice: icud/aua review paper. j urol. 2014;192(4): 1026-34. 18. erturhan s, erbagci a, seckiner i, yagci f, ustun a. plasmakinetic resection of the prostate versus standard transurethral resection of the prostate: a prospective randomized trial with 1-year follow-up. prostate cancer prostatic dis.2007;10: 97-100. 19. liu z, li yw, wu wr, lu q.long-term clinical efficacy and safety profile of transurethral resection of prostate versus plasmakinetic resection of the prostate for benign prostatic hyperplasia. urology.2017;103: 198-203. 20. otaola-arca h, álvarez-ardura m, molina-escudero r, fernández mi, páezborda á. a prospective randomized study comparing bipolar plasmakinetic transurethral resection of the prostate and monopolar transurethral resection of the prostate for the treatment of benign prostatic hyperplasia: efficacy, sexual function, quality of life, and complications. int braz j urol.2021;47: 131-144. 21. cheng x, qin c, xu p, et al.comparison of bipolar plasmakinetic resection of prostate versus photoselective vaporization of prostate by a three year retrospective observational study. sci rep.2021;11: 10142. 22. el-shaer w, abou-taleb a, kandeel w. transurethral bipolar plasmakinetic vapo-enucleation of the prostate: is it safe for patients on chronic oral anticoagulants and/or platelet aggregation inhibitors? arab j urol. 2017; 15:347-354. corresponding author: qing-lai tang. department of urology, affiliated jiangning hospital of nanjing medical university, nanjing, china. tel：+86 025 52087000 fax：+86 025 52087000 e-mail:122055623@qq.com tables and legends to figures figure 1. the flow diagram. figure 2. the functional outcomes in 3,6,12 months(‘0’ represents preoperative). table 1 the baseline characteristics and perioperative indicators variable a non–aspirin group(n=67) aspirin group (n=58) p age (year) 69.42±5.91 70.26±5.58 .417 bmi (kg/m2) 22.81±2.69 23.59±3.10 .134 pv(ml) 84.54±16.23 84.98±16.37 .880 tpsa(ng/ml) 1.90(1.00,2.70) 2.32(1.00,3.21) .413 qmax (ml/s) 6(4,15) 7(5,9) .415 pvr (ml) 82.00±17.31 83.76±17.15 .570 ipss 22.45±3.21 23.05±3.56 .320 qol 5(4,5) 5(4,5) .318 iief-5 18(15,18) 18(15,21) .571 abbreviations: bmi body mass index, pv prostate volume, tpsa total prostatespecific antigen, qmax maximum urinary flow rate,pvr postvoid residual,ipss international prostate symptom score, qol quality of life, iief international index of erectile function a data are presented as mean±sd or median and iqr table 2 perioperative indicators variablea non–aspirin group aspirin group p bll (ml) 180.67±30.24 182.76±41.24 .745 ot(min) 90.49±14.34 84.95±15.49 .040 bit(h) 39.91±8.24 42.32±6.52 .072 ict(d) 5.69±1.38 6.12±1.23 .068 hst(d) 8.52±1.55 9.09±1.50 .042 abbreviations: bll intraoperative blood loss, ot operation time, bit bladder irrigation time, ict indwelling catheter time, hst hospital stay time a data are presented as mean±sd table 3 perioperative complications and postoperative sequelae group turs ibt pb bs pus re ti bnc non–aspirin group,67(n) 0 0 4 5 5 15 10 3 aspirin group,58(n) 0 1 2 8 3 8 10 4 p .942 .812 .248 .602 .216 .725 .559 abbreviations: turs transurethral resection syndrome, ibt intraoperative blood transfusion, pb postoperative bleeding, bs bladder spasm, pus postoperative urethral stricture, re retrograde ejaculation, ti temporary incontinence, bnc bladder neck contracture table 4 the functional outcomes variabla non–aspirin group aspirin group p mean ± sd mean change mean ± sd mean change qmax (ml/s) 3 months 21.34±3.47 14.47* 21.66±2.97 14.54* .593 6 months 21.67±3.90 14.80* 21.00±3.27 13.88* .292 12 months 18.87±2.83 12.00* 19.12±3.45 12.00* .651 pvr (ml) 3 months 16.33±6.60 -65.67* 17.07±4.73 -66.69* .479 6 months 18.57±3.71 -63.43* 17.79±5.68 -65.97* .378 12 months 20.11±2.45 -61.89* 19.97±2.69 -63.79* .739 ipss 3 months 5.85±1.18 -16.60* 6.00±1.18 -17.05* .484 6 months 5.78±1.82 -16.67* 6.10±1.86 -16.95* .324 12 months 5.97±1.53 -16.48* 5.74±1.69 -17.31* .428 qol 3 months 1.85±0.80 -3.05* 1.95±0.93 -2.82* .529 6 months 1.94±0.94 -2.96* 1.86±0.71 -2.91* .604 12 months 2.01±0.90 -2.89* 2.05±0.85 -2.72* .815 iief-5 3 months 14.90±3.30 -0.02 15.27±2.73 0.06 .488 6 months 15.07±1.90 0.15 15.34±2.59 0.13 .504 12 months 15.18±2.00 0.26 14.74±1.87 -0.47 .212 abbreviations: qmax maximum urinary flow rate,pvr postvoid residual,ipss international prostate symptom score, qol quality of life, iief international index of erectile function（‘*’ means p＜0.05) a data are presented as mean±sd urol_montage.pdf endourology and stone disease 14 urology journal vol 6 no 1 winter 2009 alternate and incidental diagnoses on noncontrastenhanced spiral computed tomography for acute flank pain m hammad ather, kulsoom faizullah, ilyas achakzai, rizwan siwani, fariah irani introduction: our aim was to determine the incidence and spectrum of significant alternate or incidental diagnoses established or suggested on spiral computed tomography (ct) in a large series of patients with suspected renal colic. materials and methods: records of all patients that had undergone spiral ct (5-mm to 7-mm slice thickness) for acute flank pain during a 5-year period were reviewed. the radiological diagnoses of urinary calculi and obstruction as well as clinical entities not suspected otherwise were analyzed. results: a total of 4000 cts had been performed in the evaluation of acute flank pain. urinary calculi had been identified in 3120 patients (78.0%). there were 398 patients (9.9%) who had an alternate cause of flank pain or an incidentally detected condition on ct. of these patients, 102 (25.6%) had more than one additional finding. a total of 153 clinical conditions had been identified mimicking flank pain secondary to calculus and obstruction. in 47 patients (1.2%), incidental solid masses had been detected. conclusion: spiral ct is a valuable technique in the evaluation of acute flank pain with uncertain clinical diagnosis. a wide spectrum of alternate and additional diagnoses including abdominal solid organ tumors and other significant abdominal conditions such as pancreatitis can be established or suggested on spiral ct performed for suspected acute urinary colic. urol j. 2009;6:14-8. www.uj.unrc.ir keywords: urinary calculi, colic, spiral computed tomography, incidental findings, differential diagnosis, urologic neoplasms department of surgery, aga khan university, karachi, pakistan corresponding author: m hammad ather, md aga khan university, p o box 3500, stadium rd, karachi 74800, pakistan tel: +92 21 486 4778 fax: +92 21 493 4294 e-mail: hammad.ather@aku.edu received june 2008 accepted december 2008 introduction acute flank pain is a common presentation in emergency room, particularly in young men. in 2000, there were 108 000 000 emergency room visits in the united states, of which a total of 1 139 257 included a primary diagnosis of urinary calculus or renal colic.(1) in recent years, noncontrast-enhanced computed tomography (ct) has become the first choice in the evaluation of acute flank pain.(2,3) advantages over other diagnostic modalities include being available and less time consuming, independent of the operator, high sensitive even for small or radiolucent calculi, no need for contrast medium injection, good calculus localization, fair size estimation, and ability to detect lesions mimicking calculi that cause acute flank pain.(2-5) spiral ct has also become an accepted modality prior to treatment of urolithiasis by lithotripsy.(4,5) however, patients presenting with signs and symptoms suggestive of renal colic may have alternate conditions spiral computed tomography for acute flank pain—ather et al urology journal vol 6 no 1 winter 2009 15 which may not be apparent from history and examination and can change the management.(6-8) thus, an early diagnosis and appropriate treatment of acute flank pain is important. the use of spiral ct has popularized significantly; however, this has not resulted in increased number of negative scans for calculus. kirpalani and colleagues(6) noted that there was no significant decrease in positive results in favor of renal colic or alternate diagnoses despite a definite trend of increased use of ct during a period between 1998 and 2002. katz and colleagues noted a wide spectrum of significant alternate diagnoses including genitourinary (gu) and non-gu conditions that could be reliably established or suggested on spiral cts performed for suspected renal colic cases.(7) this study was conducted to determine the incidence and spectrum of significant alternate or incidental diagnoses established or suggested on spiral ct in a large series of patients with suspected renal colic. materials and methods we reviewed spiral ct examinations of the kidneys, ureters, and bladder performed at the department of radiology of aga khan university, during a 5-year period between 2001 and 2005. we selected spiral cts of patients with acute flank pain in whom urinary calculi were suspected according to the clinical data or a preceded ultrasonography indicating calculus or obstruction. spiral cts officially reported by the consultant radiologists with significant experience were reviewed and radiological findings other than urinary calculi were analyzed. repeated ct scans of the patients for re-evaluation of the status of the calculus were excluded. computed tomography scans in which alternate and/or incidental diagnoses had been identified were retrospectively reviewed by 2 radiologists. for these cases, a detailed chart and imaging review was performed, supplemented by phone calls to the selected patients and/or referring physicians, when necessary. the ct examinations with 5-mm to 7-mm slices had been obtained on a cti/pro single slice helical ct scanner (general electrical medical systems, milwaukee, wisconsin, usa). setting of the exposure factors had been 130 kvp and 200 mas to 250 mas. all scans had been obtained from the upper border of the t12 vertebral body to the lower border of the symphysis pubis using 5-mm collimation until 2003, and thereafter, it had increased to 7-mm in order to decrease radiation, without the use of oral or intravenous contrast medium. patients had been placed in the supine position with a full bladder at the time of the ct. additional prone films would have been taken whenever the radiologist had needed a better description of the suspected distal ureteral calculi. all other radiological, biochemical, and serological investigations and findings during the operation were also noted. the patients’ medical charts were reviewed to exclude ct-based diagnoses already known. incidental conditions identified were further classified into significant and insignificant. the significant conditions were defined as those requiring further evaluation and management. results spiral cts of 4000 patients were reviewed. the mean age of the patients was 45.0 ± 16.6 years, and 2360 of them (59.0%) were men. the spiral cts had been ordered in the emergency room for 2920 patients (73.0%), while in 1080 (27.0%), they had been ordered either in clinics or in inpatient settings. urinary calculus was the only diagnosis on 3120 examinations (78.0%). an alternate or incidental diagnosis was established or suggested on 398 examinations (9.9%). of 245 patients (6.1%) with incidental findings, 180 (4.5%) also had urinary calculi (table 1). of the remaining 12.0%, 10.5% had normal scans and 1.5% had evidence of recent passage of a calculus. patients’ distribution based on the diagnoses is depicted in the figure. calculi location frequency (%) both kidneys 1 (0.6) one kidney 88 (48.9) ureters 58 (32.2) ureterovesical junction 31 (17.2) bladder* 2 (11.1) table 1. urinary calculi identified on spiral computed tomography scans in 180 of 398 patients with findings unrelated to calculi *two patients had small bladder calculi with a dilated ureter and other secondary signs of obstruction such as perinephric stranding that indicated a recent passage. spiral computed tomography for acute flank pain—ather et al 16 urology journal vol 6 no 1 winter 2009 a total of 500 additional and alternate findings were found in the 398 patients; 2, 3, 4, and 5 additional findings were noted in 74, 20, 7, and 1 patients, respectively. there were 310 patients (77.9%) who had abnormalities outside the urogenital tract and 190 (44.7%) who had urogenital abnormalities. inflammatory conditions, masses, and miscellaneous conditions were the findings outside the urogenital tract observed in 96, 12, and 202, respectively. of the 190 urogenital findings, 5, 95, and 90 were inflammatory conditions, masses, and miscellaneous conditions, respectively. overall, spiral ct revealed solid masses in 47 patients (1.2%) which were in the urogenital tract in 36 patients and outside the urogenital tract in 11 patients. masses in the urogenital tract were renal masses in 12, bladder tumors in 6, and angiomyolipomas in 2 patients (table 2). cystic lesions were detected in 58 patients (1.5%), of which 34 were in the kidneys (58.6%), 17 in the ovaries (29.3%), and 7 in the liver (12.1%). acute flank pain was secondary to other abdominal conditions in 153 cases. clinical findings outside the urogenital tract were noted distribution of patients based on their diagnoses according to spiral computed tomography findings. *of patients with incidental diagnoses, 180 had also a urinary calculus. mass frequency (%) urogenital tumors 36 (76.6) renal masses 12 (25.5) ovarian masses 8 (22.2) bladder tumors 6 (17.0) uterine fibroids 5 (10.6) renal angiomyolipoma 2 (4.3) adnexal masses 2 (4.3) prostatic nodule 1 (2.1) nonurogenital tumors 11 (23.4) adrenal mass 5 (10.6) peri-ampullary tumors 2 (4.3) caecal mass 2 (4.3) hepatoma 2 (4.3) table 2. incidental diagnoses of solid mass lesions on spiral computed tomography in patients with acute flank pain spiral computed tomography for acute flank pain—ather et al urology journal vol 6 no 1 winter 2009 17 in 75.8% including 108 cases of gastrointestinal disorders and 8 other conditions. inflammatory conditions identified on the spiral ct which required appropriate institution of therapy are detailed in table 3. discussion the value of spiral ct for investigating acute flank pain suggestive of urinary calculi was first established by smith and colleagues.(3) many studies have shown its high sensitivity and specificity in diagnosis of calculi and urinary obstruction.(2,3,8-13) in the current work, spiral ct showed calculi in 80% of the patients in the group without additional diagnoses and in 45% of those in the group with additional findings. one of the disadvantages of ct, however, is the radiation dose per study. this is significantly higher than that of intravenous urography and a combination of plain abdominal radiography and ultrasonography. recently, kluner and associates evaluated the diagnostic yield of multislice ct using a radiation dose equivalent to that of conventional abdominal radiography. they noted that the sensitivity and specificity of detecting patients with calculi was 97% and 95% for ct and 67% and 90% for ultrasonography, respectively.(14) urinary obstruction was similarly assessed, and ct identified more alternate diagnoses than ultrasonography (p < .001). on the contrary, catalano and coworkers observed that noncontrast-enhanced helical ct and ultrasonography had comparable accuracy in diagnosing causes other than calculi.(15) the present ct protocol is comparable in diagnostic yield and radiation dose to that of plain radiography of the kidneys, ureters, and bladder. usually, noncontrast-enhanced ct is performed with 5-mm collimation for the evaluation of ureteral calculi, while many ureteral calculi are 5 mm in diameter or smaller; therefore, size measurements made at ct with 5-mm collimation may not be accurate. however, size measurement by ct does not significantly vary with slice thickness.(16) many patients presenting to the emergency rooms have nonobstructing urinary calculi on noncontrast-enhanced ct. furlan and colleagues noted that these calculi were usually not recognized as the cause of pain by physicians and may be responsible for multiple clinical and radiological evaluations.(17) in the absence of other clinical or ct evidence, these calculi are likely to be the cause of the patient’s acute pain. gynecologic, gastrointestinal, and urogenital disorders can also present as abdominal pain mimicking ureteral colic.(8-11,13) additional advantages of spiral ct in recognizing alternate findings within or outside the urinary tract have also been mentioned in some recent studies.(8-13) in the present study, various significant inflammatory conditions of the abdomen helped in triaging these patients. in-time identification of the potentially morbid conditions not only helps to reduce the time of stay in the emergency room, but also significantly reduces morbidity. in a recent study, lazarus and colleagues determined the sensitivity and specificity of ct for the diagnosis of appendicitis in pregnant women with nontraumatic abdominal pain.(18) they found a sensitivity rate of 92%, a specificity of 99%, and a negative predictive value of 99%. they noted that ct findings were normal in 51 cases (64%) and abnormal in 29 (36%). abnormal findings were appendicitis (16%), urinary tract calculi (7%), small bowel obstruction (2%), cholelithiasis (2%), pyelonephritis (2%), diaphragmatic hernia (1%), caecal bascule (1%), ileus (1), and metastatic lymphadenopathy (1%). up to one-third of cts performed because of flank pain may reveal findings unrelated to urolithiasis.(9) alternate diagnoses are gynecologic conditions (especially adnexal masses) and urogenital diseases (such as pyelonephritis and condition frequency (%) appendicitis 20 (38.5) hepatic granuloma 15 (28.8) splenic granuloma 4 (7.7) retroperitoneal fibrosis 3 (5.8) pancreatitis 3 (5.8) soft tissue emphysema 2 (3.8) paracolic abscess 1 (1.9) adnexal inflammation 1 (1.9) renal abscess 1 (1.9) diverticulitis 1 (1.9) emphysematous pyelonephritis 1 (1.9) table 3. incidental diagnoses of significant inflammatory causes of acute flank pain on spiral computed tomography spiral computed tomography for acute flank pain—ather et al 18 urology journal vol 6 no 1 winter 2009 kidney neoplasms), followed by gastrointestinal (especially appendicitis and diverticulitis), hepatobiliary, vascular, and musculoskeletal conditions. radiologists should know alternate diagnoses as well as the typical findings in favor of urolithiasis detected on ct. early diagnosis and appropriate treatment of these causes are important. computed tomography potentially gives more information and may detect alternate or additional pathologies which would be missed on intravenous urography. many abdominal cancers related to or out of the urogenital tract could be incidentally found by ct of the kidneys, ureters, and bladder. conclusion spiral ct is now the imaging method of choice for evaluation of acute flank pain, because it is not only highly sensitive and specific in identifying calculi and obstruction, but also can reveal alternate causes of flank pain and identify many significant incidental conditions such as solid organ tumors. acknowledgement we would like to thank professor jeffrey rees and dr wasim memon for their help and kind cooperation. conflict of interest none declared. references 1. brown j. diagnostic and treatment patterns for renal colic in us emergency departments. int urol nephrol. 2006;38:87-92. 2. ahmad na, ather mh, rees j. unenhanced helical computed tomography in the evaluation of acute flank pain. int j urol. 2003;10:287-92. 3. smith rc, verga m, mccarthy s, rosenfield at. diagnosis of acute flank pain: value of unenhanced helical ct. ajr am j roentgenol. 1996;166:97-101. 4. ather mh, faruqui n, akhtar s, sulaiman mn. is an excretory urogram mandatory in patients with small to medium-sized renal and ureteric stones treated by extra corporeal shock wave lithotripsy? bmc med. 2004;2:15. 5. greenstein a, beri a, sofer m, matzkin h. is intravenous urography a prerequisite for renal shockwave lithotripsy? j endourol. 2003;17:835-9. 6. kirpalani a, khalili k, lee s, haider ma. renal colic: comparison of use and outcomes of unenhanced helical ct for emergency investigation in 1998 and 2002. radiology. 2005;236:554-8. 7. katz ds, scheer m, lumerman jh, mellinger bc, stillman ca, lane mj. alternative or additional diagnoses on unenhanced helical computed tomography for suspected renal colic: experience with 1000 consecutive examinations. urology. 2000;56:53-7. 8. ather mh, memon w, rees j. clinical impact of incidental diagnosis of disease on non-contrastenhanced helical ct for acute ureteral colic. semin ultrasound ct mr. 2005;26:20-3. 9. eshed i, kornecki a, rabin a, elias s, katz r. unenhanced spiral ct for the assessment of renal colic. how does limiting the referral base affect the discovery of additional findings not related to urinary tract calculi? eur j radiol. 2002;41:60-4. 10. ahmad na, ather mh, rees j. incidental diagnosis of diseases on un-enhanced helical computed tomography performed for ureteric colic. bmc urol. 2003;3:2. 11. hoppe h, studer r, kessler tm, vock p, studer ue, thoeny hc. alternate or additional findings to stone disease on unenhanced computerized tomography for acute flank pain can impact management. j urol. 2006;175:1725-30. 12. dalrymple nc, verga m, anderson kr, et al. the value of unenhanced helical computerized tomography in the management of acute flank pain. j urol. 1998;159:735-40. 13. katz ds, lane mj, sommer fg. unenhanced helical ct of ureteral stones: incidence of associated urinary tract findings. ajr am j roentgenol. 1996;166:131922. 14. kluner c, hein pa, gralla o, et al. does ultra-low-dose ct with a radiation dose equivalent to that of kub suffice to detect renal and ureteral calculi? j comput assist tomogr. 2006;30:44-50. 15. catalano o, nunziata a, sandomenico f, siani a. acute flank pain: comparison of unenhanced helical ct and ultrasonography in detecting causes other than ureterolithiasis. emerg radiol. 2002;9:146-54. 16. dobbins jm, novelline ra, rhea jt, rao pm, prien el, dretler sp. helical computed tomography of urinary tract stones: accuracy and diagnostic value of stone size and density measurements. emergency radiology. 1997;4:303-8 17. furlan a, federle mp, yealy dm, averch td, pealer k. nonobstructing renal stones on unenhanced ct: a real cause for renal colic? ajr am j roentgenol. 2008;190:w125-7. 18. lazarus e, mayo-smith ww, mainiero mb, spencer pk. ct in the evaluation of nontraumatic abdominal pain in pregnant women. radiology. 2007;244:784-90. urol_montage.pdf urological oncology 27urology journal vol 6 no 1 winter 2009 prostate-specific antigen doubling time as a predictor of gleason grade in prostate cancer mohammad reza nowroozi, shahryar zeighami, mohsen ayati, hassan jamshidian, ali reza ranjbaran, asaad moradi, firuzeh afsar introduction: our aim was to evaluate the value of serum prostate-specific antigen doubling time (psadt) to differentiate patients with high-grade prostate cancer who require more aggressive therapy from those with lowgrade cancer. materials and methods: of 460 patients with extended 12-core transrectal ultrasonography-guided biopsy of the prostate, 59 with confirmed prostate cancer were selected. they had not received any previous treatment for prostate cancer and had at least 2 consecutive serum psa tests with a rising trend. the psadt was calculated in patients with 2 serum psa levels measured with an interval more than 3 months. results: of 59 patients with prostate cancer, 35 (59.3%) had low-grade and 24 (40.7%) had high-grade tumors. there was no difference in age between the two groups. the median psadt in patients with high-grade and low-grade tumors were 12.70 months (range, 0.7 to 44.8 months) and 25.00 months (range, 1.65 to 41.2 months; p = .001). a total of 21 patients with high-grade tumors (87.5%) had a psadt less than 12 months, while only 9 of those with low-grade tumors (25.7%) had a psadt less than 12 months. a psadt cutoff of 12 months provided a sensitivity of 74% and a specificity of 87% for differentiation of high-grade from low-grade cancers. conclusion: we concluded that men with a short psadt (< 12 months) were at a higher risk of harboring a high-grade prostate cancer. our data suggests psadt can identify patients with high-grade tumors who require more aggressive therapy. urol j. 2009;6:27-30. www.uj.unrc.ir keywords: prostate-specific antigen, prognosis, prostatic neoplasms division of uro-oncology, department of urology, imam khomeini hospital, tehran university of medical sciences, tehran, iran corresponding author: shahryar zeighami, md uro-oncology ward, imam khomeini hospital, tohid sq, tehran, iran tel: +98 917 715 1293 e-mail: zeyghamishahryar@yahoo.com received april 2008 accepted december 2008 introduction serum prostate-specific antigen (psa) measurement is widely used in the management of prostate cancer. the rate at which psa is increasing has been shown to be valuable in determining prognosis of the patients in various settings, and therefore, may be a useful marker for mortality as a result of prostate cancer.(1-6) prostate-specific antigen velocity was originally described by carter and pearson.(7) subsequently, serum psa doubling time (psadt) was described by schmid and coworkers and was studied in the patients treated by radiotherapy for prostate cancer.(8) by increasing the psa level in a linear fashion (with a constant increasing rate), psa velocity can be estimated by this formula: change in psa level the abstract of this article was first presented in the 10th congress of the iranian urological association in 2008, in tehran, iran. prostate-specific antigen doubling time—nowroozi et al 28 urology journal vol 6 no 1 winter 2009 divided by the interval between measurements. however, it seems that psa increases in an exponential fashion (constant percentage increase) in prostate cancer,(8,9) in which case the psadt is a more appropriate measure of psa kinetics. in contrast to psa velocity, the estimation of psadt requires logarithmic analysis, and thus, it may be more difficult to be applied in the clinic. in this study we investigated the value of psadt for differentiation of low-grade and high-grade prostate cancer in newly diagnosed patients materials and methods patients data of 460 patients who had been referred to our medical center for transrectal ultrasonographyguided biopsy of the prostate between april 2004 and december 2007 were collected. biopsy indications were abnormal digital rectal examination or increased psa (psa more than the normal level for age). after obtaining informed consent from each patient, digital rectal examination was performed before transrectal ultrasonography-guided biopsy. of 460 patients who underwent extended 12-core biopsy, 59 had a pathologic report of prostate cancer that had not received any previous treatment for prostate cancer and had at least 2 consecutive psa tests with more than 3 months interval. sequential psa readings were obtained from the same laboratory using a well-calibrated assay. pathologic examination all samples were examined by one expert pathologist in uropathology. every positive sample was graded using the gleason scoring system and the score was calculated from the sum of the primary and secondary grade. gleason scores less than and greater than 7 were considered to be representative of a low-grade and high-grade tumor, respectively. in case of a gleason score of 7, the total score was assigned as high grade if the primary grade was 4 or 5; otherwise, it was considered as low grade. prostate-specific antigen the psadt was estimated in patients with rising psa before the onset of treatment according to the formula: t × loge(2)/(loge[psa2] loge[psa1]) where t is the time between the two consecutive psa determinations (psa1 and psa2).(10,11) this was made possible as all psa assays for each patient were performed in a same laboratory. statistical analyses the 1-sample kolmogrov-smirov test showed that psadt and psa values had nonparametric distributions and age had a parametric distribution; therefore, data were analyzed by the mann-whitney test and the t test, where appropriate. the receiver operating characteristic curve analysis was used for determination of a cutoff value for psadt to differentiate low-grade and high-grade tumors. a p value less than .05 was considered significant. results of 59 patients with prostate cancer, 35 (59.3%) had low-grade and 24 (40.7%) had high-grade tumors. the mean age of the patients in low-grade and high-grade groups was 70.0 ± 10.9 years (range, 47 to 86 years) and 68.0 ± 5.8 years (range, 58 to 80 years), respectively (p = .47). the median time interval between the two consecutive psa tests was 5.60 months (range, 3.8 to 11.0 months). the median psadt in patients with high-grade and low-grade tumors were 12.70 months (range, 0.7 to 44.8 months) and 25.00 months (range, 1.65 to 41.2 months; p = .001). a cutoff point of 12 months was considered for differentiation of high-grade tumors from low-grade ones based on psadt. a total of 21 patients with high-grade tumors (87.5%) had a psadt less than 12 months, while only 9 of those with low-grade tumors (25.7%) had a psadt less than 12 months. the receiver operating characteristic curve showed that a psadt cutoff of 12 months provided a sensitivity of 74% and a specificity of 87% for differentiation of high-grade from low-grade cancers. the area under the curve was 82% (figure). the positive predictive value and negative predictive value were 70% and 73%, respectively. prostate-specific antigen doubling time—nowroozi et al urology journal vol 6 no 1 winter 2009 29 discussion because psa velocity and psadt are measures of the rate of psa change with time, their estimation relies on the statistical technique of regression. calculation of psa velocity is based on the assumption that serum psa increases in a linear fashion, and therefore, is implicated by linear regression analysis. in contrast for psadt, an exponential increase in psa is assumed, and therefore, it requires a complex analysis for estimation. regression techniques for the estimation of psadt require the logarithmic transformation of the available serum psa values by a somewhat daunting formula. in practice, calculation of psadt requires the use of statistical software. however, a recently published graphical tool allows the estimation of psadt in practice settings without the need for electronic resources.(12) several previous studies have shown psadt to be an appropriate tool for monitoring of prostate cancer at any step of the disease.(13) however, measurement of serum psa may be accompanied by errors due to interassay and biological variations; therefore, some precautions are needed to minimize such errors on estimates of psa. as a result, sequential psa tests should be obtained with longer intervals in order that the resulting estimate truly reflects cancer growth. on the other hand, there are some limitations in this approach including the need for expedient decision making, costs of repeating psa test, and variation in psa kinetics with time.(14) two psa tests with at least a 3-month interval appear to provide an accurate estimate of psadt; however, when possible, a minimum of 3 tests during at least 6 months should be obtained. in the present study, our analysis showed that patients with a short psadt (< 12 months) before the onset of therapy were at a higher risk of harboring a high-grade prostate cancer. pound and colleagues showed that a psadt of equal to or less than 10 months was predictive of development of metastatic disease, which was in accordance with the results reported by pollack and associates after definitive radiotherapy.(15,16) an increasing concern is the overtreatment of patients with “good-risk” prostate cancer, while undertreatment in patients with a more aggressive biological phenotype should be avoided. various criteria have been proposed to identify patients with aggressive disease, but none has been validated.(17) a rapid psadt (< 12 months) probably reflects a more aggressive phenotype. choo and coworkers analyzed the distribution of psadt in “good-risk” patients on surveillance.(18) the median psadt was 7 years in their patients; 42% and 22% of the them had a psadt more than 10 and less than 3 years, respectively, the latter of whom were at a high risk of progression and were treated radically. at 8 years, the mortality rate was less than 1% suggesting this approach to be safe. mclaren and associates showed that psadt was significantly lower in patients with progressive disease and strongly correlated with the time to treatment. they concluded that psadt was the most important indicator of disease activity.(4) our data confirms an acceptable level of accuracy for psadt to identify patients with high-grade prostate cancer who require more aggressive therapy. this indicator appears to convey prognostic information that should be considered with conventional prognostic factors such as the figure shows receiver operating characteristic curve for determining the prostate-specific antigen doubling time (psadt) threshold value for differentiation of high-grade from low-grade prostate cancer. prostate-specific antigen doubling time—nowroozi et al 30 urology journal vol 6 no 1 winter 2009 absolute serum psa concentration, clinical stage, and biopsy grade and can help in determining the prognosis years ahead.(19) the psadt is probably useful in determining outcomes after treatment and suggesting experimental multimodal therapy protocols for those with aggressive disease. finally, psadt measures may be crucial for intervention; however, further investigation is needed to determine precise cutoff levels. conclusion it seems that psadt provides useful information in the prediction of the pathological features of prostate cancer patients and selection of the patients who need more aggressive treatment. conflict of interest none declared. references 1. sengupta s, myers rp, slezak jm, bergstralh ej, zincke h, blute ml. preoperative prostate specific antigen doubling time and velocity are strong and independent predictors of outcomes following radical prostatectomy. j urol. 2005;174:2191-6. 2. roberts sg, blute ml, bergstralh ej, slezak jm, zincke h. psa doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. mayo clin proc. 2001;76:576-81. 3. d’amico av, chen mh, roehl ka, catalona wj. preoperative psa velocity and the risk of death from prostate cancer after radical prostatectomy. n engl j med. 2004;351:125-35. 4. mclaren db, mckenzie m, duncan g, pickles t. watchful waiting or watchful progression?: prostate specific antigen doubling times and clinical behavior in patients with early untreated prostate carcinoma. cancer. 1998;82:342-8. 5. d’amico av, moul jw, carroll pr, sun l, lubeck d, chen mh. surrogate end point for prostate cancerspecific mortality after radical prostatectomy or radiation therapy. j natl cancer inst. 2003;95:137683. 6. freedland sj, humphreys eb, mangold la, et al. risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. jama. 2005;294:433-9. 7. carter hb, pearson jd. psa velocity for the diagnosis of early prostate cancer. a new concept. urol clin north am. 1993;20:665-70. 8. schmid hp, mcneal je, stamey ta. observations on the doubling time of prostate cancer. the use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume. cancer. 1993;71:2031-40. 9. vollmer rt, egawa s, kuwao s, baba s. the dynamics of prostate specific antigen during watchful waiting of prostate carcinoma: a study of 94 japanese men. cancer. 2002;94:1692-8. 10. roberts sg, blute ml, bergstralh ej, slezak jm, zincke h. psa doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. mayo clin proc. 2001;76:576-81. 11. sengupta s, slezak jm, blute ml, bergstralh ej. simple graphic method for estimation of prostate-specific antigen doubling time. urology. 2006;67:408-9. 12. svatek rs, shulman m, choudhary pk, benaim e. critical analysis of prostate-specific antigen doubling time calculation methodology. cancer. 2006;106:104753. 13. bidart jm, thuillier f, augereau c, et al. kinetics of serum tumor marker concentrations and usefulness in clinical monitoring. clin chem. 1999;45:1695-707. 14. ross pl, mahmud s, stephenson aj, souhami l, tanguay s, aprikian ag. variations in psa doubling time in patients with prostate cancer on “watchful waiting”: value of short-term psadt determinations. urology. 2004;64:323-8. 15. pound cr, partin aw, eisenberger ma, chan dw, pearson jd, walsh pc. natural history of progression after psa elevation following radical prostatectomy. jama. 1999;281:1591-7. 16. pollack a, zagars gk, kavadi vs. prostate specific antigen doubling time and disease relapse after radiotherapy for prostate cancer. cancer. 1994;74:670-8. 17. ross js, jennings ta, nazeer t, et al. prognostic factors in prostate cancer. am j clin pathol. 2003;120:s85-100. 18. choo r, klotz l, deboer g, danjoux c, morton gc. wide variation of prostate-specific antigen doubling time of untreated, clinically localized, lowto-intermediate grade, prostate carcinoma. bju int. 2004;94:295-8. 19. carter hb, ferrucci l, kettermann a, et al. detection of life-threatening prostate cancer with prostatespecific antigen velocity during a window of curability. j natl cancer inst. 2006;98:1521-7. 1 publication bias in urology systematic reviews and meta-analyses amirmahdi khayyamfar, md. student research committee, school of medicine, iran university of medical sciences, tehran, iran sepehr khosravi, md. student research committee, school of medicine, iran university of medical sciences, tehran, iran robab maghsoudi, md. department of urology, firoozgar hospital, school of medicine, iran university of medical sciences behnam shakiba, md. department of urology, firoozgar hospital, school of medicine, iran university of medical sciences firoozgar clinical research development center, iran university of medical sciences, tehran, iran. corresponding author: behnam shakiba, md. behkiba@gmail.com, shakiba.b@iums.ac.ir address: urology department, firoozgar hospital, valadi st., valiasr ave., tehran, iran. potal code: 1593748711 tel: +98-8214-1303 2 keywords publication bias; systematic review; meta analysis; urology competing interests: the authors declare no conflict of interest in this study. funding: present study was a medical doctoral dissertation and was supported by firoozgar clinical research development center, iran university of medical sciences, tehran, iran. (grant number: 99-1-4-17684) 3 publication bias is one of the most important biases in systematic reviews and meta-analyses. this bias occurs when the results of an article affect its publication, in other words positive or significant findings are more likely to be published than the other probable results (1), as a result, statistically non-significant data from unpublished articles are missed out from systematic reviews and meta-analyses which can exaggerate the effect of some variables and may suggest useless or even harmful interventions and inappropriate clinical decision making (3, 4). previous studies have shown that publication bias has been a matter of concern in the metaanalysis and systematic reviews conducted in some medical fields (5-7). accordingly, we decided to assess the status of publication bias evaluation in systematic reviews and metaanalyses published in high impact urology journals. this study was performed on systematic reviews and meta-analysis published in four top urology journals based on their impact factor (european urology, the journal of urology, bju international and prostate cancer and prostatic diseases) in the last 5 years (search date: 2021/4/1). in the screening phase, two authors independently screened systematic reviews and meta-analysis with more than ten included studies for inclusion. after the identification of all systematic reviews and meta-analysis, 200 papers were randomly included using the random numbers generator. two authors extracted information independently from each paper. a total of 200 papers were included in the present study. of these, 81 (40.5%) articles were published in european urology, 53 (26.3%) in the journal of urology, 45 (22.5%) in bju international and 21 (10.5%) in prostate cancer and prostatic diseases. from the 200 included studies only 65 (32.5%) evaluated the publication bias in the review process and 31 reviews had reported publication bias in their study. according to google scholar, the mean rank of citations was 98.17 in articles which had mentioned publication bias and 102.97 in the rest of them, which shows no significant relationship between citation number and publication bias reporting (p=0.558). assessment of publication bias in the 5 years of study duration shows no meaningful difference between the studied years (p= 0.686). researchers used funnel plot, egger’s test, begg’s test and trim and fill method for publication bias assessment in the included systematic reviews and meta-analysis. 4 visual inspection of a funnel plot was the most frequent method used for evaluation of publication bias (61 from 65, 93.85%); this method was used alone in 34 articles and in combination with other methods in 27 papers. the present study confirms that publication bias was formally evaluated in a small number of reviews and meta-analysis published in urology journals. therefore, this may be a risk factor that could decrease the robustness of outcomes and results of these studies. it seems that there is an essential need for authors, reviewers, and editors to pay better attention to evaluation of publication bias besides reporting it based on the aforementioned reporting guidelines. nevertheless, further studies are strongly recommended to better evaluate the efficacy of publication bias evaluation on the quality of systematic reviews published in urology journals. the present study is one of the few studies that have assessed the reporting of publication bias evaluation in systematic reviews and meta-analysis and the first study to evaluate high impact urology journals; yet there are certain limitations that must be acknowledged. first, we limited our investigation to systematic reviews and meta-analysis published in four top ranked urology journals. therefore, results from the present study need to be interpreted in light of the selected sample and cannot be generalized to all urology journals. second, we included high impact urology journals for evaluation of high quality systematic reviews, yet we did not assess the quality of systematic reviews and meta-analysis directly. third, this study only considered the evaluation of publication bias and did not assess the existence of publication bias in studies which had not assessed this kind of bias themselves. references: 1. nissen sb, magidson t, gross k, bergstrom ct. publication bias and the canonization of false facts. elife. 2016 dec 20;5:e21451. 2. schneck a. examining publication bias—a simulation-based evaluation of statistical tests on publication bias. peerj. 2017 nov 30;5:e4115. 3. onishi a, furukawa ta. publication bias is underreported in systematic reviews published in high-impact-factor journals: metaepidemiologic study. j clin epidemiol. 2014 dec;67(12):1320–6. 5 4. 5. evaluation method single test in combination with other tests total funnel plot 34 27 61 egger’s test 2 26 28 begg’s test 1 10 11 trim and fill method 1 0 1 6. table 1. the publication bias tests used for publication bias assessment in the included systematic reviews and meta-analysis. 7. 8. impact of percutaneous nephrostomy on the efficacy of in situ shock wave lithotripsy for upper ureteral stones seung woo yang#, ji yong lee#, ju hyun shin, jae sung lim, ki hak song* purpose: to investigate whether a percutaneous nephrostomy (pcn) has any impact on the success rate of shock wave lithotripsy (swl) and to estimate the probability of stone-free rate in swl patients with upper ureter stones. materials and methods: overall, 236 patients who underwent swl for upper ureter stones between 2015 and 2019 were evaluated. forty-nine patients who underwent pcn during swl were identified. medical data of the patients were retrospectively reviewed, and possible prognostic features were evaluated. results: out of all patients, 147 patients were selected through propensity score matching. there were no significant differences between the pcn and no pcn groups, except for a lower stone-free rate (55.1% vs. 74.5%, p = .018) and one-session success rate (24.5% vs. 50.0%, p = .003) in the pcn group. in univariate analysis, a younger age, the female sex, a smaller size of the stone, lower mean stone density (msd), and absence of pcn were positive predictive factors of being stone-free in patients who underwent swl. in multivariate analysis, a smaller size, lower msd, and absence of pcn were positive predictive factors of being stone-free in patients who underwent swl. conclusion: stone size, msd, and pcn were prognostic factors that influence the outcome of swl. the presence of pcn during swl is associated with adverse success rates in patients with upper ureter stones. keywords: percutaneous nephrostomy; shockwave lithotripsy; stents; ureter; urinary calculi introduction urolithiasis is one of the most prevalent problems in patients visiting a department of urology. the commonest risk factors for the progression of urolithiasis include metabolic syndrome, dehydration, lifestyle changes, and rise in ambient temperatures(1-3). usually, upper urinary tract stones pass through the urinary tract without a problem; however, in some cases, complications arise, the most frequent being upper urinary tract obstruction and acute renal colic, which often result in excruciating pain(4). if the presence of stones is complicated by acute kidney injury with severe obstruction or infection, either percutaneous nephrostomy (pcn) or a double-j ureteral stent should be attempted as an emergency procedure to allow drainage of urine for decompression before planning further treatment(5). shock wave lithotripsy (swl) was introduced in the 1980s for the treatment of urolithiasis and was accepted immediately as a first-line option for treatment(6). a number of factors, such as position, size, and hardness of the stone determine the efficacy of treatment with swl(7). retreatment, if required, particularly in the case of large volume stone results in additional expenditure in terms department of urology, chungnam national university hospital, chungnam national university college of medicine, daejeon, korea. *correspondence: department of urology, chungnam national university hospital, chungnam national university college of medicine, 282 monwha-ro, jung-gu, daejeon, korea. tel: +82-42-280-7777.fax: +82-42-280-7206. e-mail: urosong@cnu.ac.kr # these authors contributed equally to this work and should be considered co-first authors. received march 2021 & accepted july 2021 of time and finances(8). prior evaluation of whether patients with urolithiasis will respond well to swl, prevents unnecessary wastage of resources and treatment by procedures likely to be ineffective by selecting more appropriate treatment methods for the management of urolithiasis (9). hence, it is advisable to identify in advance patients who can be better served using an alternative modality of treatment. recently, some studies have demonstrated that double-j ureteral stents reduce the success rate of swl(10-12); however, it remains uncertain and debatable whether pcn affects the success rate of swl. this study aimed to investigate whether pcn affects the success rate of swl for the treatment of ureteral stones. additionally, various patient populations and stone characteristics were evaluated using non-contrast computed tomography (ncct) for predicting the stone-free rate after swl to counsel patients on the various treatment options available for upper ureteral stones. materials and methods patient population a retrospective analysis of the database of patients of urology journal/vol 19 no. 4/ july-august 2022/ pp. 262-267. [doi: 10.22037/uj.v18i.6762] endourology and stone disease our department, who received swl for a single upper ureteral stone from january 2015 to december 2019, was performed. overall, 236 patients with previously untreated stones were registered. the inclusion criteria for the current study were a solitary stone measuring 0.5 – 2 cm in diameter, radiopaque, and located within the upper ureter on ncct. patients with the following state were excluded: uncontrolled bleeding disorders, uncorrected obstruction inferior to the stone, had a genitourinary tract abnormality, younger than 15 years, double-j ureteral stents inserted state. the medical data of these patients were reviewed to evaluate their suitability as prognostic features. the factors evaluated were age, sex, diabetes mellitus (dm), hypertension (htn), stone laterality, stone length (x, y, and z axes), stone volume, mean stone density (msd), stone heterogeneity index (shi), skin to stone distance (ssd), psoas muscle cross-sectional area, colic pain and presence of pcn before swl. pcn was performed as an emergency procedure in complicated upper ureter stone with severe obstruction and infection. an 8-french tube was introduced into the obstructed renal pelvis through a pcn puncture. all data analyses were performed according to the relevant regulations and guidelines described in the declaration of helsinki; the study was approved by chungnam national university hospital institutional ethics committee (approval no. cnuh 201807047004). stone characteristics the characteristics of the stones were interpreted using ncct, and maximum stone length was measured on axial and coronal view. the stone volume was calculated using the ellipsoid formula (π/6 × length × width × height). the msd was obtained by measuring the mean hounsfield units (hu) of the defined regions of a circle with a diameter smaller than that of the stone without including the adjacent tissue. the shi was obtained as the standard deviation of hu. the ssd was obtained by measuring distance from the center of the stone to the skin at 90o in the horizontal axis. successful swl outcome was categorized as stone-free and one-session success. stone-free was defined as an asymptomatic state with residual stone debris of less than 3 mm in the largest diameter or absence of observed stones for four weeks after the first swl. one-session success was defined as stone-free state after only once swl. swl protocol the same electromagnetic lithotripter was used for treating all patients under fluoroscopic guidance on an outpatient basis. the lithotripter was an electromagnetic lithotripter made by the direxgroup (integra sl, initia ltd., israel). the number of shock waves delivered per session was 2500 to 2800 at a low frequency (sixty times per minute). the voltage of the shock wave started from 10.0 kv and was increased stepwise to a maximum of 18.0 kv in order to reduce the risk of damage to adjacent organs. additional swl was carried out at one-week intervals if any evidence of residual stones remained. all patients underwent swl under opened pcn state. no antibiotics and diuretics were administered during swl. all patients were instructed to drink sufficient water and continue daily activities with proper exercise. statistical analyses with propensity-score matching the method of propensity-score matching was performed to further clarify patients’ characteristics after total group analysis. combined continuous and categorical factors were evaluated to produce a propensity score for each individual in the surveyed population. propensity scores were then calculated using a multivariate logistic regression model with a binomial method based on factors that demonstrated significant differences between the pcn and no pcn groups in the total groups. propensity-score analysis with 1:2 matching was performed with the nearest neighbor matching method. statistical comparisons of continuous variables were expressed as mean ± standard deviation and performed using the student’s two-sample t-test. statistical comparisons of categorical variables were performed using the pearson’s chi-square test. univariate logistic regression was used to identify factors having an effect on stone-free and one-session success. significant factors in the univariate logistic regression were further analyzed by multivariate logistic regression. p-values ≤ 0.05 were considered statistically significant. all statistical analyses used the ibm spss statistics version 23.0 (ibm corp., armonk, ny, usa). impact of percutaneous nephrostomy on swl-yang et al. table 1. demographic data and swl success rate comparisons between pcn and no pcn groups variable pcn group (n=49) no pcn group (n=187) p-value age, mean ± sd 65.31 ± 12.46 58.08 ± 14.26 .001 sex, numbers of female, % 24, 49.0 81, 43.3 .478 diabetes mellitus, % 21, 42.9 40, 21.4 .002 hypertension, % 33, 67.3 63, 33.7 <.001 stone laterality, numbers on right side, % 31, 63.3 86, 46.0 .031 stone length (mm, x-axis), mean ± sd 7.01 ± 1.56 6.41 ± 1.49 .015 stone length (mm, y-axis), mean ± sd 7.55 ± 1.21 7.22 ± 1.75 .123 stone length (mm, z-axis), mean ± sd 10.29 ± 2.95 9.08 ± 2.60 .005 stone volume (mm3), mean ± sd 308.15 ± 167.62 245.62 ± 173.10 .024 skin to stone distance (mm), mean ± sd 109.38 ± 22.33 107.90 ± 15.67 .593 mean stone density, mean ± sd 707.72 ± 276.50 790.53 ± 262.81 .053 stone heterogeneity index, mean ± sd 140.81 ± 88.13 188.47 ± 79.29 <.001 psoas muscle cross-sectional area (mm2), mean ± sd 965.98 ± 336.79 1096.98 ± 362.06 .023 colic pain, % 41, 83.7 148, 79.1 .480 stone-free, % 27, 55.1 145, 77.5 .002 one-session success, % 12, 24.5 97, 51.9 .001 abbreviations: sd = standard deviation; pcn = percutaneous nephrostomy. values are presented as mean ± standard deviation or number (%). endourology and stones diseases 263 results characteristics of patients and stones are presented in tables 1 and 2. table 1 shows the baseline characteristics of all 236 patients who received swl for upper ureteral stone. out of these patients, 20.8% (n = 49) had pcn insertion during swl for upper ureteral stone. comparisons of the pcn and no pcn groups based on characteristics of patients and stone revealed that age, dm, htn, stone laterality, size, msd, shi, and psoas muscle cross-sectional area were significantly different between the groups. there were no significant differences between the groups in sex, ssd, msd, and colic pain. stone-free was significantly less in the pcn group (55.1% vs. 77.5%), as was one-session success (24.5% vs. 51.9%) (table 1). after 1:2 propensity-score matching with the nearest neighbor algorithm, stone-free was significantly less in the pcn group (55.1% vs. 74.5%), as was one-session success (24.5% vs. 50.0%) (table 2). univariate logistic regression model proved that the following were significantly related factors of stone-free after swl for upper ureteral stone: a younger age, the female sex, a smaller stone volume, lower msd, and no inserted pcn. multivariate logistic analysis proved that a smaller stone volume, lower msd, and no inserted pcn were significantly independent predictive factors of stone-free after swl for upper ureteral stones (table 3). univariate logistic regression model proved that the following were significantly related factors of one-session success after swl for upper ureteral stone: the female sex, a smaller stone volume, shorter ssd, lower msd, and no inserted pcn. multivariate logistic analysis proved that a smaller stone volume, lower msd, and no inserted pcn were significantly independent predictive factors of one-session success after swl for upper ureteral stones (table 4). discussion since its introduction in the early 1980s, swl has been recognized as the preferred treatment for ureteral stones because it is non-invasive, has few contraindications, and demonstrates good clinical results(13). over the last 40 years, many scholars have attempted to find out the factors that determined high success and low complication rates in swl treatment of ureteral stones. in the case of swl, factors that have been reported to affect success and complication rates contain stone characteristics (size, location, composition, and density), patients’ characteristics (age, sex, and obesity), swl frequency range, lithotripter type, and any hemorrhagic tendency in the patients(14-16). additionally, pre-swl pcn has been proposed as an important method of resolving upper urinary tract obstruction. it affords satisfactory drainage, is technically simple, and is associated with fewer complications. persistent obstruction may result in subsequent decline of renal function. elevated pressure above the ureter stone also increases the tension in the wall of the ureter at the stone location and, therefore, the friction between the mucosa and stone of the ureter. moreover, high friction at the stone location injures the mucosal layer of the ureter, leading to bleeding and inflammation around the stone. this leads to swelling that narrows the lumen of the ureter and hinders spontaneous discharge of the stone. on the other hand, severe obstruction with hydronephrosis can be linked to the impaction of a ureteral stone on the ureteral mucosa(17). chronically impacted ureteral stones can cause edema of the ureteral wall and are often associated with ureteral polyps or strictures(18). these changes can also adversely affect the discharge of the ureteral stone. we consider whether performing pcn to resolve the obstruction could improve the movement of the ureteral stone and increase the success rate of swl. however, the findings did not support our expectations. our results indicated that pcn insertions could adversely affect stone-free and one-session success during swl. in our study, pcn was the only significantly different factor between both groups after 1:2 propensity-score matching. propensity-score matching was used to reduce the impact of treatment-selection bias for estimating causal treatment effects using observational data(19). the main rationale for performing decompression stentings (pcn or double-j ureteral stent) was to prevent complications related to upper urinary tract obstruction as stone debris passes through the ureter during swl. complete elimination of stones is the supreme goal; table 2. demographic data and swl success rate comparisons between pcn and no pcn groups for propensity-score matching variable pcn group (n=49) no pcn group(n=98) p-value age, mean ± sd 65.31 ± 12.46 62.70 ± 13.34 .257 sex, numbers of female, % 24, 49.0 50, 51.0 .816 diabetes mellitus, % 21, 42.9 31, 31.6 .180 hypertension, % 33, 67.3 57, 58.2 .281 stone laterality, numbers on right side, % 31, 63.3 57, 58.2 .552 stone length (mm, x-axis), mean ± sd 7.01 ± 1.56 6.54 ± 1.63 .104 stone length (mm, y-axis), mean ± sd 7.55 ± 1.21 7.32 ± 1.76 .355 stone length (mm, z-axis), mean ± sd 10.29 ± 2.95 9.50 ± 2.69 .105 stone volume (mm3), mean ± sd 308.15 ± 167.62 264.30 ± 173.43 .146 skin to stone distance (mm), mean ± sd 109.38 ± 22.33 106.34 ± 17.32 .366 mean stone density, mean ± sd 707.72 ± 276.50 755.05 ± 266.15 .317 stone heterogeneity index, mean ± sd 140.81 ± 88.13 157.97 ± 72.69 .212 psoas muscle cross-sectional area (mm2), mean ± sd 965.98 ± 336.79 997.98 ± 368.55 .611 colic pain, % 41, 83.7 79, 80.6 .651 stone-free, % 27, 55.1 73, 74.5 .018 one-session success, % 12, 24.5 49, 50.0 .003 abbreviations: sd = standard deviation; pcn = percutaneous nephrostomy. values are presented as mean ± standard deviation or number (%). impact of percutaneous nephrostomy on swl-yang et al. vol 19 no 4 july-august 2022 264 however, reducing complications during swl is another important goal in the management of urolithiasis. in most studies, decompression stents have been shown to be effective in preventing complications. regrettably, few reports show that decompression stents increase stone-free rates after swl. previous studies demonstrated that double-j ureteral stents do not improve the success rate of swl(20-22). middela et al., reported that the presence of pcn was not a significant factor in the success rate of swl(23). joshi et al., demonstrated that the outcome of swl in no decompression stent group was better than that in pcn group and double-j ureteral stent group(24). although these measures may provide more information to urologists before treatment, the precise meaning of these data in the management of stone remains controversial. our assumption was that when the friction between stone and mucosa of ureter was higher than the driving force, the stone will not be dislodged. if pcn was present, it could decompress the dilated renal pelvis and the ureter above the stones and can drain the urine through it. consequently, it reduces the pressure above the ureteral stone and the friction around the stone, but it also reduces the driving force associated with urine flow, which negatively impacts the success rate of swl. urinary tract obstruction resulting from ureteral stones is a common cause of urinary tract infection (uti)(25). in patients with acute uti, the infection should be treated first with appropriate antibiotics before commencing treatment for removal of the stone. in some cases, pcn insertion is inevitable. until stones are removed, urinary diversions can be performed empirically to prevent deterioration of renal function or aggravation of the uti. pcn is a well confirmed procedure that allow for temporary or permanent urinary diversion from the renal pelvis in urinary tract obstruction. pcn is mainly performed for patients with severe renal colic, acute kidney injury, and urosepsis caused by urinary tract obstruction(26). we had several cases of swl in patients who underwent pcn and observed that pcn could interfere with stone debris migration. as mentioned above, pcn can decrease intrarenal pressures if intrarenal urine and fluid are continuously draining through a pcn, and this may make it difficult for stones to migrate toward the distal ureter and bladder. the results of the current study suggest that physicians may consider stone volume and msd as factors that influence swl outcomes when deciding whether to perform pcn prior to swl. in patients with large upper ureteral stones and a high msd, the decision to perform pcn should be based on the degree of renal function decline and complications table 3. univariate and multivariate logistic regression models for predictive factors of stone-free following shock wave lithotripsy parameter univariate multivariate odds ratio 95% ci p-value odds ratio 95% ci p-value age 0.971 0.943-0.999 .046 0.965 0.926-1.006 .093 sex (female) 2.051 1.010-4.164 .047 1.960 0.728-5.227 .183 diabetes mellitus 1.253 0.600-2.614 .548 hypertension 0.971 0.476-1.979 .935 stone laterality (right side) 1.704 0.844-3.440 .137 stone length (mm, x-axis) 0.504 0.379-0.671 <.001 stone length (mm, y-axis) 0.546 0.418-0.713 <.001 stone length (mm, z-axis) 0.590 0.489-0.713 <.001 stone volume (mm3) 0.991 0.989-0.994 <.001 0.992 0.988-0.995 <.001 skin to stone distance (mm) 0.989 0.970-1.008 .244 mean stone density 0.996 0.994-0.997 <.001 0.996 0.994-0.998 <.001 stone heterogeneity index 1.003 0.998-1.007 .254 psoas muscle cross-sectional area (mm2) 1.000 0.999-1.001 .887 colic pain 1.943 0.826-4.569 .128 percutaneous nephrostomy 0.420 0.204-0.866 .019 0.292 0.104-0.815 .019 abbreviations: ci = confidence interval. parameter univariate multivariate odds ratio 95% ci p-value odds ratio 95% ci p-value age 1.002 0.977-1.027 .886 sex (female) 2.042 1.047-3.982 .036 1.212 0.421-3.487 .721 diabetes mellitus 1.344 0.678-2.662 .397 hypertension 1.371 0.695-2.707 .363 stone laterality (right side) 0.838 0.430-1.635 .605 stone length (mm, x-axis) 0.402 0.287-0.562 <.001 stone length (mm, y-axis) 0.471 0.351-0.633 <.001 stone length (mm, z-axis) 0.557 0.452-0.686 <.001 stone volume (mm3) 0.988 0.984-0.992 <.001 0.990 0.985-0.994 <.001 skin to stone distance (mm) 0.978 0.959-0.997 .025 0.979 0.952-1.008 .150 mean stone density 0.995 0.994-0.997 <.001 0.995 0.992-0.997 <.001 stone heterogeneity index 0.998 0.994-1.003 .443 psoas muscle cross-sectional area (mm2) 0.999 0.998-1.000 .154 colic pain 1.529 0.636-3.679 .128 percutaneous nephrostomy 0.324 0.151-0.695 .004 0.168 0.054-0.523 .002 abbreviations: ci = confidence interval. table 4. univariate and multivariate logistic regression models for predictive factors of one-session success following shock wave lithotripsy impact of percutaneous nephrostomy on swl-yang et al. endourology and stones diseases 265 caused by upper urinary tract obstruction. identifying factors that predict swl outcomes would help simplify the care of patients with stones. patients identified to be at high risk of treatment failure may be offered alternative procedures, such as flexible ureteroscopy to manage their urolithiasis. physicians can determine which types of patients are most likely to benefit from swl. in an era of limited medical insurance reimbursement, cutting down on medical costs is essential. thus, we do not recommend routine pre-swl pcn insertion; pcn insertion should be offered only when there are special indications, such as complicated upper urinary tract obstruction. the limitation of this study is that it is a retrospective study conducted at a single institution; therefore, our results were derived from a relatively small sample population. a small control group might arouse selection bias in propensity-score matching studies. also, potential limitation to propensity-score matching studies was that unrecognized risk factors might affect outcomes. despite this limitation, our study confirmed the effect of pcn on the outcomes of swl and analysis of stonefree following swl according to meaningful stone characteristics (stone volume and msd) in relation to the presence of a pcn. in the future, a well-designed prospective study with a large sample population will be required to prove our observations on the adverse effect of pcn during swl. conclusions the presence of pcn during swl was an adverse predictive factor of stone-free and one-session success in patients with upper ureteral stones. we believe the pcn insertion status can be used to predict the treatment outcomes of swl, and this may be helpful in selecting the optimal treatment option for patients with upper ureteral stones. pcn should still be used in patients with obstruction, those at risk of sepsis, and in those with unbearable pain or decreased renal function. however, if the underlying problem resolves and the general condition improves, it is suggested that performing swl after the removal or clamping of the pcn can lead to positive therapeutic effects. acknowledgements this research was supported by the chungnam national university hospital research fund. this work was supported by research fund of chungnam national university. conflict of interest there are no conflicts of interest to declare from all authors. references 1. wong y, cook p, roderick p, somani bk. metabolic syndrome and kidney stone disease: a systematic review of literature. j endourol. 2016;30:246-53. 2. geraghty rm, proietti s, traxer o, archer m, somani bk. worldwide impact of warmer seasons on the incidence of renal colic and kidney stone disease: evidence from a systematic review of literature. j endourol. 2017;31:729-35. 3. cho st, jung si, myung sc, kim th. correlation of metabolic syndrome with urinary stone composition. int j urol. 2013;20:208-13. 4. holmlund d. on medical treatment for ureteral stone expulsion. scand j urol. 2018;52:94100. 5. pearle ms, pierce hl, miller gl, et al. optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. j urol. 1998;160:1260-4. 6. holmes sa, whitfield hn. the current status of lithotripsy. br j urol. 1991;68:337-44. 7. yang sw, hyon yk, na hs, et al. machine learning prediction of stone-free success in patients with urinary stone after treatment of shock wave lithotripsy. bmc urol. 2020;20:88. 8. cone eb, eisner bh, ursiny m, pareek g. cost-effectiveness comparison of renal calculi treated with ureteroscopic laser lithotripsy versus shockwave lithotripsy. j endourol. 2014;28:639-43. 9. cone eb, pareek g, ursiny m, eisner b. costeffectiveness comparison of ureteral calculi treated with ureteroscopic laser lithotripsy versus shockwave lithotripsy. world j urol. 2017;35:161-6. 10. sfoungaristos s, polimeros n, kavouras a, perimenis p. stenting or not prior to extracorporeal shockwave lithotripsy for ureteral stones? results of a prospective randomized study. int urol nephrol. 2012;44:731-7. 11. ozkan b, dogan c, can ge, tansu n, erozenci a, onal b. does ureteral stenting matter for stone size? a retrospective analyses of 1361 extracorporeal shock wave lithotripsy patients. cent european j urol. 2015;68:35864. 12. nguyen dp, hnilicka s, kiss b, seiler r, thalmann gn, roth b. optimization of extracorporeal shock wave lithotripsy delivery rates achieves excellent outcomes for ureteral stones: results of a prospective randomized trial. j urol. 2015;194:418-23. 13. augustin h. prediction of stone-free rate after eswl. eur urol. 2007;52:318-20. 14. choi jw, song ph, kim ht. predictive factors of the outcome of extracorporeal shockwave lithotripsy for ureteral stones. korean j urol. 2012;53:424-30. 15. takahara k, ibuki n, inamoto t, nomi h, ubai t, azuma h. predictors of success for stone fragmentation and stone-free rate after extracorporeal shockwave lithotripsy in the treatment of upper urinary tract stones. urol j. 2012;9:549-52. 16. kang hw, cho ks, ham ws, et al. predictive factors and treatment outcomes of steinstrasse following shock wave lithotripsy for ureteral calculi: a bayesian regression model analysis. investig clin urol. 2018;59:112-8. 17. chang kd, lee jy, park sy, kang dh, lee hh, cho ks. impact of pretreatment impact of percutaneous nephrostomy on swl-yang et al. vol 19 no 4 july-august 2022 266 hydronephrosis on the success rate of shock wave lithotripsy in patients with ureteral stone. yonsei med j. 2017;58:1000-5. 18. mugiya s, ito t, maruyama s, hadano s, nagae h. endoscopic features of impacted ureteral stones. j urol. 2004;171:89-91. 19. austin pc. some methods of propensity-score matching had superior performance to others: results of an empirical investigation and monte carlo simulations. biom j. 2009;51:171-84. 20. argyropoulos an, tolley da. ureteric stents compromise stone clearance after shockwave lithotripsy for ureteric stones: results of a matched-pair analysis. bju int. 2009;103:7680. 21. ghoneim ia, el-ghoneimy mn, el-naggar ae, hammoud km, el-gammal my, morsi aa. extracorporeal shock wave lithotripsy in impacted upper ureteral stones: a prospective randomized comparison between stented and non-stented techniques. urology. 2010;75:4550. 22. pettenati c, el fegoun ab, hupertan v, dominique s, ravery v. double j stent reduces the efficacy of extracorporeal shock wave lithotripsy in the treatment of lumbar ureteral stones. cent european j urol. 2013;66:309-13. 23. middela s, papadopoulos g, srirangam s, rao p. extracorporeal shock wave lithotripsy for ureteral stones: do decompression tubes matter? urology. 2010;76:821-5. 24. joshi hb, obadeyi oo, rao pn. a comparative analysis of nephrostomy, jj stent and urgent in situ extracorporeal shock wave lithotripsy for obstructing ureteric stones. bju int. 1999;84:264-9. 25. bichler kh, eipper e, naber k, braun v, zimmermann r, lahme s. urinary infection stones. int j antimicrob agents. 2002;19:48898. 26. hausegger ka, portugaller hr. percutaneous nephrostomy and antegrade ureteral stenting: technique-indications-complications. eur radiol. 2006;16:2016-30. impact of percutaneous nephrostomy on swl-yang et al. endourology and stones diseases 267 sexual dysfunction and infertility 37urology journal vol 5 no 1 winter 2008 vasal irrigation with sterile water and saline solution for acceleration of postvasectomy azoospermia ali roshani,1,2 siavash falahatkar,1,2 iradj khosropanah,1,2 mohamad reza asghari golbaghi,1,2 seyed amir kiani,2 marzieh akbarpour2 introduction: vasectomy is the safest and most reliable method of all the contraception methods, but azoospermia is not achieved immediately by this method. we decided to determine whether irrigation of the vas deferens with sterile water or hypertonic saline solution irrigation during vasectomy would reduce the time needed to obtain azoospermia. materials and methods: a total of 126 fertile men presented for vasectomy were divided in 3 groups. no-scalpel vasectomy was done for all of the participants and irrigation of the vas deferens was carried out during the procedure in 2 groups with either sterile water or hypertonic saline solution (9 g/l sodium chloride solution). forty-two participants underwent vasectomy without irrigation. semen analysis was performed at 4, 8, 12, and 16 weeks after vasectomy. results: azoospermia was achieved in all of the men with sterile water after 12 weeks, while at the end of the study (16 weeks) it was achieved in 37 (88.1%) of those with saline solution and in 11 (26.2%) of those without irrigation. there were significant differences in the rates of azoospermia between the participant with sterile water and saline solution at 8 weeks (38.1% versus zero; p < .001), 12 weeks (100% versus 30.9%; p < .001), and 16 weeks (100% versus 88.1%; p = .02). no pregnancy developed during the follow-up and no complication was reported. conclusion: vasal irrigation with sterile water and hypertonic saline solution during vasectomy were effective in removing sperm from the distal vas and increasing the rate at which men achieved azoospermia. sterile water was a promising option with no complications. keywords: vasectomy, hypertonic saline solution, sterile water, vas deferens 1department of urology, razi hospital, gilan university of medical sciences, rasht, iran 2urology research center, gilan university of medical sciences, rasht, iran corresponding author: siavash falahatkar, md urology research center, razi hospital, rasht, iran tel: +98 131 323 2050 fax: +98 131 323 2050 e-mail: falahatkar_s@yahoo.com received october 2007 accepted january 2008 introduction vasectomy continues to be the most reliable form of male contraception worldwide, because vasectomy is the safest, easiest, cheapest, most effective, and most reliable method among all the methods of contraception.(1,2) the number of sterilized men is estimated to be between 40 and 60 million in the world, and vasectomy is thought to account for 5% to 10% of all contraceptive methods used.(3) previous reports suggested that the failure rate of vasectomy is nearly zero.(4,5) nonetheless, the desired endpoint of azoospermia is not achieved immediately after the surgery. it is widely accepted in clinical practice that becoming azoospermia may take up to 4 months in most men because of the sperm residing in the seminal vesicles and the vas urol j. 2008;5:37-40. www.uj.unrc.ir irrigation fluids for postvasectomy azoospermia—roshani et al 38 urology journal vol 5 no 1 winter 2008 deferens upstream from the surgical incision.(1) in most developing countries, an important factor that contributes to vasectomy failure is the negligence of the patients who assume that they are sterile shortly after vasectomy. if all spermatozoa could be flushed from the vas deferens without any adverse effect, then this disadvantage might be ameliorated.(6) many investigators have attempted vasectomy with various irrigation methods. irrigation of the vas deferens by saline solution and injection of aqueous euflavine with sterile water have been tried in some studies with varying degrees of success.(1,6-9) the purpose of this study was to evaluate and compare vasectomies using saline solution and sterile water as simple, inexpensive, and readily available irrigation fluids to reduce the time needed to reach azoospermia. materials and methods a prospective, nonrandomized, double-blinded, controlled trial was conducted between january 2003 and october 2004 to evaluate the efficacy of vasal irrigation by sterile water and saline solution during no-scalpel vasectomy compared with no-scalpel vasectomy without irrigation. a total of 126 men who attended the gilan family planning research center were enrolled in our study. the study participants had to meet the following criteria to enter study: age of 25 years or older, being in good physical and mental condition, being healthy according to physical examination, and having at least 2 living children. the exclusion criteria included inflammation or infection of the scrotal sac, abnormalities or congenital anomalies of the vas deferens, and previous sterilization. ethical approval was obtained from a relevant local ethics committee. all patients were thoroughly counseled about the study, were given information leaflets, and were provided informed consent to the operator. patients were divided into 3 groups by alternative allocation: patients in the first and second groups were selected to receive sterile water and hypertonic sodium chloride solution (9 g/l sodium chloride solution), respectively, as vasal lavage, and those in the third group were planned to receive no lavage (to act as a control group). the enrolled patients were blinded to the procedures. each group consisted of 42 participants. vasectomy was done based of united nations population fund protocols, in which semen analysis before vasectomy is not necessary. a single technique of no-scalpel vasectomy with a single midline puncture was used in all of the participants. the procedure was carried out under local anesthesia; 10 ml to 15 ml of lidocaine 1% (with no adrenaline) was used. before transecting the vas deferens a 16-gauge tube was inserted into the distal vas deferens and 40 ml of sterile water or 40 ml of hypertonic saline solution was infused for the men in groups 1 and 2, respectively. the vas deferens catheterization in the prostatic sight did not induce epithelial damaging. this method is used after distal vas exploration routinely to confirm there is no obstruction. irrigates was done for 1 minute. participants in group 3 remained as control group and underwent vasectomy without irrigation. the cut ends of the vasa deferentia were cautered in separate tissue planes. the participants were asked to provide semen sample for analysis at 4, 8, and 12 weeks after their vasectomy. the main outcome in this study was achieving azoospermia defined as the total absence of sperm from the ejaculate. analyses of data were done by the spss software (statistical package for the social sciences, version 11.5, spss inc, chicago, ill, usa), and the chi-square test was used for comparisons of the dichotomous variables. a p value less than .05 was considered significant. results participants failing to return for semen analyses were contacted via phone calls, and eventually, all the participants completed the study. the mean ages of the men in groups 1, 2, and 3 were 38.5 ± 5.2 years (range, 28 to 48 years), 39 ± 5 years (range, 29 to 50 years), and 38.5 ± 4.0 years (range, 28 to 49 years), respectively. there was no history of urogenital surgery in the subjects. the table shows the number of the participants who achieved azoospermia in the three groups irrigation fluids for postvasectomy azoospermia—roshani et al urology journal vol 5 no 1 winter 2008 39 at 4, 8, 12, 16 weeks postoperatively. while irrigation of the vas deferens resulted in azoospermia in most of the men, sperm could be found in the majority of the vasectomy cases without irrigation at the end of the follow-up period. also, there were significant differences in the rates of achieving azoospermia between the participant with sterile water lavage and saline solution lavage at 8, 12, and 16 weeks (p < .001; p < .001; and p = .02, respectively; figure). no pregnancy occurred during the follow-up. no complication was seen. discussion one probable disadvantage of vasectomy is that sterility is not achieved immediately. residual spermatozoa continue to be ejaculated for weeks or months after vasectomy, resulting in a potential risk of pregnancy during the postvasectomy waiting period. this is important, particularly in developing countries, because there is limitation in performing postoperative semen analyses to confirm achievement of azoospermia.(6) some authors have suggested that time to infertility depends on the frequency of postoperative ejaculations.(10) in a systematic review, evidence-based recommendations on the appropriate postvasectomy semen analysis protocol were proposed, according to which 1 test after 3 months and 20 ejaculations can result in azoospermia.(3) some investigators have performed vasectomy perfusion trials with different irrigation material. irrigation methods of the vas deferens can be divided into two groups based on the use of spermicides. there are many spermicides used for irrigation with varying degrees of success.(6) in a series of vasectomies with irrigation by euflavine, edwards reported that in most cases, live sperm were absent from samples collected only a few days after the operation. however, it was mentioned that its use did not preclude the need for postvasectomy seminal examination.(8) in a study of comparison between sterile water and euflavine, the first semen sample without spermatozoa was seen after an average of 11 ejaculates with sterile water and an average of 5.5 ejaculates with euflavine. the researchers concluded that while it is not ideal, euflavine is more efficient as an irrigating fluid.(8) it is also mentioned that the spermicide agents could cause destruction of other cells lining the reproductive tract, as well as inflammatory reactions of the seminal vesicles and the prostate.(11) thus, it seems that use of nonspermicidal irrigation might be appropriate and safer.(6) comparison of the number of men in whom azoospermia was achieved between groups with vasal irrigation with saline solution and sterile water. vasectomy method azoospermia irrigation with sterile water irrigation with saline solution no irrigation p achieved after 4 weeks 0 0 0 … 8 weeks 16 (38.1) 0 0 < .001 12 weeks 42 (100.0) 13 (30.9) 0 < .001 16 weeks 42 (100.0) 37 (88.1) 11 (26.2) < .001 not achieved 0 5 (11.9) 31 (73.8) < .001 achievement of azoospermia in men with vasectomy during the postoperative period* *values in parentheses are percents. ellipsis indicates not applicable. irrigation fluids for postvasectomy azoospermia—roshani et al 40 urology journal vol 5 no 1 winter 2008 eisner and colleagues found that 100% of 50 men with vasectomy and irrigation by 10 ml of saline solution and 94.6% of those without irrigation became azoospermic at 12 weeks postoperatively. they mentioned that there was no different between the 2 groups in the rate of achieving azoospermia at the end point.(1) in a study on 70 men who underwent vasectomy with or without vasal lavage with 50 ml of hypertonic saline solution, no significant differences were reported in the sterility rate at 8, 10, or 12 weeks after vasectomy.(7) however, sommer and colleagues reported a statistical difference in infertility rates when using 40 ml of sterile water in 59 patients randomly allocated to vasectomy with and without vasal lavage.(10) the present study evaluated the efficacy of vasal irrigation with two nonspermicidal fluids. hypertonic saline and sterile water were chosen because they are nonirritant and might also extend an osmotic effect on spermatozoa. moreover, both of these solutions are available and inexpensive, which can make the irrigation technique practical. we found a significant difference in the rate and time of achieving azoospermia between men with irrigation with either of these fluids and controls. furthermore, sterile water lavage was more effective than saline lavage in acceleration of reaching the sperm-free condition. our investigation was nonrandomized, with all consecutive vasectomy patients offered entry in to the study. however, we did not have any lost-tofollow up case. of other limitations of this study was lack of information on the sperm found in urine samples and frequency of ejaculations after vasectomy. these factors may have an additional impact on the rate to achieve azoospermia. conclusion we found that vasectomy using nonspermicidal fluids for irrigation of the vas deferens (such as hypertonic saline solution and sterile water) can be associated with accelerating the sperm-free rate. sterile water was a promising option with no complications. therefore, it can be used as a safe and effective irrigation fluid for achieving sterility after vasectomy within a shorter period. conflict of interest none declared. references 1. eisner b, schuster t, rodgers p, et al. a randomized clinical trial of the effect of intraoperative saline perfusion on postvasectomy azoospermia. ann fam med. 2004;2:221-3. 2. badrakumar c, gogoi nk, sundaram sk. semen analysis after vasectomy: when and how many? bju int. 2000;86:479-81. 3. griffin t, tooher r, nowakowski k, lloyd m, maddern g. how little is enough? the evidence for postvasectomy testing. j urol. 2005;174:29-36. 4. philp t, guillebaud j, budd d. complications of vasectomy: review of 16,000 patients. br j urol. 1984;56:745-8. 5. leungwattanakij s, lertsuwannaroj a, ratana-olarn k. irrigation of the distal vas deferens during vasectomy: does it accelerate the post-vasectomy sperm-free rate? int j androl. 2001;24:241-5. 6. pearce i, adeyoju a, bhatt ri, mokete m, brown sc. the effect of perioperative distal vasal lavage on subsequent semen analysis after vasectomy: a prospective randomized controlled trial. bju int. 2002;90:282-5. 7. gandrup p, berthelsen jg, nielsen os. irrigation during vasectomy: a comparison between sterile water and the spermicide euflavine. j urol. 1982;127:60-1. 8. edwards is. vasectomy: euflavine as a spermicide. med j aust. 1976;1:1021-2. 9. reichelt o, wunderlich h, weirich t, schlichter a, schubert j. computerized contrast angiosonography: a new diagnostic tool for the urologist? bju int. 2001;88:9-14. 10. sommer f, eusan a, caspers hp, esders k, reddy p, engelmann u. effect of flushing the vasa deferentia at the time of vasectomy on the rate of azoospermia. bju int. 2001;88(suppl 1):9. 11. craft i, mcqueen j. effect of irrigation of the vas on post-vasectomy semen-counts. lancet. 1972;1:515-6. comparison of early inguinal lymph node dissection and neoadjuvant chemotherapy in penile cancer patient with bulky nodal metastasis: a cohort study syah mirsya warli1,2,*, jeremy thompson ginting3, bungaran sihombing1, ginanda putra siregar1, fauriski febrian prapiska1 1 division of urology, department of surgery, faculty of medicine, universitas sumatera utara haji adam malik general hospital 2 department of urology, universitas sumatera utara hospital, universitas sumatera utara 3 department of urology, faculty of medicine, universitas indonesia haji adam malik general hospital * corresponding author: warli@usu.ac.id division of urology, department of surgery, faculty of medicine, universitas sumatera utara haji adam malik general hospital abstract introduction penile cancer is a rare malignancy, where extranodal extension in inguinal or pelvic lymph nodes is associated with decreased 5-year cancer-survival rate in this study, we try to assess survival and quality of life in a penile cancer patient with bulky lymph node. method we retrospectively reviewed data from penile cancer patients with bulky lymph nodes who underwent treatment between july 2016 and july 2021 at tertiary referral hospital care. the inclusion criteria (age >18 yr, histologically proven penile cancer, and completion of last treatment 6 months prior to this study) yielded a cohort of 20 eligible penile cancer patients with bulky lymph nodes (> 4 cm/bilateral mobile/unilateral fixed). only patients who had completed therapy at least 6 months prior to the study were included. after obtaining consent, they were asked to complete the eortc qlq-c30 questionnaire to evaluate the patient quality of life. results out of 20 patients, 5 patients underwent direct ilnd and 15 patients underwent chemotherapy. median follow-up after primary diagnosis was 114+32 months in patient with early ilnd and 52+11 months in patients who underwent delayed lymph node dissection. out of 5 patients underwent early ilnd, all of them survived during follow-up, and achieve cancer-free status without residual tumor and with excellent functional outcome (karnofsky 90). there is no significant difference in social function (p value = 0.551), physical function (p value = 0.272), role function (p value = 0.546), emotional function (p value = 0.551), cognitive function (p value = 0.453), and global health status (p value = 0.893) between patient which treated with early ilnd and neoadjuvant chemotherapy. however, patient who underwent early ilnd showed a relatively better clinical outcome. mailto:warli@usu.ac.id conclusion early ilnd followed by adjuvant chemotherapy for penile cancer with palpable lymph nodes is more favourable than neoadjuvant tip chemotherapy. keywords: penile cancer, lymph node, dissection, neoadjuvant chemotherapy, bulky nodal comparison of early inguinal lymph node dissection and neoadjuvant chemotherapy in penile cancer patient with bulky nodal metastasis: a cohort study introduction penile cancer is a rare malignancy in less than 1% of all malignancies in the united states and european countries. however, the incidence is higher in developing countries, with rates of 2.8–6.8 per 100 000. this high rate is associated with circumcision in developing countries. male neonatal circumcision is associated with a low incidence of penile cancer in countries such as israel, where the penile cancer rate is less than 0.1 %. other risk factors are phimosis, obesity, lichen sclerosis, chronic inflammation, smoking, uva phototherapy, low socioeconomic status, human papillomavirus (hpv) infection, and immune-compromised states.(1) in the early stages, penile cancer is highly treatable. social stigma, fear, and embarrassment often make patients reluctant to seek treatment and become delayed. the glans penis is the most common site for penile cancer, followed by the prepuce, glans, coronal sulcus, and shaft (uncommon). squamous cell carcinoma accounts for 95% of diagnosed lesions and is the most common histologic subtype. (1) tip is a chemotherapy treatment named after the initials of the used chemotherapy drugs: paclitaxel (taxol), ifosfamide, and cisplatin (platinum).(2) based on the current nccn penile cancer guideline 2021, neoadjuvant chemotherapy is given in the treatment of penile cancer with bulky lymph nodes/bilateral mobile/unilateral fixed follwed by bilateral ilnd if patient has complete/partial response disease after nac. after being given tip chemotherapy, the lymph node will be evaluated, and then, if complete or partial response were found, then lymph node dissection is indicated. however, this approach carries a risk of lymph nodes being unresectable if waiting longer to conduct lymph node dissection or became progressive disease. penile cancer 5-year survival rate in patients with palpable lymph nodes ranges between 5-30%, depending on metastasis status and lymph node numbers.(3) pathologic tnm staging is post-surgery prognostic stratification, and extranodal extension in inguinal or pelvic lymph nodes is associated with decreased 5-year cancer-survival rate (42% ad 22%, respectively). nomograms have been reported to predict cancer-specific survival and ln metastasis for patients following penectomy. these nomograms consist of multiple variables in addition to the stage. adding multiple variables enhances prognostication, including grade, venous or emboly in the lymphatic system, and surgery type. other studies also reported lymph node density, lack of koilocytosis, and clear cell subtype as prognostic factors.(4) in addition, molecular prognostic markers are suggested in some studies, such as p53, ki-67, e-cadherin, mmp-9 (matrix metalloproteinase-9), annexins i and iv, and decreased kai1/cd82. although hpv is associated with high-grade tumours, the impact on outcomes reamins unclear from one study to another study.(4) even though numerous studies focus on survivability in penile cancer patients, there is still not yet adequate research covering the relationship between early bilateral ilnd compare to nac tip before ilnd in bilateral mobile lymph nodes metastasis. to date, only one research focuses on the relationship between aggressiveness in surgery and quality of life in penile cancer patients. in this study, we try to assess survival and quality of life in a penile cancer with bilateral lymph nodes metastasis compare to neoadjuvant chemotherapy tip 4 cycle as it suggested by nccn penile cancer guideline 2021. method after obtaining institutional review board approval, we retrospectively reviewed data from penile cancer patients with bulky lymph nodes who underwent treatment between july 2016 and january 2022 at tertiary referral hospital care. the inclusion criteria (age >18 yr, histologically proven penile cancer, and completion of last treatment 6 months prior to this study) yielded a cohort of 20 eligible penile cancer patients with bulky lymph nodes (> 4 cm/bilateral mobile/unilateral fixed lymph nodes metastasis). all patients were contacted by mail or phone or during clinic visits. after obtaining consent, they were underwent clinical examination and asked to complete the eortc qlq-c30 questionnaire to evaluate the patient quality of life; it is a validated oncology-specific survey that evaluates global health status (ghs), cognitive, social, physical, emotional, and role functioning. the eortc qlq-c30 also assesses physical symptoms such as fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, financial burden, and treatment-specific side effects such as ototoxicity and peripheral neuropathy. a high score for a functional scale represents a healthier level of functioning, while a high score for a symptom scale represents increased severity of symptoms. result median follow-up after primary diagnosis was 24.56.7 months in patient with early ilnd and 36.89.4 months in patients who underwent nac (tip 4 cycle) followed by lymph node dissection. out of 20 patients, 5 patients underwent direct ilnd and 15 patients underwent chemotherapy. in early ilnd group follow-up was conducted since ilnd surgery, while in chemotherapy group follow-up was conducted after 4 cycle of tip chemotherapy was done. the clinical and histological characteristics of the 2 treatment groups are shown in table 1. patient and primary tumor characteristics were distributed similarly between both groups. prior to intervention, patients on both groups were in excellent condition (karnofsky score: 90). disease progression and survival as shown in the figure, the disease specific survival rate and progression was significantly better in patients with early ilnd. out of 5 patients underwent early ilnd, all of them survived during follow-up, and achieve cancer-free status without residual tumor and with excellent functional outcome (karnofsky 90). out of 15 patients that underwent chemotherapy, only 5 are eligible to underwent ilnd. among those four, only one of them. while the rest are having poorer outcome, according to recist criteria patients’s disease are progressing. mortality rate is 20% in patient who underwent neoadjuvant chemotherapy after bulky lymph node diagnosis, while three others are lost to follow-up. quality of life result there is no significant difference in social function (p value = 0.551), physical function (p value = 0.272), role function (p value = 0.546), emotional function (p value = 0.551), cognitive function (p value = 0.453), and global health status (p value = 0.893) between patient which treated with early ilnd and neoadjuvant chemotherapy. the mean values for subscales of qlq c-30 questionnaire can be seen in figure 1. however, patient who underwent early ilnd showed a relatively better clinical outcome. all of those five has an unchanged karnofsky score compared to the prior intervention. in the other hand, patients who received chemotherapy which followed by ilnd has a relatively lower body mass index, lower karnofsky score, and poorer nutritional status. discussion survival analysis and quality of life a phase ii trial by pagliaro et.al(6) shows 17.1 months of overall survival. of 30 penile cancer patients in this trial, 15 (50.0%) had an objective response, and 22 (73.3%) underwent surgery. three (10%) patients had pathologic complete response (pcr), a substantial predictor of improved survival. remember that the primary endpoints studies are progression-free survival (pfs) and overall survival (os). pfs is a period from the beginning of chemotherapy until clinically or radiologically documented disease progression or death from any causes. os is the period from the start of chemotherapy to patient death of any cause. pfs and os were calculated with kaplan–meier survival curves. the kaplan-meier survival curve is not available in the article. in conclusion, itp chemotherapy was effective in terms of conventional response rate and overall survival in 10% of patients.(6) regarding the quality of life, patients were asked to complete eq5d questionnaires before the first, third, and fifth chemotherapy cycle and between 4 and 6 weeks after the last chemotherapy cycle at the end of treatment (eot). only three patients completed the questionnaires at multiple time points. there was no difference in the scoring, whether in individual domains or in the global health score in these three patients at various time points.(6) another study involved 19 patients with advanced penile cancer receiving neoadjuvant chemotherapy of itp regimen from june 2009 to june 2016 in china. after a median followup of 39.6 months, 11 of 19 patients have progressed, and 14 patients died, with an estimated median pfs of 11 months (95% ci, 6.734 to 15.266) and os of 23 months (95% ci, 6.122 to 39.898).7 this study shows statistically significant improvement in pfs and os among patients who experienced objective response to neoadjuvant chemotherapy (group a) compared with did not respond to chemotherapy (group b) (log-rank test; p<0.001).(7) even though several studies below showed that neoadjuvant chemotherapy was effective and recommended for penile cancer with bulky lymph nodes, we found a new fact that it would be beneficial for the patient to receive early ilnd instead of neoadjuvant tip chemotherapy. the reason is are there is a risk that the cancer is chemo-resistant, which later progresses rapidly and becomes unresectable. as mentioned above, this study illustrates that the four patients who received early ilnd instead of tip chemotherapy have a similar quality of life and longer lifespan. this study could be the basis for reconsidering direct ilnd resection when compared with doing neoadjuvant chemotherapy first as directed by nccn guideline, which could lead to unresectable inguinal lymph nodes if physicians delay resection to do chemotherapy first. in our study 25% of patient whose disease progressed, have a poor prognosis and not responding even to second line chemotherapeutic agent with radiotherapy. this finding is supported by several literatures and studies. in a study conducted by galbiati et al., cutaneous squamous cell cancer is showed as a relatively chemo-resistant.(8) similar finding also presented in research conducted by gruhl et al in 2019. they found that non-metastatic pancreas scc histopathology showed poor response to chemotherapy.(9) this characteristic is likely linked to scc histopathology. a study which focuses on comparison between scc type cervical cancer and non-scc cervical cancer also provided similar result. scc type cervical cancer has a significantly higher percentage to become progressive disease (68%) compared to their non scc counterparts.(10) there are several limitations to this study. it is retrospective in nature with relatively small sample size. the qlq questionnaire is a single questionnaire at a single time point rather than a serial assessment monitoring the change in the patient's qol over time. finally, although all patients had completed treatment at least 6 months prior to enrolment, there was no standardized method regarding the specific duration from therapy completion. despite these shortcomings, this study is one of the first to explore the impact of early ilnd in terms of overall qol outcome and survival in penile cancer with bulky lymph node. conclusion in the nccn penile cancer guideline 2021, tip chemotherapy is one of the treatments of choice for penile cancer with bulky lymph nodes as neoadjuvant chemotherapy prior to ilnd. however, we found a contradictory result during our observation. out of 20 patients, five who underwent ilnd without tip chemotherapy survived and had a similar or even better quality of life and lower mortality percentage compared to their counterparts. therefore, according to our clinical observation and finding, early ilnd followed by adjuvant chemotherapy for penile cancer with palpable lymph nodes is more favourable than neoadjuvant tip chemotherapy. references: 1. douglawi a, masterson t. updates on the epidemiology and risk factors for penile cancer. tau. 2017;6:785-90. 2. [internet]. cancerresearchuk.org. 2018 [cited 1 october 2021]. available from: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancerdrugs/drugs/tip 3. aaronson nk, ahmedzai s, bergman b, bullinger m, cull a, duez nj, . the european organization for research and treatment of cancer qlq-c30: a quality-of-life instrument for use in international clinical trials in oncology. jnci. 1993;85:365–76. 4. sonpavde g, pagliaro l, buonerba c, dorff t, lee r, di lorenzo g. penile cancer: current therapy and future directions. ann. oncol. 2013;24:1179-89. 5. treatment of penile cancer, by stage [internet]. cancer.org. 2018 [cited 1 october 2021]. available from: https://www.cancer.org/cancer/penile-cancer/treating/by-stage.html 6. pagliaro l, williams d, daliani d, williams m, osai w, kincaid m et al. neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase ii study. j. clin. oncol. 2010;28:3851-7. 7. xu j, li g, zhu s, cai q, wang z, yang x et al. neoadjuvant docetaxel, cisplatin and ifosfamide (itp) combination chemotherapy for treating penile squamous cell carcinoma patients with terminal lymph node metastasis. bmc cancer. 2019;19:625. 8. galbiati d, cavalieri s, alfieri s, resteghini c, bergamini c, orlandi e, platini f, locati l, giacomelli l, licitra l, bossi p. activity of platinum and cetuximab in cutaneous squamous cell cancer not amenable to curative treatment. drugs context. 2019 dec 19;8:212611. doi: 10.7573/dic.212611. pmid: 32158481; pmcid: pmc7048124. 9. gruhl jd, garrido-laguna i, francis sr, affolter k, tao r, lloyd s. the impact of squamous cell carcinoma histology on outcomes in nonmetastatic pancreatic cancer. cancer med. 2020 mar;9(5):1703-1711. doi: 10.1002/cam4.2851. epub 2020 jan 16. pmid: 31945808; pmcid: pmc7050091. 10. muhammad s, jamsari, suharti n, hidayat y m, khatimah gh. relationships between histopathology type and neoadjuvant chemotherapy response for cervical cancer stage ib2 and iia2. open access maced. j. med. 2020 jun 15;8:507-513. doi: https://doi.org/10.3889/oamjms.2020.4019 https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/tip https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/tip https://www.cancer.org/cancer/penile-cancer/treating/by-stage.html https://doi.org/10.3889/oamjms.2020.4019 figure 1. mean values for sub-scales of the qlq c-30 questionnaire figure 2. kaplan-meier plots (with 95% cis as dotted lines) of (a) time to progression of the disease and (b) overall survival; patients are grouped by the response for (c) time to progression and (d) overall survival. 65 70 75 80 85 90 social fuction cognitive function emotional function role function physical function global health status early neoadjuvant chemotherapy early ilnd figure 3. kaplan-meier curves show pfs and os in all patients6 figure 4. kaplan-meier curves show pfs and os in patients who experienced an objective response (group a) to neoadjuvant chemotherapy compared with those among patients who did not (group b) table 1. study sample characteristics early resection neoadjuvant chemotherapy p value no. of subject 5 15 mean age 42.42.1 44.21.8 0.62 no. of death 0 3 0.003 clinical t stage t2 1 5 0.67 t3 4 10 0.38 pathological t stage t2 2 5 0.12 t3 3 10 0.14 tumor stage iiib 3 11 0.16 iv 2 4 0.36 vascular invasion absent 1 4 0.34 present 4 11 0.51 table 2. comparison of karnofsky score between early ilnd and nac + ilnd early ilnd nac + ilnd p value no. of subject 5 4 karnofsky score 90 5 1 80 1 70 2 bmi 22.30.5 18.21.8 0.048 table 3. study about chemotherapy with itp as the sole regimen3 author regimen design n surgery n (%) clinical stage clinical response pathologic complete response n (1%) median progressionfree survival median overall survival pagliaro et al.5 itp phase ii trial 30 22 (73.3) any t, n2–n3 15 (50) 3 (10) 8.1 months 17.1 months v08_no_1_print_3.pdf endourology and stone disease 14 urology journal vol 8 no 1 winter 2011 role of tamsulosin in clearance of upper ureteral calculi after extracorporeal shock wave lithotripsy a randomized controlled trial santosh kumar singh,1 devendra singh pawar,1 mahavir singh griwan,2 jag mohan indora,2 sachit sharma1 purpose: to evaluate the role of tamsulosin in stone clearance in patients with upper ureteral stone after extracorporeal shock wave lithotripsy (swl). materials and methods: this randomized controlled trial was performed on 117 patients with a single upper ureteral calculus undergoing swl. the study group received 0.4 mg tamsulosin daily while the control group received hydration and analgesic on demand for a maximum of 3 months. follow-up visits were performed at 1, 2, and 3 months after swl. efficiency of tamsulosin was evaluated in terms of success rate, time for expulsion of fragments, number of swl sessions, incidence of steinstrasse, and pain intensity. results: the clearance rate after 1, 2, and 3 months were higher in tamsulosin group than the control group (85%, 89.8%, and 91.5% versus 70.6%, 79.3%, and 86.2%; p = .01, p = .11, and p = .34, respectively). the mean time for expulsion of the fragments was 26.78 ± 11.96 days and 31.28 ± 18.31 days in tamsulosin and control groups, respectively (p = .138). steinstrasse developed in 8 patients in tamsulosin group and in 13 patients in control group (p = .167). visual analogue scale pain score was 24.92 ± 7.57 in tamsulosin group and 41.81 ± 17.24 in control group (p = .000). conclusion: tamsulosin helps in clearance of upper ureteral stones after 1 month of swl, particularly stones with size of 11 to 15 mm with less requirement of swl sessions and analgesics. urol j. 2011;8:14-20. www.uj.unrc.ir keywords: extracorporeal shockwave lithotripsy, tamsulosin, calculi, randomized controlled trial 1department of urology, pt. b. d. sharma university of health sciences, rohtak, india 2department of surgery, pt. b. d. sharma university of health sciences rohtak, india corresponding author: santosh kumar singh, md department of urology, pt b.d. sharma university of health scicences, rohtak,124001, haryana, india tel: + 91 126 221 0943 fax: +91 126 221 1308 e-mail: drsinghsantosh@yahoo.co.in received march 2010 accepted october 2010 introduction symptomatic ureteral calculi represent the most common condition encountered by a urologist in an emergency setting.(1) in the presence of normal renal function and absence of infection, observation is generally preferred for ureteral calculi with a maximum of 5 mm diameter.(2) intervention is recommended for individuals with larger stones, especially greater than 5 mm.(3) extracorporeal shock wave lithotripsy (swl) or retrograde endoscopic stone removal comprises the next line of management depending on the stone location and size, urgency of clearance, and patient’s preference.(2) extracorporeal shock wave lithotripsy has been recommended as a first-line treatment modality for upper ureteral calculi in several studies with a success rate of 80% to 90%.(4-6) tamsulosin in clearance of upper ureteral calculi after swl—singh et al 15urology journal vol 8 no 1 winter 2011 recently, medical expulsion therapy (met) has shown encouraging results in facilitating spontaneous clearance of lower ureteral calculi as well as fragments after swl for renal and/ or ureteral calculi.(7-11) tamsulosin, an 1aadrenoceptor blocker, has been used in several recent met experiments, but the results of studies are variable and most of them are being carried out on patients with lower ureteral calculi.(12-14) however, study on upper ureteral calculi is scarce. therefore, whether tamsulosin administration for patients with upper ureteral stones would improve the stone-free rate as the stone size increases is still under debate. a prospective randomized trial was thus planned to evaluate and compare the effects of tamsulosin administration after swl in patients with upper ureteral calculi of different sizes. materials and methods a prospective randomized controlled trial was conducted at our institute between january 2006 and june 2008 on outpatient department basis. the study protocol was approved by institutional review board and a written informed consent was obtained from each patient. hundred and twenty patients in the age range of 18 to 70 years with symptomatic, unilateral, and solitary upper ureteral calculi proved on plain abdominal kidney, ureter, and bladder (kub) radiography and ultrasonography of the kidney, ranging from 6 to 15 mm in major axis were included in this study. upper ureter was defined as part of the ureter between the pelvi-ureteral junction and the sacroiliac joint. exclusion criteria were as follows: active urinary tract infection, fever, acute renal failure, chronic renal failure, history of urinary tract surgery or endoscopic treatment, uncorrected distal obstruction, severe hydronephrosis, pregnancy, concomitant treatment with blockers, calcium channel blockers, or steroids, morbid obesity (bmi >30), or history of previous failed swl. prior to study, complete blood count, blood level of urea, serum level of creatinine, urine analysis, urine culture, kub x-ray after preparation, and ultrasonography of the kub region were carried out on all the patients. patients were randomly divided into 2 groups, a and b. randomization was done by using sealed envelope technique by the junior house officer and all the patients were evaluated by the doctor who was blinded to the treatment given. patients in group a received tamsulosin 0.4 mg once a day, just before the session of swl for 3 months or until the clearance of calculi, which was earlier. patients in group b did not receive tamsulosin or any other medication to facilitate expulsion of stone after swl. all the patients underwent swl in supine position with electro magnetic lithotripter (hk–eswl–vi shenzhen, china) at 12 to 15kv. stone localization was done using c-arm. in a single session, maximum of 3000 shock waves were given. all patients were advised to take 2500 cc fluid daily, and analgesic diclofenac was on demand during the study period. repeated sessions of swl were given for an incomplete fragmented calculus every 3 weeks. the patient was termed as swl failure when incomplete or no fragmentation was found after three sessions. patients were evaluated for stone clearance, time to stone clearance, number of swl sessions, pain intensity, incidence of steinstrasse, and any side effects at 1, 2, and 3 months. at each follow-up, kub x-ray, ultrasonography of kub, urine analysis as well as measurement of blood level of urea and serum level of creatinine were performed. successful results were defined as complete stone clearance or presence of less than a 3-mm clinically insignificant and asymptomatic residual calculus. those who did not complete the follow-up without clearance were excluded from the study. unsuccessful patients underwent ureteroscopy as an auxiliary procedure. the primary outcome of this study was the success rate, and the secondary outcomes were clearance time, sessions required for clearance, pain intensity, and incidence of steinstrasse. eventually, 117 patients were available for final analysis. statistical analysis was performed by spss (the statistical package for the social sciences, version 13.0, spss inc., chicago, illinois, usa) software, using chi-square test, tamsulosin in clearance of upper ureteral calculi after swl—singh et al 16 urology journal vol 8 no 1 winter 2011 fisher’s exact test, and student’s t test. p values less than .05 were considered statistically significant. results both groups were comparable in demographic profile (table 1). the clearance rate after 1, 2, and 3 months of follow-up were higher in tamsulosin group than the control group (85%, 89.8%, and 91.53% versus 70.69%, 79.3%, and 86.21%; p = .01, p = .11, and p = .34, respectively) and the difference was statistically significant (p = .01) at 1 month, but not at 2 and 3 months (p > .05). stone clearance stratified by the size of stone (table 2) stone size of 6 to 10 mm the clearance rate after 1, 2, and 3 months was higher in tamsulosin group than the control group (90%, 93%, and 93% versus 87%, 90%, and 90%, respectively) and the difference was statistically insignificant (p = .68). stone size of 11 to 15 mm the clearance rate after 1, 2 and 3 months was higher in tamsulosin group than the control group (79.3%, 86.2%, and 90% versus 53.5%, 67.8%, and 82%, respectively) and the difference was statistically significant at 1 month (p = .039), but not at 2 and 3 months (p = .09 and p = .4). stone clearance stratified by gender there was no statistically significant difference in stone clearance between men and women in both groups (p > .05) (table 3). the median value of swl sessions was 1 and 2 in tamsulosin and control groups, respectively, and the difference was statistically significant (p = .031) (table 4). the frequency of swl sessions was also compared between tamsulosin and control groups by chi-square test and a statistically significant difference was found p = .034. the mean time for expulsion of the fragments was 26.78 ± 11.96 days in tamsulosin group and 31.28 ± 18.31 days in the control group, and difference was statistically insignificant (p = .138) (table 4). steinstrasse developed in 8 patients in tamsulosin tamsulosin group (n = 59) control group (n = 58) mean patients’ age, y 32.20 ± 12.22 36 ± 13.78 gender, male/female 44/15 41/17 stone size, mm 6 to 10 mm 30 30 11 to 15 mm 29 28 table 1. demographic and clinical characteristics of study groups stone size gender 1 month 2 months 3 months tamsulosin group controlgroup tamsulosin group control group tamsulosin group control group 6 to 15 mm male 37/44 (84%) 29/41 (71%) 39/44 (89%) 32/41 (78%) 40/44 (91%) 35/41 (85%) female 13/15 (87%) 12/17 (71%) 14/15 (93%) 14/17 (82%) 14/15 (93%) 15/17 (88%) p .588 .613 .518 .507 .624 .568 table 3. stone clearance stratified by gender at 1, 2, and 3 months stone size 1 month 2 months 3 months mm tamsulosin group control group p tamsulosin group control group p tamsulosin group control group p 6 to 10 27 (90%) 26 (87%) .68 28 (93%) 27 (90%) .64 28 (93%) 27 (90%) .64 11 to 15 23 (79.3%) 15 (53.5%) .039 25 (86.2%) 19 (67.8%) .09 26 (90%) 23 (82%) .4 overall (6 to 15) 50 (85%) 41 (70.69%) .01 53 (89.8%) 46 (79.3%) .1 54 (91.53%) 50 (86.21%) .35 table 2. stone clearance stratified by size of stone at 1, 2, and 3 months tamsulosin in clearance of upper ureteral calculi after swl—singh et al 17urology journal vol 8 no 1 winter 2011 group and in 13 patients in the control group and difference was statistically insignificant (p = .167) (table 4). all of these patients had stones in the range of 11 to 15 mm. six patients were treated conservatively in tamsulosin group and passed the stone while 2 patients required ureteroscopic stone removal (urs) as an auxiliary procedure. of 13 patients in the control group, 5 required auxiliary treatment (urs) and 8 patients passed the fragment by conservative treatment. visual analogue scale pain score in tamsulosin and control groups were 24.92 ± 7.57 and 41.81 ± 17.24, respectively, and difference was statistically significant (p = .000) (table 4). discussion extracorporeal shock wave lithotripsy and flexible urs remain the first-line treatment option for patients with upper ureteral calculi measuring < 1.5 cm.(2) despite more number of auxiliary procedures associated with swl, its completely noninvasive nature makes it an attractive first choice.(15) after swl, the final clearance of the fragment from the ureter is akin to the spontaneous passage of ureteral calculi. the fragment size is an important factor that determines the passage of stone through the ureterovesical junction, the narrowest part of the ureter.(10) spasm, edema, or infection may hinder stone passage.(16,17) ureteral colic, associated with stone, is the manifestation of the visceral pain that refers to the somatic region corresponding to the spinal segment of the sympathetic supply of the ureter.(17) increased intraluminal pressure due to calculus obstruction and increased lactic acid production resulting from smooth muscle spasm may have parts in this event.(18) watchful waiting strategy is appropriate for small stones that are not causing acute symptoms and are likely to pass spontaneously.(19) ureteral calculi 4 to 5 mm in size have a 40% to 50% chance of spontaneous passage. in contrast, calculi greater than 6 mm have a less than 5% chance of spontaneous passage. majority of the stones that pass do so within a 6-week period after the onset of symptoms.(20) numerous studies have recently demonstrated promising results in increasing expulsion rate with the addition of drugs for met, including corticosteroid, glyceryl trinitrate, prostaglandin synthesis inhibitors, calcium channel blockers, and -adrenoceptor blocker. treatment with a calcium channel blocker or an blocker are suggested by recent meta analysis of nine randomized controlled trials showing that both of these mets improve the spontaneous expulsion rate of small ureteral stones by 65% obviating the need for surgical treatment.(7) alpha adrenergic receptors are found in abundance in the detrusor and intramural part of the ureter with a predominance of 1a and 1d receptor subtypes in the distal one-third of the ureter.(21,22) alpha-1 adrenergic inhibition reduces the frequency and intensity of peristalsis of the ureter with an increase in the urine flow.(23) alpha-1 antagonists work on the obstructed ureter by inducing an increase in the intraureteral pressure gradient around the stone, that is an increase in the urine bolus above the stone (and consequently an increase in intraureteral pressure above the stone) as well as decreased peristalsis below the ureter (and consequently a decrease in intraureteral pressure below the stone), in association with the decrease in basal and micturition pressure even at the bladder neck; thereby, an increased chance of stone expulsion. furthermore, the decreased frequency of phasic peristaltic contractions in the obstructed ureteral tract induced by tamsulosin might determine a decrease in the algogenic stimulus or its absence.(23) cervenakov and colleagues in 2002 concluded that tamsulosin group control group p mean expulsion time, d 26.78 ± 11.96 31.28 ± 18.31 .138 median value of extracorporeal shock wave lithotripsy sessions 1 2 .031 number of steinstrasse 8 13 .167 visual analogue scale pain score 24.92 ± 7.57 41.81 ± 17.24 .000 table 4. secondary outcome analysis tamsulosin in clearance of upper ureteral calculi after swl—singh et al 18 urology journal vol 8 no 1 winter 2011 treatment by 1-blockers not only considerably decreased lower urinary tract symptoms, but also helped to accelerate the passage of minor calculi from the terminal part of the ureter in 80.4% of patients. they also suggested that 1-blockers potentiate the spasmo-analgesic action of drugs used in standard treatment.(24) dellabella and associates in 2003 used tamsulosin as a spasmolytic drug during episodes of ureteral colic due to juxta-vesical calculi. they observed an increased stone expulsion rate with a decrease in stone expulsion time and the need for hospitalization and endoscopic procedures. particularly, good control of colic pain was provided.(23) autorino and coworkers(12) administered diclofenac (100 mg/day) in combination with aescin (80mg/day) and erturhan and colleagues(25) used tolterodine. they did not find a significant difference between two different mets regarding the expulsion time. corticosteroid drugs seem to induce more rapid stone expulsion in comparison with tamsulosin. in addition, tamsulosin alone as a met for distal ureteral calculi had excellent expulsive effectiveness.(26) tamsulosin that is commonly used in treatment of the bladder outflow obstruction was chosen for the study since it acts selectively on 1a and 1d receptor subtypes of the ureter, which are able to inhibit basal tone, ureteral contraction, and peristaltic activity and in turn dilating the ureteral lumen and facilitating stone passage with a reduction of the algogenic stimulus.(23) tamsulosin has been studied as an adjunct therapy with swl for renal stones and lower ureteral stones. in a randomized non placebo-controlled study enrolling patients with lower ureteral stone undergoing swl, kupeli and associates found a significant greater success rate in patients receiving tamsulosin 0.4 mg daily (70.8% versus 33.3.%; p = .019) with minimal side effects.(9) bhagat and colleagues reported an improved success rate with tamsulosin in 60 patients with renal and ureteral stones undergoing swl (96.6% versus 79.3%; p = .04).(10) conversely, gravas and coworkers in a cohort study on 64 patients with lower ureteral calculi found a statistically similar success rate in patients receiving or not receiving tamsulosin (66.6% versus 58.1%; p > .05).(27) the results of our study suggest that tamsulosin may play a role as an adjuvant to swl in early clearance of larger ureteral calculi. the frequency of swl sessions were less in tamsulosin group. following swl, steinstrasse was observed in 2% to 20% of plain x-rays with spontaneous passage in 65%.(28) in a randomized controlled trial with tamsulosin on ureteral steinstrasse, spontaneous clearance occurred in 75% in tamsulosin group and in 65% in placebo group.(14) in another study, salem and colleagues reported significantly higher stone expulsion rate in tamsulosin group (72.7% versus 56.8%) in patients with steinstrasse.(29) in our study, steinstrasse developed in 8 and 13 patients in tamsulosin and control groups, respectively, and difference was statistically insignificant (p = .167). in tamsulosin group, 75% of the patients passed the stone in comparison with 62% in the control group after conservative treatment. overall 2 patients in tamsulosin group required auxiliary treatment in comparison with 5 patients in the control group and the difference was statistically insignificant (p = .525). one of the most distressing symptoms of ureteral stones is colic. the number of colic episodes and the analgesic requirement have been reported to be significantly lower with the use of tamsulosin. gravas and associates studied 61 patients with lower ureteral stones undergoing swl and found that patients receiving tamsulosin required lower dose of analgesic (57 mg versus 119 mg diclofenac equivalent).(28) autorino and colleagues reported significantly lower analgesic requirement (9% versus 31%) and admission for colic (9% versus 21%) in patients receiving tamsulosin as a met.(12) in a meta-analysis, hollingsworth and coworkers reported consistent benefit of tamsulosin in various pain parameters in patients with renal stones as well as ureterolithiasis with or without swl.(7) visual analogue scale pain score in our study suggests that number and intensity of pain episodes were significantly less in tamsulosin group. when the drug was continued beyond 3 months after a single session of swl, stone clearance continued to occur in the tamsulosin group while in the control group there was only initial improvement.(8) the common side effects of tamsulosin are dizziness, nausea, diarrhea, tamsulosin in clearance of upper ureteral calculi after swl—singh et al 19urology journal vol 8 no 1 winter 2011 headache, and abnormal ejaculation. in our study, the only adverse effect was dizziness in 3 patients and nausea in 5 patients, which was tolerable. conclusion tamsulosin helps in clearance of upper ureteral stones after 1 month of swl, particularly stones with size of 11 to 15 mm with less requirement of swl sessions and analgesics. acknowledgements we are thankful to dr. manoj, statistician of our institute, and our family for helping us in preparing the manuscript. conflict of interest none declared. references 1. pak cy. kidney stones. lancet. 1998;351:1797-801. 2. lingeman je, matlaga br, evan ap. surgical management of upper urinary tract calculi. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. vol 2. 9 ed: philadelphia: saunders elsevier; 2007:1431-506. 3. kupeli b, biri h, isen k, et al. treatment of ureteral stones: comparison of extracorporeal shock wave lithotripsy and endourologic alternatives. eur urol. 1998;34:474-9. 4. mitre ai, chambo jl, nahas wc, et al. ureteral calculi: extracorporeal shock-wave lithotripsy performed in situ on an outpatient basis. world j urol. 1992;10:213-5. 5. mogensen p, andersen jt. primary in situ extracorporeal shock wave lithotripsy for ureteral calculi. scand j urol nephrol suppl. 1994;157:159-63. 6. gnanapragasam vj, ramsden pd, murthy ls, thomas dj. primary in situ extracorporeal shock wave lithotripsy in the management of ureteric calculi: results with a third-generation lithotripter. bju int. 1999;84:770-4. 7. hollingsworth jm, rogers ma, kaufman sr, et al. medical therapy to facilitate urinary stone passage: a meta-analysis. lancet. 2006;368:1171-9. 8. gravina gl, costa am, ronchi p, et al. tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones. urology. 2005;66:24-8. 9. kupeli b, irkilata l, gurocak s, et al. does tamsulosin enhance lower ureteral stone clearance with or without shock wave lithotripsy? urology. 2004;64:1111-5. 10. bhagat sk, chacko nk, kekre ns, gopalakrishnan g, antonisamy b, devasia a. is there a role for tamsulosin in shock wave lithotripsy for renal and ureteral calculi? j urol. 2007;177:2185-8. 11. naja v, agarwal mm, mandal ak, et al. tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi: results from an open-label randomized study. urology. 2008;72:1006-11. 12. autorino r, de sio m, damiano r, et al. the use of tamsulosin in the medical treatment of ureteral calculi: where do we stand? urol res. 2005;33:460-4. 13. losek rl, mauro ls. efficacy of tamsulosin with extracorporeal shock wave lithotripsy for passage of renal and ureteral calculi. ann pharmacother. 2008;42:692-7. 14. resim s, ekerbicer hc, ciftci a. role of tamsulosin in treatment of patients with steinstrasse developing after extracorporeal shock wave lithotripsy. urology. 2005;66:945-8. 15. agarwal mm, naja v, singh sk, et al. is there an adjunctive role of tamsulosin to extracorporeal shockwave lithotripsy for upper ureteric stones: results of an open label randomized nonplacebo controlled study. urology. 2009;74:989-92. 16. porpiglia f, destefanis p, fiori c, fontana d. effectiveness of nifedipine and deflazacort in the management of distal ureter stones. urology. 2000;56:579-82. 17. weiss rm. physiology and pharmacology of the renal pelvis and ureter. in: walsh pc, retik ab, vaughan ed, et al., eds. compbell’s urology. vol 1. 8 ed: philadephia: wb saunders; 2002:377-411. 18. dellabella m, milanese g, muzzonigro g. randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi. j urol. 2005;174: 167-72. 19. russell rcg, williams ns, bulstrode ckj. the kidney and ureter. bailey and love’s short practice of surgery. new york: edward arnold. 2004:1321-33. 20. marshall s. urinary stone disease in: amend wjcj, barbour s, baskin ls, berger tg, bloom al, bretan pnj, eds. smith’s general urology. 16 ed: new york: mcgraw-hill medical; 2004:256-90. 21. sigala s, dellabella m, milanese g, et al. evidence for the presence of alpha1 adrenoceptor subtypes in the human ureter. neurourol urodyn. 2005;24:142-8. 22. pricop c, novac c, negru d, ilie c, pricop a, t nase v. can selective alpha-blockers help the spontaneous passage of the stones located in the uretero-bladder junction? revista medico-chirurgical a societ ii de medici i naturali ti din ia i.108:128. 23. dellabella m, milanese g, muzzonigro g. efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. j urol. 2003;170:2202-5. 24. cervenakov i, fillo j, mardiak j, kopecny m, smirala j, lepies p. speedy elimination of ureterolithiasis in lower part of ureters with the alpha 1-blocker-tamsulosin. int urol nephrol. 2002;34:25-9. 25. erturhan s, erbagci a, yagci f, celik m, solakhan m, sarica k. comparative evaluation of efficacy of use of tamsulosin and/or tolterodine for medical treatment of tamsulosin in clearance of upper ureteral calculi after swl—singh et al 20 urology journal vol 8 no 1 winter 2011 distal ureteral stones. urology. 2007;69:633-6. 26. dellabella m, milanese g, muzzonigro g. medicalexpulsive therapy for distal ureterolithiasis: randomized prospective study on role of corticosteroids used in combination with tamsulosinsimplified treatment regimen and health-related quality of life. urology. 2005;66:712-5. 27. gravas s, tzortzis v, karatzas a, oeconomou a, melekos md. the use of tamsulozin as adjunctive treatment after eswl in patients with distal ureteral stone: do we really need it? results from a randomised study. urol res. 2007;35:231-5. 28. fedullo lm, pollack hm, banner mp, amendola ma, van arsdalen kn. the development of steinstrassen after eswl: frequency, natural history, and radiologic management. ajr am j roentgenol. 1988;151: 1145-7. 29. salem ee, gamal wm, abuzeid ae. tamsulosin as an expulsive therapy for steinstranse after extracorporal shock wave lithotripsy: a randomized controlled study. urotoday int j. 2010;32 doi:10.3834/uij.19445784.2010.02.09 1 running head: laparoscopic simple prostatectomy-zeder et al. laparoscopic simple prostatectomy: a single center experience with a long-term follow up robin zeder1, stefan heidler1, thomas alber1, orietta dalpiaz1 1 department of urology, hochsteiermark state hospital, leoben 8700, austria. keywords: benign prostatic hyperplasia; laparoscopic; minimally invasive; prostate; simple prostatectomy abstract purpose: the aim of this retrospective study is to assess the long-term outcomes and safety of laparoscopic simple prostatectomy. material and methods: between 2012 and 2019 80 patients with prostates volumes ≥ 80 ml were treated with laparoscopic simple prostatectomy at our department. uroflowmetry, post void residual volume and standardized questionnaires were assessed preand postoperatively. perioperative complications were categorized using the clavien-dindo classification. results: the mean specimen weight was 83 grams, and the mean operation time was 156 minutes. at a mean follow-up time of 40 months patients showed a significant improvement of qmax (p = .002), ipss (p < .001) and qol (p < .001). post void residual volumes decreased significantly. complications occurred in 11 patients (13.8%), nine had mild (grade 1 2) and two had severe (grade 3b 4a) complications. one conversion to open surgery due to massive prostatic adherence from previous abscess formation was recorded and one patient needed blood transfusion intraoperatively. 2 conclusion: laparoscopic simple prostatectomy is an effective and safe procedure for large volume prostate glands with a significant and stable long term symptoms improvement. 3 1 introduction benign prostate hyperplasia is the most common aetiologic factor of lower urinary tract symptoms (luts) with a prevalence of 70% in aging male (1). while men affected with mild to moderate luts are treated conservatively by either watchful-waiting or medical therapy, patients who suffer from severe obstructive luts should be treated with surgery. transurethral resection of the prostate (turp) is the current standard of surgical technique for patients with moderate to severe luts with prostate size of 30-80 ml (2). according to the eau guidelines, open simple prostatectomy (osp), laser or bipolar enucleation should be offered to men with prostate size ≥ 80 ml. osp is the oldest surgical treatment approach for large prostate glands. this extensive procedure is related with high complication rates as well as both long catheterization duration and length of hospital stay (2). with the goal of reducing those comorbidities and the invasiveness of osp, minimal invasive techniques, including laparoscopic and roboter-assisted simple prostatectomy (rasp), were implemented in the disease management of large prostate glands. the technique for laparoscopic simple prostatectomy (lsp) was first published in 2002 and for rasp in 2008 (3,4). a review of randomized controlled trials concluded, that none of the above-mentioned techniques can be considered superior to another when treating large prostate adenomas (5). another recent review found that lsp is a viable alternative to osp with comparable outcome and significant advantages in terms of blood loss, length of hospital-stay and catheterization period (6), though only a few case series were published on this matter (7–11). the aim of this study was to report outcomes and complications of lsp over a long-term followup period. 2 materials and methods study population 4 the study was performed retrospectively with a total of 80 consecutive patients who underwent lsp between 2012 and 2019 at our department. the indication for lsp was moderate to severe luts with prostate larger than 80 ml measured by transrectal ultrasonography. patients either did not respond to medical treatment or refused medical treatment but requested surgical intervention. patients with previous urinary retention and indwelling catheter were included in the study. surgical technique lsp was performed by two laparoscopically trained surgeons with an extraperitoneal approach as previously described by mariano et al (3). this study includes both of their learning curves for lsp. access to the adenoma was achieved by a transcapsular incision first performed by millin for osp (12). after extraction of the adenoma, we used two v-loc™ sutures to close the prostate capsule. on the fourth postoperative day a routine cystography was performed to confirm bladder integrity before catheter removal. outcome assessment follow-up assessments were routinely done at three and six months postoperatively and then annually with uroflowmetry, post void residual volume (pvr) and standardized questionnaires, such as ipss, iief and qol. charlson comorbidity index was used to assess comorbidities. the clavien-dindo classification of surgical complications was utilized to categorize postoperative complications (13). statistical analysis statistical analysis was performed with the wilcoxon signed-rank test using spss v 16 software program for windows (spss®, inc., chicago, il, usa). continuous variables were summarized using medians and interquartile ranges (iqr). a p-value less than 0.05 was considered statistically significant. 5 3 results preoperative characteristics are reported in table 1. the mean preoperative prostate volume was 130 ml (115 150). 35 (43.8%) of our patients had an indwelling catheter prior to operation. charlson comorbidity index showed low (1 2 points), intermediate (3 4 points) and high risk (≥ 5 points) in 29 (36%), 49 (61%) and 2 (3%) respectively. 3 patients needed bridging of their anticoagulation medication. mean surgery time was 156 minutes (134 193) with an average measured resection weight of 83g (70 104). concomitant hernia repair was performed in 15 patients (18.8%). bladder calculi were removed in one patient. one patient (1.3%) needed blood transfusion intraoperatively. a conversion to open surgery due to massive prostatic adherence from previous abscess formation was necessary in one patient (1.3%). four (5%) patients showed urine extravasate in the cystography and they all achieved bladder integrity after extending catheterization for seven days. the mean hospital stay was nine days (8 9). histopathology revealed incidental prostate cancer in 12 (15%) patients. the mean follow-up time was 40 months (25 56). five patients developed mild stress incontinence which resolved within the first three postoperative months. postoperative outcome is summarized in table 2. a significant improvement of qmax from 9.6 to 30.2 ml/s (p < .001) was recorded. the pvr decreased from 100 to zero ml. the psa levels decreased from 11 to 1 ng/ml following lsp (p < .001). both ipss and qol scores showed significant improvements (p < .001). no significant postoperative changes in iief score were recorded. during follow-up, none of our patient needed re-treatment for micturition problems. postoperative complications are reported in table 3. overall complication rate was 13.8%, most of which were grade one (7.5%). 6 4 discussion our study confirms lsp to be an effective and safe surgical technique for large prostate glands. to date there are only a few publications covering lsp, mostly with small patient series (8–11). the strength of our study is the large patient cohort in addition with the long follow-up period to evaluate the efficacy and the safety of lsp. our study confirms significant improvements in clinical parameters and qol, as reported by other studies (3,6,11). so far, the main disadvantage of lsp seems to be the longer operating times compared to osp (6). a recent review compared operating times of lsp to rasp and concluded that lsp operating time seems to be shorter than rasp’s (14). we report a mean operating time of 156 minutes which is comparable to other lsp series, furthermore we observed higher prostate volumes (130 ml) than comparable studies (94 – 122 ml), which my contribute to longer operating times (8–11,15). these findings could be biased by the learning curve of our surgeons. lombardo analyzed the impact of the learning curve on duration of lsp (16). they conclude that experienced laparoscopic surgeons needed 15 procedures to reach a plateau in operating time. another quality feature is the length of hospitalization. the mean hospital stay of our patients was nine days, while other authors report shorter hospitalization periods from two to eight days. however, in some studies patients were discharged with indwelling catheters to reduce hospitalization (8–11,15). none of our patients were discharged with indwelling catheters. laser enucleation of the prostate is already well implemented surgical technique to treat men with moderate-to-severe luts recommended by the eau for large prostate glands. randomized controlled studies concluded that holmium-laser enucleation of the prostate (holep) is as effective as osp and turp (2). recently two studies compared lsp with holep. juaneda observed similar short term functional outcomes with shorter hospital stays, shorter catheterization times and lower economic costs for the holep arm (17). 7 fuschi conducted the first prospective randomized controlled study comparing holep with lsp and rasp (18). no significant differences were found regarding functional and perioperative outcome. another recent study presented a head-to-head comparison between thulium laser enucleation of prostate and lsp. bertolo et al concluded that both surgical techniques are comparable in relieving from benign prostate obstruction (19). rasp offers many advancements of the surgical technique, as recently reported (20,21). simone et al described a complete urethral-sparing approach intended for young men interested in obtaining antegrade ejaculation (20). in a subsequent paper this new surgical approach was compared to standard rasp utilizing the bph-6 score, a validated outcome and quality of life assessment for endourological treatment of luts (22). they concluded that the urethral sparing approach significantly reduces ejaculatory dysfunction. generally, the choice of surgical treatment mainly depends on the technical equipment and the surgeon’s preference. in our population we registered mild to moderate erectile function preoperatively without deterioration postoperatively. sotelo and autorino reported no significant deterioration in erectile function too (8,23). overall, we report complications in 13% of our patients, from which the vast majority were minor. a recent large-scaled review of 843 patients who underwent lsp at 23 international institutions made a thorough breakdown of all complications. they reported 74 (8.8%) complications most of which were minor (93.3%) (23). another systematic review with a mixed field of lsp and rasp found an overall complication rate of 13.6% with hemorrhage requiring transfusion being the most common (6). the most recent literature review reported adverse events in 26.1% percent of all included lsp cases (14). 8 only 1.3% of our patients needed intraoperative blood transfusion which compared to international data (3.3% to 29.4%) implies an insignificant loss of blood at our department (8– 11,15). regarding perioperative complications a recent review found no significant difference between laparoscopic and open surgery with hemorrhage requiring blood transfusion being the most common one (6). these conclusions differ from another review which suggests that lsp is associated with lower complication rates (14). our series is not devoid of limitations. certainly, the retrospective nature of this study could imply selection bias. the before-after design is prone to regression to the mean, which must be considered in the interpretation of the outcome. 5 conclusions lsp is a safe and effective surgical technique for large prostate glands and seems to be equivalent to currently recommended treatment options with low complication rate in a trained laparoscopic center. further randomized-controlled studies need to be conducted to confirm these conclusions. 6 references 1. launer bm, mcvary kt, ricke wa, lloyd gl. the rising worldwide impact of benign prostatic hyperplasia. bju int. 2021;127:722-8. 2. 2022 management of non-neurogenic male luts uroweb (internet). (cited 2022 may 13);available from: https://uroweb.org/guidelines/management-of-non-neurogenicmale-luts 3. mariano mb, graziottin tm, tefilli mv. laparoscopic prostatectomy with vascular control for benign prostatic hyperplasia. j urol. 2002 jun;167:2528-9. 9 4. sotelo r, clavijo r, carmona o, et al. robotic simple prostatectomy. j urol. 2008;179:513-5. 5. leonardo c, lombardo r, cindolo l, et al. what is the standard surgical approach to large volume bpe? systematic review of existing randomized clinical trials. minerva urol nephrol. 2020;72:22-9. 6. lucca i, shariat sf, hofbauer sl, klatte t. outcomes of minimally invasive simple prostatectomy for benign prostatic hyperplasia: a systematic review and meta-analysis. world j urol. 2015;33:563-70. 7. andraca az, lombardo r, valencia ac, et al. laparoscopic simple prostatectomy: a large single-center prospective cohort study. minerva urol nephrol. 2021;73:107-13. 8. sotelo r, spaliviero m, garcia-segui a, et al. laparoscopic retropubic simple prostatectomy. j urol. 2005;173:757-60. 9. porpiglia f, terrone c, renard j, et al. transcapsular adenomectomy(millin): a comparative study, extraperitoneal laparoscopy versus open surgery. eur urol. 2006;49:120-6. 10. baumert h, ballaro a, dugardin f, kaisary a. laparoscopic versus open simple prostatectomy: a comparative study. j urol. 2006;175:1691-4. 11. van velthoven r, peltier a, laguna mp, piechaud t. laparoscopic extraperitoneal adenomectomy (millin): pilot study on feasibility. eur urol. 2004;45:103-9. 12. millin t. retropubic prostatectomy; a new extravesical technique; report of 20 cases. lancet. 1945;2:693-6. 13. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004;240:205-13. 14. li j, cao d, peng l, et al. comparison between minimally invasive simple prostatectomy and open simple prostatectomy for large prostates: a systematic review and meta-analysis of comparative trials. j endourol. 2019;33:767-76. 15. mccullough tc, heldwein fl, soon sj, et al. laparoscopic versus open simple prostatectomy: an evaluation of morbidity. j endourol. 2009;23:129-33. 16. lombardo r, zarraonandia andraca a, tema g, et al. how many procedures are needed to achieve learning curve of millin simple laparoscopic prostatectomy. minerva urol nephrol. 2022;74:225-32. 17. juaneda r, thanigasalam r, rizk j, perrot e, theveniaud pe, baumert h. análisis comparativo entre la enucleación prostática con láser de holmio y la adenomectomía 10 laparoscópica en el tratamiento de adenomas prostáticos mayores de 100 g. actas urol esp. 2016;40:43–8. 18. fuschi a, al salhi y, velotti g, et al. holmium laser enucleation of prostate versus minimally invasive simple prostatectomy for large volume (≥ 120 ml) prostate glands: a prospective multicenter randomized study. minerva urol nephrol. 2021;73:638-48. 19. bertolo r, dalpiaz o, bozzini g, et al. thulium laser enucleation of prostate versus laparoscopic trans-vesical simple prostatectomy in the treatment of large benign prostatic hyperplasia: head-to-head comparison. int braz j urol. 2022;48:328-35. 20. simone g, misuraca l, anceschi u, et al. urethra and ejaculation preserving robotassisted simple prostatectomy: near-infrared fluorescence imaging-guided madigan technique. eur urol. 2019;75:492-7. 21. bove am, anceschi u, ferriero m, et al. perioperative and 1-year patient-reported outcomes of freyer versus millin versus madigan robot-assisted simple prostatectomy. world j urol. 2021;39:2005-10. 22. anceschi u, bove am, misuraca l, et al. external validation of patient-measured outcomes for robot-assisted simple prostatectomy: a comparison of different surgical techniques according to bph6 index. minerva urol nephrol. 2021;73:557-9. 23. autorino r, zargar h, mariano mb, et al. perioperative outcomes of robotic and laparoscopic simple prostatectomy: a european-american multi-institutional analysis. eur urol. 2015;68:86-94. conflict of interests: the authors report no conflict of interest. corresponding author: orietta dalpiaz, md; agile group department of urology, hochsteiermark state hospital, vordernberger str. 42, 8700 leoben, austria. tel: +43 03842 4013631, e-mail: orietta.dalpiaz@kages.at abreviations: holep – holmium-laser enucleation of the prostate iqr inter quartile range lsp laparoscopic simple prostatectomy 11 luts lower urinary tract symptoms osp open simple prostatectomy pvr post void residual rasp roboter-assisted simple prostatectomy turp transurethral resection of the prostate table 1. perioperative characteristics of laparoscopic simple prostatectomy. mean inter-quartile range age, year 69 65 74 bmi, kg/m² 27 24.4 28.7 prostate volume by trus, ml 130 115 150 specimen weight, g 83 70 104 operating time, minute 156 134 193 length of stay, day 9 8-9 abbreviations: bmi, body mass index; trus, trans rectal ultrasonography. table 2. outcome of laparoscopic simple prostatectomy. abbreviations: iqr, inter quartile range; ipss, international prostate symptom score; qol, quality of life; pvr, post-void residual volume; psa, prostate-specific antigen pre-op (iqr) post-op (iqr) p-value qmax, ml/s 9.6 (5.9 11.3) 30.2 (22.2 39.8) = .002 ipss 21 (16 27) 3 (1 6) < .001 qol 5 (4 5) 1 (0 1) < .001 pvr, ml 100 (50 200) 0 (0 10) < .001 psa, ng/ml 11.0 (4.9 15.8) 1.0 (0.4 2.1) < .001 12 table 3. postoperative complications of laparoscopic simple prostatectomy. complications number (%) clavien-dindo extravasat 4 (5) 1 prevesical hematoma 2 (3) 1 epididymitis 2 (3) 2 atrial fibrillation 1 (1) 2 rebleeding 1 (1) 3b ventricular tachycardia 1 (1) 4a v08_no_1_print_3.pdf urology for people 77urology journal vol 8 no 1 winter 2011 what’s up in urology journal, winter 2011? urology for people is a section in the urology journal for providing people with a summary of what is published in this journal and describing urological entities in a simple language. important note. the findings in medical papers are usually not directly applicable in clinical practice and patients should consult their physicians before any utilization of the results of medical studies. urol j. 2011;8:77-8. www.uj.unrc.ir tapeworms and hydatid disease the term ‘tapeworm’ explains a group of parasitic worms that live in the gut of animals, including humans. these infestations are found worldwide. they can be caused when humans consume raw or undercooked animal products that contain worm larvae. humans usually become infested after close contact with animals like cats and dogs. the most sober locally acquired form of tapeworm infestation is caused by the hydatid tapeworm (echinococcus granulosus), which can infect dogs and dingoes, particularly in sheep farming areas. in the typical dog-sheep cycle, tapeworm eggs are passed in the feces of an infected dog and may subsequently be ingested by grazing sheep. they hatch into embryos in the intestine, break the intestinal lining, and are then picked up and carried by blood throughout the body to major filtering organs, mainly the liver and/or the lungs. after the developing embryos confine in a specific organ or site, they alter and develop into larval echinococcal cysts, in which many tiny tapeworm heads are produced via asexual reproduction. because humans play the same role of intermediate hosts in the tapeworm life cycle as sheep, humans also become infected by ingesting tapeworm eggs passed from an infected carnivore. this takes place most frequently when individuals handle or contact infected dogs or other infected carnivores or by mistake ingest food or drink contaminated with fecal material containing tapeworm eggs. see page 12 for full-text article kidney stones kidney stones are a common cause of blood in the urine and often severe pain in the abdomen, the flank, or the groin. kidney stones have beset humans for centuries. scientists have found evidence of kidney stones in a 7000-year-old egyptian mummy. it is estimated that one out of every ten people will develop stones in the urinary tract at some point in their lives. each year, people make almost three million visits to medical centers and more than half a million people go to emergency departments for kidney stone problems. most urinary stones develop in people at 20 to 45 years of age, and those who are susceptible to multiple attacks of kidney stones (active stone formers) usually develop their first stones during the second or third decades of life. if you have a kidney stone, you may already know how painful it can be. most kidney stones pass out of the body without help from a physician. but sometimes a stone will not pass; it may even get larger. your doctor can help. you should seek help if you have any of the following signs: severe pain in your back or side that will not subside bloody urine fever and chills nausea and vomiting urine that smells bad or appears cloudy a burning perception when you urinate most stones leave the kidney and travel through urology for people 78 urology journal vol 8 no 1 winter 2011 the urinary tract when they are still small enough to pass easily out of the body. but larger stones may be trapped in the tubes that carry urine from the kidney to the bladder (ureters). this can cause extreme pain and possibly block the urine from flowing to the bladder and out of the body. the pain may ease when the stone no longer blocks the flow of urine, and it often ceases when the stone passes into the bladder. medical or surgical treatment is often necessary for larger stones. see page 14 for full-text article cancer of the testis testis tumors account for approximately 2% of all malignant cancers in men and make up to 10% of all malignant diseases occurring within the male genitourinary system. most of these cancers occur in three age groups; infancy, late adolescence, and early adulthood. cancer usually occurs in only one testis and in less than 5%, it may happen in both testicles. some tumors grow rapidly, others more slowly. almost all tumors cause symptoms when they get large enough. when pain or a mass develops in the testicle or scrotum, one should be evaluated by a physician to rule out infection or, less commonly, a tumor. in patients with persistent pain, despite appropriate treatment, an ultrasonography is usually recommended to rule out a tumor. because of its high cure rate, testicular tumor is considered the model of success for cancer treatment. in 1970, 90% of men with metastatic cancer of the testis died of the disease. by 1990, that figure had almost reversed; nearly 90% of men with metastatic testicular tumor were cured. see page 27 for full-text article pi-rads v2 findings of mri and positive biopsy core percentage would predict pathological extraprostatic extension in patients who underwent robot assisted radical prostatectomy: a retrospective study shimpei yamashita1, yasuo kohjimoto1, hirotatsu sato2, kazuro kikkawa1, tetsuo sonomura2, isao hara1* purpose: this study aimed to examine whether preoperative prostate imaging reporting and data system v2 (pirads v2) can predict pathological extracapsular extension (epe) after radical prostatectomy. we also studied the preoperative factors which can predict epe. materials and methods: in our institute, 294 patients underwent robot assisted radical prostatectomy (rarp) between december 2012 and august 2016. in this era, we performed mri after biopsy to determine clinical stage before surgery. pi-rads v2 scores were retrospectively reviewed using biparametric mri and epe in pathological mapping of resected specimens for each lobe. results: in the excised specimen, epe was observed in 73 lobes (12%). the percentage of epe by pi-rads v2 score was score ‘1’: 6% (17/297 lobes), ‘2’: 3% (1/33 lobes), ‘3’: 12% (8/67 lobes), ‘4’: 19% (27/139 lobes), and ‘5’: 38% (20/52 lobes). the higher the pi-rads score, the higher the percentage of epe (p <0.01). when classified as pi-rads score ≥ 4 and < 4, the positive predictive value (ppv) was 24.6% (47/191 lobes, 95%ci: 0.187 – 0.313) and negative predictive value (npv) was 93.5% (371/397 lobes, 95%ci: 0.906 – 0.957). by multivariate analysis, positive biopsy core percentage ≥ 60%, and pi-rads score ≥ 4 were independent factors for predicting epe. the positive rate of epe in lobes with zero, one and two factors (pi-rads ≥ 4 and positive biopsy core percentage ≥ 60%) was 4%, 19%, and 38%, respectively. conclusion: ppv and npv of pi-rads ≥ 4 for predicting pathologic epe were 24.6% and 93.5%, respectively. pi-rads ≥ 4 and positive biopsy core percentage ≥ 60% were independent risk factors for predicting epe. the positive rate of epe in lobes with zero, one and two factors (pi-rads ≥ 4 and positive biopsy core percentage ≥ 60%) was 4%, 19%, and 38%, respectively. keywords: radical prostatectomy; positive biopsy core percentage; pi-rads v2; extraprostatic extension; prostate cancer introduction according to the cancer information service, the number of incidences of prostate cancer in japan in 2020 was 95,6000, which has the highest incidence among types of cancer in men, overtaking gastric cancer(1). radical prostatectomy and radiation as radical treatments have become increasingly important for patients with prostate cancer without metastasis. determining the extent of disease spread is crucial for not only the choice of treatment (surgery or radiation), but also the surgical approach of radical prostatectomy (preserving the neurovascular bundle or wide resection). accurate prediction of extra prostatic extension (epe) is especially highly anticipated. magnetic resonance imaging (mri) is currently a standard examination for prostate cancer. establishment of multiparametric mri (mpmri) including diffusion-weighted imaging (dwi) and dynamic contrast enhancement (dce) has dramatically improved the quality of image diagnosis compared with t2 weighted 1department of urology, wakayama medical university, wakayama, japan. 2department of radiology, wakayama medical university, wakayama, japan. *correspondence: department of urology, wakayama medical university tel: +81 73 441 0637. fax: +81 73 444 8085. e-mail: isaohara@me.com. received july 2021 & accepted february 2022 imaging (t2w) only(2). prostate imaging reporting and data system version 2 (pi-rads v2) assessment is also thought to be a major improvement in reporting of prostate mri(3). since the superiority of mri-targeted biopsy over standard systematic biopsy was demonstrated(4), it is becoming standard to perform mri before biopsy. however, mri was used to be performed after biopsy for determining clinical stage in the era when we performed this study. therefore, the initial pi-rads was designed mainly for the purpose of detection(5), many studies on pi-rads v2 have demonstrated various applications beyond that. pi-rads v2-based scoring system has shown not only improved diagnostic accuracy for epe(6), it is also considered to be a good predictive factor for psa (prostate-specific antigen) recurrence after surgery(7). mpmri may therefore play a central role for the diagnosis of prostate cancer, although there are potential drawbacks to performing dce. intravenous administration of gadolinium incurs higher financial costs and longer scanning time. moreover, gadolinium is a heavy urology journal/vol 19 no. 6/ november-december 2022/ pp. 438-444. [doi:10.22037/uj.v19i.6923] urological oncology metal, which causes accumulation in multiple organs such as renal glomeruli, the brain, and bones, with possible clinical sequelae, such as nephrogenic systemic fibrosis, when administered in patients with renal dysfunction(8). regarding diagnostic accuracy, the role of dce is weakened in pi-rads v2 compared with pirads v1(3,5). biparametric mri (bpmri) without dce has been shown to have similar rates of tumor detection to mpmri(9,10). conversely, dce has been shown to be useful for detecting cancer, and predicting tumor aggressiveness(11,12). further evidence is therefore required to elucidate the optimum method of detection. here, we studied the incidence of epe according to the pi-rads v2 score using bpmri, which can be more easily applied to patients than mpmri. we also studied the factors for predicting epe before operation. patients and methods patients between december 2012 and august 2016, 305 patients underwent robot assisted radical prostatectomy (rarp) at wakayama medical university hospital. among them, 294 patients underwent preoperative mri and could be evaluated for pathological extra prostatic extension (epe) by resected specimens. this study was approved by the wakayama medical university institutional review board (no. 1670) in accordance with the principles of the declaration of helsinki. for nccn high risk patients, we present radical prostatectomy as well as radiation therapy combined with androgen deprivation therapy. rarp was performed according to the standard techniques, as previously described(13). evaluation of preoperative mri preoperative mri were performed with a 3t mri system without use of endorectal coils. since we did not adopt mri-targeted biopsy, we performed mri for determining clinical stage after standard systematic biopsy. the bpmri (t2w+ dwi) protocol used for prostate cancer imaging is shown in table 1. t2-weighted images and diffusion-weighted images (dwi) with b = 2000 were used. apparent diffusion coefficient (adc) were generated from the dwi data. radiologists evaluated mri according to pi-rads v2(3). briefly, pi-rads v2 uses a five-point scale on the likelihood (probability) that a combination of multi parametric mri (mpmri) findings on t2w, dwi, and adc correlate with the presence of a clinically significant cancer for each lesion in the prostate gland. left and right lobes of the prostate were independently evaluated, so 588 lobes from 294 patients were scored in this study. statistical analyses a receiver operating characteristic (roc) curve with an area under the curve (auc) was generated to analyze the predictive accuracy of age, preoperative psa, biopsy gleason score, biopsy positive rate, and pi-rads score for pathologic epe. optimal thresholds were then determined by maximizing the youden index. logistic regression models were conducted for univariate and multivariate analyses. the discriminatory power of the multivariable model was quantified using c-statistic, and the internal validity of the multivariable model was assessed using k-fold cross-validation. the comparison of epe rate according to pi-rads score and risk number was performed by chi square test and fisher’s exact test. data analyses were conducted using the statistical software jmp pro 12 (sas institute, cary, usa). all p values were two-tailed, and p<0.05 was considered to be statistically significant. this study was a retrospective evaluation of archival material, and the data extracted would be of significance in the pre-operative evaluation of patients with prostate cancer. results patient demographics patient demographics of all 294 patients are shown in table 2. mean age and psa level were 67.3 years and 9.8 ng/ml, respectively. regarding nccn risk groups, 56 patients (19%) were categorized as high risk. distribution of pi-rads score in total, 588 lobes from 294 patients were evaluated according to pi-rads scores. distribution of pi-rads scores is shown in table 3. almost half of the overall lobes were scored as pi-rads 1, but 191 lobes (33%) were scored as pi-rads 4 or 5. rate of epe according to pi-rads score figure 1 shows the percentage of epe according to pi-rads scores. total percentage of epe was 73 out of 588 lobes (12%). while 18 out of 330 lobes (5.4%) showed epe in patients with pi-rads score 1 or 2, 27 out of 139 lobes (19%) and 20 out of 52 lobes (38%) showed epe in patients with pi-rads score 4 and 5, respectively. in roc analysis, the optimal cutoff value for the pi-rads score for detecting epe was pirads 4 (auc: 0.716, 95%ci: 0.652 – 0.780). when classified as pi-rads score 4 or 5 group and <4 group, factors predicting extraprosotatic extension after surgery-yamashita et al. urological oncology 439 field of view matrix size slice thickness/gap tr (msec) te (msec) echo flip receiver bandwidth number of signals averaged (mm) (mm) train length angle (hz/voxel) axial t1 tseb 200 × 200 512 × 512 3/0.3 716.5 9 3 90 365 1 axial t1 dual 230 × 230 384 × 384 4/0.4 317.6 1.2/2.3 2 70 1142 1 echo grec axial t2 tse 200 × 200 512 × 512 3/0.3 6000 110 9 90 438 1 axial fatsat 230 × 230 512 × 512 4/0.4 6000 90 19 90 238 1 t2 tse coronal t2 tse 230 × 230 512 × 512 3/0.3 6000 110 9 90 2031 1 sagittal t2 tse 250 × 250 512 × 512 3/0.3 5361 95.7 59 90 436 1 axial dwid 250 × 250 160 × 160 3/0.3 11000 59.6 35 90 3520 2 table 1. sequence parameters for bi-parametric mri of the prostate protocol performed at 3 teslaa a clinical 3 tesla systems: ingenia (philips, amsterdam, netherlands; coil: torso coil linked to posterior spine elements), b turbo spin echo, c gradient recalled echo, d dwi = diffusion weight imaging performed with spectral fat suppresion echo planar imaging with tridirecional motion probing gradients and b values of 0, 1000, 2000 mm2 /s with automatic apparent diffusion coefficient map generation the positive predictive value (ppv) and negative predictive values were 24.6% (47/191 lobes, 95%ci: 0.187 – 0.313) and 93.5% (371/397 lobes, 95%ci: 0.906 – 0.957), respectively. sensitivity and specificity were 64.4% (47/73 lobes, 95%ci: 0.523 – 0.753) and 72.0% (371/515 leaves, 95%ci: 0.679 – 0.759), respectively. factors contributing epe table 4 shows univariate and multivariate analysis of the association between various parameters and epe. according to univariate analysis, preoperative psa level, positive biopsy core percentage ≥ 60%, digital rectal examination (dre) positivity, and pi-rads score ≥ 4 were factors influencing epe. among these factors, positive biopsy core percentage ≥ 60%, and pi-rads score 4 or 5 were independent factors influencing epe by multivariate analysis. epe positive rate according to the number of risk factors we defined two factors (positive biopsy core percentage ≥ 60%, and pi-rads score 4 or 5) as risk factors predicting epe according to multivariate analysis (table 4). figure 2 shows the epe rate according to the number of risk factors. while only 12 out of 332 lobes without risk factors showed epe (4%), 34 out of 183 (19%) lobes with one factor, and 27 out of 71 (38%) lobes with two factors showed epe, respectively (p < 0.01). the discriminatory power of the multivariable model was quantified using c-statistic and auc was 0.784 (95%ci: 0.729 – 0.840). the internal validity of the multivariable model was assessed using k-fold no. patients 294 age, years 67.3 ± 5.4 psa, ng/ml 9.8 ± 5.5 isup grading group, n (%) 1 77 (26) 2 78 (27) 3 55 (19) 4 71 (24) 5 13 (4) ct stage, n (%) t1c 96 (33) t2 185 (63) t3a 13 (4) nccn risk groups low 98 (33) intermediate 140 (48) high 56 (19) table 2. patient demographics continuous variables are shown in "mean ± standaed deviation" form. psa prostate specific antigen, isup international society of urological pathology, nccn national comprehensive cancer network figure 1. distribution of pi-rads score of 588 lobes in 294 patients table 3. destribution of pi-rads score pi-rads score, n (%) 1 very low (clinically significant cancer highly unlikely) 297 (51) 2 low (clinically significant cancer unlikely) 33 (6) 3 intermediate (clinically significant cancer equivocal) 67 (11) 4 high (clinically significant cancer likely) 139 (24) 5 very high (clinically significant cancer highly likely) 52 (9) total, n (%) 588 (100) factors predicting extraprosotatic extension after surgery-yamashita et al. vol 19 no 6 november-december 2022 440 cross-validation, and auc was 0.749 (95%ci: 0.689 – 0.809). table 5 shows sensitivity, specificity, ppv and npv of each factor (positive biopsy core percentage ≥ 60%, pi-rads score 4 or 5) and combined these 2 factors for predicting epe. discussion imaging diagnosis including endoscopy is the mainstay for not only cancer detection, but also for tumor staging in most kinds of cancers. in prostate cancer, psa and systematic biopsy have been key for detection, with imaging tools such as mri and ct in an auxiliary role. however, the introduction of mpmri caused dramatic changes in the detection of prostate cancer. mri targeted biopsy was shown to be better at detecting clinically significant cancer than the traditional systematic biopsy by systematic review and meta-analysis(14). another improvement regarding prostate mri was the establishment of a scoring system, pi-rads. although the most recent version of pi-rads is v2.1(15), pi-rads v2 is still relevant in daily clinical settings(3). surgery and radiation therapy are the gold standard treatment for clinically significant cancer without metastasis. some studies showed better oncological outcomes of radical prostatectomy for locally advanced prostate cancer compared with radiation therapy(16, 17). accurate preoperative diagnosis of epe and complete resection are crucial for surgery in locally advanced prostate cancer treatment. consequently, many people have sought to further develop mri imaging for epe prediction. in pi-rads v1, irregularity (score 3), nvb thickening (score 4), bulge or loss of capsule (score 4), and measurable extra-capsular disease (score 5) were defined as criteria for epe extension. schieda et al. demonstrated that auc of roc for epe using pi-rads v1 was 0.62 and optimal sensitivity/specificity was achieved with pi-rads ≥ 3(18). compared with the previous staging method, sensitivity for epe improved with pi-rads v1(59.5% [49.1 – 68.2] vs 24.5% [16.7 – 31.2], p = 0.01), but there was no difference in specificity (62.7% [49.6 – 73.6] vs 42.0% [31.7 – 50.7], p = 0.06). conversely, lim et al. reported that the tumor volume calculated from mri and percentage of positive core biopsies were good predictive factors for epe. they also suggested that qualitative assessment of t2w-mri according to pi-rads v1was limited for the diagnosis of epe. the auc of two radiologists for detecting epe of pi-rads v1 was 0.51 and 0.46(19). the scoring system for epe was changed in pi-rads v2 to improve diagnostic accuracy(3). in pi-rads v2, the prediction of epe was dichotomized into either organ-confined disease or epe disease. morphologic features such as asymmetry or invasion of the nvb, bulging prostatic contour, obliteration of the rectoprostatic angle, and breach of the capsule with evidence of direct tumor extension or bladder wall invasion, are thought to be epe findings. these features correspond to risk score of ≥ 3 in pi-rads v1. in addition to these morphologic features, tumor-capsule contact length >10 mm was newly added to epe criteria. matsuoka et al. verified the usefulness of newly added criteria in pi-rads v2(20); figure 2. positive extra prostatic extension (epe) rate according to the number of risk factors urological oncology 441 factors predicting extraprosotatic extension after surgery-yamashita et al. kidney transplantation 136 pi-rads v2 had higher negative predictive values than from pi-rads v1 (96.3 – 97.1% vs 84.9 – 89.1%, p = 0.003 and 0.021, for each reader). pi-rads v1 and pi-rads v2 had positive predictive values of 56.9 – 70.5%, 49.1 – 50.5%, respectively (p=0.025 and 0.300, for each reader). pi-rads v2 was concluded to reduce under-staging, but over-staging remained a concern because ppv was around 50%. they also demonstrated that between 73.3 and 74.1% of the patients with a biopsy gleason score of ≤ 7 and between 35.7 and 44.4% of the patients with a biopsy gleason score of ≥ 8 were overstaged in the patients judged to be epe positive by pi-rads v2, but not by pi-rads v1. accurate prediction of microscopic epe on mri images seems to be difficult, but attempting to increase the correctness of epe by combining some complementary factors similarly to matsuoka et al. seems to be logical. our study evaluated the incidence of epe according to pi-rads v2 category. at first, we tried to investigate the relationship between the description of epe in pirads v2 and epe pathology. many vague descriptions about epe were found, however, and interpretation was often difficult. in comparison, the scoring for categories was clearly stated and easy for urologists to understand. a score of 5 in pi-rads v2 was defined as lesion ≥ 1.5 cm or definite epe behavior, so a certain percentage of epe tumors are expected to be judged as score 5. epe was diagnosed in 38% of the lesions with a score of 5 in our study. the probability of epe increased as the pirads score increased. when we set the cut off value of score ≥ 4 for prediction of epe, the percentage of epe was 24.6% (47/191). to improve diagnostic accuracy, we tried to find other factors influencing epe. we picked five factors including age, preoperative psa, biopsy gleason score ≥ 8, biopsy positive rate ≥ 60%, and dre positivity. among them, only biopsy positive rate ≥60% remained as an independent predictive factor by multivariable analysis (table 4). finally, pi-rads ≥ 4 and biopsy positive rate ≥ 60% were chosen as risk factors for predicting epe. epe was shown in 27 out of 71 lobes (38%) with these two factors. complementary factors of pi-rads v2 to predict epe have been investigated in several studies, and tumor volumes have been reported to be representative factors(6,19,21). lim et al. reported that tumor diameter was an excellent marker to predict epe and cut off value was 15 mm(6), which coincidentally corresponded to the size of score 5 in pi-rads v2. lim et al. also demonstrated that tumor volume and biopsy positive rate were significant predictive markers for epe(19). in our study, biopsy positive rate was a good predictive marker for epe. positive biopsy rate is associated with tumor volume and it could be a surrogate tumor volume marker which cannot be detected by mri. another concern is biopsy gleason grade, which was pointed out by matsuoka et al(20). although biopsy gleason score was marginally associated with epe by univariable analysis, it could not be considered as prognostic factor in multivariable analysis in our study (table 4). this study has several limitations. first, mri and pirads v2 are used to detect clinically significant cancer before prostate biopsy these days, but mri was performed for determining clinical staging after biopsy in this study. therefore, not target biopsy but only systematic biopsy has been performed. since it is very important to determine whether nvb is sacrificed or preserved in radical prostatectomy, we studied whether pi-rads v2 could predict epe, which was different from the original purpose. in fact, there are some papers similar to our study. i believe that the pi-rads v2 score is significant in epe prediction. however, analysis of the pathological findings of targeted biopsies will be conducted in the future. second, bpmri, not mpmri, was used in our study, and it remains controversial whether bpmri can completely replace mpmri(9-12). dce is becoming less important in pi-rads v2 and owing to patient convenience, bpmri was adopted in this study. third, this study was a retrospective evaluation of archival material, and the data extracted would be of significance in the pre-operative evaluation of patients with prostate cancer. lastly, the sample number (294 patients, 588 lobes) was relatively low. we will continue to evaluate more patients by this method. univariable analysis multivariable analysis or 95% ci p value or 95% ci p value age ≥ 64 years 1.79 0.92 – 3.81 0.08 1.50 0.73 – 3.34 0.27 pre operative psa ≥ 8.9 ng/ml 1.94 1.18 – 3.19 < 0.01 1.54 0.89 2.63 0.11 biopsy isup grading group ≥ 4 1.67 0.99 – 2.76 0.05 1.00 0.55 1.76 0.99 biopsy positive rate ≥ 60% 5.79 3.47 – 9.73 < 0.01 3.87 2.21 6.82 < 0.01 dre positive 2.79 1.50 – 5.03 < 0.01 1.51 0.74 – 2.94 0.24 pi-rads score ≥ 4 4.66 2.80 – 7.89 < 0.01 3.28 1.91 – 5.71 < 0.01 table 4. univariable and multivariable analyses of associations between various parameters and extraprostatic extension positive psa prostate specific antigen, isup international society of urological pathology, dre digital rectal examination, pi-rads prostate imaging reporting and data system sensitivity (95% ci) specificity (95% ci) ppv (95% ci) npv (95% ci) pi-rads score ≥ 4 0.644 (0.523 – 0.753) 0.720 (0.679 – 0.759) 0.246 (0.187 – 0.313) 0.935 (0.906 – 0.957) biopsy positive rate ≥ 60% 0.562 (0.441 – 0.678) 0.819 (0.783 – 0.851) 0.306 (0.229 – 0.391) 0.929 (0.902 – 0.951) both of above 2 factors 0.370 (0.523 – 0.753) 0.914 (0.679 – 0.759) 0.380 (0.187 – 0.313) 0.911 (0.906 – 0.957) table 5. sensitivity, specificity, ppv and npv of each factor prediciting extra prostatic extension ppv positive predictive value, npv negative predictive value factors predicting extraprosotatic extension after surgery-yamashita et al. vol 19 no 6 november-december 2022 442 conclusions ppv and npv of pi-rads ≥ 4 for predicting pathologic epe were 24.6% and 93.5%, respectively. pi-rads ≥ 4 and positive biopsy core percentage ≥ 60% were independent risk factors for predicting epe. the positive rate of epe in lobes with zero, one and two factors (pi-rads ≥ 4 and positive biopsy core percentage ≥ 60%) was 4%, 19%, and 38%, respectively. acknowledgement we acknowledge proofreading and editing by benjamin phillis at the clinical study support center, wakayama medical university. we also appreciate prof. toshio shimokawa at the clinical study support center, wakayama medical university, for critical support from the view of epidemiologist. conflict of interest the authors report no conflict of interest. references 1. institute nc. cancer information service: ganjoho.jp; [updated 2021/1/18. available from: https://ganjoho.jp/en/public/statistics/ short_pred.html. 2. oberlin dt, casalino dd, miller fh, meeks jj. dramatic increase in the utilization of multiparametric magnetic resonance imaging for detection and management of prostate cancer. abdom radiol (ny). 2017;42:1255-8. 3. weinreb jc, barentsz jo, choyke pl, cornud f, haider ma, macura kj, et al. pi-rads prostate imaging reporting and data system: 2015, version 2. eur urol. 2016;69:16-40. 4. kasivisvanathan v, rannikko as, 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ajr am j roentgenol. 2017;209:w76-w84. 21. abreu-gomez j, walker d, alotaibi t, mcinnes mdf, flood ta, schieda n. effect of observation size and apparent diffusion coefficient (adc) value in pi-rads v2.1 assessment category 4 and 5 observations compared to adverse pathological outcomes. eur radiol. 2020;30:4251-61. factors predicting extraprosotatic extension after surgery-yamashita et al. vol 19 no 6 november-december 2022 444 oncologic outcomes following positive surgical margins in patients who underwent open versus laparoscopic partial nephrectomy nasser simforoosh1*, fatemeh simforoosh2, mehdi dadpour3, hossein fowzi fard4, nasrin borumandnia5, hamed hasani6 purpose: to evaluate oncological outcomes in patient with positive surgical margin (psm) following partial nephrectomy (pn). material and methods: in this retrospective study, we enrolled the data of patients who underwent pn between 2008 and 2017. the inclusion criteria were a definite diagnosis of kidney tumor who underwent pn with at least one year follow up. results: from the 450 patients who underwent pn, the psm was found in 35 (22 male/13 female) patients. 18/237 (7.6%) and 17/213 (7.9%) of them were in open and laparoscopic group, respectively. clear cell rcc was the most prevalent pathology (18 patients) in the psm patients. the mean time of follow up was 46 ± 2.02 months. recurrence was developed in 5 (14.2%) patients. there was no correlation between recurrence and sex (p=1.00), surgery type (p = 0.658), age (p = 0.869), tumor size (p = 0.069), pathology (p = 0.258) and stage (p = 0.744) in psm patients. recurrence free survival was similar between the open and laparoscopy groups in psm patients (p = 0.619). conclusion: beside numerous advantages of minimally invasive techniques, laparoscopic approach would be comparable to conventional open partial nephrectomy in terms of oncologic outcomes. the rate of recurrence following partial nephrectomy in psm patients is considerable and closely monitoring is mandatory. keywords: partial nephrectomy; positive surgical margins; local recurrence; laparoscopy introduction over the last couple of decades, the incidence of re-nal cell carcinoma (rcc) has increased by about 2% annually because of new diagnosis techniques and incidental detection of asymptomatic small renal masses(1). today, by improving surgical techniques in nephron sparing surgery, physicians are interested to manage small renal tumors by partial nephrectomy (pn) to preserve normal renal parenchyma and kidney function, reduce risk of chronic kidney disease and renal replacement therapy (2,3). however, finding positive surgical margin (psm) on final pathology examination would be a concern and ranges from 0–10% in different published studies(4,5). although new studies suggest that the presence of psm does not adversely affect outcomes; but these patients should be managed expectantly with close follow-up. however, some specialists prefer to perform an immediate or delayed complete (radical) nephrectomy in patients with a psm(6-8). traditionally, open partial nephrectomy was the se1shahid labbafinejad hospital, shahid beheshti university of medical sciences, tehran, iran. simforoosh@iurtc.org.ir 2urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. f.simforoosh@gmail.com 3urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran.mehdi_dadpour@yahoo.com. 4urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. dr.hosseinf@gmail.com. 5urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. borumand.n@gmail.com. 6urology and nephrology research center, shahid beheshti university of medical sciences, tehran, iran. hamed_hasani_md@yahoo.com. *correspondence: urology and nephrology research center (unrc), shahid beheshti university of medical sciences. address: shahid labbafinejad hospital, 9th boostan, pasdaran avenue, tehran, iran. phone: +98-21-22588016. email: simforoosh@iurtc.org.ir. received june 2021 & accepted november 2021 lected method to treat patients with small renal tumors. nowadays laparoscopic partial nephrectomy beside robotic approach, provides the advantages of a minimally invasive technique while showing comparable to the traditional open approach in terms of oncological and functional outcomes(9-11). in this study we purpose to determinate the incidence of positive surgical margin and evaluate oncological outcomes and the risk factors of recurrence in psm patients. we also aimed to evaluate the role of laparoscopic surgery in partial nephrectomy and investigate its impact on oncological outcomes in our referral center as an endourology-laparoscopy fellowship training center. materials and methods in this retrospective study, we enrolled the data of patients who underwent partial nephrectomy in our referral center between 2008 and 2017. the inclusion criteria were a definite diagnosis of kidney tumor who underwent partial nephrectomy with at least one year urological oncology urology journal/vol 20 no. 1/ january-february 2023/ pp. 17-21. [doi:10.22037/uj.v18i.6858] follow up in alive patients. follow up included history, physical examination, blood tests, chest x ray, abdomino-pelvic computed tomography scan every 6 to 12 months in first 5 years and then annually(12). the exclusion criteria included: patients with incomplete follow up information and whose surgery converted to radical nephrectomy for any reasons or underwent further surgery to achieve negative surgical margin. this study was conducted in accordance with the declaration of helsinki. the demographic and clinical data of the patients were retrieved from the hospital’s databank. these data included age, sex, date of diagnosis, pathologic report, specimen and tumor size and the state of surgical margin. all the specimens were evaluated by an expert uro-pathologist in our center. the pathologist examined the outer layer of the specimen and if cancer cells are present to the edge of the removed tissue, he would report a positive surgical margin. any new detection of the tumor mass in the same surgery side in follow up imaging considered as local recurrence. quantitative data are shown as mean ± sd for data with normal distribution or median [interquartile range] for non-normally distributed data. quantitative data were compared between the groups by student's t-test, fisher's exact or mann-whitney test probability test, where applicable. recurrence free survival rates were calculated using the kaplan–meier survival method including a log-rank test. we utilized spss version 21.0 software (ibm corporation, armonk, ny, usa) for statistical analysis. two-tailed p-values < 0.05 were considered for the statistical level of significance. results in this study, the total number of 450 patients underwent partial nephrectomy due to renal tumor. the mean±sd age was 50.64±13.50 years. the median time of follow up was 36 months (iqr, 30-48). the mean ± sd specimen size and tumor size were 6.15±3.02 and 4.41 ± 2.37 cm, respectively. from these data, we calculated the mean normal renal parenchyma size was 1.75 ± 1.91 cm. the tumor was placed in the right side in 19 (54.3%) and in the left side in 16 (45.7%) patients. endophytic mass was found only in one patient. the pathologic reports showed that clear cell renal cell carcinoma was the most prevalent pathology (211 patients) among all participants. after clear cell rcc, angiomyolipoma (70), papillary rcc (65), chromophobe rcc (46), oncocytoma (25), cystic nephroma (18) and metanephric adenoma(6) were ranked next. the total number of 237 and 213 patients underwent open and laparoscopic partial nephrectomy, respectively. all these data are shown in table 1 separately between the open and laparoscopic partial nephrectomy groups. the positive surgical margin was found in 35 (22 male/13 female) patients’ pathologic report. 18 (51.4%) and 17 (48.6%) of them were in open and laparoscopic group, respectively. again, clear cell rcc was the most prevalent pathology (18 patients) in the psm patients’ pathology reports and papillary rcc and chromophobe rcc was reported in 9 and 8 patients, respectively. in the evaluation of the correlation between positive surgical margin and other findings, it was interesting to notice that positive surgical margin was occurred more in the smaller tumors. the mean±sd tumor size was 3.98 ± 2.26 and 4.21 ± 2 cm in positive and negative surgical margin patients, respectively (p = 0.022). recurrence was developed in 5 (14.2%) patients. the median time to recurrence was 36 months (iqr, 1842 months). fisher exact test and mann-whitney test showed that there is no correlation between recurrence and sex (2 female vs 3 male, p = 1.00), surgery type (2 open, 3 laparoscopies, p = 0.658), age (mean age 54.00 ± 10.65 vs 59.53 ± 9.49 in recurrence (+) and (-), p = 0.869), tumor size (4.08 ± 1.67 vs 3.82 ± 1.23 cm in recurrence (+) and (-), p = 0.069), pathology (3 clear cell rcc, 1 papillary rcc and 1 chromophobe rcc, p = 0.258) and stage (4 t1a and 1 t3a, p = 0.744) in psm patients. kaplan–meier survival method including a log-rank test showed that recurrence free survival was similar between the open and laparoscopy groups in psm patients (p = 0.619). discussion laparoscopic technique has been used to treat renal tumors for more than 30 years. however, there is an positive margins in partial nephrectomy-simforoosh et al. urological oncology 18 laparoscopic pn open pn p-value male/female 113/100 134/103 0.458 mean age±sd 49.9 ± 13.5 51.3 ± 13.4 0.274 tumor side (r/l) 8/9 11/7 0.505 positive surgical margin 17 18 0.247 mean specimen size±sd 5.60 ± 2.35 6.65 ± 3.34 < 0.001 mean tumor size±sd 3.91 ± 1.82 4.87 ± 2.70 < 0.001 tumor size (%) < 0.001 <4cm 141 (66.9) 114 (48.7) >4 <7 cm 62 (29.4) 87 (37.1) >7 <10cm 6 (2.8) 21 (8.9) >10cm 2 (0.9) 12 (0.05) normal renal tissue (cm) 1.71 ± 1.56 1.78 ± 2.19 0.699 surgical pathology (%) 0.722 rcc clear cell 95 (44.6) 116 (49) rcc papillary 33 (15.5) 32 (13.5) rcc chromophobe 24 (11.3) 22 (9.3) angiomyolipoma 37 (17.4) 33 (13.9) oncocytoma 14 (6.6) 11 (4.6) cystic nephroma 2 (0.9) 16 (6.7) metanephric adenoma 4 (1.8) 2 (0.8) other 4 (1.8) 5 (2.1) table 1. the characteristics and pathologic data of patients who underwent partial nephrectomy expressed concern about the oncological efficacy when minimally invasive approach is applied to treat malignancies(13,14). some physicians believe that obtaining negative surgical margins, achieving adequate hemostasis, and accurately repairing any injury to the collecting system is more convenient in conventional open approach; while several studies comparing laparoscopic nephrectomy with conventional open approach have shown no differences in feasibility and cancer control rates(15-18). as it shown in table 1, in this study, laparoscopic pn was performed more prevalent in smaller tumors but the incidence of positive surgical margins didn’t differ between open and partial groups. further analysis also showed that, there was no correlation between surgical approach (laparoscopy vs open) and recurrence in positive surgical margins and recurrence free survival is similar between positive surgical margins patients who underwent open or laparoscopic partial nephrectomy. similar to our study, in the evaluation of 1541 patients who underwent partial nephrectomy by either laparoscopy or open approach, lane et al(19) showed that surgical approach was not a predictor for positive surgical margin and recurrence. they also found that median glomerular filtration rate decrease was similar between two groups. beside tumor size, nuclear grading and pt3a stage were the most important predictors of positive surgical margin in a large systematic review of 36 retrospective study(20). in a recent systematic review and meta-analysis, you c et al(21) in the evaluation of 26 studies with 8095 patients, analyzed the current evidence on oncological, surgical, and functional outcomes between laparoscopic partial nephrectomy and open partial nephrectomy. operation time (p = 0.13), recurrence (p = 0.56), cancer-specific survival (p = 0.72), disease-free survival (p = 0.72), intraoperative complications (p = 0.94), and variations of estimated glomerular filtration rate were similar between two groups. less estimated blood loss (p < 0.00001), lower blood transfusion (p = 0.04), lower total (p = 0.03) and postoperative complications (p = 0.02), higher positive surgical margin (p = 0.005), shorter length of hospital stay (p < 0.00001), higher overall survival (p < 0.00001), and less increased serum creatinine (p = 0.002) was observed in the laparoscopic group. finally, they concluded that the lpn is a feasible and safe alternative to the opn with comparable oncologic, surgical, and functional outcomes. against our results, they founded higher positive surgical margin rate in laparoscopic partial nephrectomy group. we believe the laparoscopic learning curve play an important role in this era. we performed all the partial nephrectomy surgeries in our referral hospital, as an endourology-laparoscopy fellowship training center, the center of excellence in urology. all the surgeries were performed or supervised by endo-urology surgeons experienced in this field. higher positive surgical margin in the laparoscopic group may also be related to differences in pathological stage and follow-up time; so further prospective studies with proper design is suggested. positive surgical margin was detected in 17/213 (7.9%) of the laparoscopic group and 35/450 (7.8%), overall. in a systematic review and meta-analysis study, ficarra et al(20) evaluated the data of 45,786 patients of 36 retrospective studies who underwent partial nephrectomy and reported positive surgical margin in 3,093 (6.7%) patients (7%, 5%, and 4.3% in robot-assisted pn group, laparoscopic pn group, and open pn group, respectively). further analysis showed that in comparison with minimally invasive approach, open pn approach had a significant advantage in terms of achieving negative surgical margin. they also found that positive surgical margin risk is more favorable in robot-assisted pn group compared with laparoscopic group. against these findings, we didn’t find any difference in terms of positive surgical margin between open and laparoscopic pn groups. frozen section during surgery has been traditionally purposed to reduce positive surgical margin status following pn. however, the oncologic benefit remains unclear(22). the impact of positive surgical margin following partial nephrectomy on recurrence free survival is controversial. many studies have been conducted in this era and various results have been obtained. in the evaluation of multi-institutional database of patients who underwent robot-assisted partial nephrectomy, rothberg et al(23) reported positive surgical margin in 42/839 (5.1%) patients. they showed that positive surgical margin was not associated with worse recurrence free survival. instead, pt3a upstaging and advanced clinical stage associated with worse recurrence free survival. they concluded that patients with positive surgical margin should be carefully monitored for recurrence rather than undergo immediate secondary intervention. in a retrospective study of 314 patients who underwent partial nephrectomy with the median time of 24 months (iqr 12-40) follow up, marchinena et al(24) reported positive surgical margin in 22(6.3%) patients. recurrence was occurred in 2(9.1%) and 10 (3.5%) patients with positive and negative surgical margin, respectively. they concluded that positive surgical margin and pathological high grade (fuhrman grade iii or iv) were independent predictors of local recurrence in the multivariate analysis. in a similar retrospective study of 388 patients who underwent partial nephrectomy, carvalho et al(25) reported positive surgical margin in 16 (3.8%) patients. they showed that positive surgical margin is associated with recurrence rate (18.7% vs 4.2% in psm and nsm group, p = 0.007) and need for total nephrectomy but no impact on survival was noticed. in a retrospective study of 459 patients who underwent partial nephrectomy, psms were observed in 27 (5.9%) cases. recurrence occurred in 36(7.8%) patients. a significantly higher incidence of recurrence was showed in psm patients. recurrence rate was 22.2% in psm and 6.9% in nsm patients (p = 0.013) in the median time of 96 months (iqr, 74-131) follow up(26). similar to 3 recently discussed studies, the rate of recurrence in positive surgical margin patients is also noticeable in our study (14.2% during median time of 36 months (iqr, 30-48) follow up) and closely monitoring of these patients is mandatory. the aim of this study was to evaluate oncologic outcomes in patients with positive surgical margin who underwent open or laparoscopic partial nephrectomy. due to low rate of positive surgical margin following partial nephrectomy, a large sample size was not available for us in this retrospective study; so further well-designed prospective studies with larger sample size and longer follow up time are recommended. there are some other minor factors that it would be better to consider but positive margins in partial nephrectomy-simforoosh et al. vol 20 no 1 january-february 2023 19 unfortunately, there are not available for us to use them in this study. some of them are including patients’ bmi and renal nephrometry score. conclusions in this study, we found that recurrence free survival was similar between positive surgical margin patients who underwent laparoscopic or open partial nephrectomy. beside numerous advantages of minimally invasive techniques, laparoscopic approach would be comparable to conventional open partial nephrectomy in terms of oncologic outcomes. the rate of recurrence following partial nephrectomy in positive surgical margin patients is considerable and closely monitoring is mandatory. references 1. bansal rk, tanguay s, finelli a, et al. positive surgical margins during partial nephrectomy for renal cell carcinoma: results from canadian kidney cancer information system (ckcis) collaborative. can urol assoc j. 2017;11:182-7. 2. hollingsworth jm, miller dc, daignault s, hollenbeck bk. rising incidence of small renal masses: a need to reassess treatment effect. j natl cancer inst. 2006;98:1331-4. 3. rezaeetalab gh, karami h, dadkhah f, simforoosh n, shakhssalim n. laparoscopic versus open partial nephrectomy for stage t1a of renal tumors. urol j. 2016;13:2903-7. 4. borghesi m, brunocilla e, schiavina r, martorana g. positive surgical margins after nephron-sparing surgery for renal cell carcinoma: incidence, clinical impact, and management. clin genitourin cancer. 2013;11:5-9. 5. ani i, finelli a, alibhai sm, timilshina n, fleshner n, abouassaly r. prevalence and impact on survival of positive surgical margins in partial nephrectomy for renal cell carcinoma: a population-based study. bju int. 2013;111:e300-5. 6. raz o, mendlovic s, shilo y, et al. positive surgical margins with renal cell carcinoma have a limited influence on long-term oncological outcomes of nephron sparing surgery. urology. 2010;75:277-80. 7. sundaram v, figenshau rs, roytman tm, et al. positive margin during partial nephrectomy: does cancer remain in the renal remnant? urology. 2011;77:1400-3. 8. khalifeh a, kaouk jh, bhayani s, et al. positive surgical margins in robot-assisted partial nephrectomy: a multi-institutional analysis of oncologic outcomes (leave no tumor behind). j urol. 2013;190:1674-9. 9. link re, bhayani sb, allaf me, et al. exploring the learning curve, pathological outcomes and perioperative morbidity of laparoscopic partial nephrectomy performed for renal mass. j urol. 2005;173:1690-4. 10. allaf me, bhayani sb, rogers c, et al. laparoscopic partial nephrectomy: evaluation of long-term oncological outcome. j urol. 2004;172:871-3. 11. gill is, matin sf, desai mm, et al. comparative analysis of laparoscopic versus open partial nephrectomy for renal tumors in 200 patients. j urol. 2003;170:64-8. 12. kassouf w, siemens r, morash c, et al. follow-up guidelines after radical or partial nephrectomy for localized and locally advanced renal cell carcinoma. can urol assoc j. 2009;3:73-6. 13. lee ct, katz j, shi w, thaler ht, reuter ve, russo p. surgical management of renal tumors 4 cm. or less in a contemporary cohort. j urol. 2000;163:730-6. 14. trabulsi ej, kalra p, gomella lg. new approaches to the minimally invasive treatment of kidney tumors. cancer j. 2005;11:57-63. 15. portis aj, yan y, landman j, et al. longterm followup after laparoscopic radical nephrectomy. j urol. 2002;167:1257-62. 16. van poppel h, becker f, cadeddu ja, et al. treatment of localised renal cell carcinoma. eur urol. 2011;60:662-72. 17. zazzara m, carando r, nazaraj a, scarcia m, romano m, ludovico gm. nephron sparing surgery for the treatment of renal masses: a single center experience. urologia. 2021391560321993557. 18. introini c, di domenico a, ennas m, campodonico f, brusasco c, benelli a. functional and oncological outcomes of 3d clampless sutureless laparoscopic partial nephrectomy for renal tumors with low nephrometry score. minerva urol nefrol. 2020;72:723-8. 19. lane br, campbell sc, gill is. 10-year oncologic outcomes after laparoscopic and open partial nephrectomy. j urol. 2013;190:44-9. 20. ficarra v, crestani a, inferrera a, et al. positive surgical margins after partial nephrectomy: a systematic review and meta-analysis of comparative studies. kidney cancer. 2018;2:133-45. 21. you c, du y, wang h, et al. laparoscopic versus open partial nephrectomy: a systemic review and meta-analysis of surgical, oncological, and functional outcomes. front oncol. 2020;10:583979. 22. dagenais j, mouracade p, maurice m, et al. frozen sections for margins during partial nephrectomy do not influence recurrence rates. j endourol. 2018;32:759-64. 23. rothberg mb, paulucci dj, okhawere ke, et al. a multi-institutional analysis of the effect of positive surgical margins following robotassisted partial nephrectomy on oncologic outcomes. j endourol. 2020;34:304-11. 24. marchiñena pg, tirapegui s, gonzalez it, jurado a, gueglio g. positive surgical margins are predictors of local recurrence in conservative kidney surgery for pt1 tumors. international braz j urol. 2018;44:475-82. 25. carvalho jam, nunes p, tavares-da-silva e, et al. impact of positive surgical margins after partial nephrectomy. european urology open science. 2020;21:41-6. urological oncology 20 positive margins in partial nephrectomy-simforoosh et al. kidney transplantation 136 26. tellini r, antonelli a, tardanico r, et al. positive surgical margins predict progression-free survival after nephronsparing surgery for renal cell carcinoma: results from a single center cohort of 459 cases with a minimum follow-up of 5 years. clin genitourin cancer. 2019;17:e26-e31. vol 19 no 6 november-december 2022 442 positive margins in partial nephrectomy-simforoosh et al. vol 20 no 1 january-february 2023 21 alternative medical interventions versus conventional treatment of renal colic: an updated systematic review and network meta-analysis ghazal seghatoleslami1, mohammad sadegh sanie jahromi2, roohie farzaneh3, sara rahsepar1, mehrdad malekshoar4, majid vatankhah4, reza akhavan3, bita abbasi5, hossein akhavan6, samaneh abiri7, lohrasb taheri8, navid kalani9, mahdi foroughian3, arman hakemi10* purpose: to systematically review the recent alternative medical interventions on renal colic pain and compare their efficiency with conventional treatments. materials and methods: this was a systematic review and network meta-analysis (nma) study, based on the prisma guidelines on online databases of pubmed, scopus, and web of science. we quarried these databases with relevant keywords for clinical trial studies that aimed at reducing renal colic pain in patients refereeing to the ed from after january 2011 to february 2022. randomized clinical trials that used the visual analogue scale (vas) for assessment of renal colic pain before and after medical interventions in adult patients were included in this study. nma was conducted based on the continuous values of the mean difference of the pain after 30 and 60 minutes of the medication administration. results: twenty-four studies that were meeting the inclusion criteria were included in our review with 2724 adult participants who were mostly male. study arms included conventional medications (nsaid, opioid, paracetamol), ketamine, mgso4, desmopressin, and lidocaine. based on the qualitative synthesis, ten studies (41.7%) did not find significant differences between conventional and alternative treatments. also, there is no agreement on some more recent medications like using ketamine or desmopressin while mgso4 and lidocaine use are supported by most studies. nma revealed that desmopressin is significantly having worse pain reduction properties. nma did not show any difference between ketamine, lidocaine, and mgso4, versus the conventional treatment. conclusion: to conclude, lidocaine and mgso4 might be good alternative treatments for renal colic when conventional treatments are contraindicated or pain is not responding to those. ketamine might be indicated in patient-based circumstances. desmopressin may be agreeably avoided in further research or clinics. keywords: urolithiasis; emergency department; renal colic introduction renal colic is a severe pain caused by transient kidney stones through the urinary tract and urinary system that 12% in males and 6% in women can experience in a lifetime(1) and is a common reason for emergency room visits worldwide(2). management of renal colic pain is mainly a conservative approach that focused on treating the symptoms like pain and nausea and vomiting(3). in case of pain, renal colic pain is 1department of medicine, mashhad university of medical sciences, mashhad, iran. 2anesthesiology, critical care and pain management research center, jahrom university of medical sciences, jahrom, iran. 3department of emergency medicine, faculty of medicine, mashhad university of medical sciences, mashhad, iran. 4department of anesthesiology, anesthesiology & critical care and pain management research center, hormozgan university of medical sciences, bandar abbas, iran. 5department of radiology, faculty of medicine, mashhad university of medical sciences, mashhad, iran. 6department of pediatric, faculty of medicine, mashhad university of medical sciences, mashhad, iran. 7department of emergency medicine, jahrom university of medical sciences, jahrom, iran. 8department of surgery, jahrom university of medical sciences, jahrom, iran. 9research center for social determinants of health, jahrom university of medical sciences, jahrom, iran. 10department of emergency medicine, mashhad university of medical sciences, mashhad, iran. correspondence: department of emergency medicine, mashhad university of medical sciences, mashhad, iran. email: hakemia971@mums.ac.ir. received february 2022 & accepted august 2022 caused by a rise in prostaglandin production, which causes arterial vasodilation, vascular permeability, and ureteric edema and contractions. renal colic is characterized by referral and migratory pain, which is peculiar to renal colic due to the stone's gradual transit down the ureter(4). several major systematic reviews and meta-analyses studies have supported various medications to help achieve a longer duration of pain relief, a lower requirement for further analgesia, and fewer adverse effects(5). systematic review studies have compared many urology journal/vol 19 no. 6/ november-december 2022/ pp. 412-419. [doi: 10.22037/uj.v19i.7204] review review 413 alternative medications of renal colicseghatoleslami et al. table 1. characteristics of included studies id country setting design intervention iv age sex end clinical conclusion jaded therapy (male) points response score motov et al., usa multicenter prospective, aiv lidocaine 2019 (12) interventional, (1.5 mg/k), n = 50 100 ml iv a39.34 a-54% 60 min pain na no 5 blinded bketorolac 30 mg, normal b42.34 b56% relief rate; difference n = 50 ca+b, n = 50 saline c43.92 b56% adverse event c56% soleimanpour et al., iran single-center prospective randomized a0.1 mg/kg morphine na a35.23 ± 12.37 a-75% vas till 30 na b was better 3 2012 (13) double-blind clinical trial iv slowly, n = 120 b37.71 ± 11.08 b71% min values biv lidocaine (1.5 mg/k), n = 120 sadrabad et al., iran single-center double-blind randomized a0.1 mg/kg iv morphine a 10 cc a34.65(8.47) a27 (67.5) 10, 20 min 3 scores no difference 4 2021 (14) clinical trial sulfate (maximum of distilled b-34.97 (9.71) b30 (75) vas reduction 5 mgs), n=40 water + 20 of vas b50 mg/kg (maximum minute infusion of 2 grams) mgso4, n=40 100 cc normal saline. b100 cc normal saline for 20 minutes kumar et al., india single-center nonblind randomized a desmopressin 40 none na in detail, na in second na all patients 3 2011 (15) clinical trial gm in, n=24 matched groups detail, analagesic; in group a bdiclofenac 75 mg matcched vas at 10, received secondary im, n=24 groups 30 min and 1 h analagesic; c both, n=24 2 in group b, and 3 in group c ghafouri et al., iran single-center nonblind randomized a40 mcg of in na matched a 99 (82.5) second 30 mm no difference 5 2020 (16) clinical trial desmopressin spray, b88 (73.3) analgesic decrease n=120 biv paracetamol (morphine (15 mg/kg), n=120 use after 15 min); vas at 0, 15, 30 min and 1 h drapkin et al., usa single-center randomized, aiv lidocaine none na na vas at 0, na c is better 2018 (17) double-blind (1.5 mg/k),n = 50 15, 30 min bketorolac 30 mg, n = 50 and 1 h ca+b, n = 50 forouzan et al., iran single-center randomized, aintravenous ketamine none matched na vas at 30, na no difference 2019 (18) placebo-controlled, (0.3 mg/kg) 45, and 60 min double-blinded b intravenous morphine & adverse event (0.1 mg/kg) total 135 participants sotoodehnia et al., iran single-center randomized aintravenous ketamine na matched a71% vas till 120 na no difference 4 2019 (19) double-blind (0.6 mg/kg), n=62 b81.2% min & adverse b intravenous ketorolac event 30 mg, n=64 grill et al., 2019 (20) usa single-center randomized non blind aketorolac 30 mg, n=26 ketamine in a37.25 a75.0% 120 min 11na b was better 4 bintravenous ketamine 50 cc ns b41.69 b30.8% point vas, (0.3 mg/kg) plus ketorolac, n=8 results of md were multiplied by 1.1 pouraghaei et al., iran single-center randomized double blind a 1 mg/kg intranasal (in) none a39.39±3.7 matched vas at na no difference 5 2021 (21) ketamine, n=95 b41.27±5.2 20, 40 and b intravenous morphine 60 minutes (0.1 mg/kg) , n=89 metry et al., egypt single-center prospective, open-label, aiv pethidine 50 mg, none a39.8±11.3 an=40 vas till na b was better 4 2021(22) randomized, doubleb lornoxicam 8 mg+ b37.8±12.8 bn=38 30 min blindedn=60 0.15 mg.kg−1 ketamine, n=60 dolatabadi et al., iran single-center double-blind randomized a40 µg of intranasal none. a31.0 ± 6.5 a13 (65) vas at 10, 3 cm b is better. 4 2017 (23) clinical trial, desmopressin spray, n=20 b 34.1 ± 7.1 b 16 (80) 30, and 60 change avoid a b30 mg of iv ketorolac, n=20 min ahmed et al., egypt multi center randomized, aiv magnesium sulfate 100ml a31.96±8.29 a60.4% vas at 15, na a was better 3 2019 (24) double-blind, double50%, n=48 intravenous b31.94±8.08 b56.3% 30, 45, and dummy comparative bketorolac 30 mg iv, normal saline 60 minutes n=48 verki et al. 2019 (25) iran multicenter randomized, double-blind, a 50 mg/kg magnesium 100ml a39.43±12.089 matched vas till 30 na no difference 4 sulfate 50% +, ketorolac intravenous b37.19±10.032 min 30 mg iv, n=44 normal saline bketorolac 30 mg iv, n= 43 motamed and verki, iran single center randomized clinical a fentanyl (1.5 µg/kg), iv infusion a39.08 ± 6.64 a39 (86.7) vas at 30 na no difference 4 2017 (26) trial, double blind n=45 during 2 b 34.08 ± 9.49 b 42 (93.3) min; rescue blidocaine (1.5 mg/kg), minutes n=45 jokar et al., 2017(27) iran single center randomized double-blind a0.1 mg/kg of iv a100 ml iv a 35.16±8.97 a 29 (58%) 30 and 60 na b was better 4 morphine sulfate, 30 mg normal b33.64±8.61 b30 (60%) min vas; of iv ketorolac, and 100 saline morphine ml iv normal saline, n=50 b100 ml dose b15 mg/kg of iv normal saline magnesium sulfate 50% , within 15 minutes n=50 shirazi et al., iran single center prospective, single blind atramadol 50 mg im ly, none a39.1±8.9 a23 30 min na a was best 4 2015 (28) randomized clinical n=40 b38.8±7.6 (57.5%) vas; bdesmopressin 40 µg c36.7±9.2 b25 (62.5%) complete intranasally, n=40 c22 (55%) relief ; rescue cindomethacin 100mg rectally , n=40 types of medications and some review studies have only focused on a special medication(6). a review of 36 rcts, published in 2016, showed that many available medical choices among the medications belonging to the nsaids, opioids, and paracetamol are having comparable efficiency in relieving acute renal colic pain; while the adverse events might be different(7). one more systematic review study on 183 studies till 2020 revealed that as a common choice, opioid medications were linked to lower or equivalent efficacy to nsaids for several acute pain situations, but also a higher risk of short-term side effects(8). multiple drugs are proven to be effective for renal colic pain in individuals accused of carrying kidney stones; nevertheless, much research on novel treatment options or novel combinations of previous medications is being released that are not reviewed in recent years. as mentioned, the pain induced by urolithiasis is one of the most annoying pain experiences that an individual can sense and is responsible for a high rate of emergency department (ed) visits worldwide. multiple conventional medications (nonsteroidal anti-inflammatory drugs (nsaids) and opioids) are known to be efficient for renal colic pain in patients suspected of kidney stones, but yet some patients might still not respond to conventional methods that necessitate alternative methods. so, we aimed at conducting an updated systematic review study of the alternative methods from 2011 to 2022. materials and methods this was a systematic review study on renal colic pain treatment in the emergency department that was conducted based on the prisma guidelines. study questions were structured based on a pico model. (p)opulation of interest was acute renal colic patients. suspected or definitive cases were considered for the study. based on the icd-10 definitions [2022 icd-10-cm diagnosis code n23], renal colic was defined as “a condition characterized by intermittent and severe flank pain due to kidney stone (renal calculus) moving through the ureter or other urinary channel obstruction is the most common cause of acute discomfort in the lower back extending to the groin, scrotum, or labia. nausea, vomiting, fever, restlessness, dull discomfort, frequent urine, and hematuria are all common symptoms.” (i)ntervention was pain relief interventions (medical or non-medical). based on the preliminary search of the literature, high-quality pooled studies were available comparing nsaids, opioids, paracetamol, and desmopressin. network meta-analysis was available on different routes of nsaids and paracetamol administration(9). there was a lack of pooled data in comparison of newer interventions with previously interventions that have stood the test of time. so, we aimed at categorizing interventions into 4 categories of (i) conventional monotherapy [including monotherapy with nsaids, vol 19 no 6 november-december 2022 414 id country setting design intervention iv age sex end clinical conclusion jaded therapy (male) points response score majidi and iran single center double aiv 2cc of 50% normal a39.1 ± 13.2 a 27 (60.0) 180 min 3 no difference 4 derakhshani, blind mg sulfate, n=45 saline b35.6 ± 10.8 b32 (71.1) vas scores 2020(29) randomized biv morphine 100 ml reduction (0.1 mg/kg dose), n=45 injected of vas during 15 minutes shirvani et al., iran single center single blind a0.1 mg/kg im na matched matched 30 min vas na no difference 4 2015 (30) randomized, 60 µg of clinical trial morphine + sublingual desmopressin bmorphine + placebo total 81 cases firouzian et al., iran single center double-blind, amorphine (0.1 mg/kg) na a37.91 ± 10.76 a36 vas till 120 na a was better 4 2016 (31) randomized + lidocaine (1.5 mg/kg), b37.95 ± 12.6 b35 min for both controlled n= 47 pain and naussea trial bmorphine (0.1 mg/kg) + normal saline 0.9% [ placebo], n=42 farnia et al., iran single center prospective, a a 0.1 mg/kg diluted na a-34.75 ± 11.71 a17 30 min vas na a was better 5 2017 (32) randomized, iv morphine + in b39.25 ± 10.75 (85.0%) double-blind placebo, n=20 b12 b1 mg/kg in ketamine (60.0%) + iv placebo. n=20 abbasi et al., iran single center double amorphine 0.1 na matched matched 120 min na b was better 4 2018 (33) blind mg/kg iv and placebo, n=53 vas randomized bmorphine 0.1 mg/kg iv and clinical trial ketamine 0.15 mg/kg iv, n=53 jalili et al., 2019(34) iran single center prospective, a indomethacin na a 34.67 ± 10.03 a 70.15% 60 minvas na a was better 4 doublesuppository (100 mg) + b34.31 ± 10.73 b 69.35% blinded, , desmopressin intranasal randomized spray (4 puffs with 10 placebomicrogram per puff), n=62 controlled b indomethacin suppository clinical trial (100 mg) + palcebo intranasal spray , n=62 mozafari et al., iran single center double-blind a 1 mg/kg of intranasal na matched matched 30 min na b was better 4 2020 (35) clinical trial drops of ketamine + iv palcebo, n=65 vas; b50 µg/(kg/bw) iv fentanyl + rescue intranasal palcebo, n=65 medication; na, not addresed. alternative medications of renal colicseghatoleslami et al. opioids, and paracetamol] or combined with each other; (ii) alternative treatments; (iii) combination of the conventional and alternative methods. nonpharmacological methods were not included in the study. (c)omparisons were tried to be conducted between these three types of interventions being compared pairwise and versus the conventional treatment. the route of the medication administration was waived to observe the prerequisites of nma. (o)utccome of interest was the analgesic effects of interventions and the need for rescue treatment. based on the preliminary review, some studies of filed are not reporting rescue treatment rates that we only considered 30and 60-min pain. search strategy searches were performed from 1 january 2011 to 2022 in online databases of scopus, pubmed, and web of science. two independent researchers ran the search review 415 figure 1. prisma flowchart figure 2. network plot of included studies. (a) 30 min pairwise analysis network. (b) 60 min pairwise analysis network. each node representing a single intervention and connecting lines between nodes showing where one or more trials have compared the two therapies head-to-head. alternative medications of renal colicseghatoleslami et al. strategy of the combination of the mesh keywords. the detailed search strategy was “ (renal colic or urolithiasis or acute nephrolithiasis or nephrolithiasis or renal colic pain or urolithiasis pain or ureteric colic) and (randomized controlled trials or trial or randomized trial or blinded trial or rct) and (pain or vas or visual analogue scale or analgesia or analgesic) and emergency department” . searches were conducted by two independent researchers. the reference list of the selected articles for full-text review was also hand-quarried for relevant studies. study selection, data extraction, and quality assessment studies were limited to randomized clinical trials, in the english language, published after january 2011. the study setting was also limited to the emergency department. pre-print studies and gray literature did not include in the study. any studies on subjects with trauma to the flank or any other concurrent significant trauma were not included. the age of study subjects had to be higher than 16 years old and lower than 65 years; subjects did not have any previous renal failure. any disagreement between independent researchers was judged by a third researcher. inclusion criteria were also containing a non-conventional treatment arm of the study in rct. the quality of studies was assessed by jadad score to prevent any bias(10). a checklist containing study id, country, setting, design, minimum vas for inclusion, intervention, amount of iv therapy, age, sex, endpoints, conclusion, and clinical response definition was provided along with the amount of the mean difference between the 30 and 60 min vas pain score. network meta-analysis we used metainsight based on the “netmeta” r package to perform the meta-analysis(11). mean differences were calculated based on the baseline vas pain score and 30 and 60 min scores. lower values (more negative) of mean difference were considered desirable outcomes. the random effects model was used to pool the mean differences in each arm of intervention. network plots were used as a graphic illustration of the network of evidence to indicate pairwise interventions, as well as if there is a linked network of evidence, which is a prerequisite for nma. a forest plot was used to show the pooled effect estimate. consistencies were checked for each comparison by “netmeta”, where a p value of lower than 0.05 shows inconsistency and not achieving the perquisites of the nma. results following the literature review, our primary search came into 1654 records. after removing duplicated cases and selecting studies for abstract review based on the title, 89 potentially relevant studies were included for full-text review. seven studies were not retrieved due to having retrospective design, two were case reports, 3 studies were review studies and 7 studies had not used vas for scoring the pain. the remaining excluded studies were out of date. finally, 24 studies that were meeting the inclusion criteria were selected among those studies. continuous data was not extractable from 7 studies and one was due to a lack of reporting bassline pain, so 16 studies were entered the nma (figure 1). in this systematic review, we included 24 studies with 2724 adult participants. there were 18 studies conducted in iran, 3 in the usa, one in india, and 2 in egypt (table 1). iv therapy volume was also recorded. studies with iv infusion medications were using the maximum volume of 500 ml of normal saline. in most studies, the male participants were more than female ones. study timelines of pain reassessment after administration of the medication was ranging from a minimum of 30 minutes to 120 minutes. some studies had also evaluated the need for rescue medication if the main intervention was not able to relieve the pain. most studies had used continuous amounts of the pain based on the vas scores for statistical decisions; while some had defined clinical response. fifty percent pain reduction or 3 scores (30 mm) reduction in pain was considered for most studies. qualitative synthesis ten studies (41.7%) did not find significant differences between conventional and alternative treatments. desmopressin was showing fewer analgesic effects than conventional. only one study mentioned its combination with nsaid to be more effective than nsaid; while mgso4 and lidocaine use are supported by most studies. nma results in our nma analysis, 1759 participants were included in 30 min vas mean difference analyses and 1038 in 60 min analysis. the number of the pairwise comparifigure 3. forrest plot of nma in 30 min (a) and 60 min (b) pain reduction mean differences. alternative medications of renal colicseghatoleslami et al. vol 19 no 6 november-december 2022 416 sons is shown in figure 2, a for 30 min pain scores, and figure 2,b for 60 min. there were a total number of 8 interventions [dessmopressin, lidocaine, ketamine, mgso4, and combinations of lidocaine, ketamine, and desmopressin with conventional medicine] in 30 min nma and 7 in 60 min. 16 studies included the 30 min analysis and 9 in 60 min analysis. as shown in figure 2. we did not achieve the perquisites of head-to-head comparison in most comparisons and only desmopressin and lidocaine-based studies had such performances. consistency results are shown in supplementary tables 1&2. while there was a satisfactory number of studies that we compared different interventions individually with conventional medicines. the forest plot of the results of the studies based on the study arms is presented in figure 3. using the random-effects model, arms are compared versus conventional treatment. mean differences of vas after 30 min were not significantly higher or lower than conventional treatment in any of the evaluated arms (p > 0.05) except for the desmopressin that showed significantly lower pain decrease than conventional treatment (md=1.67, 95%ci: 0.23-3.11). mean differences of vas after 60 min were not significantly higher or lower than conventional treatment in any of the evaluated arms (p > 0.05). individual study’s mean differences are shown in supplementary figures 1&2. discussion our network meta-analysis was carried out to determine the most effective medications that can be used as an alternative treatment for renal colic pain. while many previous meta-analyses and systematic reviews are conducted in the field, those are comparing different methods of the conventional medication prescription as well as different types of the nsaids or opioids and their different routes of administration. leng et al. compared the efficacy of these conventional medications (nsaids versus opioids) and found no significant differences based on the meta-analysis(36). another systematic review suggests that some particular nsaids might act better for acute renal colic pain reliving(37). systematic review and meta-analysis by pathan et al. also showed the same results of the equivalent efficacy of nsaids, opioids, and paracetamol(7). while in some circumstances, due to pre-existing medical conditions, administration of conventional medications might get contraindicated, as well as in kidney disease and liver failure patients. so, there is a need for alternative treatments as well as for patients whose pain does not relieve by conventional medications. our review showed that there are multiple pharmacological choices as the alternative. we included desmopressin, lidocaine, ketamine, mgso4, and combinations of lidocaine, ketamine, and desmopressin with conventional medicine as the alternative treatment; while other potential interventions exist that we did not include due to not achieving saturation of the number of required studies for the meta-analysis as well as the aminophylline and hyoscine(38,39). our review showed that there were no significant differences between conventional and alternative therapies in twelve trials (41.7%). furthermore, there is no consensus on the use of certain more modern drugs, such as ketamine or desmopressin. but mgso4 and lidocaine are supported by the majority of research. desmopressin has many inferior pain-relieving abilities, according to nma. ketamine, lidocaine, and mgso4 had no superior effect compared to the standard therapy based on our nma. in the case of desmopressin, we suggest that this medication might not have a good pain-reducing capacity and should be avoided in further research and clinical management as better choices are available. in the study of jalili et al., pain relief with nsaids (e.g. indomethacin) in renal colic did not improve appreciably when administered in conjunction with intranasal desmopressin (34). kumar et al. imply that desmopressin is not efficient analgesia in renal colic, since it only has a minor analgesic effect after 30 minutes. more effective and fast-acting analgesics in the form of nsaids or opioids are more appropriate than desmopressin alone because of the agonizing character of renal colic(15). in one more study, desmopressin has been found to be less effective than ketorolac(23). but, the addition of sublingual desmopressin to morphine had no benefit(30). on the other hand. ghafouri et al. findings revealed that both iv paracetamol and intranasal desmopressin were effective in the ed for the treatment of renal colic pain, while desmopressin had a faster beginning of the action, while finally had no difference(16). our study showed that mgso4 and lidocaine use are supported by most studies. in motamed and verki's study, the mean pain severity did not change substantially between iv fentanyl and iv lidocaine at various intervals after injection, but, the treatment failure rate in the iv lidocaine group was considerably greater 15 minutes after administration(26). lidocaine may be prescribed as an effective, safe, and economical adjuvant to morphine for shortening the time it takes to get pain and nausea relief. our search was limited to english language papers that might make biased as some important studies might not get included in the review. also, there are some major limitations in combining all studies of nsaids, opioids, and paracetamol into one category; while pooled evidence in literature is showing no significant difference between these medications. we also merged all routes of the administration of medication as there were not enough studies to individually analyze routes of medication administration. conclusions our review showed that there were no significant differences between conventional and alternative therapies in twelve trials (41.7%). furthermore, there is no consensus on the use of certain more modern drugs, such as ketamine or desmopressin. but mgso4 and lidocaine are supported by the majority of research. desmopressin has many inferior pain-relieving abilities, according to nma. ketamine, lidocaine, and mgso4 had no superior effect compared to the standard therapy based on our nma. because several studies support the use of various drugs to treat renal colic pain, physicians can choose medications based on their patient's condition and response to therapy. conflict on interest none declared by the authors. review 417 alternative medications of renal colicseghatoleslami et al. summary lidocaine and mgso4 can be used for kidney pain of not responding to ordinary medications. ketamine might be useful in some circumstances. desmopressin is better to be avoided references 1. bultitude m, rees j. management of renal colic. bmj. 2012 aug 29;345. 2. kominsky hd, rose j, lehman a, palettas m, posid t, caterino jm, knudsen be, sourial mw. trends in acute pain management for renal colic in the emergency department at a tertiary care academic medical 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garcía-perdomo ha, echeverría-garcía f, lópez h, fernández n, manzano-núñez r. pharmacologic interventions to treat renal colic pain in acute stone episodes: systematic review and meta-analysis. progrès en urologie. 2017;27:654-65. 38. akbari h, foroughian m, abiri s, kalani n, rayatdoost e, safaei m, zarei mj. comparing the analgesic effect of aminophylline and hyoscine with morphine on renal colic: a randomized clinical trial. front in emerg med. 2020;4:e85. 39. foroughian m, abiri s, akbari h, shayesteh bilandi v, habibzadeh sr, alsana f, taghipour n, kalani n, rayat dost e. effectiveness of intravenous lidocaine versus intravenous morphine in reducing acute extremity trauma-induced pain: a tripleblind randomized clinical trial. koomesh. 2020;22:411-8. review 419 alternative medications of renal colicseghatoleslami et al. v07_no_4.pdf laparoscopic urology 238 urology journal vol 7 no 4 autumn 2010 intracorporeal tapering of the ureter for distal ureteral stricture before laparoscopic ureteral reimplantation akbar nouralizadeh, nasser simforoosh, samad zare, seyyed mohammad ghahestani, mohammad hossein soltani purpose: to present our experience of laparoscopic ureteral reimplantation using intracorporeal ureteral tapering for management of distal ureteral stricture. materials and methods: between april 2005 and october 2008, six patients, including 3 children and 3 adults, underwent laparoscopic modified lich-gregoir type extravesical ureteral reimplantation for distal ureteral stricture. significant dilatations of proximal segment in these patients were repaired with intracorporeal ureteral tapering. stricture etiologies were congenital ureterovesical megaureter and iatrogenic gynecologic injury in 4 and 2 patients, respectively. results: mean age of the patients was 29.3 years (range, 2 to 62 years). mean operation time and hospital stay was 185 minutes (range, 150 to 240 minutes) and 4 days (range, 2 to 6 days), respectively. no significant complications were noted intra-operatively. surgical procedure was performed in all the subjects laparoscopically and no conversion to open surgery happened. postoperatively, 2 patients were complicated with febrile urinary tract infection that were managed medically. no urinary leakage occurred in early postoperative period. all the patients had patent ureterovesical junction anastomosis in follow-up imaging and recurrence of obstruction was noted in no cases. two patients (33.3%) developed grade ii vesicoureteral reflux. conclusion: laparoscopic ureteral reimplantation with intracorporeal tapering of distal segment may be performed safely in management of patients with distal ureteral stricture and severe dilatation of proximal segment. urol j. 2010;7:238 www.uj.unrc.ir keywords: laparoscopy, reimplantation, ureter, ureteral obstruction, instrumentation urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university, mc, tehran, iran corresponding author: urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 received october 2009 accepted april 2010 introduction ischemia, iatrogenic injury from previous abdominal or pelvic surgery, endometriosis, malignancy, radiation, ureteral calculus, endoscopic instrumentation, infections such as tuberculosis and schistosomiasis, and congenital disorders are considered as common causes of ureteral stricture.(1,2) proper evaluation and treatment of a ureteral stricture is essential to preserve renal function.(3,4) indications for intervention in ureteral stricture include the need to rule out malignancy, compromised renal function, recurrent pyelonephritis, and pain associated with functional obstruction.(5) depending on the location and length of the stricture, different reconstructive ureteral tapering in laparoscopic ureteral reimplantation—nouralizadeh et al 239urology journal vol 7 no 4 autumn 2010 procedures such as end to end anastomosis, ureteroneocystostomy with or without psoas hitch, boari flap, ileal substitution, or autotransplantation can be performed. (6) recently, laparoscopic procedure has been introduced as a suitable alternative to open surgery in the management of patients with ureterovesical junction obstruction. agarwal and colleagues demonstrated feasibility of laparoscopic intracorporeal excisional tailoring of megaureter and reimplantation in three subjects. (7) in this study, we present a novel technique of intracorporeal tapering of the ureter for management of distal ureteral stricture before laparoscopic ureteral reimplantation in six patients during a short-term follow-up. materials and methods from april 2005 to october 2008, six patients with ureteral stricture have undergone laparoscopic ureteral reimplantation with intracorporeal ureteral tapering in shahid labbafinejad medical center, which is a referral urologic center. all surgical operations were performed by the same surgical team. the main symptom of the stricture was pain in 5 subjects and urinary tract infection in a 2-year-old boy. pre-operative laboratory assessments included serum level of hemoglobin, creatinine, and urine culture. abdominopelvic ultrasonography, intravenous pyelography, and voiding cystourethrography were performed in all the patients. operative time, length of hospital stay, renal function, and intra-operative and early postoperative complications were recorded. surgical technique after general anesthesia in supine position, a foley catheter was inserted in the bladder under sterile condition. the 4-port transperitoneal technique was performed (two 5-mm ports in the left and right lateral rectus abdominalis muscles, one 5-mm port in midline 5 centimeters infraumblical region, and one 10-mm umbilical camera port). after incision along the ipsilateral line of toldt, the colon was reflected medially. the ureter was identified and with attention to preservation of the adventitia, it was isolated above the level of stricture and divided just proximal to the stenotic portion. because of significantly dilated ureteral portion proximal to the obstruction, intracorporeal tapering was done over 8fr feeding tube in children and 10fr nelaton catheter in adults. after defining vascular support, an atraumatic clamp was placed over the catheter, and excess ureter was excised. a running locking 4-0 vicryl suture was used for reapproximation of proximal two-thirds of the tapered ureter, and interrupted sutures completed the repair in distal part to allow any shortening that might be necessary (figures 1 and 2). figure 1. dissection of the severely dilated ureter proximal to stricture segment. figure 2. laparoscopic intracorporeal tapering of dilated distal ureter. ureteral tapering in laparoscopic ureteral reimplantation—nouralizadeh et al 240 urology journal vol 7 no 4 autumn 2010 one hundred and eighty milliliters of saline was instilled in the bladder and then, an antrolateral seromuscular incision was made down to the bulging bladder mucosa and it was incised with electrocautery. six fr double-j stent was passed into the ureter and advanced to the renal pelvis, and its distal end was fixed in the bladder. tapered ureter was anastomosed to the bladder mucosa with continuous 4-0 vicryl sutures. a distal anchoring stitch suture was used to hold the ureter near the seromuscular tissue of the bladder. the seromuscular layer was then loosely closed over the tapered ureter. a 14fr nelaton drain was placed within the 5-mm port. ureteral stent was removed at 6 weeks after the operation. two months later, intravenous pyelography for evaluation of residual obstruction and voiding cystourethrography for evaluation of residual vesicoureteral reflux were performed in all the patients. results the mean age of the patients was 29.3 years (range, 2 to 62 years). three patients were children with the age of 2, 5, and 11 years and the other threes were adults with the age of 38, 47, and 62 years. stricture etiologies were congenital obstructive megaureter and iatrogenic gynecologic injury in 4 and 2 patients, respectively. mean operation time and length of hospital stay was 185 minutes (range, 150 to 240 minutes) and 4 days (range, 2 to 6 days), respectively. no major complication occurred during the surgery. mean blood loss was 70 ml (range, 50 to 320 ml) and no blood transfusion was required in the postoperative period. the mean hemoglobin loss was 0.5 g/dl (range, 0.2 to 0.9 g/dl). the average time to start oral intake was 16 hours (range, 12 to 36 hours). the most primary presenting symptom was pain in 5 patients that resolved completely in 3 subjects and relatively in 2 others. urine culture was negative in short-term follow-up of a 2-yearold boy presented with urinary tract infection. surgical procedure was done in all the patients laparoscopically and there was not any conversion to open surgery. two patients had fever for less than 48 hours (hospital stay, 6 days) that were figure 3. intravenous pyelogram of the patient with history of gynecologic surgery revealed a severe hydroureteronephrosis up to the distal portion of the right side ureter. figure 4. problem was resolved after laparoscopic ureteroneocystostomy. ureteral tapering in laparoscopic ureteral reimplantation—nouralizadeh et al 241urology journal vol 7 no 4 autumn 2010 managed by antibiotic therapy. urinary leakage was noted in none of the patients in immediate postoperative period. the mean time to start the normal activity in three adults was 2.9 weeks. resolution of obstruction and new occurrence of vesicoureteral reflux were assessed with intravenous pyelography and voiding cystourethrography, respectively. mean followup was 4 months (range, 3 to 8 months). all the patients had patent ureterovesical junction anastomosis in follow-up imaging and recurrence of obstruction was noted in no cases (figures 3 and 4). two patients (33.3%) developed grade ii vesicoureteral reflux. discussion initial experience of laparoscopic ureteral reimplantation for distal ureteral stricture described challenges with exposure of the ureter, trauma to the ureter, and difficulty in developing the extravesical tunnel without injury to the urothelium in addition to long operative time.(8) several modifications were introduced using laparoscopic approach that have resulted in shorter operative time and similar outcomes to open surgery.(3,9) seideman and colleagues reported that, with long-term follow-up, this technique is a proper alternative to open surgery with comparable outcomes and advantages of a minimally invasive procedure.(9) rassweiler and associates(10) and kamat and khandelwa(11) in two separated retrospective comparison of laparoscopic and open techniques revealed that mean hospital stay, analgesic requirement, and mean convalescence time for laparoscopy were significantly lower than open surgery and success rate was noticeable. mean operative time in our study was 185 minutes (range, 150 to 240 minutes) that was slightly longer than mentioned operative time in other studies. this shortcoming reflects our learning curve in reconstructive laparoscopy, especially in early cases. symons and colleagues presented their experience in 6 patients, of whom 3 underwent neoureterocystostomy and the remaining underwent boari flap technique. they reported acceptable outcomes, but mean operative time and hospital stay were not preferable.(12) ogan and colleagues performed laparoscopic ureteral reimplantation in 5 of 6 patients with long stricture of distal ureter, using a modified dome advancement technique without requiring boari flap.(13) if the ureteral portion proximal to the obstruction was significantly dilated as it was in our subjects, the lower end should be tapered. ansari and colleagues described a novel technique of extracorporeal tailoring for megaureter in 3 subjects prior to laparoscopic extravesical transperitoneal ureteral reimplantation.(1) in their report, the free ureteral end was delivered out through the ipsilateral 5-mm port. the lower end was tailored over an 8fr feeding tube. a 6fr double-j stent was placed, and finally, the whole assembly was carefully replaced in the abdomen. then, lich-gregoir type extravesical reimplantation was done. they concluded that extracorporeal tailoring for obstructing megaureter is an easy and a safe procedure, but more dissection of the ureter is required to be able to exteriorize and it may be concomitant with vascular support damage and possibly ischemia. recently, agarwal and colleagues presented their initial experience of intracorporeal excisional tailoring of megureter before laparoscopic ureteral reimplantation with acceptable results in 3 young men.(7) we accept that operative time in this technique may be longer than extracorporeal tapering in initial experience, but more dissection of the ureter for exteriorizing from the abdominal wall is a main shortcoming; thus, with steep learning curve, the time-consuming technique will be modified and popularized. likewise, to the best of our knowledge, this report is the first presentation of using this technique in children. although operative time is longer than adults, but other variables, including blood loss, hospital stay, urinary leakage, and final improvement of obstruction were not statistically dependent on the age of the patients. mean blood loss, mean hospital stay, early postoperative complications such as excessive urinary leakage, average time for return to normal activity, ureteral stent removal time, success ureteral tapering in laparoscopic ureteral reimplantation—nouralizadeh et al 242 urology journal vol 7 no 4 autumn 2010 rate, and complete resolution of stricture in our study may be acceptable and comparable to other previous reports, but accurate comparison of these items is not rationale; because various types of surgery and etiology of stricture as well as different diameter of stricture seriously affect the final conclusion. the issue of refluxing versus antirefluxing anastomosis in ureteroneocystostomy in adults has been examined previously. in a retrospective review of adult patients with ureteroneocystostomy, similar to our results, no significant difference in the preservation of renal function or risk of stenosis was identified in the refluxing versus antirefluxing procedures.(14) although the intracorporeal tapering of distal ureter is technically accessible, but it requires a high level of laparoscopic expertise and further studies should be performed with long-term follow-up in greater number of patients to propagate this technique.(15,16) conclusion it seems that laparoscopic ureteroneocystostomy with intracorporeal ureteral tapering for management of obstructive megaureter is a feasible and reproducible option in patients with ureterovesical junction obstruction. longer follow-up period and larger series of patients are necessary for validation of this technique, especially in pediatric patients. conflict of interest none declared. references 1. ansari ms, mandhani a, khurana n, kumar a. laparoscopic ureteral reimplantation with extracorporeal tailoring for megaureter: a simple technical nuance. j urol. 2006;176:2640-2. 2. fugita oe, kavoussi l. laparoscopic ureteral reimplantation for ureteral lesion secondary to transvaginal ultrasonography for oocyte retrieval. urology. 2001;58:281. 3. tulikangas pk, goldberg jm, gill is. laparoscopic repair of ureteral transection. j am assoc gynecol laparosc. 2000;7:415-6. 4. basiri a, mohammad ali beigi f, abdi h, mahmoudnejad n. laparoscopic reimplantation for single-system ectopic ureter. urol j. 2007;4:174-6. 5. puntambekar s, palep rj, gurjar am, et al. laparoscopic ureteroneocystostomy with psoas hitch. j minim invasive gynecol. 2006;13:302-5. 6. lima gc, rais-bahrami s, link re, kavoussi lr. laparoscopic ureteral reimplantation: a simplified dome advancement technique. urology. 2005;66:1307-9. 7. agarwal mm, singh sk, agarwal s, mavuduru r, mandal ak. a novel technique of intracorporeal excisional tailoring of megaureter before laparoscopic ureteral reimplantation. urology. 2010;75:96-9. 8. liapis a, bakas p, giannopoulos v, creatsas g. ureteral injuries during gynecological surgery. int urogynecol j pelvic floor dysfunct. 2001;12:391-3; discussion 4. 9. seideman ca, huckabay c, smith kd, et al. laparoscopic ureteral reimplantation: technique and outcomes. j urol. 2009;181:1742-6. 10. rassweiler jj, gozen as, erdogru t, sugiono m, teber d. ureteral reimplantation for management of ureteral strictures: a retrospective comparison of laparoscopic and open techniques. eur urol. 2007;51:512-22; discussion 22-3. 11. kamat n, khandelwal p. laparoscopic extravesical ureteral reimplantation in adults using intracorporeal freehand suturing: report of two cases. j endourol. 2005;19:486-90. 12. symons s, kurien a, desai m. laparoscopic ureteral reimplantation: a single center experience and literature review. j endourol. 2009;23:269-74. 13. ogan k, abbott jt, wilmot c, pattaras jg. laparoscopic ureteral reimplant for distal ureteral strictures. jsls. 2008;12:13-7. 14. gao j, dong j, xu a, et al. a simplified technique for laparoscopic ureteroneocystostomy without ureteral nipple or submucosal tunneling. j endourol. 2007;21:1505-8. 15. piaggio la, gonzalez r. laparoscopic transureteroureterostomy: a novel approach. j urol. 2007;177:2311-4. 16. sahai a, symes aj, challacombe bj, glass jm, popert rj, dasgupta p. laparoscopic ureteroneocystostomy for benign lower ureteric stricture: case study and literature review. int j clin pract suppl. 2005;115-7. miscellaneous 188 urology journal vol 7 no 3 summer 2010 safety and efficacy of clomiphene citrate and l-carnitine in idiopathic male infertility a comparative study mahmoudreza moradi,1 asaad moradi,1 mohsen alemi,1 hassan ahmadnia,2 hossein abdi,1 alireza ahmadi,3 shahrzad bazargan-hejazi4 purpose: to compare the effects of l-carnitine with clomiphene citrate in idiopathic infertile men. materials and methods: fifty-two men with idiopathic infertility were recruited in this randomized controlled trial. they were randomly assigned into 2 treatment groups, group 1 (n = 20) and group 2 (n = 32), who received l-carnitine 25 mg/day and clomiphene citrate 2 gr/day, respectively, for a period of 3 months. results: comparing the effect of l-carnitine and clomiphene on sperm parameters before and after the treatment, both medications had influence on sperm count and motility (p = .01). l-carnitine significantly increased the semen volume (p = .001), while clomiphene citrate was significantly associated with the motility percentage and normal morphology (p = .008). conclusion: it seems that the use of clomiphene citrate and l-carnitine, either individually or in combination, as the first step of idiopathic male infertility treatment is reasonable, safe, and effective. urol j. 2010;7:188-93. www.uj.unrc.ir keywords: semen parameters, male infertility, randomized controlled trial 1fertility-infertility research center, urology and nephrology research center, imam reza hospital, kermanshah university of medical sciences, kermanshah, iran 2department of urology, mashhad university of medical sciences, mashhad, iran 3department of anesthesiology, imam reza hospital, kermanshah university of medical sciences, iran-department of public health sciences, division of social medicine, karolinska institute, stockholm, sweden 4department of psychology, college of medicine, charles drew university of medicine and science, david geffen school of medicine, ucla, los angeles, ca, usa corresponding author: mahmoudreza moradi, md fertility-infertility research center, imam reza hospital, kermanshah university of medical sciences, iran tel: +98 918 132 4811 fax: +98 831 725 9983 e-mail: drmrmoradi@yahoo.com received july 2009 accepted november 2009 introduction infertility is considered as one of the most important issues among married couples. according to the current statistics, about 15% of married couples face with infertility at the end of the first year of their marriage, with male gender implicated in 20% of these cases. other evidence shows that in 30% to 40% of infertile cases, both man and woman play a role.(1) a male factor, therefore, plays a 50% role in the etiology of infertility.(2) idiopathic male infertility (imi), with a prevalence of approximately 25%, is a condition where abnormal semen parameters are obtained due to non specific causes. in the majority of cases, abnormal semen parameters leads to diagnosis of oligoasthenoteratospermia, and in others, it leads to isolated abnormalities of sperm concentration, motility, and morphology. due to the lack of differentiable or correctable etiology, patients with imi are often treated by varieties of empirical medications or assisted reproductive technologies. however, the meta-analysis of controlled trials on patients with imi has revealed that, with a few exceptions, the majority of the trials failed to show the efficacy of treatments. yet, due to obtained success among small number of clomiphene and/or carnitine for male infertility—moradi et al 189urology journal vol 7 no 3 summer 2010 patients with imi, efforts in medication therapy and technology assisted management of imi continue.(2) clomiphene citrate, as an anti-estrogen, is the most common prescribed medication for male infertility. however, l-carnitine, which is known to improve semen’s parameters, has recently been recognized as the most effective medication. l-carnitine molecule controls the transport of acetyl and acyl groups across the mitochondrial inner membrane and is an essential agent for mitochondrial metabolism. although the exact function of l-carnitine and acetylated carnitine in the epididymis, where these agents are found in high concentration, is not entirely known, but they seem to have a protective ability against oxidative damages. both l-carnitine and l-acetyl-carnitine are available as over-thecounter medications in the form of nutritional supplements for the treatment of imi.(2) the anti-estrogenic role of clomiphene citrate and the therapeutic role of l-carnitine in treatment of infertility are well documented;(3-7) however, literature reveals a paucity of research comparing treatment outcome of clomiphene citrate and l-carnitine in infertile men. the specific aim of this study was to compare treatment outcome of l-carnitine with the standard treatment, clomiphene citrate, in infertile men with oligoasthenoteratospermia. materials and methods this randomized longitudinal study was carried out on 107 patients who presented with idiopathic infertility to the urology clinics of kermanshah university of medical sciences between january 2006 and january 2008. of 107 patients, those who met the following inclusion criteria of: 1) a history of infertility for at least one year 2); and semen parameter abnormalities, including sperm concentration or count less than 20 × 106 spermatozoa/ml, motility less than 50% with grade “a + b” or 25% with grade “a”, and morphology less than 50%, for which no specific causes were identified, were enrolled in this study. then, a written informed consent was obtained from each patient. on the other hand, patients who presented with symptoms of hypogonadism or sperm count less than 10 million/ml, and/or any hormonal disorder detected by hormonal tests, including testosterone, prolactin, luteinizing hormone (lh), and follicle-stimulating hormone (fsh) were excluded from the study. furthermore, patients with an inguinal operation, infectious or venereal diseases, testicular atrophy, hypogonadism, varicocele, and disorders of the vas deferens and the epididymis were also excluded from the study. the study protocol was approved by the ethics committee of kermanshah university of medical sciences. the remaining 52 patients were randomly assigned into 2 groups in a double blind manner by the sealed opaque envelope technique; group 1 (n = 20) and group 2 (n = 32) who received clomiphene citrate 25 mg/day (tab. 50 mg/iran hormone co.) and l-carnitine 2 gr/day (tab. 250 mg/shahre daru co.), respectively, for 3 months. post treatment semen analyses were performed twice, within a window period of 5 days, for all the subjects who completed the 3-month treatment, to increase the accuracy of the test results and reduce test bias. the mean score for semen parameters analysis was calculated for each participant in both treatment groups. using paired sample t test, parameters, including sperm count, semen volume, motility, and morphology were compared between two groups before and after the treatment assignments. using an independent sample t test, post treatment semen measures of the subjects in both treatment groups were compared with each other. these tests allowed us to see if there were any detectable differences between the means of the study measures between and across the groups, and if the differences were statistically significant. all statistical analyses were performed using spss software (statistical package for the social science, version 14.0, spss inc, chicago, illinois, usa). results the mean age of the patients was 28.46 ± 2.67 years (range, 22 to 35 years). of a total of 52, clomiphene and/or carnitine for male infertility—moradi et al 190 urology journal vol 7 no 3 summer 2010 32 patients with the mean age of 28.44 ± 2.34 years (range, 22 to 35 years) and 20 patients with the mean age of 28.5 ± 3.21 years (range, 26 to 31 years) were treated by clomiphene citrate and l-carnitine, respectively. the mean period of infertility was 2.98 ± 4.11 years (range, 1 to 14 years) for all the patients; 3.12 ± 3.52 years (range, 1 to 7 years) in clomiphene citrate group and 2.87 ± 4.7 years (range, 1 to 14 years) in l-carnitine group. table compares changes of the semen parameters before and after the treatment with clomiphene citrate and l-carnitine. in clomiphene citrate group, the average values of semen volume, sperm counts, motility percentage, and normal morphology before the treatment were 3.21 ± 1.3 ml, 20.38 ± 16.2 million/ml, 23.78 ± 17.5%, and 45.06 ± 20.8%, respectively, which changed to 3.36 ± 1.3 ml, 42.51 ± 29.4 million/ ml, 43.38 ± 20.1%, and 58.44 ± 19.3% after the treatment. our results revealed that clomiphene citrate had considerable influence on sperm count, morphology, and motility (p = .01), but not much effect on the semen volume (p = .57). in l-carnitine group, the average values of semen volume, sperm counts, motility percentage, and normal morphology before the treatment were 2.50 ± 1.2 ml, 44.75 ± 18.1 million/ml, 38.82 ± 15.5%, and 48.40 ± 37.9%, respectively. after the treatment, these parameters altered to 4.03 ± 0.8 ml, 73.25 ± 18.5 million/ml, 48.03 ± 19.7%, and 49.45 ± 32.2%. there was a statistically significant association between l-carnitine and semen volume, sperm count, and motility (p = .01), but not with the sperm morphology (p = .698). comparing the effect of l-carnitine and clomiphene on sperm parameters before and after the treatment, both had influence on sperm count and motility (p = .01). the effect on sperm counts was not significant (p = .376). l-carnitine significantly increased the semen volume (p = .001), while clomiphene citrate was significantly associated with the motility percentage and normal morphology (p = .008). discussion clomiphene citrate is one of the most common experimental medications used for treatment of idiopathic infertility. as an anti-estrogen, clomiphene citrate links to the receptors of estradiol in the hypothalamus and stimulates the gonadotropin secretion. anti-estrogens increase the pituitary gonadotropin secretion by blocking feedback inhibition, thus, increasing both serum fsh and lh levels as well as the testicular production of testosterone. clomiphene citrate with the dosage of 25 mg per day is the standard recommended treatment for imi. higher doses of clomiphene citrate, however, may cause downregulation of the system.(1,2) in the present study, we anticipated noticing an overall improvement in the sperm count, semen volume, motility percentage, and morphology in the group receiving l-carnitine p l-carnitineclomiphene citrate parameters after treatmentbefore treatmentafter treatmentbefore treatment = .01* = .01† = .376‡ 73.25 ± 18.544.75 ± 18.142.51 ± 29.420.38 ± 16.2sperm count = .57* = .01† = .001‡ 4.03 ± 0.82.50 ± 1.23.36 ± 1.33.21 ± 1.3semen volume = .01* = .01† = .008‡ 48.03 ± 19.738.82 ± 15.543.38 ± 20.123.78 ± 17.5motility = .01* = .698† = .008‡ 49.45 ± 32.248.40 ± 37.958.44 ± 19.345.06 ± 20.8morphology comparison between changes of the semen parameters before and after the treatment with clomiphene citrate and l-carnitine *clomiphene citrate †l-carnitine ‡comparison of two drugs with each other clomiphene and/or carnitine for male infertility—moradi et al 191urology journal vol 7 no 3 summer 2010 compared to the group that received clomiphene citrate. comparing baseline measures of semen parameters with that of the follow-ups, our data showed an increase in the sperm motility and count in both groups; clomiphene citrate and l-carnitine (p = .01). however, no meaningful association was observed between semen volume and clomiphene citrate (p = .57) as well as morphology and l-carnitine (p = .698). this finding is not compatible with the finding of mićić and colleagues.(8) they randomly divided 101 patients with a history of 2-year infertility into 2 groups. fifty-six patients received 50 mg/ day clomiphene citrate for 6 to 9 months and 45 patients as the control group received no medication. in that study, sperm parameters such as semen volume and sperm motility were treated with clomiphene citrate compared to the control group (p ≤ .05).(8) khademi and coworkers studied 48 smokers and 122 non-smokers with abnormal sperms after receiving l-carnitine 3 times per day for 3 months. they observed that l-carnitine was effective in improving sperm mobility percentage, grade a sperms, and normal-shaped sperms. improvements in the non-smokers were even more noticeable. they concluded that a smoker should not be excluded from the treatment with l-carnitine.(6) in the study by cavallini and colleagues,(7) the effect of cinnoxicam supplement and l-carnitine on idiopathic infertility and varicocele was examined in 3 groups: placebo group; l-carnitine (2 gr/day) + acetyl-l-carnitine (1 gr/day) group; and l-carnitine + cinnoxicam (30 mg) group. after 6 months, sperm count, sperm motility and morphology, the amount of fertility (pregnancy rate), and complications were recorded. in placebo group, no change was observed in sperm parameters. in the group that received l-carnitine + acetyl-l-carnitine, sperm parameters increased significantly at 3 and 6 months in idiopathic infertile patients with minor varicoceles, but no improvement was observed in idiopathic infertile patients with severe varicoceles. but all the patients in group 3 had significantly increased sperm parameters with the exception of very severe varicoceles. pregnancy rates were 1.7% (group 1), 21.8% (group 2), and 38.0% (group 3) (p ≤ .01). cavallini and colleagues concluded that combination of l-carnitine and cinnoxicam could be a reliable treatment for low-grade varicoceles and idiopathic oligoasthenospermia.(7) in spite of positive effect of l-carnitine on sperm motility in the present study, sigman and colleagues did not find such statistically significant association.(9) sigman and coworkers compared the effects of l-carnitine, ie, 2000 mg/day l-carnitine and 1000 mg/day l-acetylcarnitine for 24 weeks, with placebo on idiopathic asthenospermic patients. sperm motility and the number of mobile sperms were measured at the baseline, 12 weeks, and 24 weeks post treatment. no statistically or clinically significant differences were found between the two groups at any of the measured points.(9) however, our results regarding the effect of clomiphene citrate and l-carnitine on the sperm count and sperm motility are consistent with several studies.(3-7) in the study by patankar and colleagues,(3) clomiphene citrate 25 mg/day was administered for 2 groups for 25 days, including 5 days resting period for duration of 3 months. first group included 25 men with extreme oligospermia and the second group composed of 40 men with moderate oligospermia. results of seminal fluid analysis at the end of the treatment period were as follows: the mean sperm count in the first and second group increased from 3.84 to 8.2 million/ml and from 13.05 to 24.55 million/ml, respectively. the mean motile sperms in the first group increased from 1.74 to 3.92 and in the second group from 8.27 to 10.05. the researchers concluded that the medication was more effective when there was no end-organ pathology.(3) zhou and associates in a systematic review of 9 studies reported the effects of l-carnitine on male infertility. the meta-analysis compared l-carnitine and/or l-acetyl-carnitine therapy with placebo treatment. they found significant improvement in pregnancy rate, total sperm motility, forward sperm motility, and atypical sperm cell.(5) in a study including 30 men with oligospermia, rönnberg observed that in the group who received clomiphene citrate 50 mg clomiphene and/or carnitine for male infertility—moradi et al 192 urology journal vol 7 no 3 summer 2010 per day for 3 months, the average sperm count increased from 13.3 to 28.5 million/ml (p ≤ .05). moreover, in clomiphene citrate group, 3 cases of pregnancy were observed; while none were observed in the control group.(4) still others claim that there is yet no acceptable empirical treatment for imi. (9-11) reviewing 20 years of medication therapies for imi, kumar and colleagues found no clear advantage for any of the medications used by the patients. (11) vandekerckhove and associates reviewed 10 studies consisting of 738 infertile men, to evaluate the effect of anti-estrogens like clomiphene citrate and tamoxifen on idiopathic oligoasthenospermia. they concluded that anti-estrogens appeared to have a beneficial effect on endocrines, but there was not enough evidence to evaluate the use of anti-estrogens for increasing the fertility of men with idiopathic oligoasthenospermia.(10) limitations and future directions we view this to be an incipient project and recognize its limitations. small sample size with limited statistical power, lack of placebo group, failing to consider pregnancy rate as the ultimate measure of treatment outcome, and short-term follow-up period (3 months) were the flaws of this study. however, to the best of our knowledge, it is amongst the first studies that has compared the effect of clomiphene citrate and l-carnitine regarding semen parameters abnormalities in idiopathic infertile men. l-carnitine in this study had a significant effect on improving semen parameters; it has few sideeffects and seems to be an appropriate choice for idiopathic infertile men when taken in combination with clomiphene citrate. therefore, findings of this study are encouraging enough to stimulate further similar investigations to expand our findings with the use of larger samples, inclusion of placebo/control group, and consideration of pregnancy rates as the ultimate treatment outcome measure. conclusion clomiphene citrate and l-carnitine are among the most administered, available, and effective medications for male infertility, while offering fewer complications. results of this study suggest that the treatment outcome of clomiphene citrate and l-carnitine on the sperm count is nearly equal. however, the effect of l-carnitine on the semen volume is more meaningful than clomiphene citrate (p = .001) and the effect of clomiphene citrate on motility and morphology is more meaningful than l-carnitine (p = .008). it seems that the use of clomiphene citrate and l-carnitine, either individually or in combination, as the first step of idiopathic male infertility treatment is reasonable, safe, and effective. acknowledgement the authors would like to thank all who participated in this study. financial support for this project was provided by kermanshah university of medical sciences. conflict of interest none declared. references 1. guyton ac, hall je. textbook of medical physiology. philadelphia: wb saunders; 2000:996-1009. 2. sigman m, jarow jp. male infertility. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campell-walsh urology. vol 1. philadelphia: saunders 2007:609-53. 3. patankar ss, kaore sb, sawane mv, mishra nv, deshkar am. effect of clomiphene citrate on sperm density in male partners of infertile couples. indian j physiol pharmacol. 2007;51:195-8. 4. rönnberg l. the effect of clomiphene citrate on different sperm parameters and serum hormone levels in preselected infertile men: a controlled double-blind cross-over study. int j androl. 1980;3:479-86. 5. zhou x, liu f, zhai s. effect of l-carnitine and/ or l-acetyl-carnitine in nutrition treatment for male infertility: a systematic review. asia pac j clin nutr. 2007;16 suppl 1:383-90. 6. khademi a, alleyassin a, safdarian l, hamed ea, rabiee e, haghaninezhad h. the effects of l-carnitine on sperm parameters in smoker and non-smoker patients with idiopathic sperm abnormalities. j assist reprod genet. 2005;22:395-9. 7. cavallini g, ferraretti ap, gianaroli l, biagiotti g, vitali g. cinnoxicam and l-carnitine/acetyl-l-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia. j androl. 2004;25:761-70; discussion 71-2. clomiphene and/or carnitine for male infertility—moradi et al 193urology journal vol 7 no 3 summer 2010 8. mićić s, dotlić r. evaluation of sperm parameters in clinical trial with clomiphene citrate of oligospermic men. j urol. 1985;133:221-2. 9. sigman m, glass s, campagnone j, pryor jl. carnitine for the treatment of idiopathic asthenospermia: a randomized, double-blind, placebocontrolled trial. fertil steril. 2006;85:1409-14. 10. vandekerckhove p, lilford r, vail a, hughes e. clomiphene or tamoxifen for idiopathic oligo/ asthenospermia. cochrane database syst rev. 2000;cd000151. 11. kumar r, gautam g, gupta np. drug therapy for idiopathic male infertility: rationale versus evidence. j urol. 2006;176:1307-12. unclassified urology journal/vol 20 no. 4/ july-august 2023/ pp. 261-267. [doi:10.22037/uj.v20i.7734] n-butyl cyanoacrylate glue versus nonspherical polyvinyl alcohol particles for prostatic arterial embolization to treat benign prostatic hyperplasia: safety and efficacy bilal ahmad hijazi1,2*, hai-bin shi1, sheng liu1, turki atia alqurashi2, zakir jamal sabri2 purpose: our aim is to compare n-butyl cyanoacrylate (nbca) glue and non-spherical polyvinyl alcohol (pva) particles for prostatic artery embolization (pae) for patients with benign prostatic hyperplasia (bph) to treat lower urinary tract symptoms (luts) and report their feasibility, safety, and short-term effectiveness. materials and methods: 110 patients (mean age: 72.6 years) with bph related to luts were divided into two groups, pae was performed in one group with 250 355 μm non-spherical pva particles. whereas, the other group received a mixture of nbca glue/ lipiodol for pae. results: pae was technically successful in all 110 patients (100 %). during 6 months follow up, we found that in patients who received nbca glue, the mean of prostatic volume (pv) was significantly reduced compared to baseline (67.1 ± 8.5 to 40.2 ± 5.4), international prostate symptom score (ipss) (25.7 ± 4.3 to 7.2 ± 1.09), quality of life (qol) (4.43 ± 0.27 to 1.58 ± 2.27); whereas, the mean of peak urinary flow (qmax) increased significantly from baseline to 6 months (8.6 ± 2.3 to 15.4 ± 2.3), international index of erectile function (iiefs) (9.46 ± 1.51 to 19.3 ± 1.33). meanwhile, non-spherical pva particles used in the other group show that pv significantly reduced from baseline to 6 months (68.2 ± 8.32 to 38.8 ± 6.13), ipss (25.0 ± 3.59 to7.24 ± 0.83), qol (4.43 ± 0.24 to1.56 ± 0.55). the mean for qmax increased from baseline to 6 months (7.19 ± 1.67 to15.1 ± 2.42), iiefs (9.22 ± 1.30 to 19.5 ± 0.96). conclusion: pae with nbca glue and non-spherical pva particles is feasible, safe, and effective for patients with bph related-luts. this gives the physicians options to choose between embolizing agents based on the architecture of the prostatic artery. keywords: lower urinary tract symptoms; benign prostate hyperplasia; prostate artery embolization; ncba glue; non-spherical polyvinyl alcohol introduction benign prostate hyperplasia (bph) is one of the most frequent conditions affecting the male genitourinary system, and results in lower urinary tract symptoms (luts), including a feeling of incomplete emptying, hesitancy, reduced urine stream, urinary frequency, and nocturia. it is common in males over 50 years of age.(1) those with moderate-to-severe luts may benefit from 5-α-reductase inhibitors or combination therapy (5 -α-reductase inhibitors plus α-blocker). (2,3) this log-term treatment can be useful, but has side effectssuch as erectile dysfunction, impotence, and reduced libido.(4,5) yet, there will always be patients whose treatments fail. transurethral resection of the prostate (turp) surgery is the gold-standard therapy for bph.(6) other minimal invasive options include transurethral microwave therapy (tumt), and transurethral needle ablation (tuna). nevertheless, can have side effects such as retrograde ejaculation, impotence, and bleeding.(7) the pae has early and midterm outcomes in lowering 1department of interventional radiology, jiangsu province hospital, the first affiliated hospital nanjing medical university, people's republic of china. 2department of imaging & interventional radiology, king abdulaziz hospital and research center, ksa. *correspondence: department of interventional radiology, jiangsu province hospital, the first affiliated hospital nanjing medical university, people's republic of china. e-mail: shihb@njmu.edu.cn. received march 2023 & accepted june 2023 luts and enhancing qol.(8) furthermore, it has been determined that pae, is safer and more successful than turp because of less blood loss and a shorter hospital stay.(9) the majority of investigations rely on the free-flow injection of non-spherical pva with a diameter of 300 – 500 μm. nbca has a high level of attention among interventional radiologists due to its favorable effectiveness and biological toleration. particularly noteworthy is the outstanding effectiveness nbca has demonstrated in reducing active bleeding from peripheral arteries. (10) nbca is a liquid that polymerizes when it comes in contact with ion-rich fluids like blood.(11,12) due to its excellent tension resistance and bacteriostatic and hemostatic properties, it is one of the most widely used tissue adhesives.(13) fast hemostasis is made possible by quick polymerization, which is very helpful in patients with hemodynamic instability. in narrow or tortuous arteries that are challenging to catheterize, nbca facilitates distal embolization by a flow-directed technique because of its liquid state.(14) nbca and commonly used non-spherical pva particles are two types of embolic agents that have not yet been the subject of any studies comparing their effects on pae outcomes. our study's objective was is to compare the feasibility, safety, and short-term effectiveness of nbca glue and non-spherical pva particles as embolic agents for pae in patients with symptomatic bph. materials and methods study population the study received approval from the hospital's ethical committee. urologists reviewed each patient and offered them other treatment options, such as turp. 110 patients from two groups of a tertiary center received pae who were presented with luts due to bph between july 2019 and june 2021. their age ranged from 54 to 90 years; the mean was (72.6 years). inclusion criteria were luts due to bph resistance to medical therapy for > 6 months, prostate volume (pv) > 30 ml, ipss ≥ 18 points, qol score ≥ 3, qmax ≤ 12 ml/s. the exclusion criteria included malignancy (determined by prostate specific antigen (psa), digital rectal examination, transrectal ultrasound (trus) biopsy, and mri in all patients), chronic renal failure, and any urinary issue unrelated to bph. pelvic mri was used as part of the standard diagnostic process for bph to measure the volume of the prostate. the prostate is examined by mri with a 1.5-t or 3-t magnetic field intensity. t2-weighted sequences are used to measure the whole prostatic dimensions. computing the prostate volume using the equation (transverse diameter x anteroposterior diameter x craniocaudal diameter x .52). the sample size was determined based on the specific objectives of our study. we aimed to detect meaningful and clinically relevant effects or associations within the scope of our research question. the sample size calculation took into account the desired statistical power to detect these effects, as well as the expected effect sizes or differences. we also considered practical and logistical constraints when determining the sample size. this included factors such as the availability of eligible participants, resources required for data collection and analysis, and the time frame of the study. procedures all patients stopped using their bph medications, and prophylactic antibiotics were given. an experienced interventional radiologist utilized the high-resolution digital subtraction angiography suit (axiom artis; siemens, erlangen, germany) to perform pae. under local anesthetic, right unilateral femoral technique was used for pae. initially, a pelvic angiography was done to assess the internal iliac and prostatic arteries. then, 5-f angiographic cobra catheter (yashiro catheter; terumo, tokyo, japan) was used in the anterior-posterior (ap), ipsilateral 35° oblique, and caudal-cranial angulation of -10° views with non-ionic contrast media (iomeron 350; bracco, milan, italy) to achieve selected bilateral internal iliac arteriograms. prostatic arteriography was carried out in the ap projection and catheterization of super-selective prostatic arteries done by using a 2.0-f microcatheter (progreat; terumo, tokyo, japan) and a 0.014-inch guide wire (transcend; boston scientific, natick, usa). prostatic arteries are embolized using the (perfected method) to near stasis after passing all collateral arteries, then navigated further into the parenchymal branches and embolized to complete stasis. one group of patients underwent embolization using a microcatheter positioned inside the feeding artery, 250 355μm non-spherical pva particles (contour; boston scientific, natick, usa) diluted in 20 ml of normal saline and 30 ml of contrast medium in a 2: 3 solutions, and the particles were gradually injected slowly until they reached an endpoint of near stasis of contrast agent (figure 1). while in the other group, once the microcatheter was positioned within the supplying artery, 2 mg of isosorbide dinitrate (risordan, 10 mg/10 ml vial) was given intra-arterially to cause vasodilation. to create the substance radio-opaque, nbca glue (glubran 2, gem; viareggio, italy) was diluted with iodized oil (lipiodol ultra fluid; guerbet; aulnay-sous-bois, france). two 5 ml luer-lock syringes with a homogenous nbca lipiodol combination were used for the injection. to improve the fluidity of the mixture and enable distal embolization, a high nbca dilution of 1 : 8 was used. effectiveness was observed (figure 2). the procedure was declared successful when embolic maname range age, years 54-90 iief score 6.4-11.78 ipss score 18.04-35.89 mri prostate volume, ml 50.12-83 psa, ng/ml 4.2-9.87 qmax, ml/s 2.4-9.95 qol score 4-5.03 table 1. baseline characteristics. abbreviations: mri, magnetic resonance imaging; ipss, international prostatic symptoms score; qmax, maximum urinary flow rate; psa, prostate-specific antigen; qol, quality of life; iiefs, international index of erectile function score. name min max median iqr age, years 54 90 73 17 mri prostate volume, ml 50.12 83 68.798 13.003 ipss score 18.04 35.886 24.685 5.286 qmax, ml/s 2.4 9.95 7.25 2.299 psa, ng/ml 4.2 9.867 6.917 1.625 qol score 4 5.03 4.4 0.377 iief score 6.4 11.78 9.607 2.238 abbreviations: iqr, interquartile range; mri, magnetic resonance imaging; ipss, international prostatic symptoms score; qmax, maximum urinary flow rate; psa, prostate-specific antigen; qol, quality of life; iiefs, international index of erectile function score. table 2. summary statistics of clinical parameters for patients with benign prostate hyperplasia. effect of embolizing agents for bph-hijazi et al. unclassified 262 terials embolized prostatic artery with complete stasis. evaluations data was gathered prior to pae (baseline) and follow-up visits at three and six months following pae. the ipss questionnaire has been used to evaluate clinical symptoms. scores on the ipss questionnaire can range from 0 to 35 (scores of 7 indicate mild symptoms, 8 indicate moderate symptoms, and 20 indicate severe symptoms). the ipss score change between the baseline and 6-month visit served as the primary endpoint. the international index of erectile function form 5 (iief5, with scores ranging from "0, worst," to "25, best"), prostate volume was measured by magnetic resonance imaging and/or ultrasound were considered secondary endpoints. both clinical successes defined as qol score < 3 and technical success defined as total occlusion of at least one vascularizing prostate artery were assessed. minor problems were seen after pae and examined in accordance with the quality improvement standards for percutaneous transcatheter embolization, but no substantial issues were observed in this investigation. statistical analysis statistical analyses were performed using r 4.2.2 (r foundation for statistical computing, vienna, austria). we performed shapiro-wilk or kolmogorov-smirnov tests to assess the normality assumption for each group within the independent variables. independent measurement data were analyzed using two-way anova, with factors a and b, followed by post-hoc pairwise comparisons using tukey's test. non-independent measurement data was processed using the friedman m test, followed by post-hoc pairwise comparisons using the conover-iman test. the bonferroni correction was used to adjust pairwise comparisons. for independent count data, if the theoretical frequency was between 1 and 5 and did not exceed 1 / 5, the r*c chi-square test was used for overall comparison, followed by pairwise comparisons using the adjusted standardized residuals test, but fisher's exact test is generally recommended when the sample size is small, typically with expected cell counts below 5. otherwise, the fisher exact probability method was used for overall comparison, followed by pairwise comparisons using the adjusted standardized residuals test. non-independent count data were compared using the paired chi-square test, followed by pairwise comparisons using the adjusted standardized residuals test. all tests with significance were accepted at p ≤ .05. results study population a total of 125 consecutive patients were evaluated for eligibility, among them 11 falls under exclusion criteria, whereas 4 refused to participate, and the remaining 110 patients were treated with pae. 54 patients were treated with nbca glue, and the rest 56 patients underwent non-spherical pva particles as shown in the flow chart (figure 3). technical success pae was technically successful in all 110 patients (100%). we performed bilateral pae in 109 patients (99%) and unilateral pae in one patient because of unilateral agenesis or atherosclerotic occlusion of the prostatic artery. patients characteristics range values are summarized in (table1), min, max, median, and interquartile range (iqr) were shown in (table 2), the mean ± sd values of the baseline group are shown in (table 3). the changes in values before and after pae are shown in (table 4). in this table, the mean of prostate volume in baseline group was 67.1 ± 8.5, and after nbca glue embolization, pv values significantly decreased after three and six months, their values were 56.1 ± 7.79 and 40.2 ± 5.4 respectively. on the other hand, by using the non-spherical pva particles the mri also showed pv to have significantly decreased values from baseline 68.2 ± 8.32 to 50.7 ± 7.48 and 38.8 ± 6.13 at three and six months respectively. clinical success the ipss showed to have a decline in its score after usage of nbca glue for pae, as the mean values for the ipss score in the baseline group before nbca glue exposure 25.7 ± 4.3 while after nbca glue, it was found to be 15.5 ± 2.3 and 7.2 ± 1.08 after three and six months respectively. also, the same effect of non-spherical pva particles was observed on the ipss score as it showed that before exposure to non-spherical pva particles, the ipss score was 25.0 ± 3.5 which decreased after non-spherical pva particles exposure with values 16.0 ± 2.40 and 7.24 ± 0.81 after three and variables descriptive (mean ± s.d) age, years 72.6 ±10.5 embolic: nbca glue 54 ± 49.1 non-spherical pva 56 ± 50.9 mri prostate volume, ml 68.2 ± 8.39 ipss score 25.3 ± 3.93 qmax, ml/s 7.09 ± 1.75 psa, ng/ml 6.95 ± 1.40 qol, score 4.43 ± 0.25 iief, score 9.34 ± 1.41 table 3. multivariable analysis of baseline characteristics. abbreviations: nbca, n-butyl cyanoacrylate; pva, polyvinyl alcohol; mri, magnetic resonance imaging; ipss, international prostatic symptoms score; qmax, maximum urinary flow rate; psa, prostate-specific antigen; qol, quality of life; iiefs, international index of erectile function score. nbca glue non-spherical pva characteristics baseline 3 months 6 months p-value baseline 3 months 6 months p-value pv, ml 67.7 ± 8.5 56.7 ± 7.9 40.2 ± 5.4 < .0001 68.2 ± 8.3 50.7 ± 7.4 38.8 ± 6.1 < .0001 ipss 25.7 ± 4.3 15.5 ± 2.3 7.2 ± 1.09 < .0001 25.0 ± 3.5 16.0 ± 2.4 7.2 ± 0.81 < .0001 q max, ml\s 8.6 ± 2.3 8.6 ± 2.3 15.4 ± 2.3 < .0001 7.19 ± 1.6 8.40 ± 1.9 15.1 ± 2.4 < .0001 qol score 4.43 ± 0.2 2.3 ± .4 1.5 ± 2.27 < .0001 4.43 ± 0.2 2.38 ± .4 1.56 ± 0.55 < .0001 iief score 9.4 ± 1.5 14.5 ± 1.1 19.3 ± 1.3 < .0001 9.22 ± 1.3 14.7 ± .9 19.5 ± 0.96 < .0001 abbreviations: pv, prostate volume; ipss, international prostatic symptoms score; qmax, maximum urinary flow rate; qol, quality of life; iiefs, international index of erectile function score. table 4. comparison of clinical responses at 3 time points between the two embolic agent groups. effect of embolizing agents for bph-hijazi et al. vol 20 no 4 july-august 2023 263 six months respectively. the qmax showed significant improvement, the mean qmax value was 8.6 ± 2.3 at baseline group and after using nbca glue, it was 8.6 ± 2.3 at three months and 15.4 ± 2.3 at six months. the same improvement was found after non-spherical pva particles, the values of qmax was at baseline 7.19 ± 1.67, and after injecting non-spherical pva particles it was 8.40 ± 1.98, 15.1 ± 2.42 after three and six months respectively. in addition, the mean values for qol score improved for patients who received nbca glue from baseline 4.43 ± .27 to 2.30 ± 0.36 and to 1.58 ± 2.27 after three and six months respectively. the same improvement was found after using non-spherical pva particles for embolization, as qol scores were improved from 4.43± 0.24 as baseline to 2.38 ± .40 and 1.56 ± 0.55 after three and six months. finally, the iiefs mean values significantly increased after using both nbca glue and non-spherical pva particles, the values that were found were 9.46 ± 1.51 as baseline, then 14.5 ± 1.07 and 19.3± 1.33 after three and six months respectively post nbca glue, also the iiefs values post non-spherical pva particles used were 14.7 ± .96 and 19.5 ± .96 after three months and six months and baseline was 9.22 ± 1.30. then, we want to investigate whether or not this shortterm treatment can induce a significantly greater increase in clinical observation through measurement over time. the result analysis showed that the prostate volume decreased considerably after patients received non-spherical pva particles when compared with patients who received nbca glue (figure 2a). while other characteristics, such as ipss, qmax, qol, and iiefs values had no significant changes after using nbca glue and nonspherical pva particles (figure 2 b e). no major complications were noted in this study, there was a minor complication with mild penile pain in three patients which disappeared spontaneously the day after the symptom occurred without the need for further treatment. figure 1. arteriographic images of 77-year-old patient with lower urinary tract symptoms associated with benign prostatic hyperplasia who underwent bilateral prostatic artery embolization. (a) selective catheterization demonstrating the prostate gland before embolization. (b) prostatic artery angiogram after embolization using non-spherical pva. using 250 355 μm non-spherical pva particles. figure 2. example of prostate artery embolization (pae) with n-butyl cyanoacrylate glue in a 81-year-old patient with symptomatic benign prostatic hyperplasia. (a) left prostatic artery angiogram before pae showing enhancement of the left prostatic lobe. (b) follow-up angiogram after pae with a mixture of glubran®2/lipiodol in a 1:8 ratio showing total occlusion. effect of embolizing agents for bph-hijazi et al. unclassified 264 discussion the introduction of pae to relieve from luts and decrease the gland volume without surgery is a major breakthrough. demeritt et al.(15) reported prostatic volume reduction and improvement of luts after treatment of prostatic hemorrhage with pae. while carnevale et al.(16) reported the first instance of pae, especially for the treatment of bph in two patients who had volume reductions of 47.8 % and 27.8 %. the following research revealed a range of mean prostatic volume reductions, ranging from 18% to 32 %(3). bagla et al.(17) reported early results from a u.s. trial of pae in 2014. bilateral pae was successful in 18 of figure 3. flow chart of the study design. figure 4. difference of embolic agent: (a) mri difference before and after nbca glue and non-spherical pva embolic agents treatments, (b) ipss difference before and after nbca glue and non-spherical pva embolic agents treatments, ( c) qmaxdifference before and after nbca glue and non-spherical pva embolic agents treatments,(d) qol difference before and after nbca glue and non-spherical pva embolic agents treatments, (e) iiefs difference before and after nbca glue and non-spherical pva embolic agents treatments. effect of embolizing agents for bph-hijazi et al. vol 20 no 4 july-august 2023 265 19 patients in their cohort without any complications. clinical success was found in 19 of 20 patients with significant improvement of ipss and qol. pv was decreased by 18% at 6 months. in our study, there was a significant decrease in total prostatic volume, ipss, and qol values by using non-spherical pva particles and nbca glue after 3 and 6 months follow up and it was found that the prostatic volume had a much more reduction after 6 month of treatment compared with the baseline values. on the other hand, the mean for qmax and iiefs significantly increased after patients received non-spherical pva and nbca glue compared with baseline values after 6 months of treatment. yet, it is unknown what kind of embolic agent is best. non-spherical pva particles were utilized in animal experimental research confirming the effectiveness and safety of pae(3). the utilization of non-spherical pva particles with a diameter of 250 – 355 μm has been proven in further research(18). although jeon et al.(9) claimed that non-spherical pva particles may have superior effects in pae with deeper penetration into the periphery, anastomosis between the prostatic arteries and nearby arteries raises concerns for non-target embolization(19). using appropriate embolizing agents such as non-spherical pva particles through perfected technique has promising results, as acclaimed by carnevale et al.(8) in 2014, overall immediate technical success of pae was 100 %, and perfected technique was feasible in 68 % of patients. there were significant improvements in ipss, qol, qmax, and pv compared with baseline values. there were no major complications. the same we have observed in our study, there was a significant decrease in total prostatic volume, ipss, and qol values by using non-spherical pva particles as well as the mean for qmax and iiefs significantly increased. nbca has several benefits, yet a significant number of interventional radiologists are reluctant to use it, due to a lack of skill and steep learning to use glue for peripheral endovascular applications like pae. the major benefit of nbca is the quicker procedure compared to particle embolization, which cuts down on the amount of time needed for fluoroscopy and, thus, the radiation exposure to the patient. in our investigation, the entire combination injection time was less than 40s, and the whole fluoroscopy time was under 30 min. a further benefit of nbca is the quick polymerization from surface to core, which prevents the opening of pre-existing vascular anastomosis, an occurrence reported with particles, and may reduce the risk of non-target embolization(18). furthermore, because polymerization upon interaction with blood anions is independent of coagulation function, nbca may be more effective than other embolic agents in patients with coagulopathy(21). additionally, a greater chance of adverse events is linked to smaller embolic particle size(15). other benefits of nbca / lipiodol are numerous. compared to other embolic materials that cannot be seen directly, including microparticles, lipiodol renders the embolic substance radiopaque, facilitating fluoroscopy guidance. additionally, the prostate gland absorbs the lipiodol, which makes the distribution of the treated prostatic areas and seen well in mri. according to research on the usage of nbca on liver, this distribution might be considered as marker for clinical effectiveness(22). it is to be noted that glubran 2 has the benefit of being cost–effective in many countries even though it is mixed with lipiodol, yet it is not more expensive than using microparticles. after nbca glue embolization, the possibility of ischemic consequences has been of great concern. however, our findings indicate that when compared to other widely used embolic agents such microparticles, nbca and lipiodol may not result in a larger number of ischemic consequences. the characteristics of nbca explain this observation(23). the ratio of nbca/lipiodol needs to be modified accurately on how long the segment needs to be embolized. this adjustment maintains enough viscosity to prevent excessive distal penetration into the capillary bed while still providing enough fluidity to ensure distal embolization of the feeding artery, maintaining circulation in the distal post embolic tissue via collateral channels in the intramural microcirculation(23). in order to reduce the risk of complications, precautions must be taken. important steps include flushing the microcatheter to eliminate any ionic solutions before the injection and quickly retracting the catheter thereafter to prevent nbca from becoming trapped and adhering to the vessel(15). to our knowledge, no studies have compared non-spherical pva particles in pae with nbca glue. according to (table 4), the non-spherical pva particle results were better than the nbca glue group in terms of clinical outcomes assessed by subjective (ipss and qol) and objective values (prostatic volume). statistical significance was attained for the volume decrease of the prostate gland. although, it is thought that non-spherical pva particles are more likely than nbca glue in terms of a significant drop in the volume of the prostate gland, which led to the achievement of statistical significance(11). prostatic arteries have extremely diverse origins and modest sizes of less than 2 mm. to prevent embolization failure and non-target embolization of the rectum, bladder, and penis, it is necessary to have a thorough grasp of the prostatic artery architecture. though open prostatectomy is the procedure of choice for bph larger than 80 cm3. recently, several reports have suggested that pae for prostate volume greater than 80 cm3 is safe and effective(2). these reports reflect the growing interest in pae, especially in patients who are not candidates for open surgery, turp, or minimally invasive surgery. our study has some limitations. first, our sample size is just 110 patients may have hindered our capacity to identify significant changes and may account for some inconsistencies with other research. second, there may be a chance of bias because pae was carried out by a senior interventional radiologist with his own extensive experience with pae using nbca glue and non-spherical pva particles. third, a short follow-up time of 3 and 6 months was not enough to help interventionalist to choose the appropriate embolic agent. we aimed to present the first clinical data on pae comparing two distinct embolic agents, i.e. nbca glue and non-spherical pva to treat lutss associated with bph to the best of our knowledge. therefore, it is necessary for further research with longer follow-up period to compare embolic agents. conclusions pae treatment with nbca glue or non-spherical pva particles is safe, and effective for individuals suffering from luts caused by bph. this gives the physicians effect of embolizing agents for bph-hijazi et al. unclassified 266 option to select between embolizing agents based on the patient’s clinical status and the architecture of the prostatic artery. conflict of interest the authors declare that there are no conflicts of interest. acknowledgments this study was supported by nanjing medical university. references 1. aslan g, aslan d, kizilyar a, ispahi c, esen a. a prospective analysis of sexual functions during pregnancy. int j impot res. 2005;17:154-7. 2. mcvary kt, roehrborn cg, avins al, et al. update on aua guideline on the management of benign prostatic hyperplasia. j urol. 2011;185:1793-1803. 3. roehrborn cg, andriole gl, wilson th, et al. patient-reported outcomes after 4 years of treatment with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia. urology. 2009;73:13631368. 4. madersbacher s, alivizatos g, nordling j, sanz c, emberton m, de la rosette j. j. m. c. h. eau 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (bph guidelines). eur urol. 2004;46:547–554. 5. oelke m, bachmann a, descazeaud a, et al; european association of urology. eau guidelines on the treatment and followup of nonneurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2013;64:118–140. 6. bagla s, martin cp, van breda a, et al. early results from a united states trial of prostatic artery embolization in the treatment of benign prostatic hyperplasia. j vasc interv radiol. 2014;25:47–52. 7. mcvary kt, roehrborn cg, avins al, et al. update on aua guideline on the management of benign prostatic hyperplasia. j urol. 2011;185:1793–1803. 8. lourenco t, pickard r, vale l, et al. minimally invasive treatments for benign prostatic enlargement: systematic review of randomized controlled trials. bmj. 2008;337:966–969. 9. li q, duan f, wang mq, et al. prostatic arterial embolization with small-sized particles for the treatment of lower urinary tract symptoms due to large benign prostatic hyperplasia: preliminary results. chin med j (engl). 2015;128:2072-2077. 10. gravas s, cornu jn, gacci m, gratzke c, herrmann trw, mamoulakis c, et al. management of non-neurogenic male luts. eau guidelines edn presented at the eau annual congress amsterdam 2020. 11. geevarghese r, harding j, parsons n, hutchinson c, parsons c. the relationship of embolic particle size to patient outcomes in prostate artery embolization for benign prostatic hyperplasia: a systematic review and meta-regression. clin radiol. 2020;75:366– 374. 12. abdulmalak g, chevallier o, falvo n, di marco l, bertaut a, moulin b, et al. safety and efficacy of transcatheter embolization with glubran®2 cyanoacrylate glue for acute arterial bleeding: a single-center experience with 104 patients. abdom radiol. 2018;43:723–733. 13. loffroy r, desmyttere as, mouillot t, pellegrinelli j, facy o, drouillard a, et al. tenyear experience with arterial embolization for peptic ulcer bleeding: n-butyl cyanoacrylate glue versus other embolic agents. eur radiol. 2021;31:3015–3026. 14. dadas b, alkan s, cifci m, basak t. treatment of tripod fracture of zygomatic bone by n-2-butyl cyanoacrylate glue fixation and its effects on the tissues. eur arch otorhinolaryngol. 2007;264:539–544. 15. loffroy r, mouillot t, bardou m, chevallier o. current role of cyanoacrylate glue transcatheter embolization in the treatment of acute nonvariceal gastrointestinal bleeding. expert rev gastroenterol hepatol. 2020;14:975–984. 16. carnevale fc, antunes aa, da motta jm, leal filho et al. prostatic artery embolization as a primary treatment for benign prostatic hyperplasia: preliminary results in two patients. cardiovasc intervent radiol. 2010;33:355–361. 17. jeon gs, won jh, lee bm, et al. the effect of transarterial prostate embolization in hormone-induced benign prostatic hyperplasia in dogs: a pilot study. j vasc interv radiol. 2009;20:384–390. 18. pisco jm, rio tinto h, campos pinheiro l, et al. embolization of prostatic arteries as treatment of moderate to severe lower urinary symptoms (luts) secondary to benign hyperplasia: results of shortand mid-term follow-up. eur radiol. 2013;23:2561–2572. 19. wang mq, guo lp, zhang gd, et al. prostatic arterial embolization for the treatment of lower urinary tract symptoms due to large (>80 ml) benign prostatic hyperplasia: results of midterm follow-up from chinese population. bmc urol. 2015;15:33. 20. li yj, barthes-biesel d, salsac av. polymerization kinetics of n-butyl cyanoacrylate glues used for vascular embolization. j mech behav biomed mater. 2017;69:307–317. 21. malling b, røder ma, brasso k, forman j, taudorf m, lönn l. prostate artery embolisation for benign prostatic hyperplasia: a systematic review and meta-analysis. eur radiol. 2019;29:287–298. 22. shuster a, gunnarsson t, klurfan p, larrazabal r. n-butyl cyanoacrylate proved beneficial to avoid a nontarget effect of embolizing agents for bph-hijazi et al. vol 20 no 4 july-august 2023 267 embolization of the ophthalmic artery in endovascular management of epistaxis. a neurointerventional report and literature review. interv neuroradiol. 2011;17:17–21. 23. jae hj, chung jw, kim hc, so yh, lim hg, lee w, kim bk, park jh. experimental study on acute ischemic small bowel changes induced by superselective embolization of superior mesenteric artery branches with n-butyl cyanoacrylate. j vasc interv radiol. 2008;19:755–763. effect of embolizing agents for bph-hijazi et al. unclassified 268 review 3urology journal vol 5 no 1 winter 2008 arterial stiffness in kidney transplant recipients an overview of methodology and applications ali reza khoshdel,1 shane l carney2 introduction: cardiovascular disease is still a major cause of mortality in kidney transplant patients. this is partially attributed to the nonclassic cardiovascular risk factors including arterial stiffness, an established independent predictor of mortality in several patient populations. materials and methods: an extensive search was performed to review the evolution process of the method for arterial stiffness assessment and sphygmology and their applications in chronic kidney disease before and after kidney transplantation. results: despite a marked change in methodology from the ancient medical practice to the current modern medicine, noninvasive assessment of arterial stiffness is still based on pulse analysis. currently, pulse wave velocity, augmentation index, and pulse wave reflection are preferred indexes for arterial stiffness. increased arterial stiffness has been reported in diabetes mellitus, hypertension, chronic kidney disease, cardiovascular disease, and elderly, and reduction of arterial stiffness is a key element for efficacy of the treatment and mortality reduction. conclusion: noninvasive assessment of arterial stiffness is suggested as a part of clinical assessment for kidney transplant recipients and donors and facilitates defining high-risk patients for development of cardiovascular disease. a combination of techniques is recommended for this purpose. keywords: cardiovascular disease, chronic kidney disease, kidney transplantation, arteries, arterial compliance 1faculty of medicine, aja university of medical sciences, tehran, iran 2department of nephrology, faculty of health, university of newcastle, new south wales, australia corresponding author: ali reza khoshdel, md, phd po box 16315-781 tehran, iran tel: +98 21 2232 7720 fax: +98 21 8802 1913 e-mail: alikhoshdel@yahoo.com introduction the current evidence shows the mortality rate of transplant patients is 6 and 8 times less than that of dialysis patients with and without diabetes mellitus (dm), respectively.(1) although this observation can be attributed to a younger age and a lower risk of cardiovascular disease (cvd) in patients who have been selected for transplantation, it may also indicate a reduction in the risk of cvd following transplantation.(2-5) nevertheless, cvd is still a common cause of posttransplant death.(1) a large database from a national kidney transplant registry demonstrated that despite improvement in both graft survival and patient survival over the past decade, cvds still account for a mortality rate of 22% among kidney transplant recipients.(1) however, classic risk factors cannot fully explain the risk of cvd in this population. it is reported that the framingham cardiovascular risk score significantly underestimates the risk of ischemic heart disease in transplant patients,(6) and therefore, nonclassic risk factors including c-reactive protein, homocysteine, and kidney function, as well as urol j. 2008;5:3-14. www.uj.unrc.ir arterial stiffness in kidney transplant recipients—khoshdel and carney 4 urology journal vol 5 no 1 winter 2008 arterial stiffness, may contribute to cardiovascular risk in this population.(2,7) arterial stiffness is now an established independent predictor of mortality and a risk marker for cardiovascular events.(8-14) although arterial stiffness is associated with vessel wall sclerosis,(15) it is not solely determined by structural factors within the vessel wall and distending pressure, since there are also functional regulations performed by the autonomic nervous system, vascular smooth muscle, and endothelial derived-nitric oxide. therefore, arterial stiffness is a summation marker representing many contributing factors on the risk of cvd. of paramount importance, arterial stiffness is potentially reversible and is applicable in the patients’ follow-up for evaluation of the treatment efficacy.(16-18) several methods have been used to evaluate arterial stiffness. the noninvasive methods are principally based on pulse transit time and pulse contour analysis(19); new applications of an old science: sphygmology. sphygmology: an art for all seasons! the pulse has been regarded as the basic sign of life across time and culture, and feeling the pulse is a standard part of all the great medical traditions. the significance of the pulse has been recognized for millennia with ancient egyptian, chinese, and ayurvedic traditional medicines appreciating the association of pulse abnormalities with different diseases and heart function. however, the term of sphygmopalpation was first used by paraxagoras (400 bc) and classic sphygmology appearing in scientific texts by greek physicians, particularly hippocrates and herophilus (4th century bc). this was developed by galen (2nd century ad), who realized that the pulse was the movement of blood, not air, inside the vessel and wrote extensively on pulse.(20) over centuries, sphygmology was influenced and refined by many nations; persia (iran) in particular further developed these sphygmological traditions with the addition of new concepts, theories, and classifications.(21-23) for instance, rhazes (ibn-zakariya, 865 to 925 ad) described diverse pulse formations in different diseases.(21) of particular interest, 11 features and more than 50 identifiable pulse forms were described by avicenna (ibn-sina, 973 to 1037 ad), the renowned persian physician. this warranted a separate chapter named sphygmology in his 5-volume medical text book, canon in medicine (al-quanun).(20,24) perhaps his skill in poetry, music, mathematics, and philosophy impacted his understanding of body music, the pulse and its interpretation. he comprehensively evaluated this subject and recorded the effect of a variety of conditions including environment, food, drink, age, exercise, pregnancy, emotions, and body activity on the pulse and is famous for using the pulse as a lie detector.(24) this pulse diagnosis skill gradually advanced until pulse assessment via a piece of string (strapped around the wrist) became a traditional persian diagnostic method.(22) during this era, many medical texts were written in arabic, the new official scientific language in the region, which included greek translations. the visits of persian and arab physicians to those parts of europe which were under muslim domination, such as sicily and spain, and the subsequent translation of these texts into latin laid the foundations of modern western medicine and stimulated the revolutionary discovery of the circulation by william harvey (1578 to 1657).(20,25) harvey established the pulse as a manifestation of cardiac ejection and vascular properties and even noted the impact of wave reflection. years later, stephen hales (1677 to 1761) was the first to measure arterial pressure and described peripheral vascular resistance and the vascular cushioning (windkessel) effect. the dynamics, transmission, and reflection of the pulse were further improved by thomas young (1773 to 1829) who noted that arterial elasticity is related to the velocity of propagation of the arterial pulse.(25) perhaps, the invention of the kymograph by carl ludwig in 1847 was a turning point in the history of modern medicine; since it was adopted years later by karl vierordt (1854) for pulse recording.(26) the first noninvasive sphygmograph was produced by ettiene marey in 1860.(27,28) several models were developed and exhibited with one after another becoming popular in the routine clinical practice. evaluation of cardiac function using sphygmograph records consequently arterial stiffness in kidney transplant recipients—khoshdel and carney urology journal vol 5 no 1 winter 2008 5 became a focus in medical research.(27,29) the first quantitative sphygmograph was invented by fredrick a mahomed (1851 to 1884), and the change in systolic and diastolic parts of the pulse contour in essential hypertension was described by him.(25) then, william osler (1892) in his seminal textbook explained the concepts of atherosclerosis and arteriosclerosis and their relationship with kidney function as well as their sphygmograph manifestations.(30) the beginning of the 20th century coincided with the invention of the sphygmomanometer following intensive research by scipione rivarocci and nicolai korotkoff.(25,27) this new device facilitated epidemiologic research including the importance of systolic and diastolic blood pressure (bp). while pulse and bp knowledge was expanding, cardiac catheterization then allowed a comparison of direct waveform records with indirect estimations from peripheral arteries.(26) the introduction of the new sphygmomanometry into clinics diminished the importance of the pulse wave for decades.(25,31) then in 1960, a new interpretation of pulsatile phenomena was proposed by da mcdonald where the relationship of arterial compliance with forward and backward travelling waves was suggested. pulse wave analysis was then reintroduced after accurate arterial tonometers were developed.(25) more recently, with the development of new computerized equipment, assessment of the pulse pressure wave with a sphygmograph has undergone a renaissance.(31,32) besides, the relatively recent realization of the importance of pulse pressure and central arterial pressure rather than brachial systolic or diastolic bp by michael o’rourke(33) has encouraged the return to pulse wave measurements as clinical tools. methodological aspects prior to the assessment of different methods of arterial stiffness evaluation, an important distinction must be made between (1) large conduit arteries, (2) smaller more distal arteries and branch points (reflecting sites), and (3) arterioles (resistance sites). while stiffness of the large arteries leads to an increased pulse propagation velocity and a widening of the pulse pressure, stiffening of the reflecting sites also alters the wave contour and pathologic lesions in arterioles change the mean arterial pressure.(34) also one must distinguish between the term atherosclerosis (calcified atheromatosis) and arteriosclerosis, although they may occur coincidently (table 1). whereas the former refers to segmental plaques with intimal lesions that may change the pulse pressure and wave contour but not necessarily central pulse wave velocity, the latter represents arterial wall degeneration, predominantly medial, which causes large artery stiffness and consequently alters pulse wave velocity.(25) the viscoelastic properties of the large arteries can be described in terms of compliance, distensibility, and stiffness.(35) several methods have been used to evaluate arterial stiffness. they are principally based on pulse transit time, pulse contour analysis, and direct measurement of arterial geometry.(19) there is still no gold-standard measurement method for arterial stiffness,(18,31) which cause limits for the of validation studies. however, from the clinical point of view, the central pulse wave velocity (pwv) is now established as a surrogate marker of arterial stiffness and is an independent determinant of morality,(34,36) and in the absence of a gold-standard method for measurement of arterial stiffness, central pwv is commonly used in the validation of other devices (table 2).(19,37) features arteriosclerosis atherosclerosis anatomic location diffuse in elastic arteries focal vascular location media intima vascular effect dilatation constriction consequence (distal) nil* ischemia consequence (proximal) increase left ventricular load nil table 1. contrasting features of arteriosclerosis and atherosclerosis in human arteries.(25) *current evidence demonstrates that arteriosclerosis can reduce coronary artery blood flow and accelerate end-organ damage via increased pulse pressure.(25) arterial stiffness in kidney transplant recipients—khoshdel and carney 6 urology journal vol 5 no 1 winter 2008 stiffness of the large arteries increases the systolic blood pressure and decreases the diastolic blood pressure, and therefore, creates a wide pulse pressure (pp). pulse pressure is determined by ventricular ejection and the aortic cushioning function; hence, it is the simplest achievable marker of arterial stiffness in clinical practice.(38) furthermore, pp amplification from the central to the peripheral arteries may represent the ventricular function.(39) however, there are several factors that affect pp and it could not be applied as a single surrogate of arterial stiffness. pulse wave velocity is usually assessed by the delay in the upstroke pulse between the feet of two corresponding waves in proximal and distal sensors (foot-to-foot method) divided by the distance traversed (d/∆t; figure). despite the general acceptance of the method itself and several reports of its validity and reliability,(40,41) the distance measurement between the arterial points is still debated. while many studies use surface distance between the adjacent skin d ev ic e ty pe b lo od p re ss ur e c al ib ra tio n m ea su re m en t m ec ha ni sm li m ita tio ns a pp ro xi m at e c os t, u s $ c om pl io r® r eg io na l … p ul se t ra ns it tim e de la y be tw ee n ar te ria l s ite s us in g fo ot to fo ot m et ho d fo r th e po in t d et er m in at io n s ki ll de pe nd en cy u nc er ta in ty in th e di st an ce m ea su re m en t te ch ni ca l e rr or s in o be se p at ie nt s 11 00 0 s ph yg m oc or ® r eg io na l f or p w v g lo ba l f or p w a r eq ui re d p ul se tr an si t t im e de la y us in g el ec tr oc ar di og ra ph y as th e tim in g re fe re nc e fo r p w v p re ss ur e w av e fo rm a na ly si s us in g ap pl an at io n to no m et ry a nd a ge ne ra liz ed tr an sf er fu nc tio n fo r p w a c on tr ov er si es a bo ut th e va lid at io n of a ge ne ra liz ed tr an sf er fu nc tio n c on fo un di ng fa ct or s d is so ci at io n fr om p w v in p ar tic ul ar po pu la tio ns 14 00 0 p ul se t ra ce s ys te m t m g lo ba l … v ol um e pr es su re a na ly si s us in g a fin ge r pl et hy sm og ra ph c on fo un de d by s ki n ch ar ac te ris tic s m od es t c or re la tio n w ith p w v 10 00 0 h d i/p ul se w av et m c r -2 00 0 r eg io na l r eq ui re d d ia st ol ic d ec ay a na ly si s us in g th e w in dk es se l m od el s en so r pl ac em en t p oo r ag re em en t o f c 1 w ith p w v a nd au gm en ta tio n in de x u nc le ar v al id ity in h um an 36 00 0 ta bl e 2. r ec om m en de d d ev ic es fo r a ss es sm en t o f a rt er ia l s tif fn es s in c lin ic al p ra ct ic e* *e lli ps es in di ca te n ot a pp lic ab le . p w v in di ca te s pu ls e w av e ve lo ci ty a nd p w a , p ul se w av e co nt ou r an al ys is . the principle for measurement of central pwv. pwv indicates pulse wave velocity; d, the distance between measurement sites; and δt, transit time (time delay). arterial stiffness in kidney transplant recipients—khoshdel and carney urology journal vol 5 no 1 winter 2008 7 on the measurement site (according to the manufacturer’s instructions),(42) the real distance may be overestimated or underestimated due to branching and tortuous arterial segments and individual diversity in the vascular pathway and adjacent structures. also, a large abdomen or breast can artificially increase the distance measured between the probes. furthermore, since the pulse travels between the aorta (not the carotid) and femoral artery, it is suggested that the distance between the sternal notch and the carotid probe must be subtracted from the carotid-femoral length.(43) although a different pwv result is expected with adjusted distance measurements, they must be strongly correlated and should not affect epidemiologic studies on arterial stiffness. nevertheless, the method of the distance measurement is of great concern when studies are compared or pooled. in terms of interpretation, pwv represents segmental arterial compliance (carotid-femoral or carotid-radial) and probably does not reflect the compliance of the vasculature as a whole.(37) the other method for evaluation of arterial stiffness is pulse wave contour analysis (pwa) using applanation tonometry. although the tonometer can be applied on any artery that lies on a rigid structure, such as bone, carotid tonometry is difficult, especially in persons with thick necks, and it is commonly accompanied by artifacts. this method is also uncomfortable and carries the risk of carotid plaque dislodgement. consequently, radial artery tonometry is preferred because it is easier to master and the variability is far less than other sites.(33) each pulse pressure waveform contains two major parts. the systolic part (the incident wave) is mainly determined by left ventricular ejection and the impedance of ejection.(31) approximately, 80% of this forward wave is reflected backward from the periphery (the reflected wave)(25,33) and accounts for the dicrotic wave in the diastolic part of the pulse contour. the impact of the reflected wave on the pulse contour depends on its amplitude and timing; amplitude is affected by the speed of energy transfer and luminal mismatch, and the timing itself is associated with the arterial stiffness (the stiffer the wall, the faster the wave return), aortic length, and the site of reflection.(25,38) while the arrival of the reflected wave facilitates coronary blood flow during diastole in normal circumstances, with stiff arteries, the reflected wave returns faster with augmentation of the systolic pressure wave. this increases ventricular load on the one hand and diminishes coronary blood flow on the other. the amount of augmentation is commonly expressed as the augmentation index (ai) which is the ratio of augmentation pressure to pulse pressure. since heart rate has a great impact on the waveform timing and augmentation, computer software adjusts the ai value for heart rate according to a built-in normogram. apart from the augmentation pressure, pwa provides additional information including ejection duration, the timing of the incident and the reflected waves, subendocardial viability ratio, and more importantly, an estimation of the central arterial bp. the latter is calculated according to a mathematical transfer function that has been a subject of long-term debate regarding the validity of both transfer function and ai.(33,44) this issue was recently reviewed in detail by our group.(45) but in general, the method is valid and reliable and is food-and-drug-administration approved for clinical practice. it is noteworthy, however, that the interpretation of the results in diabetic patients, the elderly, and those with chronic kidney disease (ckd) needs adequate expertise. recent studies suggest that augmentation index (ai) might be a more significant marker of arterial stiffness in younger individuals whereas aortic pwv is likely to be a better measure in older individuals.(46) therefore, a combination of the methods including pwv, ai, and central bp has been suggested for a full assessment of the arterial system.(16,36) nevertheless, method selection depends on the purpose of the measurement as well as the target population and funding. yet, the bottom line and the simplest might be the use of ambulatory pp. it is noteworthy that much of the available data about these techniques has been collected in a controlled environment and in steady-state conditions at a standard time and medication, arterial stiffness in kidney transplant recipients—khoshdel and carney 8 urology journal vol 5 no 1 winter 2008 and smoking and caffeine withheld for a defined period before testing. also, the impact of diurnal variation, fasting state, and exercise prior to testing, appear to cause a significant variability in measurement results.(18) specific attention must be paid to the accuracy of the bp measurement for a proper calibration. furthermore, since the operator expertise may markedly affect the result, standardized training and qualification are required. it is also necessary to improve the accuracy of distance measurements with pwv analysis. with respect to the utility of the results, the reliability of changes in arterial stiffness as a guide of therapeutic efficacy is yet to be confirmed,(34) and reference values must be developed and validated. associated factors with arterial stiffness arterial stiffness is influenced by a large number of modulators including physiologic, pathologic, psychologic, and pharmacologic factors. increased arterial stiffness has been proposed as a normal vascular aging process(46,47) and mainly affects central and more elastic proximal arteries.(48-50) therefore, we have constructed an age-specific reference interval for pwv which facilitates its clinical application (table 3).(51) the result of pwa is also compared with the normal values of the patients’ age. women have a greater pp and ai, but a lower pwv than men; the latter is partially attributed to the greater sympathetic activity in men.(52) also, increased cardiovascular events associated with shorter stature may be partially due to increased pwv and earlier return of the pulse wave reflection in the arterial tree(53,54); however, this cannot explain the lower pwv and the risk of cvd in women. central obesity and increased bmi have also been demonstrated to be associated with impaired arterial compliance. (55) moreover, several studies reported racial difference in the arterial compliance, demonstrating stiffer and more pressure-sensitive arteries in black and afro-caribbean populations, an ethnic diversity that is mainly expressed in peripheral arteries.(56-58) blood pressure is frequently reported as the main determinant of arterial stiffness.(31,50) therefore, the original causes of increased arterial pressure may increase arterial stiffness as well. on the other hand, pwv can be bp-independent in various conditions such as the response to bp lowering medications(33,59) and exercise training.(60) determining the effect of heart rate on arterial compliance is difficult; since an increased heart rate increases pp and decreases ai, and reports on its effect on pwv are conflicting.(61) since bp, heart rate, vasoactive hormones, and blood volume all have diurnal variations, such a fluctuation is also expected for arterial compliance as was shown by bodlaj and colleagues for ai and subendocardial viability.(62) of technical and epidemiologic importance, smoking, alcohol consumption, and caffeine can increase arterial stiffness indexes and the effect may persist for 3 hours.(50,63-67) these factors are not only important clinically, but also must be considered from a technical point of view during the measurement of arterial stiffness. finally, many drugs including antihypertensive drugs such as nitrates,(25) beta-blockers,(31) calciumchannel blockers,(68) angiotensin-converting pulse wave velocity age, y 2.5th 5th 10th 50th 75th 90th 95th 97.5th 20 5.93 6.31 6.76 8.36 9.28 10.27 10.94 11.58 30 5.72 6.15 6.66 8.45 9.47 10.58 11.33 12.05 40 5.59 6.07 6.63 8.63 9.75 11.02 11.86 12.66 50 5.57 6.10 6.71 8.90 10.14 11.51 12.43 13.30 60 5.70 6.27 6.94 9.33 10.68 12.17 13.18 14.13 70 6.01 6.63 7.36 9.96 11.38 13.06 14.15 15.19 80 6.48 7.15 7.93 10.72 12.27 14.04 15.21 16.32 90 7.15 7.87 8.70 11.68 13.39 15.23 16.48 17.67 table 3. age-specific reference index of pulse wave velocity(51) arterial stiffness in kidney transplant recipients—khoshdel and carney urology journal vol 5 no 1 winter 2008 9 enzyme inhibitors, and angiotensin receptor blockers have substantial impact on arterial stiffness, acutely and chronically.(69-71) these facts should be carefully considered in the interpretation of the results. arterial stiffness before kidney tranplantation several reports have associated arterial stiffness with a broad range of diseases. consequently, measurement of arterial stiffness in kidney transplant candidates with hypertension, dm, and ckd is of great importance in respect of its potential utility in the early diagnosis, prevention, and treatment of these chronic diseases. it is generally accepted that hypertension increases stiffness of the large arterial wall via hypertrophy and changes in the extracellular matrix, mainly due to increased collagen.(72) current evidence also shows that the treatment of hypertension must include arterial stiffness reduction, as another facet of the cardiovascular health, to be effective in reducing mortality.(33,73,74) several studies have indicated an increased arterial stiffness in ckd, particularly in end-stage renal disease (esrd).(19,35,75-77) while these patients usually have other atherogenic cardiovascular risk factors, structural changes in the intima, media, and adventitia as well as endothelial dysfunction causes the elevated arterial stiffness.(78) while hemodialysis improves arterial compliance both in short-term and long-term, dialysis membrane bioincompatibility may play a role in maintaining increased arterial stiffness during dialysis.(79) mourad and coworkers demonstrated that patients with stiffer arteries had lower bp response to dialysis and thereby are at a higher risk,(80) and covic and colleagues reported that a lack of reduction in ai after dialysis is associated with left ventricular dysfunction.(81) a variety of techniques have demonstrated that arterial compliance is reduced in dm and is associated with its complications.(60,82-85) it is also related to glucose control,(82) autonomic dysfunction,(86) and kidney function.(87) in addition, reduced arterial compliance precedes microalbuminuria(88) or even dm itself.(89,90) consequently, assessment of arterial stiffness may even facilitate the early diagnosis of dm complications. prognostic value of arterial stiffness indexes the risk of cardiovascular events is directly and independently associated with pp.(13,91-94) it is also associated with end-organ damage and cardiovascular events (except for stroke) in hypertension.(13,95,96) an elevated pp also indicated a high risk of death or dialysis in patients with primary stages of ckd(97) and predicted cvd and total morality better than systolic or diastolic bp in patients on hemodialysis.(98) however, among patients with esrd, central rather than peripheral pp predicted mortality.(8) even in mild to moderate renal insufficiency, pp and arterial stiffness are linked to plasma creatinine levels and microalbuminuria,(13) and they are associated with left ventricular hypertrophy and possibly cardiomyopathy.(99) arterial stiffness as measured by pwv has been recognized as a strong and independent predictor of mortality in patients with hypertension,(12) dm,(11) esrd,(75,100) and the elderly.(101,102) of great importance, guerin and colleagues demonstrated a decrease in mortality when aortic distensibility was improved by medication as defined by a reduced pwv.(74) nakano and colleagues found greater prevalence of cvd, ischemic heart disease, and cerebrovascular disease with a 1 m/s pwv increment in cross-sectional analysis. cerebrovascular disease was also associated with a pwv greater than 10 m/s in the follow-up period of their study.(103) augmentation index has been shown to be predictive of coronary artery disease severity in hypertensive patients(104) and future cardiovascular and all-cause mortality in esrd.(100) this index also correlated with a cardiovascular risk score in symptomatic and asymptomatic patients with cvd.(105) however, there was a marked overlap between the risk levels, and ai failed to stratify individuals in relation to risk. nevertheless, this does not indicate a low prognostic value of ai, rather it shows that ai outperforms classical risk factors.(14) arterial stiffness in kidney transplant recipients—khoshdel and carney 10 urology journal vol 5 no 1 winter 2008 other arterial stiffness indexes such as stiffness index, ambulatory arterial stiffness index, and stroke volume/pp ratio have also been demonstrated to be associated with adverse outcomes.(106-110) however, further discussion of the indexes is beyond this review. screening of arterial stiffness the above evidence suggest that a proper risk assessment of the potential kidney transplant patients could be targeted by implementation of arterial stiffness assessment, which accompanies several advantages when compared to the current evaluation program. moreover, application of this approach to evaluate potential kidney donors reveals incipient hemodynamic disorders and facilitates selection of the best candidates, and thereby, reduces the donor complications. arterial stiffness after kidney transplantation arterial stiffness is an established cardiovascular risk marker and an independent predictor of cardiovascular events and mortality in various groups of patients including kidney transplant patients.(7,10-12,101,111) several studies have also demonstrated a substantial cardiovascular risk reduction after kidney transplantation when compared to patients on hemodialysis.(2,3) while this observed difference could be due to selection bias (younger age in transplant recipients compared to patients on hemodialysis), a large study including 46 164 patients who were placed on a waiting list for kidney transplantation (virtually a homogenous population) revealed a long-term mortality reduction of 48% to 82% among patients who underwent transplant surgery.(4) this is in parallel to researches reporting improved posttransplant arterial function. for instance, kocak and colleagues reviewed 30 patients during hemodialysis and after transplantation and demonstrated an improvement in endothelial function after transplantation.(112) in addition zoungas and colleagues evaluated systemic arterial compliance and ai in 36 patients before and after transplantation and found a significant decrease in serum lipids and homocysteine, systolic and diastolic bp, and heart rate as well as ai and peripheral and central pwv following transplantation.(113) our findings in a follow-up study also demonstrated that the improvement in arterial function after kidney transplantation is continuous during the posttransplant period. however, research is required to see if this benefit continues to occur over the life of the kidney transplant as well as its cause. this is mainly attributed to the resolution of systolic and diastolic ventricular dysfunction and regression of left ventricular hypertrophy after successful kidney transplantation.(114) since the cvd is still the leading cause of mortality in the kidney transplant patients, following up the patients identifies those at risk of cvd after kidney transplantation. it is likely that the role of arterial stiffness in left ventricular systolic pressure, left ventricular hypertrophy, and ventricular oxygen and blood demand explains the higher cardiovascular morbidity in kidney transplant recipients with decreased arterial distensibility.(7) several comorbidities may have influence on the cardiovascular function in transplant patients, of which dm is one of the most important determinants. although patients with dm are not traditionally preferred candidates for kidney transplants, the number of the procedures on diabetic patients is increasing.(1) cardiac function in transplant candidates with dm is carefully evaluated prior to transplantation and left ventricular systolic and diastolic function improves shortly after a successful kidney transplant.(5,114,115) consequently, recent reports did not demonstrate a considerable difference for the outcome of kidney transplantation in patients with and without dm.(116) although hypertension is a common problem in esrd, it is less frequent among kidney transplant patients due to their posttransplant medication which in many cases includes calcium channel blockers.(113) however, it is noteworthy that reduction of the peripheral bp is not sufficient to reduce the cardiovascular risk, and central bp (which could be estimated accurately by pwa) must be reduced in order to reduce the risk.(74) arterial stiffness in kidney transplant recipients—khoshdel and carney urology journal vol 5 no 1 winter 2008 11 some posttransplant drugs cause vascular damage and increase cardiovascular risk in the kidney recipients. while some reports claim a lack of difference in arterial stiffness between patients with and without cyclosporine administration,(7) other reports indicate conversion from cyclosporine to tacrolimus improves cardiovascular risk profile.(117) parallel to this report, we recently found in our analysis advantages of mycophenolate mofetil for arterial distensibility when compared to the other immunosuppressant drugs. the benefit of mycophenolate mofetil on the graft and patient survival compared to azathioprine has been reported elsewhere.(118) conclusion arterial stiffness is an independent marker and predictor of cardiovascular risk and mortality in diverse groups of individuals including kidney transplant patients. while assessment of arterial stiffness in pretransplant ckd is beneficial, implementing this approach into the follow-up program of the patients after transplantation may enhance the value of cardiovascular risk assessment and prevent cvd mortality and morbidity in this group of patients. furthermore, assessment of arterial stiffness appears to be a reliable 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dial transplant. 2006;21:203-7. 113. zoungas s, kerr pg, chadban s, et al. arterial function after successful renal transplantation. kidney int. 2004;65:1882-9. 114. ferreira sr, moises va, tavares a, pachecosilva a. cardiovascular effects of successful renal transplantation: a 1-year sequential study of left ventricular morphology and function, and 24-hour blood pressure profile. transplantation. 2002;74:1580-7. 115. dudziak m, debska-slizien a, rutkowski b. cardiovascular effects of successful renal transplantation: a 30-month study on left ventricular morphology, systolic and diastolic functions. transplant proc. 2005;37:1039-43. 116. schiel r, heinrich s, steiner t, ott u, stein g. longterm prognosis of patients after kidney transplantation: a comparison of those with or without diabetes mellitus. nephrol dial transplant. 2005;20:611-7. 117. baid-agrawal s, delmonico fl, tolkoff-rubin ne, et al. cardiovascular risk profile after conversion from cyclosporine a to tacrolimus in stable renal transplant recipients. transplantation. 2004;77:1199-202. 118. meier-kriesche hu, ojo ao, leichtman ab, et al. effect of mycophenolate mofetil on long-term outcomes in african american renal transplant recipients. j am soc nephrol. 2000;11:2366-70. management of the distal ureter during nephroureterectomy for upper tract urothelial carcinoma: a comprehensive review of literature samuel morriss1, homayoun zargar2,3*, brendan hermenigildo dias2,3 purpose: radical open nephroureterectomy (onu) with bladder cuff excision (bce) is the traditional gold standard approach for management of high-risk non-metastatic upper tract urothelial cancer. onu involves two separate procedures; the nephrectomy and distal ureterectomy, with each of these parts being able to be performed with an open or minimally-invasive approach. multiple approaches have been described for the resection of the distal ureter and bladder cuff after mobilization of the kidney and upper ureter. materials and methods: a medline search of the literature including relevant articles up to march, 2020 was performed. search terms included “nephroureterectomy”, “upper tract urothelial carcinoma”, “upper urinary tract carcinoma or utuc”, “open or conventional or onu or conventional”, “robotic-assisted nephroureterectomy or ranu”, “laparoscop* or lnu or lrnu” and “minimally-invasive nephroureterectomy”. original articles, case series and review articles were included. results: there are no randomised studies. various techniques have been described to manage the distal ureter during nephroureterectomy. this review provides an overview of these techniques. the perioperative and oncological outcomes following open versus endoscopic techniques and minimally invasive techniques have been described. although endoscopic approaches have more favourable perioperative outcomes, this comes at the expense of increased risk of tumour spillage and recurrence compared to the traditional open approaches. minimally-invasive techniques (laparoscopic and robotic-assisted nu) largely have superior perioperative outcomes versus their open nu counterparts, with comparable oncological outcomes. conclusion: current non-randomised evidence is open to selection bias and is insufficient to support or refute endoscopic management of the distal ureter as an alternative to open bladder cuff excision. the optimal approach to nephroureterectomy and management of the distal ureter continues to remain a surgical dilemma. keywords: nephroureterectomy; ureteral neoplasms; carcinoma, transitional cell introduction upper tract urothelial carcinoma (utuc) is rare, comprising 5-10% of all urothelial cancers(1). it can involve the urothelial lining anywhere from the renal calyces down to the distal ureteric orifice. radical open nephroureterectomy (onu) with bladder cuff excision (bce) is the traditional gold standard approach for management of high-risk non-metastatic utuc, recommended by the european association of urology guidelines(2). high-risk utuc is defined as having any of the following factors present: hydronephrosis, tumour size greater than 2 cm, high-grade cytology, highgrade urs biopsy, multifocal disease, previous radical cystectomy for high-grade bladder cancer, or variant histology(2). due to the propensity for recurrence seen with this type of malignancy, the surgical approach involves complete en bloc resection of the kidney, ipsilateral ureter, and bladder cuff, regardless of the location of the lesion along the urinary tract. it is imperative this 1melbourne medical school, the university of melbourne, australia. 2department of surgery, the university of melbourne. australia 3department of urology, western health, australia. correspondence: 2/132 la scala avenue, maribyrnong, victoria 3032, australia. phone:+61 300 927427. email:homi.zargar@gmail.com received october 2021 & accepted november 2021 be done in a manner that is oncologically-sound, whereby tumour spillage and seeding are avoided(3,4). previously, surveillance following nu has remained as the standard of care for utuc, with systemic chemotherapy not being recommended(5). however, recent level 1 rct evidence from the pout trial(6) assessed the efficacy of adjuvant platinum-based chemotherapy in patients with locally-advanced utuc, showing that gemcitabine-platinum combination chemotherapy administered within 90 days after nu reduces rates of recurrence and improves disease-free survival. this study suggests that adjuvant chemotherapy be recommended as the new guideline for management post-nu. onu involves two separate procedures; the nephrectomy and distal ureterectomy, with each of these parts being able to be performed with an open or minimally-invasive approach. multiple approaches have been described for the resection of the distal ureter and bladder cuff after mobilization of the kidney and upper ureter. it has been shown that if the distal intramural ureter urology journal/vol 18 no. 6/ november-december 2021/ pp. 585-599. [doi: 10.22037/uj.v18i.7024] review distal ureter in nu-morriss et al. review 586 table 1a. contemporary (2009 – 2021) oncological data comparing endoscopic vs non-endoscopic approaches study approach to nu patients mean age length of intravesical other recurrence cfs, os, css (%) dsm and year and distal ureter (n) (years) follow-up (months) recurrence no. (%) no. (%) metastasis no. (%) (disease specific mortality), n (%) xylinas et al. transvesical 1811 68.7 61.1 388 (21.4) 526 (29) rfs: 66 css: 71 419 (23.1) 2014 (36) extravesical endoscopic 785 67.7 52.3 160 (20.3) 204 (25.9) os: 66 175 (22.3) 85 69.6 36.1 29 (34.1) 18 (21.2) rfs: 66 css: 70 11 (12.9) os: 66 rfs: 69 css: 82 os: 69 chiang et al. hand-assisted 98 67.54 25.28 26 (26.53) 12 (12.24) mets: 14 (14.29) 6 (6.12) 2011 (37) retroperitoneoscopic 110 65.2 27.88 32 (29.09) 11 (10.00) mets: 11 (10.00) 9 (8.18) transurethral bladder cuff incision-assisted fragkoulis et al. open 192 69.2 60 46 (24) css: 74 2017 (38) transurethral 186 68.7 50 (27) css: 75 kapoor et al. extravesical 316 69.9 24.6 77 (24.4) rfs: 35.6 136 (16.6) 2014 (7) intravesical 406 69.2 66 (16.3) rfs: 46.3 endoscopic 98 70.0 23 (23.5) rfs: 30.1 kim et al. hand-assisted 28 68 6 (21.4) 2014 (39) retroperitoneoscopic li et al. 2010 (40) intravesical 81 65.4 33 19 (23.5) 10 (12.3) mets: 6 (7.4) 15 (18.5) extravesical 129 39 31 (24.0) 15 (11.6) mets: 13 (10.1) 17 (13.2) transurethral 91 30 16 (17.6) 7 (7.7) mets: 5 (5.5) 9 (9.9) ou and yang hand-assisted 30 69.9 25.8 7 (23) 1 mets: 0 2014 (41) retroperitoneoscopic: no ureteral ligation hand-assisted 31 67.8 53.1 11 (35) 4 mets: 2 retroperitoneoscopic: earlier ureteral ligation cormio et al. open with transurethral 13 64.7 39.8 4 (30.1) 0 (1) 2013 (42) distal ureter balloon occlusion and detachment cormio et al. open with flexible 10 68.2 31.1 2 (20.0) 0 (0) 2014 (43) cystoscope-assisted transurethral distal ureter balloon occlusion and detachment geavlete et al. endoscopic pluck with 42 14 6 (14) 2 (5) 2 (4.8) 2012 (44) bipolar plasma vaporisation gillan et al. (45) laparoscopic 6 73.6 12 0 (0) endoscopic open 12 75.2 2 12 71.8 1 lai et al. (46) intravesical extravesical 99 69 44.2 (17.2) css: (11.1) 20 (8.1) transurethral endoscopic 96 (12.5) css: (5.2) 53 (13.2) css: (7.5) ryoo et al. (47) transvesical resection 477 64.4 36.5 157 (32.9) intravesical recurrence extravesical ligation 379 65.3 38.2 163 (43.0) free survival ivrfs: 59.9 css: 82.0 os: 79.7 ivrfs: 49.3 css: 73.8 os: 68.0 allard et al. (48) extravesical intravesical 29 72.4 22 8 (26.7) urothelial recurrence mets: 6 (20.6) transurethral incision 20 70.4 7 (35.0) : 8 (26.7) mets: 2 (10.0) 61 70.1 19 (31.1) urothelial recurrence: mets: 10 (16.4) 8 (38.1) urothelial recurrence: 20 (32.8) carrion et al. (49) endoscopic resection 32 70 32 5 (15.6) 7 (21.9) css: 84 months 5 (15.6) endoscopic bladder cuff 57 70.1 9 (15.8) 13 (22.8) css: 89 months 10 (17.5) open extravesical 21 67.8 4 (19) 11 (52.4) css: 48 months 11 (52.4) open intravesical 42 70.81 20 (47.6) 11 (26.2) css: 71 months 10 (23.8) bragayrac et al. (50) transvesical 5 70 16.2 0 (0) mets: 1 (20) laparoendoscopic single-site pang et al. (51) open transurethral 24 5 1 electrosurgery 17 4 0 transurethral endoscopic 17 2 0 two-micron thulium laser resection table 1b. contemporary (2009 – 2021) oncological data comparing onu vs minimally-invasive nu study and approach patients (n) mean age length of intravesical other cfs, os, dsm year to nu and (years) follow-up recurrence css (%) (disease-specific distal ureter (months) no. (%) metastasis no. (%) mortality), n (%) ariane et al. (52) open laparoscopic 459 69.8 40.4 css: 78.0 rfs: 50.7 150 69.5 24.5 mets: 97 (21.1) css: 90.7 rfs: 52.2 mets: 21 (14) blackmur et al. (53) open laparoscopic 13 67.5 57.0 4 (30.8) 1 (7.7) os: 73.5 pfs: 13 68.0 25.8 4 (30.8) 4 (30.8) 56.0 css: 73.5 os: 59.1 pfs: 24.0 css: 60.9 eandi ja et al. (54) robotic-assisted 11 67.4 15.2 4 (36.4) mets: 2 (18.2) 4 (36.4) fairey et al. (55) open laparoscopic 403 70.5 26 os: 67 dss: 73 446 72.4 rfs: 43 os: 68 dss: 76 rfs: 33 favaretto rl open laparoscopic 109 71 23 51 (31.5) 19 (11.7) css: 86 rfs: 38 26 (16.0) et al. (56) 53 73 15 (9.3) 14 (8.6) css: 82 rfs: 42 9 (5.6) hemal et al. (34) robotic-assisted 15 66.27 short-term 0 0 lim et al. (57) robotic-assisted 32 66.5 45.5 10 (31.3) 14 (43.8) os: 60.9 css: 75.8 7 (21.9) rfs: 68.1 park et al. (58) laparoscopic 101 66.4 14 distant + bladder distant + 6 (5.9) recurrence: 22.8 bladder recurrence: 22.8 walton et al. (59) open laparoscopic 703 68 36 165 (23.5) rfs: 73.7 css: 75.4 146 (20.8) 70 70 17 17 (24.3) rfs: 63.4 css: 75.2 9 (12.9) capitano et al. (60) open laparoscopic 979 68.3 62 total recurrence: 250 (25.5) css: 73.1 rfs: 270 70.2 total recurrence: 27 (10.0) 76.2 css: 85.8 rfs: 86.8 217 (22.8) 21 (7.8) wang et al. (61) open laparoscopic 72 66.1 42.4 18 (25.0) 7 (9.7) css: 80.3 rfs: 59.2 12 (16.7) 86 68.7 16 (18.6) 15 (17.4) css: 80.7 rfs: 62.8 10 (11.6) zou et al. (62) open laparoscopic 101 63.8 53 css: 79.2 21 63.2 css: 85.7 simone et al. (63) open laparoscopic 40 61.3 44 9 (22.5) css: 89.9 mets: 6 (15) 4 (10) 40 59.6 10 (25.0) mfs (metastasis-free 8 (20) survival): 77.4 css: 79.8 mets: 11 (27.5) mfs: 75.5 greco et al. (64) open laparoscopic 70 67.2 60 5 (7.1) dfs (disease-free 70 66.4 3 (4.3) survival):73 dfs: 75 kamihira et al. (65) laparoscopic 1003 68.6 20 (43) 134 (13.4) rfs: 42 (4) os: 70 kitamura et al. (66) open 34 69 70 css: 74.2 rfs: 57.1 hand-assisted 9 65 css: 72.9 rfs: 12.5 laparoscopic css: 87.4 rfs: 69.2 laparoscopic 65 70 lim et al. (67) robotic-assisted 38 66.5 40.6 10 (26.3) 145 (39.5) 7 (18.4) pugh et al. (68) robotic-assisted 43 68.3 9.6 6 (14) 3 (7) yang et al. (69) robotic-assisted 20 70.1 14.7 3 (15) 4 (20) mets: 4 (20) miyazaki et al. (70) open laparoscopic 527 69.5 39.0 174 (33.0) 64 (12.1) os: 69.5 css: 73.0 222 70.1 69 (31.1) 27 (12.2) mets: 186 (35.3) os: 72.4 css: 76.0 mets: 75 (33.8) stewart et al. (71) open laparoscopic 39 68.1 177 15 (39) os: 64 pfs (progression 8 (21) 23 67.4 146 9 (39) -free survival): 79 css: 80 7 (30) os: 61 prs: 76 css: 71 aboumohamed robotic-assisted 65 69.1 25.1 15 (27.2) 13 (20) os: 62.6 et al. (31) css: 92.9 rfs: 57.1 mets: 8 (13.3) ambani et al. (72) robotic-assisted 22 70.1 10 8 (36) 7 (32) 2 (9) laparoscopic 22 70.8 15 7 (37) 5 (23) 2 (9) badani et al. (33) robotic-assisted 26 66 7.8 4 (15) 0 (0) chen et al. (73) open with early ligation 42 63 28 21 (25) 5(6) of distal ureter 43 67 open with late ligation of distal ureter hattori et al. (26) laparoscopic 10 19 19 1 (10) 3 (30) 1 (10) hu et al. (74) robotic-assisted 18 70.4 6.1 2 (11.1) 0 (0) mets: 4 (22.2) 1 (5.6) hand-assisted laparoscopic 197 67.7 47.8 6 (33.3) 2 (11.1) mets: 2 (11.1) 3 (16.7) distal ureter in nu-morriss et al. vol 18 no 6 november-december 2021 587 study and approach patients (n) mean age length of intravesical other cfs, os, dsm year to nu and (years) follow-up recurrence css (%) (disease-specific distal ureter (months) no. (%) metastasis no. (%) mortality), n (%) lambert et al. (75) laparoscopic 22 65.6 20 3 (13.6) 2 (9.1) liu et al. (76) laparoscopic 31 66.8 10.5 0 (0) 0 (0) mak et al. (77) pneumovesicum-assisted 10 71.6 46 4 (40) 1 (10) laparoscopic ritch et al. (27) open laparoscopic 10 68 16 2 (20) 0 (0) mets: 0 (0) 0 (0) stapling 14 70 21 2 (14.3) 2 (14.3) mets: 2 (14.3) 1 ((7.1) laparoscopic resection 12 71 7 0 (0) 0 (0) mets: 0 (0) 0 (0) and suturing shoma et al. (78) laparoscopic 13 50 31.5 2 (15) 1 (8) 1 (8) song et al. (79) hand-assisted 67 66.2 17.6 9 (13) 9 (13) mets: 9 (13) 2 (3) laparoscopic waldert et al. (80) open laparoscopic 59 68.46 41 16 (27) 13 (22) cfs: 76 css: 80 mets: 43 65.56 41 11 (26) 5 (12) 7 (12) cfs: 79 css: 85 mets: 5 (11) ziaee et al. (81) laparoscopic nu 22 64.1 36.57 3 (4) 2 (9) 3-yr os: 95 1 (4.5) with open bce 3-yr metastasis-free survival: 90 gillan et al. (45) laparoscopic 6 73.6 12 0 (0) endoscopic 12 75.2 2 open 12 71.8 1 hora et al. (82) laparoscopic 12 71.3 25.7 1 (8.3) mets: 1 (8.3) pai et al. (83) laparoscopic 59 67 58 9 (53) 8 (47) css: 80 agarwal et al. (18) laparoscopic with poly 6 64.2 12-30 2 (33.3) 0 (0) loop ligation hoe et al. (19) laparoscopic with polyloop ligation 76 71.5 bladder rfs: 24.3 0 (0) os: 70.3 contralateral rfs 47.9: css: 84.7 local rfs: 49.8 bladder rfs: 59.6 mfs (metastasis-free local rfs: 89.0 survival): 52.5 contralateral rfs: 93.5 os: 52.5 metastasis-free survival: css: 47.9 73.5 port-site metastasis: 0 (0) carrion et al. (84) laparoscopic 117 70 20 5 (14) 36 (30) css: 61 progression-free 28 (24) survival: 52 krabbe et al. (11) laparoscopic with no 46 69.5 32.0 12 (26.1) 13 (28.3) intravesical recurrence transvesical bladder cuff free survival (ivr fs): 22 (18.0) laparoscopic with 76 68.0 33 (43.4) 10 (13.2) 71.6 months transvesical bladder cuff non-ivr fs: 120.0 css: 123.5 months ivr-fs: 82.5 months non-ivr fs: 83.9 months css: 83.0 months shigeta et al. (85) laparoscopic 129 71 31.1 61 (47.3) css: 29.5 months 31 (24.0) os: 35.6 months guo et al. (86) laparoscopic with 238 65.3 36.5 4 (10.5) 0 (0) css: 100 micrometer continuous bladder recurrence-free wave laser rate: 89 extravesical recurrence-free rate: 100 mets: 0 (0) zou et al. (87) laparoscopic one-port 6 57.2 18 0 (0) 0 (0) pneumovesicum liu et al. (88) open laparoscopic 213 62.5 44 40 (18.8) total intravesical rfs: 79 52 60.2 6 (11.5) recurrence: overall rfs: 47 109 (51.1) mets: 71 (33.3) total css: 63 recurrence: os: 61 20 (38.5) intravesical rfs: 88 overall rfs: 59 mets: 13 (25.0) css: 70 os: 55 bragayrac et al. (50) transvesical 5 70 16.2 0 (0) mets: 1 (20) laparoendoscopic single-site lee et al. (89) robotic-assisted 20 71 13.5 1 khanna et al. (90) robotic-assisted 3 69.3 17.8 0 (0) 0 (0) ghazi et al. (17) laparoscopic 8 65.3 12.1 3 (37.5) 1 (12.5) vasdev et al. (91) robotic-assisted 7 59 0 (0) lister technique distal ureter in nu-morriss et al. review 588 is not fully excised and a ureteric stump left behind, the risk of recurrence is anywhere from 33-75%(7). lughezzani et al. reported a 1.25-1.45 times increased risk of cancer-specific mortality if the bladder cuff excision was omitted(8). here we will review the various surgical techniques and current literature on the management of the distal ureter during nephroureterectomy. materials and methods a medline search of the literature including relevant articles up to march, 2020 was performed. search terms included “nephroureterectomy”, “upper tract urothelial carcinoma”, “upper urinary tract carcinoma or utuc”, “open or conventional or onu or conventional”, “robotic-assisted nephroureterectomy or ranu”, “laparoscop* or lnu or lrnu” and “minimally-invasive nephroureterectomy”. original articles, case series and review articles were included. results approaches to the distal ureter various approaches have been described as seen in figure 1. the standard practice is to remove the intramural ureter along with ureteric orifice (uo), and a cuff of bladder around the uo. ideally, this is achieved by an en bloc removal of specimen after controlled occlusion of the uo. in a systemic review and meta-analysis of clinicopathologic factors associated with intravesical recurrence after rnu by seisen et al(9) it was shown that there is significant risk of tumor recurrence in the distal ureter and its orifice. poorer cancer-specific survival and overall survival has been seen in patients who did not have a bladder cuff excision during their nu(10,11). the optimal approach to managing the distal ureter and bladder cuff has been controversial due to different techniques described. these techniques can be classified as open (intravesical/transvesical approaches), endoscopic or minimally-invasive approaches, with some techniques employing a combination of these(12). the open approach has been traditionally regarded as the gold standard(2). however, advances in minimally-invasive technology have enabled urologists to expand their armamentarium in managing the distal ureter. the challenges of all these techniques are to remove the entire specimen en bloc, without tumour spillage, and to conform to strict oncological principles in the least invasive way possible. open excision (onu) an open approach to the distal ureter is considered the gold standard for excision of the distal ureter and bladder cuff. it is generally performed after the nephrectomy is complete, occurring after either a laparoscopic or open procedure to dissect the kidney and ureter. the distal ureter may then be approached in two ways, either intravesically/transvesically or extravesically(13). the intravesical or transvesical approach begins with an anterior cystotomy to provide access to the bladder cuff, followed by dissection of the ureter. once the contralateral ureteral orifice is identified, followed by a 5-10 mm circumferential excision around the ipsilateral ureteral orifice through the full thickness of the bladder. the intramural ureter is dissected until the proximal ureteral dissection is reached, allowing the specimen to be removed en bloc. benefits to this technique include better visualisation of the contralateral ureter and intramural study approach patients mean age complication clavien mean mean length of estimated blood and year to nu (n) (years) rate, no. (%) classification operating hospital stay loss (ml) ≥ 3 (iii-v) time (min) (days), range chen et al. (73) open with early 42 63 0 (0) 220.19 9.5 105.15 ligation of distal ureter open with late ligation 43 67 0 (0) 215.73 10 110.12 of distal ureter chiang et al. (37) hand-assisted 98 67.54 144 7.3 67 retroperitoneoscopic transurethral bladder 110 65.2 173 8.8 86 cuff incision-assisted fragkoulis et al. (38) open 192 69.2 143 7.1 transurethral resection/pluck 186 68.7 115 6.9 cormio et al. (42) open with transurethral 13 64.7 1 (7.7) 0 (0) open nu: 8.1 (5-10) distal ureter balloon 108 occlusion before detachment distal ureter and bce: 21.3 cormio et al. (43) open with flexible 10 68.2 0 (0) 113.4 6.5 (5-10) cystoscope-assisted transurethral distal ureter balloon occlusion and detachment geavlete et al. (44) endoscopic pluck with 42 2 (4.8) 15 bipolar plasma vaporisation gillan et al. (45) laparoscopic 6 73.6 0 (0) 190 6.3 (4-8) 200 endoscopic 12 75.2 0 (0) 180 7.1 (5-12) 180 open 12 71.8 1 200 12 (7-19) 240 pang et al. (51) open 24 233 12.7 352.0 transurethral 17 148.1 9.8 136.5 electrosurgery transurethral endoscopic 17 126.5 9.9 141.0 two-micron thulium laser resection table 2a. contemporary (2009 – 2021) perioperative outcomes comparing endoscopic vs non-endoscopic approaches distal ureter in nu-morriss et al. vol 18 no 6 november-december 2021 589 review 590 study approach patients mean age complication clavien classification mean operating mean length of estimated and year to nu (n) (years) rate, no. (%) ≥ 3 (iii-v) time (min) hospital stay blood loss (ml) (days), range ariane et al. (52) open 459 69.8 23 (5) 19 (4.1) 180 9 (7-12) laparoscopic 150 69.5 9 (6) 7 (4.6) 240 8 (6-12) blackmur et al. (53) open 13 67.5 4 (30.8) 2 (15.4) 194 10 (5-29) laparoscopic 13 68.0 3 (23.1) 0 (0) 191 7 (3-10) eandi ja et al. (54) ralnu 11 67.4 326 4.7 200 favaretto rl open 109 71 164 5 (4-6) 250 et al. (56) laparoscopic 53 73 265 3 (3-4) 200 hemal et al. (34) robotic 15 66.27 0 (0) 183.87 2.73 (2-5) 103 -assisted lim et al. (57) robotic32 66.5 7 (28.1) 2 (6.2) 250.1 6.2 263 assisted park et al. (58) laparoscopic 101 66.4 6 (5.9) 1 (1.0) 221.4 6.3 231.7 wang et al. (61) open 72 66.1 148.5 7.3 286.1 laparoscopic 86 68.7 133.2 5.5 176.3 simone et al. (63) open 40 61.3 0 (0) 78 3.65 (3-5) 430 laparoscopic 40 59.6 82 2.3 (2-3) 104 greco et al. (64) open 70 67.2 240 190 laparoscopic 70 66.4 kamihira et al. (65) laparoscopic 1003 68.6 93 (9.3) 320 232 kitamura et al. (66) open 34 69 5 (15) 286 14.5 (5-36) 475 hand 9 65 2 (22) 325 17 (9-24) 250 assisted laparoscopic laparoscopic 65 70 7 (11) 327 10 (4-62) 220 lee et al. (92) laparoscopic 10 62.79 4 (40) 225.63 4.75 187.50 lim et al. (67) robotic38 66.5 10 (25.0) 2 (5.3) 249 6.0 264 assisted pugh et al. (68) robotic43 68.3 6 (14) 247 3 (2-87) 131 assisted trudeau et al. (93) laparoscopic 735 70.6 134 (18.2) 5.83 robotic715 70.7 85 (11.9) 5.6 assisted yang et al. (69) robotic20 70.1 0 (0) 251.6 6.7 (4-12) 50.0 assisted hanske et al. (94) minimally599 71 77 (12.9) 160 (26.7) > 282 mins 137 (22.9) > 6 days invasive (laparoscopic + robotic-assisted) open 297 69 37 (12.5) 66 (22.2) > 282 mins 135 (45.5) > 6 days stewart et al. (71) open 39 68.1 5 (12.8) 180 10 (5-29) 398 laparoscopic 23 67.4 1 (4.3) 165 7 (2-30) 280 ambani et al. (72) robotic22 70.1 8 (36.4) 1 (5) 298 3.1 380 assisted laparoscopic 22 70.8 6 (27.3) 1 (5) 251 3.1 233 badani et al. (33) robotic26 66 0 (0) 230 2 (1-15) 66 assisted chen et al. (73) open with 42 63 0 (0) 220.19 9.5 105.15 early ligation of distal ureter open with late 43 67 0 (0) 215.73 10 110.12 ligation of distal ureter hu et al. (74) robotic18 70.4 255.17 6.79 (3.7-12) 68.89 assisted hand-assisted 197 67.7 250.17 9.61 (4-26) 358.33 laparoscopic kim et al. (39) hand28 68 5 (17.9) 240 8 (5-10) 250 assisted retroperitoneoscopic lambert et al. (75) laparoscopic 22 65.6 4 227 3.5 (1-13) 158 liu et al. (76) laparoscopic 31 66.8 0 (0) 146.6 6 (4-8) 47.3 mak et al. (77) laparoscopic 10 71.6 1 (10) 7.5 10.2 (6-16) minimal ritch et al. (27) open 10 68 1 (10) 276 3.5 (2-6) 163 laparoscopic 14 70 1 (7) 152 2.7 (2-7) 209 stapling laparoscopic 12 71 1 (8) 163 2.0 (1-3) 112 resection and suturing shoma et al. (78) laparoscopic 13 50 3 (23.1) 226 7 233 song et al. (79) hand67 66.2 1 243.5 8.1 assisted laparoscopic waldert et al. (80) open 59 68.46 2 (3) 212 13.8 (9-16) 542 laparoscopic 43 65.56 1 (2) 220 8.1 (7-9) 300 table 2b. contemporary (2009 – 2021) perioperative outcomes comparing onu vs minimally-invasive nu distal ureter in nu-morriss et al. vol 18 no 6 november-december 2021 591 study approach patients mean age complication clavien classification mean operating mean length of estimated and year to nu (n) (years) rate, no. (%) ≥ 3 (iii-v) time (min) hospital stay blood loss (ml) (days), range ziaee et al. (81) laparoscopic 22 64.1 2 (9) 216 4.3 314 nu with open bce gillan et al. (45) laparoscopic 6 73.6 0 (0) 190 6.3 (4-8) 200 endoscopic 12 75.2 0 (0) 180 7.1 (5-12) 180 open 12 71.8 1 200 12 (7-19) 240 hora et al. (82) laparoscopic 12 71.3 1 (8.3) 164.9 9.3 150.0 pai et al. (83) laparoscopic 59 67 2 (3) 2 (3) 194.4 3.4 125 agarwal et al. (18) laparoscopic 6 64.2 0 (0) 27 minimal with polyloop ligation hoe et al. (19) laparoscopic 76 71.5 23 (30.3) 3 (3.9) 258 6 (3-23) with polyloop ligation guo et al. (86) laparoscopic 38 65.3 1 (2.6) 126 9.6 (5-20) 69.4 with 2-micrometer continuous wave laser zou et al. (87) laparoscopic 6 57.2 0 (0) 114 8.2 (8-9) 89 one-port pneumovesicum bragayrac et al. (50) transvesical 5 70 2 (40) 0 (0) 198 3.8 (2-8) 234 laparoendoscopic single-site roslan et al. (95) transvesical 5 57.4 1 (20) 59 5.2 (4-9) 54 laparoendoscopic single-site vasdev et al. (91) robotic7 0 (0) 241.4 3 (3-7) 101.9 assisted lister technique lee et al. (89) robotic20 71 2 (10) 0 (0) 161.3 3 (1-16) 98.8 assisted won lee et al. (96) robotic68 56 3 (4.4) 219 4.5 (1-16) 319 assisted khanna et al. (90) robotic3 69.3 1 300 3.3 183 assisted ghazi et al. (17) laparoscopic 8 65.3 1 (12.5) 157 10.2 (7-15) figure 1. overview of techniques used to manage the distal ureter during nephroureterectomy distal ureter in nu-morriss et al. ureter and enabling visual confirmation of excision of the bladder cuff. the anterior cystostomy is then closed in two layers. however, there is increased morbidity and longer patient recovery time due to an additional low abdominal incision and cystotomy. this technique should be avoided in patients with bladder urothelial carcinoma, as there is a risk of tumour seeding into the extravesical space(14). the extravesical approach involves mobilisation of the distal ureter down to its insertion into the bladder, securing the bladder cuff with a right-angle clamp, and excising the intramural ureter along with its cuff in a similar 5-10 mm circumferential excision. the specimen is then removed en bloc. compared to the transvesical approach, there is a shorter patient recovery time due to the lack of additional surgical incisions required (14). however, there is the potential for damage to the contralateral ureter and incomplete excision of the distal ureter and bladder cuff due to poorer access and visualisation of the intramural ureter and bladder cuff(3). endoscopic excision the distal ureter can also be approached endoscopically using the pluck technique, also referred to as transurethral resection/excision of the ureteral orifice, or intussusception, also known as the stripping technique. the pluck technique begins prior to nephrectomy, where the ureteral orifice and bladder cuff is endoscopically circumscribed and resected with a collins knife or resectoscope through the intramural portion of the ureter into the perivesical fat(15). following nephrectomy and after dissecting the ureter, the distal ureter is detached or ‘plucked’ from its attachment to the bladder, and removed along with the whole specimen(16). an issue with this technique includes the potential for locoregional tumour recurrence following spillage of tumour cells from an unclamped ureter into the perivesical space. other issues include fluid shifts due to usage of bladder irrigant and the potential for incomplete resection of the ureter if remnant ureter remains following plucking. the pluck technique is therefore contraindicated in patients with distal ureteral tumours(17). to minimise the risk of tumour seeding, early coagulation of the ureteral orifice before dissecting the bladder cuff and early ligation of the ureter before nephroureterectomy recommended. agarwal et al.(18) and hoe et al.(19) suggest a novel modification to this pluck technique called the agarwal loop-ligation technique involving endoscopic loop ligation in a bid to occlude the ureter. following dissection of the distal ureter and bladder cuff with the collins knife, a polyloop placed around the ureteric stump to ligate and occlude the distal ureter, preventing urine spillage from the upper tract. complete excision of distal ureter is ensured as the distal end is marked with the detachable loop. the distal ureteral stump is ligated prior to detaching the ureter or exposing the perivesical fat, providing protection against urine spillage into perivesical space. the distal ureter is then dissected by dividing the periureteric adhesions with a collins knife. although the outcomes of this technique were only analysed in a small series of 6 patients, no perioperative complications were present and with no perivesical tumour recurrence reported in the short-term. the intussusception technique takes place following nephrectomy. the ureter is dissected as distally as possible. then, a bulb-tipped ureteric catheter (chevassu catheter) is inserted past the resected and open end of the ureter. it is then folded over on itself and sutured in place. after resecting the intramural ureter and ureteral orifice endoscopically, the catheter is pulled out, bringing the intussuscepted ureter with it, thus allowing for the entire distal ureter to be removed. the patient is transferred into a lithotomy position to allow for transurethral access and the catheter is pulled inward, causing intussusception of the distal ureter into the bladder. excision is facilitated with a resectoscope(13). issues with this technique include inadequate removal of the distal ureter following stripping and the risk of tumour spillage into the perivesicle space, much like the pluck technique(17). contraindications to this technique are similar to the pluck technique, mainly urothelial carcinoma involving the distal ureter as there is a higher likelihood of incomplete resection with a positive margin. additionally, patients with duplicated ureters, ureteral strictures, prior ureteral surgery, and prior radiation should undergo a different strategy to excise the bladder cuff and distal ureter(13). minimally-invasive excision laparoscopic and robotic-assisted techniques comprise the minimally-invasive methods of managing the distal ureter, and are regarded as the contemporary counterparts to onu. in both, early ligation of the ureter during nephrectomy is performed to prevent tumour seeding to the bladder. earlier works warned about the risk of retroperitoneal metastasis and tumour spillage or port site recurrences(20,21). eau recommends that minimally-invasive techniques are contraindicated for invasive or large (t3/t4 and/or n+/m+) tumours given worse oncological outcomes(2). precautions suggested to lower the risk of tumour spillage include avoiding opening the urinary tract and avoiding direct contact between instruments and the tumour. in addition, avoiding morcellation of the tumour using an endobag for tumour extraction and en bloc removal of the kidney and ureter with the bladder cuff is suggested to ensure the procedure is in carried out in a closed system(2).in modern practice however large tumours can still be managed in a minimally invasive fashion. the first laparoscopic nu was described by clayman et al. in 1991(22), prompting a new age of minimally-invasive techniques to be applied to the treatment of utuc. the laparoscopic approach to the distal ureter and bce can include a transvesical approach using a cystoscopic secured detachment and ligation method (cdl), or it can involve an extravesical approach using a laparoscopic stapling device with the stapling technique being associated with suboptimal oncologic outcomes(23). laparoscopic nephroureterectomy can be performed transperitoneally or retroperitoneally depending on surgeon preference, with retroperitoneal nephroureterectomy having the advantages of reducing bowel mobilization, reducing the risk of visceral injury and reducing the risk of ileus. in addition, if tumor spillage present, it would be confined to the extraperitoneal space(24). the pure laparoscopic technique involves either extravesical stapling of the distal ureter or complete laparoscopic dissection of ureter and bladder cuff and suture closure of the bladder defect(25,26). however, the pure laparoscopic technique is more difficult to perform and port site seeding has been reported(21). the laparoscopic extravesical stapling approach has been associated with remnant ureteric orifice present post-excision in 50% review 592 distal ureter in nu-morriss et al. of the cases(27). robotic-assisted nu(28-30) is being increasingly utilised, with the aim of having equivalent oncological results to open surgery whilst limiting perioperative morbidity and minimising the technical challenges of laparoscopic surgery. it is less technically challenging than laparoscopic nu given the extra degrees of freedom and articulation of the robotic platform. multiple reports(31-34) have been published documenting the perioperative feasibility and safety of the robotic approach as well as encouraging early oncologic outcomes. however, there is a dearth of long-term oncological outcomes following robotic-assisted nu. early experience with this modality(35) as reported in 2008 involved patient repositioning and robot redocking throughout the procedure. however, innovations in this field have eliminated the need for this. hemal et al.(34) was the first to describe a technique of robotic-assisted nu with bce without requiring intraoperative patient repositioning or redocking of the robot. this technique allows for a seamless transition from upper tract to lower tract surgery without the need to reposition the patient or re-dock the robot. the three ports are strategically placed to allow access to the kidney, ureter, and bladder. after dividing the renal vascular structures, the ureter is clipped, though not divided. the ureter is then dissected distally as much as possible. in cases of ureteric tumours, wide dissection of the ureter is carried out to avoid a positive margin or entry into the ureter. lymphadenectomy is also carried out. bladder stay sutures are placed lateral to the ureterovesical junction to prevent retraction of the bladder once the bladder cuff is excised. it was reported that all fifteen patients were operated on successfully without perioperative complications, no positive surgical margins present and with no recurrences detected in the short-term. zargar et al.(32) describes a similar technique for robotic-assisted nu where there is also no need for patient repositioning or robot redocking. the approach to bce involves dissecting the detrusor muscle until there is tenting of the bladder mucosa, followed by placement of lateral and medial 2-0 vicryl polyglactin sutures. following circumferential excision of the bladder cuff, the two sutures are tied together to close the bladder defect and ensure watertight closure. another difference with this approach is port placement where the ports are all placed along the lateral rectus muscle to combine maximum accessibility for the nephrectomy portion of the surgery and further enabling pelvic access to facilitate proper bladder cuff dissection. there were no major complications in the thirty-one patients included in this series. nu using a three-arm robotic approach cannot only provide the surgeon with a more feasible approach for performing the operation, but also provides for a less expensive operation. comparing oncological and perioperative outcomes of endoscopic techniques with non-endoscopic techniques 17 studies were found that assessed oncological outcomes of endoscopic versus non-endoscopic techniques, as can be seen in table 1a. the largest study found was a retrospective analysis of 2681 patients undergoing an open transvesical, open extravesical or endoscopic approach by xylinas et al.(36), finding that the endoscopic approach was associated with higher rates of intravesical recurrence (34.1%) compared to the other two approaches (21.4% and 20.3%). as discussed previously, this lends credence to the issue of tumour spillage associated with the endoscopic approach. interestingly, no differences in non-bladder recurrence and survival were seen between the approaches. other large studies that compared endoscopic and non-endoscopic approaches such as kapoor et al.(7) found that in 820 patients, open intravesical excision was associated with lower intravesical recurrence in comparison to endoscopic and extravesical approaches. on the other hand, li et al.(40) analysed 301 patients and found that there was no statistically significant difference in recurrence-free and cancer-specific survival between endoscopic and non-endoscopic techniques. allard et al.(48) found similar recurrence and metastasis rates in 110 patients who underwent either open or endoscopic approaches, with lai et al.(46) also finding comparable intravesical recurrence rates, along with no statistically significant differences in cancer-specific and overall survival. novel endoscopic approaches such as that described by geavlete et al.(44) involving a variation of the pluck technique using bipolar plasma vaporisation found intravesical recurrences in 14% of patients. 8 studies were found that assessed perioperative outcomes of endoscopic versus non-endoscopic approaches as can be seen in table 2a. endoscopic approaches are generally associated with better perioperative outcomes, including shorter operating times, length of stay and less blood loss as can be seen in table 3a. fragkoulis et al.(38) collected data from 378 patients and found the endoscopic approach had a lower mean operating time of 115 minutes versus the open approach of 143 minutes. in another study, gillan et al.(45) compared laparoscopic, endoscopic and open approaches, concluding that the endoscopic approach had the shortest mean operating time and estimated blood loss. similarly, pang et al.(51) found that operating time, length of stay and blood loss were lower in the endoscopic group compared with the open approach. comparing oncological and perioperative outcomes of open with minimally-invasive techniques 51 studies were found that assessed oncological outcomes of open versus minimally-invasive techniques, as can be seen in table 1b. ariane et al.(52) found a higher cancer-specific survival and reduced metastasis rate in those who underwent a laparoscopic versus an open approach. however, in an analysis of 159 patients blackmur et al. did not find significant difference in 5-year survival between these two approaches. this was also seen with fairey et al.(55), with no significant difference in overall survival seen between the two groups. although favaretto et al.(56) also found similar rates of cancer-specific and recurrence-free survival, there was a reduced number of intravesical recurrences seen in the laparoscopic (9.3%) versus the open group (31.5%). however, walton et al.(59) found there to be no significant difference in non-bladder recurrence between the two groups. a meta-analysis by piszczek et al.(97) also concluded that laparoscopic and open nu have comparable oncological outcomes, with no statistically significant difference present among any of the measured oncological outcomes (cancer-specific survival, overall survival, intravesical recurrence-free survival, recurrence-free survival). novel minimally-invasive techniques like the agarwal polyloop ligation technique(19) has been shown to distal ureter in nu-morriss et al. vol 18 no 6 november-december 2021 593 be oncologically valid in the long-term, with no cases of intravesical recurrence detected, and cancer-specific and overall survival comparable to other studies seen in the table. moschini et al.(98) compared oncological outcomes of laparoscopic versus open approaches using a propensity matching analysis approach, concluding that there is no difference in oncological efficacy (overall recurrence and cancer-specific mortality) between the two approaches. another systematic review of open versus laparoscopic nu by peyronnet et al.(99) concluded that there are worse cancer-specific survival and overall survival in patients who have locally advanced high-risk that have underwent laparoscopic nu compared to open nu. however, in another systematic review and meta-analysis between open and laparoscopic nu, liu et al. (100) found that there was no significant difference in oncological and perioperative outcomes between the two techniques, but did note a longer mean operative time in those that underwent laparoscopic nu. nouralizadeh et al. (101) performed a meta-analysis comparing oncological and perioperative outcomes of open, laparoscopic, and hand-assisted laparoscopic nu, finding that the three techniques had comparable oncological outcomes, but with laparoscopic and hand-assisted laparoscopic nu having better perioperative outcomes when compared with open surgery. it was also found that a laparoscopic approach was associated with a longer operative time. looking at a perioperative standpoint as can be seen in table 2b, minimally-invasive techniques are on average associated with a higher mean operating time but with less blood loss. as seen in table 3b, ariane et al.(52), favaretto et al.(56), wang et al.(61), greco et al.(64), kitamura et al.(66) and hanske et al.(94) report higher mean operating times versus open approaches. favaretto et al. (56), wang et al.(61), simone et al.(63), kitamura et al.(66), waldert et al.(80) and gillan et al.(45) found lower estimated blood loss with minimally-invasive approaches versus open procedures. trudeau et al.(93) retrospectively analysed robotic-assisted nu vs laparoscopic nu and found that they perioperative complication rate for robotic-assisted nu was lower versus laparoscopic nu. in a systematic review by mullen et al.(102) comparing open versus laparoscopic versus robotic-assisted nu, laparoscopic techniques were similarly found to be oncologically comparable to open nu but with improved perioperative outcomes (estimated blood loss and length of hospital stay). the paucity of high-quality evidence surrounding the use of robotic-assisted nu was noted and therefore no conclusions with respect to this modality could be drawn. however, estimated blood loss and hospital length of stay tend to be lower in the minimally-invasive groups versus the open approach. a similar 2019 systematic review and meta-analysis of over 87,000 patients by veccia et al.(103) sought to compare robotic-assisted nu with other techniques (including open, laparoscopic and hand-assisted laparoscopic nu), also noting the lack of high quality data surrounding this topic and was unable to conclude the best technique for nu. they concluded that the techniques analysed in the review are all oncologically-valid, with more long-term oncologic data needed surrounding robotic-assisted nu. additional approaches to nu kidney-sparing surgery (kss) is utilised for low-risk utuc, as opposed to radical nu for high-risk disease. this is since radical nu significantly reduces the nephron mass by at least 50%, predisposing the patient to chronic kidney disease and associated increased risk of cardiovascular events, morbidity, and mortality. kss has been shown to have comparable oncological outcomes compared to radical nu in low-risk disease (104,105), and as a result the european association of urology(2) recommends this modality for all low-risk patients irrespective of the status of the contralateral kidney, and in select patients with ckd or that have a solitary kidney(106). low-risk disease (localised, non-metastatic disease) is defined as having all of the following features: unifocal disease, tumor size less than 2 cm, low-grade cytology, low-grade urs biopsy and no invasive aspect on ct urography. an important point to note when offering kss is that the patient must be willing to undergo repeated and stringent surveillance follow-up including upper tract imaging, flexible cystoscopy, ureteroscopy, and urine cytology(106). conclusions although endoscopic approaches have more favourable perioperative outcomes, this comes at the expense of increased risk of tumour spillage and recurrence compared to the traditional open approaches. minimally-invasive techniques (laparoscopic and robotic-assisted nu) largely have superior perioperative outcomes versus their open nu 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sk, ng cf, chan es, yip sk, cheng cw, wong ws. pneumovesicum approach to en-bloc laparoscopic nephroureterectomy with bladder cuff excision for upper tract urothelial cancer: midterm oncological results. j endourol. 2011;25:611-4. 78. shoma am. purse-string technique for laparoscopic excision of a bladder mucosal cuff in patients with transitional cell distal ureter in nu-morriss et al. carcinoma of the upper urinary tract: initial report with intermediate follow-up. bju int. 2009;104:1505-9. 79. song g, han ks, song sh, choo ms, ahn h, hong b. hand-assisted laparoscopic bladder cuff excision via the same hand port as that used for nephroureterectomy. world j urol. 2015;33:1459-65. 80. waldert m, remzi m, klingler hc, mueller l, marberger m. the oncological results of laparoscopic nephroureterectomy for upper urinary tract transitional cell cancer are equal to those of open nephroureterectomy. bju int. 2009;103:66-70. 81. ziaee sa, azizi v, nouralizadeh a, gooran s, radfar mh, mirzaei m. laparoscopic nephroureterectomy with concomitant open bladder cuff excision: a single center experience. urol j. 2012;9:652-6. 82. hora m, eret v, urge t, klecka j, kocovská p, petr s, et al. antegrade miniinvasive nephroureterectomy: laparoscopic nephrectomy, transurethral excision of ureterovesical junction and lower abdominal incision. urol int. 2009;83:264-70. 83. pai a, hussain m, hindley r, emara a, barber n. long-term outcomes of laparoscopic nephroureterectomy with transurethral circumferential excision of the ureteral orifice for urothelial carcinoma. j endourol. 2017;31:651-4. 84. carrion a, huguet j, garcía-cruz e, izquierdo l, mateu l, musquera m, et al. intraoperative prognostic factors and atypical patterns of recurrence in patients with upper urinary tract urothelial carcinoma treated with laparoscopic radical nephroureterectomy. scand j urol. 2016;50:305-12. 85. shigeta k, kikuchi e, hagiwara m, ando t, mizuno r, miyajima a, et al. prolonged pneumoperitoneum time is an independent risk factor for intravesical recurrence after laparoscopic radical nephroureterectomy in upper tract urothelial carcinoma. surg oncol. 2017;26:73-9. 86. guo g, yang y, dong j, zhenhong z, zhang x. a new 2-micrometer continuous wave laser method for management of the distal ureter in retroperitoneal laparoscopic nephroureterectomy. j endourol. 2015;29:4304. 87. zou x, zhang g, wang x, yuan y, xiao r, wu g, et al. a one-port pneumovesicum method in en bloc laparoscopic nephroureterectomy with bladder cuff resection is feasible and safe for upper tract transitional cell carcinoma. bju int. 2011;108:1497-500. 88. liu jy, dai yb, zhou fj, long z, li yh, xie d, et al. laparoscopic versus open nephroureterectomy to treat localized and/ or locally advanced upper tract urothelial carcinoma: oncological outcomes from a multicenter study. bmc surg. 2017;17:8. 89. lee z, cadillo-chavez r, lee di, llukani e, eun d. the technique of single stage pure robotic nephroureterectomy. j 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"the lister technique": a new technique for the management of the distal ureter during radical robotic nephroureterectomy. j robot surg. 2013;7:407-8. 92. lee jy, kim sj, moon hs, kim yt, lee ty, park sy. initial experience of laparoendoscopic single-site nephroureterectomy with bladder cuff excision for upper urinary tract urothelial carcinoma performed by a single surgeon. j endourol. 2011;25:1763-8. 93. trudeau v, gandaglia g, shiffmann j, popa i, shariat sf, montorsi f, et al. robot-assisted versus laparoscopic nephroureterectomy for upper-tract urothelial cancer: a populationbased assessment of costs and perioperative outcomes. can urol assoc j. 2014;8:e695701. 94. hanske j, sanchez a, schmid m, meyer cp, abdollah f, feldman as, et al. a comparison of 30-day perioperative outcomes in open versus minimally invasive nephroureterectomy for upper tract urothelial carcinoma: analysis of 896 patients from the american college of surgeons-national surgical quality improvement program database. j endourol. 2015;29:1052-8. 95. roslan m, markuszewski m, kłącz j, sieczkowski m, połom w, piaskowski w, et al. laparoscopic nephroureterectomy with transvesical single-port distal ureter and bladder cuff dissection: points of technique and initial surgical outcomes with five patients. wideochir inne tech maloinwazyjne. 2014;9:267-72. 96. won lee j, arkoncel fr, rha kh, choi kh, yu hs, chae y, et al. urologic robot-assisted laparoendoscopic single-site surgery using a homemade single-port device: a singlecenter experience of 68 cases. j endourol. 2011;25:1481-5. 97. piszczek r, nowak ł, krajewski w, chorbińska j, poletajew s, moschini m, et al. oncological outcomes of laparoscopic versus open nephroureterectomy for the treatment of upper tract urothelial carcinoma: an updated meta-analysis. world j surg oncol. 2021;19:129. 98. moschini m, zamboni s, afferi l, pradere b, abufaraj m, soria f, et al. comparing oncological outcomes of laparoscopic vs open radical 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ureter in nu-morriss et al. urol_montage.pdf urology in history 63urology journal vol 6 no 1 winter 2009 avicenna’s canon of medicine and modern urology part ii: bladder calculi seyed mohammad ali madineh in the previous issue of the urology journal, a comparison of avicenna’s canon of medicine with modern urologic findings was done in part i of this article, addressing bladder anatomy and physiology and bladder calculi. in part ii of this review, the remaining chapters of the canon of medicine on bladder calculi are reviewed. avicenna points to perineal urethrostomy (perineostomy), which is today performed as the last therapeutic line or as a temporary remedy before surgical treatment. he also describes surgery via transperineal route and warns the surgeon of the proximity of vasa deferentia, prostate gland, and neurovascular bundle and their exposure in this position. usage of grasping forceps for removal of bladder calculus and emphasis on removing all calculus fragments are the interesting points of this chapter. avicenna explains a technique similar to the use of a babcock forceps for prevention of calculus migration. complications of bladder calculus surgery and cystotomy are also addressed with scientific precision in the canon. it is noteworthy that 8 centuries before fournier described necrotizing fasciitis in male genitalia, avicenna had described fournier gangrene in his book. urol j. 2009;6:63-8. www.uj.unrc.ir urology and nephrology research center, shahid beheshti university (mc), tehran, iran corresponding author: seyed mohammad ali madineh, md mostafa khomeini hospital, italia st, tehran, iran tel: +98 21 6643 8140 fax: +98 21 6690 7895 e-mail: madinehurologist@yahoo.com introduction the famous iranian scientist and philosopher, avicenna, continued for centuries to have a great influence on the medical knowledge of the world by writing the canon of medicine (figure 1). in part i of this article, i compared chapters of avicenna’s book with modern urological findings which were on bladder physiology and anatomy as well as bladder calculi.(1) in part ii, review of book 3, part 19 is continued focusing on surgical treatment of bladder calculus. materials and methods this study is the comparison of modern urology with the urological chapters of avicenna’s canon of medicine. i used the canon in its original language (arabic),(2) along with its persian translation.(3) part 19 of the 3rd book contains subjects related to surgical treatment of bladder calculi. i compared the text to the current urological findings. selected topics from the canon are presented and a brief discussion follows each subject. a translation from the arabic version and comparison with the persian translation was done to present an accurate text. i did not enter the domain of traditional and herbal medicine such as the four cardinal humours (blood, phlegm, choler, and melancholy), temperaments, and herbal therapy which have been extensively discussed in avicenna’s books and his contemporaries. avicenna’s canon of medicine—madineh 64 urology journal vol 6 no 1 winter 2009 these subjects were beyond the aim of this paper, and i was only engaged to the items that the current modern medicine obviously and clearly proceeds with them. it should be noted that this paper is a revised version of an article by the author in persian which was published in the iranian journal of urology in 1996.(4) discussion book iii, part 19, treatise 1, chapter 6 in this chapter, entitled “treatment of bladder calculi,” avicenna first explains the medical (herbal) therapy for bladder calculi (figure 2). i pass aside this subject as i mentioned in the material and methods. then, he describes the manipulation and surgical treatment of bladder calculi: if urinary retention occurs in the presence of bladder calculus and it is not possible to incise the bladder—in other words, if there is an obstructive pathway or you are afraid of incising the bladder—in this state, some physicians make a very small incision between the rectum and the testes [perineum] by lancet and then insert a small tube and evacuate urine via that tube, and thus, they rescue the patient from death. the patient may have much discomfort due to this operation, but there is no other remedy.(2,3) discussion. in this stage, avicenna delineates 2 indications of perineal urethrostomy (perineostomy). bladder calculus secondary to infravesical obstruction such as urethral stricture is a very important and prevalent condition in figure 1. avicenna’s tomb in hamedan, iran. he was born in 980 ad in a village near bokhara (which was a city of old persia) and died in 1037 ad in hamedan, iran. figure 2. the third book (part 19, treatise 1, chapter 6) of the canon of medicine in arabic on surgical treatment of bladder calculi. adapted from the web site of the saab medical library of the american university of beirut. avicenna’s canon of medicine—madineh urology journal vol 6 no 1 winter 2009 65 which there is an obstruction in the urinary pathway. in this case, vesicolithotomy is not the definite treatment itself, and we must relieve the obstruction first. also, there are conditions in which the operation poses a high risk, eg, long urethral strictures or obstructions in which operative time is long or conditions in which complete operation cannot be done. as further examples, the use of flap or graft in the urethra is associated with infection, severe refractory diabetes mellitus, or chronic kidney failure, especially in old patients with low cardiopulmonary reservoir. in these conditions, the urologist can use temporary diversion options such as peineal urethrostomy, as avicenna proposes for rescuing the patient’s life. perineal urethrostomy even rarely can be used as a last treatment line in high-risk patients, as avicenna says, “there is no other remedy.” this operation is done as a permanent remedy by if we cannot carry out definite surgery.(5) if medical therapy failed and there was no remedy other than incision, operation must be done by a person who knows the situation and condition of the bladder best and by the one who has the knowledge of bladder anatomy. also, he must know the anatomic relations of the semen-carrier vessels [vasa deferentia] and the seminal vesicles to the bladder neck and junction of them to the bladder and the position of the fleshy substance [prostate]. otherwise due to negligence and lack of talent, he can damage the genitalia or can cause hemorrhage or incurable fistula.(2,3) discussion 1. today, urologists first use the conservative medical therapy for small urinary calculi to facilitate their spontaneous passage. if medical therapy fails and the calculus does not pass, they use minimally invasive methods (endourologic techniques such as transurethral lithotripsy by pneumatic, ultrasonic, or laser lithotripters; extracorporeal shock wave lithotripsy by ultrasonic, electrohydraulic, or electromagnetic instruments; and mechanical transurethral lithotripsy) and at last invasive open surgery.(6) discussion 2. these operations must be done by an experienced urologist who has the insight into urogenital tract anatomy and had adequate qualifications. at avicenna’s time, bladder calculus surgery would be done transperineally in the lithotomy position (and it is obvious why this position is named so). this is noteworthy that avicenna emphasizes the anatomic relations of the posterior and lateral surfaces of the bladder base with the vasa deferentia and blood vessels. he states that in this surgical approach, the prostate (named as “fleshy substance”) is exposed, make it prone to trauma to the neurovascular bundles, impotence, hemorrhage, and fistula (eg, rectovesical fistula).(7) the physician who does the operation must secure the patient in the supine position preoperatively and do prepare his or her intestine and bladder. yet, in my opinion, the incision [operation] is a great risk and i never recommend it. but, if the operation is inevitable, you conform all of my orders. you should prepare a chair and sit the patient on it. the nurse places his or her hand below the patient’s knees (and elevates them). then you remark the incision site. you should locate the calculus site in the bladder before incision, and you should fix it in its place. in men or in virgin girls, insert your finger in their anus, and in women with perforated hymen, insert your finger to their vagina up to the cervix until it reaches the bladder calculus. compress the calculus with your other hand superiorly and descend it by hand compression from up to down until it reaches the bladder neck. then, you should be very careful to stabilize the calculus about a grain size far from the incision line. you should not do something else at that time and you should not neglect that the calculus must not move directly to the incision line and exit via the incision. it is not suitable that the calculus is expelled out directly from the incision because this has the risk of death. you should not fail to care for controlling the calculus exit, because if it comes out directly from the incision, the incision expands and causes incurable fistula. after you push the calculus skillfully near the incision line, you can see that the incision line is too small for extraction of the calculus. at this time, expand the exit site slightly with lancet. re-incision must be done in a way that you ensure it does not cause severe pain and does not damage the bladder neck and the patient does not lose his or her power and force avicenna’s canon of medicine—madineh 66 urology journal vol 6 no 1 winter 2009 and continues his or her movements and speaking with you and it does not cause depression and closing of the eyes. otherwise, you immediately cause the patient’s death. if the incision is so deep that it reaches the bladder body, there is no hope in the patient’s recovery and wellbeing, and the incision line will not heal. incision must be done in the bladder neck, but it must not reach the bladder body, and you must take the necessary precautionary measures not to incise the vessels.(2,3) discussion 1. in this part, avicenna states the technique and some intra-operative and postoperative complications of transperineal access to bladder calculi. it is obvious that 1000 years ago and in the state of no progressive anesthetic techniques, the bladder calculus surgery had been a high risk and fatal operation, and as avicenna said, it can cause severe pain, shock, and death, especially in patients with cardiovascular disorders which can be associated with myocardial infarction and sudden death. apart from being out of date, avicenna’s describing the perineal technique of vesicolithotomy in the medieval time is surprisingly accurate and experimentally similar to the modern description of operational techniques and this is very interesting in. discussion 2. bladder and urethral operation with transperineal approach, can cause urinary fistula (no healing of the incision line as stated by avicenna), especially vesicovaginal or urethrovaginal fistula in women. today, there is no place for open surgery through perineal access for treatment of bladder or urethral calculus removal. today, transvaginal access to ureteral calculi is rarely recommended in women.(8) and overall, by progression of extracorporeal shock wave lithotripsy and endourological methods, there is little place for this approach. if the bladder calculus is small, it can be expelled out by hand pressure, but if it is large, the incision line must be expanded, and it is possible that you need grasping pincers to grasp and extract the calculus. sometimes, the calculus can be very large, and it is not possible that you induce a very large incision fit for the calculus size. what would you do in these conditions is to grasp the large calculus with pincers, and little by little, to break the calculus and expel all of the fragments of the crushed calculus. and you must not leave any fragments in the bladder albeit very small. because, if even a very small fragment of the calculus is not extracted from the bladder, it will grow and enlarge.(2,3) discussion 1. today in endourology, calculus grasping instruments have their special place. (9) for very large calculi, there are modern lithotripsy methods to the basis of which avicenna pointed 10 centuries ago: mechanical lithotripsy. in all of these methods, the calculus is crushed into small pieces and then exits from the body. today, the avicenna’s cited mechanical lithotripsy is used for bladder calculi too. however, urologists have expanded options for lithotripsy in addition to mechanical lithotripsy, such as laser, pneumatic, electrohydraulic, ultrasonic, and combined pneumatic plus ultrasonic lithotripsy.(6) discussion 2. as avicenna mentions, calculus fragments remaining in the bladder after lithotripsy, even if very small, lead to continuing calculus formation process. these small calculus remnants act as a foreign body and a nidus that grows and forms large calculi after a few time.(6,10) sometimes, there is a calculus in the bladder neck or infravesical (below penile urethral) area. in these conditions you must touch and compress the suprapubic area with your hand and there must be an assistant with you. at this stage, he must incise the place in which the calculus is fixed and he must expel the calculus out. in this situation, it is suitable that you close the proximal part of the fixed calculus by a thread, so that it is not pushed up. if the calculus descends down from the bladder and reaches the distal part of the urethra, you should not push it out with pressure; otherwise, it can cause an ulcer that will not heal. you should move the calculus to a suitable place in the urethra, close the proximal part of urethra by a thread, and incise the lower surface of the distal penis (urethral meatus) with lancet and expel the calculus out.(2,3) discussion 1. impacted calculi in the bladder neck or urethra can cause urinary retention which must be managed immediately. there are several methods to treat them. penile urethral calculi in men can be diagnosed by palpation of the urethral avicenna’s canon of medicine—madineh urology journal vol 6 no 1 winter 2009 67 side of the penis.(6) as avicenna points out, we should not expel the calculus out forcefully at this stage. otherwise, it causes urethral injury, hemorrhage, delayed stricture, and even cutaneous fistula. in a sterile condition, we can fill the urethra with lubricating and anesthetizing gel, and then, we can gently milk the calculus out towards the urethral meatus.(6) discussion 2. for large proximal urethral calculi that cannot be milked out, the urologist can fill the urethra with gel, and then, he or she can push up the calculus by a urethral catheter and manage it as a bladder calculus. today, urethral calculi can be fragmented by various transurethral lithotripsy methods and be extracted. discussion 3. today for palpable large chronically impacted calculi in men’s urethra, external urethrotomy can be used.(6) in this method, the penile urethra is opened by incising the skin and underlying anatomic layers, and the calculus can be removed and the urethra be closed in 2 layers. this method is not recommended because of increasing the risk of urethral cutaneous fistula.(11) today, thanks to modern lithotripsy methods, there is a small place for external urethrotomy to extract penile urethral calculi. discussion 4. if the urethral calculus is impacted in the fossa navicularis or near the urethral meatus, we can incise the urethral meatus (meatotomy) and remove it.(6) avicenna has pointed this method in his book, too. discussion 5. in open removing of urethral and especially ureteral calculi, we can close their lumen proximally or distally by a babcock forceps to prevent upward or downward migration of the calculus during the operation and then remove it. this modern method is similar to closing the urethra by a thread during operation as avicenna described.(12) one of these situations may occur intraoperatively or postoperatively: (1) occasionally, blood does not flow throughout the incision site as necessary. in this situation, there is a risk of in inflammation that is due to ruining [fesad in arabic] of the organ in which blood accumulates, but blood cannot be drained out especially if the organ loses its redness and thus its color converts to black. in this situation that the blood does not drip from the operation site as necessary and accumulates inside the organ and the organ starts being ruined and its color converts to black, you must immediately incise the site in which blood accumulates and you must drain the accumulated blood out. (2) occasionally, blood flows more than necessary from the wound. in this situation, there is risk of hemorrhage that is dangerous. if you notice that one of the great vessels or one of arteries is injured or disrupted and causes the hemorrhage, you must tightly close it, so that the hemorrhage stops and blood does not leak. (3) occasionally, blood from incision site can flow towards the bladder and coagulates in the bladder neck and causes difficulty in voiding. in this situation, you must insert your finger into incision site and free the bladder neck from this coagulated blood and extract the coagulated blood out and wash the incision site by water and vinegar [acetic acid], so that coagulated blood dissolves and exits. (4) sometimes, the operation causes infertility [engheta-e-nasl in arabic]. (5) there are signs in patients with bladder calculus that indicate a severe illness and bad condition, and they are the alarms of patient’s death. when they appear, the doctor knows that the patient’s death is imminent. these signs are: severe infra-umbilical pain, coldness of the extremities, severe fever, fever and rigor, and weakness and loss of power. there are other signs such as severe pain in the incision site, hiccup and severe malodorous diarrhea. in such situations, death of the patient in near. however, if mental state of the patient is normal and the patient has complete normal appetite and the color of his or her face is normal, these are the promises of recovery.(2,3) discussion 1. in this part, avicenna describes intra-operative and postoperative complications of transperineal operations, fournier gangrene, and mortality. in this stage, perineal and scrotal skin progresses to ruin and becomes gangrenous. avicenna’s canon of medicine—madineh 68 urology journal vol 6 no 1 winter 2009 in the presence of hematoma and abscess, blood and pus must be drained. at avicenna’s era with no antibiotics, the fournier gangrene, septicemia, and surgical mortality used to be common. as he states, blood accumulation or hematoma in the operation site can cause the propensity to infection, and it can ultimately increase the risk of the fournier gangrene, and septicemia. today with complete drainage and antibiotic administration, these complications are rarely seen. this is astonishing that 8 centuries before fournier described the signs and complications of necrotizing fasciitis in male genitalia,(13) fournier gangrene is described in the canon. discussion 2. in fournier gangrene, the injured site is ruined and blood flow is low, and thus, the anaerobic bacteria grow over there. the organ loses its healthy red color and turns into black (the name gangrene points to this sign). in this case, we should drain hematoma and pus, and we should do debridement of the ruined tissues towards the healthy and normal circulated tissues.(13) discussion 3. in continuous hemorrhage from the incision site and hematoma, we should open the site and find the origin of hemorrhage in order to ligate the vessel. avicenna has precisely elucidated these. discussion 4. as avicenna states, in severe hemorrhage from the bladder incision site or from any place in the bladder or prostatic fossa (eg, in open prostatectomy), there is high probability of urinary retention due to blood coagulation and clot retention in the bladder. today, we first insert a 3-way catheter and wash the bladder by hypertonic saline solution. in severe cases, we should open the incision line and reoperate and ligate the related vessel. today, most of the bladder and prostatic operations are endoscopic without the need to open the bladder.(14) discussion 5. ten centuries ago, in the area with no antibiotics and no preparation and draping techniques in the operating room, infection, septicemia, and thus, septic shock were one of the most prevalent and important causes of mortality following surgeries. fever, rigor, extremity coldness, and severe weakness were the signs of these conditions as avicenna explains. occasionally, in uremic conditions associated with bladder calculi, for example in kidney failure due to benign prostatic hypertrophy and obstructive bladder calculi, hiccup is one of the worst symptoms. to avicenna, hiccup meant association with poor prognosis in the area with no dialysis facility and no antibiotics. references 1. madineh sma. avicenna’s canon of medicine and modern urology. part i: bladder and its diseases. urol j. 2008;5:284-93. 2. ibn sina. al-qanun fi al-tibb. rome: typgraphia mediciea; 1593. p. 539-43. 3. abu ali sina. qanun [translated into persian by sharafkandi ar]. tehran: soroush; 2004. book iii, p. 155-60. 4. madineh sma. avicenna’s canon of medicine and modern urology. part ii: bladder and its diseases. iran j urol. 1996;3:3-10. 5. hinman f. atlas of urologic surgery. 2nd ed. philadelphia: wb saunders; 1998. p. 630. 6. ho klv, segura jw. lower urinary tract calculi. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2666-72. 7. hartke dm, resnick mi. radical perineal prostatectomy. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2983-4. 8. hinman f. atlas of urologic surgery. 2nd ed. philadelphia: wb saunders; 1998. p. 849. 9. patel u, ghani k, anson k. endourology: a practical handbook. london: taylor & francis; 2006. p. 40-3. 10. lingeman je, matlaga br, even ap. surgical management of upper urinary tract calculi. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1448. 11. jordan gh, schlossberg sm. surgery of the penis and urethra. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 1042. 12. stroller ml. urinary stone disease. in: tanagho ea, mcaninch jw, editors. smith’s general urology. 16th ed. new york: mcgraw-hill medical; 2004. p. 281. 13. schaeffer aj, schaeffer em. infections of the urinary tract. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 301. 14. han m, partin aw. retropubic and suprapubic open prostatectomy. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, editors. campbell-walsh urology. 9th ed. philadelphia: saunders; 2007. p. 2850-1. 1 running head: renal function after partial nephrectomy, yu et al. significance of glucose control for perioperative and long-term renal functions after nephron-sparing surgery for renal cancer in patients with diabetes seong hyeon yu, seong jong eun, taek won kang department of urology, chonnam national university medical school, chonnam national university hospital, gwangju, korea keywords: nephrons, sparing, surgery, risk factors, kidney, function 2 abstract purpose: this study aimed to evaluate the predictive factors for perioperative and long-term renal functions after nephron-sparing surgery (nss). materials and methods: the clinical records of 379 patients who underwent nss for a single renal tumor with a normal contralateral kidney between 2009 and 2016 were retrospectively analyzed. after surgery, the occurrence of acute kidney injury (aki) within 7 days and the progression of chronic kidney disease (ckd) 5 years later were assessed using serum creatinine (s-cr) levels. perioperative aki was defined as an increase in the s-cr level by ≥ 0.3 mg/dl or 1.5–1.9 times the baseline value. ckd was defined as the estimated glomerular filtration rate (egfr) decreasing from > 60 ml/min/1.73 m2 to < 60 ml/min/1.73 m2. results: changes in the egfr were assessed during 5 years after surgery. among 379 patients, 81 (21.4%) patients presented diabetes mellitus (dm), and 30 (7.92%) experienced uncontrolled dm. the aki occurrence and ckd progression were observed in 50 (13.2%) patients and 79 (20.8%) patients, respectively. multivariable analyses revealed that female gender (95% confidence interval [ci]: 0.16–0.91, odds ratio [or] = 0.39, p = 0.029), uncontrolled dm (95% ci: 1.05–6.60, or = 2.63, p = 0.039), and intermediate nephro score (95% ci: 1.07–3.80, or = 2.02, p = 0.03) were associated with perioperative aki. in addition, old age (95% ci: 1.10–1.18, or = 1.14, p < 0.001) and uncontrolled dm (95% ci: 1.84–11.4, or = 4.57, p = 0.001) were associated with long-term ckd progression. conclusion: uncontrolled dm is the only predictive factor for perioperative and long-term renal functions after nephron-sparing surgery. 3 introduction the incidence of renal tumors has increased during the past decades. (1) recently, the development of imaging modalities has led to a decrease in the size and stage migration of newly detected incidental renal tumors. nephron-sparing surgery (nss) is currently the treatment of choice for the surgical management of these earlier diagnosed small renal tumors because of its good overall survival (os) with no compromise in oncologic results and minimal renal function deterioration (rfd). (2) several previous studies have reported that rfd after nss may depend on the patient’s body mass index (bmi), radiologic size of the tumor, quantity of preserved functional parenchyma volume, ischemic time during surgery, and length of surgery. (3-5) the incidence of type 2 diabetes mellitus (t2dm), one of the most important causes of kidney disease, has also increased markedly in recent decades. (6) however, a few reports have mentioned the role of underlying t2dm affecting rfd after nss. (7,8) in addition, along with t2dm, well-controlled blood sugar levels may also play an important role. this study aimed to determine the factors for rfd after nss in patients with a renal tumor. materials and methods 1. subjects and the study design this retrospective study screened the patients who underwent nss for a single renal tumor in our hospitals (chonnam national university hospital and chonnam national university hwasun hospital, korea) between january 2009 and december 2016. a total of 478 patients were initially enrolled in this study. detailed medical history, including age, sex, bmi, hypertension, diabetes mellitus (dm), the operation site, total operation time, operation methods, preoperative hemoglobin level, pathologic t stage, the occurrence of perioperative aki, and progression of postoperative long-term chronic kidney disease (ckd), were collected 4 from each patient’s medical record. patients with follow-up loss within 5 years, preoperative ckd, bilateral renal tumors, and lack of medical records for perioperative aki and postoperative long-term ckd were excluded from the study. a total of 379 out of 478 patients were found eligible for the final analysis. 2. data collection, definition, and the assessment of renal functions serum creatinine (scr) levels were measured at the following periods: preoperatively, during admission, and postoperative annual follow-ups during 5 years. the zonal nephro score (comprising the nearness to collecting system and physical zones, radius, and organization of the tumor) before surgery for predicting the surgical complexity of a renal lesion was calculated as low (4–6), intermediate (7–9), or high (10–12). (9) kidney cancer staging was based on the american joint committee on cancer staging manual. (10) uncontrolled dm was defined as the level of glycosylated hemoglobin (hba1c) in the blood maintained at ≥ 7%. (11) perioperative aki within 7 days from partial nephrectomy was defined and classified according to the severity as stage 1 (increase in the scr levels by ≥ 0.3 mg/dl or 1.5–1.9 times the baseline value), stage 2 (increase in the scr level by 2.0–2.9 times the baseline value), and stage 3 (increase in the scr level by ≥ 4.0 mg/dl or ≥ 3.0 times the value at baseline or initiation of renal replacement therapy). (12) the urine output was not accounted for because the data was collected retrospectively. postoperative long-term ckd was defined as a decrease in the estimated glomerular filtration rate (egfr) < 60 ml/min/1.73 m2 5 years later from partial nephrectomy in patients with a preoperative egfr > 60 ml/min/1.73 m2. 3. statistical analyses statistical analyses were performed using stata version 16.1 (statacorp., college station, 5 texas, usa). continuous variables are represented as the mean values with standard deviations (sd); categorical variables are presented as frequencies (%). the student’s t-test for continuous variables and pearson chi-square test for categorical variables were used to compare the clinical characteristics according to the occurrence of perioperative aki and progression of postoperative long-term ckd. in addition, using multivariable logistic regression analysis by selecting significant variables through univariate analysis, the predictive factors for perioperative and postoperative long-term renal outcomes were analyzed. statistical significance was set at p<0.05 for all analyses. 4. ethics statement the study protocol was reviewed and approved by the institutional review board (irb) of the chonnam national university hospital research institute of clinical medicine (irb approval no.: cnuh-2021-367). the study was performed in accordance with the declaration of helsinki and the ethical guidelines for clinical studies. 6 results characteristics of the patients who were eligible for the final analysis are summarized in table 1. the patients’ mean age and bmi were 58.4 ± 11.9 years and 25.0 ± 3.09 kg/m2, respectively. among 379 patients, 155 (40.9%), 81 (21.4%), and 30 (7.92%) patients presented hypertension, dm, and uncontrolled dm, respectively. according to preoperative nephro score calculation, 188 (49.6%) patients exhibited intermediate risk, with ≥ 7 points. the mean operation time was 124.3 ± 45.1 min, and 277 (73.1%) patients underwent laparoscopic surgery. the numbers of patients exhibiting stages t1a, t1b, t2, and t3 renal cancer were 315 (83.1%), 59 (15.6%), 3 (0.8%), and 2 (0.5%), respectively. regarding the perioperative and postoperative long-term renal functions, 50 (13.2%) patients experienced perioperative aki, while 79 (20.8%) patients showed progression to postoperative long-term ckd. based on the results of clinical features according to the perioperative aki occurrence, the perioperative aki group was significantly associated with old age (57.9 ± 11.7 years vs. 62.0 ± 13.0 years, p = 0.021), female sex (72.0% vs. 86.0%, p = 0.036), intermediate risk of nephro score (47.4% vs. 64.0%, p = 0.029), and uncontrolled dm (6.7% vs. 16.0%, p = 0.033) compared to the other group (table 2). furthermore, comparing the clinical features according to the progression of postoperative long-term ckd revealed that the postoperative long-term ckd group was significantly associated with old age (55.8 ± 11.3 years vs. 68.5 ± 8.16 years, p < 0.001), low preoperative hemoglobin (7.3% vs. 22.8%, p < 0.001), hypertension (37.7% vs. 53.2%, p = 0.013), and uncontrolled dm (5.0% vs. 19.0%, p < 0.001) (table 3). the predictive factors associated with perioperative and postoperative long-term renal functions after nss are detailed in tables 4 and 5. univariate analyses revealed a significant association of old age, male sex, intermediate risk of nephro score, and uncontrolled dm with the occurrence of perioperative aki (p = 0.023, p = 0.041, p = 0.031, and p = 0.018, 7 respectively). in addition, multivariable analyses showed female sex (95% confidence interval [ci]: 0.16–0.91, odds ratio [or]: 0.39, p = 0.029), intermediate risk of nephro score (95% ci: 1.07–3.80, or 2.02, p = 0.03), and uncontrolled dm (95% ci: 1.05–6.60, or 2.63, p = 0.039) as significant factors associated with perioperative and postoperative long-term renal functions after nss. regarding postoperative long-term ckd, univariate analyses revealed old age, hypertension, low preoperative hgb, controlled dm, and uncontrolled dm as significant factors (p < 0.001, p = 0.013, p < 0.001, p = 0.004, and p < 0.001, respectively). however, multivariable analyses showed only old age (95% ci: 1.10–1.18, or 1.14, p < 0.001) and uncontrolled dm (95% ci: 1.84–11.4, or 4.57, p = 0.001) as significant factors associated with the progression of postoperative long-term ckd. 8 discussion with the development of imaging modalities and growing interest in individual health examinations, the incidence of newly detected incidental renal tumors is increasing. nss is recommended in the guidelines on the management of renal cell carcinoma as the standard treatment for clinical t1 stage renal tumors. (13) furthermore, nss has the advantage of preserving the renal function and potential cardiovascular and os with ckd avoidance. (2,14) however, despite successful operations, rfd after nss is common in some cases. therefore, in the present study, we focused on perioperative and long-term renal functions after nss, and our results showed that uncontrolled dm is the only independent factor affecting both functions. to date, several studies reported the possible predictive factors for rfd after nss, including the patient’s bmi and comorbidities, renal tumor size, the quantity of preserved functional parenchyma volume, intraoperative ischemic time, and total surgical time. (3-5) among these factors, many physicians have suggested that rfd can be minimized by modifiable surgeryrelated factors, such as reduced warm ischemic time (wit). theoretically, warm ischemiarelated rfd can be explained via postulated pathophysiological mechanisms, such as mechanical obstruction of microvessels by leukocytes and platelets and postischemic vasoconstriction with endothelial damage followed by reperfusion injury. (15) porpiglia et al. reported that kidney damage occurs during laparoscopic partial nephrectomy (lpn) when wit is more than 30 min. (16) erdem et al. included 127 patients who underwent elective lpn and reported that prolonged wit (> 27.75 min) was the strongest independent predictor of postoperative ckd. (17) based on these results, it has been recently recommended to avoid wit for more than 30 min. there is increasing evidence that the quantity and quality of preserved renal parenchyma play important roles in rfd in patients who received nss; hence, the effects of wit on rfd have 9 been debated continuously. in an animal study with a solitary kidney model, wit up to 90 min was well-tolerated by nephrons, and postoperative renal function was recovered within only 2 weeks. (18) similarly, prolonged wit (>27.75 min) in the human kidney can lead to a renal functional loss in the early postoperative period, but this was recovered during the intermediate term follow-up period of 2 years in patients with a contralateral functioning kidney. (17) erdem et al. recently reported that although overextended wit (> 40 min) can cause significant postoperative rfd, the functional loss can be recovered at the median follow-up period of 3 years in patients with contralateral functioning kidneys. (7) furthermore, dong et al. found that patients with wit > 35 min have lower median recovery from ischemia, although not significantly different from patients with a wit < 35 min, and warm ischemia was associated with only a 2.5% decrease in functional recovery for every additional 10 min. (19) considering these results, we carefully suggested that wit is not a significant predictive factor for longterm renal function after nss. in the present study, the investigated wit was not > 40 min (mean wit; 24.3 ± 8.88 minutes, data not shown), and total surgery time was not associated with perioperative and long-term renal functions after nss. the surgical complexity of a renal tumor can be a surgery-related factor affecting rfd after nss. this may cause intraoperative complications, including increased blood loss, prolonged ischemia time, and a greater loss of functional renal parenchyma, and thereby affect perioperative and long-term renal functions (9,20) in the present study, the surgical complexity of a renal tumor was calculated before surgery, and more than intermediate risk was associated with the perioperative aki occurrence. however, its association with the progression of postoperative long-term ckd was not observed. this might be explained by the findings that an early postoperative renal functional loss due to surgery-related factors could be recovered at the long-term follow-up period. 10 recently, patient-related factors of rfd after nss, such as bmi, hypertension, and dm, have also been considered. in fact, hypertension and dm are the most common patient-related factors affecting renal functions and are known to be significantly associated with ckd. (21) in particular, t2dm has been known to significantly reduce the os in patients with renal cell carcinoma. (22) in line with these results, several studies have evaluated the associations among patient-related factors and rfd after nss. demirjian et al. classified patients presenting a new ckd after nss into two groups, including medicallyand surgically-induced ckd. the surgically-induced ckd group had a lower rate of functional decline and less impact on survival than medically-induced ckd groups. (23) similarly, satasivam et al. found that dm was one of the crucial independent risk factors, and 42% of patients with dm progressed to stage 3 or greater ckd, whereas wit had no impact on rfd. (8) in addition, dm has been reported as the only independent predictor for both postoperative and long-term renal functions in patients who underwent nss, regardless of wit. (7) these findings might indicate that the patient-related factor has a more important role in the ckd progression during the follow-up period, whereas the surgery-related factor has only a temporary role in postoperative shortterm rfd. to our knowledge, no study has yet reported the association between blood sugar control in diabetic patients and perioperative and long-term renal functions after nss. therefore, this study is possibly the first report stating that uncontrolled dm has a significant effect on rfd after nss in patients with normal baseline kidney function. comparisons of clinical features according to perioperative aki and postoperative long-term ckd in this study showed that the percentage of uncontrolled dm patients was significantly higher in both groups. furthermore, in multivariable analyses, uncontrolled dm was found to be the only predictive factor affecting both states. patients with uncontrolled dm presented approximately 4.5-fold greater risk than 11 patients without dm, especially in postoperative long-term ckd progression at 5 years. as in previous studies, although uncontrolled dm can be thought to further affect rfd by causing serious microvascular complications, (11,24) several prospective, pathophysiologic, or molecular-level studies on the correlation of associations among uncontrolled dm, perioperative aki, and postoperative long-term ckd should be conducted in the future. in the present study, 50 patients presented perioperative aki, and 79 patients showed progression to postoperative long-term ckd. however, only 22 patients with perioperative aki showed progression to postoperative long-term ckd, while 59 patients experienced a new progression of ckd during the long-term follow-up period of 5 years. these finding implies that preserving the functional renal volume alone might not be sufficient; optimized dm control with medical reno-protection is essential for preventing rfd after surgery. additionally, further studies are needed to evaluate the patient-related factors of postoperative renal function. the present study has several limitations. first, it was a retrospective study with relatively small sample size and heterogeneity in patient characteristics and conducted at a single institution. despite partial nephrectomy being performed by urologic specialists, the quality of these tasks could present inter-performer biases. second, data on preoperative proteinuria, which is a significant contributor to kidney function, were not considered. (25) third, the severity of hypertension, which is also a predictive factor for ckd, was not assessed. (21) in the present study, hypertension was not found to be associated with perioperative aki and postoperative long-term ckd. fourth, we did not consider the ischemia time, because it was not available for approximately 25% in our database. instead of ischemia time, we assessed the total surgery time as predictive factor, it was not significant. finally, we did not use volumetric analyses or scintigraphy methods to assess preserved ipsilateral renal function. however, uncontrolled dm being first reported as the predictive factor of postoperative renal function 12 after nss, especially during the long-term follow-up period (5 years), is the strength of this study. 13 conclusion in the present study, uncontrolled dm was the only predictive factor for perioperative and long-term renal functions in patients after nss. based on this result, physicians should consider optimized dm control with medical reno-protection to be important for minimal postoperative rfd at the time of counseling of renal cell carcinoma patients scheduled for nss. summary in the presents study, we investigated the predictive factors for perioperative and long-term renal functions after nephron-sparing surgery. we identified that uncontrolled dm is the independent factor affecting both functions. our results can emphasize the significance of glucose control after nephron-sparing surgery for patients with renal cancer. conflicts of interest: the authors have nothing to disclose. acknowledgments this study was supported by a grant (cri 15 002-1) received from the chonnam national university hospital biomedical research institute. author contribution research conception and design, data acquisition, statistical analysis: seong hyeon yu, taek won kang data analysis and interpretation: seong hyeon yu, seong jong eun drafting of the manuscript: seong hyeon yu, critical revision of the manuscript for scientific and factual content: taek won kang orcid id seong hyeon yu 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their clinical impact. bju int. 2005;95:948-50. 16. porpiglia f, renard j, billia m, et al. is renal warm ischemia over 30 minutes during laparoscopic partial nephrectomy possible? one-year results of a prospective study. eur urol. 2007;52:1170-8. 17. erdem s, boyuk a, tefik t, et al. warm ischemia-related postoperative renal dysfunction in elective laparoscopic partial nephrectomy recovers during intermediate-term follow-up. j endourol. 2015;29:1083-90. 17 18. laven ba, orvieto ma, chuang ms, et al. renal tolerance to prolonged warm ischemia time in a laparoscopic versus open surgery porcine model. j urol. 2004;172:2471-4. 19. dong w, wu j, suk-ouichai c, et al. ischemia and functional recovery from partial nephrectomy: refined perspectives. eur urol focus. 2018;4:572-8. 20. kriegmair mc, mandel p, moses a, bolenz c, michel ms, pfalzgraf d. zonal nephro score: external validation for predicting complications after open partial nephrectomy. world j urol. 2016;34:545-51. 21. hart pd, bakris gl. hypertensive nephropathy: prevention and treatment recommendations. expert opin pharmacother. 2010;11:2675-86. 22. vavallo a, simone s, lucarelli g, et al. pre-existing type 2 diabetes mellitus is an independent risk factor for mortality and progression in patients with renal cell carcinoma. medicine (baltimore). 2014;93:e183. 23. demirjian s, lane br, derweesh ih, takagi t, fergany a, campbell sc. chronic kidney disease due to surgical removal of nephrons: relative rates of progression and survival. j urol. 2014;192:1057-62. 24. shahwan m, hassan n, shaheen ra, et al. diabetes mellitus and renal function: current medical research and opinion. curr diabetes rev. 2021;17:e011121190176. 25. o'donnell k, tourojman m, tobert cm, et al. proteinuria is a predictor of renal functional decline in patients with kidney cancer. j urol. 2016;196:658-63. corresponding author: taek won kang, md, phd department of urology, chonnam national university hospital and medical school 18 42, jebong-ro, dong-gu, gwangju #61469, south korea telephone: +82-62-220-6705 fax: +82-62-227-1643 e-mail: sydad@hanmail.net table 1. characteristics of the patients who received partial nephrectomy for renal tumor variables values (n = 379) age (years) 58.4 ± 11.9 bmi (kg/m2) 25.0 ± 3.09 sex male 280 (73.9) comorbidities htn 155 (40.9) dm 81 (21.4) uncontrolled dm 30 (7.92) site right 187 (49.3) methods of surgery open 102 (26.9) laparoscopy 277 (73.1) mailto:sydad@hanmail.net 19 op time (min) 124.3 ± 45.1 pre op hemoglobin (mg/dl) 14.0 ± 1.63 pre op nephro score low 191 (50.4) intermediate 188 (49.6) pathologic t stage t1a 315 (83.1) t1b 59 (15.6) t2 3 (0.8) t3 2 (0.5) post op aki 50 (13.2) post op ckd (5 years follow up) 79 (20.8) aki: acute kidney injury, bmi: body mass index, ckd: chronic kidney disease, dm: diabetes mellitus, htn: hypertension, op: operation; pre op: preoperative, post op: postoperative data are represented as mean ± standard deviation or n (%). 20 table 2. comparisons of the clinical features based on the occurrence of perioperative aki variablesa no (n=329) yes (n=50) p-value age (years) 57.9 ± 11.7 62.0 ± 13.0 0.021 bmi (kg/m2) 0.203 < 25 183 (55.6) 23 (46.0) ≥25 146 (44.4) 27 (54.0) sex 0.036 male 237 (72.0) 43 (86.0) female 92 (28.0) 7 (14.0) htn 130 (39.5) 25 (50.0) 0.160 dm 0.033 no 265 (80.5) 33 (66.0) controlled dm 42 (12.8) 9 (18.0) uncontrolled dm 22 (6.7) 8 (16.0) site 0.686 right 161 (48.9) 26 (52.0) left 168 (51.1) 24 (48.0) methods of surgery 0.384 open 86 (26.1) 16 (32.0) laparoscopy 243 (73.9) 34 (68.0) op time (min) 122.9 ± 42.83 133.5 ± 57.23 0.210 pre op hemoglobin (normal range) 298 (90.6) 41 (82.0) 0.066 pre op nephro score 0.029 21 low 173 (52.6) 18 (36.0) intermediate 156 (47.4) 32 (64.0) pathologic t stage 0.150 t1a 277 (84.2) 38 (76.0) t1b-t3 52 (15.8) 12 (24.0) aki: acute kidney injury, bmi: body mass index, dm: diabetes mellitus, htn: hypertension, op: operation; pre op: preoperative data are represented as mean ± standard deviation or n (%). a the student’s t-test for continuous variables and pearson chi-square test for categorical variables were used to compare the clinical characteristics 22 table 3. comparisons of the clinical features based on the progression of postoperative longterm ckd variablesa no (n=300) yes (n=79) p-value age (years) 55.8 ± 11.3 68.5 ± 8.16 <0.001 bmi (kg/m2) 0.199 < 25 158 (52.7) 48 (60.8) ≥25 142 (47.3) 31 (39.2) sex 0.182 male 217 (72.3) 63 (79.8) female 83 (27.7) 16 (20.2) htn 113 (37.7) 42 (53.2) 0.013 dm <0.001 no 251 (83.7) 47 (59.5) controlled dm 34 (11.3) 17 (21.5) uncontrolled dm 15 (5.0) 15 (19.0) site 0.609 23 right 146 (48.7) 41 (51.9) left 154 (51.3) 38 (48.1) methods of surgery 0.384 open 79 (26.3) 23 (29.1) laparoscopy 221 (73.7) 56 (70.9) op time (min) 125.04 ± 43.82 121.27 ± 49.63 0.508 pre op hemoglobin (normal range) 278 (92.7) 61 (77.2) <0.001 pre op nephro score 0.085 low 158 (52.7) 33 (41.8) intermediate 142 (47.3) 46 (58.2) pathologic t stage 0.150 t1a 251 (83.7) 64 (81.0) t1b-t3 49 (16.3) 15 (19.0) ckd: chronic kidney disease, bmi: body mass index, dm: diabetes mellitus, htn: hypertension, op: operation; pre op: preoperative data are represented as mean ± standard deviation or n (%). a the student’s t-test for continuous variables and pearson chi-square test for categorical variables were used to compare the clinical characteristics 24 table 4. clinical factors associated with the occurrence of perioperative aki variables univariate analysis multivariate analysis odds ratio (95% ci) p-value odds ratio (95% ci) p-value age (years) 1.03 (1.00–1.06) 0.023 1.02 (1.00–1.05) 0.082 sex male reference 25 female 0.42 (0.18–0.97) 0.041 0.39 (0.16–0.91) 0.029 bmi (kg/m2) < 25 reference ≥ 25 1.47 (0.81–2.67) 0.205 site right reference left 0.88 (0.49–1.60) 0.687 methods of surgery open reference laparoscopy 0.75 (0.40–1.43) 0.385 htn 1.53 (0.84–2.78) 0.162 dm no reference controlled dm 1.72 (0.77–3.85) 0.187 uncontrolled dm 2.92 (1.20–7.09) 0.018 2.63 (1.05–6.60) 0.039 op time (min) 1.00 (1.00–1.01) 0.120 pre op hemoglobin low abnormal reference normal 0.47 (0.21–1.07) 0.071 pre op nephro score low reference intermediate 1.97 (1.06–3.65) 0.031 2.02 (1.07-3.80) 0.03 pathologic t stage 26 t1a reference t1b-t3 1.68 (0.82–3.43) 0.153 aki: acute kidney injury, bmi: body mass index, ci: confidence interval, ckd: chronic kidney disease, dm: diabetes mellitus, htn: hypertension, op: operation; pre op: preoperative, post op: postoperative 27 table 5. clinical factors associated with the progression of postoperative long-term ckd variables univariate analysis multivariate analysis odds ratio (95% ci) p-value odds ratio (95% ci) p-value age (years) 1.14 (1.10–1.18) <0.001 1.14 (1.10–1.18) <0.001 sex male reference female 0.66 (0.36–1.21) 0.184 bmi (kg/m2) < 25 reference ≥ 25 0.72 (0.43–1.19) 0.200 site right reference left 0.88 (0.54–1.44) 0.609 methods of surgery open reference laparoscopy 0.87 (0.50–1.51) 0.620 htn 1.88 (1.14–3.10) 0.013 1.01 (0.55–1.83) 0.983 dm no reference controlled dm 2.67 (1.38–5.17) 0.004 1.61 (0.75–3.48) 0.217 uncontrolled dm 5.34 (2.45–11.66) <0.001 4.57 (1.84–11.4) 0.001 op time (min) 1.00 (0.99–1.00) 0.507 28 pre op hemoglobin low abnormal reference normal 0.27 (0.14–0.53) <0.001 0.44 (0.19–1.01) 0.053 pre op nephro score low reference intermediate 1.55 (0.94–2.56) 0.086 pathologic t stage t1a reference t1b-t3 1.20 (0.63–2.28) 0.576 bmi: body mass index, ckd: chronic kidney disease, dm: diabetes mellitus, htn: hypertension, op: operation; pre op: preoperative, post op: postoperative cribriform pattern of the prostate adenocarcinoma: sensitivity of multiparametric mri mustafa bilal tuna1*, aydan arslan2, yunus baran kök3, tunkut doganca4, omer burak argun5, ilter tufek5, betül zehra pirdal6, yesim saglican3, can obek5, ercan karaarslan7, ali riza kural5 introduction mpmri improves the detection of clinically sig-nificant prostate cancers and helps to prevent unnecessary biopsies.(1-3) pi-rads v2.1 scoring system precisely predicts the clinically significant prostate cancer, with scores of 1 and 5 reflecting a very low and very high possibility of clinically significant cancer.(4) four subtypes of gleason pattern 4 are identified (cribriform, fused, glomeruloid and poorly formed) in recent years. the cribriform pattern is accepted more aggressive and more fatal than non-cribriform gleason pattern 4 and is associated with increased risk of lymph node and distant metastasis, biochemical recurrence, and cancer-specific death.(5-7) recent studies have shown for active surveillance candidates; a cribriform pattern in the biopsy specimen is an exclusion criterion.(8) therefore; identification of the cribriform pattern is crucial in terms of oncologic outcomes and clinical decision-making. however, data to date have claimed that cribriform pattern-predominant lesions are less visible on mpmri and there are limited data on the radiologic evaluation of cribriform architecture.(9,10) in this study, we investigate the diagnostic effectiveness of mpmri for detecting cribriform pattern prostate cancer. materials and methods a total of 33 patients whose final pathologic specimen contains the cribriform pattern of prostate cancer after robot-assisted laparoscopic radical prostatectomy between september 2018 to february 2021 were included in this study. all patients had pre-operative biopsy-proven clinically significant prostate cancer. mpmri was performed for all patients by the pi-rads v2.1 guideline before the prostate biopsy and radical prostatectomy. all whole-mount step-section pathological slices were available and collected for pathological review. patients who received neoadjuvant treatment 1department of urology, acibadem maslak hospital, istanbul, turkey. 2department of radiology, umraniye training and research hospital; istanbul,turkey. 3department of pathology, acibadem mehmet ali aydinlar university school of medicine, istanbul, turkey. 4department of urology, acibadem taksim hospital, istanbul, turkey. 5department of urology, acibadem mehmet ali aydinlar university school of medicine, istanbul, turkey. 6department of public health, cerrahpasa faculty of medicine, istanbul university-cerrahpasa, kocamustafapasa, fatih, 34098 istanbul, turkey. 7department of radiology, acibadem mehmet ali aydinlar university school of medicine, istanbul, turkey. *correspondence: department of urology, acibadem maslak hospital, istanbul, 34457,turkey. tel:+905052532047, fax: +9002122190987, e-mail: mustafabilaltuna@gmail.com. received july 2022 & accepted december 2022 background: the aim of this study was to investigate the diagnostic performance of mpmri for detecting cribriform pattern prostate cancer. materials and methods: this study retrospectively enrolled 33 patients who were reported cribriform pattern prostate cancer at final pathology. the localization, grade and volumetric properties of the dominant tumors and areas with cribriform pattern at the final pathological specimens were recorded and the diagnostic value of mpmri was evaluated on the basis of the cribriform morphology detection rate. it was analyzed using wilcoxon test, the chi-square test and fisher's exact test. the significance level (p-value) was set at .05 in all statistical analyses. results: a total of 58 prostate cancer foci were (38 cribriform, 20 non-cribriform foci) identified on the final pathology. mpmri identified 36 of the 38 cribriform morphology harboring tumor foci with a sensitivity of 94.7% (95% confidence interval 82.7–98.5%). in 17 of the 33 patients mpmri detected single lesion and for these lesions; mpmri identified cribriform morphology positive areas precisely in 15 patients with significantly low adcmean and adcmin values compared to the non-cribriform cancer areas within the primary index lesion (p < .001). for the remaining 16 patients with multiple lesions; all of the tumor foci that harboring cribriform morphology were identified by mpmri but in none of them any adcmean and adcmin value divergence were detected between the cribriform and non-cribriform pattern tumor foci within the primary index lesion. conclusion: cribiform pattern should be considered in single lesions with an area of lower adc value on mpmri. keywords: cribriform pattern, multiparametric mri, prostate cancer urological oncology urology journal/vol 20 no. 1/ january-february 2023/ pp. 34-40. [doi:10.22037/uj.v19i.7382] including androgen deprivation therapy or chemotherapy and underwent mpmri after prostate biopsy were excluded from the study. this study was approved by the acibadem mehmet ali aydınlar university institutional review board (i̇stanbul, turkey), (decision number:2022-05/10), and signed informed consent were collected from all subjects before mr imaging. mri protocol and image analysis mpmri was performed with a 3.0-t mr scanner (siemens healthineers, magnetom skyra, erlangen, germany, or siemens healthineers) using either gadovist (0.1ml / kg) or dotarem, (0.2 ml/kg) as a contrast agent before the prostate biopsy. detailed prostate mpmri protocol is given in table 1. all images were evaluated by two experienced radiologists. the radiologists were blinded to the other radiologist's reports but after the evaluation of the dataset, consensus was achieved. the radiologists identified abnormalities that correspond to clinically significant prostate cancer. all tumor foci were recorded according to zone (central, peripheral, or transition zone), sector (anterior or posterior), regional part (apex, mid, or base), and laterality (left or right) using 41 sector maps in pi-rads v2.1. to make sure that all readers were scoring the same area; each reader drew on the 41 sector map. the dimensions of the lesion(maximal axial, letter 242 table 1. imaging parameters of mpmri figure 1. correlations of adcmean and adcmin values between cribriform and non-cribriform areas within the primary index lesion in cases with single mri lesion visible on mpmri unclassified 461 multiparametric mri and cribriform pattern prostate adenocarcinoma-tuna et al. vol 20 no 1 january-february 2023 35 unclassified 461 perpendicular to axial plane, and coronal plane if possible) were calculated individually. all of the lesions pi-rads ≥ 3 were scored by a radiologist according to the pi-rads v2.1. the adc values for suspicious lesions were measured by marking these areas as a region of interest(rois) on the adc map. mean and minimum adc values were recorded without knowing the pathological results after the consensus of all lesions. lastly, all of the rois were depicted manually based on tumor foci and cribriform pattern positive areas depending on the final pathology specimen with knowledge of the pathology findings. the mpmri index lesion was defined as the target with the highest pi-rads score. in case of 2 or more lesions with the same pi-rads score exists; the one regarded as clinically more suspicious by the radiologist was recorded as an index lesion. the pathology index lesion was defined as the lesion with the highest isup grade score. whole-mount histopathology radical prostatectomy specimens were sliced at 3 mm intervals from the apex to the base. two experienced genitourinary pathologists reexamined all whole-mount step-section pathological slices according to the 2014 isup modified prostate cancer criteria. the pathological workup was blinded to radiology findings. both pathologists looked at all cases and the consensus was reached. all tumor foci and cribriform pattern areas within each radical prostatectomy specimen were determined and mapped in different colors(blue&red) to a gross histopathology image that is routinely saved for each patient. from the total pathology specimen, the largest diameter of each lesion, histological type and grade, location of tumor foci, tumor spread, tumor volume, surgical margin status, lymph node involvement, and staging were documented. cribriform pattern tumor burden ratio is defined as the percentage of cribriform pattern positive tumors in the total cancer amount(including ≥ gleason 3) of the final pathology specimen. 2.4 statistical analysis spss v.21 (spss inc., chicago, il, usa) was used for statistical analysis. shapiro-wilk tests, histograms, and probability plots were used for assessing normality,. results were presented as mean ± standard deviation for normally distributed variables, and median (iqr(interquartile range)) for non-normally distributed variables. categorical variables were presented with frequency and percentage. comparisons of the groups for continuous variables were made by the mann-whitney u test. differences between the two paired groups were tested using the wilcoxon test. the chi-square test or fisher’s exact test was used to analyze categorical variables. correlation coefficients were determined using spearman rho. all tests are two-sided and the significance level was accepted as p < .05. unclassified 408 age (years), mean ± std.deviation 63.6 ± 6.9 time from mri to robot assisted radical prostatectomy (days), median (iqr) 51 (48-62.5) psa level (ng/ml), median (iqr) 6.5 (4.9-10.3) final pathologic specimen (isup grade), n (%) isup grade 2 18 (54.5%) isup grade 3 11 (33.3%) isup grade 4 1 (3%) isup grade 5 3 (9.1%) prostate volume (cm3), median (iqr) 45 (36-53.5) tumor volume (cm3), median (iqr) 4 (2.3-6.3) tumor ratio (tumor volume/prostate volume), median (iqr) 9 % (3.6-15.8) cribriform morphology tumor burden (%), median (iqr) 25% (12.5-50) pt-stage, n (%) pt2 21 (63.6%) pt3a 6 (18.1%) pt3b 6 (18.1%) pn-stage, n (%) n0 30 (90.9%) n1 3 (9.1%) surgical margin positivity, n (%) negative 28 (84.8%) positive 5 (15.1%) table 2. clinical and pathologic characteristics of the study population multiparametric mri and cribriform pattern prostate adenocarcinoma-tuna et al. categories all tumors foci visible on mpmri (53) cribriform foci visible on mpmri (36) non-cribriform foci visible on mpmri (17) p diameter (mri) (mm), median (iqr) 12 (9-16) 13 (9.3-18.8) 10 (8.5-13) .0541 diameter (final pathology) (mm) median (iqr) 13.3 (10.5-17.3) 14.5 (11.6-20.5) 10.8 (8.9-13.3) .0021 mpmri lesions, n (%) pi-rads 3 6 (11.3%) 2 (5.3%) 4 (23.5%) .0763 pi-rads 4 31 (58.5%) 19 (52.8%) 12 (70.6%) .2192 pi-rads 5 16 (31.4%) 15 (44.1%) 1 (5.9%) .0092 localization, n (%) basis 17 (32.1%) 12 (33.3%) 5 (29.4%) .7212 mid 24 (45.3%) 15 (41.7%) 9 (52.9%) apex 12 (22.6%) 9 (25%) 3 (17.6%) peripheral zone 50 (94.3%) 36 (100%) 14 (82.4%) .0293 transitional zone 3 (5.7%) 0 (0%) 3 (17.6%) table 3. mpmri characteristics of the cribriform and non-cribriform tumor foci that were visible on mpmri 1mann whitney u test, 2chi square test, 3fisher exact test urological oncology 36 results in 33 patients a total of 58 pca foci were(38 cribriform, 20 non-cribriform foci) identified on the final pathology specimen obtained after robot-assisted radical prostatectomy. the clinical and pathological characteristics of the whole study group are shown in table 2. mpmri index lesion was accordant with the prostatectomy index lesion in 31 of 33 cases (94%). mpmri precisely identified 36 of the 38 cribriform morphology harboring tumors with a sensitivity of 94.7% (95% confidence interval 82.7–98.5%) in 31 of 33 patients (94%). on the other hand; mpmri identified 17 of the 20 non-cribriform morphology tumors precisely. when the diameters of non-cribriform and cribriform tumor foci that were visible on mpmri were examined, no difference was found with mpmri, but the mean diameters of cribriform pattern harboring tumor foci were higher in the final pathology (respectively p = .054, p = .002). in our whole study group; cribriform pattern harboring tumor foci is more frequently located in pi-rads 5 lesions compared to non-cribriform tumor foci (p = .009). isup grade of the cribriform pattern positive tumors visible on mpmri was 2 in 18 foci, 3 in 13 foci, 4 in 2 foci, and 5 in 3 foci. isup grade of the non-cribriform pattern positive tumors visible on mpmri was 1 in 6 foci, 3 in 7 foci,3 in 3 foci, and 5 in 1 focus. all of the cribriform morphology positive and mpmri visible tumor foci were located in the peripheral zone. non-cribriform morphology positive and mpmri visible tumor foci were located in the transitional zone for 3 (17,6%) foci and peripheral zone for 14 (82,4%) foci. mpmri characteristics of the cribriform and non-cribriform tumor foci that were visible on mpmri are shown in table 3. in 2 of the 33 cases, mpmri could not detect cribriform morphology positive areas. one of these patients' pre-operative mpmri detected mid anterior located pirads 4 lesion with a 9x8 mm diameter. in this case, final pathology revealed; pt2, isup grade 2 prostate adenocarcinoma with a total of 1.6 cm3 tumor volume. although preoperative mpmri was concordant with the primary index lesion of the final pathology; mpmri could not detect the apical anterior located small cribriform morphology positive area. for this case, the cribriform tumor burden ratio was 5%. the other patient’s pre-operative mpmri detected a mid-anterior located 10x7 mm pi-rads 4 lesion and final pathology revealed pt2, isup grade 2 prostate adenocarcinoma with a total of 6.1 cm3 tumor volume. for this patient, pre-operative mpmri was accordant to the primary index lesion of the final pathologic specimen, but could not detect cribriform morphology positive small area that was located at the left apical region of the prostate. in this case, the cribriform tumor burden was 10%. on the other hand, 2 in the 33 cases mpmri could not identify the primary index lesion of the final pathology specimen. in one of these cases, pre-operative mpmri detected a mid posterior located pi-rads 4 lesion with an 8x5 mm diameter. for this case; the final pathology revealed pt2, isup grade 2 prostate adenocarcinoma with a total of 0.6 cm3 tumor volume. in this case, pre-operative mpmri could not detect the primary index lesion that was located in the mid apical posterior aspect of the prostate but only identified the cribriform morphology positive area that was located at the mid posterior part of the prostate. in this case; the cribriform tumor burden was 10%. the other patient's pre-operative mpmri detected a right mid-lateral located pi-rads 4 lesion with a 6x4 mm diameter. in this case, the final pathology revealed pt2, isup grade 4 prostate adenocarcinoma with a total of 1.5 cm3 tumor volume. for this case; the final pathology revealed multiple tumor foci that were located at the left mid, right mid posterior, right mid-lateral, and right apical region of the prostate and mpmri detected only cribriform morphology positive area located at the right mid-lateral region of the prostate. the cribriform tumor burden ratio of this case was 45%. in 17 of the 33 cases, mpmri detected a single lesion (6 pi-rads 5, 11 pi-rads 4) and among these cases, mpmri identified cribriform morphology positive areas precisely in 15 patients. these cribriform positive area’s adcmean and adcmin values were significantly low compared to the non-cribriform cancer areas within the primary index lesion. for the remaining 16 patients with multiple lesions (10 pi-rads 5, 20 pi-rads 4, 6 pi-rasd 3); all of the tumor foci that harbored cribriform morphology were identified by mpmri but in none of them any adcmean and adcmin value divergence were detected between the cribriform pattern tumor foci within the primary index lesion and primary index tumor. when the median adcmean and adcmin values in the cribriform and non-cribriform areas were examined in these 15 patients with single mpmri lesion, it was found that the median adcmean and adcmin values in the cribriform areas were significantly low (retrospectively p < .001, p < .001) when compared to the non-cribriform tumor areas within the primary unclassified 463 categories (n) cribriform areas non-cribriform areas p correlation median (iqr) median (iqr) r p all cases (n=31) adcmean (μm2/s), 730 (643-848) 802 (700-991) < .0011 0.834 < .0012 adcmin (μm2/s), 611 (469-756) 721 (611-878) < .0011 0.620 < .0012 cribriform pattern mpmri visible cases with single mpmri lesion (n=15) adcmean (μm2/s) 726 (538-810) 848 (725-1018) < .0011 0.771 .0012 adcmin (μm2/s) 496 (388-720) 743 (656-897) < .0011 0.588 .0212 cases with multiple mpmri lesion (n=16) adcmean (μm2/s) 755 (673-937.3) 755 (673-937,3) 1.001 1.00 adcmin (μm2/s) 666 (519.3-756) 666 (519.3-756) 1.001 1.00 table 4. comparison of cribriform and non-cribriform areas in cribriform pattern visible cases on mpmri with single mpmri lesion and cases with multipl mpmri lesion 1wilcoxon test, 2spearman correlation multiparametric mri and cribriform pattern prostate adenocarcinoma-tuna et al. vol 20 no 1 january-february 2023 37 index lesion. in these 15 patients with single mpmri lesion; there was a high positive correlation (r = 0.771, p < .001) between adcmean values in cribriform and non-cribriform areas, and a moderate positive correlation between adcmin values (r = 0.588, p = .012) (table 4, figure 1). for the remaining 16 patients with multiple lesions (10 pi-rads 5, 20 pi-rads 4, 6 pirasd 3); all of the tumor foci that harbored cribriform morphology were identified by mpmri but in none of them any adcmean and adcmin value divergence were detected between the cribriform pattern tumor foci and non-cribriform pattern tumor foci within the primary index lesion. on the other hand; the median cribriform pattern tumor burden ratio was 40% (iqr 25-50) in cases with mp mri visible cases with single mpmri lesion and 17.5% (iqr 10-57.5) in cases with multiple mpmri lesions and no statistical difference was found between them (p = .106). discusssion in the pi-rads v2.1 era; the pooled sensitivity and specificity of mpmri for detecting prostate cancer are 89% and 73% respectively.(1-3) despite these advantages; tumor volume, tumor density, gleason score, and tumor heterogeneity with underlying clinical features (presence of cribriform and intraductal carcinoma) can affect the tumor visibility.(2,11-13) cribriform morphology can be defined as having moderately differentiated glands ranging from small to large, growing in spaced-out infiltrative patterns.(14) moreover; the isup conference in 2014 arrived at a consensus that; cribriform glands should be assigned as gleason pattern 4, regardless of morphology.(15) in addition to that; to improve the prostate cancer screening for initial prostate biopsy; the erspc rotterdam risk calculator was updated in 2014 and stated that: the presence of cribriform or intraductal carcinoma should be defined as high-risk prostate cancer.(16) the visibility of the gleason 4 pattern varies depending on the morphologic features. recently aydan et. reported their experience in 58 men with 112 clinically significant prostate cancer foci to investigate the mpmri visibility of prostate cancer according to the underlying histopathological variances. they concluded that; although statistically not significant, clinically significant prostate cancer with cribriform component and without any intraductal or cribriform component are more likely to harbor mpmri invisible features than the intraductal pattern.(13) moreover; it is noteworthy to mention recent reports on larger cohorts of patients highlighting the relatively high incidence of high-grade prostate cancer with cribriform morphology in patients with negative mpmri. according to recent studies, cribriform pattern dominant prostate cancer is usually not visible at imaging and even on diffusion-weighted images of mpmri. in this respect; quantitative analyses of mpmri has shown encouraging results in peripheral tumor characterization.(17) the visibility of pure cribriform pattern tumors is reported % at 17 on mri, which was significantly lower than other gleason 4 pattern subtypes independent of tumor size.(10) the mechanism of the decreased visibility is unknown but theoretically attributed to the relatively larger luminal perforations and fewer epithelial cells of cribriform morphology.(9) gao j. et al. retrospectively collected the data of 215 prostate cancer patients who received mpmri examination, systematic biopsy combined with targeted biopsy, radical prostatectomy, and final isup scores 2 and 3. in this study; cribriform morphology was detected in 110 of 215 patients (51.2%). they concluded that: prostate-specific antigen density (p = .003), prostate imaging reporting and data system score (p < .001) and maximal biopsy gleason score (p = .004) were independent predictors for presence of cribriform morphology.(18) prendeville et al. reported their prospective study that compares biopsy detection of intraductal and cribriform pattern prostate cancer in mpmri positive and negative regions of the prostate in 151 patients. intraductal/cribriform positive tumor was detected in 23 cases. for these cases; the prior 12-core systematic biopsy was negative in 8 and isup grade 1 in 11 cases. they concluded that; the intraductal/cribriform pattern was significantly associated with pi-rads score 5 and decreasing adc values. this study shows the ability of mpmri targeted biopsy to detect high-risk intraductal/ cribriform gleason pattern 4 prostate cancer.(19) computer aided diagnostic (cad) system assistance for fusion prostate biopsy has shown to be more effective in identification of clinically significant prostate cancers. cad-assisted analyses provide enhanced graphic visualization and more precise spatial contouring of the lesion. these advantages of this system; instantly facilitate the detection of targeted areas; particularly in pirads ≤ 3 lesions.(20) moreover; tonttila et al; reported their experience to assess the diagnostic ability for detecting cribriform patterns and intraductal carcinoma in 124 patients that underwent mpmri before radical prostatectomy. they showed that mpmri detected cribriform pattern and intraductal carcinoma with 90.5% sensitivity.(21) our results correspond with their findings. in our study; we determined that; mpmri precisely identified 36 of the 38 cribriform morphology harboring tumors (%94.7) in 31 of 33 patients (94%). there is a close inverse correlation between quantitative adc measurement and clinical aggressiveness and gleason score. however, literature to date advocates that; there is no significant difference between the adcmean between the cribriform-positive and non-cribriform prostate cancer. tonttila et al. noticed a similar correlation between adc values and clinical adverse events, but the range was so wide to show its clinical value. they stated that; the adc value is not a marker to differentiate isup group 2 tumors with cribriform and intraductal carcinoma.(21) similarly; hurrel sl et al. did not find a correlation between the adc values for gleason pattern 4 with and without cribriform architecture and intraductal carcinoma.(22) gao et al. retrospectively reported their data to investigate the diagnostic performance of ga68 psma pet/ct in a total of 49 patients with 62 lesions. from these lesions, 37(59.7%) in 34 patients (69.4%) they detected cribriform morphology. although they found that; adcmean and adc10% of were similar between cribriform positive and non-cribriform groups (p > .05); they showed that psma was significantly overexpressed in cribriform-positive prostate cancer (p = .003) and suvmax was a significant predictor of cribriform morphology (p < .001).(23) our results do not correspond with the previous studies on some points. in 17 of the 33 patients with a single mpmri lesion; mpmri detected a single lesion (6 pi-rads 5, 11 pi-rads 4), and for these lesions; mpmri identified cribriform morphology posivol 19 no 6 november-december 2022 464 multiparametric mri and cribriform pattern prostate adenocarcinoma-tuna et al. urological oncology 38 unclassified 410 tive areas precisely in 15 patients. for these 15 cases; the cribriform positive area’s adcmean and adcmin values were significantly low compared to the non-cribriform cancer areas within the primary index lesion. on the other hand, in 16 patients with multiple lesions (10 pi-rads 5, 20 pi-rads 4, 6 pirasd 3); all of the tumor foci that harbored cribriform morphology were identified but in none of them any adcmean and adcmin value divergence were detected between the cribriform pattern tumor foci within the primary index lesion and primary index tumor. this may be explained by the clustering of the cribriform pattern cells in a single lesion rather than dispersing around into multiple lesions. the strengths of our study are the detailed mri analysis by two experienced radiologists and whole-mount histopathology of the primary tumor including cribriform architecture. moreover, whole-mount histopathology was evaluated based on identifying cribriform morphology by two experienced genitourinary pathologists to provide interobserver reliability. the main limitation of this study was the small (n = 33 men) sample size derived from a single tertiary center; therefore, adoption of our outcomes may not apply to community-based radiology and urology practice. conclusions despite reports of diminished visibility in the literature, multiparametric prostate mri has high sensitivity and is an effective diagnostic technique for detecting cribriform pattern prostate cancer. in patients with a single lesion on pre-operative mpmri, areas with lower adcmean and adcmin within the primary index lesion compared to the primary index lesion should be considered for cribriform pattern existence at the final pathology specimen. more randomized multi-center trials are needed to back up our findings. conflict of interest none financial disclosure none references 1. weinreb jc, barentsz jo, choyke pl, et al. pi-rads prostate imaging reporting and data system: 2015, version 2. eur urol. 2016 jan;69(1):16-40. doi: 10.1016/j. eururo.2015.08.052. epub 2015 oct 1. pmid: 26427566; pmcid: pmc6467207. 2. ahmed hu, el-shater bosaily a, et al.; promis study group. diagnostic accuracy of multi-parametric mri and trus biopsy in prostate cancer (promis): a paired validating confirmatory study. lancet. 2017 feb 25;389(10071):815-822. doi: 10.1016/s01406736(16)32401-1. epub 2017 jan 20. pmid: 28110982. 3. kasivisvanathan v, rannikko as, borghi m, et al.; 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radical prostatectomy specimens. j urol. 2018 jan;199(1):106-113. doi: 10.1016/j. juro.2017.07.037. epub 2017 jul 18. erratum in: j urol. 2017 dec 8;: pmid: 28728994. 11. miyai k, mikoshi a, hamabe f, et al. histological differences in cancer cells, stroma, and luminal spaces strongly correlate with in vivo mri-detectability of prostate cancer. mod pathol. 2019 oct;32(10):15361543. doi: 10.1038/s41379-019-0292-y. epub 2019 jun 7. pmid: 31175330. 12. schieda n, coffey n, gulavita p, al-dandan o, shabana w, flood ta. prostatic ductal adenocarcinoma: an aggressive tumour variant unrecognized on t2 weighted magnetic resonance imaging (mri). eur radiol. 2014 jun;24(6):1349-56. doi: 10.1007/s00330-0143150-9. epub 2014 apr 1. pmid: 24687527. 13. arslan a, alis d, tuna mb, sağlıcan y, kural ar, karaarslan e. the visibility multiparametric mri and cribriform pattern prostate adenocarcinoma-tuna et al. vol 20 no 1 january-february 2023 39 of prostate cancer concerning underlying histopathological variances: a single-center multiparametric magnetic resonance imaging study. eur j radiol. 2021 aug;141:109791. doi: 10.1016/j.ejrad.2021.109791. epub 2021 may 27. pmid: 34062471. 14. gleason df. classification of prostatic carcinomas. cancer chemother rep. 1966 mar;50(3):125-8. pmid: 5948714. 15. epstein ji, egevad l, amin mb, delahunt b, srigley jr, humphrey pa; grading committee. the 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. am j surg pathol. 2016 feb;40(2):244-52. doi: 10.1097/pas.0000000000000530. pmid: 26492179. 16. roobol mj, verbeek jfm, van der kwast t, kümmerlin ip, kweldam cf, van leenders gjlh. improving the rotterdam european randomized study of screening for prostate cancer risk calculator for initial prostate biopsy by incorporating the 2014 international society of urological pathology gleason grading and cribriform growth. eur urol. 2017 jul;72(1):45-51. doi: 10.1016/j. eururo.2017.01.033. epub 2017 feb 2. pmid: 28162815. 17. panebianco v, barchetti g, simone g, et al. negative multiparametric magnetic resonance imaging for prostate cancer: what's next? eur urol. 2018 jul;74(1):48-54. doi: 10.1016/j.eururo.2018.03.007. epub 2018 mar 19. pmid: 29566957. 18. gao j, zhang q, fu y, et al. combined clinical characteristics and multiparametric mri parameters for prediction of cribriform morphology in intermediaterisk prostate cancer patients. urol oncol. 2020 apr;38(4):216-224. doi: 10.1016/j. urolonc.2019.09.002. epub 2019 oct 7. pmid: 31601518. 19. prendeville s, gertner m, maganti m, et al. role of magnetic resonance imaging targeted biopsy in detection of prostate cancer harboring adverse pathological features of intraductal carcinoma and invasive cribriform carcinoma. j urol. 2018 jul;200(1):104-113. doi: 10.1016/j. juro.2018.01.081. epub 2018 feb 2. pmid: 29408568. 20. ferriero m, anceschi u, bove am, et al. fusion us/mri prostate biopsy using a computer aided diagnostic (cad) system. minerva urol nephrol. 2021 oct;73(5):616-624. doi: 10.23736/s2724-6051.20.04008-4. epub 2020 nov 12. pmid: 33179868. 21. tonttila pp, ahtikoski a, kuisma m, pääkkö e, hirvikoski p, vaarala mh. multiparametric mri prior to radical prostatectomy identifies intraductal and cribriform growth patterns in prostate cancer. bju int. 2019 dec;124(6):992998. doi: 10.1111/bju.14812. epub 2019 jun 19. pmid: 31102571. 22. hurrell sl, mcgarry sd, kaczmarowski a, et al. optimized b-value selection for the discrimination of prostate cancer grades, including the cribriform pattern, using diffusion weighted imaging. j med imaging (bellingham). 2018 jan;5(1):011004. doi: 10.1117/1.jmi.5.1.011004. epub 2017 oct 27. pmid: 29098169; pmcid: pmc5658575. 23. gao j, zhang c, zhang q, et al. diagnostic performance of 68ga-psma pet/ct for identification of aggressive cribriform morphology in prostate cancer with wholemount sections. eur j nucl med mol imaging. 2019 jul;46(7):1531-1541. doi: 10.1007/ s00259-019-04320-9. epub 2019 apr 25. pmid: 31025048. multiparametric mri and cribriform pattern prostate adenocarcinoma-tuna et al. urological oncology 40 pediatric urology 161urology journal vol 7 no 3 summer 2010 ultrasonographic screening of newborns for congenital anomalies of the kidney and the urinary tracts yilmaz tabel, zeliha sule haskologlu, hakki muammer karakas, cengiz yakinci purpose: to search for the efficiency of scanning the newborns with routine urinary system ultrasonography. materials and methods: urinary ultrasonography has been carried out on 721 infants born in or brought to our hospital. during the study, name, sex, week of birth, presence of antenatal diagnosis or urinary tract infections, and pathologies in examinations of the babies were recorded. ultrasonography analysis was done with a scanner by a radiologist. patients identified to have pathologhy, were watched closely in pediatric nephrology clinic, and advanced visualizations and treatments were carried out. results: seventy-six infants (10.5%) had congenital anomalies of the kidney and the urinary tracts that prompted medical and/or surgical intervention. of whom, 32 were diagnosed with antenatal ultrasonography and 44 during their initial postnatal ultrasonography screening. the most frequent identified pathology was hydronephrosis, in particular physiologic hydronephrosis (35.8%). the most frequent congenital urinary anomaly which caused hydronephrosis was ureteropelvic obstruction. conclusion: it is suggested to apply the urinary ultrasonography scanning to all the infants that are born or brought to the university hospital. if possible, it is to be considered to include urinary ultrasonography scanning in newborn scanning programs. urol j. 2010;7:161-7. www.uj.unrc.ir keywords: ultrasonography, newborns, congenital abnormalities, urinary tract departments of pediatric nephrology, pediatrics, and radiology, turgut ozal medical center, inonu university, malatya, turkey corresponding author: yilmaz tabel, md department of pediatric nephrology, turgut ozal tip merkezi, inonu universitesi, cocuk klinigi, 44280, malatya, turkey tel: +90 422 377 5301 fax: +90 422 341 0728 e-mail:yilmaztabel@yahoo.com received october 2009 accepted march 2010 introduction congenital anomalies of the kidney and the urinary tracts constitute major causes of renal insufficiency. in turkey, these disorders are found in upto 38.8% of pediatric cases requiring dialysis. among them, vesicoureteral reflux plays the major role (24%), whereas other congenital urological disorders (8%) and renal hypoplasia/dysplasia (7%) constitute remaining causes.(1) the prevalence of congenital urologic abnormalities is roughly the same in various geographical locations, being 45% in japan and 33% in north america.(2,3) the incidence of renal insufficiency exhibits a decline in developed countries. the unchanged incidence of congenital anomalies puts them on top of the differential list for disorders that cause renal insufficiency.(4) congenital anomalies of the kidney and the urinary tracts may be detected with a variety of screening techniques and diagnostic ultrasonography in congenital anomalies—tabel et al 162 urology journal vol 7 no 3 summer 2010 methods, including antenatal and postnatal ultrasonography, urinary analysis, and renal biopsy.(5) ultrasonography, an easily accessible, non-invasive, and real-time method, has been used since many years ago to determine renal and urinary tract anomalies.(1,6,7) in the absence of any systemic disease, the prevalence of congenital anomalies of the kidney and the urinary tracts is found to be around 0.1% with antenatal ultrasonography(8) and over 1% with postnatal ultrasonography.(9) however, not the incidence, but the severity of the clinical picture and the presence of the bilateral disease govern the clinical importance. in this study, descriptive statistics of newborns screened for renal and urinary tract anomalies are presented. furthermore, postnatal ultrasonography screening findings and their follow-ups are given. this study is the initial large-scale screening for congenital anomalies of the kidney and the urinary tracts in turkey. materials and methods this study was conducted at turgut ozal medical center, inonu university during a period of 18 months. subjects were 3 to 28-day-old infants that were delivered in our institution, admitted to our premature and neonatal intensive care units, or admitted to our outpatient clinic of pediatric nephrology. the sampling method of this study was representative. sample consisted of 721 newborns. one hundred and twenty (16.6%) subjects were screened antenatally with ultrasonography, and found to have renal and/or urinary anomalies. they were subsequently sent to our department for postnatal work-up. subjects were investigated using color doppler ultrasonography (atl hdi 5000, philips medical systems, bothell, wa) and 4-7 mhz linear array transducer with 38 mm footpath. investigations were performed in department of diagnostic radiology, always by the same radiologist and the same equipment. the kidneys were assessed for following features: their presence or absence, dimensional abnormality (length ≤ 35 mm, ≥ 65 mm) and asymmetry in the left or right kidney (difference ≥ 10 mm), presence of central echogenic complex with a grade of 2 or higher according to the society of fetal urology criteria,(10) presence or absence of normal renal echogenicity, and accompanying abnormalities such as cysts or tumors. the urinary bladder was checked for abnormalities in shape and wall. the ureters were checked for any ureteral dilation. the complete list of renal or urinary anomalies that can be diagnosed by ultrasonography in antenatal and/or postnatal period is given in table 1. subjects with abnormal findings in initial work-up underwent 12-month follow-up examination with ultrasonography. the persistence of abnormal findings mandated further examinations, including voiding cystourethrography, intravenous urography, renal scintigraphy with 99mtc-dimercaptosuccinic acid, diuretic renal scintigraphy with 99mtcdiethylenetriamine pentaacetic acid or 99mtcmercaptoacetyltriglycine, abdominal computed tomography, and abdominal magnetic resonance imaging, including magnetic resonance urography. patients were then treated and/or referred to appropriate clinics, including pediatric surgery. the procedures were in accordance with the ethical standard for human experimentations established by declaration of helsinki in 1975, revised in 1983. the study was approved by the ethics committee of inonu university and prenatal period postnatal period dysplastic kidney aplastic kidney hydronephrosis double ureter multicystic dysplastic kidney dysplastic kidney posterior urethral valve horseshoe kidney potter’s syndrome hydronephrosis prune–belly syndrome hypoplastic kidney simple renal cyst multicystic dysplastic kidney ureterocele posterior urethral valve ureteropelvic junction obstruction simple renal cyst ureterovesical junction obstruction ureterocele vesicoureteral reflux vesicoureteral reflux table 1. the list of congenital anomalies of the kidney and the urinary tracts that can be detected during ultrasonography screening (in alphabetical order) ultrasonography in congenital anomalies—tabel et al 163urology journal vol 7 no 3 summer 2010 detailed consent forms were signed by the families of all the patients, before participating in the study. data were analyzed using the spss software (statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa). pearson’s chi-square and fisher’s exact tests were used. p values less than .05 were considered statistically significant. results of 721 infants that were screened with ultrasonography, 253 (35.1%) were preterm and 468 (64.9%) were term babies, with female predominance (58.7%). seventy-six infants (10.5%) had congenital anomalies of the kidney and the urinary tracts that prompted medical and/or surgical intervention. of whom, 32 were diagnosed with antenatal ultrasonography, whereas 44 were diagnosed during their initial postnatal ultrasonography screening. demographic and clinical characteristics of the patients are presented in table 2. distributions of anomalies according to their frequency in sample group are presented in figure. the most frequent anomaly that was seen in 120 subjects that were found to have a urinary anomaly in antenatal ultrasonography was hydronephrosis. postnatal follow-ups of these subjects revealed transient hydronephrosis in 27.5%, physiological hydronephrosis in 35.8%, ureteropelvic junction obstruction in 15%, vesicoureteral reflux in 5%, multicystic dysplastic kidney in 3.3%, and posterior urethral valve in 1.6% of the patients. etiologies of antenatal hydronephrosis and postnatal first screening patients are given in table 3. in infants with antenatally diagnosed hydronephrosis, the subsequent physiological numbers of positive cases at antenatal and postnatal screening *vur, indicates vesicoureteral reflux; mdk, multicystic dysplastic kidney; and puv, posterior urethral valve. n (%) total patients (male/female) 721 (58.7/41.3) preterm/term 253 (35.1)/468 (64.9) antenatal ultrasonography (yes/no) 120 (16.6)/601 (83.4) cakut (yes/no) 76 (10.5)/645 (89.5) cakut (antenatal group/first screening) 32 (42.1)/44 (57.9) table 2. demographic and clinical characteristics of patients *cakut, indicates congenital anomaly of the kidney and the urinary tracts. etiology first postnatal screeningn (%) antenatal abnormal ultrasonography (+) n (%) physiological hydronephrosis* 17 (2.8) 43 (35.8) transient hydronephrosis* 0 33 (27.5) ureteropelvic stenosis 24 (3.4) 20 (16.6) vesicoureteral reflux 14 (2.3) 6 (5) multicystic displastic kidney 2 (0.3) 4 (3.3) posterior urethral valve 0 2 (1.6) renal agenesis 3 (0.4) 0 ektopik böbrek 1 (0.1) 0 normal 557 (92.6) 88 (73.3) total 601 120 table 3. etiological classification of antenatal hydronephrosis and postnatal first screening *physiologic and transient hydronephrosis were considered as normal group ultrasonography in congenital anomalies—tabel et al 164 urology journal vol 7 no 3 summer 2010 improvement was significantly poorer than the infants with postnatally diagnosed hydronephrosis (27.5% versus 35.8%, p < .05). in infants with persistent hydronephrosis, the frequency of left kidney involvement was significantly higher than the frequency of right kidney involvement (31% versus 13%, p < .0001). males were significantly more frequently affected than females (31.2% versus 10%, p < .01). physiological improvement of hydronephrosis in the left kidney was significantly higher than the physiological improvement of the right kidney (26.9% versus 12.1%, p < .01). increased parenchymal echogenity of the kidneys was observed in 23 subjects (3.1%), of whom 9, 10, and 4 also had acute renal failure, urinary tract infection (uti), and multicystic dysplastic kidneys, respectively. the presence of ureteropelvic junction obstruction and/or vesicoureteral reflux had statistically significant association with utis (p < .001). in 18 infants (2.4%) with congenital anomalies of the kidney and the urinary tracts, physical examinations and other diagnostic investigations detected additional extra-renal congenital anomalies. these anomalies and accompanying congenital anomalies of the kidney and the urinary tracts are listed in table 4. during the study period, 49 infants with congenital anomalies of the kidney and the urinary tracts have been treated medically with antibiotics and/or antihypertensive agents. twenty-three patients with ureteropelvic junction obstruction, 2 patients with posterior ureteral valve, and 2 patients with high grade vesicoureteral reflux underwent surgery. discussion due to the advent of preventive measures and modern treatment strategies, the incidence of chronic renal failure in pediatric population has decreased in many countries. congenital factors being mostly unpreventable became, therefore, primary causative factors. in pediatric end-stage renal disease, congenital factors are encountered in 39% of the patients in turkey, 45% of the patients in japan, and 33% of the patients in the usa.(1-3) ultrasonography is the first imaging method of choice to evaluate urinary assessment of infants both antenatally and postnatally. (11) ultrasonography has many advantages such as non-invasiveness, cost efficiency, and easy accessibility. in screening studies using ultrasonography, the frequency of urinary anomalies are usually found between 0.1% and 1%.(12,13) in the present study, the frequency of congenital anomalies of the kidney and the urinary tracts was 10.5%, which was much higher than the ones reported in other studies, such as studies by riccipetitoni and colleagues (1.04%),(9) sakuma and ogawa (3.7%),(14) tsuchiya and associates (3.5%),(2) and himmetoglu and coworkers (0.27%).(15) the higher figure was thought to be caused by the study design and the sample of the present study. the study was conducted in a tertiary institution to which many complicated pregnancies and sick newborns were referred, and also included samples from pediatric nephrology department. in addition to the above mentioned factors, the people that live in the geographical area (east anatolia) that was represented by the study have low socioeconomic level and endogamy. the anomaly n anomaly of the kidney and/or the urinary tracts congenital heart disease 9 vsd 4 2 vesicoureteral reflux, 2 hydronephrosis pda 3 1 vesicoureteral reflux, 2 hydronephrosis asd 1 vesicoureteral reflux dextrocardia 1 hydronephrosis gastrointestinal anomaly 4 omphalocele 1 hydronephrosis anal atresia 1 hydronephrosis pyloric stenosis 1 hydronephrosis cleft palate 1 hydronephrosis cns anomaly 3 myelomeningocele 2 1 vesicoureteral reflux, 1 hydronephrosis diastematomyelia 1 hydronephrosis genital anomaly 2 ambiguous genitalia 1 renal agenesis urogenitale sinus 1 hydronephrosis table 4. congenital anomalies other than urinary disorders and accompanying congenital anomalies of the kidney and the urinary tracts *vsd, indicates ventricular septal defect; pda, patent ductus arteriosus; asd, atrial septal defect; and cns, central nervous system. ultrasonography in congenital anomalies—tabel et al 165urology journal vol 7 no 3 summer 2010 study, therefore, cannot represent the general situation in turkey, but is, nevertheless, a good indicator of the status in its eastern parts. the antenatal diagnosis of congenital anomalies of the kidney and the urinary tracts or their discovery in postnatal screening has also major impact on the prevalence of the anomaly. even the screening policy that was used to detect the anomaly may be a contributing factor as shown in a very large study on 709 030 live births, stillbirths, and induced abortions that was performed to evaluate the prevalence of antenatal ultrasonography diagnoses for renal anomalies in 20 registries of 12 european countries. in that study, detection rates varied in different countries of the european community due to diverse policies or ethical and religious background. countries with no routine ultrasonography showed the lowest rates of detection.(16) however, there are also some studies in which the above mentioned factors were not found to have a significant effect on the prevalence of congenital anomalies of the kidney and the urinary tracts. in a study by raboei and colleagues on 23 000 babies, an antenatal ultrasonography examination has been performed on 19 400 newborns and the incidence of significant urinary tract malformations were found to be similar in antenatally and postnatally diagnosed infants. however, more complications occurred in the unscreened group, implicating the value of a population-screening test based on antenatal ultrasonography examination.(17) but it should be kept in mind that the antenatal discovery of urinary abnormalities does not always implicate a better prognosis. to comply with that statement, we have found that in infants with antenatally diagnosed hydronephrosis, the subsequent physiological improvement was significantly poorer than the infants with postnatally diagnosed hydronephrosis, possibly due to higher damage in former infants. in the present study, the prevalence of congenital anomalies of the kidney and the urinary tracts was higher in infants with antenatal diagnosis than ones without such diagnosis. although this is an expected finding, it still shows the efficacy of antenatal screening. of interest was the reconfirmation of pathological findings in only a fraction (32 out of 120) of these infants. this finding implicates the necessity to repeat ultrasonography in postnatal period to establish a firm diagnosis and to plan an appropriate therapeutic management. hydronephrosis, with a prevalence of 1/100 to 1/500, constitutes 2/3 of all the intrauterine urinary abnormalities,(18) with the rate of 0.6%. (19) woodward and frank had evaluated postnatal findings of antenatally diagnosed hydronephrosis and reported transitory hydronephrosis in 48%, physiological hydronephrosis in 15%, ureteropelvic junction obstruction in 11%, vesicoureteral reflux in 9%, megaureter in 4%, multicystic dysplastic kidney in 2%, and ureterocele in 2% of their subjects.(20) the results of our study are in accordance with that study regarding the order of frequency, albeit with different prevalence. of notice was the lower prevalence of transient hydronephrosis (27.5%) and the higher prevalence of physiological hydronephrosis (35.8%), possibly due to classification mismatch between two studies. this study additionally described some novel features of infantile hydronephrosis. accordingly, (i) in infants with antenatally diagnosed hydronephrosis, the subsequent physiological improvement was significantly poorer than the infants with postnatally diagnosed hydronephrosis, as stated above; (ii) in persistent hydronephrosis, left kidney was much more frequently affected than its right counterpart, but was more frequently normalized during the follow-up; and (iii) males were more frequently affected than females. congenital anomalies of the kidney and the urinary tracts in general, and vesicoureteral reflux in particular, frequently accompany with the relapsing utis in pediatric population.(21) the present study also points to the association of congenital anomalies and uti by showing higher incidence of infection in infants with ureteropelvic junction obstruction and vesicoureteral reflux. when the renal pelvis has a diameter of 10 mm or less, risk of significant uti is also known to be lower. (22) however, ultrasonography in congenital anomalies—tabel et al 166 urology journal vol 7 no 3 summer 2010 in our study group, the prevalence of uti was also significantly high in infants without hydronephrosis. this contradictory result may be attributed to the violation of rules for general hygiene and rules to prevent such infections both due to low socioeconomic status. medullary hyperechogenity is an ultrasonographic finding that may be observed in early stages of life. according to khoory and colleagues,(23) the prevalence of this abnormality is 3.9% in healthy newborns. medullary hyperechogenity may also be observed in pathological states such as hypernatremic dehydration.(24) in this study, the prevalence of medullary hyperechogenity was 3.1% (23 infants). it was accompanied by acute renal failure in 9, uti in 10, and multicystic dysplastic kidney in 4 of these patients. medullary hyperechogenity is known to spontaneously regress during the first 7 to 10 days or following the treatment of underlying causative disorder. two to 5% of live births are accompanied by some kind of major congenital abnormalities. likewise, using a multimodal approach, we observed congenital cardiac, gastrointestinal, and/or other genitourinary anomalies in 18 infants (2.4%) that were found to have congenital anomalies of the kidney and the urinary tracts. any congenital anomaly, therefore, mandates a careful investigation toward the detection of additional anomalies. conclusion this study reveals the rationale of providing ultrasonography screening of urinary system to infants that are born in tertiary medical institutions and those that are admitted to such centers for any cause. this policy may help to establish prompt diagnosis of any urinary abnormality that may get further complicated without timely treatment and/or intervention. conflict of interest none declared. references 1. registry of the nephrology, dialysis and transplantation in turkey. registry2006.istanbul,2007,45. webpage:http://www.tsn.org.tr/documents/registry/ tnd%20registry%20kure%20son.pdf. 2. tsuchiya m, hayashida m, yanagihara t, et al. ultrasound screening for renal and urinary tract anomalies in healthy infants. pediatr int. 2003;45: 617-23. 3. fivush ba, jabs k, neu am, et al. chronic renal insufficiency in children and adolescents: the 1996 annual report of naprtcs. north american pediatric renal transplant cooperative study. pediatr nephrol. 1998;12:328-37. 4. watson ar, readett d, nelson cs, kapila l, mayell mj. dilemmas associated with antenatally detected urinary tract abnormalities. arch dis child. 1988;63:719-22. 5. scott jes, renwick m. nothern region fetal abnormality survey results 1987. j ped surg. 1990;25:394-7. 6. siegel mj. urinary tract. in: siegel mj, ed. pediatric sonography. 3 ed: philadelphia, pa: lippincott williams & wilkins; 2002:385–473. 7. steinhart jm, kuhn jp, eisenberg b, vaughan rl, maggioli aj, cozza tf. ultrasound screening of healthy infants for urinary tract abnormalities. pediatrics. 1988;82:609-14. 8. fasolato v, poloniato a, bianchi c, et al. fetoneonatal ultrasonography to detect renal abnormalities: evaluation of 1-year screening program. am j perinatol. 1998;15:161-4. 9. riccipetitoni g, chierici r, tamisari l, et al. postnatal ultrasound screening of urinary malformations. j urol. 1992;148:604-5. 10. manley ja, o’neill wc. how echogenic is echogenic? quantitative acoustics of the renal cortex. am j kidney dis. 2001;37:706-11. 11. öktem f. çocuklarda ürogenital sistemin de erlendirilmesinde kullan lan konvansiyonel radyolojik incelemeler. sd ü. tip fak. derg. 2005;12:68-75. 12. helin i, persson ph. prenatal diagnosis of urinary tract abnormalities by ultrasound. pediatrics. 1986;78: 879-83. 13. livera ln, brookfield ds, egginton ja, hawnaur jm. antenatal ultrasonography to detect fetal renal abnormalities: a prospective screening programme. bmj. 1989;298:1421-3. 14. sakuma t, ogawa o. [ultrasonographic screening in healthy 3-month-old children for congenital malformations of the urinary tract]. nippon hinyokika gakkai zasshi. 1998;89:468-76. 15. himmetoglu o, tiras mb, gursoy r, karabacak o, sahin i, onan a. the incidence of congenital malformations in a turkish population. int j gynaecol obstet. 1996;55:117-21. 16. wiesel a, queisser-luft a, clementi m, bianca s, stoll c. prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 european countries. eur j med genet. 2005;48:131-44. 17. raboei e, abou-seoud m, abou-nassef n, mehboob f, saggaf a, luoma r. prenatal ultrasound screening ultrasonography in congenital anomalies—tabel et al 167urology journal vol 7 no 3 summer 2010 of the urinary tract is useful. pediatr surg int. 2002;18:432-4. 18. diamond da, peters ca. perinatal urology. in: avner ed, harmon we, niaudet p, eds. pediatric nephrology. 5 ed. philadelphia lippincott william &wilkins 2004:73–82. 19. kapadia h, lidefelt kj, erasmie u, pilo c. antenatal renal pelvis dilatation emphasizing vesicoureteric reflux: two-year follow-up of minor postnatal dilatation. acta paediatr. 2004;93:336-9. 20. woodward m, frank d. postnatal management of antenatal hydronephrosis. bju int. 2002;89:149-56. 21. hannula a, venhola m, renko m, pokka t, huttunen np, uhari m. vesicoureteral reflux in children with suspected and proven urinary tract infection. pediatr nephrol.25:1463-9. 22. dremsek pa, gindl k, voitl p, et al. renal pyelectasis in fetuses and neonates: diagnostic value of renal pelvis diameter in preand postnatal sonographic screening. ajr am j roentgenol. 1997;168:1017-9. 23. khoory bj, andreis ia, vino l, fanos v. transient hyperechogenicity of the renal medullary pyramids: incidence in the healthy term newborn. am j perinatol. 1999;16:463-8. 24. ali us, sengupta k, andankar p, saraf s, chawla a, deshpande s. reversible renal medullary hyperechogenicity in neonatal hypernatremic dehydration. pediatr nephrol. 2004;19:1050-2. v08_no_1_print_3.pdf endourology and stone disease 21urology journal vol 8 no 1 winter 2011 does bleeding during percutaneous nephrolithotomy necessitate keeping the nephrostomy tube? a randomized controlled clinical trial masoud etemadian,1 mohammad javad soleimani,1 ramin haghighi,1 mohammad reza zeighami,1 neda najimi2 purpose: to compare outcomes in two groups of patients with kept and discarded nephrostomy tube after percutaneous nephrolithotomy (pcnl) complicated with bleeding. materials and methods: two hundred patients who had undergone pcnl complicated with hemorrhage were recruited in this study. patients were randomly allocated to two groups: group a, who underwent tubeless pcnl and tract port was packed for 3 to 4 minutes after removing amplatz sheath, and group b, for whom a 24-f nephrostomy tube was left in place at the end of the procedure. patients were followed up for 3 months to check if bleeding occurred. results: the mean operation time was 68 ± 4.3 minutes in group a and 74 ± 5.6 minutes in group b (p = .098). the mean stone size was similar in groups a and b (36.26 ± 5.3 mm versus 35.35 ± 5.85 mm; p = .613). the mean hemoglobin drop was 3.65 ± 1.20 g/dl in group a and 3.13 ± 1.06 g/ dl in group b. there was no significant difference between the mean of stonefree rate in groups a and b (92.58% ± 5.97versus 89.60% ± 8.3; p = .210). patients in group a experienced a significantly less duration of hospitalization than group b (2.42 ± 0.84 days versus 3.70 ± 0.80 days; p < .001). conclusion: in the absence of clear indication, nephrostomy tube insertion after pcnl does not seem to be beneficial, and its removal does not pose patients at any additional risk. urol j. 2011;8:21-6. www.uj.unrc.ir keywords: percutaneous nephrolithotomy, hemorrhage, randomized controlled clinical trial, nephrostomy 1department of urology, hasheminejad kidney center, tehran university of medical sciences, tehran, iran 2tehran university of medical sciences, tehran, iran corresponding author: masoud etemadian, md department of urology, hasheminejad kidney center, vanak sq, tehran, iran tel: +98 21 8864 4444 fax: +98 21 8864 4447 e-mail: etemadian@hotmail.com received april 2010 accepted august 2010 introduction since the first introduction by fernstrom and johansson in 1976,(1) percutaneous nephrolithotomy (pcnl) has become an established procedure in large, complex, and shock wave lithotripsy-resistant renal stones. technical advances and increased operator experience have resulted in considerable refinement of the percutaneous approach to the renal calculi.(2,3) as the kidney is an extremely vascular organ, some degree of bleeding occurs during every pcnl.(4) major complications, including bleeding, extravasation, and fever, can be managed conservatively or minimally invasively.(5) even for the most experienced urologists, major complications can still occur in 1.1% to 7% of patients undergoing pcnl, and minor complications may occur in 11% to 25% of the patients.(6,7) pcnl bleeding and nephrostomy tube—etemadian et al 22 urology journal vol 8 no 1 winter 2011 one of the concerns regarding the tubeless pcnl technique is inability to monitor excessive hemorrhage and tract hemostasis.(8) however, recently, tubeless pcnl has been advocated increasingly in the literature. it has been found to be safe and effective in properly selected patients and has advantages of less postoperative pain and a shorter hospital stay.(9,10) this study, to the best of our knowledge, is the first study comparing outcomes of keeping nephrostomy tube with tubeless pcnl complicated with bleeding. materials and methods patients between april 2005 and april 2009, 200 patients who had undergone pcnl and experienced bleeding were studied. all patients had intravenous urography before the surgery. patients with pregnancy, abnormal coagulopathy status, recent nonsteroidal antiinflammatory drugs consumption, and urinary tract infection were excluded from the study. whereas single kidney, malrotated or horseshoe kidneys, and previous surgery were not exclusion criteria for this study. the study was approved by the regional medical ethics commission, and a written informed consent was obtained from each patient. the patients were randomly assigned to two groups by a third person who was blinded to the study. patients in group a underwent tubeless pcnl while in group b, nephrostomy tube was placed after pcnl. pre-operative routine evaluations were done for all of the patients. operation time, hemoglobin drop, stone-free rate, duration of hospital stay, and transfusion rate were recorded. ultrasonography or computed tomography scan was performed as needed. surgical technique all of the surgeries were performed by a single team. for all of the patients, a ureteral catheter was inserted in lithotomy position; thereafter, the renal access was achieved under fluoroscopic guidance preferably through the lower calyx in prone position. tract dilation was performed in one-shot method and a 30-f amplatz sheath was inserted. pneumatic with or without ultrasonic lithotriptors were used for stone fragmentation if bleeding happened during the surgery, the patient was recruited into the study and at the end of the surgery, they were randomly divided into 2 groups; a and b. in group a, tract port was packed for 3 to 4 minutes after removing amplatz sheath. in group b, a 24-f nephrostomy tube was left at the end of the procedure. postoperative care close observation was performed for all of the patients after the procedure. serum level of hemoglobin was measured pre-operatively and every 6 hours on the first postoperative day; and if there was not a significant drop, it was measured daily until the patients’ discharge. patients’ vital signs were monitored accurately. in group a, foley and ureteral catheter were removed 24 to 48 hours after the procedure, once the urine was cleared of blood. in group b, nephrostomy tube was removed after 24 to 48 hours, once the urine was cleared, and the foley and ureteral catheter were removed 6 to 12 hours after leakage from the nephrostomy tract stopped. after discharge, the patients were followed up for 3 months to check if bleeding recurred. the patients were examined and asked about the bleeding when they have been visited at clinic. we called the patients who did not attend the clinic to ask about bleedings. statistical analysis data were analyzed using spss (statistical package for the social sciences, version 13.0, spss inc, chicago, illinois, usa) software. quantitative variables were compared by independent samples t test and mann-whitney u test, and qualitative variables by chi-square test. to remove the effect of factors affecting duration of hospitalization, linear regression model was employed. in addition, quantitative variables were provided as mean ± standard deviation (sd), and p values less than .05 were considered statistically significant. pcnl bleeding and nephrostomy tube—etemadian et al 23urology journal vol 8 no 1 winter 2011 results patients consisted of 140 (68.4%) men and 60 (31.6%) women with the mean age of 45.59 ± 12.06 years (range, 22 to 75 years). most stones were located in the pelvis and/or lower calyces and rarely in the upper pole calyces. demographic and clinical characteristics of the two groups are listed in table 1. there was not any significant difference between two groups (p = .616 and p = .915). statistically significant correlations were found between duration of hospitalization and stone-free rate (spearman r = -0.578; p < .001), hemoglobin drop and stone size (spearman r = 0.458; p = .003), and hemoglobin drop and stone-free rate (spearman r = -0.332; p = .039). more analysis with linear regression model showed that placing nephrostomy tube is a significant variable to predict duration of hospitalization (p < .001). as it is shown in table 2, rather than placing nephrostomy tube, other variables such as stone-free rate (p = .004), blood transfusion (p = .005), and hemoglobin drop (p = .034) were significant variables to predict duration of hospitalization. we did not encounter severe bleedings requiring cessation of the procedure or change to open surgery in both groups. one patient in group a, who had prolonged flank pain, developed perirenal urine collection that was confirmed with non contrast computed tomography scan and was treated successfully by percutaneous drainage. another patient in the same group came back 5 days after discharge (9 days after procedure) because of gross hematuria and was managed successfully with angioembolization. lost to follow-up in our study was zero. variable a(tubeless pcnl) b (pcnl + nephrostomy tube) p age, y 44.58 ± 13.35 46.55 ± 10.94 .616 gender, % female 31.6 31.6 .915 male 68.4 68.4 operation time, min 68 ± 4.3 (95% ci = 67.16 to 68.84) 74 ± 5.6 (95% ci = 72.9 to 75.1) .098 stone size, mm 36.26 ± 5.3 (95% ci = 35.22 to 37.30) 35.35 ± 5.85 (95% ci = 34.21 to 36.49) .613 pre-operative hemoglobin, g/dl 14.79 ± 1.24 (95% ci = 14.56 to 15.02) 14.65 ± 1.14 (95% ci = 14.43 to 14.87) .706 postoperative hemoglobin, g/dl 11.14 ± 1.21 (95% ci = 10.90 to 11.38) 11.52 ± 1.30 (95% ci = 11.26 to 11.77) .354 hemoglobin drop, g/dl 3.65 ± 1.20 (95% ci = 3.41 to 3.88) 3.13 ± 1.06 (95% ci = 2.92 to 3.34) .158 transfusion rate, % 25 20 .233 stone-free rate, % 92.58 ± 5.97 (95% ci = 91.41 to 93.75) 89.60 ± 8.34 (95% ci = 87.96 to 91.23) .210 duration of hospitalization, d 2.42 ± 0.84 (95% ci = 2.26 to 2.58) 3.70 ± 0.80 (95% ci = 3.54 to 3.86) < .001† table 1. comparison of the demographic and main variables in groups a and b* *pcnl indicates percutaneous nephrolithotomy; and ci, confidence interval. †statistically significant variable unstandardizedcoefficients (std.error) standardized coefficients t p constant 4.66 (1.56) 2.98 .005 mean stone-free rate -0.05 (0.01) -0.32 -3.11 .004 placement of nephrostomy tube 1.22 (0.17) 0.59 6.94 < .001 blood transfusion 0.46 (0.15) 0.29 2.98 .005 mean hemoglobin drop 0.17 (0.08) 0.19 2.20 .034 table 2. linear regression model to predict duration of hospitalization (r2 = 0.78) pcnl bleeding and nephrostomy tube—etemadian et al 24 urology journal vol 8 no 1 winter 2011 discussion although percutaneous procedures of the kidney are associated with less morbidity than open surgery, the potential for significant complications still exists. hemorrhage is the most significant complication of pcnl.(7) staghorn stones, large stones, multiple tracts, solitary kidney, and the presence of diabetes mellitus were associated with increased renal hemorrhage during pcnl on multivariate analysis of previous studies.(11,12) however, a concern of many urologists with the tubeless technique is lack of a tamponade effect in the nephrostomy tract.(13) excessively medial punctures, punctures into the kidneys with abnormal anatomy, and renal pelvic perforation are associated with an increased risk of bleeding.(14,15) patients on anticoagulant or antiplatelet medications are also more likely to experience bleeding.(14) current managements for renal bleeding after pcnl include placement of a nephrostomy tube, a kaye nephrostomy tamponade, balloon catheter, and endovascular embolization and if these measures fail to control the hemorrhage, partial nephrectomy may be required.(16) in the majority of the subjects, the amount of blood loss during percutaneous procedures is not significant enough to require transfusion, and conservative management is generally sufficient. occasionally, blood transfusion may be warranted depending on baseline hematocrit, presence of comorbidities, and amount of blood loss. optimal renal access is the most critical factor influencing surgical success and minimizing overall blood loss.(17) the rate of transfusion after percutaneous procedures differs. segura and colleagues reported need for transfusion in only 3% of their patients,(18) whereas stroller and associates had a 23% transfusion rate.(19) their study showed that calculus morphology, its location, composition, or size did not affect total blood loss, nor did the number of fragments or stone-containing calices. furthermore, factors such as age, hypertension, urinary infection, degree of hydronephrosis, renal insufficiency, puncture site, type of fascial dilation, previous open renal surgery, previous extracorporeal shock wave lithotripsy, or function of the ipsilateral renal unit did not affect total estimated blood loss as well.(20) the only statistically significant risk factors influencing the likelihood of a blood transfusion were pre-operative anemia and total blood loss. parenchymal bleeding is usually seen at the site of the nephrostomy tract dilation. advancement of the distal segment of the working sheet into the collecting system provides effective parenchymal tamponade, allowing the procedure to continue.(21) several studies have demonstrated that dilation of the tract using balloon dilating catheters as opposed to alken metal telescopic dilators or the teflon-coated amplatz dilators results in less blood loss.(22) renal venous laceration is another source of bleeding and is not uncommon and may be also managed conservatively.(4) the reported incidence of serious arterial injuries ranges from 0.9% to 3% after percutaneous procedures.(23) martin and coworkers reported a 1% incidence of severe bleeding after pcnl requiring superselective embolization.(15)arterial bleeding is relatively rare during percutaneous renal surgery, but may be encountered intra-operatively or in the early or late postoperative period. if it occurs during dilation of the tract, the vessel is usually a tiny arteriole and tamponade may be successful.(23) delayed bleeding after percutaneous procedures is almost always secondary to pseudoaneurysms or arteriovenous fistulas. the key to successful management is renal angiography during active bleeding.(24) in our study, one of the patients in the first group came back with gross hematuria 8 days after discharge. she underwent successful angioembolization due to development of pseudoaneurysm. percutaneous nephrolithotomy should be performed by an experienced endourologist in patients at risk of severe bleeding.(12) kukreja and colleagues described strategies that may reduce blood loss and transfusion rate, including ultrasound-guided access, using amplatz or balloon dilatation systems, reducing the operation time, and staging the procedure in cases with a large stone burden or intra-operative complications.(20) pcnl bleeding and nephrostomy tube—etemadian et al 25urology journal vol 8 no 1 winter 2011 recent studies have not reported an increased risk of bleeding after tubeless pcnl.(13,25) in a prospective study, maheshwari and coworkers demonstrated no significant increase in the postoperative bleeding in 20 patients who underwent a one stage tubeless pcnl.(25) yoon and bellman reported that with tubeless pcnl, patients experienced less discomfort without increased risk of complications.(13) they modified their technique of tubeless pcnl with an indwelling double-j stent and brought it out from the flank. they have also found that in more instances, manual pressure and a deep hemostatic suture at the skin incision will adequately control any visible hemorrhage.(20) recent studies have suggested that only a few indications still remain for the standard pcnl technique, including significant collecting system injury, excessive hemorrhage with poor visualization to place an antegrade stent, pyonephrosis necessitating reliable external drainage, or need for second-loop procedure.(9) in a prospective randomized trial on 202 patients by agrawal and colleagues, tubeless pcnl was found to have significant advantages over standard pcnl. they reported that the difference in mean blood loss between the two groups was not statistically significant.(26) in another study by giusti and associates comparing tubeless and standard pcnl, hematocrit drop was not significantly different, but duration of hospitalization was significantly less in the tubeless pcnl group,(27) which agrees with our findings. the nephrostomy tube after pcnl was intended both to drain the kidney and tamponade the access tract and establish hemostasis as well; however, there is no evidence to support this assumption.(28) our study is one of the first experiences that questions the traditional role of nephrostomy tube in pcnls that face bleeding. we expected to face more patients with continuous bleeding or need to angiography in the first group, but it did not occur. this is in favor of the hypothesis that most bleedings are self-limited. we did not encounter any benefit in leaving nephrostomy tube in place after pcnl. we think if bleeding is not brisk enough to prevent continuation of surgery, self tamponade pyelocalyceal system, tract closure, and conservative management (ie, bed rest, hydration, and blood transfusion if needed) after the procedure would be sufficient to control the bleeding. however, close observation of these patients is very important in the early postoperative period. we demonstrated that these approaches do not increase morbidity, and additionally, do not affect the outcomes of procedure. moreover, the patients do not have nephrostomy tube discomfort. conclusion previously, it was thought that one of the advantages of placing nephrostomy tube is tract hemostasis, but based on our study, if the bleeding is not too much to prevent the procedure from continuing, leaving nephrostomy tube in place after pcnl in this regard does not seem to be beneficial; and its omission does not put patients at any additional risk. in most subjects, self tamponade pyelocalyceal system, tract closure, and conservative management are enough to control the bleeding. however, we questioned nephrostomy tube role in control of the bleeding associated with pcnl. it seems that studies with more sample sizes are required to validate our results. conflict of interest none declared. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. pietrow pk, auge bk, zhong p, preminger gm. clinical efficacy of a combination pneumatic and ultrasonic lithotrite. j urol. 2003;169:1247-9. 3. auge bk, sekula jj, springhart wp, zhu s, zhong p, preminger gm. in vitro comparison of fragmentation efficiency of flexible pneumatic lithotripsy using 2 flexible ureteroscopes. j urol. 2004;172:967-70. 4. carson cc. complications of percutaneous stone extraction: prevention and treatment. semin urol. 1986;4:161-9. 5. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007;51:899906; discussion pcnl bleeding and nephrostomy tube—etemadian et al 26 urology journal vol 8 no 1 winter 2011 6. lam hs, lingeman je, mosbaugh pg, et al. evolution of the technique of combination therapy for staghorn calculi: a decreasing role for extracorporeal shock wave lithotripsy. j urol. 1992;148:1058-62. 7. segura jw, preminger gm, assimos dg, et al. nephrolithiasis clinical guidelines panel summary report on the management of staghorn calculi. the american urological association nephrolithiasis clinical guidelines panel. j urol. 1994;151:1648-51. 8. choe ch, l’esperance jo, auge bk. the use of adjunctive hemostatic agents for tubeless percutaneous nephrolithotomy. j endourol. 2009;23:1733-8. 9. bellman gc, davidoff r, candela j, gerspach j, kurtz s, stout l. tubeless percutaneous renal surgery. j urol. 1997;157:1578-82. 10. delnay km, wake rw. safety and efficacy of tubeless percutaneous nephrostolithotomy. world j urol. 1998;16:375-7. 11. turna b, nazli o, demiryoguran s, mammadov r, cal c. percutaneous nephrolithotomy: variables that influence hemorrhage. urology. 2007;69:603-7. 12. el-nahas ar, shokeir aa, el-assmy am, et al. postpercutaneous nephrolithotomy extensive hemorrhage: a study of risk factors. j urol. 2007;177:576-9. 13. yoon gh, bellman gc. tubeless percutaneous nephrolithotomy: a new standard in percutaneous renal surgery. j endourol. 2008;22:1865-7; discussion 9. 14. sampaio fjb. surgical anatomy of the kidney. in: smith ad, badlani gh, kavoussi lr, eds. smith’s textbook of endourology: st louis, quality medical publishing; 1996:153-84. 15. martin x, murat fj, feitosa lc, et al. severe bleeding after nephrolithotomy: results of hyperselective embolization. eur urol. 2000;37:136-9. 16. kaye kw, clayman rv. tamponade nephrostomy catheter for percutaneous nephrostolithotomy. urology. 1986;27:441-5. 17. lee kl, stoller ml. minimizing and managing bleeding after percutaneous nephrolithotomy. curr opin urol. 2007;17:120-4. 18. segura jw, patterson de, leroy aj, et al. percutaneous removal of kidney stones: review of 1,000 cases. j urol. 1985;134:1077-81. 19. stoller ml, wolf js, jr., st lezin ma. estimated blood loss and transfusion rates associated with percutaneous nephrolithotomy. j urol. 1994;152: 1977-81. 20. kukreja r, desai m, patel s, bapat s. factors affecting blood loss during percutaneous nephrolithotomy: prospective study. j endourol. 2004;18:715-22. 21. gupta m, bellman gc, smith ad. massive hemorrhage from renal vein injury during percutaneous renal surgery: endourological management. j urol. 1997;157:795-7. 22. davidoff r, bellman gc. influence of technique of percutaneous tract creation on incidence of renal hemorrhage. j urol. 1997;157:1229-31. 23. patterson de, segura jw, leroy aj, benson rc, jr., may g. the etiology and treatment of delayed bleeding following percutaneous lithotripsy. j urol. 1985;133:447-51. 24. beaujeux r, saussine c, al-fakir a, et al. superselective endo-vascular treatment of renal vascular lesions. j urol. 1995;153:14-7. 25. maheshwari pn, andankar mg, bansal m. nephrostomy tube after percutaneous nephrolithotomy: large-bore or pigtail catheter? j endourol. 2000;14:735-8. 26. agrawal ms, agrawal m, gupta a, bansal s, yadav a, goyal j. a randomized comparison of tubeless and standard percutaneous nephrolithotomy. j endourol. 2008;22:439-42. 27. giusti g, maugeri o, taverna g, et al. tubeless percutaneous nephrolithotomy: our experience. arch ital urol androl. 2010;82:34-6. 28. srinivasan ak, herati a, okeke z, smith ad. renal drainage after percutaneous nephrolithotomy. j endourol. 2009;23:1743-9. seminal plasma exlncrna pairs: updating perspectives in the search for testicular spermatozoa retrieval biomarkers in nonobstructive azoospermia patients with mtese by wgcna haiming cao1#, chuntao wang1#, ruilin cai2, zi wan3*, lin ma4** purpose: this study aims to find candidates for testicular spermatozoa retrieval biomarkers among the seminal plasma exlncrna pairs. materials and methods: a set of exlncrna pairs with the best potential biomarkers was selected and validated in 96 noa samples. weighted correlation network analysis (wgcna) and least absolute shrinkage and selection operator were used to identify possible biomarkers for these pairs (lasso). these pairs' potential biomarkers were identified using receiver operating curves. confusion matrices and sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv), fp, false-negative rates (fnr), and f1 scores are calculated. through f1 scores, we selected the best threshold value. results: the relative differential expression of each pair in testicular spermatozoa retrieval (+) and testicular spermatozoa retrieval (-) men were validated. the six pairs displayed the best biomarker potential. among them, ccdc37.dt-loci00505685 pair and loc440934loci01929088 (xr_001745218.1) pair showed the most significant potential and stability for detecting testicular spermatozoa retrieval in the selected and validated cohort. conclusion: ccdc37.dt-loci00505685 pair and loc440934loci01929088 (xr_001745218.1) pair have the potential to become new molecular biomarkers that could help to select clinical strategies for microdissection testicular sperm extraction. keywords: nonobstructive azoospermia, seminal plasma, lncrna, prediction introduction in the case of azoospermia, there is no sperm in the ejaculate. the total number of males with azoospermia is approximately 1%, with the condition impacting approximately 15% of all infertile males(1). it is broadly classified into two types (nonobstructive azoospermia (noa) and obstructive azoospermia (oa)). the incidence of noa is higher than that of oa, at almost 60% (2). testicular causes of noa include congenital causes such as klinefelter syndrome, y chromosome microdeletions, cryptorchidism, postnatal factors such as exposure to radiotherapy and chemotherapy, genital trauma, and infectious diseases such as mumps orchitis and sars-cov-2(3). furthermore, more than 15% of cases of noa are idiopathic(4). most cases of noa are related to spermatogenic failure, which is not curable. the noa patients who achieved fertility need to seek the sole technique which is intracytoplasmic sperm injection (icsi) combined with surgical sperm retrieval (sr) techniques. for surgical sperm retrieval (sr), 1the andrology department, reproductive medicine center, the seventh affiliated hospital of sun yat-sen university, shenzhen 518000, pr china. 2the clinical medicine department, the medical school of sun yat-sen university, shenzhen 518000, pr china. 3the andrology department, the first affiliated hospital of sun yat-sen university, guangzhou 510080,pr china. 4reproductive medicine center, the seventh affiliated hospital of sun yat-sen university, shenzhen 518000, pr china. # the authors contributed equally to this work. * correspondence: 58 zhongshan second road guangzhou, the andrology department, the first affiliated hospital, sun yat-sen university, guangzhou 510080, people’s republic of china. zi_wan2012@163.com. **no.628 of zhenyuan road,518000.the reproductive medicine center, the seventh affiliated hospital of sun yat-sen university, shenzhen 518000, pr china.e mail: malin8@mail.sysu.edu.cn. received june 2022 & accepted february 2023 various techniques contain conventional testicular sperm extraction (ctese), testicular sperm aspiration (tesa), and microsurgical testicular sperm extraction (micro-tese). among them, the sr rate with micro-tese in noa improved to 77%(5-8). various factors influenced the success rate of sr techniques in noa patients in couples pursuing fertility treatment. to some extent, the experience of surgeons and laboratory expertise influence sr success. among them, sr predictors of pre-operation include clinical parameters, laboratory parameters, and the utility of adjuvant therapy before sr. by using ejaculated sperm, studies have shown that younger men can have a better chance of conceiving than older men(9). seminiferous tubules account for approximately 75–85 % of the mass of the testes(10). in general, testicular volume indicates spermatogenetic activity, with lower testicular sizes corresponding to lower sr rates. historical studies have regarded the fsh level as a testicular function marker (10-13). inhibin b levels have shown a certain degree of sensitivity and specificity in predicting sr sucurology journal/vol 20 no. 4/ july-august 2023/ pp. 246-254. [doi:10.22037/uj.v20i.7323] andrology cess (14,15). moreover, many models based on fsh, lh, testosterone, and inhibin b, may be applied to predict the success sr rates among noa patients(8,16-18). currently, the search for new effective biomarkers of the success rates of sr is driven by the need for alternative diagnostic approaches. the expression level of zmynd15 and spem1 may have the potential for the prediction of successful sr(19,20). the expression level of these genes (zmynd15, tnp1, and prm1) may have the potential for the prediction of successful sperm retrieval(21). but the analysis may be invasive; we need many non-invasive methods to predict successful sr. the seminal plasma is rich in exosomes. a population of small non-coding rnas is found in exosomes in semen. the semen exosomes serve as rich noninvasive biomarkers, such as testis-specific rna and other molecules, which indicate a better pathological process (22). long noncoding rna ( lncrna ) is a class of non-coding rna molecules with a length > 200 nt, which is closely related to the occurrence and development of many human diseases(23). in recent years, a large number of studies have shown that lncrna is particular in testicular tissue and can be used as an important regulatory molecule to participate in spermatogenesis(24-26). many of them display restricted expression in the testis, suggesting that lncrnas may be ideal biomarkers for male reproductive system disorders(27,28). yet, there exists no data with regards to the expression ratios of sperm lncrnas about successful sr concerning pairwise comparison. considering the prevalence of lncrna expression which is strongly correlated with stability, lncrna expression profiles might also reflect the stability of these correlations. infertility biomarkers might be based on 16 lncrna pairs detected in highly fertile patients with highly stable relative expression(29). the goal of this research was to find biomarkers that are most suited to assessing successful sr among stable sperm lncrna pairs. each group chose the best lncrna pairings to use in the correct diagnosis. the pairs chosen were validated using an independent cohort. materials and methods extracellular vesicle lncrna profiles in seminal plasma extracellular vesicle lncrna profiles from 96 noa samples were included. the data was downloaded from the previous study(29). totally, ninety-six noa patient data sets were randomly divided into screen (30 patients) and validation (66 patients) set by approx. 3:7. all noa patients experienced related medical therapy (such as varicocele repair or drug therapy). according to the committee opinions of the american society for reproductive medicine, non-obstructive azoospermia character screen set validation set p value n 30 66 age (mean (sd)) 30.63 (4.90) 32.23 (7.86) 0.309 fsh (iu/i) (median [iqr]) 16.74 [12.54, 25.28] 14.41 [6.16, 28.27] 0.402 lh (iu/i) (median [iqr]) 8.39 [6.48, 10.96] 8.76 [5.52, 13.18] 0.797 total testosterone (ng/ml) (median [iqr]) 3.75 [2.29, 4.26] 3.58 [2.21, 5.14] 0.915 inhibin b (pg/ml) (median [iqr]) 17.43 [4.58, 32.47] 31.44 [16.86, 73.60] 0.04 risk disease of noa (%) 0.133 azfc microdeletions 3 (10.0) 1 ( 1.5) cryptorchidism-associated noa 4 (13.3) 9 (13.6) idiopathic noa 4 (13.3) 9 (13.6) idiopathic testicular atrophy 8 (26.7) 15 (22.7) klinefelter's syndrome 1 ( 3.3) 6 ( 9.1) mumps orchitis 1 ( 3.3) 12 (18.2) partial azfb + c microdeletions 1 ( 3.3) 0 ( 0.0) partial azfb microdeletions 1 ( 3.3) 0 ( 0.0) varicocele-associated noa 7 (23.3) 14 (21.2) abbreviations: sd, standard deviation; iqr, interquartile range; noa, non-obstructive azoospermia. table 2. characteristics of screen and validation set characteristics sperm(-) sperm(+) p value n 32 64 age (mean (sd)) 28.75 (3.86) 33.22 (7.85) 0.003 fsh (iu/i) (median [iqr]) 20.13 [14.20, 31.57] 12.86 [5.94, 23.80] 0.001 lh (iu/i) (median [iqr]) 10.04 [7.01, 13.72] 7.90 [5.07, 11.62] 0.016 total testosterone (ng/ml) (median [iqr]) 3.00 [2.20, 4.12] 3.91 [2.24, 5.78] 0.047 inhibin b (pg/ml) (median [iqr]) 7.98 [5.28, 15.36] 31.44 [16.20, 60.16] 0.014 risk disease of noa (%) < 0.001 azfc microdeletions 0 ( 0.0) 4 ( 6.2) cryptorchidism-associated noa 0 ( 0.0) 13 (20.3) idiopathic noa 8 (25.0) 5 ( 7.8) idiopathic testicular atrophy 9 (28.1) 14 (21.9) klinefelter's syndrome 5 (15.6) 2 ( 3.1) mumps orchitis 0 ( 0.0) 13 (20.3) partial azfb + c microdeletions 1 ( 3.1) 0 ( 0.0) partial azfb microdeletions 0 ( 0.0) 1 ( 1.6) varicocele-associated noa 9 (28.1) 12 (18.8) table 1. characteristics of noa abbreviations: sd, standard deviation; iqr, interquartile range; noa, non-obstructive azoospermia. testicular spermatozoa retrieval biomarkers-cao et al. vol 20 no 4 july-august 2023 247 andrology 248 was diagnosed. the age and sperm concentration (106/ ml) of all patients were collected. for patients diagnosed with noa, experienced andrologists performed a first mtese. through patients’ clinical history and pathological examination, the risk disease of noa patients was divided into idiopathic noa, klinefelter’s syndrome, partial azfb microdeletions, azfc microdeletions, partial azfb b+c microdeletions, cryptorchidism-associated noa, varicocele-associated noa, mumps orchitis, idiopathic testicular atrophy (testicular volume < 6 ml). fsh (iu/i), lh (iu/i), total testosterone (ng/ml), inhibin b (pg/ml) were tested for noa patients. in the long arm of the human y chromosome (yq11) are genomic deletions (azf deletions, azoospermia factor) associated with noa. azf mirco-deletions (azfa, azfb and azfc) are caused by intrachromosomal (yq11) recombinations (deletions, duplications, inversions).(30) the procedure of mtese the mtese inclusion criteria: patients diagnosed as noa wish to assistant reproductive technology. exclusion criteria: patients diagnosed as noa refuse mtese. to gain easy access to both testes, an incision is made in the median raphe. by incising through the dartos and tunica vaginalis, the larger of two testicles are delivered first. cut the skin, flesh membrane, sheath successively, squeeze out unilateral testis, epididymis, observe the size of the testis and epididymis development is normal. under the operating microscope with magnification x20, extract some relatively good seminiferous tubules (thick, plump and opaque seminiferous tubules). in the sperm transport buffer, ivf lab doctors ripped the seminiferous tubules under high magnification to observe the presence of sperm. if no sperm was found, the testicle was separated into six regions, and the testicle tissue in the testicle lobule was completely exposed until the tunica albuginea. each location produced relatively good seminiferous tubules. testicular tissue was sent to the pathological department for examination. but if sperm is not identified, then dissection of the contralateral side proceeds. construct seminal plasma exlncrna pairs based on a previous study (29), 16 exlncrnas in seminal plasma were determined as testis-specific after evaluating the tissue expression of lncrnas (supplemental table 1.1 and 1.2, the primers used for lncrna in supplemental table 4). the statistical description of exlncrna pairs with a constant expression was assessed over normalized fpkm values of every possible exlncrnaexlncrna combination (r language base function: combn). the difference by subtracting values (normalized exlncrnaexlncrna) of the obtained pairs was calculated. weighted correlation network analysis (wgcna) with the assistance of the r environment, the wgcna was performed using the wgcna package.(31) it was determined that the exlncrna pairings should minimize noise and computational cost while guaranteeing that no significant information is lost. a weighted correlation network analysis was carried out on each exlncrna pair (screen set) and pearson correlation coefficients were calculated between how the module correlated with the sperm retrieval (+/-) to identify the module most closely related to the sperm retrieval for further analysis. least absolute shrinkage and selection operator regression (lasso regression) based on the glmnet package (version 4.1-2), the logistic lasso model is an active selection method in which the variables can be selected from a large and possibly multicollinear set to derive an interpretably relevant set of predictors(32). the function of lasso characteristics screen set validation set screen set validation set auc 95%ci auc 95%ci auc-adjusted 95%ci auc-adjusted 95%ci age (year) 0.739 0.613-0.865 0.574 0.365-0.783 na na na na fsh(iu/i) 0.74 0.618-0.863 0.634 0.427-0.841 na na na na total testosterone (ng/ml) 0.617 0.476-0.758 0.639 0.434-0.844 na na na na spata42-loci00505685 0.636 0.491-0.782 0.806 0.646-0.965 0.825 0.724-0.926 0.861 0.723-0.999 spata42-loci01929088(xr_927561.2) 0.686 0.551-0.82 0.843 0.628-1 0.852 0.762-0.943 0.866 0.737-0.995 ccdc37.dt-loci00505685 0.86 0.764-0.957 0.782 0.608-0.957 0.929 0.871-0.988 0.824 0.674-0.974 gabrg3.asi-loci00505685 0.599 0.437-0.762 0.734 0.547-0.921 0.815 0.712-0.918 0.801 0.643-0.959 loc440934-loci00505685 0.634 0.483-0.786 0.75 0.573-0.927 0.842 0.743-0.942 0.875 0.748-1 loc440934-loci01929088(xr_001745218.1) 0.81 0.705-0.914 0.81 0.654-0.967 0.879 0.79-0.968 0.856 0.724-0.989 loci01929088(xr_927561.2)-linc00343 0.778 0.664-0.892 0.736 0.551-0.921 0.915 0.85-0.91 0.819 0.655-0.984 table 3. the predictive value of exlncrna pairs and clinical parameters multiple varibles inclusion variabls variables or[95%ci] p value or[95%ci] p value age 1.20 [1.07, 1.37] 0.003 1.16 [1.06, 1.31] 0.004 fsh (iu/i) 0.97 [0.92, 1.01] 0.091 na na total testosterone (ng/ml) 1.09 [0.86, 1.52] 0.568 na na ccdc37.dt-loci00505685 0.73 [0.59, 0.88] 0.002 0.70 [0.56, 0.83] < 0.001 age 1.22 [1.08, 1.41] 0.003 1.18 [1.06, 1.34] 0.004 fsh (iu/i) 0.97 [0.92, 1.01] 0.121 na na total testosterone (ng/ml) 1.16 [0.87, 1.61] 0.356 na na loc440934loci01929088 (xr_001745218.1) 0.60 [0.46, 0.77] < 0.001 0.58 [0.44, 0.73] < 0.001 table 4. multiple variables logistics regression analysis p = exp(-3.25+0.152*age-0.258*ccdc37.dt-loci00505685)/(1+exp(-3.25+0.152*age-0.258*ccdc37.dt-loci00505685)) p = exp(-5.33+0.167*age-0.54*loc440934loci01929088 (xr_001745218.1))/(1+exp(-5.33+0.167*age-0.54*loc440934loci01929088 (xr_001745218.1))) or:odds ratio; ci:confident index testicular spermatozoa retrieval biomarkers-cao et al. is to minimize regression coefficients by continuously shrinking them. the sum of regression coefficients is reduced by constant shrinking until the coefficients obtained are precisely zero, allowing non-zero variables to remain in the model. to assess the accuracy of these selected pairs when discerning sperm retrieval, the receiver operating characteristic (roc) curve analyses (packages: 1.18.0) were performed with the use of the r (version 4.1.1). in the screen set, the area under the roc curve analysis (auc value) of each pair of exlncrnas was calculated. validation of exlncrna pairs (validation set) in these analyses, the difference by subtracting values (normalized exlncrnaexlncrna) was compared with values of sperm (+/-). based on the auc of each pair of exlncrnas, indications were drawn of the discriminatory capacity of the pairs. in this study, they were classified into excellent (auc more than 0.9), good (auc more than 0.8), fair (auc more than 0.7), poor (auc more than 0.6), and failed (auc less than 0.60). the recommended cutoff and sensitivity analysis we further analyzed the loc440934loci01929088 (xr_001745218.1) pair and the ccdc37.dt-loci00505685 pair by the multiple variables logistic regression analysis. confusion matrices comprise true positive (tp), true negative (tn), false positive (fp), and false-negative (fn) results. results are collated to output sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv), fp, and false-negative rates (fnr). for performance grading, f1 scores are calculated using f1=2*(sensitivities*specificities)/ (sensitivities+specificities). when the f1 score is equal to the maximum, the cutoff value is most optimal. p values of <.05 were considered to be significant. results clinical and demographic characteristics totally 96 noa patients (n [azfc microdeletions] = 4; n [cryptorchidism-associated noa] = 13; n [idiopathic noa] = 13; n [idiopathic testicular atrophy] = 23; n [klinefelter's syndrome] = 7; n [mumps orchitis] = 13; n [varicocele-associated noa] = 21; n [partial azfb + c microdeletions and partial azfb microdeletions] = 2). the flowchart of this study was observed in figure 1. the clinical and demographic characteristics are summarized and compared between sperm retrieval (+/-) in table 1. the patient’s age and fsh were the most highly related to the discrimination between sperm retrieval (+/-) (p = 0.003 and p = 0.001, respectively) in table 1. 96 noa patients' data sets were randomly divided into screen (30 patients) and validation (66 patients) set. but from statistical theory, patient size is insufficient for subgroup-based a on the risk disease of noa analysis. what is more, there were no significant differences between the two cohorts in table 2. p values of <.05 were considered to be significant. establishment of pairs based on seminal plasma exlncrnas based on a previous study, the fpkm values by high-throughput sequencing of long rnas in evs were transformed by the z-score. we construct seminal plasma exlncrna pair’s matrix (in supplemental table 1.1 and 1.2). these findings confirmed that lncrnas were prevalent in seminal plasmaevs and that the 120 testis-specific exlncrna pairs-candidate may be used as biomarkers. selection of potential exlncrna pairs (screen set) a co-expression network of 120 exlncrna pairs was constructed based on the wgcna algorithm. the grey variables sensitivities[95%ci] specificities[95%ci] thresholds f1 ccdc37.dt-loci00505685 0.703[0.703 ,0.875 ] 0.813 [0.813 ,0.938 ] 0.686 0.754 0.719 [0.703 ,0.875 ] 0.813 [0.813 ,0.938 ] 0.684 0.763 0.734 [0.703 ,0.875 ] 0.813 [0.781 ,0.938 ] 0.682 0.771 0.750 [0.703 ,0.875 ] 0.813 [0.781 ,0.938 ] 0.677 0.78 0.750 [0.750 ,0.906 ] 0.781 [0.781 ,0.938 ] 0.671 0.765 0.750 [0.766 ,0.938 ] 0.750 [0.781 ,0.938 ] 0.662 0.75 0.750 [0.797 ,0.938 ] 0.719 [0.781 ,0.938 ] 0.654 0.734 0.766 [0.797 ,0.938 ] 0.719 [0.750 ,0.906 ] 0.653 0.741 loc440934loci01929088 (xr_001745218.1) 0.609 [0.234 ,0.828 ] 0.938 [0.844 ,1.000 ] 0.848 0.739 0.625 [0.234 ,0.828 ] 0.938 [0.813 ,1.000 ] 0.842 0.75 0.641 [0.234 ,0.828 ] 0.938 [0.813 ,1.000 ] 0.825 0.761 0.656 [0.234 ,0.828 ] 0.938 [0.781 ,1.000 ] 0.802 0.772 0.672 [0.234 ,0.828 ] 0.938 [0.750 ,1.000 ] 0.791 0.783 0.688 [0.234 ,0.828 ] 0.938 [0.719 ,1.000 ] 0.788 0.793 0.703 [0.234 ,0.828 ] 0.938 [0.688 ,1.000 ] 0.783 0.804 0.703 [0.297 ,0.859 ] 0.906 [0.688 ,1.000 ] 0.773 0.792 0.719 [0.297 ,0.859 ] 0.906 [0.688 ,1.000 ] 0.761 0.802 0.719 [0.359 ,0.875 ] 0.875 [0.688 ,1.000 ] 0.729 0.789 0.734 [0.359 ,0.875 ] 0.875 [0.656 ,1.000 ] 0.7 0.799 0.734 [0.625 ,0.891 ] 0.844 [0.656 ,1.000 ] 0.696 0.785 0.734 [0.641 ,0.906 ] 0.813 [0.656 ,1.000 ] 0.694 0.771 0.750 [0.641 ,0.906 ] 0.813 [0.625 ,1.000 ] 0.689 0.78 0.766 [0.641 ,0.906 ] 0.813 [0.625 ,0.969 ] 0.677 0.788 0.781 [0.641 ,0.906 ] 0.813 [0.594 ,0.969 ] 0.662 0.797 0.781 [0.656 ,0.922 ] 0.781 [0.594 ,0.969 ] 0.65 0.781 0.797 [0.656 ,0.922 ] 0.781 [0.563 ,0.969 ] 0.638 0.789 0.797 [0.672 ,0.938 ] 0.750 [0.563 ,0.969 ] 0.627 0.773 0.813 [0.672 ,0.938 ] 0.750 [0.500 ,0.969 ] 0.616 0.78 table 5. thresholds, sensitivities and specificities analysis f1=2*(sensitivities*specificities)/(sensitivities+specificities). ccdc37.dt-loci00505685 with age's cutoff value:0.677; without age's cutoff value:1.29; loc440934loci01929088 (xr_001745218.1)with age's cutoff value:0.783;without age's cutoff value:-3.95. testicular spermatozoa retrieval biomarkers-cao et al. vol 20 no 4 july-august 2023 249 module (10 exlncrna pairs) is highlighted because it has the most significant correlation (r = -0.47, p < 0.001) with sperm retrieval (+/-). additionally, sperm retrieval (+/-) was negatively correlated with the brown module (r = -0.34, p < 0.001, 6 exlncrna pairs). therefore, the 16 pairs of the two modules were identified for further analysis in figure 2. then we applied logistic lasso regression in figures 3 and 4, which minimizes multi-collinearity between 16 pairs, to assess the relationship between sperm retrieval (+/-). using lasso, we also accounted for well-established sperm retrieval (+/-) predictive factors. we found 6 pairs may be potential for sperm retrieval (+/-). the six selected exlncrna pairs (spata42-loci00505685, spata42-loci01929088 (xr_927561.2), ccdc37.dt-loci00505685, loc440934-loci00505685, loc440934-loci01929088 (xr_001745218.1), loci01929088 (xr_927561.2)-linc00343) that were obtained from analysis above. in the screen set, the auc value and auc-adjusted (age, fsh, total testosterone)) value of each pair of exlncrnas was calculated and shown in table 3. validation of the selected seminal plasma exlncrna pairs (validation set) ultimately, six pairs were considered for further analysis based on the pair with the high and stable auc. the loc440934loci01929088 (xr_001745218.1) pair auc and auc-adjusted (age, fsh, total testosterone) both more than 80%. the ccdc37.dt-loci00505685 pair possessed a slight fluctuation and a high auc value. we found ccdc37.dt-loci00505685 pair and loc440934loci01929088 (xr_001745218.1) pair could become new molecular biomarkers because both were higher and stable auc values in table 3. the recommended cutoff and sensitivity analysis according to the multiple variables logistic regression analysis, we found (age+ ccdc37.dt-loci00505685) and (age+ loc440934loci01929088 (xr_001745218.1)) were independent potential predictors in table 4. utilizing cutoff of age and ccdc37.dt-loci00505685 > 0.677 (f1=0.78 is maximum) as a predictor of ssr, the cutoff point had a sensitivity of 75% figure 1. flowchart of this study. figure 2. weighted gene co-expression network analysis (wgcna) of the exlncrna. correlation analysis between modules, and the grey and brown module are most related to sperm retrieval (+/-). testicular spermatozoa retrieval biomarkers-cao et al. andrology 250 and a specificity of 81.3%. utilizing cutoff of age and loc440934loci01929088 (xr_001745218.1) > 0.783 (f1 = 0.804 is maximum) as a predictor of ssr, the cutoff point had a sensitivity of 70.3% and a specificity of 93.8% in table 5 and supplemental table 2,3. discussion noa refers to impaired spermatogenesis in the testes, excluding obstructive factors that lead to azoospermia. partial noa patients through hormone therapy may be significantly improved or even successful in infertility. other patients may need to try surgical sperm retrieval in combination with intracytoplasmic sperm injection (icsi) to conceive the next generation. one of the most common sperm retrieval procedures for noa patients is microdissection testicular sperm extraction (mdtese). its advantage is that surgeons can selectively identify the seminiferous tubules that may contain sperfigure 3. partial likelihood deviation of lasso coefficient distribution. the two vertical dashed lines represent lambda. min and lambda.1se, respectively. figure 4. plots for lasso regression coefficients over different values of the penalty parameter. testicular spermatozoa retrieval biomarkers-cao et al. vol 20 no 4 july-august 2023 251 matozoa. the md-tese is widely accepted compared to other sperm acquisition techniques. at present, there are many types of research about predicting srr before the operation, but there is still a lack of consensus predictors. this study demonstrates that seminal plasma lncrna pairs may become precise and noninvasive predictors of sperm retrieval in noa patients. the predictors assist clinicians in choosing a better treatment to accomplish precision medical treatment, reduce harm to patients, and save money for patients. the approach of considering the differential expression of two exlncrnas as a biomarker value instead of the fpkm level of a single exlncrna is mainly based on the biological implications of these pairwise fluctuations in noa patients. the analysis of the association between two exlncrna (difference of fpkm values) is more robust than the analysis of a single lncrna because the pair provides more information about spermatogenesis. so, however, the expression level of exlncrna in pairs, the global difference will reflect a variance that will be found by this pairwise analysis. auc values were used to estimate the predictive power of the selected pairings to evaluate predictors. furthermore, only the couples with high and steady auc values were considered valid potential biomarkers. the ccdc37.dt-loci00505685 pair and loc440934 loci01929088 (xr_001745218.1) pair achieved this goal. exosomes, multivesicular nanovesicles (50–500 nm) released by the fusion of the plasma membrane with multivesicular bodies, are released into the extracellular space and body fluids(33,34). many kinds of cells produce exosomes, which are nanosized membrane vesicles found in abundance in the fluids of living organisms and semen. they are packed with lipids, proteins, micrornas and mrnas, and are known to be essential for intracellular communication. their content is derived from the target cells' endosomal compartments. a wide variety of cells secrete exosomes containing epithelial cells and testis tissue. the exosomes are found in biological fluids such as plasma, saliva, and semen under normal and abnormal conditions(35,36). exosomal proteins may indicate a biomarker of male infertility. they may be essential in sperm motility, capacitation, acrosome reaction, and fertilization(37). with the advance of the global molecules tools and purification of exosomes, it is possible to find many exosomal molecules. yang et al. showed 1474 exosomal proteins in normozoospermic men. the exosomal proteins primarily relate to protein metabolism, cell growth, and maintenance(38). in the male reproductive system, altered expression of seminal plasma exosomes containing sncrna has been reported to participate in molecular events. the mirnas, such as mir-539-5p, have the potential to predict the presence of spermatozoa in the testes of noa patients(39). the mir-539-5p cannot be used to determine the existence of spermatozoa in the testes of noa patients, normozoospermic, and oligozoospermia. many long noncoding rnas play an essential role in spermatogenesis, which gives them an advantage compared with mirnas for estimating the likelihood of sperm retrieval when an individual has an abnormal sperm cycle(27). the term lncrna refers to non-protein-coding rnas with a length of at least 200 nucleotides(40). according to zhao et al., 157 have different expression levels among diverse populations of testicular cells(41). in a similar study, jan et al. found a total of 137 lncrnas were differentially expressed between different testicular cells(42). rolland et al. identified 113 known lncrnas and 20 novel unannotated transcripts important for spermatogenesis(43). new research avenues can be explored to understand the regulation of spermatogenesis through the signaling involved. human sperm contains a small amount of lncrna. sendler et al. mapped the transcriptome of fertile men's sperm and identified 155 lncrnas in human sperm(44). zhang et al. identified the testis-specific lnc32058, lnc09522, and lnc98497 showed high expression between motile and immotile human sperm(45). based on a previous study, only 16 testis-specific lncrna was identified by sequence(29). a decision-making process for noa patients has been established based on the scores of the 9-exlncrna prediction model. compared to the model, we only need one pair and age to predict, and both pairs were an effective and money-saved method for assessing sperm retrieval in patients with noa. unfortunately, although the tremendous and stable biomarker potential of the ccdc37.dt-loci00505685 pair and loc440934loci01929088 (xr_001745218.1) pair were found in our study, we needed the comprehensive analysis of pairs combined with clinical practice to make clinical decisions for noa. the noa sample size and preparation process must be further expanded, simplified and standardized. for example, the seminal plasma exosomal rna isolation kit is studied to simplify and standardize. we can cooperate with many medical centers to further expand the sample size. this is the study's key limitation since this exlncrna pair's biomarker suitability must be confirmed before it can be used for clinical diagnosis. conclusions this study suggested that the loc440934 loci01929088 (xr_001745218.1) pair auc and auc-adjusted were more than 80%. the ccdc37. dt-loci00505685 pair possessed a slight fluctuation and a high auc value. both pairs 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development. 2017;144:3659-73. 43. rolland ad, evrard b, darde ta, et al. rna profiling of human testicular cells identifies syntenic lncrnas associated with spermatogenesis. hum reprod. 2019;34:127890. 44. sendler e, johnson gd, mao s, et al. stability, delivery and functions of human sperm rnas at fertilization. nucleic acids res. 2013;41:4104-17. 45. zhang x, zhang p, song d, et al. expression profiles and characteristics of human lncrna in normal and asthenozoospermia spermdagger. biol reprod. 2019;100:982-93. testicular spermatozoa retrieval biomarkers-cao et al. andrology 254 a safe and effective two-step tract dilation technique in totally ultrasound-guided percutaneous nephrolithotomy shao-wei dong1, su-wei hu12,3, shih-ping liu4, chia-chang wu1,2,5, chu-tung lin6, kuan-chou chen1,2,3,5, chen-hsun ho6,7* purpose: to evaluate the safety and efficacy of a radiation-free 2-step tract dilation technique in totally ultrasound-guided percutaneous nephrolithotomy (pcnl). materials and methods: from oct 2018 to mar 2020, we prospectively and consecutively enrolled 18 patients with 19 kidney units with urolithiasis. the nephrostomy tracts were established by the following four steps: 1) ultrasound-guided renal puncture, 2) first-stage serial dilation to 16 fr with amplatz dilators, 3) introduce the ureteroscope through the 16fr amplatz sheath for tract adjustment and confirmation, 4) second-stage dilation with a 24-fr balloon dilator. results: the median age of the patients was 61.5 [54, 66] years, and 11 (61%) were male. the median size of the stones was 3.3 [2.7, 6.2] cm2 with an equal distribution of the laterality(right/left). successful tract establishment on the first attempt without fluoroscopy was achieved in 18 (95%) operations. the median tract establishment time was 10.2 [9.5, 12.4] mins, and the median operation time was 63.4 [29.2, 81.9] mins. the median decrease in hemoglobin level was 1.0 g/dl [0.5,1.6] and none of the patients required intraoperative or postoperative transfusion. three of the patients (16%) developed fever postoperatively. pleural injury occurred in two (11%) patients having supracostal punctures and one required drainage with a pigtail. stone-free status was achieved in 15 (79%) operations at 3 months postoperatively. conclusion: our experience suggested the radiation-free 2-step tract dilation technique is a safe and effective method for tract development in ultrasound-guided pcnl. keywords: percutaneous nephrolithotomy; ultrasound; urolithiasis; fascial dilator; balloon dilator introduction percutaneous nephrolithotomy (pcnl) has remained the treatment of choice for large and complex kidney stones, since its introduction in 1970s(1). to create an access to the collecting system, including the initial renal puncture and subsequent tract dilation, is the crucial part of this surgery which significantly affects the outcome. traditionally, fluoroscopy has been used to establish the nephrostomy tract and to date it remains the most common image modality for the guidance of pcnl(2). it facilitates the tract development by providing a clear mapping of the whole collecting system. besides, almost all kinds of tract dilators, such as amplatz, balloon, and alken telescopic metal dilators, are designed to be visible under fluoroscopy, which ensures a successful access to the collecting system. despite all 1department of urology, shuang ho hospital, taipei medical university, new taipei city, taiwan. 2tmu research center of urology and kidney (tmu-rcuk), taipei medical university, taipei, taiwan. 3graduate institute of clinical medicine, college of medicine, taipei medical university, taipei, taiwan. 4department of urology, national taiwan university hospital and college of medicine, taipei, taiwan. 5department of urology, school of medicine, college of medicine, taipei medical university, taipei, taiwan. 6division of urology, department of surgery, shin kong wu ho-su memorial hospital, taipei, taiwan. 7school of medicine, college of medicine, fu jen catholic university, new taipei city, taiwan. correspondence: division of urology, department of surgery, shin kong wu ho-su memorial hospital, taipei, taiwan. phone: +886 2 28332211 ext 2080. email: chho.uro@gmail.com. address: no. 95, wen chang road, shih lin district, taipei, taiwan received february 2022 & accepted june 2022 these advantages, there has been a persistent concern about the patients’ and the operators’ exposure to the ionizing radiation with fluoroscopic guidance(3). ultrasound-guided pcnl has gained popularity in the past few years. it has the merit of reducing or even totally avoiding radiation exposure for patients and operation personnel. ultrasound-guidance also provides advantages such as visualization of the surrounding structures, prevention of vascular injury by combining doppler imaging, and no need of wearing lead apron during the operation, etc.(4). however, although it is usually not difficult to perform renal puncture under ultrasound guidance, the subsequent tract dilation solely by ultrasound is considered challenging and sometimes impossible(5). this is mainly because of that almost all kinds of dilators are with low echogenicity and bareurology journal/vol 19 no. 6/ november-december 2022/ pp. 420-426. [doi: 10.22037/uj.v19i.7205] endourology and stone disease ly visible under ultrasound imaging(6). in the previous literature, many so-called “ultrasound-guided” pcnls actually referred to ultrasound-guided renal puncture followed by fluoroscopy-guided tract dilation(7-9). even though some authors solely used ultrasound to monitor the advancement of amplatz, telescopic metal, or balloon dilators(10,11), these generally required an advanced ultrasound technique and were considered limited to experienced hands(12). to overcome the above challenges during ultrasound-guided tract dilation, we utilized a radiation-free nephrostomy tract establishment technique in the past few years. the dilation was carried out in a 2-step manner, and in between the tract was verified with a ureteroscope. since it did not require an advanced technique to monitor the dilators’ advancement under ultrasound, this method should be much easier for surgeons with any level of ultrasound expertise. the objective of the current study was to evaluate the safety and efficacy of this radiation-free 2-step tract dilation technique in totally ultrasound-guided pcnl. materials and methods patient selection from oct 2018 to mar 2020, we consecutively enrolled 18 patients with 19 renal units who underwent pcnl for urolithiasis in our institution. a total of 19 operations were included in the study and the subjects must be at least 18 years old for inclusion. exclusion criteria included patients with uncontrolled urinary tract infections, pregnancy and bleeding disorders. all the operations were performed by a single surgeon (chh). the study was approved by taipei medical university-joint institutional review board (n201808062). surgical techniques for each surgical procedure, pcnl was performed under endotracheal general anesthesia with the patient first placed in lithotomy position. retrograde insertion of a 5-fr ureteral catheter (pahsco, taiwan) was done with a cystoscope until resistance was felt. according to our experience, the length of the catheter being inserted varied from person to person but was usually around 20 to 25 cm proximal to the ureterovesical junction. insertion of the ureteral catheter allowed normal saline irrigation via irrigation pump with pressure of 100-200cmh20 to obtain artificial hydronephrosis. the patient was then placed in prone position. ultrasonography (bk medical aps, mileparken, herlev, denmark) was performed to identify the anatomy of the collecting system and stone position. the longitudinal image of the kidney was obtained and the targeted calyx was punctured with a18-ga/20-cm chiba needle (argon medical devices, athens, tx, usa) through a needle-guidance adapter (bk medical ultrasound transducer needle guide bracket). the route of puncture was determined by the surgeon, and upper calyx was preferentially chosen in this series. the entire needle, including the shaft and the tip, should be monitored by ultrasound in real-time during the entire entry process into the collecting system. sometimes, the transverse-axis puncture was preferred to avoid rib acoustic shadowing. a 0.035-inch j-tip echogenic guidewire (boston scientific, marlborough, ma, usa) was then inserted into the collecting system through the chiba needle as long as possible under ultrasound guidance until resistance was felt. the depth of renal puncture was measured with the scale on the chiba needle. upon the first step of dilation, the tract was dilated serially with the 8-fr, 10-fr, 12-fr, 14-fr, and 16-fr amplatz dilators (boston scientific, spencer, in, usa). all the amplatz dilators were advanced according to the previously measured depth. a 16-fr amplatz sheath (boston scientific, spencer, in, usa) was then introduced into the collecting system through the 16-fr amplatz dilator. a semi-rigid 6.0/7.5-fr ureteroscope (richard wolf, vemon hills, illinois, usa) was advanced through the amplatz sheath to check whether the tract appropriately entered the collecting system. if necessary, the sheath was advanced further along the shaft of the ureteroscope to completely penetrate the renal parenchyma. this ensured the success of the second step of dilation, in which a 24-fr nephrostomy balloon dilator (ultraxxtm, cook, bloomington, in, usa) was inserted through 16-fr amplatz sheath into the collecting system. the depth of the balloon dilator inserted through the 16 fr. sheath was equal to the depth of the ureteroscope inserted into the collecting system. with the balloon dilator in place, the amplatz sheath was withdrawn and the balloon was inflated with pressure of 14 atm for 30 sec. a 24-fr sheath was then advanced through the inflated balloon with the distance according to previously measured inserted depth of the ureteroscope. once the tract was established, the stones were tract dilation in ultrasound-guided pcnl-dong et al. table 1. characteristics of the study subjects table 2. outcomes of totally ultrasound-guided p c n l age, year 61.5 [54, 66] men, n (%) 11 (61%) bmi, kg/m2 26.8 [25.5, 30.76] comorbidity, n (%) hypertension 9 (50%) type ii dm 2 (11%) smoking, n (%) 11 (61%) aspirin used, n (%) 2 (11%) stone burden, cm2 3.3 [2.7, 6.2] stone laterality, n (%) right 9 (47%) left 10 (51%) stone position, n (%) upper calyx stone 4 (21%) middle calyx stone 6 (32%) lower calyx stone 9 (47%) ureterovesical junction stone 8 (42%) stone complexity, n (%) single stone 1 (5%) multiple stone 13 (68%) staghorn stone 1 (5%) partial staghorn stone 4 (21%) calyx puncture location, n (%) upper pole 17 (90%) middle pole 0 (0%) lower pole 2 (10%) success tract establishment, n (%) 18 (95%) tract establishment time, mins 10.2 [9.5, 12.4] operation time, mins 63.4 [29.2, 81.9] stone-free status, n (%) 15 (79%) total hospital stay, days 4 [3, 7] postoperative stay, days 3 [2, 6] hb change (g/dl) -1 [-1.6, -0.5] postoperative pyuria, n (%) 8 (42%) postoperative fever, n (%) 3 (16%) pleural injury, n (%) 2 (11%) ancillary procedure, n (%) 3 (16%) endourology and stones diseases 421 fragmented with pneumatic lithotripter (karl storz, tuttlingen, germany) or holmium laser, and the stone fragments were retrieved with a grasper by 24 fr. percutaneous universal nephroscope (richard wolf, vemon hills, illinois, usa). all the calyces were examined for residual stone fragments before the operation ends. in the end of the surgery, a 6-fr double-j ureteral stent was placed by nephroscope under direct vision through the sheath in an antegrade manner. the sheath was then removed after a 10 fr. fascial dilator advanced into the renal pelvis by nephroscope. a nephrostomy tube was inserted through the fascial dilator until the resistance was felt in general. the balloon of the catheter was first inflated with 3cc distilled water and gently pulled out until resistance was felt. then the catheter was inflated with another 2cc distilled water with a total of 5cc to compress the tract against bleeding. data collection study subjects’ demographics and data regarding the stone, including size, location, and composition, were recorded. the kidney, ureters, bladder (kub) radiograph was done one week before the surgery in outpatient setting. stone burden was measured as the maximum diameter on the image. the routine hemogram including cbc/dc, coagulation function (pt/aptt), urine routine (urine culture if pyuria was noted), and biochemistry test were performed before surgery. the uncorrected coagulopathy was an absolute contraindication to percutaneous surgery. successful tract establishment was defined as the distal end of the 24-fr working sheath appropriately placed in the collecting system solely under ultrasound on the first attempt. cases in which second dilation procedure was required or fluoroscopy was applied at any time of tract establishment were considered as failures. tract establishment time was calculated from the beginning of renal puncture to the successful placement of the 24-fr working sheath. operative time was measured from the retrograde ureteral catheterization to the nephrostomy tube insertion. any postoperative events and complications were recorded. stone-free status was defined as no residual fragments greater than 4 mm determined by kub or ct at 3 months postoperatively. statistical analysis the continuous variables are expressed as the median and [q1, q3 (iqr)]; the categorical variables are expressed as count and (percentage). the statistics were carried out with a descriptive study. the analysis was conducted with spss 26.0 for windows (spss inc., usa). results the characteristics of the study subjects are shown in table 1. the median age of the patients was 61.5 [54, 66] years, and 11 (61%) were male. the median stone size was 3.3 [2.7, 6.2] cm2, and stone was located on the right side in 9 (47%) subjects. renal access was made on the upper calyx in 17 (90%) operations. successful tract establishment on the first attempt was achieved in 18 (95%) operations. in one case (5%), unintentional withdrawal of the guidewire occurred on the first stage of dilation (serial amplatz), in which we failed to regain an artificial hydronephrosis and fluoroscopy was applied to complete tract establishment. the median tract establishment time was 10.2 [9.5, 12.4] mins. the median operation time was 63.4 [29.2, 81.9] endourology and stones diseases 354 step 1 create artificial hydronephrosis. figure 1:a. insertion of a ureteral catheter allowed normal saline irrigation via irrigation pump with pressure of 100-200cmh20 to obtain artificial hydronephrosis. the ureteral catheter was taped to the foley catheter using surgical tape. step 2 renal puncture with ultrasound. b,c the longitudinal image of the kidney was obtained and the targeted calyx was punctured with needle through a needle-guidance adapter. d. the electronic dotted line on the screen will predict the path of the needle. tract dilation in ultrasound-guided pcnl-dong et al. vol 19 no 6 november-december 2022 422 mins. the overall and postoperative hospital stays were 4 [3, 7] days and 3 [2, 6] days, respectively. the median decrease in hemoglobin level was 1.0 g/dl [0.5,1.6] and none of the patients required intraoperative or postoperative transfusion. postoperatively, pyuria was noted in eight (42%) operations: the majority was asymptomatic and only three (16%) developed fever. pleural injury occurred in two (11%) operations with supracostal punctures to gain access to the upper calyx. one was asymptomatic and treated conservatively, while the other patient developed symptoms of cough and chest tightness several hours after the operation. chest x-ray was done immediately and showed blunting of the left cp angle, which suggested pleural effusion formation, with no evidence of pneumothorax. the chest surgeon was consulted and a pigtail was inserted for drainage under ultrasound guidance successfully. the aspirated fluid was clear and yellowish and hydrothorax was impressed. the symptoms subsided immediately after treatment and the pigtail was then removed after chest x-ray showed complete resolution of the effusion. among all these pcnl patients, stone-free status was achieved in 15 (79%) operations at 3 months postoperatively. three (19%) underwent an ancillary procedure of extracorporeal shockwave lithotripsy or retrograde intrarenal surgery (rirs) and one patient asked for conservative treatment by active imaging surveillance every 3 months. discussion in the current study, we described a technique of radiation-free tract establishment in totally ultrasound-guided pcnl. the collecting system was punctured under real-time ultrasound guidance. then, the tract was dilated in a 2-step technique. the tract was initially dilated from 8 fr to 16 fr with amplatz fascial dilators. then, the initially dilated tract was checked and adjusted with a ureteroscope. finally, the tract was further dilated with a 24-fr balloon dilator. the results demonstrated that the above technique achieved a high success rate of tract establishment on the first attempt without fluoroscopy. and the time required to establish the tract was consistently short. compared to ultrasound-guided tract dilation, this method did not require an advanced ultrasound technique and was considered to be easier to carry out. several mechanisms contributed to the safety and efficacy of this technique. first, the tips of small-sized amplatz dilators (8 fr to 16 fr) are relatively sharp, which tend to penetrate the kidney parenchyma and enter the collecting system successfully. this largely prevented the status of short dilation. this was supported by those studies of mini-pcnl(13,14), in which the failure rate of serial dilation up to 18 fr was generally less than 5%. on the contrary, the tips of large-sized amplatz dilators are relatively blunt and tend to push the kidney away before they enter the collecting system, which causes a status of short dilation(15,16). furthermore, we always kept the guidewire straight and dilated the tract with an axis same as the chiba needle carefully. we ensured the guidewire was movable every time after a dilator was inserted. this largely prevented the status of short dilation and guidewire kinking or slippage. second, all the small-sized (8-fr to 16-fr) amplatz dilators were advanced at a fixed depth as measured earlier. this avoided the injury to the opposite pelvic membrane in endourology and stones diseases 265 step 3 guidewire access. figure 2:a. a 0.035-inch j-tip guidewire was inserted into the collecting system through the chiba needle. step 4 first step of tract dilation (serially with the 8-fr, 10-fr, 12-fr, 14-fr, and 16-fr amplatz dilators). b. dilating with an 8 fr fascial dilator along the guidewire.c. 8-fr stylet (8/10 dilator/sheath set) was inserted along the guidewire after dilating with 12-fr fascial dilator. d. dilating with a 16 fr fascial dilator along the 8-fr dilator. tract dilation in ultrasound-guided pcnl-dong et al. endourology and stones diseases 423 the collecting system. with the above two mechanisms, we could confidently dilate the tract until a diameter of 16 fr was reached without monitoring by either fluoroscopy or ultrasound. third, after the tract was initially dilated, we checked the entrance of the 16-fr tract with a ureteroscope. in our experience, the 16-fr sheath had been perfectly placed in the collecting system at this step in the majority. although short dilation did occur in a few cases, it was not difficult to fix by the following procedures: following the guidewire, the ureteroscope was advanced into the collecting system; then the 16-fr sheath was gently advanced over the shaft of the ureteroscope. the appropriately positioned 16-fr sheath almost ensured the success of the final dilation with a balloon. a few authors reported their technique of ultrasound monitoring the dilation process, including balloon dilator(11,17), serial amplatz dilators(9), one-shot amplatz dilators(18), or telescopic metal (alken) dilators(19). among these dilators, balloon has been widely used in ultrasound-guided pcnl and has been considered relatively easy to apply under ultrasound guidance(12). in one study with 138 subjects, totally ultrasound-guided balloon dilation was achieved in 131 (94.9%), and the remaining 7 (5.1%) cases required a switch to fluoroscopy(17). in another study with 207 cases undergoing ultrasound-guided balloon dilation, the success rate of tract dilation on the first attempt was 88.4%(11). short dilation was considered to be the main cause of failure with balloon dilation(15,16). obesity was reported to be a predictor of failure for ultrasound-guided balloon dilation(6). according to previous literature, the success rate of tract dilation was 76.9% in normal weighted and 79.0% in overweighted patients, but only 45.7% in obese subjects(6). in another study, the presence of staghorn stones, previous ipsilateral open nephrolithotomy, and low pole access independently predicted a failure of tract establishment with balloon, while the presence of hydronephrosis of the target calyx increased the likelihood of success(11). in general, to monitor these dilators under ultrasound is an advanced technique and is limited to experts and is specially technically challenging in cases without hydronephrosis(16). different from the above techniques by using ultrasound to monitor the process of dilation, our method was characterized by checking the initial small-sized dilation with a ureteroscope. this was considered as a 2-step technique in the literature. wang et al.(11) reported their 2-step dilation technique. the tract was first serially dilated from 8-fr to 16-fr with fascial dilators. a 16-fr peel-away sheath was left to allow the evaluation by ureteroscope. in the second step, a 15fr metal dilator was inserted to replace the peel-away sheath, followed by further dilation with 18 to 24-fr metal dilator. compared to one-step balloon dilator, their 2-step technique achieved a significantly higher success rate of tract establishment on the first attempt (100% vs 88.6%), and the mean tract establishment time was only 6 minutes(11). the same technique was also reported by song et al.(20), who reported a success rate of 84.3% on the first attempt. in another technique of zhou et al.(5), a 10-fr fascial dilator was first used to step 5 16-fr tract establishment figure 3: a. a 16-fr amplatz sheath was introduced into the collecting system through a 16-fr amplatz dilator. b. a semi-rigid 6.0/7.5-fr ureteroscope was advanced through the amplatz sheath to check whether the tract appropriately entered the collecting system. if necessary, the sheath was advanced further along the shaft of the ureteroscope to completely penetrate the renal parenchyma. step 6 24-fr tract establishment. c. 24-fr nephrostomy balloon dilator was inserted through 16-fr amplatz sheath into the collecting system. the amplatz sheath was withdrawn and the balloon was inflated with a pressure of 14 atm for 30 sec. d. a 24-fr sheath was then advanced through the inflated balloon. tract dilation in ultrasound-guided pcnl-dong et al. vol 19 no 6 november-december 2022 424 dilate the tract along the guidewire, and a 10-fr sheath was left in place. a 6-fr ureteroscope entered the collecting system to adjust the guidewire into the ureter. then the tract was further dilated with either a balloon dilator or serial fascial dilator (from 12 fr to 22 fr). with either type of dilator, the success rate of tract establishment was high and the mean tract establishment time was short (8.9 mins versus 10.1 mins). the success rate and the tract establishment time in our study were comparable to the those of the above studies(5,11,20). our study generally confirmed that the safety and efficacy of the 2-step technique were at least not inferior to those of fluoroscopy-guided or ultrasound-guided tract dilation. and only basic ultrasound skills were demanded to complete the procedures and the operation was totally radiation-free. although, performing totally ultrasound-guided pcnl in pregnancy has been reported previously. they performed three procedures were performed in supine and lateral flank position under spinal anesthesia(21). our approach was the prone position under general anesthesia so we excluded pregnancy. the major limitation of the current study was a small case number. however, we believed that the results were still robust enough to support the feasibility of this technique. first, among the 19 consecutive operations, there was only one failure, which was due to an unintentional withdraw of the guidewire. this should not be considered as a failure of the technique itself. second, the time of tract establishment was consistent and short, suggesting that this technique was easy to perform and was highly reproducible. third, the overall complication rates, regarding the blood loss, transfusion rate, and fever were generally low and were comparable to those in the literature. there was a relatively higher rate of pleural injury, which was because that upper calyx was the primary target of puncture (supracostal) in the majority of the cases. in our study, more than 90% of the patients have complex renal stones, 13 (68%) with multiple renal stone, 1 (5%) with staghorn stone and 4 (21%) with partial staghorn stones. upper calyceal puncture provides a direct access to all the calyces and upper ureteral calculi by single tract with higher stone clearance rate. with real-time ultrasound monitoring, the risk of visceral injury by the chiba needle can be minimized. however, the pleural reflection was difficult to be identified under ultrasound guidance and may be injured during tract dilation due to the shear force or during stone manipulation due to sheath swing. for pleural injury/effusion patients, our protocol of treatment was chest tube(pigtail) insertion in symptomatic patients, oxygen supplementation and combined care with chest surgeon. we closely monitored the patients for signs of clinical deterioration and serial chest x-ray films were taken in the next few days for further evaluation. chest tubes or pigtails were then removed after the pleural effusion subsided. conclusions our experience suggested the radiation-free 2-step tract dilation technique is a safe and effective method for tract development in ultrasound-guided pcnl. step 7 nephroscopy and stone fragmentation figure.4 the stones were fragmented with pneumatic lithotripter or holmium laser, and the stone fragments were retrieved with a grasper under 24 fr. percutaneous universal nephroscope. tract dilation in ultrasound-guided pcnl-dong et al. endourology and stones diseases 425 acknowledgement this work was supported by the grant from shin kong wu ho-su memorial hospital conflict on interest the authors report no conflict of interest. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976;10:257-9. 2. andonian s, scoffone cm, louie mk, et al. does imaging modality used for percutaneous renal access make a difference? a matched case analysis. j endourol. 2013;27:24-8. 3. corrales m, doizi s, barghouthy y, kamkoum h, somani b, traxer o. ultrasound or fluoroscopy for percutaneous nephrolithotomy access, is there really a difference? a review of literature. j endourol. 2021;35:241-8. 4. lojanapiwat b. the ideal puncture approach for pcnl: fluoroscopy, ultrasound or endoscopy? indian j urol. 2013;29:208-13. 5. zhou t, chen g, gao x, et al. 'x-ray'-free balloon dilation for totally ultrasound-guided percutaneous nephrolithotomy. urolithiasis. 2015;43:189-95. 6. usawachintachit m, masic s, chang hc, allen ie, chi t. ultrasound guidance to assist percutaneous nephrolithotomy reduces radiation exposure in obese patients. urology. 2016;98:32-8. 7. ng fc, yam wl, lim tyb, teo jk, ng kk, lim sk. ultrasound-guided percutaneous nephrolithotomy: advantages and limitations. investig clin urol. 2017;58:346-52. 8. basiri a, ziaee am, kianian hr, mehrabi s, karami h, moghaddam sm. ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2008;22:281-4. 9. ding x, hao y, jia y, hou y, wang c, wang y. 3-dimensional ultrasound-guided percutaneous nephrolithotomy: total free versus partial fluoroscopy. world j urol. 2020;38:2295-300. 10. tzou dt, metzler is, usawachintachit m, stoller ml, chi t. ultrasound-guided access and dilation for percutaneous nephrolithotomy in the supine position: a step-by-step approach. urology. 2019;133:245-6. 11. wang s, zhang y, zhang x, et al. tract dilation monitored by ultrasound in percutaneous nephrolithotomy: feasible and safe. world j urol. 2020;38:1569-76. 12. beiko d, razvi h, bhojani n, et al. techniques ultrasound-guided percutaneous nephrolithotomy: how we do it. can urol assoc j. 2020;14:e104-e10. 13. xiong l, huang x, ye x, et al. microultrasonic probe combined with ultrasound-guided minipercutaneous nephrolithotomy in the treatment of upper ureteral and renal stones: a consecutive cohort study. j endourol. 2020;34:429-33. 14. zhu w, li j, yuan j, et al. a prospective and randomised trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini-percutaneous nephrolithotomy. bju int. 2017;119:612-8. 15. pakmanesh h, daneshpajooh a, mirzaei m, et al. amplatz versus balloon for tract dilation in ultrasonographically guided percutaneous nephrolithotomy: a randomized clinical trial. biomed res int. 2019;2019:3428123. 16. jin w, song y, fei x. the pros and cons of balloon dilation in totally ultrasound-guided percutaneous nephrolithotomy. bmc urol. 2020;20:82. 17. armas-phan m, tzou dt, bayne db, wiener sv, stoller ml, chi t. ultrasound guidance can be used safely for renal tract dilatation during percutaneous nephrolithotomy. bju int. 2020;125:284-91. 18. karami h, rezaei a, mohammadhosseini m, javanmard b, mazloomfard m, lotfi b. ultrasonography-guided percutaneous nephrolithotomy in the flank position versus fluoroscopy-guided percutaneous nephrolithotomy in the prone position: a comparative study. j endourol. 2010;24:135761. 19. hosseini mm, hassanpour a, farzan r, yousefi a, afrasiabi ma. ultrasonographyguided percutaneous nephrolithotomy. j endourol. 2009;23:603-7. 20. yan s, xiang f, yongsheng s. percutaneous nephrolithotomy guided solely by ultrasonography: a 5-year study of >700 cases. bju int. 2013;112:965-71. 21. basiri a, nouralizadeh a, kashi ah, et al. x-ray free tract dilation in ultrasound-guided pcnl-dong et al. vol 19 no 6 november-december 2022 426 v07_no_4.pdf urological oncology 243urology journal vol 7 no 4 autumn 2010 radical prostatectomy practice in england vishwanath s hanchanale, john e mccabe, pradip javlé purpose: as there is paucity of data on radical prostatectomy (rp) as a primary treatment for patients with localized prostate cancer, we analyzed the trends in the rp practice in england. materials and methods: this study was carried out on 14 300 patients who underwent rp for carcinoma of the prostate. database was prepared from hospital episode statistics of the department of health in england. national trends in rp practice were summarized as well as volume outcome analysis. results: annual number of rps exponentially increased from 972 (1998 to 1999) to 3092 (2004 to 2005). laparoscopic rps increased from 2 to 257 over the study period. median waiting duration increased by more than 10 days (13 days). significant decrease in median length of hospital stay from 8 (range, 7 to 10) days to 6 (range, 5 to 8) days was observed (p < .001). more than correlation was found between the hospital volume (odds ratio: 0.40) and 0.32) and shorter in-hospital stay in comparison to low volume surgeons and hospitals. conclusion: there is an exponential increase in the number of rps with an increasing trend towards laparoscopic rp in england. this study showed a significant inverse correlation between provider volume (hospital and surgeon) and outcome (in-hospital mortality and hospital stay) for rp in england; thus, supporting the recommendations for centralization of care for complex radical procedures, including rp. urol j. 2010;7: -8. www.uj.unrc.ir keywords: prostatic neoplasms, prostatectomy, laparoscopy, treatment outcome, england department of urology, leighton corresponding author: ms, mrcs department of urology, leighton united kingdom e-mail: vishwanath.hanchanale@gmail.com received october 2009 accepted march 2010 introduction prostate cancer is the most frequently diagnosed cancer in men in england.(1) with increasing patients’ awareness and widespread prostate-specific antigen testing, more than 650 000 men worldwide and approximately 26 000 men in england are diagnosed with prostate cancer every year. each year, an estimated 221 000 deaths worldwide occur from the prostate cancer, with over 8000 of such deaths being recorded annually within the united kingdom.(2) radical prostatectomy (rp) is widely used as a primary treatment in patients with localized prostate cancer.(3) due to improvements in anesthesia, peri-operative care, and surgical technique, rp is now associated with lower morbidity than early years.(4) with wide array of new treatment options for the prostate cancer, rp can only remain a preferred treatment modality if it is associated with low morbidity, mortality, and short hospital stay. as there is paucity of data on rp trends in radical prostatectomy practice—hanchanale et al 244 urology journal vol 7 no 4 autumn 2010 england, we addressed the temporal changes in the rp practice in england over 7 years. this study describes the changing trends in patients’ demographics, surgical activity, and outcomes (mortality rate and length of hospital stay) for rp. materials and methods a total of 14 300 patients who underwent rp for carcinoma of the prostate by 592 surgeons at 191 hospitals between april 1998 and april 2005 were included in this study. database was prepared from hospital episode statistics (hes) of department of health in england. national administrative databases have been used increasingly in the usa (medicare) and europe (dutch national medical register) to investigate the quality of surgical care.(5,6) hospital episode statistics is the national database of all the patients admitted to national health service (nhs) hospitals in england. it has evolved over the years following its establishment in 1989 and is the data source for a wide range of healthcare analysis for the nhs, government, and many other organizations and individuals.(7) hospital episode statistics also forms an important tool for medical research, assessment of performance, and policy development.(8-12) diagnostic coding is recorded based on the international classification of diseases, 10th revision (icd-10) criteria and procedure coding is recorded according to the office of population, census and surveys – classification of surgical operations and procedures, 4th revision (opcs4) criteria.(13,14) at the outset, database was filtered for malignant neoplasm of the prostate by icd-10 code c61-x in seven diagnostic fields and then opcs4 codes, indicating total excision of the prostate along with the capsule (m61-1), retropubic prostatectomy (m61-2), perineal prostatectomy (m61-4), rp other specified (m61-8), and rp unspecified (m61-9) in four operative fields. furthermore, laparoscopic procedures were identified by procedure codes y50x and y71x in four operative fields. patients’ outcomes were analyzed in various age groups. the major outcome variables of this study were mortality rate and length of hospital stay. patients’ characteristics and national trends for rp over the 7-year study period were also assessed. each hospital and surgeon has a unique identification code in the hes database. using these codes, we analyzed the volume outcome relationship for hospital and surgeon volume in england. annual hospital and surgeon volume thresholds were determined by dividing the patients into two equal-sized groups of high and low volume, based on the median volume (50th percentile), ie, 26 and 16 for hospital and surgical caseload, respectively. statistical analysis statistical analysis was performed using spss (statistical package for the social science, version 13.0, spss inc, chicago, illinois, usa) and ncss-pass (number cruncher statistical system and power analysis and sample size (kaysville, utah, usa, 2004) softwares. one way anova, chi-square, and kruskal-wallis tests were used for univariate analysis if appropriate. multiple logistic regressions were used to get the riskadjusted multivariate analysis for both in-hospital mortality and length of hospital stay. age, waiting time, admission method (emergency or elective), annual surgeon volume, and annual hospital volume were the independent variables used for the risk adjustment. all p values were twosided and p values less than .05 were considered statistically significant. independent variables with p values less than .1 in the univariate analysis were included in the multivariate analysis. the multivariate models were tested for goodness of fit using the hosmer-lemeshow test. results the mean age (± sd) of the patients was 62.7 (± 6.1) years. a total of 33 in-hospital deaths were reported, giving an overall mortality rate of 0.23%. the median waiting duration (date of decision to operate to date of admission for operation) and median length of hospital stay for patients having rp were 39 days and 7 days, respectively. radical prostatectomy practice—hanchanale et al 245urology journal vol 7 no 4 autumn 2010 national trends the number of rps has increased from 972 to 3092 over the study period. proportionately, laparoscopic rp has increased from 2 (1998) to 257 (2004) (figure 1). patients’ characteristics over the study period are described in table 1. the mean age of the patients has decreased significantly over the same period (p = .001). there was an increase of 13 days in the median waiting duration (p < .001). in-hospital mortality rate was very low with significant reduction over the study period (p = .029). median length of hospital stay has decreased from 8 days to 6 days. the number of hospitals performing rp has been nearly constant over the study period and in contrast, number of surgeons performing rp has increased from 194 to 234 (figure 2). the median hospital volume has increased by 2.6 times (p < .001) (figure 3) and similarly median surgeon volume has increased significantly from 8 to 20 (p < .001) over the 7 years (figure 4). patients’ age had a significant impact on clinical outcomes and waiting time (table 2). median variable year test (p) 1998 1999 2000 2001 2002 2003 2004 mean age ( ± sd), years 63.3 (6.4) 62.8 (6.0) 62.7 (6.1) 62.7 (5.9) 62.4 (6.1) 62.5 (6.0) 62.6 (5.9) anova ( .001) median (iqr) waiting time, days 32 (19 to 50) 34 (21 to 50) 39 (21 to 57) 38 (22 to 57) 40 (25 to 59) 40 (25 to 61) 45 (27 to 69) kruskal wallis = 242.911, 6df (< .001) in-hospital mortality, n (%) 6 (0.62) 2 (0.16) 8 (0.50) 4 (0.19) 4 (0.16) 3 (0.11) 6 (0.10) ( .029) median (iqr) length of stay, days 8 (7 to 10) 8 (6 to 9) 7 (6 to 9) 7 (6 to 9) 7 (5 to 8) 6 (5 to 8) 6 (5 to 8) kruskal wallis= 764.885, 6df (< .001) number of hospitals, n 120 126 122 122 122 119 122 – number of surgeons, n 194 204 212 226 234 242 234 – *iqr indicates interquartile range. table 1. patients’ characteristics for radical prostatectomy over 7-year study period figure 1. national trends of radical prostatectomy (rp and lrp) in england. figure 2. trends for total number of surgeons and hospitals performing radical prostatectomy in england. figure 3. error bar representing the annual hospital volume over the study period. radical prostatectomy practice—hanchanale et al 246 urology journal vol 7 no 4 autumn 2010 waiting time (interquartile range) in patients 17 to 53 days) and 41 days (range, 24 to 65 days), respectively. ninety-five percentage of mortality younger (< 50 years) patients. elderly patients to younger ones (< 50 years). volume outcome relationship in univariate analysis, mortality rate was year) hospitals compared to low volume (< 26 rp/year) hospitals (0.10% versus 0.30%, p < .05). in the risk adjusted multivariate analysis, mortality rate was significantly lower when comparing high volume to low volume hospitals (odds ratio: 0.40, 95% confidence interval: 0.17 to 0.90, p = .028). similarly, high volume surgeons had significantly lower mortality in comparison to low volume surgeons (0.10% versus 0.40%, p < .01). in the risk adjusted multivariate analysis, mortality rate was significantly lower when comparing high volume to low volume surgeons (odds ratio: 95% confidence interval: 0.13 to 0.75, p = .009). the median length of hospital stay was lower for high volume hospitals in comparison to low volume hospitals. likewise, high volume surgeons had shorter in-patient stay than low volume surgeons. discussion in proportion to the increase in number of newly diagnosed prostate cancer cases,(1) the annual number of rps has increased by more than threefold over 7 years. an increasing trend towards laparoscopic rp over the study period was noted. in-hospital mortality and length of hospital stay was lower in younger patients and later years of study. furthermore, mortality rate and length of in-patient stay was lower in patients treated by high volume surgeons and at high volume hospitals. our patients’ demographics are similar to previous population-based studies from the usa. (15,16) mortality rate from rp has been very low for many years, with majority of academic centers reporting 0% to 0.42%.(17-19) overall mortality rate of 0.23% (present study) is comparable to the studies from the usa (0.25%). (16) further reductions in the mortality rate (0.62% to 0.10%) over the study period could be attributed to the increase in surgical caseload and improvements in peri-operative care. length of stay is higher than medicare population-based studies from the usa by one day.(16) hu and colleagues suggested that surgeon volume is inversely related to in-hospital complications and length of stay in men undergoing rp.(20) litwin and associates reported that length of stay can be further decreased by 28% with clinical care pathway design.(21) present study has shown a significant difference in the mortality rate and length of hospital stay between the high and low volume groups in england. this analysis supports variable age range test (p) <50 50 to 59 60 to 69 total, n 283 3930 8572 1515 – median (iqr) waiting time, days 34 (17 to 53) 38 (23 to 57) 40 (24 to 60) 41 (24 to 65) kruskal wallis = 36.223, 3df (< .001) in-hospital mortality, n (%) 0 2 (0.05) 17 (0.19) 14 (0.92) median (iqr) length of stay, days 6 (5 to 8) 7 (5 to 8) 7 (5 to 9) 7 (6 to 9) kruskal wallis= 136.935, 3df (< .001) *iqr indicates interquartile range. table 2. clinical outcomes of radical prostatectomy in various age groups figure 4. error bar representing the annual surgeon volume over the study period. m ed ia n s ur ge on v ol um e, n (i nt er qu ar til e ra ng e) radical prostatectomy practice—hanchanale et al 247urology journal vol 7 no 4 autumn 2010 the volume outcome relationship studies from northern america for rp.(3,16) there was a significant increase in the number of surgeons with almost no change in the number of hospitals performing rp over the study period. the drift towards centralization has been supported by the significant increase in the annual hospital and surgeon volume. administrative databases are important resources for health services research. however, because the data were collected for reasons other than answering specific research questions, the conclusions must be balanced with caveats. in-hospital mortality rate obtained from hes database, in contrast to 30 or 60-day mortality rate, could be deceptive; as hospitals with early discharge policy have higher re-admission rate and higher 30-day mortality rate.(22-24) concerns have been raised with coding accuracy of hes database. various studies have confirmed the coding accuracy in the united kingdom to be on average 92%, especially for procedure coding. (25) furthermore, the major outcome variables (in-hospital mortality and length of hospital stay) can be extracted accurately through hes database. the audit verifying the excess deaths in bristol pediatric cardiac surgery unit attests the accuracy of hes coding.(26) one of the major strengths of this study lies in its population-based nature, which makes the results more easily generalizable and applicable to the majority of patients treated in various clinical settings. new british association of urological surgeons database of complex operations might resolve the few obstacles of hospital episodes statistics and aid in future studies. conclusion in conclusion, there is an exponential increase in the number of rps with an increasing trend towards laparoscopic rp in england. this study showed a significant inverse correlation between provider volume (hospital and surgeon) and outcome (mortality and length of hospital stay) for radical prostatectomy in england; thus, supporting the recommendations for centralization of major complex radical procedures, including radical prostatectomy. acknowledgements the authors are thankful to the department of health in england for providing the hospital episode statistics data. conflict of interest none declared. references: 1. office for national statistics: www.statistics.gov.uk (date of access, 20th march 2006). 2. prostate cancer uk incidence statistics: http://info. cancerresearchuk.org/cancerstats/types/prostate/ incidence/#geog (date of access, 20th march 2006). 3. lu-yao gl, friedman m, yao sl. use of radical prostatectomy among medicare beneficiaries before and after the introduction of prostate specific antigen testing. j urol. 1997;157:2219-22. 4. lerner se, blute ml, lieber mm, zincke h. morbidity of contemporary radical retropubic prostatectomy for localized prostate cancer. oncology (williston park). 1995;9:379-82; discussion 82, 85-6, 89. 5. birkmeyer jd, siewers ae, finlayson ev, et al. hospital volume and surgical mortality in the united states. n engl j med. 2002;346:1128-37. 6. van lanschot jj, hulscher jb, buskens cj, tilanus hw, ten kate fj, obertop h. hospital volume and hospital mortality for esophagectomy. cancer. 2001;91:1574-8. 7. hes online. hospital episode statistics. (http:// www. hesonline.nhs.uk) (date of access, 20th march 2006) 8. goddard m, mannion r, smith pc. assessing the performance of nhs hospital trusts: the role of ‘hard’ and ‘soft’ information. health policy. 1999;48:119-34. 9. michaels ja. use of mortality rate after aortic surgery as a performance indicator. br j surg. 2003;90: 827-31. 10. bloor k, maynard a, freemantle n. variation in activity rates of consultant surgeons and the influence of reward structures in the english nhs. j health serv res policy. 2004;9:76-84. 11. mccabe je, jibawi a, javle p. defining the minimum hospital case-load to achieve optimum outcomes in radical cystectomy. bju int. 2005;96:806-10. 12. kang jy, hoare j, majeed a, williamson rc, maxwell jd. decline in admission rates for acute appendicitis in england. br j surg. 2003;90:1586-92. 13. world health organization. international statistical classification of diseases and related health problems. 10th rev (icd-10). geneva, switzerland; 1994. 14. office of 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prostatectomy. j urol. 1997;157:1760-7. 20. hu jc, gold kf, pashos cl, mehta ss, litwin ms. role of surgeon volume in radical prostatectomy outcomes. j clin oncol. 2003;21:401-5. 21. litwin ms, smith rb, thind a, reccius n, blancoyarosh m, dekernion jb. cost-efficient radical prostatectomy with a clinical care path. j urol. 1996;155:989-93. 22. goldacre mj, griffith m, gill l, mackintosh a. inhospital deaths as fraction of all deaths within 30 days of hospital admission for surgery: analysis of routine statistics. bmj. 2002;324:1069-70. 23. jencks sf, williams dk, kay tl. assessing hospital-associated deaths from discharge data. the role of length of stay and comorbidities. jama. 1988;260:2240-6. 24. henderson j, goldacre mj, griffith m, simmons hm. day case surgery: geographical variation, trends and readmission rates. j epidemiol community health. 1989;43:301-5. 25. campbell se, campbell mk, grimshaw jm, walker ae. a systematic review of discharge coding accuracy. j public health med. 2001;23:205-11. 26. poloniecki j, sismanidis c, bland m, jones p. retrospective cohort study of false alarm rates associated with a series of heart operations: the case for hospital mortality monitoring groups. bmj. 2004;328:375. v08_no_1_print_3.pdf urological calendar 79urology journal vol 8 no 1 winter 2011 urological calendar urol j. 2011;8: 79-81. www.uj.unrc.ir sufu 2011 winter meeting scottsdale, arizona, usa march 1 5, 2011 e-mail: info@sufuorg.com website: www.sufuorg.com/meetings/2011/default. aspx 75th annual meeting of southeastern section of the aua new orleans, usa march 17 20, 2011 e-mail: info@sesaua.org website: www.sesaua.org 26th annual eau congress vienna, austria march 18 22, 2011 e-mail: info@eauvienna2011.org website: www.eauvienna2011.org esu organized courses, hot, education and innovation at the time of the 26th eau annual meeting vienna, austria march 18 22, 2011 e-mail: esu@uroweb.org website: www.uroweb.org 12th international eaun meeting vienna, 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office@iuga.org website: www.iuga.org female urology experiences with an extraperitoneal transvesicoscopic repair of a vesicovaginal fistula hongwook kim1,changhee hong2,janghwan kim3* purpose: a vesicovaginal fistula (vvf) is a debilitating condition for women in terms of both its personal and social impacts. a reported transperitoneal laparoscopic approach to treatment has some limitations such as risk of intra-peritoneal organ injury and unnecessary bladder dissection. we here report on our experiences with an extraperitoneal transvesicoscopic approach to a vvf repair, which overcomes these drawbacks. materials and methods: seven vvf patients were treated using the transvesicoscopic approach. under general anesthesia, patients were placed in the dorsal lithotomy position. the vvf orifice was obstructed via the vaginal canal using a foley catheter. the bladder was then filled with normal saline under cystoscopic inspection, and a 5 mm trocar was inserted into it at the suprapubic area. the bladder wall was next fixed to the anterior abdominal wall. thereafter, two 3 mm ports were punctured at the interspinous skin crease allowing the fistula margin to be cut and sutured in layers. results: six of the study subjects in whom we attempted a transvesicoscopic repair of vvf had undergone a hysterectomy due to myoma and one had an intraabdominal abscess removal with behcet's disease. one myoma patient who had a preexisting vesicoperitoneal fistula was converted to an open transabdominal vvf repair. the mean age of the 6 remaining patients was 46.0 ± 7.2 years (range, 35-57). the mean operation time was 273 ± 40.6 minutes (range, 223-323). there was no instances of significant pain or other immediate complications. five patients showed no recurrence of the fistula during the follow-up period (8.7 ± 5.1 months). conclusion: a transvesicoscopic approach is an effective modality for the repair of a vvf that is more minimally invasive and has a lower morbidity than a transabdominal procedure. keywords: vesicovaginal fistula; laparoscopy; extraperitoneal transvesical approach introduction a vesicovaginal fistula (vvf) is one of the most frequent urinary fistulas with a long history of occurrence in women.(1) hiton reported that the annual incidence of vvfs has now approached 500,000 worldwide.(2) vvf is a debilitating condition both before and after treatment that commonly causes wet soiling of clothes, bad odors, and a mistaken diagnosis venereal disease.(3) sexual intercourse is usually avoided by affected women, which can lead to marital problems and divorce if the condition is untreated.(3) after vvf repair, however, these women sometimes experience gynatresia and dyspareunia due to the severity of the damage and subsequent fibrosis.(4) in addition, the first vvf repair attempt is very important because successive attempts have an increased failure rate.(5) repeated surgical treatments can also cause more tissue damage and fibrosis. this in turn also results in lower success rates and possible difficulties in sexual relationships. effective methods of treating a vvf that minimize tissue manipulation are therefore needed. transvaginal or transabdominal approaches have been the traditional interventions for vvfs. the benefits of 1department of urology, konyang university college of medicine, daejeon, korea. konyang university myunggok medical research institute. 2department of urology, gangnam severance hospital, urological science institute, seoul, korea. 3department of urology and urological science institute,yonsei university college of medicine, seoul, korea *correspondence: department of urology and urological science institute, yonsei university college of medicine, 50-1, yonsei-ro, seodaemun-gu, seoul 03722, korea. tel: +82-2-2228-2310. e-mail: jkim@yuhs.ac. received november 2022 & accepted july 2023 a transvaginal approach include a shorter hospital stay, avoidance of an indwelling cystostomy catheter, a lower rate of blood loss.(6) these methods also have better cosmetic outcomes than a transabdominal approach. however, a transvaginal approach becomes difficult if the fistula is located in the vaginal vault. the transabdominal approach can be performed when the transvaginal approach is not deemed possible due to characteristics such as highly located fistulas, more complicated fistulas, an immobile vaginal vault, and instances where a combined surgery is needed.(7) nonetheless, a large abdominal incision, an invasion of the peritoneal space, and an opening the bladder is required for these procedures and this necessarily increases the morbidity and the recovery time. to overcome these disadvantages of transabdominal surgeries for vvf repair, a laparoscopic method has been introduced. the laparoscopic transperitoneal supravesical approach is a far more minimally invasive technique but has some of the same disadvantages as the transabdominal approach such as intra-abdominal organ injury risk. several years ago, our hospital has been conducting a transvesicoscopic approach in cohen operations for pediatric vesicoureteral reflux surgery. urology journal/vol 20 no. 4/ july-august 2023/ pp.240-245. [doi:10.22037/uj.v20i.7518] this procedure retains some the advantages of both the transvesical and laparoscopic methods such as minimal invasion and requires no violation of the peritoneal space or opening of the bladder. we have applied the transvesicoscopic approach to vvf repair. nowadays, robot-assisted laparoscopic vvf repair is performed and has many advantages. however, it is still difficult to perform widely due to relatively long operation time and high cost. therefore, we think that the transvesicoscopic approach to vvf repair, which we previously conducted, can be an alternative. we herein outline our experiences with this in a small cohort. materials and methods patients a total of seven vvf patients were treated at our hospital with the transvesicoscopic approach between april 2010 and september 2011 in our hospital. informed consent to participate in this study was received from all patients. six cases of vvf in this group occurred within figure 1. abdominal marks at the trocar insertion sites. an imaginary bladder line was drawn by filling the bladder with normal saline. transvesicoscopic repair of a vesicovaginal fistula-kim et al. vol 20 no 4 july-august 2023 241 figure 2. transvesicoscopic port insertion and fixation one month (0.25~1) of a hysterectomy (4 lavh and 2 tah) due to a uterine myoma. the remaining patient had had behcet’s disease and underwent an exploratory laparotomy due to a spontaneous bowel perforation. the fistula occurred 2 months after the repair of this perforation. conservative treatment had been unsuccessfully attempted in all of our current study patients. one of these cases (tah) had undergone a transvaginal surgical treatment for vvf prior to the transvesicoscopic repair. baseline evaluations were performed in all seven subjects including medical histories, physical examinations, pelvic examinations, and cystoscopy. following institutional review board approval (42011-0734), we retrospectively analyzed the clinical utility of an extraperitoneal transvesicoscopic repair of a vvf. all operations were performed by the same surgeon. set-up and surgical technique under general anesthesia, patients were placed in the modified lithotomy position with abducted thighs. the surgeon stood on the right side of the patient. video monitors were positioned on the left side of the patient. the camera was located on the right side of the doctor. prior to the vvf repair, all patients underwent repeat cystoscopic examinations with normal saline to determine the location and size of the fistula. a 5 fr openend catheter was inserted into the ureter through the urethra to evacuate any urine to an extravesical urine bag. this also prevented filling of the bladder and allowed for easy identification of any ureteral injury. the vvf tract was occluded using a foley catheter passed figure 3. transvesicoscopic view of a vvf after removing the obstructive foley catheter. figure 5. the fistula tract was closed layer by layer. figure 4. circular dissection of the fistula margin. figure 6. after closing the bladder. transvesicoscopic repair of a vesicovaginal fistula-kim et al. female urology 242 through the vaginal canal, and the bladder was then filled with normal saline. transvesicoscopic port insertion and fixation a small midline skin incision was made midway between the umbilicus and symphysis pubis, and a 5 mm diameter trocar was then introduced into the bladder under cystoscopic inspection (figure 1).(8) the anterior bladder wall was next fixed to the anterior abdominal wall and a 17-gauge needle was inserted beside the camera port and passed into the bladder. a loop was then made inside the bladder. a 21-gauge spinal needle was next inserted into the bladder on the opposite side of the camera port and passed into the loop. a 3-0 suture was then inserted into the loop through the 21-gauge spinal needle. this suture was trapped by the loop in the bladder and extracted outside the skin by pulling the loop upward. the suture was tied at the site of abdomen incision for fixation (figure 2). after the saline was drained, co 2 gas was instilled into the bladder. pneumovesicum of 10 mmhg was then commenced at a flow of 2l/min and a vesicoscope was inserted via the 5 mm diameter trocar. two additional lateral trocars (3 mm) were next introduced under vesicoscopic vision (or cystoscopic vision) through the anterolateral wall of the bladder along the interspinous skin crease (figure 1). the transvaginal occlusive foley catheter was removed (figure 3) and the vagina was packed with betadine gauze to prevent any gas leakage. alternatively, the vaginal introitus was occluded with a water-filled glove, if the betadine gauze occlusion was incomplete. vesicoscopic fistulectomy and suture under vesicoscopic vision, the fistula margin was cut circumferentially with a electrocautery hook (figure 4). the vaginal wall and detrusor muscle layer were then sutured separately in layers using an absorbable 4-0 synthetic absorbable monofilament surgical suture in an interrupted manner (figure 5). there is no more gas leakage after the bladder muscle layer is closed. consequently, no more vaginal packing is then needed. the bladder mucosa was closed using interrupted sutures with an absorbable 4-0 synthetic monofilament surgical suture (figure 6). wound closure a suprapubic cystostomy catheter was placed through the 5 mm trocar site which was removed 2-3weeks after surgery in all cases except the prior vvf repair patient (4 weeks). the 3 mm trocar sites were closed with subcutaneous sutures. a urethral foley catheter was also inserted at the end of the surgery and removed the next day. follow-up in the follow-up period, all patients underwent a pelvic examination and cystoscopic evaluation to confirm the vvf healing state. a telephone interview was used to check the status of each patient’s sexual relationship and dyspareunia. responses were taken during these interviews using the korean version of the female sexual function index (fsfi) questionnaire and the international consultation on incontinence modular questionnaire (iciq) for incontinence, respectively. results transvesicoscopic repair of a vvf was attempted in seven women at our hospital. one patient required conversion to an open laparotomy due to a small sizes concomitant vesicoperitoneal fistula found incidentally at the start of the surgery and because persistent co2 gas leakage prevented pneumovesicum from being achieved. she had no abdominal pain, abdominal distention and other related symptoms. the mean age of the remaining six patients was 46.0 ± 7.2 years (range, 35-57). the interval between fistula occurrence and vvf repair was 10.8± 18.2 months (range, 2-48 months). the sizes of the fistulas ranged from about 0.5-2.0 cm. the fistulas were located superior to the trigone with a narrow vagina in all of the study cases.(9) blood loss was minimal in all patients (< 50 ml) and the operation time ranged from 223-323 minutes (273 ± 40.6). in the immediate postoperative period, no patient noted any pain above a minimal level and none developed any obvious complications. oral intake was commenced on post-operative days 1-2 in all six study subjects, and the hospital stays for these cases ranged from 1-6 days (4 ± 1.7days). five patients did not show fistula recurrence by vaginal examination and cystoscopy during the mean follow-up period of 12.5 ± 8.1 months (range, 2.5-19). the behcet’s disease patient who had a history of spontaneous small bowel perforation developed a new fistula about 1 cm away from the right side of the original repair site at one-month post-surgery. she had been on immunosuppressive medication due to the behcet’s disease and died of an intra-abdominal abscess that occurred 4 months later. the remaining five patients reported a comparable sex life that prior to the vvf occurrence. one patient was a follow-up loss at 19 months but had reported no incontinence or dyspareunia up to that point. the remaining four patients conducted incontinence and sexual relationship surveys by telephone at a follow-up of 36.25 ± 9.0 months (range, 27-40). with regard to the incontinence questions, q1 and q2 on the iciq questionnaire had a response of 0 (no leakage). with regard to sexual satisfaction queries, the responses to fsfi q16 were all ‘about equally satisfied and dissatisfied’. with regard to dyspareunia, the response to q19 were all ‘very low or none at all’. all of these women were satisfied with their operation results. the surgical scars were too small to find out about in the last follow-up. discussion our approach to vvf repair showed good surgical results except for patients with underlying disease during follow-up despite the need to overcome technical difficulties and long surgical times. there are different options for the treatment of vvf. one approach is conservative therapy, which consists of an indwelling catheter and anticholinergic medication for at least 2 to 3 weeks, and may be used for small, newly developed vvfs.(7) surgical therapy is the most popular treatment and several procedures have been described. a transvaginal approach has been reported in numerous studies to date. almost all vvfs can be approached transvaginally.(6,10) the benefits of this method are its relative simplicity, shorter operating times, lower blood loss, and typically shorter hospital stay.(6) an ease of accessibility and decreased postoperative pain relative to abdominal surgery are also advantages of this option. in addition, a transvaginal approach avoids the transvesicoscopic repair of a vesicovaginal fistula-kim et al. vol 20 no 4 july-august 2023 243 need for a laparotomy and its associated complications such as intraperitoneal organ injury, prolonged ileus, and a need for drainage. however, it is especially difficult to perform this type of surgery for vvf when the fistula is in a deep location in the vagina. another surgical option for vvf is a transabdominal approach, which can be conducted in two different ways. one option is an extraperitoneal transvesical approach, and the other is a transperitoneal supravesical method. the extraperitoneal transvesical approach also avoids laparotomy-related complications but is nonetheless restricted due to narrow spaces. furthermore, it is nearly impossible to perform an interpositional flap placement between the bladder and vagina.(11,12) accordingly, many surgeons prefer the transperitoneal supravesical methods.(6) the benefits of the transperitoneal supravesical approach include the accessibility of high or retracted fistulas in narrow vaginas, the possibility of ureteral reimplantation, a correctable concomitant pelvic pathology, and applicability to multiple, large fistulas or prior failed attempts.(13) in addition, it can be used for either interpositional omental flap or peritoneal flap placement. of note however, the transperitoneal supravesical approach requires a longer recovery time, is more painful, and is associated with an increased intraperitoneal organ injury risk and larger abdominal scarring compared to the transvaginal approach. to overcome the limits of the transperitoneal supravesical approach, a number of more minimally invasive procedures have been developed. a laparoscopic transperitoneal supravesical vvf repair was first described in 1994.(14) the benefits of laparoscopic repair are the ability to magnify the surgical field during the procedure, hemostasis, decreased abdominal pain, and a shorter hospital stay with a more rapid recovery and an earlier return to work. sotelo et al(15) contended that the laparoscopic approach was an excellent alternative to the traditional open abdominal approach. nevertheless, the laparoscopic transperitoneal supravesical approach has issues such as risk of bowel injury, bowel ileus, and a requirement for indwelling drainage. the laparoscopic extraperitoneal transvesical approach can overcome the abovementioned disadvantages of a laparotomy in relation to intraperitoneal organ complications. this approach has been applied to bladder stone removal, ureteral reimplantation, and prostatectomy.(16-19) it has the laparoscopic advantages of a clear vision directly over the vvf, easy accessibility between the fistula and both ureteral orifices, the possibility of conducting simultaneous re-implantation of the ureter, no related intraabdominal organ complications, and improved cosmesis. we chose this surgical method for our current vvf cohort for these reasons. postoperative scarring from the laparoscopic extraperitoneal transvesical vvf repair was small, such as external skin wounds, because it is a minimally invasive technique and has reduced tissue manipulation. at the follow-up cystoscopic inspection in our present patient series, intravesical postoperative scarring was low and was limited to only the suture line. as previously mentioned, the outcome of the first vvf repair attempt is important because successive attempts have an increasing rate of failure due to tissue damage and subsequent fibrosis. a laparoscopic extraperitoneal transvesical surgery reduces the degree of tissue manipulation and thus lowers the risk of damage. this in turn improves tissue healing transvesicoscopic repair of a vesicovaginal fistula-kim et al. and reduces the occurrence of tissue fibrosis, leading to an improved success rate. in our current results, all patients who had long term follow-ups were satisfied with the outcomes of the surgery. sexual satisfaction was reported by only half of these women, although eastern customs where it is considered taboo to talk about sex likely contributed to this as responses to these questions were not given by all of these patients. the laparoscopic extraperitoneal transvesical approach to a vvf repair is not without limitations, which must be considered. first, the narrow working space will be less convenient for the surgeon in comparison to the open transperitoneal supravesical approach. nerli et al have also reported on the use of this method for the treatment of vvf.(20) although these authors used a 5 mm working port and instrument, they had technical difficulties at first. in our experience, the use of pediatric laparoscopic instruments could overcome this limitation because of their shorter lengths and greater ease of movement which will allow for a wider working angle. we have had an experience ourselves with adult sized 5 mm working ports and instruments for vvf repair in another hospital. the movement of this larger and longer working element in the small bladder area created difficulties with tissue manipulation and suturing. a longer operation time was also needed. a second limitation of extraperitoneal transvesical vvf repair was the longer operation time compared to the open transperitoneal supravesical approach.(21,22) this ranged from 223-323 minutes in our present cohort but did gradually decrease over subsequent surgeries. greater experience with a given technique and the instruments involved would be expected to reduce the duration of the surgeries over time. a third drawback of this approach was that our methods did not allow an interpositional omental flap or peritoneal flap placement. our approach would therefore not be suitable in cases needing an interpositional flap, such as patients with an irradiated fistula, large fistula, prior obstetric surgery, previous failed repairs, or a weakly repaired fistula. however, the causes of the vvf in our current patients were gynecologic and this concern did not apply. our present study had the following limitations of note. first, it was a retrospective study with a small sample size. second, a pediatric instrument was used instead of the widely used adult laparoscopic instrument. third, the follow-up period was short. finally, the survey results in relation to sexual satisfaction post-surgery were incomplete, likely due to cultural embarrassment. notwithstanding these issues however, with improved experience by the participating surgeons and the development of better instruments in the future, the current limitations of an extraperitoneal transvesical repair of a vvf could be significantly overcome in the near future. it will likely then become a more popular early procedure for vvf repair. conclusions a laparoscopic extraperitoneal transvesicoscopic approach to a vvf repair may be one of the more effective and less invasive modality than transabdominal interventions. this procedure can potentially become the treatment of choice for an early supratrigonal vvf repair. female urology 244 acknowledgements the authors thank dong-su jang, ba (research assistant, department of anatomy, yonsei university college of medicine, seoul, korea), for his help with the figures. conflict of interest the authors declare no conflicts of interest in relation to this study. references 1. wong, c., p.n. lam, and v.r. lucente, laparoscopic transabdominal transvesical vesicovaginal fistula repair. j endourol, 2006. 20: p. 240-3; discussion 243. 2. hilton, p., vesico-vaginal fistulas in developing countries. int j gynaecol obstet, 2003. 82: p. 285-95. 3. ahmed, s. and s.a. holtz, social and economic consequences of obstetric fistula: life changed forever? int j gynaecol obstet, 2007. 99 suppl 1: p. s10-5. 4. de ridder, d., vesicovaginal fistula: a major healthcare problem. curr opin urol, 2009. 19: p. 358-61. 5. hilton, p. and a. ward, epidemiological and surgical aspects of urogenital fistulae: a review of 25 years' experience in southeast nigeria. int urogynecol j pelvic floor dysfunct, 1998. 9: p. 189-94. 6. gerber, g.s. and h.w. schoenberg, female urinary tract fistulas. j urol, 1993. 149: p. 229-36. 7. campbell, m.f., a.j. wein, and l.r. kavoussi, campbell-walsh urology / editor-in-chief, alan j. wein ; editors, louis r. kavoussi ... [et al.], ed. e.s. rovner. 2007, philadelphia: w.b. saunders. 8. chung, m.s., et al., transvesicoscopic ureteral reimplantation in children with bilateral vesicoureteral reflux: surgical technique and results. j laparoendosc adv surg tech a, 2012. 22: p. 295-300. 9. pendergrass, p.b., et al., comparison of vaginal shapes in afro-american, caucasian and hispanic women as seen with vinyl polysiloxane casting. gynecol obstet invest, 2000. 50: p. 54-9. 10. lee, d. and p. zimmern, vaginal approach to vesicovaginal fistula. urol clin north am, 2019. 46: p. 123-133. 11. angioli, r., et al., guidelines of how to manage vesicovaginal fistula. crit rev oncol hematol, 2003. 48: p. 295-304. 12. mellano, e.m. and c.m. tarnay, management of genitourinary fistula. curr opin obstet gynecol, 2014. 26: p. 415-23. 13. lee ra fau symmonds, r.e., t.j. symmonds re fau williams, and t.j. williams, current status of genitourinary fistula. obstet gynecol, 1988. 72: p. 313-9. 14. nezhat, c.h., et al., laparoscopic repair of a vesicovaginal fistula: a case report. obstet gynecol, 1994. 83: p. 899-901. 15. sotelo, r., et al., laparoscopic repair of vesicovaginal fistula. j urol, 2005. 173: p. transvesicoscopic repair of a vesicovaginal fistula-kim et al. vol 20 no 4 july-august 2023 245 1615-8. 16. yeung ck fau sihoe, j.d.y., p.a. sihoe jd fau borzi, and p.a. borzi, endoscopic cross-trigonal ureteral reimplantation under carbon dioxide bladder insufflation: a novel technique. (0892-7790 (print)). 17. elbahnasy am fau farhat, y.a., et al., percutaneous cystolithotripsy using selfretaining laparoscopic trocar for management of large bladder stones. (1557-900x (electronic)). 18. desai mm fau fareed, k., et al., singleport transvesical enucleation of the prostate: a clinical report of 34 cases. (1464-410x (electronic)). 19. miklos, j.r., r.d. moore, and o. chinthakanan, laparoscopic and roboticassisted vesicovaginal fistula repair: a systematic review of the literature. j minim invasive gynecol, 2015. 22: p. 727-36. 20. nerli, r.b. and m. reddy, transvesicoscopic repair of vesicovaginal fistula. diagn ther endosc, 2010. 2010: p. 760348. 21. gupta np fau mishra, s., et al., comparative analysis of outcome between open and robotic surgical repair of recurrent supra-trigonal vesico-vaginal fistula. j endourol, 2010. 24: p. 1779-82. 22. ramphal, s.r., laparoscopic approach to vesicovaginal fistulae. best pract res clin obstet gynaecol, 2019. 54: p. 49-60. andrology the effect of phytosterols and fatty acids of pistachio (pistacia vera) oil on spermatogenesis and histological testis changes in wistar adult male rats soudeh khanamani falahati-pour1, soheila pourmasumi2,3, maryam mohamadi1, zahra taghipour4,5, mohammad reza mohammadinasab6, mojtaba sajadian7, fatemeh ayoobi2, ali dini1, zahra ahmadi1, sakineh khanamani falahatipour1, alireza nazari2,8* purpose: oilseeds and their related products are known to have various bioactive and health-promoting ingredients. in this research, we investigated the effects of phytosterols and fatty acids of pistacia vera on spermatogenesis process and testis histological changes in wistar male rats for the first time. materials and methods: a total number of 64 adult male wistar rats were divided randomly into eight groups including one control group, and seven test groups. test groups received phytosterols, fatty acids, and pistachio oil orally for 30 days. then, lh, fsh, and serum testosterone levels were determined. also, the spermatogenesis process and changes in testicular tissue in rats were investigated. results: the results of this research suggest that phytosterols in doses of 10 and 50 mg/kg reduce the spermatogenesis process. fatty acid in a low dose of 10 mg/kg increases spermatogenesis, but when a high dose of 50 mg/ kg was used, it harmed the spermatogenesis process. when low levels of phytosterols and fatty acids are used simultaneously in dose 5 mg/kg, improvement in spermatogenesis process is observed but when these were used together in the dose of 25 mg/kg, the spermatogenesis process was disrupted. using pistachio oil alone also improved spermatogenesis process. conclusion: it seems that phytosterols reduce spermatogenesis at high and low doses, while fatty acids increase spermatogenesis when used in low doses and reduce this process when used in high doses. the use of fatty acids extracted from pistachios to treat infertility in men seems hopeful. keywords: cma3; male infertility; short abstinence; sperm dna integrity; tunel 1pistachio safety research center, rafsanjan university of medical sciences, rafsanjan, iran. 2non-communicable diseases research center, rafsanjan university of medical sciences, rafsanjan, iran 3clinical research development unit (crdu), niknafs hospital, rafsanjan university of medical sciences, rafsanjan, iran. 4physiology-pharmacology research center, rafsanjan university of medical sciences, rafsanjan, iran 5department of anatomy, school of medicine, rafsanjan university of medical sciences, rafsanjan, iran 6student research committee, rafsanjan university of medical sciences, rafsanjan, iran 7department of clinical biochemistry, faculty of medicine, rafsanjan university of medical sciences, rafsanjan, iran. 8clinical research development unit (crdu), moradi hospital, rafsanjan university of medical sciences, rafsanjan, iran. *correspondence: shohada street, moradi hospital, rafsanjan university of medical science, rafsanjan, iran. e-mail: drnazari57@gmail.com received october 2020 & accepted july 2021 introduction in recent years, one of the problems that human so-cieties have faced is infertility in men(1). factors involved in male infertility include occupational, environmental, and nutritional factors. among these factors, diet plays an important role in reproductive health in men(2). oilseeds are widely used in the human diet; these seeds have many bioactive substances with medicinal and biological properties that have been used in the treatment of several diseases. the evidence suggests that ingestion of oilseeds may impose different cardiovascular effects thought to be due to their lipid components, which include unsaturated fatty acids, phytosterols and tocopherols(3). recent research has also shown that dietary intake of edible oil may even have more beneficial effects on total ingested seeds, possibly due to the replacement of carbohydrate diets with unsaturated fats or other oil components(4). pistachios are one of the most important oilseeds due to their high-fat content. the most important portion of pistachio fat is unsaturated fatty acids, 80% of which are oleic acid and linoleic acid(5). pistachio oil has chemical compounds that contain saturated fatty acids such as myristic acid, palmitic acid, stearic acid and unsaturated oils such as linoleic acid, oleic acid, plant sterols and elements such as selenium, zinc, calcium, potassium, iron, and magnesium(6). previous studies have shown that compounds in pistachio oil inhibit nitric oxide production. since this compound can control steroidogenesis, therefore, pistachio oil has been used as a drug for the treatment of related diseases, including increased sexual activity(7). on the other hand, it has been reported that plants containing linoleic acid have been used to treat sexual weakness. saturated and unsaturated fatty acids, for example palmitic acid, oleic acid, linoleic acid, miristic acid and stearic acid inhibit 5-alpha-reductase enzyme activity, which causes the conversion of testosterone to di-hydroxy-testosterone urology journal/vol 18 no. 6/ november-december 2021/ pp. 682-687. [doi: 10.22037/uj.v18i.6605] vol 18 no 6 november-december 2021 683 (dht), so inhibiting its activity increases the amount of testosterone in the blood(8). non-saturated fatty acids can inhibit 5-alpha-reductase enzyme activity, and saturated fatty acids increase cholesterol(9). sterols are a group of natural compounds that are derived from hydroxylation of polycyclic isopentanoids and have a structure of 1, 2-cyclopentanophenanthrene. most plant sterols contain 28 or 29 carbon and have one or two carbon-carbon double bonds in their molecular structure, one of which is dual bonds inside the rings, and the other is on the side chain of the sterol structure. more than 200 different types of plant sterols have been reported in plant species. five sterols including β-sitosterol, δ5-avenasterol, campesterol, stigmasterol and cholesterol have been identified in pistachio oil(10). in recent years, considerable attention has been paid to the study of the effect of different plants on fertility of laboratory mammals. therefore, this study aimed to investigate the effect of the extracted phytosterols and fatty acids from pistachio (pistacia vera var. akbari) oil on spermatogenesis and changes in testicular tissue in adult male wistar rats and also possibly to predict any benefits or harms of these compounds on fertility. materials and methods plant preparation the fruits of pistacia vera var. akbari were collected the effect of pistachio oil on spermatogenesis-falahatipur et al. body weight (g)a before treatment after treatment control (a group) 203.71 ± 23.26a 234.33 ± 15.00a (b group) 204.14 ± 30.17a 217.28 ± 33.50a (c group) 207.57 ± 41.92a 230 ± 38.03a (d group) 200.57 ± 34.16a 237.67 ± 11.64a (e group) 202.14 ± 40.58a 221.63 ± 22.83a (f group) 205.71 ± 44.12a 255.4 ± 17.40a (g group) 201.86 ± 40.42a 224.33 ± 29.45a (h group) 203 ± 33.98a 217.5 ± 44.65a p-value (kruskal-wallis) .999 .221 p-value (post hoc) 1 .276 table 1. body weight of mice in different treated group and control before and after treatment control group (a), and seven test groups (b to h) were treated orally by gavage for a period of 30 days. test groups received 10 mg/kg of phytosterols (b group), 50 mg/kg of phytosterols (c group), 10 mg/kg of fatty acids (d group), 50 mg/kg of fatty acids (e group), 5 mg/ kg of fatty acids plus 5 mg/kg of phytosterols (f group), 25 mg/kg of fatty acids plus 25 mg/kg of phytosterols (g group) and 50 mg/kg of pistachio oil (h group). mean values in a column followed by different letters are significantly different (p < 0.05) figure 1. histological sections of the testes of mice in different treated groups and control. control group (a), and seven test groups (b to h) were treated orally by gavage for a period of 30 days. test groups received 10 mg/kg of phytosterols (b), 50 mg/kg of phytosterols (c), 10 mg/kg of fatty acids (d), 50 mg/kg of fatty acids (e), 5 mg/kg of fatty acids plus 5 mg/kg of phytosterols (f), 25 mg/kg of fatty acids plus 25 mg/kg of phytosterols (g) and 50 mg/kg of pistachio oil (h), respectively and (i) demonstrates high magnification photomicrograph obtained from testis of rat showing: sertoli cells spermatogonia cells spermatocyte cells spermatide cells epithelial thickness seminiferous diameter vol 18 no 6 november-december 2021 138 from a garden in rafsanjan, iran and approved by a botanist at the vali-e-asr university of rafsanjan. reagents all chemicals and solvents were purchased from sigma-aldrich (st. louis, mo) and used without further purification except when mentioned specifically. pistachio oil preparation the oil of the pistachio kernels was obtained by cold-pressing the dried kernels. the oil was protected from direct sunlight and stored at 4-6 °c. preparation of phytosterol fraction unlike fatty acids, phytosterols cannot saponify. therefore, phytosterols were separated from fatty acids using their reactions with naoh. to extract the sterols, 0.1 g of the pistachio oil was mixed with 20 ml of 1 m ethanolic naoh solution and stirred for 12 h at room temperature. then, 20 ml distilled water and 40 ml diethyl ether were added to the mixture. in this step, the obtained mixture was transferred to a decanter where the sterols were separated from the saponified fatty acids and transferred into the ether phase. after, separating the sterol-rich ether phase, the extraction of the remained sterols from the aqueous phase was using 40ml of excess diethyl ether. the two ether phases were mixed and transferred to a decanter where possible saponifiable components were removed by extracting with 0.5 m ethanolic naoh solution. the sterol-rich ether phase was finally freeze-dried and the solvent-free sterols were stored at -20 °c until use(11). preparation of fatty acid fraction to extract the fatty acid fraction, 0.1 g of the pistachio oil was mixed with 20 ml ethanolic naoh solution (1 m) and stirred for 12 h at room temperature. then, the mixture along with 20 ml distilled water and 40 ml diethyl ether was transferred to a decanter. the saponified fatty acids were dissolved in water activating the aqueous phase. after separating the aqueous phase, 40 ml of naoh solution (0.5 m) was added and the extraction procedure was carried out again to extract the remaining saponified fatty acids from the ether phase. the separated aqueous phases were mixed and reacted with 20 ml hcl solution (0.5 m) to convert the saponified fatty acids to free fatty acids. after adding table 2. the testis weight of mice in different treated groups and control after treatment testis weight (g)a after treatment testis weight/bw control (a group) 1.35 ± 0.1b 0.005761 ± 0.00052a (b group) 1.31 ± 0.07b 0.006029 ± 0.0013a (c group) 1.34 ± 0.15b 0.005826 ± 0.00088a (d group) 1.31 ± 0.15b 0.005512 ± 0.0007a (e group) 1.33 ± 0.16b 0.006255 ± 0.0013a (f group) 1.44 ± 0.17a 0.005638 ± 0.00061a (g group) 1.16 ± 0.18b 0.005171 ± 0.0015a (h group) 1.25 ± 0.13b 0.005747 ± 0.0018a p-value(kruskal-wallis) .212 .843 p-value(post hoc) .119 .815 control group (a), and seven test groups (b to h) were treated orally by gavage for a period of 30 days. test groups received 10 mg/kg of phytosterols (b group), 50 mg/kg of phytosterols (c group), 10 mg/kg of fatty acids (d group), 50 mg/kg of fatty acids (e group), 5 mg/ kg of fatty acids plus 5 mg/kg of phytosterols (f group), 25 mg/kg of fatty acids plus 25 mg/kg of phytosterols (g group) and 50 mg/kg of pistachio oil (h group). mean values in a column followed by different letters are significantly different (p < 0.05) adata are presented as mean ± sd figure 2. the number of sertoli cells of mice fed on different concentrations of phytosterols and fatty acids of pistachio oil andrology 684 the effect of pistachio oil on spermatogenesis-falahatipur et al. figure 3. the result of epithelial layer thickness of mice fed on different concentrations of phytosterols and fatty acids of pistachio oil data are presented as mean ± sd. bars with same superscript letters are not significantly different whereas those with different superscript letters are significantly different (p < 0.05). vol 18 no 6 november-december 2021 685 40 ml diethyl ether, the free fatty acids were extracted to the ether phase from the aqueous phase. this procedure was repeated again and finally, the separated ether phases were mixed, freeze-dried and stored at -20 °c until use(12). experimental assays the present study was performed on 64 adult male wistar rats, weighing 200±45 g that were kept in the animal laboratory of rafsanjan university of medical sciences. in this experimental study, the animals were housed at room temperature (25 °c), and light was set at 12 h light–dark cycle. they were maintained in plastic cages separately and had free access to food and water. the study protocol was approved by the ethical committee of rafsanjan university of medical sciences under the ethical code ir.rums.rec.1396.98. they were randomly divided into eight groups (n = 8) including one control group (a), and seven test groups (b to h). test groups received 10 mg/kg of phytosterols (b group), 50 mg/kg of phytosterols (c group), 10 mg/kg of fatty acids (d group), 50 mg/kg of fatty acids (e group), 5 mg/kg of fatty acids plus 5 mg/kg of phytosterols (f group), 25 mg/kg of fatty acids plus 25 mg/kg of phytosterols (g group) and 50 mg/kg of pistachio oil (h group) orally by gavage for 30 days. at the end of the treatment period, the animals were anesthetized with ketamine (70 mg/kg) and xylazine (10 mg/kg) mixture. then, rats were killed by cervical dislocation and testicular tissues were used for the histological analysis. hormones and biochemical assays enzyme immunoassay test for serum testosterone, fsh and lh were performed according to manufacturer instructions. testosterone, fsh and lh were determined by using kits purchased from accubind elisa kit, monobind, usa. histological analysis for histological investigations, testes were quickly dissected and weighed immediately after killing the rats, then divided into small pieces and placed in 10% paraformaldehyde (ph = (7.2) for 72 h for fixation. for each group, testis tissue samples of four rats were selected table 3. the mean serum testosterone, fsh and lh levels in different treated groups and control after treatment. parametersa testosterone (ng/ml) fsh (mlu/dl) lh (mlu/dl) groups control (a group) 1.53 ± 0.08c 0.05 ± 0.003a 0.42 ± 0.04a (b group) 0.73 ± 0.05e 0.06 ± 0.008a 0.39 ± 0.02a (c group) 0.68 ± 0.06e 0.07 ± 0.005a 0.44 ± 0.05a (d group) 1.93 ± 0.04b 0.05 ± 0.006a 0.36 ± 0.02a (e group) 1.41 ± 0.7d 0.08 ± 0.009a 0.34 ± 0.01a (f group) 1.45 ± 0.09d 0.06 ± 0.004a 0.45 ± 0.07a (g group) 1.51 ± 0.08c 0.05 ± 0.001a 0.40 ± 0.08a (h group) 2.12 ± 0.12a 0.07 ± 0.002a 0.97 ± 0.02b p-value(kruskal-wallis) .002 p-value(post hoc) <.001 control group (a), and seven test groups (b to h) were treated orally by gavage for a period of 30 days. test groups received 10 mg/kg of phytosterols (b group), 50 mg/kg of phytosterols (c group), 10 mg/kg of fatty acids (d group), 50 mg/kg of fatty acids (e group), 5 mg/ kg of fatty acids plus 5 mg/kg of phytosterols (f group), 25 mg/kg of fatty acids plus 25 mg/kg of phytosterols (g group) and 50 mg/kg of pistachio oil (h group). mean values in a column followed by different letters are significantly different (p < 0.05) adata are presented as mean ± sd the effect of pistachio oil on spermatogenesis-falahatipur et al. vol 18 no 6 november-december 2021 138 randomly, then ten tissue samples were selected from each testis by a systematic random sampling protocol. tissue samples were directly dehydrated in a graded series of ethanol, cleared in xylen, impregnated in paraffin wax and embedded in paraffin block. from each sample, thin sections with a thickness of 5 μm were prepared by a rotary microtome machine, and finally 5 sections were randomly selected from each sample using the systematic uniform random sampling. all collected sections on slides were stained with hematoxylin-eosin (h & e) and were observed under an optical microscope (e-200, nikon, japan). then the microscopic fields of the slides were photographed randomly with a nikon camera and the images were transferred to a computer and analyzed with image tool software. the number of sertoli, spermatogonia, spermatocyte, spermatide cells as well as epithelial thickness and seminiferous tube diameter were determined with image tool software and statistically compared in all studied groups. statistical analysis normality of the data was tested by kolmogorov-smirnov method. results are expressed as mean ± sd. the difference between groups was compared using one-way anova. also, post hoc approach was used to compare groups with control. if significant difference was detected, multiple comparisons were made using the tukey-hsd (α = 0.05). all the statistical analyses were carried out using the spss.26 software. a p-value below 0.05 was considered statistically significant. results this study has attempted to investigate the effect of pistachio (pistacia vera) oil with phytosterols and fatty acids extracted from it on spermatogenesis and testis histological changes in wistar male rats and possibly to predict any benefits or harms of these compounds on fertility. body and testis weight the effects of pistachio oil with phytosterols and fatty acids extracted from it were investigated on body weight in male wistar rats. the mean body weights of mice in all test groups increased but no observed significant change before and after 30 days’ of treatment (p = .999 and p = .221, respectively). also, the results of the present study revealed that the body weight in all test groups no had significant value in comparison to the control group (p = .276 and p = 1, respectively) (table 1). the oral administration of phytosterols and fatty acids extracted from pistachio oil resulted in an increase in testis weight in the f group that the rats received 5 mg/ kg phytosterol + 5 mg/kg fatty acid, but this increase is not significant compared to the control group (p = .119). in addition, the ratio of testis weight to body weight in test groups showed no significant difference in comparison to the control group (p = .815) (table 2). an increase in the testis weight is related to the number of spermatids and sperm present in the tissue. serum lh, fsh and testosterone levels administration of pistachio oil, phytosterols and fatty acids in different concentrations for 30 days had no significant effect on serum level of fsh hormone in wistar male rats(p = .06). but the serum level of testosterone was decreased significantly (p = .002) in rats who received phytosterols in 10 mg/kg and 50 mg/kg concentrations (b and c groups, respectively) compared to the control group (p = 0). also, the serum level of this hormone was increased in d and h groups including rats receiving 10 mg/kg of fatty acids and 50 mg/kg of pistachio oil, in comparison to the control, respectively (p = 0). the serum level of lh was unchanged between all test groups and the control group except for the h group that increased after treatment with 50 mg/kg of pistachio oil (p = .04) (table 3). histological examinations figure 1 shows the tissue sections in all groups under study. according to the results of the histological examination of testes in all groups of study, the mean number of sertoli cells was not significantly changed in all treated groups compared to control group (figure 2). the epithelial layer thickness in all experimental groups figure 4. the diameter of seminiferous tubules of mice fed on different concentrations of phytosterols and fatty acids of pistachio oil data are presented as mean ± sd. bars with same superscript letters are not significantly different whereas those with different superscript letters are significantly different (p < 0.05). the effect of pistachio oil on spermatogenesis-falahatipur et al. vol 18 no 6 november-december 2021 687 was significantly different from the control group (p = 0). according to the results of the present study, the epithelial layer thickness was significantly decreased in b, e and g groups that received 10 mg/kg of phytosterols, 50 mg/kg of fatty acids and 25 mg/kg of fatty acids plus 25 mg/kg of phytosterols, respectively. while the epithelial layer thickness in c, d, f and h groups that received 50 mg/kg of phytosterols, 10 mg/kg of fatty acids, 5 mg/kg of fatty acids plus 5 mg/kg of phytosterols and 50 mg/kg of pistachio oil, respectively were significantly increased compared to the control group (figure 3). the diameter of seminiferous tubules was significantly decreased in the g group while in other groups it did not significantly change (figure 4). the morphological findings of the study and the spermatogonia count that used tissue sections as well as the comparison between the mean number of spermatogonia showed that there was a significant difference in spermatogonia number, between all test groups and the control group except for the b group that remained unchanged after treatment with 10 mg/kg of phytosterols. so that the number of spermatogonia was significantly decreased in the c group that received 50 mg/kg of phytosterols, while the number of spermatogonia in d, e, f, g and h groups that received 10 mg/kg of fatty acids, 50 mg.kg fatty acids, 5 mg/kg of fatty acids plus 5 mg/kg of phytosterols, 25 mg/kg of fatty acids plus 25 mg/kg of phytosterols and 50 mg/kg of pistachio oil, respectively, were significantly increased compared to control group (figure 5a). the number of spermatids was significantly decreased in b, c, e and g groups that received 10 mg/kg of phytosterols, 50 mg/kg of phytosterols, 50 mg/kg of fatty acids and 25 mg/kg of fatty acids plus 25 mg/kg of phytosterols, respectively. while the number of spermatid in d, f and h groups that received 10 mg/kg of fatty acids, 5 mg/kg of fatty acids plus 5 mg/kg of phytosterols and 50 mg/kg of pistachio oil, respectively were significantly increased compared to control group (figure 5b). discussion pistacia, a genus of flowering plants from the family anacardiaceae, contains about twenty species, among them five are more commonly recognized, including p. vera, p. atlantica, p. terebinthus, p. khinjuk, and p. lentiscus. different parts of pistacia species have been used in traditional medicine for various aims like aphrodisiac(13). various types of phytochemical constituents like terpenoids, phenolic compounds, fatty acids, and sterols have also been isolated and identified from different parts of pistacia species(13). pistacia species have oleaginous fruits considered by several researchers. the oil content in p. vera kernel is about 50–60% (14,15). the main fatty acid in kernel of p. vera is oleic acid(16,17). other fatty acids identified in these species are linolenic, palmitic, palmitoleic, stearic, myristic, eicosanoic, behenic, lignoceric, arachidonic, pentadecanoic, hexadecanoic, octadecanoic, and margaric acid(14). the most abundant sterol reported in fruits of p. vera is β-sitosterol followed by δ5-avenasterol, campesterol and stigmasterol(15). the present study aimed to investigate the effect of the extracted phytosterols and fatty acids from pistachio (pistacia vera var. akbari) oil on spermatogenesis and changes in testicular tissue in adult male wistar rats and also possibly to predict any benefits or harms of these compounds on fertility. in the f group that the rats received 5 mg/kg phytosterols + 5 mg/kg fatty acids, the thickness of epithelium layer and also the amount of spermatid and spermatogonia increased. in general, spermatogenesis process improved. in contrast, in the g group that the rats received 25 mg/kg phytosterol+ 25 mg/kg fatty acid, the thickness of the epithelium layer decreased, the diameter of tubules decreased and despite increased spermatogonia cells, the number of spermatids was decreased, resulting in a general decrease in spermatogenesis process. in the h group that received pistachio oil, the thickness of the epithelium layer, the number of spermatogonia and spermatids and the overall spermatogenesis process increased. figure 5. the number of spermatogonia (a) and spermatid (b) of mice fed on different concentrationw of phytosterols and fatty acids of pistachio oil, respectively. data are presented as mean ± sd. bars with same superscript letters are not significantly different whereas those with different superscript letters are significantly different (p < 0.05). the effect of pistachio oil on spermatogenesis-falahatipur et al. vol 18 no 6 november-december 2021 138 phytosterols extracted from pistachio oil decrease the cholesterol desmolase c activity by reducing the conversion of cholesterol to bergenolone in mitochondria, thereby reducing the synthesis of steroids including testosterone. all phytosterols have anti-androgenic effects and decrease tissue sensitivity to androgens, besides, androgen activity is decreased by inhibiting 5-alpha reductase inhibition of this enzyme reduces the conversion of testosterone to dihydrotestosterone, an active form of this hormone in tissues(18). in addition, phytosterols can treat benign prostatic hyperplasia (bph) in the prostate by reducing testosterone and dihydrotestosterone levels. phytosterols also decrease the level of steroid hormones such as testosterone by lowering cholesterol levels(19). compounds in pistachio oils such as zinc and linoleic acid can inhibit nitric oxide production. these compounds can inhibit steroidogenesis, so pistachio oil probably increases steroidogenic function in leydig cells through inhibition of the synthesis of nitric oxide and consequently increases the concentration of testosterone(7). in conclusion, the results of this study suggest that phytosterols in doses 10 and 50 mg/kg reduce spermatogenesis process. fatty acid in a low dose of 10 mg/ kg increases spermatogenesis process, but when a high dose of 50 mg/kg was used, it had a negative effect on spermatogenesis process. when low levels of phytosterols and fatty acids are used simultaneously in dose 5 mg/kg, improvement in spermatogenesis process is observed but when these were used together in high dose of 25 mg/kg, the spermatogenesis process was disrupted. using pistachio oil alone also improved spermatogenesis process. it seems that phytosterols reduce spermatogenesis process and fatty acids increase spermatogenesis when used in low doses and reduce this process when used in high doses. acknowledgements authors would like to thank pistachio safety research center, rafsanjan university of medical sciences, rafsanjan, iran for their warm cooperation. this study was financially supported by rafsanjan university of medical sciences, rafsanjan, iran, under the ethical code of ir.rums.rec.1396.98 at rafsanjan university of medical sciences. conflict of interest the authors report no conflict of interest. references 1. krausz c, forti g. clinical aspects of male infertility. in the genetic basis of male infertility, 2000. pp. 1-21: springer. 2. bansal ak, cheema rs. role of life style factors in male reproductive functions: a review. theriogenology insight-an international journal of reproduction in all animals. 2019: 9: 111-116. 3. hu fb, stampfer mj, manson je et al. frequent nut consumption and risk of coronary heart disease in women: prospective cohort study. bmj. 1998; 317: 1341-1345. 4. grundy sm, florentin l, nix d et al. comparison of monounsaturated fatty acids and carbohydrates for reducing raised levels of plasma cholesterol in man. am j clin nutr. 1988; 47: 965-969. 5. abdolshahi a, mortazavi s, naibandi s et al. effect of solvent and extraction techniques on the fatty acid composition of pistachio oil. iran food sci technol j 2014; 10. 6. ozrenk k, javidipour i, yarilgac t et al. fatty acids, tocopherols, selenium and total carotene of pistachios (p. vera l.) from diyarbakir (southeastern turkey) and walnuts (j. regia l.) from erzincan (eastern turkey). food sci technol int . 2012; 18: 55-62. 7. maran r, arunakaran j, aruldhas m. prolactin and leydig cells: biphasic effects of prolactin on lh‐, t3‐and gh‐induced testosterone/ oestradiol secretion by leydig cells in pubertal rats. int j androl. 2001; 4: 48-55. 8. clinton sk, mulloy al, li sp et al. dietary fat and protein intake differ in modulation of prostate tumor growth, prolactin secretion and metabolism, and prostate gland prolactin binding capacity in rats. j nutr. 1997; 127: 225-237. 9. abe m, ito y, oyunzul l et al. pharmacologically relevant receptor binding characteristics and 5α-reductase inhibitory activity of free fatty acids contained in saw palmetto extract. biol. pharm. bull. 2009; 32: 646-650. 10. yahyavi f, alizadeh-khaledabad m, azadmard-damirchi s. oil quality of pistachios (pistacia vera l.) grown in east azarbaijan, iran. nfs journal. 2020; 18: 1218. 11. abidi s, list g, rennick k. effect of genetic modification on the distribution of minor constituents in canola oil. jaocs. 1999; 7: 463-467. 12. ryan e, galvin k, o'connor t et al. fatty acid profile, tocopherol, squalene and phytosterol content of brazil, pecan, pine, pistachio and cashew nuts. int j food sci nutr. 2006; 57: 219-228. 13. bozorgi m, memariani z, mobli m et al. five pistacia species (p. vera, p. atlantica, p. terebinthus, p. khinjuk, and p. lentiscus): a review of their traditional uses, phytochemistry, and pharmacology. sci world j. 2013. 14. satil f, azcan n, baser k. fatty acid composition of pistachio nuts in turkey. chem. nat. compd. 2003; 39: 322-324. 15. arena e, campisi s, fallico b et al. distribution of fatty acids and phytosterols as a criterion to discriminate geographic origin of pistachio seeds. food chem. 2007; 104: 403408. 16. phillips km, ruggio dm, ashraf-khorassani m. phytosterol composition of nuts and seeds commonly consumed in the united states. j agric food chem. 2005; 53: 9436-9445. 17. aslan m, orhan i, şener b. comparison of the seed oils of pistacia vera l. of different origins with respect to fatty acids. int j food sci technol. 2002; 37: 333-335. 18. prager n, bickett k, french n et al. a randomized, double-blind, placebo-controlled the effect of pistachio oil on spermatogenesis-falahatipur et al. trial to determine the effectiveness of botanically derived inhibitors of 5-α-reductase in the treatment of androgenetic alopecia. j altern complement med. 2002; 8: 143-152. 19. ottestad i, ose l, wennersberg mh et al. phytosterol capsules and serum cholesterol in hypercholesterolemia: a randomized controlled trial. atherosclerosis. 2013; 228: 421-425. the effect of pistachio oil on spermatogenesis-falahatipur et al. case report does renal mass with venous thrombosis always indicate renal cell carcinoma? a case series hamidreza ghorbani1, mehdi farzadnia2, alireza golshan1* intravascular tumor extension in the major renal veins or their tributaries, as a rare but important clinical entity that can change the disease stage, prognosis, and approach to treatment. there is limited literature on the obstruction of renal vein and ivc by tumor thrombus in other types of renal tumors that are not of rcc type. we presented four different renal tumor cases with the presence of gross renal vein or ivc thrombosis. although the incidence of renal vein and ivc tumor thrombus might be suggestive of (often diagnosed as) rcc, the possibility of other non-rcc renal tumors should be included in the differential diagnosis. keywords: nephrectomy; renal cell carcinoma; thrombus; venous thrombosis/surgery 1kidney transplantation complications research center, mashhad university of medical sciences, mashhad, iran 2cancer molecular pathology research center, mashhad university of medical sciences, mashhad, iran. *correspondence: kidney transplantation complications research center, mashhad university of medical sciences, mashhad/ iran. e mail: golshanalirezag@gmail.com. received october 2021 & accepted september 2022 introduction renal vein tumor thrombosis describes the presence of intravascular tumor extension in the major renal veins or their tributaries, as a rare but important clinical entity that can change the disease stage, prognosis, and approach to treatment (1,2). various symptoms such as flank pain, flank tenderness, microscopic or gross hematuria, varicocele, lower extremity swelling, deterioration of renal function, proteinuria, and pulmonary embolism have been reported for tumor thrombus; however, most patients with tumor thrombus are asymptomatic(3,4). imaging modalities, such as ultrasonography, magnetic resonance imaging (mri), and computed tomography (ct) are the most accurate tools for detecting the presence of tumor thrombosis, evaluating the extension of the tumor, and differentiating it from the bland thrombus. however, differentiation and diagnosis of the exact type of renal tumors with tumor thrombosis might be challenging or might lead to misdiagnosis(5,6). histopathological evaluations and immunohistochemistry (ihc) are useful for the final diagnosis of the tumor type, and surgery is known as the primary potential treatment for renal vein tumor thrombosis in the absence of lymph node involvement and distant metastasis(7). the propagation of tumor thrombus into the renal vein or the inferior vena cava (ivc) is a well-known manifestation of malignancies, including primary renal cell carcinoma (rcc), wilms tumor, adrenal cortical carcinoma (acc), and hepatocellular carcinoma (hcc)(8,9). however, there is limited literature on the obstruction of renal vein and ivc by tumor thrombus in other types of renal tumors that are not of rcc type. in this study, we presented four different renal tumor cases, including oncocytoma, leiomyosarcoma, urothelial carcinoma and primitive neuroectodermal tumor (pnet), with the presence of gross renal vein or ivc thrombosis. figure 1(a): right renal mass with vein thrombosis.1(b) oncocytoma: polygonal neoplastic large cells with eosinophilic granular cytoplasm (h & e stained). urology journal/vol 19 no. 6/ november-december 2022/ pp. 466-471. [doi:10.22037/uj.v19i.7025] case presentation patient 1 a 61-year-old woman with right side flank pain, pallor, and no previous/familial medical history was referred to the urology ward. on clinical examination, vital signs were stable; the abdomen was fine and had no palpable mass or organomegaly. laboratory studies showed normal renal and liver function tests and hemoglobin 12.3 g/dl (normal range 12-15.5). urine analysis did not reveal hematuria and pyuria. ultrasonography (us) imaging revealed a large heteroechoic solid mass involving the right kidney, and the left kidney was normal. contrast-enhanced ct scan showed a 10×11.5×13 cm heterogeneously enhancing lesion arising from the figure 2(a).mri: tumor thrombus extended ivc near the atrium. 2(b) renal leiomyosarcoma: spindle-shaped cells with atypical large pleomorphic nucleus (h & e stained). figure 3(a). ct scan: multiple cysts on both kidneys and heteroechoeic solid mass in right kidney. 3(b) ct scan: left renal mass, renal vein thrombosis with extension to ivc. 3(c) high grade urothelial carcinoma (h&e stained). renal mass with venous thrombosis-ghorbani et al. case report 467 upper pole of the right kidney with a central scar, and revealed the presence of a tumor thrombus in the right renal vein with extension into the ivc. according to the mayo clinic grading system, tumor thrombus level 1 (figure1a), the existing symptoms and paraclinical test results were suggestive of renal cell carcinoma. the patient underwent open radical nephrectomy via an anterior subcostal incision providing exposure for tumor thrombectomy. after the exposure of the renal veins, it was possible to gently palpate the tumor in the right renal vein and adjacent ivc. nephrectomy was performed following the early ligation of the renal artery. the tumor thrombus was extracted after local control of the ivc and renal vein with a patch of ivc resected. once the kidney and the thrombosis were removed, closure of cavotomy was done with 5-0 prolene running suture. in microscopic evaluations, well circumscribed lesion with polygonal neoplastic large cells with eosinophilic granular cytoplasm, round vesicular nuclei (sometimes double nuclei) without prominent mitosis, necrosis, or sarcomatoid component in the background of hyalinized stroma were observed. ihc analyses were performed and data were consistent with the diagnosis of oncocytoma (figure1b). patient 2 a 38-year-old woman was referred with right side flank pain, weakness, lethargy, and a history of hypertension. on clinical examination, she was pale with slight lower extremities pitting edema, the vital signs were stable, and the abdomen was soft with no organomegaly. on laboratory examinations, the urine, renal, and liver function tests were in the normal range. the hematocrit was 31.8%, and hemoglobin was 9.8 g/dl (normal range 12-15.5). based on the results of us and ct, both kidneys contained multiple cysts; however, the right kidney was enlarged and had a heteroechoic solid mass measuring 9×4×8 cm arising from the upper pole. a large tumor thrombus extended into the renal vein and ivc up to the hepatic vein and near the atrium, ivc tumor thrombus level 4. mri confirmed the results, and the clinical diagnosis was rcc (figure 2a). the patient was a candidate for open right radical nephrectomy, adrenalectomy, and thrombectomy, in the open heart surgery operation room. following the general anesthesia, the patient underwent a midline incision. after renal artery ligation, thoracotomy was performed. cardiopulmonary bypass and total circulating arrest were performed. by controlling the ivc, the tumor thrombus that was extended near the right atrium completely resected through the longitudinal cavotomy, renal vein was resected. nephrectomy and adrenalectomy were done and ivc was repaired and the patient was off pump. in microscopic evaluations, a homogenous mass consisted of spindle-shaped cells with atypical large pleomorphic nucleus and acidophilic cytoplasm with highly mitotic rate and focal necrosis. degenerative vascular wall changes were present without tumoral involvement. remnant of adrenal tissue was seen adjacent to the tumor. based on histopathological and ihc findings, the final diagnosis was renal leiomyosarcoma (figure 2b). patient 3 a 69-year-old non-smoking man referred to the urology ward with microscopic (mic) hematuria (rbc 10-12). ct scan revealed a heterodense solid mass in the upper pole of the right kidney. there were multiple cysts with bosniak i on both kidneys; however, only one bosniak iif cyst was observed in the left kidney (figure 3a). he underwent a radical nephrectomy of the right side kidney. the histopathological diagnosis was clear cell rcc grade ii (t1b n0m0). six months after nephrectomy, liver and renal function tests were in normal limit, but urine analysis revealed microscopic hematuria (rbc 15-16). the us and ct revealed the presence of a solid mass in the left kidney, which corresponded with the left renal cyst with bosniak iif in the first imaging finding. there was also renal vein thrombosis with extension to ivc, ivc tumor thrombus level 1 (figure 3b). there were no signs of tumor metastasis. the preoperative diagnosis was rcc, and the patient was again a candidate for nephrectomy. under general anesthesia and midline incision, the left renal vein was exposed. the left renal artery was ligated, and the ivc was controlled proximally and distally. the renal vein tumor thrombus of renal vein was totally resected with an ivc patch. the ivc was repaired with prolene 5/0. figure 4(a) ct scan: solid mass in the left kidney. 4(b) pnet: intrarenal tumor consists of solid sheets with intervening fibrous strands (h&e), 4(c): calretinin renal mass with venous thrombosis-ghorbani et al. vol 19 no 6 november-december 2022 468 histopatholgical evaluations showed a cystic beige-colored mass with extensive necrosis. the neoplastic proliferation of elongated cells with nucleated nuclei, acidophil cytoplasm, and papillary pattern, extended to the connective tissue, sinus fat, and renal vein wall invasion were apparent. based on the morphologic findings, the diagnosis was high-grade urothelial carcinoma in the renal pyelocaliceal system and renal vein tumor thrombosis (figure 3c). patient 4 a 14-year-old girl referred to the urology ward because of chronic flank pain in the left side. clinical examination revealed a huge, mobile mass in the left upper quadrant of abdomen. there were no other signs and symptoms. a spiral ct scan with oral and intravenous contrast also showed a huge solid mass (158*92*83 mm) in the left kidney with renal vein thrombosis (figure4a). color doppler ultrasonography revealed high resistance of renal vessel flow in the left main renal vein suggesting venous thrombosis (ivc tumor thrombus level 1). hrct of thorax showed multiple sub-pleural nodules in both lungs, which was suggestive of metastases. the patient underwent laparotomy. the left renal artery was dissected and meticulously separated from renal vein and ligatured, and then the left radical nephrectomy was completed with renal vein and ivc patch resection. histopathologic examination showed sheets of small blue round cells with round nuclei, fine chromatin, and scant clear to slightly eosinophilic cytoplasm with numerous mitotic figures. immunostaining for myogenin, desmin, cd45, and other lymphoid markers were negative; however, strong immunoreactivity for cd99 (o13, mic2) was seen (figure 4(b,c). these data are consistent with the diagnosis of pnet. discussion the tendency of some tumor cells to spread to the venous system and ivc is not well understood. tumor thrombus of the renal vein and ivc is not frequently observed in kidney tumors; however, almost 4% to 10% of the rccs reveal renal vein thrombus, which is rarely seen in non-rcc renal tumors(10). the incidence of tumor thrombus can affect the staging of cancer and change the treatment strategy. in some cases, thrombosis of the renal vein has non-specific symptoms and clinical manifestation to be diagnosed early and might be detected following the presence of severe complications. there is no specific laboratory test for detecting renal vein thrombus, and imaging is the primary diagnostic tool. from march 2015 until january 2020, 572 patients with renal mass underwent open and laparoscopic nephrectomy surgeries. of these, about 18 patients were diagnosed with venous thrombosis before surgery and underwent open radical nephrectomy and thrombectomy. we presented four different rare tumors with renal and ivc tumor thrombosis including oncocytoma and renal urothelial carcinoma, leiomyosarcoma and pnet. the presented cases did not have any significant changes in laboratory findings; only one patient with urothelial carcinoma had microscopic hematuria in laboratory results. we performed different imaging modalities such as us, ct, and mri for the four cases. the imaging techniques are noninvasive approaches with 100% sensitivity and specificity in detecting the incidence of the renal vein or ivc tumor thrombosis and clarifying the extent of the thrombus; however, they were not able to distinguish the exact kidney tumor type in any of the cases, and several histopathological evaluations were required. in all four cases, imaging findings revealed a hyper-echoic kidney mass characterized as the early phase of the renal vein thrombosis in 90% of the reported cases(11). renal oncocytoma accounts for 3%-7% of kidney tumors and is a common benign renal epithelial neoplasm; however, huge oncocytoma with thrombus increases the risk of hematogenous metastasis(12). based on the larger studies on oncocytoma, the incidence of renal vein thrombosis is less than 2% in these cases. in the study of wobker et al., grossly visible tumor thrombus was reported in only two of the twenty-two oncocytoma, and the diagnosis was made only by h&e staining alone, not the ihc(14). in the study of hess et al., among the 324 patients diagnosed with oncocytoma from 1977 to 1990, tumor extension to vascular structures was grossly suspected in only five patients (1.5%). in all their patients, the final diagnosis was made following the histopathological analysis with a panel of immunochemical stains(13). similar to our patient, other presented cases of oncocytoma associated with renal vein thrombus had difficulties in distinguishing large oncocytomas from rcc via imaging modalities(12,14,15). based on the literature, oncocytic papillary rcc (prcc), succinate dehydrogenase (sdh)-deficient rcc, eosinophilic, solid and cystic rcc (e sc rcc, and eosinophilic variant of chrcc might be the differential diagnosis of oncocytoma(16). primary renal sarcomas are aggressive sarcomas with poor prognosis. they constitute lower than 1% of kidney malignancies; however, renal leiomyosarcomas as the most common type, account for almost 50% of all the renal sarcomas(17). renal leiomyosarcoma is more common in women than men, with increased risk by age. renal leiomyosarcoma patients have clinical presentations similar to the rccs, including flank pain, hematuria, and abdominal mass; therefore, the exact diagnosis is usually based on histopathological examination and ihc(18). leiomyosarcoma should be differentiated from the sarcomatoid variant of renal cell carcinoma, leiomyoma, and epithelioid angiomyolipoma following histological evaluations(15). the origin of the lesions in our cases was from intrarenal blood vessels with the highest diameter of 7 cm. the presence of renal vein and ivc thrombosis is rarely reported in cases with leiomyosarcoma of renal origin. in two similar case reports, the renal vein thrombosis was observed in cases with renal leiomyosarcoma, and the differential diagnosis was malignant renal mass, likely rcc, by imaging evaluations(19,20). renal urothelial cell carcinoma (uc) accounts for lower than 10% of the renal carcinomas, which is usually symptomatic. the incidence of renal vein and ivc tumor thrombus in uc is almost 4%-7%(21). there is little evidence regarding the macroscopic renal vein thrombus in uc of the kidney with a low number of reported cases. our case also had persistent microscopic hematuria, no lower extremity edema, and the history of right radical nephrectomy due to clear cell renal carcinoma. in renal mass with venous thrombosis-ghorbani et al. case report 469 this case, the presence of uc arising from renal calyceal with extensions to the renal vein was misdiagnosed as rcc in the preoperative differential diagnosis through imaging techniques of us and ct. in a series of 102 patients from 1990 to 2010 with renal tcc, only five patients revealed venous tumor thrombus (two had ivc involvement) with no gross hematuria(22). performing ct, mri, and contrast-enhanced ultrasonography are accurate in detecting the tumor thrombus and estimating the size and position of the tumor thrombosis (23, 24). similar to previous reports, we performed nephrectomy with thrombectomy as the primary surgery strategy in the treatment of uc with renal vein tumor thrombus. in one similar study, the presence of infiltrative renal mass with venous involvement and maintaining the reniform shape of the kidney were proposed as possible indications of the tcc(25). peripheral neuroectodermal tumor (pnet) is a rare clinical condition and poorly differentiated neoplasm with neuroectodermal origin, first described in the 1990’s. since then, most features of this neoplasm have been presented through case reports, and there are few original articles in this context(26,27). based on the literature reviewed, fewer than 100 cases of pnet of kidney have been reported to date. however, the presence of venous thrombosis is not very common in this rare condition. this neoplasm mostly occurs in young males aged between 13 and 18 years(26,28). final diagnosis of renal pnet, confirmed by histopathological and immunohistochemical studies of the nephrectomy specimen reveal a small blue round cell tumor with diffuse membranous positivity for cd99(29). the differential diagnosis of renal small round blue cell tumor includes neuroblastoma, alveolar rhabdomyosarcoma, lymphoblastic lymphoma, and blastemal wilm’s tumor(30). these tumors are high grade and their characterization without immunohistochemistry is often difficult. therefore, immunohistochemical examination is necessary for the diagnosis of these tumors(31). conclusions although the incidence of renal vein and ivc tumor thrombus might be suggestive of (often diagnosed as) rcc, the possibility of other non-rcc renal tumors should be included in the differential diagnosis. more precise preoperative and intraoperative evaluations are needed to lead to correct diagnosis and decision making for effective treatment. conflict of interest the authors report no conflict of interest. references 1. tsuji y, goto a, hara i, et al. renal cell carcinoma with extension of tumor thrombus into the vena cava: surgical strategy and prognosis. j vasc surg. 2001;33:789-796. 2. asghar m, ahmed k, shah ss, et al. renal vein thrombosis. eur j vasc endovasc surg. 2007;34:217-223. 3. llach f, papper s, massry sg. the clinical spectrum of renal vein thrombosis: acute and chronic. am j med. 1980;69:819-827. 4. wotkowicz c, wszolek mf, libertino ja. resection of renal tumors invading the vena cava. urol clin north am. 2008;35:657-671. 5. zhang l, yang g, shen w, et al. spectrum of the inferior vena cava: mdct findings. abdom imaging. 2007;32:495-503. 6. li q, wang z, ma x, et al. diagnostic accuracy of contrast-enhanced ultrasound for detecting bland thrombus from inferior vena cava tumor thrombus in patients with renal cell carcinoma. int braz j urol. 2020;46:92100. 7. vergho dc, loeser a, kocot a, et al. tumor thrombus of inferior vena cava in patients with renal cell carcinoma clinical and oncological outcome of 50 patients after surgery. bmc res notes. 2012;5:54-59 8. oltean ma, matuz r, sitar-taut a, et al. renal cell carcinoma with extensive tumor thrombus into the inferior vena cava and right atrium in a 70-year-old man. int braz j urol. 2019;13:159-79. 9. quencer kb, friedman t, sheth r, et al. tumor thrombus: incidence, imaging, prognosis and treatment. cardiovasc diagn ther. 2017;7:165-177. 10. uzzo rg, cherullo e, myles j, et al. renal cell carcinoma invading the urinary collecting system: implications for staging. j urol. 2002;167:2392-2396. 11. radermacher j.ultrasonography of the kidney and renal vessels. i. normal findings, inherited and parenchymal diseases. urologe a. 2005;44:1351-1363. 12. kondo h, okabe t, okada y, et al. a case of renal oncocytoma with renal venous tumor thrombus. the keio journal of medicine. 2018;68:39-41. 13. hes o, michal m, síma r, et al. renal oncocytoma with and without intravascular extension into the branches of renal vein have the same morphological, immunohistochemical and genetic features. virchows arch. 2008;452:285-293. 14. la rédaction là. oncocytome avec thrombus dans la veine rénale: à propos d’un cas. progrès en urologie. 2017;27:1-2. 15. weiss sw. smooth muscle tumors of soft tissue. adv anat pathol. 2002;9:351-359. 16. omiyale ao, carton j. renal oncocytoma with vascular and perinephric fat invasion. ther adv urol. 2019;11:178-188. 17. narula v, siraj f, bansal a. renal leiomyosarcoma with soft tissue metastasis: an unusual presentation. can urol assoc j. 2015;9:139-141. 18. dhawan s, chopra p, dhawan s. primary renal leiomyosarcoma: a diagnostic challenge. urology annals. 2012;4:48-50. 19. kundu r, chandra m, punia rs, et al. primary renal leiomyosarcoma arising from renal vein: a case report of rare entity with review of literature. indian j med paediatr oncol. 2019;40:139-141. 20. choudhury m, singh sk, pujani m, et al. a case of leiomyosarcoma of kidney clinically and radiologically misdiagnosed as renal cell renal mass with venous thrombosis-ghorbani et al. vol 19 no 6 november-december 2022 470 carcinoma. indian j cancer. 2009;46:241-243. 21. fernandez lopez-pelaez ms, garcia gomez jm, ortiz vico f, et al. tumor thrombosis of the left renal vein and inferior vena cava secondary to renal cell carcinoma. findings with ultrasonography, echo-doppler, and computerized tomography. actas urol esp. 2000;24:664-668. 22. huber j, teber d, hatiboglu g, et al. does a venous tumor thrombus exclude renal transitional cell carcinoma? implications for neo-adjuvant treatment strategies. anticancer res. 2014;34:1031-1035. 23. raza sa, sohaib sa, sahdev a, et al. centrally infiltrating renal masses on ct: differentiating intrarenal transitional cell carcinoma from centrally located renal cell carcinoma. ajr am j roentgenol. 2012;198:846-853. 24. bata p, tarnoki dl, tarnoki ad, et al. transitional cell and clear cell renal carcinoma: differentiation of distinct histological types with multiphase ct. acta radiol. 2014;55:1112-1119. 25. singh o, george ajp, singh jc, et al. transitional cell carcinoma of the renal pelvis with venous tumor thrombus. rev urol. 2017;19:145-148. 26. aghili m, rafiei e, mojahed m, zare m. renal primitive neuroectodermal tumor: does age at diagnosis impact outcomes?. rare tumors. 2012;4:15-16. 27. torga g, barrow w, han m. rare renal incidentaloma in pregnancy: an unusual primitive neuroectodermal tumor presentation. urol case rep. 2015;3:12–14. 28. rodriguez-galindo c, marina nm, fletcher bd, parham dm, bodner sm, meyer wh. is primitive neuroectodermal tumor of the kidney a distinct entity? cancer. 1997; 79:2243–50. 29. ellison da,parhamdm,bridge j, beckwith jb.immunohistochemistry of primary malignant neuroepithelial tumors of the kidney: a potential source of confusion?a study of 30 cases from the national wilms tumor study pathology center. hum pathol. 2007;38(2):205–11. 30. friedrichs n, vorreuther r, poremba c, schafer kl, bocking a, buettner r, et al. primitive neuroectodermal tumor (pnet) in the differential diagnosis of malignant kidney tumors. pathol res pract. 2002; 198(8):563–9. 31. thyavihally yb, tongaonkar hb, gupta s, kurkure pa, amare p, muckaden ma, et al. primitive neuroectodermal tumor of the kidney: a single institute series of 16 patients. urology. 2008; 71(2):292–6. renal mass with venous thrombosis-ghorbani et al. case report 471 v08_no_1_print_3.pdf laparoscopic urology 27urology journal vol 8 no 1 winter 2011 laparoscopic retroperitoneal lymph node dissection for stage i nonseminomatous germ cell testis tumors the first case series in iran seyed amir mohsen ziaee, ali tabibi, farzaneh sharifiaghdas, seyyed mohammad ghahestani, samad zare, mohammad samzadeh purpose: to report laparoscopic retroperitoneal lymph node dissection (rplnd) as an approach for management of low-stage nonseminomatous germ cell testis tumors (nsgct). materials and methods: between august 2002 and december 2008, 19 patients with stage i nsgct underwent rplnd in our center. results: mean operation time was 340 minutes (range, 250 to 360 minutes). procedure in 2 (10.5%) patients was converted to open. four (21%) patients had tumors with pure histopathology while other 15 (79%) had mixed histopathology. the mean number of removed lymph nodes was 11 (range, 6 to 14). pathology revealed lymph node involvement in 8 (42%) patients, including 6 (75%) viable tumors and 2 (25%) teratoma. after on average 47-month follow-up (range, 3 to 70 months), recurrence occurred in 2 (10.5%) patients, who underwent open retroperitoneal lymph node dissection after chemotherapy, and surgical pathology revealed teratoma in one and fibrotic tissue in another. no patient developed systematic metastasis during followup period. conclusion: our results show that compared with open surgery, rplnd has same oncologic outcome, but lower, and can be recommended for management of patients with low stage nsgct. urol j. 2011;8:27-30. www.uj.unrc.ir keywords: laparoscopy, nonseminomatous germ cell tumor, testis urology and nephrology research center, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran corresponding author: seyed amir mohsen ziaee, md urology and nephrology research center, no.103, 9th boustan st., pasdaran ave., tehran, iran tel: +98 21 2256 7222 fax: +98 21 2256 7282 e-mail:samziaee@hotmail.com.com received october 2009 accepted march 2010 introduction integration of medical and surgical approaches to cancer over the last three decades has made the management of the testis cancer effective.(1) effective chemotherapeutic regimens, refined minimally invasive surgery, and radiation therapy have increased the overall survival to more than 90% in patients with seminoma.(2) since the application of laparoscopic approach to retroperitoneal lymph node dissection (rplnd) in 1992, it has become more accessible and is currently suggested as a “gold standard” method for staging of nonseminomatous germ cell testis tumors (nsgct).(3) however, laparoscopic rplnd (lrplnd) as a surgical modality has met significant challenges and thus has not been widely accepted.(4) longer operation time and greater cost are among its drawbacks. it is also stated that oncologic results have not yet been proven by l-rplnd and dissection is not as complete laparoscopic rplnd in stage i nsgct—ziaee et al 28 urology journal vol 8 no 1 winter 2011 as the open approach.(5) on the other hand, l-rplnd not only decreases morbidity, hospital stay, and time to return to normal activity, but also has comparable outcome.(6) although many cases of l-rplnd have been reported in literature, but to the best of our knowledge, this is the first report from iran. materials and methods between august 2002 and december 2008, 19 l-rplnds were performed in our urology department. patients who selected surveillance or primary chemotherapy and those with general contraindications for laparoscopic surgery had been excluded. pre-operative clinical staging included tumor markers measurements, computed tomography scan of the chest and the abdomen, and chest x-ray. none of the patients had metastatic diseases. therefore, patients with clinical stage ti were candidate for l-rplnd. a modified approach was used, but in 4 (21%) subjects, surgery was converted to classic rplnd because of clearly visible intra-operative mass. patients were followed up for 47 months (range, 3 to 70 months). data regarding testis tumor characteristics, pre and postoperative serum levels of hemoglobin and creatinine, numbers and location of resected lymph nodes, operation time, hospital stay, conversion to open surgery, complications, and relapses were gathered. results mean operation time was 340 minutes (range, 250 to 360 minutes). procedure in 2 (10.5%) patients was converted to open; the first one was due to bleeding and the second one was due to severe adhesion of mass to the inferior vena cava. the primary tumor was on the right testis in 12 (63%) patients and on the left side in 7 (37%). considering primary tumor characteristics, 4 (21%) patients had tumors with pure histopathology while other 15 (79%) had mixed histopathology. primary testicular pathology after radical orchiectomy is depicted in table. accidental ureteral damage (transection) happened in 1 (5%) subject, which was repaired by end-to-end anastomosis laparoscopically without long-term complication. postoperatively, the mean hemoglobin drop and the mean creatinine raise were 0.47 mg/dl and 0.08 mg/dl, respectively. significant creatinine raise occurred in 1 patient (from 0.9 mg/dl pre-operatively to 1.7 mg/dl postoperatively). only 1 patient had a fever greater than 38°c, which improved after 4-day antimicrobial therapy. average hospital stay was 4.3 days (range, 3 to 6 days). the mean number of resected lymph nodes was 11 (range, 6 to 14). pathology revealed lymph node involvement in 8 (42%) patients; of which 6 (75%) were viable tumors and 2 (25%) eratoma. positive nodes were located in the left paraaortic, interaortocaval, and right paracaval region in 3 (37.5%), 2 (25%), and 3 (37.5%) patients, respectively. postoperative surgical staging revealed false negative computed tomography scan results in 2 (10.5%) patients. after on average 47-month follow-up (range, 3 to 70 months), there were 10.5% recurrences (2 patients). median relapse-free time was 26 months. they underwent open rplnd (o-rplnd) after chemotherapy, and surgical pathology revealed teratoma in one and fibrotic tissue in another. no patient developed systematic metastasis during follow-up period. discussion low stage nsgct is a highly curable neoplasm. the evolution of cancer control for this disease has found an effective integration of medical and surgical modalities over the last 3 decades.(7) management options for clinical stage i nsgct histopathology number(percent) group pure 2 (10.5%) 2 (10.5%) teratoma embryonal cell carcinoma mixed 15 (79%) embryonal cell carcinoma (64%) teratoma (32%) yolk sac (32%) seminoma (26.3%) choriocarcinoma (5.2%) endodermal sinus tumor (5.2%) histopathology of primary testis tumors laparoscopic rplnd in stage i nsgct—ziaee et al 29urology journal vol 8 no 1 winter 2011 include surveillance, modified rplnd, or two cycles of chemotherapy with bleomycin, etoposide, and cisplatin; the related recurrence rate is 25%, 10%, and 5%, respectively.(8) recent treatment of nsgct focuses on minimizing morbidity while maintaining consistently high cure rates as previously seen.(9) patients without evidence of lymphovascular invasion, embryonal carcinoma component predominance, or advanced pathologic stage (pt2 or greater) are at low risk for occult metastases and are good candidates for surveillance.(10) retroperitoneal lymph node dissection in experienced hands provides excellent results in patients who are not candidates for surveillance.(11) when performed perfectly, rplnd has 99.5% tumor survival for patients with clinical stage i or early stage ii and eliminates the relapse, which in turn provides psychological and emotional relief to the patient and simplifies the follow-up protocol.(12) although open rplnd remains the gold standard for pathologic staging of the retroperitoneum as well as an effective therapy for patients with minimal nodal involvement, but recently l-rplnd is also presented as an acceptable approach.(13) some studies have compared the safety and efficacy of laparoscopic versus open rplnd in patients with nsgct. castillo and colleagues performed l-rplnd on 111 patients with stage i nsgcts. mean operation time was 140 minutes (range, 60 to 300 minutes). conversion to open surgery occurred in 3 (2.7%) patients. mean hospital stay was 2 days (range, 1 to 5 days). intra-operative complications occurred in 10 (9%) subjects. five (4.5%) patients had tumor relapse, with a mean follow-up of 30 months (range, 24 to 94 months). recurrence occurred between 4 and 64 months postoperatively, and was in the retroperitoneum, the lungs, and the mediastinum.(10) based on their study, as the technique improves, it is likely that l-rplnd becomes equal if not more cost-effective than conventional rplnd. however, the oncologic outcomes, while are on a par with o-rplnds, are difficult to attribute to successful l-rplnd alone when nearly all patients with positive lymph nodes received chemotherapy postoperatively. although uncertainties exist, l-rplnd holds much future promise. poulakis and colleagues assessed the quality of life after laparoscopic and open rplnd in clinical stage i nsgct. they concluded that l-rplnd is a reasonable procedure with better postoperative quality of life and faster return to normal activity than o-rplnd for patients with clinical stage i nsgct .(11) in the literature, l-rplnd was converted to open surgery in 2% to 5% of subjects,(12) while it was 10.5% in our series. in our study, the mean operation time was 340 minutes (range, 250 to 360 minutes) that is relatively greater than other studies,(10,14) reflecting that we passed our learning curve. average hospital stay in our patients was 4.3 days (range, 3 to 6 days) that is compatible with other series.(10-12) it seems that our recurrence rate (10.5%) is relatively more than other studies,(10) which perhaps can be explained by our inexperience. the l-rplnd is associated with less blood loss and a shorter hospital stay than o-rplnd, whereas the lymph-node yield of o-rplnd is greater.(15) conclusion among 3 modalities for management of stage i nsgct, rplnd has an acceptable rate of recurrence in the retroperitoneum. our results show that l-rplnd has same oncologic outcome, but lower morbidity. therefore, it merits being an acceptable alternative to o-rplnd in experienced hands, and encourages young patients to choose it instead of primary chemotherapy or surveillance. conflict of interest none declared references 1. abdel-aziz kf, anderson jk, svatek r, margulis v, sagalowsky ai, cadeddu ja. laparoscopic and open retroperitoneal lymph-node dissection for clinical stage i nonseminomatous germ-cell testis tumors. j endourol. 2006;20:627-31. 2. albqami n, janetschek g. laparoscopic retroperitoneal lymph-node dissection in the management of clinical stage i and ii testicular cancer. j endourol. 2005;19:683-92; discussion 92. laparoscopic rplnd in stage i nsgct—ziaee et al 30 urology journal vol 8 no 1 winter 2011 3. corvin s, kuczyk m, anastasiadis a, stenzl a. laparoscopic retroperitoneal lymph node dissection for nonseminomatous testicular carcinoma. world j urol. 2004;22:33-6. 4. steiner h, peschel r, janetschek g, et al. longterm results of laparoscopic retroperitoneal lymph node dissection: a single-center 10-year experience. urology. 2004;63:550-5. 5. correa jj, politis c, rodriguez ar, pow-sang jm. laparoscopic retroperitoneal lymph node dissection in the management of testis cancer. cancer control. 2007;14:258-64. 6. hamilton rj, finelli a. laparoscopic retroperitoneal lymph node dissection for nonseminomatous germcell tumors: current status. urol clin north am. 2007;34:159-69; abstract viii. 7. yoon gh, stein jp, skinner dg. retroperitoneal lymph node dissection in the treatment of low-stage nonseminomatous germ cell tumors of the testicle: an update. urol oncol. 2005;23:168-77. 8. stephenson aj, sheinfeld j. management of patients with low-stage nonseminomatous germ cell testicular cancer. curr treat options oncol. 2005;6:367-77. 9. richie jp. open retroperitoneal lymph node dissection. can j urol. 2005;12 suppl 1:37-9. 10. castillo oa, alvarez jm, vitagliano g, ramirez d, diaz m, sanchez-salas r. [retroperitoneal laparoscopic lymphadenectomy for stage i non seminomatous testicular cancer]. arch esp urol. 2007;60:59-66. 11. poulakis v, skriapas k, de vries r, et al. quality of life after laparoscopic and open retroperitoneal lymph node dissection in clinical stage i nonseminomatous germ cell tumor: a comparison study. urology. 2006;68:154-60. 12. beltrami p, giusti g, tallarigo c, mofferdin a, mobilio g. [laparoscopic unilateral retroperitoneal lymphadenectomy in non-seminomatous neoplasms of the testis in clinical stage i]. arch ital urol androl. 1998;70:27-35. 13. nielsen me, lima g, schaeffer em, et al. oncologic efficacy of laparoscopic rplnd in treatment of clinical stage i nonseminomatous germ cell testicular cancer. urology. 2007;70:1168-72. 14. escalera almendros c, chiva robles v, pascual mateo c, rodriguez garcia n, garcia tello a, berenguer sanchez a. [post chemotherapy laparoscopic retroperitoneal lymph node dissection]. arch esp urol. 2006;59:517-23. 15. custureri f, urciuoli p, iavarone c, et al. laparoscopic retroperitoneal lymphadenectomy for stage i non-seminomatous testicular tumors. hepatogastroenterology. 2005;52:1677-80. defining the learning curve of flexible ureterorenoscopy and laser lithotripsy cem kezer1, faruk ozgor2* purpose: to investigate the impact of learning curve (lc) on flexible ureterorenoscopy (f-urs). materials and methods: patients who underwent kidney stone surgery in a urology clinic from a tertiary health care institution with f-urs were enrolled in the study. patient characteristics, the properties of kidney and kidney stones were recorded. also, f-urs-related parameters, hospitalization time, the success of the procedure, and complications were noted. patients were categorized equally into 4 groups, the first 20 f-urs cases in group 1, and the last 20 f-urs cases in group 4. groups were compared according to patient preoperative parameters, intraoperative outcomes, success rate and complication rate. results: time from the induction of anaesthesia to insertion of flexible ureterorenoscope was 18.6 min in group 1 and 17.2 min in group 2; then it significantly decreased to 15.0 min for cases 40 through 60 and 12.4 min for cases 60 through 80 (p = 0.001). operation time in group 3 and group 4 was significantly shorter than in group 1 and group 2 (p = 0.001). also, fluoroscopy time was significantly longer in group 1 (82.9 seconds) and reached a plateau in group 3 (50.3 seconds) and group 4 (41.7 seconds) (p = 0.001). additionally, after the 20th case, we achieved a significantly higher success rate in comparison to the first 20 cases (65% in group 1, 85% in group 2, 85% in group 3, and 90% in group 4, p = 0.001). conclusion: flexible ureterorenoscopy is a surgery that requires high technique and experience. the present study found that success of f-urs reached satisfactory levels after 20th cases. in addition, 40 cases may be enough for surgical proficiency regarding decreases in preparation time, operation time, and fluoroscopy time. keywords: flexible ureterorenoscopy; learning curve; lithotripsy; success introduction flexible ureterorenoscopy (f-urs) is an endoscopic surgery which is used in diagnosis and treatment of pathologies of the upper urinary system. although f-urs can be used for cancers and obstructions of the upper urinary tract, the main indication for f-urs is kidney stones(1). according to european urology association urolithiasis guidelines, f-urs is the preferred surgical method for kidney stones smaller than 20 mm, achieving higher stone free status compared to shock wave lithotripsy and associated with lower complication rates compared to percutaneous nephrolithotomy (pnl)(2). stone size, possible stone composition, anatomy of the kidney, clinician and patient preference are important factors in the choice of treatment(3). percutaneous nephrolithotomy is the gold standard treatment for kidney stones larger than 2 cm(4). for stones between 1-2 cm, all modalities may be appropriate, but the success of swl seems to be low for kidney lower pole stones(3). the learning curve (lc) is defined as the period and/ or number of operations an average surgeon requires in order to perform an operation with acceptable success and complication rates according to the literature(4). previous studies investigated the lc of different surgical procedures and studies stated that different surgical 1department of urology, erdem hospital, istanbul, turkey. 2department of urology, haseki training and research hospital, istanbul, turkey. *correspondence: haseki training and research hospital, millet street, istanbul, turkey. tel: +90 536 728 63 12. fax: +90 212 585 44 00. e-mail: md.farukozgor@gmail.com received august 2022 & accepted november 2022 procedures have unique learning curves. sahan and colleagues investigated the lc for supine mini pnl, and emphasized that surgeons achieved satisfactory success rate and complication rate after 45 mini pnl cases(6). in another study about lc in robotic-assisted laparoscopic retroperitoneal lymph node dissection, sophia et al. found significant decreases in complications and operation time after 44 cases(7). although previous reports analysed the lc of different stone surgery methods, no study has evaluated the lc for f-urs. this study is the first prospective research to investigate to lc for f-urs. materials and methods the present study was planned according to the principles of the helsinki declaration from july 2017 to july 2020. patients who underwent kidney stone surgery with f-urs were enrolled in the study. eighty patients were included in the study. all f-urs operations were done by one surgeon, who had experience of 250 ureterorenoscopy and 100 pnl cases. also, the surgeon observed 100 f-urs cases and participated in a 12-hour f-urs course including a simulation programme and dry laboratory. patients with kidney stone ≤ 20 mm were accepted as candidates for f-urs. patients with renal abnormalities, and with history of coagulopathy urology journal/vol 20 no. 1/ january-february 2023/ pp. 7-10. [doi: 10.22037/uj.v19i.7389] endourology and stone disease were excluded from the study. also, bilateral f-urs cases, patients < 18 years of age, patients with history of ureteral stenosis, and patients with positive urine culture operated under antibiotic regimen were excluded. patient characteristics and operative parameters were noted. f-urs-related parameters, hospitalization time, complications, and success were recorded. patients were categorized into four groups, as the first 20 f-urs cases in group 1, and the last 20 f-urs cases in group 4. groups were compared in regards of patient preoperative data, operative parameters, success rate, and complication rate. surgical technique under general anesthesia, a safety guide wire was inserted into renal pelvis. after, ureterorenoscopy was performed for direct visualisation of the ureter and passive dilatation of the ureter to facilitate insertion of the ureteral access sheath (11-13 fr diameter). fibre optic f-urs (storz flex-x2, tuttlingen, germany) was used and stone fragmentation was done with 200 or 273 μm laser fibre. stone retrieval was performed with nitinol baskets. at the end of the operation, 4.8 f jj stent was inserted under fluoroscopy guidance. the presence of any residual stone was evaluated by kidney-ureter-bladder (kub) graphy on the first day after the operation. final stone free status was assessed with non-contrast abdominal computed tomography in the third postoperative month. success was accepted as the absence of any stone. statistical analysis study sample size analysis was computed using the g*power (erdfelder, faul, & buchner, 1996) program. the study of jang et al. was used as a pilot study to calculate the sample size(8). to obtain a significance of α = 0.05, and 90% power (1-β = 0.9), the required sample size per group was at least 16. statistical analysis was done by using statistical package for the social sciences version 20 (spss ibm corp., armonk, ny, usa). the distribution of continuous variables was determined by shapiro–wilk test. one-way anova test was used for the comparison of continuous variables. levene’s test was performed to evaluate the homogeneity of variance. tukey test and games-howell test were used for post hoc analysis to compute pairwise comparisons. for categorical variables, chi square test was used for binary outcomes with large expected cell counts and fisher ́s exact test for small cell counts. the data were analysed at 95% confidence level and p value of less than 0.05 was accepted as statistically significant. results total 80 participants were divided into four groups and 14 patients were excluded (eight patients had jj stent, one patient had nephrostomy tube, two patients underwent bilateral f-urs operation, one patient had pelvic kidney, one patient was operated under antibiotic regimen and one patient was under 18 years of age). the mean age of participants was 44.6 ± 14.6 years, and 52 (65%) patients were male. the most common stone lolearning curve of flexible ureterorenoscopy-kezer et al. endourology and stones diseases 8 group 1 (n=20) group 2 (n=20) group 3 (n=20) group 4 (n=20) p value age (years)* 47.6 ± 13.8 46.7 ± 15.6 41.3 ± 13.6 42.6 ± 15.6 0.359 sex 0.988 male 12 (60%) 13 (65%) 14 (70%) 13 (65%) female 8 (40%) 7 (35%) 6 (30%) 7 (35%) bmi (kg/m²)* 28.3 ± 5.0 27.7 ± 5.5 27.1 ± 5.4 29.0 ± 5.3 0.692 asa score 0.920 asa 1 15 (75%) 13 (65%) 15 (75%) 15 (75%) asa 2-3 5 (25%) 7 (35%) 5 (25%) 5 (25%) history of previous stone surgery 4 (20%) 7 (35%) 3 (15%) 5 (25%) 0.565 stone opacity (non-opaque) 2 (10%) 1 (5%) 3 (15%) 0 (0%) 0.499 stone localization 0.365 upper 10 (50%) 6 (30%) 9 (45%) 6 (30%) pelvis 5 (25%) 9 (45%) 5 (25%) 9 (45%) lower 3 (15%) 2 (10%) 4 (20%) 2 (10%) multiple 2 (10%) 3 (15%) 2 (10%) 3 (15%) stone size (mm)* 12.8±4.4 11.8 ± 3.9 12.7 ± 3.6 12.6 ± 3.7 0.683 presence of hydronephrosis 12 (60%) 8 (40%) 10 (50%) 8 (40%) 0.576 operation side 0.872 right 13 (65%) 10 (50%) 11 (55%) 12 (60%) left 7 (35%) 10 (50%) 9 (45%) 8 (40%) table 2. comparison of preoperative demographic data between groups *mean ± standard deviation bmi: body mass index, asa: american society of anesthesiologists table 1. demographic and postoperative data of all patients. n = 80 age (years)* 44.6 ± 14.6 sex male 52 (65%) female 28 bmi (kg/m²)* 28.0 ± 5.2 asa score asa 1 58 (72.5%) asa 2-3 22 history of previous stone surgery 19 (23.7%) stone opacity (non-opaque) 6 (7.5%) stone localization upper 31 (38.7%) pelvis 28 (35.0%) lower 11 (13.8%) multiple 10 (12.5%) stone size (mm)* 12.5 ± 3.8 presence of hydronephrosis 38 (47.5%) operation side right 46 (57.5%) left 34 success 65 (81.2%) complications 6 (7.5%) minor (clavien-dindo grade 1-2) 5 (6.3%) major (clavien-dindo grade 3-5) 1 *mean ± standard deviation bmi: body mass index, asa: american society of anesthesiologists cation was upper calyx (31 patients, 38.7%), and ten patients had multiple renal stones. the mean stone size was 12.5 mm. overall success was 81.2% and complications occurred in six (7.5%) patients (table 1). age, sex, bmi, and asa score were comparable between all groups. also, operation side, stone size, stone location and stone opacity were not statically significant. comparison of pre-surgical parameters is summarized in table 2. time from the induction of anaesthesia to insertion of flexible ureterorenoscope was 18.6 min in group 1 and 17.2 min in group 2; then it decreased to 15.0 min for cases 40 through 60 and 12.4 min for cases 60 through 80 (p = 0.001). similarly, operation time progressively decreased (44.1 min, 38.7 min, 33.0 min, and 30.0, respectively) and operation time in group 3 and group 4 was significantly shorter (p = 0.001). also, fluoroscopy time was significantly longer in group 1 (82.9 ± 15.0 seconds) and reached a plateau in group 3 (50.3 ± 14.4 seconds) and group 4 (41.7 ± 16.4 seconds) (p = 0.001). additionally, after the 20th case, we achieved a significantly better success rate (65% in group 1, 85% in group 2, 85% in group 3, and 90% in group 4, p = 0.001). hospitalization time and complication rate were similar between the groups (p = 0.581 and p = 0.712) (table 3). discussion the learning curve is an entity to define the number of operations that a surgeon should do before reaching proficiency level. previous reports attempted to determine the lc for different procedures in urology practice(9,10), but no study evaluated the lc for f-urs yet. this study focused to determine lc of f-urs for the first time. our results showed that the success of f-urs reached a plateau after 20 cases. in addition, preparation time, operation time, and fluoroscopy duration were significantly decreased following 40 cases. the mean goal of kidney stone surgeries is to obtain stone free status without complications. stone-free rate following f-urs was reported to have a wide range, between 50% and 100% (11). although no study focused on the impact of lc on f-urs success, ziaee and colleagues investigated the number of cases required to complete the lc following pnl, and obtained sufficient stone free rates after 105 pnl operations(7). sahan et al. achieved a plateau for supine mini percutaneous nephrolithotomy stone free rates after the 45th case(6). in the present study, we achieved a satisfactory success rate after 20 f-urs cases. we believe that obtaining access to the stone is a more complicated process in percutaneous nephrolitotomy than gaining access to the kidney with flexible ureterorenoscope, which makes to lc of f-urs shorter. longer operation time is associated with anaesthetic complications, increased cost, morbidity, and even mortality. when beginning to perform a new surgical technique, unfamiliarity with surgical instruments, possible incompatibilities between the surgical team, and inability to make some decisions subcortically could make the operation time longer. tanrıverdi and colleagues found 144 minutes of mean operation time after the first 15 pnl cases, and their operation time decreased to 90 minutes between the 45th and 60th cases(12). moreover, sahan et al. faced significant decreases in supine mini pnl operation time from the 1st -15th patients to the 46th to 60th patients; however, the authors did not observe any reduction in operation time after 60 cases(6). we achieved significant reductions in preparation time and f-urs operation time after 30 cases. fluoroscopically-guided diagnostic and therapeutic processes began to be performed more commonly all over the world in recent decades. the harmful impact of fluoroscopy on cancer development, eyes, and skin is well-known(13). many studies which analyzed fluoroscopy-assisted surgeries in urology ignored this situation. tanrıverdi et al. stated that fluoroscopy time decreased from 17.5 minutes in the first 15 cases, to 8.9 minutes by the 60th case(9). also, sahan et al. found associations between increased experience in supine mini pnl and reduction in fluoroscopy time(6). in the present study, we significantly reduced fluoroscopy time from the first 20 cases to 40th – 60th cases, and fluoroscopy time reached a plateau after the 60th case. the present study, the first prospective research to evaluate lc in f-urs, has some limitations. the low number of patients could be accepted as a limitation. also, our study focused on one-month outcomes after f-urs, and the impact of lc on long-term outcomes of f-urs is lacking, which may be the subject of another study. additionally, we did not analyse the effect of lc on cost-effectiveness of f-urs, which may be clarified in further studies. lastly, the impact of lc on patient quality of life was not evaluated in this prospective study. conclusions the present study is the first to determine the learning curve of f-urs, and we found that the success of f-urs reached satisfactory levels after 20th cases. in addition, 40 cases may be enough for surgical proficiency regarding decreases in preparation time, operation time, and fluoroscopy time. robotic & laparoscopic urology 429 group 1 (n=20) group 2 (n=20) group 3 (n=20) group 4 (n=20) p value f preparation time (min)* 18.6 ± 4.8a 17.2 ± 4.7a 15.0 ± 4.9b 12.4 ± 2.2b 0.001 20.4 operation time (min)* 44.1 ± 5.8a 39.7 ± 5.8a 33.0 ± 5.0b 30.0 ± 4.4b 0.001 29.4 fluoroscopy time (sec)* 82.9 ± 15.0a 62.1 ± 16.5b 50.3 ± 14.4c 41.7 ± 16.4c 0.001 26.07 hospitalization time (hour)* 23.9 ± 7.1 24.7 ± 7.1 22.3 ± 7.9 23.3 ± 8.0 0.581 0.36 stone free rate 13 (65%)a 17 (85%)b 17 (85%)b 18 (90%)b 0.037 complications 3 (15%) 1 (5%) 1 (5%) 1 (5%) 0.712 minor (clavien-dindo grade 1-2) 2 (10%) 1 (5%) 1 (5%) 1 (5%) major (clavien-dindo grade 3-5) 1 (5%) 0 (0%) 0 (0%) *mean ± standard deviation lower-case letters are used to define the group that makes the difference. the same letters (such as a-a) define that there is no difference, different letters (such as a-b) define that there is a difference. table 3. comparison of operation data and postoperative results between groups learning curve of flexible ureterorenoscopy-kezer et al. vol 20 no 1 january-february 2023 9 references 1. sargent ma. what is the normal prevalence of vesicoureteral reflux? pediatr radiol. 2000;30:587-93. 2. peters ca, skoog sj, arant bs, et al. summary of the aua guideline on management of primary vesicoureteral reflux in children. j urol 2010;184:1134-44 3. subcommittee on urinary tract infection, steering committee on quality improvement and management. urinary tract infection: clinical practice guideline for the diagnosis and management of the initial uti in febrile infants and children 2 to 24 months. pediatrics. 2011;128:595-610. 4. tokhmafshan f, brophy pd, gbadegesin ra, gupta ir. vesicoureteral reflux and the extracellular matrix connection. pediatr nephrol. 2017;32 565–76. 5. baek m, kim kd. current surgical management of vesicoureteral reflux. korean j urol. 2013;54:732-37. 6. radmayr c, bogaert g, dogan hs, et al. guidelines on paediatric urology. european association of urology. 2020:67-9. 7. elder js, peters ca, arant bs, et al. pediatric vesicoureteral reflux guidelines panel summary report on the management of primary vesicoureteral reflux in children. j urol. 1997;157:1846–51. 8. sung j, skoog s. surgical management of vesicoureteral reflux in children. pediatr nephrol. 2012;27:551-61. 9. bayne ap, shoss jm, starke nr, cisek lj. single-center experience with pediatric laparoscopic extravesical reimplantation: safe and effective in simple and complex anatomy. j laparoendosc adv surg tech 2012;22:1026. 10. kurtz mp, leow jj, varda bk, et al. the decline of the open ureteral reimplant in the united states: national data from 2003 to 2013. urology. 2017; 100:193-7. 11. casale p, patel rp, kolon tf. nerve sparing robotic extravesical ureteral reimplantation. j urol 2008;179:1987. 12. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009;250:1987-90. 13. lopez m, varlet f. laparoscopic extravesical transperitoneal approach following the lich-gregoir technique in the treatment of vesicoureteral reflux in children. j pediatr urol. 2010;45:806-10. 14. roshani h, dabhoiwala nf, verbeek fj, kurth kh, lamers wh. anatomy of ureterovesical junction and distal ureter studied by endoluminal ultrasonography in vitro. j urol. 1999;161:1614-19. 15. tanagho ea, pugh rc. the anatomy of the ureterovesical junction. br j urol. 1963;35:151-65. 16. paquin aj. ureterovesical anastomosis: the description and evaluation of a technique. j urol. 1959;82:573-83. 17. riedmiller h, gerharz ew. antireflux surgery: lich‐gregoir extravesical ureteric tunnelling. bjui. 2008;101:1467-82. 18. kirsch aj, arlen am. evolving surgical management of pediatric vesicoureteral reflux: is open ureteral reimplantation still the ‘gold standard’?. international braz j urol. 2020;46:314-21. 19. tam pk. laparoscopic surgery in children. arch dis child. 2000;82(3):240-3. 20. bustangi n, kallas chemaly a, scalabre a, et al. extravesical ureteral reimplantation following lich-gregoir technique for the correction of vesico-ureteral reflux retrospective comparative study open vs. laparoscopy. front pediatr. 2018;6:388. 21. farina a, esposito c, escolino m, lopez m, settimi a, varlet f. laparoscopic extravesical ureteral reimplantation (levur): a systematic review. transl pediatr. 2016;5:291-4. 22. riquelme m, lopez m, landa s, et al. laparoscopic extravesical ureteral reimplantation (levur): a multicenter experience with 95 cases. eur j pediatr surg. 2013;23:143-7. 23. pérez-etchepare e, varlet f, lópez m. laparoscopic extravesical ureteral reimplantation following lich-gregoire technique. medium-term prospective study. cir pediatr. 2014;2:74-7. endourology and stones diseases 271 learning curve of flexible ureterorenoscopy-kezer et al. endourology and stones diseases 10 laparoscopic vs open extravesical ureteral reimplantation in pediatric population: a single-center experience david fernández-alcaráz1 , josé iván robles-torres2*, carlos garcía-hernández1, andres heriberto guillen-lozoya3 , sergio landa-juárez1 purpose: to evaluate the safety and efficacy of conventional laparoscopic vs open lich-gregoir ureteral reimplantation in pediatric vesicoureteral reflux. material and methods: a retrospective study was conducted in a tertiary care hospital. patients with vesicoureteral reflux who underwent open or laparoscopic lich-gregoir ureteral reimplantation from 2013-2020 were included. the primary outcome was the resolution of reflux. complications and perioperative characteristics were evaluated. the outcomes between open and laparoscopic surgery were analyzed. results: a total of 110 patients and 150 ureters were included. the mean age was 4.5 years ± 3.4 and 73.6% were females. a total of 125 ureters (83.3%) underwent laparoscopic and 25 (16.6%) open lich-gregoir vesicoureteral reimplantation (5:1 ratio). resolution was reported in 112 (89.6%) for laparoscopy and 21 (84%) for open surgery (p = .42). mean surgical time for laparoscopy and open surgery were 142.4 min ± 64.4 and 153 min ± 40, respectively (p =.29). mean bleeding (9.5 ml ± 11.2 vs 29.6 ml ± 22.8) and length of hospital stay (2.4 days ± 2.3 vs 5.05 ± 3.1) were significantly higher with open surgery (p < .001). no significant difference in complications was reported between open surgery (32%) and laparoscopic approach (22.4%) (p = .305). conclusion: conventional laparoscopic vesicoureteral reimplantation with the lich-gregoir technique has an acceptable success rate comparable with open surgery, with shorter hospital stay, less bleeding, and less need of transfusion. keywords: laparoscopy; lich-gregoir; minimally invasive surgery; pediatrics; vesicoureteral reflux; vesicoureteral reimplantation. introduction vesicoureteral reflux (vur) is a frequent urologic anomaly that affects 1% of pediatric population.(1) this condition might be asymptomatic or being a cause of recurrent urinary tract infections (uti), leading to renal scars and in long term, progression to chronic kidney disease.(2) the importance of early treatment among these patients is to avoid febrile utis, and in long term, preserve the renal function.(3,4) the current therapeutic options are pharmacological and surgical, the latter being reserved for high-grade cases above the age of one year, with refractory febrile utis, and abnormal renal parenchyma caused by vur.(5,6) open vesicoureteral reimplantation is currently the reference surgical procedure for vur among pediatric population. success rates with this procedure have been reported up to 90% in some series, showing higher success rates compared to endoscopic procedures.(5,6) differentiating by vur grades i to v, success rates are 99.1%, 99.0%, 98.3%, 98.5%, and 80.7%, respectively. (7) regarding intravesical approach, ledbetter-politano and the cohen technique have been considered the most 1servicio de urología pediátrica, centro médico nacional siglo xxi, ciudad de méxico, méxico. 2departamento de urología, universidad autónoma de nuevo león, hospital universitario “dr. josé eleuterio gonzález”; monterrey, méxico. 3clinical research fellow, advantagene inc. massachusetts, united states. *correspondence: servicio de urología, hospital universitario “dr. josé eleuterio gonzález”, calle francisco i. madero s/n, cp 64460, mitras centro, monterrey, nuevo león, méxico. phone: +526531191450. e-mail: ivan.robles25@live.com. received february 2022 & accepted july 2022 popular techniques of ureteral reimplantation with successful rate in the range of 97–99%.(8) in the last decade, several studies have shown comparable results with the conventional laparoscopic technique, with additional benefits such as low rates of vur recurrence, even in cases with complex anatomy. (9,10) nevertheless, new techniques also come with new challenges, such as higher rates of complications compared to the reference procedure.(11) minimally invasive techniques have acquired more popularity worldwide recently.(5) however, the debate between open and laparoscopic ureteral reimplantation continues and the literature among pediatric population is limited. the objective of this manuscript is to evaluate the safety and efficacy of conventional laparoscopic vs open lich-gregoir ureteral reimplantation in pediatric patients with vur. materials and methods a retrospective study was conducted in a tertiary care hospital in mexico city. patients with vur who underwent open or laparoscopic lich-gregoir veiscoureurology journal/vol 19 no. 6/ november-december 2022/ pp. 427-432. [doi: 10.22037/uj.v19i.7217] robotic and laparoscopic urolgy teral reimplantation from 2013 to 2020 were included. data was obtained from clinical records, including demographic parameters, total of ureters treated, indications for surgery, previous therapy, and characteristics of vur before and after surgery. preoperative characteristics were laterality and grade of vur, associated anatomical abnormalities such as duplex collecting system, megaureter, bladder diverticulum, ureterocele, vesicoureteral stenosis, anorectal malformations, and ectopic ureter. the periand postoperative characteristics evaluated were operation time, total bleeding, days of hospital stay, days of transurethral catheterization, days of percutaneous drainage, need of transfusion and use of opioids. the primary parameters measured were the frequency of complete resolution, decrease in the grade of reflux, and the persistence of reflux. decrease in the grade of reflux was defined as an improvement to a low-grade reflux (grade 1 or 2). persistence of reflux was defined as persistence of high-grade reflux after the procedure (grade 3, 4 or 5). complications associated with the procedure and reintervention rates were evaluated. complications were classified using the clavien-dindo classification of surgical complications.(12) vur nephropathy progression after surgery was defined as new renal scars documented in renal scintigraphy in patients with postoperative febrile uti. patients with a diagnosis of vur secondary to infravesical obstruction, lower urinary tract dysfunction, and cases managed with conservative treatment were excluded. indication for surgical management was a confirmed voiding cystourethrogram (vcug) with vur and recurrent uti or renal scars in renal scintigraphy. family members or tutors of patients who were candidates for surgery were informed about the treatment options, including an open or laparoscopic technique for ureteral reimplantation. the surgical approach (open or laparolap. and open extravesical ureteral reimplantation-fernández-alcaráz et al. table 1. study population characteristics (n=150) variables total (n=150) laparoscopy (n=125) open surgery (n=25) p-value demophraphicsa females, n (%) 81 (73.6) 70 (76.9) 11 (57.9) 0.095 age mean years ± sd 4.5 ± 3.4 4.8 ± 3.6 4.1 ± 2.4 0.329 reimplant indication recurrent urinary tract infections 131 (87.3) 116 (92.8) 15 (60) < 0.001 severe hydronephrosis 21 (14) 17 (13.6) 4 (16) 0.752b renal scars 24 (16) 19 (15.2) 5 (20) 0.555 previous treatment antibiotic prophylaxis 96 (64) 79 (63.2) 17 (68) 0.82 bulking agents 19 (12.7) 14 (11.2) 5 (20) 0.318 additional procedures 16 (10.6) 12 (9.6) 4 (16) 0.527 ureteroplasty 8 (5.3) 6 (4.8) 2 (8) bladder diverticulum resection 8 (5.3) 6 (4.8) 2 (8) reflux characteristics righta 24 (21.8) 21 (22.6) 8 (28.6) 0.852 lefta 46 (41.8) 37 (40.7) 9 (47.4) bilaterala 40 (36.4) 34 (37.4) 6 (31.6) grade of reflux grade 3 38 (25.3) 34 (27.2) 4 (16) 0.24b grade 4 61 (40.7) 46 (36.8) 15 (60) 0.044 grade 5 51 (34) 45 (36) 6 (24) 0.355 anatomic abnormalities duplex collecting system 17 (11.3) 9 (7.2) 8 (32) < 0.001 megaureter 9 (6) 7 (5.6) 2 (8) 0.645b diverticulum 8 (5.3) 6 (4.8) 2 (8) 0.166b ureterocele 4 (2.7) 3 (2.4) 1 (4) 0.999b vesicoureteral stenosis 5 (3.3) 1 (0.8) 4 (16) 0.003b anorectal malformation 1 (0.7) 1 (0.8) 0 (0) 0.989b ectopic ureter 1 (0.7) 0 (0) 1 (4) 0.167b a considering 110 patients (100%); bfisher exact test; sd= standard deviation. endourology and stones diseases 269 variables laparoscopy group open surgery group p value characteristics operation time, mean min ± sd 142.4 ± 64.4 153 ± 40 0.29 bleeding mean ml ± sd 9.5 ± 11.2 29.6 ± 22.8 < 0.001 hospital stay mean days ± sd 2.4 ± 2.3 5.05 ± 3.1 < 0.001 transurethral catheter, median (iqr) 1 (1-2) 4 (3-5) < 0.001a percutaneous drainage, median (iqr) 0.01 (0.01-0.02) 3 (3-4) < 0.001a transfusion 0 (0) 3 (12) 0.004b opioid use 19 (15.2) 6 (24) 0.281 outcomes vur resolution 112 (89.6) 21 (84) 0.42 decrease in vur grade 12 (9.6) 4 (16) 0.344 persistence of vur 1 (0.8) 0 (0) 0.999b table 2. comparison of perioperative findings and outcomes between laparoscopic and open surgery vesicoureteral reimplantation (n=150) vur= vesicoureteral reflux; a mann-whitnet u test. bfisher exact test; sd= standard deviation; iqr= interquartile range. vol 19 no 6 november-december 2022 428 scopic) was selected based on surgeons' criteria, taking into consideration history of previous abdominal procedures, and the availability of laparoscopic equipment at that time of the procedure. informed consent was obtained in all recruited cases. in this study, no contraindication for laparoscopic surgery was found among the enrolled patients, such as multiple previous abdominal surgeries, marked obesity, large ventral hernia, or cardiorespiratory conditions. surgical technique a laparoscopic extravesical transperitoneal approach was done following the lich-gregoir technique.(9,13) the procedure was performed under general anesthesia and endotracheal intubation. three ports from 3 to 5 millimeters were used. the camera port was placed subxiphoid or at the level of the umbilical scar with the conventional open hasson technique. subsequently, two para-rectal working ports were placed either subcostal or at the level of the umbilical scar under laparoscopic vision. a bladder traction suture was placed percutaneously. the bladder was filled with saline solution to facilitate its dissection; the ureter was dissected from the lateral pelvic fascia for tension-free reimplantation. a detrusotomy was performed marking the cephalic end of the incision at the level where the full bladder rests without tension on the ureter, using a monopolar electrocautery hook together with blunt dissection, taking care not to perforate the bladder mucosa. bladder distention with an intravesical irrigation solution through the transurethral catheter allows better dissection down to the submucosal plane, thus the mucosa protrudes over the detrusotomy area. a tunnel was created using paquins´ principle, with a length 4 to 5 times greater than the diameter of the ureter,(14-16) as seen in figure 1. detrusorrhaphy was performed over the ureter with an absorbable 3-0 to 4-0 monofilament stitch suture (figure 2). bladder catheterization was performed, and the catheter was typically removed the next day. open vesicoureteral reimplantation was performed using the lich-gregoir extravesical ureteroneocystostomy technique.(17) the technique was selected based on the experience and preference of the surgeon. postoperative follow-up postoperative follow-up was performed by renal and robotic & laparoscopic urology 429 variables laparoscopic group (n=125) open surgery group (n=25) p value total complications 28 (22.4) 8 (32) 0.305 clavien-dindo classification grade ≤2 4 (3.2) 2 (8) 0.264 urinary retention 0 (0) 2 (8) 0.027a urinary tract infection 22 (17.6) 5 (20) 0.776 ileus 0 (0) 3 (12) 0.004a hematuria 2 (1.6) 0 (0) 0.999a surgical wound infection 0 (0) 3 (12) 0.004a progression of nephropathy 2 (1.6) 4 (16) 0.007a grade >2a 4 (3.1) 4 (10.8) 0.078a ureteral stenosis 4 (3.2) 2 (8) 0.262a need for reintervention 1 (0.8) 0 (0) 0.999a ano clavien-dindo grade 5 complications were reported; afishers´exact test. table 3. complications of ureteral reimplantation surgery with a laparoscopic and open approach (n=150) figure 1. right extravesical ureteral reimplant. a detrusotomy is performed until the mucosa is exposed without violation (arrow). the mucosa protrudes over the detrusotomy, this being the area of the submucosal tunnel that follows paquins´ principle. the bladder is distended in order to facilitate dissection (arrowhead). a dilated ureter is observed in its distal section (asterisk). figure 2. detrusorrhaphy over the ureter with interrupted absorbable sutures developing a submucosal tunnel following paquin´s principle. lap. and open extravesical ureteral reimplantation-fernández-alcaráz et al. bladder ultrasound 1-3 months postoperatively and a vcug at 6 to 8 weeks after surgery. approval of the internal ethics committee with registration number r-2020-3603-065 was assigned. statistical analysis descriptive statistics were calculated for the variables included in the analysis. categorical variables were represented by frequencies and percentages, and continuous variables by mean and standard deviation. the results of open versus laparoscopic surgery were also compared. kolmogorov-smirnov statistic was used to assess distribution of continuous variables. for categorical variables, the pearson chi square test was used for binary outcomes with large expected cell counts and fisher´s exact test for small cell counts, and student t test for independent continuous variables. for non-normally distributed variables, the mann-whitney u test was used. statistical analysis was performed in spss v26 software. results study population a total of 110 patients and 150 ureters were included in the study. the mean age was 4.5 years ± 3.4 months and 81 patients (73.6%) were females. bilateral vur was reported in 36.4% (n=40). the most common indication for ureteral reimplantation was the presence of recurrent febrile utis (or pyelonephritis) in 87.3% (n=131) of ureters. in 64% (n=96) of treated ureters were refractory to a prophylactic antibiotic and 12.7% (n=19) to a bulking agent. the most frequent grade of reflux was grade 4 in 40.7% (n=61), followed by grade 5 in 34% (n=51). anatomical abnormalities were reported in 30%, with a duplex collecting system being the most frequent abnormality in 11.3% (n=17). one hundred and twenty five ureters underwent a laparoscopic approach and 25 an open surgery (5:1 ratio). all procedures were done with the lich-gregoir technique. an additional procedure was carried out during surgery in 12 cases (9.6%) in the laparoscopic group and 4 (16%) in open surgery (p = .527). the presence of recurrent febrile utis prior to surgery was more frequent in the laparoscopy group (92.8%) compared to the open surgery (60%) (p < .001). grade 4 vur was more frequent in the laparoscopic group (p =.044) and no significant difference was observed with grade 3 and grade 5 vur between groups. anatomical abnormalities were reported more frequently in the open surgery group (p < 0.001). the rest of population characteristics are described in table 1. effectiveness vur was resolved in 112 of 125 ureters (89.6%) by laparoscopic approach and 21 of 25 patients (84%) by open surgery (p =.42). a decrease in the grade of reflux was reported in 12 cases (9.4%) with laparoscopy and 4 cases (16%) with open surgery (p = .344). the persistence of reflux was reported in only 1 case with laparoscopy and no cases with open surgery. the mean surgical time for laparoscopy and open surgery was 142.4 min ± 64.4 and 153 min ± 40, respectively (p = .29). the mean laparoscopic bleeding was 9.5 ml ± 11.2 and for open surgery 29.6 ml ± 22.8, showing a significant difference (p < .001). hospital stay was lower in the laparoscopic approach (p < .001). the use of a transurethral catheter, (p < .001), percutaneous drainage time (p < .001), and the need of transfusion (p = .004) were lower in the laparoscopic group. the use of opioids for pain relief was not significant different between groups. table 2 describes the perioperative findings between groups. complications complications were reported in 36 cases (24%), 28 cases (22.4%) in the laparoscopic group and 8 (32%) in the open surgery group (p = .305). urinary retention was reported in 2 cases (8%) only with open surgery. ileus was significantly higher in the open surgery group (0% vs 12%, p = .004). surgical wound infection (0% vs 12%) and progression of vur nephropathy (1.6% vs 16%) were also higher between cases treated with open surgery (p = .002). all patients with progression of nephropathy had febrile uti after surgery. according to clavien-dindo classification, 8 cases reported complications grade >2, requiring additional procedures. no statistical significant differences were reported between groups for grade ≤2 and grade >2 (p = .194 and p = .078, respectively). however, there is a tendency to greater complications grade >2 in the open surgery group compared to laparoscopic approach (10.8 vs 3.1%, respectively) (see table 3 for complete description of complications). discussion multiple studies published in recent years continue to consider open surgery as the reference surgical treatment for vur with good long-term outcome and success rates up to 90%.(6) this procedure has long been touted as the “gold standard” due to its high radiographic success rates reported.(18) recently, the use of minimally invasive techniques such as the conventional or robot-assisted laparoscopic approach have gain popularity and have been used more frequently.(6,11) during the last decade, series of conventional laparoscopic ureterovesical reimplantation have shown good results and few complications, even in cases of complex anatomy. (9,10) bayne ap et al reported a retrospective study of 98 patients with vur who underwent laparoscopic ureteral reimplantation with the extravesical lich gregoir technique. the success rate was 93.5%, with complications in 24% of the sample and requiring reoperation in 7% of cases.(9) they concluded that laparoscopic technique is an effective and safe alternative for the surgical management of vur. despite a decrease in the use of open ureteral reimplantation in recent years, it continues to be a valid option in younger patients and in those with previous abdominal surgeries.(18) some cases are not suitable for laparoscopic procedures, such as patients with severe cardiac diseases, pulmonary insufficiency, bleeding disorders, repeated abdominal procedures, patients with ileus, intestinal obstruction, and abdominal sepsis.(19) in such patients, open surgery continue to be the most suitable option. recently, bustangi n et al compared open versus laparoscopic lich-gregoir technique in a multicenter retrospective study. a total of 96 patients with vur were included of which 50 were operated by open approach and 46 by laparoscopic approach. a higher operative time was reported in the laparoscopic group (127.9 vs 63.2 min, p < 0.001), shorter length of stay in laparoscopic approach (1.64 vs 5.4 days, p < .001), and shorter days of intravenous analgesia used (1.15 vs 3.9, p endourology and stones diseases 271 lap. and open extravesical ureteral reimplantation-fernández-alcaráz et al. vol 19 no 6 november-december 2022 430 < .001). there was no conversion in the laparoscopic group and only 1 case had to be reoperated for leakage. success rate was 98% with open approach and 97.8% for laparoscopic approach with a mean follow-up of 3.6 and 1.5 years, respectively. the authors concluded that laparoscopic approach was as effective as the open approach, with reduction in analgesia medication, hospital stay, and faster recovery, with the disadvantage of requiring twice the operative time.(20) in our study, the success rate with the laparoscopic approach was 89.6% with improvement in the grade of vur in 9.6% and persistence of high-grade vur in only 1 case (0.8%), similar to the reported in most series.(9,10) as compared with the results of bustangi n et al(20), our success rate was lower (89.6 vs 97.8%) in the laparoscopic and open approach (84% vs 98%). one explanation for this discrepancy is the definition of therapeutic success. they defined success rate by the absence of documented febrile uti or absence of recurrence of vur objectivized by vcug in both groups. only 5 cases in open approach and 3 in laparoscopic group had a vcug due to recurrent postoperative febrile utis. this could have influenced in subclinical vur cases to be underestimated. in our study, all patients had a postoperative vcug, and we differentiate between those patients with persistent vur from those who had a decrease in the degree of vur. complications were reported in 24% of the cases, most of them minor and requiring reintervention in a single case (0.8%). in 2016, farina et al conducted a systematic review evaluating ureteral reimplantation with laparoscopic technique. they concluded that this technique is safe and effective, comparable with open surgery.(21) they reported a success rate of up to 96%, shorter hospital stay, less bleeding and less pain compared to open surgery, similar to our study. riquelme m et al in 2013, reported a success rate of 95.8% in 81 patients, with few complications, requiring reintervention in 2 cases (2.4%).(22) other authors such as perez et al in 2014, reported success rates of 96.5% for laparoscopic reimplantation in 23 cases.(23) the laparoscopic technique has its drawbacks, for example, a greater learning curve and greater surgical dexterity to achieve success rates compared to the standard open surgery, but a remarkable set of benefits as well as shorter hospital stay. the authors consider that this technique should be the new reference procedure and the experience required for better outcomes must spread to as many centers around the globe as possible, with enough case volume and appropriate training. this study has several limitations, starting with its retrospective nature and wide distribution of the study groups. this is because in the center were the study was carried out, the laparoscopic procedure has been considered the treatment of choice when there is no contraindication. selection of surgical approach was decided by surgeons´ criteria, and not randomly assigned. further randomized prospective studies comparing open versus laparoscopic surgery using a specific reimplantation technique are needed to reinforce these findings. conclusions laparoscopic vesicoureteral reimplantation with the lich-gregoir technique is a procedure that has an acceptable success rate and a safe profile comparable to open surgery. shorter hospital stay, less bleeding, and less blood transfusion were reported using laparoscopic vesicoureteral reimplantation. summary open and laparoscopic vesicoureteral reimplantation seem to have similar success rate and comparable complication rates. however, laparoscopic approach demonstrated shorter hospital stay and less bleeding compared to the open approach. conflicts of interest the authors do not declare conflicts of interest. references 1. sargent ma. what is the normal prevalence of vesicoureteral reflux? pediatr radiol. 2000;30:587-93. 2. peters ca, skoog sj, arant bs, et al. summary of the aua guideline on management of primary vesicoureteral reflux in children. j urol 2010;184:1134-44 3. subcommittee on urinary tract infection, steering committee on quality improvement and management. urinary tract infection: clinical practice guideline for the diagnosis and management of the initial uti in febrile infants and children 2 to 24 months. pediatrics. 2011;128:595-610. 4. tokhmafshan f, brophy pd, gbadegesin ra, gupta ir. vesicoureteral reflux and the extracellular matrix connection. pediatr nephrol. 2017;32 565–76. 5. baek m, kim kd. current surgical management of vesicoureteral reflux. korean j urol. 2013;54:732-37. 6. radmayr c, bogaert g, dogan hs, et al. guidelines on paediatric urology. european association of urology. 2020:67-9. 7. elder js, peters ca, arant bs, et al. pediatric vesicoureteral reflux guidelines panel summary report on the management of primary vesicoureteral reflux in children. j urol. 1997;157:1846–51. 8. sung j, skoog s. surgical management of vesicoureteral reflux in children. pediatr nephrol. 2012;27:551-61. 9. bayne ap, shoss jm, starke nr, cisek lj. single-center experience with pediatric laparoscopic extravesical reimplantation: safe and effective in simple and complex anatomy. j laparoendosc adv surg tech 2012;22:1026. 10. kurtz mp, leow jj, varda bk, et al. the decline of the open ureteral reimplant in the united states: national data from 2003 to 2013. urology. 2017; 100:193-7. 11. casale p, patel rp, kolon tf. nerve sparing robotic extravesical ureteral reimplantation. j urol 2008;179:1987. 12. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009;250:1987-90. 13. lopez m, varlet f. laparoscopic extravesical transperitoneal approach following the lap. and open extravesical ureteral reimplantation-fernández-alcaráz et al. robotic & laparoscopic urology 431 urological oncology 200 lich-gregoir technique in the treatment of vesicoureteral reflux in children. j pediatr urol. 2010;45:806-10. 14. roshani h, dabhoiwala nf, verbeek fj, kurth kh, lamers wh. anatomy of ureterovesical junction and distal ureter studied by endoluminal ultrasonography in vitro. j urol. 1999;161:1614-19. 15. tanagho ea, pugh rc. the anatomy of the ureterovesical junction. br j urol. 1963;35:151-65. 16. paquin aj. ureterovesical anastomosis: the description and evaluation of a technique. j urol. 1959;82:573-83. 17. riedmiller h, gerharz ew. antireflux surgery: lich‐gregoir extravesical ureteric tunnelling. bjui. 2008;101:1467-82. 18. kirsch aj, arlen am. evolving surgical management of pediatric vesicoureteral reflux: is open ureteral reimplantation still the ‘gold standard’?. international braz j urol. 2020;46:314-21. 19. tam pk. laparoscopic surgery in children. arch dis child. 2000;82(3):240-3. 20. bustangi n, kallas chemaly a, scalabre a, et al. extravesical ureteral reimplantation following lich-gregoir technique for the correction of vesico-ureteral reflux retrospective comparative study open vs. laparoscopy. front pediatr. 2018;6:388. 21. farina a, esposito c, escolino m, lopez m, settimi a, varlet f. laparoscopic extravesical ureteral reimplantation (levur): a systematic review. transl pediatr. 2016;5:291-4. 22. riquelme m, lopez m, landa s, et al. laparoscopic extravesical ureteral reimplantation (levur): a multicenter experience with 95 cases. eur j pediatr surg. 2013;23:143-7. 23. pérez-etchepare e, varlet f, lópez m. laparoscopic extravesical ureteral reimplantation following lich-gregoire technique. medium-term prospective study. cir pediatr. 2014;2:74-7. lap. and open extravesical ureteral reimplantation-fernández-alcaráz et al. vol 19 no 6 november-december 2022 432 urology journal peer review dna ploidy as a potential adjunct prognostic marker of low-risk prostate cancer progression after radical prostatectomy miha pukl 1, matthieu george2, arash javanmardi2, anita carraro2, jagoda korbelik2, rebecca white2, calum macaulay2, branko palcic2, mira keyes3, metka volavšek 4, martial guillaud2 1department of urology, gh celje, 3000 celje, slovenia. mihapukl82@gmail.com 2department of integrative oncology, bc cancer, vancouver, bc, canada. mathieu.george25113@gmail.com; arashj1997@gmail.com; acarraro@bccrc.ca; jkorbeli@bccrc.ca; rebecca.white@bccancer.bc.ca; cmacaula@bccrc.ca; bpalcic@bccrc.ca; mguillau@bccrc.ca 3department of radiation oncology, bc cancer, vancouver, bc, canada. mkeyes@bccancer.bc.ca 4institute of pathology, faculty of medicine, university of ljubljana, ljubljana, slovenia. metka.volavsek@mf.uni-lj.si. corresponding author: dr. martial guillaud, bc cancer research institute, 675 west 10th avenue, v5z1l3 mguillau@bccrc.ca key words: prostate cancer, dna ploidy, biochemical recurrence, image cytometry, prognostic marker abstract purpose post prostatectomy psa kinetics and general grade groups (ggg) are the strongest prognostic markers of biochemical recurrence (bcr) and prostate cancer (pca)-specific mortality after radical prostatectomy. despite having low-risk pca, some patients will experience bcr, for some, clinically significant bcr. there is a need for an objective prognostic marker at the time of prostatectomy to improve risk stratification within this population. in this study, we investigated the prognostic potential of dna ploidy. materials and methods prostatectomy samples from 97 patients with ggg1 and ggg2 with a low-risk capra-s score were included in this study. pca tissue with the worst gleason pattern underwent tissue disaggregation, cell isolation and staining with a dna stoichiometric stain. using image cytometry, dna ploidy was measured and a ploidy score (ps) was generated. results among the 97 patients, 79 had no bcr, 18 experienced bcr, of which 14 had a psa doubling time (psa-dt) >1 year (low-risk group) and 4 had a psa-dt of <1 year (high-risk group). using logistic regression analysis, only pathological t stage (pt) and ps independently predicted bcr with ps being the most significant (p=0.001). the number of aneuploid cells was significantly higher in the high-risk group compared to the other groups (p=1.7x10-11). ps combined with ggg diagnosis further stratified mailto:mihapukl82@gmail.com mailto:mkeyes@bccancer.bc.ca mailto:metka.volavsek@mf.uni-lj.si risk groups of biochemical recurrence free survival within capra-s low-risk cohort. conclusion dna ploidy is an independent prognostic marker of bcr in low-risk pca after radical prostatectomy, which could early on identify potentially aggressive pca recurrences and introduce a more personalized approach to salvage treatments. introduction prostate cancer (pca) is one of the most common cancers diagnosed in men in the world1. more than 50% if pca cases are low-risk of death at diagnosis2, however, 5-10% of these low-risk cases will have a poor outcome even after radical treatment.3 for postoperative cases, the gleason score (gs) remains the strongest predictor of biochemical recurrence (bcr). however, gs’s subjectivity results in significant inter-observer variability, especially among general pathologists.4 gs is part of validated predictors of bcr and systemic progression, such as capra-s score.5,6 recently, it has been shown that gs and post-prostatectomy prostate-specific antigen (psa) kinetics are the strongest predictors of metastases and mortality. despite having low capra-s scores, some patients will experience bcr, and some of those will have adverse psa kinetics (psa doubling time [psa-dt] < 1 year), which would classify them into the high-risk bcr group as per the european association of urology (eau).7,8 however, salvage radiotherapy (rt) is most effective when delivered before psa levels reach 0.5 ng/ml, after which, the opportunity to avoid use of androgen deprivation therapy in conjunction with salvage radiation could be missed. there is need for a prognostic marker that could better predict bcr at time of prostatectomy and differentiate between low (psa-dt > 1 year) and high-risk (psa-dt < 1 year) bcr to aid in the decision making process regarding salvage treatments. recently, molecular panels like the decipher® prostate cancer test (genomedx biosciences, san diego, ca) are attempting to provide better prognostic information.9 unfortunately, these tests are expensive and the genetic diversity of tumors limits their use in clinical decision-making.10,11 dna ploidy analysis by detecting large-scale genomic alterations could be a promising alternative.12 dna ploidy is now accepted as an objective prognostic biomarker in epithelial cancers12-14 such as pca.12, 1417 dna ploidy correlates with recurrence-free survival and has added prognostic information to gs,12,14,18 especially in patients with gs < 7.15-17,19,20 to our knowledge, this is the first study to investigate the correlation of dna ploidy with bcr and psa kinetics after radical prostatectomy in patients with low-risk pca. materials and methods 1. patient selection and study design the study was reviewed and approved by the slovenian national medical ethics committee as well as the general hospital of celje (gh celje). the study and work comply with the principles of the declaration of helsinki. a cohort of 99 low-risk patients (capra-s scores of 0, 1 or 2, and gg1 or gg2) who have undergone radical retro-public prostatectomy (rp) without lymphadenectomy at gh celje between 2003 and 2009 were included in this study. all patients had a negative resection margin. 2. pathological evaluation radical prostatectomy gs, defined by a group of general pathologists from gh celje, was labeled general grade group (ggg) for this study. study samples were reviewed by an experienced genitourinary pathologist (mv) at the institute of pathology in ljubljana. the review was labeled as expert grade group (egg). all specimens were evaluated according to the 2014 modified gleason scoring system and isup grade groups (1-5). egg1 and egg2 would therefore represent gs 6 and gs 3+4=7, respectively. 3. follow up and endpoint patients were followed with psa every four months during the first year, every six months during the second and third years, and then annually or until bcr. van den broeck et al. developed a bcr risk group definition: egg 1 or 2 case with bcr and psa-dt <1 year is considered high-risk and a case with bcr and psa-dt >1 year is defined as low-risk bcr.7 psa-dt was calculated using the memorial sloan kettering cancer centre calculator by entering the at least two measurements of psa above 0.1 ng/ml spaced at least two months apart.21 patients with persistently elevated psa (above 0.1 ng/ml 6-8 weeks after rp) were excluded. local recurrence was identified by a choline or psma pet/ct scan or prostate bed biopsy. distant metastases were diagnosed by imaging (choline or psma pet/ct scan or ct scan and bone scintigraphy). the primary endpoint of the study was bcr. the secondary endpoint was defining or stratifying the eau bcr risk groups. 4. tissue processing and staining using the h&e section from the formalin-fixed paraffin-embedded prostatectomy sample, mv delineated the cancerous tissue on the slide. the slide with the worst gs pattern was used for this analysis. three sections were cut from the corresponding paraffin block: the first and third 5 μm thick sections were stained with h&e to confirm the presence of the cancerous tissue; the second 70 μm thick section underwent tissue disaggregation and cell isolation followed by staining with a modified feulgenthionin a stoichiometric dna stain.22 it was transferred in nylon gauze (pore size 50 μm), placed into plastic cassettes, underwent deparaffinzation in xylene and rehydration by immersion into decreasing ethanol concentrations. the rehydrated tissue was then digested with a pepsin mixture, incubated at 37 c and stopped with phosphate-buffered saline. sample was then shaken until the cells diffused into solution. after centrifugation, the resulting supernatant was removed and the remaining 2 ng/ml of solution was equally divided to each of the chambers on the cytospin slide. this slide was then centrifuged to create the cell monolayer. after air-drying, slides were stained with thionin-eosin.22 5. dna image cytometry feulgen-stained slides were scanned with the health canada-approved dna image cytometry system (icm) clearcyte (perceptionix inc.). the system uses a zeiss microscope with a 20x objective and a high-resolution monochrome ccd camera. an illumination wavelength of 600 nm was used, which corresponds to the absorption peak of the thionin stain. the effective pixel sampling was 0.37 μm. clearcyte automatically scans the area of the stained cell deposition. two spots per cytospin slide were used in order to maximize cell yield per sample. the two spots were scanned separately and the resultant files were subsequently merged. using proprietary algorithms combining morphometric features, the clearcyte software automatically classified objects into epithelial cell nuclei, inflammatory cells, overlapping cells, and out of focus cells.23 cells were visually reviewed by a cytotechnician who manually removed misclassified objects. only in focus epithelial cell nuclei were used for dna ploidy analysis. the dna content of each cell was determined by measuring their integrated optical density (iod). the dna index (di) is a normalized measure of dna content. it is obtained from cell iod divided by the average iod of the reference cell population (defined by the cytotechnician). the mean iod value of normal epithelial cells was used as an internal reference as advised by the manufacturer. 6. dna ploidy features cells were classified into 13 different groups or “bins” according to their di values. cells with a di: lower than 0.9 were moved into bin 0; between 0.91 and 0.95 were moved into bin 1; between 0.96 and 1 into bin 2; between 1.01 and 1.10 into bin 3; between 1.11 and 1.25 into bin 4; between 1.26 and 1.60 into bin 5; between 1.61 and 1.85 into bin 6; between 1.86 and 1.95 into bin 7; between 1.96 and 2.05 into bin 8; between 2.06 and 2.15 into bin 9; between 2.16 and 2.25 into bin 10; between 2.26 and 2.5 into bin 11; and finally cells with a di more than 2.5 into bin 12. cells with a di >2.5 are likely true aneuploid cells as their di is too large to correspond to cycling diploid cells. all other cells could either be normal diploid epithelial cells at different phases of the cell cycle or aneuploid cells. frequencies (#) and percentage (%) of cells in each of these bins were calculated as well as the frequency exceeding rate (e#) and the percentage exceeding rate of cells with a di higher than the corresponding value of the bins (supplement tables s1-s4). 7. statistical evaluation the r statistical package (version 1.2.1335) was used for all statistical analyses including the nonparametric wilcoxon rank sum test. differences between more than two groups were assessed by one way anova. univariate and multiple linear regression analysis were used to measure the association between one or more variables and recurrence. biochemical recurrence-free survival (bcrfs) was studied using the kaplan-meier method and the log-rank test. results among the 99 patients, two patients were excluded due to lack of tissue material. the final cohort consisted of 97 patients. clinical characteristics of this cohort are outlined in table 1. the mean observation period was 12.1 years (median = 11.24 years , iqr [9.50-12.95] the mean age of patients at rp was 61.0 years. the mean preoperative psa level was 4.8 ng/ml. three patients died, one from cancer, two from unrelated causes so the overall survival was 96%. of the 97 patients, 79 had no bcr (referred to as bcr0). among the 18 patients who experienced bcr (bcr1), 14 had a psa-dt >1 year (low-risk bcr) and 4 had a psa-dt of <1 year (high-risk bcr). mean psa-dt of high-risk patients was 0.62 years versus low-risk patients of 2.0 years. overall survival and cancer-specific survival was 95.9% and 99%, respectively. 55.6% of patients with recurrence received salvage therapy, including both high-risk and low-risk bcr patients. no patients received adjuvant radiotherapy. four patients were treated with salvage radiotherapy with or without androgen deprivation treatment (adt), being delivered at psa level above 0.5 ng/ml. six patients were treated with adt and one also underwent chemotherapy. comparisons of dna ploidy between patients with and without bcr on average, 2175 cells were analyzed per specimen (min 76, max 10799). mean and standard deviation of all dna ploidy features are given in supplemental tables 1-4. fourteen dna ploidy features were statistically different between bcr0 and bcr1 (wilcoxon test, p <0.001). all these features showed the same trend: there were significantly more aneuploidy cells or cells with a higher di in patients that experienced bcr than patients that did not. two dna ploidy histograms of specimens from a patient with bcr and without bcr are depicted in figure 1. figure 2 shows nuclear images of nuclei with increasing dis (from the specimen with bcr shown in figure 1b) dna ploidy score all features were entered into a stepwise forward linear discriminant analysis (lda) to differentiate between bcr0 and bcr1. to avoid overtraining, the number of features entered was limited to two. the algorithm selected 2.5# and 2.15#. the canonical score (linear combination of these two features) was named ploidy score (ps). using a threshold value of 0.16, patients with a ps value below 0.16 were classified as psand ps+ otherwise. the sensitivity and specificity of this ps test to detect bcr patients with a sensitivity of 44.4% (8 of 18) with a 95% ci of 22.0% to 66.0% and a specificity of 92.4% (73 of 79) with a 95% ci of 86.0% to 97.0% (table 2). we then assessed the performance of the ps in egg2 subgroup of patients. the sensitivity and specificity were 50% (6 of 12) and 100.0% (25 of 25). gleason score and bcr sensitivity and specificity of the egg to predict bcr was 66.7% (12 of 18) (95.0% ci of 41.0 to 87.05) and 68.4% (54 of 79) (95% ci of 57.0% to 78.0%) respectively. sensitivity of ggg to predict bcr was 33.3% (6 of 18) (95.0% ci of 13.0% to 59.0%) and 78.5% (62 of 79) (95.0% ci of 56.0% to 59.0%) respectively. univariate and multivariate regression analysis to be consistent and allow a more logical comparison between egg and ggg, which are intrinsically binary (grade 1 or 2, see table 1), we transformed all other variables into binary variables. patients younger than 60 years old were coded as 0 and equal or over 60 years old as 1. psa values below 6 ng/ml were coded as 0 and values between 6.01 and 10 ng/ml were coded as 1. for pathology grade, pt2 was coded as 0 and pt3 as 1. univariate analyses showed that ps, pt and egg were statistically significant predictors of bcr. age, preoperative psa and gg were not significant (table 3). multivariate regression analysis was used to access the prognostic value of ps adjusted by egg, pt, preoperative psa level and age. only ps and pt were statistically significant (table 3). correlation of dna ploidy score with high-risk bcr to investigate the potential of the ps to detect most aggressive bcr cases, we compared the distribution of ps between three groups classified as: group 0 (patients with no bcr); group 1 (patients with a psadt of >1 year); and group 2 (patients with a psa-dt of <1 year). there was a statistically significant difference in the ps and in the frequency of cells with a di higher than 2.5 (likely truly aneuploidy cells) between these three groups (figure 3). ploidy score and time to biochemical recurrence we examined the correlation between ps and egg with bcr-free survival using the kaplan-meier analysis (figure 4). mean time to bcr was significantly shorter in ps+ patients compared to ps patients: 44.7 months versus 85.2 months (log rank test, p<0.001 figure 4a). the 10-year bcrfs rates for ps+ were 42% (95% ci 22-78%) and pswere 90% (95% ci 84-97%). for egg1 and egg2, they were 93% (95% ci 87-99%) and 68% (95% ci 54-84%) respectively. using a combination of ps and egg, four risk groups were generated (figure 5). group a consists of patients with psand egg1 diagnosis with a bcr proportion of 7.5% (4/53). group b consists of patients with psand egg2 diagnosis with a bcr proportion of 20.7% (6/29). group c consists of patients with ps+ and egg1 diagnosis with a bcr proportion of 28.6 (2/7). group d consists of patients with ps+ and egg2 diagnosis with a bcr proportion of 75% (6/8). all four high-risk bcr cases were classified into group d. the cumulative proportion of patients with bcrfs decreased from group a to d (figure 5). discussion our study suggests that dna ploidy obtained on radical prostatectomy specimens can stratify patients with low-risk pca into low and high risks of subsequent bcr. dna ploidy combined with gleason groups further refines risk stratification of bcr. this implies that low-risk group based on traditional clinicopathological criteria is heterogeneous and dna ploidy has potential to tackle this issue. moreover, our data suggests that dna ploidy could identify very early on patients at high-risk of aggressive bcr (psa-dt <1year) and patients with a risk of non-significant bcr (psa-dt >1 year) much sooner than actual psa recurrence. the negative predictive value of ps for bcr was 88%, suggesting a high likelihood of excluding bcr, while a lower positive predictive value indicates that some recurrences are not detected. however, as the number of aneuploidy cells (di >2.5) is significantly higher in the high-risk patients (figure 3), ps could detect aggressive cancers. regression analysis to predict bcr showed another interesting property of dna ploidy and ggg assessment. ploidy score and expert pathologist assessment were significant in predicting bcr in univariate analysis, while general pathologist assessment was not (table 3). despite differences in prognostic performance between expert and general pathologists (table 2), multivariate analysis indicated that only pt and ps were independent variables to predict bcr, suggesting that a dna ploidy assessment adds important prognostic information despite already having an expert pathologist assessment. kaplan-meier analysis of bcr clearly showed that adding ps to egg improved risk stratification. including dna ploidy into pathology report from radical prostatectomy may refine clinical management. for example, for patients who are egg1 and ps-, a follow-up with family practitioner could be sufficient. in contrast, ps+/egg2 patients, at higher risk of early recurrence, would require early consultation with radiation oncology, consideration for adjuvant or early multimodal salvage treatment. on the other hand, a more frequent psa based follow up my be sufficient for ps+/egg1 and ps-/egg2 patients. evidence for dna ploidy-independent prognostic value in pca was summarized in two recent reviews.12,14 most studies reported statistical significance of dna ploidy in multivariate statistical models reflecting no added value of dna ploidy to ggg, however some of these studies used flow cytometry, which has poorer resolution compared to image cytometry.24-27 in these studies, expert pathologists gave ggg assessment, which may not be available in all institutions; additionally experts could have discordant reports.4 efforts have been made to incorporate genomic prognostic markers into risk stratification tools, benefitting mostly high-risk patients.9,28 genomic classification increased the cindex for 10-year distant metastasis from 0.76 to 0.81 compared to the clinical model alone.9 only one contemporary study has assessed the prognostic value of dna ploidy in favorable risk pca (pretreatment setting) showing its independent prediction of bcrfs.15 in a post-rp setting, several studies have shown that abnormal dna ploidy was a predictor of bcr in a cohort of patients with gs 7.16,19,20 a study from lau et al. determined multivariate prognostic significance of dna ploidy gs 7 cohort but not in the gs 8-10 cohort.24,29 pretorious et al. reported that dna ploidy was the only significant predictor of early recurrence in a gs 7 cohort subset.20 lennartz et al. indicated that dna aneuploidy with deletion of pten and 6q15 have shown the strongest prognostic information in subgroup of patients with gg2.16 study limitations the low number of recurrences limits the strength of our findings and a larger cohort is definitively needed. also two-thirds of recurrent patients received salvage treatments after rp, therefore evaluation of time to metastases as an endpoint was not possible. however, studies indicate that a psa threshold of 0.4 ng/ml for bcr best predicts metastases.30 conclusion abnormal dna ploidy can be an independent prognostic marker of bcr in low-risk pca and increases prognostic value when combined with gleason assessment, allowing a more personalized approach to salvage treatments. references 1. bray f, ferlay j, soerjomataram i, siegel rl, torre la, jemal a. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca: a cancer journal for clinicians. 2018;68(6). doi:10.3322/caac.21492 2. welch hg, black wc. overdiagnosis in cancer. journal of the national cancer institute. 2010;102(9). doi:10.1093/jnci/djq099 3. grimm p, billiet i, bostwick d, et al. comparative analysis of prostatespecific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. results from the prostate cancer results study group. bju international. 2012;109(suppl. 1):22-29. doi:10.1111/j.1464-410x.2011.10827.x 4. veloso sg, lima mf, salles pg, berenstein ck, scalon jd, bambirra ea. interobserver agreement of gleason score and modified gleason score in needle biopsy and in surgical specimen of prostate cancer. international braz j urol. 2007;33(5):639-646. doi:10.1590/s167755382007000500005 5. brajtbord js, leapman ms, cooperberg mr. the capra score at 10 years: contemporary perspectives and analysis of supporting studies. european urology. 2017;71(5):705-709. doi:10.1016/j.eururo.2016.08.065 6. cooperberg mr, hilton jf, carroll pr. the capra-s score: a straightforward tool for improved prediction of outcomes after radical prostatectomy. cancer. 2011;117(22):50395046. doi:10.1002/cncr.26169 7. van den broeck t, van den bergh rcn, arfi n, et al. prognostic value of biochemical recurrence following treatment with curative intent for prostate cancer: a systematic review. european urology. 2019;75(6):967987. doi:10.1016/j.eururo.2018.10.011 8. tilki d, preisser f, graefen m, huland h, pompe rs. external validation of the european association of urology biochemical recurrence risk groups to predict metastasis and mortality after radical prostatectomy in a european cohort. european urology. 2019;75(6):896-900. doi:10.1016/j.eururo.2019.03.016 9. spratt de, yousefi k, deheshi s, et al. individual patient-level metaanalysis of the performance of the decipher genomic classifier in highrisk men after prostatectomy to predict development of metastatic disease. journal of clinical oncology. 2017;35(18):1991-1998. doi:10.1200/jco.2016.70.2811 10. fine nd, lapolla f, epstein m, loeb s, dani h. genomic classifiers for treatment selection in newly diagnosed prostate cancer. bju international. 2019;124(4):578-586. doi:10.1111/bju.14799 11. wei l, wang j, lampert e, et al. intratumoral and intertumoral genomic heterogeneity of multifocal localized prostate cancer impacts molecular classifications and genomic prognosticators. european urology. 2017;71(2):183-192. doi:10.1016/j.eururo.2016.07.008 12. danielsen he, pradhan m, novelli m. revisiting tumour aneuploidy — the place of ploidy assessment in the molecular era. nature reviews clinical oncology. 2016;13(5):291-304. doi:10.1038/nrclinonc.2015.208 13. chunduri nk, storchová z. the diverse consequences of aneuploidy. nature cell biology. 2019;21(1):54-62. doi:10.1038/s41556-018-0243-8 14. böcking a, tils m, schramm m, dietz j, biesterfeld s. dna-cytometric grading of prostate cancer systematic review with descriptive data analysis. pathology discovery. 2014;2(1):7. doi:10.7243/2052-7896-2-7 15. authors. 2013 16. lennartz m, minner s, brasch s, et al. the combination of dna ploidy status and pten/6q15 deletions provides strong and independent prognostic information in prostate cancer. clinical cancer research: an official journal of the american association for cancer research. 2016;22(11):2802-2811. doi:10.1158/10780432.ccr-15-0635 17. stopsack kh, whittaker ca, gerke ta, et al. aneuploidy drives lethal progression in prostate cancer. proceedings of the national academy of sciences of the united states of america. 2019;116(23):11390-11395. doi:10.1073/pnas.1902645116 18. ben-david u, amon a. context is everything: aneuploidy in cancer. nature reviews genetics. 2020;21(1):44-62. doi:10.1038/s41576-019-0171-x 19. carmichael mj, veltri rw, partin aw, miller mc, walsh pc, epstein ji. deoxyribonucleic acid ploidy analysis as a predictor of recurrence following radical prostatectomy for stage t2 disease. the journal of urology. 1995;153(3 pt 2):1015— 1019. doi:10.1097/00005392199503001-00029 20. pretorius me, wæhre h, abeler vm, et al. large scale genomic instability as an additive prognostic marker in early prostate cancer. cellular oncology. 2009;31(4):251-259. doi:10.3233/clo-2009-0463 21. pound cr. natural history of progression after psa elevation following radical prostatectomy. jama. 1999;281(17):1591. doi:10.1001/jama.281.17.1591 22. garner dm, todorovic c, lee we. cytological stain composition and method of use. us patent no. 2,006,199,243. 2005. 23. doudkine a, macaulay c, poulin n, palcic b. nuclear texture measurements in image cytometry. pathologica. 1995;87(3):286-299. 24. lau wk, bergstralh ej, blute ml, slezak jm, zincke h. radical prostatectomy for pathological gleason 8 or greater prostate cancer: influence of concomitant pathological variables. the journal of urology. 2002;167(1):117-122. 25. bantis a, patsouris e, gonidi m, et al. telomerase rna expression and dna ploidy as prognostic markers of prostate carcinomas. tumori. 2009;95(6):744-752. doi:10.1177/030089160909500618 26. swanson gp, chen w, speights vo. failure of ploidy and proliferative fraction to predict long-term outcome after prostatectomy. world journal of oncology. 2018;9(3):69-73. doi:10.14740/wjon1111w 27. blute ml, bergstralh ej, iocca a, scherer b, zincke h. use of gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. journal of urology. 2001;165(1):119-125. doi:10.1097/00005392200101000-00030 28. hveem ts, kleppe a, vlatkovic l, et al. chromatin changes predict recurrence after radical prostatectomy. british journal of cancer. 2016;114(11):1243-1250. doi:10.1038/bjc.2016.96 29. lau wk, blute ml, bostwick dg, weaver al, sebo tj, zincke h. prognostic factors for survival of patients with pathological gleason score 7 prostate cancer: differences in outcome between primary gleason grades 3 and 4. the journal of urology. 2001;166(5):1692-1697. 30. toussi a, stewart-merrill sb, boorjian sa, et al. standardizing the definition of biochemical recurrence after radical prostatectomy—what prostate specific antigen cut point best predicts a durable increase and subsequent systemic progression? journal of urology. 2016;195(6):17541759. doi:10.1016/j.juro.2015.12.075 table 1. clinical characteristics of the study cohort (97 patients). variable mean (iqr) or number (%) observation period (years) 12.1(3.7–16.2) age at rp (y-old) 61.0 (56.6-66.3) pre-operative psa (ng/ml) 4.8 (1.0 10.0) pathological t stage pt2 88 (91%) pt3a 9 (9%) isup gg, general pathology (ggg) ggg1 74(76%) ggg2 23 (24%) isup gg, expert pathology (egg) egg1 60 (92%) egg2 37 (38%) biochemical recurrence (bcr) none 79 (82%) low-risk 14 (14%) high-risk 4(4%) salvage therapy when bcr 10 (56%) distant metastases 1 (1%) overall survival 96 (96%) cancer-specific survival 99 (99%) figures: figure 1. dna ploidy histograms of two study samples. (a) patient without biochemical recurrence and (b) patient with biochemical recurrence. figure 2. nuclear images of cells. a) diploid cells, b) cells with a dna index around 1.5 and c) cells with a dna index higher than 2.2 (highly aneuploid cells). figure 3. correlation between dna ploidy features and psa doubling time. none: no recurrence (79 cases); low-risk: psa doubling time >1 year (14 cases) and high-risk: psa doubling time ≤1 year (4 cases). (a) box plots of the ploidy score (anova, p=9.6x10-8). the bold line represents the median, the boxes represent the 50th percentile and error bars represent 5th and 95th percentile of cell frequencies. (b) number of aneuploid cells (di >2.5) (anova, p=1.7x10-11). figure 4. cumulative proportion of bcr-free survival (bcrfs) according to the ploidy score (a) (log rank test, p=4x10-7) and egg (b) (p=0.004, respectively). figure 5. kaplan-meier plot of bcr-free survival for patients grouped according to egg diagnosis and ploidy score. (a) ps/ egg1, (b) ps/ egg2, (c) ps+ / egg1 and (d) ps+ / egg2. using log-rank test, there was a significant difference between groups a and c (p = 0.04), between groups a and d (p=7x10-10) between groups b and d (p=4x10-5) and between groups b and c (p = 0.04). flexible ureteroscopic lithotripsy based on the concept of enhanced recovery after surgery: a single-centered retrospective study ling shu1, ping ao2*, zhenxing zhang2,dong zhuo2, changbin dong2 purpose: to evaluate the efficacy of flexible ureteroscopic lithotripsy (fursl) based on the concept of enhanced recovery after surgery (eras). materials and methods: this study retrospectively analyzed 435 patients diagnosed with upper urinary calculi between 2017-2020 and categorized them into eras (eras management) and control groups (traditional management). the operative time, postoperative ambulation time, postoperative hospital stay, the total cost of hospitalization, postoperative complications, and stone removal rate between the two groups were subsequently compared. results: the fursl procedure was successfully performed in 427 patients but failed in 4 patients of the eras group (n = 216) and 4 of the control group (n = 219). no postoperative complications occurred in either group except for fever and hematuria. there was no significant difference in postoperative fever and stone removal between the two groups (all p > .05). however, patients in the eras group had a shorter operative time, shorter postoperative ambulation time, less postoperative severe hematuria, shorter postoperative hospital stay, and lower total cost of hospitalization than those in the control group (all p < .05). conclusion: fursl, based on the concept of eras, is safe and reliable for the treatment of upper urinary calculi, with rapid postoperative recovery and a low cost of hospitalization. it is worthy of clinical promotion. keywords: flexible ureteroscopy; lithotripsy; laser; upper urinary calculi; enhanced recovery after surgery; retrospective study introduction enhanced recovery after surgery (eras) was first advocated by kehlet henrik in colorectal surgery at the end of the last century.(1) the concept has become increasingly popular among surgical staff since then. according to existing evidence-based medical practice, eras uses multimodal strategies to optimize perioperative related treatments, reduce body stress response, and avoid complications. eras also adopts minimally invasive techniques to improve surgical safety and patient satisfaction to accelerate patients’ recovery and shorten hospital stays.(2) studies report that eras can reduce hospital stay by approximately 30%, thereby reducing medical costs without increasing the risk of postoperative complications and readmission rates.(3-6) notably, the eras concept is relatively rare in urology despite its popularization in general surgery in recent years. in the same line, the awareness and application of eras by chinese surgeons and patients is also under continuous improvement and development, with a need to update and change some traditional concepts. urinary calculi are common and frequently-occurring diseases amongst chinese people. the overall prevalence of kidney stones is about 5.88% in china, with higher prevalences in the southern area of the yangtze river.(7) in the past, surgical treatment of urolithiasis was mainly based on open surgery and was associat1department of operating room, the first affiliated hospital of wannan medical college, wuhu 241001, china. 2department of urology, the first affiliated hospital of wannan medical college, wuhu 241001, china. *correspondence: department of urology, the first affiliated hospital of wannan medical college, wuhu 241001, china. tel: +86 15155355389, e-mail: aoping@wnmc.edu.cn received december 2021 & accepted may 2022 ed with a slow postoperative recovery process. in recent years, the rapid development of minimally invasive techniques in urology has enabled the removal of a vast majority of urinary stones through endoscopic surgery. flexible ureteroscopic lithotripsy (fursl) has been widely performed to treat upper urinary tract stones with reasonable safety and effectiveness. it is a typical representative of minimally invasive surgery in the urinary system and conforms to the core strategy of eras(2,8) currently, there are only a few reports regarding applying eras in the perioperative period of fursl. we thus conducted a retrospective case-control study to evaluate the clinical effectiveness of eras during the perioperative period of fursl. materials and methods this study was approved by the research ethics committee of the first affiliated hospital of wannan medical college. it was performed following the "helsinki declaration" and "international bioethical research involving human ethical guidelines." it included patients with upper urinary tract calculi treated using fursl procedure between january 2017 and april 2020 at the department of urology, wannan medical college. all the patients underwent the preoperative examination, including b-mode ultrasonography (b-ultrasonography) scan, plain abdominal radiography for kidney-ureurology journal/vol 19 no. 4/ july-august 2022/ pp. 268-273. [doi: 10.22037/uj.v19i.7118] endourology and stone disease ter-bladder (kub), computed tomography (ct) scan, or dual-source ct to confirm the diagnosis of urinary stones. those with normal renal function were examined using intravenous pyelography (ivp). magnetic resonance urography (mru) or computed tomography urography (ctu) was performed if necessary. patients included in the study were those with kidney or upper ureteral calculi with stone diameter less than 30 millimeters, calculi with the unsatisfactory outcome of extracorporeal shockwave lithotripsy (swl) or percutaneous nephrolithotomy (pcnl), and whose renal calculi were not suitable for pcnl because of obesity, scoliosis, or patient's wishes. patients with other urinary diseases, such as excessive hydronephrosis, renal empyema, and severe urethral or ureteral stricture were excluded from the study. the patients were categorized based on the management measures during the perioperative period of fursl. the groups included the eras group comprising patients undergoing perioperative management based on the concept of eras and the control group comprising patients undergoing traditional perioperative management. patients were divided into two groups based on the different responsible doctors. physicians in one treatment team included their patients admitted to the outpatient clinic who required fursl procedures into eras management, while physicians in the other treatment teams applied traditional management methods during the perioperative period of fursl. preoperative routine urine tests and urine culture were variables eras group (n = 216) control group (n = 219) p value or age in years, mean ± sd 50.38 ± 13.19 52.67 ± 12.62 .064a gender, male, n (%) 136 (63.0) 128 (58.4) .335b 1.209 stone location, n (%) .483b kidney 185 (85.6) 195 (89.0) upper ureteral 14 (6.5) 9 (4.1) kidney and upper ureteral 17 (7.9) 15 (6.9) stone side, n (%) .677b left 99 (45.8) 109 (49.8) right 106 (49.1) 101 (46.1) bilateral 11 (5.1) 9 (4.1) stone size (mm), m(iqr) 20 (5) 20 (5) .272a underlying diseases, yes, n (%) 107 (49.5) 95 (43.4) .198b 1.281 history of urolithiasis surgery, yes, n (%) 18 (8.3) 26 (11.9) .221b .675 type of flexible ureteroscope, n (%) .514b digital 86 (39.8) 77 (35.2) modular 107 (49.5) 113 (51.6) fiberoptic 23 (10.6) 29 (13.2) table 2. baseline characteristics of the patients abbreviations: eras, enhanced recovery after surgery; sd, standard deviation; or, odd ratio; m, median; iqr, interquartile range. a continuous variables were compared by independent samples t-test or mann-whitney test. b categorical variables were compared by pearson chi-square test. eras during the perioperative period of furslshu et al. table 1. summary of perioperative management measures eras group control group before surgery preoperative double-j stent indwelling 0-2 weeks preoperative double-j stent indwelling 2-4 weeks individualized preoperative education using multimedia traditional preoperative education with paper materials surgeons, nurses, and anesthetists formed a surgeons, nurses or anesthetists performed preoperative visits respectively multidisciplinary team for preoperative visits a list of rehabilitation plans no no preoperative bowel preparation no preoperative bowel preparation except for patients with constipation normal oral solid nutrition until 6 hours before surgery normal oral solid nutrition until 10 hours before surgery normal drinking water until 2 hours before surgery normal drinking water until 10 hours before surgery 250-400 ml carbohydrate drinks for no non-diabetic patients 2 hours before surgery during surgery combining laryngeal mask ventilation with general anesthesia combining tracheal intubation with general anesthesia selecting short-acting anesthetics as much as possible no strengthen monitoring of intraoperative body temperature no increasing the operating room temperature (24-26 ℃) general operating room temperature (22-24 ℃) warming intravenous fluids and surgical infusion no fluids when ureteroscopy goal-directed fluid therapy for intraoperative fluid administration standard intraoperative fluid regimen using syringes for saline infusion of fursl by an irrigation pump for saline infusion of fursl the assistant with hands after surgery selecting non-opioids based on patients, postoperative not deliberately avoiding opioids for analgesia analgesia needs drinking water 6 hours after surgery and then receiving oral intake after gastrointestinal function was recovered gradually resuming diet mobilization out of bed 6 hours after surgery mobilization out of bed 12-24 hours after surgery removing urinary catheter 12-24 hours after surgery removing urinary catheter 24-48 hours after surgery discharge and discharging based on the criteria, returning for kub discharging based on the criteria, returning to kub follow-up x-ray or ct scan 2 weeks later and removing double-j stent x-ray or ct scan 4 weeks later and removing double-j stent abbreviations: eras, enhanced recovery after surgery; fursl, flexible ureteroscopic lithotripsy; kub, kidney-ureter-bladder; ct, computed tomography endourology and stones diseases 269 done for patients in both groups. an anti-infective treatment was actively carried out if a patient was found to have obvious evidence of urinary tract infection (uti), such as a positive urine culture or a negative urine culture but more than two urine tests showing increased leukocyte count. the treatment involved selecting sensitive antibiotics with the guidance of a drug susceptibility test or prescribing antibiotics empirically when urine culture was negative. the fursl procedure was performed after significant improvement of the laboratory urinalysis results. table 1 outlines the perioperative management measures of the two groups. patients were discharged when they agreed and had attained a normal temperature, started feeding on a normal diet, and had normal mobilization, with no urinary catheter, serious gross hematuria, severe flank or abdominal pain, and serious dysuria. the main surgical instruments and accessory tools used included a flexible digital ureteroscope (urf-v, olympus; shinjuku-ku, tokyo, japan), modular flexible ureteroscope (pd-ps-0094, polydiagnost; hallbergmoos, freistaat bayern, germany), fiberoptic flexible ureteroscope (11278a1, karl storz; tuttlingen, baden-württemberg, germany), rigid ureteroscope (8/9.8f, richard wolf; knittlingen, baden-württemberg, germany), ureteral access sheath (12/14f, cook; west lafayette, indiana, usa), holmium laser (powersuite 100w, lumenis; yokneam, hazafon, israel), and nitinol stone baskets (2.2f, cook; west lafayette, indiana, usa). all fursl procedures were performed by senior urologists. the patients were placed on the operating table in the lithotomy-trendelenburg position after general anesthesia, followed by removal of a preoperative double-j stent using a rigid ureteroscope and retrograde placement of a 0.035-inch guidewire to guide the ureteral access sheath. a flexible ureteroscope was then inserted along the sheath to explore the renal pelvis and calyxes for stones. fragmenting of the stones was subsequently conducted under a holmium laser with a 200-μm fiber at an energy of 0.8-1.2 j and frequency of 15-20 hz. a nitinol stone basket was inserted at the end of the lithotripsy to grab larger fragments for analyzing stone composition. the final step was indwelling a 5-6f double-j stent and 16-18f catheter. patients' baseline characteristics including age, gender, stone location (kidney or upper ureteral), stone side, stone size (maximum diameter), underlying diseases (e.g., hypertension, diabetes mellitus, gout, chronic kidney disease), history of urinary stone, and type of flexible ureteroscope were collected for patients in both groups. postoperative clinical data, including operative time, ambulation time, hospital stay, the total cost of hospitalization, complications, and stone removal rate of patients in both groups, were subsequently recorded for group comparisons. operative time refers to the time from rigid ureteroscope insertion to double-j stent placement. the main complications included postoperative fever and hemorrhage. fever was defined as the axillary temperature higher than 37.3 ℃. it was further divided into lowgrade fever (37.3-38.0 ℃), moderate fever (38.1-39.0 ℃), and high-grade fever (≥ 39.1 ℃). a patient was deemed to have severe postoperative hematuria if the gross hematuria lasted more than 24 hours after surgery, urological oncology 198 variables eras group (n = 212) control group (n = 215) p value or operative time (min), m(iqr) 75 (50) 90 (50) .003a postoperative ambulation time (h), m(iqr) 10 (7) 22 (6) < .001a postoperative hospital stays (d), m(iqr) 2 (1) 3 (1) < .001a total cost of hospitalization (usd), m(iqr) 2709.6 (620.6) 2776.9 (873.1) .015a postoperative fever, n (%) .579b .887 yes 57 (26.9) 63 (29.3) no 155 (73.1) 152 (70.7) postoperative severe hematuria, n (%) .015b .477 yes 18 (8.5) 35 (16.3) no 194 (91.5) 180 (83.7) clavien-dindo classification, n (%) .784b 1.163 grade ⅰ 69(32.5) 89(41.4) grade ⅱ 6(2.8) 9(4.2) stone removal, n (%) .541b 1.151 complete 166 (78.3) 163 (75.8) incomplete 46 (21.7) 52 (24.2) abbreviations: eras, enhanced recovery after surgery; or, odd ratio; m, median; iqr, interquartile range; usd, united states dollar (converted from cny at the exchange rate on july 6, 2020). a continuous variables were compared by mann-whitney test. b categorical variables were compared by pearson chi-square test. table 3. postoperative clinical outcomes variables eras group (n = 57) control group (n = 63) p value postoperative fever, n (%) .220a low-grade 42 (73.7) 38 (60.3) moderate 13 (22.8) 19 (30.2) high-grade 2 (3.5) 6 (9.5) abbreviations: eras, enhanced recovery after surgery. a categorical variables were compared by pearson chi-square test. table 4. distribution of the patients with postoperative fever. eras during the perioperative period of furslshu et al. vol 19 no 4 july-august 2022 270 combined with blood clot formation, or the hemoglobin value continued to decrease. complete removal of stones was evaluated using kub x-ray or ct scan 2-4 weeks after surgery. small residual stones or fragments smaller than 4mm diameter did not require surgical intervention. data were analyzed using spss version 22.0 (ibm, usa) to compare the baseline characteristics and postoperative clinical data between the two groups. continuous data were expressed as means ± sd or median (interquartile range), while categorical data were expressed as percentages. two-sided independent sample t-test, mann-whitney test and chi-squared tests were performed to compare the means and percentage frequencies of the two groups. the significance threshold was set at p < 0.05. results this study enrolled 435 patients who gave informed consent. however, 8 patients, 4 from the eras group and 4 from the control group, were withdrawn because of failure of the fursl procedure. among the 4 in the eras group, 1 had a flexible ureteroscope and was unable to pass the ureteral stricture, 1 had a stricture of the renal calyx neck, 1 had no calculi after flexible ureteroscopy, and 1 had lower calyceal calculus whose treatment was changed to swl because of the restricted angle for fursl. among the other 4 in the control group, 1 had no stones after flexible ureteroscopy, 1 had lower calyceal calculus whose treatment changed to pcnl owing to the angle limitation, and 2 had a hard texture of stones whose treatment changed to pcnl. the remaining 427 patients completed the trial and were assigned to two groups: 212 patients in the eras group and 215 patients in the control group. of note, there were no significant differences between patients in the eras and the control groups in age, gender, stone location, stone side, stone size, underlying diseases, history of urinary stone, and type of flexible ureteroscope (p > .05) (table 2). no postoperative complications occurred in either group except for fever and hematuria, with no significant differences in postoperative fever and stone removal between the two groups (p > .05) (table 3 and table 4). however, patients in the eras group had shorter operative time, shorter postoperative ambulation time, less postoperative severe hematuria, shorter postoperative hospital stay, and lower total cost of hospitalization than those in the control group (p < .05) (table 3). postoperative complications mainly included fever and severe hematuria, considered grade ⅰ or grade ⅱ according to the clavien-dindo classification. notably, the majority of the postoperative fever cases in both groups were low to moderate fever (table 4). a patient in the control group having postoperative hematuria with repeated hemorrhage was finally cured using super-selective renal artery embolization for hemostasis. in the multivariate logistic regression analysis, the eras management, age, underlying diseases, and operative time were independent risk factors for severe hematuria after fursl in patients (p < .05) (table 5). discussion the current proportion of minimally invasive surgery in the field of urology is more than 90% in many regional medical institutions, a phenomenon that is in line with the requirements of eras. some studies report satisfactory outcomes of the eras program in laparoscopic radical prostatectomy, radical cystectomy, and laparoscopic radical nephrectomy.(5,9-12) however, there are only a few reports about eras application in ureteroscopy, especially a lack of specialist guidance similar to that in general surgery. in view of minimally invasive surgeries, eras has broad application prospects in the perioperative period of fursl. this study evaluated the clinical application of eras in fursl to explore the optimization and implementation of eras measures, which proved to be advantageous, especially for patients. hematuria is one of the most common complications after the fursl procedure. severe hematuria is often related to factors such as abnormal coagulation function related to the patient's age or underlying diseases, long operation time, and intraoperative renal injury. our findings were also consistent with these observations. compared with the traditional perioperative management measures, eras measures had significant advantages in shortening the operative time, decreasing postoperative hematuria, promoting recovery, and reducing hospital costs. in the eras group, an experienced assistant used a 50ml syringe for saline infusion by hands instead of an irrigation pump during the fursl procedure, thus flexibly controlling the infusion speed and timing. fluids infusion during ureteroscopy increases the hydrostatic pressure in the renal collecting system, causing harmful effects during the early term.(13) notably, the irrigation pressure may substantially increase the intraoperative renal pelvic pressure. (14) studies postulate that excessive intrarenal pressure may lead to serious infection, especially in patients with preoperative uncontrolled utis who are prone to urosepsis.(15-17) in addition, continuous high pressure in the renal pelvis may also lead to renal injury or hematoma. (18) the ureteral access sheath in place may drain most fluids to maintain low intrarenal pressure in the fursl procedure.(19) using intelligent pressure-controlled devices may also be beneficial for maintaining low pressure, increasing the hospital costs for patients.(20-21) in variables p value or 95% ci eras management .039 .343 .124.946 age .000 1.143 1.098-1.190 gender .057 .185 .033-1.048 underlying diseases .009 7.103 1.616-31.226 history of urolithiasis surgery .237 2.157 .604-7.709 operative time .000 1.022 1.010-1.035 table 5. multivariate analysis of severe hematuria after fursl in patients. abbreviations: eras, enhanced recovery after surgery; or, odd ratio; ci, confidence interval. eras during the perioperative period of furslshu et al. endourology and stones diseases 271 this study, the 12/14f ureteral access sheath achieved a great drainage effect. the excessive intrarenal pelvic pressure was effectively avoided in the eras group using inexpensive artificial irrigation in which the irrigant was timely adjusted for more suitable flow, thus enhancing the safety of surgery. studies postulate that eras intervention can alleviate the postoperative stress response in patients and accelerate their recovery.(22-24) notably, this study came to a similar conclusion. the severity of postoperative hematuria in the eras group was lower than in the control group, attributed to a milder stress response. despite patients ambulating out of bed earlier, the incidence of severe hematuria was not increased in the eras group, which may lead to less spending on medical interventions and shorter postoperative hospital stays. as a result of these two factors, although the difference in cost of surgery was limited, patients in the eras group had lower total hospitalization costs which improved their satisfaction. this study affirms that the key to implementing eras measures during the perioperative period of fursl is to change some traditional and backward medical concepts. a few medical staff, patients and their families are convinced of some traditional concepts, such as long-term fasting before surgery, preoperative bowel preparation, postoperative oral intake after the recovering of gastrointestinal function, lying without a pillow for 6 hours or more after surgery, rare mobilization out of bed, long-term indwelling catheter, excessive infusion, and antibiotic treatment, which are currently outdated in china. of note, many traditional concepts lack the support of evidence-based medicine. for example, a catheter was retained for 3 days after ureteroscopic lithotripsy, while a double-j stent was indwelt for 4 weeks before fursl during the early stages of endoscopic surgery. such seemingly safe measures increase the risk of postoperative local infection, deep vein thrombosis, backache, and urination discomfort. in the study, we decided the time of removing urinary catheters according to the different intraoperative conditions and postoperative recovery of each case. the time in eras group was controlled within 12-24 hours, while the control group within 24-48 hours. the extubation time was not exactly the same for each patient in each group, but was within the above ranges. similarly, we reduced the time to remove double-j stent from the traditional 4 weeks to 2 weeks postoperatively in the eras group. it is also reported that an appropriate amount of carbohydrate drinks and shortening of the fasting time before surgery may alleviate the patients’ thirst, hunger, nervousness, and other discomforts, thus having a positive effect on the patients during and after surgery. (10) a preoperative double-j stent in patients without ureteral stricture may inhibit the successful placement of the ureteral access sheath and complete removal of stones by fursl.(25) we believe that preoperative bowel preparation is mainly suitable for colorectal surgery patients. an enema may cause complications, such as pain, bleeding, and infection, especially in patients with hemorrhoids or the elderly. we also believe that shortterm placement of double-j stent or preparation without stent before fursl procedure should be tried if the ureter is unobstructed by imaging suggestion or the patients have a history of ureteroscopy. there was no preoperative bowel preparation for patients in the eras group in this study. those without diabetes mellitus had a carbohydrate drink (250-400 ml, 10% glucose injection) 2 hours before surgery. preoperative placement of the stent for 0-2 weeks is a measure of eras. these measures significantly relieved the negative mood, particularly in patients who were waiting for surgery, and did not increase the postoperative gastrointestinal discomfort and complications. with the prolongation of the double-j stent intubation time, the patient will have obvious lower urinary tract symptoms after the fursl procedure. in fact, 2 weeks of postoperative indwelling time of the double-j stent is sufficient for most patients, instead of the traditionally thought of 4 weeks. discomfort caused by the stent and lower urinary tract symptoms associated with the stent was also reduced in the eras group. despite the invaluable findings, this study was limited by its retrospective nature. the standard eras program was altered to fit the colorectal surgery field. some measures such as nutritionist participation, pain score, and multimodal analgesia were not strictly implemented. data on intraoperative pelvic pressure were also missing, as the pelvic pressure was not monitored in most cases during the fursl procedure. future studies should focus on conducting prospective randomized controlled trials with an adequately optimized eras protocol for fursl. conclusions eras measures can shorten the operative time, accelerate postoperative recovery, and reduce the total hospital cost of patients with fursl surgery. eras ameliorated the traditional measures regarding patients' diet, bowel preparation, anesthesia, and infusion in the perioperative period of fursl and strengthened the communication with anesthetists, nurses, and other specialists that deal with comorbidities. individualized eras measures can be developed and implemented to ensure rapid rehabilitation after surgery, as in this study. this study strongly suggests that fursl, based on the concept of eras, is safe and reliable with excellent clinical results, highlighting the worth of the eras program. nonetheless, future prospective randomized controlled studies should be conducted to evaluate whether an optimized eras protocol may improve outcomes. acknowledgement this study was approved by the first affiliated hospital of wannan medical college as a clinical research project. the work was supported by the key program of scientific research for universities in anhui department of education [grant no. sk2018a0197]. conflict on interest the authors report no conflict of interest. references 1. kehlet h. multimodal approach to control postoperative pathophysiology and rehabilitation. br j anaesth. 1997; 78:606-17. 2. mcleod rs, aarts ma, chung f, et al. development of an enhanced recovery after surgery guideline and implementation strategy based on the knowledge-to-action cycle. ann surg. 2015; 262:1016-25. 3. asklid d, segelman j, gedda c, hjern f, pekkari k, gustafsson uo. the impact of eras during the perioperative period of furslshu et al. vol 19 no 4 july-august 2022 272 urological oncology 200 perioperative fluid therapy on short-term outcomes and 5-year survival among patients undergoing colorectal cancer surgery a prospective cohort study within an eras protocol. eur j surg oncol. 2017; 43:1433-9. 4. ruiz-tovar j, munoz jl, royo p, et al. implementation of the spanish eras program in bariatric surgery. minim invasive ther allied technol. 2018; 27:365-72. 5. frees sk, aning j, black p, et al. a prospective randomized pilot study evaluating an eras protocol versus a standard protocol for patients treated with radical cystectomy and urinary diversion for bladder cancer. world j urol. 2018; 36:215-20. 6. offodile ac, gu c, boukovalas s, et al. enhanced recovery after surgery (eras) pathways in breast reconstruction: systematic review and meta-analysis of the literature. breast cancer res treat. 2019; 173:65-77. 7. zeng g, mai z, xia s, et al. prevalence of kidney stones in china: an ultrasonography based cross-sectional study. bju int. 2017; 120:109-16. 8. sener te, tanidir y, bin hamri s, et al. effects of flexible ureteroscopy on renal blood flow: a prospective evaluation. scand j urol. 2018; 52:213-18. 9. abou-haidar h, abourbih s, braganza d, et al. enhanced recovery pathway for radical prostatectomy: implementation and evaluation in a universal healthcare system. can urol assoc j. 2014; 8:418-23. 10. mir mc, zargar h, bolton dm, murphy dg, lawrentschuk n. enhanced recovery after surgery protocols for radical cystectomy surgery: review of current evidence and local protocols. anz j surg. 2015; 85:514-20. 11. rege a, leraas h, vikraman d, et al. could the use of an enhanced recovery protocol in laparoscopic donor nephrectomy be an incentive for live kidney donation? cureus. 2016; 8:e889. 12. ricotta c, cintorino d, pagano d, et al. enhanced recovery after implementation of surgery protocol in living kidney donors: the ismett experience. transplant proc. 2019; 51:2910-3. 13. benli e, ayyildiz sn, cirrik s, noyan t, ayyildiz a, cirakoglu a. early term effect of ureterorenoscopy (urs) on the kidney: research measuring ngal, kim-1, fabp and cys c levels in urine. int braz j urol. 2017; 43:887-95. 14. shao y, shen zj, zhu yy, sun xw, lu j, xia sj. fluid-electrolyte and renal pelvic pressure changes during ureteroscopic lithotripsy. minim invasive ther allied technol. 2012; 21:302-6. 15. zhong w, leto g, wang l, zeng g. systemic inflammatory response syndrome after flexible ureteroscopic lithotripsy: a study of risk factors. j endourol. 2015; 29:25-8. 16. abourbih s, alsyouf m, yeo a, et al. renal pelvic pressure in percutaneous nephrolithotomy: the effect of multiple tracts. j endourol. 2017; 31:1079-83. 17. kaygisiz o, satar n, gunes a et al. factors predicting postoperative febrile urinary tract infection following percutaneous nephrolithotomy in prepubertal children. j pediatr urol. 2018; 14:448 e441-7. 18. vaidyanathan s, samsudin a, singh g, hughes pl, soni bm, selmi f. large subcapsular hematoma following ureteroscopic laser lithotripsy of renal calculi in a spina bifida patient: lessons we learn. int med case rep j. 2016; 9:253-9. 19. rehman j, monga m, landman j, et al. characterization of intrapelvic pressure during ureteropyeloscopy with ureteral access sheaths. urology. 2003; 61:713-8. 20. deng x, song l, xie d, et al. a novel flexible ureteroscopy with intelligent control of renal pelvic pressure: an initial experience of 93 cases. j endourol. 2016; 30:1067-72. 21. huang j, xie d, xiong r, et al. the application of suctioning flexible ureteroscopy with intelligent pressure control in treating upper urinary tract calculi on patients with a solitary kidney. urology. 2018; 111:44-7. 22. yeung se, hilkewich l, gillis c, heine ja, fenton tr. protein intakes are associated with reduced length of stay: a comparison between enhanced recovery after surgery (eras) and conventional care after elective colorectal surgery. am j clin nutr. 2017; 106:44-51. 23. qi s, chen g, cao p, et al. safety and efficacy of enhanced recovery after surgery (eras) programs in patients undergoing hepatectomy: a prospective randomized controlled trial. j clin lab anal. 2018; e22434. 24. rubinkiewicz m, witowski j, su m, major p, pedziwiatr m. enhanced recovery after surgery (eras) programs for esophagectomy. j thorac dis. 2019; 11: s685-91. 25. dessyn jf, balssa l, chabannes e, et al. flexible ureterorenoscopy for renal and proximal ureteral stone in patients with previous ureteral stenting: impact on stonefree rate and morbidity. j endourol. 2016; 30:1084-8. eras during the perioperative period of furslshu et al. endourology and stones diseases 273 running head: retroperitoneal partial nephrectomy retroperitoneal nephrometry scoring system (retro) for minimal-invasive partial nephrectomy sunyi ye1*, lixian zhu2*, ping wang1, xinxing sun3, xin xu1, feng zhao4, xiaolin yao1, qiang huang5, yun dai1, dan xia1, shuo wang1* institutions: 1 department of urology, the first affiliated hospital, school of medicine, zhejiang university, hangzhou, china 2 department of thyroid disease center, the first affiliated hospital, school of medicine, zhejiang university, hangzhou, china. 3 department of operating center, the first affiliated hospital, school of medicine, zhejiang university, hangzhou, china. 4 department of radiation oncology, the first affiliated hospital, school of medicine, zhejiang university, hangzhou, china. 5 department of radiology, the first affiliated hospital, school of medicine, zhejiang university, hangzhou, china. authors contribution statement syy, lxz and sw had full aaccess to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. study concept and design: syy, lxz, pw, sw. acquisition of data: lxz, xxs, xx, fz, xly, yd. analysis and interpretation of data: syy, pw, qh, yd, dx. drafting of the manuscript: syy, lxz, dx. critical revision of the manuscript for important intellectual content: xxs, qh, dai, dx, sw. statistical analysis: lxz, fz, xly. obtaining funding: syy. administrative, technical, or material support: yd, dx, sw. supervision: dx, sw. other (specify): none. acknowledgements none. funding statement this work was supported by national natural science foundation of china (no. 81800558). conflict of interest the authors declared that there is no conflict of interest. ethics statement the study was obtained local ethic committee approval. data sharing statement we can share our data with the journal for representing analysis and interpretation of the data. however, we do not want the readers to view or download our data. abstract purpose: to propose a standardized scoring system of renal tumors suitable for partial nephrectomy based on mini-invasiveness and retroperitoneal approach. materials and methods: one-hundred and five patients in retroperitoneal group were prospectively enrolled from january 2017 to december 2018. perioperative characteristics of all patients were collected: age, gender, bmi, preoperative blood test and imaging results, operation time (the time period starts from the skin incision to the final skin closure), estimated blood lost, clamping time, complications within 30 days, american society of anesthesiologists (asa) score, pathology. an algorithm was extracted, and it was used to predict the risk of complications. results: symptoms, asa score and retro score were significantly correlated to postoperative complications, excluding tumor size, ischemia time and operation time. adjusted retro points were an independent factor to predict complication rate (p=0.006). limitation was that it did not analyze the relationship between the retro score and the long-term outcomes. conclusions: the retro score simplifies the risk evaluation of partial nephrectomy for patients with renal tumor, especially benefits those surgeries performed under robot-assisted laparoscope via retroperitoneal approach. the new retro score system that we developed is a selection criterion to perform surgery via different approach, and an accurate system to evaluate the complexity during partial nephrectomy. key words: partial nephrectomy; retroperitoneal nephrometry; surgical approach; score system; mini-invasive background partial nephrectomy (pn) is becoming the standard treatment for patients with low-stage renal tumor (1). the 2019 updated guidelines on renal cell carcinoma illustrated that localized t1 tumors are best managed by partial nephrectomy rather than radical nephrectomy, irrespective of the surgical approach (le: 1b). tan et al. analyzed more than 3000 patients with low-stage renal cell carcinoma under radical nephrectomy or partial nephrectomy, they found that the long-term overall survival was similar between radical and partial nephrectomy (2). while the risk of development of metabolic or cardiovascular disorders is increased after radical nephrectomy (3). patients with t2a also received pn, estimated blood lost and perioperative complications were higher, the all-cause mortality and oncologic outcomes were similar compared to radical nephrectomy (rn)(4,5). with the development of robot-assisted surgical technique, more and more patients received robot-assisted laparoscopic partial nephrectomy. off-clamp technique was used in totally endophytic renal tumors under robotic platform(6). there are different approaches for partial nephrectomy, transperitoneal way is undertaken by most urologists over the world. retroperitoneal approach also has its unique advantages, especially for those tumors located posterior side of the hilar, the kidney does not need to be mobilized around (7). it saves time and makes the manipulation much more easily. the nephrometry scoring system-r.e.n.a.l was reported in 2009 (8). it gave a qualitative and standardized evaluation system for various tumors. lots of other nephrometry scoring systems also emerged, padua classification, c-index method, and nephro system et al. (9-11). however, none of these scoring systems are correlated with different surgical approaches. especially for surgeons who are used to perform pn via retroperitoneal way, there is no evaluation criteria to be used. the objectives of this study are (1) to propose a standardized scoring system of renal tumors suitable for partial nephrectomy based on mini-invasiveness and retroperitoneal approach; (2) to evaluate the effectiveness and predict overall complications after pn according to this classification system. methods patients and tumors we prospectively included 122 patients who underwent robot-assisted laparoscopic partial nephrectomy (ralpn) between january 2017 and december 2018. inclusion criteria: (1) clinical stage 1 (ct1) renal tumors; (2) solitary kidney tumor; (3) age<80 years; (4) enhanced ct was performed in our medical center. patients with abnormal coagulation function or acute inflammation (temperature>38.0℃) were excluded. among these patients, 105 cases received the operation through retroperitoneal approach, 17 cases were via transperitoneal way. all these surgeries were performed by one surgeon (dr. wang), minimizing the methodological bias. all included patients received non-invasive renal angiography through computed tomography (cta) examination. three urologists independently read ct images and evaluated these parameters of each tumor: (1) diameter of the tumor (radius); (2) endophytic; (3) relationships with anterior lip (transperitoneal/retroperitoneal); (4) relationships with renal vessel trunk (vessel rete), vessel trunk includes the first and secondary renal artery/vein, or the diameter of the artery is larger than 3 mm; (5) relationships with renal polar (origin). we call it retro nephrometry classification system (table 1). when tumors locate in the front lip of the hilum, the manipulation will become difficult via retroperitoneal approach. the transperitoneal way is recommended. the definition of the “front lip” is that the space contains in the front side of the hilum, the inner boundary line is the inner edge of the kidney, the outer boundary is the line links the orifice of the hilum, the upper boundary is the line links the high point of the orifice and the up corner of the hilum, the inferior boundary is the line links the lower point to the orifice and the lower corner of the hilum (see figure 1a). this space is a “forbidden zone” when the retroperitoneal approach is used. tumors in this area are difficult to be handled, and it’s hard for surgeon to do the resection and suture. any tumor which “invades” this “forbidden zone” will be recommended to be removed from transperitoneal group (see figure 1d). otherwise, retroperitoneal way is suggested when tumors locate in other area of the kidney. the first parameter is an impression for the surgeon to judge which surgical approach is best for the patient. the maximal diameter of the tumor is also a critical factor affecting the surgical manipulation. one point is given to tumors that are 2cm or smaller, 2 points are given to tumors between 2-4 cm, 3 points are given to tumors between 4-6 cm, and each 2 cm larger gets another 1 point. no ceiling of the score is set. the classification is different from the tnm staging system, because the retroperitoneal cavity is not as large as the peritoneal space, and the diameter plays a more sensitive role (see figure 1b). another parameter is the percent of the protrusion of tumors. exophytic masses are easily to be resected than endophytic one. totally endophytic tumor is assigned 3 points. tumors that are 50% or more endophytic are assigned 2 points. tumors that are less than 50% endophytic are assigned 1 point (see figure 1c). the relationship between the tumor and main vessels also affects the surgical manipulation. main vessels include the primary or secondary artery/vein, or those with diameter larger than 3mm. the distance that is 0.6cm or larger is assigned 1 point. the distance which is less than 0.6cm is assigned 2 points. if the tumor closely touches or compresses main vessels, or vessels go through the tumor, 3 points are assigned (see figure 1e). it is assigned 1 point if tumors originate from the middle 1/3 portion of the outer boundary edge. tumors that originate from the superior or the inferior 1/3 of the outer edge are assigned 2 points. based on 2 points, tumors which are on the ventral side of kidney are assigned as 3 points (see figure 1f). patients received retroperitoneal ralpn in full flank (decubitus) position. vessel clamping was routinely used. all tumors were removed with an adequate margin to make sure the integrity of pseudo capsule. clinical features of all patients were collected: age, gender, bmi, preoperative blood test and imaging results, operation time (the time period starts from the skin incision to the final skin suture), estimated blood lost, clamping time, complications within 30 days, american society of anesthesiologists (asa) score, pathology. postoperative complications were evaluated by the clavien-dindo classification system (12,13). statistical analysis the student t test was used for continuous variables, and they were given as the mean plus standard deviation (the homogeneity of variance of each test has been assessed). the mannwhitney u test was used for non-normally distributed continuous variables, and they were given as the median and interquartile range (iqr). the pearson or likelihood ratio χ2 test was used for categorized variables. both logistic regression and roc curve were used (the multicollinearity of independent variables has been assessed). backward: conditional method was used in regression analysis. y was a dependent variable, x1, x2, x3--were independent variables, y= b0+b1x1+b2x2+---+bkxk, probability p= 𝑒𝑌 1+𝑒y . a two-sided p<0.05 was considered statistically significant. all data were analyzed with the statistical package for social sciences software, v.20.0 (spss inc., chicago, il, usa). results in retroperitoneal group, 63 patients (60.0%) were male and 42 patients (40.0%) were female. the median age was 54y (iqr: 46-63), and the median bmi was 24.3 (iqr: 22.2-26.3). in transperitoneal group, 12 patients (70.6%) were male and 5 patients (29.4%) were female. the median age was 56y (iqr: 53-63), and the median bmi was 22.6 (iqr: 20.8-25.0) (table 2). among the perioperative characteristics, most were comparable between two groups. while bmi, operation time and overall complication rate were significantly different. operation time was a little longer, and overall complication rate was also higher in transperitoneal group. bmi was higher in retroperitoneal group, that might because we preferred to use retroperitoneal approach for patients with relatively high bmi. the operation time was longer in transperitoneal group, that because the time of preparing patients’ position, placement of trocars and the skin closure were longer. the post-operative complication rate (gradeⅰ) was high in transperitoneal group, there were 14 cases (82.4%) after operation. the ischemia time was similar. it was 18 (iqr:15-22.5) minutes in retroperitoneal group, and 17 (iqr:12-27.5) minutes in transperitoneal group (p=0.891). in univariate analysis (table 3), symptoms, asa score and retro score were related to postoperative complications in retroperitoneal group. the median retro score was 7 (iqr: 5-9). and the score of retro classification could significantly affected the postoperative complication rate (p<0.05). the other factors did not impact on complication, even the radius did not affect the overall complication rate. while in the transperitoneal group, the radius was the only factor which had a significant impact on complication rate. in logistic regression analysis, the overall complication rate in retroperitoneal group was associated with symptoms, asa score and retro score. the algorithm was extracted from the logistic analysis, y=-2.413+20.909x1+0.729x2+0.972x3, x1 indicated symptoms, x2 indicated asa score, and x3 indicated retro score. complication probability p= 𝑒𝑌 1+𝑒y . retro score was classified into three categories, 4-6 was indicated 1 point, 7-10 was indicated 2 points, and ≥11 was indicated 3 points. if a patient had symptom (x1=1), asa score was 3 (x2=3), retro score was larger than 11 (x3=3), then y=2.413+20.909ⅹ1+0.729ⅹ3+0.972ⅹ3=23.599, p= 𝑒𝑌 1+𝑒y ≈1. this patient was most probably had a complication. another finding from the regression analysis was that patients with retro scored 2 were 1.85-fold higher risk of complication compared to those patients with retro scored 1. the complication risk of patients with retro scored 3 points were dramatically higher compared to those with retro scored 1 point. during the 1-year follow-up, two cases in transperitoneal group relapsed. the pathology is clear cell renal carcinoma (ccrcc, fuhrman grade ⅲ) and papillary renal cell carcinoma (prcc). the recurrence rate in transperitoneal group was significantly higher than that in retroperitoneal group (p=0.008). the 2-year progression-free survival rate in retroperitoneal group was 99%, while it was 88.2% in transperitoneal group. discussion this study originally proposed a new nephrometry scoring system for pn via retroperitoneal approach. it was named “retro” scoring system. furthermore, a formula was extracted from the logistic analysis, which could predict the probability of the post-operative complication rate. the main factors affecting the complication rate were symptoms, asa score and retro score. the fat round the kidney, especially the adhesive perinephric fat would bring difficulties during the surgery (14). the adhesive perinephric fat did have a significant influence during the laparoscopic single-site donor nephrectomy (15). all patients included in this study received operations under robot-assisted laparoscope. ralpn had lower morbidity and incidence of ckd upstaging (16-18). a novel trifecta for ralpn was conceived(19). off-clamp technique was recommended since it decreased the probability of severe chronic kidney disease in the longterm(20). the “retro” classification system includes five major parameters. the “t” indicates the approach for operation. tumors those invades “forbidden zone” do not mean that they cannot be removed through retroperitoneal way. it indicates the manipulation via retroperitoneal cavity will become very complicated. it needs more operation time and retroperitoneal experience. the other four parameters are quantitative factors. according to our experience, the nearness to major vessel is more critical than that to the collecting system. and under the 3d scope, the collecting system is more easily to be noticed and repaired. on the contrary, the vessel trunks near the mass should be more taken care of. it was reported that the hemorrhage was among 4%-5% after partial nephrectomy, and they needed invasive treatment instead of blood transfusion (21,22). thus, in our series, all cases received robot-assisted laparoscopic nephrectomy and were performed by the same surgeon. it avoided the heterogeneity caused by the surgical tools and different manipulation skills. the fourth parameter is the polar location of the mass. under retroperitoneal way, it will be easier if the mass nears the renal equator. the two polar tumors are more difficult to be exposed and make the suture more complicated. conclusions different renal tumor conditions need individualized treatment strategy. the “retro” scoring system provides an approach selection and evaluation criterion for surgeons, especially for those used to perform pn via retroperitoneal approach under mini-invasive platform, and predicts a postoperative complication rate estimation. retro nephrometry system is a beneficial addition to reanl and padua scoring systems. table 1. the specific score associated with each retroperitoneal anatomical feature included in retro classification. table 2. perioperative characteristics of included patients. table 3. factors related to complications: univariate analysis. figure 1. (a) the blue square space is the “front lip”; (b) tumor size classification; (c) endophytic degree of tumors; (d) if tumor invades the “front lip”, transperitoneal approach is recommended; (e) the relationship with major vessels; (f) polar location of the tumor. figure 2. retro score, 2+2+1+1=6; renal score, 1+2+1+a+3=7a. references: 1. ljungberg b, albiges l, abu-ghanem y, et al. european association of urology guidelines on renal cell carcinoma: the 2019 update. european urology. may 2019;75(5):799-810. 2. westerman me, cheville jc, lohse cm, et al. long-term outcomes of patients with low grade cystic renal epithelial neoplasms. urology. nov 2019;133:145-150. 3. capitanio u, terrone c, antonelli a, et al. nephron-sparing techniques independently decrease the risk of cardiovascular events relative to radical nephrectomy in patients with a t1a-t1b renal mass and normal preoperative renal function. european urology. apr 2015;67(4):683-689. 4. simone g, tuderti g, anceschi u, et al. oncological outcomes of minimally invasive partial versus minimally invasive radical nephrectomy for ct1-2/n0/m0 clear cell renal cell carcinoma: a propensity score-matched analysis. world journal of urology. may 2017;35(5):789-794. 5. mir mc, derweesh i, porpiglia f, zargar h, mottrie a, autorino r. partial nephrectomy versus radical nephrectomy for clinical t1b and t2 renal tumors: a systematic review and meta-analysis of comparative studies. european urology. apr 2017;71(4):606-617. 6. tuderti g, brassetti a, mastroianni r, et al. expanding the limits of nephron-sparing surgery: surgical technique and mid-term outcomes of purely off-clamp robotic partial nephrectomy for totally endophytic renal tumors. international journal of urology : official journal of the japanese urological association. apr 2022;29(4):282-288. 7. chiruvella m, ghouse sm, tamhankar as. "polar flip" technique for transperitoneal laparoscopic partial nephrectomy evolution of a novel technique for posterior hilar tumors. indian journal of urology : iju : journal of the urological society of india. jul-sep 2019;35(3):230-231. 8. kutikov a, uzzo rg. the r.e.n.a.l. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. the journal of urology. sep 2009;182(3):844-853. 9. ficarra v, novara g, secco s, et al. preoperative aspects and dimensions used for an anatomical (padua) classification of renal tumours in patients who are candidates for nephron-sparing surgery. european urology. nov 2009;56(5):786-793. 10. simmons mn, ching cb, samplaski mk, park ch, gill is. kidney tumor location measurement using the c index method. the journal of urology. may 2010;183(5):1708-1713. 11. hakky ts, baumgarten as, allen b, et al. zonal nephro scoring system: a superior renal tumor complexity classification model. clin genitourin canc. feb 2014;12(1):e13-e18. 12. clavien pa, sanabria jr, strasberg sm. proposed classification of complications of surgery with examples of utility in cholecystectomy. surgery. may 1992;111(5):518526. 13. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. annals of surgery. aug 2004;240(2):205-213. 14. davidiuk aj, parker as, thomas cs, et al. mayo adhesive probability score: an accurate image-based scoring system to predict adherent perinephric fat in partial nephrectomy. european urology. dec 2014;66(6):1165-1171. 15. yanishi m, kinoshita h, koito y, et al. adherent perinephric fat is a surgical risk factor in laparoscopic single-site donor nephrectomy: analysis using mayo adhesive probability score. transplantation proceedings. jan feb 2020;52(1):84-88. 16. xia l, wang x, xu t, guzzo tj. systematic review and meta-analysis of comparative studies reporting perioperative outcomes of robot-assisted partial nephrectomy versus open partial nephrectomy. journal of endourology. sep 2017;31(9):893-909. 17. chang kd, abdel raheem a, kim kh, et al. functional and oncological outcomes of open, laparoscopic and robot-assisted partial nephrectomy: a multicentre comparative matched-pair analyses with a median of 5 years' follow-up. bju international. oct 2018;122(4):618-626. 18. garisto j, bertolo r, dagenais j, et al. robotic versus open partial nephrectomy for highly complex renal masses: comparison of perioperative, functional, and oncological outcomes. urologic oncology. oct 2018;36(10):471 e471-471 e479. 19. brassetti a, anceschi u, bertolo r, et al. surgical quality, cancer control and functional preservation: introducing a novel trifecta for robot-assisted partial nephrectomy. minerva urologica e nefrologica = the italian journal of urology and nephrology. feb 2020;72(1):82-90. 20. simone g, capitanio u, tuderti g, et al. on-clamp versus off-clamp partial nephrectomy: propensity score-matched comparison of long-term functional outcomes. international journal of urology : official journal of the japanese urological association. oct 2019;26(10):985-991. 21. jung s, min ge, chung bi, jeon sh. risk factors for postoperative hemorrhage after partial nephrectomy. korean journal of urology. jan 2014;55(1):17-22. 22. baumann c, westphalen k, fuchs h, oesterwitz h, hierholzer j. interventional management of renal bleeding after partial nephrectomy. cardiovascular and interventional radiology. sep-oct 2007;30(5):828-832. *corresponding author: dr. sunyi ye1, dr. lixian zhu2, dr. shuo wang1 address: 1department of urology, the first affiliated hospital, school of medicine, zhejiang university, 79 qingchun road, hangzhou 310003, zhejiang province, china. 2department of thyroid disease center, the first affiliated hospital, school of medicine, zhejiang university, hangzhou, china. tel:+86-571-87236833;e-mail:yesy@zju.edu.cn; 10918188@zju.edu.cn; shuowang11@zju.edu.cn. mailto:shuowang11@zju.edu.cn table 1 the specific score associated with each retroperitoneal anatomical feature included in retro classification. retroperitoneal anatomical features score * radius (r) ≤2cm 1 2-4cm 2 4-6cm 3 6-8cm 4 … … endophytic (e) ≤50% 1 50-100% 2 100% 3 trans-anterior lip (t) not involved retroperitoneal approach involved transperitoneal approach relationship with renal vessel trunk (r) ≥0.6cm 1 0-0.6cm 2 0 3 originate from (o) middle 1/3 part 1 upper or lower 1/3 part 2 ventral side plus upper or lower 1/3 part 3 * easy: 4-6 points; moderate: 7-10 points; difficult: ≥11 points. table 2 perioperative characteristics of included patients retroperitoneal （n=105） transperitoneal (n=17) p value sex 0.405 male 63 (60%) 12 (70.6%) female 42 (40%) 5 (29.4%) age 0.427 median 54 56 iqr 46-63 53-63 bmi 0.039 median 24.3 22.6 iqr 22.2-26.3 20.8-25.0 charlson score 0.691 ≤1 82 14 >1 23 3 symptoms 0.358 yes 5 0 no 100 17 asa score 0.929 1 56 9 2 34 5 3 15 3 location 0.684 left 50 9 right 55 8 size 0.146 median 3.3 3.6 iqr 2.3-4.1 2.8-4.9 endophytic 0.958 ≤50% 58 9 >50% 37 6 =100% 10 2 operation time 0.010 median 90 111 iqr 75-109 97.5-136 ischemia time 0.891 median 18 17 iqr 15-22.5 12-27.5 clavien-dindo classification 60 (57.1%) 14 (82.4%) 0.048 grade ⅰ 55 14 grade ⅱ 5 0 pathology ccrcc (fuhrman grade) ⅰ 12 1 ⅱ 53 8 ⅲ 9 1 ⅳ 1 1 papillary rcc 6 1 chromophobe carcinoma 3 1 oncocytoma 5 0 angiomyolipoma 11 2 others 5 2 table 3 factors related to complications: univariate analysis surgical approaches retroperitoneal（n=105） transperitoneal (n=17) present absent p value present absent p value sex 0.421 0.218 male 34 (32.4%) 29 (27.6%) 9 (53.0%) 3 (17.6%) female 26 (24.8%) 16 (15.2%) 5 (29.4%) 0 (0%) age (yr) 0.285 0.761 ≤60 42 27 8 2 >60 18 18 6 1 bmi 0.687 0.659 ≤25 35 28 11 2 >25 25 17 3 1 charlson score 0.376 0.432 ≤1 45 37 12 2 >1 15 8 2 1 symptoms 0.047 yes 5 0 0 0 no 55 45 14 3 asa score 0.049 0.673 1 26 30 8 1 2 21 13 4 1 3 12 3 2 1 location 0.310 0.761 left 26 24 8 1 right 34 21 6 2 radius (cm) 0.074 0.043 ≤4 40 37 9 0 >4 20 8 5 3 endophytic 0.921 0.755 ≤50% 33 25 7 2 >50% 20 16 5 1 =100% 5 5 2 0 vessel rete (cm) 0.643 0.659 ≥0.6 36 29 3 1 <0.6 24 16 11 2 origin 0.08 0.633 not polar 18 21 1 0 polar or ventral hilum side 42 24 13 3 operation time (min) 0.080 0.377 ≤90 27 28 3 0 >90 33 17 11 3 ischemia time (min) 0.071 0.29 ≤25 53 44 10 3 >25 7 1 4 0 retro score 0.031 0.523 4-6 21 22 2 0 7-10 34 23 11 3 ≥11 5 0 1 0 recurrence 1 104 0.008 * 2 15 / * comparison between retro and transperitoneal group. vol 19 no 2 march-april 2022 100 comparing laparoscopic sacrocolpopexy with vaginal sacrospinous ligament fixation in the treatment of vaginal apical prolapse; the first randomized clinical trial: a pilot study azar daneshpajooh1,hamid pakmanesh1*, samira sohbati2, mahboubeh mirzaei1, ehsan zemanati yar3, tania dehesh4 purpose: to compare two methods of laparoscopic sacrocolpopexy (lscp) and sacrospinous ligament fixation (sslf) in terms of efficacy and safety in the treatment of vaginal apical prolapse. materials and methods this prospective, randomized controlled clinical trial was conducted on 32 patients with symptomatic vaginal apical prolapse, referred to the female urology clinic of kerman university, iran, during 2018-2019. the patients were re-examined at 12 months after surgery. objective success was recorded using pelvic organ prolapse quantification (pop-q) classification as primary outcome. the subjective success of the methods was determined by the quality-of-life parameters, based on pelvic floor impact questionnaire (pfiq-7), pelvic floor distress inventory (pfdi-20), and organ prolapse/urinary incontinence sexual questionnaire (pisq-12) scores as secondary outcomes. moreover, complications were recorded in both groups. results: the amount of intraoperative bleeding was significantly higher in the sslf group, compared to the lscp group (p = 0.01). persistent pain was observed in two (12%) patients in the lscp group and five (31%) patients in the sslf group (p = 0.2). the decrease in the total pfiq-7 score was in favor of the lscp group but not statistically significant (p = 0.06). the lscp group showed bigger improvement in vaginal (p = 0.04) and bowel (p = 0.03) scores. the results of the pisq-12 and pfdi-20 questionnaires as well as pop-q examination were not different in two groups. conclusion: although the surgical methods of lscp and sslf can be equally effective in the treatment of apical prolapse, lscp appears to be superior to sslf regarding less bleeding. keywords: pelvic organ prolapse; laparoscopic sacrocolpopexy; vaginal sacrospinous ligament fixation; vault prolapse introduction pelvic organ prolapse (pop) is defined as herniation of pelvic organs toward the vaginal wall in women. pop is a significant health concern, affecting almost half of women above the age of 50 years annually, with a lifetime prevalence of 30-50%(1,2,3). patients experience symptoms, such as pelvic discomfort, urinary or fecal incontinence, storage and voiding lower urinary tract symptoms, and sexual dysfunction, reducing their quality of life.(4,5) conservative pop treatments, such as vaginal pessaries, are well-known effective methods. however, patients prefer permanent treatments to maintain their body image and sexual function. apical prolapse is defined as the descent of the uterus, cervix, or vaginal vault toward the hymen following hysterectomy(6). the vaginal apex is supported by the uterosacral-cardinal ligament complex and the levator ani muscle(7), defects in this form of pelvic support occur because of childbirth, hysterectomy, aging, and some congenital anomalies, such as spina bifida.(8,9) apical prolapse usually co-occurs with anterior or posterior vaginal compartment prolapse. since the vaginal 1department of urology, shahid bahonar hospital, kerman university of medical sciences, kerman, iran 2department of obsetrics and gynecology, afzalipour hospital, kerman university of medical sciences, kerman, iran 3clinical research center, shahid bahonar hospital, kerman university of medical sciences, kerman, iran 4department of biostatistics and epidemiology, school of public health, kerman university of medical sciences, kerman, iran correspondence: associate professor of urology, endourologist, department of urology, shahid bahonar hospital, kerman university of medical sciences, kerman, iran. tel: +989133986871. fax: +983432239188. email: h_pakmanesh@kmu.ac.ir; h_pakmanesh@ yahoo.com. received october 2021 & accepted january 2022 apex is the cornerstone of vaginal support, it must be considered in the treatment of various types of prolapse to achieve long-term favorable outcomes in surgery. there are various surgical methods for repairing apical prolapse. these surgeries can be performed using a vaginal or abdominal approach (open, laparoscopic, or robotic), with or without uterine preservation. studies show that each of these methods has its own advantages and disadvantages.(10,11) with this background in mind, the present pilot study aimed to compare two minimally invasive vaginal surgeries for repairing apical prolapse, that is, laparoscopic sacrocolpopexy (lscp) and sacrospinous ligament fixation (sslf), in terms of effectiveness and complications. patients and methods this study was a pilot study. this prospective, parallel group randomized controlled trial (rct) was conducted on women with vaginal apical prolapse, who were referred to the female urology clinic. the inclusion criteria were as follows: 1 clinic of kerfemale urology urology journal/vol 19 no. 2/ march-april 2022/ pp. 131-137. [doi: 10.22037/uj.v18i.7039] man university of medical sciences, kerman, iran.) age range of 18-75 years; 2) vaginal apical prolapse stage ii or higher; 3) symptomatic prolapse; 4) no response to conservative treatments; and 5) request for the surgical treatment of prolapse. the exclusion criteria were as follows: 1) contraindications to major surgery or anesthesia; 2) any urogenital or pelvic malignancy; 3) active urogenital or pelvic infection; 4) pregnancy or lactation, and 5) history of allergy to synthetic meshes. after obtaining informed consent, patients were randomly divided into two groups, using the block randomization with a 1:1 ratio provided by the statistician. the size of each block was four. the patient and the surgeon were not blinded regarding the allocation; however, the caregiver who managed the follow-up examination, as well as the statistician, was blinded. the patients’ demographic information, including age, parity, body mass index (bmi), hormonal and menopausal status, and history of urinary and genital surgery, were recorded. a urologist completed the short forms of the pelvic floor distress inventory (pfdi-20), pelvic floor impact questionnaire (pfiq-7), and pelvic organ prolapse/urinary incontinence sexual questionnaire (pisq-12) for the patients. the pelvic examination was recorded, according to the pelvic organ prolapse quantification (pop-q) system, as the standard pelvic examination system of the international continence society (ics). urine analysis and culture and measurement of postvoid residual urine, were performed for the patients. urodynamic evaluation was performed, if patient had complained of incontinence. all surgeries were performed in a single center (shahid bahonar hospital, kerman university of medical sciences). lscp was performed by an endourologist (second author), and sslf was performed by a female urologist (first author). lscp technique three laparoscopic ports were used including one 10mm umbilical port for vision and two 5-mm ports laterally in each side between the umbilicus and the anterior superior iliac spine. the anterior peritoneum was dissected away from the vaginal apex, exposing the full thickness of the vaginal wall; dissection continued down to the rectovaginal space. the peritoneum overlying the sacral promontory was incised longitudinally down to the vaginal apex. next, the presacral adipose tissue was carefully dissected away. a y-shaped pvdf (dynamesh-prs) mesh was introduced through the 10mm port. the anterior leaf of the mesh was sutured to the vaginal apex, using a permanent 2-0 nylon suture; the posterior leaf was also sutured in a similar fashion through the proximal part of the rectovaginal fascia (in patients with uterine prolapse, bilateral windows were made in the broad ligament at the level of the cervicouterine junction lateral to the uterine artery in the avascular area, and the left and right pieces of anterior mesh arms are passed through the left and right broad ligament and attached to the cervix and upper vagina with nonabsorbable suture; then, a posterior mesh arm is fixated to the posterior vagina and cervix with nonabsorbable suture). the other side of the mesh was then brought to the sacral promontory area. after adjusting the length of the mesh, it was fixed to the anterior longitudinal ligament, using the laparoscopic anchor system to fix the mesh at the sacral promontory. finally, the peritoneum was re-approximated to cover the mesh. sslf technique the surgery was performed with the patient in the lithotomy position. a midline vaginal incision was made anteriorly in the vaginal epithelium, which is separated from the pubocervical fascia, to expose the paravesical space. after identifying the sciatic spine, the sacrospinous ligament was palpated via blunt dissection. afterward, the suture was fixed approximately 2 cm medial to the spine, using a capio suture capturing device and delayed absorbable suture (vicryl 0). in addition, bilateral sslf was performed by placing one suture on each ligament. each suture was passed through the vaginal epithelium at the level of the vault and left for later tying (in patients with uterine prolapse, the anterior cervix is exposed, and a free needle is used to pass the two sutures through the anterior cervix). the suture was tied before completely closing the vaginal wall so that the vaginal apex or cervix could be attached to the sacrospinous ligament. finally, the remainder of the vaginal incision was closed. outcome measures all information regarding the duration of surgery, length of hospitalization, decrease in the hemoglobin level, need for blood transfusion, and intraand postoperative complications were recorded. the patients were examined in the first, sixth, and lap sacrocolpopexy vs. vaginal sacrospinous fixation-daneshpajooh et al. variables lscp group (n=16) sslf group (n=16) p-value mean (range) age, years 63.1 (33.7–86.3) 65.4 (38.2–88.1) p > 0.05 mean (sd) bmi, kg/m2 25.03±3.55 23.50±2.23 0.155 obstetric history median (range) parity 2 (0–7) 2 (1-5) na c‐section 9 (56) 7 (43) 0.724 hysterectomy 9 (56) 10 (62) 0.919 history of anti-incontinence surgery 1 (6) 0 (0) 0.407 history of cystocele repair 5 (31) 4 (25) 0.994 history of other abdominal surgery 2 (12) 2 (12) 0.700 urinary incontinence 7 (43) 9 (56) 0.480 stress urinary incontinence 5 (31) 7 (43) 0.608 overactive bladder 2 (12) 2 (12) dyspareunia 7 (43) 8 (50) 0.987 menopause 12 (75) 13 (81) 0.924 table 1.the baseline characteristics of the study population data are presented as n (%) or mean (range) or mean ± sd female urology 132 vol 19 no 2 march-april 2022 100 twelfth months after surgery, when the patients completed the questionnaires again, and pelvic examination was carried out. the primary outcome was objective success that was defined as apical prolapse less than or equal to stage i on the vaginal examination, and secondary outcome was subjective success that was defined as the improvement of pfdi-20, pfiq-7, and pisq-12 scores. compliance with ethical standards this study was supported by a grant from the kerman universit of medical sciences. the authors had no financial relationships or any conflict of interest. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. ethics committee of the university approved the clinical study (ir. kmu.rec.1397.094). informed consent was obtained from all participants involved in the study. the rct registration code is irct20180106038231n1 statistical analysis and sample size as this was a pilot study, all patients that had met the inclusion criteria and completed the consent form in a specific period of time (december 2018 until december 2019) were included in the study. 16 patients were included in each group. the best procedure for comparing pre and post scores is the analysis of covariance (ancova). since the ancova underlying assumptions lscp (n=16) sslf (n=16) p-value bleeding < 200 cc 12 (75) 4 (25) 0.013 200-400cc 2 (12) 7 (44) > 400cc 2 (12) 5 (31) hemoglobin decrease 1.19 ± 0.48 3 ± 0.67 < 0.0001 blood transfusion 0 2 (12) 0.14 duration of surgery 3.56±0.51 3.31± 0.48 0.16 duration of hospitalization 3.31±0.48 3.56±0.51 0.164 table 2. comparison of different perioperative clinical characteristics of the study population data are presented as count (percent) or mean ± standard deviation data are presented as n (%) lscp (n=16) sslf (n=16) p-value preoperative pop-q 0.5 stage ii 3 (19) 4 (25) stage iii 8 (50) 7 (44) stage iv 5 (31) 5 (31) postoperative pop-q > 0.999 stage < i 15 (94) 15 (94) stage > i 1 (6) 1 (6) table 3. comparing the results of the pop-q examination stage in two groups before and after the intervention. figure 1. consort 2010 flow diagram of the study on patients with pelvic organ prolapse lap sacrocolpopexy vs. vaginal sacrospinous fixation-daneshpajooh et al. vol 19 no 2 march-april 2022 133 were not met, (the beta coefficient for the covariate was not equal among groups) the difference between post and pre scores was calculated. then this difference was divided to the pre scores, for baseline adjustment. the final score was compared using the independent-samples t-test or mann–whitney u test. the normality test was checked by shapiro–wilk test in each group. for more precision, the q-q plot was also investigated for normality assumption, and almost all points were around the line with 45 degrees, which confirmed normality. if normality and homogeneity of variances were established in both groups, the comparison between scores was performed with independent samples t-test. otherwise, mann–whitney u test was used. the chi-square test was used for the association between categorical variables. fisher’s exact test was used if at least 25 percent of cells had an expected count of less than 5. the analysis approach was intention to treat. data analysis was performed using spss version 20 software. a p-value of < 0.05 was considered statistically significant. results thirty-two patients, with the mean age of 64.2 years and the median parity of two, participated in this study (table1). perioperative data table 2 depicts the perioperative data. the duration of surgery was 3.56±0.51 hours in the lscp group and 3.31± 0.48 hours in the sslf group (p = 0.16). the mean reduction of hemoglobin level was 1.19 ± 0.48 g/dl in the lscp group and 3 ± 0.67 g/dl in the sslf group (p < 0.0001). two patients in the sslf group required blood transfusions (12%) in the postoperative period, whereas no such case was reported in the lscp group. (p = 0.14) moreover, the length of hospitalization was not different in two groups (table 2). no intraoperative complications, such as bladder and rectal injuries, were observed in any of the patients. for one patient, the laparoscopic approach was converted to open surgery due to severe adhesions. hematoma, mesh erosion, pelvic abscess, fistula, embolism, and death were not observed in any of the patients in the two groups. outcome primary outcome: all but one patient in each group showed stage less than i in postoperative popq examination (table 3). failure of surgery was identified 6 months after surgery. in one case, which was after lscp, the patient had a relative recovery and did not need reoperation. in another case, failure after vaginal surgery, the patient preferred to use a pessary. secondary outcome: both groups showed improvement in pfiq-7 scores (table 4). comparing two groups, the lscp group showed a bigger improvement in vaginal (p = 0.04) and bowel (p = 0.03) scores. the difference in the total pfiq-7 score was in favor of the lscp group but not statistically significant (p = 0.06) (table 4 and figure 2). the results of the pisq-12 and pfdi-20 questionnaires was not different in two groups. female urology 134 table 4. the mean pfiq-7 details scores before and after the surgery compared between two treatment groups. preoperative postoperative total subscales mean ± sd mean ± sd p mean ± sd p bladder lscp 11.28 ± 1.96 0.29 ± 0.45 < 0.001 -97.17 ± 4.85 0.35 sslf 12.29 ± 1.69 0.61 ± 0.50 0.002 -95.38 ± 4.15 bowel lscp 11.08 ± 1.64 0.23 ± 0.44 < 0.001 -97.97 ± 4.09 0.031 sslf 11.66 ± 1.70 0.64 ± 0.47 0.002 -94.21 ± 4.45 vagina lscp 12.96 ± 2.36 0.29 ± 0.45 < 0.001 -97.74 ± 4.03 0.041 sslf 12.35 ± 1.47 0.65 ± 0.44 0.002 -94.60 ± 4.06 total pfiq-7 lscp 35.31 ± 5.44 0.77 ± 1.34 < 0.001 -96.64 ± 3.97 0.064 sslf 36.14 ± 4.06 1.93 ± 1.46 0.002 -95.75 ± 3.96 p : p-value preoperative postoperative p total p mean ± sd mean ± sd mean ± sd popdi-6 lscp 18.25 ± 1.85 1.36 ± 1.19 < 0.001 -92.97 ± 6.15 0.95 sslf 17.78 ± 2.04 1.21 ± 1.23 0.002 -93.21 ± 6.90 crad-8 lscp 16.15 ± 1.67 3.07 ± 1.06 < 0.001 -81.06 ± 6.28 0. 95 sslf 16.15 ± 2.15 3.01 ± 1.05 0.002 -81.62 ± 5.06 udi-6 lscp 13.45 ± 1.89 1.20 ± 0.48 < 0.001 -98.86 ± 0.32 > 0.999 sslf 13.84 ± 1.56 1.32 ± 0.51 < 0.001 -98.46 ± 0.38 total pfdi-20 lscp 47.79 ± 3.28 4.41 ± 1.46 < 0.001 -90.82 ± 2.98 0.751 sslf 47.73 ± 3.11 4.16 ± 1.53 0.002 -91.27 ± 3.13 table 5. the mean pfdi-20 details scores before and after surgery compared between two treatment groups. p : p-value lap sacrocolpopexy vs. vaginal sacrospinous fixation-daneshpajooh et al. vol 19 no 2 march-april 2022 100 (tables 5,6 and figure 2) discussion surgeries used to repair apical prolapse focus on correcting the vaginal anatomy to restore the normal function of the bladder and intestines. various surgeries have been reported so far for the treatment of apical prolapse(11), with abdominal and vaginal approaches. the abdominal surgeries can be either open, laparoscopic, or robotic. sslf is a vaginal surgery, while lscp is an abdominal method; each of these methods has its advantages and disadvantages. the present study aimed to evaluate the effectiveness and complications of these two surgical methods. sslf is a surgical method, commonly used since 1982. (12) with technological advances in today’s world, it has become easier to implement this method. the advantages of this method include the short duration of surgery, lack of need for general anesthesia, simultaneous repair of defects in other vaginal compartments, and low morbidity after surgery. on the other hand, the disadvantages of this method include its ineffectiveness in orthopedic deformities, impossibility of simultaneous surgery of intraabdominal pathologies, and disorientation of vaginal alignment after surgery. sslf is usually performed via the posterior approach. in a systematic review, the success rate of this method was reported to be 84.6%, the recurrence rate of apical prolapse was preoperative postoperative p total p mean rank ± sd mean rank ± sd mean rank ± sd lscp 1.42 ± 1.02 0.62 ± 0.52 0.001 -0.62 ± 0.52 0.65 sslf 1.31 ± 1.09 0.56 ± 0.55 0.021 -0.56 ± 0.55 table 6. the mean pisq-12 scores before and after surgery compared between two treatment groups. figure 2. (a) the mean pfiq-7 total scores before and after the surgery compared between two treatment groups, (b)the mean pfdi20 total scores before and after surgery compared between two treatment groups, (c) the mean pisq-12 scores before and after surgery compared between two treatment groups lap sacrocolpopexy vs. vaginal sacrospinous fixation-daneshpajooh et al. vol 19 no 2 march-april 2022 135 5.3%, and the recurrence rate of anterior compartment prolapse was 18.3%.(13) various studies have shown the convenience and effectiveness of the anterior approach for sslf.(14,15,16) the anterior approach was selected for sslf in the present study. open abdominal sacrocolpopexy (asc) has been employed since 1962 and modified over the years. 16this surgery was performed with a laparoscopic approach in 1994. the advantages of laparoscopy include less intraoperative bleeding, faster postoperative recovery, and high effectiveness.(10) conversely, the disadvantages of the abdominal method include the risk of lumbosacral osteomyelitis and mesh erosion to the vagina, bladder, rectum, and colon.(17) more, in the abdominal approach, if vaginal vault prolapse is repaired alone and defects of other compartments are not corrected, cystocele and rectocele are likely to occur in one-third of patients after surgery, leading to dissatisfaction and need for reoperation.(18) in a review study by lee et al. the success rate of laparoscopic and robotic approaches was reported to be 91%, with a conversion rate of 3%.(19) there are many studies comparing the two methods of open asc with sslf. in this regard, benson et al., in a prospective rct, reported that asc is superior to bilateral sslf in repairing apical prolapse.(20) moreover, maher et al., in a prospective rct, indicated that the two methods of open and vaginal abdominal surgeries were highly effective in the treatment of apical prolapse. however, the patients in the abdominal surgery group underwent longer surgeries and took longer to return to daily activities.(21) a systematic review revealed that the effectiveness of abdominal and vaginal surgeries was not significantly different in terms of the improvement of prolapse symptoms. however, the recurrence rate of vault prolapse, dyspareunia, and de novo stress urinary incontinence were lower in the asc group, while the durations of surgery and recovery were longer, and the costs were higher.(22) today, use of lscp is common throughout the world, and various studies have compared it with the open method. coolen et al conducted a study to compare these two methods.(23) according to their results, the objective success rates in the laparoscopic and open methods were 83.8% and 89.2%, respectively, and the subjective success rates were 71% and 74%, respectively. moreover, in a study by freeman et al., the recovery rates of the open and laparoscopic groups were 90% and 80%, respectively.(24) in addition, the amount of intraoperative bleeding, length of hospitalization, and postoperative pain were lower in the laparoscopic group. the number of vaginal surgeries with synthetic meshes for vaginal apical prolapse has reduced in recent years due to the warnings of the united states food and drug administration (fda) about the use of mesh in vaginal and laparoscopic surgeries.(25) one of the advantages of the present study is that two surgical methods of lscp (with meshes) and sslf (without meshes) were compared, which has been less discussed in the literature. in this regard, a retrospective study by marcickiewicz examined 111 patients with apical prolapse after hysterectomy, undergoing lscp (n = 60) or sslf (n=51).(26) the surgery duration in the sslf group was significantly shorter than the lscp group (62 vs. 129 minutes). three patients in the laparoscopic group underwent open surgery (one due to bleeding, one due to colon injury, and one due to severe adhesions). the mean length of hospital stay was almost equal in the two groups (4 vs. 3.7 days). the subjective success in the lscp and sslf groups was 78% and 82%, respectively. the recurrence of vault prolapse was not observed in any of the groups, whereas cystocele was observed in 25% and 27% of patients in the lscp and sslf groups, respectively. more, 6% and 8% of patients in the lscp and sslf groups were symptomatic, respectively.(26) according to our results, the two surgical methods were similar in terms of efficacy. however, complications were significantly fewer in the lscp group, compared to the sslf group. a major limitation of this study was that it was conducted in one surgical center, and the number of participants was limited; therefore, further multicenter studies with a larger sample size are recommended in the future. more, longer follow-ups are required to confirm the results. finally, lscp and sslf were not compared in terms of cost-effectiveness. conclusions treatment of vaginal apical prolapse is a controversial clinical issue, and the best surgical method is still subject to controversy. according to the results, lscp and sslf are both effective methods for the treatment of apical prolapse; however, the laparoscopic approach seems to cause less complications. due to technological advances in laparoscopy, it seems that this method can replace conventional methods. conflict of interest the authors declare that they have no conflicts of interest. references 1. sharifiaghdas, f., daneshpajooh, a., mirzaei, m.: simultaneous treatment of anterior vaginal wall prolapse and stress urinary incontinence by using transobturator four arms polypropylene mesh. korean j urol, 56: 811, 2015 2. subak, l. l., waetjen, l. e., van den eeden, s. et al.: cost of pelvic organ prolapse surgery in the united states. obstet gynecol, 98: 646, 2001 3. maher c, feiner b, baessler k. et al.: surgery for women with anterior compartment prolapse. cochrane database of systemic reviews 2016, issue 11.art.no cd004014. 4. nygaard, i., barber, m. d., burgio, k. l. et al.: prevalence of symptomatic pelvic floor disorders in us women. jama, 300: 1311, 2008 5. swift, s., woodman, p., o'boyle, a. et al.: pelvic organ support study (posst): the distribution, clinical definition, and epidemiologic condition of pelvic organ support defects. am j obstet gynecol, 192: 795, 2005 6. abrams, p., cardozo, l., fall, m. et al.: the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn, 21: 167, 2002 female urology 136 lap sacrocolpopexy vs. vaginal sacrospinous fixation-daneshpajooh et al. vol 19 no 2 march-april 2022 100 7. delancey, j. o.: the anatomy of the pelvic floor. curr opin obstet gynecol, 6: 313, 1994 8. blandon, r. e., bharucha, a. e., melton, l. j., 3rd et al.: risk factors for pelvic floor repair after hysterectomy. obstet gynecol, 113: 601, 2009 9. mant, j., painter, r., vessey, m.: epidemiology of genital prolapse: observations from the oxford family planning association study. br j obstet gynaecol, 104: 579, 1997 10. nezhat, c. h., nezhat, f., nezhat, c.: laparoscopic sacral colpopexy for vaginal vault prolapse. obstet gynecol, 84: 885, 1994 11. toozs-hobson, p., boos, k., cardozo, l.: management of vaginal vault prolapse. br j obstet gynaecol, 105: 13, 1998 12. nichols, d. h.: sacrospinous fixation for massive eversion of the vagina. am j obstet gynecol, 142: 901, 1982 13. tseng, l. h., chen, i., chang, s. d. et al.: modern role of sacrospinous ligament fixation for pelvic organ prolapse surgery--a systemic review. taiwan j obstet gynecol, 52: 311, 2013 14. cespedes, r. d.: anterior approach bilateral sacrospinous ligament fixation for vaginal vault prolapse. urology, 56: 70, 2000 15. winkler, h. a., tomeszko, j. e., sand, p. k.: anterior sacrospinous vaginal vault suspension for prolapse. obstet gynecol, 95: 612, 2000 16. lane, f. e.: repair of posthysterectomy vaginal-vault prolapse. obstet gynecol, 20: 72, 1962 17. weidner, a. c., cundiff, g. w., harris, r. l. et al.: sacral osteomyelitis: an unusual complication of abdominal sacral colpopexy. obstet gynecol, 90: 689, 1997 18. blanchard, k. a., vanlangendonck, r., winters, j. c.: recurrent pelvic floor defects after abdominal sacral colpopexy. j urol, 175: 1010, 2006 19. lee, r. k., mottrie, a., payne, c. k. et al.: a review of the current status of laparoscopic and robot-assisted sacrocolpopexy for pelvic organ prolapse. eur urol, 65: 1128, 2014 20. benson, j. t., lucente, v., mcclellan, e.: vaginal versus abdominal reconstructive surgery for the treatment of pelvic support defects: a prospective randomized study with long-term outcome evaluation. am j obstet gynecol, 175: 1418, 1996 21. maher, c. f., qatawneh, a. m., dwyer, p. l. et al.: abdominal sacral colpopexy or vaginal sacrospinous colpopexy for vaginal vault prolapse: a prospective randomized study. am j obstet gynecol, 190: 20, 2004 22. maher, c., feiner, b., baessler, k. et al.: surgical management of pelvic organ prolapse in women. cochrane database syst rev: cd004014, 2013 23. coolen, a. w. m., van oudheusden, a. m. j., mol, b. w. j. et al.: laparoscopic sacrocolpopexy compared with open abdominal sacrocolpopexy for vault prolapse repair: a randomised controlled trial. int urogynecol j, 28: 1469, 2017 24. freeman, r. m., pantazis, k., thomson, a. et al.: a randomised controlled trial of abdominal versus laparoscopic sacrocolpopexy for the treatment of post-hysterectomy vaginal vault prolapse: las study. int urogynecol j, 24: 377, 2013 25. skoczylas, l. c., turner, l. c., wang, l. et al.: changes in prolapse surgery trends relative to fda notifications regarding vaginal mesh. int urogynecol j, 25: 471, 2014 26. marcickiewicz, j., kjollesdal, m., engh, m. e. et al.: vaginal sacrospinous colpopexy and laparoscopic sacral colpopexy for vaginal vault prolapse. acta obstet gynecol scand, 86: 733, 2007 lap sacrocolpopexy vs. vaginal sacrospinous fixation-daneshpajooh et al. vol 19 no 2 march-april 2022 137 urological oncology survival differences in high-risk prostate cancer by age clara garcía-fuentes1*, ana guijarro1, virginia hernández1, álvaro gonzalo-balbás1, estíbaliz jiménez-alcaide1, enrique de la peña1, elia pérez-fernández2, carlos llorente1 purpose: age is an established determining factor in survival in low-risk prostate cancer (pc), being this evidence weaker in high-risk tumors. our aim is to evaluate the survival of patients with high-risk pc treated with curative intent and to identify differences across ages at diagnosis. methods: we did a retrospective analysis of patients with high-risk pc treated with surgery (rp) or radiotherapy (rdt) excluding n+ patients. we divided patients by age groups: < 60, 60-70, and > 70 years. we performed a comparative survival analysis. a multivariate analysis adjusted for clinically relevant variables and initial treatment received was performed. results: of a total of 2383 patients, 378 met the selection criteria with a median follow-up of 8.9 years: 38 (10.1%) < 60 years, 175 (46.3%) between 60-70 years, and 165 (43.6%) >70 years. initial treatment with surgery was predominant in the younger group (rp:63.2%, rdt:36.8%), and with radiotherapy in the older group (rp:17%, rdt:83%) (p = 0.001). in the survival analysis, significant differences were observed in overall survival, with better results for the younger group. however, these results were reversed in biochemical recurrence-free survival, with patients < 60 years presenting a higher rate of biochemical recurrence at 10 years. in the multivariate analysis, age behaved as an independent risk variable only for overall survival, with a hr of 2.8 in the group >70 years (95%ci: 1.22-6.5; p = 0.015). conclusion: in our series, age appeared to be an independent prognostic factor for overall survival, with no differences in the rest of the survival rates. keywords: high-risk prostate cancer; age groups; survival differences 1department of urology, hospital universitario fundación alcorcón, madrid, spain. 2research unit, hospital universitario fundación alcorcón, madrid, spain. *correspondence: department of urology, hospital universitario fundación alcorcón. avda. budapest 1, 28922 alcorcón, madrid, spain. tel: +34 618271570, fax number: 916219404. email: cgarciaf@salud.madrid.org and garciafuentes.clara@gmail.com. received july 2022 & accepted december 2022 introduction prostate cancer (pc) is the most commonly diag-nosed solid organ neoplasm in men in europe and its incidence increases with age, with 60% of cases being detected in men over 65 years of age.(1) the incidence of high-risk tumors is 15-20% according to american studies. in the swedish registry, out of a total of 57187 patients with pc, 24% were classified as high risk.(2,3) in spain, according to data from the 2010 national prostate cancer registry, 89.4% of patients had localized disease, and of these, 28.8% had high-risk tumors according to the d'amico classification.(4) while there is evidence that in low-risk tumors age is a determinant of survival(5), there are not many studies that identify the impact of age on survival in high-risk tumors. our aim is to evaluate the survival of patients with highrisk pc treated with curative intent and to identify possible differences according to age at diagnosis. material and methods we performed a retrospective analysis of all patients with prostate cancer, prospectively included in our hospital database from 1998 to 2016, to reach a minimum follow-up of 5 years. review and approval by our hospital's ethics committee did not apply to this study due to the retrospective nature of the study. we selected those patients who met the d'amico criteria for high-risk disease (stage t2, psa > 20 ng/ml or gleason ≥ 8) and who had been treated with curative intent by radical prostatectomy and pelvic lymphadenectomy (rp + lfdn) or radiotherapy with neo and adjuvant hormone therapy for 2 years (rdt + ht). n+ patients were excluded. all radical prostatectomies from 2004 onward were performed laparoscopically. the approach was extraperitoneal until 2009, and from that moment on the procedure was performed transperitoneally with an extended lymph node dissection. until 2013, radiotherapy treatment was administered with radical intent with classic fractionation using imrt (54.6 gy on lymph node chains, 62.4 gy on seminal vesicles and 78 gy on the prostate) and igrt daily. from 2013 onwards, treatment was administered with moderate hypofractionation (50.4 gy on lymph node chains, 56 gy on seminal vesicles and 70 gy on the prostate that corresponds to eqd2 81gy). we divided the subjects according to age into three groups: under 60, between 60 and 70, and over 70 years of age. we performed a descriptive analysis of the demographurology journal/vol 20 no. 4/ july-august 2023/ pp. 215-221. [doi:10.22037/uj.v20i.7393] ic characteristics of the patients including age and comorbidity measured according to the charlson index, as well as the characteristics referring to prostate cancer: psa, t stage, gleason at diagnosis and type of treatment received (rp + lfdn vs rdt + ht). the analysis of the surgical specimen was analyzed by the uropathologists of our center using tnm staging system according to european recommendations and gleason according to the 2005 classification. samples from patients prior to that date were reclassified according to these criteria. the rates of biochemical recurrence and disease progression to metastasis recorded in each group (defined according to the criteria of the european guidelines) were analyzed, and the differences in survival were analyzed in terms of overall survival, cancer-specific survival, survival free of biochemical recurrence and survival free of progression to metastasis. a multivariate analysis adjusted for clinically relevant variables (age and d'amico high-risk criteria) as well as initial treatment received was performed. statistical analysis the distribution of quantitative data is presented by mean and standard deviation or median and interquartile range, according to data distribution. univariate analysis was performed to compare the distribution of clinical variables according to age groups: the chisquare test or fisher's exact test in case of small sample size for qualitative variables, and the one-way anova f test or the nonparametric kruskal–wallis test to compare quantitative variables, depending on the distribution data. overall survival time is defined as the time from the date of treatment to the date of death from any cause or to the date of end of follow-up in the case of censored data. reason for censoring is loss of follow-up. in the case of recurrence-free survival and progression-free survival, the recurrence event was considered to be biochemical recurrence (defined according to eau guidelines criteria) after treatment with curative intent, and the progression event was considered to be the development of metastases during follow-up. reason for censoring includes loss of follow-up and death without previous event. the kaplan-meier method was used to estimate the survival curves and the log-rank test was calculated to compare groups according to age: under 60, between 60 and 70, and over 70 years of age. cox proportional hazards regression models were used to estimate hazard ratios (hr) according to age groups without adjustment and adjusting for other clinical variables of interest (d’amico criteria and initial treatment received). cox proportional hazard (ph) assumption and was evaluated testing linear nonzero slope of the residuals and linearity for age was assessed with a link test for model specification. the variables that no compliance ph assumption were including in the models with time-varying coefficients. all tests were considered bilateral and p-values less than 0.05 were considered statistically significant. statistical analysis was performed using spss 17 and stata 14 data analysis packages. results of the 2383 patients included in our institutional prostate cancer database, 378 met the selection criteria. of these, 38 patients (10.1%) were younger than 60 years, prostate cancer survival by age-garcia-fuentes et al. age: n (%) < 60 years (n = 38) 60-70 years (n = 175) > 70 years (n = 165) p events recorded during the follow-up biochemical recurrence 20 (52.6%) 69 (39.4%) 44 (26.7%) 0.003 progression to metastasis 9 (23.7%) 18 (16%) 21 (12.7%) 0.227 death from any cause 7 (18.4%) 28 (16%) 53 (32.1%) 0.002 cancer-specific death 3 (7.9%) 5 (2.9%) 11 (6.7%) 0.191 estimated survival at 10 years overall survival 85% (95% ci: 16.3 – 21.0) 88% (95% ci: 16.7 – 18.7) 71% (95% ci: 11.7 – 14.1) < 0.001 cancer-specific survival 93% (95% ci: 18.9 – 22.3) 97% (95% ci: 19.6 – 20.7) 95% (95% ci: 16.3 – 18.7) 0.049 biochemical recurrence-free survival 44% (95% ci: 7.9 – 13.6) 59% (95% ci: 11.6 – 14.3) 62% (95% ci: 11.4 – 13.8) 0.019 metastasis progression-free survival 74% (95% ci: 14.6 – 20.0) 86% (95% ci: 16.6 – 18.7) 84% (95% ci: 15.7 – 17.9) 0.583 table 2. events recorded during the follow-up period and results of survival at 10 years age: n (%) < 60 years(n = 38) 60-70 years (n = 175) > 70 years (n = 165) p psa (ng/ml) a 24.49 24.58 22.73 0.036 grade group (isup) 1 6 (15.8%) 21 (12%) 14 (8.5%) 0.287 2 8 (21.1%) 22 (12.6%) 18 (10.9%) 3 2 (5.3%) 14 (8%) 15 (9.1%) 4 11 (28.9%) 84 (48%) 77 (46.7%) 5 11 (28.9%) 33 (18.9%) 41 (24.8%) t stage t1-t2b 28 (73.7%) 127 (72.6%) 114 (69.1%) 0.810 t2c 3 (7.9%) 8 (4.6%) 11 (6.7%) t3-t4 7 (18.4%) 40 (22.9%) 40 (24.2%) treatment at diagnosis pr + lfdn 24 (63.2%) 85 (48.6%) 28 (17%) 0.001 rdt + ht 14 (36.8%) 90 (51.4%) 137 (83%) table 1. clinical characteristics and treatment received at diagnosis by age group a variable expressed as mean (sd) urological oncology 216 175 (46.3%) were between 60 and 70 years, and 165 (43.6%) were older than 70 years. the mean age of each group was 55.8 (sd: 2.9), 65.7 (sd: 2.6) and 74.3 years (sd: 3.1) respectively. the median follow-up of the series was 8.9 years (iqr: 5.5-13.2). in those patients who were < 60 years-old and between 60 and 70 years it reached 10 years (10.6 and 10.4 respectively), however, in the group > 70 years-old it was slightly lower (7.5 years), being the difference statistically significant (p < 0.001). patients > 70 years had higher charlson index scores than the other two groups. specifically, 48 patients (29.1%) > 70 years had a score > 2, while in the 60-70 years group there were 29 (16.6%) and in the younger group only 5 (13.2%) (p = 0.03). the characteristics of the disease at diagnosis by age group are shown in table 1. in patients who underwent surgery, we found no differences between age groups in the pathologic findings of the prostatectomy specimen. the patients who associated lfdn were: 20 (83.4%), 68 (80%) and 19 (67.9%) respectively, with no differences in the rate of positive nodes. the mean overall survival of the total series is 16.8 years (95% ci: 15.8 17.7). the events recorded during the follow-up, defined as biochemical recurrence, figure 2. roc curve analysis of all adc values including b values for 400, 800, and 1400 to discriminate variant associated pathology. table 3. the results of multivariate regression cox models. overall survival coefficient hr ci 95% p age at diagnosis (/10 years) 0.09 1.09 0.50 2.38 0.820 high risk gleason 0.23 1.26 0.77 2.06 0.367 high risk psa 0.08 1.08 0.69 1.71 0.730 high risk t stage 0.35 1.43 0.87 2.33 0.155 treatment at diagnosis: rp + lnfd 1 rdt 0.04 1.04 0.60 1.82 0.878 time varying coefficients age at diagnosis (/10 years) 0.10 1.10 1.01 1.20 0.035 recurrence-free survival coefficient hr ci 95% p age at diagnosis (/10 years) -0.21 0.81 0.61 1.08 0.143 high risk gleason 0.65 1.92 1.24 2.97 0.003 high risk psa 0.51 1.66 1.13 2.44 0.010 high risk t stage 0.71 2.02 1.31 3.14 0.002 treatment at diagnosis: rp + lnfd 1 rdt -1.83 0.16 0.08 0.30 < 0.001 time varying coefficients rdt 0.19 1.21 1.07 1.37 0.002 progression-free survival coefficient hr ci 95% p age at diagnosis (/10 years) -0.39 0.68 0.43 1.06 0.088 high risk gleason 0.92 2.50 1.29 4.84 0.007 high risk psa 0.07 1.07 0.60 1.89 0.820 high risk t stage .05 2.86 1.52 5.36 0.001 treatment at diagnosis rp + lnfd 1 rdt -0.29 0.75 0.39 1.43 0.384 prostate cancer survival by age-garcia-fuentes et al. vol 20 no 4 july-august 2023 217 urological oncology 218 progression to metastasis and death, and the estimated 10-year survival by age group is shown are presented in table 2. kaplan-meier overall, cancer-specific, biochemical recurrence-free and metastasis progression-free survival curves are presented in figure 1. the multivariate cox ph regression model for overall survival showed that age has a time-dependent effect, with a statistically significant estimated time-varying coefficient and an estimated time-dependent hr of 1.1 (95% ci: 1.01-1.2, p = 0.035), whereby the hr is not constant over time increasing a 10% for each year during follow-up, therefore the hr is 1.2 in the first year of follow-up raising to 2.8 in the tenth year. however, in biochemical recurrence-free survival, age was no longer a risk factor, being the treatment received the one that had a significant impact, with effects change over time. the time varying coefficient estimated is statistically significant with hr of 1.2 (95% ci: 1.1-1.4) so rdt had a protect effect in first year with hr= 0.2, but this protect effect decrease over time, with null effect in tenth year of follow up. tumor-dependent variables (psa, gleason and t) were also significantly related to biochemical recurrence-free survival. finally, in metastasis progression-free survival, neither age nor initial treatment at diagnosis had an impact on survival. tumor-dependent variables gleason and t stage were significantly associated. discussion there are no studies comparing survival outcomes in high-risk prostate cancer by age group, which is the main objective of our study. we found some studies about active treatment in pc according to the recommendations of the nccn and eau guidelines most of them in young patients, without a good representation of older ones.(6) however, it has been confirmed that elderly patients with localized prostate cancer are eligible for radical treatment with curative intent with good oncologic outcomes.(7) due the aging population, several studies have emphafigure 1. kaplan-meier overall, cancer-specific, biochemical recurrence-free and metastasis progression-free survival curves. prostate cancer survival by age-garcia-fuentes et al. sized the need to change the approach of the disease by prioritizing tumour stage and biology over age, as they appear to have a greater impact on oncological outcomes.(8,9) all patients included in our series were treated according to the standard of care indicated in the guidelines. we believe that our findings may be interesting because we do not describe only the results in elderly patients, but we compare them with the rest of the patients included in our institutional database and perform a multivariate analysis to find out if age actually influences in the results obtained or if it is a confounding factor. in general terms, our data on the survival of high-risk pc patients treated with curative intent are similar to those described in the literature.(10) the results obtained in overall survival were more favorable for the younger group, without finding relevant differences in cancer-specific survival between groups. however, as described in the results, there were significant differences in the treatment of the different age groups and because of this, we must take into account that the groups are not completely comparable and the results should be interpreted with some caution. according to data from the national registry, rp is the most frequent treatment for pc in our country, followed by rdt.(11) in our study, which only includes high-risk patients, we found a higher percentage of patients treated with radiotherapy than with surgery, since it was not until 2009 that we started to perform rp associated with lymphadenectomy in high-risk patients. although there is no age threshold that limits or contraindicates surgery, it seems that patients with a life expectancy > 10 years benefit more from this therapeutic modality than those with a shorter life expectancy. (12) it has been shown that the greater number of comorbidities, the greater likelihood of mortality from other causes unrelated to prostate cancer.(13,14) based on this, and as we have seen in our results and as described in numerous studies, the patient's characteristics are the main variables to be taken into account when deciding the most appropriate type of treatment in each case. these findings are closely related to the retrospective review by park et al. investigating the efficacy of the age-adjusted charlson comorbidity index as a prognostic factor after rp in patients with very high-risk prostate cancer, confirming this hypothesis.(15) post et al. also discussed this topic, confirming in their study that comorbidity was the most important prognostic factor in localized prostate cancer, especially for those under 70 years.(16) to this date, several meta-analyses comparing rp and rdt treatments have been published. specifically, wallis et al., petrelli et al. and roach et al. report better overall survival outcomes in patients treated with surgery than in those receiving rdt. the first one describes a higher risk of overall mortality (hr = 1.63, p < 0.001) in the case of rdt, even in the analysis by risk subgroups and radiation regimen (srt, imrt, bt). the last two authors attribute this advantage to the different baseline characteristics of the patients, assuming that those undergoing pr present a lower rate of comorbidities.(17,18,19) in our series, we found no differences in overall survival according to the treatment received in the multivariate analysis. however, age does seem to be a determining factor in the evolution of the patients since, as mentioned above, advanced age is associated with a greater number of comorbidities and, consequently, with a greater probability of all-cause mortality. therefore, older patients (> 70 years) have a reduced overall survival. however, these results are not reproduced in cancer-specific survival, with the 3 age groups presenting similar survival rates. in relation to the aforementioned, hamstra et al. studied the impact of age on overall survival, cancer-specific survival and 10-year metastasis-free survival in patients with high-risk pc. broadly speaking, they agree on the relationship between age and patient survival, with the older age group (≤ 70 vs >70 years) showing a poorer overall survival (55% vs 41% respectively; p < 0.001), although better results in cancer-specific survival (18% vs 14%; p < 0.001) and metastasis-free survival (27% vs 20%; p < 0.001).(20) these results contrast with those described by lin et al. who carried out a cohort study to analyze the possible relationship between age at diagnosis, tumor characteristics and survival in patients with prostate cancer. in their case they divided the patients by age group into 35-44, 45-54, 55-64 and 64-75 years, with the youngest group showing worse results than the rest, both in overall survival and cancer-specific survival, in highrisk tumors.(5) our series also reports worse cancer-specific survival results in the younger group. we think that the type of treatment received may act as a confounding factor in the results obtained. as noted in the study by briganti et al., in high-risk prostate cancer, long-term cancer-specific mortality after radical prostatectomy is the leading cause of death in young and presumably healthy patients. in contrast, older patients (with more associated comorbidities and multiple risk factors) are more at risk of dying from other causes and therefore their cancer-specific mortality is lower although their overall survival will also be poorer.(21) when we focus on biochemical recurrence-free survival, we assume the premise given by the study of d'amico et al., who demonstrated that 29% of high-risk patients treated with radical prostatectomy remained free of disease at 10 years.(22) in our study these figures are relatively higher, 44% in younger patients, 59% in patients between 60 and 70 years of age and 62% in older patients, although we must take into account that our series includes patients treated with adjuvant rdt+ ht, and that the median follow-up for the older group does not reach 10 years, which could partly justify these results. in addition, it is important to note that, although in the univariate analysis the younger age group is the one that shows the worst results in biochemical recurrence-free survival, in the multivariate analysis it is no longer significant, observing that the variables that are independently related to recurrence-free survival are the treatment received and the characteristics of the tumor. these data contrast with those described by smith et al., who demonstrate a 10-year biochemical recurrence-free survival close to 60% in patients aged < 60 years. in fact, in younger patients (< 50 years), the results are even better with 10-year survivals around 90% (p = 0.010). after multivariate analysis adjusted for race, clinical and pathologic stage and pretreatment psa, age remained a significant prognostic factor (p = 0.033).(23) prostate cancer survival by age-garcia-fuentes et al. vol 20 no 4 july-august 2023 219 urological oncology 220 it should be noted that this study only includes patients treated with rp and not rdt as in our case. in relation to the previous discussion and according to the results obtained in our series regarding to the possible influence of the treatment received on survival free of biochemical recurrence, we must note that the criteria for biochemical recurrence after prostatectomy and after rdt are different and, therefore, these results must be interpreted with certain caution. our study is not free of the limitations inherent to an observational, retrospective, single-center study. in addition, the sample size is somewhat limited, and some of the age groups have a small number of patients. in spite of this, our series has a long follow-up and a non-negligible number of patients. admiteddly, strong conclusions cannot be drawn but our hypothesis deserves further specifically designed studies. conclusions in our series, survival of patients with high-risk pc treated with curative intent is similar to that described in the literature. age only influences in overall survival, with no impact on cancer-specific survival, free of biochemical recurrence or progression to metastasis. acknowledgements this study was developed in the department of urology, hospital universitario fundación alcorcón, as a research project. special thanks to all the authors for their contribution to this manuscript, especially to dr. guijarro and dr. llorente for their support in the preparation and revision of the manuscript. conflict of interest the authors report no conflict of interest. references 1. sung h, ferlay j, siegel rl, laversanne m, 1. siegel rl, miller kd, jemal a. cancer statistics, 2019. ca cancer j clin. 2019; 69:7-34. 2. cooperberg mr, broering jm, carroll pr. time trends and local variation in primary treatment of localized prostate cancer. j clin oncol. 2010; 28:1117-23. 3. van hemelrijck m, folkvaljon y, adolfsson j, et al. causes of death in men with localized prostate cancer: a nationwide, populationbased study. bju int. 2016; 117:507-14. 4. cózar jm, miñana b, gómez-veiga f, et al. prostate cancer incidence and newly diagnosed patient profile in spain in 2010. bju int. 2012; 110:701-6. 5. lin dw, porter m, montgomery b. treatment and survival outcomes in young men diagnosed with prostate cancer: a populationbased cohort study. cancer. 2009; 115:286371. 6. chen rc, carpenter wr, hendrix lh, et al. receipt of guideline-concordant treatment in elderly prostate cancer patients. int j radiat oncol biol phys. 2014; 88:332-38. 7. marotte d, chand-fouche me, boulahssass r, hannoun-levi jm. irradiation of localized prostate cancer in the elderly: a systematic prostate cancer survival by age-garcia-fuentes et al. literature review. clinical and translational radiation oncology. 2022; 35:1–8. 8. albertsen pc, fryback dg, storer be, et al. long-term survival among men with conservatively treated localized prostate cancer. jama. 1995; 274:626. 9. albertsen pc, fryback dg, storer be, et al. the impact of co-morbidity on life expectancy among men with localized prostate cancer. j urol. 1996; 156:127. 10. cheng x, wang zh, peng m, et al. the role of radical prostatectomy and definitive external beam radiotherapy in combined treatment for high-risk prostate cancer: a systematic review and meta-analysis. asian j androl. 2020; 22:383-89. 11. cózar jm, miñana b, gómez-veiga f, et al. registro nacional de cáncer de próstata 2010 en españa [national prostate cancer registry 2010 in spain]. actas urol esp. 2013; 37:129. 12. eau guidelines. edn. presented at the eau annual congress milan 2021. isbn 978-9492671-13-4. 13. jørgensen tl, hallas j, friis s, herrstedt j. comorbidity in elderly cancer patients in relation to overall and cancer-specific mortality. br j cancer. 2012; 106:1353-60. 14. rajan p, sooriakumaran p, nyberg t, et al. effect of comorbidity on prostate cancer-specific mortality: a prospective observational study. j clin oncol. 2017; 35:3566-74. 15. park jw, koh dh, jang ws, et al. ageadjusted charlson comorbidity index as a prognostic factor for radical prostatectomy outcomes of very high-risk prostate cancer patients. plos one. 2018; 13:e0199365. 16. post pn, hansen be, kil pj, janssenheijnen ml, coebergh jw. the independent prognostic value of comorbidity among men aged < 75 years with localized prostate cancer: a population-based study. bju int. 2001; 87:821-26. 17. wallis cjd, saskin r, choo r, et al. surgery versus radiotherapy for clinically-localized prostate cancer: a systematic review and meta-analysis. eur urol. 2016; 70:21-30. 18. petrelli f, vavassori i, coinu a, borgonovo k, sarti e, barni s. radical prostatectomy or radiotherapy in high-risk prostate cancer: a systematic review and metaanalysis. clin genitourin cancer. 2014; 12:215-24. 19. roach m 3rd, ceron lizarraga tl, lazar aa. radical prostatectomy versus radiation and androgen deprivation therapy for clinically localized prostate cancer: how good is the evidence? int j radiat oncol biol phys. 2015; 93:1064-70. 20. hamstra da, bae k, pilepich mv, et al. older age predicts decreased metastasis and prostate cancer-specific death for men treated with radiation therapy: meta-analysis of radiation therapy oncology group trials. int j radiat oncol biol phys. 2011; 81:1293-301. 21. briganti a, spahn m, joniau s, et al. impact of age and comorbidities on long-term survival of patients with high-risk prostate cancer treated with radical prostatectomy: a multiinstitutional competing-risks analysis. eur urol. 2013; 63:693-701. 22. d'amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998; 280:969-74. 23. smith cv, bauer jj, connelly rr, et al. prostate cancer in men age 50 years or younger: a review of the department of defense center for prostate disease research multicenter prostate cancer database. j urol. 2000; 164:1964-67. prostate cancer survival by age-garcia-fuentes et al. vol 20 no 4 july-august 2023 221 endourology and stone disease urology journal/vol 20 no. 2/ march-april 2023/ pp. 96-101. [doi: 10.22037/uj.v20i.7326] study of temperature changes around fibres in super pulse thulium fibre laser in vitro lithotripsy ding tianfu1, xiao bo1, zeng xue1, liang lei1, ji chaoyue1, li jianxing1* purpose: to investigate temperature changes around the fibres of the super pulse thulium fibre laser (sp-tfl) during in vitro lithotripsy. materials and methods: stones were placed in the in vitro model. the laser was continuously excited for 180 s; the probe was positioned 5 mm around the fibre; the laser power was set at 10, 15, 20, 25, and 30 w; and the irrigation rate was set at 0, 15, 25, 35 ml/min, using a domestic sp-tfl. the temperature variations around the fibre under different power settings and different irrigation rates were compared. results: without irrigation, the temperature around the fibre rapidly reached the safety threshold of 43℃ at 24 s. at an irrigation rate 15 ml/min and laser power <15 w, the temperature around the fibre was < 43℃. once the laser power increased to ≥ 20 w, the temperature around the fibre increased to >43℃ at its lowest plateau. at irrigation rate 25 ml/min and laser power ≤ 25 w, the temperature around the fibre was < 43℃. at irrigation rate 35 ml/min and laser power < 30 w, the fibre temperature was < 43℃. when laser power was ≥ 30 w, the fibre temperature was > 43℃. conclusion: in extracorporeal ureteroscope sp-tfl lithotripsy, when the laser power is ≤ 15 w, ≤ 25 w, and ≤ 30 w, the irrigation rate should be maintained at ≥ 15 ml/min, ≥ 25 ml/min, and ≥ 35 ml/min, respectively. keywords: super-pulse thulium fibre laser; temperature; lithotripsy; safety threshold introduction urological calculi are the most common disease in urology, and their incidence has increased worldwide over the past few decades.(1) with the development of endoscopic technology and the emergence of laser fibres,(2) ureteroscopic laser lithotripsy has become the most important treatment method for calculi because of its obvious advantages; it is minimally invasive, therapeutically effective, and considerable safety. among the many lasers utilised, the holmium: yttrium-aluminium-garnet (ho:yag) laser has always been the "gold standard" for laser lithotripsy in the clinics.(3) though at present, a new laser product, the super pulse thulium fibre laser (sp-tfl), has emerged in the market. unlike the ho:yag laser, the sp-tfl consists of thulium-doped quartz fibres that are triggered during laser pumping and emit lasers with a wavelength of 1940 nm. in laboratory and clinical studies, it has shown an effect superior to ho:yag laser in stone ablation and stone retropulsion.(4-6) however, as the laser’s mechanism of action can lead to an increase in ambient temperature (7) and cause thermal damage to surrounding tissue, the temperature safety limits of the laser has always been a predicament that urological surgeons pay close attention to and study extensively during surgery. there is currently no relevant research on temperature changes around the laser fibre in domestic sp-tfl lithotripsy procedures. from november to december 2021, this 1department of urology, tsinghua changgung hospital, tsinghua university, affiliated with the school of clinical medicine, tsinghua university, beijing 102218, china. * correspondence: department of urology, tsinghua changgung hospital, tsinghua university, affiliated with the school of clinical medicine, tsinghua university, beijing 102218email:lijianxing2015@163.com. received june 2022 & accepted december 2022 study investigated the temperature changes around the laser fibre during domestic sp-tfl lithotripsy procedures using an in vitro kidney model. materials and methods we used an in vitro kidney model designed by an independent research group (figure 1). the in vitro device was comprised of two parts: the external section was a constant temperature water bath system, which used a combination of a thermoregulated water tank and a water pump to provide stable 36–37°c heated water, simulating human body temperature; the interior is an open cylinder at one end, with a length of 40 mm, radius of 8 mm, and a volume of 7.5 ml. the cylinder’s open end is closed by a rubber stopper, with three openings for the ureteric access sheath (f12/14) and for two temperature probes to pass through. the stones were placed in the cylinder. the laser equipment selected was a continuous super-pulsed dual-mode output thulium-doped fibre laser surgical system with a peak of 500 w (hereinafter referred to as "sp-tfl") (lakh medical instrument co., ltd., beijing, china ), attached with a 272 μm core fibre and a pulse width of 7 ms. using a multichannel real-time thermometer (guangzhou ruiman instrument technology co., ltd., guangzhou, china), four temperature probes (recording temperature once per second) were used, with the first and second probes fixed at a position of 5 mm around the fibre to record the temperature changes in the vicinity of the fibre. the third and fourth probes, recorded and monitored the temperature of the external water flow. artificial stones (bego gmbh & co. kg germany) were used to simulate actual kidney stones. maintaining a room temperature of 22–26°c, the artificial stones were placed in an in vitro renal model (figure 1). using a flexible ureteroscope and the sptfl, a senior doctor who was blinded to the purpose of the study performed the lithotripsy procedure. various laser power settings were used: 10 w (10 hz*1 j), 15 w (10 hz*1.5 j), 20 w (10 hz*2 j), 25 w (10 hz*2.5 j), and 30 w (10 hz*3 j). along with these, different irrigation rates were employed: 0, 15, 25, 35 ml/min (irrigation solution: normal saline, at 24°c). before each experiment, the fibre was trimmed with a large core diameter fibre cutting knife and measured with a laser power meter to ensure that the laser power meets the national standard (100 ± 20%). temperature readings from the two temperature probes, wrapped 5 mm around the fibre strand, were measured once every second, and the average reading of the two probes was recorded. the sp-tfl was set on continuous excitation for 180 s. after each experiment, the temperature figure 1. in vitro kidney model a: in vitro kidney model (internal). b: in vitro kidney model (external). c: lithotripsy laser ablating a stone. d: a senior doctor using soft ureteroscopy with laser for lithotripsy. figure 2. the relationship between time and temperature, in the absence of irrigation with a power setting of 10 w, in a sp-tfl in vitro setup. the initial temperature in the in vitro renal pelvis is 24°c, and as time goes on, the water temperature incrementally increases. the temperature reaches the safety threshold of 43°c at 24 s and 89.1°c at the end of the simulation. temperature changes of tfl-tianfu et al. vol 20 no 2 march-april 2023 97 in the simulated renal pelvis was reduced to 24°c before the next experimental set up was carried out. each experiment was repeated three times under the same conditions to obtain the final average. a thermometer recorded the temperature in real time, while recording the temperature changes around the fibre under different power settings and irrigation flow rates. results in the absence of irrigation (figure 2), the ambient temperature increased by 0.3°c per minute, with the fibre reaching the safety threshold of 43°c from 24°c in 24 s. at irrigation rate 15 ml/min (figure 3) and laser power ≤ 15 w, the plateau phase temperature was 35.5– 39.6°c at the highest temperature peak around the fibre, which failed to exceed the temperature safety threshold (43°c). at laser power ≥ 20 w, the plateau phase temperature around the fibre was 39.1–44.5°c, exceeding the safety threshold of 43°c. at irrigation rate 25 ml/ min (figure 4) and laser power ≤ 25 w, the plateau phase temperature was 37.5–41.3°c when the maximum temperature around the fibre was 37.5–41.3°c, which did not exceed the safety threshold at 43°c. at laser power ≥ 30 w, the plateau phase temperature around the fibre was 40.3–43.5°c, which exceeded the safety threshold of 43°c. at irrigation rate 35 ml/ min (figure 5) and laser power ≤ 30 w, the plateau phase temperature during the highest peak temperature around the fibre was 35.7–37.2°c, which also did not exceed the safety threshold. figure 3. the relationship between time and temperature, at irrigation rate 15 ml/min, under different laser power settings. at irrigation rate 15 ml/min with laser power ≤ 15 w, the plateau phase temperature is 35.5–39.6°c when the maximum temperature around the fiber is 35.5–39.6°c; the 43°c safety threshold is not exceeded. with laser power ≥ 20 w, the plateau phase temperature around the fiber is 39.1–44.5°c, exceeding the safety threshold of 43°c. figure 4. the relationship between time and temperature, at irrigation rate 25 ml/min, under different laser power settings. at irrigation rate 25 ml/min with laser power ≤ 25 w, the plateau phase temperature is 37.5–41.3°c, and the maximum temperature around the fiber is 37.5–41.3°c; the 43°c safety threshold is not exceeded. with laser power ≥ 30 w, the plateau phase temperature around the fiber is 40.3–43.5, exceeding the safety threshold of 43°c. temperature changes of tfl-tianfu et al. endourology and stone diseases 98 discussion with the development of medical technology, laser lithotripsy has been utilised in more and more applications. the operational principle of laser lithotripsy is inherent in both its photothermal effect and photomechanical effect; its photothermal effect is caused by the accumulated heat emitted by the optical fibre which consequently ablates the stone; its photomechanical effect is caused by bubbles generated in the water through the excitation of the optical fibre, which leads to stone fragmentation. (7) the sp-tfl fibre laser operates using infrared light, with a wavelength of 1940 nm, and has a high absorption coefficient in water, leading to stone vaporisation after energy is absorbed in the stone cracks, thus ablating and dusting the stone.(8,9) as an effective and relatively safe surgical modality, ureteral laser lithotripsy has a low incidence of postoperative ureteral stenosis. (10) although the incidence is low, the complications are more severe, and laser-induced tissue damage during lithotripsy is one of the causes. according to previous studies,(11-14) tissue damage begins at 43°c; accordingly, 43°c is determined as a safe temperature threshold for laser surgery. at temperatures exceeding 54°c, tissue essentially becomes completely necrotic.(15) therefore, the damage to the surrounding tissue caused by the increase in ambient temperature during sp-tfl use is one of the most important indicators used to evaluate its safety.(16) because of the high absorption coefficient of sp-tfl in water, the change of temperature around the fibre during the ablation process is more worthy of investigation. in order to simulate an in vivo environment as closely as possible, reduce interference, and render the experiment feasible, the in vitro kidney model independently designed by a research group included an external thermoregulated water bath system, while the interior is a cylinder comparable to the actual volume of the kidney. according to peng,(17) this renal model mimics the true volumetric environment in vivo as much as possible. one end of the cylinder is sealed by a rubber stopper figure 5. the relationship between time and temperature, at irrigation rate 35 ml/min, under different laser power settings. at irrigation rate 35 ml/min with laser power ≤ 30 w, the plateau phase temperature at the peak ambient temperature of the fiber is 35.7–37.2°c, without exceeding the safety threshold. equipped with three openings for the ureteric access sheath and two temperature probes to pass through, while the optical fibre and the temperature probe are fixed to the rubber plug, and the relative distance is fixed. to fragment the stone, it is placed in the cylindrical body; the soft ureteroscope is manipulated for stone ablation, and the irrigation solution is connected to the soft ureteroscope through a water pump. subsequently, water flows out of the gap between the soft mirror and the dilated sheath. for 3d-printed kidney models, experienced soft ureteroscopic operators must operate the device, and during the operation, due to the displacement of stones or a blurred endoscopic field of view, the operator most likely stops laser excitation or adjusts the detection of temperature affected by the rate of irrigation fluid, which may result in increased experimental errors. the in vitro model we adapted for this study, is simple to operate; any first-time user can manoeuvre the endoscopic device in this experiment. additionally, the model is made of transparent materials, allowing the stone to be observed simultaneously via the uteroscope or from the outside, without the impact of an obscured field of view. furthermore, a circular spring placed in the cylinder body prevents stone displacement, so as not to affect the process of stone ablation, subsequently minimising the errors of intraoperative operation. the results of this study suggest that in laser lithotripsy, the temperature around the fibre varies under different combinations of irrigation rate and laser power. hein, (12) taratkin,(18) and peng,(17) by constructing an in vitro kidney model that excites the laser with different irrigation rates and power settings to detect changes in water temperature, concluded that laser power settings and irrigation rates play a key role in reducing water temperature, more specifically inferring that high and low irrigation rates may lead to potential tissue damage. in this study, the temperature curves caused by all laser power settings are similar to logarithmic curves, with the temperatures rising rapidly at the beginning, and then at a certain moment once the irrigation solution is balanced with heat, the curve exhibits a plateau phase. once the temperature changes of tfl-tianfu et al. vol 20 no 2 march-april 2023 99 irrigation rate is at 15 ml/min, the temperature increase caused by the laser power <15 w does not exceed the safety threshold, while the temperature increase caused by laser power ≥ 20 w exceeds the safety threshold. maximum temperatures reached 52.1°c when the laser power was 30 w, which is similar to the results of peng(17) et al., who stated that at uniform irrigation rates, 30 w of laser power will exceed the safety threshold due to the volume difference (20 ml and 7.5 ml) of the container used in the experiment; the larger volume leads to faster water flow mixing to decrease the temperature. (19) in our study, the volume selected was comparable to the volume of the renal pelvis and the results were more in line with the effect of a real in vivo experiment. nonetheless, both experiments demonstrate that at an irrigation rate of 15 ml/min, a laser power <15 w is safe and reliable. in contrast, taratkin(20) and hardy(21), whose experimental models used a double-sided unobstructed tube with a mesh screen at the bottom, where the irrigation fluid flows from one end to the other, and the heat was greatly reduced by the liquid, came up with higher irrigation rates of 25 ml and 35 ml. while our in vitro model is closed on one side, the turbulence caused by the laser may affect the water temperature to some extent, but it can simulate the irrigation in the renal pelvis or the renal calyx, as the irrigation fluid flows out from the soft ureteroscope and the ureteral dilation sheath through the obstruction of the renal pelvis and the renal calyx, which explains the disparity between our findings and those of taratkin(20) and hardy(21). moreover, we also selected the more commonly used laser power setting of 10 w, which increased with time in the absence of irrigation and reached a safety threshold at 24 s. in in vivo laser lithotripsy, due to the effects of stone retropulsion or intrarenal hypertension, the operator deliberately reduces the intraoperative irrigation flow, and even suspends flushing to avoid stone displacement. this can cause insufficient local irrigation to accommodate heat in excess of the safe temperatures tolerated by the tissue, resulting in thermal damage. thus attention should be paid to the suspension of the flushing time to avoid irreversible thermal damage to the tissue. in addition, this study observed that the temperature at the plateau phase attained using the same laser power settings decreased with increasing irrigation rates. however, caution must be practiced in increasing irrigation rates, as higher irrigation rates may lead to an increase in intrarenal pressure, which can then lead to postoperative infection complications and even the occurrence of urinary sepsis. tokas(22) has shown that intrarenal pressure in percutaneous nephrolithotomy is closely related to postoperative infection and postoperative rehabilitation. even if the intraoperative visual field is clear during soft ureteral lithotripsy, cases of intrapelvic hypertension still occur. alsyouf(23) used an irrigation pump to maintain the average irrigation flow and concluded that intraoperative intrarenal pressure changes are related to irrigation pressure and irrigation time. therefore, we did not select a high irrigation rate and restricted our irrigation fluid use to below 50 ml, which should meet the clinical requirement to avoid the occurrence of intrarenal hypertension. as this study is a preliminary in vitro experiment using domestic sp-tfl, it has certain limitations. first, the experimental device does not accurately simulate the true anatomy of the human renal system nor the flexibility of the tissues involved; however, it can still prove the relationship between the laser power settings during the lithotripsy process and the temperature changes around the optical fibre. further studies using animal models may help solve this limitation. second, intraoperative influencing factors were not considered, such as the intrapelvic pressure and intraoperative bleeding during the procedure. the secretions of the renal collection system and the renal circulatory system also play important roles in preventing damage to the surrounding tissue.(12) finally, this study only used a single energy combination, not multiple combinations, of ablation parameters. in subsequent studies, we will set up a combination of multiple ablation parameters. nonetheless, our preliminary findings provide a valuable reference for in vivo experiments and clinical applications. conclusions in summary, our preliminary findings show that in in vitro flexible ureteroscope sp-tfl lithotripsy, the safe irrigation rate is correlated with laser power. the irrigation rates should be maintained at >15 ml/min, >25 ml/ min, and > 35 ml/min for laser power <15 w, <25 w, and < 30 w, respectively. references 1. zeng ga-o, mai z, xia s, et al. prevalence of kidney stones in china: an ultrasonography based cross-sectional study. (1464-410x (electronic)). 2. coptcoat mj, ison kt, watson g, et al. lasertripsy for ureteric stones in 120 cases: lessons learned. br j urol. 1988;61:487-9. 3. fried nm, irby pb. advances in laser technology and fibre-optic delivery systems in lithotripsy. nat rev urol. 2018;15:563-73. 4. traxer oa-o, keller ea-o. thulium fiber laser: the new player for kidney stone treatment? a comparison with holmium:yag laser. (1433-8726 (electronic)). 5. kronenberg p, traxer o. the laser of the future: reality and expectations about the new thulium fiber laser-a systematic review. (2223-4691 (print)). 6. rapoport lm, gazimiev ma, korolev do, et al. [flexible ureteroscopy for lower pole renal stones: novel superpulse thulium (tm) fiber laser lithotripsy]. urologiia. 2020:89-92. 7. teichman jmh, qiu j, kang w, et al. laser lithotripsy physics. 8. wieliczka dm, weng s, querry mr. wedge shaped cell for highly absorbent liquids: infrared optical constants of water. appl opt. 1989;28:1714-9. 9. ventimiglia e, doizi s, kovalenko a, et al. effect of temporal pulse shape on urinary stone phantom retropulsion rate and ablation efficiency using holmium:yag and super-pulse thulium fibre lasers. bju int. 2020;126:159-67. 10. dong h, peng y, li l, et al. prevention strategies for ureteral stricture following ureteroscopic lithotripsy. asian j urol. 2018;5:94-100. 11. thomsen s, pearce ja. thermal damage and rate processes in biologic tissues. temperature changes of tfl-tianfu et al. endourology and stone diseases 100 12. hein s, petzold r, schoenthaler m, et al. thermal effects of ho: yag laser lithotripsy: real-time evaluation in an in vitro model. world j urol. 2018;36:1469-75. 13. aldoukhi ah, ghani kr, hall tl, et al. thermal response to high-power holmium laser lithotripsy. j endourol. 2017;31:130812. 14. sapareto sa, dewey wc. thermal dose determination in cancer therapy. int j radiat oncol biol phys. 1984;10:787-800. 15. he x, mcgee s, coad je, et al. investigation of the thermal and tissue injury behaviour in microwave thermal therapy using a porcine kidney model. int j hyperthermia. 2004;20:567-93. 16. cinman nm, andonian s, smith ad. lasers in percutaneous renal procedures. world j urol. 2010;28:135-42. 17. peng y, liu m, ming s, et al. safety of a novel thulium fiber laser for lithotripsy: an in vitro study on the thermal effect and its impact factor. j endourol. 2020;34:88-92. 18. taratkin m, laukhtina e, singla n, et al. temperature changes during laser lithotripsy with ho:yag laser and novel tm-fiber laser: a comparative in-vitro study. world journal of urology. 2020;38:3261-6. 19. andreeva v, vinarov a, yaroslavsky ia-o, et al. preclinical comparison of superpulse thulium fiber laser and a holmium:yag laser for lithotripsy. (1433-8726 (electronic)). 20. taratkin ma-ox, laukhtina e, singla n, et al. temperature changes during laser lithotripsy with ho:yag laser and novel tm-fiber laser: a comparative in-vitro study. (1433-8726 (electronic)). 21. hardy la, wilson cr, irby pb, et al. thulium fiber laser lithotripsy in an in vitro ureter model. (1560-2281 (electronic)). 22. tokas ta-o, herrmann trw, skolarikos a, et al. pressure matters: intrarenal pressures during normal and pathological conditions, and impact of increased values to renal physiology. (1433-8726 (electronic)). 23. alsyouf m fau abourbih s, abourbih s fau west b, west b fau hodgson h, et al. elevated renal pelvic pressures during percutaneous nephrolithotomy risk higher postoperative pain and longer hospital stay. (1527-3792 (electronic)). temperature changes of tfl-tianfu et al. vol 20 no 2 march-april 2023 101 case report urology journal/vol 19 no. 4/ july-august 2022/ pp. 339-342. [doi:10.22037/uj.v19i.7042] percutaneous internal drainage in symptomatic renal parapelvic cyst refractory to sclerotherapy: a case report suyoung park1, jeong ho kim1*, jung han hwang1, ki hyun lee2, sung hyun yu1 percutaneous sclerotherapy is a safe and effective treatment for renal parapelvic cysts. however, if the cyst is in communication with the adjacent renal pelvocalyceal system, sclerotherapy is contraindicated and alternative treatment should be considered. here, we report a case of a patient with a symptomatic renal parapelvic cyst that was treated using a novel technique involving percutaneous new tract formation between the cyst and renal pelvis. 1department of radiology, gil medical center, gachon university college of medicine, incheon, republic of korea. 2department of radiology, hwasung ds hospital, hwasung, republic of korea. *correspondence: department of radiology, gil medical center, gachon university college of medicine, incheon, 21565, republic of korea. tel: +82 032 4603063, fax: +82 032 4603065, e-mail: ho7ok7@gilhospital.com. received october 2021& accepted april 2022 introduction renal parapelvic cysts require treatment for complications such as hydronephrosis, infection, or pain(1). we report a patient with a parapelvic cyst treated with a novel method as percutaneous sclerotherapy was contraindicated due to communication between the cyst and renal pelvocalyces. case report a 68-year-old man with left flank pain visited our medical center. the patient had a medical history of hypertension and cerebral infarction. urinalysis results were normal. computed tomography (ct) showed a 10-cm left renal parapelvic cyst and severe left hydronephrosis (figure 1). transurethral double-j stent insertion was performed; however, the hydronephrosis remained unresolved. as the renal parapelvic cyst may have resulted in hydronephrosis, which in turn caused the flank pain, percutaneous sclerotherapy was then performed. an 8.5-fr catheter (sungwon medical, cheongju, korea) was inserted into the cyst. communication between the cyst and renal pelvocalyces was absent on fluoroscopy and cone-beam ct after injection of contrast media, immediately after aspiration of 300 ml of clear fluid (figure 2). sclerotherapy was performed using 30 ml of 99.9% ethanol as the sclerosant. after 60 min, the ethanol was completely aspirated, and the catheter was retained. the amount of drainage through the catheter was higher than 2000 ml/day, which was maintained for 3 days. the creatinine level in the fluid was 37 mg/dl, suggesting the formation of a new communicating structure with the figure 1. contrast-enhanced axial (a) and coronal (b) ct images taken in the renal excretory phase show a large left parapelvic cyst (asterisk) and associated hydronephrosis. urinary tract. tubography and cone-beam ct (figure 3) indeed showed a communication between the cyst and renal calyx, which implied a contraindication for additional sclerotherapy. alternatively, internal drainage of the cyst fluid into the renal pelvocalyx was planned. however, cannulation of the communicating tract was attempted, but failed. to overcome this issue, a new tract was created between the cyst and the renal pelvis. ultrasonographyand fluoroscopy-guided puncture of the upper renal calyx was performed via the catheter route using a 21-gauge needle (figure 4a). an 8.5-fr catheter with additional sideholes was inserted through the tract with the tip in the renal pelvis (figure 5). the catheter was maintained for 1 month to allow tract maturation and was removed after tract patency was confirmed. the cyst and subsequent hydronephrosis were resolved at the 2-month follow-up (figure 6a). 1-year follow-up noncontrast ct scan (figure 6b) showed no evidence of any relapsed parapelvic cyst. the flank pain remained absent at an outpatient follow-up 6 months after the last ct scan. discussion this report describes a novel percutaneous method for the internal drainage of a renal parapelvic cyst. percutaneous sclerotherapy is a minimally invasive treatment with low recurrence rates for renal cysts(2,3). however, if the cyst is in communication with the renal pelvocalyces, the use of a sclerosant may damage their endothelium, and alternative treatments should be considered. in our patient, sclerotherapy was performed with no evidence of communication between the cyst and pelvocalyces. however, communication between the cyst and the adjacent renal calyx subsequently appeared; thus, sclerotherapy could no longer be performed. the concept of draining a cyst into the urinary tract has been introduced as a method involving direct incision figure 2. fluoroscopy (a) and cone-beam ct (b) images taken during the first session of sclerotherapy show no contrast leakage out of the cyst. figure 3. both fluoroscopy (a) and cone-beam ct (b) images taken before the second session of sclerotherapy show communication (arrow) between the renal parapelvic cyst and adjacent renal upper polar calyx (asterisk). percutaneous internal drainage for renal parapelvic cyst-park et al. vol 19 no 4 july-august 2022 340 urology journal/vol 19 no. 3/ may-june 2022/ pp. 241-245. [doi:10.22037/uj.v18i.7297] figure 4. (a) direct puncture of renal upper polar calyx was performed through the parapelvic cyst, and the tract was dilated using a balloon catheter (b). of the cyst wall through retrograde flexible ureteroscopy or antegrade nephroscopy(4-7). to mitigate any risk, accurate information about the surrounding structures must be obtained during cyst wall incision. in this sense, ultrasonographyand fluoroscopy-guided percutaneous approaches have the advantage of allowing visual access to the surrounding tissues during surgery. we report a patient with a renal parapelvic cyst that was not eligible for additional sclerotherapy session and was successfully treated with a novel procedure involving a tract formation between the cyst and the renal pelvis. figure 5. (a) a pigtail catheter with additional sideholes is placed through the newly formed tract with the tip inside the renal pelvis, to keep the tract patent. (b) diagram shows percutaneous new tract formation and pigtail catheter placement. the catheter passes through the cyst (white arrow) and the renal pelvic wall (black arrow), and its end is located in the renal pelvis (asterisk). sideholes are marked as semicircles in the pigtail catheter. the procedure reported here could be considered as an effective alternative treatment option when percutaneous sclerotherapy is not indicated. conflict of interest no potential conflict of interest was reported by the authors. references 1. eissa a, el sherbiny a, martorana e, et al. non-conservative management of simple renal cysts in adults: a comprehensive review of literature. minerva urol nefrol. 2018;70:179192. 2. bean wj. renal cysts: treatment with alcohol. radiology. 1981;138:329-331. 3. cho ds, ahn hs, kim si, et al. sclerotherapy of renal cysts using acetic acid: a comparison with ethanol sclerotherapy. br j radiol. 2008;81:946-949. 4. luo q, zhang x, chen h, et al. treatment of renal parapelvic cysts with a flexible ureteroscope. int urol nephrol. 2014;46:19031908. 5. zhao q, huang s, li q, et al. treatment of parapelvic cyst by internal drainage technology using ureteroscope and holmium laser. west indian med j. 2015;64:230-235. 6. agarwal m, agrawal ms, mittal r, sachan v. a randomized study of aspiration and sclerotherapy versus laparoscopic deroofing in management of symptomatic simple renal cysts. j endourol. 2012;26:561-565. 7. basiri a, hosseini sr, tousi vn, sichani mm. ureteroscopic management of symptomatic, simple parapelvic renal cyst. j endourol. 2010;24:537-540. percutaneous internal drainage for renal parapelvic cyst-park et al. case report 341 figure 6. both 2-month (a) and 14-month (b) follow-up coronal ct images show resolved parapelvic cyst and hydronephrosis. percutaneous internal drainage for renal parapelvic cyst-park et al. vol 19 no 4 july-august 2022 342 miscellaneous 50 urology journal vol 5 no 1 winter 2008 laparoscopic adrenalectomy ten-year experience, 67 procedures nasser simforoosh,1 heshmatollah soufi majidpour,2 abbas basiri,1 seyyed amir mohsen ziaee,1 saeed behjati,3 faramarz mohammad ali beigi,4 alireza aminsharifi5 introduction: the purpose of this study was to evaluate the short-term and long-term results of laparoscopic adrenalectomies carried out in our center. materials and methods: a total of 67 laparoscopic adrenalectomies were performed during the 10 years between 1995 and 2005 at shahid labbafinejad medical center. a transperitoneal lateral approach was used in 65 (97.0%) of the patients, and retroperitoneal approach was used in 2 (3.0%). the clinical characteristics and the outcomes were reviewed in a retrospective study. results: indications for laparoscopic adrenalectomy in our patients were as follows: pheochromocytoma in 28 patients (41.8%), aldosteroneproducing adenoma in 15 (22.4%), pseudocyst in 6 (9.0%), cushing syndrome (macronodular adrenocortical hyperplasia) in 5 (7.5%), nonfunctioning adenoma (incidentaloma) in 5 (7.5%), myelolipoma in 2 (3.0%), almost normal adrenal tissue in 2 (3.0%), adrenal cyst in 2 (3.0%), adenocarcinoma in 1 (1.4%), and schwannoma in 1 (1.4%). the mean operative time for unilateral cases was 149.0 ± 36.1 minutes. the mean intraoperative blood loss was 126 ± 36 ml. conversion rate to open surgery was 7.5%. reoperation due to hemorrhage was performed in 1 patient. conclusion: laparoscopic adrenalectomy is a safe procedure in some adrenal tumors and a reasonable option for selected large adrenal tumors when complete resection is technically feasible and there is no evidence of local invasion. urol j. 2008;5:50-4. www.uj.unrc.ir keywords: laparoscopy, adrenalectomy, pheochromocytoma, transperitoneal approach 1department of urology, shahid labbafinejad medical center & urology and nephrology research center, shahid beheshti university (mc), tehran, iran 2department of urology, kurdestan university of medical sciences, sanandadj, iran 3department of urology, isfahan university of medical sciences, isfahan, iran 4department of urology, shahid ashrafi-isfahani hospital, shahr-ekord university of medical sciences, shahr-e-kord, iran 5department of urology, shahid faghihi hospital, shiraz university of medical sciences, shiraz, iran corresponding author: nasser simforoosh, md department of urology, shahid labbafinejad medical center, 9th boustan, pasdaran, tehran 1666679951, iran tel: +98 21 2258 8016 fax: +98 21 2258 8016 e-mail: simforoosh@iurtc.org.ir received october 2007 accepted april 2008 introduction during the past decade, minimally invasive procedures have been increasingly used, resulting in their current wide application to a variety of disorders.(1) laparoscopic adrenalectomy was promptly introduced and is now almost universally considered to be the standard technique for the management of benign adrenal masses; however, it is controversial for large and potentially malignant tumors.(2-4) we report a series of 67 laparoscopic adrenalectomies carried out during a period of 10 years in our center. materials and methods a total of 67 laparoscopic adrenalectomies performed between 1995 and 2005 were reviewed retrospectively. preoperative characteristics of laparoscopic adrenalectomy—simforoosh et al urology journal vol 5 no 1 winter 2008 51 the patients are listed in table 1. laparoscopy was limited to well-encapsulated masses without radiologic evidence of periadrenal involvement or obvious lymphadenopathy. there were 17 patients (25.5%) among our 67 cases who had a tumor larger than 6 cm in diameter. the most common indication for laparoscopic adrenalectomy in our series was pheochromocytoma (n = 28) that compromised the greatest number with adrenal tumors larger than 6 cm (table 2). five patients (7.5%) were classified as having nonfunctioning adrenal tumors. these patients had nonspecific abdominal pain, history of hypertension, and a slight increase in the preoperative 24-hour urine metanephrines. consequently, they underwent adrenalectomy for a presumed pheochromocytoma, but pathologic examination of their removed adrenal glands showed no evidence of pheochromocytoma. we had 15 patients (22.4%) with aldosteroneproducing adenoma, all of which were larger than 3 cm in diameter. two patients (3.0%) underwent adrenalectomy, but pathologic examination of specimen showed normal adrenal tissue. they had a history of hypertension and low but normal levels serum potassium with mild increase in serum aldosterone. imaging findings were indicative of a tiny nodule. urinary levels of free cortisol and vanilmandelic acid, along with plasma levels of adrenocorticotropic hormone, dehydroepiandrosterone, 17-hydroxy progestrone, testosterone, rennin, and aldosterone were measured preoperatively, as indicated. complete hormonal tests were performed preoperatively in patients with incidentally detected adrenal masses. all of the patients underwent abdominal computed tomography and magnetic resonance imaging. in case of pheochromocytoma, 131 i-metaiodobenzylguanidine scintigraphy was performed in order to detect contralateral or extra-adrenal lesions. correction of metabolic derangements in patients with cushing syndrome and hyperaldosteronism, and control of pheochromocytoma-induced hypertension was achieved with α-adrenergic or β-adrenergic blockage before surgical operation. in order to perform laparoscopic adrenalectomy, retroperitoneal approach was used in 2 patients (3.0%) with aldosteroneproducing adenoma and schwannoma during the first cases (learning curve period) to find out the applicability of the approach. afterwards, lateral transperitoneal approach was our routine in 65 patients (97.0%) since it had more space to work in and anatomy was better during the procedure. all of the patients underwent bowel preparation the day before the procedure. they were secured in a 90-degree lateral position for surgical operation. the techniques of the lateral transperitoneal approach that we used have been previously described.(1,3) in the right adrenal tumors, if the tumor size was less than 4 cm, the adrenal vein was exposed from its origin on the inferior vena cava and was clipped or coagulated by bipolar cautery. if the adrenal tumor was larger (> 4 cm), we table 1. preoperative characteristics of patients who underwent laparoscopic adrenalectomy* *values in parentheses are percents. characteristics values number of patients 67 sex male 25 (37.3) female 42 (62.8) mean age, y 39.8 ± 11.6 (22 to 61) mean tumor size, cm 6.3 ± 3.5 (2 to 13) tumor side right 29 (43.3) left 37 (55.2) both 1 (1.5) table 2. indications for laparoscopic adrenalectomy indication patients (%) pheochromocytoma 28 (41.8) aldosterone-producing adenoma 15 (22.4) cushing syndrome (macronodular adrenocortical hyperplasia) 5 (7.5) pseudocyst 6 (9.0) adenocarcinoma 1 (1.4) myelolipoma 2 (3.0) schwannoma 1 (1.4) adrenal cyst 2 (3.0) nonfunctioning adenoma (incidentaloma) 5 (7.5) almost normal adrenal tissue 2 (3.0) laparoscopic adrenalectomy—simforoosh et al 52 urology journal vol 5 no 1 winter 2008 tried to coagulate or clip the adrenal vein as close to the tumor as possible with special care not to avulse the adrenal vein from the vena cava. we performed adrenalectomy in patients with pseudcysts with thick or irregular walls, suspicious of malignancy. we also performed adrenalectomy in 2 patients with symptomatic large adrenal cysts because the cyst compromised most of the adrenal gland at laparoscopy. in 1 patient undergoing the retroperitoneal approach, an adenoma was removed and the normal adrenal gland was preserved. data on the patients’ characteristics, hospital records, and follow-up visits were collected. improvement of hypertension was defined as a lower blood pressure and/or reduction of antihypertensive medications. the results were presented as percentages and mean ± standard deviation, where appropriate. results indications for adrenalectomy in our series are listed in table 2, and the operative results are shown in table 3. the diameter of the adrenal tumor did not significantly correlate the operative time; grouping patients into 17 with large tumors (≥ 6 cm in diameter) and 50 with tumors (< 6 cm), we did not find significantly longer operative times in patients with larger tumors (159 ± 32 min versus 145 ± 36 min, p = .34). the overall intraoperative complication rate was 6.0% (4 patients). there were 2 hypertensive crisis episodes in patients with phechromocytoma, 1 bleeding episode in a patient with a right adrenal tumor less than 6 cm, and 1 iatrogenic injury to the ileum in a patient with a history of previous surgery. prompt intraoperative intervention in the patients with hypertensive crises was performed with a successful control. bleeding was massive in 1 patient and required intraoperative blood transfusion and conversion. reoperation due to hemorrhage was performed in 1 patient (insufficient hemostasis). there was 1 case of ileal injury in a patient with a history of previous abdominal surgery and dense adhesions, which were repaired laparoscopically without any postoperative complication (table 3). all complications and conversions occurred during the first 5 years of our experience, in the first 25 patients, and there were no major complications in the remaining 42 patients. in addition, the mean operative time decreased significantly in the last 3 years. nasogastric drainage usually remained in the end of the procedures and the foley catheter was removed in the morning following the operation day. all the patients required postoperative analgesics for a mean period of 2.1 ± 0.6 days (range, 1 to 51 days) and were able to resume oral intake after a mean of 2.0 ± 1.2 days (range, 1 to 4 days). postoperative mean hospital stay was 5.0 ± 2.1 days (range, 3 to 11 days). at a mean follow-up of 31 months (range, 2 to 69 months), improvement of hypertension was achieved in 41 of 44 patients (93.1%) with pheochromocytoma or hyperaldosteronism. after the operation, all of the patients were referred to an endocrinologist for evaluation. there was no evidence of biochemical relapse in hormonally active tumors. one patient in whom laparoscopic adrenalectomy was attempted to treat adenocarcinoma developed local metastasis after 6 months. the size of tumor was less than 6 cm and we had not diagnosed it preoperatively. there was no perioperative mortality and no capsular disruption during dissection. table 3. operative outcomes of laparoscopic adrenalectomy* *values in parentheses are minimum and maximum values or percentages where appropriate. †operative time for unilateral tumors was considered. ‡the patient had bowel adhesion due to appendectomy. injury was repaired laparoscopically with no further problems. outcome parameter value mean operative time, min† 149.0 ± 36.1 (130 to 290) right side 165.0 ± 33.6 (150 to 230) left side 121.0 ± 39.2 (80 to 290) mean blood loss, ml 126 ± 36 (70 to 850) conversion to open surgery 5 (7.5) reoperation for bleeding 1 (1.4) ileal injury‡ 1 (1.4) hypertension 2 (3.0) laparoscopic adrenalectomy—simforoosh et al urology journal vol 5 no 1 winter 2008 53 discussion laparoscopy has become the gold standard approach to routine adrenalectomy.(3,5,6) abandoning large incisions and minimizing bowel manipulation result in decreased preoperative morbidity, shortened hospital stay, and rapid functional recovery. concerning the treatment of adrenal masses, despite absolute contraindication of laparoscopy for large adrenal cortical carcinoma with local periadrenal invasion or venous thrombus,(1) there is still no consensus regarding the maximum tumor size for laparoscopy. while the size of an adrenal tumor is an important indicator of its malignant risk, many large adrenal tumors are benign.(2) if size is the only criterion on which the operative approach is based, many patients with benign large adrenal tumors will have an unnecessary open adrenalectomy that might increase their morbidity. several surgeons reported successful laparoscopy performed in patients with adrenal tumors larger than 5 cm.(7-9) they had similar results as other surgeons who chose 6 cm as the cutoff point.(10,11) data in our series also confirm that laparoscopy for tumors larger than 6 cm can be performed successfully without any increase in conversion rate, morbidity, or mortality. in our patients, all conversions or malignancies were seen in patients with tumors smaller than 6 cm, but we emphasize that oncological surgical principles should be considered in detail. from our data and those just reviewed, it is difficult to conclude whether laparoscopy offers the same therapeutic efficacy for malignant tumors, because in all series, malignant tumors are rare. it is very difficult to conduct a comparative study of open versus laparoscopic adrenalectomy for large or malignant tumors in a single center. also, still no reliable preoperative diagnostic test exists for determining the malignant potential of adrenal tumors.(12) in neither of our patients, preoperative laboratory or imaging evaluation indicated malignancy. during the first five years of our experience, we limited the laparoscopic approach to benign tumors less than 6 cm in diameter, and our first laparoscopic resection of adrenal tumors larger than 6 cm were performed after we had the experience of 20 laparoscopic adrenalectomies in patients with smaller adrenal tumors, and thus, we had considerable experience with this procedure before we encountered patients with this large adrenal tumors, and this may have influence our results. in our study group, the mean size of adrenal masses resected by laparoscopic adrenalectomy was 6.3 cm (range, 2 cm to 13 cm). the larger lesions, often involving numerous vessels, required special perioperative attention, but no increase in conversion rate was noted because there was no complication or conversion in large tumors. regarding the relationship between malignancy and tumor size, some authors have reported that tumors larger than 6 cm in diameter or weighing more than 100 g are highly likely to be malignant.(13,14) furthermore, inhomogeneous features visible in a computed tomography scan and elevated dehydroepiandrosterone or estradiol levels are considered reliable criteria to determine the nature of the adrenal tumor. however, the malignant potential only becomes true when confirmed by evidence of spreading beyond the adrenal capsule or adrenal vein on pathological examination. additional concerns about port-site metastases and local recurrences are theoretically justifiable, but the actual risk has remained unknown.(15-17) we did not have any port-site metastasis. conclusion our series confirmed that laparoscopic adrenalectomy is a safe and effective procedure, associated with minimal morbidity. also, we concluded that most adrenal masses are potentially amenable to a laparoscopic approach if there is no evidence of periadrenal invasion or lymphadenopathy. however, meticulous preoperative workup should be performed in order to classify the type of laparoscopic adrenalectomy—simforoosh et al 54 urology journal vol 5 no 1 winter 2008 lesion and to attain more certainty about its anatomical relations. careful preoperative planning will help the surgeon to optimize surgical indications and will minimize the occurrence of unexpected events during surgical operation. conflict of interest none declared. references 1. cuschieri a. the spectrum of laparoscopic surgery. world j surg. 1992;16:1089-97. 2. gagner m, lacroix a, bolte e. laparoscopic adrenalectomy in cushing’s syndrome and pheochromocytoma. n engl j med. 1992;327:1033. 3. gill is. the case for laparoscopic adrenalectomy. j urol. 2001;166:429-36. 4. ramacciato g, lombardi m, amodio pm, et al. laparoscopic adrenalectomy: a worthwhile procedure performed in a general surgery department. am surg. 2003;69:427-33. 5. smith cd, weber cj, amerson jr. laparoscopic adrenalectomy: new gold standard. world j surg. 1999;23:389-96. 6. staren ed, prinz ra. adrenalectomy in the era of laparoscopy. surgery. 1996;120:706-9. 7. hobart mg, gill is, schweizer d, sung gt, bravo el. laparoscopic adrenalectomy for large-volume (> or = 5 cm) adrenal masses. j endourol. 2000;14:149-54. 8. novitsky yw, czerniach dr, kercher kw, perugini ra, kelly jj, litwin de. feasibility of laparoscopic adrenalectomy for large adrenal masses. surg laparosc endosc percutan tech. 2003;13:106-10. 9. tsuru n, suzuki k, ushiyama t, ozono s. laparoscopic adrenalectomy for large adrenal tumors. j endourol. 2005;19:537-40. 10. macgillivray dc, whalen gf, malchoff cd, oppenheim ds, shichman sj. laparoscopic resection of large adrenal tumors. ann surg oncol. 2002;9:480-5. 11. naya y, suzuki h, komiya a, et al. laparoscopic adrenalectomy in patients with large adrenal tumors. int j urol. 2005;12:134-9. 12. dunnick nr, korobkin m. imaging of adrenal incidentalomas: current status. ajr am j roentgenol. 2002;179:559-68. 13. ross ns, aron dc. hormonal evaluation of the patient with an incidentally discovered adrenal mass. n engl j med. 1990;323:1401-5. 14. aso y, homma y. a survey on incidental adrenal tumors in japan. j urol. 1992;147:1478-81. 15. porpiglia f, garrone c, giraudo g, destefanis p, fontana d, morino m. transperitoneal laparoscopic adrenalectomy: experience in 72 procedures. j endourol. 2001;15:275-9. 16. nguyen nt, roberts p, follette dm, rivers r, wolfe bm. thoracoscopic and laparoscopic esophagectomy for benign and malignant disease: lessons learned from 46 consecutive procedures. j am coll surg. 2003;197:902-13. 17. lezoche e, guerrieri m, paganini am, et al. laparoscopic adrenalectomy by the anterior transperitoneal approach: results of 108 operations in unselected cases. surg endosc. 2000;14:920-5. the efficacy and safety of single-incision mini-slings for stress urinary incontinence: a network meta-analysis yuxin chen1,2, #, jiecheng zhang3, #, yankai zeng1, weidong chen1,2, fei liu1, jinchun xing1, bili zhang4,** yuedong chen1, * purpose: to evaluate the efficacy and safety of single-incision mini-sling for stress urinary incontinence based on network meta-analysis. materials and methods: we searched pubmed, embase, and cochrane libraries from august 2008 to august 2019. randomized controlled trials comparing two or more indicators of miniarc (single incision mini-slings), ajust (adjustable single-incision sling), c-ndl (contasure-needleless), tfs (tissue fixation system), ophria (transobturator vaginal tap), tvt-o (transobturator vaginal tape), and tot (trans-obturatortape) in treating female stress urinary incontinence were collected. results: totally, 3,428 patients from 21 studies were included. ajust had the highest subjective cure rate (rank = 0.52), while ophira had the worst (rank = 0.67). tfs had the highest objective cure rate, and the worst was found in ophira. tfs required the shortest operating time (rank = 0.40), while tvt-o required the longest operating time (rank = 0.47). miniarc had the least bleeding (rank = 0.47), while tvt-o had the most bleeding (rank = 0.37). c-ndl had the shortest postoperative hospital stay (rank=0.77), while ajust had the longest postoperative hospital stay (rank = 0.36). for postoperative complications, tfs performed best in groin pain (rank = 0.84), urinary retention (rank = 0.78), and repeat surgery (rank=0.45). tvt-o performed worst in groin pain (rank = 0.36), and urinary retention (rank = 0.58). miniarc had the highest repeat surgery rate (rank = 0.35). ajust had the lowest probability of tap erosion (rank=0.30), while ophira had the highest tap erosion level (rank = 0.45). miniarc showed the greatest advantage in urinary tract infections (rank = 0.84) and de novo urgency (rank = 0.60), while c-ndl had the highest incidence of urethral infections (rank = 0.51). ophira performed worst in de novo urgency (rank = 0.60). c-ndl performed the best in sexual intercourse pain (rank = 0.79) while ajust was the worst (rank = 0.49). conclusion: in view of comprehensive efficacy and safety, we recommend that tfs or ajust should be selected first for single-incision sling and the application of ophria should be minimized. keywords: single incision mini-slings; transobturator tension-free vaginal tapes; network meta-analysis; stress urinary incontinence introduction international continence society defines stress uri-nary incontinence (sui) as involuntary leakage of urine from the external urethral orifice when abdominal pressure increases, such as laughter, cough and sneezing.(1) the incidence of sui is 15~20% in women.(2) although it is a non-fatal disease, the long course of the disease can cause psychological disorders, sexual dysfunction, social anxiety disorder and urinary dermatitis, which can seriously affect the patients' quali1department of urology, first affiliated hospital of xiamen university, xiamen 361003, china. 2department of clinical medicine, fujian medical university, fuzhou 360108, china. 3department of urology, dehua affiliated hospital of huaqiao university, fujian 362500, china. 4department of obstetrics, xiamen maternity and child health care hospital, xiamen 361003, china. # these authors contributed equally to this work. * correspondence: department of urology, first affiliated hospital of xiamen university, no. 55, zhenhai road, siming district, xiamen 361003, china. tel: 0592-2139314. fax: 0592-2139314. e-mail: chenyuedong8@126.com & xmurology@126.com **department of obstetrics, xiamen maternity and child health care hospital. no. no.10, zhenhai road, siming district, xiamen 361003, china,tel: 86-0592-2662066. fax: 86-0592-2662066. e-mail: xmobstet@163.com received february 2022 & accepted february 2023 ty of life. therefore, the treatment of sui has been an important ongoing concern for decades, and new or improved therapies have emerged to treat the disease more thoroughly. most female patients are treated conservatively, including lifestyle intervention, exercise of pelvic floor muscles, biofeedback therapy, electrical stimulation and etc.(3) however, surgical intervention is necessary in patients whose conservative therapy fails or with intrinsic sphincter deficiency. surgical procedures of sui are developing in the preceding decades. burch’s procedure was considered review urology journal/vol 20 no. 4/ july-august 2023/ pp. 191-202. [doi:10.22037/uj.v20i.7218] to be the gold standard surgical procedure for sui.(4) but its application is limited by its long post-operative hospital stay and high incidence of pelvic organ prolapse caused by transabdominal operation.(5) mcguire et al.(6) improved the previous method of abdominal surgery and used the autopubic fascia sling for the first time. however, the most important milestone is the report of ulmsten et al..(7) in 1996, according to the "hammock hypothesis" proposed by delancey, the post-pubic polypropylene mesh was used to support the urethra through a tension-free vaginal tape (tvt). thereafter, in order to decrease the incidence of serious complications such as bladder perforation after tvt, de l et al. improved the previous tvt procedure by transobturator vaginal tape (tvt-o) in 2003. transobturator tension-free vaginal tape (to-tvt) is known as the second generation of tension-free sling. the first generation of sling through retropubic approach has developed into a bottom-up (tvt) and top-down (sparc) procedures. the succeeding generation of sling via obturator also derives from two procedures: outward-inward and inward-outward (tvt-o). the third generation of the sling is single incision mini-sling (sims). the sims has high cure rates as those of rp-tvt and to-tvt, and further reduces postoperative complications, thereby achieving minimal invasiveness and high safety. sims has a variety of methods and characteristics, which can be roughly divided into the following 10 types: tvt-scure, miniarc (single incision mini-slings), ajust (adjustable single-incision sling), cure mesh, c-ndl (contasure needleless), tfs (tissue fixation system), ophria (transobturator vaginal tap), minitap, alits, and, solyx.(8) among them, tvt-secur has been withdrawn from clinical practice due to unsatisfactory efficacy, while cure mesh, minitap, alits, and solyxy still have no prospects. therefore, in this study, we collected the latest information of comparative studies of miniarc, ajust, c-ndl, tfs, ophria, tvt-o, and tot through the network meta-analysis (nma). we graded the mid-term efficacy and safety of sims to provide a reference for clinical applications. to the best of our knowledge, our study is the most comprehensive nma on this topic. materials and methods search strategy we conducted a computer-based search of pubmed, embase, and cochrane library databases from august 2008 to august 2019. mesh terms and related synonyms including "stress urinary incontinence, urine presthe efficacy and safety of sims for sui-chen et al. endourology and stones diseases 8review 192 table 1. the definition of “subjective” and “objective” cure rate of the included studies study intervention follow-up (months) definition of subjective cure definition of objective cure t1/size t2/size melendez-munoz et al. (9) miniarc /121 tvt-o/ 125 12 no reported leakage with negative cst with full bladder physical exertion by iciq-ui sf pascom et al. (10) ophira/69 tot/61 36 patient reported satisfaction rate negative cst and pad test schellart p et al. (11) miniarc/97 tot/96 36 very much improved/ much negative cst with bladder volume >250 ml improved in pgi-i fernandez-gonzalez et al. (12) c-ndl/89 tot/98 average of 29 very satisfied/satisfied in questionnaire negative cst with full bladder gaber et al. (13) c-ndl/70 tvt-o/70 12 very much improved/ much improved negative cst with full bladder in pgi-i masata et al. (14) ajust/50 tvt-o/50 12 if the response to iciq-ui sf question negative cst with bladder volume >300 ml 6 "when does urine leak? "was "never/urine does not leak" dogan et al. (15) c-ndl/90 tot/89 24 if the response to iciq-ui sf question negative cst with with a 300-ml 6 "when does urine leak? "was saline-filled bladder "never/urine does not leak" xin et al. (16) ajust/184 tvt-o/184 12 very much improved/much negative cst improved in pgi-i liapis et al. (17) tot/55 tvt-o/65 12 response to appendix negative cst and pad test sivaslioglu et al. (18) tfs/40 tot/40 average of 64(we only if the patient reported negative cst use the data for the restoration of urinary continence previous 36months) but the supine cspt was positive, then treatment was regarded as a subjective cure tieu et al. (19) miniarc/49 tot/49 12 not mentioned negative cst with bladder volume >250 ml mostafa et al. (20) ajust/69 tvt-o/68 12 very much improved/much improved negative cst in pgi-i grigoriadis et al. (21) ajust/85 tvt-o/86 average of 22.3 no loss of urine with exercise, negative cst with with the bladder filled with 400 ml coughing or weightlifting scheiner et al. (22) tvt-o/40 tot/40 12 not mentioned negative cst and pad test boyers et al. (23) ajust/69 tvt-o/68 12 very much improved/much negative cst with full bladder improved in pgi-i martinez et al. (24) c-ndl/70 tvt-o/68 36 very satisfied/satisfied in questionnaire negative cst with full bladder sabadell et al. (25) ajust/30 tot/28 12 completely satisfied/ moderately negative cst satisfied in questionnaire jurakova et al. (26) ophira/45 tot/48 12 very better/much better/a little negative cst better in pgi-i abdel-fattah et al. (27) tvt-o/170 tot/171 36 very much improved/much not mentioned improved in pgi-i fu et al. (28) c-ndl/78 tot/86 12 very much improved/much not mentioned improved in pgi-i schweitzer j et al. (29) ajust/100 tvt-o/56 12 very better/much better in pgi-i negative cst with bladder volume >300 ml iciq-ui sf: international consultation on incontinence questionnaire short form; pgi-i: patient global impression of improvement; cst: cough stress test. sure urinary incontinence, transobturator band, transobturator band, middle urethral sling, single incision sling, single incision mini sling, randomized controlled trial, miniarc, ajust, c-ndl, no needle and no needle, tfs, tissue fixation system, ophria" and various keyword combinations were used in the search strategy. the search language was limited to english. we also manually searched a reference list of related publications from wiley, springlink, science direct databases, including reviews, meta-analyses, and other articles. inclusion and exclusion criteria the study inclusion criteria were: (1) randomized controlled trial (rct) focusing on females with sui. (2) the interventions included at least two surgical treatments (miniarc, ajust, c-ndl, tfs, ophria, tvt-o or tot). (3) the results observed in the study included at least one of the following effects: treatment outcome robotic & laparoscopic urology 429endourology and stone diseases 92 vol 20 no 4 july-august 2023 193 table 2. characteristics of the included studies in the meta-analysis authors years region study design experimental group(sample sizes) control group(sample sizes) follow-up (months) melendez-munoz et al. (9) 2018 australia rct miniarc /121 tvt-o/ 125 12 pascom et al. (10) 2018 brazil rct ophira/69 tot/61 36 schellart p et al. (11) 2017 belgium rct miniarc/97 tot/96 36 fernandez-gonzalez et al. (12) 2016 spain rct c-ndl/89 tot/98 29 gaber et al. (13) 2016 egypt rct c-ndl/70 tvt-o/70 12 masata et al. (14) 2016 czech republic rct ajust/50 tvt-o/50 12 dogan et al. (15) 2018 turkey rct c-ndl/90 tot/89 24 xin et al. (16) 2016 china rct ajust/184 tvt-o/184 12 liapis et al. (17) 2008 greece rct tot/55 tvt-o/65 12 sivaslioglu et al. (18) 2012 turkey rct tfs/40 tot/40 36 tieu et al. (19) 2017 america rct miniarc/49 tot/49 12 mostafa et al. (20) 2013 britain rct ajust/69 tvt-o/68 12 grigoriadis et al. (21) 2013 greece rct ajust/85 tvt-o/86 22.3 scheiner et al. (22) 2012 switzerland rct tvt-o/40 tot/40 12 boyers et al. (23) 2013 britain rct ajust/69 tvt-o/68 12 martinez et al. (24) 2014 spain rct c-ndl/70 tvt-o/68 36 sabadell et al. (25) 2016 spain rct ajust/30 tot/28 12 jurakova et al. (26) 2015 czech republic rct ophira/45 tot/48 12 abdel-fattah et al. (27) 2012 britain rct tvt-o/170 tot/171 36 fu et al. (28) 2017 china rct c-ndl/78 tot/86 12 schweitzer j et al. (29) 2015 netherlands rct ajust/100 tvt-o/56 12 figure 1. flowchart for identification and selection of research publications the efficacy and safety of sims for sui-chen et al. (objective and subjective cure rate) (table 1), perioperative outcome (operation time, bleeding volume, postoperative hospital stays), postoperative complications (postoperative groin pain, urinary tract infection, injury of bladder, tape erosion, urinary retention, repeat surgery rate, dyspareunia, and postoperative pain). (4) the follow-up period of the study was mid-term (12-36 months was defined as mid-term follow-up, less than 12 months as short-term follow-up, and more than 36 months as long-term follow-up). (5) one-arm sample size was> 25 cases. the exclusion criteria were: (1) studies involving patients underwent multiple operations for sui or with other diseases that may affect the outcome of the opendourology and stones diseases 271endourology and stones diseases 10review 194 subjective cure rate (or(95%crl]) ajust 1.55 (0.74, 3.11) c-ndl 1.51 (0.74, 3.29) 0.96 (0.47, 2.15) miniarc 2.19 (0.71, 6.50) 1.43 (0.49, 4.12) 1.45 (0.48, 4.17) ophira 1.19 (0.66, 2.24) 0.77 (0.46, 1.33) 0.79 (0.42, 1.43) 0.55 (0.22, 1.38) tot 1.09 (0.70, 1.68) 0.70 (0.41, 1.26) 0.73 (0.38, 1.31) 0.50 (0.19, 1.41) 0.91 (0.59, 1.43) tvt-o objective cure rate (or(95%crl]) ajust 1.42 (0.65, 3.20) c-ndl 1.63 (0.63, 4.45) 1.12 (0.47, 2.80) miniarc 2.32 (0.64, 8.78) 1.59 (0.50, 4.95) 1.38 (0.41, 5.23) ophira 0.74 (0.12, 4.10) 0.51 (0.09, 2.53) 0.45 (0.08, 2.33) 0.32 (0.05, 1.85) tfs 1.16 (0.51, 2.69) 0.80 (0.43, 1.54) 0.71 (0.35, 1.46) 0.51 (0.18, 1.35) 1.58 (0.36, 7.82) tot 1.07 (0.67, 1.71) 0.74 (0.38, 1.44) 0.66 (0.28, 1.52) 0.46 (0.13, 1.53) 1.46 (0.29, 8.71) 0.93 (0.45, 1.85) tvt-o operation time (or(95%crl]) ajust 4.59 (-5.43, 14.60) c-ndl 2.28 (-13.48, 16.82) -2.33 (-15.66, 10.60) miniarc 0.40 (-15.00, 15.90) -4.12 (-17.81, 9.30) -1.70 (-17.49, 14.88) ophira 5.28 (-9.44, 20.14) 0.63 (-12.27, 13.95) 3.01 (-12.85, 18.98) 4.74 (-11.23, 20.66) tfs -0.78 (-11.23, 9.25) -5.36 (-12.61, 1.65) -2.97 (-13.92, 8.29) -1.21 (-12.71, 10.08) -6.03 (-17.05, 4.93) tot -3.02 (-8.17, 2.04) -7.65 (-16.49, 1.02) -5.31 (-19.12, 9.47) -3.50 (-17.87, 11.06) -8.24 (-22.49, 5.56) -2.32 (-11.04, 6.66) tvt-o amount of bleeding (or(95%crl]) ajust -0.70 (-17.37, 21.70) c-ndl 5.20 (-21.33, 40.92) 5.77 (-18.36, 33.88) miniarc 0.42 (-26.60, 36.51) 0.86 (-24.11, 30.20) -4.95 (-34.18, 24.18) ophira -3.85 (-22.36, 24.49) -3.33 (-16.99, 15.96) -8.87 (-28.32, 11.48) -3.76 (-24.95, 17.51) tot -5.35 (-15.66, 6.56) -4.64 (-23.60, 10.07) -10.53 (-43.05, 15.08) -5.67 (-39.11, 20.15) -1.46 (-26.53, 14.95) tvt-o hospital stay after surgery (or(95%crl]) consistency model ajust 1.15 (-1.97, 4.27) c-ndl 0.04 (-2.78, 2.83) -1.13 (-2.49, 0.27) tot -0.08 (-2.06, 1.92) -1.23 (-3.63, 1.17) -0.11 (-2.09, 1.86) tvt-o inconsistency model ajust 1.12 (-1.99, 4.29) c-ndl -0.01 (-2.76, 2.80) -1.12 (-2.53, 0.29) tot -0.10 (-2.07, 1.90) -1.22 (-3.65, 1.26) -0.10 (-2.10, 1.90) tvt-o groin pain (or(95%crl]) ajust 0.70 (0.01, 61.74) miniarc 20.98 (0.15, 4245.33) 30.37(0.09, 13027.02) tfs 0.71(0.03, 13.26) 1.04(0.01, 78.32) 0.04 (0.00, 1.49) tot 0.43(0.02, 8.02) 0.61(0.02, 20.94) 0.02 (0.00, 2.12) 0.59 (0.05, 7.58) tvt-o urinary retention (or(95%crl]) ajust 0.92 (0.28, 3.64) c-ndl 4.11 (0.24, 176.44) 4.30 (0.22, 208.26) tfs 0.82 (0.28, 3.00) 0.89(0.29, 2.65) 0.22(0.01, 2.69) tot 0.55(0.26, 1.26) 0.57 (0.20, 1.61) 0.14 (0.00, 2.32) 0.65 (0.24, 1.70) tvt-o urinary tract infection (or(95%crl]) ajust 0.90 (0.09, 7.07) c-ndl 14.77(0.54, 737.78) 17.42 (0.69, 903.91) miniarc 3.09 (0.46, 24.37) 3.49 (0.60, 25.55) 0.22 (0.01, 2.81) tot 1.87 (0.52, 6.76) 2.11 (0.40, 11.83) 0.13 (0.00, 2.68) 0.59 (0.12, 2.62) tvt-o tape erosion (or(95%crl]) ajust 0.35 (0.04, 2.41) c-ndl 0.95 (0.12, 7.10) 2.66 (0.45, 18.45) miniarc 0.20 (0.01, 5.95) 0.58 (0.03, 11.68) 0.21 (0.01, 5.12) ophira 0.63 (0.02, 22.41) 1.83 (0.08, 57.38) 0.62 (0.02, 24.06) 2.99 (0.04, 185.22) tfs 0.23 (0.03, 1.32) 0.66 (0.20, 1.98) 0.24 (0.04, 1.04) 1.07 (0.08, 36.10) 0.37 (0.01, 7.02) tot 0.77 (0.18, 2.56) 2.16 (0.48, 9.81) 0.81 (0.15, 4.08) 3.58 (0.19, 137.98) 1.22 (0.03, 33.28) 3.39 (0.95, 13.40) tvt-o table 3. comparison of meta-analysis results of different surgical networks. the efficacy and safety of sims for sui-chen et al. rank 1 rank 2 rank 3 rank 4 rank 5 rank 6 rank 7 subjective cure rate (rank 1 is best, rank 6 is worst) ajust 0.52 0.2 0.15 0.08 0.04 0.01 c-ndl 0.04 0.05 0.1 0.25 0.4 0.17 miniarc 0.06 0.06 0.12 0.27 0.35 0.15 ophira 0.04 0.04 0.04 0.07 0.14 0.67 tot 0.14 0.21 0.36 0.23 0.05 0 tvt-o 0.20 0.44 0.24 0.1 0.02 0 objective cure rate (rank 1 is best, rank 7 is worst) ajust 0.23 0.28 0.18 0.15 0.09 0.05 0.02 c-ndl 0.02 0.05 0.09 0.19 0.3 0.25 0.1 miniarc 0.03 0.05 0.07 0.12 0.18 0.33 0.23 ophira 0.01 0.03 0.04 0.04 0.08 0.2 0.59 tfs 0.57 0.09 0.09 0.06 0.06 0.08 0.05 tot 0.06 0.2 0.23 0.27 0.19 0.04 0.01 tvt-o 0.08 0.29 0.29 0.17 0.1 0.05 0.01 rank 1 rank 2 rank 3 rank 4 rank 5 rank 6 rank 7 operation time (rank 1 is worst, rank 5 is best) ajust 0.06 0.25 0.18 0.19 0.17 0.1 0.05 c-ndl 0.01 0.01 0.04 0.1 0.24 0.33 0.27 miniarc 0.12 0.1 0.1 0.15 0.18 0.18 0.17 ophira 0.20 0.12 0.15 0.15 0.14 0.13 0.11 tfs 0.04 0.04 0.06 0.09 0.15 0.22 0.40 tot 0.10 0.23 0.34 0.23 0.08 0.01 0 tvt-o 0.47 0.24 0.14 0.09 0.04 0.01 0 rank 1 rank 2 rank 3 rank 4 rank 5 rank 6 rank 7 amount of bleeding (rank 1 is worst, rank 5 is best) ajust 0.08 0.19 0.14 0.17 0.23 0.19 c-ndl 0.06 0.11 0.26 0.28 0.2 0.09 miniarc 0.07 0.07 0.09 0.11 0.2 0.47 ophira 0.22 0.1 0.11 0.12 0.22 0.23 tot 0.21 0.28 0.21 0.2 0.09 0.01 tvt-o 0.37 0.25 0.19 0.12 0.06 0.01 hospital stay after surgery (rank 1 is worst, rank 4 is best) ajust 0.36 0.24 0.25 0.16 c-ndl 0.02 0.08 0.13 0.77 tot 0.32 0.25 0.41 0.02 tvt-o 0.30 0.44 0.21 0.05 rank 1 rank 2 rank 3 rank 4 rank 5 rank 6 rank 7 groin pain (rank 1 is worst, rank 5 is best) ajust 0.14 0.17 0.27 0.36 0.06 miniarc 0.29 0.18 0.18 0.27 0.08 tfs 0.02 0.02 0.03 0.09 0.84 tot 0.19 0.24 0.34 0.23 0.01 tvt-o 0.36 0.39 0.18 0.06 0.01 urinary retention (rank 1 is worst, rank 5 is best) ajust 0.06 0.22 0.23 0.39 0.1 c-ndl 0.13 0.2 0.28 0.29 0.1 tfs 0.07 0.04 0.05 0.06 0.78 tot 0.16 0.24 0.35 0.23 0.02 tvt-o 0.58 0.31 0.09 0.02 0 urinary tract infection (rank 1 is worst, rank 5 is best) ajust 0.43 0.37 0.12 0.05 0.03 c-ndl 0.51 0.28 0.15 0.05 0.01 miniarc 0.02 0.03 0.03 0.07 0.84 rank 1 rank 2 rank 3 rank 4 rank 5 rank 6 rank 7 tot 0.02 0.09 0.18 0.63 0.08 tvt-o 0.03 0.23 0.51 0.2 0.04 tape erosion (rank 1 is worst, rank 7 is best) ajust 0.02 0.03 0.06 0.13 0.19 0.27 0.3 c-ndl 0.08 0.21 0.34 0.22 0.09 0.05 0.02 miniarc 0.01 0.02 0.06 0.16 0.23 0.26 0.25 ophira 0.45 0.15 0.13 0.09 0.06 0.05 0.07 tfs 0.19 0.1 0.11 0.12 0.09 0.11 0.29 tot 0.25 0.46 0.23 0.04 0.01 0 0 tvt-o 0.01 0.02 0.07 0.24 0.34 0.26 0.07 repetitive surgery (rank 1 is worst, rank 7 is best) ajust 0.13 0.13 0.14 0.15 0.16 0.17 0.12 c-ndl 0.08 0.07 0.08 0.09 0.1 0.26 0.33 miniarc 0.35 0.31 0.18 0.1 0.05 0.02 0 ophira 0.31 0.25 0.15 0.12 0.09 0.05 0.02 tfs 0.1 0.07 0.06 0.06 0.07 0.19 0.45 tot 0 0.06 0.19 0.26 0.3 0.15 0.03 tvt-o 0.03 0.11 0.19 0.23 0.23 0.16 0.05 de novo urgency (rank 1 is worst, rank 6 is best) ajust 0.27 0.38 0.18 0.09 0.05 0.02 c-ndl 0.01 0.05 0.13 0.23 0.34 0.23 miniarc 0.07 0.1 0.07 0.08 0.09 0.6 ophira 0.6 0.16 0.09 0.05 0.06 0.04 tot 0.01 0.08 0.18 0.34 0.33 0.07 tvt-o 0.03 0.24 0.35 0.21 0.13 0.04 sexual intercourse pain (rank 1 is worst, rank 5 is best) ajust 0.49 0.21 0.14 0.1 0.06 c-ndl 0.01 0.02 0.06 0.12 0.79 miniarc 0.41 0.32 0.14 0.12 0.02 tot 0.05 0.29 0.41 0.23 0.01 tvt-o 0.04 0.15 0.25 0.43 0.13 table 4. rankings based on simulations. the efficacy and safety of sims for sui-chen et al. vol 20 no 4 july-august 2023 195 eration. (2) retrospective studies, animal studies, correspondence, case reports, reviews, meta-analyses, reviews and conference abstracts. (3) studies whose data on odds ratio (or) or standardized mean difference (smd) cannot be obtained. data extraction and quality assessment data extractions were performed independently by two investigators. an agreement was reached through consulting a third researcher when disagreement occurred. the data extracted from the included studies were as follows: the first author's name, year of publication, study design, region, follow-up duration, and relevant clinical outcomes. two independent reviewers assessed the methodological quality with the assessment tool presented by cochrane handbook for systematic reviews interventions version 5.10. for included trials, the following criteria were evaluated and given a grade of low, medium, or high-risk bias: random sequence review 196 figure 2. graph of risk bias and summary of the included studies. figure 3. comparative network of treatments. the connection indicates that there is a direct comparative study between the two treatments, and the digit represents the number of direct comparative study. the efficacy and safety of sims for sui-chen et al. generation, allocation concealment, blinding of participants, and personnel blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. disagreements in risk of bias ratings were regularly resolved through discussion by the two reviewers or consultation with a third team member. statistical analysis statistical analysis was performed using the addis figure 4. correlation levels based on the probability of intervention at different endpoints. (a) subjective cure rate; (b) objective cure rate; (c) operation time; (d) amount of bleeding. figure 5. correlation levels based on the probability of intervention at different endpoints. (a) hospital stay after surgery; (b) groin pain; (c) urinary retention; (d) urinary tract infection. the efficacy and safety of sims for sui-chen et al. vol 20 no 4 july-august 2023 197 software based on the bayesian framework (version 1.16.8). continuous variables were summarized using smd and its 95% confidence interval (95% ci) for efficacy analysis. or and its 95% ci were used as dichotomous variables for power analysis statistics. consistency was evaluated through node segmentation models and inconsistent models. when p > 0.05, there is no inconsistency. nma used a consistency model for analysis. if p < 0.05, an inconsistent model is used and the reasons for the inconsistency are analyzed. when node analysis was not possible, the results of the consistent model and the inconsistent model were compared. the potential scale reduction factor (psrf) represented convergence. the closer the psrf is to 1, the better the convergence and the more reliable the results obtained by the consensus model. psrf < 1.20 is still acceptable. in addition to or, the nma also lists the smd values and their 95% ci representative results and statistical significance, a grid relationship diagram for each indicator, a probability ranking table, and a probability ranking table. in the network diagram, links indicated a direct comparison between the two interventions, and numbers indicated the number of studies. in the probability ranking table and the ranking chart, if the result index is favorable, rank1 is the best, and rankn is the worst. conversely, if the result index is unfavorable, rank1 is the worst and rankn is the worst. results characteristics of included studies a total of 1,035 publications were obtained, of which 1013 were from three major english databases, including 323 from pubmed, 462 from embase, and 228 from cochrane and 22 of other sources. we then removed 225 duplicates and excluded 745 by filtering titles and abstracts. finally, through a full-text evaluation, we included 21 rcts, which involved 3428 patients.(9-29) among them, seven articles compared ajust and totvt, five articles compared amini and to-tvt, and five articles compared c-ndl and to-tvt. one article compared tfs with to-tvt. three articles compared tvt-o with tot. no article compared directly sims with other surgical methods. all of the trials were two-arm trials. the process of literature searching and screening for nma was shown in figure 1. characteristics of the included studies in meta-analysis were illustrated in table 2. quality assessment of methodology of included studies the methodological quality of the study was assessed according to the cochrane collaborative tool. all 21 studies mentioned randomness, of which 9 were computer-generated random sequences, 7 were random sequences generated by digital tables, and the remaining 5 did not specifically describe the sequence generation method. eight studies showed the allocation concealment method and others did not describe their procedures. data from all studies were incomplete, there were no selective reports, and it was unclear whether there are other biases. the risk profile for bias and a summary of the included studies is shown in figure 2. network meta-analysis of the treatment efficacy eighteen of all 21 studies reported subjective cure rates from a comparison of miniarc, ajust, c-ndl, ophria, tvt-o, and tot (figure 3a). eighteen studies also reported objective cure rates by comparing all seven procedures (figure 3b). no significant inconsistency was found between the various treatments (p >0.05). this means that the consistency model is reliable. in addition, the psrf is limited to 1, and this study can achieve satisfactory convergence efficiency. nma results showed no significant difference in subjective and objective cure rates between any two surgical procedures. the 95% interval of or value was over 1 (table 3). the probability ranking results showed that ajust's subjective cure rate was higher than the other 5 surgireview 198 figure 6. correlation levels based on the probability of intervention at different endpoints.(a) tap erosion; (b) repetitive surgery; (c) de novo urgency; (d) sexual intercourse pain the efficacy and safety of sims for sui-chen et al. cal methods (rank = 0.52), followed by tvt-o (rank = 0.20), and the worst was ophira (rank = 0.67) (table 4 and figure 4a). the objective cure rate of tfs was higher than the other 6 surgical methods (rank = 0.57), followed by ajust (rank = 0.23), and the worst was ophira (rank = 0.59) (table 4 and figure 4b). network meta-analysis of the perioperative outcomes twelve studies described surgical time by comparing all seven surgical procedures (figure 3c). a total of 8 studies reported bleeding volume (figure 3d), which included comparisons of miniarc, ajust, c-ndl, ophria, tvt-o and tot. four studies described length of hospital stay, including comparisons of tvt-o, tot, ajust, and c-ndl (figure 3e). no obvious inconsistency was found in various surgical time treatments, and the bleeding volume (p > 0.05). this means that the consistency model is reliable. in addition, the psrf is limited to 1, and the study can achieve satisfactory convergence efficiency. nma results showed no statistical difference between any two surgical methods and the 95% interval of smd value was over 0 (table 2). according to the probability of the grade chart, the operation time required by tfs was shorter than the other 6 surgical procedures (rank = 0.40), while tvt-o had the longest operation time (rank = 0.47) (table 4 and figure 4c). the bleeding amount of miniarc was less than the other 5 surgical methods (rank = 0.47), and that of tvt-o was the largest (rank = 0.37) (table 4 and figure 4d). the length of hospital stay after surgery was an indicator that could not be tested by node analysis because it did not form a network relationship between the included studies. therefore, we listed the results of the consistency model and the inconsistent model separately, and found that the results of the two models were consistent. there was no statistical difference between the two models. according to the possibility of the grade chart, the postoperative hospital stay of c-ndl was shorter than the other three types of surgery (rank = 0.77), while that of ajust was the longest (rank = 0.36) (table 4 and figure 5a). network meta-analysis of the postoperative complications there were 6 studies that described postoperative groin pain by comparison of miniarc, ajust, tfs, tvt-o and tot (figure 3f). a total of 13 studies reported postoperative urinary retention after comparing ajust, c-ndl, tfs comparison, tvt-o, and tot (figure 3g). eight studies described postoperative urinary tract infections and compared miniarc, ajust, c-ndl, tvt-o, and tot (figure 3h). a total of 12 studies reported the incidence of repeat surgery after comparison of all 7 surgical procedures (figure 3i). ten studies reported de novo urgency and compared six surgical procedures except tfs (figure 3j). five studies reported postoperative sexual intercourse pain by comparing miniarc, ajust, c-ndl, tvt-o, and tot (figure 3k). the adverse events of tape erosion were reported in 11 studies, including a comparison of all 7 surgical methods (figure 3l). except for postoperative sexual intercourse pain, node-slitting analysis, including consistency model and inconsistent model, was performed for statistical analysis. there was no significant inconsistency among the postoperative complications except postoperative sexual intercourse pain (p > 0.05), indicating that the consistency model is reliable. the psrf was limited the efficacy and safety of sims for sui-chen et al. to 1, suggesting the satisfactory convergence efficiency of this study. nma results showed that there was no statistical difference between any two surgical methods, and the 95% interval of or value was over 1 (table 3). according to probabilities of rank plot, tfs had the lowest incidence of groin pain (rank = 0.84) and tvt-o had the highest incidence (table 4 and figure 5b). tfs had the lowest incidence of urine retention (rank = 0.78) and tvt-o had the highest incidence (rank = 0.58) (table 4 and figure 4g). miniarc had the lowest incidence of urinary tract infections (rank = 0.84) and c-ndl had the highest (rank = 0.51) (table 4 and figures 5c and 5d). ajust had the lowest probability of occurrence of the tape erosion (rank = 0.30), and ophira had the highest probability (rank = 0.45) (table 4 and figure 6a). tfs had the lowest recurrence rate (rank = 0.45), while miniarc had the highest rate (rank = 0.35) (table 4 and figure 6b). miniarc had the lowest incidence of de novo urgency and ophira had the highest incidence (rank = 0.60) (table 4 and figure 6c). for the incidence of pain during intercourse, there was no significant difference between any two surgical methods (95% interval of or values were over 1). the probability ranking results showed that c-ndl had the lowest incidence of intercourse pain (rank = 0.79), and ajust had the highest incidence of intercourse pain (rank = 0.49) (table 4 and figure 6d). discussion standard tension-free midurethral sling is considered to be the gold standard surgical procedure for curing sui at present. tvt, as the first generation of tension-free sling, provided evident effect for the treatment of sui, however, it could cause several serious complications, such as pelvic organs injury, iliac vessels trauma and nerve injury. the modified surgical procedure tot and tvt-o could decrease the incidence of postoperative hematoma, bladder injury or perforation after tvt.(30) there seems to be no anatomical difference between tot and tvt-o. most scholars draw similar conclusions based on the autopsy results. they suggest that compared with tvt-o, the sling of tot is farther away from obturator vessel, posterior branch of obturator nerve and obturator canal,(30,31) and the difference of material and product design between tot and tvt-o also makes the evaluation of efficacy and safety different. although the second generation of sling to-tvt has been significantly improved compared with the previous generation tvt, the groin pain caused by obturator nerve injury while traversing obturator muscle group is still the most significant complication. the third generation of the sling is sims. in addition to following the basic operation principle of to-tvt, sims uses the method of single incision, and the length of the sling is shorter, usually only 6.5-12cm,(32) thus achieving minimal invasiveness and fewer complications. sims has a variety of surgical procedures, including tvt-scure, miniarc, ajust, cure mesh, c-ndl, tfs, ophria, minitap, alits, solyx, etc. sims seems to have many potential advantages, such as achieving the same urethral support as traditional midurethral slings through a single incision, which is more minimally invasive; avoiding the occurrence of tissue injury and pain through the retropubic or inguinal region during the operation, which makes the operation to be completed without sedative local anesthesia.(33) in vol 20 no 4 july-august 2023 199 addition, sims has lower complications than standard midurethral slings with comparable efficacy.(34) however, there is a lack of comparisons among different surgical procedures for sims. the purpose of this study is to rank the efficacy or complications of various sims procedures, and to give evidence for the selection of many sims procedures in clinical practice. in our study, there was no significant difference among miniarc, ajust, c-ndl, tfs, ophria, tvt-o and tot in terms of subjective cure rate, objective cure rate, perioperative outcomes and postoperative complications. thus, even if with only a slight difference, we could also sort these methods through the advantages and disadvantages of each indicator and procedure. this is also the advantage of nma. from the results of our nma, we found that: (1) for the treatment efficacy, ajust had the best subjective cure rate, while ohira had the worst; tfs had the best objective cure rate, followed by ajust; and ophira had the worst; (2) for the perioperative outcomes, the operation time of tfs was the shortest and that of tvt-o was the longest; the bleeding amount of miniarc was the least while that of tvt-o was the largest; c-ndl had the shortest hospitalization time; (3) for the postoperative complications, tfs had the greatest advantage in reducing the incidence of groin pain, urinary retention and repetitive surgery, while tvt-o had the highest incidence of groin pain and urinary retention. miniarc had the highest rate of repetitive surgery. ajust had the lowest incidence of tap erosion, while ophira had the highest. miniarc had the lowest rate of urinary tract infection and de novo urgency, while c-ndl had the highest rate of urinary tract infection and ophira had the highest rate of de novo urgency. in terms of sexual intercourse pain, c-ndl performed the best and ajust was the worst. the methodological advantages of this study were as follows: 1) the outcome measurements analyzed in this study included 12 indicators of treatment efficacy, perioperative outcomes and postoperative complications, which could comprehensively evaluate the safety and effectiveness of each surgical procedure. the 21 articles included in this study were all of high quality and reliable rcts. 2) by using addis software and nma, we could effectively compare two or more sui surgical methods without direct comparison and rank them as good or bad. 3) we use a comprehensive search strategy to reduce the risk of publication bias. however, our research still has certain limitations. first, the number of studies included in some surgical procedures was small, and the outcome indicators observed in the studies were not comprehensive. second, due to limited literature reports, only the mid-term follow-up were analyzed, and the long-term efficacy was not systematically evaluated. thus, the clinical reference value is limited. third, only 7 sims procedures were compared. conclusions in summary, there is no statistical difference in treatment efficacy, perioperative outcome, and postoperative complications among the seven procedures. sims and to-tvt are equally safe and effective. according to the probability ranking results, each procedure has its own advantages and disadvantages. the cure rates of tfs and ajust are better than others. tfs not only requires the shortest operation time, but also has the greatest advantages in postoperative groin pain, urine retention, and repeat surgery. meanwhile, ajust performs well in tap erosion. in contrast, ophria performed poorly in terms of cure rates and complications. therefore, in view of comprehensive efficacy and safety, we recommend that tfs or ajust should be selected first for sims surgery and the use of ophria 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savastano ja. experience with pubovaginal slings for urinary incontinence at the university of michigan. j urol. 1987;138:525-526. 7. ulmsten u, henriksson l, johnson p, varhos g. an ambulatory surgical procedure under local anesthesia for treatment of female urinary incontinence. int urogynecol j pelvic floor dysfunct. 1996;7:81-85; discussion 8586. 8. frydman v, cornu j. have mini-slings come of age? curr opin urol. 2015;25:296-299. 9. melendez-munoz j, braverman m, rosamilia a, young n, leitch a, lee jk. tvt abbrevo and miniarc suburethral sling in women with stress urinary incontinence a randomised controlled trial. eur j obstet gynecol reprod biol. 2018;230:141-146. 10. pascom alg, djehdian lm, bortolini mat, et al. randomized controlled trial comparing single-incision mini-sling and transobturator midurethral sling for the treatment of stress urinary incontinence: 3-year follow-up results. neurourol urodyn. 2018;37:2184-2190. 11. schellart rp, zwolsman se, lucot jp, de the 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urol. 2012;188:194-199. 19. tieu al, hegde a, castillo pa, davila gw, aguilar vc. transobturator versus single incision slings: 1-year results of a randomized controlled trial. int urogynecol j. 2017;28:461-467. 20. mostafa a, agur w, abdel-all m, et al. multicenter prospective randomized study of single-incision mini-sling vs tension-free vaginal tape-obturator in management of female stress urinary incontinence: a minimum of 1-year follow-up. urology. 2013;82:552559. 21. grigoriadis c, bakas p, derpapas a, creatsa m, liapis a. tension-free vaginal tape obturator versus ajust adjustable single incision sling procedure in women with urodynamic stress urinary incontinence. eur j obstet gynecol reprod biol. 2013;170:563566. 22. scheiner da, betschart c, wiederkehr s, seifert b, fink d, perucchini d. twelve months effect on voiding function of retropubic compared with outside-in and inside-out transobturator midurethral slings. int urogynecol j. 2012;23:197-206. 23. boyers d, kilonzo m, mostafa a, abdelfattah m. comparison of an adjustable anchored single-incision mini-sling, ajust((r)) , with a standard mid-urethral sling, tvt-o(tm) : a health economic evaluation. bju int. 2013;112:1169-1177. 24. martinez franco e, amat tardiu l. contasureneedleless(r) single incision sling compared with transobturator tvt-o(r) for the treatment of stress urinary incontinence: longterm results. int urogynecol j. 2015;26:213218. 25. sabadell j, palau-gené m, huguet e, monteroarmengol a, salicrú s, poza jl. multicentre randomized trial of the ajust™ single-incision sling compared to the align™ transobturator tape sling. int urogynecol j. 2017;28:10411047. 26. jurakova m, huser m, belkov i, et al. prospective randomized comparison of the transobturator mid-urethral sling with the single-incision sling among women with stress urinary incontinence: 1-year follow-up study. int urogynecol j. 2016;27:791-796. 27. abdel-fattah m, mostafa a, familusi a, ramsay i, n'dow j. prospective randomised controlled trial of transobturator tapes in management of urodynamic stress incontinence in women: 3-year outcomes from the evaluation of transobturator tapes study. eur urol. 2012;62:843-851. 28. fu q, lv j, fang w, et al. the clinical efficacy of needleless sling technique and tot in the treatment of female stress urinary incontinence a prospective randomized controlled trial. int j clin exp med. 2017;10:7084-7089. 29. schweitzer kj, milani al, van eijndhoven hwf, et al. postoperative pain after adjustable single-incision or transobturator sling for incontinence: a randomized controlled trial. obstet gynecol. 2015;125:27-34. 30. yao d, wei j, zhang x, et al. transobturator surgery for female stress incontinence: a comparative anatomical study of outsidein vs inside-out techniques. j clin urol. 2008:728-730. 31. achtari c, mckenzie bj, hiscock r, et al. anatomical study of the obturator foramen and dorsal nerve of the clitoris and their relationship to minimally invasive slings. int urogynecol j pelvic floor dysfunct. 2006;17:330-334. 32. naumann g, albrich s, skala c, laterza r, kolbl h. single-incision slings (sis) a new option for the surgical treatment of female stress urinary incontinence. geburtshilfe frauenheilkd. 2012;72:125-131. 33. mostafa a, lim cp, hopper l, madhuvrata p, abdel-fattah m. single-incision minithe efficacy and safety of sims for sui-chen et al. vol 20 no 4 july-august 2023 201 slings versus standard midurethral slings in surgical management of female stress urinary incontinence: an updated systematic review and meta-analysis of effectiveness and complications. eur urol. 2014;65:402-427. 34. abdel-fattah m, ford ja, lim cp, madhuvrata p. single-incision mini-slings versus standard midurethral slings in surgical management of female stress urinary incontinence: a metaanalysis of effectiveness and complications. eur urol. 2011;60:468-480. the efficacy and safety of sims for sui-chen et al. review 202 teenage childbearing as an independent risk factor for stress urinary incontinence in american women li xie1, zhuoyuan yu2, fei gao3* purpose: to evaluate the associations among teenage childbearing (age at first birth<=19 years old) with later-life risk of stress and urgency urinary incontinence (sui, uui) in american women using nationally representative data from america. materials and methods: data from the national health and nutrition examination survey (nhanes) from 2015 to 2018 were merged to include 2673 women. the question, “how old were you at the time of your first live birth?” was used to assess teenage childbearing. urinary incontinence was ascertained by self-report. multivariable logistic regression models were used to assess the association between teenage childbearing and urinary incontinence in american women, controlling for potential confounders. results: among the 2673 women with complete data, the prevalence of sui was 27.3%, and the prevalence of uui was 22.1%. overall, 856 of female had given birth at or before the age of nineteen. teenage childbearing was significantly associated with sui (or=1.9, 95%ci=1.5-2.3, p < 0.001), but teenage childbearing was not associated with uui (or=1.2, 95%ci=1.0-1.5, p = 0.0658). conclusion: after controlling for known risk factors, teenage childbearing seems to be signif-icantly related to female stress urinary incontinence. keywords: teenage childbearing; stress incontinence; urgency incontinence; urinary inconti-nence; women. 1department of urology, the first affiliated hospital of chongqing medical uni-versity, chongqing, china. 2department of urology, the first affiliated hospital of chongqing medical uni-versity, chongqing, china. 3department of urology, the first affiliated hospital of chongqing medical uni-versity, chongqing, china. *corresoindence: department of urology, the first affiliated hospital of chongqing medical university, chongqing, china. tel: 15730285046. fax: 023-68485000 . e-mail: 3329630790@qq.com. received february 2022 & accepted june 2022 introduction according to ics terminology, urinary incon-tinence(ui) is a complaint of any involuntary leakage of urine(1). two main types are described: stressurinary incontinence(sui), in which urine leaks in association with physical exertion, and urgency urinary incontinence(uui),in which urine leaks in association with a sudden compelling desire to void(2). urinary incontinence symptoms are highly prevalent among women(3), have a substantial effect on health-related quality of life and are associated with considerable personal and societal expenditure. age, obesity, gravidity, hypertension and menopause are known to be risk factors for stress ui in women(4). additionally, many studies have identified diabetes mellitus as a risk factor for in-continence in women(5). obstetric risk factors are well defined in the literature, and parities are shown to increase ui risk by 67%(6). in addition, vaginal delivery increased the risk of ui by 75% compared to c-sections(7). teenage childbearing is a major adolescent health concern worldwide. world health organi-zation (who) defines the age group 10–19 years as adolescents stage(8). the prevalence of teenage pregnancy remains high worldwide, despite recent prevention efforts, such as promo-tion of contraception use and sexual education(9). teenage births result in health consequences; children are more likely to be born pre-term, have lower birth weight, and higher neonatal mortality(10), while mothers experience greater rates of post-partum depression(11) and are less likely to initiate breastfeeding(12). teenage mothers are less likely to complete high school, are more likely to live in poverty, and have children who frequently experience health and devel-opmental problems(13). although ui is associated with pregnancy and parity(14), few studies reveal the associations among teenage childbearing with sui and uui. the national health and nutrition examina-tion survey (nhanes) represents a population-based sample of american adults who com-pleted validated urinary symptom questionnaires in select years and an assessment of self-reported ageat first live birth. hence, we used the data of the nhanes program to in-vestigating the relationship between early childbearing and later risk of ui. the focus of our paper is on longer term adult health outcomes of teen mothers. a better understanding of how ui is associated with teenage childbearing is important for clinical practice and public health interventions aimed urology journal/vol 19 no. 5/ september-october 2022/ pp. 392-397. [doi:110.22037/uj.v19i.7223] female urology at preventing teenage pregnancy. methods nhanes sample and design the nhanes program consists of cross-sectional health surveys performed by the national center for health statistics of the centers for disease control and prevention (http://www.cdc.gov/nchs/nhanes.htm). nhanes provides estimates of the health status of the united states population by selecting a nationally representative sample of the noninstitution-alized population using a complex, stratified, multistage, probability cluster design. nhanes oversampled individuals 60 years old or older and black, mexican-american, and low-income white individuals to provide more reliable estimates of these groups. the national centers for health statistics ethics review board approved the protocol, and all participants provided written informed consent. we obtained nationally representative data on demographic and health outcomes from nhanes 2015-2018. this study was a cross-sectional survey, which was carried out to investigate the relationship between teenage childbearing and ui among women. study participants we used publicly available data from the 2015-2018 nhanes for this study. nhanes rep-resents a population-based sample of american adults who completed validated urinary symptom questionnaires in select years. we restricted our analytic cohort to include female, aged 20 years or older when participating in nhanes, who responded to the “kidney con-ditions – urology” survey questionnaire and “reproductive health” survey questionnaire (n=3949). we excluded 257 participants who reported a history of bladder cancer (n=5), brain cancer (n=1), cervical or uterine cancer (n=66), stroke (n=185) since bladder cancer, brain cancer, cervical or uterine cancer and stroke may affect urinary function. participants with in-complete general survey data (n=1055) were also excluded. ultimately, 2637 women were included in the present study. for this study, a sample size calculation based on error margin of 5%, 95% confidence level and expected ratio of sui or uui of 50% was run at the sample size calculator website: http://www.surveysystem.com/sample-size-formula.htm , and the result was found to be 377. this study had a respectable sample size(2637). study variables questions regarding ui were assessed by computer-assisted personal interviews methodolo-gy (capi). the primary outcome of interest was the presence of either sui or uui ("any in past year")as ascertained by self-report. participants were asked if “during the past 12 months, have you leaked or lost control of even a small amount of urine with activity like coughing, lifting, or exercise?”(sui) or “with an urge or pressure to urinate and could not get to the toilet fast enough?” (uui). and, the question: “how frequently does this occur?” measures incon-tinence frequency. we performed a companion analysis defining sui and uui as a self-report of monthly or more, and weekly or more incontinence events. the use of this self-reported in-continence questionnaire is considered to be a reliable and valid epidemiological tool for as-sessing the presence of incontinence(15). women without the specific incontinence type of in-terest (sui or uui) were considered non-cases. according to the response to the question, “how old were you at the time of first live birth?”, we derive variables indicating whether the individual gave birth during teenager. demographics prevalence rates of incontinence (self-reported) sui%(95ci%) uui%(95ci%) overall prevalence 27.3(26.3-29.8) 22.1(20.5-23.7) age 20-39 20.8(17.6-24.0) 13.1(10.4-15.7) 40-59 28.2(25.4-31.1) 19.1(16.6-21.6) 60-79 30.9(27.7-34.0) 28.7(25.7-31.8) 80+ 37.6(30.9-44.4) 36.1(29.5-42.8) race mexican american 32.4(28.2-36.6) 23.1(19.3-26.9) other hispanic 27.1(22.3-31.9) 17.5(13.4-21.6) non-hispanic white 33.6(30.5-36.7) 25.4(22.6-28.3) non-hispanic black 18.4(15.7-21.9) 21.9(18.6-25.3) other race-including multi-racial 24.6(19.9-29.3) 16.5(12.4-20.6) education less than high school 29.9(26.4-33.4) 24.6(21.3-27.9) high school/ged 30.8(27.2-34.5) 21.5(18.2-24.7) college 25.9(23.6-28.2) 21.2(19.0-23.4) annual family income $0 to $19,999 29.9(26.5-33.3) 22.6(19.4-25.7) $20,000 to $34,999 28.3(24.8-31.7) 24.3(21.0-27.6) $35,000 to $74,999 27.1(23.8-30.4) 21.0(26.3-29.8) > $75,000 26.8(23.2-30.4) 20.4(17.2-23.7) bmi lean/normal (<25 kg/m2) 22.7(19.5-26.0) 22.4(19.2-25.6) overweight (25-30 kg/m2) 28.7(25.5-31.9) 23.9(20.9-26.9) obese (>30 kg/m2) 30.5(27.9-33.1) 20.8(18.5-23.1) parity 1 28.2(24.1-32.2) 20.9(17.3-24.6) 2 31.3(28.2-34.4) 23.4(20.6-26.2) 3 25.6(22.2-29.0) 20.5(17.4-23.6) 4 26.7(22.1-31.3) 22.5(18.2-26.8) >=5 25.2(20.0-30.3) 23.4(18.4-28.4) table 1. weighted population prevalence rates of stress and urgency incontinence (n=2673) sui in women: the role of teenage childbearing-xie et al. vol 19 no 4 july-august 2022 316vol 19 no 5 september-october 2022 393 in addition, the following covariates were included: age; race; education; annual family income; bmi; hypertension; diabetes; parity; smoking history and history of hysterectomy. those co-variates included demographic and clinical characteristics that have been associated with ui in prior studies(16-19). details of all study variables acquisition process are available at www.cdc.gov/nchs/nhanes/. statistical analysis all estimates were calculated accounting for nhanes sample weights(full sample 4-year mec examination weight of the 2015–2018). these weights consider unequal probabilities of selec-tion and nonresponse. the subgroup analysis was carried out using stratified multivariate re-gression analysis. following adjustment for covariates, we used logistic regression to examine the independent association among teenage childbearing with stress and urgency urinary in-continence (sui, uui). data were analyzed with the use of the statistical packages r (the r foundation; http://www.r-project. org; version 3.4.3) and empower (r) (www.empowerstats.com, x&y solutions, inc. boston, massachusetts). the or and 95% ci were obtained from the multivariable models with statistical significance considered at p <0.05. results prevalence rates of stress and urgency incontinence overall, the study included 2673 women. the population prevalence of sui was 27.3%(26.3%-29.8%) and uui was 22.1%(20.5%-23.7%). subgroups analyses to examine whether the associations among teenage childbearing (age at first birth < =19 years old) with stress and urgency urinary incontinence (sui, uui) existed across subgroups, uni-variate logistic regression was adopted for subgroup analyses (table 2). no increased risks of sui were found among participants whose age >=80 years old (p-value = 0.465), who belong to mexican american (p = 0.2635), whose parity is three (p = 0.15). however, increased risks of sui were observed in all the other subgroups (p < 0.05). increased odds of uui were only found among participants who belong to other race including multiracial (p = 0.0084), whose education level is college (p = 0.0032), who didn’t have diabetes (p = 0.0343). teenage childbearing was associated with the odds of sui in women four regression models were constructed: adjust 0 model adjust for: none. adjust 1 model adjust for: age; race; education; annual family income. adjust 2 model adjust for: bmi; hy-pertension; diabetes; parity; smoking history; history of hysterectomy; post-menopausal pediatric urology 317 sub-group n sui uui or (95ci) p value or (95ci) p value age 20-39 619 1.6 (1.0, 2.4) 0.0353 1.3 (0.8, 2.2) 0.2842 40-59 967 2.1 (1.5, 2.9) <0.0001 1.3 (0.9, 1.8) 0.1732 60-79 849 1.7 (1.2, 2.4) 0.0015 1.1 (0.8, 1.5) 0.5867 80+ 202 1.3 (0.7, 2.5) 0.465 0.9 (0.5, 1.8) 0.8478 race 0n-hispanic black 481 3.1 (1.9, 4.8) < 0.0001 1.3 (0.8, 2.0) 0.3137 0n-hispanic white 332 2.1 (1.2, 3.6) 0.0091 1.3 (0.7, 2.5) 0.349 mexican american 897 1.2 (0.9, 1.6) 0.2635 0.9 (0.7, 1.3) 0.756 other hispanic 606 2.1 (1.3, 3.4) 0.0021 1.8 (1.2, 2.8) 0.0084 other race including multiracial 321 2.3 (1.2, 4.5) 0.0114 1.4 (0.7, 2.8) 0.3669 education level college 655 2.5 (1.7, 3.6) < 0.0001 1.8 (1.2, 2.7) 0.0032 high school/ged 620 1.7 (1.2, 2.5) 0.0067 1.2 (0.8, 1.8) 0.3612 less than high school 1362 1.7 (1.3, 2.2) 0.0004 1 (0.8, 1.4) 0.7729 annual family income > $75,000 696 2 (1.4, 2.9) 0.0004 1.3 (0.9, 1.9) 0.1827 $0 to $19,999 654 1.6 (1.1, 2.3) 0.0209 1.2 (0.8, 1.7) 0.4342 $20,000 to $34,999 705 1.8 (1.2, 2.6) 0.0022 1.4 (1.0, 2.1) 0.0807 $35,000 to $74,999 582 2 (1.3, 3.1) 0.0012 1.1 (0.7, 1.7) 0.7517 bmi >30 kg/m2 647 1.6 (1.0, 2.4) 0.0425 1.1 (0.7, 1.6) 0.7961 <25 kg/m2 770 1.7 (1.2, 2.5) 0.0022 1.4 (0.9, 2.0) 0.0917 25-30 kg/m2 1220 2.1 (1.6, 2.7) <0.0001 1.3 (0.9, 1.7) 0.1358 hypertension yes 1297 1.9 (1.4, 2.4) < 0.0001 1.3 (1.0, 1.7) 0.1006 no 1340 1.7 (1.3, 2.3) 0.0001 1.2 (0.9, 1.6) 0.3582 parity 1 483 2 (1.1, 3.6) 0.0168 1.3 (0.7, 2.3) 0.4186 2 868 1.8 (1.2, 2.7) 0.0019 1.1 (0.7, 1.6) 0.7353 3 648 1.3 (0.9, 1.9) 0.15 1.3 (0.9, 2.0) 0.1675 4 360 2.3 (1.4, 3.7) 0.0007 1.5 (0.9, 2.5) 0.0955 >=5 278 2.3 (1.3, 3.9) 0.0036 1.3 (0.8, 2.4) 0.2964 diabetes yes 529 1.5 (1.0, 2.3) 0.0296 1.1 (0.8, 1.7) 0.5414 no 2108 2 (1.6, 2.5) < 0.0001 1.3 (1.0, 1.6) 0.0343 smoking history yes 892 1.8 (1.3, 2.4) 0.0002 1.4 (1.0, 1.9) 0.052 no 1745 1.9 (1.4, 2.4) < 0.0001 1.2 (0.9, 1.5) 0.227 table 2. results of subgroup analyses ci: confidence interval; or: odds ratio; bmi: body mass index. sui in women: the role of teenage childbearing-xie et al. female urology 394 status. adjust 3 model adjust for: age; race; education; annual family income; bmi; hypertension; diabetes; parity; smoking history; history of hysterectomy (table 2). in the fully-adjusted model, we observed a positive association between teenage childbearing and sui (or=1.9, 95% confidence interval [ci]: 1.5-2.3, p < 0.05), and sui will come up early in the life of these women (age: 20-39, or=1.6, 95% confidence interval [ci]: 1.0-2.4, p < 0.05). however, teenage childbearing were not found to be associated with uui (or = 1.2, 95% confidence interval [ci]: 1.0-1.5, p = 0.0658). discussion the present study aimed to evaluate the associations among teenage childbearing (age at first birth<=19 years old) with sui and uui in american women. in this study, we found that the risk of sui was 1.9 times higher in women whose age at first live birth less than or equal to 19 years old than in women whose age at first live birth more than 19 years old in adulthood. however, after fully adjusting for multiple risk factors, we also found no relationship between teenage childbearing and uui. the risks and realities associated with teenage childbearing are well documented(20); for exam-ple, children are more likely to be born prematurely, have lower birth weight and have higher neonatal mortality(21), and teenage mothers have higher rates of postpartum depression and are less likely to start breastfeeding(22). hoffman et al. reported that teenage mothers are less likely to finish high school, more likely to live in poverty, and children often experience health and developmental problems. despite the historic decline in the u.s. teen birth rate during 1991–2015, from 61.8 to 22.3 births per 1,000 females aged 15–19 years, many teens continue to have repeat births(23). these previous studies, along with ours, suggest that teenage childbearing may pose a significant public health hazard. to the best of our knowledge, this is the first study that explored the associations between teenage childbearing and urinary incon-tinence. ui can seriously affect one’s quality of life(24). sui is an involuntary loss of urine due to in-creased intra-abdominal pressure, while uui is caused by stimulation of bladder contractions or loss of nervous system control. in previous studies, parity(25), mode of delivery(26) and difficult birth history(27) were risk factors for ui. no statistically significant interactions were observed between teenage childbearing and uui (p = 0.0068 > 0.05), but p values between 0.05 and 0.10 were reported as marginally significant in many studies. so more studies are needed to estimate the relationship of uui and teenage childbearing. we found sui increases in women whose age at first birth less than or equal to 19 years old. based on our findings, we propose several possible hypotheses. the first is that anatomical differences in pelvis dimensions, uterine volume and hormone production between adolescents and adults(28,29) may increase the risk of pelvic floor dysfunctions after delivery, and the use of episiotomy(29) may worsen this condition. the second hypothesis is that adolescent pregnancy is often unplanned,being associated with fewer appointments, which usually start when the pregnancy is already advanced, and with lower follow-up rates compared with adult pregnan-cies(30). lack of knowledge of available prenatal care services, lack of decision-making au-tonomy, concealment of pregnancy, and financial difficulties may justify this association. ad-olescents tend not to follow medical recommendations correctly, and are more exposed to poor nutrition, drug use, smoking and alcohol consumption, as well as emotional stress(31). none-theless, our hypotheses require further investigation. strengths of this study include the nationally representative nature of the nhanes data and the large sample size, yet there are some limitations to our study. first, the cross-sectional nature of this study inhibits our ability to assess causality. second, other confounders such as histories of gynaecological disease and previous instrumental vaginal delivery were not included in or controlled for in our analyses. lastly, prevalence-incidence bias was also a problem we couldn't solve. this study does not provide further insight into the major mechanisms of progression and exacerbation of sui from teenage childbearing. future longitudinal studies are needed to examine the association of sui with teenage childbearing. conclusions these results show that teenage childbearing was not related to uui. however, an increased risk of sui was demonstrated in participants whose age at first live birth vol 19 no 4 july-august 2022 318 table 3. associations between teenage childbearing and urinary incontinence among women in nhanes 2015–2018 (n = 2673) adjust 0 adjust 1 adjust 2 adjust 3 or p or p or p or p (95%ci) (95%ci) (95%ci) (95%ci) sui age at first birth>19 ref ref ref ref age at first birth<=19 1.8 (1.5, 2.2) < 0.001 1.8 < 0.001 1.9 < 0.001 1.9 < 0.001 (1.4, 2.2) (1.5, 2.3) (1.5, 2.3) uui age at first birth>19 ref 0.0334 ref 0.108 ref 0.067 ref 0.0658 age at first birth<=19 1.2 1.2 1.2 1.2 (1.0, 1.5) (0.9, 1.4) (1.0, 1.5) (1.0, 1.5) adjust 0 model adjust for: none. adjust 1 model adjust for: age; race; education; annual family income. adjust 2 model adjust for: bmi; hypertension; diabetes; parity; smoking history; history of hysterectomy; post-menopausal status. adjust 3 model adjust for: age; race; education; annual family income; bmi; hypertension; diabetes; parity; smoking history; history of hysterectomy. sui in women: the role of teenage childbearing-xie et al. vol 19 no 5 september-october 2022 395 less than or equal to 19 years old. our findings emphasize the need for physicians and nurses to recommend proper treatment, medical help, or bring the disorder to light for teenage mothers. acknowledgments this work was supported by the national natural science foundation of china to fei gao [no. 81672893] and mei yang [no. 81971230, 81671312]. furthermore, it is supported by chongqing science and health joint project [no. 2020gdrc007], and supported by senior medical talents program of chongqing for yong and middle-aged [no. 204216qn] and re-serve talents program for academic leaders of the first affiliated hospital of chongqing medical university [no. xkts070] to fei gao. conflict of interest the authors report no conflict of interest. references 1. haylen bt, de ridder d, freeman rm, et al. an international urogynecological association (iuga)/international continence society (ics) joint report on the terminol-ogy for female pelvic floor dysfunction. neurourol urodyn. 2010;29:4-20. 2. aoki y, brown hw, brubaker l, cornu jn, daly jo, cartwright r. urinary inconti-nence in women. nat rev dis primers. 2017;3:17042. 3. milsom i, gyhagen m. the prevalence of urinary incontinence. climacteric. 2019;22:217-22. 4. schreiber pedersen l, lose g. prevalence of urinary incontinence among women and analysis of potential risk factors in germany and denmark. 2017;96:939-48. 5. lawrence jm, lukacz es, liu il, nager cw, luber km. pelvic floor disorders, dia-betes, and obesity in women: findings from the kaiser permanente continence asso-ciated risk epidemiology study. diabetes care. 2007;30:2536-41. 6. danforth kn, townsend mk, lifford k, curhan gc, resnick nm, grodstein f. risk factors for urinary incontinence among middle-aged women. am j obstet gynecol. 2006;194:339-45. 7. gyhagen m, åkervall s, molin m, milsom i. the effect of childbirth on urinary incontinence: a matched cohort study in women aged 40-64 years. am j obstet gynecol. 2019;221:322.e1-.e17. 8. 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